PMID- 10756391
TI - Recent Advances in the Treatment and Outcome of Locally Advanced Rectal Cancer.
PMID- 10756390
TI - Stage B Prostate Cancer: Correlation of DNA Ploidy Analysis With Histological and
Clinical Parameters.
AB - BACKGROUND: The ability to accurately predict tumor behavior and patient survival
is a problem in managing patients with prostate cancer. Prognostic variables in
predicting death from tumor include prostate-specific antigen (PSA) level,
histological grade, and clinical stage. Observer subjectivity is inherent in
determining grade and stage; thus, criteria that are more objective are needed to
identify patients for appropriate treatment. METHODS: The authors correlated flow
cytometric nuclear DNA ploidy with Gleason score, PSA level, and recurrence risk
in patients who underwent radical retropubic prostatectomy and bilateral pelvic
lymphadenectomy between 1987 and 1993 for histopathologic stage B prostate cancer
(T2, N0, M0). RESULTS: Of the tumors analyzed, 64% were DNA diploid with a low
proliferative fraction, 25% were DNA diploid with a high proliferative fraction,
and 11% were DNA aneuploid. DNA aneuploidy was associated with high Gleason grade
(7-10). All Gleason grade 10 tumors were DNA aneuploid. Both DNA aneuploidy and
high proliferative fraction (S+G2M) were statistically correlated with high
Gleason grade and adverse prognosis but not with PSA level or patient age.
CONCLUSIONS: A direct relationship is shown between both DNA aneuploidy and a
high proliferation index with aggressive biological behavior in stage B prostatic
cancer. Objective tumor criteria are needed to choose treatment more selectively
for individual patients.
PMID- 10756392
TI - Significance of Sentinel Node Micrometastasis.
PMID- 10756393
TI - Role of Carbogen in the Treatment of Head and Neck Cancer.
PMID- 10756394
TI - Tumor Cell Vaccines for Renal Cell Carcinoma.
PMID- 10756395
TI - Membrane Mucins and Breast Cancer.
PMID- 10756396
TI - STAT Proteins and Cancer.
PMID- 10756397
TI - Native American Community-Based Cancer Projects: Theory Versus Reality.
PMID- 10756398
TI - Oncology Journals and the Internet: A Shared Resource.
PMID- 10756399
TI - Role of nitric oxide in pentylenetetrazol-induced seizures: age-dependent effects
in the immature rat.
AB - PURPOSE: Seizure susceptibility and consequences are highly age dependent. To
understand the pathophysiologic mechanisms involved in seizures and their
consequences during development, we investigated the role of nitric oxide (NO) in
severe pentylenetetrazol (PTZ)-induced seizures in immature rats. METHODS: Four
cortical electrodes were implanted in 10-day-old (P10) and 21-day-old (P21) rats,
and seizures were induced on the following day by repetitive injections of
subconvulsive doses of PTZ. The effects of NG-nitro-l-arginine methyl ester (l
NAME; 10 mg/kg) and 7-nitroindazole (7NI; 40 mg/kg), two NO synthase (NOS)
inhibitors, and l-arginine (l-arg; 300 mg/kg), the NOS substrate, were evaluated
regarding the mean PTZ dose, seizure type and duration, and mortality rate.
RESULTS: At P10, the postseizure mortality rate increased from 18-29% for the
rats receiving PTZ only to 100% and 89% for the rats receiving l-NAME and 7NI,
respectively; whereas l-arg had no effect. Conversely, at P21, NOS inhibitors did
not affect the 82-89% mortality rate induced by PTZ alone, whereas l-arg
decreased the mortality rate to 29%. In addition, all NO-related drugs increased
the duration of ictal activity at P10, whereas at P21, l-arg and l-NAME affected
the first seizure type, producing clonic seizures with l-arg and tonic seizures
with l-NAME. CONCLUSIONS: The relative natural protection of very immature rats
(P10) against PTZ-induced deaths could be linked to a high availability of l-arg
and, hence, endogenous NO. At P21, the modulation of seizure type by NO-related
compounds may be related to the maturation of the brain circuitry, in particular
the forebrain, which is involved in the expression of clonic seizures.
PMID- 10756400
TI - Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats.
AB - PURPOSE: We evaluated the anticonvulsant efficacy of topiramate (TPM), a
structurally novel antiepileptic drug (AED), in amygdala kindled rats that had
been preselected with respect to their response to phenytoin (PHT). METHODS:
Anticonvulsant response was tested by determining the afterdischarge threshold
(ADT; i.e., a sensitive measure for drug effects on focal seizure activity). By
repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled
rats were separated: rats in which consistent anticonvulsant effects were
obtained (PHT responders), rats that showed no anticonvulsant response (PHT
nonresponders), and rats with variable responses (variable PHT responders). The
latter, largest group was used to evaluate at which doses and pretreatment times
TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was
tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1
and 4 h). The most effective treatment protocol was then used for TPM testing in
PHT responders and nonresponders. RESULTS: TPM proved to be an effective AED in
the kindling model. At 40 mg/kg, significant ADT increases were obtained after
both 1 and 4 h after administration. In addition to the effect on focal seizure
threshold, seizure severity and duration recorded at ADT were decreased by TPM,
indicating that this drug acts on both seizure threshold and seizure spread. In
PHT nonresponders, TPM significantly increased ADT, which is in line with its
proven efficacy in patients with refractory partial epilepsy in whom phenytoin
has failed. However, TPM was more efficacious in increasing ADT in PHT responders
than in nonresponders, substantiating that the difference between these groups of
kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM
indicated that, similar to PHT, there are individual kindled rats without
anticonvulsant response to TPM (i.e., TPM nonresponders). CONCLUSIONS: The data
of this study substantiate that PHT nonresponders are a unique model for the
search of new AEDs with improved efficacy in refractory partial epilepsy.
PMID- 10756401
TI - Atypical evolutions of benign localization-related epilepsies in children: are
they predictable?
AB - PURPOSE: To emphasize that, in some patients, different atypical evolutions occur
in the course of so-called benign focal epilepsies of childhood (BFEC) and to
promote interest in finding clinical and/or electroencephalographic (EEG) clues
to which patients might be prone to these risky evolutions. METHODS: Twenty-six
patients who started with the typical clinical and EEG features of benign
childhood epilepsy with centrotemporal spikes (BCECTS) but who had reversible or
persistent, serious epileptic events including status epilepticus and language,
cognitive, or behavioral impairments were followed for /=3 years of follow-up. RESULTS: LGS
onset in the 107 patients occurred at a median age of 4.0 years (range, 0.6-28.9
years). When last seen, 63% of those with symptomatic LGS had more than three
seizures a day compared with 50% of cryptogenic and 34% of indeterminate
patients. The most common seizure types were tonic (77%), atypical absence (61%),
and generalized tonic-clonic (56%). Only three patients, all part of the
indeterminate group, were seizure free at last follow-up. CONCLUSIONS: Using
stringent criteria in defining the cryptogenic subgroup resulted in no
significant difference in seizure outcome. Individuals with a normal cognitive
outcome did not segregate into one etiologic subgroup, but did have LGS onset at
an older age.
PMID- 10756404
TI - Relation of cortical language distribution and cognitive function in surgical
epilepsy patients.
AB - PURPOSE: To investigate the relation between the number and spatial distribution
of language sites and specific patient-and epilepsy-related variables. METHODS:
Patients with stimulation-induced reading or naming errors from anterior or
inferior temporal cortex (i.e., atypical temporal language sites) were compared
with those with language sites confined to Wernicke's area (WA) in the
posterosuperior temporal and inferior parietal perisylvian area. In a consecutive
series of 44 left hemisphere language dominant patients with complex partial
seizures before left temporal lobectomy, correlations were compared between
cortical language distribution and measures of cognitive function. RESULTS:
Patients with atypical temporal language sites (group 1) had significantly fewer
years of education that did patients with language sites in WA (group 2).
Patients in group 1 had poorer verbal learning and fluency than did patients in
group 2. Patients with IQ <80 were significantly more likely to have multiple
sites where stimulation disrupted language than did patients with normal IQ.
Number of language sites had significant negative correlations with full-scale
IQ, and measures of confrontation naming, verbal fluency, and immediate verbal
memory. CONCLUSIONS: Language cortex has a wider spatial distribution in epilepsy
surgery patients with lower intelligence, poorer education, and worse verbal and
memory skills.
PMID- 10756405
TI - Neuropsychological functions in idiopathic occipital lobe epilepsy.
AB - PURPOSE: Despite the benign prognoses of idiopathic partial epilepsies,
particularly regarding the response of seizures to treatment, some evidence now
exists that patients with such disorders may have subtle neuropsychological
deficits. This study was designed to investigate several modalities of
neuropsychological functioning in a group of 21 patients, ranging from 6 to 14
years of age, with idiopathic occipital lobe epilepsy (IOLE). The case patients
were compared with 21 healthy controls matched for age, sex, and socioeconomic
status. METHODS: A battery of age-appropriate neuropsychological tests was
administered individually to all the participants. Tests were chosen on the basis
of age-appropriate norms, their ability to represent a wide variety of functional
domains, and their appropriateness in a cross-cultural setting. The tests were
selected to measure functioning in six domains: intellectual functioning,
attention, memory, academic achievement, visual-motor functioning, and executive
functioning; some were further subdivided by their verbal-versus-visual modality
of functioning. RESULTS: The results revealed no significant difference in basic
neurophysiological functions between the patient and control groups, although the
case patients' performance scores were lower in attention (p < 0.01) and memory
(p < 0.01), as well as in intellectual functioning (p <.05). CONCLUSIONS: The
possibility of subtle cognitive deficits in IOLE patients should always be
considered, though further studies are necessary to elaborate their precise and
long-term effects.
PMID- 10756406
TI - Neurocognitive attention and behavior outcome of school-age children with a
history of febrile convulsions: a population study.
AB - PURPOSE: A prospective population-based case-control study was performed to
ascertain whether febrile convulsion (FC) in early childhood is associated with
neurocognitive attention deficits in school age. METHODS: A total of 103
children, confirmed to have FC by age 3 years from a population survey of 4,340
live-birth newborns in Tainan City, Taiwan, was followed up until at least age 6
years. An achievement test, behavioral ratings, and computerized neurocognitive
battery assessing various subcomponents of attention were given to 87 FC children
(FC group) and 87 randomly selected population-matched control (CC group).
RESULTS: Compared with the CC group, the FC group did not have scholastic
performance or behavioral outcome disadvantage. Overall FC group performance was
distinguished by significantly higher scores in the achievement test and fewer
missing errors (p < 0.005) and commission errors (p < 0. 05), less variability in
reaction time (p < 0.005), and a nonsignificant trend of impulsivity. Attention
performance of the FC and CC groups were comparable. Within the FC group, age at
onset, complex FC, recurrence of FC, development of unprovoked seizures, or prior
use of phenobarbital had no adverse effects on neurocognitive attention outcome.
CONCLUSIONS: This population study suggests that FC in early childhood does not
have adverse effects on behavior, scholastic performance, and neurocognitive
attention. On the contrary, the FC group demonstrated significantly better
control of distractibility and attention at school age.
PMID- 10756407
TI - Are negative mood states associated with cognitive function in newly diagnosed
patients with epilepsy?
AB - PURPOSE: The association of self-reported subclinical depressive symptoms and
negative mood states with cognitive functioning was evaluated in 51 consecutive
newly diagnosed adult persons with epilepsy. METHODS: Emotional state was
assessed with Profile of Mood States (POMS) and Brief Depression Scale (BDS) and
was correlated with a battery of neuropsychological tests. RESULTS: Patients with
epilepsy reported more depressive symptoms in BDS than in controls. They also had
more feeling of bewilderment and less vigor on POMS. Higher scores in BDS and in
POMS inefficiency scale were associated with slower nondominant hand tapping, but
emotional state did not correlate with cognitive measures within the epilepsy
group. CONCLUSIONS: Self-reported symptoms of depression and negative mood states
were not extensively or significantly associated with cognitive function, and
they do not explain the cognitive impairments observed in cognition in newly
diagnosed patients with epilepsy.
PMID- 10756408
TI - The impact of childhood epilepsy on neurocognitive and behavioral performance: a
prospective longitudinal study.
AB - PURPOSE: To assess neurocognitive and behavioral performance in children with
idiopathic epilepsy (CWE, n = 74), their siblings without epilepsy (control, n =
23), and children with migraine (CWM, n = 13), and to identify medical factors
related to learning or behavioral problems in CWE. METHODS: Subjects, ages 8-13
years with IQs of >/=80, completed a neurocognitive test battery annually for
or = 3, and RGB > or = 18,
and only 24.73% of MDDRF compounds have 0 < or = RNG < or = 2 rings, and RGB < or
= 17. The probability of identifying 'drug-like' structures increases with
molecular complexity.
PMID- 10756481
TI - A CoMFA analysis with conformational propensity: an attempt to analyze the SAR of
a set of molecules with different conformational flexibility using a 3D-QSAR
method.
AB - CoMFA analysis, a widely used 3D-QSAR method, has limitations to handle a set of
SAR data containing diverse conformational flexibility since it does not
explicitly include the conformational entropic effects into the analysis. Here,
we present an attempt to incorporate the conformational entropy effects of a
molecule into a 3D-QSAR analysis. Our attempt is based on the assumption that the
conformational entropic loss of a ligand upon making a ligand-receptor complex is
small if the ligand in an unbound state has a conformational propensity to adopt
an active conformation in a complex state. For a QSAR analysis, this assumption
was interpreted as follows: a potent ligand should have a higher conformational
propensity to adopt an 'active-conformation'-like structure in an unbound state
than an inactive one. The conformational propensity value was defined as the
populational ratio, Nactive/Nstable, of the number of energetically stable
conformers, Nstable, to the number of 'active-conformation'-like structures,
Nactive. The latter number was calculated by counting the number of conformers
that satisfied the structural parameters deduced from the active conformation. A
set of SAR data of imidazoleglycerol phosphate dehydratase inhibitors containing
20 molecules with different conformational flexibility was used as a training set
for developing a 3D structure-activity relationship by a CoMFA analysis with the
conformational propensity value. This resulted in a cross-validated squared
correlation coefficient of the CoMFA model with the conformational propensity
value (Rcross2 = 0.640) higher than that of the standard CoMFA model (Rcross2 =
0.431). Then we evaluated the quality of the CoMFA models by predicting the
inhibitory activity for a new molecule.
PMID- 10756482
TI - Chemometric rationalization of the structural and physicochemical basis for
selective cyclooxygenase-2 inhibition: toward more specific ligands.
AB - The discovery that proinflammatory prostaglandins are produced by cyclooxygenase
2 (COX-2), an inducible isoform of the constitutive cyclooxygenase-1 (COX-1),
opened a new frontier in the treatment of inflammatory diseases, because the
selective inhibition of COX-2 can lead to therapeutically effective compounds
which do not have the common side effects of classical non-steroidal
antiinflammatory drugs (NSAIDs). Different crystallographic structures of both
free COX-1 and COX-2 as well as complexes with inhibitors have been solved.
Because of the great similarity between the two enzymes, it is difficult to
detect the most important structural and physicochemical features that would be
useful for designing inhibitors with an improved selectivity. In this paper we
describe the application of a chemometric procedure to the study of COX-2
selective inhibition. This method, developed to reveal the most suitable regions
of isoenzymes for the design of selective ligands, also has a very practical
utility. GRID multivariate characterization of the enzymes and subsequent
Principal Component Analysis (PCA) of the descriptor variables allow the
identification of chemical groups that could be added to a core template
structure to increase ligand selectivity.
PMID- 10756483
TI - Global 3D-QSAR methods: MS-WHIM and autocorrelation.
AB - The recently proposed MS-WHIM indices, a set of theoretical descriptors
containing information about size, shape and electrostatic distribution of a
molecule, have been further investigated. The main objectives of this work were:
(i) to confirm the descriptive power of MS-WHIM in modelling specific biological
interactions, (ii) to analyse the dependence of MS-WHIM on the type of atomic
charges used for computing electrostatic potential and (iii) to compare the
performances of MS-WHIM with those provided by other global 3D molecular
descriptors. The spatial autocorrelation of atomic and molecular surface
properties were selected for comparison purposes. WHIM-based and autocorrelation
based vectors were calculated for two molecular sets from the literature, namely
a series of 18 HIV-1 reverse transcriptase inhibitors and a set of 36
sulphonamide endothelin inhibitors. PLS was adopted to derive statistical
predictive models that were validated by means of cross-validation. The reported
results confirmed that MS-WHIM indices are able to provide meaningful statistical
correlations with biological activity. MS-WHIM descriptors are sensitive to the
type of partial atomic charges applied and improved models were obtained using
more accurate charges. Moreover for both the datasets, MS-WHIM results, in terms
of fitting and predictive power of PLS models, were superior to those from
autocorrelation. Finally, the strengths/weaknesses of global 3D-QSAR descriptors
over local CoMFA-like methods, as well as the main differences between WHIM-based
and autocorrelation-based vectors, are discussed.
PMID- 10756484
TI - Changing internal constraints on action: the role of backward inhibition.
AB - Flexible control of action requires the ability to disengage from previous goals
or task sets. The authors tested the hypothesis that disengagement during
intentional shifts between task sets is accompanied by inhibition of the previous
task set ("backward inhibition"). As an expression of backward inhibition the
authors predicted increased response times when shifting to a task set that had
to be abandoned recently and, thus, suffers residual inhibition. The critical
backward inhibition effect on the level of abstractly defined perceptual task
sets was obtained across 6 different experiments. In addition, it was shown that
backward inhibition can be differentiated from negative priming (Experiment 2),
that it is tied to top-down sequential control (Experiment 3), that it can
account at least partially for "residual shift costs" in set-shifting experiments
(Experiment 4), and that it occurs even in the context of preplanned sequences of
task sets (Experiment 5).
PMID- 10756485
TI - Determinants of the remembered utility of aversive sounds.
AB - Retrospective evaluations of aversive episodes were studied in the context of a
general model of "judgment by prototype" that has been applied in other
situations. Unpleasant sounds of variable loudness and duration were the stimuli.
In Experiment 1, continuous reports of annoyance closely tracked variations of
noise intensity. Hypotheses about the determinants of retrospective evaluation
were examined in Experiment 2. Experiment 3 confirmed a prediction of judgment by
prototype: The effects of sound duration and intensity are additive in multitrial
experiments. Experiment 4 confirmed a robust preference for aversive episodes
that are "improved" by adding a period of reduced aversiveness.
PMID- 10756486
TI - Mood, personality, and self-monitoring: negative affect and emotionality in
relation to frontal lobe mechanisms of error monitoring.
AB - A fundamental question in frontal lobe function is how motivational and emotional
parameters of behavior apply to executive processes. Recent advances in mood and
personality research and the technology and methodology of brain research provide
opportunities to address this question empirically. Using event-related
potentials to track error monitoring in real time, the authors demonstrated that
variability in the amplitude of the error-related negativity (ERN) is dependent
on mood and personality variables. College students who are high on negative
affect (NA) and negative emotionality (NEM) displayed larger ERN amplitudes early
in the experiment than participants who are low on these dimensions. As the high
NA and -NEM participants disengaged from the task, the amplitude of the ERN
decreased. These results reveal that affective distress and associated behavioral
patterns are closely related with frontal lobe executive functions.
PMID- 10756487
TI - Differential roles for visuospatial and verbal working memory in situation model
construction.
AB - Two experiments investigated the processing of the spatial and causal dimensions
of situation models. In Experiment 1, participants read texts varying in spatial
and causal demands while responding to on-line spatial and causal probes.
Experiment 2 used the same design, but used texts that more tightly integrated
spatial and causal information. In both experiments, spatially oriented dependent
measures were generally influenced by spatial, but not causal, demands, whereas
causally oriented measures were influenced by causal, but not spatial, demands.
In addition, spatially oriented dependent measures were generally correlated with
a measure of spatial working memory capacity, whereas causally oriented measures
were correlated with a measure of verbal working memory capacity. These results
indicate that spatial and causal dimensions of situation models are maintained
and elaborated independently in different working memory subsystems.
PMID- 10756488
TI - The heuristic basis of remembering and classification: fluency, generation, and
resemblance.
AB - People use 3 heuristics (fluency, generation, and resemblance) in remembering a
prior experience of a stimulus. The authors demonstrate that people use the same
3 heuristics in classifying a stimulus as a member of a category and interpret
this as support for the idea that people have a unitary memory system that
operates by the same fundamental principles in both remembering and
nonremembering tasks. The authors argue that the fundamental functions of memory
are the production of specific mental events, under the control of the stimulus,
task, and context, and the evaluation of the coherence of those events, which
controls the subjective experience accompanying performance.
PMID- 10756489
TI - Overt and covert identification of fragmented objects inferred from performance
and electrophysiological measures.
AB - The authors investigated visual processing leading to object identification by
manipulating the number of fragments and nature of the study. During the study,
participants either named or drew objects in Experiment 1 and drew them all in
Experiment 2. During the test, participants made an identification judgment at
each of 6 different fragmentation levels for studied and new objects. Fewer
fragments were needed to identify studied than unstudied objects. Reaction times
were faster for studied than unstudied objects both at identification and at the
preceding level. Event-related brain potentials (ERPs) to unidentified objects
were characterized by a late negativity in contrast to a positivity to identified
objects. ERPs to studied but not to new objects contained a smaller and later
version of the identification positivity at level just prior to identification,
which was not due to differential response confidence. Much covert visual
analysis and even object identification may precede overt identification,
depending on the nature of prior experience.
PMID- 10756490
TI - Working memory and the vividness of imagery.
AB - The working memory framework was used to investigate the factors determining the
phenomenological vividness of images. Participants rated the vividness of visual
or auditory images under control conditions or while performing tasks that
differentially disrupted the visuospatial sketchpad and phonological loop
subsystems of working memory. In Experiments 1, 2, and 6, participants imaged
recently presented novel visual patterns and sequences of tones; ratings of
vividness showed the predicted interaction between stimulus modality and
concurrent task. The images in experiments 3, 4, 5, and 6 were based on long-term
memory (LTM). They also showed an image modality by task interaction, with a
clear effect of LTM variables (meaningfulness, activity, bizarreness, and
stimulus familiarity), implicating both working memory and LTM in the experience
of vividness.
PMID- 10756491
TI - Cost of different types of surgical therapy for abnormal uterine bleeding. A
review.
AB - Treatment of abnormal uterine bleeding by abdominal or vaginal hysterectomy has
been partially replaced by operative endoscopy. Operative endoscopy (laparoscopy
and hysteroscopy), appropriately employed, might offer numerous advantages, such
as decreased hospital stay, complications and discomfort. The cost and health
care utilization of operative laparoscopy and hysteroscopy as compared to
traditional surgical methods are less understood.
PMID- 10756492
TI - Diagnosis of polycystic ovary disease in obese women with a 24-hour hormone
profile after buserelin stimulation.
AB - OBJECTIVE: To evaluate the 24-hour hormone response to GnRH agonist stimulation
in the diagnosis of polycystic ovary disease (PCOD) in obese women. STUDY DESIGN:
Forty-three obese PCOD patients and 23 controls were randomized to 1 mg buserelin
(BSRL) stimulation (PCOD group P-1, n = 31; control group C-1, n = 12) or 0.1 mg
(PCOD group P-0.1, n = 12; control group C-0.1, n = 11). RESULTS: Whereas
following 1 mg BSRL administration, serum levels of 17 hydroxyprogesterone
(17OHP), delta 4 androstenedione, estradiol (E2) and luteinizing hormone
increment (delta LH) as well as the delta LH/delta follicle stimulating hormone
ratio were all higher in group P-1 than in group C-1 (P < .001, < .01, < .01, =
.08 and < .001, respectively), only 17OHP and E2 serum levels were higher in
group P-0.1 than in group C-0.1 (P < .001, and = .01, respectively). Whereas 24
hour LH inversely correlated with body mass index (r = .37, P = .04), 24-hour
hormone profile, and basal or glucose-stimulated serum insulin levels did not
correlate in group P-1. CONCLUSION: The 1-mg BSRL stimulation test is a
convenient diagnostic means in obesity-associated PCOD. The hormone response to
BSRL administration is related to obesity, not to insulin resistance.
PMID- 10756493
TI - AutoCyte Prep system vs. conventional cervical cytology. Comparison based on
2,156 cases.
AB - OBJECTIVE: To compare the AutoCyte Prep system (Burlington, North Carolina) with
conventional cervical cytology in a university medical center laboratory. STUDY
DESIGN: Split-sample conventional and AutoCyte Preps were examined for 2,156
cases. Same-patient conventional and Prep slides were submitted to separate
cytotechnologists blindly. The results were compared on review by a
cytopathologist. The Prep slides were subsequently scanned on the AutoCyte Screen
automated interactive system, with manual review of the flagged cases. The
results were compared with anatomic pathology follow-up when available. RESULTS:
Of the 158 squamous intraepithelial lesions (SILs) found by both methods, 78%
were found by AutoCyte Prep, while 59% were found by conventional smear (P <
.01). Among the discordant cases, thin-layer slides revealed 88% more LSIL
lesions (P < .05), a comparable number of high grade SIL lesions and a single
case of adenocarcinoma that was ambiguous on the conventional slide. The addition
of AutoCyte assisted primary screening demonstrated a net benefit, recovering
additional cases referenced as atypical glandular cells of undetermined
significance and as high grade SIL. CONCLUSION: The AutoCyte Prep system affords
excellent cellular presentations and superior sensitivity for SILs when compared
to the conventional technique. The use of AutoCyte Screen, for primary screening
demonstrated performance equivalent to manual screening, with a significant
improvement in sensitivity when measured against biopsy results.
PMID- 10756494
TI - Insulin-sensitivity index and carbohydrate and lipid metabolism in gestational
diabetes.
AB - OBJECTIVE: To study insulin action in normal and gestational diabetic pregnant
women by using an insulin tolerance test. STUDY DESIGN: Twenty-four women
diagnosed as having gestational diabetes were compared to 22 nondiabetic, matched
controls. The insulin-tolerance test (ITT) consisted of an intravenous bolus of
0.1 IU/kg of regular insulin with glucose sampling at -5, 0, 3, 5, 7, 10 and 15
minutes. The insulin sensitivity index (ISI) was assessed by using a delta G/G0
ratio (G0 = initial glycemia level, delta G = variation between G0 and glycemia
level obtained at 15 minutes by calculation of the regression plot). RESULTS: Two
women had glucose levels < 50 mg/dL at 15 minutes, without clinical symptoms.
Women with gestational diabetes had a significantly lower level than those with
normal glucose tolerance. The rate of abnormal insulin resistance (ISI) (< 10th
percentile in the control group) was significantly higher in the insulin-treated
subgroup (8/11, 72.7%, vs. 2/12, 16.6%). ISI correlated negatively with glycemia
(r = -.38, P = .01) and glycosylated hemoglobin (r = -.50, P = .001) and
correlated positively with low density lipoprotein-c (r = -.40, P = .01) and
apolipoprotein B (r = -.42, P = .01). In the gestational diabetes group, ISI was
correlated negatively with gestational age (r = -.50, P = .01) and triglycerides
(r = -.50, P = .01). CONCLUSION: ITT seems to be a safe and rapid method of
measuring in vivo insulin action in pregnant women. Women with gestational
diabetes had higher insulin resistance, especially those who needed insulin
therapy. Lipid profile in gestational diabetes was related to the level of
insulin resistance.
PMID- 10756495
TI - Birth outcome in incarcerated, high-risk pregnant women.
AB - OBJECTIVE: To compare birth outcomes in incarcerated women with a recent history
of drug use to those of nonincarcerated women in a methadone maintenance program.
STUDY DESIGN: We retrospectively analyzed pregnancy outcome in 149 women who
delivered at full term between 1993 and 1996. Thirty-one patients incarcerated
during pregnancy (group 1) were compared with 47 patients enrolled in our
methadone maintenance program (group 2) and with a control group of 71 randomly
chosen patients (group 3). Drug use, age, parity, number of visits, infant birth
weight, low birth weight and Apgar scores were compared. RESULTS: The methadone
maintenance group had significantly fewer clinic visits. All the patients in
groups 1 and 2 were cigarette smokers, whereas 12.5% of the control group smoked.
Over 78% of incarcerated women admitted using drugs immediately prior to
imprisonment as compared to 4.11% in group 3 and 100% in group 2 (P < .001). The
three groups differed significantly with respect to infant birth weight (P <
.001). CONCLUSION: Cessation of drug use followed by adoption of a health
promoting lifestyle and adequate prenatal care of incarcerated women leads to an
improvement in birth outcome. Furthermore, provision of prenatal care on site is
a suitable alternative for the care of incarcerated pregnant women and eliminates
the need to bring patients in chains to outside clinics.
PMID- 10756496
TI - Artificial insemination. Role of endometrial thickness and pattern, of vascular
impedance of the spiral and uterine arteries, and of the dominant follicle.
AB - OBJECTIVE: To assess the roles of endometrial thickness and pattern, as well as
vascular impedance of the spiral and uterine arteries and dominant follicle in
predicting the pregnancy rate in women receiving controlled ovarian
hyperstimulation (COH) following by intrauterine insemination (IUI). STUDY
DESIGN: All idiopathically infertile couples who accepted COH + IUI for the first
time were prospectively included. The COH agents included clomiphene citrate and
human menopausal gonadotropins. Endometrial thickness and pattern (trilaminar,
nontrilaminar) and vascular impedance (pulsatility index [PI], resistance index
[RI]) of the spiral and uterine arteries and ovarian dominant follicle were
measured on the day of IUI. Analyses were made of the influences on pregnancy
outcomes by endometrial thickness and pattern as well as Doppler surveys of the
spiral and uterine arteries and dominant follicle. RESULTS: A total of 110
couples with 110 cycles were enrolled, and there were 16 resulting pregnancy
cycles. Trilaminar endometrium appeared in 87.5% and 57.4% of pregnant and
nonpregnant women (P = .022), respectively. The pregnancy rates in trilaminar and
nontrilaminar groups were 17.9% and 6.3%, respectively (P = .022). Endometrial
thickness and PI/RI values for the spiral artery and uterine arteries and
dominant follicle in pregnant women (12.1 +/- 2.6; 1.28 +/- 0.33/0.68 +/- 0.12;
2.67 +/- 0.51/0.72 +/- 0.32; 0.71 +/- 0.19/0.54 +/- 0.06 mm, respectively) were
not statistically different from those for nonpregnant women (11.0 +/- 2.9; 1.46
+/- 0.49/0.71 +/- 0.21; 2.81 +/- 0.65/0.88 +/- 0.34; 0.74 +/- 0.24/0.55 +/- 0.09,
respectively). CONCLUSION: A trilaminar endometrium on the day of IUI provides a
favorable prediction of pregnancy. Endometrial thickness and Doppler surveys of
the spiral and uterine arteries and dominant follicle do not have useful
predictive value in COH + IUI.
PMID- 10756497
TI - Predicting the success of external cephalic version with a scoring system. A
prospective, two-phase study.
AB - OBJECTIVE: To develop a noninvasive and quantifiable scoring system based on
clinical parameters to predict the success of external cephalic version (ECV) in
women with breech presentation at term. STUDY DESIGN: This was a prospective, two
phase, clinical study. Phase 1 was to develop a scoring system from 53 versions
with singleton pregnancy in breech presentation at term using a standard protocol
with fetal monitoring, ultrasound assessment and tocolysis. Phase 2 was to verify
this scoring system by application to 88 versions using the same standard
protocol as in phase 1. RESULTS: The success rates for ECV in phases 1 and 2 were
64.2% and 61.4%, respectively, making the overall success rate 62.4%. The results
of phase 1 showed that there were significant differences in the following
parameters: head palpable, breech unengagement, symphysisfundal height and
uterine relaxation. A scoring system based on these four clinical parameters was
developed. When applied to 88 versions in the second phase, the likelihood ratio
of successful ECV was > 30 if the version score was > or = 3 and < 1.8 if the
version score was < or = 2. CONCLUSION: Using our scoring system, prediction of
successful ECV was possible without ultrasound scan or vaginal examination, and
counseling could be given once breech presentation was diagnosed.
PMID- 10756498
TI - Pregnancy-induced hypertension and duration of sexual cohabitation.
AB - OBJECTIVE: To evaluate the possible association between duration of sexual
cohabitation and the risk of pregnancy-induced hypertension (PIH). STUDY DESIGN:
A matched case-control design in which each case of PIH was compared with three
controls. Information was obtained about use of barrier contraception, duration
of intercourse prior to pregnancy and paternity. RESULTS: Sixty-eight cases were
included in the study. For primiparous women, a shorter duration of sexual
cohabitation without contraception was associated with a small and nonsignificant
risk of PIH. For multiparous women, a greater length of time since stopping use
of barrier contraception was associated with a greater risk of PIH. CONCLUSION:
Advising nulliparous women to prolong the duration of sexual cohabitation prior
to conception in an effort to decrease the risk of PIH is not justified, based on
the findings of this study.
PMID- 10756499
TI - Effect of decreasing cesarean births on maternal age-, parity- and ethnicity
associated cesarean rates.
AB - OBJECTIVE: To evaluate the effect of decreasing cesarean births on the rates
associated with maternal age, parity and ethnicity. STUDY DESIGN: During 1991
1997, 14,689 women delivered at our community hospital, 2,945 by cesarean
(20.0%). The clinical and demographic characteristics of these women and their
newborns were studied. The data were divided according to maternal age, parity
and ethnicity. As cesareans began to decrease in our service during 1994, the
data were also divided into two groups: group 1 (1991-1993) and group 2 (1994
1997). chi 2 analysis was used to evaluate the differences between the
proportions. A P value < .05 was considered significant. RESULTS: Maternal and
perinatal outcomes and some demographic characteristics did not change, while
cesarean rates decreased. As compared to group 1, cesarean birth rates decreased
in group 2, from 22.5% to 17.9% (P < .0001). The decrease was significant in
every maternal age-, parity- and ethnicity-related subgroup, except for women
with parity > 4 (16.7% vs. 16.3%, P = .835) and those > or = 36 years old (31.6%
vs. 30.9%, P = .798); for them, cesarean birth rate for breech presentation
increased in group 2 (1.3-4.7%, P = .002). CONCLUSION: Cesarean birth rates can
be reduced safely, and further studies should determine the factors associated
with higher cesarean rates among older women.
PMID- 10756500
TI - Vulvar vestibulitis syndrome and vaginismus. A case report.
AB - BACKGROUND: Recent reports have argued for a revision of the criteria used for
the establishment of a diagnosis of vulvar vestibulitis syndrome (VVS). On
theoretical grounds it might be hypothesized that women with VVS also suffer from
vaginismus. CASE: A young woman presented with a history, symptoms and objective
findings typical of vaginismus, yet she suffered from continuous, burning pain
and itching in the vestibule. Earlier in the course of the problem she had
received a diagnosis VVS. The patient was treated with behavioral therapy
developed for vaginismus. Notations made during the course of therapy supported
the assumption that the pain and itching were conditioned responses to
penetration in the same way that a vaginal muscular reflex is. CONCLUSION:
Differential diagnostic difficulties exist in the field of VVS and vaginismus.
Psychophysiologic theories are needed as the basis for research to clarify the
connections between different diagnostic entities associated with coital burning
pain and itching in the vestibule.
PMID- 10756501
TI - Echinococcal ovarian cyst. A case report.
AB - BACKGROUND: Echinococcal disease, although known to occur in most organs and body
areas, is extremely rare in the female reproductive system. A literature search
revealed only three anecdotal non-English language case reports of ovarian
echinococcosis. CASE: A 20-year-old woman presented with epigastric pain.
Abdominal ultrasonography and computed tomography showed three multicystic
masses, one intrahepatic, one intraperitoneal and the third situated in the left
ovary. Serologic examination confirmed the diagnosis of echinococcal disease.
Marked regression of all the cysts occurred following a short course of
albendazole. CONCLUSION: Echinococcal cysts should be included in the
differential diagnosis of multicystic ovarian lesions if the patient has cysts
elsewhere and is from an endemic area.
PMID- 10756502
TI - Complete hydatidiform mole coexisting with a live fetus after gamete
intrafallopian transfer. A case report.
AB - BACKGROUND: Molar pregnancy with a coexisting live fetus is a rare occurrence. We
report the only known case with a surviving coexistent fetus after gamete
intrafallopian transfer (GIFT). CASE: After GIFT, a 28-year-old primary
infertility patient was diagnosed as having a complete hydatidiform mole
coexisting with a live fetus at 13 weeks of gestation. At 36 weeks of gestation,
a cesarean section was performed due to elevated serum human chorionic
gonadotropin (hCG) levels, and a male infant with a normal appearance and
weighing 2,688 g was delivered. CONCLUSION: If the patient desires to try to
carry the fetus to viability after counseling on the possible associated risks of
malignancy, it is possible to achieve fetal viability if (1) there is decline in
the serum hCG level after it peaks before the second trimester, (2) ultrasound
reveals degeneration of the molar part, and (3) there are no complications of
pregnancy.
PMID- 10756503
TI - Laparoscopic management of a large ovarian cyst in an adolescent. A case report.
AB - BACKGROUND: The safety of laparoscopic management of benign ovarian cysts has
been demonstrated. The size of the benign ovarian cyst continues to be a limiting
factor for laparoscopic surgery, with most surgeons choosing laparotomy for large
cysts. CASE: A 15-year-old woman had a 22-cm, benign ovarian cyst extending above
the umbilicus that was managed successfully with laparoscopy. We performed
prelaparoscopy cyst drainage with a suprapubic Bonanno catheter (Becton
Dickinson, Rutherford, New Jersey) followed by laparoscopic cystectomy. Because
of its coiled end, the Bonanno catheter is less likely to result in cyst leakage
around the aspiration site. CONCLUSION: With proper patient selection,
laparoscopic surgery can be safely applied in a select group of patients with
large, benign ovarian cysts.
PMID- 10756504
TI - Ovarian stimulation in a woman with premature ovarian failure and X-autosome
translocation. A case report.
AB - BACKGROUND: There are only a few reports on ovulation induction in women with
premature ovarian failure resulting from an X chromosome abnormality. Up to now,
there have been no publications on ovulation stimulation in a patient with an X
autosome translocation. CASE: A healthy, 29-year-old woman had premature ovarian
failure (POF) but no other discernible pathologic clinical features. Laboratory
tests prior to initiating a stimulation cycle revealed a 46,XX t(X;16) karyotype.
Genetic counseling was proposed, and the risk of X chromosome abnormality was
discussed. The couple decided to undergo ovulation induction. For treatment of
infertility, clomiphene citrate had been administered in the past. Because those
treatments were not successful, GnRH-a and follicle stimulating hormone treatment
was recommended. The first treatment cycle was successful in inducing ovulation,
but on the 15th day after human chorionic gonadotropin administration,
menstruation occurred. The couple refused a second stimulation, and menstruation
occurred 32 days after the first. The patient then became amenorrheic again.
CONCLUSION: At least some hope can be offered to infertile women with
hypergonadotropinism and X-autosomal translocation, although it is impossible to
determine whether ovulation induction will result in pregnancy. New treatments
can be anticipated for women with POF and X chromosome aberrations who have
similar hormonal environments.
PMID- 10756505
TI - Bladder rupture associated with uterine rupture. A report of two cases occurring
during vaginal birth after cesarean.
AB - BACKGROUND: Uterine rupture occurs in < 1% of patients undergoing a trial of
labor after cesarean section. Associated injury to adjacent organs within the
maternal pelvis has likewise been very rarely reported. CASE: Two cases of
posterior bladder wall rupture occurred in association with rupture of low
transverse uterine incisions. CONCLUSION: Bladder rupture may be associated with
uterine rupture during attempted vaginal birth after cesarean. The potential for
bladder injury should be included in the patient's antepartum counseling.
PMID- 10756506
TI - Rationale for hormone replacement therapy in atherosclerosis prevention.
AB - Progestogens are clearly useful to balance the proliferative effects of estrogens
on the endometrium; however, some progestogens have been shown to attenuate the
cardiovascular benefits of estrogen, and this has been the subject of
considerable debate. Accumulating evidence confirms the deleterious effects of
medroxyprogesterone acetate on estrogen's cardioprotective effects and provides
new and compelling evidence that not all progestogens are alike in this regard.
Maintaining estrogen's cardioprotective effects is strongly dependent upon the
type of progestogen and route and method of administration. Numerous periclinical
studies conducted on nonhuman primates and other models have demonstrated that
certain progestogens, such as micronized progesterone, can be administered
concurrently with estrogen replacement therapy, providing protection against
endometrial hyperplasia without significantly affecting the beneficial effects of
estrogen on lipid profiles, atherosclerosis and vascular reactivity.
PMID- 10756507
TI - Preserving cardiovascular benefits of hormone replacement therapy.
AB - In the premenopausal period, the risk of heart disease is considerably lower in
women than in men; however, in the postmenopausal period, when estrogen levels
are considerably lower, women's risk of heart disease increases dramatically and
approaches that of men. Numerous animal studies, using a variety of models, also
confirm estrogen's cardioprotective effect. Although the results of numerous
population-based, observational studies have demonstrated a lower risk of heart
disease in women who receive estrogen replacement therapy, evidence from
prospective, randomized clinical trials is scant. The Postmenopausal
Estrogen/Progestin Intervention (PEPI) trial evaluated cardiovascular risk
factors, not events, in a large, prospective, randomized trial and found that
estrogen improved lipid profiles and other known risk factors. In addition, the
PEPI trial compared several estrogen/progestogen treatment regimens, including
both medroxyprogesterone acetate (MPA) and micronized progesterone (MP), and
found that combined hormone replacement therapy regimens including MP attenuated
the beneficial effects of estrogen less than those containing MPA. In the Heart
and Estrogen/Progestin Replacement Study (HERS), however, which prospectively
evaluated whether estrogen and MPA use reduced the number of nonfatal myocardial
infarctions and cardiovascular events, no effect was seen. Although HERS was a
null trial, the vast literature base showing a cardioprotective effect should not
be discounted. Further research will be required before blanket recommendations
on the cardioprotective effects of hormone therapy can be made.
PMID- 10756508
TI - Balancing safety and efficacy focus on endometrial protection.
AB - Estrogen replacement therapy (ERT) has demonstrated significant, long-term
benefits by improving cardiovascular risk factors and increasing bone mineral
density; however, unopposed ERT is associated with an increased incidence of
endometrial hyperplasia and progression to endometrial carcinoma in
postmenopausal women who retain their uteri. As a result, the use of combined
regimens containing both a progestogen and an estrogen is becoming the standard
course of therapy. Further study is required, however, to determine the effects
of the various available progestogens and discover optimal dosing regimens. Not
all progestogens are alike. Careful progestogen selection is critical to ensure a
high degree of patient adherence to therapy. Patients discontinue hormone
replacement therapy (HRT) for reasons including irregular or breakthrough
bleeding, progestogen intolerance and other unpleasant side effects. Working
individually with patients to optimize HRT regimens is critical to helping them
continue to use HRT long enough to achieve the long-term benefits.
PMID- 10756509
TI - Variation by race in children's alcohol expectancies.
AB - The purpose of this study was to further investigate a post-hoc finding on racial
differences in children's alcohol expectancies. This was a secondary analysis of
data originally collected for an evaluation study of longitudinal effects of a
pre-school substance abuse prevention program in Cleveland. OH. Ss were second
and third grade students who had received intervention services 3 years earlier
and a matched comparison group who had not. The samples were combined for a total
N = 69. Independent samples t-tests were used to assess differences in alcohol
expectancy scores (on the Children's Alcohol-Related Expectancies (CARE)
questionnaire). Data analysis revealed significantly higher CARE scores for black
children than for whites. Most of the variance was in a sub-scale, which measures
beliefs on how alcohol effects arousal and aggression. The finding that black
children more often reported beliefs that alcohol intensifies feelings and makes
fighting easier may suggest differential exposure to models of behavior.
Alternatively, the finding may reflect aspects of alcohol marketing in African
American communities.
PMID- 10756510
TI - Substance use and non-clinical panic attacks in a young adult sample.
AB - This study examines panic attacks and substance use in a non-clinical, young
adult sample. Two hundred seventy-nine college students completed questionnaires
that assessed non-clinical panic attacks, alcohol and drug use behavior, and
anxiety and depression symptoms. Non-clinical panickers (n = 25) were
significantly more likely than non-panickers (N = 222) to report using sedatives,
but not alcohol, cocaine, stimulants, or other drugs. Among non-clinical
panickers, sedative use was not associated with distress about panic attacks,
panic attack frequency, the occurrence of unexpected attacks, or general anxiety
or depression symptoms. Coping-motivated alcohol use, though not associated with
non-clinical panic, was significantly associated with anxiety and depression
symptoms. These results are discussed in terms of theories of the co-morbidity
between substance use and panic disorder.
PMID- 10756511
TI - Paternal alcoholism, parental psychopathology, and aggravation with infants.
AB - The purpose of this study was to examine the role of paternal alcohol problems,
antisocial behavior, and depression in predicting parental attitudes toward their
12-month-old infants. Families were recruited from birth records and the final
sample consisted of 216 families, 101 in the control group and 115 families with
alcoholic fathers (92 with light drinking partners and 23 with heavy drinking
partners). Results indicated that fathers' alcoholism was associated with higher
paternal aggravation with the infant. Further, fathers' depression mediated the
relationship between fathers' current alcohol problems and aggravation. Fathers'
alcoholism was indirectly associated with maternal aggravation and warmth through
the relationship with maternal antisocial behavior and depression. Results
suggest that at least during early infancy, parental psychopathology associated
with fathers' alcohol problems may play a more important role in predicting
parental attitudes toward their infants than alcoholism per se. Results are
further discussed in terms of their implications for parenting and later
development among infants of alcoholics.
PMID- 10756512
TI - Parental alcoholism, child abuse, and adult adjustment.
AB - Parallel findings in the adult children of alcoholics (ACOA) and child abuse
literatures are integrated and extended by assessing long-term adjustment and
childhood histories of parental alcoholism and sexual, physical, and emotional
abuse in college students (N = 333). Abuse histories were most strongly related
to adult symptom distress and social maladjustment. Parental alcoholism had no
independent effects when controlling for abuse history. Parental alcoholism
interacted with abuse history in relation to social adjustment, exacerbating the
effects of emotional abuse. This study adds to a growing literature calling for
more complex models of ACOA development that can account for the diversity of
this population.
PMID- 10756513
TI - Age-related differences in adolescent smokers' and nonsmokers' assessments of the
relative addictiveness and health harmfulness of cigarettes, alcohol, and
marijuana.
AB - The present work was undertaken to determine how general beliefs about various
substances and substance use behaviors change during adolescence. Secondary
analyses were carried out on the telephone interview responses of 1,200
adolescent smokers and nonsmokers between the ages of 12 and 17. The specific
beliefs regarding which substances were hardest to stop using and which were the
most harmful to one's health by smoking status and age were compared using Chi
squared analyses for univariate comparisons, and polytomous logistic regression
for multivariate analyses. Results revealed that the youngest cohort believed
that marijuana was the substance most difficult to stop using while the oldest
cohort believed that cigarettes were the hardest to stop using. A similar pattern
was observed regarding which substance was the most harmful to one's health.
While smokers believed that cigarettes were both the hardest to stop using and
the most harmful, nonsmokers were divided between cigarettes and marijuana as the
hardest to stop using, and indicated that marijuana, rather than cigarettes, were
most harmful. Results are discussed in terms of their implications for substance
abuse prevention and the development of relative risk assessments.
PMID- 10756514
TI - An individual in context: predictors of alcohol use and drinking problems among
Greek and residence hall students.
AB - Fraternity, sorority, and residence hall residents were compared on drinking
rates and patterns, drinking-related problems, family history of alcohol
problems, alcohol outcome expectancies, and high school drinking patterns.
Results indicated residence in a fraternity was related to more frequent alcohol
consumption and greater negative consequences even after accounting for family
history, expectancies, and high school drinking rates. Family history of alcohol
problems was only related to negative consequences for men. Only high school
drinking rates were related to amount of alcohol consumed per occasion, for both
men and women. Fraternity residence was found to be related to more negative
consequences even after accounting for current drinking habits. However, sorority
residence was found to moderate the relationship between current drinking and
negative consequences. Both high and low drinkers in sororities indicated similar
rates of alcohol-related negative consequences, whereas high frequency female
drinkers in the residence hall sample reported significantly more problems.
PMID- 10756515
TI - Differences in young adult psychopathology among drug abstainers, experimenters,
and frequent users.
AB - Shedler and Block offered the provocative proposal that individuals who
experiment with drugs are psychologically healthier than either those who abstain
completely or those who are frequent users. Not all studies have come to such
conclusions, however. In an effort to specify under what conditions Shedler and
Block's conclusions might hold, the present study examined three groups of drug
users (abstainers, experimenters, frequent users) classified according to three
different criteria: (a) marijuana use at age 20; (b) alcohol use during 10th
grade; and (c) alcohol use at age 20. The three groups were compared at age 20 in
terms of personality, deviant behavior, and psychopathology. The results revealed
that abstainers were never more psychologically impaired, and were occasionally
healthier, than experimenters. Frequent users of marijuana were consistently more
imparied than both the abstainers and experimenters, in terms of both
internalizing and externalizing disorders. Classification according to marijuana
use appeared to be more related to psychopathology than did classification
according to alcohol use.
PMID- 10756516
TI - Predicting early adolescent substance use: do risk factors differ depending on
age of onset?
AB - This study was designed to identify different risk models associated with non
use, first use, and prior substance use among a group of early adolescents. A
total of 582 students completed a self-report questionnaire at the beginning and
end of sixth grade. Nine predictor variables were used in discriminant function
analysis to classify adolescents into three groups. Five variables distinguished
non-users (never used by the end of sixth grade) and new users (first used during
sixth grade) from prior users (first used before sixth grade). Prior users were
found to have weaker decision making skills, more susceptibility to peer
pressure, more negative perceptions of school, less confidence in their skills,
and an increased likelihood of being male. A second function indicated that new
users were similar to prior users in that they had less positive peer relations,
were more likely to come from single parent families, and had less knowledge
about alcohol and drugs than did non-users. The similarities and differences
between new and prior users have implications for future research and prevention
programming.
PMID- 10756517
TI - Children's health and child-parent relationships as predictors of problem
drinking mothers' and fathers' long-term adaptation.
AB - This study examined the extent to which children's health status and child-parent
relationships affected the severity of problem-drinking parents' alcohol use
disorders, as well as the parents' psychological states and marital stressors and
resources. These issues were examined using data from an 8-year study of problem
drinking women and men. Generally, over the 8-year period, the children of
alcoholic mothers and fathers were comparable on their health status and
relationships with their parents. The severity of mothers' and fathers' drinking
problems were also generally comparable over this period. Better children's
health and child-parent relationships at baseline and 1- and 3-year follow-ups
were consistent predictors of mothers' reduced drinking and better psychological
states on the subsequent follow-ups. Associations between children's functioning
and fathers' adaptation were few and inconsistent. The results support the
possibility that an undesirable cycle might be established in which maternal
drinking and children's dysfunction coexist in an ever worsening reciprocal
relationship.
PMID- 10756518
TI - Cloning and characterization of the iutA gene which encodes ferric aerobactin
receptor from marine Vibrio species.
AB - The iutA gene from marine Vibrio species SD004, which encoded a ferric aerobactin
receptor for the uptake of iron(III), was cloned onto a multicopy plasmid, pUC
18, in Escherichia coli. Identification of the positive clone was achieved on the
basis of its deferrization activity and was detected as a halo formation on the
chrome azurol S (CAS)-containing selective plate. Nucleotide sequence analysis of
the cloned DNA fragment revealed an open reading frame (ORF) which encoded a
polypeptide of 706 amino acid residues, and the deduced molecular mass of this
polypeptide was 77.906 kD. The amino acid sequence showed a 41% homology with
that of the lutA protein from E. coli. The cloned gene was iutA, which encoded
the ferric aerobactin receptor. Another incomplete ORF was found 100 bp upstream
of the iutA gene, which was homologous (31 out of 49 amino acids) with the C
terminal region of the luc D protein of E. coli. It is suggested that aerobactin
biosynthesis and the transport genes are located tandemly on the Vibrio
chromosome and may form an aerobactin operon.
PMID- 10756519
TI - Effects of Fusobacterium necrophorum subspecies necrophorum on extracellular
matrix of tissue-cultured bovine kidney cells.
AB - The effects of Fusobacterium necrophorum subsp. necrophorum on the extracellular
matrix were investigated. The toxic preparation from the culture induced
reduction in the number of tissue-cultured bovine kidney cells. The exposed cells
often manifested partial loss of cytoplasm and were morphologically irregular.
Scanning electron microscopy demonstrated partial loss of the microvilli on the
exposed cells and roughness of the cell surfaces. Finally, sodium dodecyl
sulphate polyacrylamide gel electrophoresis profiles revealed complete
degradation of bovine collagen type 1 after treatment with the toxic preparation.
This degradation was inhibited by the addition of homologous antiserum. These
findings indicate that the degradation may contribute to the establishment of the
infection caused by F.n. subsp. necrophorum.
PMID- 10756520
TI - Biosynthesis and secretion of several enzymes in Escherichia coli dnaK and dnaJ
mutants.
AB - Escherichia coli null dnaJ and dnaKdnaJ mutants were defective in the
biosynthesis and secretion of several enzymes. The synthesis of beta
galactosidase induced in delta dnaJ and delta dnaKdnaJ mutants was abolished at
42 degrees C and significantly decreased at 30 and 37 degrees C. The activity of
alkaline phosphatase in the periplasm in both mutant strains at high temperature
was lower than in the wild-type strain. The synthesis of b-type cytochromes was
defective in two deletion mutants while the synthesis of nitrate reductase-A at
42 degrees C was influenced by dnaK mutation only. The lack of DnaK and DnaJ does
not impair the activity of catechol 2,3-dioxygenase irrespective of growth
temperature.
PMID- 10756521
TI - Physiological properties and production of siderophores detected in Yersinia
enterocolitica strain 4-32.
AB - A hydrophilic compound with siderophore activity was isolated from a culture of
Yersinia enterocolitica 4-32 grown in an iron-deficient medium. It was found that
the siderophore secreted did not belong to the catecholamide and hydroxamate type
of siderophores and not yersiniabactin. Supplementation of cultures of Y.
enterocolitica 4-32 with sodium chloride (300 mM) resulted in a decrease in the
production of siderophores.
PMID- 10756522
TI - Development of a new lysis solution for releasing genomic DNA from bacterial
cells for DNA amplification by polymerase chain reaction.
AB - A new lysis solution designated TZ, consisting of 2.0% Triton X-100 plus 2.5 mg
sodium azide/ml in 0.1 M Tris-HCl buffer at pH 8.0, yielded higher levels of
genomic DNA from Escherichia coli O157:H7 cells compared with a number of other
commonly used cell lysis methods. Ethidium bromide stained DNA bands resulting
from PCR amplification of target DNA from 100 CFU of E. coli O157:H7 were readily
detected following electrophoresis of agarose gels. In contrast, conventional
cell lysis methods failed to detect target DNA from 100 CFU after PCR
amplification. The new solution was highly effective for lysing cell suspensions
of Salmonella enteritidis, Pseudomonas putida, Lysteria monocytogenes and
Psychrobacter immobilis.
PMID- 10756523
TI - [Current perspectives of alexithymia].
AB - Although alexithymia is found in patients with various somatic disorders, it
remains unclear whether it is really related to organic disease--as proposed by
the founders of the concept.[125]. As the interplay between the experience of
emotion and possible adverse effects on health is a fundamental tenet of
psychosomatic medicine, alexithymia remains an interesting concept to be further
explored, especially concerning (1) possible pathways linking emotion to physical
illness and (2) the neurobiologic basis of emotional information processing.
Compared to the intense international discussion on the subject, in Germany there
are still many doubts concerning alexithymia: while some clinicians question the
validity of the whole concept, psychiatric and psychosomatic researchers seem
unsure about alexithymia's role in their search for a physiological basis to the
link between emotion and physical disease. Our review deals with the empirical
literature concerning that possible association and tries to tie in their data
with modern, neuro-biologically founded insights into emotional information
processing within the brain.
PMID- 10756524
TI - [Children of mentally ill parents. Research perspectives exemplified by children
of depressed parents].
AB - Children of psychiatrically ill parents represent a risk group that has received
growing attention during the last years. The risk for this group to develop a
psychiatric illness is markedly increased due to genetic and psychosocial
factors. The development of effective preventive concepts requires a thorough
knowledge of the psychosocial factors. In this paper, deficits and problems of
research in psychosocial transmission mechanism are discussed taking the example
of children of depressive parents. Conclusions from this exemplary considerations
may serve as guidelines for future research. The authors suggest that the focus
be rather placed on coping strategies and developmental psychopathology. Further,
research criteria are formulated that refer to theoretical models as well as to
study design.
PMID- 10756525
TI - [The concept of "evidence-based medicine" in psychiatry. A path to a more
rational psychiatry?].
AB - Many of the diagnostic and therapeutic procedures in psychiatry and psychotherapy
are based on opinion rather than evidence. The concept of evidence-based medicine
aims to bridge the gap between clinical research and clinical decision-making by
integrating the best available external evidence with personal expertise. In this
article, we demonstrate several examples of the non-evidence-based medicine
paradigm. Then we show the usefulness and practicability of the new evidence
based medicine paradigm by using a clinical example. Finally, we discuss the
consequences, chances, and limitations of this new model. We also examine the
role of the individual clinician's viewpoint as well as the need of institutional
re-engineering and the possible restructuring of the entire health care system
towards evidence-based methods.
PMID- 10756526
TI - [Analysis of criminal acts and forensic evaluation of psychiatric deviance].
AB - The psycho-scientific diagnosis transposed to legal terms defines and limits the
extent of the psychic disturbances that have to be considered in the test of
criminal responsibility. The analysis of the criminal act that has to be carried
out on this basis is of decisive importance. It must place particular emphasis on
the automatic nature of structural orientations and their regulation by de
actualization. The psychopathological reference system proposed by Sass can be
used to measure the severity of psychic deviance ("abnormality")--the different
forms its manifestation can take are treated separately in detail--against acute
psychosis and against delusion as two basic patterns of psychopathology. If a
severe abnormality is confirmed the analysis of the offence that has to be
undertaken independently of psychopathological comparisons must be centred on
orientations that are contrary to automatically criminal action. These can be
respected or overcome by decisions for which the perpetrator can bear the
responsibility, or restricted or negated by psychic impairment. Before the
author's concluding remarks on the place of such considerations in the
enforcement of disciplinary proceedings, some examples of severe psychic
abnormality are treated in detail. They are found more frequently in sexual
offenders and those involved in drug-related crimes than in other groups of
offenders.
PMID- 10756527
TI - [Reliability and validity of the German version of the Premorbid Adjustment Scale
(PAS)].
AB - The Premorbid Adjustment Scale (PAS) was developed by Cannon-Spoor et al. 1982
for research use and has gained importance internationally. This scale is
designed to measure the extent of attaining developmental goals premorbidly. The
German version is presented here, with first data on the reliability and validity
of the scale. In a sample of schizophrenic and schizoaffective patients (n = 86)
and healthy parents of the patients (n = 38), DSM-IV diagnosis was made and PAS
and Positive and Negative Syndrome Scale (PANSS) data were taken along with
information on the course of the disorder. Using Cronbachs alpha, the estimated
reliability for the scale and subscales lay between 0.809 and 0.931. High PAS
scores, representing poor premorbid adjustment, correlated significantly with low
age of onset, high PANSS scores, insidious onset, long hospitalisation, and
serious course of the disorder. The threshold of PAS scores between healthy and
sick probands was at 0.23. Patients with scores > 0.53 appeared to have an
unfavourable course. With test results > 0.23, an odds ratio of 27.9 was
ascertained (95% CI 9.39-82.89). The findings presented correspond with those
from previous reports in literature.
PMID- 10756528
TI - [Evaluation of standardized training for the "Positive and Negative Syndrome
Scale" (PANSS)].
AB - The present analysis comprises 3 studies on the interrater reliability of the
Positive and Negative Syndrome Scale for Schizophrenia (PANSS; German version).
To our knowledge this is the first empirical report on interrater reliability and
on results of rater training of the German version of the PANSS despite the
widespread use of the scale. In a total of 47 training participants with
different clinical experience standardized PANSS rater training was carried out
and subsequently evaluated. Therefore, concordance rates with an expert standard
(C) and weighted coefficients kappa (kappa W) were calculated. As a main outcome
of the studies, at least 3 training sessions were necessary but also sufficient
to reach acceptable interrater reliability of the PANSS (C > 80%, kw > 0.60). In
training participants with low psychiatric experience the level of interrater
reliability of schizophrenic negative symptoms did not reach the results of
positive symptoms after the training. Despite some conceptual limitations with
respect to negative symptoms, the German version of the PANSS seems highly
suitable to assess a broad spectrum of schizophrenic psychopathology in a
reliable and economic manner. The present results also underline the
practicability of our recommendations for conducting PANSS rater training in the
clinical and scientific field as part of quality control and quality assurance in
psychopathological assessment.
PMID- 10756529
TI - [Attitude of medical students to psychiatry. A study with the German translated,
expanded version of the ATP-30].
AB - Medical students' attitudes toward psychiatry are very important for the future
care of psychiatric patients and the recruitment of qualified graduates. We
examined the attitudes of 105 German medical students toward psychiatry using a
German translation of the ATP-30, a reliable, self-administered questionnaire. In
spite of a marked interest in psychiatry, most students thought it improbable
that they would become psychiatrists. Attitudes toward psychiatry were generally
positive (ATP-30 score: 104.6 +/- 13.4, where 90 represents middle, or neither
positive nor negative) but showed clear differences in some aspects. Attitudes
toward psychotherapy were markedly positive, while those toward psychiatric
therapy in general or the scientific basis of psychiatry were less positive. We
could find no influence of sex on the ATP score, whereas students having previous
experience with psychiatry showed more positive attitudes towards it.
PMID- 10756530
TI - [Psychotherapy research in psychiatry. Results of a survey of psychiatric
clinics].
AB - This paper concerns advances in the integration of psychotherapy in psychiatric
education and clinical practice and whether they go along with increasing
research activities. To find answers, a survey on psychotherapy research was
carried out in all German psychiatric hospitals and departments by means of a
questionnaire. The results indicate that psychotherapy research is done nearly
exclusively in university hospitals. About half of them had already published
psychotherapy studies and two thirds of them are presently carrying out studies,
mostly including prospective, randomized clinical trials. These studies cover the
whole spectrum of psychiatric disorders: substance abuse, schizophrenic and
affective disorders, anxiety, and obsessive compulsive and personality disorders.
To improve psychotherapy research conditions further, efforts are necessary to
increase scientific exchange, financial support, and the integration of
institutions outside the universities.
PMID- 10756531
TI - [Role of psychiatry and psychotherapy in sexual medicine after introductory
marketing of viagra].
AB - Sildenafil (Viagra) is a substance for the treatment of erectile dysfunction.
Great expectations are connected with its introduction into the market. In this
situation the multidimensionality in the control-mechanismus of the sexual
reaction and of the satisfaction in the sexual experience are pointed out. These
aspects affect the diagnostic and therapeutic competence of psychiatry and
psychotherapy in a high degree. Efficient psycho-educative and psychotherapeutic
ways of treatment for sexual dysfunction are available. Increased specific
knowledge in this area is required by psychiatrists, medical psychotherapists and
neuropsychiatrists.
PMID- 10756532
TI - [Comment on the contribution by A. Batra et al. Required consent for
electroconvulsive therapy within the scope of guardianship (section 1904 BGB)].
PMID- 10756533
TI - Recent advances in retrometabolic drug design and targeting approaches.
AB - A number of representative, recent advances achieved within the field of
retrometabolic drug design are briefly summarized. For the soft drug approach,
some of the results of recent in vivo studies of loteprednol etabonate, a soft
corticosteroid approved by the FDA in 1998, are reviewed. For the chemical
delivery system (CDS) approach, the latest advances achieved in the brain
targeting of peptides such as kyotorphin and TRH analogues are described.
PMID- 10756534
TI - Water-soluble combinations of dexanabinol: prodrugs and analogs.
AB - Design, synthesis and study of water-soluble esters of dexanabinol are described.
The solubility, stability and in vitro activity of various polar or permanently
charged derivatives resulting by acylation of the allylic hydroxyl or phenol
functionalities was investigated. Several combination can be used as water
soluble prodrugs, and others as active congeners of dexanabinol.
PMID- 10756535
TI - Marine lipids for prodrugs, soft compounds and other pharmaceutical applications.
AB - In the present review we discuss different approaches to pharmaceutical
applications of marine lipids. Investigation of the use of marine lipids as
dermal permeation enhancers, the synthesis of triacylglycerols highly enriched in
polyunsaturated fatty acids, dermal pro-drugs derivatives of unsaturated fatty
acids and diacyl glyceryl derivatives, and the possible synthesis of soft
disinfectants from marine fatty acids.
PMID- 10756536
TI - Loteprednol etabonate: a review of ophthalmic clinical studies.
AB - Loteprednol etabonate (LE) is a corticosteroid designed using the "soft drug"
concept of Bodor. LE has been extensively evaluated as a treatment for ophthalmic
inflammatory conditions. LE is administered as a sterile eye drop suspension and
is commercially available as either a 0.5% or a 0.2% suspension. Lotemax (0.5%
LE) has been demonstrated as effective in reducing the signs and symptoms of
giant papillary conjunctivitis (GPC), acute anterior uveitis and inflammation
following cataract extraction with intraocular lens (IOL) implantation. It is
also effective for the prophylaxis of seasonal allergic conjunctivitis (SAC) in
patients with a history of that condition. Alrex (0.2% LE) is effective for the
treatment of the signs and symptoms of SAC. In comparison with other steroids LE
has a superior safety profile which has been attributed to its "soft drug"
characteristics.
PMID- 10756537
TI - Synthesis and pharmacological evaluation of prodrugs of valproic acid.
AB - We report the synthesis of (+/-)-3,6-Di-O-valproil-1,2:4,5-di-O-isopropylidene
myo-inositol (5) as well as (+/-)-3,6-Di-O-valproil-4,5-O-isopropylidene-myo
inositol (6) and (+/-)-3,6-Di-O-valproil-myo-inositol (7), which results from
acid hydrolysis of the formers. The anticonvulsant activity of the compound 7
(MES test) expressed as ED50 is four times higher than that reported for valproic
acid.
PMID- 10756538
TI - Design, synthesis, and pharmacological evaluation of soft glycopyrrolate and its
analog.
AB - Glycopyrrolate is a quaternary anticholinergic drug. Like for other
anticholinergics, the usefulness of this agent is limited by its side effects. In
this study, based on the structure of glycopyrrolate, we designed a soft drug,
methoxycarbonylphenyl-cyclopentylacetoxy-N,N-dimethyl-3-p yrrolidinium methyl
sulfate (SG), and its analog, methoxycarbonylphenylcyclopentyl-acetoxyethyl-N,N,N
trimethylammon ium methyl sulfate (SGA). These soft drugs are expected to be
locally active, but systemically inactive in order to increase therapeutic index.
SG and SGA were synthesized by (i) carboxylation of methyl
phenylcyclopentylacetate, (ii) esterification with N-methyl-3-pyrrolidinol (for
SG) or 2-chloro-N,N-dimethylaminoethane (for SGA), and (iii) quarternization with
dimethyl sulfate. Receptor binding studies demonstrate that SG has muscarinic
subtype selectivity (m3/m2). Guinea pig ileum pA2 assay indicates that activity
of SG is moderate, and SG is about ten times more potent than SGA. The in vivo
characterization of SG and SGA, both in mydriasis tests and in prevention of
carbachol induced bradycardia, supported its soft nature. Applying SG or SGA into
rabbit eyes, the dilation of the contralateral (water-treated) pupils was not
observed. Glycopyrrolate application, however, caused dilation of the
contralateral pupil, indicating a systemic effect of this drug. Cardiac studies
were carried out by evaluating the protective effect of soft anticholinergics
against carbachol induced bradycardia. The results indicate that SG and SGA were
as potent as atropine-MeBr in preventing carbachol induced bradycardia in the
rat; however, their durations of action were significantly shorter. In
conclusion, the newly synthesized SG and SGA showed soft nature in the body. They
are anticholinergics with subtype selectivity and moderate potency, and can be
used as topical antiperspirants.
PMID- 10756539
TI - Cycloaromatization and DNA cleavage of novel non-conjugated aromatic enetetrayne
systems.
AB - The novel, non-conjugated aromatic enetetrayne (2) underwent thermal
cycloaromatization reaction to give polyphenylene derivative 6, forming a methyl
cation as an active intermediate, and showed DNA-cleaving activity.
PMID- 10756540
TI - Soft cannabinoid analogues as potential anti-glaucoma agents.
AB - Cannabinoids have intraocular pressure (IOP) lowering effects, thus, they have a
therapeutic potential in the treatment of glaucoma. Unfortunately, in the same
time, they show CNS and cardiovascular effects as well. Our aim was to develop a
safer, cannabinoid type anti-glaucoma agent, a topically applied soft analogue,
that has local, but no systemic effect. The lead compound chosen was a nitrogen
containing cannabinoid analogue that was shown to have IOP lowering activity. A
full library of possible soft drugs was generated and the structures were ranked
based on the closeness of calculated properties to those of the lead compound.
The lead compound has been synthesized, and a preliminary pharmacological study
was performed. The structure-activity relationship and pharmacological results
indicate a good possibility for the development of a safe, soft anti-glaucoma
agent.
PMID- 10756541
TI - Design of polymeric prodrugs of PGE1 for cell-specific hepatic targeting.
AB - Based on the relationship between in vivo disposition of macromolecules and their
physicochemical and biological characteristics obtained through clearance concept
based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1 (PGE1)
were designed stepwise and evaluated on their targeting and therapeutic
efficiencies. Although galactosylated poly-L-glutamic acid with a ethylene
diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its
PGE1 conjugate synthesized by the carbonyldiimidazole method failed to show
therapeutic effects probably due to inactivation of PGE1 during conjugation and
lack of release in the tissue. In order to overcome these problems, PGE1 was
conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via
hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1
rapidly accumulated in the liver parenchymal cells after intravenous injection.
In addition, PGE1 conjugate effectively inhibited the increase of GPT level in
plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten
times higher doses, in carbon tetrachloride-induced hepatitis mice. These
findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte
utilizing galactose recognition.
PMID- 10756542
TI - Effect of cyclodextrins on the solubility and stability of a novel soft
corticosteroid, loteprednol etabonate.
AB - To increase the aqueous solubility and stability of the soft corticosteroid
loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs),
such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HPBCD),
maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltosyl-alpha-, beta-,
and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-methyl)-beta-cyclodextrin
(DMCD), were attempted. The solubilizing and stabilizing effects of CD by itself
or combined with various co-solvents were also investigated. Micronized (5
micron) LE was mixed in various aqueous CD or CD with cosolvent solutions. After
equilibration and filtration at 23 degrees C, the solubility of LE was determined
by HPLC. Subsequently, the stability of LE in the solutions was also determined
by following the LE concentration change in the solution for an appropriate
period. CD complexation significantly increased the aqueous solubility and
stability of LE. The increase in solubility displayed a concentration dependency
on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the
solubility (4.2-18.3 mg/ml in 10-50% DMCD) and stability (t90 > 4 years at 4
degrees C, when LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding
co-solvents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA),
and polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was
further increased. Degradation of LE to the corresponding metabolites, delta 1
cortienic acid etabonate (AE) and delta 1-cortienic acid (A), in aqueous CD
solutions appeared to be a predicted, two-step kinetics. Differential Scanning
Calorimetry (DSC) was used to assist explaining the solubilizing and stabilizing
activity differences between CDs. LE/CD mixture or lyophilized LE/CD complex was
scanned at a rate of 20 degrees C/min. The exothermic peak found in the DSC
diagram with LE/DMCD sample, but not with LE/HPBCD samples, suggests a stronger
complex formed between LE and DMCD, resulting in higher solubility and stability
of LE in DMCD than in HPBCD.
PMID- 10756543
TI - Structure-based estimation of enzymatic hydrolysis rates and its application in
computer-aided retrometabolic drug design.
AB - After a brief review of the problems related to the description of enzymatic
hydrolysis rates and the quantification of steric effects, a recently developed
method that uses the inaccessible solid angle omega h calculated around different
atoms as a novel steric parameter to estimate human blood in vitro enzymatic
hydrolysis rates in noncongener ester series is summarized. Some illustrative
results obtained by the integration of this method into the expert system
developed for computer-aided soft drug design are also presented. Starting from a
lead compound, the system can provide full libraries of possible new "soft"
molecular structures, a ranking order of these candidates based on isosteric
isoelectronic analogy to the lead, and estimated hydrolytic half-lives for all
structures of interest.
PMID- 10756544
TI - Comparison of the pharmaceutical properties of sustained-release gel beads
prepared by alginate having different molecular size with commercial sustained
release tablet.
AB - Spherical alginate gel beads containing pindolol were prepared using three types
of sodium alginate with different molecular size. The rate of gelation of sodium
alginate in calcium chloride solution was in the range of 1.0 to 1.3 h-1 among
the used three alginates, but the amount of water squeezed from the alginate gel
beads during gelation increased from 5 to 40% with increasing molecular size of
the alginate. The beads prepared were similar in diameter (1.2 mm after drying),
weight (0.9 mg/bead), calcium content (27-29 micrograms/bead) and pindolol
content (40-45%). Pindolol was rapidly released from all the alginate gel beads
at pH 1.2 owing to the high solubility of pindolol, in spite of non-swelling of
beads. On the other hand, pindolol release from alginate gel beads at pH 6.8 was
dependent on the swelling of the beads and was significantly depressed compared
to drug powder. Interestingly, the release rate of pindolol and the swelling rate
of beads were markedly slow for gel beads prepared by low molecular size
alginate. However, when the alginate gel beads were administered orally to beagle
dogs, the serum levels of pindolol showed sustained-release profiles, depending
on the molecular size of the alginate. The in vivo absorption of pindolol from
alginate gel beads did not reflect their in vitro release profiles, because of a
physical strength of beads in the intestinal tract. Furthermore, the in vivo and
in vitro release of pindolol from alginate gel beads were compared with a
commercial sustained-release tablet, Carvisken showed a rapid release of 50% of
content in pH 1.2 fluid and residual 50% of pindolol were easily dissolved at pH
6.8. Although the release characteristics of pindolol from Carvisken and the
alginate gel beads were completely different, the serum levels of pindolol in
human volunteers were comparable.
PMID- 10756545
TI - Optimized therapeutic ratio of inhaled corticosteroids using retrometabolism.
AB - During recent years, the treatment of pulmonary diseases could be significantly
improved due to the introduction of modern retrometabolism-based corticosteroids
with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to
produce long lasting therapeutic effects at the pulmonary target site and to
minimize systemic side effects by rapid clearance of the absorbed drug and low
oral bioavailability. The development of PK/PD models allows predictions of drug
effects based on the administered dose. For example, the cumulative suppression
of endogenous cortisol release (CCS) as one of the major systemic side effects of
inhaled corticosteroid therapy can be described with an integrated Emax based
PK/PD model. In order to assess the predictive power of this model, a study was
conducted to compare the PK/PD-based predictions with CCS data obtained from
actual clinical trials for flunisolide, fluticasone propionate, budesonide and
triamcinolone acetonide. CCS was predicted for different single doses from
different inhaler devices for each drug and a good correlation was observed.
Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of
inhaled corticosteroids. By fully understanding the underlying mechanisms it will
be possible to further improve their therapeutic index.
PMID- 10756546
TI - Cardiovascular studies on different classes of soft drugs.
AB - Based on the inactive metabolite approach, three different classes of soft drugs
were designed and synthesized. Their cardiovascular effects and duration of
actions were studied in anesthetized male Sprague-Dawley rats compared to the
traditional drugs. During the experiments ECG (leads II, aVF) and beat-to-beat
blood pressure (BP) from the left carotid artery were recorded (except during the
anticholinergic studies). The soft anticholinergic
methoxycarbonylphenylcyclopentyl-N,N-dimethyltropinium methyl sulfate was as
potent as atropine in the prevention of carbachol induced bradycardia; however,
its action only lasted up to 15-30 min, compared to 2 h of that of atropine. In
the isoproterenol-induced tachycardia model, while bufuralol at an i.v. dose of
3.8 mumol/kg (1 mg/kg) diminished heart rate (HR) for at least 2 h, the effects
of the soft drugs lasted for only 30-40 min at equimolar doses. The methyl-,
ethyl-, isopropyl-, and tert-butyl ester-analogs of the carboxylic acid
metabolite of bufuralol showed the highest beta-blocking potencies (i.e., 30-50%
of that of bufuralol). When these compounds were infused for 10 min at doses
ranging from 2-4 mumol/kg/min, they caused a 20-40% decrease in HR and a 30-40%
reduction in mean arterial pressure (MAP). These effects were similar to those
elicited by esmolol at a dose of 20 mumol/kg/min in respect of the kinetics and
in the extent of the reductions in heart rate and MAP. The isopropyl-, the sec
butyl-, and the neopentyl-esters of the acidic metabolite of amiodarone, with
plasma hydrolytic half-lives of 60, 240 and 300 min, were tested in the
benzene/adrenaline induced ventricular tachycardia (VT) model of the rat. All
drugs were administered at a dose of 5 mumol/kg i.v. bolus immediately followed
by an infusion at 15 mumol/kg/h for 2 h. It was found, that amiodarone resulted a
complete suppression of VTs at 30 min after the start of drug administration, but
its effect lasted up to the total course of the experiment (up to 180 min). On
the contrary, both the sec-butyl and the isopropyl-analog resulted in complete
suppression of VTs already during the first benzene/adrenaline challenge after
drug administration (i.e., at 5 min). However, their effects disappeared between
15 and 30 min after discontinuation of the drug infusions in accordance with the
enzymatic inactivation (ester hydrolysis) of these soft drugs. All these three
classes of soft cardioactive drugs are good examples for highly potent but short
acting drugs whose side effects might also be reduced via the retrometabolism
based drug design.
PMID- 10756547
TI - Distribution of inorganic elements in human autopsy tissue.
AB - In the practice of forensic medicine, we find many of cases of death where the
actual cause is not determinable with autopsy, histological or toxicological
examinations. In these cases of death, we can consider cardiac dysfunction of
unknown origin, in the background of which such a physiologic cardiac
insufficiency occurs that cannot be detected with the previously mentioned
methods. The dysfunction is possibly associated with a significant change in
certain inorganic elements, primarily in the conduction system of the heart. In
the absence of published data, our goal was to determine the concentration of
inorganic elements in the specialized rhythm determining muscle cell groups in
the heart: sinus node (SN), atrioventricular node (AV), septum (SE), left
ventricle anterior wall (LVAW). With microwave technology we destroyed the muscle
tissue and measured the concentration of ions (Na, Mg, K, Ca, Mn, Fe, Cu, Zn, P,
S) using Inductive Completed Plasma Atom Emission Spectrometry (ICP-AES)
equipment. Of the 24 cases examined, the average ion concentrations in
microgram/g were the following; Sinus: Na 2602 +/- 493, Mg 120 +/- 24, K 1787 +/-
347, Ca 244 +/- 41, Mn 0.129 +/- 0.011, Fe 58 +/- 12, Cu 2.171 +/- 0.46, Zn 10.4
+/- 2.027, P 1147 +/- 227, S 2301 +/- 245; Septum: Na 1452 +/- 315, Mg 243 +/-
56, K 3269 +/- 689, Ca 105 +/- 26, Mn 0.17 +/- 0.05, Fe 74 +/- 16, Cu 3.557 +/-
0.952, Zn 25.75 +/- 8.4, P 2764 +/- 494, S 3001 +/- 523; Av: Na 2614 +/- 517, Mg
242 +/- 40.2, K 2010 +/- 395, Ca 271 +/- 27.3, Mn 0.13 +/- 0.029, Fe 54 +/- 12,
Cu 2.369 +/- 0.297, Zn 15 +/- 3.2, P 1625 +/- 291, S 2535 +/- 346; Lvaw: Na 1340
+/- 201, Mg 250 +/- 37, K 3659 +/- 532, Ca 88 +/- 22, Mn 0.175 +/- 0.05, Fe 76 +/
19, Cu 3.62 +/- 0.58, Zn 27.13 +/- 3.1, P 3025 +/- 441, S 3140 +/- 440.
PMID- 10756548
TI - Retrometabolism design concepts and realization for combinatorial libraries.
PMID- 10756549
TI - Biopharmaceutical studies on drug/conjugated metabolite interactions: application
of organic sulfonic compounds as biodistribution promoters.
PMID- 10756550
TI - New anti-cancer agent S-1: metabolism based drug combination.
PMID- 10756551
TI - Retrometabolic approaches in phytobiochemistry.
PMID- 10756552
TI - [Changes in metered dose inhaler propellants].
AB - The understanding of the damaging effect of chlorofluorocarbons (CFCs) on the
stratospheric ozone has led to international agreements calling for the total
phase-out of CFC production. The banning of CFCs in pressurized metered dose
inhalers used in airways disorders has been postponed on a temporary basis until
replacement propellants have been identified. Hydrofluoroalkanes HFA-134a and HFA
227 have been shown to have no ozone damaging potential and to be safe. However,
HFAs cannot simply be substituted for CFCs in inhalers of identical design. Their
use has required changes in many aspects of the drug formulation, inhaler design
and manufacture. This, in turn, has provided at least to some pharmaceutical
companies an opportunity to assess and enhance the performances of new inhalers.
The new products are neither technically nor pharmacologically identical to their
CFC-based counterparts. Some of them have now completed clinical trials and the
transition has already started: by the end of 1998, 2 short acting beta-agonist
HFA-based inhalers and a corticosteroid HFA-based inhaler have reached the
marketplace in France.
PMID- 10756553
TI - [Physiology of cough].
AB - Cough is a reflex phenomenon occurring when sensitive receptors located in the
larynx and upper airways are activated. These receptors generate information
which reaches the central nervous system. The central organization of the cough
reflex loop is poorly understood. The afferent pathways originate in receptors
situated under and between airway epithelial cells. Most are rapidly adapting
receptors (RAR) linked to myelinized fibers of the vagus nerve which can be
directly stimulated by cough-inducing agents. Other receptors generate
information carried by non-myelinized C fibers. When activated, these receptors
release neuropeptides leading to neurogenic inflammation which can also activate
RARs. The threshold of the cough reflex and its expression thus depends on a
complex interaction between RARs and C fiber receptors with peripheral and
central components. A better understanding of the mechanisms triggering cough and
its control would be most useful for optimal management of patients with cough
problems.
PMID- 10756554
TI - [Elimination of airborne allergens from the household environment].
AB - Exposure to allergens could be either a risk factor of sensitization and
nonspecific hyperresponsiveness in genetically predisposed patients or a risk of
onset of asthma attack in certain allergic asthma. During the past 20 years, in
western countries the houses have become higher and the number of furred pets
have increased and have been more kept inside the house which makes probable that
exposure to indoor aeroallergen has increased. The development of new methods of
allergen measurements allows a more precise identification of allergen source and
reservoirs, an assessment of allergen exposure and a monitoring of allergen
eviction methods. Concerning mite allergens, controlled studies which showed a
clinical efficacy are those with a global mite eviction and at least a 6 months
follow-up for cat and dog allergens, high efficiency-filters air cleaners or
vacuum-cleaners are able to reduce airborne cat or dog allergen levels. According
to the increasing number of papers about allergen eviction, it seems logical to
propose allergen eviction as "first line treatment" of allergic asthma. In the
future, it would be interesting to develop biological markers to identify more
accurately patients who have a clinical improvement after allergen eviction.
PMID- 10756555
TI - [Respiratory behavior].
AB - The notion of respiratory behaviour is grounded, among other approaches, on
studies of neuronal mechanisms of voluntary breathing, clinical data,
conditioning experiments and respiratory sensations. The interactions between
cortical centres of voluntary breathing and respiratory neurones in the brain
stem are poorly understood: voluntary control operates through the direct action
of corticomotor centres on respiratory motoneurones; however these cortical
structures may directly act on bulbopontine centres, and therefore indirectly on
respiratory motoneurones. Recordings in animals of brain stem neuronal activity,
brain imaging in humans, and transcortical stimulation of the diaphragm in humans
and in animal models support either one or the other hypothesis. The mutual
independence of the automatic and the voluntary controls of breathing appears in
patients with impaired bulbopontine automatism and operational voluntary control
(Central Congenital Hypoventilation Syndrome), and in patients with the reverse
impairment (locked-in syndrome). Finally, recent studies in humans and animals
show that classical conditioning affects respiratory control and sensations.
PMID- 10756556
TI - [Acute circulatory failure caused by primary pulmonary hypertension or pulmonary
embolism].
AB - Patients with acute massive pulmonary embolism or primary pulmonary hypertension
may develop acute circulatory failure and are therefore admitted in the intensive
care. The mortality rate of patients with pulmonary embolism and shock varies
between 25 and 35% whereas the corresponding figure in patients with submassive
embolism is less than 10%. Spiral computed tomography may be the most convenient
test for diagnosing pulmonary embolism in the setting of acute circulatory
failure. In the few patients who remain unstable despite adequate symptomatic
treatment, transthoracic echocardiography combined with clinical judgement is
appropriate. Inotropic support and thrombolytic therapy are clearly indicated for
patients with massive embolism and shock. The role of the latter is more
controversial in patients with right ventricular distension and normal blood
pressure. The optimal duration of anticoagulant therapy for pulmonary embolism
remains to be defined. Most patients are adequately treated with a six-month
course of oral anticoagulants. A shorter duration may be sufficient when a
transient risk factor is the cause of the initial event whereas patients with
cancer or antithrombin deficiency may require a life long treatment. Primary
pulmonary hypertension is a much more uncommon disease which can also lead to
right ventricular failure. Symptomatic treatment combines oxygen, inotropic
drugs, as well as the optimisation of right ventricular filling pressure.
Specific treatment includes inhaled nitric oxide or intravenous epoprostenol
followed by anticoagulants with either calcium channel blockers in patients
responding acutely to vasodilators or a continuous infusion of epoprostenol in
those who do not respond to acute challenge or who are not improving with calcium
channel blockers. Although the long term survival has markedly improved as a
result of epoprostenol treatment, some patients with refractory primary pulmonary
hypertension remain candidates for lung transplantation.
PMID- 10756557
TI - [Several aspects of respiratory function testing in children].
AB - Some practical aspects of respiratory function testing (RFT) are reviewed with
special interest on applications in preschool children. RFT may be used for
diagnostic, management and follow up purposes. Children may benefit from RFT in a
variety of pathological situations. Asthma and other obstructive airways diseases
certainly represent the most frequent conditions. Vital Capacity and Forced
Expiratory Volume in one second (FEV1) may usually be obtained from age 7 on. In
smaller children, the forced expiratory manoeuvre is much less successful. Non
invasive measurements such as respiratory resistance (Rrs) or specific airway
resistance (sRaw) may be used. Rrs is usually measured by the interrupter
technique or the forced oscillation technique and sRaw by body plethysmography,
not requiring the estimation of thoracic gas volume. Because much variability is
introduced by the upper airways, these parameters are less suited than FEV1 to
establish the degree of baseline airway obstruction. On the other hand, Rrs and
sRaw may quantify reversibility of airway obstruction and/or bronchial
hyperresponsiveness. Lung hyperinflation may be identified by the assessment of
Functional Residual Capacity (FRC) with a dilution method. More generally lung
growth may be followed up in longitudinal studies of FRC even in small children.
More work is needed to standardize RFT techniques and indications in the
preschool child.
PMID- 10756558
TI - [Smoking behavior and attitude to smoking of medical students (Tunisian Sahel)].
AB - Prevention of smoking is a public health goal recognized worldwide. Though the
role played by physicians is an important one, data in the literature indicate
that medical school is a poor place to learn it. In 1997, we conducted a study
among medical students at Monastir Tunisia to examine their smoking behavior and
attitudes towards smoking and their participation in prevention. The study
included 93.3% (N = 501) of the students in their 1st, 4th and 5th years of
medical school. One-third of the students (33%) were smokers, including 15%
occasional smokers. The students recognized the effect of smoking on coronary
arteries and bronchi but two-thirds of them were unaware of its role in bladder
cancer. The students did not warn their patients unless they had a disease
related to smoking. Half of the students felt they were not sufficiently prepared
for caring for smokers and desired specific training. These findings suggest
medical school authorities should design and implement appropriate basic training
aimed at better preparing medical students for their role in prevention of
smoking.
PMID- 10756559
TI - [Efficacy of docetaxel in non-small cell lung cancer patients previously treated
with platinum-containing chemotherapy. French Group of Pneumo-Cancerology].
AB - PURPOSE: Determine the response to, and toxicity of docetaxel (Taxotere) in
patients (pts) with inoperable non-small-cell lung cancer (NSCLC) previously
treated with platinum-containing chemotherapy. PATIENTS AND METHODS: Twenty-seven
patients with stage IIIB or IV NSCLC, having received one platinum-containing
regimen were treated with 100 mg/m2/3 weeks of docetaxel until tumor progression
or severe toxicity. Premedication with prednisolone and diosmin was given in all
patients. Antitumoral activity was assessable in 21/27 pts. Median age: 52 years;
WHO performance status 0-1: 77% pts, stage IV disease: 63% pts. RESULTS: 6/21
eligible pts (24%) achieved a partial response to treatment [C.I 95%: 5.6-42].
Median time to progression: 2.9 months, median survival: 8.5 months with a median
follow-up of 23.7 months (range: 13.5-27). Hematologic toxicity: grade 3-4
neutropenia: 75% pts, febrile neutropenia: 11% cycles. Non hematologic
toxicities: fluid retention, rash, alopecia, sensory neuropathy, asthenia, and
nail changes. CONCLUSION: Docetaxel (Taxotere) administered at 100 mg/m2/3 weeks
has relevant clinical activity against platinum treated NSCLC pts. Neutropenia is
the main toxicity.
PMID- 10756560
TI - [Impact of acute respiratory failure on survival of COPD patients managed with
long-term non-invasive ventilation and oxygen therapy].
AB - Our study aimed to assess the impact of acute respiratory failure (ARF) on
survival of patients with chronic obstructive pulmonary disease (COPD) receiving
long-term oxygen therapy (LTOT) plus nasal intermittent positive pressure
ventilation (NIPPV). Survival was analysed retrospectively in 24 patients with
severe COPD initiated to NIPPV in addition to LTOT. Fourteen patients were
established on NIPPV following exacerbation of acute respiratory failure which
has required mechanical ventilation (group 1). Ten patients (group 2) have never
been hospitalized for ARF. Comparison of clinical details at baseline, 6 months,
1, 2, and 3 years for the two groups failed to reveal any difference with the
exception of prior episodes of ARF. The probability of survival at 3 years was
65% (95% confidence interval [CI] 43-86) for the overall population, 46% (95% CI
15-77) in group 1, and 74% (95% CI 42-105) in group 2. The difference between the
two groups was statistically significant. We show that ARF requiring mechanical
ventilation appears to be a factor that is negatively correlated with survival
for patients treated by LTOT plus NIPPV. This data suggests that NIPPV should be
tried before ARF arising in COPD patients who present a deterioration in chronic
respiratory failure with hypercapnia.
PMID- 10756561
TI - [A rare cause of asthma exacerbation: systemic anguilluliasis].
AB - Strongyloides is an helminthic infection that may induce bronchospasm during
systemic migration of larvae. We report a case of a 60 years old man originating
from Caribbean who had corti-codependent asthma since 30 years. He was
hospitalized for severe exacerbation that worsen when steroid dosage was
increase. Sputum examination revealed the presence in great number of Larvae of
Strongyloides stercoralis. A good clinical evolution was achieved after specific
anti-helminthic treatment. Later on, it was even possible to stop completely
steroid treatment. This clinical case demonstrates the interest to look for
Strongyloides superinfection in asthmatic patients that worsen when receiving
increasing dose of steroids. This is particularly important for patients who have
resided, even many years earlier, in areas where intestinal helminthic infection
are endemic.
PMID- 10756562
TI - [Respiratory manifestations after exposure to sulfurous anhydride in wine-cellar
workers: 6 case reports].
AB - Sulfite treatment of wine [a process exploiting the biocidal and anti-oxidant
properties of sulfur dioxide (SO2)] involves the use of liquified gas, aqueous
solutions or bisulfites, i.e. the salts of sulfurous acid which slowly release
SO2. This procedure can result in repeated exposures of operators to significant
amounts of SO2. However, risks associated with the use of SO2 are greatly under
estimated by wine producers and wine-cellar workers. We report on 6 cases of
respiratory symptoms attributable to SO2 identified during a survey of wine
cellars in the French Beaujolais district. Their pathogenesis is discussed after
an overview of the occupational toxicology of SO2.
PMID- 10756563
TI - [Myxoid liposarcoma of the mediastinum].
AB - We describe a mediastinal myxoid liposarcoma case in a 47-year-old woman who
complained of dyspnea. This kind of tumor is rare and becomes symptomatic by
compression on mediastinal structures, especially on the respiratory tract. These
neoplasms are therefore often voluminous at the time the diagnosis is made.
Histopathologic examination is always necessary as much for diagnosis as
prognosis. Surgery, whether radical or palliative, obtain the best therapeutic
survival results in myxoid liposarcoma of the mediastinum.
PMID- 10756564
TI - [Severe hypoxemia with orthodeoxia due to right to left shunt in idiopathic
bronchiolitis obliterans organizing pneumonia].
AB - We report a case of BOOP with severe hypoxemia and orthodeoxia. Chest X-ray
showed bilateral infiltrative pneumonia and computed tomography scan revealed
consolidations on lower lobes. Diagnosis of right-to-left shunt was made on the
increase of alveolar-arterial oxygen difference under FIO2 100%, accented in
standing position. Contrast-enhanced echocardiography and technetium-99
macroaggregated albumin body scanning did not show anatomical right-to-left shunt
and permitted the diagnosis of intrapulmonary shunt at the capillary level
because of intra-alveolar organisation. Treatment with corticosteroids and
cyclophosphamide led to clinical, and radiological improvement with correction of
the hypoxemia and the shunt.
PMID- 10756565
TI - [Is risperidone responsible for respiratory manifestations?].
PMID- 10756566
TI - [Unusual cause of severe alveolar hypoventilation].
AB - Mesenteric panniculitis is a rare disease of the adipose tissue of mesentery.
Ascites is an unusual presentation. We report a case of panniculitis whose
initial presentation was an obesity-hypoventilation syndrome with pulmonary
hypertension. Respiratory disorders were related to abundant ascites.
Panniculitis cure and ascites disappearance allowed return to normal pulmonary
function and pulmonary artery pressure.
PMID- 10756567
TI - [Gastric volvulus associated with Zenker's diverticulum: a rare cause of
recurrent pneumopathy].
AB - We report on a case of a patient with recurrent pneumonia related to a pharygo
esophageal (Zenker's) diverticulum associated with a chronic thoracic gastric
volvulus. Mechanism, diagnosis and treatment of this rare disease are discussed.
PMID- 10756568
TI - [A pierced lung].
PMID- 10756569
TI - Sutures alone are sufficient to support regeneration across a gap in the
continuity of the sciatic nerve in rats.
AB - We have proposed that it is sufficient to provide a simple substratum on which
regenerating axons may traverse a gap in a peripheral nerve. To test this
hypothesis we set up a new experimental model in which sutures were used to
bridge a 10 mm long defect in a peripheral nerve. A defect was created
bilaterally in 25 rat sciatic nerves. The cut ends of the nerve were joined by
three laps of a continuous suture, on one side with 8/0 polyamide (non
absorbable) and on the other with 8/0 polyglactin (absorbable), leaving a 7 mm
gap. At two weeks a matrix that contained capillaries, fibroblast-like cells, and
mononuclear cells had formed between the nerve endings, and the sutures were
surrounded by foreign-body-like tissue reactions. At four weeks axons had grown
into the distal nerve segment on both sides in 65%-90% of the cases as indicated
by a response to the pinch reflex test and immunocytochemistry for presence of
neurofilament protein. Axons were organised in minifascicles and these tended to
grow larger as the demarcation of the entire regenerated segment by a perineurial
like structure improved with time. At 12 weeks axonal counts of cross-sections of
the distal tibial trunk showed many myelinated nerve fibres but no significant
difference in axonal counts or degree of myelination between the polyamide and
polyglactin sides. The results show that conventional sutures alone are
sufficient to support regeneration across a short gap in a peripheral nerve, a
method that may be of potential clinical value.
PMID- 10756570
TI - Tissue engineering of high density porous polyethylene implant for three
dimensional reconstruction: an experimental study.
AB - Three-dimensional defects have been reconstructed with carved and remodelled
frameworks wrapped within vascular carriers. If sufficient vascular penetration
can be established without any change in the size and shape of an implant, it
will be possible to cover it with a skin graft and aesthetically important fine
details can be obtained. To achieve this, we first prefabricated high-density
porous polyethylene implant in rabbits. Secondly, we applied full-thickness skin
grafts over the anterior surface of the prefabricated implant. The implants were
placed and anchored underneath the superficial inferior epigastric artery and
vein pedicle bilaterally. A total of 10 implants were prefabricated and then
grafted in five rabbits. The implants were evaluated by perfusion scintigraphy
and histological examination. Results showed that the implants were invaded by
fibroneo-vascular tissue, and that this tissue, which can be transferred as a
pedicled or a free flap, was sufficient to sustain a skin graft.
PMID- 10756571
TI - Topical application of cod liver oil ointment accelerates wound healing: an
experimental study in wounds in the ears of hairless mice.
AB - The effect of topical cod liver oil ointment on the rate of wound
epithelialisation and neovascularisation was studied using the hairless mouse ear
wound model (experiment I). The effect of local application of vitamin A in
increasing concentrations was tested in the same model (experiment II).
Experiment I: Bilateral standardised full thickness dermal wounds were created on
the ears of 42 mice divided into three groups: group I: 25% cod liver oil
ointment (n = 10) applied topically to one ear and vehicle (vaseline) to the
other; group II: 25% cod liver oil ointment (n = 10) and saline; and group III:
vehicle (n = 22) and saline. Experiment II: Using the same model and procedures
wounds were made on 12 mice randomised to vitamin A treatment in various doses
(250-3000 IU/g) on one ear and vehicle (vaseline) on the other ear. Using in-vivo
microscopy and digitised planimetry, wound epithelialisation and
neovascularisation were measured at regular intervals until the processes were
complete. Wounds treated with 25% cod liver oil ointment epithelialized
significantly (p < 0.05) faster (mean (SEM) 8.9 (0.7) days) than control ears
treated with vehicle alone (13.9 (1.9) days). Neovascularisation developed
significantly faster (p < 0.01) in the ears treated with cod liver oil ointment
(22.5 (1.3) days) compared with their vehicle control (29.1 (0.6) days).
Neovascularisation was also significantly (p < 0.05) faster in the ears treated
with cod liver oil ointment (23.1 (1.4) days) than in those treated with saline
(26.8 (1.1) days). There was no significant difference in speed of
epithelialisation between cod liver oil ointment and saline. The vitamin A dose
study showed that epithelialisation and neovascularisation of the vitamin A
treated wounds pass at the same rate as wounds treated with cod liver oil
ointment. In conclusion, topical 25% cod liver oil ointment significantly
accelerated both the epithelial and the vascular component of healing compared
with saline. Vitamin A seems to have an important role in accelerating wound
healing and could be the active component in cod liver oil.
PMID- 10756572
TI - Anatomical reasons for problems after neurectomy for blepharospasm: a study in
cadavers.
AB - The purpose of this study is to clarify the mechanisms of the problems that
develop after neurectomy for blepharospasm. The left facial nerves in 10 Japanese
cadavers were dissected under a surgical microscope. The temporal, zygomatic, and
buccal branches innervated to the orbicularis oculi muscle. These three groups
formed a well-communicating plexus posterior to the orbicularis. The most
inferior buccal branch curved in the deep layer in the lower part of the cheek.
In the cheek, both the buccal and the temporal branches had ramifications of
other facial muscles. The information given in previous anatomical textbooks did
not specifically define the denervation of the orbicularis. When neurectomy was
done in the past, the inferior buccal branch may have been kept intact, or other
facial muscles as well as the orbicularis may have been denervated which caused
the blepharospasm to recur and complications to develop after neurectomy.
PMID- 10756573
TI - Von Langenbeck or Wardill procedures for primary palatal repair in patients with
isolated cleft palate--speech results.
AB - Sixty-six patients operated on for isolated cleft palate were evaluated as
adults, and their speech was assessed clinically. Forty-four had undergone a von
Langenbeck repair at the age of 7 months and 22 a Wardill repair at the age of 18
months. Speech was judged subjectively by the patients themselves, and perceptual
assessment was made by three speech pathologists. The remaining speech problems,
mainly hypernasality, were moderate or severe in 7 (16%) of the patients in the
von Langenbeck group, and in 7 (32%) in the Wardill group. On the other hand, the
patients in the Wardill group had fewer fistulas closed, and fewer
velopharyngoplasties. There were no significant differences between the two
methods regarding speech in adulthood. The Wardill method produced significantly
more scar tissue clinically, which carries the potential risk of inhibition of
facial growth. The present speech results will therefore be weighed against the
outcome of maxillofacial growth for these patients.
PMID- 10756574
TI - Evaluation of a surgical technique for trigonocephaly.
AB - Clinically diagnosed trigonocephaly have been treated by a standard surgical
technique developed at Goteborg University Craniofacial Unit. To evaluate the
technique we designed a study to include both subjective and objective
assessments. Of 30 patients operated on between 1988-1997, 15 patients with at
least three years postoperative follow-up have been included. An evaluation of
the surgical outcome of the bitemporal width, the forehead contour, and the
intercanthal distance was made both subjectively using a visual analogue scale
(VAS) and objectively with analyses of cephalograms taken preoperatively and
postoperatively at 3 and 5 years of age. For the subjective evaluation a control
group of 10 randomly selected children from a Child Welfare Centre were selected.
For the objective evaluation the control group consisted of cephalograms from
children born with cleft lip and palate who were matched regarding sex and age.
Both cephalometric analysis and subjective studies of the outcome indicated
improvement. When the forehead contour was investigated the number of patients
who had been improved or corrected completely was higher when evaluated
subjectively. When interorbital distance on cephalograms and intercanthal
distance scores on VAS were evaluated, again the subjective study indicated
improvement in more subjects.
PMID- 10756575
TI - Efficacy of temporal musculopericranial flap for reconstruction of the anterior
base of the skull.
AB - Since March 1988 the temporal musculopericranial (TMP) flap has been used as our
flap of choice to reconstruct defects of the anterior base of the skull that are
larger than 2 x 3 cm, including the dura mater, in 33 patients. The primary
diseases were malignant head and neck tumours (n = 16), trauma (n = 15),
meningioma (n = 1), and teratoma (n = 1). The dura mater was reconstructed with a
unilateral TMP flap, after which the cranial and nasal cavities were closed with
the opposite TMP flap. In addition, bone was grafted by sandwiching the bone
between the two flaps and fixing it to the surrounding residual bone. When a
large area was resected, making it impossible to use a TMP flap, a frontal
musculopericranial (FMP) flap or a free flap (usually the rectus abdominis
myocutaneous flap) was used to close the cranial and nasal cavities. Thirty of
the 33 patients recovered with no postoperative complications. Two patients
developed extradural abscesses in the anterior base of the skull and one
developed mild meningitis, but they were successfully treated conservatively.
When bilateral TMP flaps were used for the reconstruction, no patient had
aesthetic problems in the forehead region. The TMP flap is extremely effective
for the reconstruction of the anterior base of the skull because it is minimally
invasive and causes few aesthetic problems in the forehead region.
PMID- 10756576
TI - How to dress donor sites of split thickness skin grafts: a prospective,
randomised study of four dressings.
AB - We investigated the effects of four dressings on donor sites of split thickness
skin grafts. Eighty patients undergoing elective split thickness skin grafting
were randomly allocated to one of four groups. The dressings were paraffin gauze,
polyurethane foam, polyethane film, and polyurethane film. The main outcome
measures were pain and discomfort, healing of donor sites, and time to remove
dressings. Polyurethane film caused less pain and discomfort and was also easiest
to remove. There were no differences in healing among the four groups.
PMID- 10756577
TI - Effects of transcutaneous nerve stimulation on the microcirculation in chronic
leg ulcers.
AB - The purpose of this study was to find out to what extent transcutaneous
electrical nerve stimulation (TENS) affects the blood flow in and around chronic
lower leg ulcers, as measured with a new technique, laser Doppler imaging (LDI).
Fifteen patients, mean age 73 years (range 38-85) with chronic leg ulcers of
various causes participated in the study. The duration of the ulcers ranged from
3 months to 16 years. Low-frequency (2 Hz; 10-45 mA) TENS was given for 60
minutes. The changes in blood flow were measured every 5 minutes by LDI. After 60
minutes, mean blood flow had increased in the ulcer by 35%, and in the intact
skin surrounding the ulcer by 15%. Even 15 minutes after the TENS had finished
there was still a mean blood flow increase of 29% in the ulcer and 9% in the
skin. The present results show that TENS has a stimulating effect on local blood
circulation in and around chronic ulcers.
PMID- 10756578
TI - Fluid retention in Bioplasty Misti Gold II breast prostheses with development of
capsular contracture.
AB - We compared the incidence of capsular contracture in an implant (Bioplasty Misti
Gold II) which has a textured surface and is filled with polyvinyl-pirrolidone
(PVP)-hydrogel, with that in saline-filled implants with textured surfaces when
the implants are placed subcutaneously during immediate reconstruction after
subcutaneous mastectomy. In 41 patients, mean age 55 years (range 30-81), with
breast cancer that was not suitable for breast conservation, 20 patients had 22
Misti Gold II prostheses inserted (two patients bilaterally) and 21 patients had
saline-filled prostheses (one patient bilaterally). The development of capsular
contracture was assessed using Baker's classification and applanation tonometry.
Fourteen patients with Misti Gold II implants were classified one year
postoperatively as Baker 2 and 3 compared with five with saline-filled implants
(p = 0.01). On applanation tonometry 16 of the Misti Gold II group had an
operative:postoperative ratio of < or = 0.75, compared with 50% in the saline
filled group (p = 0.096). In the 12 Misti Gold II prostheses that were removed
because of capsular contracture between 13-40 months postoperatively, the volume
in the prostheses had increased by 48%. The poor results obtained with the Misti
Gold II prosthesis can be explained by the volume that they gained after
implantation as a result of osmosis.
PMID- 10756579
TI - Assessment of functional outcome after nerve repair in a longitudinal cohort.
AB - To investigate the temporal changes in the results of clinical tests of the
functional outcome after nerve repair, we followed up 19 patients periodically
over a four year period after repair of the median or ulnar nerve at the forearm.
Between the first and last follow-up four of the instruments used--Semmes
Weinstein monofilaments, manual muscle testing, Sollerman grip test, and Jamar
dynamometer--indicated significant and moderate to large improvements. A moderate
and significant improvement was also noted during the same period in patients'
estimation of pain or discomfort. Results of the two-point discrimination test
did not change significantly over time. Most changes occurred during the first
postoperative year, and thereafter it was principally motor function that
improved. We conclude that four of the six used tests showed useful temporal
dynamics during the follow-up time. The lack of responsiveness in two-point
discrimination test suggests that other or complementary test instruments should
be used for assessment of tactile gnosis after nerve repair.
PMID- 10756580
TI - "Face to face": a new method for the treatment of polydactyly of the thumb that
maximises the use of available soft tissue.
AB - Some patients with distal phalangeal polydactyly of the thumb have severe
hypoplastic pulps that are difficult to make sufficiently large with either the
fillet flap method or a symmetrical combination, the Bilhaut-Cloquet method. We
have devised a new method to reconstruct the largest possible pulp by resecting
only a minimum amount of soft dorsal skin tissue with one nail and not resecting
any of the palmar skin of the thumbs. By contrast, other procedures require some
resectioning of soft tissue of both the dorsal and the palmar skin. We have
treated 13 cases with distal phalangeal polydactyly of the thumb since 1988 in
this way. All the thumbs were successfully reconstructed with a sufficiently
large pulp. The only problem was slight instability of the skin of the pulp after
the operation, but this condition gradually improved during a five-year follow
up. We think that this method facilitates the reconstruction of a sufficiently
large pulp when both bifid pulps are hypoplastic.
PMID- 10756581
TI - Compartment syndrome in a patient with X-linked agammaglobulinaemia and ecthyma
gangrenosum. Case report.
AB - Compartment syndrome is a surgical emergency that requires immediate
decompression. We know of no documented cases that describe ecthyma gangrenosum
as a primary cause of compartment syndrome. We present a case of a baby with x
linked agammaglobulinaemia who developed compartment syndrome associated with
systemic Pseudomonas aeruginosa infection and ecthyma gangrenosum of the leg. He
was treated by debridement and fasciotomies followed by primary closure and skin
grafting and made an uneventful recovery.
PMID- 10756582
TI - Squamous cell carcinoma of the finger masquerading as an abscess. Case report.
AB - A 43-year-old man presented with an abscess on his left ring finger, which
recurred despite multiple drainage procedures. Histological examination of the
lesion was unhelpful; it was only on histopathological examination of the finger
after ray amputation that the diagnosis of cutaneous squamous cell carcinoma was
established. This case illustrates the need to consider malignancy when dealing
with chronic finger infections.
PMID- 10756583
TI - Compression neuropathy of the superficial branch of the radial nerve. Case
reports.
AB - We present two cases of hypoaesthesia over the dorsal radial aspect of the hand
with an associated painful mass in the wrist. At operation a dorsal wrist
ganglion was compressing the superficial branch of the radial nerve at the
anatomical snuff-box. After removal of the ganglion the hypoaesthesia was
relieved.
PMID- 10756584
TI - [Self-enhancement tendency in self and other evaluations: an examination of
'better-than-average effect'].
AB - The purpose of this study was to examine self-enhancement tendency of Japanese
people when evaluating self and others, and study the relation between the
tendency and self-esteem. In Study 1, subjects were asked to evaluate themselves
and an average undergraduate of their age in terms of several attributes. Results
showed that self-evaluations were more favorable than evaluations of the average
undergraduate on such personality attributes as kindness and diligence, which
they rated more important, and less favorable on such attributes as appearance,
sociability, and financial resource. In addition, subjects with low self-esteem
were likely to appraise themselves more negatively than those with high self
esteem, but the two groups showed the same level of self-enhancement when rating
themselves on personality attributes. In Study 2, subjects provided percentile
rankings of themselves on ten attributes in relation to undergraduates of their
age. Results indicated that more than half of the subjects thought that they were
above average (better-than-average effect) on such personality attributes as
kindness.
PMID- 10756585
TI - [The process and the operation of reflective and predictive inferences in
analogical retrieval competition].
AB - The purpose of this study was to investigate the retrieval process and the
operation of inferences in systematic-level reminding within a competitive
situation. Two experiments were conducted using episodic stories in a
modification of the reminding paradigm developed by Wharton, Holyoak, Downing,
Lange, and Wickens (1994). Subjects incidentally studied four competitor pairs
and four unrelated stories. Then, subjects read other stories and were asked to
report any reminding of the studied stories. Memory retrieval was manipulated by
presenting subjects with different cue stories. Experiment 1 used both complete
cues containing a full set of thematic features and partial cues containing a
subset of the initial thematic features. Experiment 2 used both predictive cues
presenting a partial thematic structure and partial cues. Complete and predictive
cues were related to one of the competitor pairs. Partial cues were related to
both of the competitor pairs. Results indicated that (1) thematic similarity had
an influence on a selection in a retrieval process, and (2) both reflective and
predictive inferences operated on the selection during a retrieval process within
a competitive situation.
PMID- 10756586
TI - [Development of the Japanese version of the Buss-Perry Aggression Questionnaire
(BAQ)].
AB - The Aggression Questionnaire (Buss & Perry, 1992) has been used to investigate
links between personality factors and health outcomes. We developed the Japanese
version of the Buss-Perry Aggression Questionnaire (BAQ) and assessed validity
and reliability of the scale. Study I (N = 1,125 college students) used a 45-item
rating questionnaire measuring each of four components of aggression: Anger,
Hostility, Physical Aggression, and Verbal Aggression. Four aggression subscales
emerged clearly from exploratory factor analysis. Study II (N = 611 college
students) used a 24-item questionnaire and replicated factor structure and factor
loadings of Study I. The scales were shown to be highly internally consistent,
and stable at appropriate levels over 4-month time period. Normative data,
factorial validity, and external evidence of construct, convergent, and
discriminant validity for the scales were also presented.
PMID- 10756587
TI - [The effects of number of pre-target items and order of conditions on attention
in rapid serial visual presentation].
AB - Using rapid serial visual presentation, the present study attempted to show that
an attentional control error in integrating the target-definition dimension into
the response-definition dimension caused a target intrusion error. It also
examined the temporal relation between such attentional control and monitoring.
Forty-eight undergraduate and graduate students participated. Two conditions,
consistent or varied timing of target presentation, were used to manipulate
attentional control in the dimension integration. Each series of stimuli
consisted of 7 (consistent timing) or from 7 to 15 (varied timing) pre-target
items, followed by target and 8 post-target items. Results showed that timing had
an effect on mean probability of report, but not on confidence rating. In
addition, average position of reported items came later for consistent than
varied timing. These results suggested that average position of reported items
was delayed because a portion of attentional resources was allocated to
processing of timing. Further, average position of confident items was earlier
than that of reported items. It was suggested that monitoring seemed to precede
attentional control.
PMID- 10756588
TI - [Life-span developmental processes from the point of view of the elderly: an
examination of vocational life].
AB - The purpose of this study was to examine the experiences and meanings of crises
and to clarify types of the vocational life-cycle the elderly recognized in life
review. Subjects were 50 elderly persons at home (male: 39, female: 11, 66-79
years old), who took part in an individually semi-structured interview.
Vocational life processes involved school decision making, career decision
making, career development, retirement, and final retirement from the work. As a
result, more than 50% of the elderly had experienced crises at final school
decision making, and with career development in their thirties' and forties'.
Moreover, four types of vocational life-cycles were found. They were the
appreciating type, the decision making type, the career development type, and the
moderate type. The appreciating type was further sub-categorized into the
consistent type, the modifying type, the overcoming type and the unfolding type.
Finally, relationships between these types and attitudes toward retirement were
examined. Positive attitudes toward retirement were high in the consistent type,
while negative attitudes were high in the modifying type.
PMID- 10756589
TI - [On the validity of applying associative learning model to the acquisition
process of human contingency judgment].
AB - The assessment process of contingency between two binary events was examined in
the present experiments using university students. Some researchers have obtained
a learning curve in judging contingency and have thereby applied an associative
model to an explanation of human contingency judgment. Other researchers,
however, claimed that the task structure did not adequately reflect the structure
of 2 x 2 contingency tables and failed to obtain learning curves. After having
resolved methodological problems of task structure and procedure (Experiments 1 &
2), we demonstrated little evidence of learning curve in judging contingency
(Experiment 3). These results were discussed in terms of associative viewpoints
and rule-based models.
PMID- 10756590
TI - [A study of employment anxiety in college women].
AB - The purpose of this study was to develop "Employment Anxiety Scale" to understand
the structure of anxiety accompanying employment seeking. First, 30 items of
anxiety related to employment seeking were collected with an open-ended
questionnaire, for which 65 female students answered. In the main study, 465
female undergraduates filled out a questionnaire of the thirty items, a stress
scale, and a self-report depression scale. Factor analysis found three factors
for the anxiety items: employment seeking activity, vocational aptitude, and
workplace. Multiple regression analysis was performed to examine the relationship
between the mental-health scales and the anxiety. The dependent variables were
the stress and depression scores, and the predictors the subscale scores of
Employment Anxiety Scale. Results showed that anxiety accompanying employment
seeking activity was highly predictive of the mental-health scores.
PMID- 10756591
TI - [The effects of pleasantness of verbal messages on perceived deceptiveness in
romantic relationships].
AB - The present study examined the effects of pleasantness expressed in verbal
messages on their perceived deceptiveness. The hypothesis was that pleasant
messages are perceived as less deceptive than neutral or unpleasant ones. To test
the hypothesis, three types of messages were constructed: pleasant, neutral, and
unpleasant. Sixty-seven university students answered the questionnaire in which
they rated, on seven-point semantic differential scales, perceived deceptiveness
in one of the three types of messages. The result indicated that the unpleasant
messages were perceived as the most deceptive, while the pleasant ones the least
deceptive. The computer program "GPOWER" was used in order to obtain appropriate
sample size.
PMID- 10756592
TI - [Trends in research on social cognition: studies of organization of person
information and knowledge activation].
AB - Although social cognition research has a history of twenty years, this area is
not well recognized in Japan yet. This review focuses on studies on person
perception, especially on the organization of person information and knowledge
activation in social cognition. The effect of knowledge activation on behavior is
also addressed. First, the historical stream of social cognition studies is
overviewed. Second, the topics of representations of persons, top-down/bottom-up
processes in person perception, and spontaneous trait inferences are discussed.
Furthermore, the topics of construct accessibility effect, development of
assimilation/contrast effect, activation of goal concepts, and its effect on
behavior are examined. Lastly, some arguments on social cognition research are
addressed with references to the future.
PMID- 10756593
TI - [Blood lipids and adaptation to stress as risk factors for stroke prevention].
AB - Do stroke prevention patients with increased blood-fat-protein compounds (total
cholesterol, HDL- and LDL cholesterol and triglyceride) have a different method
of coping than patients with normal blood fat? 1159 stroke prevention patients
participated in the following stroke risk investigations at this hospital:
biographical and risk factor-orientated anamnesis, a neurological status
investigation, a laboratory investigation, a sonographic investigation and a
psychological investigation. The differences in the coping strategies of those
patients with normal and those with higher blood-fat-protein compounds were
investigated. Patients with higher total cholesterol showed significantly higher
values in the avoidance of stress situations (sig. 0.041) and a stronger tendency
towards escapist behaviour (sig. 0.05). Patients with normal HDL cholesterol
values indicated a tendency (sig. 0.07) to higher values in positive self
instruction in comparison to patients with reduced HDL cholesterol values. Those
prevention patients with higher LDL values showed a tendency (sig. 0.08) to
higher values in the intake of narcotic substances (nicotine, alcohol,
tranquillisers, pharmaceutical agents). Patients with increased triglyceride
indicated significantly higher values in coping by compensation (eating,
shopping, reward behaviour, watching TV; sig. 0.037) and the intake of narcotic
substances (sig. 0.044). Prevention patients with higher total cholesterol,
LDL/HDL, or triglyceride values showed significantly different coping strategies
in comparison to those patients with normal values. Increased avoidance and
escapism behaviour and also compensation and the abuse of narcotic substances
could be seen in connection with an increase in the risk of a stroke. In
contrast, a constructive coping strategy such as positive self-instruction could
reduce the risk of a stroke, which goes along with normal HDL cholesterol.
PMID- 10756594
TI - [Quality of life of the mentally ill].
AB - Object of this research project was to study the subjective quality of life of
psychiatric patients. The vulnerability of 424 out- and inpatients was assessed.
The Vulnerability Index, composed of: marital status, income, health, life
conditions, occupation, and risk factors in childhood was used. According to
their vulnerability, two groups of patients were differentiated: patients with
high and low vulnerability. We compared these objective criteria of vulnerability
with the subjective quality of life (Q-LES-Q). Quality of life was also compared
with diagnosis, severity of illness, and treatment (first contact/long-term
contacts). Quality of life of 250 patients was analysed after one year follow up.
Patients with a low vulnerability score are more satisfied with 'social
relations' than patients with a high vulnerability score. In-patients are more
satisfied with 'social relations' than out-patients. Out-patients are more
satisfied with their 'physical health', 'subjective feelings', 'leisure time
activities', and 'overall life satisfaction' than in-patients. Patients with a
mild affective disorder have a better 'life satisfaction' than patients with
severe affective disorder. Quality of life of schizophrenics and of patients with
anxiety and adjustment disorders has improved significantly after one year.
PMID- 10756595
TI - [Pharmacokinetic effects of antibiotics on the development of bacterial
resistance particularly in reference to azithromycin].
AB - Antibiotics reduce the mortality from infectious diseases but not the prevalence
of these diseases. Use, and often abuse, of antimicrobial agents encourages the
evolution of bacteria toward resistance, often resulting in therapeutic failure.
There are two factors which influence potential utility of a drug in a specific
clinical situation. The first is the measure of potency of the antibiotic for the
pathogen in question (minimal inhibitory concentration [MIC], minimal
bactericidal concentration [MBC]). The second is whichever relationship between
the concentration-time profile and potency of the antibiotic linked most robustly
to clinical outcome (time above MIC or MBC [T > MIC or T > MBC]; Peak/MIC or MBC;
area under the curve [AUC]/MIC or AUC/MBC). Herein the effects of
pharmacokinetics of antimicrobials on the evolution of antimicrobial resistance
with particular reference to azithromycin are considered.
PMID- 10756596
TI - [Fluoride treatment of osteoporosis].
AB - The development of anti-resorptive agents like vitamin D-hormones, or
bisphosphonates offers a new outlook for the fluorine salt therapy. Numerous
clinical studies have demonstrated increased bone mineral density in subjects
treated with fluoride, however, the results of these studies were controversial.
Fluoride has attracted attention as a therapeutic agent for osteoporosis because
it is an effective stimulator of osteoblasts. Therefore fluoride seems to be
useful, if the therapy is started in the early stages of osteoporosis, and
especially in patients with intact trabecular bone. The greatest therapeutic
benefit is seen with a low dose of fluoride in combination with vitamin D and
calcium. This treatment will also reduce the well known side effects of fluoride.
The treatment of osteoporosis could be improved with both, anti-resorptive agents
and osteoblasts-stimulating agents like fluoride, but further research is needed
to substantiate this therapeutical concept.
PMID- 10756597
TI - [Clinical relevance of drug interactions between sexual steroids and other
medications].
AB - Drug interactions of clinical relevance with hormonal contraceptives can occur
with antibiotics, antiepileptic agents and anticoagulants. For a prevention, non
hormonal contraceptives, short-term use of higher dosage of oral contraceptives
or, for long-term application, continuous administration (i.e. without hormonal
pause) of monophasic micro-pill preparations containing 30 micrograms ethinyl
estradiol and higher progestin doses should be preferred. The contraceptive
effect also can be impaired using barbiturates and rifampicin; the demand of
insulin or oral antidiabetics can be altered during medication with oral
contraceptives. Regarding investigations of possible drug interactions only few
studies have been performed with hormonal replacement therapy in peri- and
postmenopause. Drug interactions could develop above all treating risk patients
with internal diseases. Treatment regimens using the physiological, human hormone
estradiol instead of conjugated equine estrogens should be preferred. We
recommend transdermal hormonal application especially if hepatic drug
interactions could occur.
PMID- 10756598
TI - [Radiation in place of scalpel--early non-surgical treatment of uterine
carcinoma].
AB - We present a historical survey on the development of non-surgical therapies in
the treatment of uterine cancer in Germany (1895-1930) based on source material
with special emphasis on articles published in the "Zentralblatt fur
Gynakologie". In Germany early radiation therapy of gynaecological cancer slowly
started in the years between 1903 and 1912, to a greater extent it was used only
after 1913. A gynaecological congress taking place in the city of Halle in 1913
had an enormous impact on further radiation therapies. Together with technical
improvements of X-ray units several therapeutic schools arose, every one of them
with a radiation method of its own. Both X-ray treatment and treating with
radioactive substances were combined, different combination methods were created.
Until 1930 radiation therapy had found its place in the treatment of uterine
cancer, though still being disputed controversial.
PMID- 10756599
TI - [P53-status in primary ovarian carcinomas, ovarian metastases of neoplasms in
other sites and benign ovarian tumors: predictive value in comparison to
histopathological parameters].
AB - OBJECTIVE: The purpose of this study was to determine whether the tumor
suppressor gene p53 can be used as a prognosis factor to assess individual
patient risk in primary ovarian carcinoma. MATERIALS AND METHODS: The
concentration of the mutated, as well as the wild type p53 was examined in 98
cases of ovarian carcinoma. Among 98 ovarian tumors examined, 77 were primary
carcinomas, 14 tumors were metastasis of foreign tumors, and 7 were benign
ovarian tumors. The pan-53 ELISA from Fa. Dianova was used to test for the p53
protein. RESULTS: The p53 protein concentration exhibited a wide range in the
different tissue samples. Benign tumors contained significantly lower p53
concentrations than malignant tumors. After the data was analyzed using Kaplan
Meier, a p53 concentration of 507.1 pg/ml was established as cut-off point for
assessing cancer prognosis as good or poor. Patients exhibiting p53
concentrations over 507.1 pg/ml had a median life expectancy of 20 months, and
patients exhibiting lower tumor concentrations of p53 had a life expectancy of
over 70 months. A significant relationship between patient life expectancy could
also be shown for tumor stage and type, whereas not for tumor grading.
CONCLUSIONS: Based on the results of this study, the routine measurement of p53
may allow for a better prognostic assessment of life expectancy of patients with
primary ovarian carcinoma.
PMID- 10756600
TI - [Needle biopsy vs. conventional surgical biopsy - biochemical analysis of various
prognostic factors].
AB - OBJECTIVE: In which way is the biochemical analysis of fine needle biopsy
comparable to the biochemical analysis of conventional surgical biopsy samples in
the examination of prognosis factors in mammary carcinomas. MATERIAL AND METHODS:
Conventional surgical biopsy and fine needle biopsy were performed on 63 mammary
carcinomas. The results from the biochemical analysis of tissue samples, from
each form of biopsy, with respect to estradiol and progesterone receptor, UPA and
PAI-1, as well as Kathepsin D and the EGF receptor, were compared and
statistically analyzed. RESULTS: When compared to conventional tissue biopsy
samples, the sensitivity and specificity of the measured prognosis factors in
fine needle biopsy tissue were variable for each parameter, but fell within the
statistically safe margin of 86 to 100%. CONCLUSIONS: The biochemical analysis of
the prognosis factors found in fine needle biopsy samples showed that fine needle
biopsy is a viable alternative to intraoperative conventional surgical biopsy.
PMID- 10756601
TI - [Is there an increase of serum antisperm antibodies following surgery in the
cervical transformation zone for cervical intraepithelial neoplasia (CIN)?].
AB - OBJECTIVE: This prospective controlled study was performed to investigate whether
operative procedures of the uterine cervix lead to a change in the titre of
humoral antispermatozoal antibodies. MATERIAL AND METHODS: Humoral
antispermatozoal antibodies were measured using an ELISA in 15 patients
undergoing cervical scraping, 20 having conisation, 10 having a loop excision
before and at least 3 months after surgery as well as in 10 fertile women as a
control group. RESULTS: There were no significant differences in age between
groups, in the distribution of initial and final levels of humoral
antispermatozoal antibodies (IgG, IgA), and no significant change of the antibody
titres (pre- and postoperative) within the individual groups. CONCLUSIONS: In
patients of fertile age, the formation of humoral isoantibodies does not have to
be taken into account in selecting the method of diagnosing and treating cervical
intraepithelial neoplasia (CIN).
PMID- 10756602
TI - [Painfulness of transvaginal follicle aspiration for oocyte retrieval in in-vitro
fertilization].
AB - OBJECTIVE: The aim of this study was to analyze the painfulness of a transvaginal
ultrasound-guided follicle punction. MATERIAL AND METHODS: Patients could choose
to have either a neuroleptanalgesia or to be supported by the partner or a
psychotherapist during the oocyte pick up. Based on a questionnaire, 277 patients
tried to describe their level of pain in a horizontal alphanumeric scale divided
in 15 categories, while other painful physical interacts could be quantified,
too. Furthermore, patients were asked for the cause of sterility, former IVF-ET
treatments and whether the partner or the psychotherapist looked after them
during the oocyte retrieval. Statistical analysis was performed using a
standardized computer program (Stat View, Abacus Concepts, USA). RESULTS: The
neuroleptanalgesia reduced the intensity of pain (average value of pain: 1.21 vs
9.26 without analgesia) in a significant way (p = 0.0001). Some patients compared
the pain at oocyte retrieval with a bone fracture (8.08) or surgeries (10.12).
More painful was a colic (13.67), infections (13.5), some diagnostic surgeries
(12.09) or a delivery (11.91). Younger woman and patients with dysmenorrhea felt
significantly more pain than others. Neither the presence of the partner or
psychotherapist during punction nor the indication, number of previous IVF-ET
treatments or a following pregnancy had any influence on the statistics.
CONCLUSION: Age as well as the rate of problems with menstruation should help the
patient to decide on whether to have the follicle punction with or without
anesthesia.
PMID- 10756603
TI - [Ovarian mucinous adenocarcinoma, mucocele of the appendix and pseudomyxoma
peritonei: case report with immunohistochemical analysis].
AB - Women with pseudomyxoma peritonei may have both, appendiceal and ovarian mucinous
tumors, and there is a considerable debate regarding the site of origin of the
tumor in such cases. Recent studies which have investigated the histological and
immunohistochemical profile of these tumors showed, that ovarian tumors in most
cases are secondary to the appendiceal tumors. In our case report we demonstrate
that, despite of extensive immunohistochemical examinations (analysis of CK 7,
18, 20, CEA, HAM 56), it may be difficult to determine the histogenetic origin of
pseudomyxoma peritonei.
PMID- 10756604
TI - [Primary malignant melanoma of the female urethra].
AB - Primary malignant melanomas of the urethra are extremely rare. Clinically they
are usually mistaken for other malignant diseases or even benign lesions. The
case of a 66-year-old woman is reported, who presented with local bleeding of the
urethra. Macroscopically a polypoid tumor was seen on the meatus externus of the
urethra. A biopsy was taken and the histology report revealed a malignant
melanoma. There were no signs of metastases and therefore the treatment consisted
of a wide local excision only. A review of literature regarding therapy and
prognosis is presented.
PMID- 10756605
TI - ["Notebook computer" in combination with WWW-technology in multicenter clinical
trials and for chronic patient care].
AB - Our purpose was to determine conditions, under which the use of hand-held
computers in the diagnosis and therapy of patients with chronic diseases seems to
be handy. Two scenarios are presented showing the employment of these computers
in a doctor's office and in multicenter clinical trials. Security-related aspects
involved in transferring medical data via the internet are discussed.
PMID- 10756606
TI - [Telemedicine in clinics and practice].
AB - As a result of modern techniques of fast and flexible transmission of pictures
and sound, new chances for a use in medicine are presented. In this article the
pro's and con's of telemedicine are discussed and the technical prerequisites
described.
PMID- 10756607
TI - Time to go public on performance?
PMID- 10756608
TI - Implications of the United Kingdom Prospective Diabetes Study for general
practice care of type 2 diabetes.
PMID- 10756609
TI - A randomized trial of three marketing strategies to disseminate a screening and
brief alcohol intervention programme to general practitioners.
AB - BACKGROUND: Research findings are of little benefit to patients or society if
they do not reach the audience they are intended to influence. A dissemination
strategy is needed to target new findings at its user group and encourage a
process of consideration and adoption or rejection. AIM: To evaluate the
effectiveness and cost-effectiveness of different marketing strategies for the
dissemination of a screening and brief alcohol intervention (SBI) programme to
general practitioners (GPs). METHOD: Seven hundred and twenty-nine GPs, one per
practice, from the former Northern and Yorkshire Regional Health Authority were
randomly assigned to one of three marketing strategies: postal marketing (mailing
a promotional brochure to GPs), telemarketing (following a script to market the
programme over the telephone), and personal marketing (following the same script
during face-to-face marketing at GPs' practices). GPs who took up the programme
were asked if they would agree to use it. Outcome measures included the
proportions of GPs who took up the programme and agreement to use it. RESULTS: Of
the 614 GPs eligible for the study, 321 (52%) took the programme. There was a
significant difference in the proportions of GPs from the three marketing
strategies who took the programme (82% telemarketing, 68% personal marketing, and
22% postal marketing). Of the 315 GPs who took the programme and were eligible to
use it, 128 (41%) agreed to use the programme for three months. GPs in the postal
marketing group were more likely to agree to use the programme (55% postal
marketing, 44% personal marketing, and 34% telemarketing). Personal marketing was
the most effective overall dissemination strategy; however, economic analysis
revealed that telemarketing was the most cost-effective strategy. Costs for
dissemination per GP were: 13 Pounds telemarketing, 15 Pounds postal marketing,
and 88 Pounds personal marketing. CONCLUSION: Telemarketing appeared to be the
most cost-effective strategy for dissemination of SBI to GPs.
PMID- 10756610
TI - A RCT of three training and support strategies to encourage implementation of
screening and brief alcohol intervention by general practitioners.
AB - BACKGROUND: Providing doctors with new research findings or clinical guidelines
is rarely sufficient to promote changes in clinical practice. An implementation
strategy is required to provide clinicians with the skills and encouragement
needed to alter established routines. AIM: To evaluate the effectiveness and cost
effectiveness of different training and support strategies in promoting
implementation of screening and brief alcohol intervention (SBI) by general
practitioners (GPs). METHOD: Subjects were 128 GPs, one per practice, from the
former Northern and Yorkshire Regional Health Authority, who agreed to use the
'Drink-Less' SBI programme in an earlier dissemination trial. GPs were stratified
by previous marketing conditions and randomly allocated to three intensities of
training and support: controls (n = 43) received the programme with written
guidelines only, trained GPs (n = 43) received the programme plus practice-based
training in programme usage, trained and supported GPs (n = 42) received the
programme plus practice-based training and a support telephone call every two
weeks. GPs were requested to use the programme for three months. Outcome measures
included proportions of GPs implementing the programme and numbers of patients
screened and intervened with. RESULTS: Seventy-three (57%) GPs implemented the
programme and screened 11,007 patients for risk drinking. Trained and supported
GPs were significantly more likely to implement the programme (71%) than controls
(44%) or trained GPs (56%); they also screened, and intervened with,
significantly more patients. Costs per patient screened were: trained and
supported GPs, 1.05 Pounds; trained GPs, 1.08 Pounds; and controls, 1.47 Pounds.
Costs per patient intervened with were: trained and supported GPs, 5.43 Pounds;
trained GPs, 6.02 Pounds; and controls, 8.19 Pounds. CONCLUSION: Practice-based
training plus support telephone calls was the most effective and cost-effective
strategy to encourage implementation of SBI by GPs.
PMID- 10756611
TI - Comparison of breast cancer patient satisfaction with follow-up in primary care
versus specialist care: results from a randomized controlled trial.
AB - BACKGROUND: Routine follow-up of breast cancer patients in specialist clinics is
standard practice in most countries. Follow-up involves regularly scheduled
breast cancer check-ups during the disease-free period. The aims of follow-up are
to detect breast cancer recurrence and to provide psychosocial support to the
patient; however, little is known about patients' views on breast cancer follow
up. AIM: To assess the effect on patient satisfaction of transferring primary
responsibility for follow-up of women with breast cancer in remission from
hospital outpatient clinics to general practice. METHOD: Randomized controlled
trial with 18 months' follow-up in which women received routine follow-up either
in hospital outpatient clinics or from their own general practitioner. Two
hundred and ninety-six women with breast cancer in remission receiving regular
follow-up care at two district general hospitals in England were included in the
study. Patient satisfaction was measured by means of a self-administered
questionnaire supplied three times during the 18-month study period. RESULTS: The
general practice group selected responses indicating greater satisfaction than
did the hospital group on virtually every question. Furthermore, in the general
practice group there was a significant increase in satisfaction over baseline; a
similar significant increase in satisfaction over baseline was not found in the
hospital group. CONCLUSION: Patients with breast cancer were more satisfied with
follow-up in general practice than in hospital outpatient departments. When
discussing follow-up with breast cancer patients, they should be provided with
complete and accurate information about the goals, expectations, and limitations
of the follow-up programme so that they can make an informed choice.
PMID- 10756612
TI - The patient-centredness of consultations and outcome in primary care.
AB - BACKGROUND: There is general support for general practitioners (GPs) using
patient-centred styles. However, there is limited British evidence of beneficial
outcomes for patients from such styles. AIM: To explore whether, for patients
presenting for new episodes of care, the GP's consulting style, specifically the
patient-centredness of the consultation, is related to five generic outcomes.
METHOD: General practitioners in South Wales were recruited, and one surgery
consulting session was audiotape recorded for each participating clinician.
Questionnaires were given to consenting patients before their consultations,
immediately afterwards, and, by post, at two weeks to measure the following
outcomes: doctor-patient agreement (on the nature of the problem and management),
patient satisfaction, resolution of symptoms, resolution of concerns, and
functional health status. From the patients consulting for a new episode of care
and completing all three questionnaires, one patient was selected at random for
each GP and the audiotape of their consultation rated for patient-centredness.
Statistical analysis employed correlation coefficients and t-tests, followed by
multiple regression and logistic regression to control for potential confounders.
RESULTS: In total, 143 patients consulting 143 GPs were studied. The patient
centred score was positively and statistically significantly associated with
patient satisfaction (Pearson correlation = 0.28; P = 0.002). No other
associations were found with the other outcomes measured. CONCLUSION: The study
presents evidence that patient-centred styles of consulting produce benefits in
terms of increased patient satisfaction for patients consulting for new episodes
of care in Britain.
PMID- 10756613
TI - Controlled trial of pharmacist intervention in general practice: the effect on
prescribing costs.
AB - BACKGROUND: It has been suggested that the employment of pharmacists in general
practice might moderate the growth in prescribing costs. However, empirical
evidence for this proposition has been lacking. We report the results of a
controlled trial of pharmacist intervention in United Kingdom general practice.
AIM: To determine whether intervention practices made savings relative to
controls. METHOD: An evaluation of an initiative set up by Doncaster Health
Authority. Eight practices agreed to take part and received intensive input from
five pharmacists for one year (September 1996 to August 1997) at a cost of
163,000 Pounds. Changes in prescribing patterns were investigated by comparing
these practices with eight individually matched controls for both the year of the
intervention and the previous year. Prescribing data (PACTLINE) were used to
assess these changes. The measures used to take account of differences in the
populations of the practices included the ASTRO-PU for overall prescribing and
the STAR-PU for prescribing in specific therapeutic areas. Differences between
intervention and control practices were subjected to Wilcoxon matched-pairs,
signed-ranks tests. RESULTS: The median (minimum to maximum) rise in prescribing
costs per ASTRO-PU was 0.85 Pound (-1.95 Pounds to 2.05 Pounds) in the
intervention practices compared with 2.55 Pounds (1.74 Pounds to 4.65 Pounds) in
controls (P = 0.025). Had the cost growth of the intervention group been as high
as that of the controls, their total prescribing expenditure would have been
around 347,000 Pounds higher. CONCLUSION: This study suggests that the use of
pharmacists did control prescribing expenditure sufficiently to offset their
employment costs.
PMID- 10756614
TI - Management of deliberate self harm in general practice: a qualitative study.
AB - BACKGROUND: It has been estimated that the incidence of deliberate self harm
(DSH) is at least 10 times that of suicide. Accident and emergency discharge
figures also point to an almost doubling of reported cases of DSH in the early
1990s. AIM: To assess general practitioners' (GPs') views on, and educational
requirements for, managing patients following an episode of DSH. METHOD: A
qualitative study with 14 GPs (seven male and seven female) from two outer-London
boroughs, selected in order to provide a maximum variety sample. Interviews took
place between February and April 1997, and data were analyzed using the
principles of grounded theory. RESULTS: Most GPs felt that all patients
presenting with DSH should be assessed by a psychiatrist. They expressed a
preference for working with a community psychiatric nurse rather than a
counsellor. Suggestions to improve their working relationship with community
mental health teams included provision of one centralized point of referral and
ease of access to the service in times of crisis. GPs were sceptical of
guidelines, emphasizing that they needed joint ownership in writing them, but
most importantly that they needed adequate resources to implement them. Specific
changes to postgraduate education were suggested, such as individual educational
portfolios. CONCLUSION: Improved working relationships between GPs and community
mental health teams are needed in order to provide a more efficient and effective
service for patients. Lifelong learning needs to be adapted in a style and
approach to suit GPs' individual requirements.
PMID- 10756615
TI - Home blood pressure monitoring: its effect on the management of hypertension in
general practice.
AB - BACKGROUND: Ambulatory and home blood pressure monitoring have been shown to
improve the management of hypertension. Either can be used to diagnose 'white
coat hypertension' (WCH), which affects 10% to 20% of hypertensives and usually
does not require drug treatment. Home monitoring has been used little in primary
care. AIM: To investigate the use and acceptability of home monitoring, and to
establish the incidence of WCH as diagnosed in a primary care setting. METHOD:
Twenty practices were asked to monitor hypertensive patients, in particular those
about to start drug treatment and those who were poorly controlled. RESULTS: A
total of 660 patients were monitored. Sixty-four (27%) of the 236 untreated
patients had WCH and no medication was started in 60 (94%) of this group. Forty
five (17%) of the 258 poorly-controlled patients had WCH and, of these, 34 (76%)
continued with the same medication and 11 (24%) either reduced or stopped it.
Compliance with recording was high. Questionnaires and focus groups with doctors
and nurses showed that home monitoring represented a valuable enhancement of
their management of hypertensive patients. Patients reported a high degree of
interest and satisfaction with monitoring. CONCLUSIONS: Patients, doctors, and
nurses found monitoring valuable, and found the instruments easy to use with few
problems. The feasibility of screening for WCH with home blood pressure
monitoring was demonstrated, and, for this specific purpose, it is recommended as
the preferred alternative to ambulatory monitoring in primary care.
PMID- 10756616
TI - Iron deficiency anaemia and aspirin use in old age.
AB - Aspirin is being increasingly prescribed for cardiovascular protection, but is
also recognized to have significant gastrointestinal side-effects. Whether
chronic aspirin consumption causes iron deficiency is undetermined, and there is
little information available regarding iron deficiency and aspirin use in old
age. We studied the relationship between iron deficiency anaemia and regular
aspirin prescription in old age.
PMID- 10756617
TI - Clinical examination for abdominal aortic aneurysm in general practice: report
from the Medical Research Council's General Practice Research Framework.
AB - At the time of the 1992-1994 annual reviews in the thrombosis prevention trial,
general practitioners (GPs) carried out clinical examination for aneurysms by
abdominal palpation in 4171 men. When an aneurysm was suspected, the patient was
referred to hospital for further investigation. Aneurysm was suspected in 60 men
(1.4%) and confirmed in 25 (0.6%), the mean diameter of confirmed aneurysms being
5.0 cm (range = 3.1-8.0 cm). Of the 25 men in whom aneurysm was confirmed, 10
(40%) underwent elective surgery and one died while under investigation.
Examination by abdominal palpation for aortic aneurysm, which is not widely used
in either general practice or in hospital practice, other than vascular surgery,
is clinically worthwhile even though not all aneurysms will be detected by this
means.
PMID- 10756618
TI - Costs of antidepressant overdose: a preliminary study.
AB - There is ongoing debate regarding the relative cost effectiveness of different
classes of antidepressants. Although factors such as tolerability and
discontinuation rates have been taken into account, there has been little
consideration of the cost of overdose. In the current study we examined the cost
of antidepressant overdose at four teaching hospitals over a four-week period and
found that the cost of selective serotonin reuptake inhibitor overdose was less
than half that of tricyclic anti-depressant overdose. The cost of overdose is
often ignored and should be considered in future analyses of the cost
effectiveness of different antidepressant prescribing policies in primary care.
PMID- 10756619
TI - Age- and sex-specific antibiotic prescribing patterns in general practice in
England and Wales in 1996.
AB - Using data from 288 general practices in England and Wales contributing data to
the General Practice Research Database in 1996, we derived age-sex specific
antibiotic prescribing and exposure rates. The overall antibiotic prescribing
rate was 607 per 1000 in males and 852 per 1000 in females. In both males and
females, prescribing rates were highest in children aged 0-4 years and in the
elderly. Prescribing rates in young and middle-aged women were substantially
higher than in men of the same age. Overall, 29% of males and 39% of females were
prescribed antibiotics in 1996. Children under five years of age were most likely
to receive a prescription for an antibiotic. Antibiotic prescribing rates for the
288 practices in the study varied nearly five-fold, from 333 to 1616 per 1000.
Reducing this variation and overall antibiotic prescribing rates will be major
challenges for general practitioners.
PMID- 10756620
TI - Should general practitioners refer patients with major depression to counsellors?
A review of current published evidence. Nottingham Counselling and
Antidepressants in Primary Care (CAPC) Study Group.
AB - Major depression can be treated effectively with antidepressants. However, in the
United Kingdom, patients with depression are often referred to counsellors, and
surveys indicate that public opinion favours this approach. We carried out a
literature review to determine the evidence for the effectiveness of counselling
for depression in primary care. Because no studies were identified in which
counselling had been evaluated specifically in relation to treating depression,
we examined indirect evidence from studies evaluating the overall effectiveness
of generic counselling in primary care, and studies evaluating the effectiveness
of psychological treatments, other than counselling, for depression.
Methodological problems influencing the interpretation of such studies are
discussed. We conclude that, while specific psychological treatments have been
shown to have equivalent effectiveness as antidepressants, there is currently
insufficient evidence to recommend that generic counselling should be used alone
in the treatment of patients with major depression.
PMID- 10756621
TI - The newer, 'atypical' antipsychotic drugs--their development and current
therapeutic use.
AB - General practitioners (GPs) need to become more aware of a new generation of
antipsychotic drugs that are 'atypical' in that, unlike traditional neuroleptics,
they do not cause extrapyramidal side-effects; they may also be more effective
against both the positive and negative symptoms of schizophrenia by their actions
on various neurotransmitter pathways in the brain. This is a non-systematic
review of the development of these new drugs and outlines how they are currently
being used. It includes information found from an electronic search of the
databases MEDLINE (from 1966 to June 1998) and EMBASE (from 1980 to January 1998)
using the combined search terms 'antipsychotic agents', 'atypical', and
'schizophrenia'.
PMID- 10756622
TI - People with learning disabilities in the community: where do we go from here?
PMID- 10756623
TI - Defying the reaper.
PMID- 10756624
TI - Factors associated with the provision of anti-smoking advice by GPs.
PMID- 10756625
TI - Simulated surgery.
PMID- 10756626
TI - Antibiotic prescribing for sore throat.
PMID- 10756627
TI - Speaking out.
PMID- 10756628
TI - UK medical charities and clinical trials.
PMID- 10756629
TI - A treatment for constipation.
PMID- 10756630
TI - [Ischemic heart diseases: progress in diagnosis and treatment].
PMID- 10756631
TI - [Epidemiology of ischemic heart disease among Japanese].
PMID- 10756633
TI - [Vascular endothelial dysfunction and ischemic heart disease].
PMID- 10756632
TI - [Coronary atherosclerosis and pathology of restenosis following coronary artery
intervention].
PMID- 10756634
TI - [Insulin resistance and ischemic heart disease].
PMID- 10756635
TI - [The role of electrocardiographic diagnosis--on reperfusion therapy and
asymptomatic myocardial ischemia].
PMID- 10756636
TI - [Progress in nuclear diagnosis].
PMID- 10756637
TI - [Progress in ultrasonic diagnosis].
PMID- 10756638
TI - [Biochemical diagnosis of acute myocardial infarct].
PMID- 10756639
TI - [Treatment of angina pectoris].
PMID- 10756640
TI - [Therapy of unstable angina].
PMID- 10756641
TI - [Progress in coronary artery intervention].
PMID- 10756642
TI - [Current treatment of myocardial infarction].
PMID- 10756643
TI - [Key points in the treatment of elderly patients with ischemic heart disease].
PMID- 10756644
TI - [Treatment of potentially fatal ventricular arrhythmia accompanying myocardial
infarction].
PMID- 10756645
TI - [Prevention of recurrence of myocardial infarction].
PMID- 10756646
TI - [Clinical management of ischemic heart diseases. Discussion].
PMID- 10756647
TI - [Right atrial occupation with hepatocellular carcinoma, firstly documented of
angina-like symptom].
PMID- 10756648
TI - [Ehlers-Danlos syndrome type IV complicated by intraperitoneal hemorrhage].
PMID- 10756649
TI - [Disseminated fusarium infection in a patient with acute myelogenous leukemia].
PMID- 10756650
TI - [Increased Wilms tumor gene (WT1) expression preceded by hematological relapse in
a patient with acute myelogenous leukemia].
PMID- 10756651
TI - [Lambert-Eaton myasthenic syndrome in a patient with small cell lung cancer].
PMID- 10756652
TI - [Treatment of chronic myelocytic leukemia].
PMID- 10756653
TI - [Endocrine-disrupting chemical substances (so-called environmental hormones)].
PMID- 10756654
TI - [Cerebral MRI: recent progress].
PMID- 10756655
TI - [New concepts of steroid preparations--preclinical and clinical concepts].
PMID- 10756656
TI - [Guideline for the treatment of acute myocardial infarction in aged patients.
Committee on the "Study on the Preparation of a Guideline for the Treatment of
Acute Myocardial Infarction in Aged Patients", a comprehensive gerontological
study by the Ministry of Health and Welfare].
PMID- 10756657
TI - [How the therapy of cancer is changing].
PMID- 10756658
TI - [Research methodology in medical educational. Meeting of the Italian Society of
Medical Education (SIPEM) September 24-25, 1999, Rome].
PMID- 10756659
TI - [Lymphedema of the upper extremity in patients operated for carcinoma of the
breast: clinical experience with coumarinic extract from Melilotus officinalis].
AB - OBJECTIVES: The aim of this clinical study was to verify the therapeutic activity
of cumarinic extract of Melilotus officinalis (CEMO) in patients with chronic
lymphedema of the upper arm caused by lymphadenectomy for breast cancer.
Cumarine, in fact, has antiedemic properties due to macrophagic action that
stimulates proteolysis in the tissues affected by chronic lymphedema. PATIENTS
AND METHODS: In an open clinical study we enrolled 24 patients with chronic upper
arm lymphedema due to post-lymphadenectomy of the axilla for breast cancer. 21
patients were eligible to receive 400 mg of CEMO containing 8 mg of cumarine in a
sole daily administration for 6 months. We measure the circumference of the upper
arm at 3 and 6 months from treatment. We evaluated the symptoms and tolerability
through a questionnaire given to the patients at every clinical control. RESULTS:
Of the 21 (87.5%) patients eligible, only 14 (66.6%) were treated with CEMO
according to protocol. Of these 11 patients (52.3%) had a reduction of the
circumference of the affected arm of 5% with respect to base values. Three
patients (14.2%) had no change. In 12 patients (57.1%) symptoms improved. As for
tolerability: 3 patients (14.2%) had transitory gastrointestinal side-effects.
There was worsening of lymphedema and symptoms in 4 patients (19%) that did not
receive CEMO and were followed as controls. Three patients (14.2%) were not
evaluable because they were lost to follow-up. CONCLUSIONS: Cumarinic extract of
Melilotus officinalis (CEMO) was effective in reducing lymphedema in 79% of the
pts treated for a period of six months. The median reduction of the upper arm
circumference was modest (5% with respect to initial values) but statistically
significant (p = 0.048). Treatment with CEMO for lymphedema could be associated
to the physiotherapy given to these patients such as manual lymph drainage (MLD).
PMID- 10756660
TI - [Periungual capillaroscopy in psoriatic arthritis].
AB - PURPOSE: The aim of the study is the evaluation of the microcirculation trough
periungueal capillaroscopy in patients suffering from psoriatic arthritis.
MATERIALS AND METHODS: Eighteen patients (mean age 44 years, nine males and nine
females) were examined according to the different clinical forms (spondylitic,
mutilans, simil-rheumatoid, onyco-arthritis, oligo-articular) of the disease.
RESULTS: In most of the patients, the exam showed a reduction in ansas' density
and in capillary length and calibre as well as interstitial edema and expansion
of the ansa venular portion with coiling and kinking, demonstrating the re
organization of the veins and the neo-angiogenesis. Avascular areas and
microaneurysm have been found only in the "mutilans" form. In the "simil
rheumatoid" form, ansa reduced in length and calibre have been observed at
capillaroscopy, a pattern different from that reported by others, in rheumatoid
arthritis (characterized by thin but lengthened ansa). In the "spondylitic" form,
the video-microscopical pattern was negative. CONCLUSIONS: This study is still
ongoing in order to evaluate the results in a more representative sample.
PMID- 10756661
TI - Hepatitis C virus: a high risk factor for a second primary malignancy besides
hepatocellular carcinoma. Fact or fiction?
AB - PURPOSE: Second primary malignancies occur more and more often. But the
hepatocellular carcinoma (HCC) linked to a second primary cancer is not frequent.
MATERIALS AND METHODS: A retrospective study focused on a second primary cancer
was performed in 37 patients with HCC, aged between 46 and 81 years, 27 males and
10 females. RESULTS: 5 out of them (13.5%), 3 males and 2 females, developed a
second primary neoplasm before or after HCC. In 3 cases the second malignancy was
a carcinoma of the kidney, of the breast, and the prostate. The fourth patient
had a Hodgkin's lymphoma before HCC. The last and most unlucky case, besides HCC,
had a basal cell carcinoma, a colorectal cancer, and a bladder carcinoma. The
common data of these 5 patients were the presence of anti-HCV antibodies and the
positivity of the HCV RNA polymerase reaction. One patient was also HBV positive.
CONCLUSION: Considering that a large number of virus has been found linked to
human cancers, our results brought us to hypothesize that HCV could have played
an important role not only in the development of HCC but of the second primary
malignancy too. This is likely favoured by constitutional or acquired biological
and molecular alterations. Tumor suppressor genes alterations have been reported
to be frequently linked to cancers of kidney and breast, of colorectal and skin,
of prostate, and lymphoemopoietic tissue. Now just these organs are involved in
our patients in addition to the liver. Our results, if confirmed, are of a
relevant interest, considering that world-wide HCC is constantly increasing for
the spreading of the virus risk-factors.
PMID- 10756662
TI - [The "Eubiosia" project].
PMID- 10756663
TI - [Treatment of Alzheimer disease and the main primary degenerative dementias].
AB - In this paper we describe a brief report on the psychopharmacologic and non
pharmacologic treatment of the main degenerative dementias. We highlight the
importance of using cholinesterase inhibitor drugs; moreover we describe the
pharmacologic strategies for the related symptoms and the new pharmacologic
approaches which include estrogen, non-steroidal-antiinflammatory agents and anti
oxidant agent, like vitamin-E. At least we briefly report the news from the
ongoing clinical trials of other pharmacologic agents to improve cognitive
functions and to slacken the neurodegenerative processes and the future
pharmacological perspectives. In conclusion we briefly describe the non
pharmacological treatment with particular regard to psychoeducational,
psychosocial and cognitive strategies that can enhance quality of life on both
patients with dementia and their caregivers.
PMID- 10756664
TI - [Beta blockers and cardiac decompensation].
AB - It has been demonstrated that beta blockers are able to modify the course of the
disease, through the reduction of hemodynamic in stabilization and mortality
cases. The success of these drugs in the treatment of chronic heart failure is
related to the sympathoadrenergic activation and to renin-angiothensin-aldosteron
system. Various molecules are available at the moment. Recent research has been
done on third generation beta blockers (carvedilol, nebivolol, bucindolol). These
drugs have shown to possess some peculiar characteristics, in particular the
ability of reducing the number of side effects which may be seen while using beta
blockers of the first generations. Although it is currently difficult to give
general informations based only on the pharmacologic profile, the choice of the
type of drug to use in the single patient with chronic heart failure should be
made considering the adequacy of the pharmacologic characteristics in each
specific situation.
PMID- 10756665
TI - [Oral contraceptives and activated protein C resistance: a paradigmatic example
of genotype and environment interaction in the development of deep venous
thrombosis].
AB - A young woman, carrying factor V Leiden, developed a deep venous thrombosis after
the use of oral contraceptives. This suggests that it is appropriate to study the
most frequent causes of primary thrombophilia in all of the women beginning a
treatment with estrogens.
PMID- 10756666
TI - [Primary pneumococcal peritonitis: description of a case and review of the
literature].
AB - Streptococcus pneumoniae causes lobar pneumonitis but primary peritonitis can
occur in cyrrotic adults as well as in children affected by nephrosis and
immunopathies. In young females peritonitis can be the consequence of infection
localized at genital organs. Pneumococcal sepsis is becoming rare with the
antibiotic era but resistance to penicillin is actually frequent and is becoming
a problem for elderly. We report a case of a young woman affected by spontaneous
primary peritonitis and pneumococcal sepsis. The prevalent symptoms were
gastrointestinal: diarrhea and emesis. No infectious foci could be detected on
imaging studies and during surgery.
PMID- 10756667
TI - [Success of the chemotherapy of cancer. The cure of leukemia].
PMID- 10756668
TI - [Hepatitis C: epidemiology and therapy--with special reference to long-term
prognosis after IFN therapy].
AB - Blood transfusion or blood products are a important route for transmission of
hepatitis C virus(HCV) infection. Routes of infection other than blood
transfusion are medical treatments including hemodialysis, exposure of hospital
employees to needles contaminated with blood, drug abusers, acupuncture,
tattooing, certain types of sexual behavior and mother-to-infant infection. The
prevalence of anti-HCV antibodies in blood donors in Kumamoto Prefecture was
1.30%(1,704 of 131,376) between February and October 1992 and 0.46%(622 of
132,847) between April 1998 and May 1999, respectively. Also, the prevalence of
anti-HCV was 22.9%(126 of 550) in the highly endemic area. The prevalence of HCV
infection was evaluated in 548 patients undergoing hemodialysis, and 216 members
of the hospital dialysis staff. Of 548 hemodialysis patients, 166(30.3%) were
positive and significantly higher than those for either hospital staff
members(2.3%; p < 0.01) or healthy blood donors(1.3%; p < 0.01). Patients with a
history of blood transfusion tended to have a higher positivity rate for anti-HCV
than did the non-transfused group. Positivity for anti-HCV was related to the
duration fo hemodialysis. Although hemodialysis patients remain a high-risk group
for HCV infection, the prevalence of anti-HCV antibodies has decreased recently
thanks to the use of erythropoietin for renal anemia, the universal screening of
blood donors for anti-HCV antibodies, and improvements in infection control
measures for this virus. To evaluate the effect of interferon(IFN) therapy on the
incidence of hepatocellular carcinoma(HCC) or decompensated liver cirrhosis, 490
patients with chronic hepatitis or liver cirrhosis type C who had undergone liver
biopsy since 1987, were followed periodically. Of these patients, 411 received
IFN and 79 were untreated. The degree of liver fibrosis was assessed from stage
F0(no fibrosis) to stage F4(cirrhosis). Response to IFN was determined
virologically and biochemically. HCC developed in IFN-treated patients and in 17
untreated patients with stage F3 or F4 fibrosis. In multivariate analysis, IFN
therapy was associated with a reduced risk of HCC, especially among patients with
sustained virological response(CR), among those with persistently normal serum
ALT levels, and among those with ALT levels less than two times the upper limit
of normal(PR). Also, the cumulative incidence of decompensated liver cirrhosis
and cumulative survival in treated and untreated patients differed significantly.
None of the patients with CR or PR progressed to the decompensated state and all
patients with CR or PR have survived to date. In conclusion, IFN therapy
significantly reduces the risk for HCC or decompensated cirrhotic stage,
especially among virological or biochemical responders.
PMID- 10756669
TI - [Epidemiology of hepatitis B virus and hepatitis C virus infection].
PMID- 10756670
TI - [The clinical pathology for the twenty-first century].
AB - At first, the ideal way of the scientific convention should be reexamined. It is
approved the future direction which should do the joint with the related
societies. It has been decided that it is held at a partly congruence with Japan
Society of Clinical Chemistry in the next fiscal year. The Corporation Promotion
Committee(chairman of prof. I. Sakurabayashi) negotiates with the Ministry of
Education about the incorporation. The Society Improved Committee(chairman of
prof. K. Watanabe) is discussing about a retirement system and improved select
system of the councilor. And, though the more than 400 persons of clinical
laboratory physicians has been registered as a certified clinical laboratory
physicians, it copes in the selection committee of each university does not
always taking laboratory medical doctor as a professor of the department of
clinical laboratory. And, it becomes the name of the Japan Society of Clinical
Pathology does not suit at present state. The Appellation Revision
Subcommittee(chairman of K. Nakahara) is discussing in the ideal name of the
Society. The opinion of the most part of way will concern national medical
insurance. The clinical laboratory tests related groups(Japan Society of Clinical
Pathology, Japanese Association of Clinical Laboratory Physicians, Japan Society
of Medical technologists, Japan Registered Clinical Laboratories Association,
Japan Association of Clinical Reagents Industries, Japan Council of Clinical
Reagents wholesales) formed the Council on Clinical Laboratory Tests-Related
Organization at present, and the demanding paper was submitted to related
associations, such as Ministry of Health and Welfare, Japan Medical Association
and so on.
PMID- 10756671
TI - [Brain death judgement and clinical examinations].
AB - In September, 1997, the law of the transplantation of internal organs was
promulgated and enforced from October the same year. Since the beginning of this
year(1999), four cases of legal brain death judgement, based on after mentioned
law have reported. With regard to the branch of clinical examinations the law
designates EEG examination as a compulsory article, and the ABR(auditory brain
stem response) examination, as an article that is desirable to carry out. An EEG
examination of a highly precise level is required to confirm the "flat EEG" as
the standard of judgement, in comparison with daily clinical examinations.
Additionally, a request for an examination to ascertain whether brain death has
occurred may be required abruptly. In the examination room, it is vital to ensure
that staff have appropriate examination skills, and the guidelines on how to
proceed are set in place.
PMID- 10756672
TI - [Molecular diagnostic tests and chromosome analyses].
AB - Molecular diagnostic tests and chromosomal analyses are often used to diagnose
infectious, neoplastic and genetic diseases. However, there are only a few
genetic laboratories in university hospitals in Japan because of the high cost
and additional staff required for their management. In 1992, we started a genetic
laboratory with one technologist in Shinshu University Hospital, and mainly
performed polymerase chain reactions(PCR) for the diagnosis of several
mycobacterial species, Hepatitis C virus and cytomegalovirus. Infectious diseases
diagnosed by PCR have gradually increased over recent years. Chromosome analyses
were available in 1996 and spectral karyotyping started from April 1999. Our
genetic laboratory was staffed by 4 technologists and 3 faculty members in 1999,
and they can provide informative tests with high quality. Molecular diagnostic
tests were performed for 855 infectious diseases, 25 hematopoietic tumors and 8
solid tumors, while chromosome analyses were performed for 51 hereditary diseases
and 29 hematopoietic tumors in 1998. Establishment of a genetic laboratory in a
university hospital may not result in cost savings, but it produces a favorable
influence on other laboratories. All staff can use molecular biology techniques
to clarify limitations of routine tests and research.
PMID- 10756673
TI - [Recent advances of MEG].
AB - The number of MEG(Magnetoencephalography) channels was rapidly increased from 14
to 306 in the past decade and the detection coil array with the whole-scalp
coverage has become fairly common these days. Besides the advances of
biomagnetometer itself, there are several important technical advances around MEG
measurements. An active shielding technique can reduce the contamination of
environmental magnetic noise in the frequency range below 10 Hz. Applying
SSP(signal space projection) technique, which is known as a strong tool to
resolve multiple current sources, can be another choice to reduce this
contamination in the full frequency range. Recently the realistic head model
reconstructed from MRI data was accomplished and we can apply this model, instead
of the conventional spherical model, to the patients with TLE(temporal lobe
epilepsy) expecting further accurate dipole estimation. These advances are quite
important for the data acquisition with high S/N(signal to noise) ratio and the
reliable three-dimensional localization of current sources in the brain.
PMID- 10756674
TI - [The management of advanced clinical laboratory].
AB - Considering good laboratory management in highly specialized and sophisticated
medical services, I here focus on university hospitals, so-called special
functioning hospitals and other hospitals of equivalent size. I describe my
personal view as a medical technologist on laboratory management, which is pretty
much affected by difficult financial condition surrounding medical services.
Also, I touch upon quality assurance of laboratory tests and technologies, how to
support clinical practices and conduct business management. Of particular
importance may be cost and labor saving in laboratory practices and to develop
advanced and sophisticated medical technologies. Furthermore, it will be
essential to educate and produce excellent and multidisciplinary medical
technologists competent at laboratory practices and management so that we medical
technologists contribute to daily clinical practices and progress in medical
sciences.
PMID- 10756675
TI - [M-CSF levels during peripheral blood stem cell harvest and autologous stem cell
transplantation].
AB - Plasma macrophage colony-stimulating factor(M-CSF) levels were determined during
peripheral blood stem cell harvest and autologous stem cell
transplantation(PBSCT). Plasma of 10 patients were analyzed by using ELISA
system. The average peak values during PBSCT were quite higher than those during
harvest(20,092 vs 1,681 pg/ml). Peak values were observed mainly around leukocyte
nadir(Phase II) during harvest. On the other hand, they were detected just after
pretreatment(Phase I) during PBSCT courses. Moreover, samples showing extremely
high M-CSF values(Phase I) were associated with increase in serum LDH levels.
These data suggest that plasma M-CSF in Phase I are mainly derived from
chemotherapy-induced cellular damage during PBSCT courses, and there might be
different mechanisms to raise M-CSF around the nadir of leukocytes. It is
necessary to elucidate the biological meanings of M-CSF.
PMID- 10756676
TI - [The construction of a standard RNA synthesized for quantitative RT-PCR system].
AB - We constructed the standard RNA synthesized for the chimeric AML1-MTG8
transcripts and the house-keeping gene, glyceraldehyde-3-phosphate
dehydrogenase(GAPDH) transcripts in real-time quantitative RT-PCR system. AML
MTG8 transcripts was detectable in 10 fg of synthetic RNA(3.5 x 10(3) copies).
Linearity was from 3.5 x 10(3) to 3.5 x 10(9) copies. Threshold cycle(CT) is
defined as the fractional cycle number at which the reporter fluorescence
generated by cleavage of the probe passes a fixed threshold above baseline. The
standard curve, where the known amounts of RNAs were used, showed a good
correlation between the copies of AML1-MTG8 RNA and CT(r = -0.995). The within
run and day-to-day coefficients of variation(CV) in AML1-MTG8 RNA by this system
were 9.5-24.7%(n = 10) and 21.7-42.2% (n = 8), respectively. GAPDH transcripts
was detectable in 10 fg of synthetic RNA(6.1 x 10(4) copies). Linearity was from
6.1 x 10(4) to 6.1 x 10(8) copies. The standard curve, where the known amounts of
RNAs were used, showed a good correlation between the copies of GAPDH RNA and
CT(r = -0.993). The within-run and day-to-day CV in GAPDH RNA by this system were
9.3-14.6%(n = 10) and 14.7-15.8% (n = 10), respectively. Thus, we suggested that
synthesized RNA as a standard RNA may be useful in quantitative RT-PCR for
clinical application.
PMID- 10756677
TI - [Complement activation in heparin--plasma inhibitory effect of anticoagulants on
serum complement activation, 2nd report].
AB - Our previous study of the inhibitory effect of EDTA and citrate in plasma on
complement activation revealed that complement is activated in usual citrate
plasma but not in usual EDTA plasma. The present study is a similar one using
other anticoagulants containing heparin. CH50 and activities of C4 and C2 were
assayed in serum or plasma containing various concentrations of anticoagulant
after incubation with latex particles bearing immunoglobulin(Ig-Latex). It was
found that complement activation is inhibited by heparin in a dose-dependent
manner and that 10 U/ml of heparin does not inhibit CH50 reduction and C2
inactivation but inhibit C4 inactivation partially, indicating that complement
activation proceeds in plasma containing usual concentration of heparin. Similar
results were obtained in cases of low molecular weight heparin(LMWH) and
nafamostat mesilate(Futhan). Complement activation was not inhibited by gabexate
mesilate(FOY) in the tested range of concentrations. Thus, it was revealed that
complement activation is not inhibited by usual concentrations of heparin, LMWH,
Futhan and FOY.
PMID- 10756678
TI - [A case of intra-right atrial thrombus adhering to an intravenous
hyperalimentation catheter].
AB - We reported a clinical case of intra-right atrial giant thrombus adhering to an
intravenous hyperalimentation(IVH) catheter. The patient was a 63 years-aged
male, and was indwelled the IVH catheter for one month from right subclavian vein
to right atrium to improve a malnutrition due to his advanced gastric cancer.
Intra-cardiac mass was found in the right atrium by routine transthoracic
echocardiography for the preoperative inspection; the giant mass(22 x 20 mm) had
a low-echo density with a portion of high-echo density. In transesophageal
echocardiography, the portion of high-echo density was found to be an IVH
catheter and intra-right atrial mass was pierced by that catheter; however, it
was difficult to determine whether the mass was either a vegetation or thrombus.
The mass was removed by operation, and was diagnosed as a giant thrombus by
histopathological examination. Thrombus should be taken into account as a
possible cause of intra-right atrial mass when an IVH catheter was indwelled in
the right atrium.
PMID- 10756679
TI - [History of Matsuzawa Psychiatric Hospital over the past 120 years].
PMID- 10756680
TI - [Schizophrenia: before the onset, prodrome, and onset].
PMID- 10756681
TI - [Age of onset, frequency of the development of symptoms, and treatment outcome in
the early stage of schizophrenia--in search of guidelines for early diagnosis and
treatment of schizophrenia].
PMID- 10756682
TI - [Selection and dosages of therapeutic agents for the early stage of
schizophrenia].
PMID- 10756683
TI - [Early discovery and treatment of schizophrenia in daily clinical practice--a
follow-up study of high risk children].
PMID- 10756684
TI - [Significance of early discovery and treatment of schizophrenia].
PMID- 10756685
TI - [My practice of clinical psychiatry].
PMID- 10756686
TI - [Psychotherapy in psychiatry--the position of personal psychotherapy].
PMID- 10756687
TI - [Enjoyment is desirable. An interview with PD Dr. med. P.E. Ballmer. Interview by
Dr. Klaus Reinhardt].
PMID- 10756688
TI - [Vegetarianism yesterday and tomorrow].
PMID- 10756689
TI - [Nutrition in sports].
AB - A sports diet is qualitatively similar to a diet of a healthy adult. Its main
aspects are meeting the energy and fluid requirements, which in contrast to
sedentary people can vary to a large degree in sportsmen. The relative
contribution of the macronutrients to the energy consumption should make up 55 to
60% carbohydrates (mainly derived from low glycemic food), 10 to 15% protein, and
25 to 30% fat. The main focus of a diet for most recreational sport activities
should be on an optimal carbohydrate and fluid intake, which are the two main
limiting factors of most physical activities. Related to the body mass, the
carbohydrate intake should amount to 5 to 7 grams per kilogram. During the days
before and after an intense exercise session or competition, however, the intake
should be raised to about 10 grams per kilogram body mass to ensure an optimal
energetic preparation of and regeneration from the exercise bout. The water
intake should be about 2 to 3 liters per day with an extra 1.2 to 1.5 liters to
balance each liter of exercise-induced sweat loss.
PMID- 10756690
TI - [The hypo-allergic diet].
AB - A hypoallergenic diet in a proper sense does not exist. The prescription of a
dietary treatment for allergic diseases or intolerance reactions is highly
dependent on an exact allergologic diagnosis. An IgE-mediated allergy to food is
treated by an elimination diet. In chronic disease, e.g. chronic urticaria or
chronic abdominal symptoms, the relevance of specific IgE to food allergens can
be proved by a diagnostic elimination diet, which is followed by oral
provocation. In children at risk for atopic diseases (one or both parents or
siblings with atopic diseases) a preventive diet during the first year of life is
recommended. The cornerstones of such a diet are breast feeding during the first
six months of life, late introduction of solid food and the avoidance of
allergenic proteins such as cow's milk, eggs and fish during the first year of
life. In intolerance reaction an additive free diet or a diet with low content of
biogenic amines may be recommended. Patients with chronic urticaria or atopic
dermatitis may suffer from an intolerance to histamine. A diet with a low content
of biogenic amines may improve the condition of these patients.
PMID- 10756691
TI - [Diabetic diet 2000].
AB - Diabetes diet in the year 2000 consists essentially of carbohydrates. 50% to 60%
of the total caloric intake has to be taken in form of carbohydrate. Slowly
metabolised forms of carbohydrate should be preferred. Fat and proteins should
not exceed more than 20% of the respective total caloric intake. Vegetable fats
should be preferred compared to animal fats. Patients with type 2 diabetes who
should loose weight have to be extremely careful regarding the fat intake.
Insulin-dependent diabetics can correct mistakes in the carbohydrate intake by
injecting fast insulins provided that they have in-depth knowledge of the mode of
action of insulin and dietary experience.
PMID- 10756692
TI - [Junk food revolution or the cola colonization].
AB - In ancient times, the main problem was to get food. Nowadays the difficulty is to
decide for or against some foodstuff. In industrialized countries, this abundance
led to the fact that people eat differently from what they should. Traditional
populations were subject to periods of feast and famine. Those with a metabolism
which stored energy with high energetic efficiency had a survival advantage. This
is called the 'thrifty' genotype hypothesis. With the secured supply of calories,
coupled with a sedentary lifestyle, the thrifty genotype becomes disadvantageous,
causing obesity. Industrialization or 'cola-colonization' also leads to a
dramatic increase in obesity and non-insulin dependent diabetes mellitus in
developing countries. The spread of fast food restaurants all over the world has
changed modern nutrition fundamentally. Influence begins early in childhood.
Advertising concentrates on the selling of image over substance. However, fast
food contains high levels of fat, especially trans fatty acids. Higher
consumption of trans fatty acids was associated with a higher incidence of and
mortality from coronary heart disease.
PMID- 10756693
TI - [Kidney calculi--is nutrition a trigger or treatment?].
AB - Kidney stones occur in up to 15% of the population. The incidence of stone
disease is 0.1-0.4%, i.e. 100 to 400 out of 100,000 people form a kidney stone
every year. The recurrence rate is high, reaching 52% within 10 years and 75%
within 20 years, respectively. Since urinary supersaturation, the driving force
for crystallisation and stone formation, directly depends on nutritional habits,
dietary recommendations are an important part of stone treatment. The benefit of
urine dilution by means of a high fluid intake (urine volume at least 2.5 L/d)
has been established by several studies. On the other hand, incorrect dietary
recommendations, such as the restriction of calcium as advocated for decades, can
even promote stone formation! Indeed, large prospective trials have clearly
demonstrated that the risk for stone formation decreases with increasing daily
calcium intake. It is therefore mandatory that low-calcium diet is finally
abandoned in patients with calcium kidney stones and replaced by a sufficient
calcium consumption, i.e. 1200 mg per day. Furthermore, epidemiological studies
confirm that a diet rich in meat protein carries an increased risk for forming
upper urinary tract stones; thus, daily protein intake should not exceed 1 g/kg
body weight, which corresponds with general recommendations for a healthy diet.
Last but not least, more recent studies have shown that the consumption of high
quantities of fruits and vegetables may protect against kidney stone formation,
since it raises urinary excretion of citrate, an important inhibitor of
crystallization. The present review emphasizes on the relations between nutrition
and stone formation in the urinary tract and offers convenient and inexpensive
measures for the prevention of recurrence of nephrolithiasis.
PMID- 10756694
TI - [Nutrition and cancer].
AB - The complex process of carcinogenesis is mainly due to environmental factors and
therefore preventable. Diet may account for about 35% of cancer. This review
presents the nutritional evidence for the development of the four most common
cancers in Switzerland. The clearest risk factors for breast cancer are those
associated with hormonal and reproductive factors. In relation to dietary
factors, high alcohol intake, weight gain and adipositas (postmenopausal breast
cancer) probably increase the risk of breast cancer. The evidence is less clear
for the consumption of (animal) fat, meat, fruit and vegetables (inverse
association). Hormones may also play an important role in the development of
prostate cancer. There is no convincing evidence that any dietary factors modify
the risk of prostate cancer. Diets high in vegetables are possibly protective,
regular consumption of fat and meat possibly increase the risk. Intervention
trials revealed protective effects of supplementation with selen or alpha
tocopherol. The main cause of lung cancer is cigarette smoking, and smokers whose
diet is protective nevertheless remain at high risk. The evidence that diets high
in vegetables and fruit protect against lung cancer is convincing, but it is not
clear what constitutents are responsible for this effect. Intervention trials
revealed no protective effect of beta-carotene, and in high risk groups, lung
cancer risk was even increased. There is convincing evidence that diets high in
vegetables decrease the risk of colorectal cancer. The same is true for regular
physical activity. Alcohol and consumption of diets high in (red) meat, probably
increase the risk of colorectal cancer. For cancer prevention it is recommended
to choose a predominantly plant-based diet, to avoid obesity, to reduce the
intake of fat, (red) meat, alcohol and salt, not to smoke and to be physically
active. The main aim of nutritional therapy of cancer patients is to improve
quality of life, whereas the effect on life expectancy is very limited.
PMID- 10756695
TI - [Osteoporosis diet].
AB - Bone requires a wide variety of nutrients to develop normally and to maintain
itself after growth. Most important--in the sense that bony abnormalities are
associated with their deficiencies--are protein, calcium, phosphorus, vitamin D,
C and K, zinc, manganese and copper. The nutrients most likely to be deficient in
citizens of industrialized countries are calcium and vitamin D. In this review of
the current literature about nutritional aspects of osteoporosis, we have focused
on factors influencing calcium requirement: the principal interacting nutrients
are sodium, protein, caffeine, fiber, oxalate, phytate, and the acid/alkaline ash
character of the overall diet. Fiber and caffeine decrease calcium absorption
from the gut and typically exert relatively minor effects, while sodium, protein
and the acid/alkaline balance of the diet increase urinary excretion of calcium
and are of much greater significance for the calcium homeostasis. Alkali buffers,
whether vegetables or fruits reverse this urinary calcium loss. As long as
accompanied by adequate calcium intake, protein-rich diet is not deleterious to
bone: a calcium-to-protein ratio of 20:1 (mg calcium/g protein) is recommended.
Whether a nutrition-based therapeutic approach to osteoporosis is feasible in the
near future is yet unclear: at least there are some recent promising data from in
vitro as well as from rat studies showing that extracts taken from various
vegetables, mainly from the onion family inhibit bone resorption in a dose
dependent manner.
PMID- 10756696
TI - [The salt-free diet].
AB - The debate about the importance of salt in the pathogenesis and treatment of
hypertension is still ongoing. The importance of salt is rooted on several
factors. First, salt is one of the first factors who has been identified to be of
potential importance in blood pressure regulation. Second, during the last
decades several other pathogenetic risk factors for essential hypertension have
been identified, however, without the identification of one single predominant
risk factor. These risk factors include different genetic factors and
predispositions as well as modifiable environmental factors. For the development
of hypertension usually several of these risk factors have to be present. In
miscellaneous disease conditions, such as heart failure, salt induces a sodium
and volume retention. Accordingly it is often falsely concluded that salt will
lead to a volume retention and hypertension in all subjects and that a salt
restriction will lead to a normalization of an elevated blood pressure. Although
about 40% of the patients with essential hypertension are salt sensitive, the
concept of salt sensitivity is not valid for all subjects of a population.
Accordingly one can not conclude that a general salt restriction would be a cure
for hypertension. The therapeutic priority in the non-pharmacological prevention
and/or therapy of hypertension lies usually in the control of other risk factors
than salt intake. These risks include overweight and obesity, alcohol consumption
and physical inactivity. These concepts are supported by several recent meta
analysis.
PMID- 10756697
TI - [The Mediterranean diet--healthy but and still delicious].
AB - Mediterranean diets are characterized by a high portion of monounsaturated fatty
acids (in particular olive oil) and a low intake of saturated fatty acids (from
animal origin apart from fish). Moreover, high intakes of fruits, vegetables,
cereals (in form of bread), and moderate (regular) wine consumption are typical
for the mediterranean diet. Contrary to the current opinion, extra virgin olive
oil has no advantage compared to ordinary olive oil. Canola oil is an alternative
to olive oil because of its similar fatty acid composition. Based on the new
medical literature, mediterranean diet has strong secondary preventive effects
after myocardial infarction resulting in a decrease of total mortality, cardiac
death and non fatal reinfarction. The high portion of monounsaturated fatty acids
in olive oil cause a decrease in LDL cholesterol and an increase in HDL
cholesterol. In addition, antioxidative vitamins such as vitamin E, C and beta
carotene and phenolic substances such as the flavonoids, e.g. quercetin and
resveratrol, decrease the oxidation of LDL cholesterol and thus atherogenicity.
Mediterranean diet has at least no negative effects in the initiation and
promotion of cancer, however, its potential positive effects are so far less well
known.
PMID- 10756698
TI - [What is your diagnosis? Acrodermatitis in severe malnutrition caused by
malabsorption within the scope of Crohn disease].
PMID- 10756699
TI - The first randomized controlled trial.
PMID- 10756700
TI - The design and analysis of randomized controlled trials of treatments for lower
urinary tract symptoms.
PMID- 10756701
TI - The measurement of symptoms, quality of life and sexual function.
PMID- 10756702
TI - Urodynamic protocol and central review of data for clinical trials in lower
urinary tract dysfunction.
PMID- 10756703
TI - Other assessments: prostate size and prostate specific antigen.
PMID- 10756704
TI - A guide to undertaking economic evaluations within randomized controlled trials
of treatments for lower urinary tract symptoms.
PMID- 10756705
TI - Patient information and consent in trials for the treatment of benign prostatic
obstruction.
PMID- 10756706
TI - A review of studies published during 1998 examining the treatment and management
of benign prostatic obstruction.
PMID- 10756707
TI - Randomized controlled trials for benign prostatic obstruction: problems and
pitfalls.
PMID- 10756708
TI - The Prostate Trials Office research protocols.
PMID- 10756709
TI - Molecular chaperones.
PMID- 10756710
TI - Evidence of interactions between Gp27 and Gp28 constituents of the central part
of bacteriophage T4 baseplate.
AB - The central part of the bacteriophage T4 baseplate consists of several proteins.
However, for a number of the constituents the manner of incorporation are not
convincingly established. Recently, we have presented evidence that gp28 is the
structural component of the central part of the baseplate, which possesses a
hydrophobic region and is membrane bound [Nieradko et al., 1998]. By utilizing
extracts prepared from Escherichia coli cells that overexpressed genes 27 and 28
of phage T4, we proved that gp28 forms a complex with an another baseplate
structural components: gp27. This complex was located in the membrane fraction.
Its affinity to the inner membrane indicates that the identified complex may
function as an initiator of the central hub assembly. It was subsequently
established that these products interact in the ratio 1:1. We have also
demonstrated that the particular components of the complex can be separated by
action of SDS and to a lesser extent by Triton X-100.
PMID- 10756711
TI - Technical aspects of random amplified polymorphic DNA (RAPD) technique in
genotyping of bacterial strains.
AB - Random Amplified Polymorphic DNA (RAPD) method became widely applied for
sensitive, efficient and fast distinguishing of different isolates of a given
species, if pure culture is available. Problems with reproducibility and
discriminatory power, frequently cited in the literature, can be overcome by
precise optimization procedure allowing to achieve reliable conditions for each
species analysed. Basing on two examples of different species, H. pylori and E.
faecium, particular parameters of RAPD fingerprinting were evaluated with respect
to selection of best working primers generating medium-complex profiles, using
only high quality DNA samples and evaluation optimum for every reaction reagent.
Stable and informative amplification patterns were obtained with different best
working primers which could discriminate between all H. pylori and E. faecium
strains tested. For both analysed species different optima were found, suggesting
species-specific need of precise RAPD conditions evaluation. This study proved
high sensitivity and efficiency of optimized RAPD profiling applicable for
searching the epidemiology traces for both species.
PMID- 10756712
TI - Genotypes of Helicobacter pylori in Polish population.
AB - Here we have studied the genetic diversity of Helicobacter pylori strains
recovered from 64 individual patients, 5 family members and 13 unsuccessfully
treated patients. The recovered bacteria were finger-printed by the PCR-RFLP and
RAPD methods and virulence associated loci (cagPAI, vacA) were PCR studied.
Unique differentiation of every independently isolated strain from not-related
persons was possible by RAPD technique. In PCR-RFLP technique several profile
groups (7 and 15) for particular endonuclease tested were found. Eleven patients
carried strains of the same gene profile (PCR-RFLP) and the same overall genotype
(RAPD) before and after therapy. In the family studies, essentially the same
strain was found in different relatives in three cases, and different strains
were found in the other two cases. Island of cagPAI was present in 79% of all
strains tested, half and one-fifth of all strains tested presented, s1am2 and
s1m1 alleles of vacA gene, respectively. Independently from identity or diversity
of pre- and post-treatment strains and strains recovered from the family members
we have been observed identical cagPAI/vacA genotypes. These results suggest that
H. pylori infections in Poland can be mixed, although just one strain may often
predominate, and that inter-family transmission may be significant even in this
high risk society. The genetic feature of virulence-associated loci are similar
to those seen elsewhere in Europe, although strains that carry the cagPAI and the
potentially more toxigenic alleles of the vacA gene are more common. RAPD
technique is proven as most differentiating, however PCR-RFLP allows for easy
recognition of mixed infection with two or more different strains. Molecular
typing study in case of children therapy may allow reduce rate of relapses by
reduction of possible transmission from family source.
PMID- 10756713
TI - Anti-Lewis X IgM and IgG in H. pylori infections in children and adults.
AB - A role of autoimmune processes in the pathology of Helicobacter pylori infections
has been suggested. The Lewis determinants present in LPS molecule of H. pylori
bacteria have been indicated as the cause of antigenic mimicry. In this study,
the prevalence of IgM and IgG antibodies to Lewis X antigen in the sera from
children and adults, with or without dyspepsia, infected or not infected with H.
pylori, seropositive and seronegative for anti-H. pylori IgG were determined
immuno-enzymatically (ELISA). Our results revealed that humans may produce anti
Lewis X antibodies, particularly of IgM class, in the absence of H. pylori
infection or H. pylori independent dyspepsia. The production of such antibodies,
by healthy children who had never been infected with H. pylori suggested that
anti-Lewis X antibodies may occur naturally.
PMID- 10756714
TI - Influence of selenium on toxicity of some heavy metals in the green alga
Scenedesmus obliquus.
AB - The green alga Scenedesmus obliquus was incubated with various heavy metals
(Cd2+, Zn2+, Mn2+, Ni2+) in presence/absence of selenium. S. obliquus exhibited
higher rates of growth and some metabolic activities in cultures containing 0.1
mM Se than those containing only the heavy metals. The positive effect of Se was
found in presence of Cd2+ while that in the case of presence of Ni2+ was less
pronounced.
PMID- 10756715
TI - Growth and phenol activity of Pseudomonas aeruginosa strain 101/1 in batch
cultures.
AB - Strain 101/1, isolated from petroleum wastewater sediment was classified as
Pseudomonas aeruginosa. In wild type condition the strain tolerated phenol in
concentration 1,000 mg/L under aerobic conditions and 800 mg/L under denitrifying
conditions. As a result of adaptation to phenol the resistance of the strain to
the compound increased to 1,600 and 1,400 mg/L, respectively. Maximum phenol
activity under aerobic and denitrifying conditions was 350 and 65 mg/L x day-1,
respectively. Under denitrifying conditions a reduction in incubation temperature
from 30 degrees C to 20 degrees C resulted in two-fold drop in phenol activity of
the adapted strain and reduction in tolerance to phenol by 400 mg/L.
PMID- 10756716
TI - Intracellular growth of Listeria monocytogenes insertional mutant deprived of
protein p60.
AB - The study of the mutant strain described here demonstrates that several
characteristics contribute to maximal virulence of pathogenic strains of L.
monocytogenes. The invasion levels of L. monocytogenes JB1115, a p60-deficient
strain, were the same as for the parent strain L. monocytogenes 1043S in J774
macrophage-like cells. The invasion level of Listeria strains in Int407 cells was
100 times lower than in J774 cells. In epithelial Int407 cells, the time of
division of p60- strain L. monocytogenes JB1115 was 43% slower than for the
parent strain. In this study, two lisosomotrophic agents, ammonium chloride and
chlorquinoline were tested in experimental L. monocytogenes 1043S and p60
deprived mutant JB1115 infection in both cell lines. The presence of ammonium
chloride increased the level of infection (calculated as number of gentamicin
resistant cells) of both Listeria strains, but in the case of infection by p60
mutant, the increased amount of ammonium chloride showed only a minimal effect on
the number of isolated bacteria. In both cell lines treated with chlorquinoline
we observed a decrease in the number of viable intracellular bacteria isolated
from infected monolayers. Our observation of parental and mutated strains of
Listeria showed that phospholipase activity also depends on the presence of p60
protein. Mutated strain showed 31.46% reduction of PI-PLC activity measured in
normal growth conditions. Protein p60 plays a role not only in listeriolysin O
mediated haemolytic activity but full phospholipase C activity is also dependent
on the presence of the Iap protein.
PMID- 10756717
TI - Effect of benzylpenicillin on murein biosynthesis, turnover and structure in
Listeria monocytogenes cells.
AB - The action of beta-lactam antibiotics such as ampicillin and benzylpenicillin on
cells of Listeria monocytogenes appears to be bacteriostatic. However, after
approximately two hours in the presence of 10 x MIC of benzylpenicillin the cells
begin to rapidly lose viability without undergoing lysis. In this report we
present the results of studies on the biosynthesis of murein in L. monocytogenes
cells during the first 120 min of their exposure to benzylpenicillin as measured
by the continuous and pulse incorporation of the precursor N-acetyl-D-[1
3H]glucosamine. The turnover of the murein sacculus in the presence of penicillin
as well as the lack of discernible changes in the molecular structure of the
murein synthesised in the presence of benzylpenicillin is also discussed.
PMID- 10756718
TI - Epidemiological studies of HCMV infection in children by restriction analysis of
long-PCR products.
AB - Sequences of MIE, pol, gB gene longer fragments (2.0-2.6 kb) were amplified in
two stage PCR (nested PCR) from 46 PEG-urine extracts. Restriction of particular
amplicons with selected endonucleases identified 19 distinct HCMV genotypes: 8
for MIE, 6 for gB and 5 for pol. MIE profiling revealed highest differentiation
power. Our data showed the correlation among MIE, pol, and gB genotypes and
clinical disease, indicating that genotypes may contribute the course of HCMV
infection. For newborns with symptomatic infection, the highest level of
variability among three genes analysed was obtained in comparison to samples of
newborns with asymptomatic infection. Long PCR technique coupled with restriction
analysis may be successfully applied in HCMV genotypes differentiation in samples
taken directly from HCMV infected individuals, thus may be useful in prognosis of
clinical infection.
PMID- 10756719
TI - Evaluation of different methods for detection of Clostridium difficile toxins in
Poland.
AB - The aim of this study was to compare different methods for C. difficile toxins
detection. Fifty three stool samples taken from patients with antibiotic
associated diarrhoea were studied. TCD toxin A EIA (Becton Dickinson, USA), Tox
A/B ELISA test (TechLab, USA), cytotoxicity and neutralization assay on McCoy
cells and PCR for detection of both toxin A and B genes were performed in vivo
(in stool samples) and in vitro (in isolated strains). Reference toxigenic and
nontoxigenic and two Japanese toxin A-negative and toxin B-positive C. difficile
strains were used as a controls. TCD toxin A EIA detected in vivo only 19
positive samples. Tox A/B test detected 52 positive samples out of 53 studied.
All 53 stool samples were C. difficile culture positive (53 strains were
cultured). Toxin B was detected in 52 strain-supernatants and in all controls
(except the nontoxigenic one). Both toxin A and B genes were detected by PCR in
all 53 isolated strains, Japanese and reference strain (except the nontoxigenic
one). In vitro toxin A was detected by TCD toxin A EIA in 42 strains. These
results were compared with those obtained in Tox A/B ELISA test. We observed 52
positive strains. Toxigenic reference strain and two Japanese toxA(-)/toxB(+)
strains were also positive. Only 2 negative results were obtained with the
nontoxigenic reference strain and unique nontoxigenic isolated strain. Tox A/B
ELISA test seems to be the best for detection of C. difficile toxins in vivo and
in vitro. Test avoids the false-negative results in the case of presence of toxin
A-negative and toxin B-positive strain.
PMID- 10756720
TI - Biodegradation of phenol by bacterial strains from petroleum-refining wastewater
purification plant.
AB - The ability of four strains of bacteria derived from a biological petroleum
refining wastewater purification plant to carry out the biodegradation of phenol
was studied. Two of the strains belonging to the genus Pseudomonas were found to
be characterised by high effectiveness of the removal of phenol which was used as
sole carbon and energy source (the strains were designated P1 and P2). In turn
the effect of inoculum size, initial concentration of substrate (500 and 1,000 mg
phenol/L) and temperature (10, 20 and 30 degrees C) on the rate of phenol
degradation by strains P1, P2 and mixture of both was investigated. It was found
that strain P1 which was identified as Pseudomonas fluorescens degraded phenol
better than strain P2--Pseudomonas cepacia. The rate of phenol biodegradation was
significantly affected by size of inoculum and temperature of incubation. Phenol
was removed the fastest with the highest inoculum used. The optimal temperature
was about 20 degrees C. At 10 and 30 degrees C the process of biodegradation was
visibly inhibited. The rate of phenol utilisation was also found to decrease with
increased concentration of substrate.
PMID- 10756721
TI - Synergistic bactericidal effect of cephalexin and normal cord serum (NCS) against
Escherichia coli K1 strains isolated from children with urinary tract infections
(UTI).
AB - Investigations were performed on the bactericidal activity of cephalexin (keflex)
and normal cord serum (NCS) against Escherichia coli K1 strains isolated from
UTI. A synergistic interaction of the antibiotic and NCS was found against the
strains resistant and sensitive to the serum.
PMID- 10756722
TI - Ethical responsibilities of readers.
PMID- 10756723
TI - [The contribution of molecular biology to the progress of the physiological
sciences].
AB - Life science, physiology have an important improvement on cell sciences, by
seeing cell through a complex integrative concept. So, the notion of homeostatic
equilibrium for the whole body is applied at the cellular level. Also, molecular
biology techniques can facilitate the answer for a lot of the physiological and
pathological questions. This paper mention only some of the many examples which
justify both the importance of molecular biology for the cognitive progress of
physiological and biomedical sciences and the role of physiological notions for
the complexity view of molecular sciences.
PMID- 10756724
TI - [The role of the endothelium in normal and pathological vascular reactivity].
AB - After a short incursion concerning the morpho-chemical characteristics of the
vascular endothelium, the main normal and pathological functional implications of
the endothelial vasoactive substances are reviewed. A special attention is given
to the myorelaxing effects of EDRF, identified as nitrogen oxide (NO) and its
production mechanism, at the vascular level, with the participation of cGMP as
intracellular second messenger. The literature data are completed by a part of
the personal research regarding the changes of the vascular reactivity induced by
the endothelial NO. Experimental proves are brought in favor of influencing of
the vasconstrictor reactions produced by phenylefrin, noradrenalin and
angiotensin by the NO-cGMP system. Finally, the main patho-physiological and
pharmacological implications of endothelial NO are mentioned.
PMID- 10756725
TI - [The role of the endothelium in angiogenesis].
AB - Angiogenesis, the vessel formation process, happens both in normal and
pathological conditions, beginning with embryonic period and continuing
throughout the post-natal period during the whole life. The stimulating factors
of angiogenesis are enumerated: VEGF (vascular endothelial growth factor), PLGF
(placental growth factor), IF (Intherpheron gamma), Il1, Il8 (interleukin 1,8),
FGF (fibroblast growth factor), acid and basic, TGF (transforming growth factor),
PDGF (platelet derived growth factor), GH (growth hormone). A series of factors
act as regulators/modulators: hypoxia, PGE1, (prostaglandin E1), gangliosides,
heparin, cell-cell and cell-substrate interactions. The main inhibitors are less
numerous: trombospondin1, PF4 (platelet factor 4), TNF (tumor necrosis factor),
IF (interferon alpha). The implied mechanism are discussed: the ways, paths and
action phases of different stimulating factors, modulating or inhibiting factors.
The angiogenesis process is shown for the embryonic period, in the wound healing
process and in the development and progression of malignant tumors. The main
method employed in the study of the microvasculature are enumerated. Some
perspective in the cancer treatment are drafted.
PMID- 10756726
TI - [The physio-pharmacological and pathological implications of the endothelins].
AB - The papers of Furchgott and Zawadzki have widely enlarged the research field
concerning the dependence of the vascular smooth muscle reactivity upon the
endothelium. Besides the relaxing factors produced by the endothelium,
vasoconstrictor factors have been also emphasized. The endothelial cells are also
able to synthesize endothelin-like vasoconstrictor peptides. There were described
some types of endothelins. They all have common structural features but
substitution of certain amino-acids leads to specific effects, and all of them
keep the vasoconstrictor properties. The endothelins are normal constituents of a
lot of tissues (brain, endothelial and tumor cells, the spinal nodes) and of the
body fluids (plasma, urine, cerebrospinal fluid etc.). The endothelins accomplish
their effects by the specific receptors located in the muscle and endothelial
cell membrane (ET-A and, respectively, ET-B). The endothelins action in the cell
is basically based on the cytosolic Ca2+ raise. The endothelins have numerous
pathological implications, especially concerning the cardiovascular pathology.
PMID- 10756727
TI - [The mechanisms of the regulation of axonal growth and orientation at the border
between theory and practice].
AB - After a period of fast developing, the current philosophy of the
microneurosurgical management of the peripheral nerve injury has to overcome new
frontiers. The operating microscopes have almost reached the ultimate limit of
perfection, the atraumatic needles are at the edge of maneuverability, the
instruments are day by day more refined end more expensive, and the surgeons have
reached the limit of human technique refinement. More and more experienced
operators are convinced that, based on current clinical concepts and techniques,
new spectacular functional results in nerve regeneration after nerve repair are
not expected. They all agree that even direct neurography is considered the first
choice,in cases with nerve defect and gap the nerve graft (even vascularized) is
not an acceptable solution. It seems that the mesothelial chamber, silicone and
absorbable nerve conduits, neurotrophic and neurotropic factors are opening new
directions in reconstructive microneurosurgery. However the meaningful step
outside the experimental laboratory into the clinical routine is still to be
expected. An up-to-date review of the possibilities we may have is helpful for
those willing to combine their clinical activity with experimental research in
order to improve the long term functional outcome of their patients.
PMID- 10756728
TI - [Oxidative stress in bronchial asthma].
AB - Oxidative stress occurs when the antioxidative defence mechanism of the body are
surpassed by the intra- and/or extracellular presence of reactive oxygen species
(ROS). ROS were involved in the etiopathogenesis of many disorders, but it is
difficult to discern whether their role is decisive--as in the production of
atherosclerosis--or only aggravating, as an intermediate link, this being the
case in neoplasms. Today, the participation of ROS in the progression of some
respiratory diseases, such as bronchial asthma, is considered essential. Thus,
since the first description of asthma by Aretaeus of Cappadocia, a huge leap in
the understanding of this disease was recorded, this condition being nowadays
considered a chronic inflammatory disorders with the participation of oxidative
stress. For ascertaining the share of oxidative stress in the determinism of this
disease and the efficacy of antioxidants on its course further investigations are
needed.
PMID- 10756729
TI - [Staphylococcus--an agent of nosocomial infections].
AB - Staphylococcus is an important agent of nosocomial infection, especially: urinary
tract infections, pneumonia and intraabdominal infections in surgery. The most
important are the coagulase-negative staphylococci by their adherence and growth
on surfaces of intravenous catheters. The structural components, the enzymes and
toxins are the most important factors that take up the capacity of the agent in
developing nosocomial infections. Handwashing practices, antibiotic prophylaxis
are important, especially in the immunocompromised host.
PMID- 10756730
TI - [The potentials and limits of radiotherapy in benign diseases].
AB - The radiation treatment of benign hypertrophic and hyperplastic, inflammatory and
degenerative pathologic processes is nowadays less often used, due to
pharmacological advances or to the arrival of newer low-risk therapeutic
procedures. Radiotherapy of benign tumors in certain positions is mainly a
special indication. Radiotherapy will be used in principle, when all other
treatment means have been consumed. An appropriate procedure is necessary,
considering the physical factors of radiation: quality, doses, administration
timing and in the same time the radiosensitive organs and a careful
radioprotection.
PMID- 10756731
TI - [The role of physical training in left ventricular performance and exercise
tolerance in patients with chronic myocardial infarct].
AB - The aims of the complex rehabilitation of the patients with chronic myocardial
infarction are the improvement of the left ventricular performance and the
increasing of the exercise capacity. OBJECTIVES: The objectives of the study is
the long-term evaluation of some hemodynamic parameters at rest and during the
stress test, at patients with chronic myocardial infarction during the physical
training. METHODS: We investigated 132 patients with chronic myocardial
infarction, mean age 51.4 +/- 8.5 years, during 36.9 +/- 31 months of follow-up.
81 followed a programme of physical training (the study group); 51 did not follow
the training. There were determined the following parameters: cardiac rate (CR),
blood systolic and diastolic pressures (BSP,BDP), time-pressure index (TPI), the
metabolic equivalent (MET), the ejection fraction (EF), by echocardiographic and
systolic time intervals methods, at rest and the exercise test, for each step.
There have been followed the CR, BSP, BDP during the physical training. RESULTS:
At the study group there is a significant reduction of CR at rest (p < 0.05) and
during the training (p < 0.001). The exercise testing reveals the following: at
the study group, TPI does not modify (GR increases but BSP decrease); at the
second group there are significant increases of CR, BP and MET at all the steps
of the testing (p < 0.001-0.0001). EF improves significantly (p < 0.05) only at
patients with inferior myocardial infarction who followed the training. There is
a good correlation between the results of EF measured by echographic and by
systolic time intervals methods. CONCLUSIONS: Patients who underwent physical
training improved the CR at rest and TPI and MET at each step. There is a slight
rise of EP at the study group with inferior myocardial infarction.
PMID- 10756732
TI - [The evolution of glucose metabolic parameters in patients with chronic
myocardial infarct who have undergone physical training].
AB - Diabetes mellitus represents an important cardio-vascular risk factor, including
patients with chronic myocardial infarction. OBJECTIVES: The objectives of the
study is to assess the influence of the long-term physical training upon some
parameters of glucidic metabolism. METHODS: There have been studied 132 patients
with chronic myocardial infarction, mean age 51.4 +/- 8.5 years, for underwent
regularly physical training at 60-70% from maximal cardiac rate achieved at the
exercise testing. Another group (51 patients) did not followed the training.
There have been studied blood glucose a jeun and patients with normal values
followed the ingestion of 75 g glucose. There were following categories: normal;
know diabetes mellitus (DM); DM revealed at the loading test; impaired glucose
tolerance (IGT) and hyperinsulinism. Patients were included one of these
categories at the beginning and the control. RESULTS: The results are summarised
in the following table: [table: see text] The group who did not follow physical
training revealed an increased frequency of IGT and DM. CONCLUSION: The physical
training has a protective role preventing the development of the alterations of
glucidic metabolism.
PMID- 10756733
TI - [Inositol is necessary to sexual differentiation in Schizosaccharomyces pombe].
AB - Sexual differentiation in fission yeast Schizosaccharomyces pombe was found to be
dependent on the glucose and inositol contents of culture media. Certain
combinations in the amounts of these two compounds suppressed mating and
sporulation, while maintaining normal viability. Inositol was found to be
required for mating and sporulation in both nitrogen-rich and nitrogen-poor media
(the lack of nitrogen is most well-known factor that induces the sexual
differentiation). The experiments were performed using the wild-type strains and
standard media. Mutants carrying the pat1-114 temperature-sensitive allele
circumvented the need for inositol at the restrictive temperature.
PMID- 10756734
TI - [Melatonin and ubiquinone as endogenous antioxidant factors].
AB - We studied the effect of restraint stress upon the degree of lipidic peroxidation
in the fronto-temporal cerebral cortex, diencephalon, thymus and gastric mucosa.
We determined the malon-dialdehyde (MDA) by spectrocolorimetry, the percentage of
animals with stress gastric ulcer and the surface of gastric ulcerations. The
results demonstrated an important increase of the MDA correlated with frequency
and intensity of the gastric ulcer. In the second stage of the experiment, we
studied the influence of the ubiquinone and melatonin on the same parameters
studied in the first part. In every structures these two substances had
antioxidative effect. For ubiquinone, results showed significant variations in
the thymus and gastric mucosa, while at the cerebral level the results were
doubtful. As antioxidant and antiulcerogenic factor, melatonin was more effective
than ubiquinone, because determined significant decrease, or even disappearance
of the peroxidative process in the cerebral cortex and the thymus and
significantly diminished both peroxidation and ulcerogenesis in the gastric
mucosa.
PMID- 10756735
TI - [Essential hypertension in the context of syndrome X in obese patients].
PMID- 10756736
TI - [The reduction of dyslipidemia and oxidative stress in experimental diabetes
mellitus treated with probucol].
AB - There is considerable controversy regarding the role of oxidative stress in
development of macro and microangiopathy in diabetes--a free radical associated
disease. Increasing the oxidative glycosylation of plasma lipoproteins by
reactive oxygen species (ROS) and reduction of scavenging system under conditions
of hyperglycemia may accelerate diabetic vascular disease. We have investigated
the effect of Probucol (P) a drug with strong lipophilic radical scavenger
action, on plasma lipoproteins variations, malondialdehid (MDA) production,
atherosclerotic index (total Cholesterol/HDL Cholesterol), glycemia and
glucosuria in Wistar male alloxanic rats with/without enriched cholesterol diet.
The inhibition of lipoproteins oxidation, resulting from diminishing MDA, in our
study, would furthermore delay the absorption and penetration of lipids and
lipoproteins into deeper vascular layers and thereby reduce the risk of
atherosclerotic vascular lesion. Our result suggest that treatment with
inhibitors of lipoproteins oxidation may reduce the risk of cardiovascular
complications in diabetes.
PMID- 10756737
TI - [Pneumatic dilatation of benign pyloric stenoses: the long-term results].
PMID- 10756738
TI - [The use of echography in the diagnosis of autoimmune thyropathies].
AB - Ultrasonography is a first line method in thyroid imaging. The aim of this study
was to evaluate the usefulness of thyroid ultrasonography in the diagnosis of
thyroid autoimmune diseases (TAD): Graves' disease (GD) and autoimmune
thyroiditis (AT)--Hashimoto's and atrophic thyroiditis. Ultrasonography was
performed with a 7.5 MHz transducer in 1033 consecutive patients. The excluding
criteria was nodular goiter, irrespective of its function. Thyroid volume was
calculated using the formula of a rotating ellipsoid. Hypoechogenicity was
appreciated using a qualitative scale: 1 = absent, 2 = mild, 3 = moderate, 4 =
marked. In patients with TAD thyroid hypoechogenicity was significantly higher
than in normal subjects (2.5 +/- 1 in GD and 2.7 +/- 1 in AT, vs. 1.2 +/- 0.6 in
normal subjects, p < 0.0001). The specificity of the test in identifying TAD was
91.4%, the sensitivity was 68.6% for GD and 80.8% for AT, positive predictive
value was 91.5%, and negative predictive value 91.5%. Ultrasonography is useful
in identifying patients with probable autoimmune thyroid diseases, being useful
in epidemiological studies and having an important contribution in confirmation
of the diagnosis.
PMID- 10756739
TI - [Cephalometric changes in acromegaly].
AB - Acromegaly represents the endocrine disease which includes the somatic and
metabolic disorders secondly resulting to the augmentation of the Growth Hormone
secretion after the growth cartilages closing (in adult). In this case we can
find very important troubles which characterize all the specific elements of the
stomatognathic system. The cranio-facial skeleton has a specific configuration,
the mandible is developed in excess and the relationships between the maxilla,
the mandible and the skull are strongly modified. These and the structural bony
troubles, the bony asymmetries involve periodontal, muscular and articular
disturbances. In this study we want to describe the craniofacial cephalometric
qualitative and quantitative disorders and to emphasize their implications in the
onset and the evolution of the stomatognathic system dysfunctional syndrome.
PMID- 10756740
TI - [A comparative study of the dimensional variability in different cell types of
the human adrenal cortex in the newborn infant and the adult].
AB - The selection of the material for this study was governed by the idea that at the
newborn like at the adult, the cortex of the adrenal gland is complete, including
all the three zones, while medulla is not structured until 12-36 month; for this
reason, we used only the cellular cortical elements. The quantitative method of
evaluation of the cellular diameter, as well as the interpreting and correlation
of the values with age, have confirmed that the dynamics of the cellular
components of the adrenal gland depends on age, indicating significant
differences. The cell diameter is usually bigger at the newborn compared with the
adult (with zonal variations). The variability is relatively small which means
that the individual values are placed in a limited field.
PMID- 10756741
TI - [The imaging and electrophysiological correlations in lateral homonymous
hemianopsia of vascular origin].
AB - This paper presents 7 cases of patients suffering of lateral homonymous
hemianopia. This diagnosis was established taking into account both the clinical
exam as well as the visual field, into the context of a vascular suffering of
hemiparesis type. I worked with a Bioscript BST 2100 apparatus foreseen with
flash and with its help there could have been recorded the visual evoked
potentials (VEPs) with electrodes occipitally placed. The analysis of VEPs was
made in the correlations with the premises and the extend of the cerebral lesion.
The imaging exploration stood out lesions with the following localisations:
stretched hemispherically, internal capsule, thalamus, occipitally. The VEPs
recordings showed: the small N1 + leveling, the leveling of the whole tract,
bifid N1 + leveling, invertit N1 + leveling, diminished N1. The study of the
correlation between the lesion premises and the aspect of VEPs led to the idea
that waves N1 and P1 represent different functions of the process of the visual
stimulations rather than activities in distinct cortical areas.
PMID- 10756742
TI - Histological study of Hodgkin disease (HD), an immunohistochemical identification
of the cells surrounding Sternberg-Reed cells.
AB - In this study, we analyze histological types of 77 cases H.D. and examine
immunohistochemically the reactive cells surrounding Reed-Sternberg cells (40
cases). On the current techniques sections of lymph nodes were def ned H.D. types
after the new criteria (Bennett & col., 1985, Buttler, 1992). Immunologic marker
studies were performed on paraffin sections of H.D. tissue utilizing the avidin-
biotin peroxidase complex technique with limited panel of monoclonal antibodies
OKT3, OKB1, OKM1. On histopathologic grounds we established the diagnosis of
lymphocytic predominance type in 6 cases--8%, nodular sclerosis type in 36 cases-
47%, from which first degree--24 cases and second degree--12 cases, mixed
cellularity type in 28 cases--36% and lymphocytic depletion type in 7 cases--9%.
Immunohistochemically, in our 40 H.D. cases, the number of T. lymphocytes in all
H.D. types, was highly variable, ranging from a minority to a vast majority of
cells directly surrounding the Reed-Sternberg cells. These lymphocytes were
positive for OKT3, which were more in tissue involved by nodular sclerosis or
mixed cellularity types than in the lymphocytic predominance type. Thus, in our
few cases of lymphocytic predominance type, the reactive proliferation was
consisted of B. cells along side with a few T cells. Also the OKM1 positive
mononuclear cells were few. In conclusion, our data support the necessity to
extend of several immunohistochemical investigations used for distinguishing H.D.
disease from benign hyperplasia and from non-lymphoid malignancies, and for
concerning the functional lymphocytic composition and the role of monocyte
macrophage system in the immunological alteration in H.D.
PMID- 10756743
TI - [Morphological data correlated with the mechanism of striated muscle
contraction].
AB - The classical theory of muscle contraction (Huxley, 1957) could not entirely
explain a series of theoretical and experimental data. This theory sustains a
longitudinal sliding of thin filaments on thick ones, by the tilting of myosin
cross-bridges. Under different stimuli inducing contractions, the stereospecific
conformations of cross-bridges appear to be different as it is shown using
electron microscopy, fluorescence polarization, electron paramagnetic resonance
(EPR) spectroscopy and equatorial X-ray diffraction. Our optic microscopy data
also suggest the existence of such conformations, induced by different
contractile stimuli.
PMID- 10756744
TI - [The morphopathological aspects at autopsy of HIV infection in children].
AB - Aspects of HIV infection and AIDS in childhood have been reported since 1982.
Pathological features are due to direct action of HIV, opportunistic infection
and some tumoral processes. This report presents our own experience resulted from
27 cases of necropsy of patients diagnosed with AIDS or seropositive for HIV.
Emphasize is placed on microscopic changes in different systems and organs
(central nervous system, heart, lung, gastrointestinal tract, liver, lymphoid
organs, kidney), by comparing our results with those described in literature.
PMID- 10756745
TI - [Changes in the histoarchitectonics and enzymatic histochemistry in guinea pigs
during chemically induced stress].
AB - The adrenal glands particularly react to various chemical over-requirements.
Through the administration of aloxan to a group of thirteen guinea pigs we
investigated the different implication of the major adrenal components (the
cortex and the medulla), as well as the affecting of the enzymatic
histochemistry. Aloxan acts as a toxic both at the nuclear level and on the
cellular membranes which explains the modifications that occur especially at the
level of the zona fasciculata. The enzymatic reactions were moderately positive
even reduced here and there because aloxan is able to induce the variable levels
of the enzymatic inhibition.
PMID- 10756746
TI - [Antibiotic prophylaxis in cesarean section].
AB - The purpose of this study was to investigate the efficacy of prophylactic
antibiotics in preventing pelvic infection after cesarean section. A randomized,
prospective study was carried out between January 1, 1994 and May 15, 1995. There
had been involved 657 women without significant obstetrical differences. 305 of
them were excluded from analysis, for have received antibiotherapy after
operation. 182 women received prophylactic antibiotics (group B) consisting of
certain combinations, given in one dose. 170 women constituted the witnesses'
group (A). The rate of postoperative infection in the group who had received
antibiotic prophylaxis (group B) was lower (15.93%--29 women) than in the group A
(32.35%--55 women who had postoperative infection). Therefore, antibiotic
prophylaxis reduced the frequency of infections after cesarean section for 2.03
times. IN CONCLUSION: Prophylactic antibiotics are effective in preventing pelvic
infections after cesarean section.
PMID- 10756747
TI - [The treatment of superficial burns of the hands under controlled microclimate
conditions].
AB - In the treatment of the superficial burns of the hands, since October 1996, we
have used exclusively the method of the controlled microclimate, verified in
different variants starting early sixties. At the end of the usual primary wound
treatment, the hand covered with the chosen topic is an ordinary new polyethylene
bag. The bags are not pre-sterilized but the test showed no pathogen germs. The
patient uses the hands for the daily activities--eating, reading. He/she is
encouraged to perform active exercises (light gymnastics). We change the bags
daily or whenever necessary, after a careful of the wound. We evaluated the
healing time, the epithelial quality, secretions, mobility, patient's and medical
personnel's acceptability, and the economic aspect. Though we couldn't notice a
shorter period of healing, the epithelium showed a better quality in the early
period of regeneration. The range of mobility was faster restored but long term
results were the same as with usual dressings. We consider the method is
appropriate for standardization in superficial hand burns in inpatients or
outpatients for at least 4 reasons: comfort for the patient, his active and
conscious participation in the process of healing, high acceptability among
medical personnel, the semnificative economic advantage.
PMID- 10756748
TI - [Complicated postbulbar duodenal ulcer: the characteristics of its diagnosis and
surgical technic and management].
AB - The paper reports on the authors experience used on 90 patient with complicated
postbulbar ulcers (10% of the duodenal ulcers) with hemorrhage (23 cases),
perforation (7 cases), duodenal stenosis (19 cases) and penetration pancreatic
hepato-biliary (41 cases) period 1987-1996. The frequency of hemorrhagic
complication was of 25%. As the hemorrhage due to postbulbar ulcer is favoured by
vascular fistula, the sever character of the hemorrhage and the frequency of the
recurrence, mainly the cataclysmic one, impose the radical surgery as early as
possible. The following were used: large Reichel-Polya's gastrectomy (13 cases)
Pean's gastro-duodenectomy + vagotomy (9 cases), gastrectomy for exclusion with
hemostasis "in situ" and ligature of gastroduodenal artery + vagotomy (7 case).
In 7 cases with perforation: Reichel-Polya's gastrectomy in 2 patients, Pean's
gastrectomy in 2 cases, excision pyloroplasty (Judd) and vagotomy (3 cases). In
the postbulbar ulcers penetrating into the pancreas or into hepatic pedicle the
following were performed: Reichel-Polya's gastrectomy (8 cases), Pean's
gastrectomy (11 cases of which 8 with vagotomy) gastrectomy for exclusion of
ulcer in 22 cases of which 20 with vagotomy. In 14 patients with stenosed ulcers,
Reichel-Polya's gastric resection (4 cases), Pean's gastrectomy (8 cases),
gastrectomy for exclusion (7 cases). The conclusions may be drawn that the
postbulbar ulcers are complicated ulcers that require differential surgical
treatment, as early as possible for diminishing the postsurgical morbidity and
mortality (6.6% mortality).
PMID- 10756749
TI - [Is partial cystectomy a justified intervention in the treatment of bladder
tumors?].
AB - The authors present their experience of 122 partial cystectomy cases made on a
number of 288 vesical tumors in our clinic, during 5 years (1986-1991) from which
23 are superficial tumors and 99 are infiltrative ones. The treatment of vesical
tumors can be done in many ways; this partial cystectomy must be completed with
an other therapeutic method: irradiation on chemotherapy in conformity with the
anatomo-pathological form, the steady and tumoral grading.
PMID- 10756750
TI - [A prognostic audit in colorectal cancer: between the clinical realities and the
therapeutic principles].
AB - A clinical series of 137 cases of colorectal cancer (98 + 39) was admitted in the
IVth Surgical Clinic between 1987-1996 (double compared to the previous decade),
consisting of 101 men and 36 women with an average age of 62. The diagnosis was
established by physical examination (43 cases, most of them acutely obstructed),
completed by biological, radiological and histologic examination of the
surgically removed tumours. The pre- and postoperative staging revealed a large
number of advanced forms: stage I--6 cases (4.3%), stage II--33 cases (263%),
stage III--52 cases (36.5%) and stage IV--46 cases (32.3%). Surgery was performed
on 118 patients, the tumours being removed by different types of resections
according to location in 81 cases (operative rate of 86.1% and resectability rate
of 59.1%, both being higher compared to the previous decade 56.8% of the surgical
procedures were palliative and 41 patients (34%) underwent curative resections.
The postoperative morbidity and mortality rate was 30.5% and, respectively 4.3%
(5 deceased). The long-term survival followed on 44 cases revealed that only
20.3% were alive after 5 years from the operation.
PMID- 10756751
TI - Polipoza adenomatoasa familiala--care operatie? [Familial adenomatous polyposis-
which operation?].
AB - Familial adenomatous polyposis (FAP) syndromes are well recognized entities that
benefit from surgical treatment which should not be delayed. Screening of first
degree relatives is important. The aim of removing the colorectal mucosa with
significant potential of malignant transformation can be achieved by means of
three distinct procedures: panproctocolectomy and ileostomy, subtotal colectomy
with ileorectal anastomosis, restorative proctocolectomy with ileoanal
anastomosis. In a series of eight patients with FAP we performed mostly subtotal
colectomy with ileorectal anastomosis. Of five patients who underwent a form of
subtotal colonic resection, one was lost from follow up and two developed
carcinoma in the remaining rectal mucosa, which necessitated completion of the
resection with proctectomy and permanent ileostomy. Nevertheless, in the
increasing number of patients amenable to regular outpatient supervision, there
are strong points for recommending sphincter-saving operations.
PMID- 10756752
TI - Technical and biophysical aspects in prosthetic occlusal rehabilitation for
edentulous teenagers.
AB - The loss of anterior teeth may be transient solved by temporary adhesive bridges
(Oslo bridge, Rochette, Ellmann, Neumann, Tschemitscheck, Armatron systems).
Provisional crowns and bridges could be used for Brackets fixing. Anterior bridge
with subocclusal connector permits transversal expansion. When a successful
orthodontic treatment is followed by a prosthetic treatment, it is not important
to change the achieved occlusion, by the occlusal framework morphology. The
framework design of the metal component can contribute to the improvement of the
aesthetic aspect and reduce the cost by using a small quantity of expensive
alloy. Cytocompatibility of the used Cr-Co alloy is confirmed by cell culture
test.
PMID- 10756753
TI - [The middle cerebral artery system in fetuses: the distribution of the pial
branches].
AB - The aim of our study is to point out the influence of the cerebral development on
the evolution of the middle cerebral artery (MCA) system. Brains of 20 fresh
fetuses (16-22 weeks) were injected with gelatin-ink China mixture, observed and
dissected under surgical microscope in correlation with the evolution of the
sylvian fossa. Ending pattern of MCA and territories of distribution of its
branches were also discussed.
PMID- 10756754
TI - [The coronary collateral system in man].
AB - The aim of this work is to stand out the anastomotic network between the two
coronary arteries. This satisfies the basic myocardiac activity, but it becomes
inefficient in an increased cardiac consumption of oxygen. The anastomotic
collateral system was confirmed imagistically and by necroptic pieces. The
coronarographs in vitro, using BaSO4 as a contrast substance, proved the
existence of anastomosis between branches emerging from the same coronary artery
or from both sources. In human body, these collateral branches with a diameter
less or equal to 40 m have a minor role in cardiac perfusion economy. In case of
obstruction of a thick coronary branch, the anastomosis will develop in a few
weeks; that is confirmed by the increase of blood-flow at this level. Combined
studies of echography and angiography (1992) proved that developed anastomosis
induce a decreased frequency of pathological cases related to the dynamics of the
myocardiac wall at a lower level from the obstruction.
PMID- 10756755
TI - [Intermesenteric anastomoses].
AB - This work is based on dissection and the analysis of the arteriographies of two
mesenteric arteries and it analyses the type of intermesenteric anastomoses and
their importance in surgical practice. The morphological varieties of Riolan's
arcade depends on its pillars, as well as on the eventual presence, especially in
the middle part of the transversal mesocolon, of the secondary arcades; it seems
that the colic wall necrosis depends less upon the location of the lesion or the
level of the suture of the arcade, but more so on the stretch of the destruction
of the mesocolon. The intermesenteric trunk, a second way of intermesenteric
anastomoses is a embryological remaining, non-functional in normal conditions,
but capable to partially or completely replace the Riolan's arcade when the later
is sutured or interrupted.
PMID- 10756756
TI - [Hepatic artery variants originating from the superior mesenteric artery--the
surgical implications].
AB - The hepatic accessory (or aberrant) arteries appear as a consequence of
modifications during the embryological development of the splanchnic arterial
system. These arteries emerge from the first segment of the superior mesenteric
artery and have a variable trajectory, of importance being the relations with the
head of the pancreas and with the extra-hepatic biliary ducts. Taking into
account the appreciable frequency of these arteries (19.5%), the relations and
the surgical implications, I consider that the presence of these arteries should
be determined mandatory by means of selective pre-surgical arteriography; when
this procedure is not available the presence of extra-arteries emerging from the
superior mesenteric artery (S.M.A.) can be speculated when pulsations in the free
border of the lesser omentum are detected.
PMID- 10756757
TI - [A rare form of osteopoikilosis].
AB - The authors report a typical case of osteopoikilosis striata Voorhoeve in a 51
years-old female. In connection with case they make some consideration concerning
the diagnostic of this very infrequent sclerotic bone dysplasia.
PMID- 10756758
TI - [Carcinosarcoma of the corpus uteri--a case report].
AB - Sarcomas account for fewer than 5% of all cancers of the uterine corpus. We
present the last classification of The International Society of Gynecology
Pathologists for pure sarcomas and also for mixed epithelial-nonepithelial tumors
of the uterine corpus. The paper concerns with the study of a case of
carcinosarcoma, treated in the III-rd Clinic of Gynecology from Iasi. This
morphological diagnostic represents the most common epithelial-nonepithelial
tumor affecting the uterus. Immunohistochemistry with EMA confirms the theory of
the combined tumor with a unique origin.
PMID- 10756759
TI - [Erysipelothrix rhusiopathiae bacteremia in a child with acute leukemia].
AB - The systemic infections caused by E. rhusiopathiae and reported in literature are
very rare, majority evolving with endocarditis. The authors present a child with
acute leukemia, to whom the blood culture during a high temperature episode
allows to isolate this bacterium, without valvular lesions. The case is
interesting because of the arisen bacteriological diagnosis problems and because
of the pathogenic aspects of the infection. An animal source contact being
absent, we took in account the intestinal carriage which, under the profound
depression of the defence (the underlaying disease and the cytostatic therapy)
could result in a persistent bacteremia. The treatment with cefazolin allows the
infection to be cured.
PMID- 10756760
TI - [Cervical lymph node metastases of unknown origin].
AB - In this paper we present a three-year prospective study (1991-1993) about the
cervical lymph node metastases of unknown origin. 370 patients with lymphatic
carcinomatous metastases in the were admitted in "Sf. Spiridon" Hospital--ENT
Clinic. No primary tumor was located in 33 patients (8.9%). The diagnostic
strategy for cervical metastases of an unknown primary was reviewed. The
probability of locating the primary tumor depend on diagnostic phase.
PMID- 10756761
TI - [Adenocarcinoma of an eccrine sweat gland--the diagnostic problems].
AB - Eccrine adenocarcinomas rarely present a clinical aspect that suggests a
malignancy. We present a case of an adenocarcinoma of an eccrine sweat gland with
a moderate degree of differentiation associated with a verruca vulgaris
(papilloma). The verrucous tissue contained a large number of melanocytes giving
the macroscopical aspect of a malignant melanoma. The light microscopy elucidated
the problems of diagnosis. The immunological status may be responsible for this
association between a benign tumour of the epidermis with a viral histogenesis
and the carcinoma of an eccrine sweat gland.
PMID- 10756762
TI - [A practical study of the absorbed doses at the level of the organs at risk
during the radiotherapy of bronchopulmonary cancer].
AB - The radiotherapy of lung cancer with curative total doses (56-60 Gy), is limited
by the presence of critical organs (esophagus, spinal cord). The use of computed
TPS (Therapy Planning System) allows to the radiotherapist to calculate the
values and to obtain dose distribution to the organs at risk, in the limit of
biological tolerance levels. In our work, we present the calculation of the
absorbed doses of Co60, at the spinal cord, at a patient with a cancer of the
right lung, during irradiation.
PMID- 10756764
TI - [The concept of risk in medicine].
PMID- 10756763
TI - [Hepatic hydatid cyst and splenic hydatid cyst--their surgical treatment with
splenic preservation].
AB - The hydatid cyst located in the spleen is very rare and the association of the
liver location concomitant with the spleen location is exceptional. If the
elective surgical intervention for the hydatid cyst of the liver with abdominal
evolution is the operation Lagrot, most of the authors preferred a splenectomy in
the hydatic cyst of the spleen. It is presented the case of such an association,
pointing out the role of the echography for diagnosis and the opportunity of
deciding on the preservation of the spleen in treatment.
PMID- 10756765
TI - [Cardiac rehabilitation update].
PMID- 10756766
TI - [Nitric oxide and bronchopulmonary reactivity].
AB - After a brief review concerning NO biosynthesis, distribution and actions, its
main normal and pathological implications are presented. The NO modulatory role
on the bronchiolar and vascular smooth muscle basal tone, as well as its
involvement in local inflammatory reactions are shown. Physiopathological broncho
pulmonary NO implications are completed with data concerning its inhalatory use
in the treatment of pulmonary arterial hypertension, acute respiratory distress
syndrome and severe pneumonia.
PMID- 10756767
TI - [ANF--atrial natriuretic factor].
AB - Is produced at the right atrium and is acting upon four types of receptors. The
main effects of ANF are: renal effects, by rapid increasing and prolongation of
glomerular filtration; neuroumoral effects--the inhibition of renin-angiotensin
system and of the release of aldosterone; effects upon the vascular wall, with
vasodilatation; another effect is the regulation of the hydrosalin balance. The
therapeutical endpoints of ANF are related to its action in some diseases like:
cardiac failure, arterial hypertension, myocardia infarction, paroxysmal
arrhythmias; in some of them it is a very fiable predictive marker. ANF
represents o neuroumoral mechanism which play an important role in functional
regulation of the cardio-vascular system.
PMID- 10756768
TI - [Hypertension in chronic kidney failure (the physiopathology, clinical picture
and treatment)].
AB - Secondary hypertension in CRF is characterized by particular features;
hemodynamics--abnormal high vascular peripheral resistance relative to the
cardiac output level; circadian variability--absence of nocturnal physiological
BP decline. Hypertension is the main risk factor for renal disease progression,
irrespective of the underlying etiology, and is one of the major determinants of
the impressive cardiovascular morbidity and mortality seen in uraemic patients (>
50% cases). The atherosclerotic risk and severe retinopathy are more important in
CRF hypertension compared to other causes (including essential HTA) at similar BP
levels. Treatment targets for renal patients should be less than 130/90 mmHg. The
main treatment modality for ESRD hypertension are sodium and water removal
through diet, diuretics and dialytic ultrafiltration. Pro's and con's of
antihypertensive medication classes are discussed.
PMID- 10756769
TI - [The consensus of outpatient physicians on the diagnosis and treatment of EHT].
AB - Essential arterial hypertension is a wide spread disease, about 10% of general
population. Represents a high risk for cardiovascular diseases with renal,
cerebral complication. About 50% of deaths are because of AH last decade. This is
a problem of ambulatory care. Practitioners have to diagnosis and treat AH for
realized a good primary and secondary prevention. For a good management it has to
use TEME program.
PMID- 10756770
TI - [The etiopathogenetic hypotheses in polycystic ovary].
AB - First described in 1935, polycystic ovary syndrome (PCOS) is a frequent endocrine
disease (6% in female population). However its pathogenicity is not yet
completely understood. The possible etio-pathogenic mechanisms include:
neuroendocrine disorders (hypothalamic, as a result of congenital androgenism or
of disorders of neurotransmitters or pituitary, with excess of LH), ovarian
disorders (enhanced sensibility at LH, local growth factors, hyperactivity of Cit
P450cl7 alpha enzymes), adrenal disorders, insulin resistance, genetic
determinism, puberty onset. The authors discuss in detail this hypothesis and
these possible importance.
PMID- 10756771
TI - Prolactin secretion and the immune system.
AB - Prolactin receptors were identified on the membranes of lymphocytes have been
demonstrated to secrete prolactin. The decrease, as well as the increase of the
prolactin level in the plasma are responsible for immune disorders. Prolactin
dysfunction has been described in some autoimmune diseases, such as systemic
lupus erythematosus, immune arthritis, uveitis, experimental allergic
encephalomyelitis and thyroid disease. The normal prolactin secretion is trophic
for the lymphocytes, while the high and also the low levels of prolactin may play
an immunosuppressive role.
PMID- 10756772
TI - [Epidemiological considerations of the arbo- and arenaviruses].
AB - The complex epidemiological process of arboviral and arenaviral diseases, their
dependence on a multitudine of etiologic agents, the risk of severe
manifestations, absence of a specific treatment and difficulties in preparing the
vaccines, place these diseases among those of high concern at national and
international level. The multidisciplinary investigations carried out in Moldavia
by M. Duca, Eugenia Duca, Gr. Teodorovici, Alla Vata, St. Dumitriu, V. Luca, D.
Buiuc, A. Ivan and others have elucidated numerous aspects regarding the
epidemiology and prevention of arboviral diseases. The increased morbidity by
meningitis and meningoencephalitis recorded in Romania the interval summer--early
fall 1996 was attributed based on serologic diagnosis, to West Nile virus. The
etiological investigations were done both in our country (Cantacuzino Institute,
Institute of Virology, Laboratory of the Ministry of National Defence) and abroad
(Pasteur Institute at Paris, Colindale Institute London, CDC, Atlanta, USA). For
the Romanian population the risk for a periodical re-emergence of some arbovirus
diseases is due to favorable local conditions with the relationships with
geographical areas were these diseases have and endemic-epidemic evolution are
added.
PMID- 10756773
TI - [Hypersensitivity reactions to antilipemic drugs].
AB - Chronic utilization of hipolipemiants drugs makes possible the onset of
hypersensitivity reactions like a part of secondary reactions. From the point of
our experience the most frequent hyperreactivity appears on fibric acid
derivates. Al the cases we treated, were skin manifestations (angioedema) and
about 29%, were digestive manifestations (dyspepsia, vomiting, diarrhoea). At the
same time, chronic utilization of nicotinic acid derivates favored skin rash due
to congestive intrinsic effect of nicotinic acid.
PMID- 10756774
TI - [Trace elements and trace element therapy update].
AB - Starting from the importance of the trace elements in basic biochemical
mechanisms from the human organism, the present role of trace elements therapy,
as part of allopathic therapy, is discussed. The ideal properties of trace
elements, the therapeutic concepts regarding trace elements, the main
pharmaceutical forms that contain them, and their most important uses are
presented.
PMID- 10756775
TI - [Chronic myocardial infarct with left ventricular dysfunction: the clinical
aspects and exertion tolerance].
AB - The objective of the study is the assessment of the exercise functional capacity
of the patients with chronic myocardial infarction and left ventricular
disfunction and the relevance of some clinical peculiarities of them in contrast
with patients without left ventricular performance. METHODS: There have been
studied 105 patients with chronic myocardial infarction, in a period of time
between 1992-1995. There has been taken, as an objective criterium of the
assessment of LV disfunction, the ejection fraction (EF) measured by echo 2D at
52 patients. There were created the groups with EF 50%(32p), EF = 35-50% (12p)
and EF = 35% (8p). The clinical parameters were: the number of coronary risk
factors (CRF), the NYHA class, the exercise test and the assessment of VO2max.
The statistical comparison has been made by using an IBM computer 486, programme
FoxPro and EPI/INFO. RESULTS AND DISCUSSIONS: 50% of the patients with EF > 50%
(16/32) had a good exercise tolerance (MET > 5); 13 patients (65%) from the
patients with EF < 50% had MET < 5. Similarly, there is no correlation between
the low EF (50%) and VO2max. The analysis of the exercise tolerance correlated
with the functional class NYHA shows its diminution at patients with cardiac
failure (classes I and II) compared with those without dyspnea (67% vs 42%, p <
0.01 and respectively 80% vs 42%, p < 0.05). There are similar differences in the
assessment of VO2max at patient from classes III (p < 0.01) and II (p < 0.03)
compared with class 0. Dyspnea, as a clinical parameter, does not correlate with
low EF, but has significant association with VO2max. The study of the degree of
charge in CRF at patients with EF < 50% reveals the following: older age (p <
0.02), the presence of arterial hypertension (p < 0.01) and the greater
prevalence of DM (p < 0.05). CONCLUSION: 1. There is no correlation between the
degree of the left ventricular disfunction and the exercise capacity. 2. VO2max
is significantly lower at patients with dyspnea, especially from classes II and
III. 3. Patients with myocardial infarction and LV disfunction have statistically
more CRF, like older age, HTA, DM.
PMID- 10756776
TI - [An analysis of the evolution of body compartments in anorexia nervosa--the
bioelectrical impedance method].
AB - Body compartments can be assessed by means of bioelectrical impedance, a non
invasive, cost saving and simple physical method. The purpose of this study was
to estimate the body compartments in anorexic patients, in the under-nutrition
phase (group BMI < 17 kg/m2) and after weight restoration (BMI > 17 kg/m2). Total
body water, intracellular and extracellular water have significantly decreased
after weight restoration. The fat mass significantly (p < 0.001) increased in
group BMI > 17 kg/m2 compared with group BMI < 17 kg/m2, and we have found a
positive correlation between body mass index (BMI) and fat mass (r = 0.73, p <
0.0001). The assessment of free fat mass can provide information about the under
nutrition degree and the quality of re-feeding. The increase of free fat mass was
significant (p < 0.001) in the group BMI > 17 kg/m2 as compare with the group BMI
< 17 kg/m2). We have found a positive correlation between free fat mass and BMI
(r = 0.73, p < 0.0001).
PMID- 10756777
TI - [Experimental carbon disulfide-induced encephalopathy].
AB - The histopathological and ultrastructural aspects of cerebral cortex were
followed up in the white rat injected intraperitoneally with carbon disulphide at
5 mg/kg body weight/week, in a chronic experiment--3, 6, 10 months. Important
neuronal damages like: neuronal dystrophy's to neurolysis affecting the pyramidal
and granular cells, neuronophagy, nodular and diffuse glial reaction, in the
absence of atherosclerotic lesions were noticed. The lesions developed after 3
months and become more extended at 6 months and 10 months: it persists even after
2 months from the moment when the administration ceased.
PMID- 10756778
TI - [The role of paraclinical studies in the diagnosis of hypomagnesemia
spasmophilia].
AB - Assuming that Ca+2 and Mg+2 play an important role in the cell (especially the
neuronal and muscular ones) membrane excitability, this paper presents the place
that the paraclinical specific investigations have in the proper diagnose of
normal calcium serum level hypo-magnesium spasmophilia. A number of 52 patients
presenting significant clinical spasmophilia, of age between 21 and 55 years old,
from different professions and social classes, were selected for this study.
Paraclinical investigations (spectrophotometry) showed a normal serum calcium
level (an average of 9.22 mg%); also, a decrease of Mg+2 serum level (an average
of 1.41 mg%) and normal levels for Na+ (3.04 g/l) and K+ (0.21 g/l). The
electrophysiological investigations (EMG, EEG, VCN m, EKG) performed showed, on
the EMG recordings, in 85% of the cases the presence of the typical spasmophilic
repetitive discharges, increased when using compression ischemia and 3 minutes
hyperventilation, while on the EEG recordings, most patients demonstrated the
presence of diffuse or mainly frontal lobe cortical bioelectrical activity
alteration, either in spontaneous conditions or after specific stimulation (3
minutes hyperventilation or SLI). The muscle bioelectrical activity was analyzed
by mean of EMG recordings--a decrease of VCN m was detected on the SPE nerve
(34.4 m/s) and also on the SPI nerve (34.2 m/s) The EKG recordings performed
showed in 5% of the cases the presence of the ventricular repolarization
disturbances (flat T waves). After receiving a proper treatment which included
oral administration of calcium and magnesium gluconolactate, magnesium
gluconolactate with B6 vitamin or Trimagant, there were important changes of all
the studied parameters and so, as a specific therapy, we recommend the use of
Mg+2 compounds, because it demonstrates a significant improvement of the clinical
symptoms in spasmophilia and has no danger to precipitate in the body as Ca+2
exceeding does.
PMID- 10756779
TI - [The effect of the combination of vitamin E and C on the oxidative stress
parameters in physical exercise].
AB - The paper outlines the modification of some antioxidant enzymes and of reduced
glutathione studied on physical training induced oxidative stress model. We also
assessed vitamin E and C effect. Biochemical determinations were performed on
heart homogenate and erythrocytes. Catalase and glutathione peroxidase activity
diminished and superoxide dismutase activity increased to a different extent in
both tissue samples, while coupled vitamin E and C protection to these tissues
equally varied. The glutathione (GSH) pool decreased in erythrocytes and was
moderately enhanced in the heart. Either in red blood cells or heart tissue GSH
level constancy was maintained by simultaneous administration of vitamins through
the experiment (training period). Malondialdehyde concentration revealed a
slightly pro-oxidative behaviour of this couple of vitamins that explained the
only partial recovery of enzymatic activity to normal values as well as a
moderate lipid peroxidation process. Both phenomena were better expressed in
erythrocytes.
PMID- 10756780
TI - [The importance of the use of selenium in the role of an antioxidant in
preventing cardiovascular diseases].
AB - The evaluation of the results of the oxygen free radicals (RLO2) formation is a
current subject in biology and medicine. The oxidative stress, which is the
altering of the balance between the higher activity of oxygen and the enzymatic
or nonenzymatic protection systems, may be one of the causes that starts and
aggravates a disease. In this context, the supplementation of the diet with
selenium, superoxide dismutase, vitamins A, C, E, is considered a primary
prevention measure (for the apparently healthy persons) and a secondary one (for
those with advancing forms of disease) that is both efficient and modern by
utilization of some "drug-food" products. The transversal study realized on a
group of 39 blood donors presence of the cardiovascular risk determined by the
raising of the prevalence of some atherogenic factors (active smoking,
hypercholesterolemia) which is also expressed by the lowering of the level of
some oxidative stress indicators (glutathione peroxidase--GSH-Px < 0.139 moli/ml
and catalase < 2.20 U/ml). The simultaneous low intake of selenium from the
central drinking water supplies in the city of Iasi (0.1-1 g/l) has permitted us
to consider necessary the diet supplementation both with foods rich in vitamins
with an antioxidant role and with specific medication with selenium, as a
protective micro-element.
PMID- 10756781
TI - [Insulinemia and its evolution over time in obesity].
AB - There is a steady-state metabolism of adipose tissue ("adipose state") with a
"metabolic signal" significance. It consists of: seric levels of glucose,
insulin, free fatty acids. We studied 45 cases with uncomplicated obesity and we
correlated seric level of insulin, basal and reactive, with DAM (mean adipocyte
diameter), insulin receptor activity and obesity evolution length (age of
obesity). Level of insulin has high influence on insulin receptor function (p <
0.01). Reactive insulin level are higher with obesity age (p < 0.0001).
Hyperinsulinemia is a constant, continuous and early reference point of obesity.
PMID- 10756782
TI - [Antilipemic therapy in dyslipidemias in obese non-insulin-dependent diabetics
(ONIDDM)].
AB - There are multiple lipids anomalies on diabetes. IDDM has, because of insulin
lack, raised levels of triglycerides and afferent lipoproteins. NIDDM, especially
the obese one, directly linked with insulin-resistance and hyperinsulinemia, has
different and complex anomalies. There is a specific type named "B phenotype"
with high cardiovascular risk: raised LDL chol charged with TG and low level of
HDL chol. Our study on 58 cases with NIDDM obese concluded that only 28% had high
TG levels but 71.8% had low levels of HDL chol. We administered fibrates,
therapeutical doses, 3 months. We made lipidograms from the beginning and after
one and three months. So we proved the good effect of fibrates on lipids: rise of
HDL chol., moderate effect on LDL chol. for reduced cardio-vascular risk. There
were good results on glucose tolerability (improving 65.8%, p < 0.01).
PMID- 10756783
TI - New trends in "mystery SIDS" research.
AB - The aim of this study is to suggest some new trends of research in SIDS, leaving
from the pathologist's observations of the presence of unusual lesions in SIDS.
The histopathological study was made on 27 cases of SD, representing 1996 SIDS
cases registered to hospital. There were put in evidence the oesophageal
inflammation, the hyperplasia of submucosal laryngeal glands, different grades of
bronchiolar mucous hypersecretion and reducing of elastic lung tissue and the
hypertrophy of muscular lung small arteries. This lesions are frequently
encountered to SIDS cases.
PMID- 10756784
TI - [The importance of immunohistochemical examination in the diagnosis of malignant
lymphoproliferative diseases--the author's personal experience].
AB - A high-quality approach to lymphoproliferative diseases needs mastering the basic
principles of morphology, immunology and genetics. The diagnosis relies on both
traditional methods (histopathological analysis) and modern procedures (supported
by advanced techniques such as immunohistochemistry, flow cytometry, and
molecular biology). This paper presents a personal point of view developed by the
author as a consequence of experiencing the immunohistochemical reactions for the
diagnosis of non-Hodgkin's malignant lymphomas. Immunohistochemistry, as an
effective and currently practiced procedure, allows the identification of the
cellular line of the proliferating cells. Full details are given for material and
methods, providing a complete characterization of the used monoclonal antibodies
(DAKO-CD20, L26, DAKO-CD3, DAKO-CD68, PG-M1, DAKO-E29, EMA), as well as an
integral description of the sequenced working phases. Relevance, efficiency,
performance, limits and perspectives of the employed procedure are discussed with
direct references to the results of this personal study.
PMID- 10756785
TI - Antirheumatic effects of first-line agents in the treatment of juvenile chronic
arthritis.
AB - The main goal of the present study was to investigate comparatively (in the last
8 years) the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on a sample
of 100 children diagnosed with juvenile chronic arthritis (JCA). The patients
were divided in 3 smaller groups, as follows: group 1--prescribed diclofenac,
group 2--paduden and group 3--aspirin. Clinical features and laboratory findings
were evaluated after: a 2 months trial, 4 months trial, 6 months trial, 2 years
trial, 3 years trial and more than 5 years trial, from the beginning of the
NSAIDs therapy. The results were the followings: within the first 12 weeks of
therapy with NSAIDs a good response was obtained in 64% (group 1), 59% (group 2)
and 53% (group 3) of the managed children, respectively; after 8 years of
treatment for the children remained under medical observation in our clinic, the
remission was obtained in 68% (diclofenac), 60% (paduden) and 64% (aspirin) of
the patients on NSAIDs therapy. The incidence of side-effects in the groups
treated with diclofenac and paduden has been present in a smaller percentage and
less severe than in the aspirin's group. No child managed with diclofenac had
major gastrointestinal, hepatic or renal reactions. These results highlight the
superiority of diclofenac as a new drug over aspirin and paduden, in the
treatment of JCA.
PMID- 10756786
TI - [The effect of chemical noxae on the health status of a group of workers in the
chemical industry of Savinesti].
AB - The paper presents the study on the effect of the industrial xenobiotics against
some biochemical indicators, in view to detect, precociously, the probable
significant changes. There are presented the medium, minimum, maximum and median
value for the following parameters: total proteins, haemoglobin and glucose for
112 workers exposed or not exposed to specific noxae--benzen, phenol,
cyclohexanone. The analysis of the results shows decreased values for some
workers, even at the inferior limit, in rapport with the normal values, for the
parameters studied. These persons have been directed for complex investigations,
in view to determine the causes and to establish the adequate treatment.
PMID- 10756787
TI - [Tumors of the third ventricle].
AB - This paper presents 17 cases of tumours of the third ventricle which have been
hospitalized, explored and treated in the Neurosurgical Clinic of the St. Trinity
Hospital during the last ten years (1986-1996). There are emphasized the
histopathological features of these tumours, according to pathological anatomy
exams and to the dates in the literature, the main elements of the clinical
picture typical for these tumours, the main paraclinical investigating methods,
possibilities of healing and postoperative results. Finally, there are presented
the results on these 17 clinical observation as well as a presentation of the
further possibilities in diagnosis and treatment which will improve substantially
the number of healed cases, diminishing the incidence of postoperative morbidity
and mortality.
PMID- 10756788
TI - [The results of the Ravitch-Sutherland technic for surgical correction in pectus
excavatum].
AB - The aim of our study was to assess the functional and cosmetic results after
performing a modified Ravitch-Sutherland procedure in children presenting with
excavatum. A series of 31 children with ages ranging between 5 and 16 years,
presenting with pectus excavatum, were operated between 1986-1996 in our service.
In 5 cases surgical treatment was required by the presence of respiratory and/or
cardiac functional impairment due to the malformation. In the other 23 cases
operation was performed mainly for cosmetic reasons. In all cases a modified
Ravitch-Sutherland procedure was performed. Modification consisted in renouncing
at the plicature of the perichondra and in associating a diaphragmatic elongation
and Bedouelle laparoplasty in all cases. Longitudinal sternotomy was performed in
2 cases with severely impaired ventilatory capacity. Functional and cosmetic
results were good in all cases. In 2 cases, in which recurrence of the condition
was observed, a second identical procedure was performed, with a good result. The
interval between the operation and the moment of long-term evaluation ranged
between 3 months and 11 years. We conclude that the modified Ravitch-Sutherland
procedure represents an effective method for the treatment of pectus excavatum
cases, offering good functional and cosmetic long-term results.
PMID- 10756789
TI - [Reconstructive plastic repair in cancer of the lips].
AB - Lips neoplasm represent 20% from all maxillo-facial cancers, more than 90% being
localized on the inferior lip. This paper present the results of the
reconstructive surgery on 208 patients treated over 10 years (1984-1993) at the
Bucco-Maxillo-Facial Surgery Clinic from Iasi. The procedures were different
according with the dimensions of the tumor and several other factors regarding
there histopathological type, moment of the diagnostic, age etc.
PMID- 10756790
TI - Removable partial denture in special clinical conditions.
AB - Controversies concerning the prosthetic treatment through removable or fixed
dentures until the age of 18 existed and continue to exist due to the structural
instability of the stomatognathic system. In this communication we present a
special experience, acquired about the treatment of some clinical situations in
which the removable partial denture has been found appropriate with respect to
certain features as bone substance loss as a consequence of traumatisms or tumor
extirpations, oligodontia, cleft lip and palate. The clinical situations that
will be presented refer to a group of 29 patients treated during a period of 10
years in the Department of Prosthetic Dentistry within the Faculty of Stomatology
of Iasi, Romania. Our conclusion is that the children and teenager patients
prosthetic therapy differs with respect to the type and etiology of the teeth
loss, the affected zone, the stage of the growth and development process of the
stomatognathic system, the technological conditions, the patient social
conditions, and last but not least, by his affective attitude regarding the teeth
loss and the denture type. The removable partial denture for children and
teenagers represents, with some exceptions, an emergency or transitory solution
until the necessary conditions for other therapeutic stages are fulfilled. Taking
into consideration the tissues lability on which it is applied, the removable
partial denture requires a rigorous postprosthetic therapy.
PMID- 10756791
TI - [Dermatologic preparations with erythromycin--the correlation of the
pharmaceutical form-therapeutic effect].
AB - Erythromycin associated with progesterone and A vitamin has been included in
three dermatological pharmaceutical forms: a lotion, a L/H emulsion and a L/H
nonionogenic ointment. Aspect of these preparations has been noticed for a 90
days period. pH and electrical conductance were also determined during this
interval. All the formulations mentioned above revealed insignificant variations
of these parameters proving an appreciable physico-chemical stability. Clinical
investigative studies in juvenile acne, showed efficiency, particularly for the
emulsion form.
PMID- 10756792
TI - Oral lyophilizate--an alternative for products with low-soluble drugs.
AB - The propyphenazone, a drug with pronounced anti-inflammatory, anti-fever,
analgesic properties, is recommended in acute situations which require
therapeutic blood levels in short time after administration. The review presented
has the purpose of obtaining an oral lyophilizate, compared with the common
tablets. Also, the specific parameters for oral solid dosage forms were
determined. The procedure for the oral lyophilizate's preparation promotes the
liquid form's mobility and activity, being designed as a solid product which
disperses readily in small quantities of water. The presence of a solubilizing
agent, included in formulation, will increase propyphenazone's dissolution and
so, the analgesic, antiinflammatory effect will appear rapidly. The
lyophilization of the selected formulation with a usifroid apparatus was
conducted following the classic steps. The tablets were compared with compressed
tablets having the same content in propyphenazone (0,250 g), being observed
concerning the aspect, the diameter, the dissolution time and the percentage of
dissolved substance in one hour. In comparison with compressed tablets, the
substances associated in oral lyophilizate and the specific lyophilization
technique determine propyphenazone's release in a shorter time interval.
PMID- 10756793
TI - Prolonged gastroprotective activity of a ranitidine-dextran conjugate.
AB - The paper presents the influence of the ranitidine-dextran conjugate on the
gastric secretion stimulated with carbachol on rats with a ligated pylorus
[correction of ligaturated pilor]. The gastric lesions, the gastric juice volume
and the total acidity at 6, 24 and 48 hours after the treatment were examined.
Ranitidine serum content was determined by HPLC. Administration of the ranitidine
dextran conjugate produces a higher inhibition of gastric lesions at 48 hours
than the administration of the free drug (61.4% versus 33.9%) and a prolonged
action for more 48 hours. Synthesis of a macromolecular prodrug of ranitidine and
its in vitro behavior was reported in a previous paper (11). The present paper
studies the performances obtained in gastro-protective action by using the new
ranitidine-dextran conjugate reported (11).
PMID- 10756794
TI - Hydrazones and formazans with possible biological activity.
AB - This paper presents a synthesis about some hydrazones, formazans and copper's
complexes combinations. The structure of the new compounds was confirmed by the
results of the quantitative elementary and IR spectral analysis. The
antimicrobial and antiinflammatory activities were investigated.
PMID- 10756795
TI - [The evolution of lumbar myalgia under the influence of the product Pelnicol
administered in suppositories].
AB - After having done a wide study in vitro and in vivo reported in several
publications, we applied the lyophylized extract "Pelnicol" under the form of
suppositories, in 36 cases of secondary back diseases. The improvement with
"Pelnicol" suppositories is observed, by mean, the 6th day of treatment. It can
be seen that etiopathological factors are determining the diseases evolution,
which has to be, in first rang, considered causally. It is realised with the
"Pelnicol" suppositories.
PMID- 10756796
TI - [Experimental research on the actions of original synthetic substances on acute
inflammation in laboratory animals].
AB - There have been determined LD50 at two original synthesis substances coded S1, S2
of the class of Mannich bases and the corresponding oxime. We have study the
effects of these substances upon the acute inflammation and the immunity system
of the experimental animals. The animals for experiments have been white rats to
which have been administered 31.25 mg/Kg body/day substance S1 and 45 mg/Kg
body/day of and the substance S2. Our researches on the proinflammatory effects
of the S1 and S2 substances have shown their immunomodulating capacity.
PMID- 10756797
TI - [Ginkgo biloba extract (EGb 761) as an antioxidant factor of exogenous origin].
AB - Extracted from Ginkgo biloba leaves, the EGb 761 has a great number of
therapeutical properties and anti-stress effects, for example the antioxidant
one. We estimated in our experiment the influence of a chronic treatment with EGb
761 on the concentration of the main product of lipidic degradation-
malondialdehyde (MDA), in cerebral cortex, in diencephalon, thymus and gastric
mucosa. The experiment was performed on Wistar rats, male, young. The MDA
estimation was performed by the spectrocalorimetry. We have determined that the
stress raised the MDA concentration in all examined structures with approximately
100% and 80% of animals manifested stress ulcer. The treatment with EGb 761
before a stress inhibits the post-stress growth of MDA concentration and the
process of stress ulcer formation.
PMID- 10756798
TI - [Morphological diagnostic problems in a case of peritoneal blastomycosis].
AB - Blastomycosis is a mycotic disease, caused by a fungal infection. It has a wide
spectrum of clinical presentations, and, particularly, can mimic neoplastic
disease. Correct diagnosis of the illness requires fungal culture and biopsy. In
Romania, mycotic histopathology is insufficiently developed, and morphological
tests are recommended to very few people who present this type of pathology. The
paper discusses a case of peritoneal blastomycosis found at a patient with an
abdominal pseudotumoral mass. The microscopic exam revealed the characteristic
histologic features and budding yeast, in specific dyes, typical to the
Blastomyces dermatidis (PAS, silver-methenamin). Authors of this paper hereby
intend to draw pathologists' attention on the existence and diagnosis of mycotic
lesions, whose number is continuously increasing nowadays.
PMID- 10756799
TI - Complex investigation of Graves'-Basedow disease: case report.
AB - This paper relate a patient case, age 42, female sex, which was complex immuno
morphologically investigated, on thyroid fragments, surgically obtained. The
patient was previously diagnosed with Graves'-Basedow disease; the relapses after
conventional therapy, orientated the case for surgical treatment--subtotal
thyroidal resection. Using polyclonal and monoclonal antibodies, we may confirm
that the disease is fully active. Graves'-Basedow disease is the most common form
of autoimmune thyroiditis, responsible for the majority of the cases of
hyperthyroidism, affecting young women. It was suspected, many years ago and
recently demonstrated that the hyperthyroidism is involved in the development of
the autoimmune response, by increasing the immune reaction of the organism. Some
effects of the antithyroid drugs are mediated by the decrease of the specific
stimulator antibodies (long-acting thyroid stimulator), commonly found in Graves'
Basedow disease.
PMID- 10756800
TI - [3 cases of malignant immunoblastic lymphomas].
AB - Immunoblastic malignant lymphomas belong to the high-grade malignant lymphomas
and can be classified into B and T types, according to the origin line of the
proliferating cells. This paper presents three cases of immunoblastic malignant
lymphomas, exhibiting fairly close morphological aspects. The morphological
diagnosis based on standard methods using conventional dyes was supplemented by
immunohistochemical diagnosis with monoclonal antibodies. Thus, the cellular line
of the proliferating cells has been identified. A brief overview of the
theoretical criteria requested for defining and differentiating the two types of
immunoblastic lymphomas is also formulated.
PMID- 10756801
TI - Cytomegalovirus-induced massive small intestinal bleed. Case report and review of
the literature.
AB - We report a case of massive small intestinal bleeding in a non-HIV positive
patient treated with cyclophosphamide and steroids for polyarteritis nodosa.
Tagged red blood cell studies, endoscopy, and angiograms were performed prior to
exploratory laparotomy. Jejunal ulceration and bleeding were evident by serosal
staining. Resected segments revealed intracytoplasmic inclusions positive for
cytomegalovirus by immunoperoxidase staining. A second bleed after the resection
was controlled with oral norepinephrine, prior to effective therapy with
ganciclovir.
PMID- 10756802
TI - [The complexity of therapeutic action and the need for continuing medical
education].
PMID- 10756803
TI - [Computer-assisted instruction in the field of morphology].
AB - Visiting the image collections of normal and pathological morphology, available
with free access on the World Wide Web (www), represents a vast source of
extremely valuable material for both teaching and documentation in research
activities. The aim of this paper is to provide a brief overview of the www
facilities, which is gradually structured at the conceptual level. This overview
ranges from the exploration of various topics in medical sciences/morphology,
till the concrete aspects revealed by the construction and utilization of image
libraries, designed for internal use, in accordance with certain systematic
criteria. Examples from normal and pathological morphology illustrate the
principles envisaged by the elaboration of such libraries.
PMID- 10756804
TI - [Hybrid molecules--a new prospect in producing drugs].
PMID- 10756805
TI - [The role and place of drugs in contemporary civilization].
PMID- 10756806
TI - [Scientific medicine in obstetrics-gynecology].
PMID- 10756807
TI - [The normal functions of integrins and their involvement in pathology].
AB - Ordered cell-cell and cell-matrix adhesive interactions are a fundamental feature
of all multicellular organisms. Numerous studies in recent years have confirmed
that both types of cell adhesion are mediated by cell surface receptors known as
"adhesion molecules". These receptors can be divided into a limited number of
families. Knowledge gained from basic research into cell adhesion is now being
applied to clinical problems, and some of these have been summarized here.
Integrins are heterodimeric proteins mediating cell-cell and cell-extracellular
matrix adhesive connections and signal transduction across the plasma membrane.
The important roles of integrins are in Leukocyte Adhesion Deficiency, in viral
diseases, neural development and cancer. Suggestive data now points to roles in
functions characterized in part by morphological rearrangements, such as learning
and memory, and injury responses.
PMID- 10756808
TI - [The cellular mechanisms of photocarcinogenesis].
AB - UV radiations can act as a complete carcinogenic factor, being capable to
initiate and also to promote the tumoral process. They usually act by altering
the DNA and also the cell functions involved in cell differentiation. In the last
decade important progresses were made in understanding the genetic bases of
cancer by the discovering of the protooncogenes. Their normal function is vital
for the optimal regulation of cell growth and differentiation; alter of their
structure or regulation of their expression under the viral action, ionic
radiations or chemical substances can determine cancer development.
PMID- 10756809
TI - [High-risk breast lesions].
AB - Breast lesions with malignant potential are the morphological expression of
tissular troubles, foregoing the in situ cancer and then invasive. Breast
dysplasia, like fibro-cystic mastosis with typical epithelial ducto-lobular
proliferation can progress in a relatively long time interval towards in situ
carcinoma. Classical advising, that any breast masses should be regarded as a
potential cancer, until it's nature is not pathologically characterized, still
remains actual. The clinical and imaging diagnosis for mastopathy at risk and the
approaches for a therapeutic manner represent today a real possibility for early
treatment.
PMID- 10756810
TI - [The treatment of the long QT syndrome].
AB - General principles of long QT syndrome (LQTS) management are presented first. The
management of pause-dependent LQTS includes the following steps: A. recognition
of torsades de pointes type of ventricular tachycardia and of the ecg warning
signs, B. termination of the arrhythmia and the ecg warning signs by
interventions which do not shorten the QT interval and by interventions which
also shorten the QT interval. The management of adrenergic-dependent LQTS
includes the following steps: A. individual risk stratification, B. avoidance of
deleterious sympathetic stress, C. recognition of the arrhythmia and of the ecg
warning signs, D. termination of the arrhythmia, E. prevention of relapses using
beta-blockers, high left cervico-thoracic sympathectomy, permanent pacemakers and
automatic implantable cardioverter-defibrillators.
PMID- 10756811
TI - [The indirect assessment of arterial compliance in hypertension patients by
tonometric sphygmography].
AB - Left ventricular hypertrophy (LVH) constitutes a powerful risk factor for
cardiovascular morbidity and mortality. Clinical studies indicate that despite
their equipotent blood pressure lowering effects, there are marked differences
not only in the ability of the different types of antihypertensive drugs to
prevent or or reverse LV mass but also within the same class of pharmacological
drugs. Tonometric sphygmography may shows radial and synthesized ascending aortic
pressure waves with augmentation of late systolic aortic pressure peak that is
attributable to early return of wave reflection (marker of arterial compliance).
PMID- 10756812
TI - [Current trends in nutrition].
AB - The energy delivered by food is involved in the maintaining of the homeostasis
and in the electromechanical activities that define life. The energy expenditure
include basal metabolism, thermogenesis and the energy required for the physical
activity. Functional food extends over providing the nutrients into playing
important physiological roles into the organism. The recommendations are to
increase the consumption of fruits, vegetables and whole grains in order to
reduce the risk for degenerative diseases and cancer.
PMID- 10756813
TI - [The biological effects of liposome interactions with the endoplasmic reticulum].
AB - Liposome research is a thriving field at the confluence of biophysics, cell
biology and medicine. The principal medical application of liposomes is based on
their potential to act as carriers for a broad spectrum of drugs and other
agents, including antigens with or without immunomodulators in vaccination.
Treatment of peritoneal macrophages of rats with small unilamellar vesicles of
dipalmitoylphosphatidylcholine (DPPC SUV) potentiated their activation for tumor
cell lysis by endotoxins. The measurement of the fluorescence anisotropy of
diphenylhexatriene showed a phase transition. No phase transition was observed in
the rough endoplasmic reticulum membranes of macrophages either treated or not
treated with cholesterol/DPPC SUV. The synergistic effect of DPPC SUV on the
tumoricidal activity of macrophages induced by endotoxins appears to be
correlated with the changes in the properties of the rough endoplasmic reticulum
membranes. Both effects were transient; they had the same kinetics of induction
and reversion.
PMID- 10756814
TI - [Experimental ethanol poisoning in rats].
AB - Ethanol is one of the most used substances that produce liver lesions. The
differences between species, the pathway of administration and the genetic
variation are factors that influence the response of liver to ethanol. The
experiment used adult male Wistar rats and the hepatic lesions were assessed
using standard histological examination. The results show an increase of
triglycerides in liver cells even in acute intoxication, the most affected cells
being located in the periphery of the hepatic lobule, associated with a
dilatation of blood vessels.
PMID- 10756815
TI - The diminution of platelet activity in vitamin E-treated diabetic rats.
AB - BACKGROUND: Because vitamin E deficiency has been demonstrated in platelets
obtained from diabetic subjects, in our research we investigated the platelet
activity and the oxidative stress in alloxan diabetic rats supplemented with
vitamin E. MATERIAL AND METHODS: The platelet activity was estimated by the
adhesion index (AI) and the oxidative stress was correlated with the determined
level of malondialdehyde (MDA) an end product of lipid peroxidation. RESULTS: We
found that alloxanic diabetes was associated with significant increase in the
both MDA level and AI (p < 0.01 and p < 0.05, respectively). The AI was better
correlated to the MDA level (r = +0.60) than to the hyperglycemia. The
administration of vitamin E before and after alloxan was accompanied by a
significant decrease of both MDA level and AI comparing to untreated diabetic
rats. CONCLUSIONS: Our study suggests that vitamin E supplementation may improve
the increased platelet adhesion as a consequence of an increased oxidative stress
and therefore the incidence of diabetic angiopathy may be reduced.
PMID- 10756816
TI - [The evolutionary characteristics of the hypereosinophilic syndrome].
AB - The case here described is a young male aged 21 years who met all diagnostic
criteria for HES: (1) persistent eosinophilia of over 1500/cubic millimeter
(19.904-26.070/cubic millimeter) for longer than 6 month (12 month in our
patient); (2) lack of evidence of other known causes of secondary
hypereosinophilia (SH); (3) multiple organ involvement. The peculiar aspects
found in our case are related to organ involvement: occurrence 2 months after HES
onset of chronic myocardial infarction in four locations (apical, anteroseptal
and posteroseptal, inferior, left ventricular) demonstrated by
electrocardiographic and scintigraphic studies; early global cardiac
insufficiency (6 months after the onset); acute renal failure (since HES onset)
followed by chronic renal failure. The multiple and severe involvement of the
nervous system (up to coma) were not a life threat. It is suggested that a
possible explanation for the multiple organ involvement could be the chronic
disseminated intravascular coagulation.
PMID- 10756817
TI - [Recurrent respiratory manifestations in atopic dermatitis in small children].
AB - The aim of the present study was the retrospective analysis (in the last 5 years)
of 89 children, aged between 3 and 24 months of life, diagnosed with atopic
dermatitis (D.A.) and wheezing, in comparison with a second group of 31 children
admitted in the Paediatric Clinic for recurrent wheezing (R.W.) without atopic
cutaneous signs. Evaluating the therapeutical response on the basis of the
clinical and biological features for each child, we have noticed for the first
group (with D.A.), the followings: 30% of patients didn't experience a favourable
outcome and were complicated with "severe" asthma; 54% of subjects have
manifested airway hyperreactivity (nocturnal and early morning cough); 81% of
children have associated allergic rhinitis. The observations in the second group
have suggested that, only in 12% of patients with R.W. has been manifested asthma
as a major complication. The main risk factors for asthma in the first group were
as follows: precocious atopic eczema, personal or family history of atopy,
nourishment with non-maternal milk and passive smoke. We consider that asthma at
infants and children is underestimated because of the difficulties of diagnosis
at this age.
PMID- 10756818
TI - Ultrastructural aspects of the alveolar wall in SIDS.
AB - The aim of this study is to make a comparative analyse between light and
ultrastructural lesions of the alveolar wall in SIDS. The study was made on lung
specimens collected from autopsy of infants with sudden unexplained death. There
were studied histopathologically 10 cases of sudden death. Only in 3 cases were
made electron microscopically studies. At light microscope, there were put in
evidence interstitial and intra-alveolar oedema and the presence of many parietal
and intra-alveolar macrophages. There is a good correlation between light and
ultrastructural aspects.
PMID- 10756819
TI - [The effect of light intensity and neostigmine on the electroretinogram of
Drosophila melanogaster].
AB - In this article is presented the influence upon the electroretinogram, of some
external factors acting at different levels of the visual system in the fruit
fly, Drosophila melanogaster. The experiments revealed the effects generated by
the light intensity modification as well as by the injection of a
neuropharmaceutic--the neostigmine. The increase of the light stimuli intensity
induced the same change of the rate between the amplitudes of the main
electroretinographic components as the neostigmine does. It was used the
"flickering" excitation regime, utilizing a data acquisition system adapted to
the principal experimental device.
PMID- 10756820
TI - [The involvement of vitamins C and E in changing the immune response].
AB - Production of reactive oxygen species (ROS) is just one of mechanisms through
which activated polymorphonuclear neutrophiles contribute to the myocardium
injury in ischemia and infarct. In the employed experimental model, the physical
effort through swimming has determined the suppression of neutrophile activity
and activation of serum complement. The vitamins E and C have stimulated the
phagocytosis capacity of neutrophiles in the peripheral blood but they did not
influence the serum complement. Our results suggest that these vitamins with
their known antioxidant properties may be used together with other
immunomodulators for the adapting defence of organism.
PMID- 10756821
TI - Familial adenomatous polyposis--which operation?
AB - Familial adenomatous polyposis (FAP) syndromes are well recognized entities that
benefit from surgical treatment which should not be delayed. Screening of first
degree relatives is important. The aim of removing the colorectal mucosa with
significant potential of malignant transformation can be achieved by means of
three distinct procedures: pan-proctocolectomy and ileostomy, subtotal colectomy
with ileorectal anastomosis, restorative proctocolectomy with ileoanal
anastomosis. In a series of eight patients with FAP we performed mostly subtotal
colectomy with ileorectal anastomosis. Of five patients who underwent a form of
subtotal colonic resection, one was lost from follow up and two developed
carcinoma in the remaining rectal mucosa, which necessitated completion of the
resection with proctectomy and permanent ileostomy. Nevertheless, in the
increasing number of patients amenable to regular outpatient supervision, there
are strong points for recommending sphincter-saving operations.
PMID- 10756822
TI - Treatment of scaphoid nonunions by Russe bone grafting--a retrospective analysis.
AB - Forty-five patients with symptomatic established delayed union and nonunion of
the scaphoid were operated between January 1983 and December 1997. The Russe
anterior corticocancellous bone-grafting was performed in twenty-five cases.
Using a grading system, we analyzed the suitability of this method, for three
types of nonunion. We attained a 92% bony union rate of all nonunions grafted.
Review of the relevant literature shows that there was same significant
difference in union rates between the types of nonunion, the vascularity of the
proximal fragment and the presence of dorsal intercalated segment instability
(DISI). The aims of this procedure are to obtain a good functional wrist without
pain and to prevent late arthritis.
PMID- 10756823
TI - [Post-therapeutic complications in mandibular fractures: a retrospective study].
AB - The analysis in based on 12,096 patients with fractures of the mandible admitted
to and treated in the Clinical of Oral and Maxillofacial Surgery of Iasi in the
interval 1951-1995. Posttreatment complications were found in 10.52% of the
cases, 9.81% of them being of inflammatory type. Anatomo-clinically these
consisted in suppurations of the soft tissues, osteitis and osteomyelitis. The
prejudices caused by these complications were multiple: longer hospital stay,
additional suffering for the patient, temporary work inability, higher treatment
costs.
PMID- 10756824
TI - [The common risk factors in gallstones and cardiovascular diseases].
AB - In this study, I analyzed the principal risk factors which exist in both
diseases. OBJECTIVES: The objective of the study was to establish the
relationship between gallstone and heart diseases in a population who was
admitted in the University Hospital. METHODS: I investigated 1122 patients with
heart diseases from 2488 patients with gallstone, between 1st of January 1993
30th of June 1997. At the study group I found one or many risk factors
association in the both diseases. RESULTS: This study shows a significant
interaction between these factors and gallstone and heart disease. CONCLUSIONS:
The common risk factors have a major importance in the development of the
gallstone, or of the heart disease, or both.
PMID- 10756825
TI - [The anatomico-surgical aspects of the lumbar sympathetic network].
AB - Our article yields new statements about macroscopic anatomy of the sympathetic
lumbar chain, after the dissection of 480 corpses in a 15 years period. Our
observations state new conclusions, with implications in surgical practice, about
the function and the vegetative territory of the lumbar sympathetic chain.
PMID- 10756826
TI - [The prognostic factors for survival in advanced forms of non-small-cell lung
cancer].
AB - This study attempted to determinate the prognostic value for survival of various
clinical, biological and therapeutical prognostic factors in patients with non
resectable non-small cell lung cancer (NSCLC). METHOD: We performed a
retrospective study on 236 patients with histologically proved unresectable
NSCLC. We collected 36 variable and analysed them by univariate and multivariate
methods in order to establish their influence on survival. RESULTS: The global
estimated median survival time was 10 month. In univariate analysis were
significantly related to survival: age (> 60 years), weight loss (> 5%), local
extend of of disease, Karnofsky performance index (< 70%), stage of disease
(stage IIIA vs. IIIB, IV), hemoglobinemia (< 10 g%), calcemia, platelet count,
radiotherapy total dose (< 50 Gy), Cisplatin chemotherapy. In a Cox regression
model, the explanatory variables were: age > 60 years, Karnofsy performance index
70%, stage IIIB and IV, thoracic total radiotherapy dose < 50 Gy. These results
led to a classification of the patients into three subgroups (prognostic index).
CONCLUSION: We confirm by our analysis the role of independent factors for
survival and we obtained three prognostic groups, the best one needs a radio
chemotherapy association.
PMID- 10756827
TI - [The arterial system of the greater omentum].
AB - The aim of our study is to establish a pattern of distribution of the arteries of
greater omentum. Right omental arteries supply the anterior lamina and the left
ones the posterior lamina (in 82% there is an initial independent left-right
distribution). In 18% it is mixed, the two territories being supplied by both
anterior and posterior omental arteries. The classic pattern with three main
arterial arches (one infra-gastric and two inferior marginal) was identified in
24% cases. More frequent (45%) is the pattern with two transverse main arteries,
one superior and the other inferior (with a variable number of intermediate
arteries). In 51% cases the infra-colic arch is dominant; in 14% cases it is
thinner. The absence of arterial arches may be partly substituted by a dense
capillary network. The laminar arterial distribution of greater omentum was
expressed into more patterns.
PMID- 10756828
TI - [The pre- and postnatal development of the human lung].
AB - The bronchoalveolar structures where studied during the intrauterine evolution by
histological sections and pulmonary radiographs. This evolution depends on the
degree of "prenatal immaturity" or "dismaturity". I compared my results with data
from literature. I estimated the rate of bronchial growth as being not uniform,
the most abundant branches being encountered in the basic layers of the inferior
lobes, and some peripheral juxta-pleural bronchial bend in right angles,
continuing with branches parallel to the pleural surface. I find justified the
opinion, increasingly sustained by authors, that the epithelium of the bronchial
conduction system has an endothelial origin, while the breathing device
originates from the mesenchyme dressing the bronchial distal extremities.
However, some pathological aspects, or pulmonary congenital abnormalities, make
me sustain this double embryonal origin of the bronchoalveolar structures.
PMID- 10756829
TI - [The postnatal evolution of the extra- and intrapulmonary bronchopulmonary
airways].
AB - The follow-up of the bronchoalveolar branch development was made by the help of
radiographs performed on pulmons taken in the first 4 post-natal weeks and
injected with barium. The new environmental circumstances of life for the new
born can influence this development. If at birth the air-ways are mostly
existent, the alveolar network multiplies very much after birth, together with
the more pronounced sustaining of the alveolocapillary structures. The prematures
have primitive alveolar bags, but they can accomplish with them the gas exchange,
even if in very difficult circumstances. But the tightening of the peripheral air
ways support the frequency of the peripheral bronchial pathological events during
the early years of life, the failure of collateral venticulation also
contributing to this. The parallel development of the vascular elements,
particularly, besides the other parenchymal structures, has a special role in
this respiratory components.
PMID- 10756830
TI - The anatomical variants of the profunda femoris artery and of its collaterals.
AB - The profunda femoris artery, the main nutritive artery of the thigh, has a great
surgical significance. The high frequency of the occlusive arterial disease in
the lower limbs caused by atherosclerosis, imposes as main therapy the
reconstructive surgery. Because the profunda femoris artery remains patient in
most of the cases of the occlusive arterial disease of the lower limbs, it means
the only hope of saving an critically ischemic limb in a desperate attempt of a
surgeon to avoid amputation.
PMID- 10756831
TI - [An evaluation of interpersonal dependency in physically handicapped children].
AB - In assessing the problems of handicapped persons, the social relations represents
an important element. The emotional thrust in other persons put in evidence the
need for assistance, only 25.1% of the subjects having normal affective
relations. The lack of self-thrust and a choosing of a model from the closed
community is met in 70.1% of the cases. The expression of the autonomy depends on
the degree of motor handicap; 36.1% consider themselves as dependent, but a part
of them have only a physical dependence.
PMID- 10756832
TI - [Hydrazide derivatives with biologically active 1,2,4-triazole support].
AB - This study presents the synthesis of ten new hydrazides with 1,2,4-triazole
support. The structures of the obtained compounds were elucidates by means of the
elemental analysis data as well as by IR spectral measurements. The antimicrobial
and antifungal actions of this derivates are also tested. The results show that
the compounds with the functional group 4-chlore-2-methoxyphenyle are more
active.
PMID- 10756833
TI - Peri-implant tissue and the longevity of restoration.
AB - The clinical success was analysed several times, based upon the good results
obtained and unfortunately not on a basis of correct scientific researches, as
the cellular and ultrastructural investigations. In the randomized study a more
numerous failures are seen in the first, respectively second year, after the
application of the implant. The failures were predominantly observed in case of
mandible implants. The quality of the bone is an essential factor for the success
of the implant without correlation with the age of the patient. The most
objective choice of the patients as well as a correct conceived and executed
therapeutical plan, the follow-up cooperation with the patient, in what concerns
the strict oral hygiene, would had to an increasing number of successfully solved
cases. The success of the implant may be ensured when besides the content of the
patient, the long-term stability of the soft and bone peri-implant tissues is
achieved. By this is also obtained by morphological stability, which may be
evaluated following clinical X-ray parameters. This stability is under dependence
of the biological status. Conclusively this means an established biomechanical
balance and stable relationships between the immune defense system of the least
and the pathogenic potential of the microorganisms.
PMID- 10756834
TI - Adenomyxoma of eccrine sweat gland--case report.
AB - Although eccrine adenoma is usually situated on the distal portions of the
extremities, we present a case localized in the vicinity of a mammary gland near
axilla. The clinical diagnosis was of a mammary fibroadenoma with associated
apocrine type of adenomere, supported by a myxomatous stromal tissue. The
diagnosis was of an eccrine adenomyxoma. We continue with a review of the
problems of microscopical differential diagnosis.
PMID- 10756835
TI - [100 years of the university teaching of pediatrics in Iasi].
PMID- 10756836
TI - [Prof. Martian Cotrau (1923-1998)].
PMID- 10756837
TI - [Prof. Gr. T. Popa--the man and his works].
PMID- 10756838
TI - [From natural peptides to inhibitors of conversion enzyme synthesis].
PMID- 10756839
TI - [Intercellular communication].
AB - There are 3 modalities for intercellular communications: the chemical substances
secreted by some cells are transported at distance where they act as signals on
other cells; the surface molecules of a group of cells interact with the
neighbouring cells; some special junctions or nexus provide direct relations
between cells. In the first modality the chemical signals operate in 3 ways: a)
many cells secrete one ore more chemical signals which act as local mediators
(paracrine model); these mediators act immediately or are destroyed after they
influence the neighbouring cells; b) some specialised cells--endocrine cells-
secrete hormones, which are liberated in small amounts into the blood and exert
their effects on some target cells, able to recognise and to respond to the
hormonal signal; c) the neurones secrete chemical mediators--neurotransmitters,
which act at the level of some special junctions--the chemical synapses. Most
biologic phenomena are under the overlapping control of both systems--thus they
are regarded as neuroendocrine system. The nervous cells transmit the
informations much more rapidly than the endocrine cells. The chemical signals are
various, as regarding the structure and function: they are large polypeptides,
small polypeptides, glycoproteins, amino-acids, steroid molecules derived from
cholesterol and fatty acids. The ability of the cells to respond to an
extracellular signal molecule depends on the existence of some specific proteins,
included in the plasma membrane, called receptors. The chemical signals influence
the target cells both by altering the properties or the synthesis rate of their
own proteins or by initiating the synthesis of new proteins. The chemical signals
induce rapid and transient or slow- and long-lasting responses. All the
neurotransmitters and the majority of hormones are water-soluble; the steroid and
thyroid hormones are relatively water insoluble; the mechanisms of influencing
the target cells are dependent of this feature: the water-soluble molecules do
not pass through the target cell membrane, they bind to the surface specific
receptor while the insoluble molecules cross the plasma membrane of the target
cell and bind to the cytoplasmatic receptors. It results that the water-soluble
molecules mediate short-time responses while those insoluble--long-lasting
responses. As regarding the local chemical mediators they are secreted by mast
cells or they are represented by the large category of prostaglandins. They
produce a great diversity of biological effects, they are rapidly destroyed, and
this way, they don't penetrate into the blood stream in significant amounts. The
majority of the receptors from the surface of activated cells generate some
intracellular signals both by altering the activity of some membrane enzyme
(adenilate cyclase) with the accumulation of cyclic MPA and by modifying the
permeability of some membrane channels(Ca2+ channels). The target cell exposed to
a signal for a long period of time loose often the ability to respond to this
signal. This process called desensibilization is reversible and is explained by
endocytosis of surface receptors together with the ligand and by their lysosomal
destruction, by the degradation of the receptor molecular conformation which
becomes unable to bind the ligand or by the lack of activation of membrane
enzymes or the channels. The gap or nexus junctions are composed by some proteic
particles which form a hydrophilic channel to assure the communication between 2
neighbouring cells. These junctions allow some molecules (amino-acids,
monosaccharides, cAMP, nucleotides) to pass from a cell to another one,
facilitating the chemical and electrical coupling. These structures show a low
electrical resistance, but they are dynamic, some junctions have the capacity to
change from a low resistance to a high resistance state, isolating the cells from
communicating with their neighbours. Oxygen deprivation, the increase of
intracellul
PMID- 10756840
TI - [Mechanotransduction and tensegrity (I)].
AB - The current review deals with mechanotransduction by means of an architectural
model of cell function called tensegrity. This concept was introduced by D. E.
Ingber in order to frame more focused mechanisms of mechano-transduction, i.e.
different signaling pathways, which are less able to predict global cellular
behaviour in response to stress, into a coherent mechano-chemical theory of cell
function. Tensegrity structures are made and held up by interconnecting a
continuous series of tension elements with a discontinuous series of compression
resistant struts, in a simple "stick and string" model. These structures develops
an intrinsic stabilizing tension called prestress and reacts by global
rearrangements of their configuration to a local action of a mechanical stress.
The only requirement of a tensegrity network is that tension is continuous and
compression is local. At the cellular level the theory assumes that membrane,
nucleus and all the organelles are hard-wired by the insoluble cytoskeletal (CSK)
scaffold. More than that, the interconnection between CSK and the extracellular
matrix (ECM) provides an efficient mechanical couple responsible for changes in
cell shape and movement. Cell shape, in turn, regulates cellular function. Focal
adhesion complexes, which mediate the CSK-ECM interaction are viewed as
integrative devices for both mechanical signaling and soluble factor-dependent
signaling. Furthermore, the tensegral molecular network is considered to be a
solid-state regulatory system of all cell functions. The way tensegrity
influences molecular mechanics, cellular response tuning and coordinated
behaviour of large scale structures are also discussed. Besides its conceptual
importance, the tensegrity model has multiple applications, being used in
combined approach of cell biology, bioengineering, architecture, and biomechanics
in order both to improve cell culture and its subsequent applications and the
open the way to a more complex technology of tissular engineering.
PMID- 10756841
TI - [Peripheral vascular remodelling and changes to the skeletal muscles in heart
failure].
AB - The syndrome of heart failure causes besides a deterioration in the contractile
function of the heart significant alterations of peripheral circulation and
skeletal muscles. The distribution of the regional blood flow is influenced by
systemic and local neurohumoral factors. The local factors are released by the
vascular endothelium or are of nonendothelial origin. The diminution of cardiac
output leads to neurohumoral alterations which eventually influence the blood
flow distribution: in vital organs, such as the heart and the brain, it is
preserved; in the splanchnic, kidney, muscle and skin territories it is
diminished. Muscles changes (muscle atrophy, reduction of type I fibres and a
relative increase of type IIb fibres) are the main cause restricting the
exercise. Techniques of physical rehabilitation associated with proper medication
may lead to the improvement of these alterations.
PMID- 10756842
TI - [The diagnosis of gestational diabetes].
AB - Diabetes mellitus complicates 2 to 3 per cent of all pregnancies and 90 per cent
of these women have gestational diabetes mellitus (GDM)--the most common
complication seen in obstetrical practice today. It occurs in the second half of
pregnancy and is usually asymptomatic. It is recommended that all pregnant women
to be screened by administering a 50 g oral glucose load followed by a glucose
determination 1 hour later. The test may be performed at 24 to 28 weeks'
gestation in the fasting stage. A 1-hour test value of 140 mg/dl (7.8 mmol/l) or
more indicates the need for a 3-hour 100 g glucose tolerance test (GTT). The
patient must have a normal fasting value and two abnormal GTT glucose
determinations to be designated as GDM. Early detection and management are
important to prevent complications to mother and fetus. Patients with GDM
represent a group at significant risk for developing glucose intolerance later in
life.
PMID- 10756843
TI - [Endothelium-derived hyperpolarizing factor].
AB - Endothelial cells control the tone of the underlying smooth muscle by releasing
relaxing factors, such as nitric oxide (NO), prostacycline, endothelium-derived
hyperpolarizing factor (EDHF) and contracting factors such as thromboxane A2,
endothelins, endoperoxides and superoxide anion. The term EDHF should be
restricted to a relaxing factor(s) that differs from NO and prostacyclin. The
nature of EDHF is as yet unknown. EDHF might be a cytochrome P-450 metabolite of
arachidonic acid or an endogenous cannabinoid--anandamide. The EDHF component of
the relaxation is more important in smaller than larger arteries. In various
models of disease and in aging animals endothelium-dependent hyperpolarization is
diminished. The identification of EDHF and the understanding of its physiological
role could lead to the design of new therapies in several cardiovascular
diseases.
PMID- 10756844
TI - [Retinoids. Photodamaged skin and the prevention of nonmelanotic skin cancer].
AB - Sun radiation produce structural and functional changes in skin structures which
are known as dermatoheliosis. It becomes clinically manifest after the age of
fifty when a general involution of the skin occurs. Vitamin A (retinol) is a
critical factor in keratinocyte differentiation. A major progress in clarifying
the control mechanism of cell growth and differentiation was the finding that the
retinic acid shows hormone-like and morphogenetic effects. The retinoids, generic
name for both the term including both natural products of Vitamin A as well as
several thousands of synthetic products mimicking either its chemical structure
or its biological effects, have proved efficient in a range of skin disorders,
including dermatoheliosis. Their effectiveness comes from the overall impact on
the skin structures, the ability to change the structure of the epidermis, dermis
and sebaceous glands as well as the systemic effect on immunoreactivity. The
prophylactic effect of retinol on various types of epithelial cancers has been
well demonstrated. It has been proved lately that the association of retinoids
and cytokines significantly improves the therapy efficiency in malignancy.
PMID- 10756845
TI - [The extra-auditory effects of noise].
AB - Noise affects not only the ear, but the body as a whole. Noise exposure can
trigger a series of functional changes related or not with hearing loss,
consisting mainly in sleep disturbances, blood pressure increases, changes in the
amplitude and frequency of the respiratory movements, decreases in the visual
function and psychological disorders.
PMID- 10756846
TI - [An update on human ehrlichiosis].
AB - Human ehrlichiosis is a potentially lethal infections due to a new gram-negative
microorganism. The first human case was reported in 1953 in Japan. Two of the
animal agents are involved in human disease: Ehrlichia chaffeensis, Ehrlichia
sennetsu. A third Ehrlichia type agent causes the disease in human beings only-
Ehrlichia granulocytophila. The tick is natural vector; the highest frequency was
observed in May-July, in the United States; the most important clinical signs
are: fever, anorexia, rush, dyspnea etc.; the specific treatment consists in
tetracycline administration (doxycycline minocycline) for up to seven days.
PMID- 10756847
TI - [Traumatic scapholunate instability of ligamentous origin].
AB - A great deal of progress has been made in recent years with respect to
understanding the normal and pathological anatomy of the wrist. A careful history
and physical examination continued with a critical review of the standard
radiographs, supplemented by additional studies as indicated, allow the astute
clinician to identify specific patterns of instability and to formulate an
effective treatment program for the patients. The most frequent type of
ligamentous instability of the wrist was classical defined by Linscheid (1972) as
"carpal injury in which a loss of normal alignment of the carpal bones develops
early or late".
PMID- 10756848
TI - Peri-implantitis.
AB - Peri-implant lesions are directly linked to the relationship between the implant
and the soft tissue. These lesions are rare in the case of pure Ti smooth
implants, but appear frequently around the rough-surfaced implants. A marginal
inflammation may result in a rapid peri-implant bone loss, since the peri-implant
connective tissue constitutes in a less effective barrier than the same tissue
surrounding the tooth. The morphopathological examination of the peri-implant
tissues revealed after their removal that the gum's mucous membrane is not
inflamed, but degenerative lesions were observed both on the epithelium and
chorion. The papillary lamina propria contains few cells, but it is rich in
collagen fibers; vasodilatation and edema were also present. Multiple areas of
lysis of the intercellular junctions were also observed at the intermediary level
of the gum peri-implant epithelium (the epithelial cells undergo a process of
involution at the intermediary level of the epithelium). Important changes can be
seen both at the level of intercellular junction systems and at the junction
between the basal extremity of the epithelial cells and the basal membrane.
PMID- 10756849
TI - [Antifungals, their potentials, limits and outlook].
AB - A review of the history of antifungal therapy shows that after a long period of
empiricism the therapeutic arsenal available for the nowadays practitioner has
suffered a spectacular change. Indicated in the topical and systemic treatment of
mycoses, their practical use requires experience and responsibility. The
impartial analysis of their antifungal benefits refers to such targets as:
ergosterol, protein syntheses and mitoses from fungal cells.
PMID- 10756850
TI - Nuclear magnetic resonance spectroscopy in the diagnosis of modifications of the
oxidative stress in red blood cell during pre-eclampsia.
AB - Our study uses the technique of nuclear magnetic resonance (NMR) spectroscopy to
determine the changes of antioxidant (AO) system in red blood cells during pre
eclampsia (PEC) as compared with normal pregnancies 28 and 34 weeks of gestation.
MATERIAL AND METHOD: The study was carried out in 30 women divided into 3 groups:
Group I included 10 women with pre-eclampsia, Group II A included 10 women with
normal pregnancy, 28 weeks of gestation and Group II B included 10 women with
normal pregnancy, 34 weeks of gestation. The balance was determined by measuring
the glutathione (GSH) levels. GSH is a major scavenger in lipid peroxidation, one
of the most important events in oxidative stress. RESULTS: The results are
presented as spectra. We found a major decrease of intracellular GSH in PEC
compared with normal pregnancies. This decrease correlates well with the severity
of the disease. This AO system deficiency leaves the red blood cell completely
unprotected versus lipid peroxidation, which will lead to severe damage of the
membrane, an onset characteristic to this disease. Our study is the first to use
NMR spectroscopy in the diagnosis of PEC. The technique proves to be very useful,
especially in detecting those early changes that, if corrected, would prevent the
progression to eclampsia.
PMID- 10756851
TI - [Cytogenetic changes induced by low-intensity microwaves in the species Triticum
aestivum].
AB - Seeds of Triticum aestivum having an uniform genophond have been exposed to a
microwave flow, with a frequency of 9.75 GHz and a low intensity. The effects of
microwaves at various doses on mitotic activity have been followed. Our results
show that as compared to the controls different types of chromosomal aberrations
appeared: delayed chromosomes, micronuclei, interchromosomal bridges, chromosomal
fragments.
PMID- 10756852
TI - [The reflection of the dynamics of the serum markers CA l5.3 and CEA in breast
cancer].
AB - The aim ao this study was to evaluate the significance of the usual analysis of
CA 15.3 test in breast cancer, the efficiency of different therapies (by
observing the CA 15.3 dynamics) and to find out the possible connection between
CA 15.3 serum level, CEA and the cancer course. By the study of 23 patients
diagnosed with breast cancer in various stages, we managed to determine the serum
concentration of CA 15.3 and CEA using DELFIA, namely ELISA method, before and
after individual therapy. Before therapy, we found pathological CA 15.3 levels in
13 patients (56.5%) and after treatment in 16 patients (69.56%). After individual
therapy, we also measured the seric level of CEA, within normal ranges in 3
patients with advanced metastatic disease, who also presented pathological values
for CA 15.3. Based on the clinical and experimental data we noticed the
connection between pathological values of CA 15.3 and IIA, IIB stages (at
significant recurrence risk). The significantly increased levels of CA 15.3 and
CEA could be correlated with the locally advanced and metastatic forms.
PMID- 10756853
TI - Etiological, clinical and pathomorphological aspects of acute respiratory
distress syndrome in children.
AB - Acute respiratory distress syndrome (ARDS) is the result of severe injuries of
different etiologies of the capillary system in patients with previously healthy
lungs, resulting in noncardiogenic pulmonary edema. The authors studied 42
infants in whom the histopathologic aspects were suggestive for ARDS. The
etiologic factors of this syndrome were: severe gastroenteritis with hypovolemic
or endotoxic shock (13 cases), sepsis (9 cases), fulminans purpura (2 cases),
severe neurological disorders (13 cases), pulmonary infections (5 cases). In such
conditions, if the infant presents hyperpnea followed by generalised cyanosis,
refractory to oxygen therapy, and if there are clinical and radiologic signs of
acute pulmonary edema, the diagnosis of ARDS must be considered and a complete
intensive care therapy is compulsory in order to alleviate the severe prognosis
of this syndrome.
PMID- 10756854
TI - Value of intravenous ATP in the diagnosis and treatment of tachyarrhythmias in
children.
AB - Actual researches show that adenosine and its forerunner, ATP, can realise a
nodal block in intravenous (i.v.) administration. This effect, even if transient,
is of particular usefulness in the therapy of paroxysmal supraventricular
tachycardia (PST) in children and adults. 1 mg/kg ATP was administered i.v. to 51
children (aged 3 months to 15 years) admitted to the Intensive Care Unit for
severe regular paroxysmal tachyarrhythmias with clinical and ECG symptoms. In 31
cases, the P wave was absent on ECG. In 6 of 31 cases in whom wide QRS complexes
were found (over 0.10 sec), a WPW syndrome (4 cases) or bundle branch block (2
cases) was associated. Rapidly i.v. administration monitored
electrocardioscopically was followed by ending of PST in 43 children, including
those with wide QRS complexes. The highest effectiveness was in junctional
tachycardia by re-entering mechanism. The drug was well tolerated, had no side
effects or hemodynamic disturbances and this is very important, because in 12
infants already existed symptoms of congestive cardiac failure at their
admission. The use of i.v. digoxin with/without propranolol was necessary in 8
cases, in which the repeated ATP administration was ineffective. We consider that
i.v. ATP administration in regular tachyarrhythmias in children is very useful
for the proper diagnosis of the types with wide QRS complexes and/or when the P
wave did not appear on the ECG, and also for the treatment, because ATP has a
high effectiveness and an excellent tolerance.
PMID- 10756855
TI - [White-coat arterial hypertension in children and adolescents].
AB - Although intensively discussed and finally accepted in the last years "white coat
phenomenon" (WCF) still raises the question of the benefit of diagnosing it in
pediatric patients as its possible link with the subsequent essential
hypertension is not clear yet. This study included 1068 schoolchildren (aged 10
to 16 years) submitted to a screening program for detecting the in time
variations of blood pressure (BP). When the study was started WCP was present in
60 children (5.6%) and when it ended its frequency raised to 8.73%. In 14 of 60
children (23.3%) WCP progressed to borderline or confirmed essential
hypertension, incidence higher that that of similar forms of essential
hypertension occurring in patients with normal BP levels (20 of 955 = 2.05%).
With time, the frequency of borderline and confirmed essential hypertension has
also increased: 5.11% at the first determination to 7.85% at last one. The high
frequency of WCF and associated with the high frequency of its progression to
essential hypertension support the idea that WCP has a predictive value for the
development of essential hypertension. An early diagnosis and the prevention of
other risk factors may lower the frequency of essential hypertension in adults.
PMID- 10756856
TI - [The problems of self-image formation in children with motor deficiencies].
AB - Self-image is a representation that each person has on its own body. The
personality of an individual develops through progressive knowledge of its own
body. Children with motor deficiencies have a modified self-image. For the
evaluation of self-image a 1 to 10 self-assessment scale for three items (smart,
resourceful, beautiful), and two time periods (now and in the future) was used.
As to the dynamic components, the area "locus of control" showed significant
positive differences between present and future situations (an increase from
22.1% to 56.5% for smart item, from 35.9% to 65.5% for resourceful item and only
a small variation from 30.5% to 37.4% for handsome item, regarding the high marks
self-assentiment).
PMID- 10756857
TI - [The clinico-evolutionary considerations of 492 cases of measles hospitalized in
the Infectious Disease Clinic Iasi in 1997].
AB - Between 01.01.1997-31.12.1997 in the Infections Diseases Clinical Hospital of
Iasi were admitted 492 patients suffering from measles. The above mentioned
number of patients represents 4.92% of all the patients (10097) who were admitted
during this period of time. More than half of the patients (56.9%) are residents
in suburban arias. Teen-agers and young adults (15-24 years) were involved in
most of the cases, followed by new born babies (0-11 months). The clinical signs
were prevalent minor and the atypical exanthema was found in 1/4 of all cases.
The most frequent complications were pneumonia, bronchopneumonia and otitis
media. Of all the patients, two children (average age 1-4 years) died.
PMID- 10756858
TI - [Rhythm disorders in gallstones].
AB - In this study, I analyzed the principal rhythm disorders which I found in
gallstone. OBJECTIVES: The objective was to find if the rhythm disorders are in
relationship with gallstone or not. METHODS: From 1122 patients with gallstone
and heart diseases--261 had rhythm disorders. All of these were examined:
physical examinations, abdominal echography and ECG. RESULTS: 23.26% from the
patients had rhythm disorders, especially sinusal tachycardia and atrial
fibrillation. CONCLUSIONS: I approximate that a quarter from the patients with
gallstone can develop rhythm disorders.
PMID- 10756859
TI - [Diabetic papillae].
AB - We retrospectively reviewed the medical records of all diabetic patients with
benign, transient disc swelling who were evaluated at our institution from 1992
to 1996. The clinical profile of diabetic papillopathy can be expanded to include
people who are older or have type II diabetes and that affected eyes commonly
have retinal vascular changes and macular edema that can adversely affect the
visual outcome. Last, a small physiologic cup may represent an anatomic
predisposition to the condition.
PMID- 10756860
TI - [Parinaud's dermoepithelioma].
AB - The paper presents the clinical and histopathological findings in 18 cases with
Parinaud dermoepithelioma an uncommon tumor of the conjunctiva, in a
retrospective study made on patients who were investigated in our clinic, during
January 1975-January 1995.
PMID- 10756861
TI - [The postantibiotic effect of azithromycin on respiratory pathogens].
AB - We assessed the post-antibiotic effect (PAE) of azithromycin against 3 strains of
Streptococcus pneumoniae 2 strains of Haemophilus influenzae and 2 strains of
Moraxella catarrhalis. The strains were exposed for 2 hours to a concentration of
0.5 mg/l. A stationary phase inoculum of 1 x 10(6)-5 x 10(6) CFU/ml in
IsoSensitest Broth with 5% lysed horse blood and 20 mg/l NAD was used and shaken
for the duration of the experiment. Antibiotic was neutralised by dilution 1:1000
into pre-warmed medium. [table: see text] In conclusion, even at such low
concentration as achieved in serum, azithromycin has a PAE against the
respiratory pathogens studied. In our opinion this could allow the use of
azithromycin, in the usual regimen even in bacteremic respiratory infections.
PMID- 10756862
TI - [A retrospective clinical study on pneumococcal meningitis in 0- to 1-year-old
infants hospitalized in 1987-1996 in the Infectious Disease Clinic, Iasi].
AB - During a period of ten years (1987-1996) in Iasi Infections Diseases Hospital,
were observed 19 children, 0-1 year, with pneumococcal meningitis. This disease
represented one important cause of morbidity and mortality in children in
developing countries. Clinical symptoms in these cases were very serious,
including: fever, headache, vomiting, altered sensorium, seizures etc.
Cerebrospinal fluid analysis confirmed the diagnosis, after showing purulent,
turbid fluid. The germ was isolated in 100% of the cases through direct
examination and culture of cerebrospinal fluid. They were treated with penicillin
and chloramphenicol (55%) and ampicillin and chloramphenicol. The mortality was
52%. This study concludes that delay in diagnosis, virulence of germ, prematurity
and hypertrophy were elements of a bad prognosis.
PMID- 10756863
TI - [Glutathione peroxidase, an oxidative stress biomarker, in the menstrual cycle].
AB - The oxygen, through his toxic effects, has determined the human organism to
perfectionate multiple and efficient protection systems, especially the GSH-Px.
OBJECTIVES: To study the activity of GSHPx activity in the 0, 14 and 28 days of
the menstrual cycle in a group of women with psychiatric disorders. METHODS: The
activity of GSH-Px was investigated in 24 women inpatients from the Psychiatric
Department of Murgeni Hospital Vaslui. The GSH-Px level was determined in human
serum using Fukuzawa method, modified in the Biochemistry Lab of the "Al. I.
Cuza" University, Iasi. RESULTS: It has been no correlation between the type of
psychiatric disorders and the level of GSHPx. This activity of GSHpx is in direct
relationship with the concentration of sexual hormones, showing an hormone
dependent enzymatic induction. A growth of the GSHPx activity from the day 0 to
the 28th day of the menstrual cycle followed by a sudden decrease at menstruation
time have been observed in all age groups. This fact demonstrated the existence
of an enzymatic cycle.
PMID- 10756864
TI - [Clinical imaging correlations in lacunar infarcts].
AB - PURPOSE: This paper is a study concerning the clinical-imagistic correlations in
lacunar infarcts causes and associated lesions in these ones. We made an attempt
to find out and emphasize the risk factors, causes and pathogenic mechanisms
involved in lacunar syndromes. MATERIALS AND METHODS: We studied 138 patients
with lacunar infarcts diagnosed by clinical examination and computer tomography.
The investigation of risk factors evidenced arterial hypertension in 75 cases
(54%). The clinical features of lacunar syndromes were: 1) pure motor stroke 41c;
2) pure sensory stroke 8c; 3) ataxic hemiparesis 9c; 4) dysarthria-clumsy hand
1c; 5) sensorimotor stroke 21c; 6) Landry syndrome 1c. RESULTS: We correlated the
clinical manifestations and complementary investigations what enabled us to
charge in determining of lacunar infarcts: focal microangiopathy-small artery
disease (75c), cardio-embolic mechanism (12c), arterio-arteriolar embolic
mechanism (15c). The risk factors and pathogenic mechanisms need more adequate
research in order to find appropriate prevention and medical attendance.
PMID- 10756865
TI - Fine-needle biopsy cytology in autoimmune thyroiditis.
AB - Fine-needle biopsy is used in the thyroid pathology especially for the
differential diagnosis concerning malignant lesions. From a total of 59 cases of
thyroiditis, in 12 was possible to proceed to fine-needle biopsy, in large
goiters and nodules larger than 1 cm in diameter; in these cases were obtained
smears, stained in May-Grunwald-Giemsa technique. In 9 cases of the 12
investigated, in the smears appeared lymphocytes and macrophages, cells commonly
found in the infiltrates of the thyroid gland, in autoimmune thyroiditis, and
sometimes also few normal thyrocytes. Fine-needle biopsy is important in the
diagnosis algorithm of the thyroid nodules, involving 4, up to 7% of the general
population. It has also the advantage of reducing the number of cases solved by
surgical therapy, as it is the case with the diagnosis of Hashimoto's
thyroiditis.
PMID- 10756866
TI - Endocrine diffuse system--histological and functional aspects interrelated with
the tumoral pathology.
AB - It was first believed that all these endocrine cells are deriving from the neural
crests; in time were discovered more than 40 different types of such cells with
different origins and only 6 or 7 are deriving from the neural crests. Serotonin
secreting cells show yellow fluorescence, while those secreting cathecolamines
show a green fluorescence, with formaldehyde. The most usual method for the stain
of the cells of the endocrine diffuse system is the silver salts impregnation. In
the electron microscopy the cells show dense granules, which are modified in
appearance in the malignancies developed from such cells. Most of the hormones
secreted in the intestine were found also to be hormones secreted in the central
nervous system. The border between benign proliferation and malignant tumors
arising from these endocrine cells is not well defined. DNES--diffuse
neuroendocrine system.
PMID- 10756867
TI - [The effects of different types of pulsed electromagnetic fields on fibroblast
cell cultures].
AB - The aim of this study is to determine which is the most effective pulsed
electromagnetic field (PEMF) on a fibroblastic culture cells. MATERIAL AND
METHODS: Five different types of PEMF are generated by a pulsed generator created
by the author. The electric signal, received by a reference coil is pulse bursts
type. The growth rate of a fibroblastic culture cells is measured with and
without different types of PEMF. RESULTS: Comparative results showed the the most
effective type of PEMF is characterized by a 15 mV positive amplitude of the
signal and a 15 Hz frequency of the bursts. The intermittent stimulation (8
hours/day) was more effective than continuous stimulation.
PMID- 10756868
TI - [A free microsurgical transfer of a radial (Chinese) flap in reconstructing the
lower limb].
AB - The microsurgical transplantation of the radial flap to the hind limb has as main
advantages to offer a good quality and sensitive skin cover, the possibility to
use the flap's radial artery as a vascular bypass and to raise composite flaps
with tendon or bone in case of complex reconstruction. MATERIAL AND METHODS: The
authors present 9 free radial flap transfers to the foot. Patients' ages ranged
from 22 to 50 years. Flap dimensions varied between 7 x 5 cm and 12 x 9 cm. Two
flaps contained the flexor carpi radialis tendon to reconstruct the Achilles'
tendon and one flap included a bone graft from the radial shaft to resolve a bone
defect in the second metatarsal. All flaps were reinnervated by suturing the
antebrachial cutaneous nerve of the flap to a cutaneous nerve in the recipient
site. RESULTS: There was only one failure in an extensive crush injury. We
recommend the radial flap in reconstructing complex defects for it's versatility
and for the fact that it can include all types of tissue that may be necessary.
PMID- 10756869
TI - [The surgical problems of continuous ambulatory peritoneal dialysis: 3 years of
experience].
AB - PURPOSE: This study presents the surgical problems of CAPD catheter insertion and
mechanical complications in 37 cases (39 peritoneal dialysis catheters inserted
for CAPD), being our experience along a time period of 3 years. MATERIALS AND
METHODS: The catheters were of Tenckhoff-type, with double Dacron cuff (Fresenius
Medicale Care). We used an open-type surgical procedure with spinal anaesthesia.
RESULTS: In all the 8 cases with previous abdominal interventions the catheters
were functional. We found an early catheter obstruction only in two cases, by
means of a "greater omentum fimbriae". In the third case a partial omentectomy
was performed. In 1 patient with parietal granuloma and frequent peritonitis a
new peritoneal catheter was inserted (with a new tegumentary outlet). Hernia was
found in 1 patient and was successfully cured by means of surgical intervention.
This patient continued the CAPD treatment. In 2 cases we interrupted the CAPD
treatment (one renal transplant; one converted to hemodialysis). 25 patients had
no catheter-related complications. CONCLUSION: We wish to state that catheter
occlusion and hernia must not lead to an abandon of CAPD treatment.
PMID- 10756870
TI - [Laparoscopic cholecystectomy evolving].
AB - Between March, 31, 1993 and December, 31, 1997 in the Ist Surgical Clinic was
performed laparoscopic cholecystectomy on 1458 patients (1290 females). Clinical
selection of patients was made also by preoperative echography. Cholelithiasis
was present in 94% of cases. Chronic cholecystitis was detected in 77.7% of cases
and acute cholecystitis in 19.13% of cases. Laparoscopic cholecystectomy was
realised by retrograde dissection. Conversion to open cholecystectomy was made in
6.1% of cases. Associated laparoscopic operations: appendectomies, genital
adnexectomies, omentectomies. In uncomplicated cases (98%), evolution was good
with early postoperative mobilization and discharge after 48 hours.
PMID- 10756871
TI - [The characteristics of the removable denture treatment of the edentulous
elderly].
AB - PURPOSE: The increasing number of the elderly with in the general structure of
population, has deep implications for dentistry. Age changes upon the tissues
which make up the totally edentulous prosthetic field often lead to special
therapeutical difficulties in the provision of a comfortable denture. MATERIALS
AND METHODS: The work has at the main aim the same specific aspects met in the
removable gnathoprosthetic treatment of the edentulous elderly patients (84
cases). The treatment applied took into consideration the changes occurred upon
the tissues, general peculiarities of this age period but also the patients
request. RESULTS: The results obtained demonstrate the problems met during the
prosthetic treatment of the edentulous elderly patients to reestablish esthetic
function and the possibilities of restorative. CONCLUSION: The prosthetic
treatment of the elderly must have to the basis an integrative concept and not a
standard one, being individualized for each particular case and every
therapeutical stage must be adapted to the preestablished local and general
Geroindex.
PMID- 10756872
TI - Correlation between various investigation methods of stomatognatic dysfunction.
AB - The aim of this communication is to analyze the correlation between the
stomatognathic and cervical muscular system testing, the analysis of tomography
and the kinesiographic survey. The study has been done on 78 clinically healthy
patients (24 males and 54 females) aged between 21 and 71, presenting various
forms of stomatognathic system dysfunctions. The anamnesis comprised the Slavicek
questionnaire as well. Within the complex clinical examination the classical
clinical investigation of the masticatory muscles and the TMJ has been
supplemented by masticatory muscles, cervical spine and shoulder girdle tests
(AROM, PROM and resistive muscle tests). These tests have been correlated with
the results of the 468 tomogram analyses and kinesiography surveys for test
movements (780 traces) and for functional movements (156 records). The analysis
of tomograms has shown the dimensional asymmetry of the articular elements and
the asymmetry of the relationship between these elements in various position.
These asymmetries are correlated to the alteration of the kinesiographic
tracings. The variations of the articular gap and the P2 and P3 values are
correlated in a very interesting way with the kinesiographic record but also with
the symptoms of muscular dysfunction. The asymmetric condylar movements are
reflected in the asymmetry of the muscular contractions, put into evidence
through the insufficient response to AROM (78%), PROM (62%), resistive muscle
tests (8%) for the masticatory muscles and cervical spine (22%). These results
suggest the opportunity of extending the clinical examination at least in the
cervical area.
PMID- 10756873
TI - [The clinical, imaging and electrophysiological correlations in Paget's disease].
AB - The work presents two cases of Paget disease with a complex neurological
description. The first case, a woman of 59 years, presents a spastic paraparesis
with multiple syndrome of cranial nerves. The second case, a woman of 60 years,
presents a spastic tetraparesis with myoclonus. The cranial radiography stood out
to both patients the thickness of the bones of the skull in the context of the
existence of some grown titres of the alkaline phosphate. The examination CT to
the second patient indicates an important cerebral atrophy. Auditory evoked
potentials (AEPs) show to the first patient the increasing in time of the latency
of the first wave and to the second patient the inequality of latency from the
right to left a wave I and the growing latency of the interval I-III to the left.
Visual evoked potentials (VEPs) to the second patient indicate the delay of all
the component parts. If the radiological examination asserts the diagnosis, the
electrophysiological probings diagnose the complications and the evolution of the
disease.
PMID- 10756874
TI - Subclavian artery injury following percutaneous insertion of dialysis catheter.
AB - Iatrogenic subclavian artery injury is a rare but recognized complication of
central venous catheterization. The lesion is more severe and complex to treat
when produced by large catheters such as dialysis catheters. A case is presented
below with a discussion of vascular access for renal replacement therapy and the
principles of treating penetrating arterial trauma at this location.
PMID- 10756875
TI - [A microsurgical patient, a procedural dilemma].
AB - We are presenting a case which had five operations with the central point being
the microsurgery. The patient is admitted in our unit 48 ours after sustaining a
complex trauma of the left forearm with cvasicomplete destruction of the volar
muscles, defects on cubital and radial vasculo-nervous axes and the median nerve.
Upon arrival we performed the staged surgical debridement, ligature of the radial
and ulnar vessels, anchoring of the ends of the nerves, forearm volar and dorsal
fasciotomies, followed by skin grafting. After five months, the grafted skin is
replaced by an ipsilateral parascapular free flap. After other three months we
repaired the nerves by the mean of sural nerve grafts. The particularity of the
case consists in fact that the ulnar nerve, with a longer defect, was
reconstructed in a two stage approach. Long-time follow up (one year) shows a
very good functional clinical result, confirmed by electromyography. Apart from
the clinical challenge, this case confronted us with tactical dilemma. In a case
of the facial nerve for the best results the cross-face is performed in two
stages. Why shouldn't we do the same thing for all the nerve grafts when we are
faced to semnificative defects?
PMID- 10756877
TI - [Infectious and noninfectious pathology--interferences].
PMID- 10756876
TI - [Remodelling of the crown for occlusal equilibration in partially edentulous
patients].
AB - Two clinical cases of partial edentulous patients with irregular occlusal plane
and their treatment are presented. The authors emphasize the role of occlusal
rehabilitation before any prosthetic treatment. Gingivectomy, osteoplastic
surgery and crown reshaping are used. Occlusal relationships before fixed or
removable prosthodontics is applied, are essential to insure correct mandibular
movements and the dento-maxillary system homeostasis. Two clinical cases of
patients with irregular occlusal plane because of teeth migrations (horizontal or
vertical) after long-term edentation are presented. Both cases were by crown
reshaping after pulpectomy and gingivectomy to obtain a regular occlusal plane.
Prosthetic treatment was applied only after these preparations. We achieved good
results concerning the dento-maxillary functions.
PMID- 10756878
TI - [An update on the treatment of chronic hepatitis C].
PMID- 10756879
TI - [Heart failure due to ischemia--the adaptive mechanisms].
AB - Chronic myocardial ischemia is the leading cause of disturbances in myocardial
contractility (myocardial infarction) or hemodynamic overload upon the left
ventricle. The heart reactions consist in a series of adaptative mechanisms in
order to maintain its pump function: Frank-Starling mechanism, myocardial
hypertrophy and neurohumoral activation. In heart failure, the cardiac output is
maintained by an increase of the preload which enhances the contractility (Frank
Starling law). Myocardial ischemia influences the systolic and diastolic
function. The decrease of cardiac output leads to neurohumoral responses which,
in the initial stages of cardiac failure are compensatory; along with the
progression of the disease, they exert adverse effects. Increased activity of the
sympathetic nervous system induces high cardiac rates, chronotropic incompetence.
Activation of the renin-angiotensin system held to myocardial and vascular
hypertrophy, vasoconstriction, fluid retention. Endothelin is the most powerful
vasoconstrictor; its plasmatic concentrations correlate with the severity of the
disease. Vasodilator mediators released in cardiac failure are the natriuretic
peptide, nitric oxide, dopamine, prostacicline, bradikinin.
PMID- 10756880
TI - [An update on the polysomnographic assessment of sleep-related respiratory
disorders].
AB - The paper presents a review of recent findings in the instrumental assessment of
sleep-related breathing disorders. Basic concepts of definition, classification
and especially medical instrumentation used for polysomnography (PSG) are
introduced. The authors present standard protocols of polygraphic investigation
and solutions to some practical problems, as they appear in literature.
PMID- 10756881
TI - [Stimulation modalities in the study of visual evoked potentials].
AB - An evoked potentials (EPs) is an electrical manifestation of the brain's
reception of and response to an external stimulus. The classification of visual
evoked potentials (VEPs) depend primarily on stimulus characteristics. The visual
content of a stimulus can be divided into two types: patterned and diffuse. VEPs
to patterned stimuli are due mainly to the density of light and dark contrast
borders; VEPs to diffuse light flashes are due to change in luminance only.
Transitions between light and dark pattern elements have sharp borders in
checkerboard patterns and in bar gratings. Those transitions can be represented
by a spatial square wave. In sine wave gratings the change of luminance between
light and dark stripes is gradual. The visual angle describes the size of the
image of one light or dark element. The spatial frequency equals the number of
repetitions of one light plus one dark element.
PMID- 10756882
TI - [Individual pressure tolerance--a "target" pressure?].
AB - In literature there are many meanings for the limit between normal and
pathological intraocular pressure: "normative pressure", "critic pressure",
"individual tolerance pressure" and "target pressure". The aim of this paper is
to demonstrate that these terms are synonymous.
PMID- 10756883
TI - [Oxidative stress and antioxidants in the diet in pathological processes at the
level of the cardiovascular system].
AB - After a short review of the data on the free radicals occurring in the human body
(hydroxyl radical, superoxide, nitric acid, peroxynitrite), the possible effects
of these radical upon the cardiovascular system are presented. The preservation
of the oxidants-antioxidants balance is highly important for preventing the
cardiovascular diseases. Endogenous antioxidants are not 100 per cent effective,
reason why for the individuals with atherosclerosis and ischemic heart disease
antioxidant supplements (tocopherols, carotenes, vitamin C, selenium) are
essential especially during the seasons when diets are deficient in fruits and
vegetables.
PMID- 10756884
TI - [The current aspects of food quality].
AB - Foods may become damaging factors to the human body, both by inadequate intake
(over- and sub-nutrition), and by the accidental presence of biological agents
(bacteria, viruses, parasites), and the toxic chemical substances, which may be
normal compounds of a given product (alkaloids, antivitamins, goitrogen
substances), or may come from food altering (toxic amines, peroxide fat
compounds), may be produced by certain contaminant microorganisms (mycotoxins),
may pollute the food product (toxic metals, pesticides), or may be added
willingly (adjuvants) in higher concentrations than allowed by sanitary
legislation. Changes in of a food's quality, as long as the food may become
improper for consumption, therefore damaging to the consumer's health, is called
alteration. Altering processes are different, according to the chemical
composition of the food product and to the factors that act upon it. National and
international organisms for the safeguard of population's health are permanently
monitoring food quality and give normatives and rules that will be imposed to the
products offered for human consumption.
PMID- 10756885
TI - [Dipsogenic behavior].
AB - Hydroelectrolytic homeostasis assumes balance between the intake and elimination
of water and electrolyte, according to the necessities of the organism. The water
intake is made mainly by fluid ingestion. The necessity to drink is a subjective
sensation which is the expression of an objective situation, because it
translates the homeostatic deviations. The ingestion of water is motivated
(reparatory thirst), when it appears after hydric and electrolytic imbalances
(ex. a decrease of the fluid volume, increase in the plasmatic osmolarity) or is
manifested without an objective reason (unreparatory thirst).
PMID- 10756886
TI - [Multiparticulate systems in the controlled release of active substances in the
gastrointestinal tract].
AB - The design of multiparticulate systems as carriers for molecules that have to be
delivered at specific sites of the gastrointestinal tract must take into account
the common events that govern this region. The intrusion of the multiparticulate
systems has to face, by meanings of synthesis methods, or only by lack of
aggressiveness the host system defences. Thus, non-specific and specific defence
mechanisms are deployed to deal with the intruding material. Several strategies
can be mentioned, as (a) prevent the contact and remove if contacted (b) kill if
not remove, by the micro-fold cells that engulf bacteria and the gastrointestinal
associated lymphoid tissue. A physical barrier that adheres, prevents the
contact, en-traps and removes the foreign matter is the mucus produced by the
goblet cells.
PMID- 10756887
TI - [The causes of gingival overgrowth].
AB - Gingival overgrowth includes a series of diseases with many clinical appearances.
The pathological mechanisms being obscure there were used many terms for defining
it. Thus, "gingival hyperplasia" and "gingival hypertrophy" were the definitions
used to define this pathology. Therefore, the term of "gingival overgrowth"
replaced in last decades the above two terms. This article have the goal of
trying a classification of the entities forming the large family of gingival
overgrowth.
PMID- 10756888
TI - Laparoscopic assisted cholecystostomy.
AB - Laparoscopic assisted cholecystostomy (LAC) is a safe method for external biliary
drainage in jaundiced patients with distal common bile duct obstruction. It
consists of the retrieval of the fundus of the gallbladder through the trocar,
thus through abdominal wall followed by suture to the skin. This technique could
be an option for surgeons who manage a patients with jaundice by distal common
bile duct obstruction.
PMID- 10756889
TI - [Ocular immunopathological characteristics and the involvement of the platelet
aggregation factor and the anti-PAF at the level of the eye].
AB - This lecture tries to systematize the data about PAF (platelet activating factor)
complex implications in the different ocular immune responses, and about the
therapeutical results of PAF antagonists in experimental and clinical
inflammatory conditions.
PMID- 10756890
TI - [The primary prevention of arterial hypertension. A meta-analysis of controlled
clinical studies].
AB - OBJECTIVE: To assess the efficacy of non pharmacological primary prevention of
hypertension. METHODS: Analysis of all the available trials with a minimal one
year follow-up and one recently study with 8 weeks follow-up. The outcomes
consisted in blood pressure changes and incidence of hypertension at the end of
the study. RESULTS: Five reviewed randomized controlled trials with a minimal one
year follow-up and one recently study with eight weeks follow-up assessed the
following intervention: advice about sodium restriction, weight reduction,
physical exercise and relaxation, a diet rich in fruits vegetables and low fat
dairy foods. All the results were available according to the "intention to treat
principle". The feasibility appeared to be initially good, but decreased with
time, confirming the difficulty of long term prevention. The prevention effect
was mild with a decrease in hypertension incidence of a few percent (2%) and
blood pressure decrease of only a few mmHg reduction (mean of 3 mmHg). Three
community studies were reviewed. The prevention interventions were carried out on
entire populations. The feasibility was bad (great number of lost-follow-up). The
results on the blood pressure incidence were available in only one study and the
blood pressure decrease estimates were heterogeneous, so the results cannot be
generalized. CONCLUSION: The primary prevention of hypertension shows
disappointing results when the intervention duration is above one year. It leaves
little hope for a significant effect on blood pressure dependent cardiovascular
events.
PMID- 10756891
TI - How reproducible is diurnal blood pressure rhythm in patients with secondary
(renal) hypertension?
AB - Abnormalities (reduction in/absence of) in diurnal bp rhythm are much more
commonly seen in patients with chronic uremia than in patients with primary
hypertension or in normal subjects. Target-organ damage is greater in these
patients. However, the extent to which these diurnal bp rhythm changes are
consistent or variable is untested. We retrospectively examined 223 ambulatory
blood pressure monitoring (ABPM) traces in 92 patients with chronic uremia who
had undergone ABPM at least twice (mean 2.3 ABPM traces/patient) over the period
1991-1997. ABPM technique and analysis were constant over this period. We found
that for patients with chronic declining renal function but not yet on dialysis
therapy, 67% retained the same diurnal rhythm from one ABPM recording to the
next; if the known tendency for declining renal function to accompanied by a
greater prevalence of "non-dipping" is taken into account, 82% of all patients
had a "predictable" diurnal pattern. 79% of transplant patients, 87% of
haemodialysis patients and 100% of CAPD patients retained the diurnal rhythmicity
from one ABPM session to the next. Non-dipping was much more frequent than
dipping (67% vs 33%). We conclude that abnormalities of diurnal BP rhythm are
reasonably consistent in patients with renal hypertension, especially as renal
function declines and patients enter the renal replacement therapy programme.
PMID- 10756892
TI - [Continuous ambulatory peritoneal dialysis--the infectious complications. The
experience of the Nephrology Clinic of Iasi].
AB - 49 of 57 dialysis patients were included in CAPD programs. The age of these
patients was ranged between 20-65 years. The mean dialysis interval was 19.7
months, the number of hospital admission being 182 (mean 1.7 +/- 1.2). The mean
hospitalization interval was 26.2 +/- 2.0 days. The infectious abdominal wall
complications included: exit site infections (10%), trumel infections (10%),
properitoneal sepsis (21%). The inflammatory processes were resolved after
conservator treatment using antibiotics and antiinflammatory drugs (8%). Catheter
removal was necessary in 2% of cases and the passage to hemodialysis was decided
in other 2%. Peritonitis occurred in 0.73% patients (1 episode per 6 months of
CAPD). These clinical data are better than those reported since now.
PMID- 10756893
TI - Serum lipid picture of rabbits fed on silicate-supplemented atherogenic diet.
AB - Silicon is recognised as a protective trace element in atherosclerosis by
epidemiologic and biochemical studies. The goal of the present work was the
evaluation of the antiatheromatous effect of the natrium silicate in an
experimental trial on 30 rabbits given a standard diet (control), an atherogenic
diet (L1 lot) and a natrium silicate-supplemented atherogenic diet (L2 lot), by
comparing the variation of the lipid pictures between each of the experimental
lots and control. Levels of total lipids, cholesterol, triglycerides (TG), free
fatty acids (FFA) and phospholipids indicated that the natrium silicate
supplemented to the atherogenic diet minimised the lipid metabolism unbalance by
keeping constant the level of FFA and TG in rabbits.
PMID- 10756894
TI - [The interrelations of genital lesions-urinary tract infections in girls].
AB - This investigation was aimed at emphasizing the importance of early detection and
elimination of the favoring factors which associated with an adequate treatment
of urinary tract infection (UTI) represent the only way to prevent the
recurrences that with time might cause severe kidney dysfunctions. It is a
retrospective study of 220 girls aged 1 month to 16 years referred in the
interval 1993-1997 to Iasi Polyclinic No. 1 for pediatric gynecological
examination and diagnosed with urinary tract infection. The clinical and
laboratory evaluations were directed at determining the site of UTI, the factors
that favored the recurrences, and the effects on renal function. The following
favoring factors were found: disorders of the genital tract (22.2%), constipation
(11.6%), oxyuriasis (4.5%), urinary tract obstructions (5.9%). The genital tract
disorders were represented by inflammation (70%) (vaginitis, vulvovaginitis) and
malformations (30%) (labia minora fusion, imperforate hymen, etc). The specific
inflammation (48.5%) was mycotic (41.1%), bacterial (29.3%), the same pathogen
being detected both in urine and vaginal discharge, trichomonal (17.6%), and
gonococcal (11.6%). The high rate of recurrence in some UTI cases has proved once
again the important role played by the favoring factors (genital tract disorders,
urinary tract obstruction, constipation) and suggested that the correction of
these conditions should be the only reasonable way to prevent recurrences.
PMID- 10756895
TI - [The concordance and discordance of cardiovascular risk factors in a group of
twin children].
AB - The cross-sectional study of epidemiological screening type has permitted to
evaluate some cardiovascular risk factors in two groups of monozygotic (MZ) and
dizygotic (DZ) twins born between 1975-1990, in the town of Iasi. In the 89 MZ
pairs and 112 DZ pairs, certain constitutional and behavioural cardiovascular
risk factors have presented values of prevalence with statistical signification
(p < 0.05) in terms of their age, sex, the urbanisation time and the educational
level of their parents. In risk factors existence or absence to both of the twins
have put into evidence, to the MZ, most enhanced values of concordance as
regards: overweight (66.6%), excessive consumption of salt (56.9%), food with
atherogenic risk (50.9%). The concordance values have been less in DZ compared to
MZ concerning all the risk factors excepting compartmental type A (77.7%). By
analysing the concordance variants, an preponderant influence of the environment
has been noted in the studied MZ and heredity and environment influence in DZ. By
measuring the arterial blood pressure values at the twins and the twins parents,
a prevalence of the essential arterial hypertension is noticed to both of the
twins, 6.2% in MZ pairs and 6.9% in DZ ones.
PMID- 10756896
TI - [Epidemiological observations on the physical activities of patients with
arterial hypertension].
AB - The authors point out the results of some multidisciplinary epidemiological
researches concerning the relation between the multifactorial etiology of
arterial hypertension (AHT) in employers working in two factories and the nature
of physical activity. The results show that the highest percentage of AHT cases
is in the persons which do not have physical activity (occupational, housing or
leisure). The women with AHT, which are frequently supra-ponderously, make a low
level of physical activity. They have effort respiratory modifications in 40% of
cases. The decreasing interest for control and prevention of health risks of the
level of occupational health services has medical and social negative effects on
long term.
PMID- 10756897
TI - [The dynamics of exposure to silicotic dusts and silicosis in a foundry].
AB - This work presents the concentrations dynamics of dust in a cast iron foundry, in
parallel with the frequency and gravity dynamics of the getting sick of
silicosis. The knowing of the real risk of exposure to silicotic dust was
possible through the data processing concerning the dusting degree (the average
of working place), the content of silicon free-crystalline dioxide (SiO2 l.c.)
for the calculation of the maximum admitted concentration (C.M.A.) and the
dispersion degree of dust in a cast iron and steel foundry for the studied period
(1982-1996). New cases of silicosis appeared in this period were studied and they
were colligated with the age at declaration, the average length of service and
the profession. The values of the dusting degree outrun the C.M.A. up to 168
times, especially at the preparation of mixture and grinding with a prevalence of
particles under 3 micron (40-70%) and the Si02 l.c. content varies between 35.2%
and 64.5%. From those 98 new cases of silicosis appeared in 15 years, 82.65% were
traced out in the incipient phases of the disease. The average age in service and
the average age increase (43.1 respective 19.8 years). The coefficients of
correlation and regress (+0.286 respective +0.383) show a good correlation
between the silicosis number and the age in service. The advanced stages of
silicosis and age in service under 10 years were found at the foundry-workers and
formators, occupations which imply a high silicotic risk. The foretelling
calculations for the next 20 years show an increase of the silicosis incidence
for foundry-workers.
PMID- 10756898
TI - [Idiopathic thrombocytopenic purpura in infants and small children (1 to 3 years
old)].
AB - In infant and young children (1-3 yrs), I.T.P. (idiopathic thrombocytopenic
purpura) is an acute, self-limited disease in 6 months since the diagnosis. The
treatment with intravenous immunoglobulins or corticosteroids will be
administered in severe forms of disease(predicted by the severity of hemorrhage
and thrombocytes less than 10 G./l). A retrospective study of 29 cases with
I.T.P. in infants and young children shows that 22 out of 29 were acute I.T.P., 7
out of 29 were recurrent I.T.P., in which 3 cases were chronic I.T.P. Post
hemorrhage associated anemia was present in 10 out of 29 cases, in which 3 cases
was severe. Prolonged bleeding time appears only in severe I.T.P. Values of
thrombocytes less than 10 G/l were met in 6 cases of acute I.T.P. and in 3 cases
with recurrent I.T.P., there was no predictable correlation between the very low
value in the time of diagnosis and the following clinical course of the disease.
Neonatal I.T.P. (history of maternal I.T.P) had a favourable clinical course
after i.v. immunoglobulins treatment (1 case) and a trend to chronicity (1 case)
probably due to platelet antiphospholipid antibodies. Postvaccinal I.T.P. is a
rare and benign complication. Only 5 of 29 cases had spontaneous remission. The
clinical course was towards complete remission in 22 out of 29 cases with i.v.
immunoglobulins and/or corticosteroid therapy. In conclusion, view the natural
history of disease and the unvariables responses to treatment, spontaneous
bleeding cannot be predicted only by platelet count in I.T.P.-Infant-low age (1-3
yrs).
PMID- 10756899
TI - [Operational models in the histopathological examination of liver puncture
biopsies].
AB - The main goal of this paper is to give an overview of the personal experience in
the investigation of the hepatic biopsy. There were analyzed liver specimens from
26 children hospitalized in Clinical Hospital "Sf. Maria" Iasi. The first clinic
diagnosis was post-viral chronic hepatitis and most of the cases provided the
serologic markers. Histopathological exam revealed 2 cases of active chronic
hepatitis and 24 cases of persistent chronic hepatitis. The interpretation of the
lesions relied on Ludwig and Metavir scoring systems. The significance of these
scores is very important because they allow one to identify the grading of the
necro-inflammatory/histological activity and the staging of fibrosis. Thus, the
result of these scoring systems make it possible to classify the cases into
aggressivity based forms, indicate the therapy approach and estimate the
prognosis as well as the clinical course.
PMID- 10756900
TI - [An immunohistochemical study of the steroid hormone receptors in endometrial
hyperplasia].
AB - AIM: Evaluation of the estrogen and progesterone receptors (ER and PR) in
different degrees of endometrial hyperplasias. METHODS: 10 cases of each degree
of endometrial hyperplasia (simple, complex and atypical) were analyzed using the
avidin-biotin-peroxidase technique and monoclonal antibodies applied to formalin
fixed, paraffin-embedded tissue. RESULTS: We found similar, high level of both ER
and PR in simple and complex hyperplasias and a significant decrease of these in
atypical hyperplasia. CONCLUSIONS: Endometrial hyperplasias develop in a setting
of estrogen excess. This explains the high level of endometrial receptors and the
response to progesterone in typical hyperplasia. In atypical hyperplasia, the
decrease of steroid receptors results in a low sensibility of this lesion to
progestative therapy, but there are cases with high receptor levels which could
have a chance for hormonal therapy.
PMID- 10756901
TI - [Treatment results in aseptic necrosis of the femur head].
AB - Between 1.01.1987 and 31.12.1997, 40 patients (52 hips) were diagnosed with
avascular necrosis of the femoral head (ANFH) and treated in the Emergencies
Hospital of Iasi. ANFH was detected by clinical findings, plain radiographs and
computed tomographic scans. We used the classification of Ficat and Arlet and the
choice of treatment between core decompression (20 hips), flexion osteotomy (10),
rotation osteotomy (4) or total hip arthroplasty (18) was determined by the stage
and location of the area of necrosis. Core decompression has been attempted in
patients with Ficat stages I and II, trochanteric osteotomy has been used in
Ficat stages II and III, and in the most advanced stages of necrosis (Ficat stage
III and stage IV) total hip arthroplasty was the procedure of choice. We reviewed
the patients at 3, 6 and 12 months after the surgery. The results were evaluated
using Merle D'Aubigne score. We noted good and very good results in 75% of our
patients which were diagnosed in the early stages of necrosis. We concluded that
the earlier diagnostic and the correct indication of treatment (determined by the
stage of necrosis) are the premise for the amelioration of the severe prognostic
of ANFH.
PMID- 10756902
TI - [Adenocarcinoma in Barrett esophagus: its recurrence and long-term survival].
AB - Adenocarcinoma arising in ectopic gastric mucosa has been reported more than 40
years ago. This report reviews our experience with Barrett's adenocarcinoma over
8 years. The definition remains subject to controversy. More than 50% of patients
in our study had unfavorable course of disease. The hope for cure lies almost in
early detection of tumors at which point a truly curative resection could be
done. There is no difference in terms of survival comparing to the adenocarcinoma
arising on normal esophagus.
PMID- 10756903
TI - [Klatskin's tumor].
AB - During the period 1989-1998, 27 patients with primary proximal bile duct cancer
were treated (17 females and 10 males with a mean age of 61 years). The main
presenting symptoms were: jaundice (96.2%), itching (92.5%), weight loss (74%)
and atypical pain (33.3%). All the patients underwent ultrasound (US)
examination, 7 patients endoscopic retrograde cholangiopancreatography (ERCP) and
4 patients computed tomography (CT) examination. US examination revealed the
tumor in 51% cases; most frequently a dilatation of the intrahepatic bile ducts
was diagnosed with all methods. 8 patients underwent resection of the tumor and
one a biliary-enteric anastomosis, in 15 cases a stent was inserted. In 3 cases
the extension of the malignancy did not allowed any procedure. Three patients
died during immediate postoperative period (mortality 11.2%). The mean survival
was 13 months after stenting and 22 months after resection of the tumor. The
authors recommended an aggressive surgical therapy for Klatskin tumors.
PMID- 10756904
TI - [Cancer of the cervical stump].
AB - Subtotal hysterectomy may represent, in specific conditions, a justified
alternative to total hysterectomy. Some of the reasons may be vaginal stenosis,
preservation of the menstrual function, conservation of the erogene cervical
zone. The main disadvantage consists in developing cancer on the cervical stump.
In order to reduce the risk of developing cervical carcinoma, total hysterectomy
remains the procedure of choice for most women. Our study presents 16 cases with
carcinoma of the cervical stump after subtotal hysterectomy from the lot of 313
cases with cervical neoplasms operated on at the Division of Gynecologic Oncology
of the 4th Clinic of Obstetrics and Gynecology in Iasi. The main conclusion of
this study is illustrated by the firm conviction of the authors that subtotal
hysterectomy is an unjustified surgical procedure in women after 40 years old.
PMID- 10756905
TI - [Whole-body bone scintigraphy in the diagnosis and follow-up of the evolution of
breast cancer].
AB - We have studied 75 patients, diagnosed with breast cancer, (39 on the right, 36
on the left and 4 on the two breasts), the TNM classification being: stage I-
13.3%, stage II--36%, stage III--40% and stage IV--10.6%. Each patient has
undergone a whole body scan, 2 hours after a 20-25 mCi 99mTc MDP i.v. dose, using
a Siemens Diacam gamma camera. Three parameters where assessed: 1) the
distribution of multiple metastasis bone sites; 2) an index, the counts/pixel
ratio between the metastatic site interest region and a homologous normal bone
interest region (IMDP); 3) a graphic representation of the metastasis
heterogeneity radiotracer uptake. RESULTS: Bone metastasis have been found in 23
patients (30.6%), 16 cases having multiple sites; the rate between right and left
breast cancer, for these metastases, was 13:10, according with the previous
mentioned breast frequency. From all the 23 cases, the most involved site was the
ribs (18 cases), followed by the spine (in 17 cases), the iliac bone (9 cases),
the femur (7 cases), the skull (3 cases). On the spine, the more frequent
involved was the dorsal spine (49.23%), than the lumbosacral (26.13%) and last
the cervical spine (12.3%). On the dorsal vertebrae, in 91% the metastasis were
localized between D8 and D12. The highest values of I-MDP characterize the
femoral metastasis. The heterogeneity was high only for the vertebrae multiple
sites. In conclusion, our study show pattern characteristics on the distribution
and also on the uptake radiotracer bone metastasis quantification in breast
cancer, in respect with others neoplasm's bone metastasis.
PMID- 10756906
TI - [Weibull regression in the analysis of the aging phenomenon of biological
systems].
AB - The processing battery represented by standard regressions is totally
insufficient for the primary regression analysis of biomedical observation data.
Using only this processing system, it is possible to loose a significant amount
of information and especially to obtain false conclusions, seeming to be
"statistical justified". This conclusion is sustained by the results obtained in
this paper on 8 samples. In this paper it was created a calculation algorithm
that allows the automatic, simultaneous effectuation of 16 types of regression,
obtained by change of variable. This algorithm finally orders these regressions
according to the values of correlation coefficient and emphasizes the regression
type that mathematically fits the best the observed data. The choice of the
optimal regression type depends basically by the fact that the results supplied
by that regression corresponds with the biological characteristics of the studied
phenomena. In the specific case of optical nerve, in all the 8 samples and sub
samples analyzed, the regression that supplied the higher correlation
coefficients was the Weibull model, with exponent variable as a function of time.
PMID- 10756907
TI - Genetic algorithm in the control optimization.
AB - Genetic algorithm (GA) represents an exploratory search mathematical technique,
which uses statistical methods of selection. They are named blind search
technique as they usually operate without knowledge of the task domain. GA is
inspired from the evolutionary features of biological systems. The natural
individual selection of offspring that are better adapted will resist in time
(3). The pioneer worker in this field was John Holland and the University of
Michigan staff from 1975. The beginning study was in natural adaptive process
explanation and continues with computed artificial systems developing that
exploit the evolution natural principles. A GA technique was applied for a
controller parameter optimization that regulates the mean blood pressure. The
intelligent system adjusts the anesthetic agent in order to maintain the pressure
constant with small variations from a desired set value. This is usually
necessary for anesthesia control (mathematical model from 11, 12). Such a system
was developed and tested using computer simulations. This paper describes some
aspects about the GA mathematical method and finally the results of the
controller implementation are presented.
PMID- 10756908
TI - Tetrazolium salts and metal complexes of some formazans.
AB - This paper presents the synthesis of some tetrazolium salts and metal complexes
combinations, which are derived from aromatic and heterocyclic formazans.
Elemental quantitative analyses and spectral data confirmed the structure of the
new synthesized compounds. The new synthesized compounds were submitted to
microbiological tests.
PMID- 10756909
TI - [The reaction of 3-(R-phenyl)-6-hydrazine pyridazines with substituted isatins
(II)].
AB - This paper presents the synthesis of six hydrazones from isatin and 1
morpholinomethyl-isatin and also of their six cooper's complex salts. Their
structure was confirmed by the results of the quantitative elemental analysis and
by IR, UV-VIS spectral analysis. The biological tests point out that cooper's
complex salt of 3-(3'-phenyl-pyridazinylhydrazono)-5-methyl-indoline-2-one (1:2)
(VI a) has the smallest toxicity (DMT over 800 mg/kg.w. p.o.), a remarkable anti
inflammatory activity (inhibition 57.1%, IAR 1.1) and also a gastroprotector
coefficient of 43.3%. In the mean time, the cooper's complex salt of 3-(3'-p
anisyl-pyridazinyl-hydrazono)-5-methyl-ind oline-2-one (1:2) (VI b) has a
gastroprotector coefficient of 76.3% and a lower anti-inflammatory activity than
the first derivative (inhibition 36.9%).
PMID- 10756910
TI - [Ion-selective electrodes with a liquid membrane for determining N
butylscopolammonium bromide].
AB - Two ion-selective electrodes with liquid membrane for N-butylscopolamonium
bromide are described, with N-butylscopolamonium tetraphenylborate (I) and N
butylscopolamonium reineckate (II), respectively, solved in benzylic alcohol as
electroactive material. These electrodes have a linear response in the
concentration range of 10(-2)-10(-6) M N-butylscopolamonium bromide, with the
detection limit of 10(-7) M for both electrodes. These electrodes were used with
good results for quantitative assay by direct potentiometry of injectable
solutions of N-butylscopolamonium bromide.
PMID- 10756911
TI - [The terminal occlusal contacts of the edentulous patient with a complete
denture].
AB - For the last few decades our knowledge concerning the occlusion have developed a
lot, because of the many clinical, morphological and functional implications of
the occlusion. In the study of the terminal occlusion, it is considered to be of
functional importance the closing trajectory of the mandible in centric relation
and the closing trajectory of the mandible in maximal occlusion. The purpose of
this research is to analyse the terminal occlusion of the complete denture
patients, emphasize the link between occlusion disharmony and instability of the
complete denture. Complementary exam used is the computerized T-scan system
connected a compatible IBM computer. The study included 17 to subjects (11 males
and 6 females), with an age over-age of 63 years. When completing this study the
authors were able to classify four types of occlusal contacts.
PMID- 10756912
TI - [The treatment of segmental fractures of the middle face].
AB - During the past two decades new methods and techniques for the treatment of
middle floor facial fractures have been developed. The orthopedic approach alone
or associated with various procedures of internal suspension gradually became
obsolete. Nowadays, a successful treatment implies the early surgical exploration
and a careful restoration of bone skeletal structure. Osteosynthesis with mini
plates provides for the reduction and tridimensional stability of bone fragments.
Moreover, in the communicative fractures and in those accompanied by substance
loss, the titanium mini-plates are the best method for the immediate fixation of
bone grafts.
PMID- 10756913
TI - Esthetic principles in prosthetic dentistry.
AB - Dento-facial esthetics represents today the fourth clinical dimension in our
activity. Together with morphological, functional and biomechanical factors,
aesthetics contribute to a successful clinical result in prosthodontics. Dento
facial esthetics takes over the visual perception principles adapting them to
dental requirements. Continuously assimilating esthetics information, being a
good observer and training visual perception is important for the final complete
result in prosthetic dentistry.
PMID- 10756914
TI - [The correlations between the electromyographic display and the aspects involved
with masticatory muscle contraction and phosphorus-calcium metabolism].
AB - The neuromuscular activity at the level of the stomatognathic system has a
specific complexity, due to the multiple systemic functions, realizing the
statistical and dynamical mandibular positions and the integration of the
stomatognathic system at the level of the human body. Knowing that the
neuroendocrine system represents an important factor for the over-systemic
coordination of the stomatognathic muscular activity, we want to establish the
implication and the neuroendocrine correlation in the stomatognathic muscular
dysfunctions determined by some endocrine diseases.
PMID- 10756915
TI - [The special problems of occupational guidance].
AB - The professional guidance for the motor deficient child is a very important
problem due to the fact that our decision will influence the life of the
individual from here on. The aspect that must be taken into account when we
discuss about professional guidance is the coordination of the movements. Our
study is based on 151 school girls with neurologic deficiencies and is focus on
the job that the children are trained for. A series of tests were used in order
to asses the motricity of the girls. The results obtained showed that many
children have been improper orientated, the jobs that they are trained for
demanding more physical abilities. In order to improve the social status of the
motor deficient person we must choose a profession that will use all his
abilities but will not require skills affected by the deficiency.
PMID- 10756917
TI - [In Process Citation]
PMID- 10756916
TI - Laminoplasty--the surgical treatment of the cervical spondylotic radiculopathy.
AB - The present surgical treatment of the cervical spondylotic myelopathy and
radiculopathy consist in cervical laminoplasty. The cervical laminoplasty has
many variants since it was first proposed in the 1968's. It is presented a
variant simplified of the Hirabayashi's technique of laminoplasty, used to the
patients with unilateral cervical radiculopathy and it is proposed a technique of
"bilateral laminoplasty" using iliac bone graft stabilized with transfixed wire.
This technique is simple and permits a bilateral nerve roots decompression.
PMID- 10756918
TI - Past and present in Romanian pathophysiology teaching: Iasi experience.
AB - Discipline of Pathophysiology is now a division of the University of Medicine and
Pharmacy of Ia,si and it is included as a separate discipline for the third-year
undergraduate students. Changes have occurred in the curricula of different
disciplines that have progressively weakened the position of pathophysiology. The
medical system is the most affected because the basic course in pathophysiology
for undergraduate students is not completely satisfactory. A recent questionnaire
is illustrative in the concern of pathophysiology both as a science and as a
medical discipline. A coherent educational system regarding pathophysiology
should include a basic course in pathophysiology, lectures and stages of clinical
pathophysiology and postgraduate courses in different medical domains as well,
all to take place in an integrated department of experimental and clinical
pathophysiology.
PMID- 10756919
TI - [The factors of German influence on Romanian medical culture].
AB - The Romanian school of medicine and pharmacy was under the influence of the
Vienna and German schools from its very beginning. This influence was exercised
throughout the medium of the German language on Romanian culture in general and
on medical culture in particular in three main respects: 1) scholars from Germany
and from Austria (particularly from Transylvania, which was incorporated in the
Austro-Hungarian Empire at that time) were invited first to the rulers' courts
and then to the Moldavian and Walachian university chaire, 2) young people from
Iasi, from Bucharest and from the Transylvanian cities were sent to study in
Vienna and in German universities and 3) manuals and specialized works translated
from German into Romanian.
PMID- 10756920
TI - [The structure of the medical and pharmaceutical terminology in the Romanian
language].
AB - When we analyse diachronically the Romanian medical and pharmaceutical
terminology, we can say that it represents a lexical ensemble characterized by
heterogeneousness. It has its own dynamics due to the specific character of the
terms. New lexical elements have been added permanently in the twentieth century
to the corpus of medical terms established in the last century. Another
characteristic of the medical terminology in our century is its international
tendency. The great number of international words--among which those of Latin,
Greek and, more recent, English origin--make it easier to decode the message for
the specialists speaking different languages. The great number of words of this
type emphasize the scholarly, artificial character of the vocabulary. A well
represented class, from the point of view of its number, are the neologism of
Latin-Romantic origin, terms that have been adapted phonetically and
morphologically to the system of the Romanian language. The linguistic facts we
find in the specialty texts (in the XIX and XX centuries) confirm our belief
that, as a whole, the medical terminology is a linguistic field in a continuous
process of modeling, and mainly that is open to be renewed.
PMID- 10756921
TI - [The skin substitute center--a need in the treatment of patients with severe
burns].
AB - The treatment of the severe burned patient has two main dimensions acting in an
interdependent manner. First it is the life keeping and the second is skin
resurfacing in a fair period of time. The failure of one of these two components
leads to the patient's death. In the absence of the autografts the skin
resurfacing has to be made by permanent skin substitutes--cultured epithelium,
dermal equivalents or reconstructed skin, developed by a special unit, a Skin
Substitute Center. The paper is setting the utility of such a center in our area,
and the possible developing directions. It is our firm opinion that in case of
failure to develop such a center, despite all the financial efforts directed
toward the infrastructure of a modern Burn Unit affiliated to an University
Accident Hospital, all the surgical experience cumulated during the past 13 years
by a very motivated team, good quality results are still to be expected. Any
patient with a deep second degree burn on more than 50% TBSA will be a
potentially victim as in early 60s.
PMID- 10756922
TI - [Current data on the extrarenal renin-angiotensin system].
AB - After a brief historical incursion regarding SRA of renal origin we present the
main extrarenal angiotensin-forming enzymes, starting with isorenin, tonin,
cathepsin D si G and ending with the conversion enzyme and chymase. This is
followed by a short presentation of data concerning tissue SRA in the heart and
vessels, brain and neurocranial accessory glands, cortico-suprarenalian and
gonadal glandular territory. In the end we refer to the relations between
circulating SRA of renal origin and the tissue extrarenal one, underlying the
fact that the two SRA components cooperate and constitute a unitary hormonal
system, towards the regulation of the major functions of the organism and the
maintenance of the main homeostatic equilibria. While the circulating SRA of
renal origin is acutely activated to contribute to the accomplishment of short
term homeostatic reactions, tissue SRA, in paracrine or autocrine ways, exerts
loco-regional adaptive actions of long duration.
PMID- 10756923
TI - [Chaperone proteins--essential proteins for cellular activity].
AB - Molecular chaperones are an ubiquitous, abundant and highly conserved group of
proteins which bind and stabilize proteins at intermediate stages of folding,
assembly, translocation across membranes and degradation. They first came to
attention because of their specific induction during the cellular response of all
organisms to heat shock, but are now known to be constitutively and abundantly
expressed in the absence of any stress. Despite the obvious importance of stress
responses, only recently has scrutiny focused on the role of heat shock proteins
in the control of disease pathology. Knowledge about Hsp functions in bacteria is
much further advanced than in eukaryotes, but already some hints of Hsp
involvement in mammalian diseases have emerged.
PMID- 10756924
TI - Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs, and
gastroduodenal pathology: current status.
AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are now widely used medicines and
their relationship with gastroduodenal injury is well established. The overall
risk for serious gastrointestinal side effects in patients taking NSAIDs is three
times greater than that of control groups and this risk rises to more than five
times in elderly patients. Moreover, the risk of gastrointestinal surgery is ten
times greater in elderly patients taking NSAIDs than in controls. Therapeutic
aspects like the necessity of eradication of Helicobacter pylori (H. pylori) in
order to reduce the gastroduodenal risks for NSAIDs users, the indication for
eradication of H.pylori of those with past history of peptic ulcer and require
NSAID therapy, the role of eradication when the NSAIDs are used in association
with misoprostol.
PMID- 10756925
TI - [The cardiovascular significance of nitric oxide].
AB - Nitric oxide (NO) synthesized from L-arginine is a ubiquitous intercellular
chemical messenger involved in signal transduction in diverse mammalian cells.
The isolation of molecular clones for NO synthases has permitted the
characterization of several distinct enzyme isoforms. NO synthesized in vascular
endothelial cells plays an important role in the control of vascular tonus and
platelet aggregation, through the activation of guanylate-cyclase activity in
target tissues mediated by NO. Nitric oxide which is produced by cytokine
activated mononuclear cells plays an important role in inflammation and immunity
as a cytotoxic effector molecule and as a transducer molecule in immune cells and
in oxidative stress as a potential source of intracellular free radicals. An
increase in reactive oxygen species can produce damage to lipids, proteins and
DNA and induce necrosis or apoptosis. The implication of NO in different
pathological processes, such as atherosclerosis, diabetes, ischaemia and
reperfusion, or during inflammatory processes and the generation of free radicals
contributing to the endothelial injury associated to these processes.
PMID- 10756926
TI - [The significance of desmosomes in pathology].
AB - Considerable progress has been made in our knowledge of desmosomes and their
components. Molecular cloning of the desmosomal glycoproteins has established
that desmoglein 1 and desmoglein 3 are targets for autoantibodies in the
blistering diseases pemphigus foliaceus and pemphigus vulgaris respectively. New
evidence suggests that another desmosomal glycoprotein, desmocollin 1, is the
major target antigen in the upper epidermal form of intercellular IgA dermatosis.
In human cancer there is accumulating evidence which suggests a role for
desmosomes in the prevention of the invasion and metastasis. The possibility
exists that a mutation in a desmosomal glycoprotein gene is responsible for an
inheritable human disease, the striated form of palmoplantar keratoderma.
PMID- 10756927
TI - [Nutrition and old age].
AB - The cellular and extracellular degenerative changes that take place simultaneous
with aging in elderly will determine changes in the life style. In order to reach
the ideal age, the elderly must have a balanced diet, sufficient physical
activity and to quit smoking and drinking. In addition to this requirements, the
society must provide the economic means, that will allow the elderly a decent
life, and free access to medical services.
PMID- 10756928
TI - [Glucose metabolic changes in stress].
AB - Provision of a better understanding of the pathogenic pathways underlying injured
sugar metabolism during stress should ideally translate into a more rational
approach to the provision of nutritional support. Patients with burns, trauma,
severe injuries or infections commonly develop a hypermetabolic state that is
associated with several changes in carbohydrate metabolism. The hypermetabolic
state is induced either by the area of injury and by organs involved in the
immunologic response to stress; further it determines a glycemic milieu which
will be directed toward satisfaction of the requirements for glucose as an energy
support.
PMID- 10756929
TI - [Vanadium derivatives--a new source of antidiabetic drugs].
AB - Vanadium, a transitional element belonging to Vb group is wide-spread both in
vegetal and animal world. Although known by more a hundred years ago only in 1985
its hypoglycaemic properties were established. Recent research shown that the
hypoglycaemic properties and the toxicity are influenced both by vanadium valence
state and organic moiety that is binding it.
PMID- 10756930
TI - [Periodontitis, a risk factor for cardiovascular diseases?].
AB - Exist a statistically significant association between a diagnosis of coronary
heart disease and certain oral health parameters. These parameters are
independent and more strongly associated with coronary heart disease than were
recognized risk factors, such as serum cholesterol levels, body mass index,
diabetes and smoking status. The correlation between serum and salivary
cholesterol concentration and the role of salivary lipids in oral health have
been poorly characterized. Lipids in saliva are mostly glandular in origin,
through some may diffuse diffuse directly from the serum. The surface of the
enamel (in case of dietary fat which have an cariostatic effect) is protected
against demineralization by a mixture of salivary lipids and proteins. Salivary
lipids may have anucleating role in the early mineralization of the dental
plaque. The prevalence of periodontal disease may be increased in patients with
atherosclerosis, and dental and periodontal infections have been shown to be
associated with occurrence of acute and chronic coronary heart disease. Among the
known risk factors of atherosclerosis, high serum lipid levels, especially
cholesterol may be important with regard to periodontal health.
PMID- 10756931
TI - [The laboratory diagnosis of tuberculosis].
AB - The resurgence of tuberculosis and the increasing prevalence of multiple
resistant Mycobacterium tuberculosis strains are the reasons for the need of a
rapid diagnosis of this infection. The article provides information about
traditional and new methods in the laboratory diagnosis of tuberculosis,
comparing their efficacy and rapidity.
PMID- 10756932
TI - [Urticaria in children--the current etiopathogenetic and clinico-therapeutic
aspects].
AB - The authors present actualized data regarding urticaria, which is frequently
encountered in children. The first part presents the etiology, pathogenesis and
pathological aspects of urticaria. Next, are discussed clinical and paraclinical
data, useful for the diagnosis. An important step in the diagnosis work-up is to
establish the etiology. A large space is dedicated to the therapeutical aspects,
insisting upon the superiority (the advantages, the efficacy) of last generation
antihistaminic drugs.
PMID- 10756933
TI - [The morphofunctional characteristics of cardiac involvement in arterial
hypertension in children].
AB - The aim of the study was to investigate the main morphofunctional aspects of the
cardiac involvement in systemic hypertension in child. METHODS: 48 children with
aged ranging between 2 months-18 years, diagnosed with systemic hypertension
(SH), were followed up more than 1 year (with treatment) and investigated by
clinical examination and noninvasive methods. The etiology of SH was: * secondary
SH (40 cases): acute (8) and chronic nephropathy (20), 13 cases being dialysed;
coarctation of aorta (10) and pheochromocytoma (2 cases) and * essential SH (8
cases): "borderline" type and also confirmed. RESULTS: The echocardiographic
findings had a superior sensibility to ECG and chest X-ray findings, concerning
cardiac involvement in SH, especially in the secondary forms, with high values of
systolic and/or diastolic blood pressure and with a long period of evolution:
hypertrophy of the left ventricle (LV) (31 cases = 65%) with septal predominance
(10); * alteration of diastolic function of LV (11), but with normal systolic
function of LV (all the cases). These changes have not been observed in acute
nephropathy or they were unsignificant in essential SH. Repeated echocardiography
after minimum 6 months proved a varied regression of hypertrophy of LV and
improved diastolic function of LV in children who received antihypertensive
therapy, including spironolactone and/or angiotensin converting enzyme
inhibitors. CONCLUSION: Because such cardiac involvement are important and of
greater risk factor for the hypertensive patients, the early diagnosis by
echocardiography, the follow up of the evolution and the diminish of cardiac
disorders by the treatment mentioned above, may improve the prognosis of the
disease.
PMID- 10756934
TI - [The assessment of the exertion capacity of patients with ischemic heart
failure].
AB - Functional capacity is reduced in heart failure; this lowering is not directly
related to the severity of the disease. The intensity of the impairment of
exercise capacity is an independent prognostic factor, together with the severity
of left ventricular disfunction and the degree of neurohormonal activation. That
is the reason why the assessment of a patient with heart failure must include
also the determination of exercise capacity by exercise testing. The cardio
pulmonary testing remains "the gold standard"; if this is not available, the
testing at the ergometric bicycle and the 6 minutes walk test offer valuable
information concerning functional capacity in heart failure.
PMID- 10756935
TI - [The hemorrhagic duodenal ulcer: our experience in its diagnosis and treatment].
AB - AIM OF THE PAPER: To present our experience in the diagnosis and treatment of
hemorrhagic duodenal ulcer. MATERIAL AND METHOD: Retrospective study of 80
patients who underwent surgery in our clinic during the past 5 years. Patient's
age ranged between 19 and 76 years, the condition being most common during the
IVth and Vth decades of life. There were 61 males and 19 female, 49 of them
residing in urban areas. In 23 cases the patients presented with an acute
hemorrhagic ulcer and in 57 cases with a chronic form. Hemorrhage was by
hematemesis (30 cases), melena (36 cases) and hematemesis and melena (14 cases).
According to the severity of hemorrhage we found: hemorrhagic shock grade I (mild
hemorrhage) in 16 cases, grade II (moderate hemorrhage) in 19 cases, grade III
(severe hemorrhage) in 33 cases, grade IV (very severe) in 11 cases and grade V
(cataclysmic) in 1 case. Radiological and endoscopic examinations made the
diagnosis in 78 and 95% of the cases, respectively. Treatment was surgical in all
cases. The patients were operated in emergency, within the first 24 hours (14
cases), or delayed emergency, after 4-7 days (66 cases). Two surgical procedures
were performed: truncal vagotomy with ulcer excision/suture and Heineke-Mikulicz
pyloroplasty in 46 cases, and truncal vagotomy with antrectomy and Pean
anastomosis in 34 cases. RESULTS: Postoperative course was favorable in 76 cases,
complications causing death being recorded in 4 cases. CONCLUSIONS: Hemorrhagic
gastroduodenal ulcer is a surgical emergency requiring an adequate diagnostic and
therapeutic approach. According to our statistics, in most cases the treatment is
surgical.
PMID- 10756936
TI - [A retrospective study of 83 patients hospitalized for a jaundice syndrome in the
Surgical Clinic of Timisoara Municipal Hospital].
AB - This is a retrospective study done on 83 patients admitted to surgical department
of Timisoara Emergency Hospital in the period between 01/01/1992 and 31/03/1995;
47 patients were males, 36 females with mean age 56.1 years. All patients
suffered from jaundice mainly conjugated hyperbilirubinemia. The causes of
jaundice were: malignant tumours in 19 (22.9%), chronic diffuse parenchymatous
liver disease in 24, stone common bile duct 22, benign biliary strictures and
papillary stenosis in 6, extrinsic biliary compression and inflammation in 12.
Surgery was done in 47 patients and medical treatment in 36 patients. During
hospitalization, complications occurred in 19 patients. The condition of patients
at discharge was considered: cured in 30, improved in 38, stationary in 2 and
deteriorated in 12. Mortality occurred in one patient.
PMID- 10756937
TI - [The technic for the reoptimization of laryngeal cannulae by recoating them with
a silicone material].
AB - In the laryngeal surgical pathology area, the application of a cannula with
temporary or long term indications is necessary for ensuring the respiratory
function troubled by various causes (inflammatory, tumor or traumatic) that
obstruction the respiratory tract. The most frequently used standard cannula is
rigid and does not show proper adaptation for every clinical situation, thus
leading to local troubles. In this paper, the realization technique of a
rigid/flexible and individual cannula applied after the tracheotomy is presented.
In order to carry out the cannula, a rigid material is utilized (acrylic resin)
for maintaining the shape and dimensions of the laryngeal stoma. It is also
utilized an elastically material (acrylic resin with a retard plug--Simpa) that
ensures the optimal adaptation, tight close and tissue protection around the
stoma. In co-operation with the ORL Clinic--Recuperation Hospital, these cannulae
were applied to fifteen patients pursuing their evolution in time.
PMID- 10756938
TI - Direct evaluation of erythrocyte aggregability in human, sheep and cow blood
samples with a computerized image analysis.
AB - The non-Newtonian properties of blood are caused by the unique properties of red
blood cells to aggregate and to deform. Aggregation mechanism of erythrocytes
contributes significantly to blood viscosity. Techniques for the assessment of
red cell aggregability have major implications for medical practice. A number of
techniques based on various principles have been proposed by many researches.
However, as yet, none of these techniques have been applied on a wide basis. The
aim of the present paper is to determine red cell aggregability in sheep, cow and
human blood samples. The red cells remain in the their natural environment (their
own blood plasma). First, we had to transform an IBM-PC computer into an Image
Acquisition System, so we designed a frame-grabber and the soft driver necessary
to assure the image acquisition taken by the TV camera by means of the
microscope. These images are digitized, transformed in a standard format BMP and
can be compressed and stored or processed. The entire system software is written
in C++ assembly language. To evaluate the aggregability index in the blood sample
was determined the total area occupied by all automatically detected erythrocytes
(Stot) and the overall area occupied by the aggregated erythrocytes (Saggreg). .
EAI = (Saggreg/Stot) x 100%; EAI shows the tendency of red blood cell to form
aggregates.
PMID- 10756939
TI - [p53 and steroid receptors support double endometrial carcinogenesis].
AB - AIM: This study investigated the p53 positivity correlated with the receptor
status, in different grades and stages of endometrial carcinoma. METHODS: The
study included 88 endometrioid-type carcinomas and 5 non-endometrioid-type
carcinomas. Paraffin sections were used for the ordinary histological diagnosis
and for immunohistochemical diagnosis by avidin-biotin-peroxidase technique.
RESULTS: p53 positivity was identified in 10 endometrioid-type carcinomas (11.4%)
and 3 non-endometrioid type carcinomas (60%). Most of the p53 positive cases were
receptor negative and observed in advanced stages and histological grades. No
associated endometrial hyperplasia was p53 positive, while a positive
intraepithelial non-endometrioid carcinoma was identified. CONCLUSIONS: p53
positivity is most frequently identified in non-endometrioid type, receptor
negative adenocarcinomas, even in a precursor lesion as it is intraepithelial
carcinoma, while in endometrioid, receptor positive carcinomas it appear in late
stages of development, never being identified in precursor lesions.
PMID- 10756940
TI - [The evaluation of noninvasive samples for detecting anti-cytomegalovirus IgG
antibodies].
AB - Patients admitted in dialysis centers are at greatest risk to achieve blood-borne
infections. One of the most frequent is the cytomegalovirus infection, acquired
from transfused blood products. The aim of our study was to determine the
prevalence of IgG anti-CMV in patients on dialysis at the "C. I. Parhon" Hospital
from Iasi (Romania). In addition, the role of non-invasive samples (saliva and
capillary blood) for such epidemiological studies was determined. ELISA Wellcome
anti-CMV IgG was used for identification of specific antibodies in serum,
capillary blood, saliva. The prevalence of anti-CMV IgG in the group of study was
higher than that established in general populations and 79.06% saliva specimens
and 93.76% of capillary blood samples were positive. To establish the
specificity, sensitivity and predictive values of Wellcome anti-CMV when non
invasive samples are used, we compared the results obtained by testing saliva and
capillary blood to those obtained by testing serum. We may conclude that the non
invasive samples are useful for CMV-infection surveillance in risk groups.
PMID- 10756941
TI - [The effects of the intraventricular administration of captopril on water and ion
metabolism in the rst].
AB - The effects of the conversion enzyme on the hydroelectrolytic balance in adult
rats, maintained in standard lab conditions have been followed. The
administration protocol for the conversion inhibitor (captopril) produced a
blocking of the transformation of angiotensin I in angiotensin II only at the
level of the cerebral structures, during the whole period of the treatment (40
micrograms/kg x 3/24 hours). Following the intracerebroventricular (ICV)
administration of captopril, the fluid ingestion decreased diuresis and urinary
elimination of Na+ and Ca++ increased. The results plead for the existence of a
cerebral renin-angiotensin system, which intervenes in the control of the
hydroelectrolyte metabolism.
PMID- 10756942
TI - [The electroencephalographic aspects in stress epistaxis].
AB - The nasal haemorrhage is a symptom whose significance is seldom completely
investigated. In this paper we present the results that we have obtained in two
groups of patients: a pediatric population who presented for repeated episodes of
nasal haemorrhage and a group of first trimester pregnant women who also have
noticed the appearance of this symptom. Beside the clinical examination, a
paraclinical assessment has been performed, which included a laboratory profile
(hematology and biochemistry) and electroencephalography (EEG), in which we found
significant changes. We conclude that EEG is a valuable investigation technique
for diagnosis and monitoring purposes in nasal hemorrhage. Also, the clinical
management of the stress-related nasal hemorrhage must address multiple issues
for becoming efficient.
PMID- 10756943
TI - [The blood enzymatic antioxidative potential in bronchial asthma patients].
AB - This study aims at assessing the ability of asthma patients to defend themselves
against the noxious effects of oxidative stress, known being the inflammatory
nature of this disorder. As the anti-radical defence ability of the body is
reflected by the antioxidative potential of blood and tissues, our study was
based on the determination of the activity of superoxide dismutase (SOD),
catalase (CAT), glutathione peroxidase (GPx) and CAT/SOD and GPx/SOD ratios in
the blood. Except for SOD, the activity of which was lower in asthma patients by
34.08%, CAT and GPx had values increased by +32.18%, respectively, with a
resulting increase of CAT/SOD and GPx/SOD ratios. Our data, demonstrating a
change in per-oxidants/antioxidants balance in favour of the first ones, seem to
suggest that in the treatment of bronchial asthma the association of some
compounds with antioxidants effects would be beneficial.
PMID- 10756944
TI - [The clinical picture, treatment and prognosis of meningitis due to anaerobic and
nonfermentative bacteria].
AB - OBJECTIVES: The study of incidence, clinical manifestations and prognosis of
meningitis with anaerobic and non-fermentative bacteria. MATERIAL AND METHOD:
Retrospective study of 10 patients with severe forms of purulent meningitis
admitted in the Hospital of Infectious Diseases of Iasi, during 1.01.1990
31.12.1998. RESULTS: 3 of them were diagnosed with etiology with polymicrobial
flora and the rest had etiology with: Peptostreptococcus (2 cases), Acinetobacter
calcoaceticus (4 cases), Eikenella corrodens (1 case). The majority were male sex
(8 cases), and from rural area (9 cases). The age of patients ranged from 2.5 to
59 years (the majority being adults of group of age 50-60 years). The gate of
entrance was: iatrogenic in the majority of cases (6 cases), posttraumatic (2
cases) and othogen (2 cases); 3 cases being with cerebrospinal fluid fistula and
8 patients being in coma. The factors associated with poor prognosis were: the
immunosuppression (chronic etilism--4 cases; bronchopneumonia--2 cases, pulmonary
cancer--1 case) and the presence of the focal neurological findings on the noser
of illness. The diagnosis was established by clinical characters and confirmed by
isolating germs from cerebrospinal fluid. The treatment was done at the beginning
with first intervention antibiotic association with a high spectrum and then
according to the antibiogramme. The evolution was severe even under treatment
with 3 deaths, the mortality being of 30.0%. CONCLUSIONS: We wished to present
these cases as a general remark on the severity of illness, generally appeared on
a suppressed ground, together with the rarity of those germs implicated in the
etiology of purulent meningitis.
PMID- 10756945
TI - [Viral hepatitis A as an occupational disease in the city of Iasi].
AB - OBJECTIVES: Few studies have been carried out to evaluate the role of hepatitis A
virus (HAV) as an occupational hazard. Our analysis of data on occupational
diseases in Romania showed that hepatitis ranks as one of the first among
infectious occupational diseases. MATERIALS AND METHODS: Data on the role of
hepatitis A, as occupational disease, were obtained by testing sera obtained from
different occupational groups and compared results with the degree of immunity
found among the normal population. An ELISA technique was used to determine the
presence of each hepatitis marker (Murex kits for anti-HAV IgG). RESULTS: The
ratio of prevalence in each subset compared to the general population was used to
express relative risk. The results of our study show that hepatitis A is an
important hazard to sewerage workers. In view of these results, it should be
considered whether the occupational differences alone account for the divergence
in immunity between the groups or whether socioeconomic aspects and differences
in the standard of hygiene are also responsible for HAV infections.
PMID- 10756946
TI - [Nosocomial staphylococcal meningitis].
AB - OBJECTIVE: Clinical, bacteriological and therapeutically study on iatrogenic
staphylococcal meningitis. METHOD: Retrospective analysis of 33 cases of
iatrogenic staphylococcal meningitis admitted to the Hospital of Infectious
Diseases of Iasi in the interval 1988-1997. RESULTS: In the interval under study
the recorded incidence was 1-5 cases per year. The predisposing factors were
neurosurgical procedures for endocranial processes (12 cases), operated chronic
otomastoiditis (11 cases), ventriculoatrial or peritoneal shunt (5 cases) and
neurosurgical assessment (5 cases). The onset was slow, with persisting and mild
headache persistence recurrence of fever, vomiting and convulsions followed by
meningeal contracture and encephalitic phenomena. In 24 patients cerebrospinal
fluid was typical for purulent meningitis. The causal agents were isolated in 25
cases being Staphylococcus aureus (20 cases) and Staphylococcus epidermidis
sensitive to usual antistaphylococcal agents. Three therapeutically schemes were
used the association cefotaxim i gentamycin proving to be the most effective
vancomycin was required in but 2 cases. Three deaths were recorded. CONCLUSIONS:
The symptoms of iatrogenic staphylococcal meningitis are mild marked by the
underlying disease the most effective treatment being the association of
cefotaxim with an aminoglycoside.
PMID- 10756947
TI - The influence of some prostaglandin analogous on the female rat ovary and uterine
tube epithelium.
AB - The synthetic analogous of the prostaglandins are utilized in the obstetrical and
gynecological therapy for multiple purposes. 4 lots with 12 nonpregnant female
rats were use: the Ist received 25 g/kg/day isopropyl ester PGF2; the IInd lot
received 50 g/kg/day isopropyl ester PGF2; the IIIrd lot received 50 g/kg/day
optic active cloprostenol; the IVth lot was the witness lot. The medication was
intraperitoneally (i.p.) administrated in a unique daily dose. Prostaglandin F2
analogous at small doses (25 micrograms/kg/day) induce vasodilating effects on
the ovary blood vessels and functional luteolysis rather than structural
luteolysis. Both of the prostaglandins analogous at doses of 50 micrograms/kg/day
present obvious vasodilating and luteolytic effects, although the intensity of
the phenomenon is not the same, cloprostenol is more active, inducing a more
obvious vasodilatation and luteolysis.
PMID- 10756948
TI - [New isatin-derived hydrazones and Mannich bases with possible biological
activity].
AB - The paper presents a synthesis of six new Mannich bases, five hydrazones derived
from 1-piperidino-methyl-5-R-isatin and three copper complex compounds of 3-(3'-R
phenyl-pyridazinil-hydrazone)-indoline-2-ones (R=H, CH3, OCH3). The structure of
the new compounds was confirmed by the results of the elementary and spectral
analysis. Pharmacodynamic studies indicated that copper complex compounds present
effective biological properties. Thus, it can be seen that the experimental
carrageenan-induced inflammatory oedema was 58.3% inhibited by the complex V
(R=CH3) after oral administration. Antimicrobial tests revealed that only
compound V (R=OCH3) shows a moderate antimicrobial activity against the gram
positive and gram-negative bacteria, used in the test.
PMID- 10756949
TI - [An epidemiological study of the prevalence and clinical aspects of oral mucosal
lesions in adults].
AB - The frequency of the different lesions of oral mucosa detected in the patients
presenting for outpatient dental care was 37.6%. Cheilitis, lesions in various
areas of oral mucosa, and glossitis were prevalent. Generalized stomatitis
accounted for only 3.7%. Except for few cases with stomatitis and glossitis, the
clinical aspect of these lesions was benign, fact explaining why the patients
have not been aware of and have not presented for dental care. As some of these
lesions are believed to be precancerous states, thorough investigations are
needed for understanding their etiology, relationship with odontic, periodontal
and general disorders, and recurrent course.
PMID- 10756950
TI - [Changes in the craniomandibular relations of acromegaly patients].
AB - The dishomeostazical theory (etiopathogenic integrative concept) allows an ample
and complex vue on the stomatognathic system dysfunctional syndrome, because it
begins from the perception of the stomatognathic system (SS) as a whole in which
the alteration of each element can induce the disfunction of the entire system.
The purpose of this study is to demonstrate that the neuroendocrine suprasystemic
factor (STH hypersecretion on adult organism) disturbs every element of the SS
and induces an important alteration of the fundamental cranio-mandibular
relations.
PMID- 10756951
TI - [The correlation of lecture and clinical training in the instruction of the
student in prosthodontic treatment].
AB - The amount of information to be transmitted to the student is tremendously
increasing. Generally, the information doesn't come in pure, selected forms but
in complex forms. In order to be transmitted, each piece of information must be
transformed into a "message" considered by the professor to be the most
appropriate. The student receives the message through individual decoding,
depending on his/her personality, knowledge, ability of understanding, age,
education and psychological status. In order to be correct, the decoded
information must be identical to the information the professor has transmitted.
Experimental research has tried to establish practical rules for information
planning, organizing and transmittal from the professor to the student. There are
general rules applicable according to the specific nature of each medical
discipline. Our study, based on 30 years of experience, presents some
particularities of applying these rules to the transmittal/reception of
information concerning the dental prosthetic treatment.
PMID- 10756952
TI - [A statistical analysis of the variation in the cephalometric measures of
acromegaly patients].
AB - Acromegaly represents the endocrine disease which includes the somatic and
metabolic disorders secondly resulting to the augmentation of the Growth Hormone
secretion after the growth cartilages closing (in adult). In this study we want
to describe the craniofacial cephalometric qualitative and quantitative disorders
and to emphasize their implications in the onset and the evolution of the
stomatognathic system dysfunctional syndrome. For proving this things, we made a
statistical study using a statistics function named "standard deviation" which is
a measure of how widely values are dispersed from the average value.
PMID- 10756953
TI - [The tension induced by orthodontic forces in the dentoperiodontal system studied
by the finite element method].
AB - The aim of this study was to quantify the stress induced in the periodontal
ligaments by the orthodontic appliances. A finite element model of an orthodontic
system, applied on a lower premolar, was developed in different loading
conditions. The maximum stress values depend on the location, direction and the
magnitude of force application.
PMID- 10756954
TI - [Gram-negative anaerobic bacilli identified in the subgingival microflora
associated with fixed dentures].
AB - The prosthodontics devices have a major role in healthy state or disease of
periodontal structures. They may initiate or amplify tissues destruction when
technical features or the used material are not the most appropriate. The aim of
this study was to establish the influence of different materials on the evolution
of chronic periodontal diseases by comparison to lesions associated with natural
teeth. Lot of study was represented by 21 partial edentulous patients with
periodontitis in both natural teeth and fixed prosthodontics. Periodontal pockets
were sampled and then Gram stained smear and cultivation onto selective media
(Schadler + 5% sheep blood + nalidixic acid + vancomycin) were done. The isolated
bacteria were identified by standard methods. We observed quantitative and
qualitative differences between studied patients according to the material used
for making the fixed prosthodontics.
PMID- 10756955
TI - [A comparative study of the bacterial dental plaque formation on fixed dentures
with different surface characteristics].
AB - The accumulation of dental plaque on fixed prostheses made of various
biomaterials is influenced by the roughness of the surface. For the investigation
of this aspects it was necessary of a method rapid, facile and cheaper in
comparison with bacterial culturing and identification which is laborious and
expansive. In this study we followed the accumulation of dental plaque on
biomaterials like chrome-cobalt and gaudent polished and unpolished, at different
periods of time (3 and 14 days). We observed that after 3 days the aspect is
predominant coccoid and after 14 days is predominant bacillary. On unpolished
crowns the width of dental plaque is greater and on gaudent crowns the plaque is
structural organised around of filamentous organisms.
PMID- 10756956
TI - [The effect of a photo-developing solution on respiratory and cardiac activities
in rats when orally administered].
AB - The development of cinema art brought about the increase in the number of
laboratories which prepare photosensitive materials. In case of laboratories not
complying with rules regarding the preparation and handling of the solutions for
processing photos, these solutions can penetrate in the organism trough the skin
and be accidentally digested. The goal of the experiment is to study the effects
of developing solution for white/black Azomures photographic paper on respiratory
and cardiac activity of the Wistar rat (weight = 180-200 g) through oral
administration. Three experimental groups (lots) of animals were formed (8
animals/group). The control group was given 1 ml of distilled water; the first
(I) group was given 1 ml of 1/10 diluted photo-processing solution and the second
(II) group was given 1 ml of the same solution, but 1/4 diluted. The
administration of it was made in a single dose with a gastric drill. The
respiratory and cardiac (ECG) frequencies were monitored during a 4 hours period,
from the onset of administration. When 1/10 diluted developing solution was
administrated a decrease in the respiratory frequency was recorded after one
hour, but the effect vanished at the end of the experiment (4 hours). Fifteen
minutes after 1/4 diluted solution was administered, a decrease in respiratory
frequency per minute was determined, this result also disappeared at the end of 4
hours. However, these differences failed to reach significance (p = 0, 54). The
effect of developing solution on cardiac activity shows a decrease of cardiac
frequency in both experimental (I, II) groups. However, there is a difference in
the effect of the diluted solution on the rats. The 1/10 diluted solution
decrease the cardiac frequency over an approximate period of 1 hour and a half,
but the 1/4 diluted solution showed a decrease in cardiac frequency up until the
end of the ECG reading.
PMID- 10756957
TI - [Cervical pregnancy].
AB - The authors report a case of cervical pregnancy in a nulliparous woman (after
treatment for secondary infertility) treated systemically and locally with
methotrexate. Related to the case, they make some considerations concerning early
diagnosis and conservative treatment of ectopic cervical pregnancies, in order to
maintain the patients' fertility. The woman presented in this case report is now
5-weeks intrauterine pregnant.
PMID- 10756958
TI - [An open type-IIIB segmental fracture of the lower limb with soft-tissue
lesions].
AB - Open fractures are a challenge to the orthopaedic surgeon. The bigger the wound
the higher the risk of contamination. The prognostic depends also upon the degree
of comminution, the time of admittance, the antibiotherapy as well as the
treatment options. The latter vary according to the surgeon's preference, the
site of the fracture and the existing implants in a unit. We therefore present a
case of a young male patient with a type-IIIB fracture of the lower limb, with an
excellent result at 11 weeks postoperatively.
PMID- 10756959
TI - [The outlook for human blood component separation and the treatment of cancerous
tumors by magnetic methods].
AB - This work presents in brief some expectations related to the solution of certain
biomedical problems by using a non-conventional physical method: The high
gradient magnetic separation (HGMS). At first a short presentation of the HGMS
method is given and then its application in separation of the human blood
components is reported. The up to date intensely studied method with magnetic
carriers is then described. Among other things, this method enables the cancer
tumors treatment by intracavity radiotherapy, drug targeting, and diagnosis
exploration.
PMID- 10756961
TI - [Consciousness or unconsciousness as the priming principle].
PMID- 10756960
TI - [Only he who washes his hands can be said to be not guilty...].
PMID- 10756962
TI - [Reasonable and unreasonable hygiene measures in anesthesia in the intensive care
unit].
AB - The objective of this review is to describe which hygiene measures are
appropriate and necessary in anaesthesia and the ICU and which are not, whereby
unnecessary hygiene measures are those which are not substantiated by scientific
data. The most effective single infection control measure is still hand
disinfection between patient contacts. Unnecessary measures include routine
sampling of environmental surfaces, disinfecting the floor in the ICU, protective
gowns for visitors, so called in-line filters in the infusion system etc.
Ventilator tubes only need to be exchanged once a week, even when no HMEs are
used.
PMID- 10756963
TI - [The effect of different priming doses on the pharmacodynamics of cisatracurium].
AB - OBJECTIVE: The aim of the study was to evaluate the effect of two different
priming regimen on the onset time of 100 micrograms/kg cisatracurium, when
compared to bolus administration. METHODS: 51 patients were randomly assigned and
received either a bolus of 100 micrograms/kg cisatracurium, or a priming dose of
10 micrograms/kg cisatracurium followed after 4 min by 90 micrograms/kg
cisatracurium, or a priming dose of 15 micrograms/kg cisatracurium followed after
4 min by 85 micrograms/kg cisatracurium. The neuromuscular monitoring was
performed using a mechanomyograph (Groningen II Monitor). Anaesthesia was induced
with propofol and fentanyl and maintained by continuous infusion of propofol.
RESULTS: The priming combination of 15 micrograms/kg cisatracurium followed after
4 min by 85 micrograms/kg cisatracurium produced a statistically significant
reduction in the onset time (95% block) (180 +/- 60 s) and time to complete block
(210 +/- 48 s), when compared to the bolus group (240 +/- 60 s and 288 +/- 66 s)
(p < 0.05). CONCLUSION: Our data indicate that the "priming principle" is an
appropriate technique to shorten the onset time of cisatracurium. To achieve a
maximum effect the priming combination of 15 micrograms/kg cisatracurium followed
after 4 min by 85 micrograms/kg cisatracurium is recommended.
PMID- 10756964
TI - [The use of lithium hydroxide for carbon dioxide absorption prevents formation of
compound A during sevoflurane anesthesia].
AB - Aim of the study was the clinical investigation of sevoflurane degradation when
using water-free lithiumhydroxide versus moist Dragersorb 800 for carbon dioxide
absorption. METHODS: Concentrations of Compound A in the inspiratory gas mix and
serum fluoride levels were measured in two groups of 8 patients each. RESULTS:
When water-free lithiumhydroxide was used for carbon dioxide absorption,
concentration of Compound A in the inspiratory gas mix was ca. 1 ppm (near
minimal level of detection) as compared to ca. 20 ppm for moist Dragersorb 800.
The concentration of fluoride increased during sevoflurane anesthesia (15.0 +/-
4.8 mumol/l with lithiumhydroxide versus 21.9 +/- 4.0 mumol/l with Dragersorb 800
after 60 mins). CONCLUSIONS: When lithiumhydroxide is used, there is only minimal
formation of compound A from sevoflurane degradation. Since serum fluoride levels
increased in both patient groups, we conclude that this is caused mainly by
metabolism of sevoflurane. Capacity of lithiumhydroxide for carbon dioxide
absorption is similar to that of Dragersorb 800. Therefore, the use of
lithiumhydroxide increases patient safety.
PMID- 10756965
TI - [In vitro contracture test and gene typing in diagnosing malignant hyperthermia.
Each as an appropriate complement to the other method].
AB - BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominantly inherited
disorder, triggered in susceptible individuals by inhalation anesthetics and
depolarizing muscle relaxants such as succinylcholine. Because of its high
sensitivity (97-99%) and specificity (93.6%) as well as the genetic heterogeneity
of MH disorder, the in vitro contracture test (IVCT) following the European-MH
Group is considered to be the "Gold Standard" for phenotypical determination of
predisposed patients. On the other hand mutations in the skeletal muscle
ryanodine receptor gene (RYR1) are tightly linked with MH susceptibility. After
detecting a C1840T-mutation (Arg614Cys) in the RYR1 gene in one individual of a
large MH family, we searched for this mutation in the remaining family members
and determined the concordance with IVCT. METHODS: According to the European
standard protocol for MH, 43 individuals of a large MH pedigree were assigned the
status of MH susceptible (MHS),--negative (MHN) or--equivocal (MHE). The genetic
investigation of 44 family members for the Arg614Cys-mutation was carried out by
restriction fragment analysis: Genomic DNA was prepared from EDTA whole blood
followed by amplification of a 918 bp RYR1 gene fragment by polymerase chain
reaction. In presence of the Arg614Cys-mutation digestion with the restriction
endonuclease Rsal would result in different DNA fragments of the amplified
sequence than in absence of mutation. RESULTS: According to the response to IVCT,
25 individuals phenotypically revealed MHS, 7 MHE and 11 MHN status. Out of the
44 family members screened genetically for the Arg614Cys-mutation, the mutation
was detected in 23 individuals. Out of them 19 were MHS and one was MHEc. The
mutation was absent in 9 predisposed individuals, but six of them were MHE and
three MHS. The mutation was also present in three individuals who had no MH
screening (IVCT) before. For these last mentioned individuals the diagnosis MHS
was deduced from genetic results. CONCLUSION: Based on results of IVCT the
identification of a MH associated mutation in a MH-family can make and support a
correct MH diagnosis and can resolve MHE findings.
PMID- 10756966
TI - [Advanced emergency life support measures in resuscitation. Guidelines of the
European Resuscitation Council 1998].
PMID- 10756967
TI - [History of the development of intensive care medicine in Germany. General
considerations. 14. Vegetative blockade and analgesic sedation].
PMID- 10756968
TI - [Importance of acute PTCA in the treatment of perioperative myocardial
infarction].
AB - The mortality of perioperative myocardial infarction is still high and according
to recently published data amounts to 17 to 42%. In the seventies introduction of
thrombolytic therapy has led to a dramatic reduction in mortality of non
perioperative myocardial infarction. However, in the perioperative situation
thrombolytic therapy remains to be problematic in most cases because of expected
severe bleeding complications. In the last 4-6 years acute-PTCA has been
established in the therapy of acute myocardial infarction. Up to date no data are
available concerning the effect of acute-PTCA on mortality of perioperative
myocardial infarction. Nevertheless it can be assumed, that acute-PTCA will lead
to a considerable reduction in mortality of perioperative myocardial infarction.
Therefore, in patients with significant perioperative myocardial infarction
immediate coronary angiography and, if indicated, acute-PTCA should be performed.
In principle, thrombolytic therapy is considered to be contraindicated in the
intra- or postoperative situation. However, if coronary angiography and PTCA are
not possible, thrombolysis might be taken into consideration, in particular if
the expected bleeding complications are small in relation to the expected benefit
of thrombolysis. Since acute-PTCA has been shown to remarkably reduce mortality
in patients with cardiogenic shock after acute myocardial infarction, this group
of patients should be especially considered.
PMID- 10756969
TI - [Nitrous oxide in follicle puncture for sperm implantation].
PMID- 10756970
TI - [The alveolar gas equation].
PMID- 10756971
TI - [Precautions for propofol sedation].
PMID- 10756972
TI - [Anesthesia following organ transplantation].
PMID- 10756973
TI - Cell-to-cell variation in store-operated calcium entry in HEK-293 cells and its
impact on the interpretation of data from stable clones expressing exogenous
calcium channels.
AB - To investigate the effect of cell-to-cell variation in store-operated calcium
entry (SOCE) on the evaluation of data from stable cell clones selected following
gene transfection, we measured SOCE in 2700 individual HEK-293 cells from the
parent population and in 1900 individual cells from a clonal subpopulation of HEK
293 cells. We applied statistical resampling techniques to model conditions where
one would compare the average SOCE in n control clones to the average SOCE in n
experimental clones (n = 1-200). For an overexpression experiment with n = 1,
there is a 27% chance of observing a 100% or higher difference in SOCE between
clones, with n = 10 there is a 34% probability of observing a 20% or greater
difference in SOCE, and with n = 100, there is less than a 10% chance of seeing a
10% or greater difference in SOCE, based solely on random selection of clones
from the parent HEK-293 cell population. To assure that the degree of cell-to
cell variation was predictive of the degree of clone-to-clone variation, we
measured SOCE in 270 clones, each arising from a single cell, and found the
variation to be very similar to that observed for individual cells.
PMID- 10756974
TI - Ionic selectivity of low-affinity ratiometric calcium indicators: mag-Fura-2,
Fura-2FF and BTC.
AB - Accurate measurement of elevated intracellular calcium levels requires indicators
with low calcium affinity and high selectivity. We examined fluorescence spectral
properties and ionic specificity of three low-affinity, ratiometric indicators
structurally related to Fura-2: mag-Fura-2 (furaptra), Fura-2FF, and BTC. The
indicators differed in respect to their excitation wavelengths, affinity for Ca2+
(Kd approximately 20 microM, 6 microM and 12 microM respectively) and selectivity
over Mg2+ (Kd approximately 2 mM for mag-Fura-2, > 10 mM for Fura-2FF and BTC).
Among the tested indicators, BTC was limited by a modest dynamic range upon Ca2+
binding, susceptibility to photodamage, and sensitivity to alterations in pH. All
three indicators bound other metal ions including Zn2+, Cd2+ and Gd3+.
Interestingly, only in the case of BTC were spectral differences apparent between
Ca2+ and other metal ions. For example, the presence of Zn2+ increased BTC
fluorescence 6-fold at the Ca2+ isosbestic point, suggesting that this dye may be
used as a fluorescent Zn2+ indicator. Fura-2FF has high specificity, wide dynamic
range, and low pH sensitivity, and is an optimal low-affinity Ca2+ indicator for
most imaging applications. BTC may be useful if experimental conditions require
visible wavelength excitation or sensitivity to other metal ions including Zn2+.
PMID- 10756975
TI - Protective effects of low and high doses of cyclosporin A against reoxygenation
injury in isolated rat cardiomyocytes are associated with differential effects on
mitochondrial calcium levels.
AB - In this study we aimed to determine the concentration range of cyclosporin A
(CsA) which was effective in protecting against reoxygenation injury in isolated
cardiomyocytes, and its effects on intramitochondrial free calcium levels
([Ca2+]m). We also determined whether a high [CsA] had any deleterious effect on
normal myocyte function. Isolated adult rat ventricular myocytes were placed in a
chamber on the stage of a fluorescence microscope for induction of hypoxia.
[Ca2+]m was determined from indo-1/am loaded cells where the cytosolic
fluorescence signal had been quenched by superfusion with Mn2+. Cell length was
measured using an edge-tracking device. Upon induction of hypoxia, control cells
underwent rigor-contracture in 37 +/- 1 min (n = 99) (T1); CsA had no effect on
T1. The percentage of control cells which recovered upon reoxygenation depended
on the time spent in rigor (T2). With a T2 of 21-30 min, only 36% of control
cells recovered compared with 90% and 78% of cells treated with 0.2 microM and 1
microM CsA respectively. After 40 min in rigor, [Ca2+]m was 280 +/- 60 nM in
control-recovered cells (50% of cells) and 543 +/- 172 nM and 153 +/- 26 nM in
cells treated with 0.2 and 1 microM CsA, respectively (all CsA treated cells
recovered). In normoxic studies, CsA had no effect on cell contractility or
[Ca2+]m upon rapid pacing, even in presence of an elevated external [Ca2+]. In
conclusion, both low and high [CsA] protected against reoxygenation injury to
cardiomyocytes despite having opposing effects on [Ca2+]m, suggesting more than
one mechanism of action. CsA had no effect on either cell contractility or
[Ca2+]m in normoxic cells.
PMID- 10756976
TI - Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes.
AB - We have developed fluo-4, a new fluorescent dye for quantifying cellular Ca2+
concentrations in the 100 nM to 1 microM range. Fluo-4 is similar in structure
and spectral properties to the widely used fluorescent Ca(2+)-indicator dye, fluo
3, but it has certain advantages over fluo-3. Due to its greater absorption near
488 nm, fluo-4 offers substantially brighter fluorescence emission when used with
excitation by argon-ion laser or other sources in conjunction with the standard
fluorescein filter set. In vitro, fluo-4 exhibited high fluorescence emission, a
high rate of cell permeation, and a large dynamic range for reporting [Ca2+]
around a Kd(Ca2+) of 345 nM. We have also developed several Ca(2+)-indicators
related to fluo-4 having lower affinities for Ca2+ that are useful in cellular
studies requiring quantification of higher [Ca2+]. In a variety of physiological
studies of live cells, fluo-4 labeled cells more brightly than did fluo-3, when
challenged with procedures designed to elevate calcium levels. Fluo-4 is well
suited for photometric and imaging applications that make use of confocal laser
scanning microscopy, flow cytometry, or spectrofluorometry, or in fluorometric
high-throughput microplate screening assays. Because of its higher fluorescence
emission intensity, fluo-4 can be used at lower intracellular concentrations,
making its use a less invasive practice.
PMID- 10756977
TI - Effect of nitric oxide on endoplasmic reticulum calcium homeostasis, protein
synthesis and energy metabolism.
AB - It has been suggested that nitric oxide (NO) may contribute to ischemia-induced
cell injury. However, the mechanisms underlying NO toxicity have not yet been
fully elucidated. In the present study, we investigated the effect of NO on the
level of endoplasmic reticulum (ER) calcium stores, on ER Ca2+ pump activity, on
protein synthesis, on concentrations of high-energy phosphates, and on gadd153
mRNA levels. Primary neuronal cells were exposed to the NO-donor (+/-)-S-Nitroso
N-acetylpenicillamine (SNAP) for 1 h, 2 h, 6 h or 24 h. The level of ER calcium
stores was evaluated by measuring the increase in cytoplasmic calcium activity
induced by exposing cells to thapsigargin, an irreversible inhibitor of ER Ca(2+)
ATPase; the activity of ER Ca(2+)-ATPase was determined by measuring a
phosphorylated intermediate; SNAP-induced changes in gadd153 expression were
evaluated by quantitative PCR; SNAP-induced changes in protein synthesis were
investigated by measuring the incorporation of L-[4,5-3H]leucine into proteins,
and changes in the levels of ATP, ADP, AMP were measured by HPLC. Exposing cells
to SNAP for 1 h to 2 h induced a marked depletion of ER calcium stores through an
inhibition of ER Ca(2+)-ATPase (to 58% of control), and a concentration-dependent
suppression of protein synthesis which was reversed in the presence of
hemoglobin, suggesting NO-related effects. ATP levels and adenylate energy charge
were significantly decreased only when cells were exposed to the highest SNAP
concentration for 6 h or 24 h, excluding significant effects of NO on the energy
state of cells in the acute state, i.e. when ER calcium stores were already
completely depleted and protein synthesis severely suppressed. In light of the
regulatory role of ER calcium homeostasis in the control of protein synthesis,
the results imply that the suppression of protein synthesis resulted from NO
induced inhibition of ER Ca(2+)-ATPase and depletion of ER calcium stores, and
that NO-induced disturbances of energy metabolism are secondary to the effect of
NO on ER calcium homeostasis. It is, therefore, concluded that ER calcium stores
are a primary target of NO-toxicity.
PMID- 10756978
TI - Concentrations of caffeine greater than 20 mM increase the indo-1 fluorescence
ratio in a Ca(2+)-independent manner.
AB - The methylxanthine, caffeine, quenches the fluorescence of the ratiometric Ca2+
indicator indo-1, but does not affect the ratio (R) of indo-1 fluorescence at 400
and 500 nm in the presence of caffeine concentrations up to 10 mM [1]. We have
found that when caffeine is at concentrations of 20 mM or greater in vitro, or in
saponinpermeabilized skeletal muscle fibers, a Ca(2+)-independent increase in R
occurs, which leads to an overestimation of the free Ca2+ concentration.
Depending on experimental conditions, two factors contribute to the alteration in
R in vitro. First, when indo-1 fluorescence is low, fluorescence by caffeine, at
400 nm, can be significant. A second, and more dramatic effect, is that quenching
of indo-1 fluorescence by 20-50 mM caffeine is dissimilar at 400 and 500 nm.
Quenching at 500 nm is not linear, with respect to the concentration of caffeine,
and causes a Ca(2+)-independent increase in R, that occurs even when the
fluorescence of caffeine is a small portion of total fluorescence. However,
unlike R, the Ca2+ calibration constant of indo-1, KD beta, is unchanged in 50 mM
caffeine. Therefore, an accurate quantitation of Ca2+ in the presence of even
high concentrations of caffeine can be made in vitro by determining the Ca2+
calibration factors of indo-1 (RMIN and RMAX) for each caffeine concentration.
These effects of concentrations of caffeine greater than 20 mM are not observed
in intact cells loaded with the cell permeant form of indo-1 when caffeine is
applied extracellularly. This suggests either that the concentration of caffeine
within the cell does not reach that necessary to produce the effect, or that the
effects of caffeine on the dye are modified by the environment within the cell.
PMID- 10756979
TI - Sister chromatid exchange in chromosomes of sheep (Ovis aries).
AB - Blood lymphocyte cultures from 32 Comisana and Laticauda sheep breeds (15 males
and 17 females) raised in Southern Italy were studied using sister chromatid
exchange (SCE) test. Of the 932 cells studied, the SCE-mean value was 7.20 +/-
2.5 per cell for both breeds. Indeed, the SCE mean values were 7.12 +/- 2.45 and
7.28 +/- 2.55 in Comisana and Laticauda breeds, respectively, and the differences
were not significant. No statistical differences were noticed between male and
female cells (7.25 +/- 2.39 and 7.16 +/- 2.60, respectively). The SCE frequency
distribution did not follow a Poisson distribution. The number of SCE were
significantly higher than expected in chromosomes 1, 2 and 3 (p < 0.001) and
significantly lower than expected in the X and remaining chromosomes (p < 0.001)
on the basis of relative chromosome lengths.
PMID- 10756980
TI - Spherical scatters in the lens of Acrossocheilus hexagonolepis as revealed by
scanning electron microscopy and UV-visible spectroscopy.
AB - Scanning electron microscopy revealed the presence of spherical granules 0.25
0.75 micron in diameter in the lens fibres of the hill stream fish Acrossocheilus
hexagonolepis. The density of the granules was approximately 8,500 per mm2. The
size of the particles and their distribution pattern suggested they functioned in
spherical scattering of the light. The absorbance and transmittance of light at
different wavelengths obtained from the spectroscopic analysis of the lens
indicated that a small percentage of light was neither absorbed nor transmitted.
Since reflection usually does not take place from the ocular refractive
structure, it may be that this proportion of the light was scattered from the
lens.
PMID- 10756981
TI - Female breast carcinomas: nuclear and cytoplasmic proteins versus steroid
receptors.
AB - Nuclear and cytoplasmic proteins of human female breast cancer were analysed by
one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS
PAGE). Oestrogen receptor and progesterone receptor expression was determined by
semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method.
The electropherograms were developed by silver nitrate staining and quantitative
analysis was carried out by video densitometer using the software Gel-Pro
Analyzer. Nuclear and cytoplasmic proteins of breast carcinomas and normal tissue
differed both qualitatively and quantitatively. Nuclear polypeptides of 108, 53
and 48 kD as well as the 36 kD cytoplasmic polypeptide were specific for tumour
samples, while the 51 kD nuclear polypeptide was detected only in normal tissue.
Quantitative differences in band density were noted in the 32 kD nuclear
polypeptide. This polypeptide was expressed in greatest concentration in
infiltrating ductal carcinomas which also indicated the greatest oestrogen
receptor gene expression. This relationship appeared to be statistically
significant (p < 0.005). No correlations were evident between the 32 kD protein
expression and the progesterone receptor gene expression in any of the tissue
types examined, nor between the 32 kD protein and the patient's age or tumour
grade.
PMID- 10756982
TI - Mitotic and meiotic chromosome studies in silky anteater Cyclopes didactylus
(Myrmecophagidae: Xenarthra).
AB - The karyotype of a male pigmy anteater, Cyclopes didactylus, an endangered
species from the Amazon region, is described. The size and morphology of the X
and Y chromosomes in mitotic and meiotic analyses is recorded and discussed.
PMID- 10756983
TI - Genetic risk assessment in hookah smokers.
AB - The genotoxic effect of hookah smoke was investigated on somatic chromosomes of
35 occupationally nonexposed male hookah smokers. These were compared with an
equal number of nonsmokers matched with respect to age, sex, drug intake, if any,
and socio-economic status. The mitotic index (MI), chromosomal aberrations (CA),
sister chromatid exchanges (SCE) and satellite associations (SA) were analysed.
All the parameters showed a significant increase (p < 0.01) in the smokers
compared with control individuals, viz MI, 3.88-5.41; CA, 0.94-2.22; SCE, 3.59
5.66; and SA, 5.2-8.65. A distinct time and dose effect relationship was
observed. Hookah smoke is thus, both clastogenic and genotoxic for human beings.
PMID- 10756984
TI - Morphology of fibroblastic cells cultured on poly(HEMA-co-AA) substrates.
AB - Fibroblastic cells in culture are characteristically elongated and grow in
monolayers. This growth pattern can be modified by different factors, such as
substrate interaction. It is characteristic of hydrogels made of poly(2
hydroxyethylmethacrylate) (polyHEMA) that they inhibit cellular attachment and
spreading. Vero cells were cultured on porous samples of polyHEMA and the
copolymer poly(HEMA-co-AA) with 7.5% (w/w) and 15% (w/w) acrylic acid. Cultures
were maintained for 2 and 10 days in HAM F10 medium with 10% foetal calf serum.
Hydrogel samples were processed for light microscopy and scanning electron
microscopy. The round Vero cells proliferated on the hydrogels and were
principally located inside the pores. Some cells were aggregated, but no
extracellular matrix was found. The copolymer with 15% (w/w) acrylic acid was the
most suitable substrate and should be used in future tests of morphological
differentiation and induction of cellular function.
PMID- 10756985
TI - The influence of a single ethanol injection on normal thyroid tissue of the rat.
AB - Macro- and microscopic changes in the normal thyroid gland of rats, and in the
surrounding tissues 2 and 4 weeks after a single intrathyroidal ethanol injection
(IEI), together with the influence of such treatment on the function of the
recurrent laryngeal nerves and of the parathyroid glands, were assessed. The
intraoperative macroscopic evaluation at 2 weeks (20 rats) and 4 weeks (20 rats)
after IEI revealed the presence of a scar at the site of the IEI-treated lobe in
seven (35%) and six (30%) rats, respectively, and the reduction of lobe
dimensions in thirteen (65%) and fourteen (70%) rats, respectively. The
microscopic evaluation of the lobe after IEI showed coagulative necrosis,
reduction in thyroid follicle volume, disturbance of follicle structure,
haemorrhage, haemosiderin deposits, inflammatory infiltration and fibrosis. No
microscopic changes were observed in the tissues surrounding the thyroid, nor in
the parathyroid glands located extrathyroidally or in the second thyroid lobe. No
vocal cord dysfunction or significant changes in serum calcium levels after IEI
were detected.
PMID- 10756986
TI - Pancreatitis: computed tomography and magnetic resonance imaging.
AB - The value of CT in management of severe acute pancreatitis is well established.
Some, but not all, experimental studies suggest a detrimental effect of
intravenous iodinated contrast agents in acute pancreatitis, but although initial
clinical data tends to support this, the positive advantages of enhanced CT
outweigh the possible risks. Magnetic resonance imaging has been shown to be as
effective as CT in demonstrating the presence and extent of pancreatic necrosis
and fluid collections, and probably superior in indicating the suitability of
such collections for percutaneous drainage. Image-guided intervention remains a
key approach in the management of severely ill patients, and the indications,
techniques and results of radiological intervention are reviewed herein. Both CT
and MRI can be used to diagnose advanced chronic pancreatitis, with the recent
addition of MRCP as a viable alternative to diagnostic endoscopic retrograde
cholangiopancreatography (ERCP). Both MRCP and CT/MR imaging of the pancreatic
parenchyma still have limitations in the recognition of the earliest changes of
chronic pancreatitis--for which ERCP and tests of pancreatic function remain more
sensitive--but the clinical significance of these minor changes remains
contentious.
PMID- 10756987
TI - Signal changes in liver and spleen after Endorem administration in patients with
and without liver cirrhosis.
AB - The goal of this study was compare the effect of Endorem on the signal intensity
of the spleen in patients with normal liver tissue and in patients with liver
cirrhosis. Thirty patients with normal liver tissue and 47 with liver cirrhosis
were examined before and after i.v. Endorem administration. The patients were
examined with a 1.5-T magnet system (Magnetom Vision) using a semiflexible cp
array coil. Three different pulse sequences were used: a T1-weighted gradient
echo sequence, a T2-weighted fast spin-echo sequence with spectral fat
suppression, and a T2*-weighted gradient-echo sequence. The signal-to-noise
ratios (SNRs) of two areas of the liver and spleen were determined. The mean SNRs
of the liver and spleen in patients with and without liver cirrhosis were
compared. For assessment of statistical significance, the t-test at a level of P
< 0.05 was applied. After i.v. administration of Endorem, no differences were
seen with the T1-weighted gradient-echo sequence for the liver and spleen and,
with the T2-weighted fast spin-echo sequence, no differences were found for the
spleen. Significant differences between both groups were seen for the liver with
the T2-weighted fast spin-echo sequence. The SNR in the noncirrhotic liver group
was 57.4% lower than the SNR in the cirrhotic liver group. With the T2*-weighted
gradient-echo sequence, the SNRs of the liver and spleen in the noncirrhotic
liver group, compared with the cirrhotic liver group, were 126.8% and 45.6% less,
respectively. The effect of Endorem on the liver in patients with Child C-stage
liver cirrhosis was 32.1% less than in patients with Child B-stage liver
cirrhosis. Likewise, the Endorem effect on the spleen was 27.1% less in patients
with Child C-stage compared with Child B-stage liver cirrhosis. Hepatic and
splenic uptake of Endorem is significantly decreased in patients with liver
cirrhosis.
PMID- 10756988
TI - An experimental approach of the Doppler perfusion index of the liver in detecting
occult hepatic metastases: histological findings related to the hemodynamic
measurements in Wistar rats.
AB - Image-directed colour Doppler sonography has been successfully introduced for the
detection of hepatic haemodynamic changes in the presence of liver metastases.
The aim of our study was to correlate these haemodynamic changes with the liver
histology at the time of measurement. We experimentally induced liver metastases
in 30 male Wistar rats by inoculating Walker 256 tumour subcutaneously. The
animals were assigned into three groups of ten and were studied sonographically
at 4, 7 and 15 days after tumour implantation. Another group of ten normal
animals were used as controls. Portal vein and hepatic artery measurements
included resistance index (PVRI, HARI) and flow volume (PVFV, HAFV). Doppler
perfusion index (DPI) of the liver was calculated as the ratio of HAFV/PVFV +
HAFV. Liver histology followed each Doppler measurement. Metastases were first
encountered on day 4, as small groups of cells in the connective tissue of the
porta hepatis and the portal triads without apparent vascular association.
Distinct elevation of HAFV and DPI was recorded in comparison with the controls
(p = 0.0004 and p = 0.0005, respectively). PVFV reduction was subtle. Up to day
15 there were no significant changes in the measurements. Our data suggest that
HAFV and DPI can efficiently detect early liver metastases and this is in
accordance with existing clinical reports. Haemodynamic changes seem to originate
from the early non-vascular phase of the metastases.
PMID- 10756989
TI - CT features of gastric lymphoma.
AB - The gastrointestinal tract is the most frequent site of extranodal involvement by
lymphoma and stomach is the most frequently involved. The incidence of gastric
lymphoma appears to be rising as that of adenocarcinoma is declining. It produces
a spectrum of radiologic appearances and its distinction from adenocarcinoma is
difficult since their findings frequently overlap. The aim of this article is to
present pictorially a spectrum of CT findings of the gastric lymphoma.
PMID- 10756990
TI - Hepatic endometrioma: a case report and review of the literature.
AB - Extrapelvic endometriosis is not uncommon but hepatic endometrioma is extremely
rare. Ultrasound, CT and MR features of hepatic endometrioma are discussed and
the literature is reviewed in this report.
PMID- 10756991
TI - Rare complication of intestinal Crohn's disease: giant fibroid polyp.
AB - A 25-year-old male patient who had a brother with Crohn's disease was referred to
our clinic with bloody diarrhea and crampy abdominal pain. After a plain erect
abdominal X-ray, enteroclysis was performed, followed by abdominopelvic CT.
Besides the radiological features of CD, both enteroclysis and CT revealed a big
polypoid filling defect in the small intestine. The patient was surgically
treated and the histopathology of the specimen revealed a giant fibroid polyp
superimposed on CD, an extremely rare complication heretofore unmentioned in the
radiology literature. In this report we discuss the role of enteroclysis in the
diagnosis of complicated cases of long-standing CD. In addition, we also shed
light on the importance of both enteroclysis and CT, with their complementary
findings, in the radiological diagnosis of rare complicated cases of CD.
PMID- 10756992
TI - Age- and gender-specific differences in left and right ventricular cardiac
function and mass determined by cine magnetic resonance imaging.
AB - We examined possible age- and gender-specific differences in the function and
mass of left (LV) and right (RV) ventricles in 36 healthy volunteers using cine
gradient-recalled echo magnetic resonance imaging. Subjects were divided into
four groups (nine men and nine women in each): men aged under 45 years (32 +/-
7), women aged under 45 (27 +/- 6), men aged over 45 (59 +/- 8), and women aged
over 45 (57 +/- 9). Functional analysis of cardiac volume and mass and of LV wall
motion was performed by manual segmentation of the endocardial and epicardial
borders of the end-diastolic and end-systolic frame; both absolute and normalized
(per square meter body surface area) values were evaluated. With age there was a
significant decrease in both absolute and normalized LV and RV chamber volumes
(EDV, ESV), while LV and RV masses remained unchanged. Gender-specific
differences were found in cardiac mass and volume (for men and women,
respectively: LV mass, 155 +/- 18 and 110 +/- 16 g; LV EDV, 118 +/- 27 and 96 +/-
21 ml; LV ESV, 40 +/- 13 and 29 +/- 9 ml; RV mass, 52 +/- 10 and 39 +/- 5 g; RV
EDV, 131 +/- 28 and 100 +/- 23 ml; RV ESV, 53 +/- 17 and 33 +/- 15 ml).
Normalization to body surface area eliminated differences in LV volumes but not
those in LV mass, RV mass, or RV function. Functional parameters such as cardiac
output and LV ejection fraction showed nonsignificant or only slight differences
and were thus largely independent of age and gender. Intra- and interobserver
variability ranged between 1.4% and 5.9% for all parameters. Cine magnetic
resonance imaging thus shows age- and gender-specific differences in cardiac
function, and therefore the evaluation of cardiac function in patients should
consider age- and gender-matched normative values.
PMID- 10756993
TI - Tumors of the cardiac valves: imaging findings in magnetic resonance imaging,
electron beam computed tomography, and echocardiography.
AB - We describe the findings from various cross-sectional imaging modalities in
patients with cardiac valve adherent masses. The techniques are discussed, and
imaging findings are compared with the results of cardiac surgery. All three
patients had neurological symptoms and/or cardiac murmurs. Transthoracic and/or
transesophageal echocardiography revealed the cardiac mass in all three. For
differentiation of thrombus and cardiac neoplasm magnetic resonance imaging (MRI)
was also performed in all three patients and electron-beam computed tomography
(EBCT) in two. Fast segmented cine gradient-echo MRI techniques provided mass
depiction in all patients, while T1-weighted spin-echo imaging failed in mass
detection in one patient. None of the patients showed evidence of valve
regurgitation or stenosis in flow sensitive cine MRI. EBCT excluded mass
calcifications in both patients and reliably demonstrated the valve attached
lesions. Although echocardiography is the modality of choice in evaluating
cardiac masses and especially valve attached masses, MRI and EBCT provide
additional information about tissue characteristics and allows an excellent
overview of the cardiac and paracardiac morphology. Fast segmented cine gradient
echo MRI is especially able to depict even small tumors attached to rapidly
moving cardiac valves, and valve competence can be easily assessed within the
same examination.
PMID- 10756994
TI - Central venous catheter placement in the inferior vena cava via the direct
translumbar approach.
AB - The aim of this study was to evaluate the technical aspects and efficacy of
placing tunneled central venous access catheters (CVA) in the inferior vena cava
(IVC) via a direct translumbar approach. Between August 1994 and July 1998, 50
CVA (Hickman 13.5 F) were placed in the IVC via a direct translumbar approach in
46 patients (10 males, 36 females) with a mean age of 39.9 years (age range 10-87
years). The indications were chemotherapy administration plus leukoaphoresis (n =
39), bone marrow transplantation (n = 2) and hemodialysis (n = 5). The reasons
for placing the CVA in the IVC were cosmetic (n = 34), supradiaphragmatic venous
thrombosis (n = 8), previous catheter infection (n = 2), and non-functioning
arteriovenous fistula (n = 2). There were no immediate complications. The mean
period of time the CVA was in place was 3 months (15 days to 15 months), during
which the function was excellent. The commonest late complication was infection
(4 local, 6 bacteremia). Others included: pain (n = 2), ureteric fistula (n = 1),
pericatheter fibrin sheath formation (n = 6) and catheter-tip impaction (n = 2).
Two catheters were damaged due to postprocedural inappropriate manipulations and
two others fell off due to incorrect fixation. Due to these complications, it was
necessary to remove ten catheters, replace an additional four and reposition two.
Direct translumbar catheterization of the IVC is a safe and effective way of
placing a long-term CVA with a moderate complication rate.
PMID- 10756995
TI - Right and left ventricular volume measurements in an animal heart model in vitro:
first experiences with cardiac MRI at 1.0 T.
AB - The aim of this study was to determine the accuracy in quantifying right and left
ventricular volumes using a 1.0-T system and commercially available, standard
equipment. For exact comparison of MRI measurements and real volumes we used an
animal heart model ex vivo. Eight pig hearts were explanted and prepared by
removal of the atria. Aorta and pulmonary truncus were cannulated. Definable
volumes were injected into the ventricles. Magnetic resonance imaging was
performed at 1.0 T (Gyroscan T10 NT, Philips, Eindhoven, The Netherlands);
sequence: fast field echo-echo planar (multishot EPI); body coil; MR software:
Cardiac Application Package (Philips). Statistical analysis correlated the real
volumes and MR measurements separately for both ventricles and two investigators
(SAS, ANOVA). For both ventricles and both investigators the correlation between
real volumes and MR measurements was greater than 0.99. There was no significant
systematic false estimation for both ventricles. Magnetic resonance imaging at
1.0 T using standard hardware and software equipment enables the quantification
of right and left ventricular volumes with high approximation to the real volumes
in vitro. There is a clear restriction in translating these data into a clinical
application because under experimental conditions no motion-induced artifacts
existed.
PMID- 10756996
TI - Asymptomatic aneurysm of the proximal right subclavian artery: a rare ultrasound
diagnosis.
AB - True aneurysms of otherwise normal subclavian arteries are uncommon peripheral
vascular anomalies. Most patients with subclavian artery aneurysms are
symptomatic by presenting neurologic signs. We report a young woman who had an
asymptomatic true aneurysm of the right subclavian artery assumed to be of
congenital origin. This case is unique in that the aneurysm was in the extremely
rare anatomic location of the right supraclavicular fossa between the origins of
the right subclavian artery and the vertebral artery. Aneurysms of the right
subclavian artery may represent a potential pitfall in conventional gray-scale
ultrasound of the neck particularly the supraclavicular fossa. Differential
diagnosis includes cervical cyst, pharyngo-esophageal diverticulum, vascular
anomalies, struma, enlarged lymph node, as well benign or malignant neoplasms.
Color duplex ultrasound should be performed as the method of choice for further
analysis of suspected aneurysms. In this report the role of B-mode ultrasound and
color duplex ultrasound is discussed in relation to digital subtraction- and MR
angiography in confirmation of the diagnosis.
PMID- 10756997
TI - MRI evaluation of soft tissue hydatid disease.
AB - Infestation in soft tissue by Echinococcus granulosus is not a common disease,
and its diagnosis is based on clinical, laboratory data and radiological
findings. The aim of our retrospective study is to give an overview of the
different signs and patterns shown by MRI that can be useful in characterizing
soft tissue hydatid disease. The MRI images obtained in seven patients with soft
tissue and subcutaneous hydatidosis were reviewed. Typical signs of hydatidosis
were multivesicular lesions with or without hypointense peripheral ring ("rim
sign"). Related to the presence and absence, respectively,of viable scolices in
the microscopic exam, daughter cysts were presented either as high signal
intensity or low signal intensity on T2-weighted images. Low-intensity detached
layers within the cyst and peripheral enhancement with gadolinium-DTPA were also
presented. Atypical signs were presented in an infected muscular cyst, a
subcutaneous unilocular cyst and several unilocular cysts. Knowledge of the
different patterns in MRI of soft tissue hydatid disease can be useful in
diagnosing this entity. We observed that the "rim sign" is not as common as in
other locations, and in addition, MRI seems to be of assistance when evaluating
the vitality of the cysts.
PMID- 10756998
TI - Dedicated extremity MR imaging of the foot and ankle.
AB - The purpose of this review is to provide illustrative examples of diseases of the
foot and ankle when imaged with a low-field MR imaging system. A retrospective
review of 268 foot and ankle examinations, performed in our institution within
the past 3 years with a 0.2-T (Artoscan Esaote, Genoa, Italy) dedicated extremity
MR system was done. Additionally, illustrative comparison with conventional
radiography and high-field MR imaging is presented in patients in whom these
examinations were also performed. Although motion artifact limited the value of a
few studies, in the majority of examinations low-field MR imaging provided
diagnostic image quality for the full spectrum of disorders affecting the foot
and ankle and seemed to be a feasible alternative to high-field MR imaging in
establishing an accurate diagnosis.
PMID- 10756999
TI - The role of the reversed oblique radiograph in trauma of the foot and ankle.
AB - The objective of this study was to demonstrate the statistical significance of a
reversed oblique radiograph of the foot in patients with ankle or foot trauma. In
100 consecutive patients a reversed oblique radiograph of the foot was taken in
addition to the conventional plain films. Ten of 29 fractures were not visualised
on the conventional films of foot and ankle and could only be diagnosed on the
reversed oblique film. In 7 of these 10 cases an avulsion fracture at the
anterolateral aspect of the calcaneus was present. This additional reversed
oblique film of the foot seems to be of considerable importance, especially when
an anterolateral avulsion fracture of the calcaneus is clinically suspected.
PMID- 10757000
TI - Tracheal rupture caused by blunt chest trauma: radiological and clinical
features.
AB - The aim of this study was to assess radiomorphologic and clinical features of
tracheal rupture due to blunt chest trauma. From 1992 until 1998 the
radiomorphologic and clinical key findings of all consecutive tracheal ruptures
were retrospectively analyzed. The study included ten patients (7 men and 3
women; mean age 35 years); all had pneumothoraces which were persistent despite
suction drainage. Seven patients developed a pneumomediastinum as well as a
subcutaneous emphysema on conventional chest X-rays. In five patients, one major
hint leading to the diagnosis was a cervical emphysema, discovered on the lateral
cervical spine view. Contrast-media-enhanced thoracic CT was obtained in all ten
cases and showed additional injuries (atelectasis n = 5; lung contusion n = 4;
lung laceration n = 2; hematothorax n = 2 and hematomediastinum n = 4). The
definite diagnosis of tracheal rupture was made by bronchoscopy, which was
obtained in all patients. Tracheal rupture due to blunt chest trauma occurs
rarely. Key findings were all provided by conventional chest X-ray. Tracheal
rupture is suspected in front of a pneumothorax, a pneumomediastinum, or a
subcutaneous emphysema on lateral cervical spine and chest films. Routine
thoracic CT could also demonstrate these findings but could not confirm the
definite diagnosis of an tracheal rupture except in one case; in the other 9
cases this was done by bronchoscopy. Thus, bronchoscopy should be mandatory in
all suspicious cases of tracheal rupture and remains the gold standard.
PMID- 10757001
TI - Abnormalities on chest radiographs following radiation therapy for breast cancer.
AB - The aim of this study was to study pulmonary radiological abnormalities with
chest radiography following different radiotherapy (RT) techniques for breast
cancer with respect to regions and density, and their association with pulmonary
complications and reduction in vital capacity (VC). Chest radiographs were
performed 5 months following local or loco-regional RT in 167 breast cancer
patients. The radiological abnormalities were analysed with a classification
system originally proposed by Arriagada and evaluated according to increasing
density (0-3) and affected lung regions (apical-lateral, basal-lateral, central
parahilar). The highest-density grades in each region were added together to form
scores ranging from 0 to 9. The patients were monitored for RT-induced pulmonary
complications. The VC was measured prior to and 5 months following RT. An
independent evaluation of 51 patients was performed by a second radiologist to
control the reproducibility of the classification system. Increasing scores were
associated with loco-regional RT and pulmonary complications (P < 0.001). The
mean reduction of VC for patients scoring 0-3 (-30 ml) vs 4-9 (-161 ml) was not
statistically significant (P = 0.10). Scores of 4-9 were more frequently observed
in older patients (P < 0.001). The independent evaluations by two radiologists
revealed good agreement (P < 0.001) and no systematic inter-observer variation.
Radiological abnormalities on chest radiographs, scored according to Arriagada,
can be used as an objective end point for RT-induced pulmonary side effects in
breast cancer.
PMID- 10757002
TI - Image-guided automated needle biopsy of 106 thoracic lesions: a retrospective
review of diagnostic accuracy and complication rates.
AB - We reviewed the diagnostic accuracy and complication rates of transthoracic
needle biopsy (TNB) with an automated 18-gauge core biopsy needle and gun, using
either fluoroscopic or CT guidance. One hundred six lesions were biopsied in 103
patients between 1992 and 1998. Hard-copy images, imaging reports, pathology
reports and clinical notes were reviewed. In 3 patients it was not possible to
establish the lesion as either malignant or benign from the available follow-up,
so these were removed from the analysis of diagnostic accuracy. Adequate samples
for histological diagnosis were obtained in 104 of 106 (98%) biopsies. There were
75 of 85 (88%) true-positive core biopsies for malignant lesions and a specific
cell type was identified in 70 of 85 (82%) cases. A specific histological
diagnosis was obtained in 12 of 18 (66%) biopsies. There was a 19% rate of
pneumothorax with only 2.4% requiring drainage. Minor haemoptysis occurred in
3.8% of procedures. The TNB technique with an automated core biopsy needle
provides a high level of diagnostic accuracy, effectively distinguishes cell type
in malignancy and provides a definite diagnosis in benign disease more frequently
than fine needle aspiration (FNA). There is no increased complication rate
compared with FNA.
PMID- 10757003
TI - Image-guided percutaneous drainage of thoracic empyema: can sonography predict
the outcome?
AB - The aim of this study was to assess the safety and efficacy of image-guided
percutaneous catheter drainage (IGPCD) of thoracic empyemas, and to correlate the
outcome of IGPCD with the pre-procedural sonographic appearance. One hundred
three patients (74 males and 29 females) with thoracic empyema (age range 1 month
to 70 years, median age 28 years) underwent IGPCD. In 63 (61.17%) patients, IGPCD
was the primary treatment modality; in 40 (38.84%) patients it was used after
unsuccessful intercostal chest tube drainage (ICTD). Ultrasound was the main
modality used for guidance; CT guidance was used in only 7 patients (6.8%). Eight
to 12-F pigtail catheters or 10- to 14-F Malecot catheters were used. The
outcome was correlated with the pre-procedural US appearance (anechoic, complex
non-septated or complex septated) of the empyema. The IGPCD technique was
successful in 80 of 102 patients. Based on the US appearance, IGPCD was
successful in 12 of 13 (92.3%) patients with anechoic empyemas; 53 of 65 (81.54%)
patients with complex non-septated empyemas, and in 15 of 24 (62.5%) patients
with complex septated empyemas. A statistically significant difference (p < 0.01)
was seen in the outcome of IGPCD in the three categories. Twenty-two patients
required further treatment: ICTD (n = 9; 2 of them later also underwent surgery);
and surgery (n = 15). The duration of catheter drainage ranged from 2-60 days. No
major complications were encountered. Percutaneous catheter drainage of thoracic
empyemas with imaging guidance ensures accurate catheter placement with a high
success and a low complication rate. Pre-procedural US can predict the likelihood
of success of IGPCD.
PMID- 10757004
TI - Spontaneous lung herniation after a single cough.
AB - Herniation of the lung is commonly caused by congenital rib abnormalities, blunt
trauma, or thoracic surgery. Spontaneous hernias are rarely described in the
literature. We report a case of a spontaneous intercostal pulmonary hernia
following a single cough. In addition, a review of the literature is presented
which outlines the classification, causes, and incidence of lung hernias. Some
reference is made to possible methods of treatment.
PMID- 10757005
TI - MR urography in children: current status and future development.
AB - The normal anatomy and many pathologies of the pediatric genitourinary system can
be assessed with different imaging modalities. Most of them are based on the use
of ionizing radiation and/or invasive techniques. The contribution of magnetic
resonance imaging in this regard has opened new ways of approaching pathological
conditions in this patient group. The addition of the newly developed rapid
techniques has enhanced the superiority of MRI, and both morphological and
functional evaluation of the genitourinary system can be achieved. There are
different factors on which rely the optimization and the efficiency of magnetic
resonance urography (MRU). Of importance is adequate patient immobilization and
the use of optimal imaging sequences. The rapid technical development, including
the advent of the post-processing respiratory navigator, allows acquisition of
high-quality images independent of the patient's respiratory rate. In the future,
it is expected that MRU, due to its non-use of ionizing radiation, will become
the most important tool in the diagnostic work-up of genitourinary pathologies in
infants and small children.
PMID- 10757006
TI - The use of ultrasound-guided cutting-needle biopsy in paediatric neck masses.
AB - OBJECTIVE: Neck masses are common in children. Although there is a low incidence
of therapeutically significant pathology, biopsy is occasionally required for
evaluation. Open biopsy or fine needle aspiration may be used to obtain tissue.
Open biopsy provides material suitable for histological analysis but requires
general anaesthesia. Cytological material obtained by fine needle aspiration is
often inconclusive. A core of histological material may also be obtained by
percutaneous cutting-needle biopsy, a recognised procedure at other anatomical
sites, usually performed under local anaesthesia. MATERIALS AND METHODS: There
are few accounts using cutting needles in adult neck masses and no previous
paediatric series. We present our experience of ultrasound-guided core biopsies
of neck masses in 15 children ranging in age from three months to 16 years.
RESULTS: Thirteen biopsies were easily performed without sedation as an
outpatient procedure under topical and injected local anaesthetic. In all fifteen
cases the procedure was well tolerated and a tissue successfully obtained.
CONCLUSION: Ultrasound guided cutting needle biopsies of head and neck masses of
children can be performed under local anaesthesia in the majority of cases.
PMID- 10757007
TI - MR imaging of pituitary hyperplasia in a child with growth arrest and primary
hypothyroidism.
AB - Magnetic resonance imaging of pituitary hyperplasia has been rarely described in
children with primary hypothyroidism. We report a case of pituitary hyperplasia
in a child presented with significant growth arrest and laboratory evidence of
hypothyroidism. Magnetic resonance imaging revealed symmetrical pituitary
enlargement simulating macroadenoma. After thyroid hormone replacement therapy,
the child's height increased and pituitary enlargement regressed to normal.
Awareness of MRI appearance of pituitary hyperplasia in children with laboratory
evidence of hypothyroidism might avoid misdiagnosis for pituitary tumor, which
may also manifest as growth disorder, obviating unnecessary surgery.
PMID- 10757008
TI - Secondary involvement of breast with non-Hodgkin's lymphoma in a paediatric
patient presenting as bilateral breast masses.
AB - We report a paediatric case of non-Hodgkin's lymphoma with secondary breast
involvement. On US exam there were bilateral multiple well-defined masses.
Contrast-enhanced thorax CT demonstrated the breast lesions as well as enhancing
masses. To our knowledge, this type of lymphomatous breast involvement in a child
is rare and its CT features are very rarely demonstrated.
PMID- 10757009
TI - CT and MR findings in neoplastic perineural spread along the vidian nerve.
AB - The aims of this article are to describe the findings of perividian tumor spread
and to compare the accuracy of MRI and CT in diagnosing perineural metastasis
along the vidian nerve. Moreover, the frequency of perividian metastasis in
patients with head and neck cancer was evaluated. The CT and MR examinations of
98 consecutive untreated patients with histologically proven head and neck cancer
were retrospectively reviewed. We considered as criteria for perineural tumor
spread along the vidian nerve the following CT and MR findings: For CT (a)
enlargement of the pterygoid canal, (b) erosion of its bony wall, and (c)
obliteration of its normal fatty content; and for MR (a) enlargement of the
vidian nerve, (b) enhancement of the nerve, and (c) obliteration of fat,
particularly in the anterior part of the pterygoid canal. Ten patients met the
selected criteria for perineural metastasis, which was bilateral in 3 patients,
with a total of 13 vidian metastases. The CT scans demonstrated unilateral
involvement of the vidian nerve in 9 patients. The MRI scans showed 13 perineural
metastases. In 3 patients MR scans demonstrated involvement of four vidian nerves
that appeared normal on CT examinations. The diagnostic difference between CT and
MRI was statistically significant (Fisher's exact test; p = 0.04). Perineural
spread along the vidian nerve is an event more frequent than previously reported
and must be investigated with a careful imaging technique. Although a major
limitation of our study is the lack of histological proof, the MR finding of a
significant enhancement of the nerve, whether enlarged or normal in size, could
be considered very suggestive of this kind of metastatic spreading, particularly
if associated with simultaneous involvement of the neighboring structures
(pterygopalatine fossa, foramen lacerum, trigeminal branches, etc.).
PMID- 10757010
TI - Heparin-induced thrombocytopenia and fat necrosis of the breast.
AB - Fat necrosis of the breast is a well-known complication following trauma,
surgery, or radiotherapy. The present paper describes a rare case of fat necrosis
after heparin-induced thrombocytopenia. The mammographic, sonographic, and MR
evaluation and pathologic correlation after a 1-year follow-up period are
reported.
PMID- 10757011
TI - Mammary tuberculosis: percutaneous treatment of a mammary tuberculous abscess.
AB - It is currently very rare to find mammary involvement in cases of tuberculosis,
in either primary or secondary form. Diagnosis is classically clinical and
microbiological, and the basic techniques used in imaging diagnosis are
mammography and ultrasound. Computed tomography may define the involvement of the
thoracic wall in those cases which present as mammary masses adhering to deep
levels, and is also able to evaluate accompanying pulmonary disease, if it is
present. Traditionally, treatment has consisted of quadrantectomy and specific
antibiotic therapy. We present a case of tuberculous mammary abscess secondary to
pulmonary disease, which was treated by percutaneous drainage controlled by CT
and specific antibiotic therapy. We revise the diagnosis, differential diagnosis
and treatment of mammary tuberculosis.
PMID- 10757012
TI - Computed chest tomography in an animal model for decompression sickness:
radiologic, physiologic, and pathologic findings.
AB - This study was conducted to investigate the early pulmonary effects of acute
decompression in an animal model for human decompression sickness by CT and light
microscopy. Ten test pigs were exposed to severe decompression stress in a
chamber dive. Three pigs were kept at ambient pressure to serve as controls.
Decompression stress was monitored by measurement of pulmonary artery pressure
and arterial and venous Doppler recording of bubbles of inert gas. Chest CT was
performed pre- and postdive and in addition the inflated lungs were examined
after resection. Each lung was investigated by light microscopy. Hemodynamic data
and bubble recordings reflected severe decompression stress in the ten test pigs.
Computed tomography revealed large quantities of ectopic gas, predominantly
intravascular, in three of ten pigs. These findings corresponded to maximum
bubble counts in the Doppler study. The remaining test pigs showed lower bubble
grades and no ectopic gas by CT. Sporadic interstitial edema was demonstrated in
all animals--both test and control pigs--by CT of resected lungs and on
histologic examination. A severe compression-decompression schedule can liberate
large volumes of inert gas which are detectable by CT. Despite this severe
decompression stress, which led to venous microembolism, CT and light microscopy
did not demonstrate changes in lung structure related to the experimental dive.
Increased extravascular lung water found in all animals may be due to infusion
therapy.
PMID- 10757013
TI - Hypothenar hammer syndrome.
PMID- 10757014
TI - Magnetic susceptibility artifacts by titanium surgical clips mimicking
fibromuscular dysplasia of the renal artery in a kidney transplant.
PMID- 10757015
TI - A workshop on quality criteria for computed tomography held in Arhus, Denmark,
November 1998.
PMID- 10757016
TI - Quiz case of the month. Fibrolipomatous hamartoma of the median nerve.
PMID- 10757017
TI - Stem cell therapy and gene transfer for regeneration.
AB - The committed stem and progenitor cells have been recently isolated from various
adult tissues, including hematopoietic stem cell, neural stem cell, mesenchymal
stem cell and endothelial progenitor cell. These adult stem cells have several
advantages as compared with embryonic stem cells as their practical therapeutic
application for tissue regeneration. In this review, we discuss the promising
gene therapy application of adult stem and progenitor cells in terms of modifying
stem cell potency, altering organ property, accelerating regeneration and forming
expressional organization.
PMID- 10757018
TI - Accurate estimation of transduction efficiency necessitates a multiplex real-time
PCR.
AB - Transduction efficiency can be easily monitored during pre-clinical trials by
inclusion of marker genes. However, the use of such marker genes should be
avoided in the final clinical gene therapy application since their products are
often immunogenic, making it difficult to monitor transduction, especially if the
vector is applied in vivo. In these cases PCR-based methods like the real-time
PCR might provide a powerful tool to estimate biodistribution. To investigate the
accuracy of this method, we have developed and tested a real-time PCR assay for
the quantification of the enhanced green fluorescent protein (EGFP) gene and
compared the results with transduction efficiencies estimated by FACS analysis.
Although our real-time PCR assay itself was characterized by a high precision
over a wide dynamic range of quantification, significant differences in the
transduction efficiency compared with FACS data were initially observed. Accurate
determination could only be achieved using an optimized multiplex real-time PCR
assay, which allows the simultaneous calculation of cell number and EGFP copy
number in the same tube. In view of future needs for methods allowing precise and
accurate analysis of biodistribution in gene therapy trials, our data highlight
the necessity critically to check both parameters in the implemented assay.
PMID- 10757019
TI - Herpesvirus saimiri-based gene delivery vectors maintain heterologous expression
throughout mouse embryonic stem cell differentiation in vitro.
AB - In order to achieve a high efficiency of gene delivery into rare cell types like
stem cells the use of viral vectors is presently without alternative. An ideal
stem cell gene therapy vector would be able to infect primitive progenitor cells
and sustain or activate gene expression in differentiated progeny. However, many
viral vectors are inactivated when introduced in developing systems where cell
differentiation occurs. To this end, we have developed a mouse in vitro model for
testing herpesvirus saimiri (HVS)-based gene therapy vectors. We demonstrate here
for the first time that HVS is able to infect totipotent mouse embryonic stem
(ES) cells with high efficiency. We have transduced ES cells with a recombinant
virus carrying the enhanced green fluorescent protein (EGFP) gene and the
neomycin resistance gene (NeoR) driven by a CMV promoter and the SV40 promoter,
respectively. ES cells maintain the viral episomal genome and can be terminally
differentiated into mature haematopoietic cells. Moreover, heterologous gene
expression is maintained throughout in vitro differentiation. Besides its obvious
use in gene therapy, this unique expression system has wide ranging applications
in studies aimed at understanding gene function and expression in cell
differentiation and development.
PMID- 10757020
TI - Evaluation of recombinant alphaviruses as vectors in gene therapy.
AB - Alphavirus vectors based on Sindbis virus and Semliki Forest virus (SFV) were
characterized as potential gene transfer vectors. Initial studies were performed
using vectors engineered to transfer either lacZ or green fluorescent protein
(GFP). High levels of gene transfer were achieved in human primary fibroblasts,
BHK and 293T cells, with low levels of transduction observed in more than 20
other target cells. Alphavirus-based expression was generally very high, but
transient in every cell type. Replication-competent alphavirus was never detected
in SFV preparations but could be produced by Sindbis-based vectors at a frequency
of up to 3 x 10(-3) infectious units per ml. We constructed a human clotting
factor IX (hFIX) cDNA-containing Sindbis virus and compared it with hFIX cDNA
harboring adenoviral and retroviral vectors. In most cases, hFIX levels obtained
with Sindbis vector were initially at least an order of magnitude higher than
those obtained with other viral vectors. These data demonstrate that alphavirus
vectors compare favorably with adenovirus vectors as systems to promote high
level transient gene expression and should be considered as an alternative vector
for gene transfer and potential gene therapy studies.
PMID- 10757021
TI - Regulation of T-helper-1 versus T-helper-2 activity and enhancement of tumor
immunity by combined DNA-based vaccination and nonviral cytokine gene transfer.
AB - Intramuscular (i.m.) injections of a plasmid encoding human carcinoembryonic
antigen (CEA) elicited both humoral and cellular immune responses in mice, but
only partial inhibition of the growth of transplanted syngeneic CEA-positive P815
tumor cells (CEA/P815). Coinjection of the CEA vector with a vector encoding
either interferon-gamma (IFN gamma) or IL-12 promoted IgG2a isotype anti-CEA
antibody production, anti-CEA/P815 CTL activity and greater resistance to
CEA/P815 tumor challenge. As well, CEA/P815-stimulated IFN gamma secretion in
vitro was increased, but IL-4 diminished, consistent with a T-helper type 1 (Th1)
response. In contrast, coinjection of the CEA vector with an IL-4 vector
increased IgG1 production, but reduced CTL activity and resistance to tumor
challenge. The latter treatment inhibited CEA/P815-dependent IFN gamma production
but enhanced IL-4 secretion, consistent with a Th type 2 (Th2) response.
Antitumor immunity was enhanced when the CEA and IL-12 plasmids were coinjected
at the same muscle site, but not at separate sites despite increased serum IL-12
levels. Though the tumor cells expressed neomycin phosphotransferase, mice
immunized with vectors encoding that protein (without CEA) were not protected
against tumor growth, and produced no CTLs except for low levels when coinjected
with an IL-12 vector. Thus, we show that immunity elicited by DNA vaccination
against CEA can be biased to a protective type (high Th1 and CTL activity) or
nonprotective type (high Th2 and low CTL activity) by i.m. coinjection of
cytokine-expressing plasmids. IL-12 appears to act locally, but not systemically,
through an adjuvant effect.
PMID- 10757022
TI - Development of a hypoxia-responsive vector for tumor-specific gene therapy.
AB - We are developing new gene therapy vectors whose expression is selectively
activated by hypoxia, a unique feature of human solid tumors. As vascular
endothelial growth factor (VEGF) is upregulated by hypoxia, such regulatory
mechanisms would enable us to achieve hypoxia-inducible expression of therapeutic
genes. Constructs with five copies of hypoxia-responsive elements (HREs) derived
from the 5'-untranslated region (UTR) of the human VEGF showed excellent
transcriptional activation at low oxygen tension relevant to tumor hypoxia. In an
attempt to achieve higher responsiveness, various combinations of HREs and
promoters were examined. In addition, we also investigated whether the 3' UTR of
the VEGF gene would confer increased post-transcriptional mRNA stability under
hypoxic conditions. However, despite increases in the hypoxic/aerobic ratio of
luciferase activity, gene expression with 3' UTR was lower due to mRNA
destabilization by AU-rich elements (AREs). Thus, we found no benefit from the
inclusion of the 3' UTR in our vectors. Of all the vectors tested, the
combination of 5HRE and a CMV minimal promoter exhibited hypoxia responsiveness
(over 500-fold) to the similar level to the intact CMV promoter. We propose that
this vector would be useful for tumor selective gene therapy.
PMID- 10757023
TI - Rapid crossing of the pulmonary endothelial barrier by polyethylenimine/DNA
complexes.
AB - Intravenous administration could become a delivery route of choice for
prophylactic and curative gene therapies on condition that genes cross the
capillary barrier and reach target tissues without being degraded. We
investigated the kinetics and process of transgene delivery through mouse lung
capillaries following DNA complexation with linear polyethylenimine (L-PEI) and
intravenous injection. Using digoxin-labeled DNA we followed the cellular
localization of DNA at different times after injection and correlated these
findings with cell markers and transgene expression. At 2 h after injection some
DNA was still localized on the interior of the capillary lumen, but other
complexes had already crossed the barrier and resulted in gene expression. At 24
h after injection most labeled DNA was localised in pulmonary cells, as was
transgene expression. Only rarely was transgene expression found in endothelial
cells, suggesting that the complexes cross the capillary barrier rapidly. Levels
of caspase-1-like activity did not increase following transfection implying that
L-PEI/DNA complexes are transported across cellular barriers by a non-damaging,
physiological process, without causing inflammation. The high levels of
expression of different transgenes in pneumocytes indicates that transport of L
PEI/DNA complexes through the endothelial barrier does not affect their
transfection capacity. These findings open up new possibilities for gene delivery
and its application to the lung.
PMID- 10757024
TI - Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac
allografts in rats.
AB - Interleukin-10 (IL-10) and interleukin-4 (IL-4), two Th2-derived cytokines, are
molecules with anti-inflammatory and immunodeviating properties whose direct
expression in allografts may prolong graft survival. Recombinant adenoviruses
represent efficient vectors for gene transfer in quiescent cells in vivo.
Adenoviral vectors encoding rat IL-10 (AdIL-10), rat IL-4 (AdIL-4) or beta
galactosidase (AdlacZ) or without transgene (Addl324) were injected directly into
rat hearts at the time of transplantation in order to test their potential to
prolong heart allograft survival. Expression of vectorized sequences was
confirmed in heart biopsies, and kinetic analysis of beta-galactosidase showed
transient expression. Cardiac allograft survival was significantly prolonged
after administration of 10(9) p.f.u. of AdIL-10 (16.6 +/- 3.2 days, P < 0.05),
but not AdIL-4 (9.8 +/- 1.6 days), compared with Addl324-treated (9.3 +/- 3.3
days) or untreated groups (7.8 +/- 1.5 days). Immunohistochemical analysis of
allografts after gene transfer of IL-10 showed that leukocyte infiltration was
quantitatively equivalent to that seen in control groups but with a strong
tendency towards lower levels of CD8+ cells. Importantly, adenovirus-derived IL
10 modified the functional status of leukocytes by inducing a significant
decrease in IFN-gamma production but significantly increased transforming-growth
factor beta 1 (TGF-beta 1) expression within the grafts compared with those
treated with Addl324. These results show that expression of IL-10 by rat hearts
after gene transfer mediated by an adenoviral vector decreases allogeneic immune
responses and allows prolongation of allograft survival.
PMID- 10757025
TI - Development of synthetic promoters for radiation-mediated gene therapy.
AB - Exposure of cells to ionising radiation results in the activation of specific
transcriptional control (CArG) elements within the early growth response 1 (Egr1)
gene promoter, leading to increased gene expression. As part of a study
investigating the potential use of these elements in radiation-controlled gene
therapy vectors, we have incorporated their sequences into a synthetic gene
promoter and assayed for the ability to induce expression of a downstream
reporter gene following irradiation. In vector-transfected MCF-7 breast
adenocarcinoma cells, the synthetic promoter was more effective than the wild
type Egr1 counterpart in up-regulating expression of the reporter gene after
exposure to a single 5 Gy dose, and equally effective as the wild-type in U87-MG
glioma cells. The level of gene expression achieved using the synthetic promoter
was dependent on the inducing radiation dose for both U87-MG and MCF-7 cells,
being maximal at 3 Gy and decreasing at 5 and 10 Gy. Furthermore, induction could
be repeated by additional radiation treatments. The latter indicates that up
regulation should be additive during fractionated radiotherapy schedules. To
demonstrate the potential clinical benefit of such an approach, the synthetic
promoters were also shown to drive expression of the herpes simplex virus
thymidine kinase gene, leading to enhanced cell killing in the presence of the
prodrug ganciclovir (GCV) when compared with cells treated with radiation alone.
Our results demonstrate that the synthetic promoter is responsive to low doses of
ionising radiation and therefore isolated CArG elements function as radiation
mediated transcriptional enhancers outside their normal sequence context. The
continued development and optimisation of such radiation-responsive synthetic
promoters is expected to make a valuable contribution to the development of
future radiation-responsive vectors for cancer gene therapy.
PMID- 10757026
TI - The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human
pancreatic cancer cells in the liver of nude mice.
AB - In pancreatic cancer, the mutation of c-K-ras is a critical event of tumor growth
and metastasis. We have previously demonstrated a dominant negative effect of
N116Y on the growth of pancreatic cancer cells. To evaluate the potential of
N116Y for suppressing the metastatic growth of pancreatic tumor cells, we made a
replication-deficient recombinant N116Y adenovirus driven by the carcinoembryonic
antigen (CEA) promoter (Ad CEA-N116Y). We demonstrated that the expression of
N116Y, growth inhibition, and apoptotic death induction were all specific to
pancreatic cancer cell lines (PCI-35 and PCI-43) that were promoter positive,
whereas no growth retardation was observed in human embryonic pancreas-derived
cell line 1C3D3 after Ad CEA-N116Y infection. We examined the effect of Ad CEA
N116Y on the metastatic growth of PCI-43 colonies in liver, which was generated
by tumor injection into the spleen of nude mice. The results showed that Ad CEA
N116Y effectively reduced the number of metastatic colonies without any
complication by injecting intrasplenically 5 days after tumor cell inoculation.
Thus, N116Y can selectively suppress the metastatic growth of pancreatic tumor
cell by using the CEA promoter-driven adenovirus vector indicating that N116Y
gene therapy may be potentially useful for the treatment of pancreatic cancer
patients with liver micrometastasis.
PMID- 10757027
TI - Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of
apoptosis of rheumatoid synoviocytes but not chondrocytes.
AB - Synovial cells in the rheumatoid synovium show abnormal proliferation, leading to
joint destruction. Rheumatoid synovial cells express functional Fas antigen and
are susceptible to Fas-mediated apoptosis. We have proposed the induction of
apoptosis by Fas/Fas ligand system of proliferative rheumatoid synovium as a
novel therapy for rheumatoid arthritis (RA). We have recently reported that Fas
associated death domain protein (FADD) plays a key role in Fas-mediated apoptosis
of synovial cells in patients with RA. In this study, we determined whether FADD
gene transfer could induce apoptosis of RA synoviocytes in vitro and in vivo.
Transfection of FADD gene by adenoviral vector into cultured RA synoviocytes
induced up-regulation of FADD expression and apoptosis. In addition, local
injection of FADD adenovirus (Ad-FADD) eliminated synoviocytes in vivo by
induction of apoptosis of proliferating human rheumatoid synovium engrafted in
severe combined immunodeficiency mouse, which is the most suitable animal model
of RA for the evaluation of treatment strategy in vivo. In addition, Ad-FADD
induced apoptosis was limited to cells of the synovium tissue and did not affect
chondrocytes. Our results strongly suggest that FADD gene transfer can induce
apoptosis of RA synoviocytes both in vitro and in vivo, suggesting that FADD gene
transfer might be effective in the treatment of RA.
PMID- 10757028
TI - Transfer of the feline erythropoietin gene to cats using a recombinant adeno
associated virus vector.
AB - Chronic renal failure and the associated erythropoietin-responsive anemia
afflicts over 2 million domestic cats in the United States, resulting in
morbidity that can affect the owner-pet relationship. Although treatment of cats
with recombinant human erythropoietin (Epo) protein can be effective, response to
the drug often dissipates over time, probably due to the development of
antibodies reactive with the human protein. As an alternate approach to the
treatment of this disease, we have developed a recombinant adeno-associated virus
vector containing the feline erythropoietin gene (rAAV/feEpo). This vector, when
administered intramuscularly to normal healthy cats, caused a dose-related
increase in hematocrit over a 7-week period after injection. Thus, the rAAV/feEpo
vector holds promise as a simple, safe and effective therapy for the anemia of
chronic renal failure in domestic cats.
PMID- 10757029
TI - Approaches to the space-time modelling of infectious disease behaviour.
AB - A new approach to the space-time modelling of infectious diseases is considered.
A modulated heterogeneous Poisson process with intensity defined as a function of
a two-dimensional susceptibility field is proposed. The model is fitted to a
measles epidemic using a proportional hazards approximation.
PMID- 10757030
TI - The basic reproduction ratio for a model of directly transmitted infections
considering the virus charge and the immunological response.
AB - In order to describe mathematically the transmission of microparasites,
especially directly transmitted infections, it is usual to set up differential
equations assuming the mass action law and a homogeneously mixed population. In
this paper we analyze such a model taking into account heterogeneity with respect
to the infectivity, that is, the variability in the evolution of the interaction
between parasite and the human host during the infectious period. The well
established biological phenomenon of initial increase in parasite abundance
followed by its decrease, due to the interaction between the host's immunological
response and the parasite, has thus been taken into account. The variable amount
of microparasites eliminated by an infectious individual, and the different
(heterogeneous) immunological response build up by the host when in interaction
with parasite are present in the model. The analytical expression for the basic
reproduction ratio is derived through stability analysis.
PMID- 10757031
TI - Therapy burden, drug resistance, and optimal treatment regimen for cancer
chemotherapy.
AB - Three nonlinear models of tumour cell growth under continuous delivery of cycle
nonspecific anticancer agents are studied. A dynamical optimization problem with
the objective of minimizing the final level of tumour cells is posed for these
mathematical setups. The simplest setup does not possess toxicity constraints,
whereas the other setups contain a dynamical equation describing the therapy
burden as a toxicity criterion. In addition, the third setting contains the
dynamics of drug resistant cells. A discussion concerning the optimal strategies
of the respective models is performed.
PMID- 10757032
TI - Multidimensional counting processes and evoked neuronal activity.
AB - It is shown that the joint behaviour of n counting processes can be used for
description of neuronal spike generation in a system of n neurons with various
synaptic links. This multidimensional process is suggested as a model of neuronal
activity evoked by either a homogeneous or an inhomogeneous stimulus during a
short time period. Several situations are considered, mainly the joint activity
of pairs of neurons. The probability generating functions of the process are
obtained for different kinds of intensity functions. The first and second moments
of the process are provided as a tool for potential comparison of the model with
experimental data.
PMID- 10757033
TI - A spatial model of antipredator vigilance.
AB - Many species of animals have to perform two contradictory tasks: feeding, and
avoiding becoming food for others. A large number of theoretical and empirical
studies have investigated the trade-off between feeding and antipredator
vigilance, especially in birds. An important factor which has been neglected in
these studies is that of the area occupied by the flock. If individuals feed
close together, competition increases and feeding rates decrease. However, if
individuals space themselves widely, then vigilance efficiency goes down and
there is an increased predation risk. We develop a vigilance model which allows
birds to control the area the flock occupies as well as their vigilance rate. The
optimal strategy is found for the birds under a variety of environmental
conditions. In particular the effect of each environmental parameter on this
optimum is considered in turn. How the model can be adapted for different bird
species is also investigated.
PMID- 10757034
TI - Susceptibility to polyoma virus tumorigenesis in X-linked immunodeficient (XID)
and B-cell deficient (microMT) mice is not increased.
AB - Polyoma virus induced tumorigenesis is controlled by T-cells, while B-cells clear
virus infection. In order to study if T-cells can override the tumorigenic effect
of a long term disseminated viral infection, the tumorigenicity and persistence
of polyoma virus in antibody deficient adult and newborn infected X-linked
immunodeficient (XID) and microMT mice was followed. In newborn infected XID and
CBA control mice (sensitive to tumorigenesis), the frequency of tumor development
was similar, and viral DNA was persistent at least 10 months p.i. In polyoma
infected newborn and adult microMT, and control C57BL/6 mice (resistant to
tumorigenesis) as well as in adult XID and CBA control mice, no polyoma tumors
were observed. Nevertheless, viral DNA was detected in most tissues in all
microMT mice throughout the 5-7 month observation period, whereas in the
remaining groups of mice persistent viral infection was limited or not detected.
We suggest that the tumorigenic potential of an extensive persistent polyoma
virus infection can be overcome as long as a functional T-cell system is present.
PMID- 10757035
TI - In vivo therapeutic effects of IFN-gamma on human myelogenous leukemia in a
severe combined immunodeficiency mouse model.
AB - BACKGROUND: Results of clinical trials of IFN-gamma on the treatment of various
types of leukemia are not so promising, regardless of the antiproliferative
activity against leukemic cells and expected immunomodulatory effects. In this
study, we have re-evaluated the anti-leukemic effects of natural human IFN-gamma
(nHuIFN-gamma) using an established human myelogenous leukemia model in SCID
mice. MATERIALS AND METHODS: SCID mice transplanted with human myelogenous
leukemia cell line ML-2S received subcutaneously 5 x 10(4) IU/mouse of nHuIFN
gamma at 5 times/week for 5 weeks. RESULT: nHuIFN-gamma significantly prolonged
the lifespan of SCID mice in leukemic crisis. Percentages of ML-2S cells in the
peripheral blood were also significantly decreased by the IFN-gamma treatment.
Histopathological examination revealed that IFN-gamma treatment suppressed the
replacement of pancreatic cells by tumor cells and the formation of tumor masses
in the intestine. CONCLUSIONS: These results suggest that IFN-gamma is effective
against human myeloid leukemia, especially extramedullary tumor mass-forming type
in the peritoneal organs. Our results further suggest that studies employing SCID
mice leukemia model would help in devising appropriate therapeutic strategies of
IFN-gamma based on the specific characteristics of each leukemia subtype.
PMID- 10757036
TI - Inhibitors present in blood do not inhibit PCR from buccal cell preparations:
case report.
AB - BACKGROUND: Hemochromatosis is a common disease that is characterized by high
ferritin levels and/or high iron saturation and mutations in two alleles.
MATERIAL AND METHODS: Polymerase chain reaction (PCR) and restriction fragment
length polymorphism (RFLP) is often performed on DNA extracted from blood since
blood yields high concentrations of DNA. However, inhibitors can cause PCR
failure in DNA extracted from blood thus preventing a molecular diagnosis.
RESULTS: This report describes a case where multiple blood draws resulted in
unamplifiable DNA. Subsequently, a buccal cell sample was collected and
extracted. DNA extracted from the buccal cells yielded amplifiable DNA in
contrast to DNA extracted from the patient's blood. In addition, the patient was
identified as having a homozygous mutation for one allele of the hemochromatosis
gene. CONCLUSION: These results suggests that a buccal cell DNA extraction may be
useful in cases where blood samples contain inhibitory substances for PCR.
PMID- 10757037
TI - Differential regulation of the major cyclin-dependent kinases, cdk2 and cdc2,
during cell cycle progression in human lymphocytes exposed to heptachlor.
AB - Heptachlor, a chlorinated hydrocarbon insecticide, has been considered an
environmental contaminant with potential adverse health effects. Exposure to
heptachlor may impair immune functions including the inhibition of leukocyte
chemotaxis, which causes defects in host defense mechanisms. This study addresses
the effects of heptachlor on the cell cycle progression of human lymphocytes. It
has been found that addition of heptachlor to cultured lymphocytic cells prevents
the cells from progression into the S phase of the cell cycle, with a concomitant
accumulation of cells in G1 phase. An accompanying decrease (deactivation) in
cyclin-dependent kinase cdk2 and dephosphorylation (activation) of cdc2 was
observed. The altered cell cycle progression may trigger the cell's apoptotic
potential, as indicated by the reduced amount of Bcl-2 synthesized inside
heptachlor-treated cells. The interference of cell cycle progression by
heptachlor was also seen with chlordane and toxaphene, two other chlorinated
hydrocarbon insecticides.
PMID- 10757038
TI - Detection of herpes simplex virus DNA in maternal breast milk by in situ
hybridization with tyramide signal amplification.
AB - In this study we investigated the prevalence of herpes simplex virus 1 (HSV-1)
and 2 (HSV-2) in maternal breast milk using the technique of in situ
hybridization combined with the sensitive detection system of tyramide signal
amplification. Breast milk samples were collected from both breasts of 34
puerperals 4-5 days after delivery. HSV DNA was detected in 16 out of 34 examined
breast milk specimens. HSV DNA was found in the milk of both breasts in 10 cases
(62.5%), in that of left breast in 4 cases (25%) and in the milk of only the
right breast in 2 cases (12.5%). HSV DNA was localized in the nuclei of
mononuclear cells and to a lesser degree in the nuclei of epithelial cells. The
number of HSV infected cells ranged from a few cells per sample to 20% of cells
(mean value 9%, median value 5%). According to HSV typing, we found both HSV-1
and HSV-2 in 11 out of 16 positive cases and HSV-2 only in 5 cases. In
conclusion, our findings indicate that HSV-1 and HSV-2 are shed into breast milk
in a significant proportion of puerperals and breast-feeding may be an important
route for the transmission of these viruses to infants.
PMID- 10757039
TI - Energy metabolism in the involuting mammary gland.
AB - A strong and coordinated upregulation of the glycolytic, glutaminolytic and
pentose phosphate pathway enzymes occurs during the onset of lactation in the
normal mouse mammary gland. Induction of apoptosis by removing the pups led to an
inactivation of the same enzymes with different time courses. While the ATP
consuming glycolytic 6-phosphofructo 1-kinase and mitochondrial bound hexokinase
still remained high on days one and two of involution, the ATP-regenerating
pyruvate kinase was immediately reduced. The enzymes of the pentose phosphate and
glutaminolytic pathway were inactivated on the first two days of involution. In
accordance with such an inactivation of the enzymes ATP, GTP, UTP, ADP, NAD NADH
and lactate concentrations decreased. The synthetic product of UTP, UDP-N
acetylglucosamine, increased. AMP was found in the milk, not in the epithelial
cells. The inactivation of the enzymes was caused by partial proteolysis or by a
loss of the intact proteins from the cytosol without signs of proteolysis.
PMID- 10757040
TI - Suppressive effects of azelastine hydrochloride on CD40 expression in mice.
AB - The present study was designed to examine the influence of an anti-allergic
agent, azelastine hydrochloride (AZ) on a co-stimulatory molecule, CD40
expression in actively sensitized mice. BALB/c mice were sensitized by
intraperitoneal injection of two doses of dinitrophenylated-ovalbumin and Al(OH)3
at one-week intervals. The mice were treated orally with 0.1 mg/kg of AZ once a
day for 14 days starting the same day of booster sensitization. AZ treatment of
mice caused the significant suppression of total serum IgE concentration on Day
21 after the first sensitization. However, AZ treatment scarcely affected IL-4
concentration in aqueous spleen extracts. Flowcytometric analysis revealed the
suppressive effects of AZ on CD40 expression on sensitized-spleen cells. These
data may suggest that AZ suppresses the production of IgE through the inhibition
of CD40 expression.
PMID- 10757041
TI - Loss of growth arrest DNA damage genes expression in oral melanomas.
AB - 29 oral melanomas were stained immunohistochemically for the GADD34, GADD45 and
GADD153. GADD34 was found in 5/29 melanomas and its expression did not exceed
21%, averaging 4.1% of melanoma cells. GADD45 was observed in 8/29 oral melanomas
and cell positivity averaged 2.8%. GADD153 was found in 2/29 melanomas and the
percentage of positive cells ranged between 0 and 31%, averaging 1.2%. Not one
significant correlation between GADD genes in oral melanomas was found. Loss of
GADD gene expression and lack of correlation between them show advanced
disturbances in their cooperation, leading to a high genetic instability of oral
melanoma cells.
PMID- 10757042
TI - Comparison of sensitivities of uterine cells in their proliferation responding to
epidermal growth factor and estrogen between neonatal and postneonatal mice.
AB - The uteri of mice up to 20 days after birth show estrogen-independent growth,
although their growth is accelerated by estrogen, while the growth of the uteri
of mice after 20 days completely depends on estrogen. In the present study, we
compared the sensitivities of uterine cells in their proliferation responding to
epidermal growth factor (EGF) and diethylstilbestrol (DES) between 5-day-old and
25-day-old ovariectomized mice. A single subcutaneous injection of EGF at doses
of 0.25 and over 0.25 microgram/g body weight (BW) increased 3H-thymidine uptake
by the whole uterus dose-dependently in both 25-day-old and 5-day-old mice, and a
maximal increase in the 3H-thymidine uptake was attained at a dose of 1
microgram/g BW of EGF in both mice. A single subcutaneous injection of DES at
0.001 and over 0.001 microgram/g BW increased 3H-thymidine uptake by the whole
uterus dose-dependently in both 25-day-old and 5-day-old mice, and a maximal
increase was attained at 0.004 microgram/g BW of DES in both mice. EGF and DES
increased labeling indices of both the epithelium and stroma in both 25-day-old
and 5-day-old mice. The present results suggest that sensitivities of uterine
cells of neonatal mice in their proliferation responding to EGF and DES are
similar to those of postneonatal mice.
PMID- 10757043
TI - Opinions on and use of alternative medicine among physicians, nurses and clerks
in northern Norway.
AB - In February 1997 a questionnaire on alternative medicine was distributed to 172
physicians, 374 nurses and 96 clerks, all employed in hospitals in the northern
part of Norway. A response rate of 57% was achieved. The aim of the study was to
compare different health professions regarding views on and use of alternative
medicine. Among all respondents 56% described themselves as having a positive
attitude towards alternative medicine (16% of the physicians, 71% of the nurses
and 72% of the clerks). Twelve percent of physicians, 32% of nurses and 46% of
clerks had been using alternative medicine. Female physicians and female nurses
showed a more positive attitude and were more frequent users of alternative
medicine than their male counterparts. Physicians had confidence in acupuncture,
herbs and diets, mainly as treatment of muscle-skeletal disorders, and migraine.
Nurses and clerks on the other hand tended to believe in various alternative
methods against a broad range of disorders. Female physicians and nurses
emphasised the importance of more information, knowledge and openness towards
alternative treatments more than their male counterparts. They also believed that
traditional medicine could benefit from adopting principles from alternative
medicine.
PMID- 10757044
TI - Proinflammatory and regulatory cytokine levels in AIDS cachexia.
AB - The serum concentrations of inflammatory (Interleukin-1 beta, Tumor necrosis
alpha, Interleukin-6) and regulatory cytokines (Interleukin twelve) have been
studied in ten AIDS cachectic patients and compared to a control group. A
cytokine imbalance, and peculiarly a significant increase in proinflammatory
cytokines (Interleukin-1, Interleukin-6, Tumor necrosis Factor alpha) and a
decrease in regulatory cytokines such as Interleukin-12 were found. A significant
correlation resulted between weight loss and Interleukin-1 beta and 6. A negative
correlation between Interleukin-1 and 12 was noted, indicating that this last
cytokine has an important regulatory role also in advanced state of the disease.
PMID- 10757045
TI - Inhibitory action of roxithromycin on tumour necrosis factor-alpha production
from mast cells in vitro.
AB - This study was designed to evaluate the effects of roxithromycin (RXM), a newly
synthesized macrolide antibiotic, on cytokine production from mast cells. Mast
cells, induced by long-term culture of spleen cells from BALB/c mice, were
stimulated with 2.5 micrograms/ml concanavalin A in the presence or absence of
various concentrations of RXM. The culture supernatants were obtained 24 h after
stimulation. RXM caused a reduction in TNF-alpha levels in culture supernatants
in a dose dependent manner and was first detected at a concentration of as little
as 0.5 microgram/ml. Metabolized RXM (RU 39001, RU 44981, and RU45179) also
suppressed TNF-alpha production in a dose dependent fashion with a minimum
concentration of 0.5 microgram/ml. However, metabolized RXM, RU 28111, scarcely
affected TNF-alpha production from cultured mast cells. These results strongly
suggest that RXM inhibits mast cell function, especially inflammatory cytokine
production and may result in favorable modification in inflammatory diseases.
PMID- 10757046
TI - DNA damage, cell kinetics and ODC activities studied in CBA mice exposed to
electromagnetic fields generated by transmission lines.
AB - CBA mice were exposed outdoors to 50 Hz electromagnetic fields (EMF), with a flux
density of about 8 microT rms (root mean square), generated by a 220 kV
transmission line. Assays were performed in order to investigate, the possible
genotoxic effects after 11, 20 and 32 days of exposure, as well as the effects on
body weight, leukocytes, erythrocytes, and the level of ornithine decarboxylase
(ODC) activity in spleen and testis. DNA migration was studied on brain cells by
single cell electrophoresis (comet assay). After 32 days of exposure a highly
significant change of the tail/head ratio of the comets was observed (p < 0.001),
showing DNA-damage. Further, a decreased number of mononuclear leukocytes (0.02 <
p < 0.05) was observed in mice EMF-exposed for 20 days. In summary, our data
indicate that transmission lines of this type may induce genotoxic effects in
mice, seen as changes in the DNA migration. These results might have an important
implication for health effects.
PMID- 10757047
TI - Myoepithelial sialadenitis versus low-grade non-Hodgkin's lymphoma of the
salivary gland in FNAB: is discrimination by means of an image processing system
possible?
AB - The diagnosis of myoepithelial sialadenitis (MESA) in fine needle aspiration
biopsy may be difficult. There is a dense lymphocytic infiltration in the gland
and discrimination between a hyperimmune reaction and a low grade non-Hodgkin's
lymphoma (NHL) of B-cell origin may be impossible. To get additional
diagnostically helpful criteria, texture feature analysis on routinely obtained
FNAB's of the salivary gland was applied. In the data set 36/36 cases of low
grade B-NHL confirmed by histology and 10/13 histologically confirmed cases of
MESA could be classified correctly by means of an image processing system. The
chromatin structure of each nucleus was classified by texture features (n = 6),
which were determined according to the method of Harms et al. For statistical
analysis of the cell types a classification tree based on the commercial program
CART was applied. The data set of 49 cases was proved by the crossvalidation test
10 fold. The calculated diagnosis for each case suggests that this method may be
helpful in the cytologically doubtful cases.
PMID- 10757048
TI - Systemic effects of the occlusal destruction in guinea pigs.
AB - Although there is an increasing amount of information pertaining to the systemic
effects of malocclusion, its mechanisms still remain unclear in many ways. This
study was conducted to find out the systemic effects of the occlusal destruction
in guinea pigs. The animals showed an abnormality in posture and a reversal of
the T wave in electrocardiogram (ECG) about 6 days after the grinding of all
molar teeth. All the animals died about 7 days after the occlusal destruction. We
established the optimal condition of occlusal destruction for the induction of
the above symptoms in guinea pigs: at least 6 molars, both side premolar, 1st and
2nd molar of upper jaw, because of the ease for repair. The following results
were obtained: 1. The experimental group died about 5 days earlier than the
fasting group. 2. The animals could not hold their head positions and dropped the
head to the earth. 3. The animals died about 12 hours after the onset of postural
abnormality. 4. Ninety percent of the animals with postural abnormalities showed
T wave inversion on ECG. 5. None of the above symptoms occurred with bite rising.
These results indicate that occlusal destruction affects head position,
preventing the animals to hold their head positions and causing the head to drop
to the ground. Occlusal destruction may also cause abnormality of the masticatory
muscles, which control posture and modulate cardiac function via the trigeminal
system. This experimental model is suitable for the analysis of the systemic
effects of occlusal destruction.
PMID- 10757049
TI - Effects of proton and gamma radiation on lymphocyte populations and acute
response to antigen.
AB - BACKGROUND: The clinical use of proton radiation in the management of cancer, as
well as benign disorders, is rapidly increasing. The major goal of this study was
to compare the effects of proton and gamma (60Co) radiation on cell-mediated and
humoral immunological parameters. MATERIALS AND METHODS: C57BL/6 mice were
exposed to a single dose of 3 Gray (Gy) protons or gamma-rays and
intraperitoneally injected 1 day later with sheep red blood cells (sRBC). On 4,
10, 15, and 29 days after exposure, subsets from each group were euthanised;
nonirradiated controls (with and without sRBC injection) were included. Body and
relative spleen weights, leukocyte counts, spontaneous blastogenesis, lymphocyte
populations, and anti-sRBC titers were evaluated. RESULTS: The data showed
significant depression (p < 0.05) in nearly all assays on days 4 and 10 after
irradiation. B lymphocytes (CD19+) were the most radiosensitive, although
reconstitution back to normal levels was observed by day 15. T cell (CD3+) and T
helper cell (CD4+) recovery was evident by day 29, whereas the T cytotoxic cell
(CD8+) count remained significantly below normal. Natural killer cells (NK1.1+)
were relatively radioresistant. Anti-sRBC antibody production was slow and low
titers were obtained after irradiation. No significant differences were noted
between the two types of radiation. CONCLUSIONS: Taken together, the data show
that whole-body irradiation with protons or gamma-rays, at the dose employed,
results in marked, but transient, immunosuppression. However, at the time points
of testing and with the assays used, little or no differences were found between
the two forms of radiation.
PMID- 10757050
TI - Human proinsulin gene-transfected Chinese hamster ovary cells secrete
immunoreactive insulin.
AB - BACKGROUND: Considering the difficulties in pancreas transplantation, the
development of an artificial pancreas can be one of the new approaches. The
present study was designed to assess whether or not Chinese hamster ovary (CHO)
cells, which were transfected with the human proinsulin (hPI) gene, secrete
immunoreactive insulin (IRI) and respond to glucose loading. MATERIALS AND
METHODS: A complementary DNA encoding hPI was obtained by polymerase chain
reaction amplification from human pancreatic tissue and was inserted into the
plasmid pcDNA I/NEO to construct an expression vector for the hPI gene. CHO cells
were transfected with hPI gene using lipofectin, and the hPI gene-expressing
clones (CHO/I) were selected. RESULTS: Five clones of CHO/I cells, releasing IRI
into the culture supernatant, were separated. Immunohistochemistry with a
monoclonal antibody demonstrated the IRI in the cytoplasm of CHO/I cells, and
transmission electron microscopic examination demonstrated the prominently
developed mitochondria, but no secretion granules. ELISA assay demonstrated the
secretion of IRI into the culture supernatant of CHO/I, but CHO/I cells did not
respond to the glucose loading. When CHO/I cells were transplanted subcutaneously
into the back of nude mice, the growing tumors secreted IRI. CONCLUSIONS: These
results demonstrate that the hPI gene can be transfected into mammalian cells and
function in vivo, and suggest that this kind of gene technology may be applicable
in the development of an artificial pancreas.
PMID- 10757051
TI - Experimental echinococcus infection in the mouse model: pericystic cellular
immunity reaction and effects on the lymphoid organs of immunocompetent and
thymectomized mice.
AB - Echinococcus can infect man as an accidental intermediate host causing hydatid
disease. The infection persists and the growth of the cysts advances, while the
patient usually remains asymptomatic for years. Experimental Echinococcus
infection in mice provides a well described model for the study of the parasite
host relationship that permits the evolution of the disease despite the
activation of the host's immune system. The aim of the present study was to
assess the immune response to Echinococcus infection in normal and thymectomized
mice. For this purpose, a total of 150 mice, divided into three equal groups (A,
B and C), were infected by intraperitoneal inoculation of live protoscoleses. The
mice of groups B and C underwent thymectomy, two weeks prior and after the
infection, respectively. The mice of each group were further divided into three
subgroups and were sacrificed at three consecutive time points: 45 days, 3 and 6
months post the infection. The hydatid cysts that subsequently developed by the
metacestode-lavral stage, along with the spleen and lymph nodes were excised from
each mouse and histologically studied. The results revealed a marked activation
of the cell-mediated immunity against the parasite at the early stages of the
disease. The initial response of the host abated with time and was minimal six
months after the infection suggesting a local immunosuppression state that could
account for the advancement of the disease. In addition, the thymectomized mice
exhibited a higher susceptibility to the infection, which corresponded to the
weak and delayed cellular immunity response observed in these groups. These
results suggest that the cell-mediated immunity is crucial for the defense
against Echinococcus, especially early in the course of the disease where
suppression of larval growth is critical for the final outcome of the infection.
PMID- 10757052
TI - Status of hepatic oxidative stress and antioxidant defense systems during
chloroquine treatment of Plasmodium yoelii nigeriensis infected mice.
AB - BACKGROUND: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal
malaria infection in Swiss albino mice. Reactive oxygen species (ROS) such as
superoxide anion, hydrogen peroxide have been implicated in the pathogenesis of
malaria. OBJECTIVE: Study the effect of the chloroquine treatment on hepatic
oxidative stress and antioxidant defense indices in multiple drug resistant (MDR)
P. y. nigeriensis infected mice. METHODS: Mice were divided into four groups.
Normal group, chloroquine treated normal group, P. y. nigeriensis infected group,
and P. y. nigeriensis infected mice treated with chloroquine group (10 mg/kg body
weight, i.p.). RESULTS: P. y. nigeriensis infection resulted in a significant
decrease in the hepatic protein levels and caused a significant increase in the
hepatic oxidative stress indices such as xanthine oxidase and lipid peroxidation
and also an increase in the antioxidant defense indices viz, reduced glutathione
(GSH), and glutathione reductase, but a significant decrease in superoxide
dismutase (SOD) and catalase. The chloroquine treatment of P. y. nigeriensis (MDR
strain) infected mice did not completely cure blood parasitemia, but resulted in
a decrease of blood parasitemia. This was accompanied by decrease in hepatic
oxidative stress indices and an associated change in the antioxidant defense
indices towards normalization. CONCLUSION: Chloroquine therapy alone is not
sufficient to treat the malaria infection caused by multiple drug resistant
strain of P. y. nigeriensis. Therefore, there is a need to develop newer
antimalarials which could act alone or in combination with traditional
antimalarials to be effective against drug resistant malarial parasites.
PMID- 10757053
TI - DNA damage induced in brain cells of CBA mice exposed to magnetic fields.
AB - DNA migration, using single cell gel electrophoresis (comet assay), was studied
on brain cells of CBA mice exposed continuously to 50 Hz, 0.5 mT magnetic fields
(MF) for 2 hrs, 5 days or 14 days. No differences were observed in the groups MF
exposed for 2 hrs and 5 days compared with controls. However, in the group
exposed to MF for 14 days, a significantly extended cell DNA migration was
observed (0.02 < p < 0.05). These changes together with results from previous
studies indicate that magnetic fields may have genotoxic effects in brain cells.
PMID- 10757054
TI - Comparison of the DNA content in the different steps of cutaneous carcinoma
progression.
AB - The main aim of this study was to check the application of ploidy related
parameters for differential diagnosis between solar keratosis, Bowen's disease
and squamous cell carcinoma of the skin. 10 specimens of normal epidermis, 68
solar keratoses, 50 cases of Bowen's disease and 10 squamous cell carcinomas
(SCC) were stained with Feulgen and their ploidy status was evaluated with a
CAS200 image analyzer. Significant and highly significant differences between
groups investigated not only for 5c exceeding rate, but also for the ratios of
diploid, aneuploid, tetraploid, octaploid and 16-ploid cells are demonstrated.
With respect to ploidy associated parameters solar keratosis is closer related to
SCC of the skin than Bowen's disease. These findings are in accordance with a
higher risk of progression to SCC inspite of a generally lower degree of atypia.
PMID- 10757055
TI - cis-hydroxyproline stimulates the growth of rat mammary carcinoma cells.
AB - With the ever-increasing evidence that the extracellular matrix (ECM) can
stimulate tumor growth, it follows that inhibiting the synthesis of tumor-derived
stroma may be a potential therapeutic target of cancer progression. The proline
analog cis-hydroxyproline (CHP), an inhibitor of collagen deposition, was
examined for its effects on the growth of clonal tumor cells that differentially
produce type IV collagen and laminin. Two separate clones derived from rat
mammary carcinoma cells that produce high and low amounts of type IV collagen and
laminin were injected into the flanks of nude mice. Tumors in animals receiving
CHP treatment grew faster than tumors in control animals receiving saline,
although statistically not significant. Furthermore, upon administration of CHP
to these clones in culture, increased proliferation rates of both cell types were
observed. These results show that CHP is not useful in preventing stromal
development and growth of rat mammary tumor xenografts.
PMID- 10757056
TI - Mutations of transforming growth factor beta 1 type II receptor, BAX, and insulin
like growth factor II receptor genes in microsatellite unstable cell lines.
AB - Inactivation of the DNA mismatch repair (MMR) system allows the genome to
accumulate mutations because of failure to correct mispairing of nucleotides and
slippage mistakes at microsatellite sequences (termed microsatellite instability
?MSI?). While most mutations are acquired in noncoding regions by virtue of its
larger share of DNA, mutations may occur in exons of genes that contain
microsatellite sequences. The type II receptor for TGF beta 1 (TGF beta RII), the
insulin-like growth factor II receptor (IGFIIR), and the proapoptotic gene BAX
have been shown to contain mononucleotide microsatellites, and in MSI tumors,
mutations may occur in these sequences late in the multistep carcinogenesis
pathway. Here, we characterize 9 cell lines for MSI and mutations in TGF beta
RII, BAX, and IGFIIR by PCR-based assays. The MMR-proficient cell lines SW480 and
HT29 demonstrate stability at microsatellite sequences and do not have mutations
in TGF beta RII, BAX, or IGFIIR. The MMR-deficient cell lines LoVo, SW48, LS174t,
and HCT116 all demonstrate MSI and have only mutant alleles of TGF beta RII.
Additionally, SW48 cells were heterozygous for wild-type and mutant IGFIIR. While
LoVo and LS174t cells possessed only mutant BAX alleles, HCT116 was heterozygous
and SW48 had only the wild-type allele. The MMR-deficient ovarian cell line 2774
demonstrated MSI, but showed only wild-type TGF beta RII, IGFIIR, and BAX
alleles. In HCT116+ch2 cells, there was no genotypic change from the hMLH1
mutated HCT116 cells. In HCT116+ch3 cells, MSI was corrected, and this cell line
became heterozygous for mutant and wild-type TGF beta RII because wild-type hMLH1
and TGF beta RII are both located on chromosome 3. Thus, the presence of a
defective MMR system correlates with MSI, and the wild-type allele of TGF beta
RII was absent in all microsatellite unstable colon cell lines, whereas the
absence of wild-type BAX occurred in only two colon cell lines. In ovarian cancer
cells with MSI, mutations in TGF beta RII, BAX, and IGFIIR may be unimportant in
the genesis of this tumor.
PMID- 10757057
TI - Recombinant antibody fragments and immunotoxin fusions for cancer therapy.
AB - Recombinant immunotoxins consist of Fv regions of cancer specific antibodies
fused to truncated bacterial toxins. Many recombinant immunotoxins contain a
truncated version of Pseudomonas Exotoxin as a toxic moiety. This toxin is
modified in such a manner that by itself it does not bind to normal human cells,
but it retains all other functions of cytotoxicity. The recombinant antibody
fragments target the modified toxin to cancer cells which are killed, either by
direct inhibition of protein synthesis, or by concomitant induction of apoptosis.
Cells that are not recognized by the antibody fragment, because they do not carry
the cancer antigen, are spared. Many factors influence the in vivo anti-tumor
activity of recombinant immunotoxins. Among them are considerations of which
types of cancer and at what stages may be the best targets for immunotoxin
therapy and tumor specificity of the antigen that is targeted by the recombinant
antibody. Also the affinity of immunotoxins and their ability to enter and
penetrate into tissues and tumors, which in turn is dependent on the size of the
protein. And, because one very important factor is the stability of immunotoxins,
a great deal of protein-engineering is required to stabilize the recombinant
antibody moiety of immunotoxins. Excellent activity and specificity can be
observed for many recombinant immunotoxins in in vitro assays using cultured
cancer cells as well as in animal tumor models. Ongoing clinical trials provide
examples where the promising preclinical data correlate with successful results
in experimental cancer therapy.
PMID- 10757058
TI - Cell senescence in human aging: a review of the theory.
AB - Cell senescence limits cell divisions in normal somatic cells and may play a
central role in age-related diseases. In this review, we examine the theory that
cell senescence underlies and is a pivotal event in human aging and age-related
diseases. The model remains completely consistent with what we currently know of
cell biology, cell senescence, and the pathology of all human age-related
diseases including atherosclerosis, osteoarthritis, immune senescence, skin
aging, Alzheimer's dementia, and cancer. Although there is in vitro and ex vivo
data to support the model, there is currently no in vivo data supporting the
theory. Such data is probably obtainable using available methods and, if
confirmatory, would not only have stunning therapeutic consequences, but
significant commercial consequences as well.
PMID- 10757059
TI - Combined chemotherapy and radiation in the treatment of locally advanced head and
neck cancers.
AB - Locally advanced head and neck cancers carry a poor prognosis because of a high
rate of loco-regional recurrences as well as a high incidence of distant
metastases. Standard therapy has been surgery followed by radiation therapy.
Recent studies showed an improved survival rate when chemotherapy was added to
radiation. The goal of this article is to provide a practical overview of the
clinical trials using chemotherapy as a radiosensitizer for locally advanced head
and neck malignancies. The rationale of using chemotherapy in combination with
radiation is also discussed.
PMID- 10757061
TI - Multimodality therapy in surgically resectable early non-small cell lung cancer.
AB - Lung cancer is a global epidemic. Unfortunately only a fraction of patients can
undergo curative surgery and in these, only one-third survive five years. The
remainder die of locoregional and distant metastatic disease. With advances in
chemotherapy for systemic control and radiation therapy for local control,
responses and survivals have shown promise in extensive inoperable disease. In
order to attempt to extend survival in extensive local but operable disease
(Stage IIIa), these treatment modalities were added to the surgical regimen
either before (neoadjuvant, induction) or after (adjuvant) surgery. Several small
phase III trials substantiated the benefits. Since early lung cancer (Stage I and
II) recur in 30% of instances to distant sites as well as regionally,
multimodality therapies have recently been encouraged in global trials in an
attempt to prolong time to recurrence and survival in this latter group of
patients. A review follows:
PMID- 10757060
TI - Growth hormone and colorectal carcinoma: localization of receptors.
AB - Growth hormone (GH) plays a crucial role in stimulating and controlling the
growth, metabolism and differentiation of many mammalian cell types by modulating
the synthesis of multiple mRNA species and a paracrine or autocrine mechanism of
action has been proposed. These effects are mediated by the binding of GH to its
membrane-bound receptor and involve a phosphorylation cascade that results in the
modulation of numerous signaling pathways. To address the side/mode of action
through which GH exerts its effects, a panel of well characterized monoclonal
antibodies, directed against the hormone binding side of the receptor, was
applied to immunohistochemically determine growth hormone receptor (GH-receptor)
expression in poorly- moderate- to well differentiated col.orectal
adenocarcinomas (n = 40) from the rectum, transverse-, ascending-, descending and
sigmoid colons. Of five anti-growth hormone receptor monoclonal antibodies used,
human GH- receptor specific Mab 263 consistently resulted in strong receptor
expression in colorectal carcinoma tumour cells. Heterogeneity of
immunoreactivity was found in primary and secondary tumour lesions with a
variable range of positive cells. Staining was mainly intracellular, showing
either a monotonous or granular pattern, with some nuclei also reactive. The
presence of intracellular GH-receptors has been previously documented and is a
result of endoplasmic reticulum and Golgi localization. Immunoreactivity in
surface columnar cells, independent from pathological tissue, was weak to
moderate. Epithelial cells from normal tissue, adjacent to tumour lesions, were
of variable intensity. Goblet and mucous cells located at the crypt base
immunostained faintly or were negative for the GH-receptors. Crypt base columnar
cells strongly expressed the GH-receptor, but oligomucous cells were less
reactive. In conclusion, this study indicates that receptor expression may be
associated with malignancy of colorectal carcinoma and supports the hypothesis
that GH may act locally in colorectal tissue. The demonstration of the presence
of receptors for GH will be useful for site-specific studies of the evolution of
gastrointestinal tract tumours, providing valuable information concerning
cellular growth kinetics and tumour prognosis. It also raises questions regarding
the administration of GH to cancer-induced cachexia patients and the possible
oncogenic potential of the GH-receptor.
PMID- 10757062
TI - Mechanisms of neuronal death during development--insights from chick motoneurons.
AB - During normal development, large numbers of cells undergo a temporally and
spatially specific period of programmed cell death (PCD). The study of PCD is an
area of intense research in many disciplines, including oncology, immunology and
neurobiology. Understanding this process should provide keys to developing
therapeutic strategies based on initiating cell death, a desire in cancer
therapies, or preventing cell death in neurodegenerative diseases. This somewhat
obvious notion pinpoints the purpose of this article. Cell death research
blankets many fields contributing to an explosive acquisition of data from many
sources. These data however, have not been universally consistent with
information relevant to one area, such as mitotically active cancer cells versus
that of another area, such as postmitotic neurons. This review article will
outline some issues that we currently understand to underlie biochemical and
molecular mechanisms mediating neuronal death in the developing CNS. Considering
the amount of research currently directed toward understanding the pathways of
cell death, we will attempt to identify components that appear to be common in
all cell deaths as well as those possibly unique to neuronal death.
PMID- 10757063
TI - Aging, cancer, and wound healing.
AB - Aging processes can be described as recognizable series of molecular events
within vital organ systems whose dysfunction gradually increase with time
(reviewed by [1]). This dysfunction manifests itself as abnormal increases and
decreases in gene expression and these events occur at a rate that exceeds the
relative rate at which they can be corrected. The outcome of this progression is
a steady decline in the capacity to successfully maintain an organism's peak
physiology, which occurs approximately around the time of sexual maturation. The
resulting changes increase the likelihood that an organism will eventually
approach a state of increased vulnerability to disease and ultimately leads to
death. Within the context of both wound healing and cancer, molecular mechanisms
of aging-related changes affect an organism's ability to repair damaged cells and
tissues through disregulation of some common molecular pathways. In the case of
the former, wound healing is impaired as a result of an inability to adequately
express genes which facilitate escape from cell stasis in order to commence and
complete the healing process. In the latter case, the failure of a cell's repair
mechanism to correct damage to DNA can lead to neoplastic transformation of a
normal cell into one with unlimited growth potential. This review compares
several of the molecular and cellular events associated with cancer and wound
healing during aging.
PMID- 10757064
TI - Vascular damage after photodynamic therapy of solid tumors: a view and comparison
of effect in pre-clinical and clinical models at the University of Louisville.
AB - Microvascular damage that results in blood flow stasis is a frequent consequence
of photodynamic therapy. The magnitude of this response is dependent on the type
of photosensitizer employed for treatment, the amount of drug and light used in
therapy and the time period between drug injection and treatment. This review
highlights the mechanisms that lead to blood flow stasis in tumor and normal
tissues and discusses methods to increase the selectivity of vascular response.
PMID- 10757065
TI - A novel drug delivery system using IL-2 activated NK cells and Zyn-linked
doxorubicin.
AB - Adoptively transferred IL-2 activated NK (A-NK) cells selectively accumulate
within tumor metastases which recommends them as vehicles for locoregional drug
delivery. Zyn-Linkers are membrane-binding lipophilic dyes which can be coupled
by a variety of conjugation chemistries to therapeutic agents. We have previously
demonstrated that A-NK cells labeled with PKH26 are able to accumulate within
established B16 melanoma pulmonary metastases by 16 h at a concentration of over
600 cells/mm2 of tumor tissue (Basse et al. J. Exp. Med. 174: 479 1991). Zyn-205
is a prodrug in which doxorubicin is attached to a similar Zyn-Linker through an
acid-sensitive bond. We have optimized the ex vivo labeling conditions and found
that a 10 min incubation with 25 microM Zyn-205 results in the uptake of over
10(8) drug molecules per cell with no effect on either cell viability or
cytolytic activity up to 24 h after labeling. Given these parameters, the amount
of drug which may be carried to and concentrated in metastatic lesions represents
a local concentration of approximately 15 microM. In addition, A-NK cells
carrying Zyn-Linked doxorubicin at an equivalent dose of 25 micrograms/kg was
therapeutically comparable to a systemic dose of 8 mg/kg (320x more) in the 3LL
model of experimental metastasis. These data indicate that A-NK cells bearing Zyn
Linked chemotherapeutic agents represent a unique and feasible method to target
chemotherapeutic agents to cancer metastases and that therapeutic doses can be
attained without unwanted systemic exposure.
PMID- 10757066
TI - Atypical fibroxanthoma with osteoclast-like multinucleated giant cells.
AB - Atypical fibroxanthoma (AF) is generally considered as a low grade superficial
variant of fibrohistiocytic neoplasm. In this report we present an unusual
variant of this neoplasm arising from actinic damaged skin of an elderly
individual. The case was characterized by numerous multinucleated osteoclast-like
giant cells uniformly scattered through a pleomorfic cellular proliferation. The
osteoclasts giant cell observed represent multinucleated histiocytes rather than
true osteoclasts.
PMID- 10757067
TI - Neuroendocrine differentiation in non-small cell lung carcinomas.
AB - The immunohistochemical expression of ten neuroendocrine and neural
differentiation-related antigens in 200 specimens from patients with surgically
resected non-small cell lung carcinomas were evaluated. Poorly differentiated
adenocarcinomas and undifferentiated large cell carcinomas showed the highest
percentage of positive samples (30%-60%) for the markers evaluated with diffuse
and intense immunostaining. Poorly differentiated squamous carcinomas
bronchioalveolar adenocarcinomas, and giant cell carcinomas showed a lower
percentage of positive samples (20%) with moderate immunostaining. Well
differentiated tumors were very rarely positive for the neuroendocrine markers.
It is concluded that neoplasms positive for the neuroendocrine markers can be
considered as non-small cell carcinoma with neuroendocrine features, even if they
do not have the histological appearance of neuroendocrine lung neoplasms.
PMID- 10757068
TI - Breast cancer--interaction between ethnicity and environment.
AB - The risk to develop breast cancer varies at least five fold around the world.
Migrant women from low incidence countries to the United States experience an
increase in risk over several generations. The objectives of this paper are to
describe ethnic differences in breast cancer incidence and to review research
related to risk factors that may explain these variations. Although ethnic
differences can be partially explained by established risk factors, a large
proportion of the increase in risk remains unexplained. Hormonal factors,
including estrogens, insulin, and growth factors, may offer an explanatory
mechanism how increasing caloric intake, decreasing physical activity, changes in
nutrients, increasing height, and adiposity affect breast cancer risk. Future
research on polymorphisms in genes coding for enzymes that are involved in the
chemical activation and detoxification of environmental carcinogens, dietary
agents, and endogenous hormones may contribute to the understanding of ethnic
differences in breast cancer risk.
PMID- 10757069
TI - In search of the cause of gastric cancer.
AB - The purpose of this review was to describe the historical development of each
epidemiology, experimental pathology, endocrinology (including vitaminology), and
thermodynamics surrounding the genesis of gastric cancer in humans and non-human
mammals. Epidemiological studies from other and our laboratories were unanimous
in counting the intake of carbohydrate-rich and salty diet with vitamin C
deficiency as the risk factor of key importance. Information from experimental
pathology suggested the possible implication of some nitroso compounds in a
subject with atrophic gastritis and/or in a state of vitamin C deficiency of
which the establishment should have led to a perturbation of the steroid milieu
of the host. In endocrinology, the association of a specific steroid disorder
(depression of androgen and progestin combined with glucocorticoid excess in
urine) with gastric cancer, as noted in the case-control study of this neoplasia,
was reproduced in mice maintained under biased nutritional conditions. The use of
scurvy-prone ODS rats was found useful in elucidating the interrelation between
vitamin C and steroid metabolism. Finally, thermodynamic analysis of the data
distribution of gastric cancer risk parameter of both sexes revealed the presence
of an interaction between oncogene activation and tumor suppressor gene
inactivation in the course of the maintenance of the positive correlation with
male predominance between male gastric cancer and female gastric cancer as
regards the changes of age-adjusted incidence rate (AAIR) in space. In
conclusion, all of the information available in the field of gastric cancer
etiology is in support of the pertinence of the steroid criminal hypothesis of
gastric cancer in humans and in non-human mammals.
PMID- 10757070
TI - Loss of heterozygosity in papillary and follicular thyroid carcinoma: a mini
review.
AB - Inactivation of tumor suppressor genes is an important mechanism in the
development of most cancers. This can be detected by determining loss of
heterozygosity (LOH) on highly polymorphic loci on chromosomes. Many
investigations to determine LOH in papillary and follicular thyroid carcinoma
have been performed using bulk tissue which was fresh, snap frozen, or has been
formalin-fixed/paraffin-embedded. Loss of heterozygosity is more frequently
encountered in follicular than papillary carcinoma. Laser Capture Microdissection
(LCM) may be useful to ascertain if there is a pattern of LOH for various
histologic forms and variants of thyroid carcinoma.
PMID- 10757071
TI - The regulation of cell growth and proliferation during organogenesis.
AB - Both growth (increase in mass) and proliferation (increase in cell number)
contribute to the formation of multicellular organisms. We would like to
understand the mechanisms that normally regulate growth and proliferation because
breakdown of these mechanisms may be the basis for uncontrolled growth and
proliferation that are associated with cancerous transformation and tumor
progression. We review here classical and recent literature from diverse
experimental systems that pertains to the regulation of mass and cell number.
PMID- 10757072
TI - Susceptibility of nonhuman primates to carcinogens of human relevance.
AB - Nonhuman primates are a valuable experimental model for the evaluation of human
carcinogenic risk but have not been widely used for various reasons, such as high
cost and lack of availability. The present review discusses the findings from a
long-term carcinogenesis study in nonhuman primates that was carried out under
contract by the National Cancer Institute from 1961 to 1997. Among the classes of
compounds investigated were model rodent carcinogens, food additives, food and
environmental contaminants, heterocyclic amines, N-nitroso compounds, and
antineoplastic and immunosuppressives. Of the model rodent carcinogens tested,
only urethane was carcinogenic in monkeys. Long-term administration of saccharin
or cyclamate did not result in toxicity or carcinogenicity in nonhuman primates,
which is commonly seen in rodent models. Similar to rodent models and suspected
in the human population, the fungal toxins, aflatoxin B1 and sterimatocystin,
induced malignant liver tumors in monkeys. Relatively few animals administered
DDT developed malignant tumors, however, hepatic and CNS toxicity was commonly
observed. Hepatocellular carcinoma developed in a majority of monkeys
administered the heterocyclic amine, IQ but not the structurally similar MeIQx.
Resultant toxicity and carcinogenicity from N-nitroso compounds was variable.
While diethylnitrosamine proved to be the most potent hepatocarcinogen tested, no
malignant tumors were seen in animals administered N-methyl-N-nitro-N
nitrosoquanidine. Susceptibility of nonhuman primates to chemotherapeutic agents
was also variable. Only procarbazine and N-methyl-N-nitrosourea were highly
carcinogenic, whereas few tumors were seen as a result of cyclophosphamide,
Adriamycin, melphalan, or azathioprine.
PMID- 10757073
TI - The effects of volatile anesthetic agents on pulmonary surfactant function.
AB - The purpose of this article is to review the findings from research directed at
understanding the effects of volatile anesthetics on the respiratory surface
known as pulmonary surfactant. Anesthetics have long been known to have a
disruptive effect on biological membranes. This review will highlight the
interactions of volatile anesthetics with pulmonary surfactant. This paper has
emphasized the interaction of volatile anesthetics with the pulmonary surfactant
monolayer versus the lipid bilayer. The goal of this review is to uncover to what
extent this understanding has progressed in forty years. Although the goal is
quite broad, the information gathered and the advice given is specific. Theories
of anesthesia and surfactant structure and function are summarized and discussed
in light of early physico-chemical approaches and extend to an era where powerful
new three-dimensional structural techniques can be used to answer this question.
PMID- 10757074
TI - Comparative aspects of the Werner syndrome gene.
AB - Werner syndrome (WS) ("Progeria of the adult"; entry *27770 (1)) was originally
defined by Dr. Otto Werner in 1904 on the basis of "scleroderma-like" thin, tight
skin and bilateral cataracts in a sibship (2). Among the many systemic clinical
features of WS, the various progeroid features have drawn special attention. WS
is caused by a mutation at the Werner syndrome gene (WRN) locus, which belongs to
the family of RecQ helicases (GenBank accession number L76937)(3). This review
focuses on the comparative aspects of WRN, including differential gene action
within humans and the potential differences between species, particularly the
mouse and human.
PMID- 10757075
TI - Microarray-based expression profiling in prostate tumors.
AB - High throughput gene expression profiling is increasingly becoming a desirable
method for identifying genes differentially expressed in disease versus normal
tissues. Microarrays and gene chips containing hundreds to thousands of genes of
interest, both known and novel, can be used to establish the expression profile
of numerous genes in a single experiment. In order to validate the hits emerging
out of such an experiment it is necessary to use an appropriate panel of the cDNA
repository. We investigated the usefulness of such a method to identify prostate
cancer-specific genes. A microarray containing 588 known genes was analyzed using
cDNA probes derived from normal and three independent prostate tumors. At least
19/588 genes were found to be differentially expressed in the tumors in
comparison to the normal tissue. Among the nine test genes chosen, one gene,
Glutathione-S-transferase theta 1 (GSTT1), showed a correlation with the
microarray results when analyzed by RT-PCR. Using a comprehensive panel of normal
and tumor tissues and cancer-derived cell lines, we have rapidly validated the
expression relevance of GSTT1 in solid tumors. The microarray was also useful in
the preliminary identification of androgen-regulated genes in the prostate tumor
models. These results indicate that microarray in combination with a relevant
cDNA repository can facilitate rapid identification of potential targets for
therapy and diagnosis of prostate and other cancers.
PMID- 10757076
TI - Cancer, aging and cellular senescence.
AB - Normal cells do not divide indefinitely due to a process termed cellular or
replicative senescence. Several lines of evidence suggest that replicative
senescence evolved to protect higher eukaryotes, particularly mammals, from
developing cancer. Senescent cells differ from their presenescent counterparts in
three way: 1) they arrest growth and cannot be stimulated to reenter the cell
cycle by physiological mitogens; 2) they become resistant to apoptotic cell
death; 3) they acquire altered differentiated functions. Replicative senescence
occurs because, owing to the biochemistry of DNA replication, cells acquire one
or more critically short telomere. The mechanism by which a short telomere
induces the senescent phenotype is unknown. Recent findings suggest that certain
types of DNA damage and inappropriate mitogenic signals can also cause cells to
adopt a senescent phenotype. Thus, cells respond to a number of potentially
oncogenic stimuli by adopting a senescent phenotype. These findings suggest that
the senescence response is a fail-safe mechanism that protects cells from
tumorigenic transformation. Despite the protection from cancer conveyed by
cellular senescence and other mechanisms that suppress tumorigenesis, the
development of cancer is almost inevitable as mammalian organisms age. Why is
this the case? Certainly, aging predisposes cells to accumulate mutations,
several of which are necessary before malignant transformation occurs,
particularly in humans. However, many benign or relatively well-controlled tumors
may also harbor many potentially oncogenic mutations, suggesting that the tissue
microenvironment can suppress the expression of many malignant phenotypes.
Although the idea remains controversial, cellular senescence has also been
proposed to contribute to organismal aging. Senescent cells have recently been
shown to accumulate with age in human tissues. One possibility is that the tissue
microenvironment is disrupted by the accumulation of dysfunctional senescent
cells. Thus, mutation accumulation may synergize with the accumulation of
senescent cells, leading to increasing risk for developing cancer that is a
hallmark of mammalian aging.
PMID- 10757077
TI - Involution and neoplasms of the thymus.
AB - Mammalian ontogenesis and postnatal histogenesis involves the dynamic and
appropriate interaction of two growth related phenomena: progression and
regression. The thymus gland is the organ of the mammalian body that exhibits the
most profound involution during normal postnatal histogenesis. Involution of the
thymus can be compared to similarly regressive processes during the ontogeny of
holometabolic insects, as well as to the spontaneous regression of neoplasms. It
can be expected that in the future a better understanding of neoplastic
regression will result from the comparison of ontogenetic processes from
taxonomically far-removed regressive processes, and the evaluation of various
factors that promote progression and regression. Furthermore the thymus, as the
key organ of the cellular arm of the mammalian immune system, is intimately
involved in the determination of the eventual outcome of malignant neoplastic
disease. Primary anterior mediastinal tumors comprise a diverse group of
neoplasms accounting for 50% of all mediastinal tumor lesions. Thymic carcinomas
and thymomas are epithelial neoplasms which can be divided according to clinical
behavior into various biological subtypes. A review of the nature of thymic
neoplasms, a description of physiologic and accidental involution of the thymus
gland, and a discussion of various paraneoplastic disorders, including myesthenia
gravis, associated with thymic neoplasms are the aims of this article.
PMID- 10757078
TI - The role of adhesive proteins in the hematogenous spread of cancer.
AB - The understanding of the mechanisms that control metastasis and invasion are
critical for the identification of new targets for drug development. In this
review we focused on two major pathways that mediate hematogenous cancer spread:
the hemostatic system and cell adhesive interactions that lead to tumor invasion
and angiogenesis. We describe the contribution of platelets and a number of
adhesive proteins as well as their receptors that have recently been shown to
play a role in metastasis. In addition, enzymes and their inhibitors that
modulate cellular adhesive interactions are described. We hope that this summary
will stimulate researchers in this area to focus their efforts on molecules that
have recently been discovered. These molecules will not only lead to the fuller
understanding of the "soil and seed" hypothesis proposed more than 100 years ago
but also provide new therapeutic approaches for the treatment of metastatic
disease.
PMID- 10757079
TI - Dendritic cells in the pathophysiology of sarcoidal reactions.
AB - Dendritic cells play an important role in regulating both normal and
pathophysiologic immune responses. Complicating the interpretation of dendritic
cell function has been the observation that dendritic cells are not only rare,
but can demonstrate multiple maturation/differentiation states. Despite these
experimental limitations, the accumulating evidence suggests that dendritic cell
are a dynamic migratory population that can be recruited into areas of peripheral
inflammation. In the peripheral site of inflammation, dendritic cell function
appears to involve the processing of antigen and its subsequent presentation to T
lymphocytes. Dendritic cells also appear to be capable of transporting antigen to
the regional lymph node through the afferent lymphatics. Dendritic cells can be
found in the paracortex where they appear to be interacting with T lymphocytes to
provide both membrane-bound and soluble activation signals. The central
regulatory role of the dendritic cell in immune responses suggests that sarcoidal
reactions, and other mononuclear inflammatory processes, are likely to be
clinical entities that reflect perturbed dendritic cell function.
PMID- 10757080
TI - Metastatic melanoma to regional lymph nodes.
AB - There is an epidemic of melanoma in the United States and throughout most parts
of the word. Recent advancements in the management of this disease has provided
the patient with more options. The emerging technology of lymphatic mapping and
sentinel node biopsy results in a more conservative, less morbid procedure to
obtain nodal staging information. At the same time, providing the pathologist the
1-2 nodes from the basin most likely to contain metastatic disease, allows for a
more detailed examination of the sentinel lymph node. This more detailed
examination may include serial sectioning, immunohistochemical staining or even
molecular biology techniques based on RT-PCR to provide more accurate staging.
National trials are ongoing to examine the clinical relevance of the disease that
is detected and the 'upstaging' that occurs with more sensitive assays for occult
metastases.
PMID- 10757082
TI - Molecular detection of micrometastases and circulating tumor cells in melanoma
prostatic and breast carcinomas.
AB - The molecular detection of circulating tumor cells (CTC) and micrometastases may
help develop new prognostic markers in patients with solid tumors. In the last 10
years, numerous groups have attempted the detection of occult tumor cells in
solid malignancies using the highly sensitive reverse transcriptase polymerase
chain reaction (RT PCR) technique. These assays were in the vast majority
directed against tissue specific markers. In most studies on prostatic carcinoma,
RT PCR was able to specifically detect prostatic tissue specific markers in the
peripheral blood (PB), bone marrow (BM) and lymph nodes of patients with
localized and metastatic disease. Melanoma related transcripts were detected by
RT PCR in the PB, BM and lymph nodes of patients with localized and advanced
tumors. In most studies, melanoma related markers were shown to be specific
except when assayed in lymph nodes. RT PCR positivity rates were highly variable
between studies. Despite tFlese discrepancies, many authors have shown a
statistically significant correlation between RT PCR positivity and a poorer
outcome in both melanoma and prostatic carcinoma. In breast carcinoma, all
markers that have been extensively tested were shown to be non-specific. Because
of the many limitations of RT PCR (e.g. false positives), many groups are
developing new approaches for the detection occult tumor cells. One of these
techniques involves immunobead isolation of CTC and micrometastases prior to down
stream analysis. The tumor rich magnetic fraction can be subjected to RT PCR,
immunocytochemistry and flow cytometry. In conclusion, the molecular detection of
occult tumor cells in solid tumors seems very promising and the techniques used
for this purpose are in continuous evolution. Large prospective and
interlaboratory variability studies are necessary to determine the accuracy and
prognostic value of these assays.
PMID- 10757081
TI - Partial review of immunotherapeutic pharmacology in stem cell transplantation.
AB - In two separate lymphoma populations, we examined immune reconstitution following
high dose chemotherapy (HDT) and bone marrow transplantation (BMT). In the first
study we followed immune reconstitution for one year after HDT and BMT. In the
second study we examined the ability of the orally active immunomodulator,
Bestatin to augment immune reconstitution following HDT and BMT. The studies on
immune reconstitution following HDT and BMT were undertaken in a cohort of non
Hodgkin's lymphoma (NHL) patients (n = 35) and examined the peripheral blood (PB)
leukocyte subsets and their in vitro functions. Our results demonstrate that
monocyte and natural killer (NK) cell engraftment occurred more rapidly then did
T cell reconstitution. We also observed a significant decrease in the CD4:CD8
ratio post-transplantation as compared to normal PB donors due to a decrease in
CD4+ cells. In addition, following HDT and BMT, measures of T cell function
(phytohemagglutinin [PHA] mitogenesis) and T helper cell activity (pokeweed
mitogen [PWM] mitogenesis) were consistently depressed as compared to cells from
normal PB. Further, we demonstrate a correlation between the loss of T cell
function and the frequency of circulating monocytes, suggesting a cause-effect
relationship. Despite the dysfunction in T cells following HDT and BMT, immune
modulating agents can still augment the immune function. One such drug is
Bestatin (ubenimex), an inhibitor of aminopeptidase (AP) that binds to CD13 on
macrophage/monocytes. To examine its immune modulatory activity after HDT and
BMT, a dose finding (10, 30, 90 and 180 mg/day) phase Ib trial was conducted with
30 Hodgkin's disease (HD) and NHL patients who received no drug (control), or
Bestatin daily for 60 days following BMT. In these studies, Bestatin
administration was initiated when the absolute neutrophil count was greater than
250/mm3 on two consecutive days. These studies revealed that Bestatin
significantly increased the PHA and PWM responses in a dose-dependent manner.
Flow cytometric analysis revealed a significant increase in NK cells (CD56+), B
cells (CD19+), as well as the CD4:CD8 cell ratio. The latter observation was
associated largely with a depression in the percent of CD8+ T cells as opposed to
an increase in CD4+ T cells. We conclude that despite the peripheral tolerance
observed following HDT and BMT, Bestatin could significantly increase some, but
not all, immune surrogates.
PMID- 10757083
TI - Pathogenesis of thrombotic disorders in patients with cancer.
AB - Cancer patients experience several complications during the course of their
illness which increase their morbidity and mortality. Thromboembolic phenomena
are frequent and important events encountered in these patients. Although the
exact mechanisms of thrombosis in this population of patients are largely
unknown, speculations regarding the pathogenesis of clotting are presented in
this short review. Interactions between elements related to the underlying
neoplastic disorder, adherence to the vessel wall by cancer cells, indirect
injury of the endothelial tissue, cytokine released by the malignant clone and
disturbances in the clotting cascade to mention a few, are thought to be
responsible for hypercoaguability in patients with cancer. More experimental and
clinical studies are needed to clarify the etiology and management of these
serious complications and concomitant diseases. Thrombotic complications are
considered the second most common cause of death in patients with underlying
malignant disorders. It has been estimated that 15% of patients with cancer will
suffer from thromboembolic phenomena during their life (1,2). However,
prospective data that examine the exact incidence of these complications are
currently unavailable. Few investigators have estimated that the prevalence of
serious thrombosis may be up to 50% in post mortem analysis (3).
PMID- 10757084
TI - Sentinel node biopsy for breast cancer: showtime or dress rehearsal?
AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) may prove superior to axillary
node dissection (AND) for breast cancer staging. At issue is whether existing
clinical data support performance of SLNB without AND at this time. DISCUSSION:
The various methods of SLNB are discussed in detail. SLNB using radiocolloids and
surgical probes (with or without blue dye) yields superior SLN localization rates
as compared to blue dye alone. However, the incidence of false-negative SLNB is
variable with all methods and frequently 10% or higher (11.4% in the only
published multicenter study). CONCLUSIONS: Outside of a clinical trial, SLNB
should be performed in addition to, not instead of, AND. The sensitivity of
pathological staging is enhanced and nonaxillary SLNs are identified, while
concomitant AND apprehends all false-negative SLNBs. Two prospective randomized
cooperative trials provide excellent educational, training and research
opportunities for North American breast surgeons as they gain experience with
this new, promising staging procedure.
PMID- 10757085
TI - Proteasome inhibitor and lymphocyte function: partial inhibition of cell-mediated
cytotoxicity and implication that the lymphocyte proteasome may contain multiple
chymotryptic domains.
AB - The multicatalytic proteinase complex or proteasome possesses at least 4 distinct
proteolytic activities. We have previously reported that the chymotrypsin-like
activity of the rat natural killer cell proteasome may play a role in natural
killer (NK) cell-mediated cytotoxicity or IL-2 activated NK (A-NK) cell-mediated
cytotoxicity. Using a series of novel, Cephalon, Inc, synthetic proteasome
inhibitors (CEP-1508, CEP-1612 and CEP-3117) which have been reported to be
specific for the chymotrypsin-like activity of the proteasome, we have further
investigated the possible role of the proteasome, with emphasis on the
chymotryptic activity components, in cell-mediated cytotoxicity. We now report
that these compounds can inhibit the rat NK proteasome in a dose dependent
manner. Nevertheless, there is only a 50% inhibition of A-NK cell-mediated
cytotoxicity. These results confirm and extend our previous results that the
proteasome contributes, at least in part, to cell-mediated cytotoxicity. However,
as anticipated, since multiple molecular pathways contribute to cell-mediated
cytotoxicity, the proteasome contributes only partially to NK cell-mediated
cytolytic reactivity. The exact role of the proteasome in NK cell-mediated
killing, and whether single or multiple chymotryptic domains function directly or
indirectly, remains to be fully determined.
PMID- 10757087
TI - Neoplasms during the progression of pregnancy.
AB - Restricting this review to dealing with pregnancy and its interaction with
neoplasms limits us to the child-bearing years. Neoplasms may appear at all
stages of species with true tissues and the incidence of malignancy in pregnancy
is estimated to be 1:1,000. Almost 50% of these tumors are cervical cancers,
followed by breast cancer, with an incidence of approximately 0.03%. The pregnant
woman, in the same person, exhibits controlled growth (the pregnancy) and
uncontrolled growth (the malignancy). In younger women, the neoplasms represent
early stages of biological development and seem to arise practically from all
maternal tissues. Geriatric changes in the neoplastic growth processes are
missing. This article encompasses a review of the integration of neoplasms, the
maternal body, the fetus and the placenta. The morphological and biochemical
integration of the different processes is diversified. Mainly, we would like to
address the interaction between pregnancy and common human malignancies like
breast, cervix, and melanoma, but we will also review rare neoplastic
complications. This way it is possible to treat the combined growth processes as
they evolve from the initiated sperm, the ovum and continue via the placental
development. These processes lead to the fetus and, in the pathological sense, to
childhood complications, though most cases develop only portions of the process.
PMID- 10757086
TI - Matrix metalloproteinases of human NK cells.
AB - We have previously reported that MMP-2 and MMP-9 are present in rat A-NK cells,
and have recently documented that additional MMPs are present in rodent A-NK
cells. To our knowledge only proMMP-9 has previously been reported for human NK
and A-NK cells. Herein, we report for the first time the presence of MMP-2 and
MT1-MMP in human NK cells. The importance of these enzymes for the migration of A
NK cells into tumor metastases is of great potential relevance. MMPs may be rate
limiting in A-NK cells, following their adoptive transfer, to traverse basement
membrane and accumulate within established cancer metastases, a likely pre
requisite to their cytolytic function. Human NK cells express and produce MMP-2,
MMP-9, MT1-MMP and the inhibitor TIMP-1. Moreover, human A-NK cells degrade the
extracellular matrix equivalent (Matrigel) in a seemingly IL-2 dependent manner.
It is therefore likely that A-NK cell MMPs play crucial roles in contributing to
A-NK cell localisation and positioning the cells in vivo to allow for triggering
their cytolytic potential.
PMID- 10757088
TI - Growth inhibitors in the treatment of malignant neoplasms.
AB - Growth inhibitors are an integral part of the regulatory mechanisms involved in
the growth and differentiation of cells and tissues. Aberration in the response
to growth inhibitors leads to the escape of the cell from the cell cycle control
mechanisms and may lead to the development of malignancies. The inactivation of
tumor suppressor genes, activation of oncogenes leads to the acquisition of an
invasive and increasingly malignant immunophenotype and secretory profile by
transformed cells. The commencement of the complex process of carcinogenesis, and
subsequent, rapid tumor growth and progression of mammalian neoplasms depends
upon the continuous de novo formation of capillaries (angiogenesis). The
generation of a malignant, invasive cellular immunophenotype (CIP) and distant
metastases, as aspects of tumor progression, are also NRA-dependent processes.
Specific molecules with cytostatic/cytotoxic growth inhibitory effects represent
a very diverse group of factors. Growth inhibitors may regulate the cell cycle at
various levels, and growth inhibitors comprise a heterogeneous group of agents
including cytokines, growth factors, steroid hormones, etc. The phenomenon of
multidrug resistance to a wide spectrum of cytostatic/cytotoxic agents has posed
a major difficulty in the effective chemotherapeutical treatment of cancer
patients. The development of novel therapeutic regimens should be based on the
observations of the growth inhibitory profile of the particular malignancy, in
addition to its immunophenotype and genotype, and the devisement of
'individualized' combinations of factors, including gene and immuno-therapeutical
options, targeting different aspects of the malignant disease.
PMID- 10757089
TI - Apoptosis and pathogenesis of viral hepatitis C--an update.
AB - Hepatitis C virus is a major causative agent of chronic liver disease. Viral
genotype, mutations, virus-host interaction, expression of viral proteins and
host immune-reaction are important factors in the pathogenesis of HCV infection.
Precise pathogenesis and perpetuation of hepatocellular injury in hepatitis C
viral infection remain unclear. Proposed mechanisms include direct viropathic
effect, the host immune response mediated through cytotoxic T lymphocytes, both
viropathic and cytopathic effects, and macrophages/monocytes. Apoptosis occurs
both in acute or chronic hepatitis and has been suggested to be mediated through
Fas antigen. In HCV infection, Fas expression is up-regulated in the liver cells
in line with the severity of liver inflammation. When HCV-specific T cells
migrate into hepatocytes and recognize the viral antigen via the T cell receptor,
they become activated and express Fas ligand that transduces the apoptotic death
signal to Fas-bearing hepatocytes resulting in their destruction. Thus, the Fas
system plays an important role in liver cell injury by HCV infection. Possible
inducers of apoptosis in hepatitis C include cytokines, especially tumor necrosis
factor-alpha (TNF-alpha), released by inflammatory cells, and acting through TNF
and other cytokine receptors.
PMID- 10757090
TI - Physical properties of poly(ethylene glycol) (PEG)-based resins for combinatorial
solid phase organic chemistry: a comparison of PEG-cross-linked and PEG-grafted
resins.
AB - Three series of poly(ethylene glycol) (PEG)-based polymers were synthesized and
characterized with respect to their physical properties. Polyoxyethylene
polyoxypropylene (POEPOP), polyoxyethylene-polyoxetane (SPOCC), and
polyoxyethylene-polystyrene (POEPS-3) were synthesized respectively by anion
polymerization, cation polymerization, and radical polymerization. Both bulk and
suspension modes were used to synthesize the polymers from derivatized PEG
monomers (PEG 400, PEG 900, and PEG 1500). The three supports were compared with
two commercially available PEG-grafted supports (TentaGel S OH, ArgoGel-OH) and
two polystyrene supports (aminomethylated polystyrene [PS-NH2] and macroporous
aminomethylated polystyrene [PLAMS]) with respect to their swelling properties,
loading, NMR spectral quality, as well as solvent and reagent accessibility.
Loadings of 0.3-0.7 mmol/g were obtained for the PEG-based resins. Swelling of
the PEG-based resins was determined to be higher than that of the PEG-grafted
resins and polystyrene supports. The PEG-based resins gave better resolved high
resolution NMR spectra than the PEG-grafted resins when examined by magic angle
spinning nanoprobe (MAS) NMR spectroscopy. Moreover, fluorescence quenching of
polymer bound 2-amino-benzoate by protonation with p-toluenesulfonic acid showed
moderate to fast diffusion through the polymer depending on the solvent and the
polymer matrix.
PMID- 10757091
TI - Glycomimetics: a programmed approach toward neoglycopeptide libraries.
AB - A programmed synthesis of neoglycopeptides has been developed in which two,
similar or different, glycoside moieties could be attached either (i) at the N
terminal of short peptides or (ii) one at the N-internal and the other(s) at the
N-terminal site, in a highly flexible and controlled manner. A stepwise branching
of N-terminal peptides has been achieved by glycoside aldehyde reductive
amination followed by the glycoside carboxylic acid coupling (model 1). In
another approach, after N-alkylation with glycoside aldehyde, the N-glycosylated
derivative is subjected to peptide synthesis. This is then followed by the
attachment of the second glycoside moiety at the N-terminal using either
glycoside aldehyde or glycoside carboxylic acid derivative (model 2).
Alternatively, the attachment of second and third glycoside derivatives could be
achieved simultaneously, by reductive amination/carboxylic acid couplings (model
3). The methodologies presented here are highly versatile and combine diversity
in both peptides/pseudopeptides and glycoside moieties.
PMID- 10757092
TI - Using one- and two-dimensional NMR techniques to characterize reaction products
bound to Chiron SynPhase crowns.
AB - Solid-phase MAS techniques have proved to be very useful in characterizing
compounds bound to resin; however, little has been reported on using NMR to
characterize compounds attached to Chiron SynPhase crowns. We have used proton,
carbon, and COSY spectra obtained with a Varian Nano.nmr probe to characterize
products from a published reaction sequence attached to MD (methacrylic
acid/dimethylacrylamide copolymer) crowns. We have also performed solvent surveys
to determine the best solvents for acquiring spectra of materials bound to both
MD and PS (polystyrene) crowns.
PMID- 10757093
TI - Soluble polymer supported synthesis of alpha-amino acid derivatives.
AB - A Schiff base activated glycine supported on a soluble polymer (poly(ethylene
glycol) (PEG)) was readily alkylated with a wide variety of electrophiles in the
presence of a carbonate base in acetonitrile. The presence of the polymer
provided a phase-transfer catalysis environment which accelerated the reaction.
Effects of various carbonate bases and leaving groups have been also studied.
Completion of the PEG-supported reaction was obtained without using a large
excess of reagents or an extra phase-transfer catalyst, even in the case of
unreactive or hindered electrophiles. After cleavage from the polymer, alpha
amino esters are obtained in good yields.
PMID- 10757094
TI - Combinatorial solid-phase synthesis of hapalosin mimetics.
AB - The solid-phase synthesis of a small library of mimetics of the cyclic
depsipeptide hapalosin is described. 3-Amino-4-hydroxy-5-nitrobenzoic acid was
anchored through the anilino moiety to a backbone amide linker (BAL) handle
support. Using chemoselective reactions and without the need for protecting group
manipulations, the benzoic acid group was first amidated, then the aniline
nitrogen was acylated, and finally the nitro group was reduced to an amine and
acylated or reductively alkylated, to generate a 12-member library.
PMID- 10757095
TI - Direct-injection NMR (DI-NMR): a flow NMR technique for the analysis of
combinatorial chemistry libraries.
AB - A new tool for analyzing compound libraries by NMR has been developed. Aliquots
of solution-state samples (between 120 and 350 microL) are directly injected,
using a standard liquids handler, into an NMR (LC-NMR) flow probe. Automated NMR
software tracks--and suppresses--intense signals arising from the nondeuterated
solvents used (if any) and acquires high-sensitivity one-dimensional 1H NMR
spectra. An 88-member combinatorial library, dissolved in DMSO and stored in a 96
well microtiter plate, has been analyzed a number of ways using this technique.
This nondestructive technique, which we call direct-injection NMR (DI-NMR) and
which is embodied in our versatile automated sample changer (VAST) hardware, has
proven to be both routine and robust. Our success in automatically acquiring the
NMR data for entire plates of library compounds (within 4-8 h) has caused us to
develop new ways to display and analyze the resulting NMR data, as will be shown
here.
PMID- 10757096
TI - UPS on Weinreb resin: a facile solid-phase route to aldehyde and ketone
derivatives of "unnatural" amino acids and peptides.
AB - The solid-phase synthesis of "unnatural" amino aldehydes, amino ketones, peptide
aldehydes, and peptide ketones was accomplished from commercially available resin
in a series of room temperature reactions. The initial step involved addition of
an "unnatural" side chain to the N-terminus of a benzophenone imine-activated
Weinreb resin-bound amino acid or peptide derivative. The alkylated imine was
hydrolyzed, and the amine was converted to the Boc-, Cbz-, or naphthoyl
derivative. The resin-bound substrate was then cleaved with DIBAL-H or a Grignard
reagent to give the amino aldehyde, amino ketone, peptide aldehyde, or peptide
ketone products. Twenty-four reactions were carried out simultaneously using a
"Billboard" reaction apparatus to give products in 27-87% (59% average) isolated
yield.
PMID- 10757097
TI - Syntheses of 2-alkylamino- and 2-dialkylamino-4,6-diarylpyridines and 2,4,6
trisubstituted pyrimidines using solid-phase-bound chalcones.
AB - Several substituted 2- and 4-hydroxyacetophenones are linked to Wang resin via a
modified Mitsunobu protocol. These resin-bound acetophenones are condensed with
aromatic aldehydes, and the resulting chalcones 5 are used for the synthesis of 2
dialkylamino- (9a-d) and 2-alkylamino-4,6-diarylpyridines (11a-f), and 2-alkyl
4,6-diaryl- (14a) and 2,4,6-triarylpyrimidines (14b,c) in a manner suitable for
combinatorial applications.
PMID- 10757098
TI - Total synthesis of the fumiquinazoline alkaloids: solid-phase studies.
AB - We have previously described an efficient four-step synthesis of the
fumiquinazoline alkaloids (Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432
2433). Here, we demonstrate that this route is readily adaptable to combinatorial
synthesis on solid phase. Linear tripeptides containing a central anthranilate
unit were assembled on the Wang resin and subjected to dehydration and cyclative
release to yield the pyrazino[2,1-b]quinazoline-3,6-diones in high purity. To
demonstrate the scope of this protocol, a small library [ca. 20 compounds] of
unnatural analogues was prepared by parallel synthesis.
PMID- 10757099
TI - [Infection by cytomegalovirus in patients with ulcerative colitis requiring
colonic resection].
AB - BACKGROUND: The objective was to determine the rate of colonic infection by
cytomegalovirus (CMV) in patients with ulcerative colitis (UC) who have required
colonic resection because of lack of response to medical treatment or
complications. PATIENTS AND METHODS: Thirty nine patients (26 males, 13 females)
colectomized because of refractory or complicated UC were included. Clinical and
pharmacological characteristics were analyzed. Specific immunohistochemistry for
CMV was performed in biopsic samples of all specimens. RESULTS:
Immunohistochemistry was positive for CMV in 7 out of the 39 patients. Since 1985
to 1994 there was only one case of CMV that contrasts with the 6 cases diagnosed
from 1995 to 1998 (p < 0.05). All patients with CMV infection have received
systemic corticosteroids before surgery, and additionally cyclosporine in 5 of
them. Twenty two out of the 32 patients without CMV infection have also received
corticosteroids, cyclosporine, azatioprine or methotrexate before surgery. The
rate of immunosuppression was not different between the patients with or without
CMV infection. Length of treatment before surgery was also similar for both
groups of patients: (17 months (18-89) in non-infected group and 30 months (13
49) in CMV infected group; p = NS). Four patients infected by CMV died in the
postoperatory. CONCLUSIONS: CMV infection in patients with refractory or
complicated UC is a serious complication due to its frequency and prognosis. A
significant increase in the prevalence of CMV infection, not related with
differences in therapeutic immunosupression, has been observed in recent years.
PMID- 10757100
TI - [Efficacy and safety of posteroventral pallidotomy for the treatment of advanced
Parkinson's disease].
AB - OBJECTIVES: To analyze the results, efficacy and safety of unilateral
microelectrode guided pallidotomy for the treatment of advanced Parkinson's
disease, three months and one year after surgery. PATIENTS AND METHODS: 23
patients with advanced Parkinson's disease (mean age 58.9 years and mean disease
duration 14.4 years) were submitted to pallidotomy. Neurological evaluation,
three months (n = 23) and one year (n = 16) after surgery, was performed during
the morning in overnight "off" condition and after receiving 100-150% of their
usual l-dopa dose. Parkinsonian symptoms were evaluated in each follow up visit
through motor scales, activities of daily living scales, a dyskinesia rating
scale and motor timed tests. RESULTS: Contralateral dyskinesias improved 92%
three months after surgery and 89% at one year. Parkinsonian motor scores were
reduced by 36.5% after three months and by 26.7% one year after surgery. In the
one year follow up visit, contralateral tremor improved 48%, rigidity 36.2% and
bradykinesia 37.4%. All these changes were statistically significant (p < 0.01).
Adverse effects were minor or transient. Antiparkinsonian medication dosage did
not significantly change during the study period. CONCLUSION: Microelectrode
guided unilateral pallidotomy is an effective and safe procedure to improve
contralateral motor symptoms in Parkinson's disease, being specially useful for
the treatment of l-dopa induced dyskinesias.
PMID- 10757101
TI - [Efficacy of an intervention in smoking cessation in patients with myocardial
infarction].
AB - BACKGROUND: The aim of this study was to evaluate the efficacy of an structured
intervention based on a medical advice versus to the ordinary anti-tobacco advice
in patients with miocardial infarction who are attended in an Intensive Care Unit
(ICU). PATIENTS AND METHODS: 90 patients were randomly selected to receive either
the specific intervention (intervention group) or the ordinary advice (control
group). The medical advice was given during the ICU hospitalization and during
the second, the third and the fourth week. One year later the smoking habit was
evaluated. RESULTS: After one year 26 patients of the intervention group and 31
patients of the control group had stopped smoking (RR = 0.88 [CI 95% RR] 0.57 to
1.37). CONCLUSIONS: The percentage of patients who stop smoking after a
miocardial infarction is high. The structured medical counselling was not
effective to reduce the number of smokers at one year.
PMID- 10757102
TI - [Seroprevalence of HIV infection among sexually transmitted disease clinic
attenders. Study Group of the Seroprevalence of Anonymous HIV Unrelated to
Patients Consulting a Sexually Transmitted Disease Clinic].
AB - BACKGROUND: To estimate the seroprevalence of HIV infection among sexually
transmitted disease (STD) clinic attenders. PATIENTS AND METHODS: Unlinked
anonymous serologic survey among patients from six STD clinics in 1998. RESULTS:
Among 1,303 patients 3.7% were found to be infected by HIV. Seroprevalences were
48.3% in injecting drug users, 16.7% in homosexual men, 1.3% in prostitutes, 0.9%
in heterosexuals from sub-Saharan Africa or Caribbean, and 3.1% in other
heterosexuals. CONCLUSION: In STD clinics attenders heterosexuals from sub
Saharan Africa or Caribbean and prostitutes showed the lowest seroprevalences of
HIV infection.
PMID- 10757103
TI - [Factors related to drug consumption in children's population].
AB - BACKGROUND: To analyse the correlates of drug consumption in children's
population. METHOD: Analyse interviews corresponding to children younger than 15
years old of the Catalan Health Survey (n = 2,433). RESULTS: The 25% consumed
some drug in the previous 2 days. The factors related to drug consumption were
low age, living in Barcelona (OR = 1.3), reporting double coverage (OR = 1.6),
physician visits in the past 15 days (OR = 2.4), and reporting health problems.
CONCLUSIONS: Drug consumption in children is high. It seems necessary to improve
the education of families and health professionals related to drug consumption.
PMID- 10757104
TI - [Infection by cytomegalovirus and inflammatory bowel disease].
PMID- 10757105
TI - [Olive oil: healthy food since caliphal time to the threshold of the new
millennium].
PMID- 10757106
TI - [The human factor in clinical relations. The judgement-emotion binomial].
PMID- 10757107
TI - [The JAK-STAT signaling pathway and its role in oncogenesis, immunomodulation and
development].
PMID- 10757108
TI - [Antiaggregants of choice for prevention of pulmonary thromboembolism in patients
with prosthetic heart valves].
PMID- 10757109
TI - [Abstinence is better].
PMID- 10757110
TI - [Excellent response to lanreotide treatment of thyrotropin and prolactin
secreting pituitary macroadenoma].
PMID- 10757111
TI - [Clinical usefulness of antineutrophil cytoplasmic antibodies with special
reference to cystic fibrosis].
PMID- 10757112
TI - Increase in expression of Hsp47 and collagen in hereditary gingival fibromatosis
is modulated by stress and terminal procollagen N-propeptides.
AB - HGF is a rare oral condition characterized by a slow, progressive enlargement of
the gingiva, involving both the maxilla and mandible. HGF provides a model for
the study of regulatory features of conditions characterized by connective tissue
hyperplasia. In this study, the culture characteristics of gingival fibroblasts
derived from patients of the same family with HGF (n = 4) were similar with
regard to cell cycle analysis. Flow cytometric DNA content analysis revealed
uniform DNA diploidy for fibroblasts cultured from NG and HGF. NG cells showed a
low S-phase fraction (19.8%) and G2/M fraction (5.8%) and a relatively high G1
phase fraction (74%). In contrast, HGF cells from all members of the tested
kindred, exhibited diploid cells with a higher S-phase (40.9%) and G2/M (10.1%)
fraction and a relatively low G1 phase fraction (40.9%). Furthermore, we
demonstrated that the expression and production of Hsp47 parallels the increased
levels of collagen secretion observed in HGF. In addition, we show that Hsp47 and
collagen are coordinately regulated following stress via a feedback mechanism
mediated by N-terminal procollagen propeptides. Utilizing confocal microscopy and
antibodies directed against GST-fusion proteins encompassing the pro alpha1(I) N
propeptide globular domain (NP1) (residues 23-108), it was apparent that this
regulatory mechanism does not involve significant interaction with Hsp47's
chaperoning of procollagen.
PMID- 10757113
TI - Recombinant expression and characterization of dentin matrix protein 1.
AB - Dentin matrix protein 1 (DMP1) is an extracellular matrix noncollagenous protein
(NCP) initially isolated from dentin and now found to be present in calcified
tissues like calvaria and long bone. The characteristic feature of DMP1 is that
it contains a large number of acidic domains and has properties which implicate
it as a key participant in regulating matrix mineralization. The level of DMP1 in
the tissue is sparse and it is not easily isolated from dentin because it
copurifies with other dentin NCPs. The exact function of DMP1 is not known and
this is due to the inherent difficulty of obtaining enough protein from the
mineralized tissues. In order to understand the physiologic role for DMP1 during
the formation of mineralized tissues we have produced milligram quantities of
recombinant DMP1 in E. coli. The objective of this work was: (1) to prepare
unmodified apoprotein so that it could be used for studying the function of DMP1;
and (2) to prepare polyclonal antibody against the recombinant DMP1 antigen. The
DMP1 polyclonal antibody did not cross-react with other NCPs present in dentin or
with bone acidic glycoprotein-75 (BAG-75) present in the bone matrix, confirming
the specificity of this antibody and thus making it a valuable tool to determine
the in vivo function of DMP1.
PMID- 10757114
TI - Mature full-thickness articular cartilage explants attached to bone are
physiologically stable over long-term culture in serum-free media.
AB - Mature tissue explants containing the entire depth of articular cartilage,
calcified and uncalcified, attached to a thin layer of subchondral bone were
isolated from bovine humeral heads of 1-2-year-old steers. These explants were
placed in defined serum-free culture medium for a period of 3 weeks to
investigate their biological and mechanical stability and thus to determine their
potential utility in studies of cartilage physiology. Tissue mass remained
constant over the culture period and no evident tissue swelling or distortion was
observed. Chondrocytes were viable in all zones at the time of tissue isolation
and throughout the culture period, with the exception of a thin layer of cells at
the articular surface and the cut radial edge of the disks. Proteoglycan
metabolism attained a steady state after 5 days of culture when the rate of loss
of proteoglycan to culture media was compensated by new synthesis to maintain a
stable proteoglycan content. Collagen metabolism was also stable with a constant
content of type II collagen and a constant content of denatured collagen II
throughout culture; the content of the C-propeptide of type II procollagen as a
measure of procollagen synthesis, dropped slightly during the first week to
attain a steady state after that time. Dynamic and equilibrium mechanical
properties of these explant disks were also stable confirming maintenance of
these tissue properties during long-term culture. In addition, the disk geometry
of the system, with the cut surface in the bone parallel to the intact articular
surface, is well-suited to study tissue regulation by mechanical load. Taken
together, the stability of these indicators of tissue physiology indicates the
maintenance in serum-free conditions of normal metabolism for organ cultures
containing full-depth mature articular cartilage attached to bone.
PMID- 10757115
TI - Antibody raised to AKAAAKAAAKA sequence on tropoelastin recognizes tropoelastin
but not mature crosslinked elastin: A new tool in metabolic and structural
studies of elastogenesis.
AB - Tropoelastin, which is secreted from the cell in a soluble form, contains
specific alanine rich repeat domains that are destined to form covalent desmosine
and isodesmosine crosslinks in mature insoluble elastin. We raised a monospecific
polyclonal antibody to a AKAAAKAAAKA synthetic peptide (AKA) which represents
this alanine rich region of tropoelastin. The antibody was reactive with the
original peptide antigen and purified tropoelastin, but not with mature
crosslinked elastin isolated from several animal species. Conditioned media from
chick aorta smooth muscle cells in culture reacted in an ELISA with the AKA
antibody, but only in the presence of BAPN to block the conversion of the epsilon
amino groups to aldehydes. Immunofluorescence demonstrated that the AKA antibody
decorated newly deposited tropoelastin assembled in fine fibrils in matrix
produced by cultured human skin fibroblasts. EM-immunogold specifically localized
this antibody to the immature elastic fibers present in fetal sheep ductus
arteriosus. Moreover, immunohistochemistry demonstrated that the antibody
recognized nonpolymerized tropoelastin assembled on the periphery of elastic
fibers in the aorta of chicks raised on copper deficient and BAPN containing
diets. These studies demonstrate that this new anti-tropoelastin antibody can be
used as a useful tool to investigate elastin metabolism where it is important to
distinguish between tropoelastin and mature crosslinked elastin.
PMID- 10757116
TI - Integrin alpha2beta1 recognizes laminin-2 and induces C-erb B2 tyrosine
phosphorylation in metastatic human melanoma cells.
AB - Previous studies have shown that tumor cells with metastatic propensity secrete
more of the laminin alpha2 chain than non-metastatic tumor cells do, and that
laminin-2, which contains the alpha2 chain, promotes cell adhesion better than
laminin-1 (Jenq et al. (1994). Differentiation, 58, 29-36). The current studies
were designed to determine whether a correlation exists between the expression of
the laminin-2 isoform and the metastatic phenotype in melanoma cells. We found
that expression of the laminin-2 isoform was upregulated in the metastatic
melanoma cell lines tested. Cell attachment studies showed that metastatic
melanoma cells attached more efficiently to laminin-2 substrates. Studies on
integrin expression revealed that the presence of alpha2beta1 integrin correlated
with expression of the laminin-2 isoform in metastatic melanoma cells; anti
integrin alpha2 antibody prevented cell attachment to laminin-2 substrates. The
data suggest that the alpha2beta1 integrin is the receptor mediating cell
attachment to the laminin-2 isoform. This interaction, mediated by the
alpha2beta1 integrin, stimulates secretion of the 72 kD type IV collagenase and
induces a specific 185 kD protein tyrosine phosphorylation. The 185 kD tyrosine
phosphorylated protein was identified as the p185/C-erb B2 oncoprotein by
immunoprecipitation. These studies suggest that upregulation of expression of the
laminin-2 chain correlates with the metastatic phenotype of melanoma cells and
provides evidence that the specific p185/C-erb B2 tyrosine phosphorylation may be
involved in integrin-mediated signaling during tumor cell invasion and
metastasis.
PMID- 10757117
TI - Localization of secreted protein acidic and rich in cysteine (SPARC) expression
in the rat eye.
AB - Secreted protein acidic and rich in cysteine (SPARC) is a secreted glycoprotein
protein which modulates cell shape and cell-matrix interactions and has been
implicated in the regulation of angiogenesis, vascular permeability and cataract
formation. In situ hybridization and immunohistochemical studies for SPARC were
performed to determine the cell and tissue distribution of SPARC in rat eye.
Studies demonstrated SPARC mRNA and protein co-localization at all sites. In the
retina SPARC mRNA and protein were localized predominantly to the Muller and
ganglion cells. Within the choroid, SPARC was found in vascular endothelial cells
and fibroblasts; in the sclera SPARC was present in blood vessels and
fibroblasts. SPARC was also present in the non-pigmented epithelial cells of the
ciliary body, and in the epithelium of the lens capsule and cornea. The
demonstrated anatomical distribution of SPARC in the rat eye is consistent with
several of the biological functions ascribed to this matricellular protein and
provides a rational basis for its examination in pathological conditions.
PMID- 10757118
TI - K-ras mutation: early detection in molecular diagnosis and risk assessment of
colorectal, pancreas, and lung cancers--a review.
AB - Multiple genomic alterations are involved in the development of most human
cancers. They include alterations in oncogenes, tumor suppressor genes, DNA
mismatch repair and excision repair genes. Genetic testing for susceptibility has
been a part of the management of patients with well-defined but uncommon
hereditary cancers in which certain susceptible gene mutations are determined in
the germ line. However, a molecular diagnostic approach to sporadic cancers,
which comprise the vast majority of malignant tumors in human beings, is still
under development. One of the best characterized tumor-related genes is K-ras,
which somatically mutates in several types of sporadic human cancers. Since
mutations of this gene occur exclusively in three hot spots (codons 12, 13 and
61), and are frequently detected and well characterized in colorectal, pancreas
and lung cancers, molecular diagnosis and susceptibility (risk) assessment
targeting K-ras mutations are being developed. For this purpose, sample
collection methods that reflect the state of the entire affected organ are
important. Clinical samples used for molecular diagnosis and risk assessment
include stool and lavage fluid, pancreatic and duodenal juices, and sputum and
lavage fluids for colorectal, pancreas and lung cancers, respectively. The
reported incidence of K-ras mutations detected in these samples ranges from 7% to
80% for colorectal cancers, 25% to 87% for pancreatic cancers, and 25% to 48% for
lung cancers. Incidence of mutations clearly depends on the sensitivity of the
method for detecting the mutant K-ras allele, as well as the nature and the
quality of the clinical samples. Various methods including plaque hybridization,
dot blot hybridization, combined PCR and RFLP or SSCP, and sensitive PCR have
been used, and they exhibited high specificity (75 to 100%) in detecting
mutations. Molecular analysis is demonstrating promise in assessing
susceptibility to, or risk of developing, sporadic cancers.
PMID- 10757120
TI - Progression in transitional cell carcinoma of the urinary bladder--analysis of
Tp53 gene mutations by temperature gradients and sequence in tumor tissues and in
cellular urine sediments.
AB - The relationship between expression of p53 protein in bladder cancer and tumor
progression is known. In this paper, we attempt to study this phenomenon by
molecular-genetic techniques. One hundred thirty-seven bladder tumor tissues were
obtained from transurethral resection (TURB). Urine sediments were collected from
72 patients suffering from transitional cell carcinoma and tumor recurrence.
These patients were followed up for at least three months. Separate polymerase
chain reactions (PCR) were carried out for exons 5, 6, 7, and 8 of the Tp53 gene.
Temperature gradient gel electrophoresis (TGGE) was used to screen mutations in
the PCR products. Sequencing from reamplified mutant and wildtype bands was
excised from the TGGE. Tp53 mutation frequency is 43.1% in 137 bladder cancer
specimens, but already 32.7% of Ta-tumors (16/49) were Tp53 mutated. Four of 25
patients with Tp53 wild-type tumors suffered from progression. In the group of
patients with Tp53 mutated cancer, seven of 12 had a tumor progression. In 11 of
14 patients with Tp53 mutation in cancer tissue, the same mutation was also found
in urine sediments. In such patients, successful tumor treatment by TURB results
in loss of their Tp53 mutation in urine sediment, and tumor recurrency resulted
in reappearance.
PMID- 10757119
TI - Integrated p53 histopathologic/genetic analysis of premalignant lesions of the
esophagus.
AB - Esophageal carcinoma frequently occurs in patients with long-standing achalasia.
AIM: To examine the role of p53 alterations and PCNA in patients with
megaesophagus. METHODS: Sections of four tumors, and corresponding adjacent
areas, from patients with achalasia due to Chagas' disease were examined by
immunohistochemistry for p53 and PCNA proteins. Furthermore, 128 biopsies from 16
advanced achalasic patients were prospectively collected and evaluated for grades
of inflammation, hyperplasia, dysplasia and also for p53 and PCNA proteins. All
specimens showing p53 immunoreactivity were topographically genotyped using
microdissection, PCR amplification and direct sequencing of p53 exons 5-8.
RESULTS: Diffuse strong immunoreactivity of p53 was observed in 2/4 tumors. In
one patient, the adjacent mucosa also showed strong p53. In the adjacent mucosa,
the same areas showing p53 overexpression also had PCNA positive cells. In the
prospective group, 7/16 (43.7%) patients or 53/128 (41.4%) biopsies expressed
p53. The grade of inflammation was significantly correlated with the presence of
positive p53, in patients, p = 0.004 and in biopsies, p < 0.00001. PCNA
expression was found in the basal layer of the mucosa, and increased PCNA was
associated with p53 overexpression, p = 0.00018. Genotyping detected mutation in
exon 6, codon 213 RG, in one patient (1/16, 6.2%). CONCLUSIONS: (1.) p53
alterations, overexpression and mutational change, are an early event in patients
with achalasia; (2.) The inflammation frequently seen in these patients appears
to be associated with alterations of the p53 protein; (3.) Expression of the
tumor suppressor gene is increased in areas showing proliferation.
PMID- 10757121
TI - The CD44 receptor of the mouse LB T-cell lymphoma: analysis of the isoform
repertoire and ligand binding properties by reverse-transcriptase polymerase
chain reaction and antisense oligonucleotides.
AB - CD44 is a cell surface glycoprotein involved in cell migration and cell docking
in target organs via interactions with various ligands, including hyaluronic acid
(HA), which is the principal ligand of this receptor. Alternative splicing
generates many isoforms of CD44, including standard CD44 (CD44s) and CD44
variants (CD44v). LB T-cell lymphoma, which predominantly expresses CD44s,
acquires additional CD44v and HA binding capacity after activation with phorbol
ester. The HA9 cell line, isolated from parental LB cells, expresses CD44v and
constitutively binds HA. Downregulation of CD44v isoforms of HA9 cells, by CD44v
specific antisense inhibited their ability to bind HA, indicating that CD44v,
rather than CD44s, is associated with the activation status of this molecule.
Using the reverse transcriptase polymerase chain reaction, we found that LB cells
after infiltrating spleen and lymph nodes of BALB/c mice, contain an enriched
repertoire of CD44v, implying that the metastatic cells acquired the activated
form of this receptor.
PMID- 10757122
TI - Multifunctional activity of recombinant p14 on lymphoid cell cultures.
AB - Some effects of recombinant p14, a protein encoded by the tat gene of
immunodeficiency virus type 1 (HIV-1), were investigated on T lymphocytic cell
cultures. In particular, we detected p14 adsorption to cells, the rate of cell
replication, the expression of fibronectin (FN) and its receptor (FNR) and of
cell surface CD4 antigen in HIV-1-infected or uninfected MT-4 and H9 cells,
treated with p14. Moreover, we evaluated the proportion of apoptotic cells in
uninfected and chronically infected H9 cells in the presence of p14 and the
modulation of interferon (IFN) production induced by p14 in PBMC of healthy
subjects. The results obtained demonstrate that p14 exerts multifunctional
activities on HIV-1 infected and uninfected cells. In particular, this protein
interacts in a specific manner with cell surface, especially with that of
infected cells, and enhances the expression of FN and FNR but not that of the CD4
lymphocyte antigen. Moreover, p14 increases cell replication, IFN production and
can exert a slight modulation of apoptosis. We also propose a model to explain a
possible role in HIV-1 infection of the effects of exogenous p14.
PMID- 10757123
TI - Expression of thioredoxin and glutaredoxin, redox-regulating proteins, in
pancreatic cancer.
AB - Pancreatic cancer (pancreatic ductal carcinoma) is one of the most malignant
solid tumors with poor prognosis. There is accumulating evidence that cellular
reduction/oxidation (redox) status is deeply involved in the growth promotion and
drug resistance of cancer cells. We therefore investigated the expression of
redox-regulating proteins, such as thioredoxin (TRX) and glutaredoxin (GRX) in
surgically resected pancreatic tissues and cis-diamminedichloroplatinum (CDDP)
resistant cells. Plasma levels of TRX were also measured in subjects with
pancreatic diseases. Pancreatic ductal carcinoma tissues were
immunohistochemically more positive for TRX (24/32 cases) and GRX (29/32 cases)
than pancreatic cystadenocarcinoma or normal pancreas tissues. Plasma levels of
TRX (mean +/- SD) measured by ELISA were significantly higher in patients with
pancreatic ductal carcinoma (54.8 +/- 37.6 ng/ml, n = 60) than in healthy
controls (24.4 +/- 12.9 ng/ml, n = 81). CDDP-resistant subclones of HeLa cells,
HeLa-CP5 cells, had higher expression of TRX (1.5 fold) and GRX (1.6 fold)
compared with parental HeLa cells by immunoblotting. These results indicate the
possible association of TRX and GRX with malignant potential of pancreatic ductal
carcinoma.
PMID- 10757124
TI - Biosynthesis of Vicia graminea lectin- and Vicia unijuga lectin-binding
glycoproteins in human tumor and nontumor cells and an estimation of its epitope
structure.
AB - We investigated biosynthesis of Vicia graminea lectin (VGA)- and Vicia unijuga
lectin (VUA)-binding (Vgu) glycoproteins, which are human malignant tumor
associated antigens, in cultured human tumor and non-tumor cells by pulse
labeling experiments with [35S]-methionine, followed by immunoprecipitation using
immobilized VUA, SDS-PAGE and autofluorography. It was shown that Vgu
glycoproteins synthesized by tumor cells were 15-30 times greater than those of
non-tumor cells. It was also shown that about 40-70% of Vgu glycoproteins
synthesized by non-tumor cells were secreted from the cells while more than 80%
of the antigen synthesized by tumor cells was not secreted, and that Vgu
glycoproteins consisted of multiple molecular species with the same epitope. To
estimate the epitope structure of Vgu glycoproteins, in preliminary experiments
we prepared sialoglycoproteins and/or sialoglycopeptides from purified human
glycophorin A. Human glycophorins A(M) and A(N) (GPs-A(M) and A(N)) were treated
with Clostridium perfringens neuraminidase to remove all sialic acid residues
linked to carbohydrate chains, with Newcastle disease virus (NDV) to remove
alpha2-3 linked sialic acid residues, and by Edman's degradation to eliminate N
terminal amino acid of GP-As. Partial or complete desialylation reactions
resulted in disappearance of the reactivity of GP-A(M) and GP-A(N) with
corresponding antisera and in appearance of reactivities with VUA and VGA.
Elimination of N-terminal amino acid of GP-As also resulted in appearance of
reactivities with VUA. These results show that sialoglycoproteins with similar
serological properties of Vgu glycoprotein could be prepared from GP-As, and
suggest that the epitope structure of Vgu glycoprotein may be related to the MN
blood type-epitope structure and its sialic acid residues at N-terminal moiety of
GP-As.
PMID- 10757125
TI - Evidence for colorectal cancer micrometastases using reverse transcriptase
polymerase chain reaction analysis of MUC2 in lymph nodes.
AB - Poor survival in patients following resection for early stage colorectal cancer
is thought to be due in part to the presence of occult micrometastases at the
time of surgery. The MUC2 mucin gene is highly expressed in the colon and
associated colorectal tumors and may be a candidate marker for colorectal cancer
micrometastases. We have used RT-PCR to detect expression of MUC2 mRNA
transcripts in order to identify possible lymph node micrometastases in node
negative (Stage I and II, or Dukes A and B) colorectal cancer patients. A total
of 396 nodes (histologic stage N0) from 34 colon and nine rectal cancers were
studied by RT-PCR analysis with nested primers for MUC2 (an average of 7.6 nodes
per case). In the primary tumors, 42/43 (98.1%) were positive for MUC2 by RT-PCR.
Evidence of the presence of MUC2 was demonstrated in nodes from 0 of 10 (0%)
patients with Tis or T1, one of six (16.7%) from T2, 10 of 25 (40.0%) from T3,
and one of two (50%) from T4 tumors. MUC2 RT-PCR was negative in six nodes from
three patients with non-malignant colon disease and positive in histologically
positive lymph nodes from six of six (100%) stage III colon cancers. In this
study, using RT-PCR to detect the presence of MUC2 transcripts, we have found
preliminary evidence for possible micrometastatic disease in approximately a
third of histologically negative N0 colorectal cancer patients. The increased
presence of MUC2 expression also correlated with more advanced T stage. We
conclude that MUC2 RT-PCR may be a sensitive and specific marker for occult
micrometastases. This technique has the potential to identify a group of
colorectal cancer patients at risk for early cancer recurrence.
PMID- 10757126
TI - Significance of serum type IV collagenolytic activities and gelatinase levels for
detection of metastasis in murine RCT sarcoma.
AB - We investigated the usefulness of serum type IV collagenolytic activities and
gelatinase levels as diagnostic markers of metastasis in the animal model of
spontaneous lung metastasis by FITC-labeled type IV collagen degradation assay
and zymographic analyses. High-metastatic RCT(+) and low-metastatic RCT(-) clones
were used in the present study. The mean serum type IV collagenolytic activity in
the RCT(+) group started to increase from two weeks after hind limb amputation,
and was 0.45 and 1.29 unit/ml at three and four weeks. These values were
significantly higher than those in the control group (p < 0.01 at three weeks; p
< 0.001 at four weeks). A correlation between the number of lung nodules and
serum type IV collagenolytic activities in the RCT(+) group was found (r = 0.89,
p < 0.001). Zymographic analyses indicated that 105-kD gelatinolytic activities
of the RCT(+) group were higher than those of the RCT(-) group at three and four
weeks. Thus, type IV collagenolytic activities and serum gelatinase levels might
be valuable markers for the detection of metastasis.
PMID- 10757127
TI - Renal function and serum concentration of five tumor markers (TATI, SCC, CYFRA 21
1, TPA, and TPS) in patients without evidence of neoplasia.
AB - The aim of this study was to evaluate the relationship between renal function and
the blood level of some tumor markers that are low molecular weight proteins,
that is, tumor-associated trypsin inhibitor (TATI), squamous cells carcinoma
antigen (SCC), cytokeratin 19 fragments (CYFRA 21-1), tissue polypeptide antigen
(TPA), and M3-specific epitope of tissue polypeptide antigen (TPS). In 41 adult
patients without evidence of neoplastic disease, glomerular filtration rate (GFR)
and the blood levels of creatinine and of the tumor markers were determined. The
decrease in GFR was accompanied by an increase in serum levels of TATI, SCC,
CYFRA 21-1, and TPA. The serum level of tumor markers increased particularly when
GFR fell below 40 ml/min. On the basis of these results, the renal function must
be taken into account for the clinical evaluation of the studied tumor markers.
PMID- 10757128
TI - A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer
preventive agents (-)-epigallocatechin gallate and green tea--a review.
AB - The study of tumor promotion in rodent carcinogenesis using chemical tumor
promoters has revealed various tumor promotion pathways, such as the 12-O
tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of
protein kinase C, and the okadaic acid pathway mediated through inhibition of
protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that
application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF
alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor
of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we
found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3
methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985,
1993). This evidence demonstrates a link between the okadaic acid pathway and the
endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first
evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed
compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that
TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate
tumor promotion and progression of initiated cells as well as premalignant cells.
The first part of this paper reports on this TNF-alpha tumor promotion pathway.
In the second part, we report a promising screening method for cancer preventive
agents, based on evidence that pretreatment with agents such as tamoxifen,
sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester,
and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from
BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese
green tea, and green tea itself are acknowledged cancer preventives in Japan, and
this paper presents evidence of their effectiveness in both a high-risk group and
the general population.
PMID- 10757129
TI - Polyethylene glycol-modified concanavalin A as an effective agent to stimulate
anti-tumor cytotoxicity.
AB - The jack bean lectin, concanavalin A (Con A), was modified with 2,4-bis[O
methoxypoly(ethylene glycol)]-6-chloro-s-triazine, activated PEG2, to form PEG
Con A. The immunoreactivity of PEG-Con A towards anti-Con A antibodies was
reduced by increasing the degree of modification of amino groups in the Con A
molecule. PEG-Con A had a complete reduction of the immunogenicity in mice and
prolonged the clearance-time in blood. Although the mitogenic activity of Con A
towards murine spleen cells was reduced by the conjugation with activated PEG2,
the administration of PEG-Con A to mice enhanced the anti-tumor cytotoxicity of
peripheral lymphocytes against melanoma B16 cells.
PMID- 10757130
TI - Social control and workplace drinking norms: a comparison of two organizational
cultures.
AB - OBJECTIVE: This article reports on an investigation of the relationship of social
control mechanisms at work to drinking practices of 10,000 salaried and hourly
employees working in the same U.S. industry, with the same union, but in two
different work environments. One work environment reflected an organizational
culture that is traditional to U.S. management; the other was based on a
nontraditional Japanese transplant model. METHOD: The research team used a
combination of methods including in-home surveys (N = 1,723; 1,378 men) and
ethnography (110 semistructured interviews and 200 hours of direct observation
inside the plants). Respondents were asked about general and work-related
drinking, perceptions of drinking norms, strengths or weaknesses of alcohol
related policies and procedures for policy enforcement. RESULTS: Although overall
consumption rates in both populations were similar, significant differences
between the two samples existed regarding work-related drinking. The Traditional
(i.e., U.S.) model was associated with more permissive norms regarding drinking
before or during work shifts (including breaks) and higher workplace drinking
rates than the Transplant (i.e., Japanese) model. Analyses revealed that alcohol
policies, and the extent to which policies are actually enforced, predicted
drinking norms and alcohol availability at work. Drinking norms, in turn,
predicted work-related drinking and accounted for differences in alcohol
consumption between the two worksites. Analyses of ethnographic data provided
descriptive understandings of aspects of the two organizational cultures that
disabled mechanisms for social control of drinking in one setting and enabled
those mechanisms in the other. CONCLUSIONS: These understandings of how social
control mechanisms predict work-related drinking practices provide guidelines for
alcohol problem prevention in a specific kind of occupational environment.
However, our identification of aspects of social control that successfully
regulate workplace drinking is applicable to other kinds of occupational settings
as well.
PMID- 10757131
TI - Drinking in alcoholics following an alcohol challenge research protocol.
AB - OBJECTIVE: The present study examined the impact of participating in an alcohol
administration study on the subsequent drinking behavior of 25 non-treatment
seeking alcoholics. METHOD: Subjects attended two assessment sessions, followed
by a week-long regimen on one of three pharmacological agents (naltrexone,
nalmefene, or placebo), a day-long laboratory assessment including a standardized
alcohol administration procedure, and a debriefing session consisting of
individualized feedback and alcohol counseling. Follow-up consisted of a
telephone interview 6 weeks after the alcohol challenge session. RESULTS: At the
follow-up interview, subjects reported significant reductions in drinking
quantity and frequency from the prestudy period, and no subjects reported
increased drinking following study participation. CONCLUSIONS: These findings
suggest that alcohol administration research procedures may not be detrimental to
the poststudy drinking behavior of alcoholics. The use of such procedures could
be cautiously expanded to improve the generalizability of findings for alcoholic
populations of interest.
PMID- 10757132
TI - Alcohol dependence at the cellular level: effects of ethanol on calcium
homeostasis of IM-9 human lymphoblast cells.
AB - OBJECTIVE: Increased intracellular calcium level ([Ca2+]i) was previously
observed in peripheral blood mononuclear cells of alcoholic patients under
withdrawal. To determine whether this change in [Ca2+]i is due to direct effect
of ethanol on blood cells and shows adaptation of these cells to alcohol, we
examined the effect of alcohol on IM-9 human lymphoblast cultures. METHOD:
[Ca2+]i of IM-9 lymphoblasts. after acute and chronic alcohol treatment as well
as alcohol withdrawal, was measured fluorometrically using Quin2 as a Ca2+
indicator. RESULTS: Acute ethanol treatment induced a rapid, transient increase
in intracellular calcium concentration in a dose-dependent manner. During chronic
ethanol (50mM) administration, after the first 24 hours, basal [Ca2+]i was
significantly lower (44 +/- 8% of control, p < .025), whereas from the fifth day
[Ca2+]i was significantly higher (415 +/- 59% of control on the sixth day, p <
.01) compared with untreated cells. After a 3-day ethanol (50OmM or 100mM)
treatment, elimination of alcohol from the medium caused elevation in [Ca2+]i.
After 24-hour ethanol withdrawal, the addition of alcohol decreased the elevated
[Ca2+]i of alcohol-adapted cells to the resting level of control cells. Similar
results were observed when verapamil, diazepam or haloperidol were applied.
Moreover, when ethanol or these agents were administered at the beginning of
alcohol withdrawal, they could prevent the increase in [Ca2+]i. CONCLUSIONS:
These results suggest that alcohol dependence can develop at the cellular level,
and that changes in calcium homeostasis, likely due to direct effects of ethanol
on ion channels, may play a central role in processes leading to adaptation of
cells to alcohol.
PMID- 10757133
TI - Effects of alcohol on exogenous precueing of attention.
AB - OBJECTIVE: Transient visual events cause a rapid allocation of attention to the
event location. We studied the effect of alcohol on this aspect of attention.
METHOD: Subjects responded to targets presented either left or right of fixation
and the time between target presentation and response (reaction time: RT) was
measured both before and after ingestion of either alcohol or a placebo.
Transient cues were presented prior to each target presentation. Cues were,
variously, a brightening of either the box in which the target was to occur
("valid"), the box on the opposite side of the display from where the target was
to occur ("invalid") or the fixation stimulus ("neutral"). The interval between
cue and target presentation (stimulus onset asynchrony: SOA) was variously 50,
100, 150 or 800 msecs. RESULTS: At short SOAs, RT was faster to targets presented
following valid cues relative to the other cues. At 800 msecs the opposite
pattern was found. Alcohol selectively slowed RT only following neutral or
invalid cues at short SOAs. CONCLUSIONS: Alcohol does not disrupt the normal
attentional allocation to visual transients. It may delay the subsequent response
to events at other locations, however.
PMID- 10757134
TI - Response inhibition under alcohol: effects of cognitive and motivational
conflict.
AB - OBJECTIVE: This experiment tested the effect of cognitive and motivational
conflict on response inhibition under alcohol. METHOD: Fifty-six male social
drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of
groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a
go/stop choice reaction time task under one of four conflict conditions. One
condition (C) produced cognitive conflict by presenting "go" and "stop" signals
in the task. Another condition (IR) added motivational conflict by administering
an equal monetary reward for inhibiting responses to stop-signals, and for
responding to go-signals. The remaining two conditions resolved the motivational
conflict by administering the monetary reward only for inhibitions (I), or only
for responses (R). RESULTS: Compared with placebo, alcohol reduced inhibitions
(i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and
under motivational conflict (IR; p = .012). No significant effect of alcohol on
inhibitions was observed in conditions where conflict was resolved (i.e., I and
R). CONCLUSIONS: The study shows that alcohol can reduce the ability to inhibit a
response. However, impaired inhibitory control is not an inevitable outcome of
the drug action, because it can be counteracted by the consequences of behavior
in the situation.
PMID- 10757135
TI - Two-year mental health service use and course of remission in patients with
substance use and posttraumatic stress disorders.
AB - OBJECTIVE: Comorbid diagnoses of substance abuse/dependence and posttraumatic
stress disorder (SUD-PTSD) adversely affect substance abuse patients' treatment
outcomes. Recently, several practices have been recommended for the treatment of
SUD-PTSD patients based on empirical findings, including providing PTSD-specific
care. Accordingly, this study examines the association between outpatient PTSD
treatment and the long-term course of SUD-PTSD patients. METHOD: Male substance
abuse/dependence patients (N = 125) with a comorbid diagnosis of PTSD completed 1
and 2-year follow-ups. Based on these reports, 26 patients were stably remitted
from substance abuse, 39 were partially remitted and 60 were not remitted at
either follow-up. These three groups were compared on mental health service use
indices gathered from patients' self-reports of inpatient treatment and
nationwide Veterans Affairs (VA) databases abstracting outpatient visits.
RESULTS: SUD-PTSD patients who attended more outpatient substance abuse,
psychiatric and PTSD services in the first year following treatment (and
cumulatively over the 2-year follow-up) were more likely to maintain a stable
course of remission from substance use in the 2 years following inpatient SUD
treatment. When the three types of sessions were examined in regression analyses,
PTSD sessions in the second year and the total number of PTSD sessions over the 2
years following the index treatment episode emerged as the most significant
predictors of remission. Self-help group participation was also associated with a
remitted course for SUD-PTSD patients. CONCLUSIONS: These data suggest that PTSD
focused treatment services are an essential treatment component for substance
abuse/dependence patients with PTSD.
PMID- 10757136
TI - The validity of the MAST in psychiatric settings: a meta-analytic integration.
Michigan Alcoholism Screening Test.
AB - OBJECTIVE: Assessment of alcohol-related problems is essential in psychiatric
settings. The Michigan Alcoholism Screening Test (MAST) has been the most
commonly evaluated self-report alcohol assessment tool in psychiatric settings.
However, due to a large variation in reports of findings and conclusions, a clear
understanding of the utility of the MAST in psychiatric settings continues to be
elusive. Therefore, the major goals of this investigation were (1) to integrate
the available information pertaining to the validity of the MAST when used in
psychiatric settings, and (2) to investigate factors that may moderate the
performance of the MAST. METHOD: Using clinically determined alcohol-related
diagnosis as a criterion, a meta-analytic integration of nine published studies
investigating the criterion validity of the MAST in psychiatric settings is
presented. RESULTS: Findings revealed that the MAST is significantly valid when
used in psychiatric settings. However, sensitivity estimates were found to be of
greater magnitude than specificity estimates. Further, validity estimates of the
MAST were found to be higher in psychiatric samples that had a greater proportion
of women and in samples that exhibited higher base rates of alcohol-use disorder.
CONCLUSIONS: Results of this integration support the continued use of the MAST in
psychiatric settings as a screening instrument and suggest that those who
administer the MAST must be attentive to particular characteristics of
respondents.
PMID- 10757137
TI - HIV infection and risk behaviors in two cross-sectional surveys of heterosexuals
in alcoholism treatment.
AB - OBJECTIVE: To measure the prevalence of human immunodeficiency virus (HIV)
infection and high-risk behaviors among heterosexuals in alcoholism treatment,
comparing two cross-sectional surveys completed 2 to 3 years apart. METHOD: Two
groups of entrants to alcoholism treatment clinics were recruited, between
October 1990 and December 1991 (n = 860; 639 men) and between January 1993 and
March 1994 (n = 752; 520 men). Participants underwent a structured interview
including an assessment of demographics. substance abuse characteristics and
sexual behaviors, as well as serotesting for HIV antibodies. Associations were
examined between HIV serostatus and several factors, including demographic
variables, substance use and high-risk sexual behaviors. RESULTS: The overall HIV
seroprevalence in the first and second samples was 5% (95% CI: 3-6%) and 5% (95%
CI: 3-7%). When the two samples were compared, there were no significant
differences in prevalence of HIV infection by categories of gender, race, income
and most other demographic characteristics within either sample: history of
injection drug use (IDU) was significantly related to HIV serostatus in both
samples. Unsafe sexual practices were common in both samples. When samples were
combined, those 30 years of age or older were more likely to be HIV infected, and
men and women with no reported history of IDU still had an HIV prevalence of 3%
and 2%, respectively. More than half of the respondents had two or more partners
in the previous 6 months and reported a history of a sexually transmitted
disease. CONCLUSIONS: There was no change in the substantial prevalence of HIV
infection and high-risk behavior among heterosexual clients entering alcoholism
treatment programs over the 3.5-year study period. The HIV prevalence among non
IDU clients remained several times higher than published estimates from similar
community-based heterosexual samples. These data reinforce the concept that
heterosexual noninjection drug users are at high risk for HIV and may benefit
from intervention programs.
PMID- 10757138
TI - Rural at-risk drinkers: correlates and one-year use of alcoholism treatment
services.
AB - OBJECTIVE: The purpose of this study was to identify a community sample of rural
and urban at-risk drinkers, to compare them in terms of sociodemographics, access
measures and severity of illness, and to study them prospectively to identify
rural/urban differences in use of 12-month alcoholism treatment services. METHOD:
A brief telephone screening interview of over 12,000 respondents in six southern
states identified a sample of at-risk drinkers. A baseline interview was
administered to 733 individuals (67% men, 50% rural residents) that obtained
information on substance use and psychiatric disorders, psychosocial factors,
social support, four dimensions of access to alcoholism treatment services and
prior alcoholism service use. Interviews at 6 and 12 months obtained self-reports
of subsequent receipt of alcoholism treatment services. RESULTS: We identified
modest differences between rural and urban at-risk drinkers. The rural sample was
significantly less well-educated and reported significantly less affordability,
accessibility and acceptability of some treatment services (p < .05). Rural at
risk drinkers also appeared to possess significantly greater illness
characteristics, including more lifetime DSM-IV criteria for alcohol use
disorders, more frequent recent alcohol disorders and more chronic medical
problems (p < .05). The longitudinal sample comprised 579 participants, of whom
7% reported receiving some form of alcoholism treatment services in the year
after the initial interview. In bivariate analysis, rural drinkers in the sample
reported greater use of help for their drinking, more use of psychiatrists and
more use of inpatient, outpatient and ER treatment settings than did their urban
counterparts. However, significant independent predictors of 12-month alcoholism
treatment use in multiple logistic regression were female gender (OR = 0.3),
greater social support (OR = 2.2) and illness or severity characteristics
including recent diagnosis of alcohol dependence (OR = 3.3), social consequences
of drinking (OR = 1.7), concurrent medical problems (OR = 2.1) and prior
treatment experience (OR = 4.4). CONCLUSIONS: We found modest differences among
rural and urban at-risk drinkers and some evidence of greater barriers to
treatment and greater illness severity among rural inhabitants. Further research
is needed to know whether community interventions with social networks and other
interventions to improve social support may help bring at-risk drinkers into
treatment in both urban and rural settings as well as provide other support for
sobriety.
PMID- 10757139
TI - Collegiate alcohol involvement and role attainment in early adulthood: findings
from a prospective high-risk study.
AB - OBJECTIVE: Recent research has highlighted the magnitude of alcohol use and
alcohol-related problems on college campuses. However, the effects of alcohol use
and abuse during the college years on early adult role attainment are not well
characterized. Accordingly, this study was designed to prospectively examine
relations between alcohol involvement during the college years and early adult
educational and occupational attainment. METHOD: Participants (N = 429: 231
women) at low and high risk for the development of alcoholism were recruited at a
large midwestern university for a study of alcohol and health during the college
years. Alcohol involvement was assessed by self-report and structured clinical
interviews conducted annually for 4 years. Educational and occupational
attainment were assessed by self-report 6 years postmatriculation. RESULTS:
Alcohol involvement demonstrated a modest prospective effect on educational
attainment, with a reduced effect observed when analyses controlled for academic
aptitude and high school academic achievement. Prior academic achievement
moderated the relation between alcohol involvement and educational attainment,
such that individuals who were higher on secondary school class ranking were more
negatively affected by pathologic alcohol involvement than those with lower
levels of prior academic achievement. Less consistent evidence was found for
prospective relations between alcohol involvement and early adult occupational
attainment. CONCLUSIONS: These findings indicate a modest role for alcohol
involvement in negative educational outcomes, with a more pronounced negative
effect of alcohol involvement on educational attainment among those who were high
academic performers in high school.
PMID- 10757140
TI - The development of heavy drinking and alcohol-related problems from ages 18 to 37
in a U.S. national sample.
AB - OBJECTIVE: The purpose of this study is to add to the understanding of the
development of heavy alcohol use and alcohol-related problems by examining data
from the National Longitudinal Survey of Youth (NLSY), a general population
sample that contains information on alcohol use for the ages 18-37. A key
question in this study is how background characteristics of the individual
influence this development and whether the influence of these background
characteristics changes over time. METHOD: The data used in this study are a
general population sample (N = 7,859) from the National Longitudinal Survey of
Youth (NLSY). This study uses a multivariate outcome approach that focuses on
individual variation in trajectories over age. The statistical analysis uses
random coefficients in a latent variable framework. Across-age changes in the
importance of the influence of background variables on the outcomes are modeled
using varying centering points. RESULTS: A key finding is that dropping out of
high school has no effect on alcohol-related problems for individuals in their
mid-twenties, but is associated with significantly increased levels of alcohol
related problems for individuals in their mid-thirties. In contrast, going on to
college is associated with lower levels of heavy drinking when individuals reach
their late twenties and their thirties. Strong gender and ethnicity effects seen
in the twenties diminish when individuals reach their thirties. CONCLUSIONS: The
trajectory analysis expands the knowledge of problematic alcohol development for
individuals in their late twenties and thirties. The increasing detrimental
effect of dropping out of high school up to the age 37 endpoint of the study
raises questions about the effects in later life of dropping out of high school.
PMID- 10757141
TI - Examining drinking patterns and problems among hispanic groups: results from a
national survey.
AB - OBJECTIVE: This study examines and compares the drinking patterns and problems of
members of four Hispanic groups (Cubans, Mexican Americans, Puerto Ricans and
other Hispanics) in the United States, with information presented by gender and
age. METHOD: The 1993 National Household Survey on Drug Abuse, a recent national
probability sample of the household population aged 18 and over in the United
States, is used. Data are obtained through in-person interviews. The sample
includes 4,462 Hispanics of Cuban (n = 620), Mexican (n = 2,467), Puerto Rican (n
= 619) and Central and South American (n = 756) origin. Analyses are conducted
using SUDAAN. RESULTS: There are significant differences across the Hispanic
groups in their drinking patterns and problems. Among men, Mexican Americans
report the most frequent and heavy drinking, and the greatest prevalence of
drunkenness and alcohol-related problems. Cubans report the lowest percentages of
such respondents, and Puerto Ricans and other Hispanics are in between the other
two groups. For women, fewer ethnic differences are evidenced than for men. In
general, Puerto Ricans and Mexican Americans drink more often and heavily and
experience more problems than the other groups. Even after controlling for
predictors of adult alcohol use, some ethnic differences in drinking persist.
CONCLUSIONS: The four Hispanic groups have different drinking patterns. More
research is necessary to determine the factors associated with differences in
drinking across Hispanic groups.
PMID- 10757142
TI - Alcohol control and injury death in Alaska native communities: wet, damp and dry
under Alaska's local option law.
AB - OBJECTIVE: This article tests whether different forms of community-level alcohol
control significantly affect injury deaths in a population with extremely high
injury mortality. METHOD: The 1981 Alaska local option law provides a natural
experiment for studying how implementation of community level controls may be
associated with changes in injury deaths, most of which are alcohol-related,
among Alaska Natives living in small communities. The study compares population
and community-specific death rates under different levels of alcohol control for
the 97 communities that passed restrictions between 1980 and 1993 with the death
rates in the same communities during periods when no restrictions were in place.
RESULTS: Injury death rates were generally lower during periods when alcohol
sales, importation or possession were restricted than when no restrictions were
in place (wet). More restrictive controls (dry) significantly reduced homicides;
less restrictive control options (damp) reduced suicides. Accident and homicide
death rates fell, on average, by 74 and 66 per 100,000, respectively, for the 89
communities that banned sale and importation or possession. A control group of 61
small communities that did not change control status under the law showed no
significant changes over time in accident or homicide death rates. CONCLUSIONS:
The changes in accidental and homicide death rates are statistically significant,
although these reduced rates remain 2.5 to 7 times national death rates. The
isolated nature of Alaskan villages may explain why alcohol control has more
effect in Alaska than has been found in studies of Native Americans living in
other states.
PMID- 10757143
TI - The course of alcoholism among men in the Lundby Longitudinal Study, Sweden.
AB - OBJECTIVE: The purpose of this study is to describe the course of alcoholism
among men in the Lundby community cohort. METHOD: A subset (N = 41) of initially
nonalcoholic male subjects were diagnosed by a psychiatrist as first incidence
alcoholics (alcohol abuse and/or dependence) during the period 1957-72, all of
whom have been followed through four waves of investigation between 1947 and
1993. RESULTS: The proportion of remission of the entire 41 former alcoholic
subjects was 39%. Of the 23 survivors, 52% were remitted. The recovery started at
age 30-39 and culminated at age 40-49. CONCLUSIONS: In this 40-year follow-up of
former alcoholics, stable remissions were shown to occur at a rate of
approximately 40% (50% in survivors). Critical variables were severity and the
subjects' age at the time of recovery. The results are tentative because of the
small number of individuals.
PMID- 10757144
TI - Expectancies, evaluations and attitudes: prediction of college student drinking
behavior.
AB - OBJECTIVE: The goal of this study was to investigate a model of college student
alcohol use that not only included primary demographic and social factors shown
to influence college student drinking behavior but also measured the influence of
expectancies, evaluations of expectancies, and attitudes in prospectively
predicting drinking behavior. METHOD: Participants (N = 17) were recruited from
an introductory psychology course subject pool and were asked to complete several
questionnaires, including a modified Alcohol Expectancy Questionnaire, an
attitude questionnaire and a modified timeline follow-back measure. These
measures were completed at baseline and at a 1-month follow-up assessment. The
study was then replicated with a separate sample (N = 162). RESULTS: The results
of a series of mixed regression analyses indicated that, after accounting for
demographic variables, social norms and a college lifestyle attitude variable,
the only significant predictor consistent across drinking measures was the
general attitude variable. This was true for both the prospective and concurrent
analyses of alcohol use. The evaluations of expectancies did account for a
significant portion of the variance but appeared secondary to the general
attitude measure. The results of the study were replicated in a separate sample.
CONCLUSIONS: Contrary to previous research, the results of this study suggest
that attitudes toward alcohol use account for more variance in predicting
drinking behavior than both alcohol expectancies and evaluations of those
expectancies. The results of this study are also consistent with findings that
evaluations of alcohol-related expectancies predict drinking behavior.
PMID- 10757145
TI - Generalized expectancies for negative mood regulation and problem drinking among
college students.
AB - OBJECTIVE: Motivational models of alcohol use often invoke constructs derived
from social-learning theory, including coping styles, drinking motives and
affective distress. To date, no study has assessed the potential role of negative
mood regulation (NMR) expectancies (the extent to which one holds positive
expectations of one's ability to cope with negative affect) in promoting
problematic drinking behavior. This study evaluated the relationship between NMR
expectancies and problem-related drinking while controlling for the influence of
alcohol consumption, coping behaviors, drinking motives, demographic variables
and affective distress. METHOD: Participants (N = 136, 80% female) were college
undergraduates who completed a battery of self-report questionnaires on two
occasions that were separated by 8 weeks. RESULTS: Initial correlational analyses
indicated a strong (negative) association between NMR expectancies and problem
drinking behavior. Findings from separate hierarchical regression analyses
demonstrated that NMR expectancies add significantly to the variance in
predicting problem drinking, even when accounting for age and gender, alcohol
consumption and, in respective analyses, coping styles, affective distress and
drinking motives. Finally, simultaneous regression analyses showed that when all
variables were considered together, only NMR expectancies, alcohol consumption
and drinking-to-cope emerged as significant predictors of problem drinking.
CONCLUSIONS: These findings highlight the potential importance of NMR
expectancies as a risk factor for problem drinking, above and beyond the risk
posed by traditionally studied variables (e.g., depression and anxiety, coping
repertoire and drinking motives). Results are interpreted within a self
regulation framework of alcohol consumption.
PMID- 10757146
TI - Influence of dose and beverage type instructions on alcohol outcome expectancies
of DUI offenders.
AB - OBJECTIVE: To test the hypothesis that self-reported alcohol outcome expectancies
are situationally specific beliefs that vary depending on contextual variables,
such as the quantity and type of beverage one is instructed to imagine consuming.
METHOD: One hundred thirty DUI offenders attending a 72-hour weekend program were
randomly assigned to either a "small dose" or "large dose" instruction condition
and then completed five versions of the Comprehensive Effects of Alcohol scale, a
separate version for each of five beverage types ("alcohol," "beer," "wine,"
"mixed drinks" and "straight liquor"). RESULTS: Two separate 2 (dose) x 5
(beverage type) ANOVAs revealed that positive and negative expectancies varied
significantly as a function of both dose and beverage type. Specifically,
participants endorsed more positive outcomes and more negative outcomes when they
imagined drinking a large amount versus a small amount. In addition, participants
endorsed significantly more positive expectancies for beer and mixed drinks than
for wine. They endorsed the largest number of negative expectancies for straight
liquor and the fewest for wine. CONCLUSIONS: Expectancies are to some degree
context-bound and researchers and clinicians should consider providing explicit
dose and beverage type instructions to research participants and clients when
they use self-report questionnaires to assess alcohol outcome expectancies.
PMID- 10757147
TI - The relationship of self-efficacy expectancies to relapse among alcohol dependent
men and women: a prospective study.
AB - OBJECTIVE: We studied the relationship of self-efficacy expectancies measured
during inpatient alcohol treatment and time to first drink and time to relapse
following hospitalization. We also examined whether the relationship of in
hospital self-efficacy and posttreatment drinking outcome differed by gender.
METHOD: We measured self-efficacy expectancies using the Situational Confidence
Questionnaire (SCQ) in 100 subjects (59 men) during inpatient treatment for
alcohol dependence. We followed subjects monthly for 1 year and examined the
relationship of their in-hospital SCQ scores to posttreatment drinking behavior,
as measured by time to first drink, time to relapse and percent abstinent days.
RESULTS: Self-efficacy during hospitalization was related to relapse during the
12 months following hospitalization. Survival analysis demonstrated that in
hospital SCQ scores greater than 45 were predictive of better drinking outcomes.
The median number of days to relapse after treatment were 30 and 135,
respectively, in those with in-hospital SCQ scores less than or equal to 45
compared with those with SCQ scores greater than 45. There were no gender
differences in self-efficacy measured during hospitalization, nor were there
gender differences in the relationship of self-efficacy to time to relapse.
However, men with SCQ scores less than or equal to 45 had fewer abstinent days
during follow-up. CONCLUSIONS: Among both men and women being treated for alcohol
dependence, a cut-off score of 45 on the SCQ may be especially important in
helping clinicians assess patients who are at high risk for more rapid return to
drinking after hospitalization.
PMID- 10757148
TI - Drinking restraint versus alcohol expectancies: which is the better indicator of
alcohol problems?
AB - OBJECTIVE: The relationship between expectancies and other psychological
constructs related to drinking is unclear. The current study assesses the power
of drinking restraint, measured by the Temptation and Restraint Inventory (TRI),
along with alcohol expectancy and drinking refusal self-efficacy, measured by the
Drinking Expectancy Profile (DEP), as indicators of alcohol use and problem
drinking. METHOD: Volunteer students (N = 359), consisting of 113 men with a mean
(+/-SD) age of 25.31 +/- 10.61 years and 246 women with a mean age of 23.04 +/-
8.90, completed the TRI, DEP and Alcohol Dependence Scale (ADS) as well as
frequency and quantity measures of self-reported drinking. RESULTS: Drinking
Restraint was a stronger indicator of higher scores on the ADS, accounting for
54% and 45% of the variance for men and women, respectively, with Alcohol
Expectancies and Drinking Refusal Self-Efficacy being the better indicator of
frequency of alcohol consumption, accounting for 20% of the variance for men and
26% for women. Both measures were represented by similar variances within the
quantity of drinking measure. CONCLUSIONS: Drinking restraint and alcohol
expectancies were seen to measure kindred but unique cognitive subsets, providing
further insight into the progression of alcohol problems. Alcohol expectancies
and drinking refusal self-efficacy may be acquired early in the development of
drinking behavior, as evidenced by stronger associations with risky drinking;
drinking restraint and its associated loss of control factors appear to be more
specifically related to problem drinking. Alcohol expectancy and drinking refusal
self-efficacy may thus have broader use in the assessment of drinking behavior.
PMID- 10757149
TI - Sternal instability after midline sternotomy.
AB - The purpose of this paper is to discuss sternal instability a problem
occasionally associated with midline sternotomy, including the etiology,
predisposing conditions, diagnosis and management. Among the methods of repair,
sternal weaving and pectoralis muscle advancement are thought to be especially
effective.
PMID- 10757150
TI - The bad ventricle--revascularization versus transplantation.
AB - BACKGROUND: The proportion of patients with left-ventricular dysfunction (LVD)
undergoing high risk revascularization is increasing. In this patient group, the
perioperative risk is elevated because of the pre-existing pathophysiology.
Detailed evaluation and interdisciplinary differential therapeutic considerations
on the basis of the comparative benefit rationale, with cardiac transplantation
alternative, is mandatory. METHODS: Among 7275 patients who underwent coronary
artery bypass grafting between 1990 and 1998 in our institution, we found 51
patients who had had an ejection fraction <20%, and thus were candidates for
transplantation (group CABG); these were compared with 163 patients who were
listed for cardiac transplantation because of ischemic cardiomyopathy (group
HTX). The survival analysis was performed on the basis of the intention-to-treat
principle independent of subsequent transplantation. RESULTS: Both groups were
comparable with regard to left-ventricular ejection fraction; pulmonary capillary
wedge pressure and serum creatinine, but patients in the CAGB group were older
(63+/-11 vs 56+/-8; p = 0.001) and included a higher percentage of women (m/f:
42/9 vs 152/11; p = 0.03). Nevertheless, there was a similar 1-year survival in
both groups (group BP 71.9% vs group HTX 66.3%; p = ns). Looking at the CABG
group, the internal thoracic artery was used in 36/51 patients, an intra-aortic
balloon pump was used preoperatively in 26 patients, and intraoperatively in 6.
Left-ventricular assist devices had to be inserted in three patients,
extracorporeal membrane oxygenation once. Perioperative (30 day) survival was
88.2 %. An elevated preoperative serum creatinine and the nonusage of the
internal thoracic artery predicted an adverse outcome. In the long-term course,
the NYHA functional class improved in most cases from III preoperatively to I
after 26 (2-66) months. CONCLUSION: We conclude that patients with ischemic
cardiomyopathy, viable myocardium, and graftable vessels can be revascularized
with acceptable risk. Since for these patients a standby of mechanical
circulatory support must be anticipated perioperatively, this infrastructure
should be established within the center.
PMID- 10757151
TI - Does ischemic preconditioning require reperfusion before index ischemia?
AB - BACKGROUND: Ischemic preconditioning (IP) is initiated through one or several
short bouts of ischemia and reperfusion which precede a prolonged ischemia. To
test whether a reperfusion must precede the prolonged index ischemia, a series
without reperfusion (intraischemic preconditioning: IIP) and a series with
gradual onset of ischemia, i.e. ramp ischemia (RI), which is possibly related to
the development of hibernation, was compared to conventional IP (CIP). METHOD:
Experiments were performed an 27 blood-perfused rabbit hearts (Langendorff
apparatus) that were randomized into one of four series: (1) control (n = 7): 60
min normal flow - 60 min low flow (10%) ischemia - 60 min reperfusion. (2) CIP (n
= 7): 4 times 5 min zero flow with 10 min reperfusion each - 60 min low flow
(10%) - ischemia 60 min reperfusion. (3) IIP (n = 7): 50 min normal flow - 10 min
no flow - 60min low flow (10%) ischemia -4 60min reperfusion. (4) RI (n=6):
gradual reduction to 10% flow during 60min - 60min low flow (10%) ischemia -
60min reperfusion. At the end of each protocol, the infarcted area was assessed.
RESULTS: The infarct area in control hearts was 6.7+/-1.4% (means+/-SEM) of LV
total area, in CIP hearts 2.6+/-0.8%, in IIP hearts 3.1+/-0.5%, and in RI hearts
3.0+/-0.3% (all p<0.05 vs. control). The differences between the three protection
protocols were statistically not significant, and no protective protocol reduced
post-ischemic myocardial dysfunction. CONCLUSION: The preconditioning effect
(infarct size reduction) appears not to depend on intermittent reperfusion. Thus,
the protective mechanism of IP develops during the initial ischemia that precedes
the index ischemia. Alternatively, low-flow ischemia is effectively a sort of
reperfusion.
PMID- 10757152
TI - Arrhythmia prophylaxis after coronary artery bypass grafting: regimens of
magnesium sulfate administration.
AB - BACKGROUND: Arrhythmias are common after open heart surgery and may be related to
hypomagnesaemia due to cardiopulmonary bypass. Although perioperative
prophylactic Mg2+ administration may prevent arrhythmias after coronary artery
bypass grafting (CABG), clear indications as well as the timing of Mg2+
substitution and dose regimen need to be clarified. Aim of this study was to
evaluate the antiarrhythmic effects of Mg2+ infusion in patients who underwent
elective CABG. METHOD: Ninety-seven patients who underwent elective CABG were
divided in four Groups. In Group A 1 g of magnesium sulfate was added to the pump
prime, Group B received 1 g in the pump prime plus 5 mmol/L in the cardioplegic
solution, Group C received 5 mmol/L in the cardioplegic solution, and Group D was
a placebo control Group. Groups A, B, and C also received 24 h continuous
infusion of magnesium sulfate at 10 mmol/L. Three-channel electrocardiogram (II
V5-V6) continuous monitoring was performed 12 hours preoperatively and 48 hours
postoperatively. Blood samples were taken for subsequent Serum magnesium
measurements, at five different time points before, during and after CBP.
RESULTS: In all Groups serum Mg2+ levels were reduced during CPB (Time 2) and
statistically significant differences from pre-anaesthesia levels (Time 1) were
noted (p <0.05). In Groups A, B, and C Serum Mg2+ levels increased progressively
from Time 3 to Time 5; in Group D serum Mg2+ levels were still much lower at Time
5. Significant differences (p<0.05) were noted for Groups B and C vs Groups A and
D in atrial ectopics, atrial fibrillation, and ventricular arrhythmic events.
CONCLUSION: Our results demonstrate that Mg2+ sulfate administration regimens
used in Group B and C reduce postoperative arrhythmic events in patients
undergoing CABG.
PMID- 10757153
TI - Acute triiodothyronine administration does not reverse depressed contractile
performance following catecholamine exposure in isolated rat cardiomyocytes.
AB - BACKGROUND: It has been previously suggested that triiodothyronine (T3) may
reverse depressed cardiac contractile performance occurring after excessive
catecholamine stimulation. We therefore investigated the effects of T3 on
intracellular calcium transients and contractile performance in isolated
ventricular rat myocytes. METHODS: Isolated rat myocytes were loaded with the
calcium indicator FURA-2/AM (50 micromol/L) and superfused with Krebs-Henseleit
solution (pH 7.4). Cells were illuminated by ultraviolet light and fluorescent
images obtained with a target camera at 340 nm and 380 nm excitation wavelengths
(ratio method). Simultaneous measurements of calcium transients and cell
shortening (35 degrees C, electrical field stimulation: 0.5 Hz) were done. At
steady state conditions, FURA-2 loaded myocytes were superfused for 60 min with
epinephrine (0.1 micromol/L). After 60 min the effect of T3 (10 micromol/L) on
calcium transients and shortening were measured. As control, only the effect of
10 micromol/L T3 was analyzed. RESULTS: Epinephrine significantly increased cell
shortening and FURA-2 signals to 148.6+/-8.8% and 109.5+/-3.1% (p < 0.01: n = 21;
5 min) respectively. With longer epinephrine exposure, the increase in cell
shortening continuously declined to 134.6+/-7.9% with no change in FURA-2
fluorescence. Acute administration of T3 after epinephrine exposure lowered
contractile performance from 136.2 +/- 15.5% to 102 +/- 8.2 %, after 10 minutes.
In control experiments acute administration of T3 increased basal contractile
response from 100% to 115.8+/-3.3% (p<0.01; n = 8; 5 min). CONCLUSIONS: This
study confirms previous reports of impaired cardiac function after high
catecholamine exposure. High catecholamine exposure is associated with a
desensitization of contractile proteins for calcium. Acute T3 administration
increased contractility in untreated myocytes, but further depressed myocyte
shortening in epinephrine-treated cells. Our results show that T3 is ineffective
at restoring myocardial contractility after excessive catecholamine stimulation.
PMID- 10757154
TI - Thoracoscopic lung resection for extremely small nodular lesions using
simultaneous intraoperative real-time computed tomography.
AB - Because the localization of small lung nodules at thoracoscopic resection is
sometimes difficult, we have employed intraoperative real-time computed
tomography (CT). Two patients with lung nodules less than 1 cm in diameter were
treated using this technique. Detection of the lesion using CT and thoracoscopic
resection is performed simultaneously in the interventional radiological CT
examination room. After induction of general anesthesia with one-lung
ventilation, the patient is placed in the lateral position. The lung nodule is
detected using real-time CT and grasped with forceps. Thoracoscopic resection of
the nodule is performed in the usual fashion. Frozen section examination is
immediately performed to decide on further therapy.
PMID- 10757155
TI - Surgical repair of right-atrial aneurysm.
AB - Atrial fibrillation and embolic events are the most common clinical symptoms of
congenital right- or left-atrial aneurysms. We report an a case of righ-atrial
aneurysm, in a patient with typical history of atrial fibrillation and history of
stroke. The aneurysm was resected, but the patient suffered from acute embolic
occlusion of the left anterior descending coronary artery on the fourth
postoperative day despite of systemic heparinization with 300 IU/kg bw per 24
hours.
PMID- 10757156
TI - Pulmonary arteriovenous fistula drainage into the left atrium.
AB - Arteriovenous fistulas with venous drainage into the left atrium are a rare
anomaly. Although the etiology of pulmonary arteriovenous fistulas is unknown,
these abnormalities are considered to have occurred during early fetal
development. A case of this malformation in a 72-year-old woman successfully
treated by surgery is described.
PMID- 10757157
TI - Relocation of the internal mammary artery graft in a case of coronary-subclavian
steal.
AB - Reverse flow in the internal mammary artery coronary graft in the presence of
subclavian stenosis is rare. We describe a 67-year-old man who 7 years after
coronary artery surgery was admitted with left subclavian artery stenosis and
retrograde flow in the pedicled left internal mammary artery graft. Subsequent
redo triple coronary artery bypass grafts included regrafting the left internal
mammary artery graft to a new vein conduit.
PMID- 10757158
TI - Palliative treatment of a secondary aortoduodenal fistula by stent-graft
placement.
AB - A 64-year-old male was admitted with suspected aortoduodenal fistula 16 years
after transabdominal aortic reconstruction for aortoiliac occlusive disease.
Computed tomography (CT) and angiography revealed an aortoduodenal fistula and a
suture-line aneurysm at the proximal anastomosis. Due to the patient's poor
general condition at the time of diagnosis, endoluminal stent-graft implantation
was chosen rather than conventional surgery. Successful placement of the stent
graft without leakage of contrast medium and with complete exclusion of the
fistula was demonstrated by CT. The patient recovered uneventfully and was
discharged 10 days after the intervention. Five months later contrast CT
indicated a recurrence of the aortoduodenal fistula. Since the patient was now in
good general condition the stent graft was removed surgically and an extra
anatomic axillofemoral bypass was implanted. Endoluminal stent-graft Implantation
is effective as palliative therapy for aortoduodenal fistulas and is especially
valuable in patients with high risk for conventional surgery.
PMID- 10757159
TI - Treatment for abdominal aortic graft infection: irrigation with electrolyzed
strong aqueous acid, in-situ grafting, and omentoplasty.
AB - We report on successful surgical treatment of consecutive three patients with
infection of an abdominal aortic graft, Therapy involved a combination of removal
of the infected graft, elaborate debridement, irrigation with electrolyzed
strongly acidic aqueous solution (ESAAS), in-situ regrafting, and omentoplasty.
The use of ESAAS is discussed.
PMID- 10757160
TI - Precise adjustment of a band on the main pulmonary artery.
PMID- 10757161
TI - Myocardial protection in hypoxic immature hearts.
AB - Current myocardial protection techniques in cyanotic immature hearts are not
optimal. Despite successful surgical correction of congenital cardiac defects
causing hypoxemia, myocardial dysfunction remains the leading cause of
postoperative mortality. New studies indicate that the intraoperative
reintroduction of molecular oxygen on cardiopulmonary bypass causes a
reoxygenation injury leading to postoperative cardiac dysfunction. Biochemical
and functional changes of reoxygenation injury can be avoided by several methods
aimed at reducing oxygen free radical production and nitric oxide release. The
present investigation provides an overview of our current understanding of
pathogenesis, implication, and treatment of myocardial reoxygenation injury. New
surgical concepts of myocardial protection including normoxic CPB and controlled
reoxygenation are introduced.
PMID- 10757162
TI - Penetrating thoracic injuries: what we have learnt.
AB - BACKGROUND: Thoracic injuries, especially cardiac, vascular, and transmediastinal
injuries, are amongst the most lethal of penetrating injuries. METHOD: Our
experience at Groote Schuur Hospital is reviewed, where up to 1,000 patients were
admitted annually with penetrating chest wounds between 1982 and 1997. RESULTS:
The approximate pre-hospital mortality was 86% with penetrating cardiac injuries,
92 % with extrapericardial vascular injuries, and 11 % with pulmonary injuries.
Less than 2% of pneumothorax cases and less than 10% of haemothorax cases
required surgical intervention. Thoracoscopic evacuation of retained clots was
successful in the majority of the latter. Most penetrating injuries of the
thoracic duct required surgical exploration. The mortality of penetrating cardiac
injuries varied according to clinical presentation (moribund 52%, hypovolaemia
20% and tamponade 2-5%) and the chamber involved. Higher mortalities were
associated with atrial injuries. CONCLUSIONS: The appropriate use of intercostal
drains and therapeutic thoracoscopy are important considerations in penetrating
non-cardiac thoracic trauma. Rapid transportation, immediate triage, open-minded
use of emergency room thoracotomy, and aggressive surgical management with
liberal use of sub-xiphisternal pericardial windows are important factors in
improving the survival of penetrating cardiac trauma.
PMID- 10757163
TI - Detection and sequencing of phosphopeptides affinity bound to immobilized metal
ion beads by matrix-assisted laser desorption/ionization mass spectrometry.
AB - Consecutive enzymatic reactions of analytes which are affinity bound to
immobilized metal ion beads with subsequent direct analysis of the products by
matrix-assisted laser desorption/ionization mass spectrometry have been used for
detecting phosphorylation sites. The usefulness of this method was demonstrated
by analyzing two commercially available phosphoproteins, beta-casein and alpha
casein, as well as one phosphopeptide from a kinase reaction mixture. Agarose
loaded with either Fe3+ or Ga3+ was used to isolate phosphopeptides from the
protein digest. Results from using either metal ion were complementary. Less
overall suppression effect was achieved when Ga3+-loaded agarose was used to
isolate phosphopeptides. The selectivity for monophosphorylated peptides,
however, was better with Fe3+-loaded agarose. This technique is easy to use and
has the ability to analyze extremely complicated phosphopeptide mixtures.
Moreover, it eliminates the need for prior high-performance liquid chromatography
separation or radiolabeling, thus greatly simplifying the sample preparation.
PMID- 10757164
TI - Electrospray ionization mass spectrometry of lysoglycerophosphocholine lipid
subclasses.
AB - Lysoglycerophosphocholine lipids (lyso-GPC) are important intermediates in the
synthesis and metabolism of glycerophosphocholine lipids which are major
components of the cellular lipid bilayer. Significant differences in the
collisional induced decomposition (CID) behavior were observed for each of the
four different subtypes of lyso-GPC in both positive and negative ions. A major
difference was observed in the initial CID product ions derived from lyso-GPC [M
+ H]+ with the loss of water that was very abundant for acyl lyso-GPC which have
a fatty acid ester substituent at either the sn-1 or sn-2 positions. Loss of
neutral water was not very prominent in the case of plasmenyl and plasmanyl lyso
GPC species. The mechanism responsible for this difference in behavior of lyso
GPC subtypes was consistent with a higher proton affinity of carboxyl carbonyl
oxygen atoms and vinyl ether oxygen atoms found in acyl and plasmenyl lyso-GPC
lipids, respectively, as compared to the carbinol oxygen atom common to all lyso
GPC species. Collisional activation of lyso-GPC negative ions [M - 15]- also
revealed distinctive differences in product ions derived from acyl and ether lyso
GPC species. The acyl compounds showed the facile elimination of a highly stable
carboxylate anion, whereas plasmenyl species underwent fragmentation with loss of
a neutral aldehyde, likely a result of rearrangement involving the double bond in
the vinyl ether moiety. The alkyl ether species (plasmanyl lyso-GPC lipids) did
not undergo either decomposition reaction observed for the other lyso-GPC
subtypes which permitted differentiation of acyl, plasmenyl, and plasmanyl lyso
GPC subtypes.
PMID- 10757165
TI - Structural analysis of chromophore-labeled disaccharides by capillary
electrophoresis tandem mass spectrometry using ion trap mass spectrometry.
AB - Disaccharides tagged with p-aminobenzoic acid (ABA) were separated by capillary
electrophoresis (CE) and analyzed on-line with negative ion electrospray
ionization tandem mass spectrometry (ESI/MS/MS). The formation of glycosylamine
instead of reductive amination was selected as the derivatization reaction. In
negative ion ESI, the glycosylamine approach provides more information on linkage
and anomeric configuration than reductive amination. In CE analysis of ABA
labeled disaccharides, alpha-cyclodextrin (CD) was found to play a crucial role
in the separation of linkage isomers. Although ammonium acetate/alpha-CD provided
the best resolution of linkage isomers, the borate buffer was superior to alpha
CD in the separation of disaccharides with the same linkage but different
anomeric configuration and/or monosaccharide composition. Both alpha-CD and
borate suppressed the ion signal in ESI, and operational conditions were
successfully obtained using 10 mM alpha-CD or 10 mM borate.
PMID- 10757166
TI - Differentiation of O-acetyl and O-carbamoyl esters of N-acetyl-glucosamine by
decomposition of their oxonium ions. Application to the structure of the
nonreducing terminal residue of Nod factors.
AB - Nod factors are substituted N-acyl chito-oligomers secreted by plant symbiotic
bacteria of the Rhizobium family. Substitutions on the oligosaccharide core
specify their recognition by host plants. A method using tandem mass spectrometry
is proposed to locate the O-acetyl and O-carbamoyl substituents on the
nonreducing terminal residue of the chito-oligomers. As model compounds, all the
positional isomers of monoacetyl and monocarbamoyl esters of 1-O-methyl-N-acetyl
alpha-D-glucosamine were synthesized. Oxonium ions (MH - CH3OH)+ were generated
by liquid secondary ion mass spectrometry (LSIMS) and their decomposition was
recorded on a tandem magnetic instrument. Large differences were observed in the
relative abundances of ions resulting from elimination of water and of the O
ester substituent from metastable oxonium ions. Deuterium exchange reactions
indicated parallel elimination pathways involving either exchangeable or carbon
linked hydrogens. The intensity ratios of some of the ions generated by
collisions with helium atoms allowed the isomers to be distinguished. The main
dissociation routes were identified. Metastable and collision-induced
decomposition of the B1 ions from Nod factors of Sinorhizobium meliloti and
Azorhizobium caulinodans resembled that of the 6-O-substituted N
acetylglucosamine models. Decomposition of the B1 ion from Mesorhizobium loti and
Rhizobium etli Nod factors, was similar to that of 3-O-carbamoyl N-acetyl
glucosamine and different to that of the 4-O isomer. 6-O- and 3-O-carbamoylation
specified by the nodU and nolO genes, respectively, of Rhizobium. sp. NGR234 were
confirmed.
PMID- 10757167
TI - Effects of pH on the kinetic reaction mechanism of myoglobin unfolding studied by
time-resolved electrospray ionization mass spectrometry.
AB - In most cases, kinetic unfolding reactions of proteins follow a simple one-step
mechanism that does not involve any detectable intermediates. One example for a
more complicated unfolding reaction is the acid-induced denaturation of holo
myoglobin (hMb). This reaction proceeds through a transient intermediate and can
be described by a sequential two-step mechanism (Konermann et al. Biochemistry
1997, 36, 6448-6454). Time-resolved electrospray ionization mass spectrometry
(ESI MS) is a new technique for monitoring the kinetics of protein folding and
unfolding in solution. Different protein conformations can be distinguished by
the different charge state distributions that they generate during ESI. At the
same time this technique allows monitoring the loss or binding of noncovalent
protein ligands. In this work, time-resolved ESI MS is used to study the
dependence of the kinetic unfolding mechanism of hMb on the specific solvent
conditions used in the experiment. It is shown that hMb unfolds through a short
lived intermediate only at acidic pH. Under basic conditions no intermediate is
observed. These findings are confirmed by the results of optical stopped-flow
absorption experiments. This appears to be the first time that a dependence of
the kinetic mechanism for protein unfolding on external conditions such as pH has
been observed.
PMID- 10757168
TI - Automated reduction and interpretation of high resolution electrospray mass
spectra of large molecules.
AB - Here a fully automated computer algorithm is applied to complex mass spectra of
peptides and proteins. This method uses a subtractive peak finding routine to
locate possible isotopic clusters in the spectrum, subjecting these to a
combination of the previous Fourier transform/Patterson method for primary charge
determination and the method for least-squares fitting to a theoretically derived
isotopic abundance distribution for m/z determination of the most abundant
isotopic peak, and the statistical reliability of this determination. If a
predicted protein sequence is available, each such m/z value is checked for
assignment as a sequence fragment. A new signal-to-noise calculation procedure
has been devised for accurate determination of baseline and noise width for
spectra with high peak density. In 2 h, the program identified 824 isotopic
clusters representing 581 mass values in the spectrum of a GluC digest of a 191
kDa protein; this is >50% more than the number of mass values found by the
extremely tedious operator-applied methodology used previously. The program
should be generally applicable to classes of large molecules, including DNA and
polymers. Thorough high resolution analysis of spectra by Horn (THRASH) is
proposed as the program's verb.
PMID- 10757169
TI - Electrospray ionization Fourier transform ion cyclotron resonance analysis of
large polymerase chain reaction products.
AB - In previous work, we demonstrated the use of electrospray ionization to analyze
small differences in size or sequence of relatively small polymerase chain
reaction (PCR) products of 114 base pairs or less. The sequence information
required to answer a biological question may be only a single nucleotide
substitution or deletion. In many cases, the regions where these sequence
variations can occur are several hundred base pairs in length, and the analysis
of large PCR products is therefore desirable. Therefore, we have attempted to
expand the size range of PCR products that can be analyzed by electrospray
ionization (ESI) Fourier transform ion cyclotron resonance (FTICR) mass
spectrometry. Previous work has shown that the difficulties associated with PCR
product analysis increase with product size. A revised cleanup scheme was
employed to target the removal of detergents with ethanol wash or precipitation
steps, followed by additional desalting. Additionally, an in-trap cleanup to
collisionally induce dissociation of noncovalent salt adducts was employed. This
approach was extended to a 223 base pair PCR product yielding mass measurement
accuracy within 26 ppM. The mass measurement accuracy obtained illustrates that a
single base substitution could be identified at this size of PCR product with a 7
tesla ESI-FTICR.
PMID- 10757170
TI - Electrospray mass spectrometry of semiconductor nanoclusters: comparative
analysis of positive and negative ion mode.
AB - There has been a substantial growth in the application of mass spectrometry (MS)
methods for the analysis of inorganic materials, due to the inherent sensitivity
of mass spectrometry ionization to the specific composition and structure of the
analyzed materials. To date, few mass spectrometry studies have focused on metal
chalcogenide materials, an important class of semiconductor materials at the
nanoscale, that exhibit interesting optical and electronic properties as a
function of size. In this study, we report the application of a correlated
electrospray mass spectrometry (ESMS) study between negative-ion and positive-ion
mode under low-cone voltage to probe size, composition, and stability of metal
chalcogenide materials at the <1 nm scale. This correlation approach provides
insight into the ionization behavior and thermodynamic stability of clusters in
the <1.0 nm size domain of the form [Zn4(SPh)10][Me4N]2, [Cd4(SPh)10][Me4N]2,
[E4Zn10(SPh)16][Me4N]4, [E4Cd10(SPh)16][Me4N]4 (E = S, Se). It is demonstrated
that application of low-cone voltage ESMS can be a useful technique for the rapid
analysis of intact solid state nanomaterials when both negative and positive
ionic modes are analyzed, with a potential for extrapolation to other classes of
nanoscale materials.
PMID- 10757171
TI - Novel rearranged ions observed for protonated peptides via metastable
decomposition in matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry.
AB - C-terminal rearrangement ions [b(n-1) + H2O] (where n refers to the total number
of residues of peptides) are frequently observed for peptides which contain basic
amino acid(s), especially arginine, at or near their N termini in low- and high
energy collision-induced dissociation or post-source decay (PSD) spectra. Here we
report a novel rearrangement, associated with PSD for serine- or threonine
containing peptides that are susceptible to C-terminal rearrangement. Based on
PSD analyses of serine- or threonine-containing bradykinin and its analogs, which
have been ethyl-esterified or 18O labeled at their C termini, the [b(k) + H2O]
(where k denotes the position adjacent to the left of the Ser/Thr residue) ion is
generally thought to be formed by the transfer of the hydroxyl moiety of a serine
or threonine residue to the carbonyl group of the residue to its left accompanied
by the loss of the remaining C-terminal portion of the peptide. When the Ser/Thr
is at or near the C terminus, the present [b(k) + H2O] ion could be formed via
two pathways, i.e., the Ser/Thr-related rearrangement and the conventional C
terminal rearrangement, which has been clearly verified by 18O labeling at the C
terminus. In addition, the ions which are formally designated as [y(m)b(l) +
H2O], where y(m)b(l) denotes a b-type internal ion, are also briefly described.
PMID- 10757172
TI - Determining synthetic failures in combinatorial libraries by hybrid gas-phase
separation methods.
AB - A combinatorial tripeptide library having the general form D-Glu-Xxx-Xxx-CONH2
has been synthesized using a standard mix and split synthetic protocol that is
expected to produce 676 components. All components of the mixture were analyzed
using a new high-resolution ion mobility/time-of-flight mass spectrometer coupled
with an electrospray ionization source. In this approach ions are separated by
differences in their gas-phase mobilities prior to being introduced into the mass
spectrometer for mass-to-charge analysis. The peptide library includes a wide
range of different sequence, structural, and stereo isomers; trends in the number
of expected and resolved isomers that are observed at each m/z ratio allow
specific synthetic steps that have failed to be identified, even in the presence
of other isomers. Information about the relative abundances of different isomers
should dramatically improve the reliability of binding affinity studies from
direct analysis of mixtures.
PMID- 10757173
TI - Extraction and characterization of adenovirus proteins from sodium dodecylsulfate
polyacrylamide gel electrophoresis by matrix-assisted laser desorption/ionization
mass spectrometry.
AB - A new methodology for the extraction and characterization of proteins from
Coomassie-stained sodium dodecylsulfate polyacrylamide gel electrophoresis using
matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been
described. The utility of this methodology was demonstrated in the
characterization of adenovirus proteins. The key steps in the extraction and
destaining process involve washing the excised band with a combination of
solvents that include 10% acetic acid, acetonitrile, methanol, and formic
acid:water:isopropanol mixture. By using this procedure, we determined adenovirus
proteins with molecular weights ranging from 10,000 to 110,000 Da by MALDI-MS,
obtaining a detection limit of approximately 6 pmol. Parallel experiments were
successfully carried out to analyze adenovirus proteins from Cu-stained gels. It
was observed that increase in laser intensity resulted in significant
improvements in the quality of MALDI mass spectra for the analysis of
inefficiently destained proteins from Cu-stained gels.
PMID- 10757174
TI - Classifying the illumination condition from two light sources by color histogram
assessment.
AB - We investigate and propose a method for assessment of the illumination condition
covering two light sources. The method may be of some support for color vision
and multispectral analysis methods that rely on a specific illumination
condition. It is constrained to classifying the illumination condition for
dielectric objects illuminated by two light sources. The reflected light is
modeled by the dichromatic reflection model, which describes the light as the sum
of its body reflections and surface reflections. Further, reflected light from an
object illuminated by two light sources may give from one to four primary
reflections depending on the condition, and it may be expressed as an additive
mixture of these reflections. An additive mixture of two reflections expressed in
chromaticities is limited to falling within the area enclosed by the
chromaticities of the primary reflections of the light sources. So after finding
the set of primary chromaticities enclosing the pixel points' chromaticities, it
is possible for one to assess the current illumination condition. Since the
method operates on pixel points globally, it is independent of illumination
geometry and hence may be used on irregular objects. Two experiments are
performed. One uses regular objects in a well-controlled laboratory environment
and demonstrates that the pixel-point distribution is as expected. The second
experiment demonstrates the method's potential use in support of spectroscopic
analysis of vegetation through assessing the illumination condition of barley
plants in an outdoor illumination condition.
PMID- 10757175
TI - Daylight, biochrome surfaces, and human chromatic response in the Fourier domain.
AB - We first report Fourier analyses of a collection of 348 daylight spectral power
distributions and 1,695 biochrome surface reflectance functions. The power
spectra of the daylights are low pass with more than 99% of spectral power below
1 cycle/300 nm and 99.9% below 3 cycles/300 nm. The power spectra of reflectance
functions are also low pass with more than 99% of spectral power below 4
cycles/300 nm and 99.9% below 11 cycles/300 nm. Consequently, the resulting color
signals are typically low pass with, for our samples, an estimated frequency
cutoff of 5 cycles/300 nm. Theoretical and experimental data concerning human
chromatic response in the frequency domain show that this limit corresponds to
the highest frequency that the color system can resolve. The implications for
normal and abnormal human color vision are discussed.
PMID- 10757176
TI - Binocular three-dimensional motion detection: contributions of lateral motion and
stereomotion.
AB - When an object moves along a trajectory in three-dimensional (3-D) space, there
are potentially two orthogonal components that could be used to detect its
motion: stereomotion resulting from the difference or disparity between the
images in the right and left eyes, and lateral motion from the sum or average of
the image motions in the right and left eyes. Using a suprathreshold search task
for a target moving amid 3-D distractors, we found a range of 3-D trajectories
for which increasing the stereomotion component did not improve detection.
However, with larger stereomotion components, performance improved. The addition
of random-motion noise to only the lateral motion component adversely affected
the detection of both lateral motion and stereomotion. These data suggest that
the visual system uses the average of the monocular image motions for the
detection of a range of 3-D trajectories. In addition, a mechanism sensitive to
the changing disparity may also be used but only for a very restricted range of 3
D motions.
PMID- 10757177
TI - Separating the chaff from the wheat: possible origins of the oblique effect.
AB - The oblique effect refers to a better perception of horizontal and vertical image
features as compared with the perception at oblique angles. This effect can be
observed in both animals and humans. Recent neurophysiological data suggest that
the basis of this effect lies in the structure of the primary visual cortex,
where more cortical area is devoted to processing contours with angles at
horizontal and vertical orientations (cardinal orientations). It has been
suggested that this cortical feature has developed according to the statistical
properties of natural scenes. To examine this hypothesis in more detail, we
established six image classes and categorized the images with respect to their
semantical contents. From the images the oriented energy was calculated by using
the corresponding power spectra. We defined simple measures for the degree
(cardinal versus oblique energy ratio) and the skewness or anisotropy (aligned
energy ratio) of the alignment of energy at horizontal and vertical orientations.
Our results provide evidence that (1) alignment depends strongly on the
environment, (2) the degree of alignment drops off characteristically at higher
frequencies, and (3) in natural images there is on the average an anisotropy in
the distribution of energy at the cardinal orientations (i.e., a difference
between the amounts of vertical energy and horizontal energy). In light of our
results, we further discuss whether the observed cortical anisotropy has its
origin in phylogeny or ontogeny.
PMID- 10757178
TI - Iterative linear minimum mean-square-error image restoration from partially known
blur.
AB - We address the problem of space-invariant image restoration when the blurring
operator is not known exactly, a situation that arises regularly in practice. To
account for this uncertainty, we model the point-spread function as the sum of a
known deterministic component and an unknown random one. Such an approach has
been studied before, but the problem of estimating the parameters of the
restoration filter to our knowledge has not been addressed systematically. We
propose an approach based on a Gaussian statistical assumption and derive an
iterative, expectation-maximization algorithm that simultaneously restores the
image and estimates the required filter parameters. We obtain two versions of the
algorithm based on two different models for the statistics of the image. The
computations are performed in the discrete Fourier transform domain; thus they
are computationally efficient even for large images. We examine the convergence
properties of the resulting estimators and evaluate their performance
experimentally.
PMID- 10757179
TI - Lens-based theory of the Lau effect.
AB - A new theoretical model of the Lau effect is presented. The transmittance of a
diffraction grating can be expressed in an equivalent form as the sum of
transmittances of thin cylindrical lenses. Therefore it is possible to explain
the Lau effect on the basis of the well-known imaging properties of lenses.
According to the given approach, the Lau fringes are created by overlapped images
of the first grating that are formed by a set of lenses corresponding to the
second grating in the setup. The theory leads to an exhaustive description of the
Lau-effect parameters. In particular, one can indicate the shape of the Lau
fringes and localize planes of the fringes dependent on the axial distance
between gratings and their periods.
PMID- 10757180
TI - Electromagnetic analysis of axially symmetric diffractive lenses with the method
of moments.
AB - We present the electromagnetic analysis of axially symmetric diffractive lenses.
Analysis is performed by numerically solving the electric and magnetic field
integral equations using the method of moments, and it exploits axial symmetry to
reduce computational cost. Formulations for the analysis of loss less dielectric
and perfectly conducting lenses are presented. The analysis of binary and eight
level lenses are performed to illustrate the utility of the technique.
PMID- 10757181
TI - Isotropic scattering by penetrable cylinders.
AB - Isotropic scattering is considered for infinite cylinders thin in the sense that
ka << 1, although ?k'a? and cross-sectional shape can be arbitrary within limits
(k and k' are, respectively, free-space and interior propagation constants, and a
is a characteristic dimension of the cylinder). For circular cylinders,
scattering width is found to saturate at its perfectly conducting value, and
absorption width is found to peak, when skin depth becomes comparable with
cylinder diameter. For a variety of cylinders with and without edges, both
scattering and absorption widths are then found to be effectively identical to
those of the circular cylinder with equal cross-sectional area. A new analytical
formula is obtained for high but not infinite conductivity, and the connection
with scattering cross sections of corresponding finite cylinders is discussed.
PMID- 10757182
TI - Scattering delay time of Mie scatterers determined from steady-state and time
resolved optical spectroscopy.
AB - We have determined the scattering delay time of Mie scatterers (r = 255 nm quartz
spheres in polyester resin) from a combination of steady-state (integrating
sphere) and time-resolved (frequency-domain) measurements performed in the
multiple-scattering regime. The effective transport velocity of light was derived
from intensity and phase measurements at four different wavelengths by using the
time-integrated microscopic Beer-Lambert law. We could demonstrate a systematic
underestimation of the effective transport velocity compared with the phase
velocity in the medium. Assuming that this discrepancy was caused entirely by the
transient nature of a single-scattering process, the data presented resulted in
time delays of between 18 fs (lambda = 678 nm) and 177 fs (lambda = 1,064 nm) per
scattering event. For three out of four wavelengths investigated, the measured
values are in excellent agreement with values predicted by a theoretical model
for the scattering delay time based on Mie theory.
PMID- 10757183
TI - Isochromatic fringes in photoelasticity.
AB - The structure of the isochromatic fringe pattern in a two-dimensional
photoelastic model is investigated with the phase diagram method of the theory of
dynamic systems. Isochromatics are interpreted as phase paths (or level curves)
of a Hamiltonian system. Possible singularities of the fringe pattern are
analyzed.
PMID- 10757184
TI - Self-affinity in phase space.
AB - The expression for the Wigner distribution (WD) in polar coordinates was derived,
based on the decomposition of coherent and partially coherent fields on the
orthogonal sets of Hermite-Gauss modes. This representation allows one to analyze
easily the structure of the WD and to describe the field propagation through
first-order optical systems, including the self-imaging phenomenon.
PMID- 10757185
TI - Fast algorithm for chirp transforms with zooming-in ability and its applications.
AB - A general fast numerical algorithm for chirp transforms is developed by using two
fast Fourier transforms and employing an analytical kernel. This new algorithm
unifies the calculations of arbitrary real-order fractional Fourier transforms
and Fresnel diffraction. Its computational complexity is better than a fast
convolution method using Fourier transforms. Furthermore, one can freely choose
the sampling resolutions in both x and u space and zoom in on any portion of the
data of interest. Computational results are compared with analytical ones. The
errors are essentially limited by the accuracy of the fast Fourier transforms and
are higher than the order 10(-12) for most cases. As an example of its
application to scalar diffraction, this algorithm can be used to calculate near
field patterns directly behind the aperture, 0 < or = z < d2/lambda. It
compensates another algorithm for Fresnel diffraction that is limited to z >
d2/lambdaN [J. Opt. Soc. Am. A 15, 2111 (1998)]. Experimental results from
waveguide-output microcoupler diffraction are in good agreement with the
calculations.
PMID- 10757186
TI - Focal shift, optical transfer function, and phase-space representations.
AB - The focal shift for a lens of finite value of Fresnel number can be defined in
terms of the second moment of the intensity distribution in transverse planes.
The connection with the optical transfer function is described. The specification
of the focused amplitude in terms of the fractional Fourier transform is
discussed, and the connections among the fractional Fourier transform, the Wigner
distribution, and the ambiguity function are described, leading to a model for
effects of Fresnel number in terms of a rotation in phase space. The uncertainty
principle is discussed, including the significance of the beam propagation factor
M2 and the width of optical fiber beam modes. Calculation of the moments in terms
of the modulus and the phase of the illuminating wave is presented, and the use
of the Kaiser-Teager energy operator is also described.
PMID- 10757187
TI - Average characteristics of partially coherent electromagnetic beams.
AB - Average characteristics of partially coherent electromagnetic beams are treated
with the paraxial approximation. Azimuthally or radially polarized, azimuthally
symmetric beams and linearly polarized dipolar beams are used as examples. The
change in the mean squared width of the beam from its value at the location of
the beam waist is found to be proportional to the square of the distance in the
propagation direction. The proportionality constant is obtained in terms of the
cross-spectral density as well as its spatial spectrum. The use of the cross
spectral density has advantages over the use of its spatial spectrum.
PMID- 10757188
TI - Moire technique for spatial coherence measurements of soft-x-ray lasers.
AB - We present a novel moire diagnostic that allows the time-averaged spatial
coherence properties of soft-x-ray lasers to be measured. The technique is an
extension of the theoretical work in a recent paper [J. Opt. Soc. Am. A 16, 323
(1999)] and is based on the concept of decompositions of the far-field divergence
for partially coherent beams. An appealing feature of the approach is that the
spatial coherence width at other planes can be evaluated from the measured one at
a given plane on the assumption of shape-invariant beams.
PMID- 10757189
TI - Theory of a fixed scatterer embedded in a turbid medium: numerical results.
AB - Based on a previous theory of diffuse photon density waves by Furutsu [J. Opt.
Soc. Am. A 15, 1371 (1998)], several sets of figures are prepared to detect a
fixed scatterer (object) embedded in a turbid layer, such as a tumor in tissue,
with a source and a detector placed independently along the boundaries on
different sides. The relative total intensity of the wave is introduced such that
it is reduced to 1 in the case of no scatterer and usually less than that, owing
to a shadowing by the scatterer. Sets of curves are presented to demonstrate
shadow images of the scatterer observed along the layer boundaries depending on
the scatterer's location.
PMID- 10757190
TI - Microsphere resonators strongly coupled to a plane dielectric substrate: coupling
via the optical near field.
AB - A model is proposed that describes the essential optical process in the recently
observed resonant light scattering from a microsphere resonator that is strongly
coupled to the substrate. The experimentally observed field patterns across the
resonance can be reproduced quite well by a numerical calculation taking into
account only a few vector spherical waves that are converted from nonpropagating
to propagating waves at the substrate surface. Explicit consideration of the
multiple-reflection effect is not necessary to reproduce the experimental
results. Comparison of the experiment and the calculation suggests the splitting
of degenerate resonance modes that have different azimuthal mode numbers within a
single broad resonance line. These results are discussed on the basis of the
strongly coupled nature of the system.
PMID- 10757191
TI - Vancomycin dosage requirements among pediatric intensive care unit patients with
normal renal function.
AB - PURPOSE: The purpose of this study was to determine a vancomycin dosage regimen
among pediatric intensive care unit (PICU) patients with normal renal function
resulting in desired peak and trough serum concentration and to determine the
predictability of vancomycin peak concentrations based on reported trough
concentrations. MATERIALS AND METHODS: The medical records of all PICU patients
who received vancomycin over a 12-month period were identified through a hospital
computer search and were obtained from the hospital's Department of Medical
Records. Demographic and laboratory data as well as the patient's vancomycin
dosing history were recorded. Patients who lacked appropriately timed vancomycin
peak and trough concentrations or who exhibited renal dysfunction were excluded
from the study population. The optimal vancomycin dose and the predictability of
peak concentrations based on trough concentrations were assessed. RESULTS: A
total of 135 patients were identified as having received vancomycin therapy
during their PICU hospitalization between June 1997 and June 1998. Fifty-nine
patients were excluded due to renal dysfunction or inappropriate vancomycin
concentrations resulting in 76 patients representing our study population. The
initial mean dose of vancomycin was 47 mg/kg/day resulting in a mean peak and
trough serum concentration of 19 and 6 microg/mL, respectively. A mean of 2.2
(range, 1 to 5) and 2.1 (range, 1 to 5) peak and trough serum concentrations were
reported for each patient, respectively. A mean of 1.1 (range, 0 to 4) dosing
changes per patient was noted resulting in a final mean dose of 60 mg/kg/day
corresponding to a mean peak and trough serum concentration of 26 and 8
microg/mL, respectively. A vancomycin trough concentration >5 microg/mL was
highly predictive for a corresponding peak concentration >20 microg/mL (P >
.0001). Eighty percent of the trough concentrations <5 microg/mL were associated
with peak concentrations <20 microg/mL, whereas 81% of trough concentrations >5
microg/mL were associated with corresponding peak concentrations >20 microg/mL.
CONCLUSIONS: PICU patients required higher doses of vancomycin than are typically
prescribed to achieve conventionally accepted peak and trough vancomycin serum
concentrations. In the absence of renal impairment, we recommend an initial
dosage regimen of 60 mg/kg/day divided every 8 hours. Vancomycin trough
concentrations are highly predictive of corresponding peak concentrations and
therefore may negate the need to obtain routine peak concentrations.
PMID- 10757192
TI - Nonpulmonary organ failure and outcome in children treated with high-frequency
oscillatory ventilation.
AB - PURPOSE: The purpose of this study was to quantitate the contribution of
nonpulmonary organ failure to mortality of patients treated with high-frequency
oscillatory ventilation (HFOV) and to determine which gas-exchange differences
are associated with improvement on HFOV. MATERIALS AND METHODS: Charts of all
patients treated with HFOV in our pediatric intensive care unit from January 1992
until January 1997 were retrospectively reviewed. RESULTS: Sixty-six patients
were treated and 21 patients improved during HFOV (group 1); 45 patients did not
improve (group 2). Seventeen patients (26%) had isolated respiratory failure and
their mortality was 12%. Percentages of patients with 2, and 3 or more organ
failure were 45%, 29%, and their mortality was significantly higher, 67% and 95%,
respectively. Patients with primary respiratory failure demonstrated a
significantly greater risk of improvement on HFOV (RR ratio of 2.5, 95% CI 1.5 to
4.2). There was a significantly greater proportion of patients with primary
cardiac failure who did not improve on HFOV compared with all other patients.
Oxygenation index significantly improved over the first 72 hours for both groups,
but then significantly worsened over the next 48 hours in group 2 but not in
group 1. CONCLUSION: Patients with nonpulmonary organ failure were significantly
less likely to improve on HFOV and had a significantly higher mortality than
patients with isolated respiratory failure. Children who do not improve on HFOV
appear to reach a plateau in oxygenation indices after 3 days of HFOV.
PMID- 10757193
TI - The anticatabolic and wound healing effects of the testosterone analog
oxandrolone after severe burn injury.
AB - PURPOSE: Severe burn injury leads to marked catabolism and decreased lean mass,
which can impair healing. Anabolic agents can attenuate net catabolism. Our
purpose was to determine whether the testosterone analog, oxandrolone, given
during the acute post burn period decreased the degree of nitrogen loss and loss
of body weight while also increasing the healing rate of a skin donor site.
MATERIALS AND METHODS: Patients with burns between 40% and 70% of body surface
were studied. A randomized double-blinded placebo-controlled study design was
used. Patients were given oxandrolone 20 mg/day (n = 11) or a placebo 20 mg/day
(n = 9) beginning between days 2 and 3 post burn. Net nitrogen balance and the
healing time of a standardized donor site were measured. Patients were monitored
until transferred to a burn rehabilitation facility, an average time period of 33
+/- 9 days. RESULTS: Mean burn size was 49 +/- 8% for placebo and 53 +/- 9% of
total body surface for the oxandrolone group. Smoke inhalation was present in
approximately 50% of patients in both groups. All patients survived the burn
injury. Net weight loss was 8 +/- 3.1 kg in the placebo group compared with 3 +/-
1.9 kg in the oxandrolone group, a statistically significant decrease. Net daily
nitrogen loss over a 3-week period (days 7 to 28) was 13 +/- 4 g in placebo
treated compared with 4 +/- 1.9 g for the oxandrolone group, a statistically
significant decrease. The healing time of a standardized donor site, decreased
from the placebo group value of 13 +/- 3 days to 9 +/- 2 days for oxandrolone
treated patients, a significant improvement. No major liver dysfunction, or other
complication attributable to an anabolic steroid was seen in either group.
CONCLUSION: We found the anabolic agent, oxandrolone, significantly decreased
weight loss and net nitrogen loss and increased donor site wound healing compared
with placebo controls. We noted no complications with the use of oxandrolone.
PMID- 10757194
TI - Intermittent pneumatic compression on the calf improves peripheral circulation of
the leg.
AB - PURPOSE: The aim of this study was to examine whether intermittent pneumatic
compression (IPC) increases peripheral circulation locally in order to assess the
use of IPC for prevention of deep venous thrombosis. MATERIALS AND METHODS:
Seventy adult patients receiving major gastrointestinal surgery were studied. On
postoperative day 1, calf-length garments were fitted onto both calves and deep
temperature thermometers were put on both plantae. The IPC was applied randomly
to either the left or right calf under 40 mm Hg pressure for 150 minutes.
Bilateral plantar deep temperatures, as a reflection of peripheral circulation in
the lower extremity, the tympanic temperature, mean blood pressure, and heart
rate were recorded at 15-minute intervals. RESULTS: IPC compression was applied
to 31 left and 39 right calves. The plantar deep temperature in the compressed
calf was higher than in the noncompressed calf, and increased significantly,
whereas the noncompressed calf showed no temperature change. The tympanic
temperature, mean blood pressure, and heart rate did not change during the
experiment. CONCLUSIONS: The results suggest that IPC has the effect of improving
peripheral circulation, which supports the use of IPC to prevent deep venous
thrombosis.
PMID- 10757195
TI - Effects of N-methyl-L-arginine on cardiac and regional blood flow in a dog
endotoxin shock model.
AB - PURPOSE: Indirect evidence suggests a decrease in organ perfusion as a result of
nitric oxide (NO) inhibition in endotoxic shock. Cardiac and regional hemodynamic
responses to N-methyl-L-arginine (L-NMA), a nonspecific inhibitor of constitutive
and inducible nitric oxide synthase (NOS), were assessed in nine conscious dogs
subjected to endotoxin. MATERIALS AND METHODS: Lipopolysaccharide (LPS) was
titrated to a maximum of 200 microg/kg, IV, over 45 minutes. L-NMA was given in a
dose of 20 mg/kg, IV. Hemodynamic parameters were recorded for 6 hours following
L-NMA administration. RESULTS: LPS induced significant decreases in mean arterial
blood pressure (MAP), cardiac output (CO), first derivative of left ventricular
pressure (dP/dt), coronary blood flow, carotid blood flow, mesenteric blood flow,
renal blood flow, and a significant hepatic vasodilation. L-NMA fully reversed
the effects of LPS on MAP, heart rate, dP/dt, coronary and carotid blood flow,
and reversed mesenteric blood flow and hepatic blood flow at 1 and 3 hours,
respectively. L-NMA partially overcame the LPS-induced decrease in renal blood
flow at 30 minutes and 1 hour. Except for mesenteric and carotid circulation, L
NMA did not change regional vascular resistance. CONCLUSIONS: It is likely that
constitutive NOS is implicated in immediate cardiac, carotid, mesenteric, and
renal vascular changes, whereas inducible NOS accounted for delayed responses in
hepatic and coronary circulation.
PMID- 10757196
TI - Effects of DETANONOate, a nitric oxide donor, on hemostasis in rabbits: an in
vitro and in vivo thrombelastographic analysis.
AB - PURPOSE: The purpose of this study was to determine if whole blood
thrombelastographic variables (reaction time, K, alpha, and maximum amplitude)
would be adversely effected by exposure to the nitric oxide (NO) donor,
DETANONOate, in vitro or after alveolar instillation in vivo. MATERIALS AND
METHODS: Conscious rabbits (n = 10) had blood sampled from ear arteries
anticoagulated with sodium citrate. The blood was then incubated with 0, 1, 5,
10, or 20 mmol/L DETANONOate for 30 minutes. Arterial blood from anesthetized
rabbits (n = 4) was obtained and anticoagulated before and 60 minutes after 1
mmol/L DETANONOate (2 mL/kg) was instilled into the right lung. After incubation,
all samples were placed in a thrombelastograph and recalcified, with
thrombelastographic variables measured for 45 minutes. RESULTS: In vitro, 10
mmol/L DETANONOate significantly (P < .05) increased reaction time, K, and
decreased alpha compared with values observed after incubation with 0, 1, and 5
mmol/L DETANONOate. Twenty mmol/L DETANONOate significantly (P < .05) increased
reaction time, K, and decreased alpha and maximum amplitude values compared with
all other concentrations. In vivo, DETANONOate administration did not
significantly affect thrombelastographic variables. CONCLUSION: DETANONOate
significantly decreased hemostatic function in vitro in a dose-dependent fashion
but did not significantly affect hemostatic function in vivo.
PMID- 10757197
TI - Ionized magnesium supplementation in critically ill patients: comparing ionized
and total magnesium.
AB - PURPOSE: The purpose of this study was to assess the effect of magnesium
supplementation on total magnesium, ionized magnesium, ionized calcium,
potassium, and pH in critically ill cancer patients and to compare the validity
of the measurements. MATERIALS AND METHODS: Thirty-three consecutive critically
ill patients receiving magnesium supplementation were placed in this prospective
observational study at the Comprehensive Cancer Center, University Hospital. One
gram (4.1 mmol) magnesium in 50 mL D5W was administered to critically ill
patients, and the following were measured: total magnesium, ionized magnesium,
ionized calcium, potassium, albumin, pH, BUN, creatinine, creatinine. RESULTS:
Total magnesium and ionized magnesium increased by a mean of .11 +/- .02 and .05
+/- .01 mmol/L, respectively, after supplementation with 4.1 mmol of magnesium
sulfate (P = .0001). Total magnesium, ionized magnesium, albumin, ionized
calcium, potassium, and pH did not change significantly by the administration of
1 g of magnesium sulfate. CONCLUSION: The mean ionized magnesium (IMg+2)
relationship to total magnesium (TMg) cannot be predicted before the
supplementation with the available technology. After supplementation of 4.1
mmol/L the ionized magnesium level increased by .05 +/- .01 mmol/L. Magnesium
supplementation had no significant effect on ionized calcium, potassium, and pH.
TMg and IMg+2 should be followed independently.
PMID- 10757198
TI - Vegetarian and weight-loss diets among young adults.
AB - OBJECTIVE: Young adults frequently experiment with vegetarian and weight-loss
diets. Comparisons of their experiences on these two different diets may help in
the development of approaches to improve long-term adherence to weight-loss
regimens. In the current study vegetarian and weight-loss diets were compared on
how long and how strictly they were followed, and reasons why they were initiated
and discontinued. RESEARCH METHODS AND PROCEDURES: From 428 college students
surveyed, four groups were delineated: 1) 59 participants had been following a
vegetarian diet but not a weight-loss diet (Vegetarian), 2) 117 participants had
tried a weight-loss diet but not a vegetarian diet (Weight Loss), 3) 133
participants had followed both a vegetarian and a weight-loss diet (Both), and 4)
119 participants had not tried either diet (Neither). RESULTS: Differences were
examined by comparing the Vegetarian and Weight-Loss groups as well as by
comparing the two diets within the Both group. Duration of the vegetarian diet
was much greater than the weight-loss diet; most participants in the Vegetarian
group (62%) remained on their diet for more than 1 year, whereas the majority of
the Weight-Loss participants (61%) followed their diet for 1 to 3 months. Similar
results were found when comparing the two diets within the Both group. How
strictly the two diets were followed, however, did not differ. Analyses revealed
that reasons for discontinuing a diet varied; participants were more likely to
cite boredom as a reason for discontinuing a weight-loss diet than a vegetarian
diet (53% vs. 5% between groups and 30% vs. 10% within the Both group).
DISCUSSION: The longer duration of the vegetarian diet relative to the weight
loss diet warrants further investigation. Results could possibly be applied to
behavioral weight-loss treatment to improve long-term maintenance.
PMID- 10757199
TI - The influence of physical activity, socioeconomic status, and ethnicity on the
weight status of adolescents.
AB - OBJECTIVE: This study examined the effects of physical activity, television
viewing, video game play, socioeconomic status (SES), and ethnicity on body mass
index (BMI). RESEARCH METHODS AND PROCEDURES: The sample was 2389 adolescents, 10
to 16 years of age (12.7 +/- 1.0 years); 1240 (52%) females and 1149 (48%) males;
77% white and 23% African American; from rural (77%) and urban (23%) settings.
BMI and skinfolds were directly assessed. All other data were obtained from
questionnaires. RESULTS: Watching television on non-school days was related to
being overweight (p < 0.005). However, when BMI analyses were adjusted for
ethnicity and SES, there were no significant effects of television viewing on BMI
(p > 0.061). Increased hours of video game play enhanced the risk of being
overweight for both genders when analyses were adjusted for ethnicity and SES (p
< 0.019). In males, participation in as little as one high-intensity physical
activity 3 to 5 days a week decreased the ethnic- and SES-adjusted relative risk
of being overweight (RR = 0.646; CI: 0.427 to 0.977). For females, the ethnic-
and SES-adjusted relative risk for being overweight was not significantly altered
by physical activity. The logistic analyses further indicated the influence of
low SES and African American ethnicity overshadowed any direct effect of
television or videos. DISCUSSION: Because weight status of male adolescents
appears to be more related to exercise habits than to television or video game
habits, increased participation in high-intensity exercise appears to be
important. For females, neither videos nor exercise habits appear to be related
to risk of being overweight. However, ethnicity and SES may be important factors
that can influence body weight status, while television viewing may be of some
importance. Thus, programs to reduce obesity in female adolescent should focus
their efforts in lower SES communities.
PMID- 10757200
TI - Familial aggregation of amount and distribution of subcutaneous fat and their
responses to exercise training in the HERITAGE family study.
AB - OBJECTIVE: Investigate the familial aggregation of amount and distribution of
subcutaneous fat and their changes in response to endurance training. RESEARCH
METHODS AND PROCEDURES: A total of 483 sedentary subjects from 99 nuclear
families were recruited, trained for 20 weeks of exercising on cycle ergometers,
and measured before and after training for the following indicators of
subcutaneous fat and fat distribution: trunk fat (TRUNK = sum of abdominal,
subscapular, suprailiac, and midaxillary skinfolds), extremity fat (EXTREM = sum
of biceps, triceps, thigh, and calf skinfolds), subcutaneous fat (SF8 = sum of
the eight skinfolds), the trunk to extremity skinfolds ratio adjusted for SF8
(TER) and waist girth adjusted for body mass index (WAIST). The familial
aggregation of the age- and sex-adjusted baseline phenotypes and their responses
to training (delta) after adjustment for the baseline values was investigated
using a familial correlation model. RESULTS: Significant familial aggregation was
observed for all the phenotypes measured at baseline and for deltaTRUNK and
deltaWAIST. Transmissibility estimates reached about 30% to 35% for TRUNK,
EXTREM, and SF8 and 50% for TER and WAIST. The transmissibilities of the response
phenotypes were lower, ranging from 0% for deltaWAIST to 21% for deltaTRUNK and
the pattern of familial correlations suggested a greater within- than between
generation resemblance in the response. DISCUSSION: This study suggests that the
amount and distribution of subcutaneous fat strongly aggregates in families,
whereas the response to exercise training is characterized by a moderate and more
complex pattern of familial resemblance. We conclude that familial/genetic
factors are more important in determining the amount and distribution of
subcutaneous fat than their responses to exercise training.
PMID- 10757201
TI - Evidence of pleiotropic loci for fasting insulin, total fat mass, and abdominal
visceral fat in a sedentary population: the HERITAGE family study.
AB - OBJECTIVE: To examine whether there is a major gene effect on fasting insulin and
pleiotropic loci for fasting insulin, total fat mass (FM), and abdominal visceral
fat (AVF). RESEARCH METHODS AND PROCEDURES: A major gene hypothesis for fasting
plasma insulin levels was assessed using segregation analyses of data on 495
members in 98 normolipidemic sedentary families of white descent who participated
in the HERITAGE Family Study. RESULTS: Segregation analyses were performed on
insulin adjusted for age, on insulin adjusted for age and FM, and on insulin
adjusted for age and AVF. Before adjustment for AVF and FM, a major gene effect
on fasting insulin levels was indicated. The putative locus accounted for 54% of
the variance under a recessive inheritance pattern, affecting 11% of the sample
(i.e., allele frequency = 0.33). However, after adjusting for the effects of AVF
or FM, neither a major effect alone nor a multifactorial component alone could be
rejected, and support for a major gene was equivocal, i.e., neither the
hypothesis of Mendelian tau values or that of the equal tau(s) were rejected and
the equal tau model fit the data better than the Mendelian tau model. This
pattern (i.e., major gene evidence for insulin before but not after adjustment
for AVF or FM) suggests that there is a putative locus with pleiotropic effects
on both insulin and FM and another pleiotropic locus for both insulin and AVF.
DISCUSSION: Although these data do not directly support an additional major gene
for insulin independent of AVF and FM, such support cannot be ruled out because
there is still a significant major effect on FM- or AVF-adjusted insulin (albeit
the Mendelian nature of this effect is ambiguous).
PMID- 10757202
TI - Obesity and physical and emotional well-being: associations between body mass
index, chronic illness, and the physical and mental components of the SF-36
questionnaire.
AB - OBJECTIVE: To clarify the associations between obesity and health-related quality
of life by exploring the associations between physical and emotional well-being
in relation to obesity and the presence of other chronic illness. RESEARCH
METHODS AND PROCEDURES: The study data were collected as part of a postal-survey
within the old Oxford Regional Health Authority of England in 1997. Completed
questionnaires were returned by 8889 of 13,800 randomly selected adults aged 18
to 64 years. The main outcome measures were body mass index in five categories
(underweight, normal weight, overweight, moderately obese, morbidly obese);
chronic illness status (any vs. none and number of such illnesses 0, 1 to 2, 3+);
and mean SF-36 questionnaire score in two summary component measures reflecting
physical and emotional well-being. RESULTS: Of the subjects, 31% were overweight
and an additional 11% were obese. Body mass index was significantly associated
with health status, but the pattern varied according to whether the measure
reflected physical or emotional well-being. Physical, but not emotional, well
being deteriorated markedly with increasing degree of overweight and was limited
in subjects who were obese but had no other chronic condition; subjects with
chronic illnesses other than obesity were compromised in both dimensions. In
terms of the number of chronic illnesses reported, the additional presence of
obesity was associated with a significant deterioration in physical but not
emotional well-being. DISCUSSION: Overweight and obesity are associated with poor
levels of subjective health status, particularly in terms of physical well-being.
The limitations in emotional well-being that are reported here and in other
studies may be a result of confounding by the presence of accompanying chronic
illness.
PMID- 10757203
TI - Ethnic differences in the responsiveness of adipocyte lipolytic activity to
insulin.
AB - OBJECTIVE: The goal of this study was to quantify differences in lipid metabolism
and insulin sensitivity in black and white subjects to explain ethnic
clinicopathological differences in type 2 diabetes. RESEARCH METHODS AND
PROCEDURES: The in vitro lipolytic activity of adipocytes isolated from obese
black and white women was measured in the presence of insulin and isoproterenol.
Insulin resistance was assessed in vivo using the euglycemic hyperinsulinemic
clamp technique. RESULTS: Fasting plasma levels of insulin and nonesterified
fatty acid (NEFA) in black and white women were 67 +/- 5 pM vs. 152 +/- 20 pM (p
< 0.01) and 863 +/- 93 microM vs. 412 +/- 34 microM (p < 0.01), respectively.
Euglycemic hyperinsulinemic clamp studies showed that obese black subjects were
more insulin-resistant than their white counterparts (glucose infusion rates: 1.3
+/- 0.2 vs. 2.2 +/- 0.3 mg/kg per min; p < 0.05). Isolated adipocytes from white
women were more responsive to insulin than those from black women with 0.7 nM
insulin causing a 55 +/- 4% inhibition of isoproterenol-stimulated lipolysis
compared with 27 +/- 10% in black women (p < 0.05). DISCUSSION: The low
responsiveness of adipocyte lipolytic activity to insulin in black women in the
presence of a relative insulinopenia may account for the high plasma NEFA levels
seen in these women, which may, in turn, account for their higher in vivo insulin
resistance. High NEFA levels may also contribute to the low insulin secretory
activity observed in the obese black females. These data suggest that the
pathogenesis of insulin resistance and type 2 diabetes within the black obese
community is strongly influenced by their adipocyte metabolism.
PMID- 10757204
TI - Prevalence of pre-obesity and obesity in urban adult Mexicans in comparison with
other large surveys.
AB - OBJECTIVE: 1. To estimate the prevalence of pre-obesity and obesity in a 1992 to
1993 national survey of the Mexican urban adult population. 2. To compare our
findings with other national surveys and with data for Mexican Americans.
RESEARCH METHODS AND PROCEDURES: The national representative sample of the
Mexican urban adult population included 8462 women and 5929 men aged 20 to 69
years from 417 towns of >2500 people. Body mass index (BMI), calculated from
measured weight and height, was classified using the World Health Organization
categories of underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5 to 24.9
kg/m2), pre-obesity (PreOB = BMI 25 to 29.9 kg/m2) and obesity (OB = BMI 30+
kg/m2). Estimates for Mexican Americans were calculated from U.S. survey data.
RESULTS: Overall, 38% of the Mexican urban adult population were classified as
pre-obese and 21% as obese. Men had a higher prevalence of pre-obesity than women
did at all ages, but women had higher values of obesity. Both pre-obesity and
obesity increased with age up to the age range brackets of 40 to 49 or 50 to 59
years for both men and women. Both pre-obesity and obesity prevalence estimates
were remarkably similar to data for Mexican Americans from 1982 through 1984.
Comparison with other large surveys showed that countries differed more in the
prevalence of obesity than of pre-obesity, leading to differences in the PreOB/OB
ratio, and that countries also differed in the gender ratio (female/male) for
both pre-obesity and obesity. DISCUSSION: Pre-obesity and obesity were high in
our population and increased with age. Our approach of characterizing large
surveys by PreOB/OB and gender ratios appeared promising.
PMID- 10757205
TI - Tumor necrosis factor-alpha stimulates cell proliferation in adipose tissue
derived stromal-vascular cell culture: promotion of adipose tissue expansion by
paracrine growth factors.
AB - OBJECTIVE: Elevated levels of tumor necrosis factor-alpha (TNF-alpha) protein and
mRNA have been reported in adipose tissue from obese humans and rodents. However,
TNF-alpha has catabolic and antiadipogenic effects on adipocytes. Addressing this
paradox, we tested the hypothesis that paracrine levels of TNF-alpha, alone or
together with insulin-like growth factor-I (IGF-I), support preadipocyte
development. RESEARCH METHODS AND PROCEDURES: Cultured stromal-vascular cells
from rat inguinal fat depots were exposed to serum-free media containing insulin
and 0.2 nM TNF-alpha, 2.0 nM TNF-alpha, or 0.2 nM TNF-alpha + 1.0 nM IGF-I at
different times during 7 days of culture. RESULTS: TNF-alpha inhibited adipocyte
differentiation as indicated by a reduction in both immunocytochemical reactivity
for the preadipocyte-specific antigen (AD3; early differentiation marker) and
glycerol-3-phosphate dehydrogenase activity (late differentiation marker). Early
exposure (Days 1 through 3 of culture) to 0.2 nM TNF-alpha did not have a long
term effect on inhibiting differentiation. Continuous exposure to 0.2 nM TNF
alpha from Days 1 through 7 of culture resulted in a 75% increase in cell number
from control. There was a synergistic effect of 0.2 nM TNF-alpha + 1 nM IGF-I on
increasing cell number by Day 7 of culture to levels greater than those observed
with either treatment applied alone. DISCUSSION: These data suggest that
paracrine levels (0.2 nM) of TNF-alpha alone or in combination with IGF-I may
support adipose tissue development by increasing the total number of stromal
vascular and/or uncommitted cells within the tissue. These cells may then be
recruited to become preadipocytes or may alternatively serve as infrastructure to
support adipose tissue growth.
PMID- 10757206
TI - Familial risk of overweight and obesity in the Canadian population using the
WHO/NIH criteria.
AB - OBJECTIVE: To determine the familial risk of overweight and obesity in Canada.
RESEARCH METHODS AND PROCEDURES: The sample was comprised of 15,245 participants
from 6377 families of the Canada Fitness Survey. The risk of overweight and
obesity among spouses and first-degree relatives of individuals classified as
underweight, normal weight, pre-obese, or obese (Class I and II) according to the
WHO/NIH guidelines for body mass index (BMI) was determined using standardized
risk ratios. RESULTS: Spouses and first-degree relatives of underweight
individuals have a lower risk of overweight and obesity than the general
population. On the other hand, the risk of Class I and Class II obesity (BMI 35
to 39.9 kg/m2) in relatives of Class I obese (BMI 30 to 34.9 kg/m2) individuals
was 1.84 (95% CI: 1.27, 2.37) and 1.97 (95% CI: 0.67, 3.25), respectively, in
spouses, and 1.44 (95% CI:1.10, 1.78) and 2.05 (95% CI: 1.37, 2.73), respectively
in first-degree relatives. Further, the risk of Class II obesity in spouses and
first-degree relatives of Class II obese individuals was 2.59 (95% CI: -0.91,
6.09) and 7.07 (95% CI: 1.48, 12.66) times the general population risk,
respectively. DISCUSSION: There is significant familial risk of overweight and
obesity in the Canadian population using the BMI as an indicator. Comparison of
risks among spouses and first-degree relatives suggests that genetic factors may
play a role in obesity at more extreme levels (Class II obese) more so than in
moderate obesity.
PMID- 10757207
TI - Implications of the United Kingdom prospective diabetes study for patients with
obesity and type 2 diabetes.
PMID- 10757208
TI - Shamanism, psychosis and autonomous imagination.
AB - This paper focuses on traditional healers (balian) in Bali, Indonesia, to raise
new arguments concerning the nature of the initiatory sufferings reportedly
experienced by shamans in many cultures. Our evidence suggests that a) contrary
to our expectations, an initiatory madness or illness is experienced by a
minority rather than the majority of balian, and b) whether or not a balian
undergoes initiatory sufferings seems to be linked to gender and to the methods
of healing employed - thus women healers who employ trance possession are those
most likely to report an initiatory madness or illness. This leads to the central
argument of the paper: c) the nature of the initiatory sufferings, where they do
occur, can be clearly distinguished on several grounds from the onset of mental
illness among Balinese, both emically in terms of cultural understandings, and
ethically in terms of objective criteria. Finally we discuss the concept of
"autonomous imagination," suggesting that the key to becoming a balian is not
overcoming an initiatory madness but gaining control over this special mode of
imagery thought. We further suggest that Western ideas concerning the self and
self healing, the superficial resemblance of the initiatory sufferings to
schizophrenia, and the dramatic nature of the initiatory sufferings when they
occur, have combined to give a misleading prominence to the role of an initiatory
madness in shamanism.
PMID- 10757209
TI - The role of local knowledge in medical practice: a trans-historical perspective.
AB - This article explores the role of participant-observation and ethnographic
writing in the shaping of medical practice since Hippocrates. Drawing on a range
of historical sources and genres that include the 17th- and 18th-century medical
topographies and medical geographies, 19th-century medical ethnography and
folklore, and their marginal persistence into the 20th century in the form of
Mexican pasante reports, I argue that these writings should not be approached as
part of the history of anthropology, but as specifically medical genres related
to medical practice. The abandonment of these ethnographic practices by modern
biomedicine is, I conclude, a consequence of two related developments: the
hegemony of clinical epistemology and the depersonalization and depoliticization
of physicians' commitment to their patients.
PMID- 10757210
TI - Health development meets the end of state socialism: visions of democratization,
women's health, and social well-being for contemporary Russia.
AB - As development organizations undertake the task of improving the public health in
former socialist states, their interventions are shaped by a particular cultural
logic and predetermined frame of possible action. In the context of local
encounters, however, they often confront competing interpretations of a society's
prevailing needs. How they manage such differences may not only explain the
outcomes of a given project, but may also reveal the capacities and limitations
of development agencies to engineer post-socialist change. This article examines
a recent WHO project in St. Petersburg, Russia, which defined women's "social
well-being" as a local health concern. While the project employed a discourse of
"democracy" to promote women's empowerment in the clinic, its parameters of
intervention neither incorporated local knowledge nor addressed the structural
relations underlying clinic-level conflicts. Two kinds of results ensued: the
ideology of democracy was rejected, while WHO's recommendations were partially
appropriated as profit-making strategies.
PMID- 10757211
TI - Resilience and risk: childhood and uncertainty in the AIDS epidemic.
AB - In a study of depression and risk among HIV-affected young people (children whose
parents are infected with or have died from HIV/AIDS), subjects did not report
high risk sexual or substance use behavior. Findings are attributed to parental
participation in a community-based HIV service program that provides parents with
HIV prevention education and long term social and emotional support. Multi
generational community based models of prevention that include parents as
critical elements of instruction may also be effective in substance abuse
treatment programs and in programs for children who experience difficulty in
school.
PMID- 10757213
TI - Deciphering diabetic nephropathy: progress using genetic strategies.
PMID- 10757212
TI - Multi-hit nature of chronic renal disease.
PMID- 10757214
TI - Progress in the treatment of proliferative lupus nephritis.
AB - Lupus nephritis is often well developed at the time of diagnosis. High-dose
corticosteroids are universally accepted as the initial approach to the control
of severe inflammation in the kidney. Long-term disease control and the
minimization of iatrogenic risk usually require adjunctive therapies that target
the more fundamental immunoregulatory disturbances of lymphoid cells. Of the
available cytotoxic drugs, cyclophosphamide is currently among the most
effective, although it cannot be considered ideal in terms of efficacy or
toxicity. New prospects for the treatment of proliferative lupus nephritis
include novel immunosuppressive agents (e.g. mycophenolate, cyclosporine,
fludarabine), combination chemotherapy (e.g. cyclophosphamide plus fludarabine),
and sequential chemotherapy (e.g. cyclophosphamide-azathioprine), immunological
reconstitution using intensive cytoreductive chemotherapy (with or without stem
cell rescue), co-stimulatory molecule inhibition (e.g. humanized anti-CD154
monoclonal antibody, CTLA4-Ig). Gene therapy remains an attractive prospect, but
its feasibility clearly depends on the further definition of lupus-promoting
genes and the availability of methods to establish stable expression of disease
corrective genes in the appropriate lymphoid cells.
PMID- 10757215
TI - The nephropathies of HIV infection: pathogenesis and treatment.
AB - Several different renal syndromes have been reported in patients with HIV
infection. Patient characteristics and a syndrome approach may help the clinician
formulate a tentative diagnosis, but a renal biopsy is necessary to make a firm
diagnosis in patients with chronic renal disease in the setting of HIV infection.
The pathogenesis of the HIV nephropathies can teach us much about the
pathophysiology of common renal problems such as IgA nephropathy, immune complex
glomerulonephritis, focal segmental glomerulosclerosis, and diabetic renal
disease. HIV-associated renal disease may be the result of the interaction of the
expression of specific HIV genes in patients with distinct genetic
susceptibilities to disease in particular environments. New treatment approaches
have provided hope for patients with classic HIV-associated nephropathy.
PMID- 10757216
TI - Calcimimetic agents and the calcium-sensing receptor.
AB - Blood ionized extracellular calcium is closely regulated. To accomplish this, a
hormone-like receptor that is responsive to extracellular ionized calcium
regulates both the secretion of parathyroid hormone and the excretion of urinary
calcium (as well as other cellular processes). Several hereditary disorders have
mutations that cause either loss or gain of function of the calcium-sensing
receptor, and alterations of the calcium-sensing receptor may play a role in both
primary and secondary hyperparathyroidism. Calcimimetics are agents that act to
make the calcium-sensing receptor more sensitive to extracellular ionized
calcium; thereby they suppress the secretion of parathyroid hormone. Early trials
in animal models of secondary hyperparathyroidism and in patients with primary
hyperparathyroidism or with uremic secondary hyperparathyroidism have shown that
the first generation calcimimetic, R-568, effectively lowers parathyroid hormone
levels and is well tolerated.
PMID- 10757217
TI - The role of tubulointerstitial injury in chronic renal failure.
AB - Progressive renal failure results from a triad of glomerulosclerosis,
tubulointerstitial fibrosis and vascular sclerosis. The mechanisms by which
tubules are injured, and by which the tubular epithelial cell then excites
interstitial inflammation culminating in fibroblast activation and fibrosis have
become increasingly understood. Most current methods to prevent progressive
glomerulosclerosis would inherently prevent tubular injury and interstitial
fibrosis. The behaviour and control of the renal fibroblast is being
investigated, with the potential for direct interference with its functions.
PMID- 10757218
TI - Recent advances in the understanding and management of primary vesicoureteral
reflux and reflux nephropathy.
AB - Vesicoureteral reflux and reflux nephropathy continue to be active areas of
clinical investigation. There is conclusive evidence that vesicoureteral reflux
is inherited. Prenatal diagnosis offers the opportunity for early recognition and
intervention that may reduce the incidence of complications of vesicoureteral
reflux such as pyelonephritis episodes and the development of reflux nephropathy.
PMID- 10757219
TI - Is microalbuminuria a predictor of cardiovascular and renal disease in patients
with essential hypertension?
PMID- 10757221
TI - Renal endothelin in hypertension.
AB - Due to the potent vasoconstrictor action of endothelin-1 and its synthesis
throughout the vasculature and other tissues, most investigators believe that it
is an active participant in the pathogenesis of hypertension. However, the
autocrine and paracrine nature of the endothelin system has made its role
difficult to define. In recent years, it has become apparent that endothelin-1
contributes to the regulation of renal salt and water excretion and that it is a
major contributor to the hypertension associated with salt-dependency. Evidence
suggests that endothelin-1 within the renal medulla is activated in conditions of
salt loading and inhibits reabsorption of sodium in a nitric oxide-dependent
manner. Blockade of endothelin A receptors lowers arterial pressure in animal
models of salt-dependent hypertension. Furthermore, circulating levels of
endothelin-1 are generally higher in African-Americans compared to white
Americans as is the prevalence of salt-dependent hypertension. Therefore, it
would appear that use of endothelin A-selective receptor antagonists should be
targeted to those individuals at risk for salt-dependent hypertension. Blockade
of endothelin B receptors would not be desirable because of their important role
in eliminating a salt load.
PMID- 10757220
TI - Molecular mechanisms of sodium transport inhibition in proximal tubule during
acute hypertension.
AB - Acute hypertension provokes a rapid decrease in proximal tubule salt and water
reabsorption that increases the levels of sodium chloride at the macula densa,
the error signal to increase arteriolar resistance to autoregulate renal blood
flow and glomerular filtration rate, and contributes to pressure natriuresis. The
molecular mechanisms responsible for this critical homeostatic adjustment are
beginning to be dissected: apical sodium transporters in the proximal tubule are
redistributed out of the brush border to intermicrovillar and endosomal stores
and sodium pump activity is inhibited. These responses are strikingly similar to
the cellular responses to parathyroid hormone, and are mediated by similar
signalling pathways.
PMID- 10757222
TI - Ouabain-like factor: is this the natriuretic hormone?
AB - This review focuses on the most recent data published in the field of the sodium
potassium pump inhibitors regarding the hypothetical structure, the secretory
stimuli and the pathophysiological implications for particular diseases, such as
hypertension. On the basis of the findings published so far, we reconsider and
discuss the 'natriuretic hypothesis' for explaining the role of the endogenous
sodium-potassium ATPase inhibitor. We propose the ouabain-like factor as a
modulator of the renal sodium-potassium pump, that can be considered as a new
pharmacological target for hypertension therapy.
PMID- 10757223
TI - Are angiotensin-converting enzyme inhibitors the best treatment for hypertension
in type 2 diabetes?
AB - The influence of hypertension on the clinical course and complications of type 2
diabetes is well established. With a special focus on angiotensin-converting
enzyme inhibitors, this paper will review recently published results of
prospective studies addressing two important aspects: the degree of blood
pressure control, and the choice of antihypertensive regimen, in the prevention
of complications in hypertensive type 2 diabetic patients. None of the recent
studies have shown worse outcomes in patients treated with angiotensin-converting
enzyme inhibitor-based regimens compared with alternative treatments. Some
studies have suggested that angiotensin-converting enzyme inhibitor-based
antihypertensive regimens may be superior to alternative treatments in reducing
the risk of micro- and macrovascular complications, whereas other studies found
similar effects for beta-blockers or calcium antagonists. Several trials showed
beneficial effects of angiotensin-converting enzyme inhibitors over calcium
antagonists, and have raised concerns about the use of dihydropyridine calcium
antagonists in these patients. However, it remains to be determined whether there
should be more reserved use of calcium antagonists in such patients, in the light
of more major trials showing the safety and efficacy of calcium antagonists in
preventing cardiovascular and renal endpoints. The degree of reduction of blood
pressure rather than the choice of a particular drug may be the most important
factor. Studies focusing on renal endpoints suggest that angiotensin-converting
enzyme inhibitors have a better antiproteinuric effect than other agents, but
this phenomenon is not always reflected by a more beneficial effect of
angiotensin-converting enzyme inhibitors on the decline in glomerular filtration
rate. In many ways, the question of whether angiotensin-converting enzyme
inhibitors are the best class of agent in these patients is academic. Angiotensin
converting enzyme inhibitors are sufficiently safe, and, according to recent
evidence, equally or more effective than other classes of agents. Tight blood
pressure control is usually achievable only with a combination of agents. On the
basis of available evidence, it appears that angiotensin-converting enzyme
inhibitors, together with a low-dose cardioselective beta-blocker and a diuretic,
should be used in most hypertensive type 2 diabetes patients, with calcium
antagonists serving as reserve drugs in case of insufficient blood pressure
control.
PMID- 10757224
TI - Bibliography. Current world literature. Clinical nephrology.
PMID- 10757225
TI - Bibliography. Current world literature. Pathophysiology of hypertension.
PMID- 10757226
TI - Induced production of nitric oxide and sensitivity of alveolar macrophages
derived from mice with different sensitivity to Coxiella burnetii.
AB - We compared in vitro sensitivities to Coxiella burnetii of alveolar macrophages,
derived from mice sensitive and resistant to C. burnetii, respectively, and
examined the role of nitric oxide (NO) in the C. burnetii infection. Alveolar
macrophages of sensitive A/J mice showed a larger population of C. burnetii
antigen-positive cells than those of resistant C57BL/6 mice. C. burnetii induced
NO production in alveolar macrophages, but N-methyl-L-arginine and sodium
nitroprusside (SNP), NO inhibitor and donor, respectively, did not inhibit the
infection. Thus the NO induction seems to be independent of the cell defense
mechanism against the C. burnetii infection.
PMID- 10757227
TI - Chize virus, a new phlebovirus isolated in France from Ixodes (Trichotoixodes)
frontalis.
AB - A new phlebovirus (Bunyaviridae family, Phlebovirus genus), provisionally
designed Chize virus, was isolated from a nymph of Ixodes (Trichotoixodes)
frontalis collected on a wren (Troglodytes troglodytes) found dead in the Chize
forest, western France. Chize virus produced a lethal encephalitis in one-day-old
mice and cytopathic effect (CPE) in Vero cells. Extracellular particles with a
mean diameter of 105 nm with surface spikes characteristic of Uukuniemi (UUK)
serogroup viruses were observed in Vero cells. Chize virus reacted in complement
fixation test with several UUK serogroup viruses but was readily distinguished
from all registered viruses in the serogroup. I. frontalis is highly specific for
birds and unlikely to transmit Chize virus to humans or domestic animals; the
pathogenicity of the new virus to wild birds remains to be clarified.
PMID- 10757228
TI - Detection of Phthorimaea operculella granulovirus in vivo and in vitro by a
specific DNA probe.
AB - In analyzing populations of non-infected potato tuber moth (PTM) Phthorimaea
operculella, using a total DNA probe from Phthorimaea operculella granulovirus
(PhopGV), false positive reactions were obtained indicating homology between
cellular and viral DNAs. Using a cloned 2.1 kbp fragment of PhopGV DNA, a
specific digoxigenin-labeled probe was developed. This fragment did not show
homology using both dot and Southern blot hybridization with either the genome of
the larvae or genomes of the cell lines derived from the insect. The PhopGV
specific DNA probe detected as little as 1 ng, while the total DNA probe could
detect even 35 pg of purified viral DNA. The 2.1 kb probe was highly specific for
PhopGV. It gave negative results with two other granuloviruses isolated on
Sesamia cretica and Spodoptera littoralis. The availability of a PhopGV-specific
probe is an important prerequisite of detection of early stages of virus
infection both in vivo on P. operculella larvae and in vitro on established P.
operculella cell lines.
PMID- 10757229
TI - Effect of low pH on the hepatitis A virus maturation cleavage.
AB - Cleavage of VP0 to VP2 via intramolecular scission is known as the viral
maturation cleavage, as VP0 is found in immature particles, whilst VP2 is found
in mature particles. The effect of low pH on the kinetics of hepatitis A virus
(HAV) capsid protein VP0 cleavage in provirions was examined by Western blot
analysis. VP0 scission was found to be dramatically enhanced under acidic
conditions, similar to those encountered on entry of virus particles into the
cell via endocytosis. The cleavage of VP0 to VP2 led to an increase in the
specific infectivity of viral particles, indicating that mature virions are more
infectious than immature provirions. The data are consistent with a model where
conformational changes induced by low pH aid scission of VP0, and the increase in
kinetics of VP0 cleavage may have relevance for viral uncoating, as only mature
HAV particles are thought capable of uncoating within the host cell.
PMID- 10757230
TI - Evaluation of avidin-biotin ELISA for the detection of antibodies to goat
poxvirus using noninfectious diagnostic reagent.
AB - A noninfectious soluble antigen fraction of goat poxvirus (GPV) fractionated by
ammonium sulfate precipitation was tested for its suitability as coating antigen
in an indirect enzyme-linked immunosorbent assay (ELISA). Accordingly, an avidin
biotin ELISA for the detection of GPV antibodies was optimized and evaluated
using different groups of serum samples from goats with known or unknown immune
status. A cut-off value higher by 60% than A492 reading of control negative sera
gave a 91.8% specificity and a 94.1% sensitivity for the assay. Out of 90 goat
pox-suspect sera obtained from the field, only 2 (2.2%) were found positive in
the counter immunoelectrophoresis (CIE) test, which is so far the routinely used
diagnostic test for goat pox, while 58 (64.4%) were positive in the avidin-biotin
ELISA. The McNemar's analysis of these data showed that the avidin-biotin ELISA
was significantly more efficient than the CIE test for the detection of GPV
antibodies in goat sera.
PMID- 10757231
TI - In vitro inhibitory effects of dual combinations of picornavirus replication
inhibitors.
AB - To assess the possible interactions among picornavirus replication inhibitors,
inhibitory effects of dual combinations of enviroxime, disoxaril, arildone, S-7,
guanidine, PTU-23, and HBB on poliovirus type 1 (Mahoney) replication in FL cells
were tested. Beforehand, the 50% inhibitory concentration (IC50) in the plaque
inhibition test was been determined for each individual compound, i.e. enviroxime
0.2 micromol/l, disoxaril-0.3 micromol/l, arildone-2.7 micromol/l, (S-7)-100
micromol/l, guanidine-200 micromol/l, (PTU-23)-200 micromol/l, and HBB-300
micromol/l. Each of the dual combinations, in which enviroxime or HBB was one of
the partners, showed synergistic or additive effects. Combining disoxaril with
enviroxime, HBB or PTU-23 resulted in synergism, while combining it with
guanidine, S-7 or arildone led to antagonism. Arildone showed additive or
synergistic effects when combined with enviroxime, HBB and PTU-23, and
antagonistic ones when combined with disoxaril, S-7 or guanidine. All dual
combinations of PTU-23 were synergistic with the exception of the pair of PTU-23
+ guanidine that was antagonistic. Guanidine had additive to synergistic
interactions with HBB or enviroxime but antagonistic ones with disoxaril,
arildone and PTU-23. Guanidine or PTU-23 when combined with S-7 showed an unusual
effect - synergistic one with an antagonistic zone. The combinations of S-7 with
enviroxime or HBB were synergistic but those with disoxaril or arildone were
antagonistic. Research on interactions of picornavirus replication inhibitors
could possibly contribute to the development of efficient chemotherapy of
infectious diseases caused by picornaviruses as well as to the better
understanding of the mode of action of those inhibitors.
PMID- 10757232
TI - Differential sensitivity of purified isoforms of cucumber anionic virus-inducible
peroxidase to exogenous proteases.
AB - Three different molecular forms, isoforms, of the major virus-inducible anionic
peroxidase (PRX) of cucumber (Cucumis sativus L.) were purified to homogeneity
from crude extracts of hypersensitively reacting cotyledons and subjected to
proteolysis with five exogenous endoproteinases. The PRX isoforms were fully
resistant to degradation by trypsin and chymotrypsin even though at a prolonged
incubation. Partial proteolysis with pepsin yielded peptides which were similar
in size and serological properties. When papain was used, the peptides released
from PRX1 isoform differed both in size and number but not serologically from the
peptides released from isoforms PRX2 and PRX3 confirming similar primary
structure of polypeptide chains. PRX3 was the only substrate giving a peptide map
after incubation with protease K. Under experimental conditions used in this
work, PRXI and PRX2 were degraded completely with protease K. These results
indicate that PRX1, PRX2, and PRX3 contain similar antigenic determinants and
indicate very similar but not identical primary structures. Several practical
implications of the present study are also mentioned.
PMID- 10757233
TI - Induction of nitric oxide in bovine peripheral blood mononuclear cells by bovine
herpesvirus 1.
AB - Bovine peripheral blood mononuclear cells (PBMCs) and monocytes were stimulated
with bovine herpesvirus 1 (BHV-1), LPS and concanavalin A (Con A) to produce L
arginine-dependent nitric oxide (NO) in vitro. NO was detected as early as 12 hrs
and up to 72 hrs post stimulation (p.s.). The NO from lipopolysacharide (LPS)
stimulated PBMCs and monocytes was found to exhibit antiviral effect against BHV
1. The anti-BHV-1 effect was inhibited with N(omega)-methyl L-arginine indicating
involvement of inducible NO synthase (iNOS) in NO production.
PMID- 10757234
TI - The role of cytokines in experimental herpes simplex keratitis.
AB - Experimental corneal infection with herpes simplex virus 1 (HSV-1) resulted in 11
21 days in herpes simplex keratitis (HSK) in C.A1-20 but not C.B-17 strain of
BALB/c Igh-1-disparate mice. Formation of mRNAs of various pro-inflammatory
cytokines was analyzed in corneas and draining lymph nodes (LNs) of HSK
susceptible C.A1-20 and HSK-resistant C.B-17 mice following HSV-1 corneal
inoculation by reverse transcription-polymerase chain reaction (RT-PCR) and
Southern blot analysis. Transcripts for interleukin (IL)-2 and interferon (IFN)
gamma were expressed in LNs of susceptible but not resistant mice. The level of
IL-6 expression in the cornea correlated with the severity of keratitis in
susceptible mice, being evident at days 4 and 14 after virus inoculation and thus
showing a biphasic response. Resistant mice did not develop HSK and did not
express IL-6. The IL-1beta and IL-4 gene transcription began early (day 7) in the
corneas of resistant mice and then ceased, while in the corneas of susceptible
mice, it began later (day 11). Taken together, these results indicate that IL
1beta, IL-4, IL-6, and IL-7 participate in the local inflammatory response in
HSK.
PMID- 10757235
TI - Effects of multiple sclerosis and other inflammatory CNS disorders on tick-borne
encephalitis serology.
AB - The goal of the present study was to investigate whether a direct association
exists between false-positive recognition of IgG antibodies and inflammatory
changes in the central nervous system (CNS) and whether inflammatory diseases of
the CNS affect the specificity of the enzyme-linked immunosorbent assay (ELISA)
of tick-borne encephalitis (TBE) virus. A group of patients (1,815), treated in
the Department of Neurology, University Hospital of the Saarland, Homburg/Saar,
Germany, were tested forTBE IgG antibodies by ELISA. Several subgroups of
patients with and without inflammatory changes in the CSF as well as patients
with and without confirmed multiple sclerosis (MS) were investigated. Overall,
4.5% of all the 1,815 patients and 4.8% of the patients with inflammatory changes
in the CSF but without MS had TBE IgG antibodies. In the subgroup with
inflammatory changes in the CSF and MS, 4.4% of the patients were TBE IgG
positive. In the subgroup without inflammatory changes in the CSF, 3.8% of the
patients without MS were TBE IgG-positive and 4.9% of the patients with MS were
TBE IgG-positive. The rate of TBE IgG positivity was not significantly different
in the subgroups with and without inflammatory changes in the CSF (P = 0.45). The
comparison of the subgroups with and without MS showed no significant difference
in the TBE IgG titer (P = 0.83) as well. This indicates that the specificity of
the ELISA was affected neither by inflammatory changes in the CSF nor by MS.
PMID- 10757236
TI - Identificaton of raspberry bushy dwarf virus strains occurring in the Czech
Republic.
PMID- 10757237
TI - Introduction to the King Solomon lecture of Edward Kravitz.
PMID- 10757238
TI - Serotonin and aggression: insights gained from a lobster model system and
speculations on the role of amine neurons in a complex behavior.
AB - The amine serotonin has been suggested to play a key role in aggression in many
species of animals, including man. Precisely how the amine functions, however,
has remained a mystery. As with other important physiological questions, with
their large uniquely identifiable neurons, invertebrate systems offer special
advantages for the study of behavior. In this article we illustrate that
principal with a description of our studies of the role of serotonin in
aggression in a lobster model system. Aggression is a quantifiable behavior in
crustaceans, the amine neuron systems believed to be important in that behavior
have been completely mapped, and key physiological properties of an important
subset of these netirons have been defined. These results are summarized here,
including descriptions of the "gain-setter" role and "autoinhibition" shown by
these neurons. Results of other investigations showing socially modulated changes
in amine responsiveness at particular synaptic sites also are described. In
addition, speculations are offered about how important developmental roles served
by amines like serotonin, which have been well described by other investigators,
may be related to the behaviors we are examining. These speculations draw heavily
from the organizational/activational roles proposed for steroid hormones by
Phoenix et al. (1959).
PMID- 10757239
TI - The interplay between dancing and trophallactic behavior in the honey bee Apis
mellifera.
AB - The interplay between the recruitment dance and food-giving trophallactic
contacts of returning Apis meellifera foragers was analyzed. Dancing and
trophallactic events were recorded for bees returning from a rate feeder that
provided 50% weight on weight sucrose solution at a constant flow rate of 5
microl min(-1). Bees that had danced immediately before their trophallactic
contact had more recipients per trophallaxis compared with bees that did not
dance before. Thus, besides information coded in dancing behavior, dance
maneuvers could serve as a stimulus to increase attention of bees located on the
dance floor to receive nectar. In addition, the number of bees receiving food
during a trophallaxis showed a positive correlation with the probability of
dancing immediately after contacting. The time from arrival at the hive to when
the first or the subsequent contacts took place presented no correlation with the
probability of dancing after trophallaxis. Also, the duration of a trophallaxis
was positively correlated with the number of recipients per trophallaxis. These
results suggest that returning foragers could receive information during a
trophallactic contact with their hive mates that modify thresholds for dancing.
Dance maneuvers and trophallactic contacts performed by foraging bees seem to be
"mutually" affected.
PMID- 10757240
TI - Prey capture and accommodation in the sandlance, Limnichthyes fasciatus
(Creediidae; Teleostei).
AB - The eyes of the sandlance, Limnichthyes fas ciatus (Creediidae, Teleostei) move
independently and possess a refractive cornea, a convexiclivate fovea and a non
spherical lens giving rise to a wide separation of the nodal point from the axis
of rotation of the eye much like that of a chameleon. To investigate this
apparent convergence of the visual optics in these phylogenetically disparate
species, we examine feeding behaviour and accommodation in the sandlance with
special reference to the possibility that sandlances use accommodation as a depth
cue to judge strike length. Frame-by-frame analysis of over 2000 strikes show a
100% success rate. Explosive strikes are completed in 50 ms over prey distances
of four body lengths. Close-up video confirms that successful strikes can be
initiated monocularly (both normally and after monocular occlusion) showing that
binocular cues are not necessary to judge the length of a strike. Additional
means of judging prey distance may also be derived from partallax information
generated by rotation of the eye as suggested for chameleons. Using
photorefraction on anaesthetised sandlances, accommodative changes were induced
with acetylcholine and found to range between 120 D and 180 D at a speed of 600
720 D s(-1). The large range of accommodation (25% of the total power) is also
thought to be mediated by corneal accommodation where the contraction of a unique
cornealis muscle acts to change the corneal curvatures.
PMID- 10757241
TI - Brain biogenic amines and reproductive dominance in bumble bees (Bombus
terrestris).
AB - To begin to explore the role of biogenic amines in reproductive division of labor
in social insects, brain levels of dopamine, serotonin, and octopamine were
measured in bumble bee (Bombus terrestris) workers and queens that differ in
behavioral and reproductive state. Levels of all three amines were similar for
mated and virgin queens. Young workers that developed with or without a queen had
similar amine levels, but in queenright colonies differences in biogenic amine
levels were associated with differences in behavior and reproductive physiology.
Dominant workers had significantly higher octopamine levels compared with workers
of lower dominance status but of similar size, age, and ovary state. High
dopamine levels were associated with the last stages of oocyte development
irrespective of worker social status and behavior. These results suggest that
biogenic amines are involved in behavioral and physiological aspects of
regulation of reproduction in bumble bees.
PMID- 10757242
TI - Lateralized memory storage and crossed inhibition during odor processing by
Limax.
AB - After odor conditioning intact Limax maximus and injecting LY into their
haemocoel, labeled groups of neurons are found in either the right or left
procerebral lobe but never in both procerebral lobes. This suggests that a
competitive interaction occurs between right and left odor processing pathways of
which the procerebral lobe is a part. We use the nerve discharge in the external
peritentacular nerve evoked by applying a puff of conditioned odor to the nose to
document crossed inhibition between left and right odor processing pathways.
Responses in the external peritentacular nerve evoked by stimulating one superior
nose with a conditioned odor are strongly lateralized as responses occur only on
the stimulated side. Stimulating both superior noses simultaneously with the same
conditioned odor yields responses in both external peritentacular nerves that
resemble the sum of responses to unilateral stimulation. Simultaneously
stimulating both superior noses, each with a different conditioned odor leads to
strong inhibition of both external peritentacular nerve responses. The crossed
inhibition is also evident if both superior and inferior noses on the same side
are stimulated simultaneously. A lateral inhibitory mechanism, situated
postsynaptic to odor recognition, appears to inhibit external peritentacular
nerve responses if the two noses receive conflicting sensory inputs.
PMID- 10757243
TI - Auditory role of lateral trunk channels in cobitid fishes.
AB - In cobitid fishes the anterior part of the swimbladder is encapsulated by bone to
varying extent. This might diminish the auditory sensitivity of these otophysine
fishes by reducing the vibrations of the swimbladder wall in the sound field.
However, according to prior studies the auditory thresholds of the cobitid Botia
modesta is similar to that of other otophysine fishes. According to anatomical
investigation B. modesta has a cranial encapsulation of the anterior part of the
swimbladder (camera aerea Weberiana) as expected and in addition special channels
stretching laterally from the swimbladder to the outer body wall. These lateral
trunk channels are filled with fat and lymph. They form a muscle-free acoustic
window beneath the skin, which could be demonstrated by measuring the auditory
brainstem response at 400 Hz, 800 Hz, 1500 Hz, and 3000 Hz. Filling the lateral
trunk channels with wettex (cotton/rayon staple) resulted in an increase of the
auditory thresholds by 13.6-17.6 dB, indicating mechanical damping of the
swimbladder. Our experiments demonstrate that the intact lateral trunk channels
enhance the hearing sensitivity of cobitid fishes.
PMID- 10757244
TI - Presynaptic inhibition and the participation of GABA(B) receptors at
neuromuscular junctions of the crab Eriphia spinifrons.
AB - Presynaptic inhibition exerted by the common inhibitor on the closer and opener
muscles and by the specific inhibitor on the opener muscle was investigated in
the crab Eriphia spinifrons. In the closer muscle, activation of GABA(B)
receptors by baclofen reduced the mean quantal content of excitatory junctional
currents by about 25%. Blocking GABA(B) receptors with CGP 55845 diminished
presynaptic inhibition at a similar percentage. GABA(B) receptor-mediated
presynaptic inhibition is linked to G proteins. Application of pertussis toxin
eliminated about 25% of the inhibition exerted by the common inhibitory neuron.
GABA(B) receptors participate in presynaptic inhibition at release boutons of the
slow and the fast closer excitor at a similar percentage. In the opener muscle,
presynaptic inhibition of transmitter release from the same endings of the opener
excitor was about 15% stronger with the specific inhibitor than with the common
inhibitor. About 10% of the presynaptic inhibition produced by either one of the
two inhibitors could be abolished by blocking GABA(B) receptors. The amplitudes
of the excitatory junctional currents in the opener were reduced in the presence
of baclofen by about 25%, suggesting that synaptic terminals of the opener
excitor are endowed with a similar percentage of GABA(B) receptors as terminals
of the slow and the fast closer excitors. Baclofen had no effect on postsynaptic
inhibition, indicating that GABA(B) receptors are not involved in postsynaptic
neuromuscular inhibition.
PMID- 10757245
TI - Changes in the metabolic rate of the foraging honeybee: effect of the carried
weight or of the reward rate?
AB - The metabolic rate of free flying honeybees (Apis mellifera ligustica) foraging
on a multiple automatic feeder was measured in complete absence of perturbation.
Each time the sucrose flow rate was doubled, the metabolic rate increased by 18.2
+/- 2.0% (14.7 microl CO2 min(-1) and final crop load by 25.1 +/- 2.4% (7.04
microl). The possibility that the heavier load carried by the bees caused the
increase in the metabolic rate was analyzed in detail. It was found that, for the
same weight in the crop, the metabolic rate increased with the increasing reward
rate. Therefore, a factor other than the carried weight might account for this
increase: a motivational drive, whose intensity may depend on the reward rate at
the food source. Although at higher reward rates metabolic rate increased during
the visit, at lower reward rates it remained constant, suggesting that the effect
of the carried weight on the metabolic rate might be controlled by this
motivational drive. The hypothesis that honeybees maximize individual efficiency
by reducing their crop load loses support, as foraging costs are not determined
by the carried weight. The functional meaning of the reduction in crop load would
be to increase the informational exchange at the hive.
PMID- 10757246
TI - Octopamine modulates the sensitivity of silkmoth pheromone receptor neurons.
AB - Effects of octopamine and its antagonist epinastine on electrophysiological
responses of receptor neurons of Antheraea polyphemus specialised to the
pheromone components (E,Z)-6,11-hexadecadienyl acetate and (E,Z)-6,11
hexadecadienal were investigated. Injections of octopamine and epinastine into
the moths had no effect on the transepithelial potential of the antennal-branch
preparation nor on the spontaneous nerve impulse frequency in either type of
receptor neuron. However, in the presence of continuous low-intensity pheromone
stimulation, octopamine significantly increased the nerve impulse frequency in
the acetate receptor neuron, but not in the aldehyde receptor neuron. Octopamine
and epinastine had no significant effect on the receptor potential amplitudes
elicited in both receptor neuron types by pheromone stimulation. However, the
peak nerve impulse frequency in the response of both receptor neuron types to
pheromone was significantly affected: decreased by epinastine and increased by
octopamine over a broad range of pheromone concentrations. In control
experiments, injection of physiological saline did not significantly alter the
peak nerve impulse frequency. The effect of octopamine was established within 1 h
after injection and persisted for about 4 h. The possibility of a direct action
of octopamine on the nerve impulse generation by the receptor neurons is
discussed.
PMID- 10757247
TI - Decyl-thio-trifluoropropanone, a competitive inhibitor of moth pheromone
receptors.
AB - An earlier study (Pophof 1998) showed that the esterase inhibitor decyl-thio
trifluoropropanone inhibited the responses of two receptor neurons of the moth
Antheraea tuned to straight-chain pheromone components, an acetate and an
aldehyde, respectively. Here we report that decyl-thio-trifluoropropanone also
inhibited the responses of two pheromone receptor neurons of Bombyx mori to
bombykol and bombykal. In contrast, decyl-thio-trifluoropropanone activated
receptor neurons of the moth Imbrasia cyrtherea tuned to the pheromone component
(Z)-5-decenyl 3-methyl-butanoate. However, decyl-thio-trifluoropropanone did not
affect the responses of two receptor neurons of B. mori females specialized to
the plant volatiles benzoic acid and linalool, respectively. These results
indicate that decyl-thio-trifluoropropanone, besides inhibiting the sensillar
esterase, interferes with proteins involved specifically in the excitation of
pheromone receptor neurons. In binding studies with radiolabelled decyl-thio
trifuoroproparopnone, the inhibitor was bound by the pheromone-binding protein of
A. polyphemus. However, the amount of decyl-thio-trifluoropropanone causing
response inhibition was 300 times lower than the amount of pheromone-binding
protein present in the sensilla. Since the amount of decyl-thio
trifluoropropanone adsorbed corresponded to about the maximum number of receptor
molecules calculated per sensillum, we expect that decyl-thio-trifluoropropanone,
probably in complex with pheromone-binding protein, competitively inhibits the
pheromone receptor molecules.
PMID- 10757248
TI - Evidence-based guidelines for treating depressive disorders with antidepressants:
a revision of the 1993 British Association for Psychopharmacology guidelines.
British Association for Psychopharmacology.
AB - A revision of the British Association for Psychopharmacology guidelines for
treating depressive disorders with antidepressants was undertaken in order to
specify the scope and target of the guidelines and to update the recommendations
based explicitly on the available evidence. A consensus meeting, involving
experts in depressive disorders and their treatment, reviewed key areas and
considered the strength of evidence and clinical implications. The guidelines
were drawn up after extensive feedback from participants and interested parties.
A literature review is given which identifies the quality of evidence followed by
recommendations, the strength of which are based on the level of evidence. The
guidelines cover the nature and detection of depressive disorders, acute
treatment with antidepressant drugs, choice of drug versus alternative treatment,
practical issues in prescribing, management when initial treatment fails,
continuation treatment, maintenance treatment to prevent recurrence and stopping
treatment.
PMID- 10757249
TI - Tryptophan depletion impairs memory consolidation but improves focussed attention
in healthy young volunteers.
AB - Animal and human studies have provided evidence for serotonergic modulation of
cognitive processes. However, the exact nature of this relationship is not clear.
We used the acute tryptophan depletion (ATD) method to investigate the effects of
lowered serotonin synthesis on cognitive functions in 17 healthy young
volunteers. The study was conducted according to a placebo-controlled, double
blind, crossover design. Cognitive performance and mood were assessed at baseline
and 5 and 9 h after administration of ATD. A specific impairment of word
recognition, without effects on short-term memory, occurred during ATD. No memory
deficits were seen if ATD was induced after acquisition of new words. The Stroop
Test and dichotic listening task demonstrated a modality independent improvement
of focussed attention after ATD. Fluency was also improved after ATD. ATD did not
alter speed of information processing, divided attention or planning functions.
These results indicate that serotonin is essential in the process of long-term
memory consolidation, primarily in the first 30 min after acquisition.
Improvement of specific cognitive processes by lowered 5-HT function may be
linked to the removal of inhibitory actions of 5-HT in the cortex.
PMID- 10757250
TI - Antisaccade and smooth pursuit eye movements in healthy subjects receiving
sertraline and lorazepam.
AB - Patients suffering from some psychiatric and neurological disorders demonstrate
abnormally high levels of saccadic distractibility when carrying out the
antisaccade task. This has been particularly thoroughly demonstrated in patients
with schizophrenia. A large body of evidence has been accumulated from studies of
patients which suggests that such eye movement abnormalities may arise from
frontal lobe dysfunction. The psychopharmacology of saccadic distractibility is
less well understood, but is relevant both to interpreting patient studies and to
establishing the neurological basis of their findings. Twenty healthy subjects
received lorazepam 0.5 mg, 1 mg and 2 mg, sertraline 50 mg and placebo in a
balanced, repeated measures study design. Antisaccade, no-saccade, visually
guided saccade and smooth pursuit tasks were carried out and the effects of
practice and drugs measured. Lorazepam increased direction errors in the
antisaccade and no-saccade tasks in a dose-dependent manner. Sertraline had no
effect on these measures. Correlation showed a statistically significant, but
rather weak, association between direction errors and smooth pursuit measures.
Practice was shown to have a powerful effect on antisaccade direction errors.
This study supports our previous work by confirming that lorazepam reliably
worsens saccadic distractibility, in contrast to other psychotropic drugs such as
sertraline and chlorpromazine. Our results also suggest that other studies in
this field, particularly those using parallel groups design, should take account
of practice effects.
PMID- 10757251
TI - Antisaccade eye movement abnormalities in Tourette syndrome: evidence for cortico
striatal network dysfunction?
AB - Saccadic eye movements are rapid eye movements which act to redirect the eyes
from one object of interest to another. Accurately and objectively measurable,
their underlying neuroanatomical mechanisms have been extensively studied. The
antisaccade task allows the study of the frontocortico-striatal network involved
in the voluntary control of saccadic eye movements. In this task, the subject is
instructed to inhibit a reflex eye movement towards a peripheral target light
and, instead, to generate a movement in the equal and opposite direction. An
error occurs when the subject fails to suppress reflexive saccades towards the
target. Significantly high error rates and increased latencies in the antisaccade
task have been reported in disorders associated with dysfunction of the
frontocortico-striatal network. Increased saccadic eye movement latencies and
error rates have been reported in Tourette syndrome patients (n = 4) who were
receiving antipsychotic medication. To investigate this further, we tested the
antisaccade task on six male Tourette syndrome patients. The results were
compared with 18 age- and sex-matched mentally and physically healthy,
medication/alcohol-free controls. Antisaccade latencies were (mean +/- SD; ms)
751.2+/-186.7 for the Tourette syndrome group and 417+/-75.3 for controls, and
error rates were 59+/-14.3 for the Tourette syndrome group and 11.9+/-6.4 for
controls, respectively. These significant results may further support dysfunction
of the frontocortico-striatal network in Tourette syndrome.
PMID- 10757252
TI - The effects of some antidepressant drugs on prepulse inhibition of the acoustic
startle (eyeblink) response and the N1/P2 auditory evoked response in man.
AB - Both the acoustic startle (eyeblink) response and the N1/P2 complex of the
auditory evoked potential can be suppressed by presentation of a brief low
intensity stimulus 30-500 ms before the 'startle-eliciting' stimulus ('prepulse
inhibition', PPI). We examined the effects of three antidepressants on PPI of
these two responses. Fifteen males (19-30 years) participated in four weekly
sessions, in which they received placebo, amitriptyline (100 mg), fluvoxamine
(100 mg), and reboxetine (4 mg) (p.o.), according to a balanced double-blind
design. Twenty minute simultaneous recordings of electromyographic (EMG)
responses of the orbicularis oculi muscle of the right eye and vertex auditory
evoked potentials were carried out 195 min after drug ingestion. Sound stimuli (1
kHz) were presented in 40 trials separated by variable intervals (mean 25 s): (1)
40 ms, 115 dB ('pulse alone', 20 trials) and (2) 40 ms, 85 dB, followed after 120
ms by 40 ms, 115 dB ('prepulse/pulse', 20 trials). Under the placebo condition,
both the EMG response and the N1/P2 complex showed >50% PPI. Fluvoxamine and
reboxetine did not significantly alter the amplitude or PPI of either response.
Amitriptyline significantly reduced the amplitudes of both responses; it had no
effect on PPI of the EMG response, but significantly attenuated PPI of the N1/P2
complex. Amitriptyline also reduced arousal, as indicated by an increase in power
of low-frequency electroencephalographic waves. The results confirm the
susceptibility of the N1/P2 complex to PPI. The reduction of the amplitudes of
the EMG response and N1/P2 complex by amitriptyline may be related to its
sedative action. The differential effect of amitriptyline on PPI of the N1/P2
complex supports the suggestion that different mechanisms may be involved in PPI
of this response and PPI of the N1/P2 complex.
PMID- 10757253
TI - Antidepressant-like activity of amisulpride in two animal models of depression.
AB - Clinical reports suggest that amisulpride, in addition to its antipsychotic
efficacy, may also have antidepressant properties. The present study was designed
to evaluate potential antidepressant-like activity of amisulpride in two
behavioural procedures: the forced swim test (FST) and the chronic mild stress
(CMS) model. The duration of immobility time in FST was reduced by subchronic
(three injections over a 24 h period) administration of imipramine (10 mg/kg) and
amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent.
The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10
and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the
consumption of 1% sucrose solution was gradually reversed by chronic treatment
with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg)
or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the
effect of active doses of amisulpride in the CMS model was comparable to that of
imipramine but its onset of action was faster; at the most active dose of 10
mg/kg, amisulpride significantly increased the sucrose intake in stressed animals
within 2 weeks of treatment while imipramine required 4 weeks before first
effects on the stress-induced deficit in sucrose consumption could be observed.
These results provide further support for clinical observations that amisulpride
may possess potent and rapid antidepressant activity.
PMID- 10757254
TI - An evaluation of the abuse potential of modafinil using methylphenidate as a
reference.
AB - Modafinil is a unique wake-promoting agent. Preclinical studies indicate a
mechanism of action which is distinct from that of amphetamine or
methylphenidate. To compare the pharmacodynamic profiles of modafinil,
methylphenidate, and placebo in humans, a double-blind Latin square crossover
study was conducted in 24 male volunteers with a history of polysubstance abuse
that included the stimulant cocaine. Each subject was given single oral doses of
methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and
placebo. Measures of subjective, behavioural, and physiological responses were
evaluated at fixed intervals during 72 h after each dosing occasion. Subjects
discriminated both modafinil and methylphenidate from placebo. Subjects liked the
effects of both drugs. However, modafinil differed from methylphenidate in its
lack of a significant response on the Amphetamine Scale of the Addiction Research
Center Inventory. The profile of physiological effects for modafinil differed
from methylphenidate in that it showed greater inhibition of observed and
reported sleep, less facilitation of orthostatic tachycardia and less reduction
of caloric intake. These findings are consistent with preclinical pharmacological
data suggesting that modafinil is not an amphetamine-like agent.
PMID- 10757255
TI - Double-blind comparison of venlafaxine and amitriptyline in outpatients with
major depression with or without melancholia.
AB - The purpose of this study was to compare the efficacy and tolerability of
venlafaxine and amitriptyline in outpatients with major depression with or
without melancholia. This was an 8-week, multicentre, randomized, double-blind,
parallel-group comparison of venlafaxine and amitriptyline. Outpatients with DSM
IV major depression, a minimum score of 20 on the 21-item Hamilton Depression
Rating Scale (HAM-D), and depressive symptoms for at least 1 month were eligible.
Patients were randomly assigned to venlafaxine or amitriptyline, both drugs
titrated to a maximum of 150 mg/day until study day 15. The primary efficacy
variables were the final on-therapy scores on the HAM-D, Montgomery-Asberg
Depression Rating Scale and Clinical Global Impression severity scales. Data were
evaluated on an intent-to-treat basis using the LOCF method. One hundred and 16
patients were randomized, and 115 were evaluated for efficacy. Both drugs showed
efficacy in the treatment of depression with or without melancholia. No
significant differences were noted between treatments for any efficacy parameter.
However, significantly (p < 0.05) more patients in the amitriptyline group had at
least one adverse event. These results should support the efficacy and
tolerability of venlafaxine in comparison with amitriptyline for treating major
depression with or without melancholia.
PMID- 10757257
TI - Selective serotonin reuptake inhibitors in post-traumatic stress disorder.
AB - Post-traumatic stress disorder (PTSD) is a complex psychiatric condition, which
can be triggered by a variety of traumatic events. Lifetime prevalence rates
range from 1.3% to 10.4%, with women twice as likely as men to be affected. The
clinical management of this condition is complex, since PTSD is associated with
high rates of comorbid psychiatric disorders, particularly major depression,
other anxiety and panic disorders, substance abuse and antisocial behaviour.
Broadly, there are two main approaches to treatment: pharmacotherapy and
cognitive or behavioural therapy. This paper reviews available pharmacological
approaches for the treatment of PTSD and comorbid disorders. Although the optimal
pharmacological approach has yet to be established, there is increasing evidence
to support the use of antidepressants, and particularly selective serotonin
reuptake inhibitors (SSRIs), as first-line therapy. In addition to alleviating
the core symptoms of PTSD, some SSRIs are also effective for the treatment of
common comorbidities, such as depression, panic disorder and social anxiety
disorder; a fact which would appear to have important implications for patient
management.
PMID- 10757256
TI - Psychostimulants and psychiatrists: the Trent Adult Psychiatry Psychostimulant
Survey.
AB - This study reports upon the results of a postal questionnaire survey of 107 adult
psychiatrists which investigated their current use of psychostimulant
pharmacotherapy and their attitudes towards the diagnostic status of attention
deficit hyperactivity disorder (ADHD) in adulthood. Of the 88 respondents, only a
minority of 11 (12.5%) used psychostimulants in their usual practice, albeit very
infrequently (one or two prescriptions per year on average). Methylphenidate
hydrochloride ('Ritalin') was the prescribers' most popular agent and
'narcolepsy' was the most frequently cited clinical indication for
psychostimulants. ADHD appeared to represent only a very small area of current
clinical activity and a minority of clinicians expressed the view that it did not
exist in adults. It is concluded that psychostimulant therapy is relatively
undeveloped in British adult psychiatry and that the clinical speciality
generally appears to be unprepared for the growing numbers of adolescents with
ADHD who are currently managed by child psychiatrists and who may require ongoing
psychiatric care, including psychostimulant therapy.
PMID- 10757258
TI - Evidence-based psychopharmacology 3. Assessing evidence of harm: what are the
teratogenic effects of lithium carbonate?
AB - Critical appraisal techniques are not only useful in evaluating evidence of
therapeutic trials. In this final article of the series of evidence-based
psychopharmacology, the evidence about the teratogenic effects of lithium
carbonate is considered. This exercise highlights the importance of assessing the
evidence oneself and not relying on the interpretation others put on it.
PMID- 10757259
TI - Allopurinol for refractory aggression and self-inflicted behaviour.
AB - The impairment of the purinergic system, characterized by reduced adenosinergic
activity, has been implicated in the neurobiology of aggressive behaviour. Since
there are no direct adenosine agonists available for human use, inhibition of
purine degradation by allopurinol was conceived as a possible strategy. We report
two cases of adults with refractory aggressive behaviour due to a neurological
condition (one mainly with self-inflicted behaviour) with dramatic response to
therapy with allopurinol, 300 mg/day p.o. These preliminary results reinforce the
involvement of the purinergic system in the neurobiology of aggression,
warranting further testing of allopurinol as a new treatment for aggressive and
self-inflicted behaviours.
PMID- 10757260
TI - Mania in a patient receiving testosterone replacement postorchidectomy taking St
John's wort and sertraline.
AB - We describe the case of a patient who developed depression following bilateral
orchidectomy for cryptorchidism. He was treated with a conventional selective
serotonin reuptake inhibitor antidepressant, but continued to take St John's wort
(hypericum) against medical advice. He subsequently developed a manic episode. We
discuss postulated modes of action of St John's wort and the possible
aetiological importance of testosterone replacement and abnormal gonadotrophin
levels in this case.
PMID- 10757261
TI - PON1 and low-dose sarin in marmosets.
PMID- 10757262
TI - Blunt renal trauma: some personal thoughts.
AB - Blunt renal trauma continues to promote discussion in trauma and urology circles.
It seems that the three aspects that continue to arouse controversy are the
decisions involved in imaging minor trauma, exploring the retroperitoneal
haematoma at laparotomy and managing the major stable injury. Personal views are
advanced on these aspects based on a review of the literature.
PMID- 10757263
TI - Resistive index: an experimental study of the normal range in the pig.
AB - OBJECTIVES: To study the normal range and distribution of the resistive index
(RI) and the resistive index ratio (RIR) in the non-obstructed non-dilated
porcine kidney, and to assess the reliability of the threshold values RI 0.70 and
RIR 1.10 as prognosticators of true obstruction in the upper urinary tracts.
METHODS AND MATERIALS: Twenty female pigs of Danish land race breed were studied
under general anaesthesia. Blood pressure and urine output was monitored
throughout the experiment. Doppler evaluations were obtained from an interlobar
artery in the lower half of each kidney, and the RI was calculated as the average
of 3 x 3 cycles for each side independently. Statistical analysis of the obtained
results was performed. RESULTS: Forty renal units were studied. The RI values
ranged from 0.48-0.85 (mean 0.63). Nine renal units (22.5%) had RI values > or =
0.70. RIR values ranged from 1.00-1.38 (mean 1.07). Three RIR values (15%) were
above 1.10. There was no statistically significant relationship between RI and
laterality (p = 0.25), and no overall significant relationship between RI and
mean arterial blood pressure (r2 = 0.21) or urine output (r2 = 0.004).
CONCLUSIONS: This study shows a wide distribution of the RI normal values in the
pig model, and our results do not support the normal ranges for RI and RIR, or
the cut-off values used in clinical practice.
PMID- 10757264
TI - Possible role of endothelin-1 in the rabbit urinary bladder hyperplasia secondary
to partial bladder outlet obstruction.
AB - OBJECTIVES: Urinary bladder hypertrophy and hyperplasia are common features of
bladder outlet obstruction (BOO). The urinary bladder is known to synthesize
endothelin-1 (ET-1), which is a potent vasoconstrictor peptide with mitogenic
properties. Using an animal model of partial BOO, we investigated the potential
role of ET-1 and its receptor subtypes (ET(A) and ET(B)) in bladder smooth muscle
cell (SMC) proliferation. MATERIALS AND METHODS: Partial BOO was produced in
adult male New Zealand White rabbits. After 3 weeks, the bladder was removed and
SMCs from the dome and bladder neck were grown using standard explant
methodology. At passage 2, the cells were made quiescent and then further
incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or
partial BOO serum (BRS) in the presence or absence of ET(A)-antagonist (BQ123) or
ET(B)-antagonist (BQ788). SMC proliferation was then measured 24 h later with 5
bromo-2'deoxy-uracil and by cell counting using a haemocytometer at 48 h.
Immunostaining for alpha-actin was performed on detrusor and bladder neck cells
to confirm the presence of smooth muscle cells. RESULTS: BQ123 and BQ788 did not
influence detrusor or bladder neck SMC proliferation in FCS or CRS. However, in
the presence of BRS, BQ123 and BQ788 (100 nmol/L) significantly (p = 0.008)
inhibited detrusor and bladder neck SMC proliferation. Cell counts were
significantly reduced from the detrusor (p = 0.03, p = 0.01 with BQ123 and BQ788,
respectively) and bladder neck (p = 0.01 for both BQ123 and BQ78). CONCLUSIONS:
These results suggest that ET antagonists may have a role in preventing SMC
hyperplasia associated with partial BOO.
PMID- 10757265
TI - Electro-acupuncture in the treatment of children with monosymptomatic nocturnal
enuresis.
AB - OBJECTIVE: The aim of this study was to investigate the effects of a long series
of electro-acupuncture (EAP) sessions on bedwetting symptoms. MATERIAL AND
METHODS: Twenty-five children (age range 7-16 years) with monosymptomatic
nocturnal enuresis and treated earlier without success were included in the
study. The median number of wet nights per week was 4.7 before treatment.
Bedwetting, voided volume, sleep and nocturia were evaluated 3 weeks, 3 months
and 6 months after 20 sessions of EAP lasting 8 weeks. RESULTS: All the children,
with the exception of one, tolerated EAP treatment well. At the three follow-up
sessions it was found that the number of dry nights had increased gradually from
a median of 2.3 in the pre-test to 3.0, 4.3 and 5.0 per week, respectively.
Compared to pre-treatment findings there were more dry nights in 65% of the
children (p < 0.001) and 5 out of 23 children were responders (> 90% reduction of
the numbers of wet nights) at the 6 months' follow-up. According to the parents,
the sleep arousal threshold had decreased in about 50% of the children.
PMID- 10757266
TI - Possible role of prostaglandins in pathogenesis of nocturnal enuresis in
children.
AB - OBJECTIVE: To compare excretion of ions and prostaglandins by the kidney in
children with noctural enuresis. MATERIAL AND METHODS: Thirty-two children with
primary nocturnal enuresis and 23 normal children were examined. Osmolality and
sodium and potassium concentrations were measured in their urine and blood serum.
Prostaglandins E2, E1, and F2alpha were determined using kits for immunoenzyme
analysis. Luminal and contraluminal prostaglandin secretions were studied in frog
urinary bladder. RESULTS: Children with nocturnal enuresis have increased
nocturnal diuresis and renal sodium excretion, but no increase was found in
excretion of prostaglandins E2, E1, and F2alpha. Administration of sodium
diclofenac before bed-time eliminated episodes of nocturnal enuresis in 37% of
children; intranasal administration of Adiuretin SD had a positive effect in 69%
of enuretics. In children with nocturnal enuresis there is a correlation between
renal excretion of PGE2 and sodium ions; this correlation is absent in the
control group children, and disappears in enuretics treated with desmopressin. To
evaluate the representativeness of the data on prostaglandin secretions to urine
as compared with their release to extracellular fluid, experiments on frog
urinary bladder were performed: a correlation was found between prostaglandin
secretion to the urinary bladder lumen and to the extracellular fluid.
CONCLUSIONS: The results of the study suggest that changes in renal function are
due not to a higher secretion of prostaglandins in nocturnal enuresis but to the
relative dominance of their effect as compared with other physiologically active
substances that simultaneously act on renal tubular cells.
PMID- 10757267
TI - Surgical management of angiomyolipoma: nephron-sparing surgery for symptomatic
tumour.
AB - Angiomyolipoma (AML) is a benign renal tumour that occasionally requires
intervention. We evaluated the surgical management of symptomatic angiomyolipoma,
with special attention to the feasibility of nephron-sparing surgery. A
retrospective study was conducted enlisting 23 patients (including 3 patients
with tuberous sclerosis) who had their AML treated surgically from 1991 to 1998.
The study included 7 males and 16 females, with a mean age of 49 years (range 24
75). The mean tumour size was 12.3 cm (range 1.5-30.0) including 7 lesions < or =
4 cm and 16 lesions > 4 cm. The presenting features included abdominal/loin pain
(9 patients), spontaneous rupture (5 patients), non-specific symptoms (7
patients) and incidental findings (2 patients). AML was diagnosed by computed
tomography in 16 patients and malignancy was suspected in 7 patients. The latter
group included 5 patients with lesions smaller than 4 cm, one of them having
coexisting AML and renal cell carcinoma. All patients underwent elective surgery,
with the exception of one, who required a semi-emergency operation. Nephron
sparing surgery using frozen section in 5 patients (all diagnostic) was carried
out on 16 patients, including all 5 patients with previous haemorrhage and 2
patients with suspected lesions from preoperative studies. Total nephrectomy was
performed in 7 patients, including the other 5 patients with lesions suspected to
be malignant. There was no operative mortality. Two complications were
encountered in the entire group. We conclude that elective nephron-sparing
surgery is feasible, even for massive angiomyolipoma or after previous rupture,
especially when the diagnosis is made by preoperative imaging and/or
intraoperative frozen section.
PMID- 10757268
TI - Long-term follow-up of stone formers treated with a low dose of sodium potassium
citrate.
AB - We evaluated the clinical efficacy of long-term preventive treatment with a
single evening dose of alkaline citrate. Information was collected from the files
of 52 recurrent stone formers prescribed a daily intake of 3.75-5 g of sodium
potassium citrate (SPC; 14-18 mmol of citrate). The annual and cumulative rates
of stone formation and the rate of recurrence were compared before and during the
treatment. A comparison was also made between the patients with (Group R) and
without (Group NR) recurrent stone formation during treatment in terms of urine
composition and previous history of the disease. For all patients who started the
treatment, the number of stones was smaller during treatment (period tT) than
during a period of the same length immediately before treatment (period tB), but
greater than the number formed during a corresponding period immediately after
the diagnosis (period tA). Via questionnaire we found low treatment compliance,
with only 62% of the patients reporting consistent taking of their medication
(Group T). The patients in Group T had a smaller cumulated number of stones
during period tT than that during periods tA and tB, but the Kaplan-Meier curve
of the fraction of patients remaining stone-free during treatment was almost
identical to that recorded in 446 recurrent stone formers without medical
treatment. No significant differences were recorded in terms of relevant
pretreatment urinary risk factors between Groups T(R) and T(NR), but numerically
higher values of calcium oxalate (CaOx) supersaturation and calcium/citrate
quotients were observed in Group T(R). When 9 patients with a daily intake of SPC
and a citrate excretion below 2.5 mmol/day were compared with 16 hypocitraturic
patients only given drinking advice, the cumulated percentages of patients
without recurrent stone formation in the 2 groups after 3 years were 44% and 48%,
respectively. Although the number of patients in this study was small, our
results indicate poor long-term protection from recurrent calcium stone formation
when a single evening dose of only 3.75-5 g of SPC was taken. The rate of stone
formation was apparently slightly reduced, but the fraction of patients free of
recurrence was no different from that in patients without medical treatment.
PMID- 10757269
TI - Denervation of periurethral prostatic tissue by transurethral microwave
thermotherapy.
AB - PURPOSE: To determine whether transurethral microwave thermotherapy (TUMT)
affects innervation of the urethra and periurethral prostate. MATERIAL AND
METHODS: Ten patients with troublesome benign prostatic hyperplasia (BPH) were
treated with TUMT 1 week prior to transurethral resection of the prostate (TURP).
At surgery, a biopsy was taken for histological examination and for
immunohistochemical staining of the non-specific neuromarker protein gene product
(PGP) 9.5. Control material consisted of identical biopsies from 10 patients
undergoing TURP because of BPH, but not subjected to TUMT prior to surgery.
RESULTS: Histological examination revealed well-preserved, non-necrotic tissues
in all biopsies. Nerve fibres were completely or almost absent in the smooth
muscle layer in all but one of the TUMT cases, whereas all non-TUMT patients
exhibited large numbers of nerve fibres in the smooth muscle layer. CONCLUSIONS:
TUMT does affect innervation of the urethra and periurethral prostatic tissue.
PMID- 10757270
TI - Association of dietary elements and lower urinary tract symptoms.
AB - OBJECTIVE: The purpose of the study was to establish whether dietary elements are
related to lower urinary tract symptoms (LUTS) and thus to diseases causing LUTS.
MATERIALS AND METHODS: This population-based study was carried out in 1994; a
questionnaire was mailed to all men born in 1924, 1934 or 1944 living in Tampere
or 11 rural or semi-rural municipalities in the same county, altogether 3143 men.
Of this population, 68% were ultimately included in the study. A modified version
of the DAN-PSS-1 questionnaire (10 of the questions) was used to assess urinary
symptoms and problems arising from them. A symptom index was formed by
multiplying the symptom and problem scores for hesitancy, incomplete emptying,
urge, urge incontinence, nocturia and daytime frequency, and totalling the
products. The men were also asked to report on their medical history, how often
they ate vegetables and meat, whether they used butter, margarine or vegetable
oil in food, how much alcohol and coffee they consumed, their smoking history and
their weight and height. The risk of LUTS was estimated according to the
frequency of meat and vegetable intake and the kind of fat used. RESULTS: The
confounder-adjusted risk of LUTS was 0.68 (95% CI 0.54-0.86) among men consuming
vegetables daily compared with men consuming vegetables less frequently. Compared
with men who eat meat less frequently, the confounder-adjusted risk of LUTS was
2.08 (95% CI 1.00-4.10) among men consuming meat weekly, and 2.56 (95% CI 1.30
5.02) among men consuming meat daily. The confounder-adjusted risk of LUTS was
0.73 (95% CI 0.58-0.93) among men who consumed butter compared to those who did
not. CONCLUSIONS: Dietary elements may also have an important role in the
development of diseases causing LUTS. Direct effects of food components may
likewise influence the occurrence of LUTS.
PMID- 10757271
TI - Indication of cystoscopy in patients with asymptomatic microscopic haematuria.
AB - To establish the appropriate indication of cystoscopy in patients with
asymptomatic microscopic haematuria, we reviewed 263 cases with positive reaction
for urinary dipstick test on annual health screening examination. On initial
examination, 18 highly significant lesions, 52 moderately significant lesions and
38 insignificant lesions were detected. No underlying lesion could be found in 96
patients and no microscopic haematuria in 59 patients. However, bladder cancers
were detected in only 8 (3.0%) cases. All patients with bladder cancer were older
than 40 years. These facts suggest that cystoscopy is not necessary for patients
with a single microscopic haematuria and those younger than 40 years.
PMID- 10757272
TI - Follow-up of prostate cancer patients by on-demand contacts with a specialist
nurse: a randomized study.
AB - OBJECTIVE: The effectiveness of traditional follow-up programs and the intensive
search for disease progression in men with prostate cancer have been questioned.
The aims of this randomized multi-centre study were to evaluate medical safety,
patient satisfaction and resource utilization in an on-demand follow-up by a
specialist nurse compared with traditional follow-up by a urologist. MATERIAL AND
METHODS: Four hundred consecutively approached men with newly diagnosed or
previously known prostate cancer in any stage at three hospitals in Sweden were
randomized to follow-up in the nurse group (NG, 200 patients) or the urologist
group (UG, 200 patients). In the NG, the nurse contacted the patient by phone
every 6 months unless the patient himself initiated the contact. Patient
satisfaction was evaluated twice a year via questionnaire. The questionnaire
included the validated Hospital Anxiety and Depression Scale (HADS). The costs of
all medical interventions and adverse events related to prostate cancer were
calculated for all patients. RESULTS: Medical safety, measured as complication
frequency and lag time from symptoms to intervention, during the first 3 years of
the observation period, was similar in the NG and the UG. The total number of
interventions due to symptoms from prostate cancer was also similar in both
groups. The analysis of accessibility and the HAD scale showed no significant
differences between the groups. The mean outpatient cost (excluding
pharmaceutical costs) per patient was lower in the NG compared to the UG,
especially among patients without metastases at inclusion (37% lower cost).
CONCLUSIONS: Our study indicates that men with prostate cancer can be safely
followed up by a specialist nurse. The study results show that this alternative
follow-up is cost-effective, especially in men without metastases.
PMID- 10757273
TI - Effect of vitamins on the lipid profile of patients on regular hemodialysis.
AB - OBJECTIVE: The aim of this study was to investigate the lipid-lowering effect of
vitamins compared to placebo and their short-term supplementation safety in
patients on hemodialysis. MATERIAL AND METHODS: Eighty-four hemodialysis patients
were randomly allocated to four therapeutic groups. Each group (n = 21) received
one of the following treatments: vitamin C (200 mg), E (200 mg), D3 (50,000 IU)
or placebo daily. Serum triglyceride, total cholesterol, low-density lipoprotein
cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) were
measured before and following 3 months of vitamin therapy. RESULTS: LDL-c and
total cholesterol levels as well as the ratios of LDL-c to HDL-c and cholesterol
to HDL-c significantly decreased after vitamin C therapy. Triglyceride and the
ratio of triglyceride to HDL-c significantly decreased following vitamin D3
therapy. HDL-c increased and the ratio of LDL-c to HDL-c decreased significantly
after vitamin E therapy. No major side-effects were encountered during the 3
months' trial. CONCLUSIONS: Short-term supplementary vitamins are safe and
beneficial for treatment of lipid abnormalities in hemodialysis patients.
PMID- 10757274
TI - Xanthomonas maltophilia infection in chronic peritoneal dialysis patients.
AB - Xanthomonas maltophilia infection has only been occasionally reported in patients
receiving chronic peritoneal dialysis. We describe four cases of Xanthomonas
maltophilia infection associated with chronic peritoneal dialysis. Two patients
presented with peritonitis and two with exit site infection. All patients were
diabetics, who immediately prior to the study had not received antibiotic
therapy. Failure to respond to multiple antibiotic therapy resulted in catheter
removal in both patients with peritonitis. In those patients with only exit site
infections, dialysis could be continued following antibiotic therapy and catheter
replacement in one. Catheter loss in our patients was directly attributed to
peritonitis with Xanthomonas maltophilia infection.
PMID- 10757275
TI - Paratesticular tumour: a metastasis from primary pancreas cancer.
AB - This is a report of a rare case of metastatic paratesticular tumour from primary
pancreas cancer, the second reported case in the literature. Metastatic
paratesticular tumour can present clinically as a testicular tumour.
PMID- 10757276
TI - Inflammatory pseudotumour of the bladder: a case report.
PMID- 10757277
TI - Plasmacytoma of the urethra treated by excisional biopsy.
AB - Plasmacytoma is an unusual disease of plasma cells, its presentation in the
urethra is rare. We report the sixth known case of primary urethral plasmacytoma,
which was treated by surgical excision, without recurrence for 3 years of follow
up.
PMID- 10757278
TI - Marsupialization for bilateral pararenal lymphatic cysts.
AB - A case of bilateral pararenal lymphatic cysts associated with hypertension is
described. The cysts surrounded the renal parenchyma and were located underneath
the renal capsule. No vascular pathology explaining the cause of hypertension was
diagnosed by radiological techniques. Hypertension improved following bilateral
marsupialization.
PMID- 10757279
TI - Hypertension and pseudoaneurism on the renal artery following retrograde
endopyelotomy (Acucise).
AB - Acucise endopyelotomy has gained widespread use in the treatment of ureteropelvic
junction obstruction. Acute postoperative bleeding is a well-known complication.
We report one case with a delayed postoperative formation of pseudoaneurism, and
one case which developed arterial hypertension postoperatively.
PMID- 10757280
TI - Development of a simple in-vial liquid-phase microextraction device for drug
analysis compatible with capillary gas chromatography, capillary electrophoresis
and high-performance liquid chromatography.
AB - A simple, inexpensive and disposable device for liquid-phase microextraction
(LPME) is presented for use in combination with capillary gas chromatography
(GC), capillary electrophoresis (CE) and high-performance liquid chromatography
(HPLC). 1-4 ml samples of human urine or plasma were filled into conventional 4
ml vials, whereafter 15-25 microl of the extraction medium (acceptor solution)
was filled into a short piece of a porous hollow fiber and placed into the sample
vial. The drugs of interest were extracted from the sample solutions and into the
small volumes of acceptor solution based on high partition coefficients and were
preconcentrated by a factor of 30-125. For LPME in combination with GC, the
porous hollow fiber was filled with 15 microl n-octanol as the acceptor solution.
Following 30 min of extraction, the organic acceptor solution was injected
directly into the GC system. For LPME in combination with CE and HPLC, n-octanol
was immobilized within the pores of the hollow fiber, while the internal volume
of the fiber was filled with either 25 microl of 0.1 M HCl (for extraction of
basic compounds) or 25 microl 0.02 M NaOH (for acidic compounds). Following 45
min extraction, the aqueous acceptor solution was injected directly into the CE
or HPLC system. Owing to the low cost, the extraction devices were disposed after
a single extraction which eliminated the possibility of carry over effects. In
addition, because no expensive instrumentation was required for LPME, 10-30
samples were extracted in parallel to provide a high number of samples per unit
time capacity.
PMID- 10757281
TI - Development of membrane extraction with a sorbent interface-micro gas
chromatography system for field analysis.
AB - The commercially available portable gas chromatographs have a rather limited
scope of applications, typically allowing analysis of gaseous samples only, and
having relatively poor sensitivity. Combination of those instruments with modern
sampling/sample preparation techniques can remedy these problems. A Chrompack
micro-GC system equipped with a thermal conductivity detector has been coupled to
membrane extraction with a sorbent interface (MESI). The sorbent trap has
replaced the GC injector. The design of the trap was also modified in order to
enhance the preconcentration of analytes. The use of a thin flat sheet membrane
reduces the response time, and decreases the memory effect of the system. Rapid
separation times were achieved, and the sensitivity was significantly improved.
MESI enables semi-continuous monitoring of both gaseous and aqueous samples,
owing to the selectivity of the membrane material. The system does not use moving
parts, therefore being reliable. The sensitivity of the micro-GC system was
increased by a factor of more than 100 by the addition of the MESI system, even
with a preconcentration time as short as 1 min. Chloroform, having a
concentration lower than 1 ppb, was detected in tap water. A cup system was used
to allow headspace sampling of volatile organic compounds from aqueous matrices,
keeping the membrane away from interfering species that could be present in
water, and improving the mass transfer. A linear calibration line was obtained,
and the estimated limit of detection was 60 ppt. This represents a great
improvement for the sensitivity of the micro-GC system.
PMID- 10757282
TI - Gas chromatographic-mass spectrometric analysis of acids and phenols in distilled
alcohol beverages. Application of anion-exchange disk extraction combined with in
vial elution and silylation.
AB - A GC-MS protocol for profiling spirits, based on 19 acids and phenolic compounds,
has been proposed and evaluated. The method combined a simple preconcentration
procedure based on solid-phase (anion-exchange) disk extraction, and in-vial
elution and silylation of the analytes. The derivatized extract was directly
injected into the GC-MS system. These analytes were: C6, C8, C10, C12 acids,
pyruvic acid, 2-furoic acid, succinic acid, fumaric acid, glutaric acid, lactic
acid, glycolic acid, malic acid, tartaric acid, citric acid, vanillin,
syringaldehyde, coniferaldehyde, vanillic acid and gallic acid. The profiles of
six different spirits were found reproducible from day-to-day with <20% RSD for
measurements of most of the analytes at different concentrations. Recoveries of
individual analytes appear to be affected by the level of tannins in the spirits,
and they varied from sample to sample. The method of standard addition was used
to quantify age-related analytes. Good linearity of response with correlation
coefficients in the range of 0.992-0.999 was obtained. The results of the study
indicate that for spirits of the same brand but of different ages, the amounts of
these analytes appear to increase with the ageing period.
PMID- 10757283
TI - Kinetics of solid-phase extraction and solid-phase microextraction in thin
adsorbent layer with saturation sorption isotherm.
AB - The effects of sorbent saturation in thin adsorbent layers have been much
overlooked in earlier research and should be taken into account in both the
theory and practice of solid-phase extraction (SPE) and solid-phase
microextraction (SPME). The adsorption kinetics of a single analyte into a thin
adsorptive layer was modeled for several cases of agitation conditions in the
analyzed volume. The extraction process in the adsorbent layer was modeled using
a Langmuir isotherm approximated by the linear isotherm at low concentrations and
by a saturation plateau at concentrations exceeding the critical saturation
concentration. Laplace transformations were used to estimate the equilibration
time and adsorbed analyte concentration profile for no agitation, practical and
perfect agitation in the analyzed volume. The equilibration time may be
significantly reduced at high degrees of oversaturation and/or agitation in the
analyzed volume. The resulting models indicated that the adsorbent layer becomes
saturated at some critical value of the oversaturation degree parameter. The
critical value of the oversaturation parameter is affected by both the
concentration of the analyte in the analyzed volume and the sorbent
characteristics. It was also shown that the adsorption process is carried out via
the propagation of the saturation adsorption boundary toward the inner boundary
of the adsorbent layer. These new adsorption models should serve as "stepping
stones" for the development of competitive adsorption kinetic models for both SPE
and SPME, particularly in cases where fast sampling is used.
PMID- 10757284
TI - Application of solid-phase microextraction-gas chromatography-mass spectrometry
to characterize intermediates in a joint solar-microbial process for total
mineralization of Aroclor 1254.
AB - A combined solid-phase microextraction-GC-MS analytical technique was used to
monitor the formation of metabolites in the biodegradation of biphenyl, which
were originally obtained from the solar photodechlorination of Aroclor 1254 by
Pseudomonas pseudoalcaligenes KF707 and Burkholderia sp LB400. In both cases, the
following metabolites were detected: 2-hydroxybiphenyl (2-OH-BP), 2,3
dihydroxybiphenyl (2,3-di-OH-BP), and benzoic acid, which was detected as its
benzoate derivative 1-methylethylbenzoate. A time course study for the formation
and disappearance of these metabolites was used to construct a degradation
pathway, which in both cases, involved the formation of 2-OH-BP and 2,3-di-OH-BP.
PMID- 10757285
TI - Determination of butyltin species in water and sediment by solid-phase
microextraction-gas chromatography-flame ionization detection.
AB - A procedure for determination of tetraethyltin (TeET) and tetrabutyltin (TeBT) in
water by solid-phase microextraction (SPME) using the headspace approach has been
developed. The method has been adapted for the simultaneous determination of mono
, di- and tributyltin species (MBT, DBT and TBT) after derivatization with sodium
tetraethylborate in water and sediment samples. The analytical procedures were
optimized with respect to stirring conditions, extraction time and extraction
temperature. The pH and the amount of derivatizing reagent were also considered
in derivatization reaction procedures. The analysis was carried out using gas
chromatography equipped with flame ionization detection. The detection limits
obtained for TeET and TeBT, in equilibrium conditions (room temperature for TeET
and 40 degrees C for TeBT) were 28 and 20 ng/l (as Sn), respectively. The
detection limit for butyltin species in water, which was limited by signals which
are non-specific for the tin compounds and the sensitivity of the FID system, was
found ca. 1 microg/l (as Sn). The SPME method was validated for analysis of
sediments by analyzing the certified reference material PACS-2 finding a good
agreement with the certified values.
PMID- 10757286
TI - Use of solid-phase microextraction in the investigation of chemical communication
in social wasps.
AB - Solid-phase microextraction has been used to investigate chemical communication
in several social wasp species. Using the technique to analyse exocrine gland
secretions, we demonstrate that the results are comparable with those obtained
with the more classical methods that use solvents, eliminating, in many cases,
the shortcomings of these methods in insect pheromone analysis. As a result of
its simplicity this technique is very suitable for research on the chemical
ecology of social wasps, and on insect communication in general.
PMID- 10757287
TI - Analysis of volatile contaminants in vegetable oils by headspace solid-phase
microextraction with carboxen-based fibres.
AB - The headspace solid-phase microextraction (HS-SPME) efficiencies from vegetable
oil of the recently available Carboxen-poly(dimethylsiloxane) (PDMS) and
divinylbenzene-Carboxen-PDMS fibres were found to be much greater than those of
the PDMS fibre for a number of volatile contaminants. Using these Carboxen-based
fibres, the commonly used HS-SPME equilibration times for aqueous matrices of 30
45 min at room temperature for a number of halogenated and aromatic analytes with
volatilities ranging from 1,1-dichloroethylene to hexachlorobenzene were found to
be insufficient for the effective extraction of the less volatile analytes from
vegetable oil. HS-SPME at 100 degrees C for 45 min, followed by rapid cooling to
0 degrees C with a 10 min continuing extraction, however, significantly increased
the SPME efficiencies for the less volatile analytes. Spiking solutions were
prepared in vegetable oil instead of methanol as the latter was found to displace
analytes from the Carboxen material. Using either of the Carboxen-based fibres
and SPME at 100 degrees C, all the target analytes could be determined at low or
sub-microg kg(-1) with repeatability < or =10%, even though an equilibrium SPME
of the less volatile analytes was not achieved.
PMID- 10757288
TI - Solid-phase microextraction-gas chromatography-mass spectrometry of biologically
active substances in water samples.
AB - A solid-phase microextraction (SPME) method for determining trace amounts of
polar, biologically active substances in water systems was developed and compared
with solid-phase extraction followed by derivatization and GC-MS. SPME was
examined with respect to the simultaneous determination of pharmaceuticals such
as ibuprofen, paracetamol, phenazone, carbamazepine, and nonylphenols known to be
xenoestrogens. The extraction performance of different SPME fibre coatings was
studied. Coatings like polyacrylate and Carbowax-divinylbenzene proved to be the
best suited. The optimum extraction time was found to be 30 min and the detection
limits were between 0.2 and 50 microg/l. Low concentrations of accompanying
organic matter did not impair these limits. One of the main pharmaceutical
contaminants found in ground and river water around Leipzig (Germany) was
ibuprofen, with a concentration in the ng/l range. The enantioselective
metabolism of ibuprofen was investigated.
PMID- 10757289
TI - Development of a headspace solid-phase microextraction procedure for the
determination of free volatile fatty acids in waste waters.
AB - An analytical procedure based on headspace solid-phase microextraction (SPME)
coupled to GC-flame ionization detection/Negative Chemical Ionization Mass
Spectrometry has been developed for the determination of free volatile fatty
acids (C2-C7) in waste water samples. Five different coatings have been evaluated
and polydimethylsiloxane-Carboxen was the only fiber that allows a successful
extraction of the shortest chain fatty acids (acetic and propionic). Several
parameters such as extraction time and temperature, desorption conditions,
agitation speed and sample volume have been optimized using the
polydimethylsiloxane-Carboxen fiber. The linear dynamic range was over two-four
orders of magnitude, depending on the acid. Procedural detection limits were in
the low to medium microg/l levels and the RSDs were between 5.6% and 13.3%. To
evaluate the applicability of the developed SPME procedure on real samples,
fermented urban wastewaters were analysed.
PMID- 10757290
TI - Screening of Brazilian fruit aromas using solid-phase microextraction-gas
chromatography-mass spectrometry.
AB - Manual headspace solid-phase microextraction (SPME) coupled to gas chromatography
mass spectrometry (GC-MS) was used for the qualitative analysis of the aromas of
four native Brazilian fruits: cupuassu (Theobroma grandiflorum, Spreng.), caja
(Spondias lutea. L.), siriguela (Spondias purpurea, L.) and graviola (Anona
reticulata, L). Industrialized pulps of these fruits were used as samples, and
extractions with SPME fibers coated with polydimethylsiloxane, polyacrylate,
Carbowax and Carboxen were carried out. The analytes identified included several
alcohols, esters, carbonyl compounds and terpernoids. The highest amounts
extracted, evaluated from the sum of peak areas, were achieved using the Carboxen
fiber.
PMID- 10757291
TI - Speciation of dimethylarsinic acid and monomethylarsonic acid by solid-phase
microextraction-gas chromatography-ion trap mass spectrometry.
AB - A solid-phase microextraction (SPME) method has been developed to determine two
methylated arsenic species in human urine samples by GC-MS. The direct extraction
of the methyl arsenic compounds by SPME after thioglycol methylate derivatization
was studied. Direct extraction with SPME was suitable for the determination of
trace levels of dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) in
urine samples. Four different commercial SPME fibers were tested for the
extraction of methyl arsenic compounds, and the best results were obtained using
the polydimethylsiloxane coating. The extraction and desorption time profiles of
DMA and MMA were determined. The detection limits for DMA and MMA using the SPME
GC-MS method were 0.12 and 0.29 ng/ml, respectively. The method is linear in the
1 to 200 ng/ml range.
PMID- 10757292
TI - Automated in-tube solid-phase microextraction-high-performance liquid
chromatography for carbamate pesticide analysis.
AB - In-tube solid-phase microextraction (SPME) is an automated version of SPME that
can be easily coupled to a conventional HPLC autosampler for on-line sample
preparation, separation and quantitation. It has been termed "in-tube" SPME
because the extraction phase is coated inside a section of fused-silica tubing
rather than coated on the surface of a fused-silica rod as in the conventional
syringe-like SPME device. The new in-tube SPME technique has been demonstrated as
a very efficient extraction method for the analysis of polar and thermally labile
analytes. The in-tube SPME-HPLC method used with the FAMOS autosampler from LC
Packings was developed for detecting polar carbamate pesticides in clean water
samples. The main parameters relating to the extraction and desorption processes
of in-tube SPME (selection of coatings, aspirate/dispense steps, selection of the
desorption solvents, and the efficiency of desorption solvent, etc.) were
investigated. The method was evaluated according to the reproducibility, linear
range and limit of detection. This method is simple, effective, reproducible and
sensitive. The relative standard deviation for all the carbamates investigated
was between 1.7 and 5.3%. The method showed good linearity between 5 and 10000
microg/l with correlation coefficients between 0.9824 and 0.9995. For the
carbamates studied, the limits of detection observed are lower than or similar to
that of US Environmental Protection Agency or National Pesticide Survey methods.
Detection of carbaryl present in clean water samples at 1 microg/l is possible.
PMID- 10757293
TI - Novel simulated moving-bed method for reduced solvent consumption.
AB - Simulated moving-bed (SMB) chromatography is attractive for reducing sorbent and
solvent consumption relative to fixed-bed systems. In this contribution, we
describe a novel and versatile method for further reducing solvent consumption in
the case of reversed-phase chromatography. The method is based on the variation
of the distribution coefficients of solutes to be separated upon varying the
composition of a multi-component mobile phase. If the solvent strength of the
desorbent is set higher than the solvent strength of the feed, the components
will have smaller distribution coefficients in the extraction section of the SMB
and hence will be more easily eluted. This will result in a lower desorbent flow
and possibly also in a shorter desorbent zone, and, ultimately, in more
concentrated products. The so-called "Triangle-method" by Storti et al. [AIChE
J., 39 (1993) 471] to obtain the region of complete separation, is extended for
this novel SMB method. Theoretical evaluation of the proposed methodology
supports the anticipated solvent reduction relative to fixed-bed RP-HPLC for the
cases of the purification of the polyketide antibiotic nystatin and the
separation of bovine insulin from porcine insulin.
PMID- 10757294
TI - Comparison of the repeatability of quantitative data measured in high-performance
liquid chromatography with UV and atmospheric pressure chemical ionization mass
spectrometric detection.
AB - A detailed comparison of the repeatability of the retention times, the peak
efficiencies and the peak areas of a dozen probe compounds achieved in HPLC,
using either HPLC-UV or HPLC-MS for detection purpose, is reported. Three groups
of conventional analytes, each one separated under a different set of
experimental conditions, were selected for this study. Most of the compounds are
basic, the other ones being neutral. The repeatabilities of the retention times
do not exhibit any influence of the mode of detection. However, the
repeatabilities of the peak areas and the column efficiencies are generally
(although not always) better in HPLC-UV than that in HPLC-MS. On average, the
precision for the UV peak area detection was 2.5% versus 6.8% for MS detection.
Experimental results show that the response factor of the UV detector is more
constant than that of the MS detector, probably because the HPLC flow-rate was
sufficiently stable. The results obtained in the different tests are discussed.
PMID- 10757295
TI - On-line coupling of subcritical water extraction with high-performance liquid
chromatography via solid-phase trapping.
AB - Although ambient water is very polar and cannot dissolve many organic species,
water at elevated temperatures behaves like a polar organic solvent. Thus,
subcritical water has been proven to be an effective extraction fluid for several
classes of organic compounds. While solvent trapping was used to collect the
extracted analytes in most of previous subcritical water extractions, sorbent
trapping has also been developed for subcritical water extraction. In this study,
an on-line system for subcritical water extraction and high-performance liquid
chromatography (HPLC) was built and tested. A sorbent trap was used as the
interface between subcritical water extraction and HPLC. Several shut-off valves
have been utilized to switch the system from one mode to another (e.g., from the
extraction mode to HPLC mode). The coupling technique of subcritical water
extraction and HPLC eliminates the liquid-liquid extraction used in solvent
trapping subcritical water extraction and provides higher sensitivity. Compared
to the off-line system reported in an earlier work, the operation of this on-line
system is even easier. Some peak broadening occurred after the coupling the water
extraction with HPLC for the analytes studied. The performance of this on-line
system was evaluated by the extraction and determination of caffeine,
nitrotoluenes, polychlorinated biphenyls, chlorophenols and anilines.
PMID- 10757296
TI - Kinetics of appearance of hemorphins from bovine hemoglobin peptic hydrolysates
by a direct coupling of reversed-phase high-performance liquid chromatography and
electrospray ionization mass spectrometry.
AB - Reversed-phase high-performance liquid chromatography coupled with electrospray
ionization mass spectrometry was used to improve the preparation of three opioid
peptides (Leu-Val-Val-hemorphin-7, Val-Val-hemorphin-7 and Val-Val-hemorphin-4)
resulting from bovine hemoglobin peptic hydrolysates. Optimal conditions for the
preparation of these peptides were determined thanks to their kinetic studies of
appearance in the course of peptic hydrolyses as a function of degree of
hydrolysis of hemoglobin. We propose a low degree of hydrolysis (3%) to prepare
Leu-Val-Val-hemorphin-7, a mean degree of hydrolysis (11%) to prepare Val-Val
hemorphin-7 and a high degree of hydrolysis (21%) to prepare Val-Val-hemorphin-4.
PMID- 10757297
TI - The influence of cell adsorbent interactions on protein adsorption in expanded
beds.
AB - Expanded bed adsorption (EBA) is a primary recovery operation allowing the
adsorption of proteins directly from unclarified feedstock, e.g. culture
suspensions, homogenates or crude extracts. Thus solid-liquid separation is
combined with adsorptive purification in a single step. The concept of
integration requires that the solid components of the feed solution are regarded
as a part of the process, which influences stability, reproducibility, and
overall performance. This aspect is investigated here at the example of the
influence of presence and concentration of intact yeast cells (S. cerevisiae) on
the adsorption of model proteins (hen egg white lysozyme and bovine serum
albumin) to various stationary phases (cation and anion-exchange, hydrophobic
interaction, immobilised metal affinity). The interaction of the cells with the
adsorbents is determined qualitatively and quantitatively by a pulse response
method as well as by a finite bath technique under different operating
conditions. The consequence of these interactions for the stability of expanded
beds in suspensions of varying cell concentration is measured by residence time
distributions (RTDs) after tracer pulse injection (NaBr, LiCl). Analysis of the
measured RTD by the PDE model allows the calculation of the fraction of perfectly
fluidised bed (phi), a parameter which may be regarded as a critical quantity for
the estimation of the quality of fluidisation of adsorbents in cell containing
suspensions. The correlation between bed stability and performance is made by
analysing the breakthrough of model proteins during adsorption from unclarified
yeast culture broth. A clear relationship is found between the degree of
cell/adsorbent interaction, bed stability in terms of the phi parameter, and the
sorption efficiency. Only beds characterised by a phi value larger than 0.8 in
the presence of cells will show a conserved performance compared to adsorption
from cell free solutions. A drop in phi, which is due to interactions of the
fluidised adsorbent particles with cells from the feed, will directly result in a
reduced breakthrough efficiency. The data presented highlight the importance of
including the potential interaction of solid feedstock components and the
expanded adsorbents into the design of EBA processes, as the interrelation found
here is a key factor for the overall performance of EBA as a truly integrated
operation.
PMID- 10757298
TI - Interpreting the gas chromatographic retention of n-alkanes.
AB - Non-linear regressions were applied to n-alkanes retention data for the
determination of gas hold-up in a preceding paper. It was found that at
temperatures over 100 degrees C the reduced partial molar free energy of
solution, deltaG/RT, tends to be negligible for the solute methane in
poly(dimethylsiloxane) stationary phases. A consequence of interest can be
inferred from this fact. The C-H bonds from terminal methyl groups of n-alkane
solute molecules should not contribute significantly to deltaG/RT in these
conditions. The analysis of data confirms that, within the chromatographic
experimental error, the contributions of n-alkane end C-H bonds are also
negligible in this temperature range. Consequently, the regression parameter that
contains the phase ratio of the column only includes the gas hold-up as the
accompanying factor.
PMID- 10757299
TI - Simultaneous determination of seven major isosteroidal alkaloids in bulbs of
Fritillaria by gas chromatography.
AB - The present paper describes the development of a most simple, sensitive, and
specific gas chromatographic method to date, for the direct determination of
seven major bioactive isosteroidal alkaloids, namely ebeiedine, ebeiedinone,
ebeienine, hupehenine, isoverticine, verticine, verticinone and imperialine, in
Fritillaria species, a commonly used antitussive traditional Chinese medicinal
(TCM) herb. In the present study, a commercially available Supelco SAC-5
capillary column (30 m x 0.25 mm, 0.25 microm) specifically designed for the
analysis of steroids was utilized for the direct determination of Fritillaria
alkaloids. Calibration curves were obtained by spiking authentic compounds and
the internal standard (solanidine) into herbal samples prior to extraction.
Extraction was conducted simply by shaking the pre-alkalized diethyl ether
solution (5.0 ml) containing dried herb (0.1 g) for 2 h. All calibration curves
showed good linear regressions (r2>0.995) within test ranges. The assay was
reproducible and accurate with the overall intra- and inter-day variation and
accuracy of less than 10% and more than 90%, respectively. The developed GC
method was successfully utilized to analyze seven major bioactive alkaloids in
seven Fritillaria species, and the results demonstrate that this direct GC
analytical method is suitable for the quality control of this commonly used
antitussive TCM herb.
PMID- 10757300
TI - Gas chromatographic analysis of trace impurities in chlorine trifluoride.
AB - The gas chromatographic determination of trace gaseous impurities in highly
reactive fluorinated gaseous matrices presents unique requirements to both
equipment and techniques. Especially problematic are the gases normally present
in ambient air namely oxygen and nitrogen. Analysing these gases at the low
microl/l (ppm) level requires special equipment and this publication describes a
custom-designed system utilising backflush column switching to protect the
columns and detectors. A thermal conductivity detector with nickel filaments was
used to determine ppm levels of impurities in ClF3.
PMID- 10757301
TI - Characterization of partition and thermodynamic properties of cephalosporins
using micellar electrokinetic chromatography in glycodeoxycholic acid solution.
AB - Micellar electrokinetic chromatography (MEKC) was introduced to evaluate the
hydrophobicity of cephalosporins (cefpim, cefpirom, cefazolin, ceftazidim,
cephradin, cefuroxim, cefotaxim, cephapirin and cephalothin). Partition
coefficients of cephalosporins were calculated between a micelle and an aqueous
phases from the measurement of the migration time, provided the critical micelle
concentration and the phase ratio are known. Thermodynamic quantities such as
enthalpy and entropy changes of micellar solubilization were calculated from the
temperature dependence on the partition coefficients. Sodium glycodeoxycholate in
low-salt aqueous solutions was employed to prepare a micellar solution.
Substances for pharmaceutical purposes have to meet several requirements to be
well-tolerated. Therefore, they are often derived from naturally occurring ones,
e.g., from the bile salts in bile juice. The electrophoretic velocity of a
micelle and the phase ratio between the micelle of the glycodeoxycholic acid and
the aqueous phase were calculated. Partial specific volumes at different
temperatures (from 20 to 45 degrees C) were measured using dynamic light
scattering. The logarithm of the partition coefficients and the migration factor
in the micellar system were correlated with the logarithm of the 1-octanol-water
partition coefficients.
PMID- 10757302
TI - Preparation of various silica-based columns for capillary electrochromatography
by in-column derivatization.
AB - Chemically bonded silica gels were prepared in a capillary by pumping an
ethanolic solution of a silylating reagent, such as octadecyltrimethoxysilane, 3
aminopropyltrimethoxysilane and dimethyloctadecyltrimethoxysilylpropylammonium
chloride into a heated capillary packed with bare silica particles. The
silylation reactions were completed in a short time and thus-prepared columns
showed high column efficiency and high reproducibility. Examples are shown for
the separation of 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatives of
aldopentoses on a 3-aminopropylated silica column and benzoate homologues as well
as PMP derivatives of the component monosaccharides of glycoproteins on an
octadecylammonium column. Since the presence of frit filters hampers high
efficiency separation, an attempt was made to fix the bed of modified silica gel
particles to the capillary inner wall by a cross-linking technique. The results
indicated that this technique is promising.
PMID- 10757303
TI - Novel approach to the analysis and use of fullerenes in capillary
electrophoresis.
AB - The analysis and use of fullerenes in capillary electrophoresis (CE) was
investigated. Sodium dodecyl sulfate (SDS) was used to solubilize fullerenes C60,
C70, and a mixture of C60 and C70 in water. The behavior of the solutions of the
C60- and C70-SDS complexes was examined by CE with on-line UV-Vis diode array
detection. This study included the use of a C60-SDS complex as a new method of
micellar electrokinetic chromatography (MEKC) for the separation of polycyclic
aromatic hydrocarbons (PAHs) using CE with uniwavelength detection. Since SDS
micelles act as a pseudostationary phase in which the PAH compounds partition
with their hydrophobic interior, the addition of C60 within the micelles enhanced
separation of the PAHs. The preliminary results using C60-MEKC with SDS were
compared to those obtained with MEKC with SDS. The capillary electrophoretic
separations were performed in 10 mM borate-phosphate buffer with 100 mM SDS at pH
9.5.
PMID- 10757304
TI - Analysis of glycosaminoglycan monosaccharides by capillary electrophoresis using
indirect laser-induced fluorescence detection.
AB - Two methods for monosaccharide analysis by capillary electrophoresis (CE) using
counterelectroosmotic and coelectroosmotic modes with indirect laser-induced
fluorescence detection were optimised and compared. A mixture of seven
glycosaminoglycan-derived hexoses was separated in alkaline fluorescein-based
electrolytes and detected in both counterelectroosmotic and coelectroosmotic
conditions. The fluorescein concentration and pH of the background electrolyte,
and the influence of the reversal of electroosmotic flow by addition of
hexadimethrine bromide on the separation were studied. Coelectroosmotic CE
conditions provided better resolution and limits of detection. A 10(-6) M
fluorescein solution at pH 12.25 containing 0.0005% (w/v) hexadimethrine bromide
was used as background electrolyte. Quality parameters such as run-to-run, day-to
day precision and limits of detection were calculated, and better figures of
merit were obtained for the coelectrooosmotic conditions than for the
counterelectroosmotic mode. The coelectroosmotic method was applied to the
quantitation of the hexosamine contents in glycosaminoglycans after acid
hydrolysis. The method proved to be suitable for the determination of dermatan
sulfate in heparin down to 2% (w/w).
PMID- 10757305
TI - Isolation of pure (2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine from Blighia
sapida (Akee).
AB - The isolation of (2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (CCG I, 2) from
Blighia sapida (Akee) was achieved through column chromatography on deactivated
silica gel followed by ion-exchange chromatography. A HPLC method has also been
devised in order to assess the purity of the isolated product.
PMID- 10757306
TI - Pressurised liquid extraction of pentachlorophenol from dyestuffs and cotton.
AB - Pressurised liquid extraction (PLE) was used to extract pentachlorophenol from
cotton and dyestuffs. Five dyes and one dyed cotton were investigated for
pentachlorophenol. The dyed cotton was found to have between 5.3 and 5.9 microg
g(-1) pentachlorophenol, while the dyes were found to have between 42 and 2569
microg g(-1) pentachlorophenol present. The latter were found to be dye and
manufacturing site dependant. Recovery experiments, in all cases, were found to
be quantitative indicating appropriate sample work-up and manipulations.
PMID- 10757307
TI - Pseudo-electrokinetic packing of high efficiency columns for capillary
electrochromatography.
AB - An improved and easy electrokinetic packing procedure is presented for the
production of stable capillary columns suitable for capillary
electrochromatography (CEC). In pseudo-electrokinetic packing a high electric
field is used in conjunction with a hydrodynamic flow. The packing of silica
based reversed-phase columns can be achieved with basic, commercially available
capillary electrophoresis (CE) equipment in approximately 15 min. The procedure
is robust and a high success rate is achieved. No steps which might damage the
stationary phase are involved and only a minimum amount of packing material is
required. Columns packed according to the developed procedure are operated at
high electric field strengths during the CEC separation, without the application
of a stabilising pressure. Columns are stable for at least hundred runs and were
tested using mixtures of polycyclic aromatic hydrocarbons and positively charged
drugs. Separations were performed in a relatively high conducting ammonium
acetate buffer, with efficiencies of up to 283000 plates/m.
PMID- 10757308
TI - The potential therapeutic gain of radiation-associated gene therapy with the
suicide gene cytosine deaminase.
AB - PURPOSE: To estimate the concentration of 5-fluorocytosine (5-FC), necessary for
conversion to 5-fluorouracil (5-FU) in tumours transduced with the gene cytosine
deaminase (CD), to achieve clinically significant radiosensitization to
radiotherapy. MATERIALS AND METHODS: Starting with a tumour control probability
(TCP) of 37% from radiotherapy of 66 Gy in 2 Gy fractions, estimates were made of
increase in TCP expected from sensitizer enhancement ratios (SER) of 1.1, 1.2,
etc. SER values for 5-FU were obtained from a literature review. Clinical
toxicity of 5-FC is also reviewed. RESULTS: 5-FU has been reported to be an
effective radiosensitizer if maintained for several days after each irradiation
at concentrations of 0.6-0.9 microg/ml in surrounding medium. 5-FC is well
tolerated by patients at concentrations of 25-100 microg/ml (average 60
microg/ml) for 6 weeks in standard antifungal treatment. Sufficient 5-FU should
be available if conversion efficiency from 5-FC is 1-3%. SER values of 1.1 to 1.2
should be achievable with daily 2 Gy fractions. In vitro and xenograft
experiments are reviewed and they do not contradict the conclusions. CONCLUSIONS:
Increases in tumour control of 20 to 40% can be expected, which should be
detectable in a 2-arm randomized trial of 260 (for 20%) or 60 (for 40%) patients.
PMID- 10757309
TI - Cell death and cell-cycle arrest induced by incorporation of [3H]thymidine into
human haemopoietic cell lines.
AB - PURPOSE: To investigate the influence of [methyl-3H]thymidine ([3H]Tdr)
incorporated into human haemopoietic cell lines. MATERIALS AND METHODS: HL-60,
Molt-4, Jurkat, Raji and SKW6-CL4 cells were incubated in the presence of
[3H]Tdr. Cell proliferation, cell viability, DNA fragmentation and expression of
caspase-3 and Bcl-2 families were examined. The cell-cycle of HL-60 was analysed
using flow cytometry. RESULTS: In HL-60, Molt-4 and Jurkat, cell death was
accompanied by DNA nucleosomal fragmentation and activation of caspase-3. In Raji
and SKW6-CL4, it was accompanied by neither. Protein levels of Bcl-2 and Bad in
HL-60 and Molt-4 did not significantly change, and that of Bax was decreased
after a 3-day incubation. HL-60 incubated in the presence of 74 or 185 kBq/ml
[3H]Tdr arrested at G2/M phase, and then underwent apoptosis. In 7.4 kBq/ml, the
cell-cycle progressed after the delay in S-phase. CONCLUSIONS: Two different
modes of cell death were observed when [3H]Tdr was incorporated into the human
haemopoietic cell lines. Incorporation into HL-60 cells resulted in delay of S
phase progression, arrest at G2/M and apoptosis.
PMID- 10757310
TI - Modification of survival by DNA repair modifiers: a probable explanation for the
phenomenon of increased radioresistance.
AB - PURPOSE: The low dose (<1 Gy) survival curve of mammalian cells is characterized
by a region of hypersensitivity (HRS) followed by increased resistance (IRR).
Above 1 Gy, the survival response can be described with a smooth downward-bending
curve. Indirect evidence has indicated that the IRR response might reflect an
induced radioresistance triggered by DNA damage. The work reported here provides
experimental evidence that consolidates this hypothesis. MATERIALS AND METHODS:
Clonogenic survival of V79-379A cells was measured using automated microscopy
(DMIPS cell analyser) in the presence or absence of three known modifiers of DNA
repair processes over the X-ray dose range 0-1 Gy. RESULTS: 3-Aminobenzamide (5
microM), a potent inhibitor of poly(ADP ribose)-polymerase, inhibited the
development of increased radioresistance as indicated by a statistically
significant reduction in an RBE from 3.537 (+/-SEM (0.139)) to 2.168 (+/-0.191)
at an X-ray dose of 1 Gy, implying an involvement of DNA repair pathways that
require poly(ADP ribose)-polymerase in the IRR response. In contrast, novobiocin
(350 microM), an inhibitor of topoisomerase II, did not inhibit the development
of increased radioresistance (RBE 3.650 (+/-0.192) to 3.322+/-(0.156)) but
eliminated low-dose hypersensitivity as measured by an increase in RBE from 2.508
(+/-0.536) to 1.135 (+/-0.057) at 0.04 Gy. Ara-A (120 microM), an inhibitor of
DNA polymerase, sensitized cells at all doses. CONCLUSION: These data support the
hypothesis that DNA repair processes are likely to be involved in the development
of increased radioresistance and provide further evidence against a sensitive
subpopulation explanation for the biphasic low-dose survival response.
PMID- 10757311
TI - Hyperthermia does not affect rejoining of DNA double-strand breaks in a cell-free
assay.
AB - PURPOSE: Heat radiosensitization is poorly understood but is believed to be
caused by an inhibition in the repair of radiation-induced DNA lesions. This
inhibition in DNA repair may be caused either by direct heat inactivation of
repair enzymes, or by heat-induced protein denaturation that leads to their
precipitation onto nuclear chromatin structures, generating a barrier that
prevents repair enzymes from reaching the damage sites. MATERIAL AND METHODS: A
previously described (Ganguly and Iliakis, Int J Radiat Biol 1995, 68, 447-457)
cell-free assay was introduced to evaluate rejoining of radiation-induced DNA
double-strand breaks (dsb) in heated (45.5 degrees C, 20 min) nuclei prepared
from A549 cells, in reactions assembled with extracts of non-heated and non
irradiated HeLa cells. The assay allowed the functional evaluation of the effect
of precipitated nuclear protein on dsb rejoining. By combining heated nuclei with
extracts of non-heated cells the assay avoided complications that would otherwise
arise when intact cells are studied, where both nuclear structures and repair
factors are heated and therefore potentially altered. RESULTS: It was observed
that exposure of A549 cells to 45.5 degrees C for 20 min caused a 50% increase in
the relative protein content of isolated nuclei but had no effect on the in vitro
rejoining of dsb. In agreement with earlier reports, a greatly reduced rate of
dsb rejoining was observed either in intact A549 or HeLa cells after exposure to
heat. CONCLUSIONS: The results indicate that an increased retention of proteins
in heated nuclei is not necessarily associated with an inhibition of dsb
rejoining. While the in vitro system may only reproduce certain aspects of the in
vivo conditions, the results suggest that protein accretion as a mechanism of
heat radiosensitization requires further testing using functional assays.
PMID- 10757312
TI - Oncogenic transformation in C3H10T1/2 cells by low-energy neutrons.
AB - PURPOSE: Occupational exposure to neutrons typically includes significant doses
of low-energy neutrons, with energies below 100 keV. In addition, the normal
tissue dose from boron neutron capture therapy will largely be from low-energy
neutrons. Microdosimetric theory predicts decreasing biological effectiveness for
neutrons with energies below about 350 keV compared with that for higher-energy
neutrons; based on such considerations, and limited biological data, the current
radiation weighting factor (quality factor) for neutrons with energies from 10
keV to 100 keV is less than that for higher-energy neutrons. By contrast, some
reports have suggested that the biological effectiveness of low-energy neutrons
is similar to that of fast neutrons. The purpose of the current work is to assess
the relative biological effectiveness of low-energy neutrons for an endpoint of
relevance to carcinogenesis: in vitro oncogenic transformation. METHODS:
Oncogenic transformation induction frequencies were determined for C3H10T1/2
cells exposed to two low-energy neutron beams, respectively, with dose-averaged
energies of 40 and 70 keV, and the results were compared with those for higher
energy neutrons and X-rays. RESULTS: These results for oncogenic transformation
provide evidence for a significant decrease in biological effectiveness for 40
keV neutrons compared with 350 keV neutrons. The 70 keV neutrons were
intermediate in effectiveness between the 70 and 350 keV beams. CONCLUSIONS: A
decrease in biological effectiveness for low-energy neutrons is in agreement with
most (but not all) earlier biological studies, as well as microdosimetric
considerations. The results for oncogenic transformation were consistent with the
currently recommended decreased values for low-energy neutron radiation weighting
factors compared with fast neutrons.
PMID- 10757313
TI - WAF1 accumulation by carbon-ion beam and alpha-particle irradiation in human
glioblastoma cultured cells.
AB - PURPOSE: There have been no reports about the effects of heavy-ion beams on the
expression of the WAF1 gene, although ionizing radiation such as y-rays and X
rays is well known to induce WAF1 (p21/CIP1/sdi1) gene expression in a p53
dependent manner. In the present study, it was examined whether WAF1 accumulation
was induced after carbon-ion (C-) beam or alpha-particle irradiation in four
glioblastoma cell lines. MATERIALS AND METHODS: A colony assay for
radiosensitivity and Western blot analysis of WAF1 were applied to two human
glioblastoma cell lines, A-172 bearing wild-type p53 (wtp53) and T98G bearing
mutated p53 (mp53). A-172/neo and A-172/mp53 were transfected with a control
vector (containing only a neo selection marker) and a mp53 expression vector
respectively. RESULTS: The amount of WAF1 increased markedly after X-ray
irradiation in A-172 and A-172/neo cells but not in T98G and A-172/mp53 cells.
The level of WAF1 reached a plateau at 3-10 h after X-ray irradiation at 5 Gy in
A-172 and A-172/neo cells. Likewise, the levels of WAF1 in A-172 and A-172/neo
cells reached a plateau at 3-10 h and 6-24 h after C-beam (3.0 Gy) and alpha
particle (4.5 Gy) irradiation respectively. The amount of WAF1 increased markedly
in a dose-dependent manner 10 h after X-ray, C-beam or alpha-particle irradiation
in A-172 and A-172/neo cells but not in T98G or A-172/mp53 cells. In addition,
cell survival assay showed that these cell lines were most sensitive to C-beams,
less sensitive to alpha-particles and least sensitive to X-rays at 10% survival.
There was no difference in sensitivity among these cell lines against C-beam and
alpha-particle irradiation whereas wtp53 cells (A-172 and A-172/neo) were more
sensitive to X-rays than mp53 cells (A-172/mp53 and T98G). CONCLUSIONS: These
results indicate that C-beams and alpha-particles induce p53-dependent WAF1
accumulation as well as is the case with X-rays, suggesting that WAF1 protein
accumulation may not contribute to cell killing.
PMID- 10757314
TI - DNA as an important target in radiation-induced apoptosis of MYC and MYC plus RAS
transfected rat embryo fibroblasts.
AB - PURPOSE: This study uses a radiation chemistry approach to determine if DNA is an
important target for radiation-induced apoptosis of myc (MR4) and myc plus ras
(3.7) transfected rat embryo fibroblast cell lines. MATERIALS AND METHODS: The
radiation protection efficiency of four thiols was compared with net molecular
charge ranging from -1 to +2: mercaptopropionic acid (Z= -1), mercaptoethanol
(Z=0), cysteamine (Z= +1), N(2-mercaptoethyl)-1,3-diaminopropane (Z= +2).
Protection factors were determined for these thiols against radiation-induced
apoptosis (Apoalert assay), mitotic cell death (clonogenic assay) and double
strand break (dsb) induction (pulse field gel electrophoresis) in MR4 and 3.7
cells. Theoretical protection factors for these thiols against dsb induction were
also calculated from second-order chemical repair constants for single-strand
breaks (ssb) and the concentration of added thiols in MR4 and 3.7 cell lines.
RESULTS: The charge-dependent increases observed for measured protection factors
against radiation-induced apoptosis did not differ significantly between the two
cell lines, nor did they differ significantly from the corresponding increases
observed for radiation-induced mitotic cell killing and for induction of dsb. The
calculated protection factor for dsb also showed a thiol charge-dependent
increase similar to the measured protection factors for all of the other
parameters studied. CONCLUSIONS: These results are consistent with the hypothesis
that DNA is an important target for radiation-induced apoptosis.
PMID- 10757315
TI - Chromosome analysis of workers occupationally exposed to radiation at the
Sellafield nuclear facility.
AB - PURPOSE: To investigate the relationship between stable chromosome aberration
frequency in peripheral blood lymphocytes and occupational cumulative radiation
exposure. MATERIALS AND METHODS: Cytogenetic analysis using G-banding was
performed on peripheral blood lymphocyte cultures from 104 workers from the
British Nuclear Fuels PLC facility at Sellafield, UK. The study group comprised
61 men with lifetime cumulative doses > 500 mSv, 39 men with minimal exposure
(i.e. < 50 mSv) who formed a control group and 4 men with intermediate doses.
RESULTS: The slope of the dose-response, adjusted for smoking status, for
translocations and insertions was 0.55+/-0.31 x 10(-2)/cell/Sv. Consideration of
chromosome breakpoints for all aberrations combined in the radiation workers
revealed an excess in the C group chromosomes and a deficit in the F group
chromosomes with breakpoints being concentrated in the terminal regions whereas
the distribution in the control group did not deviate from expectation.
CONCLUSIONS: The dose-response was not significantly different from the parallel
FISH analysis (Tucker et al. 1997) and confirms that chronic radiation exposure
appears to be substantially less effective at inducing stable chromosome
aberrations in comparison with acute exposure.
PMID- 10757316
TI - Micronuclei, CREST-positive micronuclei and cell inactivation induced in Chinese
hamster cells by radiation with different quality.
AB - PURPOSE: To study the relative biological effectiveness-linear energy transfer
(RBE-LET) relationship for micronuclei (MN) and cell inactivation, in Chinese
hamster cells irradiated with low-energy protons (0.88 and 5.04 MeV, at the cell
entrance surface). Chromosome loss was also investigated by means of
antikinetochore CREST staining. MATERIALS AND METHODS: Cl-1 cells were exposed to
different doses of X-rays, gamma-rays, 7.7 keV/microm and 27.6 keV/microm
protons. The induction of MN, the distribution of MN per cell and the frequency
of CREST-positive MN were evaluated in cytokinesis-blocked binucleated cells (BN
cells) in the dose range 0.125-3 Gy. In parallel, cell survival experiments were
carried out in samples irradiated with 0.5 to 4 Gy. RESULTS: MN yield and the
frequency of BN cells carrying multiple MN (> or =2) were significantly higher
after exposure to 27.6 keV/microm protons, compared with the other radiation
types. In contrast, MN induction and MN distribution per BN cell were similar
among 7.7 keV/microm protons, X- and gamma-rays up to 1 Gy. Cell survival
experiments gave RBE values very close to those obtained with the MN assay. Both
X-rays and 27.6 keV/microm protons yielded a significant proportion of CREST
positive MN at the highest doses investigated (0.75-3 Gy). CONCLUSIONS: Good
correlations between MN induction and cell inactivation were observed for both
low- and high-LET radiation, indicating that the MN assay can be a useful tool to
predict cell sensitivity to densely ionizing radiation with implications for
tumour therapy with protons.
PMID- 10757317
TI - The use of cryopreserved lymphocytes in assessing inter-individual
radiosensitivity with the micronucleus assay.
AB - PURPOSE: The feasibility of using cryopreserved lymphocytes to detect inter
individual differences in chromosomal radiosensitivity was investigated.
Typically, such studies are conducted with fresh blood samples but, in a clinical
setting, when availability of samples is unpredictable, this is not always
convenient. The sensitivity of 23 normal healthy donors, 11 breast cancer
patients who had shown severe acute skin reactions to radiotherapy and seven
ataxia telangiectasia (A-T) heterozygotes was determined. MATERIALS AND METHODS:
Thawed lymphocytes were exposed to high (HDR) or low dose rate (LDR) gamma
irradiation (3.5 Gy) in Go, stimulated with PHA, treated with cytochalasin-B 24 h
later and then harvested at 90 h for the determination of micronucleus (MN)
yields in binucleate cells. RESULTS: Each normal donor was tested one to three
times. Mean MN yields were 76.1 +/- 9.3/100 cells at HDR and 44.5 +/- 5.3 at LDR,
giving an LDR sparing effect of 39.6 +/- 9.3%. A relatively high proportion of
tests failed to yield sufficient binucleate cells for analysis. Inter
experimental variability was also high and it was not possible to demonstrate
inter-individual differences in sensitivity in spite of the use of an internal
control sample from a single normal donor in each experiment. There was a small
but significant increase in radiation-induced MN in the breast cancer patients
compared with the normals at LDR (but not at HDR), but a complete overlap with
the normal range. There was no increase in sensitivity in the A-T heterozygotes
at HDR. The LDR samples failed because the LDR protocol reduced proliferation
rates, and radiation-induced mitotic inhibition in this group was higher than in
normals. CONCLUSIONS: In comparison with previous experience with fresh blood
samples, the use of frozen lymphocytes is not as satisfactory because: (1)
experimental failures are higher; (2) inter-experiment variability is higher: (3)
dose-rate sparing is lower, suggesting poorer repair; and (4) the ability to
discriminate between breast cancer cases and normals is probably lower.
PMID- 10757318
TI - Repopulation in mouse oral mucosa: changes in the effect of dose fractionation.
AB - PURPOSE: To define the fractionation effect, including the magnitude and kinetics
of dose compensation, on days 3 and 8 after a single priming dose of 8 Gy.
MATERIALS AND METHODS: Graded radiation doses were given to the snouts of C3H/Neu
mice in 1 to 5 fractions within a time period of < or = 36 h, or in four
fractions with intervals from 5 min to 4 h. Each protocol was terminated by a top
up dose of 2.5 Gy to a 3 x 3 mm2 test area in order to precipitate the
subclinical damage induced by the snout treatment and to generate the full dose
response. RESULTS: No significant increase in isoeffective dose by increasing
fraction numbers or by increasing interfraction intervals could be detected at
each time point after the priming treatment. This indicates that the effect of
dose fractionation was entirely lost. CONCLUSIONS: The loss of fractionation
effect may be interpreted as a substantial impairment of the processes underlying
recovery from sublethal damage as a consequence of a repopulation-inducing
priming dose given 3 days or 8 days in advance.
PMID- 10757319
TI - Irradiation of rat tubule epithelial cells alters the expression of gene products
associated with the synthesis and degradation of extracellular matrix.
AB - PURPOSE: To determine the ability of radiation to modulate kidney tubule
epithelial cell expression of various molecules involved in regulating
extracellular matrix accumulation (collagen types I and III, fibronectin,
plasminogen activator-inhibitor 1 (PAI-1), TGF-beta and tissue inhibitor of
metalloproteinases-2 (TIMP-2)) and degradation (plasminogen activators u-PA or t
PA, MMP-2 and MMP-9). MATERIALS AND METHODS: NRK52E rat tubule epithelial cells
were placed in serum-free medium 24 h prior to irradiation with single doses of
1.0-10.0 Gy 137Cs gamma-rays. After irradiation, cells were maintained in serum
free medium for up to 48 h. RESULTS: Irradiation of NRK52E cells was associated
with significant dose-dependent increases in collagen I (p<0.05) and PAI-1 (p< or
=0.002) mRNA. Collagen III mRNA levels also exhibited a dose-dependent increase;
however, this increase failed to reach levels that were statistically
significant. Fibronectin mRNA levels were unaltered following irradiation.
Radiation also led to an isoform-specific alteration in TGF-beta expression; TGF
beta1 mRNA increased, TGF-beta3 mRNA decreased. The amount of TGF-beta protein
secreted into the medium was unchanged following irradiation; however, there was
a fivefold increase in the relative amount of active TGF-beta. Irradiation was
also associated with differential changes in MMP expression: active MMP-2 levels
increased, while MMP-9 levels were unaltered; PA secretion into the medium was
unchanged following irradiation. CONCLUSIONS: Irradiation of rat kidney tubule
epithelial cells leads to altered production of various molecules associated with
extracellular matrix accumulation and degradation.
PMID- 10757320
TI - Radiation retards muscle differentiation but does not affect osteoblastic
differentiation induced by bone morphogenetic protein-2 in C2C12 myoblasts.
AB - PURPOSE: Effects of radiation on the differentiation of C2C12 myoblasts were
studied using cell cultures in which the cells differentiated into either muscle
cells or osteoblasts. MATERIALS AND METHODS: A mouse skeletal myoblast cell line,
C2C12, was cultured and irradiated at confluence. Muscle differentiation was
estimated by counting the number of myosin heavy chain (MHC)-positive
multinucleated myotubes. Osteoblast differentiation was analysed by measuring
alkaline phosphatase (ALP) activity and osteocalcin production in C2C12 cells
treated with recombinant human bone morphogenetic protein-2 (rhBMP-2). RESULTS:
Myotube formation in C2C12 cells was inhibited by 2 and 4 Gy irradiation, but
recovered to non-irradiated control levels following further culture. In
irradiated cultures, the number of MHC-positive mononucleated cells increased
significantly. Irradiation did not, however, alter the induction of osteoblastic
phenotypes induced by rhBMP-2 in C2C12. Irradiation also did not affect the
expression of MyoD mRNA and myogenin mRNA in myogenic differentiation and
induction of osteocalcin mRNA in osteoblastic differentiation. CONCLUSIONS:
During differentiation of C2C12 cells, myotube formation was delayed after
irradiation, while induction of osteoblasts with BMP-2 was unaffected.
PMID- 10757321
TI - Evaluation of the cytogenetic damage and progenitor cell survival in foetal liver
of mice exposed to gamma radiation during the early foetal period.
AB - PURPOSE: To investigate the haemopoietic response to low dose gamma irradiation
at the early foetal period when the liver is the major haemopoietic organ.
MATERIALS AND METHODS: Pregnant Swiss albino mice were exposed to 0.1-1.5 Gy of
gamma radiation on the 14th day of gestation. Twenty-four hours (15 day post
conception (p.c.)) and 72 h (17 day p.c.) after exposure, the foetuses were
dissected out, weighed, and liver weight and mean cellularity were determined.
Cytogenetic damage in liver cells was assessed by chromosome aberration analysis
and micronucleus (MN) count. The haemopoietic progenitor cell survival at 24 h
and 72 h after exposure was measured by exogenous spleen colony assay on day 8
(CFU-S8) and day 12 (CFU-S12) after intravenous injection of the foetal liver
cells into adult bone marrow-ablated recipient mice. RESULTS: The foetal body
weight at 24 h after exposure showed a significant reduction at doses of 0.5 Gy
and above, while the 72 h body weight was significantly lower than control from
0.3 Gy onwards. Liver weight showed a similar reduction for doses from 0.25 to
1.5 Gy at both the post-irradiation observation times. However, when liver
weight/body weight ratios were compared, there was no significant difference
between the irradiated and control values. Total liver cellularity at 24 h and 72
h after exposure showed a dose-dependent decrease, with significant depletion
from control at 0.25 Gy and above. When donor cells were taken at 24 h after
exposure (15 day p.c.) the CFU-S8 showed a significant decrease only at 1.0 and
1.5 Gy, while the CFU-S12 suffered such a depletion at 0.25-1.5 Gy. For donor
cells recovered at 72 h after exposure, both CFU-S8 and CFU-S12 decreased linear
quadratically with radiation dose and were significantly lower than control at
0.25 Gy. A significant increase in the percent aberrant metaphases and
micronucleus counts was seen at 0.1 Gy and 0.15 Gy, respectively, and increased
linear-quadratically with radiation dose. CONCLUSIONS: The results demonstrate
that the liver, which is the major haemopoietic organ at the early foetal period,
is highly sensitive to radiation damage from maternal irradiation. At low doses,
the lethal effect on the haemopoietic stem cells appears to develop more slowly
than at higher doses.
PMID- 10757322
TI - Radiation induced cell loss in rat submandibular gland and its relation to gland
function.
AB - PURPOSE: To understand early and late radiation-induced loss of function of the
submandibular gland, changes in cell number were documented and correlated with
data on gland function. Modulation of the radiation effect by sialogogues was
used to investigate possible mechanisms of action. MATERIALS AND METHODS: Rats
were irradiated with a single dose of 15 Gy of X-rays after pre-treatment with
either saline, the muscarinic receptor agonists methacholine or pilocarpine, the
adrenergic receptor agonist phenylephrine or methacholine plus phenylephrine.
Before and 1-240 days after irradiation, submandibular saliva flow rate was
measured. At the same time points and from comparable animals submandibular
glands were carefully extirpated, weighed and prepared for light microscopic
examination. RESULTS: Soon after irradiation (<30 days) no significant loss of
cells was observed, whereas the gland function was severely compromised.
Sialogogue pre-treatment attenuated the radiation-induced loss of gland function.
At later intervals a considerable loss of acinar cells and to a lesser extent
loss of granular convoluted tubule cells were observed. Gland function
subsequently declined slowly. Pre-treatment with sialogogues gave transient
protection against cell loss and loss of gland function. CONCLUSIONS: The lack of
cell loss observed soon after irradiation indicates that the observed reduction
in gland function was caused by a compromised functioning of the acini. The later
loss of cells is probably due to death of cells that normally proliferate,
leading to a further reduced secretory capacity. Protection of gland morphology
and function by sialogogues at later times must therefore involve resistance of
progenitor cells to radiation-induced cell death.
PMID- 10757323
TI - Radiation-induced mutations in the spleen and brain of lacZ transgenic mice.
AB - PURPOSE: To study the dose-response and molecular nature of radiation-induced
mutations in the spleen and brain of lacZ transgenic mice. MATERIALS AND METHODS:
Line 60 transgenic mice containing the bacterial lacZ gene in a plasmid
background were used. Mutants were selected using phenyl-beta-D-galactoside. The
nature of mutants was determined by sequencing DNAs of mutant lacZ genes found in
control and irradiated tissues. RESULTS: X-ray irradiation at 50 and 100 Gy
showed linear dose-responses for mutation induction in both tissues. The slope,
however, was about twice as steep in spleen than in brain. DNA sequence analyses
showed that the predominant type of mutation induced by radiation in both tissues
were large deletions. CONCLUSIONS: Radiation induces mutations in spleen and
brain at different efficiencies but the molecular nature of the induced mutations
are similar in the two issues.
PMID- 10757324
TI - Rapid and widespread microglial activation induced by traumatic brain injury in
rat brain slices.
AB - In order to assess the role of circulating blood in early microglial activation
after traumatic brain injury (TBI), controlled cortical impact injury was applied
to adult rat brain slices (400 microm in thickness) and the microglial response
was examined. The complement receptor (CR3) expression and morphological
transformation of the microglia were evaluated by OX42 immunohistochemistry. At 5
min following injury, activated microglia with intense CR3 expression appeared
throughout the hemisphere on the injured side. In contrast, the morphology and
CR3 expression of the microglia on the contralateral side were indistinguishable
from those of the resident ramified microglia seen in normal brains. At 30 min
following injury, microglial activation was more pronounced on the injured side,
while the microglia on the contralateral side still retained a ramified
morphology. These results are consistent with our previous observations made in
in vivo experiments, which indicate that, as the brain slice paradigm excludes
variables arising from the circulating blood, the rapid and widespread microglial
activation observed following TBI can not be attributed exclusively to the
infiltration of blood-borne macrophages or molecules. Rather this activation is
most likely caused by intrinsic mechanisms within the brain tissue, such as
traumatic depolarization.
PMID- 10757325
TI - Effects of hypothermia on intracranial pressure and brain edema formation:
studies in a rat acute subdural hematoma model.
AB - Acute subdural hematoma (SDH) is the most common mass lesion in severe head
injury, and brain ischemia is the leading pathophysiological mechanism in the
development of secondary brain damage following SDH. Hypothermia has been
employed as an effective neuroprotective procedure in clinical and laboratory
studies on cerebral ischemic and contusional injuries. In the present study, we
used a rat acute SDH model to assess the effect of hypothermia on the
intracranial pressure (ICP) and also on the brain edema formation at 4 h after
hematoma induction. Mild (34 degrees C) and moderate (32 degrees C) hypothermia
did not significantly affect the ICP or cerebral perfusion pressure, but they
were associated with a significant lower cortical brain edema formation beneath
the hematoma (81.09 +/- 0.49%, p<0.05; and 80.88 +/- 0.17%, p<0.01) when compared
with the normothermic control group (81.65 +/- 0.52%). This reduction in brain
edema formation was comparable to the results of MK-801 treatment (80.95 +/-
0.35%, p<0.01). The present findings indicate that hypothermia represents a
potent neuroprotective strategy. The possible protective mechanisms of
hypothermic protection afforded in this rat acute SDH model are discussed.
PMID- 10757326
TI - Sequential mRNA expression for immediate early genes, cytokines, and
neurotrophins in spinal cord injury.
AB - In this communication, we demonstrate the sequential expression of endogenous
molecules, including immediate early genes (IEGs), cytokines, neurotrophins, and
neurotrophin receptors in the injured spinal cord. In the acute phase, expression
of IEGs and cytokines mRNAs were rapidly upregulated within 1 h in nonneuronal
cells in the lesioned sites and the surrounding spinal white and gray matter.
Maximal expression was observed at 1 h for c-fos and TNF-alpha mRNAs, at 3 h for
c-jun and IL-6 mRNAs, and at 6 h for IL-1 beta mRNA, and these signals were
virtually nondetectable after 6-12 h from the onset of the injury. Some of these
genes products may promote the degeneration of damaged cells and tissues, while
others may be involved in the subsequent repair processes. In the subacute phase,
expression of NGF, BDNF, NT-3, p75LNGFR and Trk B mRNAs began to increase in the
nonneuronal cells and neuronal cells from 6 h, and peaked at 24-72 h in the area
where expression of mRNAs for IEGs and cytokines overlapped. Signals for IL-6
mRNA were also observed in motoneurons at 24-72 h after the injury, with the
suggestion that these molecules may be involved in promoting axonal sprouting in
the injured spinal cord. Of further interest was the finding that this
upregulation of IL-1 beta, BDNF, and NT-3 mRNAs in injured spinal cord was
attenuated by treatment with high dose glucocorticoids, with the suggestion that
the downregulation of BDNF and NT-3 might be disadvantageous to survival and
axonal sprouting of spinal neurons.
PMID- 10757327
TI - Role of leukocytes in spinal cord injury in rats.
AB - Spinal cord injury (SCI) is a serious condition that produces life-long
disabilities. Only limited therapeutic measures are currently available for its
treatment. This review describes the role of leukocytes in pathologic mechanisms
of trauma-induced SCI in rats, which contributes to new understanding of the
pathologic process involved in SCI and could lead to the development of new
therapeutic strategies by which leukocyte activation can be regulated. SCI
induced by trauma is a consequence of an initial physical insult that is followed
by a progressive injury process which involves various pathochemical events that
lead to tissue destruction. Therapeutic intervention in SCI should therefore be
directed at reducing or alleviating this secondary process. Although the
mechanisms are not fully understood, progressive vascular events, especially
activated neutrophil-induced endothelial cell damage, have been shown to be
implicated. We have found that some therapeutic agents, which inhibit leukocyte
activation directly or indirectly, alleviate the motor disturbances observed in a
rat model of SCI. Methylprednisolone (MPS) and GM1 ganglioside, which are the
only two pharmacological agents currently clinically available for treatment of
acute SCI, do not inhibit neutrophil activation in this rat model. Taken
together, these observations raise a possibility that pharmacological agents that
inhibit leukocyte activation used in conjunction with MPS or GM1 may have a
synergistic effect in the clinical treatment of traumatic SCI in humans.
PMID- 10757328
TI - Fate of the supraspinal collaterals of cord-projection neurons following upper
spinal axonal injury.
AB - In investigating the fate of the cord-projecting CNS neurons following spinal
axonal injury, we have demonstrated that surviving rat rubrospinal neurons have
altered electrical membrane properties so that their input/output relationship
was increased. Further, we found that the synaptic inhibition they received from
nearby reticular formation was also reduced following injury. Whether or not
these property changes were functional was dependent on the output connections of
injured neurons. In the current communication, we examined the supraspinal
efferents of the injured neurons recognizing that normal neurons innervate not
only spinal but also supraspinal targets. To this end we conducted anterograde
tracing on the injured red nucleus 8 weeks following spinal lesion. Results
showed that injured rubrospinal neurons still innervated the same supraspinal
targets, targeted by normal neurons. We subsequently evaluated the relative
intensity of the sustained supraspinal connectivity by examining, in detail, the
cerebellar projection of rubrospinal neurons of similarly injured animals using
retrograde tracing technique. Here our data revealed that the number,
distribution and labeling intensity of rubrospinal neurons projecting to the
cerebellum were unchanged following cord injury. In conclusion, although spinal
cord injury deprive cord-projecting CNS neurons of their spinal targets, injured
neurons survived with altered electrical membrane properties and intact
supraspinal projections. The sustained supraspinal connections might allow
injured cord-projecting CNS neurons to exert a different weight of influence on
higher centers following spinal cord injury.
PMID- 10757329
TI - Hypothermia modulates induction of hsp70 and c-jun mRNA in the rat brain after
subarachnoid hemorrhage.
AB - We investigated expression of hsp70 and c-jun mRNA with in situ hybridization for
evaluating hypothermia effect on the brain exposed to subarachnoid hemorrhage
(SAH). SAH was induced in Wistar rats with endovascular perforation. Animals were
divided arbitrarily into normothermic and hypothermic groups, and they were
sacrificed at 3 h or 12 h after SAH. The SAH induced hsp70 and c-jun mRNAs in the
cerebral cortex, hippocampus, thalamus, hypothalamus, and caudoputamen. Mild
hypothermia depressed hsp70 mRNA expression in the cortex, thalamus, and
hippocampus. The c-jun mRNA expression was reduced by hypothermia in the cortex,
thalamus, and CA1 of the hippocampus. Based on these findings, we speculate that
hypothermia protects the brain exposed to SAH by reducing this stress response.
Although it is yet difficult to employ hypothermia in the clinical settings, this
study suggests its utility to those patients sustaining severe subarachnoid
hemorrhage.
PMID- 10757330
TI - The striatum is the most vulnerable region in the brain to mitochondrial energy
compromise: a hypothesis to explain its specific vulnerability.
AB - The striatum, together with the hippocampus, is one of the most vulnerable
regions in the brain. Recently, genetic abnormalities or mutations have been
linked to various neurodegenerative diseases, that is, Huntington's disease,
Alzheimer's disease, amyotrophic lateral sclerosis (ALS), etc., but the processes
from genetic abnormality to the final phenotypic expression are not well
understood. Disturbances in energy metabolism especially in mitochondrial energy
compromise could facilitate genetic abnormalities and enhance neuronal cell
death. Here, we report that the striatum is the most vulnerable brain region to
systemic intoxication with 3-nitropropionic acid (3-NPA), an inhibitor of
succinate dehydrogenase inducing energy compromise. We hypothesize that the
striatum-specific lesion by 3-NPA is due to cummulative insults characteristic to
the striatum including glutamatergic excitotoxicity, dopaminergic toxicity,
vulnerability of the lateral striatal artery and high activity in the glutamate
transporter. The former two are extravascular in origin while the latter two are
intra-/perivascular. We also discuss the possibility that a high turnover rate in
metabolism of nitric oxide (NO) might underlie the vulnerability of the lateral
striatal artery. We posit that systemic intoxication with 3-NPA offers a good
animal model to investigate the pathophysiology of neuronal/glial cell death,
neurodegenerative disease, dysfunction of the blood-brain barrier (BBB),
neuroimmune disorders, and stroke.
PMID- 10757331
TI - Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an
adjunct for recognition of the vertical growth phase in malignant melanomas?
AB - Ki-67 labeling of paraffin sections has been correlated with the number of cells
in non-G(o) phases of the replicative cell cycle, and this immunohistochemical
technique has been applied to the evaluation of a variety of human neoplasms.
Similarly, immunolabeling for p53 protein has been used to detect mutations in
the corresponding gene, as a reflection of possible cellular transformation in
the same context. Both of these techniques were applied to 253 melanocytic tumors
of the skin to assess their possible utility in the diagnosis and
subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39
Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth
(SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in
radial growth (LMMs), and 23 melanomas arising in association with preexisting
compound nevi (MCN). One hundred cells were counted randomly in each tumor, and
dark, exclusively nuclear reactivity was scored as positive labeling; results
were recorded as percentages. Negligible Ki-67 and p53 labeling was seen in CN
and SN, at a level that was similar to that obtained in cases of LMM and MCN. The
largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs,
followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles
that were similar to those of melanocytic nevi, and MCN did so as well. The
prototypical malignant melanocytic tumor representing the vertical growth phase
nodular melanoma--demonstrated a statistically significant difference from all
other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53
reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold
index of 10% and a p53 index of 5% correctly indicated the presence of vertical
growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other
types were colabeled at the same levels of reactivity for the two markers (P <
.00001, chi2). Thus, although the distinction between benign and malignant
melanocytic tumors could and should not be based on immunohistology for Ki-67 and
p53, these results suggest that the latter determinants may, in fact, be used as
an adjunct to morphology in the recognition of the vertical growth phase in
cutaneous malignant melanomas.
PMID- 10757332
TI - Sinusoidal CD30-positive large B-cell lymphoma: a morphologic mimic of anaplastic
large cell lymphoma.
AB - Anaplastic large cell lymphoma (ALCL) has been recognized recently as a distinct
clinicopathologic entity, restricted to a subset of CD30-positive diffuse large
cell lymphomas of T/null lineage. Some of the characteristic features of ALCL,
such as CD30 antigen expression and the presence of large pleomorphic lymphoid
cells infiltrating lymph node sinuses, can be found rarely in diffuse large B
cell lymphomas. We collected 11 such cases, and their clinical, morphologic, and
immunophenotypic features are reviewed. The age of the patients ranged from 36 to
82 years (mean, 63.2 years) with a male to female ratio of 1:1.2. All neoplasms
were nodal with a sinusoidal infiltrative pattern, although four neoplasms also
had foci of confluent growth. Eight tumors were composed predominantly of large
pleomorphic cells with occasional Reed-Sternberg-like cells. The other three
tumors had a higher proportion of large monomorphic lymphoid cells. Necrosis and
admixed granulocytes were other common features. Immunophenotypically, all cases
were positive for CD30 and CD20 or CD79a. All eight cases examined for anaplastic
lymphoma kinase-1 immunoreactivity were negative. In situ hybridization for
Epstein-Barr virus RNA was performed in eight cases; two were positive. Excluding
one consultation case with no available clinical follow-up data, six patients
died of the disease within 3 years and one had disease relapse within 1 year. We
conclude that an unusual variant of diffuse large B-cell lymphoma can closely
mimic ALCL. However, these neoplasms can be distinguished from ALCL by virtue of
their B-lineage and lack of anaplastic lymphoma kinase-1 expression. Evidence of
Epstein-Barr virus infection can be found in a small subset of these neoplasms.
PMID- 10757333
TI - Early detection of hepatitis C allograft reinfection after orthotopic liver
transplantation: a molecular and histologic study.
AB - After orthotopic liver transplantation (OLT), patients with chronic hepatitis C
virus (HCV) infection show nearly universal persistence of viremia and
reinfection of the liver, but identifying the point at which the liver is
reinfected morphologically can be difficult. One tool that may potentially be
useful to detect reinfection is reverse transcriptase-polymerase chain reaction
(RT-PCR), which has proven to be highly sensitive for detecting HCV RNA in
formalin-fixed paraffin-embedded liver tissue. Our purpose was to gain insight
into the time frame of HCV reinfection by assaying for HCV RNA in serial
posttransplant liver biopsy specimens. Our study population consisted of 14
patients who underwent liver transplantation for hepatitis C and had confirmed
HCV RNA in pretransplant serum, absence of HCV RNA in donor livers, and available
consecutive posttransplant liver allograft specimens. We performed RT-PCR for HCV
RNA in serial posttransplant liver biopsy specimens, beginning at 1 week until at
least one biopsy from each tested positive. HCV RNA was detected in liver tissue
by RT-PCR in 1-week post-OLT liver samples in 6 of 14 (42.8%) patients, the
earliest being 5 days post-OLT. Eventually, each of the remaining eight samples
became RT-PCR positive as well; the first detections occurred in these at 3 weeks
(three cases), 4 weeks (three cases), 48 weeks (one case), and 144 weeks (one
case). Histologic identification of hepatitis C recurrence was relatively
insensitive in relation to these molecular data. These data suggest that (1) HCV
RNA reinfection is nearly universal after liver transplantation in patients with
chronic hepatitis C infection, (2) molecular reinfection by HCV occurs at a
variable interval post-OLT, with the majority of allograft livers reinfected as
early as 1 week, and (3) morphologic features of hepatitis C are usually
appreciable at the time of "molecular" recurrence.
PMID- 10757334
TI - Thyroid transcription factor-1 is expressed in extrapulmonary small cell
carcinomas but not in other extrapulmonary neuroendocrine tumors.
AB - Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription
factor that is expressed in the developing thyroid, respiratory epithelium, and
diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or
thyroid neoplasms, and it is expressed in a significant subset of pulmonary non
small cell carcinomas, small cell carcinomas, and carcinoids but not in
nonpulmonary, non-small cell carcinomas. Neuroendocrine tumors from sites other
than the lung have not been evaluated for TFF-1 expression. We examined TFF-1
expression using immunohistochemistry on formalin-fixed, paraffin-embedded
sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21
paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the
uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous
neuroendocrine) carcinomas; and 1 renal carcinoma No gastrointestinal carcinoid
tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma
expressed TFF-1. All of the medullary thyroid carcinomas strongly expressed TTF
1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive,
including four of four prostate, two of four bladder, and one of seven cervical
small cell carcinomas. We conclude that TTF-1 expression is not specific for
small cell carcinomas of pulmonary origin and should not be used to distinguish
primary from metastatic small cell carcinomas in extrapulmonary sites. However,
TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and
cutaneous metastasis of small cell carcinomas. Among well-differentiated
neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid
tumors of the lung and medullary carcinomas of the thyroid and may be of
differential diagnostic value when dealing with a metastatic well-differentiated
neuroendocrine tumor.
PMID- 10757335
TI - Contemporary theories of cervical carcinogenesis: the virus, the host, and the
stem cell.
AB - Cervical cancer is a complex disease that, by its association with human
papillomavirus (HPV), has elicited research in a broad range of areas pertaining
to its basic diagnostic and clinical aspects. The complexity of this association
lies not only in the fundamental relationship between virus and cancer but also
in its translation to pathologic diagnosis and clinical management. Offshoots
from the relationship of virus to pathology include studies targeting the link
between papillomavirus infection and cervical epithelial abnormalities, the
molecular epidemiology of papillomavirus infection, and the potential use of HPV
testing as either a screening technique or a tool for managing women who have Pap
smear abnormalities. A second variable that is critical to the pathogenesis of
cervical neoplasia is the cervical transformation zone. The wide range of
invasive and noninvasive lesion phenotypes associated with HPV infection in this
region indicate that not only the virus but also specific host target epithelial
cells in the transformation zone play an important part in the development of
cervical neoplasia. Further understanding of this relationship between the virus
and the host epithelium will hinge on determining the subtypes of epithelial
cells in the transformation zone and their phenotypic response to infection. New
technologies, such as expression arrays, promise to clarify, if not resolve, the
complexity of molecular interactions leading to the multiplicity of tumor
phenotypes associated with HPV infection of the uterine cervix.
PMID- 10757336
TI - Cytologic and histologic diagnosis and significance of controversial squamous
lesions of the uterine cervix.
AB - The interpretation and precise classification of abnormal squamous cell changes
in cervicovaginal smears (Pap tests) and tissue samples are challenging and
controversial. The cytologic category atypical squamous cells of undetermined
significance and the newly described squamous lesions atypical immature
metaplasia, papillary immature metaplasia, and transitional cell metaplasia are
representative. Their current status is reviewed, and future directions aimed at
resolving some of the controversy and challenge are suggested.
PMID- 10757337
TI - Glandular lesions of the uterine cervix.
AB - During the past 20 years, pathologists have more carefully examined and more
precisely classified glandular lesions of the endocervix, largely reflecting
increased concerns about the diagnosis and pathogenesis of adenocarcinoma of the
cervix. This review of glandular lesions of the cervix focuses on the following
six issues surrounding the histologic diagnosis of the more common types of
adenocarcinoma of the endocervix and their mimics: (1) the classification and
recognition of preinvasive glandular lesions, (2) the distinction of invasive
from preinvasive adenocarcinoma, (3) the definition and significance of
microinvasive adenocarcinoma, (4) the epidemiology and pathogenesis of
adenocarcinoma, (5) the identification and behavior of the more common subtypes
of invasive adenocarcinoma, and (6) the recognition of benign lesions that mimic
adenocarcinoma It is the author's opinion that most in situ and invasive
adenocarcinomas of the cervix can be recognized and distinguished from benign
mimics. In contrast, glandular dysplasia and microinvasive adenocarcinoma of the
cervix are currently ill-defined and irreproducible terms that should not be used
for diagnostic purposes. Although only brief descriptions of the biologic
behavior of the various lesions and their therapy are included in this review,
certain variants of endocervical adenocarcinoma have distinctive behaviors and
should be classified appropriately to provide prognostication and help to guide
therapy.
PMID- 10757338
TI - Advances in cervical screening technology.
AB - The Pap smear unquestionably is a successful screening test for cervical cancer.
However, recent advances in technology have raised questions regarding whether
the conventional Pap smear is still the standard of care. This article relates
issues of screening and cost-effectiveness to the state of the art in thin layer
preparations, cytology automation, human papillomavirus screening, human
papillomavirus vaccines, and other cervical screening adjuncts. Perhaps nowhere
in medicine is clinical decision making being more strongly influenced by market
and other external forces than in cervical cytopathology.
PMID- 10757339
TI - Hormonal pathology of the endometrium.
AB - The endometrial tissue is a sensitive target for steroid sex hormones and is able
to modify its structural characteristics with promptness and versatility. This
article discusses briefly endogenous hormonal effects (cyclic changes, luteal
phase defect, unopposed estrogen effect) and describes the histologic patterns
encountered in the most commonly used hormone therapies: oral contraceptives,
ovulation stimulation, hormone replacement therapy, and antitumoral hormone
therapy. Oral contraceptives exert a predominant progestational effect on the
endometrium, inducing an arrest of glandular proliferation, pseudosecretion, and
stromal edema followed by decidualized stroma with granulocytes and thin
sinusoidal blood vessels. Prolonged use results in progressive endometrial
atrophy. Ovulation induction therapy accelerates the maturation of the stroma and
is often associated with a discrepancy between early secretory glands and an
edematous or decidualized stroma with spiral arterioles. Hormone replacement
therapy with estrogen alone may result in continuous endometrial proliferation,
hyperplasia, and neoplasia. The use of both estrogen and progesterone elicits a
wide range of histologic patterns, seen in various combinations: proliferative
and secretory changes, often mixed in the same tissue sample; glandular
hyperplasia (in polyps or diffuse) ranging from simple to complex atypical;
stromal hyperplasia and/or decidual transformation; epithelial metaplasia
(eosinophilic, ciliated, mucinous); and inactive and atrophic endometrium.
Progesterone therapy for endometrial hyperplasia and neoplasia induces glandular
secretory changes, decidual reaction, and spiral arterioles. Glandular
proliferation is usually arrested, but neoplastic changes may persist and coexist
with secretory changes. Lupron therapy produces a shrinking of uterine leiomyomas
by accelerating their hyaline degeneration, similar to that in postmenopausal
involution. It generally produces endometrial atrophy. Tamoxifen for breast
carcinoma has an estrogen agonist effect on the uterus in approximately 20% of
patients, who develop endometrial polyps, glandular hyperplasia, adenomyosis,
and/or leiomyomata. Both endometrioid and nonendometrioid carcinomas are seen,
often in polyps. Their causal relationship to tamoxifen therapy is debatable.
PMID- 10757340
TI - Theories of endometrial carcinogenesis: a multidisciplinary approach.
AB - Historical observations have suggested that endometrial carcinomas vary in
histopathologic appearance and clinical features. More recent, systematic studies
have provided epidemiologic, clinicopathologic, and molecular support for these
observations. Specifically, studies suggest that the most common type of
endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial
hyperplasia in the setting of excess estrogen exposure and usually pursues an
indolent clinical course. In contrast, a minority of endometrial carcinomas, best
represented by serous carcinoma, do not seem to be related to estrogenic risk
factors or elevated serum hormone levels, and these tumors seem to develop from
atrophic rather than hyperplastic epithelium. We have proposed that serous
carcinomas develop from "endometrial intraepithelial carcinoma," a lesion
representing malignant transformation of the endometrial surface epithelium.
Whereas endometrioid carcinoma and endometrial hyperplasia are associated with
microsatellite instability and ras and PTEN mutations, serous carcinoma and
endometrial intraepithelial carcinoma are associated with p53 mutations and
abnormal accumulation of p53 protein. Based on these data regarding the
pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic
model of endometrial carcinogenesis incorporating a "classic" estrogen-driven
pathway and an "alternative" pathway seemingly unrelated to hormones. It is hoped
that further studies may permit the extension and modification of this model and
that these advances will lead to improved diagnosis, management, and prevention.
PMID- 10757341
TI - Problems in the differential diagnosis of endometrial hyperplasia and carcinoma.
AB - The differential diagnosis of endometrial hyperplasia and well-differentiated
endometrioid adenocarcinoma is complicated not only by the resemblance of these
lesions to each other, but also by their tendency to be overdiagnosed
(particularly hyperplasia) on the background of polyps, endometritis, artifacts,
and even normally cycling endometrium. Atypical hyperplasia may also be
overdiagnosed when epithelial metaplastic changes occur in simple or complex
hyperplasia without atypia. Low-grade adenocarcinomas are best recognized by
architectural evidence of stromal invasion, usually in the form of stromal
disappearance, desmoplasia, necrosis, or combinations of these findings between
adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers
associated with manifestations of endogenous or exogenous hyperestrogenic
stimulation and a favorable prognosis. Subtypes include adenocarcinomas with
squamous differentiation and secretory, ciliated cell and villoglandular
variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and
the estimation and reporting of myometrial invasion are presented.
PMID- 10757342
TI - Smooth muscle, endometrial stromal, and mixed Mullerian tumors of the uterus.
PMID- 10757343
TI - Surgical pathology of non-neoplastic lung disease.
PMID- 10757344
TI - Correspondence re: Cameselle-Teijeiro J, Chan JKC: Cribriform-morular variant of
papillary carcinoma: a distinctive variant representing the sporadic counterpart
of familial adenomatous polyposis-associated thyroid carcinoma?
PMID- 10757345
TI - Immunosuppression mediated by tumor cells: a challenge for immunotherapeutic
approaches.
PMID- 10757346
TI - Participation of endogenously produced interferon gamma in interleukin 4-mediated
tumor rejection.
AB - To elucidate the molecular mechanism underlying IL-4-induced tumor rejection, we
challenged mice with a mouse adenocarcinoma cell line, colon 26, genetically
engineered to express constitutively IL-4 gene (colon 26/IL-4). Immunocompetent
BALB/c mice rejected colon 26/IL-4 cells but not parental cells or cells
transduced with a control gene (colon 26/control). Moreover, on rechallenge,
parental cells and colon 26/control cells were rejected by normal BALB/c mice
that had previously rejected colon 26/IL-4. However, both nude and severe
combined immunodeficiency (SCID) mice failed to reject colon 26/IL-4 as well as
parental or colon 26/control cells. In contrast, nude mice did reject colon 26/IL
4 after transfer of lymphocytes obtained from the draining lymph nodes of BALB/c
mice injected with colon 26/IL-4. These results indicate that challenging mice
with colon 26/IL-4 tumor cells resulted in the generation of memory cytotoxic T
lymphocytes in the draining lymph nodes. At 3 days after the challenge, IFN
gamma, IL-12 p35, and p40 mRNA expression was selectively enhanced in the
draining lymph nodes of mice bearing colon 26/IL-4 cells. Finally, mice deficient
in the IFN-gamma gene did not reject colon 26/IL-4 cells. These results suggest
that IL-4-induced memory cytotoxic T lymphocyte generation requires IFN-gamma
production in the draining lymph nodes, in order to generate a protective immune
response.
PMID- 10757347
TI - Immune response to adenovirus-delivered antigens upregulates utrophin and results
in mitigation of muscle pathology in mdx mice.
AB - The upregulation of endogenous utrophin in skeletal muscle may lead to a new
approach to the treatment of Duchenne muscular dystrophy (DMD). We found that
injection of an E1, E3-deleted adenovirus vector expressing beta-galactosidase
(beta-Gal) or green fluorescent protein (GFP) into the skeletal muscle of
neonatal dystrophin-deficient mdx mice alleviated dystrophic pathology. In the
adenovirus-infected muscles, an evaluation of sarcolemma stability showed low
permeability and immunohistochemistry revealed utrophin upregulation at the
extrasynaptic sarcolemma of mature muscle fibers. This utrophin upregulation was
concomitant with endomysial cellular infiltration from a host immune reaction.
There was no evidence of active muscle regeneration. In normal C57BL/10 mice,
utrophin was also upregulated in adenovirus-injected skeletal muscles, where
upregulated utrophin often coexisted with dystrophin. FK506 and anti-CD4 antibody
administration decreased utrophin expression in adenovirus-injected mdx muscles
and prevented the dystrophic phenotype from being mitigated, suggesting that an
immune reaction is involved in utrophin upregulation. This is the first report
demonstrating the improvement of the dystrophic phenotype as a result of the
acquired overexpression of endogenous utrophin. Our findings provide an important
clue to understanding the mechanism of utrophin expression and the development of
an effective treatment for DMD.
PMID- 10757348
TI - Tumor-induced immunosuppression: a barrier to immunotherapy of large tumors by
cytokine-secreting tumor vaccine.
AB - An active immunotherapy strategy with cytokine-assisted tumor vaccine, although
often effective for small tumor burdens, is much less so for large tumor burdens.
This study examines how large tumors might suppress the T cell functions and
escape from the immune responses elicited by a granulocyte-macrophage colony
stimulating factor (GM-CSF)-secreting tumor vaccine. According to our results,
the T cells isolated from the tumor-bearing mice treated late with the vaccine
failed to confer protective activity on naive mice against a wild-type tumor
challenge, unlike those isolated from the early-treated group. Nevertheless, the
antitumor activity of the inactive T cells could be restored on in vitro
stimulation. Expression of transforming growth factor beta (TGF-beta) and
interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the
parental tumor cell line RLmale 1 (a murine T leukemia cell line), as well as in
the tumor region, the levels of which correlated with tumor progression. An in
vitro assay of T cell functions revealed that the TGF-beta in the conditioned
medium of RLmale 1 cells mainly affected the activation, whereas the IL-1male
affected the activation to a lesser extent, but significantly affected the
cytolytic activity, of tumor-specific T cells. The immunosuppressive activity of
IL-10 was also signified by the findings that administration of the conditioned
medium of RLmale 1 cultured in a serum-free medium, in which the TGF-beta
activity was then lost while the IL-10 activity still remained, or of recombinant
IL-10 to the early-treated group of mice abrogated the known efficacy of tumor
vaccine on the small tumors. These data suggested that the efficacy of cytokine
secreting tumor vaccine was blocked by the immunosuppressive factors secreted
from the large tumors. The results have important implications for the clinical
design of immunotherapeutic strategies for advanced cancer patients.
PMID- 10757349
TI - An enhanced system for construction of adenoviral vectors by the two-plasmid
rescue method.
AB - The two-plasmid rescue method of constructing Ad vectors, which relies on either
homologous or Cre-mediated recombination between two plasmids cotransfected into
293 or 293Cre4 cells, respectively, offers advantages over other approaches
because of its simplicity. We have improved the efficiency of vector construction
by both homologous and Cre-mediated recombination by replacing the single ITR in
the shuttle plasmid with a head-to-head ITR junction. We have also expanded the
versatility of this method by incorporating a Cre expression cassette into the
plasmids to permit high-efficiency Cre-mediated vector rescue using 293 cells,
abrogating the need for Cre-expressing cell lines. This new system retains the
simplicity of the original but results in an approximately 100-fold increase in
the number of recombinant viruses produced, all of which contain the foreign DNA
insert, and allows high-efficiency Cre-mediated vector isolation using any E1
complementing cell line.
PMID- 10757350
TI - Modulation of Starling forces and muscle fiber maturity permits adenovirus
mediated gene transfer to adult dystrophic (mdx) mice by the intravascular route.
AB - Duchenne muscular dystrophy (DMD) and other inherited myopathies lead to
progressive destruction of most skeletal muscles in the body, including those
responsible for maintaining respiration. DMD is a fatal disorder caused by
defects in the dystrophin gene. Recombinant adenovirus vectors (AdV) are
considered a promising means for therapeutic delivery of a functional dystrophin
gene to DMD muscles. If AdV-mediated dystrophin gene replacement in DMD is to be
successful, development of a systemic delivery method for targeting the large
number of diseased muscles will be required. In this study we investigated two
major factors preventing efficient AdV-mediated gene transfer to skeletal muscles
of adult animals after intravascular AdV administration: (1) an inability of AdV
particles to breach the endothelial barrier and enter into contact with
myofibers, and (2) a relatively nonpermissive myofiber population for AdV
infection due at least in part to insufficient levels of the coxsackie/adenovirus
attachment receptor (CAR). On the basis of established principles governing the
transendothelial flux of macromolecules, we further hypothesized that an
alteration in Starling forces (increased hydrostatic and decreased osmotic
pressures) within the intravascular compartment would facilitate AdV
transendothelial flux via convective transport. In addition, experimental muscle
regeneration was employed to increase the prevalence of immature myofibers in
which CAR expression is upregulated. Here we report that by employing the above
described strategy, high-level heterologous reporter gene expression was
achievable in hindlimb muscles of normal rats as well as dystrophic (mdx) mice
(genetic homolog of DMD) after a single intraarterial injection of AdV.
Microsphere studies confirmed enhanced transport into muscle of fluorescent
tracer particles in the size range of AdV, and there was a high concordance
between CAR upregulation and myofiber transduction after intraarterial AdV
delivery. Furthermore, in mdx mice examined 10 days after intraarterial AdV
delivery, the aforementioned procedures had no adverse effects on the force
generating capacity of targeted muscles. These findings have implications for
eventual AdV-mediated gene therapy of generalized skeletal muscle diseases such
as DMD using a systemic intraarterial delivery approach.
PMID- 10757351
TI - Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human
fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of
release and cross-correction by the murine enzyme.
AB - Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two
different disorders: GM1 gangliosidosis, which involves the nervous system and
visceral organs to varying extents, and Morquio's syndrome type B (Morquio B
disease), which is a skeletal-connective tissue disease without any CNS symptoms.
This article shows that transduction of human GM1 gangliosidosis fibroblasts with
retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to
complete correction of the enzymatic deficiency. The newly synthesized enzyme is
correctly processed and targeted to the lysosomes in transduced cells. Cross
correction experiments using retrovirus-modified cells as enzyme donors showed,
however, that the human enzyme is transferred at low efficiencies. Experiments
using a different retrovirus vector carrying the human cDNA confirmed this
observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a
retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high
levels of enzymatic activity. Furthermore, the mouse enzyme was found to be
transferred to human cells at high efficiency. Enzyme activity measurements in
medium conditioned by genetically modified cells suggest that the human beta
galactosidase enzyme is less efficiently released to the extracellular space than
its mouse counterpart. This study suggests that lysosomal enzymes, contrary to
the generalized perception in the field of gene therapy, may differ significantly
in their properties and provides insights for design of future gene therapy
interventions in acid beta-galactosidase deficiency.
PMID- 10757352
TI - Long-term persistence of human bone marrow stromal cells transduced with factor
VIII-retroviral vectors and transient production of therapeutic levels of human
factor VIII in nonmyeloablated immunodeficient mice.
AB - The potential of using bone marrow (BM)-derived human stromal cells for ex vivo
gene therapy of hemophilia A was evaluated. BM stromal cells were transduced with
an intron-based Moloney murine leukemia virus (Mo-MuLV) retroviral vector that
contained the B domain-deleted human factor VIII (FVIIIdeltaB) cDNA. This FVIII
retroviral vector was pseudotyped with the gibbon ape leukemia virus envelope
(GALV-env) to attain higher transduction efficiencies. Using optimized
transduction methods, high in vitro FVIII expression levels of 700 to 2500 mU of
FVIII/10(6) cells per 24 hr were achieved without selective enrichment of the
transduced BM stromal cells. After xenografting of 1.5-3 x 106 engineered BM
stromal cells into the spleen of nonobese diabetic severe combined
immunodeficient (NOD-SCID) mice, human plasma FVIII levels rose to 13 +/- 4 ng/ml
but declined to basal levels by 3 weeks postinjection because of promoter
inactivation. About 10% of these stromal cells engrafted in the spleen and
persisted for at least 4 months after transplantation in the absence of
myeloablative conditioning. No human BM stromal cells could be detected in other
organs. These findings indicate that retroviral vector-mediated gene therapy
using engineered BM stromal cells may lead to therapeutic levels of FVIII in vivo
and that long-term engraftment of human BM stromal cells was achieved in the
absence of myeloablative conditioning and without neo-organs. Hence, BM stromal
cells may be useful for gene therapy of hemophilia A, provided prolonged
expression can be achieved by using alternative promoters.
PMID- 10757353
TI - Vaccination of melanoma patients with an allogeneic, genetically modified
interleukin 2-producing melanoma cell line.
AB - Thirty-three metastatic melanoma patients were vaccinated according to a phase I
II study with an allogeneic melanoma cell line that was genetically modified by
transfection with a plasmid containing the gene encoding human interleukin 2 (IL
2). The cell line expresses the major melanoma-associated antigens and the HLA
class I alleles HLA-A1, -A2, -B8, and Cw7. All patients shared one or more HLA
class I alleles with this cell line vaccine. Patients were immunized by three
vaccinations, each consisting of 60 x 106 irradiated (100 Gy) melanoma cells
(secreting 120 ng of IL-2/10(6) cells/24 hr) administered subcutaneously at
weekly intervals for 3 consecutive weeks. Side effects of treatment consisted of
swelling of locoregional lymph nodes and induration at the site of injection,
i.e., a delayed-type hypersensitivity (DTH) reaction. In three patients,
vaccination induced inflammatory responses in distant metastases containing
necrosis or apoptosis along with T cell infiltration. Apoptosis occurred only in
Bcl-2-negative areas, not in Bcl-2-expressing parts of the metastases. Two other
patients experienced complete or partial regression of subcutaneous metastases.
Seven patients had protracted stabilization (4 to >46 months) of soft tissue
metastases, including one patient who developed vitiligo after vaccination.
Immune responses to the vaccine could be detected in 67% of the 27 patients
measured. Vaccination was shown to induce a variable change in the number of anti
vaccine cytotoxic T lymphocytes (CTLs) in peripheral blood, which did not
correlate with response to treatment. However, in two of five patients the
frequency of anti-autologous tumor CTLs measured was significantly higher than
before vaccination. This study demonstrates the feasibility, safety, and
therapeutic potential of vaccination of humans with allogeneic, gene-modified
tumor cells, and that frequencies of vaccine-specific CTLs among patient
lymphocytes can be determined by using a modified limited dilution analysis
(LDA).
PMID- 10757354
TI - On the mechanism of protection of distal joints after local gene transfer in
collagen-induced arthritis.
AB - Considerable interest has been generated by the observation that adenovirus
mediated gene delivery to a single arthritic joint results in suppression of
arthritis in distal joints associated with the presence of small numbers of
transduced cells in distal joints. It has been proposed that this is mediated by
trafficking of transduced cells from the injected to distal joints. There are,
however, alternative explanations that have not been explored, including the
possibility that transgene protein or infectious virions circulate to distal
sites. To investigate these possibilities, a replication-incompetent adenovirus
encoding viral IL-10 (vIL-10) was administered to naive mice and to mice with
collagen-induced arthritis by intraarticular, periarticular, or intravenous
injection. In all cases, the ability to protect distal joints correlated with
serum levels of vIL-10 protein. After intraarticular or intravenous injection,
vIL-10 cDNA could be detected not only in distal joints, but also in the liver,
which is the major target of circulating adenovirus, demonstrating that
adenovirus circulating through the bloodstream is taken up by the joint tissue.
Periarticular administration of adenovirus, which resulted in lower serum levels
of vIL-10, protected only the injected paws and failed to induce trafficking
immunoregulatory cells capable of suppressing distal disease. These observations
suggest that circulating vIL-10 protein is the major mediator of distal
protection. The presence of small numbers of transduced cells at distal sites can
be accounted for by transduction of distal synovium after entry of adenovirus
virions into the circulation.
PMID- 10757355
TI - Adenovirus vector-mediated gene transfer to regional lymph nodes.
AB - Regional lymph nodes (RLNs) possess important immune functions and represent a
major pathway of metastasis for solid tumors. Given these facts, the ability to
transfer exogenous genes to the RLNs with the goal of manipulating the local
immunological milieu would be desirable. On the basis of the hypothesis that a
significant proportion of adenovirus (Ad) gene transfer vectors traffic through
the lymphatics, E1-E3- Ad vectors were injected into the hind footpad of C3H/He
mice and the RLNs assessed for vector trafficking and transgene expression. A low
dose (10(9) particles) of an Ad vector encoding the firefly luciferase gene (Ad
CMV.Luc) resulted in luciferase expression only in the injection site and RLNs,
with no detectable systemic (liver, spleen, lung) expression. At a higher dose
(10(11) particles), some expression could be detected systemically in addition to
the RLNs, but at levels in liver 14-fold less than in the RLNs. Transgene
expression in the RLNs was transient, peaking at 1 day, decreasing markedly by 7
days. At high doses (10(11) particles), interruption of draining lymphatics
decreased the amount of systemic dissemination 22-fold, suggesting that a large
proportion of the vector trafficks through the lymphatics before reaching the
systemic circulation. Administration of a vector encoding the jellyfish green
fluorescent protein gene (AdCMV.GFP, 10(11) particles) showed that transgene
expression in the RLNs was primarily in the cortical area. After footpad
injection of a fluorescent-labeled Ad vector (Cy3-AdCMV.Null), fluorescent
virions were visualized in the draining lymph. Regional lymph collected from
animals injected in the footpad with AdCMV.Luc (10(11) particles) contained
functional vector. Augmentation of local immune function in the RLNs was achieved
by footpad administration of an Ad vector encoding murine IL-12, resulting in
high mIL-12 and IFN-gamma levels in the regional, but not distant, nodes. These
data demonstrate that expression of exogenous genes in RLNs is easily
accomplished with Ad vectors, Ad vector dissemination occurs primarily via the
lymphatics after footpad administration in mice, and basic immune functions in
the RLNs can be manipulated by Ad-mediated gene transfer in vivo.
PMID- 10757356
TI - Retroviral preparations derived from PA317 packaging cells contain inhibitors
that copurify with viral particles and are devoid of viral vector RNA.
AB - Obtaining high expression levels of a therapeutic gene in target cells could be
achieved by integrating multiple copies of a recombinant retrovirus. However, we
observed that cells retrovirally infected at high multiplicities of infection
(MOIs) carried only single or double integrated proviral copies, suggesting that
maximum retroviral transduction was achieved at relatively low MOIs. The same
results were obtained when purified virus, free of most medium components, was
used. Retroviral infection was shown to be inhibited by supernatants of other
viral producer cell lines, and this inhibition could be removed by a
centrifugation step that also removed more than 90% of infectious virus.
Quantitative-competitive PCR of retroviral preparations showed that the amount of
retroviral vector RNA present was similar to the amount expected on the basis of
virus titers. Our data suggest that retroviral preparations derived from PA317
packaging cells contain inhibitors that copurify with retroviruses and do not
contain viral vector RNA. We postulate that these inhibitor particles cannot
achieve a productive infection but interfere with transduction of the target
cells by infectious virions. This study might define an important criterion for
the selection of more effective packaging cell lines.
PMID- 10757357
TI - Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy:
alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular
instillations of adeno-associated vectors.
PMID- 10757358
TI - 50th anniversary historical article. Ischemic heart disease.
PMID- 10757359
TI - 50th anniversary historical article. Heart failure.
PMID- 10757360
TI - 50th anniversary historical article. Hypertension.
PMID- 10757361
TI - 50th anniversary historical article. The Framingham Offspring Study: a
commentary.
PMID- 10757362
TI - 50th anniversary historical article. Surgical treatment of acute myocardial
infarction.
PMID- 10757363
TI - 50th anniversary historical article. Thrombolytic therapy in acute myocardial
infarction.
PMID- 10757364
TI - 50th anniversary historical article. Perfusion imaging.
PMID- 10757365
TI - 50th anniversary historical article. Valvular heart disease.
PMID- 10757366
TI - 50th anniversary historical article. Percutaneous transluminal coronary
angioplasty.
PMID- 10757367
TI - 50th anniversary historical article. A century of cardiac arrhythmias. In search
of Jason's golden fleece.
PMID- 10757368
TI - 50th anniversary historical article. Myocardial oxygen consumption: the quest for
its determinants and some clinical fallout.
PMID- 10757369
TI - 50th anniversary historical article. Myocardial infarction and coronary care
units.
PMID- 10757370
TI - 50th anniversary historical article. Acute coronary syndromes: the degree and
morphology of coronary stenoses.
PMID- 10757371
TI - The ACC at 50: a giant grew in Bethesda. The impact of the ACC on cardiovascular
medicine. American College of Cardiology.
PMID- 10757372
TI - Demographics and cardiology, 1950-2050.
PMID- 10757373
TI - Technological advances and the next 50 years of cardiology.
AB - The fiftieth anniversary of the ACC and the end of the twentieth century are
arbitrary points in time, yet they seem to coincide with a true watershed. The
last 50 years have brought a rush of new techniques and understandings that have,
for the first time, given cardiovascular specialists real tools to prevent and
fight cardiovascular disease. Only now, for the first time, has science begun to
understand exactly what happens when plaque forms in an artery, when heart muscle
fibers cross-link and weaken, when an atrial chamber fibrillates, and when heart
muscle cells die en masse after a heart attack. We are beginning to track down
the actual chemical, mechanical, and electrical pathways by which the heart is
damaged or dies. When we can interfere with those pathways and stop the chain of
events, we will have defeated heart disease. Imagination is rapid, but progress
is often both uncertain and slow because of the many constraints of cost,
regulation, and time needed to test and evaluate new developments. Yet we can now
foresee a future in which medical science might actually defeat cardiovascular
disease the way it has defeated polio, smallpox, and other serious scourges of
the past.
PMID- 10757374
TI - The future of cardiology: utilization and costs of care.
PMID- 10757375
TI - The role of the American College of Cardiology in promoting and maintaining the
delivery of quality cardiovascular care in the future.
PMID- 10757376
TI - Gifts from surgical research. Contributions to patients and to surgeons.
PMID- 10757377
TI - Incisional endometriosis: an underappreciated diagnosis in general surgery.
AB - BACKGROUND: Incisional endometriosis is a described dinical entity in the
gynecologic literature, but it is not well recognized among general surgeons;
only 32 cases have been reported in the general surgery literature. The
preoperative diagnosis is often mistaken for a suture granuloma, lipoma, abscess,
cyst, or incisional hernia. STUDY DESIGN: We performed a retrospective review of
10 cases of incisional endometriosis at our institution to determine which, if
any, clinical factors would suggest the diagnosis preoperatively. All general
surgery patients who had the diagnosis of endometriosis in their pathology
specimens from January 1990 to December 1998 were reviewed. RESULTS: All 10
patients had previous cesarean sections through either a Pfannenstiel (n = 8) or
a lower midline (n = 2) incision. Ages ranged from 27 to 41 years (mean 33.4
years). The most common presenting symptom was a slow-growing, painful lump in
the lateral aspect of the Pfannenstiel incision. Two of the patients had a change
in symptoms with their menstrual cycle. The duration of symptoms ranged from 2
months to 3 years. All patients underwent surgical excision. The size of the
excised endometriomas ranged from 1.5 cm to 4.8 cm (mean 3.1 cm). CONCLUSIONS:
Incisional endometriosis may be more common than previously recognized. In all
cases it was found to occur in women with a history of cesarean section. Most
patients presented with a painful, slow-growing lump at the lateral edge of their
incision. Cyclic changes in pain and size of the mass with menses was elicited in
only two of these patients, but this may be from a lack of awareness and
questioning on the part of the physician. If the diagnosis is made
preoperatively, additional diagnostic studies may be avoided. An awareness of
this disease process on the part of general surgeons is necessary to guide
preoperative evaluation and therapy appropriately.
PMID- 10757378
TI - Roux-en-Y limb motility after total or distal gastrectomy in symptomatic and
asymptomatic patients.
AB - BACKGROUND: The aims of this study were to compare Roux-en-Y limb motor patterns
after total or distal gastrectomy, and to identify possible motor differences
between symptomatic and asymptomatic patients. The usefulness of preoperative
recording was also investigated. STUDY DESIGN: Sixteen patients were enrolled in
the study, 10 patients after total gastrectomy (TG group) and 6 patients after
distal gastrectomy (DG group). In 6 of 10 patients in the TG group, recordings
were obtained before and after operation. Manometric recordings in the limb
lasted 6 hours in all patients, 3 hours during fasting, and 3 hours after a 750
kcal meal. An intravenous injection of trimebutine (100-mg i.v.) was
systematically administered at the end of each recording session. Motor results
of the patients were compared with those obtained in the intact jejunum of 20
healthy controls. RESULTS: After operation, when patients were compared with
controls, phase III (ie, regular activity of the migrating motor complex) was
more frequent and more often incompletely propagated (5 of 16 patients versus 1
of 20 controls, unadjusted p < 0.05) and was significantly slower (p < 0.01
versus controls). Intravenous trimebutine induced phase III in 12 of 16 patients
within a mean of 8.8 +/- 1 (SEM) minutes, longer than in controls (delay < 2
minutes). The fed pattern was shorter than in controls in both TG and DG groups,
and the postprandial area under the curve during successive 30-minute periods was
reduced in the DG group compared with controls (p < 0.01). In patients
investigated before gastrectomy, motor parameters were not different from those
of controls. Surgery resulted in an increased number of phase IIIs and a
decreased migration velocity (p < 0.01) of phase III, a longer delay in response
after trimebutine (p < 0.0001), and a reduced postprandial motor response (p <
0.01). After the operation, 4 of 10 patients in the TG group and 5 of 6 patients
in the DG group were symptomatic. Symptomatic patients had slower and more often
incompletely propagated (p < 0.01) phase III compared with asymptomatic patients.
CONCLUSIONS: Roux-en-Y limb reconstruction mainly disturbs phase III propagation
and the motor response to a meal. Motor changes are more marked after DG than
after TG. Disturbed phase III propagation is the main difference between
symptomatic and asymptomatic patients. Successful induction of phase III with
trimebutine after gastrectomy and Roux-en-Y reconstruction indicates maintenance
of encephalinergic mechanisms.
PMID- 10757379
TI - Comparison of loop versus end ileostomy for fecal diversion after restorative
proctocolectomy for ulcerative colitis.
AB - BACKGROUND: The goal of this study was to compare the benefits versus
complications of temporary loop ileostomies and end ileostomies in a consecutive
series of patients undergoing colectomy and ileal pouch-anal anastomosis for
ulcerative colitis. STUDY DESIGN: A retrospective review was performed of all
patients undergoing restorative proctocolectomy with diverting ileostomy for
ulcerative colitis at the UCLA Medical Center during a 4-year period. An end
ileostomy (EI) was used for 38 patients and a loop ileostomy (LI) for 39. All
patients had a J pouch, with all EI patients having a hand-sewn ileoanal
anastomosis, and 33 LI patients having a double-stapled anal anastomosis. EI
closure was performed through a laparotomy, and LI closure was performed through
a periileostomy incision. RESULTS: The mean operative time for EI closure was 157
minutes, and for LI closure was 103 minutes. The wound infection rate after EI
closure was 5.3% and after LI was 10.3%. For EI patients, 2 of 38 patients
required reoperation, compared with 5 of 39 for LI. The mean hospital stay after
EI closure was 6.7 days, and after LI closure was 7.1 days. Peristomal skin
irritation was more severe, more prolonged, and occurred in more than twice as
many LI as EI patients. Home ostomy nurse care was necessary for a mean of two
visits for EI patients and five visits for LI patients. The cost ofostomy
supplies and care was more than double for LI patients compared with those with
EI. Patient satisfaction and ability to resume physical and social activities
early after ileostomy construction were much more favorable for EI than LI
patients. CONCLUSIONS: The benefit of shorter operating time for LI closure
compared with EI closure is often outweighed by the complications and costs of LI
stomal care and patient dissatisfaction. EI should be considered more frequently
for temporary ileal diversion after restorative proctocolectomy.
PMID- 10757380
TI - Beneficial effects of growth hormone and insulin-like growth factor I on
intestinal bacterial translocation, endotoxemia, and apoptosis in experimentally
jaundiced rats.
AB - BACKGROUND: This study was undertaken to investigate the effect of growth hormone
(GH) and insulin-like growth factor I (IGF-I), two well-known growth factors, on
bacterial translocation, endotoxemia, enterocyte apoptosis, and intestinal and
liver histology in a model of experimental obstructive jaundice in rats. STUDY
DESIGN: One hundred six male Wistar rats were divided into five groups: I (n =
21), controls; II (n = 22), sham operated; III (n = 22), bile duct ligation
(BDL); IV (n = 21), BDL and GH treatment; and V (n = 20), BDL and IGF-I
administration. By the end of the experiment, on day 10, blood bilirubin was
determined, and mesenteric lymph nodes, liver specimens, and bile from the bile
duct stump were cultured. Endotoxin was measured in portal and aortic blood.
Tissue samples from the terminal ileum and liver were examined histologically and
apoptotic body count (ABC) in intestinal mucosa was evaluated. Mucosal DNA and
protein content were also determined. RESULTS: Bilirubin increased significantly
after BDL (p < 0.001). Bile from the bile duct was sterile. In group III, MLN and
liver specimens were contaminated by gut origin bacteria (significant versus
group I and II, p < 0.001, respectively). GH reduced significantly positive
cultures (p < 0.01), and IGF-I had no effect. BDL resulted in significant
increase in portal and aortic endotoxemia (p < 0.001); treatment with GH and IGF
I reduced it (p < 0.001). Mucosal DNA and protein content were reduced in animals
with BDL and after treatment with GH or IGF-I; an increase to almost normal
levels was noted in DNA, but not in protein. Overall the ileal architecture
remained intact in all animal groups. The ABC increased after BDL. After GH and
IGF-I administration, the ABC decreased significantly, and there was no
difference between GH and IGF-I treated animals. After BDL, liver biopsies
displayed typical changes of biliary obstruction, which were significantly
improved after administration of GH and IGF-I. CONCLUSIONS: Treatment with GH and
IGF-I in rats with experimental obstructive jaundice reduces endotoxemia, and it
improves liver histology. Apoptosis, in the intestinal epithelium, may serve as a
morphologic marker of the ileal mucosal integrity, demonstrating the
proliferative potential of GH and IGF-I in cases of obstructive jaundice, and
this might be of potential value in patients with such conditions.
PMID- 10757381
TI - Hepatic neuroendocrine metastases: does intervention alter outcomes?
AB - BACKGROUND: In most instances, advanced neuroendocrine tumors follow an indolent
course. Hepatic metastases are common, and although they can cause significant
pain, incapacitating endocrinopathy, and even death, they are usually
asymptomatic. The appropriate timing and efficacy of interventions, such as
hepatic artery embolization (HAE) and operation, remain controversial. STUDY
DESIGN: The records of 85 selected patients referred for treatment of hepatic
neuroendocrine tumor metastases between 1992 and 1998 were reviewed from a
prospective database. A multidisciplinary group of surgeons, radiologists, and
oncologists managed all patients. Overall survival among this cohort is reported
and prognostic variables, which may be predictive of survival, are analyzed.
RESULTS: There were 37 men and 48 women, with a median age of 52 years. There
were 41 carcinoid tumors, 26 nonfunctional islet cell tumors, and 18 functional
islet cell tumors. Thirty-eight patients had extrahepatic metastases, and in 84%
of patients, the liver metastases were bilobar. Eighteen patients were treated
with medical therapy or best supportive care, 33 patients underwent HAE, and 34
patients underwent hepatic resection. Both the HAE-related mortality and the 30
day operative mortality rates were 6%. By univariate analysis, earlier resection
of the primary tumor, curative intent of treatment, and initial surgical
treatment were associated with prolonged survival (p < 0.05). On multivariate
analysis, only curative intent to treat remained significant (p < 0.04). Patients
with bilobar or more than 75% liver involvement by tumor were least likely to
benefit from surgical resection. One-, 3-, and 5-year survival rates for the
entire group were 83%, 61%, and 53%, respectively. The 1-, 3-, and 5-year
survivals for patients treated with medical therapy, HAE, and operation were 76%,
39%, and not available; 94%, 83%, and 50%; and 94%, 83%, and 76%, respectively.
CONCLUSIONS: Hepatic metastases from neuroendocrine tumors are best managed with
a multidisciplinary approach. Both HAE and surgical resection provide excellent
palliation of hormonal and pain symptoms. In select patients, surgical resection
of hepatic metastases may prolong survival, but is rarely curative.
PMID- 10757382
TI - Splenectomy in patients with hepatocellular carcinoma and hypersplenism.
AB - BACKGROUND: Hypersplenism secondary to portal hypertension is common in
hepatocellular carcinoma (HCC), but surgeons still face the unresolved problem of
how to manage HCC patients with hypersplenism. STUDY DESIGN: The records of 48
patients with HCC and hypersplenism were retrospectively examined and
postoperative changes in platelet counts, serum total bilirubin levels, and
dinical staging scores were analyzed to evaluate the clinical value of combined
splenectomy and liver resection. Hepatectomy and splenectomy were performed as a
two-stage operation in 13 patients and synchronously in 35. RESULTS:
Postoperative platelet counts were significantly increased, and serum total
bilirubin levels were significantly decreased. Clinical staging scores were also
reduced after splenectomy in patients who underwent splenectomy before
hepatectomy. CONCLUSIONS: Synchronous or metachronous splenectomy can increase
the safety of hepatectomy in selected patients with HCC by reducing both the
likelihood of bleeding complications and bilirubin overload.
PMID- 10757383
TI - Video-assisted aortic surgery.
AB - BACKGROUND: There are several laparoscopic techniques that can be used to perform
a total or video-assisted aorto-femoral bypass grafting procedure. Major
drawbacks of laparoscopic aortic surgery are the long operating times and the
steep learning curve required for these procedures. Hand-assisted laparoscopy is
a novel technique that allows surgeons to use their hands and laparoscopic
instruments in the operative field while maintaining a pneumoperitoneum. STUDY
DESIGN: A prospective nonrandomized study was conducted in a community medical
center. Any patient with aortoiliac occlusive disease or an abdominal aortic
aneurysm who was determined to be suitable for a laparoscopic aorto-femoral
bypass grafting procedure was included in the study. The main outcomes measured
were: operating time, aortic cross-clamp time, incision size, complications,
conversion rate to an open procedure, length of stay in the ICU, and
postprocedural hospital stay. A concurrent control group of 20 patients was
compared with the minimally invasive group. RESULTS: Forty-one consecutive
patients were scheduled for the laparoscopic operation. Conversion to an open
procedure was necessary in three patients. There were two major complications,
including the development of renal failure in one patient who died 28 days
postoperatively. The mean postprocedural hospital stay was 4.5 +/- 2.5 days
(range 2 to 15 days). The mean operating time was 163.1 +/- 38.7 minutes,
including an aortic cross-clamp time of 38.3 +/- 9.7 minutes. Postoperative
hospital stay and the time required in the ICU were significantly shorter after
the laparoscopic procedure compared with a conventional bypass grafting
procedure. CONCLUSIONS: Hand-assisted laparoscopy is a minimally invasive
technique with operating times and outcomes similar to those of conventional
procedures. The possibilities of this technique in patients with aortoiliac
disease should be evaluated in a prospective randomized study.
PMID- 10757384
TI - The ethics of entrepreneurial medicine.
PMID- 10757385
TI - Preliminary assessment of the value and effect of expert consultation in
telemedicine.
PMID- 10757387
TI - Optimism about superfluous injury and unnecessary suffering: a system of
measurement with potential for controls.
PMID- 10757386
TI - Benjamin Rush's death.
PMID- 10757388
TI - Images for surgeons. Intraductal papillary neoplasm of the pancreas.
PMID- 10757389
TI - Images for surgeons. Acute venous air embolism.
PMID- 10757390
TI - Caval inflow to the graft: a successful way to overcome diffuse portal system
thrombosis in liver transplantation.
AB - Portal vein thrombosis was considered to be a major contraindication to liver
transplantation before the introduction of vessel grafts from the recipient's
area of confluence of the splenic and superior mesenteric veins, behind the neck
of the pancreas, to the graft's portal vein. Refinement in surgical technique has
given rise to a large number of possibilities to overcome portal vein thrombosis
in OLT recipients, ranging from portal vein thrombectomy to several different
venous graft jump reconstructions. All these reconstructions require the presence
of a patent vein of the portal system. When neither splanchnic veins nor
sufficiently large venous collaterals are available, liver transplantation has
been considered impossible. Salvage solutions include arterialization of the
portal vein with the associated risk of liver damage in the longterm, a combined
liver and bowel transplantation has been proposed but not yet reported (and in
any case the results of combined liver and bowel transplants are not as good as
those of liver transplantation alone) and finally the use of blood inflow from
the inferior vena cava as first reported by Tzakis and coworkers. Portal flow
from the inferior vena cava may be performed as a last resort. Although the
consequences of severe pretransplantation portal hypertension remain and should
be treated before, during, and after transplantation, liver function is normal in
the short and midterm. With this new procedure, diffuse portal vein thrombosis is
no longer an absolute contraindication to liver transplantation. But this needs
to be confirmed in light of further experience and longterm followup.
PMID- 10757391
TI - Recycled use of reopened umbilical vein for venous reconstruction in
hepatopancreatobiliary surgery.
PMID- 10757392
TI - Sentinel lymph node mapping.
PMID- 10757393
TI - Is prolonged antibiotic prophylaxis after major surgery associated with an
increased risk of nosocomial bloodstream infection?
PMID- 10757394
TI - Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy: a diagnosis
that should not be made.
PMID- 10757395
TI - Diffuse-type giant cell tumor: clinicopathologic and immunohistochemical analysis
of 50 cases with extraarticular disease.
AB - The clinical and pathologic features of 50 cases of diffuse-type tenosynovial
giant cell tumor (D-TGCT), also known as extraarticular pigmented villonodular
tenosynovitis (PVNTS), are presented. Patients' ages ranged from 4 to 76 years
(median, 41 yrs), with a slight female predominance (28 women, 22 men). By
definition, all lesions presented as predominant soft tissue masses, with or
without an associated articular component. Tumor sites included the wrist (9
cases), knee (8 cases), thigh and foot (6 cases each), finger (5 cases), ankle (3
cases), hand, elbow, toes, buttock, paravertebral region (2 cases each), lower
leg, sacrococcygeal area, and retroperitoneum; 27 cases were described as
entirely extraarticular. Tumors showed infiltrative margins and, in most cases, a
sheet-like growth pattern. Striking variation in the number of osteoclast-like
giant cells, foamy cells, amount of hemosiderin, and in the degree of stromal
hyalinization were responsible for a wide morphologic spectrum. In addition to
the predominant histiocyte-like cells, we identified in most cases a
subpopulation of large dendritic, desmin-positive cells showing characteristic,
but potentially misleading, cytologic features, including abundant eosinophilic
cytoplasm, large vesicular nuclei, paranuclear eosinophilic inclusions, and
occasional nuclear inclusions. Follow-up information was available for 24
patients, with a duration ranging from 6 months to 30 years (mean, 55 mos). Local
recurrence occurred in eight cases (33%), between 4 months and 6 months after
surgery (median, 15 mos) and was repeated in five cases; recurrence did not
appear to correlate with morphologic parameters. Six cases showed atypical
histologic features and four of these contained areas of sarcomatous change.
Among the latter, one of three cases with available follow up developed pulmonary
metastases and died after 35 months. In addition, one histologically benign
lesion gave rise, after two local recurrences, to inguinal and iliac lymph node
metastases. Despite this exceedingly uncommon event, we think most cases of D
TGCT are best regarded as benign but locally aggressive neoplasms with
significant recurrent potential and should be treated, when possible, by wide
excision. Atypical features such as increased mitotic activity, necrosis,
spindling of the mononucleate cells, and cytologic atypia are not indicative of
malignancy when present individually. This study also confirms the existence of
malignant tenosynovial giant cell tumors, some of which are characterized by
aggressive behavior.
PMID- 10757396
TI - Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign
appearing variant.
AB - Pathologic diagnosis of pancreatic adenocarcinoma is frequently a challenge,
particularly in small biopsies, frozen sections, and in metastatic foci. Here we
report a deceptively benign-appearing and morphologically distinctive pattern of
ductal adenocarcinoma with prominent microvesicular cytoplasm, giving the cells a
foamy appearance similar to that described in the prostate (Am J Surg Pathol
1996;20:419). This variant, which we refer to as foamy gland pattern (FGP), was
frequently misdiagnosed in frozen sections or biopsies and its pathologic stage
underestimated in surgical specimens. Histologically, the diagnostic features
were: (1) white and crisply foamy, "microvesicular" cytoplasm; (2) often basally
located and compressed, hyperchromatic nuclei reminiscent of endocervical glands
(and so-called "adenoma malignum") or gastric foveolar glands; (3) irregular
nuclear contours forming wrinkled (raisinoid) nuclei in some areas; and (4) a
distinctive chromophilic condensation of the cytoplasmic material in the luminal
aspect of the cells forming a brush border-like zone (BLZ). Histochemically, this
BLZ was positive for mucicarmine, alcian blue, and high iron diamine, but not
PAS. The remainder of the cytoplasm was negative for all these stains. In
contrast, benign mucinous ducts, which constitute the major differential
diagnosis, had more homogeneous acidophilic cytoplasm, lacked BLZ, and showed
cytoplasmic staining with PAS. Immunohistochemically, the tumor cells were
diffusely and strongly positive for CEA and cytokeratin 8 whereas B72.3 staining
was focal and weak. MUC1 staining was largely confined to the BLZ. MUC2 was
negative. P53 staining was detected in 16 of the 20 cases studied and was strong
and diffuse in five. K-ras mutation was detected in 6 of 8 cases studied. The
clinical findings in the 20 patients in this study (4 pure and 16 mixed with
usual ductal carcinoma) did not appear to differ significantly from those of
ordinary ductal adenocarcinoma of the pancreas. Eleven patients were men and nine
were women; the mean age was 62 years and the mean tumor size was 4.4 cm. Follow
up information was available in 17 patients of whom 7 were alive at an average
follow up of 23 months (range, 7-104 mos), and 10 were dead of disease at a
median follow up of 15 months (range, 4-42 mos). The median survival of the four
patients with pure FGP was 18 months. The median survival did not appear to be
significantly longer than that of the patients with resectable ordinary ductal
adenocarcinoma in the authors' experience (109 patients, median survival of 12
mos, p = 0.48). In conclusion, foamy gland pattern of invasive pancreatic ductal
carcinoma is morphologically distinctive and is prone to misdiagnosis as a benign
process. The pathologic stage is often underestimated as a result of the lack of
its recognition and misinterpretation as mucinous ducts. Careful attention to its
microscopic features is adequate for accurate diagnosis. Histochemical and
immunohistochemical stains are useful in confirming the diagnosis of malignancy
in challenging cases.
PMID- 10757397
TI - Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases
and proposed classification of 'verruciform' penile tumors.
AB - Within the spectrum of penile squamous cell carcinomas, those that we
descriptively refer to collectively as the "verruciform" lesions are particularly
difficult to subclassify. In a review of 50 such tumors, we found 11 distinctive
neoplasms with condylomatous features conforming to the appearance of so-called
"warty (condylomatous) carcinoma." The average patient age was 55 years and the
average duration of disease was 19 months. The primary tumor involved multiple
anatomic sites (glans, coronal sulcus, and foreskin) in seven cases and a single
site (glans or foreskin) in four cases. Grossly, white to gray cauliflower-like
tumors typically measuring approximately 5 cm were noted. Histologically the
tumors were mainly papillomatous with acanthosis and hyperkeratosis. The papillae
had prominent fibrovascular cores. The most conspicuous microscopic findings were
striking nuclear atypia of koilocytotic type and clear cytoplasm. The interface
between tumor and stroma was irregular in the majority of cases; deep invasion of
corpus cavernosum was noted in five cases. The differential diagnosis included
verrucous carcinoma, low-grade papillary squamous cell carcinoma, not otherwise
specified, and giant condyloma acuminatum. Among other differences, the first two
lesions show no koilocytotic changes and the last lacks malignant features and
irregular stromal invasion. Metastatic spread occurred in two patients; both are
alive with evidence of recurrent disease 12 and 72 months after initial
diagnosis. A third patient was alive with recurrent disease 12 months after
diagnosis. Five patients were free of disease 8, 12, 24, 52, and 108 months after
diagnosis. Three patients were lost to follow up. Warty (condylomatous)
carcinomas of the penis are morphologically distinctive verruciform neoplasms
with features of human papillomavirus-related lesions and should be distinguished
from other verruciform tumors so that differences in behavior, if any, between
these tumors will become established.
PMID- 10757398
TI - Neoplastic and pre-neoplastic changes in gastrointestinal endometriosis: a study
of 17 cases.
AB - The clinicopathologic features of neoplasms arising in gastrointestinal
endometriosis have not been well characterized. In this series, we report 17
cases of gastrointestinal endometriosis complicated by neoplasms (14 cases) or
precancerous changes (three cases). Four patients, one of whom also had
hypermenorrhea, presented with chronic abdominal pain and five had obstructive
symptoms; one of these also had rectal bleeding. One patient presented with an
acute abdomen and fecal peritonitis, one had vaginal bleeding, and one had a
progressive change in bowel habits. Nine patients had a long history of
endometriosis, 11 patients had had hysterectomies, and eight of these had also
received unopposed estrogen therapy. The lesions involved the rectum (6), sigmoid
(6), colon, unspecified (2), and small intestine (3), and comprised 8
endometrioid adenocarcinomas (EA), 4 mullerian adenosarcomas (MAS), 1
endometrioid stromal sarcoma (ESS), 1 endometrioid adenofibroma of borderline
malignancy (EBA) with carcinoma in situ, 2 atypical hyperplasias (AH), and one
endometrioid adenocarcinoma in situ (ACIS). The tumors ranged in size from 2 to
15 cm and all involved the serosa and muscularis propria. Two tumors extended
into the mucosa, with mucosal ulceration in one. Follow-up was available in 11
cases. One patient with EA was dead of disease at 1 year, one had two recurrences
at 1 and 2 years, and three were alive with no evidence of disease (ANED) at 9
months to 13 years (mean, 68 mos). The patient with the EBA was ANED at 3 months.
Two patients with MAS were ANED at 2 and 3 years. The patient with ESS had a
recurrence at 3 years and was ANED 6 years after her original diagnosis. One
woman with AH was ANED at 60 months and the patient with ACIS was ANED at 16
months. One of the carcinomas was originally misdiagnosed as a primary intestinal
adenocarcinoma. The pathologist should be aware of the possibility of a tumor of
genital tract type when evaluating intestinal neoplasms in females, particularly
if they have a history of endometriosis and have received unopposed estrogen
therapy.
PMID- 10757399
TI - Blastic/blastoid transformation of follicular lymphoma: immunohistologic and
molecular analyses of five cases.
AB - Progression of follicular lymphoma to a higher-grade malignancy frequently
heralds a poor prognosis. Clinical transformation is variably accompanied by a
spectrum of histologic changes characterized by alteration in growth and
cytology. Although several cytogenetic events and potential oncogenes have been
documented in this progression, the underlying molecular mechanisms are largely
unknown. We present five patients with an unusual histologic transformation of
follicular lymphoma manifested by blastic/blastoid morphology. This
transformation is histologically distinct from other types of transformation of
follicular lymphoma. All five cases exhibited the t(14;18) translocation and
expressed the BCL-2 protein. In addition, two of the five patients showed
increased levels of the p53 protein within neoplastic cells implicating a
possible role for this oncogene in blastic/blastoid transformation. The lack of
BCL-1 and myeloid antigens by immunohistochemistry and flow cytometry studies
served to distinguish blastic/blastoid transformation of follicular lymphoma from
its morphologic mimics. This distinction is clinically important because
lymphoblastic and myeloid leukemias require significantly different therapeutic
modalities and show better prognosis. Moreover, the lack of Epstein-Barr virus
specific mRNA suggests that this virus is unlikely to participate in
blastic/blastoid transformation of follicular lymphoma.
PMID- 10757400
TI - Sex cord-stromal tumors of the testis with entrapped germ cells: a lesion
mimicking unclassified mixed germ cell sex cord-stromal tumors.
AB - The authors describe 10 sex cord-stromal tumors of the testis that incorporated
germ cells, thereby mimicking the unclassified type of mixed germ cell sex cord
stromal tumor (MGCSCST). These neoplasms occurred in patients from 3 to 48 years
old (mean age, 26 years) who presented with testicular masses. On microscopic
examination, nine tumors had a combination of tubular and cord-like arrangements
of sex cord cells with transition to spindle-shaped tumor cells. They were
diagnosed as either unclassified sex cord-stromal tumors (n = 5) or Sertoli
stromal cell tumors (n = 4). One tumor was a pure Sertoli cell tumor. The admixed
germ cells were usually at the periphery and in clusters, but occasionally were
in the center or more diffuse. In nine patients the germ cells resembled
spermatogonia, having round nuclei with uniform, dusty chromatin and
inconspicuous or small nucleoli. None of these cells stained with a variety of
markers used for neoplastic germ cells, and in one case in which the non
neoplastic Sertoli cells were strongly reactive for inhibin but the neoplastic
Sertoli cells were not, all the germ cells within the tumor occurred adjacent to
inhibin-positive Sertoli cells. With static cytophotometry, a diploid
deoxyribonucleic acid content was found in these germ cells in the two
investigated cases. In one case the germ cells had the morphologic appearance of
seminoma cells and they stained positively for the markers of neoplastic germ
cells. This case was interpreted as a "collision" tumor between a Sertoli cell
tumor and a seminoma. The authors conclude that sex cord-stromal tumors with
entrapped germ cells of the testis are more common than unclassified MGCSCSTs--a
bona fide testicular example of which has not been seen by any of the authors.
PMID- 10757401
TI - Proliferative epidermal lesions associated with anogenital Paget's disease.
AB - A series of 35 cases of Paget's disease (PD) of the vulva and perianal area were
studied to characterize the spectrum of proliferative epidermal lesions that
occur in this rare disease but generally have been overlooked. The study group
consisted of 8 men and 27 women with a median age of 66 years. Nineteen patients
(54%) had one or more benign proliferative epidermal lesions, including 7 of 22
patients (32%) with vulvar PD and 12 of 13 patients (92%) with perianal PD. Two
patients also had malignant squamous cell neoplasms. Three categories of
epidermal hyperplasia were identified: (1) squamous hyperplasia NOS (34%), (2)
fibroepithelioma-like hyperplasia (32%), and (3) papillomatous hyperplasia (29%).
Small nests of hyperplastic squamous cells protruding into the dermis simulated
microinvasive squamous carcinoma in three of these cases. None of the nine
papillomatous hyperplasias tested for HPV by in-situ hybridization were positive.
The squamous hyperplasia NOS and the papillomatous hyperplasia did not show a
predilection for an anatomic site. In contrast, fibroepithelioma-like hyperplasia
occurred in 69% of perianal PD compared with only 9% of vulvar cases. There was
no association between the type of epidermal hyperplasia and the presence of a
regional internal cancer. Two patients with vulvar PD had malignant squamous
lesions, including one with squamous cell carcinoma in-situ (CIS) of classic type
and one patient with invasive squamous cell carcinoma (InvSCC); the latter also
had invasive PD. The malignant squamous component in both patients was positive
for HPV 16/18, whereas the associated Paget's cells were HPV-negative. The
finding of fibroepithelioma-like hyperplasia in the anogenital skin should prompt
a thorough search for Paget' s cells. Papillomatous hyperplasia may be
misinterpreted as condyloma acuminatum when Paget's cells are few in number and
have koilocytotic-like vacuolar change or for warty (condylomatous) carcinoma
when pseudoinvasive foci are present. When Paget's cells are florid and diffusely
infiltrate an acanthotic epidermis, classic CIS may be misdiagnosed. Cytokeratin
7 immunostain is an excellent marker for intraepithelial and invasive Paget's
cells that aids in their distinction from hyperplastic and malignant squamous
cells.
PMID- 10757402
TI - Acute renal allograft rejection with severe tubulitis (Banff 1997 grade IB).
AB - Recent studies have correlated renal allograft function with individual
histologic lesions defined in the Banff schema of kidney transplantation
pathology. The clinical significance of severe tubulitis (Banff 97 grade t3) has
not been specifically examined. We compared the clinical course and response to
antirejection therapy in 36 patients with t3 tubulitis, and 137 patients with
milder grades of tubulitis and varying grades of intimal arteritis. Rejection
associated with severe tubulitis (grade t3) was associated with graft outcome
that was worse than mild to moderate tubulitis (grades t1 or t2) and approached
that seen in grade v1 intimal arteritis. Rejection characterized by grade v2 or
v3 intimal arteritis had worse prognosis than v1 intimal arteritis and all grades
of tubulitis without coexisting intimal arteritis. These observations validate
the Banff 97 recommendation that the severity of both tubulitis and intimal
arteritis needs to be graded in renal allograft biopsies. In addition, grade t3
tubulitis is identified as a lesion which should be a cause for clinical concern.
PMID- 10757403
TI - Reappraisal of orthodox histochemistry for the diagnosis of minimal deviation
adenocarcinoma of the cervix.
AB - Minimal deviation adenocarcinoma (MDA), or adenoma malignum, of the uterine
cervix is a diagnostically problematic disease because of the difficulty in
differentiating it histologically from normal cervical glands. To evaluate the
use of mucin phenotyping for differentiating MDA from other conditions, we
performed alcian blue pH 2.5/periodic acid-Schiff (AB-PAS) staining and high iron
diamine (HID)-AB staining on routinely processed sections of 11 MDAs, 20
unremarkable cervical glands, 9 cervical glandular hyperplasias occurring in
association with mucinous ovarian tumors, and 41 conventional cervical
adenocarcinomas. In all 11 MDAs and 11 conventional cervical adenocarcinomas, the
tumor cell cytoplasm was stained diffusely red by PAS, indicating that MDA cells
produce neutral mucin almost exclusively. The amount of acid mucins, both
sulfomucin and sialomucin, was decreased markedly by HID-AB. For four MDAs,
preoperative biopsy specimens also showed diffuse cytoplasmic neutral mucin. In
contrast, the cytoplasm of constituent cells was stained purple to violet by AB
PAS in all unremarkable cervical glands and glandular hyperplasias, indicating
that both acid and neutral mucins were produced in equal amounts, sulfomucin
being stained predominantly by HID-AB. Of the 30 conventional cervical
adenocarcinomas, 28 showed both acid and neutral mucins and two showed acid mucin
only in goblet cells, or in part of the cytoplasm or cell surface of constituent
cells, where acid mucin consisted predominantly of sulfomucin in 14 and
sialomucin in 16. AB-PAS and HID-AB are simple and orthodox histochemical methods
which are effective for differential diagnosis of MDA and can contribute to its
early detection and treatment.
PMID- 10757404
TI - The prognostic significance of tertiary Gleason patterns of higher grade in
radical prostatectomy specimens: a proposal to modify the Gleason grading system.
AB - The Gleason grading system of prostatic adenocarcinoma does not account for the
existence of a tertiary (third most prevalent) pattern, and there are no studies
concerning the latter's prognostic influence. The authors analyzed 114 radical
prostatectomies with small tertiary components, which mostly occupied less than
5% of whole tumors. These specimens were compared with a prostatectomy database
comprised of 2,276 cases without a tertiary component. The pathologic stages of
"typical" Gleason score 5 to 6 tumors (Gleason scores 2 + 3 = 5, 3 + 2 = 5, 3 + 3
= 6), which contained tertiary patterns 4 or 5, were significantly higher than
those of "typical" Gleason score 5 to 6 tumors without pattern 4 (p = 0.018) but
lower than those of "typical" Gleason score 7 tumors (p = 0.021; Gleason scores,
3 + 4 = 7, 4 + 3 = 7). Typical Gleason score 7 tumors with a tertiary pattern 5
showed significantly worse pathologic stages than typical Gleason score 7 tumors
(p = 0.008) without pattern 5 and were not different statistically from typical
Gleason score 8 (Gleason score, 4 + 4 = 8) tumors. Both typical Gleason score 5
to 6 and 7 tumors with tertiary components revealed significantly higher
progression rates than typical Gleason score 5 to 6 tumors (p <0.0001) and
Gleason score 7 tumors (p = 0.003) without tertiary components, and progressed
like typical Gleason score 7 and 8 tumors respectively. Tertiary high-grade
components have an adverse impact on biologic behavior. The authors propose that
the Gleason system for radical prostatectomy specimens be modified to take into
account small volumes of patterns 4 and 5, which are important prognostically.
PMID- 10757405
TI - Metastatic metanephric adenoma in a child.
AB - Metanephric adenoma is a recently characterized renal tumor that generally occurs
in adults and has an excellent prognosis. To date, only one atypical metanephric
adenoma has been reported to metastasize. The authors report a case of typical
metanephric adenoma that arose in the left kidney of a 7-year-old girl that was
associated with metastases to the para-aortic, hilar, and aortic bifurcation
lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial
elements arranged in tubules, short papillae, and glomeruloid bodies with
scattered psammoma bodies. No atypia and only rare mitotic activity were present.
Immunohistochemically, the tumor was negative for epithelial membrane antigen,
negative for keratin AE1, and focally positive for both keratin CAM5.2 and
cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy
of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The
authors conclude that tumors with histologic, immunohistochemical, and genetic
features characteristic of typical metanephric adenoma can present with
metastatic disease.
PMID- 10757406
TI - Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular
adenoma of the thyroid gland.
AB - The monoclonal MIB-1 antibody reacts with the nuclei of cells in the late G1, S,
G2, and M phases of the cell cycle. Previously, we found two cases of hyalinizing
trabecular adenoma that showed cell membrane and cytoplasmic immunopositivity for
the antibody. The purpose of this investigation was to confirm this exceptional
reactive pattern of MIB-1 in hyalinizing trabecular adenoma. For the study, we
collected 13 additional hyalinizing trabecular adenomas and stained a total of 15
tumors using MIB-1 antibody. Ten cases of papillary thyroid carcinoma were
studied similarly. All hyalinizing trabecular adenomas showed strong positivity
for the antibody in 90% or more of the tumor cells, localized especially to the
cell membrane and also to the cytoplasm. There was no cell membrane or
cytoplasmic MIB-1 positivity among the 10 papillary carcinomas. Luminal border of
normal extratumoral thyroid follicles rarely showed faint immunopositivity. Our
findings indicate that strong cell membrane and cytoplasmic immunoreactivity for
MIB-1 is a characteristic of the hyalinizing trabecular adenoma. Staining for MIB
1 will be useful in differentiating hyalinizing trabecular adenoma from papillary
carcinoma, which shares a number of cytologic and histologic findings with
hyalinizing trabecular adenoma.
PMID- 10757407
TI - Expression of androgen receptor and prostatic specific markers in salivary duct
carcinoma: an immunohistochemical analysis of 13 cases and review of the
literature.
AB - Salivary duct carcinoma (SDC) is an uncommon, pathologically distinct entity
characterized by its morphologic resemblance to ductal carcinoma of the breast
and highly aggressive behavior. Approximately two thirds of patients die within 4
years of initial diagnosis despite aggressive, combined surgical resection and
radiotherapy. Review of the literature indicates that androgen receptor (AR), a
marker frequently detected in prostatic carcinoma, is expressed in over 90% of
SDCs, whereas two common breast carcinoma markers, estrogen and progesterone
receptors (ER and PR), are expressed in only 1.3% and 6% of the tumors,
respectively, by immunohistochemistry. This hormonal profile suggests that SDC,
in contrast to its histiologic similarity to ductal carcinoma of the breast, is
immunophenotypically more related to prostatic carcinoma. To substantiate this
hypothesis, we performed immunohistochemical staining of 13 cases of SDC for the
presence of AR and two prostatic markers, prostate specific antigen (PSA) and
prostatic acid phosphatase (PAP). Our results showed multifocal, scattered,
moderate immunostaining for PAP and diffuse, moderate immunostaining for PSA in
seven (58.3%) and two (16.7%) cases, respectively. These results create a
potential diagnostic challenge to surgical pathologists who are dealing with a
metastatic adenocarcinoma of AR+/PSA+/-/PAP+/- phenotype, particularly in male
patients of unknown primary. Metastatic salivary duct carcinoma should be given
serious thought if clinical investigation fails to reveal a prostatic primary.
The immunophenotypic homology that exists between SDC and prostatic carcinoma
also suggests that antiandrogen therapy as used in the treatment of prostatic
carcinoma might be beneficial in patients with metastatic SDC when all other
conventional modalities fail.
PMID- 10757408
TI - Nodular lymphoid hyperplasia of the lung: a clinicopathologic study of 14 cases.
AB - Nodular lymphoid hyperplasia is a controversial entity in which its existence in
the lung has been doubted. The current opinion is that most, if not all, such
cases represent extranodal marginal zone B-cell lymphomas masquerading as
reactive lesions. We found 14 cases of nodular lymphoid hyperplasia in the files
of the Pulmonary Department at the Armed Forces Institute of Pathology from 1974
through 1998. All had clinical histories and hematoxylin-eosin slides. In 12 of
14 with paraffin blocks, we applied immunohistochemical antibodies for CD20, CD3,
CD43, CD5, bcl-2, bcl-1, CD45RA, and kappa and lambda immunoglobulin light
chains. Molecular genetic analysis was performed on paraffin sections in 10 of 14
by the polymerase chain reaction for rearrangements of the immunoglobulin heavy
chain gene and the minor and major break-point regions of the chromosomal
translocation t (14;18). There were eight women and six men ranging in age from
19 to 80 years (median, 65 yrs). Most lesions (71%) were incidental findings on
routine chest x-rays. Most patients (64%) had a single lesion by chest x-ray
whereas the remainder had two to three lesions, except for one patient who had
"multiple" lesions. There was associated regional lymphadenopathy in five of 14
cases (36%) which, on biopsy, proved to be reactive follicular hyperplasia. The
only treatment was surgical excision. Of the seven patients with follow-up
information from 8 months to 6 years (mean, 30 mos), none had clinical recurrence
and no patient died of disease. The histology and immunophenotype of the lesions
were strikingly similar, including abundant reactive germinal centers, intense
interfollicular polyclonal plasmacytosis, and a variable degree of
interfollicular fibrosis. No case showed a molecular rearrangement of the
immunoglobulin heavy chain gene or the minor or major break-point region of the t
(14;18). We conclude that nodular lymphoid hyperplasia of the lung, although
rare, does exist and deserves its place in the spectrum of reactive pulmonary
lesions that ranges from follicular hyperplasia to diffuse hyperplasia of the
bronchus-associated lymphoid tissue (lymphoid interstitial pneumonitis).
PMID- 10757409
TI - Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S
immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary
and nonpulmonary adenocarcinoma.
AB - The distinction between malignant pleural mesotheliomas and adenocarcinomas,
particularly those originating in the lung, is a difficult diagnostic problem
that can be facilitated by the use of immunohistochemical markers. In this study,
the immunoreactivity of thyroid transcription factor-1 (TTF-1), E-cadherin, BG8,
WT1, and CD44S was investigated in 50 epithelial mesotheliomas, and 40 pulmonary
and 95 nonpulmonary adenocarcinomas. After analyzing the results, it was
concluded that E-cadherin and BG8 are useful markers for distinguishing between
epithelial mesotheliomas and adenocarcinomas of various origins, including the
lung. Because TTF-1 expression is found almost exclusively in adenocarcinomas of
the lung but is absent in mesotheliomas, immunostaining for this marker is
particularly useful for distinguishing between these two malignancies. Although
WT1 immunostaining may also be useful, its value, as determined in this study, is
lower than that reported by other investigators. CD44S immunostaining does not
have any practical value in discriminating between epithelial mesothelioma and
lung adenocarcinoma.
PMID- 10757410
TI - 'Gangliocytomas' of the pituitary: a heterogeneous group of lesions with
differing histogenesis.
AB - Hamartomatous or neoplastic ganglion cells in the sella turcica are an unusual
cause of symptoms. They have been reported in association with a functioning or
nonfunctioning pituitary adenoma, with pituitary cell hyperplasia, and
occasionally as masses unassociated with an adenoma, again with variable
endocrinologic findings. Fewer than 50 cases of intrasellar ganglion cell lesions
have been reported in the literature, only six of them associated with Cushing's
syndrome. We describe the clinicopathologic features of another eight patients,
three of whom presented with acromegaly, four with apparently nonfunctioning
adenohypophyseal masses, and one with Cushing's syndrome. On histology, six of
them were found to have sparsely granulated growth hormone (GH)-producing
adenomas with ganglion cell areas, one appeared to have a gangliocytoma not
associated with an adenoma, whereas the eighth had a ganglion cell lesion in the
posterior pituitary. The morphologic and immunohistochemical findings suggest
that the ganglion cell component of seven of these tumors has resulted from
neuronal differentiation in a GH-producing adenoma, despite the lack of
demonstrable adenoma in one case. A true sellar "gangliocytoma" or hamartoma of
ectopic hypothalamic-type neurons appears to be a rarer explanation for the
presence of ganglion cells in a pituitary biopsy.
PMID- 10757411
TI - Epstein-Barr virus-associated multicentric leiomyosarcoma in an adult patient
after heart transplantation: case report and review of the literature.
AB - Epstein-Barr virus (EBV)-associated smooth muscle tumors following solid organ
transplantation are extremely rare, with only 12 cases reported in the literature
thus far. The exact pathogenetic role of EBV infection in the oncogenesis of
these soft tissue tumors in immunodeficient patients and the biologic behavior of
such tumors is still unclear. We report a 26-year-old man in whom multiple smooth
muscle tumors developed 36 to 51 months after heart transplantation. All tumors,
two synchronous liver nodules, two subsequently occurring paravertebral tumors,
and a single tumor in a vein at the left ankle were surgically resected. The
tumor tissue was processed for routine histology and immunohistochemical (IHC)
stains. Additionally, competitive polymerase-chain-reaction (PCR), reverse
transcriptase PCR (RT-PCR), as well as in situ hybridization (ISH) were used for
EBV particle quantification and gene transcription analysis. The histologic
features and immunohistochemical profiles were consistent with leiomyosarcoma in
all tumor nodules. EBV infection was detected in >95% of tumor cell nuclei by
EBER 1/2 ISH. Competitive PCR revealed 3105 EBV particles per milligram of tumor
tissue. The EBV gene expression pattern analyzed by RT-PCR and IHC corresponded
to the latency type III with specific expression of EBNA1, EBNA2, LMP1, and LMP2A
genes. Under continuous antiviral therapy (famcyclovir) the patient currently
shows no evidence of disease. Our data indicate that EBV infection plays a causal
role in the development of smooth muscle tumors following organ transplantation.
A latency type III, identical to EBV-associated posttransplant
lymphoproliferative disorders, was identified and suggests a common pathogenetic
mechanism in the development of these histogenetically distinct neoplasms. The
fact that the patient currently shows no evidence of disease may be the result of
the continuous administration of antiviral therapy because the soft tissue
recurrences of the leiomyosarcoma occurred while the patient was not receiving
antiviral prophylaxis.
PMID- 10757412
TI - Pharmacognosy in the new millennium: leadfinding and biotechnology.
PMID- 10757413
TI - Design, synthesis and evaluation of N-basic substituted 3-hydroxypyridin-4-ones:
orally active iron chelators with lysosomotrophic potential.
AB - To investigate the possibility of targeting chelators into the lysosomal iron
pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been
synthesized. As the turnover of ferritin iron is centred in the lysosome, such
strategy is predicted to increase chelator efficacy of bidentate ligands. The pKa
values of the ligands together with their distribution coefficients between 1
octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been
determined. The in-vivo iron mobilization efficacy of these basic 3
hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model.
No obvious correlation was observed between efficacy and the pKa value of the
side chain, although those with pKa > 7.0 tended to be more efficient than those
with pKa < 7.0. The imidazole-containing molecules are much less effective than
the tertiary amine derivatives. A dose-response study suggested that basic
pyridinones are relatively more effective at lower doses when compared with N
alkyl hydroxypyridinones. Optimal effects were observed with the piperidine
derivatives 4h and 4i. The derivative 4i at a dose of 150 micromol kg(-1) was
more effective than 450 micromol kg(-1) deferiprone, the widely adopted clinical
dose.
PMID- 10757414
TI - Pharmacodynamics of S-2150, a simultaneous calcium-blocking and alpha1-inhibiting
antihypertensive drug, in rats.
AB - The in-vivo pharmacodynamics of S-2150, a newly developed dual-blocking type
antihypertensive drug, was evaluated following intravenous infusion to rats.
Previous in-vitro studies showed that the drug has two distinct mechanisms of
antihypertensive effect--calcium-channel blocking activity and alpha1
adrenoceptor antagonism--which could be explained by a combination of two
different pharmacodynamic models. The present in-vivo study showed that S-2150
also displays a complex pharmacodynamic profile (as measured by the decrease in
mean blood pressure), which could be described by a combination of two sigmoid
Emax models independently connected with the central compartment and the effect
compartment. These results suggested that the dual-blocking mechanism of S-2150,
which has been observed in in-vitro experiments, was also evaluated by the
pharmacodynamic analysis of in-vivo experimental data.
PMID- 10757415
TI - In-vivo and in-vitro evidence of a carrier-mediated efflux transport system for
oestrone-3-sulphate across the blood-cerebrospinal fluid barrier.
AB - The efflux transport of oestrone-3-sulphate, a steroid hormone sulphate, across
the blood-cerebrospinal fluid barrier has been examined following its
intracerebroventricular administration. [3H]Oestrone-3-sulphate was eliminated
from cerebrospinal fluid (CSF) with an apparent efflux clearance of 205 microL
min(-1) per rat. There was 25% of unmetabolized [3H]oestrone-3-sulphate in the
plasma 5 min after intracerebroventricular administration, indicating that at
least a part of [3H]oestrone-3-sulphate is transported from CSF to the
circulating blood across the blood-CSF barrier. This efflux transport was
inhibited by co-administration of excess oestrone-3-sulphate (25 mM 10 microL =
0.25 micromol) into rat cerebral ventricle. To characterize the oestrone-3
sulphate transport process, an in-vitro uptake experiment was performed using
isolated rat choroid plexus. Oestrone-3-sulphate uptake by isolated rat choroid
plexus was found to be a saturable process with a Michaelis-Menten constant (Km)
of 18.1 +/- 6.3 microM, and a maximum uptake rate (Vmax) of 48.0 +/- 15.1 pmol
min(-1) microL(-1) of tissue. The oestrone-3-sulphate transport process was
temperature dependent and was inhibited by metabolic inhibitors such as 2,4
dinitrophenol and rotenone, suggesting an energy dependence. This uptake process
was also inhibited by steroid hormone sulphates (1 mM dehydroepiandrosterone
sulphate and 1 mM oestrone sulphate), bile acids (1 mM taurocholic acid and 1 mM
cholic acid) and organic anions (1 mM sulphobromophthalein and 1 mM
phenolsulphonphthalein), whereas 1 mM p-aminohippuric acid, 1 mM p-nitrophenol
sulphate, 0.1 mM methotrexate and the cardiac glycoside, 2.5 microM digoxin, had
little effect. In conclusion, these results provide evidence that oestrone-3
sulphate is transported from CSF to the circulating blood across the blood-CSF
barrier via a carrier-mediated efflux transport system.
PMID- 10757416
TI - Membrane permeation by multidrug-resistance-modulators and non-modulators:
effects of hydrophobicity and electric charge.
AB - This study was designed to test the hypothesis that lipophilic cationic drugs
with only roughly similar structures mediate the reversal of multidrug-resistance
(MDR) by interacting with membrane phospholipids. The permeation properties of
MDR-modulators and non-modulators were studied by quantifying their ability to
induce the leakage of Sulphan blue through the membrane of negatively charged
unilamellar liposomes. Of the 22 compounds under investigation, only those
bearing a net positive electric charge per molecule (z) > or = 0.2 induced dye
leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel
blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin
antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine,
thioacridine derivatives and quinine). The non-modulators tested, including
antineoplastic agents and steroids, did not induce any membrane permeation. The
permeation process was a co-operative one (1.1 < Hill coefficient < 4.1) and the
permeation doses inducing 50% dye leakage (PD50) were 1.9-11.2 mM. The permeation
ability of the MDR-modulators (log(1/PD50)) increased significantly with octanol
buffer distributions per unit net electric charge ((logD)/z). The results provide
evidence that a complex interplay occurs between the electric charge and the
lipophilicity of the MDR-modulators when a dye leakage is induced through model
membranes, and probably also when the MDR is reversed in leukaemic cells.
PMID- 10757417
TI - Effects of lithium on the pharmacokinetics of valproate in rats.
AB - Combined treatment with lithium and valproate has been used for bipolar disorder.
However, the studied interaction between these two drugs has not been fully
investigated. We therefore examined the effects of lithium on the
pharmacokinetics (plasma disappearance, metabolism and urinary excretion) of
valproate in rats. Lithium (2 mEq kg(-1)) was administered intraperitoneally
twice a day for ten days. Plasma disappearance curves of valproate (50 mg kg(-1),
i.v.), valproate-metabolizing activities of UDP-glucuronosyltransferase (UGT) and
cytochrome P450 (CYP) in liver microsomes and urinary excretion of free valproate
and valproate-glucuronide were examined. The metabolizing activity of UGT and CYP
were determined by enzyme assays and a fluorescence polarization immunoassay
system. Urinary valproate-glucuronide was obtained using this system by
subtracting the free level from total level, which was determined after
deconjugating the sample with heat and NaOH. The half-life of plasma
disappearance of valproate was 25% reduced by lithium pretreatment (0.428 +/-
0.031 h with repeated lithium pretreatment vs 0.578 +/- 0.062 h for controls).
The valproate-metabolizing activity of UGT and CYP were not altered by lithium
although lithium increased the urinary excretion of valproate-glucuronide. In
conclusion, lithium pretreatment causes a decrease in plasma valproate levels and
an increase in urinary excretion of valproate-glucuronide in rats.
PMID- 10757418
TI - Intestinal transport of beta-thioglycosides by Na+/glucose cotransporter.
AB - Intestinal metabolism and transport of p-nitrophenyl beta-D-thioglucoside (p
NPbetaSglc) and p-nitrophenyl beta-D-thiogalactoside (p-NPbetaSgal) by the
Na+/glucose cotransporter were studied in excised small intestine of the rat. p
NPbetaSglc and p-NPbetaSgal were stable enough on the mucosal side to be
transported to the serosal side. Transport of p-NPbetaSglc was inhibited in the
presence of phloridzin (a Na+/glucose cotransporter inhibitor), glucose, or 3-O
methylglucose (3-OMG). p-NPbetaSglc transport was dependent on Na+ concentration
in a sigmoidal manner. The activation energy for transport was 19.4 kcal mol(-1).
The distribution of transport activity of p-NPbetaSglc in each region of the
small intestine correlated well with that of 3-OMG. These results indicate that p
NPbetaSglc is transported by the Na+/glucose cotransporter in small intestine.
The order of turnover rate for glycoside transport by Na+/glucose cotransporter
was 3-OMG > p-nitrophenyl beta-O-glucoside > p-NPbetaSglc > p-NPbetaSgal,
indicating that the presence of a galactose moiety and a sulphur between the
monosaccharide moiety and aglycone decreases the turnover rate of the Na+/glucose
cotransporter in the transport of glycosides. In an inhibition study using stable
p-NPbetaSglc as a Na+/glucose cotransporter-transportable marker glucoside, it
was also shown that the Na+/glucose cotransporter recognized several types of
glycosides. In conclusion, displacement of the oxygen at carbon C-1 of glucose by
sulphur in thioglycosides decreases the turnover rate of the Na+/glucose
cotransporter, but thioglycosides are stable in the small intestine and are
transported by the Na+/glucose cotransporter.
PMID- 10757419
TI - Effect of P450 isozyme-selective inhibitors on in-vitro metabolism of retinoic
acid by rat hepatic microsomes.
AB - Cytochrome P450-mediated 4-hydroxylation of retinoic acid is an important pathway
in the termination of its biological action and the activity of certain P450
isozymes has been studied in non-induced male rat hepatic microsomes using
isozyme-selective inhibitors. The importance of the activity of the isozyme to
retinoic acid metabolism was, 2A6 (diethyl dithiocarbamate as selective
inhibitor) > 1A1/1A2 (7,8-benzoflavone) >> 1A1 (ellipticine) > 3A4 (naringenin,
ketoconazole) as shown by the respective apparent IC50 values of 0.12, 0.34, 2.7,
9.25 and 13.5 microM with 2C8-10, 2D6 and 2E1 having little effect on metabolism.
It is concluded that although the P450 3A family normally constitutes half the
total rat hepatic P450 activity, other hepatic isozymes (1A1, 1A2 and 2A6) are
also involved in retinoic acid metabolism. This suggests that the horizons for
the design of potential anticancer agents acting through inhibition of retinoic
acid metabolism may be widened to include structures which do not resemble the
established hetereocyclic base P450 3A4 inhibitors.
PMID- 10757420
TI - Effect of trimethoprim on the renal clearance of lamivudine in rats.
AB - Lamivudine undergoes minimal metabolism and renal clearance of the unchanged drug
is the predominant mechanism of clearance. The effect of trimethoprim on the
renal clearance of lamivudine was investigated in rats in-vivo. Total renal
clearance of lamivudine was about three times higher than the glomerular
filtration rate in rats receiving an infusion of tritium-labelled lamivudine.
Concomitant infusion of trimethoprim reduced the renal clearance of lamivudine to
about half, but did not affect the level of radioactivity in the renal cortex.
When rats received an infusion of lamivudine with probenecid, cimetidine or
quinidine, the renal clearance of lamivudine was only significantly reduced by co
administration of cimetidine. These findings suggest that secretion in the renal
proximal tubule takes an active part in the total renal clearance of lamivudine,
and that cationic drugs such as trimethoprim and cimetidine may inhibit the
secretion of lamivudine without greatly affecting the concentration of lamivudine
in the renal cortex.
PMID- 10757421
TI - Effects of pegylated recombinant human megakaryocyte growth and development
factor on 5-fluorouracil-induced thrombocytopenia in balloon-injured rats.
AB - We examined whether pegylated recombinant human megakaryocyte growth and
development factor (PEG-rHuMGDF) affected 5-fluorouracil-induced thrombocytopenia
without inducing more severe intimal thickening after injury to rat carotid
arteries. Rat carotid arteries were injured using a balloon catheter on day 0. 5
Fluorouracil (100 mg kg(-1)) or vehicle was intravenously administered on day 1
in balloon-injured rats. PEG-rHuMGDF (100 microg kg(-1)) or vehicle was
intravenously administered once a day on days 1-5 to balloon-injured rats given 5
fluorouracil or vehicle. 5-Fluorouracil (100 mg kg(-1), i.v.) caused a
significant decrease in the platelet count from day 3 and peaked on days 7-9 in
balloon-injured rats. PEG-rHuMGDF (100 microg kg(-1), i.v.) reduced this decrease
on days 9 and 11. The administration of PEG-rHuMGDF did not accelerate the
intimal thickening of balloon-injured arteries in rats treated with 5
fluorouracil compared with control balloon-injured rats. PEG-rHuMGDF did not
increase plasma tumour growth factor-beta1 (TGF-beta1) from days 0-9 in balloon
injured rats compared with control balloon-injured rats. These results suggest
that PEG-rHuMGDF ameliorated 5-fluorouracil-induced thrombocytopenia without
accelerating the intimal thickening of balloon-injured arteries.
PMID- 10757422
TI - Histamine release induced by antimicrobial agents and effects of antimicrobial
agents on vancomycin-induced histamine release from rat peritoneal mast cells.
AB - Vancomycin and certain fungicides may cause anaphylactoid reactions. We
investigated the effects of vancomycin, miconazole and fluconazole on histamine
release in rat peritoneal mast cells. Vancomycin and miconazole provoked
histamine release in a dose-dependent manner. In contrast, fluconazole did not
provoke histamine release at concentrations of 3 x 10(-6)-3 x 10(-3) M.
Vancomycin is efficacious in the treatment of gram-positive bacterial infections;
patients presenting themselves with mixed infections require concomitant therapy
with a second antimicrobial agent. We investigated the effect of fosfomycin
sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release.
Fosfomycin sodium inhibited vancomycin-induced histamine release but neither
cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses
used in humans. These results suggest that vancomycin and miconazole provoke
histamine release in rat mast cells, but that fluconazole probably does not,
while fosfomycin sodium may inhibit vancomycin-induced histamine release.
PMID- 10757423
TI - Inhibitory effects of glibenclamide on the contraction of human arterial conduits
used in coronary artery bypass surgery.
AB - Glibenclamide has been shown to inhibit prostanoid-induced contraction in a
number of blood vessel types. In this study, the effects of glibenclamide on the
contraction of human peripheral arteries in response to both prostanoid and non
prostanoid agonists were compared and possible mechanisms of action were
investigated. Segments of left internal mammary artery (LIMA) and radial artery,
taken from patients undergoing coronary artery bypass graft (CABG) surgery, were
mounted in organ baths containing physiological saline solution aerated with 95%
O2/5% CO2 at 37 degrees C. Contractions were obtained by either the use of a
thromboxane analogue (U46619), L-phenylephrine, KCl or CaCl2. The effects of
glibenclamide on these contractions were observed and pEC50 values were
determined after manipulation of a logistic curve-fitting equation. Concentration
dependent relaxation of U46619-contracted LIMA and radial artery was observed in
the presence of glibenclamide, with calculated pEC50 values of 4.2+/-0.17 (n = 7)
for LIMA and 3.26+/-0.48 (n = 5) for radial artery. Incubation of both LIMA and
radial artery with glibenclamide (50 microM) caused the concentration-response
curves for U46619 and L-phenylephrine to shift significantly to the right.
Similarly the KCl tension relationship was caused to shift to the right. Finally,
glibenclamide (100 microM) also had an inhibitory effect on Ca2+-induced tension
in radial artery. These results show that the inhibitory effects of glibenclamide
on human peripheral blood vessels are not restricted to prostanoid-induced
contractions. Furthermore, evidence has been provided to suggest that these
effects might be mediated through an interaction with voltage-sensitive Ca2+
channels.
PMID- 10757424
TI - Protection of rat hepatocytes exposed to CCl4 in-vitro by cynandione A, a
biacetophenone from Cynanchum wilfordii.
AB - To identify hepatoprotective agents from plant sources we use primary cultures of
rat hepatocytes injured by CCl4. The hepatoprotective agents are the compounds
that mitigate the injury caused by CCl4. Using this system we have investigated
the biochemical mechanisms involved in the hepatoprotective activity of
cynandione A, a biacetopherone, isolated from the roots of Cynanchum wilfordii
Hemsley (Asclepiadaceae). Cynandione A (50 microM) significantly reduced
(approximately 50%) the release into the culture medium of glutamic pyruvic
transaminase and sorbitol dehydrogenase from the primary cultures of rat
hepatocytes exposed to CCl4. Glutathione, superoxide dismutase, catalase and
glutathione reductase play important roles in the cellular defence against
oxidative stress. Cynandione A appeared to protect primary cultured rat
hepatocytes exposed to CCl4 from significant drops in the levels of each of these
four specific markers. Cynandione A also ameliorated lipid peroxidation by up to
50% as demonstrated by a reduction in the production of malondialdehyde. These
results suggest that cynandione A protected the hepatocytes from CCl4-injury by
maintaining the level of glutathione and by inhibiting the production of
malondialdehyde, due to its radical scavenging properties.
PMID- 10757425
TI - Chemical characterization and biological activity of Macfadyena unguis-cati
(Bignoniaceae).
AB - Macfadyena unguis-cati (L.) has been widely used in folk medicine as an anti
inflammatory, antimalarial and antivenereal. The purpose of this study was to
chemically characterize the main plant components, and to evaluate the biological
properties of some of the fractions derived from leaves (MACb) and liana (MACa)
of this plant. Chemical characterization allowed the identification of the
compounds corymboside, vicenin-2, quercitrin, chlorogenic acid, isochlorogenic
acid, lupeol, beta-sitosterol, beta-sitosterylglucoside, allantoin and lapachol.
The biological screening of fractions and/or purified substances derived from
fractions revealed antitumoral and antitrypanosomal activities in fractions
MACa/lapachol and MACb/MACb21, respectively. The anti-lipoxygenase and anti
cyclooxygenase effect seen in fractions MACa and MACb showed a partial
correlation with the anti-inflammatory property attributed to this plant.
PMID- 10757426
TI - Antiplatelet effect of marchantinquinone, isolated from Reboulia hemisphaerica,
in rabbit washed platelets.
AB - Platelet activation is involved in serious pathological situations, including
atherosclerosis and restenosis. It is important to find efficient antiplatelet
medicines to prevent fatal thrombous formation during the course of these
diseases. Marchantinquinone, a natural compound isolated from Reboulia
hemisphaerica, inhibited platelet aggregation and ATP release stimulated by
thrombin (0.1 units mL(-1)), platelet-activating factor (PAF; 2 ng mL(-1)),
collagen (10 microg mL(-1)), arachidonic acid (100 microM), or U46619 (1 microM)
in rabbit washed platelets. The IC50 values of marchantinquinone on the
inhibition of platelet aggregation induced by these five agonists were 62.0 +/-
9.0, 86.0 +/- 7.8, 13.6 +/- 4.7, 20.9 +/- 3.1 and 13.4 +/- 5.3 microM,
respectively. Marchantinquinone inhibited thromboxane B2 (TxB2) formation induced
by thrombin, PAF or collagen. However, marchantinquinone did not inhibit TxB2
formation induced by arachidonic acid, indicating that marchantinquinone did not
affect the activity of cyclooxygenase and thromboxane synthase. Marchantinquinone
did inhibit the rising intracellular Ca2+ concentration stimulated by the five
platelet-aggregation inducers. The formation of inositol monophosphate induced by
thrombin was inhibited by marchantinquinone. Platelet cAMP and cGMP levels were
unchanged by marchantinquinone. The results indicate that marchantinquinone
exerts antiplatelet effects by inhibiting phosphoinositide turnover.
PMID- 10757427
TI - Baicalin synergy with beta-lactam antibiotics against methicillin-resistant
Staphylococcus aureus and other beta-lactam-resistant strains of S. aureus.
AB - Bacterial resistance to antibiotics is a serious global problem and includes
strains of beta-lactam-resistant Staphylococcus aureus and methicillin-resistant
S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the
problem are urgently needed. The Chinese herb Xi-nan Huangqin (Scutellaria amoena
C.H. Wright) has been used in traditional Chinese medicine to treat a wide range
of infectious diseases. In this study we have examined the antibacterial action
of baicalin, a flavone isolated from the herb. When combined with 16 microg mL(
1) baicalin, minimum inhibitory concentrations (MICs) of benzylpenicillin against
MRSA and penicillin-resistant S. aureus were reduced from 125 and 250 microg mL(
1) to 4 and 16 microg mL(-1), respectively. This activity of baicalin was dose
dependent. Viable counts showed that the killing of MRSA and beta-lactam
resistant S. aureus cells by 10 to 50 microg mL(-1) ampicillin, amoxycillin,
benzylpenicillin, methicillin and cefotaxime was potentiated by 25 microg mL(-1)
baicalin. From the study it was concluded that baicalin has the potential to
restore the effectiveness of beta-lactam antibiotics against MRSA and other
strains of beta-lactam-resistant S. aureus. In view of its limited toxicity
baicalin offers potential for the development of a valuable adjunct to beta
lactam treatments against otherwise resistant strains of microorganisms.
PMID- 10757428
TI - Summation of the second meeting of the Diabetes in Pregnancy Study Group of North
America (DPSG-NA).
PMID- 10757429
TI - Preconception care of women with diabetes: the unrevealed obstacles.
AB - In spite of the widely accepted knowledge that elevated blood glucose levels in
early pregnancy are associated with a significantly increased risk of birth
defects in infants of women with established diabetes, the majority of diabetic
women do not plan their pregnancies and enter pregnancy with inadequate blood
glucose control. This article reviews the current research on circumstances and
factors associated with unplanned diabetic pregnancies and offers recommendations
to encourage effective pregnancy planning and preconception care among women with
diabetes.
PMID- 10757430
TI - A focused preconceptional and early pregnancy program in women with type 1
diabetes reduces perinatal mortality and malformation rates to general population
levels.
AB - OBJECTIVE: To evaluate the impact of a focused preconceptional and early
pregnancy program specializing in the care of women with Type 1 diabetes on
perinatal mortality and congenital malformations. METHODS: This clinical study
included women with Type 1 diabetes in an interdisciplinary Diabetes in Pregnancy
Program Project Grant (PPG) funded by the NIH (1978-1993); these women were
enrolled preconceptionally or during the first trimester (up to 14 weeks) and had
pregnancies continuing beyond 20 weeks gestation. Strict glucose control was
implemented and adherence assessed. Antepartum fetal surveillance was started at
32 weeks gestation. All live-born infants and stillbirths were examined. A
retrospective comparison analysis of the period before PPG I (1973-1978) and
after cessation of funding (1993-1999) was performed, specifically evaluating
perinatal mortality and congenital malformation rates. Data were analyzed using
analysis of variance, chi2, and Fisher's exact test. RESULTS: Three hundred and
six women were enrolled in three 5-year periods: PPG I (1978-1983) n = 111, PPG
II (1983-1988) n = 103, and PPG III (1988-1993) n = 92. Entry and interval
glycohemoglobin A1 concentrations obtained decreased with each consecutive PPG.
An emphasis on preconception care began in 1984, with preconception enrollment
reaching 23% for PPG II and increasing in PPG III to 37%. As preconception
enrollment increased, perinatal mortality rate decreased from 3% for PPG I and 2%
for PPG II, to 0% in PPG III, and the congenital malformation rate decreased to a
low 2.2% by PPG III. Comparison data collected for the period before PPG 1 (1973
1978) n = 79 revealed a perinatal mortality rate of 7% and a congenital
malformation rate of 14%. Also, a postprogram retrospective analysis of the
period 1993-1999 (n = 82) revealed an increase in perinatal mortality, with one
death compared to none in PPG III, and a congenital malformation rate of 3.65%
compared to 2.2% during PPG III. The preconception enrollment for this period
decreased (19.5%). CONCLUSIONS: A program emphasizing preconceptional care,
strict glycemic control preconceptionally and throughout gestation, and the use
of antepartum fetal surveillance was associated with a significant decrease in
the rate of perinatal mortality and congenital malformations in infants of women
with Type 1 diabetes. However, ongoing improved outcome appears to depend on the
availability of funding for a specialized preconception program.
PMID- 10757431
TI - Medical nutritional therapy in pregnant women with pregestational diabetes
mellitus.
AB - OBJECTIVE: Diabetic women now can have the same chances as nondiabetic women to
have a healthy infant. The reduction of risk associated with pregnancies
complicated by diabetes can only be assured if normoglycemia is achieved before
and during pregnancy. This review is intended to provide guidelines and
scientific evidence for the optimal diet for the Type 1 or Type 2 diabetic woman.
METHODS: The literature over the past 10 years is presented. Those diets which
achieved the best outcome of pregnancies complicated by diabetes (as evidenced by
term delivery of a healthy, normal weight infant) are then outlined. RESULTS:
Diets which provide adequate calories without causing postprandial hyperglycemia
or premeal ketosis are found to be based on body weight and gestational week of
the pregnancy. Quantity of carbohydrate in the meal plan emerges as the most
important component in achieving and maintaining glucose control. CONCLUSIONS:
The medical nutritional therapy for the Type 1 and Type 2 diabetic woman is a
necessary component of the overall strategy to achieve and maintain normoglycemia
and thus achieve the best outcome of pregnancy.
PMID- 10757432
TI - Glycemic control in the diabetic pregnancy: is tighter always better?
AB - Glucose is the principal nutrient that the mother supplies to the fetus through
the placenta by way of concentration-dependent mechanisms. In the presence of
maternal hypoglycemia, with limited glucose supply, fetal hypoglycemia and
hypoinsulinism ensue. This may be viewed as an adaptive mechanism to increase the
chances of fetal survival in the face of limited maternal supply, albeit of a
growth-restricted fetus. Fetal nutrient deprivation and the resulting
hypoinsulinism may have both short- and long-term consequences. Intrauterine
growth failure is associated with higher rates of gestational age-specific
neonatal mortality and with long-term cognitive deficits. Furthermore,
epidemiologic data suggest that diabetes, coronary artery disease, and
hypertension are more common among adults who were small for gestational age at
birth. Thus, pancreatic failure in adulthood may be either a response to
excessive exposure to glucose as a result of maternal hyperglycemia, or as a
result of hypoglycemia where nutrient deprivation leads to fetal growth
restriction and reduced islet cell proliferation. Because low mean concentrations
of maternal glucose in gestational diabetes are associated with an increased risk
of fetal growth restriction, overzealous glycemic control during pregnancy may
raise concerns regarding the possible effects on the infant. In the mother with
Type 1 diabetes, strict glycemic control is often associated with an increased
incidence of severe hypoglycemia. Up to 40% of women report at least one episode
of severe hypoglycemia during pregnancy, requiring assistance by another person
or professional intervention. It is quite possible that in some patients striving
to optimize pregnancy outcome by maintaining the best possible glycemic control
jeopardizes the well-being of the mother and the fetus. Thus, with respect to
tight glycemic control of pregnant women with diabetes, the question arises: How
tight is too tight? Is there a threshold below which the trade-off in terms of
maternal morbidity as well as fetal growth restriction and its consequences
outweighs the benefits of preventing the effects of maternal hyperglycemia?
PMID- 10757433
TI - Level of glycemia and perinatal outcome in pregestational diabetes.
AB - This article provides the reader with relevant information regarding the
association between level of glycemia and perinatal outcome in preexisting
diabetes. Although the glycemic profile is a continuum in nature, different
thresholds of glucose are associated with fetal complications such as stillbirth,
spontaneous abortion, congenital anomalies, fetal macrosomia, and metabolic and
respiratory complications. For each complication, a different targeted threshold
of normality is required. Thus, although it is not always possible to achieve
optimal glycemic control in all patients, any improvement will be beneficial
because it will reduce the rate of complications for a given glucose threshold.
PMID- 10757434
TI - New concepts and applications in the use of the insulin pump during pregnancy.
AB - Subcutaneous insulin infusion or insulin pump therapy has been advocated as an
alternative to multiple dose insulin injections for nearly two decades. These
devices provide insulin administration in a pattern which more closely resembles
that of physiologic insulin release, a basal insulin infusion during the day and
throughout the night with boluses given prior to meals. Because the number of
patients using an insulin pump is increasing, it is likely the perinatologist
will encounter women who are being treated with an insulin infusion pump or are
considering this therapy. Insulin pump therapy requires that the patient be
highly motivated and compliant. One of the most important criteria in selecting
patients for this treatment is their willingness to test their capillary glucose
levels 6 to 8 times each day. Interruption of the insulin infusion can produce
hyperglycemia in any pump user. Should this occur in the pregnant patient, the
likelihood of ketoacidosis developing is significantly greater. Ideally, insulin
pump therapy should be initiated prior to pregnancy so that glucose control can
be normalized, thereby reducing the risk for spontaneous abortion and fetal
malformations. Gradually improving glucose control prior to pregnancy can reduce
the likelihood of deterioration of retinopathy, which has been observed when
poorly controlled pregnant patients rapidly become euglycemic. The published
experience with the insulin pump has demonstrated that this therapy can achieve
glucose control and perinatal outcomes comparable to that obtained with multiple
dose insulin injection therapy.
PMID- 10757436
TI - Prenatal diagnosis of macrosomia in pregnancy complicated by diabetes mellitus.
AB - OBJECTIVE: To provide a concise review of current practices regarding prenatal
diagnosis of excess fetal growth in pregnancies complicated by diabetes mellitus.
METHODS: A literature review of relevant publications. RESULTS: Sonographic
estimation of fetal size at term is frequently undertaken in the management of
diabetic pregnancy. Considerable error in fetal weight estimations, particularly
in asymmetrically enlarged fetuses, may limit the accuracy and clinical utility
of these measurements. CONCLUSIONS: The limitations and potential inaccuracy of
current sonographic methods to detect the large-for-gestational age fetus of a
diabetic mother are acknowledged. Customized formulae are of limited benefit so
that further study of techniques aimed at assessing fetal fat content and
distribution should be undertaken. These methods may improve detection of the
large fetus and aid in clinical decision making.
PMID- 10757435
TI - Present and future perspectives on the use of free or encapsulated pancreatic
islet cell transplantation as a treatment of pregnancy complicated by type 1
diabetes.
AB - Pregnancies complicated by insulin-dependent diabetes mellitus (IDDM) pose
significant health risks to both the mother and her developing fetus. Congenital
malformations in the offspring of diabetic mothers have an incidence which is 2-5
times that seen in the background. Euglycemia in the first trimester of pregnancy
can reduce this incidence, but achieving euglycemia with conventional exogenous
insulin therapy is both costly and difficult. Even with intense insulin dosage
adjustments, the blood glucose profile of the diabetic pregnant patient does not
mimic that seen in nondiabetic patients. Both the difficulties and inadequacies
of conventional therapy for IDDM-complicated pregnancy provide a stimulus for
research to develop improved therapeutic modalities. Islet transplantation holds
great promise as a treatment for pregnancies complicated by IDDM. This article
reviews the current status of islet transplantation including the use of
immunomodulation and immunoisolation techniques and their potential use for the
treatment of IDDM pregnancies.
PMID- 10757437
TI - Sonographic EFW and macrosomia: is there an optimum formula to predict diabetic
fetal macrosomia?
AB - OBJECTIVE: To compare the accuracy of 31 published formulas for estimated fetal
weight (EFW) in predicting macrosomia (birthweight 4,000 gm or more) in infants
of diabetic mothers. METHODS: The study population comprised 165 women with
gestational or pregestational diabetes who had sonograms to estimate fetal weight
after 36 weeks of gestation and within 2 weeks of delivery. Three measures of
accuracy were compared: 1) area under the receiver operating characteristic (ROC)
curve relating EFW to macrosomia, 2) systematic error, and 3) absolute error. For
each measure, the 31 formulas were rank-ordered from 1 (best) to 31 (worst). For
each formula, the three rank scores were summed to give a total score. The
formula with the lowest total score was considered the "best" formula. RESULTS:
Macrosomia occurred in 49 cases (30%). Areas under the ROC curves ranged from
0.8361-0.8978. Differences in areas were not significantly different between the
31 formulas. The 1986 formula of Ott et al. had the lowest total score. Using
this "best" formula, an EFW of 4,000 gm or more had a sensitivity of 45% to
predict macrosomia and a positive predictive value of 81%. To achieve 90%
sensitivity with this formula would have required diagnosis of macrosomia with an
EFW of 3,535 gm or more, but this would have comprised 46% of the population with
a 42% false-positive rate. All 31 formulas were better at predicting macrosomia
than predictions based on gestational age alone, and 28 were better than
predictions based on abdominal circumference alone. CONCLUSIONS: All 31 formulas
for EFW had comparably poor accuracy for prediction of macrosomia. Delivery
decisions based on EFW will often be in error. Future studies should determine
whether specific sonographic measurements, ratios, or differences are better than
EFW or birthweight as predictors of birth trauma.
PMID- 10757439
TI - Selecting antihypertensive therapy in the pregnant woman with diabetes mellitus.
AB - The choice of an antihypertensive agent for the pregnant woman with diabetes
involves many factors. We seek to avoid adverse fetal effects while optimizing
maternal outcome, both short- and long-term. This article examines the existing
literature to define therapeutic goals of antihypertensive therapy during
pregnancy as compared to the therapeutic goals of antihypertensive therapy in the
setting of diabetes mellitus and to integrate this information for the treatment
of pregnant women in whom diabetes mellitus and hypertension coexist.
PMID- 10757438
TI - Risk factors, pregnancy complications, and prevention of hypertensive disorders
in women with pregravid diabetes mellitus.
AB - OBJECTIVE: To review the rate, risk factors, and potential prevention of
preeclampsia in women with pregravid diabetes mellitus. METHODS: Detailed review
of recent English literature describing pregnancy outcome in women with pregravid
insulin-dependent diabetes mellitus (Type 1 diabetes). The primary focus of the
review is risk factors for preeclampsia and potential methods suggested for
prevention of preeclampsia. In addition, pitfalls in diagnosis of preeclampsia
will be emphasized. RESULTS: The reported rate of preeclampsia ranged from 9% to
66%. This rate increased with increased severity of diabetes by White's
classification, with the highest rate reported in women with pregravid diabetic
nephropathy. Risk factors identified for preeclampsia were nulliparity, chronic
hypertension, microalbuminuria prior to pregnancy, nephropathy, and poor glycemic
control early in pregnancy. There is lack of agreement among reports in the
literature concerning criteria used to diagnose preeclampsia. There are two
randomized trials that included women with Type 1 diabetes who were randomized to
receive either low-dose aspirin or placebo. There was no reduction in the rate of
preeclampsia with low-dose aspirin in either trial. CONCLUSIONS: In women with
pregravid Type 1 diabetes, the rates of preeclampsia and adverse neonatal outcome
increase with increased severity of diabetes. Low-dose aspirin does not reduce
rate of preeclampsia in such women. Further studies should address the role of
good glycemic control prior to 20 weeks gestation and prevention of
microalbuminuria.
PMID- 10757440
TI - Effect of medical therapy on progressive nephropathy: influence of pregnancy,
diabetes and hypertension.
AB - Nephropathy is a complication of diabetes mellitus that can affect women in their
reproductive years. This article reviews the effects on treatment on the main
factors associated with short- and long-term complications in pregnant women with
diabetic nephropathy. Tight glycemic control, adequate treatment of elevated
blood pressure, and renal function in early pregnancy are the most significant
predictors of maternal and perinatal outcomes. Contemporary methods of perinatal
care and adequate treatment of blood pressure allow fetal survival rates of 95%.
Furthermore, pregnancy per se does not appear to worsen the natural progression
to end-stage renal disease for most women with renal insufficiency. However,
patients with moderate to severe renal impairment may experience acceleration of
renal disease.
PMID- 10757441
TI - Oxidative stress causes vascular dysfunction in the placenta.
AB - Increased production of superoxide and nitric oxide may produce oxidative stress
in the placenta by formation of the prooxidant peroxynitrite, which itself causes
vascular dysfunction. Nitrotyrosine residues, which are a marker of peroxynitrite
formation and action, are found in placental vessels of preeclamptic and diabetic
pregnancies, indicating oxidative stress. Treatment of the placental vasculature
with authentic peroxynitrite in vitro attenuates responses both to
vasoconstrictors such as the thromboxane mimetic U46619 and to vasodilators,
including glyceryl trinitrate and prostacyclin, indicating it has caused vascular
dysfunction. Further, the responses of the fetal-placental vasculature of
diabetic and preeclamptic placentae to these same vasoconstrictor and vasodilator
agents are significantly attenuated when compared to responses in normal control
placentae. Together these data suggest there may be a cause and effect
relationship between formation and action of peroxynitrite and vascular
dysfunction in the placenta of both preeclamptic and diabetic pregnancies. The
presence of such attenuated vascular responses indicates that perhaps the
placenta may not be able to adequately respond to demands for altered blood flow
in situations where this is necessary in preeclamptic or diabetic pregnancies,
thus leading to further fetal compromise.
PMID- 10757442
TI - Effect of diabetes in pregnancy on offspring: follow-up research in the Pima
Indians.
AB - OBJECTIVE: To review data on the long-term effects of prenatal exposure to the
diabetic intrauterine environment in the Pima Indians of Arizona. This population
has high rates of Type 2 diabetes mellitus that has a strong genetic component
and develops at young ages. METHODS: Since 1965, Pima Indians at least 5 years
old participated in a study of diabetes and its complications. This study
consisted of biennial examinations with measurements of obesity and glucose
tolerance and of glucose tolerance testing during pregnancy. The longitudinal
nature of the study has permitted comparisons of data collected on children and
young adults whose mothers were tested during pregnancy. RESULTS: Offspring of
women who had diabetes during pregnancy were more obese and had a higher
prevalence of Type 2 diabetes. Exposure to the diabetic intrauterine environment
was responsible for about 40% of Type 2 diabetes in 5-19-year-old children
between 1987 and 1996--approximately twice the attributable risk found between
1967 and 1976. Over 70% of persons with prenatal exposure have Type 2 diabetes at
25-34 years of age. CONCLUSIONS: The effects of the diabetic pregnancy can be
thought of as a vicious cycle, with consequences for the offspring extending well
beyond the neonatal period. The young woman whose mother had diabetes during
pregnancy is at risk of perpetuating the cycle by developing diabetes by her
childbearing years. In this population, much of the increase in childhood Type 2
diabetes can be attributed to the diabetic intrauterine environment, which may be
a factor in the alarming rise of this disease nationally.
PMID- 10757443
TI - Microsatellite instability and frameshift mutations in genes involved in cell
cycle progression or apoptosis in ovarian cancer.
AB - The loss of mismatch repair enzymes increases the mutation rate in
microsatellites and coding regions of the genome and appears to be involved in
drug resistance. The replication error (RER+) phenotype, associated with
microsatellite instability, has been widely described for both familial and
sporadic colon cancers and for gastric and endometrial tumors. For ovarian
cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We
analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for
microsatellite instability and for mutations in the coding regions of different
genes, including the recently discovered human CHK-1 gene, which has an important
role in controlling cell cycle progression and whose coding region contains a
poly(A)9 tract. Microsatellite instability and frameshift mutations in coding
regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in
ovarian cancer samples and cell lines by polymerase chain reaction (PCR).
Approximately 26% of patients showed microsatellite instability in two or more
loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX
mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our
findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer.
The low rate of mutation in genes previously reported to be altered in colon and
gastric cancer suggests that other not yet identified genes might be altered and
could play a role in tumor progression and response to treatment in RER+ ovarian
tumors.
PMID- 10757444
TI - Effects of mitomycin C and carboplatin pretreatment on multidrug resistance
associated P-glycoprotein expression and on subsequent suppression of tumor
growth by doxorubicin and paclitaxel in human metastatic breast cancer
xenografted nude mice.
AB - Overexpression of P-glycoprotein (Pgp), multidrug resistance-associated protein
(MRP), and several other proteins has been associated with development of
multidrug resistance by cancer cells, which represents a significant obstacle to
successful treatment by chemotherapy. We had previously demonstrated that a
single noncytotoxic dose of mitomycin C (MMC), carboplatin, or one of several
other DNA cross-linking agents suppressed mRNA expression of the mdr1 gene coding
for Pgp, leading to a subsequent suppression of Pgp protein levels and a
concomitant decrease in drug efflux. Pretreatment with MMC led to a 5- to 10-fold
decrease in the ED50 for cell killing by a subsequent agent such as the Pgp
substrate, doxorubicin, but did not affect killing by the non-Pgp substrate,
cisplatin. In this study, we report that MMC and carboplatin each significantly
suppressed Pgp protein levels in human MDA-MB-435 cells xenografted as solid
tumors into the lateral mammary fat pads of female nude mice, with a similar time
course as had previously been observed in cell culture. Pretreatment of mice with
MMC or carboplatin 48-72 h prior to receiving either doxorubicin or paclitaxel
caused a significantly greater reduction in tumor growth rate compared to either
agent alone or the combination given simultaneously. These data suggest that a
combination chemotherapy regimen consisting of a DNA cross-linking agent given to
modulate the MDR phenotype, followed by a second cytotoxic agent, may be an
effective treatment for human patients with de novo or late stage acquired
multidrug-resistant malignancies.
PMID- 10757445
TI - C-erbB-2 mRNA in breast cancer specimens that exhibit membrane or cytoplasmic
immunoreactivity for c-erbB-2.
AB - Immunocytochemically detected membrane staining for c-erbB-2 in 20-30% of breast
cancers correlates with a poorer prognosis for the patients. However, cytoplasmic
immunoreactivity for c-erbB-2 has also been found in some specimens using some
particular antisera, and it has been suggested that this staining arises from a
protein located in the mitochondrial membrane. It is possible that this protein
is an alternative form of c-erhB-2. In the present article, adjacent histological
sections have been stained for c-erbB-2 immunocytochemically, and for c-erbB-2
mRNA by in situ hybridization. The results show the absence of c-erbB-2 mRNA in
regions of cancer specimens that exhibit cytoplasmic staining for c-erbB-2,
strongly suggesting that cytoplasmic staining for c-erbB-2 is an
immunocytochemical artefact.
PMID- 10757446
TI - Establishment of a quantitative mouse dorsal air sac model and its application to
evaluate a new angiogenesis inhibitor.
AB - We have developed an improved mouse dorsal air sac model for quantifying in vivo
tumor-induced angiogenesis. In our improved model, tumor angiogenesis is
determined by measuring the blood volume in an area of skin held in contact with
a tumor cell-containing chamber, using 51Cr-labeled red blood cells (RBC). The
blood volume induced by murine B16-BL6 melanoma cells increased linearly with the
cell number in the range from 2 x 10(5) to 5 x 10(6). Ten of 11 human tumor cell
lines examined induced a significant increment in blood volume. For three
representative human tumor cell lines (A549, WiDr. and HT1080 cells) that showed
different angiogenic potencies, the levels of vascular endothelial growth factor
(VEGF) produced by the tumor cells cultured under conditions of hypoxia and high
cell density were correlated with the degree of in vivo angiogenesis. Using the
improved model, it was confirmed that TNP-470, a well-known inhibitor, and
borrelidin, an antibiotic from Streptomyces rochei, significantly inhibited the
WiDr cell-induced angiogenesis. Borrelidin also inhibited spontaneous lung
metastasis of B16-BL6 melanoma at the same dose that inhibited angiogenesis. Our
results suggest that the improved mouse dorsal air sac model can be used for
simple and quantitative measurement of tumor-induced angiogenesis and its
inhibition.
PMID- 10757447
TI - Sodium butyrate modulates p53 and Bcl-2 expression in human retinoblastoma cell
lines.
AB - Sodium butyrate (SB) is a potent biological modifier that can induce diverse
effects including growth inhibition, differentiation, or apoptosis of many cell
types including retinoblastoma (Rb), and modulation of genes such as c-fos and
p53. In this study we assessed the effects of SB on cell growth and expression of
p53, critical for cell cycle control, and Bcl-2, an inhibitor of apoptosis, in
two human Rb cell lines (Y79 and WERI-Rb1). Attachment cultures were treated with
1 mM SB for up to 5 days and immunocytochemistry was used to examine for the
expression of neural cell adhesion molecule (NCAM), p53, and Bcl-2. Suspension
cultures of both cell lines were also treated with 1 and 4 mM SB, and at selected
times cell extracts were prepared and the expression of p53 and Bcl-2 proteins
determined by Western blot analysis. Treatment with 1 mM SB of both cell lines
for 5 days inhibited growth and induced morphological changes including extension
of neurite-like processes. Up to 12 h after 1 mM SB treatment, p53 and Bcl-2
expressions were similar to control levels, then gradually decreased to very low
levels at 5 days. SB (4 mM) also inhibited growth associated with cell death,
which was apparent at 24 h posttreatment. Expressions of p53 and Bcl-2 were
decreased below control levels at 4 h, and by 24 h only very low levels of
protein were detected. SB-induced modulation of p53 and Bcl-2 expression may have
implications for controlling Rb growth, particularly in combination with
chemotherapy drugs, which are increasingly used in the treatment of Rb.
PMID- 10757448
TI - Thyroglobulin in serum as an indicator of iodine status during pregnancy.
AB - Serum thyroglobulin and thyrotropin as well as urinary iodine concentrations were
measured in healthy, pregnant Swedish (n=27) and Sudanese (n=21) women and the
results compared with those of healthy Swedish (n=14) and Sudanese (n=20) non
pregnant controls. The median thyroglobulin concentrations (and interquartile
range) in the Swedish pregnant women for the three trimesters were 15.5 (8-24),
10.5 (7-19) and 18.0 (13-25) microg/L, respectively. The median third trimester
concentration was higher than both the first and second trimester concentrations,
respectively (p<0.0001, p<0.0001). Compared to the control group, the Swedish
pregnant women had a significantly higher median thyroglobulin concentration in
the third trimester (p<0.05). Among the Sudanese pregnant women, the median serum
thyroglobulin concentrations (and interquartile range) were 27.5 (12-40), 25.0
(15-43) and 30.0 (15-67) microg/L during the first, second and third trimesters,
respectively. There were no significant differences between these concentrations.
Compared to the control group, the Sudanese pregnant women had a significantly
higher median thyroglobulin in the third trimester (p<0.01). The Sudanese
pregnant women also showed significantly higher median thyroglobulin
concentrations than the Swedish pregnant women in all the three trimesters of
pregnancy (p<0.05, p<0.001 and p<0.01, respectively). However, there were no
significant differences between the two non-pregnant controls. Among the Swedish
pregnant women, 40%, 23% and 30% of the subjects showed serum thyroglobulin
concentrations above 20 microg/ L during the first, second and third trimesters
of pregnancy, respectively. Corresponding figures for the Sudanese pregnant women
were 55%, 61% and 64%, respectively. A significantly negative correlation was
shown between serum thyroglobulin and urinary iodine concentrations during the
second and third trimesters in the Swedish women (r= -0.8, p=0.01 and r= -0.5,
p=0.03, respectively), and in the third trimester in the Sudanese women (r= -0.6,
p=0.03). No such correlation was observed between thyrotropin and urinary iodine
concentration in either the Swedish or the Sudanese pregnant women. It is
concluded that serum thyroglobulin is a more sensitive indicator of iodine
deficiency than serum thyrotropin during pregnancy.
PMID- 10757449
TI - Diagnostic value of the mean corpuscular volume in the detection of vitamin B12
deficiency.
AB - In clinical practice, the finding of an elevated mean corpuscular volume (MCV),
macrocytic anaemia or specific neurological symptoms is often the reason to test
for vitamin B12 (B12) deficiency. Use of the MCV as a test for the detection or
exclusion of B12 deficiency is only justified if the diagnostic accuracy is
sufficiently high. However, the sensitivity and specificity are not well known.
We performed a systematic review of the diagnostic value of an elevated MCV for
B12 deficiency in both anaemic and non-anaemic patients. Of approximately 3500
titles and/or abstracts that were screened, 37 original papers contained usable
data. The population under study proved to be the characteristic of major
influence on the study outcome. Pooling of data from different studies was
performed in subsets of the data corresponding to the different populations
studied. The cut-off levels of both MCV and serum B12 had a significant influence
on the study outcomes. The data, however, were pooled without taking these cut
off levels into account. The pooled estimates should be interpreted with this
limitation in mind. The reference standards were (1) a low serum B12
concentration and (2) a B12 deficiency confirmed by low serum B12 combined with
additional diagnostic investigations. In the population that was randomly
screened for low serum B12, the sensitivity of the MCV for B12 deficiency was
17%, whereas the sensitivity was 30% for B12 deficiency in patients with anaemia.
When measurement of serum B12 was ordered to exclude B12 deficiency as part of
the patients' treatment, the sensitivity was 30% for low serum B12 concentration,
58% for B12 deficiency and 75% for B12 deficiency in patients with anaemia. In
the population with pernicious anaemia, the sensitivity was far from perfect
(77%). In the five studies that reported data on the positive predictive value of
the MCV for B12 deficiency, this ranged from 0% (0/6) to 55% (11/20). This
systematic review shows that a considerable number of B12-deficient patients will
remain unnoticed when the MCV is used to rule in patients for further evaluation.
Depending on the population studied, up to 84% of cases will than be missed. The
MCV can be used to make the diagnosis of B12 deficiency more--or less--probable.
An elevated MCV justifies the measurement of serum B12. The MCV should not be
used as the only parameter ruling out the diagnosis of B12 deficiency.
PMID- 10757450
TI - Evaluation of argatroban and DUP 714 as anticoagulants for blood gas, electrolyte
and ionized calcium analyses.
AB - The objective of this study was to determine if the thrombin inhibitors
Argatroban and DUP 714 could anticoagulate whole blood without influencing the
analyses of blood gases, electrolytes, ionized calcium or CO-oximetry. The
anticoagulant potency of DUP 714 (0.5-68 micromol/l) and Argatroban (1.5-390
micromol/l) was evaluated using the activated partial thromboplastin time (APTT),
prothrombin time (PT) and whole blood clot time (WBCT). APTT and the PT were
measured using a Behring Fibrintimer. APTT was found to be more sensitive to
prolongation by both of the thrombin inhibitors than were the PT or WBCT assays.
DUP 714 was found to a more potent anticoagulant than Argatroban. DUP 714
anticoagulated specimens (>2.2 micromol/l) did not clot for at least 2 days,
whereas Argatroban preserved specimens (390 micromol/l) clotted within 5.5 h of
collection. No statistically significant changes in the measurement of pH, PCO2,
PO2, Na, K, ionized calcium, oxyhaemoglobin, deoxyhaemoglobin, methaemoglobin or
carboxyhaemoglobin (measured using a Corning 288 Blood Gas/Electrolyte Analyzer
and a Coming 270 CO-oximeter) were detected in DUP 714 (34 micromol/l) or
Argatroban (390 micromol/l) anticoagulated whole blood specimens. In conclusion,
DUP 714 and Argatroban are suitable anticoagulants for preserving blood prior to
blood gas and electrolyte analyses.
PMID- 10757451
TI - The euglycemic hyperinsulinemic clamp examination: variability and
reproducibility.
AB - The aim was to examine the reproducibility of the euglycemic hyperinsulinemic
clamp method. From a random population sample of 60-year-old clinically healthy
men, 32 subjects with varying degrees of insulin sensitivity were recruited.
Conventional 2-h clamp examinations were carried out at an interval of 2 weeks.
Insulin was infused intravenously (priming for 10 min and thereafter 1.0 mU/kg
body wt/min). Glucose was infused concomitantly aiming at a whole blood glucose
of 5 mmol/L. The glucose infusion rate (GIR) was adjusted for body weight or fat
free mass (FFM), the latter measured with dual-energy X-ray absorptiometry.
During the final hour of each examination (60-120 min) the mean whole blood
glucose concentrations were 5.06+/-0.15 and 5.09+/-0.17 mmol/L, respectively. Of
the different time intervals studied, the glucose infusion rate during the final
hour (GIR60-120) showed the highest correlation and lowest coefficient of
variation (GIR60-120 adjusted by FFM: r=0.70, coefficient of variation=14.7%).
Adjustment of GIR for weight instead of FFM underestimated insulin sensitivity in
obese men. GIR60-120 adjusted for FFM tended to increase during the second
examination. The measurement error was constant across all GIR. In summary, the
euglycemic hyperinsulinemic clamp method has a coefficient of variation around
15%. The glucose infusion rate should be adjusted for fat free mass.
PMID- 10757452
TI - Reference interval for serum C-reactive protein in healthy blood donors using the
Dade Behring N Latex CRP mono assay.
AB - Measurement of the serum concentration of the acute-phase reactant C-reactive
protein (CRP) provides an useful objective marker in clinical practice, both in
screening for diseases and in monitoring disease activity and response to
therapy. The aim of this study was to evaluate the analytical performance of the
assay in the concentration range from 0.2 to 15 mg/L, and to determine a
reference interval for serum CRP in healthy blood donors using the Dade Behring N
Latex CRP mono assay on the Dade Behring Nephelometer II. The assay is a particle
enhanced nephelometric immunoassay with a measuring range of 0.2-1100 mg/L. The
sample volume is 40 microL, and the assay time is 6 min. The coefficients of
variation for within-run and between-run imprecision studies were between 2.2 and
5.4% in serum pools with CRP concentrations between 1.29 and 11.98 mg/L.
Linearity studies showed excellent correlation between the theoretical and the
measured values. No interferences were detected from hemoglobin <1.0 mmol/L,
bilirubin <512 micromol/L and Intralipid <20 g/L. Blood samples were collected
from 268 healthy blood donors (107 females and 161 males) between 20 and 65 years
old. The non-parametric reference intervals for serum CRP was calculated to be
<0.2-14.7 mg/L in females and <0.2-9.16 mg/L in males. The Mann-Whitney U-test
revealed no gender-related difference for serum CRP (p-value=0.72). A common
reference interval for serum CRP for both genders was calculated to be <0.2-10.5
mg/L (median 0.98 mg/L, range <0.2-17.3 mg/L).
PMID- 10757453
TI - The link between high-fat meals and postprandial activation of blood coagulation
factor VII possibly involves kallikrein.
AB - Contrary to low-fat meals, high-fat meals are known to cause postprandial factor
VII (FVII) activation, but the mechanism is unknown. To study the postprandial
FVII activation in detail, 18 young men consumed in randomized order high-fat or
low-fat test meals. Fasting and non-fasting blood samples were collected. The
high-fat test was associated with an increase in plasma triglyceride and
kallikrein concentrations and postprandial FVII activation (p<0.001). Plasma
kallikrein was strongly associated with triglycerides in fasting and non-fasting
samples (r2=0.74-0.87, p<0.0001), suggesting that triglyceride-rich lipoproteins
may activate prokallikrein. Neither plasma triglycerides nor kallikrein and
activated FVII were statistically associated. This may suggest that additional
factors are involved in the postprandial FVII activation. No clear evidence for a
role of tissue factor expression by monocytes, factor XII or insulin in
postprandial FVII activation was observed. Tissue factor pathway inhibitor and
prothrombin fragment 1+2, a marker of thrombin generation, were not affected
postprandially after either the high-fat or the low-fat meals. Our findings
indicate that triglyceride-rich lipoproteins activate prokallikrein
postprandially, which might form an important initial event in FVII activation
after consumption of high-fat meals.
PMID- 10757454
TI - Differential responses of plasma atrial and brain natriuretic peptides to acute
alteration in atrial pressure in pigs.
AB - To describe the differential dynamic responses of atrial natriuretic peptide
(ANP), N-terminal proatrial natriuretic peptide (Nt-proANP) and brain natriuretic
peptide (BNP) to acute changes in atrial pressure, 6 pigs were studied during and
after a 24-h period of rapid atrial pacing (225 bpm). During pacing, left atrial
pressure increased acutely. ANP plasma concentrations showed a sharp initial peak
followed by a decline, but remained significantly increased throughout the 24-h
period. Nt-proANP followed a smoother pattern, increasing significantly only
after 24 h. BNP increased significantly after 8 h after pacing and even more
after 24 h. An opposite but similarly differential pattern of peptide responses
was found in the post-pacing period. The different responses in ANP, Nt-proANP
and BNP plasma concentrations may reflect the different mechanisms of regulation
of secretion as well as plasma clearance. If the present findings reflect the
acute clinical situation in humans, they may be of diagnostic relevance. An
isolated ANP elevation would indicate a recent acute pressure increase, while
elevation of two or more natriuretic peptides would point to a pressure increase
of longer duration.
PMID- 10757455
TI - Age-related reference limits for urine levels of albumin, orosomucoid,
immunoglobulin G and protein HC in children.
AB - Urine levels of albumin, orosomucoid (alias alpha1-acid glycoprotein),
immunoglobulin G (IgG) and protein HC (alias alpha1-microglobulin) were
determined in 247 healthy Swedish infants and children aged 1 day to 15 years.
Urine samples were collected and stored in conditions known to guarantee stable
protein levels. The protein levels were measured both as mass concentrations (mg
l(-1)) and as protein-creatinine ratios (mg mmol(-1)). In an effort to arrive at
practically useful upper reference limits, the variability with age for both
units was analysed. The variability with age for the levels of three of the four
proteins was considerably lower when the levels were expressed as creatinine
ratios rather than as mass concentrations. The results allowed suggestion of the
following upper reference limits, expressed as mg mmol(-1) creatinine, for use in
clinical practise: IgG, 1 month to 15 years: 1.0; protein HC, 1 month to 15
years: 0.8; orosomucoid, 1 month to 15 years: 0.5; albumin, 1 month to 1 year:
3.8; 1-5 years: 3.3; 6-10 years: 2.7; 11-15 years: 2.1. In the immediate neonatal
period the urine levels of all proteins were high and very variable.
PMID- 10757456
TI - Temperature of a test solution influences abdominal symptoms in lactose tolerance
tests.
AB - In lactose maldigesters, retarding gastric emptying (food/pharmaceuticals)
improves tolerance to lactose. The role of temperature of test solution on the
indicators of lactose intolerance was studied. After an overnight fast, 10
lactose maldigesters ingested, in three sessions, 50 g lactose in a randomized
cross-over trial. The solutions were at temperatures of 20-21 degrees C (room
temperature), 2-3 degrees C (cold) and 55-58 degrees C (hot). Gastrointestinal
symptoms and indicators measuring lactose absorption were recorded. Abdominal
pain was noticeably increased by the modification of temperature. The cold
solution reduced flatulence and abdominal bloating, whereas the hot solution
increased bloating and borborygmi. Breath hydrogen excretion tended to be
augmented and retarded after cold solution. The temperature of the solution used
in a lactose tolerance test affects the gastrointestinal symptoms, but has only
minor effects on the other indicators of lactose maldigestion. The constant
tendencies observed suggest that a room temperature solution is to be recommended
for testing lactose digestion.
PMID- 10757457
TI - The temporal organization of daily torpor and hibernation: circadian and
circannual rhythms.
AB - Mammals and birds have evolved the ability to maintain a high and constant body
temperature Tb over a wide range of ambient temperatures Ta using endogenous heat
production. In many, especially small endotherms, cost for thermoregulatory heat
production can exceed available energy; to overcome these energetic bottlenecks,
they enter a state of torpor (a regulated reduction of Tb and metabolic rate).
Since the occurrence of torpor in many species is a seasonal event and occurs at
certain times of the day, we review whether circadian and circannual rhythms,
important in the timing of biological events in active animals, also play an
important role during torpor when Tb is reduced substantially and may even fall
below 0 degrees C. The two distinct patterns of torpor, hibernation (prolonged
torpor) and daily torpor, differ substantially in their interaction with the
circadian system. Daily torpor appears to be integrated into the normal circadian
rhythm of activity and rest, although torpor is not restricted only to the normal
rest phase of an animal. In contrast, hibernation can last for several days or
even weeks, although torpor never spans the entire hibernation season, but is
interrupted by periodic arousals and brief normothermic periods. Clearly, a day
is no longer divided in activity and rest, and at first glance the role of the
circadian system appears negligible. However, in several hibernators, arousals
not only follow a regular pattern consistent with a circadian rhythm, but also
are entrainable by external stimuli such as photoperiod and Ta. The extent of the
interaction between the circadian and circannual system and hibernation varies
among species. Biological rhythms of hibernators for which food availability
appears to be predictable seasonally and that hibernate in deep and sealed
burrows show little sensitivity to external stimuli during hibernation and hence
little entrainability of arousal events. In contrast, opportunistic hibernators,
which some times use arousals for foraging and hibernate in open and accessible
hibernacula, are susceptible to external zeitgebers. In opportunistic
hibernators, the circadian system plays a major role in maintaining synchrony
between the normal day-night cycle and occasional foraging. Although the daily
routine of activity and rest is abandoned during hibernation, the circadian
system appears to remain functional, and there is little evidence it is
significantly affected by low Tb.
PMID- 10757458
TI - Probing the circadian oscillator of a mammal by two-pulse perturbations.
AB - When organisms are maintained under constant conditions of light and temperature,
their endogenous circadian rhythms free run, manifesting their intrinsic period.
The phases of these free-running rhythms can be shifted by stimuli of light,
temperature, and drugs. The change from one free-running steady state to another
following a perturbation often involves several transient cycles (cycles of free
running rhythm drifting slowly to catch up with the postperturbation steady
state). Although the investigation of oscillator kinetics in circadian rhythms of
both insects and mammals has revealed that the circadian pacemaker phase shifts
instantaneously, the phenomenon of transient cycles has remained an enigma. We
probed the phases of the transient cycles in the locomotor activity rhythm of the
field mouse Mus booduga, evoked by a single light pulse (LP), using LPs at
critically timed phases. The results of our experiments indicate that the
transient cycles generated during transition from one steady state to another
steady state do not represent the state of the circadian pacemaker (basic
oscillator) controlling the locomotor activity rhythm in Mus booduga.
PMID- 10757459
TI - Circadian activity rhythms and sensitivity to noise in the Mongolian gerbil
(Meriones unguiculatus).
AB - Since consistent data on endogenous circadian rhythms of Mongolian gerbils are
not available, the main aim of our study was to identify suitable conditions to
receive stable and reproducible free-running rhythms of activity under different
light intensities. Another objective was to determine the role of social cues as
an exogenous zeitgeber in the absence of a light-dark (LD) cycle. We performed
two long-term sets of experiments with adult male gerbils kept in climatic
chambers under various photoperiods of at least 30 days each. In all cases, the
time of lights on in the chambers differed from the daily starting hour of work
in the animal house. Always, two animals per chamber were kept separately in
cages with a running wheel while their activity was monitored continuously.
During the first set, only three of eight animals developed intra- and
interindividual variable free-running rhythms. The activity patterns seemed to be
influenced by human activities outside, indicating high sensitivity to external
factors. Subsequently, we damped the chambers and the room and restricted access
to the room. In the following noise-reduced set, all gerbils developed comparable
free-running rhythms of activity. We determined the mean of the free-running
period tau, the activity-rest relationship alpha/theta and the amount of running
wheel activity per day: tau = 23.7h +/- 0.08h under low light (5 lux) and 25.5h
+/- 0.19h under high light intensities (450 lux); alpha/theta = 0.53 +/- 0.08
under 5 lux and 0.34 +/- 0.04 under 450 lux. The amount of daily activity was 12
times as high under 5 lux as under 450 lux. There was no indication that the two
animals in one chamber socially synchronized each other. In conclusion, the
pronounced rhythm changes in accordance with Aschoff's theory support the view
that gerbils are mainly nocturnal animals.
PMID- 10757460
TI - Internal desynchronization of the circadian activity and feeding rhythm in an owl
monkey (Aotus lemurinus griseimembra): a case study.
AB - In the free-running circadian locomotor activity rhythm of a 7-year-old male owl
monkey (Aotus lemurinus griseimembra) kept under constant light and climatic
conditions (LL 0.2 lux, 25 degrees C +/- 1 degrees C, 60 +/- 5% relative humidity
[RH]), a second rhythm component developed that showed strong relative
coordination with the free-running activity rhythm of 24.4h and a 24h rhythm. The
simultaneously recorded feeding activity rhythm strongly resembled this rhythm
component. Therefore, it seems justified to infer that there was an internal
desynchronization between the two behavioral rhythms or their circadian
pacemakers, that is, between the light-entrainable oscillator located in the
suprachiasmatic nuclei (SCN) and a food-entrainable oscillator located outside
the SCN. This internal desynchronization may have been induced and/or maintained
by a zeitgeber effect of the (irregular) 24h feeding schedule on the food
entrainable oscillator. The weak relative coordination shown by the activity
rhythm indicates a much weaker coupling of the light-entrainable oscillator to
the food-entrainable oscillator than vice versa.
PMID- 10757461
TI - Association of the antidiabetic effects of bromocriptine with a shift in the
daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the
Syrian hamster.
AB - Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves
seasonal insulin resistance in Syrian hamsters. Alterations in daily rhythms of
neuroendocrine activities are involved in the regulation of seasonal metabolic
changes. Changes in circadian neuroendocrine activities that regulate metabolism
are believed to be modulated by central circadian oscillators within the
hypothalamic suprachiasmatic nuclei (SCN) of seasonal animals. We examined the
association of metabolic responses to bromocriptine with its effects on the daily
rhythms of metabolic hormones and daily monoamine profiles within the SCN, a
primary circadian pacemaker known to regulate metabolism, in Syrian hamsters.
Obese glucose-intolerant male Syrian hamsters (body weight [BW] 185 +/- 10 g)
held on 14h daily photoperiods were treated at light onset with bromocriptine
(800 microg/animal/day, ip) or vehicle for 2 weeks. Animals were then subjected
to a glucose tolerance test (GTT) (3 g/kg BW, ip). Different subsets of animals
(n = 6) from each treatment group were sacrificed at 0h/24h, 5h, 10h, 15h, or 20h
after light onset for analyses of SCN monoamines, plasma insulin, prolactin,
cortisol, thyroxin (T4), triiodothyronine (T3), glucose, and free fatty acids
(FFAs). Compared with control values, bromocriptine treatment significantly
reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT
glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma
insulin concentration was markedly reduced throughout the day in bromocriptine
treated animals without influencing plasma glucose levels. Bromocriptine reduced
the daily peak in FFA by 26% during the late light span (p < .05). Bromocriptine
significantly shifted the daily plasma cortisol peak from the early dark to the
light period of the day, reduced the plasma prolactin (mean 1.8 vs. 39.4 ng/dL)
and T4 throughout the day (mean 1.6 vs. 3.8 microg/dL), and selectively reduced
T3 during the dark period of the day (p < .01). Concurrently, bromocriptine
treatment significantly reduced SCN dopamine turnover during the light period and
shifted daily peaks of SCN serotonin and 5-hydroxy-indoleacetic acid (5-HIAA)
content by 12h from the light to the dark period of the day (p < .05). This was
confirmed by a further in vivo microdialysis study in which bromocriptine
increased SCN extracellular 5-HIAA of glucose-intolerant hamsters during the dark
phase (47% increase, p < .05) toward levels observed in normal glucose-tolerant
hamsters. Thus, bromocriptine-induced resetting of daily patterns of SCN
neurotransmitter metabolism is associated with the effects of bromocriptine on
attenuation of the obese insulin-resistant and glucose-intolerant condition. A
large body of corroborating evidence suggests that such bromocriptine-induced
changes in SCN monoamine metabolism may be functional in its effects on
metabolism.
PMID- 10757462
TI - Establishing the dose-dependent daily variations of a low molecular weight
heparin (Fraxiparine) through a population approach analysis in the rat.
AB - The effects of dose and dosing time on the anticoagulant activity of a low
molecular weight heparin (Fraxiparine) were studied in rats. Three doses were
administered at four evenly spaced dosing times. Rats were kept under a light
dark cycle of 24h, and all the main external factors were constant. The bleeding
time, the anti-Xa activity of the drug, and the activated partial thromboplastin
time (APTT) were measured. A population approach analysis to assess daily
variations was used. With standard methods, interindividual variability may mask
potential time-related effects, while the population approach analysis overcomes
this difficulty. Bleeding time was at its peak at 04:00 and at its trough at
22:00, suggesting that platelet activity was time of day dependent. For the
pharmacological activity of the drug, we compared several pharmacokinetic models
derived from a monocompartmental model. The model that describes the anti-Xa
pharmacological activity best is expressed through parameters that depend on
animal weight and drug level. The model for APTT is of a sinusoidal type for
which the clearance depends on the dosing time. The most inter esting result is
that the amplitude of this daily variation is linearly dependent on drug level.
PMID- 10757463
TI - Visual resolution in humans fluctuates over the 24h period.
AB - The present experiment was designed to assess daily fluctuations of visual
discriminability, a function reflecting the resolution power of the visual
sensitivity by measure of a differential threshold. Sixteen subjects underwent a
visual discrimination threshold task (using the constant method) in a protocol
allowing one point every 2h over the 24h period. The results show that the visual
discrimination threshold is low in the morning and increases progressively over
the day, reaching a first peak at 22:00. During the night, the same pattern
occurs, with low threshold levels at the beginning of the night and high levels
at the end. This profile is quite different from that of detection threshold
variations, suggesting that the two visual functions are under the control of
different underlying mechanisms. Two interpretations could account for this
discrepancy. The first relates to different oscillators in the eye for detection
and discrimination. The second refers to a possible linkage of visual
discriminability with the sleep-wake cycle since threshold measures were
systematically low (i.e., high resolution power) after long sleep periods.
PMID- 10757464
TI - A comparison of the immediate effects of moderate exercise in the late morning
and late afternoon on core temperature and cutaneous thermoregulatory mechanisms.
AB - Twelve healthy male subjects each undertook two bouts of moderate exercise (70%
VO2max for 30 minutes) in the morning (08:00) and late afternoon (18:00) at least
4 days apart. Measurements were made of heart rate, core (rectal) temperature,
sternum skin temperature, and forearm skin blood flow during baseline conditions,
during the bout of exercise, and throughout a 30-minute recovery period.
Comparisons were made of the changes of heart rate, temperature, and skin blood
flow produced by the exercise at the two times of day. Student t tests indicated
that baseline values for core temperature (37.15 degrees C +/- 0.06 degrees C vs.
36.77 degrees C +/- 0.06 degrees C) and sternum temperature (33.60 degrees C +/-
0.29 degrees C vs. 32.70 degrees C + 0.38 degrees C) were significantly (p < .05)
higher in the late afternoon than the early morning. Two-way analysis of variance
(ANOVA) indicated that the increases in core and sternum temperatures during
exercise were significantly less (p = .0039 and .0421, respectively) during the
afternoon bout of exercise compared with the morning, even though the work loads,
as determined by changes in heart rate, were not significantly different (p =
.798) at the two times of testing. There were also tendencies for resting forearm
skin blood flow to be higher in the afternoon than in the morning and for
exercise to produce a more rapid rise in this variable in the afternoon. The
possible mechanisms producing these responses to exercise are discussed in terms
of those that are responsible for the normal circadian rhythm of core
temperature. It is concluded that the body's ability to remove a heat load is
less in the early morning, when the circadian system is in a "heat gain" mode,
than in the late afternoon, when heat gain and "heat loss" modes are balanced
more evenly.
PMID- 10757465
TI - Effect of imidapril in dipper and nondipper hypertensive patients: comparison
between morning and evening administration.
AB - The purpose of the study was to identify differences in the patterns of efficacy
and duration of effects of imidapril administered at different times of the day
(morning versus evening) in dipper and nondipper hypertensive patients. Twenty
patients with untreated hypertension were classified into two groups: dippers (n
= 9) and nondippers (n = 11). Imidapril (10 mg) was given at 07:00 or 18:00 for 4
weeks in a crossover fashion. Blood pressure (BP) and heart rate (HR) were
monitored before and after morning and evening treatment every 30 min for 48h by
ambulatory BP monitoring (ABPM). In dipper hypertension, the mean 48h BP was
reduced with both doses. The decrease in the diurnal BP was stronger when the
drug was administered in the evening than morning, but without significant
difference. In nondipper hypertension, the systolic BP decreased at night with
both doses, but the extent of the nocturnal reduction in systolic BP was greater
after morning therapy. There were no significant differences in the decrease in
BP during the day or night between the morning and evening administrations. When
imidapril was administered in the morning, its serum concentration reached a
maximum at 16:00, and when the drug was administered in the evening, it reached a
maximum at 6:00. In dipper hypertension, the time taken for the blood
concentration of imidapril to reach a maximum changed depending on its time of
administration, and the time when the maximum antihypertensive effect of the drug
appeared was different. In nondipper hypertension, decreases in the BP were
confirmed at night regardless of the time of administration; this might be caused
by angiotensin converting enzyme (ACE) inhibitors effectively blocking the BP
from increasing by activating the parasympathetic nervous system. Therefore, when
assessing the effectiveness of antihypertensive agents, factors such as the
various patterns of BP before therapy and administration time must be considered.
PMID- 10757466
TI - Differences in rhythms of enzymatic activity of maternal and fetal blood.
AB - Blood specimens were obtained at different daily times from the umbilical cord
and brachial vein from 53 women within 10 minutes after delivery. Enzyme
activities were measured in the white blood cells (WBCs) and serum of each
sample. For each enzyme, the results were grouped according to sampling
(delivery) times and arrayed to form a 24h time series. Separate time series were
generated for maternal and fetal enzymes. Analysis of variance (ANOVA) and cosine
best-fit analyses were applied to elucidate significant differences between
enzyme activity patterns of mothers and fetuses with regard to time dependency,
number of peaks, and acrophases. These and previously documented results indicate
that not all mothers and fetuses have rhythms that are concordant. For some
enzymes of fetuses, the activity rhythms differ in phase and shape of the time
series pattern from those of the mothers; for other enzymes, the activity rhythms
develop after birth.
PMID- 10757467
TI - Are there diurnal rhythms of anxiety?
PMID- 10757468
TI - Evaluation and treatment of children with neurogenic bladders.
AB - The evaluation and treatment of children with neurogenic bladders can be
difficult because of the complexity of the neurologic deficit and the
subjectivity of the history and physical exam. The primary emphasis of the
physicians caring for these children should be to preserve renal function and
facilitate continence when possible. As knowledge of both normal and abnormal
lower urinary-tract dynamics increases, so does the ability to care for children
with abnormal bladder dynamics caused by various neurologic conditions. With
recent advancements in medical and surgical treatment of the neurogenic bladder,
most children can maintain adequate renal function and attain urinary continence.
This article reviews the pertinent innervation, anatomy, and physiology of the
lower urinary tract, and discusses current evaluation and treatment of children
with neurogenic bladders.
PMID- 10757469
TI - Langerhans cell histiocytosis and the central nervous system in childhood:
evolution and prognostic factors. Results of a collaborative study.
AB - This retrospective study detailed clinical and radiologic involvement of the
central nervous system related to Langerhans cell histiocytosis in 18 French
children. We excluded cases of isolated hypothalamic-pituitary dysfunction or
spinal involvement. Cerebellar symptoms were the most common clinical symptoms.
Two different patterns of magnetic resonance or computed tomographic images were
identified: demyelination and gliosis or atrophy, described as degenerative
lesions, mostly located in the cerebellum in 10 children, or tumor-like lesions
occurring in any part of the brain in 13 children. Six children had both types of
lesion. The clinical cerebellar syndrome correlated with the specific imaging
pattern suggestive of a cerebellar degenerative lesion, which did not show any
changes after treatment. As suggested by this study and previous clinical and
histologic reports, it is believed that brain involvement in the course of
Langerhans cell histiocytosis might arise from different disease mechanisms:
primary histiocyte proliferation and secondary atrophy or demyelination and
gliosis of unknown origin. Treatment consequently should be adapted to the
supposed mechanism of the lesion.
PMID- 10757470
TI - Relationship of cognitive functioning, whole brain volumes, and T2-weighted
hyperintensities in neurofibromatosis-1.
AB - Using quantitative magnetic resonance imaging morphometry, we report that the
whole brain volumes of patients with neurofibromatosis-1 are significantly larger
than normal, confirm the prevalence of macrocephaly as about 50%, and report that
macrocephaly in patients with neurofibromatosis-1 does not appear to be related
to the familial or sporadic origin of the neurofibromatosis-1 or to the presence
or absence of T2-weighted hyperintensities. No strong relationship emerged
between the extent of neurofibromatosis-1-associated impairment of cognitive
functions and degree of macrocephaly; however, the macrocephalic
neurofibromatosis-1 group did have a significant verbal impairment relative to
the nonmacrocephalic neurofibromatosis-1 group in vocabulary (P < .009).
PMID- 10757471
TI - Vigabatrin as a first-choice drug in the treatment of West syndrome.
AB - This is a prospective study designed to evaluate the efficacy and safety of
vigabatrin as first-choice monotherapy in infants with West syndrome. One hundred
sixteen patients with newly diagnosed West syndrome were studied in Argentina,
from June 1994 to April 1998. The follow-up ranged from 17 to 40 months (mean, 23
months). Vigabatrin was administered upon diagnosis, starting with a 50-mg/kg/day
dose and increasing 50 mg/kg every 48 hours to reach a maximum dose of 200
mg/kg/day. Twenty-nine percent of cases were considered to be cryptogenic or
idiopathic West syndrome, while 70.7% were symptomatic. Response to vigabatrin
treatment was measured according to five categories: (1) seizures free: 61.8% of
cases for cryptogenic and 29.3% for symptomatic West syndrome, (2) more than 75%
reduction in the number of infantile spasms: 14.7% for cryptogenic and 26.8% for
symptomatic West syndrome, (3) from 50% to 74% reduction in the number of
infantile spasms: 11.8% for cryptogenic and 24.4% for symptomatic West syndrome,
(4) poor or null response: 11.8% for cryptogenic and 18.3% for symptomatic West
syndrome, and (5) increase in the number of infantile spasms: one symptomatic
case (1.2%). All seizure-free cryptogenic cases showed normal neuropsychic
development. The most effective dose of vigabatrin was 150 mg/kg of body weight
per day. The most frequent adverse events were somnolence in 19 cases and
irritability in 15 cases, but none required treatment interruption.
PMID- 10757472
TI - Clinical manifestations of cerebrovascular hypoplasias in childhood.
AB - The aim of the study was to analyze cerebrovascular hypoplasia in childhood and
its clinical manifestations in a clinical population of 205 children aged 3 to 14
years. Cerebrovascular hypoplasias were diagnosed using angiography (n=63),
magnetic resonance angiography, and transcranial Doppler ultrasonography.
Hypoplasias were localized in the internal carotid artery in 41.9% of patients,
in the middle cerebral artery in 54.1%, the anterior cerebral artery in 1.0%, and
in the vertebro-basilar system in 3.0%. Clinical manifestations included
transient ischemic attacks (21% of patients), cerebral infarcts (17%),
progressive unilateral cerebral hemisphere atrophy (1.0%), focal and secondary
generalized epileptic seizures (56.1%), and migraine-like headache (4.9%).
Hypoplasias of the internal carotid artery and middle cerebral artery manifested
as focal and secondary generalized epileptic seizures, transient ischemic
attacks, cerebral infarcts, migraine-like headache, and progressive unilateral
cerebral hemisphere atrophy, in descending order of frequency. Hypoplasias in the
anterior cerebral artery or the basilar artery caused cerebral infarcts, and
hypoplasias in the vertebral arteries caused transient ischemic attacks. This
article discusses the pathophysiology of ischemia in the territory of the
hypoplastic cerebral artery in childhood, as well as possibilities for
noninvasive neuroimaging for diagnosis of cerebrovascular hypoplasias.
PMID- 10757473
TI - Heterogeneity of classic congenital muscular dystrophy with involvement of the
central nervous system: report of five atypical cases.
AB - A heterogeneous group of patients with congenital muscular dystrophy associated
with clinical or radiologic central nervous system involvement other than the
severe classic form with merosin deficiency, muscle-eye-brain disease, and Walker
Warburg syndrome is described. A probable hereditary or familial occurrence could
be suggested in all patients. One merosin-positive patient presented severe motor
incapacity and cerebral atrophy without any clinical manifestation of central
nervous system involvement. A second patient, also merosin-positive, had moderate
motor and mental handicap, and epilepsy with no changes in neuroimaging. A third
patient, found to have partial merosin deficiency by muscle biopsy, manifested
severe psychomotor retardation and cerebral atrophy with foci of abnormal white
matter signal on magnetic resonance imaging. Finally, two merosin-positive
siblings with microcephaly, mental retardation, and an incapacitating progressive
neuromuscular course, exhibited cataracts without defects of neuronal migration
or brain malformation. This report emphasizes the broad clinical spectrum and
heterogeneity of merosin-positive congenital muscular dystrophy with associated
central nervous system involvement, and illustrates the importance of further
studies on clinical, immunohistochemical, and genetic grounds for identifying new
subsets of congenital muscular dystrophy.
PMID- 10757474
TI - Linkage analysis of moyamoya disease on chromosome 6.
AB - Genetic factors have been suggested to contribute to the etiology of moyamoya
disease. The authors have previously reported an association between moyamoya
disease and several alleles for human leukocyte antigens (HLA). To further
specify the genetic component of moyamoya disease, a linkage study of moyamoya
disease using markers on chromosome 6, where the HLA gene is located, was
performed. The 15 microsatellite markers of chromosome 6 were studied in 20
affected sibling pairs. From an identical-by-descent analysis of these markers,
an allele with possible linkage to moyamoya disease was identified. Sharing of
the allele among affected members in 19 families was investigated, considering
the haplotype. The marker, D6S441, might be linked to moyamoya disease.
Considering the haplotype, the allele was shared among the affected members in 16
(82%) of the 19 families, but not in two others. In one family, sharing of the
allele could not be determined because of low heterozygosity. Further studies are
necessary to clarify multiple genetic factors that are definitely linked with
moyamoya disease.
PMID- 10757475
TI - New concepts of Guillain-Barre syndrome.
AB - Guillain-Barre syndrome is an acute autoimmune polyradiculoneuropathy with a
clinical presentation of flaccid paralysis with areflexia, variable sensory
disturbance, and elevated cerebrospinal fluid protein without pleocytosis.
Although Guillain-Barre syndrome previously had been viewed as a unitary disorder
with variations, it currently is viewed as a group of syndromes with several
distinctive subtypes. These include the principal subtype prevalent in the
Western world (acute inflammatory demyelinating polyradiculoneuropathy, and
others, each with distinctive electrodiagnostic and pathologic features,
including acute motor axonal neuropathy), acute motor-sensory axonal neuropathy,
Miller Fisher syndrome, and perhaps others. The clinical and pathologic features
of these Guillain-Barre syndrome subtypes are reviewed, and the role of
antecedent infections, particularly Campylobacter jejuni gastroenteritis, and the
role of antiganglioside antibody responses are reviewed with respect to
pathogenesis. Treatment of Guillain-Barre syndrome includes both important
supportive measures and immunotherapies, specifically high-dose intravenous
immunoglobulin and plasma exchange.
PMID- 10757476
TI - Nocturnal acute laryngospasm in children: a possible epileptic phenomenon.
AB - Respiratory difficulties are not uncommon during epileptic activity in all age
groups. Laryngospasm, as an isolated manifestation of epileptic disorder, is a
rare phenomenon described previously in only two patients. We report our
experience with five children in whom nocturnal laryngospasm was the only
clinical manifestation of their epileptic disorder. All children underwent
extensive workup and the diagnosis was made by sleep-deprived
electroencephalography (two cases) and sleep study (three cases). All patients
were treated with carbamezapine with prompt resolution of their laryngospasm.
PMID- 10757477
TI - A case of late infantile neuronal ceroid lipofuscinosis associated with
precocious puberty.
AB - Neuronal ceroid lipofuscinosis is one of the hereoffegenerative diseases for
which clinical and neuropathologic findings are well documented. We present a
patient with late infantile neuronal ceroid lipofuscinosis with true precocious
puberty; to our knowledge, this association has not been reported before. The
association could be due to an underlying disturbance of hypothalamic-pituitary
gonadal function, or to coincidence.
PMID- 10757478
TI - A study of the usage of a decision-support system for infective endocarditis.
AB - The objective of this study was to examine a design for a World Wide Web-based
decision-support system in use by clinically active physicians. A prototype
implementation of the design concerned management of infective endocarditis
patient cases. The design was based on an integration of hypertext and rule-based
knowledge. In the study sessions, physicians in the field of internal medicine
worked on managing authentic patient cases in a laboratory setting. Data was
collected from interviews with the physicians using video recordings and
stimulated recall technique. The qualitative data was analysed according to the
constant comparative method in order to develop a model of the physicians' usage
of the system. The resulting model describes perceived contributions and criteria
for usefulness of the system. The ways the physicians used the system showed that
it was able to provide patient-specific support for confirming clinical
decisions, for higher-level patient management, and for preparing for and
initiating expert consultations. Users also stated that new medical knowledge
could be gained as a side effect of using the system.
PMID- 10757479
TI - A semantic-based kernel for advanced health information systems.
AB - This paper reports on the design and development of an infrastructure allowing
one to share and exchange multimedia data in the context of a health network. A
single technology exploiting a semantic model of the hospital universe provides
users with information and data of diverse origins, generated by the various
actors or departments of the health organization. Functions provided include act
management and patient record management governed by domain semantics. The
functionality has been validated through laboratory experiments against the
requirements of protocol directed care and health networks. The functionality is
integrated into a clinician workstation exploited in the Internet/Intranet
environment thanks to a commercial browser. These results have been obtained with
the support of several projects in the frame of the Health-Care Telematics
Applications Programme of the European Community and of the Eureka Programme.
PMID- 10757480
TI - Computerized charting of case reports.
AB - Follow-up schemas are used in the planning of care delivery for patients who had
a larynx tumour resection. Because of the diversity of this population, the idea
has arisen that control schemas should be tuned to individual patient histories
in order to optimize care delivery. To arrive at refined guidelines, detailed
analysis of 300 case reports is planned. In this context a patient case report
tool PCRT has been developed to support the analysis of computerized case
reports. PCRT is based on an existing patient case report language and can
generate case report charts using a newly developed charting method implemented
with internet-based technology. This paper presents the charting method and
explains the charting algorithm.
PMID- 10757481
TI - Improving knowledge navigation with adaptive hypermedia.
AB - Web applications provide access to a tremendous amount of information: hypertext,
hypermedia and on-line databases. However, since users' knowledge, motivation and
goals are different, they cannot find the relevant information in the data being
diffused. Giving the users applications or environments that will take their
differences into account is one way of improving their access to knowledge. The
authors' objective is to improve knowledge navigation by adapting users'
navigation. Adaptive hypermedia is one way of returning information adapted to
the user. This paper presents an adaptive hypermedia system based on user
representation with the stereotype model. Both adaptive presentation and
navigation techniques are also implemented. This paper focuses on the
architecture of the general adaptive hypermedia system as well as adaptivity
management. A-TOP, a medical adaptive hypermedia prototype implemented in a
hospital intranet system, is described. Adaptive hypermedia is a preliminary
approach to the vast problem of user access to knowledge. In conclusion, we hope
to extend our reflections to the problems involved in access to knowledge on the
World Wide Web (Web).
PMID- 10757482
TI - Summary of new distribution records for mosquito species in the United States and
Canada for the period 1981-99.
AB - In order to elucidate the recent spread of mosquito species in the United States
and Canada, a summary of new records for states and provinces has been prepared
to include those reported mostly from 1981 to 1998, although some records before
1989 are also given. We are reporting 132 new records for 58 species of
mosquitoes.
PMID- 10757483
TI - Field trials of three concentrations of Laginex as biological larvicide compared
to Vectobac-12AS as a biocontrol agent for Culex quinquefasciatus.
AB - Laginex AS Biological Larvicide (Lagenidium giganteum) and Vectobac-12AS
(Bacillus thuringiensis var. israelensis) were compared in plastic pools
containing laboratory-reared Culex quinquefasciatus larvae located in a wooded
area in Panama City, FL, in August and September 1997. The pools were dipped at 2
day intervals to assess larval control. Sentinel larvae in screen-sided cups were
added to all treatment and control pools at 4-day intervals and evaluated for
infection at 48 h. Laginex produced larval control up to 20 days as compared to
the Vectobac-12AS compound, which required retreatment by the 10th day. The most
effective control was attained by the Laginex 25 treatment, which reduced larvae
in the pools by 100% for 22 days. Control in the Laginex 15 and Laginex 35
treatments dropped to 90% and 74% at day 13 and day 9, respectively. The numbers
of infected larvae remained above 50% as larval control was assessed, but dropped
and fluctuated when water temperatures were lowered at the onset of cold weather.
Organic pollution did not prove to be a significant factor in the evaluations.
PMID- 10757484
TI - Resistance and response to selection to deltamethrin in Anopheles sinensis from
Zhejiang, China.
AB - Resistance levels to deltamethrin were measured in 5 natural populations of
Anopheles sinensis. The median lethal concentrations (LC50S) of deltamethrin in
these populations were higher than those in susceptible strains originating from
the same populations, especially in the Wenzhou population, which had a
resistance ratio (RR50) of 11 relative to its susceptible strain. Resistant
strains were selected with deltamethrin for 12 generations. Resistance levels in
resistant strains were 130 to 190-fold higher than in susceptible strains, and 10
to 40-fold higher than in natural populations. Response of selection (R) in the
resistant strain from the Wenzhou population was less than 0.1, and those in
resistant strains from other natural populations were more than 0.1. This
suggests that a resistant strain from a natural population with higher resistance
has a lower increase in RR than a resistant strain from a natural population with
low resistance under identical insecticide selection. These results are discussed
in relation to mosquito control strategies.
PMID- 10757485
TI - Effects of trap design and CO2 presentation on the measurement of adult mosquito
abundance using Centers for Disease Control-style miniature light traps.
AB - Centers for Disease Control miniature light traps augmented with CO2 provide an
effective method of monitoring Culex abundance and may provide a useful
supplement to New Jersey light traps used by the California Mosquito Surveillance
Program. To assist in standardizing sampling protocols, the present research
compared the catch of adult mosquitoes collected using 4 trap designs and 3 CO2
presentation methods. When augmented with dry ice, the Arbovirus Field Station
(AFS) trap (consisting of a 3-in. fan mounted into a white polyvinyl chloride
pipe and operated without a light source or rain shield) collected as many or
more Culex females than similar traps purchased from John W. Hock and American
Biophysics, or a trap with a 4.25-in. 2-bladed fan constructed by the Orange
County Vector Control District (similar to the Encephalitis Virus Surveillance
model distributed by Bioquip). Few blooded or gravid females and males were
collected, indicating that CO2 released from the dry ice and not light probably
was the primary attractant. Catch of Culex tarsalis females in traps baited with
CO2 released at 0.5-1.5 liters/min from gas cylinders was significantly greater
than in traps baited with dry ice, even though the CO2 release rates from the dry
ice at dusk probably were comparable to that released from the cylinders and
averaged 0.4-0).5 liters/min for the night. Traps baited with 0.5 liters/ min of
CO2 gas released in 15 3- or 2-sec bursts per hour collected the fewest
mosquitoes. In all experiments, trap location effects were significant and
accounted for as much variability in catch size as trap design or CO2
presentation. Sampling efficiency of all trap designs or CO2 presentations were
consistent over time, space, and different levels of mosquito abundance.
PMID- 10757486
TI - Control of acidic drain-water-breeding mosquitoes in New South Wales, Australia,
by installing controlled leakage holes in tidal flap gates.
AB - Effects on mosquito breeding, acidity, and fish presence were assessed after
installation of a small tidal leakage port into an acidic drain's tidal exclusion
flap gate. Before gate modification the drain water had pH values as low as 2.7.
These water conditions were toxic to fish and continually held mosquito larvae.
At 4 wk after gate modification, water pH had risen to 6.0, at least 3 fish
species inhabited the drain, and mosquito larval numbers had been reduced by
99.98%.
PMID- 10757487
TI - Relationships among weather, mosquito abundance, and encephalitis virus activity
in California: Kern County 1990-98.
AB - The summer abundance of Culex tarsalis in Kern County, California, during 1990-98
was related quantitatively to rainfall, snow depth and water content, and runoff
of the Kern River. Total monthly rain that fell during winter, lagged by 4-6
months, explained only 13% of the variability in the number of host-seeking
females collected per trap night per month during summer. In contrast, regression
analysis showed that river runoff 1 month earlier explained 67% of the
variability in mosquito abundance. The water content of snowpack measured within
the Kern River watershed during winter explained 70% of the variation in average
mosquito abundance during the following summer. After being absent from Kern
County since 1983, western equine encephalomyelitis virus (WEE) returned during
the wet years of 1996-98 after the flow of the Kern River exceeded 150,000 acre
ft (450 hectare-meters) per month. Water content of snow in the Sierra Nevada
during winter provided an excellent early warning of vernal river runoff,
mosquito abundance, and enzootic WEE activity levels on the floor of the San
Joaquin Valley.
PMID- 10757488
TI - Application of geographic information technology in determining risk of eastern
equine encephalomyelitis virus transmission.
AB - Geographic information system (GIS) technology and remote sensing were used to
identify landscape features determining risk of eastern equine encephalomyelitis
virus (EEE) transmission as defined by the abundance of Culiseta melanura (the
enzootic vector) and 6 putative epidemic-epizootic vectors in Massachusetts.
Landsat Thematic Mapper data combined with aerial videography data were used to
generate a map of landscape elements at epidemic-epizootic foci in southeastern
Massachusetts. Geographic information system technology was used to determine the
proportion of landscape elements surrounding 15 human and horse case sites where
abundance data were collected for Culiseta melanura, Aedes canadensis, Aedes
vexans, Culex salinarius, Coquillettidia perturbans, Anopheles quadrimaculatus,
and Anopheles punctipennis. The relationships between vector abundance and
landscape proportions were analyzed using stepwise linear regression. Stepwise
regression indicated wetlands as the most important major class element, which
accounted for up to 72.5% of the observed variation in the host-seeking
populations of Ae. canadensis, Ae. vexans, and Cs. melanura. Moreover, stepwise
linear regression demonstrated deciduous wetlands to be the specific wetland
category contributing to the major class models. This approach of utilizing GIS
technology and remote sensing in combination with street mapping can be employed
to identify deciduous wetlands in neighborhoods at risk for EEE transmission and
to plan more efficient schedules of pesticide applications targeting adults.
PMID- 10757489
TI - Isobutyric acid from the Brindley's glands of Triatoma lecticularia.
AB - The contents of the Brindley's gland of Triatoma lecticularia (Stal)
(Heteroptera: Reduviidae: Triatominae) have been identified by gas chromatography
mass spectrometry as isobutyric acid. This compound is found in similar
secretions from certain other members of the Triatominae, and is suggested to
play a role as a defensive pheromone and for intraspecies communication.
PMID- 10757490
TI - Synonymy of subgenus Sinoaedes of genus Aedes with subgenus Mattinglyia of genus
Heizmannia.
AB - The subgenus Sinoaedes is transferred from the genus Aedes and placed in synonymy
with the subgenus Mattinglyia of the genus Heizmannia. The haplotype of
Sinoaedes, Aedes occidentayunnanus, is transferred to the subgenus Mattinglyia of
the genus Heizmannia and the spelling of the specific name is corrected to agree
in gender with Heizmannia. Rationale for these actions is provided.
PMID- 10757491
TI - Notes on phlebotomine sand flies (Diptera: psychodidae) from Amapa State, North
Brazil.
AB - Eighteen species of sand fly were collected from Amapa Sate, Brazil, with Centers
for Disease Control light traps during May 1998. Five species (Lutzomyia aragaoi,
L. inpai, L. brachipyga, L. inflata, and L. richardwardi) represent new records
for the Amapa.
PMID- 10757492
TI - Assignment of two North American species of Aedes to subgenus Rusticoidus.
AB - Aedes bicristatus and Aedes provocans are transferred to subgenus Rusticoidus
from subgenus Ochlerotatus. Primary morphologic features of Rusticoidus are
provided for separating this subgenus from all other subgenera of genus Aedes.
PMID- 10757493
TI - Separation of trap-collected adults of Anopheles atropos from species of the
quadrimaculatus complex.
AB - The presence of a moderate- to large-sized patch of dark scales on the anterior
surface of the fore coxa of Anopheles atropos can be used to separate this
species from species of the Quadrimaculatus Complex collected in coastal areas of
the United States. Identification of specimens is possible even if they have been
collected in traps and are rubbed and faded.
PMID- 10757494
TI - Mosquito repellent action of Neemos.
AB - Two to 3 ml of Neemos, when applied to the exposed body parts of human
volunteers, provided protection for 8 h from the bites of all anopheline species
in 2 villages of the Sucre municipality, Bolivar State, Venezuela. Neemos is safe
and can be used for protection from malaria in endemic countries.
PMID- 10757495
TI - Relative sparing of emotionally influenced memory in Alzheimer's disease.
AB - Studies suggest that emotionally influenced events enhance long-term memory. This
study aimed to uncover whether this phenomenon exists in Alzheimer's Disease (AD)
by comparing patients' performance with that of controls on a memory task.
Overall, controls performed better than AD subjects on a delayed recognition task
of a story containing emotional elements (95.8+/-2.4% vs 66.6+/-28.5%; mean +/-
s.d.), respectively. Among AD subjects, there was relative sparing of emotionally
influenced memory, which was not seen in controls because of a ceiling effect.
Retention of the emotional phase of the story differed significantly from that of
the neutral phases. These findings suggest that the influence of emotion on
memory is spared, at least to some degree, in AD.
PMID- 10757496
TI - An animal model of neuropathic pain employing injury to the sciatic nerve
branches.
AB - The present study was conducted to develop a new animal model of neuropathic pain
employing injury to the distal sciatic nerve branches. Under halothane
anesthesia, the tibial, sural, and/or common peroneal nerves were injured and
neuropathic pain behaviors were compared among different groups of rats.
Different types of injury produced different levels of neuropathic pain. Rats
with injury to the tibial and sural nerves showed the most vigorous mechanical
allodynia, cold allodynia, and spontaneous pain. These neuropathic pain behaviors
were not relieved by functional sympathectomy using guanethidine. The results
suggested that injury to the tibial and sural nerves, while leaving the common
peroneal nerve intact, can be used as a new animal model of neuropathic pain and
that this model represents sympathetically independent pain (SIP). The present
animal model is very simple to produce injury and can produce profound and
reliable pain behaviors. These features enable the new animal model to be a
useful tool in elucidating the mechanisms of neuropathic pain, especially SIP.
PMID- 10757497
TI - Apoptosis and impaired axonal regeneration of sensory neurons after nerve crush
in diabetic rats.
AB - We investigated the possible induction of apoptosis of dorsal root ganglion (DRG)
neurons and the defect of nerve regeneration after crush injury with reference to
the JNK/c-jun and cAMP pathway in streptozocin-induced diabetic rats. In
addition, the effects of a PGE1 analogue were tested in diabetic rats. At day 0
(before axonal injury), no TUNEL-positive DRG neurons were observed in any group.
From day 1 to 7 after axonal injury, TUNEL-positive DRG neurons were seen in
diabetic rats, but not in non-diabetic or PGE1-treated diabetic rats. The
regeneration distance at day 7 after crush injury was shorter in diabetic rats
than in the other groups of rats. The time course of JNK/c-jun phosphorylation
did not parallel apoptosis. At day 7, the cAMP content of DRG was higher than
that at day 0 in non-diabetic and PGE1-treated rats, whereas it was not increased
after 7 days in diabetic rats. These results indicate that in diabetic rats
apoptosis of DRG neurons is induced by axonal injury independently of the JNK/c
jun and cAMP pathway and that PGE1 rescues DRG neurons from apoptosis and
improves axonal regeneration in diabetic rats.
PMID- 10757498
TI - Synchronous cortical gamma-band activity in task-relevant cognition.
AB - Widespread synchronous oscillatory activity, particularly in the gamma ('40 Hz')
band, has been postulated to exist in the brain as a mechanism underlying
binding. A new method of examining phase synchronicity across multiple electrode
sites in specific EEG frequency bands as a function of time was employed, in a
conventional cognitive ERP paradigm in 40 normal subjects. A significant late
post-stimulus gamma synchronicity response occurred for task-relevant stimuli,
whereas for task-irrelevant stimuli no such response was evident. However, an
early response was seen for both task-relevant and irrelevant stimuli. This is
the first empirical demonstration that widespread synchronous high frequency
oscillations occur in humans in relation to cognition.
PMID- 10757499
TI - Cyclic GMP evoked calcium transients in olfactory receptor cell growth cones.
AB - Nitric oxide-induced calcium transients in growth cones are believed to be
mediated by cyclic nucleotides. Because nitric oxide is thought to influence the
development of olfactory receptor cells (ORCs), we have begun to explore the
effect of cyclic nucleotides on ORC growth cones. Cultured ORCs were loaded with
fluo-3 AM and confocal imaging was employed to monitor calcium transients
following cyclic nucleotide-gated channel activation. Application of 8-bromo-cGMP
at the growth cone caused transient increases in fluorescence which were
restricted to the growth cone and lasted tens of seconds. The signal was
abolished by LY83583, an inhibitor of cyclic nucleotide-gated channels. 8-Bromo
cGMP also inhibited further extension of growth cones. The data indicate that ORC
growth cones exhibit cGMP-dependent calcium transients that are consistent with
those generated by cyclic nucleotide-gated channels.
PMID- 10757500
TI - Co-localization of PKCepsilon with various GABA(A) receptor subunits in the mouse
limbic system.
AB - The distribution of PKCepsilon and its co-localization with various GABA(A)
receptor subunits within limbic structures of the mouse brain was examined by
fluorescence immunohistochemistry. Levels of PKCepsilon immunoreactivity were
highest in the cingulate cortex and dentate gyrus, moderate in the nucleus
accumbens, and lowest in the prelimbic cortex and basolateral amygdala. Co
localization of PKCepsilon immunoreactivity with the GABA(A) receptor alpha1,
beta 2/3, and gamma2 subunits varied by subunit and brain region examined, with
the majority of co-localization occuring in the dentate gyrus, nucleus accumbens
and basolateral amygdala. These results demonstrate that PKCepsilon may interact
with GABA(A) receptors in a subunit- and region-specific manner, and provide a
potential anatomical basis for recent behavioral and biochemical evidence that
PKCepsilon modulates GABA(A) receptor function.
PMID- 10757501
TI - Bi-directional interactions between visual areas in the awake behaving cat.
AB - The study of the cooperativity among cortical areas is essential to our
understanding of brain functioning. Here we investigated the relative
contributions of top-down and bottom-up directed interactions between area 17 and
area 7 of the cat visual system. Bipolar local field potentials were recorded
while the animals performed a go/no-go task or were in a quiet resting state. The
data were analyzed by applying measures of interaction based on the Wiener
Granger causality concept. We found that during the visual task top-down directed
interactions were of a similar magnitude as the bottom-up component. Second,
interareal couplings tended to increase in conditions requiring a discriminative
effort. Third, during behaviors not dominated by visual processing non-directed
interactions increased.
PMID- 10757502
TI - Perceptual auditory gap detection deficits in male BXSB mice with cerebrocortical
ectopias.
AB - Underlying impairments in rapid auditory processing may contribute to disrupted
phonological processing, which in turn characterizes developmental language
impairment (LI). Identification of a neurobiological feature of LI that is
associated with auditory deficits would further support this model. Accordingly,
we found that adult male rats with induced cortical malformations were impaired
in rapid auditory processing. Since 40-60% of BXSB mice exhibit spontaneous focal
cerebrocortical ectopias (as seen in dyslexics brains), we assessed auditory gap
detection in adult male BXSB mice. Ectopic mice were significantly worse than non
ectopics in detecting a 5 ms silent gap, but were not significantly impaired at
longer gap durations (10-100 ms). Our results confirm that focal cortical
malformations are associated with impairments in rapid auditory processing.
PMID- 10757503
TI - Survival of motor neurons and expression of beta-amyloid protein in the aged rat
spinal cord.
AB - The present study investigated expression of beta-amyloid protein (AP) and
Amyloid precursor protein (APP) in spinal motor neurons of young adult (3 month
old) and aged (26-30 month old) rats. The total number of spinal motor neurons in
the seventh cervical (C7) spinal segment was also examined in both young adult
and aged rats. There was an approximately 21% (p<0.001) decrease in the number of
motor neurons of the C7 spinal segment in aged rats compared with young ones.
Immunoreactivity (IR) of AP and APP was not observed in spinal motor neurons of
young adult rats. In contrast, approximately 50% of the spinal motor neurons of
the aged rats were APP positive. Furthermore, extensive immunoreactivity was
found in the processes of spinal motor neurons of aged rats. These results have
shown that AP and APP is coincident with the loss of motor neurons in the spinal
cord of aged rats, and might be associated with the degenerative processes of
ageing motor neurons.
PMID- 10757504
TI - Transcranial magnetic stimulation reveals an interhemispheric asymmetry of
cortical inhibition in focal epilepsy.
AB - Transcranial magnetic stimulation (TCS) was applied to both hemispheres of 16
patients affected by criptogenic focal epilepsy to evaluate the interhemispheric
symmetry of the motor cortex excitability. The amplitude of the motor evoked
potentials (MEPs) and the duration of the post-MEP silent period (SP) were
measured at threshold (THR) and at increasing TCS stimulation intensities. The
THR was significantly higher in patients than in 16 age-matched control subjects
(p < 0.01). No interhemispheric differences were found in MEP amplitude. In
controls, the correlation between SP duration and increasing TCS stimulus
intensity was linear with a symmetrical progression of the SP duration over the
two hemispheres. In patients this linear SP progression was lacking on the
'epileptic' hemisphere: the SP duration did not increase following TCS > 40%
above THR, indicating abnormal interhemispheric asymmetry. This finding suggests
a selective dysfunction of inhibition in the epileptic hemisphere as signaled by
an abnormal SP duration in response to progressively higher TCS intensities.
PMID- 10757505
TI - The modulation of ecto-nucleotidase activities by glutamate in cultured
cerebellar granule cells.
AB - Several enzymes hydrolyze ATP, producing ADP which is hydrolyzed to AMP. Ecto-5'
nucleotidase produces adenosine from AMP. Glutamate (Glu) is an excitatory
neurotransmitter and increases extracellular adenosine levels, which is
considered an important inhibitory neuromodulator. Here we show that Glu
activates ADP and AMP hydrolysis. NMDA and kainic acid (KA) also increased these
enzymatic activities, but 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) had
no effect. Dihydrokainate (DHK), an inhibitor of glutamate uptake, also blocked
glutamate-evoked activation of ecto-nucleotidases, suggesting that this
activation was also Glu transporters dependent. Therefore, we suggest that the
Glu-evoked stimulation of ecto-nucleotidases might contribute to the increase of
adenosine in extracellular space induced by Glu.
PMID- 10757506
TI - No evidence for extraocular light induced phase shifting of human melatonin,
cortisol and thyrotropin rhythms.
AB - The view that light affects the mammalian circadian clock only through the eyes
was recently challenged by a study in which the phases of human circadian rhythms
were shifted by extraocular light exposure. This finding has not been confirmed,
however. We studied the effects of light exposure (3 h, broad spectrum
fluorescent white light, 13000 lux) on abdomen and chest on the circadian rhythms
of serum melatonin, cortisol and thyrotropin in six subjects. The protocol
consisted of two 3-day sessions in a dimly lit (< 10 lux) experimental unit. In
both sessions hourly serum samples were collected for hormone analysis on days 1
and 3. The skin light exposure was delivered on day 2 from 22.00 to 01.00h in one
of the two sessions in a randomized order. In both sessions all three rhythms
tended to delay, presumably due to the endogenous circadian cycle length being
slightly longer than 24 h. However, the phase shifts did not differ significantly
between the sessions. Thus, the present study does not support the existence of
extraocular photic regulation of the circadian rhythms in humans.
PMID- 10757507
TI - Large-scale identification of differentially expressed genes during neurogenesis.
AB - We report here a modified mRNA differential display method and its application
for the analysis of differential gene expression in NGF-treated PC12 cells and in
embryonic rat spinal cord. The optimized protocol is based on low fidelity
priming of multiple cDNAs followed by high fidelity amplification. In PC12 cells
induction by nerve growth factor (NGF) altered the expression of 4% of the 466
transcripts evaluated. During neurogenesis of the spinal cord we found that 30%
of the 288 examined products changed. The differential expression of the
characterized genes was confirmed by independent quantitative PCR. We conclude
this method is suitable for the identification of increases and decreases of mRNA
levels and allows the discovery of differentially expressed unknown transcripts.
PMID- 10757508
TI - Increased expression of p75NTR by neural crest-derived cells in vivo during
mitosis.
AB - The responses to neurotrophic factors may be modulated by changes in the levels
of expression of their receptors. The aim of this study was to determine whether
neural precursors in vivo show cell cycle phase-dependent changes in expression
of p75NTR and Ret. Preparations of embryonic mouse gut were processed for Ret or
p75NTR immunohistochemistry to identify neural crest-derived cells, and cells
undergoing mitosis were identified using a fluorescent nucleic acid stain. Neural
crest-derived cells undergoing mitosis showed over twice the levels of p75NTR
immunoreactivity (pixel intensity measured on a confocal microscope) on their
surface to that shown by nonmitotic neural crest cells. However, there was no
significant difference between the levels of Ret on mitotic and nonmitotic neural
crest cells.
PMID- 10757509
TI - Imagining the impossible: intact motor representations in hemiplegics.
AB - Motor imagery is known to involve brain regions vital to the performance of motor
skills including primary motor cortex. The present results show that, following
cerebral vascular accidents (CVAs) affecting a variety of these regions, many
adults with left or right upper-limb paralysis (i.e. hemiparesis/hemiplegia)
retain the ability to accurately represent prehensile movements involving the
impaired limb. This suggests that during the acute phase of recovery many CVA
patients can use motor imagery to activate partially damaged motor networks; a
process that may facilitate functional reorganization. This ability was, however,
compromised in cases with right posterior parietal or left frontal lesions. This
pattern is consistent with the hypothesis that imagined prehension, like actual
reaching and grasping, involves a network of highly interconnected areas
distributed throughout parietal and frontal cortices.
PMID- 10757510
TI - Paraventricular nucleus injections of naloxone methiodide inhibit NPY's effects
on energy substrate utilization.
AB - Microinjection of neuropeptide Y (NPY) into the paraventricular nucleus (PVN) of
the hypothalamus stimulates eating and increases respiratory quotient. In
contrast, administration of opioid receptor antagonists reduces food intake and
suppresses NPY-induced feeding. The present study examined whether naloxone
methiodide, an opioid antagonist, would suppress the potentiation of NPY on
energy substrate utilization, when injected into the PVN. Naloxone methiodide was
injected at doses of 0.1 and 1.0 g, 10 min prior to NPY treatment. NPY was
administered immediately prior to the start of the nocturnal period and RQ was
determined using an open-circuit calorimeter. Doses of 50 and 100 pmol NPY alone
evoked reliable increases in RQ within 30min of treatment. Following naloxone
methiodide pretreatment, the stimulatory action of NPY was significantly
attenuated. These data indicate that opioid receptors in the PVN influence the
action of NPY on energy substrate utilization.
PMID- 10757511
TI - Decreased GDNF mRNA expression in dorsal spinal cord of unilateral arthritic rat.
AB - It is now well established that nerve growth factor (NGF) plays a key role in
inflammation-induced hyperalgesia. It was also reported that brain derived
neurotrophic factor (BDNF), another member of neurotrophins, contributed to the
pain pathway as a neurotransmitter in the CNS. The present work demonstrated a
down-regulation of glial cell line-derived neurotrophic factor (GDNF) mRNA
expression in dorsal spinal cord in complete Freund's adjuvant-induced unilateral
arthritic rats serving as a chronic pain model. The fast occurring and long
lasting down-regulations suggest that GDNF might contribute to pain pathway in a
way different from neurotrophins and might play a role in the maintenance of
chronic pain status.
PMID- 10757512
TI - In vivo imaging of adenovirus-mediated over-expression of dopamine D2 receptors
in rat striatum by positron emission tomography.
AB - PET was used to provide in vivo imaging of the over-expression of dopamine D2
receptor (D2R) induced by adenovirus vector-mediated gene transfer in rat
striatum. The uptake of three kinds of D2R-specific ligands, [11C]raclopride,
[11C]nemonapride and [11C]N-methylspiperone, measured by PET was higher in the
striatum injected with the vectors for D2R than the contralateral striatum
injected with a control vector 2-3 days after injection. However, the uptake of
[11C]SCH 23390, a dopamine D1 receptor specific ligand, or [11C]beta-CIT-FP, a
dopamine transporter specific tracer, was not different between bilateral
striata. Co-injection of excess unlabeled raclopride inhibited the uptake of
[11C]raclopride. At day 16 the increased uptake of [11C]raclopride declined to
basal level, consistent with past in vitro assessment of this vector. In vivo
imaging of D2R will permit longitudinal assessment of the efficiency of this and
similar vectors in rat brain that can be related to functional changes being
observed.
PMID- 10757513
TI - Cerebellar hypoactivity in frequent marijuana users.
AB - It is uncertain whether frequent marijuana use adversely affects human brain
function. Using PET, regional cerebral blood flow was compared in frequent
marijuana users and comparable, non-using controls after at least 26 h of
monitored abstention by all subjects. Marijuana users showed substantially lower
brain blood flow than controls in a large region of posterior cerebellum,
indicating altered brain function in frequent marijuana users. A cerebellar locus
of some chronic and acute effects of marijuana is plausible, e.g. the cerebellum
has been linked to an internal timing system, and alterations of time sense are
common following marijuana smoking.
PMID- 10757514
TI - Cloning and cerebral expression of the guinea pig histamine H3 receptor: evidence
for two isoforms.
AB - We cloned the full length guinea pig H3 receptor cDNA using RT-PCR amplification
with primers from the human receptor and templates from brain areas. Evidence was
obtained for two isoforms, designated H3L and H3S, differing by a 30 amino acid
stretch within the third cytosolic loop, presumably generated by alternative
splicing. In situ hybridization using a selective cRNA probe showed the gene
transcripts to be highly expressed in discrete neuronal populations, e.g.
pyramidal cells in the cerebral cortex or cerebellar Purkinje cells, in some
instances already known to express other histamine receptor subtypes.
PMID- 10757515
TI - Effects of electromagnetic field emitted by cellular phones on the EEG during a
memory task.
AB - The effects of electromagnetic fields (EMF) emitted by cellular phones on the
ERD/ERS of the 4-6 Hz, 6-8 Hz, 8-10 Hz and 10-12 Hz EEG frequency bands were
studied in 16 normal subjects performing an auditory memory task. All subjects
performed the memory task both with and without exposure to a digital 902 MHz EMF
in counterbalanced order. The exposure to EMF significantly increased EEG power
in the 8-10 Hz frequency band only. Nonetheless, the presence of EMF altered the
ERD/ERS responses in all studied frequency bands as a function of time and memory
task (encoding vs retrieval). Our results suggest that the exposure to EMF does
not alter the resting EEG per se but modifies the brain responses significantly
during a memory task.
PMID- 10757516
TI - Paradoxical actions of the NO donor SIN-I on single laryngeal motoneurons in the
nucleus ambiguus.
AB - In order to study the pharmacological action of the NO donor SIN-1 upon laryngeal
motoneurons, we focally iontophoresed SIN-1 onto single motoneurons identified by
antidromic stimulation of the recurrent nerve. SIN-1 produced opposing effects on
motoneuron activities. Of 34 identified motoneurons, 38.2% showed a statistically
significant decrease (decreasing group), while 29.4% showed an increase in their
antidromic response to SIN-1 application (increasing group), respectively. The
remaining neurons did not show any change (no change group). When the antidromic
spike amplitude during the precontrol period was compared between the three
groups, both the increasing and decreasing groups exhibited larger antidromic
spikes than those measured in the no change group. The results are discussed in
terms of dual pharmacological actions of NO.
PMID- 10757517
TI - Heat shock modulates prion protein expression in human NT-2 cells.
AB - The pathological hallmarks of Prion disease are cortical spongiform changes and
neuronal loss, which are induced by the accumulation of the scrapie-isoform prion
protein (PrP(Sc)). PrP(Sc) is derived from a post-translational modification of
the cellular form of prion protein (PrP(C)). Heat-shock proteins, a group of
molecular chaperones, are involved in the degradation of denatured proteins and
post-translational folding of newly synthesized polypeptides. In an attempt to
examine any possible relationship between heat shock stress and an induction of
prion protein (PrP), human NT-2 cells were treated with heat shock at 42 degrees
C for 30 min. After heat-shock treatment, both the level of mRNA and PrP(C)
protein were analyzed at various time points by Northern and Western blot,
respectively. There was a 1.5- to 2.5-fold increase in PrP mRNA levels 1 and 3h
following heat shock. In addition, a two-fold increase in protein level of PrP
was found 3 h after heat-shock treatment. These results suggest that cellular
stress induces the elevation of both PrP mRNA and protein synthesis. The up
regulation of prion-protein mRNA and protein, implies that PrP may play a role in
cellular stress.
PMID- 10757518
TI - Spatial, not temporal cues drive predictive orienting movements during
navigation: a virtual reality study.
AB - A fundamental property of the human brain is the ability to make predictions of
future sensory and motor events. We have recently found that steering manoeuvres
when walking along curvilinear trajectories are controlled by an anticipatory
guidance of the direction of head (and eyes). However it is unclear whether a
time-related or space-related signal triggers such anticipatory head orienting
movements. By simulating navigation along a multi-legged virtual corridor we show
that anticipatory orienting movements are triggered (in standing subjects) by
reaching specific locations rather than by the time to the approaching corridor's
bend. Similar to what happens in car driving, specific spatial features of the
route rather than time to collision seem to drive steering.
PMID- 10757519
TI - Vestibular influence on the binocular control of vertical-torsional nystagmus
after lesions in the interstitial nucleus of Cajal.
AB - The interstitial nucleus of Cajal (iC) is a center of the velocity-to-position
integration for vertical and torsional eye movements. In addition, iC has
projections to and from the vestibular nuclei. Therefore the vestibular influence
on the binocular alignment of vertical-torsional nystagmus after unilateral
reversible iC inactivations was investigated in the alert monkey using 3D
binocular search-coil recordings. The nystagmus was compared with the eye muscle
rotation axes, which were corrected for the tonic ocular torsion elicited by the
iC inactivation. Rotation axes of nystagmus were different for both eyes and
revealed a co-activation of eye muscles similar to the effects of electrical
stimulation of the anterior canal nerve. This suggests that, in addition to the
deficient neural integrator, a vestibular imbalance contributes to the vertical
torsional nystagmus after iC inactivations.
PMID- 10757520
TI - Overactivation of primary motor cortex is asymmetrical in hemiparkinsonian
patients.
AB - Regional cerebral blood flow (rCBF) was measured using PET and H2(15)O in
Parkinson's disease (PD) patients with predominantly right-sided akinetic-rigid
symptoms and in control subjects during the execution of an externally cued motor
task either with the left or the right hand. During the execution of the task
with the left, non-akinetic, hand, cerebral activation in PD patients appeared
similar to that of controls. Activated areas were the primary motor cortex,
premotor cortex, parietal cortex and cerebellum. When the task was executed with
the right, akinetic, hand cerebral activation in PD patients differed from that
of controls subjects. The most important change was a bilateral activation of the
primary motor cortex. We conclude that overactivation of primary motor cortex is
asymmetrical in hemiparkinsonian patients.
PMID- 10757521
TI - Modulation of the truncated GAD25 by estrogen in the olfactory bulb of adult
rats.
AB - The aim of our study was to investigate the influence of gonadal steroids on the
expression of different GAD isoforms. Here we show that, in addition to the adult
GAD forms, the two embryonic splice variants of GAD67 mRNA and the truncated
GAD25 are present in the adult rat olfactory bulb, a brain region with high
synaptic plasticity, which has preserved some features of the developing brain.
By Western blot analysis, we could demonstrate that the expression of the
embryonic GAD25 is cyclic in females: its quantity is higher on estrus day.
Furthermore, in ovariectomized animals 17-beta-estradiol treatment induced an
increase of GAD25 within 3 h, reaching a maximum at 9-12 h. Our data are
compatible with the interpretation that the embryonic GAD isoforms may play a
role in the neuroplastic changes induced by sexual steroids.
PMID- 10757522
TI - Alzheimer's disease in the parents of women with trisomic spontaneous abortions.
AB - We tested whether familial aggregation of Down syndrome and Alzheimer's disease
(AD) is present for trisomies of other autosomes. We compared rates of Alzheimer
like dementia in the parents of women with trisomic pregnancy losses (n = 109)
with those in parents of women with chromosomally normal losses (n = 151) and
births (n = 216). Relative risks of Alzheimer-like dementia in parents of women
with trisomic losses were 1.2 (95% CI 0.6, 2.2) and 0.9 (95% CI 0.5, 1.5) in
comparison to parents of women with chromosomally normal losses and births,
respectively. Associations were similar among women whose index pregnancy
occurred before age 35 or later. Our data do not support an association between
the occurrence of AD and trisomy of all autosomal chromosomes. They raise the
possibility that familial aggregation with AD is specific to trisomy 21.
PMID- 10757523
TI - The cAMP-dependent protein kinase mediates the expression of AChE in chick
myotubes.
AB - Calcitonin gene-related peptide (CGRP), a neuropeptide synthesized by motor
neurons, stimulates the expression of AChR and AChE at the vertebrate
neuromuscular junctions. The signaling mechanism of CGRP-induced AChE expression
in muscle was determined both in vitro and in vivo. In cultured chick myotubes,
the intracellular cAMP-dependent protein kinase (PKA) activity increased to
approximately 2-fold after the application of CGRP or PKA activators; the
induction was blocked by PKA inhibitors. in vivo transfection analysis on chick
gastrocnemius muscles showed that the transfection of cDNA encoding
constitutively active mutant Galphas increased the expression of AChE mRNA and
protein to approximately 2-fold, while the constitutively active mutant Galphai
cDNA transfection showed an opposite effect. The induced catalytic subunit of
AChE at approximately 105 kDa was determined by specific antibody. These findings
indicate that the CGRP-induced AChE expression in chick muscle is mediated by a
PKA-dependent pathway.
PMID- 10757524
TI - Extracellular S100B protein modulates ERK in astrocyte cultures.
AB - S100B is a calcium binding protein expressed and secreted by astrocytes.
Extracellular S100B stimulates the proliferation of astroglial cells and the
survival of neurons. Extracellular signal regulated kinases (ERK) are involved in
the transduction of proliferating signals in astrocytes. Here we report that
S100B significantly increases the activity of ERK in primary cultures of
astrocytes, a result which may be related to previous observations of the effect
of this protein on glial proliferation. We further confirm that conversion of
S100B to its covalent dimer by oxidation of cysteine residues increases its
extracellular activity. Although we cannot exclude S100B involvement in other
mechanisms of signal transduction, these results suggest that ERK activity in
astrocytes is modulated by extracellular S100B.
PMID- 10757525
TI - Neural plasticity detected in short- and long-term cochlear implant users using
PET.
AB - The interaction of listening to words and watching sign language in short-term
and long-term cochlear implant (CI) users who have learned sign language after
becoming deaf was measured using PET. In short-term CI users the auditory cortex
was inactive while in long-term CI users it was fully activated with the
simultaneous presentation of auditory and visual input. The result suggests the
possibility that the interference of rival modalities may be diminished with
experience and the preference switchover from the visual input to the auditory
input could be accomplished by means of the neural plasticity persisting in the
mature human auditory cortex.
PMID- 10757526
TI - Plastic changes in the auditory cortex induced by intensive frequency
discrimination training.
AB - The slow auditory evoked (wave N1m) and mismatch field (MMF) elicited by
sequences of pure tones of 1000 Hz and deviant tones of 1050, 1010 and 1005 Hz
were measured before, during and 3 weeks after subjects were trained at frequency
discrimination for 15 sessions (over 3 weeks) using an odd-ball procedure. The
task of the subject was to detect deviants differing by progressively smaller
frequency shifts from the standard stimulus. Frequency discrimination improved
rapidly in the first week and was followed by small but constant improvements
thereafter. N1m and MMF responses to the deviant stimuli increased in amplitude
during training. This enhancement persisted until training was finished, but
decreased 3 weeks later. The results suggest a plastic reorganization of the
cortical representation for the trained frequencies.
PMID- 10757527
TI - SDH activity and cell size of tibialis anterior motoneurons and muscle fibers in
SAMP6.
AB - Succinate dehydrogenase (SDH) activities and cross-sectional areas (CSAs) of
tibialis anterior motoneurons and muscle fibers were determined in 20-, 40-, and
60-week-old male senescence-accelerated mice (SAMP6), and compared with those in
age-matched accelerated-senescence resistant mice (SAMR1). The mean CSA of
motoneurons in SAMP6 decreased at 60 weeks, primarily due to a selective loss of
large (>400 microm2) motoneurons. The mean SDH activity of motoneurons with CSAs
between 100 and 400 microm2 decreased in SAMP6, but not SAMR1, at 60 weeks. The
mean muscle fiber SDH activities and CSAs in SAMP6 decreased at 60 weeks. There
were no differences in the mean SDH activity or CSA of motoneurons or muscle
fibers among 20-, 40-, and 60-week-old SAMR1. These results demonstrate that mice
which have been shown to have a variety of accelerated-senescent features also
have an earlier onset of age-related changes in motoneurons and the muscle fibers
that they innervate when compared with age-matched accelerated-senescence
resistant mice.
PMID- 10757528
TI - Cholecystokinin-B receptor antagonists attenuate morphine dependence and
withdrawal in rats.
AB - The possible effect of a cholecystokinin-8 agonist (caerulein) and antagonists
(MK-329 and L365,260) on the development of morphine dependence and withdrawal
were investigated in rats. Caerulein treatment (0.01 and 0.1 mg/kg) increased the
incidence of naloxone-induced withdrawal syndromes and delayed the extinction of
morphine-conditioned place preference in morphine-dependent animals. The signs of
the morphine withdrawal syndromes and the formation of morphine-conditioned place
preference were suppressed by pretreatment with L365,260 (0.1 and 1 mg/kg) and
not affected by pretreatment with MK-329 (0.1 and 1 mg/kg). The present study
demonstrated CCK, acting on CCK-B receptors, participates in the development of
the opiate dependence. These findings suggest that CCK-B receptor antagonists
might be of some value in the treatment and prevention the relapse of opiate
addicts.
PMID- 10757529
TI - Neonatal serotonin depletion affects developing and mature mouse cortical
neurons.
AB - The early expression of neurotransmitters and receptors in the developing brain
has brought attention to their potential contribution in modulating neuronal
developmental processes. Monoamines are among the first neurotransmitter systems
to develop during embryogenesis. Depletion of neocortical serotonin or
catecholamine afferents with selective neurotoxins resulted in a permanent
alteration of the dendritic arborization of calretinin-containing interneurons,
and a transient delay of parvalbumin and calbindin expression in a number of
cortical neurones during the second postnatal week. The expression pattern of
other developmentally regulated proteins, such as two subunits of the GABA(A)
receptor, was not altered. Depletion of serotonin, and in part catecholamines,
appeared to perturb several developmental processes of the cerebral cortex which
would interfere with both its maturation and adult circuitry.
PMID- 10757530
TI - Ultrastructural localization of activated NF-kappaB in granule cells of the rat
fascia dentata.
AB - The distribution of activated NF-kappaB (p65) was studied in granule cells of the
rat fascia dentata using confocal laser scanning microscopy and preembedding
immunogold electron microscopy. Activated NF-kappaB, detected with a monoclonal
antibody specific for the nuclear localization signal-epitope, was found in
proximal dendrites, somata, and nuclei but not in axon terminals of granule
cells. Within the nuclei of granule cells, clusters of NF-kappaB immunoreactivity
were detected. These data are in line with the proposed function of NF-kappaB as
a retrograde signal transducer which transports information from synaptic sites
to the nucleus to initiate gene expression.
PMID- 10757531
TI - The up-regulation of preprodynorphin mRNA in trigeminoparabrachial neurons after
inflammation.
AB - Inflammation of the temporomandibular joint (TMJ) produces an increase in
preprodynorphin (PPD) mRNA expression in the spinal trigeminal nucleus (Vsp) and
paratrigeminal nucleus (Pa5) of the rat. In this study, we further demonstrated
that a portion of the TMJ inflammation-induced PPD mRNA positive neurons in the
Vsp and Pa5 projected to the parabrachial nucleus (PB). In inflamed rats, the
percentage of trigemino- and paratrigeminoparabrachial neurons with up-regulation
of PPD mRNA was significantly increased in the ipsilateral Vsp (5.7+/-1.8%) and
Pa5 (22.8+/-7.4%, n = 3) when compared with the contralateral side and with
saline-treated controls (p < 0.05). These results suggest that the selective up
regulation of PPD mRNA in the Vsp and Pa5 following TMJ inflammation involves
ascending trigeminal nociceptive pathways.
PMID- 10757532
TI - Innervation of a single vibrissa in the whisker-pad of rats.
AB - Innervation of the gamma straddler vibrissa and distribution of individual gamma
vibrissal sensory nerve fibers within infraorbital nerve branches were
investigated in adult rats. In the close vicinity (2 mm) of the whisker-pad, one
fifth of the nerve fibers innervating the gamma vibrissa were still located in
nerves to neighboring (beta, delta, C1 and D1) whiskers, while one-tenth of the
innervating fibers were placed in nerves of more distant sinus hairs. This
convergence of gamma vibrissal sensory nerve fibers to single vibrissa from
neighboring nerves is suggested to be a consequence of overlapping vibrissal
representation in the Gasserian ganglion.
PMID- 10757533
TI - Unbiased stereological quantification of neurons in the human vestibular
ganglion.
AB - Vestibular ganglion (VG) neurons are bipolar neurons that relay peripheral
vestibular information to the CNS. Neuron counts in normal humans provide a basis
for quantitative studies on the effects of aging or pathological conditions in
the audiovestibular systems. No prior study has employed unbiased stereological
technique to count human VG neurons. This study used unbiased stereology in the
form of the optical fractionator to estimate the total number of human VG neurons
in archival temporal bone specimens. An average (+/- s.d.) of 27330+/-2593
neurons was found in specimens from five patients with no history of vestibular
pathology. This result, a significant departure from results of past studies,
provides the first unbiased baseline value to compare with future stereologically
based studies on the human VG.
PMID- 10757534
TI - Acoustic trauma enhances DNA binding of transcription factor AP-1 in the guinea
pig inner ear.
AB - Radiolabeled probes for the transcription factor, activator protein-1 (AP-1),
bound differentially to nuclear fractions of discrete structures of the guinea
pig cochlea (organ of Corti, lateral wall tissues, and spiral ganglion). Noise
exposure (4 kHz octave band, 115 dB, for 5 h) significantly increased AP-1
binding in both the organ of Corti and lateral wall tissues but not in the spiral
ganglion. Supershift analysis using an antibody against c-Fos protein
demonstrated that enhancement of AP-1/DNA binding was at least in part due to the
expression of c-Fos protein. These results suggest that AP-1 is involved in the
molecular mechanism(s) mediating noise-induced cochlear damage.
PMID- 10757535
TI - Down-regulation of delta opioid receptor mRNA by an anabolic steroid in neuronal
hybrid cells.
AB - Nandrolone, an anabolic androgenic steroid, reduced delta opioid receptor (DOR)
mRNA and the number of DOR binding sites in two neuronal hybrid cell lines: NG
108-15 and the GT1-1 cells. Both cell lines express DOR but only GT1-1 cells
express androgen receptors (AR). DOR mRNA levels were maximally decreased by
approximately 45% in NG 108-15 cells and by approximately 38% in GT1-1 cells
exposed for 24 h to 10(-6) M nandrolone. This action was partly due to a decrease
in the rate of transcription of DOR mRNA and was not blocked by the androgen
antagonist flutamide. Flutamide antagonized the repression of AR mRNA induced by
nandrolone. The synthetic glucocorticoid dexamethasone (10(-6) M) did not modify
DOR steady-state transcripts in either cell line. These results suggest that
nandrolone presumably regulate DOR mRNA levels through mechanisms independent of
the androgen and glucocorticoid receptors.
PMID- 10757536
TI - Phosphorylation of MARCKS in Alzheimer disease brains.
AB - Activation of the amyloid beta-protein precursor, secretary pathway through alpha
secretase has been reported to increase the secretion of neuroprotective amyloid
precursor protein and preclude the formation of amyloid beta-protein. Activation
of protein kinase C has been shown to accelerate this secretory pathway. These
results prompted us to focus on a potential links between protein kinase C and
the amyloid beta-protein-related pathology of Alzheimer disease (AD). Although
protein kinase C is reported to occur in senile plaques, its catalytic activity
has not been investigated. As the phosphorylation of myristoylated alanine-rich C
kinase substrate (MARCKS) has been used as a marker for activation of protein
kinase C in vivo, we examined its phosphorylation in brain tissues obtained from
seven AD patients and five non-demented subjects using an antibody that
specifically recognized MARCKS phosphorylated by protein kinase C.
Phosphorylation of MARCKS in cortical neurons in AD brains was weaker than that
in control brains. Interestingly, however, phosphorylation of MARCKS was detected
in microglia and dystrophic neurites within neuritic plaques, a mature form of
amyloid beta-protein deposits. These results suggest that protein kinase C
alteration is associated with AD pathology and that protein kinase C is activated
in microglia and dystrophic neurites by amyloid beta-protein in AD brains.
PMID- 10757537
TI - Effects of visual attentional load on auditory processing.
AB - Auditory evoked potentials were recorded while participants attended to visually
presented digits. The difficulty of the visual task was manipulated by requiring
participants to process only the current digit (0-back) or both the current and
the preceding digit (1-back). Tones deviating in frequency from standard tones
elicited a frontal mismatch negativity peaking around 200 ms which did not vary
with visual task. However, decreasing the visual task load enhanced a right
temporal positive wave peaking around 200 ms when tones were presented slowly,
and a frontocentral negative wave peaking around 450 ms when tones were presented
more rapidly. The degree to which task-irrelevant sounds are processed therefore
depends on the degree to which a visual task engages attentional resources.
PMID- 10757538
TI - Slow waves in the sleep electroencephalogram after daily torpor are
homeostatically regulated.
AB - Animals emerging from hibernation or daily torpor show an initial increase in
electroencephalogram slow-wave activity (SWA, power density between 0.75 and 4.0
Hz) in non-REM sleep, which subsequently declines. These typical features of
sleep following prolonged waking led to the interpretation that the animals incur
a sleep deprivation (SD) during torpor. This hypothesis has recently been
questioned because the increase in SWA disappears in ground squirrels when sleep
deprived immediately following hibernation. Here we show that in Djungarian
hamsters subjected to SD immediately after daily torpor a predictable increase in
SWA occurs during recovery. This supports the notion that the hamsters must sleep
to dissipate the pressure for SWA incurred during torpor. The similarity between
sleep after waking and torpor may provide a key for understanding sleep
regulation.
PMID- 10757539
TI - Delta opioid receptor immunoreactive boutons appose bulbospinal CI neurons in the
rat.
AB - Bulbospinal sympathoexcitatory neurons in the rostral ventrolateral medulla are
inhibited by activation of delta opioid receptors. However, it is not known
whether this opioidergic effect is pre- or post- synaptic. Here, using retrograde
tracing and immunocytochemistry in adult rats, we provide evidence that the delta
opioid receptor is located on boutons that are presynaptic to both
catecholaminergic and non-catecholaminergic neurons that project to the spinal
cord. We suggest that the sympathoinhibitory action of delta opioid receptor
activation in the rostral ventrolateral medulla is mediated presynaptically,
resulting in a reduction of excitatory neurotransmitter release from boutons that
oppose sympathoexcitatory bulbospinal neurons.
PMID- 10757540
TI - Sensory-specific satiety-related olfactory activation of the human orbitofrontal
cortex.
AB - When a food is eaten to satiety, its reward value decreases. This decrease is
usually greater for the food eaten to satiety than for other foods, an effect
termed sensory-specific satiety. In an fMRI investigation it was shown that for a
region of the orbitofrontal cortex the activation produced by the odour of the
food eaten to satiety decreased, whereas there was no similar decrease for the
odour of a food not eaten in the meal. This effect was shown both by a voxel-wise
SPM contrast (p <0.05 corrected) and an ANOVA performed on the mean percentage
change in BOLD signal in the identified clusters of voxels (p <0.006). These
results show that activation of a region of the human orbitofrontal cortex is
related to olfactory sensory-specific satiety.
PMID- 10757541
TI - Lipids and retroviruses.
AB - The role that lipids may play in enveloped viruses is reviewed. Small lipid
molecules can influence retrovirus binding to cell receptors, plasma membrane
fusion, and transcription. Palmitoylation following myristoylation of viral
glycoproteins is required at the transmembrane level for signal transduction as
well as for virion budding and maturation. Cholesterol, ether lipids,
phospholipids, platelet-activating factor, phosphatidic acids, diacylglycerols,
and several analogs and derivatives influence human immunodeficiency virus (HIV)
activity; when conjugated with inhibitors of the viral reverse transcriptase (RT)
or aspartyl protease these compounds increase drug effectiveness. On the other
hand, L-carnitine, in association with the mitochondrial cardiolipins, inhibits
myopathy due to continued prescription of drugs [AZT (zidovudine), ddl
(didanoside), or ddC (zalcitabine)], and the redox couple of alpha-lipoic
dihydrolipoic acid prevents production of the reactive oxygen species that
trigger apoptosis of infected cells, with sphingomyelin breakdown to ceramides.
Retroviral infection induces a shift from phospholipid to neutral fat synthesis
in host cells, and a long antiviral, i.e., antiprotease, treatment may lead to
lipodystrophy. Multitherapy involving lipids and their analogs in association
with anti-RT and antiproteases might enhance the inhibition of growth and
proliferation of retroviruses.
PMID- 10757542
TI - Biosynthesis of conjugated linoleic acid in humans.
AB - This paper deals with the reanalysis of serum lipids from previous studies in
which deuterated fatty acids were administered to a single person. Samples were
reanalyzed to determine if the deuterated fatty acids were converted to deuterium
labeled conjugated linoleic acid (CLA, 9c,11t-18:2) or other CLA isomers. We
found 11-trans-octadecenoate (fed as the triglyceride) was converted (delta9
desaturase) to CLA, at a CLA enrichment of ca. 30%. The 11-cis-octadecenoate
isomer was also converted to 9c,11c-18:2, but at <10% the concentration of the
11t-18:1 isomer. No evidence (within our limits of detection) for conversion of
10-cis- or 10-trans-octadecenoate to the 10,12-CLA isomers (delta12 desaturase)
was found. No evidence for the conversion of 9-cis,12-cis-octadecadienoate to CLA
(via isomerase enzyme) was found. Although these data come from four single human
subject studies, data from some 30 similar human studies have convinced us that
the existence of a metabolic pathway in one subject may be extrapolated to the
normal adult population.
PMID- 10757543
TI - Effects of dietary alpha-linolenic acid on the conversion and oxidation of 13C
alpha-linolenic acid.
AB - The effects of a diet rich in alpha-linolenic acid vs. one rich in oleic acid on
the oxidation of uniformly labeled 13C-alpha-linolenic acid and its conversion
into longer-chain polyunsaturates (LCP) were investigated in vivo in healthy
human subjects. Volunteers received a diet rich in oleic acid (n = 5) or a diet
rich in alpha-linolenic acid (n = 7; 8.3 g/d) for 6 wk before and during the
study. After 6 wk, subjects were given 45 mg of 13C-alpha-linolenic acid
dissolved in olive oil. Blood samples were collected at t = 0, 5, 11, 24, 96, and
336 h. Breath was sampled and CO2 production was measured each hour for the first
12 h. The mean (+/- SEM) maximal absolute amount of 13C-eicosapentaenoic acid
(EPA) in plasma total lipids was 0.04 +/- 0.01 mg in the alpha-linolenic acid
group, which was significantly lower (P = 0.01) than the amount of 0.12 +/- 0.03
mg 13C-EPA in the oleic acid group. Amounts of 13C-docosapentaenoic acid (DPA)
and 13C-docosahexaenoic acid (DHA) tended to be lower as well. The mean
proportion of labeled alpha-linolenic acid (ALA) recovered as 13CO2 in breath
after 12 h was 20.4% in the ALA and 15.7% in the oleic acid group, which was not
significantly different (P = 0.12). The cumulative recovery of 13C from 13C-ALA
in breath during the first 12 h was negatively correlated with the maximal
amounts of plasma 13C-EPA (r = -0.58, P = 0.047) and 13C-DPA (r = -0.63, P =
0.027), but not of 13C-DHA (r = -0.49, P = 0.108). In conclusion, conversion of
13C-ALA into its LCP may be decreased on diets rich in ALA, while oxidation of
13C-ALA is negatively correlated with its conversion into LCP. In a few pilot
samples, low 13C enrichments of n-3 LCP were observed in a diet rich in EPA/DHA
as compared to oleic acid.
PMID- 10757545
TI - Effect of DHA supplementation on DHA status and sperm motility in
asthenozoospermic males.
AB - The effects of supplementation with docosahexaenoic acid (DHA) on DHA levels in
serum, seminal plasma, and sperm of asthenozoospermic men as well as on sperm
motility were examined in a randomized, double-blind, placebo-controlled manner.
Asthenozoospermic men (n = 28; < or =50% motility) were supplemented with 0, 400,
or 800 mg DHA/d for 3 mon. Sperm motility and the fatty acid composition of
serum, seminal plasma, and sperm phospholipid were determined before and after
supplementation. In serum, DHA supplementation resulted in decreases in 22:4n-6 (
30% in the 800-mg DHA group only) and total n-6 (-6 and -12% in the 400- and 800
mg DHA groups, respectively) fatty acids. Increases were noted in DHA (71 and
131% in the 400- and 800-mg DHA groups, respectively), total n-3 fatty acids (42
and 67% in the 400- and 800-mg DHA groups, respectively), and the n-3/n-6 ratio
(50 and 93% in the 400- and 800-mg DHA groups, respectively). In seminal plasma,
DHA supplementation resulted in a decrease in 22:4n-6 (-31% in the 800-mg DHA
group only) and an increase in the ratio of n-3 to n-6 (35 and 33% in the 400-
and 800-mg DHA groups, respectively). There were insignificant increases in DHA
and total n-3 fatty acids. In sperm, decreases were noted in 22:4n-6 (-37 and
31% in the 400- and 800-mg DHA groups, respectively). There were no other
changes. There was no effect of DHA supplementation on sperm motility. The
results show that dietary DHA supplementation results in increased serum--and
possibly seminal plasma--phospholipid DHA levels, without affecting the
incorporation of DHA into the spermatozoa phospholipid in asthenozoospermic men.
This inability of DHA to be incorporated into sperm phospholipid is most likely
responsible for the observed lack of effect of DHA supplementation on sperm
motility.
PMID- 10757544
TI - A high-fat diet induces and red wine counteracts endothelial dysfunction in human
volunteers.
AB - Endothelial dysfunction is associated with atherogenesis and oxidative stress in
humans. In rat and rabbit blood vessels, wine polyphenol antioxidants induce
vascular relaxation in vitro through the NO-cGMP pathway. To assess the effect of
a regular high-fat diet (HFD) and moderate red wine consumption on endothelial
function (EF), a study was performed in healthy male volunteers. EF was measured
as flow-mediated dilatation of the brachial artery, employing high-resolution
ultrasound after an overnight fast. Other clinical and biochemical parameters
related to EF were also measured. Six volunteers received a control diet, rich in
fruits and vegetables (27% calories as fat) and five volunteers received an HFD
(39.5% calories as fat). Measurements were done twice on each volunteer: after a
period of 30 d with diet plus 240 mL of red wine/d, and after a period of 30 d
with diet, without wine. In the absence of wine, there is a reduction of EF with
HFD when compared to the control diet (P = 0.014). This loss of EF is not seen
when both diets are supplemented with wine for 30 d (P = 0.001). Plasma levels of
n-3 fatty acids (R2 = 0.232, P = 0.023) and lycopene (R2 = 0.223, P = 0.020) show
a positive correlation with individual EF measurements, but they do not account
for the significant differences observed among dietary groups or after wine
supplementation. These results help elucidate the deleterious effect of a high
fat diet and the protective role of wine, n-3 fatty acids and dietary
antioxidants in cardiovascular disease.
PMID- 10757546
TI - Effects of dietary conjugated linoleic acids on hepatic and muscle lipids in
hybrid striped bass.
AB - Conjugated linoleic acids (CLA) are the focus of numerous studies, yet the
effects of these isomers of octadecadienoic acids have not been evaluated in many
species of fish. In this study, graded amounts of CLA--0, 0.5, 0.75, or 1.0% of
the diet--were fed to juvenile hybrid striped bass for 8 wk. Dietary treatments
were fed to apparent satiation twice daily to triplicate groups of fish initially
weighing 13.4 g/fish. Feed intake and weight gain of fish fed 1.0% CLA were
significantly reduced compared to fish fed no CLA. Fish fed 0.5 and 0.75% CLA
exhibited reduced feed intake similar to fish fed 1.0% CLA, but had growth rates
that were not significantly different from those of fish fed no CLA. Feed
efficiency improved significantly in fish as dietary CLA concentrations
increased. Total liver lipid concentrations were significantly reduced in fish
fed the diets containing CLA compared to those of fish fed the control diet, and
intraperitoneal fat ratio was significantly lower in fish fed 1.0% CLA compared
to fish fed no CLA. Fish fed dietary CLA exhibited significant increases in
hepatosomatic index and moisture content of muscle and carcass. The CLA isomers
were detected in liver and muscle of fish fed the diets containing CLA, while a
low concentration of one isomer was detected in liver and muscle of fish fed the
control diet. Dietary CLA resulted in a significant increase in 18:2(c-9,c-12)
concentration in liver and muscle, but a significant reduction in 18:1n-7 in
these tissues. Furthermore, feeding CLA resulted in a significant increase in the
concentration of 20:5n-3 and 22:6n-3 in liver, but a reduction of these fatty
acids in muscle. This study showed that feeding CLA elevated tissue
concentrations of these fatty acid isomers, reduced tissue lipid contents,
improved feed efficiency, and altered fatty acid concentrations in liver and
muscle of fish.
PMID- 10757547
TI - Effects of various tocopherol-containing diets on tocopherol secretion into bile.
AB - Gamma-tocopherol is abundant in common vegetable oil, but its concentration in
plasma and liver is much lower than that of alpha-tocopherol. Discrimination
between different forms of tocopherol is thought to take place via the hepatic
alpha-tocopherol transfer protein (alpha-TTP). Gamma-tocopherol, with a low
binding capacity to alpha-TTP, is thought to be excreted via the bile. Our
previous studies showed that gamma-tocopherol administered with sesame seed
exhibits significantly higher concentrations in the plasma and liver of rats than
gamma-tocopherol alone. Thus, we attempted to confirm whether a much higher
amount of gamma-tocopherol rather than alpha-tocopherol would be secreted in the
bile, and whether sesame seed would suppress the secretion of gamma-tocopherol.
In one experiment, we examined the concentrations of alpha- or gamma-tocopherol
in the plasma, liver, and bile of rats fed diets containing 300 mg/kg of alpha
tocopherol, 300 mg/kg of gamma-tocopherol, or 300 mg/kg each of alpha-tocopherol
+ gamma-tocopherol, and in the other experiment, we compared the gamma-tocopherol
concentrations of rats fed a diet of gamma-tocopherol alone to those of rats fed
a gamma-tocopherol + sesame seed diet (each diet contained 300 mg/kg gamma
tocopherol). The bile collection was done over 6 h. The gamma-tocopherol
concentration in the bile was markedly lower than that of alpha-tocopherol,
paralleling the concentrations in the plasma and liver. Intake of alpha
tocopherol and gamma-tocopherol together further lowered the concentration of
gamma-tocopherol in the bile as well as in the plasma and liver, compared to the
intake of gamma-tocopherol alone. The gamma-tocopherol concentration in the bile,
as well as in the plasma and liver, was markedly higher in the sesame seed-fed
group than in the gamma-tocopherol alone group. We found that the concentrations
of alpha- or gamma-tocopherol in the bile showed a good correlation with the
concentrations of alpha- or gamma-tocopherol in the liver, though the
concentrations in the bile were substantially lower than those in the liver.
These findings suggest that secretion into the bile is not a major metabolic
route of alpha- or gamma-tocopherol.
PMID- 10757548
TI - Antiproliferative and apoptotic effects of tocopherols and tocotrienols on normal
mouse mammary epithelial cells.
AB - Studies were conducted to determine the comparative effects of tocopherols and
tocotrienols on normal mammary epithelial cell growth and viability. Cells
isolated from midpregnant BALB/c mice were grown within collagen gels and
maintained on serum-free media. Treatment with 0-120 microM alpha- and gamma
tocopherol had no effect, whereas 12.5-100m microM tocotrienol-rich fraction of
palm oil (TRF), 100-120 microM delta-tocopherol, 50-60 microM alpha-tocotrienol,
and 8-14 microM gamma- or delta-tocotrienol significantly inhibited cell growth
in a dose-responsive manner. In acute studies, 24-h exposure to 0-250 microM
alpha-, gamma-, and delta-tocopherol had no effect, whereas similar treatment
with 100-250 microM TRF, 140-250 microM alpha-, 25-100 microM gamma- or delta
tocotrienol significantly reduced cell viability. Growth-inhibitory doses of TRF,
delta-tocopherol, and alpha-, gamma-, and delta-tocotrienol were shown to induce
apoptosis in these cells, as indicated by DNA fragmentation. Results also showed
that mammary epithelial cells more easily or preferentially took up tocotrienols
as compared to tocopherols, suggesting that at least part of the reason
tocotrienols display greater biopotency than tocopherols is because of greater
cellular accumulation. In summary, these findings suggest that the highly
biopotent gamma- and delta-tocotrienol isoforms may play a physiological role in
modulating normal mammary gland growth, function, and remodeling.
PMID- 10757549
TI - Incorporation of polyunsaturated fatty acids into CT-26, a transplantable murine
colonic adenocarcinoma.
AB - Previous studies in our laboratory have shown that marine oils, with high levels
of eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acids (DHA, 22:6n-3),
inhibit the growth of CT-26, a murine colon carcinoma cell line, when implanted
into the colons of male BALB/c mice. An in vitro model was developed to study the
incorporation of polyunsaturated fatty acids (PUFA) into CT-26 cells in culture.
PUFA-induced changes in the phospholipid fatty acid composition and the affinity
with which different fatty acids enter the various phospholipid species and
subspecies were examined. We found that supplementation of cultured CT-26 cells
with either 50 microM linoleic acid (LIN, 18:2n-6), arachidonic acid (AA, 20:4n
6), EPA, or DHA significantly alters the fatty acid composition of CT-26 cells.
Incorporation of these fatty acids resulted in decreased levels of
monounsaturated fatty acids, while EPA and DHA also resulted in lower levels of
AA. While significant elongation of both AA and EPA occurred, LIN remained
relatively unmodified. Incorporation of radiolabeled fatty acids into different
phospholipid species varied significantly. LIN was incorporated predominantly
into phosphatidylcholine and had a much lower affinity for the ethanolamine
phospholipids. DHA had a higher affinity for plasmenylethanolamine (1-O-alk-1'
enyl-2-acyl-sn-glycero-3-phosphoethanolamine) than the other fatty acids, while
EPA had the highest affinity for phosphatidylethanol-amine (1,2-diacyl-sn-glycero
3-phosphoethanolamine). These results demonstrate that, in vitro, significant
differences are seen between the various PUFA in CT-26 cells with respect to
metabolism and distribution, and these may help to explain differences observed
with respect to their effects on tumor growth and metastasis in the
transplantable model.
PMID- 10757551
TI - Inhibition of cholesterol biosynthesis by organosulfur compounds derived from
garlic.
AB - The study was undertaken to test the inhibitory potential on cholesterogenesis of
organosulfur compounds derived from garlic. The primary rat hepatocytes
maintained in Dulbecco's modified Eagle's medium were treated with [2-14C]acetate
as substrate for cholesterol synthesis in the presence or absence of test
compounds at 0.05 to 4.0 mmol/L. Eleven water-soluble and six lipid-soluble
compounds of garlic were tested. Among water-soluble compounds, S-allyl cysteine
(SAC), S-ethyl cysteine (SEC), and S-propyl cysteine (SPC) inhibited [2
14C]acetate incorporation into cholesterol in a concentration-dependent manner,
achieving 42 to 55% maximal inhibition. Gamma-glutamyl-S-allyl cysteine, gamma
glutamyl-S-methyl cysteine, and gamma-glutamyl-S-propyl cysteine were less
potent, exerting only 16 to 29% maximal inhibitions. Alliin, S-allyl-N-acetyl
cysteine, S-allylsulfonyl alanine, and S-methyl cysteine had no effect on
cholesterol synthesis. Of the lipid-soluble compounds, diallyl disulfide (DADS),
diallyl trisulfide (DATS), and dipropyl disulfide (DPDS) depressed cholesterol
synthesis by 10 to 25% at low concentrations (< or =0.5 mmol/L), and abolished
the synthesis at high concentrations (> or =1.0 mmol/L). Diallyl sulfide,
dipropyl sulfide, and methyl allyl sulfide slightly inhibited [2-14C]acetate
incorporation into cholesterol only at high concentrations. The complete
depression of cholesterol synthesis by DADS, DATS, and DPDS was associated with
cytotoxicity as indicated by marked increase in cellular LDH release. There was
no apparent increase in LDH secretion by water-soluble compounds except S-allyl
mercaptocysteine, which also abolished cholesterol synthesis. Judging from
maximal inhibition and IC50 (concentration required for 50% of maximal
inhibition), SAC, SEC, and SPC are equally potent in inhibiting cholesterol
synthesis.
PMID- 10757550
TI - Accumulation of docosahexaenoic acid in phosphatidylserine is selectively
inhibited by chronic ethanol exposure in C-6 glioma cells.
AB - Neuronal membranes are highly enriched with docosahexaenoic acid (22:6n-3), and
its content can be altered by ethanol consumption. We have previously reported
that the 22:6n-3 status in membrane affects the biosynthesis of
phosphatidylserine (PS), a phospholipid class which contains an exceptionally
high proportion of 22:6n-3. The aim of the present study is to investigate the
effect of chronic ethanol exposure on PS accumulation in relation to the 22:6n-3
status. C-6 glioma cells were enriched with 25 microM 22:6n-3 for 48 h and the PS
accumulation was first evaluated in comparison to nonenriched cells as well as
cells enriched with arachidonic acid (20:4n-6). Electrospray liquid
chromatography-mass spectrometry analysis revealed that cells treated with 22:6n
3 showed significantly higher accumulation of PS in comparison to nonenriched or
20:4n-6-enriched cells, primarily due to an increase of 1-stearoyl-2
docosahexaenoyl-glycerophosphoserine (18:0,22:6-PS). Chronic ethanol exposure
selectively affected the accumulation of PS in 22:6n-3-enriched cells. After
cells were exposed to 20 or 50 mM ethanol for 4 wk, accumulation of 18:0,22:6-PS
upon 22:6n-3 supplementation was significantly lower, resulting in a drastic
reduction of total PS. Concomitantly, ethanol-treated cells showed lower
incorporation of serine in comparison to control cells. From these data, it was
concluded that supplementation of cells with 22:6n-3 promotes the accumulation of
PS and chronic ethanol treatment diminishes this effect at least in part through
impaired serine incorporation processes. Attenuated accumulation of 22:6n-3 in PS
and the reduction of PS thus may have significant implications in
pathophysiological effects of ethanol, especially in tissues with abundant 22:6n
3.
PMID- 10757552
TI - Mechanisms of tubulin modification by phosphatidylcholine hydroperoxides.
AB - The interaction of lipid peroxides with cellular proteins has been postulated to
contribute to cellular aging. A potential target for such effects is tubulin, the
building block of microtubules. We examined the concentration-dependent effects
of phosphatidylcholine hydroperoxides on the ability of tubulin to polymerize
into microtubules. The results demonstrated that even very low concentrations of
peroxides were sufficient to interfere with the tubulin and, therefore, the
microtubule function. Decreased tubulin activity (as measured by tubulin GTPase
activity) showed correlation with the modification of methionine and cysteine in
tubulin and a change in the tubulin conformational state as indicated by
fluorescence and ultraviolet spectroscopic measurements. As no effect on electric
conductivity was observed, indicating that modulation of ionic binding was not
involved, the interaction mechanism may be a hydrophobic one.
PMID- 10757553
TI - Biophysical studies and intracellular destabilization of pH-sensitive liposomes.
AB - We examined changes in membrane properties upon acidification of
dioleoylphosphatidylethanolamine/cholesterylhemisuccinate liposomes and evaluated
their potential to deliver entrapped tracers in cultured macrophages. Membrane
permeability was determined by the release of entrapped calcein or hydroxypyrene
1,3,6-trisulfonic acid (HPTS)-p-xylene-bis-pyridinium bromide (DPX); membrane
fusion, by measuring the change in size of the liposomes and the dequenching of
octadecylrhodamine-B fluorescence; and change in lipid organization, by 31P
nuclear magnetic resonance spectroscopy. Measurement of cell-associated
fluorescence and confocal microscopy examination were made on cells incubated
with liposomes loaded with HPTS or HPTS-DPX. The biophysical studies showed (i) a
lipid reorganization from bilayer to hexagonal phase progressing from pH 8.0 to
5.0, (ii) a membrane permeabilization for pH <6.5, (iii) an increase in the mean
diameter of liposomes for pH <6.0, and (iv) a mixing of liposome membranes for pH
<5.7. The cellular studies showed (i) an uptake of the liposomes that were
brought from pH 7.5-7.0 to 6.5-6.0 and (ii) a release of approximately 15% of the
endocytosed marker associated with its partial release from the vesicles (diffuse
localization). We conclude that the permeabilization and fusion of pH-sensitive
liposomes occur as a consequence of a progressive lipid reorganization upon
acidification. These changes may develop intracellularly after phagocytosis and
allow for the release of the liposome content in endosomes associated with a
redistribution in the cytosol.
PMID- 10757554
TI - Qualitative and quantitative analysis of lipoxygenase products in bovine corneal
epithelium by liquid chromatography-mass spectrometry with an ion trap.
AB - Electrospray ionization ion trap mass spectra of 5-, 12-, and 15
hydroperoxyeicosatetraenoic (HPETE), hydroxyeicosatetraenoic (HETE), and
ketoeicosatetraenoic (KETE) acids were recorded. The HPETE were partly dehydrated
to the corresponding KETE in the heated capillary of the mass spectrometer. 12
HPETE and 15-HPETE were also converted to KETE by collision-induced dissociation
(CID) in the ion trap, whereas CID of 5-HPETE yielded little formation of 5-KETE.
Subcellular fractions of bovine corneal epithelium were incubated with
arachidonic acid (AA) and the metabolites were analyzed. 15-HETE and 12-HETE were
consistently formed, whereas significant accumulation of HPETE and KETE was not
detected. Biosynthesis of 12- and 15-HETE was quantified with octadeuterated 12
HETE and 15-HETE as internal standards. The average biosynthesis of 15-HETE and
12-HETE from 30 microM AA by the cytosol was 38 +/- 8 and below 3 ng/mg
protein/30 min, respectively, which increased to 78 +/- 21 and 10 +/- 4 ng/mg
protein/30 min in the presence of 1 mM free Ca2+. The microsomal biosynthesis was
unaffected by Ca2+. The microsomes metabolized AA to 15-HETE as the main
metabolite at a low protein concentration (0.3 mg/mL), whereas 12-HETE and 15
HETE were formed in a 2:1 ratio at a combined rate of 0.7 +/- 0.2 microg/mg
protein/30 min at a high protein concentration (1.8 mg/mL). The level of 12-HETE
in corneal epithelial cells was 50 +/- 13 pg/mg tissue, whereas the endogenous
amount of 15-HETE was low or undetectable (<3 pg/mg tissue). Incubation of
corneas for 20 min at 37 degrees C before processing selectively increased the
amounts of 12-HETE in the epithelium fourfold to approximately 0.2 ng/mg tissue.
We conclude that 12-HETE is the main endogenously formed lipoxygenase product of
bovine corneal epithelium.
PMID- 10757555
TI - Determining double-bond positions in monoenoic 2-hydroxy fatty acids of
glucosylceramides by gas chromatography-mass spectrometry.
AB - We applied a gas chromatography-mass spectrometry (GC-MS) method using dimethyl
disulfide (DMDS) adducts and were able to determine the double-bond positions in
monounsaturated 2-hydroxy fatty acids (2-HFA). 2-HFA methyl esters, prepared from
the hydrolysate of Arabidopsis thaliana leaf glucosylceramides, were acetylated
and methylthiolated. GC-MS analysis of the resulting DMDS adducts showed simple
mass spectra with recognizable molecular ions and a series of key fragment ions
indicating the original double-bond positions in the aliphatic chain. Based on
this GC-MS elucidation, we confirmed that Arabidopsis leaf glucosylceramides have
C22, C23, C24, C25, and C26 chain length 2-HFA with monounsaturation, and all
their double bonds are placed at the n-9 position. This procedure is simple, time
efficient, and highly sensitive.
PMID- 10757556
TI - The use of reduced doses of amifostine to ameliorate nephrotoxicity of
cisplatin/ifosfamide-based chemotherapy in patients with solid tumors.
AB - This study evaluates the degree of kidney damage during cisplatin/ifosfamide
based combination chemotherapy and its possible prevention by amifostine. Thirty
one patients with solid tumors stratified according to pretreatment were
randomized to receive cisplatin/ifosfamide-based chemotherapy with or without
amifostine (1000 mg absolute) given as a short infusion prior to cisplatin.
Chemotherapy consisted of cisplatin (50 mg/m2), ifosfamide (4 g/m2) and either
etoposide (500 mg/m2) (VIP regimen) or paclitaxel (175 mg/m2) (TIP regimen)
repeated at 3 weekly intervals. For all patients the glomerular filtration rate
(GFR) measured by creatinine clearance, serum creatinine, electrolytes and
differential urinary protein excretion were determined prior to, during and after
each treatment cycle. A total of 62 cycles of chemotherapy were evaluable. In the
amifostine arm the GFR was almost completely maintained after application of two
cycles of chemotherapy (121 to 108 ml/min), whereas in the control group a 30%
reduction of the GFR (105 to 80 ml/min) was observed. In both groups marked
increases of glomerular and tubular marker profiles peaking at day 3 after
chemotherapy were found with a nearly complete reversibility of these changes
prior to the next chemotherapy cycle. Patients receiving amifostine had a lower
degree of hypomagnesemia, as well as a lower urinary excretion of N-acetyl
glucosaminidase and albumin, indicating less tubular damage compared to the
control patients. Treatment with 1000 mg amifostine resulted in an almost
complete preservation of GFR. This corresponded to a slightly reduced excretion
of tubular marker proteins and a lower incidence of hypomagnesemia during
chemotherapy in amifostine patients compared to controls. This dose of amifostine
may be sufficient for nephroprotection in patients without pre-existing risk
factors for renal damage who undergo a restricted number of chemotherapy cycles.
PMID- 10757557
TI - Phase II study of docetaxel alternating with cisplatin in chemotherapy-naive
patients with advanced non-small cell lung cancer.
AB - The objective of this study was to evaluate a regimen of full doses of docetaxel
and cisplatin, using an alternating schedule, as first-line therapy for patients
with inoperable non-small cell lung cancer (NSCLC). The standard concomitant
schedule does not allow full doses of both drugs to be administered. We wanted to
see if there was an advantage to be gained by administering full doses of both
docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was
given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and
100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three
docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were
evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90
100%) performance status. A median of five cycles was administered, for which no
dose reductions were necessary. There were 13 of 36 partial responses (36%; 95%
CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median
duration of response was 10.5 months, the median time to progression was 4.5
months and the median survival was 9 months. The 1 and 2 year survival rates were
39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23%
of patients), vomiting (18%) and neutropenia (77%). Infections were also common,
but not severe. The alternating schedule produced response, toxicity and survival
figures that compared favorable with those using the concomitant schedule. This
study could serve as a model for future studies of non-cisplatin-containing
regimens, in which full doses of docetaxel could alternate with full doses of
other new agents active against NSCLC.
PMID- 10757558
TI - Time- and dose-limiting erysipeloid rash confined to areas of lymphedema
following treatment with gemcitabine--a report of three cases.
AB - Gemcitabine is a deoxycytidine analog with broad antitumor activity. Its main
toxicities include myelosuppression, flu-like symptoms, bronchospasms and mild
skin rash. We report three cases, in which the patients developed time- and dose
limiting erysipeloid skin reactions confined to areas of impaired lymphatic
drainage after application of gemcitabine. Three patients with metastatic tumors
(breast cancer, endometrial cancer and non-small cell lung cancer) received
weekly infusions of gemcitabine (1000 mg/m2). All patients suffered from
lymphedema of different origin and developed an erysipeloid erythema 40-48 h
after chemotherapy within their preexisting lymphedema. Genuine erysipela was
ruled out by laboratory tests and clinical observation. The skin reaction was
repeatedly observed and faded after 14 days without specific treatment. Although
the pathogenesis of the observed reaction is unclear, it is suspected that the
skin symptoms were caused by gemcitabine or its metabolites. Gemcitabine is
usually metabolized fast and excreted renally. In areas with impaired lymphatic
drainage pharmakocinetics might be altered: inactivation happens slower and the
drug might accumulate in the s.c. and cutaneous tissue, thus increasing local
toxicity. Clinical judgement and biochemical parameters can help to tell apart
genuine erysipela and the erysipeloid reaction.
PMID- 10757559
TI - Characterization of human lung cancer cells resistant to 4'-O-demethyl-4beta-(2"
nitro-4"-fluoroanilino)-4-desoxypodophyllotoxin , a unique compound in the
epipodophyllotoxin antitumor class.
AB - A new semi-synthetic podophyllotoxin derivative, 4'-O-demethyl-4beta-2"-nitro-4"
fluoroanilino)-4-desoxypo dophyllotoxin (compound 1), an analog of GL-331
(compound 2), is a potent and broad-spectrum inhibitor of cultured human cancer
and drug-resistant cell growth. In general, 4'-demethylepipodophyllotoxin
analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme
DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unlike the cytotoxic
activity of compound 2, cell killing by 1 is dose-limiting and a significant
fraction of cells (30-40%) survive treatment. As an approach to investigate
mechanism of action, 1-resistant A549 (human lung cancer) sub-lines were selected
and characterized. Results of the work show that 1-resistant cells: (i) are
moderately cross-resistant (2- to 3-fold) to various cytotoxic drugs via a P
glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are
deficient in normal attachment on plastic and collagen substrata, and (iv) have
an altered plasma membrane protein composition including several proteins in the
140->200 kDa molecular mass range and a doublet of phosphoserine-containing
proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular
attachment or membrane-protein phosphorylation, the changes observed in 1
resistant cells are interpreted as a survival response to drug action.
PMID- 10757560
TI - Expression of inducible nitric oxide synthase (iNOS/NOS II) in the vestibule of
guinea pigs after the application of cisplatin.
AB - It is well known that the anti-cancer drug cisplatin has an ototoxic property;
however, the details are not yet evident. In this study, the expression of
inducible nitric oxide synthase (INOS/NOS II) in the vestibule of guinea pigs
after i.p. injections of cisplatin was examined immunohistochemically. Three days
after the injection of cisplatin (10 mg/kg) or placebo, animals were sacrificed.
Then the temporal bones were removed and subjected to Immunohistochemical studies
for iNOS. In the cisplatin group, INOS was detectable, whereas the tissue in the
control group was negative for iNOS. The vestibule, the wall of blood vessels and
the vestibular ganglion cells showed immunoreactivity for iNOS. It is known that
INOS catalyzes an inadequate quantity of NO under pathological conditions.
Increased NO levels lead to inner ear dysfunction. Therefore, our results
indicate that iNOS could also mediate the vestibulo-toxicity of cisplatin.
PMID- 10757561
TI - Antitumor activity of dextran derivatives immobilizing platinum complex (II).
AB - The in vivo antitumor activity and toxicity of a newly synthesized polymeric
prodrug of cisplatin was investigated and also compared with plain cisplatin. The
prodrug included a dicarboxymethyl-dextran conjugate of cisplatin (DCM-Dex/CDDP).
DCM-Dex/CDDP was i.v. injected in mice bearing s.c. Colon 26 mouse colon cancer
cells. The tissue distribution of platinum was thereafter determined by flameless
atomic absorption spectrophotometry. The platinic concentration of the organs
showed a high rate of retention at 24 h after injection in the DCM-Dex/CDDP
treated mice. No biochemical or hematologically adverse effects were observed. In
addition, DCM-Dex/CDDP showed a significantly higher antitumor activity than
cisplatin alone. These results indicate that DCM-Dex/CDDP may therefore be a
potentially effective cancer chemotherapy.
PMID- 10757562
TI - Anticancer drug-induced apoptosis in human monocytic leukemic cell line U937
requires activation of endonuclease(s).
AB - Anticancer agents effect tumor cell killing both in vivo and in vitro through the
induction of apoptosis. Endonuclease-mediated internucleosomal DNA fragmentation,
the most widely used biochemical marker of apoptosis, has been shown to play a
central role in apoptosis in many experimental systems. In the present
investigation, we report that activation of endonuclease(s) leading to
oligonucleosomal DNA fragmentation is common and an essential event in apoptosis,
induced by different anticancer drugs, adriamycin, etoposide and cisplatin. The
endonuclease inhibitors aurintricarboxylic acid and zinc ion prevented apoptotic
cell death in human monocytic leukemic cell line U937, as documented by DNA
fragmentation, morphological and nuclear alterations, and cell viability assay.
Additional studies suggest endonuclease(s)-mediated DNA fragmentation may not
play a central role in apoptosis in the same cell line in response to other
inducers such as heat shock and cells may undergo cell death showing all
morphological features of apoptosis even in the absence of DNA fragmentation.
PMID- 10757563
TI - Cinnamamide, an antitumor agent with low cytotoxicity acting on matrix
metalloproteinase.
AB - The antitumor activity of cinnamamide (CNM), an agent acting on matrix
metalloproteinase (MMP), was investigated in the present study. CNM displayed low
cytotoxicity. By the MTT assay the IC50 (50% inhibitory concentration) values of
CNM on cell proliferation ranged from 1.29 to 1.94 mM in human oral epidermoid
carcinoma KB cells, human hepatoma BEL-7402 cells and human fibrosarcoma HT-1080
cells. Moreover, the IC50 for human fetal lung 2BS cells reached 4.33 mM. The
administration of CNM in the range of 50-150 mg/kg (i.p. or p.o.) showed moderate
antitumor effects in mice. When administered i.p. or p.o., CNM (150 mg/kg)
inhibited the growth of transplanted hepatoma 22 by 48.8 or 40.5%, respectively.
At the dose of 100 mg/kg, CNM inhibited the growth of colon 26 carcinoma by 39.0%
and that of Lewis lung carcinoma by 53.9%. In the Lewis lung carcinoma model, CNM
at the dose of 100 mg/kg (i.p.) also reduced the lung metastasis by 59.1%.
Gelatine zymography revealed that CNM was able to decrease the level of MMP-2 in
conditioned medium of HT-1080 tumor cells in a concentration-dependent manner.
These results indicate that CNM is an antitumor agent with low cytotoxicity
acting on MMP and may serve as a lead compound in the development of antitumor
drugs.
PMID- 10757565
TI - New recommendations for uniform reporting of data following major trauma: "the
Utstein style".
PMID- 10757564
TI - Effects of KR-30035, a novel multidrug-resistance modulator, on the
cardiovascular system of rats in vivo and on the cell cycle of human cancer cells
in vitro.
AB - The present study was performed to evaluate the adverse effects of KR-30035, a
multidrug-resistance modulator, on the cardiovascular system in vivo, along with
its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In
anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in
lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg,
respectively) and in producing electrocardiogram changes. In conscious
spontaneously hypertensive rats, verapamil caused a significant antihypertensive
effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did
not significantly change either the blood pressure or the heart rate at any doses
tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and
48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM
KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer
cells greatly shifted the cell population from the G0/G1 phases towards G2/M
phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and
G2/M phases, respectively), with a similar magnitude to that of 10 microM
verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR
30035 has weaker in vivo effects on the cardiovascular system compared with
verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell
cycle.
PMID- 10757566
TI - Release of brain-specific creatine kinase and neuron-specific enolase into
cerebrospinal fluid after hypothermic and normothermic cardiopulmonary bypass in
coronary artery surgery.
AB - BACKGROUND: Coronary artery bypass (CABG) surgery is successfully managed with
normothermic cardiopulmonary bypass (CPB) using warm blood cardioplegia. The lack
of the protective effect of hypothermia, however, might make the central nervous
system vulnerable. METHODS: Thirty-six patients were randomized into normothermic
CPB (36-37 degrees C) (NTCPB group, n=18) and hypothermic CPB (28 degrees C)
(HTCPB group, n=18) in order to examine whether normothermic or hypothermic CPB
induces the release of the intracellular brain enzymes, creatine kinase (CK), its
brain-specific isoenzyme (CK-BB), and neuron-specific enolase (NSE) into
cerebrospinal fluid (CSF). In addition, clinical neurologic examination and
neuropsychologic assessment were done preoperatively, 5 d and 11-23 mo
postoperatively. RESULTS: One patient in each group suffered a stroke after
surgery. Two patients in the normothermic group had minor neurologic
complications. The cognitive decline after operation was similar in the NTCPB and
HTCPB groups. CSF enzymes from normothermic and hypothermic CABG patients without
gross neurologic complications were not significantly higher than CSF enzymes
from orthopaedic reference patients. CABG patients with neurologic complications
had higher enzyme concentrations. Cognitive decline after the operation
correlated statistically significantly with CSF enzyme concentrations in the
NTCPB group, but not in the HTCPB group. CONCLUSION: CABG operation without major
neurologic complication does not induce the release of CK, CK-BB or NSE enzymes
into CSF, irrespective of whether the CPB is normothermic or hypothermic.
PMID- 10757567
TI - The effect of sedation on weaning following coronary artery bypass grafting:
propofol versus oxycodone-thiopental.
AB - BACKGROUND: Propofol has been advocated for sedation in intensive care because of
superior recovery characteristics. We hypothesised that the use of two totally
different sedation methods after coronary artery bypass grafting should result in
differences not only in extubation time, but also in breathing pattern and gas
exchange during weaning and after extubation. METHODS: Thirty patients
participated in this randomised and controlled study. We used propofol infusion
and oxycodone-thiopental bolus dosage, titrated to sedation level 4 or 5
according to Ramsey. Weaning was performed using protocol-based pressure support
trials. RESULTS: Total (SD) fentanyl dose during operation was 33 (6) microg x
kg(-1) for propofol and 34 (6) microg x kg(-1) for oxycodone-thiopental (ns). The
target sedation was achieved equally with both methods. The time from admission
to intensive care unit to extubation was 494 (100) min for propofol and 521 (98)
min for oxycodone-thiopental (ns). Weaning times were 63 (24) min and 112 (63)
min in the propofol and oxycodone-thiopental groups, respectively (P<0.05).
Breathing frequency increased and tidal volume decreased from weaning to 2 h
postextubation. CONCLUSION: Propofol infusion and oxycodone-thiopental bolus
dosages, titrated to the same sedation end point, resulted in similar time from
admission to extubation, although the weaning period was shorter in the propofol
group. In terms of breathing pattern, gas exchange, blood gases and
haemodynamics, the methods were similar. Propofol, despite its attractive
pharmacological profile, may offer no clinical benefit in short-term sedation
after a moderate dose fentanyl anaesthesia in cardiac surgery.
PMID- 10757568
TI - Peroperative cardiovascular stability during brainstem surgery. The use of high
dose methylprednisolone compared to dexamethasone. A retrospective analysis.
AB - BACKGROUND: In neurosurgical procedures within brainstem structures,
corticosteroids are routinely administered to prevent oedema and to reduce
intraoperative trauma. After replacing the routine administration of
dexamethasone (DX) by high-dose methylprednisolone (MP) during surgery for
tumours within brainstem structures, a decreased incidence of intraoperative
haemodynamic instability events was observed. To test this hypothesis, a
retrospective analysis was performed. METHODS: Peroperative data of 62 surgical
procedures of brainstem tumours were retrospectively analysed with respect to
haemodynamic instability requiring changes in surgical strategy and/or emergence
medication with vasoactive drugs. Severe changes in haemodynamic parameters were
defined as a significant increase or decrease in heart rate and/or mean arterial
blood pressure greater than 30% compared to baseline values. From 1988 to 1994,
intravenous dexamethasone was given peroperatively in 33 patients. After a bolus
of 1 mg kg(-1) body weight (BW) 30 min preoperatively, 0.2 mg kg(-1) were given
every 4 h. From 1994 until now, methylprednisolone was administered instead of
dexamethasone in 29 patients. After an initial bolus of 30 mg kg(-1) BW
immediately before surgery, 5.4 mg kg(-1) h(-1) were given 23 h postoperatively.
RESULTS: The results of this retrospective analysis suggest that the number of
operations with episodes of bradycardia, arterial hypotension (P<0.05),
tachycardia and arterial hypertension (P<0.005) was significantly decreased in
the group of patients treated with high-dose methylprednisolone. CONCLUSION: The
retrospective analysis of the clinical data showed that the routine use of high
dose methylprednisolone was associated with a decreased incidence of haemodynamic
instability in a selected group of patients undergoing brainstem surgery. This
finding has to be proven in prospective double-blind controlled studies.
PMID- 10757569
TI - Effect of PEEP and inhaled nitric oxide on pulmonary gas exchange during gaseous
and partial liquid ventilation with small volumes of perfluorocarbon.
AB - BACKGROUND: Partial liquid ventilation, positive end-expiratory pressure (PEEP)
and inhaled nitric oxide (NO) can improve ventilation/perfusion mismatch in acute
lung injury (ALI). The aim of the present study was to compare gas exchange and
hemodynamics in experimental ALI during gaseous and partial liquid ventilation at
two different levels of PEEP, with and without the inhalation of nitric oxide.
METHODS: Seven pigs (24+/-2 kg BW) were surfactant-depleted by repeated lung
lavage with saline. Gas exchange and hemodynamic parameters were assessed in all
animals during gaseous and subsequent partial liquid ventilation at two levels of
PEEP (5 and 15 cmH2O) and intermittent inhalation of 10 ppm NO. RESULTS: Arterial
oxygenation increased significantly with a simultaneous decrease in cardiac
output when PEEP 15 cmH2O was applied during gaseous and partial liquid
ventilation. All other hemodynamic parameters revealed no relevant changes.
Inhalation of NO and instillation of perfluorocarbon had no additive effects on
pulmonary gas exchange when compared to PEEP 15 cmH2O alone. CONCLUSION: In
experimental lung injury, improvements in gas exchange are most distinct during
mechanical ventilation with PEEP 15 cmH2O without significantly impairing
hemodynamics. Partial liquid ventilation and inhaled NO did not cause an additive
increase of PaO2.
PMID- 10757570
TI - Intermittent capnography during high-frequency jet ventilation for prolonged
rigid bronchoscopy.
AB - BACKGROUND: Gas exchange during high-frequency jet ventilation (HFJV) for
prolonged rigid bronchoscopy (RBS) is usually monitored by arterial blood gas
analysis. Capnography of expired gases during brief HFJV discontinuation may be a
reliable and noninvasive supplemental method. Capnography can be performed either
for single breaths or with respiratory rate (RR) reduced to 10 x min(-1). The aim
of this study was to demonstrate that capnography during short periods of HFJV
discontinuation represents a reliable measure of PaCO2 during prolonged RBS.
METHODS: We prospectively investigated 100 consecutive patients (75 male and 25
female) undergoing HFJV for RBS. HFJV was delivered through the rigid
bronchoscope at the following settings: working pressure 1.2 bar, rate 100 x min(
1), FIO2 0.99, t(i)/t(tot)0.6. The light guiding channel ending at the distal tip
of the rigid bronchoscope was used for gas sampling. Capnograms were assessed at
5 min intervals and compared to PaCO2 from arterial blood samples drawn
simultaneously. The accuracy of single breath CO2 sampling was compared with
sampling at RR=10 x min(-1). RESULTS: Mean duration of RBS was 30+/-21 min. A
significant correlation between capnography (PetCO2) and arterial blood gas
analysis (PaCO2) was observed, being r=0.90 for the RR= 10 x min(-1) method and
r=0.91 for the single breath method. Mean difference between PaCO2 and PetCO2 was
0.37+/-0.2 kPa throughout the entire study period. No significant differences
between single breath sampling or sampling at RR=10 x min(-1) were observed.
CONCLUSION: Capnography performed during short periods of HFJV discontinuation
reliably and noninvasively reflects PaCO2 during prolonged endoscopic procedures.
Capnography during HFJV for RBS may reduce the frequency of arterial blood gas
sampling, the duration of unmonitored intervals and costs.
PMID- 10757571
TI - The risk of cardiac injury during laparoscopic fundoplication: cardiac troponin I
and ECG study.
AB - BACKGROUND: Myocardial trauma has been described during gastroesophageal reflux
laparoscopic surgery, in association with the proximity of cardiac structures. In
addition, specific haemodynamic changes induced by CO2 pneumoperitoneum could
exacerbate perioperative cardiac complication even in patients without cardiac
risk factors. The aim of this study was to evaluate the influence of
gastroesophageal reflux laparoscopic surgery on the perioperative ECG, cardiac
troponin I and myocardial enzyme changes. METHODS: Forty-two ASA I-II patients
without ischaemic heart disease or combined double-risk factors were studied.
Automated ST segment analysis was used intraoperatively. ECG, plasma myocardial
enzyme and cardiac troponin I concentrations were reported on arrival in the
recovery room (HO), 4 h (H4) and 24 h (H24) postoperatively. RESULTS:
Intraoperative ST segment changes occurred in two patients: the first during a
hypotensive episode (MAP<55 mmHg; 3/42 patients) and the second during a
hypertensive episode (MAP >110 mmHg; 3/42 patients). One case of intraoperative
subcutaneous emphysema occurred without ST disturbance. One case of pneumothorax
was observed at H0-H4 in another patient without clinical symptoms. Cardiac
troponin I and CK-MB were not increased postoperatively. Transaminase
concentrations increased (2-fold normal values) in 26/42 patients. In these 26
patients, 7 experienced 5-fold isolated transaminase increase, associated with
left hepatic artery section. CONCLUSION: According to perioperative ECG changes
and/or specific cardiac troponin I measurements, we did not identify specific
myocardial damage following gastroesophageal reflux laparoscopic surgery.
Unexpectedly, the incidence of hepatic cytolysis was frequent (62%) and has not
previously been reported in the literature.
PMID- 10757572
TI - Milrinone therapy in catecholamine-dependent critically ill patients with heart
failure.
AB - BACKGROUND: Treatment with the PDE-III inhibitor milrinone improves hemodynamics
in patients with heart failure. We examined whether therapy with milrinone is
safe and effective in critically ill patients with catecholamine-dependent heart
failure and whether treatment with milrinone facilitates weaning from prolonged
catecholamine therapy. METHODS: Twenty adult patients with reduced left
ventricular function and prolonged (7+/-4 days) catecholamine therapy in whom
attempts at catecholamine weaning had failed were examined. Patients were
prospectively randomised either to group A (addition of a fixed dose of 0.5
microg x kg(-1) x min(-1) milrinone to catecholamine therapy) or to group B
(continued catecholamine therapy without milrinone). Dobutamine and
norepinephrine treatment and fluid intake were titrated according to predefined
hemodynamic goals. Hemodynamic parameters, fluid requirements and catecholamine
dose were monitored. RESULTS: After 24 h of study treatment goup A showed a
significant increase in cardiac index (2.2+/-0.4 1 min(-1) x m(-2) to 2.7+/-0.51
min(-1) x m(-2); P<0.005), a decrease in systemic vascular resistance (1,427+/
609 dyn x s x cm(-5) to 951+/-184 dyn x s x cm(-5); P<0.005), required lower
doses of dobutamine (5.9+/-4.2 microg x kg(-1) x min(-1) to 2.2+/-3.3 microg x
kg(-1) x min(-1); P<0.02), but showed a tendency for higher vasoconstrictor
(0.14+/-0.16 microg x kg(-1) x min(-1) to 0.29+/-0.43 microg x kg(-1) x min(-1);
P=n.s.) and fluid requirements (+1,404+/-2,257 ml/24 h to +2,508+/-1,873 ml/ 24
h; P=n.s.). No significant changes occurred in group B. Weaning from
catecholamine therapy was more often achieved in group A and more milrinone
treated patients were discharged alive from the ICU (80% vs. 30%; P<0.05).
CONCLUSIONS: Milrinone improves central hemodynamics and may facilitate weaning
from prolonged catecholamine support in critically ill patients with heart
failure. Its administration in this subset of critically ill patients is safe,
but eventually is associated with additional vasoconstrictor and fluid
requirements.
PMID- 10757573
TI - Low-dose dopexamine in patients undergoing hemihepatectomy: an evaluation of
effects on reduction of hepatic dysfunction and ischaemic liver injury.
AB - BACKGROUND: Hepatic dysfunction is a common problem in patients after
hemihepatectomy. Treatment with low-dose dopamine has been shown to be beneficial
in hemihepatectomy patients. We hypothesized that dopexamine, a synthetic
vasoactive catecholamine, due to its specific pharmocodynamic profile may be more
effective in reducing hidden ischaemic episodes in the hepato-splanchnic region
during and after temporary total cross-clamping of hepatic inflow in these
patients. METHODS: The effects of low-dose dopexamine on hepatic venous
haemoglobin oxygen saturation (ShvO2), hepatic venous lactate level,
monoethylglycinxylid (MEGX) formation, hepatic synthetic function and indicators
for hepatic cell damage were studied during hemihepatectomy and for 16 h
postoperatively in hemihepatectomy patients and compared to those of low-dose
dopamine. In a prospective, double-blind clinical study 20 patients received
randomly either dopexamine (DPX) 0.5 microg kg(-1) min(-1) (n=10) or dopamine
(DO) 2.5 microg kg(-1) min(-1) (n= 10). Infusions were started after induction of
anaesthesia and continued 16 h postoperatively. Hepatic vein, radial and
pulmonary artery were catheterized. Measurements were carried out after induction
of anaesthesia, after total cross-clamping of hepatic inflow, and at 2 h and 16 h
postoperatively. RESULTS: There were no differences in systemic haemodynamics,
oxygenation, ShvO2, serum aminotransferases or MEGX levels between the groups. At
16 h postoperatively prothrombin and antithrombin III levels were significantly
lower while hepatic venous lactate was significantly higher in the DPX group
compared to the DO group. CONCLUSION: In patients undergoing hemihepatectomy, we
could not reveal superior hepatoprotective effects of low-dose dopexamine
compared to low-dose dopamine.
PMID- 10757574
TI - Differential action of spasmolytic vasodilators on platelet aggregation and
endothelial cell-dependent anti-aggregation.
AB - BACKGROUND: The perioperative use of spasmolytic vasodilators during
reconstructive or vascular surgery is an important therapeutic procedure to
prevent vascular spasm. Platelet aggregation at vascular endothelium injured by
the surgical manipulation is thought to be associated with the persistency of
spasm, although little is known about the effects of these drugs on platelet
aggregation and on anti-aggregation provoked by endothelial cells. METHODS: (1)
To test the direct effect of vasodilators against platelet aggregation, change in
light transmission through platelet-rich plasma (PRP) stimulated with 4 microg/ml
collagen was measured in the absence or presence of pentobarbital, papaverine,
prostaglandin E1 (PGE1), trinitroglycerin, nitroprusside, nicardipine, and
diltiazem. (2) Effects of these drugs on endothelial cell-dependent anti
aggregation were then evaluated. Incubation buffer of cultured porcine aortic
endothelial (PAE) cells, which were preincubated with vasodilators for 10 min
prior to a 1-min stimulation with 1 microM bradykinin, was transferred to
collagen-stimulated PRP. RESULTS: (1) Papaverine and PGE1 directly inhibited
platelet aggregation in a concentration-dependent manner. All other drugs failed
to inhibit aggregation. (2) Incubation buffer of PAE cells stimulated with
bradykinin showed a potent anti-aggregation. Pentobarbital concentration
dependently inhibited the endothelial cell-dependent anti-aggregation. Every
other drug did not inhibit the anti-aggregation by PAE cells. CONCLUSION: Because
of the direct anti-aggregatory effect without inhibiting endothelial cell
dependent anti-aggregation, we suggested that papaverine and PGE1 were the most
promising vasodilators of all drugs examined in this study while further
evaluation is required for the clinical relevance of the present study.
PMID- 10757575
TI - Does halothane or isoflurane affect hypoxic and post-hypoxic vascular response in
rabbit aorta?
AB - BACKGROUND: Halothane and isoflurane affect differently endothelium-dependent and
-independent vasorelaxation at 95% O2. In addition, hypoxic vascular response
might involve endothelium-dependent and -independent mechanisms. Therefore, we
investigated, in rabbit aortic rings, 1) the influence of halothane and
isoflurane on vasodilation at 95% O2 and on hypoxic-induced vasorelaxation at 0%
O2 and 2) the influence of halothane and isoflurane on endothelium-dependent and
independent post-hypoxic vascular response. METHODS: Endothelium-intact and
endothelium-denuded rabbit aortic rings were used. Phenylephrine precontracted
rings were exposed, at 95% O2, to acetylcholine (ACh, 10(-9) to 10(-4) M) or
sodium nitroprusside (SNP, 10(-9) to 10(-4) M) in the presence or absence of
anaesthetic at 1 or 2 MAC. Precontracted rings were also exposed to an acute
reduction in O2 from 95% to 0% followed by an acute reoxygenation with 95% O2 in
the absence or presence of anaesthetic at 1 or 2 MAC. RESULTS: At 95% O2,
halothane decreased endothelium-dependent relaxation to ACh, while endothelium
independent relaxation to SNP was decreased only at 2 MAC. Isoflurane did not
modify ACh- or SNP-induced relaxation. At 0% O2, neither halothane nor isoflurane
altered the hypoxic vascular relaxation. Post-hypoxic response was not changed
either. CONCLUSION: Our results indicate that halothane and isoflurane do not
alter vascular hypoxic response in conductance arteries.
PMID- 10757576
TI - Effects of etomidate on free intracellular amino acid concentrations in
polymorphonuclear leucocytes in vitro.
AB - BACKGROUND: Previous studies have shown the inhibitory effects of etomidate on
polymorphonuclear leucocyte (PMN) function. No reports exist, however, regarding
free intracellular amino acid metabolism, although physiological cell metabolism
and basic cell functions rely upon a balanced intracellular amino acid content
and the cell membrane-mediated separation of cellular amino acids from the
extracellular plasma amino acid pool. Thus, in the current study, we evaluated
the effects of etomidate on free intracellular amino acid metabolism in PMN.
METHODS: With ethics committee approval, blood was withdrawn from 35 healthy
volunteers and incubated (1 h) either with 0 microg/ml, 0.0156 microg/ml, 0.0625
microg/ml or 0.5 microg/ml of etomidate as well as with its additives (propylene
glycol and Lipofundin MCT 10%). The PMN were separated using standardized Percoll
gradient and centrifugation procedure before deep-freezing and lyophilization
techniques were employed. All PMN samples were dissolved in methanol/H2O, and the
concentrations of free intracellular amino acids were monitored using both novel
advanced PMN-separation and high-performance liquid chromatography techniques.
RESULTS: Etomidate influenced important free amino acid profiles in PMN in a dose
dependent manner, indicating complex changes of cellular amino acid turnover.
Neither propylene glycol nor Lipofundin MCT 10% changed free amino acid
concentrations in PMN. CONCLUSIONS: For the first time, the effects of etomidate
on free intracellular amino acid metabolism in PMN have been investigated. Our
results draw attention to the biochemical pathways which may be involved in
etomidate-induced alterations in PMN function and cellular immunocompetence.
PMID- 10757577
TI - A randomised study of lidocaine and prilocaine for spinal anaesthesia.
AB - BACKGROUND: Transient neurologic symptoms (TNS) are common after lidocaine
induced spinal anaesthesia (SA). Recent data indicate that TNS may be less
frequent after prilocaine-induced spinal anaesthesia, for which reason the
isobaric solution was compared with lidocaine. METHODS: One hundred patients
scheduled for short urologic procedures under spinal anaesthesia were randomised
to receive 80 mg prilocaine or lidocaine, both 20 mg/ml. The clinical course and
the duration of anaesthesia were monitored. The following day an
anaesthesiologist unaware of the randomisation interviewed the patients using a
structured questionnaire. RESULTS: Following prilocaine spinal anaesthesia the
mean time until 2-segment regression was 123(SD 42) min and total sensory block
lasted 221(49) min, compared to 106(26) and 181(48) min following lidocaine. TNS
occurred in 7/49 patients in the lidocaine group and in 2/50 in the prilocaine
group (ns). CONCLUSION: TNS occurred also after isobaric prilocaine SA. The
frequency was not significantly different from that following lidocaine SA but
larger studies are needed to establish the relative risk of TNS following SA
induced by the two local anaesthetics. Isobaric prilocaine has a longer duration
of action than an equal dose of lidocaine and may be an alternative drug for
spinal anaesthesia of intermediate or short duration.
PMID- 10757578
TI - A comparison of the hemodynamic effects of paracervical block and epidural
anesthesia for labor analgesia.
AB - BACKGROUND: Both paracervical block (PCB) and epidural analgesia are sometimes
associated with hemodynamic effects potentially harmful to the well-being of the
fetus. Our study was designed to test the hypothesis that PCB would have a more
profound effect on maternal and fetal blood flow than epidural analgesia.
METHODS: Forty-four healthy primiparous parturients were randomized to receive
either PCB (n=21) or epidural analgesia (n= 23) with 25 or 30 mg of bupivacaine,
respectively, for labor analgesia. Maternal blood pressure and fetal heart rate
were recorded. Blood flow was measured using a color Doppler device. The blood
flow measurements consisted of assessment of the pulsatility indices (PI) of the
right maternal femoral artery and the main branch of the uterine artery
(placental side), the umbilical artery and the fetal middle cerebral artery. The
measurements were performed before administration of analgesia and approximately
15-20 min later after the onset of analgesia. RESULTS: Both methods provided in
general good analgesia, but rescue medication was required more often after PCB.
Epidural analgesia decreased maternal blood pressure more than PCB and the PI of
maternal femoral artery decreased after onset of epidural analgesia, indicating
epidural-induced vasodilation. The PI of the uterine artery increased after the
onset of PCB, indicating vasoconstriction of this artery. No significant adverse
effects or differences in the well-being of the newborn were observed, as
indicated by similar Apgar scores and pH-status. CONCLUSION: There were small
differences in the effects of PCB and epidural analgesia on uteroplacental
circulation as well as on maternal hemodynamics. PCB may have a vasoconstrictive
effect on the uterine artery. This and the fact that the parturients required
rescue analgesia more frequently after PCB than after epidural block speaks for
the feasibility of the latter in obstetrics.
PMID- 10757579
TI - Ropivacaine-clonidine combination for caudal blockade in children.
AB - BACKGROUND: Adding clonidine to weak ropivacaine solutions (<0.2%) could
potentially enhance analgesia as well as further reduce the risk for unwanted
motor blockade. The aim of the present study was to compare the postoperative
pain-relieving quality of a ropivacaine 0.1%-clonidine mixture to that of plain
ropivacaine 0.2% following caudal administration in children. METHODS: In a
prospective, observer-blinded fashion, 40 ASA 1 paediatric patients undergoing
subumbilical surgery were randomly allocated to receive a caudal injection of
either plain ropivacaine 0.2% (1 ml/kg) (R0.2) or a mixture of ropivacaine 0.1%
with clonidine 2 microg/kg (1 ml/kg) (R0.1C). Objective pain scale score and need
for supplemental analgesia were used to evaluate analgesia during the first 24 h
postoperatively. Residual postoperative sedation was also assessed. RESULTS: A
significantly higher number of patients in the R0.1C group (18/20) could be
managed without supplemental analgesia during the first 24 h postoperatively
compared to the R0.2 group (11/20) (P=0.034). Both the degree and the duration of
postoperative sedation was similar in both groups. No signs of postoperative
motor blockade were observed. CONCLUSIONS: The combination of clonidine (2
microg/kg) and ropivacaine 0.1% is associated with an improved quality of
postoperative analgesia compared to plain 0.2% ropivacaine. The improved
analgesic quality of the clonidine-ropivacaine mixture is achieved without
causing any significant degree of postoperative sedation.
PMID- 10757580
TI - A catheter technique in ophthalmic regional anaesthesia. Cadaver experiments.
AB - BACKGROUND: Regional anaesthesia for ophthalmic surgery is generally accomplished
by peri- or retrobulbar techniques. Depending on the duration of ophthalmic
surgery, reblock might become necessary. Our goal was to invent a catheter
technique for ophthalmic regional anaesthesia that enables the user to administer
local anaesthetics intraoperatively into the peri- or retrobulbar space
continuously. METHODS: Twenty-five adult cadaver orbits of normal size and
anatomy were used for the experiments. A flexible catheter was introduced
transcutaneously or transconjunctivally into the extra- or intraconal space.
Methylene blue solution was injected through the catheter. RESULTS: Using the
same transcutaneous retro- and peribulbar technique, it was possible to introduce
flexible catheters into a proper position of the cadaver orbits. The injected dye
was found intra- or extraconally. CONCLUSION: Examining the spread of the dye in
the orbit, we concluded that it is possible to provide ophthalmic anaesthesia for
surgery through an indwelling catheter. We proved that continuous or intermittent
administration of a local anaesthetic agent into the extra- or inraconal space
can be achieved and this technique may allow us to maintain anaesthesia as long
as it is necessary.
PMID- 10757581
TI - A catheter technique in ophthalmic regional anaesthesia. Clinical investigations.
AB - BACKGROUND: Usually general anaesthesia is chosen if ophthalmic surgery of longer
duration is expected. Our goal was to introduce a flexible catheter
preoperatively into the extra- or intraconal space and to provide sufficient
anaesthesia by continuous administration of a local anaesthetic via the catheter.
METHODS: The continuous anaesthetic technique was applied in 28 patients
undergoing vitreoretinal surgery. An indwelling catheter was introduced in 20
patients into the intraconal and in 8 patients into the extraconal space. In 6
patients, the position of the catheter was controlled by ultrasound examination
prior to the injection of the local anaesthetic agent. RESULTS: For all patients
adequate anaesthesia could be achieved and maintained with continuous retrobulbar
administration (CRA) of a local anaesthetic by catheter. There were two patients
who experienced moderate pain intraoperatively during continuous peribulbar
administration (CPA). No complications occurred with the placement of the
catheters. The catheter did not disturb the surgeon or the process of the
ophthalmic surgery. CONCLUSIONS: Continuous administration of a local anaesthetic
agent via an indwelling catheter into the intraconal space allowed ophthalmic
anaesthesia without time restriction. Thus, CRA is a good alternative to general
anaesthesia for patients undergoing long-lasting ophthalmic surgery.
PMID- 10757582
TI - Comparison of hypotensive epidural anaesthesia and spinal anaesthesia on blood
loss and coagulation during and after total hip arthroplasty.
AB - BACKGROUND: Hypotensive epidural anaesthesia (HEA) is a technique for reducing
peroperative blood loss by significantly lowering mean arterial pressure (MAP).
METHODS: Thirty patients scheduled for primary total hip arthroplasty were given
HEA (n=15) or spinal anaesthesia (SPA) (n= 15) with bupivacaine in random order.
The dose of bupivacaine was titrated to provide epidural blockade up to T1-T4 and
spinal blockade at least to T10. Intravenous adrenaline infusion was adjusted to
achieve a MAP of about 50-60 mmHg in the HEA group. During SPA MAP was maintained
above 70 mmHg with ephedrine, as needed. RESULTS: Intraoperative blood loss
(median and 25th and 75th percentiles) was 400 ml (163-575) in the HEA group and
900 ml (663-1,100) in the SPA group (P<0.05). At 3 h postoperatively cumulative
blood loss was still smaller in the HEA group (600 ml versus 1,100 ml, P<0.05).
The cumulative number of transfused packed red cell concentrate (PRC) units was
smaller in the HEA group than in the SPA group during surgery and
postoperatively. Prothrombin time value was smaller in the SPA than in the HEA
group (69% versus 79%, P<0.05) at 3 h postoperatively. D-dimer concentrations
increased more in the SPA group at the end of the surgery and 3 h postoperatively
(P<0.05). CONCLUSIONS: HEA resulted in reduced blood loss due to hypotension and
reduced number of transfused PRC units during total hip arthroplasty. Based on
lower prothrombin time value and higher D-dimer concentrations in the SPA group,
the coagulation system might be better preserved during HEA than SPA.
PMID- 10757583
TI - Tracheal intubation without the use of muscle relaxants: remifentanil or
alfentanil in combination with propofol.
AB - BACKGROUND: Alfentanil-propofol combination provides adequate conditions for
tracheal intubation without neuromuscular blocking drugs in most patients.
Providing an option for intense opioid effect without compromising recovery after
short operations, remifentanil might offer benefits over alfentanil, especially
in ambulatory surgery. In this study intubating conditions after remifentanil
propofol were compared to those after alfentanil-propofol. METHODS: In a
randomized, double-blind study 60 healthy patients were assigned to one of three
groups (n=20). After intravenous atropine, remifentanil 3 or 4 microg kg(-1)
(Rem3 or Rem4) or alfentanil 30 microg kg(-1) (Alf30) was injected over 30 s
followed by propofol 2.5 mg kg(-1). Sixty seconds after the administration of
propofol, laryngoscopy and intubation were attempted. Intubating conditions were
assessed as excellent, good or poor on the basis of ease of ventilation, jaw
relaxation, position of the vocal cords, and patient response to intubation and
slow inflation of the endotracheal tube cuff. RESULTS: Overall conditions at
intubation were significantly (P<0.05) better, and the frequency of excellent
conditions was significantly (P<0.05) higher in the Rem4 group compared with the
Alf30 group. Intubation was judged to be impossible in 20%, 25% or 5% of the
patients in the Alf30, Rem3 or Rem4 groups, respectively. No patient manifested
signs of opioid-induced muscular rigidity. In terms of arterial pressures or
heart rate, there were no differences between the groups. CONCLUSION: The best
method was the combination of remifentanil 4 microg kg(-1) and propofol 2.5 mg
kg(-1). This provided satisfactory intubating conditions in 93%, and prevented
cardiovascular intubation response.
PMID- 10757584
TI - Assessment of postoperative nausea using a visual analogue scale.
AB - BACKGROUND: Assessment of postoperative nausea intensity is difficult because
nausea is a subjective and unpleasant sensation. We propose using the Visual
Analogue Scale (VAS) device to increase the efficiency and precision in the
assessment of nausea. We carried out a pilot study on postoperative patients
suffering from nausea to measure the degree of agreement between the VAS scores
and those given on a 4-point verbal descriptive scale (VDS). METHODS:
Postoperative nausea was evaluated by means of a classical VAS (0-10 cm) device
and a 4-point VDS (0=no nausea, 1=mild, 2=moderate, 3=severe) in 128 surgical
spontaneously complaining patients. Evaluation was repeated 45 min after rescue
medication given if nausea was intractable, lasted more than 10 min or at the
request of the patient. Ordinal logistic regression was used to measure the
association between VAS and VDS and to determine cut-off points on the VAS.
RESULTS: The VAS device was easily understood and used by patients. VAS scores
decreased significantly from 5.5+/-2.3 to 1.4+/-1.8 after rescue medication
(P=0.002). Application of ordinal logistic regression to pre- and post-medication
data combined yielded an agreement of 86% between VAS and VDS and the cut-off
points on the VAS were estimated as follows: 0-1 (no nausea), 1+/-4 (mild), 4+/-7
(moderate) and 7+/-10 (severe). CONCLUSION: The VAS method proved to be useful
for assessing quantitative nausea intensity and for testing the efficacy of
rescue medication. It was found that a cut-off value of 4 on the VAS may be
considered as a critical threshold triggering anaesthesiologists or nurses to
administer rescue medication.
PMID- 10757585
TI - Tubeless combined high-frequency jet ventilation for laryngotracheal laser
surgery in paediatric anaesthesia.
AB - BACKGROUND: High-frequency jet ventilation (HFJV) is an alternative ventilatory
approach in airway surgery and for facilitating gas exchange in patients with
pulmonary insufficiency. We have developed a new technique of combined HFJV
utilising two superimposed jet streams. In this study we describe the application
of tubeless supralaryngeal HFJV during laryngotracheal laser surgery in infants
and children. METHODS: Tubeless combined HFJV characterised by the simultaneous
supralaryngeal application of a low-frequency (LF) and a high-frequency (HF) jet
stream was evaluated in a clinical study in 10 children undergoing elective
laryngotracheal CO2 laser surgery. Additionally, pressure and flow
characteristics were determined with the use of a paediatric test lung. HFJV was
applied by means of a modified Kleinsasser laryngoscope with integrated metal
injectors. In addition to pulse oximetry, monitoring of ECG, heart rate and blood
pressure, supraglottic airway pressure was measured and arterial blood gases were
analysed. RESULTS: Tubeless combined HFJV was used in 10 infants and children
(mean age 4.6 yr, range 2 months-10 years) undergoing 17 consecutive endoscopic
procedures with CO2 laser microsurgery of the larynx or the trachea under general
anaesthesia. The mean duration of supralaryngeal HFJV was 46 min (range 15-75
min). Mean driving pressures of the HF and the LF jet streams were 0.75 bar and
0.95 bar, respectively. Inspiratory oxygen ratios were in the range 0.4-1.0. HFJV
resulted in mean PaO2 and PaCO2 values of 19.7 kPa and 6.1 kPa, respectively. No
complications during HFJV were observed. In the test lung, combined HFJV applied
with driving pressures of 0.7-1.0 bar and 0.9-1.2 bar for HF and LF jet
ventilation, respectively, resulted in maximum peak and baseline distal airway
pressures of 17.6 cm H2O and 5.4 cm H2O, respectively. CONCLUSION: The
application of the combined double frequency HFJV was effective in maintaining
gas exchange in the presence of laryngeal or tracheal stenoses. It provided good
visibility of anatomical structures and offered space for surgical manipulation,
avoiding the use of combustible material inside the larynx or trachea.
PMID- 10757586
TI - Evaluation of three risk scores to predict postoperative nausea and vomiting.
AB - BACKGROUND: So far there are three different scores to predict postoperative
vomiting (PV: Apfel et al., 1998) or postoperative nausea and vomiting (PONV:
Koivuranta et al., 1997; Palazzo and Evans, 1993). All three scores used logistic
regression analysis to identify and create weights for the risk factors for PV or
PONV. In short, these were sex, age, history of previous PONV, motion sickness,
duration of anaesthesia, and use of postoperative opioids. However, an external
evaluation and a comparison of these scores has not been performed so far.
METHODS: Patients undergoing a variety of surgical procedures under general
anaesthesia were studied prospectively. Preoperatively, they completed a
questionnaire concerning potential risk factors for the occurrence of PV or PONV
implemented in the three risk scores. Balanced anaesthesia (induction agent,
nondepolarising neuromuscular blocker, opioid, and inhalation agent in nitrous
oxide/oxygen) was performed. No intravenous anaesthesia or any antiemetic
prophylaxis was applied. Postoperatively, the patients were observed in the
recovery room for the occurrence of PV and PONV and were visited twice on the
ward within the 24-h observation period. Both the patients and the nursing staff
were asked whether PV or PONV was present. The severity of PONV was categorised
using a standardised scoring algorithm. A total of 1,444 patients was finally
included into the analysis. Using information of the predicted risk for the
individual patients and the actual occurrence of PV or PONV, Receiver Operator
Characteristics (ROC-curves) were drawn. The area under each ROC-curve was
calculated as a means of the predictive properties of each score and was compared
for statistical differences. RESULTS: For prediction of PONV (any severity) the
AUC-values (AUC=area under the curve) and the corresponding 95%-confidence
intervals were: Apfel: 0.70 (0.67-0.72); Koivuranta: 0.71 (0.69-0.73); Palazzo:
0.68 (0.65-0.70). For prediction of PV: Apfel: 0.73 (0.71-0.75); Koivuranta: 0.73
(0.70-0.75); Palazzo: 0.68 (0.65-0.70). Thus, all three scores appeared to have a
moderate accuracy as measured by the AUC. The score of Koivuranta predicts PONV
(P=0.007) and also PV (P=0.002) significantly better than Palazzo's score.
Furthermore, for predicting of PV the score of Apfel was also superior to
Palazzo's score (P=0.005). All three scores predict PV with the same accuracy as
PONV. CONCLUSION: The occurrence of PV and PONV in patients undergoing surgery
under balanced anaesthesia can be predicted with moderate but acceptable accuracy
using one of the available risk scores, regardless of local surgical or
anaesthesiological circumstances. For clinical practice, we recommend the score
published by Koivuranta, since its calculation is very simple.
PMID- 10757587
TI - Anaesthesia, recovery and postoperative nausea and vomiting after breast surgery.
A comparison between desflurane, sevoflurane and isoflurane anaesthesia.
AB - BACKGROUND: Whereas induction and recovery will occur more rapidly with the new
low soluble anaesthetics than with isoflurane, the quality of anaesthesia and
recovery with special emphasis on postoperative nausea and vomiting (PONV) is not
well known. METHODS: In an open (peroperatively), double-blinded
(postoperatively), randomised controlled study, we assessed anaesthesia
characteristics, recovery and 24 h PONV after breast surgery comparing
isoflurane, desflurane and sevoflurane. RESULTS: There were no significant
quality differences between the three agents during anaesthesia and recovery
except for the incidence of PONV in the postanaesthesia care unit (PACU). The
PONV rate (24 h in PACU and ward) was higher in the desflurane group (67%) than
in the isoflurane group (22%), (P<0.01). The corresponding PONV rate for
sevoflurane was 36%. CONCLUSION: The quality of anaesthesia, time to opening of
eyes and influence on respiration was similar with all three anaesthetics. As the
emergence from anaesthesia did not differ significantly between the three agents,
the choice of agent could be based on PONV rate and price. Desflurane had a
significantly higher 24 h PONV rate than isoflurane. Early PACU PONV rate was
significantly (P<0.05) lower for the more soluble isoflurane (4%) than for the
low soluble gases, desflurane and sevoflurane together (28%). The result of this
study does not give a rationale for a transition to the new low soluble agents in
breast cancer surgery.
PMID- 10757588
TI - The use of rocuronium for rapid sequence induction should be discouraged.
PMID- 10757589
TI - Interscalene block following shoulder surgery.
PMID- 10757590
TI - A new device preventing migration of epidural catheters.
PMID- 10757591
TI - Postoperative analgesia with intramuscular bupivacaine wound irrigation in renal
surgery.
PMID- 10757592
TI - The AAPM should develop protocols generically, and avoid documents that are too
strict and prescriptive, to facilitate their adoption by regulatory agencies like
the Nuclear Regulatory Commission and States.
PMID- 10757593
TI - On the beam quality specification of high-energy photons for radiotherapy
dosimetry.
AB - An overview of common photon beam quality specifiers used in radiotherapy
dosimetry introduces a reasoned discussion on the advantages and disadvantages of
TPR20,10 and PDD(10)x. It is shown that some of the potential advantages of
PDD(10)x are also present in other well known beam quality specifiers such as
d80. However, all PDD-based beam quality indices, including PDD(10)x, are subject
to electron contamination and their determination is affected by practical
limitations. The proposed filtration of contaminant electrons by Kosunen and
Rogers [Med. Phys. 20, 1181-1188 (1993)] and by Li and Rogers [Med. Phys. 21, 791
798 (1994)] is questioned, not only with regard to the adequacy of using lead as
an electron filter, but also in relation to its efficiency (if there were no
contamination, restrictions for beam calibrations at dmax would be removed) and
practical measurement. It is argued that (i) there is no unique beam quality
specifier that works satisfactorily in all possible conditions, for the entire
energy range of photon energies used in radiotherapy and all possible
accelerators used in hospitals and in standards laboratories, and (ii) TPR20,10
remains to be the most appropriate specifier for clinical photon beams as it has
less practical drawbacks than PDD-based quality indices. The final impact on
clinical photon beam dosimetry resulting from the use of different photon beam
quality specifiers, is that they are not expected to yield a significant change
(i.e., more than 0.5% and in most cases well within 0.2%) in the absorbed dose to
water in reference conditions for most clinical beams.
PMID- 10757594
TI - Comment on "On the beam quality specification of high-energy photons for
radiotherapy dosimetry" [Med. Phys. 27, 434-440 (2000)].
PMID- 10757595
TI - Comment on "AAPM's TG-51 protocol for clinical reference dosimetry of high-energy
photon and electron beams" [Med. Phys. 26, 1847-1870 (1999)].
PMID- 10757596
TI - Determination of the urethral dose in prostate brachytherapy when the urethra
cannot be visualized in the postimplant CT scan.
AB - This study investigates the feasibility of locating the urethra at the geometric
center of peripherally loaded 125I prostate implant when a urinary catheter is
not utilized for the postimplant CT scan. Twenty postimplant CT scans utilizing a
urinary catheter were randomly selected. The urethra was localized in each study
and, in addition, a surrogate urethra was localized at the geometric center of
the prostate. Dose-volume histograms of the urethra and surrogate urethra were
compiled and compared. The values obtained for the urethra D10, D25, and D50 were
in good agreement and demonstrate that the urethral dose can be determined
reliably by locating a surrogate urethra at the geometric center of the prostate
in a peripherally loaded implant when the urethra cannot be visualized.
PMID- 10757597
TI - Detection of internal organ movement in prostate cancer patients using portal
images.
AB - Previous research has indicated that the appearance of large gas pockets in
portal images of prostate cancer patients might imply internal prostate motion.
This was verified with simulations based on multiple computed tomography (CT)
data for 15 patients treated in supine position. Apart from the planning CT scan,
three extra scans were made during treatment. The clinical target volume (CTV)
and the rectum were outlined in all scans. Lateral portal images were simulated
from the CT data and difference images were calculated for all possible
combinations of CT scans per patient; each scan was used both as reference and
repeat scan but gas pockets in the reference scan were removed. Gas pockets in a
repeat CT scan then show up as black areas in a difference image. Due to gravity,
they normally appear in the ventral part of the rectum. The distances between the
ventral edge of a gas pocket in a difference image and the projection of the
delineated ventral rectum wall in the reference scan were calculated. These
distances were correlated with the "true" rectum wall shifts (determined from
direct comparison of the rectum delineations in reference and repeat scan) and
with CTV movements determined by three-dimensional chamfer matching. Gas pockets
occurred in 23% of cases. Nevertheless, about 50% of rectum wall shifts larger
than 5 mm could be detected because they were associated with gas pockets with a
lateral diameter > 2 cm. When gas pockets were visible in the repeat scan, rectum
wall shifts could be accurately detected by the ventral gas pocket edge in the
difference images (r= 0.97). The shift of the rectum wall as detected from gas
pockets also correlated significantly with the anterior-posterior shift of the
center of mass of the CTV (r=0.88). In conclusion, the simulations showed that
lateral pelvic images contain more information than the bony structures that are
normally used for setup verification. If large gas pockets appear in those
images, a quantitative estimate of the position of prostate and rectum wall can
be obtained by determination of the ventral edge of the gas pocket.
PMID- 10757598
TI - Direct measurement and analytical modeling of scatter in portal imaging.
AB - In this study a direct measurement of scatter in portal imaging for various air
gaps and scatterer thicknesses at a beam energy of 6 MV is presented. The
experimental data are compared with results from a Monte Carlo (MC) scatter
model. In the regime where the air gap is larger than 9.3 cm the MC and the
experiment agree. Based on this MC model an analytical model is developed, which
takes all important interaction processes into account. It comprises a rigorous
treatment of first order scattering and an estimation of photons scattered more
than once within the phantom. This estimation is based on the assumption that
higher order scattering can be considered as isotropically distributed around a
certain scatter origin located in the midplane of the phantom. It is found that
relative deviations between the MC model and the analytical model are of 2% to 3%
in regions where scattering is very large.
PMID- 10757599
TI - Total scatter factors and tissue maximum ratios for small radiosurgery fields:
comparison of diode detectors, a parallel-plate ion chamber, and radiographic
film.
AB - Two p-type diode detectors, a parallel-plate ion chamber, and radiographic film
were used to measure total scatter factors and tissue maximum ratios (TMRs) for a
stereotactic radiosurgery system with circular fields ranging from 5 to 50 mm in
diameter. One diode has a square detection diagonal of 2.3 mm and the other diode
has a circular detection diameter of 1 mm. It is found that the two diodes
measured essentially the same total scatter factors for all field sizes. Total
scatter factors measured by film are within 3% of diode values. Our results also
suggest that the parallel-plate ion chamber could underestimate total scatter
factors for fields as large as 15 mm in diameter, although it is recommended for
field diameters > or = 12.5 mm. The total scatter factors used in our clinic are
combined from data measured with the ion chamber and the 2-mm-diam diode. The
combined total scatter factors generally agree with published data. While film
overestimates TMRs for the smallest fields at large depths because of energy
dependence of the film, the measurements with the 1-mm-diam diode agree with
published data measured with thermoluminescent dosimeters. It is demonstrated
that the accurate measurements of total scatter factors and TMRs for small fields
can be obtained by combining results of the commercially available detectors used
in this study.
PMID- 10757600
TI - The effect of dose calculation uncertainty on the evaluation of radiotherapy
plans.
AB - Monte Carlo dose calculations will potentially reduce systematic errors that may
be present in currently used dose calculation algorithms. However, Monte Carlo
calculations inherently contain random errors, or statistical uncertainty, the
level of which decreases inversely with the square root of computation time. Our
purpose in this study was to determine the level of uncertainty at which a lung
treatment plan is clinically acceptable. The evaluation methods to decide
acceptability were visual examination of both isodose lines on CT scans and dose
volume histograms (DVHs), and reviewing calculated biological indices. To study
the effect of systematic and/or random errors on treatment plan evaluation, a
simulated "error-free" reference plan was used as a benchmark. The relationship
between Monte Carlo statistical uncertainty and dose was found to be
approximately proportional to the square root of the dose. Random and systematic
errors were applied to a calculated lung plan, creating dose distributions with
statistical uncertainties of between 0% and 16% (1 s.d.) at the maximum dose
point and also distributions with systematic errors of -16% to 16% at the maximum
dose point. Critical structure DVHs and biological indices are less sensitive to
calculation uncertainty than those of the target. Systematic errors affect plan
evaluation accuracy significantly more than random errors, suggesting that Monte
Carlo dose calculation will improve outcomes in radiotherapy. A statistical
uncertainty of 2% or less does not significantly affect isodose lines, DVHs, or
biological indices.
PMID- 10757601
TI - Accurate condensed history Monte Carlo simulation of electron transport. I.
EGSnrc, the new EGS4 version.
AB - In this report a new EGS4 version, called EGSnrc to reflect the substantial
changes made to the original code is reported, which incorporates a new any-angle
multiple elastic scattering theory, an improved electron-step algorithm, a
correct implementation of the fictitious cross section method for sampling
distances between discrete interactions, a more accurate evaluation of energy
loss, as well as an exact boundary crossing algorithm. It is demonstrated that
EGSnrc allows for an artifact free Monte Carlo simulation of ion chamber response
and backscattering, situations that have been considered in the past as the two
of the most stringent tests of condensed history Monte Carlo codes. A detailed
discussion of the effect of the various components of the condensed history
simulation of electron transport on the simulated ion chamber response is given
in the accompanying paper.
PMID- 10757602
TI - Accurate condensed history Monte Carlo simulation of electron transport. II.
Application to ion chamber response simulations.
AB - In this report the condensed history Monte Carlo simulation of electron transport
and its application to the calculation of ion chamber response is discussed. It
is shown that the strong step-size dependencies and lack of convergence to the
correct answer previously observed are the combined effect of the following
artifacts caused by the EGS4/PRESTA implementation of the condensed history
technique: dose underprediction due to PRESTA'S pathlength correction and lateral
correlation algorithm; dose overprediction due to the boundary crossing
algorithm; dose overprediction due to the breakdown of the fictitious cross
section method for sampling distances between discrete interaction and the
inaccurate evaluation of energy-dependent quantities. These artifacts are now
understood quantitatively and analytical expressions for their effect are given.
PMID- 10757603
TI - Electron spectra derived from depth dose distributions.
AB - The technique of extracting electron energy spectra from measured distributions
of dose along the central axis of clinical electron beams is explored in detail.
Clinical spectra measured with this simple spectroscopy tool are shown to be
sufficient in accuracy and resolution for use in Monte Carlo treatment planning.
A set of monoenergetic depth dose curves of appropriate energy spacing,
precalculated with Monte Carlo for a simple beam model, are unfolded from the
measured depth dose curve. The beam model is comprised of a point electron and
photon source placed in vacuum with a source-to-surface distance of 100 cm.
Systematic error introduced by this model affects the calculated depth dose curve
by no more than 2%/2 mm. The component of the dose due to treatment head
bremsstrahlung, subtracted prior to unfolding, is estimated from the thin-target
Schiff spectrum within 0.3% of the maximum total dose (from electrons and
photons) on the beam axis. Optimal unfolding parameters are chosen, based on
physical principles. Unfolding is done with the public-domain code FERDO.
Comparisons were made to previously published spectra measured with magnetic
spectroscopy and to spectra we calculated with Monte Carlo treatment head
simulation. The approach gives smooth spectra with an average resolution for the
27 beams studied of 16+/-3% of the mean peak energy. The mean peak energy of the
magnetic spectrometer spectra was calculated within 2% for the AECL T20 scanning
beam accelerators, 3% for the Philips SL25 scattering foil based machine. The
number of low energy electrons in Monte Carlo spectra is estimated by unfolding
with an accuracy of 2%, relative to the total number of electrons in the beam.
Central axis depth dose curves calculated from unfolded spectra are within
0.5%/0.5 mm of measured and simulated depth dose curves, except near the
practical range, where 1%/1 mm errors are evident.
PMID- 10757604
TI - Partially wedged radiation beams.
AB - To increase dose homogeneity within certain radiotherapy targets, we defined a
partially wedged radiation beam as a beam with wedge modification in one part of
the field only. Partially wedged beams may be beneficial in cases with curved
surfaces inside parts of the beam only, where they may compensate for missing
tissue and/or for variations in depth to the target region. Possible sites
suitable for partially wedged beams include urinary bladder and tangential breast
irradiation. Customized partially wedged beams were delivered applying dynamic
collimation techniques. Two different linear detector arrays, a semiconductor
diode array and an ionization chamber array, were used independently in the same
standard water tank to verify that the partially wedged beams were delivered
according to the definition. Dose calculations of partial wedge fields were
implemented in our treatment planning system and compared with the measured dose
distributions. We re-planned a representative treatment plan for both advanced
urinary bladder cancer and tangential breast irradiation using partially wedged
beams. For both patients the target dose homogeneity was improved, and the doses
to surrounding critical normal tissues were reduced.
PMID- 10757605
TI - Use of low-pressure tissue equivalent proportional counters for the dosimetry of
neutron beams used in BNCT and BNCEFNT.
AB - The absorbed dose in a phantom or patient in boron neutron capture therapy (BNCT)
and boron neutron capture enhanced fast neutron therapy (BNCEFNT) is deposited by
gamma rays, neutrons of a range of energies and the 10B reaction products. These
dose components are commonly measured with paired (TE/Mg) ion chambers and foil
activation technique. In the present work, we have investigated the use of paired
tissue equivalent (TE) and TE+ l0B proportional counters as an alternate and
complementary dosimetry technique for use in these neutron beams. We first
describe various aspects of counter operation, uncertainties in dose measurement,
and interpretation of the data. We then present measurements made in the
following radiation fields: An epithermal beam at the University of Birmingham in
the United Kingdom, a d(48.5) + Be fast neutron therapy beam at Harper Hospital
in Detroit, and a 252Cf radiation field. In the epithermal beam, our measured
gamma and neutron dose rates compare very well with the values calculated using
Monte Carlo methods. The measured 10B dose rates show a systematic difference of
approximately 35% when compared to the calculations. The measured neutron+gamma
dose rates in the fast neutron beam are in good agreement with those measured
using a calibrated A-150 TEP (tissue equivalent plastic) ion chamber. The
measured 10B dose rates compare very well with those measured using other
methods. In the 252Cf radiation field, the measured dose rates for all three
components agree well with other Monte Carlo calculations and measurements. Based
on these results, we conclude that the paired low-pressure proportional counters
can be used to establish an independent technique of dose measurement in these
radiation fields.
PMID- 10757606
TI - Computational validation of the stereology principle applied to the
microdosimetry of boron neutron capture therapy.
AB - High resolution quantitative autoradiography (HRQAR) is a novel technique that
has been developed in our laboratory and applied to the microdosimetry of boron
neutron capture therapy (BNCT). High resolution quantitative autoradiography is
employed to define the microdistribution of boron-10 atoms within a 1-2 microm
frozen tissue section. This microdistribution is used as input to a novel two
dimensional Monte Carlo charged particle transport calculation that computes
various microdosimetric parameters, such as the number of nuclear "hits," energy
absorbed in the nuclei, etc., within the environment of actual tissue morphology
(i.e., cell nuclei, cytoplasm, and intracellular space). Stereological
transformation is then implemented to transform the two-dimensional calculations
into effectively three-dimensional results. In the present study no seek to
demonstrate the validity of the surrogate two-dimensional 2-D computation as
being quantitatively equivalent to a hypothetical full 3-D calculation. The
results show that within the limitations of the test parameters used the
surrogate 2-D and 3-D results are completely equivalent within the statistical
constraints of the Monte Carlo calculations. Limitations of this approach also
are evaluated, including a Monte Carlo calculation of the influence of the
thickness of the histological tissue section and the track detector and the
influence of 4He and 7Li particle lateral and range straggling.
PMID- 10757608
TI - Digital mammography image simulation using Monte Carlo.
AB - Monte Carlo simulations of digital images of the contrast detail phantom and the
ACR phantom are presented for two different x-ray digital mammography modalities:
a synchrotron mammography system and a next-generation scanning slot clinical
system. A combination of variance reduction methods made it possible to simulate
accurate images using real pixel dimensions within reasonable computation times.
The complete method of image simulation, including a simple detector response
model, a simple noise model, and the incorporation of system effects (MTF), is
presented. The simulated images of the phantoms show good agreement with images
measured on the two systems.
PMID- 10757607
TI - Full breast digital mammography with an amorphous silicon-based flat panel
detector: physical characteristics of a clinical prototype.
AB - The physical characteristics of a clinical prototype amorphous silicon-based flat
panel imager for full-breast digital mammography have been investigated. The
imager employs a thin thallium doped CsI scintillator on an amorphous silicon
matrix of detector elements with a pixel pitch of 100 microm. Objective criteria
such as modulation transfer function (MTF), noise power spectrum, detective
quantum efficiency (DQE), and noise equivalent quanta were employed for this
evaluation. The presampling MTF was found to be 0.73, 0.42, and 0.28 at 2, 4, and
5 cycles/mm, respectively. The measured DQE of the current prototype utilizing a
28 kVp, Mo-Mo spectrum beam hardened with 4.5 cm Lucite is approximately 55% at
close to zero spatial frequency at an exposure of 32.8 mR, and decreases to
approximately 40% at a low exposure of 1.3 mR. Detector element nonuniformity and
electronic gain variations were not significant after appropriate calibration and
software corrections. The response of the imager was linear and did not exhibit
signal saturation under tested exposure conditions.
PMID- 10757609
TI - Trainable rule-based algorithm for the measurement of joint space width in
digital radiographic images of the knee.
AB - The progression of osteoarthritis (OA) can be monitored by measuring the minimum
joint space width (mJSW) between the edges of the femoral condyle and the tibial
plateau on radiographs of the knee. This is generally performed by a trained
physician using a graduated magnifying lens and is prone to the subjectivity and
variation associated with observer measurement. We have developed software that
performs this measurement automatically on digitized radiographs. The test data
consisted of 180 digitized radiographs of the knee (90 duplicate acquisitions)
from 18 normal (nonarthritic) subjects and 38 images from 10 subjects with OA.
These were digitized and manually cropped so that the images were free of
nonanatomical structures and the knee was approximately centered. The software
first determined the edge of the femoral condyle on 400 microm pixel subsampled
images. Contours marking the location of the tibial plateau in the medial
compartment were found on 100 microm images using the femoral edge as a
reference. The algorithm was trained using an independent but similar data set
and using a jackknife approach with the test data. The results were compared to
contours drawn by a trained reader and the duplicate acquisitions were used to
measure the reproducibility of the mJSW measurement. The reproducibility was 0.16
mm and 0.18 mm for normal and osteoarthritic knees, respectively, representing an
improvement of approximately a factor of 2 over manual measurement. The algorithm
also showed excellent agreement with the hand-drawn contours and with mJSW
determined by the manual method.
PMID- 10757610
TI - Knowledge-based segmentation of thoracic computed tomography images for
assessment of split lung function.
AB - The assessment of differential left and right lung function is important for
patients under consideration for lung resection procedures such as single lung
transplantation. We developed an automated, knowledge-based segmentation
algorithm for purposes of deriving functional information from dynamic computed
tomography (CT) image data. Median lung attenuation (HU) and area measurements
were automatically calculated for each lung from thoracic CT images acquired
during a forced expiratory maneuver as indicators of the amount and rate of
airflow. The accuracy of these derived measures from fully automated segmentation
was validated against those from segmentation using manual editing by an expert
observer. A total of 1313 axial images were analyzed from 49 patients. The images
were segmented using our knowledge-based system that identifies the chest wall,
mediastinum, trachea, large airways and lung parenchyma on CT images. The key
components of the system are an anatomical model, an inference engine and image
processing routines, and segmentation involves matching objects extracted from
the image to anatomical objects described in the model. The segmentation results
from all images were inspected by the expert observer. Manual editing was
required to correct 183 (13.94%) of the images, and the sensitivity, specificity,
and accuracy of the knowledge-based segmentation were greater than 98.55% in
classifying pixels as lung or nonlung. There was no significant difference
between median lung attenuation or area values from automated and edited
segmentations (p > 0.70). Using the knowledge-based segmentation method we can
automatically derive indirect quantitative measures of single lung function that
cannot be obtained using conventional pulmonary function tests.
PMID- 10757611
TI - A hybrid, inverse approach to the design of magnetic resonance imaging magnets.
AB - This paper describes a hybrid numerical method of an inverse approach to the
design of compact magnetic resonance imaging magnets. The problem is formulated
as a field synthesis and the desired current density on the surface of a cylinder
is first calculated by solving a Fredholm equation of the first kind. Nonlinear
optimization methods are then invoked to fit practical magnet coils to the
desired current density. The field calculations are performed using a semi
analytical method. The emphasis of this work is on the optimal design of short
MRI magnets. Details of the hybrid numerical model are presented, and the model
is used to investigate compact, symmetric MRI magnets as well as asymmetric
magnets. The results highlight that the method can be used to obtain a compact
MRI magnet structure and a very homogeneous magnetic field over the central
imaging volume in clinical systems of approximately 1 m in length, significantly
shorter than current designs. Viable asymmetric magnet designs, in which the edge
of the homogeneous region is very close to one end of the magnet system are also
presented. Unshielded designs are the focus of this work. This method is flexible
and may be applied to magnets of other geometries.
PMID- 10757612
TI - Quantitative planar imaging method for measurement of renal activity by using a
conjugate-emission image and transmission data.
AB - We are proposing a method to accurately measure renal activity in renography
using Tc-99m labeled tracers. This method uses a conjugate-view image and
transmission data for attenuation correction, the triple energy window (TEW)
method for scatter correction, and background correction techniques that consider
the source volume for accurate background activity correction. To examine this
method in planar imaging, we performed two renal phantom studies with various
uniform background activity concentrations. One study used two ideal box-shaped
kidney phantoms with a thickness of 2 or 4 cm in a water tank and the other study
employed two real kidney-shaped phantoms in a fillable abdominal cavity. For
these studies the kidney phantom-to-background activity concentration ratio (S)
was changed from 5 to infinity. The transmission data were obtained with an
external Tc-99m line array source. The anterior- and posterior-view emission
images were acquired with a dual-headed gamma camera simultaneously and the TEW
method was used to correct scatter for the emission and transmission images. The
results showed that this method with both the accurate background correction and
scatter correction could give depth-independent count rates and could estimate
the true count rate with errors of less than 5% for all S values. However, if
either accurate background correction or scatter correction was performed alone,
the absolute error increased to about 50% for the smaller S values. Our proposed
method allows one to accurately and simply measure the renal radioactivity by
planar imaging using the conjugate-emission image and transmission data.
PMID- 10757613
TI - Comment on "Effect of electron contamination on scatter correction factors for
photon beam dosimetry" [Med.Phy.26, 2099-2106 (1999)].
PMID- 10757614
TI - Rutherford, the Curies, and radon.
PMID- 10757615
TI - Comment on "Permanent prostate seed implant brachytherapy: report of the American
Association of Physicists in Medicine Task Group No. 64" [Med. Phys. 26, 2054
2076 (1999)].
PMID- 10757616
TI - Comparison of treatment planning systems using the AAPM radiation therapy
committee TG-23 test package. American Association of Physicists in Medicine.
PMID- 10757617
TI - Comment on "Intensity-modulated conformal radiation therapy and three-dimensional
treatment planning will significantly reduce the need for therapeutic approaches
with particles such as protons" [Med. Phys. 26, 1186-1187 (1999)].
PMID- 10757618
TI - Measurement of visceral adipose tissue by DXA combined with anthropometry in
obese humans.
AB - OBJECTIVE: To get accurate measurements of visceral adipose tissue (VAT) using
dual energy X-ray absorptiometry (DXA). DESIGN: DXA and anthropometric data and
their combinations were compared to the VAT area calculated from a computed
tomography (CT) single scan. SUBJECTS: 71 overweight subjects (44 women, 27 men),
age: 16-70 y, BMI: 27-52 kg/m2. MEASUREMENTS: Total body and segmental tissue
composition, and new parameters obtained from DXA, in addition to waist and hip
circumferences and abdominal sagittal diameter measurements. RESULTS: The ratio
measured at the umbilical level (sagittal diameter - subcutaneous fat width) x
(transverse internal diameter)/(height) was closely related to VAT (r=0.94 for
women and 0.88 for men). It gave the most predictive equation for VAT: y = 79.6x
(s.e. 3.9) - 149 cm2 for the whole population (r2=0.86, P<0.0001, root mean
square error=38.2 cm2. An independent relationship between lean mass or its index
(r=0.52 and 0.72, P<0.001) and VAT was also found in women. CONCLUSION: This
study demonstrates the potential usefulness of DXA to supply accurate
measurements of VAT in addition to total body composition determination in obese
subjects.
PMID- 10757619
TI - Validation of bio-impedance spectroscopy: effects of degree of obesity and ways
of calculating volumes from measured resistance values.
AB - BACKGROUND: Bioelectrical-impedance spectroscopy (BIS) is a very attractive
method for body composition measurements in a clinical setting. However,
validation studies often yield different results. This can partly be explained by
the different approaches used to transform measured resistance values into body
compartments. OBJECTIVE: The aim of this study was to compare the linear
regression (LR) method with the Hanai Mixture theory (HM). Secondly, the effect
of degree of overweight on the accuracy of BIS was analysed. DESIGN: In 90 people
(10 M, 80 F; body mass index (BMI) 23-62 kg/m2) total body water (TBW) and
extracellular water (ECW) were measured by deuterium and NaBr dilution methods,
respectively, and by BIS. Resistance values of ECW (R(ECW)) and TBW (R(TBW)) were
used for volume calculations. Data of half the group were used for LR based on
L2/R (L = length, R = resistance) to predict TBW and ECW and to calculate the
constants used in the HM (kECW), k(p)). Prediction equations and constants were
cross-validated in Group 2. RESULTS: Bland and Altman analysis showed that the LR
method underestimated TBW by 1.1 l (P < 0.005) and ECW by 1.1 l (P < 0.005). The
HM approach underestimated ECW by 0.8 l (P < 0.005). The correlations with the
dilution methods and the SEEs for TBW and ECW were comparable for the two
approaches. The prediction error of BIS for TBW and ECW correlated with BMI. The
constant kECW, and the specific resistivities of the ECW and intracellular water
(ICW) pECW and pICW were also correlated with BMI. CONCLUSIONS: The mixture
approach is slightly more accurate than linear regression, but not sensitive
enough for clinical use. The constants used in the HM model are not constants in
a population with a wide variation in degree of overweight. The physical causes
of the correlation between BMI and constants used in the model should be studied
further in order to optimize the mixture model.
PMID- 10757620
TI - Birth weight, climate at birth and the risk of obesity in adult life.
AB - OBJECTIVE: To determine whether obesity in adults is related to seasonal or
climatic conditions around the time of birth. SUBJECTS: 1750 men and women born
in Hertfordshire between 1920 and 1930. MEASUREMENTS: Height and weight measured
in the home by trained fieldworkers. RESULTS: Body mass index (BMI) rose with
increasing birth weight in men and women. In men, BMI and the prevalence of
obesity (BMI > or = 30 kg/m2) varied as a function of month of birth and was
greater among those born in January-June than among those born in July-December.
The relationship between birth weight and adult obesity was also stronger in
those born in the first 6 months of the year or following cold winters than in
those born in the last 6 months of the year or following mild winters.
CONCLUSIONS: These findings suggest that adult obesity is linked both to high
birth weight and to early cold exposure. Consequently, exposures in early life
may contribute to individual variation in susceptibility to obesity in adults.
PMID- 10757621
TI - The effect of glucagon-like peptide-1 on energy expenditure and substrate
metabolism in humans.
AB - OBJECTIVE: To investigate the effects of a near-physiological peripheral glucagon
like peptide-1 (GLP-1) infusion, during and after a breakfast of fixed energy
content, on resting energy expenditure, substrate oxidation and metabolism and
the desire to eat specific types of food in humans. DESIGN: A placebo-controlled,
randomized, blinded, cross-over study. Infusion (GLP-1, 50 pmol/kg x h or saline)
was started simultaneously with initiation of the test meals. SUBJECTS: 20
healthy, normal weight (body mass index 20.3-25.7 kg/m2) men of 20-31 y of age.
MEASUREMENTS: Energy expenditure and substrate oxidations were measured before
and for 4 h after standard breakfast (20% of calculated daily energy
requirements, 50% of energy from carbohydrates, 37% of energy from fat and 13% of
energy from protein) using a ventilated hood system. Visual analogue scales were
used throughout the experiment to assess the desire to eat specific types of food
and the palatability of the test meals. Blood was sampled throughout the day for
analysis of plasma hormone and substrate concentrations. RESULTS: Diet-induced
thermogenesis (DIT) was lower (47%) on the GLP-1 infusion than on the saline
infusion (P < 0.0001). This was due to a lower carbohydrate oxidation (P < 0.01).
No differences in fat oxidation or total 4 h protein oxidation were observed. All
hormone and substrate profiles except non-esterified fatty acids (NEFA) and
cholecystokinin (CCK) were significantly suppressed (GLP-2 completely suppressed)
during the GLP-1 infusion, whereas profiles of NEFA and CCK differed in time
course during the two treatments (treatment x time effect), P < 0.0001). GLP-1
infusion also suppressed the desire to eat all food types following the breakfast
(treatment effect: P < 0.05). CONCLUSION: Peripheral GLP-1 decreased DIT and
carbohydrate oxidation, probably secondary to a delayed absorption of nutrients,
since substrate and hormone concentrations in plasma were suppressed during GLP-1
infusion. Endogenous secretion of GLP-1 and GLP-2 was completely suppressed by
GLP-1 infusion. Finally, the desire to eat any type of food was decreased by
exogenous administrated GLP-1.
PMID- 10757622
TI - No effect of gender on different components of daily energy expenditure in free
living prepubertal children.
AB - BACKGROUND: There are limited and controversial data on the influence of gender
on metabolic rate in prepubertal children. OBJECTIVE: To assess the effect of
gender on resting energy expenditure (REE), activity-related energy expenditure
(AEE), total energy expenditure (TEE) and physical activity level (PAL) in free
living prepubertal children. DESIGN: Cross-sectional study. SUBJECTS: 40
prepubertal children (24 boys, 16 girls, 4-11 y old (mean age: 7.0 +/- 1.2 y),
BMI 13.1-32.0 kg/m2). MEASUREMENTS: Energy expenditure was measured by the
combination of indirect calorimetry and individually calibrated 24 h heart rate
monitoring. Body composition was assessed by anthropometrics and bioelectrical
impedance analysis. Socio-cultural and socio-economic factors, as well as
activities of daily living, were estimated by questionnaire for the parents. Boys
and girls were matched for fat-free mass (FFM, boys: 25.9 +/- 8.5 kg; and girls:
24.4 +/- 4.5 kg, n.s.) and fat mass (FM, boys: 11.6-5.9 kg; and girls: 10.8 +/-
3.3 kg, n.s.). RESULTS: We found no sex difference in REE, AEE and TEE. PAL was
1.4 +/- 0.3 for boys and 1.2 +/- 0.4 for girls. REE and TEE were significantly
related to FFM (r=0.62, r=0.81, r=0.60). FFM was found to be the most significant
determinant of REE (r2=0.70). REE accounted for the largest part of the variance
in TEE (r2=0.46). Gender had no significant effect. CONCLUSIONS: There is no
effect of gender on energy expenditure in prepubertal children.
PMID- 10757623
TI - One-year treatment of obesity: a randomized, double-blind, placebo-controlled,
multicentre study of orlistat, a gastrointestinal lipase inhibitor.
AB - OBJECTIVE: To assess the efficacy and tolerability of orlistat (Xenical) in
producing and maintaining weight loss over a 12-month period. DESIGN: Patients
were randomized to double-blind treatment with either orlistat 120 mg or placebo
three times daily, in conjunction with a low-energy diet, for 12 months. SETTING:
Five centres in the UK. SUBJECTS: 228 obese adult patients with body mass index
between 30 and 43 kg/m2 and mean weight 97 kg (range 74-144 kg). INTERVENTIONS:
All patients were prescribed a low-energy diet, providing 30% of energy from fat,
designed to produce an individually tailored energy deficit of approximately 600
kcal/day, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg
or placebo three times daily. MAIN OUTCOME MEASURES: Change in body weight (the
primary efficacy parameter), waist circumference and adverse events were reviewed
regularly, together with serum lipids, insulin, glucose and plasma levels of fat
soluble vitamins and beta carotene. RESULTS: Based on an intent-to-treat
analysis, after 1 y of treatment patients receiving orlistat had lost an average
of 8.5% of their initial body weight compared with 5.4% for placebo-treated
patients; 35% of the orlistat group lost at least 5% of body weight compared with
21% of the placebo group (P < 0.05), and 28% and 17%, respectively (P = 0.04)
lost at least 10% of body weight. Orlistat-treated patients showed significant
decreases (P < 0.05) in serum levels of total cholesterol, low density
lipoprotein cholesterol, and in the low density lipoprotein: high density
lipoprotein ratio in comparison with placebo. Both groups had similar adverse
event profiles, except for gastrointestinal events, which were 26% more frequent
in the orlistat group but were mostly mild and transient. To maintain normal
plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were
given to 1.8%, 8.0% and 3.6%, respectively, of orlistat-treated patients,
compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y,
the decrease in vitamin E and beta carotene was significantly greater in orlistat
treated patients compared with those receiving placebo (P < 0.001). No
significant change was found in the mean vitamin E:total cholesterol ratio in
either group after 52 weeks. CONCLUSIONS: Orlistat, in conjunction with a low
energy diet, produced greater and more frequent significant weight loss than
placebo during 1 y of treatment. One-third of orlistat-treated patients achieved
clinically relevant weight loss (> or = 5% initial body weight). There was also
an improvement in relevant serum lipid parameters. Fat-soluble vitamin
supplements may be required during chronic therapy. Orlistat was well tolerated
and offers a promising new approach to the long-term management of obesity.
PMID- 10757624
TI - Dietary restraint in normal weight and overweight children. A cross-sectional
study.
AB - OBJECTIVE: This study investigated the degree to which actual fatness and
negative self-esteem might be linked to dietary restraint in childhood. METHOD:
Subjects were 426 boys and 319 girls, aged 10.6 y (+/- 1 y). Forty-nine children
were overweight (> 30%) and 149 subjects were in the category 'moderately
overweight' (10-30% overweight). Measures of self-esteem and dietary restraint
were used in the analyses. RESULTS: Dietary restraint was observable in all
weight groups and significantly more in girls. Boys and girls with an existing
fatness problem showed more dietary restraint. Weight status, not self-esteem,
turned out to be the best predictor of dietary restraint. DISCUSSION: Because
there were good reasons to expect side-effects of the observed dietary restraint
in obese children in the long term, valuable alternatives like changes in the
life-style and interventions that enhance body image and self-esteem were
recommended.
PMID- 10757625
TI - Changes in lipolysis and hormone-sensitive lipase expression caused by
procyanidins in 3T3-L1 adipocytes.
AB - OBJECTIVE: To find out whether lipid stores are influenced by phenolic compounds
in wine. DESIGN: Differentiated 3T3-L1 cells were treated with catechin,
epicatechin or procyanidin extracts with different degrees of polymerization at
150 microM for different periods of time (0.5-24 h). SUBJECTS: Cell line 3T3-L1.
MEASUREMENTS: Cellular viability, glycerol-3-phosphate dehydrogenase activity,
glycerol release in the medium, HSL mRNA levels, triacylglycerols and protein.
RESULTS: Catechin, epicatechin and procyanidin extracts were not toxic for the
3T3-L1 cells in the conditions assayed. Glycerol-3-phosphate dehydrogenase
activity was markedly decreased by 150 microM procyanidin extracts. The release
of glycerol into the medium was increased in 150 microM procyanidin extract
treated cells and reached a plateau after 15 h exposure. Procyanidins caused a
time-dependent reduction in the HSL mRNA levels. CONCLUSIONS: These results
suggest that procyanidins from grape and wine affect lipid metabolism whilst
their monomers (catechin and epicatechin) do not. This effect is more pronounced
when the degree of polymerization is higher. Procyanidin extracts cause a time
dependent reduction in the HSL mRNA levels, inhibit triacylglycerol synthesis and
also favour triacylglycerol hydrolysis until the HSL mRNA had reached very low
levels.
PMID- 10757626
TI - A Hattori chart analysis of body mass index in infants and children.
AB - BACKGROUND: Body mass index (BMI) is widely used as an index of fatness in
paediatrics, but previous analysis of the BMI-fatness relationship has been
insufficient. OBJECTIVE: To consider the effects of variation in fat-free mass
(FFM) and fat mass (FM) on BMI in infants, children and Fomon's reference child
(Am J Clin Nutr 1982; 35: 1169-1175). SUBJECTS: 42 infants aged 12 weeks; 64
children aged 8-12 y; Fomon's reference child. METHODS: FFM was measured by
deuterium dilution. FFM index (FFMI) and FM index (FMI) were calculated. The
effects of variation in FFM and FM on BMI were explored using Hattori's body
composition chart (Am J Hum Biol 1997; 9: 573-578). RESULTS: In both infancy and
childhood, a given BMI can embrace a wide range of percentage body fat. At both
time points, the s.d. of FFMI was > 60% of the s.d. of FMI. Graphic analysis
differentiated the effects of lean tissue and fat deposition on BMI with age in
the reference child. CONCLUSION: Although valuable for assessing short-term
changes in nutritional status in individuals, and for comparing mean relative
weight between populations, BMI is of limited use as a measure of body fatness in
individuals in both infancy and childhood. The development of BMI with age may be
disproportionately due to either FFM and FM at different time points.
PMID- 10757627
TI - Cholesterol and triglyceride concentrations, birthweight and central obesity in
pre-school children. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and
Childhood.
AB - OBJECTIVE: To investigate the relationship between blood cholesterol and
triglyceride, birthweight and central obesity in pre-school children, after
controlling for height and body mass index. METHODS: This was a longitudinal
population-based study in south-west England. Research clinics were held when the
children were 31 and 43 months of age, where anthropometric measurements were
made and a non-fasting blood sample was taken and analysed for triglyceride,
total cholesterol and high-density lipoprotein (HDL) cholesterol. Low-density
lipoprotein (LDL) cholesterol values were calculated using the Friedewald
equation. Central obesity was estimated using the ratio of waist
circumference:arm circumference (WC:AC). RESULTS: Complete blood lipid and
anthropometric data were available for 385 children at 31 months and 470 children
at 43 months. Height was negatively associated with the concentration of
triglyceride, and total and LDL cholesterol. There was little evidence for a
relationship between body mass index (BMI) and blood lipids at either 31 or 43
months. The only significant relationship between birthweight and blood lipids
was a negative association with HDL (and consequently a positive association with
the ratio of total:HDL cholesterol) in boys at 43 months. Adjustment for current
height and BMI had little effect on the associations between birthweight and
blood lipid concentrations. WC:AC was positively associated with triglycerides
and negatively associated with HDL values in boys, and had a quadratic
relationship with LDL concentrations among girls. These relationships were
unchanged or became stronger on adjustment for current height and body mass
index. CONCLUSION: In the pre-school child, central obesity has a relationship
with triglyceride and HDL concentrations that is independent of current height
and BMI. We have found no evidence that increasing birthweight is associated with
a more favourable blood lipid profile at 31 and 43 months.
PMID- 10757628
TI - Influence of heredity for obesity on adipocyte lipolysis in lean and obese
subjects.
AB - OBJECTIVE: To evaluate a possible influence of a hereditary trait for obesity on
the regulation of adipocyte metabolism in vitro in subcutaneous fat cells in
obese and non-obese subjects. DESIGN: A biopsy from abdominal subcutaneous fat
was obtained from consecutive subjects with or without a family trait for
obesity. A positive family history of obesity was considered present if one or
more of the first degree relatives had a BMI of 27 kg/m2 or more. SUBJECTS: 67
non-obese and 60 obese subjects, age 19-60 y. A family trait for overweight was
present in 42 of the lean subjects and in 50 of the obese subjects. MEASUREMENTS:
Fat cells were isolated and incubated in vitro with isoprenaline (a non-selective
beta-adrenoceptor agonist), forskolin (activates the adenylyl cyclase) and
dibutyryl cyclic AMP (stimulates the protein kinase hormone-sensitive lipase
complex). Glycerol release was measured and used as lipolytic index. RESULTS:
Maximal lipolytic response per g triglycerides was about 50% lower in obese
subjects both with and without a positive heredity and in non-obese subjects with
a family trait for obesity as compared to non-obese subjects without such trait
(P=0.0001). Fat cell volume was twice as high in obese as compared to lean
subjects. Drug-induced maximal glycerol release per fat cell in the obese
subjects, regardless of family history of obesity, reached a similar level, but
did not exceed that of the lean group without heredity. CONCLUSIONS: Obesity is
associated with catecholamine resistance with a relatively ineffective lipolysis
in fat cells, and presence of a family history of obesity was not associated with
a further suppression of lipolysis. In the lean subjects, heredity for obesity
significantly influenced lipolysis to similar low levels as in the obese
subjects.
PMID- 10757629
TI - Epidemic obesity: are genetic factors involved via increased rates of assortative
mating?
AB - OBJECTIVE: Prevalence rates of obesity have been increasing in several countries
over the past two decades. Mainly secular changes in energy intake and
expenditure have been invoked to underly the increasing rates; genetic factors
have not been considered because of the very recency of this phenomenon. We
hypothesize that genetic factors might very well be involved via an increased
rate of assortative mating between obese individuals. We speculate that the
recent upsurge in social stigmatization of obese individuals underlies the
hypothesized increase in assortative mating. DESIGN: To accumulate evidence for
our hypothesis we analysed deduced rates of assortative mating among parents of
extremely obese children and adolescents, who belonged to two different large
study groups (n = 201 and n = 270). For this purpose we calculated parental body
mass indices (BMIs) based on (a) measured current heights and weights, (b) self
reported current heights and weights, and finally (c) measured current heights
and recalled weights at ages 20 and 30, respectively. BMI centiles were
determined which in turn were attributed to the respective BMI decile. Deduced
rates of assortative mating were evaluated in bivariate histograms of the
paternal and maternal BMI deciles. RESULTS: High rates of assortative mating were
observed as deduced from the bivariate histograms, which revealed a fairly
consistent pattern. Thus, in the first study group almost 35% of the parental
pairs had a BMI in the tenth decile; over 50% of the mothers and fathers had a
BMI in this top decile. Recalled parental BMIs at ages 20 and 30 also clustered
in the upper decile. These results were basically replicated in the second study
group. In addition, parental loading on the tenth decile was shown to be higher
for the subgroup of children and adolescents who had a BMI equal to or exceeding
the highest BMI of the population-based age and gender matched control group.
CONCLUSIONS: Our results indicate that assortative mating is common among parents
of extremely obese children and adolescents, ascertained between 1995 and 1997.
In addition, the parental loading on the tenth decile is most prominent for the
most obese children. Whereas we are unable to document an increased rate of
assortative mating, we interpret our results as being consistent with the
hypothesis that an increased rate of assortative mating has contributed to the
recent rise in obesity rates in several countries. Thus, assortative mating
warrants further studies to assess its impact on obesity prevalence rates through
both genetic and non-genetic mechanisms. Our results suggest that assortative
mating might especially increase the rates for extreme obesity.
PMID- 10757630
TI - Clinical measures of obesity and weight loss in men.
AB - OBJECTIVES: (1) To determine the relationship between waist circumference and
body weight in overweight men both before and after participation in a weight
loss program; and (2) to make recommendations for the appropriate use of these
measures at various stages of weight loss. DESIGN: Weight and waist circumference
measures were taken in two diverse groups of men both before and 1-2 y after
commencing a men's 'waist loss' program. Regression analyses were used to assess
the relationship between weight and waist measures. SUBJECTS: One group of 42
retired Caucasian men from New South Wales, and one group of 45 indigenous men
from the Torres Strait region of Northern Australia. RESULTS: There were
differences in the relationships of weight and waist circumference before the
program and change in weight and change in waist circumference after weight loss.
These differences were similar in both groups of men (indigenous men and retired
Caucasian men), with a 1 cm waist loss being on average equivalent to about 3/4
kg, but with wide variability, suggesting inter-individual variation in fat
losses from different depots. This variation suggests that neither weight nor
waist alone is a sufficient measure of fat loss for men. CONCLUSIONS: Weight and
waist circumference should both be used at various stages in the clinical
situation to assess change in body fat in men involved in obesity reduction.
PMID- 10757631
TI - Health risks among Japanese men with moderate body mass index.
AB - BACKGROUND: Despite the westernized lifestyle, most Japanese are not prominently
obese. As their obesity may be obscured, we want to further explore central fat
distribution and health risks among this population. METHODS: 2668 men (body mass
index (BMI) 20- < 26.4 kg/m2) were identified from 3343 men (BMI 14.0-37.7,
median of waist-to-height ratio (W/Ht) 0.50) who underwent routine health
examinations. They were divided into four groups: (1) BMI 20- < 24, W/Ht < 0.50;
(2) BMI 20- < 24, W/Ht > or = 0.50; (3) BMI 24- < 26.4, W/Ht < 0.50; and (4) BMI
24- < 26.4, W/Ht > or = 0.50. The metabolic risks and physical activities were
compared. RESULTS: W/Ht > or = 0.50 comprised 35% of the subjects of BMI 20- <
24, 91% of BMI 24- < 26.4, only 1% of BMI < 20 and up to 99% of BMI > or = 26.4.
After adjusting for age and smoking and with group 1 as the reference group, odds
ratios (ORs) were significantly higher in both groups 2 and 4 for the risk of
hypertension (1.42, 1.98), hyperglycaemia (1.49, 1.78), hypertriglyceridaemia
(1.95, 2.56), low HDL cholesterol (1.87, 2.20), hyperuricaemia (2.00, 2.51) and
fatty liver (2.57, 5.64) and additionally in group 4 for hypercholesterolaemia
(1.35). ORs in group 3 were only significantly higher for risk of hypertension
(1.86) and fatty liver (1.89). Significantly lower frequencies of regular
physical activity were noted in the higher W/Ht groups (0.75, 0.47, 1.10, 0.52
days per week, from groups 1-4, respectively). CONCLUSIONS: Measurement of waist
circumference may be a preliminary method for the survey of people at higher risk
of lifestyle-related disorders in Japanese men, especially among those with
moderate BMI.
PMID- 10757632
TI - Evolution of GH secretion in urine during an in-patient slimming course in obese
children.
AB - OBJECTIVE: To estimate the change in GH excretion in urine (GH-U) during a
slimming course, and if increased, to assess the components of the course related
to the increase in obese children. DESIGN: Observational follow-up study of
patients admitted for primary obesity to an in-patient slimming course lasting at
least 10 weeks. SUBJECTS: 48 complete observations out of 54 consecutive pre
pubertal patients admitted to a paediatric centre for treatment of primary
obesity (BMI greater than the 90th percentile of the national reference curves).
MEASUREMENTS: GH excretion in urine by immunoradiometric assay, at entry and
after 10 weeks, various anthropometric measurements, nutritional intake and
departure from the prescribed diet, time spent in physical activity, sleep
duration. RESULTS: A mean decrease of 0.90 standard deviations for BMI was
accompanied by a 34% increase of GH-U. Time spent in physical activity was the
only component of the course found to be related to the magnitude of GH-U
increase. CONCLUSION: The results of this observational study confirm that GH-U
is increased after a slimming course in children, and suggest that physical
activity is a major contributor to the restoration of normal GH-U levels.
PMID- 10757633
TI - Elevated serum leptin in patients with coronary artery disease: no association
with the Trp64Arg polymorphism of the beta3-adrenergic receptor.
AB - BACKGROUND: Serum leptin is associated with the occurrence of cardiovascular risk
factors but it is unknown whether leptin is also associated with cardiovascular
disease. Another open question is whether the Trp64Arg polymorphism of the beta3
adrenergic receptor (beta3-AR) is a determinant of circulating leptin.
OBJECTIVES: We measured serum leptin concentrations in a large group of patients
with angiographically assessed coronary artery disease (CAD) and investigated the
relationship between the Trp64Arg polymorphism of the beta3-adrenergic receptor
(AR) and serum leptin. PATIENTS AND METHODS: Leptin was measured in the fasting
state in 1000 consecutive patients with angiographically confirmed CAD by
radioimmunoassay. The codon 64 T/C polymorphism of the beta3-AR gene was analysed
by the polymerase chain reaction/restriction fragment length polymorphism
(PCR/RFLP) technique. Controls were 1000 age-, gender- and weight-matched
subjects without clinical signs of CAD. RESULTS: Serum leptin concentrations were
significantly higher in patients with CAD than in those without CAD (median: 6.8
vs 6.1 ng/ml, P < 0.001). In a multiple regression analysis leptin was found to
be a determinant of CAD (P = 0.005) along with established risk factors. No
differences in serum leptin were observed between wild-type and heterozygous
carriers of the Trp64Arg mutation of the beta3-AR gene, whereas the small group
of homozygous carriers had higher leptin due to their higher BMI. In a multiple
linear regression analysis, body mass index, gender and fasting insulin were the
main significant determinants of serum leptin, whereas the beta3-AR polymorphism
had no effect. CONCLUSIONS: Patients with coronary artery disease exhibit higher
serum leptin concentrations than age- and gender-matched controls of comparable
BMI, indicating that leptin could contribute to the development of cardiovascular
disease, possibly via activation of the sympathetic nervous system. The Trp64Arg
variant of the beta3-adrenoceptor did not influence serum leptin.
PMID- 10757634
TI - VMN dopaminergic graft and feeding pattern in obese Zucker rats.
AB - OBJECTIVE: To study the role of dopamine in the ventromedial hypothalamus (VMN)
in the regulation of meal size and meal number during obesity. METHODS: Embryonic
mesencephalic cells rich in dopaminergic neurons from lean rats were grafted into
the VMN of obese Zucker rats. Since food intake is the product of meal size and
number, these variables were measured using a rat 'eater meter'. Dopamine and
serotonin concentrations in the VMN were assayed in grafted and control rats via
in vivo microdialysis and HPLC two months after transplantation. RESULTS: Food
intake increased in grafted rats due to an increase of both meal size and meal
number 2 weeks after implantation and to an increase of meal size with
insufficient compensatory decrease of meal number 2 months after transplantation.
Grafted rats showed higher absolute dopamine and lower serotonin concentrations
in the VMN. CONCLUSION: It would appear that an increase of dopamine and a
decrease of serotonin in the VMN of grafted obese rats may correlate with
increase in meal number and meal size, respectively. Since obese Zucker rats
usually display an enlarged meal size, we deduce from the data that chronically
elevated VMN dopamine and low serotonin are involved in producing the large meal
size observed during obesity.
PMID- 10757635
TI - Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a
French population.
AB - OBJECTIVE: To investigate the impact of two common polymorphisms in the human
beta2-adrenoceptor gene (Gly16Arg and Gln27Glu substitutions) on obesity and
anthropometric measurements as well as blood variables in a large sample of a
French population. DESIGN AND SUBJECTS: Within the framework of the WHO-MONICA
project, a population study composed of 1195 subjects aged 35-64 y was randomly
sampled from the electoral rolls of the Urban Community of Lille, in northern
France. Subjects without any medical treatment (for hypercholesterolaemia,
hypertension or diabetes mellitus) susceptible to interfere with body weight and
biological variables were selected (n = 836, 419 men/417 women, age = 49.5+/-8.1
y, body mass index (BMI) = 25.7+/-4.4 kg/m2). Subjects with a body mass index >
or = 30 kg/m2 were considered as obese (n = 119, age = 49.5+/-8.2 y, BMI = 33.9+/
3.3 kg/m2 range 30-44). MEASUREMENTS: Genotyping was carried out with allele
specific oligonucleotides hybridization. Association between genotypes and
various obesity markers (body weight, body mass index, waist and waist-to-hip
ratio), lipid, glucose and insulin variables were studied. RESULTS: The Gly16Arg
and Gln27Glu polymorphisms were in complete linkage disequilibrium. Gln27Gln
subjects had an increased risk of obesity (odds ratio (OR) = 1.77, 95% CI 1.19
2.62, P = 0.005). This effect was mainly detected in men (OR = 2.40, 95% CI 1.34
4.27, P = 0.003). Men bearing the Gln27Gln genotype had higher body weight, BMI,
waist and hip circumferences and waist-to-hip ratio than others. Moreover, if
Gln27Gln men carried in addition the Arg16 allele, the increase in body weight,
BMI and waist-to-hip ratio was more important. CONCLUSION: Our results suggest
that genetic variability of the beta2-adrenoceptor gene is implicated in body
weight regulation and in the onset of obesity in French men.
PMID- 10757636
TI - The Gln27Glu polymorphism in the beta2-adrenergic receptor gene is not associated
with morbid obesity in Austrian women.
AB - OBJECTIVE: Beta-adrenergic receptors (betaARs) play an important role in the
regulation of energy expenditure and lipid mobilization. A Gl-27Glu polymorphism
in the beta2-adrenergic receptor (beta2AR) gene has recently been associated with
several indices of obesity in a female Caucasian population, while the same
polymorphism exhibited no association with obesity in another, albeit male,
population. METHODS: We have therefore studied possible associations of the
Gln27Glu and the Gly16Arg polymorphisms in the beta2AR with BMI, plasma leptin
and UCP-1 mRNA expression in the intraperitoneal adipose tissue in a population
of Caucasian women. RESULTS: The frequencies of the Gln27 and the Gly16 alleles
as well as the beta2AR haplotypes were similar in our morbidly obese and lean
subjects. Furthermore, no association was found between the Gln27Glu or the
Gly16Arg polymorphisms and plasma leptin or adipose tissue UCP-1 gene expression
in either group. CONCLUSIONS: We conclude that the two polymorphisms in the
beta2AR gene studied are not a major factor contributing to obesity in our
population.
PMID- 10757637
TI - The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2
diabetes.
AB - OBJECTIVE: Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a
key regulator of adipocyte differentiation and energy balance. Two naturally
occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently
been shown to impair the function of the PPAR gamma2 isoform of the receptor and
to be associated with obesity or diabetes-related phenotypes in different
populations. SUBJECTS: We studied the occurrence and possible associations of the
Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and
metabolic phenotypes in three independent large populations of non-obese non
diabetic, type 2 diabetic, and morbidly obese French Caucasians. RESULTS: The
Pro115Gln mutation was not found in any of the 1069 subjects screened including
626 obese patients. The frequency of the Pro12Ala mutation was similar in all
groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical
parameters tested. CONCLUSIONS: We conclude that the Pro115Gln mutation is not a
frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is
not associated with clinically significant changes in these populations.
PMID- 10757638
TI - SMA carrier testing--validation of hemizygous SMN exon 7 deletion test for the
identification of proximal spinal muscular atrophy carriers and patients with a
single allele deletion.
AB - To facilitate the detection of carriers of a hemizygous survival motor neuron
(SMN) exon 7 deletion we have modified the quantitative SMN exon 7 assay
described by McAndrew et al (1997). The major changes include quantitative
analysis of the amount of SMN exon 7-specific fluorescently-labelled PCR product
on an automated sequencer, and the monitoring of the completeness of a DraI
digestion necessary to distinguish the PCR products of exons 7 of SMN and its
copy gene. In our method the amount of SMN exon 7 PCR product is compared with
the amount of a co-amplified PCR product of the retinoblastoma (RB1) exon
containing a DraI restriction site. By co-amplification using the same primers of
plasmids included in the reaction as internal standards containing SMN exon 7
with a 36-nucleotide deletion and RB1 exon 13 with a 19-nucleotide deletion,
respectively, the relative amplification efficacy can be monitored. The assay has
been validated in 63 ascertained carriers and 28 ascertained non-carriers. The
sensitivity of the test is approximately 97%, the specificity approaches 100%. In
four out of six SMA patients without a homozygous deletion we detected a
hemizygous deletion. The implications of the use of this assay for carrier
testing and for confirmation of the clinical diagnosis of SMA are discussed.
PMID- 10757639
TI - Two novel members of the interleukin-1 receptor gene family, one deleted in
Xp22.1-Xp21.3 mental retardation.
AB - X-linked mental retardation is estimated to affect approximately 1 in 600 males.
Although numerous genes responsible for syndromic mental retardation have been
identified, the study of non-syndromic mental retardation suffers from intrinsic
issues of genetic heterogeneity. During the investigation of three brothers with
a contiguous gene deletion syndrome of Becker muscular dystrophy, glycerol kinase
deficiency, congenital adrenal hypoplasia, and mental retardation, we found their
dystrophin gene to be fused tail-to-tail with a gene encoding a novel member of
the interleukin-1 receptor family, IL1RAPL1. This gene has a close relative in
Xq22, which we call IL1RAPL2. Both IL1RAPL1 and IL1RAPL2 have novel C-terminal
sequences not present in other related proteins, and are encoded by very large
genes. The 1.8-megabase deletion in these patients removes not only the last exon
of the dystrophin gene, the entire glycerol kinase and DAX-1 genes, and the MAGE
B gene cluster, but also three exons encoding the intracellular signalling domain
of IL1RAPL1. The literature contains multiple reports of patients with non
syndromic mental retardation in association with an Xp22.1-Xp21.3 microdeletion
of a marker which lies within the IL1RAPL1 gene. The gene is also wholly or
partially deleted in patients with mental retardation as part of a contiguous
deletion syndrome. We suggest that IL1RAPL1, and perhaps IL1RAPL2, are strong
candidates for X-linked non-syndromic mental retardation loci, and that molecules
resembling IL-1 and IL-18 play a role in the development or function of the
central nervous system.
PMID- 10757640
TI - Gaucher disease: expression and characterization of mild and severe acid beta
glucosidase mutations in Portuguese type 1 patients.
AB - Type 1 Gaucher disease (GD), the most prevalent lysosomal storage disease,
results from the deficient activity of acid beta-glucosidase. Molecular analysis
of 12 unrelated Portuguese patients with type 1 GD identified three novel acid
beta-glucosidase mutations (F109V, W184R and R395P), as well as three previously
reported, but uncharacterized, lesions (R359Q, G377S and N396T). The type 1
probands were either heteroallelic for the well-characterized common lesion,
N370S, and the F109V, W184R, R359Q or N396T lesions or homoallelic for the G377S
or N396T mutations. Expression of the W184R, R359Q and R395P mutations revealed
very low specific activities based on cross-reacting immunologic material (CRIM
SAs of 0.0004, 0.016 and 0.045, respectively), consistent with their being found
only in type 1 patients who had a neuroprotective N370S allele. In contrast, the
F109V, G377S and N396T alleles had significant acid beta-glucosidase activity
(CRIM specific activities of 0.15, 0.17, 0.14, respectively), in agreement with
their being mild type 1 alleles. Thus, these studies identified additional acid
beta-glucosidase mutations in the Portuguese population and demonstrated that the
G377S and N396T mutations were neuroprotective, consistent with the mild clinical
phenotypes of the type 1 patients who were homoallelic for the G377S and N396T
lesions.
PMID- 10757641
TI - A novel expression based approach for assessing the inactivation status of human
X-linked genes.
AB - We present a novel RT-PCR-based approach for determining the inactivation status
of X-linked genes. Using cDNA from cloned female cell lines in which only the
maternal or paternally derived X chromosome is active, we are able to demonstrate
expression from only one allele in genes known to be inactivated. Following
reverse transcription, amplification across a polymorphism will yield a product
from a single allele if the gene of interest is inactivated, and products from
both alleles in a gene escaping inactivation. We have verified this approach
using the human androgen receptor and FMR1 loci which have been shown to be
subjected to normal inactivation. The potential for widespread application of
this approach was shown by the successful demonstration of inactivation at the
MAOA and HPRT loci using intronic polymorphisms.
PMID- 10757642
TI - Primary ciliary dyskinesia: a genome-wide linkage analysis reveals extensive
locus heterogeneity.
AB - Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), is an
autosomal recessive disorder affecting ciliary movement with an incidence of 1 in
20000-30000. Dysmotility to complete immotility of cilia results in a multisystem
disease of variable severity with recurrent respiratory tract infections leading
to bronchiectasis and male subfertility. Ultrastructural defects are present in
ciliated mucosa and spermatozoa. Situs inversus (SI) is found in about half of
the patients (Kartagener syndrome). We have collected samples from 61 European
and North American families with PCD. A genome-wide linkage search was performed
in 31 multiplex families (169 individuals including 70 affecteds) using 188
evenly spaced (19cM average interval) polymorphic markers. Both parametric
(recessive model) and non-parametric (identity by descent allele sharing) linkage
analyses were used. No major locus for the majority of the families was
identified, although the sample was powerful enough to detect linkage if 40% of
the families were linked to one locus. These results strongly suggest extensive
locus heterogeneity. Potential genomic regions harbouring PCD loci were localised
on chromosomes 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage
analysis using PCD families with a dynein arm deficiency provided 'suggestive'
evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only
PCD families with situs inversus resulted in 'suggestive' scores for chromosomes
8q, and 19q.
PMID- 10757643
TI - A robust test for assortative mating.
AB - Testing for random mating in human populations is difficult due to confounding
factors such as ethnic preference and population stratification. With HLA, the
high level of polymorphism is an additional problem since it is rare for couples
to share the same haplotype. Focus on an ethnically homogeneous population, where
levels of polymorphism at HLA loci are more limited, may provide the best
situation in which to detect non-random mating. However, such populations are
often genetic isolates where there may be inbreeding to an extent that is
difficult to quantify and account for. We have developed a test for random mating
at a multiallelic locus that is robust to stratification and inbreeding. This
test relies on the availability of genotypic information from the parents of both
spouses. The focus of the test is on families where there is allele sharing
between the parents of both spouses, so that potential spouses could share an
allele. Denoting the shared allele at the locus of interest by A, then under the
assumption of random mating, heterozygous parents AX should transmit allele A
equally as frequently as allele X to their offspring. When there is positive
(negative) assortative mating, A will be transmitted more (less) often than X.
The power of the test has been computed in a number of situations. Data on high
resolution HLA haplotypes from the Hutterite population were reinvestigated by
the proposed test. The test detects significant negative assortative mating when
the parental origin of the shared haplotype is taken into account.
PMID- 10757644
TI - Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28.
AB - X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited
mild myopathy. We have used 32 polymorphic markers spanning the entire X
chromosome to exclude most of the chromosome except the Xq28 region in a large
XMEA family. Using three additional families for linkage analysis, we have
obtained a significant two-point lod score with marker DXS1183 (Z = 2.69 at theta
= 0). Multipoint linkage analysis confirmed the assignment of the disease locus
with a maximal lod score of 2.74 obtained at recombination fraction zero. Linkage
of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled
out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct
sequencing of the emerin gene in three of our families.
PMID- 10757645
TI - Predictive testing for hereditary breast and ovarian cancer: a psychological
framework for pre-test counselling.
AB - Since the identification of two breast-ovarian cancer susceptibility genes
(BRCA1/2), predictive testing for hereditary breast/ovarian cancer (HBOC) has
been available. Given the complexity and uncertainties of HBOC and the potential
impact of predictive testing on psychological well-being, we offer the test
applicants a combination of information-oriented and psychological counselling.
In this paper, we describe the multidisciplinary approach for predictive testing
for HBOC as a clinical service in Leuven, hereby focusing on psychological and
decision counselling practice. Attention is paid to the theoretical framework
used for pre-test psychological counselling in Leuven. We discuss three important
interacting dimensions of psychological counselling: individual emotional
support, decision counselling and support of the family communication process.
Decision counselling consists of an evaluation of the cognitive and the emotional
processing of the information given and strategies and resources for coping. This
serves as a starting point to facilitate free informed decision making. Scenario
development is used as a decision aid.
PMID- 10757646
TI - Variable features of transient neonatal diabetes mellitus with paternal isodisomy
of chromosome 6.
AB - We describe two patients who suffered transient neonatal diabetes mellitus
(TDNM), due to paternal isodisomy of chromosome 6. One patient, now 5 years old,
had severe intra-uterine growth retardation, but recovered normal growth
parameters. The other patient, currently 12 years old, had a normal birth weight
but showed impaired post-natal growth; in addition to TNDM the patient presented
with cardiac and thyroid abnormalities. These cases may suggest that the clinical
phenotype of TNDM is more variable than previously believed. The contribution of
genetic and epigenetic factors needs to be determined to elucidate the phenotype
genotype relationships of this disease.
PMID- 10757648
TI - Age of diagnosis-based linkage analysis in type 1 diabetes.
AB - Genetic linkage studies of type 1 diabetes have produced a number of conflicting
results, suggesting a high degree of locus heterogeneity in this disease.
Approaches which model such heterogeneity will increase the power to fine map
susceptibility loci. Here, using data from a genome scan of 356 affected sib
pairs with type 1 diabetes, we performed heterogeneity analysis based on
similarity of age at diagnosis of the sib pairs. We observed linkage to the
region on chromosome 4p16.3 in sib pairs both diagnosed over the age of 10 years,
whilst there was no evidence for linkage in sib pairs diagnosed before age 10
years. In contrast the sib pairs diagnosed before the age of 10 years
demonstrated linkage to IDDM10, on chromosome 10p. Age of diagnosis-based
heterogeneity analyses in complex diseases may be particularly helpful in mapping
some susceptibility loci.
PMID- 10757647
TI - Connexin mutations associated with palmoplantar keratoderma and profound deafness
in a single family.
AB - Recently, mutations in two gap junction genes, GJB2 and GJB3 (encoding Connexin
26 and Connexin 31, respectively), have been shown to underlie either inherited
hearing loss and skin disease or both disorders. In this study, we have extended
our analysis of a small family in which palmoplantar keratoderma and various
forms of deafness is segregating. In addition to the previously described
sequence variant M34T in GJB2, two other sequence variants were identified: D66H
also in GJB2 and R32W in GJB3. As D66H segregated with the skin disease, it is
likely to underlie the palmoplantar keratoderma. The other two gap junction
variants identified may contribute to the type of hearing impairment and the
variable severity of the skin disease in the family.
PMID- 10757649
TI - Identification of a novel mutation in the ryanodine receptor gene (RYR1) in a
malignant hyperthermia Italian family.
AB - Malignant hyperthermia (MH) is an inherited autosomal dominant pharmacogenetic
disorder and is one of the main causes of death subsequent to anaesthesia. Around
50% of affected families are linked to the ryanodine receptor (RYR1) gene. To
date, 19 mutations have been identified in the coding region of this gene and
appear to be associated with the MH-susceptible phenotype. Here we report the
identification by two independent methods of a novel mutation associated with the
MH-susceptible phenotype in the RYR1 gene: the 6488G-->C transversion, resulting
in the replacement of the Arg2163 with a proline residue.
PMID- 10757650
TI - FAP and marfanoid habitus.
PMID- 10757651
TI - Discovery, scoring and utilization of human single nucleotide polymorphisms: a
multidisciplinary problem.
AB - There are great hopes that the most common form of human genetic variation,
single nucleotide polymorphisms (SNPs), can be used to improve radically
biological understanding and to advance medicine. However, considerable
controversy exists over just how SNPs can be applied to gain these insights. The
second international SNP meeting, held at Schloss Hohenkammer, Munich, Germany,
brought together leading international scientists from academia and industry to
look at these issues from a multidisciplinary perspective. Topics that were
covered spanned SNP discovery, scoring technologies, population genetics, disease
studies, commercial dimensions, pharmacogenomics, bioinformatics, and legal
considerations. SNP discovery is picking up speed; The SNP Consortium (TSC) is
set to produce 300,000 publicly available SNPs within 2 years. Improved
technologies for scoring SNPs are reducing hands-on time and cost, although truly
high-throughput methods are still lacking for genome-wide population-based
studies. Large numbers of SNPs have already been analysed in diverse populations.
The results emphasise the importance of considering population history when using
SNPs to search for genetic risk factors. Opinions on the feasibility of extensive
SNP-based analysis of complex disease vary. However, combining expertise from
several fields will be key to achieving optimal utilization of SNPs.
PMID- 10757652
TI - Safety of working conditions of glyphosate applicators on Eucalyptus forests
using knapsack and tractor powered sprayers.
PMID- 10757653
TI - Prediction and QSAR analysis of toxicity to Photobacterium phosphoreum for a
group of heterocyclic nitrogen compounds.
PMID- 10757654
TI - Polychlorinated biphenyl residues in blubber of male Atlantic bottlenose dolphins
(Tursiops truncatus) that stranded and died at Matagorda Bay.
PMID- 10757655
TI - Environmental contamination in bottlenose dolphin (Tursiops truncatus):
relationship between levels of metals, methylmercury, and organochlorine
compounds in an adult female, her neonate, and a calf.
PMID- 10757656
TI - Organochlorine chemicals in tree swallows nesting in pool 15 of the Upper
Mississippi River.
PMID- 10757657
TI - Organochlorine compounds in Florida feral pigs (Sus scofa).
PMID- 10757658
TI - Multidirectional movement of chlorpyriphos in a loamy sand soil.
PMID- 10757659
TI - Dissipation behavior of malathion and dimethoate residues from the soil and their
uptake by garden pea (Pisum sativum).
PMID- 10757660
TI - PCDDs and PCDFs in the wastewater from Chinese pulp and paper industry.
PMID- 10757661
TI - Formation of dioxins from sodium chloride-impregnated newspapers by combustion.
PMID- 10757662
TI - In vitro adsorption characteristics of paraquat and diquat with activated carbon
varying in particle size.
PMID- 10757663
TI - Polychlorinated organic compounds (PCOCs) in the Yangtse River water samples
using SPE and GC/ECD.
PMID- 10757664
TI - Persistent organochlorine pesticides (POPs) in coastal lagoons of the Subtropical
Mexican Pacific.
PMID- 10757665
TI - Erythrocyte alterations induced by malathion in Channa punctatus (Bloch).
PMID- 10757666
TI - Distribution of hexokinase and ATPase in the brain of DDT-exposed fish.
PMID- 10757668
TI - Effects of water quality on epithelial morphology in the gill of Capoeta tinca
living in two tributaries of Kizilirmak River, Turkey.
PMID- 10757667
TI - Is the digestive tract an important access route for mercury in the Chinese crab
Eriocheir sinensis (Crustacea, Decapoda)?
PMID- 10757669
TI - Effects of whole sediments from Corpus Christi Bay on survival, growth, and
reproduction of the mysid, Americamysis bahia (formerly Mysidopsis bahia).
PMID- 10757670
TI - Effects of cadmium on the reproductive system of the land snail Helix aspersa.
PMID- 10757672
TI - Cell cycle disruption in wild rodent populations as an endpoint in detecting
exposure and effect.
PMID- 10757671
TI - Feeding growing mink (Mustela vison) PCB Aroclor 1254 does not affect baculum (os
penis) development.
PMID- 10757673
TI - Characterization of glutathione S-transferase activity in the Asiatic clam
Corbicula fluminea.
PMID- 10757674
TI - Nutritional aspects of vitamin D and its metabolites in Japanese children and
adults.
PMID- 10757675
TI - Analysis of the stable levels of messenger RNA derived from different polymorphic
alleles in the vitamin D receptor gene.
AB - The association between polymorphisms in the vitamin D receptor (VDR) gene and
bone mineral density (BMD) has been studied by many investigators. However, the
question of how polymorphisms in the gene modulate the function of the VDR
remains to be answered. To address this issue, we examined the mRNA levels of the
VDR in relation to polymorphisms. First, we compared the levels of mRNA between
the allele with the polymorphic TaqI-digestive site (t) and nondigestive site (T)
located at exon 9 of the VDR gene determined by reverse transcription-polymerase
chain reaction (RT-PCR). Total RNA was extracted from peripheral mononuclear
cells in volunteers whose genotype is Tt. After the amplification of cDNA by PCR,
the amplified fragments were digested by TaqI. The digested (t) and undigested
(T) fragments were visualized by ethidium bromide and semiquantified by an image
analyzer. In 24 subjects, the mRNA levels of allele t were significantly higher
than those of allele T (1.35 fold, P < 0.001). Second, the VDR mRNA levels were
estimated by competitive RT-PCR in 60 healthy subjects (35TT, 24Tt, 1 tt). The
competitive template was 47 bases shorter than the product of the wild-type gene.
After RT-PCR, the mRNA level was determined by a comparison with the competitive
fragments. No significant difference in the mRNA level was observed between two
groups (1.75 +/- 0.84 and 1.65 +/- 0.99 10(-13)mol/g total RNA in TT and Tt,
respectively). In addition, no significant relationship was observed between the
VDR mRNA levels and BMD in the 23 subjects whose BMD data were available. In
conclusion, higher mRNA levels of allele t than T were detected, but the
difference did not result in higher levels of VDR mRNA in subjects with the Tt
genotype compared to those with the TT genotype.
PMID- 10757676
TI - Number of osteoprogenitor cells in human bone marrow markedly decreases after
skeletal maturation.
AB - Pluripotent mesenchymal stem cells in bone marrow differentiate to osteoblast
progenitor cells. When the bone marrow cells are cultured in vitro, they form
colony-forming units-fibroblastic (CFU-Fs) with exhibiting osteoblastic features
such as expression of alkaline phosphatase (ALP) and formation of calcified
nodules ex vivo. This article describes the effect of growth, maturation, and
aging of the skeleton on human CFU-Fs harvested from human iliac bone marrow.
Human bone marrow cells were harvested from the ilia of 49 women, and were
cultured ex vivo for examination. The 49 subjects ranged in age from 4 to 88
years and were without metabolic bone disease. These aspirated bone marrow cells
from human ilium exhibited osteoblastic phenotype such as alkaline phosphatase
(ALP) activity, expression of osteocalcin (OSC) and parathyroid hormone-receptor
(PTH-R) mRNA, and the formation of calcified nodules in vitro. The number of ALP
positive CFU-Fs and the ALP activity were quantified. The highest levels of ALP
positive CFU-Fs were observed in the young group, particularly in those under 10
years of age. The levels of ALP-positive CFU-Fs declined sharply after 10 years
of age; those above 20 years of age exhibited a lower number of ALP-positive CFU
Fs, with a gradual decline with increasing age. These results indicate that
change in the number of ALP-positive CFU-Fs may be associated with skeletal
growth and maturation. The results also show that osteoblastic features such as
ALP activity and capability of formation of calcification nodules were maintained
even in the older subjects. These findings suggest that decreased activity of
bone formation in the aged subjects could be, in part, caused by the decreased
number of osteoprogenitor cells differentiating into osteoblasts because the
number of ALP-positive CFU-Fs was one of the indices exhibiting bone-forming
activity in the human marrow stromal cells.
PMID- 10757677
TI - A new concept of the pattern of structural changes with bone loss by
histomorphometric analysis using bone slabs.
AB - We examined naked bone slabs (1.2 mm thick) from iliac bone biopsied cores
obtained from 33 women aged 33-89 years. The number, size, and shape of the pores
in the bone slabs were analyzed. The results revealed that the % bone area (the
percentage area occupied by bone in the slab) was linearly correlated with age
and other parameters, such as the size of pores, irregularity of pores, and pore
distance, but was not correlated to the number of pores. We found a second-degree
polynomial relationship between the % bone area and the number of pores. Based on
three parameters--% bone area, number of pores, and size of pores--cluster
analysis was performed and the specimens divided into three groups. The group
with sufficient bone mass showed few small round pores, and the group with severe
bone loss revealed a few large pores that were caved in. The characteristics of
these groups represented the relationship between bone mass and structural
change. The remaining group with moderate bone loss was divided into two
subgroups, one with an increased number of pores without expansion and one with
expanded pores without an increase in number. We presumed that the variations
between the groups were caused by differences between fine and rough structures
in the trabeculae caused during the process of bone loss. We concluded that this
analysis of bone slabs allowed the pattern of trabecular structural change that
occurred with bone loss to be determined easily and visually.
PMID- 10757678
TI - The degree of osteoporosis in patients with vertebral fracture and patients with
hip fracture: relationship to incidence of vertebral fracture.
AB - The most typical fracture that occurs in osteoporotic patients is a vertebral
fracture, whereas hip fractures are thought to occur in the most severe
osteoporotic patients. The purpose of this study was to compare the degree of
osteoporosis between patients with vertebral fractures and patients with hip
fracture by examining bone mineral density, biochemical markers of bone
metabolism, and the incidence of vertebral fractures. Subjects were 50 female
patients with vertebral fractures (VX) and 60 female patients with hip fracture
(HX). Bone mineral densities (BMD) of the lumbar spine, femoral neck (Neck), and
one-third of the radius were determined by DXA. Total and bone alkaline
phosphatase, osteocalcin, N-MID osteocalcin, PICP, free deoxypyridinoline, and
CTx were measured. All z-scores of BMD in the three areas of VX and HX patients
were negative, meaning those BMDs were lower in VX and HX than a decade-matched
normal reference. The z-score of Neck BMD was significantly lower in HX than in
VX. Deoxypyridinoline and CTx were significantly higher in HX than in VX. N-MID
osteocalcin was significantly lower in HX than in VX. VX and HX patients were
divided into four subgroups according to the number of their vertebral fractures:
VX, with a single fracture; VX, with multiple fractures; HX, without vertebral
fractures: and HX, with vertebral fractures. VX with multiple fractures and HX
with vertebral fractures had lower z-scores at all skeletal sites. HX with
vertebral fractures had the lowest median z-score at spine and Neck, whereas HX
without vertebral fractures had a low z-score only at Neck compared to VX with a
single fracture. There was no significant difference in markers among the
subgroups. The number of vertebral fractures was negatively correlated with z
scores of BMD at all three sites. We concluded that uncoupling between bone
formation and resorption is greater in hip fractures than in vertebral fractures.
Vertebral fractures are associated with general osteopenia of the total skeleton.
We suggest that there are two types of osteoporosis in patients with hip
fractures: one is that the bone mass of the femoral neck is specifically reduced,
and the other is a terminal stage of osteoporosis which follows osteoporosis with
vertebral fractures.
PMID- 10757679
TI - Comparison of bone mineral density at various skeletal sites with quantitative
ultrasound parameters of the calcaneus for assessment of vertebral fractures.
AB - This study investigated the role of quantitative ultrasound (QUS) for evaluation
of fracture risk in comparison with bone mineral density (BMD) measurement. Our
subjects were postmenopausal Japanese women (n = 260; age, 67 +/- 6.1 years) who
were examined for bone densitometry, QUS, and spinal X-ray examination at our
department between 1992 and 1996. The subjects were categorized into three groups
by the number of atraumatic fractured vertebrae: NF, no vertebral fractures: F1,
one vertebral fracture; F2, two or more vertebral fractures. We compared the
measured parameters to determine their association with the number of fractured
vertebrae. Differences among groups were compared and analyzed by Student's t
test. Odds ratios were also calculated after age adjustment, as well as age and
lumbar or calcaneal parameters. Between NF and F1, lumbar BMD and BMD of the
Ward's triangle showed more significant differences than other values, while
between F1 and F2, whole-body BMD and QUS parameters showed more significant
differences. Lumbar BMD also showed the highest age-adjusted odds ratio in
differentiating F1 from NF. Although QUS parameters showed no power to
differentiate between NF and F1, these values showed higher odds ratios than
other measurements for discriminating between F1 and F2. Adjustment for bone
density did not totally abolish the association between QUS parameters and
vertebral fracture. Additionally, the combination of lumbar BMD and QUS
("stiffness") clearly showed a high power to discriminate NF from F1 + F2. In
conclusion, we showed that QUS measurement is effective in evaluating fracture
risk in advanced osteoporosis, while lumbar dual X-ray absorptiometry is
effective in evaluating risk in early osteoporosis.
PMID- 10757680
TI - Nontraumatic lumbar vertebral compression fracture as a risk factor for femoral
neck fractures in involutional osteoporotic patients.
AB - To screen a potential risk factor for femoral neck fracture, we characterized
lumbar vertebral fractures in 120 patients with femoral neck fractures (19 men,
101 women; mean age, 78.7 years) by investigating the frequency of patients with
lumbar vertebral fracture, the number of vertebral fractures per patient, and the
severity of deformity of the fractured vertebral bodies. These findings were
compared with data gathered from a population of age- and sex-matched control
patients (20 men, 89 women; mean age, 77.6 years) who had no evidence of femoral
neck fracture. The heights of the anterior and posterior walls together with the
midpart of the lumbar vertebrae were measured on lateral radiographs to identify
fractures. The extent of height loss in the fractured vertebrae was calculated
for each group. The incidence of patients with vertebral compression fractures
was significantly higher in the femoral neck fracture group than in the control
group (65.0% vs 41.1%). In terms of age, the difference in the incidence of
vertebral fractures in the two groups was greater in the less aged (60-79 years
old) than in the more aged (>80 years old) population. The mean number of lumbar
vertebral fractures was also significantly greater in the femoral neck fracture
group than in the control group (1.59 +/- 1.39 vs 0.75 +/- 1.19; P < 0.001). The
incidence of more deformed vertebral fractures, which were defined as a vertebral
height loss of more than 50%, was also significantly higher in the group with
femoral neck fracture than in the control group (23.0% vs 7.3%). Based on these
results, we concluded that multiple and more severely deformed vertebral
fractures might represent a high risk for femoral neck fracture, particularly in
patients less than 79 years of age. Care measures that encompass fall prevention
and protection of proximal femurs in addition to drug therapy for osteoporosis
should be recommended to individuals in this category.
PMID- 10757681
TI - Characteristics of bone mineral density and soft tissue composition of obese
Japanese women: application of dual-energy X-ray absorptiometry.
AB - We studied the characteristics of bone mineral density (BMD) and soft tissue
composition in obese Japanese women using dual-energy X-ray absorptiometry.
Eighty-nine women, aged 45-85 years, were divided into three groups according to
their body mass index (BMI): a thin group (n = 38: BMI < 21), a standard weight
group (n = 31; BMI, 21-25), and an obese group (n = 20; BMI > or = 25). The mean
BMD of the second to fourth lumbar vertebrae and BMD of the lumbar spine,
thoracic spine, pelvis, legs, and ribs of the thin group were significantly lower
than those of the standard weight group or the obese group (P < 0.05), whereas no
significant difference in total body BMD was observed among the three groups.
There was a significant difference in total and regional fat mass among the three
groups (P < 0.05). Lean mass of legs and total lean mass showed a significant
difference between the thin group and the obese group (P < 0.05). The results
showed that obesity was associated with higher BMD of weight bearing-bones and
ribs, high total and regional fat mass, and high lean mass of bilateral legs and
total lean mass. We suggest that obesity may contribute to the prevention of bone
loss of weight-bearing bones and ribs and muscular atrophy of the legs.
PMID- 10757682
TI - Hypoxemia is a risk factor for bone mass loss.
AB - Time-dependent changes of bone mass in ambulant chronic respiratory failure
patients 60 or more years of age were compared between those on home oxygen
therapy (HOT) and those still free of HOT (non-HOT). HOT (n = 31) showed initial
PaO2 of slightly greater than 60 Torr and non-HOT (n = 32) had PaO2 moderately
greater than 60 Torr (64.4 Torr vs 75.1 Torr). PaCO2 in HOT was significantly
higher than that of non-HOT (44.8 Torr vs 40.0 Torr). There was no difference in
pulmonary function test results. The whole bone mineral density (BMD) as adjusted
by age and sex was significantly lower in the HOT group than that in the non-HOT.
At endpoints of the follow-up period over 2 years or more, daily bone losses in
the whole BMD, whole bone mineral content, and lumber BMD were significantly more
accelerated in HOT compared with non-HOT. When the Wistar rats were pair-fed and
their locomotion was limited, the animal group placed for 4 weeks under hypoxic
air showed a reduction in BMD as compared with the control. We suggest that
hypoxemia contributes to bone mass loss.
PMID- 10757683
TI - Changes of regional distribution of bone mineral according to age, gender, and
activity.
AB - To assess the pattern of bone mineral distribution over various parts of the
skeletal system depending on age, gender, and level of activity, bone mineral
content of the head, arms, trunk, and legs was measured and expressed as
percentage of the whole-body mineral content (H%, A%, T%, and L%) by a QDR-4,500
(Hologic) in 814 subjects between ages of 20 and 99, 205 men and 609 women. In
ambulant, self-supporting subjects classified as ADL 1, women had higher H%,
lower A%, and lower L% at each age group than in men. In subjects older than 60
years of age, H% increased and L% decreased markedly in women, whereas these
changes were milder in men. Women, but not men, showed definite fall of L% and
rise of H% along with the decrease of the level of activity. In hospitalized
female subjects with a lower level of activity, but not in ambulatory female
subjects, fall of L% and rise of H% was noted after 1 year, unlike the results in
their male counterparts. Mineral distribution changes over the whole body
characterized by age, gender, and activity may serve as new indices for
evaluation of skeletal changes caused by aging, lifestyle, and disease.
PMID- 10757684
TI - Increase in the incidence of cervical and trochanteric fractures of the proximal
femur in Niigata Prefecture, Japan.
AB - This study aimed to determine the incidence of cervical and trochanteric
fractures of the proximal femur in 1994 in Niigata Prefecture, Japan, and to
compare this incidence with those previously reported in Niigata in 1985, 1987,
and 1989. We visited all hospitals within Niigata Prefecture having an orthopedic
department and reviewed the medical records and radiographs of all patients who
sustained such fractures in 1994. The population of Niigata Prefecture was
determined in 1994 to be 2,483,879 (1,205,151 males and 1,278,728 females). The
population over 65 years of age was 428,795 (172,788 males and 256,007 females),
representing 17.3% of the total population. In 1994, there were 1,468 cervical or
trochanteric fractures in 378 males and 1,090 females, with a male-to-female
ratio of 1:2.9. The incidence of these fractures in persons over 65 years of age
was 304 fractures per 100,000 population per year. Of 528 cervical and 940
trochanteric fractures, the latter accounted for 64% of the total number. The age
specific incidence of the fractures in Niigata exhibited an exponential increase
with age, similar to those reported in Sweden and the United States. However, the
incidence was lower than in those countries. When comparing the number of
cervical and trochanteric fractures in 1994 with the numbers reported in 1985,
1987, and 1989, it is evident that the overall number and incidence of these
fractures has been increasing over this period. Even if the difference of the age
specific population among these years is adjusted, the fractures have been
increasing.
PMID- 10757685
TI - Verbal working memory and sentence comprehension in children with specific
language impairment.
AB - In this study we examined the influence of verbal working memory on sentence
comprehension in children with SLI. Twelve children with SLI, 12 normally
developing children matched for age (CA), and 12 children matched for receptive
vocabulary (VM) completed two tasks. In the verbal working memory task, children
recalled as many real words as possible under three processing load conditions
(i.e., no-load condition; single-load condition, where words were recalled
according to physical size of word referents; and dual-load condition, where
words were recalled by semantic category and physical size of word referents). In
the sentence comprehension task, children listened to linguistically nonredundant
(shorter) and linguistically redundant (longer) sentences. Results of the memory
task showed that the children with SLI recalled fewer words in the dual-load
condition than their CA peers, who showed no condition effect. The SLI and VM
groups performed similarly overall, but both groups showed poorer recall in the
dual-load condition than in the other conditions. On the sentence comprehension
task, children with SLI comprehended fewer sentences of both types than the CA
children and fewer redundant sentences relative to themselves and to the VM
children. Results were interpreted to suggest that children with SLI (a) have
less functional verbal working memory capacity (i.e., ability to coordinate both
storage and processing functions) than their CA peers and (b) have greater
difficulty managing both their working memory abilities and general processing
resources than both age peers and younger children when performing a "complex"
off-line sentence processing task.
PMID- 10757686
TI - Multisign combinations by children with intellectual impairments: an analysis of
language skills.
AB - Research suggests that people with intellectual impairments who use manual signs
to augment or substitute for speech rarely progress beyond the stage of single
signs and that word order is particularly problematic. However, the majority of
studies have focused on experimental tasks, and relatively little is known about
spontaneous sign production in naturalistic settings. The present study explored
the linguistic development in sign and speech of 10 children who relied on manual
signs (the Makaton vocabulary) as their main means of communication. Mean
utterance length in sign ranged from 1.0 to 2.5, and analysis of semantic
relations, lexical development, and word order suggested that the children had
not developed their language beyond MLU Stage I. Examination of their abilities
within the modality of sign indicated that some children were able to manipulate
features of sign at a sublexical level. The results are discussed in relation to
the language input by teachers, and inferences are drawn regarding the underlying
modality of linguistic representation in children who use manual signs.
PMID- 10757687
TI - General language performance measures in spoken and written narrative and
expository discourse of school-age children with language learning disabilities.
AB - Language performance in naturalistic contexts can be characterized by general
measures of productivity, fluency, lexical diversity, and grammatical complexity
and accuracy. The use of such measures as indices of language impairment in older
children is open to questions of method and interpretation. This study evaluated
the extent to which 10 general language performance measures (GLPM)
differentiated school-age children with language learning disabilities (LLD) from
chronological-age (CA) and language-age (LA) peers. Children produced both spoken
and written summaries of two educational videotapes that provided models of
either narrative or expository (informational) discourse. Productivity measures,
including total T-units, total words, and words per minute, were significantly
lower for children with LLD than for CA children. Fluency (percent T-units with
mazes) and lexical diversity (number of different words) measures were similar
for all children. Grammatical complexity as measured by words per T-unit was
significantly lower for LLD children. However, there was no difference among
groups for clauses per T-unit. The only measure that distinguished children with
LLD from both CA and LA peers was the extent of grammatical error. Effects of
discourse genre and modality were consistent across groups. Compared to
narratives, expository summaries were shorter, less fluent (spoken versions),
more complex (words per T-unit), and more error prone. Written summaries were
shorter and had more errors than spoken versions. For many LLD and LA children,
expository writing was exceedingly difficult. Implications for accounts of
language impairment in older children are discussed.
PMID- 10757688
TI - Predicting language production in children and adolescents with Down syndrome:
the role of comprehension.
AB - Predictors of language production skills in 12-minute narratives are investigated
cross-sectionally in 48 children and adolescents with Down syndrome (trisomy 21),
aged 5 to 20 years, in comparison to 48 control children aged 2 to 6 years
matched statistically for nonverbal mental age and mother's years of education.
Two models were evaluated by hierarchical regression analyses using predictors
drawn from the domains of group membership, chronological age, cognition,
socioeconomic status, and hearing screening status (Model I) and, additionally,
comprehension performance (Model II). Results showed that Model II was more
successful. In the DS group, it explained 68% of the variability in number of
different words, 80% in MLU, and 32% in intelligibility. Corresponding
percentages for the control group were 72%, 71%, and 26%. A mechanism linking
comprehension of input to early stages of production practice through activation
of the early speech motor area is proposed.
PMID- 10757689
TI - Spontaneous language of children with specific neurological syndromes.
AB - This paper presents data concerning the early phases of language development in 8
children with congenital neurological syndromes (NS) who are cognitively
impaired. The children are native speakers of Hebrew, and their verbal
achievements assessed on normative tests are below their age level. The
children's spontaneous speech was analyzed with respect to 13 different language
variables known to be diagnostic of a child's developmental level. No differences
were found between the children and their language-matched controls on 10
grammatical variables. The groups differed, however, in number of pragmatic
errors, errors of word choice, and errors of gender marking on animate nouns.
Profile analysis was done through the use of POSAC (partial order scalogram
analysis by base coordinates; Shye, 1985; Shye, Elizur, & Hoffman, 1994). The
analysis did not reveal differences between the children with NS and the
controls. These findings suggest the possibility of a mechanism that is
functionally akin to brain plasticity. Such a mechanism will guarantee the
preservation of basic linguistic skills in children with NS.
PMID- 10757690
TI - An assessment battery for identifying language impairment in African American
children.
AB - This investigation compares the performances of 24 African American children,
diagnosed as language impaired (LI) and receiving school-based language therapy,
to 2 groups of typically developing peers (N = 48) on 5 traditional types of
language assessment measures. Three of the measures were derived from child
centered free play language sample analyses and included average length of
communication units (MLCU), frequencies of complex syntax, and numbers of
different words. Two of the measures examined language comprehension and included
responses to requests for information in the form of Wh-questions and responses
to probes of active and passive sentence constructions. The performances of the
group of children with language impairments were significantly lower on each
measure than that of chronological age matched African American children who were
typically developing. Sensitivity and specificity of the battery appeared
excellent. The findings are discussed in terms of the potential of these informal
language measures to contribute to a culturally fair assessment protocol for
young African American children.
PMID- 10757691
TI - Age differences in the use of informative/heuristic communicative functions in
young children with and without hearing loss who are learning spoken language.
AB - Previous research has suggested that the normal development of communicative
functions proceeds from the directing or "instrumental" types to the informative
or "heuristic" types with age. This paper describes a cross-sectional study of
communicative function in children with profound hearing loss and children with
normal hearing, from ages 12-54 months. The children with hearing loss were
learning spoken English as their primary means of communication. The primary
purpose of the study was to evaluate whether the pattern of age differences seen
in the two groups of children (those with and without normal hearing) are similar
patterns that occur at differing chronological ages, or whether they are
dissimilar patterns altogether. A second purpose was to examine the relationship
between the use of informative/heuristic functions and the acquisition of
vocabulary and syntax. The data suggested a somewhat different pattern of
communicative function development in children with and without hearing loss. In
addition, the use of language for social purposes was closely related to the
achievement of traditional language milestones. In both normally hearing children
and in those with hearing loss, the correlations between the use of informative
heuristic functions and various measures of language development indicated that
the more mature uses of language co-occur with increased frequency of
communication, larger vocabulary, and longer utterance length. These results
document that when linguistic improvements such as increasing vocabulary size and
sentence length occur in deaf children learning spoken English, they are used for
appropriate and informative social purposes that are commensurate with their
language age.
PMID- 10757692
TI - The relationship between measures of working memory and sentence comprehension in
patients with Alzheimer's disease.
AB - Patients with dementia of the Alzheimer's type (DAT) and age- and education
matched older volunteers were tested on a battery of working memory tests, as
well as on two tests of sentence comprehension. Patients had reduced spans and
impaired central executive processes in working memory but showed normal effects
of phonological and articulatory variables on span. On the sentence comprehension
tasks, DAT patients showed effects of the number of propositions in a sentence
but not of syntactic complexity. Impairment in the central executive processes of
working memory in DAT patients was correlated with the effect of the number of
propositions in a sentence on the sentence comprehension tasks. The results
suggest that patients with DAT have working memory impairments that are related
to their ability to map the meanings of sentences onto depictions of events in
the world.
PMID- 10757693
TI - Factors affecting the recognition of reverberant speech by elderly listeners.
AB - Elderly listeners have been shown to experience greater difficulty with speech
understanding than young listeners. The greater difficulty with speech
understanding in elderly listeners has been attributed, primarily, to their
typical high-frequency sensorineural hearing impairment. However, not all of the
observed difficulty can be accounted for by hearing thresholds, leaving the
likelihood of additional suprathreshold processing deficits. This study
investigates speech understanding in older people and the relative contributions
of hearing threshold and age to speech understanding. Considering that temporal
processing is thought to affect speech understanding, the study also assesses the
contributions of hearing loss and age to modulation-preservation performance.
Finally, individual differences in hearing loss, age, and modulation-preservation
performance are examined to see if they are closely associated with individual
differences in speech-recognition ability, especially among older listeners. The
results of the study suggest that hearing loss is closely tied to both speech
recognition performance and to measures of modulation preservation. Although some
of the analyses at first indicated an effect of age, it was shown that this could
be attributed in part to slight elevations in hearing threshold. Finally, it was
shown that individual differences in hearing loss and measures of modulation
preservation and processing efficiency in noise are associated with speech
recognition performance and that, given these measures, speech recognition can be
predicted quite accurately.
PMID- 10757694
TI - Development of isolation-induced vocal behavior in normal-hearing and deafened
guinea pig infants.
AB - Infants in many different animal species require auditory information from
conspecifics to learn appropriate responses to important environmental and social
cues. Isolation calls are emitted by infant guinea pigs in contexts of social
separation from their mothers. The aim of the present study was to examine the
ontogeny of the isolation calls in normal-hearing and deafened infant guinea
pigs, from 2 to 40 days postpartum and to determine the role of hearing maternal
vocalization in infant guinea pig vocal responses in contexts of social proximity
and isolation. Female newborn pigmented guinea pigs (Cavia porcellus) were housed
with their birth mother and siblings. Water and dry food were available ad
libitum. One day postpartum, the cochlea of infants in the experimental group was
destroyed. The control group consisted of normal-hearing female siblings.
Vocalizations from infants in the experimental and control groups were recorded
for 6 minutes when with the mother before isolation, 6 minutes when alone, and
then 6 minutes when with the mother after reunion. Recordings were made 5 days
per week from 2 to 40 days after birth. The duration of calling was calculated
for each 6-minute period of recording. Results demonstrated that deaf infants
vocalize more than normal-hearing infants during social isolation from their
mothers. Vocal activity of isolated deaf and normal-hearing infants decreased
substantially over development, almost disappearing by the end of the study
period. These results indicate that maternal vocal behavior modulates the vocal
responses of guinea pigs early in infant development and supports other evidence
that the guinea pig offers a viable model for investigating audition in deaf and
normal-hearing human infants.
PMID- 10757695
TI - Production of sentence-final intonation contours by hearing-impaired children.
AB - Studies of intonation in the hearing impaired (HI) are often concerned with
either objective measures or listener perceptions. Less often has the focus been
on how these two aspects of communication interrelate. This study examined the
relationship between certain acoustic parameters and listeners' perceptions of
intonation contours produced by HI children. Six severe-to-profound HI children
and 6 normal-hearing (NH) children, ages 7;9 to 14;7, were individually tape
recorded while reading 10 declarative sentences and 10 phonemically matched
interrogative sentences within the context of a script. Each sentence ended with
a carefully chosen disyllabic (target) word. Twelve adult listeners,
inexperienced with the speech of the HI, listened to a randomized audio tape
presentation of all of these productions and categorized each one as a statement,
question, or other. Fundamental frequency (F0) and duration measurements were
obtained for the target (final) word of each sentence, and intensity measures
were recorded for each entire sentence. Acoustic analysis showed that all 6 of
the NH children and 4 of the 6 HI children produced acoustically different
intonation contours for declarative versus interrogative sentences. The HI
children's productions were, in general, similar to the NH children, in that they
used F0, duration, and intensity cues to mark the distinction. Their contrastive
use of these acoustic cues, however, was less pronounced than for the NH
children. Analysis of listener responses indicated that, although listeners were
able to differentiate between some of the declarative and interrogative sentences
produced by these 4 HI children, judgments corresponded with their intended type
less often for the HI than for the NH children. (Judgments of NH children's
utterances were 100% correct.) Multiple logistic regression of listeners'
responses to the HI children's utterances showed that 4 acoustic measures, all
derived from the sentence-final word, were significantly predictive: (1) sentence
final F0, (2) slope between the target word's initial and final F0, (3) duration
of the target word, and (4) dB difference between the target word's 1st and 2nd
syllables. Results were similar for the NH children's data, except that the ratio
of the 2 syllables' durations was significant, rather than total word duration.
These findings differ in several important ways from previously published data
for HI children's intonation contours and suggest that many HI children have the
ability to benefit substantially from training in the production of intonation.
PMID- 10757696
TI - Effect of compression ratio on speech recognition and speech-quality ratings with
wide dynamic range compression amplification.
AB - This project examined the effect of varying compression ratio on speech
recognition and quality. Both listeners with mild-to-moderate sensorineural
hearing loss and a control group of listeners with normal hearing participated.
Test materials were sentences from the Connected Speech Test (R. M. Cox, G. C.
Alexander, & C. Gilmore, 1987) which were digitally processed with linear
amplification and wide dynamic range compression amplification with 3 compression
ratios. Speech-recognition scores were obtained with sentences in quiet and in
noise at a 10-dB signal-to-noise ratio for each amplification condition.
Additionally, the participants rated each amplification condition in terms of
clarity, pleasantness, ease of understanding, and overall impression. Results
indicated that, for speech in quiet, compression ratio had no effect on speech
recognition scores; however, speech-quality ratings decreased as compression
ratio increased. For speech in noise, both speech-recognition scores and ratings
decreased with increasing compression ratio for the listeners with hearing loss.
These results suggest that selection of compression ratio on the basis of speech
quality judgments does not compromise speech recognition.
PMID- 10757697
TI - Identification of pathological voices using glottal noise measures.
AB - We investigated the abilities of four fundamental frequency (F0)-dependent and
two F0-independent measures to quantify vocal noise. Two of the F0-dependent
measures were computed in the time domain, and two were computed using spectral
information from the vowel. The F0-independent measures were based on the linear
prediction (LP) modeling of vowel samples. Tests using a database of sustained
vowel samples, collected from 53 normal and 175 pathological talkers, showed that
measures based on the LP model were much superior to the other measures. A
classification rate of 96.5% was achieved by a parameter that quantifies the
spectral flatness of the unmodeled component of the vowel sample.
PMID- 10757698
TI - Induced fatigue effects on velopharyngeal closure force.
AB - This investigation studied the effects of induced velopharyngeal fatigue in
speakers with normal mechanisms. Five adult female and 5 adult male subjects were
used. A force sensing bulb was placed in the velopharynx to measure
velopharyngeal closure force and intramuscular electrodes were inserted in the
levator veli polatini muscle to sample muscle activation levels. The subjects'
task was to repeat the syllable /si/100 times while an external load was placed
on the velopharyngeal mechanism. The external load consisted of various levels of
air pressure (0 as a control, 5, 15, 25, and 35 cm H2O relative to atmospheric
pressure) delivered to the nasal passages via a tube and nasal mask assembly.
Fatigue was defined as a declination of force across the series of syllables
within a pressure condition and was depicted as the slope of a linear regression
line that was fit to the data. The more negative the slope, the greater was the
rate of fatigue. Within each experimental pressure condition, small cyclic
variations in force were noted about each regression line that corresponded to
individual breath groups. This type of declination, within breath groups, has
been reported in the literature previously. Overall declination in force over an
entire series of syllables and over several breath groups is a new finding. It
was possible to induce such fatigue in most subjects, and greater rates of
fatigue generally occurred at the higher levels of external loading, i.e., at 25
and 35 cm H2O. Two subjects, 1 male and 1 female, reached exhaustion. The female
subject could not perform the syllable repetition task at 25 cm H2O, and the male
subject could not complete the task at 35 cm H2O. Three subjects, 1 female and 2
males, exhibited virtually no force declination even at the highest level (35 cm
H2O) of external loading. There were no discernable differences in patterns of
fatigue or in initial velopharygeal closure force values between the male and
female subjects.
PMID- 10757699
TI - A study of F1 coarticulation in VCV sequences.
AB - This study investigates F1 coarticulatory patterns in a large sample of VCV
sequences with 7 consonants and 2 vowels uttered by 5 Catalan speakers. Measures
of the size and the temporal extent of anticipatory and carryover coarticulation
were obtained for the consonantal effects during the adjacent vowels, for the
vocalic effects at the consonantal period, and during each transconsonantal
vowel; F1 coarticulatory patterns are interpreted in the light of coarticulation
data for the jaw and for dorsopalatal contact and F2 reported in the literature.
Results show that consonantal effects reflect trends in lingual and jaw
coarticulation, whereas vocalic effects are mostly in agreement with jaw
coarticulatory trends. This finding is consistent with the view that consonantal
and vocalic gestures overlap in VCV sequences and are ruled by relatively
independent articulatory subsystems.
PMID- 10757700
TI - Timing and intensity variability in the metronomic speech of stuttering and
nonstuttering speakers.
AB - The timing and intensity variability of 8 adults who stutter and 8 age-matched
fluent speakers was investigated under metronomic conditions. Participants were
required to produce double or triple-stress patterns at a slow speech rate (1
syllable/870 ms) when repeating the syllable /staet/or/straet/nine times.
Measures that are sensitive to cyclic rather than overall variation in syllable
timing and intensity were employed. Specifically, durational variation between
successive syllable onsets as well as intensity variation of the beginning
consonant and vowel in successive syllables were computed. Results revealed that,
although intensity variation was similar, the timing of successive syllables of
persons who stutter was significantly more variable than that of persons who do
not stutter. These outcomes are discussed in relation to previous experiments of
timing control of persons who stutter and normally fluent persons during
metronomic stimulation.
PMID- 10757701
TI - Kinematic correlates of speaking rate changes in stuttering and normally fluent
adults.
AB - Articulatory kinematics were analyzed to determine if adults who stutter are
generally poorer at speech movement pattern generation and if changing speech
rate affects their stability in the same way that it affects normally fluent
controls. Adults who stutter (n = 14) and a matched group of controls produced
fluent repetitions of a simple phrase at normal, slow, and fast rates. A
composite index of spatiotemporal stability (STI), as well as independent
measures of timing and spatial variability, revealed that adults who stutter can
operate within normal movement parameter ranges under low-demand speaking
conditions. However, some of the stuttering participants showed evidence of
abnormal instability even when repeating a simple utterance at habitual rate.
Also, measures of relative timing indicated that adults who stutter, unlike their
matched controls, are not better timers at habitual vs. nonpreferred speech
rates. Overall, the results suggest that the kinematic characteristics of the
fluent speech of adults who stutter generally overlap that of normally fluent
speakers; however, subtle differences in kinematic parameters are interpreted to
reveal their susceptibility to speech motor breakdown when performance demands
increase.
PMID- 10757702
TI - Which one of these is not like the others? An inter-hospital study of the
viscosity of thickened fluids.
AB - This investigation examined the rheological (viscosity and yield stress) and
material property (density) characteristics of the thickened meal-time and
videofluorscopy fluids provided by 10 major metropolitan hospitals. Differences
in the thickness of thickened fluids were considered as a source of variability
and potential hazard for inter-hospital transfers of dysphagic patients. The
results indicated considerable differences in the viscosity, density, and yield
stress of both meal-time and videofluoroscopy fluids. In theory, the results
suggest that dysphagic patients transferred between hospitals could be placed on
inappropriate levels of fluid thickness because of inherent differences in the
rheology and material property characteristics of the fluids provided by
different hospitals. Slowed improvement or medical complications are potential
worst-case scenarios for dysphagic patients if the difference between the thick
fluids offered by 2 hospitals are extreme. The investigation outlines the most
appropriate way to assess the rheological and material property characteristics
of thickened fluids. In addition, it suggests a plan of quality improvement to
reduce the variability of the thickness of fluids offered at different hospitals.
PMID- 10757703
TI - Influences of length and syntactic complexity on the speech motor stability of
the fluent speech of adults who stutter.
AB - The purpose of the present study was to investigate the impact of utterance
length and syntactic complexity on the speech motor stability of adults who
stutter. Lower lip movement was recorded from 8 adults who stutter and 8 normally
fluent controls. They produced a target phrase in isolation (baseline condition)
and the same phrase embedded in utterances of increased length and/or increased
syntactic complexity. The spatiotemporal index (STI) was used to quantify the
stability of lower lip movements across multiple repetitions of the target
phrase. Results indicated: (a) Adults who stutter demonstrated higher overall STI
values than normally fluent adults across all experimental conditions, indicating
decreased speech motor stability; (b) the speech motor stability of normally
fluent adults was not affected by increasing syntactic complexity, but the speech
motor stability of adults who stutter decreased when the stimuli were more
complex; (c) increasing the length of the target utterance (without increasing
syntactic complexity) did not affect the speech motor stability of either speaker
group. These results indicate that language formulation processes may affect
speech production processes and that the speech motor systems of adults who
stutter may be especially susceptible to the linguistic demands required to
produce a more complex utterance. The present findings, therefore, support the
hypothesis that linguistic complexity is one factor that contributes to the
disruptions of speech motor stability characteristic of stuttering.
PMID- 10757704
TI - Influences of utterance length and complexity on speech motor performance in
children and adults.
AB - The possible influences of utterance length and complexity on speech motor
performance were examined by assessing the effects of increased processing
demands on articulatory movement stability. Eight 5-year-old children and 8 young
adults repeated a 6-syllable phrase in isolation (baseline condition) and
embedded in sentences of low and high syntactic complexity. Lower lip movements
for the target phrase were analyzed to produce the spatiotemporal index (STI), an
index that reflects the stability of lip movement over 10 repetitions of the
phrase. It was predicted that movement stability would be lower (reflected by
higher values of the STI) for the phrase when it was spoken embedded in complex
sentences and that, compared to adults, children's movement output would be more
negatively affected by increased processing demands. The STI was significantly
increased for the phrase spoken in the complex sentences compared to the baseline
condition, and STIs of the children were consistently higher than those of the
adults across conditions. These findings provide novel evidence that speech motor
planning, execution, or both are affected by processes often considered to be
relatively remote from the motor output stage.
PMID- 10757705
TI - Kyanomycin, a complex of unusual anthracycline-phospholipid hybrids from
Nonomuria species.
AB - A blue secondary metabolite complex, named kyanomycin (2), in addition to epsilon
rhodomycinone (1), was detected in the mycelium extract of Nonomuria sp. NN 22303
by HPLC-diode array and HPLC-electrospray mass spectrometry screening. The
chemical structures of the novel compounds were determined to be unusual
anthracycline-phosphatidylethanolamine hybrids by spectroscopic and chemical
degradation experiments.
PMID- 10757706
TI - Asmarines A-F, novel cytotoxic compounds from the marine sponge Raspailia
species.
AB - Three pairs of nitrogen-containing metabolites, asmarines A-F (1-6), were
isolated from the Red Sea sponge Raspailia sp., collected in the Dahlak
Archipelago, Eritrea. Although the first pair could fully be separated to give
compounds 1 and 2, the other two pairs could only be enriched up to about 80% of
one isomer. The structures of the new compounds were established by spectroscopic
means. Besides the asmarines, methyl 3-oxo-cholan-24-oate (12) was also isolated.
The absolute configuration of asmarine A (1) was determined on the basis of CD
measurements of its unstable 18-oxo derivative (7) and mainly the Cotton effect
of the dicarbonyl derivative (9) of chelodane (8). A O,N(7')-dimethyl derivative
(10) and a second, unexpected, methylated product (11) were obtained from 2.
PMID- 10757707
TI - Preparation, stereochemistry, and cytotoxic activity of the melampolides from
Mikania minima.
AB - The semisyntheses of melampolides 1 and 2, previously found in Mikania minima,
were carried out in order to confirm their chemical structures and to establish
their absolute configurations. Their conformational analyses, performed using
molecular mechanics, experimental (1)H NMR coupling constants, and NOE
experiments, showed a preferred DU conformer in solution at room temperature. The
cytotoxic activities of 1 and 2 against three tumor cell lines were also
determined. Conjugated aldehyde 2 showed higher activity than alcohol 1.
PMID- 10757708
TI - Antiproliferative triterpene saponins from Trevesia palmata.
AB - During the course of a study of plants of the family Araliaceae,
antiproliferative activity was demonstrated by the crude saponin fraction of
Trevesia palmata. After chromatographic purification, six new bisdesmosidic
saponins (1-6), along with two known triterpenoid saponins, (7 and 8), were
isolated. The structures of 1-6 were determined by (1)H-(1)H correlation
spectroscopy (COSY-DQF, 1D TOCSY, 2D HOHAHA, 1D ROESY) and (1)H-(13)C (HSQC,
HMBC) spectroscopy. The antiproliferative activity of compounds 1-8 and of their
prosapogenins (2a-7a) prepared by alkaline hydrolysis, was evaluated using three
continuous culture cell lines.
PMID- 10757709
TI - Luteolin, a compound with adenosine A(1) receptor-binding activity, and chromone
and dihydronaphthalenone constituents from Senna siamea.
AB - Activity-guided fractionation led to the isolation of luteolin (1) from the
leaves of Senna siamea (syn. Cassia siamea). This compound was found to be an
antagonist at the adenosine A(1) receptor with a K(i) value in the low micromolar
range. Four additional nonactive compounds (2-5) were also isolated, and their
structures were elucidated. One compound was identified as cassia chromone (5
acetonyl-7-hydroxy-2-methylchromone) (2). Three other compounds are new, and they
were identified as 5-acetonyl-7-hydroxy-2-hydroxymethyl-chromone (3), 4-(trans)
acetyl-3,6,8-trihydroxy-3-methyldihydronaphthalenone (4), and 4-(cis)-acetyl
3,6,8-trihydroxy-3-methyldihydronaphthalenone (5).
PMID- 10757710
TI - Anthoptilides A-E, new Briarane diterpenes from the Australian sea pen
Anthoptilum cf. kukenthali.
AB - The Australian sea pen Anthoptilum cf. kukenthali has afforded five new briarane
type diterpenes, anthoptilides A-E. Their structures were determined on the basis
of their spectroscopic data. Single-crystal X-ray determination was performed on
anthoptilide A. Anthoptilides B and C inhibited the binding of [(3)H]1, 3
dipropyl-8-cyclopentylxanthine ([(3)H]DPCPX) on adenosine A(1) receptors.
PMID- 10757711
TI - New pyridinium alkaloids from a marine sponge of the genus Spongia with a human
phospholipase A(2) inhibitor profile.
AB - Four new bioactive pyridinium alkaloids, named spongidines A-D (5-8), have been
isolated from a Vanuatu sponge of the genus Spongia, together with known
petrosaspongiolides D (1) and G (2). Compounds 3 and 4 are 21-hydroxy derivatives
of petrosaspongiolides K and P. Structure elucidation was accomplished through
extensive 2D NMR experiments (COSY, ROESY, HMBC, HMQC) and IR, UV, and FABMS
data. All compounds significantly inhibited human synovial phospholipase A(2)
(PLA(2)) at 10 microM, with an IC(50) value of 5.8 microM for compound 4, which
is the most potent inhibitor, with a higher selectivity toward this enzyme than
the reference inhibitor manoalide. Pyridinium alkaloids (5-8) mainly inhibited
human synovial PLA(2). Compound 8, which contains a sulfonic acid group, is the
most interesting inhibitor.
PMID- 10757712
TI - Evaluation of the total peroxyl radical-scavenging capacity of flavonoids:
structure-activity relationships.
AB - The antioxidant activity of a series of flavonoids against peroxyl radicals
generated from thermal homolysis of 2, 2'-azobis-amidinopropane was determined by
the Total Oxyradical Scavenging Capacity (TOSC) assay. Seven flavonoids with
hydroxy and/or methoxy substitution were analyzed and compared to the water
soluble vitamin E analogue Trolox. The most active compound was the flavonol
quercetin, followed by its 3-glycoside derivative rutin; these were 7 and 5
times, respectively, better scavengers of peroxyl radical than Trolox. Among the
flavones with both hydroxy and methoxy substitution, the most active against
peroxyl radicals was the 5,6,4'-trihydroxy-7,8,3'-trimethoxyflavone (thymonin),
with a TOSC value 1.5 times greater than that of Trolox. The activity of the
remaining flavones was in the following relative order: 5, 4'-dihydroxy-6,7,8,3'
tetramethoxyflavone > 5-hydroxy-3,6,7,3', 4'-pentamethoxyflavone (artemetin) >
5,4'-dihydroxy-3,6, 7-trimethoxyflavone > 5,6,7,8,2',3',4',5'-octamethoxyflavone
(agehoustin A). The data suggest a potential role for dietary intake of flavonoid
containing foods in lowering the risk of certain pathophysiologies that have been
associated with free-radical-mediated events.
PMID- 10757713
TI - Antiyeast steroidal saponins from Yucca schidigera (Mohave yucca), a new anti
food-deteriorating agent.
AB - A saponin fraction from the stems of Yucca schidigera (Mohave yucca) exhibited
potent growth-inhibitory activities against certain food-deteriorating yeasts,
film-forming yeasts, and dermatophytic yeasts and fungi. From this fraction, a
number of new anti-yeast monodesmosidic spirostanol saponins, named schidigera
saponins A1 (1), A2 (2), A3 (3), B1 (4), C1 (5),C2 (6); 25(R and S) schidigera
saponins D1 (7), D2 (8), E1 (12), F1 (13); and 25(S) schidigera-saponins D3 (9),
D4 (10), D5 (11), and F2 (14) were isolated, together with several related known
saponins, and the structures were elucidated by spectroscopic methods (see Chart
1). The relationship between the antiyeast activities and the structures of these
saponins is described.
PMID- 10757714
TI - Novel extracellular diterpenoids with biological activity from the cyanobacterium
Nostoc commune.
AB - Five novel extracellular metabolites with an unprecedented diterpenoid skeleton,
5-[(5-carboxy-2-hydroxy)benzyl]-11-hydroxymethyl-2,5,6,8a, 11
pentamethyldodecahydrocyclopentanaphthalene (1), 5-[(5-carboxy-2
hydroxy)benzyl]-11-formyl-2,5,6,8a, 11-pentamethyl
dodecahydrocyclopentanaphthalene (2), 5-[(5-carboxy-2-hydroxy)benzyl]-11
carboxy-2,5,6,8a, 11-pentamethyl-dodecahydrocyclopentanaphthalene (3), 5-[(5
carboxy-2-hydroxy)benzyl]-11-dihydroxymethyl-2,5,6,8a, 11
pentamethyldodecahydrocyclopentanaphthalene (4), and 5-[(5-carboxy-2
hydroxy)benzyl]-11-acetyl-2,5,6, 8a
tetramethyldodecahydrocyclopentanaphthalene (5), have been isolated from the
culture medium of the terrestrial cyanobacterium Nostoc commune by means of
bioguided isolation. The molecules were designated as comnostins A-E. The
structures were determined by spectroscopic methods, mainly NMR and mass
spectrometry. The relative stereochemistry of comnostin A was confirmed by single
crystal X-ray structure analysis. All comnostins showed antibacterial activities.
Additionally, cytotoxic and molluscicidal activities were found for comnostin B.
PMID- 10757715
TI - Excoecarins D, E, and K, from excoecaria agallocha.
AB - Three novel diterpenoids, excoecarins D, E, and K (1-3), were isolated from
Excoecaria agallocha. The structures of 1-3 were established as 3alpha,18
dihydroxy-3beta,20-epoxybeyer-15-ene, (15R, 16S)-ent-15,16-epoxybeyeran-3-one,
and ent-3beta-hydroxykaur-16-en-2-one, respectively, on the basis of extensive
NMR experiments and, in the case of 1, by X-ray analysis.
PMID- 10757716
TI - An unusual nitrogenous terphenyl derivative from fruiting bodies of the
basidiomycete Sarcodon leucopus.
AB - A new nitrogenous metabolite with a p-terphenyl core, sarcodonin (3), has been
isolated from fruiting bodies of the basidiomycete Sarcodon leucopus. The
structure of 3 was determined through a careful study of its peracetate 4, by use
of an array of spectroscopic techniques (including (15)N NMR, gradient-enhanced,
and reverse-detected 2D NMR experiments) and chemical degradation. ROESY data and
molecular mechanics (MM+) calculations led to assignment of the absolute
configuration of 4. Compound 3 exhibited moderate cytotoxicity against KB and P
388 tumor cell cultures.
PMID- 10757717
TI - Structures of five components of the actinomycin Z complex from Streptomyces
fradiae, two of which contain 4-chlorothreonine.
AB - Structure elucidation of five components of the actinomycin Z complex (Z(1)-Z(5))
isolated from Streptomyces fradiae is described. The components were separated by
Si gel column chromatography and TLC/PLC and analyzed by ESIMS, FABMS, LC-MS of
derivatized hydrolysates, and 2D NMR techniques. This permitted determination of
the complete structures of actinomycins Z(1)-Z(5). In Z(3) and Z(5,) site 1 of
the beta-depsipeptide is occupied by the rare 4-chloro-L-threonine, an amino acid
not previously found in an actinomycin. The structural variants of the
actinomycin Z complex have the molecular architecture typical of other
actinomycins but possess greater structural diversity resulting from the presence
of several highly unusual amino acids. Actinomycins Z(3) and Z(5,) but not Z(1),
were more potent than actinomycin D in cytotoxicity assays against three tumor
cell lines.
PMID- 10757718
TI - Sesquiterpene alkaloids from Tripterygium hypoglaucum and Tripterygium wilfordii:
a new class of potent anti-HIV agents.
AB - Five new sesquiterpene pyridine alkaloids [triptonines A (1) and B (2), and
wilfordinines A (3), B (4), and C (5)] and two known compounds (peritassine A and
hypoglaunine C) were isolated from Tripterygium hypoglaucum and a clinically used
extract of Tripterygium wilfordii. The structures of 1-5 were elucidated by
spectroscopic methods. The anti-HIV activity of 1, 2, and several related
compounds was evaluated. Triptonine B (2) demonstrated potent anti-HIV activity
with an EC(50) value of <0.10 microg/mL and an in vitro therapeutic index value
of >1000.
PMID- 10757719
TI - Prenylated benzoic acid derivatives from Ferula kuhistanica.
AB - Four new prenylated benzoic acid derivatives, kuhistanols A-D (1-4), along with
one known compound, 3-farnesyl-p-hydroxybenzoic acid (5), have been isolated from
the roots of the Uzbekistan medicinal plant, Ferula kuhistanica. Their structures
were established on the basis of chemical and spectral evidence. Compound 4
showed a significant inhibitory effect on cytokine production in
lipopolysaccharide-stimulated human peripheral mononuclear cells.
PMID- 10757720
TI - Enhanced cytotoxicity in a Z-photoisomer of a benzopyran derivative of propolis.
AB - (Z)-2,2-Dimethyl-8-(3-methyl-2-butenyl)-benzopyran-6-propenoic acid (1) was
isolated from Brazilian propolis, together with the known benzopyran derivative,
(E)-2, 2-dimethyl-8-(3-methyl-2-butenyl)-benzopyran-6-propenoic acid (2). The
structure was determined by spectroscopic analyses, which included 1D and 2D (1)H
and (13)C NMR experiments, as well as MS, IR, and UV spectroscopy. Compound 2
rapidly changed to 1 under UV irradiation conditions (365 nm), and the reverse
reaction was also observed. The ratio of 1 to 2 reached 2.3 when the reaction
began from either 1 or 2, indicating a photostationary state. Compound 1
displayed an approximate 7-fold stronger cytotoxicity against human lung
carcinoma cells (HLC-2) compared with 2.
PMID- 10757722
TI - Chapecoderins A-C, new labdane-derived diterpenoids from Echinodorus
macrophyllus.
AB - A new seco-labdane-type diterpenoid, chapecoderin A (1), and two new rearranged
labdane-type diterpenoids, chapecoderins B (2) and C (3), were isolated from the
leaves of the Brazilian medicinal plant Echinodorus macrophyllus ("Chapeu-de
couro"), and their structures and relative stereochemistry were elucidated by
spectroscopic data. Chapecoderins A-C (1-3) possess in common an alpha,beta
unsaturated gamma-lactone ring in the side chain.
PMID- 10757721
TI - Synthesis of 3,3',5-trihydroxybiphenyl-2-carboxylic acid, a component of the
bitterest natural product amarogentin and its coenzyme A and N-acetyl cysteamine
thiol esters.
AB - 3,3',5-Trihydroxybiphenyl-2-carboxylic acid (6), an ester component of the bitter
tasting natural products amarogentin and amaroswerin, was synthesized in six
steps in 13.6% overall yield. Its N-acetyl cysteamine thiol ester (9) and its
coenzyme A thiol ester (8), a likely biosynthetic precursor of the amarums, were
also prepared.
PMID- 10757723
TI - Diterpenoid acids from Grindelia nana.
AB - Two new norditerpenoid acids of the labdane-type (norgrindelic acids), 4,5
dehydro-6-oxo-18-norgrindelic acid (1) and 4beta-hydroxy-6-oxo-19-norgrindelic
acid (2), as well as a new grindelic acid derivative, 18-hydroxy-6-oxogrindelic
acid (3), were isolated from the aerial parts of Grindelia nana. In addition, the
known compounds, 6-oxogrindelic acid, grindelic acid, methyl grindeloate,
7alpha,8alpha-epoxygrindelic acid, and 4alpha-carboxygrindelic acid were also
isolated. The structures of the new compounds were characterized on the basis of
spectroscopic analysis.
PMID- 10757724
TI - Structural identification of the diester preen-gland waxes of the red knot
(Calidris canutus).
AB - The intact C(32)-C(48) diester wax esters of the preen gland of the migrating
bird Calidris canutus are shown, using synthesized standards, to comprise
predominantly C(12)-C(16) alkane-1,2-diols esterified with octanoic, decanoic,
and dodecanoic acid at one position, and with predominantly even-numbered carbon
fatty acids at the other position.
PMID- 10757725
TI - Two new alkaloids from the bark of Sarcomelicope megistophylla.
AB - Two new alkaloids, megistophylline I (1) and megistophylline II (2), were
isolated from the bark of Sarcomelicope megistophylla. Their structures have been
elucidated on the basis of MS and NMR data.
PMID- 10757726
TI - 7-Epicylindrospermopsin, a toxic minor metabolite of the cyanobacterium
Aphanizomenon ovalisporum from lake Kinneret, Israel.
AB - A toxic minor metabolite, 7-epicylindrospermopsin (1), was isolated from a
culture of the cyanobacterium Aphanizomenon ovalisporum isolated from Lake
Kinneret in Israel. Homonuclear and inverse-heteronuclear 2D NMR techniques, as
well as HRMS and comparison of the NMR data with model compounds, enabled the
structure determination of the new compound. Four polymethoxy-1-alkenes, 3-6,
were isolated from the lipophilic extract of the cyanobacterium as well.
PMID- 10757727
TI - Three new triterpenoids from Peganum nigellastrum.
AB - Three new triterpenoids, 3alpha,27-dihydroxylup-20(29)-en-28-oic acid methyl
ester, 3alpha-acetoxy-27-hydroxylup-20(29)-en-28-oic acid methyl ester, and
3alpha-acetoxyolean-12-ene-27,28-dioic acid 28-methyl ester, were isolated from
the roots of Peganum nigellastrum along with four known lupene-type
triterpenoids. The structures of the new triterpenoids were determined by NMR
spectroscopic means. The new triterpene, 3alpha, 27-dihydroxylup-20(29)-en-28-oic
acid methyl ester is a DNA topoisomerase II inhibitor (IC(50) = 8.9 microM/mL).
PMID- 10757728
TI - Isolation of psammaplin A 11'-sulfate and bisaprasin 11'-sulfate from the marine
sponge Aplysinella rhax.
AB - Psammaplin A 11'-sulfate (3) and bisaprasin 11'-sulfate (4) have been isolated
from the marine sponge Aplysinella rhax, along with the known psammaplin A (1).
Their structures were determined on the basis of their spectroscopic data.
Compounds 1 and 3 inhibited [(3)H]1,3-dipropyl-8-cyclopentylxanthine binding to
rat-brain adenosine A(1) receptors.
PMID- 10757729
TI - Microbial transformation of benzosampangine.
AB - Microbial transformation studies of the synthetic antifungal alkaloid
benzosampangine (1) have revealed that 1 is metabolized by a number of
microorganisms. Using a standard two-stage fermentation technique Absidia glauca
(ATCC 22752), Cunninghamella blakesleeana (ATCC 8688a), Cunninghamella species
(NRRL 5695), Fusarium solani f. sp. cucurbitae (CSIH #C-5), and Rhizopogon
species (ATCC 36060) each produced a beta-glucopyranose conjugate of
benzosampangine (2). The identity of 2 was established on the basis of
spectroscopic data.
PMID- 10757730
TI - Proctoriones A-C: 2-acylcyclohexane-1,3-dione derivatives from peperomia
proctorii.
AB - The structures of three new compounds isolated from Peperomia proctorii, named
proctoriones A-C, have been established by spectroscopic and chemical methods as
2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms
of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec
(11Z)-enoylcyclohexane-1,3-dione (3).
PMID- 10757731
TI - Two new prenylated 3-benzoxepin derivatives as cyclooxygenase inhibitors from
Perilla frutescens var. acuta.
AB - Two novel prenyl 3-benzoxepin derivatives, perilloxin (1) and dehydroperilloxin
(2), were isolated from the dichloromethane extract of the stems of Perilla
frutescens var. acuta. Their structures were elucidated as (-)-(R)-5-methoxy-2,3
dihydrofuro[2, 3-g][3]benzoxepin and 5-methoxyfuro[2,3-g][3]benzoxepin,
respectively, based on UV, MS, (1)H and (13)C NMR, NOE, (1)H-(13)C COSY, and HMBC
spectral data. They were isolated following bioassay-guided fractionation, using
an in vitro cyclooxygenase-1 test. Compounds 1 and 2 possess inhibitory
activities, with IC(50) values of 23.2 microM and 30.4 microM, respectively.
PMID- 10757732
TI - Dulxanthones F-H, three new pyranoxanthones from Garcinia dulcis.
AB - Three new pyranoxanthones, dulxanthones F-H (1-3), have been isolated from the
leaves of Garcinia dulcis. Their structures have been determined on the basis of
extensive NMR studies.
PMID- 10757733
TI - Sculezonones A and B, two metabolites possessing a phenalenone skeleton from a
marine-derived fungus Penicillium species.
AB - Two new metabolites possessing a phenalenone skeleton, sculezonones A (1) and B
(2), were isolated from cultured broth of the fungus Penicillium sp., which was
separated from the Okinawan marine bivalve Mytilus coruscus, and the structures
were elucidated by spectroscopic data.
PMID- 10757734
TI - Nasimaluns A and B: neo-clerodane diterpenoids from barringtonia racemosa.
AB - An ethanolic extract of the roots of Barringtonia racemosa afforded two novel neo
clerodane-type diterpenoids, methyl-15, 16-epoxy-12-oxo-3,13(16),14-neo
clerodatrien-18, 19-olide-17-carboxylate (nasimalun A, 1) and dimethyl-15,16
epoxy-3, 13(16),14-neo-clerodatrien-17,18-dicarboxylate (17
carboxymethylhardwickiic acid methyl ester, nasimalun B, 2) by NMR and MS
analyses and by comparison of their spectral data with related compunds. The
relative stereochemistry of the asymmetric centers in 1 and 2 was determined by
selective 1D NOESY experiments.
PMID- 10757735
TI - Hyperforin analogues from St. John's wort (Hypericum perforatum).
AB - Three oxygenated analogues of the prenylated phloroglucinol hyperforin (3-5) were
isolated from the aerial parts of Hypericum perforatum and their structures
elucidated by spectroscopic methods.
PMID- 10757736
TI - Ganomycins A and B, new antimicrobial farnesyl hydroquinones from the
basidiomycete Ganoderma pfeifferi.
AB - Two new farnesyl hydroquinones named ganomycin A (1) and ganomycin B (2) were
isolated from Ganoderma pfeifferi, and their structures were elucidated by
spectroscopic methods. Both carboxylic acids exhibit antimicrobial activity
against several Gram-positive and Gram-negative bacteria.
PMID- 10757737
TI - Isopimarane diterpenoids from Lycopus europaeus.
AB - A reinvestigation of the diterpene metabolites of Lycopus europaeus allowed the
isolation of five new compounds, namely, four isopimarane derivatives (1-4) and
5,9-dihydroxygeranyllinalool (5). The structures of these substances were
established by chemical and spectroscopic means.
PMID- 10757738
TI - Two new spongian diterpenes from Coscinoderma mathewsi.
AB - Two new spongian diterpenes were isolated from the sponge, Coscinoderma mathewsi.
One possesses a tricyclic skeleton bearing an aldehyde function, the other is a
tetracyclic lactol. The structures of two compounds are elucidated by spectral
method.
PMID- 10757739
TI - Antifungal and larvicidal compounds from the root bark of Cordia alliodora.
AB - Two new natural products, a phenylpropanoid derivative characterized as 1-(3'
methoxypropanoyl)-2,4,5-trimethoxybenzene (1) and a prenylated hydroquinone, 2
(2Z)-(3-hydroxy-3,7-dimethylocta-2, 6-dienyl)-1,4-benzenediol (2), have been
isolated from the root bark of Cordia alliodora. Both compounds exhibited
antifungal properties against the phytopathogenic mold Cladosporium cucumerinum.
The phenylpropanoid derivative (1), whose structure is closely related to beta
asarone, also demonstrated a marked activity against larvae of the yellow-fever
transmitting mosquito Aedes aegypti.
PMID- 10757740
TI - Siamenol, a new carbazole alkaloid from Murraya siamensis.
AB - A new carbazole alkaloid, siamenol (1), and two known alkaloids, mahanimbine (2)
and mahanimbilol (3), have been isolated from the organic extract of Murraya
siamensis. The novel compound exhibited HIV-inhibitory activity.
PMID- 10757742
TI - Changes in sidechain and backbone dynamics identify determinants of specificity
in RNA recognition by human U1A protein
PMID- 10757741
TI - Adrenergic stimulation regulates Na(+)/Ca(2+)Exchanger expression in rat cardiac
myocytes.
AB - The Na/Ca exchanger protein encoded by the NCX1 gene provides the predominant
mechanism for calcium efflux during cardiac relaxation. Because beta -adrenergic
stimulation increases expression of Ca(2+)channels (Ca(2+)influx) in cardiac
myocytes, we tested the hypothesis that isoproterenol would concomitantly augment
expression of NCX1. Four hour treatment of neonatal myocytes with isoproterenol
significantly increased NCX1 gene and protein expression, and increased the rate
of transcript initiation. Alpha-adrenergic stimulation significantly decreases
NCX1 mRNA levels. Calcium transient measurements revealed that for cells that had
been pretreated with isoproterenol there was a faster relaxation rate of the
Ca(2+)transient in the presence of thapsigargin, indicating an enhanced rate of
intracellular Ca(2+)removal. We conclude that effectors that increase calcium
channel expression in neonatal myocytes also augments NCX1 gene and protein
expression over a similar time course, and that this is due to enhanced NCX1
transcription. The regulation of expression of NCX1 by adrenergic pathways may
play an important role in regulation of excitation-contraction coupling in
cardiac myocytes.
PMID- 10757744
TI - Thomas H. Jukes (1906-1999).
PMID- 10757745
TI - The neutral theory of molecular evolution.
PMID- 10757746
TI - The consequences of growth of a mutator strain of Escherichia coli as measured by
loss of function among multiple gene targets and loss of fitness.
AB - We have examined the composition of members of mutator populations of Escherichia
coli by employing an extensive set of phenotypic screens that allow us to monitor
the function of >700 genes, constituting approximately 15% of the genome. We
looked at mismatch repair deficient cells after repeated cycles of single colony
isolation on rich medium to generate lineages that are forced through severe
bottlenecks, and compared the results to those for wild-type strains. The mutator
lineages continued to accumulate mutations rapidly with each increasing cycle of
colony isolation. By the end of the 40th cycle, after approximately 1000
generations, most of the lineages had reduced colony size, 4% had died out, 55%
had auxotrophic requirements (increasing to 80% after 60 cycles), and 70% had
defects in at least one sugar or catabolic pathway. In addition, 33% had a defect
in cell motility, and 26% were either temperature-sensitive or cold-sensitive
lethals. On the other hand, only 3% of the wild-type lineages had detectable
mutations of any type after 40 cycles. By the 60th cycle, the typical mutator
cell carried 4-5 inactive genes among the 15% of the genome being monitored,
indicating that the average cell carried at least 24-30 inactivated genes
distributed throughout the genome. Remarkably, 30% of the lineages had lost the
ability to utilize xylose as a carbon source. DNA sequencing revealed that most
of the Xyl(-) mutants had a frameshift in a run of eight G's (GGGGGGGG) in the
xylB gene, either adding or deleting one -G-. Further analysis indicated that
rendering E. coli deficient in mismatch repair unmasks hypermutable sites in
certain genes or intergenic regions. Growth curves and competition tests on
lineages that passed through 90 cycles of single colony isolation showed that all
lineages suffered reduced fitness. We discuss these results in terms of the value
of mutators in cellular evolution.
PMID- 10757747
TI - Recombination enhancement by replication (RER) in Rhizobium etli.
AB - Studies in several organisms show that recombination and replication interact
closely. Recombinational repair usually requires associated replication at some
stage; moreover, additional replication can induce recombination through either
homologous or illegitimate events. In prokaryotes, stimulation of recombination
by replication is more dramatic when rolling circle replication is employed. In
contrast, theta-type replication induces only a modest increase in recombination
frequency. In this article, we show that induction of theta-type replication from
a supernumerary origin in the symbiotic plasmid (pSym) of Rhizobium etli leads to
a 1000-fold increase in deletion formation on this plasmid. These deletions span
120 kb (the symbiotic region) and have as endpoints the reiterated nitrogenase
operons. We have named this phenomenon RER, for recombination enhancement by
replication. RER is not affected by the position of the replication origin in the
pSym, the direction of advance of the replication fork, or the distance from the
origin to the recombining repeats. On the other hand, RER is dependent on an
active recA allele, indicating that it is due to homologous recombination. RER
displays a strong regionality restricted to the symbiotic region. The
similarities and differences of RER with the recombination process observed at
the terminus of replication of the Escherichia coli chromosome are discussed.
PMID- 10757748
TI - Compensatory mutations, antibiotic resistance and the population genetics of
adaptive evolution in bacteria.
AB - In the absence of the selecting drugs, chromosomal mutations for resistance to
antibiotics and other chemotheraputic agents commonly engender a cost in the
fitness of microorganisms. Recent in vivo and in vitro experimental studies of
the adaptation to these "costs of resistance" in Escherichia coli, HIV, and
Salmonella typhimurium found that evolution in the absence of these drugs
commonly results in the ascent of mutations that ameliorate these costs, rather
than higher-fitness, drug-sensitive revertants. To ascertain the conditions under
which this compensatory evolution, rather than reversion, will occur, we did
computer simulations, in vitro experiments, and DNA sequencing studies with low
fitness rpsL (streptomycin-resistant) mutants of E. coli with and without
mutations that compensate for the fitness costs of these ribosomal protein
mutations. The results of our investigation support the hypothesis that in these
experiments, the ascent of intermediate-fitness compensatory mutants, rather than
high-fitness revertants, can be attributed to higher rates of compensatory
mutations relative to that of reversion and to the numerical bottlenecks
associated with serial passage. We argue that these bottlenecks are intrinsic to
the population dynamics of parasitic and commensal microbes and discuss the
implications of these results to the problem of drug resistance and adaptive
evolution in parasitic and commmensal microorganisms in general.
PMID- 10757749
TI - Highly diverged homologs of Saccharomyces cerevisiae mitochondrial mRNA-specific
translational activators have orthologous functions in other budding yeasts.
AB - Translation of mitochondrially coded mRNAs in Saccharomyces cerevisiae depends on
membrane-bound mRNA-specific activator proteins, whose targets lie in the mRNA 5'
untranslated leaders (5'-UTLs). In at least some cases, the activators function
to localize translation of hydrophobic proteins on the inner membrane and are
rate limiting for gene expression. We searched unsuccessfully in divergent
budding yeasts for orthologs of the COX2- and COX3-specific translational
activator genes, PET111, PET54, PET122, and PET494, by direct complementation.
However, by screening for complementation of mutations in genes adjacent to the
PET genes in S. cerevisiae, we obtained chromosomal segments containing highly
diverged homologs of PET111 and PET122 from Saccharomyces kluyveri and of PET111
from Kluyveromyces lactis. All three of these genes failed to function in S.
cerevisiae. We also found that the 5'-UTLs of the COX2 and COX3 mRNAs of S.
kluyveri and K. lactis have little similarity to each other or to those of S.
cerevisiae. To determine whether the PET111 and PET122 homologs carry out
orthologous functions, we deleted them from the S. kluyveri genome and deleted
PET111 from the K. lactis genome. The pet111 mutations in both species prevented
COX2 translation, and the S. kluyveri pet122 mutation prevented COX3 translation.
Thus, while the sequences of these translational activator proteins and their 5'
UTL targets are highly diverged, their mRNA-specific functions are orthologous.
PMID- 10757750
TI - Proteasome mutants, pre4-2 and ump1-2, suppress the essential function but not
the mitochondrial RNase P function of the Saccharomyces cerevisiae gene RPM2.
AB - The Saccharomyces cerevisiae nuclear gene RPM2 encodes a component of the
mitochondrial tRNA-processing enzyme RNase P. Cells grown on fermentable carbon
sources do not require mitochondrial tRNA processing activity, but still require
RPM2, indicating an additional function for the Rpm2 protein. RPM2-null cells
arrest after 25 generations on fermentable media. Spontaneous mutations that
suppress arrest occur with a frequency of approximately 9 x 10(-6). The resultant
mutants do not grow on nonfermentable carbon sources. We identified two loci
responsible for this suppression, which encode proteins that influence proteasome
function or assembly. PRE4 is an essential gene encoding the beta-7 subunit of
the 20S proteasome core. A Val-to-Phe substitution within a highly conserved
region of Pre4p that disrupts proteasome function suppresses the growth arrest of
RPM2-null cells on fermentable media. The other locus, UMP1, encodes a chaperone
involved in 20S proteasome assembly. A nonsense mutation in UMP1 also disrupts
proteasome function and suppresses Deltarpm2 growth arrest. In an RPM2 wild-type
background, pre4-2 and ump1-2 strains fail to grow at restrictive temperatures on
nonfermentable carbon sources. These data link proteasome activity with Rpm2p and
mitochondrial function.
PMID- 10757751
TI - Isolation and characterization of par1(+) and par2(+): two Schizosaccharomyces
pombe genes encoding B' subunits of protein phosphatase 2A.
AB - Protein phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases
found in eukaryotic cells. We cloned two genes, par1(+) and par2(+), encoding
distinct B' subunits of PP2A in fission yeast. They share 52% identity at the
amino acid sequence level. Neither gene is essential but together they are
required for normal septum positioning and cytokinesis, for growth at both high
and low temperature, and for growth under a number of stressful conditions.
Immunofluorescence microscopy revealed that Par2p has a cell-cycle-related
localization pattern, being localized at cell ends during interphase and forming
a medial ring in cells that are undergoing septation and cytokinesis. Our
analyses also indicate that Par1p is more abundant than Par2p in the cell. Cross
organism studies showed that both par1(+) and par2(+) could complement the
rts1Delta allele in Saccharomyces cerevisiae, albeit to different extents, in
spite of the fact that neither contains a serine/threonine-rich N-terminal domain
like that found in the S. cerevisiae homolog Rts1p. Thus, while
Schizosaccharomyces pombe is more similar to higher eukaryotes with respect to
its complement of B'-encoding genes, the function of those proteins is conserved
relative to that of Rts1p.
PMID- 10757752
TI - Subtelomeric repeat amplification is associated with growth at elevated
temperature in yku70 mutants of Saccharomyces cerevisiae.
AB - Inactivation of the Saccharomyces cerevisiae gene YKU70 (HDF1), which encodes one
subunit of the Ku heterodimer, confers a DNA double-strand break repair defect,
shortening of and structural alterations in the telomeres, and a severe growth
defect at 37 degrees. To elucidate the basis of the temperature sensitivity, we
analyzed subclones derived from rare yku70 mutant cells that formed a colony when
plated at elevated temperature. In all these temperature-resistant subclones, but
not in cell populations shifted to 37 degrees, we observed substantial
amplification and redistribution of subtelomeric Y' element DNA. Amplification of
Y' elements and adjacent telomeric sequences has been described as an alternative
pathway for chromosome end stabilization that is used by postsenescence survivors
of mutants deficient for the telomerase pathway. Our data suggest that the
combination of Ku deficiency and elevated temperature induces a potentially
lethal alteration of telomere structure or function. Both in yku70 mutants and in
wild type, incubation at 37 degrees results in a slight reduction of the mean
length of terminal restriction fragments, but not in a significant loss of
telomeric (C(1-3)A/TG(1-3))(n) sequences. We propose that the absence of Ku,
which is known to bind to telomeres, affects the telomeric chromatin so that its
chromosome end-defining function is lost at 37 degrees.
PMID- 10757753
TI - Trinucleotide repeats are clustered in regulatory genes in Saccharomyces
cerevisiae.
AB - The genome of Saccharomyces cerevisiae contains numerous unstable microsatellite
sequences. Mononucleotide and dinucleotide repeats are rarely found in ORFs, and
when present in an ORF are frequently located in an intron or at the C terminus
of the protein, suggesting that their instability is deleterious to gene
function. DNA trinucleotide repeats (TNRs) are found at a higher-than-expected
frequency within ORFs, and the amino acids encoded by the TNRs represent a biased
set. TNRs are rarely conserved between genes with related sequences, suggesting
high instability or a recent origin. The genes in which TNRs are most frequently
found are related to cellular regulation. The protein structural database is
notably lacking in proteins containing amino acid tracts, suggesting that they
are not located in structured regions of a protein but are rather located between
domains. This conclusion is consistent with the location of amino acid tracts in
two protein families. The preferred location of TNRs within the ORFs of genes
related to cellular regulation together with their instability suggest that TNRs
could have an important role in speciation. Specifically, TNRs could serve as hot
spots for recombination leading to domain swapping, or mutation of TNRs could
allow rapid evolution of new domains of protein structure.
PMID- 10757754
TI - Analysis of Sir2p domains required for rDNA and telomeric silencing in
Saccharomyces cerevisiae.
AB - Silent information regulator (Sir) 2 is a limiting component of the Sir2/3/4
complex, which represses transcription at subtelomeric and HM loci. Sir2p also
acts independently of Sir3p and Sir4p to influence chromatin organization in the
rDNA locus. Deleted and mutated forms of Sir2p have been tested for their ability
to complement and/or to disrupt silencing. The highly conserved C-terminal domain
of Sir2p (aa 199-562) is insufficient to restore repression at either telomeric
or rDNA reporters in a sir2Delta background and fails to nucleate silencing when
targeted to an appropriate reporter gene. However, its expression in an otherwise
wild-type strain disrupts telomeric repression. Similarly, a point mutation
(P394L) within this conserved core inactivates the full-length protein but
renders it dominant negative for all types of silencing. Deletion of aa 1-198
from Sir2(394L) eliminates its dominant negative effect. Thus we define two
distinct functional domains in Sir2p, both essential for telomeric and rDNA
repression: the conserved core domain found within aa 199-562 and a second domain
that encompasses aa 94-198. Immunolocalization and two-hybrid studies show that
aa 94-198 are required for the binding of Sir2p to Sir4p and for the targeting of
Sir2p to the nucleolus through another ligand. The globular core domain provides
an essential silencing function distinct from that of targeting or Sir complex
formation that may reflect its reported mono-ADP-ribosyl transferase activity.
PMID- 10757756
TI - Bipartite structure of the SGS1 DNA helicase in Saccharomyces cerevisiae.
AB - SGS1 in yeast encodes a DNA helicase with homology to the human BLM and WRN
proteins. This group of proteins is characterized by a highly conserved DNA
helicase domain homologous to Escherichia coli RecQ and a large N-terminal domain
of unknown function. To determine the role of these domains in SGS1 function, we
constructed a series of truncation and helicase-defective (-hd) alleles and
examined their ability to complement several sgs1 phenotypes. Certain SGS1
alleles showed distinct phenotypes: sgs1-hd failed to complement the MMS
hypersensitivity and hyper-recombination phenotypes, but partially complemented
the slow-growth suppression of top3 sgs1 strains and the top1 sgs1 growth defect.
Unexpectedly, an allele that encodes the amino terminus alone showed essentially
complete complementation of the hyper-recombination and top1 sgs1 defects. In
contrast, an allele encoding the helicase domain alone was unable to complement
any sgs1 phenotype. Small truncations of the N terminus resulted in hyper
recombination and slow-growth phenotypes in excess of the null allele. These
hypermorphic phenotypes could be relieved by deleting more of the N terminus, or
in some cases, by a point mutation in the helicase domain. Intragenic
complementation experiments demonstrate that both the amino terminus and the DNA
helicase are required for full SGS1 function. We conclude that the amino terminus
of Sgs1 has an essential role in SGS1 function, distinct from that of the DNA
helicase, with which it genetically interacts.
PMID- 10757755
TI - DNA damage-inducible and RAD52-independent repair of DNA double-strand breaks in
Saccharomyces cerevisiae.
AB - Chromosomal repair was studied in stationary-phase Saccharomyces cerevisiae,
including rad52/rad52 mutant strains deficient in repairing double-strand breaks
(DSBs) by homologous recombination. Mutant strains suffered more chromosomal
fragmentation than RAD52/RAD52 strains after treatments with cobalt-60 gamma
irradiation or radiomimetic bleomycin, except after high bleomycin doses when
chromosomes from rad52/rad52 strains contained fewer DSBs than chromosomes from
RAD52/RAD52 strains. DNAs from both genotypes exhibited quick rejoining following
gamma irradiation and sedimentation in isokinetic alkaline sucrose gradients, but
only chromosomes from RAD52/RAD52 strains exhibited slower rejoining (10 min to 4
hr in growth medium). Chromosomal DSBs introduced by gamma irradiation and
bleomycin were analyzed after pulsed-field gel electrophoresis. After equitoxic
damage by both DNA-damaging agents, chromosomes in rad52/rad52 cells were
reconstructed under nongrowth conditions [liquid holding (LH)]. Up to 100% of
DSBs were eliminated and survival increased in RAD52/RAD52 and rad52/rad52
strains. After low doses, chromosomes were sometimes degraded and reconstructed
during LH. Chromosomal reconstruction in rad52/rad52 strains was dose dependent
after gamma irradiation, but greater after high, rather than low, bleomycin doses
with or without LH. These results suggest that a threshold of DSBs is the
requisite signal for DNA-damage-inducible repair, and that nonhomologous end
joining repair or another repair function is a dominant mechanism in S.
cerevisiae when homologous recombination is impaired.
PMID- 10757757
TI - Three subfamilies of pheromone and receptor genes generate multiple B mating
specificities in the mushroom Coprinus cinereus.
AB - The B mating type locus of the basidiomycete Coprinus cinereus encodes a large
family of lipopeptide pheromones and their seven transmembrane domain receptors.
Here we show that the B42 locus, like the previously described B6 locus, derives
its unique specificity from nine multiallelic genes that are organized into three
subgroups each comprising a receptor and two pheromone genes. We show that the
three genes within each group are kept together as a functional unit by being
embedded in an allele-specific DNA sequence. Using a combination of sequence
analysis, Southern blotting, and DNA-mediated transformation with cloned genes,
we demonstrate that different B loci may share alleles of one or two groups of
genes. This is consistent with the prediction that the three subgroups of genes
are functionally redundant and that it is the different combinations of their
alleles that generate the multiple B mating specificities found in nature. The
B42 locus was found to contain an additional gene, mfs1, that encodes a putative
multidrug transporter belonging to the major facilitator family. In strains with
other B mating specificities, this gene, whose functional significance was not
established, lies in a region of shared homology flanking the B locus.
PMID- 10757758
TI - An mre11 mutant of Coprinus cinereus has defects in meiotic chromosome pairing,
condensation and synapsis.
AB - The rad11 gene of the basidiomycete Coprinus cinereus is required for the
completion of meiosis and for survival after gamma irradiation. We have cloned
the rad11 gene and shown that it is a homolog of MRE11, a gene required for
meiosis and DNA repair in numerous organisms. The expression of C. cinereus mre11
is induced during prophase I of meiosis and following gamma irradiation. The gene
encodes a predicted polypeptide of 731 amino acids, and the mre11-1 (rad11-1)
mutation is a single base pair change that results in a stop codon after amino
acid 315. The mre11-1 mutant shows enhanced sensitivity to ionizing radiation,
but no enhanced sensitivity to UV radiation. It shows a delay in fruitbody
formation and a reduction in the number of mushrooms formed per dikaryon. The
mre11-1 mutant also has several meiotic defects. Pachytene chromatin condensation
is disrupted, and although some meiotic cells appear to achieve metaphase I
condensation, no further meiotic progression is observed. The mre11-1 mutant also
fails to undergo proper chromosome synapsis; neither axial elements nor mature
synaptonemal complexes are complete. Finally, meiotic homolog pairing is reduced
in the mre11-1 mutant. Thus, in C. cinereus, Mre11 is required for meiotic DNA
metabolism.
PMID- 10757759
TI - Tetrahymena micronuclear genome mapping. a high-resolution meiotic map of
chromosome 1l.
AB - The ciliate Tetrahymena thermophila is a useful model organism that combines
diverse experimental advantages with powerful capabilities for genetic
manipulation. The genetics of Tetrahymena are especially rich among eukaryotic
cells, because it possesses two distinct but related nuclear genomes within one
cytoplasm, contained separately in the micronucleus (MIC) and the macronucleus
(MAC). In an effort to advance fulfillment of Tetrahymena's potential as a
genetic system, we are mapping both genomes and investigating the correspondence
between them. With the latter goal especially in mind, we report here a high
resolution meiotic linkage map of the left arm of chromosome 1, one of
Tetrahymena's five chromosomes. The map consists of 40 markers, with an average
spacing of 2.3 cM in the Haldane function and a total length of 88.6 cM. This
study represents the first mapping of any large region of the Tetrahymena genome
that has been done at this level of detail. Results of a parallel mapping effort
in the macronucleus, and the correspondence between the two genomes, can be found
in this issue as a companion to this article.
PMID- 10757760
TI - Tetrahymena macronuclear genome mapping: colinearity Of macronuclear coassortment
groups and the micronuclear map on chromosome 1l.
AB - The genetics of the ciliate Tetrahymena thermophila are richer than for most
other eukaryotic cells, because Tetrahymena possesses two genomes: a germline
(micronuclear) genome that follows a Mendelian model of genetic transmission and
a somatic (macronuclear) genome, derived from the micronuclear genome by
fragmentation, which follows a different genetic transmission model called
phenotypic assortment. While genetic markers in the micronucleus fall into
classical linkage groups under meiotic recombination and segregation, the same
markers in the macronucleus fall into coassortment groups (CAGs) under phenotypic
assortment by the random distribution of MAC chromosome pieces. We set out to
determine whether genomic mapping in the macronucleus by genetic means is
feasible. To investigate the relationship between the micronuclear map and
coassortment groups, we systematically placed into CAGs all of the markers lying
on chromosome 1L that are also found in the macronucleus. Sixteen CAGs were
identified, 7 of which contain at least two loci. We have concluded that CAGs
represent a fundamental genetic feature of the MAC. The MIC and MAC maps on 1L
are colinear; that is, CAGs consist exclusively of markers that map to a
continuous segment in a given region of the micronuclear map, with no intervening
markers from other CAGs. These findings provide a solid foundation for exploiting
the MAC chromosome pieces to build a physical map of the Tetrahymena genome.
PMID- 10757761
TI - The allele-specific suppressor sup-39 alters use of cryptic splice sites in
Caenorhabditis elegans.
AB - Mutations in the Caenorhabditis elegans sup-39 gene cause allele-specific
suppression of the uncoordination defect of unc-73(e936). e936 is a point
mutation that changes the canonical G at the 5' end of intron 16 to a U. This
mutation activates three splice donors, two of which define introns beginning
with the canonical GU. Use of these two cryptic splice sites causes loss of
reading frame; interestingly these messages are not substrates for nonsense
mediated decay. The third splice donor, used in 10% of steady-state e936
messages, is the mutated splice donor at the wild-type position, which defines an
intron beginning with UU. In the presence of a sup-39 mutation, these same three
splice donors are used, but the ratio of messages produced by splicing at these
sites changes. The percentage of unc-73(e936) messages containing the wild-type
splice junction is increased to 33% with a corresponding increase in the level of
UNC-73 protein. This sup-39-induced change was also observed when the e936 mutant
intron region was inserted into a heterologous splicing reporter construct
transfected into worms. Experiments with splicing reporter constructs showed that
the degree of 5' splice site match to the splicing consensus sequence can
strongly influence cryptic splice site choice. We propose that mutant SUP-39 is a
new type of informational suppressor that alters the use of weak splice donors.
PMID- 10757762
TI - Effect of a neuropeptide gene on behavioral states in Caenorhabditis elegans egg
laying.
AB - Egg-laying behavior in the nematode Caenorhabditis elegans involves fluctuation
between alternative behavioral states: an inactive state, during which eggs are
retained in the uterus, and an active state, during which eggs are laid in
bursts. We have found that the flp-1 gene, which encodes a group of structurally
related neuropeptides, functions specifically to promote the switch from the
inactive to the active egg-laying state. Recessive mutations in flp-1 caused a
significant increase in the duration of the inactive phase, yet egg-laying within
the active phase was normal. This pattern resembled that previously observed in
mutants defective in the biosynthesis of serotonin, a neuromodulator implicated
in induction of the active phase. Although flp-1 mutants were sensitive to
stimulation of egg-laying by serotonin, the magnitude of their serotonin response
was abnormally low. Thus, the flp-1-encoded peptides and serotonin function most
likely function in concert to facilitate the onset of the active egg-laying
phase. Interestingly, we observed that flp-1 is necessary for animals to down
regulate their rate of egg-laying in the absence of food. Because flp-1 is known
to be expressed in interneurons that are postsynaptic to a variety of
chemosensory cells, the FLP-1 peptides may function to regulate the activity of
the egg-laying circuitry in response to sensory cues.
PMID- 10757763
TI - Multigeneration maximum-likelihood analysis applied to mutation-accumulation
experiments in Caenorhabditis elegans.
AB - We develop a maximum-likelihood (ML) approach to estimate genomic mutation rates
(U) and average homozygous mutation effects (s) from mutation-accumulation (MA)
experiments in which phenotypic assays are carried out in several generations. We
use simulations to compare the procedure's performance with the method of moments
traditionally used to analyze MA data. Similar precision is obtained if mutation
effects are small relative to the environmental standard deviation, but ML can
give estimates of mutation parameters that have lower sampling variances than
those obtained by the method of moments if mutations with large effects have
accumulated. The inclusion of data from intermediate generations may improve the
precision. We analyze life-history trait data from two Caenorhabditis elegans MA
experiments. Under a model with equal mutation effects, the two experiments
provide similar estimates for U of approximately 0.005 per haploid, averaged over
traits. Estimates of s are more divergent and average at -0.51 and -0.13 in the
two studies. Detailed analysis shows that changes of mean and variance of genetic
values of MA lines in both C. elegans experiments are dominated by mutations with
large effects, but the analysis does not rule out the presence of a large class
of deleterious mutations with very small effects.
PMID- 10757764
TI - The Drosophila ecdysone receptor (EcR) gene is required maternally for normal
oogenesis.
AB - Oogenesis in Drosophila is regulated by the steroid hormone ecdysone and the
sesquiterpenoid juvenile hormone. Response to ecdysone is mediated by a
heteromeric receptor composed of the EcR and USP proteins. We have identified a
temperature-sensitive EcR mutation, EcR(A483T), from a previously isolated
collection of EcR mutations. EcR(A483T) is predicted to affect all EcR protein
products (EcR-A, EcR-B1, and EcR-B2) since it maps to a common exon encoding the
ligand-binding domain. In wild-type females, we find that both EcR-A and EcR-B1
are expressed in nurse cells and follicle cells throughout oogenesis. EcR mutant
females raised at permissive temperature and then shifted to restrictive
temperature exhibit severe reductions in fecundity. Oogenesis in EcR mutant
females is defective, and the spectrum of oogenic defects includes the presence
of abnormal egg chambers and loss of vitellogenic egg stages. Our results
demonstrate a requirement for EcR during female reproduction and suggest that EcR
is required for normal oogenesis.
PMID- 10757765
TI - Adaptive evolution of relish, a Drosophila NF-kappaB/IkappaB protein.
AB - NF-kappaB and IkappaB proteins have central roles in regulation of inflammation
and innate immunity in mammals. Homologues of these proteins also play an
important role in regulation of the Drosophila immune response. Here we present a
molecular population genetic analysis of Relish, a Drosophila NF-kappaB/IkappaB
protein, in Drosophila simulans and D. melanogaster. We find strong evidence for
adaptive protein evolution in D. simulans, but not in D. melanogaster. The
adaptive evolution appears to be restricted to the IkappaB domain. A possible
explanation for these results is that Relish is a site of evolutionary conflict
between flies and their microbial pathogens.
PMID- 10757766
TI - The Drosophila melanogaster ade5 gene encodes a bifunctional enzyme for two steps
in the de novo purine synthesis pathway.
AB - Steps 6 and 7 of de novo purine synthesis are performed by 5-aminoimidazole
ribonucleotide carboxylase (AIRc) and 4-[(N-succinylamino)carbonyl]-5
aminoimidazole ribonucleotide synthetase (SAICARs), respectively. In vertebrates,
a single gene encodes AIRc-SAICARs with domains homologous to Escherichia coli
PurE and PurC. We have isolated an AIRc-SAICARs cDNA from Drosophila melanogaster
via functional complementation with an E. coli purC purine auxotroph. This cDNA
encodes AIRc yet is unable to complement an E. coli purE mutant, suggesting
functional differences between Drosophila and E. coli AIRc. In vertebrates, the
AIRc-SAICARs gene shares a promoter region with the gene encoding
phosphoribosylamidotransferase, which performs the first step in de novo purine
synthesis. In Drosophila, the AIRc-SAICARs gene maps to section 11B4-14 of the X
chromosome, while the phosphoribosylamidotransferase gene (Prat) maps to
chromosome 3; thus, the close linkage of these two genes is not conserved in
flies. Three EMS-induced X-linked adenine auxotrophic mutations, ade4(1),
ade5(1), and ade5(2), were isolated. Two gamma-radiation-induced (ade5(3) and
ade5(4)) and three hybrid dysgenesis-induced (ade5(5), ade5(6), and ade5(8))
alleles were also isolated. Characterization of the auxotrophy and the finding
that the hybrid dysgenesis-induced mutations all harbor P transposon sequences
within the AIRc-SAICARs gene show that ade5 encodes AIRc-SAICARs.
PMID- 10757768
TI - Detecting ancient admixture in humans using sequence polymorphism data.
AB - A debate of long-standing interest in human evolution centers around whether
archaic human populations (such as the Neanderthals) have contributed to the
modern gene pool. A model of ancient population structure with recent mixing is
introduced, and it is determined how much information (i.e., sequence data from
how many unlinked nuclear loci) would be necessary to distinguish between
different demographic scenarios. It is found that approximately 50-100 loci are
necessary if plausible parameter estimates are used. There are not enough data
available at the present to support either the "single origin" or the
"multiregional" model of modern human evolution. However, this information should
be available in a few years.
PMID- 10757767
TI - Both naturally occurring insertions of transposable elements and intermediate
frequency polymorphisms at the achaete-scute complex are associated with
variation in bristle number in Drosophila melanogaster.
AB - A restriction enzyme survey of a 110-kb region including the achaete scute
complex (ASC) examined 14 polymorphic molecular markers in a sample of 56
naturally occurring chromosomes. Large insertions as a class were associated with
a reduction in both sternopleural and abdominal bristle number, supporting
deleterious mutation-selection equilibrium models for the maintenance of
quantitative genetic variation. Two polymorphic sites were independently
associated with variation in bristle number measured in two genetic backgrounds
as assessed by a permutation test. A 6-bp deletion near sc alpha is associated
with sternopleural bristle number variation in both sexes and a 3.4-kb insertion
between sc beta and sc gamma is associated with abdominal bristle number
variation in females. Under an additive genetic model, the small deletion
polymorphism near sc alpha accounts for 25% of the total X chromosome genetic
variation in sternopleural bristle number, and the 3.4 kb insertion accounts for
22% of the total X chromosome variation in female abdominal bristle number. The
observation of common polymorphisms associated with variation in bristle number
is more parsimoniously explained by models that incorporate balancing selection
or assume variants affecting bristle number are neutral, than mutation-selection
equilibrium models.
PMID- 10757769
TI - Use of a small palindrome genetic marker to investigate mechanisms of double
strand-break repair in mammalian cells.
AB - We examined mechanisms of mammalian homologous recombination using a gene
targeting assay in which the vector-borne region of homology to the chromosome
bore small palindrome insertions that frequently escape mismatch repair when
encompassed within heteroduplex DNA (hDNA). Our assay permitted the product(s) of
each independent recombination event to be recovered for molecular analysis. The
results revealed the following: (i) vector-borne double-strand break (DSB)
processing usually did not yield a large double-strand gap (DSG); (ii) in 43% of
the recombinants, the results were consistent with crossover at or near the DSB;
and (iii) in the remaining recombinants, hDNA was an intermediate. The sectored
(mixed) genotypes observed in 38% of the recombinants provided direct evidence
for involvement of hDNA, while indirect evidence was obtained from the patterns
of mismatch repair (MMR). Individual hDNA tracts were either long or short and
asymmetric or symmetric on the one side of the DSB examined. Clonal analysis of
the sectored recombinants revealed how vector-borne and chromosomal markers were
linked in each strand of individual hDNA intermediates. As expected, vector-borne
and chromosomal markers usually resided on opposite strands. However, in one
recombinant, they were linked on the same strand. The results are discussed with
particular reference to the double-strand-break repair (DSBR) model of
recombination.
PMID- 10757771
TI - Recombination of chromosomes 3A(m) and 5A(m) of Triticum monococcum with
homeologous chromosomes 3A and 5A of wheat: the distribution of recombination
across chromosomes.
AB - Recombination of chromosomes 3A(m) and 5A(m) of Triticum monococcum with closely
homeologous chromosomes 3A and 5A of T. aestivum was compared with recombination
across corresponding homologous chromosome pairs. Differentiation between the
homeologues impacted recombination in the proximal regions of the long arms the
most and in the distal regions of the long arms the least. It is concluded that
this variation principally reflects allocation of multiple crossovers across an
arm and positive crossover interference across chromosome arms. Recombination
rates between homeologous chromosomes 5A(m) and 5A differed in the opposite
sexes.
PMID- 10757770
TI - Mutation frequency and specificity with age in liver, bladder and brain of lacI
transgenic mice.
AB - Mutation frequency and specificity were determined as a function of age in
nuclear DNA from liver, bladder, and brain of Big Blue lacI transgenic mice aged
1.5-25 months. Mutations accumulated with age in liver and accumulated more
rapidly in bladder. In the brain a small initial increase in mutation frequency
was observed in young animals; however, no further increase was observed in adult
mice. To investigate the origin of mutations, the mutational spectra for each
tissue and age were determined. DNA sequence analysis of mutant lacI transgenes
revealed no significant changes in mutational specificity in any tissue at any
age. The spectra of mutations found in aging animals were identical to those in
younger animals, suggesting that they originated from a common set of DNA lesions
manifested during DNA replication. The data also indicated that there were no
significant age-related mutational changes due to oxidative damage, or errors
resulting from either changes in the fidelity of DNA polymerase or the efficiency
of DNA repair. Hence, no evidence was found to support hypotheses that predict
that oxidative damage or accumulation of errors in nuclear DNA contributes
significantly to the aging process, at least in these three somatic tissues.
PMID- 10757772
TI - Effects of colonization processes on genetic diversity: differences between
annual plants and tree species.
AB - Tree species are striking for their high within-population diversity and low
among-population differentiation for nuclear genes. In contrast, annual plants
show much more differentiation for nuclear genes but much less diversity than
trees. The usual explanation for this difference is that pollen flow, and
therefore gene flow, is much higher for trees. This explanation is problematic
because it relies on equilibrium hypotheses. Because trees have very recently
recolonized temperate areas, they have experienced many foundation events, which
usually reduce within-population diversity and increase differentiation. Only
extremely high levels of gene flow could counterbalance these successive founder
effects. We develop a model to study the impact of life cycle of forest trees, in
particular of the length of their juvenile phase, on genetic diversity and
differentiation during the glacial period and the following colonization period.
We show that both a reasonably high level of pollen flow and the life-cycle
characteristics of trees are needed to explain the observed structure of genetic
diversity. We also show that gene flow and life cycle both have an impact on
maternally inherited cytoplasmic genes, which are characterized both in trees and
annual species by much less diversity and much more differentiation than nuclear
genes.
PMID- 10757773
TI - Segregation distortion of T-DNA markers linked to the self-incompatibility (S)
locus in Petunia hybrida.
AB - In plants with a gametophytic self-incompatibility system the specificity of the
pollen is determined by the haploid genotype at the self-incompatibility (S)
locus. In certain crosses this can lead to the exclusion of half the gametes from
the male parent carrying a particular S-allele. This leads to pronounced
segregation distortion for any genetic markers that are linked to the S-locus. We
have used this approach to identify T-DNA insertions carrying a maize
transposable element that are linked to the S-locus of Petunia hybrida. A total
of 83 T-DNA insertions were tested for segregation distortion of the selectable
marker used during transformation with Agrobacterium. Segregation distortion was
observed for 12 T-DNA insertions and at least 8 of these were shown to be in the
same linkage group by intercrossing. This indicates that differential
transmission of a single locus (S) is probably responsible for all of these
examples of T-DNA segregation distortion. The identification of selectable
markers in coupling with a functional S-allele will allow the preselection of
recombination events around the S-locus in petunia. Our approach provides a
general method for identifying transgenes that are linked to gametophytic self
incompatibility loci and provides an opportunity for transposon tagging of the
petunia S-locus.
PMID- 10757774
TI - Genetics of mutations affecting the development of a barley floral bract.
AB - Two groups of mutants that affect the morphology of the lemma, a floral bract of
barley, are described. The first comprises phenotypes associated with mutant
alleles of calcaroides loci. On the lemma of these mutants, a well-organized
neomorphic structure is formed, termed the sac. We provide a morphological
description of wild-type (WT) and mutant lemmas, based on scanning electron
microscopy (SEM), showing that both consist of similar tissues, but that the
mutant is characterized by reversed growth polarity. The sac is a unique
structure among grasses, and it is remarkable that recessive mutations at five
different genetic loci lead to the same organ. The second group of mutants carry
recessive alleles of two leafy lemma genes, both of which are necessary to cause
the transformation of the lemma into a structure having all characteristics of a
vegetative leaf, as shown by SEM analysis. The presence of sheath, blade, and
ligule in the mutant lemma suggests that wild-type lemma development is
interrupted at a leaf-like stage. The genes cal a, b, C, d, 23, lel1, and lel2
have now been mapped at precise positions on linkage groups 2, 7, 7, 3, 7, 5, and
7, respectively. The mutants considered in this article are unaffected in other
floral organs. A model for lemma development is suggested.
PMID- 10757775
TI - Symbiont survival and host-symbiont disequilibria under differential vertical
transmission.
AB - Interspecific genetic interactions in host-symbiont systems raise intriguing
coevolutionary questions and may influence the effectiveness of public health and
management policies. Here we present an analytical and numerical investigation of
the effects of host genetic heterogeneity in the rate of vertical transmission of
a symbiont. We consider the baseline case with a monomorphic symbiont and a
single diallelic locus in its diploid host, where vertical transmission is the
sole force. Our analysis introduces interspecific disequilibria to quantify
nonrandom associations between host genotypes and alleles and symbiont
presence/absence. The transient and equilibrium behavior is examined in
simulations with randomly generated initial conditions and transmission
parameters. Compared to the case where vertical transmission rates are uniform
across host genotypes, differential transmission (i) increases average symbiont
survival from 50% to almost 60%, (ii) dramatically reduces the minimum average
transmission rate for symbiont survival from 0.5 to 0.008, and (iii) readily
creates permanent host-symbiont disequilibria de novo, whereas uniform
transmission can neither create nor maintain such associations. On average,
heterozygotes are slightly more likely to carry and maintain the symbiont in the
population and are more randomly associated with the symbiont. Results show that
simple evolutionary forces can create substantial nonrandom associations between
two species.
PMID- 10757776
TI - Balancing selection at closely linked, overdominant loci in a finite population.
AB - High levels of allelic diversity and strong linkage disequilibrium are found in
the major histocompatibility (MHC) system in humans and other vertebrates. This
article proposes several descriptive statistics that quantify the extent and
pattern of strong linkage disequilibrium between pairs of highly polymorphic
loci. It also develops an approximate analytic theory incorporating the effects
of balancing selection, mutation, recombination, and genetic drift at two closely
linked loci and compares the theoretical predictions with published surveys of
the MHC class II loci, DQA1 and DQB1, in humans and nonhuman primates. The
descriptive statistics proposed include the fraction of complementary haplotypes
(haplotypes with D' = 1), the fraction of excess haplotypes, and the numbers of
alleles at each locus in complementary haplotypes with one or more alleles at the
other locus. The model assumes the infinite alleles model of mutation and the
symmetric overdominance model of selection. Analytic approximations in some cases
are obtained in the strong selection, weak mutation (SSWM) limit introduced by J.
Gillespie. The predictions of the approximate analysis are confirmed by
simulation. Both the analytic theory and simulations show that relatively few
haplotypes will be found when selection is strong and recombination is weak
relative to genetic drift. The model can reproduce many of the observed patterns
at DQA1 and DQB1 provided that the recombination rate is assumed to be very
small.
PMID- 10757777
TI - The degeneration of asexual haploid populations and the speed of Muller's
ratchet.
AB - The accumulation of deleterious mutations due to the process known as Muller's
ratchet can lead to the degeneration of nonrecombining populations. We present an
analytical approximation for the rate at which this process is expected to occur
in a haploid population. The approximation is based on a diffusion equation and
is valid when N exp(-u/s) >> 1, where N is the population size, u is the rate at
which deleterious mutations occur, and s is the effect of each mutation on
fitness. Simulation results are presented to show that the approximation
estimates the rate of the process better than previous approximations for values
of mutation rates and selection coefficients that are compatible with the
biological data. Under certain conditions, the ratchet can turn at a biologically
significant rate when the deterministic equilibrium number of individuals free of
mutations is substantially >100. The relevance of this process for the
degeneration of Y or neo-Y chromosomes is discussed.
PMID- 10757778
TI - The role of population size, pleiotropy and fitness effects of mutations in the
evolution of overlapping gene functions.
AB - Sheltered from deleterious mutations, genes with overlapping or partially
redundant functions may be important sources of novel gene functions. While most
partially redundant genes originated in gene duplications, it is much less clear
why genes with overlapping functions have been retained, in some cases for
hundreds of millions of years. A case in point is the many partially redundant
genes in vertebrates, the result of ancient gene duplications in primitive
chordates. Their persistence and ubiquity become surprising when it is considered
that duplicate and original genes often diversify very rapidly, especially if the
action of natural selection is involved. Are overlapping gene functions perhaps
maintained because of their protective role against otherwise deleterious
mutations? There are two principal objections against this hypothesis, which are
the main subject of this article. First, because overlapping gene functions are
maintained in populations by a slow process of "second order" selection,
population sizes need to be very high for this process to be effective. It is
shown that even in small populations, pleiotropic mutations that affect more than
one of a gene's functions simultaneously can slow the mutational decay of
functional overlap after a gene duplication by orders of magnitude. Furthermore,
brief and transient increases in population size may be sufficient to maintain
functional overlap. The second objection regards the fact that most naturally
occurring mutations may have much weaker fitness effects than the rather drastic
"knock-out" mutations that lead to detection of partially redundant functions.
Given weak fitness effects of most mutations, is selection for the buffering
effect of functional overlap strong enough to compensate for the diversifying
force exerted by mutations? It is shown that the extent of functional overlap
maintained in a population is not only independent of the mutation rate, but also
independent of the average fitness effects of mutation. These results are
discussed with respect to experimental evidence on redundant genes in organismal
development.
PMID- 10757779
TI - Understanding the overdispersed molecular clock.
AB - Rates of molecular evolution at some protein-encoding loci are more irregular
than expected under a simple neutral model of molecular evolution. This pattern
of excessive irregularity in protein substitutions is often called the
"overdispersed molecular clock" and is characterized by an index of dispersion,
R(T) > 1. Assuming infinite sites, no recombination model of the gene R(T) is
given for a general stationary model of molecular evolution. R(T) is shown to be
affected by only three things: fluctuations that occur on a very slow time scale,
advantageous or deleterious mutations, and interactions between mutations. In the
absence of interactions, advantageous mutations are shown to lower R(T);
deleterious mutations are shown to raise it. Previously described models for the
overdispersed molecular clock are analyzed in terms of this work as are a few
very simple new models. A model of deleterious mutations is shown to be
sufficient to explain the observed values of R(T). Our current best estimates of
R(T) suggest that either most mutations are deleterious or some key population
parameter changes on a very slow time scale. No other interpretations seem
plausible. Finally, a comment is made on how R(T) might be used to distinguish
selective sweeps from background selection.
PMID- 10757780
TI - The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist
ligand for the nuclear receptor CAR.
AB - A wide range of xenobiotic compounds are metabolized by cytochrome P450 (CYP)
enzymes, and the genes that encode these enzymes are often induced in the
presence of such compounds. Here, we show that the nuclear receptor CAR can
recognize response elements present in the promoters of xenobiotic-responsive CYP
genes, as well as other novel sites. CAR has previously been shown to be an
apparently constitutive transactivator, and this constitutive activity is
inhibited by androstanes acting as inverse agonists. As expected, the ability of
CAR to transactivate the CYP promoter elements is blocked by the inhibitory
inverse agonists. However, CAR transactivation is increased in the presence of
1,4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP), the most potent known
member of the phenobarbital-like class of CYP-inducing agents. Three independent
lines of evidence demonstrate that TCPOBOP is an agonist ligand for CAR. The
first is that TCPOBOP acts in a dose-dependent manner as a direct agonist to
compete with the inhibitory effect of the inverse agonists. The second is that
TCPOBOP acts directly to stimulate coactivator interaction with the CAR ligand
binding domain, both in vitro and in vivo. The third is that mutations designed
to block ligand binding block not only the inhibitory effect of the androstanes
but also the stimulatory effect of TCPOBOP. Importantly, these mutations do not
block the apparently constitutive transactivation by CAR, suggesting that this
activity is truly ligand independent. Both its ability to target CYP genes and
its activation by TCPOBOP demonstrate that CAR is a novel xenobiotic receptor
that may contribute to the metabolic response to such compounds.
PMID- 10757781
TI - Negative and translation termination-dependent positive control of FLI-1 protein
synthesis by conserved overlapping 5' upstream open reading frames in Fli-1 mRNA.
AB - The proto-oncogene Fli-1 encodes a transcription factor of the ets family whose
overexpression is associated with multiple virally induced leukemias in mouse,
inhibits murine and avian erythroid cell differentiation, and induces drastic
perturbations of early development in Xenopus. This study demonstrates the
surprisingly sophisticated regulation of Fli-1 mRNA translation. We establish
that two FLI-1 protein isoforms (of 51 and 48 kDa) detected by Western blotting
in vivo are synthesized by alternative translation initiation through the use of
two highly conserved in-frame initiation codons, AUG +1 and AUG +100.
Furthermore, we show that the synthesis of these two FLI-1 isoforms is regulated
by two short overlapping 5' upstream open reading frames (uORF) beginning at two
highly conserved upstream initiation codons, AUG -41 and GUG -37, and terminating
at two highly conserved stop codons, UGA +35 and UAA +15. The mutational analysis
of these two 5' uORF revealed that each of them negatively regulates FLI-1
protein synthesis by precluding cap-dependent scanning to the 48- and 51-kDa AUG
codons. Simultaneously, the translation termination of the two 5' uORF appears to
enhance 48-kDa protein synthesis, by allowing downstream reinitiation at the 48
kDa AUG codon, and 51-kDa protein synthesis, by allowing scanning ribosomes to
pile up and consequently allowing upstream initiation at the 51-kDa AUG codon. To
our knowledge, this is the first example of a cellular mRNA displaying
overlapping 5' uORF whose translation termination appears to be involved in the
positive control of translation initiation at both downstream and upstream
initiation codons.
PMID- 10757782
TI - Domains in the SPT5 protein that modulate its transcriptional regulatory
properties.
AB - SPT5 and its binding partner SPT4 regulate transcriptional elongation by RNA
polymerase II. SPT4 and SPT5 are involved in both 5,6-dichloro-1-beta-D
ribofuranosylbenzimidazole (DRB)-mediated transcriptional inhibition and the
activation of transcriptional elongation by the human immunodeficiency virus type
1 (HIV-1) Tat protein. Recent data suggest that P-TEFb, which is composed of CDK9
and cyclin T1, is also critical in regulating transcriptional elongation by SPT4
and SPT5. In this study, we analyze the domains of SPT5 that regulate
transcriptional elongation in the presence of either DRB or the HIV-1 Tat
protein. We demonstrate that SPT5 domains that bind SPT4 and RNA polymerase II,
in addition to a region in the C terminus of SPT5 that contains multiple heptad
repeats and is designated CTR1, are critical for in vitro transcriptional
repression by DRB and activation by the Tat protein. Furthermore, the SPT5 CTR1
domain is a substrate for P-TEFb phosphorylation. These results suggest that C
terminal repeats in SPT5, like those in the RNA polymerase II C-terminal domain,
are sites for P-TEFb phosphorylation and function in modulating its
transcriptional elongation properties.
PMID- 10757784
TI - Ku recruits the XRCC4-ligase IV complex to DNA ends.
AB - Genetic experiments have determined that Ku, XRCC4, and ligase IV are required
for repair of double-strand breaks by the end-joining pathway. The last two
factors form a tight complex in cells. However, ligase IV is only one of three
known mammalian ligases and is intrinsically the least active in intermolecular
ligation; thus, the biochemical basis for requiring this ligase has been unclear.
We demonstrate here a direct physical interaction between the XRCC4-ligase IV
complex and Ku. This interaction is stimulated once Ku binds to DNA ends. Since
XRCC4-ligase IV alone has very low DNA binding activity, Ku is required for
effective recruitment of this ligase to DNA ends. We further show that this
recruitment is critical for efficient end-joining activity in vitro. Preformation
of a complex containing Ku and XRCC4-ligase IV increases the initial ligation
rate 20-fold, indicating that recruitment of the ligase is an important limiting
step in intermolecular ligation. Recruitment by Ku also allows XRCC4-ligase IV to
use Ku's high affinity for DNA ends to rapidly locate and ligate ends in an
excess of unbroken DNA, a necessity for end joining in cells. These properties
are conferred only on ligase IV, because Ku does not similarly interact with the
other mammalian ligases. We have therefore defined cell-free conditions that
reflect the genetic requirement for ligase IV in cellular end joining and
consequently can explain in molecular terms why this factor is required.
PMID- 10757783
TI - A novel cold-sensitive allele of the rate-limiting enzyme of fatty acid
synthesis, acetyl coenzyme A carboxylase, affects the morphology of the yeast
vacuole through acylation of Vac8p.
AB - The yeast vacuole functions both as a degradative organelle and as a storage
depot for small molecules and ions. Vacuoles are dynamic reticular structures
that appear to alternately fuse and fragment as a function of growth stage and
environment. Vac8p, an armadillo repeat-containing protein, has previously been
shown to function both in vacuolar inheritance and in protein targeting from the
cytoplasm to the vacuole. Both myristoylation and palmitoylation of Vac8p are
required for its efficient localization to the vacuolar membrane (Y.-X. Wang, N.
L. Catlett, and L. S. Weisman, J. Cell Biol. 140:1063-1074, 1998). We report that
mutants with conditional defects in the rate-limiting enzyme of fatty acid
synthesis, acetyl coenzyme A carboxylase (ACC1), display unusually multilobed
vacuoles, similar to those observed in vac8 mutant cells. This vacuolar phenotype
of acc1 mutant cells was shown biochemically to be accompanied by a reduced
acylation of Vac8p which was alleviated by fatty acid supplementation. Consistent
with the proposed defect of acc1 mutant cells in acylation of Vac8p, vacuolar
membrane localization of Vac8p was impaired upon shifting acc1 mutant cells to
nonpermissive condition. The function of Vac8p in protein targeting, on the other
hand, was not affected under these conditions. These observations link fatty acid
synthesis and availability to direct morphological alterations of an organellar
membrane.
PMID- 10757785
TI - Cyclic AMP signaling functions as a bimodal switch in sympathoadrenal cell
development in cultured primary neural crest cells.
AB - Cells of the vertebrate neural crest (crest cells) are an invaluable model system
to address cell fate specification. Crest cells are amenable to tissue culture,
and they differentiate to a variety of neuronal and nonneuronal cell types.
Earlier studies have determined that bone morphogenetic proteins (BMP-2, -4, and
7) and agents that elevate intracellular cyclic AMP (cAMP) stimulate the
development of the sympathoadrenal (SA, adrenergic) lineage in neural crest
cultures. To investigate whether interactive mechanisms between signaling
pathways influence crest cell differentiation, we characterized the combinatorial
effects of BMP-2 and cAMP-elevating agents on the development of quail trunk
neural crest cells in primary culture. We report that the cAMP signaling pathway
modulates both positive and negative signals influencing the development of SA
cells. Specifically, we show that moderate activation of cAMP signaling promotes,
in synergy with BMP-2, SA cell development and the expression of the SA lineage
determining gene Phox2a. By contrast, robust activation of cAMP signaling
opposes, even in the presence of BMP-2, SA cell development and the expression of
the SA lineage-determining ASH-1 and Phox2 genes. We conclude that cAMP signaling
acts as a bimodal regulator of SA cell development in neural crest cultures.
PMID- 10757786
TI - TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila
development.
AB - Transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1) is a member
of the MAPKKK superfamily and has been characterized as a component of the TGF
beta/bone morphogenetic protein signaling pathway. TAK1 function has been
extensively studied in cultured cells, but its in vivo function is not fully
understood. In this study, we isolated a Drosophila homolog of TAK1 (dTAK1) which
contains an extensively conserved NH(2)-terminal kinase domain and a partially
conserved COOH-terminal domain. To learn about possible endogenous roles of TAK1
during animal development, we generated transgenic flies which express dTAK1 or
the mouse TAK1 (mTAK1) gene in the fly visual system. Ectopic activation of TAK1
signaling leads to a small eye phenotype, and genetic analysis reveals that this
phenotype is a result of ectopically induced apoptosis. Genetic and biochemical
analyses also indicate that the c-Jun amino-terminal kinase (JNK) signaling
pathway is specifically activated by TAK1 signaling. Expression of a dominant
negative form of dTAK during embryonic development resulted in various embryonic
cuticle defects including dorsal open phenotypes. Our results strongly suggest
that in Drosophila melanogaster, TAK1 functions as a MAPKKK in the JNK signaling
pathway and participates in such diverse roles as control of cell shape and
regulation of apoptosis.
PMID- 10757787
TI - A role for the Hsp40 Ydj1 in repression of basal steroid receptor activity in
yeast.
AB - In addition to its roles in translocation of preproteins across membranes, Ydj1
facilitates the maturation of Hsp90 substrates, including mammalian steroid
receptors, which activate transcription in yeast in a hormone-dependent manner.
To better understand Ydj1's function, we have constructed and analyzed an array
of Ydj1 mutants in vivo. Both the glucocorticoid receptor and the estrogen
receptor exhibited elevated activity in the absence of hormone in all ydj1 mutant
strains, indicating a strict requirement for Ydj1 activity in hormonal control.
Glucocorticoid receptor containing a mutation in the carboxy-terminal
transcriptional activation domain, AF-2, retained elevated basal activity, while
mutation of the amino-terminal transactivation domain, AF-1, eliminated the
elevated basal activity observed in ydj1 mutant strains. This result indicates
that the source of activity is AF-1, which is normally repressed by the carboxy
terminal hormone binding domain in the absence of hormone. Chimeric proteins
containing the hormone binding domain of the estrogen or glucocorticoid receptor
fused to heterologous activation and DNA binding domains also exhibited elevated
activity in the absence of hormone. Thus, Ydj1 mutants appear to increase basal
receptor activity by altering the ability of the hormone binding domain of the
receptor to repress nearby activation domains. We propose that Ydj1 functions to
present steroid receptors to the Hsp90 pathway for folding and hormonal control.
In the presence of Ydj1 mutants that fail to bind substrate efficiently, some
receptor escapes the Hsp90 pathway, resulting in constitutive activity.
PMID- 10757788
TI - In vitro assembly of human H/ACA small nucleolar RNPs reveals unique features of
U17 and telomerase RNAs.
AB - The H/ACA small nucleolar RNAs (snoRNAs) are involved in pseudouridylation of pre
rRNAs. They usually fold into a two-domain hairpin-hinge-hairpin-tail structure,
with the conserved motifs H and ACA located in the hinge and tail, respectively.
Synthetic RNA transcripts and extracts from HeLa cells were used to reconstitute
human U17 and other H/ACA ribonucleoproteins (RNPs) in vitro. Competition and UV
cross-linking experiments showed that proteins of about 60, 29, 23, and 14 kDa
interact specifically with U17 RNA. Except for U17, RNPs could be reconstituted
only with full-length H/ACA snoRNAs. For U17, the 3'-terminal stem-loop followed
by box ACA (U17/3'st) was sufficient to form an RNP, and U17/3'st could compete
other full-length H/ACA snoRNAs for assembly. The H/ACA-like domain that
constitutes the 3' moiety of human telomerase RNA (hTR), and its 3'-terminal stem
loop (hTR/3'st), also could form an RNP by binding H/ACA proteins. Hence, the 3'
terminal stem-loops of U17 and hTR have some specific features that distinguish
them from other H/ACA RNAs. Antibodies that specifically recognize the human GAR1
(hGAR1) protein could immunoprecipitate H/ACA snoRNAs and hTR from HeLa cell
extracts, which demonstrates that hGAR1 is a component of H/ACA snoRNPs and
telomerase in vivo. Moreover, we show that in vitro-reconstituted RNPs contain
hGAR1 and that binding of hGAR1 does not appear to be a prerequisite for the
assembly of the other H/ACA proteins.
PMID- 10757789
TI - Identification and characterization of a novel serine-arginine-rich splicing
regulatory protein.
AB - We have identified an 86-kDa protein containing a single amino-terminal RNA
recognition motif and two carboxy-terminal domains rich in serine-arginine (SR)
dipeptides. Despite structural similarity to members of the SR protein family,
p86 is clearly unique. It is not found in standard SR protein preparations, does
not precipitate in the presence of high magnesium concentrations, is not
recognized by antibodies specific for SR proteins, and cannot complement splicing
defective S100 extracts. However, we have found that p86 can inhibit the ability
of purified SR proteins to activate splicing in S100 extracts and can even
inhibit the in vitro and in vivo activation of specific splice sites by a subset
of SR proteins, including ASF/SF2, SC35, and SRp55. In contrast, p86 activates
splicing in the presence of SRp20. Thus, it appears that pairwise combination of
p86 with specific SR proteins leads to altered splicing efficiency and
differential splice site selection. In all cases, such regulation requires the
presence of the two RS domains and a unique intervening EK-rich region, which
appear to mediate direct protein-protein contact between these family members.
Full-length p86, but not a mutant lacking the RS-EK-RS domains, was found to
preferentially interact with itself, SRp20, ASF/SF2, SRp55, and, to a slightly
lesser extent, SC35. Because of the primary sequence and unique properties of
p86, we have named this protein SRrp86 for SR-related protein of 86 kDa.
PMID- 10757790
TI - SWI-SNF-mediated nucleosome remodeling: role of histone octamer mobility in the
persistence of the remodeled state.
AB - SWI-SNF is an ATP-dependent chromatin remodeling complex that disrupts DNA
histone interactions. Several studies of SWI-SNF activity on mononucleosome
substrates have suggested that remodeling leads to novel, accessible nucleosomes
which persist in the absence of continuous ATP hydrolysis. In contrast, we have
reported that SWI-SNF-dependent remodeling of nucleosomal arrays is rapidly
reversed after removal of ATP. One possibility is that these contrasting results
are due to the different assays used; alternatively, the lability of the SWI-SNF
remodeled state might be different on mononucleosomes versus nucleosomal arrays.
To investigate these possibilities, we use a coupled SWI-SNF remodeling
restriction enzyme assay to directly compare the remodeling of mononucleosome and
nucleosomal array substrates. We find that SWI-SNF action causes a mobilization
of histone octamers for both the mononucleosome and nucleosomal array substrates,
and these changes in nucleosome positioning persist in the absence of continued
ATP hydrolysis or SWI-SNF binding. In the case of mononucleosomes, the histone
octamers accumulate at the DNA ends even in the presence of continued ATP
hydrolysis. On nucleosomal arrays, SWI-SNF and ATP lead to a more dynamic state
where nucleosomes appear to be constantly redistributed and restriction enzyme
sites throughout the array have increased accessibility. This random positioning
of nucleosomes within the array persists after removal of ATP, but inactivation
of SWI-SNF is accompanied by an increased occlusion of many restriction enzyme
sites. Our results also indicate that remodeling of mononucleosomes or
nucleosomal arrays does not lead to an accumulation of novel nucleosomes that
maintain an accessible state in the absence of continuous ATP hydrolysis.
PMID- 10757792
TI - Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase
pathway by the raf kinase inhibitor protein.
AB - We have recently identified the Raf kinase inhibitor protein (RKIP) as a
physiological endogenous inhibitor of the Raf-1/MEK/extracellular signal
regulated kinase (ERK) pathway. RKIP interfered with MEK phosphorylation and
activation by Raf-1, resulting in the suppression of both Raf-1-induced
transformation and AP-1-dependent transcription. Here we report the molecular
mechanism of RKIP's inhibitory function. RKIP can form ternary complexes with Raf
1, MEK, and ERK. However, whereas MEK and ERK can simultaneously associate with
RKIP, Raf-1 binding to RKIP and that of MEK are mutually exclusive. RKIP is able
to dissociate a Raf-1-MEK complex and behaves as a competitive inhibitor of MEK
phosphorylation. Mapping of the binding domains showed that MEK and Raf-1 bind to
overlapping sites in RKIP, whereas MEK and RKIP associate with different domains
in Raf-1, and Raf-1 and RKIP bind to different sites in MEK. Both the Raf-1 and
the MEK binding sites in RKIP need to be destroyed in order to relieve RKIP
mediated suppression of the Raf-1/MEK/ERK pathway, indicating that binding of
either Raf-1 or MEK is sufficient for inhibition. The properties of RKIP reveal
the specific sequestration of interacting components as a novel motif in the
cell's repertoire for the regulation of signaling pathways.
PMID- 10757791
TI - A Drosophila ESC-E(Z) protein complex is distinct from other polycomb group
complexes and contains covalently modified ESC.
AB - The extra sex combs (ESC) and Enhancer of zeste [E(Z)] proteins, members of the
Polycomb group (PcG) of transcriptional repressors, interact directly and are
coassociated in fly embryos. We report that these two proteins are components of
a 600-kDa complex in embryos. Using gel filtration and affinity chromatography,
we show that this complex is biochemically distinct from previously described
complexes containing the PcG proteins Polyhomeotic, Polycomb, and Sex comb on
midleg. In addition, we present evidence that ESC is phosphorylated in vivo and
that this modified ESC is preferentially associated in the complex with E(Z).
Modified ESC accumulates between 2 and 6 h of embryogenesis, which is the
developmental time when esc function is first required. We find that mutations in
E(z) reduce the ratio of modified to unmodified ESC in vivo. We have also
generated germ line transformants that express ESC proteins bearing site-directed
mutations that disrupt ESC-E(Z) binding in vitro. These mutant ESC proteins fail
to provide esc function, show reduced levels of modification in vivo, and are
still assembled into complexes. Taken together, these results suggest that ESC
phosphorylation normally occurs after assembly into ESC-E(Z) complexes and that
it contributes to the function or regulation of these complexes. We discuss how
biochemically separable ESC-E(Z) and PC-PH complexes might work together to
provide PcG repression.
PMID- 10757793
TI - Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at
replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p
Dbf4p kinase.
AB - In Saccharomyces cerevisiae, replication origins are activated with
characteristic timing during S phase. S-phase cyclin-dependent kinases (S-CDKs)
and Cdc7p-Dbf4p kinase are required for origin activation throughout S phase. The
activation of S-CDKs leads to association of Cdc45p with chromatin, raising the
possibility that Cdc45p defines the assembly of a new complex at each origin.
Here we show that both Cdc45p and replication protein A (RPA) bind to Mcm2p at
the G(1)-S transition in an S-CDK-dependent manner. During S phase, Cdc45p
associates with different replication origins at specific times. The origin
associations of Cdc45p and RPA are mutually dependent, and both S-CDKs and Cdc7p
Dbf4p are required for efficient binding of Cdc45p to origins. These findings
suggest that S-CDKs and Cdc7p-Dbf4p promote loading of Cdc45p and RPA onto a
preformed prereplication complex at each origin with preprogrammed timing. The
ARS1 association of Mcm2p, but not that of the origin recognition complex, is
diminished by disruption of the B2 element of ARS1, a potential origin DNA
unwinding element. Cdc45p is required for recruiting DNA polymerase alpha onto
chromatin, and it associates with Mcm2p, RPA, and DNA polymerase epsilon only
during S phase. These results suggest that the complex containing Cdc45p, RPA,
and MCMs is involved in origin unwinding and assembly of replication forks at
each origin.
PMID- 10757794
TI - Deletion of the murine Duffy gene (Dfy) reveals that the Duffy receptor is
functionally redundant.
AB - All of the antigenic determinants of the Duffy blood group system are in a
glycoprotein (gp-Fy), which is encoded by a single-copy gene (FY) located on
chromosome 1. gp-Fy is also produced in several cell types, including endothelial
cells of capillary and postcapillary venules, the epithelial cell of kidney
collecting ducts, lung alveoli, and the Purkinje cells of the cerebellum. This
protein, which spans the cell membrane seven times, is a member of the
superfamily of chemokine receptors and a malarial parasite receptor. The mouse
Duffy gene (Dfy) homolog of human FY is also a single-copy gene, which maps in a
region of conserved synteny with FY and produces a glycoprotein with 60% homology
to the human protein. The mouse Duffy-like protein also binds chemokines. To
study the biological role of gp-Fy, we generated a mouse strain in which Dfy was
deleted. These homozygous Dfy(-/-) mice were indistinguishable in size,
development, and health from wild-type and heterozygous littermates. We also
examined components of the immune system and found no differences in lymph nodes
or peripheral blood leukocyte levels between knockout and wild-type mice. The
gross and histological anatomy of the thymus, spleen, lung, and brain showed no
significant differences between mutants and wild-type mice. There was no
indication of an overall difference between the knockout and wild-type mice in
systematic neurological examinations. The only significant difference between
Dfy(-/-) and Dfy(+/+) mice that we found was in neutrophil migration in
peritoneal inflammations induced by lipopolysaccharide and thioglycolate. In mice
homozygous for the deletion, there was less neutrophil recruitment into the
peritoneal cavity and neutrophil influx in the intestines and lungs than in wild
type mice. Despite this, the susceptibility to Staphylococcus aureus infection
was the same in the absence and in the presence of gp-Fy. Our results indicate
that gp-Fy is functionally a redundant protein that may participate in the
neutrophil migratory process.
PMID- 10757795
TI - The opposing transcriptional activities of the two isoforms of the human
progesterone receptor are due to differential cofactor binding.
AB - The human progesterone receptor (PR) exists as two functionally distinct
isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most
cell and promoter contexts, while hPRA is transcriptionally inactive and
functions as a strong ligand-dependent transdominant repressor of steroid hormone
receptor transcriptional activity. Although the precise mechanism of hPRA
mediated transrepression is not fully understood, an inhibitory domain (ID)
within human PR, which is necessary for transrepression by hPRA, has been
identified. Interestingly, although ID is present within both hPR isoforms, it is
functionally active only in the context of hPRA, suggesting that the two
receptors adopt distinct conformations within the cell which allow hPRA to
interact with a set of cofactors that are different from those recognized by
hPRB. In support of this hypothesis, we identified, using phage display
technology, hPRA-selective peptides which differentially modulate hPRA and hPRB
transcriptional activity. Furthermore, using a combination of in vitro and in
vivo methodologies, we demonstrate that the two receptors exhibit different
cofactor interactions. Specifically, it was determined that hPRA has a higher
affinity for the corepressor SMRT than hPRB and that this interaction is
facilitated by ID. Interestingly, inhibition of SMRT activity, by either a
dominant negative mutant (C'SMRT) or histone deacetylase inhibitors, reverses
hPRA-mediated transrepression but does not convert hPRA to a transcriptional
activator. Together, these data indicate that the ability of hPRA to transrepress
steroid hormone receptor transcriptional activity and its inability to activate
progesterone-responsive promoters occur by distinct mechanisms. To this effect,
we observed that hPRA, unlike hPRB, was unable to efficiently recruit the
transcriptional coactivators GRIP1 and SRC-1 upon agonist binding. Thus, although
both receptors contain sequences within their ligand-binding domains known to be
required for coactivator binding, the ability of PR to interact with cofactors in
a productive manner is regulated by sequences contained within the amino terminus
of the receptors. We propose, therefore, that hPRA is transcriptionally inactive
due to its inability to efficiently recruit coactivators. Furthermore, our
experiments indicate that hPRA interacts efficiently with the corepressor SMRT
and that this activity permits it to function as a transdominant repressor.
PMID- 10757796
TI - Suppression of nonsense mutations in cell culture and mice by multimerized
suppressor tRNA genes.
AB - We demonstrate here the first experimental suppression of a premature termination
codon in vivo by using an ochre suppressor tRNA acting in an intact mouse.
Multicopy tRNA expression plasmids were directly injected into skeletal muscle
and into the hearts of transgenic mice carrying a reporter gene with an ochre
mutation. A strategy for modulation of suppressor efficiency, applicable to
diverse systems and based on tandem multimerization of the tRNA gene, is
developed. The product of suppression (chloramphenicol acetyltransferase)
accumulates linearly with increases in suppressor tRNA concentration to the point
where the ochre-suppressing tRNA(Ser) is in four- to fivefold excess over the
endogenous tRNA(Ser). The subsequent suppressor activity plateau seems to be
attributable to accumulation of unmodified tRNAs. These results define many
salient variables for suppression in vivo, for example, for tRNA suppression
employed as gene therapy for nonsense defects.
PMID- 10757797
TI - Biochemical and genetic analysis of the mitochondrial response of yeast to BAX
and BCL-X(L).
AB - The BCL-2 family includes both proapoptotic (e.g., BAX and BAK) and antiapoptotic
(e.g., BCL-2 and BCL-X(L)) molecules. The cell death-regulating activity of BCL-2
members appears to depend on their ability to modulate mitochondrial function,
which may include regulation of the mitochondrial permeability transition pore
(PTP). We examined the function of BAX and BCL-X(L) using genetic and biochemical
approaches in budding yeast because studies with yeast suggest that BCL-2 family
members act upon highly conserved mitochondrial components. In this study we
found that in wild-type yeast, BAX induced hyperpolarization of mitochondria,
production of reactive oxygen species, growth arrest, and cell death; however,
cytochrome c was not released detectably despite the induction of mitochondrial
dysfunction. Coexpression of BCL-X(L) prevented all BAX-mediated responses. We
also assessed the function of BCL-X(L) and BAX in the same strain of
Saccharomyces cerevisiae with deletions of selected mitochondrial proteins that
have been implicated in the function of BCL-2 family members. BAX-induced growth
arrest was independent of the tested mitochondrial components, including voltage
dependent anion channel (VDAC), the catalytic beta subunit or the delta subunit
of the F(0)F(1)-ATP synthase, mitochondrial cyclophilin, cytochrome c, and
proteins encoded by the mitochondrial genome as revealed by [rho(0)] cells. In
contrast, actual cell killing was dependent upon select mitochondrial components
including the beta subunit of ATP synthase and mitochondrial genome-encoded
proteins but not VDAC. The BCL-X(L) protection from either BAX-induced growth
arrest or cell killing proved to be independent of mitochondrial components.
Thus, BAX induces two cellular processes in yeast which can each be abrogated by
BCL-X(L): cell arrest, which does not require aspects of mitochondrial
biochemistry, and cell killing, which does.
PMID- 10757798
TI - The human SWI-SNF complex protein p270 is an ARID family member with non-sequence
specific DNA binding activity.
AB - p270 is an integral member of human SWI-SNF complexes, first identified through
its shared antigenic specificity with p300 and CREB binding protein. The deduced
amino acid sequence of p270 reported here indicates that it is a member of an
evolutionarily conserved family of proteins distinguished by the presence of a
DNA binding motif termed ARID (AT-rich interactive domain). The ARID consensus
and other structural features are common to both p270 and yeast SWI1, suggesting
that p270 is a human counterpart of SWI1. The approximately 100-residue ARID
sequence is present in a series of proteins strongly implicated in the regulation
of cell growth, development, and tissue-specific gene expression. Although about
a dozen ARID proteins can be identified from database searches, to date, only
Bright (a regulator of B-cell-specific gene expression), dead ringer (a
Drosophila melanogaster gene product required for normal development), and MRF-2
(which represses expression from the cytomegalovirus enhancer) have been analyzed
directly in regard to their DNA binding properties. Each binds preferentially to
AT-rich sites. In contrast, p270 shows no sequence preference in its DNA binding
activity, thereby demonstrating that AT-rich binding is not an intrinsic property
of ARID domains and that ARID family proteins may be involved in a wider range of
DNA interactions.
PMID- 10757799
TI - Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange.
AB - Cells can achieve error-free repair of DNA double-strand breaks (DSBs) by
homologous recombination through gene conversion with or without crossover. In
contrast, an alternative homology-dependent DSB repair pathway, single-strand
annealing (SSA), results in deletions. In this study, we analyzed the effect of
mRAD54, a gene involved in homologous recombination, on the repair of a site
specific I-SceI-induced DSB located in a repeated DNA sequence in the genome of
mouse embryonic stem cells. We used six isogenic cell lines differing solely in
the orientation of the repeats. The combination of the three recombination-test
substrates used discriminated among SSA, intrachromatid gene conversion, and
sister chromatid gene conversion. DSB repair was most efficient for the substrate
that allowed recovery of SSA events. Gene conversion with crossover,
indistinguishable from long tract gene conversion, preferentially involved the
sister chromatid rather than the repeat on the same chromatid. Comparing DSB
repair in mRAD54 wild-type and knockout cells revealed direct evidence for a role
of mRAD54 in DSB repair. The substrate measuring SSA showed an increased
efficiency of DSB repair in the absence of mRAD54. The substrate measuring sister
chromatid gene conversion showed a decrease in gene conversion with and without
crossover. Consistent with this observation, DNA damage-induced sister chromatid
exchange was reduced in mRAD54-deficient cells. Our results suggest that mRAD54
promotes gene conversion with predominant use of the sister chromatid as the
repair template at the expense of error-prone SSA.
PMID- 10757800
TI - STRAP and Smad7 synergize in the inhibition of transforming growth factor beta
signaling.
AB - Smad proteins play a key role in the intracellular signaling of the transforming
growth factor beta (TGF-beta) superfamily of extracellular polypeptides that
initiate signaling from the cell surface through serine/threonine kinase
receptors. A subclass of Smad proteins, including Smad6 and Smad7, has been shown
to function as intracellular antagonists of TGF-beta family signaling. We have
previously reported the identification of a WD40 repeat protein, STRAP, that
associates with both type I and type II TGF-beta receptors and that is involved
in TGF-beta signaling. Here we demonstrate that STRAP synergizes specifically
with Smad7, but not with Smad6, in the inhibition of TGF-beta-induced
transcriptional responses. STRAP does not show cooperation with a C-terminal
deletion mutant of Smad7 that does not bind with the receptor and consequently
has no inhibitory activity. STRAP associates stably with Smad7, but not with the
Smad7 mutant. STRAP recruits Smad7 to the activated type I receptor and forms a
complex. Moreover, STRAP stabilizes the association between Smad7 and the
activated receptor, thus assisting Smad7 in preventing Smad2 and Smad3 access to
the receptor. STRAP interacts with Smad2 and Smad3 but does not cooperate
functionally with these Smads to transactivate TGF-beta-dependent transcription.
The C terminus of STRAP is required for its phosphorylation in vivo, which is
dependent on the TGF-beta receptor kinases. Thus, we describe a mechanism to
explain how STRAP and Smad7 function synergistically to block TGF-beta-induced
transcriptional activation.
PMID- 10757801
TI - Differential binding to and regulation of JAK2 by the SH2 domain and N-terminal
region of SH2-bbeta.
AB - SH2-Bbeta has been shown to bind via its SH2 (Src homology 2) domain to tyrosyl
phosphorylated JAK2 and strongly activate JAK2. In this study, we demonstrate the
existence of an additional binding site(s) for JAK2 within the N-terminal region
of SH2-Bbeta (amino acids 1 to 555) and the ability of this region of SH2-B to
inhibit JAK2. Four lines of evidence support the existence of this additional
binding site(s). In a glutathione S-transferase pull-down assay, wild-type SH2
Bbeta and SH2-Bbeta(R555E) with a defective SH2 domain bind to both tyrosyl
phosphorylated JAK2 from growth hormone (GH)-treated cells and non-tyrosyl
phosphorylated JAK2 from control cells, whereas the SH2 domain of SH2-Bbeta binds
only to tyrosyl-phosphorylated JAK2 from GH-treated cells. Similarly, JAK2 is
present in alphaSH2-B immunoprecipitates in the absence and presence of GH, with
GH substantially increasing the coprecipitation of JAK2 with SH2-B. When
coexpressed in COS cells, SH2-Bbeta coimmunoprecipitates not only wild-type,
tyrosyl-phosphorylated JAK2 but also kinase-inactive, non-tyrosyl-phosphorylated
JAK2(K882E), although to a lesser extent. DeltaC555 (amino acids 1 to 555 of SH2
Bbeta) that lacks most of the SH2 domain binds similarly to wild-type JAK2 and
kinase-inactive JAK2(K882E). Experiments using a series of N- and C-terminally
truncated SH2-Bbeta constructs indicate that the pleckstrin homology (PH) domain
(amino acids 269 to 410) and amino acids 410 to 555 are necessary for maximal
binding of SH2-Bbeta to inactive JAK2, but neither region alone is sufficient for
maximal binding. The SH2 domain of SH2-Bbeta is necessary and sufficient for the
stimulatory effect of SH2-Bbeta on JAK2 and JAK2-mediated tyrosyl phosphorylation
of Stat5B. In contrast, DeltaC555 lacking the SH2 domain, and to a lesser extent
the PH domain alone, inhibits JAK2. DeltaC555 also blocks JAK2-mediated tyrosyl
phosphorylation of Stat5B in COS cells and GH-stimulated nuclear accumulation of
Stat5B in 3T3-F442A cells. These data indicate that in addition to the SH2
domain, SH2-Bbeta has one or more lower-affinity binding sites for JAK2 within
amino acids 269 to 555. The interaction via this site(s) in SH2-B with inactive
JAK2 seems likely to increase the local concentration of SH2-Bbeta around JAK2,
thereby facilitating binding of the SH2 domain to ligand-activated JAK2. This
would result in a more rapid and robust cellular response to hormones and
cytokines that activate JAK2. This interaction between inactive JAK2 and SH2-B
may also help prevent abnormal activation of JAK2.
PMID- 10757802
TI - Evi9 encodes a novel zinc finger protein that physically interacts with BCL6, a
known human B-cell proto-oncogene product.
AB - Evi9 is a common site of retroviral integration in BXH2 murine myeloid leukemias.
Here we show that Evi9 encodes a novel zinc finger protein with three tissue
specific isoforms: Evi9a (773 amino acids [aa]) contains two C(2)H(2)-type zinc
finger motifs, a proline-rich region, and an acidic domain; Evi9b (486 aa) lacks
the first zinc finger motif and part of the proline-rich region; Evi9c (239 aa)
lacks all but the first zinc finger motif. Proviral integration sites are located
in the first intron of the gene and lead to increased gene expression. Evi9a and
Evi9c, but not Evi9b, show transforming activity for NIH 3T3 cells, suggesting
that Evi9 is a dominantly acting proto-oncogene. Immunolocalization studies show
that Evi9c is restricted to the cytoplasm whereas Evi9a and Evi9b are located in
the nucleus, where they form a speckled localization pattern identical to that
observed for BCL6, a human B-cell proto-oncogene product. Coimmunoprecipitation
and glutathione S-transferase pull-down experiments show that Evi9a and Evi9b,
but not Evi9c, physically interact with BCL6, while deletion mutagenesis
localized the interaction domains in or near the second zinc finger and POZ
domains of Evi9 and BCL6, respectively. These results suggest that Evi9 is a
leukemia disease gene that functions, in part, through its interaction with BCL6.
PMID- 10757803
TI - Structure of a polycomb response element and in vitro binding of polycomb group
complexes containing GAGA factor.
AB - Polycomb response elements (PREs) are regulatory sites that mediate the silencing
of homeotic and other genes. The bxd PRE region from the Drosophila Ultrabithorax
gene can be subdivided into subfragments of 100 to 200 bp that retain different
degrees of PRE activity in vivo. In vitro, embryonic nuclear extracts form
complexes containing Polycomb group (PcG) proteins with these fragments. PcG
binding to some fragments is dependent on consensus sequences for the GAGA
factor. Other fragments lack GAGA binding sites but can still bind PcG complexes
in vitro. We show that the GAGA factor is a component of at least some types of
PcG complexes and may participate in the assembly of PcG complexes at PREs.
PMID- 10757804
TI - Protein zero gene expression is regulated by the glial transcription factor
Sox10.
AB - Myelinating glia express high levels of a unique set of genes which code for
structural proteins of the myelin sheath. Few transcription factors have so far
been implicated in the regulation of any myelin gene. Here we show that the
protein zero (P(0)) gene, a myelin gene exclusively expressed in the Schwann cell
lineage of the peripheral nervous system, is controlled in its expression by the
high-mobility-group domain protein Sox10 both in tissue culture and in vivo.
Induction of wild-type Sox10, but not of other transcription factors or Sox10
mutants, strongly increased endogenous P(0) expression in tissue culture. This
activation was mediated by the P(0) promoter, which was stimulated by Sox10 in
transient transfections. Detailed analyses revealed the involvement of a proximal
and a distal promoter region. The distal region functioned only in conjunction
with the proximal one and contained a single Sox consensus binding site, which
accounted for most of its activity. In contrast, the proximal region mediated
Sox10 responsiveness on its own. It contained multiple binding sites for Sox
proteins, with two high-affinity sites being the most significant. P(0)
expression also depended on Sox10 in vivo, as evident from the analysis of
Schwann cell precursors in mouse embryos with Sox10 mutation at day 12.5 of
embryogenesis. To our knowledge this is the most conclusive link to date between
a glial transcription factor and cell-specific activation of myelin gene
expression.
PMID- 10757805
TI - ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2
complex formation: receptor overexpression does not determine growth dependency.
AB - Overexpression of the ErbB2 receptor, a major component of the ErbB receptor
signaling network, contributes to the development of a number of human cancers.
ErbB2 presents itself, therefore, as a target for antibody-mediated therapies. In
this respect, anti-ErbB2 monoclonal antibody 4D5 specifically inhibits the growth
of tumor cells overexpressing ErbB2. We have analyzed the effect of 4D5-mediated
ErbB2 inhibition on the cell cycle of the breast tumor cell line BT474. 4D5
treatment of BT474 cells resulted in a G(1) arrest, preceded by rapid
dephosphorylation of ErbB2, inhibition of cytoplasmic signal transduction
pathways, accumulation of the cyclin-dependent kinase inhibitor p27(Kip1), and
inactivation of cyclin-Cdk2 complexes. Time courses demonstrated that 4D5
treatment redirects p27(Kip1) onto Cdk2 complexes, an event preceding increased
p27(Kip1) expression; this correlates with the downregulation of c-Myc and D-type
cyclins (proteins involved in p27(Kip1) sequestration) and the loss of p27(Kip1)
from Cdk4 complexes. Similar events were observed in ErbB2-overexpressing SKBR3
cells, which exhibited reduced proliferation in response to 4D5 treatment. Here,
p27(Kip1) redistribution resulted in partial Cdk2 inactivation, consistent with a
G1 accumulation. Moreover, p27(Kip1) protein levels remained constant. Antisense
mediated inhibition of p27(Kip1) expression in 4D5-treated BT474 cells further
demonstrated that in the absence of p27(Kip1) accumulation, p27(Kip1) redirection
onto Cdk2 complexes is sufficient to inactivate Cdk2 and establish the G(1)
block. These data suggest that ErbB2 overexpression leads to potentiation of
cyclin E-Cdk2 activity through regulation of p27(Kip1) sequestration proteins,
thus deregulating the G(1)/S transition. Moreover, through comparison with an
ErbB2-overexpressing cell line insensitive to 4D5 treatment, we demonstrate the
specificity of these cell cycle events and show that ErbB2 overexpression alone
is insufficient to determine the cellular response to receptor inhibition.
PMID- 10757806
TI - Stress signals utilize multiple pathways to stabilize p53.
AB - The p53 tumor suppressor is activated by many diverse stress signals through
mechanisms that result in stabilization and accumulation of the p53 protein. p53
is normally degraded through the proteasome following interaction with MDM2,
which both functions as a ubiquitin ligase for p53 and shuttles to the cytoplasm,
where p53 degradation occurs. Stabilization of p53 in response to stress is
associated with inhibition of MDM2-mediated degradation, which has been
associated with phosphorylation of p53 in response to DNA damage or activation of
ARF. In this study we show distinct responses, as measured by phosphorylation,
transcriptional activity, and subcellular localization, of p53 stabilized by
different activating signals. Although normal cells and wild-type p53-expressing
tumor cells showed similar responses to actinomycin D and camptothecin treatment,
the transcriptional activity of stabilized p53 induced by deferoxamine mesylate,
which mimics hypoxia, in normal cells was lost in all three tumor cell lines
tested. Our results show that multiple pathways exist to stabilize p53 in
response to different forms of stress, and they may involve down-regulation of
MDM2 expression or regulation of the subcellular localization of p53 or MDM2.
Loss of any one of these pathways may predispose cells to malignant
transformation, although reactivation of p53 might be achieved through
alternative pathways that remain functional in these tumor cells.
PMID- 10757807
TI - Cid1, a fission yeast protein required for S-M checkpoint control when DNA
polymerase delta or epsilon is inactivated.
AB - The S-M checkpoint is an intracellular signaling pathway that ensures that
mitosis is not initiated in cells undergoing DNA replication. We identified cid1,
a novel fission yeast gene, through its ability when overexpressed to confer
specific resistance to a combination of hydroxyurea, which inhibits DNA
replication, and caffeine, which overrides the S-M checkpoint. Cid1
overexpression also partially suppressed the hydroxyurea sensitivity
characteristic of DNA polymerase delta mutants and mutants defective in the
"checkpoint Rad" pathway. Cid1 is a member of a family of putative
nucleotidyltransferases including budding yeast Trf4 and Trf5, and mutation of
amino acid residues predicted to be essential for this activity resulted in loss
of Cid1 function in vivo. Two additional Cid1-like proteins play similar but
nonredundant checkpoint-signaling roles in fission yeast. Cells lacking Cid1 were
found to be viable but specifically sensitive to the combination of hydroxyurea
and caffeine and to be S-M checkpoint defective in the absence of Cds1. Genetic
data suggest that Cid1 acts in association with Crb2/Rhp9 and through the
checkpoint-signaling kinase Chk1 to inhibit unscheduled mitosis specifically when
DNA polymerase delta or epsilon is inhibited.
PMID- 10757808
TI - A novel family of cell wall-related proteins regulated differently during the
yeast life cycle.
AB - The Saccharomyces cerevisiae Ygr189c, Yel040w, and Ylr213c gene products show
significant homologies among themselves and with various bacterial beta
glucanases and eukaryotic endotransglycosidases. Deletion of the corresponding
genes, either individually or in combination, did not produce a lethal phenotype.
However, the removal of YGR189c and YEL040w, but not YLR213c, caused additive
sensitivity to compounds that interfere with cell wall construction, such as
Congo red and Calcofluor White, and overexpression of YEL040w led to resistance
to these compounds. These genes were renamed CRH1 and CRH2, respectively, for
Congo red hypersensitive. By site-directed mutagenesis we found that the putative
glycosidase domain of CRH1 was critical for its function in complementing
hypersensitivity to the inhibitors. The involvement of CRH1 and CRH2 in the
development of cell wall architecture was clearly shown, since the alkali-soluble
glucan fraction in the crh1Delta crh2Delta strain was almost twice the level in
the wild-type. Interestingly, the three genes were subject to different patterns
of transcriptional regulation. CRH1 and YLR213c (renamed CRR1, for CRH related)
were found to be cell cycle regulated and also expressed under sporulation
conditions, whereas CRH2 expression did not vary during the mitotic cycle. Crh1
and Crh2 are localized at the cell surface, particularly in chitin-rich areas.
Consistent with the observed expression patterns, Crh1-green fluorescent protein
was found at the incipient bud site, around the septum area in later stages of
budding, and in ascospore envelopes. Crh2 was found to localize mainly at the bud
neck throughout the whole budding cycle, in mating projections and zygotes, but
not in ascospores. These data suggest that the members of this family of putative
glycosidases might exert a common role in cell wall organization at different
stages of the yeast life cycle.
PMID- 10757809
TI - Dual control of muscle cell survival by distinct growth factor-regulated
signaling pathways.
AB - In addition to their ability to stimulate cell proliferation, polypeptide growth
factors are able to maintain cell survival under conditions that otherwise lead
to apoptotic death. Growth factors control cell viability through regulation of
critical intracellular signal transduction pathways. We previously characterized
C2 muscle cell lines that lacked endogenous expression of insulin-like growth
factor II (IGF-II). These cells did not differentiate but underwent apoptotic
death in low-serum differentiation medium. Death could be prevented by IGF
analogues that activated the IGF-I receptor or by unrelated growth factors such
as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling
pathways involved in growth factor-mediated myoblast survival. PDGF treatment
caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and
2), while IGF-I only transiently induced these enzymes. Transient transfection of
a constitutively active Mek1, a specific upstream activator of ERKs, maintained
myoblast viability in the absence of growth factors, while inhibition of Mek1 by
the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although
both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to
similar extents, only IGF-I treatment led to sustained stimulation of its
downstream kinase, Akt. Transient transfection of a constitutively active PI3
kinase or an inducible Akt promoted myoblast viability in the absence of growth
factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively
blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these
observations demonstrate that distinct growth factor-regulated signaling pathways
independently control myoblast survival. Since IGF action also stimulates muscle
differentiation, these results suggest a means to regulate myogenesis through
selective manipulation of different signal transduction pathways.
PMID- 10757810
TI - Identification of a series of transforming growth factor beta-responsive genes by
retrovirus-mediated gene trap screening.
AB - Transforming growth factor beta (TGF-beta) plays important roles in the
regulation of proliferation, differentiation, apoptosis, and carcinogenesis. To
identify genes responsible for maintaining the phenotype induced by TGF-beta, we
performed a retrovirus-mediated gene trap screening designed to isolate TGF-beta
responsive genes in human lung carcinoma cell line A549. After screening 249 trap
lines, 21 were found to express the reporter beta-galactosidase gene in a TGF
beta-responsive manner. Interestingly, in large proportions of these trap lines,
the reporter gene was responsive also to phorbol ester and was suppressed by
gamma interferon. Fragments of all these trapped genes were recovered by 5'- and
3'-rapid amplification of cDNA ends (RACE), and in 15 out of 21 cases (71%), the
TGF-beta responsiveness of the endogenous genes was confirmed by RNA blot
hybridization. In at least five cases, the TGF-beta-induced upregulation was
found to be cycloheximide resistant, suggesting the roles of the genes in the TGF
beta-induced primary responses. Sequence analyses revealed that 43% (9 of 21) of
the trapped genes were novel and that the remainder included genes previously
reported to be upregulated by TGF-beta, such as epidermal growth factor receptor
and beta1 integrin, documenting the validity of this approach. Other known genes
include the ones encoding the proteins associated with cell proliferation
(ribosomal proteins S15a, hNRP/NAP-1, and lipocortin II), focal adhesions
(paxillin), and transcriptional regulation (thyroid hormone receptor activator
molecule 1 [TRAM-1]).
PMID- 10757811
TI - Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent
promyelocyte capable of biphenotypic differentiation to neutrophils or
macrophages, independent of enforced meis expression.
AB - The genes encoding Hoxa9 and Meis1 are transcriptionally coactivated in a subset
of acute myeloid leukemia (AML) in mice. In marrow reconstitution experiments,
coexpression of both genes produces rapid AML, while neither gene alone generates
overt leukemia. Although Hoxa9 and Meis1 can bind DNA as heterodimers, both can
also heterodimerize with Pbx proteins. Thus, while their coactivation may result
from the necessity to bind promoters as heterodimers, it may also result from the
necessity of altering independent biochemical pathways that cooperate to generate
AML, either as monomers or as heterodimers with Pbx proteins. Here we demonstrate
that constitutive expression of Hoxa9 in primary murine marrow immortalizes a
late myelomonocytic progenitor, preventing it from executing terminal
differentiation to granulocytes or monocytes in the presence of granulocyte
macrophage colony-stimulating factor (GM-CSF) or interleukin-3. This immortalized
phenotype is achieved in the absence of endogenous or exogenous Meis gene
expression. The Hoxa9-immortalized progenitor exhibited a promyelocytic
transcriptional profile, expressing PU.1, AML1, c-Myb, C/EBP alpha, and C/EBP
epsilon as well as their target genes, the receptors for GM-CSF, G-CSF, and M-CSF
and the primary granule proteins myeloperoxidase and neutrophil elastase. G-CSF
obviated the differentiation block of Hoxa9, inducing neutrophilic
differentiation with accompanying expression of neutrophil gelatinase B and
upregulation of gp91phox. M-CSF also obviated the differentiation block, inducing
monocytic differentiation with accompanying expression of the macrophage acetyl
low-density lipoprotein scavenger receptor and F4/80 antigen. Versions of Hoxa9
lacking the ANWL Pbx interaction motif (PIM) also immortalized a promyelocytic
progenitor with intrinsic biphenotypic differentiation potential. Therefore,
Hoxa9 evokes a cytokine-selective block in differentiation by a mechanism that
does not require Meis gene expression or interaction with Pbx through the PIM.
PMID- 10757812
TI - Mutations in the WRN gene in mice accelerate mortality in a p53-null background.
AB - Werner's syndrome (WS) is a human disease with manifestations resembling
premature aging. The gene defective in WS, WRN, encodes a DNA helicase. Here, we
describe the generation of mice bearing a mutation that eliminates expression of
the C terminus of the helicase domain of the WRN protein. Mutant mice are born at
the expected Mendelian frequency and do not show any overt histological signs of
accelerated senescence. These mice are capable of living beyond 2 years of age.
Cells from these animals do not show elevated susceptibility to the genotoxins
camptothecin or 4-NQO. However, mutant fibroblasts senesce approximately one
passage earlier than controls. Importantly, WRN(-/-);p53(-/-) mice show an
increased mortality rate relative to WRN(+/-);p53(-/-) animals. We consider
possible models for the synergy between p53 and WRN mutations for the
determination of life span.
PMID- 10757813
TI - Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3.
AB - The BETA2 (neuroD) gene is expressed in endocrine cells during pancreas
development and is essential for proper islet morphogenesis. The objective of
this study is to identify potential upstream regulators of the BETA2 gene during
pancreas development. We demonstrated that the expression of neurogenin 3 (ngn3),
an islet- and neuron-specific basic-helix-loop-helix transcription factor,
partially overlaps that of BETA2 during early mouse development. More
importantly, overexpression of ngn3 can induce the ectopic expression of BETA2 in
Xenopus embryos and stimulate the endogenous RNA of BETA2 in endocrine cell
lines. Furthermore, overexpression of ngn3 could cause a dose-dependent
activation on the 1.0-kb BETA2 promoter in islet-derived cell lines. Deletion and
mutation analyses revealed that two proximal E box sequences, E1 and E3, could
bind to ngn3-E47 heterodimer and mediate ngn3 activation. Based on these results,
we hypothesize that ngn3 is involved in activating the expression of BETA2 at an
early stage of islet cell differentiation through the E boxes in the BETA2
promoter.
PMID- 10757814
TI - Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon
sarcoglycan are maternally imprinted genes: identification by a subtractive
screen of novel uniparental fibroblast lines.
AB - Imprinted genes are expressed from one allele according to their parent of
origin, and many are essential to mammalian embryogenesis. Here we show that the
epsilon-sarcoglycan gene (Sgce) and Zac1 (Lot1) are both paternally expressed
imprinted genes. They were identified in a subtractive screen for imprinted genes
using a cDNA library made from novel parthenogenetic and wild-type fibroblast
lines. Sgce is a component of the dystrophin-sarcoglycan complex, Zac1 is a
nuclear protein inducing growth arrest and/or apoptosis, and Zac1 is a potential
tumor suppressor gene. Sgce and Zac1 are expressed predominantly from their
paternal alleles in all adult mouse tissues, except that Zac1 is biallelic in the
liver and Sgce is weakly expressed from the maternal allele in the brain. Sgce
and Zac1 are broadly expressed in embryos, with Zac1 being highly expressed in
the liver primordium, the umbilical region, and the neural tube. Sgce, however,
is strongly expressed in the allantoic region on day 9.5 but becomes more widely
expressed throughout the embryo by day 11.5. Sgce is located at the proximal end
of mouse chromosome 6 and is a candidate gene for embryonic lethality associated
with uniparental maternal inheritance of this region. Zac1 maps to the proximal
region of chromosome 10, identifying a new imprinted locus in the mouse,
homologous with human chromosome 6q24-q25. In humans, unipaternal disomy for this
region is associated with fetal growth retardation and transient neonatal
diabetes mellitus. In addition, loss of expression of ZAC has been described for
a number of breast and ovarian carcinomas, suggesting that ZAC is a potential
tumor suppressor gene.
PMID- 10757816
TI - Guest editorial
PMID- 10757817
TI - Soyfoods, soybean isoflavones, and bone health: a brief overview.
AB - Soyfoods have received considerable attention during the past 5 years for their
role in disease prevention, especially in relation to heart disease,
osteoporosis, and cancer. However, limited research also suggests that soy
protein favorably affects renal function. Much of the research interest in soy is
aimed at establishing the physiological effects of isoflavones. Isoflavones are
diphenolic compounds that have a very limited distribution in nature. Soybeans
and soyfoods are, for practical purposes, the only nutritionally relevant dietary
sources of isoflavones. Isoflavones are weak estrogens in that they bind to
estrogen receptors, but they also have important nonhormonal properties as well.
Initial speculation that soyfoods, and in particular isoflavones, might promote
bone health was based on the estrogenic properties of isoflavones and the
similarity in structure between isoflavones and the osteoporosis drug,
ipriflavone, which is a synthetic isoflavone. In ovariectomized rodents,
isoflavones retard bone loss almost as effectively as estrogen. Most research,
but not all, also indicates that soyfoods rich in isoflavones favorably affect
bone turnover and spinal bone mineral density in perimenopausal and
postmenopausal women. However, studies conducted thus far have been of short
duration and involved small numbers of subjects. Furthermore, no studies have
actually examined the effect of soy feeding on fracture risk. Thus, although the
data in general are encouraging, no firm conclusions can be drawn about the
relationship between soy consumption and bone health. In addition to a possible
direct effect of isoflavones on bone tissue, soy protein when substituted for
animal protein may indirectly enhance bone strength. Several studies have found
that in comparison with animal protein, soy protein decreases calcium excretion,
a result of the lower sulfur amino acid content of soy protein. Although the high
potassium content of soy is a consideration, the evidence clearly indicates that
clinicians should consider recommending that their renal patients incorporate
soyfoods into their diet.
PMID- 10757818
TI - The effect of dietary supplements on the nPCR in stable hemodialysis patients.
AB - OBJECTIVE: To investigate whether (1) dietary supplements raise the normalized
protein catabolic rate (nPCR) and/or further improve the nutritional status of
stable hemodialysis patients who have both a low nPCR and a low dietary protein
intake, <1.2 g/kg body weight/day; and if (2) protein intake measured by nPCR
reflects protein intake measured by estimated food diaries in stable patients.
DESIGN: Prospective experimental study with a single intervention group. SETTING:
Hospital outpatient hemodialysis unit. SUBJECTS: Seventeen stable chronic
hemodialysis patients (10 men, 7 women) were studied over 8 months. INTERVENTION:
Subjects with both a low nPCR and dietary protein intake <1.2 g/kg body
weight/day received dietary supplements for the first 2 months. Measurements to
assess protein intake and nutritional status were taken at baseline and repeated
at the end of 2 months, and at 6 months postintervention. MAIN OUTCOME MEASURE:
nPCR, dietary protein intake using 7-day estimated food diaries, serum urea,
serum albumin, serum creatinine, serum bicarbonate, dialysis adequacy (Kt/V), and
body mass index (BMI). RESULTS: Dietary supplements significantly increased both
the nPCR and the total protein intake at 2 months (1.21 +/- 0.26, 1.10 +/- 0.12,
respectively) compared with baseline (0.95 +/- 0.18, 0.75 +/- 0.19, respectively)
and 8 months (0.99 +/- 0.12, 0.78 +/- 0.21, respectively), P <.0001,
respectively. There was no change in the nutritional status of the subjects.
There was a significant difference between the nPCR and the dietary protein
intake at baseline, P <.004; at 2 months, P <.047; and at 8 months, P <.001.
CONCLUSION: Dietary supplements can significantly increase the nPCR and dietary
protein intake in stable hemodialysis patients with a low nPCR and dietary
protein intake. Because a low nPCR is associated with a high morbidity and
mortality rate, it may be prudent to supplement such patients. The use of the
nPCR to quantify dietary protein intake in stable hemodialysis patients should be
used with caution.
PMID- 10757815
TI - Methylation of the cyclin A1 promoter correlates with gene silencing in somatic
cell lines, while tissue-specific expression of cyclin A1 is methylation
independent.
AB - Gene expression in mammalian organisms is regulated at multiple levels, including
DNA accessibility for transcription factors and chromatin structure. Methylation
of CpG dinucleotides is thought to be involved in imprinting and in the
pathogenesis of cancer. However, the relevance of methylation for directing
tissue-specific gene expression is highly controversial. The cyclin A1 gene is
expressed in very few tissues, with high levels restricted to spermatogenesis and
leukemic blasts. Here, we show that methylation of the CpG island of the human
cyclin A1 promoter was correlated with nonexpression in cell lines, and the
methyl-CpG binding protein MeCP2 suppressed transcription from the methylated
cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of
a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in
stable transfected MG63 osteosarcoma cells was also closely associated with de
novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing
cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter
EGFP construct directed tissue-specific expression in male germ cells of
transgenic mice. Expression in the testes of these mice was independent of
promoter methylation, and even strong promoter methylation did not suppress
promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells.
Transcription from the transgenic cyclin A1 promoter was repressed in most organs
outside the testis, even when the promoter was not methylated. These data show
the association of methylation with silencing of the cyclin A1 gene in cancer
cell lines. However, appropriate tissue-specific repression of the cyclin A1
promoter occurs independently of CpG methylation.
PMID- 10757819
TI - Computer integration and time spent on direct patient nutritional care activities
in an outpatient dialysis setting.
AB - OBJECTIVE: To compare time spent in patient and administrative activities by
nutrition professionals in a group of dialysis facilities, and relate differences
to the degree of computer integration at the sites and between 2 time periods.
DESIGN: Survey design, self-administered activity form, completed in 1992 and
1997. SETTING: Three of the largest outpatient dialysis centers in western
Washington state. SUBJECTS: Ten nutrition professionals completed the activity
forms. INTERVENTION: Activity form (recording time), questionnaire (results not
reported here). MAIN OUTCOME MEASURES: Amount of time spent on administrative
activities in 1997 and the number of patients and number of hours per nutrition
professional per month spent with patients in 1997, compared with 1992. RESULTS:
Time spent on administrative activities decreased in all facilities since 1992,
with the largest decrease at the unit having the most computer integration.
CONCLUSION: Extensive computer integration seems to allow for a decrease in the
amount of time spent on administrative activities by nutrition professionals.
PMID- 10757820
TI - The effect of an educational patient compliance program on serum phosphate levels
in patients receiving hemodialysis.
AB - OBJECTIVE: This study sought to determine the effectiveness of a recently
developed educational patient compliance program (A Taste for Life [1995]; Abbott
Laboratories, Abbott Park, IL) on improving serum phosphate levels in patients
receiving hemodialysis. DESIGN: An ABA time series design was used.
PARTICIPANTS/SETTING: Eighty-one patients receiving hemodialysis participated.
The experimental group consisted of 50 participants (mean [M] = 57.9 years of
age; 92% African-American; 62% female) from a private freestanding dialysis unit
(Kinston, NC). The control group consisted of 31 control participants (M = 58.2
years of age; 90% African-American; 48% female) from a separate private
freestanding dialysis unit (Greenville, NC). INTERVENTION: The experimental group
took part in the educational patient compliance program directed at dietary and
medical regimes. The program used educational materials, interactive educational
modules, motivational posters, creative games and puzzles, videos, and an in
center achievement contest. The control group did not partake in the program, but
received individual ongoing monthly therapy that involved nutrition counseling
consistent with the National Renal Diet (American Dietetic Association, 1993) and
instruction regarding use of phosphate binders. MAIN OUTCOME MEASURE: Serum
phosphate levels were monitored monthly for 1 year (ie, 3, 3, and 6 months during
pretreatment, treatment, and posttreatment, respectively). RESULTS: No
statistically significant differences were found in serum phosphate levels
between the two groups (P >.05). There was, however, a significant difference
across time within groups. Mean serum phosphate levels significantly declined
during the treatment period and further during the posttreatment period relative
to the pretreatment baseline (P <.05). Results were not compared with a group of
patients receiving hemodialysis who received no nutrition counseling. CONCLUSION:
The findings suggest that an educational compliance program is equally effective
as standard individual ongoing counseling in affecting serum phosphate levels
among patients with end-stage renal disease who receive hemodialysis. Results
suggest that renal dietitians choose types of intervention within each patient's
continuity of care that support individual success.
PMID- 10757821
TI - Prevalence of low albumin, suboptimal energy, and muscle stores in asian dialysis
patients.
AB - OBJECTIVE: Investigate the prevalence of low serum albumin levels (<3.2 g/L) and
decreased arm muscle area percentiles and arm fat area percentiles in Asian
patients compared with non-Asian patients treated with dialysis. DESIGN: Cross
sectional study in which serum albumin and anthropometric measurements were
averaged over 6 months, and compared between patients of Asian ethnicity and
patients of non-Asian ethnicity. SETTING: Eight outpatient dialysis facilities.
SUBJECTS: Ninety-seven Asian and 513 non-Asian patients treated with hemodialysis
or peritoneal dialysis. RESULTS: Height, weight, and body mass index were
significantly lower in Asians compared with non-Asians (P <.001). Protein
catabolic rate was significantly greater in Asian (1.17 +/- 0.29 g/kg) compared
with non-Asian (0.97 +/- 0.28 g/kg) women (P <.001). Asian men (3.30 g/dL) and
women (3. 26 g/dL) had lower serum albumin compared with non-Asian men (3.35
g/dL; P =.057) and women (3.34 g/dL; P =.040). The proportion of patients with
serum albumin <3.2 g/dL was greater for both Asian women (35%) (P <.040) and men
(30%) than non-Asian women (25%) and men (20%). After adjusting for important
covariates, serum albumin remained significantly different between Asian and non
Asian patients (P <.05). The proportion below the fifth percentile for arm muscle
area was significantly greater for both Asian men (54%) and women (19%) compared
with non-Asian men (24%) and women (8%). Proportions of Asian and non-Asian women
below the 10th and 5th percentile for arm fat area were similar. However, Asian
men (54%) had a significantly greater fat depletion than non-Asian men (26%).
CONCLUSION: Mean serum albumin was significantly lower in Asian patients on
dialysis than in non-Asians. Muscle stores were depleted in Asian men and women
compared with non-Asians, and fat stores were depleted in Asian men. Based on
this study, Asian dialysis patients would seem to be at higher nutritional risk
than non-Asians, particularly Asian men. Further research is needed to assess
factors that affect serum albumin and mortality in Asian dialysis patients, and
standards need to be developed to further assess anthropometric measurements in
this population.
PMID- 10757822
TI - Glucose absorption in acute peritoneal dialysis.
AB - OBJECTIVE: During acute peritoneal dialysis (APD), it is known that glucose found
in the dialysate solution contributes to the provision of significant calories.
It has been well documented in continuous ambulatory peritoneal dialysis (CAPD)
that glucose absorption occurs. In APD, however, it remains unclear how much
glucose absorption actually does occur. Therefore, the purpose of this study was
to determine whether it is appropriate to use the formula used to calculate
glucose absorption in CAPD (Grodstein et al) among patients undergoing APD.
METHODS: Actual measurements of glucose absorption (Method I) were calculated in
9 patients undergoing APD treatment for >24 hours who were admitted to the
intensive care unit. Glucose absorption using the Grodstein et al formula (Method
II) was also determined and compared with the results of actual measurements. The
data was then further analyzed based on the factors that influence glucose
absorption, specifically dwell time and concentration. RESULTS: The mean total
amount of glucose absorbed was 43% +/- 15%. However, when dwell time and
concentration were further examined, significant differences were noted. Method I
showed a cumulative increase over time. Method II showed that absorption was
fixed. This suggests that with the variation in dwell time commonly seen in the
acute care setting, the use of Method II may not be accurate. In each of the 2
methods, a significant difference in glucose absorption was noted when comparing
the use of 1.5% and 4.25% dialysate concentrations. CONCLUSION: The established
formula designed for CAPD should not be used for calculating glucose absorption
in patients receiving APD because variation in dwell time and concentration
should be taken into account. Because of the time constraints and staffing
required to calculate each exchange individually, combined with the results of
the study, we recommend the use of the percentage estimate of 40% to 50%.
PMID- 10757823
TI - Issues in renal nutrition for persons from the former Soviet Union.
AB - Dietary practices differ greatly among individuals by race and ethnicity. The
importance of these differences is accentuated in patients with end-stage renal
disease, a population for whom dietary restrictions are often prescribed. In
addition to the known variation in dietary practices among US-born whites and
African-Americans, persons of other ethnicities often present new and unique
challenges to the dialysis-nutrition care team. The UCSF-Mt. Zion Dialysis Unit
(San Francisco, CA) is a university-affiliated dialysis unit that serves an
ethnically diverse population in San Francisco's Western Addition neighborhood.
Ten percent to 15% of patients are recent immigrants from the former Soviet
Union. This report highlights the dietary practices of this immigrant community
and the need for ethnicity-specific renal nutrition recommendations in modern
dialysis practice.
PMID- 10757824
TI - Dialysis and skin care.
PMID- 10757825
TI - Ninth annual national kidney foundation clinical nephrology meetings abstracts
april 13-16, 2000
PMID- 10757826
TI - Stroke in African Americans.
AB - There is an excess burden of cerebrovascular disease in African Americans. This
article will define possible reasons for excess stroke risk, review racial
differences in stroke subtype and stroke prevention programs in the African
American Community, and delineate sequelae of stroke. The authors provide
insights about stroke prevention in African Americans and highlight challenges to
reduce the burden of cerebrovascular disease in this high-risk group.
PMID- 10757827
TI - Stroke in Hispanic Americans.
AB - The Hispanic American population is the fastest growing minority group with
increasing representation among the older age strata. Current ethnic-specific
cerebrovascular disease data regarding stroke outcomes and risk factor status
reveal significant differences compared with other race/ethnic groups. The
authors discuss the literature on stroke incidence and mortality among Hispanic
populations. Traditional risk factors, access to care and stroke mechanism
differences are also discussed. Advances in Hispanic American specific stroke
prevention and treatment efforts demand further investigation to better define
Hispanic American stroke prevention and acute treatment strategies.
PMID- 10757828
TI - Stroke prevention: hypertension, diabetes, tobacco, and lipids.
AB - This article reviews the most recent epidemiologic evidence supporting topics
such as hypertension, diabetes, tobacco, and lipids as risks for stroke. Where
available, American Stroke Association (ASA) and National Stroke Association
(NSA) consensus statement guidelines for the treatment of these risk factors are
given.
PMID- 10757829
TI - Stroke prevention: cardiac and carotid-related stroke.
AB - The aim of this article is to discuss cardiac sources of stroke as well as the
management of symptomatic and asymptomatic carotid stenosis. The authors detail
the risks of cardioembolic stroke in the following conditions: aortic arch
atheroma, atrial fibrillation, atrial myxoma, atrial septal aneurysm, dilated
cardiomyopathy, infective endocarditis, left ventricular thrombus, mitral annular
calcification, mitral valve prolapse, patent foramen ovale, prosthetic heart
valves, valvular strands, and the optimal medical management for these
conditions. The indications for carotid endarterectomy, angioplasty, and stenting
are also outlined.
PMID- 10757830
TI - Stroke prevention: anti-platelet and anti-thrombolytic therapy.
AB - In patients with TIA or ischemic stroke of noncardiac origin antiplatelet drugs
are able to decrease the risk of stroke by 11-15%, and the risk of stroke, MI,
and vascular death by 15-22%, but not mortality. Low doses of aspirin (50-325 mg)
are as effective as high doses and cause less gastrointestinal side effects.
Severe bleeding complications are not dose-dependent. The combination of aspirin
with slow release dipyridamole is superior to aspirin alone for stroke
prevention. Ticlopidine is superior to aspirin but has slightly more serious
adverse effects (neutropenia). It will be replaced by clopidgrel which has a
better safety profile. Anticoagulation with an INR between 3.0 and 4.5 is too
dangerous. Whether anticoagulation with lower INR is safe and effective is not
yet known.
PMID- 10757831
TI - Diagnostic evaluation of stroke.
AB - Diagnostic testing in patients with ischemic stroke serves many purposes,
including confirmation of the diagnosis and providing clues as to possible
causes. Evaluation of the cerebral vasculature, the heart, the blood coagulation
system, and selected other diagnostic tests may point to a mechanism of stroke
which helps determine treatment and prognosis. With the recent advent of acute
interventions for ischemic stroke, diagnostic testing is now an important
component in the emergency management of stroke. In this article, the authors
will review the standard approach to diagnostic testing for patients with
ischemic stroke or transient ischemic attack, and new developments in neuro
imaging and their use in acute stroke assessment.
PMID- 10757832
TI - Acute ischemic stroke therapy.
AB - Acute ischemic stroke is a medical emergency that requires rapid evaluation and
treatment. Prehospital and emergency department care can be streamlined to meet
those goals. Intravenous rt-PA therapy improves outcome in selected patients with
ischemic stroke if given within 3 hours of stroke onset, but offers no benefit
beyond that time window. Intra-arterial thrombolytic therapy and intravenous
defibrogenating agents may also be beneficial in selected patients. Newer
thrombolytic agents such as aspirin and heparin in acute ischemic stroke
treatment have been clarified by recent trials.
PMID- 10757833
TI - Stroke treatment-specific considerations.
AB - Unusual causes of stroke account for a minority of all strokes, but they have
specific diagnostic and therapeutic implications which must be considered early
in the clinical course. This article focuses on arteriopathies such as arterial
dissection, vasospasm-induced stroke, and vasculitis; hematological disorders
such as hypercoagulable states, disseminated intravascular coagulation, and
sickle cell disease; migraine-induced stroke, and cerebral venous thrombosis.
PMID- 10757834
TI - Intracerebral hemorrhage.
AB - Intracerebral hemorrhage (ICH) represents a significant fraction of all strokes
and causes a disproportionate amount of stroke related morbidity and mortality,
especially in young blacks. While diagnosis of this disorder has greatly improved
in the CT era, morbidity and mortality remain essentially unchanged. Not one
currently utilized therapeutic modality has been clearly associated with a
beneficial effect on long term outcome in small prospective randomized treatment
trials for ICH. In spite of the lack of scientific data regarding therapy,
patients often require aggressive medical and surgical intervention because of
the life-threatening presentation of many patients. Recent clinical and
experimental ICH research has identified a number of potentially effective new
therapeutic strategies, and time to treatment is likely to be very important as
it is for ischemic stroke. Large prospective, randomized, placebo controlled
trials to examine the judicious application of current therapeutic modalities,
and to investigate the potential benefit of proposed new treatment modalities,
are long overdue.
PMID- 10757835
TI - Intensive care unit management of the stroke patient.
AB - Although the majority of patients with acute stroke do not require intensive
care, it is important to recognize when admission to an intensive care unit (ICU)
is warranted. Patients undergoing thrombolytic therapy, those with brainstem
infarcts referable to the basilar artery, those with large space occupying
hemispheric infarcts, and those with fluctuating neurological examinations should
be admitted to the ICU for monitoring and treatment.
PMID- 10757836
TI - Predictors of stroke outcome.
AB - Recent literature has identified many of the important factors helpful in
predicting outcome even at the very acute stage of stroke. Demographic factors,
risk factors, clinical exam findings, clinical scales laboratory tests, and
neuroimaging all provide important information that can assist the clinician in
predicting outcome. Specific factors seem to influence the effect of stroke
treatments such as thrombolysis. Consideration of these factors is important when
treatment decisions such as thrombolysis are being contemplated. New techniques
such as eco-planar MR Imaging are now being developed that seem extremely
accurate in predicting outcome. These techniques represent the "crystal ball" of
predicting stroke outcome.
PMID- 10757837
TI - Why do neuroprotective drugs work in animals but not humans?
AB - Many neuroprotective agents that seemed promising in animal studies of ischemic
brain injury prove to have no effect when tested in clinical trials, suggesting
that fundamental elements of translational research require better definition. A
number of modifications have led to improvements in preclinical and human studies
since the earliest controlled trials failed to confirm hypotheses suggested by
animal data. Continued re-evaluation and sharing of information derived from the
laboratory bench or the patient's bedside should eventually lead to effective
neuroprotection in acute stroke. Experimental data should be carefully studied to
improve the quality of agents coming to clinical trials and to design trial
phasing that effectively determines drug safety and efficacy. This article will
examine preclinical modeling and its translation to prospective studies of acute
stroke therapy and will focus on some potential solutions directed at clinical
trial design.
PMID- 10757838
TI - The future of stroke treatment.
AB - The concept of the therapeutic window of opportunity in ischemic neuronal injury
and understanding the necessity of well organized stroke services revolutionized
the management of acute ischemic stroke during the last years of the second
millennium. Thrombolysis with IV rt-PA within 3 hours from the onset of symptoms
is an established therapy for selected patients. The challenge of stroke therapy
at the outset of this millennium is how to translate basic pathophysiologic
evidence of ischemic neuronal injury into novel neuroprotective therapies either
independently or combined with thrombolysis. Great hopes are placed in
identification of pivotal molecular events in ischemic brain tissue and design of
effective pharmacological interventions to target them. Aggressive, invasive
procedures are also being developed and therapies such as intra-arterial clot
lysis, hemicraniectomy and mild hypothermia may improve the bleakest outcomes
associated with the most severe forms of ischemic stroke, but their role must be
rigorously evaluated. There is, however, no need to wait for future
breakthroughs. The existing evidence strongly implies that good care of patients
with stroke starts with organization of the entire stroke chain; from the
prehospital scene, through the emergency room, to the stroke unit. Without
structured stroke services no pharmacological or intervening therapy is likely to
improve the outcome of the patient with a stroke.
PMID- 10757839
TI - History and overview of comprehensive interdisciplinary breast centers.
AB - The comprehensive interdisciplinary breast center represents a model for
delivering breast care in an efficient and cost-effective manner. It is a better
way of caring for women with breast disease and allows for an interdisciplinary
treatment by various specialists working and communicating with each other. The
center allows for incorporation of new programs and innovations of care. As
breast cancer care undergoes further changes, the comprehensive breast center
facilitates progress and serves as a model for other disease-specific
interdisciplinary programs. The evolution of breast centers and types of models
are reviewed, and key factors of success are outlined in this article.
PMID- 10757840
TI - The Van Nuys Breast Center: the first free-standing multidisciplinary breast
center.
AB - This article describes the author's 30-year experience with the design and
development of breast centers. It describes the author's initial attempt at
developing a breast center at UCLA, the history of the Van Nuys Breast Center
(its patient population, philosophy, problems, finances, and demise), and the
development of the Harold E. and Henrietta C. Lee Breast Center. Breast centers
are defined as focused multidisciplinary facilities of excellence, dealing with
the complete range of breast problems. The main focus of this article is the Van
Nuys Breast Center, which was the prototype model for most breast centers
developed in the United States.
PMID- 10757841
TI - Private practice interdisciplinary breast centers: their rationale and impact on
patients, physicians, and the health care industry: a bicoastal perspective.
AB - This article reports on the experience of two private practice breast centers in
New York and California. It demonstrates that comprehensive breast centers
directed by full-time breast imagers have a significant impact on medical care
from the perspective of the patient, her physicians, and the health care system.
These two centers, separated by a continent, disparate in their formation and
founding philosophies, yield very similar results in breast cancer diagnosis,
reduction of the benign biopsies, and improving the cost of breast biopsies.
PMID- 10757842
TI - The Breast Health Center at Women & Infants Hospital: origin, philosophy, and
features.
AB - The Breast Health Center, a component of the program in Women's Oncology at Women
& Infants Hospital, is a multidisciplinary center devoted to the treatment and
study of benign and malignant breast diseases. The philosophy, structure, and
function of The Breast Health Center are described along with its specific
components. The Breast Health Center's three fundamental missions of patient
care, education, and research are discussed.
PMID- 10757843
TI - Disease management is the future: breast cancer is the model.
AB - The breast care continuum is characterized by a wide variety of procedures and
pathways leading to similar outcomes. This variation leads to very substantial
differences in costs and patient experience, dependant upon physician choice of
procedure or pathway. The breast center is uniquely positioned to develop disease
management for the breast, including subspecialized care, the adoption of
evidence-based protocols, and comprehensive management of outcome information.
This approach to disease management focuses on physician excellence and is the
key to increasing the quality of patient care, decreasing the overall cost of
breast cancer, and increasing reimbursement and practice satisfaction for breast
physicians.
PMID- 10757844
TI - A new era in the diagnosis of breast cancer.
AB - The regular use of high-quality mammography on asymptomatic women enables most
breast cancers to be detected in the preclinical phase. Earlier detection
dramatically rearranges the spectrum of breast cancer outcomes, resulting in
better control of breast cancer. The new era requires a shift in thinking and a
re-evaluation of the traditional diagnostic and therapeutic approaches to breast
diseases. Tumors are smaller, less often node-positive, and have a more favorable
malignancy grade. The challenge for diagnosticians is to find as many breast
cancers as possible in the preclinical phase. The challenge for therapists is to
adapt the treatment guidelines accordingly, in order to avoid over-treatment.
PMID- 10757845
TI - Oncopolitical issues: obstacles and options for success in a comprehensive breast
center.
AB - Over the last 20 years of breast center development, it has been found that for
every obstacle there is an option for resolution. The solutions are not uniform
in each setting, but rather they are a reflection of the medical staff politics,
interests, and strengths, the resources and commitment of the institution, and
the needs of the community. The most important message of this article is to
validate local medical staff issues as legitimate concerns. The crucial obstacle
is the lack of cooperation among the medical specialties and the lack of trust
between the medical staff and management. The obstacles need to be appropriately
addressed by the creation of an effective organizational structure that is
successful in the local environment and by the programmatic development that
reflects the medical staff's interests and strengths. This will ensure
comprehensive breast center success in the local political environment and
ultimately translates into enhanced expertise, pride, and higher quality patient
care.
PMID- 10757846
TI - The pathologist in breast cancer: contemporary issues in the interdisciplinary
approach.
AB - The pathologist's contribution to the interdisciplinary team approach in breast
cancer management is a cornerstone for decision-making. Continuous communication
with the radiologist, surgeon, oncologist, and radiation oncologist is essential.
Preoperative diagnosis, surgical specimen work-up with size determination,
sentinel lymph node examination, processing forms to facilitate the work-up, and
diagnostic templates are some of the items covered in this review of the
pathologist's contribution to the interdisciplinary team in breast cancer. Use of
diagnostic templates or synoptic reports routinely provide the complete
diagnostic information required for treatment decisions.
PMID- 10757847
TI - Building quality into comprehensive breast care: a practical approach.
AB - The evolution of interdisciplinary breast centers has led to a revolution in both
quality and advocacy for better breast care. This article provides new
perspectives and practical approaches in the continuing quest to define, build,
and deliver quality services. Five building blocks are described to assist breast
center leaders and other physicians as they endeavor to elevate quality standards
and lower mortality rates in their communities.
PMID- 10757848
TI - The role of medical oncology in an interdisciplinary comprehensive breast center.
AB - The management of patients with breast cancer requires physicians with diverse
expertise and skills. The comprehensive care of such patients is best
accomplished when all necessary health care providers work together using an
interdisciplinary model. Such a close working relationship has advantages for the
patient and the physician. The role of the medical oncologist has greatly
expanded during the past 3 decades. Physician participation has become necessary
at each step of a patient's diagnosis, treatment, and follow-up. This is best
accomplished when all physicians who will provide care are part of an
interdisciplinary breast center.
PMID- 10757849
TI - Psychologic issues, practitioners' interventions, and the relationship of both to
an interdisciplinary breast center team.
AB - Over the past few decades there has been an ever increasing awareness of the need
to address the psychosocial, psychologic, and sexual issues that can surface for
women who face a diagnosis of breast cancer. The comprehensive breast center has
shown itself to be one setting in which multidisciplinary teams can come together
to work efficiently and compassionately in a coordinated fashion to support women
holistically through the breast cancer experience. This article offers a review
and addresses the juxtaposition of women's needs, practitioners' potential roles,
and the preliminary knowledge to date showing comprehensive breast centers as one
setting in which women's needs are best met.
PMID- 10757850
TI - Genetics and the multidisciplinary breast center.
AB - The cancer genetics consultation and comprehensive breast centers logically go
hand in hand. Breast surgeons may be interacting for the first time with a
relatively new class of colleagues-genetics professionals, such as medical
geneticists and genetic counselors. This article introduces surgical oncologists
to the current applications of genetic counseling in oncology practice through
the involvement of genetics professionals on interdisciplinary teams, in case
conference, at grand rounds and oncology meetings, and through genetic risk
assessment, counseling, and possible susceptibility testing. Surgeons interacting
with the cancer genetics specialists have critical roles to play in the
organization of cancer genetics programs, recognition of patients and families at
increased genetic risk, appropriate referrals for genetic counseling and testing,
and management of high-risk families.
PMID- 10757851
TI - Exercise induced bronchospasm in asthmatic and non-asthmatic obese children.
AB - AIM: to investigate the spirometric response to the exercise challenge in
asthmatic and non-asthmatic obese children. PATIENTS, MATERIALS AND METHODS: it
was a prospective, longitudinal, open label clinical trial with four groups of
children from 8 to 16 years. The group 1 had 15 asthmatic non-obese children. The
group 2 had 15 asthmatic obese children. The group 3 had 15 non-asthmatic obese
children. The group 4 had 13 control healthy children. Spirometry measures were
realized at baseline, and after exercise at 2, 5, 10, 15, 20, 25, 30 and 60
minutes. Exercise challenge was performed on a walking band at 6 km/h speed and a
slope of 10 degrees with a duration of 6 to 8 minutes. Data were are analyzed by
repeated measures ANOVA. RESULTS: the mean age was 11.8 +/- 2.1, and the mean
height was 150.2 +/- 11.3 cm, the mean weight was 46.3 +/- 17.15 in the group 1,
59.4 +/- 11.9 in the group 2, 67.8 +/- 20.6 in the group 3, and 44.2 +/- 9.7 in
the group 4. The mean values of forced expiratory volume in one second (FEV1) for
each group are shown on table II. CONCLUSIONS: the non-asthmatic obese children
had a significant decrease in FEV1, meanwhile the asthmatic obese children had a
deeper decrease in FEV1 than the asthmatic non-obese children. Obesity ay be a
conditioning factor for bronchial hyperreactivity to the exercise.
PMID- 10757852
TI - The effects of daily pulmonary rehabilitation program at home on childhood
asthma.
AB - OBJECTIVE: the aim of this study is to investigate the efficacy of pulmonary
rehabilitation program in children with asthma. PATIENTS AND METHOD: twenty eight
children with mild persistent or moderate asthma were included into a double
blind, randomised study. Sixteen children (9 girls, 7 boys) with the mean age of
10.8 +/- 2.3 were assigned to receive pulmonary rehabilitation program with their
parents for 30 days (group I). Control group included 12 children (6 girls, 6
boys ) with the mean age of 10.2 +/- 2.4 (group II). Symptom and medication
scores quality of life index and pulmonary function tests were evaluated in
rehabilitation and control group in the beginning of the study and after the one
month period. RESULTS: the groups did not differ on all parameters before the
study (p > 0. 05). Statistically significant decrease were found in symptom and
medication scores in rehabilitation group (p < 0.05) and quality of life index
was increased significantly in the same group (p < 0.05). Pulmonary function
measures also significantly improved including vital capacity, forced vital
capacity, FEV1, PEF and FEF25-75 in the rehabilitation group (p < 0.05). The best
improvement were seen in FEF25-75 (10.09% increase) and PEF (7.81% increase)
values. In control group no statistically significant differences were found in
all parameters. CONCLUSION: in this study it was shown that daily pulmonary
rehabilitation at home could improve quality of life and pulmonary functions. So
pulmonary rehabilitation should be placed as a component of management in
childhood asthma.
PMID- 10757853
TI - Parental history of migraine and bronchial asthma in children.
AB - BACKGROUND: a possible association between migraine and various allergic
disorders have been reported. It was aimed in this study to inquire the
association between bronchial asthma in children and parental history of
migraine. METHODS AND RESULTS: parental history of allergic diseases and migraine
were inquired among 140 asthmatic children (91 males, 49 females) and 110 age and
sex matched control subjects who had not any allergic or hypersensitivity
disorders, followed-up at Pediatric outpatient clinics of Dicle University
Hospital. While 13 of 140 asthmatic children (9.3%) had parental history of
migraine, 2 of 110 control subjects (1.8%) had parental migraine history.
Difference between asthmatic and control subjects was significant (OR: 5.5, 95%
Cl: 1.3-25.0). Children who had parental history of migraine also had
significantly more frequent parental history of asthma, eczema and particularly
allergic rhinitis (p=0.007). CONCLUSIONS: our results suggest that children are
at increased risk of asthma if their parents have a history of migraine. Migraine
in one generation and asthma in the next lead to the conclusion that the two
disorders may have a relationship to a common denominator.
PMID- 10757854
TI - Evolution of IgA deficiency to IgG subclass deficiency and common variable
immunodeficiency.
AB - FIRST REPORT: male child with repeated pulmonary infections from the age of 4
months. He was diagnosed as IgA deficiency (undetectable IgA levels) at the age
of 3 years, when he presented repeated bouts of pneumonia and tonsillitis.
Several immunologic evaluations were made between the ages of 4 months and 8
years. At 8 years and 9 months, the diagnosis of IgA deficiency was confirmed,
and associated IgG2 and IgG4 deficiency (29.0 mg/dl y 0.01 mg/dl) with normal
total IgG serum level was found. With the administration of intravenous
gammaglobulin, the lung infections remitted and the subsequent clinical course
has been uneventful up to now. SECOND REPORT: a boy with repeated infections
since the age of 2 months. IgA deficiency was diagnosed at 1 year 7 months
(undetectable serum IgA levels). At age 51/2 years, his clinical course worsened
and more serious infections appeared. A new immunologic study revealed IgA
deficiency associated with CD4 cell deficiency (432 cells/mm3) and normal CD3,
CD19, and CD8 levels. Despite intensive antibiotic treatment and care, the child
died. The findings suggest an association of IgA deficiency and common variable
immunodeficiency.
PMID- 10757855
TI - Eosinophilic gastritis due to Anisakis: a case report.
AB - BACKGROUND: the parasite Anisakis simplex is a helminth included in the nematode
class. When man eats raw or rare fish and cephalopods infested by Anisakis
larvae, he can acquire the parasitic disease (anisakidosis). The parasite can
also originate manifestations of immediate IgE mediated hypersensitivity in
patients with sensitisation to it. METHODS AND RESULTS: we present the case of a
14 year old boy diagnosed of eosinophilic gastritis after endoscopic examination
and biopsy associated to recurrent abdominal pain. After allergologic study, a
type I hypersensitivity mechanism against Anisakis simplex is confirmed by means
of prick test, antigen specific IgE determination and antigen specific histamine
release test. Sensitisation against fish proteins is ruled out as well as
parasitic infestation. CONCLUSIONS: in this case report we demonstrate a type I
hypersensitivity mechanism against Anisakis simplex in a patient diagnosed of
eosinophilic gastritis. This can be suspected in cases of gastritis or non
filiated enteritis with a torpid evolution following the conventional treatment
and especially if the onset of the symptoms is related with the intake of fish.
The therapeutic success was reached when fish and shellfish were taken out of the
diet. After two years without seafood ingestion our patient is asymptomatic and
the allergologic study has been normalised.
PMID- 10757856
TI - [Allergic reactions and pseudoallergies in surgical interventions with general
anesthesia].
AB - The Spanish Societies of Allergology and Anesthesiology have established a
protocol for action for the performance of allergy tests for anesthesia. The
protocol was published by the General Directorate of INSALUD, along with an
informed consent form for general and loco-regional anesthesia, on 30 June 1994.
Despite this, demands for care and requests for allergologic and anesthetic
studies have increased. This review examines the diagnostic, preventive, and
therapeutic criteria for adverse reactions during general anesthesia according to
the most relevant international literature. Pseudoallergic reactions are one of
the most frequent and important adverse reactions that occur during general
anesthesia. These reactions are caused by the release of histamine and, probably,
other mediators. The histamine-releasing effect depends on the dose of the
medication. The most potent medications are morphine and almost all muscular
relaxants, in the following proportions (succinylcholine: 43%; vecuronium: 37%;
pancuronium: 13%; alcuronium: 76%; atracurion: 6.8%; galamine: 56%). Somewhat
less than 50% of all severe intraoperative allergic reactions are really
anaphylactoid reactions. The mediators involved in anaphylactic/anaphylactoid
responses are: IgE in type I hypersensitivity mechanisms, IgA, immunocomplexes,
complement activated by an alternative pathway, tryptase, and histamine. Numerous
and varied agents are involved. Table III lists general intravenous anesthetics;
table IV shows muscular relaxants. According to national studies, intraoperative
latex sensitization occurs in 1% to 5% of health-care personnel and 40% of
children with spina bifida. More than 6% of blood donors have IgE against latex.
Cross-reactions between latex and fruit proteins, such as banana and kiwi, have
been reported. As many as 50% of patients with latex allergy have such cross
reactions, according to some authors. Diagnostic methods include skin tests,
challenge, histamine release test, RIA, human basophil optical degranulation
test, and ImmunoCAP. Skin tests are the technique most often used in Allergology
Units in Spain. Risk factors are debated. Although the female sex is accepted as
predominant, atopy is controversial. The only known negative factor is the
insertion of an endotracheal tube in asthmatic patients. Prevention should begin
with the selection of less potent drugs, such as histamine releasing agents. Slow
administration of drugs, as opposed to bolus administration, has been
demonstrated to be more effective. The use of combined H1 and H2 antihistamines
as a preanesthetic medication can significantly reduce tachycardia/bradycardia,
hypotension, skin response, and even gastric pH changes induced by histamine
release.
PMID- 10757857
TI - [Trends in traffic accident mortality in Spain, 1962-1994].
AB - OBJECTIVE: To assess the evolution of the traffic accident mortality rate in
Spain from 1962 to 1994, and the role played by its four theoretical components:
motorization index (vehicles/population), accidentability index
(accidents/vehicles), harmfulness index (victims/accidents) and fatality index
(deaths/victims). METHODS: Data from the National Population Census and the
Bulletin of the Direccion General de Trafico were collected to estimate the above
mentioned indicators for all accidents and accidents in road and urban zones.
Simple and multiple partial correlation coefficients among variables were
calculated. Poisson regression models were also obtained. RESULTS: An increasing
trend during the whole period was observed for the national traffic accident
mortality rate, especially from 1982 to 1989 in the younger age groups, followed
by a decrease since 1990. The aforementioned four components were significatively
associated with the mortality rate. The strength of this association was
especially high for the motorization index and for the harmfulness index when all
accidents and road accidents were considered. For urban accidents, the fatality
index rate is the component most strongly associated with mortality rate. The
role played by the accidentability index in the magnitude of the mortality rate
seems less important. CONCLUSIONS: The growing exposure rate to traffic accidents
observed in Spain (measured by the motorization index) is not directly influenced
by public heath strategies. Therefore, it seems advisable to emphasize the
development of measures focused to control the other three components of traffic
accident mortality rate, especially those related with harmfulness and fatality.
PMID- 10757858
TI - [Geographical variability in the severity of traffic accidents in Spain].
AB - OBJECTIVE: The aim of this study is to analyze the geographical variability of
the severity of traffic accidents in Spain, from 1985 to 1994, and to compare
several severity indicators. METHODS: The mean values --from 1985 to 1994-- of
the following indicators were obtained for each province: mortality index
(deaths/accidents), harmfulness rate (victims/accidents), fatality rate
(deaths/victims), motorization index (vehicles/inhabitants) and population
density. Variability measures among provinces were obtained for each one.
Provinces were then grouped in tertiles according to the magnitude of each
indicator. Simple correlation coefficients among indicators were calculated.
Poisson regression models were obtained, using severity indicators as the
dependent variables. RESULTS AND CONCLUSIONS: Geographical variability was
especially high for mortality index and fatality rate. For all severity
indicators, lower values were found in provinces with the highest population
densities and important metropolitan areas. Harmfulness and fatality rates play
an independent role upon mortality index.
PMID- 10757860
TI - [Perinatal variables and health inequalities in a health-care district in
Caceres, Spain].
AB - OBJECTIVES: To analyze the relation between perinatal variables (gestational,
neonatal, demographic, and social) at time of delivery. To evaluate differences
between rural and urban areas --and differences between social status within
these areas-- as an approach to studying health inequality. To identify variables
associated with the risk of prematurity and low birth weight from onset of
pregnancy. METHODS: A retrospective study was made of deliveries in a 4-year
period (1993-1996) in a health-care district of the province of Caceres (Spain)
(population: 176,511 inhabitants). Data were obtained from hospital records (N =
5922 deliveries). Gestational (mother's age, multiparity), neonatal (sex, birth
weigh, weeks of gestation, twin birth), and sociodemographic variables (mother's
place of residence and social rank) were studied. A logistical regression
analysis was made to identify the main risk factors. RESULTS: The percentage of
infants with birth weight less than 2800 g (16.92%) or less than 2500 g (7.80%),
and of preterm births (6.16%) in the health-care district of Caceres were higher
than those reported for other studies made in Spain and elsewhere. The risk of
low birth weight (<2800 g) was greater for twin births (OR = 16.50; IC 95%: 9.67
28.15); female infants (OR = 1.36; IC 95%: 1.19-1.56), adolescent mothers (<20
years: OR = 1.54; IC 95%: 1.14-2. 09), older mothers (>35 years: OR = 2.12; IC
95%: 1.41-3.17), and first pregnancies (OR = 1.25, IC 95%: 1.09-1.44). The
mother's social status was a risk factor for urban marginal groups compared with
non-marginal groups (OR = 1.43, IC 95%: 1.12-1.82). The risk of preterm birth
depended mainly on the mother's age and was greater in adolescents (OR = 1.84, IC
95%: 1.17-2.89) and older women (OR = 3. 08, IC 95%: 1.81-5.24), as well as for
twin births (OR = 10.47; IC 95%: 6.49-16.89). Women in marginal urban groups had
the highest rates of multiple pregnancies and adolescent pregnancies. Women in
non-marginal urban areas had the highest rate of first pregnancies in older
women. Women in rural areas showed intermediate characteristics. CONCLUSIONS: The
percentage of low-birth-weight or preterm newborns and of adolescent mothers was
greater in women of lower socioeconomic level. The greatest differences in
perinatal variables were observed in urban areas (marginal vs. non-marginal
groups) and between regions and countries.
PMID- 10757859
TI - [Smoking habits, exposure to environmental tobacco smoke, and respiratory
symptoms in schoolchildren aged 14-15 years in Terrassa (Barcelona)].
AB - OBJECTIVES: Assessment of the prevalence of smoking habits, environmental tobacco
exposure, and asthma-related symptoms in a cross-sectional study in
schoolchildren aged 14-15 years in Terrassa (Barcelona). METHODS: A sample of 793
students from 21 schools answered a self-administered questionnaire including
information on smoking habits, environmental tobacco exposure and asthma-related
symptoms. RESULTS: The prevalence of smoking daily was 16.3% (CI 13. 7-18.9); no
difference between sexes were observed, while the proportion of occasional
smokers was higher among girls. Age, maternal habit, friend's smoking habit and
having older siblings were independently associated to the schoolchildren's
smoking habits. Overall, 13% reported a positive history of wheezing and 20.3% of
nocturnal cough during the previous year. Smoking daily and passive smoking were
positively associated with the prevalence of asthma-related symptoms, but not
with previous diagnosis of asthma. CONCLUSIONS: The prevalence of smoking among
adolescents seems to have levelled off. There is some trend toward a higher
prevalence among girls than among boys. The presence of smoking in the social
environment is a strong predictor of the smoking habits among schoolchildren.
Both active smoking and environmental exposure to tobacco smoke are associated to
increased asthma-related symptoms.
PMID- 10757861
TI - [Health care resources utilization in HIV-infected patients: creation of a data
base and cost results].
AB - OBJECTIVES: To make and validate a data base that allows to collect information
about clinical characteristics and use of health care services by HIV-infected
patients. An additional purpose is to obtain some data about costs of health care
services utilization. METHODS: We have designed an informatic data base that
includes: demographic data, clinical data and health care services utilization
during the follow up. One hundred and nine patients were selected from 5
different hospitals in Spain and they were followed for 6 months (from January to
June 1997). Analytic accounting of one hospital and official tariffs were used to
calculate costs of the health care services. RESULTS: The informatic data base
designed is useful and appropriate to collect the information of these patients.
The annual average cost is 2.5 millions dollars, ranging from 1 million dollars
for asymptomatic patients to 3.8 millions for AIDS patients. The comparison of
our results with previous studies shows an increased cost of asymptomatic
patients. CONCLUSIONS: These results give a preliminary information about health
care services utilization by HIV-infected patients and confirm the possibility of
using the designed instrument in the future. Since HIV-infection presents an
uncertain evolution and a variable prognosis, to implant a tracking system is a
necessary requirement in order to obtain a fast and accurate information system
about the evolution of clinical variables and their economic repercussions.
PMID- 10757862
TI - [Patient classification systems in intermediate and long-term stay institutions:
evolution and future perspectives].
AB - The importance of long term care sector is increasingly growing. Actually, the
use of patient classification systems is a useful tool for the planning and
management of health services for chronic and geriatric patients. Despite being
much less known, patient classification systems have had a richer and earlier
development in the long term care sector than in the acute care sector. Thus, one
could could see the evolution from classifications based on the assessment of
functional dependency to classifications progressively including variables
corresponding to clinical complexity, and finally to complex systems such as RUG
III. Patient classification systems were first utilised as tools for the
financing of long term centres, based on the patients' characteristics. Later,
their applications have spread out to objectives related to the management of
centres, assessment of quality of care, staff allocation level, control of access
and national policies. In Spain, the only experience in the use of a patient
classification system is the one used by the Catalan Health Care Administration
which uses a classification for the financing of their centres.
PMID- 10757863
TI - [Coping with the toll of heroin: 10 years of the Barcelona Action Plan on Drugs,
Spain].
AB - INTRODUCTION: The epidemic of heroin use began in Barcelona, as in the rest of
Spain, in the late 70's, to reach its peak by the end of the 80's. In a first
period, responsible officers experimented difficulties to define the specific
objectives of opiate control policies. This paper reviews the effects of the
adoption of an explicit policy on drug dependence grounded on a wide consensus in
the City of Barcelona (Catalonia, Spain). SUBJECTS AND METHODS: Over a period of
twelve years, from 1986 to 1997, both demand and offer of care and harm reduction
services were analyzed, as well as the evolution of the adverse effects of drug
use, such as mortality from acute adverse drug reaction, human immunodeficiency
virus (HIV) infection, aids incidence, and incidence of tuberculosis. Data for
city residents was compared through four different stages in this period.
RESULTS: Despite the lack of data in initial years, relevant changes are
apparent. Treatment offer changes clearly, with significant increases in initial
treatment, coverage of methadone maintenance programmes, and sterile syringes
distribution. Therapeutic compliance of tuberculous intravenous drug users IVDU
and risk of HIV infection improve. Emergency service use linked to heroin,
overdose, or withdrawal syndrome decreases. Mortality rates decline, although
this decline does not reach statistical significance. DISCUSSION: Service offer
shows a clear increase, reflected in treatment initiation, while harm reduction
services expand. With the development of this process, outcome indicators change,
both reflecting changes in the toll of the heroin epidemic (cases of tuberculosis
and aids among IVDUs, HIV infection). and changes in a more comprehensive care
(better treatment compliance of IVDUs with tuberculosis). There is a lower
distortion of emergency services. These changes occur although the predominance
of white heroin in Barcelona favors parenteral use.
PMID- 10757864
TI - Does cyclosporin A worsen liver function in patients with inflammatory bowel
disease and total parenteral nutrition?
AB - OBJECTIVE: inflammatory bowel disease (IBD), total parenteral nutrition (TPN) and
immunosuppressive treatment with cyclosporin A (CsA) are well known factors in
hepatobiliary disorders. Their association, however, has been little studied.
METHOD: we retrospectively analyzed the results of liver function tests
(transaminases, AST. ALT), total bilirubin, alkaline phosphatase, and gamma
glutamyltransferase (GGT) in a consecutive series of 50 patients (29 men, 21
women, mean age 32 years, range 16-78 years) hospitalized for a severe attack of
IBD between January 1992 and July 1997. Basal laboratory values in all patients
were normal. Thirty-eight patients had ulcerative colitis (UC) and 12 had Crohn's
disease (CD), which debuted in 28% of the patients. All patients were treated
with methylprednisolone (MP) (0.75-1.0 mg/kg daily i.v., and received TPN. 42%
(21/50) required additional treatment with CsA (5 mg/kg daily i.v.) at the
beginning or during the first week of TPN and during 7-24 days, because on
nonresponse to steroid treatment. Two study groups were defined according to
treatment: Group I consisted of 29 patients given MP + TPN, and group II
comprised 21 patients who received MP + TPN + CsA. The groups were otherwise
similar in all other variables analyzed. Liver function tests were done weekly
until the end of the study period. RESULTS: 62% of the patients (31/50) showed
hepatobiliary dysfunction, defined previously as a 2-fold or greater elevation of
two or more parameters. There was no statistically significant difference between
the two groups in the incidence of dysfunction (15/29 vs 16/21, n.s.). The
parameters that showed the greatest alterations were GGT and ALT; the greatest
elevation appeared during the third week of immunosuppressive treatment, and did
not exceed 6-fold the normal value. The alterations disappeared once TPN and
immunosuppressive treatment were discontinued. CONCLUSIONS: the hepatobiliary
dysfunction in patients treated with both TPN and CsA was no more severe than
associated with TPN alone.
PMID- 10757865
TI - Adult celiac disease and hypertransaminasemia.
AB - OBJECTIVE: to determine the incidence of hypertransaminasemia in adult patients
with celiac disease with or without relevant chronic liver disease, and to
evaluate the response after a gluten-free diet. PATIENTS AND METHODS:
retrospective study of 20 cases of adult celiac disease (> 14 years old at
diagnosis). Patients were included in the study if they fulfilled the revised
EPSGAN criteria. If laboratory tests of liver function revealed alterations,
hepatitis B and C viral serology, thyroid hormones, and use of alcohol and drugs
were investigated, and liver ultrasound scans were done. Liver biopsy and
endoscopic retrograde cholangiopancreatography were done only in patients for
whom these studies were considered necessary. RESULTS: ten patients had
hypertransaminasemia (50%), ascribed to benzodiazepine use in 1 patient, chronic
HCV hepatitis in 1, and celiac disease in 8. In all of these last patients except
1 (benzodiazepine use), laboratory values returned to normal after 4-10 months on
a gluten-free diet. CONCLUSIONS: celiac disease was frequently associated with
hypertransaminasemia. In most patients transaminase levels returned to normal
within 1 year after dietary gluten intake was restricted. If alterations in
laboratory values persist, other causes that may be related (e.g., autoimmunity
or tumors) or unrelated to celiac disease (e.g., virus) must be ruled out.
PMID- 10757866
TI - Collagenous colitis and lymphocytic colitis: clinical and endoscopic findings.
AB - OBJECTIVE: collagenous colitis (CC) and lymphocytic colitis (LC) are two entities
of unknown cause, characterized by chronic watery diarrhea, grossly normal
appearing colonic mucosa and abnormal histopathological findings in colonic
biopsies. The clinical features of the disease are based mainly on case reports
or small uncontrolled series. Although normal colonoscopic findings are, as a
rule, part of the diagnosis of CC, several cases of macroscopic colitis
associated with CC have been reported, and the spectrum of endoscopic mucosal
changes has not been described in large series. METHODS: we present a
retrospective study of all patients who underwent total colonoscopy and mucosal
biopsy in our Endoscopy Unit between 1991 and 1997. Clinical and endoscopic
findings in patients diagnosed as having CC or LC were recorded. RESULTS: of 676
patients studied, 398 suffered from chronic diarrhea. Collagenous colitis was
diagnosed in 22 patients and LC in 10. Eleven per cent of the patients with CC
and 20% of those with LC did not have diarrhea. Macroscopic colitis was observed
in 6 out of 22 patients with CC (27%) and in 4 out of 10 with LC (40%).
Macroscopic lesions included edema, erythema, abnormal vascular pattern,
superficial erosions or ulcerations and hemorrhagic lacerations. In this series
7.03% of the patients with chronic diarrhea were diagnosed as having CC or LC.
CONCLUSIONS: collagenous colitis and LC are two entities that should be
considered in the differential diagnosis of chronic diarrhea. Total colonoscopy
with multiple biopsies that include the right colon are mandatory. The presence
of macroscopic lesions on endoscopy does not rule out a diagnosis of either
entity. We identified patients who fulfilled the histopathological criteria for
CC or LC but who did not have diarrhea.
PMID- 10757867
TI - Resection of colorectal liver metastases: analysis of risk factors.
AB - OBJECTIVE: to analyze the survival after surgery to resect liver metastases from
colorectal cancer, and to investigate the influence of 15 potentially prognostic
factors on survival. METHODS: this retrospective study included all patients
diagnosed as having colorectal cancer who were operated on with curative intent
(without no evidence of tumor after surgery) during the 10-year period from 1988
to 1998. Survival analysis was done using the Kaplan-Meier method, and the
prognostic value of each factor was determined with the log-rank test. Of the 60
surgical patients we studied, 58 survived the postoperative period (< 30 days).
We analyzed their epidemiological, histological and chronopathological
characteristics, tumor markers, and type of resection. RESULTS: mean survival was
33. 06 +/- 3.2 months, and ranged from 2 to 108 months. Survival at 1, 3 and 5
years was 90.1%, 48.9% and 28.9% respectively. None of the 15 prognostic factors
studied was significantly related with survival (p < 0.05). CONCLUSIONS: surgical
treatment of liver metastases from colorectal cancer is a safe option and offers
good survival rates. The potentially prognostic factors studied here do not allow
us to identify those patients who might benefit most from this procedure.
PMID- 10757868
TI - [Cerebral venous sinus thrombosis and ulcerative colitis].
AB - Hypercoagulability is a extraintestinal manifestation of inflammatory bowel
disease, which could provoke thromboembolic phenomena. Central nervous system
venous thrombosis is a rare complication and could be unnoticed. We report on a
patient with ulcerative colitis who presented cerebral venous sinus thrombosis as
the first manifestation of a hypercoagulable state. We review the literature and
discuss about the pathogenic mechanisms of such complication.
PMID- 10757869
TI - [Intermittent intestinal ischemia associated with a tumor].
PMID- 10757870
TI - [Hyperamylasemia: it is not always acute pancreatitis].
PMID- 10757871
TI - [Body posture in gastroesophageal reflux].
PMID- 10757872
TI - [Percutaneous translumbar inferior vena cava cannulation. Alternative access for
home TPN].
PMID- 10757873
TI - Introduction to organization of the neuromuscular junction: from structure to
function.
PMID- 10757874
TI - Synaptic target recognition at Drosophila neuromuscular junctions.
AB - Every synaptogenesis begins with "synaptic target recognition," a cell-cell
recognition event in which a neuron and its target stably adhere. Despite its
importance in developing nervous systems, synaptic target recognition has been
difficult to study in complex systems. The relatively simple and genetically
accessible Drosophila NMJ model system provides a repertoire of target
recognition cues. We describe how these molecules control the targeting of
specific growth cones in either a positive (synaptogenic) or negative (anti
synaptogenic) manner. We also propose two alternate signaling paradigms to
explain how these initial cell recognition events are coupled to the
intracellular signaling pathways that begin the process of synapse maturation.
PMID- 10757875
TI - Drosophila larval neuromuscular junction: molecular components and mechanisms
underlying synaptic plasticity.
AB - Understanding the mechanisms that mediate synaptic plasticity is a primary goal
of molecular neuroscience. The Drosophila larval neuromuscular junction provides
a particularly useful model for investigating the roles of synaptic components in
both structural and functional plasticity. The powerful molecular genetics of
this system makes it possible to uncover new synaptic components and signaling
molecules, as well as their function in the intact organism. Together with the
mouse hippocampus and Aplysia dissociated cell culture, the Drosophila larval
neuromuscular junction has been among the most valuable model systems for
examining the molecular and cellular basis of neuronal plasticity.
PMID- 10757876
TI - Rodent nerve-muscle cell culture system for studies of neuromuscular junction
development: refinements and applications.
AB - Understanding of vertebrate neuromuscular junction (NMJ) development has been
advanced by experimentation with cultures of dissociated embryonic nerve and
skeletal muscle cells, particularly those derived from Xenopus and chick embryos.
We previously developed a rodent (rat) nerve-muscle coculture system that is
characterized by extensive induction of acetylcholine receptor (AChR) aggregation
at sites of axonal contact with myotubes (Dutton et al., 1995). In this article,
we report modifications of this culture system and examples of its application to
the study of NMJ development: (1) We describe improved methods for the enrichment
of myoblasts to give higher yields of myotubes with equal or greater purity. (2)
We demonstrate lipophilic dye labeling of axons in cocultures by injection of dye
into neuron aggregates and show the feasibility of studying the growth of living
axons on myotubes during synapse formation. (3) We describe the preparation of a
better-defined coculture system containing myotubes with purified rat motoneurons
and characterize the system with respect to axon-induced AChR aggregation. (4) We
demonstrate dependence of the pattern of axon-induced AChR aggregation on muscle
cell species, by the use of chick-rat chimeric co-cultures. (5) We provide
evidence for the role of alternatively-spliced agrin isoforms in synapse
formation by using single cell RT-PCR with neurons collected from co-cultures
after observation of axon-induced AChR aggregation. Microsc. Res. Tech. 49:26-37,
2000. Published 2000 Wiley-Liss, Inc.
PMID- 10757877
TI - Quantal acetylcholine release: vesicle fusion or intramembrane particles?
AB - Images of vesicle openings in the presynaptic membrane have regularly been shown
to increase in number after stimulation of cholinergic nerves. However, with a
very few exceptions, the occurrence of vesicle openings is delayed in time with
respect to the precise moment of transmitter release. In contrast, a transient
change in the size and distribution of intramembrane particles (IMPs) has
constantly been found as a characteristic change affecting the presynaptic
membrane in a strict time coincidence with the release of acetylcholine quanta.
This is illustrated here in a rapid-freezing experiment performed on small
specimens of the Torpedo electric organ during transmission of a single nerve
impulse. A marked change affected IMPs in the presynaptic membrane for 3-4 ms,
i.e., a population of IMPs larger than 10 nm momentarily occurred in coincidence
with the passage of the impulse. The nicotinic receptors, abundantly visible in
the postsynaptic membranes, also underwent very fleeting structural changes
during synaptic transmission. In conclusion, for rapidly operating
neurotransmitters like acetylcholine, a characteristic IMP change was regularly
found to coincide in the presynaptic membrane with the production of
neurotransmitter quanta, whereas images of vesicles fusion were either delayed or
even dissociated from the release process. This is discussed in connection to the
different modes of release recently described for other secreting systems.
PMID- 10757878
TI - Role of mediatophore in connection with proteins of the active zone in synaptic
transmission.
AB - Mediatophore is a protein purified from Torpedo electric organ synaptosomes,
which translocates acetylcholine (ACh) upon calcium action after reconstitution
in artificial membranes. After expression in transfected cells, it endows these
cells with a calcium-dependent release mechanism displaying clear quantal
properties. The role of mediatophore in synaptic transmission is discussed in
relation to the ultrastructural organization of the active zone and the cytosolic
high calcium microdomains that transiently appear after presynaptic membrane
depolarization.
PMID- 10757879
TI - Why so many forms of acetylcholinesterase?
AB - Acetylcholinesterase is a key molecule in the control of cholinergic
transmission. In the mammalian neuromuscular junction (NMJ), the efficiency of
this phenomenon depends on the enzyme location, between the presynaptic site
where acetylcholine is released and the postsynaptic membrane where the
acetylcholine receptors are packed. Various molecular forms of the enzyme that
possess the same catalytic activity are expressed. The relative amounts of these
forms are tissue-specific. At the subcellular level, this panoply of forms allows
the enzyme to be attached to the membrane or to the basal lamina. Analysis of the
forms secreted and their position in the cytoarchitecture of the NMJ is essential
to understand the functioning of this synapse. This review will consider the
origin of the enzyme polymorphism and its physiological implication.
PMID- 10757881
TI - Clustering of sodium channels at the neuromuscular junction.
AB - Voltage-gated sodium channels (NaChs) are highly concentrated in the postsynaptic
region of the neuromuscular junction, especially in the depths of postsynaptic
folds and in the perijunctional region. The formation of the high NaCh density
occurs during synapse maturation, approximately 2 weeks after initial synaptic
contact in the rodent. The concentration of NaChs and their localization in the
troughs of the folds increase the safety factor for neuromuscular transmission by
reducing the threshold for initiation of the action potential. There is evidence
that agrin plays a role in the formation of NaCh aggregation. Molecules such as
ankyrin and syntrophin that bind NaChs may be important for maintenance of the
high channel density at the endplate.
PMID- 10757880
TI - The torpedo electrocyte: a model system to study membrane-cytoskeleton
interactions at the postsynaptic membrane.
AB - Many aspects of the organization of the electromotor synapse of electric fish
resemble the nerve-muscle junction. In particular, the postsynaptic membrane in
both systems share most of their proteins. As a remarquable source of cholinergic
synapses, the Torpedo electrocyte model has served to identify the most important
components involved in synaptic transmission such as the nicotinic acetylcholine
receptor and the enzyme acetylcholinesterase, as well as proteins associated with
the subsynaptic cytoskeleton and the extracellular matrix involved in the
assembly of the postsynaptic membrane, namely the 43-kDa protein-rapsyn, the
dystrophin/utrophin complex, agrin, and others. This review encompasses some
representative experiments that helped to clarify essential aspects of the
supramolecular organization and assembly of the postsynaptic apparatus of
cholinergic synapses.
PMID- 10757882
TI - Regulation and functional significance of utrophin expression at the mammalian
neuromuscular synapse.
AB - Duchenne muscular dystrophy (DMD) is caused by the absence of full-length
dystrophin molecules in skeletal muscle fibers. In normal muscle, dystrophin is
found along the length of the sarcolemma where it links the intracellular actin
cytoskeleton to the extracellular matrix, via the dystrophin-associated protein
(DAP) complex. Several years ago, an autosomal homologue to dystrophin, termed
utrophin, was identified and shown to be expressed in a variety of tissues,
including skeletal muscle. However, in contrast to the localization of dystrophin
in extrajunctional regions of muscle fibers, utrophin preferentially accumulates
at the postsynaptic membrane of the neuromuscular junction in both normal and DMD
adult muscle fibers. Since it has recently been suggested that the upregulation
of utrophin might functionally compensate for the lack of dystrophin in DMD,
considerable interest is now directed toward the elucidation of the various
regulatory mechanisms presiding over expression of utrophin in normal and
dystrophic skeletal muscle fibers. In this review, we discuss some of the most
recent data relevant to our understanding of the impact of myogenic
differentiation and innervation on the expression and localization of utrophin in
skeletal muscle fibers.
PMID- 10757883
TI - The spectrin-based skeleton at the postsynaptic membrane of the neuromuscular
junction.
AB - Membrane skeletons, in particular the spectrin-based skeleton, are thought to
participate in the organization of specialized membrane domains by restricting
integral proteins to specific membrane sites. In the neuromuscular junction,
discrete isoforms of spectrin and ankyrin, the peripheral protein that links
spectrin to the membrane, colocalize with voltage-dependent sodium channels and N
CAM at the troughs of the postsynaptic membrane folds. Moreover, beta-spectrin, N
CAM, and sodium channels become clustered at the endplate during a period of time
coincident with postsynaptic fold formation and synapse maturation. These
observations suggest a role of the spectrin skeleton in directing and maintaining
postsynaptic accumulations of sodium channels and N-CAM. In addition, the
coexistence of spectrin and dystrophin at the troughs of the junctional folds
raises the question of their respective functions in this membrane domain, where
both cytoskeletal proteins have the potential to associate with sodium channels
via ankyrin and syntrophin, respectively. Possible scenarios are discussed here
with respect to accumulating evidence from studies of assembly of similar
membrane domains in neurons.
PMID- 10757884
TI - Pelvic surgery: Prevention and management of complications.
PMID- 10757885
TI - Planes of sharp pelvic dissection for primary, locally advanced, or recurrent
rectal cancer.
AB - In the design of operations for rectal cancers, the focus is often on
circumventing the local extent of disease and leaving the pelvis free of cancer.
The local extent of disease may range from minimal intramural invasion to the
direct extension of a primary tumor to pelvic sidewall structures, e.g., the
internal iliac vessels. In the absence of distant spread, understanding the
planes of pelvic anatomy may allow the knowledgeable surgeon to cure patients who
would otherwise be declared unresectable. We present the four planes (and one
rare situation) available for sharp dissection which allow for the resection of
all but a few cases of locally advanced disease.
PMID- 10757886
TI - Extrafascial excision of the rectum for cancer: a technique for the avoidance of
the complications of rectal mobilization.
AB - Serious complications can occur following mobilization of the rectum for cancer
including: ureteric injury, rectal perforation, hemorrhage, autonomic nerve
damage, and local recurrence of the tumor in the pelvis. Each of these
complications can be minimized by careful dissection in correct tissue planes in
the pelvis. The rectum and mesorectum are surrounded by the fascia propria, a
thin fascial envelope. This envelope offers a surface for dissection that leads
the surgeon to a safe plane lying inside the autonomic nerves, the ureter, and
the presacral vessels, and lying outside of the mesorectum and its associated
vessels and lymphatics. The surgical anatomy of the pelvis is presented, with
emphasis on the rectal fascia propria, as a basis for a detailed description of
the technique of extrafascial excision of the rectum.
PMID- 10757887
TI - Urologic complications of major pelvic surgery.
AB - The close proximity of pelvic organs makes the genitourinary system susceptible
to injury during major pelvic surgery. Iatrogenic injury remains the most common
cause of lower urinary tract trauma. Recent modifications in surgical technique,
such as sharp mesorectal incision and nerve-sparing radical prostatectomy, have
decreased the incidence of many of these complications. Genitourinary
complications due to pelvic surgery remain common, however, and as new surgical
advancements are made, new complications may present. An understanding of the
prevention, recognition, and treatment of urologic complications is important for
every surgeon performing major pelvic surgery.
PMID- 10757888
TI - Avoidance of female genital tract complications in relation to pelvic surgery for
cancer.
AB - As pelvic surgeons, it is essential that the colorectal surgeon and gynecologist
have knowledge of and mutual respect for the areas of expertise that each
specialty offers. The surgeon will encounter situations in which knowledge of the
gynecologic anatomy is essential if injury is to be avoided during colorectal
procedures. Gynecologic oncologists are trained not only to resect gynecologic
cancers, but to also manage any complications that may result from cancer therapy
or progressive disease. In many communities in which a gynecologic oncologist is
not available, the surgical oncologist or colorectal surgeon will be consulted to
assist in the management of gynecologic cancers. These surgeons must have the
technical prerequisites and detailed knowledge about the mechanisms of spread,
patterns of distant and local recurrences, the probability for cure, and the
treatment methods to achieve management in the various cancers. We will discuss
problems and complications of the female genital tract encountered by the
colorectal surgeon during pelvic surgery for both bowel and gynecologic cancers,
with an emphasis on prevention. Additionally, issues such as prophylactic
oophorectomy and hysterectomy, management of gastrointestinal (GI) tract
involvement in gynecologic cancer patients, the approach to peritoneal
carcinomatosis, and situations where both the gynecologic and colorectal teams
are required will be presented.
PMID- 10757889
TI - Avoiding long-term disturbance to bladder and sexual function in pelvic surgery,
particularly with rectal cancer.
AB - Urinary and sexual dysfunction are common problems after rectal cancer surgery,
and the likely cause is damage to the pelvic autonomic nerves during surgery. In
recent years, attention has been focused on preserving the autonomic nerves
through a technique which is usually combined with total mesorectal excision or
radical pelvic lymphadenectomy. The autonomic nerves consist of the paired
sympathetic hypogastric nerve, sacral splanchnic nerves, and the pelvic autonomic
nerve plexus. We will demonstrate the anatomy of the pelvic autonomic nerves and
the relation of these nerves to the mesorectal fascial planes, and review the
medical literature on sexual and urinary dysfunction after rectal cancer surgery
with and without autonomic nerve preservation.
PMID- 10757890
TI - Anastomotic leakage after colorectal anastomosis.
AB - Leakage is a problem largely confined to anastomoses within 6 cm of the anal
verge when optimal surgical technique is exercised. At such low levels, most
surgeons now use a combination of linear and circular staplers. The Moran Triple
Stapling Technique is our chosen method. Most recently, the simultaneous use of
two linear staplers to seal the specimen and wash the distal stump is a rapid
technique for anastomosis onto the dentate line within the external sphincter.
Proximal defunctioning and the short colon pouch with side-to-end colo-anal
anastomosis are currently considered optimal. A trial is under way to assess a
silastic transanal stent as an alternative. Ultra-low anastomosis, however,
remains potentially hazardous and still should be undertaken only by specialists.
PMID- 10757891
TI - Surgical approaches to obtaining optimal bowel function.
AB - Approximately 50% of patients have an unsatisfactory functional result after
traditional restorative rectal resection, and an even higher percentage, at least
in the early postoperative period, suffers from urgency, frequent bowel
movements, and occasional faecal incontinence. The rectal reservoir function is
disturbed after restorative surgery. This is related to the size of the rectal
remnant, the viscero-elastic properties, and the motility pattern of the
neorectal wall, because segments of the remaining colon can only substitute for
the rectum to a limited extent. A straight anastomosis is recommended when the
rectal remnant (measured from the anal verge) is at least 7 to 8 cm. The side-to
end anastomosis is probably preferable to the end-to-end anastomosis. In
contrast, a straight anastomosis at the levator plane cannot be recommended. If
straight anastomosis is still considered, the descending colon should be used
rather than the sigmoid colon. The colonic pouch was introduced to increase the
neorectal volume and eliminate some of the functional disturbance associated with
the reduced neorectal volume occurring after a straight colo-anal anastomosis. To
obtain optimal functional results soon after surgery, a pouch should be used when
the anastomosis is located 3 to 5 cm from the anal verge. The size of the pouch
should not be too small. A staple line of 6 to 7 cm is a fair compromise between
the low anterior resection syndrome and problems with evacuation. Since the
descending colon has a thinner wall and often is healthier than the sigmoid
colon, it should be the first choice for the anastomosis.
PMID- 10757892
TI - Reconstructive surgery of the pelvis after surgery for rectal cancer.
AB - The role of the reconstructive surgeon has increased with an increasingly
aggressive surgical approach to locally advanced rectal carcinoma. Multiple
options exist for pelvic floor reconstruction. Muscle and myocutaneous flaps for
pelvic-floor reconstruction provide well vascularized tissues which may also
serve as a biologic spacer. Flaps help to prevent post-radiation fistulae, small
bowel obstruction, and pelvic sidewall adherence; flaps also may serve as a
barrier to radiation injury. Often a more stable perineal wound closure is
achieved. In cases that involve vaginal resection, flaps make neo-vaginal
reconstruction possible. Pre-operative consultation with the reconstructive
surgeon allows planning of complex, multi-disciplinary procedures, and
facilitates patient understanding of the proposed procedure.
PMID- 10757893
TI - Complications of laparoscopic surgery for rectal cancer: avoidance and
management.
AB - Since laparoscopy was first introduced as a diagnostic tool for pelvic pathology
15 years ago, the technique has been successfully adapted by general and
specialty surgeons as a therapeutic tool for a variety of diseases. Laparoscopic
surgery has been used to treat colon and rectal pathology since 1991. The
introduction and acceptance of this new access technique also brought the
realization of specific complications associated with a laparoscopic approach.
Advanced laparoscopic skills are required for laparoscopic pelvic and, to
minimize laparoscopic-associated complications, specialized training is required.
We will review the specific complications of the laparoscopic approach in pelvic
surgery with a view to their recognition, prevention, and treatment.
PMID- 10757895
TI - In memoriam.
PMID- 10757894
TI - Results and complications of surgery combined with intra-operative radiation
therapy for the treatment of locally advanced or recurrent cancers in the pelvis.
AB - Intra-operative radiation therapy (IORT) can benefit patients with pelvic tumors
by delivering a high dose of radiation with precise delineation of tumor bed and
maximal protection of surrounding normal tissues. The IORT experience has been
particularly promising for locally advanced primary or recurrent rectal cancers
in which a gross total resection is achieved. However, its potential benefit must
be weighed against added toxicity. The main dose-limiting toxicity of pelvic IORT
is peripheral neuropathy and ureteral stenosis. We will review the techniques for
optimal IORT delivery, the results of the major studies investigating IORT
treatment of rectal cancer, and the pelvic complications associated with
combining surgery and IORT. A team of surgeons and radiation oncologists
providing close multidisciplinary coordination is essential to integrate IORT
with combined modality regimens in a safe and effective manner.
PMID- 10757896
TI - Delay of onset of candidemia and emergence of Candida krusei fungemia in
hematologic patients receiving prophylactic fluconazole.
PMID- 10757897
TI - Perioperative Coagulation Changes with Gastric Bypass: association with venous
thrombosis?
AB - Blood coagulation protein analyses were obtained before, during and after Roux-Y
gastric bypass in 82 patients to observe the individual perioperative changes
indicative of clot formation and fibrinolysis. Pneumatic compression devices were
placed on the legs during this time in order to provide deep venous thrombosis
(DVT) prophylaxis, and non-invasive venous thrombosis detection studies were
performed before and after operation. No occasions of DVT or pulmonary emboli
were detected postoperatively. Preoperative balanced ratios of antithrombin
III/plasminogen were maintained intraoperatively and were increased
postoperatively, reflecting on-going fibrinolysis. Changes in alpha-2 antiplasmin
confirmed this interpretation. Patients subdivided into super- vs morbid obese
groups showed less plasminogen reduction and a lower protein ratio during and
after operation, and less antiplasmin consumption intraoperatively, in the
heavier group. A linear regression analysis of excess weight on the protein ratio
also showed lower ratios in the heavier patients. However, calf or thigh leg
circumferences were not different between super- and morbid obese patients. These
results suggest that leg pneumatic compression should be as effective but the
immobility of super-obese patients may contribute to perioperative
hypofibrinolysis and perhaps make them more susceptible to DVT and pulmonary
embolism.
PMID- 10757898
TI - Effect of Surgically Induced Weight Loss on Asthma in the Morbidly Obese.
AB - Forty morbidly obese asthmatic patients who underwent gastric restrictive surgery
more than 2 years earlier were evaluated to determine the influence of weight
loss on asthma outcome. Mean percentage excess weight loss in this group was 68%
and body mass index (BMI) fell from a mean of 46 to 30. Following surgery, 90%
showed improvement in asthma symptoms. Complete remission of asthma occurred in
48% and a further 12.5% became asthma free on reduced medications dosage. Of
those taking daily medications for asthma before surgery, 42% were completely off
medication following weight loss surgery, and another 18.5% experienced fewer
asthma attacks on reduced medication dosage. Of the 22 patients with severe
asthma (> 10 attacks per year) on routine daily medications for asthma
preoperatively, 8(36%) required no medication after surgery, 7(32%) used
medication only on an 'as-needed' basis, and 7(32%) controlled their asthma on
reduced medication dosage. Five patients gained weight during the follow-up
period. All developed an increased incidence of asthma attacks, which again
abated after successfully losing weight following revisional surgery. Coexistent
factors of smoking and clinically apparent esophageal reflux were evaluated, but
no statistically significant correlation was shown with either smoking or reflux
and improvement in asthma. Possible etiologies of the improvement in asthma with
weight loss are discussed
PMID- 10757899
TI - The Effect of Practical Dietary Counseling on Food Variety and Regurgitation
Frequency after Gastroplasty for Obesity.
AB - After obesity surgery, the primary measurement of success is the amount of weight
lost. There has, however, been little assessment of how patients cope with the
dietary constraints imposed by gastroplasty. Similarly, dietary patterns adopted
to cope with these constraints have not been studied fully. These factors are of
great importance in terms of nutritional adequacy, patient acceptability and long
term success. A study involving 32 patients was conducted to ascertain whether
practical nutritional intervention and extensive follow-up would improve the
overall outcome of the gastroplasty operation with respect to the type of foods
tolerated and the incidence of regurgitation or vomiting experienced. To quantify
success in terms of frequency of regurgitation and variety of food intake a
vomiting/eating (V/E) score was devised. The results showed that the group of
patients with more intensive practical education and counseling had a more varied
intake of food and coped better with a wider variety of solid foods in the long
term. Despite a more solid diet they did not regurgitate food as frequently as
patients with less education, and over half the study group of patients reported
no regurgitation at all. From this study, it is proposed that patients can be
assessed and categorized postoperatively using a V/E scale. This scale
numerically scores success with diet after gastroplasty, which, when recorded in
conjunction with subsequent weight loss, can give a better quantification of
success after obesity surgery.
PMID- 10757901
TI - Invited Commentary.
PMID- 10757900
TI - Biliopancreatic Diversion with a New Type of Gastrectomy.
AB - In an attempt to improve the results of biliopancreatic diversion in the
treatment of morbid obesity, two aspects of the procedure performed at Laval
Hospital were modified to reduce adverse physiological consequences. The distal
gastrectomy was replaced by a parietal gastrectomy which preserves vagal
continuity along with the lesser curvature, and leaves intact the antro
pyloroduodenal pump. The duodenum was stapled shut and nutrients were diverted
through a duodeno-ileal anastomosis. The biliopancreatic diverting intestinal
limb was anastomosed to the nutrient ileal limb 100 cm proximal to the ileocaecal
valve instead of 50 cm proximal to it, thus doubling the length of the common
ileal absorptive segment. Weight loss after either operation was greater than 70%
of initial excess weight. Following the new operation, there was a lesser
prevalence of side-effects, especially loose stools and malodorous gas, a lesser
degree of hypocalcemia and no hypoalbuminemia. The duodenum recanalized at the
staple line in 20% of the patients who had the new operation. When data from
these patients were excluded, weight loss following the new operation was greater
than that seen after the old one. The prevalence of side-effects and the degree
of calcium and protein malabsorption remained significantly lower. Weight loss
remained satisfactory with a common limb measuring 100 cm. The parietal
gastrectomy was not restrictive as shown by the failure to lose further weight
when the duodenal stapled diversion failed. Weight loss was thus mainly a
function of biliopancreatic diversion, but increased weight loss in the new
procedure despite a doubling of the common ileal limb suggests that parietal
gastrectomy contributed to weight loss. Because duodenal recanalization can be
corrected surgically and now prevented, the modified biliopancreatic bypass is
preferred.
PMID- 10757902
TI - Minimum Excess Weight Required for Obesity Surgery: how far can we go?
AB - The classical indication for obesity surgery, in terms of excess weight, included
only patients with an excess weight of 100% or 45 kg. This review challenges this
classic indication. Sixty-four out of 170 patients treated with a biliopancreatic
diversion had an excess weight below 80%. The specific weight-related
complications, reoperations and results are compared with patients above 80%
excess weight. The different groups are comparable in complications and results.
PMID- 10757903
TI - Distal Roux-en-Y Gastric Bypass Conversion Operation for Failed Vertical Banded
Gastroplasty.
AB - Forty-five cases of failed vertical banded gastroplasty were converted to gastric
bypass with distal Roux-en-Y constructed with a 250 cm alimentary limb and a 150
cm common channel. The gastroenterostomy is side-to-side, unrestricted and is at
least 3 cm wide. We believe that this wide anastomosis is responsible for the
zero incidence of stomal ulcers in this group. A nasogastric tube is not used and
the patient is placed on ranitidine 150 mg one b.i.d. for the first 4 weeks. The
weight loss is excellent and sustained, and the resulting life-style is very
close to that of a normal person. All varieties of foods are tolerated in
adequate amounts, and diarrhea occurs only if the patient indulges in fatty
foods. Hypoproteinemia is generally mild and transient except in five early cases
where TPN was needed, and four of these required elongation of the intestinal
segments. Wound infection was 4.5%, and there was no mortality.
PMID- 10757904
TI - Salvage of Failed Horizontal Gastroplasty by the Addition of a Distal Gastric
Bypass.
AB - Thirty-one patients underwent conversion of a failed horizontal gastroplasty by
addition of a distal gastric bypass. Twenty-seven patients had complete long-term
follow-up and their data are presented. The patients were separated into three
groups depending on the initial gastroplasty pouch sizes (varying between 25 and
60 ml). At the time of surgery stoma sizes were evaluated, some being found near
10 mm, others being smaller, that were debanded, and others larger that were not
repaired. Follow-up after distal gastric bypass was 5.7 years (mean). Analysis of
the weight loss data showed that the addition of a distal gastric bypass resulted
in mean greatest excess weight losses near 80% for all groups. Over many years
excess weight losses diminished but only one patient was a weight loss failure.
Weight loss was best maintained and side-effects were fewest where the stoma size
was near 10 mm. Pouch sizes themselves could not be positively correlated with
weight loss, stoma size being much more important. Four patients had
manifestations of the acid peptic ulcer diathesis and were effectively dealt with
by means of vagotomy and hiatus herniorrhaphy.
PMID- 10757905
TI - Adjustable Silicone Gastric Banding (ASGB): the Italian experience.
AB - Adjustable silicone gastric banding (ASGB) is a recently introduced gastric
restrictive procedure. From April 1990 to April 1992, 85 patients underwent ASGB
at our Department. Patients' characteristics were: 65 females, 20 males, mean age
39.6 years (range 17-60 years); body weight (BW) 127.9 +/- 23 kg; % ideal body
weight (%IBW) 205 +/- 29; body mass index (BMI) 46 +/- 7; morbidly obese 68,
super-obese 17. Mean follow-up is 353 days. Twelve months after the operation BW
was 95.2 +/- 23 kg, % loss of excess BW 52.1 +/- 22, and % IBW 152.2 +/- 30 (45
patients). Mortality rate was zero and postoperative morbidity was insignificant.
As late morbidity, we experienced two slippages of the band and six stoma
stenosis with pouch dilatation. Therefore, a surgical revision without removal of
the band was performed in eight patients. The band was removed in one patient
because of band erosion. In conclusion, ASGB is a safe and effective bariatric
procedure. The weight loss is comparable to that produced by more extensive
operations. Moreover, ASGB is fully reversible and adjustable to the patients'
needs.
PMID- 10757906
TI - Pouch Enlargement: Myth or Reality? Impressions from Serial Upper
Gastrointestinal Series in Silicone Gastric Banding Patients.
AB - Does significant pouch enlargement in measured pouches occur with the passage of
time? In order to determine an answer to this question, 163 silicone gastric
banding (SGB) patients, both non-adjustable and stoma adjustable, with multiple
follow-up gastrointestinal (GI) series were reviewed. All SGB patients have a
baseline GI series of their measured 25 ml pouch prior to discharge. These
baseline X-rays were compared with subsequent GI series performed 12 or more
months after the procedure. Spinal vertebrae in the GI series were measured and
compared to the baseline X-rays to assure that pouch measurement results of the
follow-up and baseline pouches were comparable and not distorted by different X
ray techniques. If any differences in the techniques were found, the estimated
pouch volume was adjusted. For the purpose of this report, significant pouch
enlargement was considered to be greater than 1 50%. Follow-up GI series were
performed in 1986 (n = 74, 85% without significant change), 1988 (n = 97, 97%
without significant change), 1990 (n = 31, 97% without significant change) and
1991 (n = 28, 100% without significant change). Half of the very large pouches
occurred in the first 30 SGB patients, when pouch calibration technique was still
in the developmental stage. Follow-up X-rays performed in 1986 and 1988 in 31
patients revealed only one enlargement greater than 100%. Of the seven patients
who had three follow-up X-rays, none showed significant enlargement. These
results would seem to indicate that some enlargement will occur with time, but in
most SGB patients it is not excessive and does not affect the results of the
operation. The use of baseline and sequential follow-up GI series is at the
present time the only effective method to monitor pouch enlargement.
PMID- 10757907
TI - Laparoscopic Gastric Banding: a preliminary report.
AB - The authors describe a technique of laparoscopically applying a Molina-type band
to the stomach. This is the first report we are aware of, of the successful
application of a band for the treatment of morbid obesity. This technique should
be reproducible in suitable subjects
PMID- 10757908
TI - Complications of Vertical Banded Gastroplasty and its Modified Operative Mode, K
Gastroplasty: a preliminary report.
AB - Based on the experiences in performing vertical banded gastroplasty (VBG) for 8
years, its results were analyzed and particularly its operative complications
were examined. As a result, its weight-reducing effect and safety were favorable,
but serious complications, although few, were observed. These major complications
were the loss of gastric reduction effect due to staple-line dehiscence, gastric
band exposure, reflux esophagitis, channel narrowing, pouch ulcer, etc. As a
preventive measure against these complications, to supplement the defects of VBG
without losing its characteristics, K-gastroplasty was devised and performed; its
operative mode is discussed.
PMID- 10757909
TI - Resolution of Diabetes Following Vertical Gastroplasty in Morbidly Obese
Patients.
AB - Case reports are presented in three patients treated for morbid obesity by
vertical gastroplasty. Prior to surgery, the patients had diabetes which required
insulin, up to 200 units per day, or oral hypoglycemics for its control. Six
months after surgery the diabetes had been resolved in all three patients, and
they were no longer dependent on medication. Subjective reports from the patients
suggests that their quality of life improved significantly
PMID- 10757910
TI - Severe Compulsive Overeating: how to obtain a more accurate history through non
shaming, non-blaming interview techniques.
AB - The ability to obtain accurate histories for a comparative study of compulsive
overeating and alcoholism was severely compromised by the high degree of denial,
shame and self-blame present in these two overlapping disease entities. Areas of
overlap included similar progression of the disease, familial tendencies, and the
presence of protein enzymatic markers for alcoholism within the bariatric
population. Since both shame-based diseases tend to run in the same families,
four techniques were developed to reduce the amount of shame that obese patients
experienced when talking about family histories and their own compulsive,
obsessive disease as it progresses through five identifiable stages. These
techniques include: the use of specific non-shaming words and gestures;
normalization of patients' history and experiences; education about similar
biological, genetic, progressive, stress-related diseases to solidify the disease
concept of obesity; and a loosely structured interview format which proceeds from
the general to the specific and the past to the present, in an orderly, non
shaming fashion.
PMID- 10757911
TI - Availability and Adequacy of Diagnostic and Therapeutic Equipment for the
Morbidly Obese Patient in an Acute Care Setting.
AB - Morbid obesity is a common problem with an estimated three to five million people
in the USA being morbidly obese. The likelihood of hospital admission for this
population is increased due to their associated diseases. The treatment of the
morbidly obese can be hindered by the lack of diagnostic and therapeutic
equipment. As a Level I Trauma Center and referral facility for 29 counties in
eastern North Carolina, our institution offers advanced clinical services on an
annual basis for many morbidly obese patients. An evaluation of the availability
of specialized equipment for the morbidly obese was conducted to assure that our
institution was prepared to continue to provide high-tech clinical services.
Limitations in the availability and adequacy of equipment were identified. A
phone survey of companies that supplied equipment designed for the unique needs
of the morbidly obese was completed to identify additional products that are
available to assist in providing safe and efficient care for the obese patient.
Justifying additional capital purchases can be substantiated by survey results.
Recommendations for the number and type of equipment needed for specialized
services were developed.
PMID- 10757912
TI - Hepatic Steatosis and Morbid Obesity.
AB - One hundred and twenty-seven consecutive morbidly obese patients who presented
for bariatric surgery underwent open wedge liver biopsy at the completion of
their gastric restrictive procedure. All hepatic specimens were graded
histologically for degrees of steatosis. Three-quarters of the patients had
histological evidence of hepatic steatosis and in one-fifth this was severe and
diffuse. No patient had histological evidence of fatty hepatitis, portal
fibrosis, or cirrhosis. There was no significant correlation between the degree
of obesity (measured as percentage over ideal weight), age, sex, or preoperative
liver function tests and the degree of fatty change observed. Insufficient data
were available to Implicate alcohol and poor protein nutrition in the etiology of
the observed fatty liver change. Other factors such as diabetes mellitus or drugs
were not etiologic factors in this series of patients.
PMID- 10757913
TI - Vertical Banded Gastroplasty vs Gastric Bypass: 10 years follow-up.
AB - In 1982, a prospective study to evaluate and compare the operations for treatment
of morbid obesity, vertical banded gastroplasty (VBG) and gastric bypass (GBP),
was carried out at the Center for Surgical Treatment of Obesity In Los Angeles.
The VBG was performed as described by Dr. Mason with a 5.0 cm circumference
Marlex band. The GBP was the horizontal GBP with /= 25% excess weight
loss) to ameliorate the associated medico-sociopsycho-economic ramifications of
the obesity. The operative and postoperative significant morbidity should be less
than 20% and mortality less than 1%. The weight lost should be maintained for a
long period (>/= 5 years). The effects of the operation should be reproducible
and documentable by more than two authors working independently. For the purpose
of this paper, operations which do not meet these criteria are considered
questionable and not recommended for general use. Based on these criteria,
questionable operations for treatment of obesity include: tooth wiring,
acupuncture, hypothalamic center manipulation, liposuction, balloon insertion,
unbanded gastric partitioning, vagotomy, gastrogastrostomy, horizontal
gastroplasty, gastric wrap, gastroclip, and any variety of gastroplasty without a
reinforced stoma, intestinal bypass, duodenal bypass and biliointestinal bypass.
Data to substantiate this classification will be presented and discussed. Since
the surgical treatment of obesity is evolving, there is need to collect data from
and make modifications to improve the effects of all operations. There is not
enough data at this time to prohibit the use of any operation, but the data
presented will justify limiting the use of certain operations to institutions
dedicated to meticulous follow-up and research.
PMID- 10757922
TI - The Superiority of the Left Subcostal Incision Compared to Mid-line Incisions in
Surgery for Morbid Obesity.
AB - We describe a 13-year experience using a left subcostal incision in performing
gastroplasties and Roux-en-Y gastric bypasses (RYGBP) in morbidly obese patients.
We have also used it successfully in the general population in several other
types of surgical procedures, including Nissen fundoplications in adults and
infants, gastrectomies, truncal vagotomies, pyloroplasties, jejunoileal bypass
reversals, and elective splenectomies. Over 200 cholecystectomies have been
carried out through this incision as additional procedures with relative ease,
not requiring any further extension of the incision. There were no hernias in a
group of 1,067 primary gastroplasty and RYGBP patients, and the wound infection
rate has been quite low, apparently because of the incision's distance from the
potentially contaminated umbilicus. We feel that the use of this incision further
simplifies and therefore adds a safety factor not seen with the standard vertical
incision in this group of surgical patients.
PMID- 10757923
TI - Laparoscopic Gastric Banding: preliminary series.
AB - Gastric banding as a laparoscopic procedure was performed on 40 morbidly obese
patients. This operation matches the advantages of the gastric banding (efficacy,
reversibility and low invasivity) with the advantages of the laparoscopic
procedure (low surgical risk, short hospital stay and less complications in the
short and long term). The maximum follow-up is 6 months and so far the weight
loss results are the same as we obtained by the vertical banded gastroplasty of
Mason. The greatest problem of laparoscopic gastric banding is to get the right
tightness of the band for a stoma of 12-13 mm. In three patients the band was
replaced due to stenosis, in two of them by a laparoscopic procedure. The
adjustable band of Kuzmak should exclude the risk of stenosis and its use will be
tried by the laparoscopic procedure.
PMID- 10757924
TI - Some Tips on Preparing Slides.
AB - The author has drawn up instructions and warnings about slides for authors of
abstracts accepted for presentation at the Annual Meeting of the American Society
for Bariatric Surgery. These tips were invited for publication here, for wider
use (Editor).
PMID- 10757925
TI - Weight Loss and Caloric Intake after Regular and Extended Gastric Bypass.
AB - The morbidly obese and especially the super-morbidly obese (> 225% ideal body
weight) often require gastric bypass surgery as treatment for long-term remission
of their obesity. The extended gastric bypass Roux-en-Y (X-GBP) procedure evolved
as a result of a perceived need to increase weight loss in morbidly obese
subjects beyond the limitations of the regular gastric bypass Roux-en-Y (R-GBP).
We compared weight loss, caloric intake, and percentage of total caloric intake
from carbohydrate, protein, and fat in eight R-GBP and eight X-GBP patients at 3,
6, 9, and 12 months following surgery. We found that R-GBP and X-GBP groups were
similar in age and height, adjusting for baseline weight differences (p = 0.122).
Both groups demonstrated significant weight loss overtime (p < 0.0001), with
similar patterns of weight loss at each interval of nonsignificant interaction (p
= 0.585). Weight loss for the two groups did not differ statistically. The X-GBP
group lost 5% more weight than the R-GBP group by 12 months following surgery.
The adjusted average weight loss over 12 months was 56.82 kg for X-GBP and 46.82
kg for R-GBP patients. Furthermore, the X-GBP group ingested fewer calories than
the R-GBP group at 3, 6, 9, and 12 months following surgery. The X-GBP group
ingested a lower percentage of calories from fat than the R-GBP group at 3, 9,
and 12 months following surgery. This study depicts clinical trends in weight
loss following X-GBP and R-GBP surgeries. The greater weight loss of the X-GBP
group may be due to differences in total caloric intake or the lower percentage
of calories ingested from fat. Other possibilities for the greater weight loss
shown by the X-GBP group may include changes in malabsorption or resting energy
expenditure over time following surgery.
PMID- 10757926
TI - Intestinal Microflora Settlement in Patients with Jejunoileal Bypass for Morbid
Obesity.
AB - Intestinal microflora settlement was evaluated in this retrospective study of 49
patients with jejunoileal bypass who required reoperation. Colonic microflora was
observed in the samples of the contents of the functioning jejunum and ileum but
not in 55% of the samples from the middle of the excluded loop. Colonization of
the excluded loop was not detected in patients without clinical signs of
bacterial overgrowth but was significantly frequent (p < 0.01) in those with
clinical signs (bloating, migratory arthralgias, rashes, skin lesions). However,
positive excluded loop cultures were not always associated with clinical
manifestations. No significant correlation was observed between bacteriology of
the contents of the excluded loop and bypass results. The success of an
intestinal bypass may depend not only on anatomic and functional adaptation to
the new, surgically created conditions, but also to the attainment of
microbiological equilibrium in the intestinal ecosystem.
PMID- 10757927
TI - Long-term Outcome in a Series of Jejunoileal Bypass Patients.
AB - In 65 jejunolleal (JI) bypasses done from 1973-1979, there were nine Scott and 56
Payne (with Y-shaped anastomosis). Preoperative excess body weight (EBW)
translated to the 1983 Metropolitan Tables was 112 +/- 30%. Eight patients are
lost to follow-up. We reversed seven patients for renal stones (12%) accompanied
by a vertical banded gastroplasty (VBG) and one because she demanded a VBG. Five
patients were reversed by surgeons elsewhere for minor problems (three with an
accompanying gastric reduction operation), and all five regained and requested a
JI bypass again, which we now refused to undertake. This leaves 44 JI bypass
patients being followed: loss of EBW is 71 +/- 22% at 12-18 years. The eight
reversed by us accompanied by a VBG regained some weight (loss of EBW from
initial weight is 56 +/- 18%). Liver biopsies were done for 5 years in 31
patients, and showed improvement by 36 months. Patients took predigested collagen
capsules plus high protein and multivitamins. Injections of B12 are indicated in
18 patients, given every 3 months. Liver dysfunction has not occurred in the long
term. Low serum carotene levels persist. Migratory arthraigias were controlled by
oral metronidazole and did not occur after the fifth year. Oxalate crystals
remain on urinalysis. Potassium and magnesium replacement is not required now,
and a mean of 2.5 stools per day is not a problem, with infrequent diarrhea after
greasy foods. Metronidazole is continued in 33 patients to prevent foul flatus.
One patient developed a brain tumor, one myxedema, and one primary
hyperparathyroidism, thought to be complications of the bypass until diagnosed.
Most patients appear to be doing well.
PMID- 10757928
TI - Liver Biopsies Following Ileogastrostomy.
AB - Patients who have had ileogastrostomy for the treatment of morbid obesity require
close, long-term follow-up. One concern in patients undergoing any form of
intestinal bypass surgery is that of possible liver damage. To assess for
possible liver damage in morbidly obese patients undergoing ileogastrostomy, we
undertook a prospective study of liver biopsies in 12 consecutive patients.
Preoperative and 2-year postoperative biopsies of the liver were planned. There
were six liver biopsies available for comparison both pre- and post-operatively.
The biopsies showed changes of fatty infiltration both pro- and post-operatively.
There were no differences in the degree of fatty infiltration, or of other
histological parameters which we measured. There were no cases of cirrhosis of
the liver recorded.
PMID- 10757929
TI - A Double-Blind Placebo-controlled Trial of Ursodeoxycholic Acid in the Prevention
of Gallstones during Weight Loss after Vertical Banded Gastroplasty.
AB - One hundred and seven patients whose gallbladder was normal at the time of
vertical banded gastroplasty (VBG) were considered for entry into a randomized
placebo-controlled double-blind study to determine the effectiveness of
ursodeoxycholic acid (UDCA) in preventing cholelithiasis during the period of
weight loss. Twenty-one patients (20%) developed gallstones in the six-week
period post-VBG and prior to randomization and were therefore excluded. Eighty
six patients were randomized at 6 weeks to active medication or placebo. Of
these, 61 patients (71 %) completed the study. Twenty-five patients (29%) failed
to complete the study because of incompliance, intolerance to the medication or
pregnancy; 17 of these were in the active treatment group and eight were in the
placebo group. None of the 27 patients treated with UDCA developed gallstones,
whereas eight of 34 (24%) patients taking placebo developed gallstones. This
difference was statistically significant (p = 0.0061). These results suggest that
UDCA is fully effective in preventing gallstone formation following VBG in
patients who follow the prescribed regimen.
PMID- 10757930
TI - Preoperative Intermaxillary Fixation has no Influence on Weight Loss Induced by
Vertical Banded Gastroplasty.
AB - Surgery is the only therapeutic modality that has shown lasting results in the
treatment of morbid obesity. Ability to lose weight by voluntary dieting has been
associated with unsatisfactory weight loss after gastroplasty. This report
examines the effect of preoperative inter-maxillary fixation (IMF) on weight
reduction induced by vertical banded gastroplasty (VBG). Twenty-four patients
entered the study and were randomly assigned to either 10 weeks of IMF or 10
weeks on the waiting-list. Patient groups were similar in respect to age, gender
and Body Mass Index (BMI). All patients were urged to lose weight preoperatively.
Patients in the IMF group lost 18 kg (-12 to -36; median, range) and the waiting
list group lost 3 kg (+ 3 to -30) during the 10 weeks prior to surgery. Total
weight loss from time of inclusion to 24 months postoperatively was the same in
both groups. Our results suggest that weight loss up to 2 years after VBG is not
Influenced by short-term preoperative IMF. Although we found no obvious advantage
in having patients pre-treated by IMF, our findings indicate that jaw wiring can
be used for patients in whom moderate preoperative weight loss is desired without
endangering the effect of VBG on body weight development.
PMID- 10757931
TI - Reexploration Following Vertical Banded Gastroplasty: Technical Observations, and
Co-morbidity from Dentition, Smoking and Esophageal Pathology.
AB - This is a retrospective review of 260 consecutive patients, of one surgeon,
operated on for morbid obesity. There were 245 primary, and 15 referred
secondary, patients. For primary cases, there was a 0.8% (2/245) mortality, and
4.4% (11/245) emergency reexploration rate. Of these 2.5% (6/245) were at < 30
days (all < 5 days) and 1.6% (41245) > 30 days (all > 2 years). Ten (4.1 %) were
electively reexplored because of vertical partition staple-line disruptions. Of
the three staplers used, we show one (USS Corp. TA 90B) has demonstrably fewer
disruptions. Identifiable causes of long-term morbidity include cigarette smoking
in young females (2/245), a full set of upper dentures (2/245) and preexisting
esophageal dysmotility (1/245).
PMID- 10757932
TI - Biochemical Changes after Vertical Banded Gastroplasty.
AB - A prospective study of biochemical changes after vertical banded gastroplasty for
morbid obesity, in 94 patients (10 males and 84 females, ages ranging from 18 to
59 years) has been carried out. Liver function tests and electrolyte estimations
were performed preoperatively, during hospitalization for surgery, at 6 weeks and
at 6 months postoperatively, and demonstrated no significant changes in liver
function in these patients 6 months after surgery. The study concludes that there
is no increase in the risk of liver damage or electrolyte disturbance after
vertical gastroplasty, but that there may be subtle hepatic changes present as
gall bladder disease developed in 18 patients postoperation (19%).
PMID- 10757933
TI - Vertical Banded Gastroplasty vs Adjustable Silicone Gastric Banding in the
Treatment of Morbid Obesity: a Preliminary Report.
AB - A prospective comparative study, comparing vertical banded gastroplasty (VBG)
with adjustable silicone gastric banding (ASGB) has been undertaken. The purpose
of the study was to see if ASGB could produce weight loss as good as VBG. Patient
population was similar and patients' choice was based on informed consent. Male/
female ratio and excess body weight were comparable in both groups. Early as well
as late complications were minor and rare In both groups. The evaluation of the
results was based on excess weight loss and BMI curves. Weight loss as well as
BMI curves were quite similar in the two groups. A 50% excess weight loss has
been obtained at 6 months, In both groups.
PMID- 10757934
TI - Treatment of Protein Malnutrition and Uncontrollable Diarrhea Following Bilio
pancreatic Diversion with Pancreas Extract Viokase.
AB - Thirteen patients, following a bilio-pancreatic diversion procedure for obesity,
developed severe nutritional complications such as protein deficiency, anemia,
hypocalcemia and/or gastrointestinal problems (uncontrollable diarrhea). They
were subjected to a new therapeutic approach-the administration of pancreas
extract tablets Viokase, containing protease, lipase and amylase. This, together
with protein-rich food resulted after 2-4 weeks of treatment in a drastic
reduction in the number of daily stools: from 10-12 per day to 4-6 per day, as
well as the disappearance of the accompanying foul smell and the malodorous gas
emissions. After a further 4-8 weeks of treatment of those patients with protein
deficiency, the serum protein-albumin levels as well as the Hgb and Ca levels
rose to near normal values: protein from 4.8-5.5 g % to 6-6.5 g %; albumin from
1.8-3 g % to 3.4 g % and above; Hgb from 7-9 g/di to 11-12 g/di; and Ca from 7.5
7.8 mg% to 8-9 mg%. None of the patients treated with pancreas extract for
protein deficiency required rehospitalization for intravenous protein
replacement, nor was there any need observed for operative revision or takedown
in these patients.
PMID- 10757935
TI - Reflections on Four Years' Activity of an Interdisciplinary Centre for the
Treatment of Obese Patients.
AB - Since 1988, there has been an interdisciplinary center for obesity treatment in
Stradella's Hospital's Surgery Department,. Patients are followed by a group of
surgeons, anesthetists and dietitians, who choose the proper treatment for the
patient. The surgical treatments are two: (1) vertical banded gastroplasty; and
(2) a new technique consisting of biliopancreatic diversion plus a vertical
banded gastroplasty with stomach ad hoc. The authors explain the new surgical
procedure showing positive results, without giving final conclusions because of
the small number of patients treated.
PMID- 10757936
TI - Equal Biliopancreatic and Alimentary Limbs: An Analysis of 106 Cases over 5
Years.
AB - In 106 consecutive biliopancreatic diversion patients, the small intestine was
divided at its mid-point to create equal biliopancreatic and alimentary limbs,
because several observations had suggested that this would lead to Improved
nutrition post-operatively. In order to test this hypothesis, the progress of
these patients was compared with a similar group who had undergone a standard
Scopinaro biliopancreatic diversion with a 250 cm alimentary limb. Four
particular areas were studied: weight loss, hypoproteinemia, iron deficiency
anemia and disturbance of bone metabolism. Patients with equal limbs lost 71 % of
their excess weight at 36 months, compared to 77% in the standard diversion. With
the equal limbs the incidence of hypoproteinemia was reduced from 8% to 2% and
the incidence of iron deficiency anemia decreased from 20% to 10%. The change had
no effect on clinically symptomatic metabolic bone disturbance which occurred in
7% of the patients in both groups. In the authors opinion, these improvements
justify continued division of the small intestine at its mid-point.
PMID- 10757937
TI - Why the Operation I Prefer is the Modified Long Vertical Gastroplasty.
AB - I have performed a modified Long 'highest gastric reduction' vertical
gastroplasty (LVG) for over 10 years, and the advantages include simplicity in
principle, speed of performance, ease of revision, ease of subsequent endoscopic
examination, minimal mortality and low morbidity. The biggest advantage is the
lack of long-term nutritional disturbance and the need for lifelong surveillance
which characterizes malabsorptive procedures. The cost of surgery is relatively
low with only one application of staples, a short hospital stay and an infrequent
need for rehospitalization or investigation. A further bonus is that LVG is a
good antireflux operation in contrast to gastric banding. The individual weight
loss achieved depends greatly on the motivation and use of the operation by the
patient, and this is directly related to the quality and content of counseling
given to the patient before and after the surgery. Given good motivation, a good
operation technique and good education, patients can achieve weight loss
comparable to that from more invasive procedures.
PMID- 10757938
TI - A Gastric Band with Adjustable Inner Diameter for Obesity Surgery: Preliminary
Studies.
AB - Gastric banding for morbid obesity is theoretically an attractive method, since
it is easily reversible, does not require opening of the stomach or intestines,
and is associated with a very low surgical risk. The disadvantage is the high
rate of reoperation because of the difficulty to obtain an optimal stoma
diameter. This led us to develop a new gastric balloon band in which it is
possible to regulate the inner diameter between 0 and 40 mm. In this study of the
technical properties, we have investigated the inner pressure of the band during
filling, the breaking point of the balloon when overfilling, the strength of the
band and finally the degree of diffusion through the system. We found that there
is no pressure with filling up to 10 ml. The band is thus a low pressure system.
It can be filled with five times its normal volume before breaking. A pressure of
300 mmHg can be applied inside the system without breaking it. Finally, when the
system was filled with soya oil, there was no detectable diffusion through the
system in a one-year trial. These findings are consistent with our preset
specifications. Clinical trials have therefore been started.
PMID- 10757940
TI - Liposculpturing by Syringe Technique in Obesity.
AB - The author recommends liposuction by syringe technique instead of by the
lipoaspirator machine. This technique has been applied to obese patients who were
further stimulated to lose weight by dieting.
PMID- 10757939
TI - A Simple Band for Gastric Banding.
AB - The author has noted that flexible gastric bands have occasionally stenosed the
gastric stoma or allowed it to dilate. A band was developed using a soft outer
silicone rubber tube over a holding mechanism made out of a nylon cable tie
passed within the silicone tube. This simple, easily applied band is rigid,
resisting scar contracture and dilatation.
PMID- 10757941
TI - Invited Commentary.
PMID- 10757942
TI - Alkaline Phosphatase, Sucrase, and Insulin-like Growth Factor Receptors are
Present in Atrophied Small Bowel 14 Years after Jejunoileal Bypass.
AB - The authors obtained atrophied and hypertrophied small intestinal tissue from a
patient undergoing jejunolleal (JI) bypass reversal. Tissue from both segments
was examined for insulin, insulin-like growth factor-I (IGF-1) and IGF-11
receptors, and alkaline phosphatase and sucrase. We were interested in the
potential of the atrophied segment to respond to luminal stimulation once the
food train was re-established. Within the atrophic segment, flow cytometric
evaluation of the receptors revealed (expressed as percent positive staining
cells): insulin, 17.1%; IGF-1, 33.6%; and IGF-11, 60.8%, while the immunoreactive
sucrase was 87.7% and alkaline phosphatase was 88.6%. Actual sucrase activity
(expressed as glucose generated) in this segment was 17.9 ng/minl,ug protein and
alkaline phosphatase was 28.0 U/L/ug protein as assessed by conventional methods.
Receptor evaluation in the hypertrophic segment demonstrated 9.7% positive
staining cells for insulin, 26.6% for IGF-I and 70.2% for IGF-11. Immunoreactive
sucrase was 91.2% and alkaline phosphatase was 91.4%. Enzyme activity for sucrase
was 10.4 ng/min/ug protein and for alkaline phosphatase was 59.4 U/L/ug protein.
This data suggests that even in atrophied bowel insulin and IGF receptors as well
as sucrase and alkaline phosphatase enzymes are present and may assist in the
rapid recovery of the atrophied portion following reversal of the JI bypass.
PMID- 10757943
TI - What is the Future of Surgical Treatment of Obesity; What Will be the Place of
the American Society for Bariatric Surgery?
AB - There is focused awareness of severe obesity, its health risk and possible
solutions. Yet there remains confusion and skepticism among the medical
profession over therapeutic action. Basic questions unanswered project futility
toward solving the problem, while the general public is driven toward unsound
solutions which are costly. A cloud of cynicism pervades for those seeking to
control this problem surgically. The problem will persist. Its health risks
increasingly will demand attention, and solution will be sought by surgical means
which is the only control for comorbidity, but does not cure severe obesity.
Pressure to totally control excess weight results in undesirable side-effects.
Careful judgment must be used. Now insight is desperately needed to understand
severe obesity, its etiology and pathophysiology. This Insight is likely to come
from careful observations of those engaged in its control. Surgical control,
profound in its success, provides a model that should lead to more complete
understanding of severe obesity, as in the example of "Burns-The Universal Trauma
Model." Those experienced and engaged in this work show courage in this orphan
field of endeavor. They lead the way as general surgeons and gastrointestinal
surgeons with broad application of knowledge for this model. This society will
continue to focus the expertise and the opportunities in this area. The future
predicted is exciting and demanding.
PMID- 10757944
TI - Relative Resistance of Adipocytes from Massively Obese Persons to
Dedifferentiation.
AB - Previous studies on the etiology of obesity have revealed that human adipocytes
have the ability to revert or dedifferentiate in culture to a morphology and
replicative capacity similar to that of adipocyte precursors. To characterize
some of the events of this process, we isolated adipocytes from the greater
omentum of 61 morbidly obese and ten normal weight individuals with collagenase,
and cultured them for 0, 4, and 7 days. In both lean and obese patients, sn
glycerol-3-phosphate dehydrogenase specific activity decreased significantly
after days 4 and 7 compared to day 0. Dedifferentiation was also monitored by
phase-contrast microscopy, which revealed that adipocytes from the lean had lost
appreciable lipid and had assumed an elongated contour more rapidly than those
from the obese. Reversion was also corroborated by reverse transcription
polymerase chain reaction, which indicated a decrease in the expression of sn
glycerol-3-phosphate dehydrogenase mRNA, and an increase in actin and
glyceraidehyde-3-phosphate dehydrogenase mRNA over the 7 days. Thus, this work
has described some biochemical and molecular genetic characteristics of
dedifferentiation. The relative resistance of adipocytes from morbidly obese
patients to revert in culture may reflect the inordinately high propensity of fat
cells in massively obese persons to preserve the differentiated, triacylglycerol
overfilled state.
PMID- 10757945
TI - The Role of Psychological Factors in Bariatric Surgery for Morbid Obesity:
Identification of Psychological Predictors of Success.
AB - This paper deals with two important questions in the Outcome of surgical
treatment for morbid obesity. First, what is the impact of bariatric surgery on
psychological functioning or quality of life? Second, and perhaps more important,
can pre-surgical factors be identified that predict the outcome of surgery? These
questions are answered by a systematic review of the current literature in this
area. Throughout this paper the need for methodological rigor is stressed, and
conclusions are based only on empirically sound findings. It is concluded that
surgery is generally associated with improved psychological functioning and
quality of life for most individuals. While a significant minority of morbidly
obese individuals do not respond positively to surgery, there is no evidence to
support the theory that obesity is a psychological defense mechanism, and
therefore that bariatric surgery will produce widespread psychological problems.
On a less positive note, while some studies identify pre-surgery psychological
factors that predict weight loss following surgery, there has been no attempt to
systematically replicate findings across studies, and no consistent findings have
emerged from the literature. Due to the fact that the predictor variables
examined have not been selected on theoretical grounds, the interpretation of
isolated findings is difficult. On the basis of this review, however, distress
over obesity appears to be a potentially important psychological predictor of the
success of surgery. Unfortunately, there currently is no measure to specifically
measure distress over obesity. What is needed at this time is a theoretically
derived approach to the development of a scale to assess distress over obesity.
PMID- 10757946
TI - Quality of Life Assessment, of Ileogastrostomy.
AB - Twenty of 26 (77%) consecutive Patients undergoing ileogastrostomy, performed by
the same surgeon (IGMC) between February 1989 and May 1992, responded to a mailed
quality of life survey. Average present weight was reported as 50.9 kg less than
a mean preoperative weight of 139.7 kg. Mean time of follow-up was 24.75 months.
When comparing perceptions before and after surgery, several quality of life
improvements were noted in the areas of vocation, relationships, emotional well
being and physical well-being. Post-surgery, jobs were rated more satisfying,
eating habits improved, self-image and self-confidence increased and body
disparagement declined. Satisfaction with sexual relations increased, as did
frequency. In general, relations with partners, coworkers and friends seemed to
improve. Exercise also increased significantly. In contrast, foul flatus,
bloating, and bowel movements regularly hampered activities or caused
embarrassment when in public. Despite these physical side-effects, we observed
that a large majority of persons undergoing ileogastrostomy noted significant
improvements in quality of life.
PMID- 10757947
TI - Vertical Banded Gastroplasty: One Treatment for Esophagitis and/or Weight Gain
after Gastric Banding.
AB - Gastric banding (GB) was the method of choice for the surgical treatment of
obesity at our institution between 1981 and 1986. We abandoned the method in 1986
because of poor results. Reflux esophagus and weight gain after a period of
weight loss were common problems despite attempts at surgical correction. Of the
92 patients who underwent GB, 36 were reoperated with vertical banded
gastroplasty (VBG) due to endoscopically verified esophagus, weight gain or both.
Postoperatively, the patients reported ameliorated reflux symptoms without any
substantial weight gain after the initial weight loss during the study period.
The VBG, after GB, was performed with a rate of complications similar to that of
primary VBG performed at our institution. Five patients (14%) were reoperated
after the conversion with VBG, compared to 11% (15/134) and 55% (51/92)
reoperated patients after primary VBG and GB respectively at our Institution. GB,
by our technique, seems to be a poor procedure, and VBG is in comparison the
method of choice.
PMID- 10757948
TI - Gastric Banding for Morbid Obesity: Initial Experience with a New Adjustable
Band.
AB - A new adjustable gastric band was developed, consisting of a silicone balloon
connected to a subcutaneous port In a closed system. The stoma diameter can be
regulated within an extensive range (0-40 mm). The diameter is adjusted
individually for each patient and weight loss can therefore be controlled and
optimized. We evaluated the application of this new gastric banding procedure in
terms of technical feasibility, complication rate and weight loss, and also the
relationship between weight loss and pouch volume. Between January 1987 and April
1990 two preliminary studies of 18 and 24 patients respectively were carried out.
In the first group there were technical problems resulting in insufficient weight
loss. We therefore changed the procedure. In the second group the system
thereafter worked as expected. In the second group mean preoperative weight was
132 kg, mean excess weight 60 kg, and mean BMI 45. The mean follow-up was in 21
months. At follow-up mean weight was 91 kg, mean weight loss 41 kg, and mean BMI
31. The mean postoperative stay was 6.0 days. Pouch volume and stoma diameter
were followed by regular ondoscopy. There was a distinct relationship between
pouch volume and weight loss-the smaller the volume the greater the weight loss.
PMID- 10757949
TI - Ethnicity, Type of Obesity Surgery and Weight Loss.
AB - In our study we compared weight loss among non-Hispanic whites (NHW), black Afro
Americans (BAA) and Hispanic Americans (HA) following vertical banded
gastroplasty (VBG) and vertical banded gastroplastygastric bypass (VBG-RGB). From
a total of 1222 patients, 662 qualified for the study (471 VBG, 211 VBG-RGB)
based on type of surgery, follow-up and ethnicity. When comparing percentage
excess weight loss, VBG-RGB patients lost significantly more than VBG patients.
VBG-RGB was also a more efficacious operation when comparing each ethnic group
separately. For female patients undergoing VBG, BAA and HA lost significantly
less weight than NHW. Ethnicity plays an important role In post surgical weight
loss for VBG patients and should be considered along with other more recognized
predictors when reporting results. The discrepancy in weight loss reported by
various authors following VBG could be the result of differences in the ethnic
composition of their patients. Poor weight loss among BAA and HA females
undergoing VBG should be an Indication for a more aggressive surgical approach in
these ethnic groups. Because VBG produces only moderate weight loss, VBG-RGB is
our preferred operation.
PMID- 10757950
TI - Antiobesity Surgery: Is a Structured Support Group Desirable? Preliminary.
AB - The relevance of a post-gastroplasty physician-and dietitian-supervised support
group for weight loss, dietary habits, dietary knowledge, and exercise has been
assessed. Two post vertical banded gastroplasty groups were compared: those who
did (n = 10) and those who did not (n = 11) attend a monthly post-gastroplasty
support session. A 55-point questionnaire plus a 24-hour dietary recall and food
frequency analysis were employed. Addressed were dietary and exercise history,
eating habits, and factual dietary knowledge. At the time following surgery of
this study (support: mean 29.7 vs no support: mean 34.9 months, NS), there was no
difference in weight loss between the two groups. There was no difference in the
two groups between preoperative, length of time from surgery to interview or
weight at Interview. Those who attended the support group consumed significantly
fewer calories (1559 +/- 320 vs 2278 +/- 271, p 100 (s-1)) for the S(0), S(1), and S(2)
states. Comparisons of the (18)O exchange rates reveal that the binding affinity
for one of the substrate water molecules first increases during the S(0) to S(1)
transition, then decreases during the S(1) to S(2) transition, but stays the same
during the S(2) to S(3) transition, while the binding affinity for the second
substrate water molecule undergoes at least a 5-fold increase on the S(2) to S(3)
transition. These findings are discussed in terms of two independent Mn(III)
substrate binding sites within the O(2) evolving complex which are separate from
the component that accumulates the oxidizing equivalents. One of the Mn(III)
sites may only first bind a substrate water molecule during the S(2) to S(3)
transition.
PMID- 10757990
TI - Amino acid 305 determines catalytic center accessibility in CYP3A4.
AB - Site-directed mutagenesis has been used to replace alanine 305 with phenylalanine
(A305F) and serine (A305S) in the active site of cytochrome P450 3A4 (CYP3A4).
Enzyme kinetics for diazepam, erythromycin, nifedipine, and testosterone
metabolism have been determined for both mutants and wild-type CYP3A4. The A305F
mutation abolished diazepam oxidase activity and reduced the S(50) and V(max) for
erythromycin N-demethylase activity from 17 to 10 microM and from 3.2 to 1.2 pmol
product/min/pmol P450, respectively. The V(max) for testosterone 6beta
hydroxylase activity was also significantly reduced, from 2.3 to 0.6 pmol
product/min/pmol P450, whereas the S(50) increased from 33 to 125 microM. The
nifedipine oxidase activity was diminished to a lesser extent, down from 6.5 to
4.9 pmol product/min/pmol P450, whereas the S(50) increased from 9 to 42 microM.
The K(i) for ketoconazole, a CYP3A4 selective inhibitor, was increased more than
10-fold from 0.050 to 0.55 microM, from 0.052 to 0.73 microM, and from 0.043 to
2.2 microM by the A305F mutation when measured against erythromycin, nifedipine,
and testosterone metabolism activities, respectively. Similarly, the inhibition
constants of the broader specificity inhibitors; clotrimazole, econazole, and
miconazole were increased 3- to 15-fold by the A305F mutation. In contrast, the
A305S mutation increased testosterone 6beta-hydroxylase (V(max) = 2.9 pmol
product/min/pmol P450) and erythromycin N-demethylase (V(max) = 5.1 pmol
product/min/pmol P450) activities, but reduced nifedipine oxidase activity
(V(max) = 4.6 pmol product/min/pmol P450). K(i) values for ketoconazole and other
azole inhibitors were unchanged by the A305S mutation. It is proposed that in
CYP3A4, the mutagenesis of alanine 305 to a phenylalanine increases the steric
hindrance of the catalytic center, thereby greatly reducing azole inhibitor
binding affinity, but maintaining monoogygenase activity.
PMID- 10757991
TI - Nature of the inhibition of horseradish peroxidase and mitochondrial cytochrome c
oxidase by cyanyl radical.
AB - Previous studies established that the cyanyl radical ((*)CN), detected as 5,5
dimethyl-1-pyrroline N-oxide (DMPO)/(*)CN by the electron spin resonance (ESR)
spin-trapping technique, can be generated by horseradish peroxidase (HRP) in the
presence of hydrogen peroxide (H(2)O(2)) and by mitochondrial cytochrome c
oxidase (CcO) in the absence of H(2)O(2). To investigate the mechanism of
inhibition by cyanyl radical, we isolated and characterized the iron
protoporphyrin IX and heme a from the reactions of CN(-) with HRP and CcO,
respectively. The purified heme from the reaction mixture of HRP/H(2)O(2)/KCN was
unambiguously identified as cyanoheme by the observation of the protonated
molecule, (M + H)(+), of m/z = 642.9 in the matrix-assisted laser
desorption/ionization (MALDI) mass spectrum. The proton NMR spectrum of the
bipyridyl ferrous cyanoheme complex revealed that one of the four meso protons
was missing and had been replaced with a cyanyl group, indicating that the
single, heme-derived product was meso-cyanoheme. The holoenzyme of HRP from the
reconstitution of meso-cyanoheme with the apoenzyme of HRP (apoHRP) showed no
detectable catalytic activity. The Soret peak of cyanoheme-reconstituted apoHRP
was shifted to 411 nm from the 403 nm peak of native HRP. In contrast, the heme a
isolated from partially or fully inhibited CcO did not show any change in the
structure of the protoporphyrin IX as indicated by its MALDI mass spectrum, which
showed an (M + H)(+) of m/z = 853.6, and by its pyridine hemochromogen spectrum.
However, a protein-centered radical on the CcO can be detected in the reaction of
CcO with cyanide and was identified as the thiyl radical(s) based on inhibition
of its formation by N-ethylmaleimide pretreatment, suggesting that the protein
matrix rather than protoporphyrin IX was attacked by the cyanyl radical. In
addition to the difference in heme structures between HRP and CcO, the available
crystallographic data also suggested that the distinct heme environments may
contribute to the different inhibition mechanisms of HRP and CcO by cyanyl
radical.
PMID- 10757992
TI - Probing the ground state structure of the green fluorescent protein chromophore
using Raman spectroscopy.
AB - We present Raman spectra, obtained using 752 nm excitation, on wild-type GFP and
the S65T mutant of this intrinsically fluorescent protein together with data on a
model chromophore, ethyl 4-(4-hydroxyphenyl)methylidene-2-methyl-5
oxoimidazolacetate . In the pH range 1-14, the model compound has two macroscopic
pK(a)s of 1.8 and 8.2 attributed to ionization of the imidazolinone ring nitrogen
and the phenolic hydroxyl group, respectively. Comparison of the model
chromophore with the chromophore in wild-type GFP and the S65T mutant reveals
that the cationic form, with both the imidazolinone ring nitrogen and the
phenolic oxygen protonated, is not present in these particular GFP proteins. Our
results do not provide any evidence for the zwitterionic form of the chromophore,
with the phenolic group deprotonated and the imidazolinone ring nitrogen
protonated, being present in the GFP proteins. In addition, since the position of
the Raman bands is a property exclusively of the ground state structure, the data
enable us to investigate how protein-chromophore interactions affect the ground
state structure of the chromophore without contributions from excited state
effects. It is found that the ground state structure of the anionic form of the
chromophore, which is most relevant to the fluorescent properties, is strongly
dependent on the chromophore environment whereas the neutral form seems to be
insensitive. A linear correlation between the absorption properties and the
ground state structure is demonstrated by plotting the absorption maxima versus
the wavenumber of a Raman band found in the range 1610-1655 cm(-1).
PMID- 10757993
TI - Designing transmembrane alpha-helices that insert spontaneously.
AB - Direct measurement of the free energies of transfer of hydrophobic membrane
spanning alpha-helices from water to membranes is important for the determination
of an accurate experiment-based hydrophobicity scale for membrane proteins. An
important objective of such a scale is to account for the presently unknown
thermodynamic cost of partitioning hydrogen-bonded peptide bonds into the
membrane hydrocarbon core. We describe here the physical properties of a
transmembrane (TM) peptide, TMX-1, designed to test the feasibility of
engineering peptides that spontaneously insert across bilayers but that have the
important property of measurable monomeric water solubility. TMX-1, Ac
WNALAAVAAAL-AAVAAALAAVAAGKSKSKS-NH(2), is a 31-residue sequence with a 21-residue
nonpolar core, N- and C-caps to favor helix formation, and a highly polar C
terminus to improve solubility and to control directionality of insertion into
lipid vesicles. TMX-1 appeared to be soluble in water up to a concentration of at
least 1 mg/mL (0.3 mM). However, fluorescence spectroscopy, fluorescence
quenching, and circular dichroism (CD) spectroscopy indicated that the high
solubility was due to the formation of molecular aggregates that persisted at
peptide concentrations down to at least 0.1 microM peptide. Nevertheless, aqueous
TMX-1 partitioned strongly into membrane vesicles with apparent mole-fraction
free-energy values of -7.1 kcal mol(-1) for phosphatidylcholine (POPC) vesicles
and -8.2 kcal mol(-1) for phosphatidylglycerol (POPG) vesicles. CD spectroscopy
of TMX-1 in oriented multilayers formed from either lipid disclosed a very strong
preference for a transmembrane alpha-helical conformation. When TMX-1 was added
to preformed vesicles, it was fully helical. A novel fluorescence resonance
energy transfer (FRET) method demonstrated that at least 50% of the TMX-1 insered
spontaneously across the vesicle membranes. Binding and insertion were found to
be fully reversible for POPC vesicles but not POPG vesicles. TMX-1 was thus found
to have many of the properties required for thermodynamic measurements of TM
peptide insertion. Importantly, the results obtained delineate the experimental
problems that must be considered in the design of peptides that can partition
spontaneously and reversibly as monomers into and across membranes. Our success
with TMX-1 suggests that these problems are not insurmountable.
PMID- 10757994
TI - Energetics of S-adenosylmethionine synthetase catalysis.
AB - S-adenosylmethionine synthetase (ATP:L-methionine S-adenosyltransferase)
catalyzes the only known route of biosynthesis of the primary biological
alkylating agent. The internal thermodynamics of the Escherichia coli S
adenosylmethionine (AdoMet) synthetase catalyzed formation of AdoMet,
pyrophosphate (PP(i)), and phosphate (P(i)) from ATP, methionine, and water have
been determined by a combination of pre-steady-state kinetics, solvent isotope
incorporation, and equilibrium binding measurements in conjunction with computer
modeling. These studies provided the rate constants for substrate binding, the
two chemical interconversion steps [AdoMet formation and subsequent
tripolyphosphate (PPP(i)) hydrolysis], and product release. The data demonstrate
the presence of a kinetically significant isomerization of the
E.AdoMet.PP(i).P(i) complex before product release. The free energy profile for
the enzyme-catalyzed reaction under physiological conditions has been constructed
using these experimental values and in vivo concentrations of substrates and
products. The free energy profile reveals that the AdoMet formation reaction,
which has an equilibrium constant of 10(4), does not have well-balanced
transition state and ground state energies. In contrast, the subsequent PPP(i)
hydrolytic reaction is energetically better balanced. The thermodynamic profile
indicates the use of binding energies for catalysis of AdoMet formation and the
necessity for subsequent PPP(i) hydrolysis to allow enzyme turnover.
Crystallographic studies have shown that a mobile protein loop gates access to
the active site. The present kinetic studies indicate that this loop movement is
rapid with respect to k(cat) and with respect to substrate binding at
physiological concentrations. The uniformly slow binding rates of 10(4)-10(5) M(
)(1) s(-)(1) for ligands with different structures suggest that loop movement may
be an intrinsic property of the protein rather than being ligand induced.
PMID- 10757995
TI - Vapor pressure osmometry studies of osmolyte-protein interactions: implications
for the action of osmoprotectants in vivo and for the interpretation of "osmotic
stress" experiments in vitro.
AB - To interpret or to predict the responses of biopolymer processes in vivo and in
vitro to changes in solute concentration and to coupled changes in water activity
(osmotic stress), a quantitative understanding of the thermodynamic consequences
of interactions of solutes and water with biopolymer surfaces is required. To
this end, we report isoosmolal preferential interaction coefficients (Gamma(mu1)
determined by vapor pressure osmometry (VPO) over a wide range of concentrations
for interactions between native bovine serum albumin (BSA) and six small solutes.
These include Escherichia coli cytoplasmic osmolytes [potassium glutamate
(K(+)Glu(-)), trehalose], E. coli osmoprotectants (proline, glycine betaine), and
also glycerol and trimethylamine N-oxide (TMAO). For all six solutes, Gamma(mu1)
and the corresponding dialysis preferential interaction coefficient
Gamma(mu1),(mu3) (both calculated from the VPO data) are negative; Gamma(mu1),
(mu3) is proportional to bulk solute molality (m(bulk)3) at least up to 1 m
(molal). Negative values of Gamma(mu1),(mu3) indicate preferential exclusion of
these solutes from a BSA solution at dialysis equilibrium and correspond to local
concentrations of these solutes in the vicinity of BSA which are lower than their
bulk concentrations. Of the solutes investigated, betaine is the most excluded
(Gamma(mu1),(mu3)/m(bulk)3 = -49 +/- 1 m(-1)); glycerol is the least excluded
(Gamma(mu1),(mu3)/m(bulk)3 = -10 +/- 1 m(-1)). Between these extremes, the
magnitude of Gamma(mu1),(mu3)/m(bulk)3 decreases in the order glycine betaine >>
proline >TMAO > trehalose approximately K(+)Glu(-) > glycerol. The order of
exclusion of E. coli osmolytes from BSA surface correlates with their
effectiveness as osmoprotectants, which increase the growth rate of E. coli at
high external osmolality. For the most excluded solute (betaine),
Gamma(mu1),(mu3) provides a minimum estimate of the hydration of native BSA of
approximately 2.8 x 10(3) H(2)O/BSA, which corresponds to slightly less than a
monolayer (estimated to be approximately 3.2 x 10(3) H(2)O). Consequently, of the
solutes investigated here, only betaine might be suitable for use in osmotic
stress experiments in vitro as a direct probe to quantify changes in hydration of
protein surface in biopolymer processes. More generally, however, our results and
analysis lead to the proposal that any of these solutes can be used to quantify
changes in water-accessible surface area (ASA) in biopolymer processes once
preferential interactions of the solute with biopolymer surface are properly
taken into account.
PMID- 10757996
TI - Thermodynamic analysis of cavity creating mutations in an engineered leucine
zipper and energetics of glycerol-induced coiled coil stabilization.
AB - Protein stability in vitro can be influenced either by introduction of mutations
or by changes in the chemical composition of the solvent. Recently, we have
characterized the thermodynamic stability and the rate of folding of the
engineered dimeric leucine zipper A(2), which has a strengthened hydrophobic core
[Durr, E., Jelesarov, I., and Bosshard, H. R. (1999) Biochemistry 38, 870-880].
Here we report on the energetic consequences of a cavity introduced by Leu/Ala
substitution at the tightly packed dimeric interface and how addition of 30%
glycerol affects the folding thermodynamics of A(2) and the cavity mutants.
Folding could be described by a two-state transition from two unfolded monomers
to a coiled coil dimer. Removal of six methylene groups by Leu/Ala substitutions
destabilized the dimeric coiled coil by 25 kJ mol(-1) at pH 3.5 and 25 degrees C
in aqueous buffer. Destabilization was purely entropic at around room temperature
and became increasingly enthalpic at elevated temperatures. Mutations were
accompanied by a decrease of the unfolding heat capacity by 0.5 kJ K(-1) mol(-1).
Addition of 30% glycerol increased the free energy of folding of A(2) and the
cavity mutants by 5-10 kJ mol(-1) and lowered the unfolding heat capacity by 25%
for A(2) and by 50% for the Leu/Ala mutants. The origin of the stabilizing effect
of glycerol varied with temperature. Stabilization of the parent leucine zipper
A(2) was enthalpic with an unfavorable entropic component between 0 and 100
degrees C. In the case of cavity mutants, glycerol induced enthalpic
stabilization below 50 degrees C and entropic stabilization above 50 degrees C.
The effect of glycerol could not be accounted for solely by the enthalpy and
entropy of transfer or protein surface from water to glycerol/water mixture. We
propose that in the presence of glycerol the folded coiled coil dimer is better
packed and displays less intramolecular fluctuations, leading to enhanced
enthalpic interactions and to an increase of the entropy of folding. This work
demonstrates that mutational and solvent effects on protein stability can be
thermodynamically complex and that it may not be sufficient to only analyze
changes of enthalpy and entropy at the unfolding temperature (T(m)) to understand
the mechanisms of protein stabilization.
PMID- 10757997
TI - Native quaternary structure of bovine alpha-crystallin.
AB - Alpha-crystallin is the most important soluble protein in the eye lens. It is
responsible for creating a high refractive index and is known to be a small heat
shock protein. We have used static and dynamic light scattering to study its
quaternary structure as a function of isolation conditions, temperature, time,
and concentration. We have used tryptophan fluorescence to study the temperature
dependence of the tertiary structure and its reversibility. Gel filtration,
analytical ultracentrifugation, polyacrylamide gel electrophoretic analysis, and
absorption measurements were used to study the chaperone-like activity of alpha
crystallin in the presence of destabilized lysozyme. We have demonstrated that
the molecular mass of the in vivo alpha-crystallin oligomer is about 700 kDa
(alpha(native)) while the 550 kDa molecule (alpha(37 degrees C),diluted), which
is often found in vitro, is a product of prolonged storage at 37 degrees C of low
concentrated alpha-crystallin solutions. We have proven that the molecular mass
of the alpha-crystallin oligomer is concentration dependent at 37 degrees C. We
have found strong indications that, during chaperoning, the alpha-crystallin
oligomer undergoes a drastic rearrangement of its peptides during the process of
complex formation with destabilized lysozyme. We propose the hypothesis that all
these processes are governed by the phenomenon of subunit exchange, which is well
known to be strongly temperature-dependent.
PMID- 10757998
TI - Evidence for a role of helix IV in connecting cation- and sugar-binding sites of
Escherichia coli melibiose permease.
AB - To improve the structural organization model of melibiose permease, we assessed
the individual contributions of the N-terminal tryptophans to the transporter
fluorescence variations induced by the binding of cations and beta-configured
sugars, by replacement of the six N-terminal tryptophans by phenylalanines and
the study of the signal changes. Only two mutations, W116F located in helix IV
and W128F located in the cytoplasmic loop 4-5, impair permease activity. The
intrinsic fluorescence spectroscopy analysis of the other mutants suggests that
W54, located in helix II, W116, and W128 are mostly responsible for the cation
induced fluorescence variations. These tryptophans, W116 and W128, would also be
responsible for the beta-galactoside-induced fluorescence changes observed in the
N-terminal domain of the transporter. The implication of W116 and W128 in both
the cation- and beta-galactoside-induced fluorescence variations led us to
investigate in detail the effects of their mutations on the functional properties
of the permease. The results obtained suggest that the domains harboring the two
tryptophans, or the residues themselves, play a critical role in the mechanism of
Na(+)/sugar symport. Taken together, the results presented in this paper and
previous results are consistent with a fundamental role of helix IV in connecting
cation- and sugar-binding sites of the melibiose permease.
PMID- 10757999
TI - Dynamics of the RNA hairpin GNRA tetraloop.
AB - The dynamics of RNA hairpin tetraloops of the GNRA type [sequence G- any
ribonucleotide (N)-purine (R)-A] was analyzed by fluorescence spectroscopy and by
fluorescence-detected temperature-jump relaxation, using RNA oligomers with 2
aminopurine (2AP) substituted in two different positions of the loop sequence,
Gp2APpApA (HP1) and GpAp2APpA (HP2), as indicator. The fluorescence of HP1 is
much higher than that of HP2, indicating a lower degree of 2AP-stacking in HP1.
Addition of Mg(2+) or Ca(2+) ions leads to an increase of fluorescence in HP1,
whereas a decrease of fluorescence is observed in HP2. In both cases at least two
ion-binding equilibria are required to fit titration data. T-jump experiments
using fluorescence detection show a relaxation process with a time constant of 22
micros for HP1, whereas two relaxation processes with time constants 5 and 41
micros, are found for HP2. These results clearly demonstrate the existence of
more than the single conformation state detected by NMR analysis. The T-jump
amplitudes decrease with increasing bivalent ion concentration, indicating that
one of the states is favored in the presence of bivalent ions. The loop
relaxation processes are slower than standard stacking processes, probably
because of activation barriers imposed by a restricted mobility of loop residues,
and are assigned to a stacking rearrangement, probably between the 5' and the 3'
side. A similar process has been observed previously for the anticodon loop of
tRNA(Phe). The rate constants of the transition are in the range of 10(4) s(-1)
in the case of HP1. The data demonstrate the existence of structures that are not
resolved by standard NMR because of fast exchange and are not found by X-ray
analysis because of restrictions by crystal packing.
PMID- 10758000
TI - Efflux of cholesterol from different cellular pools.
AB - Free cholesterol is very efficiently removed from cells by 2-hydroxypropyl-beta
cyclodextrins. The efflux of cholesterol occurs from two distinct kinetic pools:
the half-times (t(1/2)) for the two pools in CHO-K1 cells are 15 +/- 5 s and 21
+/- 6 min and they represent 25% +/- 5% and 75% +/- 5% of the readily
exchangeable cell cholesterol, respectively. In this study we have determined
that the fast pool and the majority of the slow kinetic pool for cholesterol
efflux are apparently present in the plasma membrane. Numerous agents that
inhibit intracellular cholesterol trafficking are unable to affect either the
size or the t(1/2) for efflux of either kinetic pool. In contrast, treatment of
the cells with N-ethylmaleimide (NEM), exogenous lipases such as sphingomyelinase
and phospholipase C, calcium ionophore A23187, or heat resulted in the dramatic
increase in the size of the fast kinetic pool of cholesterol. These changes in
the kinetics of cholesterol efflux are not specific to the nature of the
extracellular acceptor indicating that they are a consequence of changes in the
cell plasma membrane. The above treatments disrupt the normal organization of the
lipids in the plasma membrane via either hydrolysis or randomization. The
phosphatidylcholine and sphingomyelin present in the plasma membrane are critical
for maintaining the two kinetic pools of cholesterol; any alteration in the
amount or the location of these phospholipids results in an enhancement of efflux
by redistributing cholesterol into the fast kinetic pool.
PMID- 10758001
TI - A PEST-like sequence in the N-terminal cytoplasmic domain of Saccharomyces
maltose permease is required for glucose-induced proteolysis and rapid
inactivation of transport activity.
AB - Maltose permease is required for maltose transport into Saccharomyces cells.
Glucose addition to maltose-fermenting cells causes selective delivery of this
integral plasma membrane protein to the yeast vacuole via endocytosis for
degradation by resident proteases. This glucose-induced degradation is
independent of the proteasome but requires ubiquitin and certain ubiquitin
conjugating enzymes. We used mutation analysis to identify target sequences in
Mal61/HA maltose permease involved in its selective glucose-induced degradation.
A nonsense mutation was introduced at codon 581, creating a truncated functional
maltose permease. Additional missense mutations were introduced into the mal61/HA
581NS allele, altering potential phosphorylation and ubiquitination sites. No
significant effect was seen on the rate of glucose-induced degradation of these
mutant proteins. Deletion mutations were constructed, removing residues 2-30, 31
60, 61-90, and 49-78 of the N-terminal cytoplasmic domain, as well as a missense
mutation of a dileucine motif. Results indicate that the proline-, glutamate-,
aspartate-, serine-, and threonine-rich (PEST) sequence found in the N-terminal
cytoplasmic domain, particularly residues 49-78, is required for glucose-induced
degradation of Mal61/HAp and for the rapid glucose-induced inactivation of
maltose transport activity. The decreased rate of glucose-induced degradation
correlates with a decrease in the level of glucose-induced ubiquitination of the
DeltaPEST mutant permease. In addition, newly synthesized mutant permease
proteins lacking residues 49-78 or carrying an alteration in the dileucine motif,
residues 69 and 70, are resistant to glucose-induced inactivation of maltose
transport activity. This N-terminal PEST-like sequence is the target of both the
Rgt2p-dependent and the Glc7p-Reg1p-dependent glucose signaling pathways.
PMID- 10758002
TI - Charge changes in loop 2 affect the thermal unfolding of the myosin motor domain
bound to F-actin.
AB - The thermal unfolding of Dictyostelium discoideum myosin head fragments with
alterations in the actin-binding surface loop 2 was studied by differential
scanning calorimetry. Lengthening of loop 2 without concomitant charge changes
led to decreases in the transition temperature of not more than 1.8 degrees C.
Insertions with multiple positive or negative charges had a stronger
destabilizing effect and led to reductions in the thermal transition temperature
of up to 3.7 degrees C. In the presence of nucleotide, most mutants displayed
similar or higher transition temperatures than M765. Only constructs M765(11/+6)
and M765(20/+12) with long positively charged inserts showed transition
temperatures that were more than 2 degrees C below the values measured for M765
in the presence of ADP, ADP-V(i), and ADP-BeF(3). Interaction with F-actin in the
presence of ADP shifted the thermal transition of M765 by 6 degrees C, from 49.1
to 55.1 degrees C. The actin-induced increase in thermal stability varied between
1.2 and 9.1 degrees C and showed a strong correlation with the mutant constructs'
affinity for actin. Our results show that length and charge changes in loop 2 do
not significantly affect nucleotide-induced structural changes in the myosin
motor domain, but they affect structural changes that occur when the motor domain
is strongly bound to actin and affect the coupling between the actin- and
nucleotide-binding sites.
PMID- 10758003
TI - Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'
monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by
loop 6.
AB - The conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate
(XMP) is the committed and rate-limiting reaction in de novo guanine nucleotide
biosynthesis. Inosine 5'- monophosphate dehydrogenase (IMPDH) is the enzyme that
catalyzes the oxidation of IMP to XMP with the concomitant reduction of
nicotinamide adenine dinucleotide (from NAD(+) to NADH). Because of its critical
role in purine biosynthesis, IMPDH is a drug design target for anticancer,
antiinfective, and immunosuppressive chemotherapy. We have determined the crystal
structure of IMPDH from Borrelia burgdorferi, the bacterial spirochete that
causes Lyme disease, with a sulfate ion bound in the IMP phosphate binding site.
This is the first structure of IMPDH in the absence of substrate or cofactor
where the active-site loop (loop 6), which contains the essential catalytic
residue Cys 229, is clearly defined in the electron density. We report that a
seven residue region of loop 6, including Cys229, is tilted more than 6 A away
from its position in substrate- or substrate analogue-bound structures of IMPDH,
suggestive of a conformational change. The location of this loop between beta6
and alpha6 links IMPDH to a family of beta/alpha barrel enzymes known to utilize
this loop as a functional lid during catalysis. Least-squares minimization, root
mean-square deviation analysis, and inspection of the molecular surface of the
loop 6 region in the substrate-free B. burgdorferi IMPDH and XMP-bound Chinese
hamster IMPDH show that loop 6 follows a similar pattern of hinged rigid-body
motion and indicates that IMPDH may be using loop 6 to bind and sequester
substrate and to recruit an essential catalytic residue.
PMID- 10758004
TI - Synthesis and antibacterial activity of peptide deformylase inhibitors.
AB - Peptide deformylase catalyzes the removal of the N-terminal formyl group from
newly synthesized polypeptides in eubacteria. Its essential character in
bacterial cells makes it an attractive target for antibacterial drug design. In
this work, we have rationally designed and synthesized a series of peptide thiols
that act as potent, reversible inhibitors of purified recombinant peptide
deformylase from Escherichia coli and Bacillus subtilis. The most potent
inhibitor has a K(I) value of 11 nM toward the B. subtilis enzyme. These
inhibitors showed antibacterial activity against both Gram-positive and Gram
negative bacteria, with minimal inhibitory concentrations (MIC) as low as 5
microM ( approximately 2 microg/mL). The PDF inhibitors induce bacterial cell
lysis and are bactericidal toward all four bacterial strains that have been
tested, B. subtilis, Staphylococcus epidermidis, Enterococcus faecalis, and E.
coli. Resistance evaluation of one of the inhibitors (1b) against B. subtilis
showed that no resistant clone could be found from >1 x 10(9) cells. Quantitative
analysis using a set of inhibitors designed to possess varying potencies against
the deformylase enzyme revealed a linear correlation between the MIC values and
the K(I) values. These results suggest that peptide deformylase is the likely
molecular target responsible for the antibacterial activity of these inhibitors
and is therefore a viable target for antibacterial drug design.
PMID- 10758005
TI - Overexpression of different isoforms of glucosaminyl N-deacetylase/N
sulfotransferase results in distinct heparan sulfate N-sulfation patterns.
AB - Functional interactions of heparan sulfate (HS) with selected proteins depend on
distinct saccharide sequences which are generated during biosynthesis of the
polysaccharide. Glucosaminyl N-deacetylase/N-sulfotransferases (NDSTs) catalyze
both the N-deacetylation and N-sulfation reactions that initiate the modification
of the (GlcNAc-GlcA)(n) polysaccharide backbone. The N-acetyl/N-sulfate exchange
is restricted to certain regions of the polysaccharide chains, and only these can
be further modified by glucuronyl C5-epimerization and O-sulfation at various
positions. To investigate whether NDST isoforms influenced differently the
structure of HS, murine NDST-1 was overexpressed in human kidney 293 cells, and
the structure of the HS produced was compared to HS from NDST-2 overexpressing
cells [Cheung, W. F., Eriksson, I., Kusche-Gullberg M., Lindahl, U., and Kjellen,
L. (1996) Biochemistry 35, 5250-5256]. The level of N-sulfation increased from
40% in control cells to 60% and 80%, respectively, in NDST-1 and NDST-2
transfected cells. Interestingly, the increase in N-sulfation was accompanied by
an increased chain length, while no effect on IdoA content or O-sulfation was
seen. The most extended N-sulfated domains were found in HS synthesized by NDST-2
transfected cells. Since both the N-deacetylase and the N-sulfotransferase
activities were lower in these cells than in the NDST-1 overexpressing cells, we
conclude that, in addition to the level of enzyme expression, the NDST isoform
also is important in determining the N-sulfation pattern in HS.
PMID- 10758008
TI - Antiretroviral therapy in HIV/AIDS: update from San Francisco.
PMID- 10758006
TI - Nucleotide-induced conformational changes in P-glycoprotein and in nucleotide
binding site mutants monitored by trypsin sensitivity.
AB - Limited trypsin digestion was used to monitor nucleotide-induced conformational
changes in wild-type P-glycoprotein (Pgp) as well as in nucleotide binding domain
(NBD) Pgp mutants. Purified and reconstituted wild-type or mutant mouse Mdr3 Pgps
were preincubated with different hydrolyzable or nonhydrolyzable nucleotides,
followed by limited proteolytic cleavage at different trypsin:protein ratios. The
Pgp tryptic digestion products were separated by SDS-PAGE followed by
immunodetection with the mouse monoclonal anti-Pgp antibody C219, which
recognizes a conserved epitope (VVQE/AALD) in each half of the protein. Different
trypsin digestion patterns were observed for wild-type Pgp incubated with MgCl(2)
alone, MgADP, MgAMP.PNP, MgATP, and MgATP + vanadate. A unique trypsin digestion
profile suggestive of enhanced resistance to trypsin was observed under
conditions of vanadate-induced trapping of nucleotides (MgATP + vanadate). The
trypsin sensitivity profiles of Pgp mutants bearing either single or double
mutations in Walker A (K429R, K1072R) and Walker B (D551N, D1196N) sequence
signatures of NBD1 and NBD2 were analyzed under conditions of vanadate-induced
trapping of nucleotides. The proteolytic cleavage pattern observed for the double
mutants K429R/K1072R and D551N/D1196N, and for the single mutants K429R, K1072R,
and D1196N were similar and clearly distinct from wild-type Pgp under the same
conditions. This is consistent with the absence of ATP hydrolysis and of vanadate
induced trapping of 8-azido-ADP previously reported for these mutants [Urbatsch
et al. (1998) Biochemistry 37, 4592-4602]. Interestingly, the trypsin digestion
profiles observed under vanadate-induced trapping for the D551N and D1196N
mutants were quite different, with the D551N mutant showing a profile resembling
that seen for wild-type Pgp. The different sensitivity profiles of Pgp mutants
bearing mutations at the homologous residue in NBD1 (D551N) and NBD2 (D1196N)
suggest possible structural and functional differences between the two sites.
PMID- 10758009
TI - The Seventh Conference on Retroviruses and Opportunistic Infections.
PMID- 10758011
TI - Adult AIDS Clinical Trials Group funding is renewed.
PMID- 10758010
TI - Addressing the issue of childbearing in heterosexual couples discordant for HIV.
PMID- 10758012
TI - HIV prevention grants available.
PMID- 10758013
TI - Sit out the silly season?
PMID- 10758014
TI - When and where to start: guidelines for the initiation of antiretroviral therapy.
AB - Although several sets of treatment guidelines recommend when antiretroviral
therapy should begin, no overall consensus has emerged. Factors that must be
weighed in deciding when to start include not only CD4+ cell count and viral load
but also the stage and tempo of the disease and the commitment of the patient.
Evidence suggests that a first-line, triple-nucleoside regimen may not be the
best option, especially for people with more advanced disease. Although deciding
between a protease inhibitor (PI) regimen and a non-nucleoside regimen is more
difficult, some data indicate that PIs may exert beneficial effects not seen with
other antiretrovirals. Simplifying regimens by combining agents with longer half
lives, or by combining two PIs, can make antiretroviral therapy easier to take
and more tolerable. But no current regimen will be durable without the utmost
adherence by the patient.
PMID- 10758015
TI - When to switch and what to switch to: strategic use of antiretroviral therapy.
AB - Clinical cohort studies suggest that as many as 60% of patients experience
virologic failure of a first-line antiretroviral regimen. Second-line and rescue
(or salvage) regimens have a poorer success record: Most studies presented to
date show a short-term virologic response rate of only approximately 30% in
treatment-experienced individuals. That rate will improve with better
understanding of what causes initial virologic failure, continued development of
new antiretroviral agents (including drugs with new mechanisms of action) and new
treatment strategies (including dual-protease inhibitor regimens), and more
widespread use of resistance testing. Further clinical research is needed to
improve salvage options, and physicians should consider enrolling treatment
experienced patients in clinical trials.
PMID- 10758017
TI - Developments in patient monitoring
PMID- 10758016
TI - How to manage metabolic complications of HIV therapy: what to do while we wait
for answers.
AB - Although effective treatment of antiretroviral-associated metabolic abnormalities
ultimately depends on understanding the mechanisms involved, clinicians facing
these problems are beginning to feel compelled to do something now to manage
treatment-related metabolic complications. Diet and exercise should not be
overlooked, because both can be effective in managing these complications without
causing further side effects. Fibric acid derivatives such as gemfibrozil and
statins can lower HIV-associated cholesterol and triglyceride levels, although
further data are needed on problematic interactions between statins and protease
inhibitors (PIs). Hypoglycemic agents may have some role in managing glucose
abnormalities, although troglitazone cannot be recommended for fat abnormalities
alone and metformin may cause lactic acidosis. Growth hormone and anabolic
steroids may have some role in treating lipodystrophy, but the cost of growth
hormone is prohibitive for many patients and definitive data on efficacy are
lacking. Replacing a PI with a reverse transcriptase inhibitor has improved lipid
and glucose levels in some studies. However, that strategy begs the question of
how the nucleosides might contribute to lipodystrophy.
PMID- 10758019
TI - Different guidelines for older patients and women?
PMID- 10758018
TI - Antiretroviral regimens: the more drugs, the better?
PMID- 10758020
TI - Insights on amprenavir, ABT-378/r, and nelfinavir
PMID- 10758021
TI - Osteonecrosis in patients with HIV infection
PMID- 10758022
TI - Adherence to combination antiretroviral therapy: synthesis of the literature and
clinical implications.
AB - Adherence to combination antiretroviral therapy has a strong impact on virologic
response and emergence of viral resistance. However, monitoring adherence in the
clinic is difficult. What a patient says or a clinician believes about a
patient's adherence may be misleading. Patients with suboptimal adherence may
have reduced or undetectable viral loads. On the other hand, viral load may not
decrease in patients with perfect adherence because of pretreatment resistance,
poor drug metabolism, or other factors. A multidisciplinary approach involving
patients, health care professionals, family, and friends may optimize adherence.
This article reviews the literature on adherence to antiretroviral therapy,
critiques the various adherence measures used by researchers and clinicians, and
discusses the clinical implications of adherence to antiretroviral therapy.
PMID- 10758023
TI - [Usefulness and limitations of registries in acute myocardial infarction. The
PRIAMHO Study].
PMID- 10758024
TI - [Conventional surgery continues to be the best option for surgical treatment of
aortic valve disease. Arguments in favor].
AB - It is premature to try to compare the results of aortic valve surgery obtained by
the so-called minimally-invasive techniques, with those obtained with the use of
the conventional median sternotomy approach. The experience accumulated with this
type of limited access surgery is small and remains anecdotal. We reviewed one
hundred consecutive aortic valve patients operated at the Mayo Clinic. There was
one hospital death. There were no instances of post-operative bleeding or
mediastinitis. Average duration of extracorporeal circulation was 72 minutes;
average duration of aortic cross-clamp was 50 minutes. Duration of
hospitalization in these patients averaged 6.4 days. These results compare
favorably with those reported with the minimally invasive procedures.
PMID- 10758025
TI - [Conventional surgery continues to be the best option for surgical treatment of
aortic valve disease. Arguments against].
AB - The median sternotomy is still the gold standard of cardiac surgery approaches.
The main disadvantages of this cardiac access are osteomyelitis and mediastinitis
which are infrequent but very serious; the aesthetic impact of a large and
visible scar from the median lane and lastly respiratory failure consecutive to
pain and sternal dehiscence. Other pathways have been developed in trying to
reduce these complications and lessen the length of stay, pain and costs. From
the many variants described up until now, the "J" ministernotomy seems to be the
most accepted of these techniques. Although there are many published series
describing these different cardiac approaches, the lack of prospective,
randomized studies comparing conventional and minimally invasive surgery
precludes the demonstration of the benefits of the new technique. In spite of
this, we think the "J" ministernotomy undoubtedly has aesthetic advantages,
smaller complications in patients with respiratory failure, easier repair in case
of mediastinitis or osteomyelitis and fewer adhesions in surgical redos.
PMID- 10758026
TI - [Malondialdehyde and nitric oxide behaviour in patients with myocardial
infarction].
AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to determine the potential
usefulness of malondialdehyde and nitric oxide as sensors of metabolic damage
produced during acute coronary ischaemics events. METHODS: Serum malondialdehyde
and nitric oxide levels were determined as thiobarbituric acid derivative and
nitrites respectively in 15 male patients who were admitted to the emergency ward
of the Hospital General del Sur de Maracaibo, because of acute stage of
myocardial infarction. RESULTS: Our results show, upon follow-up and afterwards
30 days a highly significant increase in the malondialdehyde level during the
acute phase of myocardial infarction (1.87 +/- 0.29 vs 45.47 +/- 8.67 mM; p <
2.01 10-5) that returns to normal levels 30 days after myocardial infarction when
compared with healthy subjects of the same age (1.87 +/- 0.29 vs 4.58 +/- 1.43
mM). As for nitric oxide, levels also increased significantly during the acute
phase of myocardial infarction (41.25 +/- 3.59 vs 164.63 +/- 12.7, p < 2.13 10-10
mM) and diminished significantly when compared with healthy adults of the same
age 30 days after the acute event (41.25 +/- 3.59 vs 40.85 +/- 4.50 mM).
CONCLUSIONS: Our results show that serum levels of malondialdehyde and nitric
oxide increased significantly during acute infarction, coming back to normal
levels 30 days after infarction, which suggest that both substances are potential
tools to predict cardiac function recovery.
PMID- 10758027
TI - [Fungal endocarditis in non drug-addict patients. 10-year experience].
AB - INTRODUCTION AND OBJECTIVES: Fungal endocarditis is an uncommon but serious
disease. Five cases of fungal endocarditis, involving non-addict patients, were
diagnosed at our hospital in the last 10 years. RESULTS: Causal organisms
included Candida albicans (3 patients), Saccharomyces (1 patient) and Torulopsis
glabrata (1 patient). The predisposing condition to fungal infection was previous
cardiac surgery in four cases (three of them with prosthetic heart valves, and
the other patient underwent total surgical correction of Tetralogy of Fallot). No
predisposing cause was found in one patient. All patients developed important
complications. Three cases underwent cardiac surgery that evolved favorably, and
two patients had contraindications for surgery and died from multiorgan septic
involvement (overall survival was 60%). CONCLUSIONS: The incidence of fungal
endocarditis involving non-addict patients has represented 3% of all cases of
infective endocarditis. Even nowadays, fungal endocarditis is a disease with a
high mortality and a precocious diagnosis is important to approach surgical
treatment and to improve its prognosis.
PMID- 10758028
TI - [Morphologic classification of hypertrophic cardiomyopathy with myocardial single
photon emission tomography. Comparison with echocardiographic classification].
AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to compare different
morphologic types of hypertrophic cardiomyopathy obtained by single photon
emission tomography to those obtained by echocardiogram. MATERIALS AND METHODS:
In 76 (64%) out of 119 patients with hypertrophic cardiomyopathy the
echocardiogram permitted an optimal visualization of all left ventricular
segments in the short axis view and consequent classification to one of the six
morphological types: type I (septal anterior hypertrophy), type II (septal
anterior and septal posterior hypertrophy), type III (septal and antero-lateral
hypertrophy), type IV (antero-lateral and/or septal posterior hypertrophy), type
V (concentric hypertrophy) and type VI (apical hypertrophy). Without knowledge of
echo data, two experienced observers included the short axis of single photon
emission tomography images at rest (99mTc-tetrofosmin) to one of those types.
RESULTS: Global concordance between echocardiogram and single photon emission
tomography was 75%. Type III was the most frequent both in echo (76%) and in
single photon emission tomography (74%) and type III produced the majority of
discrepancies. SPET identified 4 patients with a predominant septal and inferior
hypertrophy, that did not correspond to any of the 6 types of echocardiographic
classification and had been previously classified as type III by echo in 3 cases
and as type V in 1 case. CONCLUSIONS: There was agreement between echo and single
photon emission tomography in the morphological classification of most of the
patients (75%) with hypertrophic cardiomyopathy. Nevertheless, some discrepancies
were observed for the type III echocardiogram.
PMID- 10758029
TI - [Thyroid function alterations in children with congenital cardiac disease after
catheterization with iodinated contrast agents].
AB - INTRODUCTION AND OBJECTIVES: Iodinated contrast agents can block thyroid hormone
synthesis. The aims of this study were: 1st) to study the incidence of thyroid
function disturbances in children with congenital heart disease after cardiac
catheterization, 2nd) to analyze the predisposing factors that may lead to the
development of hypothyroidism after angiography, and 3rd) to determine the
duration of these hypothyroidism states. PATIENTS AND METHODS: From february 1993
to April 1997 thyrotropine (TSH) and free thyroxine (FT4) serum values were
analyzed before cardiac catheterization and in the two following weeks, in 99
children under three years of age, with congenital cardiac disease. Those
patients who showed any postangiography increase in TSH were further evaluated by
weekly measures of serum thyroid hormones and TSH until normal values were
obtained or until the initiation of hormonal replacement therapy. The patients'
data (age, previous exposure to contrast agents, cardiac disease, associated
extracardiac malformations, renal failure, severity of illness, treatment) and
the catheterism data (the dose and type of contrast and the fluoroscopy time)
were included in the univariant analysis. RESULTS: 10 mUI/ml), that persisted
beyond three weeks in six cases. The occurrence of multiple malformation
syndromes was the most clearly associated risk factor (p < 0,01) not only in the
development of postangiography hypothyroidism but also in longer hormonal
dysfunction. CONCLUSIONS: Thyroid function should be tested in every patient with
multiple malformation syndrome that undergo angiocardiography with iodinated
contrast agents.
PMID- 10758030
TI - [Effect of losartan on human platelet activation by thromboxane A2].
AB - INTRODUCTION AND OBJECTIVES: Previous studies have demonstrated that losartan, an
AT-1 receptor antagonist of angiotensin II (Ang II) could block the receptor of
thromboxane A2 (TXA2) in the vascular wall. The aim of the present study was to
assess the effect of losartan on human platelet activation. MATERIALS AND
METHODS: Platelets were obtained from 15 healthy men between the age 26 and 40.
Platelet activation was measured by changes in the light transmission of platelet
rich plasma stimulated by a synthetic TXA2 analogue, U46619 (5 x 10(-6) mol/l).
RESULTS: The U46619-stimulated platelet aggregation was significantly inhibited
by losartan in a dose-response manner. Only a high dose of EXP 3174 (5 10-5
mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619
induced platelet activation. Captopril, an angiotensin I-converting inhibitor
failed to modify U46619-induced platelet aggregation. Despite the platelets
expressing AT-1 type receptors, of Ang II exogenous Ang II did not modify
platelet aggregation induced by U46619. The binding of U46619 to platelets was
competitively inhibited by losartan in dose-dependent manner. However, only a
high dose of EXP 3174 reduced the binding of U46619. Captopril failed to modify
the binding of U46619 to platelets. CONCLUSIONS: Losartan decreased platelet
aggregation by a TXA2-dependent mechanism. EXP 3174 showed a lesser potency than
losartan to reduce TXA2-platelet activation. Captopril and exogenous angiotensin
II had no effect on human platelet activation. These results suggest that
losartan reduced TXA2-dependent platelet activation independently of the blockade
of AT-1 receptors.
PMID- 10758031
TI - [Guidelines of the Spanish Society of Cardiology on aortic diseases].
AB - Acute aortic pathology is an urgent clinical situation, of which prognosis mainly
related to prompt and accurate diagnosis as well as a quick treatment. In this
paper we review the aortic pathology, specially focused on aortic dissection. We
review its etiology, clinical presentation and diagnostic methods. In addition
the medical therapy and the surgical indications of aortic aneurysm, dissection
and aortic intramural haematoma are described.
PMID- 10758032
TI - [Guidelines of the Spanish Society of Cardiology on magnetic resonance].
AB - A wide perspective of the cardiac applications of magnetic resonance is presented
in this report, including technical aspects of the practice, recommendations on
the appropriate training of medical personnel for the practice of examination and
also, an extensively commented review of the accepted clinical indications for
the practice of a cardiac magnetic resonance imaging study at present.
PMID- 10758033
TI - [How and when to use cardioversion in atrial fibrillation at the beginning of the
year 2000].
AB - The high incidence and associated complications are causing atrial fibrillation
to emerge as a disease of uncertain prognosis, rather than an acceptable
alternative to sinus rhythm. There is accumulated evidence of an electrical and
anatomical remodelling in atrial fibrillation that facilitates the onset and
maintenance of this arrhythmia, and the capacity for these changes may be
reversed if sinus rhythm is restored. The development of new drugs that decrease
the incidence of recurrences and the advent of internal cardioversion, which has
proven to be very effective when traditional methods have failed, have widened
the indications and increased the number of patients who may benefit from this
technique. These advances pave the way for the development of an implantable
atrial cardioverter, which would allow an early treatment of atrial fibrillation
and, therefore, lessen the deleterious effects brought on by this rhythm
disorder.
PMID- 10758034
TI - [Ischemic sudden death: critical analysis of risk markers. Part VIII].
AB - Coronary artery disease is responsible for approximately 75-80% of sudden cardiac
deaths in most industrialized countries. Risk factors can be divided in those
which suggest structural heart disease and those reflecting abnormal
physiological markers. Therapeutic strategies for primary prevention of sudden
cardiac death require careful scrutiny. The systematic use of risk markers to
identify and stratify high risk groups may be of help to establish primary
prevention measures in daily practice. Different methods to stratify risk factors
using ejection fraction, ventricular arrhythmias, heart rate variability,
baroreflex sensitivity, and dispersion of repolarization are discussed in this
article.
PMID- 10758035
TI - [Balloon dilatation in acquired stenosis of the coronary sinus].
PMID- 10758036
TI - [Valve replacement in severe aortic regurgitation following valve sparing
operation with David's technique].
AB - The aortic valve sparing operation is of great interest in the treatment of
severe aortic insufficiency caused by annulus enlargement in aortic
annuloectasia. If valve leaflets are normal, and we want to prevent complications
derived from valve prosthesis and chronic anticoagulation, techniques like David
s for valve preserving surgery will be performed. Although long-term results of
these techniques are usually good, in some cases, like in the one we are dealing
with here fibrosis is produced in the native valve, which evolves into a severe
aortic insufficiency needing reoperation. We hereby describe the time related
events of aortic valve deterioration, when the reintervention was indicated, and
how the surgery was performed.
PMID- 10758037
TI - [Stent dilatation of pulmonary artery stenosis in the adult patient with
congenital heart disease].
AB - Stents have been previously used to resolve stenoses of branch pulmonary arteries
in children. We report 3 patients, with mean age of 22.7 +/- 4.7 years and
pulmonary artery stenosis after palliative surgery in whom we implanted seven
stents in four procedures. Six P308 Palmaz, overlapped two by two, were implanted
by venous femoral approach in two patients, receiving four in the first case and
the other two in the third case. In the second case, a NIR type stent was
implanted through femoral artery in the right pulmonary artery. Stenosis diameter
enlarged from 5.3 +/- 2.3 to 14.4 +/- 4.2 mm and the pressure gradient through
stenosis fell from 40.6 +/- 15.3 to 6. 5 +/- 5 mmHg. All stents are well deployed
and there are two patients waiting for total correction (previously not feasible)
during a follow-up of 30.6 +/- 6.1 months.
PMID- 10758038
TI - [Intrapericardial cisplatin for malignant tamponade].
AB - The choice therapy of malignant pericardial effusion is controversial.
Pericardiocentesis is usually successful in alleviating tamponade, but
unfortunately, that tamponade recurs frequently and patients are then again
exposed to a critical situation and need hospitalization. Several different
approaches have been advocated in order to prevent reaccumulation of the
pericardial fluid, most of them quite cumbersome. We present our experience with
intrapericardial administration of cisplatin. There were 6 patients, and the
primary tumor was breast carcinoma in 2, lung in 1, ovary in 1, mediastinal
fibrosarcoma in 1, and unknown in 1. Administration of cisplatin was virtually
uneventful and painless, and there were no recurrences, with a survival of 2 to
18 months (mean 5.6).We conclude that intrapericardial cisplatin is safe and
effective in treating malignant pericardial tamponade and preventing recurrence.
PMID- 10758039
TI - [Atrioventricular nodal reentrant tachycardia as a trigger for atrial
fibrillation].
AB - We report the case of a 43 year-old male with a long history of paroxysmal
palpitations aborted by vagal manoeuvres, where atrial fibrillation was the only
documented arrhythmia. During the electrophysiological study an AV nodal
reentrant tachycardia was demonstrated with rapid degeneration into atrial
fibrillation. After slow pathway ablation, nodal tachycardia became non
inducible. No palpitations were reported and no arrhythmic event was recorded
after a follow-up of 20 months. In selected cases, the electrophysiological study
could reveal potentially curable causes of atrial fibrillation.
PMID- 10758040
TI - Circulation online only : april 11, 2000
PMID- 10758041
TI - Catecholamines, cardiac beta-adrenergic receptors, and heart failure.
PMID- 10758042
TI - Implantable cardioverter defibrillator therapy: the sickest patients benefit the
most.
PMID- 10758043
TI - Hypertension, small arteries, and pathways for angiotensin II generation: "The
proper study of mankind is man".
PMID- 10758044
TI - Identification of coronary thrombus with a IIb/IIIa platelet inhibitor
radiopharmaceutical, technetium-99m DMP-444: A canine model.
AB - BACKGROUND: A diagnostic test that could distinguish between stable and unstable
coronary atherosclerotic plaques would be useful. We tested the ability of a new
glycoprotein IIb/IIIa platelet inhibitor DMP-444, labeled with technetium (Tc)-99
m, to identify platelet-rich thrombus by nuclear imaging in a canine model.
METHODS AND RESULTS: Combinations of a flow-limiting stenosis and 0 to 15 minutes
of endothelial electrical stimulation at a site in the left anterior descending
coronary artery were used to induce varying amounts of thrombus formation. In 10
animals with markedly positive nuclear images after the injection of Tc-99m DMP
444, the presence of platelet-rich thrombus was confirmed postmortem by gross
appearance, high nuclear counts, and abundant platelets on electron microscopy.
The 10 animals with negative images had lower counts, smaller thrombus weights
(P<0.05 for each), and fewer platelets by electron microscopy. CONCLUSIONS:
Activated platelets participating in acute thrombus formation can be accurately
detected by nuclear imaging using Tc-99 m DMP-444.
PMID- 10758045
TI - Prospective study of potentially virulent strains of Helicobacter pylori and
coronary heart disease in middle-aged men.
AB - BACKGROUND: Studies are needed to test claims that potentially virulent strains
of Helicobacter pylori are more strongly related to coronary heart disease (CHD)
than are other strains. METHODS AND RESULTS: We measured serum IgG antibodies to
mixed H pylori antigens and separately to the virulence-associated H pylori
antigen CagA (cytotoxin-associated gene product A) in 505 CHD cases and in 1025
age-matched controls "nested" in a prospective study of 7735 British men (mean
duration of follow-up in controls, 16 years). Of the 505 cases, 401 (79%) were
seropositive for H pylori antibodies compared with 740 (72%) of the 1025
controls, yielding an odds ratio for CHD of 1.55 (95% CI 1.19 to 2.03), which
fell to 1.30 (95% CI 0.88 to 1. 90) after adjustments were made for standard
vascular risk factors and indicators of socioeconomic status. Of the CHD cases,
240 (48%) were seropositive for IgG antibodies to CagA compared with 450 (44%) of
the controls. When CagA-seropositive individuals were compared with H pylori
seronegative individuals, the odds ratio for CHD was 1. 42 (95% CI 1.06 to 1.91),
which fell to 1.10 (95% CI 0.71 to 1.71) after adjustments. In an analysis
restricted to the 1141 (75%) H pylori-seropositive participants, the odds ratio
for CHD was 1.0 (95% CI 0.78 to 1.29) in CagA-seropositive men. No strong
associations were observed between H pylori seropositivity and blood lipids,
blood pressure, markers of systemic inflammation, or plasma homocysteine.
CONCLUSIONS: H pylori infection is not strongly related to the incidence of CHD
in late middle-aged men, and CagA-positive strains appear to be no more strongly
related to the disease than other strains. However, further studies are required
to confirm or refute the existence of any moderate associations, particularly at
younger ages.
PMID- 10758046
TI - Correction of arterial structure and endothelial dysfunction in human essential
hypertension by the angiotensin receptor antagonist losartan.
AB - BACKGROUND: Structural and functional alterations of the vasculature may
contribute to complications of hypertension. Because angiotensin II may be
pivotal in some of these vascular abnormalities, we tested the hypothesis that
the angiotensin type 1 (AT(1)) receptor antagonist losartan, in contrast to the
beta-blocker atenolol, would correct resistance artery abnormalities in patients
with essential hypertension. METHODS AND RESULTS: Nineteen untreated patients
with mild essential hypertension (47+/-2 years, range 30 to 65 years; 57% male)
were randomly assigned in double-blind fashion to losartan or atenolol treatment
for 1 year. Nine age/sex-matched normotensive subjects were also studied. Both
treatments reduced blood pressure to a comparable degree (losartan, from 149+/
4.1/101+/-1.6 to 128+/-3.6/86+/-2.2 mm Hg, P<0.01; atenolol, from 150+/-4.0/99+/
1.2 to 130+/-3.2/84+/-1.4 mm Hg, P<0.01). Resistance arteries (luminal diameter
150 to 350 microm) dissected from gluteal subcutaneous biopsies were studied on a
pressurized myograph. After 1 year of treatment, the ratio of the media width to
lumen diameter of arteries from losartan-treated patients was significantly
reduced (from 8.4+/-0.4% to 6.7+/-0.3%, P<0.01). Arteries from atenolol-treated
patients exhibited no significant change (from 8. 3+/-0.3% to 8.8+/-0.5% after
treatment). Endothelium-dependent relaxation (acetylcholine-induced) was
normalized by losartan (from 82.1+/-4.9% to 94.7+/-1.1%, P<0.01) but not by
atenolol (from 80. 4+/-2.7% to 81.7+/-4.6%). Endothelium-independent relaxation
(by sodium nitroprusside) was unchanged after treatment. CONCLUSIONS: The AT(1)
antagonist losartan corrected the altered structure and endothelial dysfunction
of resistance arteries from patients with essential hypertension, whereas the
beta-blocker atenolol had no effect.
PMID- 10758047
TI - Identification of patients most likely to benefit from implantable cardioverter
defibrillator therapy: the Canadian Implantable Defibrillator Study.
AB - BACKGROUND: Patients with resuscitated ventricular tachyarrhythmias (ventricular
tachycardia/ventricular fibrillation) benefit from implantable cardioverter
defibrillators (ICDs) compared with medical therapy. We hypothesized that the
patients who benefit most from an ICD are those at greatest risk of death.
METHODS AND RESULTS: In the Canadian Implantable Defibrillator Study (CIDS), 659
patients with resuscitated ventricular tachyarrhythmias were randomly assigned to
receive an ICD or amiodarone and were then followed for a mean of 3 years. There
were 98 and 83 deaths in the amiodarone and ICD groups, respectively. We used
multivariate Cox analysis to assess the impact of baseline parameters on the
mortality in the amiodarone group. Reduced left ventricular ejection fraction,
advanced age, and poor NYHA status identified high-risk patients (P=0.0001 to
0.0009). Quartiles of risk were constructed, and the mortality reduction
associated with ICD treatment in each quartile was assessed. There was a
significant interaction between risk quartile and the ICD treatment effect
(P=0.011). In the highest risk quartile, there was a 50% relative risk reduction
(95% CI 21% to 68%) of death in the ICD group, whereas in the 3 lower quartiles,
there was no benefit. Patients who are most likely to benefit from an ICD can be
identified with a simple risk score (>/=2 of the following factors: age >/=70
years, left ventricular ejection fraction /=2 risk factors. CONCLUSIONS: In CIDS, patients at highest risk of death
benefited most from ICD therapy. These can be identified easily on the basis of
age, poor ventricular function, and poor functional status.
PMID- 10758048
TI - Adventitial mast cells connect with sensory nerve fibers in atherosclerotic
coronary arteries.
AB - BACKGROUND: The number of activated mast cells is increased in the adventitia of
coronary segments with plaque rupture and in spastic atherosclerotic coronary
segments. Neurogenic activation of mast cells has been demonstrated previously in
other tissues. Here we identified and quantified contacts between mast cells and
nerves in the adventitia of normal and atherosclerotic coronary segments. METHODS
AND RESULTS: Normal (types 0 or I) and atherosclerotic (lesion types II, III, and
IV) coronary segments from 22 unselected autopsy cases were stained for mast
cells and sensory nerves by a histochemical double-labeling method. Contacts
between mast cells and sensory nerves were quantified morphometrically and also
identified by confocal microscopy. Coronary arteries obtained during heart
transplantation were stained for the neuropeptides capable of stimulating mast
cells, ie, substance P and calcitonin gene-related peptide. In the adventitia of
atherosclerotic coronary segments with type IV lesions, the numbers of mast cells
and mast cell-nerve contacts (104+/-15 mast cells/mm(2) and 30+/-5 nerve
contacts/mm(2); mean+/-SEM) were significantly greater than in segments with type
III lesions (79+/-12 [P<0.001] and 24+/-6 [P<0.001]), those with type II lesions
(54+/-4 [P<0.001] and 12+/-2 [P<0.001]), or those with normal intima (31+/-3
[P<0.001] and 4+/-1 [P<0.001]). The nerve fibers connected with mast cells
contained both substance P and calcitonin gene-related peptide, which identified
them as sensory nerves. CONCLUSIONS: Neurogenic stimulation of mast cells in the
adventitia of coronary arteries may release vasoactive compounds, such as
histamine and leukotrienes, which can contribute to the complex neurohormonal
response that leads to abnormal coronary vasoconstriction.
PMID- 10758049
TI - Coronary artery imaging in grown up congenital heart disease: complementary role
of magnetic resonance and x-ray coronary angiography.
AB - BACKGROUND: There is a high incidence of anomalous coronary arteries in subjects
with congenital heart disease. These abnormalities can be responsible for
myocardial ischemia and sudden death or be damaged during surgical intervention.
It can be difficult to define the proximal course of anomalous coronary arteries
with the use of conventional x-ray coronary angiography. Magnetic resonance
coronary angiography (MRCA) has been shown to be useful in the assessment of the
3-dimensional relationship between the coronary arteries and the great vessels in
subjects with normal cardiac morphology but has not been used in patients with
congenital heart disease. METHODS AND RESULTS: Twenty-five adults with various
congenital heart abnormalities were studied. X-ray coronary angiography and
respiratory-gated MRCA were performed in all subjects. Coronary artery origin and
proximal course were assessed for each imaging modality by separate, blinded
investigators. Images were then compared, and a consensus diagnosis was reached.
With the consensus readings for both magnetic resonance and x-ray coronary
angiography, it was possible to identify the origin and course of the proximal
coronary arteries in all 25 subjects: 16 with coronary anomalies and 9 with
normal coronary arteries. Respiratory-gated MRCA had an accuracy of 92%, a
sensitivity of 88%, and a specificity of 100% for the detection of abnormal
coronary arteries. The MRCA results were more likely to agree with the consensus
for definition of the proximal course of the coronary arteries (P<0.02).
CONCLUSIONS: For the assessment of anomalous coronary artery anatomy in patients
with congenital heart disease, the use of the combination of MRCA with x-ray
coronary angiography improves the definition of the proximal coronary artery
course. MRCA provides correct spatial relationships, whereas x-ray angiography
provides a view of the entire coronary length and its peripheral run-off.
Furthermore, respiratory-gated MRCA can be performed without breath holding and
with only limited subject cooperation.
PMID- 10758050
TI - Myofilament calcium regulation in human myocardium.
AB - BACKGROUND: We investigated whether decreased myofilament calcium contractile
activation may, in part, contribute to heart failure. METHODS AND RESULTS:
Calcium concentration required for 50% activation and Hill coefficient for fibers
from nonfailing and failing human hearts at pH 7.1 were not different. Maximum
calcium-activated force (F(max)) was also not different. However, at pH 6.8 and
6.9, differences were seen in myofilament calcium activation between nonfailing
and failing hearts. At lower pH, failing myocardium was shifted left on the
calcium axis compared with nonfailing myocardium, which suggested an increase in
myofilament calcium responsiveness. Increased inorganic phosphate concentration
decreased maximal force development by 56% in nonfailing and 36% in failing
myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus
0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0.
56 micromol/L shift toward higher intracellular calcium concentrations in
nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein
kinase A in the presence of cAMP resulted in a further rightward shift in
nonfailing human myocardium but did not further shift the calcium-force
relationship in fibers from failing hearts. cGMP also resulted in a greater
decrease in myofilament calcium sensitivity in fibers from failing hearts.
CONCLUSIONS: We propose that changes at the level of the thin myofilaments result
in differential responses to changes in the intracellular milieu in nonfailing
versus failing myocardium.
PMID- 10758052
TI - Predictive power of increased QT dispersion in ventricular extrasystoles and in
sinus beats for risk stratification after myocardial infarction.
AB - BACKGROUND: QT dispersion, commonly measured in sinus beats (QTd-S), can also be
calculated in premature ventricular beats (QTd-V). To date, no studies have
addressed the relation between these 2 variables. METHODS AND RESULTS: In 148
patients with remote myocardial infarction and premature ventricular beats on a
routine ECG, QT dispersion, defined as the difference between the maximum and the
minimum QT interval across the 12-lead ECG, was calculated separately for the
ventricular extrasystole and the preceding sinus beat. In the total group of
patients, QTd-V was greater than QTd-S (83+/-33 versus 74+/-34 ms, respectively;
P=0.001). During a follow-up period of 35+/-17 months, arrhythmic events
(sustained ventricular tachycardia, ventricular fibrillation, or sudden death)
were noted in 30 patients. A QTd-V of >/=100 ms was a stronger univariate marker
of arrhythmic events than was a QTd-S of >/=100 ms, and multivariate analysis
selected only prolonged QTd-V (hazard ratio 3.81, 95% CI 2.2 to 11.2) and low
ejection fraction (hazard ratio 3.05, 95% CI 1.6 to 7.6) as independent
predictors of arrhythmic events. CONCLUSIONS: The magnitude of QTd-V was greater
than that of QTd-S in the total group of patients. Prolonged QTd-V is associated
with a significantly increased risk for arrhythmic events in postinfarction
patients, and the prognostic significance of QTd-V exceeds that of QTd-S.
PMID- 10758051
TI - Long-term right ventricular volume overload increases myocardial
fluorodeoxyglucose uptake in the interventricular septum in patients with atrial
septal defect.
AB - BACKGROUND: Several studies have shown that long-term right ventricular (RV)
overload in animal models alters myocardial energy substrate metabolism. However,
whether long-term RV volume overload alters this metabolism in the human is
unclear. METHODS AND RESULTS: We performed positron emission tomography with
[(18)F]fluorodeoxyglucose (FDG) and single-photon emission tomography (SPECT)
with [(201)Tl]TlCl (Tl) and [(123)I]15-(p-iodophenyl)-3-R,S-methylpentadecanoic
acid (BMIPP) in 11 patients with atrial septal defect (ASD) and 11 control
subjects. In the FDG study, we calculated myocardial metabolic rate of glucose
(MMR) in interventricular septum (IVS) and left ventricular (LV) free wall. MMR
was significantly increased in IVS compared with LV free wall in the ASD patients
(420+/-35 versus 333+/-32 mol x kg(-1) x min(-1); P<0.05) but not in the control
group (347+/-27 versus 357+/-25 mol x kg(-1) x min(-1)). In both ASD and control
groups, SPECT count was not significantly different between IVS and LV free wall
in Tl (ASD, 160+/-11 versus 177+/-12; control, 141+/-12 versus 157+/-14 counts
per 15 minutes) and BMIPP studies (ASD, 203+/-14 versus 212+/-18; control, 162+/
16 versus 176+/-16 counts per 15 minutes). MMR in the IVS/LV free wall ratio in
the ASD group significantly correlated with indices related to RV volume
overload. CONCLUSIONS: Given the assumption that long-term RV volume overload did
not affect the lumped constant, the present study suggests that, unlike
myocardial perfusion or fatty acid analogue uptake, myocardial glucose
utilization in IVS relative to LV free wall is increased in relation to long-term
RV volume overload in patients with ASD.
PMID- 10758053
TI - Effects of flecainide in patients with new SCN5A mutation: mutation-specific
therapy for long-QT syndrome?
AB - BACKGROUND: Mutations in the cardiac sodium channel gene (SCN5A) can cause one
variant of the congenital long-QT syndrome. The effects of some of these
mutations on the alpha-subunit channel properties can be blocked by type Ib
antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G)
that affects the channel properties in a manner suggesting that sodium blockers
of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG
effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in
carriers of this mutation. METHODS AND RESULTS: Eight asymptomatic mutation
carriers and 5 control subjects were studied. Intravenous lidocaine was tested
first in only 2 mutation carriers and had no significant effect on any ECG
parameter. Flecainide significantly shortened all heart rate-corrected
repolarization duration parameters only in carriers and not in control subjects:
QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset
to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092).
Flecainide also normalized the marked baseline repolarization dispersion in most
mutation carriers. These effects among carriers were maintained during long-term
(9 to 17 months) outpatient flecainide therapy with no adverse effects.
CONCLUSIONS: This report is the first to describe SCN5A mutation carriers who
significantly responded to flecainide therapy yet did not respond to lidocaine.
These results have important implications for long-QT allele-specific therapeutic
strategies.
PMID- 10758054
TI - Early and delayed consequences of beta(2)-adrenergic receptor overexpression in
mouse hearts: critical role for expression level.
AB - BACKGROUND: Transgenic cardiac beta(2)-adrenergic receptor (AR) overexpression
has resulted in enhanced signaling and cardiac function in mice, whereas
relatively low levels of transgenically expressed G(alphas) or beta(1)AR have
resulted in phenotypes of ventricular failure. Potential relationships between
the levels of betaAR overexpression and biochemical, molecular, and physiological
consequences have not been reported. METHODS AND RESULTS: We generated transgenic
mice expressing beta(2)AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart,
representing 60, 100, 150, and 350 times background betaAR expression. All lines
showed enhanced basal adenylyl cyclase activation but a decrease in forskolin-
and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing
line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of
heart failure at 25+/-1 weeks of age. The 60-fold line exhibited enhanced basal
cardiac function without increased mortality when followed for 1 year, whereas
100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure,
with death occurring at 41+/-1 weeks of age. Adenylyl cyclase activation did not
correlate with early or delayed decompensation. Propranolol administration
reduced baseline +dP/dt(max) to nontransgenic levels in all beta(2)AR transgenics
except the 350-fold overexpressors, indicating that spontaneous activation of
beta(2)AR was present at this level of expression. CONCLUSIONS: These data
demonstrate that the heart tolerates enhanced contractile function via 60-fold
beta(2)AR overexpression without detriment for a period of >/=1 year and that
higher levels of expression result in either aggressive or delayed
cardiomyopathy. The consequences for enhanced betaAR function in the heart appear
to be highly dependent on which signaling elements are increased and to what
extent.
PMID- 10758055
TI - Genetic manipulation of the rabbit heart via transgenesis.
AB - BACKGROUND: Transgenesis using cardiac-specific expression has been valuable in
exploring cardiac structure-function relationships. To date, cardiac-selective
studies have been confined to the mouse. However, the utility of the mouse is
limited in certain, possibly critical, aspects with respect to cardiovascular
function. METHODS AND RESULTS: To establish the potential validity of transgenic
methodology for remodeling a larger mammalian heart, we explored cardiac
selective expression in transgenic rabbits. The murine alpha- and beta-cardiac
myosin heavy chain gene promoters were used to express a reporter gene, and
transgene expression was quantified in cardiac, skeletal, and smooth muscles as
well as in nonmuscle tissues. Although neither promoter exactly mimics endogenous
patterns of myosin heavy chain expression, both are able to drive high levels of
transgene expression in the cardiac compartment. Neither promoter is active in
smooth muscle or nonmuscle tissues. CONCLUSIONS: Directed organ-specific
expression is feasible in a larger animal with existing reagents, and cardiac
selective transgenic manipulation is possible in the rabbit.
PMID- 10758056
TI - Vascular superoxide production and vasomotor function in hypertension induced by
deoxycorticosterone acetate-salt.
AB - BACKGROUND: Angiotensin II-induced hypertension is associated with increased
vascular superoxide production, which contributes to hypertension caused by the
octapeptide. In cell culture, stretch increases endothelial and vascular smooth
muscle production of reactive oxygen species (ROS). In perfused isolated vessels,
elevations of pressure can increase vessel angiotensin II production. The effects
of low-renin hypertension on vascular ROS production remain unclear. Furthermore,
the role of ROS in vascular function and hypertension in low-renin hypertension
is undefined. METHODS AND RESULTS: Rats were treated with DOCA and saline
drinking water for 3 weeks. Both systolic blood pressure (189+/-4 versus 126+/-2
mm Hg) and aortic superoxide production (3972+/-257 versus 852+/-287, P<0. 05)
were increased compared with controls. Relaxations of vascular segments to
acetylcholine (ACh, 100+/-2% versus 75+/-2%, P<0.05) and the calcium ionophore
A23187 (92+/-2% versus 72+/-3%, P<0.05) were also impaired in DOCA-salt. Heparin
binding superoxide dismutase (1200 U/d IV for 3 days) had no effect on blood
pressure but significantly improved relaxations to ACh and A23187. Losartan (25
mg x kg(-1) x d(-1) PO) for 7 days did not correct the hypertension or
endothelium-dependent vessel relaxation in DOCA-salt rats, excluding a role of a
local renin/angiotensin II system. CONCLUSIONS: These findings indicate that
increased vascular superoxide production occurs not only in angiotensin II
induced hypertension but also in hypertension known to be associated with low
renin states. Increased superoxide production alters large-vessel endothelium
dependent vascular relaxation but does not modulate blood pressure in low-renin
hypertension.
PMID- 10758057
TI - Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial
fibrosis in hypertensive heart disease.
AB - BACKGROUND: This study was designed to investigate whether the serum
concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a
marker of collagen type I synthesis, is related to myocardial fibrosis in
hypertensive patients. METHODS AND RESULTS: The study was performed in 26
patients with essential hypertension in which ischemic cardiomyopathy was
excluded after a complete medical workup. Right septal endomyocardial biopsies
were performed in hypertensive patients to quantify collagen content. Collagen
volume fraction (CVF) was determined on picrosirius red-stained sections with an
automated image analysis system. The serum concentration of PIP was measured by
specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF
were increased (P<0.001) in hypertensives. A direct correlation was found between
CVF and serum PIP (r=0.471, P<0.02) in all hypertensives. Histological analysis
revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18
with nonsevere fibrosis. Serum PIP was higher (P<0.05) in patients with severe
fibrosis than in patients with nonsevere fibrosis. Using receiver operating
characteristic curves, we observed that a cutoff of 127 microg/L for PIP provided
78% specificity and 75% sensitivity for predicting severe fibrosis with a
relative risk of 4.80 (95% CI, 1.19 to 19.30). CONCLUSIONS: These results show a
strong correlation between myocardial collagen content and the serum
concentration of PIP in essential hypertension. Although preliminary, these
findings suggest that the determination of PIP may be an easy and reliable method
for the screening and diagnosis of severe myocardial fibrosis associated with
arterial hypertension.
PMID- 10758058
TI - Pathological effects of extensive radiofrequency energy applications in the
pulmonary veins in dogs.
AB - INTRODUCTION: The long-term complications of catheter ablation within the
pulmonary veins are unknown. The development of pulmonary vein stenosis has
recently been described after catheter ablation to treat either chronic or
paroxysmal atrial fibrillation. The purpose of this study was to examine the
pathological and hemodynamic effects of radiofrequency (RF) energy application
within the pulmonary veins. METHODS AND RESULTS: Right heart and transseptal
catheterization were performed in 9 anesthetized mongrel dogs. The pulmonary vein
ostia were cannulated and pulmonary venous pressure was measured before RF energy
application in up to 4 separate pulmonary veins. Animals were euthanized at
intervals of 2 to 4 weeks (n=3), 6 to 8 weeks (n=3), or 10 to 14 weeks (n=3)
after ablation. Repeat catheterization before euthanasia demonstrated
statistically significant differences in pulmonary capillary wedge pressure,
cardiac output, pulmonary vascular resistance, and systemic vascular resistance
(P<0.05) compared with the baseline. Luminal narrowing was observed in 22 of 33
pulmonary veins to which RF energy was applied. Of these, 7 were totally
occluded, 7 had severe stenosis, and 8 were only minimally narrowed. Histological
examination revealed intimal proliferation with organizing thrombus, necrotic
myocardium in various stages of collagen replacement, endovascular contraction,
and a proliferation of elastic lamina. CONCLUSIONS: Applications of RF current
within the pulmonary veins may result in pulmonary vein narrowing or complete
occlusion. These observations should be considered in treatment of arrhythmias
originating within the pulmonary veins.
PMID- 10758059
TI - "Bystander" chest compressions and assisted ventilation independently improve
outcome from piglet asphyxial pulseless "cardiac arrest".
AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) without assisted
ventilation may be as effective as CPR with assisted ventilation for ventricular
fibrillatory cardiac arrests. However, chest compressions alone or ventilation
alone is not effective for complete asphyxial cardiac arrests (loss of aortic
pulsations). The objective of this investigation was to determine whether these
techniques can independently improve outcome at an earlier stage of the asphyxial
process. METHODS AND RESULTS: After induction of anesthesia, 40 piglets (11.5+/
0.3 kg) underwent endotracheal tube clamping (6.8+/-0.3 minutes) until simulated
pulselessness, defined as aortic systolic pressure <50 mm Hg. For the 8-minute
"bystander CPR" period, animals were randomly assigned to chest compressions and
assisted ventilation (CC+V), chest compressions only (CC), assisted ventilation
only (V), or no bystander CPR (control group). Return of spontaneous circulation
occurred during the first 2 minutes of bystander CPR in 10 of 10 CC+V piglets, 6
of 10 V piglets, 4 of 10 CC piglets, and none of the controls (CC+V or V versus
controls, P<0.01; CC+V versus CC and V combined, P=0.01). During the first minute
of CPR, arterial and mixed venous blood gases were superior in the 3 experimental
groups compared with the controls. Twenty-four-hour survival was similarly
superior in the 3 experimental groups compared with the controls (8 of 10, 6 of
10, 5 of 10, and 0 of 10, P<0.05 each). CONCLUSIONS: Bystander CPR with CC+V
improves outcome in the early stages of apparent pulseless asphyxial cardiac
arrest. In addition, this study establishes that bystander CPR with CC or V can
independently improve outcome.
PMID- 10758060
TI - Molecular basis of cardiovascular drug metabolism: implications for predicting
clinically important drug interactions.
PMID- 10758061
TI - Images in cardiovascular medicine. Plaque rupture causing spontaneous coronary
artery dissection in a patient with acute myocardial infarction.
PMID- 10758062
TI - Coronary aneurysms in Kawasaki's disease detected by magnetic resonance coronary
angiography.
PMID- 10758063
TI - Factor XIII and fibrinolytic resistance.
PMID- 10758064
TI - Differentiation of solitary papillary muscle hypertrophy from apical hypertrophic
cardiomyopathy.
PMID- 10758066
TI - Can the results be explained by poor randomization and nonpertinent comparisons?
PMID- 10758065
TI - Is asymmetric dimethylarginine a novel marker of atherosclerosis?
PMID- 10758067
TI - Cytomegalovirus and restenosis after percutaneous transluminal coronary
angioplasty.
PMID- 10758068
TI - Exercise as cardiovascular therapy.
PMID- 10758069
TI - ICPC-2-E: the electronic version of ICPC-2. Differences from the printed version
and the consequences.
AB - BACKGROUND: In 1998, ICPC-2 was published as a book. In the process of
translating the book, and preparing an electronic version of chapter 10 (the
actual classification), ICPC-2 proved to contain many errors and inconsistencies.
Particularly, major problems were identified in the conversion between ICPC-2 and
ICD-10, which could lead to major errors when used in electronic patient records.
OBJECTIVES: We prepared an electronic version of chapter 10 of ICPC-2, ICPC-2-E,
with all necessary corrections, to be published on the Oxford University Press
web site as a part of this article. METHODS: Errors and inconsistencies were
redressed, including particularly those in the con-version structure with all
consequences on the level of inclusion and exclusion criteria, through a process
of careful checking. RESULTS AND CONCLUSION: ICPC-2-E, the electronic version of
chapter 10 of ICPC-2, is specifically to be used in an electronic patient record
and for research purposes. It is to be used together with the first nine chapters
of ICPC-2, since the book is indispensable to make a correct use of ICPC.
PMID- 10758070
TI - Medical and lay views of irritable bowel syndrome.
AB - OBJECTIVES: The purpose of this study was to investigate doctors' and patients'
views of irritable bowel syndrome (IBS) in order to assess why problems in the
doctor-IBS patient relationship seem to occur. METHODS: A qualitative study was
undertaken involving in-depth, semi-structured interviews that were tape
recorded, transcribed verbatim and analysed using the constant comparative
method. The subjects comprised 12 doctors, including six GPs and six
gastroenterologists, and 14 patients with IBS. RESULTS: Doctors hold two
definitions of IBS, one 'public' and akin to a textbook definition, the other
'private' and including experiential knowledge and absorbed prejudices about IBS
patients. Doctors are not universally hostile towards IBS patients, although the
views of gastroenterologists may tend to be more pejorative than those of GPs.
Most doctors experience frustration with IBS, and this is due as much to medical
uncertainty and shortage of effective interventions as to intolerance of the
personal characteristics of IBS patients. Doctors distinguish between 'good' and
'bad' IBS patients and manage them accordingly. Many patients tend to find their
IBS symptoms very troublesome. Patients are more satisfied if they are taken
seriously and helped to manage their symptoms, but many feel that they are
labelled as neurotic by the medical profession. They tend to feel stigmatized and
let down by doctors. CONCLUSIONS: Better partnerships could be created with
patients, and better outcomes for IBS might be achieved, if doctors recognized
the impact of medical beliefs about IBS on patients. Doctors should offer IBS
patients empowering explanations for their disorder.
PMID- 10758071
TI - The treatment of social phobia in general practice. is exposure therapy feasible?
AB - BACKGROUND: Exposure therapy is an effective treatment for generalized social
phobia. Most patients with social phobia are treated in primary care, but family
doctors are not usually trained to perform exposure therapy. We have conducted a
study in primary care of the effect of exposure therapy alone or in combination
with sertraline on generalized social phobia. OBJECTIVES: The purpose of this
article is to describe the training of GPs and the application of the treatment
programme in general practice. METHOD: Forty-five GPs were trained for
approximately 30 h in assessing patients with social phobia and conducting
exposure therapy. The training programme included scoring of videotaped
interviews of five patients on several social phobia scales, and a videotape
demonstrating different steps of an exposure therapy was used as a model for role
play in group training. RESULTS: All of the GPs completed the training programme.
The doctors expressed satisfaction with the programme and also found it useful in
the treatment of patients with conditions other than social phobia. There was a
significant difference in response between the treatment groups (P = 0.001), and
the combination of exposure therapy and sertraline seemed to be particularly
beneficial.
PMID- 10758072
TI - GPs' recognition of, and response to, influences on patients' medicine taking:
the implications for communication.
AB - BACKGROUND: Research evidence suggests that patients' beliefs about medicines
influence medicine taking. Therefore, it is important that GPs are able to both
identify and take account of such beliefs in the consultation. OBJECTIVES: The
purpose of this study was to explore GPs' awareness of asthma patients' beliefs
about medicine, and of the ways in which friends and family, television
programmes and the Campaign for Asthma may influence these beliefs. We also
wanted to consider how GPs believe they would feel, and their likely behaviour,
when a patient refers to these influences in the consultation. METHOD: Four
events, drawn from 17 semi-structured interviews previously conducted with
patients recently prescribed oral steroids (prednisolone), were used to compose a
narrative account of a hypothetical patient's behaviour. The narrative described
a series of scenarios to which GPs were asked to respond. It was sent to all GPs
in Derbyshire (n = 476). RESULTS: The response rate was 69%. Half judged that the
scenarios which presented the patients' beliefs about medicine, the influence of
friends and family and the television were not 'realistic'. GPs also reported
feeling more 'supportive' and 'sympathetic' towards the Campaign for Asthma as a
source of patient information than they were towards opinions based on advice
given by patients' family and friends. CONCLUSION: Developing 'common ground' in
the consultation will be problematic if GPs are not aware of, and sympathetic
towards, the ways in which patients use information from a range of sources to
formulate beliefs that then affect their medicine-taking behaviour. GPs should be
encouraged to open up their discussions with patients so as to encourage the
development of a partnership in which each party is aware of, and respects, the
other's point of view.
PMID- 10758073
TI - Patients' autonomy and medical benefit: ethical reasoning among GPs.
AB - BACKGROUND: During the last decades, the traditional role of GPs as decision
makers for their patients has been questioned. OBJECTIVES: The aim of this study
was to identify and discuss how GPs deal with and how they reason in situations
where there is a possible tension between the obligation to respect the patients'
right to self-determination and the obligation to promote their health. METHODS:
One hundred and twenty randomly selected Swedish GPs received a mailed
questionnaire with two vignettes, one describing a patient reluctant to have a
medically motivated intervention, the other describing a patient requesting a
medically doubtful intervention. Forty seven of these GPs subsequently were
interviewed by telephone. RESULTS: With regard to the first vignette,
approximately two-thirds of respondents to the questionnaire (n = 82) answered
that they would not accept the patient's reluctance. Older GPs were somewhat more
inclined to try to persuade the patient to come to their surgery than were
younger colleagues. In the interview, most respondents answered that the right to
self-determination ought to be given priority, but the obligation to promote
health had a greater influence on their behaviour. Regarding the second vignette,
two-thirds of respondents to the questionnaire answered that they would not give
way to the patient's request for intervention. Younger GPs said "No" more often
than did their older colleagues. In the interviews, justifications for their
response referred to medical benefit, uneasy patients, self-protection and
justice. CONCLUSION: When facing such conflicts in everyday practice, the ethical
codes of medicine are often too categorical to give any guidance. The situational
ideal of covenant would be more helpful, and ought to be emphasized by medical
teachers as well as tutoring older colleagues.
PMID- 10758074
TI - Subjective daytime sleepiness in schoolchildren.
AB - OBJECTIVES: The aim of this study was to find out how the occurrence of
subjective daytime sleepiness (SDS) in schoolchildren had changed after 2 years
follow-up and which were the predictors associated with persistence and
appearance of SDS. METHODS: A total of 107 schoolchildren with SDS (Group 1) and
an equal number without SDS (Group 2) were chosen to take part in the
questionnaire study (age range 12-20 years). The questions concerned sleeping
habits, sleep disorders and daytime sleepiness of the child and the family,
progress at school and TV/video watching of the child, and social background of
the family. A bivariate method (Pearson's chi-square) was used as a statistical
tool. RESULTS: We received 68 replies (64%) from Group 1 and 75 (70%) from Group
2. Fifty-four schoolchildren were still sleepy in Group 1 and 28% had become
sleepy in Group 2. The persistence of SDS in Group 1 was related to older age,
irregular sleeping habits, frequent night waking and the fathers' sleep
difficulties. The appearance of SDS in Group 2 was related to a high average
grade at school. CONCLUSION: A delayed sleep phase rhythm and problems staying
asleep are obvious causes of persistent SDS, but the stress of schoolwork can
also cause daytime sleepiness in schoolchildren.
PMID- 10758075
TI - Non-compliance amongst adolescents with asthma: listening to what they tell us
about self-management.
AB - BACKGROUND: Non-compliance with prescribed anti-asthma medication is considered
to be a major problem. The reasons why adolescents may fail to comply with their
regimen are poorly understood. OBJECTIVES: This study set out to understand
better the reasons for non-compliance in adolescents with asthma. METHODS: In
depth interviews were conducted with a sample of 49 adolescents, aged 14-20
years, diagnosed as asthmatic more than a year previously and attending a
hospital asthma clinic in Greater Glasgow. The interviews focused on young
people's feelings about their illness and on their illness-related behaviour,
including self-management. RESULTS: Most of the young people interviewed admitted
that they had not always complied with their self-care regimens. Reasons given
for non-compliance with prescribed medication in the past or at present were:
forgetfulness, belief that the medication is ineffective, denial that one is
asthmatic, difficulty using inhalers, inconvenience, fear of side effects,
embarrassment and laziness. CONCLUSION: Most of those interviewed believed that
compliance with prescribed medication was extremely important, with many having
formed this belief following a negative experience which they attributed to their
non-compliance. Nevertheless, barriers exist which mean that optimum self-care is
not always achieved. It is suggested that future health care initiatives in this
area be designed to provide practical information which aids the surmounting of
these barriers and helps children and adolescents to be sufficiently aware of
their own vulnerability at an early stage of their career as asthmatics. Peer
education initiatives may meet these objectives, and more thought should be given
to their development and optimum form.
PMID- 10758076
TI - Work ability assessed by patients and their GPs in new episodes of sickness
certification.
AB - BACKGROUND: Sickness certification legislation demands that work ability is
reduced due to disease or injury. Most sickness certificates are issued by GPs.
Assessment of work ability might introduce conflict in the doctor-patient
relationship. OBJECTIVES: The aim of this study was to compare the level of work
ability assessments by patients and their GPs in new episodes of sickness
certification, and to explore how medical conditions and work demands are
associated with the assessments. METHODS: Forty nine GPs supplied data about 408
patients certified sick <8 days before questionnaires were filled in. A total of
268 (66%) patients completed corresponding questionnaires. Patients and GPs
independently answered the following question using a five-point scale: "To what
degree is your (the patient's) ability to perform your (his or her) ordinary,
remunerative work reduced today?" RESULTS: Work ability was assessed by patients
as very much or much reduced in 66%, moderately reduced in 23% and not much or
hardly reduced at all in 11% of the cases. Corresponding assessments made by GPs
were 71, 27 and 2%. Patients and GPs agreed well on their assessments (+/- 1
answer category) in 81% (216/266) of the cases. The patients assessed work
ability as more reduced the more stressful or physically strenuous their jobs
were, and the older their GPs were. The GPs assessed work ability as more reduced
the more their assessments were based on clinical findings. CONCLUSIONS: The
agreement between work ability assessments made by patients and GPs was high,
despite patients' assessments being associated with work demands and GPs' with
medical conditions.
PMID- 10758077
TI - Self-medication with vaginal antifungal drugs: physicians' experiences and
women's utilization patterns.
AB - BACKGROUND: In many countries, vaginal antifungal drugs have been released on
over-the-counter (OTC) markets, yet little is known about women's management of
their symptoms. OBJECTIVES: The aim of this study was to judge the
appropriateness of self-medication with vaginal antifungal drugs by examining
utilization patterns and physicians' experiences of women's self-medication.
METHODS: An anonymous questionnaire survey was carried out in 20 pharmacies in
Finland of women buying OTC vaginal antifungal drugs in 1997. Out of the 453
questionnaires distributed, 299 (66%) were returned. A survey of a random sample
of gynaecologists (n = 169) and specialists in general practice (n = 288) was
carried out in 1996. The response rate was 77%. RESULTS: Nearly all women had
used vaginal antifungal drugs previously, 49% during the previous 6 months. Most
women did not report any difficulties with treatment, but 44% of women used the
drug against recommendations. Half of the women had symptoms that are more likely
to be related to infections other than Candida. Physicians had observed several
disadvantages of self-treatment, with unnecessary use and use for the wrong
indications being the most often reported. In all, 31% of gynaecologists and 16%
of GPs reported that these adverse events had been clinically significant, with
delay in the treatment of other infections being the most common problem.
CONCLUSION: The results raise concerns about inappropriate use and women's
ability to self-diagnose correctly. Because vaginal antifungal drugs are likely
to remain on OTC markets, two ways to address these concerns are for physicians
and pharmacy personnel to provide spontaneous information and to have more
informative advertisements on vaginal antifungal drugs.
PMID- 10758078
TI - The prevalence of potentially pathogenic bacteria in nasopharyngeal samples from
individuals with a long-standing cough-clinical value of a nasopharyngeal sample.
AB - BACKGROUND: A long-standing cough is a common cause for visits to a GP. If the
patient also has a respiratory tract infection, one of the concerns of the doctor
is to decide if the cough is caused by an underlying bacterial infection.
OBJECTIVES: Our aim was to investigate whether a nasopharyngeal sample, obtained
in routine medical practice, could yield information about the aetiology of a
long-standing cough in patients with a respiratory tract infection. METHODS: The
prevalence of potentially pathogenic bacteria (Streptococcus pneumoniae,
Haemophilus influenzae and Moraxella catarrhalis) in nasopharyngeal swab samples
from 618 healthy individuals was compared with that from 236 patients with a
respiratory tract infection and long-standing cough (>9 days) of the same age in
a defined geographical area. RESULTS: The proportion of cultures with potentially
pathogenic bacteria decreased with age and was 44% among healthy individuals of
pre-school age, 13% in schoolchildren and 6% in adults. The corresponding figures
for patients with a long-standing cough were 83, 35 and 36%, respectively. All
types of potentially pathogenic bacteria were found more frequently in pre-school
children and in adults with a long-standing cough compared with healthy
individuals of the same age. CONCLUSIONS: In patients with a respiratory tract
infection and a long-standing cough, where a bacterial infection is suspected on
clinical grounds, a nasopharyngeal culture could yield information about the
aetiology. If M.catarrhalis is found in pre-school children, or if H.influenzae
is found in adults, they are likely to be the aetiological agent.
PMID- 10758079
TI - Teenagers' views on general practice consultations and other medical advice. The
Adolescent Working Group, RCGP.
AB - BACKGROUND: The provision of health services for teenagers is of current interest
in relation to primary care. OBJECTIVES: The main objective of the study was to
look at satisfaction with the teenager's last consultation and any reasons for
dissatisfaction. A further objective was to look at common teenage health
concerns to identify how many teenagers had been concerned about them, where they
sought advice, and to look at ratings of this advice. METHOD: Questionnaires were
completed as part of a continuing evaluation of a novel sex education programme
in 38 schools in 1997 and provided the data. The particular items reported in
this study were related to satisfaction with the last GP consultation and reasons
for dissatisfaction, health concerns and who (if anybody) was approached to
address these concerns, and comments on services used. 5152 teenagers (51.8% male
and 47.8% female) completed the questionnaires in a school lesson under
conditions of complete confidentiality. RESULTS: Over 86% of adolescents were
apparently satisfied with their last consultation with a GP, although several
possible reasons were identified for any dissatisfaction. Health concerns were
identified and sources of help were considered and compared; no obvious levels of
relative dissatisfaction with services were noted. A large number of teenagers
identified apparent concerns but did not seek help for these concerns.
CONCLUSIONS: Adolescents are largely satisfied with the services available in
primary care. A number of teenagers do not seek help for their own individual
concerns. Encouraging teenagers to attend when they perceive a health problem may
help provide a more sensitive primary care service.
PMID- 10758080
TI - The impact of chronic diseases on the health-related quality of life (HRQOL) of
Chinese patients in primary care.
AB - BACKGROUND: Ageing of the population results in an increasing number of people
living with chronic diseases that can adversely affect their quality of life.
Information on the impact of chronic diseases on quality of life can make health
services more patient-centred. OBJECTIVES: The aim of this study was to determine
the impact of eight chronic diseases on the health-related quality of life
(HRQOL) of Chinese patients. METHODS: A cross-sectional case-control study was
carried out on 760 adult Chinese patients of a family medicine clinic in Hong
Kong. Each subject answered the COOP/WONCA charts and a standard questionnaire on
demographic and morbidity data. The likelihood of sub-optimal COOP/WONCA scores
of each disease group was compared with that of patients without any of the
surveyed diseases. The independent effects of each disease on the COOP/WONCA
scores were analysed by multivariate logistic regression, controlling for
demographic variables and co-morbidity. RESULTS: Depression increased the risks
for sub-optimal scores in all but one COOP/WONCA chart with odds ratios (OR)
ranging from 2.1818 to 3.8645. Hypertension increased the risk of a sub-optimal
physical fitness score (OR 1.7263). Increased risk of limitations in daily
activities was associated with stroke (OR = 1.8771), osteoarthritis of the knee
(OR = 1.5867), diseases of joints other than the knees (OR 2.0187) and
asthma/COPD (OR 2.1679). Osteoarthritis of the knees also increased the risk of
sub-optimal overall health (OR = 1.7927). CONCLUSIONS: Depression was the most
disabling disease, and osteoarthritis of the knee had more impact on the HRQOL
than many other chronic diseases. The lack of adverse effects of diabetes
mellitus and heart disease on the HRQOL of Chinese patients deserves further
studies.
PMID- 10758081
TI - Quality of life and effectiveness of diabetes care in three different settings in
Leuven.
AB - BACKGROUND: The new diabetes protocol, formulated in Belgium as a consensus
between the National Institution of Health Insurance and diabetologists,
implicitly assumes the care of type 1 diabetic patients to be more efficient at
the specialist level (SP) in hospital, although GPs frequently are involved in
diabetes care. OBJECTIVES: A study was carried out in order to highlight
differences in diabetes care between three different treatment settings (SP
alone, combined SP-GP and GP alone) METHODS: Out of a group of known diabetics,
325 patients were selected according to a stratified cluster sampling technique,
in such a way that the three types of diabetes (formerly called type 1, type 2a
and type 2b) occurred sufficiently in the three above-defined treatment settings.
Outcome data on co-morbidity and diabetes health profile as well as output data
on laboratory results were collected for each patient and compared between the
different subgroups. RESULTS: On the basis of a response rate of 47.9%, equally
distributed over the different levels, we demonstrated that GPs and SPs score
equally low on the different measures and that a better follow-up is indicated in
all settings. CONCLUSION: Diabetes care in Flanders can be upgraded
significantly. There is no evidence that specialists are performing better.
Therefore, one could argue for better follow-up of diabetes care in a primary
health care setting.
PMID- 10758082
TI - Significant event audit in practice: a preliminary study.
AB - BACKGROUND: While well described and promoted as a useful activity, there remains
a paucity of evidence on the process and experience of significant event audit
(SEA) in primary care. To date, the most comprehensive evaluation of the process
has been produced by comparing SEA with conventional audit. The current study
intends to contribute to the debate by examining the attitudes and perceptions of
a range of primary care staff who have been involved in the process. OBJECTIVES:
The aim of this study was to identify participants' perceptions of the benefits
and problems associated with SEA in the context of primary care, and to derive
suggestions which might improve the process of SEA. METHODS: Semi-structured
interviews of 12 participants from a variety of primary care disciplines were
conducted, using grounded theory to analyse the results. RESULTS: A set of six
perceptions and seven recommendations for the facilitation of SEA were produced.
CONCLUSIONS: SEA constitutes a powerful tool, which can contribute to team
building, enhanced communication and improved patient care, and represents a
vital contributor to the development of clinical governance in primary care.
However, its implementation and sustenance require sensitive handling for optimal
benefit and to minimize difficulties. Our research has enabled us to propose
suggestions to facilitate these processes.
PMID- 10758083
TI - The design and analysis of a randomized controlled trial to evaluate computerized
decision support in primary care: the COGENT study.
PMID- 10758084
TI - Recruiting patients to randomized trials in primary care: principles and case
study.
AB - BACKGROUND: There are many factors affecting recruitment to trials in primary
care, and trials are often jeopardized due to the inability to enter sufficient
patient numbers. It is generally agreed that the interest in and commitment of
GPs to the project are important, and their forgetfulness and time pressures are
major factors which mitigate against maximal recruitment. OBJECTIVES: The aim of
this study is to focus on maximizing recruitment of patients to a randomized
controlled trial of exercise classes for back pain patients. METHODS: Two
distinct methods of recruitment were used. One practice provided a computerized
list of names and asked patients' permission, by letter, to be contacted by the
researchers. The other 18 practices manually recorded referrals after the
consultation by the GP. RESULTS: Referral rates were slower than expected. Many
patients either did not fit the inclusion criteria or excluded themselves due to
domestic commitments or work. During 24 months, 1588 patients were referred. A
total of 187 patients (12%) met the criteria and could be included in the study.
The practice which referred patients through a computerized listing contributed
44% of the patients successfully included in the study. CONCLUSIONS: Recruitment
rates depended on the method and rate of GP referrals, the proportion of
referrals meeting the entry criteria and the proportion of patients available to
attend the exercise classes.
PMID- 10758085
TI - Analysis of cluster randomized trials in primary care: a practical approach.
AB - BACKGROUND: Cluster randomized trials increasingly are being used in health
services research and in primary care, yet the majority of these trials do not
account appropriately for the clustering in their analysis. OBJECTIVES: We review
the main implications of adopting a cluster randomized design in primary care and
highlight the practical application of appropriate analytical techniques.
METHODS: The application of different analytical techniques is demonstrated
through the use of empirical data from a primary care-based case study.
CONCLUSION: Inappropriate analysis of cluster trials can lead to the presentation
of inaccurate results and hence potentially misleading conclusions. We have
demonstrated that adjustment for clustering can be applied to real-life data and
we encourage more routine adoption of appropriate analytical techniques.
PMID- 10758086
TI - Nutrition and the health care agenda: a primary care perspective.
AB - The current climate of prioritizing in the NHS brings into focus the debate
surrounding efficient and effective management of conditions associated with the
modern lifestyle. In any such debate, nutrition should be considered a primary
issue as there is now international consensus regarding the optimum diet for the
prevention of both coronary heart disease and cancer. Over recent years,
government has stated that primary care is in an ideal setting to provide
nutrition education to the public. However, we present the case that there
currently is a mismatch between the attitude of the public, who appear willing to
accept dietary advice from primary care professionals, and the reluctance on
behalf of these professionals to fulfil this role. Dissatisfaction with the
quality of nutrition education received by those working in primary care is often
cited as a barrier to providing dietary advice to patients. With that in mind, we
go on to discuss educational strategies that may motivate primary care staff to
increase their involvement in providing dietary advice for their patients. The
challenge to those involved in the delivery of nutrition training to primary care
professionals is to convince them that dietary intervention is worthwhile and
that they can make a positive contribution to dietary change within the current
organization of primary care. Increasing motivation is an essential outcome of
such training, along with providing the skills and knowledge to fulfil this role.
The contribution which diet could make is significant and, in this time of
questioning priorities, the role of nutrition needs to be put firmly on the
health care agenda.
PMID- 10758087
TI - The myth of objectivity: is medicine moving towards a social constructivist
medical paradigm?
AB - Biomedicine is improperly imbued with a nomothetic methodology, which views
'disease' in a similar way to other 'natural' phenomena. This arises from a 300
year history of a positivist domination of science, meaning that objectivist
research (e.g. randomized controlled trials or biochemical research) attracts
more funding and is more readily published than 'softer' qualitative research. A
brief review of objectivism and subjectivism is followed by a definition of an
emerging medical paradigm. Current 'inappropriate' medical practices become
understandable in this broader context, and examples are given. A constructivist
paradigm can continue to incorporate 'objective' clinical findings and
interventions, as well as the recent evidence for the doctor-patient relationship
as a major contributor to patient outcomes.
PMID- 10758089
TI - WONCA news : An international forum for family doctors
PMID- 10758088
TI - Antibiotics are being overprescribed especially for respiratory tract infections.
PMID- 10758090
TI - Softness discrimination with a tool.
AB - The abilities of humans to discriminate the softness of rubber objects of
differing compliance with a hand-held tool (a stylus) was measured under
experimental conditions that differed as to how the tool was used and the kind of
sensory information available. When the subject actively tapped or pressed the
compliant objects, they discriminated softness as well by means of a stylus as
they did by contacting the objects directly with the fingerpad. Discrimination
with the stylus was unaffected by whether the stylus was controlled by one or two
fingers. While tapping or pressing a stylus held in a precision grip, the grip
force increased before, reached a maximum at the same time as, and decreased in
parallel with the compressional force. This relationship was suggestive of
anticipatory motor control based on an internal model of the motor system and the
physical properties of the object. Discrimination was significantly better when
tapping as opposed to pressing the objects with the stylus. This was hypothesized
as due to the presence of tactile cues generated by the rapid increase in force
rate as the stylus struck and indented the object during tapping. During tapping,
the magnitude and rate of compressional force produced by the stylus against the
object were greater, the harder the object. An additional cue, possibly
kinesthetic, during pressing and tapping was the magnitude of indentation of the
specimen by the stylus that was greater, the softer the object. Subjects could
discriminate differences on softness by tactile cues alone in the absence of
kinesthetic when compliant objects were tapped at approximately the same velocity
by the experimenter against a stylus in contact with the subject's passive
fingerpad. Discrimination deteriorated if the softer specimen of a pair was
tapped with a slightly greater velocity than the harder and not possible if the
specimens were pressed against the stylus without generating tactile cues of
mechanical contact. In contrast, discrimination was possible during active
pressing and unaffected by variations in velocity during active tapping. It is
concluded that during active movements, kinesthetic information and knowledge of
central efferent commands provide useful cues that are not present during passive
touch. These cues allow the observer to discriminate differences in object
compliance not confounded by differences in applied velocity.
PMID- 10758091
TI - Adenosine receptor antagonists induce persistent bursting in the rat hippocampal
CA3 region via an NMDA receptor-dependent mechanism.
AB - Adenosine receptor antagonists initiate repetitive bursting activity in the CA3
region of hippocampal slices. Although some studies have suggested that this
effect is irreversible, this has been difficult to establish because many
adenosine antagonists wash out of brain slices extremely slowly. Furthermore the
cellular mechanism that underlies persistent bursting is unknown. To resolve
these issues, we studied the effects of nonselective (8-p
sulfophenyltheophylline, 8SPT, 50-100 microM), A(l)-selective (8-cyclopentyl-1, 3
dipropylxanthine, 100 nM; xanthine carboxylic acid congener, 200 nM), and A(2A)
selective (chlorostyryl-caffeine; 200 nM) adenosine antagonists in the CA3 region
of rat hippocampal slices using extracellular recording. Superfusion with all of
the adenosine antagonists except chlorostyryl-caffeine induced bursting, and the
burst frequency after 30 min drug superfusion did not differ for the different
antagonists. Most slices showed a period of rapid initial bursting, followed
either by stable bursting at a lower frequency or a pattern of oscillating burst
frequency. In either case, the bursting continued after drug washout. Virtually
identical patterns of long-term bursting activity were observed when 8SPT was
washed out or applied continuously. Control experiments using exogenous adenosine
to characterize the persistence of 8SPT in tissue demonstrated >95% washout at 60
min, a time when nearly all slices still showed regular bursting activity. When
the N-methyl-D-aspartate (NMDA) antagonists DL-2-amino-5-phosphonovaleric acid
(AP5; 50 microM) or dizocilpine (10 microM) were applied before and during 8SPT
superfusion, bursting occurred in the presence of the NMDA antagonists but did
not persist once the 8SPT was washed out. AP5 had no effect on persistent
bursting when applied after the initiation of spiking. The selective
calcium/calmodulin-dependent protein kinase inhibitor 1-[N, O-bis-(5
isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62; 3 microM),
which has been shown to block NMDA receptor-dependent synaptic plasticity in the
CA1 region, also significantly decreased the long-term effect of 8SPT. Thus
adenosine antagonists initiate persistent spiking in the CA3 region; this
activity does not depend on continued occupation of adenosine receptors by
antagonists, and can be blocked by treatments that prevent NMDA receptor
dependent plasticity.
PMID- 10758092
TI - Striatal nitric oxide signaling regulates the neuronal activity of midbrain
dopamine neurons in vivo.
AB - A major component of the cortical regulation of the nigrostriatal dopamine (DA)
system is known to occur via activation of striatal efferent systems projecting
to the substantia nigra. The potential intermediary role of striatal nitric oxide
synthase (NOS)-containing interneurons in modulating the efferent regulation of
DA neuron activity was examined using single-unit recordings of DA neurons
performed concurrently with striatal microdialysis in anesthetized rats. The
response of DA neurons recorded in the substantia nigra to intrastriatal
artificial cerebrospinal fluid (ACSF) or drug infusion was examined in terms of
mean firing rate, percent of spikes fired in bursts, cells/track, and response to
electrical stimulation of the orbital prefrontal cortex (oPFC) and striatum.
Intrastriatal infusion of NOS substrate concurrently with intermittent periods of
striatal and cortical stimulation increased the mean DA cell population firing
rate as compared with ACSF controls. This effect was reproduced via intrastriatal
infusion of a NO generator. Infusion of either a NOS inhibitor or NO chelator via
reverse microdialysis did not affect basal firing rate but increased the
percentage of DA neurons responding to striatal stimulation with an initial
inhibition followed by a rebound excitation (IE response) from 40 to 74%. NO
scavenger infusion also markedly decreased the stimulation intensity required to
elicit an IE response to electrical stimulation of the striatum. In single
neurons in which the effects of electrical stimulation were observed before and
after drug delivery, NO antagonist infusion was observed to decrease the onset
latency and extend the duration of the initial inhibitory phase induced by either
oPFC or striatal stimulation. This is the first report showing that striatal NO
tone regulates the basal activity and responsiveness of DA neurons to cortical
and striatal inputs. These studies also indicate that striatal NO signaling may
play an important role in the integration of information transmitted to basal
ganglia output centers via corticostriatal and striatal efferent pathways.
PMID- 10758093
TI - Histamine H(2) receptor activated chloride conductance in myenteric neurons from
guinea pig small intestine.
AB - Whole cell perforated patch-clamp methods were used to investigate ionic
mechanisms underlying histamine-evoked excitatory responses in small intestinal
AH-type myenteric neurons. When physiological concentrations of Na(+), Ca(2+),
and Cl(-) were in the bathing medium, application of histamine significantly
increased total conductance as determined by stepping to 50 mV from a holding
potential of -30 mV. The current reversed at a membrane potential of -30 +/- 5
(SE) mV and current-voltage relations exhibited outward rectification. The
reversal potential for the histamine-activated current was unchanged by removal
of Na(+) and Ca(2+) from the bathing medium. Reduction of Cl(-) from 155 mM to 55
mM suppressed the current when the neurons were in solutions with depleted Na(+)
and Ca(2+). Current-voltage curves in solutions with reduced Cl(-) were linear
and the reversal potential was changed from -30 +/- 5 mV to 7 +/- 4 mV. Niflumic
acid, but not anthracene-9-carboxylic acid (9-AC) nor 4,4'
diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suppressed the histamine
activated current. A membrane permeable analogue of cAMP evoked currents similar
to those activated by histamine. A selective histamine H(2) receptor agonist
(dimaprit) mimicked the action of histamine and a selective histamine H(2)
receptor antagonist (cimetidine) blocked the conductance increase evoked by
histamine. A selective adenosine A(1) receptor agonist (CCPA) reduced the
histamine-activated current and a selective adenosine A(1) receptor antagonist
(CPT) reversed the inhibitory action. The results suggest that histamine acts at
histamine H(2) receptors to increase Cl(-) conductance in AH-type enteric
neurons. Cyclic AMP appears to be a second messenger in the signal transduction
process. Results with a selective adenosine A(1) receptor agonist and antagonist
add to existing evidence for co-coupling of inhibitory adenosine A(1) receptors
and histamine H(2) receptors to adenylate cyclase in AH-type enteric neurons.
PMID- 10758094
TI - Light-evoked responses of bipolar cells in a mammalian retina.
AB - We recorded light-evoked responses from rod and cone bipolar cells using patch
clamp techniques in a slice preparation of the rat retina. Rod bipolar cells
responded to light with a sustained depolarization (ON response) followed at
light offset by a slight hyperpolarization. ON and OFF cone bipolar cells were
encountered, both with diverse temporal properties. The responses of rod bipolar
cells were composed primarily of two components, a nonspecific cation current and
a chloride current. The chloride current was reduced greatly in axotomized cells
and could be suppressed by coapplication of the GABA(A) antagonist bicuculline
and the GABA(C) antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic
acid. This suggests that it largely reflects feedback from GABAergic amacrine
cells. The response latency of intact rod bipolar cells was shorter than that of
the axotomized cells, and the sensitivity curve covered more than twice the
dynamic range. Application of the GABA receptor antagonists partially mimicked
the effects of axotomy. These findings suggest that functional properties of the
axon terminal system-notably synaptic feedback from amacrine cells-play an
important role in defining the response properties of mammalian bipolar cells.
PMID- 10758095
TI - Glycolysis prevents anoxia-induced synaptic transmission damage in rat
hippocampal slices.
AB - Prolonged anoxia can cause permanent damage to synaptic transmission in the
mammalian CNS. We tested the hypothesis that lack of glucose is the major cause
of irreversible anoxic transmission damage, and that anoxic synaptic transmission
damage could be prevented by glycolysis in rat hippocampal slices. The evoked
population spike (PS) was extracellularly recorded in the CA1 pyramidal cell
layer after stimulation of the Schaffer collaterals. When the slice was
superfused with artificial cerebrospinal fluid (ACSF) containing 4 mM glucose,
following 10 min anoxia, the evoked PS did not recover at all after 60 min
reoxygenation. When superfusion ACSF contained 10 mM glucose with or without 0.5
mM alpha-cyano-4-hydroxycinnate (4-CIN), after 60 min reoxygenation the evoked PS
completely recovered following 10 min anoxia. When superfusion ACSF contained 20
mM glucose with or without 1 mM sodium cyanide (NaCN), after 60 min reoxygenation
the evoked PS completely recovered even following 120 min anoxia. In contrast,
when superfusion ACSF contained 4 mM glucose, following 10 min 1 mM NaCN chemical
anoxia alone, without anoxic anoxia, the evoked PS displayed no recovery after 60
min reoxygenation. Moreover, when 16 mM mannitol and 16 sodium L-lactate were
added into 4 mM glucose ACSF, following 10 min anoxia the evoked PS failed to
recover at all after 60 min reoxygenation. The results indicate that elevated
glucose concentration powerfully protected the synaptic transmission against
anoxic damage, and the powerful protection is due to anaerobic metabolism of
glucose and not a result of the higher osmolality in higher glucose ACSF. We
conclude that lack of glucose is the major cause of anoxia-induced synaptic
transmission damage, and that if sufficient glucose is supplied, glycolysis could
prevent this damage in vitro.
PMID- 10758096
TI - Neural responses to overlapping FM sounds in the inferior colliculus of
echolocating bats.
AB - The big brown bat, Eptesicus fuscus, navigates and hunts prey with echolocation,
a modality that uses the temporal and spectral differences between vocalizations
and echoes from objects to build spatial images. Closely spaced surfaces
("glints") return overlapping echoes if two echoes return within the integration
time of the cochlea ( approximately 300-400 micros). The overlap results in
spectral interference that provides information about target structure or
texture. Previous studies have shown that two acoustic events separated in time
by less than approximately 500 micros evoke only a single response from neural
elements in the auditory brain stem. How does the auditory system encode multiple
echoes in time when only a single response is available? We presented paired FM
stimuli with delay separations from 0 to 24 micros to big brown bats and recorded
local field potentials (LFPs) and single-unit responses from the inferior
colliculus (IC). These stimuli have one or two interference notches positioned in
their spectrum as a function of two-glint separation. For the majority of single
units, response counts decreased for two-glint separations when the resulting FM
signal had a spectral notch positioned at the cell's best frequency (BF). The
smallest two-glint separation that reliably evoked a decrease in spike count was
6 micros. In addition, first-spike latency increased for two-glint stimuli with
notches positioned nearby BF. The N(4) potential of averaged LFPs showed a
decrease in amplitude for two-glint separations that had a spectral notch near
the BF of the recording site. Derived LFPs were computed by subtracting a common
mode signal from each LFP evoked by the two-glint FM stimuli. The derived LFP
records show clear changes in both the amplitude and latency as a function of two
glint separation. These observations in relation with the single-unit data
suggest that both response amplitude and latency can carry information about two
glint separation in the auditory system of E. fuscus.
PMID- 10758097
TI - Reorganization of the frequency map of the auditory cortex evoked by cortical
electrical stimulation in the big brown bat.
AB - In a search phase of echolocation, big brown bats, Eptesicus fuscus, emit
biosonar pulses at a rate of 10/s and listen to echoes. When a short acoustic
stimulus was repetitively delivered at this rate, the reorganization of the
frequency map of the primary auditory cortex took place at and around the neurons
tuned to the frequency of the acoustic stimulus. Such reorganization became
larger when the acoustic stimulus was paired with electrical stimulation of the
cortical neurons tuned to the frequency of the acoustic stimulus. This
reorganization was mainly due to the decrease in the best frequencies of the
neurons that had best frequencies slightly higher than those of the electrically
stimulated cortical neurons or the frequency of the acoustic stimulus. Neurons
with best frequencies slightly lower than those of the acoustically and/or
electrically stimulated neurons slightly increased their best frequencies. These
changes resulted in the over-representation of repetitively delivered acoustic
stimulus. Because the over-representation resulted in under-representation of
other frequencies, the changes increased the contrast of the neural
representation of the acoustic stimulus. Best frequency shifts for over
representation were associated with sharpening of frequency-tuning curves of 25%
of the neurons studied. Because of the increases in both the contrast of neural
representation and the sharpness of tuning, the over-representation of the
acoustic stimulus is accompanied with an improvement of analysis of the acoustic
stimulus.
PMID- 10758098
TI - Reward-related neuronal activity during go-nogo task performance in primate
orbitofrontal cortex.
AB - The orbitofrontal cortex appears to be involved in the control of voluntary, goal
directed behavior by motivational outcomes. This study investigated how
orbitofrontal neurons process information about rewards in a task that depends on
intact orbitofrontal functions. In a delayed go-nogo task, animals executed or
withheld a reaching movement and obtained liquid or a conditioned sound as
reinforcement. An initial instruction picture indicated the behavioral reaction
to be performed (movement vs. nonmovement) and the reinforcer to be obtained
(liquid vs. sound) after a subsequent trigger stimulus. We found task-related
activations in 188 of 505 neurons in rostral orbitofrontal area 13, entire area
11, and lateral area 14. The principal task-related activations consisted of
responses to instructions, activations preceding reinforcers, or responses to
reinforcers. Most activations reflected the reinforcing event rather than other
task components. Instruction responses occurred either in liquid- or sound
reinforced trials but rarely distinguished between movement and nonmovement
reactions. These instruction responses reflected the predicted motivational
outcome rather than the behavioral reaction necessary for obtaining that outcome.
Activations preceding the reinforcer began slowly and terminated immediately
after the reinforcer, even when the reinforcer occurred earlier or later than
usually. These activations preceded usually the liquid reward but rarely the
conditioned auditory reinforcer. The activations also preceded expected drops of
liquid delivered outside the task, suggesting a primary appetitive rather than a
task-reinforcing relationship that apparently was related to the expectation of
reward. Responses after the reinforcer occurred in liquid- but rarely in sound
reinforced trials. Reward-preceding activations and reward responses were
unrelated temporally to licking movements. Several neurons showed reward
responses outside the task but instruction responses during the task, indicating
a response transfer from primary reward to the reward-predicting instruction,
possibly reflecting the temporal unpredictability of reward. In conclusion,
orbitofrontal neurons report stimuli associated with reinforcers are concerned
with the expectation of reward and detect reward delivery at trial end. These
activities may contribute to the processing of reward information for the
motivational control of goal-directed behavior.
PMID- 10758099
TI - Modifications of reward expectation-related neuronal activity during learning in
primate orbitofrontal cortex.
AB - This study investigated how neuronal activity in orbitofrontal cortex related to
the expectation of reward changed while monkeys repeatedly learned to associate
new instruction pictures with known behavioral reactions and reinforcers. In a
delayed go-nogo task with several trial types, an initial picture instructed the
animal to execute or withhold a reaching movement and to expect a liquid reward
or a conditioned auditory reinforcer. When novel instruction pictures were
presented, animals learned according to a trial-and-error strategy. After
experience with a large number of novel pictures, learning occurred in a few
trials, and correct performance usually exceeded 70% in the first 60-90 trials.
About 150 task-related neurons in orbitofrontal cortex were studied in both
familiar and learning conditions and showed two major forms of changes during
learning. Quantitative changes of responses to the initial instruction were seen
as appearance of new responses, increase of existing responses, or decrease or
complete disappearance of responses. The changes usually outlasted initial
learning trials and persisted during subsequent consolidation. They often
modified the trial selectivities of activations. Increases might reflect the
increased attention during learning and induce neuronal changes underlying the
behavioral adaptations. Decreases might be related to the unreliable reward
predicting value of frequently changing learning instructions. The second form of
changes reflected the adaptation of reward expectations during learning. In
initial learning trials, animals reacted as if they expected liquid reward in
every trial type, although only two of the three trial types were rewarded with
liquid. In close correspondence, neuronal activations related to the expectation
of reward occurred initially in every trial type. The behavioral indices for
reward expectation and their neuronal correlates adapted in parallel during the
course of learning and became restricted to rewarded trials. In conclusion, these
data support the notion that neurons in orbitofrontal cortex code reward
information in a flexible and adaptive manner during behavioral changes after
novel stimuli.
PMID- 10758100
TI - Differential effects of deep cerebellar nuclei inactivation on reaching and
adaptive control.
AB - This study examined the effects of selective inactivation of the cerebellar
nuclei in the cat on the control of multijoint trajectories and trajectory
adaptation to avoid obstacles. Animals were restrained in a hammock and trained
to perform a prehension task in which they reached to grasp a small cube of meat
from a narrow food well. To examine trajectory adaptation, reaching was
obstructed by placing a horizontal bar in the limb's path. Inactivation was
produced by microinjection of the GABA agonist muscimol (0.25-1.0 microg in 1
microL saline). Fastigial nucleus inactivation produced a severe impairment in
balance and in head and trunk control but no effect on reaching and grasping.
Dentate inactivation slowed movements significantly and produced a significant
increase in tip path curvature but did not impair reaching and grasping.
Selective inactivation of the anterior and posterior interpositus nuclei did not
impair grasping but severely decreased the accuracy of reaching movements and
produced different biases in wrist and paw paths. Anterior interpositus
inactivation produced movement slowing (wrist speed) and under-reaching to the
food well. Wrist and tip paths showed anterior biases and became more curved.
Also animals could no longer make anticipatory adjustments in limb kinematics to
avoid obstructions but sensory-evoked corrective responses were preserved.
Posterior interpositus inactivation produced a significant increase in wrist
speed and overreaching. Wrist and tip paths showed a posterior bias and became
more curved, although in a different way than during anterior interpositus
inactivation. Posterior interpositus inactivation did not impair trajectory
adaptation to reach over the obstacle. During inactivation of either interpositus
nucleus, all measures of kinematic temporal and spatial variability increased
with somewhat greater effects being produced by anterior interpositus
inactivation. We discuss our results in relation to the hypothesis that anterior
and posterior interpositus have different roles in trajectory control, related
possibly to feed-forward use of cutaneous and proprioceptive inputs,
respectively. The loss of adaptive reprogramming during anterior interpositus
inactivation further suggests a role in motor learning. Comparison with results
from our earlier motor cortical study shows that the distinctive impairments
produced by inactivation of these two nuclei are similar to those produced by
selective inactivation of different zones in the forelimb area of rostral motor
cortex. Our findings are consistent with the hypothesis that there are separate
functional output channels from the anterior and posterior interpositus nuclei to
rostral motor cortex for distinct aspects of trajectory control and, from
anterior interpositus alone, for trajectory adaptation.
PMID- 10758101
TI - Integration of foveal orientation signals: distinct local and long-range spatial
domains.
AB - Human observers can discriminate the orientation of a stimulus configuration
composed of a pair of collinear visual patterns much better than that of a single
component pattern alone. Previous investigations of this type of orientation
signal integration and of other similar visual integrative functions have shown
that, for closely spaced elements, there is integration only for stimuli with the
same contrast polarity (i.e., both lighter or both darker than the background)
but, at greater separations, integration is independent of contrast polarity. Is
this effect specific to differences in contrast polarity, which is known to be an
important parameter in the organization of the visual system, or might there be a
cluster of other stimulus dimensions that show similar effects, indicating a more
widespread distinction between the processes limiting integration at local and
long-range spatial scales? Here, we report a similar distance dependence for
orientation signal integration across stimulus differences in binocular
disparity, direction of motion, and direction of figure-ground assignment. We
also demonstrate that the selectivity found at short separations cannot be
explained only by "end-cuts," the small borders created at the junction of
abutting contrasting patterns. These findings imply the existence of two distinct
spatial domains for the integration of foveal orientation information: a local
zone in which integration is highly selective for a number of salient stimulus
parameters and a long-range domain in which integration is relatively unselective
and only requires that patterns be roughly collinear.
PMID- 10758102
TI - A model for pleiotropic muscarinic potentiation of fast synaptic transmission.
AB - The predominant form of muscarinic excitation in the forebrain and in sympathetic
ganglia arises from m1 receptors coupled to the G(q/11) signal transduction
pathway. Functional components of this system have been most completely mapped in
frog sympathetic B neurons. Presynaptic stimulation of the B neuron produces a
dual-component muscarinic excitatory postsynaptic potential (EPSP) mediated by
suppression of voltage-dependent M-type K(+) channels and activation of a voltage
insensitive cation current. Evidence from mammalian systems suggests that the
cation current is mediated by cyclic GMP-gated channels. This paper describes the
use of a computational model to analyze the consequences of pleiotropic
muscarinic signaling for synaptic integration. The results show that the resting
potential of B neurons is a logarithmic function of the leak conductance over a
broad range of experimentally observable conditions. Small increases (<4 nS) in
the muscarinically regulated cation conductance produce potent excitatory
effects. Damage introduced by intracellular recording can mask the excitatory
effect of the muscarinic leak current. Synaptic activation of the leak
conductance combines synergistically with suppression of the M-conductance (40 -
> 20 nS) to strengthen fast nicotinic transmission. Overall, this effect can more
than double synaptic strength, as measured by the ability of a fast nicotinic
EPSP to trigger an action potential. Pleiotropic muscarinic excitation can also
double the temporal window of summation between subthreshold nicotinic EPSPs and
thereby promote firing. Activation of a chloride leak or suppression of a K(+)
leak can substitute for the cation conductance in producing excitatory muscarinic
actions. The results are discussed in terms of their implications for synaptic
integration in sympathetic ganglia and other circuits.
PMID- 10758103
TI - Olfactory inputs activate the medial entorhinal cortex via the hippocampus.
AB - The lateral and medial regions of the entorhinal cortex differ substantially in
terms of connectivity and pattern of activation. With regard to olfactory input,
a detailed and extensive physiological map of the olfactory projection to the
entorhinal cortex is missing, even if anatomic studies suggest that the olfactory
afferents are confined to the lateral and rostral entorhinal region. We studied
the contribution of the medial and lateral entorhinal areas to olfactory
processing by analyzing the responses induced by lateral olfactory tract
stimulation in different entorhinal subfields of the in vitro isolated guinea pig
brain. The pattern of synaptic activation of the medial and lateral entorhinal
regions was reconstructed either by performing simultaneous multisite recordings
or by applying current source density analysis on field potential laminar
profiles obtained with 16-channel silicon probes. Current source density analysis
demonstrated the existence of a direct monosynaptic olfactory input into the
superficial 300 microm of the most rostral part of the lateral entorhinal cortex
exclusively, whereas disynaptic sinks mediated by associative fibers arising from
the piriform cortex were observed at 100-350 microm depth in the entire lateral
aspect of the cortex. No local field responses were recorded in the medial
entorhinal region unless a large population spike was generated in the
hippocampus (dentate gyrus and CA1 region) by a stimulus 3-5x the intensity
necessary to obtain a maximal monosynaptic response in the piriform cortex. In
these conditions, a late sink was recorded at a depth of 600-1000 microm in the
medial entorhinal area (layers III-V) 10.6 +/- 0.9 (SD) msec after a population
spike was simultaneously recorded in CA1. Diffuse activation of the medial
entorhinal region was also obtained by repetitive low-intensity stimulation of
the lateral olfactory tract at 2-8 Hz. Higher or lower stimulation frequencies
did not induce hippocampal-medial entorhinal cortex activation. These results
suggest that the medial and the lateral entorhinal regions have substantially
different roles in processing olfactory sensory inputs.
PMID- 10758104
TI - Cerebellar on-beam and lateral inhibition: two functionally distinct circuits.
AB - Optical imaging of voltage-sensitive dyes in an isolated cerebellum preparation
was used to study the spatiotemporal functional organization of the inhibitory
systems in the cerebellar cortex. Responses to surface stimulation of the cortex
reveal two physiologically distinct inhibitory systems, which we refer to as
lateral and on-beam inhibition following classical terminology. Lateral
inhibition occurs throughout the area responding to a stimulus, whereas on-beam
inhibition is confined to the area directly excited by parallel fibers. The time
course of the lateral inhibition is twice as long as that of the on-beam
inhibition. Both inhibitory responses increase with stimulus intensity, but the
lateral inhibition has a lower threshold, and it saturates at lower stimulus
intensity. The amplitude of the on-beam inhibition is linearly related to the
excitation at the same location, whereas that of the lateral inhibition is
linearly related to the excitation at the center of the beam. Repetitive
stimulation is required to activate on-beam inhibition, whereas the same stimulus
paradigm reveals prolonged depression of the lateral inhibition. We conclude that
lateral inhibition reflects the activation of molecular layer interneurons, and
its major role is to increase the excitability of the activated area by
disinhibition. The on-beam inhibition most likely reflects Golgi cell inhibition
of granule cells. However, Purkinje cell collateral inhibition of Golgi cells
cannot be excluded. Both possibilities suggest that the role of the on-beam
inhibition is to efficiently modulate, in time and space, the mossy fiber input
to the cerebellar cortex.
PMID- 10758105
TI - Stretch and H reflexes in triceps surae are similar during tonic and rhythmic
contractions in high decerebrate cats.
AB - During locomotion in decerebrate and spinal cats the group Ia afferents from hind
leg muscles are depolarized rhythmically. An earlier study concluded that this
locomotor-related primary afferent depolarization (PAD) does not contribute to
modulation of monosynaptic reflex pathways during locomotion. This finding
indicated that the neural network generating the locomotor rhythm, the central
pattern generator (CPG), does not presynaptically inhibit monosynaptic reflexes.
In this investigation we tested this prediction in decerebrate cats by measuring
the magnitude of reflexes evoked in ankle extensor muscles during periods of
tonic contractions and during sequences of rhythmic contractions. The latter
occurred when the animal was induced to walk on a treadmill. At the similar
levels of activity in the soleus muscle there was no significant difference in
the magnitude of the soleus H reflex in these two behavioral situations. Similar
results were obtained for reflexes evoked by brief stretches of the soleus
muscle. We also examined the reflexes evoked by ramp-and-hold stretches during
periods of rhythmic and tonic activity of the isolated medial gastrocnemius (MG)
muscle. At similar levels of background activity, the reflexes evoked in the MG
muscle were the same during rhythmic and tonic contractions. Our failure to
observe a reduction in the magnitude of H reflexes and stretch reflexes during
rhythmic contractions, compared with reflexes evoked at the same level of
background activity during tonic contractions, is consistent with the notion that
the CPG for stepping does not presynaptically inhibit monosynaptic reflexes
during the extension phase of locomotor activity. Our results indicate that
presynaptic inhibition of the monosynaptic reflex associated with normal
locomotion in cats or humans arises from sources other than the extensor burst
generating system of the central pattern generator.
PMID- 10758106
TI - Slowly inactivating sodium current (I(NaP)) underlies single-spike activity in
rat subthalamic neurons.
AB - One-half of the subthalamic nucleus (STN) neurons switch from single-spike
activity to burst-firing mode according to membrane potential. In an earlier
study, the ionic mechanisms of the bursting mode were studied but the ionic
currents underlying single-spike activity were not determined. The single-spike
mode of activity of STN neurons recorded from acute slices in the current clamp
mode is TTX-sensitive but is not abolished by antagonists of ionotropic
glutamatergic and GABAergic receptors, blockers of calcium currents (2 mM cobalt
or 40 microM nickel), or intracellular Ca(2+) ions chelators. Tonic activity is
characterized by a pacemaker depolarization that spontaneously brings the
membrane from the peak of the afterspike hyperpolarization (AHP) to firing
threshold (from -57.1 +/- 0.5 mV to -42.2 +/- 0.3 mV). Voltage-clamp recordings
suggest that the Ni(2+)-sensitive, T-type Ca(2+) current does not play a
significant role in single-spike activity because it is totally inactivated at
potentials more depolarized than -60 mV. In contrast, the TTX-sensitive, I(NaP)
that activated at -54.4 +/- 0.6 mV fulfills the conditions for underlying
pacemaker depolarization because it is activated below spike threshold and is not
fully inactivated in the pacemaker range. In some cases, the depolarization
required to reach the threshold for I(NaP) activation is mediated by
hyperpolarization-activated cation current (I(h)). This was directly confirmed by
the cesium-induced shift from single-spike to burst-firing mode which was
observed in some STN neurons. Therefore, a fraction of I(h) which is tonically
activated at rest, exerts a depolarizing influence and enables membrane potential
to reach the threshold for I(NaP) activation, thus favoring the single-spike
mode. The combined action of I(NaP) and I(h) is responsible for the dual mode of
discharge of STN neurons.
PMID- 10758107
TI - Convergent properties of vestibular-related brain stem neurons in the gerbil.
AB - Three classes of vestibular-related neurons were found in and near the prepositus
and medial vestibular nuclei of alert or decerebrate gerbils, those responding
to: horizontal translational motion, horizontal head rotation, or both. Their
distribution ratios were 1:2:2, respectively. Many cells responsive to
translational motion exhibited spatiotemporal characteristics with both response
gain and phase varying as a function of the stimulus vector angle. Rotationally
sensitive neurons were distributed as Type I, II, or III responses (sensitive to
ipsilateral, contralateral, or both directions, respectively) in the ratios of
4:6:1. Four tested factors shaped the response dynamics of the sampled neurons:
canal-otolith convergence, oculomotor-related activity, rotational Type (I or
II), and the phase of the maximum response. Type I nonconvergent cells displayed
increasing gains with increasing rotational stimulus frequency (0.1-2.0 Hz, 60
degrees /s), whereas Type II neurons with convergent inputs had response gains
that markedly decreased with increasing translational stimulus frequency (0.25
2.0 Hz, +/-0.1 g). Type I convergent and Type II nonconvergent neurons exhibited
essentially flat gains across the stimulus frequency range. Oculomotor-related
activity was noted in 30% of the cells across all functional types, appearing as
burst/pause discharge patterns related to the fast phase of nystagmus during head
rotation. Oculomotor-related activity was correlated with enhanced dynamic range
compared with the same category that had no oculomotor-related response. Finally,
responses that were in-phase with head velocity during rotation exhibited greater
gains with stimulus frequency increments than neurons with out-of-phase
responses. In contrast, for translational motion, neurons out of phase with head
acceleration exhibited low-pass characteristics, whereas in-phase neurons did
not. Data from decerebrate preparations revealed that although similar response
types could be detected, the sampled cells generally had lower background
discharge rates, on average one-third lower response gains, and convergent
properties that differed from those found in the alert animals. On the basis of
the dynamic response of identified cell types, we propose a pair of models in
which inhibitory input from vestibular-related neurons converges on oculomotor
neurons with excitatory inputs from the vestibular nuclei. Simple signal
convergence and combinations of different types of vestibular labyrinth
information can enrich the dynamic characteristics of the rotational and
translational vestibuloocular responses.
PMID- 10758108
TI - Population reconstruction of the locomotor cycle from interneuron activity in the
mammalian spinal cord.
AB - Lesion studies have shown that neuronal networks in the ventromedial regions of
the neonatal rat spinal cord are critical for the production of locomotion. We
examined whether the locomotor cycle could be accurately predicted based on the
activity recorded in a population of spinal interneurons located in these regions
during pharmacologically induced locomotion. We used a Bayesian probabilistic
reconstruction procedure to predict the most likely phase of locomotion given the
observed activity in the neuronal population. The population reconstruction was
able to predict the correct locomotor phase with high accuracy using a relatively
small number of neurons. This result demonstrates that although the spike
activity of individual spinal interneurons in the ventromedial region is weak and
varies from cycle to cycle, the locomotor phase can be accurately predicted when
information from the population is combined. This result is consistent with the
proposed involvement of interneurons within these regions of the spinal cord in
the production of locomotion.
PMID- 10758109
TI - Composition and topographic organization of signals sent from the frontal eye
field to the superior colliculus.
AB - The frontal eye field (FEF) and superior colliculus (SC) contribute to saccadic
eye movement generation, and much of the FEF's oculomotor influence may be
mediated through the SC. The present study examined the composition and
topographic organization of signals flowing from FEF to SC by recording from FEF
neurons that were antidromically activated from rostral or caudal SC. The first
and most general result was that, in a sample of 88 corticotectal neurons, the
types of signals relayed from FEF to SC were highly diverse, reflecting the
general population of signals within FEF rather than any specific subset of
signals. Second, many neurons projecting from FEF to SC carried signals thought
to reflect cognitive operations, namely tonic discharges during the delay period
of a delayed-saccade task (delay signals), elevated discharges during the gap
period of a gap task (gap increase signals), or both. Third, FEF neurons
discharging during fixation were found to project to the SC, although they did
not project preferentially to rostral SC, where similar fixation neurons are
found. Neurons that did project preferentially to the rostral SC were those with
foveal visual responses and those pausing during the gap period of the gap task.
Many of the latter neurons also had foveal visual responses, presaccadic pauses
in activity, and postsaccadic increases in activity. These two types of rostral
projecting neurons therefore may contribute to the activity of rostral SC
fixation neurons. Fourth, conduction velocity was used as an indicator of cell
size to correct for sampling bias. The outcome of this correction procedure
suggested that among the most prevalent neurons in the FEF corticotectal
population are those carrying putative cognitive-related signals, i.e., delay and
gap increase signals, and among the least prevalent are those carrying
presaccadic burst discharges but lacking peripheral visual responses. Fifth,
corticotectal neurons carrying various signals were biased topographically across
the FEF. Neurons with peripheral visual responses but lacking presaccadic burst
discharges were biased laterally, neurons with presaccadic burst discharges but
lacking peripheral visual responses were biased medially, and neurons carrying
delay or gap increase signals were biased dorsally. Finally, corticotectal
neurons were distributed within the FEF as a function of their visual or movement
field eccentricity and projected to the SC such that eccentricity maps in both
structures were closely aligned. We conclude that the FEF most likely influences
the activity of SC neurons continuously from the start of fixation, through
visual analysis and cognitive manipulations, until a saccade is generated and
fixation begins anew. Furthermore, the projection from FEF to SC is highly
topographically organized in terms of function at both its source and its
termination.
PMID- 10758110
TI - Activity of hindlimb motor units during locomotion in the conscious rat.
AB - This paper compares the activity of hindlimb motor units from muscles mainly
composed of fast-twitch muscle fibers (medial and lateral gastrocnemius: MG/LG,
tibialis anterior: TA) to motor units from a muscle mainly composed of slow
twitch muscle fibers (soleus: SOL) during unrestrained walking in the conscious
rat. Several differences in the activation profiles of motor units from these two
groups of muscles were observed. For example, motor units from fast muscles
(e.g., MG/LG and TA) fired at very high mean frequencies of discharge, ranging
from 60 to 100 Hz, and almost always were recruited with initial doublets or
triplets, i.e., initial frequencies >/=100 Hz. In contrast, the majority of SOL
units fired at much lower mean rates of discharge, approximately 30 Hz, and had
initial frequencies of only 30-60 Hz (i.e., there were no initial
doublets/triplets >/=100 Hz). Thus the presence of initial doublet or triplets
was dependent on the intrinsic properties of the motor unit, i.e., faster units
were recruited with a doublet/triplet more often than slower units. Moreover, in
contrast to units from the slow SOL muscle, the activity of single motor units
from the fast MG/LG muscle, especially units recruited midway or near the end of
a locomotor burst, was unrelated to the activity of the remainder of the
motoneuron pool, as measured by the corresponding gross-electromyographic (EMG)
signal. This dissociation of activity was suggested to arise from a
compartmentalized recruitment of the MG/LG motoneuron pool by the rhythm
generating networks of the spinal cord. In contrast, when comparing the rate
modulation of simultaneously recorded motor units within a single LG muscle
compartment, the frequency profiles of unit pairs were modulated in a parallel
fashion. This suggested that the parent motoneurons were responsive to changes in
synaptic inputs during unrestrained walking, unlike the poor rate modulation that
occurs during locomotion induced from brain stem stimulation. In summary, data
from this study provide evidence that the firing behavior of motor units during
unrestrained walking is influenced by both the intrinsic properties of the parent
motoneuron and by synaptic inputs from the locomotor networks of the spinal cord.
In addition, it also provides the first extensive description of motor-unit
activity from different muscles during unrestrained walking in the conscious rat.
PMID- 10758111
TI - Interaction between Mas and the angiotensin AT1 receptor in the amygdala.
AB - The Mas-protooncogene is a maternally imprinted gene encoding an orphan G protein
coupled receptor expressed mainly in limbic structures of the rodent CNS. Because
Mas and the product of the Mas-related gene enhance the effects of angiotensins
on cells expressing angiotensin receptors of the AT1 subtype, we first compared
the distribution of cells expressing AT1 receptors in different limbic and
thalamic brain structures in Mas-knockout mice and in wildtype mice by an
immunohistochemical approach. No significant differences could be found between
the two strains. The Mas-protooncogene seems to be implicated in the signal
transduction of angiotensin receptors and is expressed in the amygdala. Therefore
we then analyzed whether field potentials are altered by angiotensin II in brain
slices of the basolateral amygdala. An opposite action of angiotensin II was
obtained in mice lacking the Mas-protooncogene in comparison to wildtype mice.
The use of different angiotensin receptor antagonists provides the first in vitro
evidence for a functional interaction between the Mas-protooncogene and the AT1
receptor.
PMID- 10758112
TI - Effect of hyperbaric oxygen treatment on nitric oxide and oxygen free radicals in
rat brain.
AB - Oxygen (O(2)) at high pressures acts as a neurotoxic agent leading to
convulsions. The mechanism of this neurotoxicity is not known; however, oxygen
free radicals and nitric oxide (NO) have been suggested as contributors. This
study was designed to follow the formation of oxygen free radicals and NO in the
rat brain under hyperbaric oxygen (HBO) conditions using in vivo microdialysis.
Male Sprague-Dawley rats were exposed to 100% O(2) at a pressure of 3 atm
absolute for 2 h. The formation of 2,3-dihydroxybenzoic acid (2, 3-DHBA) as a
result of perfusing sodium salicylate was followed as an indicator for the
formation of hydroxyl radicals. 2,3-DHBA levels in hippocampal and striatal
dialysates of animals exposed to HBO conditions were not significantly different
from controls. However, rats treated under the same conditions showed a six- and
fourfold increase in nitrite/nitrate, break down products of NO decomposition, in
hippocampal and striatal dialysates, respectively. This increase was completely
blocked by the nitric oxide synthase (NOS) inhibitor L-nitroarginine methyl ester
(L-NAME). Using neuronal NOS, we determined the NOS O(2) K(m) to be 158 +/- 28
(SD) mmHg, a value which suggests that production of NO by NOS would increase
approximately four- to fivefold under hyperbaric O(2) conditions, closely
matching the measured increase in vivo. The increase in NO levels may be
partially responsible for some of the detrimental effects of HBO conditions.
PMID- 10758113
TI - Older adults use a unique strategy to lift inertial loads with the elbow flexor
muscles.
AB - The purpose of this study was to determine the effect of age on the ability to
exert steady forces and to perform steady flexion movements with the muscles that
cross the elbow joint. An isometric task required subjects to exert a steady
force to match a target force that was displayed on a monitor. An anisometric
task required subjects to raise and lower inertial loads so that the angular
displacement around the elbow joint matched a template displayed on a monitor.
Steadiness was measured as the coefficient of variation of force and as the
normalized standard deviation of wrist acceleration. For the isometric task,
steadiness as a function of target force decreased similarly for old adults and
young adults. For the anisometric task, steadiness increased as a function of the
inertial load and there were significant differences caused by age. Old adults
were less steady than young adults during both shortening and lengthening
contractions with the lightest loads. Furthermore, old adults were least steady
when performing lengthening contractions. These behaviors appear to be associated
with the patterns of muscle activation. These results suggest that different
neural strategies are used to control isometric and anisometric contractions
performed with the elbow flexor muscles and that these strategies do not change
in parallel with advancing age.
PMID- 10758114
TI - Permanent reduction of seizure threshold in post-ischemic CA3 pyramidal neurons.
AB - The effects of ischemia were examined on CA3 pyramidal neurons recorded in
hippocampal slices 2-4 mo after a global forebrain insult. With intracellular
recordings, CA3 post-ischemic neurons had a more depolarized resting membrane
potential but no change of the input resistance, spike threshold and amplitude,
fast and slow afterhyperpolarization (AHP) or ADP, and firing properties in
response to depolarizing pulses. With both field and whole-cell recordings,
synaptic responses were similar in control and post-ischemic neurons. Although
there were no spontaneous network-driven discharges, the post-ischemic synaptic
network had a smaller threshold to generate evoked and spontaneous synchronized
burst discharges. Thus lower concentrations of convulsive agents (kainate, high
K(+)) triggered all-or-none network-driven synaptic events in post-ischemic
neurons more readily than in control ones. Also, paired-pulse protocol generates,
in post-ischemics but not controls, synchronized field burst discharges when
interpulse intervals ranged from 60 to 100 ms. In conclusion, 2-4 mo after the
insult, the post-ischemic CA3 pyramidal cells are permanently depolarized and
have a reduced threshold to generate synchronized bursts. This may explain some
neuropathological and behavioral consequences of ischemia as epileptic syndromes
observed several months to several years after the ischemic insult.
PMID- 10758115
TI - Effects of lesions of the oculomotor cerebellar vermis on eye movements in
primate: smooth pursuit.
AB - We studied the effects on smooth pursuit eye movements of ablation of the dorsal
cerebellar vermis (lesions centered on lobules VI and VII) in three monkeys in
which the cerebellar nuclei were spared. Following the lesion the latencies to
pursuit initiation were unchanged. Monkeys showed a small decrease (up to 15%) in
gain during triangular-wave tracking. More striking were changes in the dynamic
properties of pursuit as determined in the open-loop period (the 1st 100 ms) of
smooth tracking. Changes included a decrease in peak eye acceleration (e.g., in
one monkey from approximately 650 degrees /s(2), prelesion to approximately 220
380 degrees /s(2), postlesion) and a decrease in the velocity at the end of the
open-loop period [e.g., in another monkey from a gain (eye velocity/target
velocity at 100 ms of tracking) of 0.93, prelesion to 0.53, postlesion]. In
individual monkeys, the pattern of deficits in the open-loop period of pursuit
was usually comparable to that of saccades, especially when comparing the changes
in the acceleration of pursuit to the changes in the velocity of saccades. These
findings support the hypothesis that saccades and the open-loop period of pursuit
are controlled by the cerebellar vermis in an analogous way. Saccades could be
generated by eye velocity commands to bring the eyes to a certain position and
pursuit by eye acceleration commands to bring the eyes toward a certain velocity.
On the other hand, changes in gain during triangular-wave tracking did not
correlate with either the saccade or the open-loop pursuit deficits, implying
different contributions of the oculomotor vermis to the open loop and to the
sustained portions of pursuit tracking. Finally, in a pursuit adaptation paradigm
(x0.5 or x2, calling for a halving or doubling of eye velocity, respectively)
intact animals could adaptively adjust eye acceleration in the open-loop period.
The main pattern of change was a decrease in peak acceleration for x0.5 training
and an increase in the duration of peak acceleration for x2 training. Following
the lesion in the oculomotor vermis, this adaptive capability was impaired. In
conclusion, as for saccades, the oculomotor vermis plays a critical role both in
the immediate on-line and in the short-term adaptive control of pursuit.
PMID- 10758116
TI - Modulation of H reflex of pretibial muscles and reciprocal Ia inhibition of
soleus muscle during voluntary teeth clenching in humans.
AB - A previous study has demonstrated that the soleus H reflex is facilitated in
association with voluntary teeth clenching in proportion with biting force in
humans. The present study tried to elucidate the functional significance of this
facilitation of the soleus H reflex, by examining 1) whether the facilitation of
the H reflex is reciprocal or nonreciprocal between the ankle extensors and
flexors and 2) whether the reciprocal Ia inhibition of crural muscles is
facilitated or depressed in association with voluntary teeth clenching. The H
reflex of the pretibial muscles was evoked by stimulation of the common peroneal
nerve in seven healthy subjects with no oral dysfunction. The pretibial H reflex
was facilitated in association with voluntary teeth clenching in a force
dependent manner. The facilitation started preceding the onset of
electromyographic activity of the masseter muscle. Stimulation of the common
peroneal nerve at low intensities subthreshold for evoking the M wave of the
pretibial muscles inhibited the soleus H reflex after a short latency
corresponding with a disynaptic inhibition, indicating that the reciprocal Ia
inhibition was depressed in association with voluntary teeth clenching. Thus, the
present study has shown that voluntary teeth clenching evokes a nonreciprocal
facilitation of ankle extensor and flexor muscles and attenuated reciprocal Ia
inhibition from the pretibial muscles to the soleus muscle. It is concluded that
voluntary teeth clenching contributes to improve stability of stance rather than
smoothness of movements.
PMID- 10758117
TI - Protein kinase A mediates the modulation of the slow Ca(2+)-dependent K(+)
current, I(sAHP), by the neuropeptides CRF, VIP, and CGRP in hippocampal
pyramidal neurons.
AB - We have studied modulation of the slow Ca(2+)-activated K(+) current (I(sAHP)) in
CA1 hippocampal pyramidal neurons by three peptide transmitters: corticotropin
releasing factor (CRF, also called corticotropin releasing hormone, CRH),
vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP).
These peptides are known to be expressed in interneurons. Using whole cell
voltage clamp in hippocampal slices from young rats, in the presence of
tetrodotoxin (TTX, 0.5 microM) and tetraethylammonium (TEA, 5 mM), I(sAHP) was
measured after a brief depolarizing voltage step eliciting inward Ca(2+) current.
Each of the peptides CRF (100-250 nM), VIP (400 nM), and CGRP (1 microM)
significantly reduced the amplitude of I(sAHP). Thus the I(sAHP) amplitude was
reduced to 22% by 100 nM CRF, to 17% by 250 nM CRF, to 22% by 400 nM VIP, and to
40% by 1 microM CGRP. We found no consistent concomitant changes in the Ca(2+)
current or in the time course of I(sAHP) for any of the three peptides,
suggesting that the suppression of I(sAHP) was not secondary to a general
suppression of Ca(2+) channel activity. Because each of these peptides is known
to activate the cyclic AMP (cAMP) cascade in various cell types, and I(sAHP) is
known to be suppressed by cAMP via the cAMP-dependent protein kinase (PKA), we
tested whether the effects on I(sAHP) by CRF, VIP, and CGRP are mediated by PKA.
Intracellular application of the PKA-inhibitor Rp-cAMPS significantly reduced the
suppression of I(sAHP) by CRF, VIP, and CGRP. Thus with 1 mM Rp-cAMPS in the
recording pipette, the average suppression of I(sAHP) was reduced from 78 to 26%
for 100 nM CRF, from 83 to 32% for 250 nM CRF, from 78 to 30% for 400 nM VIP, and
from 60 to 7% for 1 microM CGRP. We conclude that CRF, VIP, and CGRP suppress the
slow Ca(2+)-activated K(+) current, I(sAHP), in CA1 hippocampal pyramidal neurons
by activating the cAMP-dependent protein kinase, PKA. Together with the monoamine
transmitters norepinephrine, serotonin, histamine, and dopamine, these peptide
transmitters all converge on the cAMP cascade modulating I(sAHP).
PMID- 10758118
TI - Activity of mesencephalic vertical burst neurons during saccades and smooth
pursuit.
AB - The activity of vertical burst neurons (BNs) was recorded in the rostral
interstitial nucleus of the medial longitudinal fasciculus (riMLF-BNs) and in the
interstitial nucleus of Cajal (NIC-BNs) in head-restrained cats while performing
saccades or smooth pursuit. BNs emitted a high-frequency burst of action
potentials before and during vertical saccades. On average, these bursts led
saccade onset by 14 +/- 4 ms (mean +/- SD, n = 23), and this value was in the
range of latencies ( approximately 5-15 ms) of medium-lead burst neurons (MLBNs).
All NIC-BNs (n = 15) had a downward preferred direction, whereas riMLF-BNs showed
either a downward (n = 3) or an upward (n = 5) preferred direction. We found
significant correlations between saccade and burst parameters in all BNs:
vertical amplitude was correlated with the number of spikes, maximum vertical
velocity with maximum of the spike density, and saccade duration with burst
duration. A correlation was also found between instantaneous vertical velocity
and neuronal activity during saccades. During fixation, all riMLF-BNs and
approximately 50% of NIC-BNs (7/15) were silent. Among NIC-BNs active during
fixation (8/15), only two cells had an activity correlated with the eye position
in the orbit. During smooth pursuit, most riMLF-BNs were silent (7/8), but all
NIC-BNs showed an activity that was significantly correlated with the eye
velocity. This activity was unaltered during temporary disappearance of the
visual target, demonstrating that it was not visual in origin. For a given
neuron, its ON-direction during smooth pursuit and saccades remained identical.
The activity of NIC-BNs during both saccades and smooth pursuit can be described
by a nonlinear exponential function using the velocity of the eye as independent
variable. We suggest that riMLF-BNs, which were not active during smooth pursuit,
are vertical MLBNs responsible for the generation of vertical saccades. Because
NIC-BNs discharged during both saccades and pursuit, they cannot be regarded as
MLBNs as usually defined. NIC-BNs could, however, be the site of convergence of
both the saccadic and smooth pursuit signals at the premotoneuronal level.
Alternatively, NIC-BNs could participate in the integration of eye velocity to
eye position signals and represent input neurons to a common integrator.
PMID- 10758119
TI - Muscular responses and movement strategies during stumbling over obstacles.
AB - Although many studies have investigated reflexes after stimulation of either
cutaneous or proprioceptive afferents, much less is known about responses after
more natural perturbations, such as stumbling over an obstacle. In particular,
the phase dependency of these responses and their relation to the stumbling
behavior has received little attention. Hence response strategies during
stumbling reactions after perturbations at different times in the swing phase of
gait were studied. While subjects walked on a treadmill, a rigid obstacle
unexpectedly obstructed the forward sway of the foot. All subjects showed an
"elevating strategy" after early swing perturbations and a "lowering strategy"
after late swing perturbations. During the elevating strategy, the foot was
directly lifted over the obstacle through extra knee flexion assisted by
ipsilateral biceps femoris (iBF) responses and ankle dorsiflexion assisted by
tibialis anterior (iTA) responses. Later, large rectus femoris (iRF) activations
induced knee extension to place the foot on the treadmill. During the lowering
strategy, the foot was quickly placed on the treadmill and was lifted over the
obstacle in the subsequent swing. Foot placement was actively controlled by iRF
and iBF responses related to knee extension and deceleration of the forward sway.
Activations of iTA mostly preceded the main ipsilateral soleus (iSO) responses.
For both strategies, four response peaks could be distinguished with latencies of
approximately 40 ms (RP1), approximately 75 ms (RP2), approximately 110 ms (RP3),
and approximately 160 ms (RP4). The amplitudes of these response peaks depended
on the phase in the step cycle. The phase-dependent modulation of the responses
could not be accounted for by differences in stimulation or in background
activity and therefore is assumed to be premotoneuronal in origin. In mid swing,
both the elevating and lowering strategy could occur. For this phase, the
responses of the two strategies could be compared in the absence of phase
dependent response modulation. Both strategies had the same initial
electromyographic responses till approximately 100 ms (RP1-RP2) after
perturbation. The earliest response (RP1) is assumed to be a short-latency
stretch reflex evoked by the considerable impact of the collision, whereas the
second (RP2) has features reminiscent of cutaneous and proprioceptive responses.
Both these responses did not determine the behavioral response strategy. The
functionally important response strategies depended on later responses (RP3-RP4).
These data suggest that during stumbling reactions, as a first line of defense,
the CNS releases a relatively aspecific response, which is followed by an
appropriate behavioral response to avoid the obstacle.
PMID- 10758120
TI - Potentiation in the first visual synapse of the fly compound eye.
AB - In the first visual synapse of the insect compound eye, both the presynaptic and
postsynaptic signals are graded, nonspiking changes in membrane voltage. The
synapse exhibits tonic transmitter release (even in dark) and strong adaptation
to long-lasting light backgrounds, leading to changes also in the dynamics of
signal transmission. We have studied these adaptational properties of the first
visual synapse of the blowfly Calliphora vicina. Investigations were done in situ
by intracellular recordings from the presynaptic photoreceptors, photoreceptor
axon terminals, and the postsynaptic first order visual interneurons (LMCs). The
dark recovery, the shifts in intensity dependence, and the underlying processes
were studied by stimulating the visual system with various adapting stimuli while
observing the recovery (i.e., dark adaptation). The findings show a transient
potentiation in the postsynaptic responses after intense light adaptation, and
the underlying mechanisms seem to be the changes in the equilibrium potential of
the transmitter-gated conductance (chloride) of the postsynaptic neurons. The
potentiation by itself serves as a mechanism that after light adaptation rapidly
recovers the sensitivity loss of the visual system. However, this kind of
mechanism, being an intrinsic property of graded potential transmission, may be
quite widespread among graded synapses, and the phenomenon demonstrates that
functional plasticity is also a property of graded synaptic transmission.
PMID- 10758121
TI - Optimal sizes of dendritic and axonal arbors in a topographic projection.
AB - I consider a topographic projection between two neuronal layers with different
densities of neurons. Given the number of output neurons connected to each input
neuron (divergence) and the number of input neurons synapsing on each output
neuron (convergence), I determine the widths of axonal and dendritic arbors which
minimize the total volume of axons and dendrites. Analytical results for one
dimensional and two-dimensional projections can be summarized qualitatively in
the following rule: neurons of the sparser layer should have arbors wider than
those of the denser layer. This agrees with the anatomic data for retinal,
cerebellar, olfactory bulb, and neocortical neurons the morphology and
connectivity of which are known. The rule may be used to infer connectivity of
neurons from their morphology.
PMID- 10758122
TI - EMG activities of two heads of the human lateral pterygoid muscle in relation to
mandibular condyle movement and biting force.
AB - Electromyographic (EMG) activities of the superior (SUP) and inferior heads (INF)
of the lateral pterygoid muscle (LPT) were recorded in humans during voluntary
stepwise changes in biting force and jaw position that were adopted to exclude
the effects of acceleration and velocity of jaw movements on the muscle activity.
The SUP behaved like a jaw-closing muscle and showed characteristic activity in
relation to the biting force. It showed a considerable amount of background
activity (5-32% of the maximum) even in the intercuspal position without teeth
clenching and reached a nearly maximum activity at relatively lower biting-force
levels than the jaw-closing muscles during increment of the biting force. Stretch
reflexes were found in the SUP, the function of which could be to stabilize the
condyle against the biting force that pulls the condyle posteriorly. This notion
was verified by examining the biomechanics on the temporomandibular joint. The
complex movements of the mandibular condyle in a sagittal plane were decomposed
into displacement in the anteroposterior direction (Ac) and angle of rotation
(RAc) around a kinesiological specific point on the condyle. In relation to Ac,
each head of the LPT showed quite a similar behavior to each other in all types
of jaw movements across all subjects. Working ranges of the muscle activities
were almost constant (Ac <3 mm for the SUP and Ac >3 mm for the INF). The amount
of EMG activity of the SUP changed in inverse proportion to Ac showing a
hyperbola-like relation, whereas that of the INF changed rather linearly. The EMG
amplitude of the SUP showed a quasilinear inverse relation with RAc in the hinge
movement during which the condyle rotated with no movement in the anteroposterior
direction. This finding suggests that the SUP controls the angular relationship
between the articular disk and the condyle. On the other hand, the position of
the disk in relation to the maxilla, not to the condyle, is controlled indirectly
by the INF because the disk is attached to the condyle by tendinous ligaments.
PMID- 10758123
TI - Size of CA1-evoked synaptic potentials is related to theta rhythm phase in rat
hippocampus.
AB - Cholinergic and GABAergic neurons projecting to the hippocampus fire with
specific phase relations to theta rhythm oscillations in the electroencephalogram
(EEG). To determine if this phasic input has an impact on synaptic transmission
within the hippocampus, we recorded evoked population excitatory postsynaptic
potential (EPSPs) during different phases of theta rhythm by using techniques
similar to those described in Rudell and Fox. Synaptic potentials elicited by
stimulation of region CA3 of the contralateral hippocampus were recorded in
region CA1 and CA3. In these experiments, the initial slope of evoked potentials
showed a change in magnitude during different phases of the theta rhythm recorded
in the dentate fissure, with individual trials showing an average of 9.5% change
in slope of potentials, and the average across all experiments showing a change
of 7.8%. Evoked potentials were maximal 18 degrees after the positive peak of the
dentate fissure theta EEG. These potentials were also smaller by 18.2% during
theta as opposed to non-theta states. Phasic changes in modulation of synaptic
transmission could contribute to phase precession of hippocampal place cells and
could enhance storage of new sequences of activity as demonstrated by
computational models.
PMID- 10758124
TI - Electrical cochlear stimulation in the deaf cat: comparisons between
psychophysical and central auditory neuronal thresholds.
AB - Cochlear prostheses for electrical stimulation of the auditory nerve ("electrical
hearing") can provide auditory capacity for profoundly deaf adults and children,
including in many cases a restored ability to perceive speech without visual
cues. A fundamental challenge in auditory neuroscience is to understand the
neural and perceptual mechanisms that make rehabilitation of hearing possible in
these deaf humans. We have developed a feline behavioral model that allows us to
study behavioral and physiological variables in the same deaf animals. Cats
deafened by injection of ototoxic antibiotics were implanted with either a
monopolar round window electrode or a multichannel scala tympani electrode array.
To evaluate the effects of perceptually significant electrical stimulation of the
auditory nerve on the central auditory system, an animal was trained to avoid a
mild electrocutaneous shock when biphasic current pulses (0.2 ms/phase) were
delivered to its implanted cochlea. Psychophysical detection thresholds and
electrical auditory brain stem response (EABR) thresholds were estimated in each
cat. At the conclusion of behavioral testing, acute physiological experiments
were conducted, and threshold responses were recorded for single neurons and
multineuronal clusters in the central nucleus of the inferior colliculus (ICC)
and the primary auditory cortex (A1). Behavioral and neurophysiological
thresholds were evaluated with reference to cochlear histopathology in the same
deaf cats. The results of the present study include: 1) in the cats implanted
with a scala tympani electrode array, the lowest ICC and A1 neural thresholds
were virtually identical to the behavioral thresholds for intracochlear bipolar
stimulation; 2) behavioral thresholds were lower than ICC and A1 neural
thresholds in each of the cats implanted with a monopolar round window electrode;
3) EABR thresholds were higher than behavioral thresholds in all of the cats
(mean difference = 6.5 dB); and 4) the cumulative number of action potentials for
a sample of ICC neurons increased monotonically as a function of the amplitude
and the number of stimulating biphasic pulses. This physiological result suggests
that the output from the ICC may be integrated spatially across neurons and
temporally integrated across pulses when the auditory nerve array is stimulated
with a train of biphasic current pulses. Because behavioral thresholds were lower
and reaction times were faster at a pulse rate of 30 pps compared with a pulse
rate of 2 pps, spatial-temporal integration in the central auditory system was
presumably reflected in psychophysical performance.
PMID- 10758125
TI - Serotonin-induced spike narrowing in a locomotor pattern generator permits
increases in cycle frequency during accelerations.
AB - During serotonin-induced swim acceleration in the pteropod mollusk Clione
limacina, interneurons of the central pattern generator (CPG) exhibit significant
action potential narrowing. Spike narrowing is apparently necessary for increases
in cycle frequency during swim acceleration because, in the absence of narrowing,
the combined duration of the spike and the inhibitory postsynaptic potential
(IPSP) of a single cycle is greater than the available cycle duration. Spike
narrowing could negatively influence synaptic efficacy in all interneuron
connections, including reciprocal inhibitory connections between the two groups
of antagonistic CPG interneurons as well as the interneuron-to-motoneuron
connections. Thus compensatory mechanisms must exist to produce the overall
excitatory behavioral change of swim acceleration. Such mechanisms include 1) a
baseline depolarization of interneurons, which brings them closer to spike
threshold, 2) enhancement of their postinhibitory rebound, and 3) direct
modulation of swim motoneurons and muscles, all through inputs from serotonergic
modulatory neurons.
PMID- 10758126
TI - Brain nitric oxide changes after controlled cortical impact injury in rats.
AB - Nitric oxide (NO) and the NO end products, nitrate and nitrite, were measured at
the impact site after a 5-m/s, 3-mm deformation controlled cortical impact injury
in rats. Immediately after the impact injury and the NO and microdialysis probes
could be replaced, there was an increase from baseline in NO concentration of 83
+/- 16 (SE) nM, compared with 0.5 +/- 4 nM in the sham injured animals (P <
0.001). This marked increase in NO occurred at the time of the initial rise in
blood pressure (BP) and intracranial pressure (ICP) in response to the injury.
After the initial increase in BP and ICP, the BP decreased and stabilized at a
value which was approximately 20 mmHg below the preinjury values, and ICP
plateaued at an average value of 20 mmHg, compared with 8 mmHg in the sham
injured animals. This provided an average cerebral perfusion pressure of 40-50
mmHg, compared with 65-75 mmHg for the sham-injured animals. These values were
relatively constant for the remainder of the 3-h monitoring period. The NO values
also stabilized during this time period. By 1 h after the impact injury the NO
concentration measured directly using the NO electrode had decreased from
baseline values by an average value of 25 +/- 6 nM. NO concentration remained
significantly lower than baseline values throughout the remainder of the 3-h
monitoring period. The concentration of nitrate/nitrite in the dialysate fluid
also decreased by an average value of 341 +/- 283 nM 20-40 min after the injury.
Dialysate nitrite/nitrate concentrations remained less than the preinjury
baseline values throughout the remainder of the 3-h monitoring period. Preinjury
treatment with L-nitro-arginine methyl ester (L-NAME) blunted the injury-induced
increase in NO and resulted in more severe immediate intracranial hypertension
and more severe systemic hypotension at one hour after injury. Mortality was also
67% with L-NAME pretreatment, compared with 1% in untreated animals.
PMID- 10758127
TI - Response of cutaneous A- and C-fiber nociceptors in the monkey to controlled
force stimuli.
AB - The goal of this study was to determine the capacity of primary afferent
nociceptive fibers (nociceptors) to encode information about noxious mechanical
stimuli in primates. Teased-fiber techniques were used to record from 14 A-fiber
nociceptors and 18 C-fiber nociceptors that innervated the hairy skin. Stimulus
response functions were examined with an ascending series of force-controlled
stimuli. Stimulus-interaction effects were examined with use of a series of
paired stimuli in which the interval between the stimulus pairs was varied
systematically. Both A-fiber and C-fiber nociceptors exhibited a slowly adapting
response to the stepped force stimuli. The response of the A fibers increased
monotonically with increasing force, whereas the response of the C fibers reached
a plateau at low force levels. The slope of the stimulus-response function for
the A fibers was significantly steeper than that for the C fibers, and the total
response was greater. The A fibers also provided more discriminative information
regarding stimulus intensity. The C fibers demonstrated a significant fatigue in
response when the interstimulus interval between the paired stimuli was 80 pF) cutaneous afferents (control: 112.4 +/- 10.6 pA/pF, n = 30;
ligated: 72.6 +/- 5.0 pA/pF, n = 36; P < 0.001); no change was observed in cells
with capacitances of 45-80 pF. Isolation of the N- and P?Q-type components of the
HVA current in the large neurons using omega-conotoxin GVIA and omega-agatoxin TK
suggests a selective reduction in N-type barium current after nerve injury, as
the density of omega-CgTx GVIA-sensitive current decreased from 56.9 +/- 6.6
pA/pF in control cells (n = 13) to 31.3 +/- 4.6 pA/pF in the ligated group (n =
12; P < 0.005). The HVA barium current of large cutaneous afferents also
demonstrates a depolarizing shift in the voltage dependence of inactivation after
axotomy. Injured type 1 cells exhibited faster inactivation kinetics than control
neurons, although the rate of recovery from inactivation was similar in the two
groups. The present results indicate that nerve injury leads to a reorganization
of the HVA calcium current properties in a subset of cutaneous afferent neurons.
PMID- 10758132
TI - Physiological properties of the lamina I spinoparabrachial neurons in the rat.
AB - Single-unit extracellular recordings of spino-parabrachial (spino-PB) neurons (n
= 53) antidromically driven from the contralateral parabrachial (PB) area were
performed in the lumbar cord in anesthetized rats. All the spino-PB neurons were
located in the lamina I of the dorsal horn. Their axons exhibited conduction
velocities between 2.8 and 27.8 m/s, in the thin myelinated fibers range. They
had an extremely low spontaneous activity (median = 0. 064 Hz) and a small
excitatory receptive field ( 1. 4/A. For the larger values of beta, the transport can be
accounted for as single step superexchange-mediated hole transfer. To account for
the smaller values, hopping models have been proposed, the simplest being nearest
neighbor hopping. This model assumes that, between hops, the hole is localized on
a single base with no overlap to neighbors. Noting that an electron or hole added
to a DNA stack, as to other essentially one-dimensional entities, should distort
its structure to form a polaron, Schuster and coworkers [Henderson, P. T. ,
Jones, D., Hampikian, G., Kan, Y. & Schuster, G. B. (1999) Proc. Natl. Acad. Sci.
USA 96, 8353-8358 and Ly, D., Sanii, L. & Schuster, G. B. (1999) J. Am. Chem.
Soc. 121, 9400-9410] proposed that transport occurs by polaron hopping between
sites having approximately equal energies as a result of overlap. A recent
experimental determination by Wan et al. [Wan, C., Fiebig, T., Kelley, S. O.,
Treadway, C. R., Barton, J. K. & Zewail, A. H. (1999) Proc. Natl. Acad. Sci. USA
96, 6014-6019] of the time required for an injected hole on DNA to travel a known
distance leads to a large value of the diffusion constant. From this constant, a
mobility of 0. 2 cm(2)/V small middle dots was deduced, orders of magnitude
larger than typical hopping mobilities. We suggest that this ultrafast transport
is due to polaron drift, which has been shown to lead to similar mobilities in
chains of conjugated polymers. Using a simple model for the polaron, similar to
that used for conjugated polymers such as polyacetylene, we show that, for
reasonable values of the parameters, an injected electron or hole can form a
polaron on a DNA stack.
PMID- 10758151
TI - Inorganic polyphosphate is needed for swimming, swarming, and twitching
motilities of Pseudomonas aeruginosa.
AB - Polyphosphate kinase (PPK), encoded by the ppk gene, is the principal enzyme in
many bacteria for the synthesis of inorganic polyphosphate (poly P) from ATP. A
knockout mutant in the ppk gene of Pseudomonas aeruginosa PAO1 is impaired in
flagellar swimming motility on semisolid agar plates. The mutant is deficient in
type IV pili-mediated twitching motility and in a "swarming motility" previously
unobserved in P. aeruginosa. In swarming cultures, the polar monotrichous
bacteria have differentiated into elongated and polar multitrichous cells that
navigate the surface of solid media. All of the motility defects in the ppk
mutant could be complemented by a plasmid harboring the ppk gene. Because
bacterial motility is often crucial for their survival in a natural environment
and for systemic infection inside a host, the dependence for motility on PPK
reveals important roles for poly P in diverse processes such as biofilm
formation, symbiosis, and virulence.
PMID- 10758152
TI - Identification with a recombinant antibody of an inner-ear cytokeratin, a marker
for hair-cell differentiation.
AB - Extensive biochemical characterization of cells in the inner ear has been
hampered by a lack of tools with which to identify inner-ear proteins. By using a
single-chain antibody fragment isolated from a bacteriophage-displayed library,
we have identified a cytokeratin that is abundant in nonsensory cells of the frog
inner ear. Although the progenitors of hair cells exhibit strong immunoreactivity
to this cytokeratin, the signal declines in immature hair cells and vanishes as
the cells mature. The correlation between diminished immunoreactivity and hair
cell differentiation indicates that the cytokeratin is down-regulated during the
transition from a nonsensory to a sensory cell and suggests that the marker is an
early index of hair-cell differentiation.
PMID- 10758153
TI - Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to
infant leukemia.
AB - Chromosomal translocations involving the MLL gene occur in about 80% of infant
leukemia. In the search for possible agents inducing infant leukemia, we
identified bioflavonoids, natural substances in food as well as in dietary
supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster
region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor
hematopoietic cells from healthy newborns and adults as well as in cell lines; it
colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents,
such as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional in
vitro experiments demonstrated topoisomerase II (topo II) as the target of
bioflavonoids similar to VP16 and Dox. Based on 20 bioflavonoids tested, we
identified a common structure essential for topo II-induced DNA cleavage.
Reversibility experiments demonstrated a religation of the bioflavonoid as well
as the VP16-induced MLL cleavage site. Our observations support a two-stage model
of cellular processing of topo II inhibitors: The first and reversible stage of
topo II-induced DNA cleavage results in DNA repair, but also rarely in chromosome
translocations; whereas the second, nonreversible stage leads to cell death
because of an accumulation of DNA damage. These results suggest that maternal
ingestion of bioflavonoids may induce MLL breaks and potentially translocations
in utero leading to infant and early childhood leukemia.
PMID- 10758154
TI - The mutated human gene encoding hepatocyte nuclear factor 1beta inhibits kidney
formation in developing Xenopus embryos.
AB - The transcription factor hepatocyte nuclear factor 1beta (HNF1beta) is a tissue
specific regulator that also plays an essential role in early development of
vertebrates. In humans, four heterozygous mutations in the HNF1beta gene have
been identified that lead to early onset of diabetes and severe primary renal
defects. The degree and type of renal defects seem to depend on the specific
mutation. We show that the frameshift mutant P328L329fsdelCCTCT associated with
nephron agenesis retains its DNA-binding properties and acts as a gain-of
function mutation with increased transactivation potential in transfection
experiments. Expression of this mutated factor in the Xenopus embryo leads to
defective development and agenesis of the pronephros, the first kidney form of
amphibians. Very similar defects are generated by overexpressing in Xenopus the
wild-type HNF1beta, which is consistent with the gain-of-function property of the
mutant. In contrast, introduction of the human HNF1beta mutant R137-K161del,
which is associated with a reduced number of nephrons with hypertrophy of the
remaining ones and which has an impaired DNA binding, shows only a minor effect
on pronephros development in Xenopus. Thus, the overexpression of both human
mutants has a different effect on renal development in Xenopus, reflecting the
variation in renal phenotype seen with these mutations. We conclude that
mutations in human HNF1beta can be functionally characterized in Xenopus. Our
findings imply that HNF1beta not only is an early marker of kidney development
but also is functionally involved in morphogenetic events, and these processes
can be investigated in lower vertebrates.
PMID- 10758155
TI - The Dewar photoproduct of thymidylyl(3'-->5')- thymidine (Dewar product) exhibits
mutagenic behavior in accordance with the "A rule".
AB - In contrast to the highly mutagenic pyrimidine(6-4)pyrimidone photoproduct, its
Dewar valence isomer (Dewar product) has low mutagenic potential and produces a
broad range of mutations [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991)
Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the
mutagenic property of the Dewar product, we used experimental NMR restraints and
molecular dynamics to determine the solution structure of a Dewar-lesion DNA
decamer duplex. This DNA decamer duplex (DW/GA duplex) contains a mismatched base
pair between the 3' T residue of the Dewar lesion (T6) and an opposed G residue
(G15). The 3' T (T6) of the Dewar lesion formed stable hydrogen bonds with the
opposing G15 residue. However, the helical bending and unwinding angles of the
DW/GA duplex were much larger than those of a second duplex that contains the
Dewar lesion and opposing A15 and A16 residues (DW/AA duplex). The DW/GA duplex
showed poorer stacking interactions at the two bases of the Dewar product and at
the adjacent A7 small middle dotT14 base pair than did the DW/AA duplex. These
structural features imply that no thermal stability or conformational benefit is
obtained by incorporating a G instead of an A opposite the 3' T of the Dewar
lesion. These properties may thus facilitate the preferential incorporation of an
A in accordance with the A rule during translesion replication and lead to the
low frequency of 3' T-->C mutations observed at this site.
PMID- 10758156
TI - Muir-Torre-like syndrome in Fhit-deficient mice.
AB - To investigate the role of the Fhit gene in carcinogen induction of neoplasia, we
have inactivated one Fhit allele in mouse embryonic stem cells and produced
(129/SvJ x C57BL/6J) F(1) mice with a Fhit allele inactivated (+/-). Fhit +/+ and
+/- mice were treated intragastrically with nitrosomethylbenzylamine and observed
for 10 wk posttreatment. A total of 25% of the +/+ mice developed adenoma or
papilloma of the forestomach, whereas 100% of the +/- mice developed multiple
tumors that were a mixture of adenomas, squamous papillomas, invasive carcinomas
of the forestomach, as well as tumors of sebaceous glands. The visceral and
sebaceous tumors, which lacked Fhit protein, were similar to those characteristic
of Muir-Torre familial cancer syndrome.
PMID- 10758157
TI - RNA polymerase I transcription factor Rrn3 is functionally conserved between
yeast and human.
AB - We have cloned a human cDNA that is related to the RNA polymerase I transcription
factor Rrn3 of Saccharomyces cerevisiae. The recombinant human protein displays
both sequence similarity and immunological crossreactivity to yeast Rrn3 and is
capable of rescuing a yeast strain carrying a disruption of the RRN3 gene in
vivo. Point mutation of an amino acid that is conserved between the yeast and
human proteins compromises the function of each factor, confirming that the
observed sequence similarity is functionally significant. Rrn3 is the first RNA
polymerase I-specific transcription factor shown to be functionally conserved
between yeast and mammals, suggesting that at least one mechanism that regulates
ribosomal RNA synthesis is conserved among eukaryotes.
PMID- 10758158
TI - The three-dimensional structure of halorhodopsin to 5 A by electron
crystallography: A new unbending procedure for two-dimensional crystals by using
a global reference structure.
AB - Electron microscopy does not, in principle, require highly ordered crystals to
determine a high-resolution structure. Nevertheless, crystals of any type help to
constrain the molecules into a more limited range of orientations and positions,
from which it is easier to carry out structure determination. We describe an
improved procedure for determination of crystalline disorder, which we have
applied to poorly ordered two-dimensional crystals of the chloride pump
halorhodopsin from Halobacterium salinarum. The new image analysis procedure
involves the use of a reference projection calculated from a global three
dimensional map to carry out the initial cross-correlation analysis. Coupled with
a greater number of images taken with field emission gun microscopes, this has
allowed us to calculate a three-dimensional structure for halorhodopsin, in which
the seven transmembrane helices and certain molecular features, such as the beta
ionone ring of retinal, are now resolved.
PMID- 10758159
TI - Local and distant protein structural changes on photoisomerization of the retinal
in bacteriorhodopsin.
AB - The photoisomerization of the retinal in bacteriorhodopsin is selective and
efficient and yields perturbation of the protein structure within femtoseconds.
The stored light energy in the primary intermediate is then used for the net
translocation of a proton across the membrane in the microsecond to millisecond
regime. This study is aimed at identifying how the protein changes on
photoisomerization by using the O-H groups of threonines as internal probes.
Polarized Fourier-transform IR spectroscopy of [3-(18)O]threonine-labeled and
unlabeled bacteriorhodopsin indicates that 3 of the threonines (of a total of 18)
change their hydrogen bonding. One is exchangeable in D(2)O, but two are not. A
comprehensive mutation study indicates that the residues involved are Thr-89, Thr
17, and Thr-121 (or Thr-90). The perturbation of only three threonine side chains
suggests that the structural alteration at this stage of the photocycle is local
and specific. Furthermore, the structural change of Thr-17, which is located >11
A from the retinal chromophore, implicates a specific perturbation channel in the
protein that accompanies the retinal motion.
PMID- 10758160
TI - Evolution of the rodent eosinophil-associated RNase gene family by rapid gene
sorting and positive selection.
AB - The mammalian RNase A superfamily comprises a diverse array of ribonucleolytic
proteins that have a variety of biochemical activities and physiological
functions. Two rapidly evolving RNases of higher primates are of particular
interest as they are major secretory proteins of eosinophilic leukocytes and have
been found to possess anti-pathogen activities in vitro. To understand how these
RNases acquired this function during evolution and to develop animal models for
the study of their functions in vivo, it is necessary to investigate these genes
in many species. Here, we report the sequences of 38 functional genes and 23
pseudogenes of the eosinophil-associated RNase (EAR) family from 5 rodent
species. Our phylogenetic analysis of these genes showed a clear pattern of
evolution by a rapid birth-and-death process and gene sorting, a process
characterized by rapid gene duplication and deactivation occurring differentially
among lineages. This process ultimately generates distinct or only partially
overlapping inventories of the genes, even in closely related species. Positive
Darwinian selection also contributed to the diversification of these EAR genes.
The striking similarity between the evolutionary patterns of the EAR genes and
those of the major histocompatibility complex, immunoglobulin, and T cell
receptor genes stands in strong support of the hypothesis that host-defense and
generation of diversity are among the primary physiological function of the
rodent EARs. The discovery of a large number of divergent EARs suggests the
intriguing possibility that these proteins have been specifically tailored to
fight against distinct rodent pathogens.
PMID- 10758161
TI - Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen
regulated ubiquitination that is disrupted by deletions and missense mutations.
AB - Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates
cellular and systemic homeostatic responses to reduced O(2) availability in
mammals, including angiogenesis, erythropoiesis, and glycolysis. HIF-1 activity
is controlled by the O(2)-regulated expression of the HIF-1alpha subunit. Under
nonhypoxic conditions, HIF-1alpha protein is subject to ubiquitination and
proteasomal degradation. Here we report that missense mutations and/or deletions
involving several different regions of HIF-1alpha result in constitutive
expression and transcriptional activity in nonhypoxic cells. We demonstrate that
hypoxia results in decreased ubiquitination of HIF-1alpha and that missense
mutations increase HIF-1alpha expression under nonhypoxic conditions by blocking
ubiquitination.
PMID- 10758163
TI - Adeno-associated virus site-specifically integrates into a muscle-specific DNA
region.
AB - The nonpathogenic human virus adeno-associated virus type 2 (AAV) has evolved the
potentially unique strategy to establish latency by site-specifically integrating
its genome into human chromosome 19 (19q13.3-qter) at a locus designated AAVS1.
This nonhomologous, site-specific recombination of viral DNA with the human
genome provides a basis for developing targeted gene therapy vectors. To assess
whether the region surrounding AAVS1 might have contributed to the selection of
the specific integration site, we have investigated this locus. Here, we show
that AAVS1 is closely linked to the slow skeletal troponin T gene, TNNT1, which
has been mapped previously to 19q13.4. In support of this idea, we demonstrate
that site-specific AAV DNA integration can result in the formation of TNNT1-AAV
junctions. The question now arises whether muscle represents a natural target
tissue for latent AAV infection. This possibility is of additional interest in
view of recent observations that muscle tissue is particularly well suited for
AAV-mediated gene transfer. The question also occurs whether latent infection by
AAV can lead to phenotypic changes of the multinucleated muscle fiber cells.
PMID- 10758164
TI - Identification of progenitor cells in long-term spleen stromal cultures that
produce immature dendritic cells.
AB - Dendritic cells (DC) are produced continuously by a unique, long-term culture
(LTC) system in which hemopoiesis is supported by a splenic stromal cell layer in
the absence of added growth factors. Flow cytometric analysis reveals the
production of two distinct cell subsets. The more predominant large-cell subset
resembles highly endocytic DC that are large, granular, and possess membrane
extensions. They also express high levels of the DC markers CD11c, CD11b, DEC
205, and CD80 on their cell surface. They do not resemble mature DC because they
express low levels of MHC type II and CD86 molecules, as well as c-kit and Fc
receptor (FcR). These are known characteristics of immature DC. Small cells are
smaller and less granular than large cells, with negative to low expression of
CD11c, DEC-205, and CD86. A majority of small cells express varying levels of
CD11b and CD80. Subpopulations of small cells express low levels of c-kit, FcR,
and MHC type II, and only a 20% subpopulation is weakly endocytic. Upon transfer
to an irradiated stromal layer, cells within the small subset proliferate and
differentiate to resemble the large cells in size, complexity, membrane
extensions, and CD11c and CD86 expression. The two cell subsets produced in LTC
are developmentally linked, with the heterogeneous small-cell subset containing
progenitors of the larger homogeneous, immature DC subset. LTC represent a
valuable model system for studying DC development from hemopoietic progenitors.
PMID- 10758162
TI - Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2
mutation.
AB - A 5-week-old male infant presented with severe bacterial infections and poor
wound healing, suggesting a neutrophil defect. Neutrophils from this patient
exhibited decreased chemotaxis, polarization, azurophilic granule secretion, and
superoxide anion (O(2)(-)) production but had normal expression and up-regulation
of CD11b. Rac2, which constitutes >96% of the Rac in neutrophils, is a member of
the Rho family of GTPases that regulates the actin cytoskeleton and O(2)(-)
production. Western blot analysis of lysates from patient neutrophils
demonstrated decreased levels of Rac2 protein. Addition of recombinant Rac to
extracts of the patient neutrophils reconstituted O(2)(-) production in an in
vitro assay system. Molecular analysis identified a point mutation in one allele
of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2(D57N)).
Asp57 is invariant in all defined GTP-binding proteins. Rac2(D57N) binds GDP but
not GTP and inhibits oxidase activation and O(2)(-) production in vitro. These
data represent the description of an inhibitory mutation in a member of the Rho
family of GTPases associated with a human immunodeficiency syndrome.
PMID- 10758165
TI - Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway
critical for transformation.
AB - NF-kappaB is regulated by inhibitor proteins (IkappaBs), which retain NF-kappaB
in the cytoplasm. Signal-induced phosphorylation by the IkappaB-kinase complex
containing the IkappaB-kinases 1 and 2 (IKK-1/2 or IKK-alpha/beta) and subsequent
degradation of the IkappaB proteins are prerequisites for NF-kappaB activation.
Many signals induce NF-kappaB, one of them being oncogenic Raf kinase. We
investigated whether NF-kappaB induction is critical for Raf-mediated
transformation. Here, we demonstrate that inhibition of NF-kappaB interferes with
transformation by the Raf-oncogene, and we characterized the mechanism of NF
kappaB induction by activated Raf kinase and the tumor promoter phorbol 12
myristate 13-acetate (PMA). NF-kappaB activation by PMA and Raf critically
depends on the IkappaB-kinase complex, most notably on IKK-2. A major signaling
pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However,
different inhibitors of this cascade do not affect PMA- and Raf-mediated NF
kappaB activation. Raf does not phosphorylate the IkappaB-kinase proteins
directly. Raf rather synergizes with another membrane shuttle kinase MEKK1, and
Raf-mediated activation of NF-kappaB is blocked by a dominant negative form of
MEKK1. These results suggest that Raf induction of NF-kappaB is relayed by MEKK1,
but not by the classical mitogenic cytoplasmic kinase cascade.
PMID- 10758166
TI - Adenovirus-mediated gene transfer of endostatin in vivo results in high level of
transgene expression and inhibition of tumor growth and metastases.
AB - Inhibition of angiogenesis has been shown to be an effective strategy in cancer
therapy in mice. However, its widespread application has been hampered by
difficulties in the large-scale production of the antiangiogenic proteins. This
limitation may be resolved by in vivo delivery and expression of the
antiangiogenic genes. We have constructed a recombinant adenovirus that expresses
murine endostatin that is biologically active both in vitro, as determined in
endothelial cell proliferation assays, and in vivo, by suppression of
angiogenesis induced by vascular endothelial growth factor 165. Persistent high
serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after
systemic administration of the vector to nude mice, which resulted in significant
reduction of the growth rates and the volumes of JC breast carcinoma and Lewis
lung carcinoma (P < 0.001 and P < 0.05, respectively). In addition, the
endostatin vector treatment completely prevented the formation of pulmonary
micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical
staining of the tumors demonstrated a decreased number of blood vessels in the
treatment group versus the controls. In conclusion, the present study clearly
demonstrates the potential of vector-mediated antiangiogenic gene therapy as a
component in cancer therapy.
PMID- 10758167
TI - The protein translocation channel mediates glycopeptide export across the
endoplasmic reticulum membrane.
AB - Peptides and misfolded secretory proteins are transported efficiently from the
endoplasmic reticulum (ER) lumen to the cytosol, where the proteins are degraded
by proteasomes. Protein export depends on Sec61p, the ribosome-binding core
component of the protein translocation channel in the ER membrane. We found that
prebinding of ribosomes abolished export of a glycopeptide from yeast microsomes.
Deletion of SSH1, which encodes a ribosome-binding Sec61p homologue in the ER,
had no effect on glycopeptide export. A collection of cold-sensitive sec61
mutants displayed a variety of phenotypes: two mutants strongly defective in
misfolded protein export from the ER, sec61-32 and sec61-41, displayed only minor
peptide export defects. Glycopeptide export was severely impaired, however, in
several sec61 mutants that were only marginally defective in misfolded protein
export. In addition, a mutation in SEC63 strongly reduced peptide export from the
ER. ER-luminal ATP was required for both misfolded protein and glycopeptide
export. We conclude that the protein translocation channel in the ER membrane
mediates glycopeptide transport across the ER membrane.
PMID- 10758168
TI - Protection from nitrosative stress by yeast flavohemoglobin.
AB - Yeast hemoglobin was discovered close to half a century ago, but its function has
remained unknown. Herein, we report that this flavohemoglobin protects
Saccharomyces cerevisiae from nitrosative stress. Deletion of the flavohemoglobin
gene (YHB1) abolished the nitric oxide (NO)-consuming activity of yeast cells.
Levels of protein nitrosylation were more than 10-fold higher in yhb1 mutant
yeast than in isogenic wild-type cells after incubation with NO donors. Growth of
mutant cells was inhibited by a nitrosative challenge that had little effect on
wild-type cells, whereas the resistance of mutant cells to oxidative stress was
unimpaired. Protection conferred by yeast flavohemoglobin against NO and S
nitrosothiols was seen under both anaerobic and aerobic conditions, consistent
with a primary function in NO detoxification. A phylogenetic analysis indicated
that protection from nitrosative stress is likely to be a conserved function
among microorganismal flavohemoglobins. Flavohemoglobin is therefore a potential
target for antimicrobial therapy.
PMID- 10758171
TI - Topogenic motifs in P-type ATPases.
PMID- 10758169
TI - A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic
profile in the rat.
AB - The biochemical and behavioral effects of a nonpeptidic, selective, and brain
penetrant agonist at the ORL1 receptor are reported herein. This low molecular
weight compound [(1S,3aS)-8- (2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)-1-phenyl
1,3,8-triaza- spiro[4. 5]decan-4-one] has high affinity for recombinant human
ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the
opioid receptor family. It is a full agonist at these receptors and elicits dose
dependent anxiolytic-like effects in a set of validated models of distinct types
of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle,
and operant conflict). When given systemically, the compound has an efficacy and
potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or
diazepam. However, this compound is differentiated from a classical
benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity,
absence of anticonvulsant properties, and lack of effects on motor performance
and cognitive function at anxiolytic doses (0.3 to 3 mg/kg i.p.). No significant
change in intracranial self-stimulation performance and pain reactivity was
observed in this dose range. Higher doses of this compound (>/=10 mg/kg) induced
disruption in rat behavior. These data confirm the notable anxiolytic-like
effects observed at low doses with the orphanin FQ/nociceptin neuropeptide given
locally into the brain and support a role for orphanin FQ/nociceptin in adaptive
behavioral fear responses to stress.
PMID- 10758170
TI - HIV-1 gp120 and chemokines activate ion channels in primary macrophages through
CCR5 and CXCR4 stimulation.
AB - HIV type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for
entry into target cells. Here we show that the HIV-1 envelope gp120 (Env)
activates multiple ionic signaling responses in primary human macrophages, which
are important targets for HIV-1 in vivo. Env from both CCR5-dependent JRFL (R5)
and CXCR4-dependent IIIB (X4) HIV-1 opened calcium-activated potassium (K(Ca)),
chloride, and calcium-permeant nonselective cation channels in macrophages. These
signals were mediated by CCR5 and CXCR4 because macrophages lacking CCR5 failed
to respond to JRFL and an inhibitor of CXCR4 blocked ion current activation by
IIIB. MIP-1beta and SDF-1alpha, chemokine ligands for CCR5 and CXCR4,
respectively, also activated K(Ca) and Cl(-) currents in macrophages, but
nonselective cation channel activation was unique to gp120. Intracellular Ca(2+)
levels were also elevated by gp120. The patterns of activation mediated by CCR5
and CXCR4 were qualitatively similar but quantitatively distinct, as R5 Env
activated the K(Ca) current more frequently, elicited Cl(-) currents that were
approximately 2-fold greater in amplitude, and elevated intracellular Ca(+2) to
higher peak and steady-state levels. Env from R5 and X4 primary isolates evoked
similar current responses as the corresponding prototype strains. Thus, the
interaction of HIV-1 gp120 with CCR5 or CXCR4 evokes complex and distinct
signaling responses in primary macrophages, and gp120-evoked signals differ from
those activated by the coreceptors' chemokine ligands. Intracellular signaling
responses of macrophages to HIV-1 may modulate postentry steps of infection and
cell functions apart from infection.
PMID- 10758172
TI - Acetylcholine receptor gating is influenced by the polarity of amino acids at
position 9' in the M2 domain.
AB - Ligand-gated ion channels contain a conserved leucine at position 9' (L9') in the
M2 transmembrane domain. We used multiple substitutions at this position in the
gamma subunit of the mouse acetylcholine receptor (AChR) (gammaL9') to examine
the role of residue polarity at this position in the gating process at both the
macroscopic and single-channel levels. The midpoint of the macroscopic dose
response relationship (EC(50)) and the channel closing rate constant, alpha,
decreased as the polarity of the residue at that position increased, suggesting a
stabilization of the open state of the channel. Both parameters showed similar
dependencies on the polarity of the substituted residue. These data support the
notion that during AChR gating, the amino acid at the 9' position moves into a
polar environment, and that interactions between this residue and the polar
environment determine the stability of the open state. Since this residue is
conserved in all other members of the ligand-gated ion channel family, we suggest
that a similar mechanism applies to the other members of the family.
PMID- 10758173
TI - Mutants of the lactose carrier of Escherichia coli which show altered sugar
recognition plus a severe defect in sugar accumulation.
AB - Lactose and melibiose are actively accumulated by the wild-type Escherichia coli
lactose carrier, which is an integral membrane protein energized by the proton
motive force. Mutants of the E. coli lactose carrier were isolated by their
ability to grow on minimal plates with succinate plus IPTG in the presence of the
toxic lactose analog beta-thio-o-nitrophenylgalactoside (TONPG). TONPG-resistant
mutants were streaked on melibiose MacConkey indicator plates, and red clones
were picked. These melibiose positive mutants were then streaked on lactose
MacConkey plates, and white clones were picked. Transport assays indicated that
the mutants had altered sugar recognition and a defect in sugar accumulation. The
mutants had a poor apparent K(m) for both lactose and melibiose in transport. One
mutant had almost no ability to take up lactose, but melibiose downhill transport
was 58% (V(max)) of normal. All of the mutants accumulated methyl-alpha-d
galactopyranoside (TMG) to only 8% or less of normal, and two failed to
accumulate. Immunoblot analysis of the mutant lactose carrier proteins indicated
that loss of sugar transport activity was not due to loss of expression in the
membrane. Nucleotide sequencing of the lacY gene from the mutants revealed
changes in the following amino acids of the lactose carrier: M23I, W151L, G257D,
A295D and G377V. Two of the mutants (G257D and G377V) are novel in that they
represent the first amino acids in periplasmic loops to be implicated with
changes in sugar recognition. We conclude that the amino acids M23, W151, G257,
A295 and G377 of the E. coli lactose carrier play either a direct or an indirect
role in sugar recognition and accumulation.
PMID- 10758174
TI - Gating and permeation in ion channels formed by gramicidin A and its dioxolane
linked dimer in Na(+) and Cs(+) solutions.
AB - The association of two gramicidin A (gA) peptides via H-bonds in lipid bilayers
causes the formation of an ion channel that is selective for monovalent cations
only. In this study, two gAs were covalently linked with a dioxolane group (SS
dimer). Some functional properties of natural gA channels were compared to that
synthetic dimer in Na(+)- or Cs(+)-containing solutions. The SS dimer remained in
the open configuration most of the time, while natural gA channels had a
relatively brief mean open time. Single channel conductances to Na(+) (g(Na)) or
Cs(+) (g(Cs)) in the SS dimer were smaller than in natural gA. However, g(Na) was
considerably more attenuated than g(Cs). This probably results from a tight
solvation of Na(+) by the dioxolane linker in the SS channel. In Cs(+) solutions,
the SS had frequent closures. By contrast, in Na(+) solutions the synthetic dimer
remained essentially in the open state. The mean open times of SS channels in
different solutions (T(open, Na) > T(open,Cs) > T(open,H)) were inversely
proportional to the single channel conductances (g(H) > g(Cs) > g(Na)). This
suggests that ion occupancy inside the pore stabilizes the open configuration of
the gA dimer. The mean closed time of the SS dimer was longer in Cs(+) than in
H(+) solutions. Possible mechanisms for these effects are discussed.
PMID- 10758175
TI - Substrate selectivity and pH dependence of KAAT1 expressed in Xenopus laevis
oocytes.
AB - When expressed in Xenopus oocytes KAAT1 increases tenfold the transport of l
leucine. Substitution of NaCl with 100 mm LiCl, RbCl or KCl allows a reduced but
significant activation of l-leucine uptakes. Chloride-dependence is not strict
since other pseudohalide anions such as thyocyanate are accepted. KAAT1 is highly
sensitive to pH. It can transport l-leucine at pH 5.5 and 8, but the maximum
uptake has been observed at pH 10, near to the physiological pH value, when amino
and carboxylic groups are both deprotonated. The pH value mainly influences the
V(max) in Na(+) activation curves and l-leucine kinetics. The kinetic parameters
are K(mNa) = 4.6 +/- 2 mm, V(maxNa) = 14.8 +/- 1.7 pmol/oocyte/5 min for pH 8.0
and K(mNa) = 2. 8 +/- 0.7 mm, V(maxNa) = 31.3 +/- 1.9 pmol/oocyte/5 min for pH
10.0. The kinetic parameters of l-leucine uptake are: K(m) = 120.4 +/- 24. 2
microm, V(max) = 23.2 +/- 1.4 pmol/oocyte/5 min at pH 8.0 and K(m) = 81.3 +/-
24.2 microm, V(max) = 65.6 +/- 3.9 pmol/oocyte/5 min at pH 10.0. On the basis of
inhibition experiments, the structural features required for KAAT1 substrates
are: (i) a carboxylic group, (ii) an unsubstituted alpha-amino group, (iii) the
side chain is unnecessary, if present it should be uncharged regardless of length
and ramification.
PMID- 10758176
TI - Regulatory processes on the cytoplasmic surface of the Na(+)/Ca(2+) exchanger
from lobster exoskeletal muscle.
AB - A partially purified preparation of the lobster muscle Na(+)/Ca(2+) exchanger was
reconstituted with, presumably, random orientation in liposomes. Ca(2+) efflux
from (45)Ca-loaded vesicles was studied in exchanger molecules in which the
transporter cytoplasmic surface was exposed to the extravesicular (ev) medium.
Extravesicular Na(+) (Na(ev))-dependent Ca(2+) efflux depended directly upon the
extravesicular Ca(2+) concentration ([Ca(2+)](ev)) with a half-maximal activation
at [Ca(2+)](ev) = 0.6 microm. This suggests that the lobster muscle exchanger is
catalytically upregulated by cytoplasmic Ca(2+), as in most other species. In
contrast, at low [Na(+)](ev), the Ca(ev)-binding site (i.e., on the cytoplasmic
surface) for Ca(2+) transported via Ca(2+)/Ca(2+) exchange was half-maximally
activated by about 7.5 microm Ca(2+). Mild proteolysis of the Na(+)/Ca(2+)
exchanger by alpha-chymotrypsin also upregulated the Na(ev)-dependent Ca(2+)
efflux. Following proteolytic digestion in Ca-free medium, the exchanger was no
longer regulated by nontransported ev Ca(2+). Proteolytic digestion in the
presence of 1.9 microm free ev Ca(2+), however, induced only a 1. 6-fold
augmentation of Ca(2+) efflux, whereas, after digestion in nominally Ca-free
medium, a 2.3-fold augmentation was observed; Ca(2+) also inhibited proteolytic
degradation of the Na(+)/Ca(2+) exchanger measured by immunoblotting. These data
suggest that Ca(2+), bound to a high affinity binding site, protects against the
activation of the Na(+)/Ca(2+) exchanger by alpha-chymotrypsin. Additionally, we
observed a 6-fold increase in the Na(+)/Ca(2+) exchange rate, on average, when
the intra- and extravesicular salt concentrations were increased from 160 to 450
mm, suggesting that the lobster muscle exchanger is optimized for transport at
the high salt concentration present in lobster body fluids.
PMID- 10758178
TI - Is H(2) the Universal Energy Source for Long-Term Survival?
AB - This review revisits anabiosis (cryptobiosis or latent life); but more
specifically with the discrepancy (time factor) between the finding of viable
bacteria in ancient material and the racemization of amino acids and depurination
of DNA that would have contributed to their death. The omnipresence of H(2) in
the biosphere since life began, its ability to penetrate the microbial cell, its
low energy of activation, its ability to form protons and electrons in the
presence of Fe(II), and its (including electrons and protons) role in many
biochemical reactions make H(2) the best candidate as the energy of survival for
microbial cells. Although the concentration of H(2) in most environments is below
the threshold level for microbial growth, the surviving cells have a long period
of time to carry out the necessary metabolism to offset the racemization and
depurination processes. This paper explores a hypothesis that explains this
discrepancy.
PMID- 10758177
TI - Lateral microheterogeneity of diphenylhexatriene-labeled choline phospholipids in
the erythrocyte ghost membrane as determined by time-resolved fluorescence
spectroscopy.
AB - Choline phospholipids are the major constituents of the outer layer of the
erythrocyte membrane. To investigate their lateral membrane organization we
determined the fluorescence lifetime properties of diphenylhexatriene analogues
of phosphatidylcholine, choline plasmalogen, (the respective enolether
derivative), and sphingomyelin inserted into the outer layer of hemoglobin-free
ghosts. Fluorescence lifetimes were recorded by time-resolved phase and
modulation fluorometry and analyzed in terms of Continuous Lorentzian
distributions. To assess the influence of membrane proteins on the fluorescence
lifetime of the labeled lipids in the biomembrane, lipid vesicles were used as
controls. In general, the lifetime distributions in the ghost membranes are broad
compared to vesicles. Phosphatidylcholine and sphingomyelin exhibit very similar
lifetime distributions in contrast to an increased plasmalogen lifetime
heterogeneity in both systems. Orientational effects of side chain mobilities on
the observed lifetimes can be excluded. Fluorescence anisotropies revealed
identical values for all three labeled phospholipids in the biomembrane.
PMID- 10758179
TI - Theoretical Analysis of the Starvation Response under Substrate Pulses.
AB - A simulation model was constructed in which two model bacteria competed with each
other in a closed system to which periodic substrate additions were made. One
bacterium responded to starvation by entering into a dormant state characterized
by a decreased death rate; the other bacterium did not make this transition. The
periodicity of substrate addition was varied, and the magnitude of selection for
one bacterial type was calculated. For model parameters typical of those measured
in Escherichia coli, positive selection for the bacterium capable of the
starvation response only occurred if the time interval of substrate addition
exceeded 54 times the minimum doubling time of the bacterium. The magnitude of
the selection coefficient was most sensitive to two model parameters: the time
constant for conversion of dormant cells back to actively growing ones, and the
magnitude of the death rate of cells which did not undergo the starvation
response.
PMID- 10758180
TI - Effects of Carbon Source, Carbon Concentration, and Chlorination on Growth
Related Parameters of Heterotrophic Biofilm Bacteria.
AB - To investigate growth of heterotrophic biofilm bacteria, a model biofilm reactor
was developed to simulate a drinking water distribution system. Controlled
addition of three different carbon sources (amino acids, carbohydrates, and
humics) at three different concentrations (500, 1,000, and 2,000 ppb carbon) in
the presence and absence of chlorine were used in separate experiments. An
additional experiment was run with a 1:1:2 mixture of the above carbon sources.
Biofilm and effluent total and culturable cells in addition to total and
dissolved organic carbon were measured in order to estimate specific growth rates
(SGRs), observed yields, population densities, and bacterial carbon production
rates. Bacterial carbon production rates (ug C/L day) were extremely high in the
control biofilm communities (range = 295-1,738). Both growth rate and yield
decreased with increasing carbon concentrations. Therefore, biofilm growth rates
were zero-order with respect to the carbon concentrations used in these
experiments. There was no correlation between growth rate and carbon
concentration, but there was a significant negative correlation between growth
rate and biofilm cell density (r = -0.637, p = 0.001 control and r = -0.57, p =
0.021 chlorinated biofilms). Growth efficiency was highest at the lowest carbon
concentration (range = 12-4.5%, amino acids and humics respectively). Doubling
times ranged from 2.3-15.4 days in the control biofilms and 1-12.3 days in the
chlorinated biofilms. Growth rates were significantly higher in the presence of
chlorine for the carbohydrates, humics, and mixed carbon sources (p = 0.004, <
0.0005, 0.013, respectively). The concept of r/K selection theory was used to
explain the results with respect to specific growth rates and yields. Humic
removal by the biofilm bacteria (78% and 56% for the control and chlorinated
biofilms, respectively) was higher than previously reported literature values for
planktonic bacteria. A number of control experiments indicated that filtration of
drinking water was as effective as chlorination in controlling bacterial biofilm
growth.
PMID- 10758181
TI - Quantitation of the Population Size and Metabolic Activity of a Resin Acid
Degrading Bacterium in Activated Sludge Using Slot-Blot Hybridization to Measure
the rRNA:rDNA Ratio.
AB - The 16S rRNA:rDNA ratio is a useful parameter for measuring metabolic activity of
a selected member of a complex microbial community, as in pulp effluent activated
sludge systems. The RNA:DNA ratio of Sphingomonas sp. DhA-33, previously isolated
from a sequencing batch reactor treating pulp mill effluent, is positively
correlated with its growth rate (u) under steady-state conditions. DhA-33 was
grown in a chemostat with growth rates ranging from 0.04 to 0.15 cell divisions
per hour. DhA-33 was also able to degrade dehydroabietic acid in bleached kraft
mill effluent (BKME) plus mineral medium in batch culture. Slot-blot
hybridization with radioactively labeled species-specific oligonucleotide probes
for 16S rRNA and 16S rDNA was used to measure rRNA, rDNA, and the RNA:DNA ratio
of this strain when in a mixed sludge community. An increase in DhA-33 rDNA
indicated growth of DhA-33 within the community. The RNA:DNA ratio of DhA-33
increased sharply during exponential growth and declined as cells entered
stationary phase. The RNA:DNA ratio decreased earlier and faster in DhA-
33/sludge co-cultures than in DhA-33 pure cultures, presumably due to an earlier
depletion of nutrients. The species-specific quantification of the RNA:DNA ratio
makes it possible to estimate the metabolic activity of selected members of a
microbial community in situ.
PMID- 10758182
TI - Microbial Responses to Environmentally Toxic Cadmium.
AB - We analyzed the soil microbial communities from one uncontaminated and two metal
impacted soils and found that while cadmium adversely affected the numbers of
culturable bacteria in all soils, cadmium-resistant isolates were found from each
of the soils. With exposure to 24 and 48 ug ml(-1) soluble cadmium, the metal
contaminated soil communities were more resistant than the uncontaminated soil
community. In addition, in one metal-stressed soil, the resistant population
became more resistant with increased cadmium levels. Ribosomal 16S DNA sequencing
identified the isolates as Arthrobacter, Bacillus, or Pseudomonas spp. Further
characterization demonstrated that two of the isolates were highly resistant to
soluble cadmium with maximum resistance at 275 ug ml(-1) cadmium. These isolates
were also resistant to a variety of antibiotics, namely ampicillin, gentamicin,
penicillin, and streptomycin, but no overall correlation was found between
enhanced antibiotic resistance and cadmium resistance. One Pseudomonas isolate H1
did become more resistant with increasing cadmium levels, suggesting a different
resistance mechanism at high cadmium concentrations.
PMID- 10758183
TI - Use of 16S-rRNA Based Techniques to Investigate the Ecological Succession of
Microbial Populations in the Immature Lamb Rumen: Tracking of a Specific Strain
of Inoculated Ruminococcus and Interactions with Other Microbial Populations in
Vivo.
AB - The establishment of microorganisms in the rumen is a critical step if rumen
manipulation is to be accomplished by use of microbial inoculants. Microbial
populations in the maturing rumen undergo successional changes and, while in a
state of flux, provide a possible opportunity for the introduction of specific
strains of bacteria. While the rumen of the young lamb was maturing, we measured
changes in several microbial populations with 16S-rRNA specific oligonucleotides:
Rumincoccus, Fibrobacter, eukaryotes, Gram-positive bacteria, the Bacteroides
Porphromonas-Prevotella group, and anaerobic rumen fungi. In this study we
repeatedly dosed 15 lambs with approximately 3.4 x 10(8) to 0.8 x 10(9)
Ruminococcus cells dose(-1), twice a week, for 7 wk from 23 d to 63 d of age. Of
the five Ruminococcus strains dosed (R. albus SY3 and AR67, and R. flavefaciens
Y1, LP9155, and AR72) the most specific primers (based on 16S rDNA) were obtained
for strain SY3. There was an increase in the eukaryotic population during dosing,
and it was hypothesized that protozoal predation contributed to the disappearance
of strain SY3. At the end of dosing PCR amplification showed that SY3 were
approximately 10(9) cells ml(-1), but decreased to below the detection limit of
the PCR system (8.6 x 10(4) ml(-1)) within 28 d postdosing. These experiments
showed that fibrolytic populations increased significantly (P < 0.1) above the
controls during the dosing period and were elevated for several days postdosing.
This suggests that dosing of highly fibrolytic bacteria makes more of the fiber
available to other organisms able to degrade fiber, and in so doing increases the
overall fibrolytic activity of the rumen. Examination of the succession of gram
positive bacteria and the Bacteroides-Porphromonas-Prevotella group showed a
decline in relative abundance as the lambs matured.
PMID- 10758184
TI - The Distribution of Microbial Communities in Anaerobic and Aerobic Zones of a
Shallow Coastal Plain Aquifer.
AB - Randomly amplified polymorphic DNA (RAPD) fingerprinting was used to determine
the genetic similarity of whole-community DNA extracts from unattached
microorganisms in several groundwater wells. The study site was a shallow coastal
plain aquifer on the Eastern Shore of Virginia that contains distinct regions of
anaerobic and aerobic groundwater. Several wells in each region were sampled, and
principal component and cluster analyses showed a clear separation of the
microbial communities from the two chemical zones of the aquifer. Within these
zones, there was no relationship between the genetic relatedness of a pair of
communities and their spatial separation. Two additional sets of samples were
taken at later times, and the same clear separation between communities in the
different zones of the aquifer was observed. The specific relationships between
wells within each zone changed over time, however, and the magnitude and
direction of these changes corresponded to concurrent changes in the groundwater
chemistry at each well. Together, these results suggest that local variation in
groundwater chemistry can support genetically distinct microbial communities, and
that the composition of the microbial communities can follow seasonal
fluctuations in groundwater chemistry.
PMID- 10758185
TI - Effect of Introduced Pseudomonas fluorescens Strains on Soil Nematode and
Protozoan Populations in the Rhizosphere of Wheat and Pea.
AB - Previous studies have shown that inoculation of pea seeds with Pseudomonas
fluorescens strains F113lacZY or F113G22 increased mineralization of organic
nitrogen in the rhizosphere. In contrast, inoculation of the same strains onto
wheat seeds reduced mineralization of N from organic residues incorporated into
soil. In the present study, we report on a likely explanation of this phenomenon,
which appears to be governed by the effect of plant-microbe interactions on
bacterial-feeding nematodes and protozoa. In soil microcosm tests, inoculation of
pea seeds with Pseudomonas fluorescens strains F113lacZY or F113G22 resulted in
an increase in the number of nematodes and protozoa in the rhizosphere as
compared to noninoculated controls. This trend was repeated using a model sand
system into which the bacteriophagous nematode Caenorhabditis elegans was
introduced. It was subsequently found that non-inoculated germinating pea seeds
exerted a nematicidal effect on C. elegans, which was remedied by inoculation
with either strain F113lacZY or F113G22. This suggests that nematicidal compounds
released by the germinating pea seeds were metabolized by the microbial
inoculants before they affected nematode populations in the spermosphere or
rhizosphere of pea. In contrast, inoculation of wheat plants resulted in
significantly lower nematode populations in the rhizosphere, whereas protozoan
numbers were unaffected. No nematicidal effects of inoculated or noninoculated
wheat seeds could be found, suggesting that microfaunal populations were affected
at a later stage during plant growth. Because of their key roles in accelerating
the turnover of microbially immobilized N and organic matter, plants that support
a larger microfaunal population are likely to benefit from a higher availability
of inorganic nitrogen. Therefore, an understanding of plant-microbe interactions
and their effects on soil microfaunal populations is essential in order to assess
the effects of microbial inocula on plant mineral nutrition.
PMID- 10758186
TI - Pneumonia in stroke patients: a retrospective study.
AB - This is a retrospective study of 378 consecutive stroke patients who were
referred between June 1994 and June 1997 for videofluorographic study of
oropharyngeal swallow. Patients who had radiation therapy, brain tumor, brain
surgery, head and/or spinal cord trauma, oral-pharyngeal disease or surgery, or
other neurologic diseases in addition to the stroke were excluded from the study.
Patients were assigned to two groups: one with pneumonia and one without
pneumonia. One hundred one patients were included in the pneumonia group, and 277
patients were included in the nonpneumonia group. Within the pneumonia group,
patients were assigned to an acute pneumonia group (pneumonia within 6 months
poststroke) and a chronic pneumonia group (pneumonia more than 6 months
poststroke). Variables examined in the study included patients' medical history
and the findings from the videofluorographic studies. Pearson chi-square analysis
was used to identify those variables that were significantly different between
the pneumonia and nonpneumonia patient groups and between the acute and chronic
pneumonia groups. Results showed that stroke patients who developed pneumonia had
a significantly higher incidence of multiple-location and unspecified lesion
strokes, chronic airway disease in their medical history, and aspiration during
the videofluorographic studies when compared with patients who did not develop
pneumonia. Within the pneumonia group, the acute pneumonia group was found to
have a significantly higher incidence of hypertension and diabetes in their
medical history and a significantly higher incidence of aspiration and reduced
laryngeal elevation during the videofluorographic studies. Between 48% and 55% of
all stroke patients in the study aspirated. Patients who suffered multiple
strokes, brainstem stroke, or subcortical stroke had the greatest frequency of
aspiration.
PMID- 10758187
TI - Inter- and intrajudge reliability of a clinical examination of swallowing in
adults.
AB - This study investigates inter- and intrajudge reliability of a clinical
examination of swallowing in adults. Several investigations have sought
correlations between clinical indicators of dysphagia and the actual presence of
dysphagia as determined by videofluoroscopy. Whereas some investigations have
reported interjudge reliability for the videofluoroscopic measures employed, none
have reported reliability for clinical measures. Without established reliability
for rating clinical measures, conclusions drawn regarding the utility of a
measure for detecting aspiration can be called into question. Results of the
present study indicate that fewer than 50% of the measures clinicians typically
employ are rated with sufficient inter- and intrajudge reliability. Measures of
vocal quality and oral motor function were rated more reliably than were history
measures or measures taken during trial swallows. There is a need to define more
clearly the measures employed in clinical examinations and to be consistent in
reporting reliability for clinical measures of swallowing function in future
research.
PMID- 10758188
TI - Comparison of dysphagics and nondysphagics on pulse oximetry during oral feeding.
AB - This study was designed to determine whether significant differences in SpO(2)
levels existed among elderly individuals with dysphagia, and, more specifically,
whether pulse oximetry can discriminate dysphagic from nondysphagic individuals.
In addition, differences in SpO(2) between liquid aspirators, solid aspirators,
laryngeal penetrators, and normals was investigated in a sample of 181 subjects,
104 of whom were dysphagic. Results indicated that aspirators had lower SpO(2)
levels before, during, and after feeding compared with nonaspirators. Solid
aspirators were the most compromised. No relation was found between SpO(2) levels
and aspiration. Pulse levels rose for all subjects from before to during feeding,
declining slightly thereafter. These data were consistent with previous findings
that dysphagics have compromised pulmonary systems but at variance with studies
that indicated changes in pulse oximetry during aspiration.
PMID- 10758189
TI - Timing of events in normal swallowing: a videofluoroscopic study.
AB - Dynamic videofluoroscopic swallow studies were performed on 60 normal adult
volunteers to establish normative data for clinically useful timing measures. The
relation of swallowing gesture timing to the timing of actual bolus transit was
of particular interest because it provides insight into the physiology of larger
bolus volume accommodation. Parameters evaluated include the timing of bolus
pharyngeal transit, soft palate elevation, aryepiglottic fold elevation and
supraglottic closure, arrival of the bolus in the vallecula, hyoid bone
displacement onset and duration, arrival of the bolus at the pharyngoesophageal
sphincter, maximum pharyngeal constriction, and pharyngoesophageal sphincter
opening. These parameters represent events required for normal deglutition, can
be used to identify abnormalities in dysphagic patients, and provide a basis for
comparison of swallowing performance both within and between patients. In
addition, our experience has shown them to be reliably obtained. Other
investigators have reported some of the measurements. However, to our knowledge,
normative data for timing of aryepiglottic fold elevation, soft palate elevation
and closure, and maximum pharyngeal constriction have not been described. Other
measures included in the present study may provide alternatives when conventional
measures cannot be obtained in selected patients. The relevance and clinical
utility of new and alternative measures, in particular, are discussed.
PMID- 10758190
TI - "Wet Voice" as a predictor of penetration and aspiration in oropharyngeal
dysphagia.
AB - This article describes the results of a study that investigated how well wet
phonation can predict penetration and/or aspiration of ingested material in
dysphagic patients. Voice samples of 23 subjects with neurologic oropharyngeal
dysphagia were collected immediately after each subject had swallowed nine
different boluses on videofluoroscopy. The boluses were graded according to three
different consistencies and three different sizes. The presence of wetness in the
voice was analyzed in relation to any ingested material that remained in the
larynx or trachea after each bolus was swallowed. Results showed that there was
no association between the presence of a wet voice and penetration or aspiration
of prandial material after a swallow. The importance of detecting wet phonation
by itself was therefore not considered diagnostic in detecting prandial
penetration/aspiration by the bedside, but a wet voice may still be useful in
identifying those with dysphagia who may have laryngeal dysfunction and therefore
may be at risk of penetrating/aspirating any type of material, not just prandial
material.
PMID- 10758191
TI - Respiratory and acoustic signals associated with bolus passage during swallowing.
AB - In order to advance our understanding of the relation between respiration and
deglutition, simultaneous videofluoroscopy and respirodeglutometry was performed.
Fifteen normal, healthy, young adults (20-29 years of age) were connected to a
respirodeglutometer and positioned for simultaneous videofluoroscopic assessment
in the lateral plane. Subjects performed three swallows each of a 5-ml and a 10
ml bolus of liquid barium and a 5-ml bolus of paste barium, for a total of nine
swallows per subject. Location of the bolus head as identified with
videofluoroscopy was associated with eight respirodeglutometric variables. In
addition, temporal relations for seven respirodeglutometric variables were
calculated as a function of bolus volume and viscosity. Significant temporal
differences were found for five of the variables by volume. No significant
temporal differences were noted by viscosity. Expiration occurred before 79% and
after 96% of the swallows. The number of inspirations preceding a swallow
suggested a possible effect resulting from the need to hold a bolus in the mouth
before receiving instructions to swallow during videofluoroscopic assessment.
This effect may be important during patient evaluation. For a significant number
of swallows, respiratory flow ceased before the velum was fully elevated.
PMID- 10758197
TI - Vascular Clips in Anastomoses of Femoropopliteal Arterial Reconstruction.
AB - The vascular anastomoses are usually made with sutures. Some mainly experimental
studies have been published about a new method of doing the vascular anastomoses
with metal clips. We studied the suitability of vascular closure staple (VCS)
clip applier system for making the anastomoses in femoropopliteal and
femorotibial arterial reconstruction. During an 11-month period, VCS clips were
used in 17 out of 27 patients who were operated due to severe claudication or
incipient gangrena of the foot. Altogether 26 anastomoses were made with VCS
clips using either great saphenous vein or PTFE graft. The making of anastomosis
was easy and reliable. No postoperative bleeding was noticed. All anastomoses
were patent 4-6 weeks postoperatively studied by palpation and measured by ankle
brachial pressure index (mean 0.96). In Duplex Doppler examination all studied
patients had well patent anastomoses on an average 11 months after the operation.
With VCS clip applier system, it is possible to do anastomoses in
arteriosclerotic arteries like in femoropopliteal reconstructions. This method
helps making reliable anastomoses more easily.
PMID- 10758196
TI - Abnormal Peripheral Vasodilatory Reserve Without Endothelial Dysfunction in
Patients With Aortic Dissection.
AB - Structural changes in the aortic wall have been reported to be present in aortic
dissection (AD), while there have been no investigations concerning peripheral
vasomotion characteristics. Peripheral arterial stiffness is an important factor
in the regulation of the central aortic pressure because it produces excessive
wave reflection. The present study investigated in AD patients endothelium
dependent peripheral vasodilation and the reactive hyperemic response which is
considered to be altered by the structural abnormality of the peripheral
resistance artery. Forearm blood flow (FBF) changes induced by intra-arterial
infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and by occlusion
induced reactive hyperemia (RH) were measured plethysmographically in 10 AD
patients, 7 healthy volunteers, and 7 patients with uncomplicated hypertension
(UHT). There were no significant differences in the peak FBF response to ACh and
SNP infusion for the three groups (ACh, 14.2 +/- 1.8 vs 17.2 +/- 4.5 vs 15.7 +/-
2.3 ml/min/dl tissue, NS; SNP 9.5 +/- 1.3 vs 10.6 +/- 1.7 vs 11.9 +/- 0.8 vs
ml/min/dl tissue, NS). In the case of RH, however, peak FBF and maximum
conductance were significantly lower in AD patients than in healthy volunteers
and UHT patients (21.1 +/- 2.6 vs 36.1 +/- 4.7 and 32.4 +/- 2.6 ml/min/dl tissue
volume, p < 0.01, and 0.25 +/- 0.03 vs 0.46 +/- 0.06 and 0.37 +/- 0.03 ml/min/dl
per mmHg, p < 0.05, respectively). Peripheral vasodilatory function depending on
the endothelium and smooth muscle in AD patients was not significantly different
from that in healthy volunteers and UHT patients. However, reactive hyperemic
vasodilatory reserve, which is a well-established, noninvasive measure of
arterial structure, was significantly impaired in AD. These findings indicate
that arterial structural abnormalities rather than systemic atherosclerotic
changes represented by endothelial dysfunction may be present. We speculated that
this aspect of peripheral resistance artery might possibly have an unfavorable
effect on the postonset aortic conditions in AD patients.
PMID- 10758198
TI - The Clinical Importance of Risk Factor Modification: Looking at Both Myocardial
Viability (MV) and Myocardial Perfusion Imaging (MPI).
AB - Determination of changes in coronary artery disease (CAD) following risk factor
modification (lipid lowering and stress reduction) have focused only on changes
in myocardial blood flow (Q)/myocardial perfusion imaging (MPI) and not
myocardial viability (MV). To determine the outcome of each and to determine if
there are differences in myocardial viability versus coronary blood flow, 31
people were studied for 1 year with comparison of baseline and 1-year PET
results. One subject underwent an additional 2-year follow-up study, providing a
total of 32 comparisons. A total of 224 myocardial segments were compared with
improvement in MPI seen in 58 of 224 segments (25.9%), stabilization in 111 of
224 (49.6%) segments, and progression of disease in 55 of 224 (24.6%) segments.
MV improved in 82 of 224 segments (36.6%), showed stabilization in 83 of 224
(37.0%) of the segments, and worsening in 59 (26.3%) of 224 segments. When
improvement in either MPI or MV were added together, improvement was seen in
50.9% (p 60 msec). Infantile nystagmus also does
not cause oscillopsia, possibly because the internal spatial visual map is
reupdated before each phase of this type of nystagmus (efference copy). There is
no foveation period or adequate efference copy reupdate in acquired nystagmus.
Consequently, acquired nystagmus usually results in decreased visual acuity and
oscillopsia. For most forms of treatment, the goal is directed toward stopping
the oscillations or their visual consequences rather than towards the underlying
mechanism. Several treatment modalities have been suggested. The most success has
been found with gabapentin in the treatment of acquired pendular nystagmus and
baclofen in the treatment for acquired periodic alternating nystagmus. There is a
need for multicenter trials to evaluate systematically potential treatments of
the other types nystagmus and oscillations.
PMID- 10758215
TI - Update on hereditary optic neuropathy.
AB - Although no treatment is available for hereditary optic neuropathies, recent
localization and identification of some of the genetic loci have helped the
evaluation and management of patients with these disorders. This article
discusses the clinical features and known genetic information regarding Leber's
hereditary optic neuropathy, dominant optic atrophy, recessive optic atrophy, and
Wolfram syndrome.
PMID- 10758216
TI - Surgical management of ocular motor cranial nerve palsies.
AB - This article reviews the various surgical treatment approaches currently used in
the management of ocular motor cranial nerve palsies. Regardless of the approach,
the final goal is improved alignment, especially in the primary and reading
positions.
PMID- 10758217
TI - Glaucomatous versus nonglaucomatous optic disc cupping: clinical differentiation.
AB - Cupping of the optic nerve head associated with normal intraocular pressure (IOP)
is a common clinical presentation for which clearly defined management guidelines
have not been established. The clinical approach represents a diagnostic
challenge because the mechanism of optic nerve injury is often difficult to
objectively establish. Of paramount importance is the primary distinction between
physiologic cupping and pathologic cupping, and the accurate subclassification of
eyes with pathologic cupping. Therefore, it is essential for clinicians to
differentiate glaucomatous from nonglaucomatous disc damage. This article reviews
the clinical differentiation of eyes with glaucomatous and nonglaucomatous optic
disc cupping.
PMID- 10758218
TI - Giant cell arteritis update.
AB - Giant cell arteritis (GCA) is a systemic disorder characterized by vasculitis
involving medium and large arteries. GCA is an ophthalmologic and systemic
emergency, because devastating consequences, such as blindness and death, can
occur without treatment. With prompt recognition and appropriate treatment,
complications are almost always preventable. The prognosis for recovery of vision
already lost because of GCA is usually poor, underscoring the absolute necessity
of immediate intervention. Knowledge of the various manifestations of GCA is
essential for recognition of this disorder early enough to prevent complications.
This article highlights the important points regarding diagnosis, management, and
complications associated with treatment of GCA.
PMID- 10758219
TI - Introduction
PMID- 10758220
TI - Decreasing retinal photocoagulation damage: principles and techniques.
AB - Conventional suprathreshold retinal photocoagulation is a destructive procedure,
but chorioretinal damage can be decreased by changing laser parameters and
clinical endpoints. Laser effects can be localized by decreasing laser
wavelength, spot size, and exposure duration, as well as by adopting threshold or
subthreshold treatment protocols. Problems with short-pulse treatment regimens
can be circumvented by the use of repetitively pulsed laser photocoagulators.
Preliminary clinical results with reduced-damage photocoagulation methods are
promising and await confirmation in larger, controlled clinical trials.
PMID- 10758221
TI - Micropulse laser in the treatment of diabetic macular edema.
AB - The micropulse laser is a new development in laser therapy. Micropulsing is
frequent short pulses of subthreshold intensity applied to retinal lesions. It
has been shown to be effective in diabetic macular edema, branch vein occlusion,
and drusen. Although the initial landmark studies showed it to be effective, the
exact parameters have not been established. This article illustrates the current
state of its use.
PMID- 10758222
TI - Laser treatment of diabetic macular edema: comparison of ETDRS-level treatment
with threshold-level treatment by using high-contrast discriminant central visual
field testing.
AB - Grid laser is recognized as an extremely effective treatment of diabetic macular
edema, although it causes significant chorioretinal damage when applied and scars
that expand with time. The purpose of this study is to compare the effects of two
methods of grid laser photocoagulation for diabetic macular edema on high
contrast target discrimination in the central visual field. Grid laser
photocoagulation with the Early Treatment Diabetic Retinopathy Study intensity
burns has previously been shown to cause full retinal thickness burns. In this
study, it produced severe destruction of paraxial vision, most marked at 2
degrees to 10 degrees from fixation. Grid laser using threshold-level burns, in
contrast, appeared to produce some improvement in thresholded high-contrast
vision at eccentricities from 2 degrees to 3 degrees outward, but failed to
normalize visual parameters at these intercepts or at intercepts closer to
fixation. Therefore, the recommendations are made (1) to use screening modalities
other than biomicroscopic perception of retinal swelling to define earlier
opportunities for intervention in the diabetic maculopathic process and (2) to
use threshold or sub-threshold methods of laser grid photocoagulation for
treating leakage and/or edema.
PMID- 10758223
TI - The pathogenesis of edema in diabetic maculopathy.
AB - Diabetic maculopathy is characterized by the accumulation of extracellular fluid
in Henle's layer and the inner nuclear layer of the retina. The localization of
the edema is likely to be due, in part, to the relative barrier properties of the
inner and outer plexiform layers. The origin of the extracellular fluid is from
the intravascular compartment. Although changes to retinal blood flow may partly
explain the extravasation of fluid, the most important mechanism is breakdown of
the blood retinal barriers. Both the inner blood retinal barrier formed by the
retinal capillary endothelial cell tight junctions and the outer barrier formed
by the retinal pigment epithelial cell tight junctions can be affected. The
mechanism of breakdown of the blood retinal barriers is likely to be changes to
the tight junction proteins including occludin and ZO-1. The biochemical
messenger inducing these changes may be vascular endothelial growth factor. The
origin of this or other cofactors may be the retinal glial cells. The underlying
biochemical stimulus to the production of vascular endothelial growth factor is
chronic hyperglycaemia, but it is uncertain by what pathway this is effected.
PMID- 10758224
TI - Pathogenetic potential of leukocytes in diabetic retinopathy.
AB - Recently, increasing interest has been directed toward the role of leukocytes in
microvascular disorders including diabetic retinopathy because of their large
cell volume, high cytoplasmic rigidity, natural tendency to stick to the vascular
endothelium, and capacity to generate toxic superoxide radicals and proteolytic
enzymes. Leukocytes in diabetes are reported to be less deformable and more
activated, and may be involved in capillary non-perfusion, endothelial cell
damage, and vascular leakage in the retinal microcirculation. In fact,
histological studies show many capillary occlusions by leukocytes and capillary
dropout or degeneration associated with leukocytes in the diabetic retina. Serial
acridine orange leukocyte fluorography and fluorescein angiography studies also
identify trapped leukocytes directly associated with areas of downstream non
perfusion in the diabetic retinal microcirculation. More recent studies suggest
that adhesion molecules may mediate retinal leukocyte stasis (leukostasis) in
diabetes and a reduction in the leukostasis by anti-adhesion antibodies can
suppress retinal vascular leakage. In addition, some agents inhibiting
leukostasis are reported to improve retinal abnormalities induced by diabetes.
Thus, leukostasis in the retinal microcirculation can be a new promising target
in the treatment of diabetic retinopathy.
PMID- 10758225
TI - Molecular mechanisms of vascular permeability in diabetic retinopathy.
AB - Diabetes leads to a wide array of complications in humans, including kidney
failure, vascular disease, peripheral nerve degeneration, and vision loss.
Diabetic retinopathy causes blindness in more working-age people in the United
States than any other disease and contributes greatly to blindness in the young
and old as well. The increasing rate of diabetes occurring in our society can
only bring about a further decrease in the visual health of this country unless
new modalities are discovered to prevent and cure diabetic retinopathy. Breakdown
of the blood-retinal barrier and the resultant vascular permeability remains one
of the first observable alterations in diabetic retinopathy and strongly
correlates with vision loss. In this article, we examine the molecular components
that form this blood-retinal barrier and explore how changes in the production of
growth factors in the neural parenchyma cause an increase in vascular
permeability and contribute to retinal degeneration.
PMID- 10758226
TI - Diabetic retinopathy in pregnancy: effects on the natural course.
AB - Pregnancy can cause changes in the functioning of the eye in health and in
disease and also affect preexisting ocular conditions, such as diabetic
retinopathy. Progression of retinopathy in pregnancy depends on a variety of
factors, including severity of retinopathy at conception, adequacy of treatment,
duration of diabetes, metabolic control before pregnancy, and the presence of
additional vascular damage (ie, preexisting or concomitant hypertensive
disorder). Developments in medical, obstetrical, and ophthalmologic management of
the pregnant diabetic have greatly improved the prognosis for successful
pregnancies and maintaining vision.
PMID- 10758227
TI - Model-based assessment of pressure and flow-dependent coronary responses
following abrupt pressure drops.
AB - The response of the coronary vasculature to an experimental manoeuvre of step
like decrease of the perfusion pressure has been investigated with a model. The
coronary vasculature was simulated using a 'windkessel' scheme. Proximal
resistance and compliance were assumed to be pressure-independent. The distal
resistance, on the contrary, was controlled by a feed-back loop which accounts
for the smooth muscle activation induced by the pressure variation. Three more
parameters were introduced, and namely the smooth muscle activation time constant
and the pressure-induced and flow-induced gains. The parameter values were
assessed by comparing the model predicted coronary flow with the one actually
measured in animals.
PMID- 10758228
TI - A spreadsheet for the calculation of comprehensive statistics for the assessment
of diagnostic tests and inter-rater agreement.
AB - While advances in statistical methods allow greater insight into the
characteristics of diagnostic tests and of raters, researchers frequently rely on
incomplete or inappropriate indices of performance. Lack of available computer
software is probably an important barrier to optimal use of data collected to
evaluate diagnostic tests and agreement between raters. A spreadsheet has been
designed to provide comprehensive statistics for the assessment of diagnostic
tests and inter-rater reliability when these investigations yield data that can
be summarized in a 2x2 table. As well as a wide range of indices of test or rater
performance, confidence intervals for these quantities are also calculated by the
spreadsheet.
PMID- 10758230
TI - Selective medical image compression techniques for telemedical and archiving
applications.
AB - Selective Image Compression (SeLIC) is a compression technique where explicitly
defined regions of interest (RoI) are compressed in a lossless way whereas image
regions containing unimportant information are compressed in a lossy manner. Such
techniques are of great interest in telemedicine or medical imaging applications
with large storage requirements. In this paper we introduce and compare
techniques with different functionalities. Moreover, we investigate the impact of
using wavelet transforms and JPEG as underlying lossy compression algorithm.
PMID- 10758229
TI - Scale-independent shape analysis for quantitative cytology using mathematical
morphology.
AB - A system for automatic quantification of morphological changes of cell lines,
proposed for cytotoxicity tests of biomaterials, is presented. Light-micrographs
of cultured cells are segmented by adaptive thresholding within a local adaptive
window. Connected cells in binarized micrographs are separated by a novel
morphological multiscale method, treating cells in their size-specific scale and
hence resulting in scale-independent separations. Significant shape descriptors
correlating well with cell toxicity are extracted from single cells. Size and
compactness distributions turned out to be reliable and useful parameters,
providing an alternative to the common subjective grading of shape deformations
by visual inspection. The system is evaluated for several standardized toxical
reference substances and is now in use for clinical biocompatibility testing.
PMID- 10758231
TI - Immunoglobulin production by cultured human lymphocytes.
AB - The synthesis and secretion of immunoglobulin induced in cultured B-lineage cells
is of interest for several reasons: (i) analysing the B-cell repertoire, (ii)
recall of immunological activity retained in the circulating lymphocyte
population, and (iii) study of factors needed for clonal expansion,
immunoglobulin class switching, IgV-region mutation and maturation of cells to Ig
secretion. Methods available are outlined and alternative procedures for cell
separation and purification, helper cell provision and Ab/Ig assay systems are
discussed. The aim is to provide practical guidance for those who intend to begin
work in what is a vitally important, but experimentally difficult, area. There
are a bewildering number of methods described in innumerable publications, old
and new. The review provides a personal assessment of the present state of
knowledge and prospects for improvements when all the new observations relating
to cell-cell interactions and cytokines are integrated into existing
technologies. The survey is chiefly concerned with physiologically based
procedures, but artificial auxiliary methods are also briefly mentioned.
PMID- 10758232
TI - Molecular immunology databases and data repositories.
AB - Over recent years databases have become an extremely important resource for
biomedical research. Immunology research is increasingly dependent on access to
extensive biological databases to extract existing information, plan experiments,
and analyse experimental results. This review describes 15 immunological
databases that have appeared over the last 30 years. In addition, important
issues regarding database design and the potential for misuse of information
contained within these databases are discussed. Access pointers are provided for
the major immunological databases and also for a number of other immunological
resources accessible over the World Wide Web (WWW).
PMID- 10758233
TI - Phagocytosis of yeast: a method for concurrent quantification of binding and
internalization using differential interference contrast microscopy.
AB - In studies of phagocytosis there is a need to distinguish targets that are
internalized by the cell from those that are bound to the cell surface. The
present work describes a simple method by which internalized and surface-bound
yeast particles can be identified by differential interference contrast
microscopy, using trypan blue to stain surface-bound yeast particles. The method
has the advantage that both internalized and surface-bound particles can be
visualized without the need to switch the illumination source and/or filter sets,
thus facilitating concurrent quantitation of binding and internalization. The
method was evaluated with the phagocytosis-modulating agents horseradish
peroxidase (HRP) and cytochalasin D, using adherent resident macrophages as
phagocytic cells. When macrophages are challenged with a particular type of
target, they usually bind many more targets than they ingest. It was shown that
yeast particles were arrested in the initial binding phase of phagocytosis
depending on the region of macrophage plasma membrane where binding sites were
formed. Failure of surface-bound yeast particles to trigger internalization was
not due to modifications of the yeast particle surface. Nor was it due to binding
to non-phagocytic receptors, or low-affinity receptor-ligand interactions. The
glycoprotein HRP inhibited only the binding stage of phagocytosis, whereas
cytochalasin D, a drug that affects actin polymerization, inhibited both binding
and internalization. However, when the yeast particles were pre-incubated in
fresh mouse serum, cytochalasin D inhibited only the internalization step. The
assay described here may be useful in studies concerned with the function and
expression of phagocytosis-mediating surface lectins.
PMID- 10758234
TI - Immunoelectron microscopic detection of tissue ganglioside antigens.
AB - Glycolipid antigens are emerging as important markers of differentiated cells in
vitro and in vivo. The study of the expression of these antigens in whole tissues
by immunoelectron microscopy, using standard techniques, does not give acceptable
results. We have established conditions for the specific demonstration of
antibody binding to tissue glycolipid antigens by immunoelectron microscopy.
Dehydration of tissues with alcohol is to be avoided as it extracts the
glycolipid antigen out of the tissue. Dehydration in acetone provides good
results. Embedding of the tissue in Araldite 512 results in high non-specific
binding of the primary antibody and a decreased effective titre of the primary
antibody. Embedding of tissues in Lowicryl HM20 resin resulted in low non
specific binding. We also describe a method of curing the Lowicryl resin that
does not require a purpose built curing chamber. Quantitative analysis of
immunogold binding reveals that acetone dehydration of tissues and embedding in
Lowicryl gives greatly superior results in comparison with dehydration in alcohol
and embedding in Araldite.
PMID- 10758235
TI - Simple dipstick assay for semi-quantitative detection of neopterin in sera.
AB - Neopterin, a low-molecular-mass pteridine produced by macrophages, is closely
associated with activation of the cellular immune system. Neopterin biosynthesis
during inflammatory disease is primarily derived from interferon-activated
monocytes/macrophages and neopterin concentrations may be significantly increased
in a particular disease state compared to controls. A follow-up of serum
neopterin concentrations during the course of an infectious disease could be
useful for measuring the activity of the disease and the influence of treatment.
We have developed a simple dipstick assay for the semi-quantitative detection of
the neopterin concentration in the serum of patients during the course of an
infectious disease. Assay performance was comparable to an ELISA, but there is no
requirement for specialised equipment.
PMID- 10758236
TI - Superoxide produced by activated neutrophils efficiently reduces the tetrazolium
salt, WST-1 to produce a soluble formazan: a simple colorimetric assay for
measuring respiratory burst activation and for screening anti-inflammatory
agents.
AB - Activation of the respiratory burst of granulocytes and macrophages by invading
microorganisms is a key first line cellular defence against infection. Failure to
generate this response leads to persistent life-threatening infection unless
appropriate antibiotic treatment is given. The respiratory burst of neutrophils
is usually measured spectrophotometrically by following ferricytochrome c
reduction, and histologically by using the tetrazolium salt, nitroblue
tetrazolium, which is reduced intracellularly to an insoluble formazan. In both
assays, reduction is mediated by superoxide generated via NADPH oxidase. Because
ferricytochrome c has a high molecular mass and high background absorbance at 550
nm, the assay lacks sensitivity and is not ideally suited to microplate
measurement. We have circumvented these limitations by using the cell
impermeable, sulfonated tetrazolium salt, WST-1, which exhibits very low
background absorbance and is efficiently reduced by superoxide to a stable water
soluble formazan with high molar absorptivity. This has permitted adaptation of
the WST-1 assay to microplate format while retaining sensitivity. Reduction of
WST-1 by activated human peripheral blood neutrophils correlated closely with
ferricytochrome c reduction across a range of PMA concentrations and with time of
activation by PMA and fMLP. Reduction of WST-1 was inhibited by 98% by superoxide
dismutase (20 microg/ml) and by 88% by the NADPH oxidase inhibitor,
diphenyleneiodinium (10 microM) but was resistant to catalase, azide and the NADH
oxidase inhibitor, resiniferatoxin. WST-1 and ferricytochrome c reduction were
also compared using xanthine/xanthine oxidase to generate superoxide. Under
optimised assay conditions, both WST-1 and ferricytochrome c reduction were
directly proportional to added xanthine. WST-1 generated approximately 2-fold
greater increase in absorbance than ferricytochrome c at their respective
wavelengths, and this translated into increased assay sensitivity. Addition of
the intermediate electron acceptor, 1-methoxy phenazine methosulfate, increased
the background of the neutrophil assay but did not affect the overall magnitude
of the response. We have used the WST-1 assay to assess human neutrophil
dysfunction and to compare anti-inflammatory activity.
PMID- 10758237
TI - Mapping of B-cell epitopes in rabbits immunised with various gag antigens for the
production of HIV-1 gag capture ELISA reagents.
AB - An HIV-1 p24 capture enzyme linked immunosorbent assay (ELISA) was developed and
used in a study of B-cell epitopes in rabbits immunised with different gag p24
antigens. Rabbits were immunised with virion HIV-1/Lai, baculovirus recombinant
p24, Escherichia coli recombinant p24-15 and a mixture of synthetic peptides
representing sequences of HIV-1 gag p24 protein, respectively. Five out of nine
rabbits developed antibodies that could be used for an antigen capture ELISA. No
significant differences in IgG titers to the whole gag protein were seen when
comparing rabbits immunised with four different antigens. Three major common
linear epitope regions were mapped in the rabbits immunised with virion HIV-1/Lai
and baculovirus recombinant p24. The rabbit immunised with HIV-1 gag peptides had
the broadest linear epitope reactive responses whereas animals immunised with E.
coli recombinant antigen had the most restricted linear epitope response. The
capture ELISA method thus developed using the different rabbit anti-p24 IgG
preparations was shown to capture isolates from HIV-1 subtypes or clades A to G.
Only rabbits immunised with virion HIV-1/Lai and baculovirus recombinant p24
developed IgG that was capable of efficiently capturing HIV-1 p24 in ELISA,
indicating the importance of preparing antibodies able to recognise native or
discontinuous and linear antigen configurations.
PMID- 10758238
TI - Radioiodination of human interferon-alpha2 interferes with binding of C-terminal
specific antibodies.
AB - Radioimmunoassays based on reactivity between a monoclonal antibody (mAb) and
human 125I-interferon (IFN)-alpha2 are frequently exploited in interferon
research. In general, epitopes of antibodies specific for human IFN-alpha2 are
located on the two immunodominant structures formed in the N- and C-terminal
domains, respectively. We found that labelling of IFN-alpha2 with Na(125)I by the
chloramine-T method did not affect the binding of antibodies recognising the N
terminal region 30-53. In contrast, radioiodination of IFN was associated with a
dramatic decrease in IFN reactivity with mAbs specific for the C-terminus
(residues approximately 120-145 approximately ). We suggest that steric hindrance
araising from the incorporation of 125I into the tyrosine residues at positions
123, 130 and 136 may be responsible for the change in immunoreactivity. The
adverse effect of radioiodination of IFN-alpha2 on the binding potency of C
terminal specific mAbs must be taken into consideration in experiments based on
the interaction of such antibodies (i.e. NK2) with the labelled antigen.
PMID- 10758239
TI - Development of EIA systems for active-form MAP kinase.
AB - Quantitative sandwich enzyme immunoassay (EIA) systems, that can distinguish
between active-form subtypes of mitogen-activated protein kinases (p44 and p42
MAP kinase, also called ERK1 and ERK2), were developed employing subtype-specific
antibodies as a solid phase and an antibody specific for the phosphorylated
region of MAP kinases as the detector. Using these systems, we investigated the
dynamic changes in the activity of ERK1 and ERK2 in platelet-derived growth
factor (PDGF)-treated rat mesangial cells and nerve growth factor (NGF)-treated
PC12. Both ERK1 and ERK2 were activated immediately after stimulation, and the
activity reached a maximum at 5-10 min. The total activity of both subtypes
correlated well with that obtained using the conventional method. Compared with
the usual methods, these systems should have a higher specificity and be more
convenient and suitable for experiments with multiple samples. Moreover, as these
EIA systems can be applied not only to rat MAP kinases but also to human, mouse
and rabbit MAP kinases, they are potentially very useful for a range of
investigations.
PMID- 10758240
TI - Analysis of the interaction between monoclonal antibodies and human hemoglobin
(native and cross-linked) using a surface plasmon resonance (SPR) biosensor.
AB - To develop a stable immuno-assay system for quantification of human hemoglobin
(Hb), the interaction between various antibodies and Hb was studied using a
surface plasmon resonance (SPR) biosensor in the BIAcore equipment (Amersham
Pharmacia Biotech) with an immobilized anti-Hb antibody sensor chip. When
polyclonal antibodies were used, the immuno-reactivity of purified and
commercially available Hb decreased drastically with incubation times up to 14 h.
This instability of immuno-reactivity of Hb is attributable to the conformational
changes in Hb induced by oxidation. On the other hand, of the sixteen monoclonal
antibodies tested, four antibodies (MSU-102, -103, -106 and -115) were found to
maintain their immuno-reactivities at least up to 24 h. During long-term storage,
however, the immuno-reactivity of Hb with these monoclonal antibodies decreased
significantly. The chemical betabeta-cross-linking of Hb was effectively able to
stabilize the structure of Hb and immuno-reactivity with monoclonal antibodies
such as MSU-103 for periods at least up to 70 days. Therefore, the combination of
specific monoclonal antibodies such as MSU-103 and a betabeta-cross-linked Hb
standard could be used for the quantification of Hb.
PMID- 10758241
TI - Intracellular staining for TNF and IFN-gamma detects different frequencies of
antigen-specific CD8(+) T cells.
AB - CD8(+) T lymphocytes are important mediators of adaptive immunity against certain
viral, protozoan and bacterial pathogens. Activated CD8(+) T cells are able to
induce cytolysis of infected cells (perforin and CD95-CD95L mediated pathways)
and also elaborate cytokines, including IFN-gamma and TNF after appropriate MHC
class I-peptide recognition. New technologies for the detection of antigen
specific CD8(+) T cells, including tetrameric MHC class I-peptide complexes,
intracellular IFN-gamma staining and IFN-gamma ELISPOT analysis have revised our
understanding of the magnitude of the CD8(+) T cell response to infection. Here,
using intracellular cytokine staining, we compare detection of IFN-gamma and TNF
in the analysis of pathogen-specific CD8(+) T cell lines and CD8(+) T cells after
primary viral infection (LCMV) or secondary bacterial infection (Listeria
monocytogenes). Under multiple conditions and with multiple epitopes, we find
that staining for intracellular IFN-gamma consistently detects a higher frequency
of antigen-specific CD8(+) T cells than detection of intracellular TNF. However,
(a) intracellular staining for TNF can be used to detect antigen-specific CD8(+)
T cell responses and (b) intracellular staining for cytokines is a useful
approach for in vitro characterization of antigen-specific CD8(+) T cell lines.
PMID- 10758242
TI - Distinct subsets of dendritic cells resembling dermal DCs can be generated in
vitro from monocytes, in the presence of different serum supplements.
AB - We recently demonstrated that dendritic cells (DCs) can be generated from
monocytes in the presence of high concentrations of human serum (HS), provided
the extra-cellular pH is maintained at plasma values. Because monocyte-derived
DCs (Mo-DCs) can also be generated in the presence of fetal calf serum (FCS) or
serum-free medium, we have investigated whether these different culture
supplements influence DC generation. With this aim, purified monocytes were
cultured with GM-CSF plus IL-4 for 6 days and were further exposed to TNF-alpha
for 2 additional days, in the presence of HS, autologous plasma (AP), FCS, or X
VIVO 20, a serum-free medium. Our results show that good yields of functionally
mature DCs can reproducibly be obtained in the presence of HS or AP, as assessed
by CD83 and CD86 up-regulation, dextran-FITC uptake, allogeneic MLR assays and
the induction of an autologous response. Interestingly, the effect of serum on DC
generation was probably not only quantitative, but also qualitative, since (i)
the majority of HS- or AP-cultured DCs expressed CD83 with very weak levels of
CD1a, whereas CD83+ DCs cultured in FCS or X-VIVO were mostly CD1a++; (ii) HS-
and AP-cultured DCs were much more granular and heterogeneous than FCS- or X-VIVO
cultured DCs, and (iii) the presence of Birbeck-like granules was preferentially
observed in HS- or AP-cultured DCs, as assessed by electron microscopy. That
these different cells resemble dermal DCs (DDCs) was further supported by the
observations that most of the cells displayed intracytoplasmic FXIIIa in the
absence of Lag antigen, and expressed E-cadherin at very low levels. Altogether,
our results indicate that starting from the same monocytic population, different
subsets of DCs can be generated, depending on the culture conditions. Thus, HS or
AP favors the generation of fully mature DCs that resemble activated dermal DCs,
whereas FCS, or X-VIVO preferentially leads to the generation of less mature
CD1a++ dermal-like DCs.
PMID- 10758243
TI - The use of the CELLection kit in the isolation of carcinoma cells from
mononuclear cell suspensions.
AB - A study was performed to evaluate in vitro the sensitivity, specificity and
variability of a new immunomagnetic microbead isolation technique which provides
subsequent immunological staining of captured carcinoma cells. In a mixture of
peripheral blood mononuclear cells (PBMCs) and human carcinoma cells the
epithelial cancer cells were isolated with the Dynal((R)) RAM IgG1 CELLection Kit
using Dynabeads M-280 coated with a rat monoclonal antibody (Mab) against mouse
IgG1. The rat Mab was biotinylated and attached to Dynabeads via streptavidin and
a DNA linker. The anti-epithelial monoclonal mouse antibody Ber-EP4 was used as
the primary capture antibody. In order to permit phenotyping of the isolated
carcinoma cells the magnetic beads were removed from the carcinoma cells by
DN'ase digestion of the DNA linker between the magnetic bead and the secondary
antibody. In an ex vivo model system an average recovery of approximately 60% of
a human colon carcinoma cell line HCC-2998 seeded in 5.10(6) PBMCs was obtained,
and the recovered cells could subsequently be immunologically stained for the
surface antigen CD87 (urokinase plasminogen activator receptor). No positive
stained cells were found in control experiments with PBMCs without carcinoma
cells. Despite a relatively low recovery, the described method will be valuable
for the detection of carcinoma cells in cytospin preparations with subsequent
phenotyping of the cells for expression of surface antigens. Depending on the
chosen antibodies, the method may be useful for the isolation and
characterisation of other cell types in various cell suspensions.
PMID- 10758244
TI - A rapid method for estimating the binding of ligands to ELISA microwells.
AB - This report presents a rapid and simple assay for estimating to what extent the
surface of ELISA microwells is coated by a ligand of choice such as, for example,
proteins, peptides, hormones, polysaccharides and nucleic acids. The method also
provides a practical approach for defining the conditions required for optimal
coating, such as ligand concentration, coating buffer, temperature and duration
of coating and also for evaluating the efficiency of the reagents used to
saturate the ELISA microwells. The important advantage of this procedure is that,
in contrast to conventional ELISA procedure, the detection of the microwell
adhered ligand is not achieved by using an antibody. It is therefore the solution
of choice when, as is often the case, no primary specific antibody is available.
The test consists of three steps: first the ligand is allowed to adsorb to the
microwells. Second, alkaline phosphatase is added to bind to any residual
microwell surface not occupied by the ligand. Finally, substrate is added and the
resulting color reaction is measured. Light absorbancy is inversely correlated
with the level of ligand adherence. The results obtained by this method match
those of direct ligand quantitation, as evaluated by a regular ELISA procedure.
PMID- 10758245
TI - Cross-correlation for flow cytometric histogram background subtractions.
AB - Background subtraction is a widely encountered problem in flow cytometry
applications for which the currently available analysis techniques are
unsatisfactory. The 99% division line method, also referred to as the threshold
or marker method, is widely used because it is computationally simple but it has
poor accuracy and tends to underestimate the percentage of positive cells when
there is overlap between histograms. Model-based approaches are preferred when
there are overlapping peaks, but these methods require curve fitting and strong
assumptions regarding the shape of the underlying distributions. This report
assesses a mathematically rigorous, computationally facile, non-parametric
technique called cross correlation for the background subtraction problem. A
metric, positivity, derived from cross correlation is shown to overcome the
disadvantages of both the 99% division line and model-based methods without
compromise.
PMID- 10758246
TI - In vivo selection of single-chain antibodies using a yeast two-hybrid system.
AB - The current methodology for screening libraries of single-chain fragments of
immunoglobulin variable domains (sFvs) utilizes bacterial phage systems. We have
developed a unique in vivo selection protocol combining a modified yeast two
hybrid assay with a novel prey vector expressing sFvs. The viability of the
system is demonstrated with the screen of a sFv library cloned into a yeast two
hybrid prey vector for molecules that target the bait ATF-2, a member of the
CREB/ATF family of transcriptional regulatory proteins. The isolated sFv was
capable of recognizing ATF-2 in vitro on Western blots and in vivo in mammalian
cells.
PMID- 10758247
TI - An immuno-polymerase chain reaction assay for human interleukin-18.
AB - Conventional enzyme-linked immunosorbent assays (ELISA) are sufficient to measure
normal and elevated serum interleukin (IL)-18 concentrations, but have limited
sensitivity when measuring low concentrations of IL-18 such as in patients with
the acquired immunodeficiency syndrome. We have developed a highly sensitive
method for detecting human (h) IL-18 using an immuno-polymerase chain reaction
(PCR). A mouse monoclonal anti-hIL-18 antibody and rabbit polyclonal anti-hIL-18
antibody was used for an indirect sandwich ELISA with a detection limit of 40
ng/l and a very low background. For immuno-PCR, biotinylated DNA was produced
from the plasmid Bluescript by PCR amplification with biotinylated M13-20 primer
and nonbiotinylated M13 reverse primer. Immuno-PCR for hIL-18 was performed for
40 cycles using 1 ng/l of biotinylated DNA. This immuno-PCR has a detection limit
of 2.5 pg/l, 1.6x10(4) times lower than that of the ELISA. In addition, our
system avoids sampling error caused by heat transfer from the ELISA plate to the
PCR tube because all procedures from immobilization of the antibody to PCR
amplification can be performed in the same tube. This immuno-PCR for hIL-18 is
the most sensitive method for detecting hIL-18 reported to date.
PMID- 10758248
TI - Improved systems for hydrophobic tagging of recombinant immunogens for efficient
iscom incorporation.
AB - We have previously reported a strategy for production in Escherichia coli of
recombinant immunogens fused to a hydrophobic tag to improve their capacity to
associate with an adjuvant formulation [Andersson et al., J. Immunol. Methods 222
(1999) 171]. Here, we describe a further development of the previous strategy and
present significant improvements. In the novel system, the target immunogen is
produced with an N-terminal affinity tag suitable for affinity purification, and
a C-terminal hydrophobic tag, which should enable association through hydrophobic
interactions of the immunogen with an adjuvant system, here being
immunostimulating complexes (iscoms). Two different hydrophobic tags were
evaluated: (i) a tag denoted M, derived from the membrane-spanning region of
Staphylococcus aureus protein A (SpA), and (ii) a tag denoted MI consisting of
the transmembrane region of hemagglutinin from influenza A virus. Furthermore,
two alternative affinity tags were evaluated; the serum albumin-binding protein
ABP, derived from streptococcal protein G, and the divalent IgG-binding ZZ
domains derived from SpA. A malaria peptide M5, derived from the central repeat
region of the Plasmodium falciparum blood-stage antigen Pf155/RESA, served as
model immunogen in this study. Four different fusion proteins, ABP-M5-M, ABP-M5
MI, ZZ-M5-M and ZZ-M5-MI, were thus produced, affinity purified and evaluated in
iscom-incorporation experiments. All of the fusion proteins were found in the
iscom fractions in analytical ultracentrifugation, indicating iscom
incorporation. This was further supported by electron microscopy analysis showing
that iscoms were formed. In addition, these iscom preparations were demonstrated
to induce M5-specific antibody responses upon immunisation of mice, confirming
the successful incorporation into iscoms. The novel system for hydrophobic
tagging of immunogens, with optional affinity and hydrophobic tags, gave
expression levels that were increased ten to fifty-fold, as compared to the
earlier reported system. We believe that the presented strategy would be a
convenient way to achieve efficient adjuvant association for recombinant
immunogens.
PMID- 10758249
TI - Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood
disorders.
AB - The aim of this study was to investigate the influence of serotonin receptors 2A,
2C and 1A gene variants on lithium prophylactic efficacy in mood disorders. One
hundred and twenty-four subjects affected by bipolar (n=102) and major depressive
(n=22) disorder were followed prospectively for an average of 52 months and were
typed for 5-HT2A (T102C: n=111, HTP: n=104), 5-HT2C (n=110) and 5-HT1A (n=61)
variants. Both 5-HT2A and 5-HT2C variants were not associated with lithium
outcome. Consideration of possible stratification effects like gender, polarity,
family history, age at onset and duration of lithium treatment did not influence
results. No 5-HT1A gene variant was identified. 5-HT2A and 2C variants are not,
therefore, associated with lithium prophylactic efficacy in mood disorders.
PMID- 10758250
TI - Altered Rap1 endogenous phosphorylation and levels in platelets from patients
with bipolar disorder.
AB - Previous studies have reported abnormalities either in the cAMP-dependent
endogenous phosphorylation or in the levels of Rap1 in platelets from bipolar
patients. One limitation of these findings was that they come from different
groups of patients in independent studies. To overcome this limitation, we
designed the present study in which both these biochemicals parameters were
assessed in the same cohort of euthymic bipolar patients and healthy subjects.
The results showed that the cAMP-dependent phosphorylation of Rap1 was
significantly higher in platelets of bipolar patients with respect to healthy
subjects. Furthermore, immunoblotting experiments revealed that also the levels
of Rap1 were significantly higher in bipolar patients than in control subjects,
thus supporting that the abnormal phosphorylation can be ascribed to the
increased levels of Rap1. Taken together the results of the present study further
support that downstream components of the cAMP signal cascade could be involved
in the pathophysiology of bipolar disorders.
PMID- 10758251
TI - Charting patients' course: a comparison of statistics used to summarize patient
course in longitudinal and repeated measures studies.
AB - Investigators conducting longitudinal studies of psychiatric illnesses often
analyze data based on psychiatric symptom scales that were administered at
multiple time points. This study examines the statistical properties of seven
indices that summarize patient long-term course. These indices can be used to
compare differences between two or more groups or to test for changes in symptoms
over time. They may also be treated as outcome measures and correlated with other
clinical variables.The performance of each of the seven indices was assessed
using data from two large ongoing studies of psychiatric patients: a longitudinal
study of affective disorders and a longitudinal study of first-episode psychosis.
These two datasets were subjected to bootstrapping techniques in order to
calculate both type I error rates and statistical power for each summary
statistic. Of the seven indices, Kendall's tau performed the best as a measure of
patients' symptom course. Kendall's tau appears to offer more statistical power
to detect change in course, yet its average type I error rate was comparable to
the other indices.
PMID- 10758252
TI - Ouabain induction of cycling of multiple spike responses in hippocampal slices is
delayed by lithium.
AB - Alterations in sodium- and potassium-activated adenosine triphosphatase (Na,K
ATPase) activity have been associated with changes of mood states and lithium
treatment in bipolar illness. We examined the effects of ouabain and lithium on
evoked population responses in rat hippocampal slices. In vitro 3.3 microM
ouabain induced cycling between epliptiform activity and unresponsiveness in
18.5% of slices. In vitro ouabain, at 1-10 microM, induced epileptiform multiple
spike responses. In vivo lithium pretreatment for 10-21 days produced a
significant delay in the onset of this ouabain-induced epileptiform activity
compared to control animals. These findings are consistent with other work which
suggests that Na, K-ATPase inhibition can both activate and suppress excitable
tissues and that lithium pretreatment can mitigate these effects. The
implications of these results and others regarding the pathophysiology of bipolar
illness are discussed.
PMID- 10758253
TI - Memory and schizophrenia: differential link of processing speed and selective
attention with two levels of encoding.
AB - The purpose of this study was to investigate how underlying cognitive deficits
such as a defect in processing speed or in selective attention contributed to
different types of memory impairment observed in schizophrenia (superficial vs
deep encoding). 49 schizophrenic patients and 40 normal controls were
administered a verbal memory task. Superficial encoding was assessed by the
ability to recall items in their serial order. Deep encoding was assessed by the
ability to organise words into semantic categories. Two measures of processing
speed (Digit Symbol Substitution Test and Stroop colour time) and one measure of
selective attention (Stroop test) were used. Regression analyses were carried
out. In the patient group, processing speed contributed to both superficial and
deep encoding, and to a global verbal memory score. Selective attention only
contributed to the superficial encoding processes. Thus, slowing of processing
speed in schizophrenia seems to be more crucial for memory performance, since it
affects memory in a pervasive way.
PMID- 10758254
TI - Identification of neuropsychological subtypes in a sample of delinquent
adolescents.
AB - Although research has long recognized a relationship between neurological
dysfunction and delinquency, the nature of this relationship is unclear. Based on
the theory that there may be clusters of delinquents with different types of
neurological dysfunction which contribute to the delinquency in different ways,
the present research attempted to identify these subtypes using
neuropsychological testing. Seventy-seven such adolescents were administered the
full Luria-Nebraska Neuropsychological Battery-III (LNNB-III) and a battery of
assessments measuring behavioral functioning and substance use. A Hierarchical
Cluster Analysis yielded four identifiable neuropsychological clusters:
Verbal/Left-Hemispheric Deficits, Subcortical-Frontal Deficits, Mild-Verbal
Deficits, and Normals. The distinctiveness of these subtypes was confirmed by
univariate analyses. Results further indicated that the number of LNNB scales
that were in the abnormal range differed per subtype, with each subtype differing
significantly from one another. These neuropsychological subtypes were found to
be associated with specific psychological and behavioral problems.
PMID- 10758255
TI - No relationship between schizophrenic birth and influenza epidemics in Japan.
AB - The finding that influenza epidemics are associated with an increased risk of
adult schizophrenia has been controversial. Data was obtained from Japan's
governmental statistics, the Patient Survey. Index years were defined as
1957/1958, 1962, and 1965, and comparison years were defined 2 years before and 2
years after the index year. Subjects were patients with schizophrenia who were
born in the index years of influenza epidemics. Periods 5 months after the
influenza epidemics were defined as exposed months. Proportions of patients born
during the exposed period in the index years were compared with those of patients
born in the corresponding months in the comparison years. The proportions of
patients born in the exposed months in the index years were not significantly
different from those born in the corresponding months in the comparison years,
with odds ratios around 1 in the whole country, the Kanto area, and the
Shikoku/Kyushu area where a remarkable influenza epidemic was observed in 1957.
No difference was observed in analyses stratified by sex. In Japan, there was no
relationship between influenza epidemics and schizophrenic birth.
PMID- 10758256
TI - Obsessive-compulsive disorder in schizophrenia.
AB - OBJECTIVE: To examine the differences in demographic and clinical features of
patients with schizophrenia, with or without comorbid obsessive-compulsive
disorder (OCD). METHODS: Fifty-two subjects were recruited from clinical services
in the city of Edmonton, Alberta and assessed for schizophrenia and OCD with
structured clinical interviews and standardized clinical rating scales. RESULTS:
The prevalence of OCD in individuals meeting criteria for schizophrenia was 25%.
Those subjects having both schizophrenia and OCD scored significantly higher on
the Y-BOCS, Hollingshead scale, and GAF; plus significantly lower PANSS negative
symptoms and a trend in increased Parkinsonian symptoms compared with individuals
with schizophrenia alone. CONCLUSION: Our preliminary findings indicate that
patients with schizophrenia and OCD vary in selected demographic and clinical
measures when compared to patients with schizophrenia alone. Patients with
schizophrenia and OCD appear to have less negative symptoms, which may thus be
reflected in the decreased GAF scores. It is speculated that patients with
schizophrenia and OCD may have a greater propensity to basal ganglia dysfunction
than those with schizophrenia alone resulting in increased Parkinsonian symptoms.
PMID- 10758257
TI - Impairment in test performance and symptom dimensions of schizophrenia.
AB - Schizophrenic patients were rated on three syndromal dimensions derived from
positive and negative symptom ratings. Scores on each dimension were compared to
performance on neuropsychological tests before and after coaching instructions.
Patients evidenced significant improvement in performance on all measures
readministered immediately after instruction. Disorganization symptoms were
correlated with lower levels of performance on all pre-coaching, trial 1 tests.
Disorganization symptoms were also associated with lower levels of trial 2 post
coaching performance, independent of pre-coaching scores. These results suggest
that, within a population of schizophrenic patients, symptoms of disorganization
are associated with relatively greater impairments in performance on
neuropsychological tests and with impaired ability to improve test performance
following coaching instructions. The three symptom dimensions show promise for
reducing heterogeneity within samples of schizophrenic patients.
PMID- 10758258
TI - Posttraumatic stress disorder and platelet serotonin measures.
AB - The role of serotonin (5HT) in the pathophysiology of posttraumatic stress
disorder (PTSD) has been suggested by the overlap in clinical symptoms between
PTSD and psychiatric conditions in which a serotonin dysfunction is implicated,
as well as by the therapeutic efficiency of 5HT-related drugs (antidepressants,
selective serotonin reuptake inhibitors and monoamine oxidase inhibitors) in
alleviating symptoms in PTSD. In the present study, the blood platelet, which has
been proposed as a peripheral model for the central serotonergic neurons, has
been used to search for alterations in 5HT mechanisms in PTSD. Platelet serotonin
level and kinetics of serotonin transporter and monoamine oxidase (MAO-B) were
assessed in 63 combat-related PTSD patients and 43 sex and age-matched control
subjects. A significant reduction in maximal velocity of platelet MAO-B (approx.
30%), with no changes in the enzyme affinity was observed in our patient sample.
Conversely, no alterations in kinetic parameters (V(max), K(m)) of platelet
serotonin transporter, as well as in platelet 5HT level, were found in the PTSD
group.
PMID- 10758260
TI - Potential of combining neem (Azadirachta indica A. Juss) seed oil with varietal
resistance for the management of the cowpea bruchid, Callosobruchus maculatus
(F.).
AB - The efficacy of different rates (25, 50, 75 and 100 mg/5 g seed) of application
of neem (Azadirachta indica) seed oil (NSO) was assessed on four cowpea varieties
(Kanannado, IT89KD-391, Borno brown and IT89KD-374) with differing
susceptibilities to Callosobruchus maculatus. The different rates of NSO
significantly interacted with cowpea varietal resistance and reduced oviposition
and percentage adult emergence of C. maculatus. The interaction of the strategies
also significantly reduced percentage of cowpea seeds infested by C. maculatus.
Treatment of seeds with NSO at the rates of 50 mg/5 g and 75 or 100 mg/5 g
reduced seed damage from over 25% in controls to less than 10% and less than 5%,
respectively, in all varieties.
PMID- 10758259
TI - Quantifying behavioral disturbance in Alzheimer's disease patients.
AB - In the course of a four-month study of interventions for behavioral disturbances
in Alzheimer's disease (AD) patients, the following assessment instruments were
examined for validity: the clinical global impression of change (CGIC), Cohen
Mansfield agitation inventory (CMAI); CERAD behavioral rating scale for dementia
(BRSD), revised memory and behavioral problems checklist (RMBPC) and the agitated
behavior in dementia scale (ABID). The four specific behavioral/agitation scales
had excellent cross-sectional and longitudinal correlations with each other,
suggesting high validity, but changes as indicated by CGIC scores did not
correlate well with change scores on the other instruments. We conclude that
specific behavioral instruments are preferable to the more general CGIC for
detecting and quantifying behavioral disturbances in AD patients.
PMID- 10758261
TI - Comparisons of energy reserves among strains of Tribolium castaneum selected for
resistance to hypoxia and hypercarbia, and the unselected strain.
AB - The quantities of energy reserves and their utilization were examined in adults
of three strains of Tribolium castaneum (Herbst) before and during exposure to
two modified atmospheres. It was shown that a strain selected for resistance to
high carbon dioxide (CO(2)) content (HCC) contained significantly greater
triacylglycerol (TG) reserves than a strain selected for resistance to low oxygen
(O(2)) concentration (LOC) and an unselected strain. During exposure to HCC (65%
CO(2), 20% O(2), balance nitrogen), the major energy sources were TGs, most of
which were consumed during exposure; TG utilization by the unselected strain was
more rapid than that by the HCC-selected strain. During exposure to LOC (0.5%
O(2), 99.5% nitrogen), TGs were also utilized, but to a lesser extent, revealing
an indication of more attenuated mobilization of energy reserves. Here, too, TG
utilization by the unselected strain was more rapid than by the LOC-selected
strain. The function of TGs in enabling the insects to maintain their water
balance during exposure was considered.Concentrations of polysaccharides and
glucose were low in all strains and although they decreased during exposure to
MAs, their contribution to metabolic energy supply during exposure was small.
PMID- 10758262
TI - Some aspects of the biology and control using botanicals of the rice moth,
Corcyra cephalonica (Stainton), on some pulses.
AB - The life cycle of Corcyra cephalonica was studied under ambient laboratory
conditions (temperature range 27.5-30 degrees C and 60-73% r.h.) on groundnut,
bambara groundnut and cowpea. The mean developmental period ranged from 33.2+/
0.2 to 45.3+/-1.8 days on whole, broken and powdered forms of the food media. Egg
hatchability was found to be 83%, while adult longevity ranged from 1.5+/-0.5 to
11.9+/-1.3 days for males and 1.5+/-0.5 to 16.5+/-1.2 days for females. Sex ratio
(male symbol:female symbol) of emerged adults ranged from 1:1 to 1:2.1. Mean
fecundities ranged from 128+/-5 to 157+/-8 on the food media. In experiments to
assess the insecticidal potential of three plant materials against C.
cephalonica, Eichhornia crassipes powder showed a higher efficacy than both
Citrus sinensis peel powder and the leaf powder of Chromolaena odorata at dosages
of 0.5-2.0 g per 40 g of legume seed. At the higher dosage of 2.5 g, C. sinensis
was more effective and reduced the population of C. cephalonica by half when
compared to the population in control jars over a period of 1.5 months.
PMID- 10758263
TI - An illustrated identification key to four different species of adult Dinoderus
(Coleoptera: Bostrichidae), commonly attacking dried cassava chips in West
Africa.
AB - Bostrichids of the genus Dinoderus are commonly found as pests of dried cassava
chips in West Africa. An illustrated key facilitating the identification of the
four most frequent African species, i.e. D. bifoveolatus (Wollaston), D. minutus
(Fabricius), D. porcellus Lesne, and D. oblongopunctatus Lesne is presented.
PMID- 10758264
TI - Using five sampling methods to measure insect distribution and abundance in bins
storing wheat.
AB - Newly-harvested wheat stored in each of two bins on each of two farms in Kansas
during each of 3 years was sampled every 3-4 days at two locations (in the center
and midway between the center and bin wall) within each bin. The variation in
insect numbers between bins, locations within a bin, farms and years differed
with insect species and sampling method. Five sampling methods were used to
monitor insect populations in three regions of each bin: (1) in the head space
above the grain; (2) on the grain surface; and (3) within the top 50 cm of the
grain mass. Cryptolestes ferrugineus (Stephens) and Ahasverus advena (Waltl) were
more evenly distributed among these three regions of a bin than the other
species. Typhaea stercorea (L.) were found mainly in the head space and on the
grain surface. These distribution patterns were consistent throughout the 126-day
storage period. R. dominica (F.) were found in the head space and within the
grain mass early in the storage period, and mainly in the grain mass as grain
cooled in the autumn. The majority of Plodia interpunctella (Hubner) (91%) were
caught in sticky traps in the head space. Two of the three less abundant species,
Sitophilus oryzae (L.) and Tribolium castaneum (Herbst), tended to be found most
often on the grain surface and the other, Oryzaephilus surinamensis (L.), within
the grain mass. The sampling method often influenced the results. Emergence traps
captured greater numbers of A. advena than other species. More R. dominica were
found in grain samples than in traps in the autumn. Pushing probe traps below the
surface of the grain reduced the numbers of T. stercorea, A. advena, S. oryzae
and T. castaneum captured. Differences between species and times during the
storage period in the effectiveness of different sampling methods need to be
considered in making pest management decisions.
PMID- 10758265
TI - Loss of phosphine from unsealed bins of wheat at six combinations of grain
temperature and grain moisture content.
AB - Hard red winter wheat (1.4 t) at 11.1 or 13.5% moisture content (wet basis) and
20, 25, or 30 degrees C was fumigated with tablets of an aluminum phosphide
formulation in unsealed, cylindrical grain bins of corrugated metal. The fumigant
leakage rate was manipulated to approximate that commonly encountered in farm and
commercial-scale bins of this type. Phosphine concentration profiles were
recorded and phosphine loss and sorption were characterized to determine which
conditions provided the greatest probability of successful fumigation in these
bins. Phosphine leakage and sorption were both positively related to grain
temperature and moisture content. The fumigant concentration profiles were
compared with previously-published data relating temperature to the developmental
rate and fumigant susceptibility of lesser grain borer eggs, which are phosphine
resistant but become less resistant as they age. The mean phosphine concentration
observed at the time corresponding to one-half of the calculated egg development
time was compared to the lethal concentration (LC(99)) for a 2-day exposure at
each temperature-moisture combination. In the low-moisture grain at 20 degrees C,
the observed fumigant concentration was below the lethal concentration, due to
the long development time under these conditions. At 25 and 30 degrees C in the
low-moisture wheat, the likelihood of complete kill appeared more favorable
because the fumigant concentration remained above the published LC(99) for more
than half of the egg development time. In the wheat with 13.5% moisture content,
rapid fumigant sorption and loss resulted in phosphine concentrations below the
LC(99) at one-half of the development time at 20 or 25 degrees C. At 30 degrees
C, due to the very rapid development rate, the observed phosphine concentration
exceeded the LC(99) half-way through the egg development period despite the rapid
rate of fumigant sorption and loss. Repeated fumigation of the same grain reduced
the rate at which phosphine sorbed into the grain.
PMID- 10758266
TI - Development-inhibiting activity of some tropical plants against Sitophilus
zeamais Motschulsky (Coleoptera: Curculionidae).
AB - Thirteen tropical plants were evaluated for development-inhibiting activity
against Sitophilus zeamais. The bioassays were carried out by incorporating seeds
or leaves at various dose levels into an artificial diet for the test insect. It
was found that seeds of Basella alba and leaves of Operculina turpethum and
Calotropis gigantea were potent in delaying development and in reducing adult
emergence, and hence the capacity for population increase. At 0.5% concentration,
adult emergence in tests with B. alba, O. turpethum and C. gigantea was reduced
by 62, 95 and 70%, respectively. In B. alba and C. gigantea, the development
periods were 2.2 and 1.8 times those in the control and the capacities for
increase/day were only 0.0324 and 0.0328 compared with 0.1004 in the control. B.
alba, O. turpethum and C. gigantea were active at concentrations as low as 0.01,
0.05 and 0.1%. The potential of these materials in insect pest management is
discussed.
PMID- 10758267
TI - Measuring fig quality using near-infrared spectroscopy.
AB - Sorting of dried figs prior to inspection is labor-intensive and somewhat
complex. We examined the potential of using near-infrared spectroscopy (NIRS) to
automate sorting of dried figs. Calimyrna and Adriatic types were inspected by
hand using established criteria. For both varieties, approximately 100 passable
figs and 100 figs each for the infested, rotten, sour, and dirty defect
categories were examined using NIRS and partial least-squares regression (PLS).
Correct classifications for these varieties ranged from 83 to 100%. About twenty
PLS factors were used to make the predictions. These results indicate that the
use of NIRS to help automate inspection for dried fig processing is feasible.
However, the large number of wavelengths needed for prediction, as indicated by
PLS beta coefficients, indicates that implementing NIRS in fig sorting may
require an instrument capable of reading numerous wavelengths rather than a more
economical filter-based instrument.
PMID- 10758268
TI - Resistance and some enzyme activities in Liposcelis bostrychophila Badonnel
(Psocoptera: Liposcelididae) in relation to carbon dioxide enriched atmospheres.
AB - Two populations (S-1 and S-2) of the psocid, Liposcelis bostrychophila Badonnel
were exposed to carbon dioxide enriched atmospheres. Carbon dioxide resistance
developed at steady rates in these two populations during this study period.
Selection with 35 and 55% CO(2) resulted in resistance development as expressed
by LT(50). Resistance increased steadily under continuous selection to 4.6- and
5.3-fold by generation F(30) for S-1 and S-2, respectively. Throughout the
selection process, the slopes of regression lines were always lower than that of
the control. The results of biochemical assays showed that the activities of
carboxyl esterase (CarE) and superoxide dismutase (SOD) in vitro increased in the
selection process. Exposure to higher CO(2) content (HCC) resulted in a gradual
decrease in CarE activity in both selected and control populations. Although the
induction effect of CO(2) on SOD was brief, the induction times for the S-1 and S
2 were greater than those of the control. The elevated catalase (CAT) activity in
association with resistance development was also evident, but no statistical
correlation was found between CAT activity and HCC resistance. No significant
differences were found in acid phosphatase and alkaline phosphatase activities in
both selected and control populations during this study. This study demonstrated
that high CarE and SOD activities were positively correlated to CO(2) resistance.
PMID- 10758269
TI - Control of insects and mites in grain using a high temperature/short time (HTST)
technique.
AB - Wheat infested with grain mites (Acari) and Sitophilus granarius, and maize
infested with Prostephanus truncatus, were exposed to hot air in a CIMBRIA HTST
Microline toaster((R)). Inlet temperatures of the hot air were in the range of
150-750 degrees C decreasing to outlet temperatures in the range of 100-300
degrees C during the exposure period. A rotating drum, connected to a natural-gas
burner was fed with grain which was in constant movement along the drum and
thereby mixed thoroughly during the process. The capacity of the toaster was 1000
kg per hour.Complete control of grain mites and adult S. granarius in wheat was
obtained with an inlet temperature of 300-350 degrees C and an average residence
time in the drum of 6 s. More than 99% mortality was obtained for all stages of
S. granarius with an inlet temperature of 300-350 degrees C and an average
exposure period of 40 s. For control of P. truncatus in maize, an inlet
temperature of 700 degrees C resulted in a complete disinfestation when the
exposure time was 19 s.The reduction in grain moisture content was 0.5-1% at
treatments giving 100% control. Germination tests indicate that it is possible to
choose a combination of inlet temperatures and exposure periods which effectively
kills mites and insects in small grains, without harming the functional
properties of the grain.Economy of the method was considered to be competitive
with fumigation using phosphine.
PMID- 10758270
TI - Determination of the three-dimensional structure of toxins by protein
crystallography.
AB - Protein crystallography has significantly contributed to the development of many
areas of biochemical research, particularly in the understanding of phenomena
related to molecular recognition. Examples include the formation of enzyme
substrate complexes (and their subsequent catalysis), host cell invasion by
viruses, antigen neutralization and peptide display by proteins of the immune
system and many others. More recently, protein crystallography has also proved to
be of great value in unraveling the molecular basis of many diseases as well as
in the development of new drugs for their treatment. The X-ray diffraction
technique in the elucidation of macromolecular structures is situated at the
interface between the traditional research fields of biology, biochemistry,
chemistry and physics where researchers are united by a common interest in the
detailed understanding of macromolecule function and its relationship to three
dimensional structure. The purpose of this review is to describe, without resort
to mathematical detail, all of the necessary steps for the complete determination
of a three-dimensional structure by X-ray diffraction techniques. The basic
procedures used for protein isolation and crystallization, crystallographic data
collection and analysis and, finally, structure determination and refinement are
all briefly reviewed. As such our efforts are not directed towards the
specialist. Rather, it is our hope that the information presented will aid
interested readers from other fields in the understanding of more specialized
literature and who may wish to employ the information contained therein in the
planning of their biological research. We hope that in so doing we will make
clear both the power and limitations of the technique.
PMID- 10758271
TI - Hemostatic disturbances observed in patients with snakebite in south China.
AB - To investigate the hematological disorders after snakebite, we measured the
maximum platelet aggregation rate (MAR), antithrombin III (AT-III) activity,
alpha(2)-plasmin inhibitor (alpha(2)-PI) activity, concentration of fibrinogen
(Fg) and fibrin degradation products (FDP) in 25 samples from 17 patients with
snakebite in south China. The results obtained in the patients before application
of antivenom and patients with Ophiophagus hannah (Oh.) bite were as follows: (1)
the mean MAR values were significantly decreased in the case of the snakebites
from Vipera russellii (Vr.) and Trimeresurus mucrosquamatus (Tm.); (2) the mean
activities of AT-III were decreased in all patients in the present study; 3) the
mean activities of alpha(2)-PI were significantly decreased in patients bitten by
Deinagkistrodon acutus (Da.), Agkistrodon halys (Ah.), Vr., Trimeresurus
stejnegeri (Ts.), Tm. and Naja naja atra (Nn.); (4) the mean concentrations of Fg
were markedly decreased in patients bitten by Da., Ah., Vr., Ts. and Tm.; and (5)
the mean levels of FDP were significantly increased in cases of Da., Vr. and Ts.
bite, but not in Ah., Tm., Nn. and Oh. bite. The results of the present study
indicate that disorders of platelet aggregation and the coagulation-fibrinolysis
system are liable to occur in patients with snakebite from Da., Ah., Vr., Ts.,
Tm. and Nn. Furthermore, it appeared that disseminated intravascular coagulation
(DIC) was evoked in some patients. Specific antivenom was found to be useful for
improving the hemostatic disturbances after snakebite from Ah. and Nn.
PMID- 10758272
TI - Agelotoxin: a phospholipase A(2) from the venom of the neotropical social wasp
cassununga (Agelaia pallipes pallipes) (Hymenoptera-Vespidae).
AB - The neotropical wasp Agelaia pallipes pallipes is aggressive and endemic in
southeast of Brazil, where very often it causes stinging accidents in rural
areas. By using gel filtration on Sephadex G-100, followed by high performance
reversed phase chromatography in a C-18 column under acetonitrile/water gradient,
the agelotoxin was purified: a toxin presenting phospholipase A(2) (PLA(2))
activity, which occurs under equilibrium of three different aggregation states:
monomer (mol. wt 14 kDa), trimer (mol. wt 42 kDa) and pentamer (mol. wt 74 kDa).
The enzyme presents high sugar contents attached to the protein chain (22% [w/w])
and a transition of the values of pH optimum for the substrate hydrolysis from
7.5 to 9.0, under aggregation from monomer to pentamer. All the aggregation
states present Michaelian steady-state kinetic behavior and the monomer
polymerization caused a decreasing of phospholipasic activity due a non
competitive inhibition promoted by the formation of a quaternary structure. The
PLA(2) catalytic activity of agelotoxin changes according to its state of
aggregation (from 833 to 12533 micromol mg(-1) min(-1)) and both the monomeric
and oligomeric forms present lowest activities than the PLA(2) from Apis
mellifera venom and hornetin from Vespa basalis. Agelotoxin is also a very potent
direct hemolysin; the monomer of agelotoxin presented hemolytic actions until 200
times higher than the PbTx from P. paulista, 740 times higher than the PLA(2)
from A. mellifera, 570 times higher than that of neutral PLA(2) from N.
nigricolis and about 1250 times than that of cardiotoxin from Naja naja atra
venom.
PMID- 10758273
TI - Antagonism of botulinum toxin A-mediated muscle paralysis by 3, 4-diaminopyridine
delivered via osmotic minipumps.
AB - The ability of 3,4-diaminopyridine (3,4-DAP) to antagonize muscle paralysis
following local injection of botulinum neurotoxin A (BoNT/A) complex was
evaluated in the in situ rat extensor digitorum longus (EDL) preparation. The
minipumps were implanted 6 h prior to BoNT/A administration and delivered their
contents over a 7-day period producing a steady plasma 3,4-DAP concentration of
27-29 microM. In the absence of 3,4-DAP, a local injection of five mouse LD(50)
units of BoNT/A led to total paralysis of EDL muscles within 24 h of application.
Recovery from paralysis was slow, remaining at <30% of control 14 days after
toxin injection. 3,4-DAP delivery by osmotic minipumps antagonized the actions of
BoNT/A on neuromuscular transmission. Seven days after the onset of 3,4-DAP
infusion, indirectly elicited twitch and tetanic tensions in BoNT/A-injected EDL
muscles were 72.4 and 46.9% of control, respectively. In the absence of 3,4-DAP,
twitch and tetanic tensions were only 5.4 and 15. 1% of control. The benefits
conferred by 3,4-DAP treatment were not maintained after minipumps were removed.
Seven days after cessation of 3,4-DAP infusion, twitch and tetanic tensions were
not significantly different from those observed in muscles receiving BoNT/A
alone. It is concluded that 3,4-DAP may be useful for treatment of BoNT/A-induced
muscle paralysis, but sustained delivery of the drug would be required for the
entire period of BoNT intoxication to maintain muscle function.
PMID- 10758274
TI - Irniine, a pyrrolidine alkaloid, isolated from Arisarum vulgare can induce
apoptosis and/or necrosis in rat hepatocyte cultures.
AB - The effects of irniine, a pyrrolidine alkaloid extracted from the tubers of
Arisarum vulgare, on rat hepatocyte primary cultures and rat liver epithelial
cell line (RLEC) were studied. Cytotoxicity was first evaluated by LDH release,
MTT and NR tests and MDA production, while cellular alterations were visualized
by electron microscopy and DNA gel-electrophoresis. In hepatocyte and RLEC
cultures, a major toxicity appeared at 40 microM of irniine and was demonstrated
by an increase in LDH release and decreases in MTT reduction and NR uptake while
concentrations lower than 40 microM did not induce significant changes in these
parameters. However, we observed an increase in MDA production at 30 microM.
Important alterations of the nuclei and mitochondria were also visualized by
electron microscopy in cells treated with 50 microM. Using DNA gel
electrophoresis, we demonstrated that irniine at 40 and 50 microM induced DNA
damage. All together these results demonstrate that: (1) Irniine induces a
significant hepatotoxicity. (2) Irniine toxicity is not mediated by a metabolic
derivative since RLEC, which do not contain a monooxygenase system, were also
affected by this compound. (3) Irniine induces a significant DNA damage and
oxidative stress which leads to cell death by necrosis and/or by apoptosis.
Moreover, our data suggest that the alkaloid irniine contained in A. vulgare may
be involved in the toxic symptoms observed after medicinal use or consumption of
the plant tubers as food both by humans and animals.
PMID- 10758275
TI - Isolation and characterization of myrmexins, six isoforms of venom proteins with
anti-inflammatory activity from the tropical ant, Pseudomyrmex triplarinus.
AB - Venom from the tropical ant, Pseudomyrmex triplarinus, has anti-inflammatory
properties demonstrated by the carrageenin-induced edema animal mode. A multi
protein complex that inhibits edema was isolated from the venom and was further
characterized by high performance liquid chromatography (HPLC), matrix-assisted
laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and
amino acid sequencing. Although the complex exhibited a single band in SDS-PAGE
electrophoresis, six proteins (isoforms) were resolved and purified to
homogeneity and were designated myrmexin I-VI. They have very similar molecular
masses between 6998 and 7142 Da. Each myrmexin is a heterodimer consisting of a
small subunit (SS1 or SS2 or SS3) disulfide-linked to a larger, quite
structurally unrelated subunit (LS1 or LS2). Thus, the myrmexin complex consists
of six isoforms of venom proteins: myrmexin I (SS1/LS2), myrmexin II (SS1/LS1),
myrmexin III (SS2/LS2), myrmexin IV (SS3/LS2), myrmexin V (SS2/LS1), myrmexin VI
(SS3/LS1). Subunit SS1 is highly homologous to SS2 (96% of identity) and SS3 (87%
of identity) and LS1 is highly homologous to LS2 (79% of identity). Our study
suggests that myrmexins may represent a new class of anti-inflammatory proteins.
PMID- 10758276
TI - Purification of a novel antibacterial and haemagglutinating protein from the
purple gland of the sea hare, Aplysia dactylomela rang, 1828.
AB - Physicochemical characterisation and antibacterial and haemagglutinating
properties of a new protein isolated from purple fluid of the Aplysia dactylomela
are reported. The purification procedure consisted basically of ammonium sulphate
fractionation, ion exchange, exclusion molecular and hydrophobic interaction
chromatography. The highly purified protein, designated dactylomelin-P, is a
single chain protein of 60,000 Da by SDS-polyacrylamide gel electrophoresis and
56,200 Da by gel filtration on calibrated Superose column at pH 7.5 and contains
less than 0.05% of its weight in neutral carbohydrates. Dactylomelin-P has two
biological activities, antibacterial and haemagglutinating. The antibacterial
action is bacteriostatic but not bactericidal. The haemagglutinating activity is
preferentially against rabbit erythrocytes. The glycoprotein fetuin was able to
abolish the haemagglutinating activity but not the antibacterial one even when
used at concentrations 10 fold higher. This is the first time that a
chimeroprotein is described in the purple fluid of sea hares, which may be
involved in the chemical defence mechanism of these organisms.
PMID- 10758277
TI - Neutralization of crotaline snake venoms from Central and South America by
antivenoms produced in Brazil and Costa Rica.
AB - A study was performed on the ability of antivenoms, produced in Brazil and Costa
Rica, to neutralize lethal, hemorrhagic and coagulant activities of the venoms of
16 species of Central and South American snakes of the subfamily Crotalinae.
Neutralization of lethality was studied by two different methods routinely used
in the quality control of antivenoms at Instituto Butantan (IB) and Instituto
Clodomiro Picado (ICP). Both antivenoms neutralized the majority of the venoms
studied, but the values of effective doses 50% (ED(50)) differed markedly
depending on the method used. In general, higher potencies were obtained with the
method of ICP, where a challenge dose corresponding to 4 LD(50)s is used, than
with the method of IB, where a challenge dose of 5 LD(50)s is employed. All
venoms induced hemorrhagic activity in the mouse skin test, which was effectively
neutralized by the two antivenoms. All venoms, except those of Porthidium nasutum
and Bothriechis lateralis, induced coagulation of human plasma in vitro and both
antivenoms were effective in the neutralization of this activity. In conclusion,
our results provide evidence of an extensive cross reactivity between these
antivenoms and Central and South American crotaline snake venoms.
PMID- 10758278
TI - Molecular cloning of cDNAs encoding insecticidal neurotoxic peptides from the
spider Phoneutria nigriventer.
AB - From a Phoneutria nigriventer venom gland cDNA library several clones coding for
the insect specific neurotoxin Tx4(6-1) were isolated. cDNA analysis showed that
the encoded protein contained three distinct segments, comprising a signal
sequence of 16 amino acids, followed by a glutamate-rich sequence of 18 amino
acids and, finally, the coding region for the mature toxin. The deduced amino
acid sequence for the mature polypeptide was identical to the protein sequence
determined chemically. In addition, two new putative toxins called Pn4A and Pn4B
were characterized and their predicted complete amino acid sequence revealed
approximately 78% similarity to Tx4(6-1).
PMID- 10758279
TI - Effect of heating on the toxic, immunogenic and immunosuppressive activities of
Crotalus durissus terrificus venom.
AB - The venom of South American rattlesnake Crotalus durissus terrificus is very
toxic but poorly immunogenic and it has an immunosuppressive ability. The heating
of venom at 56, 70 or 100 degrees C for 30 min caused a diminution in the lethal,
phospholipase A(2) and myotoxic activities. SDS-PAGE analysis of the heated venom
showed that the proteins of higher molecular weights were the most affected by
heating whereas proteins with lower molecular weights (20,000-14, 000) were the
most resistant to heating. The immunosuppressive effect was studied in mice
immunized with human serum albumin (HSA) 1 h after receiving either heated venom
or heated crotoxin. The heating of venom at 70 or 100 degrees C reduced its
immunosuppressive effect whereas crotoxin had its suppressive effect reduced only
when heated at 100 degrees C. The heating of venom at 56, 70 or 100 degrees C did
not change its immunogenicity. These results suggest that heat treatment may be a
useful technique to help in the production of antiserum to crotalid venom.
PMID- 10758280
TI - Inhibitors of the kynurenine pathway.
AB - Strokes (intracranial thomboses or haemorrhaging) cause death and disability, but
effective treatments are lacking. The metabolism of tryptophan leads to the
generation of quinolinic acid, an agonist potentially neurotoxic at glutamate
receptors, and kynurenic acid, an antagonist at the same population of receptors.
The commercial development of the kynurenine pathway has included the use of
analogues of kynurenic acid as antagonists at glutamate receptors. A second has
been to use prodrugs of kynurenic acid or its analogues. Alternatively, it is
proving possible to interfere directly with the kynurenine pathway to block the
synthesis of quinolinic acid and promote the formation of kynurenic acid. This
change yields neuroprotectant and anticonvulsant compounds.
PMID- 10758281
TI - Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters,
derived from natural safrole.
AB - Anew series of antinociceptive compounds belonging to the N-acylarylhydrazone
(NAH) class were synthesized from natural safrole (7). The most analgesic
derivative represented by 10f, [(4'-N,N-dimethylaminobenzylidene-3-(3', 4'
methylenedioxyphenyl)propionylhydrazine], was more potent than dipyrone and
indomethacin, used as standards. The NAH compounds described herein were
structurally planned by molecular hybridization and classical bioisosterism
strategies on previously reported analgesic NAH in order to identify the
pharmacophoric contribution of the N-acylarylhydrazone moiety and investigate the
structure-activity relationship (SAR) in these series.
PMID- 10758282
TI - Synthesis and antifibrillatory activity of nibentan and its analogues.
AB - A series of 1,5-diaminopentane derivatives, structurally related to nibentan, was
synthesized and tested for antifibrillatory activity. Improved modifications of
some known chemical syntheses were proposed. (+/-)-N-[5-(Diethylamino)-1-(4
nitrophenyl)pentyl]-benzamide hydrochloride, (+/-)-N-[5-(diethylamino)-1-(4
nitrophenyl)pentyl]-4-nitrobenzamide hydrochloride and (+/-)-N-[5-(diethylamino)
1-(4-hydroxyphenyl)pentyl]-4-nitrobenzamide hydrochloride were more potent than
nibentan and possessed a longer duration of action (up to 5 h in comparison with
60-90 min for nibentan). The antifibrillatory activity of (+/-)-N-[5
(diethylamino)-1-(4-methoxyphenyl)pentyl]-4-nitrobenzamide hydrochloride was
comparable to that of nibentan but exceeded the potency of D-sotalol and
sematilide.
PMID- 10758283
TI - N-Butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna
1',3', 5'(10')-trien-7'alpha-yl)-undecanamide: an inhibitor of type 2 17beta
hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic
activity.
AB - It is well known that 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play a
key role in the formation and inactivation, from circulating precursors, of
several active androgens and oestrogens. These enzymes can thus regulate tumoural
cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we
discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in
a novel inhibitor of type 2 17beta-HSD, an enzyme that catalyses the
interconversions between 4-androstene-3,17-dione and testosterone, and between
oestrone and oestradiol. This finding motivated our introducing the spiro-gamma
lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'
hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien
7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological
activity was assessed in vitro. Despite the presence of a bulky alkylamide side
chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2
17beta-HSD (IC(50) = 0.35 and 0.25 microM, with and without side chain,
respectively). Furthermore, the selective inhibition by lactone 4 toward type 2
17beta-HSD (microsomal fraction of human placenta) was demonstrated by the
absence of inhibitory activity toward type 1 17beta-HSD (cytosolic fraction of
human placenta). Cell proliferation assays indicated that compound 4 had no
oestrogenic activity but did show anti-oestrogenic activity on ER(+) cell line ZR
75-1. No androgenic activity could be detected when assayed on the AR(+) cell
line Shionogi either. Based on these facts, we report the synthesis of a new
steroidal derivative, one that inhibits type 2 17beta-HSD while possessing anti
oestrogenic activity.
PMID- 10758284
TI - Synthesis and diuretic activity of bicyclic fused heterocycles containing oxime-O
sulfonic acid moiety.
AB - In order to investigate the origin of the loop-type diuretic activity of M17055
(1), several variants (3-9) were designed and synthesized by modifying the
quinolinone skeleton, and their diuretic activities were compared with the lead 1
and furosemide in dogs. It was found that the negative charge distribution
pattern afforded by the dispositional arrangement of the 4-oxime-O-sulfonic acid
and 1-N-acyl carbonyl moiety attached to the tetrahydropyridine ring system is
inevitable for the development of the activity, which strongly supports the
previously proposed model for the active site of the Na(+)-K(+)-2Cl(-)
cotransporter. Also reported is the first synthesis of the dihydrothieno[3,2
b]pyridine-7(4H)-one ring system required in the synthesis of compound 9.
PMID- 10758285
TI - Anticonvulsant properties of various acetylhydrazones, oxamoylhydrazones and
semicarbazones derived from aromatic and unsaturated carbonyl compounds.
AB - Various acetylhydrazones, oxamoylhydrazones and semicarbazones were prepared as
candidate anticonvulsants with a view to examining the viability of a putative
binding site hypothesis. Atomic charge calculations were undertaken to determine
the hydrogen bonding capacities of various molecules. The biological results
obtained revealed that in general the acetylhydrazones and semicarbazones
afforded good protection against convulsions while the oxamoylhydrazones were
significantly less active. These data suggest that terminal electron-donating
groups enhanced the hydrogen bonding capabilities and anticonvulsant properties
of these molecules.
PMID- 10758286
TI - Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin
mannich bases.
AB - Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde
and several isatin derivatives. Their chemical structures have been confirmed by
means of their IR, 1H-NMR data and by elemental analysis. Investigation of in
vitro antimicrobial activity of compounds was done by the agar dilution method
against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity
against replication of HIV-1 (III B) in MT-4 cells. The in vivo antibacterial
efficacy of selected derivatives was determined using a mouse infection model.
All the synthesized compounds are more active than norfloxacin against the 13
bacteria tested. The compounds are also more active than the standard drug
clotrimazole against Histoplasma capsulatum. Two compounds S-8 and S-9 have shown
inhibition against HIV-1 (III B) with EC(50) values of 11.3 and 13.9
microgram/mL, respectively. In the mouse protection test, two compounds S-4
(ED(50): 1.25 mg/kg) and S-9 (ED(50): 1.62 mg/kg) are more active than
norfloxacin (ED(50): 6mg/kg). Among the compounds tested, 1-ethyl-6-fluoro-1, 4
dihydro-4-oxo-7[[N(4)-[5'-bromo-3'-(4'-amino-5'-trimethoxybenzylpyr imidin-2'-yl]
imino-1'-isatinyl]methyl]N(1)-piperazinyl]-3-q uinoline carboxylicacid (S-9)
showed promising activity in all the three tests.
PMID- 10758287
TI - Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives
as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi.
AB - Pyrrolidinyl- and thiazolidinyl- dipeptide derivatives, featuring either a vinyl
sulfone-, a 2-ketobenzothiazole-, a nitrile-, or a benzimidazole group at the C
terminus, were designed and synthesized as potential inhibitors of the prolyl
specific Tc80 proteinase from Trypanosoma cruzi, the agent of Chagas' disease.
These compounds were evaluated in vitro towards the target enzyme which was
classified as a serine protease belonging to the prolyl oligopeptidase family (EC
3.4.21.26). A peptidyl nitrile and two peptidyl alpha-ketobenzothiazoles were
shown to be potent reversible and competitive inhibitors of Tc 80 proteinase,
with K(i) values in the range 38-219 nM, and compared advantageously with some
known mammalian prolyl oligopeptidase inhibitors.
PMID- 10758288
TI - Synthesis and antibacterial studies of a new series of 1,2-bis(1,3, 4-oxadiazol-2
yl)ethanes and 1,2-bis(4-amino-1,2, 4-triazol-3-yl)ethanes.
AB - The acylhydrazones 3, obtained by the treatment of succinic acid dihydrazide 2
with furfural, nitrofurfuraldehydediacetate and substituted arylfurfurals, on
oxidative cyclization with bromine in acetic acid yielded 1,2-bis(1,3,4-oxadiazol
2-yl)ethanes 4 which are further converted into 1,2-bis(4-amino-1,2,4-triazol-3
yl)ethanes 5 with hydrazine hydrate. The newly synthesised compounds are
characterised by analytical, IR, NMR and mass spectral data. Most of the newly
synthesised compounds have been found to be active against both Gram positive and
Gram negative bacteria at less than 6 microg/mL concentration.
PMID- 10758289
TI - Flexor muscle incursion into the carpal tunnel: a mechanism for increased carpal
tunnel pressure?
AB - PURPOSE: To explore the hypothesis that the extrinsic finger flexor muscles have
the potential to move into the proximal end of the carpal tunnel with wrist
extension. METHODS: The most distal muscle fibres from the deep and superficial
finger flexors were measured relative to the pisiform bone in 18 cadaveric
specimens. Muscle excursions during wrist extension were calculated using
regression equations previously reported in the literature. RESULTS: The mean
distances from the pisiform were 9.3 and 4.9 mm for the deep and superficial
flexors, respectively. Ten flexor muscle bellies were at the level of or distal
to the pisiform bone in the anatomical position, while 17 of 36 were within 5 mm.
DISCUSSION: The excursions expected with wrist extension indicate that many
muscles have the potential to enter the carpal tunnel, especially those within 5
mm of the pisiform bone. Comparing the expected excursions to recent pressure
data, corroborating support for the pressure increase is found. CONCLUSION:
Although not directly measured, the results of this study indicate incursion of
the flexor muscles into the carpal tunnel space, particularly with wrist
extension, is a plausible mechanism for increased carpal tunnel pressure.
RELEVANCE: Proposing a mechanism by which carpal tunnel pressure is elevated
during wrist and finger extension is a stepping stone to determining the etiology
of the disease itself. Finding that the flexor muscle bellies appear to enter the
carpal tunnel with wrist extension indicates that use of the flexor muscles
should be avoided when the wrist and fingers are extended.
PMID- 10758290
TI - The effect of negative intraarticular pressure and rotator cuff force on
glenohumeral translation during simulated active elevation.
AB - OBJECTIVE: The objective of this study was to determine the effect of negative
pressure in the intraarticular space and subacromial bursa, as well as rotator
cuff force, on glenohumeral translation during active elevation. DESIGN:
Glenohumeral translation during elevation in the scapular plane was measured
under greater than, less than, and equal to physiologic rotator cuff muscle
force, as well as with and without the subacromial bursa and intraarticular space
vented. BACKGROUND: Negative intraarticular pressure has been shown to help
stabilize the glenohumeral joint in passive motion, although the effect on
translation during active motion has not been investigated. METHODS: Eight
cadaverous human shoulder specimens were tested in a dynamic shoulder simulator.
Forces in the muscles of the rotator as well as the middle deltoid muscle were
simulated using servohydraulic cylinders. Joint motion was measured using an
ultrasonic motion analysis system. RESULTS: Superior translation of the humerus
increased 1.2 mm (SD, 0.4) upon venting of the bursa, and 2.1 mm (SD, 1.7) upon
venting of the joint capsule at 25 degrees of glenohumeral elevation in the
scapular plane. At 90 degrees elevation, venting the bursa did not change
superior translation but increased anterior translation 1.04 mm (SD, 1.0).
Venting of the joint capsule increased superior translation by 2.8 mm (SD, 2.5).
Decreasing rotator cuff force increased superior translation, while reducing it
did not. CONCLUSION: The muscles of the rotator cuff and the negative pressure of
the intraarticular space and the subacromial bursa stabilize the glenohumeral
joint since they restrict translation in the superior and anterior directions.
RelevanceIncreased glenohumeral translation and the resulting asymmetric loading
may lead to arthrosis and ultimately rotator cuff arthropathy.
PMID- 10758291
TI - Predicting mechanical load of the glenohumeral joint, using net joint moments.
AB - OBJECTIVE: To evaluate the relationship between net moments for the glenohumeral
joint as calculated with a model that is easy to apply (Static Strength
Prediction Program (SSPP)) and the internal forces, calculated with a simulation
model of the human shoulder (Delft Shoulder Model, DSM). DESIGN: Static
recordings of bony landmarks of the shoulder girdle during prescribed arm motions
using a three-dimensional (3D) digitizer. BACKGROUND: The SSPP is a biomechanical
model for the evaluation of workload. Concerning the shoulder the output of the
model consists of net moments in the glenohumeral joint. For the glenohumeral
joint the relationship between net joint moments and internal load predictions is
unknown, therefore it is useful to investigate whether the SSPP can be used to
predict mechanical load in the glenohumeral joint. METHODS: 3D co-ordinates of
bony landmarks of the shoulder girdle are recorded, in variable arm positions, in
four different planes. RESULTS: A strong linear relationship between compression
forces and net moments is found, which makes it reasonable to assume a direct
relationship between net moments and joint compression forces. CONCLUSIONS: (a)
Net joint moments appeared to be a good indicator for mechanical load in the
glenohumeral joint in static situations. (b) The SSPP can be used to predict
these joint moments for static situations. RELEVANCE: biomechanical models
predicting mechanical load can be used in work situations in order to prevent
overload and injuries, as well as in many other areas, for instance to evaluate
the mechanical load during wheelchair propulsion.
PMID- 10758292
TI - The relevance of the moment arm of shoulder muscles with respect to axial
rotation of the glenohumeral joint in four positions.
AB - OBJECTIVE: This study was undertaken to determine the efficiency of the shoulder
girdle muscles during axial humeral rotation based on measurements of the moment
arms. DESIGN: The instantaneous muscle moment arms of 10 shoulder muscles,
including the three portions of the deltoid, the rotator cuff muscles, teres
major, and the thoracohumeral muscle group, were measured during four specified
glenohumeral rotations. BACKGROUND: Axial humeral rotation is a commonly
performed movement during activities of daily living and is a targeted motion of
shoulder rehabilitation, particularly in those protocols emphasizing rotator cuff
strengthening. An understanding of the function of the movers and stabilizers of
the shoulder requires such basic information of muscle moment arms. METHODS: The
instantaneous moment arm values of the muscles were derived from the slope of the
plot of tendon excursion versus glenohumeral joint rotation angle. Motion studied
included axial rotation with the humerus elevated 90 degrees in the coronal,
scapular, and sagittal planes, as well as in the neutral position with the arm at
the side. RESULTS: Based on the findings, with the humerus in both neutral and
elevated positions, the infraspinatus is potentially the most powerful external
rotator, followed by teres minor and posterior deltoid. Subscapularis and
possibly pectoralis major are the most effective internal rotators in this
position. CONCLUSIONS: The moment arm in providing axial humeral rotation of 10
shoulder muscles in four planes were obtained. In general, the teres minor and
infraspinatus had the largest moment arms in external rotation, and the
subscapularis had the largest moment arm in internal rotation. The muscle
function for axial humeral rotation was found to be modified by the plane of arm
elevation. RELEVANCE: The data could be used for developing exercise programs in
physical therapy.
PMID- 10758293
TI - Passive moment about the hip in straight leg raising.
AB - OBJECTIVE: The purpose of this examine is to study the load-deformation
characteristics of the hip in straight leg raising. DESIGN: An experimental study
in which passive moment about the hip was determined as a function of hip angle.
BACKGROUND: Straight leg raising is widely employed in clinical examination, and
there is little information on its mechanical characteristics. METHODS: Fourteen
healthy volunteers were recruited for this study. Three trials of straight leg
raise tests were performed while subjects lay supine on a plinth that was fitted
with load cells. An electrogoniometer was employed to measure hip flexion during
the test. Resistive moment at the hip was determined using a dynamic
biomechanical model. RESULTS: The present experimental method was shown to be
highly reliable. The moment-angle curves of all subjects were shown to follow an
exponential function. CONCLUSION: Stiffness and strain energy of posterior hip
tissues could be derived from the moment-angle curves. Evaluation of such elastic
properties is clinically important as they may be altered with injuries of the
tissues. RELEVANCE: Clinically, contracture of hamstring muscles and other
posterior hip tissues is evaluated by measuring the available range of hip
flexion in straight leg raising. However, this does not provide any information
on the elastic properties of the tissues. The present study reports a reliable
method of evaluating such properties.
PMID- 10758294
TI - The influence of weakness in the vastus medialis oblique muscle on the
patellofemoral joint: an in vitro biomechanical study.
AB - OBJECTIVE: Investigation of the influence of weakness in the vastus medialis
oblique muscle on patellar tracking. DESIGN: In vitro biomechanical study.
BACKGROUND: Currently, the influence of weakness in the vastus medialis oblique
muscle on patellar tracking has not been well understood. METHODS: Seven human
cadaveric knees were used. The direction of loading forces in the rectus
femoris/vastus intermedius, vastus medialis oblique, and the vastus lateralis
muscles was decided by the muscle alignment of each cadaver knee measured at the
time of dissection. The loads used were 60 N in the rectus femoris, 50 N in the
vastus lateralis, and 40 N in the vastus medialis oblique, according to the ratio
calculated from the cross-sectional study. The weakness of vastus medialis
oblique was simulated at 30 N (75%), 20 N (50%), 10 N (25%), and 0 N (0%), and
the patellar position was measured for each condition using a magnetic 3 Space
Tracker System. The influence of weakness in the vastus medialis oblique muscle
on patellar position was investigated with seven cadaver knees using a magnetic 3
Space Tracker System. RESULTS: At 0 degrees and 15 degrees of knee flexion, 75%,
50%, 25% and 0% of the normal vastus medialis oblique muscle led to a significant
difference in lateral patellar shift compared to the normal (P<0.05).
CONCLUSIONS: Weakness of the vastus medialis caused the patellar lateral shift at
0 degrees and 15 degrees of knee flexion. RELEVANCE: Weakness of the vastus
medialis is thought to be an important factor causing patellar subluxation and
dislocation. Understanding the relationship between the vastus medialis weakness
and patellar tracking will be useful in diagnosis, treatment and prevention of
patellar subluxation and dislocation.
PMID- 10758295
TI - Kinematic and kinetic analysis of the walking pattern in hemiplegic patients with
foot-drop using a peroneal nerve stimulator.
AB - OBJECTIVE: To analyze the walking pattern in hemiplegic patients using a peroneal
nerve stimulator to locate possible harmful mechanical effects on the musculo
skeletal system. DESIGN: Eight hemiplegic patients participated in the study. All
patients had used a peroneal nerve stimulator regularly for more than two years
and were able to perform unassisted walking. BACKGROUND: Peroneal nerve
stimulators are widely applied for correction of foot-drop in hemiplegic
patients. The stimulators do not induce normal dorsi-flexion, but a rather
exaggerated dorsi-flexion and eventually eversion which might be harmful.
METHODS: Three-dimensional kinematic and kinetic analyses of the walking patterns
at self-selected speeds were performed with the patients walking without the
stimulator and with the stimulator turned on. RESULTS: The walking speed
increased on average from 0.77 (S.D., 0.83) to 0.84 (S.D., 0.11) (7.6%, P=0. 005)
when the stimulator was used, however no uniform changes in the walking pattern
and joint loads were observed. The total work (generation+absorption) produced by
the affected leg (both with and without the peroneal nerve stimulator) was
significantly lower (P=0. 005) than that of the contralateral leg. Deviations
from normal power profiles were observed both on the affected and the
contralateral side, and the walking efficiency was 57% lower compared to normal
subjects. The estimated peak bone-on-bone forces corresponded to about 50% of
what previously has been observed during normal walking at self-selected speed.
CONCLUSIONS: The use of the peroneal nerve stimulator do not introduce any
excessive and potential harmful mechanical loads. RELEVANCE: Applied correctly,
the peroneal nerve stimulator can be used as an aid for foot-drop correction in
hemiplegic patients without causing excessive wear on the joints in the lower
extremity.
PMID- 10758296
TI - Biomechanical adaptations of transtibial amputee sprinting in athletes using
dedicated prostheses.
AB - OBJECTIVE: To determine the biomechanical adaptations of the prosthetic and sound
limbs in two of the world's best transtibial amputee athletes whilst sprinting.
DESIGN: Case study design, repeated measures. BACKGROUND: Using dedicated sprint
prostheses transtibial amputees have run the 100 m in a little over 11 s. Lower
limb biomechanics when using such prostheses have not previously been
investigated. METHODS: Moments, muscle powers and the mechanical work done at the
joints of the prosthetic and sound limbs were calculated as subjects performed
repeated maximal sprint trials using a Sprint Flex or Cheetah prosthesis.
RESULTS: An increased hip extension moment on the prosthetic limb, with an
accompanying increase in the amount of concentric work done, was the most notable
adaptation in Subject 1 using either prosthesis. In Subject 2, an increased
extension moment at the residual knee, and an accompanying increase in the amount
of total work done, was the most notable adaptation using either prosthesis. This
later adaptation was also evident in Subject 1 when using his Sprint Flex
prosthesis. CONCLUSIONS: Increased hip work on the prosthetic limb has previously
been shown to be the major compensatory mechanism that allow transtibial amputees
to run. The increased work found at the residual knee, suggests that the two
amputee sprinters used an additional compensatory mechanism. RELEVANCE: These
findings provide an insight into the biomechanical adaptations that allow a
transtibial amputee to attain the speeds achieved when sprinting.
PMID- 10758297
TI - Plantar and dorsal foot loading measurements in patients after rotationplasty.
AB - OBJECTIVE: The present study investigated the plantar and dorsal foot loading
patterns inside the prosthesis of patients after rotationplasty. DESIGN: In vivo
foot pressure distribution measurements during free walking in rotationplasty
patients at an average follow-up of 10.4 years after surgery. METHODS: Fourteen
subjects participated in the study and were measured during free walking.
Capacitive pressure sensitive insoles were worn inside the shaft of the
prosthesis either on the plantar or the dorsal aspect of the foot. Between 5 and
15 steps (mean 10.5) during full gait were selected and averaged to present a
typical loading pattern for the individual patient. RESULTS: The measurements
were reproducible and indicated that the main loading areas of the rotated foot
inside the prosthesis are medially on the dorsal aspect and in the heel and toe
region or the heel and midfoot region on the plantar aspect. The dorsal loading
area was smaller than the plantar area (P=0.003). The force was higher on the
plantar than on the dorsal aspect (P=0.005) but the loading time was shorter
(P=0.008). In patients with callosities the high pressure areas coincided with
the affected regions. CONCLUSIONS: The information gained from the pressure
measurements support the understanding of foot loading characteristics in this
anatomically and biomechanically unusual situation. This knowledge may be used to
support the fitting process of new prosthetic designs for patients after
rotationplasty. RELEVANCE: Foot loading capacity is one of the main factors
limiting the activity level of rotationplasty patients. Therefore, a better
understanding of foot loading characteristics might help to prevent overloading
of certain foot structures and eventually improve the prosthetic fit with a
direct benefit to the individual patient.
PMID- 10758298
TI - Correlations between force plate measures for assessment of balance.
AB - OBJECTIVE: To compare different force plate measures for assessment of postural
stability during normal standing. Five types of measures were analysed: (1) The
standard deviation of the horizontal ground reaction force, (2) the standard
deviation of the centre of pressure, (3) the mean velocity of the centre of
pressure, (4) movement strategy measures, and (5) the standard deviation of the
vertical ground reaction force. BACKGROUND: Force plate measures such as types 1
3 are frequently used, but they seem to have limited usefulness for assessment of
balance on an individual level. Hence, there is a need to investigate alternative
force plate measures (such as types 4 and 5). METHODS: Force plate measures for
20 stroke patients were (a) compared to each other, and (b) compared to a
clinical balance test, called Berg's balance test. RESULTS: There was generally a
significant correlation (P<0.01) between measures of types 1-3. The movement
strategy measures were not significantly correlated to any of the other measures.
The vertical force measure was only significantly correlated to the antero
posterior mean velocity of the centre of pressure. There was a significant
correlation between (a) Berg's balance test and the vertical force measure (r(s)=
0.76), and (b) the static part of Berg's balance test and the antero-posterior
mean velocity of the centre of pressure (r(s)=-0.6). CONCLUSIONS: Measures of
type 1, 2, 4 and 5 seem to quantify different aspects of human standing. The
results also indicate that Berg's balance test and the vertical force measure
quantify a similar aspect of the postural stability. RELEVANCE: The results from
this study may facilitate the understanding and interpretation of force plate
measures.
PMID- 10758299
TI - Effects of growth on the response of the rabbit patellar tendon to stress
shielding: a biomechanical study.
AB - OBJECTIVE: To know the effect of stress deprivation on the dimensions and
mechanical properties of the patellar tendon during growth. DESIGN: The
dimensions and tensile properties of stress-shielded patellar tendons were
studied in growing rabbits and compared to those in mature animals. BACKGROUND:
Although the effects of stress deprivation on the remodeling of ligaments and
tendons have been studied in various animal models, the effect of growth on the
remodeling has not been studied well. METHOD: A stress shielding technique was
applied to 1-, 2-, and 3-month-old Japanese white rabbits to completely remove
stress in the patellar tendons for 4, 7, and 14 days. Changes in the dimensions
and mechanical properties as well as fibroblast density of the tendon were
determined. RESULTS: The tensile strength and tangent modulus of the patellar
tendons were markedly decreased by stress shielding, while the cross-sectional
area was significantly increased, with the largest changes in 1-month-old
rabbits. Fibroblast density also increased; however, the degree of increase was
highest in 3-month-old rabbits. CONCLUSION: The changes in the dimensions and
mechanical properties of the patellar tendons induced by stress shielding were
greater in younger animals. RELEVANCE: The biomechanical response of tendons and
ligaments to stress deprivation induced by, for example, limb immobilization is
greater and occurs earlier in younger subjects, which is important for the
surgical treatment and rehabilitation protocol of joint diseases in young
subjects.
PMID- 10758300
TI - Alterations of biochemical and two-dimensional biomechanical properties of human
skin in diabetes mellitus as compared to effects of in vitro non-enzymatic
glycation.
AB - OBJECTIVE: The aim of this study was to evaluate whether multiaxial analysis of
diabetes-specific biomechanical changes generated in vitro by non-enzymatic
glycation of human skin samples from healthy subjects reflect the changes seen in
skin from subjects with diabetes mellitus. DESIGN: Descriptive study. BACKGROUND:
Non-enzymatic glycation of skin in vitro causes an increased stiffness comparable
to in vivo changes seen in diabetic patients. These changes are probably due to
increased cross-linking of collagen molecules. METHODS: Skin specimens from 7
subjects with diabetes mellitus and 7 controls (age range: 74-90) were analyzed
for biomechanical changes using a multiaxial tensile testing device. Control
skins from healthy individuals in the age range of 50-65 yr were artificially
glycated. One part of these samples was coincubated with the glycation inhibitor
aminoguanidine. Glycation of tissues was determined by measuring fluorescence of
solubilized samples. Multiaxial biomechanical analysis allows the determination
of maximum (a(I)) and minimum elastic modulus (a(II)). These parameters describe
the amplitude of the elastic stress response, which is exponentially related to
strain. RESULTS: Principal stresses, both maximum and minimum, were increased in
skins from diabetic subjects as compared to controls. The increases of the
principal stresses were comparable to those obtained by in vitro glycation of
normal skins. CONCLUSION: These results, which can be detected unequivocally with
the multiaxial test mode, show that our in vitro model closely reflects changes
in skin samples from individuals with diabetes mellitus. Aminoguanidine partially
inhibited these as well as biochemical changes. RELEVANCE: Multiaxial testing of
in vitro glycated skin samples can be used as a model for in vivo changes caused
by diabetes mellitus. In addition, therapeutical effects of aminoguanidine, an
inhibitor of non-enzymatic glycation, can be monitored in this model.
PMID- 10758302
TI - Toxicity in head and neck cancer: a review of trends and issues.
AB - The quest for improved fractionation and combined modality regimens in head and
neck cancer has also yielded progressively higher rates of toxicity. Time
compression of dose delivery in accelerated fractionation has produced high rates
of severe mucositis including the early stoppage of two randomized trials. The
addition of chemotherapy has introduced systemic toxicity and can exacerbate
local tissue reactions when used concurrent with radiotherapy. Mucositis is
recognized as the principal impediment to efforts at further treatment
intensification. The development and utilization of standardized toxicity grading
criteria and accepted reporting standards has lagged toxicity production,
impeding a full appreciation of the true extent of both acute and late toxicity.
Objective data regarding acute and chronic effects on organ function are also
sorely lacking. A better characterization of the frequency, severity, and
duration of the various toxicities encountered in head and neck cancer will also
allow the rational development of toxicity interventions. New methods are needed
to summarize the global or aggregate toxicity of a treatment program. Further
research into the assessment and analysis of toxicity is not only crucial to
improvements in quality of life (QOL), but perhaps, improved rates of disease
control as well.
PMID- 10758303
TI - Common toxicity criteria: version 2.0. an improved reference for grading the
acute effects of cancer treatment: impact on radiotherapy.
AB - In 1997, the National Cancer Institute (NCI) led an effort to revise and expand
the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent,
radiation, and surgical criteria into a comprehensive and standardized system.
Representatives from the Radiation Therapy Oncology Group (RTOG) participated in
this process in an effort to improve acute radiation related criteria and to
achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the
previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and
includes more than 260 individual adverse events with more than 100 of these
applicable to acute radiation effects. One of the advantages of the revised
criteria for radiation oncology is the opportunity to grade acute radiation
effects not adequately captured under the previous RTOG system. A pilot study
conducted by the RTOG indicated the new criteria are indeed more comprehensive
and were preferred by research associates. CTC v. 2.0 represents an improvement
in the evaluation and grading of acute toxicity for all modalities.
PMID- 10758304
TI - The use of carboplatin and paclitaxel with daily radiotherapy in patients with
locally advanced squamous cell carcinomas of the head and neck.
AB - PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN)
continue to pose a significant therapeutic challenge. This report defines the
toxicities, efficacy, and prognostic factors associated with the combination of
carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with
locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were
investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III
IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary
site. Weekly chemotherapy was given during RT consisting of paclitaxel (45
mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally
advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent
had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and
survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent
of patients completed prescribed therapy. One patient died after refusing medical
management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two
patients suffered Grade 4 leukopenia. Median number of break days was two. A
clinical complete response (CR) at the primary site was obtained in 82%, with a
total (primary site and neck) CR rate of 75%. The median survival for the entire
cohort is 33 months. Response to therapy and status of the neck at presentation
were the only prognostic factors found to influence survival. The median survival
for patients who attained a CR is 49 months versus 9 months in those who did not
attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete
responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown
to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and
paclitaxel given concurrently with definitive once-daily external beam radiation
therapy is well tolerated with over 90% of patients completing prescribed
therapy. An ultimate CR rate of greater than 70% was obtained, which translated
directly into improved survival. With 48% 3-year overall survival for the entire
group, this regimen is an excellent option for this group of patients with a
historically poor prognosis.
PMID- 10758305
TI - Evidence of cell kinetics as predictive factor of response to radiotherapy alone
or chemoradiotherapy in patients with advanced head and neck cancer.
AB - PURPOSE: The aim of this study was to investigate the potential clinical
relevance of cell kinetics parameters to the locoregional control (LRC) and
overall survival of patients affected by head and neck squamous cell carcinoma
(HN-SCC) treated by conventional radiotherapy, partly accelerated radiotherapy,
or alternating chemoradiotherapy. METHODS AND MATERIALS: Between January 1993 and
June 1996,115 patients with HN-SCC at Stage III and IV entered the study.
Multiple primary tumor biopsies were obtained 6 h after in vivo infusion of
bromodeoxyuridine (BrdUrd), an analogue of thymidine that is incorporated in DNA
synthesizing cells. In vivo S-phase fraction labeling index (LI), duration of S
phase (Ts), and potential doubling time (Tpot) were obtained by analysis of the
flow cytometric content of BrdUrd and DNA. Eighty-two patients were randomly
assigned to receive either alternating chemoradiotherapy or partly accelerated
radiotherapy, whereas 33 other matching patients received conventional
radiotherapy. RESULTS: Univariate LRC analysis showed that LI value was a
prognostically significant factor, independent of type of therapy. Multivariate
analysis failed to show cell kinetics parameters as statistically significant
factors affecting LRC probability and overall survival. However, subgroup
analysis showed that LRC probability at 4 years for fast proliferating tumors
characterized by a LI >/= 8% was significantly better for patients treated either
with alternating chemoradiotherapy or partly accelerated radiotherapy than it was
for those treated with conventional radiotherapy. Conversely, LRC probability for
slow proliferating tumors (LI < 8%) treated with the three treatment modalities
was similar. CONCLUSIONS: These results showed that, independent of type of
treatment, pretreatment cell kinetics provided only a weak prognostic role of
outcome in HN-SCC. However, this report raises the hypothesis that fast growing
HN-SCC may be more likely to benefit from intensified therapy, as given in this
series. Cell kinetics parameters studied by the in vivo BrdUrd/flow cytometry
method might be considered predictive factors of response, providing information
on which type of treatment may be selected according to tumor proliferation rate.
PMID- 10758306
TI - Comparing treatment outcomes of radiotherapy and surgery in locally advanced
carcinoma of the larynx: a comparison limited to patients eligible for surgery.
AB - PURPOSE: The use of radical radiotherapy and surgery for salvage (RRSS) in
locally advanced squamous cell carcinoma (SCC) of the larynx is controversial. In
the absence of randomized studies, it is unclear if RRSS can match the rates of
locoregional control and survival reported for primary surgery in this setting.
The aim of this study was to compare treatment outcomes of radiotherapy and
surgery in comparable patients with CS III-IV SCC of the larynx. METHODS AND
MATERIALS: Eighty-two patients with untreated T2N+M0 or T3T4NM0 SCC of the larynx
were treated with a policy RRSS at the Toronto-Sunnybrook Regional Cancer Centre
between June 1980 and December 1990. The medical records at presentation were
reviewed independently by a panel of three surgical oncologists blinded as to
treatment outcome to determine patient suitability for laryngectomy and neck
dissection using eligibility criteria adopted by recent clinical trials.
Treatment outcomes for surgery-eligible patients were compared to results of
comparably staged patients in the surgical literature since 1980. RESULTS: Sixty
three patients (77%) were eligible for study. With a median follow-up of 3 years,
radiotherapy controlled the primary in 8/20 evaluable glottic primaries and 21/41
evaluable supraglottic primaries. Forty-five percent of patients surviving 5
years retained a functional larynx. Sixteen of 29 relapsing patients were
salvaged with surgery. Disease above the clavicles was controlled in 65% of
T3T4N0N+ glottic primaries (compared to a published range of 53% to 79%) and 82%
of T3N0 glottic primaries (compared to a published range of 69% to 84%). The 5
year overall survival of patients with T3T4 glottic cancer was 54% compared to a
published range of 50% to 63%. The cause-specific survival (CSS) of patients with
T3N0 glottic primaries (86% at 1 year and 73% at 2 years) was identical to the
only published report of CSS in the surgical literature. CONCLUSION: A policy of
RRSS offers a good chance of laryngeal conservation without compromising ultimate
locoregional control or survival when compared to primary laryngectomy and neck
dissection in patients with locally advanced carcinoma of the larynx meeting the
surgical eligibility of clinical trials.
PMID- 10758307
TI - Acoustic analysis after radiotherapy in T1 vocal cord carcinoma: a new approach
to the analysis of voice quality.
AB - PURPOSE: The study of acoustic voice parameters (fundamental frequency, jitter,
shimmer, and harmonics-to-noise ratio) in extended vowel production, oral reading
of a standard paragraph, spontaneous speech and a song in irradiated patients for
Tis-T1 vocal cord carcinoma. METHODS AND MATERIALS: Eighteen male patients
irradiated for Tis-T1 vocal cord carcinoma and a control group of 31
nonirradiated subjects of the same age were included in a study of acoustic voice
analysis. The control group had been rigorously selected for voice quality and
the irradiated group had previous history of smoking in two-thirds of the cases
and a vocal cord biopsy. Radiotherapy patients were treated with a 6MV Linac
receiving a total dose of 66 Gy, 2 Gy/day, with median treatment areas of 28
cm(2). Acoustic voice analysis was performed 1 year after radiotherapy, the voice
of patients in extended vowel production, oral reading of a standard paragraph,
spontaneous speech, and in a song was tape registered and analyzed by a Kay
Elemetric's Computerized Speech Lab (model CSL# 4300). Fundamental frequency,
jitter, shimmer, and harmonics-to-noise ratio were obtained in each case. Mann
Whitney analysis was used for statistical tests. RESULTS: The irradiated group
presented higher values of fundamental frequency, jitter, shimmer, and harmonics
to-noise ratio. Mann-Whitney analysis showed significant differences for
fundamental frequency and jitter in vowel production, oral reading, spontaneous
speech, and song. Shimmer only showed differences in vowel production and
harmonics-to-noise ratio in oral reading and song. CONCLUSIONS: In our study only
fundamental frequency and jitter showed significant increased values to the
control group in all the acoustic situations. Sustained vowel production showed
the worst values of the acoustic parameters in comparison with the other acoustic
situations. This study seems to suggest that more work should be done in this
field.
PMID- 10758308
TI - Accelerated radiotherapy for T1, 2 glottic carcinoma: analysis of results with KI
67 index.
AB - PURPOSE: Hyperfractionated and accelerated radiotherapy without a split was
performed to improve the local control probability of early glottic carcinomas.
We analyzed the results of this regimen by using the Ki-67 index. METHODS AND
MATERIALS: Over a 12-year period, 85 T1N0M0 glottic cancers and 50 T2N0M0 glottic
cancers were treated with conventional fractionation (CF) from 1984 to 1989 and
with accelerated fractionation (AF) since 1990. The CF program consisted of five
daily fractions of 2 Gy per week, for a total of 64 Gy. The AF program consisted
of 1.72 Gy per fraction, two fractions per day, 5 days a week, for a total of 55
or 58 Gy. The specimens, taken before radiotherapy, were immunohistochemically
stained with anti-Ki-67 antibody. RESULTS: The 5-year local control probability
for T1 tumors was 79.6 +/- 6.9% with CF treatment, whereas with AF it was 86.9 +/
5.6%. For T2 tumors it was 62.7 +/- 12.2% with CF, whereas it was 74.7 +/- 7.8%
with AF. The difference between CF and AF did not reach the point of statistical
significance. However, when T1 tumors had a Ki-67 index lower than 50%, the local
control rate achieved with AF was significantly better than that with CF (p =
0.018). When the tumors had a Ki-67 index that was 50% or more, there was no
difference in the local control rate between CF and AF, whether they were T1 or
T2. The peak mucosal reactions at the larynx and/or hypopharynx were much more
severe and appeared at smaller doses and earlier in AF than in CF. The patients
with AF showed no severe late complications. CONCLUSIONS: AF could not obtain
statistically significant improvement in local control probability of T1 or T2
glottic carcinomas.
PMID- 10758309
TI - Skin cancer of the head and neck with clinical perineural invasion.
AB - PURPOSE: To review treatment and outcomes in 62 patients with clinical and/or
gross evidence of perineural invasion from skin cancer of the head and neck.
METHODS AND MATERIALS: Sixty-two patients received radiotherapy at the University
of Florida as part or all of their treatment between January 1965 and April 1995.
All patients had clinical signs and symptoms of perineural involvement and/or
documentation of tumor extending to grossly involve nerve(s). Twenty-one patients
underwent therapy for previously untreated lesions, including 12 who received
radiotherapy alone and nine who had surgery with postoperative radiotherapy.
Forty-one patients underwent therapy for recurrent lesions, including 18 treated
with radiotherapy alone and 23 who received preoperative or postoperative
radiotherapy. RESULTS: Factors on multivariate analysis that predicted local
control included patient age, previously untreated vs. recurrent lesions,
presence of clinical symptoms, and extent of radiotherapy fields. Recurrence
patterns were predominantly local; 26 of 31 patients (84%) who developed local
recurrence after treatment had recurrent cancer limited to the primary site.
CONCLUSIONS: Many patients with skin cancer and symptomatic perineural invasion
have disease that is incompletely resectable. Approximately half these patients
will be cured with aggressive irradiation alone or combined with surgery. Age,
prior treatment, and clinical symptoms influence the likelihood of cure.
PMID- 10758310
TI - Treatment of skin carcinomas of the face by high-dose-rate brachytherapy and
custom-made surface molds.
AB - PURPOSE: To analyze the results obtained in a prospective group of patients with
basal or squamous cell skin carcinomas of the face treated by high-dose-rate
(HDR) brachytherapy via custom-made surface molds. METHODS AND MATERIALS: A total
of 136 patients with basal or squamous cell carcinomas of the face were treated
between March 1992 and March 1997 by surface molds and HDR brachytherapy with
iridium-192. Nineteen patients were treated with standard Brock applicators and
117 patients with custom-made polymethyl methacrylate applicators, built over a
plaster mold obtained of the patient's face. Minimum dose administered to the
tumor was 6000 to 6500 cGy in 33 to 36 fractions at 180 cGy/fraction in lesions
of up to 4 cm. Lesions greater than 4 cm were boosted up to 7500-8000 cGy after a
3-week pause. RESULTS: With the custom-made surface molds, the dose distribution
was uniform in the surface of the skin and at 5 mm depth in the whole area of the
applicator. Differences between the areas of maximum and minimum dose at this
depth never reached values higher than 5% of the prescribed dose. At the edges of
the custom-made molds dose gradient was sharp, with the detected dose at 5 mm
from the applicator being negligible. All the patients were complete responders.
There were 3 local recurrences, 1/73 patients treated for primary tumor and 2/63
patients treated for recurrent tumor. Actuarial local control at 5 years for all
patients was 98%, for those patients with primary tumors 99%, and for recurrent
patients 87%. The treatment tolerance was excellent in all cases. No severe,
early, or late, complications were detected. CONCLUSIONS: Radiotherapy is a
highly effective treatment of skin carcinomas of the face. Custom-made molds, to
be used in conjunction with HDR brachytherapy equipment, make possible a uniform
dose distribution, with a sharp dose gradient in the limits of applicators.
Custom-made surface molds are easy and safe to use, and they fit very accurately
for daily treatment. Local control is excellent with minimal sequelae or
complications. Probably they will become the standard way of treatment of face
skin carcinomas in the near future.
PMID- 10758311
TI - Late rectal toxicity after conformal radiotherapy of prostate cancer (I):
multivariate analysis and dose-response.
AB - PURPOSE: The purpose of this paper is to use the outcome of a dose escalation
protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate
cancer to study the dose-response for late rectal toxicity and to identify
anatomic, dosimetric, and clinical factors that correlate with late rectal
bleeding in multivariate analysis. METHODS AND MATERIALS: Seven hundred forty
three patients with T1c-T3 prostate cancer were treated with 3D-CRT with
prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal
toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric
analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy
(119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within
30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or
were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83
patients). Univariate and multivariate logistic regression was performed to
correlate late rectal bleeding with several anatomic, dosimetric, and clinical
variables. RESULTS: A dose response for >/= Grade 2 late rectal toxicity was
observed. By multivariate analysis, the following factors were significantly
correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy:
1) enclosure of the outer rectal contour by the 50% isodose on the isocenter
slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall
volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1)
smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal
D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient
age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to
these five factors, acute rectal toxicity was also significantly correlated (p =
0.05) with late rectal bleeding when patients from both dose groups were combined
in multivariate analysis. CONCLUSION: A multivariate logistic regression model is
presented which describes the probability of developing late rectal bleeding
after conformal irradiation of prostate cancer. Late rectal bleeding correlated
with factors which may indicate that a greater fractional volume of rectal wall
was exposed to high dose, such as smaller rectal wall volume, inclusion of the
rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).
PMID- 10758312
TI - Acute toxicity of three-dimensional conformal radiotherapy in prostate cancer
patients eligible for implant monotherapy.
AB - PURPOSE: To assess the acute toxicity of three-dimensional conformal radiotherapy
(3D-CRT) in prostate cancer patients eligible for implant monotherapy. METHODS
AND MATERIALS: Between December 1991 and June 1998, 198 prostate cancer patients
were treated with 3D-CRT at the University of California Davis Medical Center.
Fifty-two of these patients had a prostate-specific antigen (PSA) level /= Grade 3, e.g.,
hourly nocturia, gross hematuria, diarrhea requiring parenteral support,
narcotics for pain control, or catheterization for acute urinary retention, was
observed. CONCLUSION: Although relatively high doses of radiation are delivered
to prostate cancers with 3D-CRT compared with conventional radiotherapy, 3D-CRT
is surprisingly well-tolerated. No patients in the cohort eligible for implant
monotherapy experienced acute toxicity >/= Grade 3.
PMID- 10758313
TI - Temporal resolution of urinary morbidity following prostate brachytherapy.
AB - PURPOSE: To report the short-term urinary morbidity for prostate brachytherapy
patients without a preimplant history of a transurethral resection of the
prostate gland and who received prophylactic and prolonged alpha-blockers. alpha
blockers may decrease radiation-induced urethritis and increase urinary flow.
Multiple clinical and treatment parameters were evaluated to identify factors
associated with increased acute urinary morbidity. MATERIALS AND METHODS: One
hundred seventy consecutive patients without a prior history of a transurethral
resection of the prostate gland underwent transperineal ultrasound guided
prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. For
all patients, an alpha-blocker was initiated prior to implantation and continued
at least until the international prostate symptom score (IPSS) returned to
baseline levels. Clinical parameters evaluated for short-term urinary morbidity
included patient age, clinical T stage, preimplant IPSS (obtained within 3 weeks
of implantation), and prostate ultrasound volume. Treatment parameters included
the utilization of neoadjuvant hormonal manipulation, the utilization of moderate
dose external beam radiation therapy before implantation, the choice of isotope,
the urethral dose, the total implant activity in millicuries, and a variety of
dosimetric quality indicators (D(90) and V(100)/V(150)/V(200)). Catheter
dependency and the duration of alpha-blocker dependency was also evaluated. On
average, 11.2 IPSS surveys were obtained for each patient. RESULTS: One hundred
fifty of the 170 patients (88.2%) had the urinary catheter permanently removed on
day 0. Only one patient required an urinary catheter for > 5 days. Two patients
(1.2%) required a subsequent transurethral resection of the prostate gland
because of prolonged obstructive/irritative symptoms. To date, no patient has
developed an urinary stricture or urinary incontinence. The IPS score on average
peaked at 2 weeks following implantation. This score returned to within 1 point
of the antecedent value at a median of 6 weeks and a mean of 13.3 weeks. At 26
and 50 weeks, 85% and 56% of the patients, respectively, continued with alpha
blockers. Of the clinical and treatment parameters evaluated for short-term
urinary morbidity, only variants of the IPSS such as the maximum, maximum
increase, and preimplant IPSS values correlated with time to return to the
referent zone with p < 0.05. CONCLUSION: The return of the IPS score to baseline
occurred more rapidly in our series than what has previously been reported. The
1.2% incidence of transurethral resections also compares favorably with the
published literature. We believe these results may be due to maintaining the
average urethral dose to approximately 115% of the prescribed dose and the
prophylactic and long-term use of alpha-blockers.
PMID- 10758314
TI - Comparison of biochemical disease-free survival of patients with localized
carcinoma of the prostate undergoing radical prostatectomy, transperineal
ultrasound-guided radioactive seed implantation, or definitive external beam
irradiation.
AB - PURPOSE: This retrospective study compares the long-term biochemical disease-free
survival for patients undergoing radical prostatectomy, transperineal ultrasound
guided (125)Iodine implantation, or external beam irradiation alone in a tertiary
referral community-based hospital. METHODS AND MATERIALS: Five hundred forty
patients were available for evaluation, which included: external beam, 132;
(125)I, 186; and radical prostatectomy, 222. For the 318 patients referred to the
Department of Radiation Oncology, those with T3 disease underwent external beam
irradiation while patients with T1 or T2 underwent (125) 0.2 ng/mL or if they had
three consecutive increases in their PSA or an increase in their postoperative
PSA warranting intervention with androgen ablation or external beam irradiation
to the pelvis. RESULTS: Patients were stratified by pretreatment risk groups
predicting for post-treatment PSA recurrence. Patients were considered to be at a
low or intermediate risk for recurrence if their clinical stage was T1c, T2a,
T2b, pretreatment PSA level was 20, or Gleason score was >/= 7. For 132
patients undergoing external beam irradiation, 28 of 37 low or intermediate risk
obtained a 1 year nadir PSA of < 1 (76%) while 40% of high risk patients obtained
nadir < 1. Of 186 patients undergoing (125)I, 112 of 147 low or intermediate risk
(76%) obtained a nadir PSA < 1. Twenty of 39 (51%) high risk obtained a nadir PSA
< 1. Of the 222 patients undergoing prostatectomy, 83 of 88 (94%) low or
intermediate risk had undetectable levels of PSA at 1 year. One hundred seventeen
of 134 (86%) were high risk and had undetectable levels of PSA at 1 year. The
biochemical disease-free survival for patients with low or intermediate risk at 5
years is approximately 70% with no significant difference between those patients
treated with radical prostatectomy, external beam, or (125)I. For those patients
with high risk factors for recurrence, there is no significant difference between
ultrasound-guided implant or external beam, but there is a significant
improvement in biochemical disease-free survival with radical prostatectomy.
CONCLUSION: For patients with low or intermediate risk disease, external beam,
ultrasound-guided (125)I, or a radical prostatectomy give comparable long-term
biochemical disease-free survival. For patients with high risk disease, a radical
prostatectomy provides a significantly improved biochemical disease-free
survival. Our current protocols utilize androgen ablation in combination with
conformal three-dimensional external beam irradiation or androgen ablation in
conjunction with external beam irradiation and (103)Pd seed implantation for
patients at high risk for extra capsular disease. It is too early to determine if
this combination therapy will give results comparable to radical prostatectomy.
For patients who obtain a 1 year nadir PSA of < 1, the biochemical disease-free
survival is durable with little risk of subsequent recurrence.
PMID- 10758315
TI - Breast conserving therapy in breast cancer patients presenting with nipple
discharge.
AB - PURPOSE: To retrospectively review the outcome of conservatively treated breast
cancer patients who present with nipple discharge at initial diagnosis. METHODS
AND MATERIALS: The charts of 1097 patients undergoing conservative surgery and
radiation therapy between January 1970 and December 1990 were reviewed. All
patient data, including clinical, pathologic, treatment, and outcome variables
were entered onto a computerized database. For the current study, specific
attention was directed to the initial presenting symptoms and patients were
divided into two groups: those presenting at initial diagnosis with nipple
discharge (D/C-YES, n = 17), and those presenting without nipple discharge (D/C
NO, n = 1080). RESULTS: As of August 1998, with a median follow-up of 12 years,
the 10-year actuarial survival, distant metastasis-free survival, and breast
relapse-free survival rates for the overall population were 73%, 78%, and 83%,
respectively. Although the D/C-YES and D/C-NO groups were well balanced with
respect to the majority of clinical factors, the D/C-YES patients had a higher
percentage of DCIS histology (7.3% vs 1.2%, p < 0.01), were less likely to
undergo reexcision (12% vs 35%), and were more frequently under age 40 (35% vs
12%) than the D/C-NO patients. Over the time span of this study, status of the
final surgical margin was indeterminate in the majority of cases. Local relapses
occurred in 6 of the 17 patients in the D/C-YES group, resulting in a 10-year
actuarial breast relapse-free survival rate of 50%, which was signifcantly lower
than the 10-year breast relapse-free survival rate of 86% in the D/C-NO
population. Among the patients presenting with nipple discharge, those with
sacrifice of the nipple areolar complex had a lower local relapse rate than those
patients who had conservation of the nipple areolar complex (20% vs 42%),
although this difference did not reach statistical significance. CONCLUSIONS:
Although patients presenting with nipple discharge may be suitable candidates for
radiation therapy, local relapse rates were higher than those presenting without
nipple discharge. The limitations of the study and implications regarding breast
conserving management in patients presenting with nipple discharge are discussed.
PMID- 10758316
TI - Occult breast carcinoma presenting as axillary metastases.
AB - PURPOSE: Breast carcinoma presenting with axillary lymphadenopathy and no
clinical or radiological evidence of a primary tumor is a rare presentation. We
aimed to examine the management of the breast by observation, radiation therapy,
or mastectomy. METHODS AND MATERIALS: Departmental records from 1979 to 1996 of
unknown primary presentations and cases of T0N1-2M0 breast carcinoma were
reviewed to find cases of occult breast carcinoma presenting as axillary
lymphadenopathy with no clinical or imaging evidence of a primary tumor. RESULTS:
There were 6047 presentations of breast carcinoma with 20 cases of occult breast
carcinoma meeting the criteria. The breast was treated by observation in 6 cases,
mastectomy in 2 cases, and radiotherapy to the intact breast in 12 cases. Eighty
three percent of patients (5 of 6 patients) who had observation of the breast had
a local recurrence, compared to 25% who had radiotherapy to the intact breast (3
of 12 patients) and 0% who had a mastectomy (0 of 2 patients). The median
recurrence-free survival was 7 months in patients who had observation of the
breast, compared to 182 months in patients who had local treatment. Three of the
6 patients who underwent breast observation have died whereas 1 of the 14 who had
local treatment have died, with a mean follow-up of 73 months. It was found that
patients having observation of the breast had a poorer recurrence-free survival
(p = 0.003) and overall survival (p = 0.05) compared to those having local
treatment of the breast. CONCLUSIONS: Patients with such a presentation should
have a complete physical examination, mammography, ultrasound, and MRI of the
breasts. If there remains no evidence of a primary tumor, an axillary dissection
should be carried out and the breast treated by radiotherapy or mastectomy.
Observation of the breast is not a recommended option.
PMID- 10758317
TI - Quality of life after palliative radiotherapy in non-small cell lung cancer: a
prospective study.
AB - PURPOSE: The purpose of this study was to investigate changes in respiratory
symptoms and quality of life (QoL) in patients with locally advanced and
metastatic non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy.
Additionally, the correlation between the level of symptom relief and objective
tumor response was investigated. METHODS AND MATERIALS: Sixty-five patients were
entered in this prospective study. The EORTC QLQ-C30 and EORTC QLQ-LC13 were used
to investigate changes in QoL. Assessments were performed before radiotherapy and
2 weeks, 6 weeks, and 3 months after radiotherapy. RESULTS: The QoL response
rates were excellent for hemoptysis (79%); good for arm/shoulder pain (56%),
chest wall pain (53%), and cough (49%); moderate for dyspnea (39%); and minimal
for the general symptoms fatigue (22%) and appetite loss (11%). The QoL response
rates for the five functioning scales of the QLQ-C30 varied from 35% for role
functioning to 57% for emotional functioning. Global QoL improved in 37% of the
cases. In general, there was a tendency for better palliation of symptoms and
improvement of QoL among patients with an objective tumor response than among
those without objective tumor response, which was statistically significant for
dyspnea (p = 0.02) and social functioning (p = 0.04). CONCLUSIONS: This study
confirms that conventional thoracic radiotherapy offers palliation of respiratory
symptoms and improved QoL in a substantial proportion of patients with locally
advanced and metastatic NSCLC. Tumor reduction is only one of the mechanisms by
which palliation of symptoms and improvement of QoL is achieved.
PMID- 10758318
TI - High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal
sarcomas.
AB - PURPOSE: Retroperitoneal sarcomas represent a formidable challenge to the
treating oncologist due to their location, large size, and poor prognosis. The
purpose of this study was to determine if the addition of high-dose-rate
intraoperative radiation therapy (HDR-IORT) to surgery and external beam
radiotherapy (EBRT) would improve the outcome in these patients. METHODS AND
MATERIALS: Thirty-two patients with retroperitoneal soft tissue sarcoma were
prospectively treated according to a protocol that included maximal tumor
resection, HDR-IORT, and postoperative EBRT when feasible. Twelve patients
presented with primary and 20 with locally recurrent disease. The tumors were
high-grade in 20 patients and low-grade in 12 patients. Complete gross resection
was achieved in 30 patients. HDR-IORT was given to a dose of 12-15 Gy. Additional
EBRT was given to 78% of patients to a dose of 45-50.4 Gy. The two patients with
gross residual disease received an additional I-125 permanent implant to a median
peripheral dose of 140-160 Gy. The median follow-up was 33 months (range 1-77
mo). RESULTS: The 5-year actuarial local control rate for the whole group was
62%. For patients with primary disease, the local control rate was 74% compared
to 54% in patients with recurrent disease (p = 0.4). The overall 5-year distant
metastasis-free survival rate was 82%. In patients with high-grade tumors the
rate was 70% vs. 100% in those with low-grade tumors. This difference was
statistically significant, p = 0.05. The 5-year disease-free and overall survival
rates were 55% and 45%, respectively. The most common type of post-treatment
complication was gastrointestinal obstruction (18%) followed by fistula formation
(9%), peripheral neuropathy (6%), hydronephrosis (3%), and wound complication
(3%). CONCLUSIONS: We are encouraged by the favorable local control rate and the
acceptable morbidity with this new technique applied to a challenging patient
population.
PMID- 10758319
TI - Low-dose-rate intraoperative brachytherapy combined with external beam
irradiation in the conservative treatment of soft tissue sarcoma.
AB - PURPOSE: Conservative treatment of soft tissue sarcomas most often implies
combination of surgical resection and irradiation. The aim of this study was to
evaluate low-dose-rate intraoperative brachytherapy, delivered as a boost, in the
local control of primary tumors, with special concern about treatment
complications. METHODS AND MATERIALS: Between 1986 and 1995, 112 patients
underwent intraoperative implant. This report focuses on the group of 58 patients
with primary sarcomas treated by combination of conservative surgery,
intraoperative brachytherapy, and external irradiation. Most of the tumors were
located in the lower limbs (46/58-79%). Median size of the tumor was 10 cm, most
of the lesions being T2-T3 (51/58-88%), Grade 2 or 3 (48/58-83%). The mean
brachytherapy dose was 20 Gy and external beam irradiation dose 45 Gy. In 36/58
cases, iridium wires had to be placed on contact with neurovascular structures.
RESULTS: With a median follow-up of 54 months, the 5-year actuarial survival was
64.9%, with a 5-year actuarial local control of 89%. Of the 6 patients with local
relapse, 3 were salvaged. Acute side effects, essentially wound healing problems,
occurred in 20/58 patients, late side effects in 16/58 patients (7 neuropathies
G2 to G4). No amputation was required. The only significant factor correlated
with early side effects was the location of the tumor in the lower limb (p =
0.003), and with late side effects the vicinity of the tumor with neurovascular
structures (p = 0.009). CONCLUSION: Brachytherapy allows early delivery of a
boost dose in a reduced volume of tissue, precisely mapped by the intraoperative
procedure. Combined with external beam irradiation, it is a safe and efficient
treatment technique leading to high local control rates and limited functional
impairment.
PMID- 10758320
TI - Neonatal neoplasms.
AB - PURPOSE: To describe neoplasms diagnosed in children or =1.9 cm(2)/m(2). The 30-day mortality was higher in group 1 than in
group 2 (18.2 vs. 4.1%, P=0.005). Multivariate logistic regression analysis of
the determinants of the 30-day mortality rendered a small valve area index (<1.9
cm(2)/m(2)) as an independent risk indicator: relative risk 4.3 (95% CI 1.6-9.5;
P=0. 0043). The difference in overall survival between the two groups was
entirely due to the high 30-day mortality in the patients with small valve area
indices, congestive heart failure being the main cause of death. CONCLUSIONS: By
concentrating on the extreme lower tail of the normal distribution of the valve
area index, a strong and independent relation was found between relatively small
valves (valve area index <1.9 cm(2)/m(2)) and 30-day mortality. We found no
influence of valve size on late mortality beyond the first 30 days.
PMID- 10758380
TI - Are blood and valve cultures predictive for long-term outcome following surgery
for infective endocarditis?
AB - OBJECTIVE: To evaluate whether perioperative bacteria identification in blood
and/or in valve cultures can predict early and late outcome of surgery for
infective endocarditis, a retrospective study was performed. METHODS: Between
January 1978 and December 1998, 232 patients, 79 (34.1%) female and 153 (65.9%)
male with mean age of 44. 95+/-1.03 years (range 8-79) underwent surgery for
infective endocarditis on a native (162 cases) or prosthetic (70 cases) valve.
Patients were divided into three groups according to the perioperative x of
microbiological tests: Group A: patients with preoperative positive blood
cultures (83 cases); Group B: patients with positive valve cultures (35 cases);
Group C: patients with negative blood and valve cultures (114 cases). Categorical
values were compared by chi(2) analysis, whereas continuous data were compared by
ANOVA and Bonferroni correction for post hoc comparisons. Analysis of late
survival and complications was performed with Kaplan-Meier and Log Rank test.
Late mortality, reoperation, perivalvular leak, recurrence of infection were
considered as treatment failure. All data were presented as mean+/-standard
error. RESULTS: Hospital mortality was 10.8% (9/83) in Group A, 8.6% (3/35) in
Group B, and 14.9% (17/114) in Group C (P=0.52; not significant (NS)). Ten-year
survival was 62.7+/-8% in Group A, 43.9+/-19% in Group B and 62.7+/-7% in Group C
(P=0.38; NS). Ten-year freedom from reoperation was 85.2+/-6% in Group A, 37.9+/
20% in Group B and 80+/-6% in Group C (P=0.0034). Ten-year freedom from treatment
failure was 56.3+/-8% in Group A, 31.6+/-16% in Group B and 55. 3+/-7% in Group C
(P=0.46; NS). CONCLUSIONS: Positive blood and tissue cultures are not predictive
for hospital mortality and late treatment failure in patients with infective
endocarditis. Positive valve cultures, a common finding in patients with
staphylococcal endocarditis, are predictive for a higher risk of reoperation.
PMID- 10758381
TI - Emergency myocardial revascularization for acute myocardial infarction: survival
benefits of avoiding cardiopulmonary bypass.
AB - OBJECTIVE: Emergency coronary artery bypass grafting (CABG) for acute myocardial
infarction (AMI) is associated with increased operative mortality. It has been
suggested that this mortality might be reduced by performing the operation
without cardiopulmonary bypass (CPB). METHODS: Between January 1992 and April
1998, 77 patients underwent emergency CABG within 48 h of AMI. Thirty seven were
operated on with CPB, and 40 without CPB. The two groups were similar regarding
age, gender, left-ventricular ejection fraction (EF) and preoperative use of
intra-aortic balloon pump (IABP; 50%). The mean number of grafts/patient was 3 in
the CPB group, and 1.9 in the No-CPB group (P<0.0001). RESULTS: Operative
mortality in the CPB group was 24% (nine of 37) compared to 5% (two of 40)
without CPB (P=0.015). Follow-up ranged between 6 and 66 months. There were no
late deaths in the CPB group compared to nine (22%) in the No-CPB group
(P<0.0066). Patients operated on with CPB had lower rates of recurrent angina (0
versus 15%; P=0.04) and re-interventions (0 versus 15%; P=0.04). CONCLUSIONS: Our
experience suggests that CABG without CPB is the preferred method of myocardial
revascularization, due to the fact that it carries lower mortality than CABG with
CPB. The trade-off includes increased rates of recurrent angina, re-interventions
and late mortality.
PMID- 10758382
TI - Partial left ventriculectomy, ventriculoplasty or valvular surgery for idiopathic
dilated cardiomyopathy - the role of intra-operative echocardiography.
AB - BACKGROUND: The partial left ventriculectomy (PLV) is known to work in some
patients with dilated cardiomyopathy (DCM), although this procedure does not work
well in all patients and the operative mortality is higher than the other cardiac
surgeries. In addition to PLV, left ventriculoplasty to exclude antero-septal
wall or valvular surgery without left ventricle (LV) surgery can be also
effective in patients with DCM. To improve the surgical results for dilated
cardiomyopathy, we introduced echo-guided volume reduction test and evaluated the
surgical procedures and the results on the surgery for DCM. METHODS: Between
December 1996 and July 1999, 56 patients with DCM (50 with idiopathic DCM, six
with dilated hypertrophic cardiomyopathy) were surgically treated. Under the
standard cardiopulmonary bypass, left ventricular motion was determined with
color kinesis of echocardiogram and the lesion of akinetic wall was removed or
excluded. RESULTS: After the initial PLV in 18 patients (initial group),
operative procedures were selected in 21 with PLV, five with LV plasty, or 12
with valve surgery without LV surgery according to the findings of the LV wall
motion by intraoperative echogram (select group). There were six hospital deaths
and late follow-up deaths within 1 year in initial group, however, the mortality
decreased significantly after the selection of the operative procedures; three
hospital deaths and two late deaths in the select-group (P<0.05). Significant
decrease of left ventricular diameter, the LV ejection fraction and endosystolic
volume index were demonstrated after the LV surgery. The survival rate improved
significantly after the selection of the operative procedures; 14 months survival
rates was 50.0% in initial group and 73.1% in select group (P<0.05). CONCLUSION:
Operative mortality decreased and late follow-up results improved after the
selection of operative procedures according to the intraoperative volume
reduction test.
PMID- 10758383
TI - Early post-pneumonectomy complications in the elderly.
AB - OBJECTIVE: The surgical treatment of non-small cell lung cancer (NSCLC) in
elderly patients presents a serious challenge to thoracic surgeons. As there is
considerable divergence of opinion about both the mortality and morbidity rates,
it is important to set guidelines for proper patient selection. METHODS: Early
post-operative complications in 42 patients aged over 70 years who had undergone
pneumonectomy because of NSCLC (Group I) were analyzed. The control group (Group
II) consisted of 48 patients, also aged over 70 years, but who had undergone
lobectomy or wedge resections. In both groups, the pre-operative conditions and
30-day morbidity and mortality were evaluated. RESULTS: Postoperative
complications occurred significantly more frequently in pneumonectomy patients
(78.5%) than in Group II (58%). Transient or long-standing arrhythmias were noted
in 20 patients (47.6%) from Group I and in 17 (35.4%) from Group II. Pulmonary
complications occurred in 17 patients (40.4%) from Group I and 16 (33.3%) from
Group II. The most important factors contributing to post-operative complications
in pneumonectomy patients were performance status (WHO), chronic obstructive
pulmonary disease (COPD) and elevated level of blood urea nitrogen (BUN). The
highest impact on early mortality in pneumonectomy patients was exerted by COPD,
arterial hypertension, formation of broncho-pleural fistula (BPF), the need for
re-thoracotomy and high level of BUN. CONCLUSIONS: (1) Pneumonectomy in patients
over the age of 70 carries a considerable risk of severe post-operative
complications and death, when compared to patients with less extensive pulmonary
resections. (2) Elderly patients with impaired Performance Status (WHO 2 or more)
and co-existing arterial hypertension, COPD and elevated level of BUN should be
considered for pneumonectomy very carefully and cautiously.
PMID- 10758384
TI - Management of tuberculous empyema.
AB - OBJECTIVE: In an attempt to establish a treatment protocol for tuberculous
empyema, we retrospectively reviewed our experience over a 3-year period.
METHODS: Between January 1996 and December 1998, 26 patients (23 male and three
female) with an average age of 33.8 years (range 18-61 years) presented with
tuberculous empyema. The empyema was right-sided in 13, left-sided in 12 and
bilateral in one patient. Patients presented with respiratory symptoms for a mean
duration of 4.43 months (range 1-48 months). All patients had a computerized scan
of the chest and managed according to the stage of empyema. RESULTS: In patients
with exudative empyema (n=4) the fluid was aspirated, but one patient required
intercostal tube (ICT) drainage for 6 days. There were four patients with
fibrinopurulent empyema treated with thoracoscopic drainage with a mean post
operative stay of 8 days (range 4-12 days). In the organizing stage (n=18),
initial drainage with large ICT was performed. The pleura was less than 2 cm in
thickness in eight patients, for which repeated installation of streptokinase was
performed (three to seven times). Satisfactory results were achieved in six
patients (75%) and the remaining two required decortication. Of the ten patients
with thick cortex, one required a window and nine had decortication, two of which
had additional lobectomy and two had pneumonectomy. All patients fully recovered
with no mortality and with a mean duration of drainage of 18 days (range 3-61
days). CONCLUSION: Its stage and the state of the underlying lung should guide
surgical treatment for tuberculous empyema. This protocol aims to achieve cure
utilizing the least invasive approach and acceptable hospital stay.
PMID- 10758385
TI - Subtotal median sternotomy for heart surgery.
AB - OBJECTIVE: Many approaches for minimally invasive heart surgery are available.
Although they have many advantages, inadequate exposure, mammary artery injury
and special tool requirements are known problems. Subtotal median sternotomy
(SMS) was developed to overcome such limitations. Comparing the SMS with the
standard sternotomy (SS) is the purpose of this study. METHODS: SMS was used in
210 patients (group I) requiring coronary artery bypass grafting and or valvular
surgery. This was compared with another 210 patients (group II) in which SS was
used. The technical difficulties, incisional discomfort, wound infection, patient
satisfaction and hospital stay are the comparison criteria. RESULTS: (1) SMS
takes an average of 24 min longer, P<0.15. (2) Incisional discomfort graded (I
'least' to III 'greatest'), group I: (27 Grade I, 176 Grade II, seven Grade III).
Group II: (21 Grade I, 183 Grade II, six Grade III), P<0.1. (3) Wound infection:
two superficial, two deep in group I, four superficial and one deep in group II,
P<0.06, (4) 99% satisfaction and 5.4 days mean hospital stay in group I, 63% and
7.1 days in group II, P<0.01 and <0.03, respectively. CONCLUSION: When comparing
the SMS technique with the SS: (1) SMS has statistically significant better
patient satisfaction; (2) can be very cost effective due to the short hospital
stay and the absence of a need for special instruments.
PMID- 10758386
TI - Aortic root replacement with coronary button re-implantation: low risk and
predictable outcome.
AB - OBJECTIVE: Cardiac morbidity in aortic root replacement often occurs through
myocardial ischaemia. We analyzed a 10 year experience of all root replacement
operations by one surgeon to determine the incidence of coronary complications
and risk factors for early mortality. METHODS: The study included 140 aortic root
replacement patients (aged from 2 to 77 years; median 53 years) operated between
1988 and 1999. Thirty-four had Marfan's syndrome. Eleven had root infection
requiring homograft replacement. Nineteen were reoperations (14%). Concomitant
procedures were arch replacement (16), mitral replacement (five), and coronary
bypass (22). Mobilization and reimplantation of the coronary ostia was performed
in 139 patients. We performed the distal graft anastomosis before right coronary
reimplantation. RESULTS: There were eight hospital deaths (5.7%). Risk factors
for hospital mortality were: preoperative NYHA class IV, shock, LVEF < or =30%,
acute dissection, concomitant mitral valve replacement, pump time > or = 60 min,
reentry for bleeding, and postoperative renal failure. Neither myocardial
ischaemia nor right ventricular dysfunction contribute to mortality. There were
18 late deaths with an actuarial survival of 79% at 5 years. There were no late
coronary false aneurysms. CONCLUSIONS: Button reimplantation with the sequence
described is predictable and safe. Wrap-around is unnecessary. Coronary aneurysms
have been eliminated.
PMID- 10758387
TI - Surgical management of atherosclerotic aortic arch aneurysms using selective
cerebral perfusion: 7-year experience in 52 patients.
AB - OBJECTIVE: Patients with atherosclerotic aortic arch aneurysms are at greater
risk for brain complication. We report our techniques and results of operation
using selective cerebral perfusion. METHODS: We retrospectively analyzed 52
consecutive patients with atherosclerotic aortic arch aneurysms (mean age, 70
years, range, 53-86 years), who underwent operation between April 1992 and March
1999. The operation was non-elective in 11 patients (21.1%). Concomitant
operations included eight coronary artery bypass grafting and one aortic valve
replacement. Simultaneous distal aortic reconstruction was performed in three
patients. The operation was performed through median sternotomy. To avoid brain
embolism, total arch replacement with a branched prosthesis was performed in 48
patients, in an attempt to exclude affected segments of aorta. In addition,
retrograde femoral artery perfusion was avoided and cerebral circulation was
isolated before aortic manipulation. To achieve even blood flow distribution, we
employed perfusion and continuous pressure monitoring of all the three arch
vessels. The perfusion rate was 12+/-2 ml/kg per min and the pressure was kept
around 50 mmHg. Deep hypothermic arrest of the lower torso (bladder temperature,
22 degrees C) was used during open distal aortic anastomosis. RESULTS: The
hospital mortality rate was 11.5% (six of 52), and 7.3% (three of 41) for
elective cases. Only one patient (1. 9%) developed permanent focal neurological
deficit. Six other patients showed temporary brain complications, which was
global (delirium) in three and focal in three others. CONCLUSIONS: Selective
cerebral perfusion is a safe brain protection method, and our strategy seems
effective for embolic stroke prevention.
PMID- 10758388
TI - Increased aortic compliance maintains left ventricular performance at lower
energetic cost.
AB - OBJECTIVE: The aim of this study was to investigate left ventricular
contractility and energetic cost of cardiac ejection under conditions of acute
increase in aortic compliance. METHODS: In six anaesthetized pigs, ascending
aortic compliance was increased by adding a volume chamber in parallel to the
ascending aorta. Systemic vascular parameters, including characteristic
impedance, peripheral resistance, total vascular compliance, and inertance, were
estimated with a four-element windkessel model. Arterial elastance was derived
from these parameters. Left ventricular systolic function was assessed by end
systolic pressure-volume relationship (end-systolic elastance), and stroke work.
Pressure-volume area was used as a measure of myocardial oxygen consumption.
Heart rate remained constant during the experimentation. RESULTS: Adding the
aortic volume chamber significantly increased vascular compliance from 0. 95+/
0.08 to 1.17+/-0.06 ml/mmHg (P<0.01), while inductance, characteristic impedance,
peripheral resistance, and arterial elastance remained statistically at basal
values, respectively 0. 0020+/-0.0003 mmHg.s(2)/ml, 0.105+/-0.009 mmHg.s/ml,
1.27+/-0.12 mmHg.s/ml, and 2.43+/-0.21 mmHg/ml. During the same interval, stroke
work and pressure-volume area decreased respectively from 2700+/-242 to 2256+/-75
mmHg.ml (P<0.01), and from 3806+/-427 to 3179+/-167 mmHg.ml (P<0.01). Stroke work
and pressure-volume area decreased at matched end-diastolic volumes. In contrast,
end-systolic elastance, ejection fraction, and stroke volume remained
statistically unchanged, respectively at 2.29+/-0.14 mmHg/ml, 48.1+/-2.1 %, and
32. 4+/-1.7 ml. CONCLUSIONS: These data suggest that, when facing an increased
aortic compliance, the left ventricle displays unchanged contractility, but the
energetic cost of cardiac ejection is significantly decreased. These data may be
of clinical importance when choosing an artificial prosthesis for ascending
aortic replacement.
PMID- 10758389
TI - Preoperative high dose methylprednisolone attenuates the cerebral response to
deep hypothermic circulatory arrest.
AB - OBJECTIVE: The aim of this study was to assess the effects of preoperative high
dose methylprednisolone on cerebral recovery following a period of deep
hypothermic circulatory arrest (DHCA). METHODS: Sixteen 1-week-old piglets were
randomized to placebo (n=8), or 30 mg/kg intramuscular methylprednisolone sodium
succinate (MPRED) given at 8 and 2 h before induction of anaesthesia. All piglets
underwent cardiopulmonary bypass, cooling to 18 degrees C, 60 min of circulatory
arrest followed by 60 min of reperfusion and rewarming. The radiolabelled
microsphere method was used to determine the global and regional cerebral blood
flow (CBF) and cerebral oxygen metabolism (CMRO(2)) at baseline before DHCA and
after 60 min of reperfusion. RESULTS: In controls, mean global CBF (+/-1 standard
error) before DHCA was 53.7+/-2.4 ml/100 g per min and fell to 23.8+/-1.2 ml/100
g per min following DHCA (P<0.0001). This represents a post-DHCA recovery to
45.1+/-3.3% of the pre-DHCA value. In the MPRED group recovery of global CBF post
DHCA was significantly higher at 63.6+/-5.2% of the pre-DHCA value (P=0.009). The
regional recovery of CBF in the cerebellum, brainstem and basal ganglia was 80,
75 and 69% of pre-DHCA values in the MPRED group respectively compared to 66, 60
and 55% in controls (P<0.05). Global CMRO(2) in controls fell from 3.9+/-0.2
ml/100 g per min before to 2. 3+/-0.2 ml/100 g per min after DHCA (P=0.0001).
This represents a post-DHCA recovery to 58.6+/-4.4% of the pre-DHCA value. In the
MPRED group, however, recovery of global CMRO(2) post-DHCA was significantly
higher at 77.9+/-7.1% of the pre-DHCA value (P=0.04). CONCLUSIONS: Treatment with
high dose methylprednisolone at 8 and 2 h preoperatively attenuates the normal
cerebral response to a period of deep hypothermic ischaemia. This technique may
therefore offer a safe and inexpensive strategy for cerebral protection during
repair of congenital heart defects with the use of DHCA.
PMID- 10758390
TI - Graft revision after transit time flow measurement in off-pump coronary artery
bypass grafting.
AB - OBJECTIVE: To determine whether coronary graft patency can be predicted by
transit time flow measurement (TTFM). METHODS: From May 1 1997 to December 31
1998, TTFM was prospectively evaluated in 409 patients undergoing coronary artery
bypass grafting (CABG) without cardiopulmonary bypass (CPB). All grafts (1145)
were tested with TTFM. RESULTS: Thirty-seven out of 1145 grafts (3.2%) were
revised in 33 patients (7.6%). In six cases (18.1%) use of CPB was necessary
during revision due to hemodynamic instability. The remaining patients underwent
revision off-pump. Thirty-four grafts (91.9%) were revised for both low flow and
abnormal flow curve patterns. Findings at revision included: thrombosis of the
anastomosis (n=6), stenosis at the toe or heel of the anastomosis (n=8), coronary
flap or dissection (n=5), dissection of the internal mammary artery (n=5), graft
kinking (n=4), flap at proximal anastomosis (n=1), coronary stenosis distal to
the graft (n=3), and no findings (n=2). After revision all flow values and flow
patterns improved. Although three additional grafts (8.1%) were revised for low
flow (<7 ml/min) despite normal flow patterns, there were no findings at revision
and flow values and curves remained unchanged after revision. Postoperatively,
one patient developed a stroke (3%), one had an acute myocardial infarction (MI)
(3%), one had a sternal wound infection (3%), and one required prolonged
ventilatory support (3%). CONCLUSION: Evaluation of TTFM is valuable in
determining the status of a coronary graft after CABG. Correct interpretation of
flow patterns allows for correction of abnormalities prior to chest closure.
PMID- 10758391
TI - Postoperative radial artery angiography for coronary artery bypass surgery.
AB - OBJECTIVE: To compare radial artery (RA) patency with internal mammary artery
(IMA) patency for coronary artery bypass surgery in our early experience.
METHODS: Symptomatic as well as asymptomatic patients with > or =1 RA coronary
graft underwent postoperative angiography. Each anastomosis was considered
separately. A string sign referred to a diffusely narrowed conduit, which did not
fill the grafted coronary artery, as well as all occluded conduits. The raw value
of P was adjusted for the testing of multiple hypotheses (P'). The patency data
for each conduit was divided into two parts. 'Cut-off' stenosis for a conduit was
the lowest dividing coronary stenosis at which a difference in patency rate with
P< or =0.05 occurred. RESULTS: One-hundred-and-twenty-nine patients had 137
radial arteries and 157 angiograms. Only the most recent angiogram was analyzed
for each patient at 13+/-0.7 months (n=129). Overall patency for arterial conduit
91% (n=404) was not different from venous conduit 91% (n=42) and patency for RA
90% (n=226) was not different from IMA 92% (n=178), (P'=0.999). Cut-off stenosis
for RA was 70% and IMA was 40%. Patent arterial conduit had a mean coronary
stenosis of 85% and non-patent conduit 64%, (P'<0.001). Right coronary territory
patency was 82 vs. 94% for other territories (P'=0.022). No overall differences
in patency were noted for patients with sequential anastomoses, symptoms or
coronary disease at the anastomosis at the time of surgery. Reversible ischaemia
was detected in the distribution of only two of 14 string signs in patients
undergoing sestamibi exercise protocol following angiogram. CONCLUSION: There
were no differences in patency between radial artery and internal mammary artery
at 13 months post-operative. Lower coronary stenosis and right coronary territory
predicted lower patency. The clinical importance of a string sign remains to be
determined.
PMID- 10758392
TI - Activation of myocardial constitutive nitric oxide synthase during coronary
artery surgery.
AB - OBJECTIVE: The role of nitric oxide (NO) in myocardial ischemia/reperfusion is
controversial. While some studies have shown cardioprotective effects of NO,
others suggested that increased myocardial NO release secondary to ischemia may
contribute to reperfusion injury. However, the impact of cardioplegia-induced
myocardial ischemia/reperfusion on the activity of the NO-producing enzyme
constitutive NO-synthase (cNOS or NOS-III) has not been investigated. METHODS:
Twenty elective CABG patients were randomized to receive myocardial protection
using either intermittent cold blood cardioplegia with 'hot-shot' (CBC; n=10) or
continuous warm blood enriched with the ultra-fast-acting beta-blocker esmolol
(WBE; n=10). We collected transmural LV biopsies prior to cardiopulmonary bypass
(CPB), at the end of the cross-clamp period, and at the end of CPB. Specimen were
subjected to immunocytochemical staining against myocardial NOS-III and cGMP
using polyclonal antibodies. NOS-III activity was determined using TV
densitometry (gray units) and cGMP content using a semiquantitative score. Global
myocardial metabolism was assessed by arterio-coronary sinus lactate
concentration difference (a-csD(LAC)). For LV function determination we measured
the fractional area of contraction (FAC) using TEE. RESULTS: In CBC hearts a
csD(LAC) was significantly decreased following cross-clamp removal as compared to
pre-CPB indicating global ischemia during cross-clamp. In contrast, a-csD(LAC)
was unchanged in WBE hearts indicating absence of relevant ischemia in this
group. In CBC hearts NOS-III activity did not change from pre-CPB (35.6+/-11.1 U)
to the end of the cross-clamp period (38. 0+/-8.1 U; P=0.2), but increased
significantly to 48.5+/-12.1 U at the end of CPB following initial warm blood
reperfusion (P=0.026). In WBE hearts NOS-III activity remained unchanged
throughout (29. 2+/-10.8, 35.1+/-11.8, and 32.2+/-14.7 U, respectively; 0.3). At
the end of CPB, nine CBC hearts, but only one WBE heart showed increased cGMP
content (P=0.002). Compared to pre-CPB, FAC in the CBC group was 109+/-25%
following weaning off CPB (P=0.26), but was slightly decreased to 87+/-22% at 4 h
post-CPB (P=0.03). In the WBE group FAC remained unchanged compared to pre-CPB
throughout (103+/-21 and 96+/-37%, respectively; 0.5). CONCLUSIONS: Our data show
that global myocardial ischemia and reperfusion induced by CBC is associated with
myocardial NOS-III activation and increased cGMP content suggesting increased NO
release. In contrast, avoidance of ischemia by use of WBE prevented NOS-III and c
GMP increase. As LV function was decreased at 4 h post-CPB in the CBC group,
these data suggest that increased NO release secondary to NOS-III activation may
have contributed to ischemia-reperfusion injury as has been shown experimentally.
PMID- 10758393
TI - Evaluation of a new device for quick sutureless coronary artery anastomosis in
surviving sheep.
AB - OBJECTIVE: A new device for performing quick sutureless vascular anastomosis by
means of stent technology has recently been developed by Jomed International,
Helsingborg, Sweden. The efficacy of this GraftConnector was studied in a sheep
model. METHODS: In adult sheep, a left anterior thoracotomy under the fourth rib
extended across the sternum gave good access to the left anterior descending
branch (LAD) and the right internal mammary artery (RIMA). On beating hearts, the
GraftConnector group had the RIMA connected to the LAD by means of the new
device, while the control animals had the same anastomoses sutured with
continuous 7-0 polypropylene sutures. The time for completing the anastomosis
(ischemic time) was recorded and the blood flow in the RIMA was recorded with the
proximal LAD open and closed, respectively. An intra-operative fluoroscopy with
contrast injection directly into the graft was done. Finally the proximal LAD was
ligated. The surviving animals are to be followed up. RESULTS: Seven (46%) of the
15 animals operated on with the traditional suturing technique and seven (63%) of
the 11 GraftConnector sheep survived the procedures and are to be followed up.
The 11 anastomoses done with the GraftConnector were completed in 2.41+/-0.2 min,
and the 14 anastomoses sutured with continuous suture were completed in 6.93+/
0.419 min (P<0.0001). The RIMA blood-flows in the two groups were comparable and
are presented. All the surviving animals had open anastomoses at fluoroscopy.
CONCLUSIONS: Quick coronary artery anastomoses without suturing on beating hearts
can be completed with the new GraftConnector. The GraftConnector creates
reproducible anastomoses in much less time than suturing, the per-operative
mortality in the GraftConnector Group was accordingly lower. Long-time follow-up
of the patency in surviving animals is pending. The presented device may
ultimately permit quick anastomoses endoscopically.
PMID- 10758394
TI - Vasorelaxant properties of nicorandil on human radial artery.
AB - OBJECTIVE: The radial artery is becoming popular as a conduit for coronary artery
surgery but there is concern about its tendency to vasospasm. Diltiazem is used
clinically in an effort to prevent vasospasm but there are suggestions that it is
relatively ineffective. The first aim of the study was to test the effectiveness
of Ca(2+) antagonists against vasospasm evoked by vasoconstrictor agonists.
Because a large component of vasospasm was resistant to Ca(2+) antagonists, the
second aim was to test if a different class of vasodilator, nicorandil, might
relax the residual tone. METHODS: Isometric tension was recorded in human radial
artery segments harvested from patients undergoing myocardial revascularization
surgery. RESULTS: Diltiazem at 10 microM, which strongly inhibits L-type voltage
gated Ca(2+) channels, induced partial relaxation (mean+/-SEM, 44.6+/-3.5%, n=31)
of phenylephrine-evoked contraction, but only 14.0+/-4.1% (n=10) and 12. 2+/-4.2%
(n=10) relaxation of U46619- (a thromboxane A(2) analogue) or endothelin-1-evoked
contraction. Strikingly, nicorandil relaxed agonist-evoked contractions that were
resistant to diltiazem or nicardipine. In the absence of a Ca(2+) antagonist,
nicorandil (30 microM) evoked 74.1+/-5.6% (n=24), 36.8+/-9.3% (n=10) and 64.5+/
7. 9% (n=14) relaxation of phenylephrine-, U46619- and endothelin-1-evoked
contractions. CONCLUSIONS: Nicorandil has a marked relaxant effect on
contractions evoked by three different vasoconstrictor agonists, and relaxes
vasospasm that is resistant to conventional Ca(2+) antagonists. These in vitro
data suggest that nicorandil might be a useful drug for the inhibition of radial
artery vasospasm in myocardial revascularization surgery.
PMID- 10758395
TI - Pulmonary function after biventricular bypass for autologous lung oxygenation.
AB - OBJECTIVE: Biventricular bypass (BVB) with autologous lung perfusion is an
attractive concept to ameliorate systemic inflammatory response by eliminating
the oxygenator from the extracorporeal circulation. The effect of biventricular
bypass as compared to heart-lung bypass (HLB) on pulmonary function parameters
was therefore studied in an experimental model. METHODS: Heart-lung bypass using
a membrane oxygenator or biventricular bypass using the autologous lung for gas
exchange was performed for 120 min in an alternating series of 12 mongrel dogs
with the heart arrested for 90 min by crystalloid cardioplegia and 30 min
reperfusion, followed by a 120 min observation period. Systemic (CO, SVR) and
pulmonary hemodynamics (PVR), extravascular lung water (EVLW, double indicator),
gas exchange (FiO(2), PaO(2), PaCO(2)), lung compliance (PC), and ventilation
(RMV) at FiO(2)=0.5 required to maintain PaCO(2) at 40 mmHg, were measured. Blood
cell counts (Leuco, Thrombo) were performed. RESULTS: All animals were weaned
from extracorporeal circulation without inotropes, no differences were observed
in cardiac output and blood pressures. The following data were obtained in %
change from pre-bypass values 60 min after extracorporeal circulation (*:P<0.05,
HLB vs. BVB): PVR, +108 vs. +45*; EVLW, +21 vs. -2*; PC, -12 vs. +4*; PaO(2), -8
vs. +21; RMV, +21 vs. +2*; Leuco, -65 vs. -12*; Thrombo, -62 vs. -35*.
CONCLUSION: During and after heart-lung bypass the lung is subject to severe
ischemia-reperfusion injury as indicated by edema, cell trapping, and impaired
gas exchange. The data demonstrate superior preservation of pulmonary mechanics
and function after biventricular bypass as compared to heart-lung bypass and
support the clinical strategy of using biventricular bypass in patients with
impaired lung function.
PMID- 10758397
TI - Simple method of hemostasis in implantation and explantation of HeartMate left
ventricular assist device.
AB - We described a simple method of hemostasis in implantation and explantation of
HeartMate left ventricular assist device. Wrapping of the inflow cannula, outflow
conduit and outflow graft with Vascutek tube graft can localize the bleeding due
to patient's coagulopathy, imperfect coating and device defect. During
explantation, bivalving the tube graft, leaving the graft in place and no-touch
of the adhesion between graft and soft tissue can minimize the dissection and
prevent the potential bleeding.
PMID- 10758396
TI - Effect of high dose platelet inhibitor treatment on thromboembolism in Novacor
patients.
AB - BACKGROUND: Thromboembolism and bleeding are among the most hazardous
complications following implantation of long-term left ventricular support
systems. This report focuses on the effect of high dose platelet inhibitor
treatment in patients with the Novacor system to prevent thromboembolic events.
METHODS: Thirty-eight (out of 58) Novacor patients (43+/-11 years old) were
studied in a non-randomized manner. Postimplantation: 20 patients were treated
with heparin only (control group), whereas in the other 18 patients aspirin
(3x330 mg/day) and dipyridamol (3x75 mg/day) were added to the treatment protocol
(aspirin group). RESULTS: Age, body size, underlying heart disease and support
interval were comparable among both groups, however, patients in the aspirin
group were much sicker with regard to urgency status, postoperative right heart
failure and hematologic disorders. Cerebral thromboembolic complications were
lower in the aspirin group (33% of patients, 0.4+/-0.7 events) as compared to the
control group (55% (P=0.18), 1.4+/-2.3 events (P=0. 048)). Non-cerebral
thromboembolism of surgical relevance was rare. The incidence of bleeding
complications was mildly increased in the aspirin group. CONCLUSION: The addition
of high dose platelet inhibitors seems to lower the incidence of thromboembolism
in Novacor patients.
PMID- 10758398
TI - The wrecking ball effect of a right atrial myxoma.
PMID- 10758399
TI - Introduction
PMID- 10758400
TI - Innate recognition systems in insect immunity and development: new approaches in
Drosophila.
AB - Phagocytosis is important in immune defense and development in vertebrates and
invertebrates. It leads to swift ingestion of microorganisms and dying cells by
phagocytes. How particles are recognized is not well understood. Studies in
insects, and Drosophila in particular, argue that these are powerful model
systems to dissect this process.
PMID- 10758401
TI - Toll-like receptors.
AB - Toll-like receptors (TLRs) are a growing family of molecules involved in innate
immunity. Accumulating evidence suggests that TLR molecules are involved in
signalling receptor complexes which recognise components of Gram-positive and
Gram-negative bacteria and mycobacteria. Differential expression and regulation
as well as distinct though overlapping ligand recognition patterns may underlie
the existence of a vast TLR family. Apparent structural and functional redundancy
may render certain outputs of the TLR family robust.
PMID- 10758402
TI - The role of dendritic cells in the innate immune system.
AB - Dendritic cells (DCs) are bone-marrow-derived leucocytes that are specialised
antigen-presenting cells capable of stimulating a primary T-lymphocyte response
to specific antigen. In this chapter we discuss the role DCs play in the innate
response acting as a critical link with the adaptive response and the influence
of the innate response on dendritic cells.
PMID- 10758403
TI - Collectins and innate immunity in the lung.
AB - Evidence from both in vitro and in vivo studies suggests that the collectins are
important elements in host innate immune defences against infectious agents.
Study of the collectins in specific disease settings now raises the prospects of
developing therapies exploiting these mechanisms of innate immunity.
PMID- 10758404
TI - Macrophage lectins in host defence.
AB - Macrophage lectins contribute to host defence by a variety of mechanisms. The
best characterised, mannose receptor (MR) and complement receptor three (CR3),
are both able to mediate phagocytosis of pathogenic microbes and induce
intracellular killing mechanisms. The regulation of the effector functions
induced via MR is complex, and may involve both host and microbial factors.
Therefore, MR is likely to play a dynamic role in the response to infection; it
may act as a classical pattern recognition receptor in phagocytosis, whereas
other poorly characterised factors may make a more decisive contribution to its
function in physiologic settings. In contrast, the lectin site of CR3 appears to
lack host-derived ligands and may be a true pattern recognition receptor. Further
studies are required to evaluate the roles of other macrophage lectins in
recognition of and responses to microbes.
PMID- 10758405
TI - CR3: a general purpose adhesion-recognition receptor essential for innate
immunity.
AB - CR3 (CD11b/CD18), a beta(2) integrin, has a key role in innate antimicrobial
defenses, as evidenced by the leukocyte adhesion (CD18) deficiency syndrome in
humans and the CD11b knockout mouse. CR3 is a highly versatile pattern
recognition receptor that activates leukocytes via signaling complexes and actin
reorganization, mediates phagocytosis, and promotes leukocyte transmigration.
PMID- 10758406
TI - CD14, new aspects of ligand and signal diversity.
AB - The glycosyl-phosphatidylinositol-linked glycoprotein CD14 is expressed in
myeloid cells and serum. It binds Gram-negative and -positive bacterial cell wall
components and endogenous phospholipids. Toll-like receptors, NF-kappaB and MAP
kinases participate in CD14 signaling of inflammation. Alterations of CD14 in
inflammatory diseases support a pathogenic role for this microbial receptor.
PMID- 10758407
TI - The role of scavenger receptors in the innate immune system.
AB - Akey aspect of the innate immune system is the ability to discriminate between
self and infectious nonself. This is achieved through pattern recognition
receptors which directly recognise molecular epitopes expressed by microbes.
Scavenger receptors (SRs) have been studied primarily due to their ability to
bind and internalise modified lipoproteins, suggesting an important role in foam
cell formation and the pathogenesis of atherosclerosis. However, the ability of
some SRs to function as pattern recognition receptors through their binding of a
wide variety of pathogens indicates a potential role in host defence. This review
will detail our current understanding of the function of SRs in innate immunity,
and in the initiation of aquired immune responses.
PMID- 10758408
TI - The macrophage receptor MARCO.
AB - MARCO (macrophage receptor with collagenous structure) belongs to the class A
scavenger receptor molecules. The structure and function of the molecule is
described. Although it is expressed on subsets of macrophages, it can be
upregulated on other macrophages after bacterial infection. The strategic
position of MARCO-expressing cells in lymphoid organs suggests an important role
for this bacteria-binding molecule in removal of pathogens.
PMID- 10758409
TI - Understanding the multiple functions of Nramp1.
AB - Nramp1 regulates macrophage activation in infectious and autoimmune diseases.
Nramp2 controls anaemia. Both are divalent cation (Fe(2+), Zn(2+), and Mn(2+))
transporters; Nramp2 a symporter of H(+) and metal ions, Nramp1 a H(+)/divalent
cation antiporter. This provides a model for metal ion homeostasis in
macrophages. Nramp2, localised to early endosomes, delivers extracellularly
acquired divalent cations into the cytosol. Nramp1, localised to late
endosomes/lysosomes, delivers divalent cations from the cytosol to
phagolysosomes. Here, Fe(2+) generates antimicrobial hydroxyl radicals via the
Fenton reaction. Zn(2+) and Mn(2+) may also influence endosomal metalloprotease
activity and phagolysosome fusion. The many cellular functions dependent on metal
ions as cofactors may explain the multiple pleiotropic effects of Nramp1, and its
complex roles in infectious and autoimmune disease.
PMID- 10758410
TI - Human inhibitory and activating Ig-like receptors which modulate the function of
myeloid cells.
AB - There is increasing evidence that myeloid cells express several receptor
families, which include both inhibitory and stimulatory isoforms. The expression
of receptor isoforms with similar specificities but opposite functions on the
same cell is intriguing. What might be the interplay between these receptors?
Some clues to the answer to this question may come from recent studies on two
myeloid receptor families: the ILT/LIR/MIR (immunoglobulin-like
transcript/leukocyte Ig-like receptor/monocyte/macrophage Ig-like receptor) and
the SIRP (signal-regulatory protein).
PMID- 10758412
TI - Benefits of membership
PMID- 10758411
TI - Chemokines and myeloid cell recruitment.
AB - Chemokine-chemokine receptor interactions mediate constitutive leukocyte
trafficking and leukocyte recruitment to sites of infection and inflammation. We
suggest that a multiplicity of leukocyte chemoattractants exists to increase the
selectivity of leukocyte recruitment in a range of physiological and pathological
settings.
PMID- 10758413
TI - TNF-alpha but not IL-1alpha is correlated with PGE1-dependent protection against
acute D-galactosamine-induced liver injury.
AB - BACKGROUND: Prostaglandin E1 (PGE1) treatment of humans and rodents during acute
hepatic failure ameliorates different parameters of hepatic dysfunction. PURPOSE:
To investigate whether prevention of acute liver injury induced by D
galactosamine (D-GalN) with preadministration of PGE1 is correlated with a change
in the concentration of two proinflammatory cytokines, as tumour necrosis factor
alpha (TNF-alpha) and interleukin (IL)-1alpha, and/or nitrite+nitrate (NOx), as
nitric oxide-related end products in serum. RESULTS: D-GalN significantly
increased alanine aminotransferase (ALT) and TNF-alpha concentration in serum 5
and 10 mins, respectively, after treatment compared with the control group (P< or
=0.05). D-GalN did not change the IL-1alpha concentration at any time during the
study. Preadministration of PGE1 to D-GalN-treated rats significantly reduced the
ALT content and increased significantly the TNF-alpha concentration in serum 1,
2.5, 5 and 10 mins after D-GalN treatment compared with the D-GalN group (P< or
=0.05). Nitric oxide was not involved in either the toxic effect due to D-GalN or
the protection observed with PGE1 against D-GalN toxicity. CONCLUSIONS: Acute
liver injury induced by D-GalN is correlated with an increased TNF-alpha release.
Preadministration of PGE1 to D-GalN-treated rats exerted a priming effect on
inflammatory cells to release enhanced levels of TNF-alpha but not IL-1alpha.
These findings indicate that stimulation of TNF-alpha release may be involved in
the acute D-GalN-induced liver injury and also in PGE1 protection from
hepatotoxicity in clinical and experimental studies.
PMID- 10758414
TI - Gallbladder carcinomas: an immunoprognostic evaluation of P53, Bcl-2, CEA and
alpha-fetoprotein.
AB - The p53 gene is the most frequently mutated gene in many human cancers, including
those of the colon, breast, lung, esophagus, liver and brain. Such genetically
mutated tumours are generally associated with progression of the disease and poor
clinical outcome. One hundred cases of documented gallbladder carcinomas were
reviewed. Twenty-eight cases were randomly selected to evaluate the expression of
P53, Bcl-2, carcinoembryonic antigen (CEA) and alpha-fetoprotein, in both the in
situ (19 cases) and invasive components (28 cases) of the tumour by the avidin
biotin complex method of immunohistochemistry. These results were correlated with
the mean survival intervals in an effort to clarify the progression of the
disease and evaluate their role as prognostic markers. Staining to alpha
fetoprotein and Bcl-2 remained consistently negative to weak insignificant
staining in both the in situ and invasive components of the tumour in all cases.
P53 staining of the invasive part of the tumour was seen in 24 (86%) of the cases
and in 17 (89%) of the in situ component. The in situ staining patterns of P53
were not statistically significant in relation to the mean survival. However, in
the invasive component, moderate to strong staining tumours, as seen in 15 (54%)
cases, were associated with a mean survival of 8.8 months. A similar trend was
also observed with staining patterns to CEA. Eighty-nine per cent of the invasive
and 84% of the in situ components of the tumour stained positive to CEA. Moderate
to strong staining of both the in situ and the invasive components of the tumours
was associated with a mean survival of 10.6 months in 76% of cases. This study
shows that altered expressions of P53 and CEA are detectable by
immunohistochemistry in gallbladder carcinomas. Tumours with increased expression
of P53 and CEA of a strong to moderate staining were associated with poor
clinical outcomes as evidenced by their mean survival. A stepwise progression of
altered CEA and P53 expression may reflect ongoing progression of the disease
from the in situ to the invasive phase. However, such trends need to be evaluated
in larger numbers and are thus not considered to be true independent prognostic
markers.
PMID- 10758416
TI - From bench to bedside to bug: an update of clinically relevant advances in the
care of persons with Helicobacter pylori- associated diseases.
AB - In-depth meetings of the XIth International Workshop on Gastroduodenal Pathology
and Helicobacter pylori led to the presentation and discussion of extensive new
data on H. pylori and its diseases. The mode of transmission of H. pylori remains
unclear, and it remains unknown why only a small proportion of infected
individuals develop duodenal or gastric ulcer disease and even fewer develop
gastric cancer. The role of H. pylori eradication in persons with uninvestigated
dyspepsia remains controversial. New clinical trials of H. pylori treatment show
symptom relief and improvement in the quality of life of persons with functional
dyspepsia, especially in those with ulcer-like or reflux-like dyspepsia. Clearly
the move is toward symptom-based management of persons with dyspepsia, with fewer
endoscopies being needed in the otherwise healthy young dyspeptic patients. It
remains controversial whether eradicating H. pylori in duodenal ulcer or
functional dyspepsia increases the risk of subsequent development of
gastroesophageal reflux disease. The one-week proton pump inhibitor-based triple
regimens remain the gold standard of H. pylori therapy, but some of the
ranitidine bismuth citrate plus two antibiotic regimens also achieve an 80% H.
pylori eradication rate on an intention-to-treat basis. While the urea breath
test remains the noninvasive test of choice, interesting new data are available
on the use of stool antigen testing to diagnose H. pylori infection. The number
of H pylori-associated gastroduodenal diseases grows to include possible liver,
vascular, immune and skin conditions.
PMID- 10758417
TI - Emergency endoscopy.
AB - The need for emergency endoscopy is a matter of debate. The time interval for
emergency procedures remains to be defined. Most authors propose a time span of
24 h as emergency time, while some define a period of 72 h (especially in acute
pancreatitis). Several studies have shown a possible benefit for a select group
of patients. Four main indications are established for emergency endoscopy: acute
gastrointestinal bleeding (variceal and nonvariceal), acute biliary pancreatitis
and acute cholangitis. In the case of upper gastrointestinal bleeding, emergency
endoscopy enables exact diagnosis and appropriate therapy, and provides important
prognostic information. There is some evidence that emergent endoscopic injection
therapy improves clinical outcome and reduces mortality in patients with acute
ulcer bleeding. Patients do not benefit if endoscopy is performed only as a
diagnostic procedure. Controversial results were published recently for emergency
endoscopy in acute biliary pancreatitis. There is good evidence that emergency
endoscopic retrograde cholangiopancreatography is helpful in patients with severe
pancreatitis and stone impaction if performed within the first 24 h after onset
of symptoms. However, emergency endoscopic retrograde cholangiopancreatography is
not beneficial for patients with mild pancreatitis if performed later than 72 h
(or 24 h) after onset of symptoms. There is a limited number of well established
evidence-based indications for emergency endoscopy. Some other indications are
still a matter of debate, and controversial opinions have been published.
PMID- 10758415
TI - Prospective, controlled, multicentre study of loperamide in pregnancy.
AB - BACKGROUND: Loperamide is a synthetic piperidine derivative used for the
treatment of both acute and chronic diarrhea. Little is known about its safety
and risk in pregnancy. Human data are limited to one surveillance study of
Michigan Medicaid patients, with 108 women exposed in the first trimester. In
this study there were six major birth defects, three of which were cardiovascular
anomalies. OBJECTIVES: To determine whether loperamide use in pregnancy is
associated with an increased risk of major malformations. The secondary end
points were rates of minor malformations, spontaneous and therapeutic abortions,
and premature births, and mean birth weights. PATIENTS AND METHODS: Women
counselled by five teratogen information centres on the safety and risk of
loperamide in pregnancy were followed after delivery and compared with a similar
group of women matched for age, smoking, alcohol and other exposures. RESULTS:
One hundred and five follow-ups were completed; 89 of the women were exposed to
loperamide in the first trimester of pregnancy. There were no statistically
significant differences between the study group and the control group in any of
the end points that were analyzed. However, of women who took loperamide
throughout their pregnancy, 21 of 105 had babies who were 200 g smaller than
babies in the control group. CONCLUSIONS: The results of this study suggest that
the use of loperamide during pregnancy is not associated with an increased risk
of major malformations.
PMID- 10758418
TI - Inflammatory bowel disease: progress toward a gene.
AB - The pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD) is still
unknown, but the importance of genetic susceptibility has been clearly shown by
epidemiological data from family and twin studies. Linkage studies have
identified two susceptibility loci for inflammatory bowel disease (IBD) on
chromosomes 12 and 16. Importantly, these linkages have been replicated by
independent investigators, and studies of positional candidates within these
regions continue, together with fine mapping strategies. Regions of 'suggestive'
linkage on chromosomes 1, 3, 4, 6, 7, 10, 22 and X have also been reported in
individual studies. Other important candidate genes investigated include the
interleukin-1 receptor antagonist, MUC3 and genes of the human leukocyte antigen
(HLA) system. The apparently conflicting data in different studies from around
the world may be explained by ethnic differences, case mix and genetic
heterogeneity. Replicated class II HLA associations include HLA DRB1*0103 and DR2
(DRB1*1502), involved in UC susceptibility, and HLA DRB1*03 and DR4 as resistance
alleles for CD and UC respectively. Animal studies have provided insights from
targeted mutations and quantitative trait locus analysis. The goals of continuing
research include narrowing the regions of linkages and analysis of candidate
genes, and possibly the application of newly developed methods using single
nucleotide polymorphisms. Advances in IBD genetics hold the potential to provide
knowledge about the disease pathogenesis at the molecular level, with ensuing
benefits for clinical practice.
PMID- 10758419
TI - Esophageal motility disorders: current concepts of pathogenesis and treatment.
AB - Current concepts of esophageal motility disorders are summarized. Primary data
sources were located via MEDLINE or cross-citation. No attempt was made to be
comprehensive or inclusive of the literature because fewer than 10% of citations
are discussed. Instead, emphasis was placed on new developments in diagnosis,
therapeutics and practice patterns. Controlled therapeutic trials and
pathophysiological observations are emphasized. Achalasia is a rare disease of
failed lower sphincter relaxation and aperistalsis. Diffuse esophageal spasm
(DES), an equally rare disease, is defined by nonpropagated esophageal
contractions. Nonspecific motility disorders, including nutcracker esophagus and
hypertensive lower esophageal sphincter, are identified only by manometry and are
10 times as prevalent. Neuromuscular pathology is evident only with achalasia
(myenteric plexus neuron destruction). Pharmacological therapies have limited
efficacy with achalasia, more limited efficacy with DES and no efficacy with the
nonspecific motility disorders. More efficacious therapies for the nonspecific
disorders are directed at associated reflux disease or psychiatric disorders.
Pneumatic dilation is effective therapy for achalasia in 72% of instances but
frequently requires repeat dilation and is complicated by a 3% perforation rate.
Surgical myotomy is effective in 88% of patients with achalasia; morbidity from
thoracotomy has been the major limitation but has been sharply reduced with a
laparoscopic approach. In conclusion, although it has been suggested that
esophageal motility disorders are distinct clinical entities, critical review of
the literature supports this only in the case of achalasia, a disease of well
defined pathophysiology, functional disturbance and therapies. This clarity
diminishes progressively for DES and nonspecific esophageal motility disorders.
PMID- 10758420
TI - Genetic cholestasis: lessons from the molecular physiology of bile formation.
AB - Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic
cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by
cholestasis and a low to normal serum gamma-glutamyltransferase (GGT) activity,
whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2
occur due to mutations in loci at chromosome 18 and chromosome 2, respectively.
The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are
caused by transport defects in the liver affecting the hepatobiliary secretion of
bile acids and phospholipids, respectively. Benign recurrent intrahepatic
cholestasis (BRIC) is linked to a mutation in the same familial intrahepatic
cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be
difficult to differentiate from these transport defects. Intrahepatic cholestasis
of pregnancy (ICP) appears to be related to these cholestatic diseases. For
example, heterozygosity in families with PFIC type 3 is associated with ICP, but
ICP has also been reported in families with BRIC. In Dubin-Johnson syndrome there
is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is
affected. This, therefore, is a mild disease, and patients have a normal
lifespan.
PMID- 10758421
TI - Gastric carcinoid tumours and pernicious anemia: case report and review of the
literature.
AB - Patients with pernicious anemia are at risk of developing carcinoid tumours of
the stomach. A patient with pernicious anemia and multifocal carcinoid tumours of
the gastric fundus that regressed after antrectomy is presented. The frequent
occurrence of gastric carcinoid tumours in patients with long-standing pernicious
anemia suggests that surveillance gastroscopy and biopsies of the fundus might be
indicated. Compete functional antrectomy may effectively cause these tumours to
regress by removing their excessive gastrin hormonal stimulation. However,
incomplete antrectomy can result in persistently elevated serum gastrin and
failure of total disappearance of the carcinoid tumours.
PMID- 10758422
TI - [Relationship between psychosocial stress and mental disease: community study].
AB - INTRODUCTION: We investigate the relationship between life events stress and
psychiatric disorders in a random sample of urban population older than 16 in the
Tenerife Island. METHOD: A two-stage cross-sectional study was conducted. In the
first stage 660 persons were interviewed using the GHQ-28 as a screening
questionnaire and the DSM-III-Axis IV for the psychosocial stressors valoration.
In the second stage were interviewed all persons screening positive on the GHQ
and similar number of the screening negative ones, using the Clinical Interview
Schedule. RESULTS: The psychosocial stressors prevalence was 36,5% and the
pathology psychiatric prevalence was 12, 90%: among 3.3% of the people who do not
refer psychiosocial stress and 29.5% of the people who do refer. CONCLUSION: We
confirmed a significant relationship between psychosocial stress and psychiatric
disorders in both sexes.
PMID- 10758423
TI - [Subtypes of schizophrenics patients with attempted suicide].
AB - INTRODUCTION: During the last decades, numerous research works have tried to
determine what risk factors are associated with the schizophrenic patient's
suicidal behavior but they have yielded contradictory results. Thus we
hypothesized that these results' variability could be due, among other reasons,
to the heterogeneity of suicidal schizophrenic population. MATERIAL AND METHOD:
Thirty-two Schizophrenics patients who had made Attempted suicide were studied.
They were assessed through a battery of Clinical scales for negative, positive,
hopelessness, insight and depressive symptoms. RESULTS: Two suicidal subtypes
were identified according to the reasons that patients stated for attempting
suicide. These two subtypes showed significant differences in two of the analyzed
variables, namely hopelessness and PANSS positive subscale. DISCUSSION: Clinical
implications coming from these results are discussed in the present paper.
PMID- 10758424
TI - [Referral of patients with mental disorders from primary care to mental health
units].
AB - INTRODUCTION: Most part of the patients suffering from mental disorders are
treated by non-psychiatrist physicians, mainly by general practitioners (GPs).
The aim of this study has been to analyse the factors influencing the referral of
patients with mental illness to psychiatric services. METHODS: Using data of
referrals from two Primary Care Centres (population: 28.039) to a Mental Health
Unit in one year period, we analysed clinical records, information provided with
the referral, and the opinion of GPs about mental illness. RESULTS: Out of the
486 referrals, the 153 patients without previous consultations were included in
the analysis. Men, and those with higher educational status were referred more
frequently. A 34% of the referrals included information about psychopathological
symptoms, and 70% included clinical diagnosis. Primary care physicians
specialised in family medicine included more data regarding psychopathological
symptoms, and included a specific request more often than GPs without specialised
training. Diagnostic accuracy (61%) were lower for adjustment and personality
disorders, and in those patients with an urgent referral. Patients with an urgent
referral did not present different clinical features, nor different severity than
those with an ordinary referral. CONCLUSIONS: Management of patients with mental
disorders in PHC should be improved with guidelines about treatment and referral.
Different levels of care should be co-ordinated.
PMID- 10758425
TI - [Psychiatric care policies and deinstitutionalization in South America].
AB - INTRODUCTION: The process of restructuring psychiatric care in South America
began in the 80's and increased in the 90's. This process had its landmark in the
Declaration of Caracas (1990), which reinforced the need for alternative services
to the mental hospital. OBJECTIVES: to analyse the current situation of the
psychiatric care in South America, with special emphasis on Psychiatric Units in
General Hospitals (PUGHs). METHODS: Two mail surveys were carried out.
Questionnaires were sent to all Ministries of Health, Psychiatric Societies and
key informants. RESULTS: All countries were represented in the returned
questionnaires. In 7 countries there is a mental health plan. Material and human
resources are inadequate in most countries. There has been a decrease in the
total number of psychiatric beds over the last tem years. PUGHs were created in
all the countries surveyed. CONCLUSIONS: All South America countries have a
mental health program. A higher percentage of the programs is devoid of an
evaluation system and almost all the countries lack budget estimates for mental
health care. It was observed that the total number of psychiatric beds has been
decreasing in most countries, and that the PUGHs and other decentralized centers
were adopted as an alternative to the mental hospital.
PMID- 10758426
TI - [Schizophrenia: a brain disease. II. Functional neuroimaging].
AB - Functional neuroimaging techniques constitute formidable tools to investigate the
human brain in vivo. This possibility has led to a growing interest in these
techniques in psychiatric research, particularly in the study of neural mechanism
involved in schizophrenia. Three main lines of research have been developed in
this field: 1. Patterns of brain activity in a rest condition or during cognitive
task performance, 2. correlations between psychopathology and brain activity, and
3. investigations of neurochemical characteristics (neurotransmitters and
neuroreceptors) of schizophrenic patients. However, despite of the great effort
developed lately these studies have yielded little in the way of coherent
pathophysiologic theories of schizophrenia. Future studies combining molecular
biology and genetic techniques with structural and functional neuroimaging
studies are needed in our purpose to explore the neural mechanisms involved in
schizophrenia.
PMID- 10758427
TI - [Cocaine and psychiatric comorbidity].
AB - A bibliographic review of psychiatric comorbidity in cocaine users was done in
last ten years (Medline, IME, HealthSTAR, Cinahl). It was valued the prevalence
of psychiatric disorders in cocaine users and that of consume of this substance
in-patients with psychiatric disorders. Their relationship, influence over the
evolution and consequences on the treatment were studied as well. Epidemiologic
studies showed an increase of affective disorders, anxiety disorders and
personality disorders in cocaine users and an increase of consume of this
substance in those patients who are presented psychosis and anxiety disorders.
The relationship of these disorders was analysed, as well as the influence oh the
comorbidity in the evolution and repercussion on the treatment.
PMID- 10758428
TI - [Neurobiology and psychoanalysis].
AB - Psychiatry obtains benefits from integrating the findings of neurobiology with
the knowledge of depth psychology. In this paper, relevant recent research in
neuroscience is reviewed from the perspective of psychoanalytic theory.
Psychoanalytic experience and hypotheses have stimulated numerous experiments and
research projects in neurobiology. Neurobiological findings have brought forward
the neurophysiological substrate of clinical phenomena described by
psychoanalysts, assisting in the specification of some theoretical notions, and
making us modify others that were considered as already established. From a
neurobiological viewpoint, some studies considered pertinent are commented upon
on associations, apperception and unconscious perception, memory, and hemispheric
specialisation and its psychological corollary.
PMID- 10758429
TI - [Persisting and late onset psychotic disorder due to consumption of ecstasy
(MDMA)].
AB - Let us present a case of recurrent paranoid psychotic episodes in a patient with
a history of abuse of <> (MDMA: 3, 4-methylenedioxymethamphetamine),
that persisted after a long withdrawal time, that, in our opinion, after an
exhaustive differential diagnosis, may be attributed to that consumption. The
carachteristics of this case are formally and naturally equivalent to those
referred to in other papers about paranoid psychosis after abuse of MDMA, in
which the sudden appearance, and the symptomatolgy of an intense feeling of
threat and physical violence outstands, accompanied by abnormal corporal
perceptions. In the case hereby presented, the withdrawal time is longer than
that described in other publications. Even though in some authors' opinion this
should be considered as comorbility or dual diagnosis, in our opinion enough
facts exist suggesting that this is not a case of functional mental disorder but
an organic disorder secondary to the neurotoxic effect of MDMA.
PMID- 10758430
TI - [Water intoxication and hyponatremia: report of two cases].
AB - Two psychiatric patients suffering from psychogenic polydipsia, hyponatremia and
water intoxication were evaluated at emergency room. Both of them showed organic
psychiatric disease which improve with medical treatment. We illustrated the
physiological and clinical features of polydipsia, hyponatremia and water
intoxication as well as treatment modalities.
PMID- 10758431
TI - [Usefulness of spect with 99mTc-tetrofosmin and stimulus with dipyridamole in
patients with left bundle branch block of His].
AB - BACKGROUND: In patients with left bundle branch block, the 201Tl scintigraphic
studies show high sensitivity, but with low specificity, in the diagnosis of
coronary artery disease. OBJECTIVE: [corrected] To assess the value of 99mTc
tetrofosmin Single Photon Emission Computed Tomography (SPECT) and dipyridamole
administration in patients with left bundle branch block. METHODS: 22 patients
with angina and left bundle branch block were retrospectively studied by cardiac
catheterization and Tc-Tf after dipyridamole administration (0,142 mg/kg/min.
i.v.) and at rest. RESULTS: The mean number of territories with perfusion defects
was 1.5+/-1.0, and the average number of diseased vessels in the coronariographic
study was 1.6+/-1.3 (r = 0.77, p<0.001). Sensitivity, specificity, positive
predictive value, negative predictive value, total predictive value and Kappa
index in the diagnosis of multivessel disease were 92%, 90%, 92%, 90%, 91% and
0.82, respectively. In the diagnosis of anterior descending artery disease, these
values were 83%, 70%, 77%, 78%, 77%, and 0.54, respectively. CONCLUSION: In
patients with angina and left bundle branch block, SPECT with Tc-Tf-dipyridamole
is of great value in the study of coronary artery disease extension. Sensitivity
and specificity for the diagnosis of anterior descending artery disease were
similar to that shown in series with thallium-dipyridamole.
PMID- 10758432
TI - [Dual isotope myocardial scintigraphy (201thallium at rest/99 M technetium
tetrofosmin with exercise) in the detection of reversible hypoperfusion].
AB - The dual-isotope technique (rest 201Tl and stress 99mTc-sestamibi) is useful to
assess myocardial perfusion in coronary disease patients. 99mTc-labeled
tetrofosmin is a radiopharmaceutical whose characteristics are similar to
sestamibi. Thus, we decided to use it to detect reversible myocardial
hypoperfusion in patients with a background of myocardial infarction and
ischemia. A sequential dual-isotope scintigraphy (3 mCi rest 201Tl and 25 mCi
stress 99mTc-tetrofosmin) with 24-hour 201Tl redistribution (RD) was performed in
20 patients with previously confirmed myocardial infarction and clinical and
ergometric signs of ischemia. Each patient also underwent a stress-redistribution
protocol with redistribution at 4 and 24 hours post injection with 201Tl
scintigraphy within two weeks of the first study. The qualitative uptake analysis
showed no significant differences in the number of myocardial segments with
severe reduction of tracer uptake on stress that improved at rest or in RD
images, even if 24-hour RD images were considered. The quantitative global uptake
analysis showed a similar defect reversibility with both protocols; however if 24
hour RD images were considered the uptake improvement was significant only when
compared with the rest 201Tl images in dual-isotope scintigraphy protocol (75+/
8% vs. 81+/-9% of peak activity, rest vs. 24-hour RD; p<0.01) and not when
compared with the 4-hour RD in the 201Tl scintigraphy. On the other hand, when
only the segments with severely reduced uptake (<50% of peak activity) were
analyzed, the 24-hour RD improved myocardial uptake significantly (p<0.001 vs.
rest and vs 4-hour RD) in both protocols. We conclude that a sequential dual
isotope rest 201Tl/stress 99mTc-tetrofosmin scintigraphy is comparable with
stress-redistribution 201Tl scintigraphy to detect reversible myocardial
hypoperfusion; however in both cases, the addition of 24-hour images increases
its usefulness in severely hypoperfused segments, if the uptake of the
radiopharmaceutic is quantified.
PMID- 10758433
TI - [Correction of movements in cardiac SPECT studies].
AB - OBJECTIVES: Patient movement during SPECT acquisition of images is a frequent
cause of artefacts in myocardial perfusion SPECT studies. In this paper we
propose an algorithm for the correction of longitudinal movements. MATERIALS AND
METHODS: The method is based on the calculation of the correlation between
unidimensional functions obtained from successive projections with a window
obtained automatically to eliminate unwanted data points before calculating the
correlation. The algorithm was assessed on studies obtained from a cardiac
phantom and from those corresponding to ten patients. Seven of these patients had
significant movement during SPECT acquisition and those corresponding to the
other three studies, in which no movement was observed, were used as a control.
RESULTS: In the phantom studies obtained, the mean error of the calculated
displacements was less than 0.5 pixels when the window proposed was employed. The
error reached 2.8 pixels when the length of the window increased. In patient
studies, the method succeeded in reducing the patient motion in all cases and the
three control studies remained unchanged. When no window was used to limit the
correlation, three out of the seven studies that originally presented movements
did not improve and one control study got worse. CONCLUSION: The results obtained
indicate the utility of the algorithm and demonstrate the need to window the data
before calculating the correlation.
PMID- 10758434
TI - [Scintigraphic pattern in a case of Tarlov cyst].
AB - We report the case of a 40-year-old man remitted to our department with a history
of lower back pain and sciatica with no history of trauma. The laboratory
analyses showed normal values whereas plain radiographs showed a sacrum
rarefaction area. A 99mTc-MDP bone scintigraphy was performed to evaluate the
lumbosacral area. Planar images did not show any abnormality. SPECT images
revealed photopenic abnormality in the second sacral vertebral right hemibody,
with no peripherally increased radiotracer accumulation. Subsequent MRI and CT
myelography demonstrated the nature of the photopenic area as secondary to
vertebral erosion by sacral perineurial cyst (Tarlov cyst).
PMID- 10758435
TI - [Nuclear cardiology: technical bases and clinical applications].
AB - Although the role of nuclear cardiology is currently well consolidated, the
addition of new radiotracers and modern techniques makes it necessary to
continuously update the requirements, equipment and clinical applications of
these isotopic tests. The characteristics of the radioisotopic drugs and
examinations presently used are explained in the first part of this text. In the
second, the indications of them in diagnostic and prognostic evaluation of the
different coronary diseases are presented.
PMID- 10758436
TI - Anaesthesia organizations in europe: a coming together
PMID- 10758437
TI - Questions about the macintosh laryngoscope and technique of laryngoscopy.
PMID- 10758438
TI - Haemodynamic management of a patient with septic shock.
AB - For supportive therapy in sepsis, an adequate volume loading is likely the first
step, and possibly the most important step in the treatment of patients with
septic shock. However, it is still a matter of debate what kind of fluids,
endpoints for resuscitation and monitoring techniques should be used.
Nevertheless, therapies which closely control volume loading and regional
perfusion are becoming more utilized. An elevated global O2-supply (DO2) may be
necessary and beneficial in most of these patients but the increase of DO2 should
be guided by the measurement of parameters assessing global and regional
oxygenation. Routine strategies for elevating DO2 by the use of very high dosages
of catecholamines cannot be recommended. Vasopressors should be used to achieve
an adequate perfusion pressure. With norepinephrine, no negative effects on
regional perfusion have been demonstrated when the patient is adequately volume
resuscitated and the DO2 is normal or even slightly elevated. In contrast,
epinephrine should be avoided because it seems to redistribute blood flow away
from the splanchnic region. There is controversy whether dopamine should still be
used as a first-line drug in patients with septic shock, because there are some
clinical and experimental data that indicate unfavourable effects on mucosal
perfusion of the gut. To date, there are no convincing data to support the
routine use of low-dose dopamine or dopexamine in patients with sepsis. Neither
low-dose dopamine nor dopexamine have been proven to prevent renal failure in
septic patients. Furthermore, there is evidence that low-dose dopamine may reduce
mucosal perfusion in the gut in some patients. Dopexamine has been suggested to
improve splanchnic perfusion but because these effects remain somewhat
controversial, there is as yet no reason for a general recommendation for
dopexamine in septic patients. These recommendations are currently limited by the
lack of sufficient outcome studies and studies which evaluate regional perfusion.
Until the various catecholamine regimes are more fully examined, recommendations
for catecholamine support in sepsis must be considered 'conditional'.
PMID- 10758439
TI - Disposition of propofol between red blood cells, plasma, brain and cerebrospinal
fluid in rabbits.
AB - The disposition of propofol in the blood and brain of New Zealand rabbits was
studied in three groups of six rabbits. One group received a single anaesthetic
dose; a second group received a 1-h infusion; and a third group was studied after
the rabbits were judged to have recovered from a 1-h infusion. There was a high
concentration of propofol in the red blood cell fraction and in the brain,
however, the red blood cell concentration largely exceeded the one found in the
brain in all groups of animals. This is consistent with the high fat solubility
of diisopropylphenol. The possible effects of propofol sequestered in red blood
cells is discussed.
PMID- 10758440
TI - Dolasetron for the prevention of postoperative nausea and vomiting following
outpatient surgery with general anaesthesia: a randomized, placebo-controlled
study. The Dolasetron PONV Prevention Study Group.
AB - In a multicentre, randomized, double-blind, placebo-controlled dose-ranging
study, 1030 patients undergoing outpatient surgery with general anaesthesia
received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The
principal outcome measure was the proportion of patients who were free of emesis
or rescue medication for the 24-h period after the study drug was given; the
subsidiary outcome measure was survival time without rescue medication. Effects
on nausea were quantified using a visual analogue scale. Compared with placebo, a
complete response was significantly higher when all four dolasetron doses were
combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron
provided maximum clinical benefit (effectiveness compared with adverse events),
with no additional benefit in complete response rates or nausea visual analogue
scale scores at higher doses. No significant differences were observed in
complete response for any dolasetron dose in males compared with placebo. The
majority of adverse events reported were mild or moderate. Dolasetron provided
well-tolerated, safe, and effective prophylaxis for post-operative nausea and
vomiting with maximum effectiveness observed at a dose of 12.5 mg.
PMID- 10758441
TI - Inhalational versus intravenous induction. A survey of emergency anaesthetic
practice in the United Kingdom.
AB - A survey was constructed to ascertain the views of The Royal College of
Anaesthetists tutors regarding the acceptability of inhalational induction with
sevoflurane for emergency anaesthesia. A questionnaire was sent to all tutors
asking them to indicate their preferred choice of anaesthetic technique, and
whether they believed inhalation induction with sevoflurane to be acceptable, in
each of four scenarios: acute epiglottis; bleeding after tonsillectomy;
appendicitis; and laparotomy in the shocked patient. Two hundred and sixty-two
(89%) completed questionnaires were received from 294 college tutors. We have
shown that the majority of The Royal College of Anaesthetists tutors would use
sevoflurane for patients with an acutely compromised airway. One in four college
tutors would accept the use of sevoflurane for a shocked patient for laparotomy.
Anaesthetists who manage critically ill patients with an inhalational induction
should be reassured by the fact, that a significant proportion of their
colleagues would find this technique acceptable.
PMID- 10758442
TI - Alkalinization of amide local anaesthetics by addition of 1% sodium bicarbonate
solution.
AB - A number of methods exist by which the pH of local anaesthetic solutions may be
increased. Most commonly, these require the addition of differing amounts of
sodium bicarbonate solution according to the local anaesthetic drugs. Sodium
bicarbonate (1%) was titrated against pH in six commonly used local anaesthetic
solutions. Titration curves of pH and volume of sodium bicarbonate solution added
are shown for this group of local anaesthetics. This study demonstrates that 1 mL
of 1% sodium bicarbonate solution may be used to alkalinize this range of local
anaesthetics without the risk of precipitation. We also conclude that Ropivacaine
(at concentration 0.75% and 1.0%), is unsuitable for alkalinization since it
precipitates at a pH of 6.0.
PMID- 10758443
TI - An audit of patient perception compared with medical and nursing staff estimation
of pain during burn dressing changes.
AB - In order to prescribe appropriate analgesia for burns dressing changes the pain
experienced by 30 burned patients during this procedure was recorded. Patients
received analgesia prior to their dressing changes according to the current
protocol in the burns unit. During the same period the medical and nursing staff
in the unit who were involved in prescribing and administering the analgesia for
the dressing change, were asked to assess the severity of pain that they thought
patients experienced during dressing changes. Patients recorded their worst pain
as none or mild in 64% of procedures. In contrast, no surgeon and only one nurse,
rated pain as none or mild. The discrepancy between severity of pain recorded by
patients and the pain predicted by staff prescribing and administering analgesia
has clinical implications.
PMID- 10758444
TI - Use of an illuminated flexible catheter for light-guided tracheal intubation
through the intubating laryngeal mask by nurses.
AB - We evaluated the ability of inexperienced personnel in using a prototype
illuminated flexible catheter to assist tracheal intubation through the
intubating laryngeal mask in anaesthetised, paralysed patients. The device
consists of a completely flexible thin plastic catheter, a bulb attached to its
distal end and a 15-mm concentric adapter at its proximal end. The illuminated
catheter is placed into a straight silicone tracheal tube in such a way that the
bulb is placed at the distal end of the tracheal tube. Six nurses inexperienced
in tracheal intubation followed a 2-hr training program by using the device
through the intubating laryngeal mask in a mannequin and then intubated 10
patients each, with instruction from an anaesthetist. All patients (n=60) were
ASA 1-2, scheduled to undergo general anaesthesia for elective surgery. After
fentanyl/propofol induction the intubating laryngeal mask was inserted. When an
adequate airway was established, patients received atracurium and the
endotracheal tube preloaded with the device was inserted through the intubating
laryngeal mask and by observing the glow in the neck was advanced into the
trachea. The final outcome and the duration of the procedure were recorded. The
intubating laryngeal mask was inserted successfully in all patients. The success
rate of intubation was 57/60 (95%); 38 patients at first attempt and 19 after two
or three attempts. The mean (+/-SD) duration of the procedure in the first five
patients in the series of each nurse was 74+/-40 s while in the last five
patients it was diminished to 52+/-23 s (P=0.01). We conclude that the described
methodology has the potential for more widespread use of tracheal intubation
through the intubating laryngeal mask even by inexperienced personnel.
PMID- 10758445
TI - Effect of epidural and intravenous clonidine on the neuro-endocrine and immune
stress response in patients undergoing lung surgery.
AB - The effects of intravenous and epidural clonidine, 4 microg kg-1, combined with
epidural morphine, 40 microg kg-1, on the neuro-endocrine and immune stress
responses to thoracic surgery are reported. A control group received only
epidural morphine. Anaesthesia was induced and maintained with propofol.
Catecholamines, vasopressin, cortisol, beta-endorphin concentrations and
leucocyte counts were measured before drug administration, immediately after
intubation of the trachea, after thoracotomy and at the end of surgery.
Catecholamines did not change in any of the groups. The other stress hormones
increased during surgery, the pattern being similar in the three groups. Total
leucocyte and neutrophil counts were increased in all groups at the end of
surgery, but the increase was least in the epidural clonidine group. The number
of lymphocytes was reduced at the end of surgery in the epidural and intravenous
group, compared with the control group in which the number of lymphocytes did not
change. The effects are more pronounced with epidural than with intravenous
administration. We conclude that clonidine can modulate the immune stress
response to thoracic surgery.
PMID- 10758446
TI - The effects of propofol on heart rate, arterial pressure and adelta and C
somatosympathetic reflexes in anaesthetized dogs.
AB - The effects of propofol on mean arterial pressure, heart rate and Adelta and C
somatosympathetic reflexes, recorded in renal nerves, evoked by repeated
individual supramaximal electrical stimuli applied to radial nerves, were
observed in anaesthetized, paralysed and artificially ventilated dogs. Propofol
was infused at rates from 0.4 to 2.0 mg kg-1 min-1. Mean C and Adelta reflexes
were abolished at plasma concentrations (mean, SEM) of 24.3 (3.3) and 29.2 (2.6)
microg mL-1 (P < 0.05), respectively, when mean arterial pressure and mean heart
rate were reduced by approximately 55% (P < 0.01) and 26% (P > 0.05),
respectively. Recovery of Adelta and C reflexes occurred at plasma concentrations
of 13.1 (2.3) and 9.9 (1.3) microg mL-1 (P > 0.05), respectively. There was a log
arithmically linearly related fall in mean arterial pressure by 70% up to a
plasma concentration approximately 97 microg mL-1 (r 2=0.7) with a 28% reduction
in heart rate which was uncorrelated with the plasma concentrations (r 2=0.12).
In conclusion, propofol abolished Adelta and C responses at comparable plasma
concentrations and caused a major reduction in both mean arterial pressure and
heart rate which is consistent with resetting of the baroreflexes. The reduction
in mean arterial pressure was logarithmically, linearly correlated with a
progressive increase in plasma concentrations without evidence of a ceiling
effect.
PMID- 10758448
TI - Foundation for european education in anaesthesiology fondation Europeenne
d'Enseignement en Anesthesiologie (FEEA)
PMID- 10758449
TI - Anaesthesiology directors: more support on the way as association of anesthesia
clinical directors goes international
PMID- 10758447
TI - Granisetron/dexamethasone combination for the prevention of postoperative nausea
and vomiting after laparoscopic cholecystectomy.
AB - Dexamethasone decreases chemotherapy-induced emesis when added to an antiemetic
regimen. This study was undertaken to evaluate the efficacy of
granisetron/dexamethasone combination for preventing postoperative nausea and
vomiting (PONV) after lapIaroscopic cholecystectomy (LC). In a prospective,
randomized, double-blind manner, 120 patients (83 females), aged 25-65 years,
were assigned to receive granisetron 40 microg kg-1 alone or granisetron 40
microg kg-1 plus dexamethasone 8 mg (n=60 of each) intravenously immediately
before the induction of anaesthesia. A standardized general anaesthetic procedure
and postoperative analgesia were used. A complete response, defined as no PONV
and no need for another rescue antiemetic, during 0-3 h after anaesthesia was 83%
with granisetron and 98% with granisetron plus dexamethasone, respectively
(P=0.008); the corresponding incidence during 3-24 h after anaesthesia was 83%
and 98% (P=0.008). No clinically important adverse events were observed in any of
the group. In conclusion, prophylactic therapy with granisetron/dexamethasone
combination is more effective than granisetron alone for the prevention of PONV
after LC.
PMID- 10758450
TI - Haemodynamic effects of a left stellate ganglion block in ASA I patients. An
echocardiographic study.
AB - In anaesthetized dogs, stellate ganglion blockade led to a moderate disturbance
in left ventricular diastolic function. We investigated the effect of a left
sided block, following injection of 10 mL bupivacaine 0.5%, on echocardiographic
variables of ventricular function in eight otherwise healthy patients with
sympathetically mediated pain syndromes. After the blockade, heart rate (control:
66+/-3 (mean+/- SEM), block: 64+/-3 min-1) and mean arterial blood pressure
(88.5+/-6.0 vs. 84.0+/-8.1 mmHg) were unchanged, but afterload decreased (end
systolic meridional wall stress; 69.6+/-9.9 vs. 59.8+/-7.1, P < 0.05). Stroke
volume increased from 71.2+/-8.1 to 79.6+/-7.4 mL, P < 0.05. Variables of
systolic function were unchanged, but relaxation was prolonged (isovolumic
relaxation time; 71+/-5 vs. 81+/-4 ms, P < 0.05). In patients who were ASA I,
there was a small impairment in echocardiographic variables during ventricular
relaxation after a left stellate ganglion blockade. This small effect did not
compromise ventricular function, and the heart responded with a small stroke
volume increase to the simultaneous afterload reduction.
PMID- 10758451
TI - The effect of a single intravenous dose of metamizol 2 g, ketorolac 30 mg and
propacetamol 1 g on haemodynamic parameters and postoperative pain after heart
surgery.
AB - Although nonopiate analgesics may be particularly useful in the immediate
postoperative period after major surgery, their use has been associated with
haemodynamic adverse effects during postoperative pain treatment and in
critically ill patients in intensive care. The effect of a single intravenous
dose of metamizol (dipyrone) 2 g, ketorolac 30 mg and propacetamol 1 g on
haemodynamic variables and pain control in the immediate postoperative period
after heart surgery is compared. Seventy-two patients undergoing elective
coronary and/or heart valve surgery, were included in a cohort study of 1-years
duration (1998). After weaning from mechanical ventilation and extubation,
haemodynamic variables and a 4-point verbal rating pain scale were asseseed at
base-line and 60 min after the administration of a single doses of metamizol,
ketorolac or propacetamol. The Student's t-test for paired samples was used to
compare changes produced by the study medications. A significant, but small,
decrease in radial artery blood pressure was observed in all treatment groups
which had little clinical relevance; no vasodilator effects were observed and
ventricular function showed only minor changes: propacetamol decreased cardiac
index by 10% and a 15% decrease in right ventricular work was also observed.
Metamizol and ketorolac produced a 10% decrease in the left ventricular work
index. Pain scores showed a statistically significant decrease in all treatment
groups. The analgesic effects of metamizol, ketorolac and propacetamol were not
associated with a clinically significant impairment in haemodynamic function when
administered to haemodynamically stable patients.
PMID- 10758452
TI - Electronic data collection by trainee anaesthetists using palm top computers.
AB - The Royal College of Anaesthetist requires that trainees wishing to specialise in
Anaesthesia register with the College and keep a logbook documenting their
experience and training in clinical anaesthesia. There are a number of advantages
if such logbooks are kept in an electronic format. For the first time in the
United Kingdom, we have evaluated the usefulness in a district general hospital
of introducing a computerized system of record keeping based on a portable palm
top computer. This has enabled the careful analysis of the individual work load
of each trainee in the department by means of a specific program designed to
generate a comprehensive report after the information from each individual has
been downloaded on to a standard desk top computer. We have found a number of
interesting and unexpected results and have highlighted ways in which the system
may be improved.
PMID- 10758453
TI - Evaluation of standard haemodynamic tests of autonomic function and HbA1c as
predictors of delayed gastric emptying in patients with type 1 diabetes mellitus.
AB - We examined the relation between chronic glycaemic control (using glycosylated
haemoglobin), haemodynamic autonomic function and rate of gastric emptying in 16
patients with type 1 diabetes mellitus. Gastric emptying was measured using a
paracetamol absorption technique. Parameters of gastric emptying include area
under the plasma paracetamol concentration time curve. Patients were classified
as diabetic autonomic neuropathy positive or negative using five standardized
haemodynamic reflex tests. Area under the plasma paracetamol concentration time
curve in the neuropathy positive (10.36 (4.5) mmol.-1. min) and negative (9.84
(3.0) mmol.-1. min) groups were similar (.P.=0.42) using unpaired Student's.t.
tests. Glycosylated haemoglobin concentration and area under the plasma
paracetamol concentration time curve (.n.=16) demonstrated a Pearson's
correlation co-efficient of 0.24. Neither tests of haemodynamic autonomic
function, nor concentration of glycosylated haemoglobin, are predictive of
diabetic gastroparesis.
PMID- 10758454
TI - The influence of the alpha2-adrenoceptor agonist, clonidine, on the EEG and on
the MAC of isoflurane.
AB - We investigated the influence of intravenous clonidine 2, 4 and 6 microg kg-1 on
the electroencephalogram and on the minimal alveolar concentration of isoflurane
in 40 patients aged 20-60 years undergoing elective surgery. Minimal alveolar
concentration was determined using the Dixon 'up-and-down' method. Thirty min
after the clonidine infusion anaesthesia was induced with etomidate, 0.25 mg kg
1. Skin incision was made after stable end-tidal isoflurane concentrations had
been maintained for at least 15 min. Clonidine caused significant decreases in
the spectral edge (95%) and median power frequency of the electroencephalogram
and in the bispectral index. The minimal alveolar concentration of isoflurane
decreased in a dose-dependent manner from 1.32% (95% CI, 1.28%-1.36%) in the
control group to 1.03% (0.9%-1.18%) in patients given clonidine 6 microg kg-1.
Clonidine 4 and 6 microg kg-1 was associated with a moderate reduction in heart
rate and arterial systolic blood pressure. We recommend the use of clonidine
intravenously as an adjunct to general anaesthesia in a dose of 4 microg kg-1
given 15 min before induction of anaesthesia.
PMID- 10758455
TI - Reducing the demand for admission to intensive care after major abdominal surgery
by a change in anaesthetic practice and the use of remifentanil.
AB - We have used a remifentanil-based anaesthetic for patients undergoing major
abdominal surgery who would normally have gone to the intensive care unit in this
hospital. Avoiding intensive care unit admission was considered an advantage as a
shortage of intensive care unit beds was leading to the cancellation of
operations. We first used remifentanil as part of a safety and efficacy study.
The aim was to see if the rapid and complete awakening obtained when using this
drug would allow us to avoid the need for admission to an intensive care unit and
use a high dependency unit instead. This was shown to be practicable. In
comparison with a group of patients matched retrospectively for the type of
operation before remifentanil was used there was a reduction in the length of
time (mean+/- SD) patients' lungs were ventilated (612+/-417 vs. 9.9+/-28.9 min
P< 0.0001). There was no saving in cost ( pound808.71+/- pound187.06 vs.
pound795.27+/- pound253.49). When remifentanil was used routinely (after the
safety and efficacy study), there were significant reductions in the time to
tracheal extubation (612+/-417 vs. 4+/-10 min P < 0.0001) and costs (808.71I vs.
392.10 I P < 0.0001) compared with other patients in whom it was not used.
Patients waiting for a liver transplant were also being cancelled when a donor
organ became available because of the shortage of intensive care unit beds. Based
on our other experience with remifentanil, we used a similar anaesthetic
technique for these patients. It proved possible to extubate the trachea in 12 of
15 patients at the end of the operation. No patient needed re-intubation. The
need for intensive care and therefore cancellation of surgery was reduced. In
contrast, only one patient's trachea was extubated immediately after surgery in
the group of patients anaesthetized before the introduction of remifentanil. A
remifentanil-based technique in combination with a change in organization has
therefore enabled us to avoid admission to the intensive care unit for these
patients.
PMID- 10758456
TI - Brachial plexus block using a new subclavian perivascular technique: the proximal
cranial needle approach.
AB - We describe the proximal cranial needle approach for brachial plexus blockade;
clear surface markings and cranial direction of the needle lead to satisfactory
results with a low incidence of complications.
PMID- 10758457
TI - Small dose midazolam or droperidol reduces the hypnotic dose of propofol at the
induction of anaesthesia.
AB - We investigated the effect of a small dose of midazolam, ketamine, droperidol or
lidocaine on the propofol dose required for hypnosis during induction of general
anaesthesia. These drugs were randomly administered to 100 patients about to
undergo scheduled surgery. Propofol was then infused at a rate of 250 microg kg-1
min-1 and the hypnotic dose to produce hypnosis was evaluated. Midazolam (20
microg kg-1) and droperidol (20 microg kg-1) significantly reduced the mean
hypnotic dose of propofol (mean) S.D.) compared with the placebo (43.7 +/- 17.8
mg, 61.9 +/- 10.6 mg and 72.5 +/- 27.7 mg after pretreatment with midazolam,
droperidol and placebo, respectively), whereas ketamine (0.1 mg kg-1) and
lidocaine (1 mg kg-1) did not significantly affect the hypnotic dose of propofol
(63. 1 +/- 25.6 mg and 65.1 +/- 24.8 mg, respectively). Only midazolam when
compared with saline administration, (176 +/- 66 s and 298 +/- 126 s,
respectively), shortened the time to achieve hypnosis. The changes in blood
pressure (non-invasive) and heart rate were not significantly different in all
groups during the induction of anaesthesia and oro-tracheal intubation. These
results raise the possibility that new combinations of central nervous system
drugs, such as droperidol and propofol, have a potential to reduce the dose of
intravenous anaesthetics, including propofol, that produce hypnosis without
significant adverse effects.
PMID- 10758458
TI - Epinephrine, potassium and the electrocardiogram during regional anaesthesia.
AB - Epinephrine lowers the serum potassium level through an effect on the beta2
receptor. It is therefore difficult to evaluate whether depression of the ST
level and the T wave on the electrocardiogram, during regional anaesthesia, is
caused by a high plasma epinephrine level, a low serum potassium level, or both.
For this purpose, we studied the relation between electrocardiogram and the
plasma epinephrine and serum potassium concentrations during 20 intra-abdominal
operations performed under combined epidural and general anaesthesia and in 18
subjects receiving intercostal nerve blockade. The results show that the
hypokalaemic effect of epinephrine was reduced when the plasma epinephrine
concentration exceeded 3 nmol L-1. A multiple regression analysis demonstrated
that the ST level and the T-wave amplitude were most consistently affected by a
low serum potassium level, while a high plasma epinephrine level correlated only
to a depression in the T-wave amplitude. During surgery, only serum potassium
correlated with these ECG variables.
PMID- 10758460
TI - Confederation of european national societies of anaesthesiology (CENSA)
PMID- 10758459
TI - Sevoflurane provides better recovery than propofol plus fentanyl in anaesthesia
for day-care surgery.
AB - To compare ease of maintenance and recovery characteristics of sevoflurane and
propofol plus fentanyl in day-care anaesthesia, 60 outpatients undergoing
elective surgery of up to 3 h duration were randomized to receive sevoflurane or
propofol as their primary anaesthetic. Induction was always carried out with
propofol, but a fentanyl bolus 5 microg kg-1 was added in the propofol group.
Anaesthesia was supplemented with up to 70% N2O. Significantly shorter times to
extubation (10.03 min +/- 3.2 SD vs. 17.2 +/- 7.3; P < 0.001) and emergence (10.4
+/- 3.1 vs. 16.8 +/- 6.4; P < 0.001) were observed in the sevoflurane group.
Patients treated with sevoflurane felt less confused, showed better performances
in the digit symbol substitution test and achieved higher modified Aldrete scores
sooner in the post-operative course. Maintenance of anaesthesia with sevoflurane
produces faster emergence and recovery than propofol plus fentanyl after
anaesthesia of short to intermediate duration.
PMID- 10758461
TI - What does the bispectral EEG index monitor?
PMID- 10758462
TI - Staff exposure to anaesthetic gases in theatre and non theatre areas.
AB - Environmental monitoring of anaesthetic gases was carried out in theatre areas in
eight hospitals as well as in Delivery suites, radiology, radiotherapy and Dental
suites. High staff exposures occurred in nontheatre areas although exposures in
theatres were generally satisfactory. Environmental control measures are required
where staff exposures exceed legal standards.
PMID- 10758463
TI - The effect of hyperoxia on cerebral blood flow: a study in healthy volunteers
using magnetic resonance phase-contrast angiography.
AB - A small decrease in cerebral blood flow (approximately 10%) in response to 100%
oxygen (O2) administration is well recognized. This observation was based on
human volunteer studies, which employed a nitrous oxide washout method for the
measurement of cerebral blood flow. Because this method is now appreciated to be
subject to potential errors we have examined the cerebral blood flow response to
100% oxygen using a magnetic resonance imaging technique to quantify changes in
carotid and basilar artery flow. The study, was performed in 12 normal male
subjects aged 23-42 years. We report decreases in cerebral blood flow ranging
from 9 to 31% with a mean value of over 20%. The decrease in cerebral blood flow
was greater in seven young subjects (aged 23-26 years) with decreases in cerebral
blood flow of 19.3-31.4% (mean 26.8%). In five older subjects (aged 32-42 years),
decreases in CBF were smaller (mean 16. 2%). The administration of 100% O2 was
accompanied by a small decrease in end-tidal CO2 (3.7-7.1%), insufficient to
explain the changes in cerebral blood flow. We conclude that the decrease in
cerebral blood flow in response to O2 administration is greater than previously
described and appears to be greater in young adults.
PMID- 10758464
TI - Nitric oxide delivery to the lung: a model.
AB - Dedicated nitric oxide equipped ventilators are now available commercially but
are not yet common in clinical practice. With other ventilators, there is no
standardized procedure for the administration or monitoring of nitric oxide. We
describe the use of nitric oxide in conjunction with a simple time-cycled,
pressure regulated, flow generating ventilator attached to a model infant-sized
lung. The measured nitric oxide concentrations were always less than calculated.
Infusion site, minute ventilation and sampling port all affected nitric oxide
concentration (P < 0.05). Increasing minute ventilation lowered measured nitric
oxide concentration exponentially. Mixing of gases improved when nitric oxide was
infused closer to the ventilator. Acid contamination was found in water samples
from humidifier, water trap and ventilator gas outlet. Acidification was reduced,
without change in measured nitric oxide delivery, when infused prehumidifier. We
recommend, when used as therapy, nitric oxide levels in inspired gases should
always be measured.
PMID- 10758465
TI - Cardiovascular responses to pulmonary artery catheterization.
AB - This study compares prospectively the cardiovascular and catecholamine responses
to central venous and pulmonary artery catheterization before and after induction
of general anaesthesia. Twenty patients for elective coronary artery surgery were
randomized into two groups. One group had central venous and pulmonary artery
catheterization performed awake using local anaesthesia. The other group had
these catheters inserted following induction of general anesthesia. In all
patients heart rate, arterial blood pressure, ST segment analysis and epinephrine
and norepinephrine levels were measured prior to central venous cannulation and
at 2-min intervals until placement of the lines was achieved. There were no
statistically significant changes in any cardiovascular or catecholamine variable
with time compared with the base-line measurements. There were no statistically
significant differences in plasma catecholamine levels between the awake and the
anaesthetized groups.
PMID- 10758466
TI - A retrospective survey of fibrinolysis as an indicator of poor outcome after
cardiopulmonary bypass and a possible early sign of systemic inflammation
syndrome.
AB - A retrospective survey was undertaken of 142 adults who had undergone cardiac
surgery with cardiopulmonary bypass. According to the manufacturer's instructions
for thromboelastography, patients were identified as showing evidence of
fibrinolysis if after coming off bypass the Ly30 index was > or =7.5%. In the 20
fibrinolytic patients, fibrinolysis was readily corrected by tranexamic acid but
these patients needed more colloid and more vasopressor support than the non
fibrinolytic patients. There were three deaths, all in the fibrinolytic patients.
It is possible that fibrinolysis is a marker for onset of systemic inflammation
syndrome. It is recommended that, until the association between fibrinolysis and
worse outcome is investigated further, patients showing fibrinolysis early after
cardiopulmonary bypass should not be discharged too soon from intensive care.
PMID- 10758467
TI - The effect of oral etilefrine premedication on the incidence of hypotension
during spinal anaesthesia.
AB - This study was designed to determine the efficacy of oral etilefrine in
preventing hypotension induced by spinal anaesthesia. Forty patients, ASA grade I
or II, aged 23-60 years, scheduled for orthopaedic surgery involving the lower
extremity under spinal anaesthesia were studied. The patients were randomly
allocated to one of two groups; the etilefrine group (n = 20) received oral
etilefrine 15 mg (30 drops), 60 min before the subarachnoid block, and the
control group (n = 20) received no etilefrine. Patients were given 0.5% isobaric
bupivacaine intrathecally. Hypotension was defined as a 30% decrease from base
line for systolic arterial pressure and mean arterial pressure or systolic value
<90 mmHg, and was treated with intravenous boluses of etilefrine 2 mg. The
overall incidence of spinal anaesthesia induced hypotension was 25%, ranging from
20% in the etilefrine group to 30% in the control group. The fall in systolic
arterial pressure and mean arterial pressure was significantly greater in the
control group than in the etilefrine group (P < 0.05). The patients in the
etilefrine group received less etilefrine supplement than those in control group
and no subject in the etilefrine group required repeat etilefrine doses, while in
the control group five patients received multiple etilefrine doses (P < 0.05).
The mean heart rate remained fairly stable throughout the study periods. We
conclude that oral etilefrine, given 60 min before surgery, reduces the fall in
blood pressure during spinal anaesthesia.
PMID- 10758468
TI - The use of EMLA reduces the pain associated with digital ring block for ingrowing
toenail correction.
AB - Treatment of ingrowing toenail is commonly performed under local anaesthesia with
a digital ring block. Ring block can be associated with significant pain, caused
by needle insertion and deposition of the local anaesthetic agent. EMLA, a
topical anaesthetic cream, is widely used to alleviate the pain of venepuncture.
The aim of this study was to investigate whether the discomfort of digital block
could be reduced by prior application of EMLA. Fifty-five patients who were
scheduled for ingrowing toenail under local anaesthesia were randomized into two
groups. In Group 1 (n = 30), EMLA was applied around the base of the affected
hallux for at least 1 h before ring block. In Group 2 (n = 25), a placebo cream
was used. In this double-blind study, patients assessed the pain caused by a
standardized ring block using 100-mm visual analogue pain score. The mean visual
analogue pain score in Group 1 was 28.1 and 50.1 in Group 2 (P < 0.0001). We
conclude that EMLA significantly reduces the pain associated with digital ring
block.
PMID- 10758469
TI - Continuous axillary brachial plexus analgesia with low dose morphine in patients
with complex regional pain syndromes.
AB - In this prospective pilot study, nine patients suffering from complex regional
pain syndrome of the arm were treated with morphine 0.16 mg h-1 (3.84 mg day-1)
applied continuously through an axillary brachial plexus catheter. In all of them
an oral analgesic medication including the less potent opioid tramadol had not
provided sufficient pain relief. During regional treatment, patients were kept in
hospital and physiotherapy was carried out frequently in order to improve
strength and function of the affected arm. Pain at rest and during movement as
well as grip strength were assessed at first visit, during morphine infusion and
at a long-term follow-up visit. All assessments improved significantly during
plexus analgesia. There were no major opioid related side-effects. The results
from this pilot study indicate that continuous axillary brachial plexus analgesia
with low dose morphine might be beneficial in patients suffering from complex
regional pain syndrome of the arm.
PMID- 10758471
TI - Postoperative nausea and vomiting after breast surgery: efficacy of prophylactic
ondansetron and droperidol in a randomized placebo-controlled study.
AB - Postoperative nausea and vomiting (PONV) is a common adverse phenomenon following
breast surgery. The efficacy of ondansetron and droperidol in preventing post
operative nausea and vomiting in women undergoing breast surgery was compared in
this randomized, double-blind, placebo-controlled study. Altogether 207 women
were randomly assigned to receive either a single intravenous dose of droperidol
(1.25 mg) (n = 69), ondansetron (8 mg) (n = 67) or saline (n = 71) immediately
after induction of general anaesthesia with thiopental, fentanyl, atracurium,
nitrous oxide in oxygen and isoflurane. Complaints of nausea, vomiting and
requests for rescue antiemetics were recorded during a 24-h period
postoperatively. During the initial 2 h in the postanaesthesia care unit, the
incidence of postoperative nausea and vomiting was 15%, 6% and 12% in the
placebo, droperidol and ondansetron groups, respectively (NS). The incidence of
post-operative nausea and vomiting during the first 24 h was 61%, 48% and 45% in
the placebo, droperidol and ondansetron treatment groups, respectively (NS).
Postoperative analgesic requirements and the length of stay in the post
anaesthesia care unit were equal in all three treatment groups. It is concluded
that the intravenous pretreatment with single doses of ondansetron or droperidol
did not substantially prevent postoperative nausea and vomiting after breast
surgery.
PMID- 10758470
TI - A comparative study of patient-controlled epidural diamorphine, subcutaneous
diamorphine and an epidural diamorphine/bupivacaine combination for postoperative
pain.
AB - This randomized double blind study investigates the relative efficacies of
controlled analgesia (PCA) regimens in three different patient groups: epidural
diamorphine 2.5 mg followed by PCA bolus 1 mg with a 20-min lockout (Gp1),
subcutaneous diamorphine 2.5 mg followed by PCA bolus with a 10-min lockout
period (Gp2) and epidural diamorphine 2.5 mg in 4 mL of 0.125% (w/v) bupivacaine
followed by a PCA bolus of 1 mg diamorphine in 4 mL 0.125% (w/v) bupivacaine with
a 20-min lockout (Gp3). Patients were evaluated at 0, 1, 2, 3, 4, 8, 12, 16, 20,
24 and 48 h. Patients in Gp2 consumed significantly more diamorphine than those
in Gp1 or Gp3 (P < 0.05), but their pain scores were higher only at 1, 2 and 3 h
(P < 0.05) with respect to Gp3 and at 1 h with respect to Gp1. Fewer side effects
(sedation, pruritus and nausea as assessed by anti-emetic requirements) occurred
in Gp2 compared to Gp1 (P < 0.05). Fewer patients in Gp2 required catheterization
than in Gp3 (P < 0.05). This study indicates that the use of PCA epidural
diamorphine, either alone or in combination with bupivacaine, reduces the dose
requirement for analgesia but offers little clinical advantage over subcutaneous
PCA diamorphine.
PMID- 10758472
TI - Airway ignition during CO2 laser laryngeal surgery and high frequency jet
ventilation.
AB - We present a case of a patient submitted for extirpation of a neoplasm of the
larynx, by means of carbon dioxide laser surgery. High frequency jet ventilation
was applied by means of orotracheal intubation with two Teflon catheters, 2 mm in
external diameter and 30 cm in length, attached with three equally placed strips
of adhesive paper tape. One catheter was used to inject the jet volume and the
other used to measure the airway pressure. The adhesive strips were moistened and
FiO2 was lower than 50%. After 30 min using the laser, an airway fire was
noticed. Ventilation was interrupted and the catheters were removed. The patient
was reintubated with an endotracheal tube of 6 mm ID and the surgical procedure
was continued until the tumour was removed. Two factors contributed to the airway
fire: the ignition of the lowest adhesive strip that had dried and the use of the
laser in the mode of continuous pulsation.
PMID- 10758473
TI - Successful epidural blood patch in a patient with headache for 6 months after
lumbar root decompression.
AB - Prolonged headache following dural puncture is an uncommon problem that may occur
after a spinal tap, often as a complication of epidural anaesthesia. This problem
has also been described after long-term epidural or spinal anaesthesia,
myelography or spinal surgery. A case of prolonged postdural puncture headache
following lumbar nerve root decompression is described in a healthy young man. No
other cause could be found either clinically or with the aid of scanning by
computerized tomography or magnetic resonance imaging techniques at the spinal
level involved. The symptoms were successfully treated with an epidural blood
patch performed seven months following the original surgical operation.
PMID- 10758474
TI - Awake fibreoptic intubation following failed regional anaesthesia for caesarean
section in a parturient with Still's disease.
AB - The anaesthetic management of a 25-year-old parturient with juvenile rheumatoid
arthritis (Still's disease) and a difficult airway presenting for elective
Caesarean section is described. Inadequate block after epidural anaesthesia
necessitated general anaesthesia. This was safely accomplished by securing the
airway with awake oral fibreoptic intubation before general anaesthesia was
induced. The problems of performing an awake fibreoptic intubation in a pregnant
patient are discussed and a simple method for performing the technique is
described.
PMID- 10758475
TI - Functional rescue of a bacterial dapA auxotroph with a plant cDNA library selects
for mutant clones encoding a feedback-insensitive dihydrodipicolinate synthase.
AB - Dihydrodipicolinate synthase (DHDPS; EC4.2.1.52) catalyses the first reaction of
lysine biosynthesis in plants and bacteria. Plant DHDPS enzymes are strongly
inhibited by lysine (I0.5 approximately 10 microM), whereas the bacterial enzymes
are less (50-fold) or insensitive to lysine inhibition. We found that plant dhdps
sequences expressing lysine-sensitive DHDPS enzymes are unable to complement a
bacterial auxotroph, although a functional plant DHDPS enzyme is formed. As a
consequence of this, plant dhdps cDNA clones which have been isolated through
functional complementation using the DHDPS-deficient Escherichia coli strain
encode mutated DHDPS enzymes impaired in lysine inhibition. The experiments
outlined in this article emphasize that heterologous complementation can select
for mutant clones when altered protein properties are requisite for functional
rescue. In addition, the mutants rescued by heterologous complementation revealed
a new critical amino acid substitution which renders lysine insensitivity to the
plant DHDPS enzyme. An interpretation is given for the impaired inhibition
mechanism of the mutant DHDPS enzyme by integrating the identified amino acid
substitution in the DHDPS protein structure.
PMID- 10758476
TI - Allocation of raffinose family oligosaccharides to transport and storage pools in
Ajuga reptans: the roles of two distinct galactinol synthases.
AB - Raffinose family oligosaccharides (RFOs) are important phloem transport and
storage carbohydrates for many plants. Ajuga reptans, a frost-hardy evergreen
labiate, ideally combines these two physiological roles and served as our model
plant to study the regulation and importance of RFO metabolism. Galactinol is the
galactosyl donor for the synthesis of raffinose (RFO-trisaccharide) and stachyose
(RFO-tetrasaccharide), and its synthesis by galactinol synthase (GolS) is the
first committed step of the RFO biosynthetic pathway. Two cDNAs encoding two
distinct GolS were isolated from A. reptans source and sink leaves, designated
GolS-1 and GolS-2, respectively. Warm- and cold-grown sink and source leaves were
compared, revealing both isoforms to be cold-inducible and GolS-1 to be source
leaf-specific; GolS-1 expression correlated positively with GolS activity.
Conversely, GolS-2 expression was comparatively much lower and its contribution
to the total extractable GolS activity is most probably only minor. These
observations, together with results from phloem exudation and leaf shading
experiments suggest that GolS-1 is mainly involved in the synthesis of storage
RFOs and GolS-2 in the synthesis of transport RFOs. Furthermore, in situ
hybridization studies showed GolS-1 to be primarily expressed in the mesophyll,
the site of RFO storage, and GolS-2 in the phloem-associated intermediary cells
known for their role in RFO phloem loading. A model depicting the spatial
compartmentation of the two GolS isoforms is proposed.
PMID- 10758477
TI - Disruption of putative anion channel gene AtCLC-a in Arabidopsis suggests a role
in the regulation of nitrate content.
AB - In animals and yeast, voltage-dependent chloride channels of the CLC family play
a role in basic cellular functions such as epithelial transport, plasma membrane
excitability, and control of pH and membrane potential in intracellular
compartments. To assess the function of CLCs in plants, we searched for CLC
insertion mutants in a library of Arabidopsis lines transformed by Agrobacterium
tumefaciens transferred DNA (T-DNA). Using a polymerase chain reaction-based
screening procedure, an Arabidopsis line that carries a T-DNA insertion within
the C-terminus of the AtCLC-a coding sequence was identified. Progeny from this
plant line, clca-1, showed dramatically altered transcription of the AtCLC-a
gene. Plants homozygous for the clca-1 mutation exhibited normal development and
a morphology indistinguishable from the wild-type. However, their capacity to
accumulate nitrate under conditions of nitrate excess was reduced in roots and
shoots, by approximately 50%, while chloride, sulphate and phosphate levels were
similar to the wild-type. In addition, the herbicide chlorate, an analogue of
nitrate, induced a faster and more pronounced chlorosis in mutant plants.
Hypersensitivity to chlorate as well as decreased nitrate levels co-segregated
with the T-DNA insertion. They were found at various time points of the clca-1
life cycle, supporting the idea that AtCLC-a has a general role in the control of
the nitrate status in Arabidopsis. Concordant with such a function, AtCLC-a mRNA
was found in roots and shoots, and its levels rapidly increased in both tissues
upon addition of nitrate but not ammonium to the culture medium. The specificity
of AtCLC-a function with respect to nitrate is further supported by a similar
free amino acid content in wild-type and clca-1 plants. Although the cellular
localization of AtCLC-a remains unclear, our results suggest that AtCLC-a plays a
role in controlling the intracellular nitrate status.
PMID- 10758478
TI - Defective splicing of the first nad4 intron is associated with lack of several
complex I subunits in the Nicotiana sylvestris NMS1 nuclear mutant.
AB - In this work, we provide evidence for the existence of a nuclear factor involved
in the splicing of a specific mitochondrial intron in higher plants. In the
Nicotiana sylvestris nuclear NMS1 mutant, defective in both vegetative and
reproductive development, the first intron of the nad4 transcript encoding the
complex I NAD4 subunit is not removed, whatever the tissue analysed. Transcript
patterns of other standard mitochondrial genes are not affected in NMS1. However,
numerous polypeptides are missing in two-dimensional in organelle mitochondrial
protein synthesis patterns and several nuclear and mitochondrial complex I
subunits are present in trace amounts. This indicates that translational or post
translational steps in the synthesis of other mitochondrial proteins are
affected. All of these defects co-segregated with the abnormal phenotype in the
offspring of a NMS1 x wild-type cross, showing that they are controlled by the
same nuclear gene (MS1) or tightly linked loci. Such a complex situation has been
described in chloroplasts and mitochondria of fungi, but never in higher plant
mitochondria.
PMID- 10758479
TI - Dof1 and Dof2 transcription factors are associated with expression of multiple
genes involved in carbon metabolism in maize.
AB - Dof proteins are transcription factors that appear to be unique to plants. Maize
Dof1 has been suggested to be a regulator for C4 photosynthetic
phosphoenolpyruvate carboxylase (C4PEPC) gene expression. The present study
demonstrates that Dof1 also enhances transcription from the promoters of both
cytosolic orthophosphate dikinase (cyPPDK) genes and a non-photosynthetic PEPC
gene, which are not present in animals. Expression of Dof1-specific antisense RNA
or the DNA-binding domain of Dof1 alone reduced the activities of these promoters
in maize leaf protoplasts. Electrophoretic mobility shift assays revealed several
Dof1-binding sites in these promoters. The cyppdk1 promoter contained two Dof1
binding sites, one of which was linked to the binding site of a plant bZIP
protein. By using deleted or mutated cyppdk1 promoters, both Dof1-binding sites
were shown to be functional. Furthermore, Dof1 elevated the activities of the
cyppdk and pepc promoters more strongly in greening protoplasts than in etiolated
protoplasts, in accordance with the different activities of these promoters in
two types of protoplasts. Another Dof protein of maize, Dof2, suppressed the
activity of the C4pepc promoter but was able to activate certain other promoters.
These results suggest that Dof proteins may play regulatory roles in multiple
gene expressions associated with the plant-specific pathway for carbon metabolism
in maize. In addition, the primary characteristic of Dof proteins, i.e. different
activities in distinct types of cells and opposite actions on promoters in
different contexts, suggests the potential of Dof proteins to differentially
regulate diverse promoters in a variety of plant tissues. Speculation raised by
these results concerning the evolution of the C4pepc gene is also discussed.
PMID- 10758480
TI - A membrane-potential dependent ABC-like transporter mediates the vacuolar uptake
of rye flavone glucuronides: regulation of glucuronide uptake by glutathione and
its conjugates.
AB - In this paper we present results on the vacuolar uptake mechanism for two flavone
glucuronides present in rye mesophyll vacuoles. In contrast to barley flavone
glucosides (Klein et al. (1996) J. Biol. Chem. 271, 29666-29671), the flavones
luteolin 7-O-diglucuronyl-4'-O-glucuronide (R1) and luteolin 7-O-diglucuronide
(R2) were taken up into vacuoles isolated from rye via a directly energized
mechanism. Kinetic studies suggested that the vacuolar glucuronide transport
system is constitutively expressed throughout rye primary leaf development.
Competition experiments argued for the existence of a plant MRP-like transporter
for plant-specific and non-plant glucuronides such as beta-estradiol 17-(beta-D
glucuronide) (E217G). The interaction of ATP-dependent vacuolar glucuronide
uptake with glutathione and its conjugates turned out to be complex: R1 transport
was stimulated by dinitrobenzene-GS and reduced glutathione but was inhibited by
oxidized glutathione in a concentration-dependent manner. In contrast, R2 uptake
was not increased in the presence of reduced glutathione. Thus, the transport
system for plant-derived glucuronides differed from the characteristic
stimulation of vacuolar E217G uptake by glutathione conjugates but not by reduced
glutathione (Klein et al. (1998) J. Biol. Chem. 273, 262-270). Using tonoplast
vesicles isolated with an artificial K+ gradient, we demonstrate for the first
time for plant MRPs that the ATP-dependent uptake of R1 is membrane-potential
dependent. We discuss the kinetic capacity of the ABC-type glucuronide
transporter to explain net vacuolar flavone glucuronide accumulation in planta
during rye primary leaf development and the possibility of an interaction of
potential substrates at both the substrate binding and allosteric sites of the
MRP transporter regulating the activity towards a certain substrate.
PMID- 10758481
TI - Cloning and functional expression of the gene encoding the key enzyme for
chlorophyll b biosynthesis (CAO) from Arabidopsis thaliana.
AB - Chlorophyll (Chl) biosynthesis and degradation are the only biochemical processes
on Earth that can be directly observed from satellites or other planets. The bulk
of the Chls is found in the light-harvesting antenna complexes of photosynthetic
organisms. Surprisingly little is known about the biosynthesis of Chl b, which is
the second most abundant Chl pigment after Chl a. We describe here the expression
and properties of the chlorophyllide a oxygenase gene (CAO) from Arabidopsis
thaliana, which is apparently the key enzyme in Chl b biosynthesis. The
recombinant enzyme produced in Escherichia coli catalyses an unusual two-step
oxygenase reaction that is the 'missing link' in the chlorophyll cycle of higher
plants.
PMID- 10758482
TI - Induction of competence for elicitation of defense responses in cucumber
hypocotyls requires proteasome activity.
AB - The epidermal cells of hypocotyls from etiolated cucumber seedlings are not
constitutively competent for elicitation of the rapid H2O2 defense response.
However, elicitor competence developed while conditioning the surface-abraded
seedlings by rotating them in buffer for 4 h. Competence development was greatly
potentiated by inducers of systemic acquired resistance and suppressed by
specific inhibitors of proteasome activity, clastolactacystin beta-lactone (LAC)
and carboxybenzoyl-L-leucyl-L-leucyl-L-leucinal (LLL). In the freshly abraded
seedlings, chitinase gene activation became evident approximately 4 h after
elicitor addition. Accumulation of chitinase mRNA was enhanced upon conditioning
prior to elicitation and was inhibited by LAC and LLL, indicating that the
process which leads to H2O2 elicitation competence is also superimposed on the
elicitation of chitinase mRNA. LAC and LLL caused an accumulation of ubiquitin
conjugated proteins and enhanced the expression of a proteasome alpha-subunit,
suggesting that proteasome activity was specifically inhibited and that the
effect observed on gene expression was not due to impaired gene induction in
general. Together, our results suggest that the ubiquitin-proteasome system may
play a crucial role in a process which switches the signaling pathway for diverse
plant defense responses into a functional state, as is known for many basic
cellular processes in both animals and yeast.
PMID- 10758483
TI - Maize high chlorophyll fluorescent 60 mutation is caused by an Ac disruption of
the gene encoding the chloroplast ribosomal small subunit protein 17.
AB - The maize mutation high chlorophyll fluorescence 60-muTable 1 (hcf60-m1),
generated through Activator (Ac) tagging, has insufficient photosynthetic
electron transport. Here we show that the Hcf60 gene encodes a protein with
substantial amino acid similarity to plant plastid and bacterial ribosomal small
subunit protein 17 (RPS17) proteins. The lack of detectable HCF60 transcripts in
mutant leaves, and insertion of the transposed Ac element 17 bp upstream of the
start of translation in the mutated locus, suggest that little if any RPS17 is
produced. The mutant phenotype is consistent with reduced plastid translation.
Seedling lethal hcf60-m1 plants display temperature and light-dependent
chlorophyll deficiencies, a depletion of plastid rRNA pools, and few high
molecular-weight polysomal complexes. Growth under moderate light conditions (27
degrees C, 100 microE m-2 sec-1) allows for substantial chlorophyll accumulation
in mutant leaves, yet the number of functional photosystem II complexes appears
low. Nevertheless, the presence of a limited but intact C4 system indicates that
some plastid translation occurs.
PMID- 10758484
TI - Characterization of salicylic acid-responsive, arabidopsis Dof domain proteins:
overexpression of OBP3 leads to growth defects.
AB - Dof proteins are unique to plants and contain a single zinc finger DNA-binding
domain called the Dof domain. OBP1, an Arabidopsis Dof protein, was previously
isolated through an interaction with OBF4, an ocs element-binding protein. Two
additional Dof proteins, called OBP2 and OBP3, were isolated through homologous
screening. All three OBP proteins contain transcriptional activation domains in
their C-terminal region. While no significant differences were found between the
OBP proteins in terms of their DNA and protein-binding properties, tissue
specific RNA expression patterns were found. The RNA expression levels of all
three OBP proteins increased following treatment with auxin, salicylic acid (SA)
or cycloheximide, although the level of induction varied among the different
proteins and in the tissues tested. These results suggest that even though they
have similar DNA binding and protein-protein interaction properties, the
different OBP proteins are likely to have distinct functions in specific parts of
the plant. There is a good correlation between the expression of the OBP proteins
and the ocs element, a stress-response element which is also induced by auxin, SA
and cycloheximide. To begin to analyze the function of the OBP proteins,
transgenic lines overexpressing OBP3 were generated. These plants showed a severe
growth defect with altered root development and yellowish leaves. The severity of
the growth defects correlated with OBP3 expression levels and in some cases led
to death, suggesting that some Dof proteins play important roles in plant growth
and development.
PMID- 10758485
TI - Modes of interaction between the Arabidopsis Rab protein, Ara4, and its putative
regulator molecules revealed by a yeast expression system.
AB - Ara4, a member of the Rab/Ypt GTPase family derived from Arabidopsis thaliana,
causes severe growth inhibition when expressed in several yeast ypt mutants.
Mutational analysis of ARA4 indicated that the Ara4 protein titrates at least
three factors in yeast, including the GDP dissociation inhibitor (GDI). The
coexpression of AtGDI1 (Arabidopsis GDI) suppressed the growth defect caused by
Ara4 in yeast ypt1, suggesting that Ara4 and AtGDI1 interact in yeast to
compensate for the titration of yeast GDI. We screened an Arabidopsis cDNA
library for other suppressors that may also interact with Ara4 physiologically. A
novel suppressor, SAY1, encoded a hydrophilic protein with two putative coiled
coil regions, which showed partial similarity to the yeast Vps27 protein. To
understand the structural requirements of Ara4 for interacting with these
molecules, we examined whether AtGDI1 and SAY1 could suppress the growth defect
of ypt1 caused by various mutant versions of ARA4. The results indicated that the
interaction between Ara4 and AtGDI1 depends on the conserved C-terminal Cys-motif
and Thr44 in the effector domain of Ara4. In contrast, neither of these motifs is
necessary for the interaction between Say1 and Ara4. This approach provides a
powerful method to dissect complex interactions between a GTPase and its
regulators.
PMID- 10758486
TI - Molecular cloning of SVP: a negative regulator of the floral transition in
Arabidopsis.
AB - Flowering time mutants represent genetic functions in control of the floral
transition, an important developmental phase switch in the life cycle of higher
plants. Many such mutants have been identified and characterized, particular in
Arabidopsis. Here we describe the identification and initial characterization of
a new early flowering mutant of Arabidopsis. The corresponding gene, SVP (SHORT
VEGETATIVE PHASE), was cloned through transposon tagging and represents a new
member of the MADS-box gene family of transcription factors. Analysis of its
transcriptional activity revealed the presence of differently sized transcripts
that were confined to vegetative tissues and floral primordia and absent from
developed flowers and siliques. The function of SVP as a repressor of the floral
transition is discussed.
PMID- 10758487
TI - Characterization of a nitrate-permeable channel able to mediate sustained anion
efflux in hypocotyl cells from Arabidopsis thaliana.
AB - We have characterized a new anionic current in Arabidopsis hypocotyl cells. This
current, activated by membrane depolarization, has slow activation and
deactivation kinetics in the 10 sec range. It presents many distinct properties
from the rapid-type anion current already described on the same membrane. The
slow-type channel is highly permeable to nitrate with a PNO3-/PCl- close to 20,
but totally impermeable to sulphate. Activation of the channel requires cytosolic
ATP and the slow current is partially inhibited by staurosporin, suggesting that
channel regulation involves protein phosphorylation. The slow anion channel
displays a unique pharmacological profile different from that of the rapid
channel: the slow channel is inhibited by DIDS (4, 4'-diisothiocyanatostilbene
2,2'-disulfonic acid) with an IC50 of 26 microM. The slow and rapid anion
channels are probably dedicated to specific functions: the first is able to
mediate sustained anion efflux, while the second is a good candidate to be
involved in fast electrical signalling.
PMID- 10758488
TI - Diurnal regulation of Hsp70s in leaf tissue.
AB - Steady-state mRNA levels for three Hsp70s were found to be regulated by a
distinctive light/dark mechanism in spinach leaves. Messenger RNAs for the
chloroplast stromal and two cytosolic forms displayed a diurnal expression
pattern under isothermal conditions that appeared to be independent of circadian
control. While protein blot data showed relatively constant Hsp70 protein levels,
the higher Hsp70 mRNA levels in the light paralleled the diurnal cycle of total
cell protein synthesis. Fractionation studies showed that the major cytosolic
Hsp70 cognate group was associated with polysomes. Therefore, the variation of
Hsp70 mRNAs is consistent with the diurnal metabolic activity of plant
photosynthetic cells in which the demand of protein biogenesis for chaperone
function and tissue temperature are highest during the day.
PMID- 10758489
TI - The Arabidopsis Cdc2a-interacting protein ICK2 is structurally related to ICK1
and is a potent inhibitor of cyclin-dependent kinase activity in vitro.
AB - Cyclin-dependent kinases (CDKs) are important regulators of the eukaryotic cell
division cycle. To study protein-protein interactions involving plant CDKs, the
Arabidopsis thaliana Cdc2aAt was used as bait in the yeast two-hybrid system.
Here we report on the isolation of ICK2, and show that it interacts with Cdc2aAt,
but not with a second CDK from Arabidopsis, Cdc2bAt. ICK2 contains a carboxy
terminal domain related to that of ICK1, a previously described CDK inhibitor
from Arabidopsis, and to the CDK-binding domain of the mammalian inhibitor
p27Kip1. Outside of this domain, ICK2 is distinct from ICK1, p27Kip1, and other
proteins. At nanogram levels (8 nM), purified recombinant ICK2 inhibits p13Suc1
associated histone H1 kinase activity from Arabidopsis tissue extracts,
demonstrating that it is a potent inhibitor of plant CDK activity in vitro. ICK2
mRNA was present in all tissues analysed by Northern hybridization, and its
distribution was distinct from that of ICK1. These results demonstrate that
plants possess a family of differentially regulated CDK inhibitors that contain a
conserved carboxy terminal but with distinct amino terminal regions.
PMID- 10758490
TI - Reversible binding of the starch-related R1 protein to the surface of transitory
starch granules.
AB - Intact starch granules were isolated from leaves of Solanum tuberosum L. (and
from Pisum sativum L.), and the patterns of starch-associated proteins were
determined by SDS-PAGE. Depending on the pretreatment of the leaves the protein
patterns varied: a 160 kDa compound was present in the starch-associated protein
fraction when the leaves were darkened and performed net starch degradation.
However, following illumination (i.e. during net starch biosynthesis) the 160 kDa
protein was recovered almost exclusively in a soluble state. The 160 kDa protein
was identified to be the recently described starch-related R1 protein. In in
vitro assays recombinant R1 did bind to starch granules isolated from either
illuminated or darkened leaves. However, binding to the latter was more
effective. It is concluded that, depending upon the metabolic state of the cells,
the starch granule surface changes and thereby affects binding of the R1 protein.
PMID- 10758491
TI - AtBI-1, a plant homologue of Bax inhibitor-1, suppresses Bax-induced cell death
in yeast and is rapidly upregulated during wounding and pathogen challenge.
AB - Extensive searches have so far failed to identify functional plant homologues of
the mammalian apoptotic machinery. Here we report the isolation and
characterisation of an Arabidopsis thaliana homologue of human Bax Inhibitor-1,
AtBI-1, isolated during a differential screen of plants challenged with the
phytopathogen Pseudomonas syringae. AtBI is a member of a small gene family in
Arabidopsis, members of which display extensive amino acid identity to human BI
1. AtBI-1 is also functionally similar to BI-1 in its ability to suppress the
lethal phenotype in yeast conferred by expression of the mammalian proapoptotic
protein, Bax. Expression of AtBI-1 is rapidly upregulated in plants during
wounding or pathogen challenge, suggesting a role in responses to biotic and
abiotic stress. AtBI-1 upregulation appears R gene independent and is not
markedly affected by mutations required for specific classes of R genes. However,
the accumulation of AtBI-1 message is significantly reduced in coi1, in which
defence responses to insects, pathogens and wounding are compromised.
PMID- 10758492
TI - Gene regulation during late embryogenesis: the RY motif of maturation-specific
gene promoters is a direct target of the FUS3 gene product.
AB - The Arabidopsis mutants fus3 and abi3 show pleiotropic effects during
embryogenesis including reduced levels of transcripts encoding embryo-specific
seed proteins. To investigate the interaction between the B3-domain-containing
transcription factors FUS3 and ABI3 with the RY cis-motif, conserved in many seed
specific promoters, a promoter analysis as well as band-shift experiments were
performed. The analysis of promoter mutants revealed the structural requirements
for the function of the RY cis-element. It is shown that both the nucleotide
sequence and the alternation of purin and pyrimidin nucleotides (RY character)
are essential for the activity of the motif. Further, it was shown that FUS3 and
ABI3 can act independently of each other in controlling promoter activity and
that the RY cis-motif is a target for both transcription factors. For FUS3, which
is so far the smallest known member of the B3-domain family, a physical
interaction with the RY motif was established. The functional and biochemical
data demonstrate that the regulators FUS3 and ABI3 are essential components of a
regulatory network acting in concert through the RY-promoter element to control
gene expression during late embryogenesis and seed development.
PMID- 10758493
TI - Activation of a diverse set of genes during the tobacco resistance response to
TMV is independent of salicylic acid; induction of a subset is also ethylene
independent.
AB - Through differential screening of a cDNA library, we cloned six groups of genes
that are expressed relatively early in the inoculated leaves of tobacco resisting
infection by tobacco mosaic virus (TMV). Induction of all these genes was
subsequently detected in the uninoculated leaves; thus, their expression is
associated with the development of both local and systemic acquired resistance.
Exogenously applied salicylic acid (SA) was observed to induce these genes
transiently. However, analyses with transgenic NahG plants, which are unable to
accumulate SA, demonstrated that expression of these genes in TMV-inoculated
leaves is mediated via an SA-independent pathway. Because the expression kinetics
of these genes differ from those associated with the well-characterized
pathogenesis-related protein (PR-1) and phenylalanine ammonia-lyase (PAL) genes,
we propose that they belong to a group which we designate SIS, for SA
independent, systemically induced genes. Interestingly, the expression of several
SIS genes in the uninoculated leaves of TMV-infected NahG plants was delayed
and/or reduced, raising the possibility that SA is involved in activating some of
these genes in systemic tissue. Most of the SIS genes were induced by exogenous
ethylene. However, analyses of infected NahG plants treated with ethylene action
and/or synthesis inhibitors indicated that the TMV-induced expression of several
SIS genes is independent of ethylene as well as SA.
PMID- 10758494
TI - Arabidopsis thaliana SHAGGY-related protein kinases (AtSK11 and 12) function in
perianth and gynoecium development.
AB - In higher plants, the correct patterning of the floral meristem in terms of organ
type, number and form is the result of a concerted expression of a network of
genes. We describe phenotypes of flower patterning, resulting from a reduction of
transcript levels of the Arabidopsis SHAGGY-related protein kinase genes
AtSK11(ASKalpha) and AtSK12(ASKgamma). The AtSK genes are plant homologues of the
Drosophila shaggy (SGG) gene and the mammalian Glycogen-Synthase Kinase-3 (GSK
3). The SGG protein kinase is a key component of the wingless signalling pathway
and is required for the establishment of tissue patterning and cell fate
determination. The expression patterns of the AtSK11(ASKalpha) and
AtSK12(ASKgamma) genes during wild-type Arabidopsis inflorescence development,
detected by in situ hybridisation, have been shown to be consistent with a
possible role in floral meristem patterning. AtSK11(ASKalpha) and
AtSK12(ASKgamma) transcripts were detected at the periphery of the inflorescence
meristem and in the floral meristem. At later stages the expression of the AtSK
genes became localised in specific regions of developing flower organ primordia.
Furthermore, we have obtained and analysed transgenic plants containing
AtSK11(ASKalpha) and AtSK12(ASKgamma) gene specific antisense constructs. These
plants developed flowers showing a higher number of perianth organs and an
alteration of the apical-basal patterning of the gynoecium.
PMID- 10758495
TI - Lesions in the sterol delta reductase gene of Arabidopsis cause dwarfism due to a
block in brassinosteroid biosynthesis.
AB - The brassinosteroid (BR) biosynthetic pathway, and the sterol pathway which is
prerequisite to the BR pathway, are rapidly being characterized because of the
availability of a large number of characteristic dwarf mutants in Arabidopsis.
Here we show that the Arabidopsis dwarf5 mutants are disrupted in a sterol Delta7
reduction step. dwf5 plants display the characteristic dwarf phenotype typical of
other BR mutants. This phenotype includes small, round, dark-green leaves, and
short stems, pedicels, and petioles. Metabolite tracing with 13C-labeled
precursors in dwf5 verified a deficiency in a sterol Delta7 reductase activity.
All six independent alleles contain loss-of-function mutations in the sterol
Delta7 reductase gene. These include a putative mRNA instability mutation in dwf5
1, 3' and 5' splice-site mutations in dwf5-2 and dwf5-6, respectively, premature
stop codons in dwf5-3 (R400Z) and dwf5-5 (R409Z), and a mis-sense mutation in
dwf5-4 (D257N). The dwf5 plant could be restored to wild type by ectopic
overexpression of the wild-type copy of the gene. Both the Arabidopsis dwf5
phenotype and the human Smith-Lemli-Opitz syndrome are caused by loss-of-function
mutations in a sterol Delta7 reductase gene, indicating that it is required for
the proper growth and development of these two organisms.
PMID- 10758496
TI - A bifunctional epimerase-reductase acts downstream of the MUR1 gene product and
completes the de novo synthesis of GDP-L-fucose in Arabidopsis.
AB - L-Fucose is a monosaccharide found as a component of glycoproteins and cell wall
polysaccharides in higher plants. The MUR1 gene of Arabidopsis thaliana encodes a
GDP-D-mannose 4,6-dehydratase catalyzing the first step in the de novo synthesis
of GDP-L-fucose from GDP-D-mannose (Bonin et al. 1997, Proc. Natl Acad. Sci. USA,
94, 2085-2090). Plant genes encoding the subsequent steps in L-fucose synthesis
(3,5-epimerization and 4-reduction) have not been described previously. Based on
sequence similarities to a bacterial gene involved in capsule synthesis we have
cloned a gene from Arabidopsis, now designated GER1, which encodes a bifunctional
3, 5-epimerase-4-reductase in L-fucose synthesis. The combined action of the MUR1
and GER1 gene products converts GDP-D-mannose to GDP-L-fucose in vitro
demonstrating that this entire nucleotide-sugar interconversion pathway could be
reconstituted using plant genes expressed in Escherichia coli. In vitro assays
indicated that the GER1 protein does not act as a GDP-D-mannose 3, 5-epimerase,
an enzymatic activity involved in the de novo synthesis of GDP-L-galactose and L
ascorbic acid. Similarly, L-ascorbate levels in GER1 antisense plants were
unchanged indicating that GDP-D-mannose 3,5-epimerase is encoded by a separate
gene.
PMID- 10758497
TI - Sucrose transport into barley seeds: molecular characterization of two
transporters and implications for seed development and starch accumulation.
AB - In order to understand sucrose transport in developing seeds of cereals at the
molecular level, we cloned from a caryopses library two cDNAs encoding sucrose
transporters, designated HvSUT1 and HvSUT2. Sucrose uptake activity was confirmed
by heterologous expression in yeast. Both transporter genes are expressed in
maternal as well as filial tissues. In a series of in situ hybridizations we
analysed the cell type-specific expression in developing seeds. HvSUT1 is
preferentially expressed in caryopses in the cells of the nucellar projection and
the endospermal transfer layer, which represent the sites of sucrose exchange
between the maternal and the filial generation and are characterized by transfer
cell formation. HvSUT2 is expressed in all sink and source tissues analysed and
may have a general housekeeping role. The rapid induction of HvSUT1 gene
expression in caryopses at approximately 5-6 days after fertilization coincides
with increasing levels of sucrose as well as sucrose synthase mRNA and activity,
and occurs immediately before the onset of rapid starch accumulation within the
endosperm. Starch biosynthesis requires sucrose to be imported into the
endosperm, as direct precursor for starch synthesis and to promote storage
associated processes. We discuss the possible role of HvSUT1 as a control element
for the endospermal sucrose concentration.
PMID- 10758499
TI - Over-expression of a pepper plastid lipid-associated protein in tobacco leads to
changes in plastid ultrastructure and plant development upon stress.
AB - Proteins homologous to fibrillin, a pepper plastid lipid-associated protein
involved in carotenoid storage in fruit chromoplasts, have been recently
identified in leaf chloroplasts from several species and shown to be induced upon
environmental stress. To further investigate the role of the protein, transgenic
Nicotiana tabacum plants over-expressing fibrillin using a constitutive promoter
were generated. Transgenics grown under standard light intensities (300 micromol
photons m-2 sec-1) were found to contain substantial amounts of fibrillin in
flowers and leaves. In leaves, the protein was immunolocalized within
chloroplasts in both stromal and thylakoid subfractions. No change was noticed in
thylakoid structures from transgenics, but chloroplasts contained an increased
number of plastoglobules organized in clusters. In petals, leucoplasts were also
found to contain more agglutinated plastoglobules. The effects of environmental
factors on fibrillin gene expression and protein localization were studied in
tobacco leaves. Less fibrillin was present in plants grown under low light
intensities, which can be explained by the involvement of a light-dependent
splicing step in the control of fibrillin gene expression in leaves. Analysis of
protein subfractions from plants subjected to drought or high light showed that
both stresses resulted in fibrillin association with thylakoids. Whereas no
growth difference between wild-type (WT) and transgenic plants was noticed under
low light conditions, transgenics exhibit a longer main stem, enhanced
development of lateral stems and accelerated floral development under higher
light intensities. These data suggest that fibrillin-related proteins fulfil an
important function in plant development in relation to environmental constraints.
PMID- 10758498
TI - Stability determinants in the chloroplast psbB/T/H mRNAs of Chlamydomonas
reinhardtii.
AB - The chloroplast gene psbB encodes the chlorophyll-a binding protein P5 (CP47),
one of the core subunits of photosystem II (PSII). The psbB mRNA and the
downstream psbT and psbH transcripts fail to accumulate in the Chlamydomonas
reinhardtii nuclear mutant 222E affected in the Mbb1 gene (Monod et al. 1992,
Mol. Gen. Genet. 231, 449-459). By introducing chimeric genes consisting of
sequences from psbB and the reporter gene aadA into the chloroplast, the target
site of Mbb1 was mapped in the psbB 5' untranslated region (UTR). Primer
extension analysis indicates that the psbB RNA exists in a less abundant long
form and a more abundant short form, with 5' ends at positions -147 and -35
relative to the AUG initiation codon, respectively. The longer transcript is
present both in the wild type (WT) and 222E mutant, but the shorter one
accumulates only in the WT. Two putative stem-loop structures in the longer 5'
UTR can be deleted individually without affecting psbB mRNA accumulation.
Insertion of a poly G cassette in the long leader stabilizes a chimeric psbB
transcript in the 222E mutant, suggesting the involvement of a 5'-3' exonuclease.
We also show that psbH and psbT are transcribed from the upstream psbB gene
promoter, and that the psbH mRNA has its own target sequence for Mbb1 function.
We discuss the role of this nucleus-encoded factor, required for specific
chloroplast gene expression, in the assembly of the multi-protein PSII complex.
PMID- 10758500
TI - Technical advance: display and isolation of transposon-flanking sequences
starting from genomic DNA or RNA.
AB - Insertion mutagenesis using transposons has become a powerful tool for the
isolation of genes involved in any given biochemical or developmental pathway. We
describe here ligation-mediated PCR techniques for the isolation of sequences
flanking the transposable elements En/Spm, Mu1 and Cin4 in Zea mays and
Arabidopsis thaliana. Two versions of this transposon insertion display (TID)
method use biotinylated linkers or biotinylated primers to rapidly isolate
transposon-flanking sequences starting from digested genomic DNA. TID protocols
have been employed to clone several genes from En/Spm insertion mutants of
Arabidopsis. A novel procedure, expression TID (ETID), is also introduced, which
provides a direct approach for the isolation of transposon insertions that tag
transcribed portions of genes. ETID uses RNA as a starting material and exploits
5' RACE PCR to identify transposon copies that form parts of gene transcripts.
The detection of several En/Spm insertion mutations in Arabidopsis illustrates
the power of this method. ETID offers important advantages for the isolation of
mutant alleles of novel genes that are expressed in specific tissues in plants
and animals.
PMID- 10758501
TI - AtRAD1, a plant homologue of human and yeast nucleotide excision repair
endonucleases, is involved in dark repair of UV damages and recombination.
AB - Plants are unique in the obligatory nature of their exposure to sunlight and
consequently to ultraviolet (UV) irradiation. However, our understanding of plant
DNA repair processes lags far behind the current knowledge of repair mechanisms
in microbes, yeast and mammals, especially concerning the universally conserved
and versatile dark repair pathway called nucleotide excision repair (NER). Here
we report the isolation and functional characterization of Arabidopsis thaliana
AtRAD1, which encodes the plant homologue of Saccharomyces cerevisiae RAD1,
Schizosaccharomyces pombe RAD16 and human XPF, endonucleolytic enzymes involved
in DNA repair and recombination processes. Our results indicate that AtRAD1 is
involved in the excision of UV-induced damages, and allow us to assign, for the
first time in plants, the dark repair of such DNA lesions to NER. The low
efficiency of this repair mechanism, coupled to the fact that AtRAD1 is
ubiquitously expressed including tissues that are not accessible to UV light,
suggests that plant NER has other roles. Possible 'UV-independent' functions of
NER are discussed with respect to features that are particular to plants.
PMID- 10758502
TI - Repair of UV damage in plants by nucleotide excision repair: Arabidopsis UVH1 DNA
repair gene is a homolog of Saccharomyces cerevisiae Rad1.
AB - To analyze plant mechanisms for resistance to UV radiation, mutants of
Arabidopsis that are hypersensitive to UV radiation (designated uvh and uvr) have
been isolated. UVR2 and UVR3 products were previously identified as photolyases
that remove UV-induced pyrimidine dimers in the presence of visible light. Plants
also remove dimers in the absence of light by an as yet unidentified dark repair
mechanism and uvh1 mutants are defective in this mechanism. The UVH1 locus was
mapped to chromosome 5 and the position of the UVH1 gene was further delineated
by Agrobacterium-mediated transformation of the uvh1-1 mutant with cosmids from
this location. Cosmid NC23 complemented the UV hypersensitive phenotype and
restored dimer removal in the uvh1-1 mutant. The cosmid encodes a protein similar
to the S. cerevisiae RAD1 and human XPF products, components of an endonuclease
that excises dimers by nucleotide excision repair (NER). The uvh1-1 mutation
creates a G to A transition in intron 5 of this gene, resulting in a new 3'
splice site and introducing an in-frame termination codon. These results provide
evidence that the Arabidopsis UVH1/AtRAD1 product is a subunit of a repair
endonuclease. The previous discovery in Lilium longiflorum of a homolog of human
ERCC1 protein that comprises the second subunit of the repair endonuclease
provides additional evidence for the existence of the repair endonuclease in
plants. The UVH1 gene is strongly expressed in flower tissue and also in other
tissues, suggesting that the repair endonuclease is widely utilized for repair of
DNA damage in plant tissues.
PMID- 10758503
TI - Functional, c-myc-tagged Cf-9 resistance gene products are plasma-membrane
localized and glycosylated.
AB - The Cf-9 resistance gene from tomato confers resistance to races of the fungal
pathogen Cladosporium fulvum that express the corresponding avirulence gene,
Avr9. Avr9 encodes a secreted peptide. To investigate Cf-9 function, we tagged
the Cf-9 protein with a triple myc epitope at either the amino- or carboxy
terminus of the mature protein. Tobacco plants carrying these constructs activate
a defence response to Avr9 peptide. The Cf-9 sequence predicts a protein of 94
kDa, with 22 glycosylation sites. Using c-myc antibodies, c-myc : Cf-9 protein
was detected as a unique band with a molecular size of 160 kDa. The band shifted
to approximately 105 kDa after glucosidase treatment, indicating that Cf-9
protein is highly glycosylated. Plasma membranes were isolated using two-phase
partitioning, and c-myc : Cf-9 was enriched in these fractions, indicating that
Cf-9 is a plasma membrane protein. This was confirmed by silver-enhanced
immunogold labelling of tobacco protoplasts carrying the amino-terminal c-myc
tag; a higher labelling density was observed on the surface of protoplasts
derived from c-myc : Cf-9 tobacco compared to untransformed control. The presence
of Cf-9 in the plasma membrane is consistent with its role in conferring
recognition of the extracellular Avr9 peptide.
PMID- 10758504
TI - Matrix polysaccharide precursors in Arabidopsis cell walls are synthesized by
alternate pathways with organ-specific expression patterns.
AB - The expression pattern of the single-copy gene UDP-glucose dehydrogenase (Ugd)
was analysed in transgenic Arabidopsis plants by promoter:GUS and GFP fusions,
Western blots, activity assays and histochemical activity staining. The enzyme
oxidizes UDP-glucose to UDP-glucuronic acid and thus directs carbohydrates
irreversibly into a cell wall-specific pool of nucleotide sugars. UDP-glucuronic
acid is the central intermediate in the interconversion pathway to other
nucleotide sugars, including the UDP-derivatives of arabinose, xylose, apiose and
galacturonic acid which account for half the biomass of a typical Arabidopsis
leaf cell wall. These activated sugars are needed as substrates for the
biosynthesis of matrix polysaccharide polymers. In plants up to 5 days old the
Ugd gene is strongly expressed in young roots, but very little in hypocotyls.
Older plants show a more uniform expression pattern with a preference for the
vascular system. A complex expression pattern was observed in flowers with high
activity in the stamen, stigma and nectaries. Meristems in the leaf axil of
rosette and inflorescence leaves exhibit a high level of activity of the Ugd
gene. Although many of the growing tissues show high activity levels of the Ugd
gene, others such as the hypocotyl and the cotyledons of young seedlings do not.
Instead these tissues efficiently incorporate 3H-inositol into their cell walls.
This indicates the biosynthesis of UDP-glucuronic acid through an alternative
pathway via the oxidation of inositol to glucuronic acid and subsequent
activation to the nucleotide sugar. The data strongly suggest two alternative
pathways for matrix polysaccharide precursors with spatial and developmental
regulation.
PMID- 10758505
TI - Evidence that auxin promotes gibberellin A1 biosynthesis in pea.
AB - In shoots of the garden pea, the bioactive gibberellin (GA1) is synthesised from
GA20, and the enzyme which catalyses this step (a GA 3-oxidase -- PsGA3ox1) is
encoded by Mendel's LE gene. It has been reported previously that decapitation of
the shoot (excision of the apical bud) dramatically reduces the conversion of
[3H]GA20 to [3H]GA1 in stems, and here we show that endogenous GA1 and PsGA3ox1
transcript levels are similarly reduced. We show also that these effects of
decapitation are completely reversed by application of the auxin indole-3-acetic
acid (IAA) to the 'stump' of decapitated plants. Gibberellin A20 is also
converted to an inactive product, GA29, and this step is catalysed by a GA 2
oxidase, PsGA2ox1. In contrast to PsGA3ox1, PsGA2ox1 transcript levels were
increased by decapitation and reduced by IAA application. Decapitation and IAA
treatment did not markedly affect the level of GA1 precursors. It is suggested
that in intact pea plants, auxin from the apical bud moves into the elongating
internodes where it (directly or indirectly) maintains PsGA3ox1 transcript levels
and, consequently, GA1 biosynthesis.
PMID- 10758506
TI - Degradation of Aux/IAA proteins is essential for normal auxin signalling.
AB - The growth substance auxin mediates many cellular processes, including division,
elongation and differentiation. PSIAA6 is a member of the Aux/IAA family of short
lived putative transcriptional regulators that share four conserved domains and
whose mRNAs are rapidly induced in the presence of auxin. Here PSIAA6 was shown
to serve as a dominant transferable degradation signal when present as a
translational fusion with firefly luciferase (LUC), with an in vivo half-life of
13.5 min in transgenic Arabidopsis seedlings. In a transient assay system in
tobacco protoplasts using steady-state differences as an indirect measure of
protein half-life, LUC fusions with full-length PSIAA6 and IAA1, an Aux/IAA
protein from Arabidopsis, resulted in protein accumulations that were 3.5 and 1.
0%, respectively, of that with LUC alone. An N-terminal region spanning conserved
domain II of PSIAA6 containing amino acids 18-73 was shown to contain the
necessary cis-acting element to confer low protein accumulation onto LUC, while a
fusion protein with PSIAA6 amino acids 71-179 had only a slight effect. Single
amino acid substitutions of PSIAA6 in conserved domain II, equivalent to those
found in two alleles of axr3, a gene that encodes Aux/IAA protein IAA17, resulted
in a greater than 50-fold increase in protein accumulation. Thus, the same
mutations resulting in an altered auxin response phenotype increase Aux/IAA
protein accumulation, providing a direct link between these two processes. In
support of this model, transgenic plants engineered to over-express IAA17 have an
axr3-like phenotype. Together, these data suggest that rapid degradation of
Aux/IAA proteins is necessary for a normal auxin response.
PMID- 10758507
TI - Premature termination codons destabilize ferredoxin-1 mRNA when ferredoxin-1 is
translated.
AB - Ferredoxin-1 (Fed-1) mRNA is poorly translated in dark-treated tobacco (Nicotiana
tabacum) leaves, resulting in destabilization of Fed-1 mRNA and a differential
light/dark accumulation of the mRNA. Insertion of nonsense codons within the Fed
1 coding sequence disrupts the light regulation of Fed-1 mRNA abundance. Here we
show that the nonsense codon effect results primarily from lowering the Fed-1
mRNA stability in light-treated leaf tissue and in rapidly growing tobacco cell
cultures, but not in dark-treated leaf tissue. These results suggest that
nonsense codons trigger a decay pathway distinct from that seen for Fed-1 mRNA in
the dark. We propose that nonsense-mediated decay of nonsense-containing Fed-1
mRNA occurs in light-treated leaves and in non-photosynthetic tobacco culture
cells where Fed-1 mRNA is being actively translated.
PMID- 10758508
TI - Arbuscular mycorrhizal fungi induce the non-mevalonate methylerythritol phosphate
pathway of isoprenoid biosynthesis correlated with accumulation of the 'yellow
pigment' and other apocarotenoids.
AB - Plants and certain bacteria use a non-mevalonate alternative route for the
biosynthesis of many isoprenoids, including carotenoids. This route has been
discovered only recently and has been designated the deoxyxylulose phosphate
pathway or methylerythritol phosphate (MEP) pathway. We report here that
colonisation of roots from wheat, maize, rice and barley by the arbuscular
mycorrhizal fungal symbiont Glomus intraradices involves strong induction of
transcript levels of two of the pivotal enzymes of the MEP pathway, 1-deoxy-D
xylulose 5-phosphate synthase (DXS) and 1-deoxy-D-xylulose 5-phosphate
reductoisomerase (DXR). This induction is temporarily and spatially correlated
with specific and concomitant accumulation of two classes of apocarotenoids,
namely glycosylated C13 cyclohexenone derivatives and mycorradicin (C14)
conjugates, the latter being a major component of the long-known 'yellow
pigment'. A total of six cyclohexenone derivatives were characterised from
mycorrhizal wheat and maize roots. Furthermore, the acyclic structure of
mycorradicin described previously only from maize has been identified from
mycorrhizal wheat roots after alkaline treatment of an 'apocarotenoid complex' of
yellow root constituents. We propose a hypothetical scheme for biogenesis of both
types of apocarotenoids from a common oxocarotenoid (xanthophyll) precursor. This
is the first report demonstrating (i) that the plastidic MEP pathway is active in
plant roots and (ii) that it can be induced by a fungus.
PMID- 10758509
TI - Technical advance: stringent control of transgene expression in Arabidopsis
thaliana using the Top10 promoter system.
AB - We show that the tightly regulated tetracycline-sensitive Top10 promoter system
(Weinmann et al. Plant J. 1994, 5, 559-569) is functional in Arabidopsis
thaliana. A pure breeding A. thaliana line (JL-tTA/8) was generated which
expressed a chimeric fusion of the tetracycline repressor and the activation
domain of Herpes simplex virus (tTA), from a single transgenic locus. Plants from
this line were crossed with transgenics carrying the ER-targeted green
fluorescent protein coding sequence (mGFP5) under control of the Top10 promoter
sequence. Progeny from this cross displayed ER-targeted GFP fluorescence
throughout the plant, indicating that the tTA-Top10 promoter interaction was
functional in A. thaliana. GFP expression was repressed by 100 ng ml-1
tetracycline, an order of magnitude lower than the concentration used previously
to repress expression in Nicotiana tabacum. Moreover, the level of GFP expression
was controlled by varying the concentration of tetracycline in the medium,
allowing a titred regulation of transgenic activity that was previously
unavailable in A. thaliana. The kinetics of GFP activity were determined
following de-repression of the Top10:mGFP5 transgene, with a visible ER-targeted
GFP signal appearing from 24 to 48 h after de-repression.
PMID- 10758510
TI - New insights into our understanding of the regulation and organization of cell
factories.
PMID- 10758511
TI - Genetically modified foods: economic aspects and public acceptance in Brazil.
PMID- 10758512
TI - The impact of biotechnology on the chemical industry in the 21st century.
AB - Although the overall size of the industrial chemicals business is US$1.4 trillion
worldwide, growth has slowed in some market segments. In order to reestablish and
sustain growth, materials with higher information content and improved economics
based on renewable resources will be required. These challenges have motivated
the pursuit of biotechnology by several traditional chemical companies, such as
DuPont, Dow, BASF and Monsanto. Even though each company might differ in their
strategic approach, their common goal is the same: to create high-value materials
using biotechnology.
PMID- 10758513
TI - Therapeutic cloning: concepts and practicalities.
AB - The concept of using embryonic stem (ES) cells as a source of multiple cell types
for use in tissue repair has existed for approximately 20 years. Recent
breakthroughs in somatic nuclear transfer and human ES cell derivation have
produced a flurry of new activity in this area, with the recognition that ES cell
lines that are customized and genetically identical to those of the patient are a
distinct possibility. This article examines the background of and prospects for
these exciting new developments.
PMID- 10758514
TI - Biotransformations monitored in situ by proton nuclear magnetic resonance
spectroscopy.
AB - One-dimensional Fourier-transform proton nuclear magnetic resonance (1H-NMR)
spectroscopy can be used to study biotransformations in situ, in vivo and in aqua
(1H2O). Although an insensitive method, it rapidly provides solution-structural
information of mixtures of diverse compounds that are used and formed during
enzymic reactions and culture fermentations; the samples do not require any
physical or chemical processing for analysis. The absolute stereochemistry of
some reactions can also be determined, and assessments of metabolic fluxes made.
This technique, with appropriate modifications, is of obvious value for on-line
assessments of industrial fermentation processes.
PMID- 10758515
TI - Ambiguities in the preclinical quality assessment of microparticulate vaccines.
AB - Vaccination techniques do not always stimulate immunity because of the
inappropriate mobilization of immune responses, and the frequency of vaccinations
required is impractical in many developing countries. Such limitations have
spurred the development of new vaccine-delivery approaches. Microparticles made
of poly(lactide-co-glycolide) can induce adaptive immunity after a single
administration of a vaccine. However, the preclinical assessment of such vaccines
is not standardized, making it difficult to compare pharmaceutical with
immunological data. The relevance of and the ambiguity in the assessment of
microparticulate vaccines with respect to the current knowledge on immunity are
discussed, in addition to the application of this knowledge to rational vaccine
design.
PMID- 10758516
TI - Recent advances in the design and construction of synthetic peptides: for the
love of basics or just for the technology of it.
AB - Advances in the methods used for the chemical synthesis of peptides, and in the
accumulation and analysis of numerous X-ray crystallographic and nuclear magnetic
resonance protein and peptide structures, have enabled the design and
construction of peptides for investigating basic folding principles, making novel
structural motifs, modifying functional activities, developing pharmaceutical
drugs and creating new biomaterials. The focus of this review is on recent trends
in the design and construction of synthetic peptides for basic science and for
various biotechnological applications.
PMID- 10758517
TI - Artificial chromosomes: ideal vectors?
AB - Artificial chromosomes are DNA molecules of predictable structure, which are
assembled in vitro from defined constituents that behave with the properties of
natural chromosomes. Artificial chromosomes were first assembled in budding yeast
and have since been useful in many aspects of yeast genetics. Several attempts
have been made at building artificial chromosomes in mammals, although these have
been met with limited success. Consequently, mini-chromosomes of defined
structure have been developed to address questions regarding mammalian chromosome
function and for biotechnological applications. Here we review progress in these
areas and consider how it influences plans to build artificial chromosomes in
plants and parasites.
PMID- 10758518
TI - So we say?
PMID- 10758519
TI - Work-related musculoskeletal disorders in physical therapists: prevalence,
severity, risks, and responses.
AB - BACKGROUND AND PURPOSE: Physical therapists are at risk for work-related
musculoskeletal disorders (WMSDs). Little is known of how therapists respond or
of what actions they take to prevent injury. The purpose of this study was to
investigate the prevalence and severity of WMSDs in physical therapists,
contributing risk factors, and their responses to injury. SUBJECTS: As part of a
larger study, a systematic sample of 1 in 4 therapists on a state register
(n=824) was surveyed. METHODS: An 8-page questionnaire was mailed to each
subject. Questions investigated musculoskeletal symptoms, specialty areas, tasks
and job-related risk factors, injury prevention strategies, and responses to
injury. RESULTS: Lifetime prevalence of WMSDs was 91%, and 1 in 6 physical
therapists moved within or left the profession as a result of WMSDs. Younger
therapists reported a higher prevalence of WMSDs in most body areas. Use of
mobilization and manipulation techniques was related to increased prevalence of
thumb symptoms. Risk factors pertaining to workload were related to a higher
prevalence of neck and upper-limb symptoms, and postural risk factors were
related to a higher prevalence of spinal symptoms. CONCLUSION AND DISCUSSION:
Strategies used to reduce work-related injury in industry may also apply to
physical therapists. Increased risk of thumb symptoms associated with
mobilization techniques suggests that further research is needed to establish
recommendations for practice. The issues for therapists who move within or leave
the profession are unknown, and further research is needed to better understand
their needs and experiences.
PMID- 10758520
TI - Passive ankle stiffness in subjects with diabetes and peripheral neuropathy
versus an age-matched comparison group.
AB - BACKGROUND AND PURPOSE: Patients with diabetes mellitus and peripheral neuropathy
(DM and PN) often complain of joint stiffness. Although stiffness may contribute
to some of the impairments and functional limitations found in these patients, it
has not been quantified in this population. The purpose of this study was to
quantify and compare passive ankle stiffness and dorsiflexion (DF) range of
motion in subjects with DM and PN versus an age-matched comparison group.
SUBJECTS: Thirty-four subjects were tested (17 subjects with DM and PN and 17
subjects in an age-matched comparison group). There were 10 male subjects and 7
female subjects in each group. METHODS: A Kin-Com dynamometer was used to measure
passive plantar flexor torque as each subject's ankle was moved from plantar
flexion into dorsiflexion at 60(/s. The following variables were compared using a
Student t test: initial angle (angle of onset of plantar flexor torque), maximal
dorsiflexion angle, plantar flexor muscle excursion (difference between initial
angle and maximal dorsiflexion angle), slope of the first half of the plantar
flexor torque curve (stiffness 1 measurement), and slope of the second half of
the plantar flexor torque curve (stiffness 2 measurement). RESULTS: The subjects
with DM and PN had smaller maximal dorsiflexion angles and less plantar flexor
muscle excursion than the comparison group. There was no difference in initial
angle, stiffness 1 measurement, or stiffness 2 measurement. CONCLUSION AND
DISCUSSION: Although the subjects with DM and PN had less dorsiflexion range of
motion than did the comparison group, there was no difference in stiffness
between the groups. This finding suggests that people with DM and PN have "short"
versus "stiff" plantar flexor muscles.
PMID- 10758521
TI - Effectiveness of a bed positioning program for treating older adults with knee
contractures who are institutionalized.
AB - BACKGROUND AND PURPOSE: Although contractures in patients in long-term care
institutions are an important issue, there have been only a few studies that have
evaluated interventions for contractures. The purpose of this study was to
determine the effectiveness of a bed positioning program (BPP) for the treatment
of patients with knee flexion contractures. SUBJECTS: Sixteen patients with a
high level of cognitive and functional impairment (mean age=82 years, SD=6.48,
range=71-93) in a chronic care hospital participated in the study. METHODS: The
BPP consisted of stretching a patient's knee into extension and then securing and
maintaining the position for a period of 40 minutes, 4 times per week.
Participants were randomly assigned to 2 groups (n=8 in each group). One group
received a BPP for 8 weeks, followed by 8 weeks of no intervention. The other
group received the intervention in the reverse order. Once a week, participants
were assessed for range of knee extension, knee pain, and skin integrity.
RESULTS: Twelve participants completed the study. There was no improvement in
participants' range of knee extension during the intervention period. Overall,
there was no difference in mean range of knee extension between the intervention
period and the no-intervention period. CONCLUSION AND DISCUSSION: The results of
this study do not support the use of a BPP for treating patients with knee
flexion contractures.
PMID- 10758522
TI - Effects of attentional focus, self-control, and dyad training on motor learning:
implications for physical rehabilitation.
AB - In this article, the authors review recent studies on 3 factors that have been
shown to affect the learning of motor skills-the performer's attentional focus,
self-control, and practice in dyads-and discuss their implications for
rehabilitation. Research has shown that directing learners' attention to the
effects of their movements can be more beneficial for learning than directing
their attention to the details of their own actions. Furthermore, giving learners
some control over the training regimen has been found to enhance learning, unlike
prescriptive training protocols that dictate when feedback will be delivered, how
often, and the order that tasks will be practiced. Finally, not only can practice
in dyads (or larger groups) reduce the costs of training, but it can also result
in more effective learning than individual practice sessions. The incorporation
of these factors into rehabilitation practice can potentially enhance the
effectiveness and efficiency of rehabilitation.
PMID- 10758523
TI - Examination and treatment of a patient with hypermobility syndrome.
AB - BACKGROUND AND PURPOSE: The purpose of this case report is to present the patient
examination, evaluation/diagnosis/prognosis, intervention, and outcome of a
patient with hypermobility syndrome (HMS). Hypermobility syndrome has been widely
recognized in the rheumatology literature, but it has seldom been discussed in
the orthopedic literature and has only recently been described in the physical
therapy literature. The signs and symptoms of HMS are common among patients seen
in orthopedic physical therapy clinics; however, the underlying HMS may be
overlooked while treating individual joints or tissues causing pain. CSE
DESCRIPTION: The patient was a 28-year-old woman with complaints of chronic,
multiple-joint pain. After years without a diagnosis, a rheumatologist had
recently diagnosed underlying HMS. OUTCOMES: Following intervention that
emphasized patient education and activity modification, the patient's complaints
decreased. DISCUSSION: Recognition of HMS underlying common orthopedic problems
may facilitate appropriate patient education and management.
PMID- 10758524
TI - Plantar pressure assessment.
PMID- 10758525
TI - An alternative conclusion.
PMID- 10758526
TI - Cough in patients with SCI.
PMID- 10758527
TI - Listening to Immelmann.
PMID- 10758528
TI - The evolution.
PMID- 10758530
TI - Managing Esophageal Cancer.
PMID- 10758529
TI - Physical therapy-past, present, and future.
PMID- 10758531
TI - Barrett's Esophagus and Barrett's Associated Neoplasia: Etiology and Pathologic
Features.
AB - BACKGROUND: The incidence of Barrett's esophagus (BE) has been increasing in
recent years. Patients with BE have 30- to 125-fold increased risk of developing
adenocarcinoma. New techniques allowing early diagnosis, in addition to the
identification of markers capable of predicting tumor progression, are needed.
METHODS: The authors discuss the diagnostic features of BE and BE-associated
neoplasia. RESULTS: BE can exhibit different types of metaplastic mucosa, but
only the specialized (intestinal) mucosa has the potential to progress to
dysplasia and carcinoma. The problems associated with diagnosing BE and with
predicting the behavior of this condition are outlined. CONCLUSIONS: Studies are
underway to identify molecular markers capable of predicting which BE patient
will progress to carcinoma. Brush cytology and flow cytometry may become useful
tools in the early detection of this disease.
PMID- 10758532
TI - Endosonographic Staging of Esophageal Cancer.
AB - BACKGROUND: Endosonography (ES) is an important tool for staging malignant
esophageal cancer with the TNM staging classification. ES is a safe procedure and
an accurate method of staging tumor invasion (T) and lymph node involvement (N).
METHODS: The author reviewed the literature on the comparative roles of computed
tomography and ES as complementary staging procedures. RESULTS: Advantages of ES
in staging esophageal cancer include the ability to accurately determine the
layer depth of mural infiltration and to detect metastatic involvement of
regional lymph nodes. Its disadvantages include its inability to identify distant
metastases, to differentiate inflammation from malignant infiltration of wall
layers or in lymph nodes, and to examine beyond obstructing tumors unless
esophageal dilation is performed. A recent review indicates the accuracy for T
staging to be 84% and N staging to be 77%. CONCLUSIONS: ES is a valuable tool in
staging esophageal cancer and should be used in combination with computed
tomography for highest accuracy.
PMID- 10758533
TI - Surgical Approaches to Esophageal Cancer.
AB - BACKGROUND: Esophageal cancer is a highly lethal malignancy. Esophageal resection
remains the primary treatment in most centers. A number of approaches to
esophageal resection have been described. METHODS: The authors review the current
approaches to esophageal resection and adjuvant therapy for esophageal cancer.
RESULTS: Transthoracic, transhiatal, and minimally invasive techniques are
currently employed in esophageal surgery for malignancy. A number of authors
favor extended mediastinal and cervical lymphadenectomy in hopes of improving
survival. Combined chemotherapy and radiotherapy in the neoadjuvant setting
appears to offer some promise. CONCLUSIONS: No consensus of opinion exists
regarding the optimal approach or extent of esophageal resection for cancer.
Prospective, randomized trials of neoadjuvant therapy may determine its efficacy.
Newer approaches may enhance quality of life.
PMID- 10758534
TI - Neoadjuvant Therapy for Cancer of the Esophagus.
AB - BACKGROUND: The standard of care for esophageal cancer has historically been
surgical resection. However, survival following surgical treatment of esophageal
cancer remains poor. In inoperable patients, both radiation therapy and
chemotherapy alone and in combination have been used with some success.
Consequently, these therapies have been utilized in the neoadjuvant setting to
improve palliation and prolong survival. METHODS: The author reviewed the
literature regarding clinical trials that employed neoadjuvant chemotherapy and
radiation therapy in the treatment of squamous cell carcinoma and adenocarcinoma
of the esophagus. RESULTS: In most patients, surgery alone is noncurative
therapy, even when performed with curative intent. Most phase III trials of
neoadjuvant therapy have not been designed with adequate statistical power to
detect clinically relevant improvement. The available data are insufficient to
determine a benefit to preoperative radiation therapy alone. Preoperative
chemotherapy with 5-FU plus cisplatin followed by surgery probably offers little
or no improvement over surgery alone. Trials of combined preoperative
chemoradiation therapy have yielded promising but not definitive results.
CONCLUSIONS: Outside of a clinical trial, neoadjuvant therapy for esophageal
cancer should be reserved for only a select group of patients. Future clinical
trials may determine a role for neoadjuvant chemoradiation and identify more
active chemotherapeutic agents and populations most likely to benefit.
PMID- 10758535
TI - The Role of Radiation Therapy in the Management of Esophageal Cancer.
AB - BACKGROUND: Esophageal cancer is a challenging clinical problem with an estimated
12,300 new cases diagnosed in 1998. METHODS: A detailed review of pertinent
literature is used to describe the epidemiology and management of this disease.
RESULTS: Radiation therapy remains an important cornerstone of therapy. In
combination with chemotherapy and/or surgery, radiation therapy may offer an
improved therapeutic outcome. CONCLUSIONS: Radiation therapy remains an important
therapy in the treatment of esophageal cancer.
PMID- 10758536
TI - Nutritional Management of Patients With Esophageal and Esophagogastric Junction
Cancer.
AB - BACKGROUND: Malnutrition is common in patients with esophageal and
esophagogastric cancer. Compared to patients with other digestive and
extradigestive neoplasia, the highest incidence (78.9%) was found in those with
esophageal cancer. Malnutrition is associated with postoperative complications,
increased morbidity, and prolonged hospital stays. METHODS: The authors review
the impact and causes of malnutrition in esophageal cancer patients and present
strategies that can be used to preserve or restore the nutritional status in this
patient population throughout treatment. RESULTS: Patients usually are unable to
sustain weight on oral intake alone and require additional means of nutritional
support. Several methods can be used to provide nutritional care to the
esophageal cancer patient, such as diet modification, oral supplementation, and
enteral or parenteral nutrition. The enteral route is preferred due to
preservation of gut integrity, reduced risk of complications, and less expense.
In terminally ill patients, minimal nutritional intervention may be all that is
needed to achieve patient comfort. CONCLUSIONS: In order to improve clinical
outcomes and the quality of life for patients with esophageal and esophagogastric
cancers, the extent of malnutrition must be identified and treated.
PMID- 10758537
TI - Palliation of Dysphagia of Esophageal Cancer by Endoscopic Lumen Restoration
Techniques.
AB - BACKGROUND: Cure of patients with esophageal cancer has remained rare over the
past four decades. The overall five-year survival rate for squamous cell and
adenocarcinoma of the esophagus currently is reported as 12% in whites and 8% in
blacks. The five-year survival rate for localized disease at initial staging is
only 26% for whites and 13% for blacks. With regional involvement, these rates
are 11% and 7%, respectively. METHODS: The author reviews the literature on
optimal endoscopic lumen restoration techniques, including dilation, thermal
laser and chemical ablation, photodynamic therapy, and stents. Procedures for
pain relief and nutritional support are also presented. RESULTS: Lumen
restoration to relieve dysphagia and provide the opportunity for sustaining
reasonable peroral nutrition is an essential element in the overall management.
Nonsurgical lumen restoration procedures have much to offer for dysphagia
palliation and are briefly reviewed in this presentation. The major options
include ablation of intraluminal tumor mass by thermal laser, photodynamic laser,
chemical ablation, peroral dilation, and placement of esophageal stents. Most
patients require more than one palliative method to sustain lumen patency during
the course of their disease. CONCLUSIONS: Most patients with esophageal cancer
will require palliation for the multiple problems that develop during their
limited life span. The responsibility of the palliation therapist is to provide
the patient with safe and cost-effective treatments that provide the best
possible dysphagia relief.
PMID- 10758538
TI - Imaging in Bone Marrow Transplantation.
PMID- 10758539
TI - Laparoscopic Adrenal Resection: Changing Techniques for Established Indications.
PMID- 10758540
TI - Palliative Care and Mainstream Medicine: An Overdue Collaboration.
PMID- 10758541
TI - Reforming the Care System to Support Those Coming to the End of Life.
AB - BACKGROUND: Health care has shifted its focus regarding dying patients toward
improving care rather than striving for cure. METHODS: The Center to Improve Care
of the Dying and the Institute for Healthcare Improvement sponsored a quality
improvement collaborative from July 1997 through July 1998 to learn how to
accomplish this. RESULTS: (1) Classifying persons as "dying" or "not dying" does
not help to ensure quality care at the end of life. The impossibility of
predicting time of death in many illnesses demands not only a shift to asking
whether a patient is sick enough to die of the current illness, but also
targeting special services to those patients. (2) Quality improvement strategies
in this arena regularly yield important gains in such fields as pain control,
bereavement support, and advance planning. (3) Serious reform probably must
originate in system design and routine practice rather than in exhortations to
customize decision making. The Study to Understand Prognoses and Preferences in
Outcomes and Risks of Treatment (SUPPORT) found that 80% of the substantial
variation in the rate of death at home correlated with hospital bed supply.
CONCLUSIONS: Based on the inadequacy of the current classification system and on
the unpredictability of the timing of death, a conceptual model is proposed for
many patients that mixes conventional "aggressive" care with palliative care and
is triggered by illness severity rather than by prognosis. High leverage reform
in end-of-life care is available now through quality improvement strategies.
PMID- 10758542
TI - Trends in Cancer Pain Management.
AB - BACKGROUND: Pain is a prevalent symptom in cancer patients, affecting up to 50%
of patients undergoing active cancer treatment and up to 90% of those with
advanced disease. Although adequate relief can be achieved in the majority of
cancer patients, pain is often treated inadequately in traditional settings.
METHODS: The authors use their experience and that of others to review the
evaluation and diagnosis of pain syndromes and the principles of management.
RESULTS: The World Health Organization and other governmental agencies have
recognized the importance of pain management as part of routine cancer care.
Conducting a comprehensive assessment, competently providing analgesic drugs, and
communicating with the patient and family allow effective management of pain in
the cancer patient. CONCLUSIONS: Several approaches can promote adequate
management of cancer pain, such as enhancing clinician knowledge of pain
syndromes, improving pain assessment, and updating medical information related to
pain and symptom control.
PMID- 10758543
TI - Physician-Assisted Suicide: The Influence of Psychosocial Issues.
AB - BACKGROUND: Physician-assisted suicide (PAS) is perhaps the most compelling and
clinically relevant mental health issue in palliative care today. The desire for
death, the consideration of suicide, the interest in PAS, and the relationship of
these issues to depression and other psychosocial issues appear to be of
paramount importance. METHODS: Psychiatric and psychosocial perspectives are used
to understand the factors contributing to the interest in PAS, as well as to
guide interventions in the clinical care of patients with advanced disease.
RESULTS: Research and clinical experience suggest that attending to issues of
depression, social support, and other psychosocial issues in addition to pain and
physical symptom control are critical elements in interventions that are useful
in reducing the distress of patients who desire hastened death. CONCLUSIONS:
Psychosocial and psychiatric issues are among the most powerful predictors of
desire for death and interest in PAS. Evaluation and intervention in these areas,
particularly depression, is a critical component of compassionate care.
PMID- 10758544
TI - Ethical Issues in End-of-Life Care.
AB - BACKGROUND: Physicians who treat patients approaching the end of life often face
moral, ethical, and legal issues involving shared decision making, futility, the
right to refuse medical treatment, euthanasia, and physician-assisted suicide.
METHODS: The author examines cases that involve these issues and also reviews the
ethical principles that guide current medical practice. Issues such as end-of
life ethical questions, the right to life-sustaining therapy, medical futility,
the distinction between killing and allowing to die, and physician-assisted
suicide are discussed. RESULTS: The principal problem involves the appropriate
use of technology at the end of life. While developments in technology have
enhanced our ability to prolong life, issues have also arisen regarding the
resulting quality of life, the sometimes marginal benefits to our patients, and
the burdens that this technology imposes on patients, families, and society.
CONCLUSIONS: Legal and ethical issues continue to confront patients, courts, and
physicians. A better understanding of these issues and an awareness of the
availability of effective palliative care will help physicians, patients, and
families adequately address the end-of-life issues that are an intrinsic part of
medical care.
PMID- 10758545
TI - Advanced Cancer and Comorbid Conditions: Prognosis and Treatment.
AB - BACKGROUND: Nonmalignant comorbid medical conditions, such as heart failure and
emphysema, may complicate cancer treatment. METHODS: Guidelines from the National
Hospice Organization for cancer and selected nonmalignant diseases are outlined,
and treatment principles for end-stage heart failure and emphysema are reviewed.
RESULTS: Estimates by clinicians of survivability in advanced cancer and
nonmalignant disease are important in order to allow patients and family members
to begin realistic advance planning. As disease progresses through its end stages
to death, optimal management may include both disease-modifying and symptom
relieving interventions. CONCLUSIONS: A well-managed end of life is an important
therapeutic option in informed consent discussions with seriously ill patients
and their families.
PMID- 10758546
TI - Pelvic Radiation Therapy: Implications for the Small Bowel.
PMID- 10758547
TI - Significance of p53 and Bcl-2 Protein Expression in Human Breast Ductal
Carcinoma.
PMID- 10758549
TI - World Health Organization Guidelines: Problem Areas in Cancer Pain Management.
PMID- 10758548
TI - Recurrence of Multidrug-Resistant Enterococci in a Neutropenic Patient.
PMID- 10758550
TI - Assessing and Managing Narcotic-Induced Constipation in Adults With Cancer.
PMID- 10758551
TI - Breast Cancer Treatment: Prospects for the Future.
PMID- 10758552
TI - HER-2 as a Prognostic, Predictive, and Therapeutic Target in Breast Cancer.
AB - BACKGROUND: An expanded understanding of the biology of breast cancer has led to
the identification of the HER-2 receptor as an important growth factor. This
receptor possesses intrinsic tyrosine kinase activity and has been associated
with aggressive biological behavior and poor clinical outcome. METHODS: Data have
been reviewed regarding the role of HER-2 expression as a prognostic variable, as
a predictive factor for response to chemotherapy and hormonal therapies, and as a
directed therapeutic target for breast cancer. RESULTS: Therapy with a humanized
monoclonal antibody to HER-2 (trastuzumab) can be effective treatment in some
patients with metastatic breast cancer, either given alone or in combination with
some chemotherapeutic agents. Cardiac toxicity limits concurrent use with
anthracyclines. Clinical trials will further define optimal combination regimens
with this agent, and its value in patients with localized or locally advanced
stages. CONCLUSIONS: Trastuzumab is a significant addition to the armamentarium
against breast cancer. Standardization of the optimal method to evaluate for HER
2 overexpression is necessary to better define its role as a prognostic,
predictor, and therapeutic target in this disease.
PMID- 10758553
TI - Bisphosphonates in the Management of Breast Cancer.
AB - BACKGROUND: Bone is the most frequent site of metastasis in patients with breast
cancer. Bone metastasis, particularly osteolytic bone destruction, is usually
associated with significant morbidity and deterioration of quality of life.
Bisphosphonates are specific inhibitors of osteoclast activity used in the
treatment of hypercalcemia of malignancy and osteolytic bone disease. METHODS: We
reviewed pertinent literature on the use of bisphosphonates therapy to treat
metastatic breast cancer. RESULTS: The use of bisphosphonates in the management
of osteolytic bone metastases results in improved palliation of symptoms. Use of
these agents in the adjuvant setting may help to prevent bone metastases.
CONCLUSIONS: Bisphosphonates represent an effective palliative treatment when
combined with chemotherapy and hormonal therapy for the management of osteolytic
bone metastases. Identifying the exact mechanism of action requires further
investigation to better define the possibility of a direct antitumor effect. The
role of bisphosphonates in the adjuvant setting is still controversial, pending
the results of large randomized trials.
PMID- 10758554
TI - New Hormonal Therapies for Breast Cancer.
AB - BACKGROUND: There has been an explosion in the development of hormonal therapies
for the treatment of breast cancer. Several new agents have been approved for the
treatment of breast cancer in the metastatic setting, and trials are ongoing in
the adjuvant and prevention setting to improve hormonal therapy for the
prevention and treatment of breast cancer. METHODS: The literature on new
hormonal therapies for the treatment of breast cancer is reviewed, with an
emphasis on newer agents. RESULTS: Two antiestrogens are now approved in the
United States for the treatment of metastatic breast cancer. Other antiestrogens
have activity in metastatic breast cancer as well as in osteoporosis. Newer pure
antiestrogens may overcome resistance to tamoxifen. Several aromatase inhibitors
are available for the treatment of metastatic breast cancer. CONCLUSIONS: Many
hormonal agents are now available for both adjuvant and advanced disease
settings. Developments will depend on clarifying mechanisms of resistance to
antiestrogens and identifying new classes of agents that lack cross-resistance to
standard therapy.
PMID- 10758555
TI - Is Fatigue a Long-term Side Effect of Breast Cancer Treatment?
AB - BACKGROUND: Fatigue is one of the most common and distressing symptoms
experienced by breast cancer survivors. Despite its prevalence, relatively little
is known about the characteristics, etiology, or treatment of fatigue in breast
cancer survivors. METHODS: This report reviews studies that assessed fatigue in
breast cancer patients previously treated with adjuvant radiotherapy, adjuvant
chemotherapy, or autologous bone marrow transplantation. RESULTS: A review of the
literature suggests that breast cancer patients who undergo adjuvant chemotherapy
or autologous bone marrow transplantation experience clinically significant
levels of fatigue for months or even years following the completion of active
treatment. In contrast, there is little evidence that patients who receive only
regional therapy (ie, surgery plus adjuvant radiotherapy) experience clinically
significant fatigue as a long-term treatment side effect. CONCLUSIONS: A growing
body of evidence indicates that persistent fatigue can be a long-term side effect
of certain forms of breast cancer treatment. The challenges for the future will
be to determine the etiology of fatigue among breast cancer survivors and to
develop interventions that are effective in preventing or reducing fatigue
following breast cancer treatment.
PMID- 10758556
TI - Ductal Carcinoma In Situ of the Breast.
AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is detected more often since the
advent of mammography. A standardized pathologic staging and grading system does
not exist, but nuclear grade is assuming greater importance. The history of DCIS
is long, and its treatment is a controversial issue in breast cancer today.
METHODS: Data have been reviewed regarding the role of HER-2 expression as a
prognostic variable, as a predictive factor for response to chemotherapy and
hormonal therapies, and as a directed therapeutic target for breast cancer.
RESULTS: The NSABP protocol B06 revealed a recurrence rate of 43% in patients
treated with local excision alone. Half of recurrences are still DCIS, but 50%
are invasive. Local control is markedly improved by the addition of radiation.
Recurrence is also minimized by careful cytologic review of margins. Sentinel
lymph node biopsy has resulted in more accurate nodal staging. CONCLUSIONS: As a
heterogeneous lesion, DCIS may not lend itself to a uniform treatment approach.
Careful analysis of resection margins is required. As our understanding of the
diagnosis and treatment of this disease develops, a coordinated team approach is
optimal.
PMID- 10758558
TI - Evaluation of a Pancreatic Mass.
PMID- 10758557
TI - Pregnancy After Breast Cancer.
AB - BACKGROUND: The issue of pregnancy following the diagnosis and treatment of
breast cancer is important because the incidence of breast cancer is increasing
in women of childbearing age. The fact that many women are delaying childbearing,
whether for educational, professional, or personal reasons, increases the number
of women who will undergo breast cancer treatment before completing childbearing.
METHODS: Data on pregnancy in breast cancer survivors are limited and consist
only of retrospective data. This paper reviews the published literature on the
influence of subsequent pregnancy on breast cancer, including three recent large
scale population-based studies. RESULTS: The survival of women with breast
carcinoma who subsequently become pregnant is not reported to be decreased in any
of the published series. However, several biases may be present that justify the
concern regarding the conclusions. CONCLUSIONS: Further research on the safety of
subsequent pregnancy after breast carcinoma treatment is needed. To address these
issues, patients are currently being accrued for a large, prospective,
multicenter study of young breast carcinoma patients.
PMID- 10758559
TI - Pathologic and Radiologic Features of Primary Bone Tumors.
PMID- 10758560
TI - Infectious Causes of Malignancy.
PMID- 10758562
TI - The Future Direction of Gynecologic Oncology: Treatment in the New Millennium.
PMID- 10758561
TI - Surgery for Diagnosis and Treatment: Sentinel Lymph Node Biopsy in Breast Cancer.
PMID- 10758563
TI - Testing for Hereditary Risk of Ovarian Cancer.
AB - BACKGROUND: Approximately one out of every 10 ovarian cancers is caused by
inherited mutations in identified genes. The characterization of hereditary
ovarian cancer as an autosomal dominant disorder of specific gene mutations is
more specific and useful than descriptive clinical syndromes such as "Lynch II,"
"site-specific ovarian cancer," or "breast-ovarian cancer." METHODS: The author
reviewed recent studies of the biology, epidemiology, and medical management of
hereditary ovarian cancer risk. RESULTS: Most hereditary ovarian cancer is
attributable to two genes, BRCA1 and BRCA2, with other genes accounting for a
smaller fraction. Women who inherit a mutation in any of these genes are far more
likely than the general population to develop an epithelial malignancy of the
ovary. Appropriate evaluation of family history can identify women most likely to
have hereditary cancer risk, and genetic testing can definitively identify women
with germline mutations that place them and their family at increased risk of
ovarian cancer. CONCLUSIONS: Hereditary risk assessment, including genetic
testing, can enhance medical management when used appropriately and should be
accompanied by patient education and counseling.
PMID- 10758564
TI - Vaccines for Ovarian Carcinoma.
AB - BACKGROUND: Metastasis to the abdominal cavity is the primary cause of morbidity
and mortality in patients with ovarian cancer. Beyond surgery and chemotherapy
combinations, strategies that target tumor cells in vivo are being investigated,
such as the use of recombinant cytokines to up-regulate or modulate the cell
mediated or humoral immune response. METHODS: The authors report on their
experience with tumor vaccines, including first-generation vaccines, peptide
vaccines, and polynucleotide vaccines, in the treatment of ovarian cancer.
RESULTS: Cytokines may stimulate proliferation or activation of effector cells
that mediate either major histocompatibility restricted cytotoxicity (adaptive
immunity) or natural (innate) immunity. Cytokines are often pleiotropic, and
their effects may depend on concentration, scheduling, and responsiveness of the
cell populations to which they are directed. They also have been used to enhance
the efficacy of tumor vaccines that have reached a higher level of
sophistication. Recently designed tumor vaccines are capable of stimulating
antitumor immune responses that recognize tumor cell epitopes or that have the
potential to act synergistically with cytokines such as interleukin-2 and
interleukin-12. CONCLUSIONS: Enthusiasm for antitumor vaccine strategies is
supported by accumulating clinical reports of responses following treatments
using a variety of vaccines. Additional research is needed to determine optimum
vaccine approaches for the treatment or prevention of ovarian cancer.
PMID- 10758565
TI - Modification of the Radiation Response of Patients With Carcinoma of the Uterine
Cervix.
AB - BACKGROUND: The purpose of this review is to summarize clinical trials for
patients with cervical cancer treated with irradiation and modifiers of the
irradiation response. METHODS: The MEDLINE database was used to identify clinical
studies that evaluated modifiers of the irradiation response for patients with
carcinoma of the uterine cervix from 1970 through 1998. The studies included were
prospective, randomized phase III clinical trials comparing irradiation alone to
irradiation plus a chemical modifier for carcinoma of the uterine cervix.
RESULTS: Various chemical agents have been combined with irradiation in the
treatment of patients with carcinoma of the uterine cervix. These agents include
hyperbaric oxygen, hydroxyurea, nitroimidazoles, neoadjuvant chemotherapy, and
concurrent chemotherapy. CONCLUSIONS: Many prospective, randomized studies
evaluating the use of chemical agents to modify the irradiation response in
patients with carcinoma of the uterine cervix indicate no improvement over
radiation therapy alone. However, the February 1999 NCI clinical announcement
describes a survival advantage for cisplatin-based therapy and concurrent
irradiation.
PMID- 10758566
TI - Concurrent Chemoradiation for Cervical Cancer.
PMID- 10758567
TI - Adenocarcinoma of the Endometrium: An Institutional Review.
AB - BACKGROUND: Many oncologists regard endometrial cancer as a relatively benign and
easily treatable gynecologic tumor. Inadequate care can result in poor outcomes.
METHODS: The authors review the epidemiology and pathology of the disease, and
they compare disease characteristics and outcomes of FIGO staging with their own
11-year experience at a tertiary referral center. RESULTS: Patients referred to
tertiary referral centers tend to present with more advanced stages of disease
than those reported by FIGO, although the profile of histologic types is similar.
CONCLUSIONS: Prevention and early detection of endometrial cancer can minimize
the impact of this disease. Complete staging and tumor removal including
extrafascial hysterectomy with bilateral salpingo-oophorectomy, pelvic
lymphadenectomy, and selective paraaortic lymphadenectomy are the cornerstones of
surgical therapy.
PMID- 10758568
TI - Chemotherapy for Advanced Gastric Cancer: Focus on New Agents and Combinations.
AB - BACKGROUND: Although many treatments for advanced gastric cancer have been
developed, systemic therapy remains elusive. METHODS: The author reviewed data on
recent phase II and III trials of the main new agents and combinations. RESULTS:
Chemotherapy appears to improve survival of patients with advanced disease,
albeit slightly. New drugs that might improve response rates and survival include
the taxanes. CONCLUSIONS: New combinations, including the taxanes, must be
designed and evaluated to further improve the outcome for patients with advanced
gastric cancer.
PMID- 10758569
TI - Pulmonary Opacities in a Patient with Essential Thrombocytopenia.
PMID- 10758570
TI - Reasoning by Identifying Goals of Treatment.
PMID- 10758572
TI - Controlling Chemotherapy-Induced and Postoperative Nausea and Vomiting.
PMID- 10758571
TI - Tumor Markers of Radiation Sensitivity.
PMID- 10758573
TI - Malignant Melanoma: Staging and Treatment of Localized and Advanced Disease.
PMID- 10758574
TI - Pharmacologic Treatment of Cancer: New Developments.
PMID- 10758575
TI - Signal Transducers and Activators of Transcription: Novel Targets for Anticancer
Therapeutics.
AB - BACKGROUND: Through specific activation of gene expression, the family of
proteins known as signal transducers and activators of transcription (STATs)
converts extracellular stimuli into diverse biological responses. Beyond the
normal signaling functions of STATs, recent evidence indicates that aberrant
activation of STATs contributes to neoplastic transformation. METHODS: Current
literature pertaining to the role of STAT proteins in oncogenesis is presented.
Also, the rationale for developing novel approaches to disrupt STAT signaling is
discussed, and the potential of STATs as anticancer targets in treating human
cancer is reviewed. RESULTS: The discovery that certain oncoproteins
constitutively activate specific STATs, coupled with observations that elevated
STAT activity occurs frequently in a spectrum of human tumors, establishes a
direct link between STAT activation and neoplastic transformation. Significantly,
abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo
systems. These results make STATs attractive targets for rational design of small
molecule inhibitors and gene therapy approaches to disrupt STAT signaling.
CONCLUSIONS: As a result of genetic, biochemical, and crystallographic analyses,
the functional domains of STAT proteins have been well characterized. Based on
these data, selective inhibitors of STAT function can be designed. Because
disrupting STAT signaling has proven effective in blocking neoplastic
transformation, it is proposed that STAT proteins represent promising targets for
development of novel molecular therapeutics to treat human cancer.
PMID- 10758576
TI - Angiogenesis and Cancer Control: From Concept to Therapeutic Trial.
AB - BACKGROUND: There is extraordinary interest in developing angiosuppressive agents
for cancer treatment. Several new agents appear promising for the treatment of a
variety of human cancers. Current concepts and new agents in clinical trials are
the focus of this article. In particular, the introduction of a new treatment for
human brain tumors is presented in detail, using an antiangiogenic agent,
penicillamine, and depletion of an obligatory cofactor of angiogenesis, copper.
METHODS: The explosive increase in literature on antiangiogenesis is reviewed
using computerized search, findings presented at the recent national cancer and
angiogenesis meetings. A specific protocol, NABTT 97-04, "Penicillamine and
Copper Reduction for Newly Diagnosed Glioblastoma," is presented as an example of
angiotherapeutic drug discovery. RESULTS: A number of promising molecular
approaches are being introduced to suppress tumor angiogenesis. Major categories
of angiogenesis antagonists include protease inhibitors, direct inhibitors of
endothelial cell proliferation and migration, suppression of angiogenic growth
factors, inhibition of endothelial-specific integrin/ survival signaling,
chelators of copper, and inhibitors with specific other mechanisms. The
preliminary results of early trials offer a glimpse into how antiangiogenesis
therapy will be integrated into future care of the patient with cancer.
CONCLUSIONS: Thirty-five antiangiogenesis therapies are currently being evaluated
in clinical trials. As we learn more about the fundamental mechanisms of
angiogenesis, eg, the role of copper in growth factor activation, effective
methods of cancer control will be implemented.
PMID- 10758577
TI - Review of Three New Agents That Target Angiogenesis, Matrix Metalloproteinases,
and Cyclin-Dependent Kinases.
AB - BACKGROUND: Many potential new antineoplastic agents are currently in various
stages of clinical development. Three areas of drug development include
antiangiogenic compounds, agents that inhibit matrix metalloproteinases, and
agents that modulate cyclin-dependent kinases. METHODS: The authors reviewed the
available data for endostatin, COL-3, and flavopiridol, each of which is being
developed with one of the above-mentioned proposed mechanisms of action. These
agents are among the first drugs to reach clinical testing that is focusing on
these novel targets. RESULTS: Endostatin has finished preclinical testing and the
first human trials are about to be initiated. COL-3 is in phase I testing in
several locations. Phase I studies for flavopiridol have been completed and
several phase II studies are underway. It is unknown at this point if any of
these agents will provide clinical benefit to patients at doses that do not cause
unacceptable toxicity. CONCLUSIONS: These agents are currently at various stages
of clinical testing. Albeit promising as potential modulators in molecular and
biochemical pathways, continued research is needed into the toxicities and
clinical usefulness of these agents.
PMID- 10758578
TI - Pharmacology of Chemotherapy in the Older Cancer Patient.
AB - BACKGROUND: The incidence of cancer among the elderly population is increasing.
The aging process can deplete functional reserve of many organ systems and thus
affects the treatment goals for this age-group. METHODS: The pharmacologic
consequences of the aging process on elderly cancer patients are reviewed, and
guidelines are suggested for assessing and treating this patient population with
antitumor drugs. RESULTS: Individualized management of the older cancer patient
reflects the results of a comprehensive geriatric assessment. Factors that affect
treatment decisions include estimates of the extent of treatment toxicity, the
impact of treatment on quality of life, estimates of life expectancy, and the
influence of age on pharmacokinetic parameters. CONCLUSIONS: Management of older
patients with cancer includes individual assessments that consider the effects of
aging on the pharmacodynamics, therapies, and complications of treatment for this
population. Treatment can be made safer and more effective by adjusting
chemotherapy dosage, maintaining hemoglobin levels, and using hemopoietic growth
factors when appropriate.
PMID- 10758579
TI - Evaluation of Palliative Endpoints in Oncology Clinical Trials.
AB - BACKGROUND: In recent years, there has been a growing recognition that
improvements in quality of life may be as important as improvements in quantity
of life in patients with advanced cancer. With this goal in mind, many oncology
trials now seek to evaluate palliative endpoints as well as disease progression
and survival. METHODS: Methodologic advances and challenges in evaluating
palliative endpoints in oncology clinical trials are reviewed. RESULTS: Valid and
reliable self-report measures have been developed that permit evaluation of
palliative endpoints. Issues to consider in conducting research on palliative
endpoints include the selection of appropriate outcome measures, the number and
timing of outcome assessments, and the handling of missing data. CONCLUSIONS: The
inclusion of palliative endpoints into clinical trials in oncology has the
potential to advance clinical care by identifying chemotherapeutic agents that
are effective in improving the quality of life of patients with advanced cancer.
PMID- 10758580
TI - Thalidomide in Oncology: The Peril and the Promise.
PMID- 10758581
TI - Nucleic Acid Amplification Testing: The New Infectious Disease Testing Method for
Donor Blood.
PMID- 10758582
TI - [Where is the bur?].
PMID- 10758583
TI - [New data on the diagnosis and treatment of urinary stress incontinence in
women].
PMID- 10758584
TI - [Endoscopic para-aortic dissection by the extraperitoneal approach: clinical
study of 37 patients].
AB - OBJECTIVE: To give the preliminary results of a series of 37 operations for a
para-aortic endoscopic curage by the extraperitoneal passage. MATERIAL AND
METHODS: Thirty-seven patients, with an average age of 45.8 +/- 12 years, were
operated on for cervical cancer, with an average tumor diameter of 4.9 +/- 1 cm.
The indications were: the tumor's diameter > or = 4 cm (N = 24), one FIGO stage >
or = IIb distal (N = 10), N+ pelvic (N = 3). The irradiation was pelvic (if N-)
or abdominopelvic (if N+). RESULTS: The operation lasted 125.3 +/- 36.8 min, and
the average number of ganglions removed was 21.2 +/- 10.2. The upper limit of the
curage was submesenteric for nine patients and subrenal for 28. The immediate
postoperatory complications were: a retroperitoneal hematoma, an acute intestinal
occlusion treated by laparotomy, and a ureteral wound on a fixed ganglion,
treated by an endoprosthesis. The number of N+ was ten in all, of which three
were macroscopic: 0/1 for stage Ib1; 2/12 (16.7%) for Ib2; 4/14 (28.6%) for IIb
proximal; 4/10 (40%) for IIb distal or more. There were 6/26 (23.1%) N+
microscopic cases for subrenal curages, versus 1/8 (12.5%) for submesenteric.
(Excluding 3 N+ microscopic cases). All were given postoperatory radiotherapy
except for one, who had a widened hysterectomy (N-). After an average follow-up
of 9.5 +/- 5.9 months, there were two pelvic recurrences and six at a distance
(of which four died). We had a lymphocele superinfection at six weeks on the
diverticular sigmoiditis. There was an enteritis in a patient who had an
abdominal irradiation after a laparotomy for acute occlusion. CONCLUSION: Out of
36 patients having postoperatory radiotherapy, para-aortic extraperitoneal curage
diagnosed seven N+ microscopic cases, allowing 26 uniquely pelvic irradiations.
PMID- 10758585
TI - [Coasting: a response to excessive ovarian stimulation].
AB - The ovarian hyperstimulation treatment increases results of in vitro
fertilization. However, the risk of ovarian hyperstimulation syndrome must be
carefully evaluated for each patient. An excessive response increases
complication and cancellation rates. Coasting could be applied when an excessive
response occurred. This method requires stopping gonadotropin administration
while GnRH agonist is continued. When the estradiol rate decreases, the hCG
administration is allowed. In the literature, results shows adequate pregnancy
rates, between 26 and 64%. It seems oocyte quality was not spoiled. However,
coasting does not eliminate definitively the risk of ovarian hyperstimulation
syndrome. Coasting method could be a safe and efficient method to treat an
excessive ovarian response during in vitro fertilization protocol. Pregnancy
rates seem to be preserved.
PMID- 10758586
TI - [Reproducibility of cytologic diagnosis: study of CRISAP Ile-de-France].
AB - The cervical Pap smear is the method of choice for early detection of
precancerous cervical lesions. However, the sensitivity of the Pap smear is not
perfect, nor is the specificity, in particular for minor atypia; quality control
is the best method to improve the efficiency of the test. The "Centre de
regroupement informatique et statistique des donnees en anatomie pathologique"
(CRISAP) Ile-de-France has initiated an external quality control with a protocol
aimed at assessing diagnosis reproducibility among observers. Thirteen
pathologists agreed to participate on a voluntary basis fur this protocol, which
consisted of the rereading of 650 slides chosen at random. Each participant
reread 50 cases and sent 50 cases to be reread anonymously. The diagnosis was
given according to the Bethesda classification. The reproducibility was assessed
using the percentage of agreement and kappa statistics. The percentage of
agreement for the whole group was 65% and the weighted kappa 0.66. When normal
and unsatisfactory cases were combined as negative and atypical squamous cells of
undetermined significance (ASCUS), low-grade squamous intraepithelial lesion
(LGSIL) and high-grade squamous intraepithelial lesion (HGSIL) as positive, the
percentage of agreement was 83% and Kappa 0.66. When normal, unsatisfactory and
ASCUS were combined as negative and LGSIL and HGSIL as positive, the percentage
agreement raised to 90% and kappa to 0.76. This attempt at assessing the
reproducibility of cytologic diagnosis using an informal method had led to good
participation among participants. A fairly good agreement for overall cytologic
diagnosis was found, though some variability remained concerning the diagnosis of
unsatisfactory and those labelled as ASCUS. These results should lead the
participants to reflect upon and eventually reassess their criteria on these
specific cases.
PMID- 10758587
TI - [Secondary cytoreductions in the treatment of ovarian cancers].
AB - The aim of this study was to investigate the potential benefit of secondary
cytoreductive surgery for recurrent ovarian cancer. METHODS: Between 1980 and
1993, 85 patients (11 stage Ic, 4 stage IIc, 70 stage III) with an epithelial
ovarian cancer were treated after initial surgery with an intraperitoneal and
intravenous Cis Platin-based immunochemotherapy. Twenty patients of the 41 who
relapsed underwent secondary cytoreductive surgery. RESULTS: Complete resection
was achieved in 13 patients (65%) and was optimal with a < 0.5 cm residual
disease left in one case. One patient died postoperatively. Surgery was
suboptimal for six patients (30%). At a mean follow-up from recurrence of more
than 54 months for the surviving patients, five of the 20 reoperated are still
alive. All 21 patients who were not reoperated died with a median survival time
from recurrence of eight months (10.5 months for the patients who refused to be
reoperated and seven months for the patients rejected by the surgeons) against 29
for the 20 reoperated patients (P < 0.004). CONCLUSION: This series is too small
to enable us to draw definitive conclusions. Nevertheless, our results seem to
suggest the interest of secondary cytoreductive surgery. Indeed, only reoperated
patients, above all if surgery was complete or at least optimal, have a chance of
long survival. In our opinion, secondary surgical procedure should be proposed to
relapsing patients to enhance efficacy of rescue chemotherapy, which is of
limited value in bulky tumors.
PMID- 10758588
TI - [Multiple voluntary abortions].
AB - Repetitive abortions reveal an ambivalence towards contraception. The desire for
pregnancy does not always go along with a desire for motherhood. It is a neurotic
expression full of guilt that shows that these women did not overcome a childish
rivality with their mothers, and remain within a symbiotic relationship with
them.
PMID- 10758589
TI - [Hemorrhage during delivery].
PMID- 10758590
TI - [Screening for fetal chromosomal anomalies--recent aspects].
PMID- 10758591
TI - [International consensus on combined oral estrogen-progestagen contraception and
cardiovascular diseases].
PMID- 10758592
TI - [Ovulation induction +/- intra-uterine insemination].
PMID- 10758593
TI - [Should insemination and ovarian stimulation always be associated in
infertilities with permeable tubes?].
PMID- 10758594
TI - [Multiple genetic typing (vitamin D receptors and estrogens) in the assessment of
the risk of fractures].
AB - BACKGROUND: Several studies suggested that some vitamin D receptor (VDR) and
estrogen receptor (ER) polymorphisms influence bone mass. However, others did not
confirm these results. This study was undertaken to determine if the genotypes
revealed by the combined analysis of VDR and ER polymorphisms are associated with
clinically significant differences in peak bone mass and the risk of osteoporotic
fractures. PATIENTS AND METHODS: Restriction fragment length polymorphisms of VDR
were determined with the enzymes Bsml, Apal, Taql, and Fokl. Enzymes Xbal and
Pvull were used as polymorphic markers of the ER. The study group comprised 149
young control women (18-34 years), 66 postmenopausal controls, 99 women with hip
fracture and 76 women with osteoporotic vertebral fractures. Bone mineral density
(BMD) was measured by DEXA. RESULTS: We did not find significant differences in
lumbar spine or hip BMD among young women with different genotypes (determined
with either single or multiple polymorphic markers). Likewise, there were no
differences in the frequency distributions of VDR or ER alleles between control
and fractured women. The study had a 77% power to detect a fracture odds ratio of
2 in case of genotypes present in at least 15% of the population. CONCLUSIONS:
These results suggest that the polymorphic markers used in this study do not have
enough discriminant power to be clinically useful in the assessment of fracture
risk.
PMID- 10758595
TI - [Prevalence of tuberculosis infection in Maghrebian immigrants].
AB - BACKGROUND: Maghrebian immigrants are a high-risk group for tuberculosis. The
special features of this group (non-familial grouping [nFG], communication
difficulties, illegal status) may have a negative influence on tuberculosis.
SUBJECTS AND METHODS: A descriptive crossover study. Maghrebian immigrants older
than 14 years attended at Centro de Salud Collado-Villalba, Madrid, Spain (n =
520). SELECTION: a random, proportional, age and sex-stratified sample (n = 142).
Individuals completed a questionnaire in arabic and were subjected to
tuberculosis screening tests till they were assigned one of the definitive
diagnostic classes of the American Thoracic Society. Data are shown for three cut
points of Mantoux: 5, 10 and 15 mm. The univariate and multivariate analysis were
based on logistic regression. RESULTS: 80 individuals were tested. Sex ratio 4:1.
The prevalence of tuberculosis infection was: Mantoux > or = 5 mm = 76.3%,
Mantoux > or = 10 mm = 72.5%, Mantoux > or = 15 mm = 66.3%. Three tuberculosis
cases were diagnosed (annual incidence 1.9%). Whatever the cut point considered
for Mantoux: masculine sex, age, nFG, years as immigrant living in nFG and,
amongst married people, living without their partners in Spain, were identified
as risk factors. The number of years as immigrant living in a familiar grouping
and the number of family members per house were identified as protective factors.
In the sex-adjusted multivariate analysis, age and living in nFG were associated
to a higher incidence of infection, whereas the number of people per house was a
protective factor. CONCLUSIONS: The prevalence of tuberculosis infection in
Maghrebian immigrants residents in Spain is very high. The particular living
conditions of this group may have a negative influence.
PMID- 10758596
TI - [Factors related to functional outcomes and quality of life after knee
arthroplasty].
AB - BACKGROUND: The aim of this work was to describe the early evolution of
functional capacity and health related quality of life (HRQL) in patients in
rehabilitation after knee arthroplasty, and to identify predictive factors of
better outcomes. PATIENTS AND METHODS: Prospective cohort of 141 patients with
knee arthroplasty which immediately after the intervention were referred to the
rehabilitation unit. The functional capacity (Knee Society Score, KSS) and the
HRQL (Medical Outcomes Study Survey Form 36, MOS SF36) were administrated in the
first visit and at 3 months of follow-up. Changes between the interval and
factors associated to better outcomes were analysed with nonparametric test and
multivariate analyses. RESULTS: Patients with knee arthroplasty experienced an
important improvement in the KSS score and in 6 dimensions of the MOS-SF36
(except emotional role and general health). Worst functional status and quality
of life at the time of starting rehabilitation, rheumatoid arthritis diagnosis
and gender (women) were associated with worse prognosis. Age, comorbidity, study
level, work situation, social help, live alone and ambulatory treatment were not
associated with outcomes. CONCLUSIONS: Patients in rehabilitation after knee
arthroplasty improve their functional status and quality of life. The
identification of factors with worst prognosis could be useful to modify
treatments in some patient's groups.
PMID- 10758597
TI - [HIV infection and cervical cancer: a note of caution for clinicians and health
planners].
AB - BACKGROUND: To estimate the association between HIV infection and cervical
intraepithelial neoplasia (CIN). PATIENTS AND METHODS: Cross-sectional study
based on data from 251 women from a Sexually Transmitted Diseases clinic.
Patients with CIN were compared with those without CIN in terms of HIV infection
and exposure to other risk factors, calculating the corresponding adjusted odds
ratio (ORA) by logistic regression. RESULTS: HIV infection (ORA = 7.5; CI 95%:
2.5-22.1), having previous cytologies with cellular changes associated with human
papillomavirus infection (ORA = 3.6; CI 95%: 1.3-10.2) and history of condylomas
(ORA = 3.2; CI 95%: 1.2-8.4) were associated with CIN. CONCLUSIONS: The strong
association observed between HIV and CIN, shows that it is necessary for health
services planners and clinicians caring for HIV infected women to ensure that the
latter receive the appropriate care to guarantee its early detection.
PMID- 10758598
TI - [Tuberculosis and immigration].
PMID- 10758599
TI - [Nosocomial infections due to opportunistic fungi: analysis of a news outbreak in
the Spanish press].
AB - BACKGROUND: To study an outbreak of media news related to nosocomial infections
due to opportunistic fungi in Spanish hospitals. METHOD: CASE DEFINITION: any
news related to possible nosocomial infection due to opportunistic fungi in
Spanish hospitals, published in national or local daily newspapers, over the pre
epidemic (July-December, 1998) and epidemic periods (January-June, 1999). All
news were reviewed and identified using global press reports summaries, prepared
by two independent sources, and were analyzed by three different observers.
RESULTS: Over the pre-epidemic period there were not any news related to
nosocomial infections due to opportunistic fungi. Over the epidemic period, a
total of 218 news were identified, 154 (71%) published in national newspapers and
64 (29%) in local ones. We analyzed separately 18 editorials or opinion articles
related to this subject. The epidemic curve (distribution of news by week) showed
an incidence news peak at week 5 (102 news, 46.7% of all news published). The
media mentioned up to 19 different hospitals as institutions with possible cases
of nosocomial fungal infections. After week 8, news incidence drop, and remain
thereafter at minimum levels. CONCLUSIONS: The example provided by the analysis
of this outbreak of media news, related to nosocomial infections by Aspergillus
an other opportunistic fungi, is useful to allow us understand how some medical
news arise, develop and were transmitted. The public alert situation created in
Spain was remarkable, and it is likely that there was a transient loss of
confidence in the safety of public health institutions. Today's medicine requires
a great and better openness to the media, and a better cooperation between both
parts.
PMID- 10758600
TI - [Parenteral combined vaccines in the planning of systematic vaccination].
PMID- 10758601
TI - [Long lasting arterial hypertension in a 71 year-old man with sarcoidosis].
PMID- 10758602
TI - [Torsades de pointes induced by cocaine].
PMID- 10758603
TI - [Xanthogranulomatous cholecystitis: preoperative diagnosis by fine-needle
aspiration].
PMID- 10758604
TI - [Acute cocaine intoxication in a body-stuffer].
PMID- 10758605
TI - Differentiated thyroid cancer and pregnancy.
PMID- 10758606
TI - Reporter gene imaging: effects of ganciclovir treatment on nucleoside uptake,
hypoxia and perfusion in a murine gene therapy tumour model that expresses herpes
simplex type-1 thymidine kinase.
AB - Perfusion, hypoxia and nucleoside uptake during ganciclovir therapy were
determined in a murine HSV-1 TK-expressing tumour model (KBALB-STK). HSV-1 TK
mRNA transcription in this cell line was confirmed by RT-PCR. BALB/c mice bearing
KBALB-STK tumours accumulated (E)-5-(2-[125I]iodovinyl)-2'-fluoro-2'-deoxyuridine
([125I]IVFRU) (2.54% injected dose.g-1) and could be readily detected with planar
imaging following administration of [131I]IVFRU. However, a single dose of
ganciclovir (100 mg.kg-1 intraperitoneally) decreased tumour uptake of
[125I]IVFRU to 0.33% injected dose.g-1. Subsequent single daily doses of
ganciclovir over 3 consecutive days had a negligible effect on [125I]IVFRU
uptake, which remained low. Tumour perfusion during 3 days of ganciclovir
treatment was monitored with intravenous [99Tcm]HMPAO. Tumour perfusion increased
from day 0 (no ganciclovir treatment) with 1.83% injected dose.g-1 tumour, to a
maximum at day 2 (3.77% injected dose.g-1). In the same animals, accumulation of
[3H]misonidazole decreased from 0.70% injected dose.g-1 at day 0 to a minimum at
day 3 (0.24% injected dose.g-1), indicating that tumour tissue had become less
hypoxic over the ganciclovir regimen. The uptake of [125I]IVFRU into the acid
insoluble fraction of KBALB-STK cells in vitro in the presence of ganciclovir
(2.0 microM) was completely inhibited, leading to a 57% decrease in total
cellular accumulation of radioactivity. However, cytosolic entrapment of
[125I]IVFRU was not affected by the presence of ganciclovir. These results
indicate that the mechanisms leading to IVFRU exclusion during ganciclovir
treatment of HSV-1 TK-expressing tumours can be attributed, at least partially,
to inhibition of [125I]IVFRU-nucleotide incorporation into DNA.
PMID- 10758607
TI - Impairment of cerebrovascular reactivity to acetazolamide in patients with normal
pressure hydrocephalus.
AB - Cerebrovascular reactivity (CVR) to acetazolamide was investigated in 41 patients
with normal pressure hydrocephalus (NPH). The aetiology was subarachnoid
haemorrhage in 20 patients, trauma in nine, brain tumour in three and idiopathic
in nine. Mean cerebral blood flow (CBF) of the whole brain was measured by
performing first-pass radionuclide angiography using 99Tcm-hexamethylpropylene++
amine oxime. Cerebrovascular reactivity was measured as the percentage change
from the baseline mean CBF value after the administration of 500 mg of
acetazolamide. Cerebrovascular reactivity was significantly (P < 0.001) reduced
in patients with the complete triad of NPH (1.4 +/- 3.1%), regardless of the
aetiology, compared with normal controls (14.7 +/- 3.3%). Patients with the
incomplete triad also showed significantly (P < 0.05) reduced CVR (9.6 +/- 5.4%).
Patients with the complete triad had significantly (P < 0.001) lower CVR than
those with the incomplete triad. Post-operative CVR in both groups (20 patients
with the complete triad and 9 patients with the incomplete triad) increased
significantly, from 1.5 +/- 3.5% to 10.0 +/- 5.5% (P < 0.001) and from 8.7 +/-
4.9% to 14.9 +/- 5.4% (P < 0.05), respectively. Cerebrovascular reactivity is
impaired in patients with NPH regardless of the aetiology and improves after
shunting.
PMID- 10758608
TI - Immediate thallium re-injection after stress imaging for the detection of
myocardial viability.
AB - Myocardial perfusion imaging with thallium is an established method to assess the
presence of ischaemic and viable myocardium. Using planar imaging, images
acquired 1 h after immediate thallium re-injection have been shown to be
comparable to those of 3 h redistribution. The aim of this study was to clarify
this using SPET. Twenty patients with chronic coronary artery disease with at
least two perfusion defects on post-exercise images participated in this study.
All patients received thallium re-injection after post-stress SPET and all had 1
h, 3 h and 24 h redistribution imaging. The thallium myocardial tomograms were
divided into 14 segments for each patient. A total of 78 segments were studied.
When the frequency of reversibility on 1 h, 3 h and 24 h redistribution images is
compared, of the 78 SPET defects 18 (23.1%) showed reversibility by 1 h, 34
(43.6%) by combined 1 h and 3 h imaging (P < 0.05) and 50 (64.1%) by combined 1
h, 3 h and 24 h imaging (P < 0.05). Our results show that, compared to 3 h
images, images acquired 1 h after immediate thallium re-injection underestimate
the extent of viable myocardial segments and the incidence of late reversibility
was not reduced by the immediate re-injection of thallium.
PMID- 10758609
TI - Severity and extent of perfusion defects provoked by transient coronary occlusion
compared with myocardial damage observed after infarction.
AB - A peripheral perfusion tracer injection at the time of coronary occlusion during
percutaneous transluminal coronary angioplasty (PTCA) may delineate the
myocardial 'area at risk' related to a given artery. To evaluate the location,
size and severity of the corresponding scintigraphic defects, we conducted a
prospective study of 36 patients who received a 99Tcm-sestamibi injection during
single-vessel coronary angioplasty (PTCA = 18 LAD, 16 RCA and 2 LCX) followed by
SPET. For comparison, a reference group of 36 successive patients examined during
the early phase of myocardial infarction (MI), matched for the same vascular
territories (18 anterior, 16 inferior and 2 lateral), were analysed in the same
way after standard stress/reinjection 201Tl SPET. The imaging characteristics of
both groups showed excellent agreement as well degree of uptake defects, in terms
of topography and extent. A defect index, taking into account both size and
severity, was in the same range for PTCA and MI patients (mean +/- standard
deviation): for LAD vs anterior = 28.4 +/- 13.5% (PTCA), 27.1 +/- 12.2% (MI
stress) and 24.2 +/- 10.0% (MI-reinjection); for RCA vs inferior = 15.5 +/- 10.2%
(PTCA), 14.7 +/- 9.7% (MI-stress) and 13.2 +/- 8.2% (MI-reinjection). Sectoral
correlations between PTCA and MI groups were also highly significant.
PMID- 10758611
TI - A comparison of 99Tcm-MDP and 99Tcm-MIBI in the detection of breast cancer.
AB - In this study, we made an intra-individual comparison of the uptake of 99Tcm-MDP
and 99Tcm-MIBI in breast cancer. Twenty women with large breast masses (one
dimension > or = 3 cm on mammography) underwent SPET in the supine position with
both agents. All transverse sections demonstrating tumour activity were added
together and the net (total) tumour uptake in a region of interest was compared
to that of surrounding tissue activity (background). We also evaluated maximum
tumour uptake versus background activity. Tumour uptake was observed in all
examinations. In contrast to MIBI, eight MDP examinations showed increased uptake
in normal breast parenchyma in addition to tumour uptake. There was no
significant difference in net tumour uptake between the two tracers and non
parenchymal (indifferent) background activity, but the maximum tumour activity of
MIBI was significantly higher than that of MDP. In the eight MDP examinations
with parenchymal activity, mammograms were required to identify tumour uptake
correctly. In conclusion, MDP may provide similar images to MIBI in
postmenopausal women not receiving hormone replacement therapy. For other
patients, MIBI gives better tumour depiction.
PMID- 10758610
TI - 99Tcm-HMPAO leucocyte labelling in orofacial granulomatosis and gastrointestinal
Crohn's disease in childhood and early adulthood.
AB - Orofacial granulomatosis is a granulomatous inflammatory disorder, affecting the
soft tissues of the face and mouth. The predominant feature is disfiguring lip
swelling. Patients with this condition may be exhibiting a Type IV
hypersensitivity reaction to dietary or environmental allergens, or these may be
the orofacial manifestations of underlying gastrointestinal Crohn's disease. The
results of 99Tcm-HMPAO leucocyte labelling of the gastrointestinal tract in 14
patients with orofacial granulomatosis and 15 patients with known
gastrointestinal Crohn's disease are presented, indicating that this is a useful
and non-invasive screening test for the identification of gastrointestinal
Crohn's disease in paediatric and young adult patients presenting with orofacial
granulomatosis.
PMID- 10758612
TI - The role of 67Ga in the early detection of spinal epidural abscesses.
AB - In this study, we evaluated the role of 67Ga whole-body and single photon
emission tomographic (SPET) imaging in the early diagnosis and lesion
localization of spinal epidural abscess before confirmation by gadolinium
enhanced magnetic resonance imaging (MRI). Six patients with fever of unknown
origin had a 67Ga whole-body scan, four of whom also underwent SPET imaging. For
further confirmation of a spinal epidural abscess, gadolinium-enhanced MRI was
performed in all patients. All patients had increased 67Ga uptake in a spinal or
paraspinal area on the whole-body scan. They were later confirmed to have a
spinal epidural abscess after gadolinium-enhanced MRI. Of these six patients,
five underwent surgical drainage plus parenterally administered antibiotics, and
had complete or partial recovery. One died before operation due to sepsis. In
conclusion, we suggest performing a 67Ga whole-body survey as early as possible
in patients with fever of unknown origin, fever and back pain and/or the spinal
syndrome, before MRI is performed. If a spinal epidural abscess is strongly
suspected, SPET is needed for further confirmation of spinal versus non-spinal
and contiguous versus non-contiguous lesion(s). If MRI is unavailable, then 67Ga
scintigraphy is a satisfactory method for investigating spinal epidural
abscesses.
PMID- 10758613
TI - 99Tcm-MAA lung scintigraphy in patients with Behcet's disease: its value and
correlation with clinical course and other diagnostic modalities.
AB - Behcet's disease, initially described as local vasculitis involving the oral,
genital mucosa and eyes, can affect many organ systems with a varying clinical
course. Pulmonary lesions associated with Behcet's disease are rare and reported
to have a prevalence of 1.0-7.7%. In this prospective study, 29 patients aged 16
60 years (mean +/- s: 34 +/- 10.5) were investigated for pulmonary involvement
with direct radiography, computerized tomography (CT) and intravenous digital
subtraction angiography. Lung scintigraphy was also performed to determine its
diagnostic value. In addition, patients had a fibreoptic bronchoscopic
examination, spirometric test, carbon monoxide diffusion test and methacholine
test. Of the 29 patients with Behcet's disease, 17 had pulmonary involvement. The
diagnostic criteria for pulmonary vasculitis and tracheobronchial tree
involvement were: (1) hilar vascular prominence or mass, new alveolar and
reticulonodular infiltrates on chest X-ray; (2) aphthous lesions, bleeding
ulcerations, inflamed mucosal appearance on bronchoscopy; (3) vascular thrombosis
or aneurysms on CT; (4) occlusion or aneurysms of the main pulmonary arteries or
its branches. The value of lung scintigraphy and its correlation with other
imaging modalities were investigated to determine if a lung perfusion scan alone
can be used to detect pulmonary involvement in Behcet's disease. Twenty-six
patients were investigated with lung scintigraphy. Thirteen of 14 patients with
lung involvement were identified. Perfusion lung scintigraphy provided true
diagnostic information in 96% of our patients. In eight patients without
pulmonary involvement, the lung scans were normal. Although DSA specifically
demonstrates pulmonary aneurysms, it involves administration of contrast media
and cannot show abnormalities distal to the third pulmonary arterial branches.
Although vasculitis caused by collagen disorders is physiologically
indistinguishable from pulmonary emboli, most perfusion defects resolve within 3
months, which can be used as a differential diagnostic criterion in the
appropriate clinical setting. Therefore, pulmonary perfusion imaging can be used
to screen patients suspected of having lung involvement, especially in the
absence of thrombophlebitis. In patients with thrombophlebitis, a repeat
examination at 3 months is recommended to differentiate pulmonary involvement
from pulmonary embolism.
PMID- 10758614
TI - Bone-scan-like pattern with 99Tcm(V)-DMSA scintigraphy in patients with
osteomalacia and primary hyperparathyroidism.
AB - The aim of this study was to assess the role of 99Tcm(V)-dimercaptosuccinic acid
(99Tcm(V)-DMSA) scintigraphy in the evaluation of patients with metabolic bone
disease. The study group comprised eight women aged 17-72 years, six with
osteomalacia and two with primary hyperparathyroidism. Six patients were imaged
scintigraphically before their treatments were started, whereas the other two
underwent treatment during the time of examination. All six patients who had not
previously been treated had prominent skeletal 99Tcm(V)-DMSA uptake, revealing a
bone-scan-like pattern. In the two patients receiving medical therapy, their
99Tcm(V)-DMSA scans revealed a normal physiological distribution. Many of the
fracture and pseudofracture sites detected on bone scans were also discerned with
99Tcm(V)-DMSA scintigraphy. Our results suggest that 99Tcm(V)-DMSA scintigraphy
might have the potential as a screening method in patients with metabolic bone
disease.
PMID- 10758615
TI - Total plasma clearance of 51Cr-EDTA: variation with age and sex in normal adults.
AB - Although inulin clearance measured during constant infusion is still considered
the reference method, single-injection of 51Cr-EDTA with subsequent plasma
sampling has become the most popular technique for the routine assessment of
glomerular filtration rate. Despite the fact that the technique has been in use
for 30 years, there are only a few reports of normal values calculated directly
from 51Cr-EDTA data and normal ranges have generally been produced by conversions
of inulin data. The aim of this study was to measure the variation in total
plasma clearance, calculated directly from 51Cr-EDTA measurements, in normal
males and females, of Saudi Arabian origin, over a wide range. Altogether, 201
potential kidney donors aged 16-60 years were studied. No statistically
significant association of total plasma clearance with age or sex could be
demonstrated; however, predictive equations suggesting a small decline in total
plasma clearance with age were developed. The figures presented suggest that the
reduction in total plasma clearance of 51Cr-EDTA with age is relatively shallow
up to the age of at least 60 years and that normal ranges produced by conversion
of inulin data may overestimate the decline with age.
PMID- 10758616
TI - Plasma clearance of 99Tcm-MAG3: accuracy of five single-sample methods.
AB - The aim of this study was to compare the accuracy of five single-injection,
single-sample methods for the assessment of plasma clearance of 99Tcm-MAG3 in
adults. In 51 patients, a reference plasma clearance was determined on the basis
of 16 blood samples. It ranged from 13 to 313 ml.min-1. In patients with a plasma
clearance less than 75 ml.min-1, there was a large difference between the
clearance obtained by a single-sample method and the reference method. Thus
single-sample methods should not be used with these patients. In patients with a
plasma clearance higher than 75 ml.min-1, the relative difference was (mean +/-
s): 6.07 +/- 9.96% (Russell et al., 1989), 14.22 +/- 8.08% (Muller-Suur et al.,
1991), 7.29 +/- 6.21% (Bubeck et al., 1992), 6.64 +/- 7.71% (Russell et al.,
1996) and 17.39 +/- 7.39% (Piera et al., 1997). Reference clearance was
overestimated by all five single-sample methods, especially by the methods of
Muller-Suur et al. and Piera et al. The smallest standard deviation was obtained
using the method of Bubeck et al. This method is recommended for use in patients
with a plasma clearance greater than 75 ml.min-1.
PMID- 10758617
TI - An alternative to the reference method for testing the radiochemical purity of
99Tcm-tetrofosmin.
AB - The recommended method for controlling the radiochemical purity (RCP) of 99Tcm
labelled tetrofosmin is thin-layer chromatography (TLC) with silica gel as the
stationary phase and acetone:dichloromethane (35:65, v/v) as the mobile phase.
However, this test is time-consuming and uses a toxic substance. We propose an
alternative method to control RCP, based on a solid-phase extraction method (SPE)
using a Sep Pak C18 cartridge. We used both methods to analyse 35 samples and to
determine the percentages of colloid, radiopharmaceutical and free 99Tcm
pertechnetate. Normal labelling processes were modified to obtain a wide range of
values. The range of RCP values obtained was 63.4-96.5% (median = 93.8%) by the
standard TLC method and 70.1-96.4% (median = 94.1%) by the SPE method. A
significant difference was observed only for the percentage of free 99Tcm
pertechnetate (P < 0.05). The agreement between the two methods, using 90% RCP as
the limit, gave a kappa index = +1 (P < 0.001), indicating total agreement
between them. The proposed method is useful to control RCP because it yields
results that are in good agreement with those of the standard method, and because
it is safer and less time-consuming.
PMID- 10758618
TI - Stump the professor.
PMID- 10758619
TI - Estimating fetal weight in the management of macrosomia.
AB - The purpose of this review is to examine the evidence that, including estimates
of fetal macrosomia in patient care, will decrease adverse perinatal outcomes. A
literature search for the years 1980 to 1999 was used. Shoulder dystocia and
brachial plexus injuries occur more often in macrosomic than in non-macrosomic
neonates. However, 26 to 58 percent of shoulder dystocias and 24 to 44 percent of
brachial plexus injuries occur to babies weighing less than 4000 gm. Persistence
of impairment is extremely rare. Neither historical nor clinical factors have
strong positive predictive values for macrosomia. From 15 to 81 percent of the
babies predicted to be macrosomic are confirmed by birth weight. Of babies
determined to be macrosomic at birth, only 50 to 100 percent were successfully
predicted. Shoulder dystocia and brachial plexus injuries are unpredictable
events. Available evidence suggests that planned interventions based on estimates
of fetal weight do not reduce the incidence of shoulder dystocia and do not
decrease adverse outcomes attributable to fetal macrosomia.
PMID- 10758620
TI - Sonographic methods to detect fetal anemia in red blood cell alloimmunization.
AB - Published reports, case studies, and articles from the English language regarding
ultrasonographic detection of fetal anemia in red blood cell alloimmunization
were obtained from a MEDLINE search from 1966 to November 1999 using the keywords
Rh disease, hemolytic disease of the newborn, ultrasound, and Doppler flow
studies and combinations thereof. All articles were cross-referenced. Ultrasound
techniques including early findings associated with immune hydrops fetalis,
multiple morphologic ultrasound markers, and Doppler flow studies that have been
used to detect fetal anemia are reviewed and critically evaluated. Noninvasive
sonographic techniques may reduce the number of invasive procedures that
traditionally are used to follow fetuses at risk for anemia and decrease the
associated risks from these procedures.
PMID- 10758621
TI - Orthostatic intolerance: a disorder of young women.
AB - Orthostatic intolerance (OI) is a cause of significant disability in otherwise
healthy women seen by gynecologists. Orthostatic tachycardia is often the most
obvious hemodynamic abnormality found in OI patients, but symptoms may include
dizziness, visual changes, discomfort in the head or neck, poor concentration,
fatigue, palpitations, tremulousness, anxiety, and, in some cases, fainting
(syncope). It is the most common disorder of blood pressure regulation after
essential hypertension, and patients with OI are traditionally women of
childbearing age. Estimates suggest that at least 500,000 Americans suffer from
some form of OI, and such patients comprise the largest group referred to centers
specialized in autonomic disorders. This article reviews recent advances made in
the understanding of this condition, potential pathophysiological mechanisms
contributing to orthostatic intolerance, and therapeutic alternatives currently
available for the management of these patients.
PMID- 10758622
TI - [Diagnostic imaging in cardiac diagnosis].
AB - PURPOSE: Cardiac imaging includes determination of the size and structure of the
cardiac chambers, valves, great vessels and the coronary arteries, chamber and
valvular function, myocardial perfusion, viability and metabolism. MATERIAL AND
METHODS: Chest roentgenography, angiography, echocardiography and nuclear imaging
are commonly used but computed tomography and magnetic resonance imaging also
offer a promising potential. RESULTS: Coronary angiography is the gold standard
in assessing coronary anatomy. Fast CT technologies such as electron-beam and
multi-low-CT are promising non-invasive imaging modalities in the assessment of
coronary artery disease. With intravascular ultrasound early stages of coronary
atherosclerosis can be detected. For the assessment of myocardial perfusion and
viability as well as cardiac function, scintigraphic methods are widely accepted.
However, MRI methods have also reached a high degree of accuracy. Evaluation of
chamber and valvular function is, due to its wide availability, the field of
echocardiography. CONCLUSIONS: In clinical routine chest roentgenography,
angiography, echocardiography and nuclear imaging are well established. The value
of computed tomography and magnetic resonance imaging in the evaluation of
coronary artery disease, myocardial perfusion, viability and metabolism is yet to
be defined.
PMID- 10758623
TI - [Cardiac imaging with rapid, retrospective ECG synchronized multilevel spiral
CT].
AB - PURPOSE: In this paper a method for cardiac imaging with fast multi-slice CT and
retrospectively ECG-gated spiral acquisition is presented. METHODS: A fast multi
slice CT system with 4 simultaneously acquired slices and 0.5 s rotation time is
used (Siemens Somatom VolumeZoom). Continuous spiral data of the entire heart
volume is acquired together with the patient's ECG and reconstructed with
dedicated spiral algorithms providing 250 ms temporal resolution. Three
dimensional image data sets are built up from overlapping slices that are
reconstructed in an arbitrary, user-defined phase of the heart cycle (e.g.
diastolic phase). To evaluate the capability of the method for functional imaging
complete three-dimensional image volumes are reconstructed from the same spiral
data set in different phases of the heart cycle. RESULTS: A spiral data set of
the entire heart volume may be acquired within a single breath-hold. Typical scan
times for standard examinations with 3 mm slice width are 10-15 s, and for high
resolution CT angiographies of the coronary arteries with 1.25 mm slice width
about 30-35 s. Motion-free reconstruction of the heart and coronary arteries with
high spatial resolution is possible in the diastolic phase of the heart cycle.
Multi-phase reconstructions from the same spiral scan data set are possible,
however, motion artifacts in heart phases with fast cardiac motion may not be
completely avoided. CONCLUSION: Fast multi-slice spiral CT with retrospectively
ECG-gated spiral reconstruction is well suited for three-dimensional and
functional imaging of the heart, especially for high-resolution imaging of
calcified coronary plaques and CT-angiography of the coronary arteries.
PMID- 10758624
TI - [Initial experiences with multi-slice detector spiral CT in diagnosis of
arteriosclerosis of coronary vessels].
AB - PURPOSE: Multi-row-detector-spiral-CT (MSCT) allows for 250 ms effective exposure
time. The purpose of this study was to demonstrate the possibilities and
limitations of this CT technology for non enhanced and contrast enhanced
investigation of the coronary arteries. METHODS: Investigation of the coronary
arteries without contrast medium for quantification of coronary calcifications
was performed in an obese patient (140 kg) with MSCT and electron beam CT (EBCT).
In 56 patients contrast enhanced CT angiography of the coronary arteries was
performed to determine image quality depending on the heart rate. RESULTS: In the
obese patient superior image quality could be achieved with MSCT allowing for
reliable quantification of coronary calcifications. With MSCT angiography of the
coronary arteries good image quality was achieved in patients with a heart rate
of 59 +/- 8 beats per minute. CONCLUSION: Even if there are limitations in
patients with higher heart rates with an effective exposure time of 250 ms MSCT
has clear advantage of image quality in the assessment of non enhanced and
contrast enhanced coronary arteries.
PMID- 10758625
TI - [Optimizing temporal resolution in CT with retrospective ECG gating].
AB - PURPOSE: Spiral CT of the heart using the established ways of ECG synchronization
is hampered by the relatively long acquisition times of 250 to 500 ms. This only
allows to acquire diastolic images in patients with moderate heart rates. In this
work, algorithms for time-optimized retrospective cardiac gating are presented,
and their potential to improve temporal resolution is investigated. MATERIAL AND
METHODS: These algorithms use data from multiple gantry rotations for image
reconstruction, which is possible for multi-scans at fixed slice positions as
well as for overlapping spiral scans. Temporal resolution was quantified using
computer simulations and compared to experimental data from pigs. RESULTS: Using
a conventional sub-second CT scanner, considerably higher temporal resolutions
are possible with spiral scanning. A temporal resolution of 170 ms already
provides systolic images with little motion artifacts. Higher temporal
resolutions of up to 70 ms are demonstrated for multi-scans, which allows to
depict ventricle wall movement over the complete cardiac cycle. DISCUSSION: The
method of time-optimized retrospective cardiac gating broadens the spectrum of
conventional spiral-CT for cardiac imaging. It can be directly transferred to
multi-slice scanners. Here it can be used clinically because of reduced scan
time. Potential applications are the determination of functional cardiac
parameters like ejection fraction and the detection of disorders of ventricle
wall movement.
PMID- 10758626
TI - [Proximal anastomoses of aortocoronary bypasses. Evaluation with ECG-triggered
single-slice computerized tomography].
AB - PURPOSE: Assessment of coronary artery bypass graft (CABG) patency with computed
tomography methods has been demonstrated as an alternative to coronary
angiography. The evaluation of the bypass anastomoses is still of limited
success. Prospective ECG triggering of conventional CT scanners allows heart
phase-triggered single-slice acquisition in the sub-second range. The goal of
this study was to evaluate whether the use of ECG triggering can optimize the
evaluation of proximal CABG anastomoses. MATERIALS AND METHODS: In ten patients
after CABG surgery, ECG-triggered CT with thin (2 mm), contiguous slices was
performed in the region of the proximal bypass anastomoses in the ascending
aorta. The data evaluation was done on axial images and on reconstructed 2D and
3D data sets. RESULTS: The applied technique demonstrated good imaging quality,
which allowed evaluation of the CABG anastomoses in all cases. Overall 18 CABG
anastomoses could be visualized; 17 anastomoses could be assessed as normal, non
stenotic and patent. DISCUSSION: ECG-triggered thin-slice CT permits reliable
assessment of proximal CABG anastomoses and expands the usage of CT in the
evaluation of CABG.
PMID- 10758627
TI - [Determining left and right ventricular volume ejection fractions (VEF) with MRI
at 1.0 T. Comparison of manual and semi-automated endocardium detection].
AB - PURPOSE: To evaluate method- and user effects as well as the required time in the
determination of left- and right ventricular ejection fractions in comparing
manual and semiautomatic border detection of the endocardium. METHODS: In 22
patients with varying cardiac diseases endocardial borders were detected either
manually or semi-automatically (seeded ROI) and subsequently the right and left
ventricular volume ejection fractions were computer-calculated. Two investigators
defined the endocardial borders for both ventricles using both methods. For
statistical analysis two-factorial analyses of variance were performed for the
four variables: VEF right ventricle, VEF left ventricle, required time right
ventricle, required time left ventricle (SAS, Anova). RESULTS: There was no user
or method effect detectable for both ventricles. The required time for both
ventricles also did not reveal a user effect, but there was a dramatic method
effect concerning a reduction of the required time for analysis for both
ventricles > 50%. CONCLUSIONS: The semiautomatic mode for detecting the
endocardial borders in determining right and left ventricular ejection fractions
did not demonstrate results differing from the results of the manual method, but
is significantly superior concerning the time required for analysing ejection
fractions of both ventricles with a reduction of over 50%. This might
significantly reduce the expenditure for personnel.
PMID- 10758628
TI - [Flow quantification in coronary and bypass vessels with MR phase contrast
technique].
AB - PURPOSE: To evaluate accuracy of velocity encoded cine MR imaging for
determination of blood flow in coronary arteries and coronary bypass grafts.
MATERIALS AND METHODS: 12 patients with 22 coronary bypass grafts underwent
intraoperative flow quantification using the transit time ultrasound method.
These values were compared to postoperative MR phase shift measurements. Flow
measurements were performed preoperatively in 28 coronary arteries of 20
patients. For flow measurement, we used a velocity-encoded k-space segmented
gradient echo sequence with a temporal resolution of 110 or 125 ms, respectively.
6-8 pase shift images could be acquired during one cardiac cycle. RESULTS: There
was a significant correlation between intraoperative and flow measurements using
velocity-encoded MR imaging (r = 0.74, p < 0.0001, t-test). Flow volumes
determined by MR imaging were systematically larger than those determined by the
transit time ultrasound method. Mean flow in coronary arteries was reduced in
severely stenosed vessels (> 70%) compared to normal vessels. Intra- and
interobserver variability were 10.5 and 15% (coronary bypass grafts), and 12.3
and 15.8% (coronary arteries), respectively. CONCLUSIONS: Velocity-encoded MR
imaging enables determination of flow in coronary artery bypass grafts and
coronary arteries. Future developments should aim at the improvement of spatial
and temporal resolution of the method.
PMID- 10758629
TI - [Evaluating signal intensity of movement-impaired myocardial segments in MR
delayed images after administration of Gd-DTPA. Correlation of regional increase
in contraction after revascularization].
AB - PURPOSE: The aim of the study was to correlate delayed contrast enhancement of
dysfunctional regions of the myocardium after injection of Gd-DTPA with the
improvement of regional contractility 3 months after revascularization. MATERIAL
AND METHODS: Eleven patients with coronary artery disease and wall motion
abnormalities underwent MR imaging before and 3 months after revascularization
therapy (PTCA or CABG). Short-axis images were acquired using a cine gradient
echo sequence. After revascularization, a representative slice was analyzed 14 +/
1 min after injection of 0.1 mmol/kg Gd-DTPA using a T1-weighted turbo fast low
angle shot sequence. Improved systolic wall thickening 3 months after
revascularization served as criterion of viability and was correlated with
delayed contrast enhancement patterns. RESULTS: After revascularization, 6
patients showed complete recovery of the dysfunctional area, 1 patient partial
recovery, and 4 patients remained unchanged. All 4 patients with persisting wall
motion abnormalities, 1/6 patients with recovery and the patient with partial
recovery revealed a delayed enhancement. CONCLUSIONS: Three months after
revascularization, delayed enhancement of dysfunctional myocardium is evident in
patients without regional wall motion improvement, while the lack of delayed
enhancement correlates with improvement of regional contractility.
PMID- 10758630
TI - [Myocardial perfusion at rest and during stress. MR signal characteristics of
persistent and reversible myocardial ischemia].
AB - AIM: Performance of combined rest/stress MR perfusion studies and the analysis of
qualitative signal intensity parameters in comparison with 99mTc-SestaMIBI SPECT
in patients with known coronary artery disease (CAD). METHODS: Sixteen patients
with CAD underwent MR myocardial perfusion assessment at rest and after
dipyridamole-induced hyperemia. Qualitative parameters (SI increase, SI upslope)
of the SI time-curves were evaluated and characteristics of normal, reversible
and persistent hypoperfused myocardium as assessed by 99mTc-SestaMIBI SPECT were
compared. RESULTS: Compared with the rest values, normal myocardium showed a
significant increase of the SI upslope during hyperemia (P < 0.001), whereas
persistent (P = 0.07) and reversible (P = 0.15) hypo-perfusions showed only minor
changes. SI increase over baseline also showed a significant increase only in
normal myocardium (P < 0.001). At rest, reversible ischemic areas showed no
significant differences from normal myocardium, whereas during hyperemia SI
increase was significantly lower (P = 0.02). CONCLUSIONS: Qualitative SI
parameters of a combined rest/stress MR myocardial perfusion study allow to
differentiate normal from reversibly or persistently hypoperfused myocardium.
PMID- 10758631
TI - [Cardiac energy metabolism in heart valve diseases with 31P MR spectroscopy].
AB - PURPOSE: Heart valve disease combined with left ventricular hypertrophy leads to
derangements in cardiac energy metabolism, which can be detected non-invasively
by 31P-MR-spectroscopy. The purpose of the present study was to examine whether
the derangements in cardiac metabolism are reversible after surgical valve
replacement. PATIENTS AND METHODS: 10 healthy volunteers and 10 patients with
aortic stenosis (pressure gradients > 60 mmHg) were included. For assessment of
energy metabolism, 31P-MR spectra were obtained with a double oblique 3D-CSI
technique (voxel size 25 cm3). In 5 of 10 patients, follow-up examination was
performed 3 months after surgical valve replacement (SVR). Left ventricular (LV)
function was analyzed by cine MRI. RESULTS: Before SVR the myocardial
phosphocreatine to adenosinetriphosphate (PCr-ATP) ratio was significantly (p =
0.0002) reduced to 0.80 +/- 0.25 in patients compared to 1.65 +/- 0.21 in
volunteers. 3 months after SVR, LV mass had significantly (p = 0.04) decreased
from 238 +/- 33 g to 206 +/- 47 g. At the same time a significant (p = 0.04)
increase of the PCr-ATP ratio from 0.80 +/- 0.25 to 1.28 +/- 0.22 was observed. A
slight, but not significant, reduction of the phosphodiester ATP ratio was
observed before SVR, with a trend towards normalization after SVR. CONCLUSIONS:
After SVR, the deranged energy metabolism shows a trend towards normalization.
Further follow-up is necessary to determine whether complete normalization of the
energetic derangement can be observed over longer periods of time following SVR.
PMID- 10758632
TI - [Volumetric analysis and visualization of cardiologic ultrasound data].
AB - BACKGROUND: Echocardiography is a standard imaging technique for the assessment
of heart valve disease. The good spatial and temporal resolution is the basis for
different methods which provide information about the severity of such defects.
Dynamic colour visualisation and volumetric measurements of regurgitant jets are
a new evaluating tool for the assessment of heart valve insufficiencies. METHODS:
The regurgitant jet volume of 58 patients was evaluated on an external work
station after segmentation of the left atrium and compared to regurgitant volume;
the correlation was good. This result is valid for central jets as well as for
eccentric jets. CONCLUSIONS: Measurement of regurgitant jet volume is a method
which considers the three-dimensional shape of the examined volume. Real-time
visualisation techniques which support the interactive clipping of morphological
structures provide dynamic visualisation of intracardiac flow during the heart
cycle. Dynamic colour visualisation of jets together with myocardial structures
allows the assignment of intracardiac flow to morphological structures.
PMID- 10758633
TI - [Early detection of breast cancer in Germany. Time to deal with the problem].
AB - In Germany there is still an urgent need for action in regard to screening for
breast cancer. The announcement of research projects for mammography screening
proves this. The following reports the results of the Munich field study. In 2
years, 2489 breast cancer cases were registered (status 6/98). Screening data
were available for 1319 patients. The reduction in mortality, found in randomized
studies, due to mammography in women over 50 years old was confirmed. A relative
reduction of 44.8% in 10-year mortality could be estimated through mammography
and 25.1% through palpation, in comparison with "doing nothing." We could also
estimate the participation of screening and the used methods in the Munich
region. If the mammographies carried out today were used at 2-year intervals for
women aged between 50 and 70 years, then the mammography screening could be
performed with no additional costs for 70% of the women. The known facts
regarding the population-based mortality and regarding the acceptance of the
palpation screening and frequency of mammography are additional aspects for
inclusion in the discussion of what research projects in Germany are and what
they should fulfill.
PMID- 10758634
TI - [Inflammatory skeletal changes of the upper thoracic aperture and mandible. SAPHO
syndrome with chronic osteomyelitis of the upper thoracic aperture and mandible].
PMID- 10758635
TI - [Ethics in medicine. Needs and forms].
PMID- 10758636
TI - [An overview of fertility statistics and milk production data of 15 dairy
operations in southeast Friesland].
AB - In 1988 the collection of data on fertility and milk production was initiated by
the veterinary practice in Oosterwolde in the context of a veterinary herd health
programme. An automated management and production control programme, VAMPP, was
used for this purpose. Although it is not possible to give the precise effect of
veterinary herd health programmes on technical farm results, because a control
group is lacking, it is possible to discern trends in data collected over 10
years. The field data, show that the first insemination pregnancy rate decreased
by 10.1%, from 55.5% to 45.4% (p = 0.002). The number of cows showing first heat
decreased by 1.3% (p = 0.46) between 0-15 days post partum, 2.6% (p = 0.41)
between 15-30 days post partum, by 4.9% (p = 0.07) between 30-50 days post partum
and by 11.4% (p = 0.008) between 50-70 days post partum. In the same period, the
milk production increased from 7558 kg 4% fat corrected milk in 305 days to 8744
kg (p = 0.0004). These data may be useful for veterinarians working in veterinary
herd health on dairy farms. Furthermore, the described trends and especially the
discussed differences between farms may be a stimulus for both farmers and
veterinarians to continue with herd health programmes.
PMID- 10758637
TI - [Hypocalcemia in a four-week-old foal].
AB - Intake of Rumex, a plant genus of the Polygonaceae family, probably led through
the assimilation of oxalic acid, to hypocalcaemia in a four-week old foal. This
foal was presented with muscle rigidity and a stiff gait. Both the total and
ionized calcium concentrations were low, 1.38 mmol/l and 0.54 mmol/l
respectively. The foal was treated with a total of 150 ml of a 20% calcium
solution IV. The foals neuromuscular signs resolved within a few hours after
receiving calcium solution.
PMID- 10758638
TI - [Interview with Ton de Ruijter. New chairman wishes to better profile
veterinarians. Interview by Sophie Deleu].
PMID- 10758640
TI - [Classification of vascular lesions of the brain and spinal cord according to ICD
10].
PMID- 10758639
TI - [S.S. Korsakov on the structure of psychiatric hospitals (introduction by V.S.
Iastrebov)].
PMID- 10758641
TI - [The specifics of clinical course and pathogenesis of mild brain injury in
children].
AB - Clinical peculiarities and pathogenesis of mild cerebrocranial trauma (CCT) in
106 children aged 1-14 years were studied. The boys made up 66.03% of this group.
Neurologic, immunologic (CIC, immunoglobulins A, M, G) and biochemical (level of
thyobarbituric acid, TBA-active products) investigations were performed on day 1
and 10 after the trauma. There were increased levels of CIC and TBA-active
products on the 1st day, while after the recovery (to the 10th day) elevation of
these indices was less pronounced pronounced. The authors made a conclusion about
participation of both immunologic and biochemical alterations in pathologic
process resultant in disorders of metabolism and microcirculation. Thus, such
children need longer pathogenetic therapy to prevent development of neurologic
complications in the remote period of CCT.
PMID- 10758642
TI - [Clinical-psychological analysis of the development of movement, perceptual,
intellectual and speech functions in children with cerebral palsy].
AB - 105 children with cerebral paralysis at the age under 3 years were examined. CNS
damages in children of early age with disneuroontogenesis may be divided into 4
degrees of severity. This enables to estimate objectively both the patients'
state and the results of their therapy in the groups with the same degree of
severity of CNS damage. High efficiency of the complex method of metameric
stimulation of the development of static-motor and psychospeech functions allows
to recommend this method for treatment of children with cerebral paralysis.
Application of this method in children of early age with disorders of neurologic
development in some cases prevents neurologic disability.
PMID- 10758643
TI - [The formation of the deviant behavior in adolescents (psychopathological and
psychological aspects)].
AB - Psychopathological manifestations of deviant behavior, self-estimation
psychological characteristics and accentuation of the personality were studied in
180 girls aged 12-17 years with deviant and 80 girls with normal behavior. 5
psychopathological variants of deviant behavior were singled out: psychopath
like, psychopath-like with hysteric episodes, asthenic, astheno-depressive,
astheno-neurotic with hysteric episodes. The notion "total deviation" is
introduced which allow to define the level of deviant disorders.
PMID- 10758644
TI - [The influence of the correction of motor disorders on the functional status of
the brain in infantile cerebral palsy].
AB - Analysis of functional state of the brain in 32 juveniles with residual stage of
infantile cerebral paralysis (ICP) was performed basing on electroencephalography
data in correction of motor disorders with the method LK-92 "Adely" to optimize
proprioceptive afferent current. In all the cases a positive brand was observed:
a) gradual changes of EEG-pattern in one direction, b) decrease of the power of
slow-waived part of the spectrum, c) increase of the spectral power in alpha
range (60%), d) increase of its amplitude by 10-25 microV, and e) increase of the
frequency alpha-range by 0.5-1 Hz in 28% of the cases. Normalization of zonal
distribution of biopotentials on convexital surface of the cortex was found in
90%. The data obtained reflect pronounced rearrangement of bioelectric activity
of the brain, due to weakening of the pathologic influences on the cortex and
strengthening of the mechanism of cortical inhibition.
PMID- 10758645
TI - [Tanakan in the treatment of perinatal injuries of the central nervous system].
AB - Clinical laboratory investigation of the efficiency of Tanakan (Beaufour Ipsen,
France) was performed in 30 children (20 girls, 10 boys) of 2-7 months old with
hypoxic-ischemic encephalopathy. Tanakan was taken per os 2 times a day (in the
morning and dinner time) as a 0.25 ml of standard solution for 2 months. Other
vasoactive, nootropic and antiaggregative drugs weren't used. Clinical
neurologic, neurosonographic studies, ultrasonic dopplerography of intracranial
arteries were performed before and after the course of treatment. Efficiency of
Tanakan was established in hypoxic-ischemic encephalopathy in children of an
early age. By increasing a cerebral blood flow and decreasing intracranial
pressure, the drug had positive influence on the motor functions and
psychoemotional sphere, promoting a considerable decrease of vegetovisceral and
vegetovascular disorders. Side-effects of Tanakan administration were not
observed.
PMID- 10758646
TI - [Selective serotonin reuptake inhibitors in the therapy of various types of
endogenous depressions].
AB - In order to specify differential indications for the use of selective serotonin
reuptake inhibitors (SSRI) their therapeutic effect was investigated in apathic
adynamic, melancholic and anxious depressions. Group of 151 patients received
monotherapy with one of SSRI-drugs: citalopram--22 patients (mean daily dosage-
27.4 mg), paroxetine--47 patients (23 mg), sertraline--19 patients (107 mg),
fluvoxamine--28 patients (162 mg), fluoxetine--35 patients (20 mg). The state of
the patients was estimated 5 times during 42 days of therapy by clinical
estimations and according to Hamilton Depression Scale (HAM-D). Therapeutic
effects of the drugs were determined according to the degree of reduction of the
total HAM-D scores and they were considered as "significant" (a reduction of the
scores by 50% and more), "moderate" (by 21-49%), and "insignificant" (by 1-20%).
Positive antidepressive effect, including "significant" was obtained in the case
of the use of all the drugs studied. Differential evaluation of the three
components of antidepressive activity (thymoleptic, sedative-anxiolytic, and
stimulative) according to the degrees and data of expression of drugs'
therapeutic effect has allowed to determine indications for the therapy of
endogenous depressions by each of SSRI: to recommend cytalopram for the treatment
of various types of depressive states mainly, for anxious and apatho-adynamic
types; paroxetin--for treatment of melancholic depressions as well as for anxious
and apatho-dynamic ones; sertralin++--for depression with anxiety and fobic
disorders; fluvoxamine--for melancholic and anxious depression; fluoxetine--for
apatho-adynamic depressions.
PMID- 10758647
TI - [The effectiveness of sertraline (zoloft) in the therapy of maladaptation in the
outpatient setting].
PMID- 10758648
TI - [Clinical instrumental and immunological studies of multiple sclerosis in
children].
AB - The results of clinical examination, data of analysis of the visual evoked
potentials, computer and magneto-resonance tomography allowed to diagnose a
reliable multiple sclerosis in 25 children (16 girls and 9 boys). The age of the
onset of the disease was from 4 to 14 years, the duration of the follow-up--from
1 to 12 years. Monosymptomatic onset, remittent course with frequent
exacerbations and successful recovery of the functions during the remissions
prevailed. Purposeful treatment allowed to achieve a stable remission in 2/3 of
the cases, while a gradual increase of the neurologic deficit was observed in the
other patients. Phenotyping by HLA-system revealed association of demyelinating
diseases in children with HLA-B12 (RR = 6.0; p < 0.025), together with the
absence of HLA-B18 antigen. The authors made a conclusion that multiple sclerosis
may be diagnosed in childhood and that it has some clinical and immunologic
peculiarities.
PMID- 10758649
TI - [Nerve growth factor auto-antibodies in children with various forms of mental
dysontogenesis and in schizophrenia high risk group].
AB - The level of autoantibodies (AAb) to nerve growth factor was evaluated in blood
serum of 163 children with different forms of mental dysontogenesis of endogenic,
residual-organic, psychogenic and deprivative origin. Significant elevation of
the level of AAb was found in all forms of psychic dysontogenesis. The most
significant elevation of the level of AAb (p < 0.01), as compared with the
controls (45 children), was characteristic for endogenic forms of dysontogenesis
(schizophrenia, early children's autism, schizotypic diathesis). The level of AAb
was also found as an indicator of the acuteness of the pathologic state. Besides,
its elevation was observed 1-2 weeks prior to the onset of the clinical
exacerbation. Elevation of AAb level was also found in psychic dysontogenesis of
residual-organic nature (children with perinatal encephalopathy), but it was not
so significant as compared with the controls (p < 0.05%). The analysis in the age
dynamics of children from this group revealed, that AAb level may serve as some
prognostic index of the severity of psychic dysontogenesis. The level of AAb
differs some states in schizotypic diathesis and deprivative dysontogenesis,
which are clinically quite similar. The method for the estimation of serum AAb
level may be proposed as screening in prophylactic medical examination of
children from the first year of life under conditions of pediatric outpatient
service for identification of risk-groups by psychic dysontogenesis to perform
early special psychoprophylaxis.
PMID- 10758650
TI - [Extra-hospital death of children with congenital defects and organic injuries of
the nervous system].
AB - The paper presents the results of the analysis of extrahospital mortality of
children with defects of nervous system. Both social-hygienic and expert methods
were used in all the cases of extrahospital death of children with anomalies of
the development of nervous system, registered in the region of Penza in 1984-1996
(total = 238 cases). It was found that risk-group of sudden death included
children with inborn anomalies of the development of nervous system, with
hereditary diseases, with infantile cerebral paralysis and consequences of
neuroinfections. Extrahospital death of children was registered mainly in rural
regions. Risk-factors of death of children with inborn defects appeared to be
seasonal deviations, especially in the period of the season change. The direct
causes of the death depended on the type of the defect. A priority of practical
neonatology, perinatology and children's neurosurgery is introduction of the
methods of antenatal diagnosis and surgical methods for the correction of inborn
defects of CNS.
PMID- 10758651
TI - [Nervous-mental health of children who had perinatal damage of the nervous
system].
AB - The paper presents the results of somatic, neurologic and neurophysiologic
examination of 614 children which had hypoxic-ischemic encephalopathy of a
moderate degree during the period from the birth till 3 years old. A period of
gestation was characterised by some signs of fetoplacental insufficiency in 44.3%
of children. Disorders in labor activity were revealed in 83.7% of mothers. Delay
in nervous-mental development (77.3%), deviations in forming rhythmic EEG
activity (75%), signs of morphologic immaturity of brain (38.8%) testified to
inhibition of postnatal neuroontogenesis. All that together with high frequency
of motor disorders (73.3%) and disorders in cerebral blood flow (43.8%) during
the 1-st year of life were found to underlie development of psychoneurologic
diseases in children of early age and necessitates early rehabilitation of these
children.
PMID- 10758652
TI - [A.M Khaletskii (for the 100th anniversary of his birth)].
PMID- 10758653
TI - [Multiple sclerosis in children].
PMID- 10758654
TI - Unguided percutaneous transthoracic fine needle aspiration cytology in the
diagnosis of the peripheral lung lesions.
AB - Percutaneous transthoracic fine needle aspiration cytology (PTFNAC) of lung was
done in 614 cases at the department of Pathology of Institute of Diseases of
Chest and Hospital (IDCH), Dhaka, during the period from July 1994 to July 1996.
A definite diagnosis was possible in 417 cases (78.83%). More than half (57.65%)
of the cases were proved to have malignant diseases. PTFNAC detected malignant
lesion in these patients for the first time as because no other investigation was
able to establish the diagnosis. Diagnostic accuracy was 74%. Only 12 (1.95%)
patients developed pneumothorax and mild haemoptysis occurred in 23 (3.74%)
patients. So unguided PTFNAC is a simple, time saving, safe and inexpensive
method of diagnosis of peripheral lung lesions.
PMID- 10758655
TI - Pulsed electromagnetic fields for the treatment of bone fractures.
AB - The effectiveness of electrical stimulation and Pulsed Electro Magnetic Field
(PEMF) stimulation for enhancement of bone healing has been reported by many
workers. The mechanism of osteogenesis is not clear, therefore, studies look for
empirical evidence. The present study involved a clinical trial using low
amplitude PEMF on 19 patients with non-union or delayed union of the long bones.
The pulse system used was similar in shape to Bassett's single pulse system where
the electric voltage pulse was 0.3 mSec wide repeating every 12 mSec making a
frequency of about 80 Hz. The peak magnetic fields were of the order of 0.01 to
0.1 m Tesla, hundred to thousand times smaller than that of Bassett. Among the 13
who completed this treatment schedule the history of non-union was an average of
41.3 weeks. Within an average treatment period of 14 weeks, 11 of the 13 patients
had successful bone healing. The two unsuccessful cases had bone gaps greater
than 1 cm following removal of dead bone after infection. However, use of such a
low field negates Bassett's claim for a narrow window for shape and amplitude of
wave form, and justifies further experimental study and an attempt to understand
the underlying mechanism.
PMID- 10758656
TI - Effect of Momordica charantia (Karolla) extracts on fasting and postprandial
serum glucose levels in NIDDM patients.
AB - Effect of Momordica charantia, a bitter vegetable popularly known as Karolla, on
fasting and post prandial (2 hours after 75 gm oral glucose intake) serum glucose
levels were studied in 100 cases of moderate non-insulin dependent diabetic
subjects. Drinking of the aqueous homogenized suspension of the vegetable pulp
led to significant reduction (p < 0.001) of both fasting and post-prandial serum
glucose levels. This hypoglycaemic action was observed in 86 (86%) cases. Five
cases (5%) showed lowering of fasting serum glucose only.
PMID- 10758657
TI - Peripheral blood cells transplantation--a review article.
AB - In the twelve years since the first PBSCT were reported, impressive advancements
in BCT techniques have made it easy to perform, effective, less costly, rapid
haematologically recoverable, reduced morbidity and mortality, shorten overall
duration of cancer treatment and hospital stay. Development of high-dose
chemotherapy and new novel effective antitumor drugs otherwise limited by
haematological toxicities may now become possible. Treatment of haematological
malignancies with purged autologous PBPCT, e.g. Ph Chromosome negative progenitor
cells in CML or with immunologically manipulated allogeneic PC having preserved
GVL but not GVHD action, with hopeful prospects, is now becoming possible.
Tailoring of BC for ex-vivo selection and expansion of specially active T
Iymphocytes, NK cells and other immune effector cells will enable adoptive
immunotherapeutic approach and treatment of Minimal residual disease [MRD] after
high-dose chemotherapy both in grafts and in patients. The discovery of a
nonhaematopoietic, engraftment facilitator cell form donor BM may usher in
further precision in GVHD prevention by purification and in adoptive
immunotherapeutic approach. Therefore, it is likely that BCT will supersede BMT,
though the follow-up is too short to draw conclusions.
PMID- 10758658
TI - The incidentally discovered asymptomatic adrenal tuberculous mass mimicking
malignancy.
AB - Tuberculous adrenal mass without any tuberculous changes in other sites is a rare
entity. In this study we describe such a case. A male patient of 47 years with 6
months history of anorexia and weakness was presented. Ultrasonography and
computed tomography revealed a mass in the right adrenal gland. It was mistaken
as a malignant neoplasm and the diagnosis was confirmed by surgical exploration.
PMID- 10758660
TI - The SYBAR system: integrated recording and display of video, EMG, and force plate
data.
AB - A new system--called SYBAR--is introduced, that employs digital video for
registration of the movements of a patient while simultaneously recording
electromyogram signals of relevant muscles and ground reaction forces (for the
lower extremities in gait studies). All information is stored in a multimedia
record, which can be viewed by the clinician with a simple user interface. This
setup allows an integrated and more detailed view of the movement of the patient
and related information (i.e., muscle physiology). It is used by clinicians to
assess the causes of movement disorders in their patients. This paper describes
the SYBAR system and focuses on the employed methods of data synchronization for
both the time and the spatial domains. It is concluded that, although SYBAR was
developed for clinical gait studies, the technology can be applied in all
situations in which the relation between physiological signals and human or
animal behavior is studied.
PMID- 10758659
TI - Behavior and autonomic nervous system function assessed via heart period
measures: the case of hyperarousal in boys with fragile X syndrome.
AB - Physiological responses may inform us about and help us to interpret behavioral
responses. For example, hyperarousal may be a source of behavior problems in
children with fragile X syndrome (FXS). To evaluate this approach, we examined
heart period data in specific contexts in boys with FXS and in normally
developing chronological-age-matched boys. Spectral analysis was used to evaluate
the parasympathetic and sympathetic nervous systems' contributions to heart
period. Boys with FXS had shorter interbeat intervals, lower parasympathetic
activity, and similar sympathetic activity. Also, the groups were differentially
responsive to experimental challenge. These results have important implications
for our understanding of the basic nervous system dysfunction in FXS and for the
strategies likely to be effective in terms of pharmacological intervention with
these children. These methods can be applied to a variety of contexts and
populations, including children who are sensory defensive, socially avoidant,
inattentive, or hyperactive.
PMID- 10758661
TI - Measurement and meaning of head movements in everyday face-to-face communicative
interaction.
AB - Methodological approaches in which data on nonverbal behavior are collected
usually involve interpretative methods in which raters must identify a set of
defined categories of behavior. However, present knowledge about the qualitative
aspects of head movement behavior calls for recording detailed transcriptions of
behavior. These records are a prerequisite for investigating the function and
meaning of head movement patterns. A method for directly collecting data on head
movement behavior is introduced. Using small ultrasonic transducers, which are
attached to various parts of an index person's body (head and shoulders), a
microcomputer determines receiver-transducer distances. Three-dimensional
positions are calculated by triangulation. These data are used for further
calculations concerning the angular orientation of the head and the direction,
size, and speed of head movements (in rotational, lateral, and sagittal
dimensions). Further analyses determine relevant changes in movements, identify
segments of movements, and classify the quantifications of movement patterns. The
measured patterns of nonverbal behavior can be accurately related to features of
verbal communication and other time-related variables (e.g., psychophysiological
measures). To estimate the possible meanings of behavioral patterns, a heuristic
is proposed that includes the situational context as the basis of interpretation.
PMID- 10758662
TI - The study of emotional processes in communication: I. Measuring emotionalization
in everyday face-to-face communicative interaction.
AB - The drawbacks of traditional research into emotional processes have led us to
develop a set of methodologies for investigating them in everyday face-to-face
communication. The conceptual basis of these procedures is a model of the
eliciting conditions of emotional processes as well as a conceptualization of the
emotional processes themselves. On the basis of the assumption of conversation as
a rule-governed process, one can describe its default temporal, formal, and
functional features, for which we use the MAS EDIT and SEQ programs, and the
minimal model of communicative exchange, respectively. Violations of these
default rules can be identified as unexpected/temporally unpredictable events
eliciting emotionalization. The nature of emotionalization is determined by the
psychological principle of "standard and deviation." Its investigation under
natural conditions requires the following: A noninvasive method of data
acquisition (including procedures for rejecting faulty or missing values),
measurement (high-resolution recording of physiological, psychomotor, and vocal
variables), and the (nonstatistical) construction of an inventory or "relevant
effects" (contrastive and template analysis). Finally, we depict three routes of
investigating time courses of activation changes as dependent and independent
variables and as a target of modification and reflection.
PMID- 10758663
TI - The study of emotional processes in communication: II. Peripheral blood flow as
an indicator of emotionalization.
AB - Traditional methods of analyzing human peripheral blood flow (PBF) do not account
for its continuous nature or small-scale variation. Sequel transformation is
presented as a new methodology for measuring these variations. This analysis
generates a richer record of aspects of activation of the autonomous nervous
system than traditional interbeat-interval (IBI) measurement. Presumably, in
addition to heartbeat (i.e., IBI), other information can be extracted that is
consistent with the influence of several physiological and psychological factors.
This kind of variation is reflected in the PBF signal. After determining and
extracting relevant events from vascular volume data generated by sequel
transformation, we demonstrate the use of template analysis to analyze patterns
of events as time courses of activation. All procedures are included in the
computer program VASC Analyzer.
PMID- 10758664
TI - Classifying postures of freely moving rodents with the help of Fourier
descriptors and a neural network.
AB - A computerized method for classifying the postures of freely moving rodents is
presented. The behavior of the rats was recorded on videotape by means of a
camera hanging perpendicular to an open field. An automatic tracking system (10
images/sec) was used to transform the video images of postures into a binary
image, thereby providing silhouettes in a computer format. The contours of these
silhouettes were used for determining their characteristic features with the help
of a Fourier transformation. The resulting features were classified with the help
of a Kohonen network composed of 32 neurons. The four best winning neurons,
rather than the usual one, were used for the classification. The resolution
(11,090 distinct classes of postures), reliability (96.9%), and validity of this
method were determined. With the use of the same approach, the effectiveness of
this method for classifying behaviors was illustrated by analyzing grooming (247
grooming images vs. 4,950 nongrooming images). We found 15.4% false positives and
2.5% false negatives.
PMID- 10758665
TI - Classification of rat behavior with an image-processing method and a neural
network.
AB - Video recordings of 11 rats were digitized at five frames per second, and
parameters describing the shape and the position of the rat were calculated. The
behavior displayed by the rats was observed by an experienced observer. Separate
neural networks were trained and validated, using the data for each individual
rat. The neural networks correctly classified an average of 76.53% of the frames
in the validation set and 98.18% of the frames in the training set. A single
neural network was trained with 6 rats and validated with 5 rats. The neural
network correctly classified 63.74% of the frames in the validation set and
82.85% of the frames in the training set.
PMID- 10758666
TI - Image-processing algorithms for behavior analysis of group-housed pigs.
AB - Computational algorithms of image processing were developed and evaluated to
select, by motion detection, images of resting artificial pigs and to segment the
pigs (mixture of black and white pigs) from their background. Motion detection of
the pigs was implemented by detecting interframe differences of postural
behavioral images. This algorithm combines the advantages of likelihood ratio
method and shading model method and shows a stable performance under noisy and
dynamic illumination conditions. Segmentation of the pigs from their background
was implemented by employing multilevel thresholding and background reference
techniques. The algorithm automatically determines the number of thresholds
needed and produces satisfactory segmentation when both black and white pigs with
different image intensities are present at the same time (the most complicated
situation). The reference background image is updated so that temporal changes in
illumination and/or spatial changes of the pen condition have little effect on
the performance of image segmentation. The algorithm employs statistical models
of the pigs and background and Bayes hypothesis testing to obtain and update the
exposed portion of the reference background. Linear filters were used in this
process for updating the parameters. These algorithms will serve as essential
components for a novel, behavior-based, interactive approach to assess and
control thermal comfort of group-housed pigs, which is expected to result in
enhanced animal health and well-being.
PMID- 10758667
TI - Graze: a program to analyze recordings of the jaw movements of ruminants.
AB - Graze is a user friendly, Microsoft Windows 95/NT program for analyzing jaw
movement recordings taken with the IGER Behavior Recorder. The program displays a
plot of the jaw movement amplitude (vertical axis) against time (horizontal
axis). Individual jaw movements can be automatically identified, using amplitude
and frequency criteria specified by the user. Bouts of jaw movements can then be
analyzed and are automatically identified as either grazing or ruminating.
Behaviors other than grazing and ruminating (such as drinking or eating
supplements) can also be identified and marked by the user. Identified jaw
movements and bouts of behavior are superimposed on the jaw data display.
Finally, the user can perform a bout analysis, which discriminates between bites
and chews during eating and generates a summary file.
PMID- 10758668
TI - Discovering hidden time patterns in behavior: T-patterns and their detection.
AB - This article deals with the definition and detection of particular kinds of
temporal patterns in behavior, which are sometimes obvious or well known, but
other times difficult to detect, either directly or with standard statistical
methods. Characteristics of well-known behavior patterns were abstracted and
combined in order to define a scale-independent, hierarchical time pattern type,
called a T-pattern. A corresponding detection algorithm was developed and
implemented in a computer program, called Theme. The proposed pattern typology
and detection algorithm are based on the definition and detection of a particular
relationship between pairs of events in a time series, called a critical interval
relation. The proposed bottom-up, level-by-level (or breadth-first) search
algorithm is based on a binary tree of such relations. The algorithm first
detects simpler patterns. Then, more complex and complete patterns evolve through
the connection of simpler ones, pattern completeness competition, and pattern
selection. Interindividual T-patterns in a quarter-hour interaction between two
children are presented, showing that complex hidden T-patterns may be found by
Theme in such behavioral streams. Finally, implications for studies of
complexity, self-organization, and dynamic patterns are discussed.
PMID- 10758669
TI - Resampling approach to statistical inference: bootstrapping from event-related
potentials data.
AB - We propose the use of the bootstrap resampling technique as a tool to assess the
within-subject reliability of experimental modulation effects on event-related
potentials (ERPs). The assessment of the within-subject reliability is relevant
in all those cases when the subject score is obtained by some estimation
procedure, such as averaging. In these cases, possible deviations from the
assumptions on which the estimation procedure relies may lead to severely biased
results and, consequently, to incorrect functional inferences. In this study, we
applied bootstrap analysis to data from an experiment aimed at investigating the
relationship between ERPs and memory processes. ERPs were recorded from two
groups of subjects engaged in a recognition memory task. During the study phase,
subjects in Group A were required to make an orthographic judgment on 160
visually presented words, whereas subjects in Group B were only required to pay
attention to the words. During the test phase all subjects were presented with
the 160 previously studied words along with 160 new words and were required to
decide whether the current word was "old" or "new." To assess the effect of word
imagery value, half of the words had a high imagery value and half a low imagery
value. Analyses of variance performed on ERPs showed that an imagery-induced
modulation of the old/new effect was evident only for subjects who were not
engaged in the orthographic task during the study phase. This result supports the
hypothesis that this modulation is due to some aspect of the recognition memory
process and not to the stimulus encoding operations that occur during the
recognition memory task. However, bootstrap analysis on the same data showed that
the old/new effect on ERPs was not reliable for all the subjects. This result
suggests that only a cautious inference can be made from these data.
PMID- 10758670
TI - A conceptual and graphical method for converging multisubject behavioral
observational data into a single process indicator.
AB - Typically, in observational research, each behavior of a subject is assigned a
code that represents theoretically relevant and contextually sensitive events.
These discrete behavioral acts are then strung together to denote a process. With
multiple interactants, the investigator has two choices: ignore subject
interdependence and analyze as if the data strings are discrete, or treat the
strings as interdependent and create a summary index that represents the combined
codes across subjects. This article illustrates a method of combining discrete
within-subjects behavioral indicators into behavior-specific domains and then
conglomerating the disparate domain strings across subjects in such a way that
the aggregate reflects the observed process. This aggregation is represented by a
coordination index, expressed as either interactant disparity or coherence. Also,
animation and visualization methods are presented that illustrate how social
processes can be modeled by using either the coordination index or the separate
domain values.
PMID- 10758671
TI - Quantification of swim patterns in the Morris water maze.
AB - Spatial learning and memory in rodents is most often assessed in the Morris water
maze. Neurobiologists have to distinguish behavioral patterns to unravel
underlying neuronal systems. We analyzed swim patterns of mice videotaped before
and after training with a multi-trial procedure in the water maze. In addition to
traditional parameters, the animals' position in relation to trained and other
possible platform locations was estimated five times per second by an image
analysis system. This parameter, cumulative distance to platform, was correlated
with time spent in the platform quadrant but not with latency to and crossings of
the platform location. We detected a subgroup of animals with concentric patterns
within the group of spatial/persistent patterns. Random patterns were classified
as well. Swim patterns before training were not predictive for the one after
training. In summary, image analysis systems have made it very convenient to
quantify behavior. Using their capacity, we have further improved the analysis of
swim patterns, revealing animals' different approaches to solve a problem.
PMID- 10758672
TI - The analysis system COGITAT for the study of cognitive deficiencies in rodents.
AB - COGITAT is an automated hole board system that, following minimal experimental
interventions, makes it possible to measure a variety of parameters associated
with learning, memory, relearning, cognition, and cognitive shifts, but also
changes in exploratory and sensorimotor performance in rodent models. The
individual parameters--that is, overall exploratory activity, number of visits
(deep in the hole) into or inspections of (at the upper surface) holes, number of
baited, unbaited, or previously baited holes visited or inspected, reinspections
of or revisits into any holes, number of pellets eaten, time to find pellets,
serial order collection (without intermediate inspections or visits), and
reference and working memory errors (visits, inspections, or total)--are obtained
simultaneously, and the results are immediately available after the end of each
experiment. The system appears to be well suited to neurophysiological,
neuropharmacological, and gene-technological investigations in rodent models.
PMID- 10758673
TI - Visualization of multiple influences on ocellar flight control in giant honeybees
with the data-mining tool Viscovery SOMine.
AB - Viscovery SOMine is a software tool for advanced analysis and monitoring of
numerical data sets. It was developed for professional use in business, industry,
and science and to support dependency analysis, deviation detection, unsupervised
clustering, nonlinear regression, data association, pattern recognition, and
animated monitoring. Based on the concept of self-organizing maps (SOMs), it
employs a robust variant of unsupervised neural networks--namely, Kohonen's Batch
SOM, which is further enhanced with a new scaling technique for speeding up the
learning process. This tool provides a powerful means by which to analyze complex
data sets without prior statistical knowledge. The data representation contained
in the trained SOM is systematically converted to be used in a spectrum of
visualization techniques, such as evaluating dependencies between components,
investigating geometric properties of the data distribution, searching for
clusters, or monitoring new data. We have used this software tool to analyze and
visualize multiple influences of the ocellar system on free-flight behavior in
giant honeybees. Occlusion of ocelli will affect orienting reactivities in
relation to flight target, level of disturbance, and position of the bee in the
flight chamber; it will induce phototaxis and make orienting imprecise and
dependent on motivational settings. Ocelli permit the adjustment of orienting
strategies to environmental demands by enforcing abilities such as centering or
flight kinetics and by providing independent control of posture and flight
course.
PMID- 10758674
TI - Living together, feeding apart: how to measure individual food consumption in
social house mice.
AB - In many studies with animals kept in groups, scientists need information about
each individual's food access without disturbance or separation of the animals.
We developed an automatic feeding device that allows measurement of individual
food consumption and experimental manipulation of individual food availability in
small social mammals, such as house mice. The feeding device is based on radio
frequency identification that triggers access to a motor-driven metal arm filled
with food pellets and is mediated with the help of subcutaneously implanted
transponders.
PMID- 10758675
TI - Behavioral test systems in marmoset monkeys.
AB - A number of neurobehavioral methods have been developed to test behavior in
marmoset monkeys. These test systems are (1) the bungalow test, which quantifies
spontaneous explorative behavior, (2) the hand-eye coordination test, which tests
a learned task of coordinated motor behavior, and (3) the fear-potentiated
startle response, which tests and quantifies pathological anxiety manifested by a
response of fright. The test systems are extensively discussed, and the value of
these test systems is exemplified by applying them to neurological disorders to
register disease activity and drug efficacy.
PMID- 10758676
TI - The AXS battery and "neurological fingerprints": meeting the challenge of
individual differences in human brain/behavior relations.
AB - A new test battery, the Auditory Cross-Section (AXS) Battery, offers a relatively
inexpensive, noninvasive means of describing a "neurological fingerprint" for
each individual. The battery's "access to axes" combines physiological and
behavioral measures so that a large set of dependent variables can be used to
profile an individual and can serve as a context for additional anatomical,
behavioral, and physiological data for the same subject. Physiological tests
included in the battery described here include (1) otoacoustic emissions (OAEs);
(2) the repeated evoked potentials version of the auditory brainstem response
(REPs/ABR); and (3) quantitative electroencephalography (qEEG). Complementary
behavioral tests were chosen to assess capabilities related to functional
asymmetries, such as phonemic awareness and fine motor control, and/or to
demonstrate temporal correlations that link behavioral and neural function.
Applications of the AXS battery include (1) documentation of individual
differences and similarities in neural organization that are related to specific
behaviors, such as learning styles or clinical symptoms; (2) provision of
contextual data for neuroimaging studies that aid in interpreting individually
specific patterns of activation; and (3) development of a neurotypology of human
brain/behavior relations, linking characteristics of neuroanatomy and
neurophysiology with features of behavior, and general body health.
PMID- 10758677
TI - P-SPACE: a program for simulating spatial behavior in small groups.
AB - P-SPACE is a computer program that simulates spatial behavior in a small group of
individuals. The program describes how interpersonal distances change through
time as a result of changes in microlevel features, such as the minimization of
local dissatisfaction. Agents are located in a two-dimensional lattice and can
move some discrete space units at each discrete time unit within their
neighborhood. A nonsymmetrical matrix of ideal distances between agents must be
specified. Agents move in order to minimize their dissatisfaction, defined as a
function of the discrepancy between possible future distances and ideal distances
between agents. At each iteration, agents will move to those cells in their
neighborhoods for which the function is minimized. Depending on the specific
values in the ideal-distance matrix, different kinds of social dynamics can be
simulated.
PMID- 10758678
TI - The Observer Video-Pro: new software for the collection, management, and
presentation of time-structured data from videotapes and digital media files.
AB - The Observer Video-Pro is a system for collecting, managing, analyzing, and
presenting observational data. It integrates The Observer software with time code
and multimedia hardware components. It extends the functionality of a
conventional real-time event recording program in various ways. Observational
data can be collected, reviewed, and edited with synchronized display of the
corresponding video images. For optimal visual feedback during coding, one can
display the video image in a window on the computer screen. Video playback from
either a VCR or a digital media file can be controlled by the computer, allowing
software-controlled jog, shuttle, and search functions. Besides a wide range of
VCRs, The Observer Video-Pro supports all major digital video file formats. The
software allows the user to summarize research findings in numerical, graphical,
or multimedia format. One can create a time--event plot for a quick glance at the
temporal structure of the observed process, or run specific analysis procedures
and generate reports with statistics. An Event Summary function is available for
exploratory and qualitative analysis. Video material can be summarized in a Video
Play List, which allows on-screen summary presentations or the creation of
highlight compilations on tape, CD, or other media. Video images can be captured
and saved as disk files, for use as illustrations in documents, slides for
presentations, and so forth. In this paper we describe the design and operation
of the system, illustrated with a case study from research on Repetitive Strain
Injury (RSI).
PMID- 10758679
TI - OTS: a program for converting Noldus Observer data files to SDIS files.
AB - A program for converting Noldus Observer data files (ODF) to sequential data
interchange standard (SDIS) files is described. Observer users who convert their
data files can then take advantage of various flexible and powerful data
modification and computational procedures available in the Generalized Sequential
Querier, a program that assumes SDIS-formatted files.
PMID- 10758680
TI - Dental notation.
PMID- 10758681
TI - Dental therapy.
PMID- 10758682
TI - Dental notation.
PMID- 10758683
TI - BDJ readership survey.
AB - Over the summer, BDJ readers were surveyed about the BDJ as part of a series of
BDJ surveys conducted since 1992. As well as assessing general views about the
BDJ, the survey also aimed to discover how successful the 1998 BDJ redesign had
been in incorporating reader's views from earlier surveys. The findings from the
1999 survey showed that the BDJ and BDA News continue to be the most read dental
publications. Readers turn to the BDJ before any other UK dental journal for
finding a job and reports on research. The full results of the survey are
reported below.
PMID- 10758684
TI - The healthcare professional and the Bolam test.
AB - This article will cover the history of the tort of negligence and how the
judgement in the case of Donoghue v Stevenson enabled the courts to 'develop the
law' to allow the concept of a 'duty of care' to develop which was extended to
include healthcare professionals. The Bolam test is then described and how it has
come to play such a prominent role in assisting the courts to assess if an
appropriate standard has been achieved in medical negligence litigation. Attempts
by the courts to move away from Bolam are discussed and the difficulties
encountered because of the reluctance of the appellate courts to approve such
decisions. Finally the recent House of Lords decision in Bolitho v City and
Hackney Health Authority is examined and the implications this may have on the
Bolam test.
PMID- 10758685
TI - Ameloblastoma--a diagnostic problem.
AB - A 50-year-old female was referred by her dental practitioner. She had a
periapical radiolucency associated with the lower right second premolar tooth.
The tooth was root treated and subsequently apicected. Tissue curetted at the
time of surgery was shown to be a solid ameloblastoma which was managed initially
by marginal excision. Histopathological examination of the resection specimen
demonstrated tumour at the inferior margin. A segmental resection of the mandible
with an immediate reconstruction using a free tissue transfer of the iliac crest
was therefore performed. The case shows the need for vigilance in dealing with
periapical pathology and underlines the importance of sending all tissue
specimens for histopathological analysis.
PMID- 10758686
TI - The mandibular first premolar as an abutment for distal-extension removable
partial dentures: a modified clasp assembly design.
AB - Sound mandibular first premolars can be used as sole abutments for bilateral
distal-extension removable partial dentures, if the denture is designed to
minimise the torque applied to the abutment teeth. A simplified modification of
the conventional torque-releasing clasp-assembly designs is suggested for these
teeth. This modification entails a mesial rest on each abutment tooth connected
to the distal proximal plate via a lingual bracing arm. A circumferential clasp
arm is optional for buccal retention of the removable partial denture. As with
conventional designs, the metal framework is designed to permit some rotational
tissueward movement of the distal extension bases, yet not compromise the
retention and stability of the prosthesis.
PMID- 10758687
TI - Economic evaluation of healthcare--is it important to us?
AB - Economic evaluation is now an accepted method for the appraisal of healthcare
programmes. Although it is used widely in medicine, its use in the field of
dentistry is only just beginning to achieve popularity. Economic evaluation in
dentistry is likely to become increasingly important in the future and this paper
aims to introduce the basics of the technique as well as describing some of the
dental settings in which it is currently being used.
PMID- 10758688
TI - Delays in the referral and treatment of oral squamous cell carcinoma.
AB - OBJECTIVE: To investigate the delays in referral and treatment of patients with
oral cancer. DESIGN: A retrospective study. SETTING: District General Hospital
Maxillofacial Unit (MFU). SUBJECTS: 100 consecutive patients with invasive
squamous cell carcinoma of the oral cavity referred to Rotherham District General
Hospital Maxillofacial Unit (RDGH MFU) between 15th March 1993 and 16th January
1998. METHOD: Information collected at the time of referral and treatment was
examined retrospectively. RESULTS: In the patients studied 72% were male, mean
age 61.2 years (sd = 11.2, range 37 to 88) and 28% female, mean age 65.6 years
(sd = 16.7, range 29 to 90). The majority of referrals were from medical
practitioners (56%) and most of the remainder being referred by dental
practitioners (36%). The patient delay was found to be the most significant with
only 39% presenting within 4 weeks, 29% delayed more than 3 months. There was no
statistical correlation between T-stage, alcohol or cigarette use and the patient
delay in presentation. Having presented to a medical or dental practitioner 69%
were referred within 1 week. There were no significant differences between the T
stages presenting to either medical or dental practitioners or in their delay in
referral for each stage. There was no significant difference in age or sex
distribution between the populations presenting to general medical or general
dental practitioners. General medical practitioners were more likely to refer a
patient urgently. Patients referred directly to the MFU were seen quickly but
those referred via an indirect route were delayed. 95% of patients were treated
within 6 weeks of first consultation. CONCLUSION: The majority of practitioners
refer patients with oral cancer within 1 week. The most significant delay is that
caused by the patient. Some practitioners referred patients to inappropriate
specialties, leading to indirect referrals. This results in additional delay in
the referral and treatment pathway. Education of the public and primary health
care workers should continue. Opportunistic screening of the oral mucosa should
be part of the dental check up, with possible targeting of patients at greatest
risk, particularly heavy drinkers and smokers.
PMID- 10758689
TI - Sealing ability of amalgam, super EBA cement, and MTA when used as retrograde
filling materials.
AB - OBJECTIVE: To compare apical microleakage of MTA following reverse retrograde
root filling with that following amalgam and EBA retrofilling. DESIGN:
Prospective random control trial. SETTING: It was conducted at the University of
Jordan in 1998. MATERIALS AND METHODS: The root canals of 79 extracted teeth were
instrumented and obturated with vertically condensed gutta-percha. Each tooth was
apically resected and the apex was prepared ultrasonically to 3 mm depth and the
root surface isolated with nail varnish. Teeth were divided randomly into three
groups of 25 teeth each. First group was retrofilled with amalgam, second group
with EBA and the third group with MTA. Following immersion in 1% methylene blue
dye for 72 hours, the roots were sectioned and the depth of dye penetration was
evaluated by a stereomicroscope at x10 magnification. INTERVENTIONS: Super EBA is
a reinforced zinc oxide cement based on a mixture of 32% eugenol and 68% ethoxy
benzoic acid (EBA). MTA is a mineral trioxide aggregate cement (MTA) based on a
mixture of sterile water. MAIN OUTCOME MEASURES: The sealing effectiveness of the
retrograde filling materials used in this study was determined by their ability
to inhibit dye penetration. RESULTS: 56% of the group filled with amalgam and 20%
of the group filled with EBA showed dye leakage beyond the retrofilling material
whereas the MTA group showed none, two samples from MTA group were eliminated
because of their fractured roots. The chi-squared test revealed a statistically
significant difference among all three groups (P < 0.05). CONCLUSION: MTA cement
provides a better seal than amalgam and EBA cement when used as retrograde
filling, but the extrapolation of this result into a clinical practice may be
questionable.
PMID- 10758690
TI - Out-of-hours dental services: a survey of current provision in the United
Kingdom.
AB - OBJECTIVE: To describe the variety of arrangements for providing out-of-hours
dental care in the UK. DESIGN: A telephone interview survey of health authorities
and health boards. SETTING: United Kingdom. SUBJECTS: 104 health authority
contacts, usually consultants in dental public health, dental advisers or others
in a position to describe the local dental service arrangements. RESULTS: At
weekends, 25 authorities have no formal dental care arrangements for unregistered
patients, 55 have separate arrangements for registered and unregistered patients,
and 44 have 'universal access' arrangements--for anyone in an area, regardless of
their registration status. On weekday nights over two-thirds (82/124) of UK
health authorities have no formal arrangements for unregistered patients. Where
there are separate 'safety-net' services intended for unregistered patients only
they are usually (in 48 of 55 authorities) emergency treatment sessions. A fifth
of authorities reported planned changes to their local out-of-hours arrangements,
including the introduction of telephone triage, and moves to make care available
at more times, to more people or from centralised premises. CONCLUSIONS: There is
extremely wide geographical variation in the organisation of out-of-hours dental
services provided in the United Kingdom. In many parts of the UK there are no
formal out-of-hours care arrangements for unregistered patients, even at
weekends. This unequal provision will mean inequitable access for many
unregistered patients. With increasing demands from a growing unregistered
population, and various government initiatives to make primary care services more
integrated and accessible, the highly fragmented pattern of provision in many
areas may no longer be acceptable.
PMID- 10758691
TI - Operation Safe Haven: an evaluation of health surveillance and monitoring in an
acute setting.
AB - From May to June 1999, 3,920 ethnic Albanians from Kosovo arrived in Australia as
part of Operation Safe Haven. These people were evacuated from refugee camps in
the former Yugoslav Republic of Macedonia. Initial processing in Australia
occurred at East Hills Reception Centre, and accommodation for the duration of
stay was provided in eight Haven Centres in five States. The arrival of a large
number of refugees in a short time frame is unprecedented in Australia. A health
surveillance system was developed and critical health data were collected to
assess health status and needs, plan care, monitor for potential outbreaks of
communicable diseases, track service use, to meet international reporting
requirements and document our response to this crisis. In this article the health
surveillance system is evaluated and suggestions are offered for the formulation
of specific guidelines necessary for health surveillance in acute settings.
PMID- 10758692
TI - Adverse events following immunisation associated with the 1998 Australian Measles
Control Campaign.
AB - The Measles Control Campaign (MCC) conducted in Australia from August to November
1998 resulted in a total of 1.7 million school children being vaccinated. This
article reports on the Adverse Events Following Immunisation (AEFI) associated
with measles-mumps-rubella vaccine (MMR) administered as part of the MCC. Reports
of adverse events that occurred within 30 days of administration of the MMR
vaccine were assessed by an expert panel that assigned a causality rating to each
AEFI. Reports with missing onset dates or uncertain causality were excluded.
Eighty-nine AEFI were classified as associated with MMR vaccine and the overall
rate of adverse events was 5.24 per 100,000 doses of vaccine administered. Of
these 46 were thought to be certainly caused by MMR vaccine, 23 were probably and
20 were possibly associated with the vaccine. Although 46 reactions were
categorised to be certainly caused by the MMR vaccine, the majority of these were
syncopal fits, syncope, local reactions, and allergic reactions that were short
lived, and all of these children recovered. The most commonly occurring adverse
reaction was syncopal fit with a rate of 1.24 per 100,000. There was only one
anaphylactic reaction, giving a rate of 0.06 per 100,000. The combined rate for
anaphylaxis, anaphylactoid and allergic reactions was 1.06 per 100,000
administered doses. The rate of seizures (febrile and afebrile) was 0.30 and
encephalopathy was 0.06 per 100,000 doses administered. Of the 89 children who
had an AEFI, 43 did not require hospitalisation or medical attention while 13
were seen in an emergency room, 14 were hospitalised and 19 were seen by a
doctor. There were no deaths reported resulting from the administration of the
MMR vaccine during the period of the campaign. All children who had an AEFI have
recovered although 9 children could not be followed up for reasons of
confidentiality. The overall rate of adverse events was lower than that observed
in the 1994 measles campaign conducted in the United Kingdom. On comparing the
risks and benefits of MMR vaccine, the benefits of this MCC far outweigh the
incidence of serious adverse events associated with immunisation.
PMID- 10758693
TI - Communicable diseases surveillance.
PMID- 10758694
TI - [Why folic acid?].
PMID- 10758695
TI - [Control of inhaled triggering factors decreases prolonged drug therapy
requirements in patients with asthma].
AB - The past decade of research has led to a greater understanding of the
pathogenesis of asthma and, in particular, the pivotal role of the underlying
inflammatory process. Along with inheritance in atopic patients, the presence of
inhaled triggering allergens are considered the predominant predisposing factors
in the development of the disease. We have conducted a longitudinal clinical
therapeutic study, which included 45 pediatrics patients with asthma, in order to
evaluate whether the removal of any potential inhaled triggering factor, could
decrease the requirement of drug based anti-inflammatory therapy. Patients
admitted in this study presented at least, two monthly asthma attacks during the
last four months. A single treatment with theophylline (group A), beclomethasone
(group B) or salbutamol (group C), was prescribed during the first 2 weeks, along
with specific instructions to avoid inhaled allergens. Regardless of the drug
used, patients showed impressive and prolonged clinical improvement during 6
months, reduction of total IgE serum levels in the three groups (p < 0.02; 0.005
and 0.02 respectively) and favorable modification of force expiratory volume at
the first second, forced vital capacity and flow expiratory peak. During the
observation period a constant monitoring of mites allergens concentrations was
performed, showing a decrease of these antigens, associated with clinical
improvement, and only in those patients who remained symptomatic (group A 31%,
group B 29% and group C 9%), failures performing the measures designed to reduce
their exposure to environmental allergens, was demonstrated. These results
suggest that reduction of inhaled triggering factors may decrease the requirement
of anti-inflammatory drug therapy to control the symptoms in patients with
asthma.
PMID- 10758696
TI - [Comparative study of indirect immunofluorescence (IIF) and ELISA techniques in
the detection of parvovirus B19].
AB - To determine the seroprevalence of IgG and IgM antibodies against Parvovirus B19
(P. B19), we studied the sera of 53 patients with different hematologic disorders
and the sera of 15 controls using indirect immunofluorescence (IFI) and the ELISA
method. The prevalence of IgG in the control group was 46.6%, in patients with
aplastic crisis was 83.3% (IFI) and 66.7% (ELISA) and, in patients without crisis
was 68.9% (IFI) and 72.4% (ELISA). IgM was negative except for patients with
crisis: 8.3% (IFI) and 29.1% (ELISA). The higher seroprevalence (IgG) found in
patients in comparison with controls might be due to a greater exposure of of
patients to the virus. The agreement for both techniques was 81%(IgG) and 93%
(IgM) however ELISA technique was more sensitive for detecting IgM of P. B19. In
spite of serologic evidence and evaluating a simple serum sample per patient, we
could establish an association between aplastic crisis and viral infection for
IgM ELISA but not for IgG between hematologic disorders and infection for the P.
B19.
PMID- 10758697
TI - [Prevalence of the activated protein C resistance in indigenous and Black
populations of the western Venezuela].
AB - The Activated Protein C Resistance (APCR) is the common phenotype of Factor V
Leiden (arg506gln), which is considered as a thrombotic risk factor. The aim of
this study was to determine the prevalence of APCR and its association with
Factor V Leiden in indian and black populations from Zulia State in western
Venezuela. Blood samples were taken from 80 Yukpa indians from Sierra de Perija
and 91 black individuals from the southeast of Lago de Maracaibo. APCR was
determined by the Dahlback's method with the modifications of Jorquera et al. and
Trossaert et al. The results were expressed as n-APC-SR (positive value < or =
0.75). Factor V Leiden genotype was identified by PCR and restriction analysis
standard methods at the Institute of Human Genetics (Greifswald, Germany). No
significative difference was found between n-APC-SR from indians (mean +/- SEM
1.13 +/- 0.02, CI 95% = 1.07-1.19) and black people (1.07 +/- 0.02, CI 95% = 1.03
1.12). APCR prevalence from indians was 1.25% (1 out of 80) who was heterozygote
case for F V Leiden and 4.4% (4 out of 91) from blacks (one case was heterozygous
for F V Leiden). No thrombotic event personal or familial was demonstrate. Our
data represent the first report related to the association between APCR and F V
Leiden in venezuelan indian and black individuals. APCR without the Factor V
Leiden expression suggest a different type of mutation in the Factor V molecule.
In spite of high endogamy in the indian group, we can not discard the role of
foreign genes in both populations. The determination of the prevalence of this
phenotype and its molecular marker in various ethnic groups is important for the
interpretation of their role as risk factors for thrombotic disease.
PMID- 10758698
TI - [Intestinal parasites in school children at a public institution in Maracaibo
municipality, Venezuela].
AB - To determine the prevalence and epidemiological parameters of intestinal
parasites in schoolchildren, a faecal analysis was performed in 349 individuals
of both sexes, between 5 and 16 years of age. The methodology used included, a
fresh test, formol-ether technique and faecal egg counts by the Kato-Katz method.
Eighty three per cent of the children presented enteroparasites, with a high
prevalence of polyparasitism (71.6%). There was not significative difference
between parasitoses, sex and age. However, it was observed an increase of
helminthiasis and protozooses in children between 7 and 10 years of age. The
principal enteroparasites founded were: Trichuris trichiura (41.8%), Ascaris
lumbricoides (35.2%), Blastocystis hominis (48.1%) and Endolimax nana (22.9%).
When the intensity of infestation was studied by the faecal egg counts, it was
observed that the highest percentage of children with T. trichiura had light
infestations (84.3%), while 45.9% of the children with A. lumbricoides had severe
infestations. The Abundance, Mean Intensity and Aggregation Coefficient (k)
values show an over-dispersed spatial disposition of both helminths, where only
few children harbour heavy burdens and eliminate a large quantity of eggs. This
aggregation was higher for T. trichiura (k = 0.298) than for A. lumbricoides (k =
1.138).
PMID- 10758699
TI - [Cortical dysplasias and epilepsy].
AB - Cortical dysplasias are a spectrum of malformations of the cerebral cortex that
arise during development and are associated with epilepsy and mental retardation.
New neuroimaging techniques have helped an in vivo" diagnosis of these conditions
and the definition of specific clinical syndromes. This article reviews the
etiology of these disorders, and briefly discusses the clinical and neuroimaging
findings, and the prognosis of the epilepsy secondary to these malformations.
PMID- 10758700
TI - Abortion, breast cancer, and informed consent.
AB - The purpose of this article is to show that the current level of scientific
evidence linking induced abortion with increased breast cancer risk is sufficient
to support an ethical and legal duty to disclose fully the risk to women who are
considering induced abortion. The article examines the relationship between this
evidence and the elements of a medical malpractice claim alleging failure to
obtain informed consent. The first part focuses on the elements of informed
consent, which require the plaintiff to establish that the physician had a duty
to disclose information, which he failed to disclose, that this failure to
disclose was a legal cause of the plaintiff's decision to undergo the procedure,
and the procedure was a legal cause of the plaintiff's injury. The second part
compares two prevalent standards for determining which risks a physician has a
duty to disclose. Part three reviews the scientific evidence of the
abortion/breast cancer (ABC) link and explains why it survives both the Frye and
the Daubert tests for admissibility of expert testimony. The fourth part assesses
the materiality of the risk posed by the ABC link. Parts five and six discuss
evidentiary issues and the possibility of punitive damage awards.
PMID- 10758701
TI - Death, dying, and euthanasia: Australia versus the Northern Territory.
AB - The purpose of this article is to explain what has happened in the euthanasia
debate in the Australian States and Territories, and to give a more detailed
account of how the Northern Territory's euthanasia laws were overturned by the
Federal Government. Dr. Fleming begins with a review of euthanasia legislation in
each State and Territory, then proceeds with an analysis of the events in the
Northern Territory leading to reversal of its euthanasia laws, and includes the
effect of the euthanasia law on the Aboriginal people. He concludes that the
repeal of the 1995 Northern Territory's Rights of the Terminally Ill Act was a
significant setback for the pro-euthanasia movement not only in Australia, but
worldwide.
PMID- 10758702
TI - Hope Clinic vs. Ryan.
PMID- 10758703
TI - Human cloning. Position paper of the Catholic Medical Association.
PMID- 10758704
TI - An open letter of the Dutch Physicians' League [Nederlands Artsenverbond].
PMID- 10758705
TI - Obstetrical outcome following epidural analgesia in 506 consecutive deliveries.
AB - We relate the experience of 506 consecutive deliveries under epidural analgesia
in the same hospital, by the same obstetrician (JSS). 336 patients delivered
without epidural analgesia during the same period. In the epidural group (n =
506), 93 patients had a normal spontaneous vaginal delivery, 357 had a low
forceps, 22 had a mid-forceps, 4 had an assisted breech extraction, and 30
delivered by cesarean section. There were 24 cases (out of 506) of significant
hypotension; all of them responded to an intravenous bolus of ephedrine. There
was one case of accidental dural puncture that was treated with a blood patch.
The degree of pain relief obtained by the epidural was deemed satisfactory in 456
patients (90%). The primary cesarean section rate in patients who received an
epidural was not higher than that in patients who did not. Eleven newborns in the
epidural group had one-minute Apgar scores between 4 and 6, but they all had
excellent Apgar scores at five minutes. None had a one-minute Apgar score below
4. We conclude that epidural analgesia is a safe and highly effective method of
pain relief during labor.
PMID- 10758706
TI - Recommendations for the school health physical examination in Lebanon.
AB - School health developed gradually over the years; starting with efforts to keep
contagion out of schools to global programs of comprehensive services. One of its
components, school medicine, covers screening examinations, record maintenance,
emergency care, immunization monitoring and health counseling. This paper
proposes the essential health activities to be performed during a screening
school examination in Lebanon. The recommendations are based on a combination of
international literature review of evidence and the existence of Lebanese
epidemiological reports identifying specific problems. Vaccination record review,
tuberculin testing, vision, hearing, dental and skin disorders screening
procedures are proposed as essential activities of the school physical
examination.
PMID- 10758707
TI - Diagnosis and management of chronic hepatitis C.
AB - Chronic HCV infection is a major cause of chronic liver disease, cirrhosis and
hepatocellular carcinoma worldwide. The disease is indolent or subclinical in the
majority of patients but alcohol consumption and older age at infection may be
associated with an accelerated course. Current diagnostic modalities are highly
sensitive and specific in confirming the diagnosis and may help predict response
to therapy. Treatment with interferon is effective in clearing the virus in a
small number of patients but the addition of ribavirin results in an enhanced
overall chance of viral eradication. The development of an effective vaccine to
HCV is presently encumbered by the presence of multiple viral genomic subtypes
and the high rate of spontaneous viral mutation leading to limited efficacy of
neutralizing antibodies.
PMID- 10758708
TI - [Arterial essential hypertension and associated pathologies].
PMID- 10758709
TI - [Report on world health 1999: toward a real change].
PMID- 10758710
TI - [Thrombolytic treatment of obstructions of mechanical valve prostheses. Apropos
of 4 cases and analysis of the literature].
AB - The obstruction of the mechanical valve prothesis (OMVP) is a serious
complication. The treatment of this complication was classically surgical.
Recently, the thrombolytic treatment was introduced as an alternative approach
for patients with high perioperative risk and for those in whom the mechanism of
the obstruction is a recently formed thrombus. The authors report four cases of
OMVP treated by a thrombolytic agent (Streptokinase, SK, Streptase). Immediate
success was obtained in all theses four cases. One late recurrence with fatal
issue was noted. All four prostheses were Saint Jude medical (SJM), three in
mitral and one in aortic position respectively. The details of the clinical
presentation (acute or progressive dyspnea) as well as the contribution of the
echocardiography to the diagnosis were presented. The evolution of this
therapeutic approach and the international recommendations were reviewed.
PMID- 10758711
TI - Mirizzi syndrome. Case presentation with review of the literature.
AB - Mirizzi syndrome is a rare pathology of the extrahepatic biliary system caused by
a large gallbladder calculous either compressing or eroding into the collecting
biliary tree. This paper describes a case of Mirizzi syndrome with atypical
presentation. A review of the literature including diagnostic and therapeutic
modalities are reported.
PMID- 10758712
TI - [A rare manifestation of hypothyroidism: intestinal obstruction. Report of 2
cases and review of the literature].
AB - Gastrointestinal manifestations of hypothyroidism are unfrequent. They consist
particularly in hypomotility, intestinal atony, and pseudoobstruction. A high
index of suspicion must exist, especially in elder subjects, in order to avoid
unnecessary and even harmful investigation and intervention. We are reporting two
cases of intestinal occlusion due to hypothyroidism with review of the
literature.
PMID- 10758713
TI - Effects of runaway health care costs.
PMID- 10758714
TI - Lessons learned.
AB - Mental health care reform in the public sector remains a local proposition.
Oregon has thus far been able to avoid major failures and has modest successes to
report. Although the road to achieving all that was envisioned at the outset
remains long, the inclusive process followed gives reason for hope.
PMID- 10758715
TI - Overview of Medicaid managed behavioral health care.
AB - The Oregon Health Plan is being implemented at a time when many states are
revising their Medicaid mental health programs. A national overview places this
state's efforts into context.
PMID- 10758716
TI - Background on the Oregon Health Plan.
AB - Because of limited resources, the health care industry has been forced to choose
how funds are spent. Public fee-for-service systems have begun to face the hard
choices inherent in managed care. The Oregon Health Plan was designed to provide
a rational approach to addressing these changes directly.
PMID- 10758717
TI - John Kitzhaber and the Oregon Health Plan.
AB - The Oregon Health Plan could not have developed into its current form without
strong leadership. Criticism, which has shifted from the political left to the
right, has been a constant companion, making integration of mental health
services more precarious.
PMID- 10758718
TI - State goals for mental health services.
AB - As Oregon moved its Medicaid services into the managed care plan, mental health
goals were similar to those on the physical health side--cost control, expansion
of services, and increased flexibility.
PMID- 10758719
TI - Integrating mental health into the Oregon Health Plan.
AB - Public mental health has long struggled to be accepted as a part of health care.
Its interface with social services and its broad spectrum of professionals make a
clear definition of public mental health's boundaries difficult, fueling
policymakers' skepticism about such acceptance. The Oregon Health Plan was the
result of a process that explicitly included mental health but recognized that
the tools for doing so need to be carefully developed.
PMID- 10758720
TI - The mental health organizations.
AB - The mental health organizations in the mental health phase-in were Oregon's
pioneers moving into public managed care. A delicate balance between county
mental health authority and private expertise was struck locally to yield a
variety of organizational models across the state.
PMID- 10758721
TI - Measuring change: the first two years.
AB - A clear measurement strategy was required to offer the mental health
organizations the flexibility they sought, yet ensure accountability. Early
findings show mixed results.
PMID- 10758722
TI - Quantitative results.
AB - Detailed analysis of information obtained is still under way, but initial trends
appear to show stable enrollment, maintenance of minimum service levels, and
lower hospital utilization.
PMID- 10758723
TI - Costs and financial results.
AB - Initial financial information appears to indicate that rates were adequate in the
phase-in regions and that state payments were about in the range that was
expected.
PMID- 10758724
TI - Consumers' experiences of mental health policymaking.
AB - Consumers' roles are changing from passive recipients of mental health services
to active participants. The Oregon Health Plan provided an opportunity to hasten
this development, which required learning by all.
PMID- 10758725
TI - Multicultural mental health services.
AB - Oregon has a significant Indochinese minority community. Seen through the eyes of
this group, few of the difficulties minorities encounter when seeking culturally
competent services have changed under the Oregon Health Plan.
PMID- 10758726
TI - Systemic impact of risk-sharing arrangements.
AB - The overall complexity and systemic impact of what is ostensibly a simple change
in payment methods were the most important lessons to learn.
PMID- 10758727
TI - The Oregon experience: a point of view.
AB - What has not been addressed is how Oregon will maintain and expand the early
breakthrough of the statewide consensus dialogue that created the "list" of
prioritized medical conditions.
PMID- 10758728
TI - [Is a 1-week treatment enough and safe for the healing of peptic ulcer?].
PMID- 10758729
TI - [Cell cycle and cancer--from the tumor cell line to the patient].
AB - In normal cells the cell cycle is precisely regulated by a set of different gene
products. Cyclins move cells along into the cycle while cyclin-dependent kinase
inhibitors function as cell cycle brakes. Mutations in such genes are frequent in
cancer and may exert a profound effect on their biology. Overactive cyclins may
push cells into inadequate cycling. Inactivation of cell cycle brakes might
likewise provide a proliferation advantage to tumour cells over normal cells.
Basic research in cell biology and molecular biology has greatly enlarged our
knowledge in this timely field. The detection of gene alterations impinging on
the cell cycle machinery in cancer is of increasing practical relevance. Mutated
genes such as the inactivated p53 tumour suppressor gene may be prognostically
relevant in human cancer, or predict the appropriate choice of treatment. Precise
knowledge of cell cycle disturbances will eventually pave the way towards gene
therapy of cancer although achievement of this goal is still in the distant
future.
PMID- 10758730
TI - [Adhesion molecules].
AB - Phagocytosis by specialized cells was, expressed in evolutionary terms, one of
the first defense strategies of organisms in order to eliminate foreign
materials. Migration of professional phagocytic cells to a lesion thus represents
one of the most basic aspects of host defense. The article describes different
families of adhesion molecules and their contribution to this process.
PMID- 10758731
TI - [Kidney function from the molecular viewpoint].
AB - Over the last 10-15 years the use of cellular and molecular biology permitted the
analysis of kidney function at a cellular/molecular level. These advances allow a
more detailed understanding of physiological/pathophysiological mechanisms. By
taking examples from our studies on the renal handling of inorganic phosphate
this gain in knowledge' is illustrated.
PMID- 10758732
TI - [New therapeutic possibilities in chronic hepatitis C].
AB - This article briefly reviews the results of antiviral treatment of chronic
hepatitis C with interferon-alpha. Its relation to the natural course of the
illness is discussed. Interferon monotherapy achieves definitive viral
elimination in a small minority of patients only. The therapeutic response rate
can be enhanced by combining interferon-alpha with ribavirin as well as by
increasing interferon dosage or prolonging treatment. A number of questions
remain unanswered with regard to the optimal treatment modality and cost
effectiveness. Thus the current recommendation is to treat suitable patients
within the frame of controlled studies.
PMID- 10758733
TI - [Hematuria and proteinuria--old names, new horizons].
AB - Gradually advanced diagnostic standards for the analysis of urine specimens
during the last years led to improved clinical arguments providing important
clues. Unnecessary diagnostic procedures like IVP or cytoscopy in suspected
glomerular hematuria may for instance be prevented, the patients comfort enhanced
and costs reduced. A possible diagnostic algorithm in a case with suspected
urologic pathology is shown.
PMID- 10758734
TI - [Post-traumatic knee joint effusion. Juvenile chronic arthritis].
PMID- 10758735
TI - Susceptibility of Streptococcus pneumoniae isolated from the respiratory tract of
hospitalized children with respiratory tract infections.
AB - The most frequent nasopharyngeal carriers of Streptococcus pneumoniae are young
children. Frequent use of antimicrobial therapy in children facilitates the
selection of penicillin-resistant strains in this population. These strains,
especially if highly resistant, may cause serious therapeutic problems. Aim of
the study was to monitor penicillin- and multidrug-resistant S. pneumoniae
strains in hospitalized children with respiratory tract infections. Hospitalized
children up to five years were examined for S. pneumoniae presence in their upper
respiratory tract. Susceptibility to penicillin, erythromycin,
trimethoprim/sulfamethoxazole, tetracycline, and chloramphenicol was determined
by the disk-diffusion method. The minimal inhibitory concentrations (MIC) of
penicillin, erythromycin and trimethoprim/sulfamethoxazole were measured by the E
test. S. pneumoniae strain was isolated from 60 (34.7%) out of 173
microbiologically examined children; 2 different strains were isolated in 9
cases. Nine strains (13.0%) were penicillin resistant with MICs ranging from 1.5
to 8 mg/L, and 17 strains (24.6%) had intermediate susceptibility. Seventeen
(24.6%) strains were erythromycin resistant (MIC > or = 1 mg/L). Eighteen strains
(26.1%) were resistant and 7 strains (10.1%) were intermediately susceptible to
trimethoprim/sulfamethoxazole. Ten strains (14.5%) were not susceptible to
tetracycline, and 11 (15.9%) to chloramphenicol. Non-susceptibility (resistance
or intermediate susceptibility) to the tested antimicrobials was more prevalent
in penicillin-nonsusceptible strains. The current level of S. pneumoniae
resistant to antimicrobial drugs in children with respiratory tract infections in
the hospital department monitored in our study do not cause problems in the
choice of antibacterial therapy. Penicillins still can remain the drug of choice
in cases when typical bacterial causing agents of respiratory tract infections
are suspected. (Tab. 3, Fig. 2, Ref. 31.)
PMID- 10758736
TI - [Is PLA1/A2 gene polymorphism of platelet membrane glycoprotein IIIa a risk
factor for myocardial infarct?].
AB - BACKGROUND: The PlA1/A2 polymorphism of the human platelet membrane glycoprotein
IIIa gene cause T-->C transition in the exon ii (position 1565) resulting in the
leucine-->proline substitution in amino-acid sequence. This polymorphism was
shown to be associated with increased risk of myocardial infarction (MI). AIM: To
test genetic parameters of the PlA1/A2 polymorphism in our population and to
assess the relation between mutant PlA2 allele and MI. METHODS: DNA was isolated
from peripheral blood, collected from 40 patients with MI and with present risk
factors (hypertension, hypercholesterolaemia, diabetes, obesity, smoking...), 33
patients with MI without risk factors, 34 controls with equivalent average age to
both groups of the MI-patients, 58 control probands without MI in their family
history and 33 healthy controls randomly recruited. After PCR amplification the
resulting 267 bp fragment was digested with the restriction endonuclease NciI and
subfragments were separated electrophoretically in 12% polyacrylamide gel.
RESULTS: The frequency of the PlA2 allele was 0.121 in patients with MI without
risk factors, 0.205 in patients with present risk factors, 0.162 in controls of
the equivalent average age to the MI-patients, 0.172 in controls without MI in
their family history and 0.20 in healthy controls randomly recruited. Genotype
frequencies were in all groups in genetic equilibrium. Although the groups
differed significantly (p < 0.01) in serum concentrations of total cholesterol,
HDL-cholesterol, LDL-cholesterol, apolipoprotein A-1, apolipoprotein B and
malondialdehyde, no significant differences in the serum concentrations of these
metabolites between A1/A1, A1/A2 and A2/A2 genotypes were observed. CONCLUSIONS:
PLA1/A2 polymorphism is associated with MI, however not as a dominant risk
factor, but as a part of environmentally influencable multigene system. There is
no relation between genotypes of the PLA1/A2 polymorphism and the lipoproteins
plasma concentrations. (Tab. 4, Ref. 17.)
PMID- 10758737
TI - [Leber's hereditary optic nerve neuropathy].
AB - The authors present a case report of 26 years old man with bilateral optic nerve
neuropathy. Detection of heteroplasmic mutation of mitochondrial DNA at G3460A
site confirmed the suspicion on Lebers hereditary optic nerve neuropathy (LHON).
Genetic and environmental factors of the disease and various accompanying
neurologic and other symptoms, which can together with the optic nerve defect
participate in the development of of the LOHN clinical pattern are discussed.
(Ref. 12.)
PMID- 10758738
TI - [Objective auditory examination of neonates using otoacoustic emissions].
AB - Auditory examination performed by an objective examination method in newborns is
aimed to early identify possible permanent auditory defects. Detection of
permanent auditory defect already in the first days after birth enables early
treatment and rehabilitation with the help of hearing apparatus and later
possibly with cochlear implants. The paper presents principles of auditory
examinations with the help of otoacoustic emissions and analyzes the results of a
screening using otoacoustic emissions performed in a group of 596 newborns and
the cause of deafness in a group of 101 prelingually deaf children. On the basis
of the results and literature data the authors recommend gradual introduction of
universal auditory screening of newborns in Slovak republic. (Tab. 3, Fig. 4,
Ref. 13.)
PMID- 10758739
TI - [Auditory screening of neonates using an objective method--otoacoustic
emissions].
AB - Screening for hearing loss in children in Slovak republic with non-objective
methods detects only deaf children, mean age of the diagnosis establishment is
even 2.5 years. It is necessary for healthy child development to detect and treat
a child with bilateral defect before 1 year of age. Preliminary results of
auditory screening in 456 newborns with objective method of otoacoustic emissions
(OAE) proved the necessity of otoacoustic screening in all risk newborns. In one
of 204 risk newborns serious hearing loss was proved with BERA examination and in
next 8 of them it is suspected according to the OAE results and additional
tympanometric examination with the A curve. Until now in newborn without risk of
hearing loss in history were not detected bilateral hearing loss, only
unilateral, not requiring treatment. (Fig. 1, Tab. 2. Ref. 9.)
PMID- 10758740
TI - [The hypothalamo-hypophyseal-adrenocortical axis: organization, dynamic aspects
and the effect of stress on corticotropin-releasing hormone activity in neurons].
AB - Hypothalamic-hypophyseal-adrenocortical (HPA) axis, often termed stress axis,
together with the peripheral sympathetic nervous system and the adrenomedullar
hormonal system very sensitively and promptly responds to both external and
internal stimuli endangering homeostasis. HPA helps to maintain the physiological
equilibrium. The HPA axis forms the first line in the protection of the organism,
monitoring the negative factors affecting the stability of the organism by
responding by secretion of glucocorticoids. The exaggerated activity of HPA axis
is harmful for the organism since it induces a number of disorders including
hyperlipidemia, muscle atrophy, hypertension etc., not excluding brain damage.
The alterations of the HPA axis lead to hypersecretion of glucocorticoids which
may play an important role in the pathology of psychical and neurological
diseases. (Tab. 3, Fig. 2, Ref. 31.)
PMID- 10758741
TI - [The concept and use of artificial neural networks in medicine].
AB - The use of neural networks in medicine is concentrated mainly on classification
purposes. In particular, neural networks applications in spectroscopy are
discussed, where this approach offers powerful algorithmic tools for
interpretation of spectral data and elucidation of chemical structure of
compounds. Neural networks are effective also for the classification and
prediction of chemical reactivity and structure of proteins and also for QSAR and
QSRR studies. At present the most successful use of neural networks in clinical
medicine is image analysis and analysis of wave forms--ECG or EEG pattern
recognition and classification and partly also clinical diagnosis and prognosis.
(Tab. 7, Fig. 2, Ref. 170.)
PMID- 10758742
TI - [Use of simulations and phantoms in stomatology education--yesterday and today].
AB - Authors offer the concise historical survey of the education of preclinical
stomatology from the year 1953 to the present. They direct specially to
application simulators and simulation in the dental education and importance of
this way. Authors emphasize the importance of quality of preclinical erudition
for students of stomatology; they lay stress upon the development of psychomotor
skill of students. This is not possible without the modern didactic technique.
(Ref. 5.)
PMID- 10758743
TI - Short-term effects of a chicken egg shell powder enriched dairy-based products on
bone mineral density in persons with osteoporosis or osteopenia.
AB - Based on the high calcium content, chicken egg shells are an interesting source
of calcium. We studied the short-term effects on bone mineral density (BMD) of
the lumbar spine and hip in 9 women and one man (mean age +/- SD, 63.9 +/- 8.1
years) with osteoporosis or osteopenia. Also the effects on pain and general well
being were monitored. Ten women (62.5 +/- 5.0 years) from a population study on
BMD served as a control group. During a study period of 4-8 months, the
intervention group consumed twice daily a dairy-based supplement which resulted
in a daily intake of, among others, 3.0 g of egg shell powder, 400 IU of vitamin
D3 and 400 mg of magnesium. BMD of the lumbar spine (anteroposterior (AP) and
lateral (LA) position) and hip were measured by dual-energy X-ray absorptiometry.
After the intervention period, BMDs of the lumbar spine, total proximal femur and
trochanter were significantly (p < 0.05) increased with (median) 4.4%: (range)
1.7 to 10.4% (lumbar spine AP), 5.7%: -1.3 to 15.9% (lumbar spine LA), 2.2%: -1.9
to 9.4% (total proximal femur), 1.8%: -1.8 to 9.0% (trochanter). Within a period
of 4 months, an important reduction in pain was reported and as a consequence an
improvement in general well-being. In the control group, BMDs of the lumbar spine
AP and of the femoral neck significantly decreased over a period of 8 months with
-0.7% (-1.3 to 0.2%) and -0.9% (-2.4 to -0.1%) respectively. Six women of the
intervention group continued to use the supplement on their own free will and
without any check on compliance, up to 24 months. They consumed the supplement
only once daily except for the last three months when they were asked to take the
double dosage again. After 24 months BMDs did not differ from baseline. This
study shows that egg shell powder is a source of bioavailable calcium.
Furthermore, this pilot study indicates that the chicken egg shell powder
enriched dairy-based supplement increases BMD of subjects with a low bone mass in
the short term and as a consequence delays bone demineralisation for a longer
period. (Tab. 3, Fig. 1, Ref. 23.)
PMID- 10758744
TI - [Surgical treatment of total anomalous pulmonary venous return].
AB - BACKGROUND: Total abnormal pulmonary venous return (TAPVR), mainly the
obstructive type represents the most riskful critical congenital heart defect
requiring urgent surgery immediately after birth. THE AIM OF THE STUDY: Analysis
of surgical correction of TAPVR results performed from December 1992 to December
1998. METHODS: Twenty-seven patients underwent surgery for TAPVR. 13 of them
(48%) presented with hemodynamically severe obstruction. Mean age in the group
with obstruction was 3.6 +/- 3.2 days with mean weight of 3282 +/- 537 grams.
RESULTS: From the 27 studied patients 5 (18.5%) died. Mean duration of the study
in the whole group is 1.91 +/- 2.01 years. Actuarial survival in the first month
is 85%, in the second month 81% and remains identical in the 1., 2., 3., 4., 5.,
6. year of the study. Univariate analysis identified operation before the year
1996 (p = 0.0056) as a risk factor of immediate mortality. Introduction of
ultrafiltration significantly eliminated mortality (p = 0.0101). Remaining
variables (age, weight, sex, obstructive TAPVR, TAPVR, extracorporeal circulation
duration, pulmonary hypertension) did not significantly influence the survival (p
more than 0.05). Multivariate analysis defined operation before the year 1996 as
the sole risk factor of mortality (p = 0.0033). In patients operated on in the
year 1996 (n = 15) was the survival in the studied period 100%. CONCLUSION: Since
the year 1996 the results of surgical treatment of TAPVR significantly improved.
The key role in the improvement have better urgent diagnostic and surgery,
improvement of surgical technique and myocardial protection, introduction of
modified ultrafiltration and the quality of postoperative care. Psychomotor
development of children after correction is comparable with healthy population,
all patients are in NYHA I class. (Tab. 2, Fig. 4, Ref. 9.)
PMID- 10758745
TI - [Endovascular and vascular surgical reconstruction in the treatment of ischemia
of the lower extremities].
AB - The authors analyze the importance of PTA, EAE and vascular reconstructive
surgery of obliterative atherosclerosis on lower extremities. According to their
own experiences the advantages and also negatives of particular treatment methods
are discussed and studied group of patients is presented. On the basis of the
achieved results the authors suppose that ischemic syndrome of lower extremities
is attractive not only for vascular surgeon, but also for interventional
radiologist. When properly indicated, particular treatment modalities can have
substantiation in the treatment of obliterative atherosclerosis. (Tab. 9, Fig. 5,
Ref. 29.)
PMID- 10758746
TI - [Emergency ERCP and acute biliary pancreatitis].
AB - In the period from 1992 to 1997, a total of 130 urgent therapeutic ERCPs were
performed at the 2nd Department of Surgery of the Faculty of Medicine in Brno.
The examination was indicated because of acute pancreatitis, acute septic
cholangitis, and papillary ileus. Fifty nine patients with proven acute biliary
pancreatitis and successful endoscopic papillosphincterotomy were followed up
subsequently. Information on 44 patients could be retrieved (75%). The results
were evaluated and compared with a group of patients treated for acute biliary
pancreatitis at the 2nd Department of Surgery in Brno before introduction of
urgent therapeutic ERCPs. In addition to lower mortality, in the group of
patients who underwent endoscopy a decrease in the percentage of surgical
revisions needed was reached, and in the group with conservative treatment,
statistically significant reduction of hospitalization was duration achieved.
(Tab. 3, Fig. 1, Ref. 14.)
PMID- 10758747
TI - [Comprehensive treatment of crural ulcers].
AB - The authors present 65 patients treated in the stage C6 of chronic venous
insufficiency. Conservative therapy was performed in the cases with large ulcers
associated with crural edema. Recovery was observed in 47 cases (73%) during 5
months. Recurrence authors in 3 patients (5%) and the treatment was not
successful in 7 cases (10%). In 8 patients primary or secondary surgical
treatment was performed. The average period of treatment was 1.6 months. (Tab. 1,
Ref. 24.)
PMID- 10758748
TI - [Endoscopic disruption of perforators in the leg].
AB - Since September 15, 1994 endoscopic eliminations of perforators in Linton's line
of the leg were performed in the Surgical Sanatorium in Brno Vinicni 235. Before
January 1, 1999 80 of these operations were performed. Based on the results
subfascial ligatures on the leg according to Linton can be adequately replaced by
less multilating operations, i.e. by endoscopic elimination of perforators in
Linton's line of the leg. (Ref. 4.)
PMID- 10758749
TI - [Personal experience in the use of magnetotherapy in diseases of the
musculoskeletal system].
AB - Therapeutic application of pulsatile electromagnetic field in disorders of
motility is recently becoming more frequent. Despite this fact information about
the effectiveness of this therapy in the literature are rare. The aim of this
study was therefore the treatment of 576 patients who suffered from vertebral
syndrome, gonarthritis and coxarthritis. For application of pulsatile
electromagnetic field MTU 500H Therapy System was used. Pulsatile electromagnetic
field had a frequency valve of 4.5 mT in all studied groups and magnetic
induction valve 12.5-18.75 mT in the 1st group. In the 2nd group the intensity
was 5.8-7.3 mT and in the 3rd group it was 7.6-11.4 mT. The time of
inclination/declination in the 1st group was 20/60 ms, in the 2nd group 40/80 ms
and in the 3rd group 40/90 ms. The electromagnetic field was applied during 10
days. In the 1st-3rd day during 20 minutes and in the 4th-10th day during 30
minutes. The therapy was repeated in every patient after 3 months with values of
intensity higher by 50%. In the time of pulsatile electro-magnetotherapy the
patients were without pharmacotherapy or other physiotherapy. The application of
pulsatile electromagnetic field is a very effective therapy of vertebral
syndrome, gonarthritis and coxarthritis. The results have shown that the therapy
was more effective in patients suffering from gonarthrosis, than in patients with
vertebral syndrome and least effective in patients with coxarthosis. Owing to
regression of oedema and pain relieve the motility of patients improved. (Tab. 3,
Ref. 19.)
PMID- 10758750
TI - [Malignant fibrous histiocytoma of the hand].
AB - Most soft tissue sarcomas are malignant tumors of the mesodermal tissue of the
head and neck, trunk, retroperitoneum or extremities, although neurosarcomas and
primitive neuroectodermal tumors are of ectodermal origin. Soft-tissue sarcomas
of the upper extremity constitute 14% of all soft-tissue sarcomas, they are one
third as common as those of the lower extremity. A case of patient with malignant
fibrous histiocytoma of the fourth finger of the left hand is presented. (Tab. 2,
Fig. 10, Ref. 15.)
PMID- 10758751
TI - [The role of risk factors in developmental diagnosis].
AB - Cerebral Palsy (CP) is a chronic disorder of motion and postural balance caused
by defect or damage of immature brain. Possibility of primary prevention of CP is
not big, the most important is early diagnosis. 120 newborns admitted to the
Developmental department of Pediatric Clinic as "child at risk" were
investigated. The average gestational age was 37.18 weeks, average birth weight
was 2820.09 g. In the group of prematurely born children CP has developed in 15
out of 50 children (30%), in the group of term children it was present in 17 out
of 57 children (29.83%). 32 children (29.92%) had birth weight below 2500 g.
Among them there were 7 cases of CP (21.88%). Children with birth weight of over
2500 g (75 children, 70.09%) had CP in 25 cases (33.33%). There was no
statistically significant difference between boys and girls, and between healthy
and children with CP. There was high rate of correlation between gestational age,
birth weight and score of neonatal optimality, as well as score of pregnancy
optimality, score of delivery optimality and neonatal optimality. The important
correlation appeared between score of delivery optimality and score of neonatal
optimality. There was high correlation between score of perinatal optimality and
all three of its components. Diagnosis of "child at risk" made only on the basis
of risk factors during pregnancy, delivery and neonatal period is out of
discussion, it is not pointing out the developmental outcome. Evaluation by the
methods of clinical examination is necessary for prediction of neurological
development.
PMID- 10758752
TI - [Allergy skin-prick tests and standard inhalation of allergens in children up to
3 years of age].
AB - There were 27 children tested on standard inhalation allergens. The number of
children till one year old was 7, from one year till two years old were 8
children, and from two till three years of age were 12 children. Six children in
the first group had a positive response to the histamine, only one child had a
positive finding on house duct (urtica 5 mm, and histamine 2 mm). In the second
group, from one till two years all children had histamine positive finding. Two
children had positive finding on house dust, three of them had positive finding
on dermatophagoides pteronisimus, while one child was positive on fungus. The
remaining three children had regular finding. In the third group all children had
positive finding on histamine, eight children were positive on house dust, three
of them on dermatophagoides pteronisimus and one child on grass pollen. We think
that the age of children is not a limit to application of allergy tests as a part
of allergy examinations.
PMID- 10758753
TI - [Multicenter pediatric therapeutic interventional heart catheterization 1996
1998].
AB - The aim of the study is to evaluate choice, efficacy and safety of transcatheter
therapy in patients (pts) with congenital heart disease which has been performed
in Europe on pts from the Paediatric Clinic of Sarajevo. From January 1996 to
August 1998 out of 20 transcatheter therapeutic interventions, 5 have been done
in pts whose congenital heart lesions: ductus arteriosus persistence (DAP),
atrial septal defect (ASD), pulmonary artery valve stenosis (PS), aortic valve
stenosis (AS), were diagnosed in first year of life. Pts were followed 11 months
post interventions (the longest period of follow-up 19 months). All pts are well
and asymptomatic. DAP closure has been done using "coil" devices in 2 pts (in
Italy and Monaco) age 5 and 7.5 years. Duct diameter was 3.5 mm and 4 mm with
percent of success within 24 hrs of 100%. With PW Doppler no residual ductual
shunt has been proven. Transcatheter closure of ASD type secundum diameter 9 mm,
using the "amplatz" device has been performed in Germany. No residual shunt has
been proven by echocardiography. Balloon pulmonary valvuloplasty successfully was
done in 1 pt in Austria age 3/12 with normal flow of right ventricle outflow
tract post intervention. Balloon aortic valvuloplasty was performed in Sweden in
neonate with decrease of pressure gradient of AS for 70%. Using Pencil Doppler,
8/12 post intervention in that pt restenosis occurred. The therapeutic
catheterizational technique has been successful in alternating surgical approach
to resolve congenital heart disease. With further development of catheter
systems, techniques and longer periods of follow-up, possibilities of simpler,
faster, safer and more efficient solvation of cardiac lesions will brightening up
the future of paediatric interventional catheterisation.
PMID- 10758754
TI - [Diagnosis of aortic coarctation using digital techniques].
AB - PURPOSE: In order to analyse a contribution of digital techniques in diagnostics
of the aortic coarctation (CoA), a grow up of patients in whom the aforesaid
disease was found, has been described. MATERIAL AND METHODS: There were examined,
within 1986 and 1998, 12 patients suspected of CoA and 2 patients were subjected
to medical check up of state after operation of this anomaly. There was 12 (86%)
men and 2 (14%) women. Six patients were children. Average age of the patients
was 25 years. The youngest was 6 and the oldest 51 years old. 12 patients
underwent the intravenous digital subtraction angiography, 3 patients underwent
computed tomography, and 1 patient was subjected to magnetic resonance imaging.
RESULTS: There has been found CoA in 10 male patients and pseudo-coarctation of
the aorta in 2 female patients advanced in years. A satisfactory diagnostics was
possible by use of any of the three methods. CONCLUSION: Noninvasive methods of
examination, intravenous-digital subtraction angiography (IV-DSA), computed
tomography (CT), and magnetic resonance (MR) are and more alternatives to
invasive angiographic examinations. Magnetic resonance is suitable especially in
pediatrics since radiation could be avoided.
PMID- 10758755
TI - [Advantages and disadvantages in the use of central venous catheters in children
with malignant diseases].
AB - The authors report the problem of central venous catheter appliance to the
children with malignant diseases, employed for the first time in Bosnia and
Herzegovina with the aim of pediatric oncologic patients treatment. During 1997
central venous catheter type Hickman was used in nine children between two and
half to eleven years old (average six years and one months). The average time of
catheter placement was six months, in two cases catheter were eliminated after
two and three months respectively since application (spontaneous elimination and
repeated septic attacks, caused bu resistant bacterial strains). Gram-positive
bacteria have been isolated with eight children (Staphylococcus aureus and
Staphylococcus epidermidis), and gram-negative enterobacteriaceae (Serratia
marcescens, Pseudomonas aeruginosa, Klebsiella oxytocia and pneumoniae,
Escherichia coli, Salmonella group C and Enterococcus faecalis) in samples taken
from the catheter and hemoculture. The central venous catheter is useful in
treating oncological patients, but may cause serious consequences, like local
infections or septicaemia.
PMID- 10758756
TI - [Radiologic diagnosis of congenital anomalies of the digestive tract].
AB - The aim of the study is to analyze the frequency of the congenital anomalies of
the digestive tract in the period of 1993-1998. The patients and methods: Our
group included 67 patients (47 males and 20 females; age range 1-12 months)
suspected of digestive tract anomalies. First, all of them have been examined by
pediatric surgeon. At the first place, we used the most conventional radiological
procedures for digestive tract examination. They were followed by US in cases
with suspicion on hypertrophic pyloric stenosis and biliary atresia (bile-duct
atresia). CT and MR were performed in patients with anorectal anomalies. In cases
with suspected associated anomalies of other organs, intravenous urography and
chest radiography were used. RESULTS: Congenital anomalies and abnormalities of
the digestive tract were diagnosed in 25 patients. The most frequent anomaly was
hypertrophic pyloric stenosis (n = 14), followed by invagination (n = 12) and
megacolon congenitum (n = 9), all predominant in male sex. All radiological
findings we confirmed at surgery (100%). CONCLUSION: Conventional radiology is
still extremely useful in the diagnosis of the digestive tract anomalies; also US
revealed to be essential in the diagnosis of the hypertrophic pyloric stenosis
and the intestinal invagination. Recognition of the associated anomalies should
lead to application of the other examination techniques like CT and MR. MR might
be useful in the anorectal malformations and hepatobiliary tract anomalies, but
we have no experience in that field, till now.
PMID- 10758757
TI - [Characteristics of computerized tomography of the brain in congenital
hemiparesis].
AB - Congenital hemiparesis is defined as an unilateral disorder of movement and
posture, with clinical signs of spasticity with flexor hypertonicity, increased
tendon reflexes and characteristic posturing. We have examined a group of 26
children with congenital hemiparesis (14 boys and 12 girls) with mean age of 3.5
years (range 6 months to 9 years). 24 had been born at term (% weeks gestation)
and 2 were preterm (% completed weeks gestation). From the neuroimaging point of
view, congenital hemiparesis form a rather heterogeneous group. CT scans
revealed: porencephalic cyst (6), unilateral ventricular enlargement (2),
cortical atrophy with unilateral ventricular enlargement (1), hypodense zones
resulting from previous hemathermous (4), normal CT scans (6), and 7 cases have
not had CT scans for technical reasons (war conditions). Congenital hemiparesis
mainly affects term children with prenatal origin in majority of cases. Vascular
occlusions (in utero stroke) originating from various pathophysiological factors,
maternal or fetal, may result in congenital hemiparesis. Normal CT findings
should be revised by using MRI, which provides direct evidence of white matter
lesions.
PMID- 10758759
TI - [Remission of nephrotic syndrome in children treated with corticosteroids and
other immunosuppressive therapy].
AB - Hypoproteinaemia, proteinuria and edema are the main features of Nephrotic
syndrome (NS) and are the result of greater permeability of glomerular basal
membrane for proteins. It is difficult to predict course of disease and outcome.
During 1989-1998 year 18 children were followed up, 9 boys and 9 girls, at the
age of 2 to 14 years and diagnosis of NS. Therapy with pronison was initiated in
all children according to the protocol of ISKDC. Children were then divided in
two groups, depending on success of therapy. In the first group (13 patients,
72.22%) were the patients that had remission, and the second group consisted of 5
patients that did not have remission. In the first group relapses occurred in 7
patients (53.84%), because of side effect of pronison therapy was discontinued in
3 patients. Those 3 patients along with 5 patients from second group were then
turned to immuno-suppressive therapy. One patient responded well to
cyclophosphamide, rest of them with regular follow up. Two years latter two of
them had relapse but responded well on pronisone therapy in the full dose.
Biopsies that were done showed that 2 had minimal changes, 2 had focal segmental
sclerosis and one membranous proliferative glomerulonephritis. One patient
developed chronic renal insufficiency. We conclude that our experience shows that
if there is not favorable effect of corticosteroid therapy cyclosporine A is the
first choice in NS, without regarding of the patho-hystological findings.
PMID- 10758758
TI - [Acute renal insufficiency in children].
AB - Acute renal failure (ARF) is not rare in hospitalized children, especially in
newborns and infants. Sudden disorganization of a glomerular and tubular function
is the most often transitory and require a quick make of diagnosis and early
therapy in order to obtain a adequate kidney function recovery and to reduce
mortality. In this article 51 children with ARF were included from newborn period
to 16 years of age (25 female: 26 male). We described the most often causes of
ARF, diagnosis procedures and nondialytic treatments. The diagnosis was made by
history, physical examination, laboratory and radiology findings. Causes of ARF
were divided on prerenal, renal and postrenal. The treatment of ARF in all cases
was conservative with good success in 45 patients and in 6 children followed
death because of the nature of primary diseases. The results of study show that
the accent is on the prevention, early diagnosis and early therapy of diseases
which lead to ARF. We conclude that a multidisciplinary therapeutic approach is
imperative for successful management of ARF.
PMID- 10758760
TI - [Septic conditions: a syndrome of multiorgan dysfunction].
AB - Using a new concept of terminology for sepsis syndrome, septic shock and
multiorgan dysfunction/failure syndrome (MODS/MOSF) as a framework, we have
evaluated 21 cases of severe sepsis of new admitted newborns in Neonatology
Department of Pediatric clinic of Clinical center University of Sarajevo during
last 2 years. We found that the most common etiologic agents were gram negative
organisms (Klebsiella pn. and E. coli) and staphylococci. We did not observed any
streptococcus group B sepsis despite of high incidence of these infections in
developed countries. In 12 (60%) of 21 patients with severe sepsis MODS was
developed, involving at least two organ systems, 3 of them also had the other
acute insult (emergency surgery and asphyxia) as a possible trigger for MODS. The
incidence of specific organ failure was: CNS (58%), respiratory (50%),
cardiovascular (41%), the other systems were less involved. The overall mortality
rate of patients with sepsis was 28%, whereas the overall mortality rate of
MODS/MOSF was 50%.
PMID- 10758761
TI - [Neonatal hyperbilirubinemia: evaluation and treatment].
AB - We investigated 185 newborns with hyperbilirubinemia hospitalised in Neonatal
Unit of Pediatric clinic during 1997. We identified an apparent cause for the
jaundice in 76 newborns (41.0%), but in 109 newborns (58.8%) no cause for the
jaundice was found. Contributing factors for this jaundice were: male sex,
preterm bith, breast feeding, considerable weight loss, instrumental or induced
delivery as well as genetic factors. Exchange transfusion was done in only 2
cases (1.08%) with Rh isoimmunisation and positive Coombs test, which is
according to attitude that blood exchange transfusion as an expensive procedure
with high mortality and morbidity has largely been replaced by phototherapy
because of its relative freedom from complications together with its non-invasive
nature. The average duration of hospitalisation of hyperbilirubinemic newborns
lasted 4.8 days. We consider to make all efforts to short duration of
hospitalisation time, because separation of newborn from the mother during
phototherapy has a negative impact on early mother-infant social and emotional
interaction.
PMID- 10758762
TI - [Single ventricle--case report].
AB - A case of congenital heart disease (single ventricle) has been reported in nine
and half years old child. This congenital heart disease is uncommon, but its
diagnosis and treatment are complex. Complete noninvasive and invasive diagnostic
procedure has been performed with this child. This congenital heart disease is
proclaimed as inoperable because pulmonary hypertension has been developed.
PMID- 10758763
TI - [Scabies in infants--problems in differential diagnosis].
AB - Scabies is very often parasites dermatosis. Diagnostic problems are not rare
considering the fact that the clinical picture of scabies in infant population is
different compared to the adult population. The scabies that is untreated or non
adequately treated has a long course followed by complications. In hospital in
Tuzla in a period 1995-1997 we have done retrospective study which included 64
infants with scabies followed with complications. Skin changes have appeared
approximately 2-6 months before admission to the hospital. In 55.3% cases the
scabies stayed unrecognized and the aforementioned patients were treated under
other diagnosis: Dermatitis allergic 50%, Piodermia 30%, Dermatitis seborrhoica
10%, Dermatosis 10%. Problem is the medical treatment of only sick child, and not
of complete family. That makes possibility for inter-family infestation and
prolongs course of scabies as disease as well as its medical treatment. In
infants with skin changes we should also consider possibility of infection by
parasite Sarcoptes scabiei var. hominis. Medical treatment and appropriate
diagnostic as well as treatment of all members of the families without the matter
of existence of skin changes makes the course of disease shorter.
PMID- 10758764
TI - [Epidemiology of childhood leukoses at the Pediatric Clinic in Sarajevo over the
past 2 years].
AB - In retrospective study we analyzed 19 patients who were diagnosed and cured
because of leukemia at Pediatric clinic in Sarajevo during last two years. From
that number, 15 children (78.9%) were with acute lymphoblastic leukemia (ALL), 3
(15.7%) were with acute myeloic leukemia (AML) and 1 was with chronic myeloic
leukemia. Among all pediatric malignancies percent of leukemias was 40.4%. Most
of children with leukemia from Canton of Zenica-Doboj (42.1%) and then from
Canton of Sarajevo (31.5%). Illness began mostly in winter months (36.5%), than
in early spring (26.3%), and in autumn (26.3%), but there were no newly diagnosed
in summer (July and August). More children with leukemia were from rural areas
(57.8%), than from urban areas (42.2%).
PMID- 10758765
TI - [Lead poisoning in children in Bosnia and Herzegovina].
AB - Our children live in lead-polluted environments. Lead can affect almost every
organ and system in the body. Exposure to lead is more dangerous for young and
unborn children because children absorb lead more readily than adults and because
their developing nervous system are more vulnerable to lead effects. The amount
of lead in polluted air in Tuzla has been fifteen times higher in the 1996, in
relationship to 1985.
PMID- 10758766
TI - [Vigabatrin in childhood epilepsy--personal experience].
AB - Vigabatrin has been in clinical use for 18 years. It has not been used widely in
our country because of unavailability and costs of therapy. After the end of war
in Bosnia and Herzegovina we started to use it in treatment of childhood
epilepsies. We studied 19 patients that received vigabatrin as add on therapy and
monotherapy. Follow up period was 6 months to 2 years. Nine of those patients
were diagnosed as West syndrome, three had tuberous sclerosis, seven had
intractable partial epilepsies. In the group with West syndrome 7 patients (5 as
add on therapy and 2 as monotherapy) responded with complete control of seizures
and disappearing of hypsarrhythmia in electroencephalographic recordings. One
patient responded with reduction of seizures for 50%, one did not respond. In the
group with tuberous sclerosis 1 was completely seizure free, one had reduction of
seizures for 75%, one did not respond. Out of 7 patients with intractable partial
epilepsies 3 responded with reduction of seizures between 75%-100%, 1 with
reduction of seizures of 25%-50%, and 3 did not respond. Vigabatrin was well
tolerated, we did not experience any serous adverse reactions. This antiepileptic
drug can be a major improvement in treatment of some of the epileptic syndromes
and needs further investigation.
PMID- 10758767
TI - Convex and concave, Part I: Images of emptiness in women.
PMID- 10758768
TI - The Pied Piper of Hamelin: folklore encounters malevolent cults.
PMID- 10758769
TI - A psychoanalytic unconscious and emotional availability: aspects in the
development of analysts and analytic therapists.
PMID- 10758770
TI - The subject of reading and the colonial unconscious: countertransference in J. M.
Coetzee's Waiting for the barbarians.
PMID- 10758771
TI - Induced recall of Mozart's Requiem in Amadeus.
PMID- 10758772
TI - Effects of intrahippocampal infusion of interleukin-6 on passive avoidance and
nitrite and prostaglandin levels in the hippocampus in rats.
AB - Bilateral infusion of interleukin-6 (IL-6) 80 ng into the hippocampus has been
shown to impair retention of a step-through passive avoidance task via shortening
the step-through latency in testing. This infusion with IL-6 also increased the
levels of nitrite and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in rat
hippocampus. In addition, intraperitoneal injection of NG-nitro-L-arginine (CAS
2149-70-4) 100 mg/kg for 5 days improved the retention impairment induced by IL-6
and meanwhile antagonized the increase in nitrite levels. Furthermore,
intraperitoneal injection with indometacin (CAS 53-86-1) 10 mg/kg daily for 5
days reduced the IL-6-induced increase in 6-keto-PGF1 alpha levels. These results
indicate that IL-6 impairs retention of passive avoidance probably via the
overproduction of nitric oxide (NO) and suggest that IL-6 may possess an
inducible effect on NO synthase and cyclo-oxygenase in the hippocampus. These
findings support the hypothesis that central IL-6 participates in the
pathogenesis of Alzheimer's disease, and the overproduction of nitric oxide in
the brain may partially mediate the amnesic effect of IL-6.
PMID- 10758773
TI - Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine
oxidase inhibition.
AB - A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional
tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine
(CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5
hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64
04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily
for 5 days) were those known to possess anti-stress properties in other animal
models. In contrast to the reference substances investigated (nialamide (CAS 51
12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did
not exhibit any activity indicative of MAO inhibition. It was concluded that MAO
inhibition was not the mechanism primarily responsible for EGb 761's anti-stress
activity.
PMID- 10758774
TI - Cardiovascular pharmacological studies on JTV-506, a new potassium channel
opener. 1st communication: effects on myocardium and vasculature.
AB - The effects of JTV-506 ((-)-(3S,4R)-2,2-bis(methoxymethyl)-4-[(1,6-dihydro-1
methyl-6-oxo-3- pyridazinyl)amino]-3-hydroxychroman-6-carbonitrile hemihydrate,
CAS 170148-29-5), a novel coronary vasodilator, on hemodynamics, cardiac function
and cardiac oxygen consumption were evaluated in anesthetized dogs. In
anesthetized, open-chest dogs, JTV-506 (0.3-10 micrograms/kg i.v.) induced a
marked increase in coronary blood flow in a dose dependent manner, while at these
doses it had smaller effects on vertebral and mesenteric blood flow and almost no
effect on renal blood flow. JTV-506 (1-10 micrograms/kg i.v.) showed a tendency
to decrease oxygen consumption of the heart and elevate myocardial oxygen
pressure without cardiac suppression. Effects of JTV-506 on hemodynamics and the
respiratory system following i.v. administration (0.3-300 micrograms/kg) were
investigated in spontaneously breathing anesthetized dogs. The effective dose to
induce hemodynamic changes was more than 3 micrograms/kg. JTV-506 did not have a
crucial influence on electrocardiogram. JTV-506 caused marked increase in
coronary blood flow and myocardial oxygen pressure with slight change in blood
pressure. It is concluded that JTV-506 is a potent vasodilator, with particularly
pronounced effect on vasculature of the heart. These results suggest that JTV-506
may be useful in the treatment of angina pectoris.
PMID- 10758775
TI - Bioequivalence of two tablet formulations of atenolol after single oral
administration in healthy volunteers.
AB - The pharmacokinetic parameters of two oral formulations of 100 mg tablets of
atenolol (CAS 29122-68-7; Azectol as test and another commercially available
preparation as reference) were compared in an open-label, randomized, single oral
dose, two-period cross-over design to 17 healthy volunteers under fasting
conditions. Serial blood samples were collected prior to each administration and
at 17 points within 36 h after dosing. Plasma concentrations of atenolol were
measured by a validated HPLC assay with fluorometric detection. The parametric
90% confidence intervals of the geometric mean values of the test/reference
ratios were 94.4% to 112.9% (point estimate: 103%) for AUC0-infinity, 93.7% to
112.8% (point estimate: 103%) for AUC0-36, and 88.3% to 112.1% (point estimate:
100%) for Cmax, within the acceptance criteria for bioequivalence (80%-125%).
Tmax values were analyzed by the nonparametric Wilcoxon test and the difference
was not statistically significant. Therefore, it is concluded that the test and
reference atenolol formulations are bioequivalent for both the extent and the
rate of absorption.
PMID- 10758776
TI - Characterization of the renal action of pranidipine in the rat.
AB - Although calcium antagonists elicit predominant dilation of afferent arterioles
that might be associated with glomerular hypertension, there have been reported
diverse observations demonstrating the effect of calcium antagonists on the
progression of renal injury. The present study examined the effect of pranidipine
(CAS 99522-79-9) on the renal microvascular tone in the isolated perfused
hydronephrotic rat kidney, and the progression of renal insufficiency in
subtotally nephrectomized spontaneously hypertensive rats. In the hydronephrotic
kidney, angiotensin II caused marked constriction of both afferent and efferent
arterioles. The subsequent addition of pranidipine (10 nmol/l, 100 nmol/l, 1
mumol/l) elicited dose-dependent afferent arteriolar dilation, with 97 +/- 3%
reversal at 1 mumol/l. In contrast, efferent arterioles were resistant to
pranidipine, with only 20 +/- 4% reversal at 1 mumol/l. In subtotally
nephrectomized rats, 10-week treatment with pranidipine (3.0 mg/kg/day) markedly
decreased blood pressure (from 270 +/- 6 to 158 +/- 8 mmHg) and improved renal
histopathological changes, including glomerular and arteriolar sclerosis.
Proteinuria was also less than than in the control rats (233 +/- 5 vs. 305 +/- 26
mg/day). Thus, although glomerular hypertension might develop as a consequence of
preferential afferent arteriolar dilation, pranidipine actually improved the
renal injury in subtotally nephrectomized SHR. These ostensibly discrepant
observations could be attributed to the simultaneous reduction in blood pressure
and the salutary actions of this agent mediated by non-hemodynamic mechanisms.
PMID- 10758777
TI - Studies on the antithrombotic and antiplatelet activities of NQ304, a newly
synthesized naphthoquinone derivative.
AB - The effect of p6304 (2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone) as a
novel antithrombotic agent was investigated. NQ304 was found to inhibit platelet
aggregation in human platelets in vitro and in rat ex vivo, and murine pulmonary
thrombosis in vivo. NQ304 potently inhibited adenosine diphosphate (ADP),
collagen, epinephrine and calcium ionophore-induced human platelet aggregation in
vitro dose-dependently. In the ex vivo study, oral administration of NQ304
significantly inhibited platelet aggregation in rats. However, NQ304 was found
not to affect the coagulation system, since it did not change the prothrombin
time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT).
The agent prevented death due to pulmonary thrombosis by the platelet aggregates
in mice in vivo. In the mouse tail bleeding time test, NQ304 showed a significant
prolongation of the tail bleeding time in conscious mice. These results suggest
that a principal antithrombotic effect of NQ304 may be due to the antiplatelet
aggregation activity but not to anticoagulation activity.
PMID- 10758778
TI - Efficacy of Artichoke dry extract in patients with hyperlipoproteinemia.
AB - Efficacy and tolerability of artichoke dry extract (drug/extract ratio 25-35:1,
aquous extract, CY450) as coated tablets containing 450 mg extract (tradename:
Valverde Artischocke bei Verdauungsbeschwerden) was investigated in the treatment
of hyperlipoproteinemia and compared with placebo. 143 adult patients with
initial total cholesterol of > 7.3 mmol/l (> 280 mg/dl) were included in a double
blind, randomized, placebo controlled, multi-center clinical trial. Patients
received 1,800 mg artichoke dry extract per day or placebo over 6 weeks. Changes
of total cholesterol and LDL-cholesterol from baseline to the end of treatment
showed a statistically significant superiority (p = 0.0001) of artichoke dry
extract over placebo. The decrease of total cholesterol in the CY450 group was
18.5% compared to 8.6% in the placebo group. LDL-cholesterol decrease in the
CY450 group was 22.9% and 6.3% for placebo. LDL/HDL ratio showed a decrease of
20.2% in the CY450 group and 7.2% in the placebo group. There were no drug
related adverse events during this study indicating an excellent tolerability of
artichoke dry extract. This prospective study could contribute clear evidence to
recommend artichoke dry extract CY450 for treating hyperlipoproteinemia and,
thus, prevention of atherosclerosis and coronary heart disease.
PMID- 10758779
TI - Synthesis of some new thienyl and 1,3-thiazolyl-aminoketones with anti
inflammatory activity.
AB - Eight thienyl and 1,3-thiazolyl-aminoketones were synthesised and tested as anti
inflammatory agents. pKa and log P were theoretically calculated. The compounds
were tested for antioxidant activity, as hydroxyl radical scavengers, as
superoxide anion scavengers and for their ability to interact with 1,1-diphenyl-2
picryl hydrazyl stable free radical (DPPH). The effects of the synthesised
compounds on inflammation were studied using the carrageenan induced mice paw
oedema model. Both anti-inflammatory and antioxidant activities depended on some
structural characteristics of the synthesised compounds.
PMID- 10758780
TI - Binding of kebuzone to human serum albumin studied by high performance liquid
affinity chromatography.
AB - The binding of the anti-inflammatory agent kebuzone (CAS 853-34-9) to human serum
albumin (HSA) was examined by means of high performance liquid affinity
chromatography. Phenylbutazone and diazepam, the binding properties of which were
an object of our previous work, were used as markers for the major supposed
binding sites on HSA. It was established that kebuzone binds to the high-affinity
phenylbutazone binding sites as well as to the low-affinity diazepam binding
sites. The estimated values of the equilibrium affinity constants were 5.9 x
10(4) l/mol and 1.7 x 10(3) l/mol, respectively, suggesting a low binding
affinity for kebuzone. A stepwise mechanism of the binding process could be
proposed: primary at phenylbutazone sites, and secondary at the diazepam sites.
The binding behavior of kebuzone was very similar to that of the structurally
related compound phenylbutazone. The observed lower affinity is well explained in
view of the lower lipophilicity of kebuzone.
PMID- 10758781
TI - Prediction of the efficacy of cutaneously applied nonsteroidal anti-inflammatory
drugs from a lipophilic vehicle.
AB - The maximum cutaneous fluxes of 12 nonsteroidal anti-inflammatory drugs (NSAIDs),
determined in a preceding study from the lipophilic vehicle light mineral oil in
vivo on 24 healthy volunteers, were related to data concerning their intrinsic
activities. From the multiplication of the relative intrinsic activities with the
relative maximum fluxes, both related to indometacin (CAS 53-86-1) as standard,
the percutaneous activities result as parameters for the prediction of the
efficacy of cutaneous preparations with NSAIDs. According to the results of the
calculations, the percutaneous activities of ibuprofen (CAS 15687-27-1) and
nabumetone (CAS 42924-53-8) from lipophilic vehicles are remarkable because of
their very high maximum fluxes. NSAIDs with still high percutaneous activities
are ketoprofen (CAS 22071-15-4), naproxen (CAS 22204-53-1), piroxicam (CAS 36322
90-4) and diclofenac (CAS 15307-86-5). In contrast, the systemically highly
effective NSAIDs indometacin and acemetacin (CAS 53164-05-9) show rather low
percutaneous activities, when applied in lipophilic vehicles. Especially
nabumeton and also tenoxicam (CAS 59804-37-4), both not yet commercially used
cutaneously, can be recommended for lipophilic skin preparations.
PMID- 10758782
TI - Antinociceptive and anti-oedematogenic properties of astilbin, taxifolin and some
related compounds.
AB - Astilbin (3-0-alpha-1-rhamnosyl-(2R,3R)-dihydroquercetin), the major constituent
isolated from Hymeneae martiana and some derivatives obtained by structural
modification, such as taxifolin and two related compounds, were evaluated as
analgesics by using both writhing test and formalin test in mice. Their anti
oedematogenic actions were also analysed against paw oedema caused by
carrageenan, dextran and bradykinin in rat. The results indicated that some
compounds, such as taxifolin (2) and its tetramethylated derivative (4) exhibited
potent and dose-dependent antinociceptive action against acetic acid-induced
abdominal constriction when administered intraperitoneally or orally. They were
more potent than acetylsalicylic acid and paracetamol (acetaminophen), two
standard drugs used for comparison. Compounds 2 and 4 were also more potent than
these drugs in attenuating to the second phase of the formalin-induced licking.
Moreover, both compounds showed significant anti-oedematogenic effect, inhibiting
the paw oedema formation induced by dextran. In contrast pentaacetylated
taxifolin (3) was capable of inhibiting the paw oedema induced by bradykinin.
PMID- 10758783
TI - Bioavailability investigation of two different oral formulations of
methylprednisolone.
AB - Two different oral methylprednisolone (CAS 83-43-2) formulations
(Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of
a reference preparation (R)) were investigated in 16 healthy volunteers in order
to prove bioequivalence between these preparations. A single 8 mg oral dose was
given according to a randomised two-way crossover design in the fasted state.
Blood samples for determination of methylprednisolone plasma concentrations were
collected at pre-defined time points up to 16 h following drug administration. A
washout period of 3 days separated both treatment periods. Methylprednisolone
plasma concentrations were determined by means of a validated HPLC method. Values
of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation)
for the parameter AUC0-infinity demonstrate an nearly identical extent of drug
absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were
achieved for test and reference preparation. Time to reach maximum plasma
concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity
values were tested parametrically by the two one-sided t-test procedure.
Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios
were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the
results obtained in this study, bioequivalence between Methylprednisolone
ratiopharm and the reference preparation was demonstrated.
PMID- 10758784
TI - Efficacy on climacteric symptoms and safety of low dose estradiol transdermal
matrix patches. A randomized, double-blind placebo-controlled study.
AB - Two estradiol (E2) transdermal patches releasing 25 micrograms/day E2 (D-25) or
37.5 micrograms/day E2 (D-37.5) were compared to a placebo patch on 156 patients
in natural or surgical menopause suffering from at least 5 hot flushes per day,
randomly and blindly assigned to three parallel groups of 52 patients each, to be
treated continuously for 12 weeks, without progestin opposition. "Responders"
(patients with less than 3 hot flushes per day at the end of treatment), were 82%
and 90% under D-25 or D-37.5, respectively, both significantly (p < 0.001) more
than under placebo (44%). Comparable efficacy was observed on severity of hot
flushes, Kupperman Index and on the self-rated efficacy. Systemic adverse events
occurred in 10%, 10% and 8% of patients, respectively, under D-25, D-37.5 or
placebo. Occasional mild and transient itching and/or erythema on the site of
application was reported by few patients and did never require discontinuation of
application. In conclusion D-25 and D-37.5 were significantly more effective than
placebo in relieving climacteric symptoms and were systemically and locally as
well tolerated as placebo. D-25 (Demestril 25) releasing 25 micrograms/day E2 can
therefore be recommended for low-dosed estrogen replacement therapy.
PMID- 10758785
TI - DNA sequence-recognizing properties of minor groove alkylating agents. Effects of
the replacement of N-methylpyrrole by an N-methylimidazole on tallimustine and
its own homologue.
AB - The linkage of an heterocycle, like N-methylimidazole, to minor DNA groove
binders containing two or three pyrroles lead to a new class of oligopeptides
with reduced antitumor activity both in vitro and in vivo if compared to
tallimustine (CAS 115308-98-0) and its tetrapyrrole homologue 9. In the present
paper is reported the correlation between the cytoxicity of tallimustine and its
derivatives 9-11 with their ability to inhibit polymerase chain reaction (PCR)
amplification of oestrogen receptor and Ha-ras gene sequences, containing A + T
rich and G + C rich regions, respectively. Tallimustine and its tetrapyrrole
homologue 9 were found to have higher sequence selectivity for the human
oestrogen receptor (ER) gene with respect to the relative imidazole-containing
analogues.
PMID- 10758786
TI - Mutagenicity of recombinant antihemophilic factor (GC-gamma AHF).
AB - This study was carried out to evaluate the mutagenic potential of recombinant
antihemophilic factor VIII (GC-gamma AHF). Salmonella typhimurium (S.
typhimurium) reversion assay with/without histidine moiety, chromosomal
aberration assay on Chinese hamster lung (CHL) fibroblast cells and in vivo
micronucleus assay using mouse bone marrow cells and supravital micronucleus
assay using peripheral blood were performed. GC-gamma AHF containing histidine
did show inconsistent and irregular mutagenic effects on S. typhimurium TA98,
TA100, TA1535 and TA1537 both in the absence and presence of the metabolic
activation system, however, GC-gamma AHF without histidine showed no mutagenic
effects regardless of the metabolic activation system, thus suggesting that the
histidine moiety in GC-gamma AHF might cause inconsistent mutagenic effect. Also
GC-gamma AHF did not increase the number of cells having structural or numerical
chromosome aberration in the cytogenetic test. In classical and supravital
micronucleus assay, no significant increases were observed in the occurrence of
micronucleated polychromatic erythrocytes and micronucleated peripheral
lymphocytes in male ICR mice. These results strongly indicate that GC-gamma AHF
has no genetic toxicity under these experimental conditions.
PMID- 10758787
TI - Recurrent pregnancy loss associated with endometrial hyperechoic areas
(endometrial calcifications): a case report and review of the literature.
AB - Endometrial calcifications occur sporadically and are associated with
infertility. Previous uterine trauma during instrumentation and/or uterine
infection are likely involved in their pathogenesis. The association between
endometrial calcifications and recurrent pregnancy loss has been very
infrequently reported. A 28-year-old woman with a history of two consecutive
first trimester pregnancy losses presented with ultrasonographic hyperechoic
endometrial areas associated with histologic endometrial calcification foci. A
third pregnancy conceived before starting micronized oral progesterone
supplementation also spontaneously aborted at eight weeks. During the fourth
pregnancy, progesterone supplementation was taken for the initial 12 weeks. The
endometrial lesions were no longer detectable and the pregnancy progressed to
term without complications. Endometrial calcifications, related to intrauterine
bone tissue, have been previously treated with curettage or with endoscopic
surgery, and to the best of our knowledge, have not been reported to disappear
spontaneously. In this case, regression of the endometrial calcifications and a
favorable pregnancy outcome occurred in concert with oral micronized progesterone
supplementation. A combination of transvaginal ultrasonography and endometrial
biopsy appears to be an effective method for diagnosing and monitoring of this
rare condition.
PMID- 10758788
TI - Atrial natriuretic factor (ANF) after laparoscopy and morphine application for
pain therapy.
AB - OBJECTIVE: ANF is a potent diuretic, natriuretic and vasorelaxant hormone. The
objective of the present study was to examine the effect of opioid receptor
stimulation by morphine on endogenous ANF production and diuresis after surgery.
METHODS: Prospectively, nine women undergoing surgery for either uterine
leiomyomas, chronic pelvic discomfort or desire for definitive contraception by
laparoscopy were evaluated. Venous samples were collected at fixed times.
Concentrations of ANF were measured by commercially available radioimmunassay
test kits. Statistical analysis was performed by the Friedman Two-way ANOVA,
Kruskal-Wallis 1-way ANOVA and Mann-Whitney U-Wilcoxon Rank Sum W Test. The level
of significance was set at a probability below 0.05. RESULTS: There were no
statistically significant changes in serum levels of ANF (p = 0.98), in diastolic
blood pressure (p = 0.14) or pain score (p = 0.86) after surgery. Systolic blood
pressure (p = 0.0032), pulse rate (p = 0.019) and urinary flow rate (p < 0.0001)
showed significant changes during observation. CONCLUSION: Our results show that
i.v. administered morphine induces a potent diuretic effect via activation of
opioid receptors but it can not be suggested that this effect is due to an
enhanced release of ANF.
PMID- 10758789
TI - Crohn's disease and tubal infertility: the effect of adhesion formation.
AB - The purpose of this paper was to assess the management of tubal disease in women
with Crohn's disease. We are presenting a case series describing four patients
with Crohn's disease who were treated at a tertiary infertility clinic within an
university hospital. Fertility investigations and appropriate therapy plans in
these patients with Crohn's disease who also had tubal infertility are outlined.
The clinical outcome in all four cases demonstrated interference with the
management and surgical therapy of the tubal infertility by extensive adhesion
formation. We conclude that adhesion formation complicates the investigation and
surgical therapy of patients with Crohn's disease.
PMID- 10758790
TI - Thawing of frozen shoulder in menopausal women treated with a Japanese herbal
medicine, Kanzo-to extract: report of two cases.
AB - We report here two patients with frozen shoulder syndrome and severe menopausal
symptoms. Short-term administration of Kanzo-to extract thawed the shoulders
completely enough for the patients to move their cervical and shoulder joints
without any restriction or pain. Their menopausal symptoms were cured
simultaneously. Kanzo and Shakuyaku were found to have different effects on
shoulder stiffness and disability in shoulder joints.
PMID- 10758791
TI - Effect of sequential estrogen/progestin treatment on biochemical vasoactive
markers in postmenopausal women comparing oral and transdermal application.
AB - PURPOSE: Estrogen replacement in postmenopause can elicit vasodilatory effects
which may be important for cardiovascular protection. Progestin addition can
antagonise this beneficial effect, but until now, only a few studies have been
performed on this issue. In the present study the effect of estradiol as well as
of added norethisterone acetate (NETA), a C19-progestin, on the renal excretion
of various biochemical markers which can reflect vasoactive actions was
investigated. METHODS: 37 postmenopausal women were treated for one sequential
estrogen/progestin treatment cycle, i.e. two weeks with estradiol alone followed
by two weeks with an estradiol/progestin combination. Both oral (n = 20) as well
as 'complete' transdermal (n = 17) hormone substitution was applied, and the
excretion of the following vasoactive substances or the stable metabolites,
respectively, were measured in nocturnal urine prior to treatment, after 14 and
28 days: cGMP, which can reflect the production of nitric oxide, prostacyclin,
thromboxane and serotonin. RESULTS: The excretion of cGMP was increased with both
forms of administration during the estrogen phase as well as during the
consecutive estrogen/progestin treatment. The prostacyclin-thromboxane quotient
increased during estrogen phases, but decreased significantly by the addition of
oral, but not with transdermal NETA, reflecting possible vasoconstrictory
effects. Serotonin excretion increased, but this only was significant after the
oral estrogen-only phase (2 weeks treatment), and after one cycle of complete
transdermal treatment (4 weeks treatment), respectively. CONCLUSION: The observed
effects can be explained by vasodilatory actions during the estrogen phases which
can be maintained or even increased during the consecutive estrogen/progestin
treatment suggesting a time-dependent beneficial estrogen effect. However, oral
progestin addition may antagonise this effect already within two weeks of
treatment whereby the prostacyclin-thromboxane quotient seems to be the most
sensitive marker surrogating on vasoconstrictory progestin action.
PMID- 10758792
TI - A randomized trial of pulsatile vs continuous oxytocin infusion for labor
induction.
AB - In a prospective randomized study, 560 pregnant women were subjected to labor
induction with continuous or pulsed intravenous oxytocin infusion. There were no
significant differences with respect to maternal history, Bishop score and
perinatal morbidity. The mean induction to delivery interval was shorter in the
pulsed infusion group than in the continuous infusion group (325 +/- 63 vs 433 +/
67 min in primiparous, p < 0.001 and 204 +/- 52 vs 236 +/- 87 min in multiparous
women, p < 0.01). The mean amount of oxytocin administered in the pulsed infusion
group was also significantly lower than in the continuous infusion group (4.7 +/-
0.6 mU/min versus 9.6 +/- 3.4 mU/min in primiparous, p < 0.001 and 2.1 +/- 0.4
mU/min versus 5.2 +/- 2.3 mU/min in multiparous women, p < 0.001). Our study
demonstrates that pulsatile administration of oxytocin is as safe as continuous
intravenous infusion, requires less oxytocin and is more effective as it reduces
labor duration.
PMID- 10758793
TI - Postpartum ovarian vein thrombosis.
AB - OBJECTIVE: Ovarian vein thrombosis (OVT) is known as a rare but serious
postpartum complication. The condition is often clinically not distinguishable
from endometritis, appendicitis or pyelonephritis. OVT may cause sepsis, septic
pulmonary thromboembolism, and thrombosis of the inferior vena cava and the renal
veins, and is potentially fatal. The objective of this study was to report the
clinical findings and outcome of two patients with diagnosed ovarian vein
thrombosis after delivery managed at this institution. METHOD: Two patients fit
the study criteria of documented ovarian vein thrombosis after delivery. An
imaging diagnosis (CT) of ovarian vein thrombosis was required for final study
inclusion. RESULTS: We present two patients with ovarian vein thrombosis. The
symptoms of one patient disappeared two days after beginning heparin and
antibiotic therapy. The control-CT 93 days after the diagnosis of POVT showed
unsuspected ovarian veins. The other patient suffered from POVT 13 days after
spontaneous delivery. Because of lethal embolisms she died during the operation
for embolectomy. CONCLUSION: On the basis of our series and other recent series,
OVT may likely be more common than previously thought and may become clinically
apparent only when complicated by infection, expansion of the thrombus or
pulmonary embolism. POVT is a potentially fatal condition most commonly seen as a
complication of pelvic surgery or inflammatory disease.
PMID- 10758794
TI - The role of antibiotics after dilatation and curettage in women with metrorrhagia
in the prevention of pelvic inflammatory disease.
AB - A follow-up study was carried out in 67 healthy women with negative vaginal
cervical cultures after an endometrial curettage for metrorrhagia. The women were
separated into two treatment groups and clinically followed for one month after
the operation. The first group included 33 women (aged 23-67, mean 43) who
received doxycycline 200 mg daily for a period of one week after the procedure.
The second group included 34 women (aged 28-70, mean 43.5) who did not receive
any antibiotic regimen after the dilatation and curettage. Four and three women
from the 1st and 2nd group, respectively, developed PID during follow-up; a
difference not statistically significant.
PMID- 10758795
TI - Collection of fetal stem cells and newborn effects.
AB - The aim of this work was to test fetal stem cells (FSC) number modification in
relation to clamping time and newborn effect. The results show that a fast
sample, between 20 and 40 seconds, from umbilical cord after fetus birth and
before placental detachment assured a greater quantity of blood useful for the
transplants; and that it was necessary to enrich the collected blood in CD34+
cells with specific clonogenic culture, as this is otherwise a small number for a
donation to an adult. In the "new donors" the effects of the unconscious donation
always depend on the clamping time, which should be the shortest possible to
avoid blood overload, which is very dangerous in the presence of heart
malformation.
PMID- 10758796
TI - Heparin-induced thrombocytopenia type II with pulmonary embolism after cesarean
section.
PMID- 10758797
TI - Sonographic parameters and hormonal status in lean and obese women with
polycystic ovary syndrome.
AB - A total of 34 patients with the diagnosis of polycystic ovary syndrome (PCOS)
were recruited for this study. Weight distribution in lean PCOS women (n = 17)
was 93.5% to 110.5% of normal weight for height and age. In obese women (n = 17)
this distribution was 119.5 to 146.5%. Serum testosterone (T),
dehydroepiandrosterone sulfate (DHEA-S), delta 4-androstendione (delta 4-A), sex
hormone binding globulin, (SHBG), 17-hydroxyprogesterone (17-OH PRG), 17b
oestradiol (17b-E2), cortisol (CORT), follicle stimulating hormone (FSH),
luteinizing hormone (LH), prolactin (PRL) and insulin (INS) were measured. Serum
SHBG levels were lower in obese PCOS women (72.9 +/- 16.2 nmol/l) than in lean
PCOS women (99.6 +/- 10.5) (p < 0.001). Fasting insulin levels were higher in
obese PCOS women (30.4 +/- 4.5 mUI/ml) than in lean PCOS women (14.2 +/- 7.6
mUI/ml) (p < 0.001). Mean ovarian volume did not differ significantly between
lean and obese PCOS women (12.5 +/- 3.7 ml vs 16.1 +/- 5.3, p > 0.5). Endometrial
thickness was roughly similar between the two groups. Endometrial surface area in
lean PCOS women (7.6 +/- 2.2 cm2) was lower than in obese PCOS women (10.1 +/-
1.9 cm2) and the difference was significant (p < 0.01).
PMID- 10758798
TI - Laparoscopic hysterectomy using ultrasonic instruments in at risk women with
cardiovascular disease: 2 cases reports.
PMID- 10758799
TI - Renin-aldosterone system alterations during abdominal gynaecological operations
under general or combined general and epidural anaesthesia.
AB - Alterations of plasma renin-activity and aldosterone levels were comparatively
studied in 41 premenopausal patients who were subjected to total abdominal
hysterectomy. Twenty-one women received general anaesthesia (group A) and 20
received a combination of general and epidural anaesthesia (group B). Five blood
specimens were drawn from each patient in order to determine plasma aldosterone
levels (PA) and plasma renin activity (PRA) by radioimmunoassay (RIA). The rise
of PA levels in group A occurred 30 min after the initiation of surgery and at
that time there was a statistically significant difference as compared with the
epidural anaesthesia (EA) group (p < 0.001). PRA levels in both groups showed a
rise of limited statistical significance at 30 minutes after the initiation of
surgery (p < 0.05). During the remaining time intervals, group A did not show any
significant changes, whereas group B showed a reduction of limited statistical
significance (p < 0.05). General anaesthesia for gynecological abdominal surgery
without the use of volatile agents significantly increases plasma aldosterone
levels. Combined anaesthesia does not totally inhibit intraoperative
hyperaldosteroism but it is much slower and is of great advantage for the
patient.
PMID- 10758800
TI - Induced abortion and contraception: survey of 576 young women in Naples.
AB - The aim of the study was to investigate the link between induced abortion and
contraceptive methods. Five hundred and seventy-six women who underwent induced
abortions at the Obstetrics and Gynecology Institute of the Second University of
Naples were interviewed. They were asked about their knowledge of contraception
methods; age, school attendance rate and marital status were also considered. The
women were 27.8 (mean age) years old, high school educated (58.5%), married
(41%), nulliparous (63%). Twenty-four percent of the women admitted a previous
induced abortion. Withdrawal (176 women), condoms (104) and oral contraceptives
(74 women) were the most widely used contraceptive methods. Withdrawal (37%)
resulted in being the most utilized method during the cycle in which conception
occurred; no method had been employed by 31% of the women. We found that 35% of
the women had used their contraceptive method in a regular way but become
pregnant nevertheless. Another group of 40% had forgotten to use their
contraceptives for a few days and became pregnant by accident. In the last group
of 25% of the women had not used any contraceptive methods. The diffusion of
modern methods of fertility regulation influences the number of induced abortions
as shown by its reduction since 1982. Our data confirm that induced abortion is
the consequence of an insufficient use of modern contraceptives. Therefore more
information is necessary to get women and men to use contraceptive methods
regularly.
PMID- 10758801
TI - Simple ovarian cysts: frequency and outcome in girls aged 2-9 years.
AB - Many studies have examined the sonographic appearance of human ovary in the
childhood period and showed the presence of heterogenecity in the ovary due to
cyst formation which may be age-related or because of hormonal stimulation. These
studies classified these simple cysts into microcyst (< 9 mm) and macrocyst (> 9
mm). Also some of the studies reported that these cysts are frequent during
childhood while others did not. We conducted this study to examine the prevalence
and outcome of these simple ovarian cysts in girls aged between 2 and 9 years.
One-hundred and eight girls aged 2 to 9 years were studied prospectively at
Prince Zaid Hospital (PZH) in south Jordan during the period from 1 April, 1998
to 30 May, 1999. Simple cysts (micro- and macrocysts) were the aim of the study.
Visualization of the ovaries was performed using a 5-MHz transducer with monthly
follow-up. Among 108 girls examined, 183 ovaries were imaged and 65 simple
ovarian cysts were seen with an incidence of 35.5%. Microcysts accounted for
83.1% and macrocysts for 16.9%. There was no significant difference regarding the
visualization of the right or left ovary and the distribution of ovarian cysts (p
> 0.2); 89.1% of ovarian cysts resolved within 6 months, and 10.9% persisted more
than 6 months. Interestingly, all persisting ovarian cysts were macrocysts. No
adverse consequences for these ovarian cysts were noted. We have concluded that
simple ovarian cysts can be seen in all age groups between 2 to 9 years. They are
not clinically significant, and the majority resolve within 6 months.
PMID- 10758802
TI - Hormonal reproductive status of women at menopausal transition compared to that
observed in a group of midreproductive-aged women.
AB - OBJECTIVE: To compare the serum levels of follicle stimulating hormone (FSH),
luteinizing hormone (LH), prolactin (PRL), estradiol (E2), testosterone (T) and
dehydroepiandrosterone sulfate (DHEA-S) in perimenopausal women to the levels of
the same reproductive hormones in younger women. METHODS: This was a case control
study which compared the hormonal status (circulating levels of FSH, LH, PRL, T,
E2, DHEA-S) between women at menopausal transition and younger mid-reproductive
aged controls. The t-test for independent samples was used. RESULTS: FSH, LH and
E2 were higher, and T and DHEA-S were lower in perimenopausal women. CONCLUSION:
The reproductive hormonal patterns in perimenopausal women favor a relatively
hypergonadotropic hyper-estrogenic milieu.
PMID- 10758803
TI - Atrial fibrillation in the WPW syndrome during pregnancy.
PMID- 10758804
TI - Physical therapy in a patient with bilateral obturator nerve paralysis after
surgery. A case report.
AB - Obturator nerve injury can result from surgical procedures. Bilateral obturator
nerve injury developed in our patient as a result of edema in the obturator fossa
after a debulking operation. In the postoperative period, neuromuscular
electrical stimulation, electromyographic (EMG) biofeedback, exercise and a home
treatment program were used as the physical therapy approach. The patient became
symptom-free after the physiotherapy program.
PMID- 10758805
TI - Laparoscopic salpingo-oophorectomy during pregnancy: a case report.
PMID- 10758806
TI - The placenta in meconium staining: lesions and early neonatal outcome.
AB - PURPOSE: To evaluate the immediate neonatal outcome and the presence of various
placental lesions in 96 pregnancies with meconium-stained amniotic fluid.
MATERIALS AND METHODS: The patients were divided into a group with acute (N = 41)
and subacute and chronic (N = 55) meconium staining of the placenta. Apgar
scores, arterial cord pH and admission to the neonatal intensive care unit (NICU)
were determined in addition to the findings on gross and microscopic examination
of the placentas. RESULTS: Of the 53 live births with subacute and chronic
meconium staining, 13% had Apgar Scores < or = 7 at 5 minutes compared to 7% with
acute meconium staining. Similarly, a significantly lower umbilical artery pH was
determined in the former group [(32%) versus (7%)], (p < 0.01). When 9 different
pathologic lesions of the placenta were evaluated microscopically, the frequency
of villous vascular thrombosis (25.4%), infarcts (38%), acute chorioamnionitis
(20%), villous edema (9.1%) and villitis (14.5%) was significantly higher in the
group with longer meconium exposure compared to the other group (2.4%), (9.7%),
(7.3%), (0%), and 1 (2.4%), respectively. In addition, when tested for 4
different lesions, cases with acute meconium were less likely to have one or more
lesions. When one or more placental lesions were found, NICU admission rate was
significantly higher in the patients with subacute and chronic meconium.
CONCLUSION: Subacute and chronic meconium discharge is associated with
significant placental lesions and an increased risk of adverse pregnancy outcome
in the immediate neonatal period.
PMID- 10758807
TI - Prenatal diagnosis of epignathus in the first half of pregnancy: a case report
and review of the literature.
AB - Congenital teratomas of the oral cavity commonly present as tissue masses
projecting from the mouth. The important prognostic determinants are: the age of
presentation, technical problems during surgical removal of the mass, associated
anomalies, and the nature of the composing tissues. This study reports one case
of epignathus (an extremely rare oropharyngeal teratoma) that was diagnosed by
ultrasonography at 19 weeks of gestation and reviews the relevant literature.
PMID- 10758808
TI - The effects of abdominal and bimanual pelvic examination and transvaginal
ultrasonography on serum CA-125 levels.
AB - The need for the early detection of ovarian cancer continues to be one of the
most important issues in women's health care. The three most extensively
evaluated screening methods for ovarian cancer are pelvic examination,
transvaginal ultrasonography, and serum CA-125 levels. The answers to questions
such as should the levels of CA-125 be measured before bimanual pelvic
examination or transvaginal ultrasonography or do abdominal examinations effect
the levels of CA-125 are obscure. Fifty-four otherwise healthy female volunteers
at the preovulatory phase of the menstrual cycle complaining of vaginal
candidiasis were divided into 3 groups. Abdominal (group 1), bimanual pelvic
(group 2), and transvaginal ultrasonography (group 3) examination was performed
and serum CA-125 levels were evaluated prior to examination and 10 minutes, 6
hours, and 24 hours after the examination. As a result, serum CA-125 levels
(U/ml) were found to be 8.13 +/- 4.76, 8.23 +/- 5.05, 8.32 +/- 4.88, and 8.33 +/-
4.94 in the group of abdominal examination, respectively, 8.23 +/- 4.89, 8.45 +/-
5.15, 8.77 +/- 4.96, and 8.79 +/- 5.50 in the group of bimanual pelvic
examination, respectively, and 8.19 +/- 4.56, 8.30 +/- 5.10, 8.81 +/- 5.56, and
8.88 +/- 5.71 in the group of transvaginal ultrasonography, respectively. The
serum CA-125 levels detected prior to examinations were statistically
insignificant when compared with the results obtained at 10 minutes, 6 hours, and
24 hours later in all three groups. We concluded that physical examination,
either abdominal or pelvic, and transvaginal ultrasonography do not change the
serum levels of CA-125.
PMID- 10758809
TI - Exercise and hypertension.
AB - Randomized, well-controlled exercise intervention studies have shown consistently
that regularly performed aerobic exercise significantly lowers blood pressure in
patients with essential hypertension. Mild to moderate intensity exercise may be
more effective in lowering blood pressure than higher intensity exercises. Such
exercise is also safe and effective in lowering blood pressure in treated
patients with severe hypertension and left ventricular hypertrophy. A significant
reduction in blood pressure and regression of left ventricular hypertrophy may be
achieved in these patients even after substantial reductions in antihypertensive
medication. Recent findings have also shown that exercise training attenuates
exaggerated blood pressure response during physical exertion. The safety and
efficacy of mild to moderate exercise has significant and positive clinical
implications for all hypertensive patients. Exercise-induced reductions in
resting blood pressure and prevention of abnormal increases in blood pressure
during physical exertion can lead to fewer cardiovascular events. They may also
reduce antihypertensive medication requirements, cost, and medication-related
side-effects, and improve quality of life.
PMID- 10758810
TI - Effects of exercise on insulin resistance syndrome.
PMID- 10758811
TI - Exercise and obesity.
AB - The prevalence of obesity has increased dramatically during the past decade in
the USA. This is despite an estimated 50 million Americans who try to lose weight
each year. The increasing prevalence of obesity is particularly alarming due to
the numerous health implications associated with this condition, including
coronary artery disease, hypertension, diabetes, hyperlipidemia, cancer, and
various musculoskeletal conditions. The economic impact of treating illnesses
associated with obesity has been estimated to be US$40 billion in the USA.
Dieting is largely ineffective in maintaining initial weight loss as numerous
studies suggest the majority of dieters regain all lost weight with 3-5 years.
On, the other hand, regular exercise has been shown to be one of the best
predictors of successful weight maintenance. Moreover, studies indicate that
improved fitness through regular physical activity reduces cardiovascular
morbidity and mortality for overweight individuals even if they remain
overweight. Providing advice about exercise to overweight or obese individuals
requires explicit information about the frequency, intensity, duration, and type
of physical activity that should be performed. The ultimate goal for the
exercising obese patient is to make a life-long commitment to achieving
reasonable energy expenditure through routine physical activity.
PMID- 10758812
TI - Exercise and endothelial function.
PMID- 10758813
TI - Exercise and thrombosis.
AB - Long-term moderate or strenuous physical activity is associated with a
considerable reduction in cardiovascular morbidity and mortality. This article
reviews the evidence to suggest that part of the effect is mediated through the
effects on thrombogenic factors. Fibrinogen has been convincingly shown to be an
independent cardiovascular risk factor. Other hemostatic and fibrinolytic
parameters that are predictive of coronary events include factor VII, platelet
hyperreactivity, plasminogen activator inhibitor-1, and tissue-plasminogen
activator. The effects of exercise on fibrinogen have been studied intensively.
One randomized, controlled trial, two other intervention studies and a large
number of population-based cross-sectional studies have consistently found an
inverse relationship between various measures of sport activity or leisure
activity and plasma levels of fibrinogen. The magnitude of the effect might be
associated with a sizeable reduction in major coronary events. Relatively few
data are available on endurance exercise and markers of the fibrinolytic system.
Acute exercise leads to a transient activation of the coagulation system, which
is accompanied by an increase in the fibrinolytic capacity in healthy subjects.
However, patients with ischemic heart disease, who cannot increase their
fibrinolytic potential, may be at considerable risk for acute ischemic events if
they are exposed to unaccustomed strenuous physical exertion. It is concluded
that physical activity has profound effects on thrombogenic factors and that
these mechanisms could contribute to its beneficial cardiovascular effects.
PMID- 10758814
TI - Exercise and autonomic function.
AB - The complex interplay between the dichotomous subdivisions of the autonomic
nervous system establishes and maintains a delicately tuned homeostasis in spite
of an ever-changing environment. Aerobic exercise training can increase activity
of the parasympathetic nervous system and decrease sympathetic activity.
Conversely, it is well-documented that cardiac disease is often characterized by
attenuated parasympathetic activity and heightened sympathetic tone. A
correlation between autonomic disequilibrium and disease has led to the
hypothesis that exercise training, as a therapy that restores the autonomic
nervous system towards normal function, may be associated with, and possibly
responsible for, outcome improvements in various populations. This is merely one
of the many benefits that is conferred by chronic exercise training and reviewed
in this issue.
PMID- 10758815
TI - Coronary risk profiles in men with coronary artery disease: effects of body
composition, fat distribution, age and fitness.
AB - BACKGROUND: Few studies have investigated the influence of body composition,
abdominal obesity, age and fitness on coronary risk factors in populations of
patients with coronary heart disease (CHD). We investigated whether abdominal
obesity or generalized adiposity is a better predictor of cardiovascular risk in
men with coronary artery disease (CAD), and the effects of exercise training on
coronary risk factors in younger and older patients with CAD. METHODS: The study
population consisted of 81 male patients aged 33-83 years (mean +/- SD 60.0 +/-
13.3 years) with established CAD. We studied the relationships among body
composition, body fat distribution, dietary intake, peak aerobic capacity, lipid
concentrations, and plasma glucose and insulin concentrations. We subsequently
measured the influence of exercise training on these components. RESULTS: The
study population was characterized by a high prevalence of obesity, particularly
in younger patients. Body mass index, rather than body fat distribution, was the
best anthropometric predictor of plasma triglyceride concentrations (r2 = 0.11, P
< 0.05) and cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio (r2 =
0.13, P < 0.01). Body weight, rather than body fat distribution, was the best
predictor of plasma HDL-C concentration (r2 = 0.14, P < 0.01) and fasting glucose
concentrations (r2 = 0.10, P < 0.05). Fat mass was the best anthropometric
predictor of fasting plasma insulin concentrations (r2 = 0.38, P < 0.0001) and
for the glucose-insulin ratio (r2 = 0.39, P < 0.0001) in men with CAD. Younger
patients tended to have greater improvements in HDL-C concentrations and the
cholesterol:HDL-C ratio than did older individuals, as a result of exercise
training. CONCLUSION: In men with CAD, general measures of obesity, such as body
weight, body mass index, and fat mass are better predictors of coronary risk
factors than body fat distribution. Younger and older men with CAD experienced
similar improvements in body composition and body fat distribution after an
exercise training program.
PMID- 10758816
TI - Development of an animal model of selective coronary atherosclerosis.
AB - BACKGROUND: Atherosclerosis causes over 40% of all deaths in the USA and Western
Europe. Although several hypotheses have been proposed, the etiology and
pathogenesis of the atherosclerosis remain unknown. OBJECTIVE: To develop a model
of selective coronary atherosclerosis in pigs. DESIGN: An animal model of
selective coronary atherosclerosis was developed by combining a guide-wire
induced endothelial injury and cholesterol-enriched diet. METHODS: Twelve pigs
were subjected to guide-wire-induced injury to endothelium of left anterior
descending (LAD) coronary artery. Six animals (control group) were fed a standard
pig food; the remaining six animals (cholesterol group) were fed a 6%-cholesterol
enriched diet. Three animals from the control group were killed immediately after
the endothelial injury (acute control group). The other three animals in the
control group (chronic control group) and all animals in the cholesterol-fed
group were killed 4 weeks after the injury. RESULTS: The endothelial surface and
the media of the left circumflex coronary artery LCX in all animals were intact.
Long eccentric areas of endothelial injury were found in the LAD coronary
arteries of animals in the acute control group. Numerous fibrous atherosclerotic
plaques in LAD coronary arteries were found in animals in the chronic control
group as well as in animals in the cholesterol-fed group, but were highly
pronounced in animals in the last group. No accumulation of lipids was found in
the plaques of animals in both groups. CONCLUSIONS: Administration of a 6%
cholesterol diet for 6 weeks is not sufficient to cause coronary atherosclerosis
in pigs. Selective coronary atherosclerosis can be induced within 4 weeks with
the same diet when the blood vessel has been injured with a guide wire.
PMID- 10758817
TI - The comparable diagnostic accuracies of dobutamine-stress and dipyridamole-stress
echocardiographies: a meta-analysis.
AB - BACKGROUND: Dobutamine-stress and dipyridamole-stress echocardiographies are
widely used for pharmacological stress echocardiography, with wide geographical
variations. OBJECTIVE: To assess whether evidence derived from the literature
indicates or disapproves that either stress modality confers diagnostic
superiority. METHODS: We performed a meta-analysis of peer-reviewed literature of
published trials with head-to-head comparison, on the same population, of high
dose (0.84 mg/kg) dipyridamole-stress versus high-dose (up to 40 micrograms/kg
per min) dobutamine-stress echocardiography. Data from 12 studies performed in 12
institutions in seven countries were analysed. Angiographic information about 818
patients was considered. RESULTS: The diagnostic accuracies of the two tests were
similar (631 of 818, 77%, for dipyridamole versus 654 of 818, 80%, for
dobutamine, NS). Overall sensitivities were 403 of 568 (71%) for dipyridamole and
437 of 568 (77%) for dobutamine (P < 0.05). Sensitivities for patients with
single-vessel disease were 177 of 275 (64%) for dipyridamole and 203 of 275 (74%)
for dobutamine (P < 0.05). Sensitivities for patients with multivessel disease
were 162 of 203 (80%) for dipyridamole and 163 of 203 (80%) for dobutamine (NS).
Specificities were 232 of 250 (93%) for dipyridamole and 217 of 250 (87%) for
dobutamine (P < 0.05). Data from an additional 26 studies with dipyridamole alone
and 47 studies with dobutamine alone were analysed. The diagnostic accuracies
were 80% for dipyridamole (n = 2038 patients; 95% confidence interval 75-82%) and
82% for dobutamine (n = 4264 patients; 95% confidence interval 79-84%).
CONCLUSION: High-dose dobutamine-stress and high-dose dipyridamole-stress
echocardiographies have comparable diagnostic accuracies, with a slightly higher
sensitivity with dobutamine and a slightly higher specificity with dipyridamole.
PMID- 10758818
TI - On-line vectorcardiography during elective coronary angioplasty indicates
procedure-related myocardial infarction.
AB - BACKGROUND: Increased creatine kinase concentrations after elective percutaneous
transluminal coronary angioplasty (PTCA) have been shown to be associated with
increased late cardiac mortality. OBJECTIVE: To evaluate the potential of
continuous on-line vectorcardiography during elective PTCA to identify procedure
related myocardial infarction. METHODS: Patients (n = 192, ages 58 +/- 10 years),
treated with elective and initially successful PTCA, were studied using
vectorcardiogram (VCG) recordings. VCG monitoring was started 5 min before start
of the PTCA and was carried out during the entire procedure, for at least 30 min
after the first balloon inflation. ST-segment vector magnitude (ST-VM) and ST
segment change vector magnitude (STC-VM) were monitored. RESULTS: Fifteen (7.8%)
procedure-related myocardial infarctions occurred. Indicators of procedure
related myocardial infarction were maximum value of ST-VM (P < 0.001) and STC-VM
(P < 0.001), total ischemic time of all ST-VM episodes (P < 0.001) and STC-VM
episodes (P < 0.001). The variable most closely related to a procedure-related
myocardial infarction was the maximum STC-VM value during the procedure. With an
optimized cutoff value, maximum STC-VM predicts a procedure-related myocardial
infarction with a sensitivity of 93%, a specificity of 59% and a negative
predictive value of 99%. Patients who had a stent implanted had significantly
greater VCG values (P < 0.05-P < 0.001) than the group without a stent. There was
a trend (P < 0.06) to a relation between increased creatine kinase concentration
and stent implantation. In patients both with and without an implanted stent,
greater STC-VM values were associated with procedure-related myocardial
infarction (P < 0.01). CONCLUSION: Continuous VCG monitoring during elective PTCA
is a promising method for immediate detection of patients at increased risk of
procedure-related myocardial infarction.
PMID- 10758819
TI - Effects of trimetazidine on clinical symptoms and tolerance of exercise of
patients with syndrome X: a preliminary study.
AB - BACKGROUND: Trimetazidine diminishes angina and improves tolerance of exercise of
patients with ischemic heart disease, and has no influence on blood pressure and
heart rate. OBJECTIVE: To determine the effect of trimetazidine on angina
symptoms and exercise tolerance in patients with syndrome X. METHODS: We
investigated the effect of trimetazidine on the clinical symptoms and tolerance
of exercise of 34 patients (20 women and 14 men, aged 32-60 years) with syndrome
X (angina pectoris, positive result of exercise test, and normal coronary
angiogram). The exercise test was performed before initiation of oral
administration of trimetazidine therapy (20 mg three times a day) and 1 and 6
months thereafter. RESULTS: We obtained negative results of exercise treadmill
tests for four patients (11.76%) after 1 month and five patients (14.71%) after 6
months of trimetazidine treatment. There was also a decrease in the incidence of
effort angina after 6 months of treatment (26 patients or 76.47% before treatment
versus 13 patients or 38.23% after 6 months of treatment). The drug had no
significant influence on the heart rate and blood pressure. The duration for
which patients could exercise was significantly prolonged by 1 month (652.9 +/-
206.2 versus 563.4 +/- 190.4 s, P = 0.0047) and 6 months (650.3 +/- 207.8 s, P =
0.0094) of treatment with trimetazidine. CONCLUSION: Treatment with trimetazidine
decreases signs of angina during exercise and improves tolerance of exercise of
patients with syndrome X.
PMID- 10758820
TI - Beneficial effect of HEPES buffer in repeated coronary reperfusion.
AB - BACKGROUND: We have demonstrated previously that, when repeated reperfusion is
performed after reocclusion, there is a decrease in the amount of myocardial
salvage, despite early reperfusion. Treatment with nisoldipine induced a
beneficial effect by reduction of infarct size in this experimental model.
OBJECTIVE: To study the effect of HEPES buffer on infarct size, using a repeated
reperfusion model. METHODS: The left anterior descending coronary artery was
occluded in anesthetized dogs. Thirty minutes after the occlusion, dogs were
allocated randomly to either the treatment group (n = 7; HEPES 0.64 mmol/l
infused intravenously throughout the experiment) or the control group (n = 8;
saline). Occlusion was maintained for 2 h, followed by 1 h of reperfusion, then 1
h of reocclusion and 2 h of second reperfusion. An in-vivo area at risk was
determined by gentian violet staining, and infarct size was defined and
quantitated by triphenyl-tetrazolium chloride staining. RESULTS: Hemodynamic
measurements were similar in both groups. Mass of necrosis/mass at risk was
significantly smaller in the HEPES group (30.7 +/- 1.6%, mean +/- SEM) compared
with controls (50.6 +/- 3.8%, P < 0.001). CONCLUSION: Treatment with HEPES
induces a beneficial effect by reduction of infarct size in repeated coronary
reperfusion.
PMID- 10758821
TI - Early angiotensin converting enzyme inhibitor therapy enhances the benefits of
late coronary artery reperfusion on infarct expansion.
AB - BACKGROUND: Individually, both late reperfusion and early angiotensin converting
enzyme (ACE) inhibitor treatment prevent infarct expansion after acute myocardial
infarction. OBJECTIVE: To examine the effect and mechanism of early post
myocardial infarction ACE inhibitor treatment, when used in combination with late
coronary artery reperfusion, on infarct expansion. METHODS: Sprague-Dawley rats
underwent 8 h of coronary occlusion followed by permanent reperfusion. The
treatment group received enalapril, started 1 h after coronary occlusion and
continued for 13 days. A control group received placebo. Two weeks after acute
myocardial infarction, hemodynamic, morphometric and histologic analyses were
performed. RESULTS: Hemodynamic parameters were similar in both groups (P = NS).
Infarct size was similar in the ACE inhibitor and placebo treatment groups (44 +/
4% compared with 39 +/- 4%, P = NS). Septal thickness was also similar in the
two groups (2.8 +/- 0.3 mm compared with 2.7 +/- 0.3 mm, P = NS). The ACE
inhibitor-treated group had thicker infarcts than those in the placebo-treated
group (0.93 +/- 0.07 mm compared with 0.76 +/- 0.04 mm, P < 0.05) and these
infarcts were less expanded (expansion index 1.17 +/- 0.12 compared with 1.57 +/-
0.12, P < 0.05). ACE inhibitor treatment was associated with hypertrophy of
viable myocytes within the scar compared with placebo treatment (cell diameter
11.1 +/- 0.5 microns compared with 8.9 +/- 0.4 microns, P < 0.01). CONCLUSIONS:
Early post-myocardial infarction ACE inhibitor treatment enhances the benefits of
late coronary reperfusion on infarct expansion. The benefits may be related to
hypertrophy of still-viable myocytes within the infarcted zone.
PMID- 10758823
TI - Bibliography. Current world literature.
PMID- 10758822
TI - Does ischemic preconditioning limit infarct size in non-Q-wave myocardial
infarction?
PMID- 10758824
TI - [The effect of nitric oxide on the contractile activity of skinned preparations
of the smooth muscles of the rat portal vein].
AB - The effects of nitric oxide donors sodium nitroprusside and nitroglycerin on the
contractile activity of the skinned rat portal vein were investigated. The
skinned strips of rat portal vein were prepared by treatment 0.1 mg/ml saponin
for 20 min. Maximally pCa 4.0 activated strips were exposed to nitric oxide
donors. Both sodium nitroprusside and nitroglycerin induced dose-dependent
decrease of the isometric force of the contraction. The inhibitor of soluble
guanylyl cyclase methylene blue (50 microM) did not blocked this effect. This
result shows the existence of the mechanism of NO actions on vascular smooth
muscle which is not associated with the changes of intracellular Ca2+ and the
activation of the soluble guanil cyclase.
PMID- 10758825
TI - [The effect of measured hypoxia on the development of situational osteopenia].
AB - The influence of gas mixture with low PO2 (90-110 mm Hg) on calcium-phosphorus
metabolism and biomechanical properties of femur bones at rats, who were kept
under condition of hind-limb unloading during 28-days, has been studied. Loss of
calcium and phosphorus during a day was less in rats, who was received gas
mixture with lower PO2, than rats who was kept in condition of hind-limb
unloading only. Hypoxic gas mixture stabilized mechanical properties of bones
tissue in femoral bone of rats. Gas mixture with lower pressure of oxygen retard
development of osteopenia and may be used with other corrective methods for
situation osteopenia prevention.
PMID- 10758826
TI - [A chronic hyperimmunocomplex process and its interrelationship with free radical
generating systems].
AB - On chronic hyperimmunocomplex process (CHIP) model in rats of Wistar line
(Cochrane C., Koffen D., 1973) we determined cAMP and cGMP concentration,
nitrogen oxide (NO), urine, urine acid,--in muscle and clearance organs, and also
in plasma. In result of carried out investigations there was determined the
increase of large and middle CIC in blood plasma, their fixation on endothelium
of aorta bifurcation and glomerula basal membrane, partially on liver cells.
There was revealed considerable disbalance of cyclic nucleotides concentration in
kidneys homogenates, spleen and plasma, with guanils fall (adenil index, what is
interconnected with NO level lowering in all cases and urine increase in plasma,
simultaneously with its decrease in number--in kidneys and spleen. Urinic acid
increased in number in kidneys, spleen, plasma. These changes create favourable
background for damaging of endothelium-neutrophil-thrombocyte cooperation through
hemokinin, moleculo-adhesive, fermentative mechanism with further development of
proliferative-remodulating processes in vessel wall.
PMID- 10758827
TI - [The participation of L-arginine in correcting the activity of the membrane
transport enzymes Na+,K(+)-, Ca2(+)- and Na(+)-ATPases in experimental
hypercholesterolemia].
AB - The influence of precursor of biosynthesis of nitric oxide L-arginine on the
level of transport enzymes Na+, K(+)-, Ca(2+)- and Na(+)-ATPases activity under
rabbits experimental hypercholesterolemia have been studied. The significant
changes in Na+, K(+)-, Ca(2+)- and Na(+)-ATPases activity in different tissues
(the cortex of kidney, the endothelium of aorta, the epithelium of small
intestine, the liver) had been found for the rabbits with inhibition of the
activity of this enzymes to the different levels in all these tissues. Injection
of L-arginine during the hypercholesterolemia caused the recovery of Na+, K(+)-,
Ca(2+)- and Na(+)-ATPases approximately to the control levels. Obtained results
demonstrate that exogenous L-arginine may participate in the correction of the
activity of membrane transport enzymes under the condition of the rabbits
experimental hypercholesterolemia. The authors discuss the possible mechanisms of
L-arginine effect on the studied transport enzymes under the experimental
atherosclerosis.
PMID- 10758828
TI - [The comparative characteristics of the anti-inflammatory action of chorionic and
placental extracts].
AB - On the model of the caragenan-induced acute aseptic peritonitis in rats it was
shown that in comparison with the extract of placenta the use of the chorion
cryoextract leads to the faster completion of neutrophilic and higher stimulation
of macrophagal and fibroblastic reaction in the inflammatory focus. Therefore, a
new drug of the chorion cryoextract possesses stronger anti-inflammatory actions
than the pharmacological preparation of placenta extract used in the same dose.
PMID- 10758829
TI - [The effect of oxytocin on Langerhans beta-islet cell function and on
carbohydrate metabolic indices in intact rats and in rats with diabetes].
AB - The experiments were carried out on male Wistar rats. Synthetic oxytocin was
administrated to intact and streptozotocin-diabetic animals during 10 days by
intracerebroventricular and intraperitoneal injections. The state of pancreatic b
cells was studied by a method of indirect immunofluorescence with the following
results computing on VIDAS-386 image analyzing system. The measurement of the
area of immunofluorescence and Langerhans islets and determination of insulin
concentration and its contents in islets was provided automatically. Insulin and
glucose concentration in blood was determined with standard techniques. Oxytocin
central injections to intact animals stimulated insulin synthesis and secretion
without changing of islets area. Peptide administration to diabetic animals
resulted in braking of islets destruction, increasing of its area and contents of
insulin. These changes were accompanied with the reducing of glycemia level.
Thus, oxytocin administration stimulates insulin synthesis and secretion in
intact and diabetic animals and this effect is more expressed with central
injections. Besides it is necessary to note the oxytocin braking effect on beta
cells destruction in diabetic animals.
PMID- 10758830
TI - [Recurrent inhibition of the flexor muscle motoneurons of the human forearm under
the effect of vibration and static muscle strain].
AB - By use of H-reflex technique reflex flexor muscles motoneurons recurrent
inhibition was studied for man forearm muscle. It was observed the reduce of this
inhibition with the muscles strain. The vibration, acting to the strained muscle,
showed a disappearance of inhibition. It was marked that these features can be
connected to both segmental or supraspinal action to motoneurons or Renshaw
cells. The recurrent inhibition is reduced more effectively under complex
vibration and muscle strain influence than under only strain factor, and it is
connected to the vibration. It seems to be connected to the more activated
receptors number. It is suggested that supraspinal inhibiting action on Renshaw
cells is preferred in this mechanism. Possible role of the presynaptic inhibition
is discussed that can be effective through skin or joint afferents of flexor
reflex.
PMID- 10758831
TI - [The effect of verapamil on the resumption of meiosis and the formation of the
first polar body by mouse oocytes in vitro].
AB - Resumption of the first meiotic division and extrusion of the first polar body
from the cumulus enclosed and cumulus-free oocytes isolated from mouse ovaries in
diestrus, proestrus, estrus (I and II) were registered in the medium containing
various concentration of verapamil. In this study, the competence of the oocytes
to resumed the first meiotic division and to extruded the first polar body were
dependent from verapamil concentration (in proestrus and estrus I) and from
cumulus cell presence.
PMID- 10758832
TI - [The role of arachidonic acid derivatives in generating membrane potential
oscillations of the rat aorta endothelium].
AB - Involvement of metabolites of arachidonic acid in electrical responses of rat
aortic endothelium evoked by the agonist of aa1-adrenoreceptors, phenylephrine
has been investigated. Our experiments suggest that phenylephrine evokes
synthesis of thromboxane A2 in the rat aorta that is involved in the
phenylephrine-evoked oscillations probably by increasing excitatory effect of the
vasoconstrictor on vascular smooth muscle by the mechanism of positive feedback.
PMID- 10758833
TI - [The lipid composition characteristics of the blood serum and aortic wall in the
modelling of different types of arteriosclerosis].
AB - Executed was modelling of Monckeberg's arteriosclerosis by injection into rabbits
monoiodacetat, ergocalciferol; cholesterol atherosclerosis and combined type of
lesion by simultaneous intake of cholesterol and monoiodacetat. Examined was the
content of lipoproteins of different classes in blood serum, in aorta tissue-
cholesterol, triglycerides, phospholipids. During all implemented ways of actions
the change in comparative content of lipoproteins was indicated, what can be
estimated as atherogenic. Monoiodacetat model of arteriosclerosis is accompanied
with denominated accumulation of lipids in aorta walls, ergocalciferol model with
accumulation of triglycerides only.
PMID- 10758834
TI - [The pathogenetic aspects of an ulcerative lesion of the duodenal mucosa].
AB - Basing upon the histochemical study of SDG and NO-synthase activity in 68
biopsies taken from patients with duodenal ulcer the connection between the
clinical specificity and the activity of the disease the SDG activity decreases,
while that of NO-synthase increases. At the phase of cicatrization the opposite
process is going on. The authors connect the phenomena under investigation with
the vasodilatory and protective abilities of the nitrogen oxide.
PMID- 10758835
TI - [The functional dynamics of attention and its relation to the individual
typological properties of the nervous system in middle-aged and elderly persons].
AB - The age dynamics of attention's function and its correlation with functional
mobility of nervous processes at adults in age from 21 to 74 years old were
studied. It was determined that this period of ontogenesis characterized gradual
and irregular determination this function. It was revealed that mean exponents of
attention's qualities and peculiarities its age dynamics depended from individual
typological properties of nervous system et adults and old men. The adults with
high exponents of function mobility of nervous processes at all age groups have
high level of development of attention's function and slower changing and delay
of beginning of involution this mental function. The adults with low exponents of
function mobility of nervous processes characterized earlier beginning and
intensive deterioration of attention's function.
PMID- 10758836
TI - [The characteristics of autonomic regulation in persons with different levels of
mental work capacity].
AB - The aim of the study was investigation of efficiency of mental activity in people
with different types of vegetative regulation. The 32 operators Chernobyl atomic
station aged 26-54 were examined. The mental activity was studied by two
computer's tests. The registration and analysis cardio-intervals were processing
in set time interval. The results of investigation are showed that efficiency of
operator's activity related with quality, productivity and information processing
speed. In successful operators are showed transition from determination to
stochastic types of heart rhythm regulation. In non-successful operators are
showed transition from stochastic to determination types of heart rhythm
regulation. Thus the increase of determinate organization of heart rhythm system
regulation related with changes of mental activity algorithm and with
intensification of psychophysiological functions tension.
PMID- 10758837
TI - [The metabolic characteristics of the adaptation of athletes to cyclic types of
sports to the point of physical loading].
AB - The article considers problems of peculiarities of energetic adaptation of
athletics of cyclic sports activity for significant sports loadings by POL
indices, antioxidant system. ATP before and after veloergometric test by PWC 170.
Adaptation of high class sportsmen for acute and chronic stress was taking place
at the expense of more economic consumption of ATP at rest. Optimal indices of
energy supply and metabolic adaptation were found at sportsmen with high level of
physical state, while a slight disbalance was found at the sportsmen with average
level of physical state.
PMID- 10758838
TI - [The characteristics of the functional development of higher nervous activity in
middle-school pupils during long-term physical loading].
AB - Longitudinal studies of main nervous processes and functions of momentary memory
in schoolgirls (11-15 y.) were conducted. A comparative analysis of results of
investigation of girls from sportive and control classes showed that the
individual characteristics of the basic nervous processes play an role in the
development of functions of the momentary memory. Dynamics of creation of the
relationships between individually typological characteristics of the basic
nervous processes mobility development in the sportive classes pupils has some
particularities in contrast with their peers of control classes. Schoolgirls with
high functional mobility level and high cerebrum capacity of work were
characterized with high momentary memory indexes, unlike their peers with low
features of these. Direct positive significant correlation were established
between functional mobility level of nervous processes and the momentary memory
functional indexes.
PMID- 10758840
TI - [Social transformation of sexuality in the past decades. An overview].
AB - The societies of the Western world have witnessed a tremendous cultural and
social transformation of sexuality during the eighties and nineties, a process
Sigusch refers to as "the neosexual revolution". Up to now, this transformation
and reassessment of sexuality has proceeded rather slowly and quietly. Yet both
its real and its symbolic effects may indeed be more consequential that those
brought about in the course of the rapid, noisy sexual revolution of the sixties
and seventies. The neosexual revolution is dismantling the old patterns of
sexuality and reassembling them anew. In the process, dimensions, intimate
relationships, preferences and sexual fragments emerge, many of which had
submerged, were unnamed or simply did not exist before. In general, sexuality has
lost much of its symbolic meaning as a cultural phenomenon. Sexuality is no
longer the great metaphor for pleasure and happiness, nor is it so greatly
overestimated as it was during the sexual revolution. It is now widely taken for
granted, much like egotism or motility. Whereas sex was once mystified in a
positive sense--as ecstasy and transgression, it has now taken on a negative
mystification characterized by abuse, violence and deadly infection. While the
old sexuality was based primarily upon sexual instinct, orgasm and the
heterosexual couple, neosexualities revolve predominantly around gender
difference, thrills, self-gratification and prosthetic substitution. From the
vast number of interrelated processes from which neosexualities emerge, three
phenomena have been selected for discussion here: the dissociation of the sexual
sphere, the dispersion of sexual fragments and the diversification of sexual
relationships. The outcome of the neosexual revolution could be described as self
disciplined and self-optimized "self-sex".
PMID- 10758839
TI - [The enterosorbents belosorb and panzysorb in the treatment of acute experimental
pancreatitis in rats].
AB - Enterosorption with highly dispersed fibrous carbon adsorbent Belosorb or enzyme
containing fibrous carbon adsorbent Panzysorb was applied for the treatment of
experimental acute pancreatitis (EAP) in the rats. Panzysorb was obtained by
immobilization of digestive hydrolases (proteases and amylase) on Belosorb as
matrix. It was shown that oral administration of Panzysorb (100 mg/kg body
weight) significantly decreased amylolytic and lipolytic activity of blood serum
by the third hour after EAP induction. The course of enterosorption (ten days)
with the Panzysorb led to the appearance of regeneration focuses in injured
organ.
PMID- 10758841
TI - [Origins of dialogue: phenomenological theories of intersubjectivity in
developmental perspectives and as a foundation of psychotherapeutic processes].
AB - Recognizing the other with his/her psychic peculiarity is an important assumption
for psychotherapy. But how is empathy possible? Answers are to be expected by
phenomenological-philosophical approaches concerning intersubjectivity and infant
research. They are described in a comprehensive way and related to each other in
spite of their epistemological differences. As can be seen in the beginning of
showing and reading maternal emotions (so-called "social referencing") an infant
is able to show intersubjective behaviour from the age of nine months on.
Research on the reflected image of the infant and the development of shame shows
that consciousness of the ego is not built before the age of one and a half
years. These empirically well established results contradict those
phenomenological approaches claiming that the other cannot be experienced
directly but via cognitive analogies of own emotions (Lipps, Husserl). They
better fit an anthropology that states the human being as an innate dialogically
structured one and therefore being capable of empathy. Therefore the base for a
deeper understanding of the following results of psychotherapy-research is
established: 1. Early infant's memories probably do not exist as isolated images
but are embedded in interactional structures. 2. Strict therapeutical abstinence
may be experienced as a denial of communication and may have a retraumatic
effect. 3. Quality of therapeutical relationship is crucial for the success of
psychotherapy.
PMID- 10758842
TI - [Thiamine treatment in psychiatry and neurology].
AB - Every physician knows that alcohol dependence, alcohol withdrawal and Wernicke
Korsakow-syndrome require substitution with thiamine, in acute stages even
parenterally. This would be trivial if there was not the widespread fear of
anaphylactic, even lethal reactions to parenteral thiamine application. The
present article reviews the literature published on thiamine since 1936, when the
first synthetic, parenteral thiamine preparation became available, and, on this
basis, tries to give practical advice and therapeutic regimens for the treatment
of thiamine deficiency states. Controlled clinical studies on indications and
differential thiamine therapy have not been published. From the data that are
available, the following conclusions can be drawn: 1) Acute mortality of Wernicke
Korsakow-syndrome is about 20%. 2) Oral thiamine is safe. 3) The risk for an
anaphylactic shock due to parenteral thiamine administration is below 1 to
100,000. 4) Not only alcohol but any condition with either increased metabolic
need (pregnancy, consuming diseases) or deficient nutrition (including eating
disorders) can lead to thiamine deficiency. Therefore, we suggest: 1) Oral
thiamine substitution with at least 50 mg per day and supply of a sufficient and
complete diet should be given to any person that might be at risk for thiamine
deficiency. 2) Any patient suspicious for acute thiamine deficiency needs to be
treated under inpatient conditions and there needs to receive 50 to 100 mg
thiamine intravenously 3 to 4 times a day. 3) General practitioners,
psychiatrists and neurologists should take care of the oral supplementation of
thiamine, sufficient nutrition, and they are the physicians to diagnose early
stages of thiamine deficiency.
PMID- 10758843
TI - [The role of diffuse axonal injury in psychiatric assessment of brain-head
trauma].
AB - The concept of diffuse axonal injury is presented and the relevance in
medicolegal assessment of brain injured patients is discussed. The lesion pattern
of diffuse axonal injury not only plays a significant role in the acute
management and rehabilitation of brain injured patients but also in issues of
litigation. Brain imaging techniques are most important in the evaluation of
structural damage to the brain and play a pivotal role in the detection of
diffuse axonal injury. While computer-tomography follow-up studies may be
valuable for the detection of diffuse axonal injury, magnetic resonance imaging
is superior due to better sensitivity and contrast-resolution. The article
presents selected case studies and illustrates the different lesion patterns.
PMID- 10758844
TI - [Visual hallucinations in Parkinson and Charles Bonnet Syndrome patients. A
phenomenological and pathogenetic comparison].
AB - Visual hallucinations (VH) are seen in about a third of all patients with
Parkinson's disease (PD) and are usually considered to be an early marker or
clinical component of a dopaminergic psychosis. Their peculiar phenomenology has
not yet been studied in a systematic manner. METHODS: A semi-structured interview
was performed twice in 62 PD patients. Different motoric and cognitive disease
scales were used. The patients were not demented or depressed and had no other
psychotic features other than hallucinations. Their visions was at least 0.6.
RESULTS: 22 patients (36%) reported complex visual hallucinations or illusions in
both interviews. These patients were not different from the non-hallucinating
patients in terms of age, duration and stage of the disease, dosage and type of
medication and frequency of cataracts. VH were diurnal in 41% of the patients,
nocturnal in 18% of the patients and mixed in 41 patients. They were seen at
least once weekly in 67% and they lasted always less than an hour. VH most
frequently involved adults, children and pets. They were often mobile and had
normal size and physiognomy. Notable emotional reactions were only reported by
18% of the patients. DISCUSSION: The phenomenology of VH in PD differs from VH in
exogenous or endogenous psychoses, but is similar to the Charles Bonnet-syndrome
(CBS), appearing in elderly patients with different visual deficits. As PD
patients suffer regularly from visual deficits of contrast and color perception,
a similar pathogenesis to CBS can be hypothesized, with these "minor" and benign
VH being due to "release phenomena" in relation to partial visual deprivation.
The lack of multimodality hallucinations and of secondary paranoia as well as the
clear sensorium are helpful features in distinguishing them from toxic psychosis.
PMID- 10758845
TI - [Acupuncture in patients with minor depressive episodes and generalized anxiety.
Results of an experimental study].
AB - In a placebo-controlled, randomized, modified double-blind study we investigated
the effects of body needle acupuncture (n = 10) in 43 patients with minor
depression (ICD 10 F32.0, F32.1) and 13 patients with generalized anxiety
disorders (ICD10 F41.1). The severity of the disease was assessed by the Clinical
Global Impression Scale (CGI). Treatment response was defined as a significant
improvement in CGI. An intent-to-treat analysis was performed to compare
treatment responses between verum- and placebo acupuncture. After completing an
total of 10 acupuncture sessions the verum acupuncture group (n = 28) showed a
significantly larger clinical improvement compared to the placebo group (Mann
Whitney test, p < 0.05). There were significantly more responders in the verum
compared to the placebo group (60.7% vs. 21.4%; chi-square test, p < 0.01). In
contrast, no differences in the response rates were evident just after 5
acupuncture sessions. A multivariate analysis with the independent factor
acupuncture (verum vs. placebo) and the results of the results of the additional
rating scales (total score of HAMA, HAMD, Bf-S, BL) as dependent variables
(ANOVA, 1:54 D.F.) revealed a clear trend towards lower HAMA scores in the verum
group after completing 10 acupunctures (F3.29, p = 0.075). This corresponds well
to the high response rate of 85.7% in patients with generalized anxiety
disorders, in whom verum acupuncture was applied. Our results indicate that
needle acupuncture (Du.20, Ex.6, He.7, Pe.6, Bl.62) leads to a significant
clinical improvement as well as to a remarkable reduction in anxiety symptoms in
patients with minor depression or with generalized anxiety disorders. The total
sum of acupuncture sessions and the specific location of acupuncture needle
insertions might be important factors for bringing about therapeutic success.
PMID- 10758846
TI - Phenotypic and genotypic characterization of Vibrio viscosus sp. nov. and Vibrio
wodanis sp. nov. isolated from Atlantic salmon (Salmo salar) with 'winter ulcer'.
AB - Two groups of Vibrio strains isolated from Atlantic salmon with 'winter ulcer'
were characterized phenotypically and genotypically. The data obtained indicated
that each of the two groups represented a new species in the genus Vibrio. The
names Vibrio viscosus sp. nov. [type strain NVI 88/478T (= NCIMB 13584T)] and
Vibrio wodanis sp. nov. [type strain NVI 88/441T (= NCIMB 13582T)] are proposed
for the new species. V. viscosus strains exhibited a similar total DNA RFLP
pattern and a similar plasmid DNA profile. DNA relatedness (hydroxyapatite
method) of the V. viscosus type strain to nine other V. viscosus strains was 81
93% at 60 degrees C. Divergence within related sequences was 0.0-1.5% and
relatedness at 75 degrees C was 74-100%. V. wodanis strains exhibited marked
heterogeneity on the basis of RFLP analysis and plasmid profiles. DNA relatedness
of the V. wodanis type strain to 10 other V. wodanis strains was 66-94% at 60
degrees C. Divergence within related sequences was 0.0-1.5% and relatedness at 75
degrees C was 55-97%. Relatedness between V. viscosus and V. wodanis type strains
was approximately 20%. Among other Vibrio species, the closest relative of V.
viscosus was Vibrio marinus (ATCC 15381T) (43% relatedness at 60 degrees C) and
that of V. wodanis was Vibrio logei (ATCC 15382) (57% relatedness at 60 degrees
C). These same pairs were the closest phenotypic relatives. DNA sequence analysis
of the 16S rRNA gene of V. viscosus indicated an intimate relationship to V.
marinus. A total evaluation of the results, however, supports V. viscosus to be a
separate species in the genus Vibrio. The analysis of the sequence of the 16S
rRNA gene of V. wodanis supports that V. logei (ATCC 15382) was the most related
species. Ability to degrade casein, oxidative production of acid from trehalose
and production of lysine decarboxylase are important biochemical tests that will
differentiate between V. viscosus, V. wodanis, V. marinus (ATCC 15381T) and V.
logei (ATCC 15382).
PMID- 10758848
TI - Hyphomonas adhaerens sp. nov., Hyphomonas johnsonii sp. nov. and Hyphomonas
rosenbergii sp. nov., marine budding and prosthecate bacteria.
AB - Three strains of prosthecate, budding bacteria, MHS-2T, MHS-3T and VP6T, were
isolated from marine habitats including the open ocean (the pelagic zone), the
offshore region (the neritic zone) and the hydrothermal vent region. A polyphasic
approach including 16S rDNA sequencing, phenotypic analyses, serology, fatty acid
analyses, membrane protein profiles and DNA-DNA hybridizations was used to place
these strains in the genus Hyphomonas, a taxon of the alpha-Proteobacteria. The
results of these analyses also showed that strains MHS-3T, MHS-2T and VP6T each
represent a new species of Hyphomonas. The names Hyphomonas adhaerens (type
strain MHS-3T, ATCC 43965T), Hyphomonas johnsonii (type strain MHS-2T, ATCC
43964T) and Hyphomonas rosenbergii (type strain VP6T, ATCC 43869T) are proposed
for the new species. With these additions, Hyphomonas now contains eight species.
PMID- 10758847
TI - Alicyclobacillus hesperidum sp. nov. and a related genomic species from
solfataric soils of Sao Miguel in the Azores.
AB - Several acidophilic, slightly thermophilic or thermophilic Gram-positive isolates
were recovered from solfataric soil at Furnas on the Island of Sao Miguel in the
Azores. Phylogenetic analysis of the 16S rRNA gene sequence showed that these
organisms represented two novel species of the genus Alicyclobacillus. Strains FR
11T and FR-1b had an optimum growth temperature of about 50 degrees C, whereas
strains FR-3 and FR-6T had an optimum growth temperature of about 60 degrees C.
Biochemical, physiological and chemotaxonomic characteristics did not distinguish
isolates FR-3 and FR-6T from the type strain of Alicyclobacillus acidocaldarius;
however, strains FR-11T and FR-1b could be easily distinguished from the type
strain of Alicyclobacillus acidoterrestris by the carbon source assimilation
pattern and the fatty acid composition. On the basis of the phylogenetic
analysis, physiological and biochemical characteristics, and fatty acid
composition the name Alicyclobacillus hesperidum is proposed for the species
represented by strains FR-11T and FR-1b; a formal name for the new genomic
species represented by strains FR-3 and FR-6T is not proposed at this time.
PMID- 10758849
TI - Comparative analysis of the genes encoding 23S-5S rRNA intergenic spacer regions
of Lactobacillus casei-related strains.
AB - In this study, investigations into the 23S-5S rRNA intergenic spacer regions
(ISRs) of the Lactobacillus casei group were performed. A 1.6 kb fragment, from
Lactobacillus paracasei strain ATCC 27092, containing part of the 5S rRNA gene
(60 bp), the 5S-23S spacer region (198 bp) and part of the 23S rRNA gene (1295
bp) was cloned and sequenced (GenBank no. AF098107). This fragment was used as a
probe to determine the rRNA restriction fragment length polymorphism (RFLP)
patterns of nine strains belonging to the Lactobacillus casei group, along with
four other non-Lactobacillus casei lactobacilli species. A pair of PCR primers,
23-Fl and 5-Ru, was designed and used for PCR amplification of the 23S-5S rRNA
ISRs of these strains. The ISR length and sequence polymorphisms provided
additional information for the taxonomic study of the Lactobacillus casei group.
The spacer-length polymorphism of Lactobacillus rhamnosus was distinct from those
of the other strains and this observation is consistent with the classification
of Lactobacillus rhamnosus proposed by Mori et al. For all Lactobacillus casei
and Lactobacillus paracasei strains, two major bands (approx. 250 and 170 bp in
size) were obtained except in the case of Lactobacillus paracasei subsp. tolerans
strain NCIMB 9709T, which yielded only one amplified product (250 bp). The
sequencing data of the PCR products of seven well-characterized Lactobacillus
casei and Lactobacillus paracasei strains revealed the presence of a 76/80 bp
insertion/deletion with some random, single-base substitutions between the longer
and shorter spacers for each respective strain. A few base variations were also
detected within different strains in this group although the overall sequence
similarity was very high (95.9-99.5%). The rRNA RFLP and the spacer sequence of
Lactobacillus casei type strain ATCC 393T exhibited unique identities in this
cluster. On the other hand, Lactobacillus casei strain ATCC 334 showed a high
level of similarity with the other Lactobacillus casei strains tested. These
observations lend some support to the request for the reassignment of strain ATCC
334 as the neotype of Lactobacillus casei subsp. casei in place of strain ATCC
393T.
PMID- 10758850
TI - Characterization of Vibrio viscosus and Vibrio wodanis isolated at different
geographical locations: a proposal for reclassification of Vibrio viscosus as
Moritella viscosa comb. nov.
AB - Vibrio viscosus and Vibrio wodanis are recently described species of
psychrotropic bacteria that have been found associated with a disease called
'winter ulcer', affecting salmonid fish reared in saline water in Norway, Iceland
and recently in Scotland. V. viscosus and V. wodanis strains initially isolated
from fish in Iceland and Norway were subjected to characterization using
biochemical tests, SDS-PAGE of whole-cell proteins and a novel DNA fingerprinting
method, amplified fragment length polymorphism (AFLP). The V. viscosus strains
isolated from diseased fish grouped into homogeneous subgroups according to
geographical origin and challenge experiments revealed that representatives of
these groups are virulent. The results revealed that the V. wodanis strains are
heterogeneous genotypically and phenotypically. Sequencing of almost complete 16S
rRNA genes of V. viscosus and V. wodanis revealed that V. viscosus showed a 99.1%
sequence similarity to Moritella marina and V. wodanis showed a 98.8% sequence
similarity to Vibrio logei CIP 103204. A reclassification of Vibrio viscosus as
Moritella viscosa comb. nov. is proposed.
PMID- 10758851
TI - Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic
archaeon from a deep-sea hydrothermal vent chimney.
AB - A novel barophilic, hyperthermophilic archaeon was isolated from a deep-sea
hydrothermal vent chimney at the Myojin Knoll in the Ogasawara-Bonin Arc, Japan.
The cells were found to be irregular cocci and motile with multiple polar
flagella. Growth was observed between 60 and 88 degrees C (opt. 83 degrees C; 30
min doubling time), pH 4.0 and 8.0 (opt. pH 6.0), 20 and 73 g sea salts l-1 (opt.
47 g l-1) and 0.1 and 60 MPa (opt. 30 MPa). The isolate was a strictly anaerobic
chemoorganotroph capable of utilizing proteinaceous substrates such as yeast
extract, peptone, tryptone and casein in the presence of elemental sulfur or
ferrous iron. The G + C content of the genomic DNA was 53.5 mol%. Phylogenetic
analysis based on 16S rDNA sequences indicated that the isolate was a member of
an ancient lineage of the Thermococcales that diverged prior to the formation of
the two genera Thermococcus and Pyrococcus. On the basis of the physiological and
molecular properties of the new isolate, the name Palaeococcus ferrophilus gen.
nov., sp. nov. is proposed. The type strain is strain DMJT (= JCM 10417)
[corrected].
PMID- 10758852
TI - Leptospirillum gen. nov. (ex Markosyan 1972), nom. rev., including Leptospirillum
ferrooxidans sp. nov. (ex Markosyan 1972), nom. rev. and Leptospirillum
thermoferrooxidans sp. nov. (Golovacheva et al. 1992).
AB - The name Leptospirillum ferrooxidans is not in the Approved Lists of Bacterial
Names (1980), nor has it been subsequently validly published. In accordance with
the rules of the International Code of Nomenclature of Bacteria, the name
Leptospirillum for the genus (gen. nov., nom. rev.) and Leptospirillum
ferrooxidans for the species (sp. nov., nom. rev.) is revived here. The type
species is Leptospirillum ferrooxidans strain L15T (= DSM 2705T). The second
species in the genus is Leptospirillum thermoferrooxidans (Golovacheva et al.
1992) (type strain L-88T; Institute of Microbiology, INMI, Moscow, Russia).
PMID- 10758853
TI - Streptomyces thermocoprophilus sp. nov., a cellulase-free endo-xylanase-producing
streptomycete.
AB - The taxonomic position of a thermophilic actinomycete strain isolated from
poultry faeces was examined using a polyphasic approach. The isolate, designated
B19T, was assigned to the genus Streptomyces on the basis of chemotaxonomic and
morphological criteria. An almost complete 16S rRNA gene (rDNA) sequence obtained
for the test strain was compared with those of representative streptomycetes,
notably thermophilic streptomycetes. 16S rDNA sequence data not only supported
the assignment of the strain to the genus Streptomyces but also showed that the
isolate formed a distinct phyletic line within the evolutionary branch composed
of Streptomyces thermodiastaticus and related species. The strain was
distinguished from related validly described Streptomyces species by a number of
phenotypic properties. It is, therefore, proposed that strain B19T be classified
in the genus Streptomyces as Streptomyces thermocoprophilus sp. nov.
PMID- 10758854
TI - Reclassification of some species of Thiobacillus to the newly designated genera
Acidithiobacillus gen. nov., Halothiobacillus gen. nov. and Thermithiobacillus
gen. nov.
AB - The species of the genus 'Thiobacillus' fall into the alpha-, beta- and gamma
subclasses of the Proteobacteria, the type species Thiobacillus thioparus being
located in the beta-subclass. 'Thiobacillus' species exhibit almost as much
diversity in DNA composition and physiology as is found collectively in all other
proteobacterial groups. On the basis of physiological characters and 16S rRNA
gene sequence comparisons, eight of the existing Thiobacillus species are
proposed for reassignment to three newly designated genera within the gamma
subclass of the Proteobacteria, namely Acidithiobacillus, Halothiobacillus and
Thermithiobacillus.
PMID- 10758855
TI - Saccharococcus caldoxylosilyticus sp. nov., an obligately thermophilic, xylose
utilizing, endospore-forming bacterium.
AB - Several closely related, xylanolytic, thermophilic bacilli were isolated from
local soils on xylose-containing minimal medium. On the basis of morphology and
biochemical characteristics, one of the isolates, designated strain S1812T (T =
type strain), was studied further. Strain S1812T was a xylanolytic, sporulating,
Gram-positive, rod-shaped bacterium. Its Gram-positive nature was confirmed by
electron microscopic examination of thin sections of the cells. The isolate was a
thermophilic (optimum temperature for growth, 65 degrees C), facultative anaerobe
that grew on a wide range of carbon sources including glucose, lactose, starch
and xylose. It expressed high levels of both xylose isomerase and xylulokinase on
xylose and also on glucose. The DNA G + C content was 44 mol%. rRNA gene sequence
analysis placed strain S1812T in Bacillus cluster 5; it was more closely related
to Saccharococcus thermophilus than to thermophilic Bacillus species. DNA-DNA
hybridization also indicated its close relationship to S. thermophilus. Based on
the evidence presented, it is proposed that strain S1812T be designated
Saccharococcus caldoxylosilyticus sp. nov. Strain S1812T is the type strain (=
ATCC 700356T = DSM 97-987T).
PMID- 10758856
TI - Methanobacterium oryzae sp. nov., a novel methanogenic rod isolated from a
Philippines ricefield.
AB - A rod (0.3-0.4 micron x 3-10 microns) to filamentous (up to 40 microns) non
motile methanogenic bacterium, designated strain FPiT (T = type strain), was
isolated from ricefield soil in the Philippines. The strain uses H2 + CO2 or
formate for growth and produces CH4. Optimum growth temperature is 40 degrees C;
no growth is observed at 15 degrees C or 45 degrees C. Optimum pH for growth is
7; no growth is observed at pH 5.5 or 9.0. Strain FPiT is halotolerant and grows
at NaCl concentrations of 0-25 g l-1. The G + C content of its DNA is 31 mol%.
Based on 16S rRNA gene sequence analysis, the isolate was identified as a new
species of the genus Methanobacterium: Methanobacterium oryzae sp. nov. The type
strain is FPiT (= DSM 11106T).
PMID- 10758857
TI - Marmoricola aurantiacus gen. nov., sp. nov., a coccoid member of the family
Nocardioidaceae isolated from a marble statue.
AB - A Gram-positive, aerobic bacterium with coccoid cells occurring singly, in pairs
and in clusters was isolated from the surface of a marble statue. The
peptidoglycan contain LL-diaminopimelic acid as diagnostic diamino acid and a
single glycine residue as interpeptide bridge (type A3 gamma). The major
menaquinone is MK-8(H4). The cellular fatty acid pattern consists of straight
chain saturated and monounsaturated components and 10-methyl octadecanoic
(tuberculostearic) acid as the only branched chain fatty acid.
Phosphatidylinositol, phosphatidylglycerol and diphosphatidylglycerol occur as
characteristic polar lipids. The DNA G + C composition is 72 mol%. According to
its phylogenetic position and 16S rDNA signature nucleotides, the organism is a
member of the family Nocardioidaceae. The combination of chemotaxonomic
characteristics is unique within this family and supports the description of a
new genus and new species, Marmoricola aurantiacus. The type strain is strain BC
361T (= DSM 12652T).
PMID- 10758858
TI - Clostridium scatologenes strain SL1 isolated as an acetogenic bacterium from
acidic sediments.
AB - A strictly anaerobic, H2-utilizing bacterium, strain SL1, was isolated from the
sediment of an acidic coal mine pond. Cells of strain SL1 were sporulating,
motile, long rods with a multilayer cell wall. Growth was observed at 5-35
degrees C and pH 3.9-7.0. Acetate was the sole end product of H2 utilization and
was produced in stoichiometries indicative of an acetyl-CoA-pathway-dependent
metabolism. Growth and substrate utilization also occurred with CO/CO2,
vanillate, syringate, ferulate, ethanol, propanol, 1-butanol, glycerine,
cellobiose, glucose, fructose, mannose, xylose, formate, lactate, pyruvate and
gluconate. With most substrates, acetate was the main or sole product formed.
Growth in the presence of H2/CO2 or CO/CO2 was difficult to maintain in
laboratory cultures. Methoxyl, carboxyl and acrylate groups of various aromatic
compounds were O-demethylated, decarboxylated and reduced, respectively. Small
amounts of butyrate were produced during the fermentation of sugars. The acrylate
group of ferulate was reduced. Nitrate, sulfate, thiosulfate, dimethylsulfoxide
and Fe(III) were not utilized as electron acceptors. Analysis of the 16S rRNA
gene sequence of strain SL1 demonstrated that it is closely related to
Clostridium scatologenes (99.6% sequence similarity), an organism characterized
as a fermentative anaerobe but not previously shown to be capable of acetogenic
growth. Comparative experiments with C. scatologenes DSM 757T demonstrated that
it utilized H2/CO2 (negligible growth), CO/CO2 (negligible growth), formate,
ethanol and aromatic compounds according to stoichiometries indicative of the
acetyl-CoA pathway. CO dehydrogenase, formate dehydrogenase and hydrogenase
activities were present in both strain SL1 and C. scatologenes DSM 757T. These
results indicate that (i) sediments of acidic coal mine ponds harbour acetogens
and (ii) C. scatologenes is an acetogen that tends to lose its capacity to grow
acetogenically under H2/CO2 or CO/CO2 after prolonged laboratory cultivation.
PMID- 10758859
TI - Confirmation of Thiobacillus denitrificans as a species of the genus
Thiobacillus, in the beta-subclass of the Proteobacteria, with strain NCIMB 9548
as the type strain.
AB - Thiobacillus denitrificans is physiologically similar to the type species of the
genus Thiobacillus, Thiobacillus Thioparus, and both are located in the beta
subclass of the Proteobacteria. T. denitrificans is distinguished from all other
Thiobacillus species by its ability to grow as a facultatively anaerobic
chemolithotroph, coupling the oxidation of inorganic sulfur compounds to the
reduction of nitrate, nitrite and other oxidized nitrogen compounds to
dinitrogen. A definitive description of this species is provided and strain NCIMB
9548T is designated as the type strain of the species, thereby correcting an
earlier error in the literature.
PMID- 10758860
TI - Description of strain 3CB-1, a genomovar of Thauera aromatica, capable of
degrading 3-chlorobenzoate coupled to nitrate reduction.
AB - A Gram-negative bacterium, strain 3CB-1, isolated from a 3-chlorobenzoate
enrichment culture inoculated with a sediment sample is capable of degrading
various aromatic compounds and halogenated derivatives with nitrate as electron
acceptor. Compounds capable of serving as carbon and energy sources include 3
chlorobenzoate, 3-bromobenzoate, 2-fluorobenzoate, 4-fluorobenzoate, benzoate, 3
hydroxybenzoate, 4-hydroxybenzoate, 3-aminobenzoate, protocatechuate, m-cresol
and p-cresol. Oxygen, nitrate and nitrite were used as electron acceptors for
growth. Cells are Gram-negative short rods with peritrichous flagellation. The
predominant fatty acids are cis-9-hexadecenoic acid (16:1 omega 7c), hexadecanoic
acid (16:0), octadecanoic acid (18:0), octadecenoic acid (18:1), 3
hydroxydecanoic acid (10:0 3OH) and dodecanoic acid (12:0). The sequence of the
16S rRNA gene, as well as the fatty acid composition, indicate that the strain is
a member of the genus Thauera in the beta-subclass of the Proteobacteria and very
close to Thauera aromatica. DNA-DNA hybridization and nutrient screening indicate
that strain 3CB-1 is a genomovar of Thauera aromatica with the proposed name
Thauera aromatica genomovar chlorobenzoica.
PMID- 10758861
TI - Thermohalobacter berrensis gen. nov., sp. nov., a thermophilic, strictly
halophilic bacterium from a solar saltern.
AB - A new thermophilic, strictly halophilic, anaerobic, non-sporulating rod-shaped
bacterium, measuring 0.5 x 3.0-8.0 microns and designated strain CTT3T, was
isolated from a solar saltern. Strain CTT3T stained Gram-negative, was motile by
means of laterally inserted flagella, had a genome G + C content of 33 mol% and
grew optimally at 65 degrees C and pH 7.0 with 5% NaCl. The strain also grew
readily at 70 degrees C in the presence of 15% NaCl. Strain CTT3T fermented
cellobiose, fructose, glucose, maltose, mannitol, mannose, sucrose, glycerol, N
acetylglucosamine, starch, pyruvate and bio-Trypticase. It produced acetate,
ethanol, H2 and presumably CO2 from glucose. 16S rRNA gene sequence analysis
indicated that it is a member of cluster XII of the Clostridiales and related
genera of the subphylum of the Gram-positive bacteria containing genomes of low G
+ C content. Its phenotypic and phylogenetic characteristics clearly
differentiated it from all other members of this cluster. Based on the findings
it is proposed that strain CTT3T be designated as a new species of a new genus,
Thermohalobacter berrensis gen. nov., sp. nov. The type strain is CTT3T (= CNCM
105955T).
PMID- 10758862
TI - Pseudoalteromonas peptidolytica sp. nov., a novel marine mussel-thread-degrading
bacterium isolated from the Sea of Japan.
AB - A new bacterial species belonging to the genus Pseudoalteromonas is described on
the basis of phenotypic characterization, and sequence analysis of its 16S rRNA
coding and gyrase B (gyrB) genes. Ten strains, isolated from sea water of Yamato
Island, Sea of Japan, were Gram-negative, yellow, motile, polarly flagellated,
aerobic, rod-shaped eubacteria and had a G + C content of 42 mol%. Analysis of
the 16S rDNA sequence revealed a clear affiliation between these strains and
members of the gamma-Proteobacteria. High similarity values were found with
members of the genus Pseudoalteromonas and this was supported by fatty acid
profiles. The 16S rDNA sequence similarity between strain F12-50-A1T and
Pseudoalteromonas piscicida was very high (99.1%). However, molecular
characterizations employing small subunit 16S rDNA sequences were at the limits
of resolution for the differentiation of species in this genus. As a result, DNA
DNA hybridization and sequence analyses of a more rapidly evolving gyrB gene were
performed. Our assertion that this strain represents a distinct bacterial species
within the genus Pseudoalteromonas was supported by both of these molecular
analyses. Species-specific PCR probes were designed for the gyrB gene and used
for the rapid screening of F12-50-A1T-like strains, thereby confirming the
species. As these strains cleave complex protein compounds of the Mytilus edulis
foot by secreting proteases, the name Pseudoalteromonas peptidolytica sp. nov. is
proposed, with strain F12-50-A1T (= MBICC F1250A1T) as the type strain.
PMID- 10758863
TI - Mycobacterium septicum sp. nov., a new rapidly growing species associated with
catheter-related bacteraemia.
AB - Rapidly growing mycobacteria are capable of causing several clinical diseases in
both immunosuppressed and immunocompetent individuals. A previously unidentified,
rapidly growing mycobacterium was determined to be the causative agent of central
line sepsis in a child with underlying metastatic hepatoblastoma. Four isolates
of this mycobacterium, three from blood and one from the central venous catheter
tip, were studied. Phenotypic characterization, HPLC and genetic analysis
revealed that while this organism most closely resembled members of the
Mycobacterium fortuitum complex and Mycobacterium senegalense, it differed from
all previously described species. Phenotypic tests useful in differentiating this
species from similar rapidly growing mycobacteria included: growth at 42 degrees
C, hydrolysis of acetamide, utilization of citrate, production of arylsulfatase
(3-d), acidification of D-mannitol and i-myo-inositol, and susceptibility to
erythromycin, vancomycin and tobramycin. The name Mycobacterium septicum is
proposed for this new species. The type strain has been deposited in Deutsche
Sammlung von Mikroorganismen und Zellkulturen as DSM 44393T and in the American
Type Culture Collection as strain ATCC 700731T.
PMID- 10758864
TI - Revision of species delineation in the genus Ectothiorhodospira.
AB - When the type strains and other strains of the six currently defined species of
the genus Ectothiorhodospira were examined by DNA-DNA reassociation and RFLP of
16S/23S rDNA (ribotype), only four genospecies could be found. The possibility of
defining taxonomically meaningful species corresponding to these four genospecies
was investigated by combining DNA relatedness and ribotype data with other
genotypic and phenotypic characters already described in the literature, an
approach known as polyphasic taxonomy. Following this comparison, the type strain
and another strain of Ectothiorhodospira vacuolata were found to be very similar
to the type strain of Ectothiorhodospira shaposhnikovii and have been transferred
to this latter species. Also, the type strain of Ectothiorhodospira marismortui
and another previously unidentified strain were found to be very similar to the
type strain of Ectothiorhodospira mobilis and have been transferred to this
latter species. Due to the limited degree of reciprocal DNA relatedness, strains
belonging either to Ectothiorhodospira marina or to Ectothiorhodospira
haloalkaliphila are still considered as belonging to separate species, even
though they show a remarkable phenotypic similarity. This revision has led to the
delineation of only four species in the genus Ectothiorhodospira, namely E.
mobilis, E. shaposhnikovii, E. marina and E. haloalkaliphila. E. vacuolata is
recognized as a junior synonym of E. shaposhnikovii and E. marismortui as a
junior synonym of E. mobilis.
PMID- 10758865
TI - Three isolates of novel polyphosphate-accumulating gram-positive cocci, obtained
from activated sludge, belong to a new genus, Tetrasphaera gen. nov., and
description of two new species, Tetrasphaera japonica sp. nov. and Tetrasphaera
australiensis sp. nov.
AB - Two isolates of Gram-positive cocci (Ben 109T and Ben 110) which could accumulate
polyphosphate and were microscopically similar in appearance to so-called 'G
bacteria', appearing as tetrads, were isolated from samples of activated sludge
biomass by micromanipulation and grown in axenic culture. On the basis of their
phenotypic and chemotaxonomic characters and 16S rDNA sequences, these isolates,
together with strain T1-X7T isolated and described previously in Japan, belong to
a new genus. These isolates are phylogenetically different from Tessaracoccus
bendigoensis, Friedmanniella spumicola and Friedmanniella capsulata, Gram
positive cocci isolated previously in this laboratory. They are characterized by
type A1 gamma peptidoglycan, with meso-diaminopimelic acid as the diagnostic
diamino acid. The main cellular fatty acid of Ben 109T, Ben 110 and T1-X7T is 14
methylpentadecanoic acid (i-C16:0). The major menaquinones of Ben 109T are MK
8(H4), with MK-8(H2) and MK-8 in trace amounts. In Ben 110 MK-8(H4) and MK-6(H4)
are the major menaquinones, while T1-X7T has MK-8(H4), MK-7(H4) and MK-6(H4) as
its menaquinones. All three contain phosphatidylinositol, phosphatidylglycerol
and diphosphatidylglycerol as their polar lipids. These properties, together with
16S rDNA sequence data, suggest that they all belong to a single new genus for
which the name Tetrasphaera gen. nov. is proposed. However, the lipid, cellular
fatty acid profiles and DNA-DNA similarity data suggest that Ben 109T and Ben 110
are sufficiently different from T1-X7T to represent a different species of the
genus Tetrasphaera. Strain T1-X7T represents the type species Tetrasphaera
japonica sp. nov. of this new genus, and strains Ben 109T and Ben 110 belong to
the other species, Tetrasphaera australiensis sp. nov.
PMID- 10758866
TI - Phylogenetic position of the North American isolate of Pasteuria that parasitizes
the soybean cyst nematode, Heterodera glycines, as inferred from 16S rDNA
sequence analysis.
AB - A 1341 bp sequence of the 16S rDNA of an undescribed species of Pasteuria that
parasitizes the soybean cyst nematode, Heterodera glycines, was determined and
then compared with a homologous sequence of Pasteuria ramosa, a parasite of
cladoceran water fleas of the family Daphnidae. The two Pasteuria sequences,
which diverged from each other by a dissimilarity index of 7%, also were compared
with the 16S rDNA sequences of 30 other bacterial species to determine the
phylogenetic position of the genus Pasteuria among the Gram-positive eubacteria.
Phylogenetic analyses using maximum-likelihood, maximum-parsimony and neighbour
joining methods showed that the Heterodera glycines-infecting Pasteuria and its
sister species, P. ramosa, form a distinct line of descent within the
Alicyclobacillus group of the Bacillaceae. These results are consistent with the
view that the genus Pasteuria is a deeply rooted member of the Clostridium
Bacillus-Streptococcus branch of the Gram-positive eubacteria, neither related to
the actinomycetes nor closely related to true endospore-forming bacteria.
PMID- 10758867
TI - Salinivibrio costicola subsp. vallismortis subsp. nov., a halotolerant
facultative anaerobe from Death Valley, and emended description of Salinivibrio
costicola.
AB - Strain DVT, a halotolerant, Gram-negative, facultatively anaerobic bacterium, was
isolated from a hypersaline pond located in Death Valley, California. The cells
were non-spore-forming, motile, curved rods (1.0-1.8 x 0.5-0.6 microns) and
occurred singly, in pairs or rarely in chains. Strain DVT was oxidase-, catalase
, Voges-Proskauer-, amylase-, gelatinase- and lipase-positive and indole
negative. Nitrate, sulfate and fumarate were not used as electron acceptors.
Carbohydrates served as energy sources both aerobically and anaerobically. Strain
DVT grew optimally at 37 degrees C (temperature range 20-50 degrees C) with 2.5%
NaCl (NaCl range 0-12.5%) and pH 7.3 (pH range of 5.5-8.5) in a glucose/yeast
extract medium with a doubling time of 20 min (aerobically) or 41 min
(anaerobically). The end products of glucose fermentation were ethanol,
isobutyrate, propionate, lactate, formate and CO2. Strain DVT was resistant to
penicillin, D-cycloserine, streptomycin and tetracycline (200 micrograms ml-1).
The G + C content was 50 mol%. 16S rRNA gene sequence analysis indicated that it
was closely related to Salinivibrio costicola (97.7%) and this was confirmed by
DNA-DNA hybridization (93% relatedness). However, phenotypic characteristics such
as halotolerance, gas production, growth at 50 degrees C, antibiotic resistance,
sugar-utilization spectrum and phylogenetic signatures are sufficiently different
from Salinivibrio costicola to warrant designating strain DVT as a new subspecies
of Salinivibrio costicola, Salinivibrio costicola subsp. vallismortis subsp. nov.
(= DSM 8285T).
PMID- 10758868
TI - Clostridium algidixylanolyticum sp. nov., a psychrotolerant, xylan-degrading,
spore-forming bacterium.
AB - A psychrotolerant Clostridium species was isolated from vacuum-packed,
temperature-abused raw lamb. Colonies of this micro-organism on sheep-blood agar
were circular with an entire margin, grey-white, translucent and beta-haemolytic.
Cells were single, tapered, motile rods. Elliptical subterminal spores were
produced in the late stationary growth phase. Spores did not cause swelling of
the maternal cells. The micro-organism was obligately anaerobic. In peptone yeast
extract glucose starch (PYGS) broth at pH 7.0, the micro-organism grew optimally
between 25.5 and 30.0 degrees C. The temperature range for growth was 2.5-32.2
degrees C. At 26 degrees C, the micro-organism grew optimally at pH 6.8 to 7.0.
The pH range for anaerobic growth was 4.7-9.1. The micro-organism was
saccharoclastic, hydrolysed starch and degraded xylan. The fermentation products
formed in PYGS broth were acetate, formate, lactate, ethanol, butyrate, butanol,
hydrogen and carbon dioxide. The G + C content of the DNA was 38.4 mol%.
Phylogenetic analyses indicated that the strain belongs to cluster XIVa of the
genus Clostridium (sensu Collins et al. 1994). The new strain differed from
phylogenetically related clostridia in terms of cellular fatty acid composition,
soluble protein profiles and phenotypic properties. On the basis of phenotypic
and genotypic characterization data, the strain was assigned to a new species,
namely Clostridium algidixylanolyticum. The type strain is strain SPL73T (= DSM
12273T).
PMID- 10758869
TI - Denitrobacterium detoxificans gen. nov., sp. nov., a ruminal bacterium that
respires on nitrocompounds.
AB - A new group of anaerobic, Gram-positive, high G + C (56-60 mol%) bacteria was
isolated from the bovine rumen. Of four strains characterized, all were non
motile and none produced spores. The isolates did not produce indole or H2S and
did not hydrolyse gelatin. Cells of each strain exhibited similar rod-shaped
morphology (0.5-1.0 x 1.0-1.5 microns) although bulbous ends were sometimes
present. None of the four strains were able to grow via oxidation of a variety of
potentially fermentable substrates but rather obtained energy for growth via
anaerobic respiration processes, oxidizing hydrogen, formate or lactate for
reduction of various oxidized nitrogen compounds. Trimethylamine oxide and DMSO
were also used as electron acceptor. All four strains shared greater than 99% 16S
rRNA gene sequence identity. The closest match found between the 16S rRNA gene
sequence of all four strains, NPOH1T, NPOH2, NPOH3 and MAJ1, to sequences
available in GenBank was that of Coriobacterium glomerans (86% sequence
similarity), a phenotypically dissimilar anaerobe within the class
Actinobacteria. To accommodate these bacteria the creation of a new genus and
species, Denitrobacterium detoxificans, for placement within the family
Coriobacteriaceae is proposed. The type strain, NPOH1T (ATCC 700546T), grew
equally well over a narrow range of incubation temperatures tested (32-39 degrees
C).
PMID- 10758870
TI - Desulfovirga adipica gen. nov., sp. nov., an adipate-degrading, gram-negative,
sulfate-reducing bacterium.
AB - A novel, mesophilic, Gram-negative bacterium was isolated from an anaerobic
digestor for municipal wastewater. The bacterium degraded adipate in the presence
of sulfate, sulfite, thiosulfate and elemental sulfur. (E)-2-Hexenedioate
accumulated transiently in the degradation of adipate. (E)-2-Hexenedioate, (E)-3
hexenedioate, pyruvate, lactate, C1-C12 straight-chain fatty acids and C2-C10
straight-chain primary alcohols were also utilized as electron donors. 3
Phenylpropionate was oxidized to benzoate. The G + C content of the DNA was 60
mol%. 16S rDNA sequence analysis revealed that the new isolate clustered with
species of the genus Syntrophobacter and Desulforhabdus amnigenus. Strain TsuAS1T
resembles Desulforhabdus amnigenus DSM 10338T with respect to the ability to
utilize acetate as an electron donor and the inability to utilize propionate
without sulfate in co-culture with Methanospirillum hungatei DSM 864. Strains
TsuAS1T and DSM 10338T form a 'non-syntrophic subcluster' within the genus
Syntrophobacter. Desulfovirga adipica gen. nov., sp. nov. is proposed for the
newly isolated bacterium, with strain TsuAS1T (= DSM 12016T) as the type strain.
PMID- 10758871
TI - Pelospora glutarica gen. nov., sp. nov., a glutarate-fermenting, strictly
anaerobic, spore-forming bacterium.
AB - The strictly anaerobic, Gram-negative, spore-forming bacterium strain WoGl3T had
been enriched and isolated in mineral medium with glutarate as the sole source of
energy and organic carbon. Glutarate was fermented to a mixture of butyrate,
isobutyrate, CO2 and small amounts of acetate. Strain WoGl3T grew only with the
dicarboxylates glutarate, methylsuccinate and succinate. 16S rDNA sequence
analysis revealed an affiliation of strain WoGl3T to the family
Syntrophomonadaceae. This monophyletic group is comprised of strain WoGl3T and
the genera Syntrophomonas, Syntrophospora and Thermosyntropha, within the phylum
of Gram-positive bacteria with a low DNA G + C content. Overall intra-group 16S
rRNA sequence similarities of 89.2-93.9% document a separate phylogenetic status
for strain WoGl3T. Strain WoGl3T (= DSM 6652T) is described as the type strain of
a new species within a new genus, Pelospora glutarica gen. nov., sp. nov.
PMID- 10758872
TI - Reassessment of the taxonomic structure of the diazotrophic genus Azoarcus sensu
lato and description of three new genera and new species, Azovibrio restrictus
gen. nov., sp. nov., Azospira oryzae gen. nov., sp. nov. and Azonexus fungiphilus
gen. nov., sp. nov.
AB - The taxonomic structure of members of the genus Azoarcus sensu lato was
reassessed in a polyphasic approach. Two species, Azoarcus communis and Azoarcus
indigens, three unnamed species containing diazotrophs associated with Kallar
grass roots (groups C, D) and a group of strains (E) isolated from fungi were
analysed. They were compared by PAGE analyses of cellular proteins, genomic
fingerprints, morphological and nutritional features to new isolates from rice
roots. All strains within groups C, D and E containing 5-12 isolates showed group
specific cell and colony morphology and carbon source utilization patterns, with
exception of the obligately microaerobic strain BS20-3, a member of group C. All
strains, with this exception, also had almost indistinguishable electrophoretic
protein patterns and genomic fingerprints generated with tDNA-directed primers,
suggesting they belong to the same species. Phylogenetic analyses of almost
complete 16S rDNA sequences carried out with three different algorithms
(neighbour-joining, maximum-likelihood, parsimony) revealed that Azoarcus sensu
lato is not monophyletic. Groups C, D and E formed three distinct lineages
located between the Azoarcus/Thauera and the Rhodocyclus clusters. Phylogenetic
distances between groups C, D and E were as large as between other genera (93-94%
sequence similarity). This suggested they have the rank of three different
genera. Since it was possible to differentiate them from each other and other
related bacteria by phenotypic features, three new genera with one type species
each are proposed: Azovibrio restrictus gen. nov., sp. nov., Azospira oryzae gen.
nov., sp. nov. and Azonexus fungiphilus gen. nov., sp. nov.
PMID- 10758873
TI - Reclassification of Actinomyces humiferus (Gledhill and Casida) as Cellulomonas
humilata nom. corrig., comb. nov.
AB - The placement of Actinomyces humiferus within the genus Actinomyces has always
been controversial. A humiferus differs from typical members of the genus both
phenotypically and in possessing a relatively high DNA G + C content. Comparative
16S rRNA gene sequencing has shown that A. humiferus is related only distantly to
other species of the genus Actinomyces and is, in fact, a member of the genus
Cellulomonas. On the basis of phylogenetic evidence, it is proposed that A.
humiferus be reclassified in the genus Cellulomonas as Cellulomonas humilata nom.
corrig., comb. nov.
PMID- 10758874
TI - Comparison of AFLP and rep-PCR genomic fingerprinting with DNA-DNA homology
studies: Xanthomonas as a model system.
AB - The genus Xanthomonas contains a large number of strains, which have been
characterized by a variety of phenotypic and genotypic classification methods.
The Xanthomonas collection constitutes one of the largest groups of bacteria that
have been characterized phylogenetically by DNA-DNA homology studies and genomic
fingerprinting. Presently, a total genomic DNA-DNA homology value of 70%
represents an internationally accepted criterion to define bacterial species
levels. However, the complexity of DNA-DNA reassociation kinetics methods
precludes the rapid analysis of large numbers of bacterial isolates, which is
imperative for molecular microbial diversity studies. Therefore, the aim of this
study was to compare more facile PCR-based genomic fingerprinting techniques,
such as repetitive-sequence-based (rep)-PCR and AFLP genomic fingerprinting, to
DNA-DNA hybridization studies. Using three different primer sets, rep-PCR genomic
fingerprint patterns were generated for 178 Xanthomonas strains, belonging to all
20 previously defined DNA-DNA homology groups, and one Stenotrophomonas
maltophilia strain. In addition, AFLP genomic fingerprints were produced for a
subset of 80 Xanthomonas strains belonging to the 20 DNA-DNA homology groups and
for the S. maltophilia strain. Similarity values derived from rep-PCR- and AFLP
generated fingerprinting analyses were calculated and used to determine the
correlation between rep-PCR- or AFLP-derived relationships and DNA-DNA homology
values. A high correlation was observed, suggesting that genomic fingerprinting
techniques truly reveal genotypic and phylogenetic relationships of organisms. On
the basis of these studies, we propose that genomic fingerprinting techniques
such as rep-PCR and AFLP can be used as rapid, highly discriminatory screening
techniques to determine the taxonomic diversity and phylogenetic structure of
bacterial populations.
PMID- 10758875
TI - Description of Mogibacterium pumilum gen. nov., sp. nov. and Mogibacterium vescum
gen. nov., sp. nov., and reclassification of Eubacterium timidum (Holdeman et al.
1980) as Mogibacterium timidum gen. nov., comb. nov.
AB - A new genus, Mogibacterium, is proposed for anaerobic, non-spore-forming, Gram
positive, rod-shaped bacteria which have been isolated from the periodontal
pockets of adult human patients with periodontal disease and infected root
canals. The novel isolates, strains D2-18T, BA11a-f and D5-2T, were inert in most
of the conventional biochemical tests and phenotypically resemble asaccharolytic
Eubacterium species. The protein profiles of whole cells on SDS-PAGE gels and
Western immunoblotting reaction analysis distinguished these organisms from type
strains belonging to the previously described Eubacterium species. The G + C
content of the DNA is 45-46 mol% for Mogibacterium pumilum and 46 mol% for
Mogibacterium vescum. The levels of DNA-DNA relatedness of these new species to
other Eubacterium species, including Eubacterium limosum, Eubacterium brachy,
Eubacterium lentum, Eubacterium nodatum, Eubacterium saphenum, and the more
recently proposed Eubacterium minutum and Eubacterium exiguum (reclassified as
Slackia exigua), are less than 2%. The DNA-DNA hybridization value between M.
pumilum and M. vescum was 30%. Eubacterium timidum exhibited DNA homologies with
Mogibacterium species which were low (17 and 18%) but clearly higher than with
all the other Eubacterium species. Phylogenetic analysis based on 16S rRNA gene
sequences revealed that the closest phylogenetic neighbour of Mogibacterium
species was E. timidum, and that these three species represent a novel lineage
distinct from the previously described genera of Gram-positive, rod-shaped
bacteria. On the basis of phenotypic characteristics and 16S rRNA gene sequence
comparisons, it is also proposed that E. timidum is transferred to the genus
Mogibacterium gen. nov. as Mogibacterium timidum gen. nov., comb. nov. (type
strain ATCC 33093T).
PMID- 10758876
TI - The value of rRNA gene restriction site polymorphism analysis for delineating
taxa in the genus Staphylococcus.
AB - A total of 101 staphylococcal strains were ribotyped using EcoRI and HindIII as
restriction enzymes and plasmid pBA2 as the rDNA probe. Isolates from 10 newly
described staphylococcal taxa were among those examined. All the ribotypes were
added to our database, Staph DB, which now contains the sizes of the bands of 135
EcoRI and 120 HindIII ribotypes from 408 strains belonging to 42 staphylococcal
taxa. The relatedness of ribotypes was evaluated by using the Dice coefficient.
The ribotypes, and thus the strains, were clustered by the unweighted pair group
method with averages (UPGMA). Separation into clusters correlated well with the
delineation of the staphylococcal species but not with that of the different
subspecies. No discrimination was possible between Staphylococcus vitulinus and
Staphylococcus pulvereri. Ecovar-specific groups were evident within
Staphylococcus intermedius and Staphylococcus hyicus. The data increase the
usefulness of rRNA gene restriction site polymorphism analysis for staphylococcal
taxonomy.
PMID- 10758877
TI - Lactobacillus nagelii sp. nov., an organism isolated from a partially fermented
wine.
AB - A Gram-positive rod was isolated from a commercial grape wine undergoing a
sluggish/stuck alcoholic fermentation. The organism produced DL-lactic acid from
glucose without gas formation, produced dextran from sucrose, hydrolysed aesculin
and fermented galactose, D-glucose, D-fructose, D-mannose, L-sorbose, rhamnose,
mannitol, sorbitol, methyl alpha-D-glucoside, N-acetylglucosamine, amygdalin,
salicin, cellobiose, maltose, sucrose, trehalose and beta-gentiobiose. 16S rRNA
gene sequence analysis revealed that the isolate was phylogenetically a member of
the genus Lactobacillus and formed a distinct subline within the Lactobacillus
casei cluster of species. On the basis of phenotypic and phylogenetic evidence,
Lactobacillus nagelii sp. nov. ATCC 700692T is proposed as a new species.
PMID- 10758878
TI - 'Candidatus Nostocoida limicola', a filamentous bacterium from activated sludge.
AB - Five strains of 'Candidatus Nostocoida limicola' were isolated by
micromanipulation from two activated sludge plants. Two (Ben17 and Ben18) were
from Sunbury, Victoria, Australia, and three (Ben67, Ver1 and Ver2) were from
Verona, Italy. The near complete 16S rDNA sequences were determined for five
strains and the phylogenetic location of this important bulking filament in the
actinomycete subphylum is reported for the first time. Phylogenetically, the Ben
strains formed one group with 99.4% 16S rDNA similarity, and the Ver strains
formed another with 99.9% 16S rDNA similarity. The mean similarity between the
two groups was 97.4%. By 16S rDNA comparison, the closest relative to all strains
was Terrabacter sp. strain DPO1361 (95.0-95.5% identical). On R2A medium, all
strains generally grew as short filaments or clumps of cocci, whereas on glucose
sulfide (GS) medium, all grew as irregular twisting filaments comprising Gram
positive and Gram-negative cells, which is close to their in situ morphology.
Polyphosphate was stored either as granules (R2A) or throughout the trichomes
(GS). None of the strains could grow without added nitrogen, reduce nitrate to
nitrogen gas or grow anaerobically, whereas all could grow at 15-30 degrees C,
produce catalase and reduce nitrate to nitrite. All were inactive in the Hugh &
Leifson test. This paper describes 'Candidatus Nostocoida limicola'.
PMID- 10758879
TI - Taxonomic implications of synthesis of poly-beta-hydroxybutyrate and other poly
beta-hydroxyalkanoates by aerobic pseudomonads.
AB - Whereas poly-beta-hydroxybutyrate (PHB) production by Pseudomonas species is
rare, synthesis of medium-chain-length poly-beta-hydroxyalkanoates (mcl-PHAs)
other than PHB, has been observed in fluorescent and non-fluorescent species.
Contrary to original reports, Pseudomonas corrugata and Pseudomonas ficuserectae
accumulate mcl-PHAs and not PHB. The taxonomic implications of these
characteristics are discussed.
PMID- 10758880
TI - Characterization of Micrococcus antarcticus sp. nov., a psychrophilic bacterium
from Antarctica.
AB - A Gram-positive, cold-adapted, aerobic, spherical actinobacterium (strain T2T)
with a quite low cardinal growth temperature was isolated from Chinese Great-Wall
station in Antarctica. Sequence comparisons of the 16S rDNA indicated the isolate
to be a phylogenetic member of the genus Micrococcus, family Micrococcaceae, in
which it represents a novel lineage. The phylogenetic distinctness of the isolate
with respect to the type strains Micrococcus luteus and Micrococcus lylae was
supported by DNA-DNA similarity values of less than 40%. Chemotaxonomic
properties supported the placement of the isolate in the genus Micrococcus. The
diagnostic diamino acid of the cell-wall peptidoglycan is lysine. The predominant
menaquinones are MK-8 and MK-8(H2). The G + C content of the DNA of the isolate
is 66.4 mol%. Genotypic, morphological and physiological characteristics were
used to describe a new species of Micrococcus, for which the name Micrococcus
antarcticus is proposed. The type strain is T2T (= AS 1.2372T).
PMID- 10758881
TI - Orenia salinaria sp. nov., a fermentative bacterium isolated from anaerobic
sediments of Mediterranean salterns.
AB - A diverse range of fermentative bacteria have been isolated from the commercial
salterns of Salin-de-Giraud (Camargue, France). One of these isolates, strain SG
3902T, has many of the morphological and physiological characteristics of the
genus Orenia, as was confirmed by a phylogenetic study based on 16S rRNA gene
sequencing. The closest species is Orenia marismortui, with a similarity of only
95.1%. However, strain SG 3902T, unlike O. marismortui, does not ferment mannose,
glycogen or starch. The G + C contents of the DNA also differ significantly,
being 29.6 mol% for O. marismortui and 33.7 mol% for strain SG 3902T. On the
basis of these physiological and genetic differences, it is proposed that strain
SG 3902T should be considered as a representative of a new species belonging to
the genus Orenia, under the name Orenia salinaria sp. nov. The type strain is SG
3902T (= ATCC 700911).
PMID- 10758882
TI - Phylogenetic characterization of a novel radiation-resistant bacterium from
irradiated pork: description of Hymenobacter actinosclerus sp. nov.
AB - A phylogenetic analysis was performed on a red-pigmented, radiation-resistant,
Gram-negative, rod-shaped organism originating from irradiated pork. Comparative
16S rRNA gene sequencing showed the bacterium was a member of the Cytophaga
Flavobacterium-Bacteroides line of descent and represents a new subline within
the genus Hymenobacter. A new species, Hymenobacter actinosclerus, is described
for this novel radiation-resistant bacterium. The type strain of Hymenobacter
actinosclerus is CCUG 39621T.
PMID- 10758883
TI - Tepidimonas ignava gen. nov., sp. nov., a new chemolithoheterotrophic and
slightly thermophilic member of the beta-Proteobacteria.
AB - A bacterial isolate with an optimum growth temperature of about 55 degrees C was
recovered on a medium composed of one part Kligler's iron agar and four parts of
Thermus Agar from the host spring at Sao Pedro do Sul in central Portugal.
Phylogenetic analyses using the 16S rRNA gene sequence of strain SPS-1037T
indicated that the new organism represented a new genus and species of beta
Proteobacteria. The major fatty acids of strain SPS-1037T are C16:0 and C17:0.
Ubiquinone 8 is the major respiratory quinone, and the major polar lipids are
phosphatidylethanolamine and phosphatidylglycerol. The new isolate is aerobic and
chemolithoheterotrophic. Thiosulfate and tetrathionate were oxidized to sulfate.
The growth yield of the organism was improved by the addition of thiosulfate to
media containing organic carbon sources, but the organism did not grow
autotrophically under the conditions examined. Heterotrophic growth of strain SPS
1037T occurs on amino acids and organic acids, but this organism does not
assimilate carbohydrates. On the basis of the phylogenetic analyses, and
physiological and biochemical characteristics, it is proposed that strain SPS
1037T represents a new genus and a new species for which the name Tepidimonas
ignava is proposed.
PMID- 10758884
TI - Burkholderia kururiensis sp. nov., a trichloroethylene (TCE)-degrading bacterium
isolated from an aquifer polluted with TCE.
AB - A trichloroethylene (TCE)-degrading bacterium was isolated from an aquifer sample
collected at a TCE-polluted site in Japan by enriching with phenol as sole carbon
source. The isolate, designated strain KP23T, was a Gram-negative, oval-shaped
micro-organism. A phylogenetic study based on 16S rRNA gene sequences indicated
that strain KP23T should be placed in the genus Burkholderia. Cellular fatty
acids of the strain were mainly composed of C16:0, cyclopropanic acid C17:0 and
cyclopropanic acid C19:0. Strain KP23T also contained notable amounts of C13:1
and C17:1. The G + C content of total DNA was 64.8 mol%. Strain KP23T oxidized
various sugars and sugar alcohols as sole carbon source such as galactose,
glucose, mannose, maltose, glycerol, inositol and mannitol. Comparisons of its
phenotypic and genotypic characteristics with other known species belonging to
the genus Burkholderia suggested that strain KP23T represents a new species in
the genus. The name Burkholderia kururiensis is proposed for this species, with
strain KP23T as the type strain (= JCM 10599T).
PMID- 10758885
TI - Dyadobacter fermentans gen. nov., sp. nov., a novel gram-negative bacterium
isolated from surface-sterilized Zea mays stems.
AB - A Gram-negative bacterium, designated NS114T, was isolated from duplicate
treatments of surface-sterilized Zea mays stems. The plants were grown in
synthetic soil under greenhouse conditions and watered with fertilizer containing
no nitrogen. Strain NS114T could not be isolated from plants watered with the
standard level or 20% (w/v) of the standard level of nitrogen. Cells occurred as
pairs in young cultures that attached to form angled arrangements in R2A broth
and occasionally formed rounded, horseshoe arrangements in YM broth. Cell
variation resulted in flocculent chains of coccoid cells in old cultures. Strain
NS114T fermented glucose and sucrose. The G + C content was 48 mol%. Phylogenetic
analysis of the 16S rRNA gene showed that the strain was a member of the domain
Bacteria and branched from a point equidistant from an aquatic organism, Runella
slithyformis and a marine isolate, 'Microscilla furvescens'. Phenotypic and
genotypic analyses indicated that strain NS114T could not be assigned to any
recognized genus; therefore a new genus and species, Dyadobacter fermentans gen.
nov., sp. nov., is proposed, for which NS114T is the type strain.
PMID- 10758886
TI - Streptococcus didelphis sp. nov., a streptococcus with marked catalase activity
isolated from opossums (Didelphis virginiana) with suppurative dermatitis and
liver fibrosis.
AB - beta-Haemolytic, catalase-positive, Gram-positive cocci that formed chains in
broth media but did not react with Lancefield group antisera were isolated from
skin lesions, spleen, liver and lungs of nine opossums, including eight from a
research colony and one from a wildlife rehabilitation organization. The isolates
had vigorous catalase activity that was retained on initial passage on non-blood
containing media, but this activity was lost in subsequent passages. The use of
standard phenotypic tests did not lead to satisfactory identification of these
organisms beyond the genus level, even if the aberrant catalase reaction was not
considered. The 16S rRNA gene sequence of the isolates was most similar (96%) to
Streptococcus dysgalactiae, but distinct from that species as 16S rRNA gene
similarity of different strains of S. dysgalactiae was > 99%. Characterization of
biochemical reactions and cell-wall fatty acid profiles also revealed significant
differences between the opossum isolates and all other known Streptococcus spp.,
thus it is proposed as a new species with the name Streptococcus didelphis, sp.
nov. The type strain is ATCC 700828T.
PMID- 10758887
TI - DNA-DNA reassociation among a bloom-forming cyanobacterial genus, Microcystis.
AB - DNA base composition and DNA-DNA hybridization among the cyanobacterial genus
Microcystis were determined using nine axenic Microcystis strains, including the
three 'morphological' species of Microcystis aeruginosa, Microcystis viridis and
Microcystis wesenbergii. These Microcystis species showed a similar DNA base
composition (42.1-42.8 mol% G + C) and demonstrated more than 70% DNA
relatedness, confirming their synonymy based on bacterial criteria.
PMID- 10758888
TI - Syntrophothermus lipocalidus gen. nov., sp. nov., a novel thermophilic,
syntrophic, fatty-acid-oxidizing anaerobe which utilizes isobutyrate.
AB - A new anaerobic, thermophilic, syntrophic, fatty-acid-oxidizing bacterium
designated strain TGB-C1T was isolated from granular sludge in a thermophilic
upflow anaerobic sludge blanket (UASB) reactor. The cells were slightly curved
rods and were weakly motile. Spore formation was not observed. The optimal
temperature for growth was around 55 degrees C and growth occurred in the range
45 to 60 degrees C. The pH range for growth was 5.8-7.5, and the optimum pH was
6.5-7.0. Crotonate was the only substrate that allowed the strain to grow in pure
culture. However, in co-culture with the thermophilic, hydrogenotrophic
Methanobacterium thermoautotrophicum strain delta H, the isolate could
syntrophically oxidize saturated fatty acids with 4-10 carbon atoms, including
isobutyrate. During the degradation of isobutyrate by the co-culture, isobutyrate
was isomerized to butyrate, which was then oxidized. The strain was not able to
utilize sulfate, sulfite, thiosulfate, nitrate, fumarate or Fe(III) as electron
acceptor. The DNA base composition was 51.0 mol%. 16S rDNA sequence analysis
revealed that the strain belongs to the family Syntrophomonadaceae, but it was
only distantly related to other known species of beta-oxidizing syntrophs. Hence,
the name Syntrophothermus lipocalidus is proposed for TGB-C1T as a new species of
a new genus.
PMID- 10758889
TI - A recA gene phylogenetic analysis confirms the close proximity of Frankia to
Acidothermus.
AB - The closer proximity of Frankia and Acidothermus cellulolyticus relative to the
morphologically close Geodermatophilus found previously was confirmed by
resequencing the rrs gene of Acidothermus cellulolyticus and the housekeeping
gene, recA. The diagnostic sugar 2-O-methyl-D-mannose was detected only in
Frankia, while hopanoid lipids were present at high levels in both Acidothermus
and Frankia.
PMID- 10758890
TI - Analysis of cellular fatty acids and phenotypic relationships of Agrobacterium,
Bradyrhizobium, Mesorhizobium, Rhizobium and Sinorhizobium species using the
Sherlock Microbial Identification System.
AB - Previous studies have demonstrated that cellular fatty acid analysis is a useful
tool for identifying unknown strains of rhizobia and establishing taxonomic
relationships between the species. In this study, the fatty acid profiles of over
600 strains belonging to the genera Agrobacterium, Bradyrhizobium, Mesorhizobium,
Rhizobium and Sinorhizobium were evaluated using the gaschromatography-based
Sherlock Microbial Identification System (MIS). Data collected with the MIS
showed that the three phylogenetically defined biovars of the genus Agrobacterium
formed discrete clusters, whilst species belonging to the genus Mesorhizobium
formed three subclusters which were easily distinguished. These three subclusters
contained Mesorhizobium ciceri and Mesorhizobium mediterraneum, Mesorhizobium
tianshanense fatty acid group I and Mesorhizobium plurifarium, and Mesorhizobium
huakuii and Mesorhizobium loti. The genus Sinorhizobium was composed of an
individual position for Sinorhizobium meliloti and a large cluster comprising
Sinorhizobium fredii, Sinorhizobium saheli, Sinorhizobium terangae, Sinorhizobium
kostiense and Sinorhizobium arboris. S. meliloti contained significantly higher
levels of the fatty acid 19:0 cyclo omega 8 cis and clustered with Rhizobium sp.
(Hedysarum coronarium). However, discrimination between the species of genera
Sinorhizobium and Rhizobium was a function of the concentration of 16:0 3-OH. The
genus Rhizobium contained a single cluster containing Rhizobium sp. (Hedysarum
coronarium), Rhizobium gallicum, Rhizobium leguminosarum and Rhizobium etli,
along with individual positions for Rhizobium giardinii, Rhizobium tropici,
Rhizobium galegae and Rhizobium hainanense. R. tropici and R. hainanense
exhibited similarity to Agrobacterium biovar 2, whilst R. galegae was similar to
Agrobacterium biovar 1. R. giardinii appeared unique, with comparatively little
similarity to the other species. Analysis of the genus Bradyrhizobium revealed
large differences from the other genera studied. Two subgroups of Bradyrhizobium
elkanii were detected and easily distinguished from Bradyrhizobium japonicum.
Bradyrhizobium liaoningense and Bradyrhizobium sp. (Arachis hypogaea), a group
isolated from Chinese peanut plants, showed similarities to B. japonicum, whilst
a subgroup of M. tianshanense appeared identical to Bradyrhizobium sp. (Arachis
hypogaea).
PMID- 10758891
TI - Nocardia paucivorans sp. nov.
AB - Chemotaxonomic and 16S rDNA sequence analyses of an isolate from the sputa and
bronchial secretions of a patient with chronic lung disease clearly demonstrated
that it belongs to the genus Nocardia. DNA-DNA hybridization data, as well as the
biochemical characteristics of the isolate, indicate that it belongs to a new
species that differs from previously described members of the genus Nocardia. The
name Nocardia paucivorans sp. nov. is proposed for this isolate and is
represented by strain IMMIB D-1632T (= DSM 44386T).
PMID- 10758892
TI - Genotypic characterization of xanthomonad strains isolated from passion fruit
plants (Passiflora spp.) and their relatedness to different Xanthomonas species.
AB - The genetic diversity of 55 xanthomonad strains isolated from passion fruit
plants (Passiflora spp.) and identified as Xanthomonas campestris pv. passiflorae
was initially assessed by randomly amplified polymorphic DNA (RAPD) analysis. The
strains showed a high level of polymorphism with almost unique fingerprints.
Fifteen clusters with a similarity of approximately 70% were identified, three of
which were prevalent. There was a correlation between the clusters and the
geographic origin of the strains. A representative strain of each cluster,
together with the pathovar reference strain, were used to verify the
relationships of these strains to 18 Xanthomonas species and Pseudomonas syringae
pv. passiflorae. All Xanthomonas species yielded a unique RAPD profile and no
consistent relatedness to the X. campestris pv. passiflorae strains was observed.
Amplification products were also analysed by repetitive (rep) primers (BOX, ERIC
and REP), RFLP of the 16S-23S rDNA intergenic spacer and SDS-PAGE of whole-cell
proteins. All of these approaches generated profiles characteristic for each
Xanthomonas species but the taxonomic position of the X. campestris pv.
passiflorae strains could not be unequivocally assigned. Finally, DNA-DNA
hybridization allowed a sound taxonomic allocation of the strains to Xanthomonas
axonopodis pv. passiflorae.
PMID- 10758893
TI - Asaia bogorensis gen. nov., sp. nov., an unusual acetic acid bacterium in the
alpha-Proteobacteria.
AB - Eight Gram-negative, aerobic, rod-shaped and peritrichously flagellated strains
were isolated from flowers of the orchid tree (Bauhinia purpurea) and of plumbago
(Plumbago auriculata), and from fermented glutinous rice, all collected in
Indonesia. The enrichment culture approach for acetic acid bacteria was employed,
involving use of sorbitol medium at pH 3.5. All isolates grew well at pH 3.0 and
30 degrees C. They did not oxidize ethanol to acetic acid except for one strain
that oxidized ethanol weakly, and 0.35% acetic acid inhibited their growth
completely. However, they oxidized acetate and lactate to carbon dioxide and
water. The isolates grew well on mannitol agar and on glutamate agar, and
assimilated ammonium sulfate for growth on vitamin-free glucose medium. The
isolates produced acid from D-glucose, D-fructose, L-sorbose, dulcitol and
glycerol. The quinone system was Q-10. DNA base composition ranged from 59.3 to
61.0 mol% G + C. Studies of DNA relatedness showed that the isolates constitute a
single species. Phylogenetic analysis based on their 16S rRNA gene sequences
indicated that the isolates are located in the acetic acid bacteria lineage, but
distant from the genera Acetobacter, Gluconobacter, Acidomonas and
Gluconacetobacter. On the basis of the above characteristics, the name Asaia
bogorensis gen. nov., sp. nov. is proposed for these isolates. The type strain is
isolate 71T (= NRIC 0311T = JCM 10569T).
PMID- 10758894
TI - Phylogenetic characterization of marine bacterium strain 2-40, a degrader of
complex polysaccharides.
AB - The marine bacterium strain 2-40 was isolated from the salt marsh cord grass,
Spartina alterniflora, in the Chesapeake Bay watershed, VA, USA. It is Gram
negative, requires sea salts and is a strict aerobe. It degrades numerous complex
polysaccharides and synthesizes eumelanin. By 16S rDNA analysis, the isolate was
shown to be a member of the gamma-subclass of the Proteobacteria, related to
Microbulbifer hydrolyticus and to a cellulolytic nitrogen-fixing bacterium.
PMID- 10758895
TI - Phylogenetic analysis of psychrophilic bacteria isolated from the Japan Trench,
including a description of the deep-sea species Psychrobacter pacificensis sp.
nov.
AB - Phylogenetic positions of psychrophilic bacteria isolated from the Japan Trench
were determined by sequencing analysis of PCR-amplified bacterial small subunit
(16S) rRNA genes. Between surface and deep-sea psychrophiles, distinct positions
clearly differed within the gamma-Proteobacteria. In phylogenetic analysis using
neighbour-joining, maximum-parsimony and maximum-likelihood, strains from surface
seawater were inferred to be located in the Halomonas aquamarina-meridiana clade
within the family Halomonadaceae. Strains from deep seawater (5000-6000 m),
however, formed a novel monophyletic clade within the Moraxella-Psychrobacter
branch in the family Moraxellaceae, showing separation from terrestrial and
Antarctic relatives. These deep-sea strains were also discriminated from other
known Psychrobacter species in phenotype, e.g. limited growth in the absence of
NaCl (optimum at about 3% NaCl), positive urease activity, acid production from
xylose and arabinose, and the presence of multiple fimbriae. DNA relatedness
values among six deep-sea strains were > 85% in DNA-DNA hybridization experiments
and > 98% in aligned 16S rDNA sequences. From this evidence, a new species,
Psychrobacter pacificensis, is proposed for these deep-sea psychrophiles; the
type strain of Psychrobacter pacificensis is strain NIBH P2K6T (= IFO 16270T).
Occurrence of psychrobacters in cold Japan Trench deep seawater and at the
Antarctic sea surface suggests that deep-sea bacterial habitation and evolution
have been mediated by global deep-ocean circulation linked to the sinking of
cooled seawater in polar regions.
PMID- 10758896
TI - 'Candidatus Xenohaliotis californiensis', a newly described pathogen of abalone,
Haliotis spp., along the west coast of North America.
AB - Withering syndrome is a fatal disease of wild and cultured abalone, Haliotis
spp., that inhabit the west coast of North America. The aetiological agent of
withering syndrome has recently been identified as a member of the family
Rickettsiaceae in the order Rickettsiales. Using a combination of morphological,
serological, life history and genomic (16S rDNA) characterization, we have
identified this bacterium as a unique taxon and propose the provisional status of
'Candidatus Xenohaliotis californiensis'. The Gram-negative, obligate
intracellular pleomorphic bacterium is found within membrane-bound vacuoles in
the cytoplasm of abalone gastrointestinal epithelial cells. The bacterium is not
cultivable on synthetic media or in fish cell lines (e.g. CHSE-214) and may be
controlled by tetracyclines (oxytetracycline) but not by chloramphenicol,
clarithromycin or sarafloxicin. Phylogenetic analysis based on the 16S rDNA of
'Candidatus Xenohaliotis californiensis' places it in the alpha-subclass of the
class Proteobacteria but not to the four recognized subtaxa of the alpha
Proteobacteria (alpha-1, alpha-2, alpha-3 and alpha-4). The bacterium can be
detected in tissue squashes stained with propidium iodide, microscopic
examination of stained tissue sections, PCR or in situ hybridization. 'Candidatus
Xenohaliotis californiensis' can be differentiated from other closely related
alpha-Proteobacteria by its unique 16S rDNA sequence.
PMID- 10758897
TI - Characterization of Borrelia burgdorferi strains isolated from Korea by 16S rDNA
sequence analysis and PCR-RFLP analysis of rrf (5S)-rrl (23S) intergenic spacer
amplicons.
AB - Haenam strains of Borrelia burgdorferi, which had been isolated from Ixodes
granulatus and Apodemus agrarius in Haenam, Korea, were characterized by PCR-RFLP
analysis of rrf (5S)-rrl (23S) intergenic spacer amplicons and by sequence
analysis of the 16S rRNA gene (rDNA). The Msel and Dral restriction patterns of
the 5S-23S intergenic spacer amplicons of Haenam strains differed from those of
other B. burgdorferi sensu lato strains. Furthermore, in the phylogenetic tree
based on the 16S rDNA sequences, Haenam strains formed a distinctive cluster,
clearly separated from the other members of B. burgdorferi sensu lato. These
results suggest that, apart from Borrelia garinii and Borrelia afzelii, other
genotypes of B. burgdorferi sensu lato exist in Korea and the Haenam strain is a
newly identified one.
PMID- 10758898
TI - Campylobacter lanienae sp. nov., a new species isolated from workers in an
abattoir.
AB - Campylobacter-like organisms were isolated from the faeces of healthy individuals
during a hygiene survey of abattoir workers. The strains, which exhibited
characteristics of Campylobacter, being non-glucose-fermenting, oxidase- and
catalase-positive, Gram-negative, motile rods, were identified to the genus level
by a PCR assay. Nucleotide sequence analysis of the 16S rRNA gene, DNA homology
experiments and determination of G + C content demonstrated that they constituted
a previously undescribed species, whose nearest phylogenetic neighbours were
Campylobacter hyointestinalis subsp. hyointestinalis, Campylobacter fetus and
Campylobacter mucosalis. The name Campylobacter lanienae sp. nov. is proposed for
this taxon and species-specific PCR primers were evaluated which will find use in
the study of its epidemiology, prevalence and pathogenicity.
PMID- 10758899
TI - Clostridium akagii sp. nov. and Clostridium acidisoli sp. nov.: acid-tolerant, N2
fixing clostridia isolated from acidic forest soil and litter.
AB - Two anaerobic acid-tolerant bacteria, CK58T and CK74T, were isolated from acidic
beech litter and acidic peat-bog soil, respectively. Both bacteria were spore
forming, motile rods with peritrichous flagella. The capacity to sporulate
decreased with prolonged cultivation. Cells of CK58T formed chains or aggregates
and were linked by a connecting filament that consisted of a core and a
surrounding sheath. Cellobiose, glucose, xylose, arabinose, maltose, mannose and
salicin supported growth of CK58T. These substrates, as well as mannitol,
lactose, sucrose, glycerol, melezitose, raffinose and rhamnose, supported growth
of CK74T. Sorbitol, trehalose, H2/CO2, CO/CO2, vanillate, Casamino acids,
peptone, and various purines and pyrimidines did not support the growth of either
organism. Growth of CK58T and CK74T on glucose yielded butyrate, lactate,
acetate, formate, H2 and CO2 as end products. Growth of CK58T and CK74T was
observed at pH 3.7-7.1 and 3.6-6.9, respectively. CK58T and CK74T grew in
nitrogen-free medium at pH 3.7 under an N2 atmosphere and reduced acetylene at
rates approximating 1 nmol min-1 (mg protein)-1. CK58T and CK74T did not contain
carbon monoxide dehydrogenase or cytochromes, produce methane, or dissimilate
nitrate or sulfate. Thus, CK58T and CK74T were characterized as nonacetogenic, N2
fixing, fermentative chemo-organotrophs. The G + C contents of CK58T and CK74T
were 31.4 and 30.7 mol%, respectively. CK58T and CK74T were phylogenetically most
closely related to Clostridium pasteurianum. The 16S rRNA gene sequence
similarity values of CK58T and CK74T to C. pasteurianum and each other did not
exceed 96.5%, and it is proposed that strains CK58T and CK74T be named
Clostridium akagii CK58T (DSM 12554T) and Clostridium acidisoli CK74T (DSM
12555T), respectively. These results suggest that previously uncharacterized
clostridial species reside and might fix N2 in the annoxic microzones of acidic
forest soil and litter.
PMID- 10758900
TI - 16S-23S rDNA spacer of Pectinatus, Selenomonas and Zymophilus reveal new
phylogenetic relationships between these genera.
AB - The 16S-23S rDNA spacer regions of two Pectinatus species, two Zymophilus species
and one Selenomonas species were cloned after PCR amplification. The results of
PCR amplification showed that these species had two types of spacer regions which
differ in molecular size (long and short). Only the long spacer regions in these
bacteria contained one or two tRNA genes (alanine and/or isoleucine). The spacer
regions in these bacteria had a relatively high level of homology. Homology was
particularly high for bacteria belonging to the same genus. Interestingly, the
order of the two tRNA genes present in the long spacer regions of Pectinatus and
Selenomonas was the reverse of that which had been previously reported for other
bacteria. The results of spacer homology analysis and the order of the tRNA genes
suggest that the taxonomic classification of anaerobic bacteria isolated from the
brewing process should be re-examined.
PMID- 10758901
TI - Description of Pandoraea gen. nov. with Pandoraea apista sp. nov., Pandoraea
pulmonicola sp. nov., Pandoraea pnomenusa sp. nov., Pandoraea sputorum sp. nov.
and Pandoraea norimbergensis comb. nov.
AB - A polyphasic taxonomic study was performed on a group of isolates tentatively
identified as Burkholderia cepacia, Ralstonia pickettii or Ralstonia paucula
(formerly known as CDC group IVc-2). The isolates were mainly cultured from
sputum of cystic fibrosis patients or from soil. SDS-PAGE of whole-cell proteins
and AFLP fingerprinting distinguished at least five different species, and this
was confirmed by DNA-DNA hybridizations. 16S rDNA sequence analysis of
representative strains indicated that these organisms belong to the beta-subclass
of the Proteobacteria, with the genera Burkholderia and Ralstonia as closest
neighbours. Based on genotypic and phenotypic characteristics, the organisms were
classified in a novel genus, Pandoraea. The DNA base composition of the members
of the new genus is between 61.2 and 64.3 mol%. This novel genus includes four
new species, Pandoraea apista (the type species) (type strain is LMG 16407T),
Pandoraea pulmonicola (type strain is LMG 18106T), Pandoraea pnomenusa (type
strain is LMG 18087T) and Pandoraea sputorum (type strain is LMG 18819T), and
Pandoraea norimbergensis (Wittke et al. 1997) comb. nov. (type strain is LMG
18379T). The available clinical data indicate that at least some of these
organisms may cause chronic infection in, and can be transmitted amongst, cystic
fibrosis patients.
PMID- 10758902
TI - Idiomarina gen. nov., comprising novel indigenous deep-sea bacteria from the
Pacific Ocean, including descriptions of two species, Idiomarina abyssalis sp.
nov. and Idiomarina zobellii sp. nov.
AB - Two bacterial strains, KMM 227T and 231T, were isolated from seawater samples
collected from the north-western Pacific Ocean at a depth of 4000-5000 m and were
characterized using polyphasic taxonomy. Both were Gram-negative,
psychrotolerant, heterotrophic, aerobic and required NaCl for growth (0.6-15.0%).
The temperature for growth was 4-30 degrees C. Both strains were rod-shaped, with
a single flagellum. However, strain KMM 231T revealed a single long fimbrium.
Cellular fatty acids detected in the isolates were predominantly odd-numbered and
iso-branched, with 15 and 17 carbons (ca. 70%). Also present were saturated and
monounsaturated straight-chain fatty acids. Results of phylogenetic analyses,
employing three tree-making methods, strongly indicated that the two strains
formed a distinct lineage within a clade containing the genera Alteromonas,
Colwellia and Pseudoalteromonas, in the gamma-Proteobacteria. The two strains
shared 16S rDNA sequence similarity of 96.9% and genomic DNA relatedness of 27%;
the latter was determined by dot-blot hybridization. The strains were
differentiated by the presence of fimbria, production of chitinase, ability to
grow on 15% NaCl and BIOLOG profiles. Given the polyphasic evidence accumulated
in this study, it is proposed that the two deep-sea isolates be classified in the
genus Idiomarina gen. nov., as Idiomarina abyssalis sp. nov. (type strain is KMM
227T) and Idiomarina zobellii sp. nov. (type strain is KMM 231T).
PMID- 10758903
TI - Differentiation of newly described antarctic bacterial isolates related to
Roseobacter species based on 16S-23S rDNA internal transcribed spacer sequences.
AB - The 16S-23S rDNA internal transcribed spacer (ITS) of Roseobacter denitrificans,
Roseobacter litoralis, Ruegeria algicola and strains of the recently described
species Antarctobacter heliothermus and Roseovarius tolerans were analysed in
order to examine DNA sequence variations and to draw conclusions about inter- and
intraspecific relationships. A. heliothermus included four strains with an ITS
fragment length of 1092 bp. Roseovarius tolerans was described on the basis of
eight strains. Five of these harboured two ITS fragments of different lengths
(959 and about 1100 bp), while the others had one fragment of either 1083 bp (two
strains) or 1165 bp (one strain). ITS lengths of the related species Roseobacter
denitrificans, Roseobacter litoralis and Ruegeria algicola were found to be 980,
984 and 1158 bp, respectively. Phylogenetic analyses of the DNA sequences allowed
species affiliation of strains with sequence length differences of > 200 bp and
recognition of relationships based on a well-supported ITS tree. The strains of
A. heliothermus and Roseovarius tolerans each formed a monophyletic branch and
they were separated from each other by Ruegeria algicola. This species was now
clearly separated from Roseobacter denitrificans and Roseobacter litoralis, which
corresponded to the new genus affiliation of Ruegeria algicola. These data were
additionally supported by analyses of the structure, relative position and order
of genes for tRNA(Ile) and tRNA(Ala) found within the ITS of each strain.
Comparative DNA sequence analyses of ITS and 16S rDNA revealed limitations, on
species and strain levels, with respect to the phylogenetic resolution of the 16S
rDNA due to the limited number of informative (variable) sites, while ITS
sequence analyses provided more variable and sufficiently conserved positions to
discriminate between strains and to reconstruct their taxonomic relationships.
PMID- 10758904
TI - Staircase electrophoresis profiles of stable low-molecular-weight RNA--a new
technique for yeast fingerprinting.
AB - Staircase electrophoresis (SCE) in polyacrylamide gels was used to analyse the
stable low-molecular-weight (LMW) RNA profiles of several yeast species and
genera. As in prokaryotes, this new electrophoretic technique results in good
separation of molecules forming LMW RNA profiles in yeasts. In this study it is
reported that, while LMW RNA profiles in prokaryotes include only 5S rRNA, and
class 2 and class 1 tRNA, these profiles in eukaryotes also include 5.8S rRNA.
Differences in the number and distribution of RNA bands in these profiles allowed
identification of differences among the yeast species and genera assayed. LMW
RNAs, analysed by SCE, provide a yeast fingerprint that allows them to be clearly
differentiated and will in the future enable the rapid assignment of yeast
isolates to already described species and the detection of new ones.
PMID- 10758905
TI - Emended descriptions of Tilletiopsis washingtonensis, Tilletiopsis cremea and
Tilletiopsis lilacina.
AB - For species discrimination, DNA relatedness, nuclear DNA (nDNA) base compositions
and internal transcribed spacer (ITS) regions were studied in strains of the
'washingtonensis group' consisting of the type strains of Tilletiopsis
washingtonensis, Tilletiopsis cremea and Tilletiopsis lilacina as wells as nine
strains previously identified as any one of the three species. T. washingtonensis
is the neotype of the genus Tilletiopsis while T. cremea and T. lilacina are
currently recognized as conspecific with T. washingtonensis. The G + C content of
the DNA of the strains examined in this study was 66-68 mol%. The type strains of
T. washingtonensis, T. cremea and T. lilacina were clearly discriminated on the
basis of DNA complementarity. These genospecies should be treated as species.
Moreover, an unrooted dendrogram constructed from ITS nucleotide sequences showed
that the 'washingtonensis group' was divided into three clusters, corresponding
to the three species T. washingtonensis, T. cremea and T. lilacina, respectively.
The species descriptions of T. washingtonensis, T. cremea and T. lilacina are
emended accordingly.
PMID- 10758906
TI - Non-radioactive dot-blot DNA reassociation for unequivocal yeast identification.
AB - Unequivocal and rapid classification of yeast cultures cannot be accomplished
exclusively on the basis of unstable phenotypic traits, but requires molecular
tests relating to the whole genome (or the largest possible portion of it). DNA
DNA reassociation meets this requirement, although many procedures proposed for
calculating overall sequence similarity are expensive and time-consuming, thus
restricting the possibility of unequivocal classification to a few specialized
laboratories. A novel method, based on non-radioactive dot-blot hybridization of
whole genomic DNA, has shown high and reproducible proportionality between the
detected signal and the amount of double-stranded DNA effectively present on the
membrane. This procedure has been optimized to obtain, within two working days,
DNA relatedness values between unknown cultures and the type strains of the
species previously indicated by a few conventional tests. The effective ability
of the method to discriminate strains belonging to different species has been
tested within taxonomic models consisting of yeast type cultures already
certified by spectrophotometric reassociation.
PMID- 10758907
TI - Legionella taurinensis, a new species of Legionella isolated in Turin, Italy.
PMID- 10758908
TI - What is the type species of the genus Paenibacillus? Request for an opinion.
AB - The taxonomic status of the type species of the genus Paenibacillus cannot be
easily determined according to the rules of the Bacteriological Code since the
rules may be interpreted in an ambiguous way. Depending upon how the rules are
applied the type species may be either Paenibacillus polymyxa or Paenibacillus
durus. In addition, depending upon the way in which the Bacteriological Code is
interpreted, the question of whether the name P. durus (Collins et al. 1994) has
been validly published must also be addressed.
PMID- 10758909
TI - Proposal of Salmonella paratyphi sp. nov., nom. rev. and request for an opinion
to conserve the specific epithet paratyphi in the binary combination Salmonella
paratyphi as nomen epitheton conservandum.
AB - We propose Salmonella paratyphi sp. nov., nom. rev., by raising Salmonella
choleraesuis subsp. choleraesuis serovar Paratyphi A to species status and
request an Opinion to include the specific epithet paratyphi in the binary
combination of Salmonella paratyphi in the list of epitheta specifica
conservanda.
PMID- 10758910
TI - Recognition of nomenclatural standing of Salmonella typhi (Approved Lists 1980),
Salmonella enteritidis (Approved Lists 1980) and Salmonella typhimurium (Approved
Lists 1980), and conservation of the specific epithets enteritidis and
typhimurium. Request for an opinion.
AB - In 1994, the Judicial Commission of the ICSB announced that Le Minor and Popoff's
Request for an Opinion in 1987 to designate Salmonella enterica sp. nov., nom.
rev. as the type and only species of the genus Salmonella was denied. Thus, the
current species of the genus Salmonella are Salmonella typhimurium, Salmonella
enteritidis, Salmonella typhi, Salmonella choleraesuis (including six subspecies)
and Salmonella bongori, with the type species, S. choleraesuis (Smith 1894)
Weldin 1927 (Approved Lists 1980). Because the decision of the Judicial
Commission about the request by Le Minor in 1987 was suspended for 7 years, the
non-validated name 'S. enterica' has been used among microbiologists and has
caused confusion in the nomenclature of Salmonella. In order to overcome such
confusion, and because of their importance as human pathogens, we herein propose
to recognize the nomenclatural status of S. typhi, S. enteritidis and S.
typhimurium as species and request to issue an Opinion to conserve the specific
epithets enteritidis and typhimurium in the species names Salmonella enteritidis
and Salmonella typhimurium.
PMID- 10758911
TI - The intellectual property landscape in the field of plasmid-based gene therapy.
AB - As plasmid-based gene therapy products progress through clinical trials
commercial entities begin to focus on the intellectual property associated with
the methods and specific compositions used in these therapies. As the number of
patents covering gene therapy components and methods increases it becomes
increasingly difficult for a single entity to collect all of the necessary rights
to be able to offer gene therapy products to consumers. The present report
briefly describes the relevance of patents to product commercialization and
describes certain key patents that may affect the ultimate commercialization
potential of this new and exciting technology.
PMID- 10758912
TI - Gene delivery and expression in human retinal pigment epithelial cells: effects
of synthetic carriers, serum, extracellular matrix and viral promoters.
AB - Non-viral gene therapy is a potential treatment to many incurable retinal
diseases. To fulfill this promise, plasmid DNA must be delivered to the retinal
target cells. We evaluated the efficacy of synthetic DNA complexing compounds in
transfecting primary human retinal pigment epithelial (RPE) cells in vitro. Fetal
human RPE cells were cultured with or without extracellular matrix (ECM),
produced using calf corneal endothelial cells. Plasmids encoding nuclear
localizing beta galactosidase or luciferase (pRSVLuc, pCLuc4, pSV2Luc) were
complexed in water at various +/- charge ratios using cationic lipids
(Lipofectin, DOTAP, DOGS), polyethylene imines (25 and 750 kDa), and with
degraded 6th generation starburst polyamidoamine dendrimers. Luciferase was
quantified using a luminometric assay and beta galactosidase with X-gal staining.
Toxicities of transfections were evaluated with the MTT-assay. Using beta
galactosidase as the reporter gene naked DNA did not transfect RPE cells at
measurable levels whereas 1-5% of the cells expressed histochemically detectable
amounts of the gene after transfection with cationic lipid DNA complexes. In RPE
cells, Rous sarcoma virus and cytomegalovirus (CMV) were more efficient promoters
than SV40 in driving luciferase expression, and CMV was chosen for further
experiments. At optimal complex charge ratios, expression levels of luciferase
were > 10(9) light units/mg protein after transfection using dendrimers and
PEI25, while transfection mediated with the other carriers resulted in luciferase
expression levels of 10(7)-10(9) light units/mg protein or less. In general,
dendrimers and large molecular weight PEI were less toxic than cationic lipids or
PEI25 to RPE cells. Serum and ECM decreased gene expression to the RPE cells with
all carriers. Despite low percentage of transfected cells the transgene
expression per RPE cell is high, important feature in the retinal tissue with
small dimensions, in particular in the case of secreted gene products. Degraded
dendrimers and high molecular weight PEI exhibited the best combination of high
activity and low toxicity in RPE cell transfection.
PMID- 10758913
TI - Encapsulation of plasmid DNA in stabilized plasmid-lipid particles composed of
different cationic lipid concentration for optimal transfection activity.
AB - In previous work (Wheeler et al. (1999) Gene Therapy 6, 271-281) we have shown
that plasmid DNA can be entrapped in "stabilized plasmid lipid particles" (SPLP)
using low levels (5-10 mol%) of cationic lipid, the fusogenic lipid
dioleoylphosphatidylethanolamine (DOPE), and a polyethyleneglycol (PEG) coating
for stabilization. The PEG moieties are attached to a ceramide anchor containing
an arachidoyl acyl group (PEG-CerC20). However, these SPLP exhibit low
transfection potencies in vitro as compared to plasmid/cationic lipid complexes
formed with liposomes composed of cationic and neutral lipid at a 1:1 lipid
ratio. The objective of this study was to construct SPLPs with increased cationic
lipid contents that result in maximum transfection levels. A phosphate buffer
detergent dialysis technique is described resulting in formation of SPLP
containing 7-42.5 mol% DODAC with reproducible encapsulation efficiency of up to
80%. An octanoyl acyl group was used as anchor for the PEG moiety (PEG-CerC8)
permitting a quick exchange out of the SPLP to further optimize the in vitro and
in vivo transfection. We have demonstrated that this technique can be used to
encapsulate either linearized DNA or supercoiled plasmids ranging from 3-20 kb.
The SPLP formed could be isolated from empty vesicles by sucrose density gradient
centrifugation, and exhibited a narrow size distribution of approximately 75 +/-
6 nm as determined by cryo-electron microscopy. The high plasmid-to-lipid ratio
observed corresponded to one plasmid per particle. The SPLP consist of a lipid
bilayer surrounding the plasmid DNA as visualized by cryo-electron microscopy.
SPLP containing a range of DODAC concentrations were tested for in vitro and in
vivo transfection. In vitro, in COS-7 cells transfection reached a maximum after
48 h. The transfection efficiency increased when the DODAC concentration in the
SPLP was decreased from 42.5 to 24 mol% DODAC. Decreasing the cationic lipid
concentration improved transfection in part due to decreased toxicity. In vivo
studies using an intraperitoneal B16 tumor model and intraperitoneal
administration of SPLP showed maximum transfection activity for SPLP containing
24 mol% DODAC. Gene expression observed in tumor cells was increased by
approximately one magnitude as compared to cationic lipid/DNA complexes. The SPLP
were stable and upon storage at 4 degrees C no significant change in the
transfection activity was observed over a one-year period. Thus this phosphate
buffer detergent dialysis technique can be used to generate SPLP formulations
containing a wide range of cationic lipid concentrations to determine optimal
SPLP composition for high transfection activity and low toxicity.
PMID- 10758914
TI - Stabilized plasmid-lipid particles: pharmacokinetics and plasmid delivery to
distal tumors following intravenous injection.
AB - A previous study has shown that plasmid DNA can be encapsulated in lipid
particles (SPLP, "stabilized plasmid lipid particles") of approximately 70 nm
diameter composed of 1,2-dioleoyl-3-phosphatidyl-ethanolamine (DOPE), the
cationic lipid N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC) and
poly(ethylene glycol) conjugated to ceramide (PEG-Cer) using a detergent dialysis
process (Wheeler et al. (1999) Gene Therapy 6, 271-281). In this work we
evaluated the potential of these SPLPs as systemic gene therapy vectors,
determining their pharmacokinetics and the biodistribution of the plasmid and
lipid components. It is shown that the blood clearance and the biodistribution of
the SPLPs can be modulated by varying the acyl chain length of the ceramide group
used as lipid anchor for the PEG polymer. Circulation lifetimes observed for
SPLPs with PEG-CerC14 and PEG-CerC20 were t(1/2) = approximately 1 and
approximately 10 h, respectively. The SPLPs are stable while circulating in the
blood and the encapsulated DNA is fully protected from degradation by serum
nucleases. The accelerated clearance of SPLPs with PEG-CerC14 is accompanied by
increased accumulation in liver and spleen as compared to PEG-CerC20 SPLPs.
Delivery of intact plasmid to liver and spleen was detected. Significant
accumulation (approximately 10% of injected dose) of the long circulating SPLPs
with PEG-CerC20 in a distal tumor (Lewis lung tumor in the mouse flank) was
observed following i.v. application and delivery of intact plasmid to tumor
tissue at approximately 6% injected dose/g tissue is demonstrated.
PMID- 10758915
TI - Cationic lipid structure and formulation considerations for optimal gene
transfection of the lung.
AB - Enhanced gene transduction to the lung using cationic lipids could be attained
through optimization of the structure of the lipids and the formulation of the
cationic lipid:plasmid DNA (pDNA) complexes. We have expanded on our earlier
observation of the importance of the structural orientation of the cationic lipid
headgroup. Through the synthesis of a number of matched pairs of cationic lipids
differing only in the configuration of their headgroup, we confirmed that those
harboring a T-shape headgroup are more active than their linear counterparts, at
least when tested in the lungs of BALB/c mice. Additionally, we demonstrated that
not only are the structural considerations of these cationic lipids important,
but also their protonation state, the free base being invariably more active than
its salt counterpart. The salt forms of cationic lipids bound pDNA with greater
avidity, which may have affected their subsequent intracellular dissolution and
transit of the pDNA to the nucleus. Inclusion of a number of frequently used
solutes in the vehicle severely inhibited the gene transfection activity of the
cationic lipids. The selection of neutral co-lipids was also an important factor
for overall transfection activity of the formulation, with significant gains in
transfection activity realized when diphytanoylphosphatidylethanolamine or
dilinoleoylphosphatidylethanolamine were used in lieu of
dioleoylphosphatidylethanolamine. Finally, we showed that a transacylation
reaction could occur between the cationic lipid and neutral co-lipid which
reduced the transfection activity of the complexes. It is the hope that as our
understanding of the many factors that influence the activity of these cationic
lipid:pDNA complexes improves, formulations with much greater potency can be
realized for use in the treatment of pulmonary diseases.
PMID- 10758916
TI - Comparison of cardiac troponin T versus creatine kinase-MB for risk
stratification in a chest pain evaluation unit.
AB - We evaluated cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) for risk
stratification of chest pain unit (CPU) patients. We studied 383 consecutive
patients with chest pain assigned to our CPU by emergency department physicians.
At baseline all had normal or nondiagnostic electrocardiograms, no high-risk
clinical features, and negative CK/CK-MB. CK-MB and electrocardiograms were taken
at 0, 4, 8, and 12 hours and cTnT at 0, 4, and 8 hours. Eight patients (2.1%)
were CK-MB positive and 39 (10.2%) were cTnT positive, including all but 1 CK-MB
positive patient. All marker-positive patients were detected by 8 hours. Seven
cTnT-positive patients and 1 cTnT-negative patient had myocardial infarction (p
<0.0001). cTnT-positive patients were older, less likely to be women or smokers,
and more often had diabetes mellitus or known coronary disease (CAD). Seventy-one
percent of patients underwent diagnostic testing. cTnT-positive patients more
often underwent angiography (46% vs 20%) and underwent stress testing less often
(28% vs 57%) than cTnT-negative patients. When performed, their stress tests were
more often positive (46% vs 14%) and they more often had angiographically
significant lesions (89% vs 49%) and multivessel disease (67% vs 29%). There were
no short-term deaths. Long-term mortality was higher in cTnT-positive patients
(27% vs 7%, p <0.0001). Thus, cTnT identified more CPU patients with myocardial
necrosis and multivessel CAD than CK-MB and a population with high long-term
mortality risk. Routine use of cTnT in CPUs could facilitate risk stratification
and management.
PMID- 10758917
TI - Clinical profile and long-term prognosis of women < or = 50 years of age referred
for coronary angiography for evaluation of chest pain.
AB - A significant lack of information exists regarding risk factors, preventive
strategies, diagnostic testing, and treatment of women with coronary artery
disease (CAD), especially in the young age group. We studied the clinical
profile, angiographic results, and long-term follow-up of 135 women aged < or =50
years referred for coronary angiography because of chest pain. The most prominent
risk factor was hyperlipidemia (60%), followed by a family history of coronary
disease (44%), systemic hypertension (40%), cigarette smoking (31%),
postmenopausal state (23%), and diabetes mellitus (21%). Angiographically
significant CAD was demonstrated in 79 of 135 patients (58%), most of whom (61%)
had 1-vessel CAD. Women with compared to those without significant CAD had a
higher prevalence of hyperlipidemia (71% vs 45%; p = 0.002) and of the post
menopausal state (30% vs 16%; p = 0.028). There was no difference in the
incidence of positive noninvasive evaluation (ergometry or thallium scan) before
catheterization between women with or without significant coronary lesions. At a
follow-up period of 2 to 7 years, 3 women had acute myocardial infarction, all of
whom demonstrated coronary lesions on prior angiography. No difference was found
regarding the recurrence of chest pain on follow-up between women with or without
significant CAD. Mortality and congestive heart failure were observed more
frequently in women with CAD (6% vs 0%; p = 0.0516 and 12% vs 2%; p = 0.047,
respectively).
PMID- 10758918
TI - Coronary angiographic findings and troponin T in patients with unstable angina
pectoris.
AB - This study sought to identify differences in coronary anatomic pathology in
patients with unstable angina and elevated versus nonelevated serum troponin T
values. Previous studies have shown a worse prognosis in unstable angina patients
with elevated serum troponin T values. Consecutive patients (n = 117) with
Braunwald class IIIB angina were included in the study. Serum samples for
troponin T were obtained at admission and every 6 to 8 hours for 18 to 24 hours.
Acute myocardial infarction was excluded by routine creatine kinase measurements.
All patients underwent coronary angiography before discharge. Cardiac events
including cardiac death and myocardial infarction were recorded. Two thirds of
the patients with unstable angina had no increase in serum troponin T (<0.1
microg/L) (n = 80). They had a lower incidence of 3-vessel disease (26% vs 46%, p
<0.001), left main disease (5% vs 16%, p = 0.04), visible thrombus (4% vs 22%, p
= 0.006), and less severe stenosis of the culprit artery (65% vs 84%, p <0.004)
than patients with elevated serum troponin T values (> or =0.1 microg/L) (n =
37). The 1-year cardiac event rate was 0% versus 19% in patients with troponin T
values <0.1 microg/L compared with patients with serum troponin T values > or
=0.1 microg/L (p <0.0001). It was concluded that patients with unstable angina
and no release of troponin T have less severe coronary artery disease, and have
an excellent prognosis. It is suggested that these patients may be managed more
conservatively and without invasive evaluation before discharge.
PMID- 10758919
TI - Heart rate variability in patients with acute myocardial infarction undergoing
primary coronary angioplasty.
AB - Depressed heart rate variability (HRV) has been associated with adverse outcome
during and after acute myocardial infarction (AMI). The effects of reperfusion in
AMI on the course of HRV have not been well characterized as yet. We analyzed 123
consecutive patients with a first AMI who underwent successful reperfusion
(Thrombolysis In Myocardial Infarction grades 2 and 3) by primary percutaneous
transluminal coronary angioplasty (PTCA). Time- and frequency-domain HRV was
measured from 24-hour Holter monitoring, which began at hospital admission. Mean
RR interval increased significantly after successful PTCA. Reperfusion
immediately caused an immediate transient depression of HRV, which was followed
by a significant increase of HRV. Quantitative markers of sympathetic activity
and sympathovagal balance, such as SD of the averages of NN intervals in all 5
minute segments, and low- and/or high-frequency ratio continuously decreased
within the observation period. Patients with anterior AMI exhibited the same
pattern of temporal changes of HRV, with, however, lower absolute values for HRV
and mean RR interval than patients with non-anterior AMI. Subgroup analysis in 21
patients with reperfusion > 12 hours after onset of pain showed that the biphasic
profile of HRV and the marked increase of mean RR interval was absent.
Furthermore, in patients with late reperfusion, HRV was significantly lower
compared with those with early reperfusion. Thus, timely reperfusion in AMI leads
to a biphasic effect on autonomic tone, characterized by a transient suppression,
followed by a significant activation of the vagal tone, as well as an attenuation
of sympathetic activity. Recovery of HRV may contribute to the benefits of early
reperfusion in AMI.
PMID- 10758920
TI - Clinical and angiographic outcome after coronary arterial stenting with the
carbostent.
AB - The Carbostent is a new balloon-expandable, stainless steel, tubular stent with
innovative multicellular design and unique turbastratic carbon coating
(Carbofilm). This open nonrandomized 2-center study assesses the immediate and
long-term clinical and angiographic outcomes after Carbostent implantation in
patients with native coronary artery disease. The Carbostent was implanted in 112
patients with 132 de novo lesions. Most patients (55%) had unstable angina, and
38% of lesions were type B2-C. The mean lesion length was 12.5 +/- 7.0 mm, and
29% of lesions were > 15 mm in length. No stent deployment failure occurred, as
well as acute or sub-acute stent thrombosis. The 6-month event-free survival was
84 +/- 4%. One patient with a stented right coronary artery and no restenosis at
the angiographic follow-up died after 6 months of fatal infarction due to abrupt
closure of a nontarget vessel. In-hospital non-Q-wave myocardial infarction
occurred in 1 patient, and 11 patients had repeat target lesion revascularization
(target lesion revascularization rate 10%). The 6-month angiographic follow-up
was obtained in 108 patients (96%) (127 lesions). Angiographic restenosis rate
was 11%. The loss index was 0.29 +/- 0.28. The results of this study indicate a
potential benefit of Carbostent for the prevention of stent thrombosis and
restenosis in these relatively high-risk patients. A larger trial is being
planned to confirm these promising results.
PMID- 10758921
TI - Quantitative effects of functional bundle branch block in patients with
atrioventricular reentrant tachycardia.
AB - Changes in the retrograde conduction time (ventriculoatrial [VA]) interval during
functional bundle branch block (BBB) have been used to separate septal from free
wall accessory pathways (APs), but different values of the VA interval
prolongation (deltaVA) have been described in different reports. A total of 95
patients with single nondecremental APs who developed BBB during atrioventricular
reentrant tachycardia were studied. Free wall APs were found in 60 patients, and
35 had septal APs. For patients with free wall APs, complete and incomplete BBB
ipsilateral to the atrial insertion site of APs were observed in 39 of 60
patients (65%) and 31 of 60 patients (52%), respectively. For patients who had
both complete (QRS > or = 120 ms) and incomplete (QRS <120 ms) BBB during
atrioventricular reentrant tachycardia, deltaVA for patients with complete BBB
was significantly greater than in those with incomplete BBB, 59 +/- 19 ms versus
30 +/- 11 ms, p <0.001. For patients with septal APs and complete and incomplete
BBB during tachycardia, the mean deltaVA for those with complete BBB was 31 +/-
20 ms and was significantly longer than in patients with incomplete BBB (14 +/- 6
ms), p <0.001. There was no significant difference in deltaVA between those with
free wall APs and incomplete BBB compared with those with septal APs and complete
BBB. The criteria of QRS > or = 120 ms associated with deltaVA > or =40 ms served
to best separate free wall from septal APs with a sensitivity of 88% and a
specificity of 89%. Left anterior fascicular block was associated with marked
lengthening of deltaVA for those with left free wall APs, whereas a left
posterior fascicular block pattern resulted in a marked increase in the deltaVA
for patients with posteroseptal APs. In the absence of fascicular block patterns,
a deltaVA > or =40 ms provides strong evidence of a free wall AP, with a
sensitivity of 95% and a specificity of 100%. The left posterior fascicle appears
to provide predominant innervation of the posterior septum.
PMID- 10758922
TI - Serial evaluation of left atrial dimension after cardioversion for atrial
fibrillation and relation to atrial function.
AB - The size of the left atrium is usually increased during atrial fibrillation (AF).
The aim of the present study was to evaluate changes in left atrial (LA)
dimension after cardioversion for AF, and the relation between LA dimension and
atrial function. The initial study population included 171 consecutive patients.
Patients who had spontaneous cardioversion to sinus rhythm (56 patients) were
compared with patients who had random cardio-version with drugs (50 patients) or
direct-current (DC) shock (50 patients). Echocardiographic evaluations included
LA size and volume. LA passive and active emptying volumes were calculated, and
LA function was assessed. Atrial stunning was observed in 18 patients reverted
with DC shock and in 7 patients reverted with drugs. The left atrium was dilated
in all patients during AF (48 +/- 5 mm). The size of the left atrium decreased
after restoration of sinus rhythm in all patients with spontaneous reversion to
sinus rhythm, in 73% of patients reverted with drugs, and in 50% of patients
reverted with DC shock. The comparison between patients with a normal mechanical
atrial function and patients with reduced atrial function showed that a higher
atrial ejection force was associated with a more marked reduction in LA size
after restoration of sinus rhythm. A relation between LA volumes and atrial
ejection force was observed in the group of patients with depressed atrial
mechanical function (r = -0.78; p <0.001). The active emptying fraction was
lower, although not significantly, in this group, whereas the conduit volume was
increased. Thus, a depressed atrial mechanical function after cardioversion for
AF was associated with a persistence of LA dilation.
PMID- 10758923
TI - Prognostic usefulness of the tricuspid annular plane systolic excursion in
patients with congestive heart failure secondary to idiopathic or ischemic
dilated cardiomyopathy.
AB - The prognostic value of ultrasound evaluation of right ventricular (RV)
performance in patients with congestive heart failure (CHF) is still a matter of
investigation. We studied 140 consecutive patients with chronic CHF and a left
ventricular ejection fraction <35%. All patients underwent a complete
echocardiographic evaluation that systematically included the measurement of the
tricuspid annular plane systolic excursion (TAPSE). During a follow-up period of
24 +/- 14 months, 45 patients died and 7 underwent emergency heart
transplantation. At the multivariate survival analysis (Cox regression model)
backward stepwise selection identified a prognostic model with 2 parameters: New
York Heart Association (NYHA) class III or IV and TAPSE < or =14 mm (p <000). In
a subgroup of 97 patients in sinus rhythm in whom mitral inflow Doppler variables
could be measured, survival was further analyzed according to a model in which
the significant parameters were included in the same order as usually used in
routine clinical practice: clinical variables first, left ventricular function
data second, mitral Doppler variables third, and indexes of right ventricular
(RV) function last. TAPSE < or =14 mm added significant (p <0.03) prognostic
information to NYHA class III or IV, left ventricular ejection fraction of <20%,
and mitral deceleration time of < 125 ms. In conclusion, in patients with CHF,
TAPSE adds significant prognostic information to the NYHA clinical
classification, to the echocardiographic evaluation of left ventricular function,
and to mitral Doppler variables. Furthermore, the measurement of TAPSE is easy to
obtain in all patients, irrespective of heart rate and rhythm.
PMID- 10758924
TI - Plasma clearance of polyfructosan and extracellular body fluid distribution in
idiopathic dilated cardiomyopathy and after heart transplantation.
AB - The total extracellular fluid volume and distribution in plasma and interstitial
spaces, and the microvascular permeability properties were studied in 16
nonedematous patients with congestive heart failure (CHF) due to idiopathic
dilated cardiomyopathy and 17 such patients who underwent heart transplantation
(HT) by analyzing the 3-hour plasma disappearance curve of polyfructosan.
Eighteen healthy subjects served as controls. Polyfructosan (3.5 kD) is an
extracellular marker and inulin analog transported almost solely by diffusion.
The initial capillary membrane plasma clearance (i.e., the permeability-surface
area product), the interstitial plasma clearance determined at 10 minutes
(clearance[10), and the extracellular volume were determined from the
polyfructosan curves. I-131-albumin was used as a plasma volume reference.
Permeability-surface area product was elevated in both patient groups (6.6 +/-
1.9 ml/ kg/min in the CHF group and 6.7 +/- 2.0 ml/kg/min in the HT group vs 5.1
+/- 1.3 ml/kg/min in controls, p <0.01 for both), whereas clearance(10) was
normalized in the HT group (4.5 +/- 0.9 ml/kg/min in the HT group, 4.4 +/- 0.7
ml/kg/min in controls vs 5.0 +/- 0.9 ml/kg/ min in the CHF group, p <0.1 and p
<0.05, respectively). The normalization of interstitial plasma clearance of
polyfructosan was associated with time since HT (r = 0.49, p <0.05). Plasma
volumes were similar in all 3 groups (41 +/- 8 ml/kg in controls, 44 +/- 13 in
the CHF group and 39 +/- 8 in the HT group). In contrast, total extracellular
volume was elevated in both patients groups (177 +/- 27 ml/kg in the CHF group
and 173 +/-27 in the HT group vs 152 +/- 12 in controls, p <0.01). The results
strongly suggest a microvascular permeability defect in both patient groups that
perhaps plays a role in the extravascular distribution of the excess
extracellular fluid volume.
PMID- 10758925
TI - Comparison of electrocardiographic findings in patients with AL (primary)
amyloidosis and in familial amyloid polyneuropathy and anginal pain and their
relation to histopathologic findings.
AB - To assess the prevalence of chest pain and ischemic electrocardiographic (ECG)
changes and relate them to histopathologic findings of coronary arteries in
cardiac amyloidosis, 33 patients with AL (primary) amyloidosis and 60 patients
with familial amyloid polyneuropathy (FAP) were examined. Five patients (15%)
with AL amyloidosis had recurrent anginal pain with exertion and 2 of them also
experienced anginal pain after orthostatic hypotension. The chest pain was
associated with transient downsloping or horizontal ST-segment depression with or
without T-wave inversion in right precordial leads, whereas the remaining
patients with AL amyloidosis and all patients with FAP did not show anginal pain
or ischemic ST-T changes. Histologic sections of coronary arteries were obtained
in 12 patients with AL amyloidosis, including 4 of the 5 patients who had angina
pectaris and in 25 patients with FAP. Three patients with anginal pain had
variable degrees of stenoses of the intramural coronary arteries by amyloid
deposition predominantly in the media with normal or nearly normal epicardial
arteries. One patient with AL amyloidosis who had effort angina showed marked
stenosis and complete occlusion of the small coronary vessels by transmural
amyloid deposition. The remaining 8 patients with AL amyloidosis and 25 with FAP
without chest pain did not exhibit any stenosis or occlusion of both the
epicardial and intramural vessels. These findings suggest that ischemic ST-T
changes with chest pain are not so rare in patients with AL amyloidosis, and that
markedly decreased myocardial oxygen supply due to diffuse stenotic or occlusive
disease of the small coronary vessels by amyloid deposition contributes to the
development of clinically significant ischemic heart disease in these patients.
PMID- 10758926
TI - Echocardiographic follow-up after Ross procedure in 100 patients.
AB - The Ross procedure could provide an ideal aortic valve replacement method in
children and young adults. We evaluated midterm echocardiographic results to
assess pulmonary homograft function as well as pulmonary autograft dimensions and
function. In all, 105 patients (26 women and 79 men) underwent the Ross
procedure; median age at implant was 29 years. All patients underwent free root
replacement. Transvalvular gradients and autograft dimensions were measured at 3
levels (annulus, sinuses of Valsalva, and proximal aorta) at discharge, at 6
months, and annually thereafter. Perioperative mortality was 4.7%. The mean
period for echocardiographic follow-up in 100 patients was 32.7 months (range 0.5
to 7 years), during which 4 noncardiac-related deaths occurred. Two patients
underwent late reintervention. No moderate or severe regurgitation was recorded.
There was 1 case of mild homograft regurgitation and 4 of mild autograft
regurgitation at late follow-up. Autograft peak gradients were low and
reproducible (5 +/- 2.8 mm Hg at discharge vs 5.5 +/- 3.5 mm Hg at last follow
up, p = NS). Homograft peak gradients increased significantly without severe
obstruction (7.8 +/- 5.7 mm Hg at discharge vs 15.8 +/- 9.2 mm Hg at last follow
up). The diameter of the autograft annulus was stable during follow-up, whereas
autograft dimensions at sinuses and proximal aorta increased significantly. One
group of patients was identified with sinus diameter increases >20% (group A).
The 90 remaining patients were classified into group B. The only parameter
significantly different between the 2 groups was the sinus diameters measured at
discharge (1.74 cm/m2 (group A) vs 1.92 cm/m2 (group B); p = 0.036). In 100
patients and with echocardiographic follow-up for up to 7 years, the Ross
procedure showed excellent results. For 10% of patients, we observed a 20%
dilation of sinus diameters, but in only 3 patients (3%) was this beyond the
upper normal limit.
PMID- 10758927
TI - Plasma beta-endorphin and adenosine concentration in pulmonary hypertension.
AB - To determine whether beta-endorphin plays a role in the regulation of pulmonary
vascular tone in patients with pulmonary hypertension, we investigated the
relations between hemodynamics and beta-endorphin and adenosine concentrations in
3 clinical situations: (1) normal hemodynamics (7 subjects, mean pulmonary artery
[PA] pressure 18.5 +/- 1 mm Hg); (2) moderate pulmonary hypertension secondary to
chronic obstructive pulmonary disease (COPD) (8 patients, mean PA pressure 31 +/-
3 mm Hg); and (3) severe primary pulmonary hypertension (PPH) (8 patients, mean
PA pressure 70 +/-5 mm Hg). Plasma beta-endorphin and adenosine were measured in
a distal PA and in the femoral artery in room air and during oxygen inhalation.
Beta-endorphin levels were similar in the pulmonary and systemic circulations. No
difference was observed between patients with COPD and PPH, but relative to
controls, both had significantly higher beta-endorphin levels. Pulmonary
adenosine was significantly lower in patients with pulmonary hypertension than in
controls (-60% in COPD [p <0.005] and -70% in PPH [p <0.001]). Pure oxygen
administration significantly decreased adenosine and beta-endorphin levels, much
more so in patients with COPD and PPH. We found a negative correlation between
beta-endorphin and adenosine concentrations (r = -0.751, p <0.001): the higher
the adenosine, the lower the beta-endorphin level. These observations suggest
that because adenosine release by pulmonary vascular endothelium is reduced in
pulmonary hypertension, the resulting worsened hypoperfusion and tissue
oxygenation may cause increased beta-endorphin release.
PMID- 10758928
TI - Suture-mediated closure of the femoral access site after cardiac catheterization:
results of the suture to ambulate aNd discharge (STAND I and STAND II) trials.
AB - Despite advances in other aspects of cardiac catheterization, manual or
mechanical compression followed by 4 to 8 hours of bed rest remains the mainstay
of postprocedural femoral access site management. Suture-mediated closure may
prove to be an effective alternative, offering earlier sheath removal and
ambulation, and potentially a reduction in hemorrhagic complications. The Suture
To Ambulate aNd Discharge trial (STAND I) evaluated the 6Fr Techstar device in
200 patients undergoing diagnostic procedures, with successful hemostasis
achieved in 99% of patients (94% with suture closure only) in a median of 13
minutes, and 1% major complications. STAND II randomized 515 patients undergoing
diagnostic or interventional procedures to use of the 8Fr or 10Fr Prostar-Plus
device versus traditional compression. Successful suture-mediated hemostasis was
achieved in 97.6% of patients (91.2% by the device alone) compared with 98.9% of
patients with compression (p = NS). Major complication rates were 2.4% and 1.1%,
and met the Blackwelder's test for equivalency (p <0.05). Median time to
hemostasis (19 vs 243 minutes, p <0.01) and time to ambulation (3.9 vs 14.8
hours, p <0.01) were significantly shorter for suture-mediated closure. Suture
mediated closure of the arterial puncture site thus affords reliable immediate
hemostasis and shortens the time to ambulation without significantly increasing
the risk of local complications.
PMID- 10758929
TI - Prevalence of autoantibodies against contractile proteins in coronary artery
disease and their clinical implications.
AB - In this initial study, we found that autoantibodies against actin and myosin were
present during and after an acute coronary syndrome. Moreover, they correlated
with persistent troponin-I elevation at follow-up, and with late myocardial
infarction.
PMID- 10758930
TI - Factors predicting coronary artery disease in patients with giant negative T
waves.
AB - Seventy-four patients with giant negative T waves were studied to determine which
electrocardiographic variables predicted the presence of coronary artery disease.
The absence of left ventricular hypertrophy and the presence of symmetric T-wave
inversion predicted coronary artery disease.
PMID- 10758931
TI - Selective parasympathetic denervation following posteroseptal ablation for either
atrioventricular nodal reentrant tachycardia or accessory pathways.
AB - Baroreflex gain and coronary sinus norepinephrine and epinephrine levels were
measured before and immediately after radiofrequency ablation in the
posteroseptal region in 9 patients with atrioventricular nodal reentrant
tachycardia or posteroseptal accessory pathways. Arterial baroreflex gain was
significantly reduced after radiofrequency ablation (p = 0.046), whereas coronary
sinus epinephrine and norepinephrine levels did not change significantly compared
with preablation levels.
PMID- 10758932
TI - Transient ST elevation after transthoracic cardioversion in patients with
hemodynamically unstable ventricular tachyarrhythmia.
AB - The significance of ST-segment elevation after resuscitation from arrhythmias not
associated with ischemia was examined in a group of patients who received
transthoracic shocks for hemodynamically unstable ventricular tachyarrhythmias
during electrophysiologic studies. ST-segment elevation was seen in 15.4%, was
transient, and was not associated with clinical evidence of myocardial
infarction.
PMID- 10758933
TI - Role of left ventricular activation sequence in the genesis of isovolumic
relaxation flow in the Wolff-Parkinson-White syndrome.
AB - In patients with left Kent bundle, the initial phase of isovolumic relaxation
flow was directed basally at pre-excited beats, but apically at nonpreexcited
beats or after successful ablation of the Kent bundle. This suggests an important
role of the left ventricular activation sequence in the direction of isovolumic
relaxation flow.
PMID- 10758934
TI - Electrocardiographic and echocardiographic abnormalities in patients with
arrhythmogenic right ventricular cardiomyopathy and in their pedigrees.
AB - Electrocardiographic and echocardiographic evaluations in 18 patients with
arrhythmogenic right ventricular cardiomyopathy (ARVC) and 29 family members (25
males and 25 females from 7 pedigrees) aged 5 to 64 years (mean +/- 1 SD 30 +/-
16) revealed that 5 of 28 ARVC family members (17%) fulfilled ARVC Task Force
criteria. Indexes on late potentials of the signal-averaged electrocardiogram had
a significant linear correlation with the age of patients with ARVC and of family
members with echocardiographic wall motion abnormality.
PMID- 10758935
TI - Accuracy of exercise echocardiography to detect coronary artery disease in left
bundle branch block unassociated with either acute or healed myocardial
infarction.
AB - To search for the value of treadmill exercise echocardiography in the detection
of coronary artery disease in noninfarcted patients with left bundle branch
block, we studied 35 patients (17 with coronary artery disease). We found high
sensitivity, specificity, and accuracy (76%, 83%, and 80%, respectively).
PMID- 10758936
TI - Spontaneous paroxysmal atrioventricular block in patients with positive tilt
tests and negative electrophysiologic studies.
AB - A subgroup of patients with neurocardiogenic syncope and negative
electrophysiologic studies and adenosine tests (in 5 of 6 cases), who developed
symptomatic paroxysmal atrioventricular block in the natural, ambulatory state,
had positive tilt tests without advanced block. Lack of concordance between
electrocardiographic changes may have reflected differential effects of the
autonomic nervous system in the sinus and atrioventricular nodes, occurring in
diverse circumstances and less likely because of the protocol used for tilt
testing.
PMID- 10758937
TI - Effect of Valsalva maneuver on surface electrocardiographic P-wave dispersion in
paroxysmal atrial fibrillation.
AB - The purpose of this study was to investigate the effect of the Valsalva maneuver
on P-wave durations and dispersion. After the Valsalva maneuver, we found that
maximum P-wave duration increased, minimum P-wave duration decreased, and P-wave
dispersion increased in controls, whereas the opposite was true for unselected
patients with paroxysmal AF. It was concluded that patients with paroxysmal AF
performing the Valsalva maneuver normalized their P-wave dispersion, thereby
correcting the inhomogeneous intra-atrial conduction.
PMID- 10758938
TI - Significance of accelerated idioventricular rhythm in idiopathic dilated
cardiomyopathy.
AB - Holter monitoring was performed in 202 patients with idiopathic dilated
cardiomyopathy, which revealed accelerated idioventricular rhythm in 16 patients
(8%) and nonsustained ventricular tachycardia in 70 patients (35%). During 32 +/-
15-month prospective follow-up, no significant difference was observed for major
arrhythmic events and transplant-free survival between patients with and without
accelerated idioventricular rhythm, whereas patients with nonsustained
ventricular tachycardia had a significantly higher incidence of major arrhythmic
events and a lower transplant-free survival rate.
PMID- 10758939
TI - Left ventricular volume after correction of isolated aortic coarctation in
neonates.
AB - To determine the capacity of the left ventricle to expand after biventricular
repair of left ventricular (LV) outflow tract obstruction, we studied pre- and
postoperative echocardiographic variables from 14 infants (< 2 months old) who
underwent successful repair of isolated aortic coarctation. We show that in this
lesion, LV volume is a dynamic entity, and that the left ventricle achieves a
larger cavity size once surgery relieves compression and normalizes loading
conditions.
PMID- 10758940
TI - The electrocardiogram in morbid obesity.
AB - Electrocardiographic variables that occurred with significantly higher frequency
in morbidly obese patients than in lean controls were low QRS voltage, leftward
shift of the P, QRS, and T axes and multiple electrocardiographic criteria for
left ventricular hypertrophy and left atrial enlargement. P-terminal force, RaVL,
SaVR, and R/S ratio in lead V1 values were significantly higher in morbidly obese
than in lean subjects.
PMID- 10758941
TI - Electrocardiographic patterns in posterior chest leads (V7, V8, V9) in normal
subjects.
AB - The electrocardiographic patterns in leads V7, V8, and V9 were studied in 225
young, normal men (age range 17 to 21 years). The prevalence of 0.5- to 1.0-mm ST
segment elevation in leads V7, V8, and Vg 0.08 second after the J point was 8.9%,
5.8%, and 3.1%, respectively; the ST-segment elevation was not >1.0 mm in any
subject.
PMID- 10758942
TI - Chronic treatment with phentermine combined with fenfluramine lowers plasma
serotonin.
AB - As expected on the basis of published research in both humans and animals,
treatment with phentermine/fenfluramine lowers plasma 5-hydroxytryptamine
[corrected], whereas treatment with phentermine had no significant effect. In
light of these findings, future research should focus on mechanisms other than
increased plasma 5-hydroxytryptamine [corrected] to explain how fenfluramine
increases the risk of primary pulmonary hypertension and valvular heart disease.
PMID- 10758943
TI - Case 3: Insulin-dependent diabetes mellitus.
AB - Dyslipidemia secondary to insulin-dependent diabetes mellitus is common among
patients whose plasma glucose levels are poorly controlled. Because of the high
mortality associated with diabetes, prompt intervention to correct the
dyslipidemia is warranted.
PMID- 10758944
TI - Case 4: A patient with systemic hypertension and congestive heart failure.
AB - Hypertension in the setting of symptomatic congestive heart failure requires
aggressive treatment. The optimal antihypertensive agent in such patients is one
that effectively controls blood pressure without compromising the failing heart.
PMID- 10758945
TI - More on the word "stent".
PMID- 10758946
TI - Effect of fluvastatin on QT dispersion: a new pleiotropic effect?
PMID- 10758947
TI - Generalizing the findings of "exaggerated initial response to warfarin following
heart valve replacement" to other hospitalized patients.
PMID- 10758948
TI - Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease.
AB - New strategies for profound inhibition of platelet activity at the injured
coronary plaque focus on blockade of the platelet surface membrane glycoprotein
IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor
and crosslinks platelets as the final common pathway to platelet aggregation.
Intravenous agents directed against this receptor include the chimeric monoclonal
antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide
mimetics tirofiban and lamifiban. Over 33,000 patients have been evaluated in 11
large-scale, placebo-controlled trials of these agents. During percutaneous
coronary intervention, an absolute reduction of 1.5% to 6.5% in the 30-day risk
of death, myocardial infarction or repeat urgent revascularization has been
observed, with some variability in treatment effect among the agents tested
(abciximab, eptifibatide and tirofiban). Treatment effect is achieved early with
every modality of revascularization and is maintained over the long-term (up to
three years). Increased bleeding risk may be minimized by reduction and weight
adjustment of concomitant heparin dosing. In the acute coronary syndromes without
ST segment elevation, absolute 1.5% to 3.2% reductions in 30-day rates of death
or myocardial (re-) infarction have been achieved with two to four day courses of
eptifibatide or tirofiban. Clinical benefit accrues during the period of drug
infusion and is durable. Treatment effect may be enhanced among patients
undergoing early coronary revascularization, with evidence of stabilization
before intervention and suppression of postprocedural ischemic events. Thus,
blockade of the platelet glycoprotein IIb/IIIa receptor reduces ischemic
complications when used as an adjunct to percutaneous coronary intervention or
the management of acute ischemic syndromes.
PMID- 10758949
TI - Eight-year mortality in the Emory Angioplasty versus Surgery Trial (EAST)
AB - OBJECTIVES: To evaluate the long-term outcome of patients randomized to coronary
bypass surgery or coronary angioplasty. BACKGROUND: The Emory Angioplasty versus
Surgery Trial (EAST) is a single center randomized comparison of a strategy of
initial coronary angioplasty (n = 198) or coronary bypass surgery (n = 194) for
patients with multivessel coronary artery disease. The primary end point (death,
myocardial infarction or a large ischemic defect at 3 years) was not different,
and repeat revascularization was significantly greater in the angioplasty group.
Subsequently, the National Heart, Lung and Blood Institute supported a five-year
extension of the trial. METHODS: After the three year anniversary visit, annual
questionnaires, telephone contact and examination of medical records were
accomplished until death or the eight year anniversary in 100% of the patients
surviving at 3 years. RESULTS: Survival at 8 years is 79.3% in the angioplasty
group and 82.7% in the surgical group (p = 0.40). Patients with proximal left
anterior descending stenosis and those with diabetes tended to have better late
survival with surgical intervention although not reaching statistical
significance. After the first 3 years, repeat interventions remained relatively
equal for both treatment groups. CONCLUSIONS: Long-term survival is not
significantly different between angioplasty and surgery, and late (three to eight
year) revascularization procedures were infrequent. Patients without treated
diabetes had similar survival in both groups.
PMID- 10758950
TI - Seven-year outcome in the Bypass Angioplasty Revascularization Investigation
(BARI) by treatment and diabetic status.
AB - OBJECTIVES: To compare seven-year survival in the Bypass Angioplasty
Revascularization Investigation (BARI) patients randomly assigned to percutaneous
transluminal coronary angioplasty (PTCA) versus coronary artery bypass grafting
(CABG). BACKGROUND: The primary results of BARI reported no significant
difference in five-year survival between CABG and PTCA groups. However, among
patients with treated diabetes mellitus, a subgroup not specified a priori, a
striking difference was seen in favor of CABG. METHODS: Symptomatic patients with
multivessel disease (n = 1,829) were randomly assigned to initial treatment
strategy of CABG or PTCA and followed for an average of 7.8 years. The intention
to-treat principle was used to extend the initial five-year BARI treatment
comparisons. RESULTS: Kaplan-Meier estimates of seven-year survival for the total
population were 84.4% for CABG and 80.9% for PTCA (p = 0.043). This difference
could be explained by the 353 patients with treated diabetes mellitus for whom
estimates of seven year survival were 76.4% CABG and 55.7% PTCA (p = 0.0011).
Among the remaining 1,476 patients without treated diabetes, survival was
virtually identical by assigned treatment (86.4% CABG, 86.8% PTCA, p = 0.72). The
PTCA group had substantially higher subsequent revascularization rates than the
CABG group (59.7% vs. 13.1%, p < 0.001); however, the changes between the five-
and seven-year rates were similar for the two groups. CONCLUSIONS: At seven
years, there was a statistically significant survival advantage for patients
randomized to CABG compared with PTCA. Among patients with treated diabetes
mellitus, the benefit of CABG over PTCA seen at five years was more pronounced at
seven years; among nondiabetic patients, there was essentially no treatment
difference.
PMID- 10758951
TI - Diabetes and the cardiologists: a call to action.
PMID- 10758952
TI - Long-term clinical events following creatine kinase--myocardial band isoenzyme
elevation after successful coronary stenting.
AB - OBJECTIVE: We sought to evaluate the impact of intermediate creatine kinase
myocardial band isoenzyme (CK-MB) elevation on late clinical outcomes in patients
undergoing successful stent implantation in native coronary arteries. BACKGROUND:
Elevations of CK-MB after percutaneous coronary interventions are frequent. An
association between high level of CK-MB elevation (>5 times normal) and late
mortality after balloon and new device angioplasty has been reported previously.
However, significant controversy remains on the long-term clinical importance of
lower CK-MB elevations (one to five times normal) after percutaneous coronary
revascularization. Moreover, the incidence and prognostic importance of cardiac
enzyme elevation after coronary stenting have not been well established. METHODS:
Prospectively collected data from 900 consecutive patients (1,213 lesions)
undergoing successful stenting in native vessels were analyzed. Based on the CK
MB levels after coronary stenting, patients were classified into three groups:
normal group 1 (n = 585), elevation of >1 to 5 times normal group 2 (n = 238) and
elevation of >5 times normal group 3 (n = 77). RESULTS: Patients in group 3 had
more in-hospital recurrent ischemia (p = 0.001) and pulmonary edema (p = 0.01)
than patients in groups 1 and 2. Long-term clinical end points were similar
between groups 1 and 2. However, patients in group 3 had an increased incidence
of late mortality compared with patients in groups 2 and 1 (6.9%, 1.2% and 1.7%,
respectively, p = 0.01). Multivariate analysis showed that patients with CK-MB >5
times normal after coronary stenting had an increased risk of major adverse
clinical events (relative risk: 1.70, p < 0.05) and death (relative risk: 3.25, p
< 0.05) that was not observed in patients with lower CK-MB rise. CONCLUSIONS:
Patients with CK-MB elevation >5 times normal had higher late mortality and more
unfavorable event-free survival than those patients with normal or lower CK-MB
rise after coronary stenting. While intermediate CK-MB elevation (>1 to 5 times
normal) is frequent after coronary stenting (26%), this was not associated with
an increased risk of late mortality or major adverse clinical events.
PMID- 10758953
TI - Cardiac enzyme elevations after percutaneous coronary intervention: myonecrosis,
the coronary microcirculation and mortality.
PMID- 10758954
TI - Bifurcation lesions: two stents versus one stent--immediate and follow-up
results.
AB - OBJECTIVES: The purpose of this study was to evaluate two different techniques of
stent placement in bifurcation lesions. BACKGROUND: Although stent placement with
dedicated techniques has been suggested to be a useful therapeutic modality for
bifurcation lesions, limited information is available if stent placement on the
side branch and on the parent branch provides any advantage over a simpler
strategy of stenting the parent vessel and balloon angioplasty of the side
branch. METHODS: Between March 1993 and April 1999, we treated a total of 92
patients with bifurcation lesions with two strategies: stenting both vessels
(group B, n = 53) or stenting the parent vessel and balloon angioplasty of the
side branch (group P, n = 39). Paired angiograms were analyzed by quantitative
angiography, and clinical follow-up was obtained. RESULTS: Stent placement on
both branches resulted in a lower residual stenosis (7.4 +/- 10.9% vs. 23.4% +/-
18.7%, p < 0.001) in the side branch. Acute procedural success was similar in the
two groups (group B: 87% vs. Group P: 92%). In-hospital major adverse cardiac
events (MACE) occurred only in group B (13% vs. 0%, p < 0.05). At the six-month
follow-up, the angiographic restenosis rate (group B: 62% vs. Group P: 48%) and
the target lesion revascularization rate (38% vs. 36%, respectively) were similar
in the two groups. There was no difference in the incidence of six-month total
MACE (51% vs. 38%). CONCLUSIONS: For the treatment of true bifurcation lesions, a
complex strategy of stenting both vessels provided no advantage in terms of
procedural success and late outcome versus a simpler strategy of stenting only
the parent vessel.
PMID- 10758955
TI - End-diastolic wall thickness as a predictor of recovery of function in myocardial
hibernation: relation to rest-redistribution T1-201 tomography and dobutamine
stress echocardiography.
AB - OBJECTIVES: The study assessed whether end-diastolic wall thickness (EDWT),
measured with echocardiography, is an important marker of myocardial viability in
patients with suspected myocardial hibernation, and it compared this index to
currently established diagnostic modalities of dobutamine stress echocardiography
(DSE) and rest-redistribution thallium-201 (T1-201) scintigraphy. BACKGROUND:
Because myocardial necrosis is associated with myocardial thinning, preserved
EDWT may provide a simple index of myocardial viability that is readily available
from the resting echocardiogram. METHODS: Accordingly, 45 patients with stable
coronary artery disease and ventricular dysfunction underwent rest 2D
echocardiograms, DSE and rest-redistribution T1-201 tomography before
revascularization and a repeat resting echocardiogram > or =2 months later.
RESULTS: Global wall motion score index decreased from 2.38 +/- 0.73 to 1.94 +/-
0.82 after revascularization (p < 0.001). Thirty-eight percent of severely
dysfunctional segments recovered resting function. Compared to segments without
recovery of resting function, those with recovery had greater EDWT (0.94 +/- 0.18
cm vs. 0.67 +/- 0.22 cm, p < or = 0.0001) and a higher T1-201 uptake (78 +/- 13%
vs. 59 +/- 21%; p < 0.0001). An EDWT >0.6 cm had a sensitivity of 94% and
specificity of 48% for recovery of function. Similarly, a T1-201 maximal uptake
of > or =60% had a sensitivity of 91% and specificity of 50%. Receiver operating
characteristic curves for prediction of recovery of regional and global function
were similar for EDWT and maximum T1-201 uptake. Combination of EDWT and any
contractile reserve during DSE for recovery of regional function improved the
specificity to 77% without a significant loss in sensitivity (88%). CONCLUSIONS:
End-diastolic wall thickness is an important marker of myocardial viability in
patients with suspected hibernation, and it can predict recovery of function
similar to T1-201 scintigraphy. Importantly, a simple measurement of EDWT < or
=0.6 cm virtually excludes the potential for recovery of function and is a
valuable adjunct to DSE in the assessment of myocardial viability.
PMID- 10758956
TI - Reperfusion syndrome: relationship of coronary blood flow reserve to left
ventricular function and infarct size.
AB - OBJECTIVES: We tested the hypothesis that the reperfusion syndrome (RS), defined
as an additional elevation of the ST segment upon reperfusion, may be a marker of
microcirculatory reperfusion injury during acute myocardial infarction (AMI).
BACKGROUND: The pathophysiology of the RS is unknown, and its prognostic
implications are controversial. METHODS: Twenty-one patients with an anterior AMI
treated < or =12 h after onset by primary coronary angioplasty (PTCA) were
studied. Coronary velocity reserve (CVR), an index of microcirculatory function,
was measured using a Doppler guidewire. Left ventricular (LV) ejection fraction,
infarct size (percent defect) and LV end-systolic volume index (LVESVi) were
evaluated by radionuclide ventriculography, 201T1 single-photon emission computed
tomography and contrast ventriculography, respectively. RESULTS: Baseline ST
elevation and pain-to-TIMI 3 time were similar in patients with and without RS.
Patients with RS (10/21) had a lower post-PTCA CVR than patients without RS
(median [95% confidence interval]: 1.2 [1-1.3] vs. 1.6 [1.5-1.7], p < 0.005).
Even though predischarge CVR was similar in the two groups, infarct size at six
weeks (26 [21 to 37] vs. 14 [10-17]% 201T1 defect, p = 0.001) and predischarge
LVESVi (45% [40 to 52] vs. 30% [29 to 38] mL/m2, p = 0.001) were larger, and LV
ejection fraction at six weeks (40% [37 to 46] vs. 55% [50 to 60], p = 0.004) was
lower in patients with RS than in patients without RS. CONCLUSIONS: Patients with
RS during primary PTCA for an anterior AMI have a transiently lower CVR than
patients without RS, but sustained LV dysfunction and larger infarct size,
suggesting that RS is a marker of microcirculatory reperfusion injury.
PMID- 10758957
TI - Transmyocardial revascularization with CO2 laser in patients with refractory
angina pectoris. Clinical results from the Norwegian randomized trial.
AB - OBJECTIVES: The purpose of the study was to evaluate clinical effects, exercise
performance and effect on maximal oxygen consumption (MVO2) of transmyocardial
revascularization with CO2-laser (TMR) in patients with refractory angina
pectoris. BACKGROUND: Transmyocardial laser revascularization is a new method to
treat patients with refractory angina pectoris not eligible for conventional
revascularization. Few randomized studies comparing TMR with conventional
treatment have been published. METHODS: One hundred patients with refractory
angina not eligible for conventional revascularization were block-randomized in a
1:1 ratio to receive continued optimal medical treatment (MT) or TMR in addition
to MT. The patients were evaluated at baseline and at three and 12 months with
end points to symptoms, exercise capacity and MVO2. RESULTS: Transmyocardial
laser revascularization resulted in significant relief in angina symptoms after
three and 12 months compared to baseline. Time to chest pain during exercise
increased from baseline by 78 s after three months (p = NS) and 66 s (p < 0.01)
after 12 months in the TMR group, whereas total exercise time and MVO2 were
unchanged. No significant changes were observed in the MT group. Perioperative
mortality was 4%. One year mortality was 12% in the TMR group and 8% in the MT
group (p = NS.) CONCLUSIONS: Transmyocardial laser revascularization was
performed with low perioperative mortality and caused significant symptomatic
improvement, but no improvement in exercise capacity.
PMID- 10758958
TI - Mild hypercholesterolemia and premature heart disease: do the national criteria
underestimate disease risk?
AB - OBJECTIVES: To determine the frequency of hospital admissions for acute coronary
syndrome in young adults and to examine the risk factors that predispose to the
development of premature heart disease. BACKGROUND: Significant coronary heart
disease (CHD) is considered rare in the young adult. Current guidelines do not
recommend treatment of mild cholesterol abnormalities for primary prevention of
CHD in the young. METHODS: This is a large case series of 449 adults (< or =50
years) admitted to the hospital with acute coronary syndrome. A history of
cardiovascular risk factors and lipid profile were recorded. The presence and
extent of CHD were established. RESULTS: Mean patient age was 44 +/- 6 years.
Documented CHD was present in 61% of hospital admissions. Multivariate analysis
revealed that history of hypercholesterolemia, history of smoking and diabetes
were independently associated with premature CHD. The fasting lipid profiles were
only borderline to mildly abnormal. Serum total cholesterol, low-density
lipoprotein (LDL) and triglyceride levels were not different in cases compared
with control subjects. Nearly half (49%) of those with LDL levels of > or =160
mg/dl had only one additional risk factor or none. Despite this, a history of
hypercholesterolemia had independent and incremental value on other risk factors
for the likelihood of premature CHD. CONCLUSIONS: The magnitude of hospital
admissions relating to premature CHD is high. In this population, the presence of
borderline or mild hypercholesterolemia has significant effects on the
development of premature CHD. These observations have significant implications in
the development of guidelines for primary prevention of premature CHD.
PMID- 10758959
TI - Independent association of serum squalene and noncholesterol sterols with
coronary artery disease in postmenopausal women.
AB - OBJECTIVES: The purpose of the study was to investigate whether cholesterol
metabolism is associated with coronary artery disease (CAD) in postmenopausal
women. BACKGROUND: Although hypercholesterolemia, a predominant risk factor of
CAD, is related to cholesterol metabolism, the association between cholesterol
metabolism and CAD is not well known. METHODS: In addition to conventional
coronary risk factors, fasting serum squalene, delta8-cholestenol, desmosterol,
lathosterol (indicators of cholesterol synthesis), cholestanol, campesterol and
sitosterol (indicators of cholesterol absorption) were measured in 48 50- to 55
year-old consecutive women with angiographically verified CAD and in 61 age
matched healthy controls. RESULTS: The coronary patients had elevated ratios of
squalene (p < 0.001), desmosterol (p = 0.005), campesterol (p = 0.028) and
sitosterol (p = 0.022) to cholesterol, but had lower respective lathosterol value
(p = 0.041) compared with the controls, despite similar serum cholesterol levels.
Adjusted for age, body mass index, family history of CAD, smoking, hypertension,
serum triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein
(HDL) cholesterol level and glycosylated hemoglobin A1c% (GHbA1c), the ratios of
squalene (odds ratio, 1.36; 95% confidence interval, 1.17 to 1.57), lathosterol
(0.98; 0.97 to 0.99), campesterol (1.01; 1.00 to 1.01) and sitosterol (1.01; 1.00
to 1.03) were significantly associated with the risk of CAD. In addition, family
history of CAD and GHbA1c% were also independently related to the presence of
CAD. CONCLUSIONS: The results suggest that women with elevated ratios of serum
squalene, campesterol and sitosterol to cholesterol and low respective
lathosterol values have enhanced risk for CAD. Thus, enhanced absorption and
reduced synthesis of cholesterol may be related to coronary atherosclerosis.
PMID- 10758960
TI - Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and
epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City
Heart Study.
AB - OBJECTIVES: We tested the hypothesis that risk of ischemic heart disease (IHD)
differs as a function of apolipoprotein E (APOE) genotype in women and men.
BACKGROUND: Apolipoprotein E genotype influences lipids and lipoproteins and,
therefore, possibly the risk of IHD. METHODS: We genotyped 9,241 white women and
men from the general population and 940 white women and men with IHD. RESULTS:
Test of interaction suggested that APOE genotype may influence risk of IHD
differently in women and men (p = 0.07). After age adjustment, the odds ratio
(OR) for IHD for epsilon32 versus epsilon33 women was 0.57 (95% confidence
interval [CI]: 0.35 to 0.94) while epsilon43 and epsilon44 versus epsilon33 men
had ORs of 1.16 (0.96 to 1.41) and 1.58 (1.01 to 2.45). After adjustment for age
and other conventional cardiovascular risk factors, the equivalent ORs were for
epsilon32 women 0.38 (0.18 to 0.79), for epsilon43 men 1.35 (1.02-1.78) and for
epsilon44 men 1.58 (0.80 to 3.08). Equivalent ORs for epsilon43 and epsilon44
versus epsilon33 women and for epsilon32 versus epsilon33 men were all close to
1.0 and nonsignificant. Of the total risk of IHD relative to the epsilon33
genotype, the fraction attributed to epsilon32 in women was -9%, while the
fractions attributed to epsilon43 and epsilon44 in men were +8% and +2%.
CONCLUSIONS: Relative to epsilon33 individuals, epsilon32 women are protected
while epsilon43 and epsilon44 men are particularly susceptible to IHD.
PMID- 10758961
TI - Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in
patients with coronary vasospasm.
AB - OBJECTIVES: The purpose of this study is to determine whether lipoprotein(a)
(Lp[a]) is an independent risk factor for coronary spasm and occurrence of acute
myocardial infarction (AMI) in patients with coronary spasm. BACKGROUND: Although
elevated serum Lp(a) levels are known to be associated with coronary
atherosclerosis and AMI, the association between the elevated level of this
lipoprotein and coronary spasm remains to be elucidated. METHODS: Serum Lp(a)
levels were measured using a latex immunoassay in 77 patients with coronary spasm
but without a significant (>75%) fixed coronary stenosis, including 16 with prior
myocardial infarction (MI), in 177 patients with a fixed stenosis but without
rest angina, including 114 with prior MI and in 81 control subjects without
coronary artery disease. RESULTS: The serum Lp(a) level in patients with coronary
spasm (median; 17 mg/dl) was higher (p < 0.01) than in control subjects (12
mg/dl) but lower (p < 0.01) than in patients with a fixed stenosis (23 mg/dl).
The incidence of subjects with higher (>25 mg/dl) serum Lp(a) levels was higher
in patients with a fixed stenosis (46%, p < 0.01) but not in patients with
coronary spasm (27%), compared with control subjects (21%). Among the patients
with coronary spasm, the incidence of higher Lp(a) levels was higher in patients
with than in those without a history of prior MI (56% vs. 21%, p < 0.05). The
patients with higher Lp(a) levels had a higher incidence of prior MI than those
without (41% vs. 13%, p < 0.05). The multivariate analysis confirmed that higher
serum Lp(a) level is an independent determinant for prior MI in these patients
(odds ratio, 4.19; 95%, confidence interval, 1.03 to 17.00). CONCLUSIONS:
Elevated serum level of Lp(a) was found to be associated with a history of prior
MI in patients with coronary spasm, suggesting that Lp(a) may play an important
role in the genesis of thrombotic coronary occlusion and the occurrence of AMI
subsequent to coronary spasm.
PMID- 10758962
TI - The effect of resting ST segment depression on the diagnostic characteristics of
the exercise treadmill test.
AB - OBJECTIVES: The aim of this study is to demonstrate the effect of resting ST
segment depression on the diagnostic characteristics of the exercise treadmill
test. BACKGROUND: Previous studies evaluating the effect of resting ST segment
depression on the diagnostic characteristics of exercise treadmill test have been
conducted on relatively small patient groups and based only on visual
electrocardiogram (ECG) analysis. METHODS: A retrospective analysis of data
collected prospectively was performed on consecutive patients referred for
evaluation of chest pain. One thousand two hundred eighty-two patients without a
prior myocardial infarction underwent standard exercise treadmill tests followed
by coronary angiography, with coronary artery disease defined as a 50% narrowing
in at least one major epicardial coronary artery. Sensitivity, specificity,
predictive accuracy and area under the curve of the receiver operating
characteristic (ROC) plots were calculated for patients with and without resting
ST segment depression as determined by visual or computerized analysis of the
baseline ECG. RESULTS: Sensitivity of the exercise treadmill test increased in
206 patients with resting ST segment depression determined by visual ECG analysis
compared with patients without resting ST segment depression (77 +/- 7% vs. 45 +/
4%) and specificity decreased (48 +/- 12% vs. 84 +/- 3%). With computerized
analysis, sensitivity of the treadmill test increased in 349 patients with
resting ST segment depression compared with patients without resting ST segment
depression (71 +/- 6% vs. 42 +/- 4%) and specificity decreased (52 +/- 9% vs. 87
+/- 3%) (p < 0.0001 for all comparisons). There was no significant difference in
the area under the curve of the ROC plots (0.66-0.69) or the predictive accuracy
(62-68%) between the four subgroups. CONCLUSIONS: The diagnostic accuracy and
high sensitivity of the exercise treadmill test in a large cohort of patients
with resting ST segment depression and no prior myocardial infarction support the
initial use of the test for diagnosis of coronary artery disease. The
classification of resting ST segment depression by method of analysis (visual vs.
computerized) did not affect the results.
PMID- 10758963
TI - Feasibility and safety of early exercise testing using the Bruce protocol after
acute myocardial infarction.
AB - OBJECTIVE: To assess the feasibility and safety of exercise testing (ET) using a
Bruce protocol (BPR) within three days of an acute myocardial infarction (AMI)
with the data obtained from a prospectively managed database. BACKGROUND:
Exercise testing after AMI is usually done between days 4 and 6 and often using a
"low-level" protocol. Earlier testing with BPR may allow for efficient triage.
METHODS: Patients were considered for early ET when off intravenous
nitroglycerine with no rest angina, uncontrolled cardiac failure or arrhythmias.
RESULTS: Of 300 consecutive AMI patients who underwent an ET, 216 (72.0%; M =
163, F = 53; age mean 59 +/- 0.8 SEM, range 34 to 83 years) had ET within three
days of admission. There were 124 (57%) negative, 56 (26%) positive and 36 (17%)
indeterminate tests. The maximum heart rate achieved was 116 +/- 1 beats/min
(range 64 to 163), which was 72.2 +/- 0.8% of predicted maximum (86.6% on beta
adrenergic blocking agents at ET; exercise duration = 6.7 +/- 0.2 min). Reasons
for termination: maximum effort-89 (41%); low-level test target (stage III/IV of
BPR)-63 (29%); positive ST segment change-19 (9%); severe chest pain-12 (5.5%);
reaching 90% predicted maximum heart rate-6 (3%); nonsustained ventricular
tachycardia-1 (0.5%); other-26 (12%). Fourteen (6.5%) patients had minor
complications (i.e., drop in systolic pressure, chest pain >5 min) with no
cardiac arrests, AMIs or deaths. After the ET, 87 (40%) patients were discharged
the same day, 73 (34%) the next day. CONCLUSIONS: The majority of ETs after an
AMI can be done using the Bruce protocol within three days of admission with a
very low incidence of complications. This can lead to early triage and potential
cost savings.
PMID- 10758964
TI - Ventricular contraction abnormalities in dilated cardiomyopathy: effect of
biventricular pacing to correct interventricular dyssynchrony.
AB - OBJECTIVE: To measure ventricular contractile synchrony in patients with dilated
cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on
contractile synchrony and ejection fraction. BACKGROUND: Dilated cardiomyopathy
is characterized by abnormal ventricular activation and contraction.
Biventricular pacing may promote a more coordinated ventricular contraction
pattern in these patients. We hypothesized that biventricular pacing would
improve synchrony of right ventricular and left ventricular (RV/LV) contraction,
resulting in improved ventricular ejection fraction. METHODS: Thirteen patients
with DCM and intraventricular conduction delay underwent multiple gated
equilibrium blood pool scintigraphy. Phase image analysis was applied to the
scintigraphic data and mean phase angles computed for the RV and LV. Phase
measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and
during atrial sensed biventricular pacing (BiV). RESULTS: The degree of
interventricular dyssynchrony present in normal sinus rhythm correlated with LV
ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile
synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p =
0.01). The degree of interventricular dyssynchrony present in sinus rhythm
correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p
< 0.001). Left ventricular ejection fraction increased in all thirteen patients
during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated
significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p <
0.001). CONCLUSIONS: Dilated cardiomyopathy with intraventricular conduction
delay is associated with significant interventricular dyssynchrony. Improvements
in interventricular synchrony during biventricular pacing correlate with acute
improvements in LV ejection fraction.
PMID- 10758965
TI - Prolonged recovery of cardiac output after maximal exercise in patients with
chronic heart failure.
AB - OBJECTIVES: The aim of this study was to characterize the kinetics of cardiac
output during recovery from maximal exercise in patients with chronic heart
failure (CHF). BACKGROUND: Recent studies have shown that oxygen uptake kinetics
during recovery from exercise are delayed in patients with CHF. However, the
kinetics of cardiac output during recovery from maximal exercise in CHF has not
been examined. METHODS: Thirty patients with CHF performed maximal upright
ergometer exercise with respiratory gas analysis. Kinetics of oxygen uptake (VO2)
and carbon dioxide output (VCO2) during recovery were characterized by T1/2, the
time to reach 50% of the peak values. Cardiac output was measured at 1-min
intervals during exercise and recovery. Kinetics of cardiac output during
recovery were characterized by the ratios of cardiac output during the first 4
min of recovery to cardiac output at peak exercise. Overshoot of cardiac output
was defined as a further increase in cardiac output at 1 min of recovery above
the cardiac output at peak exercise. RESULTS: Both T1/2 VO2 and T1/2 VCO2
increased as CHF worsened. The ratios of cardiac output during recovery to
cardiac output at peak exercise were significantly correlated with T1/2 VO2 (r =
0.47 to 0.62, p < 0.05) and T1/2 VCO2 (r = 0.40 to 0.70, p < 0.05). There was a
negative correlation between cardiac index at peak exercise and both T1/2 VO2 (r
= -0.65, p < 0.001) and T1/2 VCO2 (r = -0.60, p < 0.001). Overshoot of cardiac
output was recognized in 11 of 30 patients. Cardiac index at peak exercise was
significantly lower in patients with overshoot (4.5 +/- 0.9 L/min/m2) than in
those without overshoot (6.1 +/- 2.1 L/min/m2, p < 0.05). However, because of a
continued increase in cardiac output at 1 min of recovery in patients with
overshoot, there were no differences in cardiac index after the first minute of
recovery. Heart rate at peak exercise and recovery of heart rate did not differ
between these groups. Overshoot of cardiac output was caused by a rebound
increase in stroke volume which was due to a reduction in systemic vascular
resistance. CONCLUSIONS: Prolonged kinetics of VO2 or VCO2 during recovery from
maximal exercise represent impairment of circulatory response to exercise and
delayed recovery of cardiac output after exercise. Overshoot of cardiac output at
1 min of recovery was characteristic of severe CHF with poor cardiac output
response to exercise.
PMID- 10758966
TI - Echocardiographic predictors of clinical outcome in patients with left
ventricular dysfunction enrolled in the SOLVD registry and trials: significance
of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction.
AB - OBJECTIVES: To assess the relation of left ventricular (LV) and left atrial (LA)
dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of
patients with LV dysfunction enrolled in the Studies of Left Ventricular
Dysfunction (SOLVD) Registry and Trials. BACKGROUND: Data are lacking on the
relation of LV mass to prognosis in patients with LV dysfunction and on the
interaction of LV mass with other measurements of LV size and function as they
relate to clinical outcome. METHODS: A cohort of 1,172 patients enrolled in the
SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic
measurements and follow-up for 1 year. RESULTS: After adjusting for age, New York
Heart Association (NYHA) functional class, Trial vs. Registry and ischemic
etiology, a 1-SD difference in EF was inversely associated with an increased risk
of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization
(risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were
adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and
ischemic etiology. A 1-SD difference in LV mass was associated with increased
risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio
of 1.17, p = 0.018). Similar results were observed with the LA dimension
(mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p <
0.04). Likewise, LV mass > or =298 g and LA dimension > or =4.17 cm were
associated with increased risk of death and CV hospitalization. An end-systolic
dimension >5.0 cm was associated with increased mortality only. A protective
effect of EF was noted in patients with LV mass > or =298 g (those in the group
with EF >35% had lower mortality) but not in the group with LV mass <298 g.
CONCLUSIONS: In patients with LV dysfunction enrolled in the SOLVD Registry and
Trials, increasing levels of hypertrophy are associated with adverse events. A
protective effect of EF was noted in patients with LV mass > or =298 g (those in
the group with EF >35% fared better) but not in the group with LV mass <298 g.
These data support the development and use of drugs that can inhibit hypertrophy
or alter its characteristics.
PMID- 10758967
TI - Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new
health status measure for heart failure.
AB - OBJECTIVES: To create a valid, sensitive, disease-specific health status measure
for patients with congestive heart failure (CHF). BACKGROUND: Quantifying health
status is becoming increasingly important for CHF. The Kansas City Cardiomyopathy
Questionnaire (KCCQ) is a new, self-administered, 23-item questionnaire that
quantifies physical limitations, symptoms, self-efficacy, social interference and
quality of life. METHODS: To establish the performance characteristics of the
KCCQ, two distinct patient cohorts were recruited: 70 stable and 59 decompensated
CHF patients with ejection fractions of <40. Upon entry into the study, patients
were administered the KCCQ, the Minnesota Living with Heart Failure Questionnaire
and the Short Form-36 (SF-36). Questionnaires were repeated three months later.
RESULTS: Convergent validity of each KCCQ domain was documented by comparison
with available criterion standards (r = 0.46 to 0.74; p < 0.001 for all). Among
those with stable CHF who remained stable by predefined criteria (n = 39),
minimal changes in KCCQ domains were detected over three months of observation
(mean change = 0.8 to 4.0 points, p = NS for all). In contrast, large changes in
score were observed among patients whose decompensated CHF improved three months
later (n = 39; mean change = 15.4 to 40.4 points, p < 0.01 for all). The
sensitivity of the KCCQwas substantially greater than that of the Minnesota
Living with Heart Failure and the SF-36 questionnaires. CONCLUSIONS: The KCCQis a
valid, reliable and responsive health status measure for patients with CHF and
may serve as a clinically meaningful outcome in cardiovascular research, patient
management and quality assessment.
PMID- 10758968
TI - Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and
Doppler-echocardiographic study.
AB - OBJECTIVES: The objective was to determine the independent association between
atrial fibrillation (A-Fib) and activation of natriuretic peptides. BACKGROUND:
The association of A-Fib with activation of N-terminal atrial and brain
natriuretic peptides (N-ANPs and BNPs, respectively) is uncertain but of great
importance for the diagnostic utilization of natriuretic peptides. This
uncertainty is related to the lack of appropriate controls, with left ventricular
(LV) and atrial overload similar to A-Fib. METHODS: We prospectively measured N
terminal atrial and BNPs and endothelin-1 levels in 100 patients and 14 age- and
gender-matched control subjects. The 32 patients with A-Fib were compared with 68
patients in sinus rhythm and similar LV and atrial overload (due to mitral
regurgitation or LV dysfunction) measured simultaneously with hormonal levels
with comprehensive Doppler echocardiography. RESULTS: Patients with A-Fib
compared with those in sinus rhythm had similar symptoms, comorbid conditions,
cardioactive medications, pulmonary pressure, left atrial volume, and LV ejection
fraction and filling characteristics but demonstrated higher N-ANP levels (2,613
+/- 1,681 vs. 1,654 +/- 1,323 pg/ml, p = 0.007) even after adjustment for the
underlying cardiac disease (p < 0.0001). Conversely, BNP levels were similar in
both groups (165 +/- 163 vs. 160 +/- 269 pg/ml, p = 0.9). In multivariate
analysis, a higher N-ANP level was associated with A-Fib (p = 0.0003), symptom
class (p < 0.0001) and endothelin-1 level (p = 0.032) independently of left
atrial volume and LV ejection fraction. Conversely, BNP showed no independent
association with and was most strongly associated with LV ejection fraction (p <
0.0001). CONCLUSIONS: Atrial fibrillation is an independent determinant of higher
N-ANP levels and blurs its association with LV dysfunction. Conversely, the BNP
is not independently associated with A-Fib and is strongly determined by LV
dysfunction, for which it is an independent marker.
PMID- 10758969
TI - Depressed heart rate variability identifies postinfarction patients who might
benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The
European Myocardial Infarct Amiodarone Trial).
AB - OBJECTIVES: This substudy tested a prospective hypothesis that European
Myocardial Infarct Amiodarone Trial (EMIAT) patients with depressed heart rate
variability (HRV) benefit from amiodarone treatment. BACKGROUND: The EMIAT
randomized 1,486 survivors of acute myocardial infarction (MI) aged < or =75
years with left ventricular ejection fraction (LVEF) < or =40% to amiodarone or
placebo. Despite a reduction of arrhythmic mortality on amiodarone, all-cause
mortality was not changed. METHODS: Heart rate variability was assessed from
prerandomization 24-h Holter tapes in 1,216 patients (606 on amiodarone). Two
definitions of depressed HRV were used: standard deviation of normal to normal
intervals (SDNN) < or =50 ms and HRV index < or =20 units. The survival of
patients with depressed HRV was compared in the placebo and amiodarone arms. A
retrospective analysis investigated the prospective dichotomy limits. All tests
were repeated in five subpopulations: patients with first MI, patients on beta
adrenergic blocking agents, patients with LVEF < or =30%, patients with Holter
arrhythmia and patients with baseline heart rate > or =75 beats/min. RESULTS:
Centralized Holter processing produced artificially high SDNN but accurate HRV
index values. Heart rate variability index was < or =20 U in 363 (29.9%) patients
(183 on amiodarone) with all-cause mortality 22.8% on placebo and 17.5% on
amiodarone (23.2% reduction, p = 0.24) and cardiac arrhythmic mortality 12.8% on
placebo and 4.4% on amiodarone (66% reduction, p = 0.0054). Among patients with
prospectively defined depressed HRV, the largest reduction of all-cause mortality
was in patients with first MI (placebo 17.9%, amiodarone 10.3%, 42.5% reduction,
p = 0.079) and in patients with heart rate < or =75 beats/min (placebo 29.0%,
amiodarone 19.3%, 33.7% reduction, p = 0.075). Among patients with first MI and
depressed HRV, amiodarone treatment was an independent predictor of survival in a
multivariate Cox analysis. The retrospective analysis found a larger reduction of
mortality on amiodarone in 313 (25.7%) patients with HRV index < or =19 U: 23.9%
on placebo and 17.1% on amiodarone (28.4% reduction, p = 0.15). This was more
expressed in patients with first MI: 49.4% mortality reduction on amiodarone (p =
0.046), on beta-blockers: 69.0% reduction (p = 0.047) and with heart rate > or
=75 beats/min: 37.9% reduction (p = 0.054). CONCLUSION: Measurement of HRV in a
large set of centrally processed Holter recordings is feasible with robust
methods of assessment. Patients with LVEF < or =40% and depressed HRV benefit
from prophylactic antiarrhythmic treatment with amiodarone. However, this finding
needs confirmation in an independent data set before clinical practice is
changed.
PMID- 10758970
TI - Body surface mapping of counterclockwise and clockwise typical atrial flutter: a
comparative analysis with endocardial activation sequence mapping.
AB - OBJECTIVES: This study was directed at developing spatial 62-lead
electrocardiogram (ECG) criteria for classification of counterclockwise (CCW) and
clockwise (CW) typical atrial flutter (Fl) in patients with and without
structural heart disease. BACKGROUND: Electrocardiographic classification of CCW
and CW typical atrial Fl is frequently hampered by inaccurate and inconclusive
scalar waveform analysis of the 12-lead ECG. METHODS: Electrocardiogram signals
from 62 torso sites and multisite endocardial recordings were obtained during CCW
typical atrial Fl (12 patients), CW typical Fl (3 patients), both forms of
typical Fl (4 patients) and CCW typical and atypical atrial Fl (1 patient). All
the Fl wave episodes were divided into two or three successive time periods
showing stable potential distributions from which integral maps were computed.
RESULTS: The initial, intermediate and terminal CCW Fl wave map patterns
coincided with: 1) caudocranial activation of the right atrial septum and
proximal-to-distal coronary sinus activation, 2) craniocaudal activation of the
right atrial free wall, and 3) activation of the lateral part of the
subeustachian isthmus, respectively. The initial, intermediate and terminal CW Fl
wave map patterns corresponded with : 1) craniocaudal right atrial septal
activation, 2) activation of the subeustachian isthmus and proximal-to-distal
coronary sinus activation, and 3) caudocranial right atrial free wall activation,
respectively. A reference set of typical CCW and CW mean integral maps of the
three successive Fl wave periods was computed after establishing a high degree of
quantitative interpatient integral map pattern correspondence irrespective of the
presence or absence of organic heart disease. CONCLUSIONS: The 62-lead ECG of CCW
and CW typical atrial Fl in man is characterized by a stereotypical spatial
voltage distribution that can be directly related to the underlying activation
sequence and is highly specific to the direction of Fl wave rotation. The mean
CCW and CW Fl wave integral maps present a unique reference set for improved
clinical detection and classification of typical atrial Fl.
PMID- 10758971
TI - Catastrophic outcomes of noncardiac surgery soon after coronary stenting.
AB - OBJECTIVES: To assess the clinical course of patients who have undergone coronary
stent placement less than six weeks before noncardiac surgery. BACKGROUND:
Surgical and percutaneous transluminal coronary angioplasty revascularization
performed before high-risk noncardiac surgery is expected to reduce perioperative
cardiac morbidity and mortality. Perioperative and postoperative complications in
patients who have undergone coronary stenting before a noncardiac surgery have
not been studied. METHODS: Forty patients who underwent coronary stent placement
less than six weeks before noncardiac surgery requiring a general anesthesia were
included in the study (1-39 days, average: 13 days). The records were screened
for the occurrence of adverse clinical events, including myocardial infarction,
stent thrombosis, peri- and postoperative bleeding and death. RESULTS: In 40
consecutive patients meeting the study criteria, there were seven myocardial
infarctions (MIs), 11 major bleeding episodes and eight deaths. All deaths and
MIs, as well as 8/11 bleeding episodes, occurred in patients subjected to surgery
fewer than 14 days from stenting. Four patients expired after undergoing surgery
one day after stenting. Based on electrocardiogram, enzymatic and angiographic
evidence, stent thrombosis accounted for most of the fatal events. The time
between stenting and surgery appeared to be the main determinant of outcome.
CONCLUSIONS: Postponing elective noncardiac surgery for two to four weeks after
coronary stenting should permit completion of the mandatory antiplatelet regimen,
thereby reducing the risk of stent thrombosis and bleeding complications.
PMID- 10758972
TI - Percutaneous mitral commissurotomy for restenosis after surgical commissurotomy:
late efficacy and implications for patient selection.
AB - OBJECTIVES: The results of percutaneous mitral commissurotomy were assessed in
patients with restenosis after surgical commissurotomy. BACKGROUND: Balloon
dilation is feasible in patients with restenosis after surgical commissurotomy,
but little is known about its late efficacy. METHODS: We studied 232 patients who
had undergone percutaneous mitral commissurotomy a mean of 16 +/- 8 years after
surgical commissurotomy. Mean age was 47 +/- 14 years; 81 patients (35%) had
valve calcification. All patients had restenosis with bilateral commissural
fusion as assessed by echocardiography. Technical failure occurred in 9 patients
and the procedure used a single balloon in 7 patients, a double balloon in 95,
and the Inoue balloon in 121. RESULTS: Complications were death in 1 patient
(0.4%) and mitral regurgitation >2/4 in 10 (4%); 191 patients (82%) had good
immediate results (valve area > or =1.5 cm2 without regurgitation >2/4).
Predictors of poor immediate results in multivariate analysis were older age (p <
0.001), lower initial valve area (p = 0.01) and the use of the double-balloon
technique (p = 0.015). In the 175 patients who underwent follow-up, 8-year
survival without operation and in New York Heart Association class I or II was 48
+/- 5%, and 58 +/- 6% after good immediate results. In this latter group, poor
late functional results were predicted by higher cardiothoracic index (p <
0.0001), previous open-heart commissurotomy (p = 0.05) and lower final valve area
(p < 0.0001) in a multivariate Cox model. CONCLUSIONS: Percutaneous mitral
commissurotomy is safe and provides good immediate results in selected patients
with restenosis after surgical commissurotomy. After good immediate results, the
conditions of more than half of the patients remained improved at 8 years,
enabling reoperation to be deferred.
PMID- 10758973
TI - Ultrasonographic demonstration of manipulation-related aortic injuries after
cardiac surgery.
AB - OBJECTIVES: This study was performed to evaluate the frequency and risk factors
associated with new aortal lesions induced by surgical manipulation and their
correlation with postoperative stroke. BACKGROUND: Little is known about the
causative mechanism of intraoperative atheroembolism after cardiac surgery.
METHODS: Epiaortic echocardiography was performed before cannulation and after
decannulation in 472 patients undergoing cardiac surgery with extracorporeal
circulation. RESULTS: A new lesion in the ascending aortal intima was identified
in 16 patients (3.4%) after decannulation. New lesions were severe, with mobile
lesions or disruption of the intima in 10 patients. Six of the severe lesions
were related to aortic damping and the other four to aortic cannulation. Three
patients in this group had postoperative stroke. Univariate analysis identified
only the maximal thickness of the atheroma near the aorta manipulation site as a
predictor of new lesions. The incidence of new lesions was 11.8% if the atheroma
was approximately 3 to 4 mm thick and as high as 33.3% if the atheroma was >4 mm,
but only 0.8% when it was <3 mm. Total 10 patients (2.1%) sustained neurological
complications. Arteriosclerosis obliterans, atherosclerosis of the aorta and new
mobile lesions were identified as predictors of strokes. CONCLUSIONS: This study
demonstrated an association between new lesions created by surgical maneuvers and
postoperative stroke. Embolic strokes were more likely to occur if new lesions
were complicated with intimal disruption, especially of the mobile type.
Modifications in surgical procedures will be needed if thick plaque (especially
>4 mm) is noted near the manipulation site.
PMID- 10758974
TI - Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of
recurrent neurological events following transcatheter device placement.
AB - OBJECTIVES: We report the largest and the longest follow-up to date of patients
who underwent transcatheter patent foramen ovale (PFO) closure for paradoxical
embolism. BACKGROUND: Closure of a PFO has been proposed as an alternative to
anticoagulation in patients with presumed paradoxical emboli. METHODS: Data were
collected for patients following PFO closure with the Clamshell, CardioSEAL or
Buttoned Devices at two institutions. RESULTS: There were 63 patients (46 +/- 18
years) with a follow-up of 2.6 +/- 2.4 years. Fifty-four (86%) had effective
closure of the foramen ovale (trivial or no residual shunt by echocardiography)
while seven (11%) had mild and two (3%) had moderate residual shunting. There
were four deaths (leukemia, pulmonary embolism, sepsis following a hip fracture
and lung cancer). There were four recurrent embolic neurological events following
device placement: one stroke and three transient events. The stroke occurred in a
56-year-old patient six months following device placement. A follow-up
transesophageal echocardiogram showed a well seated device without residual
shunting. Two of the four events were associated with suboptimal device
performance (one patient had a significant residual shunt and a second patient
had a "friction lesion" in the left atrial wall associated with a displaced
fractured device arm). The risk of recurrent stroke or transient neurological
event following device placement was 3.2% per year for all patients. CONCLUSION:
Transcatheter closure of PFO is an alternative therapy for paradoxical emboli in
selected patients. Improved device performance may reduce the risk of recurrent
neurological events. Further studies are needed to identify patients most likely
to benefit from this intervention.
PMID- 10758975
TI - Reinterventions after repair of common arterial trunk in neonates and young
infants.
AB - OBJECTIVES: To determine rates of reintervention after repair of common arterial
trunk in the neonatal and early infant periods. BACKGROUND: With improving
success in the early treatment of common arterial trunk, the need for
reinterventional procedures in older children, adolescents and adults will become
an increasingly widespread concern in the treatment of these patients. METHODS:
We reviewed our experience with 159 infants younger than four months of age who
underwent complete primary repair of common arterial trunk at our institution
from 1975 to 1998, with a focus on postoperative reinterventions. RESULTS: Of 128
early survivors, 40 underwent early reinterventions for persistent mediastinal
bleeding or other reasons. During a median follow-up of 98 months (range, 2 to
235 months), 121 reinterventions were performed in 81 patients. Actuarial freedom
from reintervention was 50% at four years, and freedom from a second
reintervention was 75% at 11 years. A total of 92 conduit reinterventions were
performed in 75 patients, with a single reintervention in 61 patients, 2
reinterventions in 11 patients and 3 reinterventions in 3 patients. Freedom from
a first conduit reintervention was 45% at five years. The only independent
variable predictive of a longer time to first conduit replacement was use of an
allograft conduit at the original repair (p = 0.05), despite the significantly
younger age of patients receiving an allograft conduit (p < 0.001).
Reintervention on the truncal valve was performed on 22 occasions in 19 patients,
including 21 valve replacements in 18 patients and repair in 1, with a freedom
from truncal valve reintervention of 83% at 10 years. Surgical (n = 29) or
balloon (n = 12) reintervention for pulmonary artery stenosis was performed 41
times in 32 patients. Closure of a residual ventricular septal defect was
required in 13 patients, all of whom underwent closure originally with a
continuous suture technique. Eight of 16 late deaths were related to
reintervention. CONCLUSIONS: The burden of reintervention after repair of common
arterial trunk in early infancy is high. Although conduit reintervention is
inevitable, efforts should be made at the time of the initial repair to minimize
factors leading to reintervention, including prevention of branch pulmonary
artery stenosis and residual interventricular communications.
PMID- 10758976
TI - Evaluation of the effects of intramyocardial injection of DNA expressing vascular
endothelial growth factor (VEGF) in a myocardial infarction model in the rat-
angiogenesis and angioma formation.
AB - OBJECTIVES: The effects of direct intramyocardial injection of the plasmid
encoding vascular endothelial growth factor (phVEGF165) in the border zone of
myocardial infarct tissue in rat hearts were investigated. BACKGROUND:
Controversy exists concerning the ability of VEGF to induce angiogenesis and
enhance coronary flow in the myocardium. METHODS: Sprague-Dawley rats received a
ligation of the left coronary artery to induce myocardial infarction (MI). At
33.1 +/- 6.5 days, the rats were injected with phVEGF165 at one location and
control plasmid at a second location (500 microg DNA, n = 24) or saline (n = 16).
After 33.1 +/- 5.7 days, the hearts were excised for macroscopic and histologic
analysis. Regional blood flow ratios were measured in 18 rats by radioactive
microspheres. RESULTS: phVEGF165-treated sites showed macroscopic angioma-like
structures at the injection site while control DNA and saline injection sites did
not. By histology, 21/24 phVEGF165-treated hearts showed increased focal
epicardial blood vessel density and angioma-like formation. Quantitative
morphometric evaluation in 20 phVEGF165-treated hearts revealed 44.4 +/- 10.5
vascular structures per field in phVEGF165-treated hearts versus 21.4 +/- 4.7 in
control DNA injection sites (p < 0.05). Regional myocardial blood flow ratios
between the injection site and noninfarcted area did not demonstrate any
difference between phVEGF,165-treated hearts (0.9 +/- 0.2) and saline-treated
hearts (0.7 +/- 0.1). CONCLUSIONS: Injection of DNA for VEGF in the border zone
of MI in rat hearts induced angiogenesis. Angioma formation at the injection
sites did not appear to contribute to regional myocardial blood flow, which may
be a limitation of gene therapy for this application.
PMID- 10758977
TI - Inhibition of neointima formation by tranilast in pig coronary arteries after
balloon angioplasty and stent implantation.
AB - OBJECTIVES: We evaluated the effect of orally administered tranilast, N-(3,4
dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes
after angioplasty or stent implantation in pig coronary arteries. BACKGROUND:
Tranilast, which has antikeloid and antiallergic properties and therefore may
modulate the fibrotic and inflammatory tissue responses to angioplasty and
stenting, has been shown to inhibit angiographic restenosis in small clinical
trials. However, its effect on histomorphometric changes in coronary arteries
after angioplasty and stenting is unknown. METHODS: Following initial
pharmacokinetic studies in two pigs to determine desirable plasma levels of
orally administered tranilast, 36 crossbred juvenile pigs were randomized to
placebo or tranilast before undergoing balloon angioplasty in both the left
anterior descending and left circumflex plus stent implantation in the right
coronary artery. Oral tranilast was administered at 3 g/day starting 3 days
before coronary injury and continued for 28 days until euthanasia. Injured
vessels were harvested and sections analyzed by computer-assisted microscopic
planimetry. RESULTS: In balloon-injured vessels, tranilast was associated with a
37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs.
0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized
to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries,
neointimal area normalized to injury score was 32% lower in the tranilast-treated
group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01).
CONCLUSIONS: In pig coronary arteries, tranilast was associated with a reduction
in neointima formation and adventitial reaction after balloon injury. In stented
vessels, tranilast was associated with a reduction in neointima formation
normalized to injury score.
PMID- 10758978
TI - Cytokine-induced nitric oxide production inhibits mitochondrial energy production
and impairs contractile function in rat cardiac myocytes.
AB - OBJECTIVES: The present study examined whether nitric oxide (NO) produced by
inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy
metabolism and impair cell function in interleukin (IL)-1beta,-stimulated cardiac
myocytes. BACKGROUND: Recent reports have indicated that excessive production of
NO induced by cytokines can disrupt cellular energy balance through the
inhibition of mitochondrial respiration in a variety of cells. However, it is
still largely uncertain whether the NO-induced energy depletion affects
myocardial contractility. METHODS: Primary cultures of rat neonatal cardiac
myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured
using Griess reagent. RESULTS: Treatment with IL-1beta (10 ng/ml) increased
myocyte production of NOx in a time-dependent manner. The myocytes showed a
concomitant significant increase in glucose consumption, a marked increase in
lactate production, and a significant decrease in cellular ATP (adenosine 5'
triphosphate). These metabolic changes were blocked by co-incubation with N(G)
monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium
nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose
dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo
cGMP), a cGMP donor, had no effect on these parameters. The activities of the
mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQreductase,
but not oligomycin-sensitive ATPase, were significantly inhibited in the IL
1beta, or SNP-treated myocytes. Both IL-1beta and SNP significantly elevated
maximum diastolic potential, reduced peak calcium current (I(Ca)), and lowered
contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein
kinase, did not block the electrophysiological and contractility effects.
CONCLUSIONS: These data suggest that IL-1beta-induced NO production in cardiac
myocytes lowers energy production and myocardial contractility through a direct
attack on the mitochondria, rather than through cGMP-mediated pathways.
PMID- 10758979
TI - Coronary vascular responses to short-term cocaine administration in conscious
baboons compared with dogs.
AB - OBJECTIVES: Cardiovascular complications of cocaine use represent an important
clinical problem, yet the mechanisms by which cocaine predisposes to myocardial
ischemia are poorly understood. BACKGROUND: The effects of cocaine on the
coronary circulation have been studied extensively in experimental animal models,
but have failed to recapitulate the clinical findings reported in humans who use
cocaine. METHODS: We studied 12 conscious, chronically instrumented dogs and 5
conscious, chronically instrumented baboons to determine whether there were
important species differences in the response to cocaine. RESULTS: Comparable
doses of intravenous cocaine caused similar increases in left ventricular
systolic, diastolic and mean arterial pressure in the two species. However, the
peak coronary blood flow response in baboons (+8 +/- 3 from 47 +/- 6 ml/min) was
less compared with dogs (+15 +/- 4 from 41 +/- 4 ml/min), while the coronary
vascular resistance response was greater in baboons (+0.60 +/- 0.09 from 1.94 +/-
0.09 mm Hg/ml/mm) compared with dogs (+0.35 +/- 0.09 from 2.24 +/- 0.10 mm
Hg/ml/min). Although myocardial oxygen consumption responses were similar between
species, there was a significant difference (p < 0.05) in oxygen delivery between
baboons (+164 +/- 47 from 705 +/- 59 ml of oxygen per minute) and dogs (+397 +/
51 from 656 +/- 33 ml of oxygen per minute) that was attributable to a
significant (p < 0.05) increase in hemoglobin concentration in dogs (+2.1 +/- 0.5
g/dl) that was not observed in baboons. Consequently, cocaine caused a
significant increase in myocardial oxygen extraction and decreased coronary sinus
pH in baboons, but not dogs. CONCLUSIONS: Cocaine caused greater coronary
vasoconstriction and greater requirements for oxygen extraction in baboons
compared with dogs.
PMID- 10758980
TI - Ingenuous interpretation of elevated blood levels of macromolecular markers of
myocardial injury: a recipe for confusion.
AB - Several assumptions about elevations of macromolecular markers of myocardial
injury in blood require critical consideration. The dichotomy of modest,
persistent elevations of troponins I and T as prognostic factors in patients with
unstable angina and absent elevations of isoenzymes of creatine kinase is
presently unexplained. Factors influencing the appearance of macromolecular
markers of myocardial injury in blood are considered, including the need to
estimate baseline values, to consider elevations as deviations from baseline
rather than simply points within a distribution of baseline values in normal
subjects, to recognize operative biochemical and physiologic determinants of
marker release from injured myocytes and washout and to take into account the
influence of apoptosis. Elucidation and consideration of mechanisms underlying
the appearance of specific macromolecular markers in blood appear likely to
improve diagnosis and explain the prognostic power of the troponins in patients
with unstable angina. Detection of proteolytic breakdown products of troponins in
blood is likely to explain the modest, persistent elevations seen in some
patients with unstable angina and their prognostic implications.
PMID- 10758981
TI - Poverty and health.
PMID- 10758982
TI - President's page: predicting the future.
PMID- 10758983
TI - Prognostic value of heart rate variability in idiopathic dilated cardiomyopathy.
PMID- 10758984
TI - Coronary flow reserve assessment from average peak velocity profiles alone must
be judged with caution.
PMID- 10758985
TI - Routine elective cesarean section is not justified for women with mechanical
heart valves.
PMID- 10758986
TI - Introduction and background: the International Angiographic Compression study.
PMID- 10758987
TI - American College of Cardiology/European Society of Cardiology International Study
of Angiographic Data Compression Phase I: The effect of lossy data compression on
recognition of diagnostic features in digital coronary angiography.
AB - OBJECTIVES: This study intended to determine the effect of varying degrees of
lossy Joint Photographic Experts Group (JPEG) compression on detection of
coronary angiographic features. BACKGROUND: Compression of digital coronary
angiograms facilitates playback of images and decreases cost. There are little
data on the effect of compression on the accuracy of coronary angiography.
METHODS: At six centers, 71 angiographers each reviewed a set of 100 angiographic
sequences. The 100 sequences were divided into four, 25-sequence subsets. Each
subset of 25 was displayed either as original images or at one of three
compression ratios (CRs) (6:1, 10:1 or 16:1). The effect of lossy compression on
the sensitivity and specificity for detection of diagnostic features was
determined. The effect of compression on subjective measures of image quality
graded by the angiographers was also examined. RESULTS: Lossy compression at a
ratio of 16:1 decreased the sensitivity for the detection of diagnostic features
(76% vs. 80% p = 0.004). The largest effect was in the detection of calcification
(52% vs. 63% at 16:1 compression vs. original images, p < 0.001). Subjective
indicators of image quality indicated a reduction in confidence in interpretation
at CRs of 10:1 and 16:1. CONCLUSIONS: With increased ratios of lossy compression,
a degradation of digital coronary angiograms occurs that results in decreased
diagnostic accuracy. The sensitivity for detection of common diagnostic features
was decreased, and subjective assessment of image quality was impaired. Caution
is warranted in the interpretation of coronary angiograms that have been
subjected to lossy JPEG compression beyond a ratio of 6:1.
PMID- 10758988
TI - American College of Cardiology/European Society of Cardiolgoy International Study
of Angiographic Data Compression Phase II: the effects of varying JPEG data
compression levels on the quantitative assessment of the degree of stenosis in
digital coronary angiography. Joint Photographic Experts Group.
AB - OBJECTIVES: This report describes whether lossy Joint Photographic Experts Group
(UPEG) image compression/decompression has an effect on the quantitative
assessment of vessel sizes by state-of-the-art quantitative coronary
arteriography (QCA). BACKGROUND: The Digital Imaging and Communications in
Medicine (DICOM) digital exchange standard for angiocardiography prescribes that
images must be stored loss free, thereby limiting JPEG compression to a maximum
ratio of 2:1. For practical purposes it would be desirable to increase the
compression ratio (CR), which would lead to lossy image compression. METHODS: A
series of 48 obstructed coronary segments were compressed/decompressed at CR 1:1
(uncompressed), 6:1, 10:1 and 16:1 and analyzed blindly and in random order using
the QCA-CMS analytical software. Similar catheter and vessel start- and end
points were used within each image quartet, respectively. All measurements were
repeated after several weeks using newly selected start- and end-points. Three
different sub-analyses were carried out: the intra-observer, fixed inter
compression and variable inter-compression analyses, with increasing potential
error sources, respectively. RESULTS: The intra-observer analysis showed
significant systematic and random errors in the calibration factor at JPEG CR
10:1. The fixed inter-compression analysis demonstrated systematic errors in the
calibration factor and recalculated vessel parameter results at CR 16:1 and for
the random errors at CR 10:1 and 16:1. The variable inter-compression analysis
presented systematic and random errors in the calibration factor and recalculated
parameter results at CR 10:1 and 16:1. Any negative effect at CR 6:1 was found
only for the calibration factor of the variable inter-compression analysis, which
did not show up in the final vessel measurements. CONCLUSIONS: Compression ratios
of 10:1 and 16:1 affected the QCA results negatively and therefore should not be
used in clinical research studies.
PMID- 10758989
TI - American College of Cardiology/European Society of Cardiology International Study
of Angiographic Data Compression Phase III: measurement of image quality
differences at varying levels of data compression.
AB - OBJECTIVES: We sought to investigate up to which level of Joint Photographic
Experts Group JPEG) data compression the perceived image quality and the
detection of diagnostic features remain equivalent to the quality and
detectability found in uncompressed coronary angiograms. BACKGROUND: Digital
coronary angiograms represent an enormous amount of data and therefore require
costly computerized communication and archiving systems. Earlier studies on the
viability of medical image compression were not fully conclusive. METHODS: Twenty
one raters evaluated sets of 91 cine runs. Uncompressed and compressed versions
of the images were presented side by side on one monitor, and image quality
differences were assessed on a scale featuring six scores. In addition, the
raters had to detect pre-defined clinical features. Compression ratios (CR) were
6:1, 10:1 and 16:1. Statistical evaluation was based on descriptive statistics
and on the equivalence t-test. RESULTS: At the lowest CR (CR 6:1), there was
already a small (15%) increase in assigning the aesthetic quality score
indicating "quality difference is barely discernible-the images are equivalent."
At CR 10:1 and CR 16:1, close to 10% and 55%, respectively, of the compressed
images were rated to be "clearly degraded, but still adequate for clinical use"
or worse. Concerning diagnostic features, at CR 10:1 and CR 16:1 the error rate
was 9.6% and 13.1%, respectively, compared with 9% for the baseline error rate in
uncompressed images. CONCLUSIONS: Compression at CR 6:1 provides equivalence with
the original cine runs. If CR 16:1 were used, one would have to tolerate a
significant increase in the diagnostic error rate over the baseline error rate.
At CR 10:1, intermediate results were obtained.
PMID- 10758990
TI - Sensorineural hearing loss among sickle cell disease patients from southern
Brazil.
AB - PURPOSE: A case-control study was done to confirm the higher prevalence of
sensorineural hearing loss (SNHL) among sickle cell patients (HbSS) from southern
Brazil. PATIENTS AND METHODS: Twenty-eight patients and 28 matched normal
controls were studied. Besides complete anamneses and physical otolaryngological
examination, all individuals had audiometric and tympanometric testings to
determine the presence of SNHL or middle ear problems. The only significant
difference between groups was the presence of a positive history of otologic
symptoms (hearing loss, dizziness or tinnitus) and neurological sequelae in the
HbSS patients. RESULTS: Six patients (21.4%) presented with SNHL compared with
one control (3.6%) (Fisher's one-tailed P = .05; OR, 7.36 (95% CI, 0.82, 65.83).
The average age of HbSS diagnosis was higher among the patients with SNHL (10
years +/- 8.3) than those without SNHL (5.43 years +/- 5.65), but this was not
significant (analysis of variance P > .05). More patients 25 years and older on
the examination date had SNHL than younger patients (Fisher's 2-tailed P < .05).
Sixty-seven percent of the patients with SNHL had alterations in the acoustic
reflex, and a surprising 27% of the patients without NSHL also presented with
some elevation or an absence of acoustic reflex. CONCLUSIONS: These data indicate
that patients with HbSS from southern Brazil are more predisposed to the
development of sensorineural hearing problems than the general population.
PMID- 10758991
TI - Epstein-Barr virus early ribonucleic acids as a diagnostic adjunct for relapsed
metastatic tumors in patients with cured primary undifferentiated nasopharyngeal
carcinoma.
AB - PURPOSE: Epstein-Barr virus (EBV) has been consistently shown to be associated
with undifferentiated nasopharyngeal carcinoma (NPC). In this article, the
authors attempt to detect Epstein-Barr virus in distant relapsed metastatic sites
in undifferentiated NPC patients with cured primary cancer. MATERIALS AND
METHODS: In situ hybridization (ISH) technique is a reliable method to detect EBV
early RNAs (EBERs) within NPC cells. We used a nonisotopical ISH technique to
examine the presence of EBERs in paraffin-embedded tissues obtained from 1 paired
specimen of primary NPC and its metastatic counterpart at liver and 2 metastatic
specimens of retroperitoneal lymph nodes and bone. RESULTS: All the primary
lesions and the metastatic tumors of NPC with undifferentiated histology
contained EBERs that could be clearly detected in the nuclei of cancer cells.
CONCLUSIONS: This article shows that EBERs can be successfully detected in cells
of the distant relapsed metastatic sites. These results suggest that this
nonisotopical ISH method of EBERs can be potentially used to diagnose NPC
patients developing distant relapsed metastatic lesions with cured primary cancer
early. It can offer quick information as to institute suitable salvage
chemotherapy for these patients.
PMID- 10758992
TI - Hemilaryngeal transplantation in the canine model: technique and implications.
AB - PURPOSE: There is no ideal method for reconstruction of hemilaryngeal defects
because there is no autologous flap or graft that can reproduce the unique
structural properties of the larynx. In this article, the technique, potential
research, and clinical applications of hemilaryngeal transplantation are
addressed. MATERIALS AND METHODS: In a canine model, transplantation of a
hemilarynx was performed. The thyroarytenoid muscle was reinnervated, and an
arytenoid adduction was performed to ensure a competent larynx during the early
postoperative period. RESULTS: The canine tolerated the procedure well and the
transplanted larynx remained healthy and well vascularized during the
postoperative period. Electromyography of the transplanted thyroarytenoid muscle
verified reinnervation 2 months after the procedure. During induced phonation,
vibration was symmetrical with a normal-appearing laryngeal geometry.
CONCLUSIONS: Preliminary experience indicates that this technique has unique
advantages compared with other available techniques for laryngeal reconstruction.
Only with additional progress in transplantation medicine could this procedure be
considered an option for reconstruction of human partial laryngeal defects.
PMID- 10758993
TI - Outcome differences in younger and older patients with laryngeal cancer: a
retrospective case-control study.
AB - PURPOSE: Younger or older age has a significant impact on the outcome of patients
with head and neck cancer. However, the data regarding outcomes based on age are
conflicting. The aim of this article is to determine the impact of age on the
outcome of laryngeal cancer. MATERIALS AND METHODS: A retrospective study was
performed including all patients with squamous cell carcinoma of the larynx for
over a 9-year period. The patients were divided into 3 groups based on age. The
younger age group included patients 40 years of age and younger, the older group
included patients over 80 years of age, and the remaining patients served as the
control group. Descriptive statistics were used to summarize study data.
Nonparametric quantitative and qualitative analyses were performed using the Mann
Whitney U test and Fisher's exact test, respectively. Survival analysis was
performed using the generalized Wilcoxon test. The Cox proportional hazards model
was used for multivariate analysis. RESULTS: Of the 209 patients with laryngeal
carcinoma presenting to our institution over a 9-year period, 20 (10%) were < or
=40 years and 15 (7%) were > or =80 years of age. No differences in TNM stage at
presentation, treatment, or treatment-associated complications were observed
based on age. However, younger patients were less likely to report tobacco (50%;
P < .001) or alcohol (57%; P = .03) use and more likely to have human
immunodeficiency virus infection (50%; P< .001). Older patients showed a trend
toward having a worse baseline medical status. Recurrence was significantly more
common in older patients (P = .02) and cause-specific survival significantly
poorer for both younger and older patients (P = .002). CONCLUSIONS: The
presentation and outcome of laryngeal cancer is influenced by the age at
presentation. The differences may be related exact reason for the observed
survival differences needs to be determined.
PMID- 10758994
TI - Pediatric sleep-related breathing disorders.
AB - Sleep-related breathing disorders (SRBD) can occur at any age. Obstructive sleep
apnea, upper airway resistance syndrome and obstructive hypopnea syndrome all lie
on the pathological continuum of SRBD. These disorders can have a great impact on
a child's quality of life and can progress to significant complications. The
symptoms, signs, work-up, and treatment of SRBD in children are discussed.
PMID- 10758995
TI - Nasopharyngeal cysts.
PMID- 10758996
TI - Malignant teratoma of the thyroid: review of literature and report of a case.
PMID- 10758997
TI - Otosclerosis: computed tomography and magnetic resonance findings.
PMID- 10758998
TI - Leiomyoma of the trachea: a case report and a novel surgical approach.
PMID- 10758999
TI - Laryngeal tuberculosis.
AB - Since the introduction of antituberculous medications, the incidence of laryngeal
tuberculosis (TB) has decreased and remains stable. However, with the incidence
of TB increasing, mainly caused by the acquired immunodeficiency syndrome
epidemic, the incidence of laryngeal involvement may be on the rise. The main
presenting symptom of laryngeal TB is dysphonia. The diagnosis is confirmed with
the identification of granulomatous inflammation, caseating granulomas, and acid
fast bacilli on histopathologic examination of biopsied laryngeal tissue.
However, making the diagnosis difficult can be the presence of
pseudoepitheliomatous hyperplasia, which mimics squamous cell carcinoma.
Treatment is primarily with antituberculous medications with surgery reserved for
those cases of airway compromise. Laryngeal complications can occur; thus, long
term follow-up is recommended. We report a case of laryngeal TB in a human
immunodeficiency virus-negative patient and review the literature.
PMID- 10759000
TI - Salivary gland choristoma of the middle ear: a case report.
AB - A choristoma is a nonneoplastic proliferation of histologically normal tissue
that forms at an abnormal site. It is extremely uncommon in the middle ear space.
It appears to be a developmental abnormality and may be associated with
abnormalities of adjacent structures. It usually occurs with unilateral
conductive hearing loss and requires a differential diagnosis from other mass
lesions in the middle ear cavity. This article discusses a case of salivary gland
choristoma of the middle ear that we believe to be the 24th case reported on this
subject.
PMID- 10759001
TI - Ossifying fibroma of the temporal bone.
PMID- 10759002
TI - Carcinosarcoma of the parotid gland: report of a case with parapharyngeal
presentation.
PMID- 10759003
TI - Angiotensin converting enzyme insertion/deletion polymorphism is associated with
plasma antigen levels of plasminogen activator inhibitor-1 in healthy Japanese
population.
AB - Plasminogen activator inhibitor-1 (PAI-1) has a central role in the regulation of
the fibrinolytic enzyme system. An elevated plasma PAI-1 level is associated with
thrombotic disorders. In vitro and in vivo studies indicate that the renin
angiotensin system is involved in the regulation of PAI-1. A 287-bp
insertion/deletion (I/D) polymorphism in the gene-encoding angiotensin converting
enzyme (ACE) is associated with cardiovascular disorders. We evaluated the
association between the ACE I/D polymorphism and plasma PAI-1 antigen levels in
110 healthy Japanese male subjects. Subjects with the D-allele of the gene
encoding ACE had higher levels of PAI-1 (26.3 +/- 14.7 ng/ml, mean +/- standard
deviation) compared with those without (21.0 +/- 12.0; P = 0.0491). A multiple
linear regression model with independent variables (age, body-mass index, total
cholesterol level, triglyceride level, ACE I/D genotype, and PAI-1 genotype due
to a single guanine I/D polymorphism in the PAI-1 gene) demonstrated that the
triglyceride level (P = 0.0059) and ACE I/D genotype (P = 0.0372) were
independent predictors of plasma PAI-1 antigen levels in a subset of the subjects
without diabetes mellitus that were not taking lipid-lowering drugs. These
findings suggest that the ACE I/D polymorphism is a genetic factor for the
regulation of plasma PAI-1 antigen levels in the healthy Japanese population.
PMID- 10759004
TI - The effect of steroid and intravenous immunoglobulin on thrombopoietin levels in
pediatric patients with immune thrombocytopenic purpura.
AB - Thrombopoietin (TPO), which is the main regulator of megakaryo/thrombopoiesis,
has been recently cloned and purified, and shown to be useful in discriminating
thrombocytopenia due to decreased production or increased platelet destruction.
However, there are no detailed investigations about the drug effects on TPO
levels during childhood. This study was conducted to measure the TPO levels of
children with immune thrombocytopenic purpura (ITP) during steroid and
immunoglobulin treatment. Twelve patients with acute ITP were treated with high
dose methyl prednisolone and five patients were treated with intravenous
immunoglobulin. Neither steroids nor immunoglobulin were found to have any effect
on TPO levels.
PMID- 10759005
TI - Measurement of antithrombin activity by thrombin-based and by factor Xa-based
chromogenic substrate assays.
AB - Functionally active antithrombin can be quantified by chromogenic substrate
assays utilizing the heparin cofactor activity of antithrombin and the inhibition
rates of thrombin or of activated factor X (FXa). Thrombin-based assays but not
FXa-based assays may overestimate the antithrombin activity due to their
sensitivity toward heparin cofactor II. We focused on the question whether an
overestimation of antithrombin activity by thrombin-based assays involves the
risk of misdiagnosing antithrombin-deficient individuals as being non-deficient.
We determined antithrombin using two thrombin-based assays and one FXa-based
assay in 27 plasma samples from patients with acquired antithrombin deficiency
spiked with lepirudin, in antithrombin-deficient plasma and in mixtures of
antithrombin-deficient plasma and normal plasma. We also measured antithrombin in
healthy subjects, in patients with inherited and acquired antithrombin deficiency
and in patients under high-dose heparin treatment. At therapeutic final
concentrations of lepirudin, antithrombin activities were considerably
overestimated by the thrombin-based assays but not by the FXa-based assay. The
residual antithrombin activities in antithrombin-deficient plasma determined by
the thrombin-based assays were markedly higher than the corresponding values
obtained with the FXa-based assay. The thrombin-based assays also overestimated
antithrombin activity in patients under high-dose heparin. However, the degree of
overestimation in the range between 50 and 100 IU/dl was too low to misidentify
individuals with inherited or acquired antithrombin deficiency as normal. We
conclude that functionally active antithrombin can be reliably determined using
FXa-based chromogenic substrate assays in all settings examined. Thrombin-based
assays must not be used in patients under treatment with hirudin or other direct
thrombin inhibitors.
PMID- 10759006
TI - Monitoring unfractionated heparin therapy: relationship between eight anti-Xa
assays and a protamine titration assay.
AB - Several studies have demonstrated that heparin assays, such as anti-activated
factor X (anti-Xa) assays, can be successfully substituted for activated partial
thromboplastin time for heparin dosage monitoring. A number of different assays
are available and the relationship between results with different techniques is
largely unknown. The aim of the present study was to assess the relationship
between heparin assays by protamine titration and anti-Xa assays. Samples were
collected from 43 patients receiving unfractionated heparin (UFH). In each
sample, the heparin level was determined using a protamine titration assay and
eight commercially available anti-Xa assays. The mean heparin level by protamine
titration was 0.31 U/ml. Mean anti-Xa activity results ranged from 0.40 to 0.42
IU/ml for the three clotting-based assays, and from 0.32 to 0.40 IU/ml for five
chromogenic assays. Thus mean results of different anti-Xa assays varied by up to
30%. The range of anti-Xa activity equivalent, on average, to 0.2-0.4 U/ml by
protamine titration, considered to be the therapeutic range, was approximately
0.25-0.5 IU/ml, depending on the assay. The relationship between results of
clotting and chromogenic methods was similar irrespective of whether or not
warfarin-induced prolongation of international normalized ratios was present.
PMID- 10759007
TI - The cleavage and inactivation of plasminogen activator inhibitor type 1 and
alpha2-antiplasmin by reptilase, a thrombin-like venom enzyme.
AB - Reptilase, defibrase and ancrod are thrombin-like venom enzymes that cleave
fibrinogen to release fibrinopeptide-A and generate fibrin monomers. Although
these enzymes decrease fibrinogen levels in vivo, presumably by enhancing
fibrinolytic activity, the mechanism has not been identified. In the present
study, we analyzed their effects on the inhibitors of fibrinolysis. Plasminogen
activator inhibitor-1 (PAI-1) was cleaved at its C-terminus by reptilase and lost
its specific activity. Alpha2-antiplasmin (alpha2-AP) was cleaved both at the
Pro19-Leu20 peptide bond and at its C-terminus by reptilase, and also lost its
specific activity. The apparent second-order rate constants (mol/l per min per
Batroxobin unit) were 0.22 for the cleavage of PAI-1 (3.2 micromol/l) and 0.19
for that of alpha2AP (6.4 micromol/l), which were approximately 200-fold lower
than that (47.0) for the cleavage of fibrinogen (1.1 micromol/l). Neither
defibrase nor ancrod cleaved and inactivated these inhibitors. Only reptilase
enhanced euglobulin clot lysis in vitro at high concentration, due probably to
PAI-1 inactivation. Since all these three enzymes enhance fibrinolysis similarly
during defibrination therapy, the neutralization or inactivation of the
inhibitors of fibrinolysis appeared not to represent the main mechanism for the
enhancement.
PMID- 10759008
TI - Successful use of recombinant VIIa (Novoseven) and endometrial ablation in a
patient with intractable menorrhagia secondary to FVII deficiency.
AB - Menorrhagia is a well-recognized complication of inherited bleeding disorders. In
the past, the only viable option for women who were unresponsive to medical
therapy was hysterectomy. Endometrial ablation has been recently developed as an
alternative therapy for these patients and is associated with decreased
morbidity. We report the successful use of activated recombinant factor VII
(FVIIa) and endometrial ablation in the treatment of excessive menstrual blood
loss in a 34-year-old women with severe factor VII (FVII) deficiency. Recombinant
FVIIa (40 microg/kg) was administered pre-operatively and every 6 h (20
microg/kg) for 24 h postoperatively. The procedure was uncomplicated with a 200
ml surgical blood loss. FVIIa was used because it allowed FVII replacement with a
recombinant product and also has the ability to bind to tissue factor expressed
at the site of vascular injury, resulting in site-specific thrombin generation.
We believe that endometrial ablation with recombinant VIIa should be considered
in patients with severe FVII deficiency and menorrhagia unresponsive to medical
therapy.
PMID- 10759009
TI - Elevated levels of homocysteine increase IL-6 production in monocytic Mono Mac 6
cells.
AB - Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis. The aim
of this study was to analyze if exposure of monocytic cells to increased levels
of homocysteine (HCY) induces the accumulation of inflammatory mediators.
Interleukin (IL)-6 production by monocytic cell line Mono Mac 6 (MM6) was 1.7
fold increased in the presence of 50 micromol/l HCY and 3.5-fold with 200
micromol/l HCY. Incubation with homocystine resulted in a comparable dose
dependent increase, but neither cysteine nor methionine stimulated IL-6
accumulation. Elevated homocysteine concentrations did not affect the production
of IL-8 and monocytic chemotactic protein-1 (MCP-1) in MM6. Furthermore,
lipopolysaccharide (LPS) stimulation of MM6, cultured with elevated HCY (200
micromol/l) levels, resulted in a 3.5-fold increased response after 18 h, whereas
no effect on LPS-induced IL-8 and MCP-1 response was observed. In conclusion,
increased concentrations of homocysteine induce IL-6 accumulation in monocytic
cells. After treatment with homocysteine, monocytic cells become more susceptible
to endotoxin. This study is in favor of an association between homocysteine and
monocytic IL-6 production.
PMID- 10759010
TI - Platelets and cytokines in concert with endothelial activation in patients with
peripheral arterial occlusive disease.
AB - We tested the hypothesis whether circulating oncostatin-M (OSM), a cytokine that
in vitro promotes fibrinogen biosynthesis and smooth muscle cell proliferation,
or soluble CD40 ligand (CD40L; CD154), a leukocyte and platelet surface marker
that stimulates endothelial cells, were associated: (a) with fibrinogen and other
soluble cell adhesion molecules, such as P-selectin, vascular cell adhesion
molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 and platelet
endothelial cell adhesion molecule-1; or (b) with restenosis and platelet
activation in 71 patients with peripheral arterial occlusive disease undergoing
peripheral angioplasty (PTA). Platelet membrane activation markers (CD62P, CD63,
activated GPIIb/IIIa) were immunologically measured at 0, 1, 24 and 48 h, and 3
and 6 months after PTA. Soluble cell adhesion molecules, endothelial markers and
various hemostatic variables were measured before PTA. Of the patients, 42.3%
developed restenosis within 6 months, defined as a >50% reduction of the lumen at
the site of balloon dilatation. Soluble CD40L was not higher in the restenosis
group. Interestingly, patients with high CD40L showed significantly higher
soluble VCAM-1 (P < 0.01) and thrombomodulin (P < 0.01), as well as trends for
higher soluble P- and E-selectin. Platelet activation was found uniformly
increased mostly at 1 and 24 h, as well as at 3 and 6 months. OSM was measurable
in 53.5% (6.9 +/- 9.4 pg/ml) of the patients and undetectable in the others. No
differences in the rate of restenosis was found in these two groups, which did
not differ with respect to fibrinogen (3.14 +/- 1.00 versus 3.21 +/- 0.70 g/l),
or the other parameters. In conclusion, soluble CD40L is associated with higher
endothelial biological markers that might implicate its involvement in
endothelial activation. Platelet activation, probably intermittent, might play a
significant role through the expression of CD40L as a source of activation
signals to the endothelial cells. Free circulating OSM does not seem to correlate
directly with fibrinogen or with other acute phase reaction proteins, the
synthesis of which it could influence in vitro. This might well not mean,
however, that OSM lacks this activity in vivo.
PMID- 10759011
TI - Beneficial effects of postmenopausal hormone replacement therapy with transdermal
estradiol on sensitivity to activated protein C.
AB - Many hemostatic and fibrinolytic parameters have been evaluated following hormone
replacement therapy (HRT) but little is known about its influence on the
anticoagulant response to activated protein C (APC-sensitivity). For this
purpose, we studied the effect of transdermal 17-beta-estradiol (50 microg/24 h)
by a continuous regimen on the APC-sensitivity, in 28 postmenopausal
hysterectomized women (mean age, 47 years; range, 44-65 years). We also measured
the plasma proteins directly involved in the protein C anticoagulant pathway,
such as activities of factor VIII (VIII:C), factor V and free protein S. Von
Willebrand factor (vWF) antigen, the carrier protein of factor VIII, was also
determined. Blood sampling was done at baseline and after 16-week therapy. A
significant increase in the normalized APC-sensitivity ratio (n-APC-SR) values
(mean +/- SD: pre-trial, 0.88 +/- 0.14; post-trial, 1.01 +/- 0.12; P < 0.001) and
a significant decrease of factor VIII:C plasma levels (pre-trial, 1.13 +/- 0.29
IU/ml; post-trial, 0.98 +/- 0.20 IU/ ml; P = 0.001) were found. No difference was
observed in factor V, protein S and vWF plasma levels. Correlation studies
demonstrated only a significant negative correlation between the percent change
in n-APC-SR and the percent change in factor VIII:C (r = -0.574; P = 0.001). Our
findings clearly show that HRT with transdermal estradiol improves the
anticoagulant response to APC, probably as a result of a decreased factor VIII:C.
We also suggest that a similar but opposite mechanism may occur for perorally
administered estrogens used in the HRT. These results may have some clinical
implications about the reported increase of the risk for venous thromboembolism
following HRT.
PMID- 10759012
TI - Multiple analysis of three common genetic alterations associated with
thrombophilia.
AB - We have previously reported the use of a novel mini-sequencing protocol for
detection of the factor V Leiden variant, the first nucleotide change (FNC)
technology. This technology is based on a single nucleotide extension of a
primer, which is hybridized immediately adjacent to the site of mutation. The
extended nucleotide that carries a reporter molecule (fluorescein) has the power
to discriminate the genotype at the site of mutation. More recently, the
prothrombin 20210 and thermolabile methylene tetrahydrofolate reductase (MTHFR)
677 variants have been identified as possible risk factors associated with
thrombophilia. This study describes the use of the FNC technology in a combined
assay to detect factor V, prothrombin and MTHFR variants in a population of
Australian blood donors, and describes the objective numerical methodology used
to determine genotype cut-off values for each genetic variation. Using FNC to
test 500 normal blood donors, the incidence of Factor V Leiden was 3.6% (all
heterozygous), that of prothrombin 20210 was 2.8% (all heterozygous) and that of
MTHFR was 10% (homozygous). The combined FNC technology offers a simple, rapid,
automatable DNA-based test for the detection of these three important mutations
that are associated with familial thrombophilia.
PMID- 10759013
TI - Influence of triflusal on platelet activation after coronary artery bypass graft.
AB - The aim of the study was to investigate the effects of the antiplatelet agent
triflusal on the changes in platelet function in patients who underwent a
cardiopulmonary bypass for coronary arteries (CABG). In 20 surgical patients,
blood was sampled before and at the conclusion of surgery, 48 h later (in the
intensive care unit), and after 10 days of treatment with 600 mg/day triflusal
(triflusal was administered from the first day after surgery). Adenosine
diphosphate (ADP) and collagen-induced platelet aggregation in whole blood,
granular release of beta-thromboglobulin and platelet release of thromboxane B2
were measured. Basal values were compared with results in a group of ten healthy
volunteers. All platelet determinations of activation were higher in coronary
patients than in healthy volunteers. Immediately after CABG, the platelet
reactivity to ADP and collagen were significantly lower, and release of beta
thromboglobulin and thromboxane B2 were higher, than in the pre-CABG samples.
During the patient's stay in the intensive care unit, all values tend to return
to pre-CABG values. Triflusal inhibits both platelet beta-thromboglobulin (63%
with respect to the post-CABG value) and thromboxane B2 (91% with respect to the
post-CABG value) release. Platelet aggregation after 10 days of triflusal
treatment tended to return to the pre-CABG values. In conclusion, Triflusal
reduces platelet activation caused by the coronary artery bypass graft surgery.
PMID- 10759014
TI - Risk of major bleeding in unselected patients with venous thromboembolism.
AB - PURPOSE: To evaluate the risk of major bleeding in unselected patients given
anticoagulant treatment (heparin overlapped and followed by oral anticoagulants)
because of deep vein thrombosis (DVT) or pulmonary embolism (PE). SUBJECTS AND
METHODS: We screened the database of 1590 outpatients suspected of DVT and PE in
prospective diagnostic studies conducted in Geneva between 1992 and 1998.
RESULTS: Four hundred and eleven of 1590 patients (26%) were anticoagulated for
confirmed venous thromboembolism (PE, 300; DVT, 111). One patient was excluded
because of concomitant thrombolytic therapy. Five (1.2%; 95% confidence interval,
0.4-2.8) of the remaining 410 patients experienced a major hemorrhagic event
during the 3-month follow-up, including two fatal events. All bleedings occurred
during the first month of therapy (heparin, two; oral anticoagulants, two;
combined treatment, one) and the median age of the patients who bled was 80
years. At least one serious comorbid condition associated with higher bleeding
risk was present in four patients and, in one case, the bleeding was clearly
related to an excessive intensity of anticoagulation. CONCLUSION: The rate of
bleeding events in this population of unselected outpatients is similar to that
reported in controlled therapeutic trials. The hemorrhagic events occurred early
in the course of anticoagulant therapy and concerned old patients mostly affected
by at least one comorbid condition. Particular care should be used to avoid the
risk of overtreatment.
PMID- 10759015
TI - Pasteurized, monoclonal antibody factor VIII concentrate: establishing a new
standard for purity and viral safety of plasma-derived concentrates.
AB - A factor VIII concentrate (Monoclate-P) manufactured using a combination of
pasteurization and immunoaffinity chromatography has been chosen to compare and
contrast manufacturing aspects of plasma-derived factor VIII concentrates.
Pasteurization is a virucidal method with a long safety record in clinical
practice, while immuno-affinity chromatography selectively isolates and purifies
the procoagulant protein of factor VIII, and partitions potential viral
contaminants and nonessential proteins to the unbound fraction. The complete
Monoclate-P production process reduces human immunodeficiency virus by > or =
10.5 log10, Sindbis (a model for hepatitis C virus) by > or = 6.5 log10, and
murine encephalomyocarditis virus (a non-enveloped model virus) by 7.1 log10. The
viral safety of Monoclate-P has been further demonstrated in clinical studies in
patients not previously treated with blood or plasma-derived products.
Additionally, the manufacture of Monoclate-P includes careful donor screening and
plasma testing for antibodies to syphilis and human immunodeficiency, hepatitis
B, and hepatitis C viruses to enhance source plasma safety. Combined with donor
selection and plasma testing, multiple viral reduction steps effectively
eliminate both lipid-enveloped viruses (e.g. human immunodeficiency, hepatitis B
and C) and non-lipid-enveloped viruses (e.g. hepatitis A). In addition,
polymerase chain reaction-based nucleic acid detection tests for hepatitis B and
C viruses and for human immunodeficiency virus-1 have been introduced as part of
an investigational new drug mechanism.
PMID- 10759016
TI - Factor XIII does not stimulate growth of human cultured tumor cells.
PMID- 10759017
TI - Neuroendocrine sequelae of visceral fat accumulation: implications for
cardiovascular disease and diabetes.
PMID- 10759018
TI - Perceived barriers to the implementation of diabetes guidelines in hospitals in
The Netherlands.
AB - OBJECTIVE: To determine the organisational and personal barriers to the
implementation of diabetes guidelines in hospitals in The Netherlands and relate
them to structural factors of diabetes care. METHOD: In a written survey
internists specialised (or with a specific interest) in diabetes in all general
hospitals in The Netherlands (n = 120) were asked to indicate the perceived
organisational and personal barriers to adherence to the diabetes guidelines. In
the same questionnaire their activities related to diabetes care and the working
hours of the additional personnel involved were measured. RESULTS: There was at
least one specialised diabetes nurse employed in all hospitals, although the
extent of the appointment varied widely from 0.2 to 6.9 full-time equivalent
(average 1.5). In most hospitals (90%) a diabetes care team had been established,
while podiatrists were working in only 72% of the hospitals. Furthermore, 65-80%
of the hospitals organised special consultation hours for diabetic patients, had
a protocol for diabetes treatment, or patient held administration booklets. The
most frequently mentioned barriers to the implementation of diabetes guidelines
were high workload, no adequate financial compensation, and a shortage of
necessary personnel. CONCLUSION: A number of preconditions for structured
diabetes care, like the presence of a diabetes team and a specialised diabetes
nurse, were in place. However, large differences between the hospitals in the
organisation of diabetes care and the availability of staff, together with the
related perceived barriers to the implementation of the guidelines showed that
there are still many opportunities for improvements.
PMID- 10759019
TI - Effect of metformin on glycaemic control in type 2 diabetes in daily practice: a
retrospective study.
AB - INTRODUCTION: Recently the UKPDS study revealed the potency of metformin therapy
in obese type 2 diabetic patients. A retrospective study was performed to assess
the efficacy of metformin therapy in improving metabolic control in everyday
practice. PATIENTS AND METHODS: Type 2 diabetic patients were included if they
met the following criteria: metformin had been added when the previous treatment
failed to optimise glycaemic control expressed in HbA1c level; duration of
metformin therapy had to be at least six months. Efficacy of metformin therapy,
expressed as a decrease in HbA1c, was measured with a median follow-up of 32
(range 6-60) months. Variables were analysed using a paired t-test. RESULTS: One
hundred and sixty-three patients were treated with metformin. 98 patients were
excluded, because of absence of an HbA1c value prior to treatment with metformin
mainly (n = 78). The mean HbA1c of included patients had decreased 1.4% (p <
0.001) after 6 months (n = 65), 1.6% (p < 0.001) after 24 months (n = 45) and 1.5
(p < 0.001) after 36 months (n = 28). During follow-up there was no significant
weight gain or loss. CONCLUSION: Metformin can be considered an effective
treatment to improve glycaemic control in obese type 2 diabetic patients.
PMID- 10759020
TI - The low dose (1 microg) ACTH stimulation test for assessment of the hypothalamo
pituitary-adrenal axis.
AB - Traditional testing of the hypothalamo-pituitary-adrenal axis function has relied
essentially upon the insulin tolerance test or the metyrapone challenge: both
tests are not only uncomfortable, but carry also real dangers. The standard ACTH
stimulation test uses an extremely hyperphysiological amount (250 microg) of ACTH
to evaluate a physiologic response, which may result in false normal responses.
The proposed low dose (1 microg) ACTH test is more physiological and more
sensitive, especially in cases of mild adrenal insufficiency and allows also to
assess pituitary-adrenal suppression after long-term treatment with
glucocorticoids. According to the rules of evidence-based medicine, the low dose
ACTH test should replace the conventional 250 microg test when evaluating for
central adrenal insufficiency.
PMID- 10759021
TI - Pseudohypoparathyroidism type Ia. Albright hereditary osteodystrophy: a model for
research on G protein-coupled receptors and genomic imprinting.
AB - Pseudohypoparathyroidism type Ia (PHP Ia) is a hereditary endocrine disorder,
characterised by resistance to parathyroid hormone (PTH), causing disturbance of
calcium homeostasis, and to several other polypeptide hormones. Patients with PHP
Ia exhibit a complex of somatic abnormalities, termed Albright hereditary
osteodystrophy (AHO). Treatment with vitamin D derivatives alleviates symptoms of
hypocalcemia and may prevent bone demineralisation. PTH, like many polypeptide
hormones, exerts its effects via a G protein-coupled cell surface receptor. PHP
Ia is caused by a heterozygous, inactivating mutation in the gene for the alpha
subunit of the Gs protein, which disrupts Gs-protein-coupled signal transduction
pathways. Several mutations have been described. When the mutation is inherited
from the mother, the offspring will develop PHP Ia, i.e., both hormonal
resistance and somatic abnormalities. When the mutation is derived from the
father, children will have normal hormone responses while exhibiting the somatic
features of AHO; this form of the disorder is called
pseudopseudohypoparathyroidism (PPHP). A combination of tissue-specific genomic
imprinting and haploinsufficiency may explain the occurrence of PPHP, and the
fact that not all Gs-mediated polypeptide hormone actions are affected equally.
PHP may therefore serve as a model in studying the pleiotropic consequences of
impaired Gs-mediated signal transduction.
PMID- 10759022
TI - Triglycerides and atherosclerosis: to feast or fast.
PMID- 10759023
TI - Hyperhomocysteinaemia as a cardiovascular risk factor: an update.
AB - There is overwhelming epidemiological evidence that hyperhomocysteinaemia is an
independent and graded cardiovascular risk factor, although a cause-and-effect
relationship is still unproven. Acquired causes of hyperhomocysteinaemia include
B-vitamin deficiencies and renal insufficiency. The most important inherited
cause is a point mutation in methylenetetrahydrofolate reductase gene, which is,
remarkably, not associated with an increased cardiovascular risk. A methionine
loading test identifies substantially more subjects with hyperhomocysteinaemia
compared with a fasting homocysteine determination alone. Repeated blood sampling
is necessary due to an intra-individual variability in homocysteine
concentrations up to 25%. A conservative reference value for fasting homocysteine
is 15 micromol/l, although there seems to be no definite threshold in the
presumed linear relation between homocysteine concentration and cardiovascular
risk. The pathophysiological mechanism of homocysteine-induced cardiovascular
disease is still not elucidated. The concept of endothelial dysfunction,
demonstrated by impaired endothelium-dependent vasodilation, by oxidant damage
has been confirmed in hyperhomocysteinaemic healthy adults. Folic acid
supplementation (0.5 mg daily) can be considered the optimum homocysteine
lowering therapy, with the exception of renal failure patients. Ongoing large
prospective, randomised controlled clinical trials are investigating the
potential beneficial effect of homocysteine lowering therapy on cardiovascular
morbidity and mortality in subjects with hyperhomocysteinaemia.
PMID- 10759024
TI - The slime loosener strikes again!
PMID- 10759025
TI - Molecular mechanisms of calcium-dependent excitotoxicity.
AB - Excitotoxicity is thought to be a major mechanism contributing to
neurodegeneration during central nervous system ischemia, trauma, and other
neurological disorders. Briefly, synaptic overactivity leads to the excessive
release of glutamate, the major excitatory neurotransmitter in the mammalian
central nervous system. Glutamate activates a number of postsynaptic cell
membrane receptors, which upon activation open their associated ion channel pore
to produce ion influx or efflux. This leads to a disturbance of the intracellular
ionic environment, the best characterized feature of which is the influx of
sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular
Ca2+-dependent signaling cascades that eventually lead to neuronal cell death.
Despite intensive research in the field of Ca2+-dependent neurotoxicity the
precise molecular mechanisms leading to cell death remain poorly understood. In
particular, the question of the precise relationship between Ca2+ loading and
neurotoxicity has been controversial. Many glutamate receptors are clustered and
localized at the postsynaptic density. Recently, increasing knowledge of the
molecular composition of the postsynaptic density has allowed us to extend our
understanding of the molecular mechanisms of Ca2+-dependent excitotoxicity and to
propose that distinct, membrane receptor-specific, neurotoxic signaling pathways
transduce Ca2+-dependent excitotoxicity. These findings may have significant
implications in the search for precisely targeted therapeutic drugs for a range
of neurological disorders.
PMID- 10759026
TI - Transient receptor potential channels as molecular substrates of receptor
mediated cation entry.
AB - Calcium is a versatile multitarget intracellular second messenger in eukaryotic
cells. In addition to calcium release from intracellular stores and influx via
voltage- or ligand-operated channels, agonist-induced calcium entry constitutes
one of the main pathways by which cytosolic calcium is elevated. Receptor
stimulated currents are initiated in response to agonist binding to G-protein
coupled receptors and to receptor tyrosine kinases. Within the past few years our
knowledge about the molecular identity of receptor-stimulated channels has
expanded substantially. Drosophila melanogaster visual transduction channels
associated with the transient receptor potential (trp) and the trp-like (trpl)
mutant visual phenotypes were the first members of this category of channels to
be identified at the molecular level. Since then an entire mammalian gene family
of TRP homologues has been discovered by homology cloning. Only now are we
beginning to fully understand the functional roles of TRP channels in mammalian
cells. We review recent findings in TRP channel research and discuss the role of
these proteins for receptor-activated cation entry.
PMID- 10759027
TI - Cyclic ADP-ribose.
AB - The Ca2+-mobilizing natural compound cyclic ADP-ribose was discovered in sea
urchin egg homogenates. Recently the involvement of cyclic ADP-ribose in Ca2+
signaling has been demonstrated in diverse biological systems spanning protozoa,
plants, and cells from invertebrate, mammalian, and human sources. ADP-ribosyl
cyclases synthesize cyclic ADP-ribose. Several candidate proteins for these
enzymes have been proposed, including membrane-bound NAD+ glycohydrolases such as
CD38 and soluble enzyme activities from various tissues and cells. Ca2+
mobilization by cyclic ADP-ribose is believed to proceed via the ryanodine
receptor/Ca2+ channel, probably via binding proteins for cyclic ADP-ribose.
Several antagonistic derivatives of cyclic ADP-ribose have been synthesized, some
of which have been successfully used to demonstrate the involvement of cyclic ADP
ribose in sea urchin egg fertilization, glucose-dependent insulin secretion in
pancreatic beta-cells, and activation and proliferation of human T-lymphocytes.
PMID- 10759029
TI - Identification of an alpha-helical epitope region on the PM/Scl-100 autoantigen
with structural homology to a region on the heterochromatin p25beta autoantigen
using immobilized overlapping synthetic peptides.
AB - The polymyositis-scleroderma overlap syndrome (PM/Scl) autoantigen is a nucleolar
multiprotein particle, presumably participating in the maturation of 5.8S rRNAs.
The major target antigens of this particle are two polypeptides with apparent
molecular masses of 100 and 75 kDa. In this study we identified the major linear
epitopes along the PM/Scl-100 protein sequence by probing overlapping
oligopeptides with anti-PM/Scl autoantisera. A major epitope region was
identified between amino acids 231 and 245 of the PM/Scl-100 polypeptide.
Mutational analysis of the corresponding peptide LDVPPALADFIHQQR by glycine-walk
followed by immunodetection of the resulting peptides indicated that amino acids
234, 237, 240, and 241 of the PM/Scl-100 autoantigen are essential for binding of
the corresponding antibodies. These results allow us to propose a local alpha
helical secondary structure for the PM/Scl-100 major epitope region. A homology
search with the peptide LDVPPALADFIHQQR against the Swiss-Model three-dimensional
database reveals some topological homology of the PM/Scl-100 major epitope region
with the heterochromatin modifier protein p25beta, a known autoantigen recognized
by antibodies from a subset of scleroderma patients.
PMID- 10759028
TI - A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum
locus: high-resolution mapping and genomic structure.
AB - We have recently mapped the genetic defect underlying pseudoxanthoma elasticum
(PXE), an inherited disorder characterized by progressive calcification of
elastic fibers in skin, eye, and cardiovascular system, to chromosome 16p 13.1.
Here we report further data on the fine-mapping and genomic structure of this
locus. Haplotype analysis of informative PXE families narrowed the locus to an
interval of less than 500 kb located between markers D16B9621 and D16S764. Three
overlapping YAC clones were found to cover this region through YAC-STS content
mapping. An overlapping BAC contig was then constructed to cover this interval
and the surrounding region. About 80% of this chromosomal region has been fully
sequenced using the BAC shotgun technique. Gene content and sequence analysis
predicted four genes (MRP1, MRP6, PM5, and a novel transcript) and two
pseudogenes (ARA and PKDI) within this interval. By screening a somatic cell
hybrid panel we were able to precision-map the breakpoint of Cy185 and the
starting point of a chromosomal duplication within 20 kb of BAC A962B4. The
present data further refine the localization of PXE, provide additional physical
cloning resources, and will aid in the eventual identification of the genetic
defect causing PXE.
PMID- 10759030
TI - Improvement of immune functions in HIV infection by sulfur supplementation: two
randomized trials.
AB - To determine the therapeutic effect of sulfur amino acid supplementation in HIV
infection we randomized 40 patients with antiretroviral therapy (ART; study 1)
and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl
cysteine or placebo at an individually adjusted dose according to a defined
scheme. The main outcome measures were the change in immunological parameters
including natural killer (NK) cell and T cell functions and the viral load. Both
studies showed consistently that N-acetyl-cysteine causes a marked increase in
immunological functions and plasma albumin concentrations. The effect of N-acetyl
cysteine on the viral load, in contrast, was not consistent and may warrant
further studies. Our findings suggest that the impairment of immunological
functions in HIV+ patients results at least partly from cysteine deficiency.
Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl
cysteine treatment may be recommended for patients with and without ART. Our
previous report on the massive loss of sulfur in HIV-infected subjects and the
present demonstration of the immunoreconstituting effect of cysteine
supplementation indicate that the HIV-induced cysteine depletion is a novel
mechanism by which a virus destroys the immune defense of the host and escapes
immune elimination.
PMID- 10759031
TI - Cocaine use and HIV risk in out of treatment drug abusers.
AB - During the initial phases of the HIV epidemic, epidemiological and prevention
initiatives included a necessary focus on injection drug use which targeted, for
the most part, heroin injectors. More recently, cocaine users have become a
central focus for many HIV prevention interventions. This illustrates how
researchers and public health practitioners have adapted to the changing and
intersecting epidemics of HIV and drug abuse in order to more efficiently prevent
the spread of HIV among drug abusers. In this special issue of Drug and Alcohol
Dependence, the contributing authors focus attention on the HIV risk behaviors of
cocaine abusers using data from the National Institute on Drug Abuse (NIDA)
Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research
Program. The Cooperative Agreement consists of 23 sites, with 22 sites located in
the US (including Puerto Rico) and one site in Brazil, and has included over
28,000 subjects recruited using street outreach. All Cooperative Agreement
subjects were administered the NIDA risk behavior assessment (RBA) which provides
detailed information about injection drug use behaviors, crack cocaine use and
sexual behaviors. The RBA serves as the source of basic data for all papers in
this issue which includes work describing local studies in St. Louis, North
Carolina and Brazil as well as analysis of the National Database from researchers
in Denver, Washington and Kentucky. In general, the studies focus on the etiology
of HIV risk behaviors by empirically identifying the antecedents of individual
HIV risk behaviors among cocaine users. These predictors of risk and protective
behavior include the severity of crack cocaine, comorbid antisocial personality
disorder and depression, alcohol consumption, and typologies of crack and
injection drug use. Overall, the studies show that NIDA's prevention intervention
is feasible and effective in many settings. The success of the studies which are
included in this special issue is a testament to the feasibility of NIDA's
science-based prevention interventions.
PMID- 10759032
TI - Sex related HIV risk behaviors: differential risks among injection drug users,
crack smokers, and injection drug users who smoke crack.
AB - This study was designed to assess differences in sex-related risk behaviors
between drug injectors who did not smoke crack cocaine, crack smokers who did not
inject drugs, and drug users who both injected drugs and smoked crack. Current
drug users (i.e. used within the past 30 days) from 22 cities were recruited and
assessed. The sample (n = 26,982) included 28% who injected only, 42% who smoked
crack only, and 30% who both injected and smoked crack. Results showed that
active drug users were at risk of HIV infection through sexual transmission: in
the 30 day period prior to their interview, 28% reported sex with two or more
individuals, 23% had an IDU sex partner, and 24% had exchanged sex for drugs or
money. In addition, more than 80% did not use a condom during sex. Crack only
smokers and crack smoking injectors were more likely than injectors only to
report multiple sex partners and exchanging sex. Because of these high risk
behaviors, condom use was of particular importance. The number of days of alcohol
use and having an IDU sex partner were independently associated with not using a
condom. Crack smoking injectors reported the highest average number of days of
alcohol consumption and were the most likely to have had an IDU sex partner.
PMID- 10759033
TI - Frequency and intensity of crack use as predictors of women's involvement in HIV
related sexual risk behaviors.
AB - Recent trends in the progression of the AIDS epidemic in the United States
indicate that women's rates of acquiring HIV are escalating more rapidly than are
men's. Consequently, there has been both an increasing interest in and a need for
research targeting substance-abusing women's involvement in HIV risk behaviors.
In recent years, strong suggestive evidence has arisen to suggest that women who
use crack cocaine are at an elevated risk for acquiring HIV, probably as a result
of their involvement in high-risk sexual behaviors. The present study is based on
a sample of 1723 women from 22 locales around the United States who used crack
cocaine at least once during the previous 30 days but who reported never having
injected drugs at any point in their lifetime. Women were divided into four
groups based on their frequency and intensity of using crack. In subsequent
analyses, this grouping was used to predict the extent to which female crack
users engage in five sexual risk behavior measures (number of sexual partners,
number of drug-injecting sexual partners, number of times having sexual relations
while high on alcohol and/or other drugs, number of times trading sex for drugs
and/or money, and proportion of all sexual acts involving the use of protection).
The data revealed that the women who used crack with the greatest frequency and
the greatest intensity were the most heavily involved in risky sexual behaviors.
They differed quite sharply from their lower-intensity and/or lower-frequency
crack-using counterparts in terms of their HIV risk behavior involvement and in
terms of their actual HIV seroprevalence rates.
PMID- 10759034
TI - Sexual and drug use behaviors among female crack users: a multi-site sample.
AB - The purpose of this paper was to compare female crack users who report exchanging
sex for drugs and/or money with female crack users who did not report exchanging
sex for drugs and/or money. A multi-site sample of (n = 4667) female crack users
who participated in the National Institute of Drug Abuse (NIDA) AIDS Cooperative
Agreement Project from 20 sites were interviewed. Statistical analysis compared
two groups on selected variables of interest: women crack users who reported
exchanging sex for drugs and/or money (n = 2658) and women crack users who did
not report exchanging sex (n = 2009). Results indicated that both groups of women
had frequent unprotected sex. However, women who exchanged sex had more sexual
partners, had sex more often, used drugs before and during sex more often, and
had a higher rate of STDs than women who did not exchange sex. In addition,
African-American women, homeless women, and women who reported past substance
abuse treatment were about twice as likely to exchange sex. Regional differences
were also examined.
PMID- 10759035
TI - The effects of psychiatric comorbidity on response to an HIV prevention
intervention.
AB - Drug abusers with psychiatric comorbidity are at high risk for becoming exposed
to HIV. To address this compelling public health issue, our randomized HIV
prevention study compares the effectiveness of the NIDA standard HIV testing and
counseling protocol to a four session, peer-delivered, educational intervention
for out-of-treatment cocaine users with and without antisocial personality
disorder (ASPD) and major depression. Among the 966 out-of-treatment cocaine
users who have completed the 3 month follow-up, all groups, regardless of
assignment to standard vs. peer-delivered intervention or psychiatric status,
improved significantly in: crack cocaine use, injection drug use, number of IDU
sex partners and overall number of sex partners, but not in condom use.
Nevertheless, when stratified by psychiatric status, ASPD was associated with
significantly less improvement in crack cocaine use (P = 0.04) and with a trend
for less improvement in having multiple sex partners and having IDU sex partners
(P = 0.06 and 0.08, respectively). ASPD status was not associated with change in
injection drug use or condom use. Depression was associated with a trend (P =
0.07) for greater improvement in crack cocaine use but not in any of the other
behaviors. When examining the standard and peer intervention groups separately,
no consistent differences in the association of psychiatric comorbidity with
outcome were discerned between the two groups. We conclude that persons with ASPD
and depression respond well to standard HIV prevention interventions, but these
psychiatric disorders respectively attenuate and enhance response somewhat.
Behavioral interventions tailored for persons with these conditions may be
indicated if long-term change in HIV risk behaviors is to be achieved.
PMID- 10759036
TI - Patterns of HIV risk and alcohol use among African-American crack abusers.
AB - Although the association between heavy alcohol use and HIV risk has been studied
in treatment populations, we know little about patterns of alcohol use and HIV
risk among out-of-treatment African-American drug users. This study examines the
extent to which alcohol use affects HIV risk in a sample of 495 African-American
crack users who did not inject drugs. We present differences between levels of
alcohol and crack use with regard to sexual practices (including sex while
impaired), number of partners, frequency of sexual activity, and condom use. The
findings suggest an intimate relationship between alcohol use, crack use, and
sexual risks for HIV infection. Respondents who reported frequent use (15-30 days
in the last 30 days) of alcohol, crack, or both displayed significantly greater
risk than those who reported less than frequent use.
PMID- 10759037
TI - Indigence, marginalization and HIV infection among Brazilian cocaine users.
AB - In recent years the HIV/AIDS epidemic in Brazil has increasingly affected younger
and more impoverished segments of the population. The rate of infection among
drug users has also risen dramatically over the past decade. Despite these
alarming trends, epidemiologic studies of indigent drug users in Brazil are
virtually nonexistent. In order to fill this void, a research demonstration
program was initiated in Rio de Janeiro which targeted drug users from the
poorest strata of society, assessed their HIV risk behaviors and serostatus, and
provided HIV prevention counseling, hygiene materials, and follow-up. Because
participation in the intervention program appeared to impact on drug use and
sexual risk behaviors, the implementation of successful prevention programs with
this population appears feasible. In that HIV prevalence among this sample of
poor injectors was markedly lower than that reported in previous studies of
higher socioeconomic status injectors, the timely and widespread implementation
of risk reduction strategies assumes great importance for the prevention of HIV
infection in the most marginalized segments of Brazilian society.
PMID- 10759038
TI - Neuroimaging variables related to development of Secondary Attention Deficit
Hyperactivity Disorder after closed head injury in children and adolescents.
AB - OBJECTIVE: To characterize children who develop Secondary Attention Deficit
Hyperactivity Disorder (S-ADHD) after severe and moderate closed head injury
(CHI) according to neuroimaging variables. METHOD: Ninety-nine children from 4-19
years who suffered severe and moderate CHI were prospectively followed for a year
after injury. Premorbid psychiatric status was determined by administration to
the parent of a structured psychiatric interview. This interview was
readministered 1 year after injury to determine the presence of post-closed head
injury S-ADHD. An MRI was performed 3 months after injury to define lesion
locations and volumes. RESULTS: A set of multiple logistic regression models
determined that the odds of developing S-ADHD were 3.64 times higher among
children with thalamus injury, and 3.15 times higher among children with basal
ganglia injury. There was no significant difference in lesion volumes in any of
the locations of interest between the group who developed S-ADHD and the group
who did not develop S-ADHD. CONCLUSION: The data support an association between S
ADHD and injury in either or both the thalamus and basal ganglia, but they do not
definitively demonstrate whether injury in either structure has an effect on S
ADHD in the absence of injury in the other.
PMID- 10759039
TI - A randomized trial of two treatments for mild traumatic brain injury: 1 year
follow-up.
AB - The purpose of this study was to provide 1 year follow-up data to a previous
paper that compared single-session (SS) treatment to treatment-as-needed (TAN)
outcomes for mild traumatic brain injury (MTBI) survivors at 3 months post
injury. Participants were 105 adults with MTBI who were recruited from
consecutive admissions to two hospital emergency wards, and randomly assigned to
either the SS or TAN modality. No group differences in outcome were evident at 12
months post-injury. As well, improvements seen in the groups after 3 months were
maintained at 12 months. As improvements between 3 and 12 months were negligible,
self-reported improvement after a treated MTBI typically occurred within the
first 3 months. Brief educational intervention given soon after MTBI appears to
be as helpful as more intensive treatment for most MTBI survivors for at least 12
months post-injury.
PMID- 10759040
TI - Attentional deficits in patients with closed head injury: a further study to the
discriminative validity of the test of everyday attention.
AB - This study aimed to explore the attentional performance of patients with closed
head injury (CHI) and to examine the discriminative validity of the Test of
Everyday Attention (TEA) in this clinical population. A sample of 21 patients
with CHI was recruited for this study. Another sample of matched controls was
also recruited for comparison. In addition, other clinical tests of attention and
questionnaires on everyday life cognitive failures were also given to the
participants during the assessment session. The results showed that patients with
CHI exhibited significant differences in most of the TEA subtests, as well as
clinical tests of attention, as compared with the matched controls. These
findings suggest that the majority of the TEA subtests are able to discriminate
out those patients with attentional deficits from the normal population in terms
of sustained attention, selective attention, divided attention, and attentional
switching.
PMID- 10759041
TI - Acute oxygen deprivation: neuropsychological profiles and implications for
rehabilitation.
AB - OBJECTIVE: To investigate areas of neuropsychological functioning in severe
anoxia survivors that have received little prior attention but that have
significant implications for rehabilitation. DESIGN: Residents of a long-term
neurobehavioural rehabilitation facility were administered comprehensive
neuropsychological protocols. Areas assessed were arousal and attention,
executive abilities, reasoning, language, visuospatial abilities, motor, praxis,
memory, affective regulation, and insight into deficits. RESULTS: Subjects were
impaired in all areas except in performing automatized tasks. Areas of
dysfunction not previously emphasized included praxis, affective regulation, and
verbal fluency. CONCLUSION: Areas of compromise not previously emphasized were
identified. Their routine assessment can assist rehabilitation professionals in
better serving anoxic encephalopathy survivors, particularly those with profound
behavioural dysregulation.
PMID- 10759042
TI - Relationships: importance for patients with cerebral tumours.
AB - OBJECTIVE: To investigate the influence of relationships on psychosocial status
in patients with Stage III and IV brain tumours. PATIENTS AND METHODS: Thirty
three outpatients at a university medical centre were referred to the study by
their treating physician prior to the initiation of aggressive chemotherapy. All
subjects underwent a comprehensive psychosocial assessment. RESULTS: Depressive
and anxious complaints were common, but not related to gender. Single/divorced
status suggested greater vulnerability to anxiety as 88% of singles and only 48%
of patients with partners reported clinical levels of anxiety. Single patients'
anxiety was related to inactivity (r = 0.78, p < 0.05) and fears of financial
difficulties (r = 0.72, p < 0.05). State and trait anxiety related differently to
married patients' complaints. Married patients more frequently reported clinical
levels of depressive symptoms (44% partnered vs 28% singles). Depression among
married patients was predicted by problems with sex, finances, marital
difficulties, and inactivity [R2 = 0.803; F = 20.420, df(4,20), p < 0.0001)].
Problems with relationships were disassociated from problems with sex. Married
patients' problematic relationships were predicted by overprotection, inactivity,
concerns of bodily deterioration, depression, and anxiety [R2 = 0.775, F =
13.060, df(5, 19) < 0.0001]. CONCLUSIONS: Married neuro-oncology patients may
experience depressive symptoms arising from the marriage, but appear to be
buffered from anxiety when compared with single/divorced patients. The prevalence
of anxiety among single patients suggests modifications of interventions by
relationship status.
PMID- 10759043
TI - Evaluating the usage of droperidol in acutely agitated persons with brain injury.
AB - The objective of this study was to compare the effectiveness and safety of
intramuscular droperidol to other intramuscularly administered agents used in the
management of acutely agitated patients. Twenty-seven inpatients with a history
of brain injury were prospectively monitored over a period of 2 months. Data
collected for each episode of agitation include: dose, number of doses, time to
achieve an adequate response or calming effect, post-episodic functioning,
treatment-emergent side effects, and other patient demographics. A retrospective
medical records review was also performed on the same cohort, to compare clinical
outcomes associated with other intramuscular agents previously used for acute
agitation. Time to achieve calming was significantly shorter with intramuscular
droperidol (mean = 27.0 minutes) compared to intramuscular haloperidol,
lorazepam, or diphenhydramine (group mean = 36.2 minutes, p = 0.02). Of the three
comparative agents, the time to achieve calming was the fastest with lorazepam
(mean = 35.0 minutes), and slower with diphenhydramine (mean = 42.6 minutes) and
haloperidol (mean = 43.0 minutes). Single doses of droperidol controlled
agitation more frequently than did single doses of comparative agents, and there
was less post-episodic sedation with droperidol following release from seclusion
or restraints. Both groups were similar in regard to the incidence of treatment
emergent events. This data represents the first published experience supporting
the effectiveness of droperidol in reducing acute agitation in persons with brain
injury. Follow-up studies with prospective, double-blind, parallel treatment
groups should be performed to validate these preliminary findings.
PMID- 10759044
TI - The trauma of paediatric and adolescent brain injury: issues and implications for
rehabilitation specialists.
AB - The purpose of this article is to define critical issues facing rehabilitation
specialists providing services to children or adolescents with a brain injury and
their families. These issues will be identified as they evolve temporally--from
the period immediately after the injury to many years post-trauma. As the young
person heals, the focus of the issues and the recommendations (based on both the
clinical experience of the authors as well as the extensive body of literature
already in existence) will change from those more appropriate to rehabilitation
specialists working in the medical environment to those employed in education and
the psychosocial realm. However, the boundaries between these realms, because of
the all encompassing nature of the injury, are fluid. Finally, the purpose of
this article is also to establish the need for rehabilitation specialists who are
educated about traumatic brain injury; who are well versed in the physical,
cognitive and emotional sequellae of the injury; who recognize the unique needs
and expectations of this population and are willing to adjust; and who are
willing to face the challenge that their clients face.
PMID- 10759045
TI - Minor head injury: predicting follow-up after discharge from the Emergency
Department.
AB - BACKGROUND: Up to 50% of ED patients discharged within a minor head injury (MHI)
will develop postconcussive syndrome (PCS) within 1 month of injury. The follow
up visit is an important opportunity to identify and treat PCS before it becomes
persistent. OBJECTIVE: To identify factors predictive of follow-up (FU) after ED
discharge in patients presenting with MHI. METHODS: Prospective, observational
study of a convenience sample of 71 MHI presenting within 24 hours of injury to
the ED of a university teaching hospital between February 1996 and October 1997.
MHI defined as loss of consciousness not greater than 10 minutes or amnesia, GCS
15, no skull fracture on PE, no new focality to neurologic exam and no brain
injury on CT if one was done. Neurobehavioural test scores, clinical information
and demographic data collected via use of standardized patient encounter form.
All patients were discharged with written instructions to FU with their private
physician within 1-2 weeks. Patients without a follow-up physician were assigned
one. At 1 month post-injury, all patients were telephoned to determine if they
had followed-up. ANALYSIS: Stepwise, multivariate, logistic regression. RESULTS:
Thirty one out of 71 (43.7%) reported FU with a physician within 1 month. Factors
associated with FU were performance of a head CT in the ED (OR = 3.58, 95% CI =
1.12-11.37), associated laceration (OR = 8.84, 95% CI = 1.69-42.55), female
gender (OR = 3.19, 95% CI = 1.04-9.82), and African-American race (OR = 0.36, 95%
CI = 0.13-0.99). CONCLUSIONS: Several factors predict FU after ED discharge for
MHI. Patients unlikely to FU may benefit from an assessment of PCS risk before
they leave the ED.
PMID- 10759046
TI - Music and the brain: the impact of music on an oboist's fight for recovery.
AB - A 20-year-old female, alias Sara, was an aspiring professional oboist who studied
music performance at college level. While wading across a river she lost her
balance, was swept down river, and suffered profound injuries including severe
hypothermia, cardiac arrest, and hypoxic brain injury. While recovering, her
family and friends surrounded Sara with music. Her oboe teacher placed Sara's
oboe in her hand and played tapes of Sara's past performances. Her mother played
recordings of her favourite music in hopes that the music would remind her of her
life's passion and, thus, stimulate her mind and soul while she recovered. Two
years post-injury, Sara continues to strive to improve her quality of life. In
this case study, Sara's musical and medical recovery is detailed using
quantitative and qualitative data. This data gathered allows one to provide an
analysis of the powerful role of music in Sara's fight to recover.
PMID- 10759047
TI - Retrieved memories of childhood sexual abuse.
AB - About a century ago Freud sparked off a bitter controversy concerning alleged
recollections of childhood sexual abuse: Were they fact or fiction? Recently this
debate has been revived with intensity, with some professionals stubbornly taking
up entrenched and polarized positions. On the one side there are those who
continue to deny the veracity of all 'recovered memories', and thus also of the
implicated psychological defences of repression and dissociation. At the other
extreme are those therapists who assume that particular symptoms invariably imply
sexual abuse. There is a growing corpus of anecdotal, clinical and, more
recently, research evidence supporting the contention that childhood sexual
abuse, like all other trauma, can be forgotten for days, and even for many years,
before being recalled. However, the reconstruction of these memories is a complex
and, at times, a somewhat fallible process.
PMID- 10759048
TI - Attachment style in the context of clinical and health psychology: a proposal for
the assessment of valence, incongruence, and accessibility of attachment
representations in various working models.
AB - By combining the Adult Attachment Interview and the Autobiographical Memory Test,
a structured interview was developed as a 'quick and dirty' measure for the
assessment of attachment representations in clinical settings. The interview
intends to assess valence, incongruence, and accessibility of the attachment
representations that are organized in various mental models of relationships. In
this study the mental models of relationships involving parents and current
partner were addressed, as well as the more general model of self in
relationships with significant others. Validity was examined in a sample of
couples from the general community. Interrelationships between the different
models of attachment relationships were strong enough to warrant the conclusion
that each contributes to the same construct (style). Correlations with
theoretically proposed consequences of insecure attachment style showed salience
of specific working models: valence of self and partner (but not of parents)
representations, and incongruence of parental representations related to
depressive symptomatology, trait anxiety, relational quality, and communication
efficiency. Results indicated that assessment of representations in the working
models of different attachment relationships might prove useful in clinical
settings, as it might enable localization of those representations that are
related to the individual's experience of adversity in interpersonal
relationships and affect regulation. Methodological shortcomings are discussed in
this context.
PMID- 10759049
TI - Attachment research in eating disorders.
AB - AIM: In a recent review, disturbances in attachment have been linked with eating
disorder symptomatology. However, because of the limitations of study design, few
inferences could be drawn about these processes in the aetiology and maintenance
of eating disorder. Since that review, there has been further development in the
instruments used and the publication of several further studies of attachment
processes in eating disorders. We reviewed the field, expecting that greater
clarity may have emerged in the 3 years since the previous review. METHOD: A
review of the literature was carried out, using the computer search PsychLIT,
Medline, Embase and The Cochrane Library. RESULTS: There have been more studies
published in this area in the last 3 years than in the entire period up until
then. These can broadly be divided into those carried out in clinical and non
clinical populations, with greater weight ascribed to the former. The vast
majority of studies found that attachment processes, by whatever method measured,
are abnormal in eating disordered populations. Attachment style (dismissing
versus preoccupied) may be linked with eating disorder diagnostic subgroup.
CONCLUSIONS: Insecure attachment is common in eating disordered populations, with
implications for therapy. Further work with refined instruments may clarify
whether or not there is a specific association between attachment style and
eating disorder subgroup. However, such an association is likely to be
complicated and it may be more fruitful to study specific aspects of attachment,
rather than global attachment style, in relation to eating disorder behaviour.
The transgenerational transmission of attachment is a fruitful area for further
investigation in eating disordered populations.
PMID- 10759050
TI - The personal construction of death in anorexia nervosa.
AB - This paper reports a study concerned with an attempt to understand the manner in
which individuals at high objective risk of death through their own behaviour,
understand the phenomenon of death, and their own death. It is an extension of an
earlier empirical study (Warren et al., 1994) which in turn, set out to test a
hypothesis advanced by Jackson and Davidson (1986) that disturbed death ideation
was aetiologically significant in anorexia nervosa; and an extension of earlier
work on death constructions, and death education (Warren, 1984, 1989). Constructs
were elicited from a sample of hospitalized sufferers of anorexia nervosa. These
participants also completed the provided construct, Death Threat Index. Repertory
grids were analysed for the information they yield concerning death constructions
in sufferers of anorexia nervosa. Various quantitative measures were also derived
and compared with similar measures from a control group.
PMID- 10759051
TI - Anorexia nervosa: some connections with the religious attitude.
AB - This paper examines the religious and ascetic features of anorexia nervosa. The
concept of asceticism in the Judeo-Christian culture and the many connections
between the ascetic religious attitude and the anorexic are described. Whilst
empirical evidence for religious themes in anorexia is not strong, in the family
therapy literature there are indications of ethical codes of sacrifice, loyalty
and sexual denial in the families of anorexics. The themes of sin, denial and
self-punishment in the Judeo-Christian tradition are then discussed and the
significance of the original sin with respect to both eating and sex emphasized.
The psychological features of the ascetic mode are then described. It is argued
that there exist many connections between the religious ascetic and the anorexic
and that there are many psychopathological features common to both. Both anorexia
and asceticism are considered to be connected conceptually in the process of
idealization. It is suggested that this line of enquiry can enrich clinical
approaches to the understanding and treatment of this neurotic disorder and
stimulate further research.
PMID- 10759052
TI - Preventing psychological trauma in soldiers: the role of operational stress
training and psychological debriefing.
AB - Armed conflict is associated with significant long-term psychiatric morbidity.
Interventions to reduce the incidence of psychiatric disorder following
psychological trauma may be classified into three categories. Primary prevention
includes the selection, preparation and training of individuals likely to be
exposed to potentially traumatizing events. Secondary prevention comprises a
variety of brief psychological techniques immediately or shortly after
traumatizing life events, the best known of which is Psychological Debriefing.
Tertiary interventions comprise the treatment of established PTSD and others.
Psychiatric morbidity was studied in 106 British soldiers returning from UN peace
keeping duties in the former Republic of Yugoslavia. All 106 soldiers received an
Operational Stress Training Package prior to their deployment and a randomly
selected group also received a post-operational PD. Very low rates of PTSD and
other psychopathology were found overall and the Operational Stress Training
Package may have contributed to this. Elevated CAGE scores suggestive of
significant alcohol misuse were observed in both groups and chemical avoidance
behaviours arising from this may have masked psychopathology. CAGE scores
diminished significantly in the debriefed group by the end of the follow-up
period suggesting that PD may have been of benefit despite the apparent absence
of PTSD. This study also demonstrates that a high incidence of psychiatric
morbidity is not an inevitable consequence of military conflict.
PMID- 10759054
TI - Measuring communication skills of medical students to patients with cancer.
AB - Progress in improving doctors' communication skills has been hampered by a lack
of consistent theoretical underpinning. Resource constraints have contributed
other problems, including difficulties in evaluating medical students'
communication skills. Although use of unpaid evaluators has helped to alleviate
these, differences between evaluator groups have led to a second generation of
problems concerning accuracy and reliability. To address these issues, a
conceptual clarification of doctor-patient communication is suggested. On its
basis, seven communication skills needed by doctors are identified and then
operationalized as a questionnaire measure of medical students' communication
skills when talking to patients about cancer. An unusual feature is that the
questionnaire can be used by lay and professional raters with only 1 hour of
training. An empirical study was undertaken of the properties of the
questionnaire. Generalizability theory, as well as more conventional approaches
to reliability, was used to examine systematically the differences between
simulator patient, psychologist and general practitioner raters. Results
suggested that the questionnaire was of satisfactory overall reliability and
validity. An unexpected finding was that more efficient future use of it might
accrue if general practitioner raters are not used. Further uses of the
questionnaire in theoretical and applied fields are suggested.
PMID- 10759053
TI - The influence of occupational debriefing on post-traumatic stress symptomatology
in traumatized police officers.
AB - Certain individuals, such as police officers, are exposed to traumatic events as
part of their occupational roles. In an effort to prevent psychological
illnesses, notably the post-traumatic stress disorder, from arising out of work
related traumatic incidents, psychological interventions have been developed such
as Critical Incident Stress Debriefing (Mitchell, 1983; Mitchell & Everly, 1996).
The present study tests the hypothesis that debriefing reduces the psychological
morbidity caused by work-related incidents. Because debriefing techniques were
not designed for application on a 'one-off' basis (Robinson & Mitchell, 1993),
the procedure studied here consisted of three successive debriefing sessions (at
24 hours, 1 month and 3 months post-trauma), which included traumatic stress
education. In a sample of 243 traumatized police officers, a subgroup of
debriefed officers (N = 86) was compared with non-debriefed internal (N = 82) and
external (N = 75) control groups. No differences in psychological morbidity were
found between the groups at pre-test, at 24 hours or at 6 months post-trauma. One
week post-trauma, debriefed subjects exhibited significantly more post-traumatic
stress disorder symptomatology than non-debriefed subjects. High levels of
satisfaction with debriefing were not reflected in positive outcomes. The
findings are translated into recommendations for the future use of debriefing in
police practice.
PMID- 10759055
TI - Availability bias in clinical formulation: the first idea that comes to mind.
AB - This study tested whether initial client formulations are based simply on the
ideas that come most readily to mind, irrespective of the validity of these
ideas. This phenomenon is known in decision theory literature as availability
bias. The study tested the influence of two possible sources of availability bias
in formulation: (a) theoretical orientation; and (b) a suggestion in a referral
letter. Forty-four qualified and 20 trainee clinical psychologists participated
in a procedure designed to reflect clinical practice. Clinical materials
consisted of a fictional referral letter describing a client with adult
attachment difficulties and post-traumatic stress disorder. Participants recalled
information from the referral letter, described their areas of further interest
and initial hypotheses. Results showed no evidence of an availability bias in
clinical formulation as a result of theoretical orientation. Theoretical
orientation towards attachment did appear to influence the availability of
attachment ideas and predicted clinicians taking a stronger attachment focus when
discussing the client. In particular, a self-report measure of theoretical
orientation demonstrated high predictive validity. However, orientation towards
attachment did not predict bias in the sense of selective recall of attachment
information or neglect of alternative psychological frameworks. The study
provided an inadequate test of availability bias as a result of a suggestion in
the referral letter, possibly due to a ceiling effect, and no conclusions can be
drawn as to clinical materials as a potential source of availability bias. The
discussion addresses implications for further research and for a scientist
practitioner approach to individual case formulation.
PMID- 10759056
TI - Psychometric properties of the Hospital Anxiety and Depression Scale with a
population of members of a depression self-help group.
AB - This paper reports the psychometric properties of the Hospital Anxiety and
Depression Scale when used with 341 members of a self-help group for people with
depression. We report internal reliability and factor structure for the complete
data set and factor structure for groups split by gender, previous
hospitalization for depression and current use of medication for depression. In
each instance the factor structure reflects the intended depression and anxiety
subscales. We comment on the usefulness of the HADS in studies of cognitive
processes in depression and anxiety.
PMID- 10759057
TI - Attitudes towards emotional expression, relational competence and psychological
distress.
AB - The association between life events and psychological distress was found to be
mediated by attitudes towards emotional expression for those with low social
support but not for those with high social support. Passive interpersonal
behaviour significantly accounted for additional variance in psychological
distress to that accounted for by life events and attitudes.
PMID- 10759058
TI - Weight gain and hormone replacement therapy: are women's fears justified?
AB - Fear of weight gain is one of the main factors contributing to the poor
compliance seen with hormone replacement therapy (HRT). Although an increase in
weight can be a result of rehydration, (which in turn may alleviate some of the
effects of skin ageing), many women consider weight gain to be cosmetically
unacceptable. Moreover, excess body weight or certain patterns of body fat
distribution can lead to health problems such as cardiovascular disease and
breast cancer. The menopause is associated with a decrease in the resting
metabolic rate that reduces the utilisation of calories and hence increases body
weight. A number of studies have shown that weight gain is greatest in the peri
menopausal years. There also appears to be a redistribution of fat mass at the
time of the menopause, with an increase in the waist-to-hip ratio. Although it is
a common belief that HRT inevitably causes weight gain, available evidence
suggests that this is not true. Indeed, some HRT regimens, such as continuous
17beta-oestradiol 2 mg/day combined with sequential dydrogesterone 10 mg/day for
14 days/cycle (Femoston), may actually help to prevent an increase in body fat
mass and fat redistribution. Informing women about the effects of the menopause
on body weight/fat distribution and the potential beneficial effects of some HRT
regimens should help to improve HRT compliance.
PMID- 10759059
TI - Libido: the biologic scenario.
AB - Libido is a comprehensive and yet elusive word that indicates basic human mental
states--and their biological counterparts--involved in the beginning of sexual
behavior. It has three main roots: biological, motivational-affective and
cognitive. All these dimensions may be variably affected in the post menopause,
contributing to a progressive decrease of sexual drive that parallels the process
of aging. Loss of estrogens and, specifically, of androgens deprives female
libido of major biological fuel. The effect of this loss is pervading, affecting
the central nervous system, the sensory organs that are the major windows to
environmental sexual stimuli and the quality of sexual response, central,
peripheral non-genital and genital. Prolactin increase may further inhibit
libido. Arousal disorders, dyspareunia, orgasmic difficulties, dissatisfaction,
both physical and emotional, may contribute to a secondary loss of libido.
Depression, anxiety and chronic stress, may interfere with central and peripheral
pathways of the sexual response, reducing the quality of sexual function mostly
in its motivational root. Relational conflicts and/or marital delusions and
partner-specific problems, erectile deficit first, may contribute to the fading
of sexual drive in the post-menopausal years. Well tailored HRT, including
androgens in selected cases, may reduce the biological causes of loss of libido.
A comprehensive treatment requires a balanced evaluation between biological and
psychodynamic factors.
PMID- 10759060
TI - Hormonal replacement regimens and bleeding.
AB - Hormone replacement therapy may increase the quality of life of postmenopausal
women. Any regimen need to offer long-term endometrial safety. It is a standard
to consider the co-administration of a sequential progestogen when estrogen
replacement should be initiated in non-hysterectomized women. It is almost
impossible to decide which combination of an estrogen and a progestogen seems to
be optimal as individual tolerance of HRT may very well limit acceptability
despite metabolic benefits and proven endometrial safety of a given combination.
Several combinations of oral and transdermal estradiol or conjugated equine
estrogens, oral progestogens, transdermal norethisterone acetate and
levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety.
It is noteworthy that there is no uniform correlation between the timing of onset
of bleeding induced by any sequential estrogen and progestogen replacement and a
certain pattern of histology. Therefore, although it is likely, there is no
absolute reassurance that regular bleeding on or after day 11 of progestogen
administration rules out abnormal histopathology. Transvaginal sonography seems
not to be of pivotal importance to screen asymptomatic women on replacement
therapy for detection of serious abnormal endometrial findings such as
hyperplasia and endometrial cancer. Continuous combined hormone replacement
therapy or the use of tibolone may be an alternative in postmenopausal women, who
do not want any uterine bleedings after menopause. However, spottings or
bleedings most often occur at the beginning of treatment. Vaginal administration
of estriol and estradiol for urogenital symptoms of estrogen deficiency may
stimulate the endometrium unintentionally. Available data suggest that use of
oral estriol may be associated with endometrial hyperplasia and endometrial
carcinoma relatively more often compared to sequential HRT. Raloxifene, a
benzothiophene derivative acting as a selective estrogen receptor modulator
approved for prevention of vertebral osteoporosis, rarely causes uterine
bleeding. There is no ideal therapy available to suit women looking for a
permanently bleed-free hormonal replacement therapy today.
PMID- 10759061
TI - Urinary problems around the menopause; emotional and psychological consequences;
can we help our patients to cope with them?
PMID- 10759062
TI - Contraception and the menopause.
PMID- 10759063
TI - Current source density analysis of ON/OFF channels in the frog optic tectum.
AB - In the vertebrate retina, it is well known that an ON/OFF dichotomy is present.
In other words, ON-center and OFF-center cells participate in segregated pathways
morphologically and physiologically. However, there is no doubt that integration
of both channels is necessary to generate the complicated response properties of
visual neurons in higher optic centers. So far, functional organization of the ON
and OFF channels in the optic centers has not been demonstrated at the level of
neuronal populations. In this review article, we summarize our experimental
approaches to demonstrate functional organization of the ON and OFF channels
using current source density (CSD) analysis in the frog optic tectum. First, we
show that one-dimensional CSD analysis, assuming constant conductivity, is
applicable in the tectal laminated structure. The CSD depth profile of a response
to electrical stimulation of the optic tract is composed of three current sinks
(A, B, and D) in the retinorecipient layers and two current sinks (C and E) below
those layers. This result is in agreement with previous morphological and
physiological findings, and shows that CSD analysis is very useful to demonstrate
the flow of visual information processing. Second, CSD analysis of tectal
responses evoked by diffuse light ON and OFF stimuli reveals obviously different
distributions of synaptic activity in the laminar structure. Two or three current
sinks (I, II and III) are generated in response to ON stimulation only in the
retinorecipient layers, while up to six current sinks (IV, V, VI, VII, VIII and
IX) to OFF stimulation throughout the tectal layers. Based on well known
properties of retinal ganglion cells of the frog, possible neuronal mechanisms
underlying each current sinks and their functional roles in visually guided
behavior are considered.
PMID- 10759064
TI - JNK and p38 stresskinases--degenerative effectors of signal-transduction-cascades
in the nervous system.
AB - The c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases.
SAPKs) and p38 kinases constitute together with extracellular signal-regulated
kinases (ERKs) the family of MAP kinases. Whereas the functions of JNKs under
physiological conditions are largely unknown, there is raising evidence that JNKs
are potent effectors of apoptosis or degeneration of neurons in vitro and in the
brain. The activation of the inducible transcription factor c-Jun by N-terminal
phosphorylation is a central event in JNK-mediated degenerative processes that
depend on de novo protein synthesis. At the post-translational level, cytoplasmic
degenerative actions of JNKs might comprise inhibition of Bcl-2 and steroid
hormone-receptor signaling or hyperphosphorylation of tau; and at transcriptional
level, JNKs might trigger the induction of the apoptotic effectors p53 and Fas
Ligand by phosphorylation of c-Jun. The role of p38 is the nervous system is
poorly understood, but its activation is also considered as part of the neuronal
stress response. This review informs about the genetic processing, the regulation
of activity and the biochemical actions of JNK and p38 isoforms in general. In
the second part, we summarize the findings on expression and activation of JNKs
and p38 under neurodegenerative condition. A particular focus is also put on the
putative function of JNK under physiological conditions and for neuroprotection.
PMID- 10759065
TI - Neural development and neurodegeneration: two faces of neuropathy target
esterase.
AB - Neuropathy target esterase (NTE) is an integral membrane protein in vertebrate
neurons. Recent evidence suggests that NTE plays an important role in neural
development, possibly via involvement in a signalling pathway between neurons and
glial cells. NTE is a member of a novel protein family, represented in organisms
from bacteria to man. NTE comprises an N-terminal regulatory domain (with some
sequence similarity to cyclic nucleotide-binding proteins) and a C-terminal
catalytic domain: the latter has three predicted transmembrane segments and
requires membrane-association for activity. In vitro, NTE potently catalyses
hydrolysis of phenyl valerate: however, its physiological substrate is likely to
be a metabolite of a much longer chain carboxylic acid, possibly associated with
cell membranes. NTE was discovered originally as the primary target for those
organophosphorus esters (OPs) which cause a delayed neuropathy with degeneration
of long axons in peripheral nerves and spinal cord. Paradoxically, NTE's
catalytic activity appears redundant in adult vertebrates. Neuropathic OPs react
covalently with NTE in a rapid two-step process which not only inhibits catalytic
activity but also leaves a negatively-charged OP group attached to the active
site serine. The latter event is proposed to induce a toxic gain of function in
NTE. OP-modified NTE somehow engenders a "chemical transection of the axon". In
turn, this leads to calcium entry, elevation of axonal calpain activity and
Wallerian-type degeneration. The net damage to peripheral nerve axons is a
balance between ongoing degenerative and repair processes: the latter involve
serine hydrolases which can be inhibited by the same OPs used to modify NTE.
PMID- 10759066
TI - Neuronal nicotinic receptors in the human brain.
AB - Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand gated
ion channels which are widely distributed in the human brain. Multiple subtypes
of these receptors exist, each with individual pharmacological and functional
profiles. They mediate the effects of nicotine, a widely used drug of abuse, are
involved in a number of physiological and behavioural processes and are
additionally implicated in a number of pathological conditions such as
Alzheimer's disease, Parkinson's disease and schizophrenia. The nAChRs have a
pentameric structure composed of five membrane spanning subunits, of which nine
different types have thus far been identified and cloned. The multiple subunits
identified provide the basis for the heterogeneity of structure and function
observed in the nAChR subtypes and are responsible for the individual
characteristics of each. A substantial amount of information on human nAChR
structure and function has come from studies on neuroblastoma cell lines which
naturally express nAChRs and from recombinant nAChRs expressed in Xenopus
oocytes. In vitro brain nAChR distribution can be mapped with a number of
appropriate agonist and antagonist radioligands and subunit distribution may be
mapped by in situ hybridization using subunit specific mRNA probes. Receptor
distribution in the living human brain can be studied with noninvasive imaging
techniques such as PET and SPECT, with a significant reduction in nAChRs in the
brains of Alzheimer's patients having been identified with [11C] nicotine in PET
studies. Despite the significant body of knowledge now accumulated about nAChRs,
much remains to be elucidated. This review will attempt to describe the current
knowledge on the nAChR subtypes in the human brain, their functional roles and
neuropathological involvement.
PMID- 10759067
TI - Validation of an ion-trap gas chromatographic-mass spectrometric method for the
determination of cocaine and metabolites and cocaethylene in post mortem whole
blood.
AB - The coingestion of cocaine (COC) and ethanol is a very frequent occurrence and is
known to increase the risk of morbidity and mortality. The formation occurs of a
transesterification product, the cocaethylene (CE), which is even more toxic than
cocaine. In order to study the role of ethanol as an agent of interaction in
lethal cocaine intoxication, and to establish its influence in post mortem
cocaine concentrations, an ion-trap gas chromatographic-mass spectrometric method
(GC-MS) was validated to quantify simultaneously the agent and its
biotransformation products, benzoylecgonine (BE), ecgoninemethylester (EME) and
the 'biomarker' of the interaction, the CE present in whole blood. Deuterated
internal standards were added to 2 ml of post mortem whole blood and extracted in
Bond Elut Certify columns. The residues were evaporated and derivatized with N
methyl-N-t-butyldimethylsilyltrifluoroacetamide (MTBSTFA). Detection was
performed by electron impact ionization. The monitored ions were m/z 82/85 for
EME-tert-butyldimethylsilyl (TBDMS)/EME-d3-TBDMS; m/z 182/185 for COC/COC-d3; m/z
196/199 for CE/CE-d3 and m/z 282/285 for BE-TBDMS/BE-d3-TBDMS. The limits of
detection and quantification were found to be 25 ng and 50 ng ml(-1),
respectively, for COC and CE, and 50 and 100 ng ml(-1) for BE and EME. Accuracy
was different for each of the compounds, varying from 65 to 98%. The dynamic
range of the assay was 50-2000 ng ml(-1).
PMID- 10759068
TI - Forensic anthropology in Latin America.
AB - Forensic anthropology has been one of the fastest growing medico-legal
disciplines both in its contribution to the practical needs of the legal system
and research accomplishments. New anthropological standards were developed to
apply to a specific population of a region. The purpose of this paper is to
analyze a large sample of anthropological forensic cases and to review pertinent
literature that deals with anthropological standards developed for the population
of the continent of Central and South America. Using Uruguay as an example, there
was not a single office or anthropologist assigned to analyze human skeletal
remains in Uruguay. In 1991 the Laboratorio de Antropologia Forense at the Morgue
Judicial of Montevideo was created. A total of 189 forensic anthropological cases
(276 individuals) were analyzed since this date. Twenty six percent of cases
involving human remains were positively identified. The majority came from the
Departamento de Montevideo, the largest population district of the country. Most
of the cases fell into the 60 to 69 years old age range (35%). Females
represented 32% of the total. Since the establishment of the laboratory, the
number of forensic cases increased considerably from 20 in 1991 to 40 in 1997.
The case studies were accompanied with skull-photo superimposition and facial
reconstruction when no other evidence for positive identification was available.
This service provided by the laboratory was quickly known to coroners, law
enforcement agencies, and other legal authorities and thus utilized not only in
Uruguay but also in several other countries in the continent. Because of the
obvious need for an anthropologist, there are now university programs to provide
forensic anthropological education. Yet, research has lagged behind considerably.
Deficiencies are obvious in basic osteological standards of estimating age,
calculating stature, determining sex and assessing race that can be applied to
populations of the continent. Regional standards are also needed to estimate
postmortem interval, to identify culture specific causes of trauma and other
forensic phenomena. Some of these can be remedied if there is a database where
the available literature is stored and osteometric information is shared.
PMID- 10759069
TI - Estimation of short-term postmortem interval utilizing core body temperature: a
new algorithm.
AB - The use of temperature-based short-term postmortem interval (PMI) estimation
methods can be useful to homicide investigators at the scene of a questionable
death; however, a number of current PMI estimation techniques have high error
rates such that they are of limited utility to law enforcement investigators and
forensic professionals. These methods fail to control confounding errors present
in individual data. An averages-based method of short term postmortem interval
estimation was compared to eight other methods, and found to predict postmortem
interval considerably more accurately, and for much longer periods of time.
PMID- 10759070
TI - Temperature-correction of abdominal impedance: improved relationship between
impedance and postmortem interval.
AB - The relationship between extracellular abdominal impedance and postmortem
interval (PMI) reflects the combined effects, on impedance, of postmortem cooling
of the tissues and of autolysis per se. This study was performed in order to
eliminate temperature change as a major factor contributing to the time course of
postmortem change in abdominal impedance. Dissociation of thermal and autolytic
influences was achieved by recording deep abdominal temperature at the time of
impedance measurement, followed by correction of all measured impedances to their
theoretically predicted values at an arbitrarily chosen temperature of 40 degrees
C. Uncorrected abdominal impedance increased from 82+/-12 Ohmz, 1 h after death,
to 108+/-21 Ohmz after 12 h. Impedance then decreased to 96+/-23, 89+/-22, 75+/
19, 66+/-21 and 59+/-19 Ohmz at postmortem intervals of 24, 36, 48, 60 and 72 h,
respectively. In contrast, corrected abdominal impedance decreased progressively
from 63+/-7 Ohmz, 1 h after death, to 61+/-9, 56+/-11, 51+/-10, 46+/-10, 39+/-11
and 35+/-10 Ohmz at postmortem intervals of 12, 24, 36, 48, 60 and 72 h,
respectively. The improved relationship between (corrected) abdominal impedance
and PMI is of potential value in estimating time since death.
PMID- 10759071
TI - A sandwich enzyme immunoassay for pulmonary surfactant protein D and measurement
of its blood levels in drowning victims.
AB - A sensitive sandwich enzyme immunoassay for human pulmonary surfactant protein D
(SP-D) was developed and used to examine the blood SP-D levels of drowning
victims. Human SP-D was purified from amniotic fluid by chromatographic methods,
and an antibody against human SP-D was prepared. A polystyrene ball coated with
anti-SP-D IgG was incubated with purified human SP-D, and then with anti-SP-D
Fab'-peroxidase conjugate. Peroxidase activity bound to the polystyrene ball was
assayed by fluorometry using 3-(4-hydroxyphenyl)propionic acid as the hydrogen
donor. The detection limit of human SP-D was 5.2 pg per assay tube. Examination
of cross-reactions of this sandwich enzyme immunoassay with proteins from other
human organs showed it to be highly specific for lung, and Northern blot analysis
detected specific SP-D mRNA expression only in lung. The SP-D concentration of
normal human serum was 6.4+/-2.7 (mean+/-S.D.) ng ml(-1) (n=20). The recovery
rates of 0.52 ng and 5.2 ng SP-D added to 5 microl normal human serum were 93.6+/
2.7% and 93.6+/-6.1%, respectively. Blood SP-D levels of victims from the
saltwater drowning group (n=14) revealed higher concentrations (105.8+/-53.7 ng
ml(-1)), while freshwater drowning victims (n=12) were estimated to be 74.1+/
43.9 ng ml(-1). The SP-D levels of 15 subjects who died of hemorrhage (n=5),
heart failure (n=8), traumatic shock (n=1), and electrocution (n=1) were lower
(22.0+/-8.5 ng ml(-1)), and those of asphyxia victims (n=10) were slightly higher
(36.2+/-17.1 ng ml(-1)) than those of other causes of death, except for drowning.
These results suggest that in drowning victims, SP-D flowed into the systemic
circulation by physiological and physical mechanisms, and the differences of
blood SP-D levels between saltwater drowning and freshwater drowning victims are
presumed to be influenced by the type of agony and/or the length of survival time
in water.
PMID- 10759072
TI - The epidemiological study on registered cases of sudden infant death syndrome
(SIDS) in Tokyo: examination of the effect of autopsy on diagnosis of SIDS and
the mortality statistics in Japan.
AB - In the United States and most of European countries, a diagnosis of sudden infant
death syndrome (SIDS) may be given only after an autopsy has been performed.
Under the new definition of SIDS in Japan, an autopsy is now mandatory for the
diagnosis of SIDS. However, according to the official records on autopsies, the
proportion of autopsy for sudden infant death in Japan is still low (less than
30%). If a physician suspects SIDS from a review of the patient's medical history
and medical findings, he can write 'suspected SIDS' as the cause of death on the
death certificate without performing an autopsy. Such a clinical diagnosis is
entered in the Vital Statistics section by the Japanese Ministry of Health and
Welfare. In this report, a comparative epidemiological survey of registered cases
of SIDS--after autopsy and with no autopsy--was carried out by examining the data
from the death certificates registered by the Japanese Ministry of Health and
Welfare (vital statistics in Tokyo from January 1979 to December 1996). There
were 369 cases of SIDS registered in Tokyo. We found 247 diagnosed after autopsy
(66.9%) and 122 with no autopsy (33.1%). The following epidemiological variables
were used: address of the deceased (a specific area in Tokyo), sex, year of
death, time of death, month of death, age at death, occupation of householders,
and place of death. There were epidemiological differences at the 0.05
significance level between registered cases diagnosed after autopsy and those
diagnosed without autopsies, as follows: year (P=0.016) and place of death
(P=0.037). In addition, there were slight epidemiological differences at the 0.10
significance level between registered cases diagnosed after autopsy and with no
autopsy, as follows: month of death (P=0.076) and age at death (P=0.082). This
suggests that the quality of diagnosis of SIDS is not completely guaranteed. With
respect to the area of residence, the incidence of SIDS is high in those areas
where autopsy is performed frequently. In Tokyo, the medical examiner system is
enforced only in the urban area and there is a possibility that SIDS is being
underdiagnosed in the rural area of the Metropolitan Tokyo. It is likely that the
diagnosis of SIDS without autopsy will influence the quality of SIDS diagnoses.
The administrative inadequacy in the autopsy system in Japan should be corrected
to improve the accuracy of SIDS diagnosis.
PMID- 10759073
TI - Coping with post-lingual severe-profound hearing impairment: a grounded theory
study.
AB - The purpose of this study was to describe the experiences of coping with
demanding auditory situations in everyday life from the perspective of
individuals with severe-profound hearing impairment. Seventeen individuals (11
women and 6 men), with post-lingual severe-profound hearing impairment
participated in the study. All were patients at the Department of Audiology,
Sahlgrenska University Hospital in Goteborg, Sweden. Inclusion criteria were a
hearing impairment exceeding 70 dB HL at the frequency of 1 kHz in the better
ear, and full-time employment. Data were assessed by in-depth interviews lasting
about one hour. The interviews were transcribed verbatim and analysed line-by-in
line in accordance with the grounded theory tradition. Six theoretical
constructs, or categories, were grounded in the data. These categories were
labelled 'coaching', 'belonging to two worlds', 'self-efficacy', 'hardiness' and
'directing coping strategies'. In a grounded theory the central phenomenon on
which all the other categories are integrated is known as the 'core category'.
The core category, which emerged in the present study, was labelled 'finding flow
and entering a positive circle'. This was described as a condition necessary for
successful coping with the demanding situation of being a profoundly hearing
impaired person working full-time. According to the core category, there is a
small 'margin' within the positive circle (a space where smaller mistakes may
occur). However, if mistakes are too severe, or too many, individuals will no
longer find flow in the positive circle, rather they enter a negative circle. In
the present study subjects' personalities were characterized by hardiness. It is
suggested that coaching behaviour and the hearing-impaired individuals'
personality dispositions of hardiness and self-efficacy function as resistance
resources, buffering stressful events in everyday life.
PMID- 10759074
TI - Prediction of quality of life in patients with tinnitus.
AB - According to epidemiological studies of tinnitus prevalence, 0.5-1% of
respondents report that tinnitus severely affects their ability to lead a normal
life. In the present investigation quality of life and its association with
tinnitus-related factors: psychological, psychosomatic and audiological, was
studied based on a sample of 122 patients, who attended the hearing clinic for
distress due to tinnitus. A stepwise regression analysis was performed with
quality of life as a dependent variable. Six of 13 variables included in the
model proved to be significant regressors and to explain 65% of the variance. The
six predictor variables were: impaired concentration, feeling depressed,
perceived negative attitudes, hypersensitivity to sounds, average hearing level
(best ear) and tinnitus duration (the shorter the duration of tinnitus the more
negative impact on quality of life). The three most significant predictors were
directly related to perceived psychological distress and explained most of the
variance in quality of life in tinnitus patients included in this study. An
unexpected finding was that fluctuations in tinnitus, vertigo, headache or
perceived social support did not prove to belong to the significant regressors.
The results are discussed in view of the construct of quality of life, depressive
cognitions and social support in general, as well as in tinnitus-specific life
circumstances.
PMID- 10759075
TI - Comparison of the NAL(R) and Cambridge formulae for the fitting of linear hearing
aids.
AB - This paper describes a laboratory-based comparison of the effectiveness of two
formulae for fitting linear hearing aids, the NAL(R) formula and the Cambridge
formula. The formulae prescribe the desired insertion gain as a function of
frequency, based on the audiometric threshold. The two formulae have a similar
rationale; both are based on the goal that, for speech with a moderate level, all
frequency bands should be equally loud (equal loudness per critical band) over
the frequency range important for speech (400-5000 Hz), and the overall loudness
should be comfortable. However, the formulae differ; generally the Cambridge
formula leads to slightly more high-frequency gain (above 2 kHz) and slightly
less mid-frequency gain (between 500 Hz and 2000 Hz) than the NAL(R) formula. The
two formulae were implemented using an experimental digital hearing aid whose
frequency-gain characteristic could be controlled very precisely. A loudness
model (Moore and Glasberg, 1997) was used to adjust the overall gains for each
subject and each formula so that a speech-shaped noise with an overall level of
65 dB SPL would give the same loudness as for a normally hearing person
(according to the model). The adjustments were, on average, smaller for the
Cambridge than for the NAL(R) formula. A condition was also used with all
insertion gains set to zero, simulating unaided listening. Evaluation was based
on: (1) subjective ratings of the loudness, intelligibility and quality of
continuous discourse presented in quiet at levels of 45, 55, 65 and 75 dB SPL and
in babble at an 0-dB speech-to-babble ratio, using speech levels of 55, 65 and 75
dB SPL; (2) measures of the speech reception threshold (SRT) in background noise
for two noise levels (65 and 75 dB SPL) and four types of background noise.
Neither the subjective ratings nor the measures of the SRTs revealed any
consistent difference between the results obtained using the two formulae,
although both formulae led to lower (better) SRTs than for simulated unaided
listening. It is concluded that the differences between the NAL(R) formula and
the Cambridge formula are too small to have measurable effects, at least in a
laboratory setting.
PMID- 10759076
TI - A modified pure tone audiometry technique for medico-legal assessment.
AB - A modified method of pure tone audiometry (PTA) in which the auditory threshold
is approached from silence in ascending steps, with tone presentations of 1-4
seconds and interval durations of 1.5-5 seconds was assessed against the British
Society of Audiology (BSA) method of PTA in terms of its ability to establish
valid thresholds in cases of non-organic hearing loss, prevalent in medico-legal
testing. The results reveal that the modified technique of PTA is a valid
threshold measurement for honest subjects, and yields less non-organic overlay
than the standard method of PTA in cases of non-organic hearing loss.
PMID- 10759077
TI - A five-year longitudinal study of hearing in a Danish rural population aged 31-50
years.
AB - This paper aims to report changes in hearing sensitivity over five years in a
rural population aged 31-50 years and to identify risk factors associated with
hearing deterioration. The study is prospective and based on data from pure tone
audiometry and questionnaires in the Ebeltoft Health Promotion Project in
Denmark. A representative sample of 705 subjects had a complete follow-up,
including audiometry. The median hearing deterioration was 2.5 dB at 3-4 kHz and
0 dB at 0.5-2 kHz. There was a high degree of individual variability in
deterioration. The overall deterioration of hearing sensitivity of the population
was largely predicted from the cross-sectional findings reported previously. In
the analysis of risk factors, hearing deterioration was defined as an average
deterioration 10 dB/5 years at 3-4 kHz in at least one ear. Deterioration was
present in 23.5% of the sample. The 41-50-year-olds had a relative risk of
deterioration of 1.32 (95% CI 1.01-1.73) compared with the 31-40-year-olds. Males
had a relative risk of 1.35 (1.03-1.76) compared with females. The risk was not
significantly elevated for a range of other possible risk factors confirmed by
logistic regression analysis. In conclusion, deterioration in hearing sensitivity
on population level can be predicted on the basis of cross-sectional findings.
Hearing sensitivity deteriorated mainly at 3-4 kHz. The deterioration increased
with age and was higher in males than in females. Other risk factors were not
found. The present study does not support the hypothesis that hypertension or
tobacco smoking is associated with deterioration in hearing.
PMID- 10759078
TI - Hearing assessment in general practice, schools and health clinics: guidelines
for professionals who are not qualified audiologists. Education Committee of the
British Society of Audiology.
PMID- 10759079
TI - Managing the transition to universal neonatal hearing screening--the missing
link.
PMID- 10759080
TI - Plasmodium falciparum EBA-175 kDa protein peptides which bind to human red blood
cells.
AB - Solid experimental evidence indicates that EBA-175 is used as a ligand by the
Plasmodium falciparum merozoite to bind to human RBC, via different binding
processing fragments. Using synthetic peptides and specific receptor-ligand
interaction methodology, we have identified 6 high-activity binding sequences
from the EBA-175 CAMP strain; peptide 1758 (KSYGTPDNIDKNMSLIHKHN), located in the
so-called region I for which no binding activity has been reported before,
peptides 1779 (NIDRIYDKNLLMIKEHILAI) and 1783 (HRNKKNDKLYRDEWWKVIKK), located in
region II, in a sub-region known as 5' Cys F2, previously reported as being a
binding region, and peptides 1814 (DRNSNTLHLKDYRNEENERH), 1815
(YTNQNINISQERDLQKHGFH) and 1818 (NNNFNNIPSRYNLYDKKLDL), in region III-V where
antibodies inhibit merozoite invasion of erythrocytes. The affinity constants
were between 60 and 180 nM and the critical amino acids involved in the binding
were identified. The binding of these peptides to enzyme-treated RBC was
analysed; binding of peptide 1814, located in the III-V region, was found to be
sialic acid dependent. Some of these high binding peptides were able to inhibit
in vitro merozoite invasion and to block the binding of recombinant RII-EBA to
RBC. Several of these peptides are located in regions recognized by protective
immune clusters of merozoites (ICMs) eluted antibodies.
PMID- 10759081
TI - A microsatellite marker reveals population heterogeneity within human and animal
genotypes of cryptosporidium parvum.
AB - Isolates of the protozoan parasite Cryptosporidium parvum have been
differentiated into 2 genotypes: genotype 'H', which is associated only with
human infections, and genotype 'C', which is associated with both human and
animal infections. To date, the analysis of polymorphisms of genes and of the
small subunit ribosomal DNA have revealed no heterogeneity within the 2
genotypes. In the present study, a locus containing simple sequence repeats
(microsatellites) was PCR amplified and sequenced from 94 C. parvum isolates,
which were collected from humans (immunocompetent and immunocompromized
individuals, outbreak and single cases) and from several animal hosts in 3
continents. The analysis revealed that genotype 'H' can be further differentiated
into 2 subgenotypes, and genotype 'C' can be further differentiated into 4
subgenotypes. The 6 subgenotypes differ in terms of expansions/contractions of
the microsatellite repeats and by point mutations. Some subgenotypes showed a
wide geographical distribution, whereas others were restricted to specific
regions. Therefore, microsatellites are informative markers for more defined
studies on the epidemiology, the transmission routes, and the population
structure of this parasite.
PMID- 10759082
TI - Detection of Theileria annulata in cattle and vector ticks by PCR using the Tams1
gene sequences.
AB - A Polymerase Chain Reaction (PCR) and Southern blot hybridization for the
detection of Theileria annulata are described. The PCR used primers amplifying a
785 base-pair fragment of the T. annulata gene which encodes the 30 kDa major
merozoite surface antigen, Tams1. The sensitivity of the PCR in bovine blood was
1 piroplasm in 1 microl of blood. T. buffeli, T. parva, Babesia bigemina, B.
bovis and B. divergens were not detected. The PCR detected down to 1 infected
acinus/tick in resting and partially fed adult Hyalomma anatolicum anatolicum
ticks and was negative for T. lestoquardi and T. equi, which are transmitted by
this tick but are not infective to cattle. The specificity of the PCR was checked
using 30 stocks of T. annulata, all of which were detected. Three stocks of T.
lestoquardi, 4 of T. equi and 1 each of T. buffeli, T. parva, B. bigemina, B.
bovis and B. divergens were used to ascertain there were no cross-reactions. A
nested PCR using separate primers for the first reaction and the same primers for
the second reaction detected T. annulata to the same sensitivity and specificity
in saponin-extracted DNA samples stored for long periods at -20 degrees C.
PMID- 10759083
TI - Coccidiosis in the European badger (Meles meles) from England, an epidemiological
study.
AB - In total 445 faecal samples were collected from 259 European badgers (Meles
meles) in Wytham Woods, Oxfordshire, UK (462080). Microscopical examination
revealed infection with 2 species of coccidia Eimeria melis and Isospora melis.
From the initial examination of each animal, point prevalence rates of 0.44 and
0.35 were calculated for Eimeria and Isospora respectively. The intensity of
infection was significantly greater for Eimeria than Isopora and the distribution
of intensities was highly skewed for both species, with a few individuals
shedding the majority of oocysts. Incidence and recovery rates for both coccidia
species were calculated from longitudinal data collected at 3-monthly intervals
from a subset of the adult badger population, and the predicted prevalence rates
based on these were similar to the point prevalence rates. This suggests little,
if any, parasite-induced mortality in the adult population. In contrast, there
was a marked and significant reduction in the point prevalence and intensity of
infection with Eimeria from cub to adult badger suggesting a degree of acquired
immunity to Eimeria melis on initial exposure and/or that there is significant
Eimeria-associated mortality in the cub population. No such relationship was
found for Isospora infection. In those adult badgers with co-infections there was
a direct relationship between the intensity of Eimeria and Isospora. The
taxonomic status of these parasites suggests a heteroxenous life-cycle for I.
melis, and direct transmission of E. melis. However, the greater than expected
prevalence of co-infection is consistent with a common source of infection, such
as communal latrines.
PMID- 10759084
TI - The use of statistical classifiers for the discrimination of species of the genus
Gyrodactylus (Monogenea) parasitizing salmonids.
AB - This study applies flexible statistical methods to morphometric measurements
obtained via light and scanning electron microscopy (SEM) to discriminate closely
related species of Gyrodactylus parasitic on salmonids. For the first analysis,
morphometric measurements taken from the opisthaptoral hooks and bars of 5
species of gyrodactylid were derived from images obtained by SEM and used to
assess the prediction performance of 4 statistical methods (nearest neighbours;
feed-forward neural network; projection pursuit regression and linear
discriminant analysis). The performance of 2 methods, nearest neighbours and a
feed-forward neural network provided perfect discrimination of G. salaris from 4
other species of Gyrodactylus when using measurements taken from only a single
structure, the marginal hook. Data derived from images using light microscopy
taken from the full complement of opisthaptoral hooks and bars were also tested
and nearest neighbours and linear discriminant analysis gave perfect
discrimination of G. salaris from G. derjavini Mikailov, 1975 and G. truttae
Glaser, 1974. The nearest neighbours method had the least misclassifications and
was therefore assessed further for the analysis of individual hooks. Five
morphometric parameters from the marginal hook subset (total length, shaft
length, sickle length, sickle proximal width and sickle distal width) gave near
perfect discrimination of G. salaris. For perfect discrimination therefore,
larger numbers of parameters are required at the light level than at the SEM
level.
PMID- 10759086
TI - Interferon-gamma induces secretion of trypanosome lymphocyte triggering factor
via tyrosine protein kinases.
AB - Bidirectional signalling between Trypanosoma brucei brucei and CD8+ T cells
involves reciprocal action of the parasite-derived trypanosome derived lymphocyte
triggering factor (TLTF) and lymphocyte-derived IFN-gamma. Herein we further
characterize this relationship and report quantitation of TLTF secretion into
culture supernatants using a newly developed ELISA. Secretion is induced by IFN
gamma in a dose-response manner, with 100 U/ml giving maximal yields of bioactive
TLTF as assessed by ELISA and ELISPOT. This is a constitutive and active
secretion. Furthermore, IFN-gamma-induced secretion was dependent on tyrosine
protein kinase activity. Specific blockers of this signalling system resulted in
lower yields of TLTF in the culture supernatants.
PMID- 10759085
TI - Parasitology and immunology of mice vaccinated with irradiated Litomosoides
sigmodontis larvae.
AB - This study was performed with Litomosoides sigmodontis, the only filarial species
which can develop from the infective larvae to the patent phase in
immunocompetent laboratory BALB/c mice. Parasitological features and immune
responses were analysed up to 3 months before and after challenge inoculation, by
comparing 4 groups of mice: vaccinated challenged, challenged only, vaccinated
only, and naive mice. Male larvae were very susceptible to irradiation and only
female irradiated larvae survived in vivo. Protection, assessed by a lower
recovery rate, was confirmed and was established within the first 2 days of
challenge. This early reduction of the recovery rate in vaccinated challenged
mice was determined by their immune status prior to the challenge inoculation.
This was characterized by high specific IgM and IgG subclass (IgG1, IgG2a and
IgG3) levels, high specific IL-5 secretion from spleen cells in vitro and a high
density of eosinophils in the subcutaneous connective tissue. Six h after the
challenge inoculation, most tissue eosinophils were degranulated in vaccinated
challenged mice. Thus, in the protocol of vaccination described, protection
appeared mainly to result from the stimulation of a Th2 type response and
eosinophils seemed to be the main effectors for the increased killing of
infective larvae in vaccinated challenged mice. Two months after challenge
inoculation, the percentage of microfilaraemic mice was lower in vaccinated
challenged mice as a consequence of this overall reduction in the worm load. In
both vaccinated challenged and challenged only groups, the in vitro splenocyte
proliferative capacity was reduced in microfilaraemic mice.
PMID- 10759087
TI - Survival and transmission of Anguillicola crassus Kuwahara, Niimi & Itagaki, 1974
(Nematoda) in seawater eels.
AB - The study aims were to quantify the survivorship of Anguillicola crassus in eels
in seawater and investigate transmission in estuarine (50% seawater) and marine
(100% seawater) simulated conditions. Most A. crassus were able to survive and
reproduce in 50% and 100% seawater eels for up to 6 months and therefore could
survive during the spawning migration of eels to the Sargasso Sea. Up to 10% of
the parasite metapopulation were damaged after long-term exposure to 50% or 100%
seawater. Transmission of A. crassus was completed in 50% and 100% seawater in
the laboratory, although infection levels in 100% seawater hosts were always
lower. Transmission in estuaries is ecologically possible since the copepod
Eurytemora affinis is susceptible to infection and is the dominant autochthonous
species in most tidal estuaries in the Northern hemisphere. Transmission at sea
is unlikely due to lack of suitable intermediate hosts. The data support the
suggestion that dissemination of A. crassus has been facilitated by natural
movement of eels in coastal waters. It is possible that A. crassus could impair
the success of the eel spawning migration to the Sargasso Sea, although there is
no direct evidence to support this.
PMID- 10759088
TI - Life-history strategies and population dynamics of abomasal nematodes in Svalbard
reindeer (Rangifer tarandus platyrhynchus).
AB - The observation that the total abundance of adult nematodes in the abomasum of
Svalbard reindeer increases between October and April suggests adaptation to cope
with the Arctic winter. Here we investigate the extent to which selection has led
to similar life-history strategies in the 3 most numerous trichostrongyle
species. The life-histories are found to differ markedly. We use flexible
statistical models for the abundance and dispersion of parasites in the host
population. One of the taxa, Marshallagia marshalli, was most abundant and had
its highest egg output in the winter. In contrast, the abundance of the most
common taxa, Ostertagia gruehneri, m. gruehneri was stable or declined from
autumn to late winter, and the closely related taxa, O. gruehneri, m. arcticus,
showed a similar over winter drop. The faecal egg output of these 2 taxa was
highest in summer, as found in temperate trichostrongyle species. Despite the
apparent contamination of summer pastures with O. gruehneri, calves showed
negligible burdens until their second summer and the abundance of infection
reached an asymptote within their third year. In contrast, the abundance of M.
marshalli in calves showed a rapid increase over the first summer and by late
winter was similar to peak levels found in adults (8000 worms). This increase
could not be accounted for by the developing abomasum larvae population and is
therefore evidence for transmission over the winter for this taxa. While M.
marshalli showed little between-year variation, O. gruehneri showed 2-fold
fluctuation in the abundance of infection. O. gruehneri may therefore play a role
in the fluctuating population dynamics of the host. Since there was no apparent
decline in abundance with host age in any of the 3 taxa there was no evidence of
reindeer mounting an immune response.
PMID- 10759089
TI - Predation of beetles (Tenebrio molitor) infected with tapeworms (Hymenolepis
diminuta): a note of caution for the manipulation hypothesis.
AB - Previous laboratory studies have indicated that tenebrionid beetles infected with
Hymenolepis diminuta display behavioural alterations. These are assumed to
increase the likelihood of this intermediate host being predated by the Rattus
sp. definitive host, and hence provide support for the Manipulation Hypothesis.
We tested this hypothesis by both assessing beetle behaviour and predation rates
in semi-naturalistic environments. Behavioural assays showed that infected
beetles were more often exposed (not concealed under boxes) than uninfected
beetles. However, there were no differences in predation rates between infected
and uninfected beetles. We discuss this in terms of the historical and
evolutionary contexts under which such altered behaviours could evolve and their
implications for the Manipulation Hypothesis.
PMID- 10759090
TI - Epidemiology and optimal foraging: modelling the ideal free distribution of
insect vectors.
AB - Existing models of the basic case reproduction number (R0) for vector-borne
diseases assume (i) that the distribution of vectors over the susceptible host
species is homogeneous and (ii) that the biting preference for the susceptible
host species rather than other potential hosts is a constant. Empirical evidence
contradicts both assumptions, with important consequences for disease
transmission. In this paper we develop an Ideal Free Distribution (IFD) model of
host choice by blood-sucking insects, predicated on the argument that vectors
must have evolved to choose the least defensive hosts in order to maximize their
feeding success. From a re-analysis of existing data, we demonstrate that the
interference constant, m, of the IFD can vary between host species. As a result,
the predicted distribution of insects over hosts has 2 desirable and intuitively
plausible behaviours: that it is heterogeneous both within and between host
species; and that the intensity of heterogeneity varies with host and vector
density. When the IFD model is incorporated into R0, the relationship with the
vector:host ratio becomes non-linear. If correct, the IFD could add considerable
realism to models which seek to predict the effect of these ecological parameters
on disease transmission as they vary naturally (e.g. through seasonality in
vector density or host population movement) or as a consequence of artificial
manipulation (e.g. zooprophylaxis, vector control). It raises the possibility of
targeting transmission hot spots with greater accuracy and concomitant reduction
in control effort. The robustness of the model to simplifying assumptions is
discussed.
PMID- 10759091
TI - The effects of propranolol on cognitive function and quality of life: a
randomized trial among patients with diastolic hypertension.
AB - PURPOSE: We sought to determine whether propranolol has adverse effects on
cognitive function, depressive symptoms, and sexual function in patients treated
for diastolic hypertension. SUBJECTS AND METHODS: We performed a placebo
controlled trial among 312 men and women, 22 to 59 years of age, who had
untreated diastolic hypertension (90 to 104 mm Hg). Patients were randomly
assigned to treatment with propranolol (80 to 400 mg/day) or matching placebo
tablets. Thirteen tests of cognitive function were assessed at baseline, 3
months, and 12 months. Five tests measured reaction time to, or accuracy in,
interpreting visual stimuli; one test measured the ability to acquire, reproduce,
and change a set of arbitrary stimulus-response sets; and seven tests measured
memory or learning verbal information. Depressive symptoms and sexual function
were assessed by questionnaires at baseline and 12 months. RESULTS: There were no
significant differences by treatment assignment for 11 of the 13 tests of
cognitive function at either 3 or 12 months of follow-up. Compared with placebo,
participants treated with propranolol had slightly fewer correct responses at 3
months (33 +/- 3 [mean +/- SD] versus 34 +/- 2, P = 0.02) and slightly more
errors of commission at 3 months (4 +/-5 versus 3 +/- 3, P = 0.04) and at 12
months (4 +/- 4 versus 3 +/- 3, P = 0.05). At 12 months, depressive symptoms and
sexual function and desire did not differ by treatment assignment. CONCLUSIONS:
Treatment of hypertension with propranolol had limited adverse effects on tests
of cognitive function that were of questionable clinical relevance, and there
were no documented adverse effects on depressive symptoms or sexual function.
Selection of beta-blockers for treatment of hypertension should be based on other
factors.
PMID- 10759092
TI - Cost effectiveness of ribavirin/interferon alfa-2b after interferon relapse in
chronic hepatitis C.
AB - PURPOSE: Many patients with chronic hepatitis C who are treated with interferon
suffer a relapse after an initial response. About half of these patients have a
sustained virological response to retreatment with the combination of ribavirin
and interferon alfa-2b. The aim of this study was to estimate the cost
effectiveness of retreatment with combination therapy versus interferon alone for
patients who have previously relapsed after interferon. SUBJECTS AND METHODS:
Data from a randomized trial among 345 relapsed patients that compared
combination therapy with interferon alone were used to project lifelong clinical
and economic outcomes. Natural history and economic estimates (discounted at 3%
per year) were based upon published literature, expert panel estimates, and cost
and reimbursement data. RESULTS: Compared with retreatment with interferon alone,
combination therapy should prolong life expectancy by about 2 discounted quality
adjusted life years (3 life years, undiscounted) while increasing costs modestly.
The results were robust, maintaining an advantage to combination therapy in
sensitivity analysis for all subgroups and with reasonable variations in all
model parameters. CONCLUSION: For patients with chronic hepatitis C who relapse
after an initial response to interferon alone, retreatment with the combination
of ribavirin and interferon alfa-2b should prolong life and be cost effective.
PMID- 10759093
TI - Acute myocardial infarction complicated by systemic hypoperfusion without
hypotension: report of the SHOCK trial registry.
AB - BACKGROUND: Cardiogenic shock is usually characterized by inadequate cardiac
output and sustained hypotension. However, following a large myocardial
infarction, peripheral hypoperfusion can occur with relatively well maintained
systolic blood pressure, a condition known as nonhypotensive cardiogenic shock.
The aim of this study was to determine the characteristics of patients with this
condition. METHODS: The SHOCK trial registry prospectively enrolled patients with
suspected cardiogenic shock complicating acute myocardial infarction. We
identified a group of 49 patients who presented with nonhypotensive shock,
defined as clinical evidence of peripheral hypoperfusion with a systolic blood
pressure >90 mm Hg without vasopressor circulatory support. Clinical
characteristics, hemodynamic data, and outcomes in these patients were compared
with a group of 943 patients with classic cardiogenic shock with hypotension. The
age, gender, and distributions of coronary risk factors were similar in both
groups. RESULTS: Patients with nonhypotensive shock were more likely to have an
anterior wall myocardial infarction (71% versus 53%, P = 0.03). Both groups of
patients had similar rates of treatment with thrombolytic therapy, angioplasty,
and bypass surgery. Patients with nonhypotensive shock had an in-hospital
mortality rate of 43% as compared with a rate of 66% among patients who had
classic cardiogenic shock with hypotension (P = 0.001). Mortality among 76
patients who presented with a systolic blood pressure <90 mm Hg but no
hypoperfusion was 26%. CONCLUSIONS: Even in the presence of normal blood
pressure, clinical signs of peripheral hypoperfusion, which may be subtle, are
associated with a substantial risk of in-hospital death following acute
myocardial infarction.
PMID- 10759094
TI - The prognosis of a first Q-wave versus non-Q-wave myocardial infarction in the
reperfusion era.
AB - PURPOSE: To compare the prognosis of patients with a first Q-wave versus non-Q
wave myocardial infarction (MI) in the reperfusion era. METHODS: Patients with a
first MI were compared according to type of infarct-Q-wave (n = 1,786) versus non
Q-wave (n = 722)-and by treatment with thrombolysis. RESULTS: Patients with non-Q
wave MI were more likely to be female and to have undergone previous coronary
revascularization. Their 30-day mortality rate was 7%, as compared with a rate of
9% among patients with Q-wave infarction (adjusted odds ratio [OR] = 0.6, 95%
confidence interval [CI]: 0.4 to 0.9). However, the subsequent 30-day to 1-year
mortality rates were similar in patients with Q-wave or non-Q-wave MI. Patients
who were not treated with thrombolysis and who had a non-Q-wave MI had a lower 30
day mortality rate (OR = 0.6, 95% CI: 0.3 to 0.9) but a similar 30-day to 1-year
mortality rate (hazard ratio [HR] = 1.5, 95% CI: 0.9 to 2.5) as compared with
their counterparts who developed Q-wave infarction. Among thrombolysis-treated
patients, 30-day (OR = 0.8, 95% CI: 0.4 to 1.5) as well as 30-day to 1-year (HR =
1.2, 95% CI: 0.5 to 3.0) mortality rates were similar between patients who
developed either Q-wave or non-Q-wave MI. CONCLUSIONS: Patients who received
thrombolysis had similar early and late mortality rates after the index
infarction regardless of whether they had a Q-wave or non-Q-wave MI. Conversely,
among patients who were not treated with thrombolysis, patients with a non-Q-wave
MI had lower early mortality rates but similar long-term mortality rates as those
with Q-wave MI.
PMID- 10759095
TI - Epidemiology and prevention of coronary heart disease in families.
AB - Although family histories are used primarily to aid in diagnosis and risk
assessment, their value is enhanced when the family is considered as a unit for
research and disease prevention. The value of a family history of coronary heart
disease (CHD) is increased when the age, sex, number of relatives, and age at
onset of disease are incorporated in a quantitative family risk score. Medical
and lifestyle risk factors that aggregate in families include dyslipidemia,
hypertension, obesity, hyperfibrinogenemia, diabetes mellitus, smoking habits,
eating patterns, alcohol consumption, physical activity, and socioeconomic
status. Advances in detecting and understanding interactions between genetic
susceptibility and modifiable risk factors should lead to improvements in
prevention and treatment. However, working with families can be difficult. In the
United States, families are usually small, are often widely dispersed, and may
not be intact. Family histories may be unknown, affected relatives may be dead,
and secular trends mask similarities among generations. Many exposures occur
outside the home, and families change over time. Ethical, legal, and social
issues arise when dealing with families. Nevertheless, opportunities are missed
when research, clinical practice, and prevention focus on individual patients.
Greater emphasis on families is needed to reduce the burden of CHD.
PMID- 10759096
TI - Sleep-related breathing disorders and cardiovascular disease.
AB - Sleep-related breathing disorders, ranging from habitual snoring to the increased
upper airway resistance syndrome to sleep apnea, are now recognized as major
health problems. The majority of patients have excessive daytime sleepiness and
tiredness. Neuropsychological dysfunction results in poor work performance,
memory impairment, and even depression. Until recently, the coexistence of
cardiovascular and cerebrovascular diseases with sleep-related breathing
disorders was thought to be the result of shared risk factors, such as age, sex,
and obesity. However, in the past 5 years several epidemiologic studies have
demonstrated that sleep-related breathing disorders are an independent risk
factor for hypertension, probably resulting from a combination of intermittent
hypoxia and hypercapnia, arousals, increased sympathetic tone, and altered
baroreflex control during sleep. Sleep apnea may lead to the development of
cardiomyopathy and pulmonary hypertension. Early recognition and treatment of
sleep-related breathing disorders may improve cardiovascular function.
PMID- 10759097
TI - Apoptotic mechanisms in acute renal failure.
AB - It has been generally accepted that a catastrophic breakdown of regulated
cellular homeostasis, known as necrosis, is the mode of cellular injury in
various forms of acute renal failure. One of the major advances in our
understanding of cell death has been the recognition that the pathways
traditionally associated with apoptosis as described in the landmark study by
Kerr, Wyllie, and Currie in 1972 maybe very critical in the form of cell injury
associated with necrosis. The pathway that is followed by the cell varies with
both nature and severity of insults and may evolve from an apoptotic to a
necrotic form of cell death. It is also likely that there are some common
pathways that are shared and regulated in the two modes of cell death. In this
review, we first describe evidence for the role of apoptotic pathways in ischemic
acute renal failure, and then consider the potential mechanisms that may
participate in this model of acute renal tubular injury. We then summarize the
current information of apoptotic pathways related to other common causes of acute
renal failure including endotoxin-induced, toxic acute renal failure and
transplant rejection. A better understanding of the mechanisms of apoptosis could
lead to safer and more specific therapeutic interventions for acute renal
failure.
PMID- 10759098
TI - Flexible sigmoidoscopy for the detection of microscopic colitis.
PMID- 10759099
TI - Is there an association between lipid-lowering drugs and cholecystectomy?
PMID- 10759100
TI - Treatment of a severely bleeding patient without preexisting coagulopathy with
activated recombinant factor VII.
PMID- 10759101
TI - A new variant of Hermansky-Pudlak syndrome due to mutations in a gene responsible
for vesicle formation.
PMID- 10759102
TI - The search for high-yield, low-risk antihypertensive treatment.
PMID- 10759103
TI - Encounters between physicians and pharmaceutical sales representatives.
PMID- 10759104
TI - Physicians and drug company sales representatives.
PMID- 10759105
TI - Use of critical pathways to improve the care of patients with acute myocardial
infarction.
PMID- 10759106
TI - An unexpected factor VIII inhibitor in a patient with Sweet's syndrome being
treated with corticosteroids.
PMID- 10759107
TI - Antiphospholipid antibody syndrome and appendicitis.
PMID- 10759108
TI - Community-acquired pneumonia: reality revisited.
PMID- 10759109
TI - A prognostic rule for elderly patients admitted with community-acquired
pneumonia.
PMID- 10759110
TI - Famotidine and acquired long QT syndrome.
PMID- 10759111
TI - Effect of oral administration of L-arginine on senile dementia.
PMID- 10759112
TI - The significance of integrative medicine for the future of medical education.
PMID- 10759113
TI - Protecting the faces of America.
PMID- 10759114
TI - The use of bispectral analysis in patients undergoing intravenous sedation for
third molar extractions.
AB - PURPOSE: The bispectral (BIS) index has been used to interpret
electroencephalogram (EEG) recordings to predict the level of sedation and loss
of consciousness in patients undergoing general anesthesia. It was the purpose of
this project to assess the usefulness of BIS technology in determining the level
of sedation in patients undergoing third molar extraction under conscious
sedation. PATIENTS AND METHODS: Twenty-five subjects undergoing third molar
extraction in an outpatient setting were analyzed. The EEG activity was recorded
continually during surgery using a microcomputer (Aspect-1050 Monitor; Aspect Co,
Natick, MA) with real-time bispectral data obtained by EEG skin electrodes
through a frontotemporal montage. The Observer's Assessment of Alertness and
Sedation (OAA/S) scale was used to subjectively assess the level of sedation
observed by the anesthetist before initiating the sedation procedure and then at
5-minute intervals until the end of the procedure. The BIS level was
simultaneously recorded. The initial sedation was accomplished using a standard
dose of midazolam (0.05 mg/kg) and fentanyl (1.5 microg/kg) followed by a 10- to
30-mg bolus of propofol until a level of sedation at which the patient's eyes
were closed and he or she was responsive only to vigorous stimulation or repeated
loud calling of their name (OAA/S level of 1 to 2). Local anesthesia was then
administered. Additional doses of sedative medication (midazolam or propofol)
were given during the procedure to maintain the desired level of sedation (an
OAA/S level of 2 to 3). The time and dose of the drug given were recorded. The
level of sedation based on a single anesthetist's interpretation (OAA/S) and the
BIS readings were then compared. RESULTS: A strong positive relationship between
the BIS index and OAA/S readings was found (P < .0001). Pairwise comparisons of
mean BIS index and its corresponding OAA/S level were significantly different
from each other (P < .003) except for OAA/S levels 2 and 3 (P = .367).
CONCLUSION: BIS technology offers an objective, ordinal means of assessing the
depth of sedation. There was a strong relationship between the objective BIS
values and subjective assessment (OAA/S scale) of the depth of anesthesia. This
can be invaluable in providing an objective assessment of sedation in oral and
maxillofacial surgery where it may be difficult to determine the level of
sedation clinically.
PMID- 10759115
TI - Measure of bite force and occlusal contact area before and after bilateral
sagittal split ramus osteotomy of the mandible using a new pressure-sensitive
device: a preliminary report.
AB - PURPOSE: This study examined bite force and occlusal contact area in prognathic
patients before and after bilateral sagittal split ramus osteotomy of the
mandible using a newly developed pressure-sensitive sheet (Dental-Prescale, Fuji
Photo Film Co, Tokyo, Japan). PATIENTS AND METHODS: Twenty-five prognathic
patients were examined. Bite force and occlusal contact area were measured
preoperatively, at 2, 4, and 8 weeks, and at 3 and 6 months after surgery. The
bite force and occlusal contact area of 20 healthy subjects were also measured.
RESULTS: Both bite force and occlusal contact area of the patients were the
lowest 2 weeks after surgery and recovered to the preoperative level between 8
weeks and 3 months. Subsequently, they increased slowly and exceeded the
preoperative level at 6 months after surgery. However, even at 6 months, both the
bite force and the occlusal contact area of the patients were still only about
half or less than that of healthy subjects. CONCLUSION: This pressure-sensitive
device can be used as a simple indicator of postoperative recovery and occlusal
improvement in patients following orthognathic surgery.
PMID- 10759116
TI - Effects of mandibular setback on the temporomandibular joint: a comparison of
oblique and sagittal split ramus osteotomy.
AB - PURPOSE: This investigation studied the changes in temporomandibular joint
function and condylar position after mandibular setback using different ramus
osteotomies. PATIENTS AND METHODS: The sample consisted of 50 Chinese adults with
mandibular prognathism. Twenty-eight of the patients underwent intraoral oblique
ramus osteotomy (IORO), and 22 received sagittal split ramus osteotomy (SSRO)
with rigid internal fixation (RIF). TMJ symptoms and radiographic findings were
evaluated preoperatively and postoperatively. RESULTS: After surgery in the IORO
group, the TMJ radiographs showed a significant anterior-inferior displacement of
the condyle. Seventy-five percent of the preoperatively symptomatic patients
reported fewer or no TMJ symptoms and no preoperatively asymptomatic patients
developed new TMJ symptoms. In the SSRO group, the TMJ radiographs showed a
posterior displacement of the condyle. Sixty percent of the preoperatively
symptomatic patients had no improved TMJ function and 8% of asymptomatic patients
developed TMJ symptoms after surgery. CONCLUSION: The results of this study show
that IORO with MMF appears to be more favorable to the TMJ than the SSRO with
RIF; IORO is particularly good in orthognathic surgery patients with preoperative
TMJ symptoms.
PMID- 10759117
TI - Use of short endosseous implants and an overdenture in the extremely resorbed
mandible: a five-year retrospective study.
AB - PURPOSE: A retrospective study was performed to assess the success of short
endosseous implants in combination with an implant-retained overdenture in the
extremely resorbed mandible. PATIENTS AND METHODS: Patients included had a
mandible not exceeding a median height of 12 mm measured on a standardized
lateral cephalometric radiograph. Seventeen patients (14 women, 3 men; mean age,
65 years) with 68 endosseous implants were clinically and radiographically
evaluated. RESULTS: During the follow-up period (mean, 77 months; range, 60 to 97
months), 8 implants were lost, bringing the cumulative survival rate to 88%. The
peri-implant tissues were in good condition, and the bone loss around the
implants was minimal. CONCLUSION: Because of the relative simplicity and low
morbidity of this treatment strategy, it is a justified treatment option.
PMID- 10759118
TI - Application of the buccal fat pad in oral reconstruction.
AB - PURPOSE: This report evaluates the use of the buccal fat pad in reconstruction of
defects of the hard and soft palate. PATIENTS AND METHODS: Twenty-nine patients
with different indications (oroantral fistula, tumor of the hard and soft palate,
posterior fistula in cleft patients, covering of bone transplants in augmentation
procedure) were treated with a pedicled buccal fat pad without lining. The
maximum reconstructed defect was 5.5 x 4 cm. RESULTS: All inserted fat grafts
healed well without any aesthetic disturbances. The surface of the fat converted
to normal mucosa. CONCLUSIONS: Use of the buccal fat pad is a safe and easy
method to reconstruct defects in the posterior maxilla and soft palate. Good
vascularization, ease of access, and minimal donor site morbidity make it a
reliable soft tissue graft.
PMID- 10759119
TI - The effect of mandibular third molar presence and position on the risk of an
angle fracture.
AB - PURPOSE: This study assessed the relationship between the presence and position
of mandibular third molars (M3) and angle fractures. PATIENTS AND METHODS: A
retrospective cohort study design and a sample composed of patients admitted for
treatment of mandible fractures between January 1993 and April 1998 were used.
Data sources were the patients' medical records and radiographs. The predictor
variables were the presence and position of M3. M3 position was grouped into 9
categories based on the Pell and Gregory classification. The outcome variable was
the presence of an angle fracture. Other study variables included age, sex, race,
mechanism of injury, and fracture location. RESULTS: The eligible sample was
composed of 437 patients, of whom 367 had data available for analysis. Patients
with M3 present had a 1.9 times (95% confidence interval = 1.2 to 2.9) greater
chance of an angle fracture than patients without M3s (P = .003). There was a
statistically significant variation in the risk for an angle fracture, depending
on M3 position (P = .049). CONCLUSION: The study results confirm other reports
that patients with M3 present have an increased risk for angle fractures.
Furthermore, it also showed that the risk for an angle fracture varied depending
on M3 position.
PMID- 10759120
TI - Changes in chewing pattern after surgically induced disc displacement in the
rabbit temporomandibular joint.
AB - PURPOSE: This study investigated whether surgically induced disc displacement
(DD) in the rabbit temporomandibular joint leads to joint dysfunction. MATERIALS
AND METHODS: Fourteen adult Japanese white rabbits were divided into two groups.
Eight animals had surgically induced DD, and 6 were used as a sham operation
group. Jaw movement trajectories during chewing were recorded preoperatively and
2 weeks after induction of DD. Postoperative recordings after administration of a
nonsteroidal anti-inflammatory drug (NSAID) were also performed to eliminate any
influence of joint pain on chewing. Vertical and horizontal ranges of chewing
movement, duration of the opening and closing phase, and total cycle of chewing
were analyzed. Thereafter, the presence of induced DD was confirmed
histologically. RESULTS: In the sham group, the rhythm and pattern of chewing
were almost the same as preoperatively. In the experimental group, increase in
the cycle duration and decrease in the vertical and horizontal ranges of movement
were observed. When the sham and experimental groups were compared, there was a
decreased ratio of vertical movement in the experimental animals. There was no
effect of preadministration of the NSAID in either the DD or sham group. All of
the experimental animals had total anterior DD histologically. CONCLUSION:
Changes in the chewing pattern of the experimental animals occurred from
mechanical interference of the displaced disc. This animal model can be used as a
model for human internal derangement.
PMID- 10759121
TI - doc-1--mediated apoptosis in malignant hamster oral keratinocytes.
AB - PURPOSE: Cell cycle mediators involved in inducing apoptosis are frequently
deregulated during carcinogenesis. Deleted in oral cancer-1 (doc-1) is an S-phase
regulator that is inactivated during oral carcinogenesis. Transfection of doc-1
into malignant oral keratinocytes leads to increased cell loss. It is
hypothesized that ectopic expression of doc-1 in hamster oral cancer cells
induces apoptosis. MATERIALS AND METHODS: Malignant hamster oral keratinocytes
(wt-HCPC-1), which lack measurable doc-1 mRNA and protein, were previously
transfected with either a CMV-doc-1 expression vector construct (doc-HCPC-1) or
the parental control vector pcDNA3 (cv-HCPC-1). A trypan blue exclusion assay was
performed to examine cell death in the parental or wild-type HCPC-1
keratinocytes, HCPC-1 transfected with the parental pcDNA3 vector, and the doc-1
transfected HCPC-1 cells. To examine whether ectopic expression of doc-1 mediates
gross cellular changes consistent with apoptosis, toluidine blue-safranin
differential staining and the quantitative fluorescent microscopy assays were
performed. To identify early apoptotic cytochemical changes observed in the cell
membrane and nucleus, annexin V/propidium iodide (PI) fluorescence-activated cell
sorter (FACS) analysis and the terminal deoxytransferase-mediated dUTP nick-end
labeling (TUNEL) assay were performed. RESULTS: Doc-HCPC-1 showed elevated
numbers of dead cells over wt-HCPC-1 and cv-HCPC-1 in the trypan blue exclusion
assay. Toluidine blue-safranin staining and quantitative fluorescent microscopy
showed significant morphologic changes in the doc-1 transfectants consistent with
apoptosis (P < .05). TUNEL assays (P < .05) and annexin V/PI FACS analysis (P <
.05) also showed early cytochemical changes in the doc-HCPC-1 transfectants,
confirming that ectopic expression of doc-1 induces apoptosis. CONCLUSIONS: These
data suggest that doc-1 induces apoptosis in malignant hamster oral
keratinocytes. It is hypothesized that doc-1 is a mediator of apoptosis that is
inactivated during hamster oral carcinogenesis.
PMID- 10759122
TI - The lower labial branches of the mental nerve: anatomic variations and surgical
relevance.
AB - PURPOSE: The purpose of this study was to determine the cause of injuries of the
lower labial branches (LLB) of the mental nerve (MN) after biopsy of minor
salivary glands (BMSG), labial nodule excision, or symphyseal bone procedures
using a labial approach. PATIENTS AND METHODS: Thirty-two MN were dissected in 16
cadavers to trace the labial branches. The following factors were recorded: 1)
the number of LLB; 2) the angle between the medial LLB and the fibers of the
orbicularis oris muscle; 3) the anastomoses between the lateral branches; and 4)
the midline crossover innervation of the LLB. The number of branches on each
side, as well as values of the angle between the nerves and superficial fibers of
the orbicularis oris muscle, were compared using the Wilcoxon test. RESULTS: The
mean number of LLB was 2 (SEM, 1; range, 1 to 4); the average angle between the
medial LLB and the fibers of the orbicularis oris muscle was 36 degrees (SEM, 2
degrees ), without any statistical difference between the two sides (P = .78); an
anastomosis between the 2 lateral branches of the LLB was observed in only 1
case; and the mean midline crossover innervation of the LLB was 25% (SEM, 14%) of
the intercommisural distance. This crossover innervation was present only on the
ventral surface of the lip. CONCLUSIONS: These data suggest that injuries to the
LLB could be prevented if the incision(s) are made horizontally on the dorsal
aspect of the lower lip, and the angle between the incision and the long axis of
the lip is approximately 36 degrees . In the case of symphyseal bone procedures
using a labial route, a "U"-shaped incision parallel to the LLB is suggested.
PMID- 10759123
TI - Nonsurgical management of epistaxis.
PMID- 10759124
TI - Concomitant occurrence of squamous cell carcinoma and myxoma of the mandible: a
case report.
PMID- 10759125
TI - Mandibular intraosseous carcinoma coexisting with ameloblastoma.
PMID- 10759126
TI - Surgical repositioning of a malposed, unserviceable implant: case report.
PMID- 10759127
TI - Intraosseous sarcoidosis of the maxilla: case report.
PMID- 10759128
TI - Aneurysmal bone cyst of the mandibular condyle: report of a case.
PMID- 10759129
TI - Staged sinus augmentation and implant placement in a patient with osteogenesis
imperfecta.
PMID- 10759130
TI - Postsurgical lagophthalmus treated with gold eyelid weights.
PMID- 10759131
TI - Painful angiomyoma of the oral cavity: report of a case and review of the
literature.
PMID- 10759132
TI - An alternative material for maxillofacial compression dressings.
PMID- 10759133
TI - Single-stage implant surgery using a tissue punch.
PMID- 10759134
TI - Spread of actinomycosis to the temporal space.
PMID- 10759135
TI - Calcium, dairy products and osteoporosis.
AB - Osteoporosis is a multifactorial disorder in which nutrition plays a role but
does not account for the totality of the problem. 139 papers published since 1975
and describing studies of the relationship of calcium intake and bone health are
briefly analyzed. Of 52 investigator-controlled calcium intervention studies, all
but two showed better bone balance at high intakes, or greater bone gain during
growth, or reduced bone loss in the elderly, or reduced fracture risk. This
evidence firmly establishes that high calcium intakes promote bone health.
Additionally, three-fourths of 86 observational studies were also positive,
indicating that the causal link established in investigator-controlled trials can
be found in free-living subjects as well. The principal reason for failure to
find an association in observational studies is the weakness of the methods
available for estimating long-term calcium intake. While most of the investigator
controlled studies used calcium supplements, six used dairy sources of calcium;
all were positive. Most of the observational studies were based on dairy calcium
also, since at the time the studies were done, higher calcium intakes meant
higher dairy intakes. All studies evaluating the issue reported substantial
augmentation of the osteoprotective effect of estrogen by high calcium intakes.
Discussion is provided in regard to the multifactorial complexity of osteoporotic
response to interventions and to the perturbing effect in controlled trials of
the bone remodeling transient, as well as about how inferences can validly be
drawn from the various study types represented in this compilation.
PMID- 10759136
TI - Folates and dairy products: a critical update.
AB - In recent years, folates have come into focus due to their protective role
against child birth defects, for example, neural tube defects. In addition,
folates may have a protective role to play against coronary heart disease and
certain forms of cancer. During the last few years most countries have
established increased recommended intakes of folates, for example, between 300
400 microg per day for adults. This review of folates in milk and dairy products
compares some recent data based on high pressure liquid chromatography (HPLC)
analyses and radioprotein-binding assays, with previous data based on
microbiological assays. All three methods show similar ranges for folates in
cow's milk, 5-10 microg per 100 g, the variation being due to seasonal
variations. Data on folates in fermented milk (buttermilk and yogurt) are also
similar for these methods. Different starter cultures, however, might explain
some of the variations in folate content and folate forms. Most cheese varieties
contain between 10 microg and 40 microg folate per kg, with slightly higher
values for whey cheese. Ripened soft cheeses may contain up to 100 microg folate
per 100 g. Most previous and recent studies using HPLC indicate that 5-methyl
tetrahydrofolate (5-methyl-THF) is the major folate form in milk, but more
studies are needed concerning folate forms in other, especially fermented dairy
products. Relatively new data on actual concentrations in different dairy
products show folate-binding proteins (FBP) to occur in unprocessed milk, but
also in pasteurised milk, spray-dried skim milk powder and whey. In contrast, UHT
milk, fermented milk and most cheeses only contain low levels or trace amounts.
PMID- 10759137
TI - Conjugated linoleic acid and disease prevention: a review of current knowledge.
AB - Conjugated linoleic acid (CLA), a derivative of a fatty acid linoleic acid (LA),
has been reported to decrease tumorigenesis in animals. CLA is unique because
unlike most antioxidants which are components of plant products, it is present in
food from animal sources such as dairy foods and meats. CLA concentrations in
dairy products typically range from 2.9 to 8.92 mg/g fat of which the 9-cis, 11
trans isomer makes up to 73% to 93% of the total CLA. Low concentrations of CLA
are found in human blood and tissues. In vitro results suggest that CLA is
cytotoxic to MCF-7 cells and it inhibits the proliferation of human malignant
melanoma and colorectal cancer cells. In animal studies, CLA has inhibited the
development of mouse epidermal tumors, mouse forestomach cancer and rat mammary
cancer. Hamsters fed CLA collectively had significantly reduced levels of plasma
total cholesterol, non-high-density lipoprotein cholesterol, (combined very-low
and low-density lipoprotein) and triglycerides with no effect on high-density
lipoprotein cholesterol, as compared to controls. Dietary CLA modulated certain
aspects of the immune defense but had no obvious effect on the growth of an
established, aggressive mammary tumor in mice. It is now thought that CLA itself
may not have anti-oxidant capabilities but may produce substances which protect
cells from the detrimental effects of peroxides. There is, however, insufficient
evidence from human epidemiological data, and very few of the animal studies have
shown a dose-response relationship with the quantity of CLA feed and the extent
of tumor growth. Further research with tumor models is needed to test the
efficacy and utility of CLA in cancer and other disease prevention and form the
basis of evaluating its effect in humans by observational studies and clinical
trials.
PMID- 10759138
TI - The bioavailability of dietary calcium.
AB - This update focuses on the bioavailability of dietary calcium for humans.
Fundamentals of calcium metabolism, intestinal absorption, urinary excretion and
balance are recalled. Dietary factors, especially lactose and other milk
components, influencing calcium bioavailability at intestinal and renal levels
are reviewed. A critical examination of all the methods used for evaluating
calcium bioavailability is made. This includes in vitro assays, classical and
isotopic balances, urinary excretion, isotope labeling in the urine, plasma and
bones, long term evaluation of bone mineralization and the use of biological bone
markers. Importance and advantages of animal models are discussed. The state of
the art in the comparative bioavailability of calcium in foods is detailed
including a comparison of sources of calcium (dairy products and calcium salts)
in human studies and in some animal studies, casein phosphopeptides, proteins,
lactose and lactase and their relation with calcium bioavailability (in humans
and rats). An update on the consumption of dairy products and bone mass is
presented. Emphasis on peculiarities and advantages of calcium in milk and dairy
products is given.
PMID- 10759139
TI - Effect of lactic acid bacteria on diarrheal diseases.
AB - Microbial balance is an important factor in the maintenance of intestinal
homeostasis, and yogurt or fermented milk supplementation has been proposed to
control diarrheal diseases. A number of studies using animal models and clinical
studies in humans have confirmed the beneficial effect of such fermented products
in case of lactose intolerance, viral diarrhea or antibiotics-associated
diarrhea. The mechanisms by which lactic acid bacteria exert their effects are
multiple. Bacterial lactase improves the absorption of lactose, but fermented
products slow down the intestinal transit facilitating the action of residual
intestinal lactase. The transient passage of lactic acid bacteria in the
digestive tract may represent a microbial barrier against the development of
pathogenic bacteria, probably due to the release of compounds contributing to the
maintenance of colonization resistance to pathogens. The beneficial effects are
mainly described in the presence of live bacteria, but inactivated bacteria may
also present preventive or curative capacities in diarrheal diseases. Moreover,
lactic acid bacteria has been described as reinforcing the non-specific immune
defence but also specific immunity, particularly the secretory immune system
mediated by secretory IgA or IgM in response to particulate infectious antigens
and perhaps to soluble food antigens. Other possible mechanisms include the
trophic effect on the intestinal layer, and a down-regulatory activity in cow's
milk allergy as well as anti-inflammatory effects have also been suggested.
PMID- 10759140
TI - Benefits of dairy product consumption on blood pressure in humans: a summary of
the biomedical literature.
AB - The inverse relationship between intake of dairy products and blood pressure
levels was first suggested by several epidemiologic surveys in the early 1980's
that revealed low calcium intake in populations with increased prevalence of
hypertension. Subsequent laboratory and clinical investigations provided further
evidence of the association between calcium and blood pressure, but the results
of these studies were often inconsistent due to variations in study design and
methods, study participants and calcium sources. The recently published results
of the large and carefully executed Dietary Approaches to Stop Hypertension
Study, "DASH," which demonstrated a dramatic blood-pressure lowering effect of
diets rich in dairy products, fruits and vegetables, addressed many of the issues
contributing to the inconsistencies in the blood pressure-calcium data. In the
following review, we discuss the evolution of the scientific evidence of the
association between dietary calcium intake and blood pressure, the findings and
significance of the DASH trial and the consensus that now exists among health
professionals regarding the importance of adequate dairy product intake for
optimal blood pressure regulation.
PMID- 10759141
TI - Lactose intolerance.
AB - Lactose maldigestion has been under intensive research since its discovery in the
1960's. We know the prevalence of lactose maldigestion in a great number of
countries and ethnic groups. However, there is often no provision made for the
secondary type of maldigestion, and the study populations have sometimes been
selected rather than picked at random. New methods for the measurement of lactose
digestion have been developed, and its genetic mechanisms have received a great
deal of attention during the last few years. However, in many studies the
measurement and/or reporting of symptoms has quite often been overlooked. In this
review, various topics related to lactose intolerance are discussed with a
special emphasis on its symptoms.
PMID- 10759142
TI - Milk and diabetes.
AB - Type 1 diabetes is based on autoimmunity, and its development is in part
determined by environmental factors. Among those, milk intake is discussed as
playing a pathogenic role. Geographical and temporal relations between type 1
diabetes prevalence and cow's milk consumption have been found in ecological
studies. Several case-control studies found a negative correlation between
frequency and/or duration of breast-feeding and diabetes, but this was not
confirmed by all authors. T-cell and humoral responses related to cow's milk
proteins were suggested to trigger diabetes. The different findings of studies in
animals and humans as well as the potential underlying mechanisms with regard to
single milk proteins (bovine serum albumin, beta-lactoglobulin, casein) are
discussed in this review. In contrast to type 1 diabetes, the etiology of type 2
diabetes, characterized by insulin resistance is still unclear. In a population
with a high prevalence of type 2 diabetes, the Pima Indians, people who were
exclusively breastfed had significantly lower rates of type 2 diabetes than those
who were exclusively bottlefed. Studies in lactovegetarians imply that
consumption of low fat dairy products is associated with lower incidence and
mortality of diabetes and lower blood pressures. In contrast, preference for a
diet high in animal fat could be a pathogenic factor, and milk and high fat dairy
products contribute considerably to dietary fat intake. Concerning milk fat
composition, the opposite effects of various fatty acids (saturated fatty acids,
trans-fatty acids, conjugated linoleic acid) in vitro, in animals and in humans
have to be considered.
PMID- 10759143
TI - Nutritional and physiological criteria in the assessment of milk protein quality
for humans.
AB - Dietary protein quality is influenced by several factors and especially amino
acid composition as well as the bioavailability of the protein. The method to
assess the dietary protein quality recommended by the FAO/WHO (1985, 1990) is
based on the ability of the protein to satisfy the indispensable amino acid
requirements. The Protein Digestibility Corrected Amino Acid Score (PD-CAAS) has
been proposed as a quality index and takes into account both the indispensable
amino acid composition and the protein digestibility. This index can easily be
used routinely, but some conceptual and methodological limits must be considered,
such as the determination of both nitrogen and indispensable amino acid
requirements, the bioavailability of dietary protein and the validation of the
quality indexes. Another level in the evaluation of protein quality considers
more specific activities related to specific protein-derived components. The
compounds responsible for these activities include enzymes, immunoglobulins,
mediator and hormone-like substances. These actions are linked to native proteins
or to peptides cleaved from protein during digestion.
PMID- 10759144
TI - Chromosomal rearrangements and mental retardation.
PMID- 10759145
TI - Immunologic tolerance and dietary antigens.
PMID- 10759146
TI - Perinatal hypoxia-ischemia and brain injury.
PMID- 10759147
TI - American Pediatric Society presidential address 1999: The Joy of Academic
Pediatrics.
PMID- 10759148
TI - Genetic analysis of fetal development and parturition control in the mouse.
AB - The application of targeted gene inactivation methodologies to the study of late
fetal development and control of the timing for parturition in mice has yielded
insight into the mechanisms that enhance fetal survival. An essential role for
glucocorticoids in promoting lung maturation sufficient for viability ex utero
before the onset of normal parturition has been demonstrated in corticotropin
releasing hormone-deficient mice. In contrast, maternal deficiency in the
prostaglandin synthetic enzyme cyclooxygenase-1 results in the markedly delayed
onset of labor and fetal demise because of postdates gestation. The complex
interplay of factors that govern the onset of labor is highlighted by mice
deficient in both cyclooxygenase-1 and oxytocin. Whereas mice deficient in
oxytocin demonstrate normal parturition, simultaneous cyclooxygenase-1 and
oxytocin deficiency rescues the delayed onset of labor found in cyclooxygenase-1
knockout mice but results in the prolonged duration of labor. The consequences of
complete deficiency of molecules involved in parturition in mice suggest novel
interventions for human preterm labor.
PMID- 10759149
TI - Golgi targeting of the GLUT1 glucose transporter in lactating mouse mammary
gland.
AB - Lactose, the major carbohydrate of human milk, is synthesized in the Golgi from
glucose and UDP-galactose. The lactating mammary gland is unique in its
requirement for the transport of glucose into Golgi. Glucose transporter-1
(GLUT1) is the only isoform of the glucose transporter family expressed in
mammary gland. In most cells, GLUT1 is localized to the plasma membrane and is
responsible for basal glucose uptake; in no other cell type is GLUT1 a Golgi
resident. To test the hypothesis that GLUT1 is targeted to Golgi during
lactation, the amount and subcellular distribution of GLUT1 were examined in
mouse mammary gland at different developmental stages. Methods including
immunohistochemistry, immunofluorescence, subcellular fractionation, density
gradient centrifugation, and Western blotting yielded consistent results. In
virgins, GLUT1 expression was limited to plasma membrane of epithelial cells. In
late pregnant mice, GLUT1 expression was increased with targeting primarily to
basolateral plasma membrane but also with some intracellular signal. During
lactation, GLUT expression was further increased, and targeting to Golgi,
demonstrated by colocalization with the 110-kD coatomer-associated protein beta
COP, predominated. Removal of pups 18 d after delivery resulted in retargeting of
GLUT1 from Golgi to plasma membrane and a decline in total cellular GLUT1 within
3 h. In mice undergoing natural weaning, GLUT1 expression declined. Changes in
the amount and targeting of GLUT1 during mammary gland development are consistent
with a key role for GLUT1 in supplying substrate for lactose synthesis and milk
production.
PMID- 10759150
TI - Effect of alpha-phenyl-N-tert-butyl nitrone (PBN) on fetal cerebral energy
metabolism during intrauterine ischemia and reperfusion in rats.
AB - The objective of the present study was to explore whether a free radical spin
trap agent, alpha-phenyl-N-tert-butyl nitrone (PBN), influences bioenergetic
failure induced in the 20-day-old fetal brain by 30 min of intrauterine ischemia
in Wistar rats. Fetal brains were frozen in situ at the end of ischemia and after
1, 2, and 4 h of recirculation for analysis of ATP, ADP, AMP, and lactate. PBN or
vehicle was given 1 h after recirculation. Tissue oxygen tension was evaluated in
placental and fetal cerebral tissues throughout the whole periods of 30 min of
ischemia and 4 h of recirculation. Ischemia was associated with a decrease in ATP
concentration and an increase in lactate concentration (p < 0.001). Recirculation
(1 and 2 h) led to a recovery of ATP concentration, but continued reflow (4 h)
was associated with a secondary deterioration of high-energy phosphates (p <
0.01). Lactate concentration increased during this recovery period. This
deterioration was prevented by PBN (p < 0.05). After 30 min of ischemia, tissue
oxygen tension in placenta and fetal brain decreased to about 30% and 50% of
control, respectively. However, recirculation brought about a recovery of oxygen
delivery. The results indicate that although during the early time period after
ischemia fetal cerebral energy metabolism is maintained by an acceleration of the
anaerobic glycolytic rate, secondary deterioration of cellular bioenergetic state
develops in the immature fetal brain. This deterioration may be due to
mitochondrial dysfunction, which may be induced by oxygen-derived free radicals,
and not by compromised microcirculation.
PMID- 10759151
TI - Impaired acetylcholine-induced vascular relaxation in low birth weight infants:
implications for adult hypertension?
AB - Low birth weight is associated with an increased risk of adult hypertension. To
elucidate whether this association reflects altered vascular physiology already
at birth, we studied acetylcholine-induced vasodilation. Forty newborn infants
and their mothers were studied 3 d after delivery. Vasodilation in skin was
induced by local application of acetylcholine and local heating to 44 degrees C.
Perfusion changes were measured with the laser Doppler technique. In response to
acetylcholine, the mean skin perfusion increased by 240% in low birth weight
infants compared with 650% in normal birth weight controls (p < 0.001). In
contrast, mothers of low birth weight infants showed a mean increase in perfusion
of 1100% after acetylcholine administration compared with 680% in mothers of
control infants (p < 0.05). The perfusion increase at 44 degrees C local skin
temperature did not differ between the two groups of infants or between their
mothers. Blood pressure was normal in all subjects. We conclude that low birth
weight infants show signs of endothelial dysfunction at birth. Such findings may
help us understand the link between low birth weight and adult hypertension.
PMID- 10759152
TI - Mode of delivery and childhood blood pressure.
AB - A number of studies have shown that children born by cesarean section have lower
blood pressure during the neonatal period. The aim of this study was to
investigate whether mode of delivery influenced childhood blood pressure: at age
7.5 to 8 y in a cohort of 756 children born preterm, at 7 to 9 y in a pilot study
of 166 children born at term in the United Kingdom, and in a cohort of 650
Tasmanian children born at term. In the preterm cohort, systolic blood pressure
was significantly lower in children born by cesarean section rather than
delivered vaginally (99.3+/-10.0 versus 101.4+/-9.4 mm Hg; 95% confidence
interval, -0.69 to -3.46; p = 0.003), with a significant trend to having a higher
pressure in those born by breech versus forceps versus spontaneous vaginal
delivery versus cesarean section. These findings were not replicated in the term
cohorts. This raises the hypothesis that there is a sensitive period for
programming later blood pressure by factors associated with mode of delivery and
that this period does not extend to full-term.
PMID- 10759153
TI - Effects of prematurity on arousal from sleep in the newborn infant.
AB - The incidence of sudden infant death syndrome has been found to be consistently
higher in preterm and low birth weight infants than in infants born at term.
Failure to arouse from sleep is one possible mechanism for sudden infant death
syndrome. This study compared the arousal responses to nasal air-jet stimulation
in a longitudinal study between groups of healthy preterm and term infants.
Preterm infants (n = 9) were born at 31-35 wk gestation with normal birth weights
for gestational age and studied on three occasions: a preterm study at 36 wk, at
2-3 wk post-term, and at 2-3 mo post-term. Term infants (n = 22) were born at 37
42 wk and were studied at 2-3 wk and 2-3 mo post-term. Arousal thresholds were
determined in both active sleep (AS) and quiet sleep (QS). In preterm infants,
there was no state-related difference in arousal thresholds at either the 36 wk
or 2-3 wk study; however, at 2-3 mo, arousal threshold was significantly greater
in QS than AS (p < 0.05). In contrast, in term infants, arousal thresholds were
significantly elevated in QS compared with AS at both 2-3 wk and 2-3 mo (p <
0.001). Arousal thresholds in AS were not different between the two groups of
infants, with both groups of infants remaining readily arousable. However, in QS
at 2-3 mo, arousal thresholds were significantly lower in the preterm infants (p
< 0.05). This study has demonstrated that arousability is altered by gestational
and postnatal age. The lower arousability that characterizes QS in term infants
regardless of age is not evident in preterm infants until 2-3 mo post-term age.
PMID- 10759154
TI - Long-term consequences of early linear growth retardation (stunting) in Swedish
children.
AB - Linear growth retardation (stunting) is prevalent (10-80%) in developing
countries. It takes place between 6 and 18 mo of age and can be characterized by
the delayed onset of the childhood phase of growth. The objective of this work
was to study the existence of stunting in early life and, when present, its
lifelong effects on final height in a normal healthy population in a developed
country. A total of 2432 children with longitudinal height data from birth to
adulthood were analyzed. The series represents a normal healthy population-based
sample of full-term children born around 1974 in Goteborg, Sweden. We found the
incidence of stunting to be about 10% as indicated by delayed onset of the
childhood phase of growth (>12 mo of age): 14% in boys and 8% in girls. In a
multiple linear regression model, final height was described by length at 6 mo of
age, age at onset of the childhood phase of growth, and age at peak height
velocity during puberty. All three measures contributed significantly (p < 0.05)
to final height with a total R2 of 0.33. A final height difference of 5.0 cm
could be explained by abnormal onset of the childhood phase of growth in this
normal population. The timing of the childhood onset of growth did not correlate
with the timing of puberty. For the first time, we can conclude that stunting in
early life is not only a problem in developing countries. Its importance on final
height achieved is clearly shown, even after controlling for the timing of
puberty.
PMID- 10759155
TI - Dihydrotestosterone stimulates branching morphogenesis, cell proliferation, and
programmed cell death in mouse embryonic lung explants.
AB - Early gestation lung development is characterized by branching morphogenesis of
the airways and basic lung structure formation. Androgens delay late-gestation
lung development if the androgen exposure begins in early gestation. We
hypothesized that there would be effects of early gestation androgens on lung
development. Embryonic mouse lungs (d 11.5) were cultured with
dihydrotestosterone (DHT), DHT plus flutamide, or with nothing as controls.
Branching morphogenesis was significantly increased after 24, 48, and 72 h of
culture. This effect was blocked by simultaneous flutamide treatment. Fetal sex
did not influence the DHT response. DHT increased cell proliferation as measured
by [3H]thymidine incorporation into DNA. Autoradiography showed prominent
[3H]thymidine labeling of epithelia and mesenchyme in regions of new bud
formation. DHT treatment significantly increased the thymidine-labeling index of
fibroblasts and airway epithelial cells. Programmed cell death, which is found in
developing organs in association with cell proliferation during structure
formation and tissue remodeling, was studied using terminal deoxyribonucleotidyl
transferase-mediated dUTP-digoxigenin nick end labeling assay. In control lungs,
programmed cell death occurred in the peripheral mesenchyme surrounding newly
forming buds and underlying airway branch points. DHT treatment increased
programmed cell death in association with increased branching morphogenesis.
Evaluation of near-adjacent sections (control and DHT-treated lungs) showed that
apoptotic mesenchymal cells were flanked by [3H]thymidine-labeled fibroblasts and
epithelial cells, suggesting a coordination of these processes in the progression
of branching morphogenesis. We conclude that androgen enhances the process of
early lung morphogenesis by increasing cell proliferation and programmed cell
death and by promoting the structural progression of branching morphogenesis.
PMID- 10759156
TI - Detection by mass spectrometry of highly increased amount of S-sulfonated
transthyretin in serum from a patient with molybdenum cofactor deficiency.
AB - Serum transthyretin has several isoforms, most of which are caused by disulfide
linkage with cysteine residue at position 10. We found an ion peak 80 D larger
than unmodified transthyretin by electrospray ionization mass spectrometry and
assigned it to S-sulfonated transthyretin. The peak height was <2% of total
transthyretin in control sera from more than 200 individuals including infants.
Transthyretin from a patient with molybdenum cofactor deficiency was analyzed,
and the peak was prominent, higher than 85% of total transthyretin. In patients
with this disease, the presence of elevated levels of sulfite leads to the
formation of S-sulfonated cysteine. The peak can be used as a diagnostic marker
for molybdenum cofactor deficiency, although more sera from patients with this
disease should be tested.
PMID- 10759157
TI - Maturation-dependent neurotoxicity of 3-hydroxyglutaric and glutaric acids in
vitro: a new pathophysiologic approach to glutaryl-CoA dehydrogenase deficiency.
AB - Glutaryl-CoA dehydrogenase deficiency is a neurometabolic disorder with a
specific age- and region-dependent neuropathology. Between 6 and 18 mo of age,
unspecific illnesses trigger acute encephalopathic crises resulting in acute
striatal and cortical necrosis. We hypothesized that acute brain damage in
glutaryl-CoA dehydrogenase deficiency is caused by the main pathologic
metabolites 3-hydroxyglutaric and glutaric acids through an excitotoxic sequence.
Therefore, we investigated the effect of 3-hydroxyglutaric acid and glutaric acid
on primary neuronal cultures from chick embryo telencephalons and mixed neuronal
and glial cell cultures from neonatal rat hippocampi. Exposure to glutaric acid
and 3-hydroxyglutaric acid decreased cell viability in a concentration- and time
dependent fashion. This neurotoxic effect could be totally prevented by
preincubation with an N-methyl-D-aspartate receptor subunit 2B (NR2B)-specific
antagonist, NR2B antibodies, and an unspecific N-methyl-D-aspartate receptor
blocker and was partially blocked with an NR2A-specific antagonist but not with
NR2A antibodies or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor
and metabotropic glutamate receptor antagonists. Furthermore, metabolite toxicity
increased in parallel with the increasing expression of the NR2B subunit on
cultured neurons from second to sixth day in vitro. We conclude from these
results that 3-hydroxyglutaric acid and glutaric acid act as false
neurotransmitters, in particular through NR1/2B, and that the extent of induced
neurotoxicity is dependent on the temporal and spatial expression of NR1/2B in
the CNS during maturation. Beyond favorable implications for treatment and long
term prognosis, glutaryl-CoA dehydrogenase deficiency is the first neurologic
disease in which specific neuropathology could be experimentally linked to
ontogenetic expression of a particular neurotransmitter receptor subtype.
PMID- 10759159
TI - Predictive markers of clinical outcome in vertically HIV-1-infected infants. A
prospective longitudinal study.
AB - We have investigated the relationship between disease progression and several
immunologic and virologic markers of HIV infection. Plasma samples from infants
born to HIV-1-infected mothers were collected at birth and at 1, 2, 4, 6, 9, 12,
15, and 18 mo of age and subsequently were assayed every 6 mo for viral load,
viral phenotype, and lymphocyte populations. A cutoff level of 25% indicative of
a preserved immunologic status, both of CD4+ and CD8+ blood T cells, was
associated with significant differences in disease progression (p = 0.04 and
0.02, respectively). Infants with median CD4+ T cells <25% had a relative risk of
progression to AIDS 3.35-fold higher than those with CD4+ above this level (p =
0.05). The relative risk of progression to AIDS for infants with median CD8+ <25%
was 4.95-fold higher than for those with CD8+ percent above this threshold (p =
0.03). Similarly, a cutoff level of viral load of 5.5 log10 copies/mL was
indicative of a worse prognosis. Infants with median viral load >5.5 log10
copies/mL had a relative risk of progression to AIDS 23.72-fold higher (p =
0.0001) than those with median viral load below this threshold. Interestingly,
changes from a slow replication and low titer to a rapid replication and high
titer of virus and from nonsyncytium-inducing to syncytium-inducing viral
phenotype were indicative of progression to AIDS. Our results indicate that
biologic phenotype of viral isolates and CD8+ T-lymphocyte percentages in
peripheral blood as well as viral load and CD4+ T-lymphocyte percentages could
predict rapid progression to advanced HIV-1 disease in HIV-1-infected infants.
PMID- 10759158
TI - Failure of the loop diuretic torasemide to improve renal function of hypoxemic
vasomotor nephropathy in the newborn rabbit.
AB - The use of diuretic therapy in vasomotor nephropathy is a controversial topic. It
is generally agreed that diuretics in this situation enhance urinary output,
reduce the degree of volume expansion, and improve cardiac and especially the
compromised lung function. It is less clear whether diuretic therapy improves
kidney function. The present study evaluates the effects of intravenous
torasemide on renal function in 25 anesthetized ventilated hypoxemic newborn New
Zealand White rabbits with vasomotor nephropathy. This well-established animal
model mimics the renal physiology of the human newborn and, in particular, that
of the premature infant. Three groups of hypoxemic rabbits were studied. The
animals of group 1 (n = 8) received no diuretic therapy (hypoxemic control), and
those of group 2 (n = 9) were given a single intravenous dose of torasemide (1
mg/kg) in a curative fashion 2 h after hypoxemia was induced. In the third group
of animals (n = 8), torasemide was given preventively; a bolus intravenous dose
of torasemide (0.2 mg/kg) was given before the induction of hypoxemia and
sustained by the addition of 0.2 mg x kg(-1) x h(-1) of the drug to the
continuous intravenous infusion given throughout the entire 3-h hypoxemic period.
Hypoxemia alone (group 1) caused acute renal insufficiency with a significant
fall in mean arterial blood pressure, GFR, and renal blood flow; the renal
vascular resistance increased, and the filtration fraction was unchanged. The
curative dose of torasemide (group 2) induced a significant diuresis and
natriuresis with minimal augmentation of urinary potassium excretion, converting
mildly oliguric to nonoliguric acute renal insufficiency. In this group of
animals, torasemide did not improve the glomerular dysfunction. The preventive
dose of torasemide (group 3) even somewhat worsened the already impaired renal
functions without further increasing the diuretic effect of the drug. We conclude
that in hypoxemic newborn animals with renal dysfunction, torasemide is an
effective potassium-sparing diuretic that unfortunately does not improve renal
blood flow and GFR. The failure of torasemide to attenuate the glomerular
dysfunction of hypoxemic vasomotor nephropathy in the newborn rabbit is
disturbing. These data certainly caution against the overzealous use of loop
diuretics in hypoxemic oliguric neonates.
PMID- 10759160
TI - Hemodynamic homeostasis during acute hypoxia in septic and nonseptic piglets:
differential role of prostaglandins and nitric oxide.
AB - We studied the hemodynamic responses of 29 anesthetized and mechanically
ventilated piglets to acute hypoxia [reduction of Pao2 from 130 to 38 mm Hg
induced by inhalation of 7% fraction of inspired oxygen (Fio2) for 7.5 min]
before and during group B beta-hemolytic streptococci (GBS) sepsis. During
hypoxia, nonseptic piglets maintained stable systemic blood pressure [105+/-9
(SD) to 97+/-14 mm Hg] and cardiac output (CO) (667+/-72 to 685+/-113 mL/min).
However, during GBS/hypoxia, systemic blood pressure fell from 94+/-17 to 49+/-25
mm Hg, CO fell from 397+/-146 to 223+/-142 mL/min (both p < 0.001 versus pre
GBS), and cardiac arrest often ensued. We tested three hypotheses that might
underlie GBS-induced intolerance to systemic hypoxia: 1) GBS-induced reduction of
systemic CO/systemic oxygen delivery (QO2) below a critical QO2 beyond which the
superimposition of hypoxia becomes intolerable; this mechanism is unlikely as
nonseptic piglets with comparable reductions in CO/QO2 (induced by inflation of a
left atrial balloon) tolerated hypoxia well; 2) GBS-induced inhibition of nitric
oxide (NO) synthesis that is vital to tolerance of hypoxia; this mechanism is
unlikely as infusion of the NO substrate L-arginine did not restore tolerance to
hypoxia during GBS infusion (as it did after inhibition of NO synthesis during
infusion of N-nitro-L-arginine in nonseptic piglets); and 3) GBS-induced
production of pathologic prostaglandins that impaired the piglet's capacity to
tolerate hypoxia; this mechanism finds support in the observation that inhibition
of prostaglandins with the cyclooxygenase inhibitor indomethacin completely
restored the ability of septic piglets to tolerate hypoxia. Further evaluation of
GBS-induced intolerance to systemic hypoxia may provide insight into the
incompletely understood mechanisms by which sepsis induces circulatory collapse
in experimental animals and in humans.
PMID- 10759161
TI - Chemiluminescence because of the production of reactive oxygen species in the
lungs of newborn piglets during resuscitation periods after asphyxiation load.
AB - Reactive oxygen species are regarded as a possible cause of many diseases.
However, there are few reports offering in vivo and in situ proof of the direct
involvement of reactive oxygen species in the pathogenesis of disease. In the
present study, the luciferin derivative 2-methyl-6-[4-methoxyphenyl]-3,7
dihydroimidazo [1,2-alpha] pyrazin-3-one (MCLA) was used to investigate the
amount of reactive oxygen species produced during resuscitation after
asphyxiation load in newborn piglets. The animals were first asphyxiated by
stopping respiration for 4 min, and then resuscitated using 100% oxygen. When
physiologic saline solution was administered, lung surface chemiluminescence had
a mean value of 2, whereas with MCLA, a maximum luminescence of 580 was seen,
demonstrating the possibility of measuring reactive oxygen species in vivo and in
situ using MCLA. In a group in which resuscitation after acute asphyxiation was
performed with 21% oxygen, the relative maximum lung surface chemiluminescence
was 59.5+/-39, whereas that for a group in which resuscitation was performed
using 100% oxygen had a significantly higher value of 186.1+/-72.5. Consequently,
ventilation and especially resuscitation by 100% oxygen may represent a potential
danger.
PMID- 10759162
TI - Longitudinal survey of lymphocyte subpopulations in the first year of life.
AB - Age-matched reference values for lymphocyte subpopulations are generally obtained
via cross-sectional studies, whereas patients are followed longitudinally. We
performed a detailed longitudinal analysis of the changes in lymphocyte
subpopulations in a group of 11 healthy infants followed from birth up to 1 y of
age, with special attention for early developmental markers, markers of
maturation, and markers of activation. We found that T and B lymphocytes
increased at 1 and 6 wk of age, respectively. In contrast, NK cells showed a
sharp decline directly after birth, suggesting that they are more important
during pregnancy than thereafter. CD45RA+--mainly CD4+--naive T lymphocytes were
high at birth, and increased further during the first year of life; they form a
large expanding pool of cells, ready for participation in primary immune
responses. The absolute counts of CD45RO+ memory T lymphocytes were similar in
infants and adults, albeit with a lower level of expression of CD45RO on infant T
lymphocytes. Almost all infant T lymphocytes expressed CD38 throughout the first
year of life. The abundant expression of CD38 on an infant's T lymphocytes might
be related to a greater metabolic need of the large population of naive
untriggered cells that are continually involved in primary immune responses
during the first year of life. The high B lymphocyte counts in infants mainly
concerned CD38+ B lymphocytes throughout the first year of life. Also, the
relative frequencies of CD1c+ and CD5+ B lymphocytes were higher throughout the
first year of life than in adults. Therefore, CD1c, CD5, and CD38 could be
markers of untriggered B lymphocytes. In conclusion, our longitudinal survey of T
and B lymphocytes, NK cells, and their subpopulations during the first year of
life helps to complete the picture of lymphocyte development in infants. This
information contributes to the correct interpretation of data from infants with
possible immune disorders.
PMID- 10759163
TI - A common polymorphism in the human relaxin-like factor (RLF) gene: no
relationship with cryptorchidism.
AB - The incidence of impaired testicular descent (cryptorchidism) is high; 1-2% of
boys at the age of 3 mo are diagnosed for this condition in western countries.
Recent data on mice with targeted disruption of the Insl3/relaxin-like factor
(RLF) gene proposed that this factor plays a role in testicular descent in fetal
life. Male RLF-/- mice exhibit bilateral cryptorchidism due to developmental
abnormalities of the gubernaculum, associated with abnormal spermatogenesis and
infertility. In the present study, we have sequenced the promoter region and both
exons of the RLF gene in a cohort of 30 boys, seven of whom presented with a
possible familial form of cryptorchidism and 23 with sporadic cryptorchidism. One
of the nucleotide substitutions detected, G to A at position 178, predicted amino
acid change. The mutation was localized to the C-peptide region, resulting in an
alanine to threonine change and therefore classified as a conservative mutation.
Four of the 30 cases analyzed were homozygous (13%), and 15 were heterozygous for
the mutation (50%). However, the same mutation was also found in a control group
of 89 men; 10% of them were homozygous, and 39% were heterozygous. Our results
indicate that mutations in the RLF gene are not a common reason for
cryptorchidism and that the common G178A polymorphism has no apparent
relationship with this condition.
PMID- 10759164
TI - Ethics in pediatric research.
PMID- 10759165
TI - Ethics in pediatric research.
PMID- 10759166
TI - Transcranial magnetic stimulation studies of cognition: an emerging field.
AB - In this short review, we consider the application of transcranial magnetic
stimulation (TMS) to the study of cognitive function. Following an introduction
to the technique, we consider its possible mechanisms of action. We then review
the studies that have applied TMS to the investigation of cognition. In the
majority of these investigations, TMS has been applied to disrupt function and
demonstrate that a particular cortical area is essential for performance of the
task under study. Finally, we highlight pertinent design and procedural issues
and consider other types of questions that can be addressed by future TMS studies
of cognitive function.
PMID- 10759167
TI - The feedback circuit connecting the superior colliculus and central mesencephalic
reticular formation: a direct morphological demonstration.
AB - The central mesencephalic reticular formation (cMRF) has been distinguished from
the surrounding reticular formation due to its involvement in the control of
saccades. A role in saccade function has been proposed for this region based on
electrical-stimulation experiments, its neuronal activity, and its pattern of
connections. The present study was undertaken in an attempt to further
characterize the location of the central mesencephalic reticular formation by
anatomical methods and to examine its connections with the superior colliculus at
the neuronal level. Biotinylated dextran amine (BDA) was injected into the
superior colliculus of two cynomolgus monkeys (Macaca fascicularis). This
resulted in the retrograde labeling of a large number of neurons in a restricted
area of the mesencephalic reticular formation. They were distributed bilaterally,
with an ipsilateral predominance, forming a cellular band in the ventral half of
the midbrain reticular formation that was 2.7 mm in its rostrocaudal extent. Its
rostral pole lay dorsolateral to the red nucleus and ventrolateral to, but not
immediately adjacent to, the interstitial nucleus of Cajal. The cell band was
widest caudally, where it occupied an area of approximately 2.7 mm wide and 2 mm
in depth. Labeled neurons displayed a wide variety of multipolar somatic shapes
and sizes, with long, slightly tapering, sparsely branched dendrites. Tectal
terminal arbors were also labeled within the mesencephalic reticular formation.
They were concentrated bilaterally, with an ipsilateral predominance, in the same
areas that contained retrogradely labeled neurons. Numerous, primarily en passant
labeled boutons of various sizes and shapes were seen in close association with
both labeled and unlabeled neurons. They formed axosomatic and, more commonly,
axodendritic relationships with labeled neurons. The extensive relationship of
labeled terminals and labeled cells suggests the existence of a strong
interconnection between the deeper layers of the colliculus and the central
mesencephalic reticular formation neurons projecting back to the tectum. The
bidirectional neural circuit directly demonstrated in this study presumably
provides an anatomical substrate for feedback modification of gaze signals
generated in the colliculus. However, the presence of tectal terminals around
unlabeled reticular neurons suggests that the collicular signal may also be fed
forward to the downstream targets of the central mesencephalic reticular
formation.
PMID- 10759168
TI - Coordination of the eyes and head: movement kinematics.
AB - When the head is restrained, saccades are characterized by lawful relationships
between movement amplitude, peak velocity, and duration. In addition, the
spatiotemporal progression of saccades (i.e., movement kinematics) is predictable
if saccade amplitude and direction are known. However, when the head is free to
move, changes in the direction of the line of sight (gaze shifts) often involve
saccades associated with simultaneous head movements. The metrics (duration,
amplitude, peak velocity) and kinematics of saccades occurring in conjunction
with head movements cannot be predicted on the basis of saccade amplitude and
direction alone. For example, when the head is unrestrained, velocity profiles of
35 degree eye movements can be symmetrical and might have peaks approximately 600
degrees/s. But, 35 degrees eye movements can also have peak velocities of
approximately 300 degrees/s and have velocity profiles with two pronounced peaks:
an initial peak followed by a reduction and subsequent increase in velocity.
Saccade amplitude and direction are insufficient to predict the shape of the
velocity profile. However, as illustrated in this report, if the amplitude of the
concurrent head movement is taken into account, saccade kinematics are
predictable even during gaze shifts with large head components. The data
presented here are indicative of an interaction between eye and head motor
systems in which head movement commands alter the execution of concurrent
saccades.
PMID- 10759169
TI - Reorganization of vibrissal motor representation following severing and repair of
the facial nerve in adult rats.
AB - This study examined the ability of adult rat motor cortex to reorganize its
relationship with the somatic musculature following the severing and regeneration
of a motor nerve. For this purpose experiments were performed on ten male albino
rats where the facial nerve on one side was severed, sutured and allowed to
regenerate for 6 months. Cortical motor output organization was assessed by
mapping the vibrissal movement area extension and thresholds evoked by
intracortical electrical stimulation in anesthetized rats. In all ten animals,
the cortical output pattern of the motor cortex contralateral to the normal side
was compared with that contralateral to the reinnervated side. After facial nerve
reinnervation, the most notable differences in primary motor cortex (M1) output
organization in the hemispheres contralateral to the reinnervated side were: (a)
the area from which vibrissa movements could be evoked at low thresholds was
smaller (mean 1.2+/-0.38 mm, range 0.75-1.75 mm), decreasing to 64.2% below those
in hemispheres contralateral to the normal side (mean 3.4+/-0.52 mm, range 2.5-4
mm). The reorganized vibrissa area consisted of contiguous or discontinuous
points shrunken to the medialmost portion of normal M1 vibrissal representation.
(b) There was a clear medial extension of the forelimb representation, and a more
modest lateral expansion of eye representation, into the vibrissa territory. The
mean threshold required to evoke vibrissa movements was significantly higher in
the hemispheres contralateral to the reinnervated side than in the other
hemispheres (normal 23.9+/-9.7 microA vs reinnervated 37.8+/-11.9 microA; P< or
=0.0001; t-test). The stimulation currents required to evoke other types of body
movements were similar in the normal and reinnervated sides. Similar results were
observed in all rats. In conclusion, these results indicate that motor nerve
reinnervation is sufficient to produce long-lasting changes at a higher motor
cortical level. This supports the notion that central supranuclear mechanisms may
also be involved in the disorder of facial movements observed after facial nerve
reinnervation.
PMID- 10759170
TI - Cross-correlated and oscillatory visual responses of superficial-layer and tecto
reticular neurones in cat superior colliculus.
AB - The present study examined, in the superior colliculus (SC) of anaesthetised
cats, the functional connectivity between superficial-layer neurones (SLNs) and
tectoreticular neurones (TRNs: collicular output cells). TRNs were antidromically
identified by electrical stimulation of the predorsal bundle. The auto- and cross
correlation histograms of visual responses of both types of neurones were
recorded and analysed. A delayed, sharp peak in cross-correlograms allowed us to
verify whether SLN and TRN cells were coupled; in addition, oscillatory
activities were compared to verify if rhythmic responses of SLN sites were
transmitted to TRN sites. We found that oscillatory activity was rarely observed
in spontaneous activity of superficial (1/74) and TRN sites (1/48). Moving light
bars induced oscillation in 31% (23/74) of the superficial-layer and in 23%
(11/48) of the TRN sites. The strength of the rhythmic responses was determined
by specific ranges of stimulus velocity in 83% (19/23) and 64% (7/11) of
oscillating SLN and TRN sites, respectively. Frequencies of oscillations ranged
between 5 and 125 Hz and were confined, for 53% of the cells, to the 5-20 Hz
band. Thus, the band-width of frequencies of the stimulus-related oscillations in
the superior colliculus was broader than the gamma range. Analysis of cross
correlation histograms revealed a significant predominant peak with a mean delay
of 2.7+/-0.9 ms in 46% (17/37) of SLN-TRN pairs. Most correlated SLN-TRN pairs
(88%: 15/17) had superimposed receptive fields, suggesting they were functionally
interconnected. However, individual oscillatory frequencies of correlated and
oscillatory SLN and TRN cells were never the same (0/8). Together, these results
suggest that the neurones in collicular superficial layer contact TRNs and,
consequently, support the idea that the superficial layers contribute to
collicular outputs producing eye- and head-orienting movements.
PMID- 10759171
TI - Immunohistochemical localization of substance P and substance P receptor (NK1) in
the olivary pretectal nucleus of the rat.
AB - The olivary pretectal nucleus (OPN) is the first central nucleus in the pupillary
light reflex arc (PLR). Substance P (SP) is a neuropeptide present in the OPN.
The present immunohistochemical study, performed at the ultrastructural level,
aimed to determine the synaptic localization of SP and SP receptor in the OPN.
Three types of SP-positive terminals were found. The most abundant type was of
retinal origin, characterized by electron-lucent mitochondria and round vesicles,
organized in glomerular structures, making asymmetric synaptic contacts with
dendrites, and profiles containing pleomorphic vesicles, also making synaptic
contacts with dendrites. The second type of SP-immunoreactive terminal contained
electron-dense mitochondria and pleomorphic vesicles. This type made symmetric
synaptic contacts and may originate from the ventral part of the lateral
geniculate nucleus. The third type of SP-immunoreactive terminals contained
electron-dense mitochondria, clear round vesicles, and made an asymmetric
synaptic contact. This type originates from the contralateral OPN. SP receptors
of the NK1 subtype were revealed to be on dendrites and were part of the
glomerular-like arrangement. On account of the present observations, it can be
concluded that retinal projections to the OPN use SP as a neuromodulator and
synapse on NK1 receptor-containing dendrites of large neurons projecting to the
Edinger-Westphal nucleus. Since SP also modulates the parasympathetic component
of the PLR, we postulate that SP plays a modulating role in all components of the
PLR.
PMID- 10759172
TI - Glial cell proliferation in the spinal cord after dorsal rhizotomy or sciatic
nerve transection in the adult rat.
AB - Proliferation of glial cells is one of the hallmarks of CNS responses to neural
injury. These responses are likely to play important roles in neuronal survival
and functional recovery after central or peripheral injury. The boundary between
the peripheral nervous system (PNS) and CNS in the dorsal roots, the dorsal root
transitional zone (DRTZ), marks a distinct barrier for growth by injured dorsal
root axons. Regeneration occurs successfully in the PNS environment, but ceases
at the PNS-CNS junction. In order to understand the role of different glial cells
in this process, we analysed the proliferation pattern of glial cells in central
(CNS) and peripheral (PNS) parts of the dorsal root and the segmental white and
grey spinal cord matter after dorsal rhizotomy or sciatic nerve transection in
adult rats 1-7 days after injury. Monoclonal antibody MIB-5 or antibodies to
bromodeoxyuridine were used to identify proliferating cells. Polyclonal
antibodies to laminin were used to distinguish the PNS and CNS compartments of
the dorsal root. Dorsal root lesion induced glial cell proliferation in the CNS
as well as PNS beginning at 1 day, with peaks from 2 to 4 days postoperatively.
After sciatic nerve injury, cell proliferation occurred only in the CNS, was
minimal at 1 day, and peaked from 2 to 4 days postoperatively. Double
immunostaining with specific glial cell markers showed that after dorsal root
transection 60% of the proliferating cells throughout the postoperative period
examined were microglia, 30% astrocytes and 10% unidentified in the CNS, while in
the PNS 40% were Schwann cells, 40% macrophages and 20% unidentified. After
sciatic nerve injury virtually all proliferating cells were microglia. These
findings indicate that non-neuronal cells in the CNS and PNS are extremely
sensitive to the initial changes which occur in the degenerating dorsal root
axons, and that extensive axonal degeneration is a prerequisite for astroglial
and Schwann cell, but not microglial cell, proliferation.
PMID- 10759173
TI - Developmental and lesion-induced changes in the distribution of the glucose
transporter Glut-1 in the central and peripheral nervous system.
AB - The active transport of D-glucose from the vascular to the neural compartment
requires the presence of a carrier molecule at the blood-brain and the blood
nerve barrier. The glucose transporter 1 (Glut-1) seems to be the main carrier in
blood-tissue barriers of endothelial and perineurial type. The distribution of
Glut-1 was assessed in the normal central and peripheral nervous system of young
and adult animals and compared with changes after nerve injury. Immuno
histochemistry, in situ hybridization, and perfusions with Evans Blue were
carried out. Glut- I was not expressed in the perineurium of peripheral nerves at
birth, but appeared in the perineurium of peripheral nerves, spinal roots, in the
capsule of dorsal-root ganglia, and in the pia mater of adult animals. The
perineurium of peripheral nerves subjected to Wallerian degeneration presented a
faint Glut-1 immunoreaction, which was restored after regeneration. Glut-1 was
expressed in capillaries of the gray substance of the spinal cord. Perineurial
derived lamellar cells of Pacinian corpuscles exhibited a strong Glut-1-like
immunoreactivity in response to denervation and during development. Merkel cells
and Meissner corpuscles were found to be Glut-1 negative. Glut-1 seems to reflect
the quality of an adult, mature perineurial and blood-nerve barrier.
PMID- 10759174
TI - Modulation of simple reaction time on the background of an oscillatory action:
implications for synergy organization.
AB - The hypothesis put forward here is that simple reaction time (SRT) modulation on
the background of an oscillatory motor action is due to central neural coupling
between signals to the effectors involved in the focal and the oscillatory
action. The strength of the coupling may be defined by various factors ranging
from anatomy to personal lifetime practice or to a particular task context. In
one experiment, subjects performed an SRT task (ipsi or contralateral elbow
flexion or ipsilateral ankle plantar flexion) in response to a visual imperative
signal presented during a continuous oscillatory movement of the right wrist.
Discrete elbow movements lead to nearly simultaneous large bursts of activity in
both biceps and the wrist flexor of the arm. Strong modulation of premotor time
(peak to peak changes of about 80 ms) with the phase of oscillatory action
(f(OSC)) was seen in both biceps and wrist flexor when the two movements were
performed by joints of the same limb but not when they were performed by joints
of different limbs. The order of recruitment of proximal and distal muscles was
also dependent on the phase of oscillatory action: the typical proximal-to-distal
order was seen at relatively long premotor times (PMTs) while simultaneous muscle
activation was seen at the shortest PMTs. In the second experiment, the subjects
held a cylindrical plastic cup in the left hand and applied sine-like isometric
force to the bottom of the cup with the other hand. The SRT in the task requiring
a quick increase in the grip force in response to a visual imperative stimulus
was modulated with the phase of the oscillatory action. This modulation
disappeared when the right hand applied similarly modulated force to another
surface. The conclusion is that an interaction between control signals for the
focal and oscillatory actions at a supraspinal level led to the observed
modulation of the SRT during the phase of oscillatory action. The possible role
of cortical and subcortical mechanisms is discussed.
PMID- 10759175
TI - Adaptation to visual feedback delays in a human manual tracking task.
AB - The time-course of human adaptation to spatial perturbations of visuomotor
function (e.g. with prisms) is very short. However, it is not clear how rapid the
adaptation to other aspects of perturbed feedback is. In this paper we report the
adaptation to delayed visual feedback. Three groups of six subjects tracked
unpredictable, continuously moving targets using a hand-held joystick while
visual feedback of the joystick position was delayed (0 ms, 200 ms or 300 ms).
Subjects clearly adapted to the delay, with a significant drop in tracking error,
but changes in more subtle aspects of their tracking behaviour (such as changes
in intermittency and their "impulse response functions") were not consistently
observed. We suggest that the adaptation seen was consistent with the idea of
there being a "delay component" in the internal processes used in manual
tracking, as proposed in models such as the Smith predictor model.
PMID- 10759176
TI - A systematic directional error in 2-D arm movements increases with increasing
delay between visual target presentation and movement execution.
AB - Forty-seven normal subjects performed two-dimensional arm movements on a
digitizer board using a mouse device. The movements were projected on a computer
monitor. Subjects were instructed to move the mouse using the whole arm from a
center position to a peripheral target so that the projected movement would pass
over the target without stopping on the target. A large number of targets (360)
were used to cover the entire directional continuum. The direction of the arm
movement was the parameter of interest, which was measured at an initial
position, at one third of the distance towards the target, and at the vicinity of
the target. Four conditions of delay between target presentation and movement
execution were used (0, 2, 4, 6 s). A systematic directional error was observed
at the initial portion of the trajectory. This error resulted from a clustering
of movement directions on an axis that was perpendicular to the axis of the
resting forearm before movement onset. This pattern of errors can be explained by
the initial inertial anisotropy of the arm. As the trajectory evolved, a
different directional error emerged, resulting from a clustering of movement
directions in two orthogonal axes. This pattern of directional error increased in
amplitude as the delay increased, in contrast to the error at the initial portion
of the trajectory which remained invariant with increasing delay. Finally, the
information transmitted by the movement direction was shown to increase with the
evolution of the trajectory. The increase in delay resulted in a decrease in
directional-information transmission. It is proposed that the directional bias
towards the end of the movement trajectory might reflect the action of "movement
primitives", that is patterns of muscle activation resulting from spinal
interneuronal activation. It is further proposed that the directional bias
observed at the vicinity of the target might reflect a loss of cortical
directional information with increasing delay between target presentation and
movement onset.
PMID- 10759177
TI - Effects of stimulus orientation on spatial frequency function of the visual
evoked potential.
AB - Visual performance is better in response to vertical and horizontal stimuli than
oblique ones in many visual tasks; this is called the orientation effect. In
order to elucidate the electrophysiological basis of this psychophysical effect,
we studied the effects of stimulus orientation on the amplitudes and latencies of
visual evoked potentials (VEPs) over different spatial frequencies of the visual
stimulation. VEPs to sinusoidal gratings at four orientations (vertical,
horizontal, and oblique at 45 degrees and 135 degrees) with eight spatial
frequencies (0.5-10.7 cycles/deg) at reversal rates of 1 Hz and 4 Hz were
recorded in nine subjects. At 1-Hz stimulation, the amplitude and latency of P100
were measured. At 4-Hz stimulation, VEPs were Fourier-analyzed to obtain phase
and amplitude of the second harmonic response (2F). At 1-Hz stimulation, P100
latencies were decreased for oblique stimuli compared with those for horizontal
and vertical stimuli at lower spatial frequencies. Conversely, those for oblique
stimuli were increased compared with those for horizontal and vertical stimuli at
higher spatial frequencies. At 4-Hz stimulation, spatial tuning observed in 2F
amplitude of the oblique gratings shifted to lower spatial frequencies when
compared with those of vertical stimulation. The alteration of the VEP spatial
frequency function caused by the oblique stimuli was in good agreement with the
orientation effect observed in psychophysical studies. Our study may have a
clinical implication in that VEP testing with stimuli in more than one
orientation at slow and fast temporal modulations can be useful in evaluating
neurological disease affecting the visual system.
PMID- 10759178
TI - Cell death and immunohistochemistry of p53, c-Fos and c-Jun after spermine
injection into the rat striatum.
AB - Administration of polyamines into the central nervous system results in tissue
damage, possibly through the excitotoxic actions of the NMDA receptor. Direct
injection of 100 nmol of spermine into the rat striatum produced a lesion
equivalent to approximately 50% of the striatum. Analysis of the DNA in this
region revealed the distinct ladder-like pattern of degradation often associated
with apoptosis. This DNA fragmentation was confirmed in vivo using terminal
deoxynucleotidyl-transferase-mediated biotinylated deoxyuridine triphosphate nick
end labelling (TUNEL). The morphology of the TUNEL-positive cells showed marked
differences at the needle tract when compared with cells in damaged areas away
from the needle tract, suggesting a differential mechanism of cell death in these
two regions. The patterns of p53, c-Fos and c-Jun protein expression were
determined using immunohistochemistry. The number of p53-immunoreactive cells
increased up to 14 h and returned to basal levels by 24 h. c-Fos protein
expression transiently increased, peaking at 8 h after injection. c-Jun exhibited
a protracted pattern of expression, remaining elevated up to 24 h. p53 protein
expression was colocalised with TUNEL staining in areas away from the needle
tract, but not in cells at the needle tract, suggesting once again a differential
mechanism of cell death. At 14 h, c-Fos and c-Jun were not colocalised with TUNEL
staining, suggesting that they are either not involved with the cell death
process or that the time course of protein expression and the onset of DNA
fragmentation do not overlap. This work represents the first characterisation of
processes associated with cell death induced by spermine in vivo.
PMID- 10759179
TI - Changes in muscle responses to stimulation of the motor cortex induced by
peripheral nerve stimulation in human subjects.
AB - The aim of this study was to determine whether prolonged, repetitive mixed nerve
stimulation (duty cycle 1 s, 500 ms on-500 ms off, 10 Hz) of the ulnar nerve
leads to a change in excitability of primary motor cortex in normal human
subjects. Motor-evoked potentials (MEPs) generated in three intrinsic hand
muscles [abductor digiti minimi (ADM), first dorsal interosseous (FDI) and
abductor pollicis brevis (APB)] by focal transcranial magnetic stimulation were
recorded during complete relaxation before and after a period of prolonged
repetitive ulnar nerve stimulation at the wrist. Transcranial magnetic stimuli
were applied at seven scalp sites separated by 1 cm: the optimal scalp site for
eliciting MEPs in the target muscle (FDI), three sites medial to the optimal site
and three sites lateral to the optimal stimulation site. The area of the MEPs
evoked in the ulnar-(FDI, ADM) but not the median-innervated (APB) muscles was
increased after prolonged ulnar nerve stimulation. Centre of gravity measures
demonstrated that there was no significant difference in the distribution of
cortical excitability after the peripheral stimulation. F-wave responses in the
intrinsic hand muscles were not altered after prolonged ulnar nerve stimulation,
suggesting that the changes in MEP areas were not the result of stimulus-induced
increases in the excitability of spinal motoneurones. Control experiments
employing transcranial electric stimulation provided no evidence for a spinal
origin for the excitability changes. These results demonstrate that in normal
human subjects the excitability of the cortical projection to hand muscles can be
altered in a manner determined by the peripheral stimulus applied.
PMID- 10759180
TI - Pathological and experimentally induced blindness induces auditory activity in
the cat primary visual cortex.
AB - Early blindness in humans and experimental visual deprivation in animal models
are known to induce compensatory somatosensory and/or auditory activation of the
visual cortex. An abnormal hydrocephalic cat with extreme malformation of the
visual system, born in our breeding colony, rendered a good model system for
investigating possible cross-modal compensation in such a pathological case. For
comparison, we used normal and neonatally enucleated cats. When introduced to a
novel environment, the abnormal cat behaved as if it was completely blind, yet it
responded normally to auditory stimuli. As anticipated, single cells in the
visual cortex of normal cats responded to visual, but not to auditory stimuli. In
the visual cortex of enucleated cats, flashes of light did not elicit field
evoked potentials or single-unit responses. However, several cells did respond to
various auditory stimuli. In the remnant visual cortex of the abnormal cat,
auditory stimuli evoked field potentials and single-cell responses. Unexpectedly,
however, unlike the enucleated cats, in the abnormal cat, flashes of light also
elicited field-evoked potentials. Judging by its behavior, it is very likely that
this deformed cat had completely lost its ability to perceive images, but had
probably retained some sensitivity to light.
PMID- 10759181
TI - Spinocerebellar ataxia type 1--modeling the pathogenesis of a polyglutamine
neurodegenerative disorder in transgenic mice.
AB - Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inherited
neurodegenerative diseases caused by a mutant expansion of a polyglutamine
repeated sequence within the affected gene. One of the major cell types affected
by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinje cell. Targeted
expression of mutant ataxin-1 in Purkinje cells of transgenic mice produces an
ataxic phenotype with pathological similarities to the human disease. Other
transgenic experiments using altered forms of mutant ataxin-1 have shown that
nuclear localization of the mutant protein is necessary for pathogenesis and that
nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and
other polyglutamine diseases, are not a requirement for pathogenesis in
transgenic models of SCA1. Present and future generations of transgenic mouse
models of SCA1 will be valuable tools to further address mechanisms of
pathogenesis in polyglutamine-related disorders.
PMID- 10759182
TI - Amyloid beta-induced neuronal death is bax-dependent but caspase-independent.
AB - Fibrillar amyloid beta (Abeta) peptides are major constituents of senile plaques
in Alzheimer disease (AD) brain and cause neuronal apoptosis in vitro. Bax and
caspase-3 have been implicated in the pathogenesis of AD and are components of a
well-defined molecular pathway of neuronal apoptosis. To determine whether Abeta
induced neuronal apoptosis involves bax and/or caspase-3 activation, we examined
the effect of Abeta on wild-type, bax-deficient, and caspase-3-deficient
telencephalic neurons in vitro. In wild-type cultures, Abeta produced time- and
concentration-dependent caspase-3 activation, apoptotic nuclear changes, and
neuronal death. These neurotoxic effects of Abeta were not observed in bax
deficient cultures. Caspase-3 deficiency, or pharmacological inhibition of
caspase activity, prevented caspase-3 activation and blocked the appearance of
apoptotic nuclear features but not Abeta-induced neuronal death. Neither calpain
inhibition nor microtubule stabilization with Taxol protected telencephalic
neurons from Abeta-induced caspase activation or apoptosis. These results have
potential implications regarding the underlying pathophysiology of AD and towards
AD treatment strategies.
PMID- 10759183
TI - Interferon-gamma modulates human oligodendrocyte susceptibility to Fas-mediated
apoptosis.
AB - Interferon gamma (IFN-gamma) has been shown to be produced within multiple
sclerosis (MS) lesions by infiltrating lymphocytes; systemic administration of
this cytokine induces exacerbation of the disease. The aim of the current study
was to establish the contribution of IFN-gamma to oligodendrocyte (OL) injury.
Our studies utilized cultured human OLs, obtained by dissociation of surgically
derived non-MS adult brain tissue. Neither cell survival nor myelin basic protein
(MBP) gene expression were affected after 96 hours of treatment with IFN-gamma
(100 U/ml), as assessed by LDH release, nucleosome enrichment assay, and RT-PCR.
Expression of the death receptor Fas (CD95, APO-1) was, however, significantly
increased. Furthermore, IFN-gamma-treated OLs became susceptible to Fas-mediated
apoptosis when compared with untreated cells, and were protected by pretreatment
with the caspase inhibitor ZVAD. TNF-alpha augmented the IFN-gamma-induced
effect. Our results thus indicate that IFN-gamma is not directly cytotoxic for
human OLs in culture, but could indirectly modulate functional injury-related
responses by upregulating Fas on the cell surface.
PMID- 10759184
TI - Cytoskeletal disruption following contusion injury to the rat spinal cord.
AB - Following experimental spinal cord injury (SCI), there is a delayed loss of
neurofilament proteins but relatively little is known regarding the status of
other cytoskeletal elements. The purpose of the present study was to compare the
extent and time course of the MAP2 loss with that of neurofilament proteins, and
to examine tau protein levels and distribution following SCI. Within 1 to 6 hours
following SCI, there is rapid loss of MAP2, tau, and nonphosphorylated
neurofilament proteins at the injury site. In contrast, the loss of
phosphorylated neurofilament proteins was not significant until 1 week
postinjury. In addition to the loss of MAP2 protein, there was extensive beading
of MAP2-immunoreactive dendrites extending into the white matter. This was most
pronounced 1 hour after injury and gradually resolved such that beading was no
longer evident 2 weeks after SCI. The time course of beading resolution is
similar to that of behavioral recovery following SCI, but the functional
significance of the beading remains to be determined. Together, these results
demonstrate that there are 2 phases of cytoskeletal disruption following SCI; a
rapid loss of MAP2, tau, and nonphosphorylated neurofilament proteins, and a
delayed loss of phosphorylated neurofilaments.
PMID- 10759185
TI - Pathology of nerve terminal degeneration in the skin.
AB - To characterize the pathology of epidermal nerve degeneration and regeneration,
we investigated temporal and spatial changes in skin innervation of the mouse
footpad. Within 24 hours after sciatic nerve axotomy, terminals of epidermal
nerves appeared swollen and there was a mild reduction in epidermal nerve density
(5.7 +/- 2.8 vs 12.7 +/- 2.2 fibers/mm, p < 0.04). Epidermal nerves completely
disappeared by 48 hours (0.2 +/- 0.2 vs 14.2 +/- 0.9 fibers/mm, p < 0.001).
Concomitant with the disappearance of epidermal nerves, the immunocytochemical
pattern of the subepidermal nerve plexus became fragmented. At the electron
microscopic level, the axoplasm of degenerating dermal nerves was distended with
organelles and later became amorphous. Beginning from day 28 after axotomy,
collateral sprouts from the adjacent saphenous nerve territory extended into the
denervated area with a beaded appearance. They never penetrated the epidermal
dermal junction to innervate the epidermis. In contrast, 3 months after nerve
crushing, the epidermis on the surgery side resumed a normal innervation pattern
as the epidermis on the control side (10.3 +/- 3.9 vs 10.6 +/- 1.5 fibers/mm, p =
0.1). This study demonstrates the characteristics of degenerating and
regenerating nerves, and suggests that successful reinnervation mainly originates
from regenerating nerves of the original nerve trunks. All these findings provide
qualitative and quantitative information for interpreting the pathology of
cutaneous nerves.
PMID- 10759186
TI - The cholinergic deficit coincides with Abeta deposition at the earliest
histopathologic stages of Alzheimer disease.
AB - Effective therapeutic intervention in Alzheimer disease (AD) will be most
effective if it is directed at early events in the pathogenic sequence. The
cholinergic deficit may be such an early event. In the present study, the brains
of 26 subjects who had no history of cognitive loss and who were in early
histopathologic stages of AD (average Braak stage less than II) were examined at
autopsy to determine whether a cortical cholinergic decrement was associated with
Abeta concentration or deposition. In the superior frontal and inferior temporal
gyri, the choline acetyltransferase (ChAT) activity of plaque-containing cases
was significantly decreased (p < 0.05, unpaired, two-tailed t-tests), measuring
70.9% and 79.5%, respectively, relative to plaque-free cases. In the inferior
temporal gyrus, Spearman's rank correlation analysis showed that ChAT activity
had a significant inverse correlation with Abeta concentration (p = 0.075; r =
0.3552). The results indicate that the cholinergic deficit is established at an
early histopathologic stage of AD, before the onset of clinical symptoms.
PMID- 10759187
TI - Decreased vasopressin gene expression in the biological clock of Alzheimer
disease patients with and without depression.
AB - Circadian rhythm disturbances are frequently present in Alzheimer disease (AD).
In the present study, we investigated the expression of vasopressin (AVP) mRNA in
the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on
formalin-fixed paraffin-embedded material was improved to such a degree that we
could, for the first time, visualize AVP mRNA expressing neurons in the human SCN
and carry out quantitative measurements. The total amount of AVP mRNA expressed
as masked silver grains in the SCN was 3 times lower in AD patients (n = 14;
2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11;
6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the
amount of AVP mRNA between AD patients with depression (n = 7) and without
depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2,
respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons
showed a marked day-night difference in controls under 80 years of age. The
amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/-
1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02),
whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD
patients. There was no relationship between the amount of AVP mRNA in the SCN and
age at onset of dementia, duration of AD and the neuropathological changes in the
cerebral cortex. These findings suggest that the neurobiological basis of the
circadian rhythm disturbances that are responsible for behavioral rhythm
disorders is located in the SCN. It also explains the beneficial effects of light
therapy on nightly restlessness in AD patients.
PMID- 10759189
TI - Nuclear localization and mutation of beta-catenin in medulloblastomas.
AB - The adenomatous polyposis coli (APC) gene, a member of the Wingless/Wnt signal
transduction pathway, has been implicated in the development of medulloblastomas
in Turcot's syndrome. beta-catenin also functions in this highly conserved
signaling pathway and is instrumental in growth and development. Mutations in
either APC or beta-catenin can stabilize beta-catenin protein. Stabilized beta
catenin complexes with Tcf/Lef transcription factors and moves from the cytoplasm
into the nucleus where it regulates the transcription of c-Myc and other genes.
Nuclear localization of beta-catenin therefore implies activation of the
signaling pathway. We have analyzed the subcellular localization of beta-catenin
in 51 sporadic medulloblastomas and in 1 medulloblastoma arising in a patient
with Turcot's syndrome. Nuclear beta-catenin staining was present in 9 of the
sporadic tumors (18%) and in the 1 medulloblastoma from a Turcot's patient. The
remaining 41 cases did not show nuclear staining. This confirms earlier
observations that Wingless/Wnt signaling is involved in a subset of sporadic
medulloblastomas. We also examined 48 glial and meningeal CNS tumors, all of
which were negative for nuclear beta-catenin. Exon 3 of beta-catenin was
sequenced in 6 of the 9 sporadic medulloblastomas with nuclear beta-catenin
staining. Five of the 6 tumors sequenced had mutations affecting highly conserved
beta-catenin phosphorylation sites involved in protein stability. These data
suggest a simple immunohistochemical method to screen for beta-catenin mutations
in medulloblastomas.
PMID- 10759188
TI - Allograft inflammatory factor-1 is expressed by macrophages in injured skeletal
muscle and abrogates proliferation and differentiation of satellite cells.
AB - Secretion of regulatory peptides by macrophages in injured skeletal muscle
constitutes a pivotal determinator of tissue homeostasis. We analyzed expression
of a novel Ca2+- binding peptide expressed by activated macrophages, the
allograft inflammatory factor-1 (AIF-1), in rat devascularized skeletal muscle.
AIF-1 expression was observed in 94% of all macrophages at the site of the injury
48 hours postdevascularization. The physiological function of AIF-1 in injured
skeletal muscle was analyzed using a rat in-vitro model of satellite cell
proliferation and differentiation. Addition of AIF-1 to the culture medium
resulted in a concentration-dependent and reversible reduction of the total
number of cells expressing M-cadherin (p < or = 0.0001), a mediator of the
differentiation process of skeletal muscle cells, the proliferation associated
PCNA (p < or = 0.0001), and the initiator of muscle differentiation myogenin (p <
or = 0.0001). These results provide convincing evidence that activated AIF-1
expressing macrophages constitute the predominant cell type in skeletal muscle 48
hours postinjury, and that AIF-1 regulates reduced proliferation,
differentiation, and activation of satellite cells.
PMID- 10759190
TI - Tornado disaster in rural Georgia: triage response, injury patterns, lessons
learned.
AB - Our objective was to characterize the medical response and injury patterns from a
recent tornado disaster in rural southeastern Georgia. We conducted a
retrospective review of 11 patients treated at a Level I trauma center after
sustaining injuries due to an April 9, 1998 F3 tornado. Data were obtained from
trauma registry and medical records. Of 11 victims, 8 (73%) were male. Ages
ranged from 5 to 54 years. Two patients were triaged directly by military
helicopter, six arrived as secondary triage from local rural hospitals (2 by air,
4 by ground), and three arrived by delayed secondary transfer. Six patients were
thrown by the tornado, and five were struck by flying debris. All victims were
either in exposed areas or mobile homes. Injuries by anatomic region included the
chest (45%), abdomen (27%), extremity (91%), and head (45%). Nine (82%) of the
patients required surgical intervention. These included three laparotomies, one
thoracotomy, six orthopedic procedures, and one neurosurgical procedure. The
average Injury Severity Score (ISS) was 23. Among patients who were thrown mean
ISS was 31; among those struck by debris, mean ISS was 12. Hemodynamically
significant pelvic fractures occurred in three patients (27%). The major
complication, sepsis due to Serratia marcescens was seen in three patients, all
of whom had been thrown and had clinically significant wound contamination. Both
patients who died had Serratia sepsis and multiorgan system failure. The injuries
and inclement weather characteristic of tornado disasters stress regional trauma
triage responses, cause significant injury, and disrupt communities. Injury
patterns involve multiple systems and require coordinated efforts among
caretakers. Infectious complications are common and frequently involve Gram
negative bacilli and are associated with soil-contaminated wounds. Trauma
severity increases if the victim is thrown rather than struck by flying debris.
PMID- 10759191
TI - Heartburn is more likely to recur after Toupet fundoplication than Nissen
fundoplication.
AB - Toupet (270 degrees) fundoplication is commonly recommended for patients with
gastroesophageal reflux (GER) and esophageal dysmotility. However, Toupet
fundoplication may be less effective at protecting against reflux than Nissen
(360 degrees) fundoplication. We therefore compared the effectiveness and
durability of both types of fundoplication as a function of preoperative
esophageal motility. From January 1992 through January 1998, 669 patients with
GER underwent laparoscopic fundoplication (78 Toupet, 591 Nissen). Patients
scored heartburn, regurgitation, and dysphagia preoperatively, and at 6 weeks and
1 year postoperatively, using a 0 ("none") to 3 ("severe") scale. We compared
symptom scores (Wilcoxon rank sum test) and redo fundoplication rates (Fisher
exact test) in Toupet and Nissen patients. We also performed subgroup analyses on
81 patients with impaired esophageal motility (mean peristaltic amplitude, <30 mm
Hg or peristalsis <70% of wet swallows) and 588 patients with normal esophageal
motility. Toupet and Nissen patients reported similar preoperative heartburn,
regurgitation, and dysphagia. At 6 weeks after operation, heartburn and
regurgitation were similarly improved in both groups, but dysphagia was more
prevalent among Nissen patients. After 1 year, heartburn and regurgitation were
re-emerging in Toupet patients, and dysphagia was again similar between groups.
Patients with impaired motility who have Nissen fundoplication are no more likely
to suffer persistent dysphagia than their counterparts who have Toupet
fundoplication. In addition, patients with normal motility are more likely to
develop symptom recurrence after Toupet fundoplication than Nissen
fundoplication, with no distinction in dysphagia rates. We conclude that since
Toupet patients suffer more heartburn recurrence than Nissen patients, with
similar dysphagia, selective use of Toupet fundoplication requires further study.
PMID- 10759192
TI - The use of water-soluble contrast in evaluating clinically equivocal small bowel
obstruction.
AB - This study seeks to determine whether a 6-hour abdominal radiograph after oral
Gastrografin is a reliable indicator for nonoperative treatment in patients with
a clinically equivocal small bowel obstruction. We collected retrospective data
from medical records. Patients who received a Gastrografin transit time (GGTT)
study between January 1995 and September 1998 were included in the study.
Patients who did not appear to be obvious operative candidates, but had signs of
intestinal obstruction, underwent a GGTT study. Serial plain abdominal
radiographs were taken. If the contrast was in the colon within 6 hours, then the
result was negative. A total of 418 GGTT studies were reviewed. Contrast reached
the colon within 6 hours in 283 (68%) patients, and 247 (88%) of these patients
were managed nonoperatively. The positive predictive value, negative predictive
value, sensitivity, and specificity of Gastrografin reaching the colon within 6
hours were 48, 87, 64, and 78, respectively. False negatives included high-grade
partial obstructions that ultimately required surgery. Recent operation preceded
the GGTT in 128 (31%) cases. Of these 128 patients, only 17 (14%) received an
operation. Although the decision to operate or not should never be based on a
GGTT study alone, GGTT studies are of significant help in the clinical management
of patients suspected to have a small bowel obstruction. GGTT allows for the
judicious selection of the appropriate patient for nonoperative management. GGTT
studies are cost effective, safe, and clinically useful when attempting to treat
patients conservatively.
PMID- 10759193
TI - Laparoscopic colon resections: a five-year retrospective review.
AB - In recent years, laparoscopic surgery has become a matter of growing interest. It
has been shown that laparoscopic colectomy is well tolerated and safe for benign
disease. However, there is some uncertainty about using this method for malignant
disease when curative resection is the aim. These uncertainties mainly consist of
spread of cancer to port site, long-term survival, and adequacy of resection. The
majority of laparoscopic colectomies are technically assisted procedures in which
anastomosis is performed outside the abdomen. However, some surgeons are now
performing this surgery totally laparoscopically with the anastomosis performed
inside the abdomen. Laparoscopic colectomy is currently practiced with great
frequency by general surgeons. Its performance requires a steep learning curve
and a large number of cases to obtain proficiency. The indications for
laparoscopic colectomy are different from one institution to another. In some
institutions all patients with colorectal disease are candidates for laparoscopic
colectomy and in others it may be limited to benign disease only. The purpose of
this review is to analyze all laparoscopic colectomies performed at our medical
center since 1992. We conducted a retrospective chart review of both hospital and
clinic charts of patients who underwent colectomies at our hospital. A total of
338 patient charts were reviewed. In a comparison of both laparoscopic (n = 285)
and converted (n = 53) methods, the age and operative time were about the same.
Age average and operating room time average were similar for both groups. With
laparoscopy, there was a 3-day drop in length of hospital stay as well as a 1-day
earlier regaining of bowel function. Hospital cost dropped 5000 dollars average
for the laparoscopic colectomy. The conversion rate at our center was 15 per
cent. Complication rates were lower in the laparoscopic group. Recurrence of
cancer at the port site (0.7%) was no higher than in the converted group
(incisional recurrence, 1.8%). We conclude that laparoscopic colectomy does show
an improvement in return of bowel function, hospital cost, and shorter hospital
stay. Long-term follow-up will be necessary to determine the effectiveness of
laparoscopic colon resection for colorectal cancer.
PMID- 10759194
TI - Surgery for T4 breast carcinoma: implications for local control.
AB - Despite increasing public awareness and widespread availability of mammography,
many patients will present with locally advanced breast cancers. The role of
surgery remains controversial. Between 1993 and 1998, 47 of 393 (11.9%) breast
cancer patients presented with T4 (inflammatory or locally advanced) carcinoma.
We reviewed multimodality management, clinical response to neoadjuvant therapy,
perioperative course and complications, and local control. Forty-six women and
one man were diagnosed with clinical T4 breast cancer. There were 24 white and 23
African-American patients. Mean age at presentation was 54.5 (range, 31-88)
years. Twenty-three patients had clinical metastases to axillary nodes, and five
had distant metastases at the time of diagnosis. For these women, intent was for
personal hygiene and control of pain. Neoadjuvant chemotherapy was given for 34
of 47 (72%) with 25 of 34 (73.5%) having partial or complete clinical response.
There was no response or progression of disease in 9 of 34(26.5%). Forty-six
patients underwent radical or modified radical mastectomy, whereas a single
patient underwent breast conservation treatment. Twelve required tissue transfer
for wound coverage. Although eight developed minor wound complications
(cellulitis/flap separation), there were no major wound complications.
Pathologically negative margins were achieved in all but one patient. To date,
five women have developed local recurrence in either the chest wall (three) or
axilla (two). Average time to local recurrence was 7.8 months. There is no
evidence of local failure in the remaining 87 per cent. Locally advanced breast
cancer is a common occurrence in certain populations. Multimodality management
remains the standard of care. Surgical resection may allow for successful local
control and, in certain situations, long-term cure.
PMID- 10759195
TI - Failure of percutaneous catheter drainage of pancreatic pseudocyst.
AB - Percutaneous catheter drainage (PCD) of symptomatic pancreatic pseudocysts under
CT radiologic guidance is a valuable adjunct or alternative to operative
pseudocyst management. PCD failure is characterized by the development of
recurrent pseudocysts or external pancreatic fistulas. The purpose of this study
is to define the cause and management of PCD failure patients. A retrospective
review and analysis of patients with symptomatic pancreatic pseudocysts managed
with PCD who required subsequent operative treatment because of PCD failure was
undertaken. There were 23 study patients (18 men, 5 women) with a mean age of 44
years identified over a 13-year time period. Pancreatitis etiology was alcohol
abuse in 10, gallstones in 7, pancreas divisum in 3, trauma in 2, and sphincter
of Oddi dysfunction in 1. Endoscopic retrograde cholangiopancreatography findings
were: 13 genu strictures, 4 main pancreatic duct dilations, 2 head strictures, 1
body stricture, 1 stricture in the tail, 1 intact duct, and 1 unknown. Operations
used to manage PCD failures were: lateral pancreaticojejunostomy (LPJ) in 9
patients, Roux-en-Y pancreatic fistula jejunostomy in 7, distal pancreatectomy in
3, caudal pancreatectomy in 2, pancreatoduodenectomy in 1, cyst gastrotomy in 1,
and caudal pancreatojejunostomy in 1. Follow-up has ranged from 1 to 13 years
(mean, 5 years). Five patients who underwent pancreatic fistula jejunostomy
developed recurrent pseudocysts or pancreatitis. There have been no recurrent
pseudocysts or fistulas in patients managed with LPJ or pancreatic resection.
Genu strictures were the cause of PCD failure in the majority of patients. LPJ is
the treatment of choice for genu strictures but may not always be possible
because of chronic inflammatory changes. Roux-en-Y pancreatic fistula jejunostomy
is an acceptable alternative. Recurrent pseudocysts in the head and body are
treated with LPJ with cyst incorporation. Pancreatic resection is appropriate for
certain strictures of the head, body, and pancreatic tail. Failure of PCD is
associated with an underlying ductal disorder that needs to be defined
preoperatively with endoscopic retrograde cholangiopancreatography to select the
appropriate operation.
PMID- 10759196
TI - Choledocholithiasis: evolving intraoperative strategies.
AB - In the era of open cholecystectomy, common bile duct stones were approached by
traditional choledocholithotomy. Retained or recurrent stones discovered after
cholecystectomy were approached by endoscopic extraction techniques or repeat
surgery. With the advent of laparoscopic cholecystectomy, the approach to
choledocholithiasis became more problematic as techniques for laparoscopic
extraction were rudimentary. Preoperative endoscopic retrograde
cholangiopancreatography rapidly became an adjunct to laparoscopic
cholecystectomy when common duct stones were likely. Experience, however,
revealed that many of these procedures were unnecessary. With developing
sophistication of laparoscopic techniques, a variety of approaches to common duct
stones developed. These included: transcystic extraction, direct laparoscopic
choledocholithotomy, intraoperative endoscopic retrograde
cholangiopancreatography, antegrade sphincterotomy, and transcystic placement of
a common duct stent with subsequent endoscopic sphincterotomy and stone
extraction. It is the purpose of this article to define the current role of each
of these methods in the laparoscopic approach to choledocholithiasis.
PMID- 10759197
TI - Initial neck exploration for untreated hyperparathyroidism.
AB - This study represents the experience of the Department of Surgery at the
University of Louisville over a 21-year interval. Many aspects of surgical
management of hyperparathyroidism have changed over the last 2 decades;
controversies regarding the extent of exploration and the value of preoperative
localization studies remain unresolved. One hundred ninety-three patients
underwent neck exploration for hyperparathyroidism from 1976 to 1997. Data were
collected from four University of Louisville-affiliated hospitals by independent
evaluators. One hundred sixty patients with untreated hyperparathyroidism
underwent neck exploration. Preoperative localization was carried out in 52 per
cent (83 of 160). The exact location of the abnormal gland was indicated in 55
per cent (46 of 83), and the correct side of the neck was identified in 74 per
cent (61 of 83). Technetium sestamibi scan was most reliable and identified the
abnormality in 83 per cent (24 of 29). The average operative time with
preoperative localization was 118 minutes compared with 137 minutes without
preoperative localization. Intraoperative methylene blue was used in 42 of 160
neck explorations. Average operative time with methylene blue was 102 minutes
compared with 124 minutes without methylene blue. Thirty-seven per cent (59 of
160) of patients underwent unilateral neck exploration. Sixty-three per cent (101
of 160) underwent bilateral exploration. Successful exploration was conducted in
98 per cent of the unilateral group and 91 per cent of the bilateral group.
Postoperative local complications were essentially the same in both groups (3%),
whereas temporary hypocalcemia occurred in 24 per cent (24 of 101) of the
bilateral group compared with 3 per cent (2 of 59) of the unilateral group. We
conclude that neck exploration for hyperparathyroidism is a highly successful,
safe treatment with no mortality and minimal morbidity. Preoperative localization
studies modestly reduced the duration of surgery without improving outcome.
PMID- 10759198
TI - Deep venous thrombosis in the pediatric trauma population: an unusual event:
report of three cases.
AB - The incidence of deep venous thrombosis (DVT) in the pediatric population has
been reported to be lower than in adults. Pediatric trauma patients have
predisposing risk factors for DVT similar to those in the general trauma
population. We reviewed the records of 2746 children under 16 years of age
admitted to our Level I pediatric trauma service from 1989 to 1997. Only three
cases of DVT were documented, all adolescents. DVT was located in the upper (n =
1) and lower (n = 1) extremity venous system. One patient presented with
pulmonary embolism alone without identifiable DVT. Risk factors found were venous
system manipulations, including atriocaval shunt, subclavian central line, and
hyperinflated medical antishock trousers garment. Therapy consisted of heparin
followed by warfarin anticoagulation. A vena cava filter was inserted in one
patient for whom systemic anticoagulation was contraindicated. No DVT was seen in
1123 closed head injury patients or 29 spinal cord injury patients without
associated risk factors. The thrombotic risk in pediatric trauma patients is low.
Routine screening or prophylaxis is not indicated except for patients who are
likely to remain immobile for an extended period of time and require prolonged
rehabilitation, have venous manipulations, or present with clinical symptoms.
Hematologic evaluation in patients with diagnosed DVT is necessary to identify
individual risk factors.
PMID- 10759199
TI - Experience with the insertion of vena caval filters in acutely burned patients.
AB - The use of inferior vena caval filters in patients at high risk of pulmonary
emboli is a standard practice in many types of patients. The usefulness of such
filters in acutely burned patients has yet to be established. Twenty inferior
vena caval filters were inserted in burn patients. Five were inserted because of
preexisting thromboembolic disease. Fifteen were placed prophylactically because
of high-risk states, including prolonged immobilization, old age, bleeding
problems, and obesity. There were no complications due to filter insertion. No
postinsertion emboli were recognized. There were no cases of postinsertion
thrombophlebitis. In this small series, the procedure appears to be effective and
safe.
PMID- 10759200
TI - Sentinel lymphadenectomy for staging patients with intermediate-level melanoma.
AB - Sentinel lymph node dissection (SLND) as originally described by D.L. Morton et
al. (Surg Oncol Clin North Am 1992;1:247-59), is currently being used at most
tertiary institutions for staging patients with intermediate-level melanomas.
Identification and subsequent surgical resection of occult metastasis before the
development of clinical disease may improve survival in these patients. This
study is a retrospective review of patients with intermediate melanomas treated
by the senior author (P.S.D.). Isosulfan blue dye and a radioactive technetium
labeled dye were used to identify the sentinel node. Sentinel nodes were
evaluated by routine hematoxylin and eosin staining, immunohistochemical staining
for S-100 and HMB-45, and later in the study with multipanel reverse
transcriptase-polymerase chain reaction analysis. All patients were followed
closely. Fifty-seven patients with primary melanoma were evaluated between
December 1995 and June 1998. Thirty-two patients underwent SLND; two patients
underwent SLND on two separate drainage basins, for a total of 34 procedures. The
median age was 49 years (range, 19-77). There were 11 females and 21 males. The
locations of the primary melanoma were: head and neck, seven; extremity, 8; and
trunk, 18; 1 patient had a dual primary melanoma at presentation. Clark's levels
of invasion among the patients were level III, 5; and level IV, 27; median
Breslow thickness was 1.4 mm (range, 0.45-3.8 mm). A sentinel node was not
identified in four procedures (11.1%). Twenty-two nodes (73%) were negative by
all methods, and eight (27%) were positive by at least one method. All positive
patients underwent complete lymphadenectomy, and routine hematoxylin and eosin
stains identified no additional positive nodes. Median follow-up was 21 months (6
36 months). Two patients developed recurrent disease. The other 30 patients
remain disease free at last follow-up. SLND is a low-morbidity technique that
accurately stages patients with intermediate-level melanoma. Early intervention
with complete therapeutic lymphadenectomy and possible interferon therapy may
improve the survival of patients with stage III melanoma. A complete discussion
of the technique for SLND and an update of this data is presented.
PMID- 10759201
TI - Traumatic shock alias posttrauma critical illness.
AB - Trauma is the most common cause of death under the age of 45. Many trauma
patients die of multiple organ failure, especially acute respiratory distress
syndrome. The basic cause of traumatic shock has only partially been elucidated.
Data resources include research papers on the subject of trauma and shock from
1875 to the present. These papers numbered more than 40,000. Almost all of the
papers proposed that traumatic shock was due to hypovolemia. The concept of a
shock toxin as promulgated during World War I is correct. This toxin is a
thrombogenic aminophospholipid that occurs only on the inner layer of all cell
membranes and is liberated by cell destruction. It causes disseminated
intravascular coagulation, which may obstruct the microcirculation of any and all
organs producing multiple organ failure by microclots. These microclots may be
lysed by plasminogen activator and circulation to the organs restored.
PMID- 10759202
TI - Sentinel lymph node dissection for primary cutaneous melanoma: a community
hospital's initial experience.
AB - Management of the regional lymph nodes remains the most controversial aspect of
treating patients with intermediate-thickness cutaneous melanoma. Prospective
studies have failed to demonstrate a significant survival advantage for patients
undergoing elective lymph node dissection. The sentinel lymph node dissection
(SLND) technique has been proposed as a method of accurately identifying patients
with occult metastases in whom a regional lymph node dissection would be
indicated. The majority of studies evaluating this technique have come from
academic centers, most with dedicated melanoma clinics. This report describes the
initial experience with SLND at a community hospital. Fifteen patients with
intermediate-thickness primary cutaneous melanoma underwent preoperative
lymphoscintigraphy with 99Tc-sulfur colloid. In addition, intraoperative
lymphatic mapping using intradermally injected isosulfan blue was performed.
Dissection was guided by radioactivity levels (in counts per second) as measured
by a hand-held gamma probe. The resected lymph node or nodes were evaluated for
micrometastases using routine hematoxylin and eosin staining and
immunohistochemistry with S-100 and HMB-45. All patients were followed clinically
for any evidence of recurrence. A sentinel node(s) was identified on preoperative
lymphoscintigraphy in all 15 patients (100%). A single sentinel node was
identified in 11 of 15 (73%), two nodes in 3 (20%), and one node in 1 (6.7%). The
hand-held gamma probe reading correlated well with the site marked the "hot spot"
(600-15,320 cps for the hot spot versus 10-350 cps for background). The sentinel
lymph node was successfully identified and resected in all 15 patients. Blue
stained lymphatics and/or lymph nodes were present in 8 of 15 (53%) cases.
Histopathology was negative for evidence of occult micrometastases in all
patients. At mean follow-up of 221 days, all 15 patients remain with no evidence
of disease. The outcomes for mapping and harvesting the sentinel node at a
community institution compare favorably with results at major academic
institutions. SLND may therefore be offered to patients with intermediate
thickness cutaneous melanoma in the community hospital setting with regional
lymph node dissection and adjuvant interferon alpha-2b as options for patients
with nodal micrometastases.
PMID- 10759203
TI - Evaluating the role of physical and radiographic examinations in assessing bullet
tract termination for gunshot victims.
AB - Knowledge of the path of a bullet and how it terminates is critical for
expeditious assessment and optimal management of patients with gunshot wounds. To
assess the accuracy of physical examination and X-rays in these patients, a
prospective study was undertaken for all gunshot victims seen for a 1-year period
on a single trauma service. The paramedics and trauma surgeons' physical
examinations were evaluated for whether a bullet tract could be accurately
categorized as 1) through and through, 2) graze, 3) palpable under dermis, or 4)
retained (ie, not palpable). The impact of X-rays was assessed with regard to how
it affected the trauma surgeons' categorization. A total of 78 patients were seen
with a total of 120 bullet tracts. Seventy-seven per cent were injured by
assault, and 64 per cent were shot with a 9-mm or .38-caliber handgun. Twenty of
60 (33%) bullet tracts on the torso terminated with a missile that was palpable
under dermis, but only 2 of 10 neck (20%), 1 of 28 extremity (4%), and 1 of 22
head/face (5%) did so. Paramedics evaluated 15 torso bullet tracts that ended
palpable under dermis, of which they detected 5 (33%). Upon initial examination,
the trauma surgeon detected 11 of 20 torso bullet tracts that ended palpable
under dermis (55%), and detected 14 of the 20 after X-rays were done (70%).
Overall, obtaining X-rays changed the categorization for 15 of 111 bullet tracts
(13%). We conclude that bullet tracts on the torso result in a subcutaneously
palpable bullet one-third of the time, much more frequently than in other body
regions. Paramedics only detect one-third of subcutaneously palpable missiles on
the torso. X-rays change the categorization of bullet tracts infrequently. We
recommend that a careful examination of the skin of the torso to detect palpable
missiles be incorporated into the secondary survey of patients with wounds to
that body region.
PMID- 10759204
TI - Detection of surgical glove integrity.
AB - Surgical glove integrity is essential for universal precautions; glove safety is
verified by the water load test (WLT). Concerns regarding glove injury have
prompted newer testing methodologies, including electrical conductance testing
(ECT); however, the sensitivities of these tests are not known. We compared the
sensitivity of WLT and ECT in detecting glove needle-stick injury in two commonly
used brands of surgical gloves. Punctures were made with hollow-bore and solid
surgical needles of various configurations. The WLT failed to detect glove holes
from the smallest-caliber needles and only detected the injury in 60 per cent for
the largest caliber. The ECT provided a graded index of glove injury in all holes
made by both solid surgical needles and hollow-bore needles. The WLT is a poor
test for clinical defects in latex surgical gloves; the ECT is significantly more
sensitive and provides a gauge of the cross-sectional area of the defect.
Interbrand differences in self-sealing properties of surgical gloves were
evidenced and may be clinically relevant after glove perforation.
PMID- 10759205
TI - Heterotopic pregnancy presenting as an acute abdomen: a diagnostic masquerader.
AB - Simultaneous intrauterine and extrauterine pregnancy is called heterotopic
pregnancy. It is a rare complication of pregnancy, especially in the absence of
predisposing factors. It is known to present with a variety of symptoms and signs
often leading to a delay in establishing the correct diagnosis. We report the
case of a 29-year-old woman, known to be 14 weeks pregnant, presenting with acute
abdominal pain. The confirmation of a viable intrauterine pregnancy led to a
general surgery consultation. A heterotopic ruptured right ectopic tubal
pregnancy was found. Right salpingectomy was performed. The patient recovered
uneventfully. The intrauterine pregnancy was not affected. This case illustrates
the variable presentation of heterotopic pregnancy and the need for general
surgeons to be suspicious of pregnancy related complications, even in the
presence of a viable intrauterine pregnancy.
PMID- 10759206
TI - A minimally invasive approach to bile peritonitis after blunt liver injury.
AB - The advent of nonoperative management of liver injuries has made it imperative
that surgeons be familiar with the potential delayed complications of this
approach. In this report, we describe a minimally invasive strategy for the
management of bile peritonitis following nonoperative management of blunt liver
injuries. Two cases are presented in which bile peritonitis with massive bile
ascites was managed with laparoscopic localization and drainage of the bile leak,
irrigation of the peritoneal cavity, and postoperative endoscopic retrograde
cholangiography with bile duct stenting. In both cases the bile leak ceased, and
the patients recovered without adverse sequelae. The combination of laparoscopic
surgery and endoscopic stenting provides a minimally invasive approach to this
entity.
PMID- 10759207
TI - The medicinal leech: past and present.
PMID- 10759208
TI - Re: Clinical characteristics and antibiotic utilization in surgical patients with
Clostridium difficile-associated diarrhea.
PMID- 10759209
TI - Molecular characterization of the ligand-receptor interaction of the neuropeptide
Y family.
AB - Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to
the NPY hormone family and activate a class of receptors called the Y-receptors,
and also belong to the large superfamily of the G-protein coupled receptors.
Structure-affinity and structure-activity relationship studies of peptide
analogs, combined with studies based on site-directed mutagenesis and anti
receptor antibodies, have given insight into the individual characterization of
each receptor subtype relative to its interaction with the ligand, as well as to
its biological function. A number of selective antagonists at the Y1-receptor are
available whose structures resemble that of the C-terminus of NPY. Some of these
compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in
vivo investigations of the NPY-induced increase in food intake. Y2-receptor
selective agonists are the analog cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY and
the TASP molecule containing two units of the NPY segment 21-36. Now the first
antagonist with nanomolar affinity for the Y2-receptor is also known, BIIE0246.
So far, the native peptide PP has been shown to be the most potent ligand at the
Y4-receptor. However, by the design of PP/NPY chimera, some analogs have been
found that bind not only to the Y4-, but also to the Y5-receptor with
subnanomolar affinities, and are as potent as NPY at the Y1-receptor. For the
characterization of the Y5-receptor in vitro and in vivo, a new class of highly
selective agonists is now available. This consists of analogs of NPY and of
PP/NPY chimera which all contain the motif Ala31-Aib32. This motif has been shown
to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be
the key motif for high Y5-receptor selectivity. The results of feeding
experiments in rats treated with the first highly specific Y5-receptor agonists
support the hypothesis that this receptor plays a role in the NPY-induced
stimulation of food intake. In conclusion, the selective compounds for the
different Y receptor subtypes known so far are promising tools for a better
understanding of the physiological properties of the hormones of the NPY family
and related receptors.
PMID- 10759210
TI - Non-sequential vasopressin peptides. Stereochemistry and biological activity.
AB - Two cyclic disulfides of structure Cys-Tyr-Arg-Arg-Tyr-Cys-NH2 (1) and Cys
Tyr(Me)-Arg-Arg-Tyr(Me)-Cys-NH2 (2), two nonapeptide derivatives of 1 extended at
the C-terminal with Pro-Arg-Gly-NH2 (3) or Pro-D-Arg-Gly-NH2 (4) and derivatives
of 3 and 4 having Mpr in position 1, i.e. analogs (5) and (6), respectively, were
synthesized, and their stereochemistry and biological activity were studied. All
the peptides displayed low dose-dependent uterotonic activity in vitro and
antidiuretic activity in vivo. None of the peptides increased the blood pressure
of the experimental animals. Compounds 2, 4 and 6 showed a low inhibitory effect
on AVP pressor activity; compound 6, in addition, displays a significant and long
lasting vasodepressor effect. NMR measurements indicated the existence of
hydrogen bond between the amino acid residues in positions 2,5 and 3,4 of
peptides 1 and 2, and side-chain interactions between amino acid residues in
positions 2,3 and 4,5 of peptide 1. No such side-chain interactions were detected
in peptide 2.
PMID- 10759211
TI - Synthesis of differentially protected N-acylated reduced pseudodipeptides as
building units for backbone cyclic peptides.
AB - Backbone cyclization has become an important method for generating or stabilizing
the bioactive conformation of peptides without affecting the amino acid side
chains. Up to now, backbone cyclic peptides were mostly synthesized with bridges
between N-amino- and N-carboxy-functionalized peptide bonds. To study the
influence of a more flexible backbone on the biological activity, we have
developed a new type of backbone cyclization which is achieved via the N
functionalized moieties of acylated reduced peptide bonds. As described in our
previous publications, the formation of N-functionalized dipeptide units
facilitates the peptide assembly compared with the incorporation of N-alkyl amino
acids. Besides the racemization-free synthesis of Fmoc-protected pseudodipeptide
esters with reduced peptide bonds, the new type of backbone modification allows
the use of a great variety of omega-amino- and alpha,omega-dicarboxylic acids
differing in chain length and chemical properties. Best results for the coupling
of the omega-amino- and alpha,omega-dicarboxylic acids to the reduced peptide
bond were obtained by the formation of mixed anhydrides with alkyl
chloroformates. Whereas the protecting group combination of Z/OBzl in the
dipeptide unit and Boc/OtBu for the N-functionalized moiety leads to the
formation of 2-ketopiperazine during hydrogenation, the combination of Fmoc/OtBu
and Alloc/OAll is very suitable for the synthesis of backbone cyclic peptides on
solid support.
PMID- 10759212
TI - Synthesis of beta-(1-azulenyl)-L-alanine as a potential blue-colored fluorescent
tryptophan analog and its use in peptide synthesis.
AB - Acetyl-beta-(1-azulenyl)-D,L-alanine has been synthesized in high overall yield
by the malonic ester condensation procedure, and the racemate has been
enzymatically resolved with acylase I from Aspergillus melleus. The
enantiomerically pure L-amino acid is of interest as a blue-colored fluorescent
tryptophan analog. The bioactivity data of a heptagastrin analog containing it
suggests that the planar aromatic azulene moiety may indeed mimic the tryptophan
side chain to some extent, and the spectral properties of the azulene moiety
makes beta-(1-azulenyl)-L-alanine of potential value as a UV and fluorescence
probe in synthetic peptides, and possibly even in proteins if bioincorporation
succeeds with chemically misacylated tRNAs.
PMID- 10759213
TI - Role of mucosal blood flow: a conceptional review in gastric mucosal injury and
protection.
AB - The present article overviews the role of gastric mucosal blood flow (MBF) in
gastric mucosal injury and protection. The MBF maintains the structure and
function of the stomach and, thereby, is closely associated with the pathogenesis
and the healing of gastrointestinal lesions. Gastric blood flow was regulated and
modified by systemic and also local metabolic factors, such as prostaglandin,
leukotrienes and other endogenous chemical mediators, in the mucosa. In the
present article, we review the role of endothelin (ET) and nitric oxide (NO) in
the development of gastric mucosal injury and protection via mucosal
microcirculation. Endothelin-1 was increased under various stressful conditions
and caused microcirculatory disturbances resulting in mucosal injury. Inhibitors
of NO aggravated mucosal injury induced by ethanol, which produced mucosal
congestion. Thus, regionally disturbed gastric circulation is closely associated
with the pathogenesis of ethanol- and non-steroidal anti-inflammatory drug
induced gastric lesions. The endothelium-derived vasoactive substances ET and NO
regulate gastric mucosal microcirculation and an imbalance of endothelium-derived
factors may play an important pathophysiological role in the development of
gastric lesions.
PMID- 10759214
TI - Mechanism of gastric mucosal proliferation induced by gastrin.
AB - Gastrin has a potent trophic effect on gastric fundic mucosa. When serum
concentrations of gastrin are elevated, proliferation of both the progenitor
cells in the glandular neck zone and enterochromaffin-like (ECL) cells in the
bottom of the glands is stimulated. Because ECL cells have gastrin receptors,
their proliferation is directly stimulated by gastrin. However, because the
proliferation of progenitor cells cannot be directly stimulated (so far there has
been no gastrin receptor demonstrated on these proliferating cells), some
indirect mechanisms must be involved. Enterochromaffin-like and parietal cells
are only two types of cells that have demonstrated a strong gene expression of
the gastrin receptor. Furthermore, they secrete several growth factors, such as
Reg protein, heparin-binding epidermal growth factor-like growth factor (HB-EGF)
and amphiregulin (AR). Reg protein production by ECL cells, as well as HB-EGF and
AR production by parietal cells, is stimulated by gastrin and these growth
factors are potent trophic agents of progenitor cells in the neck zone of the
gastric fundic mucosa. Accordingly, gastrin may stimulate the proliferation of
gastric mucosal cells indirectly via these growth factors in addition to its
direct trophic effect on ECL cells.
PMID- 10759215
TI - Role of heat shock proteins in gastric mucosal protection.
AB - Heat shock proteins (HSP) are crucial for the maintenance of cellular homeostasis
during normal cell growth and for survival during and after various cellular
stresses. Gastric surface mucous cells are the first line of defence against
insults derived from ingested foods and Helicobacter pylori infection. Primary
cultures of gastric surface mucous cells from guinea-pig fundic glands exhibited
a typical heat shock response after exposure to elevated temperature or metabolic
insults, such as ethanol and hydrogen peroxide, and they were able to acquire
resistance to these stressors. Restraint and water immersion stress rapidly
activated heat shock factor 1 (HSF1) in rat gastric mucosa within 15 min and
induced HSP70 mRNA expression and its protein accumulation. The extent of the
induction inversely correlated with the severity of mucosal lesions, suggesting
an important role of HSP70 in gastric mucosal defence. This heat shock response
appeared to be mediated by the alpha1A-adrenoceptor. The HSP70 family functions
as a molecular chaperone and reduces stress-induced denaturation and aggregation
of intracellular proteins. In addition to its chaperoning activities, HSP70 has
been suggested to exert its cytoprotective action by protecting mitochondria and
by interfering with the stress-induced apoptotic programme. Recently, we
introduced geranylgeranylacetone as a non-toxic HSP70 inducer. This compound
weakly stimulated HSP70 induction in cultured gastric mucosal cells and gastric
mucosa by directly activating HSF1 and markedly augmented HSP70 induction in
response to subsequent exposure to stress. Thus, non-toxic HSP70 inducers may
have a potential benefit for the prevention and treatment of stress ulcer.
PMID- 10759216
TI - Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury.
AB - The hepatotoxic effects of alcohol have been described in detail, but factors
responsible for its hepatotoxicity have only partially been characterized. For
example, it is known that chronic ethanol ingestion increases hepatotoxicity and
produces fatty liver, hepatitis and cirrhosis. However, acute ethanol consumption
reduces endotoxin hepatotoxicity. It now appears that Kupffer cells participate
in several aspects of these phenomena. Previously, most studies on the effects of
alcohol on liver function have focused chiefly on the hepatocyte. Recently,
attention has been directed towards the effect of ethanol ingestion on Kupffer
cell function, which is stimulated by gut-derived endotoxins
(lipopolysaccharides) via mechanisms dependent on increased gut permeability and
the possible relationship between Kupffer cells and alcohol-induced liver injury.
Here we will review new evidence for the proposal that Kupffer cells and
endotoxins play a pivotal role in hepatotoxicity following alcohol exposure,
based on studies using the continuous intragastric enteral feeding model
developed by Tsukamoto and French and an acute model developed by us.
PMID- 10759217
TI - Molecular mechanism of the reversibility of hepatic fibrosis: with special
reference to the role of matrix metalloproteinases.
AB - The participation of matrix metalloproteinases (MMP) and their specific
inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMP), in both
the formation and degradative recovery processes of liver fibrosis were mainly
reviewed from the molecular biological aspect. Since authors first reported
increased activity of interstitial collagenase in the early stage of hepatic
fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol
chronically and in patients with alcoholic fibrosis, other investigators have
also demonstrated increased activity biologically and histochemically. However,
species-specific differences in response have been found and gene-level research
on the rat model has not demonstrated increased mRNA transcription of
collagenase. It has also been clarified that activated stellate cells can also
produce matrix components. Very recently, authors observed the participation of
interstitial collagenase in the recovery from experimental hepatic fibrosis by
using polymerase chain reaction northern blotting and in situ hybridization. The
in situ hybridization findings not only demonstrated the cells responsible for
interstitial collagenase, but also suggested a great deal about the mechanism of
recovery from fibrosis. Hepatic stellate cells are activated via the expression
of c-myb and nuclear factor-kappaB (NFkappaB) which is induced by oxidative
stress, and inhibited by antioxidant (1-alpha-tocopherol) and butylated
hydroxytoluene. The activation mechanism is now being revealed. The relationship
between the activation mechanism of stellate cells and the production and
secretion of MMP and TIMP in the formation and recovery process of hepatic
fibrosis should be investigated from the promoter gene level. This approach might
help develop a new strategy for the treatment of liver fibrosis.
PMID- 10759218
TI - Gene therapy for liver cirrhosis.
AB - Liver cirrhosis is the irreversible end result of chronic liver disease and is
characterized by fibrous scarring and hepatocellular regeneration. It is a major
cause of morbidity and mortality worldwide and is induced by factors such as
chronic hepatitis virus infection, drug abuse and alcohol abuse. The ideal
strategy for the treatment of liver cirrhosis should include prevention of
fibrogenesis, stimulation of hepatocyte mitosis and reorganization of the liver
architecture. Hepatocyte growth factor (HGF) gene therapy has been investigated
in a rat model of liver cirrhosis. In rats with lethal liver cirrhosis produced
by dimethylnitrosamine, repeated transfection of the HGF gene into skeletal
muscle induced a high plasma level of HGF and tyrosine phosphorylation of the c
Met/HGF receptor. Hepatocyte growth factor gene transduction inhibited
fibrogenesis and hepatocyte apoptosis and also produced resolution of fibrosis in
the cirrhotic liver. Hepatocyte growth factor gene therapy may have the potential
to be useful for the treatment of patients with liver cirrhosis.
PMID- 10759219
TI - Regulatory mechanism of acid secretion in the damaged stomach: role of endogenous
nitric oxide.
AB - The present article overviews the regulatory mechanism of acid secretion in the
stomach after damage with taurocholate (TC), one of the bile acids. Mucosal
exposure of a rat stomach to 20 mmol/L TC for 30 min caused a decrease of acid
secretion with a concomitant increase in nitric oxide (NO) and prostaglandin (PG)
E2 (PGE2) as well as Ca2+ in the luminal contents. Prior administration of N(G)
nitro-L-arginine methyl ester (L-NAME), as well as indomethacin, significantly
attenuated the reduction of acid secretion by TC and acid secretion was even
increased in the presence of L-NAME. The acid stimulatory effect of L-NAME in the
damaged stomach was not mimicked by aminoguanidine and was antagonized by co
administration of L-arginine but not D-arginine. Increased NO release in the
damaged stomach was suppressed by pretreatment with L-NAME or co-application of
EGTA and the latter also inhibited the increase in luminal Ca2+. The enhanced
acid secretory response in the presence of L-NAME was also inhibited by
cimetidine, FPL-52694 (a mast cell stabilizer) or sensory deafferentation.
Mucosal exposure to TC caused an increase in luminal histamine output, together
with a decrease in the number of mucosal mast cells in the stomach. These changes
were prevented by FPL-52694 and sensory deafferentation and were also partly
suppressed by indomethacin. In addition, the acid stimulatory action of L-NAME in
the damaged stomach was significantly mitigated when indomethacin was
administered together with L-NAME. We conclude that: (i) damage in the stomach
may activate acid a stimulatory pathway in addition to a PG-, NO- and Ca2+
dependent inhibitory mechanism, but the latter effect overcomes the former,
resulting in a decrease in acid secretion; (ii) acid stimulation in the damaged
stomach is mediated by histamine released from the mucosal mast cell, a process
interacting with capsaicin-sensitive sensory nerves; (iii) the increase in
luminal Ca2+ plays a role in increasing NO production and, hence, in regulating
acid secretion; and (iv) PG may have a dual role in the regulation of acid
secretion in the damaged stomach: an inhibitory effect at the parietal cell and
an excitatory effect, probably through enhancing the release of mucosal
histamine.
PMID- 10759220
TI - Role of apoptosis in Helicobacter pylori-associated gastric mucosal injury.
AB - Apoptosis, a programmed cell death, was ignored, just like Helicobacter pylori,
only to reappear recently. However, the number of current publications dealing
with apoptosis or H. pylori has increased exponentially. Although gastric
epithelial apoptosis is a programmed physiological event in the superficial
aspect of the mucosa and is important for healthy cell turnover, H. pylori
infection reportedly promotes such a cell death sequence. Because apoptosis
regulates the cycle of cell turnover in balance with proliferation, dysregulation
of apoptosis or proliferation evoked by H. pylori colonization would be linked to
the gastric carcinogenesis. In other words, a reduced level of apoptosis could
contribute to the generation of gastric cancer. Herein, we review apoptosis as
well as its associated pathological events, such as hyperproliferation, in H.
pylori-colonized gastric mucosa.
PMID- 10759221
TI - Helicobacter pylori infection and gastric carcinoma in animal models.
AB - Many epidemiological studies have shown a strong association between chronic
Helicobacter pylori infection and the subsequent development of gastric carcinoma
in humans. To confirm this link more clearly, it is necessary to use this
bacterium in experimental studies to develop gastric carcinoma in suitable
experimental animals. Persistent H. pylori infection has recently been achieved
in the Mongolian gerbil model, with results demonstrating that the sequential
histopathological changes in the gastric mucosa closely mimic the gastric mucosal
changes caused by H. pylori infection in humans. These studies have demonstrated
that H. pylori infection enhances gastric carcinogenesis in combination with
known carcinogens, such as N-methyl-N-nitroso-urea and N-methyl-N-nitro-N'
nitrosoguanidine and have also demonstrated that H. pylori infection alone can
result in the development of gastric carcinoma. These important results provide a
starting point for further studies to clarify the mechanism of gastric
carcinogenesis as a result of H. pylori infection and assist the planning of
eradication therapy to prevent gastric carcinoma.
PMID- 10759222
TI - Functional dyspepsia and Helicobacter pylori infection: a recent consensus up to
1999.
AB - With accumulated evidence for a close relationship between Helicobacter pylori
infection and many gastric disorders, the idea that this infection may invoke
dyspeptic symptoms appears realistic. If curative therapy for H. pylori can bring
about relief of symptoms in these patients, we would possess a new therapeutic
tool for functional dyspepsia. Although there have been many clinical trials on
this issue, the benefits of H. pylori treatment have been controversial. However,
several large-scale clinical studies have been very recently published, and
suggest a specific direction on this clinical question. From these results, the
current consensus is that H. pylori infection does not directly affect symptoms
in patients with functional dyspepsia. However, most clinical trials have been
performed on Western populations, and there are few reports from Asian countries.
Our recent study on the Japanese population also supported the consensus, that
is, a negative relationship between H. pylori infection and symptoms in
functional dyspepsia patients.
PMID- 10759223
TI - Early colorectal cancer: flat or depressed type.
AB - The present review describes the changes in views about the early forms of
colorectal cancers. In 1985, a concept of 'flat adenoma' was born in Japan. At
around the same time, depressed type early colorectal cancers started to be
reported by Japanese colonoscopists. Neither flat adenomas nor depressed lesions
have been frequently reported in Western countries, but increasing numbers of
such cases are now described. The problem is that flat adenomas and depressed
lesions seem to have been confused by many researchers. The biological
aggressiveness of these lesions is quite different. The rate of submucosal
invasion is very high in depressed lesions, but fairly low in small flat
adenomas. Some adenomas may even look depressed at first, but such lesions should
not be mistaken for truly depressed lesions. Ignorance or resistance to the
concept may inhibit the detection of flat or depressed lesions. Differences of
diagnostic criteria between Japanese and Western pathologists may influence the
apparent frequency of mucosal cancers, but not that of invasive carcinomas. Many
small adenomas do not grow if followed, but depressed lesions grow rapidly and
invade the deeper layers and, as a result, may look elevated as a whole. Many
cases in previously published papers suggest that small depressed carcinomas of
the large intestine may develop without a precursory stage of an adenomatous
polyp. At least two carcinogenic pathways, one through adenomatous polyps and one
de novo, should be recognized. In addition, the importance of small depressed
cancers should be emphasized.
PMID- 10759224
TI - Pathophysiological role of cholecystokinin in humans.
AB - Cholecystokinin (CCK) is a major gastrointestinal hormone that plays an important
role in stimulation of pancreatic secretion and gall-bladder contraction,
regulation of gastrointestinal motility and induction of satiety. Ingestion of
fat and protein induces significant increases in plasma CCK. Intraluminal
mediators of CCK secretion, luminal CCK releasing factor and diazepam-binding
inhibitor, were purified from rat intestinal secretion. These CCK-releasing
factors (RF) are secreted tonically by the small intestine and stimulate CCK
release. Another kind of CCK-RF named 'monitor peptide' was purified from the rat
pancreatic juice that stimulates CCK secretion when introduced into rat
intestine. Bile exclusion from the duodenum causes an increase in basal CCK and
enhances stimulated plasma CCK release, and bile salt replacement reverses these
effects. Thus, the CCK-RF are spontaneously secreted into the intestinal lumen in
humans, while the CCK-producing cells are under constant suppression by
intraduodenal bile acids. In acute pancreatitis, plasma CCK levels are high in
patients with gallstone pancreatitis, but not in patients with pancreatitis from
other causes, such as alcoholic and idiopathic pancreatitis. A transient
disturbance of bile flow into the duodenum by stones or oedema of the pancreas
together with impairment of pancreatic exocrine function might cause the increase
in plasma CCK release in gallstone pancreatitis. Patients with chronic
pancreatitis with mild to moderate impairment of exocrine function and abdominal
pain, had significantly higher plasma CCK concentrations, whereas patients with
pancreatic insufficiency had a significantly lower plasma CCK response to a test
meal than the healthy subjects. The increased CCK may further aggravate
pancreatitis and worsen the prognosis of pancreatitis by stimulating the injured
pancreas, resulting in the vicious circle via endogenous CCK release. The CCK-A
receptor antagonist might be therapeutically useful in acute pancreatitis by
stopping the vicious circle.
PMID- 10759225
TI - Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis
and carcinoma.
AB - Herbal medicines, which have been used in China for thousands of years, are now
being manufactured in Japan, in standardized form in terms of quality and
quantities of ingredients. The Chinese herbal medicine Sho-saiko-to is a mixture
of seven herbal preparations, which is widely administered in Japan to patients
with chronic hepatitis and cirrhosis. In a prospective study, this herbal
medicine was found to play a chemopreventive role in the development of
hepatocellular carcinoma in cirrhotic patients. However, little is known about
the mechanism by which Sho-saiko-to protects against hepatic fibrosis and
carcinoma. Several laboratories, including ours, have clearly demonstrated the
preventive and therapeutic effects of Sho-saiko-to on experimental hepatic
fibrosis, as well as its inhibitory effect on the activation of hepatic stellate
cells, which are the major types of collagen-producing cells. We provided
evidence that Sho-saiko-to functions as a potent anti-fibrosuppressant via the
inhibition of oxidative stress in hepatocytes and hepatic stellate cells and that
its active components are baicalin and baicalein. In addition, Sho-saiko-to has
anti-carcinogenic properties in that it inhibits chemical hepatocarcinogenesis in
animals, acts as a biological response modifier and suppresses the proliferation
of hepatoma cells by inducing apoptosis and arrests the cell cycle. Among the
active components of Sho-saiko-to, baicalin, baicalein and saikosaponin-a have
the ability to inhibit cell proliferation. It should be noted that baicalin and
baicalein are flavonoids with chemical structures very similar to silybinin,
which shows anti-fibrogenic activities. This may provide valuable information on
the search for novel anti-fibrogenic agents.
PMID- 10759226
TI - Molecular biology of hepatitis A virus: significance of various substitutions in
the hepatitis A virus genome.
AB - Hepatitis A virus (HAV) is the sole member of the hepatogenus of Picorna viridae.
This virus can now be propagated in cell culture and in primates. Molecular
biological studies of HAV have disclosed its genomic structure and the functional
significance of the viral proteins to some extent. Hepatitis A virus has a
positive-stranded RNA of approximately 7.5 kb that encodes a large polyprotein.
Translation of the protein is influenced by the function of the internal
ribosomal entry site in the 5' non-translating region. It is generally agreed
that the polyprotein is processed to four structural and seven non-structural
proteins by the proteinase encoded in the 3C region. Replication efficiency seems
to be controlled by amino acid substitutions in the 2B and 2C regions. The
virulence of HAV in primates may be determined by substitutions in the 2C region.
Although the severity of hepatitis A was thought to be determined by
immunological reactions of the host to the virus, the potential virulence of the
variant viruses themselves may need further examination. Recent progress in
polymerase chain reaction technology has made possible an analysis of the HAV
sequence in clinical specimens; such analysis is of importance in the disclosure
of differences in HAV subspecies in different clinical conditions.
PMID- 10759227
TI - Mucosectomy for gastric cancer: current status in Japan.
AB - Advances in techniques of image diagnosis have enabled the detection of minute or
small cancer lesions in the stomach. Patients with such cancer, in principle,
were treated surgically, but accumulated histopathological data on surgical
cancer specimens revealed that many of these patients did not have any metastatic
lesions. For those localized cancers, local treatment of primary lesions by
endoscopy gives curative results. It has been demonstrated that endoscopic
therapy is curative in mucosal well-differentiated adenocarcinoma not more than
20 mm in diameter without ulceration. Efforts to cure early gastric cancer
without surgery yielded fruitful results and a new treatment concept was
established. Even if there is a recurrence of the residual or metachronous
lesions, they can be treated by further endoscopic treatment.
PMID- 10759228
TI - Postprandial response of gastric slow waves: correlation of serosal recordings
with the electrogastrogram.
AB - Controversial interpretations have been given to the postprandial increase in the
dominant power (amplitude) of the electrogastrogram (EGG). The aim of this study
was to find an appropriate interpretation of the postprandial EGG power changes.
Simultaneous serosal and cutaneous recordings of gastric myoelectrical activity
were made in 11 patients with gastroparesis in the fasting state and after the
ingestion of 8 oz of water. The dominant frequency and corresponding power of the
recording before and after water were computed using the power spectral analysis
method. It was found that the dominant frequency of the EGG was the same as that
of the serosal recording in 10 patients. One patient showed a substantial amount
of dysrhythmia and no obvious dominant frequency was noted. A decrease in the
dominant frequency was found in these 10 patients after the ingestion of water.
Tachygastria of higher than 4 cycles/min was observed in one of 11 patients both
in the prewater and postwater states. Consistent changes in amplitude after a
drink of water were noted in both serosal recording and EGG. Statistical analysis
demonstrated that the dominant power change after water computed from the EGG was
correlated with that observed in the serosal recording (r = 0.757, P = 0.007). In
conclusion, exogenous stimulation, such as ingestion of water, may change the
amplitude of the gastric slow wave and this change is reflected in the EGG,
suggesting that the change of the slow-wave amplitude is an important
contributing factor to the postprandial change in the EGG dominant power.
PMID- 10759229
TI - Entrainment of segmental small intestinal slow waves with electrical stimulation
in dogs.
AB - The aim of this study was to derive effective pacing parameters for the
entrainment of segmental intestinal myoelectrical activity. The study was
performed in 12 dogs. Four pairs of electrodes were implanted on the serosa of
the jejunum. Electrical stimulation of the small intestine was performed via the
most proximal pair. For the slow waves within a distance of 5 cm, a complete
entrainment was achieved with a pacing frequency of 1.1 times the intrinsic
frequency (IF), a pulse width of 140 msec, and an amplitude of 4 mA. The time
required for the entrainment was 25.6 +/- 2.7 sec. The maximum driven frequency
was 1.38 +/- 0.03 IF. The percentage of the entrainment at this frequency was
44.0 +/- 3.9%. The data indicate that pacing is able to completely entrain
segmental intestinal myoelectrical activity, suggesting that normalization of
intestinal myoelectrical dysrhythmia is feasible with pacing.
PMID- 10759230
TI - Backwards and forwards with anorectal manometry probes.
PMID- 10759231
TI - Differential expression of human spasmolytic polypeptide (trefoil factor family
2) in pancreatic carcinomas, ampullary carcinomas, and mucin-producing tumors of
the pancreas.
AB - Human spasmolytic polypeptide (hSP) is a member of the trefoil peptide group,
thought to be involved in mucin production and cell growth. It has been reported
that hSP protein is expressed in digestive cancers but not in normal pancreas.
The expression of hSP in pancreatic neoplasms has not been investigated in
detail. The immunohistochemical expression of hSP protein was investigated in
pancreatic carcinomas, ampullary carcinomas, mucin-producing tumors, serous
cystadenomas and islet cell tumors of the pancreas. hSP was expressed in 23% of
pancreatic duct cell carcinomas, and hSP protein was more frequently detected in
cases of early-stage or histologically low-grade duct cell carcinomas than in
cases of late-stage or histologically high-grade carcinomas. Patients with hSP
protein expression showed a better prognosis than did those with negative hSP
expression. hSP expression was detected in 92% of mucin-producing tumors, but was
not detected in serous cystadenoma or islet cell tumors. Immunohistochemical hSP
expression is related to differentiation and a better prognosis in pancreatic
duct cell carcinomas. Furthermore, hSP protein is related to the pathogenesis and
clinical characteristics of mucin-producing tumors of the pancreas.
PMID- 10759233
TI - Apolipoprotein E polymorphism in alagille syndrome and progressive familial
intrahepatic cholestasis.
AB - The aim of the study was to assess the apolipoprotein E polymorphism (apoE) in
two familial cholestatic diseases-Alagille syndrome (AS) and progressive familial
intrahepatic cholestasis (PFIC)-and to estimate its association with gallstone
formation, cholesterol levels, and response to UDCA treatment. We investigated 16
children with AS age 8.8 +/- 5.7 years (mean +/- SD) and 18 children with PFIC
age 6.3 +/- 4.6 years. The frequency of the epsilon-2 allele in AS and PFIC was
higher and the frequency of the epsilon-3 allele was lower than in controls.
Gallstones were diagnosed in nine children with PFIC and different apoE
phenotypes. No association between phenotype and cholesterol levels or response
to UDCA therapy was observed in the patients studied. In conclusion, the allele
epsilon-2 is overrepresented in AS and PFIC, similar to primary biliary
cirrhosis, although this does not seem to contribute to different cholesterol
levels, gallstones, and response to UDCA therapy.
PMID- 10759232
TI - Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the
mouse.
AB - The role of repetitive acute injury in the pathogenesis of chronic pancreatitis
remains unknown. To determine if repetitive injury induced by pancreatic
hyperstimulation would reproduce the characteristic features of human chronic
pancreatitis, acute reversible pancreatic injury was induced in mice by twice
weekly cerulein treatment, 50 microg/kg/hr x 6 hr, for 10 weeks. Procollagen
alpha1(I) mRNA was markedly increased by week 2. Sirius red staining of
interstitial collagen demonstrated progressive accumulation of extracellular
matrix surrounding acinar units and in interlobular spaces. Atrophy,
transdifferentiation of acinar units to ductlike tubular complexes, and
dilatation of intraacinar lumina also developed. Electron microscopy demonstrated
the presence of stromal cells in areas of fibrosis with morphologic
characteristics of pancreatic stellate cells. These findings demonstrate that, in
a murine model, repetitive acute injury to the pancreas by hyperstimulation can
reproduce the major morphological characteristics of human chronic pancreatitis.
PMID- 10759234
TI - Asymptomatic primary sclerosing cholangitis with marked hepatic fibrosis.
PMID- 10759235
TI - Quantification of serum hepatitis C virus RNA with daily or standard interferon
doses plus ribavirin in nonresponder patients with chronic hepatitis C.
AB - Less than 10% of patients with chronic hepatitis C infected with genotype 1
achieve a sustained response with 12 months of interferon therapy. Viral kinetics
studies have shown that HCV may replicate in less than 24 hr, generating over
10(12) copies per day and suggesting the need for more aggressive therapy. The
aim of the study was to determine the effect of a higher and daily dosage of IFN
alpha2b plus ribavirin on the viral load and on the response rate in patients
infected by genotype 1 and previous nonresponders to interferon. Ten patients
with chronic hepatitis C infected with genotype 1 were allocated to receive IFN
alpha2b, 5 MU daily or three times a week for four weeks followed by 5 MU three
times a week until week 24 plus ribavirin for the entire period. At week 4 of
therapy, a 2 log reduction in HCV RNA levels was achieved in three (60%) patients
in the daily group and in one (20%) patient in the three times a week group. At
week 24, HCV RNA was negative in four of the five patients in the three times a
week group, and three of the four patients in the daily group had a virological
response. However, in follow-up, none of these patients experienced a sustained
response. The safety of and ability to tolerate the combination therapy was good,
anemia being the most common adverse effect. In conclusion, patients previously
not responding to interferon achieved a greater virological reduction early in
combination therapy compared to a three times a week interferon schedule.
However, the virological response at the end of therapy was similar between the
two regimens, and no sustained response was observed in any of the treatment
groups.
PMID- 10759236
TI - A randomized, controlled study of thymosin-alpha1 therapy in patients with anti
HBe, HBV-DNA-positive chronic hepatitis B.
AB - No consistently effective therapy is yet available for the treatment of chronic
HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that
the response rates are not significantly different when patients with anti-HBe
positive hepatitis are treated with six-month course of thymosin-alpha1 or of
interferon-alpha. However, since among these patients, interferon's real efficacy
is still debated, with sustained biochemical response achieved in only a few of
the treated patients, we conducted this controlled study to investigate the
safety and efficacy of thymosin-alpha1 as compared with no treatment. Forty-four
chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA
positive, were randomized, with stratification for the presence of cirrhosis at
baseline liver biopsy, to receive either thymosin-alpha1 at a dose of 900
microg/m2 twice a week for six months or no treatment. At entry, both groups of
patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and
HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range
12-32 months) after completion of therapy: one dropped out, and one developed
hepatocellular carcinoma at six months. Thymosin-alpha1 treatment had no side
effects. Six months after the end of the therapy, HBV-DNA was negative and ALT
had normalized in 14% of treated cases and in 4.5% of control group, while IgM
anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the
controls. Among the treated patients, the median ALT levels stayed significantly
lower compared to the pretreatment values during the treatment period and six
months of follow-up. During the first year, there were six flares of hepatitis in
the control group and five among the treated patients (P = NS), yielding a per
year average of 0.3 and 0.23 flares per patient, respectively. Among the treated
patients, median IgM anti-HBc levels were low with respect to baseline values 4
10 months after treatment started. None became HBsAg negative. In conclusion,
these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B,
thymosin-alpha1 therapy alone does not increase the response rate, but may
contribute to reduce the immune-mediated liver cell necrosis as indirectly
assessed by ALT and IgM anti-HBc levels.
PMID- 10759237
TI - Portal hypertension and refractory ascites associated with multicentric
Castleman's disease.
PMID- 10759238
TI - Parathyroid hormone-related protein in liver cirrhosis.
PMID- 10759239
TI - Wilson's disease presented with fulminating hepatic failure in children.
PMID- 10759240
TI - Effect of casein-derived peptides on D-xylose absorption assessed by H2 breath
test in normal volunteers.
AB - Studies have shown a promoting effect of food on small intestinal absorption.
Casein hydrolysate seems be more effective in increasing of D-xylose absorption
in dogs than the whole protein and lactulose. The purpose this study was to
analyze the effect of groups of peptides derived from casein hydrolysate on the
absorption of D-Xylose and intestinal transit time in normal subjects. Seven
normal volunteers participated in the study. Three peptide fractions were
isolated from casein enzymatic hydrolysate by means of a preparative HPLC silica
column. On separate days subjects drank test solutions containing lactulose, D
xylose, and D-xylose with one of three peptide groups. The hydrogen breath test
was used to indirectly estimate D-xylose absorption and orocecal transit time.
Two peptide fractions when added to D-xylose were followed by an increased
absorption characterized by decreased H2 production. A nonstatistically
significant increase of orocecal transit time was observed with these peptides.
PMID- 10759241
TI - Intestinal microvascular patterns during hemorrhagic shock.
AB - While injuries due to a hypoxic state commonly appear later in both intestinal
crypts and basal portion of the villi than in the apical portion, a
nonhomogeneous distribution of blood flow in the intestinal mucosa may be
supposed. The presence of two different microvascular plexuses inside the mucosa,
corresponding to the cryptal plexus and the villous plexus, supports the above
hypothesis. This work studies the intestinal microvasculature in shocked versus
normal rats. Forty-five rats were divided into four groups to study the
histological damage and the microvascular bed by ink injection, fluorescent
microsphere infusion, and resin injection for scanning electron microscopy (SEM)
of vascular corrosion cast (VCC) observations. An infusion pressure of 100 +/- 5
mm Hg was used in control animals, while 30 +/- 5 mm Hg infusion pressure was
adopted for controls as well as for shocked animals to simulate physiological or
shock conditions. Hemorrhagic shock was induced by removing blood and maintaining
a mean arterial pressure of 30 +/- 5 mm Hg for 45-120 mins. A close connection
among the patterns of microvasculature obtained with VCC and ink injection
technique can be appreciated. In normal rats the whole microvasculature was
visualized, but in both normal and shocked animals injected at low pressure
different patterns could be found, generally showing a highly incomplete
visualization of the vascular network. A significant decrease of visualization of
both the entire microvasculature and the villous plexus is present in shocked
animals when compared to unshocked controls, while no difference in the cryptal
plexus visualization was observed. These observations suggest that the cryptal
plexus is perfused preferentially during hemorrhagic shock, as a consequence of
its peculiar microvascular organization. This may explain the relative resistance
of the crypts, compared to villi, to hypoxic injuries in order to sustain
endocrine function and the regenerative capability of the mucosa after prolonged
hypoperfusion conditions that can lead to villous damage and temporary loss of
the intestinal barrier function.
PMID- 10759242
TI - Detection and sequencing of measles virus from peripheral mononuclear cells from
patients with inflammatory bowel disease and autism.
AB - It has been reported that measles virus may be present in the intestine of
patients with Crohn's disease. Additionally, a new syndrome has been reported in
children with autism who exhibited developmental regression and gastrointestinal
symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is
not known whether the virus, if confirmed to be present in these patients,
derives from either wild strains or vaccine strains. In order to characterize the
strains that may be present, we have carried out the detection of measles genomic
RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's
disease, three patients with ulcerative colitis, and nine children with autistic
enterocolitis. As controls, we examined healthy children and patients with SSPE,
SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque,
followed by reverse transcription using AMV; cDNAs were subjected to nested PCR
for detection of specific regions of the hemagglutinin (H) and fusion (F) gene
regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H
region) or 5325-5465 (from noncoding F to coding F region). One of eight patients
with Crohn disease, one of three patients with ulcerative colitis, and three of
nine children with autism, were positive. Controls were all negative. The
sequences obtained from the patients with Crohn's disease shared the
characteristics with wild-strain virus. The sequences obtained from the patients
with ulcerative colitis and children with autism were consistent with being
vaccine strains. The results were concordant with the exposure history of the
patients. Persistence of measles virus was confirmed in PBMC in some patients
with chronic intestinal inflammation.
PMID- 10759243
TI - Serotonin and gastrin cells in rat gastrointestinal tract after
thyroparathyroidectomy and induced hyperthyroidism.
AB - Thyroidectomy appears to reduce the serotonin content in the rat brain, whereas
hyperthyroidism has the opposite effect. As it is not known whether the serotonin
producing cells of the gastrointestinal tract are influenced by these conditions,
the effects of thyroparathyroidectomy and induced hyperthyroidism were studied
experimentally, particularly as regards the serotonin- and gastrin-immunoreactive
cells of the gastrointestinal tract. Immunocytochemical and quantification
techniques were used to localize and determine the numbers of serotonin and
gastrin cells. In thyroparathyroidectomized rats the intestine was significantly
shorter and the mucosa thinner than in sham-operated and untreated controls,
whereas the converse was found in the hyperthyroid rats. Following
thyroparathyroidectomy, there were fewer gastrin-immunoreactive cells in antrum
and the serotonin-immunoreactive cells were significantly less dense throughout
the gastrointestinal tract. In hyperthyroid rats, gastrin-immunoreactive cells
were more numerous, as were the serotonin-immunoreactive cells in the small
intestine, whereas these cells were fewer in antrum and caecum. In conclusion,
the thyroid gland exerts a significant influence on the gastrointestinal tract
and on the serotonin-and gastrin-immunoreactive cells. The observed alterations
may reflect a direct effect of the thyroid hormones, although indirect factors
must also be considered.
PMID- 10759244
TI - Regulation of keratinocyte growth factor (KGF) and KGF receptor mRNAs by nutrient
intake and KGF administration in rat intestine.
AB - The aim of this study was to investigate the regulation of keratinocyte growth
factor (KGF) and KGF receptor mRNAs by diet and KGF treatment in rat intestine.
Fasting for three days up-regulated KGF and KGF receptor mRNA levels in ileum and
increased KGF receptor mRNA expression in colon. KGF and KGF receptor mRNA levels
returned toward control values with ad libitum refeeding but remained elevated
when refeeding was limited to 25% of ad libitum intake. KGF treatment during
nutrient repletion did not alter intestinal KGF mRNA levels but increased KGF
receptor mRNA abundance in ileum and colon. We conclude that the increase in KGF
and KGF receptor mRNAs induced by malnutrition may be an adaptive response to
attenuate gut mucosal atrophy in this setting. The gut-trophic effects of KGF
treatment may be mediated, in part, by up-regulation of the KGF receptor mRNA in
small bowel and colon.
PMID- 10759245
TI - Temporal expression of tumor necrosis factor-alpha and nitric oxide synthase 2 in
rat small intestine after endotoxin.
AB - Temporal changes in tumor necrosis factor-alpha (TNF-alpha) and nitric oxide
synthase 2 (NOS 2) were evaluated in segments of duodenum, jejunum, and ileum
removed from male Sprague-Dawley rats 30, 60, 120, 180, and 240 min after
lipopolysaccharide (LPS), 5 mg/kg, intraperitoneally. Plasma was assayed for TNF
alpha and for nitrate/nitrite (NOx). Intestinal and plasma TNF-alpha were
elevated by 60 min after LPS and were back to control levels by 180 min. For
control rats, NOS 2 was detected in the ileum, but not in the duodenum or the
jejunum. In rats treated with LPS, NOS 2 was detected in all areas of the
intestine at 120 min and was greatest at 240 min. Plasma NOx was elevated at 120
min and continued to increase to 240 min. The time course of changes in
intestinal TNF-alpha and NOS 2 were similar to those reported for other tissues
and suggest that the early and late actions of the LPS on the intestine may
involve both mediators.
PMID- 10759246
TI - Cyclosporine A inhibits partially spermine-induced differentiation but not cell
loss of suckling rat small intestine.
AB - The polyamines are of great importance in several biological processes, such as
cell proliferation, and differentiation. The ingestion of spermine by suckling
rats induces the precocious maturation of their small intestine. This phenomenon
is preceded by a cell elimination at the villus tip. We hypothesize that these
two phenomena could be mediated by the immune system and thus inhibited by an
immunosuppressive agent such as cyclosporine A. Cyclosporine A inhibits, at least
partially, the spermine-induced increase of the maltase- and sucrase-specific
activities in the small intestine but failed to inhibit lactase-specific activity
decrease and cell loss. Spermine does not act by the same mechanism in
differentiation and in cell loss. Moreover, spermine acts in a different way on
lactase-specific activity compared to maltase- or sucrase-specific activity. We
hypothesize that spermine acts on differentiation by a T-cell/IL-2-dependent
mechanism.
PMID- 10759247
TI - No significant difference in antigenicity or tissue transglutaminase substrate
specificity of Irish and US wheat gliadins.
AB - The prevalence of clinical celiac disease has been shown to vary both across time
and between genetically similar populations. Differences in wheat antigenicity
and transglutaminase substrate properties are a possible explanation for these
differences. This study assessed the antigenicity and transglutaminase substrate
specificities of gliadins from regions of high and low celiac disease prevalence.
Gliadin was extracted from three commercial US wheat sources and two Irish
sources. SDS-PAGE and western blotting revealed minor, but significant variations
in the gliadin extracts. However, ELISA showed no difference in the antigenicity
of these gliadins. Transglutaminase pretreatment of gliadin resulted in no
significant change in gliadin antigenicity and kinetic studies showed that the
Kms of the various gliadins were very similar. Purified IgA and IgG had no effect
on transglutaminase activity. In summary, minor variations in wheat gliadins are
unlikely to explain the observed differences in disease expression across
genetically similar populations.
PMID- 10759248
TI - Mechanisms of Helicobacter pylori-induced rat gastric mucosal microcirculatory
disturbances in vivo.
AB - The exact mechanisms by which Helicobacter pylori infection results in gastric
mucosal injury are unclear. However, it has been demonstrated that surface
protein extracts of the bacterium can induce a number of disturbances within the
rat gastric mucosal microcirculation, including platelet aggregation and
macromolecular leakage (MML) of labeled albumin. This study aimed to determine
the mechanisms involved in inducing these events using the technique of
fluorescent in vivo microscopy. Male Wistar rats were pretreated with either
ketotifen, a mast cell stabilizer (1 mg/kg), pyrilamine, an H1-receptor
antagonist (30 mg/kg), hexanolamine-PAF, a PAF-receptor antagonist (10
microg/kg), L-arginine, the nitric oxide precursor (300 mg/kg) or vehicle,
saline. Then 0.5 ml of H. pylori extract was administered to the exteriorized
gastric mucosa of the anesthetized rat. Alterations in fluorescein-labeled
albumin leak, vessel diameters, and acridine red-labeled leukocyte and platelet
activity were determined over a 2-hr period. Saline pretreated animals
demonstrated significant MML with a peak at 5 min (11%, P<0.02). This was
prevented with ketotifen and pyrilamine, but not with hexanolamine-PAF (17.5%,
P<0.05) and L-arginine (13%, P<0.05). Significant numbers of platelet emboli and
thrombi were observed within mucosal capillaries and postcapillary venules with
vehicle pretreatment; this was prevented with hexanolamine-PAF and L-arginine,
but not with ketotifen and pyrilamine. In conclusion, these studies demonstrate
that more than one mediator is involved in inducing the rat gastric mucosal
microcirculatory disturbances associated with H. pylori administration. Mast
cells and histamine are linked to MML, with PAF, probably not derived from mast
cells, involved in platelet activation.
PMID- 10759249
TI - Apoptotic depletion of infiltrating mucosal lymphocytes associated with Fas
ligand expression by Helicobacter pylori-infected gastric mucosal epithelium:
human glandular stomach as a site of immune privilege.
AB - H. pylori infection almost invariably results in chronic gastritis, but only a
proportion of patients develops severe destruction of epithelial glandular
structure or peptic ulcer. To confirm the recent data obtained in testis and eye,
showing that Fas ligand is involved in the phenomenon of "immune privilege,"
expression of Fas receptor and its ligand of the stomach was investigated in a
panel of gastric biopsies obtained from patients H. pylori-positive (N = 42) and
with H. pylori-negative (N = 18) by two-color flow cytometry. The results show
that membrane-bound Fas ligand protein is constitutively expressed on freshly
isolated human gastric mucosal epithelium coupled with infiltrating lymphocytes.
There was significant overexpression of Fas receptor and its ligand, and a higher
frequency of apoptotic cell death detected by TUNEL in epithelium and
infiltrating lymphocytes in H. pylori-infected patients. These findings suggest
that involvement of Fas receptor and its ligand system contributes to some extent
to mucosal damage in H. pylori-associated gastritis. However, the more specific
findings are apoptotic depletion of invading mucosal lymphocytes associated with
Fas ligand expression by gastric epithelium. These provide the first direct
quantitative evidence to support Fas receptor counterattack and/or paracrine
fratricide as a mechanism of immune privilege in vivo in the H. pylori-infected
glandular stomach.
PMID- 10759250
TI - Serologic response to lower-molecular-weight proteins of H. pylori is related to
clinical outcome of H. pylori infection in Taiwan.
AB - The study aimed to examine the serum serological response among H. pylori
infected patients with various upper gastrointestinal diagnoses; to ascertain
whether it could be predictive to the diagnostic outcome of dyspepsia. One
hundred seventy H. pylori-infected patients with dyspeptic symptoms but without
previous treatment were enrolled, including those with duodenal ulcer disease (N
= 47), gastric ulcer (N = 23), nonulcer dyspepsia (N = 60), gastric cancer (N =
34), and MALToma (N = 6). Sera from dyspeptic patients without H. pylori
infection (N = 33) were used as controls. During endoscopy, gastric biopsies were
taken for CLO-test, histology, and culture for the detection of H. pylori
infection, defined by a positive culture or positive results of both CLO-test and
histology. Total H. pylori IgG antibody was tested by an ELISA method. Antibody
responses to specific H. pylori proteins were tested by a western blotting
system. Of patients with H. pylori-infected gastroduodenal diseases, 76.5%,
42.9%, 23.6%, 46.7%, 84.1%, 76.5%, 82.9%, and 32.4% on average, showed responses
to the 116-kDa (CagA), 89-kDa (VacA), 60-kDa, 45-kDa, 35-kDa, 30-kDa, 26.5-kDa,
and 19.5-kDa H. pylori-specific proteins, respectively. A significant association
was found between the serological response to 19.5-kDa and 26.5-kDa proteins and
malignant outcome of H. pylori infection (P<0.02). Among patients without
malignancy, the absence of a band at 19.5 kDa was statistically associated with
the presence of an ulcer (P<0.05). The presence of serum antibody against CagA is
not different between patients with ulcer and with malignancy in clinical
diagnosis. The serum test for detecting antibodies against lower-molecular-weight
proteins of H. pylori, such as those of 19.5 and 26.5 kDa, could be useful to
identify H. pylori-infected patients at risk of peptic ulcer or malignancy.
PMID- 10759251
TI - Analysis of Helicobacter pylori vacA gene and serum antibodies to VacA in Japan.
AB - Vacuolating cytotoxin, VacA, is one of the most important pathogenetic factors
produced by Helicobacter pylori. However, it is not clear whether the diversity
in disease outcome may be ascribed to variations in strain and/or to the host
responses to virulence factors. In this study, we analyzed the vacA middle region
sequence among 65 Japanese isolates to clarify the variation in strain and
assayed antibody titer to VacA by ELISA using purified VacA to evaluate the host
response to cytotoxin. The nucleotide sequence identities compared among Japanese
isolates were 92.8 +/- 3.56%, and compared to 88.3 +/- 2.89% in tox+ strains
reported in GenBank. Positive correlation was found between the antibody titers
and the severity of atrophic change of the stomach. In Japan the nucleotide
sequences of the vacA middle region were highly homologous and genetically closer
to tox+ strains. Antibody titers and host response to cytotoxin may be associated
with atrophy of the stomach.
PMID- 10759252
TI - Long-lasting binding of IT-066 to human histamine H2 receptor.
AB - Based on animal models, IT-066, a histamine H2-receptor antagonist, is reported
to possess potent and long-lasting antagonisms on histamine H2 receptor (H2R)
mediated effects. However, no reports have been published concerning its
interaction with the human H2R. The aim of this study is to characterize its
interaction with human H2R. Chinese hamster ovary cell lines stably expressing
human H2Rs were obtained. The effects of IT-066, famotidine, and ranitidine on
tiotidine binding and histamine-stimulated cAMP production were analyzed. IT-066
inhibited [3H]tiotidine binding and histamine-stimulated cAMP production more
potently than famotidine or ranitidine. In addition, preincubation with 10(-5) M
IT-066, but not with 10(-5) M famotidine or 10(-4) M ranitidine, had marked
inhibitory effects long after extensive washing. Paraformaldehyde fixation of the
cells blunted inhibition of [3H]tiotidine binding induced by preincubation with
IT-066, but not that by preincubation with famotidine or ranitidine. IT-066 has
potent and long-lasting antagonisms on human H2R. At least one of the IT-066
binding sites is not shared by famotidine, ranitidine, or tiotidine and is
affected by paraformaldehyde fixation.
PMID- 10759253
TI - Famotidine prevents deep histologic lesions induced by 0.6N HCl in rat gastric
mucosa: role of parietal cells.
AB - The assessment of the protective actions of H2-receptor antagonists against
gastric mucosal lesions by necrotizing agents relies on the gross observation of
the gastric mucosa only. We examined the activity of famotidine against 0.6 N HCl
induced damage and the role of parietal cells by light and transmission electron
microscopy. Rats received famotidine 0.3-10 mg/kg intragastrically. Sixty minutes
later 0.6 N HCl (1 ml/rat) was given and after an additional 30 min the stomachs
were removed. Macroscopically visible lesions were measured. Histologic lesions
were scored on the basis of the depth. The ultrastructure of parietal cells in
the isthmus-neck region was examined. Pretreatment with famotidine resulted in a
slight increase of macroscopically visible gastric lesions in response to HCl.
While the extent of total histologic damage was not modified, the antisecretory
dose significantly reduced only lesions deep within the mucosa. Famotidine alone
determined the dose-dependent occurrence of a distinct parietal cell
morphological state, suggestive of inhibition of the secretory system. A causal
link between the protective effect on the region where parietal cells are
located, the percentage of cells shifting to the inhibited morphological state,
and the inhibitory effect on acid secretion is proposed.
PMID- 10759254
TI - Upper gastrointestinal symptoms in North America: prevalence and relationship to
healthcare utilization and quality of life.
AB - The aim of this study was to determine the prevalence of upper gastrointestinal
symptoms (UGIS) in a general population and quantify the relationship of those
symptoms to healthcare utilization and quality of life. In-person interviews were
conducted with 2056 United States and Canadian residents selected at random.
Subjects reported frequency and severity for 11 symptoms, prescription and over
the-counter medication use, primary care and specialty physician visits in prior
three months, and completed the Psychological General Well-Being Scale. For
analyses, subjects were classified into four mutually exclusive symptom groups:
gastroesophageal reflux disease (GERD) -like, GERD plus motility-like (GERD+),
ulcerlike, and motility-like. Of the total sample, 51.4% reported the occurrence
of at least one UGIS in the prior three months. Subjects in the GERD+ and ulcer
groups used more prescription medications and were more likely to see a physician
about the symptoms (P<0.001). Subjects with symptoms demonstrated poorer quality
of life compared to subjects with no symptoms. The prevalence of UGIS in the
general population is high and symptoms are associated with significant health
care utilization and poorer quality of life.
PMID- 10759255
TI - Changes in bone metabolism and body composition after total gastrectomy: results
of a longitudinal study.
AB - Decreased bone mineral density and an increased risk of fracture have been
reported many years after gastric resections due to peptic ulcer disease.
Corresponding information after total gastrectomy is, however, contradictory and
incomplete. Twenty-two gastric cancer patients who were long-term survivors after
total gastrectomy (mean of eight years) were investigated. They had whole body
DXA scans performed both after a mean of five and eight years after the
operation. Serum levels of relevant blood tests were determined. Our patients
lost 3.2 kg of their body weight (P<0.006) with a corresponding loss of lean body
mass (P<0.0001). We were unable to demonstrate any difference in bone density
from values seen in age- and sex-matched controls. We found a slight elevation of
osteocalcine levels but only a minor increase in parathyroid hormone levels. Body
weight had the greatest impact on the T score. The impact of total gastrectomy on
calcium homoeostasis and bone mineral density seems to be marginal. The close
relationship between bone mineral density and body weight suggest the pivotal
importance of maintaining weight control.
PMID- 10759256
TI - Cardiovascular autonomic function in patients with primary achalasia.
AB - Impaired gastrointestinal function outside the esophagus has been found in
achalasic patients. Moreover, achalasia may occur in diseases in which a systemic
dysautonomia is evident. These findings raise the question of whether a
generalized subclinical alteration of autonomic control is also present in
primary achalasia. Cardiovascular reflex tests and power spectral analysis of
heart rate variability were studied in patients with primary achalasia to
establish whether autonomic nervous system changes are present in districts other
than the gastrointestinal tract. Nineteen normotensive patients with untreated
primary achalasia and with no history of cardiac, renal, or endocrinological
diseases were examined. Cardiovascular reflex tests included: the tilt test (10
min at 65 degrees), Valsalva maneuver (40 mm Hg for 15 sec), deep breathing (6
breaths/min), and sustained handgrip (30% of maximal effort for 5 min). The
parameters evaluated were systolic and diastolic blood pressure (continuously
recorded), ECG, oronasal and thoracic respiration, tachogram, and plethysmogram.
To evaluate the balance between parasympathetic and sympathetic functions, power
spectral analysis of the heart rate variability was carried out. Each patient was
paired with two sex- and age-matched healthy controls. In achalasic patients the
head-up tilt test, Valsalva maneuver, deep breathing test, and sustained handgrip
did not show significant differences from the control group. Low-frequency (LF)
and high-frequency (HF) spectral powers and the ratio of LF to HF did not differ
in both groups. This study failed to disclose impaired cardiovascular autonomic
control in achalasic patients. We suggest that in primary achalasia the defect is
limited to the gastrointestinal tract.
PMID- 10759257
TI - Involvement of capsaicin-sensitive sensory neurons in stress-induced
gastroduodenal mucosal injury in rats.
AB - The pathogenesis of stress-induced gastroduodenal mucosal injury is complex and
incompletely understood. The aim of this investigation was to examine the
involvement of gastric and duodenal capsaicin-sensitive neurons in mucosal damage
associated with water-restraint stress (WRS) in rats. Following WRS,
gastroduodenal mucosal injury was quantitated by macroscopic and microscopic
methods. Calcitonin gene-related peptide (CGRP) content was measured by
radioimmunoassay. WRS-induced mucosal erosive injury in the stomach and duodenum
(40.9 +/- 4.2 and 5.1 +/- 0.6 mm2, respectively) was reduced significantly (by
88% and 67%, respectively) by acute intragastric capsaicin administration prior
to WRS. In contrast, sensory denervation by chronic capsaicin significantly
increased the area of gastric injury and duodenal damage. WRS alone caused a
significant reduction (by 52% and -35%, respectively) in gastric and duodenal
CGRP content, which was prevented by acute capsaicin treatment. The data suggest
that gastric and duodenal sensory neurons and CGRP are involved in the
pathogenesis of stress-induced mucosal injury to the stomach and duodenum.
PMID- 10759258
TI - Anaemia in pregnancy in developing countries.
PMID- 10759259
TI - The pathophysiology of pulmonary oedema with the use of beta-agonists.
PMID- 10759260
TI - Anaemia in pregnancy in southern Malawi: prevalence and risk factors.
AB - OBJECTIVE: To determine prevalence of anaemia in pregnancy in southern Malawi,
and to establish if an 'at risk' group can be identified for targeted
intervention. DESIGN: Prospective cross-sectional study. SETTING: A semi-urban
hospital and a rural health clinic in southern Malawi. POPULATION: Pregnant women
attending the antenatal clinic for their booking visit. METHODS: Haemoglobin
concentration (g/dL) measured from a capillary blood sample (fingerprick) by
battery operated HemoCue machine. RESULTS: In urban Blantyre 57% of women were
anaemic by WHO standards (haemoglobin < 11.0 g/dL) and 3.6% were severely anaemic
(haemoglobin < 7.0 g/dL). The prevalence was higher in the rural area; 72% and
4.0%, respectively. Primiparae were at slightly increased risk for overall
anaemia and severe anaemia but the effect of targeting this group alone for
interventions would mean at least 65% of anaemic women and over half of the women
with severe anaemia would be excluded. When the effect of age was examined
separate from gravidity, adolescents were not found to be at increased risk of
anaemia. Anaemia was more prevalent in the wet season and in women who booked
late for antenatal care. CONCLUSION: The prevalence of anaemia in pregnancy in
our population is unacceptably high and deserves more attention. Prophylaxis of
all women rather than an 'at risk' group based on age or gravidity is
recommended.
PMID- 10759261
TI - Comparative trends in cause-specific fetal and neonatal mortality in twin and
singleton births in the North of England, 1982-1994.
AB - OBJECTIVE: To examine trends in cause- and birthweight-specific fetal and
neonatal mortality rates in twins and singletons. DESIGN: Descriptive analysis
based on a regional register. SETTING: The Northern Health Region of England,
1982-1994. SAMPLE: Two hundred and thirty-six fetal and 356 neonatal twin deaths;
2,687 fetal and 2,301 neonatal singleton deaths from a population of 10,734 twins
and 505,477 singletons. MAIN OUTCOME MEASURES: Fetal and neonatal autopsy rates,
cause- and birthweight-specific fetal and neonatal mortality rates in twins and
singletons. RESULTS: The extended perinatal mortality (including stillbirths and
neonatal deaths) rate (EPMR) was 55.2 per 1,000 in 1982-1994 in twins compared
with 9.9 per 1,000 in singletons. The relative risk for twin compared with
singleton deaths was 5.6 (95% CI 5.1-6. 1) being highest for immaturity (12.9,
95% CI 11.1-15.0). A significant decrease in the EPMR occurred in both twins and
singletons in 1988-1994 compared with 1982-1987. The EPMR decreased mainly due to
a reduction of deaths from antepartum asphyxia in twins and intrapartum asphyxia
and trauma in singletons, as well as a reduction in congenital malformations in
both groups. In both twins and singletons, birthweight-specific mortality rates
improved between 1982-1987 and 1988-1994. CONCLUSION: The higher relative risk
for twin deaths remained stable due to a similar decrease in the EPMR for both
twins and singletons. The cause-specific relative risk in twins declined for
antepartum asphyxia. The mortality rate resulting from lethal congenital
malformations decreased in twins and singletons mainly due to earlier detection
and subsequent termination of pregnancy.
PMID- 10759262
TI - The continuing fall in incidence of hypoxic-ischaemic encephalopathy in term
infants.
AB - OBJECTIVE: To examine trends in incidence of hypoxic-ischaemic encephalopathy in
term infants over a twenty-one year period. DESIGN: A retrospective analysis of
medical records of all term infants admitted to a neonatal unit with hypoxic
ischaemic encephalopathy during the years 1992-1996 (period C) and a comparison
with data from the years 1976-1980 (period A) and 1984-1988 (period B) from the
same unit (previously published). SETTING: A District Health Authority in Central
England serving a population of about 450,000. SAMPLE: All term infants admitted
with clinical features of hypoxic-ischaemic encephalopathy. MAIN OUTCOME
MEASURES: Incidence of three grades of hypoxic-ischaemic encephalopathy,
disability and mortality. RESULTS: In each five year period there were similar
numbers of births. Over the time-span of this study the stillbirth rate and
neonatal mortality rate has consistently fallen. The overall incidence of hypoxic
ischaemic encephalopathy in term infants was significantly lower (P < 0.001; OR
0.42 CI 0.29-0.59) in the present study period (C) compared with the earlier
study period B (1.9 vs 4.6 per 1,000 total live births). The fall in moderately
and severely affected infants between the present and the first study period was
significant (1.2 vs 2.6 per 1,000 total live births, P < 0.001: OR 0.46 CI 0.29
0.72). The number of deaths and the incidence of cerebral palsy in survivors fell
progressively over the 21 years spanned by this study. CONCLUSION: This study
shows that the incidence of hypoxic-ischaemic encephalopathy and its sequelae in
term infants has fallen significantly. The use of cardiotocography and caesarean
section rates have risen but the relative contributions of changes in clinical
practice are uncertain.
PMID- 10759263
TI - Decision to delivery intervals for assisted vaginal vertex delivery.
AB - OBJECTIVE: To describe the time interval between decision for assisted vaginal
delivery and the birth of the baby in different clinical circumstances. DESIGN: A
prospective analysis of 225 consecutive women with a singleton fetal cephalic
presentation in the second stage of labour requiring an operative vaginal
delivery for various reasons. SETTING: A maternity unit in a district general
hospital delivering more than 6,000 women annually. MAIN OUTCOME MEASURES: The
decision to delivery interval and the immediate and short term maternal and
neonatal outcomes according to indication for operative vaginal delivery.
RESULTS: The mean (SD) decision to delivery interval was 34.4 minutes (28.3) with
a range of 5 to 101 minutes. For those delivered because of suspected fetal
distress, the interval of 26.5 minutes (14.0) was significantly shorter than for
those performed without fetal distress 39.5 minutes (19.0) (P < 0.0001); for
cases with fetal distress, forceps were significantly quicker at 23.3 minutes
(14.3) than the ventouse 29.2 minutes (13.2) (P = 0.04). The longer the interval
in cases of fetal distress the less favourable the condition of the neonate at
birth, although this trend did not reach statistical significance and was not
seen for deliveries expedited for other reasons. Perineal repair was required
following 96% forceps deliveries compared with 87% ventouse (P = 0.015). Perineal
trauma was not influenced by the interval between decision and delivery.
CONCLUSIONS: If speed of delivery is important, use of forceps results in a
quicker birth than use of the ventouse, without any compromise to the condition
of the baby at delivery, and with similar rates of perineal trauma.
PMID- 10759264
TI - The influence of bowel atresia in gastroschisis on fetal growth, cardiotocograph
abnormalities and amniotic fluid staining.
AB - OBJECTIVES: To investigate the relationship between intestinal atresia and fetal
growth, intrapartum cardiotocograph abnormalities and staining of the amniotic
fluid in gastroschisis pregnancies. DESIGN: Observational study of 115
gastroschisis pregnancies conceived between 1980 and 1996. SETTING: South West
Region of England. MAIN OUTCOME MEASURES: Birthweight, intrapartum
cardiotocograph abnormality, staining of amniotic fluid and Apgar score. RESULTS:
There was no statistically significant difference between the Apgar scores or the
frequency of amniotic fluid staining of gastroschisis cases with or without
atresia. Patent bowel gastroschisis was associated significantly with more
cardiotocograph abnormalities (61% vs 26%, P = 0.026) and reduced growth (P =
0.02), when compared with cases with intestinal atresia. CONCLUSIONS: Bile
vomiting may be an important cause of amniotic fluid staining. Bowel atresia
protects against the increased incidence of cardiotocograph and growth
abnormality found in cases of gastroschisis which may reflect their aetiology.
PMID- 10759265
TI - Parvovirus B19 infection: association with third-trimester intrauterine fetal
death.
AB - OBJECTIVE: To identify the presence of parvovirus B19 infection as a possible
cause of fetal loss in the third trimester. DESIGN: Prospective study of women
experiencing third-trimester intrauterine fetal death (IUFD). SETTING: All cases
of IUFD at Danderyd Hospital from 1992 to 1998. POPULATION: Ninety-three women
with IUFD in 33,759 deliveries (0.3%). METHODS: Detection of B19 DNA by
polymerase chain reaction (PCR) in placental and fetal tissue. Placental
pathology and B19-specific immunohistochemistry. Maternal serology in consecutive
samples. RESULTS: Among 93 cases of IUFD, seven (7.5%) had detectable B19 DNA in
freshly-frozen placental tissue. The detection of B19 DNA in these tissues was
confirmed by detection of B19 DNA in six separately stored paraffin-embedded
placental tissues. No other explanations for the fetal deaths were found. None of
the women had experienced any clinical signs of infection prior to fetal demise.
None of the seven fetuses were hydropic. Histopathologic examination of the
placentas revealed only minor abnormalities. Serology on maternal samples at
birth revealed delayed or absent B19 IgG responses in five of seven cases. Two
women were B19 IgG seropositive at the time of delivery but had unusual infection
patterns; persistent viraemia for at least five months before birth in one case
and likely persistence or re-infection by B19 in the other. CONCLUSION: In our
study, 7.5% of IUFDs in the third trimester may have been caused by parvovirus
B19 infection, without signs of fetal hydrops. This finding indicates that B19
PCR should be included in the routine investigation of IUFD.
PMID- 10759266
TI - The outcome of pregnancy in Kell alloimmunisation.
AB - OBJECTIVE: To assess management and outcome of pregnancies with anti-Kell in the
West Midlands in the UK over 13 years. DESIGN: A retrospective review of
casenotes. SETTING: A regional referral clinic for red cell alloimmune disease
and fetal medicine unit at a university hospital. POPULATION: Sixty-five
pregnancies were identified in 52 Kell-sensitised women with Kell positive
partners from the records of the Birmingham Blood Transfusion Centre. METHODS:
Information from the casenotes was entered on a database and comparisons were
made using the SPSS for Windows statistics package. MAIN OUTCOME MEASURES: Mode
of sensitisation, degree of fetal or neonatal anaemia, need for transfusion,
gestation at delivery, birthweight and pregnancy outcome. RESULTS:
Alloimmunisation was transfusion-related in 29 pregnancies and pregnancy-induced
in 33. The cause could not be identified in three cases. There were 22 proven
Kell positive fetuses, of which 18 were affected, in which alloimmunisation was
pregnancy-related in 12 cases and transfusion-related in five. Antibody titres
and amniotic fluid OD450 were not helpful in management. Severe or very severe
disease occurred in 50% of the affected pregnancies (9/18). There was no
difference in pregnancy outcome between transfusion or pregnancy induced
sensitisation. CONCLUSIONS: Anti-Kell alloimmunisation is an uncommon cause of
serious anaemia in a significant proportion of affected pregnancies. There
appears to be no difference between that caused by pregnancy or transfusion.
Estimation of fetal haemoglobin concentration by cordocentesis is recommended, as
antibody titres and amniocentesis are not helpful.
PMID- 10759267
TI - Organisation and cost-effectiveness of antenatal haemoglobinopathy screening and
follow up in a community-based programme.
AB - OBJECTIVE: To consider the organisation cost and effectiveness, of universal,
community-based antenatal screening for the haemoglobinopathies, and to estimate
the cost-effectiveness of programmes at different levels of prevalence and mix of
haemoglobinopathy traits. DESIGN: Retrospective review of laboratory and Sickle
Cell and Thalassaemia Centre worksheets with costing of capital equipment,
consumables, salaries and overheads, and estimation of costs in a range of
circumstances. SETTING: A haematology department, including a Sickle Cell and
Thalassaemia Centre, providing antenatal and neonatal screening programmes in
Inner London. PARTICIPANTS: Two thousand one hundred and one women booking at the
antenatal clinic whose samples were referred for screening during 1994. MAIN
OUTCOME MEASURES AND RESULTS: In addition to assessing the cost-effectiveness of
antenatal haemoglobinopathy screening in a number of settings, the following
specific financial information was assembled for the service in Brent: 1. cost of
identifying abnormal haemoglobin in mother (l209); 2. cost of identifying at-risk
fetus before confirmation by prenatal diagnosis (l2,455); 3. cost of providing
genetic information and counselling to mother with abnormal haemoglobin (l109);
4. programme savings from cases averted (l61,000). Conclusions Antenatal
screening with follow up counselling can be self-financing at most prevalences of
haemoglobinopathy traits, with greater savings where a high proportion of the
traits are beta thalassaemia. There is a net financial cost (l1,350) only at
prevalences below 2.5% of traits if these are mainly for sickle cell disease.
Since there are other benefits is it likely that antenatal screening will be
considered cost-effective even at quite low levels of trait prevalence.
PMID- 10759268
TI - The maternal cerebral circulation in pre-eclampsia: investigations using Laplace
transform analysis of Doppler waveforms.
AB - OBJECTIVE: To compare the maternal cerebral circulation in pre-eclampsia and
normal pregnancy using an alternative method of Doppler waveform analysis called
the Laplace transform analysis, which provides haemodynamic data additional to
standard Doppler indices. DESIGN: A prospective cross-sectional study. SETTING:
Department of Obstetrics and Gynaecology, Nottingham University Hospital. SAMPLE:
The study involved 17 women in the third trimester of a normal pregnancy, 11 with
pregnancy-induced hypertension and 26 with pre-eclampsia. METHODS: Doppler
recordings were obtained from the internal and external carotid and middle
cerebral arteries, with the measurements in hypertensive women being carried out
before any treatment was given. The waveforms were then subjected to Laplace
transform analysis which provides information on vessel wall stiffness and
upstream and downstream flow conditions. MAIN OUTCOME MEASURES: The determination
of the Laplace transform analysis parameters, including alpha, the natural
frequency of oscillation and real pole, and pulsatility index. RESULTS: Laplace
transform analysis demonstrated a significant increase in vessel wall stiffness
in all the arteries in hypertensive pregnancies, but this was more marked in pre
eclampsia. The data were also consistent with, but do not prove, increased
downstream resistance in the middle cerebral artery in women with pre-eclampsia
but not in those with pregnancy-induced hypertension. CONCLUSIONS: The Laplace
transform analysis of Doppler waveforms yields important physiological
information concerning the cerebral circulation in pre-eclampsia, not detected
using conventional Doppler indices. The results suggest that both pre-eclampsia
and pregnancy-induced hypertension are associated with increased cerebral
arterial wall stiffness and that, in addition, there may be cerebral
vasoconstriction in pre-eclampsia.
PMID- 10759269
TI - Effects of maternal dexamethasone administration on fetal Doppler flow velocity
waveforms.
AB - OBJECTIVE: To investigate the effects of maternal dexamethasone administration on
umbilical and fetal cerebral artery flow velocity waveforms. DESIGN: Cross
sectional study. SETTING: Department of Obstetrics and Gynaecology, Robert
Ballanger Hospital, Aulnay-sous-Bois, France. SAMPLE: Twenty-six pregnant women
with singleton pregnancies considered at risk for preterm delivery. At baseline,
all pregnancies had normal fetoplacental vascular resistance. METHODS: These
women were given weekly six intravenous doses of 4 mg of dexamethasone eight
hours apart. MAIN OUTCOME MEASURES: Doppler studies were performed from both
umbilical artery (UA) and fetal middle cerebral artery (MCA) before (day 0),
during (day 2), immediately after (day 4) and shortly after (day 7) every steroid
course. RESULTS: No significant variation was noted in both umbilical artery
pulsatility index (PI) and fetal heart rate through dexamethasone therapy.
Compared with mean initial values, we found on day 4 a significant decrease in
MCA PI of 0.28 (F = 7.17, P < 0.001) and a significant increase in UA:MCA PI
ratio of 0.08 (F = 3.85, P = 0.013); in contrast no significant change was
documented on days 2 and 7 in both MCA pulsatility index and UA:MCA PI ratio.
After multiple regression analysis, only the decrease in fetal middle cerebral
artery pulsatility index on day 4 remained significant (F= 5.84, P= 0.001).
CONCLUSIONS: The current study finds in healthy fetuses a transient, significant
and unexplained decrease in fetal middle cerebral artery impedance on the fourth
day following maternal dexamethasone administration. Further basic research and
clinical studies including larger sample sizes or pregnancies with fetoplacental
dysfunction are needed.
PMID- 10759270
TI - Is an atherogenic lipoprotein profile in the fetus a prerequisite for placental
vascular disease?
AB - OBJECTIVE: To measure the blood apolipoprotein A-1 and apolipoprotein B in the
fetal circulation in normal pregnancy and in pregnancy with evidence of vascular
disease in the fetal umbilical placental circulation defined in the antenatal
period by Doppler ultrasound study. DESIGN: An observational study to compare
fetal plasma apolipoprotein levels in normal and complicated pregnancy. SETTING:
A university hospital tertiary referral obstetric unit. SAMPLES: Umbilical vein
blood was collected at delivery from 22 normal fetuses delivered by elective
caesarean section for non fetal reasons and 30 fetuses with evidence of umbilical
placental vascular disease identified antenatally by Doppler ultrasound study.
METHODS: Plasma apolipoprotein A-1 and B were determined using an enzyme-linked
immunosorbent assay (ELISA) methods. MAIN OUTCOME MEASURES: Fetal plasma levels
of apolipoprotein A-1 and B were measured. RESULTS: There was a significantly
lower level of fetal plasma apolipoprotein A-1 in placental insufficiency
[placental insufficiency vs normal pregnancy, median 0.30 g/L (interquartile
range 0.24, 0.39 g/L) vs 0.35 g/L (0.31, 0.42 g/L), P = 0.045]. In contrast, the
levels of fetal plasma apolipoprotein B in placental insufficiency [0.20 g/L
(0.17, 0.26 g/L)] were significantly increased compared with normal pregnancy
[0.16 g/L (0. 14, 0.20 g/L), P = 0.03]. The ratio of fetal plasma apolipoprotein
B to A-1 was also substantially higher in placental insufficiency [0.68 (0.55,
0.83)] than in normal pregnancy [0.45 (0.36, 0.60), P = 0.0003]. CONCLUSIONS: Our
study has demonstrated that levels of fetal plasma apolipoprotein A-1,
apolipoprotein B and the ratio of apolipoprotein B to A-1 were altered in the
fetuses who are victims of umbilical placental insufficiency in the same
direction as in adults associated with a high risk of atherogenesis.
PMID- 10759271
TI - Correlation between placental bed biopsy findings, vascular cell adhesion
molecule and fibronectin levels in pre-eclampsia.
AB - OBJECTIVE: To determine the correlation between placental bed biopsy findings,
and blood levels of the vascular cell adhesion molecule (VCAM-1) and fibronectin
in pre-eclampsia/eclampsia, and to evaluate the relationship between these
variables and severity of the disease. DESIGN: A prospective case-control study.
SETTING: Department of Obstetrics and Gynaecology, Cerrahpasa Medical Faculty,
Istanbul. SAMPLE: Thirty-five women with pre-eclampsia/eclampsia were compared
with 25 healthy women with uncomplicated pregnancies. Twenty-one placental bed
biopsies from pre-eclamptic pregnancies were compared with 17 from normal
pregnancies. MAIN OUTCOME MEASURES: Peripheral venous blood levels of VCAM-1 and
fibronectin, measured by enzyme-linked immunoassay and radial immune diffusion
technique. RESULTS: In pre-eclampsia/eclampsia, blood VCAM-1 and fibronectin
levels were higher than in normal pregnancy. Levels of both fibronectin and VCAM
1 correlated significantly with the diastolic blood pressure (r = 0.49 and r =
0.65, P < 0.001). There was also a significant direct linear correlation between
plasma fibronectin and VCAM-1 levels (r = 0.57, P < 0.001). Normotensive women
all had normal placental bed biopsy findings and the incidence of pathological
placental bed biopsy findings increased with the severity of the pre-eclampsia.
CONCLUSION: Inadequate trophoblastic invasion of spiral arteries, and elevated
levels VCAM-1 and fibronectin were found in women with pre-eclampsia. The
magnitude of defective trophoblastic invasion, and blood levels of VCAM-1 and
fibronectin correlate with the clinical severity of pre-eclampsia.
PMID- 10759272
TI - Epidemiological assessment of misoprostol teratogenicity.
AB - OBJECTIVE: To verify if any of the 15 congenital defects already reported in
association with misoprostol can be found within an epidemiological registry of
congenital defects. DESIGN: Case-control study including case-sick and case
health controls. METHODS: Comparison of misoprostol exposure for each specific
defect, using the exposure for the rest of defects as a reference group.
POPULATION: Four thousand six hundred seventy-three consecutive newborn infants
with malformations of unknown aetiology, in the Latin American Collaborative
Study of Congenital Malformation. RESULTS: There was no difference in exposure
rate between the malformed (34/4,673) and nonmalformed (23/4,980) newborns. Four
of the five more frequently cited defects in the literature were found to be in
excess: constriction ring, terminal transverse-limb defects, hydrocephalus, and
arthrogryposis. Equinovarus feet had a normal frequency in our study. Thirteen
different defects not described in the literature were seen in our misoprostol
exposed cases, but only holoprosencephaly and bladder exstrophy significantly
exceeded the expected number. CONCLUSIONS: The confirmation from an
epidemiological registry of an association for four of the five more commonly
observed congenital defects among misoprostol exposed children described in the
literature seems indicative of a real teratogenic effect. The defects are of
vascular disruption type. However, additional attempts to achieve abortion could
not be excluded as a concurrent contribution.
PMID- 10759273
TI - Comparison of two doses of mifepristone in combination with misoprostol for early
medical abortion: a randomised trial.
AB - OBJECTIVES: To compare the efficacy of two different regimens of mifepristone
followed by misoprostol for medical abortion in women with menstrual delay of <
or = 35 days. DESIGN: Double-blind, randomised controlled trial. SETTING:
Seventeen centres internationally. PARTICIPANTS: We enrolled 1,589 healthy
pregnant women with menstrual delay of < or = 35 days who were requesting
nonsurgical abortion. INTERVENTIONS: Within gestational age strata, we randomly
assigned women to receive a single oral dose of mifepristone, either 200 mg or
600 mg, followed in 48 h by misoprostol 400 microg by mouth. We concealed the
allocation assignments from investigators and participants and maintained double
blinding throughout the study. MAIN OUTCOME MEASURES: Complete abortion was the
principal outcome measure. We also compared rates of side effects such as
abdominal pain. RESULTS: The complete abortion rate with the lower dose of
mifepristone was similar to that with the higher dose (89.3% vs 88.1%) The crude
relative risk of failure to achieve complete abortion with the 200 mg dose
compared with the 600 mg dose was 0.9 (95% CI 0.7 to 1.2). The likelihood of
complete abortion was inversely related to gestational age, although this finding
is exploratory in nature. Among failures the percentage of women with continuing
pregnancies increased from 1.4% at menstrual delay of two weeks or less to 9.0%
when the delay was 4-5 weeks. Low efficacy led to stopping enrolment at 29 to 35
days' menstrual delay. Stopping criteria were also met at completion of the study
in the group with 22-28 days' menstrual delay. No significant differences emerged
in the frequency of side effects between the two mifepristone groups.
CONCLUSIONS: Both regimens had similar efficacy. Women with a menstrual delay of
four to five weeks had twice the risk of failure to abort compared with those who
received treatment within two weeks of the expected menses. The efficacy of the
mifepristone-prostaglandin regimen was not reduced by decreasing the dose of
mifepristone from 600 mg to 200 mg. The regimens of 600 mg or 200 mg of
mifepristone, followed by a single oral dose of misoprostol 400 microg 48 hours
later, were not sufficiently efficient in inducing abortion when the menstrual
delay was > 21 days.
PMID- 10759274
TI - Has endometrial ablation replaced hysterectomy for the treatment of dysfunctional
uterine bleeding? National figures.
AB - OBJECTIVES: To describe trends in the use of endometrial ablation and
hysterectomy for the treatment of dysfunctional uterine bleeding. DESIGN:
Analysis of hospital admissions data. SETTING: National Health Service Hospitals
in England. POPULATION: Women who underwent a hysterectomy or endometrial
ablation for dysfunctional uterine bleeding between 1989 and 1996. MAIN OUTCOME
MEASURES: Annual operation rates and standardised operation ratios for England
and for the National Health Service Regions within it, and proportion of
operations for dysfunctional uterine bleeding that were endometrial ablations or
hysterectomies. RESULTS: There was an initial rise in operation rates for
endometrial ablation until 1992/3, since when the rates have fallen. Hysterectomy
rates have remained relatively steady since the introduction of endometrial
ablation. The total operation rates for dysfunctional uterine bleeding initially
increased but have tended to fall since 1992/3. The ratio of hysterectomy to
endometrial ablation for dysfunctional uterine bleeding troughed at 3:1 in
1992/3, but by 1995/6 had increased to 4:1. CONCLUSIONS: Rather than replacing
hysterectomy in the treatment of dysfunctional uterine bleeding, endometrial
ablation appears to have added an alternative operative technique. This led to an
increase in the total number of operations for this condition, perhaps by
lowering the threshold for intervention.
PMID- 10759275
TI - Guidelines in gynaecology: evaluation in menorrhagia and in urinary incontinence.
AB - OBJECTIVE: To evaluate the effectiveness of national guidelines and local
protocols in improving hospital care (process and outcome) for women with
menorrhagia and for women with urinary incontinence. DESIGN: 2 x 2 balanced
incomplete block controlled before and after study. SETTING: Gynaecology units in
four district general hospitals across Scotland. INTERVENTION: National
guidelines were adapted locally to protocols, which were disseminated at specific
local educational meetings and implemented by placing a copy of the appropriate
protocol in women's hospital casenotes prior to consultation. POPULATION: Four
hundred and ninety-seven women with menorrhagia and 449 women with urinary
Incontinence. MAIN OUTCOME MEASURES: Process of care within six key areas of
clinical practice: initial hospital assessment; appropriate use of hospital
investigations; inappropriate use of hospital investigations; appropriate first
line treatments; appropriate pre-surgery assessment; and use of surgical
treatments. Outcome of care using condition-specific outcome measures and four
domains of SF-36 at zero, six and twelve months following intervention. RESULTS:
There were significant improvements with the introduction of guidelines and
protocols in two (initial hospital assessment and appropriate pre-surgery
assessment) of the six key areas of clinical practice assessed. In the other
areas there were no significant improvements or deteriorations observed. There
was no evidence of effect of guidelines and protocols on the condition-specific
outcome measures or on the four domains of the SF-36. CONCLUSIONS: There were
only very modest benefits observed from the introduction of guidelines and
protocols on the hospital management of the two conditions. The reasons for this
lack of impact of the guidelines is unclear. Experience of this study raises
important methodological issues for future research in this area.
PMID- 10759276
TI - Randomised comparison of Burch colposuspension versus anterior colporrhaphy in
women with stress urinary incontinence and anterior vaginal wall prolapse.
AB - OBJECTIVE: To compare the Burch colposuspension and the anterior colporrhaphy in
women with both stress urinary incontinence and advanced anterior vaginal wall
prolapse (cystocele). DESIGN: Prospective randomised study. SETTING: Secondary
referral centre, Urogynaecology Unit, San Gerardo Hospital, Monza, Italy. SAMPLE:
Seventy-one women undergoing surgery for primary genuine stress incontinence and
concurrent grade 2 or 3 cystocele (descending at or outside the vaginal
introitus). METHODS: Full urodynamic investigation performed pre-operatively and
repeated six months after surgery. Clinical follow up continued for 8 to 17
years. MAIN OUTCOME MEASURES: Subjective (patient history) and objective
(negative stress test result) cure of stress incontinence. Assessment of
cystocele recurrence. RESULTS: Thirty (86%) of the 35 evaluable women who had the
Burch colposuspension and 17 (52%) of the 33 evaluable women who had the anterior
colporrhaphy were subjectively cured (OR 5.6, 95% CI 1.6 to 21.6; P = 0.005).
Objective cure rates were 74% (26 of 35) and 42% (14 of 33), respectively (OR
3.9, 95% CI 1.3 to 12.5; P = 0.02). A recurrent cystocele of grade 2 or 3 with or
without prolapse at other vaginal sites was recorded in 34% (12 of 35) and 3% (1
of 33) of women, respectively (OR 16.7, 95% CI 2.0 to 368.1; P = 0.003).
CONCLUSIONS: The Burch colposuspension was better in controlling stress
incontinence but it lead to an unacceptable high rate of prolapse recurrence. The
anterior colporrhaphy was more effective in restoring vaginal anatomy but it was
accompanied by an unacceptable low cure rate of stress incontinence. Neither of
the two operations is recommended for women who are suffering from a combination
of stress incontinence and advanced cystocele.
PMID- 10759277
TI - An audit of the management of uterine malignancy within the West Midlands. West
Midlands Gynaecological Oncology Group.
AB - OBJECTIVE: To audit the management of uterine malignancy. DESIGN: Retrospective
casenote analysis. SETTING: Cancer units/centres within the West Midlands.
SAMPLE: The last 100 cases managed by each hospital in 1997. RESULTS: Ninety-six
cases of uterine malignancy from ten hospitals were analysed. Only six hospitals
were able to provide a complete data set. Eighty-eight cases (92%) presented with
abnormal, usually postmenopausal, vaginal bleeding. Over 90% of the cases were
primary endometrial carcinomas. Of the 15 standards audited, 11 were met by at
least one hospital. No hospital met all the standards, although every hospital
was able to meet at least one. Standards concerned with initial referral and
diagnostic intervals were universally failed. Outpatient diagnosis was made in
only 30%. The availability of Rapid Access Clinics neither promoted outpatient
diagnosis nor sped up diagnosis. Once the diagnosis had been made, surgery was
usually performed within six weeks. CONCLUSIONS: This audit has provided valuable
baseline data for future activity. Serious attention must be given to improvement
in clinical cancer data collection. Referral pathways for women with suspected
uterine cancer, and endometrial cancer in particular, need improvement. It is
recommended that the current standards remain unaltered, and after the West
Midlands Gynaecological Oncology Group had the opportunity to consider and
implement the necessary changes, the audit be repeated.
PMID- 10759278
TI - Lateral distribution of nonendometriotic benign ovarian cysts.
AB - To investigate the left- and right-sided distribution of nonendometriotic benign
ovarian cysts, data were collected on 406 women undergoing first-line surgery for
tumours with various histotypes. Considering the unilateral cysts, the observed
proportion of left lesions was 65/129 (50.4%) in the serous, 38/79 (48.1%) in the
mucinous, 59/134 (44.0%) in the dermoid, 11/21 (52.4%) in the parovarian, and 3/7
(42.9%) in the miscellaneous cysts group, without significant differences from
the expected 50%. This contrasts with the finding of a significantly more
frequent development of endometriomas on the left ovary, and suggests that the
pathogenesis of endometriotic and nonendometriotic cysts is different.
PMID- 10759279
TI - Is ureteral endometriosis an asymmetric disease?
AB - Six cases of endometriosis obstructing the left ureter were observed among 1,054
consecutive patients undergoing surgery in an eight-year period. In addition, 125
women with ureteral endometriosis (left-sided, n = 66; right-sided, n = 40;
bilateral, n = 19) were described in 62 articles identified in a systematic
review of the English language literature between 1980 and 1998. Considering only
the patients with unilateral ureteral endometriosis and combining the published
figures with those of our surgical series, the observed proportion of left
lesions (72/112, 64%; 95% CI 55% to 73%) was significantly different from the
expected proportion of 50% (chi2(1), 9.14, P = 0.002). The lateral asymmetry
found in the location of ureteral endometriosis is compatible with the menstrual
reflux theory and with the anatomical differences of the left and right
hemipelvis.
PMID- 10759281
TI - Prothrombin 20210 G-->A, MTHFR C677T mutations in women with venous
thromboembolism associated with pregnancy.
AB - Over 50 unselected women with maternal venous thromboembolism were screened for
the prothrombin 20210 G-->A and MTHFR C677T mutations, in addition to screening
for other thrombophilias. The prevalence of thrombophilia in these women was
compared with its prevalence in the general population in our area. The
prothrombin (OR 4.4; 95% CI 1.2-16) and factor V Leiden (OR 4.5; 95% CI 2.1-14.5)
mutations were more common in our patients, compared with the general population,
whereas women homozygous for the C677T mutation in the methylene tetrahydrofolate
reductase gene (OR 0.45; 95% CI 0.13-1.58) were not. It is recommended that women
with a personal or strong family history of venous thromboembolism should be
screened for the prothrombin mutation either before or early in pregnancy, in
addition to screening for other thrombophilias. Screening for the MTHFR mutation
does not appear to identify women at increased risk of maternal venous
thrombosis.
PMID- 10759280
TI - Double-blind randomised controlled trial of glyceryl trinitrate spray for
external cephalic version.
AB - A placebo controlled trial of glyceryl trinitrate was carried out in women whose
first attempt at external cephalic version without tocolysis had been
unsuccessful. No significant differences between groups were found and no side
effects were noted. It is recommended that a larger, possibly multicentre study,
should be undertaken.
PMID- 10759282
TI - Neonatal abstinence syndrome due to prolonged administration of fentanyl in
pregnancy.
PMID- 10759283
TI - Massive necrosis of cervical ectopic decidua presenting in labour.
PMID- 10759284
TI - Misoprostol for induction of labour at term.
PMID- 10759285
TI - A randomised controlled study of uterine exteriorisation and repair at caesarean
section.
PMID- 10759286
TI - Are we prescribing multiple courses of antenatal corticosteroids? A survey of
practice in the UK.
PMID- 10759287
TI - Are we prescribing multiple courses of antenatal corticosteroids? A survey of
practice in the UK.
PMID- 10759288
TI - Obesity not only holds cardiovascular diseases, it also hold tumors.
PMID- 10759289
TI - Leptin concentration in non-obese and obese children with type 1 diabetes
mellitus.
AB - Leptin, the product of the ob gene, is an adipocyte-derived hormone that
positively correlates with body fat percantage and body mass index (BMI). There
are many data which demonstrate a significant relationship between leptin and
insulin, but the mechanism underlying the changes of leptin induced by insulin
and vice versa remains to be studied in more detail. In this review, we analysed
the data on the behaviour of serum leptin levels in non-obese and obese children
with type 1 diabetes mellitus. It has been shown that the diminished serum leptin
concentrations in patients with newly discovered insulin-dependent diabetes
mellitus (IDDM) could be caused by insulin deficiency and/or increased lipolysis.
Moreover, while in some studies in diabetic children with good metabolic control
the serum leptin levels are similar to those of healthy children, in other
studies children with IDDM have leptin levels higher than non diabetic children;
it is possible that in some diabetic children intensified insulin therapy could
cause chronic hyperinsulinemia with high leptin levels. The mean serum leptin
concentrations in the obese diabetic subjects were significantly higher when
compared with non-obese diabetics. Obese diabetic patients showed no significant
differences in leptin concentrations in comparison to the non diabetic obese
group matched by age, sex and BMI. In obese diabetics, during weight loss,
independent of the quality of metabolic control, serum leptin concentration
declines. The changes of leptin in diabetes seem to be similar to those observed
in healthy obese subjects.
PMID- 10759290
TI - Treatment of diabetes in patients with severe obesity.
AB - Besides genetic predisposition, obesity is the most important risk factor for the
development of diabetes mellitus, and weight reduction has been shown to markedly
improve blood glucose control in obese subjects with type 2 diabetes. Therapeutic
strategies for the obese diabetic patient include: 1) promoting weight loss
through lifestyle modifications (hypocaloric diet and exercise) and anti-obesity
drugs (orlistat, sibutramine, etc.); 2) improving blood glucose control,
essentially through the reduction of insulin resistance (metformin, eventually
thiazolidinediones) or insulin need (alpha-glucosidase inhibitors) and, at a
later stage, the correction of defective insulin secretion (sulphonylureas,
repaglinide) or low circulating insulin levels (exogenous insulin); and 3)
treating common associated risk factors, such as arterial hypertension and
dyslipidaemias, to improve cardiovascular prognosis. When morbid obesity is
present, both restoring a good glycemic control and correcting associated risk
factors can only be obtained through marked and sustained weight loss. This
primary objective justifies more aggressive weight reduction programmes,
including very low-calorie diets and bariatric surgery, but only within a
multidisciplinary approach and in well-selected patients.
PMID- 10759291
TI - Duration of obesity and risk of non-insulin-dependent diabetes mellitus.
AB - Although obesity is one of the major risk factors for diabetes mellitus, the
association of the duration of obesity with glucose intolerance or insulin
dysregulation has not yet been clarified. Thirteen articles were picked up from
the MEDLINE database by using the four key-word phrases, "duration of obesity,"
"duration of overweight," "prolonged obesity," and "prolonged overweight."
Although the definition of overweight was similar among the children-based
studies (> = 20% or 2 SD over ideal weight), the cutoff point for adults ranged
from 25.0 to 30.0 kg/m2 of body mass index. With regard to the definition of the
duration of obesity, the articles were roughly divided into two groups, with some
researchers bearing the definition on the number of years from the onset of
overweight and some calculating using the person-years method. The prevalence or
incidence of non-insulin-dependent diabetes mellitus (NIDDM) or impaired glucose
tolerance (IGT) are probably associated with the duration of obesity. The effect
of prolonged obesity on insulin dysregulation is still unclear.
PMID- 10759292
TI - Inhibition of liver metastases and tumor cell invasion in spontaneous liver
metastasis model (LMFS) by sodium D-glucaro-delta-lactam (ND2001).
AB - We examined the inhibitory effect of sodium D-glucaro-delta-lactam (sodium 5
amino-5-deoxy-D-glucosaccharic acid-delta-lactam: ND2001) upon liver metastases
of the LMFS tumor. A permanent cell line, LMFS, was established from a
spontaneously occurring murine retroperitoneal tumor of BALB/c mouse origin, and
after a subcutaneous injection, the LMFS cells proliferated at the inoculation
site (100% take) with liver metastases. ND2001 had little effect on the cell
growth, cell cycle and phagokinesis of the LMFS cells in vitro. However, when the
invasive activity was measured by the Boydem chamber method, the number of LMFS
cells was reduced, with inhibition rates of 98.0%. After the LMFS cells treated
with ND2001 in vitro, the numbers of hepatic metastases of subcutaneous
inoculation of treated cells were reduced dose-dependently, and those of
intravenous inoculation were not found by microscopical study. When the LMFS
tumor-bearing mice were treated with ND2001 (0, 30, 100 mg/kg/d) from day 1,
ND2001 (30 mg/kg) inhibited the liver metastases with a rate of 56.4%, and when
given from day 15, ND2001 (100 mg/kg) inhibited with a rate of 47.5%. But ND2001
showed neither cytocidal nor anti-tumor activity. Combination therapy of primary
tumor resection and ND2001 administration revealed that preoperative use of
ND2001 was more effective in preventing liver metastases. These results suggested
that ND2001 might have a potential use as an anti-metastatic agent for operative
patients without metastasis.
PMID- 10759293
TI - Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol
fed hamsters.
AB - We have investigated the activity of the calcium antagonist lacidipine in male
hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals
were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed
the atherogenic diet and without lacidipine treatment, there were significant
increases in serum levels of total cholesterol, triglycerides and lipoproteins;
these values were approximately similar at week 24. Lacidipine treatment at 0.3,
1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and
lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet,
the area of the fatty streak in the aortic arch covered a mean area of 375 +/-
145 micron2 x 100, which accounted for 2.7% of the total surface area of the
aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at
0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion
was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in
lacidipine-treated animals, both the incidence and degree of severity of the
lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in
comparison with non-lacidipine-treated control animals. Ultrastructural
examination demonstrated that the early changes in the aorta in hamsters fed the
atherogenic diet involved the intima and smooth muscle cells; lacidipine
treatment reduced the severity of the intimal lesions significantly. With SEM,
lacidipine administration was seen to reduce endothelial irregularity and the
presence of crater-like lesions. At TEM, treatment with lacidipine reduced the
number of foam cells and the presence of liposomes in the subendothelium. This
investigation demonstrates that in the hyperlipidemic hamster, lacidipine
treatment decreases atheromatous lesions without lowering serum lipids. It is
suggested that lacidipine influences the atherogenic process by an unusual
mechanism which may be related to a combination of both the long-lasting calcium
antagonism of the drug and significant antioxidant activity.
PMID- 10759294
TI - Epidemiologic studies of multiple sclerosis: a review.
AB - There is evidence for genetic factors in multiple sclerosis (MS). The evidence
come from epidemiologic studies, racial predilection, risk in family members
(sibs, half sibs, adoptees) and twins studies. MS is not a Mendelian inherited
disease; only the susceptibility to the disease is inherited, the risk of MS
being also related to an environmental factor. Many candidate genes were
screened, and there are four research groups trying to study the whole genome. MS
seem to be an oligo- or multigenic disorder with an apparently similar phenotype
for the different genes involved.
PMID- 10759295
TI - Genetics of multiple sclerosis.
AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the
central nervous system. Although environmental risk factors are clearly involved
in MS, the importance of genetic factors has been strongly supported by the
results of studies on multiplex families, though a weak association with major
histocompatibility complex (MHC) has been the only genetic feature of MS
consistently observed to date. Other candidates genes have been pointed out, but
none has been confirmed. Recent genome scans suggest that no single MS
susceptibility locus is necessary or sufficient to cause MS, and this finding is
compatible with a polygenic etiology. Furthermore, MS is a heterogeneous
disorder, and thus different genes may influence its course or presentation.
Actually, some candidate genes have been proposed, which contribute to the
genotype-phenotype interactions in MS.
PMID- 10759296
TI - Antithrombotic and prothrombotic activities of the vascular endothelium.
AB - Vascular endothelium plays a key role in the control of haemostasis and
thrombosis. The main reactions involved in the regulation of platelet reactivity,
blood coagulation and fibrinolysis take place at the luminal surface of
endothelial cells. Following exposure to certain pathological stimuli, remarkable
functional changes of the endothelial cells occur, including downregulation of
antithrombotic mechanisms and upregulation of prothrombotic activities. Based on
the recent knowledge of vascular endothelial function, a better understanding of
the pathogenesis of atherothrombosis is expected.
PMID- 10759297
TI - Characterization of heterotopic cell clusters in the hippocampus of rats exposed
to methylazoxymethanol in utero.
AB - Cortical disorganization represents one of the major clinical findings in many
children with medically intractable epilepsy. To study the relationship between
seizure propensity and abnormal cortical structure, we have begun to characterize
an animal model exhibiting aberrant neuronal clusters (heterotopia) and
disruption of cortical lamination. In this model, exposing rats in utero to the
DNA methylating agent methylazoxymethanol acetate (MAM; embryonic day 15)
disrupts the sequence of normal brain development. In MAM-exposed rats, cells in
hippocampal heterotopia exhibit neuronal morphology and do not stain with
immunohistochemical markers for glia. In hippocampal slices from MAM-exposed
animals, extracellular field recordings within heterotopia suggest that these
dysplastic cell clusters make synaptic connections locally (i.e. within the CA1
hippocampal subregion) and also make aberrant synaptic contact with neocortical
cells. Slice perfusion with bicuculline or 4-aminopyridine leads to epileptiform
activity in dysplastic cell clusters that can occur independent of input from
CA3. Taken together, our findings suggest that neurons within regions of abnormal
hippocampal organization are capable of independent epileptiform activity
generation, and can project abnormal discharge to a broad area of neocortex, as
well as hippocampus.
PMID- 10759298
TI - An automated drug delivery system for focal epilepsy.
AB - Previous studies have demonstrated the ability to stop seizures in animal models
with injection of antiepileptic medication directly onto the seizure focus. The
present experiments describe automated detection and focal therapy for seizures
in the laboratory setting. Focal seizures were created in Sprague-Dawley rats
using bicuculline, a GABA antagonist. Computerized detection of seizures was
linked to a programmable infusion pump to deliver either diazepam (DZP) or pH
balanced vehicle (VEH) directly onto the seizure focus. Mean numbers of seizures
following initial delivery of drug were 2.9+/-1.45 for the VEH-treated group and
0.2+/-0.42 for the DZP-treated group (P<0.0001, Student's t-test, nonpaired, one
tailed). In another series of experiments, early injection of DZP shortened
seizure duration. Three DZP-treated animals died. This model provides proof-in
principle for the development of a clinically applicable treatment for
intractable partial epilepsy. Such therapy might avoid some of the problems
inherent to systemic administration of antiepileptic drugs.
PMID- 10759299
TI - Effect of vigabatrin addition on carbamazepine blood serum levels in patients
with epilepsy.
AB - Because vigabatrin (VGB) is not metabolized by liver enzymes and does not bind
with serum proteins, there is little theoretical chance of it interacting with
other antiepileptic drugs. However, our observations have shown that if VGB is
added to carbamazepine (CBZ) monotherapy, some patients respond with adverse,
toxic symptoms suggesting possible carbamazepine-vigabatrin interaction. This
article presents the results of a study of 66 epileptic patients (27 women and 39
men), age 10-66 years (mean, 28.2 years), with focal seizure onset with or
without secondary generalization. In these patients, in addition to CBZ therapy
with an average dose of 16.7 mg/kg per day (8.6-26.8), VGB, average dose 31.1
mg/kg per day (7.1-57.9), was added. CBZ concentration was measured twice: prior
to VGB introduction and 5-12 weeks after the final dose of VGB was reached. In
our study 69.7% of patients responded to VGB addition with a significant increase
(by at least 10%) in CBZ concentration. A correlation between the value of the
increase and the initial level of CBZ prior to VGB addition was found also.
Correlational analysis (Pearson's r) revealed a negative correlation between CBZ
concentration and increased concentration after VGB addition (r = -0.47, df = 64,
P < 0.001). This negative correlation means that if the initial CBZ level is
lower, its concentration value after VGB addition is higher.
PMID- 10759300
TI - Depression in patients with temporal lobe epilepsy is related to mesial temporal
sclerosis.
AB - Depression is a frequent psychiatric symptom in epilepsy and has been related to
epilepsy of temporal origin, especially of left-sided foci. No study
differentiated the precise localization of the epileptogenic lesion within the
temporal lobe. Regarding this issue, we evaluated depression assessed by the Beck
Depression Inventory in 60 patients with temporal lobe epilepsy, with particular
consideration of morphological abnormalities within the temporal lobe (mesial
temporal sclerosis (MTS) versus neocortical lesions) and lateralization of the
lesion. Multivariate analyses indicated significant higher depression scores in
MTS independent of the lateralization of the lesion. Depression was a good
indicator for MTS but not vice versa. Hence, MTS can be discussed as a
predisposing factor for the development of mood disorders in focal epilepsy.
PMID- 10759301
TI - Association analysis between a regulatory-promoter polymorphism of the human
monoamine oxidase A gene and idiopathic generalized epilepsy.
AB - Monoaminergic neurotransmission plays an important role in the regulation of
neuronal network excitability and seizure activity. Therapeutic inhibition of the
mitochondrial enzyme monoamine oxidase A (MAO-A), which is involved in the
degradation and inactivation of monoaminergic neurotransmitters, has been shown
to confer a potent anticonvulsant effect. These and other findings suggest a
possible role of the X-linked MAO-A gene in epileptogenesis. Therefore, our study
was designed to test for an association between a novel MAO-A gene promoter
polymorphism and common subtypes of idiopathic generalized epilepsy (IGE). The
length of a 30-bp repetitive sequence approximately 1.2 kb upstream of the ATG
initiation codon was assessed in 126 patients with juvenile myoclonic epilepsy
(JME), 122 patients with idiopathic absence epilepsy (IAE), and 248 healthy
controls of German descent. Both sexes were analyzed separately. Although we
observed a trend towards a lower number of heterozygotes carrying the 3 and 4
copy alleles in female IAE patients (chi2 = 3.813, df = 1, P = 0.053), allele
frequencies did not deviate significantly between patients and controls. Thus,
our results do not provide evidence for a contribution of the functional MAO-A
gene promoter polymorphism to the pathogenesis of common IGE subtypes.
PMID- 10759302
TI - Temporal profile of neuronal injury following pilocarpine or kainic acid-induced
status epilepticus.
AB - Systemic administration of pilocarpine and kainic acid (KA) has been extensively
used to model temporal lobe epilepsy in rats. Here the regional distribution of
selectively vulnerable neurons and the temporal evolution of such neuronal injury
after status epilepticus (SE) are compared in both models. Using the silver
staining technique of Gallyas, argyrophilic neurons were measured on a 0-3 (least
most) scale in 53 different brain areas. Few neurons were silver-stained 2.5 h
after kainate-induced SE, but many silver-stained cells could be seen in most
neocortical, hippocampal, amygdaloid and hypothalamic structures for pilocarpine
group. In general, 8 or 24 h intervals between SE onset and perfusion times
yielded the most intense neuronal silver-impregnation. Pilocarpine-induced
neuronal silver impregnation was more prominent than that induced by kainate
treatment for many areas in cortex, hippocampus, endopiriform nucleus, amygdaloid
complex and hypothalamus. On the other hand, in the thalamus, some cortical
areas, claustrum, lateral septum and caudoputamen, kainate-induced neuronal
silver staining was also prominent, but occurred later than in pilocarpine
treated animals. Neuronal injury was found in almost the same brain areas in both
models of SE but with different intensity levels and time course profiles. It was
suggested that such differences in the temporal profile of cell damage should be
taken into account when searching for neuroprotective agents.
PMID- 10759303
TI - Seizures and neuronal damage in mice lacking vesicular zinc.
AB - Synaptically released zinc has neuromodulatory capabilities that could result in
either inhibition or enhancement of neuronal excitability. To determine the net
effects of vesicular zinc release in the brain in vivo, we examined seizure
susceptibility and seizure-related neuronal damage in mice with targeted
disruption of the gene encoding the zinc transporter, ZnT3 (ZnT3-/- mice). ZnT3-/
mice, which lack histochemically reactive zinc in synaptic vesicles, had
slightly higher thresholds to seizures elicited by the GABA(A) antagonist,
bicuculline, and no differences in seizure threshold were seen in response to
pentylenetetrazol or flurothyl. However, ZnT3-/- mice were much more susceptible
than wild-type mice to limbic seizures elicited by kainic acid, suggesting that
the net effect of hippocampal zinc on acute seizures in vivo is inhibitory. The
hippocampi of ZnT3-/- mice showed typical seizure-related neuronal damage in
response to kainic acid, demonstrating that damage to the targets of zinc
containing neurons can occur independently of synaptically released zinc. Mice
lacking the neuronal zinc-binding protein metallothionein III (MT-III) are also
more susceptible to kainic acid-induced seizures. Double knockout (ZnT3 and MT3)
mice show the same response to kainic acid as ZnT3-/- mice, suggesting that ZnT3
and MT-III function in the same pathway.
PMID- 10759304
TI - Do seizures cause neuronal damage in rat amygdala kindling?
AB - Using unbiased stereology, we estimated total neuronal numbers in the lateral,
basal and accessory basal nuclei of the amygdala and in the hilus of the dentate
gyrus 6 months after the induction of amygdala kindling. In kindled rats, there
was no decrease in the total number of neurons in the various amygdaloid regions
or the hilus compared to sham-operated animals. Furthermore, there was no
correlation between the total duration of afterdischarges or the number of
electrical stimulations and the number of neurons. Our data indicate that when
using unbiased stereological methods, total neuronal number in the amygdala or
hilus are not reduced after few amygdala-induced seizures.
PMID- 10759305
TI - Safety of pyrethroid-treated mosquito nets.
AB - The use of insecticide treated nets (ITNs) for personal protection against
malaria vector Anopheles mosquitoes (Diptera: Culicidae) has become popular
during the past decade. With the precautions outlined in this paper, field use of
pyrethroids--at concentrations recommended for treatment of mosquito nets--poses
little or no hazard to people treating the nets or to users of the treated nets.
With frequent exposure to low concentrations of pyrethroids, the risk of toxicity
of any kind is remote. Pyrethroids entering the systemic circulation are rapidly
metabolized to much less toxic metabolites. Toxicologically, pyrethroids have a
useful characteristic--the production of skin paraesthesia--which gives an early
indication of exposure. This reversible symptom of exposure is due to transient
stimulation of peripheral sensory nerves and not a toxic effect. In the retail
market, for home use, the provision of proper packaging and labelling, with clear
instructions on safe and effective use of the product are most important. Because
many domestic users of pyrethroid 'home treatment kits' for ITNs may not be fully
literate, it is essential that 'instructions for use' should be portrayed via
pictograms with supporting text in appropriate local language(s).
PMID- 10759306
TI - Repellency of deet to nymphs of Triatoma infestans.
AB - The repellency of N,N-diethyl-3-methylbenzamide (deet) to Triatoma infestans
(Klug) (Hemiptera: Reduviidae) was evaluated using third-instar nymphs and a
video tracking technique. Three experimental designs were used: (a) the test
arena floor was divided into two halves, only one of which was treated with deet;
(b) the arena floor was divided into an inner circle and an outer ring, only the
latter treated with deet; (c) half of the test arena was covered by a filter
paper roof treated with deet (out of reach of the nymphs). In all three types of
experiment, a repellent effect was demonstrated proportional to the dose of deet.
When a host (pigeon) was shielded by deet-treated gauze, the rate of blood
feeding by the nymphs was inhibited. Topical pre-treatment of the nymphs with N
ethylmaleimide, to block chemoreception, inhibited the repellency.
PMID- 10759307
TI - Biochemical characterization of insecticide resistance in the German cockroach,
Blattella germanica, from Malaysia.
AB - The possible insecticide resistance mechanisms of four Malaysian field-collected
strains of the German cockroach, Blattella germanica (Linnaeus) (Dictyoptera:
Blattellidae), were characterized with biochemical assays and native
polyacrylamide gel electrophoresis (PAGE). Elevated esterase activity (at low to
moderate frequency) and altered acetylcholinesterase (low frequency) were
detected in all field strains, while elevated glutathione S-transferase levels
were present in only two strains. Seven esterase bands were separated by native
PAGE; a greater intensity occurred in three bands in the resistant strains
compared to the susceptible strain. Inhibition studies using specific inhibitors
on polyacrylamide gels suggested that the slowest of these three esterases is a
cholinesterase, while the other two are carboxylesterases with a preference for
beta- over alpha-naphthyl acetate.
PMID- 10759308
TI - Distribution of domestic triatominae and stratification of Chagas Disease
transmission in Oaxaca, Mexico.
AB - Mexico has 18 species of Triatomine bugs (Hemiptera: Reduviidae) reported to be
vectors of Trypanosoma cruzi. Chagas Disease is widespread in Mexico, with up to
3.5% seropositivity of human transfusion blood. The State of Oaxaca has the
longest history of endemic Chagas Disease, based on acute and chronic case
reports, and of entomological surveys in the country. However, the State health
care services need more information on current risks of vector transmission. In
order to identify and characterize areas of transmission in Oaxaca and to
stratify the vector potential, the distribution of domestic Triatominae was
surveyed during 1996-98 in collaboration with the primary health care services
and local communities. Villages were studied in 11% of 570 municipalities in
Oaxaca. Eight triatomine species were found in domestic and peri-domestic
habitats: Triatoma barberi Usinger, T. bolivari Carcavallo et al., T. dimidiata
(Latreille), T. mazzottii Usinger, T. nitida Usinger, T. pallidipennis (Stal), T.
phyllosoma (Burmeister) and Rhodnius prolixus Stal. For each triatomine species
in Oaxaca, the range of distribution and habitat characteristics are described.
Habitat partitioning, principally based on altitude and mean annual
precipitation, limited the overlap of distribution between species. Relatively
consistent altitude of human settlements facilitates the dispersion of individual
species within microregions. Entomological indices of house infestation were used
to estimate that approximately 50% of the human population (1,874,320
inhabitants) would be at risk of vector transmission, with a minimum of 134,320
infected people and 40,280 chronic cases of Chagas Disease currently in Oaxaca.
PMID- 10759309
TI - Effects of temperature and larval diet on development rates and survival of the
dengue vector Aedes aegypti in north Queensland, Australia.
AB - Immature development times, survival rates and adult size (wing-lengths) of the
mosquito Aedes aegypti (L.) (Diptera: Culicidae) were studied in the laboratory
at temperatures of 10-40 degrees C. The duration of development from egg eclosion
(hatching of the first instar) to adult was inversely related to temperature,
ranging from 7.2 +/- 0.2 days at 35 degrees C to 39.7 +/- 2.3 days at 15 degrees
C. The minimum temperature threshold for development (t) was determined as 8.3 +/
3.6 degrees C and the thermal constant (K) was 181.2 +/- 36.1 day-degrees above
the threshold. Maximum survival rates of 88-93% were obtained between 20 and 30
degrees C. Wing-length was inversely related to temperature. The sex ratio
(female:male) was 1:1 at all temperatures tested (15, 20, 25 and 35 degrees C)
except 30 degrees C (4:3). Under field conditions at Townsville and Charters
Towers, north Queensland, the duration of immature development varied according
to the container position (i.e. shaded or exposed) and the availability of food
resources, as well as inversely with temperature. These data indicate that
containers with an abundance of organic matter (e.g. those used for striking
plant cuttings) or those amongst foliage or under trees (e.g. discarded plastic
tubs and tyres) tended to produce the largest adult Ae. aegypti, which had faster
development and better immature survival. As such progeny have been linked to a
greater risk of dengue transmission, it would seem important to focus on control
of such containers.
PMID- 10759310
TI - Body size variation of the floodwater mosquito Aedes albifasciatus in Central
Argentina.
AB - An inverse relationship between larval density and adult body size has been
reported for several mosquito species, affecting their survival and vector
competence, response to repellents and other factors. Larvae of the floodwater
mosquito Aedes (Ochlerotatus) albifasciatus (Macquart) (Diptera: Culicidae)
develop quickly in temporary pools, so intraspecific competition (for food or
space) might regulate population abundance and affect the size of adult
mosquitoes. We investigated the temporal variation of adult female wing-length
(an index of body-size) in natural populations of Ae. albifasciatus, using adults
collected during each phase of the rainy season. The relationships between adult
mosquito abundance, female wing-length, rainfall and temperature were analysed
through simple regressions. Skewness of the frequency distribution of wing
lengths showed a strong negative relationship with mean wing-length. The
distribution of wing-lengths varied seasonally and was correlated with rainfall 7
15 days previously as the major consequence of breeding site volume. Thus
temporal variation of body size in natural populations of Ae. albifasciatus
reflected density-dependent changes in the aquatic habitat where immature stages
develop, influenced more by rainfall than by temperature or other environmental
variables.
PMID- 10759311
TI - Tissue distribution and prevalence of Wolbachia infections in tsetse flies,
Glossina spp.
AB - Tsetse flies Glossina spp. (Diptera: Glossinidae) harbor three different
symbiotic microorganisms, one being an intracellular Rickettsia of the genus
Wolbachia. This bacterium infects a wide range of arthropods, where it causes a
variety of reproductive abnormalities, one of which is termed cytoplasmic
incompatibility (CI) that, when expressed, results in embryonic death due to
disruptions in fertilization events. We report here that in colonized flies,
Wolbachia infections can be detected in 100% of sampled individuals, while
infections vary significantly in field populations. Based on Wolbachia Surface
Protein (wsp) gene sequence analysis, the infections associated with different
fly species are all unique within the A group of the Wolbachia pipientis clade.
In addition to being present in germ-line tissues, Wolbachia infections have been
found in somatic tissues of several insects. Using a Wolbachia-specific PCR-based
assay, the tissue tropism of infections in Glossina morsitans morsitans Westwood,
Glossina brevipalpis Newstead and Glossina austeni Newstead were analysed. While
infections in G. m. morsitans and G. brevipalpis were limited to reproductive
tissues, in G. austeni, Wolbachia could be detected in various somatic tissues.
PMID- 10759313
TI - Annual and spatial activity of dung flies and carrion in a Mediterranean holm-oak
pasture ecosystem.
AB - The annual activity and spatial distribution of Muscidae and Calliphoridae were
investigated in a holm-oak ('dehesa') ecosystem in western Spain over two years
in pasture and woodland habitats, using wind-orientated traps baited with a
mixture of fresh cattle faeces, liver and sodium sulphide solution. Lucilia
sericata (Meigen) was always the dominant species and, with Chrysomya albiceps
(Weidemann), Hydrotaea ignava (Harris), Muscina levida (Harris) and Muscina
prolapsa (Harris), was more abundant during the second than the first year. By
contrast, Calliphora vicina Robineau-Desvoidy, Calliphora vomitoria (L.),
Hydrotaea armipes (Fallen), Hydrotaea penicillata (Rondani) and Hydrotaea
dentipes (Fabricius) were more numerous during the first than the second year of
the study. In summer, the Diptera sampled were significantly more abundant in a
wooded than a pasture area. However, in autumn, while H. penicillata remained
significantly more abundant in woodland, L. sericata became more abundant in the
pasture, whereas C. vicina was captured in open and wooded areas in similar
proportions. During winter and spring the populations sampled were relatively
small. The changing patterns of abundance are discussed in relation to
differences in climate within and between years.
PMID- 10759312
TI - Insecticide resistance in Brazilian Triatoma infestans and Venezuelan Rhodnius
prolixus.
AB - Resistance levels to insecticides used in control of Chagas Disease vectors were
assessed in two species of bugs (Hemiptera: Reduviidae): Triatoma infestans
(Klug) from Brazil and Rhodnius prolixus Stal from Venezuela. The resistance
ratios, compared to susceptible laboratory strains, were determined by topical
application bioassays. The T. infestans PA strain exhibited resistance ratios of
7x to deltamethrin, 3.6x to beta-cyfluthrin and 3.3x to cypermethrin, but was
susceptible to beta-cypermethrin and lambda-cyhalothrin. Rhodnius prolixus CA
strain showed resistance to all the pyrethroids evaluated, the resistance ratios
ranging between 4.5x to lambda-cyhalothrin and 12.4x to cypermethrin.
Deltamethrin resistance in both strains was decreased by piperonyl butoxide,
suggesting oxidative metabolism as cause of resistance.
PMID- 10759314
TI - Sugars in the gut of the sandfly Phlebotomus orientalis from Dinder National
Park, Eastern Sudan.
AB - The sandfly Phlebotomus orientalis Parrot (Diptera: Psychodidae) is the vector of
visceral leishmaniasis in eastern and Upper Nile regions of Sudan, where vector
infection rates of over 7% have been reported. Sugars are known to be important
for development of the parasite and for increasing the survival and oviposition
rates of several species of sandflies. In the present study we have analysed the
sugars present in the guts of individuals and groups of male and female P.
orientalis and compared these with sugars from several potential local plant
sources: Acacia seyal, Balanites aegyptiaca and Combretum kordofanum. The
distribution of these trees in Sudan is closely correlated with that of P.
orientalis. Only 20% of individually analysed female sandflies had significant
amounts of sugars present suggesting that P. orientalis either digest their sugar
meal quickly or do not require regular sugar meals. Interestingly, the sugars
present in the males were significantly different to those found in the females,
indicating that they had fed on different sugar sources. There was evidence that
fruit sugars from Balanites aegyptiaca, Combretum kordofanum and aphid or coccid
honeydew are utilized by male and female P. orientalis. There was evidence to
indicate that female P. orientalis feeds directly on honeydew. There was no
evidence to indicate that direct feeding on leaves is a typical source for the
sugar meal. There was no melizitose and only a very small amount of turanose
present in the male, suggesting that honeydew was not an important sugar source
for males.
PMID- 10759315
TI - Evolution and structural organisation of mitochondrial DNA control region of
myiasis-causing flies.
AB - This study reports the molecular characterization of the mtDNA control region
(called the A+T-rich region in insects) of five dipteran species which cause
myiasis: Cochliomyia hominivorax Coquerel, Cochliomyia macellaria Fabricius,
Chrysomya megacephala Fabricius, Lucilia eximia Wiedemann (Diptera:
Calliphoridae) and Dermatobia hominis Linnaeus Jr (Diptera: Oestridae). The
control region in these species varies in length from 1000 to 1600 bp. Two
structural domains with specific evolutionary patterns were identified. These
were (1) conserved sequence blocks containing primary sequence motifs, including
dinucleotide pyrimidine-purine series and long T-stretches, located at the 5' end
adjacent to the tRNA(Ile) gene and (2) a hypervariable domain at the 3' end
characterized by increased nucleotide divergence and size variation. A high
frequency of A<-->T transversions at nucleotide substitution level indicated
directional mutation pressure. The phylogenetic usefulness of the insect control
region is discussed.
PMID- 10759316
TI - Modifications of pyrethroid effects associated with kdr mutation in Anopheles
gambiae.
AB - Effects of knockdown resistance (kdr) were investigated in three pyrethroid
resistant (RR) strains of the Afrotropical mosquito Anopheles gambiae Giles
(Diptera: Culicidae): Kou from Burkina Faso, Tola and Yao from Cote d'Ivoire;
compared with a standard susceptible (SS) strain from Kisumu, Kenya. The kdr
factor was incompletely recessive, conferring 43-fold resistance ratio at LD50
level and 29-fold at LD95 level, as determined by topical application tests with
Kou strain. When adult mosquitoes were exposed to 0.25% permethrin-impregnated
papers, the 50% and 95% knockdown times (KdT) were 23 and 42 min for SS females,
compared with 40 and 62 min for RS (F1 Kou x Kisumu) females. On 1% permethrin
the KdT50 and KdT95 were 11 and 21 min for SS compared with 18 and 33 min for RS
females. Following 1 h exposure to permethrin (0.25% or 1%), no significant
knockdown of Kou RR females occurred within 24 h. Permethrin irritancy to An.
gambiae was assessed by comparing 'time to first take-off' (TO) for females. The
standard TO50 and TO95 values for Kisumu SS on untreated paper were 58 and 1044
s, respectively, vs. 3.7 and 16.5 s on 1% permethrin. For Kou RR females the
comparable values were 27.3 s for TO50 and 294 s for TO95, with intermediate RS
values of 10.1 s for TO50 and 71.9 s for TO95. Thus, TO values for RS were 2.7
4.4 times more than for SS, and those for RR were 7-18 times longer than for SS.
Experiments with pyrethroid-impregnated nets were designed to induce hungry
female mosquitoes to pass through holes cut in the netting. Laboratory 'tunnel
tests' used a bait guinea-pig to attract mosquitoes through circular holes (5 x 1
cm) in a net screen. With untreated netting, 75-83% of laboratory-reared females
passed through the holes overnight, 63-69% blood-fed successfully and 9-17% died,
with no significant differences between SS and RR genotypes. When the netting was
treated with permethrin 250mg ai/m2 the proportions that passed through the holes
overnight were only 10% of SS vs. 40-46% of RR (Tola & Kou); mortality rates were
100% of SS compared with 59-82% of RR; bloodmeals were obtained by 9% of Kou RR
and 17% of Tola RR, but none of the Kisumu SS females. When the net was treated
with deltamethrin 25 mg ai/m2 the proportions of An. gambiae that went through
the holes and blood-fed successfully were 3.9% of Kisumu SS and 3.5% of
Yaokoffikro field population (94% R). Mortality rates were 97% of Kisumu SS vs.
47% of Yaokoffikro R. Evidently this deltamethrin treatment was sufficient to
kill nearly all SS and half of the Yaokoffikro R An. gambiae population despite
its high kdr frequency. Experimental huts at Yaokoffikro were used for overnight
evaluation of bednets against An. gambiae females. The huts were sealed to
prevent egress of mosquitoes released at 20.00 hours and collected at 05.00
hours. Each net was perforated with 225 square holes (2 x 2 cm). A man slept
under the net as bait. With untreated nets, only 4-6% of mosquitoes died
overnight and bloodmeals were taken by 17% of SS vs. 29% of Yaokoffikro R
(P<0.05). Nets treated with permethrin 500 mg/m2 caused mortality rates of 95%
Kisumu SS and 45% Yao R (P<0.001) and blood-feeding rates were reduced to 1.3% of
SS vs. 8.1% of Yao R (P<0.05). Nets treated with deltamethrin 25 mg/m2 caused
mortality rates of 91% Kisumu SS and 54% Yao R (P<0.001) and reduced blood
feeding rates to zero for SS vs. 2.5% for Yao R (P>0.05). (ABSTRACT TRUNCATED)
PMID- 10759317
TI - The use of direct sequencing of dengue virus cDNA from individual field-collected
Aedes aegypti for surveillance and epidemiological studies.
AB - The relative efficiencies of four methods to extract viral RNA from individual
dengue-2 virus (D-2V)-infected mosquitoes, Aedes aegypti (L.) (Diptera:
Culicidae), were compared. The most efficient of these methods was then used to
extract viral RNA for the preparation of cDNA from the abdomens of six engorged D
2V-infected mosquitoes and sera from three dengue fever (DF) patients collected
in an isolated rural town in Colombia. Comparisons of viral envelope (E) gene
sequences from each of these strongly suggested that the D-2V population which
circulated in this study area was a homogeneous genotype which was unrelated to
any of the D-2 viruses isolated from elsewhere in the world. When coupled with
our rapid method to identify viruses in individual mosquitoes (Romero-Vivas et
al. (1998) Medical and Veterinary Entomology, 12, 101-105), the methodology we
describe should be useful for epidemiological and surveillance studies of dengue
viruses and other arboviruses.
PMID- 10759318
TI - Dispersal range of Simulium neavei in an onchocerciasis focus of western Uganda.
AB - The dispersal range of the vector Simulium neavei Roubaud (Diptera: Simuliidae)
was investigated in an onchocerciasis focus in Kabarole district, western Uganda,
adjacent to the Itwara Forest Reserve, where the species breeds in phoretic
association with the river crab Potamonautes aloysiisabaudiae (Nobili) (Decapoda:
Potamonautidae). Biting rates were highest at the edge of the forest, but blood
seeking flies were collected up to a distance of about 4 km from the forest.
Entomological data did not agree with the geographical distribution of
onchocerciasis, which is hyperendemic in larger distances from the forest. The
possible reasons are discussed.
PMID- 10759319
TI - Cleptohaematophagy of the Triatomine bug Belminus herreri.
AB - The Triatomine bug Belminus herreri, previously known only from Panama, is
reported for the first time from Colombia. Three adult B. herreri were collected
from a chicken coop and a viable egg was found on a Bactris palm at Carmen
municipality in humid forest zone at 680 m altitude. From 44 eggs produced, five
progeny were reared to adulthood. During early instars they were unable to take
bloodmeals directly from vertebrate hosts, but they fed successfully by
cleptohaematophagy on blood from replete Rhodnius prolixus.
PMID- 10759320
TI - Shared salinity tolerance invalidates a test for the malaria vector Anopheles
farauti s.s. on Guadalcanal, Solomon Islands.
AB - Among the Punctulatus Group of Anopheles mosquitoes (Diptera: Culicidae), first
instar larvae of the medically unimportant freshwater Anopheles farauti species
No. 7 survives a seawater tolerance test (SST) that was previously thought to be
diagnostic for the saltwater-tolerant malaria vector species, An. farauti Laveran
s.s. Salt tolerance in these two closely related isomorphic species appears to be
a shared derived character within the Farauti Complex. Failure to differentiate
An. farauti s.s. from An. farauti No. 7 will overestimate potential malaria
vector numbers and waste limited larval control resources. Use of the SST should
therefore be discontinued on Guadalcanal and other techniques such as allozyme
electrophoresis used instead.
PMID- 10759321
TI - Susceptibility of British head lice, Pediculus capitis, to imidacloprid and
fipronil.
AB - The head louse, Pediculus capitis De Geer (Phthiraptera: Pediculidae) has
developed resistance to organochlorines, the organophosphate malathion and to
pyrethroids in the U.K. Therefore, headlice from Bristol school children were
bioassayed against two new insecticides, fipronil and imidacloprid. Pediculus
capitis was fully susceptible to imidacloprid, but it required a relatively high
dose and acted slowly. Fipronil acted faster at lower dose, but seemed to be
affected by cross-resistance in a small proportion of P. capitis.
PMID- 10759322
TI - Treatment preference in hypochondriasis.
AB - Promising cognitive-behavioral and medication treatments for hypochondriasis are
in the early stages of evaluation. Little is known about the treatment
preferences and opinions of individuals seeking help for this problem. In this
exploratory study, 23 volunteers from the community with a DSM-IV diagnosis of
hypochondriasis were recruited through a newspaper advertisement. Participants
were presented with a survey which included balanced descriptions of both a
medication and a cognitive-behavioral treatment for intense illness concerns
(hypochondriasis). The brief descriptions of the treatments discussed the time
commitment required as well as the major advantages and disadvantages of each.
Results showed that, relative to medication treatment, cognitive-behavioral
treatment was predicted to be more effective in both the short and long terms and
was rated as more acceptable. Psychological treatment was indicated as the first
choice by 74% of respondents, medication by 4%, and 22% indicated an equal
preference. Forty-eight percent of respondents would only accept the
psychological treatment.
PMID- 10759323
TI - A reattributional training program as a therapeutic strategy for fear of flying.
AB - In this study the results for the validation of a reattributional training
program applied to the fear of flying are presented. The program is made up of 13
(+/- 1) sessions and consists of three phases: Information; reattributional
training; and the elaboration and application of the treatment designed by the
patient with the help of the therapist. The program was applied to 24 patients
while 24 other patients made up the waiting control group. The therapeutic
success was evaluated by means of self-report scales, and by recording
psychophysiological variables in a situation in which subjects viewed a video
tape of a flight. Significant differences were obtained from the ANOVAs between
experimental and control groups in all of the self-reported variables (p < 0.001)
and in some of the psychophysiological variables (p < 0.05). The results support
the effectiveness of the program.
PMID- 10759324
TI - Attention fixation training: training people to form cognitive maps help to
control symptoms of panic disorder with agoraphobia.
AB - Nine individuals diagnosed with panic with agoraphobia received three elements of
Attentional Fixation Training (AFT): Directed attention to the external
environment, directed topographical synthesis, and directed orientation in space
time to control characteristics of panic. They then walked a standard 2.5 km
route and practiced these elements upon entering one of the five panic-inducing
situations: (a) walking alone near a busy street with the examiner following at
20 m, (b) walking alone near a busy street with the examiner out of client's
visual field, (c) shopping with the examiner present, (d) traveling on a bus
alone, and (e) shopping alone. Heart rate was monitored in each of these five
situations. Except for the case of using public transport, heart rate activity
decreased to a considerable extent during AFT practice suggesting AFT elements
provided a good way to control symptoms of panic in vivo. Results were discussed
within the confines of a model suggesting that an attentional deficit, which
produces a spatial disorientation disorder that maintains both panic and
agoraphobia, can efficiently be overcome by means of all three AFT tools.
PMID- 10759326
TI - Fear of cognitive dyscontrol in relation to depression symptoms: comparisons
between original and alternative measures of anxiety sensitivity.
AB - Previous research has found that a facet of anxiety sensitivity (AS), referred to
as fear of cognitive dyscontrol or fear of mental incapacitation, is associated
with severity of depressed mood. Other research has extended the "fear of fear"
concept to include fear of losing control over emotion in general (including
depression). Because anxiety and depression share the common feature of general
distress (Clark & Watson, 1991. Journal of Abnormal Psychology, 93, 19-30), the
present study took a conservative approach and statistically controlled for the
effect of trait anxiety and negative affectivity before contributions of AS to
depression were examined. In a large college student sample (N = 348), facets of
the original and alternative measures of AS were evaluated in attempts to predict
severity of depression symptoms. Fear of cognitive dyscontrol facets from both
measures of AS were significant predictors in the regression analyses. A new set
of items reflective of control over emotions was also significant and both
cognitive and emotional control added to the prediction of depression symptoms in
a complementary fashion. Implications of these findings for identifying a
proposed "depression sensitivity" are discussed.
PMID- 10759325
TI - Comparing the effectiveness of similar and dissimilar competing responses in
evaluating the habit reversal treatment for oral-digital habits in children.
AB - In the present study 26 children with chronic oral-digital habits were randomly
assigned to 1 of 3 conditions. Group 1 received habit reversal using a similar
competing response. Group 2 received habit reversal using a dissimilar competing
response, and Group 3 served as a wait-list control group. Three videotaped
observations were taken at pretreatment and again at posttreatment. In addition,
social acceptability data were collected on the treatment groups at
posttreatment. Results showed that the similar and dissimilar groups were
engaging in significantly less oral-digital behavior at posttreatment when
compared to the control group. However, the two treatment groups did not differ
from each other in terms of treatment gains or acceptability. These results
suggest that habit reversal is an effective treatment for oral digital habits in
children. In addition, it appears that the competing response does not function
as a physically incompatible behavior. Implications of the findings are
discussed.
PMID- 10759327
TI - The successful treatment of long-term selective mutism: a case study.
AB - This study describes the successful treatment of a seventh grade boy who had
selective mutism in school since kindergarten. Treatment consisted of systematic
desensitization, consultation with school personnel, and training in social
speaking skills. The student made significant gains with respect to frequency of
verbalizations to teachers and peers, number of individuals spoken to, anxiety
related to speaking, school attendance, and involvement in school-based
extracurricular activities. At one year follow-up, the student's rate of speech
was indistinguishable from his classmates'. Special issues concerning the
treatment of long-term selective mutism are discussed.
PMID- 10759328
TI - Cognitive behavior therapy for chronic fatigue syndrome: a case study.
AB - The case of a 26-year old woman with Chronic Fatigue Syndrome (CFS) is presented.
Multidimensional assessment showing severe debilitating fatigue and considerable
psychological, social and occupational impairment confirmed the diagnosis.
Cognitive behavior therapy (CBT) was based on a tested causal model of CFS and
individual behavioral analyses. Key elements in CBT were process variables from
the CFS model, like sense of control, causal attributions, physical activity and
focusing on bodily functions. Goals were recovery from fatigue, returning to work
and relapse prevention. The course of therapy is described in detail to
illustrate difficulties in treating CFS. Assessments were made five times, at
baseline and at 8, 14, 21 and 33 months. Comparison of the pretest, post-test and
follow-up scores of the outcome variables, fatigue and functional impairment and
of the process variables showed clinically significant improvement from the range
of CFS patients to the range of healthy controls.
PMID- 10759329
TI - The complex association of pulmonary function with panic disorder: a rejoinder to
Ley (1998).
AB - In a commentary on our paper entitled "Pulmonary function in panic disorder:
evidence against the dyspnea-fear theory", Ley (1998) provides a critical
analysis of our study. He concludes that our failed attempt to replicate a
relationship between pulmonary function and the severity of panic-related
symptoms in panic disorder patients may have been a consequence of a lack of
comparability between studies, a statistical anomaly, and experimenter-demand
effects. After discussing his comments (with most of them we do not agree) in
depth, we maintain our conclusion that: (a) pulmonary impairment is not directly
associated with panic symptoms; and (b) that the existence of a distinct subgroup
of panic disorder patients with signs of actual airways obstruction leading to
uncontrollable dyspnea and fear of suffocation remains questionable.
PMID- 10759330
TI - The role of heart rate in the modulation of the decreased cardiac output induced
by acute nitric oxide synthesis inhibition in anaesthetized dogs.
AB - 1. The role of the heart rate modulating the decrease in cardiac output induced
by the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L
NAME) was investigated in anaesthetized dogs. This was achieved in dogs in which
a positive pacemaker (PM) cable was located at the right ventricle. 2. The
haemodynamic events were evaluated: mean arterial blood pressure (MABP), systemic
vascular resistance index (SVRI), stroke volume index (SVI), heart rate (HR) and
cardiac index (CI). 3. The infusion of L-NAME (0.01-10 mg kg(-1)) in the animals
with the PM off caused a dose-dependent rise in MABP and SVRI, accompanied by
significant decreases of HR and SVI. A resulting decrease in CI was observed at
all doses of L-NAME used. 4. In the animals with the PM on, HR was maintained
stable. Under this condition, the increase in MABP and SVRI as well as the
decrease in SVI induced by the L-NAME infusion did not significantly differ from
the PM-off animals. However, the resulting decreased CI was markedly attenuated
compared to PM-off animals but significant decreases in CI were still observed at
higher doses of L-NAME. 5. The results suggest that HR plays an important role in
the L-NAME-mediated decreased cardiac output but other factors might also be
involved.
PMID- 10759331
TI - Comparison of the effects of nitric oxide synthase, guanylate cyclase and
potassium channel inhibition on vascular contractions in vitro in the rat.
AB - 1. We have investigated the differences between the nitric oxide synthase
inhibitor L-NMMA, the guanylate cyclase inhibitor methylene blue and the
potassium channel blockers apamin and charybdotoxin or apamin and iberiotoxin, in
their abilities to increase vasoconstrictor responses in rat small mesenteric
arterial rings. 2. When administered during the maintained contraction to
PGF2alpha (10 microM), L-NMMA (100 microM) or the combination of apamin (0.7
microM) and charybdotoxin (0.1 microM) significantly increased the contractile
response. Methylene blue (10 microM) increased the contraction, but this did not
reach significance. However, apamin (0.7 microM) and iberiotoxin (0.1 microM)
also significantly increased the contractile response. 3. The combination of L
NMMA or methylene blue with apamin/charybdotoxin produced significantly greater
increases in the contractile response to PGF2alpha than achieved individually. 4.
Relaxations to acetylcholine (10 microM) were significantly reduced by L-NMMA or
methylene blue but not by apamin in combination with charybdotoxin or
iberiotoxin. 5. Since apamin/iberiotoxin had similar effects to
apamin/charybdotoxin, it is likely that the actions of these agents involve
direct actions on smooth muscle potassium channels rather than inhibition of
endothelium-derived hyperpolarising factor (EDHF). These results suggest that
endothelium-derived nitric oxide but not EDHF has a major role in modulating
vascular tone under these conditions.
PMID- 10759332
TI - Endothelium-dependent vasodilatation mechanisms by histamine in simian but not in
canine femoral arterial branches.
AB - 1. The vascular response of isolated, perfused canine and simian femoral
arteries, which distribute blood to deep skeletal muscles, were investigated. 2.
The vascular responses to histamine, 2-pyridylethylamine (2-PEA), dimaprit and
alpha-methylhistamine were pharmacologically analyzed in canine and simian
vessels, using diphenhydramine (DPH, a histamine H1 receptor antagonist),
cimetidine (a histamine H2 antagonist) and saponin which readily removed the
endothelium. 3. In canine arteries, alpha-methylhistamine showed no vascular
response, but in simian preparations, it caused a slight vasoconstriction. 4. In
canine arteries, histamine and 2-PEA consistently induced a vasoconstriction in
preconstricted and non-preconstricted preparations. However, in simian arteries
histamine usually produced a vasodilatation at small doses (less than 10(-7) mol)
and a vasoconstriction at large doses in preconstricted preparations. 5.
Vasoconstrictor responses to histamine and 2-PEA were significantly inhibited by
DPH in both species. In simian vessels, histamine- and dimaprit-induced
vasodilatations were significantly inhibited by cimetidine. 6. After removal of
the endothelium by intraluminal treatment with saponin in canine femoral
arteries, the vascular responses to histamine, 2-PEA and dimaprit were not
significantly affected. On the other hand, in simian femoral arteries, the
vasodilatation responses to histamine and 2-PEA were significantly depressed by
the removal of endothelium. 7. It is concluded that (1) in both simian and canine
femoral arterial branches, there are abundant histamine H1 and H2 receptors (2)
in simian but not in canine arteries, there exist histamine H3 receptors,
although their role is not clear (3) histamine induces a vasoconstriction
mediated via histamine H1 receptors and a vasodilatation via H2 receptors which
exist in vascular smooth muscle, and (4) in simian but not in canine arteries,
there are endothelium-dependent vasodilatation mechanisms.
PMID- 10759333
TI - Enhancement of acetylcholine-induced desensitization of guinea-pig ileal
longitudinal muscle in Ca2+-free conditions.
AB - 1. To determine the role of cellular Ca2+ in desensitization, acetylcholine(ACh)
induced desensitization was studied under Ca2+-free condition in guinea-pig ileal
longitudinal muscle. 2. Pretreatment of the tissue with 10(-4) M ACh
(desensitizing treatment) in normal Tyrode solution caused desensitization of the
responses both to ACh and histamine. The desensitizing treatment performed in
Ca2+-free solution enhanced desensitization of the responses to ACh and histamine
significantly. 3. The desensitizing treatment with ACh caused suppression of the
responses to high K+ (tonic component) and Bay K 8644. The desensitizing
treatment performed in Ca2+-free solution potentiated the suppression of the
responses to high K+ and Bay K 8644 significantly. 4. ACh-induced desensitization
was enhanced significantly in the presence of a protein kinase C inhibitor, 1-(5
isoquinolinesulfonyl)-2-methylpiperazine(H-7, 10(-4) M) to a similar extent as
desensitization obtained under Ca2+-free condition, but not in the presence of a
non-specific and less potent kinase inhibitor, N-(2-guanidinoethyl)-5
isoquinolinesulfonamide hydrochloride (HA1004, 10(-4) M). 5. These results
suggested that voltage-gated Ca2+ channels were involved in ACh-induced
desensitization and that intracellular Ca2+, which was increased during the
stimulation with ACh, inhibited desensitization through the activation of protein
kinase C. This kinase could have activated or protected Ca2+ channels during the
desensitization process to reduce desensitization.
PMID- 10759334
TI - The effects of histamine on the isolated mouse uterus.
AB - 1. A study is made of the contractile and relaxant effects, and mechanism of
action, of histamine on isolated uterus from mice treated with
diethylstilboestrol, employing acetylcholine and adrenaline as contractile and
relaxant standard agents. 2. Concentration-response curves for histamine agonists
were obtained in the absence and presence of selective histaminergic blocking
drugs (clemizole, ranitidine and thioperamide) and indomethacin. A number of
experiments were carried out in uterus from reserpinised mice. Concentration
response curves for acetylcholine and adrenaline were also obtained in the
absence and presence of their selective antagonist (atropine and propranolol). 3.
In isolated oestrogenised mouse uterus, histamine and acetylcholine produced a
concentration-related contractile response. When the uterus was precontracted
with KCl, histamine at lower doses produced a slight contraction, though in the
presence of clemizole it induced concentration-related relaxation, reminiscent of
that produced by adrenaline. Atropine and propranolol antagonised the contractile
and relaxant effects of acetylcholine and adrenaline, respectively. 4. In
isolated uterus from reserpinised mice, histamine and 2-pyridylethylamine, but
not 4-methylhistamine, produced a concentration-related contractile response.
Ranitidine potentiated the contractile effect of histamine, though clemizole--in
the presence of ranitidine--competitively antagonised the contractile effect of
histamine (pA2 = 10.50 +/- 0.81). The concentration-relaxant curve of histamine
in the presence of clemizole was not modified by ranitidine or indomethacin, but
shifted to the right with thioperamide. The same displacement was also observed
in the presence of clemizole plus ranitidine. 5. In mouse isolated uterus,
histamine mainly produced contraction mediated by histamine H1-receptors, though
the existence of histamine H2- or H3-receptors mediating relaxation could not be
excluded.
PMID- 10759335
TI - Vascular actions of 17beta-oestradiol in rat aorta and mesenteric artery.
AB - 1. It has been proposed that the cardiovascular protective actions of 17beta
oestradiol may involve calcium antagonistic actions. We have examined the effects
of 17beta-oestradiol on contractions to noradrenaline and KCl in male rat small
mesenteric artery and aorta. 2. In rat mesenteric artery, 17beta-oestradiol (10
microM) significantly reduced the maximum contraction to noradrenaline (67.7 +/-
5.8% of control) and KCl (38.8 +/- 3.1% of control) without affecting potency. 3.
In rat aorta, 17beta-oestradiol (10 microM) also significantly reduced
contractions to noradrenaline (77.5 +/- 4.8% of control), and the effects were
mimicked by droloxifene (10 microM). The effect of oestrogen was not prevented by
the protein synthesis inhibitor cycloheximide (10 microM). In experiments carried
out in calcium-free solution in which calcium stores were depleted, 17beta
oestradiol (10 microM) significantly reduced the contraction to calcium
restoration in rat aorta. 4. In aorta from female rats, 17beta-oestradiol (10
microM) significantly reduced contractions to noradrenaline (73.6 +/- 10.8% of
control), but this effect of oestrogen was not prevented by cycloheximide (10
microM). 5. In summary, 17beta-oestradiol diminishes the maximum contractile
response to noradrenaline in both rat small mesenteric artery and aorta, an
effect which at least in the aorta is mimicked by the oestrogen receptor
antagonist/partial agonist droloxifene, and may be due to restriction of calcium
entry by a nongenomic action.
PMID- 10759336
TI - Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized,
controlled study in mild-moderate depression.
AB - Treatment with St John's wort extract tablets (hypericum Ze 117) and the commonly
used slow serotonin reuptake inhibitor (SSRI) fluoxetine was compared in patients
with mild-moderate depression with entry Hamilton Depression Scale (HAM-D) (21
item) in the range 16-24, in a randomized, double-blind, parallel group
comparison in 240 subjects; fluoxetine: 114 (48%), hypericum: 126 (52%). After 6
weeks' treatment, mean HAM-D at endpoint decreased to 11.54 on hypericum and to
12.20 on fluoxetine (P < 0.09), while mean Clinical Global Impression (CGI) item
I (severity) was significantly (P < 0.03) superior on hypericum, as was the
responder rate (P = 0.005). Hypericum safety was substantially superior to
fluoxetine, with the incidence of adverse events being 23% on fluoxetine and 8%
on hypericum. The commonest events on fluoxetine were agitation (8%), GI
disturbances (6%), retching (4%), dizziness (4%), tiredness, anxiety/nervousness
and erectile dysfunction (3% each), while on hypericum only GI disturbances (5%)
had an incidence greater than 2%. We concluded that hypericum and fluoxetine are
equipotent with respect to all main parameters used to investigate
antidepressants in this population. Although hypericum may be superior in
improving the responder rate, the main difference between the two treatments is
safety. Hypericum was superior to fluoxetine in overall incidence of side
effects, number of patients with side-effects and the type of side-effect
reported.
PMID- 10759337
TI - Multicentre, double-blind, comparison of fluvoxamine and clomipramine in the
treatment of obsessive-compulsive disorder.
AB - The aim of this prospectively randomized, double-blind, parallel group,
multicentre study was to compare the efficacy and tolerability of fluvoxamine and
clomipramine in patients suffering from obsessive-compulsive disorder (OCD) (DSM
III-R). Fourteen centres participated in this trial. Sixty-eight patients were
randomized to receive fluvoxamine and 65 to receive clomipramine. The duration of
the study was 10 weeks. The two treatment groups showed a marked improvement of
obsessive-compulsive symptomatology, as determined by the Yale-Brown Obsessive
Compulsive Scale, the National Institute of Mental Health Obsessive-Compulsive
Global Scale and Clinical Global Impression. No statistically significant
differences were found between fluvoxamine and clomipramine in terms of efficacy
during the study. A similar number of patients in each group withdrew from the
study prematurely, but there were more dropouts due to adverse events in the
clomipramine group. Concerning tolerability, there were significantly more
reports of constipation and dry mouth in the clomipramine group. The results show
that fluvoxamine and clomipramine have similar efficacy in the treatment of
patients suffering from OCD, but fluvoxamine is better tolerated. In view of the
superior safety profile of fluvoxamine compared to clomipramine in terms of a
risk-benefit assessment, the use of fluvoxamine would appear to be advantageous
for this patient population.
PMID- 10759338
TI - Dosage of conventional neuroleptic medication and subjective cognitive
functioning in schizophrenia.
AB - Subjective cognitive and perceptual disturbances as assessed with the Frankfurt
Complaint Questionnaire (FCQ) were correlated with chlorpromazine equivalents in
40 schizophrenic inpatients, who were treated with conventional neuroleptics. In
line with previous research using 'objective' neuropsychological tests, both
correlations and partial correlations (controlling for the effects of
psychopathology, extrapyramidal symptoms and length of illness) confirmed that
higher neuroleptic doses significantly worsen several cognitive and perceptual
domains (r = 0.44 -0.54; P < or = 0.005 -0.05) with the possible exception of
mnestic functions (r = 0.21 -0.24, n.s.) and language (r = 0.37 -0.38, P < 0.1).
The clinical importance of self-report scales for evaluating both the risks and
benefits of neuroleptic treatment is discussed.
PMID- 10759339
TI - The effect of citalopram treatment on platelet serotonin function in panic
disorders.
AB - We investigated the effect of the selective serotonin reuptake inhibitor (SSRI)
citalopram after 6-8 weeks and 6 months of treatment on clinical and peripheral
indexes for central serotonergic function: platelet [14C]serotonin uptake and
[3H]paroxetine- and [3H]LSD-binding to platelets membranes in 33 patients with
panic disorder. Basal data from patients were compared with data from a control
material consisting of 33 healthy volunteers. Bmax for platelet [3H]paroxetine
binding was significantly lower in patients than in controls. There were no
differences in serotonin uptake or [3H]LSD-binding between patients and controls.
The degree of anxiety and depression was assessed using the Beck Anxiety
Inventory (BAI) and Beck Depression Inventory self-assessment scales, and the
Clinical Anxiety Scale and the Montgomery Asberg Depression Rating Scale for
clinical evaluation. Complete remission was found in one third of the patients
after 6-8 weeks and in two-thirds after 6 months of treatment. The reduction in
assessment scores was parallelled with similar reductions in platelet 5-HT2
receptor density, [3H]LSD affinity variable (Kd) and Vmax for platelet [14C]5-HT
uptake. Citalopram treatment did not alter Bmax and Kd for platelet
[3H]paroxetine-binding. A positive correlation was found between Vmax for the
platelet [14C]5-HT uptake and BAI after 6 months citalopram treatment. The
present study shows that citalopram has a therapeutic effect in panic disorders.
A prerequisite of responding to treatment might be plasticity in the serotonergic
system.
PMID- 10759340
TI - Changes in the platelet intracellular calcium response to serotonin in patients
with major depression treated with electroconvulsive therapy: state or trait
marker status.
AB - Platelet serotonin type 2A receptor (5-HT2A) sensitivity changes have previously
been documented in depression, although it is unclear if this represents a stable
trait marker of the illness, or whether it represents an acute state marker of
depression that would change with treatment. Electroconvulsive therapy (ECT) may
be a useful intervention to separate out trait and state marker status avoiding
the potential confounding effects of pharmacotherapy on receptor function. Using
spectrofluorometry, the platelet 5HT2A, receptor sensitivity as reflected by the
intracellular calcium response to serotonin stimulation, was measured every week
in patients suffering from major depression and undergoing ECT. There was a
significant drop in the platelet response to serotonin stimulation over a course
of ECT, with an associated progressive decrease in Hamilton Rating Scale of
Depression (HAM-D) scores. This may suggest either decreased sensitivity of
platelet 5HT2A receptors as a mechanism of action of ECT, or changes in second
messengers such as the inositide phospholipid system. This suggests that the
enhanced sensitivity of platelet 5HT2A receptors may be a state marker of major
depression.
PMID- 10759341
TI - Long-term pharmacological treatment of generalized anxiety disorder.
AB - Generalized anxiety disorder (GAD) is one of the most common anxiety disorders
and has a poor prognosis, although it is often thought to be a minor complaint.
This disorder has a chronic course of 5-15 years and longer. Long-term treatment
with the commonly used benzodiazepines is controversial because of concerns over
tolerance and dependence. We performed a thorough search of the literature for
clinical trials of a duration of over 2 months conducted in patients with
generalized anxiety disorder in order to identify any successful long-term
treatment of this disorder. Only eight long-term reports of studies conducted in
well-defined homogeneous groups of patients diagnosed with generalized anxiety
disorder were found with the methodology of these studies presenting a number of
limiting factors. The results are inconclusive and no reference drug could be
identified. In addition, an adequate evaluation of the long-term treatment of GAD
has not yet been performed.
PMID- 10759342
TI - Cost-effectiveness of fluoxetine plus pindolol in patients with major depressive
disorder: results from a randomized, double-blind clinical trial.
AB - Some preliminary studies have suggested that the beta-adrenoceptor 5-HT1A
antagonist pindolol (PIN) could increase the effect of selective serotonin
reuptake inhibitors (SSRIs). We prospectively estimated the cost-effectiveness of
fluoxetine and pindolol versus fluoxetine plus placebo, using results from the
first double-blind randomized clinical trial comparing both treatments. Efficacy
and medical care resource utilization were collected prospectively in a parallel,
randomized, double-blind clinical trial conducted in a single centre in Spain.
Average cost-effectiveness (cost/% response and cost/% remission) as well as the
incremental cost-effectiveness were calculated for both treatments. A 'bootstrap'
method was used to calculate confidence limits around the incremental cost
effectiveness ratio. A significantly greater percentage of patients (one-tailed P
< 0.05) in the fluoxetine FLX + PIN group than in the FLX + PLA group had
experienced a therapeutic response (74.5% versus 58.97%) at 6 weeks. Direct
medical costs were lower in the FLX + PIN group (mean 2508 pesetas per patient)
than in the FLX + PLA group (mean 31870 pesetas per patient). Hospital admissions
due to worsening of depressive symptoms were significantly lower (P < 0.05) in
the FLX + PIN group (0/55) than in the FLX + PLA group (4/56). The observed
differences in average costs and percentage response in the study were -29362
pesetas (< 0) and 15.6% (> 0), respectively, and the resulting cost-effectiveness
ratio was negative. These outcomes indicate that the FLX + PIN option completely
dominates FLX + PLA. These results suggest that, over a course of 6 weeks of
treatment, the combination of fluoxetine and pindolol incurs lower direct medical
costs than treatment with fluoxetine placebo. Despite their limitations, economic
assessments in addition to clinical trials allow a 'dynamic assessment' on the
potential success of the drug, both from a clinical and an economic point of
view, allowing decisions on priorities to be made earlier.
PMID- 10759343
TI - Bupropion-induced isolated impairment of sensory trigeminal nerve function.
AB - Bupropion is increasingly used for nicotine withdrawal and in the treatment of
major depression, especially in bipolar patients. We present the case of a 38
year-old female schizoaffective, rapid-cycling patient treated with bupropion for
a depressive episode. After 4 weeks of successful treatment (300 mg/day), the
patient developed a circumscribed unilateral impairment of sensory trigeminal
nerve function. Symptoms completely recovered after discontinuation of bupropion.
When re-exposed to bupropion, mild symptoms reappeared, leading to final
discontinuation of bupropion. With this natural on-off-on-off design, a causative
role of bupropion for trigeminal impairment in this patient can be assumed. To
our knowledge, a similar side-effect of bupropion has not been described to date.
PMID- 10759344
TI - Treatment of Charles Bonnet syndrome with valproate.
AB - Charles Bonnet syndrome (CBS), as described in the psychiatric literature, refers
to pseudohallucinations in elderly people who frequently suffer from reduced
visual acuity. There is no established treatment for CBS. We report two cases
involving elderly women with CBS who were successfully treated with valproate.
The present results suggest that valproate can be useful for CBS in some
patients.
PMID- 10759345
TI - Non-Asian hepatocellular carcinoma: correlation between histologic features and
echogenicity.
AB - Studies of hepatocellular carcinoma in Asia have revealed a correlation between
lesion hyperechogenicity and five histologic features: nonliquefied necrosis,
sinusoidal dilatation, hemorrhage, fatty metamorphosis, and fibrosis. However,
this correlation has not been investigated for non-Asian hepatocellular
carcinoma, despite substantial differences between the Asian and non-Asian forms
of this carcinoma. We retrospectively reviewed records of 29 patients seen at one
United States institution who had hepatocellular carcinoma lesions that were
either completely hyperechoic or completely hypoechoic. Tissue specimens obtained
surgically (n = 7) or percutaneously (n = 22) were evaluated microscopically for
the presence of nonliquefied necrosis, sinusoidal dilatation, hemorrhage, fatty
metamorphosis, and fibrosis. A statistically significant correlation was
identified between the number of histologic features identified and lesion
diameter (P = 0.04) but not between the number of histologic features identified
and the likelihood of hyperechogenicity (P = 0.11). Two lesions (50%) with three
histologic features, four lesions (40%) with two histologic features, and six
lesions (55%) with one histologic feature were hypoechoic. The echogenicity of
non-Asian hepatocellular carcinoma lesions cannot be attributed to the histologic
features that are believed to underlie echogenicity of the Asian type of
hepatocellular carcinoma.
PMID- 10759347
TI - Obstetric fistula: evaluation with ultrasonography.
AB - Twenty-two patients with 24 fistulae were examined prospectively with real-time
sonography. Sonographic findings were compared with those of intravenous urograms
and correlated with the findings at examination under anesthesia and at surgery.
Various genital abnormalities not revealed by intravenous urography were
demonstrated by sonography preoperatively. These included cervical injuries,
vesicovaginal fistula showing "flat tire" sign and hourglass deformities, and
identification of the site, size, and course of fistulae in seven (29%) of the
cases. However, the demonstration of the fistulae by sonography is poor relative
to that of examination under anesthesia, in which 21 (87%) of the fistulae were
identified. The factors responsible for the difficulty in demonstrating the
fistulae on sonography, which included size and multiplicity, are discussed.
Sonography is complementary to examination under anesthesia in preoperative
evaluation of the patients with obstetric fistulae in general and in those with
previous unsuccessful repairs in particular.
PMID- 10759346
TI - Is a full bladder still necessary for pelvic sonography?
AB - The objective was to determine whether a full bladder is routinely necessary for
a complete sonographic evaluation of the female pelvis. Over the course of 1
month, all women having a gynecologic sonogram were scanned initially
transabdominally through a full bladder by the sonographer (standard images
taken). A physician then joined the sonographer and scanned the patient
transvaginally without prior knowledge of the findings seen transvesically. The
physician finished the examination transabdominally, with the bladder empty. The
physician and sonographer then determined (1) whether the scan was sufficient
transvaginally only, (2) whether the scan was sufficient transvaginally and
transabdominally with an empty bladder, or (3) or whether a full bladder was
necessary. Two hundred and six consecutive patients were scanned prospectively.
The transvaginal scan alone was sufficient to demonstrate all findings for 172
(83.5%) patients. The transvaginal and transabdominal scans through an empty
bladder were needed for 31 (15.1%) patients. Three patients (1.5%) required a
full bladder in addition to the other two techniques to visualize one normal
ovary each. In conclusion, transvaginal scanning with an adjunctive
transabdominal empty bladder approach can replace the full bladder technique for
routine pelvic sonography. The transabdominal scan with an empty bladder is
necessary, particularly for patients with enlarged uteri. It is no longer
reasonable, however, to subject all patients undergoing pelvic sonography to
bladder distention.
PMID- 10759348
TI - Use of quantitative ultrasonography in differentiating osteomalacia from
osteoporosis: preliminary study.
AB - The aim of this work was to use ultrasonographic technology to differentiate
osteoporosis from osteomalacia on the basis of different patterns of the graphic
trace. Three patients with osteomalacia and three with osteoporosis, all with the
same lumbar spine bone mineral density, were studied. The velocity of the
ultrasound beam in bone was measured by a DBM Sonic 1,200/I densitometer at the
proximal phalanges of the hands in all the patients. The ultrasound beam velocity
was measured when the first peak of the waveform reached a predetermined minimum
amplitude value (amplitude-dependent speed of sound) as well as at the lowest
point prior to the first and second peaks, before they reached the predetermined
minimum amplitude value (first and second minimum speeds of sound). The graphic
traces were further analyzed by Fourier analysis, and both the main frequency
(f0) and the width of the peak centered in the f0 (full width at half maximum)
were measured. The first and second minimum speeds of sound were significantly
lower in the patients with osteomalacia than in the osteoporosis group. The first
minimum speed of sound was 2,169 +/- 73 m/s in osteoporosis and 1,983 +/- 61 m/s
in osteomalacia (P < 0.0001); the second minimum peak speed of sound was 1,895 +/
59 m/s in osteoporosis and 1,748 +/- 38 m/s in osteomalacia (P < 0.0001). The f0
was similar in the two groups (osteoporosis, 0.85 +/- 0.14 MHz; osteomalacia, 0.9
+/- 0.22 MHz; P = 0.72), and the full width at half maximum was significantly
higher in the osteomalacia patients (0.52 +/- 0.14 MHz) than in the osteoporosis
patients (0.37 +/- 0.15 MHz) (P = 0.022). This study confirms that
ultrasonography is a promising, noninvasive method that could be used to
differentiate osteoporosis from osteomalacia, but further studies should be
carried out before this method can be introduced into clinical practice.
PMID- 10759349
TI - Metastatic tumors to the breast: mammographic and ultrasonographic findings.
AB - We evaluated the mammographic (n = 16) and ultrasonographic (n = 15) findings of
18 patients with metastatic breast carcinoma. Fifteen patients showed multiple or
diffuse lesions and three patients showed single lesions. Ten patients (55.6%)
had bilateral lesions. Mammography revealed high density (15 cases, 93.8%), round
to oval (11 cases, 68.8%) lesions with poorly defined or obscured margins (12
cases, 75.0%). No associated calcification was found in any lesion.
Ultrasonographically, poorly defined (8 cases, 53.3%), irregularly shaped (8
cases, 53.3%), hypoechoic (14 cases, 93.3%), heterogeneous (8 cases, 53.3%)
lesions were predominantly distributed superficially (11 cases, 73.3%). Axillary
lymphadenopathy was detected in six patients (33.3%). The longest diameter of
most of the lesions was less than 2.0 cm (13 cases, 81.3%). We conclude that
metastatic tumors to the breast appear as relatively small, superficially
located, poorly defined, irregular nodules without calcification on mammography
and ultrasonography. However, when the metastatic lesion is diffuse, the
appearance is indistinguishable from that of inflammatory breast carcinoma.
PMID- 10759351
TI - Transrectal ultrasonography of distal ureteral calculi: comparison with
intravenous urography.
AB - In a prospective fashion, transrectal ultrasonography and intravenous urography
were performed in 48 patients with distal ureteral calculi. We compared the
ability of the two modalities to detect calculus and to determine the size of the
calculus, the degree of obstruction, and the degree of hydroureter. In 11 cases
(23%), the calculus was not seen at intravenous urography, while transrectal
ultrasonography detected calculus in each patient. In 37 cases in which calculi
were detected by both modalities, the average diameter of the calculus determined
by ultrasonography was significantly larger (P < 0.05) than that obtained by
plain radiography. Positive correlations were obtained in the assessment of
degree of obstruction (correlation coefficient = 0.587, P < 0.05) and hydroureter
(correlation coefficient = 0.794, P < 0.05) between the two techniques.
Transrectal ultrasonography appears to be a useful adjunctive method to evaluate
distal ureteral calculus, particularly if the results of intravenous urography
are inconclusive.
PMID- 10759350
TI - Imaging in the diagnosis and follow-up evaluation of vertebral artery dissection.
AB - The purpose of this report is to discuss the value of ultrasonographic
examination in the diagnosis and follow-up evaluation of vertebral artery
dissection. We collected data on 8 patients with 11 pathologic vessels: 9 were
affected intracranially and 6 were affected extracranially. Four vessels were
affected in both intracranial and extracranial segments. Extracranial color-flow
duplex sonography could detect abnormalities in every extracranial vertebral
artery dissection. Most abnormal findings were non-specific, including severely
reduced flow, absence of flow, and absence of diastolic flow. A specific finding
(intramural hematoma) was noted in one artery. Abnormal transcranial color-coded
sonographic findings included absence of flow, reduced velocity and reversed flow
direction. Three intracranial dissecting arteries showed normal findings on
transcranial color-coded sonography. Ultrasonographic follow-up study revealed
evidence of improvement; this was noted almost exclusively in the extracranial
segments of the vertebral artery but infrequently in the intracranial segment.
Extracranial color-flow duplex sonography is sensitive in the detection of
extracranial vertebral artery dissection, both in initial diagnosis and in follow
up evaluation.
PMID- 10759352
TI - Renal artery aneurysm: evaluation with color Doppler ultrasonography before and
after percutaneous transarterial embolization.
PMID- 10759353
TI - Conservative management of an extrarenal pseudoaneurysm after percutaneous needle
biopsy of a renal allograft.
PMID- 10759355
TI - Prenatal sonographic depiction of fetal mediastinal immature teratoma.
PMID- 10759354
TI - Prenatal sonographic findings in fetal cirrhosis secondary to hemochromatosis.
PMID- 10759356
TI - Group A beta-haemolytic streptococcal (GABHS) tonsillopharyngitis is still a
common problem.
PMID- 10759357
TI - Group A streptococci in the 1990s.
AB - The last decade has witnessed a remarkable change in the epidemiology of group A
streptococcal infections. There has been a marked increase globally in the
reporting of invasive infections caused by Streptococcus pyogenes, Lancefield
group A streptococci. Many of these cases were deep-seated infections associated
with shock and multi-organ failure and are defined as streptococcal toxic shock
syndrome. In addition, reports of streptococcal sequelae, in particular, acute
rheumatic fever, have re-emerged and remain a serious health threat in developed
countries. It appears that these infections are related to the type distributions
of the organism among the general population, with the re-emergence of more
'virulent' strains, such as the M1 serotype which in earlier decades was
primarily seen in cases of either superficial disease or scarlet fever.
Population-based surveillance studies have clearly indicated the importance and
relevance of type identification for epidemiological purposes. There have also
been suggestions that certain extracellular products and toxins play a major role
in the so-called 'increased virulence' of the organism; these include cell
surface molecules such as the M protein, opacity factor, the hyaluronic acid
capsule, C5a peptidase and streptococcal inhibitor of complement (SIC), in
addition to secreted proteins, pyrogenic exotoxins, cysteine proteinase,
streptolysins O and S, hyaluronidase, streptokinase and other enzymes. All these
factors, and events during the last decade, strongly emphasize the need for a
better understanding of the epidemiology, pathogenesis, treatment and prevention
of group A streptococcal infections.
PMID- 10759358
TI - Rheumatic fever--is it still a problem?
AB - The incidence of rheumatic fever has declined in industrialized countries since
the 1950s and now has an annual incidence of around 0.5 cases per 100,000
children of school age. In developing countries it remains an endemic disease
with annual incidences ranging from 100 to 200 per 100,000 school-aged children
and is a major cause of cardiovascular mortality. Interest in the pathogenesis of
rheumatic fever was rekindled by outbreaks in the USA (1985-1987) and the rare
cases still seen in industrialized countries. The current concept is that the
disease results from the host's poorly adapted autoimmune response to group A
beta-haemolytic streptococci. The risk of developing rheumatic fever following
untreated tonsillopharyngitis is 1% in the civilian population. Knowledge of
virulence factors has been greatly enriched by progress in molecular biology. One
of the key elements is protein M, a surface protein on the bacterial wall which
carries specific epitopes. Several serotypes which lead to rheumatic fever have
been recognized among more than 80 identified serotypes. However, the reason why
specific strains within a given serotype have increased rheumatogenic virulence
remains unknown. The causal strain adheres to the oral and pharyngeal cells and
then releases its degradation products. These products present antigenic
determinants which cross-react with certain human tissues, particularly in
cardiac valve tissue and myocardium. Diagnosis is now difficult owing to the low
incidence. Late diagnosis can have serious consequences and acute rheumatic fever
is a therapeutic emergency requiring immediate antibiotic and anti-inflammatory
treatment. In most of Europe there is tacit agreement that all cases of
pharyngitis and tonsillitis should be treated with antibiotics without
identification of the causal agent despite the fact that only about 20% of the
cases are caused by group A beta-haemolytic streptococci, and could lead to
rheumatic fever.
PMID- 10759359
TI - Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral
penicillin V regimen in the treatment of tonsillopharyngitis.
AB - Oral penicillin V given three times daily in doses of 50,000-100,000 IU daily has
been the standard treatment for tonsillopharyngitis for the last few decades.
These regimens, initially recommended by the American Heart Association, were
extrapolated from i.v. dosing with long-acting forms of penicillin which had been
shown to prevent post-streptococcal sequelae. More recently, several antibiotics,
including cefuroxime axetil, have been shown to be at least as effective as
penicillin G in eradicating group A beta-haemolytic streptococci (GABHS) but
their influence on post-streptococcal sequelae has never been assessed in a large
scale trial. The German Society for Pediatric Infectious Diseases (DGPI)
undertook a large study of culture-proven tonsillopharyngitis involving several
agents and included a 1 year follow-up to establish the effect on sequelae. In
one arm of this study, cefuroxime 250 mg bid was compared with 50,000 IU
penicillin V given in three divided doses. Cefuroxime axetil was more effective
than oral penicillin V in eradicating GABHS at the assessment 2-4 days post
treatment (441/490 (90%) patients versus 1196/1422 (84%) patients; P = 0.001).
Clinically, the two agents were equivalent in efficacy, and carriage rates were
similar (11.1% and 13.8%, respectively) in patients receiving cefuroxime axetil
and penicillin V, 7-8 weeks post-treatment. One case of glomerular nephritis
occurred in a patient given penicillin V. There were no post-streptococcal
sequelae confirmed for patients treated with cefuroxime axetil. The findings
confirm the previously reported efficacy of short-course (4-5 day) treatments
with cefuroxime axetil and indicate that short-course treatment is comparable to
the standard oral penicillin V regimen in preventing post-streptococcal sequelae.
PMID- 10759360
TI - Treatment of recurrent tonsillopharyngitis.
PMID- 10759361
TI - Recommendations for the housing and care of domestic cats in laboratories.
AB - In recent years, with increasing interest in applied ethology and animal welfare,
research has been carried out on the behaviour and welfare of cats kept in
different environments. These include laboratories, animal shelters, quarantine
and boarding catteries and the home. This article presents a review of this
research, makes recommendations for the housing and care of cats in laboratories,
and comments on existing Codes of Practice.
PMID- 10759362
TI - Orbital sinus blood sampling in rats: effects upon selected behavioural
variables.
AB - The question addressed was whether the behaviour of rats is changed after orbital
sinus blood sampling while they are under diethyl-ether anaesthesia. Twelve rats
were subjected to sham anaesthesia, diethyl-ether anaesthesia and anaesthesia
plus orbital puncture according to a Latin square. After each treatment, the
behaviour of the rats was automatically monitored using the so-called LABORAS
method, which discriminates between grooming, locomotion and inactivity.
Treatment ended, and behaviour monitoring began, when the light period changed
over to the dark period. The various behaviours were quantified as relative
duration and frequency. Anaesthesia versus sham anaesthesia reduced the relative
duration of grooming during the first 5 h after treatment. Anaesthesia plus
orbital puncture versus anaesthesia alone did not significantly influence
grooming, but orbital puncture did reduce the relative duration and the frequency
of locomotion during the entire 20 h period, which was mainly due to a decrease
in the dark period. After orbital puncture, the animals were also less frequently
inactive. It is concluded that orbital puncture has an effect on behaviour
superimposed on that of diethyl-ether anaesthesia. This observation may
contribute new arguments to the debate on the acceptability of the orbital
puncture technique.
PMID- 10759363
TI - The effect of chronic food and water restriction on open-field behaviour and
serum corticosterone levels in rats.
AB - In operant conditioning experiments, two methods are commonly used to motivate
laboratory rats to perform designated tasks. The first is restricting food so
that rats are forced to lose 20% of body weight within one week, followed by
maintenance at 80% of the baseline weight for the remainder of the experiment.
The second is restricting access to water to 15 min in each 24 h period. These
methods are effective in motivating the animals. There is, however, little
information available on the effects on performance in tests of behaviour that
are not related to operant conditioning. In addition, it is not clear if these
commonly used methods of food and water restriction will lead to physiological
stress as indicated by an elevation of serum corticosterone. Male rats were
either food-restricted to reduce and maintain their weight at 80% of baseline
weight, or were restricted to 15 min access to water every 24 h. Activity in the
open field was significantly greater in food-restricted rats than in water
restricted or control rats, but freezing behaviour was similar in all
experimental groups. Food-restricted rats had a higher mean serum corticosterone
level than water-restricted and control rats 37 days after the start of the
experimental period. These data suggested that chronically restricting food and
maintenance of body weight at 80% of baseline body weight led to significant
behavioural changes and physiological stress. In contrast, water restriction did
not lead to changes in behaviour or corticosterone levels. A second experiment
was conducted to compare the effects of food restriction to 80% of baseline body
weight, as described above, with a less stringent protocol in which test rats
were initially reduced to 80% of baseline weight, but were then maintained at 80%
of an ad libitum fed control rat's weight. Serum corticosterone levels and
adrenal gland weights were measured after the initial week of forced weight loss
and after maintenance for 21 days. Forced loss of 20% of body weight in the first
week led to significantly increased serum corticosterone levels and adrenal gland
weights compared to ad libitum fed controls. Serum corticosterone levels and
adrenal gland weights in rats maintained at 80% of their initial body weight for
21 days remained higher than ad libitum fed control rats. However, rats
maintained at 80% of an ad libitum fed control rat's weight did not differ from
control rats in serum corticosterone levels or adrenal gland weights at the end
of the 21-day study period. Adjustment of the feeding regimen in this manner
eliminated physiological evidence of chronic stress.
PMID- 10759364
TI - Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and
pharmacokinetics (0.4 mg/kg) with bioavailability determination.
AB - Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18
+/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of
0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study
with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally
(i.n.) in a cross-over protocol with a one-week wash-out period between each. In
series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min,
without a significant difference between 0.2 and 0.4 mg/kg doses for any of the
studied parameters. In series 2, after intranasal midazolam administration of 0.4
mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5
min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The
bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal
route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable
with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal
intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and
reliable sedation, adapted to laboratory piglets.
PMID- 10759365
TI - Potency of propofol, thiopentone and ketamine at various endpoints in New Zealand
White rabbits.
AB - Effective plasma concentrations of propofol, thiopentone and ketamine were
determined at different endpoints in a study with randomized, crossover design in
nine New Zealand White rabbits. A continuous infusion was used (30 ml/h) with
concentrations of 10 mg/ml for propofol, 25 mg/ml for thiopentone and 20 mg/ml
for ketamine. The endpoints were loss of the righting reflex, loss of purposeful
reactions to tail clamping (as an example of a peripheral pain stimulus) or to
intranostril insufflation of ammonia vapour (as an example of a central reflex
stimulus), and the recovery of these reflexes and reactions. According to the
ED50 values the potency ratios of propofol, thiopentone and ketamine were at the
loss of righting reflex 1:1.8:1.2, at the loss of reaction to ammonia vapour
1:1.5:1.6, and at the loss of reaction to tail clamping 1:1.5:3.9, respectively.
Recovery was significantly faster after propofol than after thiopentone and
ketamine. Measuring the effective plasma concentrations of intravenous
anaesthetics provides a method of relating dose to effect, but there still
remains a variable gap between plasma concentration and effect.
PMID- 10759366
TI - Immunological characterization of C3H mice congenic for Fas(lprcg), C3h/HeJ
Fas(lprcg)/Fas(lprcg).
AB - Fas(lpr) (lpr) and Fas(lprcg) (lpr(cg)) are allelic mutations of the Fas gene
that is involved in apoptosis or programmed cell death. Lpr greatly reduces the
expression of functional Fas and lpr(cg) expresses the death domain-disabled, non
functional Fas on the cell surface. C3H/HeJ mice congenic for lpr(cg) (C3H
lpr(cg)) were established and compared with C3H/HeJ-lpr/lpr (C3H-lpr) mice for
their immunological and pathological features. Lymphadenopathy, splenomegaly,
development of CD4- CD8- B220+ or double-negative (DN) T cells, renal pathology,
and lymphoid cell infiltration in the lung and liver were not significantly
different between C3H-lpr(cg) and C3H-lpr mice. Noticeably, however, the
production of serum immunoglobulin, autoantibodies against double-strand DNA and
serum immune complexes were significantly lower in C3H-lpr(cg) than in C3H-lpr
mice. The results indicate that the death signal through the death domain of Fas
is responsible for lymphoproliferation due to the accumulation of DN T cells and
suggest that the region of Fas outside the death domain may be involved in
autoantibody production. The newly-developed congenic C3H-lpr(cg) mice will
provide a powerful tool for research into the function of Fas apart from
apoptosis.
PMID- 10759367
TI - A porcine ex vivo paracorporeal model of lung transplantation.
AB - A technique is described which allows perfusion of an isolated, ventilated pig
lung with an extracorporeal veno-venous circuit from a support animal. This model
is stable for up to 4 h, and avoids some of the disadvantages of alternative
small animal and large animal models of lung transplantation. It may be useful in
the investigation of factors affecting lung preservation and reperfusion injury.
PMID- 10759368
TI - Continuous intravenous infusion in athymic (nude) rats: an animal model for
evaluating the efficacy of anti-cancer agents.
AB - The athymic (nude) rat (rnu/rnu) has been used for a number of years in research
into various human tumours involving xenotransplantation. We now report the
validation of a continuous intravenous infusion method in nude rats using a tail
cuff tether, which enables the study of the efficacy of novel anti-cancer
materials in this mutant strain, using intravenous infusion and with no
restriction of the animals or of the tumour implantation sites by jackets. Ten
animals each had a cannula surgically implanted into the vena cava via the
femoral vein and exteriorized via a tail cuff. Animals were housed singly in
conventional cages following surgery. Following a recovery period of 5 days all
animals were continuously infused with physiological saline at an infusion rate
of 0.5 ml/h for a further 37 days. Body weights and food consumption were
recorded weekly. Blood samples were taken approximately 14 days post-surgery and
analysed for haematology and clinical chemistry parameters. All animals were
successfully cannulated, and no unexpected adverse clinical signs were noted
during the recovery period and the 37 days of infusion. The results demonstrate
that it is possible to surgically cannulate the femoral vein of athymic (nude)
rats and infuse them in conventional cages for a period of up to 37 days with
minimal adverse effects. The minimal restraint required provides benefits both to
the animal and to the conduct of studies such as assessment of tumour growth in
the absence of a jacket. Recent work has demonstrated that the same techniques
can be successfully applied to the nude mouse.
PMID- 10759369
TI - Comparison of male reproductive parameters in three rat strains: Dark Agouti,
Sprague-Dawley and Wistar.
AB - The choice of experimental animal can have a large impact on experimental
results, an example is the anecdotal evidence suggesting that Dark Agouti (DA)
rats have a lower reproductive capacity than other rat strains. In this paper we
report on an investigation into male reproductive characteristics in three rat
strains--Wistar, Sprague-Dawley (outbred strains) and DA (an inbred strain).
Reproductive organ weights, blood testosterone levels and sperm counts were
measured in mature age-matched male rats. DA animals had significantly smaller
testis weights than the Sprague-Dawley and Wistar animals, and this did not
appear to be related to the overall smaller body mass of the DAs. There were no
differences between the three strains in testicular histology or sperm counts
(per gram testis). Although there was also no significant difference in
epididymal sperm count, the DA animals had a much greater variability in sperm
count than the other strains. There were no differences in relative (to body
weight) epididymal, seminal vesicle or ventral prostate weights or in the blood
testosterone levels. These results suggest that differences in reproductive
capacity in DAs are neither the result of morphological differences in the
reproductive organs nor in circulating testosterone levels. Sperm production
appears to be normal but the lowered testicular weight and variability in
epididymal sperm counts suggests that there are other factors in the testicular
or epididymal environment which alter male reproductive function.
PMID- 10759370
TI - Ten-year long monitoring of laboratory mouse and rat colonies in French
facilities: a retrospective study.
AB - From 1988 to 1997, a total of 69 mouse colonies and 36 rat colonies were examined
for the presence of antibodies to 14 indigenous viruses of mice and rats. Among
mouse viruses, high positivity rates were observed with mouse hepatitis virus
(MHV), Theiler's encephalomyelitis virus (THEMV), minute virus of mice (MVM),
Sendai virus and pneumonia virus of mice (PVM); the prevalence rates were high in
rats with Khilam's rat virus (KRV), THEMV, Toolan's H-1 virus, Sendai virus,
Parker's rat coronavirus (RCV/SDA) and PVM. During the last decade, the
prevalence of some agents such as MHV, Sendai virus, THEMV, PVM and MVM has
apparently decreased although they were still present in 1997 (except for PVM).
Another point is the constant increase of colonies found free of viruses through
this decade, demonstrating the efforts of the French research community to
increase the quality of hygiene in laboratory animals.
PMID- 10759371
TI - A pathophysiological study of abdominal organs following intraperitoneal
injections of chloral hydrate in rats: comparison between two anaesthesia
protocols.
AB - Chloral hydrate (CH) is used as an anaesthetic agent in laboratory rats. Side
effects occurring with high concentrations have mainly occurred in abdominal
organs. The objective of the present study was to minimize these side effects
following intraperitoneal administration of CH using lower concentrations.
Animals were evaluated using different procedures including a general necropsy,
intraperitoneal white cell counts, histology and duodenal peristalsis and
acetylcholine-induced contractions. Results clearly show that lower
concentrations of CH while keeping the same anaesthetic dose (400 mg/kg) will
minimize the irritancy of CH on abdominal organs while providing the same level
of anaesthesia.
PMID- 10759372
TI - Euthanasia of rats with carbon dioxide--animal welfare aspects.
AB - A method of inducing euthanasia by carbon dioxide (CO2) inhalation in the home
cage of an animal is described and tested for distress by behavioural as well as
by hormonal measures. The animals were maintained in their home cage while CO2
was induced at a flow of 6 l/min. The behaviour of the animals was measured
continuously as were the serum concentrations of glucose, ACTH and corticosterone
30, 75 and 120 s after the CO2 was introduced into the cage. In order to test for
distress, two groups of rats were pre-treated with acepromazine (orally) and
pentobarbiturate (i.p. injection) respectively, in order to reduce possible
distress caused by CO2 euthanasia, and were compared with control groups. There
were no signs of distress by behavioural or by hormonal changes. All changes seen
could be attributed to experimental effects and, especially as there was no
difference between the pre-treated and the control groups of rats, it must be
assumed that the described method of euthanasia is in concordance with animal
welfare, it leads to rapid death without severe distress or pain, and it seems
therefore to be 'humane'.
PMID- 10759373
TI - Determination of major and trace elements in the liver of Wistar rats by
inductively coupled plasma-atomic emission spectrometry and mass spectrometry.
AB - Inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled
plasma-atomic emission spectrometry (ICP-AES) were used to determine age-related
changes in the concentrations of constituent elements in the livers of Wistar
rats of 1 week to 12 months old. At first, sample preparation and analytical
conditions were investigated in order to set up a simple routine procedure for
measuring multiple elements simultaneously. Seventeen elements in the standard
reference samples of bovine and pork livers as well as rat liver samples could be
determined with a reasonable precision and reproducibility. They were P, K, Na,
Fe, Mg, Ca, Zn, Rb, Cu, Mn, Mo, Al, Co, Sr, Cs, Pb, and Cd in order of the levels
of concentration in the adult rat livers. Of these elements, the five major
elements (P, K, Na, Fe, Mg, Ca) were determined with ICP-AES and the others with
ICP-MS. Although the number of animals was too small to draw a statistically
definite conclusion, it seems that age-related changes in the concentrations of
these elements could be categorized into three general patterns: (1) remaining
essentially constant throughout the animal ages, as observed for P, K, Na, Mg,
Ca, Rb, Sr, Cs, and Pb, (2) increasing with age, as observed for Fe, Mn, Mo, Co,
and Cd, and (3) decreasing with age, especially in the early stages of growth, as
observed for Cu and Zn.
PMID- 10759374
TI - Adrenal gland tumours in two cotton-top tamarins (Saguinus oedipus oedipus).
AB - Two adrenal gland tumours in captive born cotton-top tamarins (Saguinus oedipus
oedipus) are described. One was a pheochromocytoma in a 14-year-old male, the
other one a cortical adenoma in a 7.5-year-old female. Both were associated with
morphological signs of myocardial damage and circulatory problems. The findings
are discussed and compared to adrenal gland tumours in man.
PMID- 10759375
TI - Identification of select lymphocyte homing molecules and vascular addressins in
lymphotoxin-alpha deficient mice.
AB - The transmigration of lymphocytes across vascular endothelium is a critical step
for the localization of lymphocytes to lymph nodes in both naive and immune
reactive states. Mice deficient in lymphotoxin-alpha (LT-alpha) lack peripheral
and gut associated lymph nodes. Lymphocyte function and homing ability are
reported to be normal in these mice yet information regarding cell adhesion
molecules and counterpart vascular addressins is lacking. The phenotype of
peripheral lymphocytes from LT-alpha deficient mice was investigated by the use
of fluorescent activated cell sorting and immunohistochemistry. No difference was
detected in the splenocyte and tissue expression of L-selectin, alpha4beta7 or
its individual integrin components, mucosal addressin cell adhesion molecule
(MAdCAM-1), intracellular adhesion molecule (ICAM-1), peripheral node addressin
(PNAd), or platelet/endothelial cell adhesion molecule (PECAM-1) between wild
type and LT-alpha deficient mice. Therefore, impaired expression of these
lymphocyte homing and vascular addressin molecules is apparently not included in
the phenotype of the LT-alpha deficient mouse.
PMID- 10759376
TI - What is your diagnosis? Filaroides hirthi infection.
PMID- 10759377
TI - Ischaemic heart disease in the dog: a review of 65 cases.
AB - Sixty-five dogs are reviewed with histopathologically confirmed intramural
arteriosclerosis. Clinical data (clinical signs, electrocardiographic findings
and ultrasound parameters) on these animals were collected from nine small animal
clinics in Sweden: 16 dogs had died suddenly, with few or no previous clinical
signs; 13 dogs died or were euthanased during or shortly after general
anaesthesia or sedation; 30 dogs developed acute (14) or chronic (16) congestive
heart failure; and six dogs died or were euthanased for causes unrelated to
cardiac disease. Electrocardiography of 23 of the dogs revealed several types of
arrhythmias, with atrial fibrillation and sinus tachycardia being most commonly
detected. Ultrasonographic examinations of 24 dogs found a relatively high number
(19) with decreased indices of contractility. Dogs that had died suddenly and in
relation to general anaesthesia or sedation had a higher incidence (25 of 29) of
purely arteriosclerotic changes in the myocardial vessels, whereas just over half
the dogs with congestive heart failure (16 of 30) had other concomitant heart
lesions (in most cases endocardiosis). The incidence of myocardial infarcts was
high (51 of 65 cases). It is postulated that arteriosclerosis in the dog may be
an important reason for sudden death and death during general anaesthesia.
Coronary arterial disease should also be a consideration in the clinical
evaluation of dilated cardiomyopathy and may contribute to the decreased
myocardial contractility when it is present in dogs with mitral regurgitation.
PMID- 10759378
TI - Diagnosis, treatment and outcome of orbital neoplasia in dogs: a retrospective
study of 44 cases.
AB - Forty-four dogs with confirmed orbital neoplasia were studied. Eighteen tumour
types were represented and 95 per cent of the neoplasms were classified as
malignant. The tumour types most commonly diagnosed were osteosarcoma,
fibrosarcoma and nasal adenocarcinoma. Thirty-six per cent of the dogs had at
least one clinical sign that was compatible with a diagnosis of orbital
abscessation or cellulitis. Fifty-six per cent of the dogs, where follow-up
information was available, were euthanased or had died within six months of
diagnosis, while 19 per cent of the total were still alive after one year post
diagnosis. Cytological examination was diagnostic for orbital neoplasia in 49 per
cent of the fine needle aspirates of the retrobulbar space. In contrast, 56 per
cent of the non-surgical biopsies were diagnostic for orbital neoplasia. Of those
dogs that had died or been euthanased within six months of diagnosis, only 22 per
cent had undergone some form of therapy for orbital neoplasia. In comparison, 86
per cent of dogs surviving longer than six months post-diagnosis had undergone
such therapy.
PMID- 10759379
TI - Aortic and iliac thrombosis in six dogs.
AB - Six dogs had signs of pelvic limb weakness, pain and collapse as a result of
occlusion of the distal aorta and/or the iliac arteries by a thrombus. Antemortem
diagnosis was made on the basis of clinical signs, angiography and
ultrasonography. Five dogs had concurrent disease that probably predisposed to
thrombosis, including hyperadrenocorticism (three dogs), neoplasia and cardiac
disease. Two dogs died shortly after the episode of thrombosis. Dogs that
survived the acute episode received aspirin in an attempt to prevent thrombosis
occurring again and all regained pelvic limb function. For dogs that survived
longer than one month after the acute episode, repeat thrombosis was uncommon;
hence the prognosis was related to the underlying disease. Aortic and iliac
thrombosis in dogs is an uncommon condition that usually arises secondarily to a
predisposing disease process; it carries a more favourable prognosis than feline
aortic thromboembolism.
PMID- 10759380
TI - Omentalisation of perinephric pseudocysts in a cat.
AB - An 11-year-old male domestic shorthaired cat was presented with behavioural
disturbances and abdominal distension of two days' duration. Haemobartonella
felis was found on routine haematology and serum biochemistry showed mild
azotaemia. Abdominocentesis revealed a transudate. Bilateral perinephric fluid
accumulations were observed on ultrasonography and chronic nephrosclerosis was
diagnosed on needle biopsies of the kidney. A celiotomy with resection of the
major portion of both cyst walls was performed. The omentum was extended along
the floor of the abdomen, across the ventral aspect of both kidneys and attached
to the remnants of the pseudocyst wall. Ongoing physiological drainage was
secured and cyst recurrence was prevented. Perirenal fluid was not detected at
clinical and ultrasound follow-up examinations 14 days and seven months
postoperatively. Mild azotaemia and refractory Haemobartonella infection were,
however, still present.
PMID- 10759381
TI - Cervical neoplasia originating from the vagus nerve in a dog.
AB - An eight-year-old intact male Bernese mountain dog was referred with a history of
chronic vomiting, coughing and signs of respiratory distress. Other historical
findings included lethargy, weight loss and choking. On presentation, clinical
findings were Horner's syndrome, ipsilateral laryngeal hemiplegia, coughing,
gagging, respiratory distress and vomiting. Lateral cervical radiographs showed
ill-defined mineralisation in the soft tissue ventral to the third cervical
vertebra, while ultrasonography of the neck revealed a well marginated
heterogeneous mass with focal hyperechogenic lesions and acoustic shadowing.
Results of an ultrasound-guided fine needle aspirate suggested neoplasia. At
necropsy, a large tumour was detected in the ventral cervical region, originating
from the right vagosympathetic trunk. In view of the infiltrating pattern, the
cellular pleomorphism and the numerous mitoses on histopathological examination,
the tumour was classified as a malignant peripheral nerve sheath tumour.
PMID- 10759382
TI - Use of the Ilizarov method to manage a septic tibial fracture nonunion with a
large cortical defect.
AB - The use of a 'hybridised' Ilizarov ring fixator is described in the salvage of a
septic nonunion of a comminuted tibial fracture with a large diaphyseal cortical
sequestrum in an 11-month-old German shepherd dog. A ring fixator assembly
incorporating half pin application was chosen to provide flexibility of fixation
placement options in limited bonestock which had previously been subject to
conventional Kirschner-Ehmer external fixation. Diaphyseal regeneration was
achieved by stimulating bone trophism through the axial loading properties of the
Ilizarov fixator and the biological osteoinductive properties of cancellous bone
autograft. The young age of the dog was considered to make it an optimal
candidate for salvage in spite of its highly excitable temperament. Fully
functional fracture union with resolution of osteomyelitis was achieved at eight
weeks following revision without recourse to intercalary transportation or
cortical grafting. Problems with postoperative management of the dog resulted in
minor complications and mechanical failure of some of the frame components.
PMID- 10759383
TI - Cor triatriatum sinister in a cat.
AB - A heart murmur was detected in a five-month-old Persian chinchilla cat. The
animal was referred to Nihon University Animal Medical Center where radiographic
examination revealed an enlarged heart with dilation of pulmonary arteries and
veins and pulmonary oedema. Echocardiography revealed partition of the left
atrium, with turbulent blood flow within the left atrium. The patient was placed
under continuous care at the facility, but died at seven months of age.
Postmortem examination revealed that the left atrium was partitioned by a
fibromuscular septum, with a 1 mm diameter perforation, consistent with a
diagnosis of cor triatriatum sinister.
PMID- 10759384
TI - Procedure for microchipping chelonians.
PMID- 10759385
TI - Animal welfare--problems and solutions.
PMID- 10759386
TI - FELASA guidelines for education of specialists in laboratory animal science
(Category D). Report of the Federation of Laboratory Animal Science Associations
Working Group on Education of Specialists (Category D) accepted by the FELASA
Board of Management.
PMID- 10759387
TI - A comparison of pre- and post-surgical administration of bupivacaine or
buprenorphine following laparotomy in the rat.
AB - The effects of bupivacaine, a long-acting local anaesthetic, and buprenorphine,
an opioid analgesic, administered either pre- or post-operatively, were
investigated in a rat laparotomy model. Surgical anaesthesia was induced and
maintained with halothane. The type of analgesic treatment was a significant
factor in the reduction in body weight and food and water intake which occurred
following surgery. The largest reductions were seen in the bupivacaine-treated
groups and those animals which received no analgesics. The timing of
administration of analgesics had no influence on the effect of bupivacaine
administration. The group receiving buprenorphine before surgery showed less
depression in food intake than the group receiving buprenorphine at the end of
surgery. Animals which received buprenorphine showed less depression of activity
than those receiving saline or bupivacaine.
PMID- 10759388
TI - Anaesthesia of the common marmoset (Callithrix jacchus) using continuous
intravenous infusion of alphaxalone/alphadalone.
AB - A safe means of anaesthetizing common marmosets (Callithrix jacchus) for a study
using magnetic resonance imaging (MRI) to investigate cerebral ischaemia was
required. Continuous infusion of alphaxalone/alphadalone was used to anaesthetize
37 marmosets for non-recovery and recovery experiments. This was found to give
safe, reliable anaesthesia when coupled with pulse oximetry and
electrocardiographic (ECG) monitoring.
PMID- 10759389
TI - The laryngeal mask airway in experimental pig anaesthesia.
AB - The pig is used as a large animal model in many research projects. Standard
practice for airway maintenance under general anaesthesia is using endotracheal
(ET) intubation after intravenous induction to a near surgical plane. This is a
technically demanding skill, requiring the assistance of an experienced
technician. A technique is required which simplifies pig anaesthesia. This study
examined the feasibility and potential advantages of using the laryngeal mask
airway (LMA) in 10 pigs during laparotomy under spontaneous breathing
anaesthesia. The results show that the LMA can be inserted rapidly, with minimal
time for airway control by researchers relatively inexperienced in anaesthesia
and is associated with few complications. By removing the need for intravenous
induction, an entire step in the anaesthetic process is removed. The LMA designed
for humans fits well in the pig hypopharynx; all pigs could be manually
ventilated with no detectable gas leak. Although the pigs in this study were
spontaneously breathing it is proposed that the LMA should be further
investigated in studies of artificially ventilated pigs.
PMID- 10759390
TI - Short-term immobilization of mice by methohexitone.
AB - The feasibility of short-term immobilization for <5 min of female mice by
methohexitone sodium was studied. In C3H/Neu mice, methohexitone at a dose <40
mg/kg did not result in chemical restraint, doses >50 mg/kg caused considerable
lethality. A dose of 44 mg/kg, applied intraperitoneally at a concentration of
6.46 mg/ml, is suitable for immobilization without complications. This
concentration was chosen in order to achieve an injection volume of about 0.15 ml
for a mouse with an average body weight of 22 g, corresponding to about 1
mg/mouse. Complete immobilization, defined as absence of the righting reflex, was
observed within 3.3 +/- 0.8 min (mean +/- SD, n = 10) after the injection and
lasted for 1.5 +/- 0.7 min. Recovery of the animals was complete after a total
period of 10 to 15 min post-injection. No gross pathomorphological changes were
induced when intraperitoneal injections of methohexitone were repeated 10 times
within 10 days. In the present study, complete immobilization of the mice was
safely achieved after 87 out of 90 injections. In conclusion, immobilization by
intraperitoneal injection of methohexitone is a feasible and reliable method in
the experimental studies of female mice.
PMID- 10759391
TI - Induction of anaesthesia with sevoflurane and isoflurane in the rabbit.
AB - The effects of induction of anaesthesia with sevoflurane and isoflurane were
studied in rabbits. All rabbits had periods of apnoea (ranging from 30-180 s)
during induction which resulted in moderate hypercapnia and acidosis. Arterial
pCO2 rose from 4.1 +/- 0.3 kPa to a peak of 7.6 +/- 0.4 kPa (mean +/- SD) (both
agents). All animals showed a significant reduction in heart rate (P < 0.05).
Heart rate (HR) fell from 226 +/- 33 to a minimum during induction of 57 +/- 32
(sevoflurane) and 199 +/- 41 to 45 +/- 11 (isoflurane). Most animals struggled
violently during induction. Use of sevoflurane did not prevent the breath-holding
response seen during induction of anaesthesia with other volatile anaesthetics in
this species, and the severe apnoea which occurs may represent a significant
hazard. The behaviour of the animals indicated that both sevoflurane and
isoflurane are aversive, suggesting that this technique should be avoided
whenever possible.
PMID- 10759392
TI - EEG evaluation of reflex testing as assessment of depth of pentobarbital
anaesthesia in the rat.
AB - Electroencephalography (EEG) was applied to evaluate the validity of the paw
pinch reflex as an indicator of anaesthetic depth in rats which are anaesthetized
with a single intraperitoneal dose of pentobarbital. After induction of the
anaesthesia, characterized by the rapid loss of the animals' ability to maintain
upright posture, the EEG of 10 out of 11 rats was dominated by paroxysmal (burst
suppression) activity, associated with unconsciousness. In seven out of 11 rats,
the paw pinch reflex was lost after onset of paroxysmal electroencephalographic
activity. However, the paw pinch reflex remained present in four out of 11
animals, demonstrating that the response is independent of cortical activity. In
five out of seven rats, the EEG still showed paroxysmal activity when the paw
pinch reflex was regained. However, in two other rats the EEG returned to a
pattern similar to that shown by awake animals, 4 and 21 min respectively, before
the reflex was regained. These data indicate that in the pentobarbital
anaesthetized rat, presence of the paw pinch reflex is not related to the level
of depression of electrical activity in the cerebral cortex, and consequently is
probably not related to the level of consciousness. Based upon these findings it
is concluded that the paw pinch reflex is unreliable as a sole indicator of
anaesthetic depth.
PMID- 10759393
TI - Methods for exposure of laboratory animals to ultraviolet radiation.
AB - Two different sources of ultraviolet B (UVB) radiation, an electronically
controlled UVB exposure unit, containing FS40 tubes, and a hand-held Kromayer
lamp, were evaluated for actual irradiance in W/m2 and spectra (physical
dosimetry and biological dosimetry (skin effects in rodents)). The technical
studies of the FS40 sources demonstrated that the flux intensity of the lamps
could be changed electronically, without affecting the spectrum. Thus it was
possible to standardize UVB exposure electronically. The biologically effective
doses of these sources were analysed in RIV-Tox Wistar rats and BALB/c mice.
After low doses of UVB radiation, histopathological changes such as acanthosis,
hyperkeratosis and dermal inflammation were observed in the skin without the
presence of major side effects such as erythema and oedema. After higher doses of
UVB radiation erythema and oedema were clearly visible. Quantitative studies
showed that the minimal erythema dose, as a biological parameter, correlated well
to the emission in J/m2. In addition, biological parameters such as acanthosis
and inflammation in the skin correlated well to the actual exposure in J/m2 and
were sensitive biomarkers for UVB-induced skin toxicity. Thus, in addition to
minimal erythemal doses, acanthosis and inflammation may also be applied as
biologically relevant doses for studies of the biological effects of UVB
radiation.
PMID- 10759394
TI - A procedure to secure a jugular vein catheter system onto the neck of the
hamster.
AB - We describe a procedure to secure a jugular vein catheter system at the dorsal
nape of the neck in the hamster. An 8-cm piece of silicone tubing is connected
with a 2.6 cm L-shaped metal tubing which is embedded in prosthetic material. The
prosthetic material is placed underneath the neck skin of the hamster and keeps
the metal end of the catheter system in a sturdy, upright position.
PMID- 10759395
TI - Comparison of immunospecific antibody response in young and old chickens
immunized with human IgG.
AB - Three groups of 18-month-old chickens and three groups of 5-month-old chickens
were immunized with human immunoglobulin G (IgG) using one of three adjuvants in
the first injection (Freund's Complete Adjuvant (FCA), Freunds Incomplete
Adjuvant (FIA) and Hunter's TiterMax (HTM)) following the same immunization
scheme. The specific antibody response in serum was measured by ELISA. In both
older and younger chickens the serum antibody response in the FCA group reached a
significantly higher level (P < 0.01) than in the FIA group and in the HTM group
on week 5. The FCA group also had a significantly higher (P < 0.01) response on
week 10 compared to the HTM group. Other than that, there was no significant
difference between the three adjuvant groups in specific serum antibody response
in older chickens. In the younger chickens the specific serum antibody response
in the FCA group was significantly higher (P < 0.05) than the response in the HTM
group. There was no significant difference in the chicken serum antibody response
between the FCA and the FIA groups, nor was there a significant difference
between the FIA and the HTM groups. Comparing the younger chickens and the older
chickens immunized using the same adjuvant, the older chickens had consistently
higher titres than the younger chickens, although the difference was not always
significant.
PMID- 10759396
TI - Pluripotent haemopoietic progenitor cells (CFU-Sd8) in peripheral blood of
hereditarily anaemic Belgrade (b/b) rats.
AB - The unique anaemic syndrome of the Belgrade laboratory (b/b) rat is due to an
intracellular iron deficiency which is induced by a not yet defined mutation,
resulting in impairment of haemopoiesis. We investigated the CFU-Sd8 number and
concentration in the peripheral blood of b/b rats to study the relationship
between medullary and extramedullary haemopoiesis in this anaemic syndrome. The
results show normal concentration of CFU-Sd8 in the peripheral blood of b/b rats.
This finding was unexpected in the state of severe anaemia and disturbed growth
factor production in b/b rats, where the mobilization of CFU-Sd8 from bone marrow
to blood is expected. The results suggest that severe anaemia is not regularly
accompanied by the mobilization of pluripotent progenitors from bone marrow to
the blood.
PMID- 10759397
TI - Mouse urine collection using clear plastic wrap.
AB - Qualitative urinalysis using Multistix reagent strips for the detection of
urinary pH, protein, glucose, bilirubin, blood, ketone, urobilinogen and
creatinine can be carried out with a few drops of mouse urine. The use of
metabolic cages is not practical for such qualitative studies particularly when
several animals are involved. Here we describe two different methods for
collecting pure mouse urine. The single animal method (SAM) involves allowing a
single mouse to urinate on Glad cling wrap outside of the animal cage. The
multiple animal method (MAM) involves partitioning seven mice into seven
different make-shift compartments laid out on top of the cling wrap and allowing
them to urinate. The voided urine, in each case, is then aspirated into micro
centrifuge tubes using a Pipetman. Without coercion pure urine was obtained as
early as 12 s. Volumes in the range of 10-250 microl were obtained. Modifications
of the SAM could prove useful for rat or mouse urine collection under conditions
of microgravity.
PMID- 10759398
TI - Arcobacter butzleri isolated from a diarrhoeic non-human primate.
AB - The bacteriological examination of a faecal specimen from a 20-year-old female
rhesus macaque (Macaca mulatta) with diarrhoeal illness revealed the presence of
a large number of a relatively new enteric pathogen, Arcobacter butzleri. The
animal was from a closed colony of about 60 females, some of them were showing
intermittent diarrhoea possibly related to Giardia spp. Conditions for the
isolation and identification of A. butzleri are reported, as well as discussions
about its role as a primary pathogen and its zoonotic potential.
PMID- 10759399
TI - Serological relationship of some V-factor dependent Pasteurellaceae (Haemophilus
sp.) from guineapigs and rabbits.
AB - Culture of guinea pig and rabbit respiratory tracts for bacteria using X-
(haemin) and V- (NAD) factor in agar media detected infection by V-factor
dependent Pasteurellaceae (Haemophilus sp.) in three colonies of guinea pigs and
a group of rabbits. The 12 Haemophilus strains comprised three API NH codes
classed as Haemophilus parainfluenzae and two codes classed as Haemophilus
aphrophilus/paraphrophilus. Six cell wall lipid profiles were detected, but these
were not related to API NH codes. Both bacteriological properties were used to
select strains for serological studies but any relationship between
bacteriological and serological properties of the Haemophilus strains was not
evident. Varying serological relationships occurred between the newly isolated
Haemophilus strains, [Pasteurella] pneumotropica NCTC 8284 and Haemophilus
strains previously isolated from rats.
PMID- 10759400
TI - A sensitive docetaxel assay in plasma by solid-phase extraction and high
performance liquid chromatography-UV detection: validation and suitability in
phase I clinical trial pharmacokinetics.
AB - We have developed a specific and sensitive method aiming at docetaxel (Taxotere)
determination in plasma of treated patients. This involved solid-phase extraction
of 1 ml of plasma onto carboxylic acid (CBA) grafted silica cartridges followed
by reversed-phase liquid chromatography with UV detection. The best selectivity
was obtained through the use of C18 Uptisphere as stationary phase. The low limit
of quantitation obtained (LOQ: 5 ng/ml) allowed measurements of docetaxel up to
24 hours after one-hour infusions with low dosages of drug (60 mg/m2). The method
was applied successfully to monitor docetaxel plasma levels within two protocols
associating fixed dosages of either methotrexate or gemcitabine with escalating
doses of Taxotere.
PMID- 10759401
TI - Activation-induced apoptosis of peripheral lymphocytes treated with 7
hydroxystaurosporine, UCN-01.
AB - 7-hydroxystaurosporine (UCN-01) is a new anticancer agent which exerts an
inhibitory effect on cell cycle check points and is currently under phase I
clinical trials in US and Japan. Preliminary clinical data indicated that UCN-01
remained in plasma at high concentrations for long periods of time. This
unavoidable high plasma drug exposure is likely to lead to hematological
toxicities in patients. In the present study, cultured human peripheral blood
lymphocytes (PBLs) were used to evaluate the possible hematological toxicities of
UCN-01 treatment. UCN-01 induces apoptosis, and the induction of apoptosis
related surface markers were also examined to investigate the involvement of
these molecules in UCN-01-induced apoptosis in PBLs. In vitro viability of PBLs
was decreased by high dose of UCN-01 (25 microM, 3-day exposure). This effect of
UCN-01 was significantly suppressed by the presence of human serum, suggesting
that some specific inhibitory factor(s) in human serum may antagonize the
lympholytic effect of UCN-01. The percentage of annexin V-positive PI-negative
cells increased with exposure to UCN-01 in a time- and dose-dependent manner; by
up to 30.3% after exposure to 25 microM UCN-01 for 3 days. At the same time, the
expression of both interleukin-2 receptor (IL-2R, CD25) and Fas (CD95), analyzed
by flow cytometry, was induced. Con A-stimulated PBLs were more sensitive to UCN
01-induced apoptosis than non-stimulated lymphocytes and UCN-01 increased the
sFas-L released into culture medium from con A-stimulated PBLs. Therefore,
lymphocyte depletion mediated by activation-induced apoptosis is likely to occur
in patients treated with UCN-01 at high doses.
PMID- 10759402
TI - Orthotopic metastatic mouse models for anticancer drug discovery and evaluation:
a bridge to the clinic.
AB - Currently used rodent tumor models, including transgenic tumor models, or
subcutaneously-growing human tumors in immunodeficient mice, do not sufficiently
represent clinical cancer, especially with regard to metastasis and drug
sensitivity. In order to obtain clinically accurate models, we have developed the
technique of surgical orthotopic implantation (SOI) to transplant histologically
intact fragments of human cancer, including tumors taken directly from the
patient, to the corresponding organ of immunodeficient rodents. It has been
demonstrated in 70 publications describing 10 tumor types that SOI allows the
growth and metastatic potential of the transplanted tumors to be expressed and
reflects clinical cancer. Unique clinically-accurate and relevant SOI models of
human cancer for antitumor and antimetastatic drug discovery include: spontaneous
SOI bone metastatic models of prostate cancer, breast cancer and lung cancer;
spontaneous SOI liver and lymph node ultra-metastatic model of colon cancer,
metastatic models of pancreatic, stomach, ovarian, bladder and kidney cancer.
Comparison of the SOI models with transgenic mouse models of cancer indicate that
the SOI models have more features of clinical metastatic cancer. Cancer cell
lines have been stably transfected with the jellyfish Aequorea victoria green
fluorescent protein (GFP) in order to track metastases in fresh tissue at ultra
high resolution and externally image metastases in the SOI models. Effective
drugs can be discovered and evaluated in the SOI models utilizing human tumor
cell lines and patient tumors. These unique SOI models have been used for
innovative drug discovery and mechanism studies and serve as a bridge linking pre
clinical and clinical research and drug development.
PMID- 10759403
TI - Geldanamycin as a potential anti-cancer agent: its molecular target and
biochemical activity.
AB - Heat shock protein 90 is one of the most abundant cellular proteins. Although its
functions are still being characterized, it appears to serve as a chaperone for a
growing list of cell signaling proteins, including many tyrosine and
serine/threonine kinases, involved in proliferation and/or survival. The
benzoquinone ansamycin geldanamycin has been shown to bind to Hsp90 and to
specifically inhibit this chaperone's function, resulting in client protein
destabilization. Its ability to simultaneously stimulate depletion of multiple
oncogenic proteins suggests that geldanamycin, or other molecules capable of
targeting Hsp90 in cancer cells, may be of clinical benefit.
PMID- 10759404
TI - Oncolytic viruses.
AB - Viruses capable of inducing lysis of malignant cells through their replication
process are known as "oncolytic" viruses. Clinical trials in oncology have been
performed with oncolytic viruses for nearly fifty years. Both systemic and
intratumoral routes of administration have been explored. Toxicity has generally
been limited to injection site pain, transient fever and tumor necrosis.
Responses with early crude materials were usually short in duration; however,
recent trials with gene attenuated viruses suggest more prolonged duration to
responses observed.
PMID- 10759405
TI - Matrix metalloproteinase inhibitors: applications in oncology.
AB - Matrix metalloproteinases (MMP) are a group of zinc dependent enzymes which
include the interstitial collagenases, stromelysins, gelatinases and membrane
type metalloproteinases. They are involved in the remodelling and turnover of the
extracellular matrix proteins. They play a role in wound healing and the
pathogenesis of arthritis. In malignancies they play a role in tumor invasion,
metastasis and angiogenesis. A number of synthetic matrix metalloproteinase
inhibitors (MMPIs) have been developed for clinical use. In preclinical tumor
models they have shown promising activity in achieving inhibition of MMPs and
reducing tumor growth and metastatic spread. Some have also shown additive or
synergistic effects with cytotoxic agents. Phase I and II studies in human
subjects have defined the main side effects of these agents as being
musculoskeletal pains or arthralgias. As they are cytostatic agents rather than
cytotoxic in activity conventional measurements of radiological response for
assessment are not applicable in trials. Biological activity has been
demonstrated in certain cancers by the effects on levels of tumor markers as
surrogate markers of tumor response and also by a fibrotic stromal reaction seen
in tumor tissue. Newer agents have been developed with selective inhibition of
certain MMPs in an attempt to reduce the side effects. A number of phase III
human clinical trials evaluating MMPs are being carried out at present but only
one has been formally reported so far. This study suggested that marimastat had
no survival advantage when compared to chemotherapy with gemcitabine in advanced
pancreatic carcinoma. Current trials are assessing efficacy of MMPIs in
maintenance of remission after other modalities of therapy or in combination with
cytotoxic agents. MMPs have also been demonstrated to play an important role in
the articular cartilage destruction seen in both rheumatoid arthritis and
osteoarthritis. The use of MMPIs in both ex vivo and in vivo models have shown
promising results and trials are in process to assess their potential role in the
control of articular destruction. The true therapeutic role of MMPIs await the
results of these randomized studies.
PMID- 10759406
TI - Oral topoisomerase 1 inhibitors in adult patients: present and future.
AB - The renewed interest in topoisomerase 1 inhibitors, based on new insights on the
mechanism of action and the development of semi-synthetic derivates of
camptothecin with a more favourable toxicity profile, has led to extensive
preclinical and clinical research. Significant levels of anti-tumor activity in
human tumor xenografts were seen especially with prolonged duration of exposure.
Since oral drug delivery is a more convenient method for prolonged drug
administration, and preferred by patients, further development of oral
formulations seems attractive. Common concerns in the development of oral
formulations are their sometimes low oral bioavailability and the frequently
large intra- and interpatient variation in systemic exposure. Efforts to improve
absorption and minimize intestinal metabolism/efflux of the oral chemotherapeutic
agent using new formulas might lead to better bioavailability. Pharmacokinetic
and pharmacodynamic evaluations have enabled guidance in recommendations of
schedules. Given the interpatient variation in exposure it is interesting to note
that flat dosing of topotecan resulted in the same systemic exposure compared
with the more complex dosing per body surface area. In order to diminish the
interpatient variation in exposure to 9-AC a limited sampling model for oral 9-AC
was developed, enabling prediction of the systemic exposure for 9-AC and
optimizing treatment for any given patient. Drug sequencing plays a key role in
the combination topotecan/cisplatin and might be important for combination with
other classes of drugs. Therefore, forthcoming phase 1 trials on combination
therapy with oral topoisomerase 1 inhibitors should include studies on sequence
dependence and pharmacokinetic analyses to evaluate any mutual interaction.
PMID- 10759408
TI - The antimicrobial treatment of periodontal disease: changing the treatment
paradigm.
AB - Over the last 100 years, methods of surgical periodontal treatment have enjoyed a
history of success in improving oral health. The paradigm of care is based on the
"non-specific plaque hypothesis"--that is, the overgrowth of bacterial plaques
cause periodontal disease, and the suppression of this overgrowth reduces disease
risk. The central feature of this approach to care is the removal of inflamed
gingival tissue around the teeth to reduce periodontal pocket depth, thereby
facilitating plaque removal by the dentist and by the patient at home. Over the
last 30 years, with the recognition that periodontal disease(s) is caused by
specific bacteria and that specific antimicrobial agents can reduce or eliminate
the infection, a second paradigm has developed. This new paradigm, the "specific
plaque hypothesis", focuses on reducing the specific bacteria that cause
periodontal attachment loss. The contrast between the two paradigms can be
succinctly stated as follows: The antimicrobial therapy reduces the cause, while
the surgical therapy reduces the result of the periodontal infection. The
specific plaque hypothesis has two important implications. First, with the
increasing attention to evidence-based models for prevention, treatment, outcome
assessment, and reimbursement of care, increasing attention and financial effort
will be channeled into effective preventive and treatment methods. Second, the
recent observations that periodontal infections increase the risk of specific
systemic health problems, such as cardiovascular disease, argue for the
prevention and elimination of these periodontal infections. This review
highlights some of the evidence for the specific plaque hypothesis, and the
questions that should be addressed if antimicrobial agents are to be used
responsively and effectively.
PMID- 10759407
TI - Toward checkmate: biology and breast cancer therapy for the new millennium.
AB - A better understanding of the biology of breast cancer should lead to the
rational development of new treatments and the ability to customize therapy for
individual patients. Though promising in theory, translating advances in
biological knowledge to the clinic has been difficult. Recently several areas of
research have produced treatments which have entered clinical trials: three will
be reviewed here. The growth of breast cancer is regulated by growth factors and
their receptors; amplification or overexpression is associated with poor
prognosis. As such inhibition of growth factors and/or growth factor receptors
may provide an ideal therapeutic target. Herceptin binds to c-erbB-2, a member of
the epidermal growth factor receptor family. Significant responses were seen in
patients with c-erbB-2 overexpressing breast cancer with Herceptin administered
as a single agent or in combination with chemotherapy. Herceptin was approved by
the Food and Drug Administration in late 1998. Breast cancer invasion and
metastasis requires degradation of the surrounding basement membrane by matrix
metalloproteinases and other proteolytic enzymes. Synthetic inhibitors of these
enzymes are now in clinical trials. Breast cancers must stimulate angiogenesis,
the growth of new blood vessels, in order to grow beyond a few millimeters in
diameter. This nascent vascular network provides another opportunity for therapy.
Preclinical models support the critical role of angiogenesis and the therapeutic
benefit of angiogenesis inhibition; clinical trials are underway.
PMID- 10759409
TI - In vivo gene transfer to salivary glands.
AB - Considerable progress has occurred recently in transferring foreign genes to
different tissues in vivo. Gene transfer to salivary glands has mirrored progress
in the general field. Most salivary studies have utilized replication-deficient,
recombinant adenoviruses as gene transfer vectors in rat models. These vectors
are able to transduce almost all rat salivary epithelial cell types and lead to
relatively high levels of transgene expression. Additionally, successful, though
quite modest, gene transfer to salivary glands has been achieved with retroviral
vectors and with different plasmid conjugates (liposomes; nonrecombinant
adenoviruses). Salivary gland gene transfer has been used for two potential
clinical goals: (i) the repair of hypofunctional gland parenchyma, and (ii) the
production of secretory transgene products for either systemic or upper
gastrointestinal tract pharmaceutical use. Gene transfer can also be used as a
powerful tool to alter cellular phenotype in vivo and probe cell biological
questions. The current spectrum of studies demonstrates the potential broad and
profound influence gene transfer can make on salivary physiology and
pathophysiology.
PMID- 10759411
TI - The Ruffini ending as the primary mechanoreceptor in the periodontal ligament:
its morphology, cytochemical features, regeneration, and development.
AB - The periodontal ligament receives a rich sensory nerve supply and contains many
nociceptors and mechanoreceptors. Although its various kinds of mechanoreceptors
have been reported in the past, only recently have studies revealed that the
Ruffini endings--categorized as low-threshold, slowly adapting, type II
mechanoreceptors--are the primary mechanoreceptors in the periodontal ligament.
The periodontal Ruffini endings display dendritic ramifications with expanded
terminal buttons and, furthermore, are ultrastructurally characterized by
expanded axon terminals filled with many mitochondria and by an association with
terminal or lamellar Schwann cells. The axon terminals of the periodontal Ruffini
endings have finger-like projections called axonal spines or microspikes, which
extend into the surrounding tissue to detect the deformation of collagen fibers.
The functional basis of the periodontal Ruffini endings has been analyzed by
histochemical techniques. Histochemically, the axon terminals are reactive for
cytochrome oxidase activity, and the terminal Schwann cells have both non
specific cholinesterase and acid phosphatase activity. On the other hand, many
investigations have suggested that the Ruffini endings have a high potential for
neuroplasticity. For example, immunoreactivity for p75-NGFR (low-affinity nerve
growth factor receptor) and GAP-43 (growth-associated protein-43), both of which
play important roles in nerve regeneration/development processes, have been
reported in the periodontal Ruffini endings, even in adult animals (though these
proteins are usually repressed or down-regulated in mature neurons). Furthermore,
in experimental studies on nerve injury to the inferior alveolar nerve, the
degeneration of Ruffini endings takes place immediately after nerve injury, with
regeneration beginning from 3 to 5 days later, and the distribution and terminal
morphology returning to almost normal at around 14 days. During regeneration,
some regenerating Ruffini endings expressed neuropeptide Y, which is rarely
observed in normal animals. On the other hand, the periodontal Ruffini endings
show stage-specific configurations which are closely related to tooth eruption
and the addition of occlusal forces to the tooth during postnatal development,
suggesting that mechanical stimuli due to tooth eruption and occlusion are a
prerequisite for the differentiation and maturation of the periodontal Ruffini
endings. Further investigations are needed to clarify the involvement of growth
factors in the molecular mechanisms of the development and regeneration processes
of the Ruffini endings.
PMID- 10759410
TI - GTP-binding proteins and regulated exocytosis.
AB - Regulated exocytosis, which occurs in response to stimuli, is a two-step process
involving the docking of secretory granules (SGs) at specific sites on the plasma
membrane (PM), with subsequent fusion and release of granule contents. This
process plays a crucial role in a number of tissues, including exocrine glands,
chromaffin cells, platelets, and mast cells. Over the years, our understanding of
the proteins involved in vesicular trafficking has increased dramatically.
Evidence from genetic, biochemical, immunological, and functional assays supports
a role for ras-like monomeric GTP-binding proteins (smgs) as well as
heterotrimeric GTP-binding protein (G-protein) subunits in various steps of the
vesicular trafficking pathway, including the transport of secretory vesicles to
the PM. Data suggest that the function of GTP-binding proteins is likely related
to their localization to specific cellular compartments. The presence of both G
proteins and smgs on secretory vesicles/granules implicates a role for these
proteins in the final stages of exocytosis. Molecular mechanisms of exocytosis
have been postulated, with the identification of a number of proteins that
modify, regulate, and interact with GTP-binding proteins, and with the advent of
approaches that assess the functional importance of GTP-binding proteins in
downstream, exocytotic events. Further, insight into vesicle targeting and fusion
has come from the characterization of a SNAP receptor (SNARE) complex composed of
vesicle, PM, and soluble membrane trafficking components, and identification of a
functional linkage between GTP-binding and SNARES.
PMID- 10759412
TI - Interstitial fluid pressure in normal and inflamed pulp.
AB - Tissue pressure is the hydrostatic pressure in the interstitial fluid which
surrounds the pulpal cells. This pressure outside the vessels is normally
considerably lower than the blood pressure inside the vessels. The dental pulp
has a relatively low interstitial compliance due to its enclosure between rigid
dentin walls. Accordingly, even a modest increase in pulpal fluid volume will
raise the tissue pressure, which may compress blood vessels, leading to ischemia
and necrosis. Inflammation may lead to an increase in both interstitial fluid
volume and blood volume in the low-compliant pulp and thereby increase the tissue
pressure. However, the increased tissue pressure may, in turn, initiate increased
lymph flow and absorption of fluid into capillaries in nearby non-inflamed
tissue. Both of these latter factors will transport fluid out of the affected
area and subsequently out of the tooth and consequently lower the tissue
pressure. Increased tissue pressure, whether caused by increased blood volume or
increased capillary filtration, will promote outward flow of fluid through
exposed dentin tubules and thereby help to protect the pulp against entry of
harmful substances. It seems physiologically beneficial, therefore, for the pulp
to have a high tissue pressure, which promptly increases when blood flow
increases due to its low compliance.
PMID- 10759413
TI - Adhesion receptors in health and disease.
AB - Cell adhesion molecules have been recognized to play a major role in a variety of
physiological and pathological phenomena. They determine the specificity of cell
cell binding and the interactions between cells and extracellular matrix
proteins. Some of them may also function as receptors that trigger intracellular
pathways and participate in cellular processes like migration, proliferation,
differentiation, and cell death. The receptors that mediate adhesion between
epithelial cells that are discussed in this review include integrins, selectins,
the immunoglobulin superfamily members, and cadherins. The intent of this review
is to inform the reader about recent advances in cellular and molecular functions
of certain receptors, specifically those that are considered important in cell
adhesion. We have deliberately not provided all-inclusive detailed information on
every molecule, but instead, have presented a generalized overview in order to
give the reader a global perspective. This information will be useful in
enhancing the reader's understanding of the molecular pathology of diseases and
recognizing the potential role of these receptors and ligands as therapeutic
agents.
PMID- 10759414
TI - Oral colonization by Candida albicans.
AB - Candida albicans is a commensal yeast normally present in small numbers in the
oral flora of a large proportion of humans. Colonization of the oral cavity by C.
albicans involves the acquisition and maintenance of a stable yeast population.
Micro-organisms are continually being removed from the oral cavity by host
clearance mechanisms, and so, in order to survive and inhabit this eco-system, C.
albicans cells have to adhere and replicate. The oral cavity presents many niches
for C. albicans colonization, and the yeast is able to adhere to a plethora of
ligands. These include epithelial and bacterial cell-surface molecules,
extracellular matrix proteins, and dental acrylic. In addition, saliva molecules,
including basic proline-rich proteins, adsorbed to many oral surfaces promote C.
albicans adherence. Several adhesins present in the C. albicans cell wall have
now been partially characterized. Adherence involves lectin, protein-protein, and
hydrophobic interactions. As C. albicans cells evade host defenses and colonize
new environments by penetrating tissues, they are exposed to new adherence
receptors and respond by expressing alternative adhesins. The relatively small
number of commensal Candida cells in the oral flora raises the possibility that
strategies can be devised to prevent oral colonization and infection. However,
the variety of oral niches and the complex adherence mechanisms of the yeast mean
that such a goal will remain elusive until more is known about the contribution
of each mechanism to colonization.
PMID- 10759415
TI - Post-extraction remodeling of the adult mandible.
AB - Following tooth loss, the mandible shows an extensive loss of bone in some
individuals. This may pose a significant problem in the prosthodontic restoration
of function and esthetics. The many factors which have been proposed as being
responsible for the inter-individual variation in post-extraction remodeling mean
that a perfunctory analysis of the literature, in which well-controlled, relevant
studies are scarce, may not provide the whole story. This article reviews the
local and systemic factors which may play a role in the post-extraction
remodeling of the mandible. Since severe residual ridge resorption may occur even
when the bone status in the rest of the skeleton is good and vice versa, it is
concluded that local functional factors are of paramount significance. It is now
essential to determine how they can be modified and applied to help maintain
ridge height and quality in our aging, edentulous population.
PMID- 10759416
TI - Chewing gum--facts and fiction: a review of gum-chewing and oral health.
AB - The world market for chewing gum is estimated to be 560,000 tons per year,
representing approximately US $5 billion. Some 374 billion pieces of chewing gum
are sold worldwide every year, representing 187 billion hours of gum-chewing if
each piece of gum is chewed for 30 minutes. Chewing gum can thus be expected to
have an influence on oral health. The labeling of sugar-substituted chewing gum
as "safe for teeth" or "tooth-friendly" has been proven beneficial to the
informed consumer. Such claims are allowed for products having been shown in vivo
not to depress plaque pH below 5.7, neither during nor for 30 minutes after the
consumption. However, various chewing gum manufacturers have recently begun to
make distinct health promotion claims, suggesting, e.g., reparative action or
substitution for mechanical hygiene. The aim of this critical review--covering
the effects of the physical properties of chewing gum and those of different
ingredients both of conventional and of functional chewing gum--is to provide a
set of guidelines for the interpretation of such claims and to assist oral health
care professionals in counseling patients.
PMID- 10759417
TI - Molecular and genetic analyses of Actinomyces spp.
AB - Members of the genus Actinomyces are predominant primary colonizers of the oral
cavity and play an important role in initiating plaque development. These
bacteria have evolved unique mechanisms that favor colonization and persistence
in this micro-environment. The expression of cell-surface fimbriae is correlated
with the ability of these bacteria to adhere to specific receptors on the tooth
and mucosal surfaces, and to interact with other plaque bacteria. The elaboration
of sialidase is thought to enhance fimbriae-mediated adherence by unmasking the
fimbrial receptors on mammalian cells. The presence of certain cell-associated or
extracellular enzymes, including those involved in sucrose or urea metabolism,
may provide the means for these bacteria to thrive under conditions when other
growth nutrients are not available. Moreover, these enzyme activities may
influence the distribution of other plaque bacteria and promote selection for
Actinomyces spp. in certain ecological niches. The recent development of a
genetic transfer system for Actinomyces spp. has allowed for studies the results
of which demonstrate the existence of multiple genes involved in fimbriae
synthesis and function, and facilitated the construction of allelic replacement
mutants at each gene locus. Analyses of these mutants have revealed a direct
correlation between the synthesis of assembled fimbriae and the observed
adherence properties. Further genetic analysis of the various enzyme activities
detected from strains of Actinomyces should allow for an assessment of the role
of these components in microbial ecology, and their contribution to the overall
success of Actinomyces spp. as a primary colonizer and a key player in oral
health and disease.
PMID- 10759418
TI - Apoptosis and predisposition to oral cancer.
AB - The term apoptosis, also known as programmed cell death (PCD), was coined by
developmental biologists a number of years ago to describe a form of cell death
characterized by several unique morphological and biochemical features. Genetic
studies of the round worm Caeneorhabditis elegans, a simple multicellular
organism, first revealed apoptosis to be an integral part of the developmental
program. Subsequently, the importance of apoptosis in higher organisms was
demonstrated in several eukaryotic systems. [n mammals, apoptosis is widespread
during embryogenesis and in adult tissues. It is required for normal tissue
homeostasis and for clonal selection in the immune system. In both developing and
adult organisms, apoptosis plays a central role in reinforcing appropriate
cellular patterns and in regulating cell number by eliminating cells that are
harmful or no longer needed. It is becoming increasingly clear that disruption in
the apoptosis pathway can contribute to the development of a number of
developmental, inflammatory, degenerative, and neoplastic diseases. The effector
arm of the apoptotic program includes members of the Bcl-2 gene family that
function as either death agonists or death antagonists. These proteins
participate in an elaborate genetically controlled biochemical pathway that
functions to maintain tissue and organ homeostasis and serve as a critical
defense mechanism to guard against malignant transformation. Cancer is the result
of a series of genetic lesions that include activation of oncogenes and
inactivation or loss of tumor suppressor genes. Several groups of investigators
have observed that deregulated expression of oncogenes can subvert apoptotic
pathways, resulting in prolonged cell survival. In pathological settings such as
cancer, members of the Bcl-2 gene family are able to synergize with oncogenes and
tumor suppressor genes to transform cells. In this review, we describe the
process of apoptosis in mammalian cells and define the role and biochemical
pathways through which the Bcl-2 gene family induce and/or protect cells from
apoptosis. Last, we will discuss the evidence which suggests that alterations in
this pathway may play a central role in tumorigenesis by allowing genetically
damaged cells normally destined for elimination to persist, predisposing them to
additional mutations and driving them to malignancy.
PMID- 10759419
TI - Angiogenesis in the development of head and neck cancer and its inhibition by
chemopreventive agents.
AB - Squamous cell carcinoma is an aggressive malignancy that often develops as
multiple independent lesions throughout the mucosa of the upper aerodigestive
tract. Therefore, the comprehensive treatment of this disease must not only
address the initial primary neoplasm, but also prevent the progression of the
premalignant lesions lurking throughout the rest of the mucosal surfaces. The
need to treat these lesions has resulted in a search for chemopreventive agents
that can halt or even reverse their malignant progression. The biologic and
molecular mechanisms by which most chemopreventive agents act have remained
unclear and controversial. Recent work from several laboratories has demonstrated
that some drugs may act in part by inhibiting the ability of tumors to induce
blood vessel growth. Angiogenesis, the growth of new blood vessels from pre
existing ones, is absolutely required for solid neoplasms to grow beyond 2-3 mm
in diameter. Therefore, chemopreventive agents that act to inhibit angiogenesis
may provide a very powerful modality by which one may limit the growth of both
pre-malignant lesions and small nests of tumor cells. This review will outline
the basic changes that occur in tumor cells that result in the switch from an
anti-angiogenic to an angiogenic phenotype. In addition, it will discuss the
mechanisms by which some chemopreventive agents, presently under clinical
investigation, inhibit tumor angiogenesis. Finally, this paper will present a
rationale for the use of multiple anti-angiogenic agents as a means of developing
new chemopreventive protocols that result in reduced patient toxicity while
maintaining similar clinical efficacies.
PMID- 10759420
TI - Bone marrow stromal cells: characterization and clinical application.
AB - The bone marrow stroma consists of a heterogeneous population of cells that
provide the structural and physiological support for hematopoietic cells.
Additionally, the bone marrow stroma contains cells with a stem-cell-like
character that allows them to differentiate into bone, cartilage, adipocytes, and
hematopoietic supporting tissues. Several experimental approaches have been used
to characterize the development and functional nature of these cells in vivo and
their differentiating potential in vitro. In vivo, presumptive osteogenic
precursors have been identified by morphologic and immunohistochemical methods.
In culture, the stromal cells can be separated from hematopoietic cells by their
differential adhesion to tissue culture plastic and their prolonged proliferative
potential. In cultures generated from single-cell suspensions of marrow, bone
marrow stromal cells grow in colonies, each derived from a single precursor cell
termed the colony-forming unit-fibroblast. Culture methods have been developed to
expand marrow stromal cells derived from human, mouse, and other species. Under
appropriate conditions, these cells are capable of forming new bone after in vivo
transplantation. Various methods of cultivation and transplantation conditions
have been studied and found to have substantial influence on the transplantation
outcome. The finding that bone marrow stromal cells can be manipulated in vitro
and subsequently form bone in vivo provides a powerful new model system for
studying the basic biology of bone and for generating models for therapeutic
strategies aimed at regenerating skeletal elements.
PMID- 10759421
TI - BMP receptors in limb and tooth formation.
AB - Members of the TGF-beta superfamily signal through receptor complexes comprised
of type I and type II receptors. These receptors, which are serine/threonine
kinases, form two new classes of transmembrane receptor kinases. The activity of
both of the kinases is necessary for signal transduction in response to ligand
binding. Bone morphogenetic proteins (BMPs), which are members of the TGF-beta
superfamily, bind to multiple type I and type II receptors. There is growing
evidence to support the hypothesis that the BMP receptors are differentially
regulated during development and that they have both unique and overlapping
functions. Thus, the nature and distribution of the BMP receptors, which are
reviewed here in the context of the development of limbs and teeth, appear to be
critical in the control of the diverse activities of BMPs.
PMID- 10759422
TI - Chloride channels and salivary gland function.
AB - Fluid and electrolyte transport is driven by transepithelial Cl- movement. The
opening of Cl- channels in the apical membrane of salivary gland acinar cells
initiates the fluid secretion process, whereas the activation of Cl- channels in
both the apical and the basolateral membranes of ductal cells is thought to be
necessary for NaCl re-absorption. Saliva formation can be evoked by sympathetic
and parasympathetic stimulation. The composition and flow rate vary greatly,
depending on the type of stimulation. As many as five classes of Cl- channels
with distinct gating mechanisms have been identified in salivary cells. One of
these Cl- channels is activated by intracellular Ca2+, while another is gated by
cAMP. An increase in the intracellular free Ca2+ concentration is the dominant
mechanism triggering fluid secretion from acinar cells, while cAMP may be
required for efficient NaCl re-absorption in many ductal cells. In addition to
cAMP- and Ca(2+)-gated Cl- channels, agonist-induced changes in membrane
potential and cell volume activate different Cl- channels that likely play a role
in modulating fluid and electrolyte movement. In this review, the properties of
the different types of Cl- currents expressed in salivary gland cells are
described, and functions are proposed based on the unique properties of these
channels.
PMID- 10759423
TI - Salivary gland P2 nucleotide receptors.
AB - The effects of ATP on salivary glands have been recognized since 1982. Functional
and pharmacological studies of the P2 nucleotide receptors that mediate the
effects of ATP and other extracellular nucleotides have been supported by the
cloning of receptor cDNAs, by the expression of the receptor proteins, and by the
identification in salivary gland cells of multiple P2 receptor subtypes.
Currently, there is evidence obtained from pharmacological and molecular biology
approaches for the expression in salivary gland of two P2X ligand-gated ion
channels, P2Z/P2X7 and P2X4, and two P2Y G protein-coupled receptors, P2Y1 and
P2Y2. Activation of each of these receptor subtypes increases intracellular Ca2+,
a second messenger with a key role in the regulation of salivary gland secretion.
Through Ca2+ regulation and other mechanisms, P2 receptors appear to regulate
salivary cell volume, ion and protein secretion, and increased permeability to
small molecules that may be involved in cytotoxicity. Some localization of the
various salivary P2 receptor subtypes to specific cells and membrane subdomains
has been reported, along with evidence for the co-expression of multiple P2
receptor subtypes within specific salivary acinar or duct cells. However,
additional studies in vivo and with intact organ preparations are required to
define clearly the roles the various P2 receptor subtypes play in salivary gland
physiology and pathology. Opportunities for eventual utilization of these
receptors as pharmacotherapeutic targets in diseases involving salivary gland
dysfunction appear promising.
PMID- 10759424
TI - Treatment outcome in cleft lip and palate: issues and perspectives.
AB - In the last 40 years, great progress has been made toward a better understanding
of many aspects of the cleft lip and palate defect, but there is still a long way
to go before there is agreement on the optimal treatment procedures. With regard
to the primary operations, it can be stated, in a somewhat simplified form, that
there are two main schools of thought in cleft treatment. One advocates early
closure of the lip and palate, a procedure which imparts a high priority to early
speech function. The other recommends delayed closure of the hard palate, thereby
according a high priority to the growth of the maxilla. A number of intercenter
and multicenter studies have been carried out recently in an effort to elucidate
which procedures give the best result, both esthetically and functionally. The
results are ambiguous, and this has led a number of researchers to suggest that
the randomized clinical trial is the only way to resolve the ambiguity. The fact
that it has proved difficult to identify the optimal procedures in the field of
cleft lip and palate treatment need not only be due to a less than optimal
research design; a contributory factor might also be the great variability in
craniofacial morphology and in the response to treatment in patients who have
exactly the same cleft lip and palate diagnosis. Intensive research has made it
possible to state categorically that clefts occur due to many different factors
in an interplay between genetics and environment. Therefore, it is not likely
that a single gene can be responsible for clefting. Since scar tissue presents
many problems-for instance, impairment of growth-the reduction or prevention of
scar formation has long been a desirable goal. The discovery that a fetus can
heal without scar formation has led to many animal experiments. The timing of the
surgical intervention on fetuses is critical, since late-gestation fetuses heal
with adult-like scarring. There are still many unsolved problems connected with
fetal surgery, and at present prenatal surgery for repair of cleft lip and palate
is not ethically defensible in humans. On the other hand, it appears that there
are considerable possibilities for the reduction of human scarring after surgery
with the introduction of various wound-healing medications.
PMID- 10759425
TI - Dental injury models: experimental tools for understanding neuroinflammatory
interactions and polymodal nociceptor functions.
AB - Recent research has shown that peripheral mechanisms of pain are much more
complex than previously thought, and they differ for acutely injured normal
tissues compared with chronic inflammation or neuropathic (nerve injury) pain.
The purpose of the present review is to describe uses of dental injury models as
experimental tools for understanding the normal functions of polymodal
nociceptive nerves in healthy tissues, their neuroinflammatory interactions, and
their roles in healing. A brief review of normal dental innervation and its
interactions with healthy pulp tissue will be presented first, as a framework for
understanding the changes that occur after injury. Then, the different types of
dental injury that allow gradation of the extent of tissue damage will be
described, along with the degree and duration of inflammation, the types of
reactions in the trigeminal ganglion and brainstem, and the type of healing. The
dental injury models have some unique features compared with neuroinflammation
paradigms that affect other peripheral tissues such as skin, viscera, and joints.
Peripheral inflammation models can all be contrasted to nerve injury studies that
produce a different kind of neuroplasticity and neuropathic pain. Each of these
models provides different insights about the normal and pathologic functions of
peripheral nerve fibers and their effects on tissue homeostasis, inflammation,
and wound healing. The physical confinement of dental pulp and its innervation
within the tooth, the high incidence of polymodal A-delta and C-fibers in pulp
and dentin, and the somatotopic organization of the trigeminal ganglion provide
some special advantages for experimental design when dental injury models are
used for the study of neuroinflammatory interactions.
PMID- 10759426
TI - The developmental control of osteoblast-specific gene expression: role of
specific transcription factors and the extracellular matrix environment.
AB - Bone formation is a carefully controlled developmental process involving
morphogen-mediated patterning signals that define areas of initial mesenchyme
condensation followed by induction of cell-specific differentiation programs to
produce chondrocytes and osteoblasts. Positional information is conveyed via
gradients of molecules, such as Sonic Hedgehog that are released from cells
within a particular morphogenic field together with region-specific patterns of
hox gene expression. These, in turn, regulate the localized production of bone
morphogenetic proteins and related molecules which initiate chondrocyte- and
osteoblast-specific differentiation programs. Differentiation requires the
initial commitment of mesenchymal stem cells to a given lineage, followed by
induction of tissue-specific patterns of gene expression. Considerable
information about the control of osteoblast-specific gene expression has come
from analysis of the promoter regions of genes encoding proteins like osteocalcin
that are selectively expressed in bone. Both general and tissue-specific
transcription factors control this promoter. Osf2/Cbfa1, the first osteoblast
specific transcription factor to be identified, is expressed early in the
osteoblast lineage and interacts with specific DNA sequences in the osteocalcin
promoter essential for its selective expression in osteoblasts. The OSF2/CBFA1
gene is necessary for the development of mineralized tissues, and its mutation
causes the human disease, cleidocranial dysplasia. Committed osteoprogenitor
cells already expressing Osf2/Cbfa1 must synthesize a collagenous ECM before they
will differentiate. A cell:ECM interaction mediated by integrin-type cell-surface
receptors is essential for the induction of osteocalcin and other osteoblast
related proteins. This interaction stimulates the binding of Osf2/Cbfa1 to the
osteocalcin promoter through an as-yet-undefined mechanism.
PMID- 10759427
TI - Proliferative and apoptotic responses in cancers with special reference to oral
cancer.
AB - The study of signal transduction pathways for mechanisms of apoptosis and
proliferation has significantly advanced our understanding of human cancer,
subsequently leading to more effective treatments. Discoveries of growth factors
and oncogenes, especially those that function through phosphorylation on tyrosine
residues, have greatly benefited our appreciation of the biology of cancer. The
regulation of proliferation and apoptosis through phosphorylation via tyrosine
kinases and phosphatases is discussed, as well as the contributions of other
systems, such as serine and threonine kinases and phosphatases. Receptors with
seven-transmembrane domains, steroid hormones, genes, and "death domains" will
also be discussed. This review attempts to compare the regulation of the growth
of normal tissues and cancers with an effort to highlight the current knowledge
of these factors in the growth regulation of oral/oropharyngeal cancers. Despite
the strides made in our understanding of growth regulation in human cancers, the
study of oral/oropharyngeal cancer specifically lags behind. More research must
be done to further our understanding of oral cancer biology, if we are to develop
better, more effective treatment protocols.
PMID- 10759428
TI - Bone sialoprotein.
AB - The search for a protein nucleator of hydroxyapatite crystal formation has been a
focus for the isolation and characterization of the major non-collagenous
proteins in bone. Of the proteins characterized to date, bone sialoprotein (BSP)
has emerged as the only bona fide candidate for nucleation. BSP is a highly
glycosylated and sulphated phosphoprotein that is found almost exclusively in
mineralized connective tissues. Characteristically, polyglutamic acid and
arginine-glycine-aspartate (RGD) motifs with the ability to bind hydroxyapatite
and cell-surface integrins, respectively, have been conserved in the protein
sequence. Expression of the BSP gene, which is induced in newly formed
osteoblasts, is up-regulated by hormones and cytokines that promote bone
formation and down-regulated by factors that suppress bone formation. Thus, BSP
has the biophysical and chemical properties of a nucleator, and its temporo
spatial expression coincides with de novo mineralization in bone and cementum.
Moreover, BSP has been associated with mineral crystal formation in several
pathologies, including breast carcinomas. However, the ability of BSP to mediate
cell attachment and to signal through the RGD motif points to alternate functions
for BSP which need further investigation. In combination, the hydroxyapatite
binding polyglutamic acid sequences and the RGD provide bi-functional entities
through which BSP may mediate the targeting and attachment of normal and
metastasizing cells to the bone surface.
PMID- 10759429
TI - Denture plaque and adherence of Candida albicans to denture-base materials in
vivo and in vitro.
AB - The aim of this paper is to review our understanding of the mechanisms and
clinical significance of adhesion of C. albicans to denture-base materials in
relation to denture plaque and denture-related stomatitis. Earlier reports in the
literature of a 65% prevalence level of denture-related stomatitis seem to be
exaggerated. More recent studies indicate that denture-related stomatitis is
considerably less common, particularly in normal healthy subjects. The etiology
of the condition is discussed in this review, and although much of the literature
supports the view that the condition is strongly associated with C. albicans,
this is not always so. In some subjects, the cause appears to be related to a non
specific plaque. This review also considers the role of denture plaque in the
pathogenesis of denture-related stomatitis, the sequential development of denture
plaque, and its colonization by Candida organisms. Designing controlled in vivo
studies is difficult, and as a consequence, many investigators have had to resort
to in vitro studies. The majority of these studies have attempted to investigate
the hydrophobicity of C. albicans, relating the surface free-energy of denture
base materials, particularly acrylic resin, to that of the organism. Surprisingly
little work has been directed at surface roughness and how it affects retention
of organisms. Further, no attention has been paid to the properties and character
of the surface, other than average surface roughness, as it affects adhesion. A
comparison of results from in vitro studies on the effect on adhesion of pre
coating the surfaces of denture-base materials with saliva has produced equivocal
conclusions. This is largely due to little standardization of experimental
protocols between studies, particularly in the collection and handling of the
saliva used. In conclusion, the review strongly supports the suggestion that
adherence of C. albicans to denture-base materials in vitro is related to the
hydrophobicity of the organism. The clinical significance of the observation and
the mechanisms for the development and maturation of denture plaque are yet to be
understood. There is a clear need for further investigation of other factors that
may moderate the adhesion of organisms and subsequent colonization of denture
base materials.
PMID- 10759430
TI - Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual
maturation and thyroid activity in the female rat. A focus on the EDSTAC
recommendations.
AB - In 1996, the US Environmental Protection Agency was given a mandate by Congress
to develop a screening program that would evaluate whether variously identified
compounds could affect human health by mimicking or interfering with normal
endocrine regulatory functions. Toward this end, the Agency chartered the
Endocrine Disruptor Screening and Testing Advisory Committee in October of that
year that would serve to recommend a series of in vitro and in vivo protocols
designed to provide a comprehensive assessment of a chemical's potential
endocrine-disrupting activity. A number of these protocols have undergone
subsequent modification by EPA, and this review focuses specifically on the
revised in vivo screening procedure recommended under the title Research Protocol
for Assessment of Pubertal Development and Thyroid Function in Juvenile Female
Rats. Background literature has been provided that summarizes what is currently
known about pubertal development in the female rat and the influence of various
forms of pharmaceutical and toxicological insult on this process and on thyroid
activity. Finally, a section is included that discusses technical issues that
should be considered if the specified pubertal endpoints are to be measured and
successfully evaluated.
PMID- 10759431
TI - Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual
maturation and thyroid function in the male rat. A focus on the EDSTAC
recommendations. Endocrine Disrupter Screening and Testing Advisory Committee.
AB - Puberty in mammalian species is a period of rapid interactive endocrine and
morphological changes. Therefore, it is not surprising that exposure to a variety
of pharmaceutical and environmental compounds has been shown to dramatically
alter pubertal development. This concern was recognized by the Endocrine
Disrupter Screening and Testing Advisory Committee (EDSTAC) that acknowledged the
need for the development and standardization of a protocol for the assessment of
the impact of endocrine-disrupting compounds (EDC) in the pubertal male and
recommended inclusion of an assay of this type as an alternative test in the
EDSTAC tier one screen (EPA, 98). The pubertal male protocol was designed to
detect alterations of pubertal development, thyroid function, and hypothalamic
pituitary-gonadal (HPG) system peripubertal maturation. In this protocol, intact
23-day-old weanling male rats are exposed to the test substance for 30 days
during which pubertal indices are measured. After necropsy, reproductive and
thyroid tissues are weighed and evaluated histologically and serum taken for
hormone analysis. The purpose of this review was to examine the available
literature on pubertal development in the male rat and evaluate the efficacy of
the proposed protocol for identifying endocrine-disrupting chemicals. The
existing data indicate that this assessment of puberty in the male rat is a
simple and effective method to detect the EDC activity of pesticides and toxic
substances.
PMID- 10759432
TI - The natural history of acute and chronic thromboembolic disease: the search for
the missing link.
PMID- 10759433
TI - The airway smooth muscle cell: a major contributor to asthma?
PMID- 10759434
TI - Is pulmonary embolism a common cause of chronic pulmonary hypertension?
Limitations of the embolic hypothesis.
AB - The hypothesis that chronic thromboembolic pulmonary hypertension results from
unresolved pulmonary embolism has strongly influenced the diagnosis and
management of this disease since the 1960s. However, it is nearly impossible to
induce chronic pulmonary hypertension in any animal species by means of repeated
embolization of thrombotic material. The haemodynamic effects of thrombotic
pulmonary embolism of different degrees of magnitude have also been studied in
humans and there is little to suggest that chronic pulmonary hypertension is a
likely long term outcome. Furthermore many conditions which predispose to venous
thromboembolism do not appear to cause thromboembolic pulmonary hypertension.
Other arteriopathic and atherosclerotic risk factors, are found in patients with
chronic thromboembolic pulmonary hypertension, but not in those with venous
thrombosis, suggesting that these may be unrelated conditions. Thrombosis in situ
of the pulmonary arteries is common in severe pulmonary hypertension of any
cause. Such thrombosis cannot usually be distinguished from pulmonary embolism.
It is hypothesized that in situ thrombosis and pulmonary arteriopathy are common
causes of vascular occlusion which is usually diagnosed as "chronic
thromboembolic pulmonary hypertension" and that venous thromboembolism is
unlikely to be a common cause of chronic pulmonary hypertension. It is further
hypothesized that pulmonary embolism is seldom the sole cause of "chronic
thromboembolic pulmonary hypertension".
PMID- 10759435
TI - Pharmacogenetics of asthma.
PMID- 10759436
TI - Endothelial signal transduction system enhances neutrophil-induced pulmonary
vascular permeability.
AB - The mechanism by which stimulated polymorphonuclear leukocytes and neutrophils
(PMNs) damage pulmonary vascular endothelium was investigated. The authors
assessed the ability of unstimulated and mechanically stimulated PMNs to adhere
to pulmonary endothelial cells and, thereby, alter pulmonary vascular
permeability, measured as the pulmonary filtration coefficient (K) and
haemodynamics. PMNs were stimulated by gentle agitation in a glass vial for 10 s.
Perfusing lungs with the stimulated PMNs (n=6) resulted in significant
accumulation of PMNs within the lungs, assessed by myeloperoxidase levels, and
elicited a 4-fold increase in K and a 2-fold increase in pulmonary vascular
resistance as compared to lungs perfused with unstimulated cells (n=6). The
increases in K were completely blocked by GF109203X, a protein kinase C inhibitor
(n=6); however, GF109203X only partially attenuated the increase in vascular
resistance and had little effect on the accumulation of stimulated PMNs. An
agonist of protein kinase C, phorbol myristate acetate, elicited dose dependent
increases in both K and pulmonary vascular resistance even in the absence of PMNs
(n=6). These findings indicate that the increases in pulmonary filtration
coefficient and pulmonary vascular resistance induced by polymorphonuclear
neutrophils result from endothelial cell injury mediated by activation of protein
kinase C within the endothelial cells themselves.
PMID- 10759437
TI - The effect of amlodipine on respiratory and pulmonary vascular responses to
hypoxia in mountaineers.
AB - Calcium antagonists are known to reduce the incidence of high-altitude pulmonary
oedema, but the mechanism is unclear. The aim of this study was to examine the
effects of the calcium antagonist, amlodipine, on cardiac and respiratory
responses in normoxia and hypoxia. Fourteen normal subjects aged 31+/-4 yrs who
had climbed to altitudes of 5,000-7,500 m without problems were randomly assigned
to a double-blind crossover trial of amlodipine versus placebo, using sea-level
inspiratory hypoxia to simulate altitude. Doppler echocardiographic estimates of
resting pulmonary haemodynamics and cycle ergometer test results of
cardiorespiratory responses to exercise were recorded in normoxia and hypoxia. It
was found that, although hypoxic pulmonary vasoconstriction (HPV) was not
significantly reduced by amlodipine, the effect of the drug on HPV was inversely
related to the serum level of amlodipine. Amlodipine did not alter left
ventricular function measured echocardiographically. During exercise, amlodipine
increased breathlessness, measured using standard scales, in both normoxia and
hypoxia but had no effect on ventilatory variables. It was concluded that
amlodipine has the potential to block hypoxic pulmonary vasoconstriction as
evidenced by a drug concentration-related decrease in resting tricuspid
regurgitation jet velocity without any change in resting myocardial
contractility. However, with amlodipine, the subjects felt more breathless during
exercise. The reasons for this increase in breathlessness are not clear.
PMID- 10759438
TI - Asthma morbidity 6 yrs after an effective asthma self-management programme in a
Maori community.
AB - A 6-month Maori community-based asthma self-management programme, involving a
"credit card" asthma self-management plan, has previously been shown to be an
effective and acceptable system for reducing asthma morbidity. The effectiveness
of the asthma self-management programme and participants' self-management
behaviour was assessed 6 yrs after the formal end of the programme. Participants
were surveyed at the time of enrollment, and 1, 2, and 6 yrs after completing the
programme. In each survey, participants were questioned on markers of asthma
morbidity and use of medical services during the previous 12 months. Self
management behaviour was assessed using a questionnaire at 2 years and 6 yrs. Of
the 69 original participants, 47 (68%) were surveyed after 6 yrs. They generally
had reduced severe asthma morbidity and emergency use of health services from
baseline. In particular, the proportion who had an emergency visit to a general
practitioner had decreased from 41% to 18% (p=0.02). However, the percentage of
nights woken due to asthma had returned to preintervention levels, and the
proportion of participants taking prescribed regular inhaled steroid had
decreased from 91% to 53% (p<0.001). Compared with 2 yrs after completion of the
asthma programme, self-management behaviour had also deteriorated, with 29%
versus 73% (p<0.001) using their peak flow meter daily when their asthma was
"getting bad" and 41% versus 86% (p<0.001) using the "credit card" plan to
increase the amount of inhaled steroids in the last year. Although the programme
participants were still experiencing reduced morbidity from their asthma 6 yrs
after the end of the self-management programme, the benefits were less than those
observed at 2 yrs. These findings suggest that under-recognition and under
treatment of asthma with appropriate amounts of inhaled steroids is a major
factor contributing to asthma morbidity in this indigenous rural community. To
obtain enduring benefits from a self-management system of care continued
reinforcement of self-management skills seems to be an essential component of any
follow-up.
PMID- 10759439
TI - Relationships of active smoking to asthma and asthma severity in the EGEA study.
Epidemiological study on the Genetics and Environment of Asthma.
AB - The role of smoking as potential risk factor, selection factor ("healthy smoker"
effect) and modifying factor (severity) of asthma was studied in the
Epidemiological study on the Genetics and Environment of Asthma, bronchial
hyperresponsiveness and atopy (EGEA). The analysis involved 200 adult asthmatic
cases recruited in chest clinics, 265 nonasthmatic controls and 586 relatives of
asthmatics (147 with asthma). Asthma in childhood was not associated with a
reduced take-up of smoking (odds ratio (OR)=1.06 in males and 0.98 in females),
but smoker asthmatic cases quit more often than controls (OR = 2.20 (95%
confidence interval (95% CI) 1.11-4.34) in males and 2.76 (1.19-6.42) in
females). Adult onset asthma was unrelated to ever smoking (OR 1.07 in males and
1.02 in females). In asthmatic cases, active smoking was associated with asthma
severity. Current smokers, compared to never and exsmokers, had more asthma
symptoms, more frequent (> or =1 attack x day(-1)) asthma attacks (OR 2.39 (95%
CI 1.06-5.36)) and higher asthma severity scores. No clear pattern regarding the
relationships of smoking habits with asthma was observed in first degree
relatives. It is concluded that active smoking is not a risk factor for asthma in
adulthood, but that smoking increases asthma severity.
PMID- 10759440
TI - Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect
on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen
induced T-cell proliferation.
AB - The authors have investigated whether the steroid-sparing effect of methotrexate
(MTX) in severe orally glucocorticoid-insensitive asthmatics may be accounted for
by the ability of this drug to increase the T-cell responsiveness sensitivity to
dexamethasone in vitro. In addition the authors have investigated whether low
dose MTX treatment is associated with anti-inflammatory effects in peripheral
blood and the bronchial mucosa. In eight patients with severe atopic asthma,
using > or =15 mg x day(-1) prednisolone, the inhibitory effect of dexamethasone
on mitogen stimulated peripheral blood mononuclear cells (PBMC) in vitro was
tested before and after 8 weeks of uncontrolled treatment with MTX. Endobronchial
biopsies were taken before and after MTX therapy in seven subsequent patients,
and analysed using immunohistochemistry. In eight patients, serum was drawn for
measuring levels of free interleukin (IL)-8. The in vitro sensitivity of PBMC to
dexamethasone (at 1.6 x 10(-9) and 3.2 x 10(-10) mol x L(-1)) was significantly
lower in the asthmatics before treatment when compared with the control subjects
(p=0.03 and =0.001) but increased significantly after MTX treatment (p=0.04 and
=0.02) to normal responsiveness. This was not associated with a decrease in
peripheral blood T-cell numbers or activation. Except for a significant increase
in the numbers of CD3+ (p=0.04), no significant numerical changes in activated T
cells, eosinophils, or mast cells were found (p>0.05). However, MTX treatment was
associated with a significant fall in serum levels of free IL-8 (p=0.03). It is
hypothesized that the steroid-sparing effect of methotrexate originates from
increased sensitivity of lymphocytes to the inhibitory effects of
glucocorticoids. The absence of an inhibitory effect on inflammatory cells in
blood and mucosa suggests that this effect is achieved by modulating cell
function rather than cell number.
PMID- 10759441
TI - Clinical judgement of airway inflammation versus sputum cell counts in patients
with asthma.
AB - The inflammatory component of asthma is usually assessed indirectly by symptoms
and spirometry, these may be inaccurate. It can now be assessed directly and
reliably by the examination of sputum cell counts. There is no information on how
clinical assessment of the presence and type of airway inflammation compares with
actual measurements. In this single-centre observational study, sputum was
collected from 76 consecutive adults with asthma attending a tertiary chest
clinic after their physicians had recorded the expected cell counts in sputum.
The authors examined the extent of agreement between clinical judgement of sputum
cell counts and actual counts in asthmatic patients (Cohen's Kappa) and the
possible predictors of agreement (multiple logistic regression). Sixty-seven of
the 76 sputum samples were suitable for analysis. Agreement between expected and
actual cell counts occurred in 30/67 patients. The overall agreement for the
different cell types was poor (estimated K=0.14, 95% confidence interval
(CI)=0.02, 0.26). The experience of the physician in using sputum cell counts in
clinical practice, steroid requirement at the time of assessment, and control of
asthma as assessed by the physician or by the patient could not predict the
chances of agreement or disagreement. Unaware of the sputum results, the
physicians often changed treatment in a way that seemed inappropriate for the
cell counts present. There is poor agreement between clinical judgement of the
presence and type of airway inflammation in asthmatic patients and sputum cell
counts. The impact of sputum examination on the outcomes of anti-inflammatory
treatment now needs investigation.
PMID- 10759442
TI - Local production and detection of (specific) IgE in nasal B-cells and plasma
cells of allergic rhinitis patients.
AB - Allergic diseases are characterized by allergic complaints in the shock organ and
specific immunoglobulin (Ig)E in serum. Literature data indicate that the nasal
mucosa itself could produce at least a large part of the specific IgE in allergic
rhinitis patients. In order to investigate this hypothesis, nasal mucosal
biopsies from the inferior turbinate were taken from symptomatic grass pollen
allergic rhinitis patients, symptomatic house dust mite allergic rhinitis
patients and nonallergic healthy controls, confirmed by radioallergosorbent test
and skin-prick test. Immunohistochemical double-staining was performed for B
cells (CD19) with IgE, plasma cells (CD138) with IgE and plasma cells with
biotinylated allergens. Significantly more IgE-positive B-cells and IgE-positive
plasma cells were found in the nasal mucosa of allergic patients than in that of
nonallergic controls. Double staining with biotinylated allergens and plasma
cells showed allergen-positive plasma cells in the nasal mucosa of allergic
patients and no allergen-positive plasma cells in the nasal mucosa of nonallergic
patients. Blocking experiments using polyclonal antibodies directed against IgE
showed a significant reduction in the number of allergen-positive cells in
contrast to experiments using polyclonal antibodies directed against IgG, IgA or
IgM. This study describes new evidence that specific immunoglobulin E is produced
locally in the nasal mucosa in patients with seasonal allergic rhinitis and
perennial allergic rhinitis, but not in nonallergic controls.
PMID- 10759443
TI - Effects of biphasic positive airway pressure in patients with chronic obstructive
pulmonary disease.
AB - Biphasic positive airway pressure (BiPAP) is a ventilatory mode in which two
pressure levels (higher (Phigh) and lower (Plow)) acting as continuous positive
airway pressure (CPAP) alternate at preset time intervals. BiPAP combines
pressure-controlled ventilation with unrestricted spontaneous breathing. BiPAP
has not yet been evaluated in patients with chronic obstructive pulmonary disease
(COPD). Therefore, the effects of BiPAP (15 cmH2O Phigh and 5 cmH2O Plow)
pressure support (PS; 15 cmH2O and positive end-expiratory pressure (PEEP) 5
cmH2O) and CPAP (5 cmH2O) on respiratory mechanics in COPD patients were
compared. Twenty-one COPD patients were supported in randomized order with BiPAP,
PS and CPAP. Pressure-time product (PTP), work of breathing (WOB), change in
oesophageal pressure (deltaPoes), mouth occlusion pressure (P0.1), intrinsic PEEP
(PEEPi), tension time index (TTI), respiratory frequency, and tidal volume (VT)
were measured. During BiPAP, the COPD patients showed a significantly higher PTP,
WOB, deltaPoes, P0.1, TTI and PEEPi than during PS. Comparing the Plow phases of
BiPAP and CPAP, the breaths during the Plow phases of BiPAP had a lower VT and a
greater WOB and PTP due to a higher PEEPi than on CPAP alone. In conclusion,
biphasic positive airway pressure carries the risk of increased work of breathing
in spontaneously breathing chronic obstructive pulmonary disease patients.
Pressure support is superior for reducing their respiratory muscle effort.
PMID- 10759444
TI - N-acetylcysteine prevents cigarette smoke induced small airways alterations in
rats.
AB - This study investigated the effect of cigarette smoke exposure and the potential
protection N-acetylcysteine (NAC) in rat lungs. Forty-eight rats were exposed to
cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral
intake of NAC 200 mg x rat(-1) x day(-1), or to fresh air (Control). All rat
lungs were assessed in terms of lung function, ventilation distribution
(nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry
(airway wall thickening of small, medium and large bronchi). The small bronchi,
defined as the airways with an internal perimeter <1,000 microm showed
significantly thicker airway walls in the CS than in the Control group. By
contrast, no airway wall thickening was observed in the CS+NAC group with respect
to Control. Except for decreased lung volumes and compliance in CS and CS+NAC
groups, which were entirely attributable to smaller body weight gain, lung
function was indistinguishable from Control. Phase III slopes were significantly
increased only in the CS group. In conclusion, smoke-induced alterations in the
rat lungs were reflected in wall thickening of the small bronchi and increased
ventilation maldistribution. These smoke-induced morphometric and ventilation
distribution alterations were prevented by N-acetylcysteine.
PMID- 10759445
TI - Subepithelial immunopathology of the large airways in smokers with and without
chronic obstructive pulmonary disease.
AB - Previous work has shown an increase in CD8+ T-cells, neutrophils and eosinophils
in small airway subepithelium in smokers. The authors have now investigated
whether similar changes occur in the large airways. Immunohistochemistry on
frozen sections of bronchial biopsies were obtained at bronchoscopy in 11
nonsmokers, eight asymptomatic smokers and 11 smokers with chronic bronchitis and
chronic obstructive pulmonary disease (COPD). There was an increase in the number
of CD8+ cells infiltrating the bronchial subepithelium in the COPD group compared
to the asymptomatic smokers (305 (109-400) versus 92 (41-550) cells x mm(-2),
p=0.030). There was a negative correlation between the number of CD8+ cells and
the forced expiratory volume in one second (FEV1) %predicted (p=0.005, r=-0.62),
and a positive correlation between the number of CD8+ cells and the number of
pack years smoked (p=0.017, r=0.42). There was a negative correlation between the
activated/total eosinophils ratio and the FEV1 % pred (p=0.017, r=-0.51). There
was a negative correlation between pack years smoked and the number of
neutrophils (p=0.022, r=-0.36). Smokers who develop chronic obstructive pulmonary
disease have increased numbers of CD8+ T-cells in large airways when compared to
asymptomatic smokers. Airway obstruction was associated with an increase in the
proportion of eosinophils that were activated.
PMID- 10759446
TI - Comparison of effects of supervised versus self-monitored training programmes in
patients with chronic obstructive pulmonary disease.
AB - The effects of two 8 week programmes of reconditioning in chronic obstructive
pulmonary disease (COPD) patients were studied. Forty one subjects (mean+/-SD)
644.5) yrs; forced expiratory volume in one second (FEV1) 1.09+/-0.16 L; 40.6+/
6.2% predicted were randomly assigned either to supervised training on a
treadmill, 4 days x week(-1) (group S; n=21) or walking 3 or 4 km in 1 h 4 days x
week(-1), self-monitored with a pedometer, with weekly visits to encourage
adherence (group SM; n=20). Patients were evaluated with the chronic respiratory
diseases questionnaire (CRQ) and two exercise tests on a treadmill: incremental
(IT) and constant (CT), above lactic threshold or 70% of maximal oxygen uptake
(VO2, max) with arterial blood lactate determinations. Estimated mean work rate
of training was 69+/-27 W and 25+/-5 W respectively for groups S and SM. Both
types of training produced similar changes in the four dimensions of the CRQ. In
group S reconditioning yielded significant (p<0.05) increases in VO2, max and
increases in duration, with decreased lactate accumulation, ventilation, CO2
output (VCO2), heart rate (HR) and diastolic blood pressure (DBP) at the end of
CT. They also adopted a deeper slower pattern of breathing during exercise. The
SM group showed significant (p<0.05) increases in duration, lower HR and DBP at
the end of CT. Significantly (p<0.05) different effects between S and SM
programmes were changes in VO2, max 100+/-101 mL x min(-1) versus 5+/-101 mL x
min(-1)), duration of the CT (8.1+/-4.4 min versus 3.9+/-4.7 min), VCO2 (-94+/
153 mL x min(-1) versus 48+/-252 mL x min(-1)), lactate accumulation (-1.3+/-2.2
mmol x L(-1) versus 0+/-1.2 mmol x L(-1) and respiratory rate at the end of CT
(4.3+/-3.4 min(-1) versus -1+/-4.2 min(-1)). Supervised, intense training yields
physiological improvements in severe chronic obstructive pulmonary disease
patients not induced by self-monitored training. The self-monitored, less intense
training, increases submaximal exercise endurance, although to a lesser degree.
PMID- 10759447
TI - Preservation of intraalveolar surfactant in a rat lung ischaemia/reperfusion
injury model.
AB - Ischaemia/reperfusion (I/R) injury, a major problem in clinical lung
transplantation, is associated with surfactant dysfunction. The present study
aimed to test the hypothesis that preservation related improvements in post
ischaemic lung function are associated with improved ultrastructural preservation
of pulmonary surfactant. Rat lungs were flush perfused with modified Euro-Collins
solutions (ECS), stored for 2 h at 4 degrees C, and reperfused for 40 min. Lungs
were preserved with conventional (ECS 115: 115 mmol x L(-1) K+), medium-K+ (ECS
40: 40 mmol x L(-1) K+), or low-K+ (ECS 10: 10 mmol x L(-1) K+) ECS. Functional
parameters were monitored during reperfusion (n=10 per group). After reperfusion,
left lungs were prepared for electron microscopical and stereological analysis of
surfactant (n=5 per group). In all three experimental groups notable I/R injury
developed which was lowest in ECS 40 as indicated by significantly less
intraalveolar oedema, higher perfusate oxygenation, and lower peak inspiratory
pressure. This was associated with a significantly superior preservation of the
ultrastructure of the surface active surfactant subtype tubular myelin in ECS 40
compared with ECS 115 and ECS 10. Stereological analysis revealed that the
relative amount of tubular myelin was highest in ECS 40 (mean+/-SEM; 6.2+/-0.8%)
compared with ECS 115 (3.0+/-1.0%) and ECS 10 (2.7+/-1.6%). Analysis of
surfactant in its natural location within the organ showed that the severity of
ischaemia/reperfusion injury correlates with differences in intraalveolar
surfactant composition. Improved post-ischaemic respiratory function achieved by
medium-K+ Euro-Collins solution is associated with superior ultrastructural
preservation of tubular myelin. It is concluded that the integrity of surface
active tubular myelin represents an important criterion for the assessment of
lung preservation quality.
PMID- 10759448
TI - Surfactant function affected by airway inflammation and cooling: possible impact
on exercise-induced asthma.
AB - Pulmonary surfactant maintains patency of narrow conducting airways. An
inflammation, with a leakage of plasma proteins into the airway lumen, causes
surfactant to lose some of this ability. Will a lowering of temperature aggravate
the deteriorating effect of an inflammation? Calf lung surfactant extract (CLSE)
with proteins added was studied with a capillary surfactometer (CS) at
temperatures of 25-42 degrees C. BALB/c mice were infected with respiratory
syncytial virus (RSV). Six days later the lungs were lavaged and the surfactant
in the lavage fluid was studied with the CS at temperatures of 25-42 degrees C.
Lavage fluid from allergen challenged asthmatics was examined for its content of
surfactant inhibitors at reduced temperatures. It was shown that CLSE with
proteins gradually lost its ability to maintain patency as the temperature was
lowered. Lavage fluid from the RSV infected mice showed a similar dysfunction at
low temperatures. Lavage fluid from the airways of human asthmatics, when
challenged with antigen but not with saline, contained agents inhibiting surface
activity, particularly at reduced temperatures. Airway inflammation causes
surfactant to lose its ability to maintain patency, particularly as the
temperature is reduced. That might be a reason for the increased airway
resistance observed in asthma patients hyperventilating in cold weather.
PMID- 10759449
TI - Sniff nasal inspiratory pressure as a marker of respiratory function in motor
neuron disease.
AB - Vital capacity (VC) and maximum mouth pressures are often used to monitor
respiratory function in motor neuron disease (MND), but require the use of a
mouthpiece. Sniff nasal inspiratory pressure (SNIP) is a simple and reliable
means of measuring inspiratory muscle strength; it does not involve the use of a
mouthpiece and might therefore be better than VC or mouth pressures for assessing
patients with bulbar disease. SNIP, maximum inspiratory (MIP) and expiratory
mouth pressure (MEP), VC and arterial carbon dioxide tension (Pa,CO2) were
measured in 59 consecutive patients attending a specialist MND clinic. Thirty-one
had bulbar involvement on clinical grounds. Both SNIP and VC were inversely
related to Pa,CO2 in nonbulbar patients only. Neither MIP nor MEP were related to
Pa,CO2. The 10 patients with an elevated Pa,CO2 (>6 kPa) had significantly lower
SNIP and VC than normocapnic patients. Sniff nasal inspiratory pressure can be
used to monitor respiratory function in motor neuron disease. It is quick and
easy for patients to perform, but otherwise appears to offer little advantage
over vital capacity measurement. Patients with bulbar disease are often poor at
performing sniff nasal inspiratory pressure manoeuvres, possibly because of upper
airway collapse or inability to close the mouth completely during the manoeuvre.
PMID- 10759450
TI - Four decades of surgery for bronchogenic carcinoma in one centre.
AB - Since the authors' initial experience in the surgical management of bronchogenic
carcinoma in 1956, more than 40 years have passed. The purpose of this report was
to review the authors' data and compare the results by decade (1956-1966; 1967
1976; 1977-1986; and 1987-1996) in order to assess the changing patterns in
bronchogenic carcinoma. A total of 1,597 thoracotomies have been performed.
Between the first and last decades of the study, patients' mean age increased
from 57 to 63 yrs, the ratio of males to females decreased from 19:1 to 3:1 and
the proportion of adenocarcinoma cases increased from 10 to 34%. The operative
mortality decreased from 10% in 1967- 1976 to 4% in 1987-1996 and the overall 5
yr survival improved from 27 to 36% during the same period. The rate of lobectomy
progressively increased from 32% in 1956-1966 to 61% in 1987-1996, whereas that
of pneumonectomy and exploratory thoracotomy decreased from 42 to 28% and from 20
to 4%, respectively. Changing patterns of patient characteristics, histology and
type of surgery were associated with a constant improvement in the overall 5-yr
survival. This improvement was particularly evident among patients with advanced
stage carcinoma.
PMID- 10759451
TI - P53 immunohistochemistry can identify bronchial dysplastic lesions proceeding to
lung cancer: a prospective study.
AB - Dysplasia is an important step in bronchial carcinogenesis and smokers present
more dysplastic lesions than nonsmokers. These lesions not always lead to
malignancy, so there is a need for additional, preferentially objective,
diagnostic markers. To verify whether immunohistochemical overexpression of p53
protein in dysplastic areas could be a predictive marker of the development of
lung cancer, we investigated p53 overexpression in 22 bronchial dysplastic
lesions obtained by fibrebronchoscopy from heavy smokers who were not diagnosed
as having lung cancer and were followed for a 4-yr period. Nine (41%) lesions
showed p53-positivity. Seven lung cancers (78%), mostly squamous cell carcinomas,
were detected within the follow-up in these patients and 3 in 13 (23%) patients
with p53-negative lesions. Lung cancer occurred in all seven patients with
dysplastic lesions showing >10% p53 positive nuclei. The positive predictive
value of p53 immunostaining for lung cancer was 78%. The negative predictive
value of p53 was 77%. p53 staining was not detected in squamous metaplasia
lesions without atypia and in normal bronchial epithelium. Our findings provide
evidence that p53-overexpression in bronchial dysplastic areas may be a
clinically useful marker for identifying patients proceeding to, at least,
squamous cell carcinoma and, in addition, may facilitate the detection of occult
tumours.
PMID- 10759452
TI - PM10 elemental composition and acute respiratory health effects in European
children (PEACE project). Pollution Effects on Asthmatic Children in Europe.
AB - The ability of particles with a 50% cut-off aerodynamic diameter of 10 microm
(PM10) to cause respiratory health effects possibly depends on their composition.
This study evaluated whether the soluble elemental concentrations in PM10 were
related to acute respiratory health effects. The Pollution Effects on Asthmatic
Children in Europe (PEACE) study is a multicentre study of the acute effects of
PM10 and other air pollution components on the respiratory health of children
with chronic respiratory symptoms in urban and suburban panels. Children, 1208,
divided among 17 panels were followed for > or =2 months. Exposure to air
pollution was monitored on a daily basis. Health status was monitored by twice
daily peak expiratory flow (PEF) measurements and a symptom diary. Median
concentrations of iron ranged 105-1,110 ng x m(-3) in the urban and 32-517 ng x
m(-3) in the suburban locations. The daily concentrations of most elements were
not associated with daily variation in PEF, prevalence of respiratory symptoms or
bronchodilator use. Silicon and iron concentrations tended to be negatively
associated with PEF, and positively associated with the prevalence of phlegm. In
two pollutant models, PM10 effect-estimates on phlegm prevalence were reduced and
lost significance, whereas the effect-estimates of iron or silicon remained
essentially unchanged. The effects of silicon and iron could not be separated. In
conclusion, this study provides only weak support for the hypothesis that daily
fluctuations in soluble elemental concentrations in ambient particulate matter
are responsible for acute health effects.
PMID- 10759453
TI - Farming practices and the respiratory health risks of swine confinement
buildings.
AB - This study investigated whether clean swine confinement buildings (SCB) are less
harmful to the respiratory system than older and dirtier facilities. Eight
healthy volunteers were exposed for 4 h, at 1 week intervals, to eight SCB
representing the widest possible range of cleanliness. Each volunteer and a
technician rated the SCB for cleanliness from 1-10, 1 being the cleanest
possible. Airborne dust, bacteria, endotoxin levels, molds, and ammonia were
measured. For each volunteer measured, before and after each exposure, forced
expiratory flows (forced expiratory volume in one second (FEV1), and forced vital
capacity), white cells in nasal wash and venous blood, and nasal lavage levels of
interleukin (IL)-8 and serum levels of IL-6. A methacholine challenge was
obtained at baseline and following each exposure. Cleanliness scores ranged 1.5
8.25. Mean airborne levels were: dust 3.54 mg x m(-3) bacteria 4.25 x 10(5) CFU x
m(-3); endotoxins 404 EU x m(-3); molds 883 CFU x m(-3); ammonia 20.7 parts per
million (ppm). Expiratory flows decreased after exposure (FEV1 from 4.8+/-0.7 to
4.4+/-0.7, p<0.001), neutrophils in the nasal wash and white blood cells
increased (28.5+/-37 to 424+/-207 x 10(3), 5.4+/-1.0 to 7.4+/-1.7 x 10(9) cells x
mL(-1) respectively), IL-8 increased from 158+/-311 to 2679+/-639 pg x mL(-1), IL
6 from 0.15+/-0.26 to 2.34+/-0.92 pg x mL(-1), (p<0.001). All SCB were similarly
harmful. In conclusion, modern farming has not succeeded in making swine
confinement buildings inoffensive to exposed subjects.
PMID- 10759454
TI - In vitro assessment of an ultrasonic flowmeter for use in ventilated infants.
AB - An ultrasonic flowmeter could be advantageous over a differential pressure
pneumotachograph having a constant error in varying conditions. The in vitro
accuracy of ultrasonic tidal volume (VT) estimates for ventilated infants were
evaluated. Flow linearity and frequency response were tested, as was the
influence of humidity and oxygen content on the accuracy of VT estimates. The
linearity was within the 5% limits between -350 and 350 mL x sec(-1) and was not
affected by the presence of an endotracheal tube (ET). The frequency response was
flat and unaffected by an ET up to 4.5 Hz. The VT in the range 7-100 mL, in air
showed a mean error of 0.1% (95% confidence interval (CI) -0.2-0.4%) with a
maximum and minimum of 6.5 and -3.5% respectively. Humidity did not affect
accuracy. After calibration in air, the maximal mean error for measurements in
pure oxygen was 3.0% (95% CI 1.9-4.1%). Repeated measurements over 5.5 h had a
mean error of 0.4% (95% CI -0.7-0.1%). The in vitro evaluation of an ultrasonic
flowmeter showed stable accuracy in mechanical ventilation conditions. Changing
connection geometry and oxygen content did not increase the error to a clinically
relevant degree. The flowmeter could therefore be a better alternative than the
pneumotachograph for ventilated infants.
PMID- 10759455
TI - Detection of inspiratory flow limitation during sleep by computer assisted
respiratory inductive plethysmography.
AB - The potential of respiratory inductive plethysmography (RIP) to detect
inspiratory flow limitation during sleep was investigated. Sixteen sleep apnoea
patients underwent polysomnography. Airflow by a flowmeter attached to a nasal
mask, oesophageal and mask pressure were recorded along with calibrated RIP.
Presence of inspiratory flow limitation was defined by constant or decreasing
flow without pressure dependence throughout significant portions of inspiration,
its absence by a linear or mildly alinear pressure:airflow relationship. Based on
this standard, three of various computerized RIP derived parameters, with highest
performance to detect flow limitation, were identified. They were combined to an
inspiratory flow limitation, (IFL)-Index(RIP), which was validated prospectively
in another 10 sleep apnoea patients. RIP derived fractional inspiratory time,
peak to mean inspiratory flow ratio, and ribcage contribution to tidal volume had
the highest accuracy to detect flow limitation (area under the receiver operating
characteristic (ROC) curves 0.81, 0.76, 0.76, respectively, 160 comparisons).
Prospective validation revealed an area under the ROC curve for the IFL
Index(RIP) to detect flow limitation of 0.89 (95% confidence interval 0.85 to
0.93, 200 comparisons) with sensitivity and specificity at the point of equality
of 80%. It is concluded that inspiratory flow limitation may be assessed by
computer assisted analysis of respiratory inductive plethysmography derived
breathing patterns with clinically acceptable accuracy.
PMID- 10759456
TI - Anti-inflammatory properties of ebselen in a model of sephadex-induced lung
inflammation.
AB - Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound
which protects tissues against oxidative stress. Furthermore, recent data has
suggested that this compound possesses a range of anti-inflammatory properties.
In this study the authors have investigated the effects of ebselen on Sephadex
induced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)
alpha and endothelin(ET)-1 levels in rats. Sephadex administration induced lung
oedema which was accompanied by an increase in BAL TNF-alpha and ET-1 levels.
Ebselen administration (1-30 mg x kg(-1), i.p. at 0, 4 and 12 h post Sephadex)
significantly inhibited lung oedema (dose that produced 50% of the maximum
inhibition of lung oedema 4.6 mg x kg(-1)) and BAL TNF-alpha levels in a dose
related manner with no effect on ET-1 levels. These data suggest that ebselen may
be a useful therapy in lung pathologies in which bronchiolar inflammation is a
feature.
PMID- 10759457
TI - Constitutive nuclear factor-kappaB activity in human upper airway tissues and
nasal epithelial cells.
AB - Respiratory epithelial cells are actively involved in the host defence and
inflammatory reactions of the airways. Nuclear factor-kappaB (NF-kappaB) is a
transcription factor that plays a pivotal role in many cellular responses to
environmental changes. The inducible nitric oxide synthase (iNOS) isoform has
been implicated in airway inflammation as well as in normal airway function. In
this study, the hypothesis that NF-kappaB may be associated with iNOS expression
in airway epithelium, not only in inflammatory processes but also under
physiological conditions was examined. NF-kappaB deoxyribonucleic acid-binding
activity was assayed by means of electrophoretic mobility shift assay (EMSA) and
iNOS expression examined using immunohistochemical techniques in healthy nasal
mucosa and chronically inflamed nasal polyps. Further NF-kappaB activity was
assayed; by means of EMSA, in nasal epithelial cells isolated from both tissues.
NF-kappaB was activated in nasal polyps, but also to the same extent in healthy
nasal mucosa. Uniform iNOS expression was localized within the airway epithelium
in both inflamed and noninflamed tissues. Along with iNOS expression, concomitant
NF-kappaB activation was found in nasal epithelial cells obtained from both
tissues and no differences were observed when nasal mucosa and nasal polyp were
compared. These results suggest that constitutive nuclear factor-kappaB and
concurrent inducible nitric oxide synthase expression in epithelial cells may
play a physiological role in airway function.
PMID- 10759458
TI - Steering simulation performance in patients with obstructive sleep apnoea and
matched control subjects.
AB - Patients with obstructive pulmonary disease (OSA) have an increased rate of
driving accidents, perhaps due to poor vigilance or impaired cognitive skills
that influence their driving ability. The authors have assessed whether patients
with OSA perform differently to control subjects on a steering simulator which
allows the separate assessment of the two visual tasks required for steering a
car, immediate positioning on road with reference to the road edges, and
assessment of the curve of the oncoming road which allows faster driving. Twelve
patients with OSA and 12 control subjects, matched for age, sex and driving
experience, performed three 30-min drives with either all the oncoming road
visible, only the near part of the road visible, or only the distant part of the
road visible. Steering was assessed by measuring the SD around the theoretical
perfect path (steering error) and the number of times the driver went "off road".
Subjects identified the appearance of target numbers at the four corners of the
screen as quickly as possible, thus making the test a divided attention task.
Patients with OSA performed significantly less well on the three different road
fields as measured by steering error (p<0.001), time to detect the target number
(p<0.03), and off road events (p<0.03). The patients appeared to be particularly
impaired on the two drives when only part of the road ahead was available to
guide steering. This steering simulator, with its more realistic view of the road
ahead, identifies impaired performance in patients with obstructive sleep apnoea.
In addition it suggests that patients with obstructive sleep apnoea may be more
disadvantaged compared to normal subjects when the view of the road ahead is
limited (such as in fog).
PMID- 10759459
TI - Assessment of diaphragm paralysis with oesophageal electromyography and
unilateral magnetic phrenic nerve stimulation.
AB - The purpose of this study was to establish a sensitive and reliable method of
diagnosing diaphragm paralysis by recording the diaphragm compound muscle action
potential (CMAP) using a multipair oesophageal electrode and unilateral magnetic
phrenic nerve stimulation. An oesophageal electrode catheter was designed
containing six coils (1 cm wide and 3 cm apart), creating an array of four
sequential electrode pairs. The oesophageal catheter was taped at the nose with
the proximal electrode pair 40 cm from the nares. Eight patients with unilateral
(n=5) or bilateral (n=3) diaphragm paralysis were studied. Five to seven phrenic
nerve stimulations were performed at 80% of maximum magnetic stimulator output
and the CMAPs were recorded simultaneously from the four pairs of electrodes. In
the five patients with unilateral diaphragm paralysis, the CMAP amplitudes and
latencies were 1.16+/-0.29 mV and 7.6+/-1.5 ms for functioning sides. No
diaphragm CMAP could be detected when stimulating nonfunctioning phrenic nerves.
This study shows that diaphragm paralysis can be reliably diagnosed by unilateral
magnetic stimulation combined with a multipaired oesophageal electrode.
PMID- 10759460
TI - The contractile apparatus and mechanical properties of airway smooth muscle.
AB - The functional properties of airway smooth muscle are fundamental to the
properties of the airways in vivo. However, many of the distinctive
characteristics of smooth muscle are not easily accounted for on the basis of
molecular models developed to account for the properties of striated muscles. The
specialized ultrastructural features and regulatory mechanisms present in smooth
muscle are likely to form the basis for many of its characteristic properties.
The molecular organization and structure of the contractile apparatus in smooth
muscle is consistent with a model of force generation based on the relative
sliding of adjacent actin and myosin filaments. In airway smooth muscle,
actomyosin activation is initiated by the phosphorylation of the 20 kDa light
chain of myosin; but there is conflicting evidence regarding the role of myosin
light chain phosphorylation in tension maintenance. Tension generated by the
contractile filaments is transmitted throughout the cell via a network of actin
filaments anchored at dense plaques at the cell membrane, where force is
transmitted to the extracellular matrix via transmembrane integrins. Proteins
bound to actin and/or localized to actin filament anchorage sites may participate
in regulating the shape of the smooth muscle cell and the organization of its
contractile filament system. These proteins may also participate in signalling
pathways that regulate the crossbridge activation and other functions of the
actin cytoskeleton. The length-dependence of active force and the mechanical
plasticity of airway smooth muscle may play an important role in determining
airway responsiveness during lung volume changes in vivo. The molecular basis for
the length-dependence of tension in smooth muscle differs from that in skeletal
muscle, and may involve mechano-transduction mechanisms that modulate contractile
filament activation and cytoskeletal organization in response to changes in
muscle length. The reorganization of contractile filaments may also underlie the
plasticity of the mechanical response of airway smooth muscle. Changes in the
structural organization and signalling pathways of airway smooth muscle cells
resulting form alterations in mechanical forces in the lung may be important
factors in the development of pathophysiological conditions of chronic airway
hyperresponsiveness.
PMID- 10759461
TI - Inspiratory vocal cord dysfunction, a new approach in treatment.
AB - Vocal cord dysfunction is a well recognized respiratory condition in which
adduction of the vocal cords during either inspiration or expiration, or both,
causes functional airways obstruction. Diagnosis is usually made by
laryngofibreoscopy, however treatment of this condition has generally been
unsatisfactory, requiring a multi-disciplinary approach consisting of speech
therapy, psychological counselling, sedatives and anaesthetic agents. Here we use
an innovative approach which requires relatively inexpensive and simple
anaesthetic equipment in order to manipulate airways resistance and thus reduce
any vocal cord dysfunction as it occurs. The patient involved found instant
relief when using this simple device which is easy to use and is portable.
PMID- 10759462
TI - Detection of measles virus genome in bronchoalveolar lavage cells in a patient
with measles pneumonia.
AB - Measles is frequently complicated with pneumonia that could be fatal in numerous
occasions. However, a prompt and precise diagnosis of measles is not easily made
particularly in the early stage of the disease, or in immunocompromised
individuals because of the lack of typical clinical features or the defect in
antigen-specific antibody production. In the present paper, we describe a 27-yr
old male who developed fever, skin rash typical of measles, and diffuse pulmonary
infiltrates associated with respiratory failure. Infection of lung cells with
measles virus was proved by detection of viral genome ribonucleic acid within
alveolar macrophages and lymphocytes recovered by bronchoalveolar lavage using
reverse transcription-polymerase chain reaction amplification. These techniques
may offer a useful tool to make the swift and precise diagnosis of measles
pneumonia, thus allowing appropriate therapeutic approaches to the disease.
PMID- 10759463
TI - Pulmonary manifestation of systemic mast cell disease.
AB - Systemic mast cell disease is a rare disease of unknown aetiology. Systemic
infiltration and proliferation of mast cells in skin, bone marrow,
gastrointestinum and lymph nodes is the central pathological feature. This study
reports a patient with mastocytosis of the skin (urticaria pigmentosa) for 10
yrs. The patient was referred to hospital for dyspnoea. Chest radiograph showed
moderate reticular infiltration of both lungs, computerized tomography revealed
multiple lymph nodes of the mediastinum and faint nodular lesions of middle and
upper areas of lungs. Transbronchial biopsy demonstrated mast cell infiltration
of the lung with formation of mast cell granuloma. According to the current
literature, systemic mast cell disease with pulmonary involvement is a very rare
entity. After a treatment with interferon alpha-2a over 6 months, the patient's
condition and particularly dyspnoea showed improvement in parallel with an
amelioration of the lesions as demonstrated by thorax computed tomography.
PMID- 10759464
TI - Montelukast and Churg-Strauss syndrome.
PMID- 10759465
TI - Faster is better--it's rarely that simple!
PMID- 10759466
TI - Risk stratification in acute coronary syndrome using cardiac troponin I.
PMID- 10759467
TI - Rapid screening of high-risk patients for disorders of purine and pyrimidine
metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or
urine-soaked filter paper strips.
AB - BACKGROUND: A rapid and specific screening method for patients at risk of
inherited disorders of purine and pyrimidine metabolism is desirable because
symptoms are varied and nonspecific. The aim of this study was to develop a rapid
and specific method for screening with use of liquid urine samples or urine
soaked filter paper strips. METHODS: Reverse-phase HPLC was combined with
electrospray ionization (ESI), tandem mass spectrometry (MS/MS), and detection
performed by multiple reaction monitoring. Transitions and instrument settings
were established for 17 purines or pyrimidines. Stable-isotope-labeled reference
compounds were used as internal standards when available. RESULTS: Total analysis
time of this method was 15 min, approximately one-third that of conventional HPLC
with ultraviolet detection. Recoveries were 96-107% in urine with added analyte,
with two exceptions (hypoxanthine, 64%; xanthine, 79%), and 89-110% in urine
soaked filter paper strips, with three exceptions (hypoxanthine, 65%; xanthine,
77%; 5-hydroxymethyluracil, 80%). The expected abnormalities were easily found in
samples from patients with purine nucleoside phosphorylase deficiency, ornithine
transcarbamylase deficiency, molybdenum cofactor deficiency, adenylosuccinase
deficiency, or dihydropyrimidine dehydrogenase deficiency. CONCLUSIONS: HPLC-ESI
MS/MS of urine allows rapid screening for disorders of purine and pyrimidine
metabolism. The filter paper strips offer the advantage of easy collection,
transport, and storage of the urine samples.
PMID- 10759468
TI - Clinical efficacy of three assays for cardiac troponin I for risk stratification
in acute coronary syndromes: a Thrombolysis In Myocardial Infarction (TIMI) 11B
Substudy.
AB - BACKGROUND: Significant analytic variability exists between the multiple assays
for cardiac troponin I (cTnI) approved for clinical use. Until adequate cTnI
standardization is possible, an evidence-based approach evaluating each assay at
specific thresholds appears warranted. METHODS: We examined the efficacy of three
cTnI assays for predicting death, myocardial infarction (MI), or the composite of
death, MI, or urgent revascularization at 43 days among patients with non-ST
elevation acute coronary syndromes enrolled in the Thrombolysis In Myocardial
Infarction (TIMI) 11B study. RESULTS: Six hundred eighty-one patients with serum
samples obtained at baseline and/or 12-24 h had cTnI determined using all three
assays. Baseline cTnI was > or = 0.1 microg/L for 368, 395, and 418 patients with
the Bayer Immuno 1(TM), ACS:180, and Dimension RxL assays, respectively.
Correlation coefficients for the RxL with the ACS:180 and Bayer Immuno 1 results
were 0.89 (P = 0.0001) and 0.87 (P = 0.0001), with a coefficient of 0.92 (P =
0.0001) for the ACS:180 and Bayer Immuno 1 assays. Patients with cTnI > or = 0.1
microg/L were at increased risk fo death or MI by 43 days (relative risk, 2.2
3.0; P <0.0006), regardless of the assay used. This prognostic capacity persisted
among those with creatine kinase MB isoenzyme concentrations within the reference
interval. Moreover, cTnI was the strongest multivariate predictor of death, MI,
or urgent revascularization with adjusted odds ratios of 2.1-2.9 (P <0. 0006).
CONCLUSION: This study demonstrates the prognostic efficacy of three
independently developed cTnI assays at a threshold of 0.1 microg/L for the
prediction of adverse clinical outcomes among patients with non-ST-elevation
acute coronary syndromes.
PMID- 10759469
TI - Evaluation of four automated high-sensitivity C-reactive protein methods:
implications for clinical and epidemiological applications.
AB - BACKGROUND: C-reactive protein (CRP) can provide prognostic information about the
risk of developing atherosclerotic complications in apparently healthy patients.
This new clinical application requires quantification of CRP concentrations below
those traditionally measured in the clinical laboratory. METHODS: The Dade
Behring BN II, the Abbott IMx, the Diagnostic Products Corporation IMMULITE, and
the Beckman Coulter IMMAGE are four automated analyzers with high-sensitivity CRP
(hs-CRP) methods. We evaluated these assays for precision, linearity, and
comparability with samples from 322 apparently healthy blood donors. RESULTS: The
imprecision (CV) of the BN II, IMx, IMMULITE, and IMMAGE methods was < or = 7.6%,
< or = 12%, < or = 9.8%, and < or = 9.7% at 3.5 mg/L, respectively. The BN II,
IMx, IMMULITE, and IMMAGE methods were linear down to < or = 0.30, < or = 0.32, <
or = 0.85, and 2.26 mg/L, respectively. CRP concentrations demarcating each
quartile in a healthy population were method dependent. The IMx method gave
results comparable to the BN II method for values in the reference interval. The
IMMULITE method had a positive intercept compared with the BN II method. The
IMMAGE method demonstrated more scatter and a positive intercept compared with
the BN II method, which may reflect the fact that it is a less sensitive assay.
CONCLUSIONS: The four hs-CRP methods exhibited differences in results for a
healthy population. Additional standardization efforts are required to ensure
that hs-CRP results can be related to large-scale epidemiologic studies.
PMID- 10759470
TI - Development of a kinetic assay for band 5b tartrate-resistant acid phosphatase
activity in serum.
AB - BACKGROUND: Band 5 tartrate-resistant acid phosphatase (TrACP; EC 3. 1.3.2)
consists of two isoenzymes, bands 5a and 5b, of which band 5b TrACP is considered
to be derived from bone. However, no kinetic method for the specific measurement
of band 5b TrACP in serum is available. Our aim was to develop a kinetic assay
method for the specific measurement of band 5b TrACP in serum. METHODS: Band 5b
TrACP was measured kinetically in serum as tartrate-resistant fluoride-sensitive
heparin-resistant ACP with 2, 6-dichloro-4-acetylphenyl phosphate as substrate at
pH 6.6. RESULTS: Heparin inhibited band 5a TrACP but had no effect on band 5b
TrACP in serum or in bone extract. The presence of EDTA or ascorbic acid had no
effect, but dithiothreitol inhibited enzyme activity. The within-run (n = 20) and
between-run (n = 20) CVs of band 5b TrACP activity were 3.3-5.8% and 5.0-7.3%,
respectively. The mean +/- SD values of band 5b TrACP activity in males (n = 25)
and females (n = 57) 20-29 years of age by this method were 8.0 +/- 2.2 U/L and
6.4 +/- 1.8 U/L, respectively. The band 5b TrACP value was significantly higher
in females >50 years of age compared with the younger subjects (20-29 years). The
highest band 5b TrACP values were among children younger than 15 years.
CONCLUSIONS: This kinetic assay is a simple and specific method for the
measurement of band 5b TrACP in serum samples and is useful in the evaluation of
bone turnover activity.
PMID- 10759471
TI - Analysis of free prostate-specific antigen (PSA) after chemical release from the
complex with alpha(1)-antichymotrypsin (PSA-ACT).
AB - BACKGROUND: Prostate-specific antigen (PSA), a marker for prostate cancer (CaP),
forms a covalent complex with alpha(1)-antichymotrypsin (ACT) in human blood.
Structural analysis of the PSA-ACT complex is difficult, and complexation may be
a reason for biased immunological assays when compared with the analysis of free
PSA. We developed a method to cleave the PSA-ACT complex chemically. The
liberated PSA was thus available for analysis as free PSA (F-PSA). METHODS: PSA
was released from the PSA-ACT complex by cleaving the interprotein ester bond
with ethanolamine under alkaline conditions. The release was followed by reversed
phase HPLC and an immunoassay for F-PSA. Released PSA obtained from human blood
was further immunopurified and analyzed by matrix-assisted laser desorption
induced time of flight (MALDI-TOF) mass spectrometry. RESULTS: In vitro-prepared
PSA-ACT complex was completely cleaved by treatment with nucleophilic compounds
such as ethanolamine at pH 9-10. The released PSA was stable under these
conditions and could be measured by reversed-phase HPLC as well as the ENZYMUN
immunoassay for F-PSA. When plasma from a CaP patient [containing 190 microg/L F
PSA and 1890 microg/L total PSA (T-PSA)] was treated under similar conditions, a
concentration of approximately 1600 microg/L F-PSA was measured at the end of the
incubation, indicating that the PSA-ACT complex was completely cleaved. Two
benign prostatic hyperplasia and CaP sera panels (12 and 13 sera, respectively)
containing 4-45 microg/L T-PSA were similarly treated. The concentrations of F
PSA measured after incubation were, on average, 85% of the T-PSA values of the
untreated sera. Finally, the PSA released from the complex of the CaP plasma was
isolated by immunosorption, analyzed by MALDI-TOF mass spectrometry, and compared
to PSA obtained from semen. The intact PSA as well as the peptides observed after
digestion with endoproteinase Lys C did not reveal any structural difference
between the PSA from these two sources. CONCLUSIONS: PSA complexed to ACT in
plasma of a CaP patient seems to be structurally very similar to the PSA
reference material from semen. The release of PSA from the PSA-ACT complex allows
F-PSA and T-PSA to be measured by the same immunological assay, thus eliminating
any possible bias between two different assays.
PMID- 10759472
TI - Investigation by isoelectric focusing of the initial carbohydrate-deficient
transferrin (CDT) and non-CDT transferrin isoform fractionation step involved in
determination of CDT by the ChronAlcoI.D. assay.
AB - BACKGROUND: The introduction of a new set of reagents for the determination of
carbohydrate-deficient transferrin (CDT) as a marker of chronic alcohol abuse
requires an independent evaluation of the analytic specificity of the test. This
information is needed for correct interpretation and classification of test
results. METHODS: Isoelectric focusing on the PhastSystem(TM) followed by
immunofixation, silver staining, and densitometry was used to validate the
initial transferrin isoform fractionation step on anion-exchange microcolumns
involved in the ChronAlcoI.D. assay. RESULTS: The in vitro transferrin iron load
was complete and stable. The CDT and non-CDT transferrin fractionation on anion
exchange microcolumns was reliable and reproducible (CV < or = 10%). Except for
quantitatively unimportant traces of trisialo-Fe(2)-transferrin (<5% of total
CDT), only asialo-, mono-, and disialo-Fe(2)-transferrin were detected in the
microcolumn eluates (n = 170). There was a loss of proportionally similar amounts
of asialo-Fe(2)-transferrin (during column rinsing) and disialo-Fe(2)-transferrin
(on the anion exchanger). Thus, the peak height ratios for disialo- and asialo
Fe(2)-transferrin did not change from >1 (serum) to <1 (eluates) as described for
the CDTect assays. The transferrin patterns in the ChronAlcoI.D. eluates were
representative of those in serum. Transferrin D variants with isoelectric points
close to that of trisialo-Fe(2)-transferrin C1 did not cause overdetermination of
CDT by the ChronAlcoI.D. test. CONCLUSIONS: The initial CDT and non-CDT
fractionation step involved in determination of CDT by the ChronAlcoI.D. assay is
efficient for eliminating non-CDT transferrins from serum before quantification
of CDT in the final turbidimetric immunoassay. We recommend IEF for validation of
other (commercial) CDT analysis methods and of odd CDT results.
PMID- 10759474
TI - Analytical and clinical performance of a detergent-based homogeneous LDL
cholesterol assay: a multicenter evaluation.
AB - BACKGROUND: LDL-cholesterol (LDL-C) concentrations currently are determined in
most clinical laboratories using the Friedewald calculation. This approach has
several limitations and may not always meet the current total error
recommendation in LDL-C measurement of 4 g/L (r = 0.91). Bias
(2.88% +/- 12%) and total error (7.84%) were unchanged at TG concentrations up to
18.5 g/L. Electrophoresis predicted National Cholesterol Education Program cut
points with <0.04 g/L error, exactly and appropriately classified 79% and 96% of
the subjects, and divided by 2.4 (all subjects) and 5.8 (TGs >1.5 g/L) the
percentage of subjects underestimated by calculation. One-half of the patients
with TGs >4 g/L had LDLC >1.30 g/L. For HDLC, correlation was better with
precipitation (r = 0.87) than ultracentrifugation (r = 0.76). Error (-0.10% +/-
26%) increased when HDLC decreased (<0.35 g/L). Direct assessment of the
LDLC/HDLC ratio detected 45% more high-risk subjects than the
calculation/precipitation combination. CONCLUSIONS: Electrophoresis provides
reliable quantification of LDLC, improving precision, accuracy, and concordance
over calculation, particularly with increasing plasma TGs. Implementation of
methods to detect low cholesterol concentrations could extend the applications
for HDLC assessment.
PMID- 10759476
TI - Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone
sulfate concentrations in patients with hyperthyroidism and hypothyroidism.
AB - BACKGROUND: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate
(DHEA-S) have been suggested to have protective effects against cardiovascular
disease, cancer, immune-modulated diseases, and aging. We examined serum
concentrations of DHEA, DHEA-S, and pregnenolone sulfate (PREG-S) in patients
with thyroid dysfunction. METHODS: Steroids extracted with methanol from serum
sample were separated into an unconjugated fraction (DHEA) and a monosulfate
fraction (DHEA-S and PREG-S), using a solid-phase extraction and an ion-exchange
column. After separation of unconjugated steroids by HPLC, the DHEA concentration
was measured by enzyme immunoassay. The monosulfate fraction was treated with
arylsulfatase, and the freed steroids were separated by HPLC. The DHEA and PREG
fractions were determined by gas chromatography-mass spectrometry, and the
concentrations were converted into those of DHEA-S and PREG-S. RESULTS: Serum
concentrations of DHEA, DHEA-S, and PREG-S were all significantly lower in
patients with hypothyroidism (n = 24) than in age- and sex-matched healthy
controls (n = 43). By contrast, in patients with hyperthyroidism (n = 22), serum
DHEA-S and PREG-S concentrations were significantly higher, but the serum DHEA
concentration was within the reference interval. Serum concentrations of these
three steroids correlated with serum concentrations of thyroid hormones in these
patients. Serum albumin and sex hormone-binding globulin concentrations were not
related to these changes in the concentration of steroids. CONCLUSIONS: Serum
concentrations of DHEA, DHEA-S, and PREG-S were decreased in hypothyroidism,
whereas serum DHEA-S and PREG-S concentrations were increased but DHEA was normal
in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these
steroids, and DHEA sulfotransferase might be increased in hyperthyroidism.
PMID- 10759477
TI - Simple microplate method for determination of urinary iodine.
AB - BACKGROUND: Urinary iodine is a good biochemical marker for control of iodine
deficiency disorders. Our aim was to develop and validate a simple, rapid, and
quantitative method based on the Sandell-Kolthoff reaction, incorporating both
the reaction and the digestion process into a microplate format. METHODS: Using a
specially designed sealing cassette to prevent loss of vapor and cross
contamination among wells, ammonium persulfate digestion was performed in a
microplate in an oven at 110 degrees C for 60 min. After the digestion mixture
was transferred to a transparent microplate and the Sandell-Kolthoff reaction was
performed at 25 degrees C for 30 min, urinary iodine was measured by a microplate
reader at 405 nm. RESULTS: The mean recovery of iodine added to urine was 98%
(range, 89-109%). The theoretical detection limit, defined as 2 SD from the zero
calibrator, was 0.11 micromol/L (14 microg/L iodine). The mean intra- and
interassay CVs for samples with iodine concentrations of 0.30-3.15 micromol/L
were < or = 10%. The new method agreed well with the conventional chloric acid
digestion method (n = 70; r = 0.991; y = 0.944x + 0.04; S(y|x) = 0.10) and with
the inductively coupled plasma mass spectrometry method (n = 61; r = 0.979; y =
0.962x + 0.03; S(y|x) = 0.20). The agreement was confirmed by difference plots.
The distributions of iodine concentrations for samples from endemic areas of
iodine deficiency diseases showed similar patterns among the above three methods.
CONCLUSIONS: Our new method, incorporating the whole process into a microplate
format, is readily applicable and allows rapid monitoring of urinary iodine.
PMID- 10759478
TI - Simple and sensitive binding assay for measurement of adenosine using reduced S
adenosylhomocysteine hydrolase.
AB - BACKGROUND: Adenosine has been suggested to play an important role in the
regulation of renal function. We developed a simple and sensitive binding assay
for the detection of adenosine based on the displacement of [(3)H]adenosine from
S-adenosylhomocysteine (SAH) hydrolase in its reduced form. METHODS: SAH
hydrolase was purified to apparent homogeneity from bovine kidney by standard
chromatographic methods. SAH hydrolase was converted in its reduced form, which
had the advantage that the SAH hydrolase is enzymatically inactive. This reduced
enzyme retains its ability to bind adenosine with high affinity. To determine
adenosine in urine or tissues, samples must be deproteinized (e.g., with 10 g/L
sulfosalicylic acid or 0.6 mol/L perchloric acid). RESULTS: The reduced SAH
hydrolase bound adenosine with a dissociation constant of 33.0 +/- 2 nmol/L.
Displacement of adenosine binding by the adenine 5'-nucleotides, adenine and
hypoxanthine, required >1000-fold higher concentrations than adenosine itself.
The intra- and interassay imprecision (CV) was <3.9% and 7.8%, respectively, and
the values obtained showed acceptable correlation with those by HPLC.
CONCLUSIONS: The highly sensitive adenosine-binding protein assay is a simple
test that allows detection of adenosine in samples with small volumes without
purification, and is in this respect superior to HPLC.
PMID- 10759479
TI - Clinical outcomes of point-of-care testing in the interventional radiology and
invasive cardiology setting.
AB - BACKGROUND: Point-of-care testing (POCT) can provide rapid test results, but its
impact on patient care is not well documented. We investigated the ability of
POCT to decrease inpatient and outpatient waiting times for cardiovascular
procedures. METHODS: We prospectively studied, over a 7-month period, 216
patients requiring diagnostic laboratory testing for coagulation (prothrombin
time/activated partial thromboplastin time) and/or renal function (urea nitrogen,
creatinine, sodium, and potassium) before elective invasive cardiac and
radiologic procedures. Overall patient management and workflow were examined in
the initial phase. In phase 2, we implemented POCT but utilized central
laboratory results for patient management. In phase 3, therapeutic decisions were
based on POCT results. The final phase, phase 4, sought to optimize workflow
around the availability of POCT. Patient wait and timing of phlebotomy,
availability of laboratory results, and therapeutic action were monitored. Split
sampling allowed comparability of POCT and central laboratory results throughout
the study. RESULTS: In phase 1, 44% of central laboratory results were not
available before the scheduled time for procedure (n = 135). Mean waiting times
(arrival to procedure) were 188 +/- 54 min for patients who needed renal testing
(phase 2; n = 14) and 171 +/- 76 min for those needing coagulation testing (n =
24). For patients needing renal testing, POCT decreased patient wait times
(phases 3 and 4 combined, 141 +/- 52 min; n = 18; P = 0.02). For patients needing
coagulation testing, wait times improved only when systematic changes were made
in workflow (phase 4, 109 +/- 41 min; n = 12; P = 0.01). CONCLUSIONS: Although
POCT has the potential to provide beneficial patient outcomes, merely moving
testing from a central laboratory to the medical unit does not guarantee improved
outcomes. Systematic changes in patient management may be required.
PMID- 10759480
TI - Seasonal and biological variation of blood concentrations of total cholesterol,
dehydroepiandrosterone sulfate, hemoglobin A(1c), IgA, prolactin, and free
testosterone in healthy women.
AB - BACKGROUND: Concentrations of physiological response variables fluctuate over
time. The present study describes within-day and seasonal fluctuations for total
cholesterol, dehydroepiandrosterone sulfate (DHEA-S), hemoglobin A(1c) (HbA(1c)),
IgA, prolactin, and free testosterone in blood, and estimates within- (CV(i)) and
between-subject (CV(g)) CVs for healthy women. In addition, the index of
individuality, prediction intervals, and power calculations were derived.
METHODS: A total of 21 healthy female subjects participated in the study. Using a
random effects analysis of variance, we estimated CV(g) and total within-subject
variation (CV(ti)), i.e., the combined within-subject and analytical variation,
from logarithmically transformed data. Analytical variation was subtracted from
CV(ti) to give CV(i). CV(i) was estimated from samples taken monthly during 1
year (CV(iy)), weekly during 1 month (CV(im)), and six times within 1 day
(CV(id)). RESULTS: A cyclic seasonal variation was demonstrated for total
cholesterol, DHEA-S, HbA(1c), prolactin, and free testosterone. Within-day
variation was shown for prolactin and free testosterone. The overall mean values
for the group and the variability (CV(iy) and CV(g)) were: 5.1 mmol/L, 13%
[corrected], and 12% [corrected] for total cholesterol; 6.6 micromol/L, 20%
[corrected], and 49% [corrected] for DHEA-S; 30% [corrected], 7.0% [corrected],
and 7.5% [corrected] for HbA(1c)/hemoglobin(total); 2.1 g/L, 5.9%, and 13% for
IgA; 136 mIU/L, 58% [corrected], and 63% [corrected] for prolactin; and 5.4
pmol/L, 55% [corrected], and 68% [corrected] for free testosterone. CONCLUSIONS:
Collecting samples at specific hours of the day or times of the year may reduce
high biological variation. Alternatively, the number of individuals may be
increased and a paired study design chosen to obtain adequate statistical power.
PMID- 10759481
TI - Fluorimetric measurement of plasma alpha-L-fucosidase activity with a centrifugal
analyzer: reference values in a healthy French adult population.
PMID- 10759482
TI - Lipid and carbohydrate metabolism in acatalasemia.
PMID- 10759483
TI - Effect of prolonged storage on the activities of superoxide dismutase,
glutathione reductase, and glutathione peroxidase.
PMID- 10759484
TI - Response to acute osteoclast activity inhibition assessed by the determination of
C-telopeptide of type I collagen in serum.
PMID- 10759485
TI - Effects of nine hemoglobin variants on five glycohemoglobin methods.
PMID- 10759486
TI - Preliminary evaluation of the Vitros ECi cardiac troponin I assay.
PMID- 10759487
TI - Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical
and anatomic findings.
AB - Propofol, a central-acting sedative agent, has been implicated in the development
of rhabdomyolysis in children. We describe two adults who developed
rhabdomyolysis after receiving high rates of propofol infusion. Rhabdomyolysis of
both skeletal and cardiac muscle was suggested in both patients by marked
increases of creatine kinase (>170 000 U/L) and cardiac troponin I (11 and 46
microg/L in patients one and two, respectively). Creatine kinase and cardiac
troponin I values were highly correlated in each patent (r = 0.786 and 0.988 in
patients one and two, respectively). Autopsy of one patient confirmed the
diagnosis of skeletal and cardiac rhabdomyolysis.
PMID- 10759488
TI - Evaluation of a minipool reverse transcription-PCR screening method for the
detection of hepatitis C virus infection in hemodialysis patients.
PMID- 10759489
TI - Increased carbohydrate-deficient transferrin concentration and abnormal protein
glycosylation of unknown etiology in a patient with achondroplasia.
PMID- 10759490
TI - Effects of carboxyhemoglobin on hemoglobinometers.
PMID- 10759491
TI - A representative of HemoCue AB responds:
PMID- 10759492
TI - Hepatitis B surface antigen: decreased need for confirmation of reactive results.
PMID- 10759493
TI - Compiled by David E. Bruns, Editor (dbruns@aacc.org) : The Clinical Chemist.
PMID- 10759494
TI - Recent progress toward understanding biosynthesis of the amylopectin crystal.
PMID- 10759495
TI - Plant cells are not just green yeast.
PMID- 10759496
TI - Activation tagging in Arabidopsis.
AB - Activation tagging using T-DNA vectors that contain multimerized transcriptional
enhancers from the cauliflower mosaic virus (CaMV) 35S gene has been applied to
Arabidopsis plants. New activation-tagging vectors that confer resistance to the
antibiotic kanamycin or the herbicide glufosinate have been used to generate
several tens of thousands of transformed plants. From these, over 30 dominant
mutants with various phenotypes have been isolated. Analysis of a subset of
mutants has shown that overexpressed genes are almost always found immediately
adjacent to the inserted CaMV 35S enhancers, at distances ranging from 380 bp to
3.6 kb. In at least one case, the CaMV 35S enhancers led primarily to an
enhancement of the endogenous expression pattern rather than to constitutive
ectopic expression, suggesting that the CaMV 35S enhancers used here act
differently than the complete CaMV 35S promoter. This has important implications
for the spectrum of genes that will be discovered by this method.
PMID- 10759497
TI - Purification, characterization, and molecular cloning of the gene of a seed
specific antimicrobial protein from pokeweed.
AB - A small cysteine-rich protein with antimicrobial activity was isolated from
pokeweed (Phytolacca americana) seeds and purified to homogeneity. The protein
inhibits the growth of several filamentous fungi and gram-positive bacteria. The
protein was highly basic, with a pI higher than 10. The entire amino acid
sequence of the protein was determined to be homologous to antimicrobial protein
(AMP) from Mirabilis jalapa. The cDNA encoding the P. americana AMP (Pa-AMP-1)
and chromosomal DNA containing the gene were cloned and sequenced. The deduced
amino acid sequence shows the presence of a signal peptide at the amino terminus,
suggesting that the protein is synthesized as a preprotein and secreted outside
the cells. The chromosomal gene shows the presence of an intron located within
the region encoding the signal peptide. Southern hybridization showed that there
was small gene family encoding Pa-AMP. Immunoblotting showed that Pa-AMP-1 was
only present in seeds, and was absent in roots, leaves, and stems. The Pa-AMP-1
protein was secreted into the environment of the seeds during germination, and
may create an inhibitory zone against soil-borne microorganisms. The disulfide
bridges of Pa-AMP-1 were identified. The three-dimensional modeling of Pa-AMP-1
indicates that the protein has a small cystine-knot folding, a positive patch,
and a hydrophobic patch.
PMID- 10759498
TI - Plasma membrane intrinsic proteins from maize cluster in two sequence subgroups
with differential aquaporin activity.
AB - The transport of water through membranes is regulated in part by aquaporins or
water channel proteins. These proteins are members of the larger family of major
intrinsic proteins (MIPs). Plant aquaporins are categorized as either tonoplast
intrinsic proteins (TIPs) or plasma membrane intrinsic proteins (PIPs). Sequence
analysis shows that PIPs form several subclasses. We report on the
characterization of three maize (Zea mays) PIPs belonging to the PIP1 and PIP2
subfamilies (ZmPIP1a, ZmPIP1b, and ZmPIP2a). The ZmPIP2a clone has normal
aquaporin activity in Xenopus laevis oocytes. ZmPIP1a and ZmPIP1b have no
activity, and a review of the literature shows that most PIP1 proteins identified
in other plants have no or very low activity in oocytes. Arabidopsis PIP1
proteins are the only exception. Control experiments show that this lack of
activity of maize PIP1 proteins is not caused by their failure to arrive at the
plasma membrane of the oocytes. ZmPIP1b also does not appear to facilitate the
transport of any of the small solutes tried (glycerol, choline, ethanol, urea,
and amino acids). These results are discussed in relationship to the function and
regulation of the PIP family of aquaporins.
PMID- 10759499
TI - Spatio-temporal accumulation and activity of calcium-dependent protein kinases
during embryogenesis, seed development, and germination in sandalwood.
AB - Western-blot analysis and protein kinase assays identified two Ca(2+)-dependent
protein kinases (CDPKs) of 55 to 60 kD in soluble protein extracts of embryogenic
cultures of sandalwood (Santalum album L.). However, these sandalwood CDPKs
(swCDPKs) were absent in plantlets regenerated from somatic embryos. swCDPKs
exhibited differential expression (monitored at the level of the protein) and
activity in different developmental stages. Zygotic embryos, seedlings, and
endosperm showed high accumulation of swCDPK, but the enzyme was not detected in
the soluble proteins of shoots and flowers. swCDPK exhibited a temporal pattern
of expression in endosperm, showing high accumulation and activity in mature
fruit and germinating stages; the enzyme was localized strongly in the storage
bodies of the endosperm cells. The study also reports for the first time to our
knowledge a post-translational inhibition/inactivation of swCDPK in zygotic
embryos during seed dormancy and early stages of germination. The temporal
expression of swCDPK during somatic/zygotic embryogenesis, seed maturation, and
germination suggests involvement of the enzyme in these developmental processes.
PMID- 10759500
TI - Five geranylgeranyl diphosphate synthases expressed in different organs are
localized into three subcellular compartments in Arabidopsis.
AB - Geranylgeranyl diphosphate (GGPP) is the precursor for the biosynthesis of
gibberellins, carotenoids, chlorophylls, isoprenoid quinones, and
geranylgeranylated proteins in plants. There is a small gene family for GGPP
synthases encoding five isozymes and one related protein in Arabidopsis, and all
homologs have a putative localization signal to translocate into specific
subcellular compartments. Using a synthetic green fluorescent protein (sGFP), we
studied the subcellular localization of these GGPP synthases. When these fusion
proteins were expressed by the cauliflower mosaic virus 35S promoter in
Arabidopsis, GGPS1-sGFP and GGPS3-sGFP proteins were translocated into the
chloroplast, GGPS2-sGFP and GGPS4-sGFP proteins were localized in the endoplasmic
reticulum, and the GGPS6-sGFP protein was localized in the mitochondria. Both
GGPS1 and GGPS3 proteins synthesized in vitro were taken up into isolated intact
pea chloroplasts and processed to the mature form. RNA-blot and promoter-beta
glucuronidase (GUS) analysis showed that these GGPP synthases genes are organ
specifically expressed in Arabidopsis. GGR and GGPS1 were ubiquitously expressed,
while GGPS2, GGPS3, and GGPS4 were expressed specifically in the flower, root,
and flower, respectively. These results suggest that each GGPP synthase gene is
expressed in different tissues during plant development and GGPP is synthesized
by the organelles themselves rather than being transported into the organelles.
Therefore, we predict there will be specific pathways of GGPP production in each
organelle.
PMID- 10759501
TI - Coordinate regulation of the nuclear and plastidic genes coding for the subunits
of the heteromeric acetyl-coenzyme A carboxylase.
AB - Plastidic acetyl-coenzyme A (CoA) carboxylase (ACCase) catalyzes the first
committed reaction of de novo fatty acid biosynthesis. This heteromeric enzyme is
composed of one plastid-coded subunit (beta-carboxyltransferase) and three
nuclear-coded subunits (biotin carboxy-carrier, biotin carboxylase, and alpha
carboxyltransferase). We report the primary structure of the Arabidopsis alpha
carboxyltransferase and beta-carboxyltransferase subunits deduced from nucleotide
sequences of the respective genes and/or cDNA. Co-immunoprecipitation experiments
confirm that the alpha-carboxyltransferase and beta-carboxyltransferase subunits
are physically associated. The plant alpha-carboxyltransferases have gained a C
terminal domain relative to eubacteria, possibly via the evolutionary acquisition
of a single exon. This C-terminal domain is divergent among plants and may have a
structural function rather than being essential for catalysis. The four ACCase
subunit mRNAs accumulate to the highest levels in tissues and cells that are
actively synthesizing fatty acids, which are used either for membrane biogenesis
in rapidly growing tissues or for oil accumulation in developing embryos.
Development coordinately affects changes in the accumulation of the ACCase
subunit mRNAs so that these four mRNAs maintain a constant molar stoichiometric
ratio. These data indicate that the long-term, developmentally regulated
expression of the heteromeric ACCase is in part controlled by a mechanism(s) that
coordinately affects the steady-state concentrations of each subunit mRNA.
PMID- 10759502
TI - Dg93, a nodule-abundant mRNA of Datisca glomerata with homology to a soybean
early nodulin gene.
AB - We have isolated a 590-bp full-length cDNA clone designated Dg93, an mRNA that is
highly expressed in symbiotic root nodules of the actinorhizal host Datisca
glomerata. Dg93 mRNA encodes a deduced polypeptide of 105 amino acids with
significant identity (74%) to the soybean (Glycine max) early nodulin (ENOD) gene
GmENOD93 (Kouchi and Hata, 1993). Dg93 mRNA is abundant in nodules at 4 weeks
post inoculation, the earliest time assayed, and steady-state mRNA levels remain
elevated 11 weeks after inoculation. Spatial patterns of Dg93 mRNA expression are
complex, with transcript accumulation in the nodule lobe meristem, early
infection zone, periderm, and cells of the vascular cylinder, but not in the
surrounding uninfected cortical cells. Dg93 is encoded by a small gene family in
D. glomerata. To our knowledge, this is the first report of a gene from an
actinorhizal host that is expressed in the nodule meristem and that shares
sequence homology with an early nodulin gene from a legume.
PMID- 10759503
TI - Gibberellins and seed development in maize. I. Evidence that gibberellin/abscisic
acid balance governs germination versus maturation pathways.
AB - Abscisic acid (ABA) is required for the regulation of seed maturation in maize
(Zea mays L.). Mutants blocked in ABA synthesis (such as viviparous-5) do not
mature to quiescent, desiccation-tolerant seeds, but germinate on the ear midway
through kernel development. Because gibberellins (GA) and ABA act
antagonistically in many aspects of plant development, we hypothesized that ABA
antagonizes a positive GA signal for precocious germination in maize. In these
experiments, we show that a GA deficiency early in seed development, induced
genetically or via biosynthesis inhibitors, suppresses vivipary in ABA-deficient
developing kernels. The resulting seeds have both desiccation tolerance and
storage longevity. Temporal analysis of GA accumulation in wild-type kernels
revealed the accumulation of bioactive GA(1) and GA(3) prior to the peak in ABA
content. We speculate that these GAs stimulate a developmental program leading to
vivipary in the absence of normal amounts of ABA, and that a reduction of GA
content re-establishes an ABA/GA ratio appropriate for suppression of germination
and induction of maturation. In contrast, the induction of a GA deficiency did
not suppress vivipary in viviparous-1 mutant kernels, suggesting that VP1 acts
downstream of both GA and ABA in programming seed development.
PMID- 10759504
TI - Gibberellins and seed development in maize. II. Gibberellin synthesis inhibition
enhances abscisic acid signaling in cultured embryos.
AB - Abscisic acid (ABA) is required for seed maturation in maize (Zea mays L.) and
other plants. Gibberellins (GAs) are also present in developing maize embryos,
and mutual antagonism of GAs and ABA appears to govern the choice between
precocious germination or quiescence and maturation. Exogenous ABA can also
induce quiescence and maturation in immature maize embryos in culture. To examine
the role of GAs versus ABA in regulating maize embryo maturation, the effects of
modulating GA levels were compared with those of ABA in embryos cultured at
successive stages of development. The effects of GA synthesis inhibition or
exogenous GA application differed markedly in embryos at different stages of
development, indicating changes in both endogenous GA levels and in the capacity
for GA synthesis as embryogenesis and maturation progress. In immature embryos,
the inhibition of GA synthesis mimicked the effects of exogenous ABA, as shown by
the suppression of germination, the acquisition of anthocyanin pigments, and the
accumulation of a variety of maturation-phase mRNAs. We suggest that GA
antagonizes ABA signaling in developing maize embryos, and that the changing
hormone balance provides temporal control over the maturation phase.
PMID- 10759505
TI - The expression of small heat shock proteins in seeds responds to discrete
developmental signals and suggests a general protective role in desiccation
tolerance.
AB - To learn more about the function and regulation of small heat shock proteins
(sHSPs) during seed development, we studied sHSP expression in wild-type and seed
maturation mutants of Arabidopsis by western analysis and using an HSP17.4
promoter-driven beta-glucuronidase (GUS) reporter gene in transgenic plants. In
the absence of stress, GUS activity increases during development until the entire
embryo is stained before desiccation. Heat-stressed embryos stained for GUS at
all stages, including early stages that showed no detectable HSP17. 4::GUS
activity without heat. Examination of HSP17.4 expression in seeds of the
transcriptional activator mutants abi3-6, fus3-3 (AIMS no. CS8014/N8014), and
lec1-2 (AIMS no. CS2922/N2922) showed that protein and HSP17.4::GUS activity were
highly reduced in fus3-3 and lec1-2 and undetectable in abi3-6 seeds. In
contrast, heat-stressed abi3-6, fus3-3, and lec1-2 seeds stained for GUS activity
throughout the embryo. These data indicate that there is distinct developmental
and stress regulation of HSP17.4, and imply that ABI3 activates HSP17.4
transcription during development. Quantitation of sHSP protein in desiccation
intolerant seeds of abi3-6, fus3-3, lec1-2, and line24 showed that all had <2% of
wild-type HSP17.4 levels. In contrast, the desiccation-tolerant but embryo
defective mutants emb266 (AIMS no. CS3049/N3049) and lec2-1 (AIMS no.
CS2728/N2728) had wild-type levels of HSP17.4. These data correlate a reduction
in sHSPs with desiccation intolerance and suggest that sHSPs have a general
protective role throughout the seed.
PMID- 10759506
TI - Role of hormones in the induction of iron deficiency responses in Arabidopsis
roots.
AB - In "strategy I" plants, several alterations in root physiology and morphology are
induced by Fe deficiency, although the mechanisms by which low Fe levels are
translated into reactions aimed at alleviating Fe shortage are largely unknown.
To prove whether changes in hormone concentration or sensitivity are involved in
the adaptation to suboptimal Fe availability, we tested 45 mutants of Arabidopsis
defective in hormone metabolism and/or root hair formation for their ability to
increase Fe(III) chelate reductase activity and to initiate the formation and
enlargement of root hairs. Activity staining for ferric chelate reductase
revealed that all mutants were responsive to Fe deficiency, suggesting that
hormones are not necessary for the induction. Treatment of wild-type plants with
the ethylene precursor 1-aminocyclopropane-1-carboxylic acid caused the
development of root hairs in locations normally occupied by non-hair cells, but
did not stimulate ferric reductase activity. Ectopic root hairs were also formed
in -Fe roots, suggesting a role for ethylene in the morphological responses to Fe
deficiency. Ultrastructural analysis of rhizodermal cells indicated that neither
Fe deficiency nor 1-aminocyclopropane-1-carboxylic acid treatment caused transfer
cell-like alterations in Arabidopsis roots. Our data indicate that the
morphological and physiological components of the Fe stress syndrome are
regulated separately.
PMID- 10759507
TI - A tomato peroxidase involved in the synthesis of lignin and suberin.
AB - The last step in the synthesis of lignin and suberin has been proposed to be
catalyzed by peroxidases, although other proteins may also be involved. To
determine which peroxidases are involved in the synthesis of lignin and suberin,
five peroxidases from tomato (Lycopersicon esculentum) roots, representing the
majority of the peroxidase activity in this organ, have been partially purified
and characterized kinetically. The purified peroxidases with isoelectric point
(pI) values of 3.6 and 9.6 showed the highest catalytic efficiency when the
substrate used was syringaldazine, an analog of lignin monomer. Using a
combination of transgenic expression and antibody recognition, we now show that
the peroxidase pI 9.6 is probably encoded by TPX1, a tomato peroxidase gene we
have previously isolated. In situ RNA hybridization revealed that TPX1 expression
is restricted to cells undergoing synthesis of lignin and suberin. Salt stress
has been reported to induce the synthesis of lignin and/or suberin. This stress
applied to tomato caused changes in the expression pattern of TPX1 and induced
the TPX1 protein. We propose that the TPX1 product is involved in the synthesis
of lignin and suberin.
PMID- 10759508
TI - Removal of feedback inhibition of delta(1)-pyrroline-5-carboxylate synthetase
results in increased proline accumulation and protection of plants from osmotic
stress.
AB - The Delta(1)-pyrroline-5-carboxylate synthetase (P5CS; EC not assigned) is the
rate-limiting enzyme in proline (Pro) biosynthesis in plants and is subject to
feedback inhibition by Pro. It has been suggested that the feedback regulation of
P5CS is lost in plants under stress conditions. We compared Pro levels in
transgenic tobacco (Nicotiana tabacum) plants expressing a wild-type form of
Vigna aconitifolia P5CS and a mutated form of the enzyme (P5CSF129A) whose
feedback inhibition by Pro was removed by site-directed mutagenesis. Transgenic
plants expressing P5CSF129A accumulated about 2-fold more Pro than the plants
expressing V. aconitifolia wild-type P5CS. This difference was further increased
in plants treated with 200 mM NaCl. These results demonstrated that the feedback
regulation of P5CS plays a role in controlling the level of Pro in plants under
both normal and stress conditions. The elevated Pro also reduced free radical
levels in response to osmotic stress, as measured by malondialdehyde production,
and significantly improved the ability of the transgenic seedlings to grow in
medium containing up to 200 mM NaCl. These findings shed new light on the
regulation of Pro biosynthesis in plants and the role of Pro in reducing
oxidative stress induced by osmotic stress, in addition to its accepted role as
an osmolyte.
PMID- 10759509
TI - The expression of D-cyclin genes defines distinct developmental zones in
snapdragon apical meristems and is locally regulated by the Cycloidea gene.
AB - Three D-cyclin genes are expressed in the apical meristems of snapdragon
(Antirrhinum majus). The cyclin D1 and D3b genes are expressed throughout
meristems, whereas cyclin D3a is restricted to the peripheral region of the
meristem, especially the organ primordia. During floral development, cyclin D3b
expression is: (a) locally modulated in the cells immediately surrounding the
base of organ primordia, defining a zone between lateral organs that may act as a
developmental boundary; (b) locally modulated in the ventral petals during petal
folding; and (c) is specifically repressed in the dorsal stamen by the cycloidea
gene. Expression of both cyclin D3 genes is reduced prior to the cessation of
cell cycle activity, as judged by histone H4 expression. Expression of all three
D-cyclin genes is modulated by factors that regulate plant growth, particularly
sucrose and cytokinin. These observations may provide a molecular basis for
understanding the local regulation of cell proliferation during plant growth and
development.
PMID- 10759510
TI - Independent action of ELF3 and phyB to control hypocotyl elongation and flowering
time.
AB - Light regulates various aspects of plant growth, and the photoreceptor
phytochrome B (phyB) mediates many responses to red light. In a screen for
Arabidopsis mutants with phenotypes similar to those of phyB mutants, we isolated
two new elf3 mutants. One has weaker morphological phenotypes than previously
identified elf3 alleles, but still abolishes circadian rhythms under continuous
light. Like phyB mutants, elf3 mutants have elongated hypocotyls and petioles,
flower early, and have defects in the red light response. However, we found that
elf3 mutations have an additive interaction with a phyB null mutation, with phyA
or hy4 null mutations, or with a PHYB overexpression construct, and that an elf3
mutation does not prevent nuclear localization of phyB. These results suggest
that either there is substantial redundancy in phyB and elf3 function, or the two
genes regulate distinct signaling pathways.
PMID- 10759511
TI - Role of magnesium chelatase activity in the early steps of the tetrapyrrole
biosynthetic pathway.
AB - Magnesium-protoporphyrin IX chelatase (Mg-chelatase) is located at the
branchpoint of tetrapyrrole biosynthesis, at which point protoporphyrin IX is
distributed for the synthesis of chlorophyll and heme. We investigated the
regulatory contribution of Mg-chelatase to the flow of metabolites. In plants,
the enzyme complex consists of three subunits, designated CHL D, CHL I, and CHL
H. Transgenic tobacco (Nicotiana tabacum) plants expressing antisense RNA for the
Mg-chelatase subunit CHL H were analyzed to elucidate further the role of Mg
chelatase in the distribution of protoporphyrin IX into the branched
tetrapyrrolic pathway. The transgenic plants displayed a reduced growth rate and
chlorophyll deficiency. Both phenotypical properties were correlated with lower
Mg-chelatase activity. Unexpectedly, less protoporphyrin IX and heme accumulated,
and a decrease in 5-aminolevulinate (ALA)-synthesizing capacity and ALA
dehydratase activity paralleled the progressive reduction in Mg-chelatase
activity in the transformants compared with control plants. The reduced
activities of the early enzymatic steps corresponded with lower levels of
transcripts encoding glutamyl-tRNA reductase and ALA-dehydratase. The decreased
expression and activities of early enzymes in the pathway could be explained by a
feedback-controlled mechanism in response to lower Mg-chelatase activity. We
discuss intercompartmental signaling that synchronizes the activities of the
first steps in tetrapyrrolic metabolism with the late steps for the synthesis of
end products.
PMID- 10759512
TI - Reduction and coordination of arsenic in Indian mustard.
AB - The bioaccumulation of arsenic by plants may provide a means of removing this
element from contaminated soils and waters. However, to optimize this process it
is important to understand the biological mechanisms involved. Using a
combination of techniques, including x-ray absorption spectroscopy, we have
established the biochemical fate of arsenic taken up by Indian mustard (Brassica
juncea). After arsenate uptake by the roots, possibly via the phosphate transport
mechanism, a small fraction is exported to the shoot via the xylem as the
oxyanions arsenate and arsenite. Once in the shoot, the arsenic is stored as an
As(III)-tris-thiolate complex. The majority of the arsenic remains in the roots
as an As(III)-tris-thiolate complex, which is indistinguishable from that found
in the shoots and from As(III)-tris-glutathione. The thiolate donors are thus
probably either glutathione or phytochelatins. The addition of the dithiol
arsenic chelator dimercaptosuccinate to the hydroponic culture medium caused a 5
fold-increased arsenic level in the leaves, although the total arsenic
accumulation was only marginally increased. This suggests that the addition of
dimercaptosuccinate to arsenic-contaminated soils may provide a way to promote
arsenic bioaccumulation in plant shoots, a process that will be essential for the
development of an efficient phytoremediation strategy for this element.
PMID- 10759513
TI - Abscisic acid inhibition of radicle emergence but not seedling growth is
suppressed by sugars.
AB - Low concentrations of sugars altered the sensitivity of seed germination to
inhibition by exogenous abscisic acid (ABA). Germination of wild-type and ABA
insensitive (abi) Arabidopsis seeds was assayed on media containing ABA and a
variety of sugars and sugar alcohols. The inhibitory effects of ABA were strongly
repressed in the presence of 15 to 90 mM glucose (Glc), sucrose, or fructose, but
not by comparable concentrations of sorbitol or mannitol. Several features of the
response to Glc are inconsistent with a purely nutritional effect: The optimal
sugar concentration is low and differs between the wild type and the abi mutants.
Furthermore, Glc suppression of ABA inhibition is light dependent and limited to
the process of radicle emergence.
PMID- 10759514
TI - The rug3 locus of pea encodes plastidial phosphoglucomutase.
AB - Two cDNA clones were isolated from pea (Pisum sativum L.) and their deduced amino
acid sequences shown to have significant homology to phosphoglucomutases from
eukaryotic and prokaryotic sources. The longer cDNA contained a putative transit
peptide-encoding sequence, supporting the hypothesis that the isolated clones
represent the cytosolic and plastidial isoforms of phosphoglucomutase in pea.
Plastid protein import assays confirmed that the putative plastidial isoform was
targeted to the plastid stroma where it was proteolytically processed.
Expression, co-segregation, linkage, and molecular analyses have confirmed that
the rug3 locus of pea encodes plastidial phosphoglucomutase. Mutations at this
locus result in a near-starchless phenotype of the plant.
PMID- 10759515
TI - The plastidic phosphoglucomutase from Arabidopsis. A reversible enzyme reaction
with an important role in metabolic control.
AB - An Arabidopsis cDNA (AtPGMp) encoding the plastidic phosphoglucomutase (PGM)
predicted a 623-amino acid protein with an N-terminal sequence typical of a
plastid signal peptide. Expression of a recombinant protein in Escherichia coli
confirmed its enzyme activity. The recombinant enzyme had an apparent K(m) value
of 98.5 microM and a V(max) of 4.48 micromol min(-1) (mg protein)(-1). The Calvin
cycle intermediates fructose-1,6-bisphosphate and ribulose-1, 5-bisphosphate
exerted an inhibitory effect on PGM activity, supporting its proposed involvement
in controlling photosynthetic carbon flow. A point mutation was identified in the
AtPGMp gene of the Arabidopsis pgm-1 mutant. The mutation in the mutant
transcript generated a stop codon at about one third of the wild-type open
reading frame, and thus rendered the polypeptide nonfunctional. Storage lipid
analysis of the pgm-1 mutant seeds showed a 40% reduction in oil content compared
with that of wild type. Our results indicate that plastidic PGM is an important
factor affecting carbon flux in triacylglycerol accumulation in oilseed plants,
most likely through its essential role in starch synthesis.
PMID- 10759516
TI - Inactivation of photosystems I and II in response to osmotic stress in
Synechococcus. Contribution of water channels.
AB - The effects of osmotic stress due to sorbitol on the photosynthetic machinery
were investigated in the cyanobacterium Synechococcus R-2. Incubation of cells in
1.0 M sorbitol inactivated photosystems I and II and decreased the intracellular
solute space by 50%. These effects of sorbitol were reversible: Photosynthetic
activity and cytoplasmic volume returned to the original values after removal of
the osmotic stress. A blocker of water channels prevented the osmotic-stress
induced inactivation and shrinkage of the intracellular space. It also prevented
the recovery of photosynthetic activity and cytoplasmic volume when applied just
before release from osmotic stress. Inhibition of protein synthesis by lincomycin
had no significant effects on the inactivation and recovery processes, an
observation that suggests that protein synthesis was not involved in these
processes. Our results suggest that osmotic stress decreased the amount of water
in the cytoplasm via the efflux of water through water channels (aquaporins),
with resultant increases in intracellular concentrations of ions and a decrease
in photosynthetic activity.
PMID- 10759517
TI - Metabolic relations of inositol 3,4,5,6-tetrakisphosphate revealed by cell
permeabilization. Identification of inositol 3,4,5, 6-tetrakisphosphate 1-kinase
and inositol 3,4,5,6-tetrakisphosphate phosphatase activities in mesophyll cells.
AB - Using a permeabilization strategy to introduce Ins(3,4,5,6) P(4) into mesophyll
protoplasts of Commelina communis, we have identified Ins(3,4,5,6) P(4) 1-kinase
activity in mesophyll cells. Multiple InsP(3) isomers were identified in
Spirodela polyrhiza and Arabidopsis. Only two of these, Ins(1,2,3) P(3) and
Ins(3,4,6) P(3), have previously been identified in plants and only in monocots.
The isomers detected in S. polyrhiza included D- and/or L-Ins(3,4,5) P(3), D-
and/or L-Ins(3,5,6) P(3), and D- and/or L-Ins(2,4,5) P(3). Ins(1,4,5) P(3), if
present, was only a tiny fraction of total InsP(3) species. We have also
identified inositol polyphosphate phosphatase activities, Ins(3,4,5,6) P(4) 6
phosphatase and Ins(3,4, 5, 6) P(4) 4-phosphatase, whose action on endogenous
inositol polyphosphates explains the presence of D- and/or L-Ins(3,4,5) P(3) and
D- and/or L-Ins(3,5,6) P(3) in mesophyll cells. Inositol trisphosphates
identified in Arabidopsis include Ins(1,2,3) P(3) and D- and/or L-Ins(3,4,6)
P(3), suggesting that dicots may share pathways of InsP(6) biosynthesis and
breakdown in common with monocots.
PMID- 10759518
TI - Is there a role for oligosaccharides in seed longevity? An assessment of
intracellular glass stability.
AB - We examined whether oligosaccharides extend seed longevity by increasing the
intracellular glass stability. For that purpose, we used a spin probe technique
to measure the molecular mobility and glass transition temperature of the
cytoplasm of impatiens (Impatiens walleriana) and bell pepper (Capsicum annuum)
seeds that were osmo-primed to change oligosaccharide content and longevity.
Using saturation transfer electron paramagnetic resonance spectroscopy, we found
that the rotational correlation time of the polar spin probe 3-carboxy-proxyl in
the cytoplasm decreased, together with longevity, as a function of increasing
seed water content, suggesting that longevity may indeed be regulated by
cytoplasmic mobility. Osmo-priming of the seeds resulted in considerable
decreases in longevity and oligosaccharide content, while the sucrose content
increased. No difference in the glass transition temperature was found between
control and primed impatiens seeds at the same temperature and water content.
Similarly, there was no difference in the rotational motion of the spin probe in
the cytoplasm between control and primed impatiens and bell pepper seeds. We
therefore conclude that oligosaccharides in seeds do not affect the stability of
the intracellular glassy state, and that the reduced longevity after priming is
not the result of increased molecular mobility in the cytoplasm.
PMID- 10759519
TI - Compartmentation of ATP:citrate lyase in plants.
AB - Extracts prepared from young leaves of Pea (Pisum sativum), tobacco (Nicotiana
tabacum), rape (Brassica napus), and spinach (Spinacia oleracea) all contained
ATP:citrate lyase (ACL) activity, which was most active in rape leaflets (130
nmol min(-1) g fresh weight). In rape and spinach, ACL activity was predominantly
localized in the plastids (between about 78% and 90% of the total activity),
whereas in pea and tobacco, distribution was mainly cytosolic (about 85% and 78%,
respectively, of the total). These distributions were calculated from the
relative distributions of plastid and cytosol marker enzymes. Cross-reactivity
between plant and rat ACL antibody was carried out by immunoblot analysis and, in
rape and spinach, showed that a 120-kD protein, presumably indicating homomeric
ACL proteins, was present in both cytosolic and plastidic fractions. In pea, two
cross-reacting proteins were detected, the major material being in the cytosol
fraction. Therefore, ACL occurs both in the cytosol and plastids of higher
plants, but the distribution of activity changes according to the species. The
plastidic ACL is proposed to function for the supply of acetyl-coenzyme A for
lipid biosynthesis de novo, whereas the cytosolic ACL may provide acetyl-coenzyme
A for the mevalonate pathway or fatty acid elongation.
PMID- 10759520
TI - Genetic enhancement of fatty acid synthesis by targeting rat liver ATP:citrate
lyase into plastids of tobacco.
AB - ATP:citrate lyase (ACL) catalyzes the conversion of citrate to acetyl-coenzyme A
(CoA) and oxaloacetate and is a key enzyme for lipid accumulation in mammals and
oleaginous yeasts and fungi. To investigate whether heterologous ACL genes can be
targeted and imported into the plastids of plants, a gene encoding a fusion
protein of the rat liver ACL with the transit peptide for the small subunit of
ribulose bisphosphate carboxylase was constructed and introduced into the genome
of tobacco. This was sufficient to provide import of the heterologous protein
into the plastids. In vitro assays of ACL in isolated plastids showed that the
enzyme was active and synthesized acetyl-CoA. Overexpression of the rat ACL gene
led to up to a 4-fold increase in the total ACL activity; this increased the
amount of fatty acids by 16% but did not cause any major change in the fatty acid
profile. Therefore, increasing the availability of acetyl-CoA as a substrate for
acetyl-CoA carboxylase and subsequent reactions of fatty acid synthetase has a
slightly beneficial effect on the overall rate of lipid synthesis in plants.
PMID- 10759521
TI - Ectoine, the compatible solute of Halomonas elongata, confers hyperosmotic
tolerance in cultured tobacco cells.
AB - 1,4,5,6-Tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoine) functions as a
compatible osmolyte in the moderate halophile Halomonas elongata OUT30018.
Ectoine is biosynthesized by three successive enzyme reactions from aspartic beta
semialdehyde. The genes encoding the enzymes involved in the biosynthesis, ectA,
ectB, and ectC, encoding L-2,4-diaminobutyric acid acetyltransferase, L-2, 4
diaminobutyric acid transaminase, and L-ectoine synthase, respectively, have been
previously cloned. To investigate the function of ectoine as a compatible solute
in plant cells, the three genes were individually placed under the control of the
cauliflower mosaic virus 35S promoter and introduced together into cultured
tobacco (Nicotiana tabacum L.) cv Bright Yellow 2 (BY2) cells. The transgenic BY2
cells accumulated a small quantity of ectoine (14-79 nmol g(-1) fresh weight) and
showed increased tolerance to hyperosmotic shock (900 mOsm). Furthermore, the
transgenic BY2 cells exhibited a normal growth pattern even under hyperosmotic
conditions (up to 530 mOsm), in which the growth of the untransformed BY2 (wild
type) cells was obviously delayed. These results suggest that genetically
engineered synthesis of ectoine results in the increased hyperosmotic tolerance
of cultured tobacco BY2 cells despite the low level of accumulation of the
solute.
PMID- 10759522
TI - The Arabidopsis HKT1 gene homolog mediates inward Na(+) currents in xenopus
laevis oocytes and Na(+) uptake in Saccharomyces cerevisiae.
AB - The Na(+)-K(+) co-transporter HKT1, first isolated from wheat, mediates high
affinity K(+) uptake. The function of HKT1 in plants, however, remains to be
elucidated, and the isolation of HKT1 homologs from Arabidopsis would further
studies of the roles of HKT1 genes in plants. We report here the isolation of a
cDNA homologous to HKT1 from Arabidopsis (AtHKT1) and the characterization of its
mode of ion transport in heterologous systems. The deduced amino acid sequence of
AtHKT1 is 41% identical to that of HKT1, and the hydropathy profiles are very
similar. AtHKT1 is expressed in roots and, to a lesser extent, in other tissues.
Interestingly, we found that the ion transport properties of AtHKT1 are
significantly different from the wheat counterpart. As detected by
electrophysiological measurements, AtHKT1 functioned as a selective Na(+) uptake
transporter in Xenopus laevis oocytes, and the presence of external K(+) did not
affect the AtHKT1-mediated ion conductance (unlike that of HKT1). When expressed
in Saccharomyces cerevisiae, AtHKT1 inhibited growth of the yeast in a medium
containing high levels of Na(+), which correlates to the large inward Na(+)
currents found in the oocytes. Furthermore, in contrast to HKT1, AtHKT1 did not
complement the growth of yeast cells deficient in K(+) uptake when cultured in
K(+)-limiting medium. However, expression of AtHKT1 did rescue Escherichia coli
mutants carrying deletions in K(+) transporters. The rescue was associated with a
less than 2-fold stimulation of K(+) uptake into K(+)-depleted cells. These data
demonstrate that AtHKT1 differs in its transport properties from the wheat HKT1,
and that AtHKT1 can mediate Na(+) and, to a small degree, K(+) transport in
heterologous expression systems.
PMID- 10759523
TI - Phytoene desaturase is localized exclusively in the chloroplast and up-regulated
at the mRNA level during accumulation of secondary carotenoids in Haematococcus
pluvialis (Volvocales, chlorophyceae).
AB - The unicellular green alga Haematococcus pluvialis Flotow is known for its
massive accumulation of ketocarotenoids under various stress conditions.
Therefore, this microalga is one of the favored organisms for biotechnological
production of these antioxidative compounds. Astaxanthin makes up the main part
of the secondary carotenoids and is accumulated mostly in an esterified form in
extraplastidic lipid vesicles. We have studied phytoene desaturase, an early
enzyme of the carotenoid biosynthetic pathway. The increase in the phytoene
desaturase protein levels that occurs following induction is accompanied by a
corresponding increase of its mRNA during the accumulation period, indicating
that phytoene desaturase is regulated at the mRNA level. We also investigated the
localization of the enzyme by western-blot analysis of cell fractions and by
immunogold labeling of ultrathin sections for electron microscopy. In spite of
the fact that secondary carotenoids accumulate outside the chloroplast, no extra
pathway specific for secondary carotenoid biosynthesis in H. pluvialis was found,
at least at this early stage in the biosynthesis. A transport process of
carotenoids from the site of biosynthesis (chloroplast) to the site of
accumulation (cytoplasmatic located lipid vesicles) is implicated.
PMID- 10759524
TI - A novel alliinase from onion roots. Biochemical characterization and cDNA
cloning.
AB - We have purified a novel alliinase (EC 4.4.1.4) from roots of onion (Allium cepa
L.). Two isoforms with alliinase activity (I and II) were separated by
concanavalin A-Sepharose and had molecular masses of 52.7 (I) and 50.5 (II) kD on
sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and 51 (I) and 57.5
(II) kD by gel filtration fast-protein liquid chromatography. Isoform I had an
isoelectric point of 9.3, while isoform II had isoelectric points of 7.6, 7.9,
8.1, and 8.3. The isoforms differed in their glycosylation. Both contained
xylose/fucose containing complex-type N-linked glycans, and isoform II also
contained terminal mannose structures. Both isoforms had activity with S
alk(en)yl-L-cysteine sulfoxides. Unlike other allium alliinases, A. cepa root
isoforms had cystine lyase activity. We cloned a gene from A. cepa root cDNA and
show that it codes for A. cepa root alliinase protein. Homology to other reported
allium alliinase genes is 50%. The gene coded for a protein of mass 51.2 kD, with
two regions of deduced amino acid sequence identical to a 25- and a 40-amino acid
region, as determined experimentally. The A. cepa root alliinase cDNA was
expressed mainly in A. cepa roots. The structure and function of the alliinase
gene family is discussed.
PMID- 10759525
TI - Selenium assimilation and volatilization from dimethylselenoniopropionate by
Indian mustard.
AB - Earlier work from our laboratory on Indian mustard (Brassica juncea L.)
identified the following rate-limiting steps for the assimilation and
volatilization of selenate to dimethyl selenide (DMSe): (a) uptake of selenate,
(b) activation of selenate by ATP sulfurylase, and (b) conversion of
selenomethionine (SeMet) to DMSe. The present study showed that shoots of
selenate-treated plants accumulated very low concentrations of
dimethylselenoniopropionate (DMSeP). Selenonium compounds such as DMSeP are the
most likely precursors of DMSe. DMSeP-supplied plants volatilized Se at a rate
113 times higher than that measured from plants supplied with selenate, 38 times
higher than from selenite, and six times higher than from SeMet. The conversion
of SeMet to selenonium compounds such as DMSeP is likely to be rate-limiting for
DMSe production, but not the formation of DMSe from DMSeP because DMSeP was the
rate of Se volatilization from faster than from SeMet and SeMet (but no DMSeP)
accumulated in selenite- or SeMet-supplied wild-type plants and in selenate
supplied ATP-sulfurylase transgenic plants. DMSeP-supplied plants absorbed the
most Se from the external medium compared with plants supplied with SeMet,
selenate, or selenite; they also accumulated more Se in shoots than in roots as
an unknown organic compound resembling a mixture of DMSeP and selenocysteine.
PMID- 10759526
TI - Identification of a Hsp70 recognition domain within the rubisco small subunit
transit peptide.
AB - The interaction between SStp, the transit peptide of the precursor protein to the
small subunit of Rubisco (prSSU) and two Hsp70 molecular chaperones, Escherichia
coli DnaK and pea (Pisum sativum) CSS1, was investigated in detail. Two
statistical analyses were developed and used to investigate and predict regions
of SStp recognized by DnaK. Both algorithms suggested that DnaK would have high
affinity for the N terminus of SStp, moderate affinity for the central region,
and low affinity for the C terminus. Furthermore, both algorithms predicted this
affinity pattern for >75% of the transit peptides analyzed in the chloroplast
transit peptide (CHLPEP) database. In vitro association between SStp and these
Hsp70s was confirmed by three independent assays: limited trypsin resistance,
ATPase stimulation, and native gel shift. Finally, synthetic peptides scanning
the length of SStp and C-terminal deletion mutants of SStp were used to
experimentally map the region of greatest DnaK affinity to the N terminus. CSS1
displayed a similar affinity for the N terminus of SStp. The major stromal Hsp70s
affinity for the N terminus of SStp and other transit peptides supports a
molecular motor model in which the chaperone functions as an ATP-dependent
translocase, committing chloroplast precursor proteins to unidirectional movement
across the envelope.
PMID- 10759527
TI - ATMPK4, an Arabidopsis homolog of mitogen-activated protein kinase, is activated
in vitro by AtMEK1 through threonine phosphorylation.
AB - The modulation of mitogen-activated protein kinase (MAPK) activity regulates many
intracellular signaling processes. In animal and yeast cells, MAP kinases are
activated via phosphorylation by the dual-specificity kinase MEK (MAP kinase
kinase). Several plant homologs of MEK and MAPK have been identified, but the
biochemical events underlying the activation of plant MAPKs remain unknown. We
describe the in vitro activation of an Arabidopsis homolog of MAP kinase, ATMPK4.
ATMPK4 was phosphorylated in vitro by an Arabidopsis MEK homolog, AtMEK1. This
phosphorylation occurred principally on threonine (Thr) residues and resulted in
elevated ATMPK4 kinase activity. A second Arabidopsis MEK isoform, ATMAP2Kalpha,
failed to phosphorylate ATMPK4 in vitro. Tyr dephosphorylation by the Arabidopsis
Tyr-specific phosphatase AtPTP1 resulted in an almost complete loss of ATMPK4
activity. Immunoprecipitates of Arabidopsis extracts with anti-ATMPK4 antibodies
displayed myelin basic protein kinase activity that was sensitive to treatment
with AtPTP1. These results demonstrate that a plant MEK can phosphorylate and
activate MAPK, and that Tyr phosphorylation is critical for the catalytic
activity of MAPK in plants. Surprisingly, in contrast to the animal enzymes,
AtMEK1 may not be a dual-specificity kinase but, rather, the required Tyr
phosphorylation on ATMPK4 may result from autophosphorylation.
PMID- 10759528
TI - Cloning and expression of cytochrome P450 enzymes catalyzing the conversion of
tyrosine to p-hydroxyphenylacetaldoxime in the biosynthesis of cyanogenic
glucosides in Triglochin maritima.
AB - Two cDNA clones encoding cytochrome P450 enzymes belonging to the CYP79 family
have been isolated from Triglochin maritima. The two proteins show 94% sequence
identity and have been designated CYP79E1 and CYP79E2. Heterologous expression of
the native and the truncated forms of the two clones in Escherichia coli
demonstrated that both encode multifunctional N-hydroxylases catalyzing the
conversion of tyrosine to p-hydroxyphenylacetaldoxime in the biosynthesis of the
two cyanogenic glucosides taxiphyllin and triglochinin in T. maritima. This
renders CYP79E functionally identical to CYP79A1 from Sorghum bicolor, and
unambiguously demonstrates that cyanogenic glucoside biosynthesis in T. maritima
and S. bicolor is catalyzed by analogous enzyme systems with p
hydroxyphenylacetaldoxime as a free intermediate. This is in contrast to earlier
reports stipulating p-hydroxyphenylacetonitrile as the only free intermediate in
T. maritima. L-3,4-Dihydroxyphenyl[3-(14)C]Ala (DOPA) was not metabolized by
CYP79E1, indicating that hydroxylation of the phenol ring at the meta position,
as required for triglochinin formation, takes place at a later stage. In S.
bicolor, CYP71E1 catalyzes the subsequent conversion of p
hydroxyphenylacetaldoxime to p-hydroxymandelonitrile. When CYP79E1 from T.
maritima was reconstituted with CYP71E1 and NADPH-cytochrome P450 oxidoreductase
from S. bicolor, efficient conversion of tyrosine to p-hydroxymandelonitrile was
observed.
PMID- 10759529
TI - Programmed cell death during pollination-induced petal senescence in petunia.
AB - Petal senescence, one type of programmed cell death (PCD) in plants, is a
genetically controlled sequence of events comprising its final developmental
stage. We characterized the pollination-induced petal senescence process in
Petunia inflata using a number of cell performance markers, including fresh/dry
weight, protein amount, RNA amount, RNase activity, and cellular membrane
leakage. Membrane disruption and DNA fragmentation with preferential
oligonucleosomal cleavage, events characteristic of PCD, were found to be present
in the advanced stage of petal senescence, indicating that plant and animal cell
death phenomena share one of the molecular events in the execution phase. As in
apoptosis in animals, both single-stranded DNase and double-stranded DNase
activities are induced during petal cell death and are enhanced by Ca(2+). In
contrast, the release of cytochrome c from mitochondria, one commitment step in
signaling of apoptosis in animal cells, was found to be dispensable in petal cell
death. Some components of the signal transduction pathway for PCD in plants are
likely to differ from those in animal cells.
PMID- 10759530
TI - Expression of allene oxide synthase determines defense gene activation in tomato.
AB - Allene oxide synthase (AOS; hydroperoxide dehydratase; EC 4.2.1.92) catalyzes the
first step in the biosynthesis of jasmonic acid from lipoxygenase-derived
hydroperoxides of free fatty acids. Using the AOS cDNA from tomato (Lycopersicon
esculentum), in which the role of jasmonic acid in wound-induced defense gene
activation has been best described, we examined the kinetics of AOS induction in
response to wounding and elicitors, in parallel with that of the wound-inducible
PIN II (proteinase inhibitor II) gene. AOS was induced in leaves by wounding,
systemin, 12-oxophytodienoic acid, and methyl jasmonate. The levels of AOS mRNA
started declining by 4 h after induction, whereas the levels of PIN II mRNA
continued to increase up to 20 h after induction. Salicylic acid inhibited AOS
and PIN II expression, and the addition of 12-oxophytodienoic acid or methyl
jasmonate did not prevent the inhibition of PIN II expression in the presence of
salicylic acid. Ethylene induced the expression of AOS, but the presence of
ethylene alone did not produce an optimal induction of PIN II. The addition of
silver thiosulfate, an ethylene action inhibitor, prevented the wound-induced
expression of both AOS and PIN II. Products of hydroperoxide lyase affected
neither AOS nor PIN II, but induced expression of prosystemin. Based on these
results, we propose an updated model for defense gene activation in tomato.
PMID- 10759531
TI - Subcellular localization and speciation of nickel in hyperaccumulator and non
accumulator Thlaspi species.
AB - The ability of Thlaspi goesingense Halacsy to hyperaccumulate Ni appears to be
governed by its extraordinary degree of Ni tolerance. However, the physiological
basis of this tolerance mechanism is unknown. We have investigated the role of
vacuolar compartmentalization and chelation in this Ni tolerance. A direct
comparison of Ni contents of vacuoles from leaves of T. goesingense and from the
non-tolerant non-accumulator Thlaspi arvense L. showed that the hyperaccumulator
accumulates approximately 2-fold more Ni in the vacuole than the non-accumulator
under Ni exposure conditions that were non-toxic to both species. Using x-ray
absorption spectroscopy we have been able to determine the likely identity of the
compounds involved in chelating Ni within the leaf tissues of the
hyperaccumulator and non-accumulator. This revealed that the majority of leaf Ni
in the hyperaccumulator was associated with the cell wall, with the remaining Ni
being associated with citrate and His, which we interpret as being localized
primarily in the vacuolar and cytoplasm, respectively. This distribution of Ni
was remarkably similar to that obtained by cell fractionation, supporting the
hypothesis that in the hyperaccumulator, intracellular Ni is predominantly
localized in the vacuole as a Ni-organic acid complex.
PMID- 10759532
TI - Calcium-independent activation of salicylic acid-induced protein kinase and a 40
kilodalton protein kinase by hyperosmotic stress.
AB - Reversible protein phosphorylation/dephosphorylation plays important roles in
signaling the plant adaptive responses to salinity/drought stresses. Two protein
kinases with molecular masses of 48 and 40 kD are activated in tobacco cells
exposed to NaCl. The 48-kD protein kinase was identified as SIPK (salicylic acid
induced protein kinase), a member of the tobacco MAPK (mitogen-activated protein
kinase) family that is activated by various other stress stimuli. The activation
of the 40-kD protein kinase is rapid and dose-dependent. Other osmolytes such as
Pro and sorbitol activate these two kinases with similar kinetics. The activation
of 40-kD protein kinase is specific for hyperosmotic stress, as hypotonic stress
does not activate it. Therefore, this 40-kD kinase was named HOSAK (high osmotic
stress-activated kinase). HOSAK is a Ca(2+)-independent kinase and uses myelin
basic protein (MBP) and histone equally well as substrates. The kinase inhibitor
K252a rapidly activates HOSAK in tobacco cells, implicating a dephosphorylation
mechanism for HOSAK activation. Activation of both SIPK and HOSAK by high osmotic
stress is Ca(2+) and abscisic acid (ABA) independent. Furthermore, mutation in
SOS3 locus does not affect the activation of either kinase in Arabidopsis
seedlings. These results suggest that SIPK and 40-kD HOSAK are two new components
in a Ca(2+)- and ABA-independent pathway that may lead to plant adaptation to
hyperosmotic stress.
PMID- 10759533
TI - Changes in Hechtian strands in cold-hardened cells measured by optical
microsurgery.
AB - Optical microsurgical techniques were employed to investigate the mechanical
properties of Hechtian strands in tobacco (Nicotiana tabacum) and Ginkgo biloba
callus cells. Using optical tweezers, a 1. 5-microm diameter microsphere coated
with concanavalin A was inserted though an ablated hole in the cell wall of a
plasmolyzed cell and attached to a Hechtian strand. By displacing the adhered
microsphere from equilibrium using the optical trapping force, the tensions of
individual strands were determined. Measurements were made using both normal and
cold-hardened cells, and in both cases, tensions were on the order of 10(-12) N.
Significant differences were found in the binding strengths of cold-hardened and
normal cultured cells. An increased number density of strands in cold-hardened G.
biloba compared with normal cultured cells was also observed. Although no
Hechtian strands were detected in any Arabidopsis callus cells, strands were
present in leaf epidermal cells. Finally, the movement of attached microspheres
was monitored along the outside of a strand while cycling the osmotic pressure.
PMID- 10759534
TI - Extracellular H(2)O(2) induced by oligogalacturonides is not involved in the
inhibition of the auxin-regulated rolB gene expression in tobacco leaf explants.
AB - alpha-1,4-Linked oligogalacturonides (OGs) inhibit auxin-regulated
transcriptional activation of a rolB-beta-glucuronidase (GUS) gene fusion in
tobacco (Nicotiana tabacum) leaf explants (D. Bellincampi, M. Cardarelli, D.
Zaghi, G. Serino, G. Salvi, C. Gatz, F. Cervone, M. M. Altamura, P. Costantino,
G. De Lorenzo [1996] Plant Cell 8: 477-487). In this paper we show that
inhibition by OGs is very rapid, with a short lag time, and takes place even
after rolB promoter activation has initiated. OGs also induce a transient and
catalase-sensitive accumulation of H(2)O(2) in the leaf explant culture medium.
OGs with a degree of polymerization from 12 to 15 are required for both the
inhibition of the auxin-induced rolB-driven accumulation of GUS and the induction
of H(2)O(2) accumulation(.) However, OG concentration for half-maximal induction
of H(2)O(2) accumulation is approximately 3-fold higher than that for half
maximal inhibition of rolB promoter activity. The inhibition of rolB promoter
activity is not influenced by the addition of catalase or superoxide dismutase,
suggesting that H(2)O(2) and superoxide are not involved in this effect. A fungal
oligo-beta-glucan elicitor induces extracellular H(2)O(2) accumulation at
comparable or higher levels than those observed with OGs, but does not prevent
the auxin-induced accumulation of GUS. We conclude that H(2)O(2) produced upon
treatment with OGs is not involved in the inhibition of the auxin-induced
expression of the rolB gene.
PMID- 10759535
TI - Enhancement of Na(+) uptake currents, time-dependent inward-rectifying K(+)
channel currents, and K(+) channel transcripts by K(+) starvation in wheat root
cells.
AB - Excessive low-affinity Na(+) uptake is toxic to the growth of glycophytic plants.
Recently, several reports have suggested that the interaction between K(+) and
Na(+) uptake might represent a key factor in determining the Na(+) tolerance of
plants. We investigated the effects of K(+) starvation on Na(+) and K(+) uptake
mechanisms in the plasma membrane of wheat (Triticum aestivum L.) root cortex
cells using the patch-clamp technique. Unexpectedly, K(+) starvation of wheat
seedlings was found to enhance the magnitude and frequency of occurrence of time
dependent inward-rectifying K(+) channel currents (I(K)(+)(in)). We examined
whether the transcription of a wheat root K(+)(in) channel gene is induced by
K(+) starvation. A cDNA coding for a wheat root K(+) channel homolog, TaAKT1
(accession no. AF207745), was isolated. TaAKT1 mRNA levels were up-regulated in
roots in response to withdrawal of K(+) from the growth medium. Furthermore, K(+)
starvation caused an enhancement of instantaneous Na(+) currents (I(Na)(+)).
Electrophysiological analyses suggested that I(K)(+)(in) and I(Na)(+) are not
mediated by the same transport protein based on: (a) different activation curves,
(b) different time dependencies, (c) different sensitivities to external Ca(2+),
and (d) different cation selectivities. These data implicate a role for I(Na)(+)
in Na(+) uptake and stress during K(+) starvation, and indicate that K(+)(in)
channels may contribute to K(+)-starvation-induced K(+) uptake in wheat roots.
PMID- 10759536
TI - The effects of elevated CO(2) concentrations on cell division rates, growth
patterns, and blade anatomy in young wheat plants are modulated by factors
related to leaf position, vernalization, and genotype.
AB - This study demonstrates that elevated [CO(2)] has profound effects on cell
division and expansion in developing wheat (Triticum aestivum L.) leaves and on
the quantitative integration of these processes in whole-leaf growth kinetics,
anatomy, and carbon content. The expression of these effects, however, is
modified by intrinsic factors related to genetic makeup and leaf position, and
also by exposure to low vernalizing temperatures at germination. Beyond these
interactions, leaf developmental responses to elevated [CO(2)] in wheat share
several remarkable features that were conserved across all leaves examined. Most
significantly: (a) the contribution of [CO(2)] effects on meristem size and
activity in driving differences in whole-blade growth kinetics and final
dimensions; (b) an anisotropy in cellular growth responses to elevated [CO(2)],
with final cell length and expansion in the paradermal plane being highly
conserved, even when the rates and duration of cell elongation were modified,
while cell cross-sectional areas were increased; (c) tissue-specific effects of
elevated [CO(2)], with significant modifications of mesophyll anatomy, including
an increased extension of intercellular air spaces and the formation of, on
average, one extra cell layer, while epidermal anatomy was mostly unaltered. Our
results indicate complex developmental regulations of sugar effects in expanding
leaves that are subjected to genetic variation and influenced by environmental
cues important in the promotion of floral initiation. They also provide insights
into apparently contradictory and inconsistent conclusions of published CO(2)
enrichment studies in wheat.
PMID- 10759537
TI - Purified gamma-glutamyl transpeptidases from tomato exhibit high affinity for
glutathione and glutathione S-conjugates.
AB - gamma-Glutamyl transpeptidases (gammaGTases) are the only enzymes known to
hydrolyze the unique N-terminal amide bonds of reduced glutathione (gamma-L
glutamyl-cysteinyl-glycine), oxidized glutathione, and glutathione S-conjugates.
Two gammaGTases (I and II) with K(m) values for glutathione of 110 and 90 microM
were purified 2,977-fold and 2,152-fold, respectively, from ripe tomato
(Lycopersicon esculentum) pericarp. Both enzymes also hydrolyze dipeptides and
other tripeptides with N-terminal, gamma-linked Glu and the artificial substrates
gamma-L-glutamyl-p-nitroanilide and gamma-L-glutamyl(7-amido-4-methylcoumarin).
They transfer the glutamyl moiety to water or acceptor amino acids, including L
Met, L-Phe, L-Trp, L-Ala, or the ethylene precursor 1-aminocyclopropane-1
carboxylic acid. gammaGTase I and II were released from a wall and membrane
fraction of a tomato fruit extract with 1.0 M NaCl, suggesting that they are
peripheral membrane proteins. They were further purified by acetone
precipitation, Dye Matrex Green A affinity chromatography, and hydrophobic
interaction chromatography. The two gammaGTases were resolved by concanavalin A
(Con A) affinity chromatography, indicating that they are differentially
glycosylated. The native and SDS-denatured forms of both enzymes showed molecular
masses of 43 kD.
PMID- 10759538
TI - Iron-superoxide dismutase expression in transgenic alfalfa increases winter
survival without a detectable increase in photosynthetic oxidative stress
tolerance.
AB - To determine whether overexpression of Fe-superoxide (SOD) dismutase would
increase superoxide-scavenging capacity and thereby improve the winter survival
of transgenic alfalfa (Medicago sativa L.) plants, two genotypes were transformed
with the vector pEXSOD10, which contains a cDNA for Arabidopsis Fe-SOD with a
chloroplast transit peptide and cauliflower mosaic virus 35S promoter. A novel Fe
SOD was detected by native PAGE in both greenhouse- and field-grown transgenic
plants, but activity varied among independent transgenic plants. The increased Fe
SOD activity was associated with increased winter survival over 2 years in field
trials, but not with oxidative stress tolerance as measured by resistance of
leaves to methyl viologen, a superoxide generator. Total shoot dry matter
production over 2 harvest years was not associated with Fe-SOD activity. There
was no detectable difference in the pattern of primary freezing injury, as shown
by vital staining, nor was there additional accumulation of carbohydrates in
field-acclimated roots of the transgenic alfalfa plants. We did not detect any
difference in growth of one transgenic plant with high Fe-SOD activity compared
with a non-transgenic control. Therefore, the improvement in winter survival did
not appear to be a consequence of improved oxidative stress tolerance associated
with photosynthesis, nor was it a consequence of a change in primary freezing
injury. We suggest that Fe-SOD overexpression reduced secondary injury symptoms
and thereby enhanced recovery from stresses experienced during winter.
PMID- 10759539
TI - Effects of acetate on facultative autotrophy in Chlamydomonas reinhardtii
assessed by photosynthetic measurements and stable isotope analyses.
AB - The green alga Chlamydomonas reinhardtii can grow photoautotrophically utilizing
CO(2), heterotrophically utilizing acetate, and mixotrophically utilizing both
carbon sources. Growth of cells in increasing concentrations of acetate plus 5%
CO(2) in liquid culture progressively reduced photosynthetic CO(2) fixation and
net O(2) evolution without effects on respiration, photosystem II efficiency (as
measured by chlorophyll fluorescence), or growth. Using the technique of on-line
oxygen isotope ratio mass spectrometry, we found that mixotrophic growth in
acetate is not associated with activation of the cyanide-insensitive alternative
oxidase pathway. The fraction of carbon biomass resulting from photosynthesis,
determined by stable carbon isotope ratio mass spectrometry, declined
dramatically (about 50%) in cells grown in acetate with saturating light and
CO(2). Under these conditions, photosynthetic CO(2) fixation and O(2) evolution
were also reduced by about 50%. Some growth conditions (e.g. limiting light, high
acetate, solid medium in air) virtually abolished photosynthetic carbon gain.
These effects of acetate were exacerbated in mutants with slowed electron
transfer through the D1 reaction center protein of photosystem II or impaired
chloroplast protein synthesis. Therefore, in mixotrophically grown cells of C.
reinhardtii, interpretations of the effects of environmental or genetic
manipulations of photosynthesis are likely to be confounded by acetate in the
medium.
PMID- 10759540
TI - The sucrose transporter of celery. Identification and expression during salt
stress.
AB - In celery (Apium graveolens L.), long-distance transport of reduced carbon occurs
both in the form of sucrose (Suc) and mannitol. The presence of mannitol has been
related to the resistance of celery to salt stress. To investigate the transport
events occurring during salt stress, we have cloned the H(+)/Suc transporter of
celery AgSUT1 (A. graveolens Suc uptake transport 1) from a mature leaf cDNA
library. The function of the encoded protein was confirmed by expression in
yeast. AgSUT1 is a H(+)/Suc transporter with a high affinity for Suc (K(m) of 139
microM). Another closely related cDNA (AgSUT2) was also identified. AgSUT1 is
mainly expressed in mature leaves and phloem of petioles, but also in sink organs
such as roots. When celery plants were subjected to salt stress conditions (30 d
watering with 300 mM NaCl) favoring mannitol accumulation (J.D. Everard, R.
Gucci, S.C. Kann, J.A. Flore, W.H. Loescher [1994] Plant Physiol 106: 281-292),
AgSUT1 expression was decreased in all organs, but markedly in roots. The results
are discussed in relation to the physiology of celery.
PMID- 10759541
TI - The electronic plant gene register
PMID- 10759542
TI - Sterol regulation of human fatty acid synthase promoter I requires nuclear factor
Y- and Sp-1-binding sites.
AB - To understand cholesterol-mediated regulation of human fatty acid synthase
promoter I, we tested various 5'-deletion constructs of promoter I-luciferase
reporter gene constructs in HepG2 cells. The reporter gene constructs that
contained only the Sp-1-binding site (nucleotides -82 to -74) and the two tandem
sterol regulatory elements (SREs; nucleotides -63 to -46) did not respond to
cholesterol. Only the reporter gene constructs containing a nuclear factor-Y (NF
Y) sequence, the CCAAT sequence (nucleotides -90 to -86), an Sp-1 sequence, and
the two tandem SREs responded to cholesterol. The NF-Y-binding site, therefore,
is essential for cholesterol response. Mutating the SREs or the NF-Y site and
inserting 4 bp between the Sp-1- and NF-Y-binding sites both resulted in a
minimal cholesterol response of the reporter genes. Electrophoretic mobility
shift assays using anti-SRE-binding protein (SREBP) and anti-NF-Ya antibodies
confirmed that these SREs and the NF-Y site bind the respective factors. We also
identified a second Sp-1 site located between nucleotides -40 and -30 that can
substitute for the mutated Sp-1 site located between nucleotides -82 and -74. The
reporter gene expression of the wild-type promoter and the Sp-1 site (nucleotides
-82 to -74) mutant promoter was similar when SREBP1a [the N-terminal domain of
SREBP (amino acids 1-520)] was constitutively overexpressed, suggesting that Sp-1
recruits SREBP to the SREs. Under the same conditions, an NF-Y site mutation
resulted in significant loss of reporter gene expression, suggesting that NF-Y is
required to activate the cholesterol response.
PMID- 10759544
TI - Reevaluation of the accepted allosteric mechanism of phosphofructokinase from
Bacillus stearothermophilus.
AB - The binding of phosphoenolpyruvate (PEP) to the single allosteric site on
phosphofructokinase (EC ) from Bacillus stearothermophilus (BsPFK) diminishes the
ability of the enzyme to bind the substrate fructose 6-phosphate (Fru-6-P).
Comparisons of crystal structures with either Fru-6-P or phosphoglycolate, an
analog of PEP, bound have shown that Arg-162 interacts with the negatively
charged Fru-6-P. Upon the binding of phosphoglycolate, Arg-162 is virtually
replaced by Glu-161, which introduces a potential coulombic repulsion between
enzyme and substrate [Schirmer, T. & Evans, P. R. (1990) Nature (London) 343, 140
145]. It has previously been proposed that this structural transition explains
the allosteric inhibition in BsPFK, and this explanation has appeared in
textbooks to illustrate how an allosteric ligand can influence substrate binding
at a distance. Site-directed mutagenesis has been employed to create three
mutants of BsPFK that substitute an alanine residue for Glu-161, Arg-162, or
both. The E161A mutation does not affect the inhibition of BsPFK by PEP at 25
degrees C, and while the R162A mutation decreases BsPFK's affinity for Fru-6-P by
approximately 30-fold, R162A diminishes the effectiveness of PEP inhibition by
only 1/3. Combining E161A and R162A produces behavior comparable to R162A alone.
These and other data suggest that the movement of Glu-161 and Arg-162 does not
play the central role in producing the allosteric inhibition by PEP as originally
envisioned in the Schirmer and Evans mechanism.
PMID- 10759543
TI - Augmentation of immune responses to HIV-1 and simian immunodeficiency virus DNA
vaccines by IL-2/Ig plasmid administration in rhesus monkeys.
AB - The potential utility of plasmid DNA as an HIV-1 vaccination modality currently
is an area of active investigation. However, recent studies have raised doubts as
to whether plasmid DNA alone will elicit immune responses of sufficient magnitude
to protect against pathogenic AIDS virus challenges. We therefore investigated
whether DNA vaccine-elicited immune responses in rhesus monkeys could be
augmented by using either an IL-2/Ig fusion protein or a plasmid expressing IL
2/Ig. Sixteen monkeys, divided into four experimental groups, were immunized with
(i) sham plasmid, (ii) HIV-1 Env 89.6P and simian immunodeficiency virus mac239
Gag DNA vaccines alone, (iii) these DNA vaccines and IL-2/Ig protein, or (iv)
these DNA vaccines and IL-2/Ig plasmid. The administration of both IL-2/Ig
protein and IL-2/Ig plasmid induced a significant and sustained in vivo
activation of peripheral T cells in the vaccinated monkeys. The monkeys that
received IL-2/Ig plasmid generated 30-fold higher Env-specific antibody titers
and 5-fold higher Gag-specific, tetramer-positive CD8+ T cell levels than the
monkeys receiving the DNA vaccines alone. IL-2/Ig protein also augmented the
vaccine-elicited immune responses, but less effectively than IL-2/Ig plasmid.
Augmentation of the immune responses by IL-2/Ig was evident after the primary
immunization and increased with subsequent boost immunizations. These results
demonstrate that the administration of IL-2/Ig plasmid can substantially augment
vaccine-elicited humoral and cellular immune responses in higher primates.
PMID- 10759545
TI - Latitudinal gradients of species richness in the deep-sea benthos of the North
Atlantic.
AB - Latitudinal species diversity gradients (LSDGs) in the Northern Hemisphere are
the most well established biogeographic patterns on Earth. Despite long-standing
interest in LSDGs as a central problem in ecology, their explanation remains
uncertain. In terrestrial as well as coastal and pelagic marine ecosystems, these
poleward declines in diversity typically have been represented and interpreted in
terms of species richness, the number of coexisting species. Newly discovered
LSDGs in the bathyal (500-4,000 m) benthos of the North Atlantic may help to
resolve the underlying causes of these large-scale trends because the deep sea is
such a physically distinct environment. However, a major problem in comparing
surface and deep-sea LSDGs is that the latter have been measured differently, by
using species diversity indices that are affected by both species richness and
the evenness of relative abundance. Here, we demonstrate that deep-sea isopods,
gastropods, and bivalves in the North Atlantic do exhibit poleward decreases in
species richness, just as those found in other environments. A comprehensive
systematic revision of the largest deep-sea gastropod family (Turridae) has
provided a unique database on geographic distributions that is directly
comparable to those used to document LSDGs in surface biotas. This taxon also
shows a poleward decline in the number of species. Seasonal organic enrichment
from sinking phytodetritus is the most plausible ecological explanation for deep
sea LSDGs and is the environmental factor most consistently associated with
depressed diversity in a variety of bathyal habitats.
PMID- 10759546
TI - Selective in vivo suppression of T lymphocyte responses in experimental measles
virus infection.
AB - During and after measles virus (MV) infection humans are highly susceptible to
opportunistic infections because of a marked immunosuppressive effect of the
virus. The mechanisms by which the virus induces this phenomenon is not well
understood. In particular, detailed information is missing on the targets of
suppression in relation to antigen-specific T and B cell responses. Because such
studies require animal experiments, we used the cotton rat model, in which the MV
causes a respiratory tract infection. Primary as well as secondary T cell
responses were impaired in vivo and ex vivo by MV infection. The proliferation of
T cells was greatly reduced, but their effector functions, such as cytolysis or
cytokine secretion, were not. In contrast, primary and secondary B cell responses
in vivo as measured by the frequency of antigen-specific plasma cells in an
enzyme-linked immunospot (ELISPOT) assay were not altered by MV infection. Only
the secretion of immunoglobulins was reduced slightly in animals primarily
infected with MV after 2 weeks. These data demonstrate that MV-induced
immunosuppression acts primarily on the T cell responses in vivo.
PMID- 10759547
TI - Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1
expression and cancer progression.
AB - Beta-catenin can function as an oncogene when it is translocated to the nucleus,
binds to T cell factor or lymphoid enhancer factor family members, and
transactivates its target genes. In this study, we demonstrate that cyclin D1 is
one of the targets of beta-catenin in breast cancer cells. Transactivation of
beta-catenin correlated significantly with cyclin D1 expression both in eight
breast cell lines in vitro and in 123 patient samples. More importantly, we found
that high beta-catenin activity significantly correlated with poor prognosis of
the patients and was a strong and independent prognostic factor in breast cancer.
Our studies, therefore, indicated that beta-catenin can be involved in breast
cancer formation and/or progression and may serve as a target for breast cancer
therapy.
PMID- 10759548
TI - Impairment of synaptic transmission by transient hypoxia in hippocampal slices:
improved recovery in glutathione peroxidase transgenic mice.
AB - There is increasing evidence that oxygen free radicals contribute to ischemic
brain injury. It is unclear, however, to what extent specific antioxidant enzymes
can prevent or reverse the impairment of synaptic function caused by transient
hypoxia. In this study, we investigated in transgenic (Tg) mice whether a
moderate increase in glutathione peroxidase-1 (GPx1) may improve the capacity of
CA1 pyramidal cells to recover synaptic transmission after a short period of
hypoxia in vitro. In control hippocampal slices, transient hypoxia (7-9 min)
produced irreversible loss of excitatory postsynaptic potentials. Complete
recovery of synaptic transmission was observed with homozygous Tg-MT-GPx-6 mice
after reoxygenation, and, after repeated episodes of hypoxia, synaptic
transmission was still viable in most Tg slices, in contrast to non-Tg slices.
Moreover, hypoxic episodes abolished the capacity of hippocampal slices to
generate long-term potentiation in area CA1 of control mice, whereas a
significant extent of long-term potentiation expression was still preserved in Tg
tissues. We also demonstrated that susceptibility to N-methyl-d-aspartate
mediated oxidative injury was reduced in Tg hippocampal slices. In conclusion,
our results suggest that a moderate GPx increase can be sufficient to prevent
irreversible functional damage produced by transient hypoxia in the hippocampus
and to help maintain basic electrophysiological mechanisms involved in memory
formation.
PMID- 10759549
TI - Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy
of human malignant neoplasias.
AB - High mobility group I (HMGI) proteins are overexpressed in several human
malignant tumors. We previously demonstrated that inhibition of HMGI synthesis
prevents thyroid cell transformation. Here, we report that an adenovirus carrying
the HMGI(Y) gene in an antisense orientation (Ad-Yas) induced programmed cell
death of two human thyroid anaplastic carcinoma cell lines (ARO and FB-1), but
not normal thyroid cells. The Ad-Yas virus led to death of lung, colon, and
breast carcinoma cells. A control adenovirus carrying the lacZ gene did not
inhibit the growth of either normal or neoplastic cells. Ad-Yas treatment of
tumors induced in athymic mice by ARO cells caused a drastic reduction in tumor
size. Therefore, suppression of HMGI(Y) protein synthesis by an HMGI(Y) antisense
adenoviral vector may be a useful treatment strategy in a variety of human
malignant neoplasias, in which HMGI(Y) gene overexpression is a general event.
PMID- 10759550
TI - Cadherin interaction probed by atomic force microscopy.
AB - Single molecule atomic force microscopy was used to characterize structure,
binding strength (unbinding force), and binding kinetics of a classical cadherin,
vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary
cells as cis-dimerized full-length external domain fused to Fc-portion of human
IgG. In physiological buffer, the external domain of VE-cadherin dimers is a
approximately 20-nm-long rod-shaped molecule that collapses and dissociates into
monomers (V-shaped structures) in the absence of Ca(2+). Trans-interaction of
dimers is a low-affinity reaction (K(D) = 10(-3)-10(-5) M, k(off) = 1.8 s(-1),
k(on) = 10(3)-10(5) M(-1) x s(-1)) with relatively low unbinding force (35-55 pN
at retrace velocities of 200-4,000 nm x s(-1)). Higher order unbinding forces,
that increase with interaction time, indicate association of cadherins into
complexes with cumulative binding strength. These observations favor a model by
which the inherently weak unit binding strength and affinity of cadherin trans
interaction requires clustering and cytoskeletal immobilization for
amplification. Binding is regulated by low-affinity Ca(2+) binding sites (K(D) =
1.15 mM) with high cooperativity (Hill coefficient of 5.04). Local changes of
free extracellular Ca(2+) in the narrow intercellular space may be of
physiological importance to facilitate rapid remodeling of intercellular adhesion
and communication.
PMID- 10759551
TI - Genetic mapping of a naturally occurring hereditary renal cancer syndrome in
dogs.
AB - Canine hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis
(RCND) is a rare, naturally occurring inherited cancer syndrome observed in dogs.
Genetic linkage analysis of an RCND-informative pedigree has identified a linkage
group flanking RCND (CHP14-C05.377-C05.414-FH2383-C05. 771-[RCND-CPH18]-C02608
GLUT4-TP53-ZuBe Ca6-AHT141-FH2140-FH2594) thus localizing the disease to a small
region of canine chromosome 5. The closest marker, C02608, is linked to RCND with
a recombination fraction (theta) of 0.016, supported by a logarithm of odds score
of 16.7. C02608 and the adjacent linked markers map to a region of the canine
genome corresponding to portions of human chromosomes 1p and 17p. A combination
of linkage analysis and direct sequencing eliminate several likely candidate
genes, including tuberous sclerosis 1 and 2 genes (TSC1 and TSC2) and the tumor
suppressor gene TP53. These data suggest that RCND may be caused by a previously
unidentified tumor suppressor gene and highlight the potential for canine
genetics in the study of human disease predisposition.
PMID- 10759552
TI - Bean alpha-amylase inhibitor 1 in transgenic peas (Pisum sativum) provides
complete protection from pea weevil (Bruchus pisorum) under field conditions.
AB - Two alpha-amylase inhibitors, called alphaAI-1 and alphaAI-2, that share 78%
amino acid sequence identity and have a differential specificity toward mammalian
and insect alpha-amylases are present in different accessions of the common bean
(Phaseolus vulgaris). Using greenhouse-grown transgenic peas (Pisum sativum), we
have shown previously that expression of alphaAI-1 in pea seeds can provide
complete protection against the pea weevil (Bruchus pisorum). Here, we report
that alphaAI-1 also protects peas from the weevil under field conditions. The
high degree of protection is explained by our finding that alphaAI-1 inhibits pea
bruchid alpha-amylase by 80% over a broad pH range (pH 4.5-6.5). alphaAI-2, on
the other hand, is a much less effective inhibitor of pea bruchid alpha-amylase,
inhibiting the enzyme by only 40%, and only in the pH 4.0-4.5 range.
Nevertheless, this inhibitor was still partially effective in protecting field
grown transgenic peas against pea weevils. The primary effect of alphaAI-2
appeared to be a delay in the maturation of the larvae. This contrasts with the
effect of alphaAI-1, which results in larval mortality at the first or second
instar. These results are discussed in relationship to the use of amylase
inhibitors with different specificities to bring about protection of crops from
their insect pests or to decrease insect pest populations below the economic
injury level.
PMID- 10759553
TI - Expression of alpha 1D subunit mRNA is correlated with L-type Ca2+ channel
activity in single neurons of hippocampal "zipper" slices.
AB - L-type voltage-sensitive Ca(2+) channels (L-VSCCs) play an important role in
developmental and aging processes, as well as during normal function of brain
neurons. Here, we tested a prediction of the hypothesis that membrane density of
functional L-VSCCs is regulated by the level of gene expression for its alpha(1D)
pore-forming subunit. If so, alpha(1D) mRNA and L-VSCC activity should be
positively correlated within individual neurons. Conventional methods of
aspiration and/or acute cell dissociation used in prior single-cell studies have
generally yielded variable and incomplete recovery of intracellular mRNA. Thus,
quantitative relationships between channel function and expression have been
difficult to define. In this study, we used the partially dissociated ("zipper")
hippocampal slice preparation as a method for collecting a single neuron's mRNA
complement. This preparation, developed to expose neuronal somata for recording,
also enables the extraction of a neuron with major processes largely intact.
Thus, single-cell measures of gene/mRNA expression can be based on approximately
the cell's full set of mRNA transcripts. In adult and aged rat hippocampal zipper
slices, L-VSCC activity was first recorded in CA1 neurons in cell-attached patch
mode. The same neurons were then extracted and collected for semiquantitative
reverse transcriptase-PCR analysis of alpha(1D) and calmodulin A (CaM) mRNA
content. Across multiple single neurons, a significant, positive correlation was
found between the rank orders of L-VSCC activity and of alpha(1D), but not CaM,
mRNA expression. Thus, these studies support the possibility that the level of
alpha(1D) gene expression regulates the density of functional L-VSCCs.
PMID- 10759554
TI - Involvement of multiple intracellular release channels in calcium sparks of
skeletal muscle.
AB - In many types of muscle, intracellular Ca(2+) release for contraction consists of
brief Ca(2+) sparks. Whether these result from the opening of one or many
channels in the sarcoplasmic reticulum is not known. Examining massive numbers of
sparks from frog skeletal muscle and evaluating their Ca(2+) release current, we
provide evidence that they are generated by multiple channels. A mode is
demonstrated in the distribution of spark rise times in the presence of the
channel activator caffeine. This finding contradicts expectations for single
channels evolving reversibly, but not for channels in a group, which collectively
could give rise to a stereotyped spark. The release channel agonists imperatoxin
A, ryanodine, and bastadin 10 elicit fluorescence events that start with a spark,
then decay to steady levels roughly proportional to the unitary conductances of
35%, 50%, and 100% that the agonists, respectively, promote in bilayer
experiments. This correspondence indicates that the steady phase is produced by
one open channel. Calculated Ca(2+) release current decays 10- to 20-fold from
spark to steady phase, which requires that six or more channels be open during
the spark.
PMID- 10759555
TI - Genome organization in dicots: genome duplication in Arabidopsis and synteny
between soybean and Arabidopsis.
AB - Synteny between soybean and Arabidopsis was studied by using conceptual
translations of DNA sequences from loci that map to soybean linkage groups A2, J,
and L. Synteny was found between these linkage groups and all four of the
Arabidopsis chromosomes, where GenBank contained enough sequence for synteny to
be identified confidently. Soybean linkage group A2 (soyA2) and Arabidopsis
chromosome I showed significant synteny over almost their entire lengths, with
only 2-3 chromosomal rearrangements required to bring the maps into substantial
agreement. Smaller blocks of synteny were identified between soyA2 and
Arabidopsis chromosomes IV and V (near the RPP5 and RPP8 genes) and between soyA2
and Arabidopsis chromosomes I and V (near the PhyA and PhyC genes). These
subchromosomal syntenic regions were themselves homeologous, suggesting that
Arabidopsis has undergone a number of segmental duplications or possibly a
complete genome duplication during its evolution. Homologies between the
homeologous soybean linkage groups J and L and Arabidopsis chromosomes II and IV
also revealed evidence of segmental duplication in Arabidopsis. Further support
for this hypothesis was provided by the observation of very close linkage in
Arabidopsis of homologs of soybean Vsp27 and Bng181 (three locations) and purple
acid phosphatase-like sequences and homologs of soybean A256 (five locations).
Simulations show that the synteny and duplications we report are unlikely to have
arisen by chance during our analysis of the homology reports.
PMID- 10759556
TI - Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA
by the nucleotide excision-repair pathway in human cells.
AB - Exposure of cellular DNA to reactive oxygen species generates several classes of
base lesions, many of which are removed by the base excision-repair pathway.
However, the lesions include purine cyclodeoxynucleoside formation by
intramolecular crosslinking between the C-8 position of adenine or guanine and
the 5' position of 2-deoxyribose. This distorting form of DNA damage, in which
the purine is attached by two covalent bonds to the sugar-phosphate backbone,
occurs as distinct diastereoisomers. It was observed here that both
diastereoisomers block primer extension by mammalian and microbial replicative
DNA polymerases, using DNA with a site-specific purine cyclodeoxynucleoside
residue as template, and consequently appear to be cytotoxic lesions. Plasmid DNA
containing either the 5'R or 5'S form of 5',8-cyclo-2-deoxyadenosine was a
substrate for the human nucleotide excision-repair enzyme complex. The R
diastereoisomer was more efficiently repaired than the S isomer. No correction of
the lesion by direct damage reversal or base excision repair was detected. Dual
incision around the lesion depended on the core nucleotide excision-repair
protein XPA. In contrast to several other types of oxidative DNA damage, purine
cyclodeoxynucleosides are chemically stable and would be expected to accumulate
at a slow rate over many years in the DNA of nonregenerating cells from xeroderma
pigmentosum patients. High levels of this form of DNA damage might explain the
progressive neurodegeneration seen in XPA individuals.
PMID- 10759557
TI - A causal link between respiration and senescence in Podospora anserina.
AB - Senescence, a progressive degenerative process leading to age-related increase in
mortality, is found in most eukaryotes. However, the molecular events underlying
aging remain largely unknown. Understanding how longevity is regulated is a
fundamental problem. Here we demonstrate that the respiratory function is a key
factor that contributes to shortening lifespan of the filamentous fungus
Podospora anserina. In this organism, senescence is systematically associated
with mitochondrial DNA instabilities. We show that inactivation of the nuclear
COX5 gene encoding subunit V of the cytochrome c oxidase complex leads to the
exclusive use of the alternative respiratory pathway and to a decrease in
production of reactive oxygen species. This inactivation results in a striking
increase of longevity associated with stabilization of the mitochondrial
chromosome. Moreover, accumulation of several senescence-specific mitochondrial
DNA molecules is prevented in this nuclear mutant. These findings provide direct
evidence of a causal link between mitochondrial metabolism and longevity in
Podospora anserina.
PMID- 10759558
TI - A sequence resembling a peroxisomal targeting sequence directs the interaction
between the tetratricopeptide repeats of Ssn6 and the homeodomain of alpha 2.
AB - The tetratricopeptide repeat (TPR) is a 34-aa sequence motif, typically found in
tandem clusters, that occurs in proteins of bacteria, archea, and eukaryotes.
TPRs interact with other proteins, although few details on TPR-protein
interactions are known. In this paper we show that a portion of a loop in the
homeodomain of the DNA-binding protein alpha2 is required for its recognition by
the TPRs of the corepressor Ssn6. The amino acid sequence of this loop is similar
to the sequences recognized by the TPRs of an entirely different protein, Pex5,
which directs peroxisomal import. We further show that alpha2 can be made to bind
specifically in vitro to the TPRs of Pex5 and that a point mutation that disrupts
the alpha2-Ssn6 interaction also disrupts the alpha2-Pex5 interaction. These
results demonstrate that two different TPR proteins recognize their target by a
similar mechanism, raising the possibility that other TPR-target interactions
could occur through the same means.
PMID- 10759559
TI - Damage-induced neuronal endopeptidase (DINE) is a unique metallopeptidase
expressed in response to neuronal damage and activates superoxide scavengers.
AB - We isolated a membrane-bound metallopeptidase, DINE (damage-induced neuronal
endopeptidase), by differential display PCR using rat normal and axotomized
hypoglossal nuclei. The most marked properties of DINE were neuron-specific
expression and a striking response to axonal injury in both the central nervous
system and peripheral nervous system. For instance, cranial and spinal nerve
transection, ischemia, corpus callosum transection, and colchicine treatment
increased DINE mRNA expression in the injured neurons, whereas kainate-induced
hyperexcitation, immobilization, and osmotic stress failed to up-regulate DINE
mRNA. Expression of DINE in COS cells partially inhibited C2-ceramide-induced
apoptosis, probably because of the activation of antioxidant enzymes such as
Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and glutathione peroxidase
through the proteolytic activity of DINE. These data provide insight into the
mechanism of how injured neurons protect themselves against neuronal death.
PMID- 10759560
TI - Predicting protein function from structure: unique structural features of
proteases.
AB - We have noted consistent structural similarities among unrelated proteases. In
comparison with other proteins of similar size, proteases have smaller than
average surface areas, smaller radii of gyration, and higher C(alpha) densities.
These findings imply that proteases are, as a group, more tightly packed than
other proteins. There are also notable differences in secondary structure content
between these two groups of proteins: proteases have fewer helices and more
loops. We speculate that both high packing density and low alpha-helical content
coevolved in proteases to avoid autolysis. By using the structural parameters
that seem to show some separation between proteases and nonproteases, a neural
network has been trained to predict protease function with over 86% accuracy.
Moreover, it is possible to identify proteases whose folds were not represented
during training. Similar structural analyses may be useful for identifying other
classes of proteins and may be of great utility for categorizing the flood of
structures soon to flow from structural genomics initiatives.
PMID- 10759561
TI - Cytotoxic T cell immunity against telomerase reverse transcriptase in humans.
AB - Telomerase is a ribonucleoprotein enzyme which has been linked to malignant
transformation in human cells. Telomerase activity is increased in the vast
majority of human tumors, making its gene product the first molecule common to
all human tumors. The generation of endogenously processed telomerase peptides
bound to Class I MHC molecules could therefore target cytotoxic T lymphocytes
(CTL) to tumors of different origins. This could advance vaccine therapy against
cancer provided that precursor CTL recognizing telomerase peptides in normal
adults and cancer patients can be expanded through immunization. We demonstrate
here that the majority of normal individuals and patients with prostate cancer
immunized in vitro against two HLA-A2.1 restricted peptides from telomerase
reverse transcriptase (hTRT) develop hTRT-specific CTL. This suggests the
existence of precursor CTL for hTRT in the repertoire of normal individuals and
in cancer patients. Most importantly, the CTL of cancer patients specifically
lysed a variety of HLA-A2(+) cancer cell lines, demonstrating immunological
recognition of endogenously processed hTRT peptides. Moreover, in vivo
immunization of HLA-A2.1 transgenic mice generated a specific CTL response
against both hTRT peptides. Based on the induction of CTL responses in vitro and
in vivo, and the susceptibility to lysis of tumor cells of various origins by
hTRT CTL, we suggest that hTRT could serve as a universal cancer vaccine for
humans.
PMID- 10759562
TI - Nebular and auroral emission lines of [Cl III] in the optical spectra of
planetary nebulae.
AB - Electron impact excitation rates in Cl III, recently determined with the R-matrix
code, are used to calculate electron temperature (T(e)) and density (N(e))
emission line ratios involving both the nebular (5517.7, 5537.9 A) and auroral
(8433.9, 8480.9, 8500.0 A) transitions. A comparison of these results with
observational data for a sample of planetary nebulae, obtained with the Hamilton
Echelle Spectrograph on the 3-m Shane Telescope, reveals that the R(1) = I(5518
A)/I(5538 A) intensity ratio provides estimates of N(e) in excellent agreement
with the values derived from other line ratios in the echelle spectra. This
agreement indicates that R(1) is a reliable density diagnostic for planetary
nebulae, and it also provides observational support for the accuracy of the
atomic data adopted in the line ratio calculations. However the [Cl iii] 8433.9 A
line is found to be frequently blended with a weak telluric emission feature,
although in those instances when the [Cl iii] intensity may be reliably measured,
it provides accurate determinations of T(e) when ratioed against the sum of the
5518 and 5538 A line fluxes. Similarly, the 8500.0 A line, previously believed to
be free of contamination by the Earth's atmosphere, is also shown to be generally
blended with a weak telluric emission feature. The [Cl iii] transition at 8480.9
A is found to be blended with the He i 8480.7 A line, except in planetary nebulae
that show a relatively weak He i spectrum, where it also provides reliable
estimates of T(e) when ratioed against the nebular lines. Finally, the diagnostic
potential of the near-UV [Cl iii] lines at 3344 and 3354 A is briefly discussed.
PMID- 10759563
TI - Inhibition of the expression of penicillin resistance in Streptococcus pneumoniae
by inactivation of cell wall muropeptide branching genes.
AB - Penicillin-resistant strains of Streptococcus pneumoniae contain low affinity
penicillin-binding proteins and often also produce abnormal indirectly
crosslinked cell walls. However the relationship between cell wall abnormality
and penicillin resistance has remained obscure. We now show that the genome of S.
pneumoniae contains an operon composed of two genes (murM and murN) that encode
enzymes involved with the biosynthesis of branched structured cell wall
muropeptides. The sequences of murMN were compared in two strains: the penicillin
susceptible strain R36A producing the species-specific pneumococcal cell wall
peptidoglycan in which branched stem peptides are rare, and the highly penicillin
resistant transformant strain Pen6, the cell wall of which is enriched for
branched-structured stem peptides. The two strains carried different murM
alleles: murM of the penicillin-resistant strain Pen6 had a "mosaic" structure
encoding a protein that was only 86.5% identical to the product of murM
identified in the isogenic penicillin-susceptible strain R36A. Mutants of R36A
and Pen6 in which the murMN operon was interrupted by insertion-duplication
mutagenesis produced peptidoglycan from which all branched muropeptide components
were missing. The insertional mutant of Pen6 carried a pbp2x gene with the same
"mosaic" sequence found in Pen6. On the other hand, inactivation of murMN in
strain Pen6 and other resistant strains caused a virtually complete loss of
penicillin resistance. Our observations indicate that the capacity to produce
branched cell wall precursors plays a critical role in the expression of
penicillin resistance in S. pneumoniae.
PMID- 10759564
TI - The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus
transformed B lymphocytes in vitro and in vivo: A potential approach to
prevention and treatment of posttransplant lymphoproliferative disorders.
AB - Whereas the standard immunosuppressive agents foster development of
posttransplant lymphoproliferative disorders (PTLDs), the impact of RAD, a
macrolide with potent immunosuppressive properties, and other immunosuppressive
macrolides on these disorders remains undetermined. We found that RAD had a
profound inhibitory effect on in vitro growth of six different PTLD-like Epstein
Barr virus+ lymphoblastoid B cell lines. Similar to normal T cells, RAD blocked
cell-cycle progression in PTLD-like B cells in the early (G(0)/G(1)) phase.
Furthermore, RAD increased the apoptotic rate in such cells. The drug also had a
profound inhibitory effect on the growth of PTLD-like Epstein-Barr virus+ B cells
xenotransplanted s.c. into SCID mice. The degree of the RAD effect varied among
the three B cell lines tested and was proportional to its effects on the cell
lines in vitro. In this in vivo xenotransplant model, RAD markedly delayed growth
or induced regression of the established tumors. In one line, it was able to
eradicate the tumor in four of eight mice. When RAD treatment was initiated
before tumor cell injection, a marked inhibition of tumor growth was seen in all
three lines. In two of them, the drug prevented tumor establishment in
approximately 50% of mice (5/11 and 5/8). In summary, RAD is a potent inhibitor
of PTLD-like cells in vitro and in vivo. These findings indicate that, in
contrast to the standard immunosuppressive agents, macrolides such as RAD may be
effective in prevention and treatment of PTLDs.
PMID- 10759565
TI - Identification and characterization of a host protein required for efficient
template selection in viral RNA replication.
AB - Biochemical studies suggest that positive-strand RNA virus replication involves
host as well as viral functions. Brome mosaic virus (BMV) is a member of the
alphavirus-like superfamily of animal and plant positive-strand RNA viruses.
Yeast expressing the BMV RNA replication proteins 1a and 2a supports BMV RNA
replication and mRNA synthesis. Using the ability of BMV to replicate in yeast,
we show that efficient BMV RNA replication requires Lsm1p, a yeast protein
related to core RNA splicing factors but shown herein to be cytoplasmic. Haploid
yeast with an Lsm1p mutation was defective in an early template selection step in
BMV RNA replication, involving the helicase-like replication protein 1a and an
internal viral RNA element conserved with tRNAs. Lsm1p dependence of this
interaction was suppressed by adding 3' poly(A) to the normally unpolyadenylated
BMV RNA. Our results show Lsm1p involvement in a specific step of BMV RNA
replication and connections between Lsm1p and poly(A) function, possibly through
interaction with factors binding mRNA 5' ends.
PMID- 10759566
TI - The synaptic glycoprotein neuroplastin is involved in long-term potentiation at
hippocampal CA1 synapses.
AB - Neuroplastin-65 and -55 (previously known as gp65 and gp55) are glycoproteins of
the Ig superfamily that are enriched in rat forebrain synaptic membrane
preparations. Whereas the two-Ig domain isoform neuroplastin-55 is expressed in
many tissues, the three-Ig domain isoform neuroplastin-65 is brain-specific and
enriched in postsynaptic density (PSD) protein preparations. Here, we have
assessed the function of neuroplastin in long-term synaptic plasticity.
Immunocytochemical studies with neuroplastin-65-specific antibodies
differentially stain distinct synaptic neuropil regions of the rat hippocampus
with most prominent immunoreactivity in the CA1 region and the proximal molecular
layer of the dentate gyrus. Kainate-induced seizures cause a significant
enhancement of neuroplastin-65 association with PSDs. Similarly, long-term
potentiation (LTP) of CA1 synapses in hippocampal slices enhanced the association
of neuroplastin-65 with a detergent-insoluble PSD-enriched protein fraction.
Several antibodies against the neuroplastins, including one specific for
neuroplastin-65, inhibited the maintenance of LTP. A similar effect was observed
when recombinant fusion protein containing the three extracellular Ig domains of
neuroplastin-65 was applied to hippocampal slices before LTP induction.
Microsphere binding experiments using neuroplastin-F(c) chimeric proteins show
that constructs containing Ig1-3 or Ig1 domains, but not Ig2-3 domains mediate
homophilic adhesion. These data suggest that neuroplastin plays an essential role
in implementing long-term changes in synaptic activity, possibly by means of a
homophilic adhesion mechanism.
PMID- 10759567
TI - Early Cretaceous lineages of monocot flowering plants.
AB - The phylogeny of flowering plants is now rapidly being disclosed by analysis of
DNA sequence data, and currently, many Cretaceous fossils of flowering plants are
being described. Combining molecular phylogenies with reference fossils of known
minimum age makes it possible to date the nodes of the phylogenetic tree. The
dating may be done by counting inferred changes in sequenced genes along the
branches of the phylogeny and calculating change rates by using the reference
fossils. Plastid DNA rbcL sequences and eight reference fossils indicate that
approximately 14 of the extant monocot lineages may have diverged from each other
during the Early Cretaceous >100 million years B.P. The lineages are very
different in size and geographical distribution and provide perspective on
flowering plant evolution.
PMID- 10759569
TI - Resources used by general practitioners for advising travelers from New Zealand.
AB - BACKGROUND: The risks of the destination and any specific requirements for travel
health advice may be obtained from a variety of resources. This study was
designed to investigate the usefulness of various resources available in New
Zealand for providing travel health advice and the extent to which GPs used these
resources in providing travel health advice. METHOD: Four hundred GPs (400/2830)
were randomly selected from the register of the New Zealand Medical Council and
sent self-administered questionnaires. Two reminders were sent. RESULTS: Three
hundred and thirty-two (332/400, 83%) GPs responded. The usefulness of various
resources was reported, including Health Advice for Overseas Travellers (277/289,
96%), New Ethicals (256/278, 92%), New Zealand Public Health Report (79/164,
48%), International Travel and Health (41/144, 28%), computerized databases
(6/122, 5%), journals (14/130, 11%), and other resources (44/139, 32%). Health
Advice for Overseas Travellers was regarded as significantly more useful than
International Travel and Health (x2 = 4,68, df = 1, p <.05). Only 23% (70/309) of
respondents indicated that they always used these resources in their practice of
travel medicine. Fifty percent (154/309) of respondents indicated that they
usually used these resources, while 27% (83/309) of respondents indicated that
they used these resources sometimes. Only 1% (2/309) of GPs did not use resources
at all for their practice of travel medicine. CONCLUSIONS: The most useful
resource was Health Advice for Overseas Travellers, which outlines the New
Zealand recommendations for medical practitioners providing travel health advice.
It may be useful for GPs to gain access to and training in association with a
greater range of specialist resources to use in conjunction with the provision of
travel health advice. These might include international guidelines, journals, and
access to computerized databases and the internet. With the recent introduction
of a widely accessible computerized database in New Zealand, follow-up studies
could be instituted to determine if GPs' use of computerized databases becomes
more widespread and whether access to and use of these computerized databases
influences the provision of travel health advice by GPs. Further studies are
needed to examine the appropriateness of the advice provided by the various
resources used by GPs in New Zealand.
PMID- 10759568
TI - SUMO-1 conjugation to topoisomerase I: A possible repair response to
topoisomerase-mediated DNA damage.
AB - Ubiquitin/26S proteasome-dependent degradation of topoisomerase I (TOP1) has been
suggested to be a unique repair response to TOP1-mediated DNA damage. In the
current study, we show that treatment of mammalian cells or yeast cells
expressing human DNA TOP1 with camptothecin (CPT) induces covalent modification
of the TOP1 by SUMO-1/Smt3p, a ubiquitin-like protein. This conclusion is based
on the following observations: (i) Mammalian DNA TOP1 conjugates induced by CPT
were cross-reactive with SUMO-1/Smt3p-specific antibodies both in yeast
expressing human DNA TOP1 as well as mammalian cells. (ii) The formation of TOP1
conjugates was shown to be dependent on UBC9, the E2 enzyme for SUMO-1/Smt3p.
(iii) TOP1 physically interacts with UBC9. (iv) Ubc9 mutant yeast cells
expressing human DNA TOP1 was hypersensitive to CPT, suggesting that UBC9/SUMO-1
may be involved in the repair of TOP1-mediated DNA damage.
PMID- 10759570
TI - A dengue outbreak among camp participants in a Caribbean island, 1995.
AB - BACKGROUND: Dengue, a mosquito-transmitted viral disease, is a risk for visitors
in tropical and subtropical areas. Several participants in a community-assistance
program in Tortola, British Virgin Islands, in August, 1995, reported dengue-like
symptoms either before or soon after leaving the island. METHODS: We conducted a
retrospective cohort study to determine the extent of the outbreak, risk factors
for illness, and the proportion of inapparent infections. Program participants
were interviewed by telephone or mail, and asked to submit a serum sample for
dengue diagnosis. A clinically-diagnosed case of dengue was defined as a person
with fever and two or more of the following: headache, retro-orbital pain,
myalgia, arthralgia, rash, or hemorrhagic manifestations. Serum specimens were
tested for virus isolation, polymerase chain reaction (PCR), plaque-reduction
neutralization (PRNT) or anti-dengue IgM and IgG antibody. RESULTS: Thirty-two
(97%) of the 33 program participants responded; 21 of the 32 (66%) provided at
least one serum sample for study. The median age was 17 years; 20 (62%) were
women. Of 32 respondents, 22 (69%) met the clinical case definition for dengue:
15 of them (68%) had a positive IgM antibody response and 7 did not submit a
serum sample. Dengue 1 virus (DEN-1) was identified by PCR in one case and all 11
positive PRNT results. No asymptomatic infections were identified. No respondent
used effective mosquito repellent, and only 2 (6%) used bednets. CONCLUSIONS: A
DEN-1 outbreak with a high attack rate (69%) occurred in a group of young short
term community aid workers. There were no asymptomatic infections documented.
Participants' rare use of bednets or effective mosquito repellent highlights the
importance of providing travelers to tropical areas with information about dengue
fever and the recommended precautions to protect against infection.
PMID- 10759571
TI - Medical repatriation of British diplomats resident overseas.
AB - BACKGROUND: The aim of this study was to analyse medical evacuations and short
tours (collectively known as medevacs) in British Foreign and Commonwealth Office
(FCO) staff and dependents residing overseas. Further aims were to look for
groups with a disproportionate number of medical evacuations/short tours, and to
identify events which may have been predictable in retrospect. For the purposes
of this study, a medical evacuation was defined as a journey to the UK or an
appropriate regional referral center for medical treatment or review, and a
medical short tour was an early termination of posting for medical reasons.
METHOD: The medical records of all staff and dependents who had been medically
evacuated/short toured in 1995 were retrospectively analysed. Information
collected included demographic details, whether the medevac was an emergency or a
predicted necessity, why the medevac was required, the diagnosis, and the time
from medical clearance to medevac. RESULTS: In 1995, 160 medevacs involving 137
individuals were authorized. This represented 3.08% of individuals overseas, with
only 0.4% of individuals posted overseas being evacuated with new medical events
within 1 year of medical clearance. The proportion of medevacs for staff was
significantly higher than for dependents (spouses and children), and staff in
their 20s and fast-stream diplomats (young "high-flyers" with a university
education) were over-represented in the evacuee group. Non-physical problems were
predominant in the latter groups. The main reason for evacuation (70%) was that
medical facilities were considered unsuitable, and just over half of the medevacs
(51%) were considered by the investigating team to have been unpredictable.
CONCLUSIONS: Only a small percent of individuals posted overseas required
medevac. The likelihood of evacuation was significantly higher in staff when
compared to dependents, and certain grades/age groups appeared to be over
represented in the evacuee group. These groups are possibly more vulnerable,
particularly to non-physical problems, and this is a potential area for future
research. A prospective study of medical events overseas is proposed to see if
these results are reproduced. If these findings are confirmed, medical clearance
and FCO posting procedures may need to be altered for groups which are identified
as being vulnerable.
PMID- 10759572
TI - Epidemiology of giardiasis in German travelers.
AB - BACKGROUND: Giardiasis has been well characterized in individuals traveling from
areas of low to high endemicity. METHODS: Clinical features, travel and medical
histories in 352 patients with giardiasis who presented to a German outpatient
clinic for Infectious and Tropical Diseases were investigated in order to
identify common epidemiological factors and potential strategies of prevention.
RESULTS: Compared to the total patient population of the outpatient clinic during
the period of investigation (n=13, 566 patients), patients who presented with
giardiasis traveled longer (median 28 days versus 19 days, p <.001). While only
19.2% of the total patient population had traveled to the Indian subcontinent
prior to referral, 32.1% of the patients with giardiasis acquired the infection
there (p <.0001). Similar results were obtained for West Africa: in contrast to
19% of patients with giardiasis (p <. 0001), only 5.4% of the total patient
population traveled there. CONCLUSION: The risk of infection appears to be
highest when making an extended journey to the Indian subcontinent. Short-time
visitors to other parts of Asia and Latin America are apparently at a markedly
lower risk. Risk factors such as type, duration and destination of the journey
should be considered in pretravel counseling.
PMID- 10759573
TI - Does the concurrent administration of an inactivated hepatitis A vaccine
influence the immune response to other travelers vaccines?
AB - BACKGROUND: Travelers seeking protection from hepatitis A also often need
protection against other infections, prevalent at their destinations. METHODS: A
total of 396 volunteers received not only a hepatitis A vaccine but also either a
vaccine against polio, hepatitis B, diphtheria, tetanus, yellow fever, Japanese
encephalitis, typhoid fever or rabies according to their individual needs. We
investigated the potential influence of the hepatitis A vaccination on the immune
response to the other travelers vaccines that were administered concurrently.
RESULTS: With seroprotection rates of 100% for yellow fever, Japanese
encephalitis and rabies immunization and tetanus boosters our data demonstrate
that the concurrent administration of hepatitis A vaccine does not compromise the
immune response of these vaccines. Also for oral typhoid, hepatitis B and
diphtheria vaccination we did not detect a negative influence of concurrent
hepatitis A vaccine administration as compared with respective vaccinations when
given alone. Prior to vaccination, more than one third of our subjects lacked
protective antibody levels against diphtheria and only 44% of initially
seronegative travelers seroconverted to an anti-diphtheria titer > or = 0.01
mIU/mL, supporting a need for an additional dose. Furthermore, only two thirds of
the vaccinees tested prior to vaccination were protected against polio type 3,
and the seroconversion rate following the administration of oral polio vaccine,
was lower for viral type 3 (80%), as has been previously demonstrated in settings
without concurrent other vaccinations. CONCLUSION: No negative effect of
concurrent travelers vaccinations on the immune response of a hepatitis A vaccine
has been detected in a previous report, and, likewise our data suggest no
impairment of the antibody response of these travelers vaccines by the concurrent
administration of the hepatitis A vaccine.
PMID- 10759574
TI - Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine
as chemoprophylaxis against malaria in Danish travelers.
AB - BACKGROUND: The aim of the study was to provide data on the relative frequency of
reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and
mefloquine. METHOD: The study was an open, nonrandomized study recording self
reported events in travelers recruited consecutively from two travel clinics in
Copenhagen, Denmark. The main outcome measures were the relative proportion of
travelers reporting particular symptoms in the three prophylaxis groups,
compliance, hospitalization and premature termination of the travel. RESULTS:
From May 1996 to April 1998 5, 446 travelers were included and 4,158
questionnaires (76.3%) returned. Compliance was significantly better in
mefloquine users with 83.3% of short term travelers compared to 76.3% in
chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine,
chloroquine plus proguanil, and mefloquine respectively reported no symptoms and
0.6%, 1.1% and 2.8% reported "unacceptable" symptoms. Compared to chloroquine,
mefloquine users had a significantly higher risk of reporting depression, RR 5.06
(95% CI 2.71 - 9.45), "strange thoughts," RR 6.36 (95% CI 2.52 - 16.05) and
altered spatial perception, RR 3.00 (95% CI 1.41 - 6.41). CONCLUSION: Overall
mefloquine is tolerated at least as well as chloroquine plus proguanil and shows
better compliance, however, symptoms related to the central nervous system are
more prevalent in mefloquine users and when symptoms develop, they are perceived
as more severe.
PMID- 10759575
TI - Sources of health advice given to travelers.
AB - One of the biggest problems for health professionals and the travel industry has
been getting travelers to present for pretravel health advice from a qualified
source. Behrens1 stated that one of the most important factors in whether
travelers seek health advice at all was the perceived risk and severity of
tropical diseases. Travelers may obtain this health advice from the travel
industry itself, or from health professionals in travel clinics, hospitals,
public health units, general practices or other centers. They may also obtain
advice by telephone directly from these areas. It is likely however that travel
agents and the travel industry, especially various publications, are an important
source of preliminary information on health and safety for travelers.
PMID- 10759576
TI - Imported histoplasmosis in Spain.
AB - Histoplasma capsulatum is a dimorphic fungus endemic in the American continent
but not in Europe, where cases are usually imported. Its favorite habitat is in
warm humid soils. Guano from birds and bats enhance the sporulation of the
mycelial phase.1 Man acquires H. capsulatum through inhalation of spores. Most
people infected by this fungi remain asymptomatic, but around 10-50% can start an
illness ranging from acute pulmonary histoplasmosis to chronic histoplasmosis. In
both, there is close clinical resemblance to pulmonary tuberculosis.
Immunodepressed patients undergo a more severe form of the disease, usually
presenting in the acute disseminated form. We present seven immunocompetent
patients with histoplasmosis acquired after traveling to several American
countries.
PMID- 10759577
TI - Vibrio cholerae O2 as a cause of a skin lesion in a tourist returning from
Tunisia.
AB - Isolates of Vibrio cholerae other than O1 and O139 (non O1 Vibrio cholerae) are
associated with sporadic diarrheal disorders, and limited outbreaks of diarrhea,
and have often been reported in association with extraintestinal infections. The
majority of cases of non O1 Vibrio cholerae infection involve immunocompromised
patients with hematologic malignancies or cirrhosis. In Italy, very few cases of
gastrointestinal and extraintestinal infections due to non O1 Vibrio cholerae
have been described in the past years. We describe a case of non O1 Vibrio
cholerae infection with cutaneous bullous lesions in a tourist returning from
Tunisia.
PMID- 10759578
TI - Hospital admissions for malaria in Basel, Switzerland: an epidemiological review
of 150 cases.
AB - The increase in international travel and immigration from tropical countries has
led to a growing number of imported malaria cases in industrialized countries. We
analyzed the charts of every patient hospitalized for malaria from 1970-1992 in
Basel, Switzerland. A period lasting from 1970-1986 was compared to 1987-1992.
There were 150 malaria-episodes recorded. Over time, the number of immigrants
increased from 12 to 27% (p <.05). More patients were admitted with Plasmodium
falciparum-infection (49 vs. 75%, p <.005). The number of untypable malaria
decreased from 30 to 9% (p <.005). In the more recent period, more diagnosis were
done within a week (66 vs. 50%, p <.05). Twenty-three (15%) patients were
admitted to the ICU, four (2. 6%) patients died of cerebral malaria. Twenty-seven
(18%) patients developed malaria while taking correct prophylaxis. Despite some
progress, malaria is still causing considerable morbidity and mortality. Non
adherence to chemoprophylaxis was a major risk factor for acquiring malaria in
hospitalized patients.
PMID- 10759579
TI - Malaria and Borrelia co-infection.
AB - Severe anemia requiring blood transfusion may complicate falciparum malaria, but
is rare in nonfalciparum malaria. We present a case of a young man with high
fever, severe hemolytic anemia, and a blood film containing massive co-infection
with Plasmodium vivax and with Borrelia. The possible importance of the co
infection on the magnitude of hemolysis will be discussed.
PMID- 10759580
TI - Introduction to the Acta Physiologica Scandinavica International Symposium on
Skeletal Muscle Oxygen Availability and Utilization.
PMID- 10759581
TI - Structural and functional limits for oxygen supply to muscle.
AB - Environmental oxygen is transported by the respiratory cascade to the site of
oxidation in active tissues. Under conditions of heavy exercise it is ultimately
the working skeletal muscle cells that determine the aerobic demand as over 90%
of energy is spent in muscle cells. Oxygen is transported in the circulation
bound to haemoglobin of erythrocytes while substrates are transported in the
plasma. The supply of oxygen must be continuous because there are only minimal
oxygen stores in the body of most mammalian species while substrates are stored
in significant quantities both within muscle cells as also in organismic
substrate stores. The pathways for oxygen and substrates ultimately converge in
muscle mitochondria. In mammals, a structural limitation of carbohydrate and
lipid transfer from the microvascular system to muscle cells is reached at a
moderate work intensity (i.e. at less than 50% of VO2max). At higher work rates
intracellular substrate stores must be used for oxidation. It is therefore not
surprising to find larger intramyocellular carbohydrate and lipid stores in
'athletic' species as well as in endurance-trained human athletes. The transfer
limitations for carbohydrates and lipids presumably occur on the level of the
sarcolemma. These findings imply that the design of the respiratory cascade from
lungs to muscle mitochondria has to be analysed with regard to satisfying the
demand for oxygen of the working muscle cells. Substrate stores are replenished
at low flux rates during periods of rest and are stored intracellularly. They are
therefore locally available to mitochondria for aerobic work at high intensities.
PMID- 10759582
TI - Muscle oxygen uptake in humans at onset of and during intense exercise.
AB - This review presents data on human muscle oxygen consumption in the initial phase
of exercise as well as on muscle maximal oxygen uptake. It also discusses
mechanistic limiting factors related to oxygen utilization at the onset of
exercise and of maximal aerobic power of skeletal muscle. Direct measurements of
oxygen utilization of a well-defined muscle show that contracting muscles utilize
oxygen within a few seconds of exercise onset and that it takes some 45 s before
oxygen extraction is maximal. The delayed oxygen utilization in the initial phase
of intense exercise does not appear to be caused by insufficient oxygen
availability. But it may rather be the result of a non-optimal distribution of
blood flow in the exercising muscles and a limitation in the rate of oxygen
extraction by the contracting muscle cells. The latter limitation does not appear
to be caused by an insufficient activation of the enzyme pyruvate dehydrogenase.
The maximal oxygen uptake of skeletal muscle is around 300-400 mL min-1 kg-1.
This uptake rate corresponds to a TCA cycle rate of 4-5 mmol min-1 kg-1, which is
of the same magnitude as the activity of oxyglutarate dehydrogenase and pyruvate
dehydrogenase, suggesting that these enzymes may be rate limiting for oxygen
uptake when an isolated muscle is exercising.
PMID- 10759583
TI - Oxygen tension and content in the regulation of limb blood flow.
AB - During submaximal exercise, muscle blood flow increases when arterial oxygen
content (CaO2) is reduced. The increase in blood flow is brought about by
elevating cardiac output (CO) and enhancing leg vascular conductance. Conversely,
increased CaO2 elicits lower limb blood flow (LBF) and CO. During maximal
exercise, the influence of CaO2 on muscle blood flow is modulated depending on
the amount of muscle mass recruited. When a small muscle mass is activated and
the pumping capacity of the heart is not limited, changes in CaO2 barely
influence the level of blood flow attained at peak exercise. However, when a
large muscle mass is engaged in the exercise, as occurs for example during
cycling and running, muscle blood flow is decreased if maximal CO is reduced, as
happens during exercise in severe hypoxia. In contrast, maximal muscle blood flow
and CO are maintained at peak exercise when CaO2 is increased. As such, exercise
intensity, muscle mass and CaO2 appear to be the critical factors determining
muscle blood flow during exercise.
PMID- 10759584
TI - Human skeletal muscle mitochondrial capacity.
AB - Under aerobic work, the oxygen consumption and major ATP production occur in the
mitochondria and it is therefore a relevant question whether the in vivo rates
can be accounted for by mitochondrial capacities measured in vitro. Mitochondria
were isolated from human quadriceps muscle biopsies in yields of approximately
45%. The tissue content of total creatine, mitochondrial protein and different
cytochromes was estimated. A number of activities were measured in functional
assays of the mitochondria: pyruvate, ketoglutarate, glutamate and succinate
dehydrogenases, palmitoyl-carnitine respiration, cytochrome oxidase, the
respiratory chain and the ATP synthesis. The activities involved in carbohydrate
oxidation could account for in vivo oxygen uptakes of 15-16 mmol O2 min-1 kg-1 or
slightly above the value measured at maximal work rates in the knee-extensor
model of Saltin and co-workers, i.e. without limitation from the cardiac output.
This probably indicates that the maximal oxygen consumption of the muscle is
limited by the mitochondrial capacities. The in vitro activities of fatty acid
oxidation corresponded to only 39% of those of carbohydrate oxidation. The
maximal rate of free energy production from aerobic metabolism of glycogen was
calculated from the mitochondrial activities and estimates of the DeltaG or ATP
hydrolysis and the efficiency of the actin-myosin reaction. The resultant value
was 20 W kg-1 or approximately 70% of the maximal in vivo work rates of which 10
20% probably are sustained by the anaerobic ATP production. The lack of aerobic
in vitro ATP synthesis might reflect termination of some critical interplay
between cytoplasm and mitochondria.
PMID- 10759586
TI - Metabolic modulation of sympathetic vasoconstriction in exercising skeletal
muscle.
AB - The tight coupling of oxygen supply and utilization in exercising skeletal muscle
is the result of complex interactions between local mechanisms that control
muscle blood flow and substrate utilization and systemic mechanisms that control
cardiac output and arterial pressure. The role of the sympathetic nervous system
in the integration of these responses, specifically the interaction between
sympathetic activation and local vasodilator mechanisms in exercising muscle, has
been an active area of research for many years yet remains incompletely
understood. The functional consequence of sympathetic activation in exercising
skeletal muscle has been the subject of considerable debate. Previous studies in
animals and humans have suggested that sympathetic vasoconstricton in active
muscle is (a) well maintained and serves to limit active hyperaemia, thereby
preventing muscle blood flow from outstripping cardiac output in order to
preserve blood pressure and vital organ perfusion or (b) greatly attenuated in
order to optimize muscle perfusion, a concept that has been termed 'functional
sympatholysis'. Studies performed over the past 70 years have provided
conflicting evidence regarding the relative importance of sympathetic
vasoconstriction vs. functional sympatholysis in exercising skeletal muscle. The
focus of this review is mainly on recent studies in anaesthetized animal
preparations and in conscious humans that have provided evidence for the
metabolic modulation of sympathetic vasoconstriction in contracting skeletal
muscle and have identified a number of key underlying mechanisms that extend the
initial concept of sympatholysis.
PMID- 10759585
TI - Neurogenic vasodilation in human skeletal muscle: possible role in contraction
induced hyperaemia.
AB - Whether or not neurally mediated vasodilation contributes to the rise in skeletal
muscle blood flow during exercise in humans remains unknown. Such a mechanism
might serve as an important 'feed-forward' regulatory signal causing blood flow
to rise prior to the development of a metabolic demand. Research in animal
species has identified three neurally mediated vasodilating mechanisms with the
potential to increase skeletal muscle blood flow during exercise. These include
sympathetic vasodilator nerves, the potential for substances released by motor
nerves to evoke vasodilation and the possibility of an 'intrinsic' vasodilator
nerve system within the walls of blood vessels. In humans, sympathetic
vasodilator nerves are present in several vascular beds (e.g. cutaneous).
However, more recent information suggests that the human skeletal muscle is not
innervated by this class of nerves. Along these lines, the vasodilator response
to exercise is unaffected by sympathectomy or by blockade of the traditional
transmitters associated with neurally mediated vasodilation. The possibility that
spillover of substances released from motor neurones evokes vasodilation is
provocative. For example, acetylcholine could produce both skeletal muscle
contraction via nicotinic receptors and vasodilation via endothelial muscarinic
receptors. However, in many species including humans, atropine has no effect on
exercise hyperaemia. While the concept of an 'intrinsic' vasodilator pathway
within the walls of the skeletal muscle vascular bed is fascinating, limited
information is available on this mechanism in animals and none is available in
humans. Taken together, the current information suggests that neurally mediated
vasodilating mechanisms may not exist in human skeletal muscle. Additionally,
even if such mechanisms exist, they do not play an obligatory role in governing
the rise in muscle blood flow during exercise in humans.
PMID- 10759587
TI - Large arterioles in the control of blood flow: role of endothelium-dependent
dilation.
AB - Although it is generally assumed that small arterioles form the major site of
vascular resistance, microcirculatory studies revealed that 40-55% of the total
network resistance can reside in large arterioles and small arteries. Thus, the
mechanisms that control smooth muscle tone in these vessels have a major impact
on the overall conductance of the vascular network. These control mechanisms are
different from those in small arterioles: Aside from an apparently reduced
sensitivity to metabolites, the large resistance vessels are normally too far
away from the capillary areas which they feed to be reached by diffusing
metabolites from dependent cells within a reasonable period of time. Rather,
recent intravital microscopic studies suggest that large resistance vessels are
under tight control of endothelial factors such as nitric oxide and endothelium
derived hyperpolarising factor (EDHF). Nitric oxide opposes myogenic
constrictions of large arterioles that potentially would impair tissue perfusion
and oxygenation. Moreover, nitric oxide and EDHF play an important role in the co
ordination of large and small resistance vessel behaviour that is pivotal for the
adaptation of blood flow to altered tissue oxygen demands.
PMID- 10759588
TI - Integration of blood flow control to skeletal muscle: key role of feed arteries.
AB - Blood flow control reflects dynamic, integrated changes in the diameter of
vessels that comprise resistance networks. Vasoconstriction and vasodilation can
travel rapidly along the vessel wall via the conduction of electrical signals
between endothelial and/or smooth muscle cells through gap junctions. Within the
hamster cheek pouch, these conducted responses reflect complementary mechanisms
for co-ordinating both increases and decreases in arteriolar diameter. In the
hamster retractor muscle, vasodilation also conducts along arterioles and into
feed arteries, yet vasoconstriction appears constrained to the site(s) of smooth
muscle activation. Thus, mechanisms for co-ordinating vasomotor control in
resistance networks can vary between tissues that differ in structure and
function. The resistance vessels of the retractor (and other skeletal) muscle are
richly innervated by sympathetic nerves, which are absent from the cheek pouch.
Propagation along sympathetic nerves rapidly co-ordinates smooth muscle cell
contraction throughout the resistance network by releasing noradrenaline along
the innervation pathway. Passive extension of the retractor muscle activates
periarteriolar sympathetic nerves. This activity propagates antidromically into
feed arteries and may complement the central (autonomic) vasoconstrictor response
to exercise. In a reciprocal manner, muscle contraction evokes arteriolar
dilation that is conducted (i.e. 'ascends') into feed arteries and may thereby
counteract sympathetic vasoconstriction. With feed arteries anatomically
positioned to control blood flow into skeletal muscle, the integration of dilator
and constrictor stimuli in these vessels is a key determinant of muscle blood
flow during exercise.
PMID- 10759589
TI - Nutritive and non-nutritive blood flow: rest and exercise.
AB - There is growing evidence to support the notion of two vascular routes within, or
closely associated with skeletal muscle. One route is in intimate contact with
muscle cells (hence is known as 'nutritive') and the other functions as a
vascular shunt (and has had the interesting misnomer of 'non-nutritive'). Recent
findings suggest that the 'non-nutritive' route may, in part, be those vessels in
closely associated (interlacing?) connective tissue that nourishes attached fat
cells, and may form the basis of 'marbling' of muscle in obesity. In addition,
embolism studies using various size microspheres indicate that the 'non
nutritive' vessels are likely to be capillaries fed by terminal arterioles that
branch from the same transverse arterioles as those supplying terminal arterioles
of the muscle capillaries (i.e. two vascular systems operating in parallel). The
proportion of flow distributed between the two routes is tightly regulated and
controls muscle metabolism and contraction by regulating hormone and substrate
delivery as well as product removal. Because a high proportion of nutritive flow
may elevate the set point for basal metabolism, a low proportion of nutritive
flow in muscle at rest confers an evolutionary advantage, particularly when food
is scarce. In addition, the proportion of flow that is carried by the non
nutritive routes at rest affords a flow reserve that can be switched to the
nutritive route to amplify nutrient supply during exercise. Alternatively the non
nutritive route may allow flow to escape when active muscle contraction
compresses its nutritive capillaries. Thus rhythmic oscillation of blood flow
between the non-nutritive and nutritive networks may aid the muscle pump.
PMID- 10759590
TI - Coupling of muscle metabolism and muscle blood flow in capillary units during
contraction.
AB - Muscle blood flow is tightly coupled to the level of skeletal muscle activity:
Indices of skeletal muscle metabolic rate, for example oxygen consumption or
muscle work, are directly related to the magnitude of the change in muscle blood
flow. Despite the large amount that is known about individual aspects of local
metabolic vasodilation, the mechanisms underlying integrated aspects of the
response remain largely unknown. Arteriolar dilation serves both to increase
blood flow through the muscle and also to recruit capillaries and control
capillary blood flow distribution. Conceptually, these two apparently separate
functions of larger vs. more terminal arterioles (where larger vessels subserve
conductance changes while the smaller more distal vessels have a primary role in
capillary blood flow control) can be met, at least in part, by differential
sensitivity of large vs. small arterioles to metabolites and agonists relevant to
the metabolic response. However, longitudinal differences in sensitivity through
the arteriolar network will not by themselves account for observed
heterogeneities in capillary perfusion or for the close matching between blood
flow and metabolism that occurs even in mixed muscles. In mixed skeletal muscles,
fibres of widely different metabolic profile are dispersed throughout the muscle
and even fibres of a single motor unit are not perfused by common arterioles but
are matched with arterioles arising from widely disparate regions within the
microvascular network. In this review we present findings that support the notion
that capillaries are an integral part of the mechanism underlying this close
matching between blood flow and metabolism. We review studies that indicate that
capillaries are capable of responding to stimuli in their immediate environment
and, importantly, are able to communicate with arterioles located remotely
upstream in the arteriolar tree. Not only can skeletal muscle capillary
endothelial cells induce remote arteriolar vasodilatory and vasoconstrictor
responses to pharmacological stimuli such as acetylcholine or noradrenaline, but
they can also initiate these remote arteriolar responses in response to skeletal
muscle contraction. Capillary endothelial cells respond to skeletal muscle
contraction by transmitting a dilatory signal to at least three branch orders of
arterioles proximal to the capillary; these upstream dilations present a
mechanism whereby capillaries can initiate their own recruitment, and whereby
increased blood flow can be directed only to those exchange vessels associated
with the contracting muscle fibres and where, presumably, the initiating signal
is sensed. This signal involves KATP channels, although their location (on
endothelial, vascular smooth muscle or skeletal muscle cells) is not yet known
and has a nitric oxide-dependent component. The studies reviewed here thus
indicate that capillaries have the capacity to play an active role in co
ordination of muscle blood flow responses to changed muscle metabolism. Much more
remains to be learned, however, about the mechanisms underlying the signals
generated by the contracting muscle and the mechanisms of transmission of the
signals upstream.
PMID- 10759591
TI - Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450
enzymes.
AB - This short review summarizes the potential role of cytochrome P450 (P450) in
regulating blood flow in the brain tissue and in the skeletal muscle. We provide
data showing that pressure-induced myogenic activity in the brain is largely
responsible for autoregulation of CBF. This myogenic response to pressure is
maintained, in part, by 20-HETE formation in arterial muscle cells through a P450
omega-hydroxylase coded for by a P450 4A cDNA. Autoregulation of CBF is a
hallmark of the cerebral circulation and provides adequate nutritive blood flow
despite large fluctuations in arterial pressure. Given the importance of
oxidative metabolism in the brain, support of neuronal activity is mediated by
functional hyperaemia to active neurones providing adequate delivery of oxidative
substrate. We provide data demonstrating that this functional hyperaemia in the
brain is regulated by astrocytes which sense neural activity and release dilator
metabolites which shunt blood flow to active neurones. One of the metabolites
released by astrocytes in this regard are epoxygenated products of arachidonic
acid (AA) formed by P450 enzymes. These AA metabolites of P450 enzymes are
epoxyeicosatrienoic acid (EETs). One of these P450 enzymes is coded by a 2C11
cDNA present in astrocytes. Furthermore, astrocytes are capable of inducing
capillary angiogenesis which appears to be mediated, in part, by P450-derived
EETs.
PMID- 10759592
TI - The red blood cell as an oxygen sensor: what is the evidence?
AB - The matching of oxygen supply with demand requires the existence of a mechanism
within the tissue capable of both sensing tissue oxygen need and inducing
alterations in vascular perfusion necessary to meet that need. Historically,
localized sites within the tissue and the vessels themselves have been
investigated with the sensor site failing to be determined. Within the last
decade, studies have focused on the red blood cell, the efficient carrier of
oxygen, as a possible candidate. The red blood cell is clearly capable of sensing
oxygen levels, as its extent of haemoglobin desaturation (decrease in oxygen
content) is intimately tied with tissue oxygen demand. In addition, numerous
studies have indicated that the red blood cell is capable of releasing increased
amounts of adenosine 5'-triphosphate (ATP) as oxygen content falls and its
haemoglobin becomes desaturated. Within the vasculature, intraluminal ATP has
been shown to induce a vasodilator response which is conducted along the vessels
resulting in augmentation of tissue perfusion. While details of the red blood
cell's role are still under investigation, evidence presented here supports the
intriguing idea that the mobile red blood cell may itself be able to augment
blood flow and oxygen delivery wherever and whenever the need might arise. Such a
mechanism eliminates the requirement for a diverse network of sensing sites
throughout the vasculature and should provide a more efficient means of
appropriately matching oxygen supply with demand.
PMID- 10759593
TI - Adenosine and muscle vasodilatation in acute systemic hypoxia.
AB - Adenosine is released by skeletal and cardiac muscles when their metabolism
increases: it serves to couple O2 supply with O2 demand by causing
vasodilatation. This review argues that adenosine plays a similar role in
skeletal muscle in systemic hypoxia. It accounts for approximately 50% of the
increase in muscle vascular conductance and, within muscle, it causes dilatation
of individual arterioles, thus maximizing the distribution of O2 and allowing O2
consumption to remain constant when O2 delivery is reduced. In vivo and in vitro
studies have indicated that adenosine can induce dilatation in several different
ways. This review argues that during systemic hypoxia, adenosine is predominantly
released from the endothelium and acts on endothelial A1 receptors to produce
dilatation in a nitric oxide (NO)-dependent manner. A1 receptor stimulation
increases the synthesis of NO by a process initiated by opening of ATP-sensitive
K+ (KATP) channels. Moreover, recent findings suggest that prostaglandins also
make a major contribution to the hypoxia-induced dilatation, but that the dilator
pathways for adenosine, NO and prostaglandins are interdependent. In addition,
adenosine released from the skeletal muscle fibres contributes indirectly to the
dilatation by stimulating A1 and A2 receptors on the muscle fibres, opening KATP
channels and allowing efflux of K+, which is a vasodilator. Finally, by acting on
endothelial A1 receptors, adenosine attenuates the vasoconstrictor effects of
constant or bursting patterns of sympathetic activity. This limits the extent to
which the sympathetic nervous system can reduce O2 delivery to muscle when it is
already compromised by systemic hypoxia.
PMID- 10759594
TI - Adenosine and nitric oxide in exercise-induced human skeletal muscle
vasodilatation.
AB - The vasoactive substances adenosine and nitric oxide (NO) are credible candidates
in the local regulation of skeletal muscle blood flow. Adenosine and NO have both
been shown to increase in skeletal muscle cells and interstitial fluid during
exercise and the enzymes responsible for their formation, AMP 5'-nucleotidase and
NO synthase (NOS), have been shown to be activated upon muscle contraction. In
vitro as well as in vivo evidence suggest that the contraction-induced increase
in interstitial adenosine concentration largely stems from extracellular
formation via the membrane-bound ecto-form of AMP 5'-nucleotidase. It remains
unclear whether the exercise-induced NO formation in muscle originates from
endothelial NOS in the microvascular endothelium, or from neuronal NOS (nNOS) in
nerve cells and muscle fibres. Functional evidence for the role of adenosine in
muscle blood flow control stems from studies using adenosine receptor agonists
and antagonists, adenosine deaminase or adenosine uptake inhibitors. The majority
of these studies have been performed on laboratory animals and, although the
results show some discrepancy, the majority of studies indicate that adenosine
does participate in the regulation of muscle blood flow. In humans, evidence is
lacking. The role of NO in the regulation of skeletal muscle blood flow has
mainly been studied using NOS inhibitors. Despite a large number of studies in
this area, the role of NO for the contraction-induced increase in skeletal muscle
blood flow is uncertain. The majority, but not all, human and animal studies show
that, whereas blockade of NOS reduces muscle blood flow at rest and in recovery
from exercise, there is no effect on the exercise-induced increase in muscle
perfusion. Conclusive evidence for the mechanisms underlying the precise
regulation of the multiphased increase in skeletal muscle blood flow during
exercise and the role and potency of various vasoactive substances, remain
missing.
PMID- 10759595
TI - Oxygen supply to contracting skeletal muscle at the microcirculatory level:
diffusion vs. convection.
AB - An adequate supply of oxygen is essential for the normal function of all cells.
Because skeletal muscle cells have the ability to vary their oxygen demand by
over an order of magnitude on going from rest to vigorous contraction, it is
important that mechanisms be in place to ensure that the supply of oxygen is
maintained at sufficient levels. Microcirculation plays a critical role in this
process, as the terminal branches of this intricate network of blood vessels
determine the distribution of perfusion, as well as the structural framework for
diffusion. The oxygen supply depends on proper functioning of both the convective
and diffusive components of the transport system. Convection is responsible for
the long-range, rapid transport of oxygen by bulk flow of the blood and diffusion
is the efficient mechanism for transport over the short distances between
capillaries and muscle cells. Convective transport is dominated by the movement
of red blood cells, as virtually all the oxygen at normal haematocrit is carried
inside them, reversibly bound to haemoglobin. Over the years, specialized
techniques, many of them video-based, have been developed for use in intravital
microscopy to measure the parameters needed to quantify convection and diffusion
in both capillaries and the larger microvessels, arterioles and venules. Most of
our knowledge of oxygen transport in the microcirculation of muscle pertains to
the resting condition, because one must be able to visualize the structures of
interest, such as microvessels and muscle cells, and the large tissue movements
that occur during contraction preclude measurements during that time. In resting
muscle it has been found that the arterioles are the primary site of the
diffusion of oxygen from the circulation, where the oxygen is utilized by nearby
muscle cells or diffuses directly to nearby venules or capillaries. Diffusive
interactions among neighbouring capillaries have also been observed. In
contracting muscles, microvessels observed immediately following the period of
stimulation exhibit enhancements of both convective (increased flow of red blood
cells) and diffusive (increased perfused capillary surface area) transport. The
use of computational models in the interpretation of experimental studies is
leading to an increased understanding of the processes that underlie the oxygen
transport system in skeletal muscle.
PMID- 10759596
TI - Perfusion, diffusion and their heterogeneities limiting blood-tissue O2 transfer
in muscle.
AB - The relative roles of blood flow (perfusion) and diffusion in O2 supply to
exercising muscle can be estimated using a simple model consisting of an O2
consuming tissue block in contact with blood (perfusion Q, slope of O2
equilibirum curve beta) through a resistance to O2 diffusion (O2-diffusing
capacity D). The decisive variable is the 'equilibration index' Y=D/(Qbeta). With
decreasing Y, diffusion limitation increases and perfusion limitation decreases
(Y > 3 indicates predominant perfusion limitation; 3 > Y > 0.1, combined
perfusion and diffusion limitation, Y < 0.1, prevailing diffusion limitation). On
the basis of literature data on humans at maximum O2 uptake, O2 supply to muscle
is shown to be always limited by both perfusion and diffusion. In nomoxia,
perfusion limitation is prevalent, but in hypoxia diffusion limitation becomes
predominant. The underlying model assumes perfect homogeneity of muscles with
respect to O2 requirement, diffusion conditions and blood flow. In numerous
studies on isolated and in situ muscles a pronounced heterogeneity of blood flow
has been found, also during exercise and at maximal O2 uptake. It is shown that
with unequal distribution of blood flow and/or O2-diffusing capacity the
efficiency of O2 transfer is reduced with reference to the homogeneous model.
Therefore, the diffusing capacity value calculated on the basis of the
homogeneous model is an underestimate of the true diffusing capacity and
diffusion limitation is overestimated.
PMID- 10759597
TI - Diffusive resistance to O2 transport in muscle.
AB - Although it has been generally well-accepted since the work of August Krogh at
the start of the 20th century that O2 travels between muscle microvascular red
cells and muscle mitochondria by diffusion, the importance of this process to
maximal O2 flux remains in question. This review presents data that suggest
maximal rates of diffusion of O2 in muscle are limited by both the amount of
capillary structure and the haemoglobin concentration in the blood. On the other
hand, diffusional conductance appears unrelated to muscle fibre size and thus to
distance. Functional data further suggest that the limited rate of diffusion acts
to constrain O2 unloading from muscle capillaries and thus also maximal Vo2, at
least in the trained state. In fact, the calculated sensitivity of VO2max to
muscle diffusional conductance is about as great as that for muscle blood flow.
While additional impairment of O2 unloading from perfusion/metabolism
heterogeneity cannot yet be excluded (for lack of methodology), it seems evident
that the process of O2 transport between the muscle microvasculature and the
mitochondria is subject to significant limits, even in health, that have
substantial effects on maximal Vo2.
PMID- 10759598
TI - Near-infrared spectroscopy for monitoring muscle oxygenation.
AB - Near-infrared spectroscopy (NIRS) is a non-invasive method for monitoring oxygen
availability and utilization by the tissues. In intact skeletal muscle, NIRS
allows semi-quantitative measurements of haemoglobin plus myoglobin oxygenation
(tissue O2 stores) and the haemoglobin volume. Specialized algorithms allow
assessment of the oxidation-reduction (redox) state of the copper moiety (CuA) of
mitochondrial cytochrome c oxidase and, with the use of specific tracers,
accurate assessment of regional blood flow. NIRS has demonstrated utility for
monitoring changes in muscle oxygenation and blood flow during submaximal and
maximal exercise and under pathophysiological conditions including cardiovascular
disease and sepsis. During work, the extent to which skeletal muscles deoxygenate
varies according to the type of muscle, type of exercise and blood flow response.
In some instances, a strong concordance is demonstrated between the fall in O2
stores with incremental work and a decrease in CuA oxidation state. Under some
pathological conditions, however, the changes in O2 stores and redox state may
diverge substantially.
PMID- 10759599
TI - Deciphering the mysteries of myoglobin in striated muscle.
AB - Myoglobin (Mb) is a large protein that reversibly binds oxygen in the muscle cell
and is thought to be critical for O2 supply to the mitochondria during exercise.
The role of Mb in aerobic function is evaluated based on the physical properties
of Mb as an O2 carrier and experimental evidence of Mb function in vivo. This
role depends on the reversible binding of O2 by Mb depending on PO2, which
results in: (1) storage of O2; (2) buffering of PO2 in the cell to prevent
mitochondrial anoxia; and (3) parallel diffusion of O2 (so-called, 'facilitated
diffusion'). The storage role is well established in diving mammals and buffering
of cell PO2 above anoxic levels is shown here by in vivo magnetic resonance
spectroscopy (MRS). However, the quantitative role of Mb in 'facilitated' or
parallel diffusion of O2 is controversial. Evidence in support of this role is
from MRS analyses, which reveal rapid Mb desaturation with exercise, and from the
proportionality of Mb content of a muscle to the O2 diffusion limitation. Recent
experiments with myoglobin knockout mice demonstrating high levels of aerobic
function in normal and myoglobin-free mice argue against a link between Mb and
oxidative phosphorylation. Thus, the current evidence supports the role of Mb in
the physical diffusion of O2; however, the unimpaired aerobic function of Mb
knockout mice indicates that this role may not be critical to O2 supply in active
muscle.
PMID- 10759600
TI - Role of the creatine/phosphocreatine system in the regulation of mitochondrial
respiration.
AB - The mechanism of metabolic regulation of mitochondrial respiration in cardiac
muscle cells was studied experimentally in the permeabilized heart fibres of mice
and by computer modelling in silico. The experiments showed that the rate of
mitochondrial respiration could be controlled by local production of ADP by
mitochondrial creatine kinase in the intermembrane space of mitochondria. The
spatially inhomogenous reaction-diffusion model of compartmentalized energy
transfer was used to analyse which metabolite level in cytoplasm may be important
for regulation of respiration. At low and moderate workloads, up to VO2 equal to
70 micromol min-1 g-1 dry weight, the only factor to which respiration responded
was inorganic phosphate. At the values of VO2 higher than 70 micromol min-1 g-1
dry weight, the respiration rate responded mostly to changes in creatine,
phosphocreatine and then time-averaged (over the contractile cycle) ADP
concentrations in the cytoplasm. These results are taken to show that under
conditions of moderate workloads, creatine kinase activity at given physiological
creatine and phosphocreatine concentrations (apparent maximal activity achievable
under these conditions) is in excess to oxidative phosphorylation rate, which is
controlled by Pi concentration changes starting from very low values of the
latter. At higher workloads mi-CK should be upregulated by increasing creatine
and decreasing phosphocreatine concentrations, and only at very high workloads
the ADP diffusion flux should be increased to upregulate oxidative
phosphorylation. Thus, on the basis of the study in silico of compartmentalized
energy transfer by phophocreatine/creatine system, the authors conclude that
there exist multiple parallel regulatory factors controlling the rate of oxygen
consumption in dependence of the workload. If creatine kinase is inhibited (and
there is no myokinase activity), respiration requires high diffusive flux of ADP
back into mitochondria, which is the sole regulator of respiration. This needs,
however, increased ADP concentrations in the cytoplasm, which in turn result in
inhibition of contraction.
PMID- 10759601
TI - Lactate as a fuel for mitochondrial respiration.
AB - Lactate production in skeletal muscle has now been studied for nearly two
centuries and still its production and functional role at rest and during muscle
contraction is a subject of debate. Historically, skeletal muscle was seen mainly
as the site of lactate production during contraction and lactate production
associated with a lack of muscle oxygenation and fatigue. Later, it was
recognized that skeletal muscle not only plays an important role in lactate
production but also in lactate clearance and this in turn has led to a renewed
interest in the metabolic fate of lactate in skeletal muscle and also in other
tissues. Studies using lactate isotopes have shown that skeletal muscle extracts
lactate from the circulation despite a substantial net lactate release, and that
skeletal muscle has a large capacity for lactate oxidation; these processes being
enhanced with exercise. Lactate dehydrogenase (LDH) controls the formation of
lactate and may regulate the turnover of lactate in the muscle cell. Skeletal
muscle contains five LDH isoforms (LDH1-5). Of the five LDH isoforms, the heart
specific LDH1, 2 is generally suggested to favour the reaction of lactate to
pyruvate whereas the muscle-specific LDH4,5 isoform favours lactate formation.
However, in this paper, it is argued that compartmentalization of the muscle cell
and LDH association with cell structures may play a more predominant role in
whether the LDH reaction proceeds towards lactate or pyruvate formation. The
model for skeletal muscle lactate metabolism presented is in essence based on a
synthesis of old and more recent studies on skeletal muscle lactate transport,
uptake, release, oxidation, and the role of LDH at rest and during exercise.
PMID- 10759602
TI - Anaplerosis of the citric acid cycle: role in energy metabolism of heart and
skeletal muscle.
AB - Efficient energy transfer in heart and skeletal muscle requires a series of
moiety-conserved cycles. The intermediaries of the metabolic cycles are finely
regulated to maintain a dynamic state of equilibrium. In heart muscle, depletion
of the citric acid cycle (TCA cycle) through a block of 2-oxoglutarate
dehydrogenase results in a rapid decline of contractile function, which is
reversed by the addition of substrates promoting flux through the carboxylating
enzymes, malic enzyme, pyruvate carboxylase and propionyl-CoA carboxylase.
Anaplerosis describes a pathway, which replenishes a metabolic cycle. We show
that enzymes for anaplerosis of the TCA cycle are expressed in heart and skeletal
muscles. The role of anaplerosis of the TCA cycle in skeletal muscle is not
entirely clear, but there is substantial evidence for its operational control
during exercise. While the anaplerotic flux of carbon into the TCA cycle exceeds
the removal of cycle intermediates, this process is only transient and reverses
with prolonged exercise. It remains to be determined, however, whether the
initial increase in TCA cycle intermediates is obligatory in order to attain high
rates of TCA cycle flux, or primarily reflects a mass action phenomenon owing to
increased substrate availability for anaplerotic pathways.
PMID- 10759603
TI - Nitric oxide as a competitive inhibitor of oxygen consumption in the
mitochondrial respiratory chain.
AB - Nitric oxide (NO) and its derivatives inhibit mitochondrial respiration by
various means. The author and others have shown that low (nanomolar)
concentrations of NO immediately, specifically and reversibly inhibit cytochrome
oxidase in competition with oxygen, in isolated cytochrome oxidase, mitochondria,
nerve terminals, cultured cells and tissues. Primary astrocytes and a macrophage
cell line, activated by cytokines and endotoxin to express the inducible isoform
of NO synthase, strongly and reversibly inhibited their own respiration and that
of co-incubated cells by this means. Primary aortic endothelial cells transiently
inhibited their own respiration when NO production was acutely stimulated with
bradykinin or ATP, and basal NO release increased the apparent Km for oxygen of
respiration in these cells. Thus the NO inhibition of cytochrome oxidase may be
involved in the physiological and/or pathological regulation of respiration rate
and its affinity for oxygen.
PMID- 10759604
TI - Endogenous nitric oxide in the control of skeletal muscle oxygen extraction
during exercise.
AB - Our previous studies uncovered an inhibitory effect of nitric oxide (NO) on leg
skeletal muscle respiration in dogs at rest. The role of NO in the modulation of
O2 consumption and O2 extraction in hindlimb muscle during elevated metabolic
states was investigated in chronically instrumented dogs while walking and at
three exercise intensities which markedly increased hindlimb blood flow. Walking
resulted in increased O2 consumption by 17 +/- 4 mL min-1 and O2 extraction from
24 +/- 1 to 37 +/- 8%, with no alteration in hindlimb blood flow (BFLeg) and
vascular resistance (VRLeg). Running at the highest speed (9.1 mph) resulted in
an increase in BFLeg from 0.67 +/- 0.05 to 2.2 +/- 0.1 L min-1, a reduction of
VRLeg and elevation of hindlimb O2 consumption from 33 +/- 3 to 226 +/- 21 mL min
1 and O2 extraction from 29 +/- 2 to 61 +/- 5%, with a decrease in leg venous PO2
from 38 +/- 1 to 25 +/- 1 mmHg. After nitro-L-arginine (NLA) (35 mg kg-1, i.v.)
to inhibit endogenous NO synthesis, walking caused greater increases in hindlimb
O2 consumption (29 +/- 5 mL min-1) and O2 extraction (43 +/- 1 to 60 +/- 3%)
(both P < 0.05), with no significant change in BFLeg. During running at the
highest speed, BFLeg was 1.9 +/- 0.1 L min-1 (P < 0. 05) and VRLeg was higher,
accompanied by increases in hindlimb O2 consumption from 49 +/- 7 to 318 +/- 24
mL min-1 and O2 extraction from 41 +/- 2 to 79 +/- 4% (both P < 0.05), with a
greater decrease in leg venous PO2 from 33 +/- 1 to 20 +/- 1 mmHg (P < 0.05).
Similar results were found for intermediate levels of exercise. Our results
indicate that NO modulates hindlimb skeletal muscle O2 extraction and O2 usage
whether blood flow increased or not during exercise.
PMID- 10759605
TI - [Ca2+]i following extrasystoles in guinea-pig trabeculae microinjected with fluo
3 - a comparison with frog skeletal muscle fibres.
AB - Force production of cardiac muscle is highly dependent on the interval between
the excitations. The aim was to investigate relations between intracellular
calcium ([Ca2+]i) and force when a stimulus protocol, with three extrasystoles
(ESs) at various intervals, was used. The relation between [Ca2+]i and force was
compared with that in frog skeletal muscle fibre. Fluo-3 was microinjected into
thin cardiac trabeculae to monitor [Ca2+]i. During steady-state [Ca2+]i consisted
of a rapid rise (phase 1) that lasted until peak dF/dt (rate of force
development) and was followed by a slower rise (phase 2) that coincided with the
action potential and had a peak after peak force. The decline in [Ca2+]i
outlasted the duration of the contraction. As the ES intervals were prolonged,
there was a gradual restitution of force and of the amplitude and rate of rise of
phase 1 [Ca2+]i. Peak dF/dt was linearly related to the amplitude of phase 1
[Ca2+]i during restitution and potentiation of force. Skeletal muscle fibres were
loaded with fluo-3-AM. From [Ca2+]i the amount of calcium bound to troponin ([Ca
T]) as a function of time was estimated. Force production of the skeletal muscle
fibre could be predicted from [Ca-T] when the signal was delayed (time constant
36 ms). This finding indicates that the recorded [Ca2+]i in skeletal muscle
represents activator calcium. In cardiac muscle probably only phase 1 [Ca2+]i
represents activator calcium. Phase 2 [Ca2+]i probably represents calcium entry
during the action potential and does not activate the contractile system to any
significant extent.
PMID- 10759606
TI - Changes in reactivity of rat arteries subjected to dynamic stretch.
AB - The effect of dynamic stretch on the reactivity of the rat tail and mesenteric
artery segments was studied. Segments mounted on a myograph were stretched by a
computer-controlled motorized micromanipulator. Dynamic stretch (1, 5 or 7 Hz)
inhibited the artery constriction induced by noradrenaline (10 microM), 5
hydroxytryptamine (0.7 microM), or electrical field stimulation of intramural
nerves. In contrast, dynamic stretch enhanced the tetrodotoxin-insensitive
dilation induced by electrical field stimulation of noradrenaline-contracted
arteries. Maximal increase of dilation evoked by electrical field stimulation
(24.5 +/- 5.0% in mesenteric and 50.3 +/- 15.6% in the tail artery) was observed
at a dynamic stretch-frequency of 5 Hz. An inhibitor of nitric oxide synthesis,
NG-nitro-L-arginine (100 microM), abolished the difference in reactivity between
static and dynamic conditions. The results indicate that dynamic stretch of the
arteries activates nitric oxide synthesis/secretion, thus reducing constrictor
and increasing dilator responses to the stimuli used.
PMID- 10759607
TI - Factors regulating renal angiotensin-converting enzyme activity in the rat.
AB - Changes in angiotensin-converting enzyme (ACE) activity appear to be important in
mediating the natriuresis which ensues after administration of an oral or gastric
sodium load. In this study, we sought to determine the time course of the changes
in ACE activity in the kidney which occur after sodium ingestion. In addition, we
sought to investigate mechanisms which might underlie these changes. Angiotensin
converting enzyme activity was measured by generation of histidyl-leucine in
homogenates of kidneys harvested at varying time-points after gastric sodium
administration. The effects of intravenous sodium loading, solution osmolality
and of changes in renal nerve activity were also investigated. Intragastric
instillation of both the sodium-containing solution and its iso-osmotic urea
control solution resulted in significant increases in renal ACE activity (NaCl: P
< 0.0005; Urea: P < 0.01). The increase in renal ACE activity after gastric
sodium loading was more prolonged than after the urea control (P < 0.025, NaCl
vs. urea at 90 min). This prolonged increase in renal ACE activity appeared to
reflect a response to absorbed sodium as intravenous sodium administration caused
a significant increase in renal ACE activity at 90 min (P < 0.0005). In contrast
to these stimuli which increased renal ACE activity, renal denervation caused a
significant decrease in ACE activity in the kidney (P < 0.05). We conclude that
gastric sodium loading increases renal ACE activity. This effect appears to be
due initially to a response to an increase in gastric lumenal osmolality and
later to absorbed sodium. These changes in renal ACE activity are not mediated by
a decrease in renal nerve activity.
PMID- 10759608
TI - Gastrin has a specific proliferative effect on the rat enterochromaffin-like
cell, but not on the parietal cell: a study by elutriation centrifugation.
AB - Gastrin has a general growth-promoting effect on gastric oxyntic mucosa, and a
more pronounced one on the enterochromaffin-like (ECL) cell. Whether gastrin has
a proliferative effect on the parietal cell lineage beyond the general effect is
uncertain. Hypergastrinaemia was evoked in rats using pantoprazole (group II: 100
micromol kg-1, group III: 400 micromol kg-1) for 45 days. Plasma gastrin was 43
+/- 8 pmol L-1 (control), 283 +/- 54 pmol L-1 (group II) and 577 +/- 63 pmol L-1
(group III). Gastric mucosal cells were isolated and fractionated by elutriation
centrifugation. Total cell number, percentage and number of ECL and parietal
cells, and histamine were determined in each fraction. The number of mucosal
cells increased 1.5-fold in both hypergastrinaemic groups. Enterochromaffin-like
cell content was 2.6 +/- 0.5% (control), 6.0 +/- 0.6% (group II) and 9.0 +/- 0.8%
(group III). Histamine concentration in oxyntic mucosal cells rose similarly. The
size of the ECL cells was 8.5 +/- 0.1 microm (control), 10.8 +/- 0.2 microm
(group II) and 12.1 +/- 0.2 microm (group III), and the increased size was
confirmed by shifted distribution in elutriation fractions. Histamine per ECL
cell increased with cell size. The number of parietal cells increased parallel to
the total number of mucosal cells (1.5-fold). Parietal cell size and percentage,
assessed by image analysis and distribution in elutriation fractions, were
unchanged after pantoprazole dosing. Gastrin has a pronounced, concentration
dependent specific trophic effect on ECL cells and a general proliferative effect
on gastric mucosa, including parietal cells.
PMID- 10759609
TI - Tonometric assessment of jejunal mucosal nitric oxide formation in anaesthetized
pigs.
AB - Nitric oxide (NO) in the gut has attracted increasing interest as a regulatory
factor for a wide variety of intestinal functions. This study was performed to
evaluate some methodological aspects and jejunal sources for NO synthesis. Bench
side evaluations and an animal model using chloralose-anaesthetized pigs were
used. Immunohistochemistry was performed on samples from pig intestine and direct
measurements of intestinal NO formation were performed using intraluminal
tonometry. Tonometric measurements were quantitatively accurate and with high
reproducibility. A substantial NO formation was assessed which was markedly
inhibited by luminal administration of the non-selective NOS inhibitor L-NAME.
Intravenous administration of L-NAME also reduced jejunal NO formation but to a
lesser extent. Immunohistochemistry revealed staining for the inducible type of
NOS in the mucosal surface epithelium whereas endothelial and neuronal subtypes
were located in deeper layers of the jejunal wall. The study argues for that the
source of jejunal NO production, as measured by intraluminal tonometry, is
located in close proximity with the intestinal mucosa. The NOS in this
compartment is predominantly of the inducible type.
PMID- 10759610
TI - An upper arm model for simulated weightlessness.
AB - This investigation examined the effects of 4 weeks of non-dominant arm unloading
on the functional and structural characteristics of the triceps brachii muscle of
six normo-active college-age males (age: 23 +/- 1 years, height: 176 +/- 4 cm,
weight: 76 +/- 6 kg). The primary intention of this study was to determine if arm
unloading is an effective analogue for simulating the effects of weightlessness
on human skeletal muscle. Subjects were tested 2-3 days preceding unloading in a
standard arm sling and following removal of the sling. The sling was worn during
waking hours to unload the arm. Subjects were allowed to remove the sling during
sleep and bathing. Torque production (Nm) during maximal isometric extension at
90 degrees significantly declined (P < 0.05) in response to unloading (53.93 +/-
5.07 to 47.90 +/- 5.92; 12%). There was no significant change (P > 0.05) in the
force-velocity attributes of the triceps over the other measured velocities
(1.05, 1.57, 2.09, 3.14, 4.19, 5.24 rad.s-1). Cross-sectional muscle area (CSA)
of the upper arm was smaller (44.3 +/- 2.7 to 42.4 +/- 2.5 cm2; 4%) following 4
weeks of unloading (P < 0.05). Histochemical analysis of individual muscle fibres
demonstrated reductions in fibre CSA of 27 and 18% for type I and type II fibres,
respectively. However, these changes were not statistically significant.
Electrophoretic analysis of muscle samples revealed a significant increase (40 +/
7 to 58 +/- 4%, pre- and post-, respectively) in myosin heavy chain (MHC) type
II isoforms following unloading. Reductions in type I MHC isoform composition
failed to reach statistical significance (P < 0.08). Amplitude of the integrated
electromyographic (IEMG) signal during maximal isometric contraction of the long
head of the triceps decreased by 21% in response to the 4-week unloading period
(P < 0.05). The changes in triceps, muscle structure and function found with arm
unloading are similar in magnitude and direction to data obtained from humans
following exposure to real and simulated weightlessness. These findings
demonstrate that arm unloading produces some of the effects seen in response to
weightlessness in muscles of the upper arm and provides potential for an
additional model to simulate the effects of microgravity on human skeletal
muscle.
PMID- 10759611
TI - Changes in height of jump, maximal voluntary contraction force and low-frequency
fatigue after 100 intermittent or continuous jumps with maximal intensity.
AB - Healthy untrained males (age 25.4 +/- 1.7 years, n=12) gave their informed
consent to take part in all experiments within the study. After 100 intermittent
(every 20 s) drop jumps from the height of 0. 4 m, jumps with counter-movement to
90 degrees angle in the knee and immediate maximal rebound (eccentric-concentric
exercise; E-C) and 100 continuous jumps (five bouts of 20 jumps with counter
movement to 90 degrees angle in the knee with 10 s between bouts) (maximal
exercise; M) with maximal intensity, the height of vertical jump decreased in a
similar way, and this decrease did not depend on the performance mode of jumps.
After E-C and M jumping exercises, there was a significant (P < 0.001) decrease
in maximal voluntary contraction force, as well in the force generated by
electrical stimulation at all stimulation frequencies, and these values were not
restored to the initial level even after 24 h. After the E-C exercise, however,
the muscle contraction force generated at different stimulation frequencies and,
especially, at low-stimulation frequencies (1-20 Hz) decreased to a significantly
(P < 0.05-0.001) greater extent than after M exercise. Twenty minutes after the
end of M exercise, there was still a greater increase in low-frequency fatigue
(LFF) and it was no different from the LFF registered 20 min after the end of E-C
exercise. Twenty-four hours after the M exercise, however, LFF was smaller than
its respective value after E-C exercise. There was no significant relationship
between the values of LFF after E-C and M exercises. This may indicate that there
are differences in the origin of the LFF after the E-C and M exercises.
PMID- 10759612
TI - Electrically evoked eccentric and concentric torque-velocity relationships in
human knee extensor muscles.
AB - The torque-velocity relationship, obtained during in situ conditions in humans,
demonstrates a levelling-off of eccentric torque output at the isometric torque
level, at least for knee extensor actions. In contrast, the in vitro force
velocity relationship for animal muscle preparations is characterized by a sharp
rise in eccentric force from isometric maximum. A force-regulating 'protective'
mechanism has been suggested during maximal voluntary high-tension eccentric
muscle actions. To investigate this phenomenon, maximal voluntary and three
different levels of submaximal, electrically induced torques were compared during
isometric and low velocity (10, 20 and 30 degrees s-1) isokinetic eccentric and
concentric knee extensor actions in 10 healthy, moderately trained subjects.
Eccentric torque was higher than isometric during electrically evoked, but not
during maximal voluntary muscle actions. In contrast, concentric torque was
significantly lower than isometric for both maximal voluntary and submaximal,
electrically evoked conditions. Comparisons of normalized torques (isometric
value under each condition set to 100%) demonstrated that the maximal voluntary
eccentric torque had to be increased by 20%, and the isometric by 10% in order
for the maximal voluntary torque-velocity curve to coincide with the electrically
stimulated submaximal ones. These results support the notion that a tension
regulating mechanism is present primarily during eccentric maximal voluntary knee
extensor actions.
PMID- 10759613
TI - Sequential changes of [H]forskolin, [H]cyclohexyladenosine and [H]PN200-110
binding sites in the brain of 6-hydroxydopamine-lesioned rats.
AB - Receptor autoradiographic technique was studied to investigate sequential changes
in adenylyl cyclase, adenosine A1 receptors and L-type calcium channels in the
striatum and substantia nigra 1-8 weeks after unilateral 6-hydroxydopamine
injection of the medial forebrain bundle in rats. [3H]Forskolin,
[3H]cyclohexyladenosine (CHA) and [3H]PN200-110 were used to label adenylyl
cyclase, adenosine A1 receptors and L-type calcium channels, respectively. The
degeneration of the nigrostriatal pathway caused a significant increase in
[3H]forskolin binding in the striatum of both the ipsilateral and contralateral
sides from 2 to 4 weeks post-lesion. The ipsilateral substantia nigra showed a
transient increase in [3H]forskolin binding 4 weeks post-lesion. In contrast,
[3H]CHA binding showed no significant change in most brain areas after lesioning.
On the other hand, a conspicuous decrease in [3H]PN200-110 binding was observed
in the dorsolateral striatum of ipsilateral side 4 weeks post-lesion. Thereafter,
the striatum of both the ipsilateral and contralateral sides showed a significant
decrease in [3H]PN200-110 binding 8 weeks post-lesion. These results demonstrate
that unilateral 6-hydroxydopamine into the medial forebrain bundle of rats can
experimentally cause a significant increase in adenylyl cyclase binding sites in
the striatum and substantia nigra, whereas no conspicuous change in adenosine A1
receptors is observed in these areas during post-lesion. In contrast, L-type
calcium channels were progressively damaged in the striatum after unilateral 6
hydroxydopamine treatment. These findings suggest that adenylyl cyclase and
calcium system may contribute to the degeneration processes of the dopaminergic
neurones.
PMID- 10759614
TI - Deficits in nitric oxide production after tetanic stimulation are related to the
reduction of long-term potentiation in Schaffer-CA1 synapses in aged Fischer 344
rats.
AB - In the present study, we investigated whether nitric oxide (NO) production after
tetanic stimulation is involved in long-term potentiation (LTP) in Schaffer-CA1
synapses in both young adult and aged rats. The changes in both the population
spike amplitude and NO metabolites, nitrite (NO2-) and nitrate (NO3-), in the CA1
region were simultaneously determined before and after tetanic stimulation.
Increases in NOx (NO2- plus NO3-) levels in the CA1 region were observed after
tetanic stimulation in young adult rats as well as increase in the population
spike amplitude. In aged rats, LTP was significantly inhibited compared with that
in young adult rats. No increase in NOx level after tetanic stimulation was
observed in aged rats. These findings directly demonstrated that NO production
might be involved in the process of LTP formation in Schaffer-CA1 synapses of the
rat hippocampus, and that the deficiency of hippocampal NO production might be
responsible for reduction of LTP formation in aged rats.
PMID- 10759615
TI - Review article: recognition and treatment of eating disorders in primary and
secondary care.
AB - Eating disorders are serious illnesses affecting 1-2% of young women. Patients
may present to any doctor, sometimes atypically (e.g. unexplained weight loss,
food allergy, infertility, diarrhoea), delaying diagnosis and leading to needless
investigation. The cardinal signs are weight loss, amenorrhoea, bingeing with
vomiting and other compensatory behaviours, and disturbances in body image with
an exaggeration of the importance of slimness. When other causes have been
excluded, useful investigations are serum potassium, bone mineral density
scanning and pelvic ultrasound. In emaciated patients multiple systems may fail
with pancytopaenia, neuromyopathy and heart failure. Clinical assessment of
muscle power is used to monitor physical risk. Treatment may involve individual,
group or family sessions, using cognitive-behavioural, psychodynamic and family
approaches. More severe or intractable illness is treated with day care, with in
patient care in a medical or specialist psychiatric unit reserved for the most
severely ill patients. Antidepressants have a place in the treatment of bulimia
nervosa unresponsive to psychological approaches, and when severe depressive
symptoms develop. The children of people with eating disorders may have an
increased risk of difficulties. Support for the patient and family, and effective
liaison between professionals, are essential in the treatment of severe eating
disorders.
PMID- 10759616
TI - Review article: the initial management of uninvestigated dyspepsia in younger
patients-the value of symptom-guided strategies should be reconsidered.
AB - Several major management guidelines on dyspepsia (upper abdominal pain or
discomfort) recommend an initial 'test-and-treat' policy (non-invasive
Helicobacter pylori testing with eradication therapy if positive) in
uninvestigated patients less than about 45 years old. However, the evidence that
this is the optimal strategy is limited. Data from the few available randomized
controlled trials provide evidence that this policy improves symptomatology more
than a 'test-and-endoscope' approach (in which only H. pylori-positive patients
undergo early endoscopy) in those with upper abdominal pain. The balance of cost
effectiveness data from clinical studies and decision analyses indicates that
both 'test-and-treat' and empirical anti-secretory therapy approaches are more
cost-effective than the 'test-and-endoscope' strategy. Therefore, given concerns
about the safety of widespread H. pylori eradication, initial empirical anti
secretory therapy may be a cost-effective alternative to the 'test-and-treat'
policy in some younger dyspeptic patients. The effectiveness of such an empirical
approach might well be improved by symptom-guided therapy and there is growing
evidence that the predominant dyspeptic symptom may provide this guide. The
diagnostic, therapeutic and economic utility of this approach merits further
clinical investigation.
PMID- 10759617
TI - The omeprazole test is as sensitive as 24-h oesophageal pH monitoring in
diagnosing gastro-oesophageal reflux disease in symptomatic patients with erosive
oesophagitis.
AB - BACKGROUND: Ambulatory 24-h oesophageal pH monitoring and a short course of high
dose omeprazole can be used as diagnostic modalities for GERD. However,
comparative studies of the diagnostic accuracy and reliability of both strategies
have not been performed. AIM: To compare the omeprazole test to ambulatory 24-h
oesophageal pH monitoring in diagnosing GERD in symptomatic patients using
endoscopically proven erosive oesophagitis as a gold standard. METHODS: Patients
with heartburn underwent an upper endoscopy. Only those with erosive oesophagitis
were included in the study. Subsequently, patients underwent ambulatory 24-h
oesophageal pH monitoring and an 'omeprazole test.' Daily symptoms were recorded
during the first week (baseline) and repeated during the second week on therapy
(omeprazole 40 mg in the morning and 20 mg in the evening). RESULTS: Thirty-five
patients were included in the study. The omeprazole test was significantly more
sensitive in diagnosing GERD than total acid contact time on 24-h oesophageal pH
monitoring (83% vs. 60%; P < 0.03). However, the sensitivity of the pH test
increased to 80% after adding patients with a positive symptom index, and
patients with abnormal acid exposure in the supine or erect positions despite
normal total acid contact time. Patients with a normal pH test were significantly
younger (49 +/- 2.6 years) than those with abnormal test (59 +/- 1.8; P=0.002).
CONCLUSIONS: In this study an omeprazole test was at least as sensitive as
ambulatory 24-h oesophageal pH monitoring in diagnosing GERD in patients with
erosive oesophagitis.
PMID- 10759618
TI - Clinical and fiscal impact of lansoprazole intolerance in veterans with gastro
oesophageal reflux disease.
AB - BACKGROUND: Omeprazole was replaced by lansoprazole as the only proton pump
inhibitor on the Veterans Affairs (VA) formulary in February 1997. We aimed to
assess the clinical and fiscal impact of this conversion at two VA hospitals.
METHODS: We identified lansoprazole intolerant patients using pharmacy databases.
We reviewed medical records to obtain data regarding reasons for lansoprazole
intolerance. The costs of the formulary change and the savings to the VA were
calculated. RESULTS: A total of 3833 patients required long-term proton pump
inhibitor therapy; 2224 (58%) were started on lansoprazole and 1479 (39%) were
converted from omeprazole to lansoprazole. The remaining 130 (3.4%) patients were
never converted from omeprazole to lansoprazole. Of the 3833 patients, 325 (8.5%)
currently receive omeprazole therapy; of these, 195 out of 3703 (5.3%) patients
are true lansoprazole failures; 172 of these 195 patients completed the study.
Most (87%) of the lansoprazole intolerant patients received prior omeprazole.
Discontinuation of lansoprazole was due to poor symptom control in 69% and/or
side-effects (22%) including diarrhoea (10%), abdominal pain (5%), or hives (1%).
The 1-year cost of managing lansoprazole failure in 195 patients was $61 690.
However, the savings to the VA during the same time period, which totalled $321
360, more than offset the costs associated with the conversion. CONCLUSIONS:
Lansoprazole intolerance requiring omeprazole conversion occurred in 5% of
veterans on proton pump inhibitor therapy for chronic gastro-oesophageal reflux
disease (GERD) symptoms and in 10% of patients with prior omeprazole success. The
VA realized substantial cost savings in association with the formulary change.
PMID- 10759619
TI - Pharmacokinetic interaction between proton pump inhibitors and roxithromycin in
volunteers.
AB - BACKGROUND: Triple therapy including two antibiotics and a proton pump inhibitor
is a rational approach to the treatment of Helicobacter pylori induced peptic
ulcer disease. The interaction of antimicrobial therapy and acid suppression is
not yet well elucidated. AIMS: To investigate the effects of proton pump
inhibitors on roxithromycin levels in plasma and gastric tissue under steady
state conditions in volunteers. METHODS: In two crossover studies omeprazole 20
mg b.d., lansoprazole 30 mg b.d., roxithromycin 300 mg b.d., and the combination
of roxithromycin with either omeprazole or lansoprazole were administered to 12
healthy volunteers over 6 days. Blood plasma levels of the drugs were measured.
In addition, roxithromycin concentrations were also determined in gastric juice
and gastric tissue obtained during endoscopy. RESULTS: The proton pump inhibitors
and roxithromycin did not alter the blood plasma pharmacokinetics of each other.
When compared to roxithromycin administered alone, its combination with a proton
pump inhibitor significantly increased the roxithromycin concentrations in
gastric juice (3.0-5.0 microg/mL vs. 0.3-0.4 microg/mL) and gastric tissue
(antrum: 3.8-4.0 vs. 2.8 microg/g, fundus: 5.9-7.4 vs. 4.2-4.4 microg/g).
CONCLUSIONS: Proton pump inhibitors and roxithromycin do not alter the systemic
bioavailability of each other. However, proton pump inhibitors increase the local
concentration of roxithromycin in the stomach which may contribute to the
clinically proven synergic beneficial action in eradication therapy of H. pylori.
PMID- 10759620
TI - Dyspepsia workload in urban general practice and implications of the British
Society of Gastroenterology Dyspepsia guidelines (1996).
AB - AIM: To define the characteristics of patients consulting with active dyspeptic
symptoms in urban general practice, and to consider the implications of applying
the British Society of Gastroenterology Dyspepsia management guidelines. DESIGN:
Prospective observational study over a period of 12 months. SETTING: Two
multipartner, two-centre general practices in the City of Leeds (UK) with a
combined target population of 11 011 registered patients. SUBJECTS: A total of
340 patients consulting with active dyspeptic symptoms (52% male; mean age 53
years, range 16-89 years). RESULTS: Of the practice population, 3% consulted with
dyspepsia (first-time consulter: 19%; previous consulter not yet investigated:
30%; previously investigated: 51%). Of 168 undiagnosed patients, 43% had upper
abdominal pain (dysmotility-like symptoms in 42%), 35% had reflux symptoms, 22%
had mixed symptoms, 12% had 'alarm' symptoms and 18% had a history of NSAID use.
Patients < 45 years old with simple dyspepsia accounted for 32% of undiagnosed
cases. A fifth of the workload was in dealing with undiagnosed dyspeptics over 45
years old. One per cent of the population would require endoscopy if all
undiagnosed cases either > 45 years or with complicated dyspepsia were
investigated. Of 172 previously investigated patients, 29% had negative tests,
25% had 'minor' findings, and 45% had evidence of acid-peptic disease. Patients
with duodenal ulcer disease accounted for 12% of the total workload. CONCLUSIONS:
A knowledge of the characteristics of patients consulting with dyspepsia in
primary care should allow the adaptation of guidelines, to ensure advice is
relevant to local case mix and compatible with local resources.
PMID- 10759621
TI - Comparative palatability of 22 liquid antacids.
AB - OBJECTIVE: To compare the palatability, acid neutralizing capability, and costs
of different antacids. METHODS: Volunteers between the ages of 18 and 60 years
were given 22 antacids. All antacids were given during a 4-h period in two groups
of 11 antacids each. Subjects sampled each antacid in a manner similar to wine
tasting and rated each antacid on its smell, taste, texture and aftertaste using
a scale of 1-9; 1 being the worst and 9 the best. RESULTS: A total of 73 adults
completed the study. Mylanta Lemon Twist and Mylanta Cherry Creme were the most
palatable antacids; however, overall the palatability of all the antacids was
poor. Maalox MS Cool Mint and ES Gaviscon were the least palatable. The extra
strength antacids had the most acid neutralizing capability, and thus would
require smaller doses. Amphogel was the most costly antacid per mEq of acid
neutralized. Age and gender did not affect the palatability scores. CONCLUSION:
Although the regular strengths of Mylanta Lemon Twist and Mylanta Cherry Creme
were the most palatable, the extra strength versions of these products have twice
the acid neutralizing capability and thus, half the volume is required for each
dose. Therefore, these agents may be the antacids of choice.
PMID- 10759622
TI - Helicobacter pylori infection is associated with milder gastro-oesophageal reflux
disease.
AB - BACKGROUND: We have previously demonstrated a negative relationship between the
prevalence of Helicobacter pylori and gastro-oesophageal reflux disease (GERD).
AIM: To study the effects of H. pylori infection on the severity of GERD.
METHODS: Ethnic Chinese patients with frequent heartburn and/or endoscopic
oesophagitis were studied. Endoscopic examination was performed to assess the
severity of oesophagitis (modified Savary-Miller grading) and the presence of
hiatus hernia. Biopsies were taken for rapid urease testing and confirmation of
Barrett's oesophagus. Risk factors which may affect the severity of oesophagitis
(age, sex, smoking, drinking, diabetes mellitus, hiatus hernia, H. pylori status
and body mass index) were evaluated by a multiple regression model. The cagA
status of H. pylori infected GERD and age-and-sex matched controls were
determined by Western blot. Age-and-sex matched non-reflux patients were
recruited as controls for comparison. RESULTS: Two hundred and twenty-five
patients with GERD were studied, of whom 77 (34%) were infected with H. pylori.
Oesophagitis and Barrett's oesophagus were found in 140 patients (62%) and six
patients (3%), respectively. H. pylori infected patients had significantly less
severe oesophagitis compared to the uninfected group (P=0.022). All patients with
Barrett's oesophagus were uninfected. Factors that predicted severe oesophagitis
included age over 60 years (P < 0.001) and hiatus hernia (P < 0.001). H. pylori
infection was the only factor that showed a negative correlation with severe
oesophagitis (P=0.011). The prevalence of the cagA positive strain in endoscopy
negative GERD, erosive oesophagitis and control subjects was 70, 76 and 78%,
respectively (P=0.75). CONCLUSIONS: H. pylori infection is associated with milder
GERD.
PMID- 10759623
TI - Diagnosis of Helicobacter pylori after triple therapy in uncomplicated duodenal
ulcers--a cost-effectiveness analysis.
AB - BACKGROUND: The cost-effectiveness of determining Helicobacter pylori status
after treatment remains to be established. AIM: To determine the benefit of post
treatment assessment of H. pylori eradication in patients with uncomplicated
duodenal ulcer. MATERIALS AND METHODS: A decision analysis was performed in
patients with uncomplicated duodenal ulcer who were H. pylori-positive and had
received eradication therapy. A decision tree was devised to compare the costs
per patient of two different strategies: (a) systematic performance of post
treatment urea breath test and new treatment if positive; and (b) clinical follow
up, 13C-urea breath test if dyspeptic symptoms recurred and eradication treatment
if the test was positive. RESULTS: Post-eradication 13C-urea breath test was
notably more expensive than clinical follow-up, both in a low-cost per care
setting (197 vs. 132 Euros) and in a high-cost per care (614 vs. 340 US $)
scenario. This conclusion remained stable for a wide range of variations of the
variables included in the decision tree (e.g. cure rates of eradication
treatment, cost of the urea breath test or sensitivity, and specificity of urea
breath test to detect eradication). CONCLUSION: In patients with uncomplicated
duodenal ulcer, evaluation of eradication after H. pylori treatment markedly
increases costs with no clear improvement in results and therefore should not be
performed routinely.
PMID- 10759624
TI - Safety and efficacy of nabumetone in osteoarthritis: emphasis on gastrointestinal
safety.
AB - AIM: To compare the efficacy and gastrointestinal (GI) safety of nabumetone with
two comparator non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac SR and
piroxicam. METHODS: Two randomized, double-blind, multicentre, parallel group
trials were carried out in patients with moderate to severe osteoarthritis of the
hip or knee. During the 6 month treatment phase, the safety and efficacy of
nabumetone (1500-2000 mg/day) was compared to diclofenac SR (100 mg/day) or
piroxicam (20-30 mg/day). GI safety was evaluated by reviewing all adverse events
reported during the trials and presenting all cases of ulcers (complicated and
uncomplicated), as well as other bleeding events that may have been associated
with NSAID administration. RESULTS: Most of the efficacy parameters showed no
significant differences between the NSAIDs, although diclofenac SR was
significantly better than nabumetone in one of 18 efficacy parameters. Nabumetone
treated patients experienced significantly fewer ulcer and bleeding events
compared to patients treated with the comparator NSAIDs [1.1% (4/348) vs. 4.3%
(15/346), P = 0.01]. Bleeding events, including outright upper or lower GI
bleeding or a significant decline in haemoglobin, occurred in significantly fewer
patients treated with nabumetone than with the comparator NSAIDs [1.1% (4/348)
vs. 3.5% (12/346), P < 0.05]. More importantly, complications associated with
either ulcers (perforation) or bleeding (leading to hospitalization or
withdrawal) occurred in significantly fewer patients receiving nabumetone [0%
(0/348)] than with comparator NSAIDs [1.4% (5/346), (P < 0.05)]. CONCLUSION: The
results suggest that nabumetone was similar in efficacy by most criteria to
diclofenac SR and piroxicam in relieving the symptoms of osteoarthritis; however,
nabumetone's GI safety profile was generally superior to that of both comparator
NSAIDs. In the pooled analysis, nabumetone was associated with a significantly
lower total incidence of ulcers and bleeding events, and a significantly lower
incidence of complications associated with these events.
PMID- 10759625
TI - The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal
motility and lower oesophageal sphincter characteristics in GERD patients.
AB - BACKGROUND: ABT-229, a motilin agonist without antibacterial activity, has been
shown to enhance both lower oesophageal sphincter pressure in cats and gastric
emptying in humans. AIM: To investigate the effect of oral treatment with ABT-229
10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal
reflux, lower oesophageal sphincter pressure, transient lower oesophageal
sphincter relaxations and symptoms in GERD patients. METHODS: Twenty-four GERD
patients completed the study. A randomized, double-blind, placebo-controlled,
three-period incomplete crossover design was used with three dosing periods of 7
days. All patients received ABT-229 10 mg b.d. and placebo during two of the
three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d.
and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal
pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures
were performed on day 7 using an assembly incorporating a Dent sleeve connected
to a portable water-perfused manometric system. RESULTS: Oesophageal acid
exposure was not affected by ABT-229 or cisapride, but the incidence of reflux
episodes was reduced by cisapride. None of the drugs affected oesophageal
motility, lower oesophageal sphincter pressure or the incidence of transient
lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride
reduced the severity of daytime heartburn. CONCLUSION: The value of ABT-229 in
the treatment of GERD appears to be limited.
PMID- 10759626
TI - Interferon alfa-2b plus ribavirin for chronic hepatitis C patients who have not
responded to interferon monotherapy.
AB - BACKGROUND: The role of combination therapy is poorly defined in chronic
hepatitis C patients who are non-responders to interferon. AIM: To assess the
efficacy, safety and tolerance of interferon alfa-2b plus ribavirin in chronic
hepatitis C patients who do not respond to interferon monotherapy. METHODS: A
total of 127 non-responder patients with chronic hepatitis C received 3 mU t.i.w.
of interferon alfa-2b plus 1000-1200 mg ribavirin daily for 48 weeks. Effects of
therapy were evaluated by serum aminotransferases and hepatitis C virus (HCV) RNA
levels. RESULTS: Twenty-nine (23%) patients had an end-of-treatment response. Six
months after treatment, 20 (16%) patients were sustained responders. Early loss
of HCV RNA was the strongest predictor of a sustained response (P < 0.0001).
Remission was also more frequent in patients with genotype 1b (P < 0.02),
elevated alanine aminotransferase (P < 0.03) and low gamma glutamiltranspeptidase
(P < 0.002). Treatment was discontinued in 21 (17%) patients: in 14 for
intolerance and in seven due to side-effects. CONCLUSIONS: Combination therapy
with interferon plus ribavirin produced a sustained response in 16% of chronic
hepatitis C patients who were non-responders to interferon. This combination was
safe and well tolerated.
PMID- 10759627
TI - Effects of dietary fibre and olestra on regional apparent viscosity and water
content of digesta residue in porcine large intestine.
AB - BACKGROUND: Increased consumption of non-digested, non-absorbed substrates, such
as dietary fibre, can lead to an increase in colonic transit rate and stool
output. The effects of dietary fibre and olestra on the consistency and water
content of digesta residue within the large bowel were not known. AIM: The aim of
this study was to determine the effects of dietary fibre and olestra on regional
dehydration and apparent viscosity of digesta residue throughout the large bowel.
METHODS: Seventy-eight pigs were fed diet alone (control) or supplemented with 40
g/day or 80 g/day dietary fibre or olestra and sacrificed 24, 48, 96 or 192 h
after initiation of dosing. The large bowel was removed, divided into 13
segments, and the digesta residue/stool was analysed for apparent viscosity (peak
force for extrusion) and percentage water content. RESULTS: In control animals,
digesta residue occurred as a continuum, from liquid in the cecum (87.9% water)
to solid in the rectum (71. 5% water). The relatively small decrease in
percentage water content (16.4%) resulted in a marked increase in mean apparent
viscosity (liquid = 87 g peak force; solid=3919 g peak force). Dietary fibre
increased the percentage water content of digesta residue throughout the large
bowel. In contrast, olestra decreased the percentage water content of digesta
residue in the mid and distal large bowel. At 40 g/day, dietary fibre showed a
significant (P < 0.05) digesta residue/stool softening effect for all time
points, beginning at 24-h (single dose). Olestra 40 g/day did not significantly
soften digesta residue/stool until 48 h (2 doses, P < 0.05), and was not
different from control at 96 h. At 80 g/day, both dietary fibre and olestra
significantly (P < 0.01) softened digesta residue/stool at all time points. There
were no liquid or oily stools at any dose or time-point. CONCLUSIONS: Relatively
small changes in water content result in large changes in digesta residue/stool
apparent viscosity. Dietary fibre increased digesta residue/stool water content
throughout the bowel, resulting in softer digesta residue/stool. In contrast,
olestra decreased stool water content, yet had a similar stool softening effect
compared to dietary fibre.
PMID- 10759628
TI - Selective action of a CCK-B/gastrin receptor antagonist, S-0509, on pentagastrin
, peptone meal- and beer-stimulated gastric acid secretion in dogs.
AB - BACKGROUND: The pharmacological effects of a novel CCK-B/gastrin receptor
antagonist, S-0509, on gastric acid secretion in dogs remain unknown. AIM: To
evaluate the antisecretory effects of S-0509 on gastric acid secretion and to
compare such effects with famotidine or atropine in dogs stimulated with various
gastric stimulants. METHODS: Ten beagle dogs with a denervated Heidenhain pouch
and three beagle dogs with an innervated gastric fistula were used. Gastric acid
secretion was stimulated by either continuous intravenous administration of
pentagastrin, carbachol or histamine, or oral administration of a peptone meal or
beer. RESULTS: In the Heidenhain pouch model, both intravenously administered and
orally administered S-0509 significantly inhibited the gastric acid secretion
stimulated by pentagastrin, peptone meal and beer. Nonetheless, the drug had
little or no effect on carbachol-stimulated or histamine-stimulated acid
secretion. Famotidine extensively inhibited all gastric acid secretion stimulated
by the above stimulants in a non-selective manner. Atropine also significantly
inhibited the acid secretion stimulated by pentagastrin, peptone meal, beer or
carbachol, but was not able to inhibit stimulation due to histamine. Oral
administration of peptone meal or beer significantly increased the plasma gastrin
level. Similarly to the Heidenhain pouch model, even in the gastric fistula (GF)
model, S-0509 significantly inhibited pentagastrin-stimulated gastric acid
secretion, yet the drug had no effect on carbachol-stimulated secretion.
CONCLUSIONS: S-0509 is a selective CCK-B/gastrin receptor antagonist in dogs that
inhibits gastric acid secretion stimulated by pentagastrin and gastrin-releasing
substances, but does not inhibit histamine-stimulated and carbachol-stimulated
acid secretion.
PMID- 10759629
TI - Endothelial changes precede mucosal ulceration induced by indomethacin: an
experimental study in the rat.
AB - BACKGROUND: Indomethacin has been shown to damage the villous microvasculature
concomitant with alterations in villous blood flow in the rat. AIM: To test the
hypothesis that alterations in blood flow result from ultrastructural damage to
microvasculature endothelium. METHODS: In anaesthetized rats, jejunal villi were
exteriorized in a chamber and blood flow in surface capillaries visualized by
fluorescence microscopy. Villi were exposed both luminally and systemically to
indomethacin (100 microg/mL) for 10 min or until blood slowing or stasis had
occurred in superficial capillaries (n=3 per group). Control animals received
both a luminal and intravenous vehicle for 45 min (n=3). The small intestines
were vascular perfusion-fixed with 1.5% glutaraldehyde and studied by
transmission electron microscopy. RESULTS: All controls appeared to be
ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon
the epithelium but resulted in mild endothelial vacuolization and the development
of small finger-like projections into the lumen of villus surface
microvasculature. At the point of blood slowing, villus tip epithelium was again
normal but the endothelial vacuolization and finger-like projections became more
obvious. The endothelial projections and vacuolization became severe at the point
of blood stasis; this also coincided with epithelial degeneration. CONCLUSION:
This study shows that villus surface microvasculature is the earliest site of
morphological damage after indomethacin exposure.
PMID- 10759630
TI - On dissonances, Helicobacter pylori and NSAIDs.
PMID- 10759632
TI - First latin american congress for artificial organs and biomaterials
PMID- 10759633
TI - Polypropylene hollow fiber oxygenators: effect of the sorption of
perfluoropolyethers.
AB - The introduction of microporous polypropylene hollow fibers in recent years has
brought considerable advances to blood oxygenators. However, lifetime and
assembly problems are still unresolved. In this work we tried to rate the oxygen
permeation velocity by turning the fibers more hydrophobic through the sorption
of a perfluorocarbon. Fomblin HC/25, a perfluoropolyether, is well known for its
low surface tension and high affinity for oxygen. Celgard X10, X20, and X30
commercial hollow fibers were tested. The hollow fibers showed high affinity for
the perfluoropolyether; swelling was clearly shown. A new system for the
measurement of oxygen permeation velocity was developed. The oxygen transport
velocity was not significantly changed after sorption. The Celgard microporous
hollow fibers impregnated with perfluoropolyether showed no water permeation
after 2 months of use, reducing one of the most serious problems in the lifetime
of these types of fibers.
PMID- 10759634
TI - Artificial articular cartilage: mechanoelectrical transduction under dynamic
compressive loading.
AB - The search for biomaterials to be used as an artificial articular cartilage in
joint restoration is a challenging research area. Because the articular cartilage
plays a fundamental role in joint function, the biomaterial has to be able to
mimic the behavior of the natural healthy surface. Articular cartilage is a
biphasic material composed by a solid extracellular matrix and a fluid phase, the
synovial fluid. When the tissue is pressed, there is a mechanoelectrical
transduction that is believed to modulate the cellular activity of chondrocytes,
being fundamental for tissue repair. This work aimed at the development of
hydrogels for use as an artificial articular cartilage. Hydrogels with negative
groups fixed in the macromolecular network were obtained by copolymerizing 2
hydroxyethyl methacrylate with acrylic acid. The obtained hydrogels showed a
mechanoelectrical transduction under dynamic compressive loading with potential
amplitude increasing with fixed charge density values.
PMID- 10759635
TI - Pathological mineralizations: calcifications and Si-bearing particles in soft
tissues and their eventual relationship to different prostheses.
AB - Polarizing microscopy (PM), scanning electron microscopy (SEM), x-ray dispersive
analysis (EDAX), x-ray diffraction (XRD), and infrared spectrometry (IR) were
used to study the following pathological mineralizations: calcifications and
silicon(Si)-bearing mineralizations in cerebral tissue from an epileptic child;
traces of Si-bearing particles in periprosthesic mammarian tissue, and
calcifications in capsular mammarian tissue from a patient with a silicone gel
mammarian implant, and 2 calcium-bearing compounds, a typical apatitic
calcification, and a nonphosphorous-bearing calcification in arterial tissues. In
this tissue we also found Si-bearing particles due to an artifact from glassware.
PMID- 10759636
TI - In vitro evaluation of open heart surgery tubing coated with heparin and lipid.
AB - The aim of this work was to evaluate in vitro the tromboresistence, hemolysis
tendency, platelet adhesion, cytotoxicity, physicochemical properties, and
stability of open-heart tubing coated with fractionated heparin-benzalkonium
chloride and/or lipid dipalmitoyl L-alpha-phosphatidylcholine (DPPC). The
tendency for clot formation and platelet adhesion was greater in noncoated and
lipid-coated tubing than in heparin-coated tubing. There were no significant
differences between the hemolytic potentials of coated and noncoated tubing. The
coatings were stable during the time of the experiment. The coatings did not
present cytotoxicity and physicochemical alterations.
PMID- 10759637
TI - Artificial grasping system for the paralyzed hand.
AB - Neuromuscular electrical stimulation has been used in upper limb rehabilitation
towards restoring motor hand function. In this work, an 8 channel microcomputer
controlled stimulator with monophasic square voltage output was used. Muscle
activation sequences were defined to perform palmar and lateral prehension and
power grip (index finger extension type). The sequences used allowed subjects to
demonstrate their ability to hold and release objects that are encountered in
daily living, permitting activities such as drinking, eating, writing, and
typing.
PMID- 10759638
TI - Tracing an unhandled suspect lesion through a gamma probe.
AB - This article describes the efforts of the authors in developing a handheld gamma
detection probe and addresses a tentative surgical protocol for tracing an
unhandled suspect lesion through an albumine-aggregate 99Tcm tracer operative
mapping. The electronic and software design for the system is discussed as well
as its electronic and nuclear calibration. A phantom model mimicking a breast was
built in order to help in the calibration of the system. Earliest results in an
external detection procedure using the model and a 0.3 ml tracer sample (7 MBq
activity) are presented.
PMID- 10759639
TI - Development of anthropomorphic upper limb prostheses with human-like
interphalangian and interdigital couplings.
AB - This article presents a model for the couplings of the movements between the
phalanges and fingers in a hand when they execute certain functions. It also
shows the importance of knowing these couplings, suggests methods for obtaining
them, and discusses how to apply them to the construction of artificial upper
limbs, highlighting the important mechanical aspects for achieving such a goal.
Thus, it gives support for projects of upper limb prosthesis with anthropomorphic
characteristics.
PMID- 10759640
TI - Ultrasonic pulsed Doppler blood flowmeter for use in extracorporeal circulation.
AB - In cardiac surgeries, it is frequently necessary to make the external blood
circulation and oxygenation artificially. This procedure is called extracorporeal
circulation (EC) or heart-lung bypass. During EC, one of the most important
parameters, which demands continuous monitoring, is the blood flow. In many
cases, the blood flow is estimated by the pump velocity (in roller pumps) or
measured with transducers based on electromagnetic methods (in centrifugal
pumps). This article presents an ultrasonic Doppler blood flowmeter to be used in
the arterial line of an extracorporeal circulation system. The ultrasonic probe
is coupled to a half-inch tube connector of the extracorporeal arterial line, is
not disposable, and does not need sterilization. The developed flowmeter revealed
itself to be efficient and reliable and can be inserted in a closed-loop pump
controller system or be used as stand-alone equipment.
PMID- 10759641
TI - Devices for use as an artificial articular surface in joint prostheses or in the
repair of osteochondral defects.
AB - The covering of ultra high molecular weight polyethylene (UHMWPE) and calcium
hydroxyapatite (HA)/tricalcium phosphate (TCP) porous solid substrate with
polyHEMA hydrogel has been studied aiming at the development of devices to be
used as artificial articular surfaces in joint prosthesis or osteochondral repair
grafts. Commercial porous UHMWPE was used. Ceramic porous substrate was prepared
by load compaction of an HA and TCP powder mixture obtained by aqueous
precipitation technique. Two different compaction loads and grain size
distribution was used. Polymer particles were added to the powder mixture in
order to increase the substrate porosity after the sintering process. The porous
substrate was covered with polyHEMA hydrogel by in situ polymerization.
Morphological analysis (SEM) showed that a hydrogel layer formed in the porous
solid top surface was fixed to the substrate by mechanical interlocking because
the porous surface was filled by the hydrogel. After hydrogel covering, the
resultant devices showed a decrease in the compressive elastic modulus that was
influenced by the porous substrate material.
PMID- 10759642
TI - Preparation of bioabsorbable nerve guide tubes.
AB - The use of bioabsorbable polymers in applications as temporary structural
function, recovering damage in live tissues, is a promising research area.
Membranes of poly(lactic acid) (PLA) may act as support to adhesion and cellular
invasion or as devices for guided tissue regeneration (GTR). In this study, the
same casting technique used to prepare membranes was used to prepare PLA tubes.
These tubes can be used for tests in nerve guided regeneration (NGR). To improve
flexibility of the device, a bioabsorbable plasticizer was added to the polymer.
The initial results showed that the proposed technique allowed the preparation of
flexible tubes that can be used for NGR.
PMID- 10759643
TI - Importance of uniform heparin coating on biopolymers.
AB - Cardiopulmonary surgeries need connectors for extracorporeal circulation. The
patient's blood in contact with the tube surfaces modifies its plasmatic
proteins, promotes platelet aggregation, and activates the complement system,
unleashing thrombus formation. Thus, it becomes necessary for an anticoagulant to
keep the circuit free from these events. Heparin is the anticoagulant used even
after reports about its disadvantages. Platelet adherence seems to be very
dependent on the quality from the surfaces that can promote cellular
proliferation, aggregation, and thrombosis. In this study, we compare the quality
of the heparin-coated and uncoated surfaces. We used a blood cell culture and
scanning electron microscopy (SEM) to visualize the platelet aggregation. It was
concluded that there are groove areas that permit platelet adherence, and if they
are not coated totally by the heparin, aggregation still occurs although in lower
scale than on the uncoated tubes.
PMID- 10759644
TI - Fiber reinforced calcium phosphate cement.
AB - The term calcium phosphate cement was introduced by Gruninger et al. (1). This
type of cement can be prepared by reacting a calcium phosphate salt with an
aqueous solution, which causes it to set by the crossing of the precipitated
crystals. These cements offer a series of advantages that allow their use as
grafts and substitutes of damaged parts of the bone system. However, these
cements have low mechanical strength compared to human bones. This work studied
the influence of the use of polyamide fibers in the mechanical properties of a
calcium phosphate cement based on alpha-tricalcium phosphate as well as the
mechanisms involved in the increase of mechanical strength. The results
demonstrate the feasibility of the use of polymeric fibers to increase mechanical
strength and the need for coupling agents for the effective performance of the
fibers as reinforcement in these materials.
PMID- 10759645
TI - Preparation and characterization of collagen-elastin matrices from blood vessels
intended as small diameter vascular grafts.
AB - This study describes the selective removal of cell and cell residues from small
and large diameter blood vessels for the preparation of tubular collagen:elastin
matrices intended for small diameter vascular prosthesis. The results showed that
total or partially devitalized collagen:elastin matrices may be conveniently
prepared without denaturation of the collagen:elastin matrix with a high degree
of preservation of the proteins. The efficiency of cell removal and the extent
collagen and elastic fiber preservation were dependent on the segment and the
type of blood vessel under study, with arteries characterized by a higher
susceptibility of cell removal and better preservation of the collagen-elastin
matrix.
PMID- 10759646
TI - Nonstoichiometric hydroxyapatite-anionic collagen composite as support for the
double sustained release of gentamicin and norfloxacin/ciprofloxacin.
AB - This work studied the sustained release of ciprofloxacin or norfloxacin and
gentamicin from nonstoichiometric hydroxyapatite (nHA) and anionic collagen
composite. Within the first 24 and 48 h, the total antibiotic supply was
significantly higher than the minimal inhibitory concentration required for the
majority of the gram-negative bacteria. Although gentamicin was completely
released from the matrix after 48 h by a normal diffusion mechanism,
ciprofloxacin or norfloxacin release was characterized by a 2-phase release
mechanism due to binding to nHA by complexation with calcium ion. Under the
conditions studied, most of the norfloxacin or ciprofloxacin only will be
disposable due to bioresorption or dissociation of the complexes. In conclusion,
due to its biocompatibility nHA-anionic collagen composite may be a convenient
support for the double sustained release of the antibiotics gentamicin and
ciprofloxacin/norfloxacin for the control of bone infection while promoting bone
tissue growth.
PMID- 10759647
TI - Development of catheters with low fiber background signals for Raman
spectroscopic diagnosis applications.
AB - Utilization of optical-fiber catheters can turn the Raman spectroscopy system
into a powerful remote biomedical diagnostic probe. An in vivo (a qualitative and
a quantitative) biochemical diagnosis of biotissues is possible by developing the
Raman-fiber probes with a good flexibility and less background signals generated
in the probes themselves. Considering the isotropic nature of Raman scattering,
the amount of Raman signal guided through the fiber is expected to depend on the
numerical aperture (NA) of the fiber. To study the dependence for catheter probes
experimentally, various flexible probes (with small diameter fibers) with
different combinations of numerical apertures and with different assembling
materials (biocompatible) have been developed. The catheter probes have been
characterized by collecting the near infrared excited Raman scattered light from
cholesterol powder. The results demonstrate that the catheters with a combination
of lower NA (0.12) fibers used for laser excitation and relatively higher NA
(0.22) fibers for Raman signal collection will have lower background signals
generated in the probes. Furthermore, the catheters with a black Teflon tubing
cover and black epoxy resin adhesives were found to give better results.
PMID- 10759648
TI - Comparative blood flow study of arteriovenous fistulae in canine femoral
arteries: modified latero-lateral and end-lateral techniques.
AB - The aim of this study was to evaluate the blood flow of an arteriovenous fistula
comparing the modified latero-lateral (LLM) and end-lateral (TL) techniques in
canine femoral arteries. Ten mongrel dogs were submitted to 2 arteriovenous
fistulae each, with a LLM on one side and a TL procedure on the other side.
Cranial and caudal average blood flow as well as average venous flow were
measured by an electronic fluxometer 15, 20, and 25 min after surgery. Mann
Whitney, Friedman, and Wilcoxon nonparametric tests were used for data analysis
(alpha 4 mm safe?
AB - OBJECTIVE: To determine the safety of the conservative management of ureteric
calculi of > 4 mm in diameter, using mercapto-acetyltriglycine (MAG3)
radioisotope renography to monitor renal parenchymal function. PATIENTS AND
METHODS: Patients with symptomatic unilateral ureteric calculi were recruited
prospectively. After confirming the position of the stone using contrast
urography, a MAG3 radioisotope renogram was taken within 48 h of admission and
again 1 month after the patients became stone-free. The indications for
intervention were ipsilateral loss of function (>/= 5% loss), infection, pain or
any combination of these factors. The recovery of function was determined by
follow-up renography. RESULTS: In all, 54 patients were recruited; 18 were
initially allocated to conservative treatment although four later required
intervention for pain. The remainder required early intervention for pain
(eight), diminished function only (15) or diminished function with infection
(13). Of the 54 patients, 28% had 'silent' loss of renal function at
presentation. No calculi of > 7 mm diameter passed without intervention. The mode
of initial management was determined according to individual clinical need. The
upper tracts of all patients were relieved of obstruction and all patients were
rendered stone-free. Intervention for reduced function only (at 1 point increase in QOL score, and > 2.5 mL/s increase in
Qmax. Adverse reactions potentially related to the study drugs were recorded
throughout the treatment period. RESULTS: Both terazosin and tamsulosin produced
statistically significant improvements in subjective and objective variables.
Neither treatment affected systolic or diastolic blood pressure or pulse rate.
Adverse reactions were noted in four patients (three in the terazosin group and
one in the tamsulosin group). However, there was no statistically significant
difference in the incidence of adverse effects between the groups. CONCLUSIONS:
Despite the limitations of small sample size and relatively short treatment
periods, terazosin and tamsulosin were equally effective in the treatment of
symptomatic BPH in Japanese patients, using relatively lower doses than those
used in Western countries.
PMID- 10759665
TI - Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a
randomized controlled study.
AB - OBJECTIVES: To determine the effect of antibiotic prophylaxis on infective
complications after transrectal needle biopsy of the prostate. PATIENTS AND
METHODS: Between June 1996 and September 1998, 231 patients who satisfied the
inclusion and exclusion criteria entered the study; the patients were randomized
into three groups. Each patient underwent transrectal needle biopsy of the
prostate after a cleansing enema at 06:00 hours. Patients in group 1 (75) then
received a placebo tablet twice a day for 3 days; those in group 2 (79) were
given a single dose of ciprofloxacin (500 mg) and tinidazole (600 mg), while
those in group 3 (77) were given the same combination twice a day for 3 days.
Urine cultures were obtained 48 h after the biopsy and blood cultures only from
patients who developed fever. The complications (categorized as infective or
noninfective) occurring in the three groups were compared using the chi-square
test. RESULTS: Noninfective complications included were lower urinary tract
symptoms, rectal bleeding, haematuria and perineal pain. The infective
complications included urinary tract infection and fever. There was no
significant difference among the three groups in noninfective complications (27,
29 and 31 in groups 1-3, respectively) but the incidence of infective
complications (19, six and eight, respectively) was significantly higher in group
1 (P = 0.003). However, the difference was significant only for urinary tract
infection (P = 0.01) and not for fever. CONCLUSIONS: In selected patients a
single dose of ciprofloxacin-tinidazole is adequate prophylaxis for transrectal
needle biopsy of the prostate. The present urinary infection rate was higher if
no antibiotics were used. Continuing the antibiotic prophylaxis for 3 days
offered no benefit over single-dose prophylaxis.
PMID- 10759666
TI - A comparison of six commercial assays for total and free prostate specific
antigen (PSA): the predictive value of the ratio of free to total PSA.
AB - OBJECTIVE: To evaluate the clinical utility of six commercial assays for free
prostate specific antigen (fPSA) and the derived ratio of fPSA to total PSA in
distinguishing between patients with prostate cancer or benign prostate
hyperplasia (BPH). MATERIALS AND METHODS: Each assay was evaluated against a
panel of serum samples comprising those from patients with prostatic disease,
other malignancies, normal subjects and sera containing substances which might
interfere with the immunoassay. RESULTS: The levels of total (tPSA), fPSA and
their ratio (f/tPSA) were compared among the different samples. All assays showed
similar specificities for prostate carcinoma but differed in the positive
predictive values of f/tPSA. CONCLUSIONS: Although all six assays were equimolar,
there were differences in calibration, particularly for fPSA. The ability of
f/tPSA to discriminate between benign and malignant prostatic disease depended on
the assay used. The f/tPSA is not valid when the tPSA and fPSA assays are
obtained from different manufacturers.
PMID- 10759667
TI - Differential response of prostate specific antigen to testosterone surge after
luteinizing hormone-releasing hormone analogue in prostate cancer and benign
prostatic hyperplasia.
AB - OBJECTIVE: To investigate any differences in changes in serum prostate specific
antigen (PSA) levels in patients with benign and malignant prostatic disease in
response to the testosterone surge after administering a luteinizing hormone
releasing hormone (LHRH) analogue. PATIENTS AND METHODS: The study included 54
patients referred to the urology clinic with intermediate PSA levels (4-10 ng/mL)
or an abnormal digital rectal examination. Forty-five patients received a single
injection of LHRH analogue depot each at one week before prostate biopsy and nine
served as a control group. Changes in PSA levels in response to the testosterone
surge from the LHRH analogue were recorded after 5 and 7 days, and were
correlated with the biopsy results. The PSA changes were compared with basal PSA
levels and the free/total PSA ratio(f/tPSA). RESULTS: Of the 45 patients who
underwent prostate biopsy, histopathology showed prostate cancer in 11, benign
prostatic hyperplasia in 33 and prostatic intraepithelial neoplasia in one.
Patients with cancer had a significantly greater increase in serum PSA levels
during the first week after LHRH injection than those in the benign and control
groups. Receiver operating characteristic curves showed that the percentage
change in PSA level on day 5 was more diagnostic than total PSA and f/tPSA.
CONCLUSIONS: There was a marked difference in the PSA response of patients with
benign or malignant disease to the testosterone surge produced by the LHRH
analogue. Although a larger study would be needed before LHRH-induced provocation
could be proposed as a clinical test, in this small series the response was
better than that for total PSA or f/tPSA in differentiating benign and malignant
disease.
PMID- 10759668
TI - The relationship between early biochemical failure and perineural invasion in
pathological T2 prostate cancer.
AB - OBJECTIVES: To evaluate, in patients with pathologically localized prostate
cancer, the relationship between early biochemical failure, i.e. an increasing
prostate-specific antigen (PSA) level, and perineural invasion (PNI) on final
pathology. PATIENTS AND METHODS: The records were reviewed of 171 patients with
prostate cancer who underwent prostatectomy at one institution between January
1992 and December 1995. Data on the histology, therapy and PSA level were
collected and evaluated. RESULTS: Of the 171 patients with pathologically
localized (pT2) prostate cancer, 131 were evaluable; 17 (13%) had a detectable
PSA level in the first 5 years after surgery and 63 had PNI in the pathological
specimen. Of those with PSA recurrence, 14 had PNI, one had no PNI and in two
there was no comment on PNI. In comparison, only 10 of the 17 patients with
recurrence had a Gleason sum of >/= 7. CONCLUSION: Perineural invasion seems to
be an important predictor of early outcome in patients with organ-confined
prostate cancer treated by prostatectomy. In this series it was the most
sensitive predictor of biochemical failure. A more detailed pathological
evaluation of prostate cancer may allow the clinician to provide closer
surveillance and better informed clinical decision-making.
PMID- 10759669
TI - Deferred treatment of localized prostate cancer in the elderly: the impact of the
age and stage at the time of diagnosis on the treatment decision.
AB - OBJECTIVE: To assess the clinical behaviour of clinically localized prostate
cancer in elderly patients monitored until progression, and the impact of
clinical variables, i.e. clinical stage, Gleason score, the dynamics of prostate
specific antigen (PSA) and age, on the natural history of the disease. PATIENTS
AND METHODS: Between February 1991 and January 1998, 54 patients (mean age 76.4
years, median 77 at the time of diagnosis) with clinically localized prostate
cancer who elected for watchful waiting were identified. They were monitored
regularly and treatment deferred until progression. Progression was defined as
local stage progression (as assessed on a digital rectal examination),
biochemical progression or metastasis. All patients who progressed were offered
either radiation therapy or hormonal treatment. Each clinical variable was
assessed by univariate and multivariate analysis to predict disease progression.
The mean follow-up was 47 months. RESULTS: Of the 54 patients, 28 (52%)
progressed; 10 had biochemical, 11 local and four biochemical and local
progression, and three developed metastasis. All the patients who progressed
elected to receive hormonal treatment. The mean time to progression was 35
months. Gleason score ( 6), age ( 75 years) and serum PSA
level ( 10 ng/mL) were statistically significant predictors of
disease progression (P = 0.04, < 0.001 and 0.02, respectively). The clinical
stage at the time of diagnosis had a borderline effect on disease progression (P
= 0.06). On multivariate analysis, Gleason score and PSA level were statistically
significant predictors of disease progression. CONCLUSION: These results suggest
that the treatment of prostate cancer should not be deferred in patients aged >
75 years with a good performance status when the biopsy has a Gleason score >/= 6
and the serum PSA level is >/= 10 ng/mL.
PMID- 10759670
TI - Twelve prostate biopsies detect significant cancer volumes (> 0.5 mL).
AB - OBJECTIVES: To compare, in a retrospective study, pathological specimens of
prostate cancer detected in additional areas of a 12-core biopsy with tumours
detected using traditional sextant biopsy. PATIENTS AND METHODS: The study
included 27 patients who had undergone radical prostatectomy (RP) for prostate
cancer. Prostatectomy specimens of cancers detected using standard sextant
biopsies were compared with those detected using six additional core biopsies.
The RP specimens were analysed for cancer volume, Gleason score, tumour grade
(Mostofi) and pathological stage. RESULTS: Of the 27 patients, six (29%) had
cancer detected in the extra six biopsy cores which would have otherwise have
been undetected using sextant biopsy. Only two insignificant cancers were
detected. The mean Gleason score was 6.1 for cancer detected by the sextant or 12
core method (P = 0.907); the mean grade (Mostofi) was 2.1 and 2. 33, respectively
(P = 0.29). The final tumour stage in the 21 patients undergoing sextant biopsy
was pT2 in 13 and pT3 in eight, compared with six pT2 tumours in the six patients
diagnosed using extra biopsies. The mean (median, range) tumour volume was 5.7
(3.5, 0.312-23.75) mL for cancers detected on sextant biopsy and 1.99 (1. 85, 0.4
3.6) mL in the six cancers detected using extra cores (P = 0. 0138). CONCLUSION:
The detection of prostate cancer was increased using extra biopsy cores. There
was a significant difference in tumour volume but not in Gleason score, Mostofi
grade or final pathological tumour stage between tumours diagnosed using 12 cores
and those detected on sextant biopsy.
PMID- 10759671
TI - The significance of the free-to-complexed prostate-specific antigen (PSA) ratio
in prostate cancer detection in patients with a PSA level of 4.1-10.0 ng/mL.
AB - OBJECTIVE: To compare the ratio of free prostate specific antigen (fPSA), total
PSA (tPSA) and complexed PSA (cPSA, measured using a novel immunoassay) with
other variables used to detect prostate cancer in patients with intermediate
serum PSA levels of 4.1-10.0 ng/mL. PATIENTS AND METHODS: From July 1997 to
August 1998, 140 consecutive patients were assessed; all had intermediate serum
PSA levels and/or abnormal findings on a digital rectal examination. All patients
underwent transrectal ultrasonography (TRUS)-guided biopsy, and the prostate and
transition zone volumes were determined by TRUS. Free and tPSA were measured
using the Tandem-R assay (Hybritech Corp., San Diego, CA). PSA complexed with
alpha1-antichymotrypsin (cPSA) was measured using an appropriate assay. The
ability of cPSA, free-to-total PSA ratio (f/tPSA), free-to-complexed PSA ratio
(f/cPSA), tPSA density of the whole prostate (PSAD), of the transition zone
(tPSATZ), and cPSA density of the whole prostate (cPSAD) and of the transition
zone (cPSATZ) to improve the power of PSA in detecting prostate cancer was
evaluated using receiver operating characteristic (ROC) curves. Results Of the
140 patients, 126 had histologically confirmed benign disease and 14 had prostate
cancer. The cPSA alone had better specificity for detecting prostate cancer than
had tPSA alone but the difference was not significant. The area under the ROC
curve for f/cPSA was larger than those for all other variables. With a 93%
sensitivity for detecting prostate cancer, a f/cPSA threshold of 25% would result
in fewer unnecessary biopsies (40% f/cPSA specificity) than with all other PSA
variables. The difference in the resolution was significant between f/cPSA and
tPSA, cPSA, tPSAD and tPSATZ, but not with f/tPSA, cPSAD or cPSATZ. In patients
with a prostate volume of < 30 mL, the cPSATZ showed better specificity for
prostate cancer than tPSA alone. CONCLUSION: Measuring the level of cPSA and its
derivatives may provide better differentiation of prostate cancer and benign
disease than tPSA alone in patients with a tPSA level of 4.1-10.0 ng/mL.
PMID- 10759672
TI - The use of isolated caecal bowel segment in complicated vaginal reconstruction.
AB - OBJECTIVE: To report a one-stage procedure, using a segment of caecum, both to
overcome failed previous procedures and for primary vaginal replacement in
patients with congenital vaginal aplasia, where primary reconstruction often
results in vaginal obstruction and fistula formation. PATIENTS AND METHODS: The
vagina was reconstructed using a 15-cm isolated caecal segment placed between the
bladder and rectum and anastomosed to the introitus. Between 1985 and 1997 the
technique was used in 17 patients (mean age 23 years). Indications included
congenital malformations and vaginal loss through anterior exenteration or
trauma. Seven of the 17 patients had undergone previous complex reconstructions;
four of these had undergone previous fistula formation. Fourteen patients were
followed for a mean of 3.6 (1-9) years. The surgical outcome was evaluated using
a questionnaire completed by the patients. RESULTS: The postoperative course was
unremarkable in all patients. Four patients developed an introital stenosis
requiring surgical intervention. Two patients were minors at the time of follow
up, while all the others had had sexual intercourse and reported that they were
very satisfied with the functional and cosmetic result. CONCLUSION: In patients
in whom previous vaginal reconstruction has failed, the caecal segment should be
used to create a neovagina. By considering the patient's age, the surgeon can
optimize the surgical result.
PMID- 10759673
TI - Ejaculatory duct obstruction in infertile men.
AB - OBJECTIVE: To analyse our experience of ejaculatory duct obstruction (EDO) in
infertile men, evaluating the diagnostic steps and the outcome of management
according to the aetiology. PATIENTS AND METHODS: Over a 7-year period, 50
infertile men were diagnosed with EDO as a contributory factor to male
infertility. Diagnostic criteria included a history, physical examination, semen
analyses, semen fructose measurement, hormonal study, testicular biopsy,
transrectal ultrasonography (TRUS) and/or vasography. Thirty-one patients with
EDO were treated by transurethral resection (26) or forced lavage via a vasotomy
(five). RESULTS: In 45 of the 50 men, semen analyses showed the typical
characteristics of complete EDO. Seminal values were variable in five cases of
partial EDO; the semen fructose levels were < 1.4 g/L in all five. The main cause
of EDO was a midline cyst in 16, Wolffian malformation in four, tuberculosis in
17, previous genitourinary infection in five and idiopathic in eight men. In 17
patients the seminal vesicles appeared to be atrophied on TRUS; 15 of these
patients had a history of pulmonary tuberculosis and subsequent vasography in
five showed multiple bilateral vasal obstruction. TRUS findings correlated well
with vasography except in one case. The overall rate of improved semen values and
paternity was 61% and 26%, respectively. Of 16 patients with midline cysts, 14
had improved semen variables and achieved paternity, seven after transurethral
resection. CONCLUSIONS: TRUS should be the first diagnostic procedure used when
infertile men are suspected of having EDO, but vasography should still be
considered for a more comprehensive diagnosis. In patients with atrophic seminal
vesicles on TRUS and with a history of pulmonary tuberculosis, further study is
unnecessary and microscopic epididymal sperm aspiration is recommended for in
vitro fertilization. The measurement of semen fructose may be helpful in
diagnosing partial EDO. Patients with midline cysts who are treated by
transurethral resection are expected to have the best outcome.
PMID- 10759674
TI - Comparison of the perimeatal-based flap (Mathieu) and the tubularized incised
plate urethroplasty (Snodgrass) in primary distal hypospadias.
AB - OBJECTIVES: To determine whether the perimeatal-based flap technique or the
tubularized incised-plate repair is the more appropriate treatment for distal
hypospadias in terms of fistula rate, cosmesis of the meatus and operative
duration. PATIENTS AND METHODS: Between July 1997 and August 1998, 60 children
(none of whom had previously undergone a procedure for hypospadias) underwent
primary distal hypospadias repair in a prospective randomized trial. Thirty
patients were allocated to undergo a Mathieu repair (mean age 24.9 months, range
9-72) and 30 a Snodgrass procedure (mean age 23.1 months, range 7-19). The mean
follow-up was 15.4 months. RESULTS: The mean duration of surgery was
significantly lower for the Snodgrass procedure than for the Mathieu repair (75
vs 115 min, P < 0.05). Three children undergoing a Mathieu repair had
complications (two a urethrocutaneous fistula and one a meatal stenosis),
compared with only one in the Snodgrass group (glanular dehiscence). The
resultant meatus was slit-like in all patients undergoing the Snodgrass repair
whereas those with a Mathieu repair had a rounded and horizontal meatus.
CONCLUSION: The overall complication rate was lower and the surgery significantly
quicker with the Snodgrass urethroplasty, which also had a better cosmetic
outcome. The Snodgrass technique is recommended as a primary treatment for distal
hypospadias.
PMID- 10759675
TI - Anatomical studies of the urethral plate: why preservation of the urethral plate
is important in hypospadias repair.
AB - OBJECTIVE: To describe the detailed anatomy of the urethral plate in relation to
its controversial role in hypospadias surgery. MATERIALS AND METHODS: A newborn
penis with proximal penile hypospadias and two fetal penises with distal shaft
hypospadias were included in the study; 30 normal fetal penises served as the
control. Specimens were embedded in paraffin and serially sectioned (6 microm)
after formalin fixation. Every 10th section was stained with haematoxylin and
eosin. Immunohistochemical staining for nerves (S100), smooth muscles (alpha
actin), blood vessels (factor VIII) and epithelium (cytokeratins 7, 14 and 18)
were used on selected sections, with particular attention to the urethral plate.
Masson's trichrome and Sirius Red stains were used to localize collagen. RESULTS:
There were extensive blood vessels, glands and smooth muscle under the urethral
plate in the hypospadias specimens. These relatively well organized tissues
corresponded to an abnormally formed corpus spongiosum. The glands underneath the
urethral plate and adjacent to the normal urethra showed positive staining for
cytokeratins 7 and 18, respectively (markers of endodermal origin) but were
negative for cytokeratin 14 (a marker of ectodermal origin). Penile skin and
urethral plate epithelium stained positively for cytokeratin 14 but not for
cytokeratin 7 and 18. The urethral plate has a rich nerve supply, as determined
by S100 staining. Collagen intensity under the urethral plate was no different
from that in normal areas. Tunica albuginea stained intensely for type I and III
collagen. CONCLUSION: These results show that the urethral plate is well
vascularized, has a rich nerve supply and an extensive muscular and connective
tissue backing. These features may explain the lower complication rate with onlay
flaps than with tube flaps. Therefore, from these anatomical findings, we
continue to advocate preservation of the urethral plate and the onlay island flap
for hypospadias reconstruction.
PMID- 10759677
TI - Melatonin administration prevents the nephrotoxicity induced by gentamicin.
AB - OBJECTIVE: To investigate the effect of melatonin on the antioxidant enzyme
activity and renal tubular necrosis induced by gentamicin. MATERIALS AND METHODS:
Twenty-four adult male Sprague-Dawley rats were divided into three equal groups.
In group 1, the rats were injected with vehicle (controls), in group 2 they were
injected with gentamicin for 5 days and in group 3 injected with gentamicin plus
melatonin for 5 days. At 24 h after the last injection, rats were killed and the
renal cortex separated from the medulla. Most of the cortex was homogenized but a
small sample was fixed in formaldehyde solution for histological examination by
light microscopy. Blood samples were also taken to assess the serum levels of
urea, creatinine, Na+, K+ and gamma-glutamyl transpeptidase (gamma-GT); before
death, urine samples were analysed for protein content. Crude extracts of the
cortex were used to determine lipoperoxides, reduced glutathione (GSH-Px),
catalase and superoxide dismutase (SOD). The results were compared using the Mann
Whitney U-test. RESULTS: Compared with the controls rats, gentamicin caused
hyperproteinuria, an increase in the level of gamma-GT in serum, a marked
increase in lipoperoxides and a significant decrease of GSH-Px, catalase and SOD
activity in the kidney. In the rats in group 3 there was a marked restoration in
lipid peroxidation, GSH-Px, catalase, SOD activity and proteinuria, and in gamma
GT in serum. In rats in group 2 there was widespread tubular necrosis (grade 2-4)
but in rats in group 3 there was a marked reduction in the extent of tubular
damage. There was no significant difference in serum levels of Na+, K+, blood
urea nitrogen and creatinine. CONCLUSION: These results indicate that melatonin
prevents the tubular necrosis induced by gentamicin in rats, presumably because
it is a potent antioxidant and restores antioxidant enzyme activity in the rat
kidney.
PMID- 10759676
TI - Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human
haemoglobin.
AB - OBJECTIVE: To examine the effect of HbA1c, an isoform of glycosylated haemoglobin
(GHb, a product of non-enzymatic reactions between elevated blood glucose and
haemoglobin), on nitric oxide-mediated corpus cavernosal smooth muscle
relaxation, and to categorize the mechanisms involved. MATERIALS AND METHODS:
Corpus cavernosal tissue from Wistar rats (300-350 g body weight) was prepared
for the measurement of isometric tension. After equilibration in Krebs solution
gassed with 95% O2/5% CO2 at 37 degrees C for 90 min, optimal resting tension was
applied. Tissue was precontracted with 1 micromol/L noradrenaline (NAd) and
either relaxed with incremental doses of acetylcholine (ACh) or sodium
nitroprusside (SNP). After washout, strips were again precontracted with NAd and
then incubated with pyrogallol (100 micromol/L), 100 microL of haemoglobin or 100
microL of GHb in the presence of either L-arginine (100 micromol/L), indomethacin
(10 micromol/L), allopurinol (100 micromol/L), deferoxamine (100 micromol/L),
catalase (600 IU/mL), or superoxide dismutase (SOD) (120 IU/mL) before ACh- or
SNP-induced relaxation responses were repeated. RESULTS: Haemoglobin and GHb
significantly impaired the relaxation of rat corpus cavernosum to ACh in a dose
dependent manner. L-arginine reversed the impairment caused by Hb, but not GHb. A
donor of superoxide anions, pyrogallol, mimicked this impairment to ACh when
added to control strips. Catalase, deferoxamine, indomethacin and allopurinol had
no significant effect on the impaired relaxation response to ACh, whilst L
arginine partially reversed it. SOD completely reversed the GHb-induced impaired
relaxation; GHb did not alter the relaxation response to SNP. CONCLUSION: GHb
significantly impairs endothelial NO-mediated corpus cavernosal relaxation in the
rat, in vitro. This effect is caused partly by the generation of superoxide
anions and the extracellular inactivation of NO.
PMID- 10759678
TI - Photodynamic therapy of rat bladder and urethra: evaluation of urinary and
reproductive function after inducing protoporphyrin IX with 5-aminolaevulinic
acid.
AB - OBJECTIVE: To assess the urinary and reproductive function of rats after inducing
protoporphyrin IX with 5-aminolaevulinic acid (ALA) and subsequent intraurethral
photodynamic therapy (PDT). Materials and methods Twelve female Wistar rats were
given ALA orally or intravesically (four each), followed by intraurethral PDT
through a 10-mm cylindrical fibre at 100 mW for 500 s (argon laser, 632 nm).
Urinary frequency, the number of gestations and histological changes were then
evaluated and compared with a group of eight control rats. RESULTS: There was
only a slight increase in urinary frequency during the first 2 weeks after PDT in
the group given oral ALA, while the same degree of urinary frequency was evident
for up to 4 weeks in those given intravesical ALA. Despite the occurrence of
urinary incontinence from undefined causes in two rats, reproductive function
remained unchanged. There was no histological evidence of damage to the
reproductive system adjacent to the bladder. CONCLUSIONS: PDT of the urethra with
ALA is relatively safe and carries few risks of inducing permanent urological
complications.
PMID- 10759679
TI - Comparison of the depth of the desiccated zone with selected vaporizing-cutting
electrodes: a basic study in animals.
AB - OBJECTIVE: To evaluate in an animal model the haemostatic efficacy of vaporizing
cutting (VC) electrodes recently developed for use in high-energy transurethral
resection of the prostate (TURP). MATERIALS AND METHODS: Four VC electrodes were
assessed for their haemostatic efficacy in the muscle and liver of pigs (in
vitro) and dogs (in vivo). The devices tested were the roller-cutting and Vapor
Cut (Karl Storz GmbH, Germany); the Wedge (Boston Scientific Corp., Boston, USA);
and the Uroloop (Endocare Inc., Irvine, CA). In each the depth of the desiccated
zone was compared with that produced by a standard cutting loop electrode. Each
electrode was attached to a scanning system (developed previously) that allowed
the electrode pressure on the tissue surface (in 3% sorbitol solution) and the
running speed to be adjusted. The same generator was used with all devices. The
tissue (muscle or liver) was cut by running the electrode over the surface at
200, 250 or 300 W, with the loop electrode used as the reference. After
completing the procedure, the surgical wound and the surrounding tissue were
dissected out and the depth of the heat-affected zone (HAZ, defined as the
desiccated zone) measured. RESULTS: In pig muscle (stroke speed 5 mm/s) there was
no significant difference in the depth of the HAZ between the four VC electrodes
and the loop, or among the VC electrodes at any of the power levels tested. In
pig liver (stroke speed 5 mm/s), the roller cutting and Vapor Cut electrodes
produced a thicker HAZ than the loop at all power levels tested (P < 0.01). The
Wedge electrode produced a significantly thicker HAZ than the loop at 200 and 300
W (P < 0.01). There were no significant differences in HAZ among the VC
electrodes at any power level. In dog muscle in vivo (stroke speed 10 mm/s), the
roller cutting, Vapor Cut and Wedge electrodes produced a significantly thicker
HAZ at 250 W than the loop at 150 W (the usual power for TURP) (P < 0.01). There
was no significant difference among the VC electrodes. In dog liver in vivo
(stroke speed 10 mm/s), the roller cutting electrode produced a significantly
thicker HAZ at 250 W than the loop at 150 W (P < 0.01). CONCLUSIONS: The present
VC electrodes produced a thicker desiccation zone at higher powers (200-300 W)
than the standard loop at the usual power (150 W). The four VC electrodes
produced a similar desiccation zone. With pig muscle and liver in vitro, regular
loops used at a higher power created a desiccation zone that was 70-80% of the
depth created by the VC electrodes.
PMID- 10759680
TI - Adenovirus-mediated suicide-gene therapy using the herpes simplex virus thymidine
kinase gene in cell and animal models of human prostate cancer: changes in tumour
cell proliferative activity.
AB - OBJECTIVES: To determine the feasibility and efficacy of suicide-gene therapy
using adenovirus (Ad)-mediated herpes simplex virus thymidine kinase (HSV-TK) and
the prodrug acyclovir, and to evaluate changes in the biological phenotype for
tumour cell proliferative activity after suicide-gene therapy in animal models of
human prostate cancer. MATERIALS AND METHODS: Using a replication-defective
adenoviral vector (cytomegalovirus, CMV) containing the beta-galactosidase gene
(Ad-CMV-beta-gal) as a control and Ad-CMV-TK as the therapeutic vector under the
transcriptional control of the CMV promoter, transduction efficiency was assessed
in vitro by infecting LNCaP and PC-3 androgen-dependent and independent human
prostate cancer cells with Ad-CMV-beta-gal, and using X-gal staining. The TK
activity in prostate cancer cells infected with Ad-CMV-TK was determined by
measuring TK-mediated [3H]-gancyclovir phosphorylation. The sensitivity of LNCaP
and PC-3 cells to Ad-CMV-TK in vitro was determined after infection with the
therapeutic vector with or without acyclovir. The inhibition of PC-3 tumour
growth in vivo induced by the Ad-CMV-TK/acyclovir suicide-gene system was
assessed in separate and controlled experiments using human prostate cancer mouse
models. Ki-67 proliferative antigen and proliferating cell nuclear antigen
(PCNA), both useful proliferative indices, were evaluated using
immunohistochemical staining (MIB-1 monoclonal antibody and monoclonal anti-PCNA
antibody) in formalin-fixed, paraffin-embedded tissues from gene therapy-treated
and control animals. RESULTS: The mean TK activity was significantly higher in
LNCaP and PC-3 cells infected with Ad-CMV-TK than in cells infected with Ad-CMV
beta-gal, used as a control (P < 0.05). The growth of human prostate cancer cells
with Ad-CMV-TK was significantly inhibited by adding acyclovir in vitro (P <
0.05). In the in vivo experiments using the PC-3 human prostate cancer mouse
model, tumour volume and growth was lower in mice treated with Ad-CMV
TK/acyclovir than in those treated with Ad-CMV-TK only, acyclovir only or
untreated (controls) (P < 0.05). Histochemical staining of tumour tissues showed
that Ad-CMV-TK/acyclovir destroyed PC-3 tumours through tumour cell death and
apoptosis, with local lymphatic infiltration. The mean PCNA labelling index in
prostate cancer cells of mice treated with Ad-CMV-TK/acyclovir was significantly
lower than that in untreated controls (P < 0.05, Mann-Whitney U-test). The Ki-67
labelling index in prostate cancer cells of mice treated with Ad-CMV-TK/acyclovir
was also lower than that in untreated controls (P < 0.05, Student's t-test).
Adenovirus-mediated suicide-gene therapy using the HSV-TK gene decreased the
proliferative activity of PC-3 human prostatic cancer cells in vivo. CONCLUSIONS:
Adenovirus-mediated suicide-gene therapy using an HSV-TK/acyclovir system
provided effective therapy in an experimental human prostate cancer mouse model,
by significantly inhibiting tumour growth and decreasing the proliferative
activity of human prostate cancer cells. Such therapy could be developed as a
novel method for treating patients with androgen-independent prostate cancer.
PMID- 10759681
TI - The protective effects of nitric oxide on the contralateral testis in prepubertal
rats with unilateral testicular torsion.
AB - OBJECTIVE: To investigate histological changes in the contralateral testis of
rats with unilateral testicular torsion and the protective effects of nitric
oxide (NO) on possible damage. MATERIAL AND METHODS: Twenty-eight prepubertal
male Sprague-Dawley rats were divided into four equal groups. Group 1 underwent a
sham operation of the right testis under general anaesthesia. Group 2 underwent a
similar operation but the right testis was rotated 720 degrees clockwise for 6 h,
maintained by fixing the testis to the scrotum, and saline infused during the
procedure. Group 3 underwent similar torsion but L-arginine methyl ester (a
precursor of NO) was infused during the procedure. In Group 4, NG-nitro-L
arginine-methyl ester, a NO synthase inhibitor, was infused separately during the
administration of L-arginine methyl ester and torsion. All the left (untwisted)
testes were removed from rats 21 days after surgery and evaluated histologically,
assessing seminiferous tubule diameter, loss of sperm and spermatids, loss of
germ cell layers, disarray of germ cell layers, rupture of tubules, Leydig cell
proliferation and reaction in the ruptured tubules, and oedema. RESULTS: There
was a significant difference in the indicators of histological damage between
groups 2 and 4 and groups 1 and 3, except for the Leydig cell reaction in the
ruptured tubules and oedema. The damage was significantly less in group 3 than in
groups 2 and 4. CONCLUSION: These results suggest that long-term
histopathological changes in the contralateral testes are important after
unilateral testicular torsion and that NO has a protective effect on the
contralateral testis.
PMID- 10759682
TI - Malabsorption after augmentation cystoplasty: the role of ileo-caecal
reconstitution.
PMID- 10759683
TI - Bladder carcinoma presenting as prostatitis syndrome.
PMID- 10759684
TI - Paracetamol, alcohol and the liver.
AB - It is claimed that chronic alcoholics are at increased risk of paracetamol
(acetaminophen) hepatotoxicity not only following overdosage but also with its
therapeutic use. Increased susceptibility is supposed to be due to induction of
liver microsomal enzymes by ethanol with increased formation of the toxic
metabolite of paracetamol. However, the clinical evidence in support of these
claims is anecdotal and the same liver damage after overdosage occurs in patients
who are not chronic alcoholics. Many alcoholic patients reported to have liver
damage after taking paracetamol with 'therapeutic intent' had clearly taken
substantial overdoses. No proper clinical studies have been carried out to
investigate the alleged paracetamol-alcohol interaction and acute liver damage
has never been produced by therapeutic doses of paracetamol given as a challenge
to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and
chronic ethanol have opposite effects. In animals, chronic ethanol causes
induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity
as expected (ethanol primarily induces CYP2E1 and this isoform is important in
the oxidative metabolism of paracetamol). However, in man, chronic alcohol
ingestion causes only modest (about twofold) and short-lived induction of CYP2E1,
and there is no corresponding increase (as claimed) in the toxic metabolic
activation of paracetamol. The paracetamol-ethanol interaction is not specific
for any one isoform of cytochrome P450, and it seems that isoenzymes other than
CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in
man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in
animals and man. This protects against liver damage in animals and there is
evidence that it also does so in man. The protective effect disappears when
ethanol is eliminated and the relative timing of ethanol and paracetamol intake
is critical. In many of the reports where it is alleged that paracetamol
hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been
the case because alcohol was actually taken at the same time as the paracetamol.
Chronic alcoholics are likely to be most vulnerable to the toxic effects of
paracetamol during the first few days of withdrawal but maximum therapeutic doses
given at this time have no adverse effect on liver function tests. Although the
possibility remains that chronic consumption of alcohol does increase the risk of
paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis),
there is insufficient evidence to support the alleged major toxic interaction. It
is astonishing that clinicians and others have unquestion-ingly accepted this
supposed interaction in man for so long with such scant regard for scientific
objectivity.
PMID- 10759685
TI - Therapeutic drug monitoring of psychotropic medications.
AB - Therapeutic drug monitoring (TDM) of a number of psychotropic medications has
proven to be of value, enabling minimization of the limitations of considerable
genetic variability in their metabolism and the high rates of poor compliance
with many psychiatric disorders. Therapeutic ranges have been established for
lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been
shown to be useful in avoiding toxicity (as many psychotropics have narrow
therapeutic indices), particularly that due to interactions with other compounds.
PMID- 10759686
TI - Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to
the metabolism of albendazole by human liver microsomes.
AB - AIMS: Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a
broad spectrum anthelmintic whose activity resides both in the parent compound
and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism
in animals but relatively few in humans. We have investigated the sulphoxidation
of ABZ in human liver microsomes and recombinant systems. METHODS: The specific
enzymes involved in the sulphoxidation of ABZ were determined by a combination of
approaches; inhibition with an antiserum directed against cytochrome P450
reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in
human liver microsomes, the capability of expressed CYP and FMO to mediate the
formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in
human liver microsomes against selective P450 substrates and regression analysis
of the rate of ABS sulphoxidation against CYP expression measured by Western
blotting. RESULTS: Comparison of Vmax values obtained following heat inactivation
(3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO
with methimazole and addition of an antiserum directed against cytochrome P450
reductase indicate that FMO and CYP contribute approximately 30% and 70%,
respectively, to ABS production in vitro. Comparison of CLint values suggests CYP
is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n
= 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%),
methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition
with ketoconazole and methimazole was 69 +/- 8% (n = 3). ABS production in heat -
treated microsomes (3 min at 45 degrees C) correlated significantly with
testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on
Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant
human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control
microsomes, with those expressing CYP3A4 producing threefold more ABS than those
expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4
and FMO3 were similar. CONCLUSIONS: We conclude that the production of ABS in
human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP
component being the major contributor.
PMID- 10759687
TI - Dose loading with delayed-release mesalazine: a study of tissue drug
concentrations and standard pharmacokinetic parameters.
AB - AIMS: Tissue concentrations of 5-aminosalicylic acid (5ASA) and its metabolites
may influence the clinical course of inflammatory bowel disease. Since the
factors that determine tissue drug concentrations are unknown we have studied the
relationships between the oral dose of delayed-release mesalazine, rectal tissue
drug concentrations and standard pharmacokinetic parameters. METHODS: Twelve
healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8
g of delayed-release mesalazine daily. 5-aminosalicylic acid and N-acetyl 5
aminosalicylic acid concentrations were measured in serum, urine, stool and
rectal tissue biopsies. RESULTS: Serum concentrations and 24 h urinary excretion
of 5ASA and N-acetyl 5ASA increased as the oral dose of mesalazine was increased
from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3.
9, 15.4 and 46.8 microg ml-1 h, P < 0.0001; N-acetyl 5ASA = 17.2, 30. 9 and 57.8
microg ml-1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P <
0.0001; N-acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal
5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did
not increase further with 4.8 g daily dosing whereas faecal N-acetyl 5ASA
excretion was similar at all three doses. Rectal tissue concentrations of 5ASA
increased markedly, and N-acetyl 5ASA increased modestly, as the dose of oral
mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with
4.8 g daily dosing. CONCLUSIONS: The relationship between the ingested dose of
delayed-release mesalazine and rectal tissue drug concentrations is complex.
Factors other than dose are likely to be important determinants of rectal tissue
drug concentrations.
PMID- 10759688
TI - Sensitivity of repeated interdigital web pinching to detect antinociceptive
effects of ibuprofen.
AB - AIMS: The aim of the current study was to assess the viability of the
interdigital web pinch model as a test for analgesic activity in volunteer-based
early phase drug development. METHODS: Pain thresholds and sensitization to a
series of four sessions of interdigital web pinching (12 Newtons force) were
measured in 26 male volunteers before and 1 and 3 h after oral dosing with
ibuprofen (800 mg) or placebo to ibuprofen. Within each time point, the pain
thresholds were measured by calculating the average visual analogue scores (VAS)
for the first session of pinching (VAS-1). Sensitization to pinching was assessed
by calculating the average changes in these scores for the three subsequent
sessions of pinching (VAS-2). Moreover, the difference between the VAS score
after the first session of pinching and that obtained at the end of the fourth
session of pinching was calculated as a secondary endpoint (VAS-3). RESULTS:
Treatment with ibuprofen had no significant effect on VAS-1 at either 1 or 3 h
after dosing. However, the mean values of VAS-2 and VAS-3, were significantly
reduced (P < 0.05) following treatment with ibuprofen. CONCLUSIONS: This model
has been able to detect an antinociceptive effect with ibuprofen. However, large
numbers of subjects were required in order to demonstrate this effect and this
feature would restrict the model's utility in early phase clinical trials where
small numbers of subjects are normally employed.
PMID- 10759689
TI - Interaction between the LMWH reviparin and aspirin in healthy volunteers.
AB - AIMS: To investigate potential interactions between reviparin and acetylsalicylic
acid (ASA 300 mg o.d. from day 1-5). METHODS: In an open, randomized, three-way
cross over study nine healthy volunteers received reviparin (s.c. injection of
6300 anti-Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300
mg) or placebo from days 1 to 5. Assessments included bleeding time (BT),
collagen (1 microg ml-1) induced platelet aggregation (CAG), heptest, plasma
antifactor Xa-activity and activated partial thromboplastin time (aPTT). RESULTS:
Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA
alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment
reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of
reviparin with ASA were not different from those after ASA alone. aPTT was
prolonged to 32 s after reviparin; this effect was not modified if subjects
received ASA. Combined treatment with ASA and reviparin had no effect on plasma
anti-Xa-activity and heptest compared with reviparin alone. CONCLUSIONS: We could
not entirely exclude a small interaction between reviparin and ASA on bleeding
time, but the effect is probably without clinical significance.
PMID- 10759690
TI - In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet
drug ticlopidine: potent effect on CYP2C19 and CYP2D6.
AB - AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome
P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant
human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9,
2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL.
Preliminary data were generated to simulate an appropriate range of substrate and
inhibitor concentrations to construct Dixon plots. In order to estimate
accurately inhibition constants (Ki values) of TCL and determine the type of
inhibition, data from experiments with three different HLMs for each isoform were
fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin.
RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5
microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the
therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also
a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of
CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/-
48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be
a broad-spectrum inhibitor of the CYP isoforms, but clinically significant
adverse drug interactions are most likely with drugs that are substrates of
CYP2C19 or CYP2D6.
PMID- 10759691
TI - Polypharmacy in a general surgical unit and consequences of drug withdrawal.
AB - AIMS: To identify drug usage/withdrawal in surgical patients and the relative
risk this imposes on postoperative surgical complications. METHODS: A prospective
survey of patients' medicines, oral intake (food/fluids/ medicines) and
postoperative complications was carried out in the General Surgical Unit, Dunedin
Hospital, Dunedin, New Zealand. RESULTS: One thousand and twenty-five general
surgical patients aged >/= 16 years, were entered into the study. Half of the
patients were taking medicines unrelated to surgery. On average these patients
received 9 different drugs (range 1-47) from a selection of 251, of which 21%
were released in the last 10 years. The mean number of these drugs taken
increased with age, vascular surgery and other major procedures. The majority of
patients (53%) were taking drugs for cardiovascular problems. Only 8% of
admissions were on the drugs more traditionally recognized to be of importance to
the surgery, i.e. steroids and diabetic therapy. With respect to risk, taking a
drug unrelated to surgery was associated with an increased relative risk of a
postoperative complication by 2.7 (95% C.I. 1.76-4.04) compared with those who
were not taking any drug. Cardiovascular drugs contributed significantly to this
risk; when they were excluded from analysis, the risk dropped to 1.8 (95% C.I.
1.14-2.93). Death may be more common in those taking ACE inhibitors. Drug
withdrawal and complications were analysed and as the time without medicines
increased (range 1-42 days) so did the complication rate (chi2 = 14.7, DF = 2, P
= 0.007). Of those patients who were taking a cardiovascular medicine and were
without their normal medicines for a period of time postoperatively, 12% suffered
a cardiac complication. CONCLUSIONS: Many patients admitted to a general surgical
ward, are taking medicines unrelated to surgery. Drug therapy unrelated to
surgery is a useful predictor for increased postoperative complications and one
for which preventive action can be taken. This study provides evidence that
withdrawal of regular medicines may add significant risk to the surgery and
further complicate outcome. The longer patients were without their regular
medicines the more nonsurgical complications they suffered. Reintroduction of
patients' regular medicines early in their postoperative course may decrease
morbidity and mortality in-patients.
PMID- 10759692
TI - Drug utilization evaluation of nonprescription H2-receptor antagonists and
alginate-containing preparations for dyspepsia.
AB - AIMS: To evaluate the use, efficacy and adverse effects of nonprescription H2
receptor antagonists and alginate-containing preparations obtained from community
pharmacies. METHODS: Questionnaires were distributed to customers from 39
pharmacies in Scotland and Wales. RESULTS: Of 767 customers recruited, 608
(79.3%) returned an initial questionnaire and 472 (61.5%) customers a second
questionnaire. The vast majority of respondents (424, 69.7%) had suffered their
symptoms on three or more occasions and 369 (60.7%) had previously tried
medicines to relieve their symptoms. Referrals to a doctor were less frequent
than recommended in guidelines and few of those who were referred actually saw a
doctor. Over a quarter of those returning the second questionnaire claimed to be
taking more than one product simultaneously for symptom control. Eight customers
who were taking prescribed ulcer-healing drugs obtained H2-receptor antagonists.
The majority of respondents (355/472, 75. 2%) obtained some or complete symptom
relief using the product obtained and 369/472 (78.2%) were completely satisfied
with their product. H2-receptor antagonists were more likely to produce complete
relief of symptoms than alginate-containing preparations (P < 0.05). Only 14
respondents (3.0%) reported side-effects from the product used which were mostly
gastro-intestinal. CONCLUSIONS: The study demonstrated that drug utilization
studies are feasible to carry out in a community pharmacy setting. While the
results support published evidence of the efficacy and minimal toxicity of these
products, they also highlight the possibility of H2-receptor antagonists being
used outwith their licenced indications.
PMID- 10759693
TI - Drug interactions avoided-a useful indicator of good prescribing practice.
AB - AIMS: To develop an index of quality prescribing in general practice by
investigating the incidence of potential drug interactions when medicines were
coprescribed within the State supported General Medical Services (GMS) in
Ireland. METHODS: We determined an odds ratio (OR), as a measure of the relative
risk of being exposed to a potential interaction, comparing the use of the H2
receptor antagonist, cimetidine, with that of the noninteracting agents
ranitidine, famotidine and nizatidine in users and nonusers of warfarin,
phenytoin and theophylline. RESULTS AND CONCLUSIONS: In 86 510 prescriptions for
the H2-receptor antagonists potentially interacting drugs were dispensed to 8188
(9%) patients in the Eastern Health Board Region of the GMS. We found that
prescribers were significantly less likely to use cimetidine (OR = 0.20,95% CI 0.
17-0.21, P < 0.001) in those patients who were coprescribed warfarin, suggesting
good prescribing practice within the GMS. Similarly there was preferential use of
the noninteracting H2-receptor antagonists in patients receiving phenytoin or
theophylline and the extent of this selective prescribing was in keeping with the
rank order of severity of interaction with these drugs. This novel
pharmacological index may be a sensitive marker of good prescribing practice.
PMID- 10759695
TI - Reply
PMID- 10759694
TI - Dramatic inhibition of amiodarone metabolism induced by grapefruit juice.
AB - AIMS: Grapefruit juice increases blood concentrations of many drugs metabolized
by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The
aim of this study was to determine amiodarone kinetics when administrated with
and without grapefruit juice. METHODS: Eleven healthy adult volunteers took part
in a single sequence, repeated-measures design study. Each subject, who had been
evaluated 6 months previously for amiodarone pharmacokinetics, was given a single
oral dose of amiodarone (17 mg kg-1) with three glasses of 300 ml of grapefruit
juice on the same day. RESULTS: Grapefruit juice completely inhibited the
production of N-DEA, the major metabolite of amiodarone, in all subjects and
increased the area-under-the-curve (AUC) and maximum concentration of amiodarone
(Cmax) by 50% and 84%, respectively, as compared with the control period during
which water had been administrated instead of grapefruit juice (AUC: 35.9 +/-
14.3 vs 23.9 +/- 11.2 microg ml-1 h, P < 0.005 and Cmax: 3.45 +/- 1.7 vs 1.87 +/-
0.6 microg ml-1, P < 0. 02, respectively) (means +/- s.d.). This inhibition of N
DEA production led to a decrease in the alterations caused by amiodarone on PR
and QTc intervals. CONCLUSIONS: Grapefruit juice dramatically alters the
metabolism of amiodarone with complete inhibition of N-DEA production. These
results are in agreement with in vitro data pointing to the involvement of CYP3 A
in the metabolism of amiodarone and suggests that this interaction should be
taken into account when prescribing this antiarrhythmic drug.
PMID- 10759696
TI - Binding of propofol to blood components.
PMID- 10759698
TI - Proceedings of the dutch society for clinical pharmacology and biopharmacy
PMID- 10759697
TI - Reply
PMID- 10759699
TI - Compound heterozygosity for haemoglobin S and haemoglobin E.
PMID- 10759700
TI - Can we prevent cytotoxic disasters?
PMID- 10759701
TI - Implications of recent insights into the pathophysiology of paroxysmal nocturnal
haemoglobinuria.
PMID- 10759702
TI - A new mutation (G51C) in the iron-responsive element (IRE) of L-ferritin
associated with hyperferritinaemia-cataract syndrome decreases the binding
affinity of the mutated IRE for iron-regulatory proteins.
AB - Hereditary hyperferritinaemia-cataract syndrome is an autosomal dominant disorder
characterized by a constitutively increased synthesis of L-ferritin in the
absence of iron overload. The disorder is associated with point mutations in the
iron-responsive element (IRE) of L-ferritin mRNA. We report a new mutation, G51C,
identified in two members of a Canadian family, presenting a moderate increase in
serum ferritin and a clinically silent bilateral cataract. Gel retardation assays
showed that the binding of the mutated IRE to iron-regulatory proteins (IRPs) was
reduced compared with the wild type. Structural modelling predicted that the G51C
induces a rearrangement of base pairing at the lateral bulge of the IRE structure
which is likely to modify IRE conformation.
PMID- 10759703
TI - Investigation of the effect of marathon running on leucocyte counts of subjects
of different ethnic origins: relevance to the aetiology of ethnic neutropenia.
AB - Healthy subjects of African ancestry, including Afro-Caribbeans, have been
observed to have lower total white cell counts and neutrophil counts than healthy
Caucasian subjects. The cause of this ethnic neutropenia is unclear. We have
previously found no evidence that increased margination of neutrophils is
responsible. In this study, we have investigated mobilization of neutrophils from
the bone marrow granulocyte reserve by endurance exercise. We investigated
subjects of different ethnic origins before and after they had competed in a
marathon race. Before the race, the neutrophil counts of Africans/Afro-Caribbeans
were significantly lower than those of Caucasians (means 2.49 and 3.21 x 109/l
respectively; P = 0.043). After the race, the difference was greater, as was the
degree of significance (means 10.21 and 12.33 respectively; P = 0.017). The
percentage increment was almost identical whereas the absolute increment was
considerably less, although of marginal statistical significance (increment 7.72
and 9. 12 x 109/l respectively; P = 0.10). Similar changes were observed in the
monocyte count. Before the race, the difference in the means was of marginal
statistical significance (0.35 and 0.41 x 109/l respectively; P = 0.105), whereas
after the race the difference was greater and was highly significant (means 0.75
and 1.05 x 109/l respectively; P = 0.001). These observations support the results
of our earlier study, both of which suggested that ethnic neutropenia is likely
to result from a diminished bone marrow reserve rather than being consequent on
altered distribution of neutrophils within the blood stream.
PMID- 10759704
TI - Differential constitutive and activation-dependent expression of prion protein in
human peripheral blood leucocytes.
AB - The cellular isoform of the prion protein (PrPC) is a cell surface glycoprotein
that has recently been shown to play a role in haemopoietic cell activation and
proliferation. We have characterized the constitutive expression of PrPC on human
peripheral blood (pB) cell populations, using PrP-specific antibodies in a
multiparameter flow cytometry approach. We found that T cells, NK cells and
monocytes exhibit similar PrPC levels, whereas PrPC surface staining on B cells
was significantly lower and was virtually absent on granulocytes. Within the T
cell compartment, CD8+ cells showed a significantly higher PrPC expression than
CD4+ cells. Similarly, CD3+ cells co-expressing the activation marker CD56 (N
CAM) exhibited significantly higher PrPC expression levels than their CD56-
counterparts. Culture of CD14+ pB monocytes for 12-48 h in the presence of
interferon gamma (IFN-gamma) resulted in a significant increase in PrPC
expression in a time- and concentration-dependent manner. This effect was
partially abrogated by the addition of the metabolic inhibitor cycloheximide,
indicating the role of protein synthesis in this process. Our results show that
PrPC expression on human haemopoietic cells correlates with the activation and
developmental status of these cells, suggesting an important functional role of
PrPC in the haemopoietic system.
PMID- 10759705
TI - Interleukin 10 regulates cellular responses in monocyte/endothelial cell co
cultures.
AB - Adhesive interactions between monocytes and vascular endothelial cells increase
the expression of the inflammatory genes, tissue factor (TF) and E-selectin, thus
contributing to the inflammatory process. In this study, we have shown that these
responses could be regulated by the immunomodulatory cytokine interleukin 10 (IL
10). IL-10 reduced TF generation in monocyte/endothelium co-cultures (64. 3 +/-
3.3% reduction, P < 0.01, n = 4) by acting directly on monocytes, whereas IL-4
inhibited TF expression in both monocytes and endothelium. Similarly, IL-10
reduced the induction of endothelial E-selectin by monocytes (100% reduction at
21 h), but had no effect on cytokine-induced E-selectin expression. IL-10 itself
was not able to induce E-selectin protein or mRNA in endothelial cells. IL-10
mRNA was detected in monocytes after 6 h co-culture with endothelial cells, and
was sustained for up to 30 h. Finally, IL-10 significantly reduced the adhesion
of monocytes to endothelium (45% reduction), which may account in part for the
inhibitory actions of IL-10. We conclude that IL-10 has an anti-inflammatory
effect on monocyte/endothelium interactions, and may itself be produced as a
result of such interactions.
PMID- 10759706
TI - Splenectomy in haemophagocytic lymphohistiocytosis: report of histopathological
changes with CD19+ B-cell depletion and therapeutic results.
AB - The pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in children without
a known familial pattern of inheritance is often difficult to establish. Splenic
enlargement, one of the main clinical findings in this disorder, has led to the
use of splenectomy for uncontrollable coagulopathy, persistent cytopenia or both.
This procedure is also thought to be a useful tool in making a differential
diagnosis in cases of the immunochemotherapy-resistant HLH. We report here five
cases of splenectomized childhood HLH, in which subsets of mononuclear spleen
cells were analysed either by flow cytometry or immunohistochemistry, and the
results were compared with those from cases of hereditary spherocytosis
(controls). There was a statistically significant depletion of CD19+ B cells in
the HLH cases (3.8 +/- 3.2% vs. 52.6 +/- 4.5%, P < 0. 0001) associated with an
increase of T cells in three cases and of natural killer cells in another. The
histopathological findings included atrophic white pulps, B-cell depletion with
fibrosis and haemosiderosis in all five cases. Despite temporary therapeutic
benefits, three of the HLH patients had a rapidly deteriorating post-splenectomy
course and all three eventually died. These results demonstrate striking
depletion of B cells in the enlarged spleens of children with HLH, which may be
an intrinsic feature of HLH pathogenesis. Further study is needed to establish
the therapeutic value of splenectomy in this disease.
PMID- 10759707
TI - Genetic studies of three Japanese patients with p22-phox-deficient chronic
granulomatous disease: detection of a possible common mutant CYBA allele in Japan
and a genotype-phenotype correlation in these patients.
AB - Chronic granulomatous disease (CGD) is a disorder caused by defects in the NADPH
oxidase responsible for superoxide generation in phagocytes. Cytochrome b558, an
essential component of this enzyme, is a heterodimer formed by a 91 kDa
glycoprotein (gp91-phox) and a 22 kDa polypeptide (p22-phox). Mutations in the
p22-phox gene (CYBA) locus in 16q24 result in one of the rare autosomal recessive
forms of CGD. We performed mutation analysis in three female CGD patients
suspected of having this form of the disease and found two novel mutations in
CYBA. Whereas patient 1 with severe phenotype had a homozygous nonsense mutation
in exon 1 (C-35 --> T, Gln-3 --> stop), patients 2 and 3 with mild phenotype
shared the same homozygous missense mutation in exon 2 (G-98 --> A, Gly-24 -->
Arg). None of the parents of patients 2 and 3 is related. Therefore, this
mutation could be a hot-spot or a common mutation in the Japanese population.
Patients 2 and 3, but not patient 1, were demonstrated to have detectable p22
phox expression and significant granulocyte respiratory burst (ROB) activity. In
this study, we were able to demonstrate an excellent correlation between
genotype, p22-phox expression, ROB activity and clinical phenotype in these
patients.
PMID- 10759708
TI - Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute
promyelocytic leukaemia.
AB - Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other
leukaemias by the high potential for early haemorrhagic death. Several processes
are involved, such as disseminated intravascular coagulation and
hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor)
was identified as a link between coagulation and fibrinolysis. TAFI can be
activated by thrombin, and in its activated form potently attenuates fibrinolysis
by removing C-terminal lysine and arginine residues that are important for the
binding and activation of plasminogen. Activation of TAFI by the coagulation
system results in a down-regulation of fibrinolytic activity and, thereby,
prevents a rapid dissolution of the fibrin clot. To establish whether TAFI was
involved in the severity of the bleeding complications in APL, the TAFI antigen
and activity levels were determined in a group of 15 patients. The TAFI antigen
concentration was normal, but the activity of TAFI was severely reduced in APL by
approximately 60%. The reduction of TAFI activity was most probably caused by the
action of plasmin on TAFI because in vitro experiments revealed that plasmin
slightly reduced antigen levels but severely reduced TAFI activity. The acquired
functional TAFI deficiency in APL may contribute to the severity of the
haemorrhagic diathesis because of the impaired capacity of the coagulation system
to protect the fibrin clot from fibrinolysis.
PMID- 10759709
TI - Octreotide in the treatment of gastrointestinal bleeding caused by angiodysplasia
in two patients with von Willebrand's disease.
AB - Two cases of von Willebrand's disease and angiodysplasia with intractable
gastrointestinal bleeding are presented. Replacement therapy with cryoprecipitate
and variable purity von Willebrand factor (VWF) was ineffective, as were other
treatments including steroids, immunoglobulin and hormonal replacement. Both
patients required massive blood transfusion and product support. The efficacy of
somatostatin and an analogue is described. In one patient, we observed a rise in
von Willebrand factor activity after octreotide infusion.
PMID- 10759710
TI - Treatment of an acute flush reaction caused by subcutaneous r-hirudin with
pegylated hirudin.
AB - We report a patient who was treated with recombinant (r)-hirudin for heparin
induced thrombocytopenia and developed a flush reaction twice upon re-exposure to
25 mg of subcutaneous r-hirudin. Antihirudin IgG antibodies developed. The
patient received 50 mg of PEG-hirudin subcutaneously over 2 days. No side-effects
occurred. The level of IgG antihirudin antibodies increased. Ecarin clotting time
and thrombin inhibition S2238 assay were not influenced by the patient's IgG
antihirudin antibody. PEG-hirudin may be used in patients with intolerance to r
hirudin because of a dissociation of the allergenic and immunogenic properties of
the pegylated drug.
PMID- 10759711
TI - The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a
report on the medical research council UKALLR1 study.
AB - We have examined the toxicity and overall outcome of the Medical Research Council
UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic
leukaemia (ALL). Second remission was achieved in over 95% of patients. Two
patients died during induction and seven patients died of resistant disease. The
overall actuarial event-free survival (EFS) at 5 years for all patients
experiencing a first relapse was 46% (95% CI 40-52). Duration of first remission,
site of relapse, age at diagnosis and sex emerged as factors of prognostic
significance. Five-year EFS was only 7% for children relapsing in the bone marrow
within 2 years of diagnosis, but was 77% for those relapsing without bone marrow
involvement > 2.5 years from diagnosis. All analyses in this report are by
treatment received. For those receiving chemotherapy alone, the 5-year EFS was
48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%;
for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS
was 45%. The groups, however, were not comparable with respect to risk factor
profile, and therefore direct comparison of EFS is misleading. Adjustment for
time to transplant and prognostic factors was used to reduce the effects of
biases between treatment groups, but did not suggest benefit for any particular
treatment. There was failure of our planned randomization scheme in this trial
with only 9% of those eligible being randomized, which highlights the
difficulties in running randomized trials especially in patients who have
relapsed from a previous trial. The optimal treatment for relapsed ALL therefore
remains uncertain. Alternative approaches are clearly needed for those with early
bone marrow relapse if outcome is to improve.
PMID- 10759712
TI - The spectrum of Fusarium infection in immunocompromised patients with
haematological malignancies and in non-immunocompromised patients: a single
institution experience over 10 years.
AB - Fusarium is a newly emerging fungal pathogen associated with significant
morbidity and mortality in the immunocompromised host. We have reviewed our
hospital's experience with Fusarium between 1985 and 1995. Fusarium species were
isolated from 22 specimens, representing 11 patients. Cases were not clustered by
time period. The median age of the patients was 36.5 years (range 17-69 years).
The sources of the organism were 12 skin lesions from eight patients, seven blood
cultures from two patients and one specimen each from a Hickman catheter tip,
nail clippings and a bronchoalveolar lavage. Seven of the patients had
chemotherapy-induced neutropenia when the Fusarium was isolated. Five of them
developed invasive fusarosis during acute leukaemia induction treatment. They
remained neutropenic, and none survived. The other two patients recovered from
neutropenia and were treated successfully for this infection. The remaining four
patients were not neutropenic or immunocompromised. Three grew Fusarium from skin
or nail clippings and one from bronchial alveolar lavage (BAL). There was no
evidence of invasive disease in any of the four. None of them received antifungal
therapy, and they were all alive at last follow-up. We conclude that Fusarium is
a newly emerging infection in neutropenic patients. A high index of suspicion,
especially for skin lesions, will help in early diagnosis before systemic and
visceral dissemination. Excision of the initial focus of infection and antifungal
therapy, aided by speedy neutrophil recovery, are likely to protect patients
threatened with these fatal infections. Fusarium isolated from non-neutropenic,
non-immunosuppressed patients is not significant and does not merit systemic
antifungal treatment.
PMID- 10759713
TI - Spontaneous monoclonal immunoglobulin-secreting peripheral blood mononuclear
cells as a marker of disease severity in multiple myeloma.
AB - Peripheral blood from patients with multiple myeloma (MM) contains a small number
of plasma cells related to the bone marrow tumour cells by their cytoplasmic
immunoglobulin (Ig), their cell membrane antigen expression and/or their gene
rearrangements, but hitherto the monoclonal Ig (M-Ig) production by circulating
cells has not been reported. Using a two-colour ELISPOT assay, Ig-secreting cells
(Ig-SCs) were detected in the blood of 28 MM and five Waldenstrom's
macroglobulinaemia (WM) patients. The number of cells that spontaneously produced
an Ig isotype similar to that of the M-Ig in serum was greater than that of the
other Ig-SCs. MM patients presented an excess of circulating heavy-chain (alpha
or gamma) Ig-SCs (0.38% of the PBMC) with kappa or lambda light chains (0.48%)
compared with the number of cells secreting the other heavy- (0.02%) and light
chain isotypes (0.03%). WM patients also presented high numbers of cells
secreting the mu-heavy-chain isotype (0.66%). The Ig synthesized in vitro was
characterized as monoclonal, and the M-Ig secretory capacity of the peripheral
blood cells was similar to that observed for Ig-SCs from polyclonal activated B
cells in vivo. The number of these monoclonal cells was significantly increased
in patients in an advanced stage of MM (I/II vs. III, P < 0.001) and correlated
with the serum beta-2 microglobulin concentration (r = 0. 69; P < 0.0003). The
number of M-Ig-SCs in MM patients could be a useful marker for evaluating the
progression of multiple myeloma.
PMID- 10759714
TI - Four novel non-random chromosome rearrangements in B-cell chronic lymphocytic
leukaemia: 6p24-25 and 12p12-13 translocations, 4q21 anomalies and monosomy 21.
AB - Nine patients with previously unreported chromosome changes were identified among
209 B-cell chronic lymphocytic leukaemia (CLL) cases: three patients had a
translocation involving 6p24-25; three had a 12p12-13 translocation; two had 4q21
involvement (one with coexisting 6p anomaly); and two had monosomy 21. Interphase
fluorescence in situ hybridization (FISH) detected some cryptic aberrations (+12,
6q-, 17p-, 11q-) in those patients with 6p translocations, whereas only a
cytogenetically undetected 13q14 deletion was found in the remaining cases.
Atypical morphology was noted in six cases, including both cases with monosomy
21, two cases with 6p and 4q21 anomaly and one case with 12p involvement. Four of
these cases also had more than one phenotype deviation with respect to the
classical CLL phenotype. Disease progression after 21-51 months (median 41) was
noted in two cases with 6p and 4q21 involvement and in one case with 12p anomaly
and monosomy 21. We arrived at the following conclusions: (i) 6p24-25 and,
possibly, 4q21 lesions represent non-random events in CLL, occurring in
association with other well-known unbalanced rearrangements; (ii) 12p
rearrangements and monosomy 21 may possibly represent early chromosome defects
that are not associated with the classical DNA gains and losses known to be
present in the majority of CLL; and (iii) atypical morphology and immunophenotype
as well as disease progression were frequently observed in these cases
PMID- 10759715
TI - Constitutive levels of cAMP-dependent protein kinase activity determine
sensitivity of human multidrug-resistant leukaemic cell lines to growth
inhibition and apoptosis by forskolin and tumour necrosis factor alpha.
AB - The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) signal
pathway regulates cell proliferation, differentiation and cell death. It may also
regulate the multidrug resistance (MDR) phenotype in leukaemic cells. These data
showed that MDR1+ K/Dau600 cells exhibited a higher basal level of PKA activity
than MDR- parental cells. The significance of this on tumour necrosis factor
alpha (TNFalpha)-induced apoptosis and cytostasis was investigated further. In
comparison with MDR1- parental cells, K/Dau600 cells had a higher expression of
PKA regulatory subunit RIalpha and nuclear catalytic subunit PKAcalpha. They were
also more susceptible to inhibition of proliferation and induction of apoptosis
by TNFalpha and/or forskolin, but this could be attenuated by H89. An increase in
cAMP was associated with the apoptosis in the K/Dau600 cell line. Forskolin
inactivated NF-kappaB in K/Dau600 cells but not in K562 cl. 6 cells, whereas TNF
activated NF-kappaB in K562 cl.6 cells but not in K/Dau600 cells. 8-Cl-cAMP
exhibited similar inhibitory effects on the proliferation of all of the cell
lines used via its metabolite 8-Cl-adenosine, which indicates that these effects
were independent of residual PKA or cAMP. Therefore, the differential sensitivity
to apoptosis and/or growth inhibition could be mediated via cAMP, partly through
PKA via NF-kappaB and partly by PKA-independent pathways.
PMID- 10759716
TI - Induction of mitochondrial manganese superoxide dismutase confers resistance to
apoptosis in acute myeloblastic leukaemia cells exposed to etoposide.
AB - We investigated the possible roles of mitochondrial manganese superoxide
dismutase (MnSOD) and bcl-2 in etoposide-induced cell death in acute myeloblastic
leukaemia (AML) using two subclones of the OCI/AML-2 cell line, the etoposide
sensitive (ES) and the etoposide-resistant (ER), as models. Cell death after 24 h
exposure to 10 micromol/l etoposide was about 60% and 70% in the ES subclone and
about 20% and 25% in the ER subclone, when analysed by trypan blue and annexin V
respectively. Cytochrome c efflux from mitochondria to cytosol was observed after
4 h of exposure in both subclones, whereas the activation of caspase-3 was not
detectable until after 12 h of exposure in the ES subclone and 24 h of exposure
in the ER subclone, using Western blotting. The decrease in mitochondrial
membrane potential, when analysed by the JC-1 probe fluorocytometrically, also
appeared to take place later in the ER than in the ES subclone. Both subclones
showed evident basal expression of MnSOD and bcl-2 by Western blotting. Etoposide
caused a potent induction of MnSOD, more than 400% at 12 h, in the ER but not in
the ES subclone. No significant change in bcl-2 expression could be observed in
either of the subclones during exposure to etoposide when analysed by Western
blotting or flow cytometry. In conclusion, we suggest that MnSOD might have a
special role in the protection of AML cells against etoposide-induced cell death.
Although unable to influence the cytochrome c efflux to cytosol, MnSOD might
prevent the disruption of mitochondrial membrane potential, which evidently leads
to cell death by releasing various activators of apoptosis.
PMID- 10759717
TI - Effects of antithymocyte globulin on bone marrow CD34+ cells in aplastic anaemia
and myelodysplasia.
AB - The mechanism of action of antithymocyte globulin (ATG) in the treatment of
aplastic anaemia (AA) and myelodysplastic syndromes (MDS) is poorly understood
and may involve many different mechanisms. The aim of this in vitro study was to
investigate further the effect of ATG on haemopoietic progenitor cells. A total
of 16 patients (10 AA and 6 MDS) and 12 normal control subjects were studied.
Purified bone marrow (BM) CD34+ cells were cultured in committed progenitor assay
in the presence of ATG and autologous serum, then scored on day 14 for
granulocyte-monocyte colony-forming units (CFU-GM) and erythroid colonies. ATG
was found to be inhibitory to haemopoietic progenitor cells at high
concentrations (1000 microg/ml and 100 microg/ml). This was confirmed by CD34
FITC and 7AAD staining of purified normal CD34+ cells after overnight incubation
with ATG. In contrast, at lower doses (0.1-10 microg/ml), ATG produced an
increase in colony growth in most normal, MDS and AA BM CD34+ cells. The greatest
effect was in patients with non-severe AA, in whom the greatest increase in CFU
GM was seen at 0.5 microg/ml (P < 0.02) and 0.1 microg/ml (P = 0.02) and
erythroid colonies at 0.1 microg/ml (P < 0.05). Serum ATG levels peaked during
infusion to levels that were found to be toxic to haemopoietic progenitor cells
in vitro and fell thereafter to levels that were associated with the highest
colony numbers (0.1 and 0.5 microg/ml) in vitro. These results suggest that an
increase in haemopoietic progenitor cells by ATG may be one of several important
mechanisms for haematological recovery in AA and MDS.
PMID- 10759718
TI - IgA myeloma of donor origin arising 7 years after allogeneic renal transplant.
AB - We report the case of a 38-year-old man who developed IgA myeloma of donor origin
7 years after allogeneic renal transplant. The diagnosis of multiple myeloma was
unequivocal and based on positive results from serum electrophoresis, skeletal
survey and bone marrow investigations. The donor origin of the myeloma cells was
confirmed by DNA fingerprinting. We believe this is the first reported case of
disseminated multiple myeloma of donor origin developing after allogeneic renal
transplant and, as such, gives some insight into the natural history and biology
of the disease.
PMID- 10759719
TI - Peripheral blood stem cell (PBSC) mobilization and transplantation after
fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the
European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of
the EBMT Chronic Leukaemias Working Party (CLWP).
AB - We performed a survey from 122 centres of the European Group of Blood and Marrow
Transplantation (EBMT) concerning peripheral blood stem cell (PBSC) mobilization
after fludarabine treatment of patients with chronic lymphocytic leukaemia (CLL).
A total of 101 leucaphereses from 29 patients was performed. The median cell
numbers collected were: CD34+ cells, 2.2 x 106/kg (0.1-15.3); granulocyte
macrophage colony-forming units (GM-CFU), 4.29 x 104/kg (0.4-177); and
mononuclear cells, 6.4 x 108/kg (1.3-63). In univariate and multivariate
analyses, the numbers of cells collected were not significantly influenced by the
nature of mobilizing regimen and there was a trend towards the collection of a
higher number of CD34+ cells from patients who received fludarabine only before
mobilization. There was a significant correlation between the median number of
CD34+ cells collected and the number of courses of fludarabine (higher CD34+ cell
numbers were related to more than six courses) and the interval between the last
dose of fludarabine and the start of mobilizing therapy (higher CD34+ cell
numbers were related to a delay > or = 2 months). Sixteen patients have
subsequently undergone autologous transplantation and showed rapid engraftment.
In conclusion, the results reported favour early stem cell mobilization in CLL
patients who are in remission after first-line therapy. However, attention should
be given to the timing of mobilization with respect to the time since the last
dose of fludarabine.
PMID- 10759720
TI - Comparative analyses of megakaryocytes derived from cord blood and bone marrow.
AB - Thrombocytopenia is typically observed in patients undergoing cord blood
transplantation. We hypothesized that delayed recovery of the platelet count
might be caused by defects in the megakaryocytic differentiation pathway of cord
blood progenitors. To test this hypothesis, we compared the features of in vitro
megakaryocytopoiesis between cord blood progenitors and those in bone marrow
cells after isolation of CD34+ cells as progenitors. The proliferative responses
of the progenitors in cord blood are higher than those in bone marrow cells in
the presence of interleukin (IL)-3, stem cell factor (SCF) and thrombopoietin
(TPO). However, the ability to generate mature megakaryocytes was higher in bone
marrow progenitors than in cord blood in the same in vitro culture system, when
examined by the expression of CD41, polyploidy and proplatelet formation.
Furthermore, an earlier induction of c-mpl protein, a receptor for TPO, was
observed in the progenitors from bone marrow than in those from cord blood in the
presence of SCF and IL-3. Therefore, the ability to generate mature
megakaryocytes in bone marrow progenitors is superior to that in cord blood, and
the delayed engraftment of platelets after cord blood transplantation might be
attributed to the features of cord blood megakaryocyte progenitors.
PMID- 10759721
TI - CD34+/CD105+ cells are enriched in primitive circulating progenitors residing in
the G0 phase of the cell cycle and contain all bone marrow and cord blood
CD34+/CD38low/- precursors.
AB - A subset of circulating CD34+ cells was found to express CD105 antigen. Sorting
experiments showed that most granulocyte-macrophage colony-forming units (GM-CFU)
and burst-forming units - erythroid (BFU-E) were retained in the CD34+/CD105-
fraction, whereas rare GM-CFU/BFU-E were generated from CD34+/CD105+ cells.
Megakaryocytic aggregates were entirely retained in the CD34+/CD105+ fraction.
Neutralizing doses of an anti-TGF-beta1 antibody demonstrated CD34+/CD105+ cells
capable of colony-forming activity without any significant effect on CD34+/CD105-
cells. Cloning of secondary colonies revealed that CD34+/CD105+ cells had a
significantly higher secondary cloning efficiency than CD34+/CD105- cells.
CD34+/CD105+ cells had a significantly higher long-term culture-initiating cell
(LTC-IC) frequency than CD34+/CD105- cells. Kinetic analysis showed that 75% of
CD34+/CD105+ cells consisted of DNA 2n G0Ki-67- cells whereas 82% of CD34+/CD105-
were DNA 2n G1Ki-67+ cells, and this latter subset showed a RNA content
consistently higher than CD34+/CD105+ cells. CD34+/CD105+ progenitors were CD25+,
whereas CD34+/CD105- contained a small CD25+ subset. Three-colour analysis of
bone marrow and cord blood CD34+ cells demonstrated that all the CD34+/CD38low/-
primitive precursors were contained in CD34+/CD105+ cells. Extensive
characterization of these CD105+ precursors indicated that they have biological
properties associated with primitive haematopoietic precursors.
PMID- 10759722
TI - Cell cycle distribution of cord blood-derived haematopoietic progenitor cells and
their recruitment into the S-phase of the cell cycle.
AB - The objective of this study was to evaluate the cycling status of cord blood (CB)
derived colony-forming cells (CFC) and long-term culture-initiating cells (LTC
IC), and their recruitment into the S-phase of the cell cycle. By using the
cytosine arabinoside (Ara-C) suicide approach, we found that only small
proportions of both CFC and LTC-IC were in the S-phase of the cell cycle. These
estimates were confirmed by flow cytometric DNA analysis, which showed that 96 +/
2% of CB-derived CD34+ cells were in G0/G1 and only 1.6 +/- 0.4% in the S-phase.
Staining of CD34+ cells with an antistatin monoclonal antibody, a marker of the
G0 phase, indicated that among CD34+ cells with a flow cytometric DNA content
typical of the G0/G1 phase 68 +/- 7% of cells were in the G0 phase of the cell
cycle. Incubation (24 h) with interleukin 3 (IL-3), recombinant human stem cell
factor (SCF) and granulocyte colony-stimulating factor (G-CSF) significantly
increased the proportion of cells in the S-phase for both CFC and LTC-IC without
inducing any loss in numbers. Flow cytometric DNA analysis also showed an
increase in CD34+ cells in the S-phase upon continuous exposure to these
cytokines. Our findings indicate that: (i) very few CB-derived CFC or LTC-IC were
in the S-phase of the cell cycle; (ii) a substantial amount of CD34+ cells with a
flow cytometric DNA content typical of the G0/G1 fraction was cycling, as found
in the G1 phase of the cell cycle; and (iii) 24-h incubation with IL-3, SCF and G
CSF could drive a proportion of progenitor cells into the S-phase without
reducing their number. These data might be useful for gene transfer protocols and
the ex vivo expansion of CB-derived progenitor cells.
PMID- 10759723
TI - Effect of ex vivo cytokine treatment on human cord blood engraftment in NOD-scid
mice.
AB - Umbilical cord blood transplantation is considered an alternative to traditional
bone marrow transplantation for patients who do not have matched sibling donors.
In this study, we examined the effects of ex vivo treatment of human cord blood
cells with cytokine mixtures and assessed the ability of treated cells to engraft
in NOD-scid mice. We incubated the cord blood with a four-factor cytokine mixture
of interleukin (IL)-3, IL-6, IL-11 and stem cell factor, or with a two-factor
cytokine mixture of thrombopoietin and flt-3. Incubation of cord blood for 48 h
with either cytokine mixture did not affect progenitor cell number or
proliferative potential as measured by the high proliferative potential (HPP)
assay. Cytokine-treated cord blood injected into irradiated NOD-scid mice
resulted in multilineage human engraftment. Overall, incubation with cytokines
resulted in variable levels of engraftment with different cord blood samples.
Incubation of cord blood with the four-factor cytokine mixture resulted in
increased survival of irradiated NOD-scid recipients. These results demonstrate
that short-term ex vivo treatment of human progenitor cells gives variable
results on in vivo multipotential capabilities.
PMID- 10759724
TI - Local and systemic effects after adenoviral transfer of the murine granulocyte
macrophage colony-stimulating factor gene into mice.
AB - Vectors encoding immunostimulatory genes are under investigation for their use as
adjuvants for immunotherapy. Granulocyte-macrophage colony-stimulating factor (GM
CSF) is a prominent candidate gene for this approach because this cytokine can
prime immune responses to 'self' tumour or other weak antigens. Prior studies
suggested that GM-CSF induces accumulation and differentiation of antigen
presenting cells, particularly dendritic cells that can initiate immunity. To
evaluate this model in vivo, we performed i.m. and i.p. injections of an
adenovirus vector encoding murine GM-CSF (Ad-mGM-CSF) and evaluated local and
systemic effects. After intramuscular injection, local changes were characterized
by the accumulation of myeloid cells, a subsequent infiltration of lymphocytes
and then myonecrosis. Intraperitoneal injection also induced an accumulation of
myeloid cells, an increase in CD3-positive T and a decrease in B220-positive B
lymphocytes. Expression of the dendritic cell marker CD11c on 48 +/- 9% of the
peritoneal cells (n = 6) along with high levels of surface MHC class II, a
characteristic morphology, and endocytosis of FITC-dextran suggested in vivo
differentiation of dendritic cells after i.p. injection of Ad-mGM-CSF. Systemic
effects were observed after i.m. and i.p. injection of Ad-mGM-CSF. All mice
developed hepatosplenomegaly resulting from extramedullary haematopoiesis. These
changes were specific to GM-CSF as they were not seen in mice injected with an
adenovirus vector without a transgene. Our observations indicate that adenoviral
transfer of GM-CSF is a powerful tool for inducing local and systemic expansion
of haematopoietic cells. The local expansion of myeloid cells displaying signs of
dendritic cell differentiation, as characterized for the peritoneal cell
compartment, can explain the potency of GM-CSF when used as an adjuvant in
genetic immunotherapy.
PMID- 10759725
TI - Transfusion of platelet concentrates cryopreserved with ThromboSol plus low-dose
dimethylsulphoxide in patients with severe thrombocytopenia: a pilot study.
AB - We have recently reported the possibility of supporting the phase of severe
thrombocytopenia after high-dose chemotherapy (HDC) and stem cell transplantation
using 5% dimethylsulphoxide (DMSO)-cryopreserved autologous platelet concentrates
(PCs). The aim of the present study was to evaluate the therapeutic potential of
ThromboSol (a recently developed platelet storage solution) plus PCs
cryopreserved in 2% DMSO in patients undergoing myeloablative chemotherapy and
autologous transplantation. PCs were collected from 14 women with breast cancer
by a single plateletapheresis and cryopreserved in ThromboSol/2% DMSO by either
direct insertion in a -80 degrees C freezer or in liquid nitrogen after computer
controlled rate (CR) freezing. When required, PCs were thawed, centrifuged to
remove the cryoprotectants and transfused. In vitro studies on thawed platelets
showed loss of epitopes of surface glycoproteins and a marked reduction of
functional activity compared with fresh platelets. Transfusion of CR-frozen PCs
was associated with a mean 1 h corrected count increment (CCI) of 9.2 +/- 5.4 x
109/l and only one allogeneic PC was required in this group. In contrast, six out
of seven patients required additional allogeneic transfusions in the -80 degrees
C group (CCI = 2.7 +/- 1.4 x 109/l). ThromboSol-treated PCs have the ability to
overcome thrombocytopenia if processed by a CR freezing protocol, but appear
ineffective when frozen by direct placing at -80 degrees C.
PMID- 10759726
TI - Occult insulinoma.
PMID- 10759728
TI - Committee on publication ethics
PMID- 10759727
TI - Generating an idea: will it be publishable?
PMID- 10759729
TI - An unexpectedly normal-looking adrenal gland.
PMID- 10759730
TI - Non-operative treatment of abdominal gunshot injuries.
AB - BACKGROUND: Non-operative treatment is a management option that challenges the
traditional mandatory laparotomy for abdominal gunshot injuries. METHODS: All
published relevant clinical reports were retrieved by searching through the
Medline database and manually. The theoretical arguments in favour of non
operative management as well as the results of the reviewed reports are analysed
and evaluated. RESULTS AND CONCLUSION: Patients with proven non-penetration of
the abdominal cavity can be offered conservative treatment with a satisfactory
outcome. Greater caution should be exercised in the presence of a documented
visceral injury until the safety of this option has been established by further
clinical trials.
PMID- 10759731
TI - Smoking and disease recurrence after operation for Crohn's disease.
AB - BACKGROUND: There is increasing speculation about the role of smoking in the
pathogenesis of inflammatory bowel diseases. The purpose of this study is to
review the impact of smoking on disease recurrence after operation for Crohn's
disease. METHODS: A Medline-based literature review (1966-1999) was carried out;
ten studies examined the relationship between smoking and disease recurrence
after operation. RESULTS: Approximately half of the patients were smokers at the
time of operation. In most studies smoking significantly increased the risk of
postoperative disease recurrence. Smokers had an approximately twofold increased
risk of recurrence compared with non-smokers and the effect of smoking was dose
dependent. The increased risk of recurrence among smokers was more prominent in
women than in men, and a longer duration of smoking increased the risk of
recurrence. Ex-smokers had a similar recurrence rate to non-smokers and giving up
smoking soon after operation was associated with a lower probability of
recurrence. CONCLUSION: Smoking significantly increases the risk of recurrence of
disease after operation for Crohn's disease, especially in women and heavy
smokers. Encouraging patients to stop smoking is an important part of the
management of Crohn's disease.
PMID- 10759732
TI - Prognostic significance of oestrogen receptor beta in breast cancer.
AB - BACKGROUND: Endocrine therapy for breast cancer is now well established and with
the identification of a second oestrogen receptor, ERbeta, 3 years ago it is
timely to review the possible significance of this receptor in breast cancer
management. METHODS: An up-to-date review of the current literature concerning
the role and possible implications of ERbeta in human breast cancer was
undertaken. RESULTS: Wild-type and variant ERbeta are expressed in human breast
tumours. Expression of ERbeta correlates with accepted prognostic indicators
including lymph node status and tumour grade. Furthermore, levels of ERbeta
messenger RNA alter during carcinogenesis and are upregulated in breast tumours
that develop antioestrogen resistance. CONCLUSION: ERbeta has potential as a
novel clinical prognostic marker in breast cancer, particularly in determining
tumours that are resistant to tamoxifen.
PMID- 10759733
TI - Randomized clinical trial of haemorrhoidectomy under a mixture of local
anaesthesia versus general anaesthesia.
AB - BACKGROUND: Application of a topical anaesthetic agent may facilitate
infiltration of local anaesthetic at haemorrhoidectomy. METHODS: A randomized
clinical trial of 53 consecutive patients requiring elective haemorrhoidectomy
was carried out. One group underwent haemorrhoidectomy under general anaesthesia,
while the second group had topical anaesthetic cream (containing lignocaine and
prilocaine) applied followed by local anaesthetic infiltration for surgical
anaesthesia. RESULTS: There were no differences between the two groups in terms
of operating time, postoperative pain, nausea or vomiting, pain-free interval
after operation, analgesic requirements or patients' satisfaction with the method
of anaesthesia. Postoperative oxygen saturation and pulse rate were similar in
the two groups. CONCLUSION: Topical anaesthetic and local anaesthesia can be used
effectively for haemorrhoidectomy and provide an alternative to general
anaesthesia.
PMID- 10759734
TI - Surgical management of polypoid lesions of the gallbladder.
AB - BACKGROUND: With improvements in ultrasonography more polypoid lesions of the
gallbladder (PLGs) are being detected. The management of these is controversial.
METHODS: The demographic, radiological and pathological data of 38 patients with
ultrasonographically detected PLGs were reviewed. A Medline search for such
lesions was performed and a review of the literature is presented. RESULTS:
Thirty-four patients underwent cholecystectomy and four were advised against or
declined operation. Of the 34 who had cholecystectomy, 11 had macroscopic and
histopathologically proven PLGs. Of these, seven had cholesterol polyps, two had
adenomas, one had a carcinoid tumour and one had an adenocarcinoma of the
gallbladder. One patient had a histopathologically normal gallbladder. The
remainder had chronic cholecystitis with or without gallstones. All of the
patients with neoplastic lesions of the gallbladder had solitary polyps greater
than 1.0 cm in diameter. CONCLUSION: A protocol for the management of
ultrasonographically detected PLGs is proposed. In this protocol it is suggested
that patients with a PLG should undergo surgery if they are symptomatic, or if
the PLG is 1.0 cm or more in diameter.
PMID- 10759735
TI - Regional and para-aortic lymphadenectomy in radical surgery for advanced
gallbladder carcinoma.
AB - BACKGROUND: There have been no reports on the routine use of regional and para
aortic lymphadenectomy for gallbladder cancer. The aim of this study was to
elucidate nodal status, its prognostic influence and the efficacy of
lymphadenectomy. METHODS: A retrospective analysis was made of 60 patients who
underwent radical resection and routine regional and para-aortic lymphadenectomy.
RESULTS: Of the 60 patients, 73 per cent had node-positive disease and 38 per
cent had positive para-aortic nodes. Postoperative survival was extremely poor in
patients with minimal distant metastasis, and similarly in patients with para
aortic disease. The survival of patients with metastasis limited to the regional
nodes was significantly better than that of those with distant metastasis (P =
0.029) or para-aortic disease (P = 0.017) and was not significantly different
from that of patients with no metastasis (P = 0.82). CONCLUSION: Regional and
para-aortic lymphadenectomy provides no survival benefit for patients with para
aortic disease, which has an influence on poor prognosis equivalent to that of
distant metastasis. It has the potential to bring survival benefit only in
selected patients with metastasis limited to the regional nodes. A sampling
biopsy of the para-aortic nodes before starting radical surgery is recommended
because they are involved more frequently than expected.
PMID- 10759736
TI - Pancreaticojejunostomy versus pancreaticogastrostomy in reconstruction following
pancreaticoduodenectomy.
AB - BACKGROUND: Pancreaticogastrostomy (PG) after pancreaticoduodenectomy has been
reported to have a lower incidence of pancreatic fistula than
pancreaticojejunostomy (PJ) but this was not confirmed in a recent prospective
randomized study. METHODS: Different methods of reconstruction after
pancreaticoduodenectomy were used between January 1994 and January 1999 in two
university-affiliated hospitals, PJ (n = 69) in one hospital and PG (n = 73) in
the other. Operations at both hospitals were performed by the same surgical team.
All pancreatic anastomoses were carried out in two layers with pancreatic duct
stents. Pancreatic fistula was identified by the presence of more than 1000
units/l of amylase-rich fluid in the drains 7 days or more after operation, by
radiography from the pancreatic duct stent and by water-soluble contrast upper
gastrointestinal studies. RESULTS: The two groups of patients were similar in
terms of age, sex, findings at preoperative assessment, disease status, operative
time, intraoperative blood loss and nature of non-tumorous pancreatic tissue. The
amylase level in ascites at 7 days after operation was significantly lower after
PG than PJ (P = 0.032). The incidence of pancreatic fistula in the PG group
(zero) was significantly less than that after PJ (13 per cent) (P = 0.014). Intra
abdominal haemorrhage and intra-abdominal abscess occurred in three (4 per cent)
and four patients (6 per cent) respectively, with two hospital deaths (3 per
cent) in the PJ group, but these complications did not occur after PG.
CONCLUSION: This controlled clinical study supports the hypothesis that PG is
safer than PJ, particularly with regard to the incidence of pancreatic fistula.
PMID- 10759737
TI - Changes in pancreatic resection for chronic pancreatitis over 28 years in a
single institution.
AB - BACKGROUND: Because of advances in knowledge over recent years there is reason to
believe that surgical attitudes towards patients with chronic pancreatitis may
have changed. METHODS: Some 547 patients were treated surgically for chronic
pancreatitis from 1971 to June 1998. Anastomoses were performed in 80 per cent
(438 patients) and resections in 20 per cent (109 patients). Indications and type
of operation were analysed, as were mortality and morbidity rates and long-term
follow-up results, in patients undergoing resection both over the period as a
whole and after dividing the series into two subperiods of 14 years. RESULTS: In
the second 14-year period, there was a significant reduction in the percentage of
resections compared with anastomoses (28 per cent (69 of 244 patients) versus 13
per cent (40 of 303); P < 0.0001), and a significant change in the type of
resection with a substantial increase in resections of the head compared with
those of the body and tail. Statistically significant reductions occurred in
operating times, number of units of blood transfused (mean(s.d.) 4.7(3.6) versus
1.2(1.6) units; P = 0.0001) and mean hospital stay (18 versus 14 days for pylorus
preserving and 12 versus 8 days for left pancreatectomy with splenectomy; P < 0.
01); mortality and morbidity rates also tended to decrease, but not
significantly. CONCLUSION: A different pattern has emerged over the years as
regards both the type and number of resections performed.
PMID- 10759738
TI - Functional and morphological changes in the pancreatic remnant following
pancreaticoduodenectomy with pancreaticogastric anastomosis.
AB - BACKGROUND: The aim was to evaluate pancreatic exocrine and endocrine function,
pancreatic atrophy and main pancreatic duct dilatation in the pancreatic remnant
following pancreaticoduodenectomy and pancreaticogastrostomy. METHODS: Nineteen
patients who underwent pancreaticoduodenectomy and pancreaticogastrostomy for
benign or malignant pancreatic tumours with a histologically normal pancreatic
resection margin were studied prospectively. The median interval between
operation and evaluation was 32 (range 12-120) months. Pancreatic exocrine
insufficiency was assessed by measuring 72-h faecal fat concentrations and faecal
1 elastase. Fasting blood glucose, haemoglobin A1c, serum peptide C and insulin
levels were used to assess endocrine function. Pancreatic parenchymal thickness
and main pancreatic duct diameter were measured before operation and at
evaluation using computed tomography (CT). RESULTS: Faecal fat excretion was
raised in 16 of 17 patients; faecal-1 elastase was reduced in all 17 patients.
None of the 17 non-diabetic patients had developed diabetes mellitus at follow
up. A significant decrease in pancreatic parenchymal thickness and increased
dilatation of the main pancreatic duct were observed on CT at evaluation (P =
0.01 and P = 0.01 respectively). Pancreatic atrophy, assessed by subtracting the
diameter of the pancreatic duct from the total gland thickness, tended to develop
over time, but at the limit of statistical significance (P = 0.06). CONCLUSION: A
median of 3 years following pancreaticoduodenectomy and pancreaticogastrostomy,
patients remained free from diabetes but developed marked pancreatic exocrine
insufficiency. Presented in part to the Societe Nationale Francaise de
Gastroenterologie in Nantes, March 1999, and published in abstract form as
Gastroenterol Clin Biol 1999; 23: A81
PMID- 10759739
TI - Bacterial translocation in patients undergoing abdominal aortic aneurysm repair.
AB - BACKGROUND: Bacterial translocation occurs in humans and is associated with an
increased incidence of septic morbidity. The aims of this study were to determine
the prevalence of bacterial translocation in patients undergoing open abdominal
aortic aneurysm (AAA) repair and to identify any association with postoperative
septic complications. METHODS: This was a prospective observational study in
which patients undergoing aneurysm repair were assessed for evidence of bacterial
translocation by culture of a mesenteric lymph node (MLN), small bowel serosal
exudate and thrombus within the aneurysm. All postoperative septic complications
were recorded. RESULTS: A total of 51 patients was studied (40 men, 11 women;
median age 72 years). Enteric bacteria were isolated from the MLNs of five
patients (prevalence of bacterial translocation 10 per cent), one of whom also
yielded growth from the serosal exudate. Septic morbidity occurred in four of
five patients in whom bacterial translocation was identified, compared with nine
of 46 in those without translocation (P = 0.013, Fisher's exact test, mid P). One
patient in whom Escherichia coli was grown from the MLN developed an aortoenteric
fistula, with a coliform species isolated from the graft. CONCLUSION: This study
suggests that bacterial translocation occurs in patients undergoing AAA repair.
It is associated with an increased incidence of postoperative septic morbidity
and provides a possible mechanism for infection of prosthetic aortic grafts.
PMID- 10759740
TI - Comparison of cognitive function and quality of life after endovascular or
conventional aortic aneurysm repair.
AB - INTRODUCTION: The long-term effects of endovascular aortic aneurysm repair on
cognitive function and quality of life are not known. METHODS: The cognitive
function and quality of life of 82 patients undergoing aortic aneurysm repair (34
endovascular and 48 conventional procedures) were assessed before and 6 months
after operation. Cognitive function was quantified using a battery of
psychometric tests. Quality of life was assessed with the Medical Outcomes Short
Form 36 (SF-36) questionnaire. RESULTS: Data at 6 months were available for 78
per cent of patients. As a group the patients showed a significant decline on one
cognitive function test (visual search) and on two domains of the SF-36 (physical
function and vitality) when they were reassessed. There were no significant
differences between patients undergoing endovascular or conventional aneurysm
repair after 6 months in cognitive function or quality of life. CONCLUSION:
Endovascular aneurysm surgery had a similar impact on health-related quality of
life and cognitive function compared with conventional aneurysm repair. Patients
in both groups demonstrated a significant decline in cognitive function.
PMID- 10759741
TI - Aminoguanidine attenuates endotoxin-induced mesenteric vascular hyporeactivity.
AB - BACKGROUND: The aim of this study was to investigate the effects of inducible
nitric oxide synthase inhibition by aminoguanidine on endotoxin-induced reduction
in mesenteric blood flow. METHODS: Twenty Sprague-Dawley rats (180-230 g)
allocated into four groups were administered either Escherichia coli endotoxin 1
mg/kg intraperitoneally or its solvent saline and were pretreated with either
aminoguanidine (15 mg/kg intraperitoneally 20 min before and 2 h after endotoxin
injection) or saline. Some 4 h after endotoxin injection, animals were
anaesthetized, arterial blood pressure and mesenteric blood flow were measured
and the resistance in the mesenteric vascular beds was then calculated. The
effect of phenylephrine (1-30 microg/kg intravenously) on these parameters was
also investigated. RESULTS: Endotoxin did not significantly modify the mean
arterial blood pressure but decreased mesenteric blood flow by increasing the
vascular resistance (mean(s.e.m.) 7.8(1.0) versus 13.7(1.2) mmHg per min per ml
for control versus endotoxin groups; n = 5, P = 0.0099). Aminoguanidine alone had
no effect on either the mean arterial blood pressure or mesenteric blood flow,
but it completely blocked the effects of endotoxin. On the other hand, endotoxin
significantly attenuated the responsiveness to phenylephrine which was restored
by aminoguanidine. CONCLUSION: The present results indicate that endotoxin
decreases the mesenteric vascular blood flow by increasing vascular resistance
and decreases responsiveness to phenylephrine. The effects of endotoxin were
inhibited by aminoguanidine. The mesenteric vasoconstriction in response to
endotoxin might not be explained by the overproduction of nitric oxide; other
actions of aminoguanidine may explain its inhibitory effect. Presented in part to
the 10th Annual Meeting of the Surgical Infection Society - Europe, Istanbul,
Turkey, May 1997
PMID- 10759742
TI - Arterial intervention and reduction in amputation for chronic critical leg
ischaemia.
AB - BACKGROUND: Untreated chronic critical leg ischaemia (CLI) usually leads to an
amputation or death of a patient. Surgical and endovascular interventions may
improve arterial flow. Long infrainguinal reconstruction may be the most useful
method for preventing amputations. The value of different reconstruction methods
was assessed by their impact on amputation incidence. METHODS: A nationwide 2
year analysis of the incidence of major amputations and reconstructions for CLI
was done in Finland (population 5.1 million). Incidences were compared in
hospital regions with more than 150 000 inhabitants. RESULTS: The overall
amputation incidence was 216 per million inhabitants per year. The corresponding
incidence of arterial reconstructions was 203 per million inhabitants per year.
There were large variations in the incidence of amputations and reconstructions;
20-fold differences in infrapopliteal surgical reconstructions and 30-fold
differences in endovascular procedures were found. There was a correlation
between a high incidence of infrapopliteal surgical reconstructions and a low
incidence of amputations. This correlation was found for below-knee amputations
only. CONCLUSION: These results suggest that long surgical reconstructions
improving perfusion directly to the ischaemic tissue can improve leg salvage.
PMID- 10759743
TI - Near-infrared spectroscopy grades the severity of intermittent claudication in
diabetics more accurately than ankle pressure measurement.
AB - BACKGROUND: The aim of this study was to evaluate near-infrared spectroscopy
(NIRS), combined with a treadmill-walking test, as a method of assessment of
intermittent claudication (IC) in diabetic patients. METHODS: Some 208
symptomatic legs in 153 consecutive patients who complained of calf IC due to
atherosclerotic disease were studied with NIRS and resting ankle : brachial
pressure index (ABPI). RESULTS: There was good reproducibility of NIRS
measurements. Three distinct types of IC were detected by NIRS. ABPI was
significantly different between these three types in non-diabetic patients, but
could not grade the severity of IC in diabetic patients. Recovery time (RT) of
muscle oxygenation differentiated more accurately between severe and moderate
claudication than ABPI in diabetics, although RT and ABPI had similar accuracy in
non-diabetics. There was a significant correlation between RT and ABPI in non
diabetic patients and patients who had been diabetic for less than 10 years,
while there was no correlation in patients who had had diabetes for over 10
years. CONCLUSION: Measurement of muscle oxygenation during exercise by NIRS
graded the severity of IC in diabetic patients more accurately than resting ABPI.
An abstract based on this paper was presented to the symposium of the 18th World
Congress of the International Union of Angiology in Tokyo, Japan, September 1998
PMID- 10759744
TI - Morbidity and mortality of inadvertent enterotomy during adhesiotomy.
AB - BACKGROUND: Inadvertent enterotomy is a feared complication of adhesiotomy during
abdominal reoperation. The nature and extent of this adhesion-associated problem
are unknown. METHODS: The records of all patients who underwent reoperation
between July 1995 and September 1997 were reviewed retrospectively for
inadvertent enterotomy, risk factors were analysed using univariate and
multivariate parameters, and postoperative morbidity and mortality rates were
assessed. RESULTS: Inadvertent enterotomy occurred in 52 (19 per cent) of 270
reoperations. Dividing adhesions in the lower abdomen and pelvis, in particular,
caused bowel injury. In univariate analysis body mass index was significantly
higher in patients with inadvertent enterotomy (mean(s.d.) 25.5(4.6) kg/m2 ) than
in those without enterotomy (21.9(4.3) kg/m2 ) (P < 0.03). Patient age and three
or more previous laparotomies appeared to be independent parameters predicting
inadvertent enterotomy (odds ratio (95 per cent confidence interval) 1.9 (1.3
2.7) and 10.4 (5.0-21.6) respectively; P < 0.001). Patients with inadvertent
enterotomy had significantly more postoperative complications (P < 0.01) and
urgent relaparotomies (P < 0.001), a higher rate of admission to the intensive
care unit (P < 0.001) and parenteral nutrition usage (P < 0.001), and a longer
postoperative hospital stay (P < 0.001). CONCLUSION: The incidence of inadvertent
enterotomy during reoperation is high. This adhesion-related complication has an
impact on postoperative morbidity
PMID- 10759745
TI - Audit of time to emergency trauma laparotomy.
AB - BACKGROUND: An analysis of the process of care may improve quality of care within
a trauma system. Early operative control of haemorrhage is vital and any delay
before surgery may adversely affect outcome. METHODS: Times from activation of
the aeromedical team to arrival in the emergency department and the operating
room for patients with liver or spleen injury were analysed to identify factors
that delayed laparotomy. These results were compared with those of a national
database. RESULTS: The median time from emergency call to operation was 127 min
(140 min for blunt and 86 min for penetrating injuries). Time from arrival in the
emergency department to the operating room was 54 min (56 min for blunt and 37
min for penetrating injuries). An audit filter, set at the upper quartile of the
emergency call to operating room time, selected 21 patients whose records were
examined; five correctable delays were identified. Compared with the national
trauma database, these patients had longer on-scene times, but significantly
shorter times to operation from the emergency call (127 versus 161 min) and
arrival at the emergency department (54 versus 115 min), although the patients
were more severely injured (median Injury Severity Score 34 versus 24).
CONCLUSION: The time to emergency trauma laparotomy may be used effectively as an
audit of process for the clinical governance of a trauma system. Presented to the
British Trauma Society, Bath, October 1997 and the Faculty of Accident and
Emergency Medicine, Glasgow, December 1997, and published in abstract form as J
Accid Emerg Med 1998; 15: 134
PMID- 10759746
TI - Belching and bloating: facts and fantasy after antireflux surgery.
AB - BACKGROUND: Fundoplication is commonly complicated by belching difficulty and
abdominal bloating. Postoperative belching ability, however, is difficult to
assess; subjective patient reporting is often used but may be unreliable.
Manometric measurement of the gastro-oesophageal 'common cavity' is an objective
marker of gastro-oesophageal gas reflux. METHODS: Twenty patients who had
undergone Nissen fundoplication and 11 healthy controls underwent oesophageal
manometry at rest and during gastric distension for 10 min with 750 ml of gas.
RESULTS: Half of the patients reported an inability to belch; the other half
reported varying degrees of belching difficulty, most of whom were rarely able to
relieve bloating by belching. During gastric distension, none of the patients had
transient lower oesophageal sphincter relaxation, while the controls had a median
of 1 (range 0-1). Patients had fewer common cavities than controls; however, none
of the belch urges experienced during gastric distension in patients was
associated with a common cavity, compared with 48 per cent in controls.
CONCLUSION: After fundoplication, patients do not belch as a result of gastro
oesophageal gas reflux; rather it may be due to oesophagopharyngeal reflux of
swallowed air. Subjective reporting of belching ability is inaccurate and
manometric measurement of common cavities provides a better means of assessment.
PMID- 10759747
TI - Laparoscopic needle catheter jejunostomy.
PMID- 10759748
TI - Reliability of sentinel lymph node biopsy for staging melanoma.
AB - BACKGROUND: The aim of this study was to evaluate the reliability of sentinel
lymph node biopsy for staging melanoma. METHODS: Two hundred consecutive patients
with a cutaneous melanoma of at least 1. 0 mm Breslow thickness, without palpable
regional lymph nodes, were included from 1993 in a prospective cohort study in a
single tertiary care hospital. One day after lymphoscintigraphy, sentinel node
biopsy was performed, guided by a gamma probe and patent blue dye. Lymph node
dissection was performed only if metastasis was found in a sentinel node. Median
follow-up was 32 (range 3-61) months. No patient was lost to follow-up. RESULTS:
A sentinel node was removed in 199 of 200 patients (mean 2.2 nodes per patient).
Forty-eight patients (24 per cent) had metastasis in a sentinel node. Fifteen
patients developed recurrence after removal of a tumour-negative sentinel node;
six relapsed in the previously mapped basin (false-negative rate 11 per cent (six
of 54)). The overall survival at 3 years was 93 per cent if the sentinel node was
negative and 67 per cent if it was positive. Sentinel node status and Breslow
thickness were strong predictors of recurrence and survival. Minor complications
were seen in 18 patients. CONCLUSION: The sentinel node status was a strong
prognostic factor, even with a false-negative rate of 11 per cent. Published in
abstract form as Eur J Nucl Med 1999; 26(Suppl): S57
PMID- 10759749
TI - The parameters of early language screening.
PMID- 10759750
TI - Screening for developmental language disability in 3-year-old children.
Experiences from a field study in a Swedish municipality.
AB - This study evaluates a screening instrument for identification of severe
developmental language disability (DLD) in 3-year-old children, which is used as
a routine assessment at several child health centres (CHCs) in Sweden. The
results are reported in terms of clinical outcome (false- and true-positive
rates), kind and extent of DLD, signs of comorbidity and relation between nurses'
and parents' observations. More than 60 CHC nurses, all with experience of the
screening instrument, assessed in all 2359 3-year-old children (98% of the whole
population) by direct observation of their language comprehension, language
production and level of co-operation. In addition to the screening parents
answered a questionnaire. Children who failed the screening had their hearing
assessed and were clinically examined by trained speech and language therapists.
Forty-four (34 boys and ten girls) of the 65 referred children were clinically
examined. Apart from two false-positive cases most of them were diagnosed as
generally and severely language disabled. According to the nurses' observations
attention deficit was common among the referred boys, which was later confirmed
by the speech therapist in two-thirds of them. Agreement between nurses and
parents was poor and only half of the parents were concerned about their child's
language development. In the light of this result, continued application of the
screening and the use of parent questionnaires is discussed.
PMID- 10759751
TI - An investigation into aspects of the Mayo early language screening test.
AB - The concurrent validity and inter-tester agreement on the Mayo early language
screening test (MELST), and the concurrent validity of parental anxiety about
speech and language development as a screening measure were investigated. A
sample (aged 18 months to 5 years) comprising 120 children referred to the Mayo
speech and language therapy department during 1995 and 80 controls, was assessed
on the MELST by their local public health nurse. Within a calendar month each
child was reassessed on the MELST by the therapist, who also administered the
Reynell developmental language scales (RDLS) and the Edinburgh articulation test
(EAT) as criterion measures. Overall, the MELST achieved moderately high
sensitivity and specificity measures. Phonological problems were identified with
more accuracy than language problems and the test was equally sensitive to
impairments in comprehension and expression. The test tended to over-refer and
was least accurate in screening the language skills of children at the highest
age level (4-5 years). A significant association was found between parental
concern and pass/failure on each of the MELST, RDLS and EAT. As a screening
measure, parental anxiety achieved high sensitivity, moderate specificity and a
moderate positive predictive value. However, it also tended to over-refer, and
was also least accurate in identifying speech and/or language disorders at the
highest age level. Moderately high inter-tester agreement measures were found,
with greater agreement between scoring for controls than referrals. The phonology
sections were scored significantly higher by the public health nurses than by the
therapist. The results of this study imply that the MELST is sufficiently
accurate and reliable to recommend its continued use in child surveillance
programmes.
PMID- 10759752
TI - Detecting language disorders in 4-year-old French children. An application of the
ERTL-4.
AB - This paper discusses the development of the ERTL-4 (Epreuve de reperage des
troubles du langage lors du bilan medical de l'enfant de quatre ans), a measure
developed in Nancy, France specifically for the purpose of identifying children
with language difficulties in the 3.9-4.6 years age range. The test has been
designed to identify 10-15% of the population and allows the assessing primary
care doctor to ascertain whether difficulties occur in language, voice, fluency,
hearing or perception on the basis of a 5-min assessment.
PMID- 10759753
TI - Evidence-based approach to developmental and behavioural surveillance using
parents' concerns.
AB - Half of all children with disabilities are not identified before school entrance,
which precludes their participation in early intervention programs. Such programs
have known value in reducing high school drop-out rates, increasing employment,
delaying child-bearing and reducing criminal behaviour. Although there are many
screening tests that can greatly improve detection rates, these have not been
popular in primary care due to test length, difficulty managing children's
behaviour, etc. An alternative is to carefully elicit and interpret parents'
concerns. Research shows that parents' concerns are as accurate as quality
screening tests and that parents are equally able to raise important concerns
regardless of differences in education and child-rearing experience. Parents'
concerns can be elicited quickly and 92% of parents can answer questions in
writing while in exam or waiting rooms. Unlike screening tests, use of parents'
concerns facilitates an evidenced-based approach to comprehensive surveillance
and aids in making a range of other important decisions about children's
developmental and behavioural needs. These include when to: offer suggestions on
developmental promotion; watch children more vigilantly; screen for emotional and
behavioural problems; advise families about behaviour management; offer
reassurance and routine monitoring of development that is likely normal;
administer a second screening test; or refer for additional testing and the kinds
of testing needed.
PMID- 10759754
TI - Early detection of speech and language delays in the Netherlands. The case for
integrating primary and secondary prevention.
AB - The early detection of speech and language delays has been an important feature
of the child health services in the Netherlands for some 15 years. During this
period ideas about both the purpose of screening and the methods themselves have
changed considerably. There are four key outstanding issues: What is the best age
to identify children? What screening measures are available? How can we detect
speech and language delays in multilingual children? Which groups are best able
to detect speech and language difficulties: parents, teachers, playgroup leaders,
doctors, nurses, or speech and language therapists? These questions are
influenced by social, demographic developments and an increase in the
understanding of language delay. This article examines the Dutch solutions to
these problems. The conclusion reached is that early language screening can only
be part of the answer to early detection both because the available measures are
not yet sufficiently accurate and because the growing group of multilingual
children (e.g. in Amsterdam more than 50% of the children under the age of 4
years are multilingual) makes the application of specific measures at a
population level unworkable. An alternative method is suggested, namely primary
prevention by giving information and support to parents, playgroup leaders,
doctors, etc.
PMID- 10759755
TI - Introduction to immunodeficiency reviews
PMID- 10759756
TI - The Wiskott-Aldrich syndrome.
PMID- 10759757
TI - The mouth--an accessible region for gluten challenge.
PMID- 10759758
TI - Effect of IL-5, glucocorticoid, and Fas ligation on Bcl-2 homologue expression
and caspase activation in circulating human eosinophils.
AB - IL-5 is a potent eosinophil viability-enhancing factor that has been strongly
implicated in the pathogenesis of IgE-mediated inflammation in vivo. Recently
published data have suggested that IL-5 (and related cytokines) may act by
altering the expression of the anti-apoptotic regulator Bcl-2 or its homologues,
but this is controversial. The behaviour of the recently described pro-apoptotic
cysteine proteases (caspases) in eosinophils after IL-5 treatment has not been
explored. We examined the effect of IL-5 on the expression of four major Bcl-2
homologues, as well as on the expression/activation of key members of the caspase
cell death cascade in cultured circulating human eosinophils. The effect of
relevant inducers of eosinophil apoptosis (glucocorticoid and Fas ligation) on
these regulatory proteins was also examined. We observed baseline expression of
the anti-apoptotic Mcl-1 and pro-apoptotic Bax proteins in immunoblots of
eosinophil lysates, but not Bcl-x, Bcl-2. IL-5 treatment had the effect of
maintaining this basal level of expression over time without altering the balance
of Bcl-2 homologues. The (upstream) caspase 8 and (downstream) caspase 3
proenzymes were detected in eosinophils at baseline, and were processed during
spontaneous and stimulated eosinophil death. IL-5 completely blocked caspase
processing in spontaneous and dexamethasone-induced cell death, and significantly
slowed processing during Fas ligation. Our data do not support the theory that IL
5 acts by altering the balance of anti-apoptotic and pro-apoptotic Bcl-2
homologues, but suggest that it may act by regulating activation of the caspase
cell death cascade.
PMID- 10759759
TI - IL-17 regulates gene expression and protein synthesis of the complement system,
C3 and factor B, in skin fibroblasts.
AB - Human IL-17 is a cytokine secreted by CD4+-activated memory T cells with the
profile of effects of a Th1 cytokine. The effects of IL-17 on many cellular
constituents of joints suggest that it may participate in inflammatory joint
diseases. Proteins of the complement system are known to be regulated by pro- and
anti-inflammatory cytokines. The purpose of this work was to study the effect of
IL-17 alone and combined with tumour necrosis factor (TNF) on the expression and
synthesis of factor B and C3. Fibroblasts were stimulated with the relevant
cytokine or cytokines, pulse labelled with 35S-methionine, and the newly
synthesized proteins were immunoprecipitated and subjected to SDS-PAGE. Gene
expression was determined by Northern blot analysis. IL-17 10 ng/ml induced
increases in gene expression and protein synthesis of C3, 2.25 +/- 0.26- and 2.7
+/- 0.7-fold, respectively with concomitant non-significant effects on factor B,
1.5 +/- 0.45- and 2.2 +/- 1. 2-fold, respectively. When both IL-17 and TNF were
present simultaneously, the synthesis of factor B increased by 85% more than the
expected additive effects of these cytokines separately, while for C3 the effect
of both cytokines was 19% lower than the expected additive effect
(observed/expected = 0.81). IL-4 reduced the synergistic effect by 50%. We
conclude that IL-17 has a regulatory role on C3 expression and synthesis and an
amplifying effect on TNF-induced factor B synthesis. Taken together with the
evidence that TNF is a major cytokine involved in the inflammation of rheumatoid
arthritis, it suggests that IL-17 has a proinflammatory role in the inflammation
process of joints. The distinct effects of IL-4, IL-17 and TNF on the synthesis
of factor B in fibroblasts suggest that factor B and the alternative pathway of
the complement system may play an important role in joint inflammation.
PMID- 10759760
TI - Cellular localization of complement C3 and C4 transcripts in intestinal specimens
from patients with Crohn's disease.
AB - It has been suggested that the increase in C3 and C4 levels in jejunal perfusates
of patients with Crohn's disease (CD) results from local intestinal synthesis of
complement. The present study evaluated the expression of these complement genes
in inflamed tissues from patients with CD. Surgically resected specimens from
patients with CD and control tissue obtained from subjects with adenocarcinoma of
the colon were evaluated for C3 and C4 gene expression by the use of 35S-labelled
anti-sense RNA probes. All tissue samples, diseased and normal tissue, expressed
C4 mRNA throughout in the intestinal epithelium. C3 mRNA was not detected in
epithelial cells in histologically normal tissue, but in diseased specimens there
was a focal distribution of C3 mRNA in epithelial cells of the crypts, but not in
villous epithelium. Focal C3 gene expression correlated with crypt abscess
formation and the presence of polymorphonuclear leucocytes in the lumen of the
crypts. In addition, C3 mRNA was also found in macrophages of the submucosa.
These macrophages were CD68+, fusiform with faint cytoplasm and morphologically
different from the large rounded lamina propria macrophages, which do not express
C3 mRNA. Multinucleated giant cells did not express either C3 or C4 genes. In
addition to its presence in intestinal epithelium, C4 mRNA was also expressed in
mast cells, which however did not express C3 mRNA. These observations identify
cells in the intestinal wall expressing complement genes and support the
hypothesis that there is local regulated production of complement in the
intestine of patients with CD, and subsequent complement activation may
contribute to the inflammatory process.
PMID- 10759761
TI - Local challenge of oral mucosa with gliadin in patients with coeliac disease.
AB - In coeliac disease, gluten-containing diet challenges over many years are
sometimes required for diagnosis, especially if the initial diagnosis was
equivocal. The rectal gluten challenge has been proposed to simplify coeliac
disease diagnosis. We were interested in studying whether the oral mucosa could
be used for local challenge with gliadin as an aid in finalizing the diagnosis of
coeliac disease. The study groups consisted of 37 treated coeliac disease
patients and 10 controls. The challenges on the oral mucosa were performed either
supramucosally with gliadin powder (coeliac disease patients) or by submucosal
injection of dissolved gliadin (10 microg/ml) (coeliac disease patients and
controls). A control challenge with submucosal gliadin solvent was made in the
coeliac disease patients. B and T cells, mast cells and T cell subsets were
counted and HLA-DR expression was determined. Biopsies were taken from each
provoked area 24 h post-challenge. A significant increase in the number of CD4+
lymphocytes in the lamina propria (observed in 27/37 patients), but a decrease in
the number of mast cells was observed in treated coeliac disease patients after
submucosal challenge with gliadin. Following supramucosal challenge with gliadin
the counts of intraepithelial CD4+ (in 25/37 patients) and CD8+ T cells (in 27/37
patients) increased significantly and the number of CD4+ T cells in the lamina
propria was also significantly increased. Control subjects were tested by
submucosal gliadin challenge and no significant changes in the number of cells
were observed. HLA-DR expression did not show increased positivity in coeliac
disease patients on submucosal challenge. For the first time the oral mucosa has
been used for immunological testing and shown to react to gliadin challenge in
coeliac disease patients. Recruitment of T cells upon submucosal gliadin
challenge occurred towards the lamina propria, whereas it occurred towards the
epithelium in supramucosal gliadin challenge. The numbers of T cells increased in
the lamina propria after submucosal challenge. The results suggest that local
oral challenge with gliadin may be used as a diagnostic method in coeliac
disease; however, further studies in untreated coeliac disease patients are
needed to evaluate the usefulness of this method.
PMID- 10759762
TI - Oral administration of antigens from intestinal flora anaerobic bacteria reduces
the severity of experimental acute colitis in BALB/c mice.
AB - Homeostasis between indigenous intestinal flora and host response may be broken
in inflammatory bowel disease. The present study explores whether repeated oral
administration of intestinal flora antigens can protect mice against dextran
sodium sulphate (DSS)-induced colitis. Sonicates of Gram-positive, Gram-negative,
or anaerobic resident bacteria isolated from mouse intestinal flora were fed to
BALB/c mice by gastric gavage, with or without cholera toxin. After four weekly
doses of 1 mg of these antigen preparations (or of PBS as control), DSS colitis
was induced. One week later colitis was evaluated by clinical scores and
histology. Mice fed a pool of the three sonicates had decreased inflammation
scores (5 (1-14); median (range)) compared with PBS-fed control animals (15 (7
19); P < 0.05). Decreased inflammation was observed in mice fed anaerobic
bacteria antigens (7 (6-11); P < 0.05 versus control), but not in mice fed a pool
of Gram-positive and -negative sonicates (16 (12-16)). Inflammation scores of
mice fed antigens with cholera toxin were similar to those of PBS-fed control
animals. DSS-induced colitis can be suppressed by oral administration of normal
intestinal flora antigens containing anaerobes.
PMID- 10759763
TI - Therapeutic effect of intracolonically administered nuclear factor kappa B (p65)
antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis.
AB - Cytokines such as IL-1, tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8
are increased in inflamed colonic mucosa after administration of mouse DSS.
Nuclear factor kappaB (NF-kappaB) is a transcription factor which regulates the
expression of these cytokine genes. The effect of intracolonically administered
NF-kappaB (p65) antisense phosphorothioate oligonucleotide was examined in mouse
DSS-induced colitis using drinking water containing 5% DSS. When antisense
oligonucleotide was given on day 0, the disease activity index (DAI) representing
clinical symptoms improved and the histological score decreased; furthermore, IL
1, IL-6, and TNF-alpha concentrations in rectal mucosa were lower compared with
the control group. Clinical and histological improvement was also observed when
antisense oligonucleotide was begun on day 2 but not on day 7. In addition, the
distribution of antisense oligonucleotides was investigated by confocal laser
microscopy. In colonic mucosa, oligonucleotides were predominantly localized to
cells in the lamina propria, but also in the epithelium. Western blot analysis
using homogenized rectal mucosa showed the decreased expression of NF-kappaB p65
in the antisense oligonucleotide-treated group, although it was increased in the
colitis group. These results suggest that intracolonic administration of NF
kappaB antisense oligonucleotide may be effective in ulcerative colitis.
PMID- 10759764
TI - Nuclear factor-kappa B activity and intestinal inflammation in dextran sulphate
sodium (DSS)-induced colitis in mice is suppressed by gliotoxin.
AB - In acute DSS-induced colitis nuclear factor (NF)-kappaB-dependent inflammatory
cytokines including IL-1 and tumour necrosis factor-alpha (TNF-alpha) are up
regulated. Here we examined the effects of gliotoxin, a fungal metabolite known
to inhibit NF-kappaB activity, on cytokine production by a mouse cell system in
vitro and on intestinal inflammation and NF-kappaB activation in vivo. In vitro
gliotoxin decreased TNF-alpha gene expression and protein production by RAW-264.7
mouse macrophage-like cells stimulated with lipopolysaccharide. In vivo,
gliotoxin treatment of mice was begun on day 3 of 5% DSS application dissolved in
the drinking water and continued until day 8. Gliotoxin treatment dose
dependently down-regulated colonic inflammation as assessed histologically and in
parallel there was a suppression of colonic TNF-alpha and IL-1alpha mRNA
expression on day 8 as analysed by semiquantitative reverse transcriptase
polymerase chain reaction (P < 0.01). Furthermore, colonic NF-kappaB DNA-binding
activity was increased in DSS-induced colitis and was suppressed by gliotoxin.
These results demonstrate the essential role of NF-kappaB in DSS-induced colitis
and indicate a molecular approach to the treatment of intestinal inflammatory
disorders.
PMID- 10759765
TI - Cultured human monocytes secrete fibronectin in response to activation by
proinflammatory cytokines.
AB - We studied the effects of the cytokines IL-1alpha, IL-6, tumour necrosis factor
alpha (TNF-alpha), IL-4, IL-10, IL-13 and transforming growth factor-beta (TGF
beta) on fibronectin (FN) production by cultured-human monocytes. IL-1alpha, IL-6
and TNF-alpha all increased FN production, an indicator of monocyte activation.
These cytokines increased FN production in a dose-dependent fashion, with a 4-h
treatment being sufficient to measure FN production by radioimmunoassay.
Conversely, IL-4, IL-10 and IL-13 strongly inhibited cytokine-induced FN
production, while TGF-beta only partially inhibited FN production. The
combination of suboptimal doses of cytokines (IL-1alpha + IL-6, IL-1alpha + TNF
alpha, IL-6 + TNF-alpha), which could not singly induce substantial amounts of
FN, were able to induce FN production by cultured monocytes. Northern blot
analysis with a cDNA specific for FN confirmed the expression of FN mRNA in
cultured monocytes stimulated with a single cytokine or a combination of
cytokines. Our data demonstrate that monocytes may not always require high
concentrations of cytokines for activation in vitro, and that the synergistic or
additive action of low levels of cytokines on monocyte activation may be
sufficient to promote immune or inflammatory reactions. Our data also suggest
that certain T cell cytokines may regulate monocyte activation.
PMID- 10759766
TI - Thromboxane A2 (TXA2) receptor blockade suppresses monocyte chemoattractant
protein-1 (MCP-1) expression by stimulated vascular endothelial cells.
AB - In a previous study, it was reported that stimulation with a TXA2 receptor
agonist, U46619, augments the expression of adhesion molecules by human umbilical
vein endothelial cells (HUVEC). In the present study we showed that U46619
augments the expression of MCP-1 in HUVEC, both at the protein and mRNA levels.
Pretreatment with TXA2 receptor antagonists greatly diminishes the extent of
tumour necrosis factor-alpha (TNF-alpha)-, platelet-activating factor (PAF)-, or
U46619-induced mRNA accumulation and production of MCP-1. Protein kinase C (PKC)
inhibitors diminish U46619-induced mRNA accumulation and production of MCP-1.
NAC, which inhibits nuclear factor kappaB (NF-kappaB) activation and activating
protein 1 (AP-1) binding activity, inhibits the expression of MCP-1 at the
protein and mRNA levels. These results indicate that in HUVEC stimulation via the
TXA2 receptors augments MCP-1 production by induction of the NF-kappaB and AP-1
binding activity through the PKC system.
PMID- 10759767
TI - Effects of anti-rheumatic gold salts on NF-kappa B mobilization and tumour
necrosis factor-alpha (TNF-alpha)-induced neutrophil-dependent cytotoxicity for
human endothelial cells.
AB - We have previously shown that the gold-containing disease-modifying anti
rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce
human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and
neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion
molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E
selectin. Since tight adhesion is critical for PMN to damage EC, we tested
whether these drugs modulated human PMN-mediated injury to TNF-alpha-activated
HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-alpha caused
a prominent PMN-mediated cytotoxicity that was dose-dependently reduced when AF
and GSTM were added to the assay system. We also found that a potent inhibitor of
NF-kappaB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired
TNF-alpha-induced cytotoxicity, indicating a role of NF-kappaB activation in
cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF
alpha-induced NF-kappaB activation this was measured in HUVEC nuclear extracts by
an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNF-alpha
induced NF-kappaB activation in HUVEC. Thus, in this in vitro model of
vasculitis, AF and GSTM dose dependently reduced TNF-alpha-mediated neutrophil
dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-kappaB
mobilization, thereby providing possible mechanisms for effects of AF and GSTM.
PMID- 10759768
TI - Cross-reactive epitopes and HLA-restriction elements in human T cell recognition
of the Mycobacterium leprae 18-kD heat shock protein.
AB - We have previously demonstrated that the Mycobacterium leprae 18-kD heat shock
protein (HSP18) is represented among the antigenic targets of human T cell
responses induced by M. leprae immunization and that the peptide 38-50 serves as
an immunodominant epitope recognized by CD4+ T cell clones. By using peripheral
blood mononuclear cells and T cell lines from the same donor group, we have in
this study shown that the M. leprae HSP18 and peptide 38-50 were recognized by
memory T cells 8 years after immunization with M. leprae. The finding that M.
bovis BCG-induced T cell lines responded to M. leprae HSP18, but not to the
peptide 38-50, suggested the existence of additional T cell epitopes of a cross
reactive nature. Consistent with this, testing of the T cell lines for
proliferative responses to the complete HSP18 molecule, truncated HSP18 (amino
acid (aa) residues 38-148) and overlapping synthetic peptides, made it possible
to identify two cross-reactive epitope regions defined by aa residues 1-38 and 41
55. While peptide 38-50-reactive T cell clones showed limited cross-reactivity by
responding to M. leprae, M. avium and M. scrofulaceum, the T cell lines specific
to the epitopes 1-38 and 41-55 were broadly cross-reactive, as demonstrated by
their response to M. leprae, M. tuberculosis complex, M. avium and other
mycobacteria. MHC restriction analysis of the HSP18-responding T cell lines
showed that the epitopes 1-38 and 38-50 were presented by one of the two HLA-DR
molecules expressed from self HLA-DRB1 genes, whereas the epitope 41-55 was
recognized in the presence of autologous as well as HLA-DR and HLA-DQ mismatched
allogeneic antigen-presenting cells. The results obtained in this study made it
possible to identify cross-reactive T cell epitopes of the M. leprae HSP18, and
provide an explanation for T cell recognition of this antigen in individuals
infected with species of the M. tuberculosis complex or environmental
mycobacteria.
PMID- 10759769
TI - Interaction between chronically HIV-infected promonocytic cells and human
umbilical vein endothelial cells: role of proinflammatory cytokines and
chemokines in viral expression modulation.
AB - HIV type 1 expression was significantly up-regulated in chronically infected
promonocytic cell line (U1) co-cultured with human umbilical vein endothelial
cells (HUVEC). Virus replication, evaluated as supernatant p24 release, was
higher when U1 were co-cultured with IL-1beta-activated HUVEC than with
unstimulated HUVEC. When non-adherent U1 were removed from co-cultures, the
remaining U1 cells adherent to the endothelial monolayer still showed enhanced
HIV replication in comparison with an equal number of U1 cultured alone. While
addition of adhesion molecule blocking antibodies (anti-intercellular adhesion
molecule-1 (ICAM-1), -vascular cell adhesion molecule-1 (VCAM-1), -CD18 and -very
late antigen-4 (VLA-4)) strongly inhibited adherence of U1 cells to endothelial
monolayers, such treatment resulted in only a partial reduction in p24 release.
Furthermore, HIV replication in U1 cells was enhanced on culture in HUVEC
conditioned media. Such data suggest that soluble mediators secreted by
endothelial monolayers may modulate HIV-1 expression. Indeed, addition of
cytokine and chemokine antagonists to both U1/HUVEC co-cultures and to U1
cultured in HUVEC-conditioned media clearly down-regulated p24 release. Anti-IL
6, anti-tumour necrosis factor-alpha (TNF-alpha) and, particularly, anti-MCP-1
MoAbs reduced p24 release, while anti-IL-8 polyclonal antiserum and IL-1 receptor
antagonist (IL-1Ra) had no significant effect. Thus, the interaction between
HUVEC and infected monocytic cells up-regulates HIV-1 replication predominantly
through production of endothelium-derived soluble factors including MCP-1, TNF
alpha and IL-6. This phenomenon may influence the passage of HIV-1 from latency
to productive replication and enhance virus spreading during physiological and/or
pathological contact of monocytes with endothelium.
PMID- 10759770
TI - Effects of therapy with highly active anti-retroviral therapy (HAART) and IL-2 on
CD4+ and CD8+ lymphocyte apoptosis in HIV+ patients.
AB - The kinetics and effects of in vivo spontaneous apoptosis and activation-induced
cell death (AICD) upon CD4+ and CD8+ lymphocyte subsets and CD4 naive cell
numbers were studied in HIV+ subjects with CD4 pretreatment values > 200/mm3, who
were subsequently treated for 48 weeks with HAART alone or in combination with
six cycles of subcutaneous IL-2. Irrespective of the type of treatment, patients
showed a statistically significant increase in CD4 cell counts after 4 weeks,
although the CD4 naive subset only increased significantly in the IL-2-treated
subjects at the end of treatment. The percentage of CD4 cells undergoing
spontaneous apoptosis and AICD was significantly reduced in all patients after 4
weeks and this reduction was maintained until the end of therapy; however, the
level always remained significantly higher in comparison with healthy subjects. A
statistically significant reduction in CD8 apoptosis levels required at least 24
weeks of therapy. Together these data suggest that a reduction in the level of
apoptosis may contribute to the early rise in CD4 numbers measured after HAART,
but that later on HAART is unable to improve further this biological parameter.
Although the use of IL-2 had no additional effects on spontaneous apoptosis and
AICD, it may be beneficial by stimulating a late increase in the numbers of CD4
naive cells in HIV-treated subjects.
PMID- 10759771
TI - Impact of highly active anti-retroviral therapy (HAART) on cytokine production
and monocyte subsets in HIV-infected patients.
AB - HIV infection is associated with cytokine production by monocytes and expansion
of a monocyte subset that expresses high levels of CD16. Our study was designed
to investigate the effects of anti-retroviral therapies on these immune
parameters. Four groups of HIV+ patients were included in the study. The first
group comprised drug-naive patients (n = 20); the second included patients who
received two inhibitors of HIV reverse transcriptase (n = 45); the third group
received a therapy combining these two inhibitors and one inhibitor of HIV
protease (HAART) (n = 35); the fourth consisted of patients who had stopped their
treatment (n = 20). The release of inflammatory cytokines (tumour necrosis
factor, IL-1beta, IL-6) and immunoregulatory cytokines such as IL-10 by monocytes
was determined by ELISA. The monocyte subsets expressing low or high levels of
CD16 were studied by flow cytometry. Monocytes from patients naive of treatment
released higher amounts of inflammatory cytokines and IL-10 than HIV-
individuals. Each anti-retroviral therapy restored a normal pattern of cytokine
secretion. Nevertheless, the release of cytokines increased again after the
arrest of the treatment. The expansion of the monocyte subset that expresses high
levels of CD16 was significantly decreased by HAART but not by the treatment
including two inhibitors of reverse transcriptase. These results suggest that
only HAART controls monocyte activation in the treatment of HIV infection.
PMID- 10759772
TI - Chemokine synthesis and cellular inflammatory changes in lungs of mice bearing
p40tax of human T-lymphotropic virus type 1.
AB - To elucidate the pathogenic mechanisms of human T-lymphotropic virus type 1 (HTLV
1)-associated lung inflammation, we conducted a histopathological and molecular
analysis study using transgenic mice bearing pX region of this virus. In these
mice, accumulations of inflammatory cells consisting mainly of lymphocytes were
present in peribronchiolar and perivascular areas and alveolar septa, while
control littermate mice did not show such changes. In situ hybridization showed
that the anatomic distribution of p40tax mRNA was similar to that of inflammatory
cells, typically in peribronchiolar areas and to a lesser extent in perivascular
and alveolar septa. Inflammatory cytokines, including IL-1beta, tumour necrosis
factor-alpha and interferon-gamma, and several chemokines, such as monocyte
chemotactic protein-1 (MCP-1), RANTES, macrophage inflammatory protein-1alpha
(MIP-1alpha) and IP-10, were detected in lungs of transgenic mice but not control
mice. Semiquantitative analysis using reverse transcription-polymerase chain
reaction showed a significant correlation between MCP-1 mRNA expression and
p40tax mRNA, but not with other chemokines. The gene expression of the above
chemokines, with the exception of MIP-1alpha, correlated with the severity of
histopathological changes in the lung. Considered together, our results suggested
that p40tax synthesis may be involved in the development of lung lesions caused
by HTLV-1 through the induction of local production of chemokines.
PMID- 10759773
TI - Neutrophils play a critical role in the pathogenesis of experimental cerebral
malaria.
AB - The role of neutrophils in experimental cerebral malaria (ECM) is not well
understood. In this study we used a MoAb, RB6-8C5, to deplete the peripheral
neutrophils of ECM-susceptible CBA/NSlc mice 24 h before Plasmodium berghei ANKA
(PbA) infection. We found that early neutrophil depletion prevented the
development of ECM and dramatically decreased the sequestration of monocytes and
microhaemorrhage in the brain. The depletion of neutrophils also down-regulated
tumour necrosis factor-alpha, interferon-gamma and IL-2 mRNAs and abrogated IL
12p40 mRNA expression in the brain as examined by competitive reverse
transcriptase-polymerase chain reaction. Although depletion of neutrophils
decreased the expression of Th1 cytokines in both spleen and brain, our results
did not show the shift of a Th1 to a Th2 immune response since there was no
obvious augmentation of expression of Th2 cytokine mRNAs (IL-4 and IL-10). We
conclude that neutrophils play a role in the pathogenesis of ECM via enhancement
of the expression of Th1 cytokines in the brain.
PMID- 10759774
TI - Vaccination of BALB/c mice with Leishmania major amastigote-specific cysteine
proteinase.
AB - Cellular immune mechanisms resulting in interferon-gamma (IFN-gamma) production
are essential for protection against cutaneous leishmaniasis. Antigens of the
intracellular amastigote form of the parasite, found in mammalian hosts, are
likely to be good candidates for the induction of T cell response and protection
from development of leishmaniasis. We purified a stage-specific antigen from
amastigote soluble antigen (A-SLA) of Leishmania major by immunoaffinity
chromatography. The purified protein was characterized as a cysteine proteinase
with enzymatic activity which is inhibited by E-64, and it was named the
amastigote cysteine proteinase (ACP). BALB/c mice were immunized by two
intraperitoneal injections, at a month interval, of 5 microg of ACP or A-SLA in
Freund's complete adjuvant (FCA). Animals were challenged 4 weeks later with 106
L. major promastigotes and examined 4 months after the last injection. The
immunized animals developed significantly smaller or no lesions compared with
controls. Spleen cells from immunized mice showed a significant proliferative
response and produced a high level of IFN-gamma in response to ACP, suggesting
the induction of Th1 cells after immunization. These results make 24-kD ACP a
possible component for an eventual cocktail vaccine against L. major infection.
PMID- 10759775
TI - Identification and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase
in murine macrophages.
AB - Receptors for 1,25(OH)2vitaminD3 are found in most immune cells and important
immunological effects have been described in vitro, reflected by its capacity to
prevent autoimmunity and to prolong graft survival. The aim of this study was to
examine the presence and nature of the enzyme responsible for final activation of
the molecule, 1-alpha-hydroxylase, in murine macrophages and to analyse its
regulation and possible role in the immune system. Peritoneal macrophages from
C57Bl/6 mice were incubated with lipopolysaccharide (LPS; 100 microg/ml),
interferon-gamma (IFN-gamma; 500 U/ml) or a combination of both. By quantitative
reverse transcriptase-polymerase chain reaction, using primers based on the
murine renal cDNA sequence, low levels of 1-alpha-hydroxylase mRNA were detected
in freshly isolated cells (18 +/- 7 x 10-6 copies/beta-actin copies). Analysis of
the cDNA sequence of the gene revealed identical coding sequences for the
macrophage and renal enzymes. mRNA levels rose three-fold with LPS (NS), but a
six-fold increase was seen after IFN-gamma stimulation (P < 0.05). Combining LPS
and IFN-gamma did not result in a major additional increase, but addition of
cyclosporin A further increased levels 2.5-fold both in IFN-gamma- and
combination-stimulated cells (P < 0.05). Time course analysis revealed that up
regulation of 1-alpha-hydroxylase was a late phenomenon, preceded by the up
regulation of activating macrophage products such as IL-1 and tumour necrosis
factor-alpha. Finally, a defect in 1-alpha-hydroxylase up-regulation by immune
stimuli was found in autoimmune non-obese diabetic mice. In conclusion, we
propose that the up-regulation of 1-alpha-hydroxylase in activated macrophages,
resulting in the synthesis of 1,25(OH)2D3, might be a negative feedback loop in
inflammation. A defect in this system might be an additional element in tipping
the balance towards autoimmunity.
PMID- 10759776
TI - Multiple sclerosis is associated with an imbalance between tumour necrosis factor
alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by
interferon-beta (IFN-beta) treatment.
AB - The up-regulated B cell responses detectable in cerebrospinal fluid (CSF) and the
augmented myelin antigen-specific T cell responses observed in the CSF as well as
systematically in patients with multiple sclerosis (MS) suggest the involvement
of cytokines in disease development and perpetuation. Here we report on the
parallel involvement of TNF-alpha, IL-6, IFN-gamma and IL-10 in MS and controls,
using enzyme-linked immunospot (ELISPOT) assays to detect and enumerate cytokine
secreting mononuclear cells (MNC) prepared from blood and, for IL-6 and IL-10,
from CSF without in vitro stimulation. MS is associated with elevated levels of
TNF-alpha-secreting blood MNC when compared with levels in groups of control
patients with myasthenia gravis (MG) and other neurological diseases (OND) or
healthy subjects. This elevation was confined to patients with untreated MS and
not present in those examined during ongoing treatment with IFN-beta. Untreated
patients with MS had lower numbers of IL-10-secreting blood MNC compared with the
three control groups. In patients undergoing treatment with IFN-beta, numbers of
IL-10-secreting cells were in the same range as in controls. Normalization of TNF
alpha from elevated, and of IL-10 from decreased levels could be one reason for
the beneficial effects of IFN-beta in MS, although it remains to be shown whether
these changes reflect phenomena primarily involved in MS pathogenesis or
secondary changes. In CSF, levels of IL-10-secreting cells were higher than in
blood in both MS and OND, with no difference between these groups. Systemic
aberrations of IL-6 and IFN-gamma and of IL-6 in CSF in MS versus controls were
only minor, irrespective of treatment with IFN-beta.
PMID- 10759777
TI - Selective expansion of T cells in gingival lesions of patients with chronic
inflammatory periodontal disease.
AB - Chronic inflammatory periodontal diseases are characterized by a cellular
infiltrate and are similar in many respects to other chronic inflammatory
diseases. While periodontopathic bacteria have been recognized as the principal
causative agent and the immune response to these bacteria is thought to be
responsible for the tissue destruction, the full aetiological spectrum is still
incompletely understood. In addition to many cell types such as polymorphonuclear
leucocytes and macrophages, T cells have been implicated in pathogenesis and are
considered to have regulatory roles in progression of the disease. Based on our
recent studies demonstrating biased expression of several Vbeta families in
periodontitis tissues, the aim of this study was to characterize further the T
cells relevant to the disease process by reverse transcription-polymerase chain
reaction-single-strand conformation polymorphism (RT-PCR-SSCP) and subsequent
nucleotide sequence analysis of complementarity-determining region 3 (CDR3) of
the TCR beta-chain. In spite of the likely involvement of numerous bacteria, the
present study has clearly shown the oligoclonality of infiltrating T cells in
periodontitis lesions in contrast to low clonality of peripheral blood T cells as
evidenced by the appearance of distinct bands in gingival tissue samples and
smear pattern of peripheral blood on SSCP gels. These were confirmed by the DNA
sequencing of the CDR3 of Vbeta16 of selected samples. The analysis of deduced
amino acid sequences demonstrated amino acid motifs in the CDR3 region of the
periodontitis lesion-derived sequences from each patient. The results indicate
that gingival tissue-infiltrating T cells recognizing a limited number of
antigens or epitopes are involved in the disease process.
PMID- 10759778
TI - Anti-MHC autoimmunity in Behcet's disease: T cell responses to an HLA-B-derived
peptide cross-reactive with retinal-S antigen in patients with uveitis.
AB - Immune response to retinal autoantigens plays a central role in the pathogenesis
of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B
molecules associated with uveitis, such as HLA-B27 and 51, which shares amino
acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was
shown to be immunogenic in human and experimental uveitis in the rat. In this
study we investigated T cell responses to B27PD and PDSAg in patients with
Behcet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in
comparison with non-Behcet anterior uveitis (AU, n = 14), Behcet's patients
without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day
proliferation assay. Patients with BD and posterior uveitis had significantly
higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5
+/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD
(P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis
patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/
0.3) and HC (SI 1.1 +/- 0.6) (P < 0. 0001). A significant correlation between
the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated
levels of IL-2 and tumour necrosis factor-alpha were also observed in culture
supernatants obtained from peripheral blood mononuclear cells after stimulation
with the peptides, but no correlation was found between the proliferative
responses and cytokine levels. These results suggest that cellular immunity to
cross-reactive HLA-B and S-Ag-derived peptides might play a role in the
pathogenesis of posterior uveitis in BD.
PMID- 10759779
TI - Complex pattern of Th1 and Th2 activation with a preferential increase of
autoreactive Th1 cells in BALB/c mice with proteoglycan (aggrecan)-induced
arthritis.
AB - The central role of CD4+ T cells and the balance between T helper (Th)
subpopulations in the pathogenesis of autoimmune diseases have been extensively
studied. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a murine model for
rheumatoid arthritis (RA), which is characterized by a Th1 dominance at the onset
of the disease. In addition to CD4+ T cells, antigen-presenting B cells and
autoantibodies seem to play an important role in the development and regulation
of PGIA. To identify proteoglycan-specific CD4+ T cell subsets and Th1- and Th2
supported antibody isotypes during the progression of PGIA, spleen cells of
proteoglycan-immunized BALB/c mice were harvested at different times of
immunization, and at different stages of the disease, and their cytokine
production and antigen-specific antibody isotype profiles were determined by
enzyme-linked immunospot (ELISPOT) assays. Both Th1 and Th2 cytokine-producing
cells, with the predominance of IL-4/IL-5-secreting cells, were detected during
the prearthritic stage, and a shift toward a Th1 dominance was observed at the
time of onset of arthritis. Tissue homogenates of acutely inflamed joints
contained significantly higher levels of interferon-gamma than IL-4. The
prearthritic period and both the acute and chronic phases of joint inflammation
were characterized by IgG1 dominance in the sera and this correlated with the
number of IgG1-secreting B cells in the spleen. However, the ratio of
autoreactive IgG1/IgG2a-secreting cells decreased in arthritic animals. These
results indicate the activation and possible regulatory roles of both Th1 and Th2
subsets in the autoimmune process, with the necessity of a relative increase of
autoreactive Th1 cells for the induction of joint inflammation.
PMID- 10759780
TI - Down-regulation of the T cell receptor CD3 zeta chain in rheumatoid arthritis
(RA) and its influence on T cell responsiveness.
AB - T cells implicated in chronic inflammatory diseases such as RA respond weakly
when stimulated in vitro with mitogen or antigen. The mechanism behind this
hyporesponsiveness is unclear, but a depressed expression of the T cell receptor
(TCR)-associated CD3zeta chain has been suggested. In the present work we
describe a low expression of CD3zeta in synovial fluid (SF) T cells from RA
patients compared with peripheral blood (PB) T cells, but no difference in
CD3zeta expression between RA and healthy control PB T cells. In vitro studies
demonstrated that granulocytes but not SF macrophages are able to down-regulate
the expression of CD3zeta. Through stimulation with anti-CD3 antibodies we
demonstrated that the TCR-dependent proliferative response was decreased in SF T
cells compared with PB T cells. Stimulation with phorbol ester and ionomycin also
resulted in a low proliferative response of SF T cells, indicating that both
signal transduction through the TCR (stimulation with anti-CD3) and events
further downstream in the signalling pathways (stimulation with phorbol ester and
ionomycin) are affected. A similar depression of T cell activity was observed
when induction of IL-2 and IL-4 was measured. However, SF T cells were not
defective in the induction of interferon-gamma (IFN-gamma) when stimulated with
phorbol myristate acetate (PMA)/ionomycin, in contrast to the diminished IFN
gamma response observed after stimulation with anti-CD3. This indicates that the
hyporesponsiveness of SF T cells can not be generalized to all T cell functions.
The differential response to external stimuli is likely to be of importance for
the capacity of SF T cells to influence inflammatory reactions.
PMID- 10759781
TI - Humoral autoreactivity directed against surfactant protein-A (SP-A) in rheumatoid
arthritis synovial fluids.
AB - SP-A is found principally in the lung, and has been associated with lamellar
bodies also found in the synovial joint. Both SP-A and C1q contain collagen-like
regions, and SP-A and C1q have some structural similarities, both having a
globular head region and a collagen-like tail. Here we are able to show that (i)
autoreactivity to SP-A, as expressed by IgG and IgM autoantibodies, is present in
synovial fluid (SF) isolated from patients with rheumatoid arthritis (RA); (ii)
in absorption experiments only a limited degree of cross-reactivity between
autoantibodies reactive with C1q and SP-A is observed; (iii) there is no cross
reactivity between autoantibodies reactive with type II collagen (CII) and those
reactive with SP-A or C1q; (iv) autoantibodies react with polymeric (dimers and
larger) SP-A, but not with monomeric SP-A subunits, indicating that a degree of
quaternary structure is required for antibody binding. Unlike CII, which not
accessible in the normal joint, both SP-A and C1q are available within the SF in
patients with RA and may therefore provide antigens driving an autoimmune
response directed against collagen-like structures.
PMID- 10759782
TI - An autoantibody targeting glycated IgG is associated with elevated serum immune
complexes in rheumatoid arthritis (RA).
AB - Advanced glycation end-products (AGE) play a role in diabetes complications and
in RA. An autoantibody to IgG-AGE has been shown to correlate with RA disease
activity. Thus we sought to analyse serum immune complexes (IC) and AGE-modified
proteins in Caucasians and North American Indians to see if the presence of anti
IgG-AGE influenced their composition. Polyethylene glycol precipitation of IC
from the serum of anti-IgG-AGE-positive or -negative RA patients, and healthy and
diabetic controls were examined. Concentrations of circulating IC were highest in
anti-IgG-AGE+ RA patients, followed by anti-IgG-AGE- RA patients, which were
greater than healthy controls. IC amounts in the Ojibwe were consistently higher
than in Caucasians. Affinity purification of AGE-modified proteins from IC and
immunoblotting with antibodies against Ig gamma and mu heavy chains, kappa and
lambda light chains, and AGE Nepsilon(carboxymethyl)lysine and imidazolone
yielded similar results: anti-AGE+ RA patients had elevated levels relative to
those without the autoantibody. Levels in both RA groups were higher than in
controls. Glycated albumin amounts followed a similar distribution, but were not
influenced by the presence of anti-AGE antibodies. A heavily glycated kappa-chain
was present primarily in IC from anti-IgG-AGE+ patients. These studies indicate
that anti-AGE antibodies have a direct impact on the accumulation of IgG-AGE but
not glycated albumin, and may block the normal clearance of IgG-AGE through AGE
receptors.
PMID- 10759783
TI - Increased synovial fluid levels of soluble CD23 are associated with an erosive
status in rheumatoid arthritis (RA).
AB - Synovial fluid (SF) levels of soluble CD23 (sCD23) were determined in 96 patients
presenting with an inflammatory knee effusion (73 with RA and 23 with reactive
arthritis (ReA) serving as a control inflammatory non-erosive group) and were
correlated with the degree of joint destruction, with local immune parameters (IL
1beta, IL-3, IL-4, IL-6, IL-8, IL-10, IL-12 and sCD25) and with serum markers of
inflammation, C-reactive protein and erythrocyte sedimentation rate. RA patients,
classified as erosive or not according to Larsen's grade, were separated as
follows: (i) 13 patients with non-erosive RA; (ii) 16 RA patients with erosions
in hands but not in knees, matched for disease duration with the first group;
(iii) 44 RA patients with hand and knee erosions, matched with the second group
for rheumatoid factor positivity but of longer disease duration. SF sCD23 levels
were significantly increased in both erosive RA groups compared with non-erosive
diseases, whether RA or ReA (P < 0.05), whose SF levels were not different. SF IL
10 showed a similar profile to that of SF sCD23 and was the only other parameter
characteristic of erosive RA, but no direct correlation was found between the
two. SF sCD23 was significantly correlated with IL-12 (r = 0.65, P = 0.0001) and
sCD25 (r = 0.39, P = 0.0019) exclusively in the two erosive RA populations. In
conclusion, these data showing that increased levels of sCD23 are not only found
in the SF of erosive joints but also in knee SF of patients with erosive RA but
without knee x-ray-diagnosed erosions suggest that this parameter might be of
predictive value for joint destruction. Longitudinal studies are however needed
to confirm its potential clinical interest.
PMID- 10759784
TI - Immunohistochemical study of lymphoid tissues in adjuvant arthritis (AA) by image
analysis; relationship with synovial lesions.
AB - The aim of this study was to examine leucocyte populations in lymphoid organs
during AA and to ascertain the relationship with lesions in synovial joints.
Popliteal lymph nodes, spleen and knee synovial membranes were removed from both
healthy and AA rats at intervals of 3-4 days over a 3-week period. Cryostat
sections were stained with MoAbs directed against lymphocyte and macrophage
subpopulations, and studied by image analysis. Throughout the arthritic period,
high numbers of ED1+ and ED3+ macrophages were seen in both lymphoid compartments
and intercellular adhesion molecule-1 (ICAM-1) expression also increased in some
zones of lymph nodes and spleen. The percentages of CD4+ and CD8+ cells rose in
the splenic zones studied but fell in the lymph node cortex. Very few natural
killer (NK) cells were found in lymphoid tissues, but the number rose after AA
induction. In synovia from AA rats, ED2+ macrophages proliferated but alpha/beta
T cell infiltration was only occasionally observed, accompanied by ED1+ cells and
ICAM-1 expression. In conclusion, synovitis developing after AA induction seems
to be caused directly by macrophages and indirectly by lymphocytes placed both in
popliteal lymph nodes and spleen.
PMID- 10759785
TI - Association of neutropenia in systemic lupus erythematosus (SLE) with anti-Ro and
binding of an immunologically cross-reactive neutrophil membrane antigen.
AB - SLE is associated with the production of autoantibodies to self-constituents. In
particular, certain ribonucleoprotein particles are targeted. Despite the
multitude of autoantibodies produced and the remarkable concentrations of these
antibodies in the sera of SLE patients, there have been little data that the
autoantibodies found in SLE are involved in the pathogenesis of disease or its
manifestations. The present work demonstrates that anti-Ro (or SSA) is associated
with granulocytopenia, binds the surface of granulocytes and fixes complement to
this membrane surface. Binding is a property of anti-Ro Fab fragments and can be
inhibited by 60-kD Ro. However, the antigen bound on the surface of granulocytes
is a 64 000 mol. wt protein that is a novel autoantigen in SLE. As suggested by
inhibition studies, sequence identity between 60-kD Ro and eight tandem repeats
in the 64-kD antigen may be responsible for the observed serologic cross
reactivity. These data imply that anti-Ro antibodies that also bind the 64-kD
protein mediate neutropenia in patients with SLE.
PMID- 10759787
TI - Statistical report for 1999
PMID- 10759786
TI - Autoepitopes on autoantigen centromere protein-A (CENP-A) are restricted to the N
terminal region, which has no homology with histone H3.
AB - Anti-centromere autoantibodies (ACA) are commonly found in the serum of patients
with a limited type of scleroderma and other systemic autoimmune diseases. CENP-A
is one of the major antigens against ACA and a histone H3-like protein. To
analyse the autoantigenic epitopes of CENP-A, a series of truncated peptides of
human CENP-A were expressed in Escherichia coli and immunoblotting analysis was
performed with 91 ACA+ sera. Eighty sera (88%) with the ACA reacted to the 52
amino acids N-terminal region which is not homologous to H3, while no sera
reacted to the C-terminus which has a sequence similarity with H3. Moreover,
ELISA was also employed in this study using two synthetic peptides corresponding
to the amino acid sequences 3-17 (peptide A) and 25-38 (peptide B). Peptides A
and B were reactive to 78 (86%) and 79 (87%) of ACA, respectively. Core antigens
of hepatitis B virus (HBV) and hepatitis C virus (HCV) have similar sequences to
peptide A and/or peptide B, but three sera containing HBV without ACA and five
sera containing HCV without ACA were found to be reactive to neither peptide.
Centromere localization of CENP-A is dependent on the H3-like C-terminal domain
which is not autoantigenic, while the antigenic N-terminal domain, which might
play unidentified functional roles, should be an important region for the
induction of ACA.
PMID- 10759788
TI - Toxins 99, new information about the botulinum neurotoxins.
PMID- 10759789
TI - Review of sentinel lymph node biopsy and systemic interferon for melanoma:
promising but investigational modalities.
AB - BACKGROUND: There is conflicting data regarding the efficacy of systemic
interferon as adjuvant therapy for high-risk cutaneous melanoma. Sentinel lymph
node biopsy has recently gained acceptance in the surgical management of high
risk melanoma, despite a lack of data supporting its efficacy. OBJECTIVE: To
review the evidence concerning interferon and lymph node biopsy in the management
of melanoma. METHODS: A systematic review of all randomized, controlled trials
involving adjuvant interferon and sentinel lymph node biopsy in management of
melanoma is presented. RESULTS: Current data regarding the efficacy of adjuvant
interferon in the management of melanoma is conflicting. The conflicting results
of studies involving both low-dose and high-dose systemic interferon for the
adjuvant treatment of melanoma remain unresolved. There is no randomized,
controlled data to support the use of sentinel lymph node biopsy in the
management of melanoma, despite its widespread acceptance. CONCLUSION: Sentinel
lymph node biopsy and systemic interferon remain promising modalities in the
management of melanoma, although there is no affinitive evidence to support their
efficacy.
PMID- 10759790
TI - The history of hair transplantation.
PMID- 10759791
TI - Patients with port-wine stains and their psychosocial reactions after
photothermolytic treatment.
AB - BACKGROUND: Since the pulsed dye laser (PDL) was introduced in the late 1980s the
question has been raised whether one should treat congenital capillary
malformations, commonly called port-wine stains (PWSs), early or not. OBJECTIVE:
There are pros and cons, but studies have mainly emphasized the clinical
treatment results. The psychosocial importance of an early treatment needs also
to be clarified. METHODS: This retrospective study includes 163 patients with PWS
treated with the PDL until there was either total clearing or until there was no
further improvement. When a period from a few months to 8 years had elapsed after
the treatments, the patients were given a questionnaire, which had been developed
in cooperation with a psychiatrist, in order to evaluate the psychosocial
implications of the PWS and the consequences of treatment. RESULTS: . Eighty
percent of the patients more than 7 years of age had not fully accepted their PWS
with increasing age and 80% thought that their life would change for the better
if their PWS could be eliminated. Eighty-five percent thought their PWS
influenced their life in some negative way. Forty-five percent of the patients
considered themselves to have a lower self-esteem than their own age group. The
majority of the patients considered themselves negatively influenced by their
PWS. Most psychosocial parameters, such as self-esteem, contact with the opposite
sex, social relationships, school contacts, the need to cover their PWS with make
up or clothes, and meeting new people, improved significantly after PDL
treatment. Older patients had higher negative scores than the younger ones,
indicating the advantage of early treatment. Patients who were treated earlier
with other methods producing less favorable results scored unfavorably compared
to previously untreated patients. CONCLUSION: Patients with PWS treated at our
clinic consider their psychosocial status to be improved after treatment. An
early treatment seems to be favorable for these patients.
PMID- 10759792
TI - Hematoxylin and safranin O staining of frozen sections.
AB - Currently the hematoxylin and eosin staining procedure is the most popular among
Mohs surgeons for histology. However, safranin O, a cheaper and relatively safer
stain which is predominantly used for plant histology, should be considered as it
offers similar or improved accuracy in the diagnosis of frozen sections of basal
and squamous cell carcinomas.
PMID- 10759793
TI - Mast cells and dendritic cells in basal cell carcinoma stroma.
AB - BACKGROUND: The interaction of tumors with the surrounding stroma has become an
important topic in tumor biology. Basal cell carcinoma (BCC) stroma has been
characterized as hypervascular and rich in mast cells. The presence of dermal
dendrocytes thought to have both antigen presenting and wound healing functions
has recently been reported in BCC stroma. GP1b-alpha is a newly described
vascular adhesion molecule with potential significance in tumor biology.
OBJECTIVE: To further characterize the cellular phenotype of BCC stroma. METHODS:
Eleven BCCs (8 nodular, 2 sclerosing, 1 adenoid-cystic) were examined using
immunohistochemical techniques for the presence of antigens specific to vascular
endothelium, mast cells, and dermal dendrocytes. RESULTS: The stroma of all BCCs
demonstrated increased vascularity, increased numbers of mast cells, and
increased numbers of dermal dendrocytes expressing both CD34 and GP1b-alpha
adjacent to tumor nests. No differences in antigen expression were observed
between histologic subtypes of BCC. CONCLUSION: The close proximity of stromal
mast cells and dermal dendrocytes surrounding BCC nests suggests a biologically
significant interaction. The pattern observed is similar to that observed in
healing wounds.
PMID- 10759794
TI - Hair removal using a 5-msec long-pulsed ruby laser.
AB - BACKGROUND: Unwanted hair is a widespread cosmetic problem. Many temporary
methods of hair removal exist, with laser hair removal rapidly becoming the most
widely used modality. OBJECTIVES: Our objective was to evaluate the efficacy and
side effects of a long-pulsed ruby laser for epilation in patients with varying
skin types and hair color 6 weeks and 6 months after treatment. METHODS: Seventy
four patients received one to four treatments with a long-pulsed ruby laser (694
nm, 5-msec pulse length, 6 mm spot size, 17.5-32 J/cm2) in different body areas.
RESULTS: After a mean number of treatments of 1.98 (range 1-4) the mean clearance
was 51-75% after 6 weeks and less than 25% after 6 months. A lower percentage of
hair regrowth was observed in the facial region than on the trunk or legs and in
dark hair compared to blond hair. CONCLUSION: Laser epilation provides a quick
and relatively comfortable, but nonpermanent modality for hair removal with few
side effects.
PMID- 10759795
TI - Angiolymphoid hyperplasia with eosinophilia successfully treated with a long
pulsed tunable dye laser.
AB - BACKGROUND: To date, both surgical excision and laser treatments for
angiolymphoid hyperplasia with eosinophilia (ALHE) have resulted in scarring.
OBJECTIVE: Based on the principle of selective photothermolysis, we considered
employing the newer long-pulsed tunable dye laser in the treatment of ALHE, as
less scarring would be expected and deeper blood vessels could be ablated.
METHODS: After punch biopsy specimens confirmed the diagnosis, the patient was
treated on two separate occasions, 2 months apart with a long-pulsed tunable dye
laser. RESULTS: The lesions flattened after the initial treatment and resolved
after a second treatment. No scarring was detectable and no recurrence was noted
in follow-up after 1 year. CONCLUSION: We conclude that the long-pulsed tunable
dye laser can be employed successfully to treat superficial lesions of ALHE,
particularly in cosmetically sensitive areas.
PMID- 10759796
TI - Double butterfly suture for high tension: a broadly anchored, horizontal, buried
interrupted suture.
AB - BACKGROUND: The excision of skin lesions such as tumors, nevi, and scars
frequently results in tension on surgical wound margins. This tension is commonly
counteracted surgically with buried, intracutaneous, interrupted sutures of
absorbable material which are anchored vertically in the corium. METHOD: The
horizontal, buried, intracutaneous butterfly suture has been described elsewhere.
It is firmly anchored in the corium, everts wound margins, and adapts them nearly
as broadly as two vertical sutures. It can also be laid as a double butterfly
suture, as described here, and then has the shape of an "8." This double
butterfly suture is equivalent to three vertical sutures because of its broad
base in the corium. Moreover, it can cope with much greater tension because of
its "pulley" effect. A single double butterfly suture usually suffices for small
defects, particularly when the wound edges are cut obliquely with a longer rim of
epidermis. MATERIALS: We have laid the traditional butterfly suture in more than
35,000 skin lesion excisions since 1985 and the double butterfly suture alone or
as a supplement in more than 10,000 sutures since 1992. We use 2-0 to 6-0
polydioxanone for these procedures, since it has proven in trials to be the best
absorbed suture material. RESULTS: In most cases, the resulting scars were narrow
and smooth in spite of high tension. Results were unsatisfactory in only 6.2% of
procedures. CONCLUSION: The double butterfly suture described here has the
advantages of withstanding tension better while everting wound margins and
requiring fewer stitches for wound closure. However, it is important that the
suture knot be deeply anchored beneath the corium.
PMID- 10759797
TI - Modern aspects of wound healing: An update.
AB - Wound healing is an area of cutaneous medicine in which there have been many
recent advances. Interest has focused on the development of an in vitro
reconstructed skin, although neither the commercially available products nor the
products currently described in experimental studies are able to fully substitute
for natural living skin. The substitution of the main component of each wound,
the connective tissue matrix, is an advance. Once dermis is reconstructed, the
covering of the wound surface with both in vitro expanded epidermis and
autologous split-skin transplants is significantly easier and has an improved
chance of success. Epidermal stem cells may facilitate functionality of the
superficial part of such a system. New experimental and clinical trials are
currently under way.
PMID- 10759798
TI - Botulinum toxin therapy for palmar hyperhidrosis with ADG needle.
PMID- 10759799
TI - Successful removal of freckles in Asian skin with a Q-switched alexandrite laser.
AB - BACKGROUND: : Although freckles are light-brown macules most frequently observed
in individuals with red or blond hair and blue or gray eyes, freckles are common
to Asian people, including Koreans. Treatment may be requested on cosmetic
grounds. OBJECTIVE: : The objective of this study was to determine the
effectiveness of the Q-switched alexandrite laser (wavelength 755 nm; pulse width
100 nsec) in treating the 197 cases of Asian skin with freckles and to observe
any side effects such as pigmentary changes or scarring. METHODS: : One hundred
ninety-seven patients with freckles were treated with the Q-switched alexandrite
laser at 8-week intervals and clinically analyzed. RESULTS: : More than 76%
removal of freckles required an average of 1.5 treatment sessions with 7.0 J/cm2.
No scarring, long-standing pigmentary changes, or textural changes were seen in
laser-irradiated skin. CONCLUSION: : The Q-switched alexandrite laser is a safe
and highly effective modality for removing freckles without scarring or permanent
pigmentary changes in Asian skin.
PMID- 10759800
TI - Principles of CO2/erbium laser safety.
AB - BACKGROUND: There are a variety of potential hazards with laser technology.
METHODS: A review of the literature. OBJECTIVE: To summarize the potential
hazards of CO2 and erbium laser technologies and the safety guidelines and
equipment developed to minimize them. RESULTS: Laser hazards can be divided into
the following categories: mechanical, environmental, macrobiologic,
microbiologic, and iatrogenic. CONCLUSION: At the conclusion of this learning
activity, the reader should be able to discuss the mechanical, environmental,
macrobiologic, microbiologic, and iatrogenic hazards of resurfacing laser
technology, the literature cited to support current safety guidelines, and the
equipment developed to promote laser safety.
PMID- 10759801
TI - Efficacy, tolerability, and safety of a long-pulsed ruby laser system in the
removal of unwanted hair.
AB - BACKGROUND: Unwanted hair growth is a common, usually physiologic phenomenon.
OBJECTIVE: In this study the efficacy and tolerability of a long-pulsed ruby
laser system was compared with needle electrolysis and hot wax on three parts of
the body. METHODS: Thirty volunteers were treated three times on the forearm (n =
10), on the face (n = 10), or in the pubic area (n = 10) with 25 J/cm2 laser, 40
J/cm2 laser, needle electrolysis, and hot wax therapy. RESULTS: The 25 J/cm2 and
40 J/cm2 laser treated sites showed a statistically significant decrease (38% and
49%, respectively) in the number of hairs at the first visit after the last
treatment compared to the pretreatment hair counts. No significant decrease was
observed in the needle electrolysis and hot wax treated sites. Laser therapy
yielded better results on the forearm than on the face or pubic area and was
scored as the least painful. CONCLUSION: The long-pulsed ruby laser is a
promising, well-tolerated method of epilation.
PMID- 10759803
TI - Surgical management of stable vitiligo: A review with personal experience.
AB - BACKGROUND: Various modalities are available for surgical management of stable,
localized patches of vitiligo, which are resistant to conventional medical
treatment. Cutaneous surgeons often struggle to select among various methods of
surgical treatment that include camouflage tattooing, melanocyte transplants,
excision, and melanocyte culture. The advantages, disadvantages, and limitations
of all the available modalities are reviewed. OBJECTIVE: The purpose of this
review is to find out if any guidelines can be drawn regarding the surgical
management of stable vitiligo. METHODS: This article is based on a review of the
medical literature and the author's personal experience over the last decade.
RESULTS: It is difficult to draw any fixed guidelines from this review. Treatment
must be individualized depending upon the site and the extent of involvement.
CONCLUSION: Although the retrospective nature of this article limits its
validity, discussing the various therapeutic options is of value as continuing
medical education. Surgical treatment may be individualized to obtain the best
possible cosmetic result.
PMID- 10759802
TI - The effect of medical elastic compression stockings with different slope values
on edema. Measurements underneath three different types of stockings.
AB - BACKGROUND: Medical elastic compression stockings are widely used in venous
diseases. Their effects on the venous system have been shown in the past. Up to
now, little is known about the slope or stiffness factor of stockings. OBJECTIVE:
To evaluate the effect of different slope and stiffness factors of medical
elastic compression stockings on the venous system. METHODS: Examinations were
carried out in 29 legs of 25 different patients (12 men, 13 women) with a mean
age of 66.0 years. All patients were known with chronic venous insufficiency. On
all these patients three different elastic medical compression stockings were
tested; one with a low slope, one with a high slope, and one with a low slope but
a higher pressure at the ankle. The tests were carried out by determining
capillary filtration rate (CFR) with air-plethysmography (APG) while wearing the
stockings. RESULTS: The mean value of the CFR without wearing a stocking was 4.65
ml/min (SD = 1.68), with Compriform (low slope, 30 mmHg) the mean CFR was 3.54
ml/min (SD = 1.22), with Bellavar (high slope, 30 mmHg) a mean CFR of 3.15 ml/min
(SD = 1.17) was found, and the mean CFR related to Fast-fit (low slope, 34.5
mmHg) was 3.02 ml/min (SD = 1.12). There is a highly statistically significant
difference in CFR between no stockings and wearing a stocking (paired Student's t
test; P < 0.01). Regarding the individual stocking, there is a highly
statistically significant difference in CFR between the Compriform and the other
two stockings (paired Student's t-test; P < 0.01). Between Bellavar and the Fast
fit the difference was not statistically significant. CONCLUSIONS: There is a
statistically significant difference in CFR, and consequently in the development
of edema, between not wearing an elastic compression stocking and wearing an
elastic compression stocking. There is also a statistically significant
difference in CFR between elastic compression stockings with the same
compression, but a low slope profile and a high slope profile. Stockings with a
low slope, but a higher compression may perform as well as stockings with a
higher slope but a lower compression in reducing the CFR. In patients with a
strong tendency to develop edema it may be advisable to prescribe stockings with
a high slope profile.
PMID- 10759804
TI - Using a side effect to therapeutic advantage: the darkening of red eyebrow tattoo
pigment following Q-switched laser treatment.
AB - BACKGROUND: Q-switched lasers are commonly used to achieve tattoo removal,
utilizing the principle of selective photothermolysis. However, certain tattoo
pigments may darken following laser pulsing. OBJECTIVE: To determine whether this
side effect can be used to therapeutic advantage in a woman who previously had
her eyebrows enhanced with a dark tattoo that spontaneously changed to a reddish
hue over time. METHOD: The woman's eyebrows were pulsed with the Q-switched
Nd:YAG laser at both 532 nm and 1064 nm. RESULTS: The test areas pulsed with the
1064 nm laser revealed partial clearing. However, 532 nm Q-switched Nd:YAG pulses
produced darkening of tattoo pigment both at the test sites and in the subsequent
treatment. CONCLUSION: Q-switched lasers can produce darkening of red tattoo
pigment. In some cases this side effect can be used to therapeutic advantage.
PMID- 10759805
TI - Cutaneous metastasis of chordoma.
AB - BACKGROUND: Chordomas are rare neoplasms that arise from the notochord remnant.
They develop in the sacrococcygeal (50%) or cervical (15%) region and are
generally regarded as a locally aggressive tumor with a slow progressive growth
rate and a metastatic incidence ranging from 3 to 48%. Skin involvement by
chordoma is rare, but can occur by direct extension, by local recurrence and by
metastases. OBJECTIVE: To illustrate by a case report the clinical presentation
and management of this disease. METHODS: We present a case of sacral chordoma
with metastases over a 10-year period to the lungs, the soft tissue of the chest
wall, the triceps tendon, and distant cutaneous metastases to the back and the
nose. RESULTS: The cutaneous metastases were treated by excision. CONCLUSION:
Chordoma is a slow growing tumor of the notochord remnant that may metastasize to
the skin. Physicians and pathologists should be aware of this entity.
PMID- 10759806
TI - Liposuction surgery for the treatment of large hematomas on the leg.
AB - BACKGROUND: Post-traumatic hematomas overlying the muscular fascia on the lateral
aspect of the leg are common in elderly patients, particularly those receiving
oral anticoagulant therapy. When large collections of blood accumulate within
this region, the pressure within the hematomas may exceed the blood pressure in
the dermal and subdermal vessels. Large areas of necrosis of the overlying skin
may then result. OBJECTIVE: To decrease the pressure of evolving and long
standing hematomas, thereby reducing inflammation and pain. METHODS: Liposuction
surgery was employed as a means of decompressing both evolving and long-standing
hematomas. RESULTS: Liposuction surgery has been found to be useful in the
treatment of hematomas on the leg, and has the added benefit of producing
cosmetically elegant results. An elastic compression bandage placed
postoperatively reduces the risk of relapse. CONCLUSION: Liposuction surgery may
be used to remove large leg hematomas without producing long and cosmetically
unacceptable scars. The technique is easy to perform and permits rapid evacuation
of hematomas, thereby minimizing patient discomfort.
PMID- 10759807
TI - American Society for Dermatologic Surgery Guidelines of Care for Liposuction.
PMID- 10759808
TI - The tie-over suture for re-creating the nasofacial sulcus.
PMID- 10759809
TI - Concepts of sliding and lifting tissue movement in flap reconstruction.
AB - BACKGROUND: The optimal design of a skin flap requires an understanding of the
concepts of tissue movement. OBJECTIVE: The purpose of this manuscript was to
demonstrate concepts of sliding and lifting tissue movement for flap
reconstruction. METHODS: Six similar defects located in the forehead-temple
eyebrow region were repaired using a different skin flap. RESULTS: The specific
flap design for a given defect is based on the answer to three predictable events
that result from tissue transfer: Where is the tension? Where are the final
incision lines? Where is the redundant tissue? CONCLUSION: A mental exercise
assessing all available reconstruction options should be performed for each
individual patient and defect. Both patient and defect considerations need to be
assessed. A thorough understanding of both anatomy and tissue movement is
necessary for optimal skin flap reconstruction.
PMID- 10759810
TI - The significance of orbital anatomy and periocular wrinkling when performing
laser skin resurfacing.
AB - Knowledge of orbital anatomy and the interaction of muscle contractions,
gravitational forces and photoagingis fundamental in understanding the
limitations of carbon dioxide (CO2) laser skin resurfacing when rejuvenating the
skin of the periocular area. Laser resurfacing does not change the mimetic
behavior of the facial muscles nor does it influence gravitational forces. When
resurfacing periocular tissue, the creation of scleral show and ectropion are a
potential consequence when there is an over zealous attempt at improving the
sagging malar fat pad and eyelid laxity by performing an excess amount of laser
passes at the lateral portion of the lower eyelid. This results in an inadvertent
widening of the palpebral fissure due to the lateral pull of the Orbicularis
oculi. Retrospectively, 85 patients were studied, who had undergone periorbital
resurfacing with a CO2 laser using anew treatment approach. The Sharplan 40C CO2
Feather Touchlaser was programmed with a circular scanning pattern and used just
for the shoulders of the wrinkles. A final laser pass was performed with the same
program over the entire lower eyelid skin surface, excluding the outer lateral
portion (e.g. a truncated triangle-like area),corresponding to the lateral
canthus. Only a single laser pass was delivered to the lateral canthal triangle
to avoid widening the lateral opening of the eyelid, which might lead to the
potential complications of scleral show and ectropion. When the area of the
crows' feet is to be treated, three passes on the skin of this entire lateral
orbital surface are completed by moving laterally and upward toward the hairline.
Patients examined on days 1, 7, 15, 30, 60, and one year after laser resurfacing
showed good results. At two months after treatment, the clinical improvement was
rated by the patient and physician as being "very good" in 81 of the 85 patients
reviewed. These patients underwent laser resurfacing without complications. The
proposed technique of periocular resurfacing prevents complications of scleral
show and laxity in the lateral eyelid opening and even ectropion, because
treatment conforms to the osseo-muscular anatomical relationship of eyelid
structures.
PMID- 10759811
TI - Lessons on dermoscopy. Diagnosis: seborrheic keratosis.
PMID- 10759812
TI - The National Comprehensive Cancer Network (NCCN) guidelines of care for
nonmelanoma skin cancers.
PMID- 10759813
TI - A call for dermatologic surgeons to take the board examination in dermatologic
cosmetic surgery from the American Board of Cosmetic Surgery.
PMID- 10759814
TI - The history and evolution of Mohs micrographic surgery.
PMID- 10759815
TI - Microfine zinc oxide is a superior sunscreen ingredient to microfine titanium
dioxide.
AB - BACKGROUND: Microfine zinc oxide and microfine titanium dioxide are particulate
sunscreen ingredients that absorb broad-spectrum ultraviolet (UV) irradiation.
OBJECTIVE: We compare microfine zinc oxide and microfine titanium dioxide for
their abilities to attenuate UVA radiation and their relative whiteness in
cosmetic formulations. METHODS: UVA attenuation was measured by diffuse
reflectance spectroscopy on normal human skin in vivo. Whiteness was determined
by reflectance density of dried coatings on a black background of the two
particulates at varying concentrations. RESULTS: Microfine zinc oxide
demonstrates superior protection compared to microfine titanium dioxide in the UV
spectrum between 340 and 380 nm. Microfine zinc oxide is less white than titanium
dioxide at all concentrations. CONCLUSION: Microfine zinc oxide is superior to
microfine titanium dioxide as a sunscreen ingredient. It is more protective
against long-wave UVA and is less white at a given concentration.
PMID- 10759816
TI - Powered liposuction.
AB - BACKGROUND: Although Arpad and Giorgio Fischer initially employed blades within
cannulas in their early research while inventing liposuction, hollow cannulas
have become the standard instrument for this procedure for the last quarter
century. Ultrasonic liposuction was developed in the 1990s to facilitate the
passage of cannulas through subcutaneous tissue while liquefying fat. However,
these instruments had a number of drawbacks including seromas and tissue burns.
Powered cannulas were introduced in 1995 by Gross for "liposhaving." This
technique was used on the neck with open surgery under direct observation.
OBJECTIVE: Based on these principles, a new powered liposuction device has been
designed for body liposuction. METHOD: An oscillating blade within a cannula
facilitates removal of fat, especially in fibrous areas such as male flanks and
breasts. This instrument has proven to be safe in numerous body areas. Powered
reciprocating cannulas also have been recently introduced. These simulate the "to
and fro" motion of manual liposuction and appear to be safe. CONCLUSION: Powered
liposuction may provide the advantages of ultrasonic liposuction with fewer
complications.
PMID- 10759817
TI - Treatment of multiple cutaneous leiomyomas with CO2 laser ablation.
AB - BACKGROUND: Cutaneous leiomyomas are benign tumors that can be exquisitely
painful. Symptomatic lesions often necessitate treatment, but many options are
inadequate or create substantial morbidity. Without a definitive therapy of first
choice, the search continues for alternative methods to alleviate discomfort in
affected patients. OBJECTIVE: To describe the use of CO2 laser ablation for the
symptomatic treatment of a 73-year-old woman with multiple cutaneous leiomyomas
in whom pharmacologic therapy was contraindicated and surgical excision was
impractical. METHODS: CO2 laser ablation of six symptomatic cutaneous leiomyomas
was performed under local anesthesia. After initial success, all remaining
symptomatic lesions were treated. RESULTS: There was complete pain relief in the
originally treated lesions 9 months postoperatively, and in all remaining treated
lesions 3 months postoperatively. CONCLUSION: CO2 laser ablation may be an
effective alternative treatment for symptomatic cutaneous leiomyomas.
PMID- 10759818
TI - Color duplex-guided sclerotherapy for the treatment of venous malformations.
AB - BACKGROUND: Although surgical extirpation is the standard method for the
treatment of vascular malformations, this procedure often leads to loss of motor
function, nerve damage, and massive bleeding if the excision is extensive.
Sclerotherapy is an alternative method of treatment for venous malformations.
OBJECTIVE: This study was conducted to assess the effect of color duplex
ultrasound-guided sclerotherapy on venous malformations and the coagulability
induced by sclerosing solution. METHODS: Twenty-eight patients with venous
malformations underwent percutaneous sclerotherapy by direct puncture under
duplex ultrasound guidance. Intravenous catheters were inserted into duplex
ultrasound-confirmed venous spaces and fine plastic tubing filled with normal
saline was attached to the needle. When the needle tip was observed to pierce the
vein wall, aspiration of the blood confirmed its intraluminal position. The mean
volume of 3.6 ml of 3% polidocanol was injected. Subfascial ligation of the
lateral marginal venous collector was performed in patients with Klippel
Trenaunay syndrome. D-dimer (DD) and thrombin-antithrombin III (TAT) were
measured preoperatively and on the first and fifth postoperative days. RESULTS:
The head and neck, which was the most common site of venous malformations were
involved in 57% of the patients. Venous malformations disappeared in 44% of the
patients and decreased in 28%. Localized pain was the most common complication,
occuring in 82% of the patients. Sclerotherapy for venous malformations produced
significant swelling in 75% of the patients, which required 5-7 days to subside.
Significant differences were detected in both DD and TAT concentrations on the
first and fifth postoperative days. CONCLUSIONS: Color duplex-guided
sclerotherapy was effective in 82% of the patients. This procedure prevents intra
arterial injection accidents. Although patients with venous malformations showed
greater coagulability, no serious thrombotic sequelae were found.
PMID- 10759819
TI - The efficacy of external ultrasound-assisted liposuction: a randomized controlled
trial.
AB - BACKGROUND: Use of high-intensity, high-frequency external ultrasound before
liposuction has been reported to enhance the ease of fat extraction, increase the
amount of fat extracted, and decrease patient discomfort during liposuction.
OBJECTIVE: The purpose of this study was to compare the effect of application of
high-intensity continuous wave ultrasound to extremely low-intensity ultrasound
(placebo) prior to tumescent liposuction. METHODS: A total of 19 patients (25
sites) completed the double-blind study. We used a split treatment area design so
that each patient could serve as their own control. After tumesing the treatment
area, a 3 W/cm2 continuous wave 1 MHz ultrasound was applied for 10 minutes. The
placebo control was treated with 0.3 W/cm2 1 MHz for 10 minutes. Traditional
tumescent liposuction followed ultrasound application. Doctors completed a visual
analog scale rating the following: rate of extraction, degree of resistance to
cannula movement, and color of fat. Patients also completed a questionnaire after
the procedure and at 1 month postoperatively. Histologic samples of the fat
treated with external ultrasound were taken from two patients. RESULTS: In 14 of
19 patients the doctors graded either no difference between treatment and control
sides or found a better response on the nontreated side in rate of fat removal
and resistance to cannula advancement giving a P value of .0096. Only 5 of 19
aspirates were graded as differing in redness between treatment and control
sides. Four of these were more red on the control side and one was more red on
the treatment side. Therefore 15 of 19 had no better result with treatment,
giving a P value of .0022. Seven patients graded the sensation during suctioning
and/or postoperative course as better on the control side, four graded these
variables as better on the treatment side, four showed no difference between the
two sides, and four had mixed results. This gives only 4 of the 19 patients
showing any advantage in treatment with a P value of .0022. CONCLUSION: When the
placebo effect is eliminated, there is no advantage to the application of
external ultrasound prior to liposuction.
PMID- 10759820
TI - Efficacy of hydroquinone cream (USP 4%) used alone or in combination with
salicylic acid peels in improving photodamage on the neck and upper chest.
AB - BACKGROUND: Salicylic acid, hydroquinone, and glycolic acid have been proved
effective in the treatment of photodamaged facial skin. Few reports are available
on the treatment of photodamage on the neck and upper chest. OBJECTIVE: This
study's purpose was to evaluate the efficacy of a cream containing 4%
hydroquinone and 2% glycolic acid (LUSTRA) used alone or with salicylic acid
peels in reversing actinic damage on the neck and upper chest. METHODS: Nineteen
women with moderate to advanced photodamage on the neck and upper chest applied a
cream containing 4% hydroquinone and 2% glycolic acid twice daily on photodamaged
areas for 12 weeks. Nine of these subjects had salicylic acid peels every 3
weeks. Improvements were assessed by the investigator, the subjects, and
Mexameter readings measuring melanin and erythema levels. RESULTS: The result
shows that there was a 33-71% improvement in photodamage, hyperpigmentation,
texture, fine lines, dryness, tone, and clarity in both groups. There were no
significant differences between the two treatments. CONCLUSION: Hydroquinone 4%
cream with 2% glycolic acid is safe and effective in improving photodamage on the
neck and upper chest when used alone or in combination with salicylic acid peels.
PMID- 10759821
TI - A pilot study to evaluate the treatment of basal cell carcinoma with 5
fluorouracil using phosphatidyl choline as a transepidermal carrier.
AB - BACKGROUND: In certain situations, successful topical therapy of basal cell
carcinoma (BCC) without the inconvenience, risk, and expense of surgery would be
of great value to patients. Placing 5-fluorouracil (FU) in an appropriate carrier
may solve these problems. Phosphatidyl choline (PC) penetrates effectively
throughout the epidermis of shaved rabbits and may be able to carry small water
soluble molecules such as nucleotides across lipid barriers when applied
topically. OBJECTIVE: We propose that employing PC as a vehicle will facilitate
the penetration of 5-FU and increase efficacy as compared to petrolatum-based 5
FU cream. METHODS: This pilot study is a double-blinded and randomized
therapeutic trial. Thirteen patients with 17 biopsy-proven, moderate thickness
BCCs were randomized to receive either cream A (5% 5-FU in a PC vehicle) or cream
B (Efudex(R): 5% 5-FU in a petrolatum base). Patients applied cream A or cream B
twice a day for 4 weeks. The patients underwent an excisional biopsy of the
treated BCC site at week 16. RESULTS: There was a 90% cure rate (9/10) in those
lesions treated with 5% 5-FU in PC cream and a 57% cure rate (4/7) in those
treated with 5% 5-FU in a petrolatum-based cream. CONCLUSION: Although the study
was unable to detect any statistically significant differences in outcome between
the study groups, this small pilot study shows preliminary findings which may
indicate an increase in the short-term eradication of BCC using a PC-based
vehicle as compared to conventional petrolatum-based formulations.
PMID- 10759822
TI - Wound care following CO2 laser resurfacing using Kaltostat, Duoderm, and Telfa
for dressings.
AB - BACKGROUND: There are a variety of dressings available for wound care following
CO2 laser resurfacing. OBJECTIVE: To share the experience of using Kaltostat and
Duoderm for wound care following laser resurfacing. METHODS: A total of 27
patients underwent laser resurfacing, including 12 for wrinkles and 15 for acne
scars. Kaltostat pads and Duoderm sheets were cut into appropriate shapes to
cover the laser-treated areas. The patients' families changed the dressings when
the exudate accumulating under Duoderm began to leak. Kaltostat pads were used
only for the first 2-3 days when the amount of discharge was profuse. Telfa pads
were used rather than Kaltostat in two cases. Duoderm alone was used thereafter
to the day of complete reepithelialization. Patients returned to the hospital on
days 4, 7, and 10. RESULTS: Complete reepithelialization occurred by day 7 in
patients with wrinkles and day 10 in patients with acne scars. The degree of
postoperative erythema was mild to moderate. CONCLUSIONS: Duoderm worked well for
postresurfacing wound healing. Kaltostat fibers were difficult to remove totally.
Telfa pads can be used instead of Kaltostat.
PMID- 10759823
TI - Donor harvesting: a new approach to minimize transection of hair follicles.
AB - BACKGROUND: There are several methods for harvesting donor hairs, including punch
excision, single-bladed knife excision, and multibladed knife excision. All of
these procedures are blind and thus result in transection of hair follicles.
Transection of hair follicles during harvesting results in fewer follicles being
available for transplantation, detrimentally affecting the final cosmetic result.
OBJECTIVE: To explore a new method of donor hair harvesting called "donor
dissecting." This new procedure is an open technique because hair follicles are
directly visualized during the harvesting process. METHODS: The technique of
donor dissecting utilizes a #15 scalpel blade to excise the donor hair ellipse
from the occiput while maintaining meticulous hemostasis. This enables individual
hair follicles to be visualized and protected from transection during the
harvesting process. Once the donor ellipse is harvested, it is then further
divided into individual mini- and micrografts using direct visualization of
individual follicles to again prevent transection. RESULTS: The technique of
donor dissecting was utilized in 50 consecutive hair transplant patients.
Utilizing this new technique, only 1.9% of hair follicles in the donor ellipse
were transected during the harvesting process. The dissection of the donor
ellipse 1.2% follicles being transected in the graft cutting process. Combining
the donor dissection technique with dissection of the individual grafts, we were
able to transect 1.59% of hair follicles harvested for transplantation.
CONCLUSION: The technique of donor dissection minimizes the transection of hair
follicles in the donor hair harvesting phase of hair transplantation. This
technique is superior to the blind methods of donor harvesting which have been
plagued by the problem of hair follicle transection.
PMID- 10759824
TI - Comparison of electrodessication with CO2 laser for the treatment of actinic
cheilitis.
AB - BACKGROUND: Actinic cheilitis is a common premalignant condition that is most
often treated with destructive therapy. The most effective technique is usually
considered to be CO2 laser resurfacing. Little has been written on the use of
electrodessication for this condition. OBJECTIVE: We designed a study to compare
these two treatment modalities for the treatment of biopsy-confirmed actinic
cheilitis. METHODS: A random half of the lower lip was treated with
electrodessication. The contralateral half was then treated with CO2 laser.
Healing time, subjective pain during healing, and clinical outcome at 3 months
was compared. RESULTS: The side treated with electrodessication took
significantly longer to heal than the side treated with the CO2 laser (23 versus
14 days, P <.001). There was no difference in subjective pain or clinical
appearance at 3 months. CONCLUSION: Although the healing time is longer with
electrodessication, this modality represents an inexpensive practical ablative
treatment method for actinic cheilitis.
PMID- 10759825
TI - A review of the bilobed flap's design with particular emphasis on the
minimization of alar displacement.
AB - BACKGROUND: The bilobed flap excels in the surgical reconstruction of the distal
nose. Unfortunately the aesthetic success of the flap is occasionally limited by
the production of distracting alar displacement. OBJECTIVE: To review elements of
the bilobed flap's design with a particular emphasis on understanding techniques
to minimize distortion of the alar margins. CONCLUSION: With a proper
understanding of the bilobed flap's intricate design, the surgeon can anticipate
those factors that are most likely to produce temporary or permanent alar
asymmetry. Appropriate prospective flap design and meticulous surgical technique
can significantly minimize the risk of a poor surgical outcome.
PMID- 10759826
TI - Dog-ears: a review.
AB - BACKGROUND: The closure of any circular or asymmetric wound results in puckering
or excess of tissue known as dog-ears. OBJECTIVE: Facility in managing dog-ears
is an invaluable tool in cutaneous surgery due to its common presentation.
METHODS: Methods for correcting dog-ears are extensively detailed in both the
plastic and dermatologic surgery literature. This review provides a practical
outline of nine methods of dog-ear correction along with pertinent schematic and
clinical illustration. RESULTS: A comprehensive approach to dog-ears requires
knowledge of tissue dynamics, adherence to proper surgical technique, and
strategies for the management of dog-ears. CONCLUSIONS: A thorough understanding
of dog-ear formation and correction allows the surgeon to choose the most
appropriate management for dog-ears in any clinical setting.
PMID- 10759827
TI - Botulinum toxin type A for the treatment of axillary Hailey-Hailey disease.
AB - BACKGROUND: Hailey-Hailey disease is an inherited acantholytic disorder affecting
the intertriginous areas of the body which is exacerbated by sweat, moisture, and
friction. The disease is frequently resistant to conventional nonsurgical
treatment. OBJECTIVE: To evaluate whether chemodenervation of sweat glands would
improve the course of the disease in a patient with Hailey-Hailey. METHODS: We
used low-dose treatment of the left axilla with botulinum toxin type A, the right
axilla being used as a control, followed by treatment of both axillae with the
optimal dose routinely used for the treatment of axillary hyperhidrosis. RESULTS:
After one treatment with a low dose of botulinum toxin type A, we observed
partial improvement of the treated axilla. With subsequent treatment of both
axillae with the recommended dose for axillary hyperhidrosis, we observed a
sustained complete remission of the disease in the treated axillae. CONCLUSION:
Botulinum toxin type A may be an effective and safe nonsurgical alternative for
the treatment of benign familial pemphigus in intertriginous areas such as the
axillae.
PMID- 10759828
TI - Pleomorphic lipoma: case report and literature review.
AB - BACKGROUND: Pleomorphic lipoma is a rare, benign, pseudosarcomatous, soft tissue
neoplasm typically involving the subcutis of the neck and shoulder in middle-aged
to elderly men. It is characterized histologically by atypical, multinucleated
giant cells and grossly as a well-circumscribed mass. Since this neoplasm can
resemble a sarcoma, histopathologic diagnosis is critical in preventing
unnecessary surgery. OBJECTIVE: To describe a case of pleomorphic lipoma in the
neck and to review the clinical and histopathologic characteristics of this
neoplasm. METHODS: We present a case report and review of the literature.
RESULTS: Local excision to completely extirpate this neoplasm has proven curative
at 10 months of follow-up. CONCLUSION: Pleomorphic lipoma is superficially
located and may be encountered in a dermatologic setting. Thus the dermatologist
should become familiar with its clinical presentation and microscopic appearance.
PMID- 10759829
TI - Serial excision of a large facial skin cancer.
AB - BACKGROUND: In the management of large facial neoplasms, the dermatologic surgeon
must consider local factors affecting the success of closures. OBJECTIVE: Large
facial neoplasms can be removed serially with Mohs micrographic surgery. Serial
excision facilitates recruitment of adjacent normal skin for replacement of
lesional skin, minimizing the risks of necrosis. METHODS: A large morpheaform
basal cell carcinoma was excised serially. The initial defect was closed with an
O to L advancement flap. The final excision and repair 2 months later consisted
of a combination of primary closure with marsupialization and pursestring
closure. A full-thickness skin graft was used to close the final defect. RESULTS:
The patient had optimal cosmesis at 2-year follow-up. CONCLUSION: Large facial
neoplasms can be excised serially. This technique, performed in the setting of
Mohs micrographic surgery, takes advantage of "mechanical and biologic creep,"
resulting in excellent cosmesis and function.
PMID- 10759830
TI - A simple method of identifying the spinal accessory nerve.
AB - The spinal accessory nerve (nerve XI) constitutes a unique and readily
encountered hazard in cutaneous and subcutaneous surgery of the head and neck.
Presented is a simple method of using pinprick hyperaesthesia to accurately
identify the course of this nerve. Delineating this nerve prior to performing
surgery in the lateral neck and shoulder region is crucial to avoid the
potentially disastrous complication of severing this nerve.
PMID- 10759831
TI - Reconstruction conundrums
PMID- 10759832
TI - Liposuction of neck and jowls: five-incision method combining machine-assisted
and syringe aspiration.
AB - BACKGROUND: Liposuction of the jowl region is difficult from a single submental
incision and must be done conservatively in order to avoid overresection of fat.
The neck region may be suctioned much more completely. OBJECTIVE: A new method
for liposuction of the neck and jowls that uses five incisions and that combines
syringe suctioning of the jowls and machine-assisted suctioning of the neck has
been developed. METHODS: The neck was suctioned from submental and infra
auricular incisions. The jowls were suctioned from the infra-auricular and
additional infrajowl incisions. RESULTS: This method has been used on 68 patients
over a 3-year period. Three additional patients underwent syringe liposuction of
only the jowls. Volumes of fat aspirated from bilateral jowls were consistently
nearly equal. The incidence of adverse events was low. CONCLUSION: This method
enables conservative removal of jowl fat and thorough removal of neck fat, with a
low incidence of adverse sequalae.
PMID- 10759833
TI - Treatment of axillary hyperhidrosis: combination of the starch-iodine test with
the tumescent liposuction technique.
AB - OBJECTIVE: To evaluate and permanently improve axillary hyperhidrosis.
BACKGROUND: Excessive sweating of the axillae is a common problem for which
patients frequently seek dermatologic advice and therapy. Many treatments,
including aluminum chloride, topical and systemic anticholinergic agents,
tranquilizers, iontophoresis, direct surgical excision, botulinum toxin
injection, and thoracic sympathectomy, have been employed to control this
problem. All have drawbacks of one sort or another. METHODS: The starch-iodine
technique for delineation of preoperative and postoperative axillary sweating is
described in detail. A method of sweat gland removal utilizing tumescent
liposuction is discussed. RESULTS AND CONCLUSION: The combination of the starch
iodine technique and tumescent liposuction is safe and effective for therapy of
axillary hyperhidrosis.
PMID- 10759834
TI - Lessons on dermoscopy. Compound congenital melanocytic nevus.
PMID- 10759835
TI - Mohs surgery: debulking specimens--to submit or discard--that is the question.
PMID- 10759836
TI - Overexpression of enzymes that repair endogenous damage to DNA.
AB - A significant contribution to human mutagenesis and carcinogenesis may come from
DNA damage of endogenous, rather than exogenous, origin. Efficient repair
mechanisms have evolved to cope with this. The main repair pathway involved in
repair of endogenous damage is DNA base excision repair. In addition, an
important contribution is given by O6-alkylguanine DNA alkyltranferase, that
repairs specifically the miscoding base O6-alkylguanine. In recent years, several
attempts have been carried out to enhance the efficiency of repair of endogenous
damage by overexpressing in mammalian cells single enzymatic activities. In some
cases (e.g. O6-alkylguanine DNA alkyltransferase or yeast AP endonuclease) this
approach has been successful in improving cellular protection from endogenous and
exogenous mutagens, while overexpression of other enzymatic activities (e.g.
alkyl N-purine glycosylase or DNA polymerase beta) were detrimental and even
produced a genome instability phenotype. The reasons for these different outcomes
are analyzed and alternative enzymatic activities whose overexpression may
improve the efficiency of repair of endogenous damage in human cells are
proposed.
PMID- 10759837
TI - Characterization and crystallization of an active N-terminally truncated form of
the Escherichia coli glycogen branching enzyme.
AB - The prokaryotic glycogen branching enzymes (GBE) can be divided into two groups
on the basis of their primary structures: the first group of enzymes, which
includes GBE from Escherichia coli, is characterized by a long N-terminal
extension that is absent in the enzymes of the second group. The extension
consists of approximately 100 amino-acid residues with unknown function. In order
to characterize the function of this region, the 728 amino-acid residue, full
length E. coli GBE, and a truncated form (nGBE) missing the first 107 amino-acid
residues were overexpressed in E. coli. Both enzymes were purified to homogeneity
by a simple purification procedure involving ammonium sulphate precipitation, ion
exchange chromatography, and a second ammonium sulphate precipitation. Purified
full-length enzyme was poorly soluble and formed aggregates, which were inactive,
at concentrations above 1 mg.mL-1. In contrast, the truncated form could be
concentrated to 6 mg.mL-1 without any visible signs of aggregation or loss of
activity on concentration. The ability to overexpress nGBE in a highly soluble
form has allowed us to produce diffracting crystals of a branching enzyme for the
first time. A comparison of the specific activities of purified GBE and nGBE in
assays where amylose was used as substrate demonstrated that nGBE retained
approximately half of the branching activity of full-length GBE and is therefore
a suitable model for the study of the enzymes' catalytic mechanism.
PMID- 10759838
TI - A pea nuclear protein that is induced by dehydration belongs to the vicilin
superfamily.
AB - The purification to homogeneity of p16, a protein with an electrophoretic
mobility compatible with an apparent molecular mass of 16 kDa, from nuclei of
ungerminated pea embryonic axes is described. A cDNA clone of its gene, which was
designated psp54, was also isolated. The psp54 cDNA contains an open reading
frame coding for a 54.4-kDa polypeptide (p54). p16 corresponds to the C-terminal
third of p54, although the mechanisms by which the primary polypeptide could be
processed are not yet known. The sequence of p54 is 60% identical with that of
the precursor of a sucrose-binding soybean protein, and, to a lesser extent (31
34%), it shares homology with some storage proteins. p16 is also 30% homologous
with Nhp2p, a yeast nuclear protein. The psp54 gene, present in a single copy in
pea genome, starts being expressed during seed desiccation. Soon after
rehydration in seed germination, p54 mRNA disappears and is no longer detectable
in vegetative tissues, except in response to hydric stress (exposure to abscisic
acid, osmolites or desiccation). p16 can be recovered from nuclei cross-linked to
histone H3, when the disulfide bridges that occur in vivo are preserved. On the
other hand, p16 shares some properties with dehydrins, which are thought to
protect cellular structures against desiccation. We propose that the possible
precursor polypeptide p54 belongs to the vicilin superfamily, members of which
play a variety of roles. The function of p16 may be related to the protection of
chromatin structure against desiccation during seed development.
PMID- 10759839
TI - Activity of wheat alpha-amylase inhibitors towards bruchid alpha-amylases and
structural explanation of observed specificities.
AB - Plant alpha-amylase inhibitors show great potential as tools to engineer
resistance of crop plants against pests. Their possible use is, however,
complicated by observed variations in specificity of enzyme inhibition, even
within closely related families of inhibitors. Five alpha-amylase inhibitors of
the structural 0.19 family were isolated from wheat kernels, and assayed against
three insect alpha-amylases and porcine pancreatic alpha-amylase, revealing
several intriguing differences in inhibition profiles, even between proteins
sharing sequence identity of up to 98%. Inhibition of the enzyme from a
commercially important pest, the bean weevil Acanthoscelides obtectus, is
observed for the first time. Using the crystal structure of an insect alpha
amylase in complex with a structurally related inhibitor, models were constructed
and refined of insect and human alpha-amylases bound to 0.19 inhibitor. Four key
questions posed by the differences in biochemical behaviour between the five
inhibitors were successfully explained using these models. Residue size and
charge, loop lengths, and the conformational effects of a Cys to Pro mutation,
were among the factors responsible for observed differences in specificity. The
improved structural understanding of the bases for the 0.19 structural family
inhibitor specificity reported here may prove useful in the future for the
rational design of inhibitors possessing altered inhibition characteristics.
PMID- 10759840
TI - Sequencing and analysis of the Mmethylococcus capsulatus (Bath) solublemethane
monooxygenase genes.
AB - The soluble methane monooxygenase (sMMO) hydroxylase is a prototypical member of
the class of proteins with non-heme carboxylate-bridged diiron sites. The sMMO
subclass of enzyme systems has several distinguishing characteristics, including
the ability to catalyze hydroxylation or epoxidation chemistry, a multisubunit
hydroxylase containing diiron centers in its alpha subunits, and the requirement
of a coupling protein for optimal activity. Sequence homology alignment of known
members of the sMMO family was performed in an effort to identify protein regions
giving rise to these unique features. DNA sequencing of the Methylococcus
capsulatus (Bath) sMMO genes confirmed previously identified sequencing errors
and corrected two additional errors, each of which was confirmed by at least one
independent method. Alignments of homologous proteins from sMMO, phenol
hydroxylase, toluene 2-, 3-, and 4-monooxygenases, and alkene monooxygenase
systems revealed an interesting set of absolutely conserved amino-acid residues,
including previously unidentified residues located outside the diiron active site
of the hydroxylase. By mapping these residues on to the M. capsulatus (Bath) sMMO
hydroxylase crystal structure, functional and structural roles were proposed for
the conserved regions. Analysis of the active site showed a highly conserved
hydrogen-bonding network on one side of the diiron cluster but little homology on
the opposite side, where substrates are presumed to bind. It is suggested that
conserved residues on the hydroxylase surface may be important for protein
protein interactions with the reductase and coupling ancillary proteins and/or
serve as part of an electron-transfer pathway. A possible way by which binding of
the coupling protein at the surface of the hydroxylase might transfer information
to the diiron active site at the interior is proposed.
PMID- 10759841
TI - Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal
fragments thereof, correlates to formation of beta-sheet structure and fibrils.
AB - The non-Abeta component of Alzheimer's disease amyloid (NAC) and its precursor
alpha-synuclein have been linked to amyloidogenesis in Alzheimer's disease (AD),
Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Previously we have
shown that NAC forms beta-sheet structures and fibrils [El-Agnaf, O.M.A., Bodles,
A.M., Guthrie, D.J.S., Harriott, P. & Irvine, G.B. (1998) Eur. J. Biochem. 258,
157-163]. As a measure of their neurotoxic potential we have examined the ability
of fresh and aged NAC and fragments thereof to inhibit the reduction of the redox
dye 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide by rat
pheochromocytoma PC12 cells. Micromolar concentrations of NAC and fragments
thereof display varying degrees of toxicity. On immediate dissolution and after
an incubation period for 3 days at 37 degrees C the full-length peptide and
fragments NAC(3-18) and NAC(1-18) scrambled sequence [NAC(1-18 s)] were toxic,
whereas fragments NAC(1-13) and NAC(6-14) were not. CD indicates that NAC(3-18)
and NAC(1-18 s) exhibit beta-sheet secondary structure in aqueous solution,
whereas NAC(1-13) and NAC(6-14) do not. NAC(3-18) aggregates, as indicated by
concentration of peptide remaining in solution after 3 days measured by an HPLC
assay, and forms fibrils, as determined by electron microscopy. However, although
some fibrils were detected for NAC(1-18 s) it does not come out of solution to a
significant degree. Fragments NAC(1-13) and NAC(6-14) form few fibrils and remain
in solution. These findings indicate that the ability of the central region of
NAC to form beta-sheet secondary structures is important for determining the
toxicity of the peptide. This contrasts with what has been reported previously
for most Abeta peptides as their toxicity appears to require the peptide to have
formed fibrillary aggregates as well as displaying beta-sheet. These results
suggest that an intermediate, which exhibits beta-sheet structure, may be
responsible for the toxic properties of NAC and provides further evidence for the
role of NAC in the pathogenesis of AD, PD and DLB.
PMID- 10759842
TI - High-molecular-mass complexes formed in vivo contain smHSPs and HSP70 and display
chaperone-like activity.
AB - Stress can have profound effects on the cell. The elicitation of the stress
response in the cell is often accompanied by the synthesis of high-molecular-mass
complexes, sometimes termed heat shock granules (HSGs). The presence of the
complexes has been shown to be important for the survival of cells subjected to
stress. We purified these complexes from heat-stressed BY-2 tobacco cells. HSG
complexes formed in vivo contain predominantly smHSPs, HSP40 and HSP70 and
display chaperone-like activity. Tubulins as well as other proteins may be part
of the complex or its substrate. The proteins, except smHSPs and to some extent
HSP70, were hypersensitive to proteolysis, suggesting that they were partially
denatured and not an integral part of the HSG complexes. When citrate synthase
was used as the substrate, in vivo generated HSG complexes exhibited strong
nucleotide-dependent in vitro chaperone activity. Measurable ATP-mediated
hydrolytic activity was detected. Isolated HSG complexes are stable until ATP is
added, which leads to rapid dissociation of the complex into subunits. It is
proposed that smHSPs form the core of the complex in association with ATP
dependent HSP70 and HSP40 cochaperones. Implications of these findings are
discussed.
PMID- 10759843
TI - The central domain of bovine submaxillary mucin consists of over 50 tandem
repeats of 329 amino acids. Chromosomal localization of the BSM1 gene and
relations to ovine and porcine counterparts.
AB - We previously elucidated five distinct protein domains (I-V) for bovine
submaxillary mucin, which is encoded by two genes, BSM1 and BSM2. Using Southern
blot analysis, genomic cloning and sequencing of the BSM1 gene, we now show that
the central domain (V) consists of approximately 55 tandem repeats of 329 amino
acids and that domains III-V are encoded by a 58.4-kb exon, the largest exon
known for all genes to date. The BSM1 gene was mapped by fluorescence in situ
hybridization to the proximal half of chromosome 5 at bands q2. 2-q2.3. The amino
acid sequence of six tandem repeats (two full and four partial) were found to
have only 92-94% identities. We propose that the variability in the amino-acid
sequences of the mucin tandem repeat is important for generating the
combinatorial library of saccharides that are necessary for the protective
function of mucins. The deduced peptide sequences of the central domain match
those determined from the purified bovine submaxillary mucin and also show 68-94%
identity to published peptide sequences of ovine submaxillary mucin. This
indicates that the core protein of ovine submaxillary mucin is closely related to
that of bovine submaxillary mucin and contains similar tandem repeats in the
central domain. In contrast, the central domain of porcine submaxillary mucin is
reported to consist of 81-amino-acid tandem repeats. However, both bovine
submaxillary mucin and porcine submaxillary mucin contain similar N-terminal and
C-terminal domains and the corresponding genes are in the conserved linkage
regions of the respective genomes.
PMID- 10759844
TI - Rough and smooth forms of fluorescein-labelled bacterial endotoxin exhibit
CD14/LBP dependent and independent binding that is influencedby endotoxin
concentration.
AB - Lipopolysaccharide (LPS, or endotoxin), is a major constituent of the outer
membrane of Gram-negative bacteria. Bacteria express either smooth LPS, which is
composed of O-antigen (O-Ag), complete core oligosaccharides, and the lipid A, or
rough LPS which lack O-Ag but possess lipid A and progressively shorter core
oligosaccharides. CD14 has been described as the receptor for complexes of LPS
with LPS-binding protein (LBP). Using flow cytometry we have compared the binding
of Salmonella minnesota rough LPS (ReLPS) and Escherichia coli smooth LPS
labelled with fluorescein isothiocyanate (FITC-LPS) to Chinese hamster ovary
(CHO) cells transfected with human CD14 gene (hCD14-CHO), to MonoMac 6 cells and
to endothelial cells. Our results showed that both forms of LPS display the same
binding characteristics, and that the binding of FITC-LPS to cells was both CD14-
and LBP-dependent for LPS concentrations up to 100 ng.mL-1. At LPS concentrations
higher than 100 ng.mL-1 we observed CD14/LBP-independent binding. CD14/LBP
dependent binding was dose dependent, saturable, and enhanced in the presence of
human pooled serum (HPS), and the monoclonal anti-CD14 antibody (MY4) or
unlabelled LPS could outcompete it.
PMID- 10759845
TI - Structure-function relationships in the carboxylic-ester-hydrolase superfamily.
Disulfide bridge arrangement in porcine intestinal glycerol-ester hydrolase.
AB - CNBr fragments from porcine intestinal glycerol-ester hydrolase were separated by
SDS/PAGE under reducing and nonreducing conditions, and their amino-acid
sequences were analysed. Two intra-chain disulfide bridges were identified,
namely Cys70-Cys99 (loop A) and Cys256-Cys267 (loop B). As the Cys71 sulfhydryl
group could not be alkylated with iodoacetamide, it is suggested that the residue
is blocked rather than being present in the free form. The two disulfide bridges
of intestinal glycerol-ester hydrolase are present in the cholinesterase family,
although the enzyme showed only about 35% identity with these proteins.
Furthermore, the finding that glycerol-ester hydrolase was partly inactivated
under reducing conditions suggests that one or both disulfide bridges are
important for the enzyme conformation. Lastly, glycerol-ester hydrolase was also
found to hydrolyse cholinergic substrates, although residues Trp86 and Asp74
which are considered to be the main constituents of the 'anionic' subsite
responsible for substrate binding in cholinesterases were absent from loop A.
Other amino-acid residues in the glycerol-ester hydrolase may therefore be
responsible for the binding of cholinergic substrates to the enzyme.
PMID- 10759846
TI - Pressure denaturation of beta-lactoglobulin. Different stabilities of isoforms A
and B, and an investigation of the Tanford transition.
AB - Beta-lactoglobulin, the main whey protein in bovine milk, exists in several
isoforms of which the most abundant are isoforms A and B. We have previously
reported the denaturation of beta-lactoglobulin A by hydrostatic pressure
[Valente-Mesquita, V.L., Botelho, M.M. & Ferreira, S.T. (1998) Biophys. J. 75,
471-476]. Here, we compare the pressure stabilities of isoforms A and B. These
isoforms differ by two amino-acid substitutions: Asp64 and Val118 in isoform A
are replaced by glycine and alanine, respectively, in isoform B. Replacement of
the buried Val118 residue by the smaller alanine side-chain is not accompanied by
significant structural rearrangements of the neighbouring polypeptide chain and
creates a cavity in the core of beta-lactoglobulin. Pressure denaturation
experiments revealed different stabilities of the two isoforms. Standard volume
changes (DeltaVunf) of - 49 +/- 8 mL.mol-1 and -75 +/- 3 mL.mol-1, and unfolding
free energy changes (DeltaGunf) of 8.5 +/- 1.3 kJ.mol-1 and 11.3 +/- 0.4 kJ.mol-1
were obtained for isoforms A and B, respectively. The volume occupied by the two
methyl groups of Val118 removed in the V118A substitution is approximately 40 A3
per monomer of beta-lactoglobulin, in excellent agreement with the experimentally
measured difference in DeltaVunf for the two isoforms (DeltaDeltaVunf = 26 mL.mol
1, corresponding to approximately 43 A3 per monomer). Thus, the existence of a
core cavity in beta-lactoglobulin B may explain its enhanced pressure sensitivity
relative to beta-lactoglobulin A. beta-Lactoglobulin undergoes a reversible pH
induced conformational change around pH 7, known as the Tanford transition. We
have compared the pressure denaturation of beta-lactoglobulin A at pH 7 and 8.
Unfolding free energy changes of 8.5 +/- 1.3 and 8.3 +/- 0.3 kJ.mol-1 were
obtained at pH 7 and 8, respectively, showing that the thermodynamic stability of
beta-lactoglobulin is identical at these pH values. Interestingly, DeltaVunf was
dependent on pH, and varied from -49 +/- 8 mL.mol-1 to -68 +/- 2 mL.mol-1 at pH 7
and 8, respectively. The large increase in DeltaVunf at pH 8 relative to pH 7
appears to be associated with an overall expansion of the protein structure and
could explain the increased pressure sensitivity of beta-lactoglobulin at
alkaline pH.
PMID- 10759847
TI - The C1-C2 interface residue lysine 50 of pig kidney fructose-1, 6-bisphosphatase
has a crucial role in the cooperative signal transmission of the AMP inhibition.
AB - To understand the mechanism of signal propagation involved in the cooperative AMP
inhibition of the homotetrameric enzyme pig-kidney fructose-1,6-bisphosphatase,
Arg49 and Lys50 residues located at the C1-C2 interface of this enzyme were
replaced using site-directed mutagenesis. The mutant enzymes Lys50Ala, Lys50Gln,
Arg49Ala and Arg49Gln were expressed in Escherichia coli, purified to homogeneity
and the initial rate kinetics were compared with the wild-type recombinant
enzyme. The mutants exhibited kcat, Km and I50 values for fructose-2,6
bisphosphate that were similar to those of the wild-type enzyme. The kinetic
mechanism of AMP inhibition with respect to Mg2+ was changed from competitive
(wild-type) to noncompetitive in the mutant enzymes. The Lys50Ala and Lys50Gln
mutants showed a biphasic behavior towards AMP, with total loss of cooperativity.
In addition, in these mutants the mechanism of AMP inhibition with respect to
fructose-1,6-bisphosphate changed from noncompetitive (wild-type) to
uncompetitive. In contrast, AMP inhibition was strongly altered in Arg49Ala and
Arg49Gln enzymes; the mutants had > 1000-fold lower AMP affinity relative to the
wild-type enzyme and exhibited no AMP cooperativity. These studies strongly
indicate that the C1-C2 interface is critical for propagation of the cooperative
signal between the AMP sites on the different subunits and also in the mechanism
of allosteric inhibition of the enzyme by AMP.
PMID- 10759848
TI - Purification of proctolin-binding proteins from the foregut of the insect
Blaberus craniifer.
AB - A membrane protein that specifically binds the insect neuropeptide proctolin was
purified using standard chromatography from cockroach foregut membranes.
Proctolin-binding sites were efficiently solubilized with either the nonionic
detergent digitonin or the zwitterionic detergent Chaps, as indicated by the
specific binding of 3H-proctolin to solubilized samples. A solubilized sample
obtained from 1600 foregut membranes was subjected to a five-step chromatographic
purification including chromatofocusing, anion-exchange and size-exclusion
chromatographies. The final size-exclusion separation resulted in the isolation
of approximately 100 pmol of purified proctolin-binding proteins, eluting as a
single peak at approximately 74 kDa. Analysis of the purified sample using
SDS/PAGE and silver staining showed two bands at 80 kDa and 76 kDa. Densitometric
analysis of the gel indicated that each band contained approximately 7-8 microg
of protein, suggesting that one band corresponds to the proctolin-binding
activity. Proctolin-binding proteins were thus purified 1800-fold using standard
chromatography.
PMID- 10759849
TI - An anti-idiotypic antibody with an internal image of human interferon-gamma and
human interferon-gamma-like antiviral activity.
AB - D9D10, a monoclonal antibody that inhibits the biological activity of human
interferon-gamma (IFN-gamma), was used to generate monoclonal anti-idiotypic
antibodies. After a first selection, the monoclonal anti-idiotypic antibody AA1E5
was chosen to be fully characterized. To the best of our knowledge this is the
first description of a monoclonal antibody with an IFN-gamma-like antiviral
activity; AA1E5 competed with IFN-gamma for binding to D9D10 indicating its anti
idiotypic character. However, AA1E5 also fully mimics HuIFN-gamma as it not only
binds to the HuIFN-gamma-receptor, where it competes with HuIFN-gamma, but more
importantly AA1E5 and its Fv fragment, cloned and expressed in Escherichia coli,
mimic the antiviral activity of HuIFN-gamma. Indeed, 15 microg of AA1E5 and 2.5
microg of its Fv fragment had an effect comparable to that of 10 IU of HuIFN
gamma in an antiviral assay on A549 cells. Sequence comparison between the
complementarity determination regions of the antibody and the sequence of HuIFN
gamma revealed that both the heavy chain variable domain, VH, and the kappa light
chain variable domain, Vkappa, have epitopes of 3-4 amino acids that are present
in the HuIFN-gamma sequence, some of which contribute to receptor binding, as
identified by Walter et al. [M. R. Walter, W. T. Windsor, T. L. Nagabhushan, D.
J. Lundell, C. A. Lunn, P. J. Zauodny & S. K. Narula (1995) Nature 376, 230-235].
PMID- 10759850
TI - Deduced amino-acid sequence and possible catalytic residues of a novel pectate
lyase from an alkaliphilic strain of Bacillus.
AB - The nucleotide sequence of the gene for a highly alkaline, low-molecular-mass
pectate lyase (Pel-15) from an alkaliphilic Bacillus isolate was determined. It
harbored an open reading frame of 672 bp encoding the mature enzyme of 197 amino
acids with a predicted molecular mass of 20 924 Da. The deduced amino-acid
sequence of the mature enzyme showed very low homology (< 20.4% identity) to
those of known pectinolytic enzymes in the large pectate lyase superfamily (the
polysaccharide lyase family 1). In an integrally conserved region designated the
BF domain, Pel-15 showed a high degree of identity (40.5% to 79.4%) with pectate
lyases in the polysaccharide lyase family 3, such as PelA, PelB, PelC, and PelD
from Fusarium solani f. sp. pisi, PelB from Erwinia carotovora ssp. carotovora,
PelI from E. chrysanthemi, and PelA from a Bacillus strain. By site-directed
mutagenesis of the Pel-15 gene, we replaced Lys20 in the N-terminal region,
Glu38, Lys41, Glu47, Asp63, His66, Trp78, Asp80, Glu83, Asp84, Lys89, Asp106,
Lys107, Asp126, Lys129, and Arg132 in the BF domain, and Arg152, Tyr174, Lys182,
and Lys185 in the C-terminal region of the enzyme individually with Ala and/or
other amino acids. Consequently, some carboxylate and basic residues selected
from Glu38, Asp63, Glu83, Asp106, Lys107, Lys129, and Arg132 were suggested to be
involved in catalysis and/or calcium binding. We constructed a chimeric enzyme
composed of Ala1 to Tyr105 of Pel-15 in the N-terminal regions, Asp133 to Arg159
of FsPelB in the internal regions, and Gln133 to Tyr197 of Pel-15 in the C
terminal regions. The substituted PelB segment could also express beta
elimination activity in the chimeric molecule, confirming that Pel-15 and PelB
share a similar active-site topology.
PMID- 10759851
TI - Determinants of substrate specificity of a second non-neuronal secreted
acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis.
AB - We recently reported on a non-neuronal secreted acetylcholinesterase (AChE B)
from the nematode parasite Nippostrongylus brasiliensis. Here we describe the
primary structure and enzymatic properties of a second secreted variant, termed
AChE C after the designation of native AChE isoforms from this parasite. As for
the former enzyme, AChE C is truncated at the carboxyl terminus in comparison
with the Torpedo AChE, and three of the 14 aromatic residues that line the active
site gorge are substituted by nonaromatic residues, corresponding to Tyr70 (Ser),
Trp279 (Asn) and Phe288 (Met). A recombinant form of AChE C was highly expressed
by Pichia pastoris. The enzyme was monomeric and hydrophilic, and displayed a
marked preference for acetylthiocholine as substrate. A double mutation
(W302F/W345F, corresponding to positions 290 and 331 in Torpedo) rendered the
enzyme 10-fold less sensitive to excess substrate inhibition and two times less
susceptible to the bis quaternary inhibitor BW284C51, but did not radically
affect substrate specificity or sensitivity to the 'peripheral site' inhibitor
propidium iodide. In contrast, a triple mutant (M300G/W302F/W345F) efficiently
hydrolysed propionylthiocholine and butyrylthiocholine in addition to
acetylthiocholine, while remaining insensitive to the butyrylcholinesterase
specific inhibitor iso-OMPA and displaying a similar profile of excess substrate
inhibition as the double mutant. These data highlight a conserved pattern of
active site architecture for nematode secreted AChEs characterized to date, and
provide an explanation for the substrate specificity that might otherwise appear
inconsistent with the primary structure in comparison to other invertebrate
AChEs.
PMID- 10759852
TI - The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in
human platelets.
AB - U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen
activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated
human platelets ADP activated p38 MAP kinase in both a time-and concentration
dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires
generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2
receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate,
either alone or together, nor indomethacin blocked ADP-induced p38 kinase
activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2,
and PGF2alpha, failed to activate p38 kinase in aspirin-treated platelets. Hence,
ADP must be generating an agonist, other than thromboxane A2, via an aspirin
sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC
(platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist,
did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective
agonist, alpha, beta-methylene ATP, failed to activate p38 MAP kinase. On the
other hand, the P2Y1 receptor selective antagonist, adenosine-2'-phosphate-5'
phosphate inhibited ADP-induced p38 kinase activation in a concentration
dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced
generation of the p38 kinase-activating factor. These results demonstrate that
ADP causes the generation of a factor in human platelets, which can activate p38
kinase, and that this response is mediated by the P2Y1 receptor. Neither the
P2TAC receptor nor the P2X1 receptor has any significant role in this response.
PMID- 10759853
TI - The antiproliferative effect of beta-carotene requires p21waf1/cip1 in normal
human fibroblasts.
AB - In normal human fibroblasts, beta-carotene induces a cell-cycle delay in the G1
phase independent of its provitamin A activity via a mechanism not yet
elucidated. In this study we provide biochemical evidence showing that delayed
progression through the G1 phase occurs concomitantly with: an increase in both
nuclear-bound and total p21waf1/cip1 protein levels; an increase in the amount of
p21waf1/cip1 associated with cdk4; the inhibition of cyclin D1-associated cdk4
kinase activity; and a reduction in the levels of hyperphosphorylated forms of
retinoblastoma protein, and particularly, in phosphorylated Ser780. The role of
p21waf1/cip1 in the antiproliferative effect of the carotenoid was further
supported by genetic evidence that neither changes in cell-cycle progression nor
in the phosphorylation status of retinoblastoma protein were observed in
p21waf1/cip1-deficient human fibroblasts treated with beta-carotene. These
results clearly demonstrate that p21waf1/cip1 is involved directly in the
molecular pathway by which beta-carotene inhibits cell-cycle progression.
PMID- 10759854
TI - Structure of the human oxytocinase/insulin-regulated aminopeptidase gene and
localization to chromosome 5q21.
AB - The human oxytocinase/insulin-regulated aminopeptidase (OTase/IRAP) is a 1024
amino acid type II integral membrane protein that is expressed mainly in fat,
muscle and placenta tissues. It has been thought to be involved mainly in the
control of onset of labour but recently rat OTase/IRAP was shown to participate
in the regulation of glucose transporter isoform 4 vesicle trafficking in
adipocytes as well. To approach an understanding of OTase/IRAP gene regulation
the organization of the human gene was determined. Accordingly, three overlapping
genomic clones were isolated and characterized. The human OTase/IRAP gene (OTASE)
was found to span approximately 75 kb containing 18 exons and 17 introns. The
gluzincin aminopeptidase motif: GAMEN-(31 amino acids)-HELAH-(18 amino acids)-E
associated with Zn2+-binding, substrate binding and catalysis is encoded by exons
6 and 7. A major and a minor transcriptional initiation site in OTASE were
identified by primer extension 514 bp and 551 bp, respectively, upstream of the
translation start codon. Chloroamphenicol acetyltransferase-reporter assays
revealed a functional CpG-rich promoter/enhancer region located between
nucleotide -621 and the major transcriptional initiation site. Human OTASE was
assigned to chromosome 5 by hybridization to genomic DNA from characterized
somatic cell hybrids. Finally, the OTASE and the human aminopeptidase A gene were
subchromosomally localized to 5q21 and 4q25, respectively, by in situ
hybridization.
PMID- 10759855
TI - Aprotinin binding to amyloid fibrils.
AB - Different low molecular mass ligands have been used to identify amyloid deposits.
Among these markers, the dyes Thioflavin T and Congo Red interact specifically
with the beta-sheet structure arranged in a cross-beta conformation, which is
characteristic of amyloid. However, the molecular details of this interaction
remain unknown. When labelled with technetium-99m, the proteinase inhibitor
aprotinin has been shown to represent a very important radiopharmaceutical agent
for in vivo imaging of extra-abdominal deposition of amyloid in amyloidosis of
the immunoglobulin type. However, no information is available as to whether
aprotinin binds other types of amyloid fibrils and on the nature and
characteristics of the interaction. The present work shows aprotinin binding to
insulin, transthyretin, beta-amyloid peptide and immunoglobulin synthetic amyloid
fibrils by a specific dot-blot ligand-binding assay. Aprotinin did not bind
amorphous precipitates and/or the soluble fibril precursors. A Ka of 2.9 microM-1
for the binding of aprotinin to insulin amyloid fibrils was determined by
Scatchard analysis. In competition experiments, analogues such as an aprotinin
variant, a spermadhesin and the soybean trypsin inhibitor were tested and results
suggest that both aprotinin and the spermadhesin interact with amyloid fibrils
through pairing of beta-sheets of the ligands with exposed structures of the same
type at the surface of amyloid deposits. An electrostatic component may also be
involved in the binding of aprotinin to amyloid fibrils because important
differences in binding constants are observed when substitutions V15L17E52 are
introduced in aprotinin; on the other hand beta-sheet containing acidic proteins,
such as the soybean trypsin inhibitor, are unable to bind amyloid fibrils.
PMID- 10759856
TI - Modulation of the phosphatase activity of calcineurin by oxidants and
antioxidants in vitro.
AB - Previous research has indicated that oxidants, antioxidants and the intracellular
redox state regulate the activities of a variety of protein tyrosine kinases,
protein tyrosine phosphatases, phospholipases and transcription factors. In order
to explore the redox regulation of the serine/threonine phosphatase calcineurin,
we have investigated the effects of a variety of oxidants and antioxidants on
calcineurin phosphatase activity in vitro. The oxidants hydrogen peroxide,
superoxide and glutathione disulfide inhibited the phosphatase activity of
calcineurin in a dose-dependent manner. Incubation of purified calcineurin with
the antioxidants ascorbate, ascorbate 2-phosphate, alpha-lipoic acid, N-acetyl-L
cysteine and glutathione increased phosphatase activity relative to untreated
controls. In contrast, several other commonly used antioxidants, including
butylated hydroxytoluene, butylated hydroxyanisole, TEMPOL (4-hydroxy-2,2,6, 6
tetramethylpiperidine-N-oxyl), Trolox (6-hydroxy-2,5,7, 8-tetramethyl-chroman-2
carboxylic acid) and dihydrolipoic acid decreased the activity of purified
calcineurin, possibly through prooxidative mechanisms. Although the antioxidant
pyrrolidine dithiocarbamate increased the activity of purified calcineurin, it
significantly inhibited the activity of calcineurin present in crude fibroblast
lysates. These results support and extend the hypothesis that redox factors
modulate the phosphatase activity of calcineurin and suggest that further in vivo
studies are warranted.
PMID- 10759857
TI - Glycerol kinase of Trypanosoma brucei. Cloning, molecular characterization and
mutagenesis.
AB - Trypanosoma brucei contains two tandemly arranged genes for glycerol kinase. The
downstream gene was analysed in detail. It contains an ORF for a polypeptide of
512 amino acids. The polypeptide has a calculated molecular mass of 56 363 Da and
a pI of 8.6. Comparison of the T. brucei glycerol kinase amino-acid sequence with
the glycerol kinase sequences available in databases revealed positional
identities of 39.0-50.4%. The T. brucei glycerol kinase gene was overexpressed in
Escherichia coli cells and the recombinant protein obtained was purified and
characterized biochemically. Its kinetic properties with regard to both the
forward and reverse reaction were measured. The values corresponded to those
determined previously for the natural glycerol kinase purified from the parasite,
and confirmed that the apparent Km values of the trypanosome enzyme for its
substrates are relatively high compared with those of other glycerol kinases.
Alignment of the amino-acid sequences of T. brucei glycerol kinase and other
eukaryotic and prokaryotic glycerol kinases, as well as inspection of the
available three-dimensional structure of E. coli glycerol kinase showed that most
residues of the magnesium-, glycerol- and ADP-binding sites are well conserved in
T. brucei glycerol kinase. However, a number of remarkable substitutions was
identified, which could be responsible for the low affinity for the substrates.
Most striking is amino-acid Ala137 in T. brucei glycerol kinase; in all other
organisms a serine is present at the corresponding position. We mutated Ala137 of
T. brucei glycerol kinase into a serine and this mutant glycerol kinase was over
expressed and purified. The affinity of the mutant enzyme for its substrates
glycerol and glycerol 3-phosphate appeared to be 3. 1-fold to 3.6-fold higher
than in the wild-type enzyme. Part of the glycerol kinase gene comprising this
residue 137 was amplified in eight different kinetoplastid species and sequenced.
Interestingly, an alanine occurs not only in T. brucei, but also in other
trypanosomatids which can convert glucose into equimolar amounts of glycerol and
pyruvate: T. gambiense, T. equiperdum and T. evansi. In trypanosomatids with no
or only a limited capacity to produce glycerol, a hydroxy group-containing
residue is found as in all other organisms: T. vivax and T. congolense possess a
serine while Phytomonas sp., Leishmania brasiliensis and L. mexicana have a
threonine.
PMID- 10759858
TI - Self-assembly and cross-linking of Volvox extracellular matrix glycoproteins are
specifically inhibited by Ellman's reagent.
AB - A major impediment to the biochemical characterization of extracellular matrices
from algae (as well as higher plants) is the extensive covalent cross-linking
that exists in the matrix, rendering most components insoluble and resistant to
conventional extraction procedures. In the multicellular green alga Volvox,
biogenesis of the extracellular matrix (ECM) is initiated immediately after the
process of embryonic inversion. At this stage of development, the sulfhydryl
reagent 5, 5'-dithio-bis(2-nitrobenzoic acid), known as Ellman's reagent,
interferes in a highly specific manner with ECM biogenesis. Treated post
inversion embryos are no longer able to assemble an intact ECM and consequently
dissociate into a suspension of single cells. Dissociated cells remain viable and
continue to secrete ECM proteins into the growth medium, as documented by the
identification of several members of the pherophorin family. Cross-linked ECM
polymers such as sulfated surface glycoprotein 185 remain in a soluble state.
Thus, treatment with Ellman's reagent opens a simple approach for the isolation
and characterization of otherwise inaccessible monomeric precursors.
PMID- 10759859
TI - Digestion of single crystals of mannan I by an endo-mannanase from Trichoderma
reesei.
AB - The enzymatic degradation of single crystals of mannan I with the catalytic core
domain of a beta-mannanase (EC 3.2.1.78 or Man5A) from Trichoderma reesei was
investigated by transmission electron microscopy and electron diffraction. The
enzyme attack took place at the edge of the crystals and progressed towards their
centres. Quite remarkably the crystalline integrity of the crystals was preserved
almost to the end of the digestion process. This behaviour is consistent with an
endo-mechanism, where the enzyme interacts with the accessible mannan chains
located at the crystal periphery and cleaves one mannan molecule at a time. The
endo mode of digestion of the crystals was confirmed by an analysis of the
soluble degradation products.
PMID- 10759860
TI - Combining phage display and molecular modeling to map the epitope of a
neutralizing antitoxin antibody.
AB - Crotoxin is a potent presynaptic neurotoxin from the venom of the rattlesnake
Crotalus durissus terrificus. It is composed of the noncovalent and synergistic
association of a weakly toxic phospholipase A2, CB, and a nontoxic three-chain
subunit, CA, which increases the lethal potency of CB. The A-56.36 mAb is able to
dissociate the crotoxin complex by binding to the CA subunit, thereby
neutralizing its toxicity. Because A-56.36 and CB show sequence homology and both
compete for binding to CA, we postulated that A-56.36 and CB had overlapping
binding sites on CA. By screening random phage-displayed libraries with the mAb,
phagotopes bearing the (D/S)GY(A/G) or AAXI consensus motifs were selected. They
all bound A-56.36 in ELISA and competed with CA for mAb binding, although with
different reactivities. When mice were immunized with the selected clones,
polyclonal sera reacting with CA were induced. Interestingly, the raised
antibodies retained the crotoxin-dissociating effect of A-56.36, suggesting that
the selected peptides may be used to produce neutralizing antibodies. By
combining these data with the molecular modeling of CA, it appeared that the
functional epitope of A-56.36 on CA was conformational, one subregion being
discontinuous and corresponding to the first family of peptides, the other
subregion being continuous and composed of amino acids of the second family.
Phage-displayed peptides corresponding to fragments of the two identified regions
on CA reacted with A-56.36 and with CB. Our data support the hypothesis that A
56.36 and CB interact with common regions of CA, and highlight residues which are
likely to be critical for CA-CB complex formation.
PMID- 10759861
TI - Morphine-like substance in leech ganglia. Evidence and immune modulation.
AB - Binding experiments followed by measurement of nitric oxide release revealed an
opiate alkaloid high affinity receptor with no affinity to opioids, representing
a new mu-subtype receptor in the brain of the leech Theromyzon tessulatum. In
addition, evidence of morphine-like substances was found in immunocytochemical
studies and HPLC coupled to electrochemical detection (500 mV and 0.02 Hz). Based
on previous evidence of the involvement of morphine as an immune response
inhibitor, we demonstrate that in leech ganglia injection of lipopolysaccharide
(LPS; a potent immunostimulatory agent derived from bacteria) provoked an
increase in the level of ganglionic morphine-like substances after a prolonged
latency period of 24 h (from 2.4 +/- 1.1 pmol per ganglion to 78 +/- 12.3 pmol
per ganglion; P < 0.005; LPS injected 1 microg x mL-1); this effect is both
concentration- and time-dependent. Finally, we have demonstrated that morphine,
after binding to its own receptor, inhibits leech immunocyte activation through
adenylate cyclase inhibition and nitric oxide release. This report confirms that
morphine is an evolutionarily stable potent immunomodulator.
PMID- 10759862
TI - Alu-DNA repeat-binding protein p68 is a part of Alu-RNA containing alpha-RNP.
AB - An Alu-DNA repeat-binding protein with a molecular mass of 68 kDa (p68) is
identified in the somatic human cell nucleoplasm. Gel mobility shift assay
(GMSA), South-western blotting and affinity purification on DNA attached to the
carrier were used in the identification. GMSA revealed multiple complexes with
the exponential dependence of their relative mobility. A narrow binding site of
the p68 was revealed using synthetic oligonucleotides. It is located between the
A-box and B-box of the RNA polymerase III promoter and is identical to that
reported for the Alu-binding protein from human spermatozoids. The same narrow
binding site, the similarity of the isolation procedure from germ and somatic
cells, and similar binding properties and molecular masses suggest homology of
the two proteins. Antibodies raised against Alu-protein complexes led to
hypershift of the complexes in GMSA and stained p68 in active fractions in human
spermatozoids and in Alu-RNA-containing alpha-RNP particles. Immunofluorescence
of a HeLa cell monolayer revealed an intranuclear dot pattern with the dots
corresponding to euchromatin areas and some dots located at the cell periphery in
the cytoplasm. alpha-RNP particles bound Alu-DNA in vitro and contained p68 as
shown using the immunogold procedure. Alu-DNA binding activity was revealed in
cytoplasm as well as in nucleoplasm. The possible nature of the main Alu-DNA
binding protein and its involvement in the particle structure are discussed.
PMID- 10759863
TI - Structure of the O polysaccharide and serological classification of Pseudomonas
syringae pv. ribicola NCPPB 1010.
AB - The O polysaccharide (OPS) moiety of the lipopolysaccharide (LPS) of a
phytopathogenic bacterium Pseudomonas syringae pv. ribicola NCPPB 1010 was
studied by sugar and methylation analyses, Smith degradation, and 1H- and 13C-NMR
spectroscopy, including 2D COSY, TOCSY, NOESY and H-detected 1H,13C HMQC
experiments. The OPS structure was elucidated, and shown to be composed of
branched pentasaccharide repeating units (O repeats) of two types, major (1) and
minor (2), differing in the position of substitution of one of the rhamnose
residues. Both O repeats form structurally homogeneous blocks within the same
polysaccharide molecule. Although P. syringae pv. ribicola NCPPB 1010
demonstrates genetic relatedness and similarity in the OPS chemical structure to
some other P. syringae pathovars, it did not cross-react with any OPS-specific
mAbs produced against heterologous P. syringae strains. Therefore, we propose to
classify P. syringae pv. ribicola NCPPB 1010 in a new serogroup, O8.
PMID- 10759864
TI - Determination of glycosylation sites, disulfide bridges, and the C-terminus of
Stereum purpureum mature endopolygalacturonase I by electrospray ionization mass
spectrometry.
AB - Stereum purpureum endopolygalacturonase (endoPG; EC 3.2.1.15) is a causal protein
for silver-leaf disease in apple trees. Endopolygalacturonase I, is a mixture of
three components (Ia, Ib, and Ic) that produce three bands on SDS/PAGE but have
the same polypeptide and sugar chains. Electrospray ionization mass spectrometry
(ESI-MS) analysis of three endoPG I proteins and deglycosylated endoPG Ia
revealed a molecular mass of 37 068, 38 285, and 39 503 for Ia, Ib, and Ic,
respectively; the number of N-binding sugar chains matches that of a high-mannose
type of sugar chain. Two, three, and four sugar chains are present in endoPG Ia,
Ib, and Ic, respectively. Deletion of 44 amino acids from the deduced sequence
occurred in the C-terminal region. Positions of the glycosylation sites and
disulfide bridges were decided by tryptic digestion followed by liquid
chromatography-electrospray mass spectrometry (LC-ESI-MS) analysis of reductive
and nonreductive pyridylethylated endoPG I proteins. The glycosylated asparagines
were determined to be Asn92 and 161; Asn92, 161, 279, or 302; and Asn92, 161,
279, and 302 in Ia, Ib, and Ic, respectively. Three disulfide bridges were noted
at Cys3-Cys17, Cys175-Cys191, and Cys300-Cys303. These results are the first
findings for fungal endoPG and may contribute to clarification of the
relationship between stereostructure and catalytic activity.
PMID- 10759865
TI - The crystal structure of the Fab fragment of a rat monoclonal antibody against
the main immunogenic region of the human muscle acetylcholine receptor.
AB - The crystal structure of the Fab fragment of a rat monoclonal antibody, number
192, with a very high affinity (Kd = 0.05 nM) for the main immunogenic region of
the human muscle acetylcholine receptor (AChR), has been determined and refined
to 2.4 A resolution by X-ray crystallographic methods. The overall structure is
similar to a Fab (NC6.8) from a murine antibody, used as a search model in
molecular replacement. Structural comparisons with known antibody structures
showed that the conformations of the hypervariable regions H1, H2, L1, L2, L3 of
Fab192 adopt the canonical structures 1, 1, 2, 1, and 1, respectively. The
surface of the antigen-binding site is relatively planar, as expected for an
antibody against a large protein antigen, with an accessible area of 2865 A2.
Analysis of the electrostatic surface potential of the antigen-binding site shows
that the bottom of the cleft formed in the center of the site appears to be
negatively charged. The structure will be useful in the rational design of very
high affinity humanized mutants of Fab192, appropriate for therapeutic approaches
of the model autoimmune disease myasthenia gravis.
PMID- 10759866
TI - Antitermination in bacteriophage lambda. The structure of the N36 peptide-boxB
RNA complex.
AB - The solution structure of a 15-mer nutRboxB RNA hairpin complexed with the 36-mer
N-terminal peptide of the N protein (N36) from bacteriophage lambda was
determined by 2D and 3D homonuclear and heteronuclear magnetic resonance
spectroscopy. These 36 amino acids include the arginine-rich motif of the N
protein involved in transcriptional antitermination of phage lambda. Upon complex
formation with boxB RNA, the synthetic N36 peptide binds tightly to the major
groove of the boxB hairpin through hydrophobic and electrostatic interactions
forming a bent alpha helix. Four nucleotides of the GAAAA pentaloop of the boxB
RNA adopt a GNRA-like tetraloop fold in the complex. The formation of a GAAA
tetraloop involves a loop-closing sheared base pair (G6-A10), base stacking of
three adenines (A7, A8, and A10), and extrusion of one nucleotide (A9) from the
loop, as observed previously for the complex of N(1-22) peptide and the nutLboxB
RNA [Legault, P., Li, J., Mogridge, J., Kay, L.E. & Greenblatt, J. (1998) Cell
93, 289-299]. Stacking of the bases is extended by the indole-ring of Trp18 which
also forms hydrophobic contacts to the side-chains of Leu24, Leu25, and Val26.
Based on the structure of the complex, three mutant peptides were synthesized and
investigated by CD and NMR spectroscopy in order to determine the role of
particular residues for complex formation. These studies revealed very distinct
amino-acid requirements at positions 3, 4, and 8, while replacement of Trp18 with
tyrosine did not result in any gross structural changes.
PMID- 10759867
TI - Complementation of deletion mutants in the genes encoding the F1-ATPase by
expression of the corresponding bovine subunits in yeast S. cerevisiae.
AB - The F1F0 ATP synthase is composed of the F1-ATPase which is bound to F0, in the
inner membrane of the mitochondrion. Assembly and function of the enzyme is a
complicated task requiring the interactions of many proteins for the folding,
import, assembly, and function of the enzyme. The F1-ATPase is a multimeric
enzyme composed of five subunits in the stoichiometry of
alpha3beta3gammadeltaepsilon. This study demonstrates that four of the five
bovine subunits of the F1-ATPase can be imported and function in an otherwise
yeast enzyme effectively complementing mutations in the genes encoding the
corresponding yeast ATPase subunits. In order to demonstrate this, the coding
regions of each of the five genes were separately deleted in yeast providing five
null mutant strains. All of the strains displayed negative or a slow growth
phenotype on medium containing glycerol as the carbon source and strains with a
null mutation in the gene encoding the gamma-, delta- or epsilon-gene became
completely, or at a high frequency, cytoplasmically petite. The subunits of
bovine F1 were expressed individually in the yeast strains with the corresponding
null mutations and targeted to the mitochondrion using a yeast mitochondrial
leader peptide. Expression of the bovine alpha-, beta-, gamma-, and epsilon-, but
not the delta-, subunit complemented the corresponding null mutations in yeast
correcting the corresponding negative phenotypes. These results indicate that
yeast is able to import, assemble subunits of bovine F1-ATPase in mitochondria
and form a functional chimeric yeast/bovine enzyme complex.
PMID- 10759868
TI - Analysis of a binding difference between the two dsRNA-binding domains in TRBP
reveals the modular function of a KR-helix motif.
AB - Double-stranded RNA-binding proteins constitute a large family with conserved
domains called dsRBDs. One of these, TRBP, a protein that binds HIV-1 TAR RNA,
has two dsRBDs (dsRBD1 and dsRBD2), as indicated by computer sequence homology.
However, a 24-amino-acid deletion in dsRBD2 completely abolishes RNA binding,
suggesting that only one domain is functional. To analyse further the
similarities and differences between these domains, we expressed them
independently and measured their RNA-binding affinities. We found that dsRBD2 has
a dissociation constant of 5.9 x 10-8 M, whereas dsRBD1 binds RNA minimally.
Binding analysis of 25-amino-acid peptides in TRBP and other related proteins
showed that only one peptide in TRBP and one in Drosophila Staufen bind TAR and a
GC-rich TAR-mimic RNA. Whereas a 25-mer peptide derived from dsRBD2 (TR5) bound
TAR RNA, the equivalent peptide in dsRBD1 (TR6) did not. Molecular modelling
indicates that this difference can mainly be ascribed to the replacement of Arg
by His residues. Mutational analyses in homologous peptides also show the
importance of residues K2 and L3. Analysis of 15-amino-acid peptides revealed
that, in addition to TR13 (from TRBP dsRBD2), one peptide in S6 kinase has RNA
binding properties. On the basis of previous and the present results, we can
define, in a broader context than that of TRBP, the main outlines of a modular KR
helix motif required for binding TAR. This structural motif exists independently
from the dsRBD context and therefore has a modular function.
PMID- 10759869
TI - Inhibition of inositol uptake in astrocytes by antisense oligonucleotides
delivered by pH-sensitive liposomes.
AB - An oligonucleotide of 20 bases, complementary to a region of the sodium/myo
inositol cotransporter (SMIT) mRNA, was used to investigate the uptake efficiency
and activity of transferred antisense oligonucleotides with regard to substrate
uptake. We compared the efficiency of oligonucleotide delivery after application
of either free or liposome-encapsulated material. Delivery of liposome
encapsulated material (marker or oligonucleotides) into astrocytoma cells and
primary astrocyte cultures was more effective with pH-sensitive liposomes
[dioleoylphosphatidylethanolamine (DOPE)/cholesteryl hemisuccinate (CHEMS)] than
with non-pH-sensitive liposomes (soy lecithin) or free material in solution.
Antisense activity was evaluated by determination of myo-inositol uptake and
detection of SMIT transcripts by RT-PCR. Encapsulation of oligonucleotides in pH
sensitive liposomes increased the inhibition of inositol uptake at least 50-fold
compared with application of free oligonucleotides in solution.
PMID- 10759870
TI - Structural analysis of the core region of lipopolysaccharides from Proteus
mirabilis serotypes O6, O48 and O57.
AB - The structure of lipid A core region of the lipopolysaccharides (LPS) from
Proteus mirabilis serotypes O6, O57 and O48 was determined using NMR, MS and
chemical analysis of the oligosaccharides, obtained by mild acid hydrolysis,
alkaline deacylation, and deamination of LPS: [see text for structure].
Incomplete substitutions are indicated by bold italic type. All sugars are
present in pyranose form, alpha-Hep is the residue of L-glycero-alpha-D-manno
Hep, alpha-DD-Hep is the residue of D-glycero-alpha-D-manno-Hep, L-Ara4N is 4
amino-4-deoxy-L-arabinose, Qui4NAlaAla is the residue of 4-N-(L-alanyl-L-alanyl)
4-amino-4,6-dideoxyglucose. All sugars except L-Ara4N have D-configuration. beta
GalA* is partially present in the form of amide with 1,4-diaminobutane
(putrescine)-HN(CH2)4NH2 or spermidine-HN(CH2)3NH(CH2)4NH2.
PMID- 10759871
TI - Diphospho-myo-inositol phosphates during the life cycle of Dictyostelium and
Polysphondylium.
AB - The intracellular amounts of diphospho-myo-inositol phosphates and InsP6 were
determined in Dictyostelium discoideum AX2 throughout the life cycle, including
exponential growth, starvation, differentiation, sporulation and spore
germination. Similar experiments were performed with the closely related species
Polysphondylium pallidum under conditions resulting in microcyst formation. A
distinct accumulation of these compounds is observed during the early starvation
phase of the cell population before the onset of the actual differentiation
program. When exponentially growing D. discoideum cells were shifted to
starvation conditions, a 25-fold accumulation of 5,6-bis-PP-InsP4 within 3 h was
observed. In P. pallidum, the 5,6-bis-PP-InsP4 pool rises around 20-fold within 8
h during the formation of microcysts from vegetative cells. Finally, the
diphosphoinositol phosphates are deposited in spores or microcysts and are
degraded when spores or microcysts germinate at low cell density.
PMID- 10759872
TI - Functional and structural differences between the prion protein from two alleles
prnp(a) and prnp(b) of mouse.
AB - The prion protein is a glycoprotein expressed by neurones and other cells. In its
holo-form it binds copper and exhibits superoxide dismutase activity. Studies in
mice have led to the description of two distinct alleles. Differences in these
alleles are linked to long and short incubation times following infection with
scrapie. We studied recombinant mouse protein corresponding to the products of
either allele and two intermediates carrying single amino-acid residue
substitutions. The different forms of the prion protein exhibited differences in
superoxide dismutase (SOD) activity and conformation. Intermediates with single
substitutions were less stable than either allelic product. The findings provide
insight into the differences between the two alleles and might have consequences
for understanding differences in susceptibility to prion disease.
PMID- 10759873
TI - Telomerase activity in needle biopsies from prostate cancer and benign prostates:
the influence of sampling bias.
PMID- 10759874
TI - Effects of glucose ingestion on cardiac autonomic nervous system in healthy
centenarians: differences with aged subjects.
AB - BACKGROUND: Spectral analysis of heart rate variability (HRV) investigates the
cardiac autonomic nervous system (ANS) activity. In particular, low
frequency/high frequency (LF/HF) is considered an index of cardiac sympatho-vagal
balance and is stimulated by glucose ingestion in healthy subjects. No studies
have evaluated the effect of glucose ingestion on cardiac ANS in centenarians.
MATERIALS AND METHODS: In 30 healthy centenarians (HC) and 25 aged subjects (AS)
power spectral analysis of HRV was investigated during an oral glucose ingestion.
RESULTS: Glucose ingestion rose LF/HF ratio in both groups studied. Such
stimulatory effects were restrained to the first 60 min of the study. Independent
of age, gender, body mass index (BMI) and fasting plasma norepinephrine and FT3
concentrations, HC had basal total power (1318 +/- 546 vs. 1918 +/- 818 msec2, P
< 0.01), lower low frequency (LF) (33 +/- 21 vs. 50 +/- 11 n.u., P < 0. 03), and
higher high frequency (HF) (74 +/- 18 vs. 43 +/- 15 n.u., P < 0.05) than AS.
Consequently, LF/HF ratio (0.43 +/- 0.07 vs. 0.91 +/- 0.05, P < 0.02) was also
lower in HC than in AS. In AS, but not in HC, the baseline LF/HF ratio correlated
significantly with BMI (r = 0.48, P < 0.01), waist-hip-ratio (WHR) (r = 0.45, P <
0.02), fasting plasma insulin (r = 0.49, P < 0.01) and norepinephrine (r = 0.57,
P < 0.02) concentration. Glucose ingestion was associated with a significant rise
in LF/HF ratio in both groups studied but per cent changes in glucose mediated
stimulation of LF/HF was lower in HC than in AS. In a control study, water
administration did not affect power spectral parameters of HRV. CONCLUSION: Our
study demonstrates that basal- and glucose-stimulated LF/HF, an indirect index of
cardiac sympatho-vagal balance, are lower in HC than in AS.
PMID- 10759875
TI - Effect of digoxin on circadian blood pressure values in patients with congestive
heart failure.
AB - BACKGROUND: The aim of the study was to investigate the effect of chronic digoxin
treatment on circadian blood pressure profile in normotensive patients with mild
congestive heart failure. METHODS: In a randomized double-blind, placebo
controlled cross-over protocol, 12 normotensive patients with mild congestive
heart failure took digoxin or placebo for a total of 7 days. Automatic 24-h
ambulatory blood pressure measurements were carried out at day 7, of either
digoxin or placebo. RESULTS: Diastolic blood pressure significantly decreased and
systolic blood pressure significantly increased during overnight sleep in the
digoxin phase compared to placebo. Digoxin had no effect on either systolic or
diastolic blood pressure during daytime. Heart rate decreased in the overnight
sleeping phase but did not differ significantly between placebo and digoxin
phase. CONCLUSIONS: Digoxin significantly decreases diastolic blood pressure
during overnight sleep in patients with congestive heart failure. This effect is
likely to be caused by reduction of sympathetic activity or increase of
parasympathetic activity. Increase of systolic blood pressure during sleep is
probably caused by the positive inotropic effect of the drug.
PMID- 10759876
TI - beta-adrenoceptor-stimulated lipolysis of subcutaneous abdominal adipocytes as a
determinant of fat oxidation in obese men.
AB - BACKGROUND: To verify whether an impaired lipolytic capacity of subcutaneous
adipocytes may contribute to low rate of fat oxidation. DESIGN: Relationships
between adipose tissue lipolysis of subcutaneous (subc) abdominal and femoral
isolated adipocytes and respiratory quotient (RQ) were investigated in 20 obese
men (age: 44 +/- 5 years; means +/- SD) studied in a fasting state. RESULTS:
Maximal isoproterenol-induced lipolysis was greater in subcutaneous abdominal
than in femoral fat cells even if glycerol release was corrected for variation in
cell surface area (P < 0.01). On the other hand, no regional variation was
observed in the adipose cell lipolytic responses to postadrenoceptor agents such
as dibutyryl-cyclic AMP, forskolin and theophylline. Maximal isoproterenol
induced lipolysis of subc abdominal, but not of femoral adipocytes, was inversely
related to RQ (r = - 0.61; P < 0. 01) and positively associated to fat oxidation
(r = 0.57; P < 0.01). These relationships were independent of possible
confounding factors such as fat mass, fat-free mass, waist girth and subc
abdominal adipose tissue accumulation assessed by computed tomography, as maximal
isoproterenol-induced lipolysis of subcutaneous abdominal adipocytes was the only
variable retained as a significant predictor of RQ levels (38% of variance) and
of fat oxidation (30% of variance). CONCLUSION: These results suggest that
adipose tissue lipolytic activity of subc abdominal adipocytes acts as a
determinant of fat oxidation in obese men.
PMID- 10759877
TI - Alcohol consumption and insulin resistance in young adults.
AB - BACKGROUND: Alcohol may have a cardioprotective effect. One possible mechanism is
by reducing insulin resistance, a known cardiovascular risk factor. The aim of
this study was to assess the relationship between alcohol consumption, insulin
resistance and other parameters determining glucose tolerance in 154 young men
and women. SUBJECTS AND METHODS: Subjects completed a questionnaire documenting
weekly alcohol consumption. Insulin sensitivity and glucose tolerance were
measured using the intravenous glucose tolerance test with minimal model
analysis. Height, weight, usual level of exercise, smoking habits and socio
economic status were also recorded. RESULTS: Insulin sensitivity correlated
inversely with body mass index (r = - 0.529, P < 0.001) but not with level of
physical fitness. Women were significantly less insulin sensitive than men (4.19
and 5.63 104 min-1 pmol-1 L-1, respectively; P < 0.001). Insulin sensitivity
correlated positively with alcohol consumption and this trend remained
significant allowing for body mass index and gender (beta = 0.17, P < 0.014).
First-phase insulin secretion showed a weak but non-significant trend in the
opposite direction. Fasting glucose, fasting insulin and glucose tolerance showed
no relationships with alcohol consumption. CONCLUSION: These data suggest a close
relationship between alcohol consumption and insulin resistance in young adults.
Regular alcohol consumption is associated with decreased insulin resistance and
this may partly explain the cardioprotective effect of alcohol.
PMID- 10759878
TI - Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not
associated with whole body insulin resistance in obese nondiabetic or in type-2
diabetic subjects.
AB - BACKGROUND: An association with subcutaneous adipose tissue TNFalpha expression
and insulin resistance has been suggested in obesity/type-2 diabetes, but this
has not been examined directly. In the first part of the study we investigated
whether this association is present in 7 lean, 10 obese nondiabetic and 9 type-2
diabetic men. In the second part of the study we examined the relationship
between adipose tissue TNFalpha mRNA levels and BMI in 81 nondiabetic subjects
spanning a wide range of BMIs. METHODS: Subcutaneous adipose tissue TNFalpha mRNA
levels and insulin sensitivity were determined with quantitative RT-competitive
PCR and hyperinsulinaemic clamp, respectively. RESULTS: Subcutaneous adipose
tissue TNFalpha mRNA levels were similar in 7 lean and 10 obese nondiabetic and 9
type-2 diabetic men (P = 0.68), and did not change in response to 240-min
hyperinsulinaemia. TNFalpha mRNA levels and insulin sensitivity were not
correlated. Unexpectedly, no correlation between TNFalpha mRNA and BMI was found.
The relationship between adipose tissue TNFalpha mRNA and BMI was examined
further in 31 male and 50 female nondiabetic subjects. The subcutaneous adipose
tissue TNFalpha mRNA level correlated with BMI in all subjects (rS = 0.32, P <
0.01), and in a subgroup analysis in men (rS = 0.55, P < 0.01) but not in women
(rS = - 0.08). The correlation in men was dependent on a fourfold higher TNFalpha
mRNA level in 5 morbidly obese men while there was no difference in TNFalpha mRNA
levels in lean or obese men. CONCLUSIONS: Subcutaneous adipose tissue TNFalpha
expression does not correlate with insulin sensitivity in nondiabetic or type-2
diabetic men; is not regulated by acute hyperinsulinaemia; and is increased only
in morbidly obese men.
PMID- 10759879
TI - Ultrastructural changes of human cardiac atrial nerve endings in diabetes
mellitus.
AB - BACKGROUND: Autonomic neuropathy resulting from long-term diabetes mellitus may
affect heart innervation. However, so far diabetes induced morphological changes
of cardiac nerves are not well-known. In this study human cardiac atrial tissue
from diabetic patients was analysed by electron microscopy for structural
alterations as a result of diabetic neuropathy. METHODS: In coronary bypass
surgery, an edge of the right auricle was routinely resected for reason of
extracorporal circulation. Thin cardiac tissue sections of 100 nm were studied by
electron microscopy. Atrial tissue samples were collected from 5 patients with
long-standing diabetes (for at least 8 years) and compared to atrial tissue
samples from 5 patients without diabetes, equally undergoing coronary bypass
surgery. RESULTS: In all atria-free nerve endings with unmyelinized, axons were
observed. Cross sections of 479 axons from diabetic patients were compared to 419
axons of nondiabetic patients. The number of altered axons was significantly
higher in cardiac tissue of diabetic patients (32%) in comparison to normal
subjects (17%). In diabetic patients, 20% of the intra-axonal mitochondria were
condensed or hydropic, whereas in nondiabetic patients only 4% of the
mitochondria were altered. Membrane fragments were present in 21% of the axons in
atria of diabetic patients compared to 10% in nondiabetic subjects. Only in
cardiac axons from diabetic patients there were lamellar bodies, dissolved
axoplasma and junctions between neighbouring axons in a minor number. Few
vacuoles were present in axons of both groups. CONCLUSION: In myocardial atrial
free nerve fibre bundles of diabetic patients, the amount of degenerative changes
was higher in comparison to atrial cardiac tissue from nondiabetic subjects.
These morphological alterations may indicate manifestation of diabetic neuropathy
and might contribute to the impairment of autonomic neural control affecting the
heart in long-standing diabetes mellitus.
PMID- 10759880
TI - Gallbladder motility and cholesterol crystallization in bile from patients with
pigment and cholesterol gallstones.
AB - BACKGROUND: Little is known about gallbladder motility in patients with black
pigment stones when compared to cholesterol gallstone patients, or about their
relationship to biliary composition, crystallization and stone characteristics.
DESIGN: Fasting and postprandial gallbladder volumes were studied by
ultrasonography in 49 gallstone patients with pigment (n = 14) or cholesterol (n
= 35) stones and 30 healthy controls. After cholecystectomy stone composition,
gallbladder wall inflammation, cholesterol saturation index and appearance of
platelike cholesterol crystals in bile were evaluated in gallstone patients.
RESULTS: Fasting gallbladder volume was significantly (P < 0.05) increased in
cholesterol stone patients (31.7 +/- 1.9 mL) but not in pigment stone patients
(21.9 +/- 3.1 mL), compared to controls (21.0 +/- 1.5 mL). Postprandial emptying
was delayed in patients (half-emptying time: 31 +/- 2 min, 35 +/- 3 min, 24 +/- 2
min in cholesterol stone patients, pigment stone patients and controls,
respectively, P < 0.05) and incomplete (residual volume: 43.2 +/- 2.7%, 40.0 +/-
4.3%, 15.8 +/- 1.6% min in cholesterol stone patients, pigment stone patients and
controls, respectively, P < 0.05). The inflammation of the gallbladder wall was
mild or absent in all cases. Biliary cholesterol saturation index was 152.3 +/-
8.5% and 92.9 +/- 4.8% in patients with cholesterol and pigment stones,
respectively (P < 0.01). Whereas cholesterol crystals never appeared during 21
days in biles from patients with pigment stones, crystal observation time in
patients with cholesterol gallstone was 5 days (median) and was significantly
shorter in patients with multiple (4 days) than in patients with solitary (12
days) cholesterol stones (P = 0.0019). CONCLUSIONS: Patients with black pigment
stones who do not have excess cholesterol and do not grow cholesterol crystals in
bile have decreased gallbladder emptying, although to a lesser extent than
patients with cholesterol stones. Thus, gallbladder stasis is likely to put a
subset of subjects at risk for the formation of pigment gallstones, and
pathogenic mechanisms need to be further investigated.
PMID- 10759881
TI - Lack of MEN1 gene mutations in 27 sporadic insulinomas.
AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant
familial cancer syndrome characterized by tumours of the parathyroids, anterior
pituitary gland and endocrine pancreas. Since the cloning of the MEN1 gene
(encoding menin) on chromosome 11q13 by Chandrasekharappa et al. in 1997, it has
become possible to identify mutations that are responsible. We examined whether
MEN1 gene mutations are present in sporadic insulinomas, a rare sporadic tumour
that is seen more frequently in patients with the MEN 1 syndrome. PATIENTS AND
METHODS: We sequenced the coding part of the MEN1 gene (exons 2-10) in tumour
tissue of 27 patients suffering from an insulinoma (24 benign, three malignant).
To validate our methods we also examined tumour tissue from five patients with
primary hyperparathyroidism (HPT) at a younger age and/or multiple gland disease,
with increased risk of MEN 1. RESULTS: We found no mutations in the nine coding
exons of the MEN1 gene in the insulinoma tissues. We could confirm three benign
polymorphisms (S145S, R171Q, D418D) reported previously. In the control patients
we found two new point mutations (one mis-sense, one non-sense mutation) and one
deletion. CONCLUSION: Mutations of the MEN1 gene do not play an important role in
the pathogenesis of sporadic insulinomas. Therefore genetic screening is not cost
effective in sporadic insulinoma patients without other indicators of MEN 1.
Patients with primary HPT at a younger age and/or multiple gland disease should
be screened for MEN1 gene mutations.
PMID- 10759882
TI - Telomerase activity in needle biopsies from prostate cancer and benign prostates.
AB - BACKGROUND: Telomerase activation is thought to be essential for the immortality
of cancer cells. It may be a prognostic factor in small volume well
differentiated prostate cancers and hence a guide for the aggressiveness of the
approach. The length of the chromosome tips (telomeres) are maintained by a
specific enzyme (telomerase) independently of the normal cell division cycle.
Although telomerase is not expressed in most normal human tissues, it is
expressed in most human tumours. For the detection of telomerase in small
prostate needle biopsy samples a recently developed telomeric repeat
amplification protocol (TRAP) assay was used. The aim of the present study was:
to measure telomerase activity in human prostate samples, and to evaluate the
applicability of this assay on specimens from a prostate biopsy. MATERIALS AND
METHODS: From 36 patients referred for lower urinary tract symptoms (LUTS) or
suspicion of having prostate cancer a total of 288 prostate biopsy samples were
obtained (8 in each patient). When the digital rectal examination was abnormal
and/or when the PSA level was elevated in L.U.T.S., or asymptomatic patients'
tissue samples were obtained by transrectal ultrasound (TRUS) guided biopsies.
Samples were tested for telomerase activity by a modified TRAP and forwarded for
histology. RESULTS: In 19 out of 36 patients prostate cancer was diagnosed on
histology. In 11 of these 19 tumours substantial telomerase activity was
detected, whereas only very low telomerase activity existed in 2 of 17 samples
from benign prostatic hypertrophy (BPH) patients. In this small series the
relative telomerase activity in prostate cancer correlated with histopathological
grade. CONCLUSIONS: Our results show the applicability of a TRAP assay to measure
telomerase activity in small needle biopsied prostate samples. In poorly
differentiated and metastatic cancer we observed that levels of telomerase
activity were high. To establish accuracy and to distinguish the 'relative good
from the ugly' further study is needed.
PMID- 10759883
TI - Intrapleural administration of tumour necrosis factor-alpha (TNFalpha) in
patients with mesothelioma: cytokine patterns and acute-phase protein response.
AB - BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has been found to be very
effective in the isolated limb perfusion setting for advanced extremity tumours.
In a phase I study of intrapleural administration of TNFalpha 5 patients were
followed for inflammatory response patterns. PATIENTS AND METHODS: Malignant
mesothelioma patients were treated with repeated intrapleural administration of
0. 1-0.2 mg recombinant TNFalpha. Samples of serum and pleural fluid were taken
at different time-points before and after TNFalpha-administration. Levels of
TNFalpha, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP)
and secretory phospholipase A2 (sPLA2) were measured using enzyme-linked
immunosorbent assays (ELISAs). Alpha 1-acid glycoprotein (alpha1-AG) was measured
by nephelometry. RESULTS: In pleural fluid TNFalpha and IL-8 reached peak levels,
up to 50-700 ng mL-1 and 6-60 ng mL-1, respectively, 24 h after administration of
TNFalpha. IL-6 (peak levels up to 250 ng mL-1) and sPLA2 peaked after 48 h. A
slower and less dramatic pattern was observed for the levels of CRP and alpha1
AG. In serum no detectable levels of TNFalpha and no IL-8 were observed, whereas
serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural
administration of TNFalpha. Cytokines and acute-phase proteins showed the same
pattern during subsequent cycles even up to 12 cycles. Tumour regression was not
observed. CONCLUSIONS: In the setting of a phase I study of repetitive
intrapleural administration of TNFalpha in mesothelioma patients, we studied the
characteristics of the inflammatory response. Intrapleural administration was
followed by a clear inflammatory response locoregionally. In spite of TNFalpha
peak levels as high as 700 ng mL-1 systemic levels were never detectable. The
secondary cytokine response led to very high intrapleural IL-6 and IL-8 levels.
Systemically IL-8 levels were never detectable whereas high IL-6 levels were
induced systemically initially, with a decreased response to each intrapleural
TNFalpha administration over time. The acute-phase response in contrast remained
remarkably constant throughout the course of repeated intrapleural
administrations of TNFalpha. Intrapleural administration of TNFalpha is well
tolerated but associated with inconsistent and rather moderate impact on
production of pleural fluid. This can be achieved by other simpler and cheaper
treatment, thus we see no justification for further studies.
PMID- 10759884
TI - Molecular and electrical heterogeneity of circulating human erythropoietin
measured by sensitive enzyme immunoassay.
AB - BACKGROUND: We set up a sensitive sandwich enzyme immunoassay (EIA) of human
erythropoietin (EPO) and further investigated molecular weight and structural
heterogeneity, and electrical heterogeneity of the circulating EPO in normal
human plasma without any concentrating procedure. MATERIALS AND METHODS: We set
up a sensitive sandwich EIA of EPO using anti-EPO rabbit Fab'-peroxidase
conjugate and anti-EPO IgG coated polystyrene balls. Standard EPO and plasma
samples obtained from three normal subjects were applied to gel chromatographic
analysis. Plasma samples obtained from three normal subjects were subjected to
preparative isoelectric focusing with a column (pH 3.5-10). RESULTS: The minimal
detectable quantity was 0. 15 mIU mL-1 using 100 microL sample. There was a good
parallelism between diluted human plasma samples and the standard EPO in the
assay. Rat plasma EPO was cross-reacted in the assay. There was a good
correlation between EPO levels determined by the EIA and those of
radioimmunoassay (y = 0.897x + 0.564, r = 0.957). Gel chromatographic analysis of
standard EPO revealed a single peak. On the other hand, gel chromatographic
analysis of unconcentrated plasma samples obtained from three normal subjects
revealed at least four components of immunoreactive EPO. Preparative
isoelectrical focusing revealed at least four major components and some other
small peaks in normal human plasma samples. CONCLUSION: These findings indicate
the first evidence for molecular and electrical heterogeneity of circulating EPO
in normal human plasma without any concentrating procedure.
PMID- 10759885
TI - Localization and characterization of antigen-presenting dendritic cells in the
gastric mucosa of murine and human autoimmune gastritis.
AB - BACKGROUND: Activated CD4+ T cells and inflammatory cytokines are implicated in
the pathogenesis of experimental autoimmune gastritis. However, there is a
paucity of information about the cells that induce them. Antigen-presenting
dendritic cells (DCs) play a cardinal role in the formation and survival of
activated lymphocytes. MATERIALS AND METHODS: Autoimmune gastritis was induced in
neonatal BALB/c mice by thymectomy. DCs were detected in situ in the gastric
mucosa from thymectomized mice and in patients with autoimmune gastritis, by
immunohistochemistry and immunoelectron microscopy. The expression of MHC class
II and CD86 antigens on DCs in the gastric mucosa and spleen was evaluated in
dual-colour flow cytometry. RESULTS: DCs were detected in the gastric mucosa of
mice with autoimmune gastritis, and the number of DCs increased as the levels of
gastritis became more severe as time passed following thymectomy. Flow cytometric
analyses revealed that more than 60% of the DCs in the gastric mucosa had a
mature phenotype (expressed MHC class II and/or CD86 antigens) both at 4 and 16
weeks after thymectomy. Activated and mature DCs were localized in the gastric
mucosa from patients with autoimmune gastritis. CONCLUSIONS: This is the first
report on the localization and phenotypes of DCs in the gastric mucosa of
autoimmune gastritis. The presence of mature DCs in the gastric mucosa of murine
and human autoimmune gastritis, in spite of their absence in the gastric mucosa
of normal mice, suggests that mature DCs play a role in the pathogenesis of
autoimmune gastritis.
PMID- 10759886
TI - Antithrombin III and local serum application: adjuvant therapy in peritonitis.
AB - BACKGROUND: Patients with diffuse peritonitis show an overall mortality of about
20%, probably caused by the breakdown of local defence mechanisms combined with a
systemic outspread of bacteria and toxins, which often results in sepsis
syndrome. DESIGN: In a prospective, randomized, controlled study 50 patients with
diffuse secondary peritonitis were included. Patients in the therapy group were
treated with an adjuvant medication consisting of a continuous intravenous
infusion of antithrombin III and two intraperitoneal instillations of fresh
frozen human donor serum. The aim of the study was the reduction of mortality and
incidence of multiple organ failure. RESULTS: Mean antithrombin III plasma levels
in the therapy group were raised above 140% for 4 days and were significantly
higher than in the control group. With the intraperitoneal application of fresh
frozen serum and antithrombin III opsonic capacity as well as thrombin,
inhibitory activity in the exudate could be significantly elevated over 2 days.
The 90-day-mortality rate was 6/26 (23%) in the control group and 6/24 (25%) in
the therapy group. Although no improvement of mortality was achieved, a slight
but not significant reduction of the severity of the multiple organ failure was
seen. CONCLUSIONS: The chosen therapeutic approach was feasible and showed no
side-effects. Yet, neither mortality nor multiple organ failure were
significantly improved by the applied short-term adjuvant therapy. Thus, for
future trials in severely-ill patients a longer treatment period and/or
combinations of antithrombin III with other anti-inflammatory agents should be
considered.
PMID- 10759887
TI - Cytochrome P450 2D6 and glutathione S-transferase M1 genotypes and migraine.
AB - BACKGROUND: Migraine is thought to be a disease of the brain and
trigeminovascular system. Migraine patients often claim that stress, food, and
beverages trigger their attacks. Chemical substances in these foodstuffs with the
property of triggering migraine attacks have not yet been characterised.
Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase M1 (GSTM1) are thought
to be present in the brain. They metabolise numerous environmental compounds. The
genes exhibit genetic polymorphism that is associated with altered enzyme
activity. The aim of this study was to determine if the genotypes of these two
enzymes are associated with migraine. MATERIALS AND METHODS: The study included
100 female patients and 245 female controls from the general population. Genomic
DNA was isolated from whole blood. Allele specific PCR methods were used to
identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4
alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1
null (-) variants. All samples positive for GSTM1 were further analysed for the
presence of allelic variants GSTM1*A and GSTM1*B. RESULTS: None of the CYP2D6 and
GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for
the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5-3.6) and for the
GSTM1 null genotype of 1.0 (95% CI = 0.6-1.5). CONCLUSION: The results of this
study indicate that deficient metabolism because of mutated CYP2D6 alleles or
GSTM1 allele variants is not important in the aetiology of migraine.
PMID- 10759888
TI - Bacterial cell death induced by human pro-apoptotic Bax is blocked by an RNase E
mutant that functions in an anti-oxidant pathway.
AB - BACKGROUND: Bax is a member of the Bcl-2 family and induces apoptosis of
mammalian cells. We have shown that a trace amount of human Bax induces the cell
death of Escherichia coli, accompanied by damage to DNA, and that the region of
Bax which is lethal to E. coli is also responsible for apoptosis-inducing
activity in the mammalian cells. RESULTS: We isolated a Bax-resistant mutant from
E. coli cells that survive in the presence of paraquat, a generator of
superoxide, by screening a library constructed from the random insertion of a
transposon. Psb1 (paraquat-resistant, suppressor of Bax-1) mutant had a Tn 10
transposon inserted in the rne gene of E. coli, splitting the RNase E gene (rne)
into N- and C-terminal halves. The introduction of the truncated 5' end of rne
specifically enhanced resistance to paraquat, prevented cell death induced by Bax
and decreased the intracellular H2O2 concentration. The region responsible for
the paraquat- and Bax-resistance was not the catalytic site for the
endoribonuclease activity of RNase E. CONCLUSIONS: The N-terminal region of the
RNase E protein inhibits bacterial death induced by human Bax as well as paraquat
through a unique mechanism that is distinct from RNA digestion. This study
implies that the protection of bacterial death induced by Bax is associated with
an anti-oxidant pathway and that a mutant RNase E has a novel function as an anti
oxidant.
PMID- 10759889
TI - Large-scale screening of intracellular protein localization in living fission
yeast cells by the use of a GFP-fusion genomic DNA library.
AB - BACKGROUND: Intracellular localization is an important part of the
characterization of a gene product. In an attempt to search for genes based on
the intracellular localization of their products, we constructed a green
fluorescent protein (GFP)-fusion genomic DNA library of S. pombe. RESULTS: We
constructed the S. pombe GFP-fusion genomic DNA library by fusing, in all three
reading frames, random fragments of genomic DNA to the 5' end of the GFP gene in
such a way that expression of potential GFP-fusion proteins would be under the
control of the own promoters contained in the genomic DNA fragments. Fission
yeast cells were transformed with this plasmid library, and microscopic screening
of 49 845 transformants yielded 6954 transformants which exhibited GFP
fluorescence, of which 728 transformants showed fluorescence localized to
distinct intracellular structures such as the nucleus, the nuclear membrane, and
cytoskeletal structures. Plasmids were isolated from 516 of these transformants,
and a determination of their DNA sequences identified 250 independent genes. The
intracellular localizations of the 250 GFP-fusion constructs was categorized as
an image database; using this database, DNA sequences can be searched for based
on the localizations of their products. CONCLUSIONS: A number of new
intracellular structural components were found in this library. The library of
GFP-fusion constructs also provides useful fluorescent markers for various
intracellular structures and cellular activities, which can be readily used for
microscopic observation in living cells.
PMID- 10759890
TI - NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation.
AB - BACKGROUND: NF-kappaB is an ubiquitously expressed transcription factor that
plays an important role in the immune, anti-apoptotic and inflammatory responses.
NF-kappaB is normally sequestered in the cytoplasm by interacting with inhibitory
IkappaB molecules. Upon stimulation, IkappaB is phosphorylated and subsequently
degraded by the proteasome, allowing NF-kappaB to translocate into the nucleus
where they regulate target gene expression. Two kinases, IKK-alpha and IKK-beta,
which are responsible for IkappaB phosphorylation were recently identified. We
have recently identified a cytokine inducible IKK-i, a kinase related to IKK
alpha and -beta. IKK-i significantly induced NF-kappaB activation upon over
expression, as did IKK-alpha and IKK-beta. Unlike IKK-alpha and IKK-beta, IKK-i
phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF
kappaB by distinct mechanisms from the conventional IKKs. RESULTS: I-TRAF/TANK
was isolated as a molecule that interacts specifically with inducible IkappaB
kinase (IKK-i) by the yeast two-hybrid screening procedure. The association of
IKK-i and I-TRAF is mediated via the interaction between the N-terminal domain of
I-TRAF and the C-terminal portion of IKK-i. In vitro kinase assays demonstrate
that IKK-i phosphorylates I-TRAF in the middle portion that associates with
TRAF2. Interestingly, TRAF2 is freed from the I-TRAF/TRAF2 complex after I-TRAF
phosphorylation. NF-kappaB activation by IKK-i is significantly blocked by
coexpression of the N-terminal domain of I-TRAF, dominant negative TRAF2, and
dominant negative NIK and IKK-beta. IKK-i over-expression also induced c-Jun N
terminal kinase. These results show that I-TRAF is a substrate of IKK-i. NF
kappaB activation by IKK-i may be mediated through phosphorylation of I-TRAF by
IKK-i and subsequent liberation of TRAF2. CONCLUSION: These results indicate that
NF-kappaB activation by IKK-i is mediated through phosphorylation of I-TRAF/TANK
by IKK-i and subsequent liberation of TRAF2.
PMID- 10759891
TI - Association of synapse-associated protein 90/ postsynaptic density-95-associated
protein (SAPAP) with neurofilaments.
AB - BACKGROUND: Synapse-associated protein (SAP) 90/Postsynaptic density (PSD)-95
associated protein (SAPAP) (also called Guanylate kinase-associated protein/hDLG
associated protein) interacts with the guanylate kinase domains of PSD-95 and
synaptic scaffolding molecule (S-SCAM) via the middle region containing 5 repeats
of 14 amino acids. SAPAP also binds the recently identified proteins, nArgBP2 and
synamon (also called Shank 1a), via the proline-rich region and the C-terminus,
respectively. SAPAP is highly enriched in the Triton X-100-insoluble PSD
fraction, and recruits PSD-95 into the Triton X-100-insoluble fraction in
transfected cells. We have further characterized here the Triton X-100
insolubility of SAPAP and tried to identify the Triton X-100-insoluble structures
which SAPAP interacts with. RESULTS: N-Methyl-D-aspartate receptors were
recruited into the Triton X-100-insoluble fraction with PSD-95 by SAPAP. The N
terminal region of SAPAP was Triton X-100-insoluble, whereas the middle and C
terminal regions were Triton X-100-soluble. We identified proteins interacting
with 35S-methionine-labelled SAPAP in the overlay assay, determined their amino
acid sequences, and found them to be neurofilaments. SAPAP interacted with
neurofilaments via the N-terminal region, was co-immunoprecipitated with
neurofilaments from the rat brain, and co-localized with neurofilaments in
transfected cells. CONCLUSION: SAPAP associates with neurofilaments via the N
terminal region and may link various components of the PSD to neurofilaments.
PMID- 10759892
TI - Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3,
first mapped on mouse distal chromosome 12 and human chromosome 14q.
AB - BACKGROUND: The paternal duplication of mouse distal chromosome 12 leads to late
embryonal/neonatal lethality and growth promotion, whereas maternal duplication
leads to late embryonal lethality and growth retardation. Human paternal or
maternal uniparental disomies of chromosome 14q that are syntenic to mouse distal
chromosome 12 have also been reported to show some imprinting effects on growth,
mental activity and musculoskeletal morphology. For the isolation of imprinted
genes in this region, a systematic screen of maternally expressed genes (Megs)
was carried out by our subtraction-hybridization method using androgenetic and
normally fertilized embryos. RESULTS: We have isolated seven candidate clones of
the mouse Meg gene. Among them, we identified a novel maternally expressed
imprinted gene, Meg3, on mouse distal chromosome 12 and showed that it was
identical to the Gtl2 gene. We also found that the human homologue MEG3 on
chromosome 14q was also monoallelically expressed. CONCLUSIONS: This is the first
identification of the imprinting gene, both on mouse distal chromosome 12 and on
human chromosome 14q, respectively. Because there are no obvious open reading
frames in either the mouse Meg3/Gtl2 or human MEG3, the function of these genes
remains unclear. However, this result will provide a good basis for the further
investigation of several important imprinted genes in this chromosomal region.
PMID- 10759893
TI - A human homologue of yeast anti-silencing factor has histone chaperone activity.
AB - BACKGROUND: Structural changes in chromatin play essential roles in regulating
eukaryotic gene expression. Silencing, potent repression of transcription in
Saccharomyces cerevisiae, occurs near telomeres and at the silent mating-type
loci, as well as at rDNA loci. This type of repression relates to the
condensation of chromatin that occurs in the heterochromatin of multicellular
organisms. Anti-silencing is a reaction by which silenced loci are de-repressed.
Genetic studies revealed that several factors participate in the anti-silencing
reaction. However, actions of factors and molecular mechanisms underlying anti
silencing remain unknown. RESULTS: Here we report the functional activity of a
highly evolutionarily conserved human factor termed CIA (CCG1-interacting factor
A), whose budding yeast homologue ASF1 has anti-silencing activity. Using yeast
two-hybrid screening, we isolated histone H3 as an interacting factor of CIA. We
also showed that CIA binds to histones H3/H4 in vitro, and that the interacting
region of histone H3 is located in the C-terminal helices. Considering the
functional role of CIA as a histone-interacting protein, we found that CIA forms
a nucleosome-like structure with DNA and histones. CONCLUSIONS: These results
show that human CIA, whose yeast homologue ASF1 is an anti-silencing factor,
possesses histone chaperone activity. This leads to a better understanding of the
relationship between chromatin structural changes and anti-silencing processes.
PMID- 10759896
TI - Psychosocial correlates and impact of chronic tension-type headaches.
AB - OBJECTIVES: To examine the psychosocial correlates of chronic tension-type
headache and the impact of chronic tension-type headache on work, social
functioning, and well-being. METHODS: Two hundred forty-five patients (mean age =
37.0 years) with chronic tension-type headache as a primary presenting problem
completed an assessment protocol as part of a larger treatment outcome study. The
assessment included a structured diagnostic interview, the Medical Outcomes Study
Short Form, Disability Days/Impairment Ratings, Recurrent Illness Impact Profile,
Beck Depression Inventory, State-Trait Anxiety Inventory-Trait Form, Primary Care
Evaluation for Mental Disorders, and the Hassles Scale Short Form. Comparisons
were made with matched controls (N = 89) and, secondarily, with Medical Outcomes
Study data for the general population, arthritis, and back problem samples.
RESULTS: About two thirds of those with chronic tension-type headache recorded
daily or near daily (> or =25 days per month) headaches with few (12%) recording
headaches on less than 20 days per month. Despite the fact that patients reported
that their headaches had occurred at approximately the present frequency for an
average of 7 years, chronic tension-type headache sufferers were largely lapsed
consulters (54% of subjects) or current consulters in primary care (81% of
consulters). Significant impairments in functioning and well-being were evident
in chronic tension-type headache and were captured by each of the assessment
devices. Although headache-related disability days were reported by 74% of
patients (mean = 7 days in previous 6 months), work or social functioning was
severely impaired in only a small minority of patients. Sleep, energy level, and
emotional well-being were frequently impaired with about one third of patients
recording impairments in these areas on 10 or more days per month. Most patients
with chronic tension-type headache continued to carry out daily life
responsibilities when in pain, although role performance at times was clearly
impaired by headaches and well-being was frequently impaired. Chronic tension
type headache sufferers were 3 to 15 times more likely than matched controls to
receive a diagnosis of an anxiety or mood disorder with almost half of the
patients exhibiting clinically significant levels of anxiety or depression.
Affective distress and severity of headaches (Headache Index) were important
determinants of headache impact/impairment. CONCLUSIONS: Chronic tension-type
headache has a greater impact on individuals' lives than has generally been
realized, with affective distress being an important correlate of impairment. If
treatment is to remedy impairment in functioning, affective distress, as well as
pain, thus needs to be addressed.
PMID- 10759897
TI - An analysis of the "carry-over effect" following successful short-term treatment
of transformed migraine with divalproex sodium.
AB - OBJECTIVE: To determine whether successful short-term prophylactic treatment of
transformed migraine may be followed by a continued respite from headaches once
the treatment has been discontinued ("carry-over effect"). BACKGROUND: The
optimal duration of prophylactic treatment for pervasive headache and for
migraine, in particular, is unknown. METHODS: We prospectively evaluated a series
of patients with transformed migraine, all of whom were managed according to a
uniform treatment protocol involving prophylactic therapy with divalproex sodium
for a period not exceeding 12 weeks. All patients reporting a positive treatment
response were followed for at least 2 months after the discontinuation of
divalproex sodium, and the incidence of the carry-over effect in that group was
assessed. RESULTS: A short-term carry-over effect occurred in 12 (60%) of 20
patients, but more sustained relief occurred in only 8 (40%). CONCLUSIONS: The
successful short-term treatment of transformed migraine with divalproex sodium
will often produce a short-term carry-over effect, but this response will be
sustained only in a minority of patients.
PMID- 10759898
TI - Pregnancy outcome following prescription for sumatriptan.
AB - BACKGROUND: Some 2.5% of fertile Danish women use sumatriptan, and the drug is
also taken during pregnancy. Although sumatriptan reacts selectively in brain
vessels, the possibility of reactions with placental blood flow and uterotonic
activity cannot be ruled out. The aim of our study was to examine the association
between sumatriptan exposure during pregnancy and the risk of preterm delivery
and low birth weight. METHODS: Data from the Pharmaco-Epidemiological
Prescription Database of North Jutland county regarding all women who had given
birth in the county of North Jutland from 1991 to 1996 were linked to the Danish
Medical Birth Registry. Women who were exposed to sumatriptan during pregnancy
were identified (n = 34), and using logistic regression models their pregnancy
outcome was compared with two groups of pregnant women: (1) healthy women (n = 15
955) and (2) migraine controls (n = 89), defined as migraine patients who did not
redeem prescriptions for migraine treatment during pregnancy. RESULTS: The risk
of preterm delivery was elevated among women exposed to sumatriptan compared with
migraine controls (odds ratio [OR] 6.3, 95% confidence interval [CI] 1.2-32.0)
and healthy women (OR 3.3, 95% CI 1.3-8.5). The odds ratio for having a newborn
with a low birth weight was increased (OR 3.0, 95% CI 1.3-7.0) for all migraine
patients who delivered at term (n=115) compared with the outcome of healthy
pregnancies. CONCLUSIONS: We found that sumatriptan exposure during pregnancy was
associated with an increased risk of preterm delivery and low birth weight. These
findings may be due to drug exposure, but they may also reflect the impact of
disease severity rather than the treatment itself, or confounding, or chance.
PMID- 10759899
TI - Headaches in a pediatric emergency department: etiology, imaging, and treatment.
AB - OBJECTIVE: To assess the spectrum of diagnoses, the use of CT scans of the brain,
and pharmacological treatments in patients presenting to a pediatric emergency
department with headaches as the chief complaint. METHODS: A 1-year retrospective
chart review of all children who presented to the emergency department with a
headache as the chief complaint. RESULTS: One hundred thirty patients (0.7% of
all pediatric emergency department visits, mean age = 9.3 years) were included in
the study. Primary headaches included 11 migraine (8.5%) and 2 tension headaches
(1.5%). Most of the secondary nonneurological headaches were associated with
viral and respiratory illnesses (n=37, 28.5%), while the majority of the
secondary neurological headaches included 26 posttraumatic (20%), 15 possible
ventriculoperitoneal shunt malfunctions (11.5%), and 3 cases of aseptic
meningitis (2.3%). The neurological etiology in 9 of these children (6.9%) was
found to be serious (subdural hematoma, epidural hematoma, proven
ventriculoperitoneal shunt malfunction, brain abscess, pseudotumor cerebri, and
aseptic meningitis). Fifteen patients could not be etiologically classified,
either because no specific etiology was found or their discharge diagnoses could
not clearly explain the headache. Approximately 10% (5/53) of the CT scans of the
head that were performed showed new abnormal findings including hydrocephalus
secondary to ventriculoperitoneal shunt malfunction (2), subdural hematoma (1),
epidural hematoma (1), and skull fracture (1). Forty-two patients (32%) were
treated pharmacologically. Thirty-nine of the 42 treated patients (93%) were
given over-the-counter analgesics, and 9 (21%) were given prescribed analgesics.
CONCLUSIONS: The majority of the headaches in the pediatric emergency department
were secondary to concurrent illness and minor head trauma, and required no
pharmacological treatment or only treatment with minor analgesics. In a small
minority of patients, headaches were secondary to serious neurological
conditions, which required immediate medical attention. Computed tomography scans
showed new abnormalities in a minority of patients and should be reserved for
those with neurological diagnoses such as head trauma and ventriculoperitoneal
shunt, as well as for those patients with recent onset of headaches with no clear
etiological explanation, and for those with high-risk medical conditions, such as
hypocoagulabilities. Future prospective studies are needed to assess the efficacy
of the various pharmacological treatments in this population.
PMID- 10759900
TI - Prophylactic treatment of migraine with beta-blockers and riboflavin:
differential effects on the intensity dependence of auditory evoked cortical
potentials.
AB - OBJECTIVE: To investigate the influence of different pharmacological treatments
on the intensity dependence of auditory evoked cortical potentials in
migraineurs. BACKGROUND: Between attacks, patients with migraine show
abnormalities in cortical information processing and decreased brain
mitochondrial energy reserve. Both are most probably relevant for migraine
pathogenesis, and they could be differentially modified by prophylactic drug
therapy. Design.-The intensity dependence of the auditory evoked cortical
potentials is, on average, increased in migraine. We have studied this intensity
dependence in 26 patients before and after a 4-month period of prophylaxis with
beta-blockers (n = 11, all migraine without aura; metoprolol or bisoprolol) or
riboflavin (n = 15, migraine without aura: 13, migraine with aura: 2). Recordings
were performed at least 3 days before or after an attack. RESULTS: After the
treatment with beta-blockers, the intensity dependence of the auditory evoked
cortical potentials was significantly decreased (before: 1.66+/-1.02 microV/10
dB; after: 0.79+/-1.06 microV/10 dB, P=.02). The decrease in intensity dependence
was correlated significantly with clinical improvement (r = .69, P = .02). There
was no change in intensity dependence after riboflavin treatment (before: 1.80+/
0.81 microV/10 dB; after: 1.56+/-0.83 microV/10 dB, P = .39), although the
majority of patients showed improvement. CONCLUSIONS: These results confirm that
beta-blockers and riboflavin act on two distinct pathophysiological mechanisms.
Combining both treatments might enhance their efficacy without increasing central
nervous system side effects.
PMID- 10759901
TI - Influence of colors on habituation of visual evoked potentials in patients with
migraine with aura and in healthy volunteers.
AB - OBJECTIVE: To investigate whether colored glasses influence the habituation of
visual evoked potentials. BACKGROUND: We have previously shown that during
pattern-reversal stimulations lasting 2 minutes the amplitude of the visual
evoked potential increases in migraine with and without aura between attacks,
whereas it decreases in healthy volunteers. Red light was found to increase
visually evoked EEG fast activity only in children with migraine with aura.
Wearing rose-tinted glasses for 4 months decreased attack frequency in parallel
with a reduction of the visually evoked EEG fast activity. METHODS: We compared
the change in amplitude of the visual evoked potential using five different
tinted glasses in 12 patients with migraine with aura and in 10 healthy
volunteers. During continuous stimulation at 3.1 Hz, five blocks of 50 responses
were sequentially averaged using red, yellow, green, blue, and grey glasses and
without glasses in a random order and analyzed in terms of latencies and N1-P1
amplitudes. Amplitude changes were calculated for each block by comparison with
the first block in every condition and analyzed statistically using Zerbe's
method. RESULTS: In healthy volunteers, the visual evoked potential amplitude
increased with red glasses compared to without glasses (P = .05) or with green
glasses (P = .03). In patients with migraine with aura, no significant difference
was detected using colored glasses. Our findings in healthy volunteers are in
line with earlier reports of increased excitability of the human visual cortex
when exposed to red light. The lack of such a pattern in patients with migraine
with aura suggests that the visual cortex is interictally hypoexcitable rather
than hyperexcitable, which is consistent with studies of transcranial magnetic
stimulation.
PMID- 10759902
TI - Alteration in nature of cluster headache during subcutaneous administration of
sumatriptan.
AB - OBJECTIVES: To document the relationship between the 5-HT receptor agonist
sumatriptan and a change in the nature of cluster headache in four cases. To
relate the findings to the literature on the use of sumatriptan in both cluster
headache and migraine. BACKGROUND: Studies of the efficacy and adverse effects of
long-term treatment with sumatriptan in cluster headache are limited and report
conflicting findings. METHODS: Four cases are described. RESULTS: All four
patients developed a marked increase in the frequency of attacks 3 to 4 weeks
after initiating treatment with the drug for the first time. Three patients also
developed a change in headache character, and 2 experienced prolongation of the
cluster headache period. Withdrawal of the drug reduced the frequency of
headaches and eliminated the newly developed type of headache. CONCLUSIONS:
Determination of the effects of long-term use of sumatriptan will result in more
precise guidelines for the frequency and duration of treatment with this
otherwise extremely beneficial drug.
PMID- 10759903
TI - Patients with acenocoumarol treatment and migraine.
AB - OBJECTIVE: The aim of our study was to investigate the possible effect of
acenocoumarol, which is indicated for nonneurological disease, on headache.
BACKGROUND: It has been suggested that anticoagulation can have beneficial
effects in the control of migraine attacks. METHODS: Four hundred randomized
patients on oral anticoagulant therapy were asked to complete a questionnaire
regarding their headaches. RESULTS: Headache was present before or during oral
anticoagulation in 166 (66 migraineurs and 100 nonmigraineurs) of 326
respondents. The major finding was that oral anticoagulation produced improvement
in 63% of patients with migraine versus 38% of patients with nonmigranous
headache. Improvement was related to the severity of migraine but not to age.
CONCLUSIONS: Oral anticoagulant therapy can improve migraine. The way in which
anticoagulant therapy acts on migraine is unknown, but potential mechanisms
include its effect on platelet aggregability and pharmacological effects such as
suppression of enhanced nitric oxide.
PMID- 10759904
TI - Baclofen in cluster headache.
AB - Cluster headache is a rare, severe, clinically well-characterized disorder that
occurs in both episodic and chronic forms. The painful short-lived attacks occur
unilaterally and are associated with signs and symptoms of autonomic involvement.
They are difficult to treat, and reported prophylactic therapies include
ergotamine, steroids, methysergide, lithium carbonate, verapamil, valproate,
capsaicin, leuprolide, clonidine, methylergonovine maleate, and melatonin.
Baclofen, an antispastic agent, has been shown to have an antinociceptive action.
Its efficacy in the treatment of neuralgias, central pain following spinal
lesions or painful strokes, migraine, and medication misuse chronic daily
headache suggested that it may prevent cluster headache attacks. Nine cluster
headache patients received baclofen, 15 to 30 mg, in three divided doses. Within
a week, six of nine patients reported the cessation of attacks. One was
substantially better and became attack free by the end of the following week. In
the remaining two patients, the attacks worsened and corticosteroids were
prescribed. In this pilot study, baclofen seemed to be effective and well
tolerated for the prevention of cluster headache.
PMID- 10759905
TI - Migraine with prolonged aura.
AB - We present the case of a 29-year-old man with a long history of migraine with
aura, in whom migraine with prolonged aura was induced after the sudden
withdrawal of prophylactic therapy.
PMID- 10759906
TI - Simultaneous occurrence of ipsilateral cluster headache and chronic paroxysmal
hemicrania: a case report.
AB - A 42-year-old man came to our headache unit in October 1995 complaining of
recurrent attacks of headache, which had begun in February 1991. Chronic cluster
headache was diagnosed, and he was given verapamil, 360 mg per day. The attacks
ceased in the following months and verapamil was stopped in March 1996. In May
1997, a recurrence of the attacks required the readministration of verapamil, 360
mg per day. The attacks decreased (one to three per week), but after 2 months the
patient reported a worsening in his condition due to the appearance of shorter
attacks, which were diagnosed as chronic paroxysmal hemicrania. The
administration of indomethacin, 225 mg per day, resulted in the disappearance of
the short attacks. The concomitant occurrence of attacks of cluster headache and
chronic paroxysmal hemicrania suggests the presence of shared factors in the
pathophysiology of the two forms of headache. This hypothesis is supported by
previous reports in the literature.
PMID- 10759907
TI - Spinal cord infarction during use of zolmitriptan: a case report.
AB - A 50-year-old woman with a history of migraine without aura, predominantly
occurring around her menstrual periods, developed a spinal cord lesion following
the use of zolmitriptan. The partial lesion of the cord at T7 predominantly
involved the spinothalamic pathways on the left side. Clinical features suggested
that the lesion was an ischemic infarct, and this was confirmed by an MRI scan.
There were no other known risk factors for vascular disease. There has been mild
improvement of her symptoms, but most of the symptoms did not resolve. There are
isolated case reports of stroke secondary to the use of triptans, however, this
is the first case of spinal cord infarction reported following the use of this
group of drugs. The temporal relationship suggests that the spinal cord
infarction may be related to the use of zolmitriptan.
PMID- 10759908
TI - Prophylactic pharmacological treatment of chronic daily headache.
AB - OBJECTIVE: To review all the prophylactic pharmacological treatments for chronic
daily headache from the past decade. BACKGROUND: Chronic daily headache is among
the most common diagnoses seen in specialized headache centers. Prior to 1988,
there were no criteria for the diagnosis of chronic tension-type headache and
chronic daily headache. An expanded chronic daily headache classification has
been proposed. METHODS: A MEDLINE search was performed using the following key
words: chronic daily headache, intractable headache, transformed migraine,
chronic tension headache, and chronic tension-type headache. We limited our
review to those studies published in English in the last decade, including
published abstracts and letters to the editor. Double-blind studies carried out
prior to 1988 were also included. RESULTS: Pharmacological treatments for chronic
daily headache include antidepressants (tricyclics, tetracyclics, monoamine
oxidase inhibitors, selective serotonin reuptake inhibitors), anticonvulsants,
muscle relaxants, 5-HT1 agonists, ergots, 5-HT2 antagonists, antianxiety agents,
and miscellaneous drugs. Many of these reports are anecdotal, and most are open
rather than double-blind studies. CONCLUSIONS: There is a great variety of
pharmacological treatments available for chronic daily headache. Only the
antidepressants have been extensively studied. Other medications may be used if
these fail. Recommendations based on our experience at the Headache Unit of the
Montefiore Medical Center are outlined here.
PMID- 10759909
TI - Low migraine headache recurrence with naratriptan: clinical parameters related to
recurrence.
AB - OBJECTIVE: To evaluate clinical parameters that may affect the incidence of
headache recurrence or the time to headache recurrence, or both, in migraineurs
treated with naratriptan, 2.5-mg tablets. BACKGROUND: The incidence of headache
recurrence within 24 hours of treatment with naratriptan, 2.5-mg tablets (17%
28%), is lower than that reported for other currently available selective
serotonin agonists. Identifying clinical parameters that influence headache
recurrence may further reduce the incidence of headache recurrence or prolong the
time to recurrence, or both, for naratriptan-treated patients. METHODS: We
examined the effects of three clinical parameters (predose pain severity,
headache duration prior to treatment, and relief status 4 hours post dose) on the
incidence of and time to headache recurrence across four placebo-controlled
naratriptan clinical trials. The impact of these parameters on headache
recurrence was examined individually and in combination. RESULTS: Predose pain
severity had no effect on the incidence of headache recurrence (overall 23%;
moderate 22%, severe 23%). The median time to recurrence was longer for patients
with moderate pain before treatment compared with patients with severe pain
before treatment (14.5 hours versus 9.3 hours, respectively). Overall time to
headache recurrence was 11.8 hours. Patients with headache recurrence reported a
longer time until they treated the headache compared with patients without
headache recurrence (median, 145 minutes versus 97.5 minutes). Patients who
treated headache pain within 3 hours of onset had a lower incidence of headache
recurrence (20%) than patients who treated their headache more than 3 hours after
onset (28%). Patients with no pain 4 hours post dose had a lower incidence of and
a longer time to headache recurrence compared with patients with mild pain 4
hours post dose (17% versus 32%; median, 17.8 hours versus 8.1 hours,
respectively). The interaction of all three clinical parameters was significant
in predicting headache recurrence. CONCLUSIONS: The overall incidence of headache
recurrence is low after naratriptan, 2.5 mg, compared with other currently
available selective serotonin agonists. Predose pain severity, time to treatment,
and 4-hour relief status appear related to the incidence of or time to headache
recurrence, or both. Treating less severe migraine attacks, treating earlier
within an attack, and obtaining complete relief post dose may enhance the low
incidence of headache recurrence and achieve longer times to recurrence with
naratriptan, 2.5 mg.
PMID- 10759910
TI - Life event stress and headache frequency revisited.
AB - Life stress is found to be related to headache frequency in some studies, but not
others. Research designs that find a relationship between the two tend to
evaluate young subjects and employ large sample sizes. The purpose of this study
was to evaluate the relationship between headache frequency and life stress,
while considering gender and age differences that may be present in the
relationship. In addition, as depression or presence of headache at the time of
assessment may influence the report of headache frequency, an attempt to control
for these factors was employed. Several self-report measures of headache
symptomatology, headache presence, depression, and life stress were completed by
1289 subjects. Negative life event stress was found to be modestly but
significantly related to headache frequency. The relationship between the 2
variables was stronger for women than for men and, after the influence of
depression and headache state was removed, the relationship between life stress
and headache frequency remained significant only for women. In the oldest 10% of
the sample, there was no evidence of a relationship between negative life event
stress and headache frequency.
PMID- 10759911
TI - A comparative trial of zolmitriptan and sumatriptan for the acute oral treatment
of migraine.
AB - OBJECTIVE: This randomized, double-blind, parallel group multicenter study
compared response rates and tolerability of zolmitriptan with sumatriptan in the
acute treatment of migraine. METHODS: A sample consisting of 1445 outpatients
with an established diagnosis of migraine was randomized to zolmitriptan, 2.5 mg
or 5 mg, or sumatriptan, 25 mg or 50 mg. Patients took 1 tablet for
moderate/severe migraine and a second identical tablet, if necessary, for
recurrent headache of moderate/severe intensity 4 to 24 hours after the initial
dose. Up to six attacks were treated during a 6-month period. The primary outcome
measure was headache response 2 hours after the initial dose. Secondary end
points included 1-hour and 4-hour headache response and pain relief over 24
hours. RESULTS: A headache response at 2 hours was noted in 67.1% of patients
taking zolmitriptan, 2.5 mg, and 64.8% of those taking zolmitriptan, 5 mg, versus
59.6% of patients taking sumatriptan, 25 mg, and 63.8% of those taking
sumatriptan, 50 mg. At 2 and 4 hours, the differences between zolmitriptan, 2.5
mg, and sumatriptan, 25 mg, were statistically significant (odds ratio=1.49 and
1.67, respectively; both P<.001). Statistically significant differences between
zolmitriptan, 2.5 mg, and sumatriptan, 50 mg, were seen at 2 and 4 hours post
dose (odds ratio=1.21 and 1.23, respectively; both P<.05). At 1 hour post dose,
the headache response rate for zolmitriptan, 2. 5 mg, was numerically higher than
response rates for sumatriptan, 25 mg and 50mg (odds ratio=1.16, odds ratio=1.06,
though they failed to reach statistical significance; P=.061, P=.461
respectively). Differences between zolmitriptan, 5 mg, and sumatriptan, 25 mg,
were statistically significant at 1, 2, and 4 hours (odds ratio=1.43, 1. 46, and
1.78, respectively; all P<.001) and at 1 and 4 hours versus sumatriptan, 50 mg
(odds ratio=1.28, P=.002; odds ratio=1.29, P=.012, respectively). Although not
statistically significant at 2 hours, more patients responded to zolmitriptan, 5
mg, than to sumatriptan, 50 mg (odds ratio=1.16, P=.064). Patients receiving
zolmitriptan, 2. 5 mg or 5 mg, achieved more pain relief over 24 hours than
patients receiving sumatriptan, 25 mg (odds ratio=1.47, and 1.54 respectively,
both P<.001) or sumatriptan, 50 mg (odds ratio=1.17, P=.021; odds ratio=1.22,
P=.005, respectively). All treatments were well tolerated. CONCLUSIONS:
Zolmitriptan, 2.5 mg and 5 mg, was at least as effective as sumatriptan, 25 mg or
50 mg, for all parameters studied. Zolmitriptan, 2.5 mg, was significantly more
effective than sumatriptan, 50 mg, in terms of headache response at 2 and 4
hours. Patients taking zolmitriptan were significantly more likely to have pain
relief over 24 hours than those taking sumatriptan.
PMID- 10759912
TI - Decision making in migraine patients taking sumatriptan: an exploratory study.
AB - Until recently, much of the medical and psychological literature has examined and
conceptualized the taking of medication from the viewpoint of adherence to or
compliance with recommendations from health professionals. However, some authors
have argued that medication taking is mostly determined by patient decision
making. In order to investigate the factors and processes influencing the
patient's decision to take or not take abortive therapy for migraines, 20
migraineurs (according to International Headache Society criteria) were asked,
using a semistandardized interview, what factors influenced their decision to
take or not take sumatriptan when they had a migraine. Qualitative analysis
revealed a 2-stage decision-making process. First, the patient collects
information from interoceptive and environmental cues (symptom monitoring) to
predict whether the headache that is beginning will become a migraine. Then, if
the patient decides it is a migraine, he or she weighs various factors to decide
whether to take sumatriptan. These results are consistent with the current
cognitive psychology literature on decision-making processes and could lead to
significant improvements in understanding the process by which patients make
decisions about taking sumatriptan and, ultimately, could lead to better patient
education and more effective headache control. They also open a whole new field
in the empirical investigation of medication-taking behavior.
PMID- 10759913
TI - Permeation of sumatriptan through human vaginal and buccal mucosa.
AB - Continued interest in the various routes by which sumatriptan may be administered
prompted us to investigate its passage through buccal mucosa. Because human
buccal mucosa is scarce, we proposed using the relatively abundant vaginal
mucosa, which has been shown to have comparable diffusion rates for a number of
widely varying molecules, as a model of buccal mucosa. In addition, by comparing
these two tissues with respect to their permeability to sumatriptan, the human
vaginal/buccal mucosa model could be further evaluated. Clinically healthy human
vaginal and buccal mucosa specimens were used in the permeability studies.
Permeability to sumatriptan was determined using a continuous flow-through
diffusion system in the presence and absence of permeation enhancers. No
statistically significant differences in permeability could be demonstrated for
both mucosae toward sumatriptan. Flux values obtained in the absence and presence
of glycodeoxycholate and lauric acid (1:1 molar ratio) to sumatriptan of buccal
and vaginal mucosa, respectively, were not significantly different. The results
obtained further support the hypothesis of the vaginal/buccal mucosal in vitro
permeability model and suggest that this model may be used in conjunction with
various absorption enhancers. Further studies on the buccal route of absorption
of sumatriptan are thus warranted.
PMID- 10759914
TI - Dynamic assessment of abnormalities in central pain transmission and modulation
in tension-type headache sufferers.
AB - OBJECTIVE: To examine and compare central pain processing and modulation in young
tension-type headache sufferers with that of matched healthy controls using an
induced headache "challenge" paradigm. BACKGROUND: Recent research has suggested
that abnormalities in central pain processing and descending pain modulation may
contribute to chronic tension-type headache. These abnormalities, if they
contribute to headache pathogenesis, should be present in young adult tension
type headache sufferers. Recent research using static measures of physiological
variables, such as muscle tenderness and exteroceptive suppression, has
identified chronic muscle tenderness as a characteristic of young tension-type
headache sufferers, but other central nervous system functional abnormalities may
require a dynamic "challenge" to be observed. METHODS: Twenty-four young women
meeting the International Headache Society diagnostic criteria for tension-type
headache (headache-prone) and a matched group of 24 healthy women who reported
fewer than 10 problem headaches per year (control) participated in a double
blind, placebo-controlled, crossover study. Subjects completed jaw clenching and
a placebo condition on different days in counterbalanced order. Pericranial
muscle tenderness, pressure-pain thresholds on the temporalis, and exteroceptive
suppression periods were assessed before and after each procedure. Head pain was
recorded for 12 to16 hours following each condition. RESULTS: Headache-prone
subjects were more likely than controls to experience headaches after both the
jaw clenching and placebo procedures, but neither group was significantly more
likely to experience headaches following jaw clenching than placebo. In
pretreatment measurements, headache-prone subjects exhibited greater muscle
tenderness than controls, but pressure-pain detection thresholds and
exteroceptive suppression periods did not differ in the two groups. Control
subjects showed increases in muscle tenderness and exteroceptive suppression
periods following both the clenching and placebo procedures, whereas headache
prone subjects exhibited no significant changes in any of the physiological
measures following either experimental manipulation. CONCLUSIONS: These results
confirm previous findings indicating abnormally high pericranial muscle
tenderness in young tension headache sufferers even in the headache-free state.
In addition, the results suggest that the development of headaches following
noxious stimulation is more strongly related to headache proneness and associated
abnormalities in central pain transmission or modulation (indexed by pericranial
muscle tenderness and exteroceptive suppression responses) than muscle strain
induced by jaw clenching.
PMID- 10759915
TI - Genetic and environmental factors associated with migraine in schoolchildren.
AB - OBJECTIVE: The aim of this study was to find the prevalence of migraine and
headache in schoolchildren in the United Arab Emirates and to determine the
genetic and environmental factors associated with these conditions. METHODS: A
cross-sectional population study was performed from October 1995 to June 1996.
Subjects were selected by a multistage stratified sampling procedure. Data were
collected by screening questionnaires followed by clinical interviews. Twelve
primary schools and 1400 schoolchildren of United Arab Emirates nationality
resident in the Al Ain City, Dubai, and Sharjah emirates were recruited for this
study. A total of 1159 (82.7%) schoolchildren gave their consent to the study.
RESULTS: The estimated prevalence rates for headache and migraine were 36.9% and
13.7%, respectively. The prevalence of headache is increased with age, the
highest prevalence being in 13-year-old children (17.5%). Of the 159 children who
fulfilled the diagnostic criteria for migraine, 76 were boys whose mean age (+/-
SD) was 10.3 years +/- 2. 8 years, and 83 were girls (mean age 9.9 +/- 2.5
years). Of the children who had migraine, 20 (12.6%) had migraine without aura,
and 13 (8.2%) had migraine with aura. The most common migraine symptoms in
schoolchildren had been aggravated by physical activity (47.2%) and a positive
family history of migraine (46.5%). The most common illnesses were infectious
illnesses (41.5%). There was a strong relationship between migraine and the
timing of examinations (46.5%). The most common environmental exposure for
migraine was found to be playing on a computer (45.9%), followed by loud noise
(41.5%), and a hot climate (37.1%). In familial occurrence of headache among
immediate relatives, the most frequently affected relative was the mother
(17.6%). CONCLUSION: .-Headache and migraine are common in childhood and may be
influenced by social, familial, environmental, and psychological factors.
PMID- 10759916
TI - Montelukast in the prophylaxis of migraine: a potential role for leukotriene
modifiers.
AB - OBJECTIVE: Clinical observation of a decrease in migraine frequency in patients
with comorbid asthma taking montelukast, a specific D4 leukotriene receptor
antagonist, or zafirlukast, another leukotriene receptor antagonist, prompted us
to explore a possible role for leukotriene modifiers in the treatment of
migraine. (A further prompt was a pharmacist colleague's observation that a
number of patients on these agents reported a decreased sensitivity to perfume
triggers and improvement in migraine.) BACKGROUND: Nonsteroidal anti-inflammatory
agents have been used widely in the treatment of migraine. Another class of anti
inflammatory agents, known as leukotriene modifiers, have not been studied to
date with regard to their possible role in the treatment of migraine. The name
"leukotriene is derived both from the parent molecule, which was originally
isolated from leukocytes, and from its three double-bond carbon backbone or
triene structure. Both prostaglandins and leukotrienes are derived from the
metabolism of arachidonic acid, with prostaglandins coming off the cyclooxygenase
pathway and leukotrienes derived via the enzyme 5-lipoxygenase. Both
prostaglandins and leukotrienes mediate inflammatory responses. The latter have
been studied with regard to their role in the pathophysiology of asthma. METHODS:
A prospective, open-label study evaluating the efficacy of montelukast, 10 mg or
20 mg, in the prophylaxis of migraine in 17 patients is presented in this paper.
All 17 patients completed the study that consisted of a 2-month baseline run-in
period and a 3-month treatment phase. RESULTS: Montelukast was extremely well
tolerated, and no adverse events were reported by any of the patients. Fifty
three percent showed a reduction of greater than 50% (P<.025) in the frequency of
severe attacks, with 41% showing a reduction of greater than 60%. Responders,
including modest responders, rated the drug as excellent. CONCLUSIONS: We
conclude, given the limitations of an open-label study design and the small
sample size, that montelukast shows potential as an effective, well-tolerated
prophylactic agent in migraine. Double-blinded, placebo-controlled studies are
warranted. In addition, the leukotrienes, as suggested previously in the
literature, may play a role in the pathogenesis of migraine.
PMID- 10759917
TI - Hungarian migraine epidemiology.
AB - OBJECTIVE: A population-based epidemiological survey of migraine without aura and
migraine with aura completed by mailed questionnaire in Hungary. The diagnosis
and classification of migraine was according to the criteria of the International
Headache Society. METHODS: The validity of the self-administered headache
questionnaire was evaluated by a neurologist using clinical interviews. The study
population was a random sample of 2000 men and women aged between 15 and 80
years. The questionnaire was completed by 813 of 1910 people (392 men and 421
women), providing a 42.6% participation rate. RESULTS: Sixty-seven percent of
these people experienced some kind of headache during their lives. The 1-year
prevalence of migraine without aura was 7.6% (the female/male ratio was 3:1),
while the 1-year prevalence of migraine with aura was 2% (female/male ratio was
2:1). Most migraineurs experienced headache attacks 1 to 4 times monthly, which
lasted 24 hours. The most characteristic accompanying signs were nausea and
phonophobia. Stress, sleep deprivation, hot weather, and fasting were the most
common precipitating factors of a migraine attack. In the migraine with aura
group, the most common aura was a visual disturbance. Only 43% of migraineurs had
ever consulted a physician for headache, and only 15% of patients had missed work
or school because of a migraine attack in the previous year. Most of the patients
suffering from migraine without aura were between 20 and 40 years old, while
migraineurs with aura were over 40 years old. According to this investigation,
the prevalence of migraine was not lower than in Western countries.
PMID- 10759918
TI - Acquired transient stuttering during a migraine attack.
AB - Stuttering is an abnormality in the fluency of speech, which is characterized by
interruption of the normal rhythm due to involuntary repetition and prolongation,
or arrest, of uttered letters or syllables. The aphasic syndrome and dysarthria
can be associated with classic migraine, but, to our knowledge, no study has so
far described stuttering as the only neurological symptom accompanying an attack.
PMID- 10759919
TI - Benign hot bath-related headache.
AB - We describe three cases of women with hot bath-related headache who reported that
their severe paroxysmal headache could be provoked by pouring hot water over
themselves or by soaking in a hot bath. In one patient, the headache was also
brought on by exposure to cold wind. Another patient had headaches after she
dived into a pool and started swimming. Neurological examination, routine
laboratory tests, electroencephalography, and brain imaging showed no abnormality
in any of the patients. Hot bath-related headache is a benign headache
unassociated with a structural lesion.
PMID- 10759920
TI - Predictability of exogenous hormone effect on subgroups of migraineurs.
AB - OBJECTIVE: To evaluate whether self-reported past migraine response to
reproductive life events (menses, pregnancy, menopause) alters the likelihood of
worsening of migraine with exogenous hormone use. METHODS: A retrospective study
was conducted on 451 female patients at the University Headache Center who had a
diagnosis of migraine with or without aura. RESULTS: The majority of migraineurs
recalled no change in headaches with oral contraceptive use or hormone
replacement therapy (67.2% and 77%, respectively). Worsening of migraines with
oral contraceptive use was associated with a menstrual trigger, worsening during
pregnancy, and a diagnosis of migraine without aura. Worsening with hormone
replacement therapy was associated with worsening during prior oral contraceptive
use, improvement during pregnancy, worsening during menopause, and a diagnosis of
migraine without aura. CONCLUSIONS: Prospective studies are needed to confirm
these associations.
PMID- 10759921
TI - The wavelength of light causing photophobia in migraine and tension-type headache
between attacks.
AB - OBJECTIVE: To ascertain the wavelength of light that patients with migraine and
tension-type headache find uncomfortable between attacks. BACKGROUND: Photophobia
is an abnormal perceptual sensitivity to light experienced by most patients with
headache during and, also, between attacks. METHODS: We examined the discomfort
threshold to light of low, medium, and high wavelengths in a group of patients
with migraine (n=21), patients with tension-type headache (n=19), and healthy
controls (n=21). RESULTS: The results indicate that the migraine group had
significantly lower discomfort thresholds at the low (P=.001) and high (P=.031)
wavelengths compared with both the tension-type headache and control groups; the
latter two groups had similar average discomfort levels at these two wavelengths.
With the medium wavelength, the control group had significantly higher discomfort
thresholds than the migraine (P=.002) and tension-type headache (P=.031) groups;
the latter two groups had similar discomfort levels at this wavelength. With
unfiltered (white) light, the migraine group had the lowest discomfort threshold
and the control group the highest (P=.026), whereas the tension-type headache
group had an intermediate discomfort threshold. CONCLUSIONS: There were
significant differences between migraineurs, patients with tension-type headache,
and healthy controls in the wavelengths that are uncomfortable between attacks.
PMID- 10759922
TI - Acute headache in children and adolescents presenting to the emergency
department.
AB - OBJECTIVES: Our goals were (1) to investigate the causes of acute headache in
childhood from the emergency department perspective and (2) to search for
clinical clues that might distinguish headache associated with serious underlying
disease. BACKGROUND: The clinical presentation of headache in children and
adolescents can be separated into 5 temporal patterns: acute, acute-recurrent,
chronic progressive, chronic nonprogressive, and mixed. Few data exist regarding
acute headache in children. METHODS: Consecutive children who presented to our
emergency department with the abrupt onset of severe headache were prospectively
evaluated. The headache character, location, severity, and associated symptoms,
as well as underlying causes, were recorded using a standardized survey. RESULTS:
One hundred fifty children, aged from 2 to 18 years, 87 boys and 63 girls, were
enrolled over a 10-month period. Upper respiratory tract infection with fever
(viral upper respiratory tract infection 39%, sinusitis 9%, streptococcal
pharyngitis 9%) was the most frequently identified cause of acute headache (57%).
Other causes included migraine (18%), viral meningitis (9%), posterior fossa
tumors (2.6%), ventriculoperitoneal shunt malfunction (2%), epileptic seizure
(postictal headache) (1.3%), concussion (postconcussive headache) (1. 3%),
intracranial hemorrhage (1.3%), and undetermined (7%). Two clinical features were
found to have statistically significant associations with serious underlying
disease: occipital location of headache and an inability of the patient to
describe the quality of the head pain. All children with surgically remediable
conditions had clear and objective neurological signs. CONCLUSIONS: In children
and adolescents, the abrupt onset of severe headache is most frequently caused by
upper respiratory tract infection with fever, sinusitis, or migraine. Special
attention is warranted if the acute headache is occipital in location and if the
affected patient is unable to describe the quality of the pain. Serious
underlying processes such as brain tumor or intracranial hemorrhage are uncommon
and, when present, are accompanied by multiple neurological signs (ataxia,
hemiparesis, papilledema).
PMID- 10759923
TI - Validity and reliability of the migraine-specific quality of life questionnaire
(MSQ Version 2.1).
AB - OBJECTIVE: To assess the scaling properties, reliability, and validity of the
revised Migraine-Specific Quality of Life Questionnaire (MSQ) (Version 2.1)
BACKGROUND: The MSQ is a disease-specific, quality-of-life instrument with three
hypothesized scales that has been developed, tested, and revised. METHODS: The
study used a multicenter, nondrug, prospective, parallel group, quasi
experimental design. Patients with migraine were recruited at outpatient headache
specialty practices and were administered the MSQ, the Medical Outcomes Study 36
Item Short Form Health Survey (SF-36), and migraine symptom questionnaires at
baseline, 4 weeks, and 12 weeks. Internal consistency (Cronbach alpha) and 4-week
test-retest reproducibility (intraclass correlation coefficients) were estimated
to assess reliability. Construct validity was assessed using an adaptation of the
Campbell and Fiske multitrait-multimethod approach and by correlating MSQ scores
with symptom measures. RESULTS: A total of 267 subjects enrolled in the trial.
The criteria for summated rating scales were all met. The internal consistency
coefficients ranged from 0.86 to 0.96, and the intraclass correlation
coefficients ranged from 0.57 to 0.63 across the three dimensions. As
anticipated, the MSQ dimensions had low-to-modest correlations with the two
component scores of the SF-36 and were modestly to moderately correlated with
migraine symptoms. CONCLUSIONS: The MSQ is a reliable instrument in the
assessment of quality of life for patients with migraine with items that can be
summed without weights. The MSQ has demonstrated evidence of construct validity.
PMID- 10759924
TI - Incidence of medically recognized migraine: A 1989-1990 study in Olmsted County,
Minnesota.
AB - OBJECTIVE: To investigate the incidence of medically recognized migraine in
Olmsted County, Minnesota, during the years 1989 to 1990. METHODS: We used the
records-linkage system of the Rochester Epidemiology Project to identify all
subjects who sought medical attention for their headache and had their initial
visit for migraine within the study period. Incident cases were classified using
specified criteria. RESULTS: From 9837 records screened, we found 713 incident
cases. The average annual incidence rate (new cases per 100 000 person-years) was
343.0 in both sexes combined, 481.6 in women, and 194.4 in men. In women,
incidence rates were low at the extremes of age and higher among those aged
between 10 and 49 years, with a striking peak at the age of 20 to 29 years.
Migraine without aura was the most common type of migraine in women. Men had a
more constant risk of migraine throughout life with a lesser peak at the age of
10 to 19 years, and they were equally affected by all types of migraine. Women
had consistently higher incidence rates than men at all ages, and there were
strikingly higher incidence rates of migraine without aura in women than in men.
CONCLUSIONS: Although our incidence rates were restricted to medically recognized
cases of migraine, we confirmed previously reported epidemiological patterns.
PMID- 10759925
TI - Intravenous propofol: unique effectiveness in treating intractable migraine.
AB - OBJECTIVE: To report the unique effectiveness of propofol, an intravenous
anesthetic agent, in treating refractory migraines and other headaches in the
setting of an outpatient headache center. BACKGROUND: We initially observed the
dramatic abolition of ongoing migraine in patients (n=6) being treated with
propofol in preparation for epidural and other nerve blocks in the headache and
pain clinic. The reduction of headache severity was virtually 100%. We decided to
treat an additional cohort of patients with intravenous propofol in the headache
clinic; these patients had intractable migraines that were refractory to the
usual abortive treatments. Subanesthetic doses of propofol were employed in this
study. This is the first known report of the utility of this agent specifically
for the treatment of intractable headache. METHODS: Seventy-seven patients were
treated for intractable headache in the clinic with intravenous propofol, for
both migraine and nonmigrainous headache refractory to the usual methods of
abortive treatment. RESULTS: The average reduction in headache intensity was
95.4% after an average of 20 to 30 minutes of intravenous propofol treatment,
using a patient-rated visual analog scale of 0 to 10. Sixty-three of 77 patients
reported complete abolition of their headache. The average dose of propofol was
110 mg, which is well within the usual range of preanesthetic doses and is
clearly subanesthetic. Moreover, only three of the treated patients reported a
return of the headache on the day following treatment. The neuropharmacology of
propofol and the putative multiple mechanisms of action upon various
neurotransmitter systems in the brain, particularly gamma aminobutyric acid A
receptor subtypes, are discussed to explain the results in our patients.
CONCLUSIONS: The use of intravenous propofol may represent a new, rapid, and
highly effective form of abortive headache treatment in the headache clinic or
emergency room setting and may offer an alternative to other treatment modalities
for acute migraine and other severe intractable headaches. The effectiveness of
propofol raises many new questions about the pathophysiology of migraine and
other headaches.
PMID- 10759926
TI - Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot
study.
AB - OBJECTIVE: To see whether therapy with botulinum toxin A may prove to be an
effective treatment for headache of musculoskeletal origin. BACKGROUND: Headache
is a common finding associated with neck injury. Cervicogenic headache, which is
believed to be attributable to injury of the ligaments, muscles, or joints of the
cervical spine, is centered in the occipital region with pain referred to the
frontotemporal region. Botulinum toxin A produces prolonged muscle relaxation,
which is dose dependent and can be easily targeted to affected muscles. METHODS:
This randomized, double-blind, placebo-controlled study compares outcome measures
in 26 patients suffering from chronic headache subsequent to a cervical whiplash
injury. One half of the patients received botulinum toxin A, 100 units, diluted
in 1 mL of saline, while the other half received just saline (1 mL). Five
cervical trigger points received 0.2 mL each of injectant via a 30-gauge needle.
Outcome measures included subjective head pain based on visual analog scales, as
well as range of neck motion. Follow-up assessments were carried out at 2 and 4
weeks after treatment. RESULTS: Fourteen subjects who received botulinum toxin A
and 12 who received saline completed the study. At both 2 and 4 weeks post
injection, the treatment group showed a significant improvement in pain and range
of motion from preinjection levels (P<.01). The placebo group demonstrated no
statistically significant changes at any posttreatment time.
PMID- 10759927
TI - Nasal surgery for contact point headaches.
AB - Headache due to the pressure on nasal mucosa of anatomical variations, nasal
polyps, or mucosal swelling in the absence of inflammation of the paranasal
sinuses is a clinical entity that has gained wide acceptance. In this paper, the
outcomes of surgical treatment in 30 patients whose headaches were believed to be
the result of intranasal contact points are presented. Total relief of the
headache and significant improvement were achieved in 43% and 47% of the
patients, respectively, after endoscopic endonasal surgery. The intensity of the
headache was the same as preoperatively in 10% of the patients. In the absence of
any other identifiable etiological factors, intranasal mucosal contacts must be
kept in mind as a cause of the headache.
PMID- 10759928
TI - Etiology and distribution of headaches in two Brazilian primary care units.
AB - OBJECTIVES: To determine (a) which patients seek primary care services with a
complaint of headache, (b) the percentages of the various types of headache in
this population, and (c) the impact of the care provided to these patients on the
basic health care network. BACKGROUND: Headache is one of the most frequent
symptoms reported in medical practice, resulting in significant medical services
costs and loss of patient productivity, as well as reduced quality of life.
METHODS: A prospective study was conducted in two towns (Ribeirao Preto and Sao
Carlos) in the State of Sao Paulo, Brazil. The participants in the study
consisted of 6006 patients (52.4% women) with highly varied acute symptoms. The
patients ranged in age from 14 to 98 years. RESULTS: Headache as the main
complaint was reported by 561 (9.3%) of the patients considered, with 312 (55.6%)
of those patients presenting with primary headache, 221 (39.4%) with headaches
secondary to systemic disorders, and 28 (5.0%) with headaches secondary to
neurological disorders. Migraine, the most prevalent primary headache, accounted
for 45.1% of patients reporting headache as the single symptom. The most frequent
etiologies of headaches secondary to systemic disorders were fever, acute
hypertension, and sinusitis. The most frequent headaches secondary to
neurological disorders were posttraumatic headaches, headaches secondary to
cervical disease, and expansive intracranial processes. Of the 26 cases of drug
abuse, 20 were secondary to alcohol (hangover). Headaches secondary to systemic
disorders were more frequent in the extreme age ranges. CONCLUSIONS: Headache is
a very frequent symptom among patients seen at primary health care units and
should be considered a public health problem. The dissemination of the diagnostic
criteria of the International Headache Society among primary health care
physicians is urgently needed in order to avoid the repeated return of patients
or their referral to more differentiated emergency units, which overburden an
already insufficient health care network.
PMID- 10759929
TI - Valproate prophylaxis for migraine induced by selective serotonin reuptake
inhibitors.
AB - We report the successful use of valproate in a 44-year-old woman with migraine
induced by selective serotonin reuptake inhibitors. Valproate should be
considered for those patients who develop serious migraine for the first time, or
worsening of previous migraine, after the initiation of treatment with selective
serotonin reuptake inhibitors and for whom continued treatment with this class of
drugs is important.
PMID- 10759930
TI - Hyposerotonin-induced nitric oxide supersensitivity in the cerebral
microcirculation.
AB - OBJECTIVE: To investigate the relationship between hyposerotonin and cranial
microvascular responses to nitric oxide (NO). BACKGROUND: Although the mechanism
underlying NO supersensitivity in migraine is still unclear, an alteration of the
serotonin system is a possible explanation. METHODS: Wistar rats were divided
into control and hyposerotonin groups. Serotonin was depleted by intraperitoneal
injection with 300 mg/kg of para-chlorophenylalanine (PCPA), a tryptophan
hydroxylase inhibitor. Three days after PCPA pretreatment, the animals were
prepared for assessment of their NO-induced vasomotor response using glyceryl
trinitrate (GTN: 8 to 10 mg/kg, intravenously) as an NO donor. Pial circulation
was visualized by the intravital fluorescein videomicroscopic technique. Images
of vessels at 0, 5, 15, 30, and 60 minutes post GTN infusion were digitized and
measured. At the end of monitoring, the rat brains were removed for
ultrastructural study of the brain microvessels. RESULTS: Infusion of GTN
produced dose-dependent pial arteriolar dilatation. This vasodilator effect was
significantly increased in the PCPA-treated groups, especially at 30 and 60
minutes. The percentage change from baseline diameter at 30 minutes after the 8
mg/kg GTN infusion was 42.6 +/- 3.1 for the hyposerotonin group and 16.8 +/- 2.9
for the control group (P<.001). Electron microscopic study revealed that exposure
to the NO donor produced considerable changes in cerebral microvessels,
characterized by focal ballooning of endothelial cells, increased microvillous
formation, and increased endothelial pinocytosis. These anatomical changes were
significantly more prominent in the hyposerotonin group. CONCLUSIONS: A
hyposerotoninergic condition can facilitate the NO-induced physiological and
pathological responses in meningeal and cerebral microvessels and, therefore, is
a possible explanation for the supersensitivity to NO observed in patients with
migraine.
PMID- 10759931
TI - Cluster headache is not associated with signs of a systemic inflammation.
AB - OBJECTIVE: To investigate whether there is clinical or biochemical evidence for a
transient systemic inflammation during active periods of cluster headache.
METHODS: Twenty-seven male and female consecutively selected patients with
episodic cluster headache filled in questionnaires aiming at detecting any
concurrent systemic vasculitic or rheumatoid disease. They were physically
examined by both a neurologist and a rheumatologist independent of each other.
Blood and urine samples were taken one to three times during an active cluster
period and once in remission. The following analyses were performed: hemoglobin,
erythrocyte sedimentation rate, C-reactive protein, complete blood counts
including differential counts, creatinine, albumin, creatine kinase,
electrophoreses of serum (with haptoglobin, orosomucoid, IgG, IgM), von
Willebrand's factor, antinuclear antibodies, rheumatoid factor, cytoplasmic
antineutrophil cytoplasmic autoantibodies, perinuclear antineutrophil cytoplasmic
autoantibodies, and routine urinary tests. An age- and sex-matched control group
of 99 consecutive patients attending the Outpatient Department of Neurology for
symptoms/diseases other than severe headache completed the same questionnaire as
the patient group. RESULTS: Only one patient with cluster headache showed
clinical signs (livedo reticularis) that could have been due to an ongoing
systemic vasculitis. Most symptoms were equally or even more prevalent in the
control group than among the patients with cluster headache. However, cold feet
were about twice as prevalent among female patients with cluster headache than in
the control group. This was considered due to their smoking habits. Laboratory
tests showed no statistically significant differences between the active cluster
periods and remission. There were some slightly abnormal values in single
laboratory tests, some of which were probably due to concurrent upper respiratory
infections. The findings of laboratory tests for one patient could have been due
to nephritis. All patients were negative for cytoplasmic antineutrophil
cytoplasmic autoantibodies and perinuclear antineutrophil cytoplasmic
autoantibodies. CONCLUSIONS: These results were taken as evidence that no
systemic inflammation is present during the active cluster headache period.
However, whether a local retro-orbital inflammation underlies the pathophysiology
of cluster headache remains obscure.
PMID- 10759932
TI - The migraine ACE model: evaluating the impact on time lost and medical resource
Use.
AB - OBJECTIVE: To describe the Migraine Adaptive Cost-Effectiveness Model in the
context of an analysis of a simulated population of Canadian patients with
migraine. BACKGROUND: The high prevalence of migraine and its substantial impact
on patients' ability to function normally present a significant economic burden
to society. In light of the recent availability of improved pharmaceutical
treatments, a model was developed to assess their economic impact. METHODS: The
Migraine Adaptive Cost-Effectiveness Model incorporates the costs of time lost
from both work and nonwork activities, as well as medical resource and medication
use. Using Monte Carlo techniques, the model simulates the experience of a
population of patients with migraine over the course of 1 year. As an example,
analyses of a Canadian population were carried out using data from a
multinational trial, surveys, national statistics, and the available literature.
RESULTS: Using customary therapy, mean productivity losses (amounting to 84 hours
of paid work time, 48 hours of unpaid work time, and 113 hours of leisure time
lost) were estimated to cost $1949 (in 1997 Canadian dollars) per patient, with
medical expenditures adding an average of $280 to the cost of illness.
CONCLUSIONS: With customary treatment patterns, the costs of migraine associated
with reduced functional capacity are substantial. The migraine model represents a
flexible tool for the economic evaluation of different migraine treatments in
various populations.
PMID- 10759933
TI - Magnetic resonance imaging of intracranial hypotension syndrome with
pathophysiological correlation.
AB - OBJECTIVE: To correlate the pathophysiology of intracranial hypotension syndrome
with abnormalities in the brain and spine found through magnetic resonance
imaging. METHODS: In a series of 11 patients with intracranial hypotension
syndrome, brain magnetic resonance scans were evaluated for the thickness,
distribution, morphology, and pattern of meningeal enhancement coincident with
subdural fluid collections and the descent of the brain toward the skull base.
Spinal magnetic resonance studies were reviewed for extra-arachnoid fluid
collections, meningeal enhancement, and distended epidural veins. RESULTS:
Diffuse, continuous dural-arachnoid enhancement was present in all patients with
abnormal brain studies. The dura was thickest in patients with very low
intracranial pressures. Subdural fluid collections and descent of the brain were
seen in patients with the thickest meninges and were not present in the absence
of meningeal enhancement. Extra-arachnoid or paraspinal fluid collections were
found in all patients who had spinal magnetic resonance scans. CONCLUSIONS: In
the brain, diffuse dural-arachnoid enhancement is the most common imaging
abnormality and is probably the earliest magnetic resonance manifestation of
intracranial hypotension syndrome, while subdural fluid collections and descent
of the brain are indicators of a more severe hypotensive state. Extra-arachnoid
fluid collections are common spinal imaging abnormalities.
PMID- 10759934
TI - Treatment of tension-type headache with botulinum toxin type A: a double-blind,
placebo-controlled study.
AB - OBJECTIVE: To determine whether injections of botulinum toxin could be of
therapeutic value in the treatment of tension-type headache. BACKGROUND:
Botulinum toxin A is very effective at reducing muscle tenderness and pain in
many diseases. Increased muscle tension may contribute to tension-type headache.
METHODS: We performed a double-blind, placebo-controlled study with 21 patients
fulfilling the International Headache Society criteria for tension-type headache.
Participants were randomly assigned to treatment (pericranial injection of 10 x
20 mouse units botulinum toxin A) or placebo (injection of isotonic saline in the
same manner). RESULTS: After 4, 8, and 12 weeks, no significant differences
between placebo and treatment could be observed (with respect to visual analog
scale, frequency and duration of headache attacks, consumption of analgesics,
pressure pain threshold, total tenderness score, and quality-of-life parameters).
CONCLUSIONS: The findings of our study strongly support the hypothesis that
peripheral mechanisms, such as increased muscle tenderness, only play a minor
role in the pathogenesis of tension-type headache.
PMID- 10759935
TI - Chronic daily headache: a time perspective.
AB - OBJECTIVE: To determine the development and outcome of chronic daily headache in
258 headache practice patients, consisting of 50 men and 208 women. Chronic daily
headache was defined as headaches occurring on at least 5 days per week for at
least 1 year. METHODS: Two hundred fifty-eight patients with headache were
interviewed and evaluated. Ninety-one patients were contacted by telephone for
follow-up. RESULTS: Twenty-two percent of the patients had daily headaches from
the onset, and 78% initially experienced intermittent headaches. Of the patients
with initially intermittent headaches, 19% experienced an abrupt transition into
daily headaches and 81%, a gradual one. In the patients with gradual transition,
the transition of the initial, intermittent headaches into daily headaches took
an average of 10.7 years. The initial headaches were mild in 33% of the patients
and severe in 67%. The severe headaches were associated with nausea and vomiting
significantly more often than the mild ones. However, the daily headaches that
these patients ultimately developed were the same, regardless of whether the
initial headaches were mild or severe. The patients who gradually developed daily
headaches from initially intermittent headaches were contacted to determine the
outcome of their headaches. Of these patients, 33% continued to have daily
headaches and 67% again experienced intermittent headaches. Of the latter group,
88% of the patients who now had migraine also had migraine initially.
PMID- 10759936
TI - Use of percutaneous electrical nerve stimulation (PENS) in the short-term
management of headache.
AB - OBJECTIVE: To evaluate the short-term effects of percutaneous electrical nerve
stimulation (PENS) in the management of three types of chronic headache.
BACKGROUND: Traditional electroanalgesic therapies have been reported to be
effective in the management of acute headache symptoms. However, no controlled
studies have been performed in patients with chronic headache. METHODS: Thirty
patients with either tension headache, migraine, or posttraumatic headache
symptoms of at least 6 months' duration were randomized to receive PENS (needles
with electricity) or "needles alone" according to a crossover study design. All
treatments were administered for 30 minutes, three times a week for 2 consecutive
weeks with 1 week off between the two different treatments. For the PENS
treatments, an alternating electrical stimulation frequency of 15 and 30 Hz was
used. Pain, activity, and sleep scores were assessed using a 10-cm visual analog
scale, with 0 corresponding to the best and 10 to the worst, during the 48-hour
period prior to the beginning of the two treatments, immediately before and after
each treatment session, and 48 hours after completing each treatment modality.
RESULTS: Compared with the needles alone, PENS therapy was significantly more
effective in decreasing the overall VAS pain scores for tension-type headache,
migraine and posttraumatic headache (58%, 59%, and 52% versus 20%, 15%, and 20%,
respectively). Similarly, PENS therapy produced greater improvement in the
patients' physical activity (41% to 58% for PENS versus 11% to 21% for needles
only) and quality of sleep (41% to 48% for PENS versus 12% to 20% for needles
only). However, there were no differences in the pattern of the response to PENS
therapy among the three headache groups. CONCLUSIONS: Percutaneous electrical
nerve stimulation appears to be a useful complementary therapy to analgesic and
antimigraine drugs for the short-term management of headache. Interestingly, the
analgesic response to PENS therapy appears to be independent of the origin of the
headache symptoms.
PMID- 10759937
TI - Sumatriptan in patients with postdural puncture headache.
AB - OBJECTIVE: To determine the efficacy of sumatriptan in the management of patients
presenting for an epidural blood patch for the management of postdural puncture
headache. BACKGROUND: Postdural puncture headache can be quite severe, requiring
invasive therapy (ie, epidural blood patch). Sumatriptan has been used
successfully in patients with postdural puncture headache, however, its use has
not been investigated in a controlled fashion. METHODS: Ten patients with
postdural puncture headache presenting for an epidural blood patch were given
either saline or sumatriptan subcutaneously. The severity of the headache was
evaluated at baseline and 1 hour following injection. If the headache remained
severe, an epidural blood patch was performed. RESULTS: Only one patient in each
group received relief from the injection. CONCLUSIONS: We do not recommend
sumatriptan in patients who have exhausted conservative management of postdural
puncture headache.
PMID- 10759938
TI - Limb-threatening ischemia due to ergotamine: case report with angiographic
evidence.
AB - A 29-year-old woman presented with severe leg pain that had lasted for several
weeks. During that period, she had taken painkillers in order to achieve sleep.
In the week before she was admitted to hospital, she had noticed numbness and a
cold feeling below her knees. There were no arterial pulsations below her groin,
the skin of her legs being cold and pale. She had a history of chronic daily
headache and had ingested Cafergot compound corresponding to ergotamine 2 to 3 mg
daily for the previous 2 or 3 months. Angiography demonstrated severe narrowing
of both superficial femoral arteries for a distance of about 5 to 6 cm and a
subtotal stenosis of the right popliteal artery. After discontinuation of
ergotamine, the patient's symptoms gradually disappeared within a few days.
Angiography was repeated 2 days after the first examination and demonstrated
regression of the spasms in the femoral arteries and reestablished flow in the
distal vessels. Ergotamine tartrate can induce life-threatening ischemia of an
extremity. Discontinuation of ergotamine is usually sufficient to reverse the
ischemia, however, intravenous infusion of sodium nitroprusside may occasionally
be necessary to avoid limb amputation.
PMID- 10759942
TI - Editorial
PMID- 10759939
TI - Transient global amnesia, migraine, thalamic infarct, dihydroergotamine, and
sumatriptan.
AB - This case report describes an episode of transient global amnesia that occurred
during a migraine attack, which had been treated with vasoconstrictors. Magnetic
resonance imaging showed a small lesion with an ischemic appearance in the right
thalamus.
PMID- 10759943
TI - gammadelta T-cell lymphomas: a homogeneous entity?
AB - gammadelta T-cells comprise an immunologically distinct lymphoid population,
characterized by specific morphological, phenotypical and functional properties.
Therefore it seems reasonable to speculate that neoplasms derived from this
particular T-cell subset display distinct features. Indeed, the prototype
gammadelta T-cell lymphoma, hepatosplenic T-cell lymphoma constitutes a unique
clinicopathological entitity which is intimately associated with a gammadelta T
cell phenotype. However, gammadelta T-cell lymphomas have also been described in
other extranodal sites where, unlike reactive gammadelta T-cells and
hepatosplenic gammadelta T-cell lymphomas, they display an important
morphological heterogeneity. Moreover, these nonhepatosplenic gammadelta T-cell
lymphomas are essentially not that different from their alphabeta T-cell receptor
for antigen (TCR)-expressing counterparts and thus may be incorporated in the
established T-cell lymphoma subclasses. However, subtle differences regarding
their histopathological appearance as well as their biological behaviour indicate
that further studies to determine the exact significance of TCR expression are
required. Such inquiries may contribute to the general understanding of T-cell
lymphomagenesis in general, which is still obscure.
PMID- 10759944
TI - Hot spot microvessel density and the mitotic activity index are strong additional
prognostic indicators in invasive breast cancer.
AB - AIMS: Recent studies have drawn attention to intratumoral microvessel density
(MVD) as a prognostic factor in invasive breast cancer. Various methods have been
applied to assess MVD and the prognostic value of MVD in different studies varies
considerably. Counting of microvessels in the most highly vascularized area (hot
spot) of a tumour is the method most widely used. In this study we compared three
counting methods. METHODS AND RESULTS: To assess MVD in 112 cases of invasive
breast cancer with long-term follow-up we performed microvessel counting in the
hot spot of the tumour in four and 10 fields of vision (HS-MVD4 and HS-MVD10) and
microvessel counting in 10 fields of vision distributed systematically over the
whole tumour area (global MVD). The HS-MVD4, HS-MVD10 and global MVD showed good
correlations with each other. HS-MVD4 provided the highest number of microvessels
(median value 71) followed by HS-MVD10 and global MVD, with median values of 58
and 39, respectively. HS-MVD4 showed the best prognostic value for overall
survival (P = 0.0001) whereas HS-MVD10 showed less (P = 0.01) and the global MVD
showed no (P = 0.75) prognostic value. In univariate analysis, the HS-MVD4 was
the second strongest prognostic factor after tumour size. In multivariate
survival analysis, the HS-MVD4, mitotic activity index (MAI), lymph node status
and tumour size were found to be independent prognostic factors. When combining
MVD4 and MAI in lymph node negative patients, none of the patients with low MVD
(< 71/mm2) and a low MAI (< 10 per 10 HPF) died, in contrast to patients with a
high MVD or high MAI who have a 10-year survival of 57%. CONCLUSIONS: These data
suggest that the hot spot MVD in four fields of vision is a major independent
prognostic factor for overall survival in invasive breast cancer. For the first
time, it is shown that hot spot MVD provides additional prognostic information to
well established factors like lymph node status and the MAI, and may therefore be
useful for designing treatment strategies in invasive breast cancer.
PMID- 10759945
TI - c-met tyrosine kinase receptor expression is associated with abnormal beta
catenin expression and favourable prognostic factors in invasive breast
carcinoma.
AB - AIMS: Receptor-type tyrosine kinases are important in cell signal transduction
and proliferation. Abnormal expression of tyrosine kinases often leads to
malignant transformation. c-met is a tyrosine kinase receptor and its ligand is
hepatocyte growth factor (HGF). In this study, we have evaluated c-met expression
in 69 invasive breast carcinomas and statistically analysed this expression with
known clinicopathological prognostic parameters and patients' survival. We also
studied for the first time c-met expression in association with E-cadherin and
beta-catenin expression. METHODS AND RESULTS: Immunohistochemistry (ABC-HRP
method) was peformed for the detection of c-met, E-cadherin and beta-catenin. c
met immunoreactivity was observed in 58% of cases and was associated with the
lobular type of breast carcinomas (P = 0.012), low histological grade ductal
carcinomas (P = 0.05), favourable prognostic and predictive factors such as
oestrogen and progesterone receptor immunohistochemical expression and negative c
erbB-2 expression (P = 0.05, P = 0.014 and P = 0.03, respectively). c-met
immunoreactivity did not correlate with lymph node status, tumour size and stage
of the disease. Cox's proportional hazard regression model demonstrated that
tumours with positive c-met immunoreactivity correlated significantly with
favourable patients' survival (P = 0.028). When c-met staining was compared with
E-cadherin and beta-catenin expression, a statistical significant correlation was
established between c-met immunoreactivity and abnormal beta-catenin expression
(P = 0.025) suggesting possible involvement of c-met in the downregulation of the
E-cadherin-catenin complex, possibly through tyrosine phosphorylation of beta
catenin. CONCLUSION: c-met immunohistochemical expression seems to be associated
with abnormal beta-catenin expression, good prognostic and predictive factors and
favourable outcome in breast cancer patients.
PMID- 10759946
TI - Overexpression of 27-kDa heat shock protein relates to poor histological
differentiation in human oesophageal squamous cell carcinoma.
AB - AIMS: Various stress conditions such as heat, chemical and mechanical stresses
are known to play a major role in oesophageal squamous cell carcinoma
development. Our goal was to evaluate whether changes in stress-induced 27-kDa
heat shock protein (HSP27) expression could be demonstrated during oesophageal
carcinogenesis. METHODS AND RESULTS: HSP27 expression was studied using
immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections from 21
oesophageal squamous cell carcinomas occurring in smokers and/or alcohol abusers.
Oesophagus from healthy patients (controls) (five), chemical (eight) and
infectious oesophagitis (six) were also included in the study. In normal
oesophagus, the protein is present only in the upper epithelial layers. In
contrast, in chemical or infectious oesophagitis its expression is strong and
occurs in all the epithelial layers including the basal layer. In non-tumoral
oesophageal mucosa from smoking and/or drinking patients adjacent to invasive
carcinoma, the distribution of the protein is patchy and irregular. In malignant
areas, HSP27 protein expression increases drastically from dysplastic lesions to
invasive carcinoma, being highest in the less differentiated areas. CONCLUSIONS:
In human oesophagus, HSP27 expression is induced by various stresses but alcohol
and tobacco generate focal perturbations in the stress response. Tumour
immunoreactivity for this protein increases with the anaplasia of the tumour, as
in some other tumours in which it is considered to play a role in drug
resistance. To our knowledge, these data have not been previously described for
oesophageal squamous cell carcinoma.
PMID- 10759947
TI - Basaloid squamous carcinoma of the oesophagus: a distinct neoplasm with
multipotential differentiation.
AB - AIMS: Basaloid squamous carcinoma (BSC) is an uncommon variant of squamous cell
carcinoma, with its prevalent sites being the hypopharynx, tongue base and
larynx. In the oesophagus, BSC is rarer than in the head and neck region. This
study was aimed to document the clinicopathological features of BSCs of the
oesophagus, and to present their relative incidence and immunohistochemical
findings. METHODS AND RESULTS: Eighteen cases of BSC of the oesophagus,
comprising 3.6% of 502 oesophageal carcinomas, were reviewed for their
pathological and clinical features, and examined for the immunohistochemical
expression of neuroendocrine markers, cytokeratins, p53, pRb and bcl-2.
Oesophageal basaloid squamous carcinomas tended to be biphasic or multiphasic
carcinomas, most commonly with basaloid and squamous components (eight cases), or
with additional adenocarcinoma (three cases) or with small cell carcinoma (two
cases). Each component was microscopically clearly distinguishable from the
others, and metastasized separately, chiefly the basaloid component. The
remaining five cases were apparently pure basaloid carcinomas, being
characterized by lobules and nests of monotonous round undifferentiated cells
with frequent comedo necrosis. They resembled, but were differentiated from, the
small cell carcinoma on the basis of neuroendocrine markers and cytokeratin
expression. p53, pRb and bcl-2 oncoprotein, which are known to normally present
in the basal/parabasal cells of the oesophageal epithelium, were detected in 40
50% of cases, with a heterogeneous expression pattern. The patients were all
male, with the age ranging 47-74 years (median 57) and presented at variable
stages. The plotted 3 years survival rate was 51%, and the immunohistochemical
expression of p53, pRb and bcl-2 was not related to the survival of the patients.
CONCLUSION: Basaloid squamous carcinoma of the oesophagus is a peculiar neoplasm
with a capacity of multidirectional differentiation, often with heterogeneous
oncogene expression, probably reflecting the pluripotential stem cell origin.
PMID- 10759948
TI - HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers
for mesothelioma and adenocarcinoma.
AB - AIMS: To evaluate HBME-1, WT1, calretinin and MOC-31 in the differential
diagnosis of pleural mesothelioma and adenocarcinoma of the lung. METHODS AND
RESULTS: Paraffin-embedded formalin-fixed blocks from six reactive pleuras, 42
mesotheliomas and 40 adenocarcinomas were used. Sections were stained for Leu-M1,
HBME-1, calretinin, WT1 and MOC-31. Leu-M1 was positive or equivocal in 34% of
mesotheliomas and in 78% of adenocarcinomas; reactive pleuras were all negative.
HBME-1 was positive or equivocal in 76% of mesotheliomas and in 73% of
adenocarcinomas; five reactive pleuras were positive. Calretinin was positive or
equivocal in 92% of mesotheliomas and in 73% of adenocarcinomas; two reactive
pleura were equivocal and four were positive. WT1 was positive or equivocal in
72% of mesotheliomas (excluding autopsy cases) and in 20% of adenocarcinomas; all
reactive pleuras were positive. MOC-31 was positive or equivocal in 5% of
mesotheliomas and in 90% of adenocarcinomas; all reactive pleuras were negative.
The reaction with Leu-M1 was graded as equivocal in 25% of the adenocarcinomas.
All 24 of the autopsy cases of mesothelioma were negative for WT1 and in many
operative specimens only the periphery was stained. CONCLUSIONS: Neither
calretinin nor HBME-1 are sufficiently discriminatory to be of use, even as
members of a panel of antibodies. WT1 shows some promise, but it cannot be used
on autopsy material. The utility of MOC-31 is confirmed, and outperforms Leu-M1.
PMID- 10759949
TI - Smooth muscle metaplasia in ovarian endometriosis.
AB - AIMS: Little is known about smooth muscle metaplasia (SMM) in ovarian
endometriosis. The clinicopathological significance of SMM in ovarian
endometriosis is analysed. METHODS AND RESULTS: Three hundred and twenty-seven
consecutive cases of ovarian endometriosis, including 58 cases associated with
malignant ovarian epithelial tumour, between 1987 and 1996 were retrieved from
hospital files and clinicopathologically analysed. The ages of the patients who
showed SMM in ovarian endometriosis ranged from 28 to 70 years (average, 43. 8
years). SMM was observed in 58 cases (17.7%); in 51 of 269 cases without tumour
(19.0%) and in seven of 58 with tumour (12.1%). The differences in the incidence
of SMM in cases with and without tumour were not statistically significant. SMM
was a focal, microscopic change and there was neither smooth muscle tumour nor
uterus-like mass. Sixteen cases had short fascicles or stellate foci of SMM in
the endometriotic stroma, an incomplete rim of SMM surrounding the endometriotic
cysts was present in 32 cases, and 10 cases showed SMM in both the endometriotic
stromal and incomplete rim of the endometriotic cysts. There was no significant
histological difference in SMM between cases with and without malignant ovarian
epithelial tumour. CONCLUSIONS: SMM in ovarian endometriosis is not an uncommon
phenomenon. SMM may be explained in two ways. First, smooth muscle originates
from metaplastic endometrial stromal cells in endometriotic foci. Second, it
originates from metaplastic ovarian stromal cells in the rim of endometriosis.
PMID- 10759950
TI - Varied B-cell immunophenotypes of Hodgkin/Reed-Sternberg cells in classic
Hodgkin's disease.
AB - AIMS: Recent analyses have suggested that Hodgkin's or Reed-Sternberg (HRS) cells
in most cases of classic Hodgkin's disease are derived from germinal centre B
cells. However, there is controversy over which B-cell antigens are expressed in
HRS cells. METHODS AND RESULTS: We studied 51 cases of classic Hodgkin's disease
to immunohistochemically characterize HRS cells for pan-B-cell markers and
specific markers for plasma cells. HRS cells expressed CD20 (L26) in 18 cases
(35%), CD19 (B4) in nine (18%) and CD79a (mb-1) in 13 (25%). Furthermore, HRS
cells were positive for CD138 (B-B4) in 24 cases (45%) and for PCA-1 in 24 (45%).
In 41 (80%) cases, HRS cells expressed more than one B-cell marker. We then
subclassified cases into those positive for plasma cell markers (n = 27) (group
1) and those negative for them (n = 24) (group 2). The average age in group 1 (40
years) was younger than in group 2 (54 years) (P < 0.05). The percentage of
nodular sclerosis (NS) subtype in group 1 (52%) was 1.5 times greater than in
group 2 (33%) (P < 0.05). With regard to Epstein-Barr virus encoded small RNA
(EBER) in-situ hybridization, 14 cases (64%) were positive in group 2, but only
seven cases (31%) were positive in group 1 (P < 0.025). CONCLUSION: In most cases
of classic Hodgkin's disease, HRS cells expressed later stage of B-cell
development. We consider that two different clinicopathological groups may
correlate with the two different expressions of B-cell markers.
PMID- 10759952
TI - The gene gun: current applications in cutaneous gene therapy.
PMID- 10759951
TI - Neutrophil and endothelial cell activation in the vasa vasorum in vasculo-Behcet
disease.
AB - AIM: The aim of this study was to analyse the immunopathological mechanisms of
vasculo-Behcet disease, which were also compared to cases of Takayasu's arteritis
and inflammatory aneurysm to evaluate differences in inflammatory mechanisms.
METHOD AND RESULTS: We reviewed six cases of vasculo-Behcet disease, four of
Takayasu's arteritis and seven inflammatory aneurysms which underwent surgical
repair. Immunohistochemical studies were performed on paraffin-embedded tissue
using a labelled streptavidin-biotin method, as was in-situ hybridization for
Epstein-Barr virus. Microscopically, neutrophils and lymphocytes accumulated
around the vasa vasorum. Neutrophils were prominent as compared to Takayasu's
arteritis and inflammatory aneurysm. Elastic fibres were not severely destroyed.
Endothelial cells (ECs) of most vasa vasorum expressed HLA-DR. The number of vasa
vasorum around which inflammatory infiltrating cells were observed in vasculo
Behcet disease was significantly greater than in inflammatory aneurysms and
Takayasu's arteritis (P < 0.001). The cytokines IL-1alpha, TNF-beta and IFN-gamma
were expressed in neutrophils and lymphocytes which were distributed around vasa
vasorum, as well as neutrophils adherent to HLA-DR positive ECs. CONCLUSION: Our
results suggest that vasculo-Behcet disease should be classified as a
neutrophilic vasculitis targeting the vasa vasorum. Aneurysm formation may be
related to degeneration of arterial wall caused by inflammation of the vasa
vasorum.
PMID- 10759953
TI - Mirror-image lesions in cutaneous malignancies.
PMID- 10759954
TI - Malignant melanoma in the 21st century.
PMID- 10759955
TI - Malaria mosquitoes favor the human skin and not expired air.
PMID- 10759957
TI - The urokinase plasminogen activator system in angiosarcoma, Kaposi's sarcoma,
granuloma pyogenicum, and angioma: an immunohistochemical study.
AB - Background Extracellular matrix proteolysis is one of the most important steps in
angiogenesis. The urokinase-type plasminogen activator system (uPAS), consisting
of the urokinase plasminogen activator (uPA), the uPA receptor (uPA-R), and their
corresponding inhibitors, PAI-1 and PAI-2, is thought to play a role in this
process. METHODS: We investigated the expression of the components of uPAS in
angiosarcoma (AS, n = 4), Kaposi's sarcoma (KS, n = 31), granuloma pyogenicum
(GP, n = 25), angioma (AN, n = 15), and healthy controls (CO, n = 15) with
immunohistochemical methods. RESULTS: We found positive immunostaining for uPA-R
and uPA in all cases of AS. Only two of four cases were positive for PAI-1,
whereas all cases were negative for PAI-2. In KS, we observed positive
immunostaining in 16 of 31 (51.6%) cases for uPA-R, in 11 of 31 (35.5%) cases for
uPA, in 3 of 31 (9.6%) cases for PAI-1, and in 2 of 31 (6.4%) cases for PAI-2.
The GP cases showed the following positive results: 4 of 25 (16%) for uPA-R, 6 of
25 (24%) for uPA, 10 of 25 (40%) for PAI-1, and 11 of 25 (44%) for PAI-2. Four
cases (26.6%) of AN were positive for PAI-1 and five cases (25%) for PAI-2. In AN
(n = 15), there was staining for neither uPA nor uPA-R. In none of the controls
(n = 15) was immunostaining for the components of uPAS found in blood vessels.
CONCLUSIONS: uPAS is involved in malignant, benign, and reactive proliferative
angiomatous lesions, but is absent in normal blood vessels. The upregulation of
uPA and its corresponding receptor, uPA-R, in AS and KS supports the hypothesis
of the proliferative nature of these lesions; however, the upregulation of the
inhibitors (PAI-1 and PAI-2) in benign and reactive proliferative angiomatous
lesions (GP and AN) shows how this process may be limited.
PMID- 10759956
TI - Deletion patterns of the STS gene and flanking sequences in Israeli X-linked
ichthyosis patients and carriers: analysis by polymerase chain reaction and
fluorescence in situ hybridization techniques.
AB - BACKGROUND: Deletion of the entire steroid sulfatase (STS) gene is the most
common molecular defect in X-linked ichthyosis (XLI) patients. Usually,
additional flanking sequences are also missing. The aim of this study was to
estimate the extent of deletions in an ethnically heterogeneous population of
Israeli XLI patients. METHODS: Multiplex polymerase chain reaction (PCR) and
fluorescence in situ hybridization (FISH) techniques were applied in the analysis
of blood samples of 24 patients and amniotic cells of seven affected fetuses from
22 unrelated families. RESULTS: In 19 families, a large deletion of the 2-3
megabase was found. It included the whole STS gene and spanned adjacent areas up-
and downstream between the loci DXS 1139 and DXS 1132. Two unrelated families of
Iraqi ancestry had a partial deletion of the gene and its centromeric adjacent
sequence. In another family, the telomeric end of the extragenic segment was only
partially missing. Application of FISH on metaphase blood cells and interphase
amniotic cells confirmed the diagnosis of XLI in all patients, except the three
with partial intragenic deletion. In those cases, the remaining fraction of the
gene was sufficient to provide a false negative result. Diagnosis of carriers and
prenatal diagnosis in uncultured cells was applicable only by FISH. CONCLUSIONS:
Our study revealed a remarkable heterogeneity in the deletion pattern among
Israeli patients with XLI. This heterogeneity could not be attributed to specific
ethnic groups because of the small size of the study group. More studies
involving patients of various ancestries should be carried out. In addition, this
study demonstrated the usefulness of the FISH technique in the prenatal diagnosis
of fetuses with suspected XLI.
PMID- 10759958
TI - Dermatologic manifestations among human immunodeficiency virus patients in south
India.
AB - BACKGROUND: Human immunodeficiency virus (HIV) may be associated with a large
number of dermatologic manifestations, which may at times constitute the
presenting symptoms. These skin lesions are well delineated in the Western
literature, but there is a paucity of information from the southern part of the
Indian subcontinent. Objective We evaluated 833 persons with HIV to determine the
types of dermatologic lesions present. RESULTS: The various lesions observed were
oral candidiasis (45.0%), multidermatomal herpes zoster (11.2%), dermatophytosis
of the skin (8.0%), herpes genitalis (7.7%), papular pruritic dermatitis (7.7%),
staphylococcal infection of the skin (2.9%), oral hairy leukoplakia (2.3%),
molluscum contagiosum (1.3%), genital warts (1.2%), and scabies (0.5%). Alopecia,
intractable itching, dry skin, Addisonian pigmentation, and Kaposi's sarcoma were
also noted. A correlation between the dermatologic manifestations and CD4 cell
counts was found. CONCLUSION: Although the pattern of cutaneous lesions was
comparable with that from the West, there is a strikingly lower incidence of
Kaposi's sarcoma.
PMID- 10759959
TI - Diabetic bullae: 12 cases of a purportedly rare cutaneous disorder.
AB - BACKGROUND: Spontaneous bullae are a characteristic type of skin lesion occurring
in patients with diabetes mellitus. These diabetic bullae are considered to be a
rare phenomenon; only about 100 cases have been described in the literature since
the disorder was first reported 70 years ago. METHODS: We collected a series of
patients with diabetic bullae who were referred to us at a Veterans Affairs
Medical Center Clinic specializing in diabetic foot problems. We then reviewed
the medical literature for similar cases and summarized the available
information. RESULTS: We saw 12 patients with typical diabetic bullae over an 8
year period in our clinic. The clinical presentation and outcome of the lesions
in these patients were similar to those in previously reported cases. The
patients were mostly elderly, all but one had lesions located on the lower
extremities, all had peripheral neuropathy, two had secondary staphylococcal
infection of their bullae, and in all patients the lesions healed without
scarring. Although most of the patients had had previous similar lesions, the
diagnosis of diabetic bullae had not been previously reported in any of them.
CONCLUSIONS: We have reviewed the clinical syndrome of diabetic bullae and
presented brief clinical details of these cases; we offer several vignettes and
photographs of these lesions to remind clinicians of what we believe is a not so
rare cutaneous disorder.
PMID- 10759960
TI - Scanning electron microscopic examination of the egg of the pubic louse
(Anoplura: Pthirus pubis).
AB - OBJECTIVE: The purpose of the study was to examine the eggs of pubic lice with
consideration of their clinical relevance. STUDY DESIGN: Pubic lice eggs were
examined by scanning electron microscopy (SEM). RESULTS: The egg is totally
encased by a proteinaceous sheath, except for the operculum, by which oxygen
exchange occurs. CONCLUSION: Pubic lice have proved resilient to human therapies
through the ages. The anatomical target of topical insecticides for ovicidal kill
is the operculum and the protective layers that surround the developing embryo.
More research into these structures is warranted.
PMID- 10759961
TI - Lipoid proteinosis.
AB - A 21-year-old man presented with a complaint of hoarseness as well as lesions
along the eyelids and on his knees, elbows, and fingers. Hoarseness had developed
in childhood, followed by lesions along the eyelids and on the elbows and
fingers. He had developed lesions on the knees, feet, scrotum, penis, and axilla
over the last 2 years. His parents were relatives, but nobody in the family
showed similar features. His physical examination was normal. On dermatologic
examination, there were beaded papules along the eyelids and small, yellow-white
infiltrations on the tongue, buccal mucosa, palate, scrotum, and penis (Fig. 1).
His tongue was firm and its mobility was limited. He also had infiltration of the
frenulum (Fig. 2) and warty and hyperkeratotic papular and nodular lesions on the
hands, knees, elbows (Fig. 3), and axilla. The laboratory findings and
laryngoscopic examination were normal. Ophthalmologic, neurologic, and
psychiatric examinations were also normal. Electroencephalogram (EEG),
electromyogram (EMG), craniography, and cranial computed tomography (CT) scanning
revealed no abnormality. The histopathologic examination of the skin biopsy
specimens obtained from the axilla, elbow, and dorsum of the hand showed
hyperkeratosis and periodic acid-Schiff-positive (PAS(+)) staining hyaline
material around the dermal capillaries and sweat glands, and confirmed the
diagnosis of lipoid proteinosis.
PMID- 10759962
TI - Leishmaniasis recidiva cutis.
PMID- 10759963
TI - Two cases of linear focal elastosis: different histopathologic findings.
PMID- 10759964
TI - Localized toxic follicular pustuloderma.
PMID- 10759965
TI - Lichen myxedematosus associated with chronic hepatitis C.
PMID- 10759966
TI - A granulomatous dermatitis associated with idiopathic ulcerative colitis.
PMID- 10759967
TI - Experience with low-dose thalidomide therapy in chronic discoid lupus
erythematosus.
AB - BACKGROUND: Low-dose thalidomide therapy (median dose 100 mg/day, 50-200 mg/day)
in chronic discoid lupus erythematosus was studied with regard to efficacy,
tolerance, and toxicity in 22 patients. Intense contraceptive precautions were
taken in women patients of childbearing age. METHODS: An open uncontrolled trial
was conducted. Age, the total drug intake, disease duration, extent/severity, and
adverse reactions were studied with regard to the final clinical outcome. The
follow-up duration was 1.8 years (range 1 month to 3 years). RESULTS: With the
exception of age (inverse correlation, P < 0.01), the parameters studied did not
influence the final clinical amelioration: complete responders numbered 54.5%,
partial responders 22.7%, and 13.6% were withdrawn from the trial with complaints
of intolerance. The initial (first month) clinical response correlated
significantly with the final one (P < 0.01). Drowsiness (40.9%) and somnolence
(18.2%) were the most common side-effects, without affecting seriously the daily
life of the participants. No case of real neurotoxicity was confirmed. Relapses
occurred within 39.4 +/- 21.4 days after drug withdrawal, presenting a milder
clinical picture. CONCLUSIONS: In the context of a predictable final outcome, low
dose thalidomide therapy is effective as an alternative choice in cases resistant
to the usual treatment.
PMID- 10759968
TI - Cryosurgery in difficult to treat basal cell carcinoma.
AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common human malignancy.
Although BCC has a low mortality, it has a large morbidity. Patients frequently
present with difficult to treat BCC because of the lesion itself, the condition
of the patient, or both. Satisfactory results have been reported in the
cryosurgery of low-risk BCC. There is no agreement, however, about indication,
cure rate, technical modalities, and results of cryosurgery in tumors larger than
1 cm, in critical locations, and of aggressive histologic type. OBJECTIVE: The
purpose of the study was to establish the cure rate, functional preservation,
cosmetic results, acceptance, and complications of cryosurgery in difficult to
treat BCC. METHODS: One hundred and thirty six consecutive patients with 171
difficult to treat BCC (because of size, location, nature, or patient condition)
were treated by the mixed technique of curettage followed by liquid nitrogen
application. RESULTS: After an average follow-up of 5.2 years (6 months to 9.1
years), a cure rate of 91.8% was achieved. The treatment was well tolerated,
widely accepted by the patients, of low cost, and with good functional and
cosmetic results. Complications were few and minor. CONCLUSION: Cryosurgery is a
well-tolerated therapeutic modality that offers an acceptable cure rate and good
functional and cosmetic results in difficult to treat BCC.
PMID- 10759969
TI - Plasmapheresis as a steroid saving procedure in bullous pemphigoid.
AB - BACKGROUND: Bullous pemphigoid is an immunobullous disease affecting
predominantly older patients. In severe cases, high-dose corticosteroids and/or
other immunosuppressants are often needed long term to control the disease. These
can be associated with serious side-effects in this patient population. Objective
To evaluate the benefit of plasmapheresis as a steroid saving agent in a cohort
of 10 patients. RESULTS: Plasmapheresis was effective as a steroid saving
therapy. All patients went into remission with a lower daily dosage of oral
prednisone at 3 and 6 months postplasmapheresis. Two patients had side-effects
from therapy that, while significant, did not interfere with long-term
improvement in their disease. Eight patients had circulating immunoglobulin G
(IgG) antibodies reactive with bullous pemphigoid antigen 1, and three of these
had circulating antibodies reactive with bullous pemphigoid antigen 2 on Western
immunoblot. CONCLUSIONS: Plasmapheresis was an effective steroid sparing therapy
in these patients. Due to its high cost and potential morbidity, plasmapheresis
should not be recommended as routine therapy for bullous pemphigoid, but it is a
useful adjunct in resistant cases.
PMID- 10759970
TI - The 'cues' to diagnosis: describing the monitoring activities of women undergoing
diagnostic investigations for breast disease.
AB - Waiting to ascertain the nature of an undiagnosed breast abnormality is an
intensely stressful experience for many women. Uncertainty surrounding the
aetiology of symptoms is underpinned by the threat of malignancy, and the 'need
to know' the diagnosis is of primary concern at this time. Seeking out threat
relevant information through a process known as 'monitoring' attempts to fulfil
this need. This paper details the qualitative phase of a multimethod research
study that investigated the psychological impact of diagnosing breast disease.
This involved focus interviews with a subset of 40 women from the original study
cohort. Several types of threat-related cues were identified by respondents and
were categorized as temporal, interpersonal, procedural and spatial. In the
context of uncertainty (and in some cases suspicion) these cues were interpreted
as 'indicators' of the pending diagnosis. The manner in which particular aspects
of the environment are identified, interpreted and designated as 'threat
relevant' cues is discussed. Furthermore, the implications for health
professionals working with patients during this stage of 'pre-diagnosis' are
considered.
PMID- 10759971
TI - 'I really feel I've let him down': supporting family carers during long-term care
placement for elders.
AB - This paper considers placing a relative in a nursing home from a carer's
perspective. A largely structured, interviewer-administered, questionnaire survey
was conducted with 48 carers in the United Kingdom and 54 carers in the United
States of America. While the data highlight differences between the two
countries, shared experiences emerge which suggest that carers often have to make
difficult decisions without adequate support. Implications for practice are
considered. The need to develop more robust support mechanisms is stressed.
PMID- 10759972
TI - 'All the services were excellent. It is when the human element comes in that
things go wrong': dissatisfaction with hospital care in the last year of life.
AB - Patient satisfaction surveys are seen as an important way of obtaining 'user
views' of health service provision. However, there is a growing body of research
and theoretical literature that questions the validity of the concept of 'patient
satisfaction' and hence the use of this type of survey. A postbereavement survey
of people who registered a random sample of cancer deaths in an inner London
health authority was undertaken in 1996/7. The survey questionnaire (VOICES)
included 14 open-ended questions which asked respondents to add any comments they
felt were relevant about the care of the deceased. This paper uses these data to
examine the causes of dissatisfaction with hospital-based care. Of the 229
informants responding to the questionnaire, 138 included some written comment
about care in hospital. At least one negative comment was made by 59% (82) of
those making any comment. Of these, 55% (44) rated the care given by doctors as
'excellent' or 'good' and 63% (50) rated that given by nurses as 'excellent' or
'good'. Qualitative analysis of responses to open questions suggest that
expressions of dissatisfaction arise from a sense of being 'devalued',
'dehumanized' or 'disempowered' and from situations in which the 'rules'
governing the expected health professional-patient relationships were broken. As
such, the causes of dissatisfaction for this particular group of patients are
similar to the causes of dissatisfaction with health care in general reported
elsewhere. The palliative care approach emphasizes patient- and family-centred
care and aims to promote physical and psychosocial well-being. The study findings
suggest that adoption of the palliative care approach could reduce the experience
of dissatisfaction for many service users, not only those whose deaths are
anticipated.
PMID- 10759973
TI - The importance of 'knowing the patient': community nurses' constructions of
quality in providing palliative care.
AB - This paper reports findings from a study conducted in one community health care
trust where 62 members of the district nursing team (grades B-H) were
interviewed. An adaptation of the critical incident technique was used to
determine factors which contributed or detracted from high quality care for a
number of key areas including palliative care. The centrality of knowing the
patient and his/her family emerged as an essential antecedent to the provision of
high quality palliative care. Factors enabling the formation of positive
relationships were given prominence in descriptions of ideal care. Strategies
used to achieve this included establishing early contact with the patient and
family, ensuring continuity of care, spending time with the patient and providing
more than the physical aspects of care. The characteristics described by the
community nurses are similar to those advocated in 'new nursing' which identifies
the uniqueness of patient needs, and where the nurse-patient relationship is
objectified as the vehicle through which therapeutic nursing can be delivered.
The link with 'new nursing' emerges at an interesting time for community nurses.
The past decade has seen many changes in the way that community nursing services
are configured. The work of the district nursing service has been redefined,
making the ideals of new nursing, for example holism, less achievable than they
were a decade ago. This study reiterates the view that palliative care is one
aspect of district nursing work that is universally valued as it lends itself to
being an exemplar of excellence in terms of the potential for realizing the
ideals of nursing practice. This is of increasing importance in the context of
changes that militate against this ideal.
PMID- 10759974
TI - Wound care in the community setting: clinical decision making in context.
AB - Sixty-two community nurses in northern England of grades B and D to H were
interviewed by a team of four researchers. The interviews were semi-structured,
and were tape-recorded, fully transcribed and content analysed. They were
conducted as part of a larger study, the aim of which was to examine community
nurses' perceptions of quality in nursing care. One of the main themes the work
focused on was decision-making as an element of quality. Data relating to wound
care were considered from the perspective of the insights they offered into
clinical decision-making. Data were interpreted in the light of a literature
review in which a distinction had been made between theories which represented
clinical decision-making as a linear or staged process and those which
represented it as intuitive. Within the former category, three sub-categories
were suggested: theorists could be divided into 'pragmatists', 'systematisers'
and those who advocated 'diagnostic reasoning'. The interpretation of the data
suggested that the clinical decisions made by community nurses in the area of
wound care appeared largely intuitive, yet were also closely related to
'diagnostic reasoning'. They were furthermore based on a range of sources of
information and justified by a number of different types of rationale.
PMID- 10759975
TI - The information content of the nurse change of shift report: a comparative study.
AB - The information content of the nurse change of shift report: a comparative study
This study examines the role which the nursing change of shift report may have in
aiding nurses to process information and plan care. It also aims to identify
whether any of the information found in the shift report can be considered as
'forceful feature' information, the key features of a situation which allow an
individual to access appropriate knowledge within their long-term memory store.
The content of the medical notes, nursing documentation and shift reports for a
total of 60 patients, selected from two acute medical and two acute surgical
wards across two National Health Service Hospital Trusts in south-east England
were subjected to content analysis. The types and amount of information contained
in each source were examined, along with the order of information given in the
shift reports. A multidimensional scalogram analysis (MSA) was also carried out
on the data to examine the patterns of information content across sources. In
general, more information was recorded in the patients' notes than communicated
during the shift report. However, both the frequency data and the MSA plots
indicated that particular types of information (identified here as global
judgements) were often communicated in the shift report but not recorded in the
patient notes. The results suggest that there is evidence that the change of
shift report contains 'forceful feature' information. The presence of such
'forceful features' may facilitate the processing of patient information during
the shift report communication, leading to more efficient care planning.
PMID- 10759976
TI - Levels of satisfaction of 'low-risk' mothers with their current health visiting
service.
AB - AIMS AND OBJECTIVES: To assess the expressed levels of satisfaction of 'low-risk'
mothers with the current health visiting service. Setting Sheffield, England,
Autumn 1997. METHODOLOGY: Self-completion, postal questionnaire (initial postcard
reminder followed by a second letter and questionnaire) to a sample of 403
mothers assessed as 'low priority' by their health visitor. Questions largely
related to maternal opinion of the adequacy of the health visiting service
delivered during the first 9-12 months. The local research ethics committee
approved the study. RESULTS: A corrected response rate of 75% with little
evidence of significant bias. A high proportion (86%) of women stated that they
were either 'fairly' or 'very' satisfied with the service they had received from
their health visitor with regard to their baby. A lower proportion (72%) was
equally satisfied with the service they had received in respect of their own
health. Despite an average number of approximately 10 contacts in relation to
infant health with the health visitor during the first year of life, some 6% of
women wanted more frequent contacts, particularly in the first few weeks. Study
limitations The questionnaire was designed specifically for the study and
validation was limited. The study population comprised a selected, 'low-risk'
group. CONCLUSIONS: The number of reported contacts with the health visitor
seemed to greatly exceed those indicated by a basic child health surveillance
programme. The overall level of maternal satisfaction is high, though a minority
of women would like more support. Dissatisfaction was expressed with the lack of
an appointment system for clinics, poor punctuality in home visits, and
inappropriate or inadequate advice.
PMID- 10759977
TI - Weaving the seamless web of care: an analysis of parents' perceptions of their
needs following discharge of their child from hospital.
AB - Changes in children's nursing services in the United Kingdom in recent years have
focused on the need for adequate and efficient services to be provided in the
interests of the child. Early discharge is now the norm and children are often
sent home in an earlier recovery stage than adults with comparable conditions.
Whilst the contributions of paediatric community nursing services have gone some
way to providing specialist nursing care for children and their families in their
own homes, the majority of children are discharged home without such support
being available. This may place an overwhelming responsibility of caring for a
recovering child onto parents. The purpose of the qualitative research reported
in this paper was to identify any gaps in nursing services for acutely sick
children and their families following discharge, and to suggest ways to improve
integration and communication between hospital and primary care to facilitate a
'seamless web of care' for families. Families were surveyed following discharge
(n=164) and interviews carried out with those experiencing problems (n=20).
General practitioners were also surveyed for their opinion as key contributors of
primary care. Findings revealed the isolation felt by parents following
discharge, with their need for information about a child's illness and expected
recovery, and for reassurance and specific advice through some means of support,
which was clearly not being met. The perceived benefit of continuity of care was
a common theme, with both parents and professionals acknowledging the importance
of closer liaison between hospital and primary health care services. This study
is valuable in providing preliminary qualitative information regarding the gaps
in children's nursing services and how these can be overcome by using our present
resources more imaginatively, in order to ensure the delivery of cost-effective
and quality health care services in the best interests of local need.
PMID- 10759978
TI - Acute childhood illness at home: the parents' perspective.
AB - This critical review of British literature explores the phenomenon of acute
childhood illness at home from the parents' perspective. The Literature was
searched using four CD-ROM databases: CINAHL, MEDLINE, ASSIA and PSYCHLIT,
augmented by hand searching of current journal issues. Sandelowski's (1995)
stages of qualitative data analysis were used to develop a rigorous approach to
conducting qualitative overviews. The majority of childhood illness is of short
duration and takes place in the child's own home. Yet the research which
addresses this area is limited. Mothers constantly monitor their child's health,
identifying illness as a change in behaviour of the child from their perception
of normal. Their usual response to illness is nonprofessional care, including
general nursing care and 'over the counter' medicines. When mothers do seek help
this is usually from the family doctor. Mothers are often dissatisfied with the
help and advice they receive. This is partially explained by the mismatches which
occur concerning the perceptions of mothers and of health care professionals
regarding appropriate use of services and the needs of these mothers and their
children. The literature reviewed indicates a need to address the service users
perceptions of the services provided. Areas where further research is required
are identified.
PMID- 10759979
TI - The information needs and source preferences of women with breast cancer and
their family members: a review of the literature published between 1988 and 1998.
AB - A comprehensive and critical literature review was conducted to examine the
information needs and source preferences of women with breast cancer and their
family members. Relevant papers published between 1988 and 1998 were reviewed and
despite their having several methodological weaknesses, a number of conclusions
can still be drawn. First, women with breast cancer have distinct needs for
information throughout their breast cancer journeys, indicating that information
needs change with time since diagnosis and with treatment-related events. Second,
family members of women with breast cancer also have substantial needs for
information. Third, women with breast cancer and their family members often
prefer verbal forms of information from health care professionals (HCPs),
particularly around the time of diagnosis. Women with breast cancer, however, are
often dissatisfied with the information they receive from HCPs. Further, the
family members of women with breast cancer often perceive their information needs
to be ignored by HCPs. Finally, few studies have focused specifically on the
information needs and source preferences of family members of women with breast
cancer. These findings have a number of implications for nursing, both for
clinical practice and nursing research, and these are discussed in the review.
PMID- 10759980
TI - Clinical problem-solving in nursing: insights from the literature.
AB - This paper reviews the literature surrounding the research on how individuals
solve problems. The purpose of the review is to heighten awareness amongst nurses
in general, and nurse academics in particular about the theories developed,
approaches taken and conclusions reached on how clinicians problem-solve. The
nursing process, which is heavily used and frequently described as a problem
solving approach to nursing care, requires a deductive reasoning process which is
not the problem-solving process in use during care-giving activities. More
knowledge is required on what process is in place as we develop as a profession.
The literature highlights the complexities involved in attempting to uncover
thinking processes. The main research approaches to discovering problem-solving
strategies in the past three decades have been from a cognitive perspective, with
two main theories, decision-theory and information processing-theory,
underpinning the majority of studies conducted. None of the research approaches
used to date has resulted in the identification of a general model of problem
solving that is consistent across tasks or disciplines. However, early hypothesis
activation with subsequent testing of the hypothesis seems to be consistent in
clinicians across disciplines.
PMID- 10759981
TI - Situated learning in the practice placement.
AB - Nurses who had just completed their training in Scotland were interviewed with
regard to their experiences on placements. The nurses had either completed a
traditional training course or came from the first cohort of the Project 2000
diploma level course. The interviews focused on the way in which the student
nurses had learned in their practice placements. The results suggest that the
placement is a complex social and cognitive experience in which there are
elements of situated learning. Acceptance into the community of practice is
important but this can be separated, conceptually at least, into a social
acceptance which might be extended to any student and a professional acceptance
which relies on the display of appropriate competence. The nurses described the
way in which their mentors had interacted with them in terms which suggested that
cognitive apprenticeship strategies had been used to further their learning in
practice. It is concluded that, in view of the central importance of the
placement for training nurses, explicit use of mentoring techniques derived from
situated learning and cognitive apprenticeship might be beneficial.
PMID- 10759982
TI - Project 2000: a study of expected and experienced stressors and support reported
by students and qualified nurses.
AB - The present study was conducted in the light of major reforms to nurse education
which have taken place in the United Kingdom since 1989. The study aimed to
identify initially perceived stressors and coping resources and subsequently, to
compare these with actually reported stressors and available resources, during a
critical period in nurses' careers. Three groups of nurses participated who were
undertaking, or had recently completed, the first Project 2000 course at a
university in the south of England. Participants were given an open-ended
questionnaire and asked to describe potential difficulties, and the coping
resources they anticipated using, in a subsequent 6-month period. Following
analysis of the descriptors a structured questionnaire was developed to measure
actually experienced difficulties and coping resources that were reported; this
was completed by the three groups 6 months after the initial phase of the study.
Both student and staff nurse groups reported fewer stressors and more resources
than they had predicted. Students anticipated difficulties with competence but
actually reported financial difficulties. They experienced support from mentors
although this was not anticipated. Newly qualified staff nurses experienced fewer
difficulties with meeting personal expectations of the role than they had
anticipated. They reported more use of emotion-focused coping and less
professional support than the student groups. The results are discussed in
relation to training needs.
PMID- 10759983
TI - Education and training consortia: leading the way for the new British NHS.
AB - In November 1997 The New NHS - Modern, Dependable was published, describing the
British Labour government's plans to introduce major changes to the NHS (National
Health Service). Education and Training Consortia (ETCs) were only briefly
referred to and no direct changes were proposed to them. It can be argued that
this was because they had not fitted well within the Conservative government's
competitive culture of the NHS internal market. Education Consortia members share
information, make plans collectively and work collaboratively, activities much
more appropriate for the 'New NHS' which is underpinned by the concepts of
partnership, openness and local ownership. In this paper it is argued that there
are many valuable lessons that the key individuals involved in implementing the
policies of the New NHS can learn from Education and Training Consortia. Data
have been drawn from a qualitative study in which the aim was to explore the
development, implementation and management of consortia and contracting for non
medical education and training (NMET) from a stakeholder's perspective. One of
the unexpected themes that emerged from the analysis of the data, was that the
development of ETCs could be utilized as a model for many of the innovations in
the New NHS, particularly in relation to the formation of primary care groups.
PMID- 10759984
TI - Manual handling activities and injuries among nurses: an Australian hospital
study.
AB - The aims of this study were to identify patterns of manual handling activities
and their associated injuries and consequences among nurses working at a large
teaching and referral medical centre in Melbourne, Australia. A self-report 140
item questionnaire was distributed to 523 registered nurses working full time at
the medical centre. Of the 269 (51.4%) nurses who completed the questionnaire,
108 (40.1%) retrospectively reported an injury associated with manual handling
activity, of which 75.9% (82) comprised back injuries. When all full-time nurses
working at the medical centre are considered, the prevalence of all manual
handling injuries was 20.6% (n=108) and 15.7% (n=87) for back injuries. About two
thirds (67.6%) of all manual handling injuries were associated with direct
patient care activities and another third (32.4%) with non-direct patient care
activities. Approximately one-third (34.3%) of all injuries were associated with
lifting patients and this activity comprised one half of all causes associated
with injuries arising from direct patient care activities. The consequences of
injuries were significant. Recommendations for reducing manual handling
activities and injuries are made and future research directions are discussed.
PMID- 10759985
TI - Effort-reward imbalance and burnout among nurses.
AB - This study among a sample of 204 German nurses tested the hypothesis that an
imbalance of high extrinsic efforts spent (i.e. job demands) and low extrinsic
rewards obtained (e.g. poor promotion prospects) are associated with the burnout
syndrome: the depletion of nurses' emotional resources. The results of a series
of analyses of variances confirmed this hypothesis, by showing that those nurses
who experienced an effort-reward imbalance (ERI) reported higher levels on two of
the three core dimensions of burnout (i.e. emotional exhaustion and
depersonalization) than those who did not experience such an imbalance. Moreover
as additionally hypothesized - significant interaction effects indicated that
burnout (i.e. emotional exhaustion and reduced personal accomplishment) was
particularly prevalent among those nurses who experienced ERI and put relatively
high intrinsic effort into their jobs, as reflected by their strong tendency to
be personally in control over job conditions.
PMID- 10759986
TI - Mother, daughter, patient, nurse: women's emotion work in aged care.
AB - This paper examines emotion work within the predominantly female environment of
aged-care nursing, identifying phenomena which must be accounted for in a theory
of emotional labour. These phenomena include the blurring of public and private
in women's experiences and maternal models of care. Initial findings demonstrate
the high levels of stress experienced by staff, related to emotional labour and
to conflicts around the erosion of care standards. Sixteen women, from rural
Australia, participated in the first stage of the research. The oldest was in her
sixties, the youngest in her thirties. Length of aged-care experience ranged from
2 to 33 years. Although most of the women expected to still be in aged care in 5
years' time, they were negative in their attitudes to personal ageing, suggesting
an ambivalence in their feelings about working in aged care. Three women nurses
are the particular focus of this paper. Their narratives illustrate the
intersection of private and public caring in nurses' lives and the implications
of this for emotional labour. Phenomena such as dual caring, conflicts in insider
outsider roles, and transference are revealed in their narratives. We argue that
the welfare of the recipient of gerontic nursing is linked to the well-being of
the nurse-carer but that a cultural change is needed so as to recognize and value
emotion work. However, endorsing Staden, we agree that such a change is dependent
on the politicization of 'caring'. There is also need for further and broader
research concerning the nature of emotional labour and the ethics of care.
PMID- 10759987
TI - Dreams that lie in tatters: the changing fortunes of nurses who left the British
NHS to own and run residential homes for elderly people.
AB - During the 1980s many nurses left the British National Health Service to own and
run private residential care homes for elderly people. At the time, a public
policy of guaranteed financial support for residents underpinned the rapid
expansion in the sector and residential homes were considered as profitable low
risk business ventures. However, since the introduction of the 1990 National
Health Service and Care in the Community Act, this automatic funding has been
withdrawn and residential homes have had to compete amongst each other for a
finite number of clients funded by limited local budgets. The withdrawal of
guaranteed state support and the introduction of social care markets have had
negative impacts on many residential home businesses. Indeed, many homes are
facing financial difficulties. This paper considers the actions and attitudes of
former nurse proprietors under the new conditions based on a three-stage survey
in Devon, England. Proprietors are experiencing increased levels of stress and
many are unhappy with their current work experiences. The paper concludes that
although the small business private sector may seem attractive to nurses, any
move into private sector ownership has an associated risk. Social policy
conditions may change with concurrent consequences for businesses and business
owners.
PMID- 10759988
TI - Researching ethnic diversity in the British NHS: methodological and practical
concerns.
AB - The collection of data on ethnic groupings has become an increasingly pervasive
feature of contemporary health policy and research in the United Kingdom, with
attention concentrating primarily on monitoring access to and utilization of
services by different ethnic groups, together with epidemiological data on
morbidity and mortality. At the same time, the collection of data on ethnic
populations by census and health agencies has been the subject of a wide-ranging
and contentious debate and there is a growing critique that challenges the
collection and use of such data on political, methodological and practical
grounds. This paper explores the nature of these debates as they apply to health
research. Issues of validity and reliability arising from the application of pre
defined ethnic categories, such as those used within the National Health Service
derived from the 1991 census, are considered and alternative approaches which
utilize a range of variables such as language, religion and length of residency
in a country suggested. Experiences derived from an ethnographic study of the
provision of district nursing care to patients from different ethnic backgrounds
are used to illustrate some of the practical issues of researching ethnic
diversity. Strategies for addressing some of the methodological and practical
concerns are proposed.
PMID- 10759989
TI - A case for case studies: exploring the use of case study design in community
nursing research.
AB - The case study has become an accepted vehicle for conducting research in a
variety of disciplines. However, the meaning behind the term is not always made
explicit by researchers and this has given rise to a number of assumptions which
are open to challenge, and to questions about the robustness of the method. This
paper explores some of the issues arising from one particular definition of case
study research, used in a study by Yin which examined the practice of case
management in community nursing. Four main areas are discussed. First, defining
'case' is seen to pose questions about the relationship of the phenomenon to its
context, the degree of researcher control over case definition, the limits to
what may constitute a 'case' and what is meant by the term 'unit of analysis'.
Second, the relevance of external validity to case study research is supported
through the use of a number of tactics, in particular Yin's concept of
replication logic, which involves generalizing to theory, rather than to
empirical data. Third, the use of method triangulation (multiple methods of data
collection) is advanced as a means of enhancing construct validity in research
where data converge around a particular theory. Finally, the relationship of the
case study to theory construction, through the prior development of
'propositions' is discussed. Each of these issues is applied to the design and
conduct of a research study based closely on Yin's multiple case study framework.
Thirteen 'cases' were selected of case management practice and data were
collected through interviews and examination of literature and documentation, to
explore the suitability of community nurses for the role. It is concluded that,
given the appropriate subject matter, context and research aims, the case study
method may be seen as a credible option in nursing research.
PMID- 10759990
TI - Sampling for a longitudinal study of the careers of nurses qualifying from the
English pre-registration Project 2000 diploma course.
AB - This paper describes the processes involved in selecting a sample, from the eight
English regional health authorities, of nurse qualifiers from all four branches
of the Project 2000 pre-registration diploma course, for a longitudinal study of
nurses' careers. A simple random sample was not feasible since accurate
information about the population could not be obtained and the study design
involved recruiting participants by personal visit. A multi-stage approach was
therefore adopted in which 'college of nursing' was taken as the primary sampling
unit. Sampling was further complicated by the fact that adult branch students
could generally only be visited in larger groups than was ideal. Information
obtained during pilot work about the accuracy of data about the population,
course completion rates and the proportion of students who were likely to agree
to participate was used to calculate required sampling fractions. The final
sample was therefore a function of this information and the practicalities of
recruiting nurses into the study.
PMID- 10759991
TI - An international psychometric testing of the care dependency scale.
AB - In an international study, psychometric properties of the Care Dependency Scale
(CDS) were examined by analysing data gathered in Dutch, Canadian, Italian and
Norwegian nursing homes. For that purpose, from these countries a convenience
sample was developed consisting of 525 patients with dementia. The English,
Italian and Norwegian research instruments were translations of the original
Dutch CDS. Psychometric evaluations of the CDS were carried out for each country
separately as well as for the four countries combined. High alpha coefficients
between 0.94 and 0.97 were calculated. Subsequent test-retest and inter-rater
reliability revealed moderate to substantial Kappa values. Factor analysis
resulted in a one-factor solution. The scalability of the CDS was demonstrated by
means of Mokken scale analysis. One of the main outcomes of the cross-cultural
comparison was that the findings in the four countries show more similarities
than differences, so that the scale can be used appropriately in nursing home
practice.
PMID- 10759992
TI - Clinical supervision, death, Heidegger and Freud come 'out of the sighs'.
AB - In his recent paper on clinical supervision, 'Out of the sighs' - an existential
phenomenological method of clinical supervision: the contribution to palliative
care', in this journal, Jones weds psychoanalytical ideas with Heidegger's
existential-phenomenological concepts to provide a theoretical framework for
clinical supervision in palliative nursing. Although this is an interesting
undertaking, theoretical diversity is not a simple matter of merely interchanging
concepts. Rather, it is a complex process that must account for varying
philosophical assumptions upon which any theory attempts to explain or understand
reality. This paper examines the major themes identified by Jones. In particular,
it focuses on the spirit of ontological hermeneutics and psychoanalysis,
represented by their respective founders, Heidegger and Freud, and in general,
refers to other thinkers and ideas mentioned by Jones - as for instance, Schon's
reflective practice, Polanyi's personal commitment, Husserl's lived experience,
Schutz's intersubjectivity and Yalom's existential disidentification. Here,
discussion concerns the subject-object polarity. The paper argues that many of
these philosophies are incompatible. In particular, psychoanalysis and
existentialism imply inconsistent aims in that psychology does not equate with
fundamental ontology - and Jones has not adequately distinguished between these
in his supervision discourse. The implications of the accompanying conceptual
problems for the practice of clinical supervision in palliative nursing are
exemplified by Jones's case study of Lindsey, a dying patient.
PMID- 10759993
TI - The nurse-patient relationship: a consideration of its discursive context.
AB - This paper is a theoretical exploration of the discursive context that shapes the
nurse-patient relationship. It represents a feminist poststructural consideration
of the broader institutional and social context that influences the dynamics of
that relationship. The characteristics of that relationship can be regarded as
performances of subjectivity shaped by managerial, medical and nursing
discourses. Both nurse and patient signify particular discursively constituted
meanings to each other which shape the relationship. It is proposed that the
discourses which inform how each should respond to the other encourage the
utilization of disciplinary tactics by the nurse which relay to the patient what
is expected of him/her. An effect of these disciplinary procedures is to rein in
the caring potential of nursing practices. However, nursing's relationship with
women's work and the social history of caring may provide it with a discursive
context that recognizes the social significance of this work.
PMID- 10759994
TI - A response to Dawson's critical analysis of 'spirituality as "integrative
energy"'.
AB - Dawson's reply to 'spirituality as integrative energy', particularly his
objection to the appropriation of energy as a conceptual descriptor, demonstrates
a woefully inaccurate and grossly misleading interpretation of my work. The
purpose of this response is to challenge Dawson's assertion that such
reformulation effectively strips spirituality of its historical meaning and to
provide evidence of its appropriateness. I briefly consider the precepts
underlying holism as a moral imperative for professional nursing, the traditional
role of spirituality in health and illness, the rise of medical science and its
eventual disjunction from metaphysics, and the his torical evolution of nursing.
I also comment on the privileged nature of the nurse-client relationship and the
social and moral obligation of nurses to engage in holistic practice. Finally, I
suggest that the reconceptualization of spirituality as 'integrative energy'
represents its dynamic, unifying nature and reassert my contention that
'integrative energy' is an entirely appropriate and eminently suitable definition
of spirituality.
PMID- 10759995
TI - Hospital ownership and preventable adverse events.
AB - OBJECTIVE: To determine if type of hospital ownership is associated with
preventable adverse events. DESIGN: Medical record review of a random sample of
15,000 nonpsychiatric, non-Veterans Administration hospital discharges in Utah
and Colorado in 1992. MEASUREMENTS AND MAIN RESULTS: A two-stage record review
process using nurse and physician reviewers was used to detect adverse events.
Preventability was then judged by 2 study investigators who were blinded to
hospital characteristics. The association among preventable adverse events and
hospital ownership was evaluated using logistic regression with nonprofit
hospitals as the reference group while controlling for other patient and hospital
characteristics. We analyzed 4 hospital ownership categories: nonprofit, for
profit, major teaching government (e.g., county or state ownership), and minor or
nonteaching government. RESULTS: When compared with patients in nonprofit
hospitals, multivariate analyses adjusting for other patient and hospital
characteristics found that patients in minor or nonteaching government hospitals
were more likely to suffer a preventable adverse event of any type (odds ratio
[OR] 2.46; 95% confidence interval [CI], 1.45 to 4.20); preventable operative
adverse events (OR, 4.85; 95% CI, 2.44 to 9.62); and preventable adverse events
due to delayed diagnoses and therapies (OR, 4.27; 95% CI, 1.48 to 12.31).
Patients in for-profit hospitals were also more likely to suffer preventable
adverse events of any type (OR, 1.57; 95% CI, 1.03 to 2.38); preventable
operative adverse events (OR, 2.63; 95% CI, 1.42 to 4.87); and preventable
adverse events due to delayed diagnoses and therapies (OR, 4.15; 95% CI, 1. 84 to
9.34). Patients in major teaching government hospitals were less likely to suffer
preventable adverse drug events (OR, 0.38; 95% CI, 0.16 to 0.89). CONCLUSIONS:
Patients in for-profit and minor teaching or nonteaching government-owned
hospitals were more likely to suffer several types of preventable adverse events.
Further research is needed to determine how these events could be prevented.
PMID- 10759996
TI - Cardiovascular disease prevention practices by U.S. Physicians for patients with
diabetes.
AB - OBJECTIVE: Cardiovascular diseases account for the majority of morbidity and
mortality in patients with type 2 diabetes mellitus. We describe patterns of
cardiovascular disease primary prevention practices used for patients with
diabetes by U.S. office-based physicians. MEASUREMENTS AND MAIN RESULTS: We
analyzed a representative sample of 14,038 visits from the 1995 and 1996 National
Ambulatory Medical Care Surveys (NAMCS), including 1,489 visits by patients with
diabetes. Physicians completed visit forms describing diagnoses, demographics,
services provided, and current medications. Diabetes was defined by diagnostic
codes; patients with ischemic heart disease or younger than 30 years were
excluded. We estimated national visit volumes by extrapolation using NAMCS
sampling weights. Independent determinants of prevention practices were evaluated
using multiple logistic regression. Actual visits sampled translated into an
estimated 407 million office visits in 1995 and 1996, of which 44.8 million (11%)
were by patients with diabetes. Overall, patients with diabetes received more
cardiovascular disease prevention services than patients without diabetes,
including cholesterol reduction (8% vs 5%, P <.001) and exercise counseling (22%
vs 13%, P <.001), blood pressure measurement (82% vs 72%, P <.001), and aspirin
prescription (5% vs 2%, P <.001). Patients with diabetes and hyperlipidemia were
more likely to receive lipid-lowering medications than patients without these
diagnoses (67% vs 51%, P =.007), but those who had diabetes and hypertension or
who smoked were no more likely than those without to receive antihypertensive
medications or smoking cessation counseling, respectively. These effects
persisted in multiple logistic regression analyses controlling for potential
confounders. CONCLUSIONS: Patients with diabetes visiting U.S. physicians in 1995
and 1996 received somewhat more cardiovascular disease prevention services than
patients without diabetes. Absolute rates of services, however, remained lower
than desired based on national recommendations. Current evidence suggests that
wider implementation of these recommendations can be expected to reduce the
burden of cardiovascular disease in patients with diabetes.
PMID- 10759997
TI - Breast cancer screening use by African Americans and Whites in an HMO.
AB - OBJECTIVE: To examine racial differences in breast cancer screening in an HMO
that provides screening at no cost. DESIGN: Retrospective cohort study of breast
cancer screening among African-American and white women. Breast cancer screening
information was extracted from computerized medical records. SETTING: A large HMO
in New England. PATIENTS/PARTICIPANTS: White and African-American women (N =
2,072) enrolled for at least 10 years in the HMO. MAIN RESULTS: Primary care
clinicians documented recommending a screening mammogram significantly more often
for African Americans than whites (70% vs 64%; P <.001). During the 10-year
period, on average, white women obtained more mammograms (4.49 vs 3.93; P <.0001)
and clinical breast examinations (5.35 vs 4.92; P <.01) than African-American
women. However, a woman's race was no longer a statistically significant
predictor of breast cancer screening after adjustment for differences in age,
estimated household income, estrogen use, and body mass index (adjusted number of
mammograms, 4.47 vs 4.25, P =.17; and adjusted number of clinical breast
examinations, 5.35 vs 5. 31, P =.87). CONCLUSIONS: In this HMO, African-American
and white women obtained breast cancer screening at similar rates. Comparisons
with national data showed much higher screening rates in this HMO for both white
and African-American women.
PMID- 10759998
TI - Clinical implications of body image among rural African-American women.
AB - OBJECTIVE: To increase understanding of body image among rural, African-American
women through open-ended interviews. DESIGN: Individuals' perceptions of body
image were investigated using open-ended, in-depth interviews that were tape
recorded, transcribed, and analyzed to identify common themes and to compare
thematic data across three body mass index categories (obese, overweight, and
normal). SETTING: University-affiliated rural community health center.
PARTICIPANTS: Twenty-four African-American women, aged 21 to 47 years. MAIN
RESULTS: Respondents reported the following common themes: dissatisfaction with
current weight; fluctuating levels of dissatisfaction (including periods of
satisfaction); family and social pressure to be self-accepting; and social and
physical barriers to weight loss. The interviews revealed ambivalence and
conflicts with regard to body image and weight. Among these women, there was
strong cultural pressure to be self-accepting of their physical shape, to "be
happy with what God gave you," and to make the most of their appearance.
CONCLUSIONS: The pressure to be self-accepting often conflicted with these obese
women's dissatisfaction with their own appearance and weight. Although the
respondents believed they could lose weight "if [they] put [their] mind to it,"
those women wanting to lose weight found that they lacked the necessary social
support and resources to do so. The conflicts stemming from social pressures and
their own ambivalence may result in additional barriers to the prevention of
obesity, and an understanding of these issues can help health care providers
better address the needs of their patients.
PMID- 10759999
TI - Recognition of patient referral desires in an academic managed care plan
frequency, determinants, and outcomes.
AB - OBJECTIVE: To determine the frequency and determinants of provider nonrecognition
of patients' desires for specialist referral. DESIGN: Prospective study. SETTING:
Internal medicine clinic in an academic medical center providing primary care to
patients enrolled in a managed care plan. PARTICIPANTS: Twelve faculty internists
serving as primary care providers (PCPs) for 856 patient visits. MEASUREMENTS AND
MAIN RESULTS: Patients were given previsit and postvisit questionnaires asking
about referral desire and visit satisfaction. Providers, blinded to patients'
referral desire, were asked after the visit whether a referral was discussed, who
initiated the referral discussion, and whether the referral was indicated.
Providers failed to discuss referral with 27% of patients who indicated a
definite desire for referral and with 56% of patients, who indicated a possible
desire for referral. There was significant variability in provider recognition of
patient referral desire. Recognition is defined as the provider indicating that a
referral was discussed when the patient marked a definite or possible desire for
referral. Provider recognition improved significantly (P <.05), when the patient
had more than one referral desire, if the patient or a family member was a health
care worker and when the patient noted a definite desire versus a possible desire
for referral. Patients were more likely (P <.05) to initiate a referral
discussion when they had seen the PCP previously and had more than one referral
desire. Of patient-initiated referral requests, 14% were considered "not
indicated" by PCPs. Satisfaction with care did not differ in patients with a
referral desire that were referred and those that were nor referred. CONCLUSIONS:
These PCPs frequently failed to explicitly recognize patients' referral desires.
Patients were more likely to initiate discussions of a referral desire when they
saw their usual PCP and had more than a single referral desire.
PMID- 10760000
TI - Patients' perceptions of physicians' recommendations for comfort care differ by
patient age and gender.
AB - OBJECTIVE: To determine patient characteristics associated with patient and proxy
perceptions of physicians' recommendations for life-prolonging care versus
comfort care, and with acceptance of such recommendations. DESIGN: Cross
sectional. SETTING: Five teaching hospitals in Denver, Colo. PATIENTS: We studied
239 hospitalized adults believed by physicians to have a high likelihood of dying
within 6 months. MEASUREMENTS AND MAIN RESULTS: Interviews with patients or
proxies were conducted to determine perceptions of physicians' recommended goal
of care and roles in decision making. RESULTS: Patients' mean age was 66.6 years;
44% were women. In adjusted analysis, age greater than 70 years and female gender
were associated with a higher likelihood of believing that comfort care had been
recommended by the physician (odds ratio [OR], 3.70; 95% confidence interval
[CI], 1.89 to 7.24; OR, 1.99; 95% CI, 1.04 to 3. 84, respectively). Patients and
proxies gave substantial decision-making authority to physicians: 29% responded
that physicians dominate decision making, 55% that decision making is equally
shared by physicians and patients, and only 16% that patients make decisions.
Increasing age was associated with an increased likelihood of believing that
physicians should dominate decision making (P <.005). CONCLUSIONS: Among patients
with advanced illness, perceived comfort care recommendations were related to
patient age and gender, raising concern about possible gender and age bias in
physicians' recommendations. Although all patients and proxies gave significant
decision-making authority to physicians, older individuals were more likely to
give physicians decision-making authority, making them more vulnerable to
possible physician bias.
PMID- 10760001
TI - Effect of language barriers on follow-up appointments after an emergency
department visit.
AB - OBJECTIVE: To determine whether patients who encountered language barriers during
an emergency department visit were less likely to be referred for a follow-up
appointment and less likely to complete a recommended appointment. DESIGN: Cohort
study. SETTING: Public hospital emergency department. PARTICIPANTS: English- and
Spanish-speaking patients (N = 714) presenting with nonemergent medical problems.
MEASUREMENTS AND MAIN RESULTS: Patients were interviewed to determine
sociodemographic information, health status, whether an interpreter was used, and
whether an interpreter should have been used. The dependent variables were
referral for a follow-up appointment after the emergency department visit and
appointment compliance, as determined by chart review and the hospital
information system. The proportion of patients who received a follow-up
appointment was 83% for those without language barriers, 75% for those who
communicated through an interpreter, and 76% for those who said an interpreter
should have been used but was not (P =. 05). In multivariate analysis, the
adjusted odds ratio for not receiving a follow-up appointment was 1.92 (95%
confidence interval [CI], 1.11 to 3.33) for patients who had an interpreter and
1.79 (95% CI, 1.00 to 3.23) for patients who said an interpreter should have been
used (compared with patients without language barriers). Appointment compliance
rates were similar for patients who communicated through an interpreter, those
who said an interpreter should have been used but was not, and those without
language barriers (60%, 54%, and 64%, respectively; P =.78). CONCLUSIONS:
Language barriers may decrease the likelihood that a patient is given a follow-up
appointment after an emergency department visit. However, patients who
experienced language barriers were equally likely to comply with follow-up
appointments.
PMID- 10760002
TI - Health of homeless women with recent experience of rape.
AB - There is limited understanding of the physical health, mental health, and
substance use or abuse correlates of sexual violence against homeless women. This
study documents the association of rape with health and substance use or abuse
characteristics reported by a probability sample of 974 homeless women in Los
Angeles. Controlling for potential confounders, women who reported rape fared
worse than those who did not on every physical and mental health measure and were
also more likely to have used and abused drugs other than alcohol. Results should
serve to alert clinicians about groups of homeless women who may benefit from
rape screening and treatment interventions.
PMID- 10760003
TI - Fatal distraction: finance vs vigilance in our nation's hospitals.
PMID- 10760004
TI - Postnatal corticosteroids in preterm infants: systematic review of effects on
mortality and motor function.
AB - BACKGROUND: Postnatal corticosteroid therapy has been proved in randomized
controlled trials to reduce ventilator dependence and the rate of chronic lung
disease in preterm infants with few serious short-term side effects. However,
there are other consequences that might follow postnatal corticosteroid therapy
that are more important, including mortality or cerebral palsy. OBJECTIVES: To
review the evidence from reported randomized controlled trials on the effects of
postnatal corticosteroid on long-term mortality and motor dysfunction, including
cerebral palsy. METHODS: The methods involved a meta-analysis of reported
randomized controlled trials, following guidelines of the Cochrane Collaboration,
including calculation of event rate differences (ERD) and 95% confidence
intervals (CI). RESULTS: The mortality rate difference was non-significant both
statistically and clinically (ERD - 0.1% favouring corticosteroids, 95% CI -2.9%
to 2.8%). There were no subgroups in which a beneficial effect of postnatal
corticosteroids on survival could be demonstrated. The rate of motor dysfunction
in survivors was significantly higher in survivors from the postnatal
corticosteroid group (ERD 11.9% favouring controls, 95% CI 4.6% to 19.2%). The
rate of survival, free of motor dysfunction, was significantly lower in the
postnatal corticosteroid group (ERD 7.8% favouring controls, 95% CI 0.5% to
15.1%). CONCLUSIONS: Although postnatal corticosteroids have short-term benefits,
they do not increase the survival rate, and they may cause motor dysfunction in
survivors. A large-scale, placebo-controlled randomized trial, with survival free
of sensorineural impairments and disabilities as the major endpoint, is urgently
needed.
PMID- 10760005
TI - Congenital and neonatal varicella in Australia.
AB - OBJECTIVE: To establish the incidence and severity of congenital and neonatal
varicella in Australia. METHODOLOGY: Demographic and clinical details were
obtained by postal questionnaire regarding cases notified to the Australian
Paediatric Surveillance Unit by over 930 participating clinicians in 1995-97
inclusive. RESULTS: Seven cases of congenital varicella (1: 107 000
pregnancies/year) followed maternal infection at 8-26 weeks: five had defects,
two did not. Four of the seven infants with congenital varicella developed herpes
zoster in the first 15 months of life. Forty-four infants had neonatal varicella
(1: 17 000 pregnancies/year). CONCLUSION: : There is an ongoing, albeit low,
incidence of congenital and neonatal varicella in Australia.
PMID- 10760006
TI - The prevalence of recurrent abdominal pain in 11- to 16-year-old Malaysian
schoolchildren.
AB - OBJECTIVE: To determine the prevalence of recurrent abdominal pain (RAP) among
Malaysian school children aged from 11 to 16 years. METHODOLOGY: A preliminary
cross-sectional survey in which three urban schools and three rural schools were
selected randomly. Two classes were selected randomly from each year. A
questionnaire was given to each child asking him or her about whether they had
experienced abdominal pain occurring at least three times over a period of at
least 3 months, interfering with normal daily activity. 1 Interfering with normal
daily activity was defined as missing school and/or having to stop doing a
routine daily activity on account of the pain. Girls whose pains were related to
periods were excluded. After the forms had been completed, each child was again
interviewed to ensure that Apley's criteria1 was fulfilled in cases of RAP.
RESULTS: The overall prevalence of RAP among 1549 schoolchildren (764 boys; 785
girls) was 10.2% (95% confidence interval (CI), 8.8-11.8). There appeared to be a
higher prevalence in rural schoolchildren (P = 0.008; odds ratio (OR) 1.58), in
those with a lower family income (P < 0.001; OR 2.02) and in children whose
fathers have a lower educational attainment (P = 0.002; OR 1. 92). There were no
significant differences in the prevalence of RAP among children of different sex,
age, ethnic group and family size. CONCLUSION: : In spite of differences in time
and culture, the overall prevalence of 10.2% found in this study is similar to
that determined by Apley.1 There are significant differences in the prevalence of
RAP between children from rural and urban schools, among children with different
family incomes and among children whose parents have different educational
backgrounds.
PMID- 10760007
TI - Bed sharing patterns in a cohort of Australian infants during the first six
months after birth.
AB - OBJECTIVE: To measure bed sharing (BS) activity in healthy term infants.
METHODOLOGY: The sleep-wake behaviour and place of infant sleep were recorded for
infants aged between 2 and 24 weeks. Infants were then identified as BS or non
bed sharing (NBS) according to each of four different definitions of bed sharing.
RESULTS: The mean proportion of infants who spent any time BS during a 24-h
period was significantly greater (P < 0.05) between 2 and 12 weeks (40.9 +/- 1.
4%) than between 13 and 24 weeks (36.5 +/- 1.5%). A significantly greater
proportion (P < 0.005) of infants bed shared for more than 2 h (25 +/- 1%) than
for either 1-2 h (10.5 +/- 1.1%) or for less than 1 h/24 h (3.2 +/- 0.5%) during
the whole study period. Each of the definitions of BS used in the study separated
infants on the basis of the amount and frequency of BS activity. CONCLUSION: :
Bed sharing activity was common and varied in this cohort. It was possible, using
quantitative definitions, to identify those infants who routinely bed share.
PMID- 10760008
TI - The effect of draw-up volume on the accuracy of electrolyte measurements from
neonatal arterial lines.
AB - OBJECTIVES: Contamination by infusate of blood samples withdrawn from arterial
lines has been recognized but not well documented for neonates. The aim of this
study was to investigate, using in vitro and in vivo studies, the effects of
different draw-up volumes (withdrawn from the line prior to the sample being
taken) on the concentration of sodium. METHODS: In-vitro study: The tip of an
umbilical artery catheter (dead space 0.6 mL), infused with half normal saline
containing 1 unit/mL of heparin was placed in a beaker of normal saline. The line
was flushed with 1 mL of this infusate just before each sample was taken. Volumes
from 0.5 mL to 2.0 mL of infusate/normal saline were withdrawn in 0.1 mL
increments from a three-way tap and discarded. A sample was then taken from the
line into a blood gas syringe for analysis of the sodium concentration by the 860
Blood Gas Analyzer (Chiron Diagnostics, Bayer, Scoresby). Control samples were
taken from the beaker. In-vivo study: A 22 gauge intravenous catheter was
inserted into a vein of an adult male volunteer. The dead space was also 0.6 mL.
The line was flushed with 5 mL of half-normal saline immediately before sampling.
Draw-up volumes of 0.6, 0.9, 1.3, and 1.6 mL were withdrawn and discarded. 10 mL
was used as a control. A 0.5-mL blood sample was then taken and the electrolyte
concentrations analysed immediately. RESULTS: In-vitro: A minimum draw-up volume
of 1.3 mL was required before the sodium concentration was not significantly
different from the control samples. In-vivo: A minimum draw-up volume of 1.6 mL
was required before the sodium concentration was not significantly different from
the control samples. There were similar trends in the effect of draw-up volume
for glucose, calcium, potassium, chloride and lactate. CONCLUSION: : A minimum
volume of 1.6 mL should be withdrawn from neonatal arterial lines (dead space 0.6
mL) before taking blood for analysis.
PMID- 10760009
TI - Invasive Haemophilus influenzae type b infections in Singapore children: a
hospital-based study.
AB - OBJECTIVE: A 6-year (1990-95) hospital-based retrospective study was carried out
to investigate the pattern of invasive Haemophilus influenzae type b (Hib)
disease. METHODOLOGY: Cases with Hib isolated from sterile sites (blood,
cerebrospinal fluid, or joint aspirate) were identified from the hospital's
microbiological records, and their reviewed case records. Patients with pyogenic
meningitis in the same study period were also identified to estimate the
incidence of Hib meningitis. RESULTS: Twelve patients had positive cultures from
sterile sites, of whom nine children were less than 5 years of age. These
included seven cases of meningitis, one patient with acute epiglottitis, and one
case of pneumonia. Three of the seven patients with meningitis had significant
long-term sequelae. Our data also suggests a relatively low proportion of ethnic
Chinese children with invasive disease. It was estimated that 18.4% to 41.1% of
pyogenic meningitis in children admitted to the National University Hospital were
due to Hib. The estimated annual attack rate of invasive Hib disease was at most
3.3 per 100 000 children aged less than 5 years (95% confidence interval: 2.6
3.5/100 000). CONCLUSION: : Invasive Hib infections are relatively uncommon in
our community. This justifies the need for a cost effectiveness study before a
universal Hib vaccination program is implemented.
PMID- 10760010
TI - Prevalence of childhood asthma, allergic rhinitis and eczema in Urumqi and
Beijing.
AB - OBJECTIVE: To assess the prevalence of asthma and other allergies in children in
Urumqi and Beijing, compared with that in Hong Kong. METHODS: A total of 7754
primary school students were randomly selected to participate in the study. Data
were collected in 1995-96 using the International Study of Asthma and Allergies
in Childhood (ISAAC) protocol for 6- and 7-year-olds. The study design and data
quality assurance in all aspects followed the protocol, including the double
entry of data. RESULTS: The questionnaire response rate was high (98.9%). Beijing
children reported significantly more asthma than those living in Urumqi in three
categories: wheezing or whistling in the chest in the past year (6.0%, 95%
confidence interval (CI): 5.1-6.9% vs 2.9%, 2.3-3.5%, P < 0.001), sleeping
disturbed due to wheezing (1.3%, 0.9-1.7% vs 0.6%, 0.3-0.9%, P < 0. 03) and
having experienced asthma ever (10.7%, 9.6-11.8% vs 7.6%, 6. 6-8.6%, P < 0.001).
The prevalence of allergic rhinitis (30.0% vs 31. 1% estimated as 12-month nasal
symptoms in Beijing and Urumqi, respectively) and eczema (2.8% vs 2.0% recorded
as 12-month itchy rash) in the two cities were not significantly different. A
similar study was also performed in Hong Kong in 1995 using the same ISAAC
protocol. The children in Urumqi and Beijing had fewer (P < 0.05) allergic
symptoms compared to those living in Hong Kong (n = 3618). The 12-month
prevalence of wheezing, nasal symptoms and itchy rash found in Hong Kong were
9.2% (95% CI: 8.2-10.2%), 35.1% (33.5-36.7%) and 4.2% (3.5-4.9%), respectively.
CONCLUSION: : Urumqi, Beijing and Hong Kong represent communities at different
stages of westernization and the results from these three cities reflect a
worldwide trend for an increasing prevalence of allergies along with
westernization. These three cities could assist in identifying risk factors
involved in the increase in asthma, allergic rhinitis and eczema.
PMID- 10760011
TI - A follow-up pilot study of objective measures in children with attention deficit
hyperactivity disorder.
AB - OBJECTIVES: Attention deficit hyperactivity disorder (ADHD) is a common childhood
problem requiring stimulant medications in a significant proportion of cases. The
aim of this pilot study was to assess the effects of prolonged stimulant
medication therapy on a continuous performance test, the Test of Variables of
Attention (TOVA), which measures objectively features of ADHD. METHODS: Eighteen
children aged 8 to 16 years who were diagnosed with ADHD, based on the Diagnostic
and Statistical Manual of Mental Disorders 4th edn criteria, were included in the
study. Assessment on a continuous performance test (TOVA) was performed initially
and the children were administered stimulant medications for at least 12 months.
The medications were stopped for 1 week, followed by a repeat TOVA assessment
which was compared to the initial TOVA assessment. RESULTS: Follow up TOVA scores
showed a significant improvement in mean commission errors (impulsivity) after
the stimulant medication therapy. No significant improvement was found in
omission errors (inattention), response time and variability. There was a
significant positive correlation between commission and omission scores (P value
0.0001). CONCLUSIONS: The results of this pilot study indicate that there is
objective improvement in impulsivity in children with ADHD after a prolonged
period of stimulant medication therapy. The study suggests that it would be
useful to perform formal studies to investigate this further and also to assess
the role of continuous performance test (TOVA) as a method for monitoring the
need for ongoing therapy.
PMID- 10760012
TI - Magnetic resonance imaging findings in cerebral palsy.
AB - OBJECTIVE: To review all cases of cerebral palsy (CP) that had magnetic resonance
imaging (MRI) over a defined period of time. METHODOLOGY: The MRI brain scans of
42 children (12 premature, 30 full-term) with CP were studied. The scans were
performed at the Royal Children's Hospital, Melbourne, between January 1995 and
June 1996. RESULTS: Abnormalities were found in 39 of the 42 scans. Five children
had cortical malformations and three children had white matter hypoplasia,
indicating insults during the second trimester of pregnancy. Twenty-one children
had hypoxic-ischaemic lesions (eight premature, 13 full-term) with patterns of
periventricular leucomalacia, subcortical lesions or cortical infarction
indicating insults perinatally or in the third trimester. Only 10 children had
scans that could not be categorized into these groups. CONCLUSIONS: In this study
sample of children with CP, MRI was useful in revealing underlying brain
abnormalities, most of which were due to events in the third trimester or the
perinatal period.
PMID- 10760013
TI - Social factors associated with ethnic differences in alcohol and marijuana use by
Vietnamese-, Arabic- and English-speaking youths in Sydney, Australia.
AB - OBJECTIVE: To describe the use of marijuana and alcohol among Arabic- and
Vietnamese-speaking senior school students compared with English-speaking
background senior school students in Sydney Australia. METHOD: A quantitative
survey of 2573 school students attending Years 10 and 11 from 12 high schools
with a high Vietnamese and Arabic population was conducted in Sydney in 1998.
Self-reported marijuana use, school and cultural background information was
collected. RESULTS: Students from an English-speaking background, both males and
females, had almost double the prevalence of marijuana use (once or more) during
their lifetime (48.3 and 43.6%), the 12 months (40.9 and 36.3%) and 1 month prior
to survey administration (23.1 and 13.4%) than the group with the second highest
frequency of use (students of European and other backgrounds). Female Vietnamese
(7.3% lifetime use) and Arabic students (8.6% lifetime use) had the lowest
marijuana use rates, which were less than half that of male Vietnamese (23.5%
lifetime use) and Arabic students (28% lifetime use). A similar pattern was found
for three types of alcohol use. Spending three or more evenings a week out with
friends was associated with higher alcohol use for Vietnamese students (relative
risk ratio of 2.76). CONCLUSIONS: These results confirm lower marijuana and
alcohol use among students from Vietnamese- and Arabic-speaking backgrounds
compared with students from an English-speaking background. Harm minimization
strategies may be learned from some migrant communities.
PMID- 10760014
TI - Neutrophil functions of Chinese neonates.
AB - OBJECTIVE: To delineate neutrophil function of preterm and full-term neonates of
Chinese origin. METHODS: Chinese neonates admitted to two major Hong Kong
neonatal units were randomly selected for the study. Candidacidal activity,
phagocytosis, chemotaxis and nitroblue tetrazolium reduction scores were
evaluated from blood. RESULTS: Except for chemotactic activity, the neutrophil
functions of Chinese preterm neonates were similar to Chinese full-term neonates.
The candidacidal activity of males was significantly lower when compared with
female neonates. Compared with adult controls, both term and preterm infants had
similar phagocytic activities although their candidacidal activities and
chemotactic index were significantly decreased. Neutrophil function of Chinese
infants was nearer to that of adult controls than historically reported for
western infants. CONCLUSION: : Preterm Chinese neonates had similar neutrophil
function to full-term infants. Neutrophil function of Chinese infants was more
mature than that of western infants.
PMID- 10760015
TI - General practitioners: their contact with maternal and child health nurses in
postnatal care.
AB - OBJECTIVE: To assess the level of contact of general practitioners (GP) with
maternal and child health nurses (MCHN) in postnatal care. METHODOLOGY: A postal
survey of 1104 Victorian GP was used, with a response rate of 70%. To account for
the clustered sampling frame, hierarchical data analysis techniques were used.
RESULTS: Half of the GP (351/710) had no contact with their local MCHN in the
previous month; and one in 10 had four or more contacts. Eighty-eight per cent of
GP described the contact as helpful. In 56% of cases the MCHN was reported as the
usual initiator of the contact. The most common reason for contact concerned the
baby's physical problems (42%). After adjusting for the number of women seen for
the routine 6-week postnatal review and other GP characteristics, male GP were as
likely as female GP to report MCHN contact (odds ratio (OR) = 1.00; 95%
confidence interval (CI) = 0.67-1.62). General practitioners aged 31-40 years
were more likely to report contact with MCHN than GP aged 51-60 (OR = 0.45; 95%
CI = 0.22-0.86) as were GP with the FRACGP qualification (OR = 1.64; 95% CI =
1.21-2.45). CONCLUSIONS: This study provides baseline information on the level of
GP contact with MCHN as they provide postnatal care. Although there were GP in
Victoria who maintained a level of contact with MCHN, almost half reported no
contact in the previous month. Most GP who reported contact with MCHN found it
useful. This finding should encourage GP and MCHN coordination to improve
continuity and postnatal care outcomes.
PMID- 10760016
TI - Rates of breastfeeding in Australia by State and socio-economic status: evidence
from the 1995 National Health Survey.
AB - OBJECTIVE: To estimate rates of breastfeeding in the first year of life in
Australia, according to state and socio-economic status. METHODOLOGY: Analysis of
data from the 1995 Australian National Health Survey. RESULTS: Estimated
breastfeeding rates are 81.8% on discharge from hospital, 57.1% fully breastfed
at 3 months and 62.6% fully or partially breastfed at 3 months. At 6 months, it
is estimated that 18.6% of babies are fully breastfed and 46.2% fully or
partially breastfed. At 1 year, 21.2% of infants are receiving some breast milk.
Comparison between states demonstrates that there is considerable variation in
breastfeeding practice within Australia. Rates of breastfeeding also vary
according to the socio-economic status of the geographic area in which the child
is living, with a strong inverse relationship between rates of breastfeeding and
socio-economic status. CONCLUSION: : Australia's target for breastfeeding in the
year 2000 is to have 80% of babies at least partially breastfed for the first 6
months of life. Although Australia has good rates of initiation of breastfeeding,
these levels are not maintained over time, and it seems unlikely that we will
reach the year 2000 targets.
PMID- 10760017
TI - Echocardiography on neonatal intensive care units in Australia and New Zealand.
AB - OBJECTIVE: To establish the number of neonatal intensive care units (NICU) in
Australia and New Zealand where echocardiography is performed by neonatologists,
and to establish attitudes to the training of neonatologists in echocardiography.
METHODOLOGY: A survey was conducted of the directors of all 29 level 3 NICU in
the Australian and New Zealand Neonatal Network. Replies were received from all
NICU. RESULTS: In 41% of NICU, a neonatologist provides the primary
echocardiography service, with half these units having more than one
neonatologist with skills. Sixty-eight per cent of the other units would like a
neonatologist to develop these skills in the future. Units without a
neonatologist with echocardiographic skills were generally less satisfied with
their service, benefits and problems for both types of unit are described. Eleven
per cent of units felt neonatologists should not be doing echocardiography and
96% of units felt training guidelines should be established. CONCLUSIONS:
Ultrasound in neonatology and other specialties is moving beyond its traditional
boundaries and becoming part of the acute care doctors' diagnostic repertoire.
This trend needs to be recognized in the specialty training and the ultrasound
accreditation processes.
PMID- 10760018
TI - Epilepsy and associated psychopathology in young people with intellectual
disability.
AB - OBJECTIVE: This study aimed to investigate the role of epilepsy in
psychopathology among an epidemiological sample of young people with intellectual
disability (ID). The study also compared behavioural and emotional problems in
young people on medication to control their epilepsy with those not on
medication, and young people with epilepsy who were having current seizure
activity with those with no current seizure activity. METHODOLOGY: An
epidemiological cohort of 392 participants, representative of the general
Australian population of young people with ID, were used in the study. One
hundred and fifteen individuals from this cohort were identified as suffering
from epilepsy. The Developmental Behaviour Checklist was used to measure symptoms
of behavioural and emotional disturbance. RESULTS: Results confirmed that young
people with ID and epilepsy did not differ from controls without epilepsy on
measures of psychopathology. Furthermore, those with epilepsy on medication had
no difference in levels of problem behaviours than epileptics not on medication.
CONCLUSIONS: The results suggest that epilepsy has little or no influence on
problem behaviours for young people with ID. Our attempt to understand the
pathogenesis of behaviour problems in persons with ID may be better directed
towards understanding genetic mechanisms than epilepsy pathologies.
PMID- 10760019
TI - Fire deaths in children in South Australia from 1989 to 1998.
AB - A study was undertaken of childhood deaths caused by fires in South Australia
over a 10-year period from 1989 to 1998. A total of 23 deaths of children
occurred with an age range of 2 months to 16 years (mean 5 years 10 months; M:F =
13:10). Fourteen deaths were associated with house fires, four with fires in cars
and four were miscellaneous or unspecified. While house fire deaths remained the
major cause of childhood fire deaths (65%), deaths in car fires accounted for a
significant proportion of cases (17%). Although the numbers are small, cars
represented a specific danger because of their confined space with highly
flammable interiors, lockable doors, and built in non-childproof lighters. Cars
should not be regarded as suitable places to leave young children, or for
children to play in unsupervised.
PMID- 10760020
TI - Instructive case: a swollen eye.
PMID- 10760021
TI - Neonatology for the generalist: human milk banks and evidence-based medicine.
AB - Human milk (HM) banks provide pasteurised milk from screened donors for infants
in many countries but not in Australia. There are potential benefits and risks
from feeding donor milk with the benefits most likely for preterm infants. A
randomized clinical trial is required to provide conclusive evidence. Promotion
of breast-feeding with the establishment of HM banks may prove to be an important
primary health care activities for infants in Australia.
PMID- 10760022
TI - Congenital varicella syndrome in the absence of cutaneous lesions.
AB - A case of congenital varicella syndrome characterized by intrauterine growth
retardation, ocular and neurologic abnormalities, but no cutaneous lesions is
reported. This case highlights the risk of embryopathy from varicella infection
during pregnancy in non-immune women.
PMID- 10760023
TI - Congenital varicella syndrome diagnosed by polymerase chain reaction--scarring of
the spinal cord, not the skin.
AB - A term infant with congenital varicella syndrome (CVS) is reported. Monoplegia of
the left arm and paraplegia were present with no evidence of dermatomal skin
scarring. Following death at 12 days of age, autopsy documented severe atrophy
and gliosis of the spinal cord. Testing for varicella-zoster virus by the
polymerase chain reaction method on brain tissue was positive. This case extends
the current understanding of the clinical and pathological features of CVS.
PMID- 10760024
TI - Elevated aminotransferase as a presenting finding in a patient with occult muscle
disease.
AB - We report a patient with occult muscle disease who presented with raised serum
aminotransaminases. This case report emphasises the importance of considering
muscle disease in the differential diagnosis of raised serum aminotransaminases,
as it may negate the need for invasive investigations such as liver biopsy.
PMID- 10760025
TI - Diverticular rectal duplication with heterotopic gastric mucosa in a child: a
rare cause of rectal bleeding.
AB - This report describes a rare case of rectal bleeding and proctalgia in a child
due to diverticular duplication of rectum associated with heterotopic gastric
mucosa.
PMID- 10760026
TI - Infantile botulism: clinical and laboratory observations of a rare neuroparalytic
disease.
AB - A 3-month-old male infant was admitted to the University Hospital of Los Andes
with a history of constipation, weak crying, poor feeding, flaccidity and later
bilateral ptosis and hyporeflexia. The admission diagnosis was septicaemia until
an electrophysiological study reported postetanic facilitation with 50 Hz/seg
stimulations four days later. The Clostridium botulinum toxin type B was isolated
from the infant's stool samples and the organism grew in anaerobic cultures. The
patient recovered completely and was discharged 2 months later. Although infant
botulism is an uncommon disease in our environment, this diagnosis must be
suspected in all afebrile infants with constipation, affected cranial nerves and
generalized hypotonia. The principal differential diagnoses are Landry-Guillain
Barre syndrome, poliomyelitis, myasthenia gravis and infant muscular atrophy.
PMID- 10760027
TI - An evidence-based approach to paediatric training and practice: more questions
than answers.
PMID- 10760028
TI - The hepatic flaviviridae: summary.
AB - Hepatitis C envelope proteins (E1, E2) induce protective neutralizing antibodies.
The extent of sequence diversity reflects the host's ability to control viral
populations and the response to antiviral therapy. Attempts to prepare effective
vaccines against HCV are foiled by lack of prolonged protective immunity. Plasmid
vaccines and the use of uninfectious virus-like particles are being developed.
HCV induces a cellular humoral immune response, but this is inadequate to clear
the virus and the disease becomes chronic. In any patient, the natural history of
HCV infection depends on the age when infected, and the presence of other
diseases. The transfusion-related disease has a worse prognosis than that
transmitted by syringes and needles. The outlook in 'healthy blood donors' is
uncertain. Interferon therapy for 3 or preferably 6 months results in a sustained
response in about 30% of patients. Negative serum HCV RNA and normal AST values
after 3 months of therapy indicates that there may be a sustained response.
Whether or not to stop treatment at that time if HCV is still positive remains a
matter of debate. The role of interferon treatment in preventing progression to
cirrhosis and hepatocellular cancer is still uncertain. Ribavirin therapy alone
reduces transaminases and hepatic histology improves. Improved results follow the
combination of ribavirin with interferon. Ribavirin may have immuno-modularity
and anti-inflammatory actions. Hepatitis G virus (HGV) is unlikely to play a
significant role in liver disease in man.
PMID- 10760029
TI - Hepatitis viruses and the safety of blood donations.
AB - Since the beginning of blood transfusions concomitant transmission of viral
hepatitis has been a frequent and serious side-effect. A first measure to reduce
the frequency of transmission was the screening of blood donors for elevated
levels of liver enzymes in the blood, which was introduced in Germany in the
1960s, but not in most other countries. After the discovery of hepatitis B virus
(HBV), donors in all countries have been screened since the 1970s for its surface
antigen (HBsAg). When it was realized that there was at least one other type of
virus that was even more frequently transmitted, screening for liver enzymes and
HBV antibodies (anti-HBc) was introduced as a surrogate marker in most, but not
all, countries in the 1980s. Furthermore, donors at risk for parenterally
transmitted viruses were excluded. The discovery of the hepatitis C virus (HCV)
genome and the development of sensitive anti-HCV assays has meant that reliable
detection of persistently infected HCV carriers has been possible since 1991.
Recently infected donors, however, are infectious for several weeks or months
before anti-HCV is detectable. Therefore, starting in April 1999 all donations in
Germany have to be tested, by nucleic acid amplification tests, for the presence
of HCV RNA, although preliminary experience shows that such recent HCV infections
are very rare. Newly detected viruses, named GBV-C or HGV and TTV, have been
detected in patients with non-A-E post-transfusion hepatitis, but their
association with the disease seems to be coincidental. These viruses cause
persistent viraemia and are quite prevalent world-wide, but do not cause any
known disease. At present, transfusion-transmitted hepatitis has been virtually
eliminated, and any improvement in safety will be very small and will require
huge costs.
PMID- 10760030
TI - Visualization and characterization of GB virus-C particles: evidence for a
nucleocapsid.
AB - GB virus type C (GBV-C) is a member of the hepacivirus genus within the
Flaviviradae. Persistent GBV-C infection is common in humans, yet it remains
unclear if GBV-C causes any disease. Although GBV-C infection has been associated
with acute non-A to non-E post-transfusion hepatitis, it does not appear to cause
chronic hepatitis. GBV-C is closely related to hepatitis C virus (HCV), but
indirect evidence suggests that it does not encode a core protein at the amino
terminus of the open reading frame (ORF). This has led to speculation that GBV-C
does not have a nucleocapsid. We evaluated the buoyant density of GBV-C, and
found very low density particles consistent with virions, and intermediate
density particles consistent with nucleocapsids in GBV-C-infected people. In
addition, electron microscopy demonstrated an apparent nucleocapsid within an
enveloped particle. Although these biophysical data strongly suggest that GBV-C
utilizes a nucleocapsid, they do not indicate the origin of the protein content
of this particle. To assess this, we evaluated patient plasma for reactivity with
a synthetic oligopeptide representing a conserved region near the amino terminus
of the predicted ORF. Specific antibody was detected in some individuals, similar
to data of Feucht et al. who identified antibody against a recombinant core
protein in GBV-C-infected people. These data indicate that GBV-C particles
contain nucleocapsids. At least in some patients, the region upstream of the GBV
C E1 protein coding region appears to be expressed, and this region may represent
the structural protein of the nucleocapsid.
PMID- 10760031
TI - Mechanisms of hepatitis C virus NS3 proteinase inhibitors.
AB - The NS3 serine proteinase is regarded as one of the preferred targets for the
development of therapeutic agents against hepatitis C virus (HCV). Possible
mechanisms of NS3 inhibitors include: (i) interference with the activation of the
enzyme by its NS4A cofactor; (ii) binding to the structural zinc site; and (iii)
binding to the active site. These mechanisms have been explored in detail by
structural analysis of the enzyme. (i) The NS4A cofactor binds to the amino
terminal beta-barrel domain of the NS3 proteinase bringing about several
conformational changes that result in enzyme activation. The interaction between
NS3 and NS4A involves a very large surface area and therefore it is not a likely
target for the development of inhibitors. (ii) The NS3 proteinase contains a
structural zinc binding site. Spectroscopic studies have shown that changes in
the conformation of this metal-binding site correlate with changes in the
specific activity of the enzyme, and the NS3 proteinase is inhibited by compounds
capable of extracting zinc from its native coordination sphere. (iii) Based on
the observation that the NS3 proteinase undergoes inhibition by its cleavage
products, potent, active site-directed inhibitors have been generated. Kinetic
studies, site-directed mutagenesis, and molecular modelling have been used to
characterize the interactions between the NS3 proteinase and its product
inhibitors.
PMID- 10760032
TI - Cellular immune response to the hepatitis C virus.
AB - Hepatitis C virus (HCV) infection is most often clinically inapparent and rarely
associated with symptoms of acute hepatitis. Most patients, however, fail to
resolve the acute infection and proceed to develop chronic hepatitis with the
risk of liver cirrhosis and hepatocellular carcinoma later in life. Since the
kinetics of the earliest events of virus-host interaction are likely to determine
the outcome of infection, research has focused on the characterization of the
strength and kinetics of the antiviral immune response in different stages of
disease. The identification of the immunological correlates of viral clearance is
pivotal for the development of vaccines and efficient therapies.
PMID- 10760033
TI - Role of the specific T-cell response for clearance and control of hepatitis C
virus.
AB - T cells are believed to be the main players in antiviral defence. To investigate
the role of the specific CD4+ T cell response for clearance and control of the
hepatitis C virus we studied patients with acute hepatitis C (AHC) during the
phase of spontaneous viral clearance and during follow up after elimination of
the virus and resolution of disease. Symptomatic AHC has a self-limited course in
50% of patients, whereas the other half show virus persistence and develop
chronic course of disease. Patients who were able to mount a vigorous,
polyclonal, multispecific, TH1 lymphokine dominated CD4+ T-cell response showed
viral clearance and a self-limited course of disease. In contrast, absence of
this T-cell response in patients with AHC invariably led to viral persistence and
chronic hepatitis. The characteristics of the T-cell response were as follows: it
was mainly directed against nonstructural proteins of the virus, it was
multispecific and demonstrated immunodominant epitopes, and the majority of T
cell clones established from our patients responded to a single peptide (NS3
amino acid 1248-1261) within the helicase region of HCV. Presentation of the
peptide was HLA DR specific, the peptide showed promiscuous binding, and it had
high binding affinity to 10 of the most common 13 HLA DR alleles, thus patients
with diverse HLA DR backgrounds could mount an immune response. Furthermore, the
epitope was conserved in 100% of 33 HCV strains published in databases. This
strong initial CD4+ T-cell response is not sufficient for a definitive recovery
from AHC, it has to be maintained to control the hepatitis C virus. Loss of the
response after initial resolution of disease is followed by relapse. Even 20
years after an episode of self-limited AHC with elimination of HCV, we have
observed a significant virus-specific CD4+ T-cell response. Our data indicate the
decisive role of the virus-specific CD4+ T-cell response for clearance and
control of HCV, and contribute to our understanding of immune mechanisms by which
the host defends the HCV virus. This is a prerequisite for the development of new
strategies to efficiently defend the virus by manipulating or modulating the
immune response.
PMID- 10760034
TI - Evolution of the hypervariable region of hepatitis C virus.
AB - Despite being the most intensively studied part of the hepatitis C virus genome,
our understanding of the function of the hypervariable region (HVR) at the NH2
terminus of the E2 protein remains very limited. During chronic infection the HVR
usually changes over time, with changes usually mirrored by those of HVR-specific
antibodies. Evidence is presented suggesting that the HVR is subject to
constraint in its length, amino acid composition, and in the amino acid
replacements that are tolerated at different positions. These constraints, and
the pattern of HVR variation during chronic infection, suggest that it has an
important role in virus infection. A causal relationship between HVR variation
and persistence of HCV remains to be demonstrated.
PMID- 10760035
TI - Hepatitis C virus (HCV) NS5A protein: role in HCV replication and resistance to
interferon-alpha.
AB - The hepatitis C virus (HCV) non-structural (NS) 5A protein appears to play an
important regulatory role on viral replication and could also be involved in
viral pathogenesis. HCV resistance to interferon is a complex mechanism involving
multiple causes, among which certain NS5A functions could play a role.
PMID- 10760036
TI - Pathogenicity of GBV-C/HGV infection.
AB - Extensive studies of GBV-C/HGV in acute and chronic hepatitis non-A-non-E have
failed to provide hard evidence for a major role in this disease. Persistent GBV
C/HGV viraemia is in most cases associated with normal ALT levels, and only in a
minority of patients are mild elevations of aminotransferases found. Its disease
inducing capacity is questionable and the findings accumulated so far are best
explained by looking at GBV-C/HGV as a well-adapted, predominantly parenterally
transmitted, persistent virus; it might be transmitted concomitantly with
another, still unidentified hepatitis non-A-non-E virus. This does not exclude
the possibility that GBV-C/HGV might, in some rare cases and under certain
circumstances, induce a hepatitis-like illness as seen with other viruses such as
EBV or CMV. GBV-C/HGV definitely plays a minor role only, if any, in post
transfusion and community-acquired hepatitis non-A-non-E.
PMID- 10760037
TI - Interim analysis of a randomized controlled trial of combination of ribavirin and
high dose interferon-alpha in interferon nonresponders with chronic hepatitis C.
AB - This trial investigated the efficacy of a combination of high-dose interferon
alpha (IFN-alpha) with ribavirin in IFN nonresponders. STUDY PROTOCOL: 304
patients with chronic hepatitis C were treated with 5 MU IFN-alpha2b (IntronA(R),
Schering-Plough) per TIW for 3 months. Nonresponders (defined by HCV-RNA
positivity in serum after the 3 months of therapy) were randomized either to
continue with IFN (5 MU IFN per TIW followed by 10 MU per TIW for each 3 months)
alone (group A) or in combination with ribavirin (1-1.2 g per day) (group B). ALT
was measured in monthly intervals, HCV-RNA in 3 monthly intervals. Pretreatment
characteristics of the randomized patients were as follows: group A, n = 76; m/f,
54/22; 16% cirrhosis, age, 45. 7 +/- 12 years; ALT (U per litre), 66 +/- 35;
group B, n = 81; m/f, 57/24; 17% cirrhosis, age, 48.2 +/- 12; ALT, 71 +/- 40.
After 9 months of treatment, nine (11.6%) and 27 (32.5%, P = 0.0066) patients
were HCV-RNA negative and 51 and 39 were HCV-RNA positive, in groups A and B,
respectively. There were 17 drop-outs in group A and 15 in group B. Six months
after treatment only two patients in group A (2.5%) and five (6%, P = 0.06) in
group B had normal ALT and no detectable HCV-RNA in serum. In addition to the
well-known side-effects of IFN the mean haemoglobin concentration dropped by 2 g
per litre in group B. These data indicate that a combination of high-dose IFN
with ribavirin is effective in inducing a short-lasting complete response in one
third of IFN nonresponders. Prolonged treatment with IFN/ribavirin may be
necessary to obtain a sustained response.
PMID- 10760038
TI - Recurrent hepatitis C after liver transplantation: clinical and therapeutical
issues.
AB - Hepatitis C virus (HCV) reinfection after liver transplantation is almost
constant, assessed by the persistence of HCV RNA in 90% of cases. Acute hepatitis
appeared in 75% of patients at a median of 4 months' post-transplantation. The 5
year actuarial rate of acute and chronic hepatitis on the graft is 75% and 60%,
respectively. The rate of HCV cirrhosis on the graft is variable from 8 to 25% at
5 years. After transplantation, HCV viraemia is dramatically increased and
correlates with the occurrence of acute hepatitis on the graft. Intrahepatic
levels of HCV are high at the time of acute hepatitis, and decrease with
constitution of chronic graft hepatitis lesions, implying an immunological
response to the viral infection. A relationship between genotype 1b and the
prevalence of HCV hepatitis on the graft has been suggested in European but not
American series. The influence of the age of the recipient, quasispecies, viral
compartmentalization, immunosuppressive treatment, and of HLA matching is being
evaluated. The 5-year patient survival is around 65-80%. However, the occurrence
of cirrhosis with a risk of graft failure may decrease the 10 and 15-year patient
survival. Attempts to give prophylactic post-transplant antiviral treatment are
under evaluation. Antiviral treatment of post-transplant graft lesions with
combination therapy interferon-ribavirin gave promising results but indications
and duration of treatment should be evaluated. In conclusion, HCV reinfection is
frequent, but medium-term survival is good. However, the long-term graft and
patient survival remains unknown, and efficient prevention and treatment of HCV
graft is mandatory.
PMID- 10760039
TI - Intrafamilial transmission of hepatitis C virus: a systematic review.
AB - To examine the risk of hepatitis C virus (HCV) transmission between patients
infected with HCV and their household members (siblings, offspring and parents),
as well as their stable heterosexual partners, a systematic search of the MEDLINE
database was undertaken for all relevant articles published up to June 1997.
English language publications or those supplemented with an English abstract that
reported studies concerning hepatitis C, and household, intrafamilial, sexual and
intraspousal transmission of HCV, were reviewed. Data from uncontrolled and
controlled studies were collected and analysed separately. Studies reporting the
exclusive use of first-generation anti-HCV antibodies without supplemental tests
were excluded. Pre- or postnatal mother-to-child transmission of HCV and
homosexual and heterosexual transmission of HCV among non-permanent couples were
not included. Unweighted data from individual studies were pooled for each
category of family member. Data were also analysed separately for Japanese and
non-Japanese studies because there is evidence that intrafamilial transmission
may differ, based on endemicity of the viral infection. Comparisons were drawn
only from controlled studies that reported the prevalence of HCV in family
members of both HCV-positive and HCV-negative controls. Pooled odds ratios (OR)
and 95% confidence intervals (CI) were calculated for each family category. In
uncontrolled studies, the pooled prevalence of anti-HCV among 4250 stable sexual
contacts of patients with HCV-related chronic liver disease (CLD) was 13.48%,
while the pooled prevalence of anti-HCV among 580 stable sexual contacts of
patients who contracted HCV as a result of multiple transfusions was 2.41%. In
controlled studies, the pooled prevalence of anti-HCV among 175 siblings and
household contacts of patients with CLD was 4.0% compared with 0% among 109
contacts of anti-HCV-negative controls (OR 9.75, 95% CI 0.91 ad infinitum). The
pooled prevalence of anti-HCV among offspring of Japanese HCV-infected CLD
patients was 17% compared with 10.4% among offspring of HCV-negative Japanese
controls (OR 1.77, 95% CI 1.21-2. 58, P=0.002). The pooled prevalence of anti-HCV
among spouses of non-Japanese HCV-infected CLD patients was 15.2% compared with
0.9% in the spouses of non-Japanese HCV-negative controls (OR 20.57, 95% CI 6.05
84.08, P=0.0001). The prevalence of anti-HCV among non-Japanese offspring and
Japanese spouses of HCV-infected patients was not increased compared with
controls. HCV genotype homology and mutant analysis studies in pairs of HCV
infected patients and their HCV-infected contacts showed that concordant genotype
homology was found in 66% of non-sexual contacts and in 74% of sexual contacts.
Sequence homology of greater than 92% was found in 19 out of 35 pairs. Hence,
evidence exists that familial, non-sexual and sexual transmission of HCV does
occur. In Japanese patients, transmission probably occurs in younger family
members while, in non-Japanese patients, transmission probably occurs at an older
age, after contact with an HCV-infected spouse.
PMID- 10760040
TI - Influence of the administration of human annexin V on in vitro binding of small
hepatitis B surface antigen to human and to rat hepatocytes and on in vitro
hepatitis B virus infection.
AB - Previously, we have determined that human annexin V (hAV), a Ca2+-dependent
phospholipid-binding protein, and not rat AV, binds specifically to small
hepatitis B surface antigen (SHBsAg), and that transfection of a rat hepatoma
cell line with a construct containing the hAV gene led to hAV expression and
conferred susceptibility to hepatitis B virus (HBV) infection. In this work, we
have examined the effect of administration of hAV on in vitro binding of SHBsAg
to human and to rat hepatocytes and on in vitro HBV infection. The results showed
that hAV could bind to human as well as to rat hepatocytes. Because of this
property, excess hAV was unable to prevent HBV infection in primary cultures of
human hepatocytes. On the other hand, it enabled rat hepatocytes to specifically
bind SHBsAg and conferred susceptibility to HBV infection. After infection of
primary cultures of rat hepatocytes in the presence of hAV, HBV mRNA, covalently
closed circular (ccc) DNA, replicative intermediates, hepatitis B surface antigen
(HBsAg), hepatitis B core antigen (HBcAg) and secreted HBV DNA were detected.
After infection in the absence of hAV, no markers of HBV replication were
detected. Hence, from the present study we conclude that hAV is involved in
facilitating HBV entry, leading to successful HBV infection in primary cultures
of rat hepatocytes, while it is not effective in preventing HBV infection in
primary cultures of human hepatocytes.
PMID- 10760041
TI - Frequent integration of precore/core mutants of hepatitis B virus in human
hepatocellular carcinoma tissues.
AB - The development of hepatitis B virus (HBV)-associated hepatocellular carcinoma
(HCC) frequently follows persistent HBV infection and may arise in individuals
who are hepatitis B e antigen (HBeAg) negative, indicating the possible presence
of precore/core mutants. It is unclear whether precore/core mutants are
associated with tumour development or are selected for after chromosomal
integration of the wild-type viral DNA. We studied the status and sequence
variation of the precore/core region of HBV in 56 patients with HBV-associated
HCC and in various corresponding non-tumour tissues by Southern blot analysis,
polymerase chain reaction and direct sequencing. Southern blot showed that
integrated HBV DNA existed in 43 of 56 HCC tissues. Sequence analysis revealed
mutations in 65% of the HCC (26/40) and 45% (14/31) of the corresponding non
tumour tissues. The mutation at nucleotide (nt) 1896, known to prevent HBeAg
synthesis, was detected in 40% (16/40) of the tumours and in 35.4% (11/31) of the
non-tumour tissues. Other mutations were found at nt 1899 (eight of 40 in HCC;
three of 31 in non-tumour tissues), nt 1898 (seven of 40 in HCC; two of 31 in non
tumour tissues), nt 1912 (seven of 40 in HCC; none of 31 in non-tumour tissues)
and nt 1886 (three of 40 in HCC; none of 31 in non-tumour tissues). To determine
whether this finding merely reflected the prevalence of such mutants in this
geographical region, HBV DNA from the sera of patients (also in this region) with
acute and chronic hepatitis were sequenced. The nt 1896 mutant was found in 5.6%
(one of 18) of patients with acute hepatitis B and in 22.8% (nine of 35) of
patients with chronic hepatitis B. However, the nt 1898 mutation was not found in
any of these sera. The precore/core mutant was observed with increasing frequency
from acute hepatitis to chronic hepatitis, non-tumour and HCC, and this
difference in frequency was significant between HCC and acute hepatitis B groups
(P < 0.01), suggesting that the precore/core mutant or hepatocytes harbouring
this mutant may be under immune selection and that such mutations may facilitate
integration and subsequent tumour development.
PMID- 10760042
TI - Hepatitis C virus genotypes in a non-cirrhotic Italian population with chronic
hepatitis C: correlation with clinical, virological and histological parameters.
Results of a prospective multicentre study.
AB - To identify correlations between the distribution of hepatitis C virus (HCV)
genotypes and demographic, pathological and virological parameters of HCV
infected patients, we prospectively recruited 650 patients with biopsy-proven
chronic hepatitis C without histological aspects of cirrhosis; none had been
treated with antiviral therapy. Data regarding gender, age, mode of HCV
transmission, alanine aminotransferase (ALT) and HCV RNA levels, immunoglobulin M
(IgM) anticore values, liver histology and histological activity were obtained
from each patient and correlated on multivariate analysis with infecting HCV
genotype. Fifty-five per cent of the patients were infected with HCV genotype 1,
20% with HCV genotype 2, 18% with HCV genotype 3 and 7% with HCV genotype 4. Non
transfusional HCV transmission, low ALT levels, IgM anticore reactivity and a low
histological grading score were independent variables associated with HCV
genotype 1. Older age, female gender, post-transfusional transmission and a high
histological grading score were related to HCV genotype 2, whilst younger age,
history of current/previous drug abuse, high ALT values, low IgM anticore
reactivity and high viraemic levels were associated with HCV genotype 3. History
of illicit use of intravenous drugs and low HCV RNA levels were the only
independent variables correlated with HCV genotype 4. Genotype 1 remains
predominant in Italy but the prevalence of HCV genotypes is changing in relation
to age and mode of transmission: Italian patients with HCV genotype 3 are younger
and exhibit higher levels of ALT and HCV RNA than patients with other genotypes.
PMID- 10760043
TI - Impact of hepatitis C virus infection on healthy subjects on an Italian island.
AB - Field studies in large numbers of subjects unselected for risk factors are needed
to assess the true prevalence and health burden of hepatitis C virus (HCV)
infection. We assessed the prevalence, virological characteristics, risk factors
and evidence of liver disease in a population of healthy subjects from an urban
area of Sardinia. Hepatitis B virus (HBV) markers were also studied. The
prevalence of antibodies to HCV (anti-HCV) (recombinant immunoblot assay [RIBA]
confirmed positive results) was 3.19% in 3324 workers and 7.11% in 225 elderly
subjects, with a cumulative anti-HCV prevalence of 2.70% (95% CI 2.17-3.24).
Males were more frequently positive than females (P < 0.01). The age-specific
prevalence of HCV infection increased progressively in females. It showed two
peaks in males: one in the fourth decade, the other in the seventh decade. HCV
RNA was detected in 63.16% of the RIBA-positive sera, in 10% of the RIBA
indeterminates and in none of the RIBA-negative specimens. Only 1.75% of anti-HCV
positive subjects had elevated transaminases. The frequency of HCV genotype 1b
was 32.79%; of 1a, 21.31%; of 3a, 19.67%; of 4, 13.11%; and of 2a, 13.11%. HBV
markers were found in 28.03% of workers. On multivariate analysis, male gender
and tattooing were significantly associated with HCV and HBV infections:
transfusion and travel with HCV, and age over 40 with HBV. The age prevalence
rates of HCV infection in the Cagliari area reflect different risk factors that
have been operative at different times. In this urban area, the large majority of
HCV infections run a subclinical course.
PMID- 10760044
TI - Prevalence and risk factors for the presence of serum cryoglobulins in patients
with chronic hepatitis C.
AB - To assess the prevalence and risk factors for cryoglobulinaemia associated with
hepatitis C virus (HCV) infection, we studied 360 consecutive patients with
chronic hepatitis C (191 men, median age 57 years; 86 [24%] with cirrhosis). One
hundred and sixty-eight (47%) had circulating cryoglobulins (mean levels 208 +/-
256 mg l-1), predominantly of type III (80%; and 20% type II). Cryoglobulins were
more common in women than in men (56% vs 39%, P=0.001) and in patients with
cirrhosis than in those with chronic hepatitis (57% vs 43%, P=0.024).
Cryoglobulinaemic patients more frequently had high levels of serum
immunoglobulin M (IgM) (57% vs 30%, P=0.001), immunoglobulin G (IgG) (84% vs 70%,
P=0.002) and rheumatoid factor (45% vs 16%, P=0.001); low levels of serum C3 (15%
vs 4%, P=0.001) and C4 (51% vs 26%, P=0.001); and low numbers of platelets (21%
vs 12%, P=0.018), than patients without cryoglobulins. The presence of
cryoglobulins was not correlated with hepatitis duration (cryopositives, 12 +/- 7
years; cryonegatives, 11 +/- 8 years) or HCV genotype (HCV 1b, 48% vs 53%; HCV
2a, 35% vs 29%, cryopositive vs cryonegative patients respectively). By
multivariate analysis, female gender (odds ratio [OR] 1.675; confidence interval
[CI] 1. 055-2.661), elevated serum IgM (OR 2.296; CI 1.438-3.665), IgG (OR 1.
952; CI 1.114-3.422), rheumatoid factor (OR 3.213; CI 1.889-5.465) and low C4 (OR
1.859; CI 1.138-3.038) could reliably predict the presence of cryoglobulins. When
the pathogenic variables IgG, rheumatoid factor and C4 were excluded from
analyses, only levels of serum cholinesterase activity < 4500 U independently
predicted (OR 3. 663, CI 1.258-10.184) the presence of cryoglobulins. Fifty per
cent of the patients with chronic hepatitis C circulated cryoglobulins, with
preference for those with a greater impairment of liver function, as revealed by
serum cholinesterase activity.
PMID- 10760045
TI - Statistical models for predicting response to interferon-alpha and spontaneous
seroconversion in children with chronic hepatitis B.
AB - To develop prognostic models for identifying children with hepatitis B who are
likely to respond to interferon-alpha (IFN-alpha) or to spontaneously
seroconvert, we evaluated results of a multinational controlled trial comprising
70 children with chronic hepatitis B who received IFN-alpha and 74 children who
did not receive therapy. Prognostic models were developed using SMILES
(similarity of least squares), which is a data analysis network that incorporates
multidimensional relationships in the clinical data of complex diseases. Commonly
collected clinical data included age, gender, serum aminotransferase (aspartate
aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus
(HBV) DNA levels, and IFN-alpha dose. Additional data included pretreatment
directional information (e.g. increases or decreases in serum aminotransferase
and HBV DNA levels), liver biopsy results, race and transmission mode. Using data
available prior to initiation of treatment, the SMILES models achieved
prospective predictions of 89% for responders, 96% for non-responders, 100% for
seroconverters and 93% for non-seroconverters. Although not predictive by
themselves, the variables that had the greatest impact on predictions for IFN
alpha response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-alpha
dose and gender. The variables that had the greatest impact on predictions for
spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA
level, age and AST pretreatment direction. Therefore, these models may be useful
in determining, in children with hepatitis B, the likelihood of response to IFN
alpha and spontaneous seroconversion.
PMID- 10760046
TI - Hepatitis C virus mixed genotype infection in patients on haemodialysis.
AB - Hepatitis C virus (HCV) has been classified into different genotypes/subtypes
with demonstrated clinical implications. Whether there is biological difference
between genotypes is unknown. We determined HCV genotype in 120 anti-HCV-positive
patients with end-stage renal disease and on haemodialysis, by both serological
assay (which showed evidence of previous exposure) and by two molecular assays:
restriction fragment length polymorphism (RFLP) and line-probe reverse
hybridization (LiPA). In mixing experiments, RFLP and LiPA was able to detect the
minor HCV genotypes (if present) in 5-30% and 1-2% of the viral population,
respectively. Of the 120 patients studied, genotype-specific antibodies were
detected in 50 (42%), and eight patients had reactivities to peptides derived
from multiple genotypes (genotypes 1 and 2 and/or 3). Only genotype 1 infection
was found by RFLP/LiPA in these eight patients with reactivities to multiple HCV
genotypes. One-hundred and five of the 120 (88%) patients were positive for HCV
RNA by reverse transcription-polymerase chain reaction (RT-PCR) analysis and 14
were found to have mixed genotype infection. Follow-up serum samples (4-21 months
later) were available in five patients (genotype 1a with another
genotype/subtype). All five patients had a reduced number of HCV genotypes
detected during follow-up; four of the five patients still had detectable
genotype 1a, and one patient lost genotype 1a and was positive for genotype 2b
only. These data showed that HCV mixed infection can be reliably detected by
molecular methods and, in patients with end-stage renal disease and mixed
genotype infection, there is a trend that during follow-up, HCV genotype 1 may
prevail, or 'take over' the genotype 2 and 3 infection.
PMID- 10760048
TI - Introduction
PMID- 10760047
TI - Inhibition of the replication of the DNA polymerase M550V mutation variant of
human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and
lobucavir.
AB - Several nucleoside analogues (penciclovir, lobucavir, dioxalane guanine [DXG], 1
beta-2,6-diaminopurine dioxalane [DAPD], L-FMAU, lamivudine) and acyclic
nucleoside phosphonate analogues (adefovir, tenofovir) that are in clinical use,
in clinical trials or under preclinical development for the treatment of
hepatitis B virus (HBV) infections, were evaluated for their inhibitory effect on
the replication of a la- mivudine-resistant HBV variant containing the methionine
--> valine substitution (M550V) in the polymerase nucleoside-binding domain. The
antiviral activity was determined in the tetracycline-responsive HepAD38 and
HepAD79 cells, which are stably transfected with either a cDNA copy of the wild
type pregenomic RNA or with cDNA containing the M550V mutation. As expected,
lamivudine was much less ( approximately 200-fold) effective at inhibiting
replication of the M550V mutant virus than the wild-type virus. In contrast,
adefovir, tenofovir, lobucavir, L-FMAU, DXG and DAPD proved almost equally
effective against both viruses. A second objective of this study was to directly
compare the antiviral potency of the anti-HBV agents in HepG2 2.2.15 cells (which
are routinely used for anti-HBV drug-screening purposes) with that in HepAD38
cells. HepAD38 cells produce much larger quantities of HBV than HepG2 2.2.15
cells, and thus allow drug screening in a multiwell plate format. All compounds
were found to be almost equally effective at inhibiting HBV replication in
HepAD38 cells (as in HepG2 2.2.15 cells), except for penciclovir, which was
clearly less effective in HepAD38 cells.
PMID- 10760049
TI - Role of molecular chaperones in subnuclear trafficking of glucocorticoid
receptors.
AB - The delivery of activated steroid receptors to high-affinity genomic sites must
be efficient enough to account for the rapidity and selectivity of many
transcriptional responses to steroid hormones. Thus, the signal transduction
capacity of steroid hormone receptors will be influenced by the efficiency of
receptor trafficking both between different subcellular compartments (that is,
the cytoplasm and nucleus) and within a specific compartment (that is, the
nucleus). Molecular chaperones, such as heat shock proteins, have long been
recognized to play important roles in the management of protein folding in both
stressed and nonstressed cells. In recent years, the participation of these
proteins in various signal transduction pathways (for example, steroid hormone
responses) has also been recognized. In this review, recent results that
implicate a role for distinct heat shock proteins in subnuclear trafficking of
glucocorticoid receptors are discussed. These studies also highlight the
importance of mobilizing the cellular chaperone machinery for managing steroid
receptor folding within the nucleus.
PMID- 10760050
TI - Mechanistic aspects of mineralocorticoid receptor activation.
AB - Aldosterone exerts its biological effects through binding to mineralocorticoid
receptor (MR). Ligand binding induces a receptor transconformation within the
ligand-binding domain and dissociation of associated proteins from the receptor.
The ligand-activated receptor binds as a dimer to the response elements present
in the promoter region of target genes and initiates the transcription through
specific interactions with the transcription machinery. The glucocorticoid
hormone cortisol binds to the human MR (hMR) with the same affinity as
aldosterone, but is less efficient than aldosterone in stimulating the hMR
transactivation. The antimineralocorticoid spirolactones also bind to the hMR but
induce a receptor conformation that is transcriptionally silent. In this report,
we describe the key residues involved in the recognition of agonist and
antagonist ligands and propose a two-step model with a dynamic dimension for the
MR activation. In its unliganded state, MR is in an opened conformation in which
folding into the ligand-binding competent state requires both the heat shock
protein 90 and the C-terminal part of the receptor. An intermediate complex is
generated by ligand binding, leading to a more compact receptor conformation.
This transient complex is then converted to a transcriptionally active
conformation in which stability depends on the steroid-receptor contacts.
PMID- 10760051
TI - Specificity in mineralocorticoid versus glucocorticoid action.
AB - The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) share
considerable structural and functional homology. Overlapping effects on
epithelial sodium transport are observed in vivo; in vitro, both are able to bind
and transactivate through a common hormone response element. This has led several
investigators to suggest that specificity is conferred primarily by prereceptor
mechanisms, and we have addressed this question using both in vitro and in vivo
approaches. Although the MR has been regarded as less transcriptionally active
than the GR in vitro, significant differences are observed when epithelial rather
than fibroblast cell lines are used. These differences are mediated by the N
termini of the receptors. Activation of intracellular signaling pathways
differentially modulates MR- versus GR-mediated transactivation. Although these
studies identify mechanisms by which specificity may be achieved, they do not
prove that this occurs in vivo. Such studies have been limited by an absence of
MR-regulated genes. Known candidate aldosterone-responsive genes have been
examined in the rat distal colon; the time course and the specificity of the
response to a single parenteral dose of corticosteroid has been characterized.
The epithelial sodium channel beta and gamma subunit genes are both up-regulated
within 60 minutes by either MR or GR activation. Similar responses are observed
for the serum and glucocorticoid-regulated kinase and channel-inducing factor
genes. All four genes show clear and rapid up-regulation of their mRNA levels by
aldosterone, which is paralleled by GR-mediated up-regulation of expression.
While they are indeed aldosterone-responsive genes, genes that are uniquely
aldosterone-regulated remain to be identified.
PMID- 10760052
TI - BAG-1M: a potential specificity determinant of corticosteroid receptor action.
AB - BAG-1M is a eukaryotic cochaperone that associates with several proteins,
including the glucocorticoid receptor (GR). It down-regulates GR-mediated
transactivation by a mechanism that requires its prior recruitment by the
liganded receptor from cytoplasm into the nucleus. In the nucleus, it uses a
repeated sequence motif ([EEX4]8) at its NH2 terminus to inhibit DNA binding, as
well as transactivation functions of the receptor. The mineralocorticoid receptor
(MR), a structural and functional homologue of the GR, is unable to translocate
BAG-1M into the nucleus, and its transactivation function is also not affected by
this protein. This differential regulation of GR and MR activity could be
relevant in classic mineralocorticoid tissues such as the kidney in which GR
activity needs to be repressed to allow the MR to exert its action. In in situ
hybridization studies, we show that BAG-1M is expressed in the kidney. Its
expression pattern, especially in the developing kidney, correlated well with
that of the GR. We therefore postulate that BAG-1M may be a specificity
determinant in GR and MR action, and may feature prominently in the control of GR
activity in kidney development.
PMID- 10760053
TI - Regulation of the epithelial Na+ channel by aldosterone: open questions and
emerging answers.
AB - Aldosterone is the principal adrenal steroid controlling Na+ retention in
amphibians and mammalians. It acts primarily by increasing the apical Na+
permeability through activation of the epithelial Na+ channel (ENaC). The
cellular events mediating the hormonal action are mostly unknown. Early studies
have provided evidence that the hormone functions to activate or translocate pre
existing channels by a yet undefined mechanism. In addition, enhanced de novo
channel synthesis appears to take place as well. The molecular cloning of the
three ENaC subunits has provided new powerful tools for testing and confirming
this hypothesis, as well as for characterizing mechanisms by which ENaC is
regulated. Another important development is the recent identification of several
cDNAs corresponding to aldosterone-induced and suppressed mRNAs. The study of
these genes and their putative interactions with ENaC is likely to provide
important clues to the mechanisms by which aldosterone controls the apical Na+
permeability of tight epithelia. This article reviews recent developments in the
field that may lead to the elucidation of the mechanisms by which the hormone
controls Na+ transport.
PMID- 10760054
TI - Pleiotropic action of aldosterone in epithelia mediated by transcription and post
transcription mechanisms.
AB - The aldosterone-induced increase in sodium reabsorption across tight epithelia
can be divided schematically into two functional phases: an early regulatory
phase starting after a lag period of 20 to 60 minutes, during which the pre
existing transport machinery is activated, and a late phase (>2.5 h), which can
be viewed as an anabolic action leading to a further
amplification/differentiation of the Na+ transport machinery. At the
transcriptional level, both early and late responses are initiated during the lag
period, but the functional impact of newly synthesized regulatory proteins is
faster than that of the structural ones. K-Ras2 and SGK were identified as the
first early aldosterone-induced regulatory proteins in A6 epithelia. Their mRNAs
also were shown to be regulated in vivo by aldosterone, and their expression
(constitutively active K-Ras2 and wild-type SGK) was shown to increase the
function of ENaC coexpressed in Xenopus oocytes. Recently, aldosterone was also
shown to act on transcription factors in A6 epithelia: It down-regulates the
mRNAs of the proliferation-promoting c-Myc, c-Jun, and c-Fos by a post
transcriptional mechanism, whereas it up-regulates that of Fra-2 (c-Fos
antagonist) at the transcriptional level. Together, these new data illustrate the
complexity of the regulatory network controlled by aldosterone and support the
view that its early action is mediated by the induction of key regulatory
proteins such as K-Ras2 and SGK. These early induced proteins are sites of
convergence for different regulatory inputs, and thus, their aldosterone
regulated expression level tunes the impact of other regulatory cascades on
sodium transport. This suggests mechanisms for the escape from aldosterone
action.
PMID- 10760055
TI - Role of SGK in mineralocorticoid-regulated sodium transport.
AB - Mineralocorticoids stimulate electrogenic Na+ transport in tight epithelia by
altering the transcription of specific genes. Although the earliest
mineralocorticoid effect is to increase the activity of the epithelial sodium
channel (ENaC), ENaC mRNA and protein levels do not change. Instead, physiologic
observations suggest that a mineralocorticoid target gene(s) encodes an ENaC
regulator(s). To begin to identify and characterize mineralocorticoid-regulated
target genes, we used suppression-subtractive hybridization to generate a cDNA
library from A6 cells, a stable cell line of Xenopus laevis of distal nephron
origin. A serine-threonine kinase, SGK, was identified from this screen. Sequence
comparison revealed that frog, rat, and human SGK are 92% identical and 96%
similar at the amino acid level. SGK mRNA was confirmed by Northern blot to be
strongly and rapidly corticosteroid stimulated in A6 cells. In situ hybridization
revealed that SGK was strongly stimulated by aldosterone in rat collecting duct
but not proximal tubule cells. Low levels of SGK were present in rat glomeruli,
but SGK was unregulated in this structure. Finally, SGK stimulated ENaC activity
approximately sevenfold when coexpressed in Xenopus laevis oocytes. These data
suggest that SGK is an important mediator of aldosterone effects on Na+ transport
in tight epithelia. In view of the existence of SGK homologues in invertebrates,
it is interesting to speculate that SGK is an ancient kinase that was adapted to
the control of epithelial Na+ transport by early vertebrates as they made the
transition from a marine to a freshwater environment.
PMID- 10760056
TI - The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates
the epithelial sodium channel.
AB - The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates
the epithelial sodium channel. Aldosterone increases sodium reabsorption in tight
epithelia. The early phase of this stimulatory effect is thought to involve
activation of apical sodium channels. To identify immediate-early genes that
initiate this effect, we used a combination of polymerase chain reaction-based
subtractive hybridization and differential display techniques. This review
summarizes our recent findings. Aldosterone rapidly increases mRNA levels of a
putative Ser/Thr kinase, sgk (or serum- and glucocorticoid-regulated kinase), in
the native mineralocorticoid target cells, that is, in cortical collecting duct
(CCD) cells. The induction of sgk mRNA occurs within 30 minutes of the addition
of aldosterone and does not require de novo protein synthesis, indicating that
sgk is an immediate/early aldosterone-induced gene. Induction of sgk by
aldosterone is mediated through mineralocorticoid receptors (MRs), since it is
prevented by ZK91857, an MR antagonist, but not by RU486, a glucocorticoid
antagonist. In addition to aldosterone, RU28362, a pure glucocorticoid receptor
agonist, also induced sgk mRNA, both in primary cultures of rabbit CCD cells and
in the M-1 mouse CCD cell line. Sgk mRNA levels are also influenced by changes in
the osmolality of the medium. In M-1 cells, incubation of cells for one hour in a
mildly hypotonic medium decreased sgk mRNA levels, whereas incubation in
hypertonic medium brought about opposite changes. To determine whether sgk is
involved in the regulation of the epithelial sodium channel (ENaC), we
coexpressed the full-length sgk cRNA in Xenopus oocytes with the three ENaC
subunits. Expression of sgk resulted in a significant increase in the amiloride
sensitive Na current, suggesting that this protein kinase plays an important role
in the early phase of aldosterone-stimulated Na transport. These results indicate
that sgk is an aldosterone-induced immediate/early gene in native MR target
cells, and is involved in the regulation of ion transport and possibly cell
volume.
PMID- 10760057
TI - Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism.
AB - The mineralocorticoid receptor (MR) binds aldosterone and glucocorticoids with
equal affinity. In aldosterone target tissues, like the epithelial cells of the
distal colon and the principal cells of the collecting ducts in the kidney, the
MR is protected from glucocorticoids by the action of the enzyme 11beta
hydroxysteroid-dehydrogenase type 2 (11betaOHSD2), allowing aldosterone to
specifically activate the receptor. However, in MR-expressing cells, which lack
11betaOHSD2, like the neurons of the limbic system in the brain, MR is mainly
activated by glucocorticoids. MR knockout mice die in the second week after
birth, showing at day 8 symptoms of pseudohypoaldosteronism with hyponatremia,
hyperkalemia, high renal salt wasting, and a strongly activated renin-angiotensin
aldosterone system (RAAS). The activity of the amiloride-sensitive epithelial Na+
channel (ENaC) is strongly reduced in colon and kidney, but there is no down
regulation of the mRNA abundance of the three ENaC subunits. Daily subcutaneous
injections of isotonic NaCl solution until weaning and continued oral NaCl supply
lead to survival of the MR knockout mice. The NaCl-rescued MR knockout mice
display a strongly enhanced fractional renal excretion of Na+, hyperkalemia, and
a persistently strongly activated RAAS. There is almost no renal ENaC activity.
The renal mRNA abundance of alphaENaC is reduced by 30%, whereas betaENaC and
gammaENaC are not altered.
PMID- 10760058
TI - Transgenic mouse models to study human mineralocorticoid receptor function in
vivo.
AB - The mineralocorticoid receptor (MR) is a transcription factor that mediates
aldosterone action. MR is expressed in a wide variety of tissues, most notably in
sodium-transporting epithelia, but also in nonepithelial cells of the
cardiovascular and central nervous systems. However, molecular mechanisms
underlying mineralocorticoid signaling and the primary mineralocorticoid
regulated genes are not fully identified. We recently showed that the human MR
(hMR) gene possesses two first 5'-untranslated exons 1alpha and 1beta, and
demonstrated that the 5'-flanking regions of these exons, named P1 and P2,
respectively, are functional promoters that differ by their basal and
corticosteroid-regulated transcriptional activities. To gain insight into the
tissue-specific expression and function of MR, we have established transgenic
mouse models using both targeted oncogenesis and receptor overexpression
strategies. P1 and P2 promoters were used to direct expression of the large T
antigen (TAg) of SV40 in constitutively MR-expressing cells. P1.TAg mice
developed lethal hibernomas, while P2.TAg animals died from cerebral
neuroectodermal tumors and leiomyosarcomas. Quantification of TAg messenger RNA
levels revealed that P1 and P2 were differentially utilized. P1 promoter was
transcriptionally active in all MR-expressing tissues and importantly directed an
appropriate transgene expression in the distal nephron. Conversely, P2 activity
was weak and spatially restricted. Several immortalized cell lines were
established, thus constituting valuable models to investigate on aldosterone
regulated proteins. We also used P1 and P2 to target overexpression of hMR cDNA
in mice. Phenotypic characterization of these mice is currently under
investigation. Some transgenic lines should represent useful systems to further
explore multiple functions of MR in vivo.
PMID- 10760059
TI - Expression of the 11beta-hydroxysteroid dehydrogenase 2 gene in the mouse.
AB - Aldosterone acts via mineralocorticoid receptors (MRs) to control salt and water
flux in epithelial organs such as the kidney and colon to maintain circulatory
homeostasis. Inappropriate glucocorticoid-mediated activation of MRs in
aldosterone-target tissues is prevented by the glucocorticoid-metabolizing enzyme
11beta-hydroxysteroid dehydrogenase type 2 (HSD2). We have studied HSD2
expression in the mouse at the level of gene transcription and further analyzed,
with HSD1, its pattern of tissue-restricted gene expression. The mouse HSD2 gene,
including upstream regulatory regions, has been cloned, and its transcription
start site has been mapped in colon and kidney. A 2.5 kb upstream region has been
sequenced, and its proximal promoter region has been analyzed. We have compared
the relative expression of HSD1 and HSD2 in a variety of tissues from male mice
using ribonuclease protection analysis. HSD1 was expressed in liver, kidney,
adrenal, lung, spleen, thymus, fat, small intestine, stomach, heart, skin, and
epididymis. HSD2 was expressed in kidney, colon, small intestine, stomach, and
epididymus. No expression of either HSD1 and HSD2 was detected in bladder,
testis, seminal vesicles, vas deferens, prostate, or skeletal muscle. Finally, to
investigate the specific roles of HSD2 in vivo, we have created "floxed" HSD2
alleles using gene targeting in mouse embryonic stem cells with the aim to create
tissue-specific ablation of HSD2 in mice via Cre recombinase mediated gene
targeting.
PMID- 10760060
TI - Dysfunction of epithelial sodium transport: from human to mouse.
AB - The highly amiloride-sensitive epithelial sodium channel (ENaC) is an apical
membrane constituent of cells of many salt-absorbing epithelia. In the kidney,
the functional relevance of ENaC expression has been well established. ENaC
mediates the aldosterone-dependent sodium reabsorption in the distal nephron and
is involved in the regulation of blood pressure. Mutations in genes encoding ENaC
subunits are causative for two human inherited diseases: Liddle's syndrome, a
severe form of hypertension associated with ENaC hyperfunction, and
pseudohypoaldosteronism (PHA-1), a salt-wasting syndrome caused by decreased ENaC
function. Transgenic mouse technologies provide a useful tool to study the role
of ENaC in vivo. Different mouse lines have been established in which each of the
ENaC subunits was affected. The phenotypes observed in these mice demonstrated
that each subunit is essential for survival and for regulation of sodium
transport in kidney and colon. Moreover, the alpha subunit plays a specific role
in the control of fluid absorption in the airways at birth. Such mice can now be
used to study the role of ENaC in various organs and can serve as models to
understand the pathophysiology of these human diseases.
PMID- 10760061
TI - Physiologic resistance to the action of aldosterone.
AB - The collecting duct is one of the major targets for aldosterone's action.
Experiments conducted several years ago suggested that the major site of action
on Na+ and K+ transport was the cortical portion, the cortical collecting duct
(CCD). Subsequent studies have shown that the entire collecting duct is capable
of responding to aldosterone, but does so differently according to the region.
The inner medullary collecting duct (IMCD), while exhibiting a relatively low
rate of Na+ transport in isolated, perfused tubules, can develop substantial
rates of Na+ transport when put in primary culture. The IMCD, in contrast to the
CCD, usually secretes little K+. Investigations into the mechanisms for the lower
rates of Na+ transport have revealed that transforming growth factor-beta (TGF
beta), which is endogenously produced in the inner medulla, can markedly reduce
the natriferric action of aldosterone. This action of TGF-beta is not apparent
within the first few hours of exposure, but its effects, even after removal, last
for over 48 hours. The mechanism of this antagonism appears to involve pathways
that are parallel and independent of the major transcriptional effects of
aldosterone.
PMID- 10760062
TI - Aldosterone and potassium secretion by the cortical collecting duct.
AB - BACKGROUND: : Aldosterone has been implicated in the regulation of both Na and K
concentrations in the plasma. Release of the hormone is known to be stimulated by
high plasma K, and infusion of aldosterone lowers plasma K. However, the
correlation between changes in mineralocorticoid levels and rates of K secretion
is not perfect, suggesting that other factors may be involved. METHODS: : Patch
clamp recordings were made of K-channel activity in the split-open cortical
collecting tubule of the rat. Estimates of channel density were made in cell
attached patches on the luminal membrane of principal cells of this segment.
RESULTS: : Most of the K conductance of the apical membrane is mediated through
low-conductance "SK" channels. The number of conducting SK channels is increased
when animals are placed on a high-K diet. However, increasing plasma aldosterone
levels by infusion of the hormone or by sodium restriction failed to change the
number of active channels. CONCLUSIONS: : At least two circulating factors are
required for the regulation of renal K secretion by the cortical collecting
tubule. Aldosterone mainly stimulates secretion by increasing the driving force
for K movement through apical channels. A second, as yet unidentified, factor
increases the number of conducting K channels.
PMID- 10760063
TI - Brain mineralocorticoid receptors and centrally regulated functions.
AB - Mineralocorticoid receptors (MRs) expressed in limbic neurons, notably of
hippocampus, retain both aldosterone and corticosterone. Basal concentrations of
corticosterone already substantially occupy the limbic MR type, suggesting that
in hippocampal neurons, MR activity rather than ligand bioavailability is rate
limiting. The periventricular region expresses MRs involved in the control of
salt homeostasis, which are aldosterone selective because of the presence of
11beta-hydroxysteroid dehydrogenase. MR is in hippocampal CA1, CA2, and dentate
gyrus colocalized with glucocorticoid receptors (GRs). Both receptor types
mediate in a coordinate manner the corticosterone action on information
processing critical for behavioral adaptation and associated neuroendocrine
responses to stress. MRs operate in proactive mode determining the sensitivity of
the stress response system, while GRs facilitate recovery from stress in reactive
mode. On the neuronal level, MR-mediated action maintains a stable excitatory
tone and attenuates the influence of modulatory signals. In contrast, GR-mediated
effects suppress excitability transiently raised by excitatory stimuli. MR is
also involved in control of autonomic outflow and volume regulation. This was
demonstrated by the effect of an MR antagonist, which was administered centrally,
because mdr P-glycoproteins hamper the access of synthetic steroids to the brain.
The MR antagonist attenuates pressor responses to a stressor, such as experienced
during tail sphygmography. Diuresis and urinary electrolyte excretion are
increased after the MR antagonist, but this effect is abolished after bilateral
denervation of the kidney. It is presently unknown in which brain cells the MR
mediated effects on these aspects of central cardiovascular regulation occur.
PMID- 10760065
TI - Cardiac aldosterone production and ventricular remodeling.
AB - An intracardiac production of aldosterone has been recently reported in rat. This
production is increased both acutely and chronically by angiotensin II,
observations suggesting that the heart contains a steroidogenic system that is
regulated similarly to the adrenal one. Cardiac production of aldosterone is
small compared with that of the adrenal, raising the question of its function in
normal conditions. Moreover, the regulation of this synthesis in pathophysiologic
states remains unknown. In an analysis of the effects of a one-month myocardial
infarction (MI) on the cardiac steroidogenic system, it was observed that
aldosterone-synthase mRNA and the aldosterone concentration were increased by 2-
and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle.
MI also induced a 1. 9-fold increase in the cardiac angiotensin II level.
Losartan prevented these changes, and the MI-induced collagen deposition in
noninfarcted area of the left ventricle was reduced by 1.6- and 2. 5-fold by both
spironolactone and losartan treatments, respectively. Thus, these observations
indicate that MI is associated with tissue-specific activation of myocardial
aldosterone synthesis. This activation is mediated by cardiac angiotensin II via
the angiotensin II type 1 (AT1) receptor, and the resultant increase of
intracardiac aldosterone level may be involved in post-MI ventricular remodeling.
PMID- 10760064
TI - The amygdala: site of genomic and nongenomic arousal of aldosterone-induced
sodium intake.
AB - BACKGROUND.: Mineralocorticoids act on the brain to influence sodium intake, and
they do so via intracellular type I receptors and possibly also via a direct
membrane action, as they do in the kidney. One brain area implicated by lesion
studies investigating the regulation of sodium appetite aroused by adrenal
steroids is the amygdala. METHODS: To examine the mechanism by which
mineralocorticoids act in the amygdala to arouse salt intake via a genomic and or
membrane mode of action, rats were bilaterally fitted with cannulae directed to
terminate in the amygdala. The genomic action of mineralocorticoids in arousing
sodium intake was investigated by the administration of antisense
oligodeoxynucleotides (ASDNs) against the mineralocorticoid receptor, and its
effects on deoxycorticosterone (DOCA)-induced sodium intake over the course of
several days was examined. The nongenomic action of mineralocorticoids on sodium
intake was investigated by implantation into the amygdala of DOCA, aldosterone
(ALDO), or their A-ring-reduced tetrahydro derivatives, 15 minutes prior to
access to saline. Sodium intake was monitored immediately thereafter. RESULTS:
Treatment of rats in the amygdala with ASDN against the mineralocorticoid
receptor inhibited DOCA-induced sodium intake, whereas ASDN against the
glucocorticoid receptor or sense/scrambled sequences had no effect. DOCA and ALDO
increased saline intake within 15 minutes after steroid application. Similarly,
the application of A-ring-reduced 3beta,5beta tetrahydroaldosterone and 5 alpha
tetrahydrodeoxycorticosterone produced the same increases in sodium intake.
CONCLUSIONS: Together, the data imply that adrenal steroids, in addition to
acting through classic cytosolic receptors, may also act on membrane receptor
systems, producing rapid changes in behavior.
PMID- 10760066
TI - 11beta-hydroxysteroid dehydrogenase in human vascular cells.
AB - Aldosterone selectivity in mineralocorticoid target tissues is mainly due to
11beta-hydroxysteroid dehydrogenase (11betaHSD), which converts cortisol to its
inactive metabolite cortisone in humans. The defect of dehydrogenase activity
would thus allow type 1 mineralocorticoid receptor (MR) to be occupied mostly by
cortisol. It has been postulated that 11betaHSD type 2 (11betaHSD2) plays a
significant role in conferring ligand specificity on the MR. We have demonstrated
the diminished dehydrogenase activity in resistance vessels of genetically
hypertensive rats. However, the mechanism that could link impaired vascular
11betaHSD activity and elevated blood pressure has been unclear. In this study,
we showed the enzyme activity in human coronary artery smooth muscle cells.
Glucocorticoids and mineralocorticoids increase vascular tone by up-regulating
the receptors of pressor hormones such as angiotensin II (Ang II). Next, we found
that physiological concentrations of a cortisol-induced increase in Ang II
binding were significantly enhanced by the inhibition of dehydrogenase activity
with an antisense DNA complementary to 11betaHSD2 mRNA, and the enhancement was
partially but significantly abolished by a selective aldosterone receptor
antagonist. This may indicate that impaired dehydrogenase activity in vascular
wall results in increased vascular tone by the contribution of cortisol, which
acts as a mineralocorticoid. In congenital 11betaHSD deficiency and after the
administration of 11betaHSD inhibitors, suppression of dehydrogenase activity in
the kidney has been believed to cause renal mineralocorticoid excess, resulting
in sodium retention and hypertension. These results show that vascular 11betaHSD
activity could influence blood pressure without invoking renal sodium retention.
PMID- 10760067
TI - Aldosterone and mineralocorticoid receptors: orphan questions.
AB - Classically, mineralocorticoid receptors (MR) are activated by aldosterone to
promote unidirectional transepithelial sodium transport. Activation of MR in
nonepithelial tissues has been shown to elevate blood pressure (central nervous
system; CNS) and to cause hypertrophy and fibrosis (heart). For both epithelial
and nonepithelial tissues, there remain a variety of questions regarding MR which
are not only unanswered but also essentially not addressed. Seven such questions
include: (1) how the physiologic glucocorticoids (cortisol and corticosterone)
can mimic aldosterone action in epithelial MR, but act as antagonists in the
heart and AV3V region; (2) how salt facilitates the nonepithelial,
pathophysiologic effects of aldosterone; (3) how aldosterone activates
unprotected AV3V MR in the face of orders of magnitude higher circulating
glucocorticoid concentrations; (4) how unprotected nonepithelial MR act as
"always occupied" receptors in guinea pigs and other species; (5) how, when
11beta hydroxysteroid dehydrogenase type 2 is active, epithelial MR occupied by
physiologic glucocorticoids appear transcriptionally inactive; (6) how
aldosterone activates epithelial MR in the face of approximately 103-fold higher
glucocorticoid levels, plasma binding and 11beta hydroxysteroid dehydrogenase
type 2 activity notwithstanding; and (7) how aldosterone produces changes in
urinary [K+] before [Na+].
PMID- 10760068
TI - Mineralocorticoid selectivity: molecular and cellular aspects.
AB - Aldosterone acts in mineralocorticoid-sensitive cells by binding to the
mineralocorticoid receptor (MR). Because the MR displays similar affinity for
aldosterone and glucocorticoid hormones and because these latter hormones are 100
to 1000-fold more abundant than aldosterone in the plasma, mechanisms are
required to avoid permanent illicit occupancy of MR by glucocorticoid hormones.
The main mechanism of mineralocorticoid selectivity is enzymatic: the 11beta
hydroxysteroid dehydrogenase (HSD2) metabolizes glucocorticoid hormones into
derivatives with a low affinity for MR. The cell biology and regulation of HSD2
are reviewed in this article, as well as its implications in human hypertension.
Other factors play a role in mineralocorticoid selectivity: the MR itself, the
possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid
receptor). All of these cellular events participate to successive dynamic
equilibriums, which allow fine tuning of transcriptional regulation of target
genes, depending on the target tissue and the hormonal status.
PMID- 10760069
TI - Interactions of mineralocorticoids and glucocorticoids in epithelial target
tissues.
AB - BACKGROUND: : In Na+-transporting epithelial target tissues, such as mammalian
kidney and the isolated toad bladder, glucocorticoids (GCs) do not normally
elicit Na+ retention. In mammalian kidney, however, they do cause kaliuresis. The
presence of 11beta-hydroxysteroid dehydrogenase isoform 2 (11beta-HSD2) in these
target tissues inactivates the GCs, preventing them from accessing
mineralocorticoid receptors (MRs) and stimulating Na+ transport. RESULTS: : The
usually observed Na+ retention elicited by the mineralocorticoid aldosterone was
blunted when the GC corticosterone was coadministered along with aldosterone.
However, when corticosterone was administered along with a 11beta-HSD2 inhibitor,
a strong Na+ transport was elicited by an MR-mediated mechanism. 11
Dehydrocorticosterone also blunted aldosterone-elicited Na+ transport in these
target tissues. CONCLUSIONS: : 11beta-HSD2 appears to play two important roles in
the epithelial target tissues, kidney and toad bladder. The first is to protect
GC access to MR, and the second involves the product of the enzyme to regulate
the magnitude of aldosterone-induced Na+ retention.
PMID- 10760070
TI - Role of the 11beta-hydroxysteroid dehydrogenase type 2 in blood pressure
regulation.
AB - The renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme
inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective
mineralocorticoid receptor (MR) from occupation by glucocorticoids. The gene is
highly expressed in all sodium-transporting epithelia, but also in human
placenta, pancreas, and thyroid. Mutations in the HSD11B2 gene cause a rare
monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess
(AME). In AME, compromised 11betaHSD2 enzyme activity results in overstimulation
of the MR by cortisol, causing sodium retention, hypokalemia, and salt-dependent
hypertension. Recent evidence suggests a role of the 11betaHSD2 in essential
hypertension. We found hypertension with no other characteristic signs of AME in
the heterozygous father of a child with AME and in a girl with a homozygous gene
mutation resulting in a mild deficiency of 11betaHSD2. Moreover, some studies in
patients with essential hypertension showed a prolonged half-life of cortisol and
an increased ratio of urinary cortisol to cortisone metabolites, suggesting a
deficient 11betaHSD2 activity. These abnormalities may be genetically determined.
A genetic association of a microsatellite flanking the HSD11B2 gene and
hypertension in black patients with end-stage renal disease has been reported. We
recently analyzed a CA-repeat allele polymorphism in unselected patients with
essential hypertension, but did not find any correlation between this marker and
blood pressure. However, we did find an association between this polymorphic CA
microsatellite marker and salt sensitivity. Moreover, the activity of the
11betaHSD2, as shown by elevated mean ratios of urinary cortisol to cortisone
metabolites, was decreased in salt-sensitive compared with salt-resistant
subjects. These findings indicate that variants of the HSD11B2 gene contribute to
the enhanced blood pressure response to salt in humans.
PMID- 10760071
TI - Nongenomic effects of steroids on the nicotinic acetylcholine receptor.
AB - A fast signaling mode of natural and synthetic steroids is exerted on some ion
channels and cell-surface receptors. This activity contrasts with their classic
mode of action, via intracellular receptors. Early studies from our laboratory
demonstrated that spin-labeled androstanol and cholestane interact with the
nicotinic acetylcholine receptor (AChR) and that lipid mobility at the lipid belt
surrounding the AChR is reduced relative to that of the bulk membrane lipid. The
occurrence of discrete and independent sites for phospholipids and sterols, both
accessible to fatty acids, was subsequently disclosed in the native membrane.
Synthetic and natural glucocorticoids were found to act as noncompetitive
inhibitors of AChR function. The influence of different substituent groups in the
cyclepentane perhydrophenanthrene ring on the channel-shortening potency of
various steroids has also been assayed in muscle-type AChR, and we found a
certain selectivity of this effect. Some organochlorine pesticides are
xenoestrogens, that is, environmental agents capable of disrupting endocrine
system signaling. We determined their effects on the AChR membrane using novel
fluorescence techniques.
PMID- 10760072
TI - Specific nongenomic actions of aldosterone.
AB - BACKGROUND: According to the traditional model, steroid hormones modulate gene
transcription and protein synthesis. The considerable latency of these genomic
steroid effects is the consequence of these time-consuming steps of action. Over
the years, it has become increasingly clear that rapid actions of steroids exist
that are incompatible with this "classic" genomic model of action. These rapid,
nongenomic effects, which recently have been shown for virtually all groups of
steroids, are likely to be transmitted by specific membrane receptors. METHODS: A
review of data mainly focusing on the nongenomic in vitro and in vivo effects of
aldosterone is presented. RESULTS: For rapid aldosterone effects, a prominent
example of a receptor/effector cascade for nongenomic steroid effects has been
described in various cell types. Nonclassic membrane receptors with a high
affinity for aldosterone, but not for cortisol, seem to be involved. As an
important second messenger, [Ca2+]i is consistently increased within minutes
after the addition of aldosterone. The effects are half maximal at physiological
concentrations of free aldosterone (approximately 0.1 nmol/L), while the classic
mineralocorticoid antagonist canrenone is ineffective in blocking the action of
aldosterone. In addition, cortisol is active only at supramicromolar
concentrations. Aldosterone rapidly acts on further cell signaling systems, for
example, phosphoinositide hydrolysis and cAMP generation. CONCLUSIONS: For a
better understanding of nongenomic aldosterone action even in a clinical context,
future research will have to target the cloning of the first membrane receptor
for aldosterone and the evaluation of the clinical relevance of rapid steroid
effects in general.
PMID- 10760073
TI - Nongenomic effects of aldosterone on Ca2+ in M-1 cortical collecting duct cells.
AB - BACKGROUND: Aldosterone at physiological levels induces rapid (<5 min) increases
in intracellular protein kinase C (PKC) activity and a rise in calcium and pH in
mineralocorticoid hormone target epithelia, such as distal colon and sweat gland.
The end targets of these rapid responses in epithelia are Na+/H+ exchange and K+
channels. METHODS: The mouse cortical collecting duct (CCD) M-1 cell line was
grown to confluency and loaded with Fura-2 for spectrofluorescence measurements
of intracellular free calcium at 37 degrees C bathed in Krebs solution. RESULTS:
Aldosterone (1 nmol/L) produced a rapid, transient peak increase in [Ca2+]i in M
1 cells. This effect was abolished upon removal of extracellular Ca2+, but was
unaffected by pretreatment with spironolactone (10 micromol/L) or actinomycin D
(10 micromol/L). However, pretreatment with the specific PKC inhibitor
chelerythrine chloride (1 micromol/L) prevented the aldosterone-induced rise in
[Ca2+]i. Dexamethasone, at a concentration 10,000-fold higher than aldosterone
(10 micromol/L), also produced a transient increase in [Ca2+]i, but this response
was significantly smaller than that of aldosterone. In contrast, hydrocortisone
had no effect on [Ca2+]i at either nmol/L or micromol/L concentrations. Both of
the sex steroids, 17beta-estradiol (10 nmol/L) and progesterone (10 nmol/L),
induced protein kinase C-dependent increases in [Ca2+]i. CONCLUSIONS: Aldosterone
and sex steroid hormones activate intracellular calcium signaling in CCD cells
via a nongenomic PKC-dependent pathway, which may have important implications for
renal transport.
PMID- 10760074
TI - Effects of gender and genotype on the phenotypic expression of nonmodulating
essential hypertension.
AB - Nonmodulation describes a subset of the normal/high renin essential hypertensive
population. It is an inherited trait. This report reviews the genetic and gender
data recently available that discuss the modification of the expression of the
nonmodulating phenotype. Both the adrenal and the renal blood flow markers for
nonmodulation are associated with a single nucleotide polymorphism (SNP) in the
coding region of the angiotensinogen gene at codon 235. Even though the
nonmodulating phenotype is associated with a somatic gene, gender modifies its
expression. In women, the expression of the nonmodulating phenotype is
approximately half of that in men. Additional analysis suggests that this gender
difference is almost entirely explained by a difference in the frequency of
nonmodulation in younger premenopausal women. In older, likely postmenopausal
women, there is no gender difference. This suggests that the expression of the
nonmodulating phenotype, presumably secondary to changes in the expression of the
angiotensinogen gene, is modulated by female sex hormones.
PMID- 10760075
TI - Mineralocorticoid receptor antagonists: the evolution of utility and
pharmacology.
AB - For more than 30 years after the discovery of aldosterone, scientists believed
that its sole site of action was at epithelial tissues, most notably the kidney,
where it mediated the transport of Na and K. It was soon recognized aldosterone
contributed to several diseases by causing edema. Armed with this information,
scientists set out more than 30 years ago to develop an antagonist of the
mineralocorticoid receptor for the treatment of edematous states. From this
effort, spironolactone (Aldactone was discovered. Spironolactone acts
functionally as a competitive inhibitor of the mineralocorticoid (aldosterone)
receptor, and although spironolactone is an effective mineralocorticoid receptor
antagonist, it is not without limitations. These limitations include unwanted
progestational and antiadrogenic side effects that limit its use in the chronic
treatment of disease. In addition to its actions at the collecting tubule,
aldosterone can participate in pathophysiology by actions at the heart,
vasculature, and kidney, and it is likely that the most significant contributions
to cardiovascular disease are due to actions at these sites rather than those
related to Na and water retention. This is underscored by the recent clinical
results from the RALES-004 Trial in which treatment with Aldactone demonstrated a
significant benefit on mortality in patients with severe heart failure. The
limited utility of spironolactone owing to the aforementioned steroid-related
side effects has been especially frustrating, given the newly recognized role of
aldosterone in cardiovascular disease. To obviate these limitations, eplerenone
is currently being developed by Searle. Eplerenone is a competitive antagonist of
the mineralocorticoid receptor that takes advantage of replacing the 17alpha
thoacetyl group of spironolactone with a carbomethoxy group, conferring excellent
selectivity for the mineralocorticoid receptor over other steroid receptors. The
pharmacological profile of eplerenone positions it to be an effective and
selective mineralocorticoid receptor antagonist.
PMID- 10760076
TI - Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming.
AB - Epidemiological studies in many distinct human populations have associated low
weight or thinness at birth with a substantially increased risk of cardiovascular
and metabolic disorders, including hypertension and insulin resistance/type 2
diabetes, in adult life. The concept of fetal "programming" has been advanced to
explain this phenomenon. Prenatal glucocorticoid therapy reduces birthweight, and
steroids are known to exert long-term organizational effects during specific
"windows" of development. Therefore, we hypothesized that fetal overexposure to
endogenous glucocorticoids might underpin the link between early life events and
later disease. In rats, birthweight is reduced following prenatal exposure to the
synthetic glucocorticoid dexamethasone, which readily crosses the placenta, or to
carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta
HSD2), the physiological feto-placental "barrier" to endogenous glucocorticoids.
Although the offspring regain the weight deficit by weaning, as adults they
exhibit permanent hypertension, hyperglycemia, and increased hypothalamic
pituitary-adrenal axis activity. Moreover, physiological variations in placental
11beta-HSD2 activity near term correlate directly with fetal weight. In humans,
11beta-HSD2 gene mutations produce a low birthweight, and some studies show
reduced placental 11beta-HSD2 activity in association with intrauterine growth
retardation. Moreover, low birthweight babies have higher plasma cortisol levels
throughout adult life, indicating that hypothalamic-pituitary-adrenal axis
programming also occurs in humans. The molecular mechanisms of glucocorticoid
programming are beginning to be unraveled and involve permanent and tissue
specific changes in the expression of key genes, notably of the glucocorticoid
receptor itself. Thus, glucocorticoid programming may explain, in part, the
association between fetal events and subsequent disorders in adult life.
PMID- 10760077
TI - Therapy of heart failure.
AB - The incidence and prevalence of heart failure is on the rise. It has become the
single most expensive health care item in the United States and the number one
discharge diagnosis in the elderly. The goals of therapy include both prevention
and treatment of heart failure. In recent years research studies and randomized
clinical trials have revolutionized the understanding of the pathophysiology and
treatment of this disease. This article focuses on the medical management of
chronic systolic heart failure based on the pathophysiology of the disease.
Systolic heart failure is characterized by a decrease in left ventricular
function and cardiac output, which results in activation of several neurohormonal
compensatory systems. The long term effects of this neurohormonal activation
leads to further deterioration of cardiac function. The use of hydralazine and
nitrates to reduce the systemic vascular resistance was the first to show an
improvement in mortality and morbidity. Then angiotensin converting enzyme
inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater
improvement in mortality and morbidity. More recently the inhibition of the
sympathetic stimulation with beta-blockers has been shown to have an additive
effect on morbidity and mortality in combination with angiotensin-converting
enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms
and decreasing hospitalizations but have not been shown to decrease mortality.
The most recent advance in the treatment of cardiac failure is the demonstration
that the aldosterone antagonists, spironolactone decreases morbidity and
mortality.
PMID- 10760078
TI - Hepatocyte growth factor in renal failure: promise and reality.
AB - Can science discover some secrets of Greek mythology? In the case of Prometheus,
we can now suppose that his amazing hepatic regeneration was caused by a peptide
growth factor called hepatocyte growth factor (HGF). Increasing evidence
indicates that HGF acts as a multifunctional cytokine on different cell types.
This review addresses the molecular mechanisms that are responsible for the
pleiotropic effects of HGF. HGF binds with high affinity to its specific tyrosine
kinase receptor c-met, thereby stimulating not only cell proliferation and
differentiation, but also cell migration and tumorigenesis. The three fundamental
principles of medicine-prevention, diagnosis, and therapy-may be benefited by the
rational use of HGF. In renal tubular cells, HGF induces mitogenic and
morphogenetic responses. In animal models of toxic or ischemic acute renal
failure, HGF acts in a renotropic and nephroprotective manner. HGF expression is
rapidly up-regulated in the remnant kidney of nephrectomized rats, inducing
compensatory growth. In a mouse model of chronic renal disease, HGF inhibits the
progression of tubulointerstitial fibrosis and kidney dysfunction. Increased HGF
mRNA transcripts were detected in mesenchymal and tubular epithelial cells of
rejecting kidney. In transplanted patients, elevated HGF levels may indicate
renal rejection. When HGF is considered as a therapeutic agent in human medicine,
for example, to stimulate kidney regeneration after acute injury, strategies need
to be developed to stimulate cell regeneration and differentiation without an
induction of tumorigenesis.
PMID- 10760079
TI - Association between high von willebrand factor levels and the Thr789Ala vWF gene
polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study
Group and the DESIR Study Group.
AB - BACKGROUND: A genetic susceptibility for diabetic kidney disease is suspected
since diabetic nephropathy occurs in only 30 to 40% of type I diabetic patients.
As elevated von Willebrand factor (vWF) plasma concentrations have been reported
to precede the development of microalbuminuria in type I diabetes, we addressed a
possible implication of vWF as a genetic determinant for diabetic nephropathy.
METHODS: Three known vWF gene polymorphisms were genotyped in a group of 493 type
I diabetic subjects, all showing proliferative retinopathy, but with various
stages of renal involvement, which ranged from no microalbuminuria, despite a
mean duration of diabetes of 31 years, to advanced nephropathy (GENEDIAB Study):
Thr789Ala (Rsa I), M-/M+ (Msp I) (intron 19), and Ala1381Thr (Hph I). Plasma vWF
and factor VIII (F VIII) levels were also measured in this population. RESULTS:
Plasma vWF and F VIII levels were increased in diabetic subjects with nephropathy
(P < 0.001) or with coronary heart disease (CHD; P < 0.001), but there was no
interaction of both conditions on plasma levels. The Msp I polymorphism (M-/M+)
was weakly associated with nephropathy (P = 0. 04), but this association was not
more significant when other risk factors were used in a logistic regression
analysis. The vWF Thr789Ala polymorphism was associated with CHD (P = 0.002) and
with plasma vWF levels. Logistic regression analysis indicated an independent and
codominant effect of the Thr789Ala polymorphism on CHD, but not on nephropathy,
with a maximal risk for Ala/Ala homozygotes (OR = 4.2, 95% CI, 1.8 to 9.9, P =
0.0008). CONCLUSION: It is unlikely that polymorphisms in the vWF gene contribute
to the risk for nephropathy in type I diabetic patients. However, the Thr789Ala
polymorphism might affect the risk for CHD in this population through modulation
of plasma vWF levels.
PMID- 10760080
TI - Location of mutations within the PKD2 gene influences clinical outcome.
AB - BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic
kidney disease type 2 (PKD2), approximately 40 different mutations of that gene
have been reported to be associated with the disease. The relationship between
the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed
clinical information was collected for PKD2 families in which the underlying
mutation had been identified. Logistic regression analysis was employed to assess
the influence of age and sex on hypertension, hematuria, renal calculi, and
urinary tract infections, and a clinical phenotype score was computed. Patients
were then grouped according to the relative location of their mutation within the
cDNA sequence, and differences in the mean phenotypic score between groups were
tested for statistical significance by means of a multiple pairwise t-test.
RESULTS: While phenotypic scores for each mutational group revealed a
considerable degree of intragroup variability, the variability in phenotypic
scores was significantly higher between mutational groups than within groups. A
group-wise comparison of the mean phenotypic scores confirmed the observation of
significant nonlinear variation in disease severity, with high- and low-scoring
mutational groups interspersed along the gene sequence. CONCLUSION: The
identification of groups of mutations in the PKD2 gene, which differ
significantly with respect to clinical outcome, is to our knowledge the first
description of a genotype/phenotype correlation in autosomal dominant polycystic
kidney disease. It also provides evidence against complete loss of function of
the mutant PKD2 gene product.
PMID- 10760081
TI - Comprehensive gene expression profile of the adult human renal cortex: analysis
by cDNA array hybridization.
AB - BACKGROUND: Profiling of gene expression in healthy and diseased renal tissue is
important for elucidating the pathogenesis of renal diseases. Comprehensive
information about the genes expressed in renal tissue is unavailable. The
recently developed cDNA array hybridization methodology allows simultaneous
monitoring of thousands of genes expressed renal tissue. METHODS: Complex [alpha
33P]-labeled cDNA probes were prepared from histopathologically uninvolved
remnants of nine renal tissues obtained by nephrectomy. Each probe was hybridized
to a high-density array of 18,326 paired target genes. The radioactive
hybridization signals by phosphorimager screens were quantitated by special
software. Bioinformatics from public genomic databases were used to assign a
chromosomal location of each expressed transcript and gene function. Cluster
analysis was used to arrange genes according to the similarity in pattern of gene
expression. RESULTS: A total of 7563 different gene transcripts was detected in
the nine tissue samples. Approximately 870 of these genes were full-length mRNA
human transcripts (HT), and the remaining 6693 were expressed sequence tags
(ESTs). The full-length transcripts were classified by function of the gene
product and were listed with information of their chromosomal positions. To allow
a comparison between gene expression in clinical and experimental studies, the
mouse genes with known similar function to the human counterpart were included in
the bioinformatics analysis. Cluster analysis of 502 full-length genes that are
expressed in four or more renal tissues revealed more than 110 genes that are
highly expressed in all the renal specimens. CONCLUSIONS: The presented data
constitute a comprehensive preliminary transcriptional map of the adult human
renal cortex. The information may serve as a resource for speeding up the
discovery of genes underlying human renal disease. The integrated listing of the
full-length expressed human and mouse genes is available through e-mail
(Abdalla_Rifai@Brown.edu).
PMID- 10760082
TI - cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by
activating the extracellular signal-regulated kinase pathway.
AB - BACKGROUND: : Cellular proliferation is a key factor in the enlargement of renal
cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the
extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in
vitro proliferation of cyst epithelial cells derived from human ADPKD cysts.
METHODS: : Epithelial cells from cysts of individuals with ADPKD and from normal
human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects
of agonists and inhibitors on the rate of cellular proliferation and the
activation of extracellular signal-regulated kinase (ERK1/2) were determined.
RESULTS: : 8-Br-cAMP (100 micromol/L) stimulated the proliferation of cells from
eight different ADPKD subjects to 99.0% above baseline; proliferation was
inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%).
Forskolin (10 micromol/L), which activates adenylyl cyclase, increased
proliferation 124%, and receptor-mediated agonists arginine vasopressin,
desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2
stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The
mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD
cell proliferation in response to cAMP agonists, but genistein, a receptor
tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP
agonists increased the activity of ERK above control levels within five minutes.
In contrast to ADPKD, proliferation and ERK activity of cells derived from normal
HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was
increased by these agonists in both ADPKD and HKC cell monolayers. CONCLUSIONS: :
We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC
epithelial cells through PKA activation of the ERK pathway at a locus distal to
receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway
may have a unique role in determining the rate of cyst enlargement in ADPKD
through its actions to stimulate cellular proliferation and transepithelial
solute and fluid secretion.
PMID- 10760083
TI - Very low-density lipoprotein stimulates the expression of monocyte
chemoattractant protein-1 in mesangial cells.
AB - BACKGROUND: Elevated plasma levels of very low-density lipoprotein (VLDL) are
associated with an increased risk for focal glomerulosclerosis, which is
analogous to atherosclerosis. One feature of focal glomerulosclerosis is the
presence of foam cells derived from the infiltration of circulating monocytes.
Mesangial cells are able to express monocyte chemoattractant protein-1 (MCP-1).
In this study, the ability of VLDL to stimulate MCP-1 expression in mesangial
cells and consequent monocyte adhesion was investigated. METHODS: For adhesion
studies, mesangial cells isolated from Sprague-Dawley rats were treated with VLDL
for six hours, followed by a one-hour incubation with Tamm-Horsfall protein-1
(THP-1) cells. Mesangial MCP-1 mRNA levels were determined by reverse
transcription-polymerase chain reaction. MCP-1 protein was determined by solid
phase immunoassay. RESULTS: VLDL (100 to 300 microg/mL) significantly enhanced
the expression and secretion of MCP-1 (54 to 285 ng/well) in mesangial cells.
Such an effect was accompanied by the increased adhesion of monocytes to
mesangial cells and later the formation of foam cells from monocytes after
ingesting excessive amounts of VLDL lipids. VLDL-induced MCP-1 expression and
monocyte adhesion were blocked by a protein kinase C inhibitor (staurosporine),
as well as a calcium channel blocker (diltiazem). CONCLUSIONS: Our results
demonstrate that elevated levels of VLDL, through the action of MCP-1, may
contribute to the infiltration of monocytes into the mesangium and subsequent
foam cell formation. Hence, VLDLs may play a role in the pathogenesis of focal
glomerulosclerosis. One of the mechanisms of such effect may be mediated through
the calcium-dependent protein kinase C pathway.
PMID- 10760084
TI - Intermittent administration of parathyroid hormone (1-37) improves growth and
bone mineral density in uremic rats.
AB - BACKGROUND: Parathyroid hormone (PTH) is secreted in a pulsatile fashion.
Continuous infusion of PTH(1-84) resulted in a net decrease in trabecular bone
volume. Differential effects have been reported following an intermittent
application of PTH. We investigated the effects of a continuous infusion and of
an intermittent (2 times daily subcutaneously) administration of PTH(1-37) on
growth and bone mineral density (BMD) in healthy and uremic rats. METHODS: Two
stage subtotal nephrectomy was performed on 130 g female Sprague-Dawley rats.
PTH(1-37) or solvent was administered through minipumps in sham-operated and
uremic rats (60 microg/kg x day for 2 weeks). The effect of intermittent
administration was tested with a subcutaneous injection of solvent: 30 microg/kg
PTH(1-37) two times per day, 100 pmol calcitriol (C)/kg two times per day, or
both. The length (snout-tailtip) and BMD were measured at the start of uremia and
at sacrifice. BMD was measured by peripheral quantitative computer tomography at
the proximal tibia, 6 and 12 mm distal of the kneejoint space. Femur bone
morphology was assessed by x-rays, and calcium content was measured by atomic
absorption spectrophotometry. RESULTS: Length gain was not altered by the
continuous infusion of PTH. In contrast, it was significantly increased by
intermittent PTH (control solvent 5.35 +/- 0.37 cm vs. control PTH 6.19 +/- 0.47
cm; uremia solvent 4.78 +/- 0.20 cm vs. uremia PTH 6.17 +/- 0.36 cm; P < 0.05).
Intermittent PTH but not C increased BMD in uremic rats (Delta total BMD 134 +
13.3 vs. 76.3 +/- 11.5 mg/mL; P < 0.05). X-rays revealed increased bone mass
following treatment with PTH but not with C. Uremia decreased bone calcium
content (64 +/- 0.3 vs. 73. 3 +/- 2.5 mg/mL), which was normalized by PTH (80 +/-
3.6 mg/mL, P < 0.05) but not by C (69 +/- 1.9 mg/mL). CONCLUSION: Pulsatile
administration of PTH does not adversely affect, but improves longitudinal growth
independent of concomitant treatment with C. At the same time PTH increases BMD
and the calcium content of bone.
PMID- 10760085
TI - Angiotensin II blockade and low-protein diet produce additive therapeutic effects
in experimental glomerulonephritis.
AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) overexpression plays a key
role in the accumulation of extracellular matrix in acute and chronic renal
diseases. Recent studies have suggested that the degree of reduction in
pathological TGF-beta overexpression can be used as a therapeutic index to
evaluate the antifibrotic potential of pharmacological angiotensin II (Ang II)
blockade in renal disease. Using this target, we found that treatment with the
angiotensin I-converting enzyme inhibitor enalapril or the Ang II type 1 receptor
antagonist losartan reduced TGF-beta overexpression more effectively at doses
clearly higher than those required to control blood pressure. However, both forms
of Ang II blockade were only partially effective in normalizing TGF-beta
expression. This study investigated whether a greater antifibrotic, TGF-beta
reducing benefit can be achieved when Ang II blockade is combined with dietary
protein restriction. METHODS: Mesangioproliferative glomerulonephritis was
induced in male Sprague-Dawley rats on a normal-protein diet. Treatment with a
low-protein diet and/or maximally effective doses of enalapril or losartan was
started one day after disease induction. On the fifth day, 24-hour urine protein
excretion was measured. On the sixth day, cortical kidney tissue was taken for
periodic acid-Schiff staining. Isolated glomeruli were used for mRNA extraction
or were placed in culture for determination of production of TGF-beta1, the
matrix protein fibronectin, and the protease inhibitor plasmin activator
inhibitor type 1 (PAI-1) by enzyme-linked immunosorbent assay. RESULTS: Compared
with untreated nephritic animals on a normal-protein diet, a single treatment
with enalapril, losartan, or low-protein diet significantly reduced glomerular
TGF-beta production, albeit to a similar degree of approximately 45%. A moderate,
but significant further reduction in pathological TGF-beta expression of a total
of 65% for enalapril and 60% for losartan was achieved when these drugs were
combined with low-protein feeding. This reduction in TGF-beta overexpression
paralleled decreased proteinuria, glomerular matrix accumulation, and
overproduction of fibronectin and PAI-1. CONCLUSIONS: Ang II blockade and low
protein diet have additive effects on disease reduction, suggesting that disease
progression in humans with chronic renal failure may be slowed more effectively
when Ang II blockade and low-protein diet are combined. Since maximal
pharmacological Ang II inhibition was used, it is likely that dietary protein
restriction further reduces pathological TGF-beta overexpression by mechanisms
different from those of enalapril or losartan.
PMID- 10760086
TI - Enhanced expression of vsmNOS mRNA in glomeruli from rats with unilateral
ureteral obstruction.
AB - BACKGROUND: The vasodilatory/cytotoxic gas, nitric oxide (NO), is associated with
an alteration in glomerular hemodynamics seen after the induction of ureteral
ligation. As yet the type of nitric oxide synthase (NOS) protein involved in the
mechanism has not been clearly established in the unilateral ureteral obstruction
(UUO) model. METHODS: Using reverse transcription (RT)-polymerase chain reaction
(PCR), the expression and localization of vascular smooth muscle-derived nitric
oxide synthase (vsmNOS) mRNA were examined in glomeruli from sham-operated
control (SOC) rats and rats with UUO of three hours duration. Moreover, the
effect of endogenous angiotensin II on the expression of vsmNOS mRNA in glomeruli
was explored using SOC rats and rats with UUO that were pretreated or not with
enalapril, an angiotensin-converting enzyme inhibitor. RESULTS: The expression of
vsmNOS mRNA was significantly greater in glomeruli of rats with UUO than in those
of SOC rats. In rats with UUO, the expression of vsmNOS mRNA was substantially
increased in glomeruli of the obstructed kidney (OK) compared to the
contralateral, nonobstructed kidney (CLK). Suppression of angiotensin II
production in vivo with enalapril restored the expression of vsmNOS mRNA in
glomeruli of the CLK and OK from rats with UUO to levels comparable to that seen
in glomeruli from SOC rats. In addition, the in situ RT-PCR analysis, a novel
method for mRNA identification in cells and tissue, revealed that vsmNOS mRNA was
expressed in the cytoplasm of glomerular mesangial and epithelial cells in SOC
rats and rats with UUO. CONCLUSIONS: An increase in vsmNOS mRNA expression in
glomeruli of the CLK and OK from rats with UUO may be mediated by increased
action of endogenous angiotensin II that occurs after the onset of ureteral
obstruction. Enhanced expression of vsmNOS mRNA in glomeruli of the OK compared
to the CLK may be due to differences in levels of angiotensin II acting on the
two kidneys in vivo. Additionally, the expression of vsmNOS mRNA in glomeruli
originates in mesangial and epithelial cells in SOC rats and rats with UUO.
PMID- 10760087
TI - Induction of experimental proteinuria in vivo following infusion of human plasma
hemopexin.
AB - BACKGROUND: The human plasma constituent hemopexin (Hx), following incubation
with renal tissue, is able to induce glomerular alterations in vitro that are
similar to those seen in minimal change disease (MCD). Whether this acute phase
reactant is also able to induce proteinuria and minimal change-like alterations
in vivo is questioned. METHODS: In the first set of experiments, Hx (4.0 mg in
5.0 mL saline) or equal amounts of control fraction, that is, heat-inactivated Hx
(HI-Hx), were infused into conscious rats (N = 6) that had been surgically
equipped with a cannula inserted into the suprarenal artery (SRA), enabling
direct contact of the infusate and the renal microvasculature. Each animal
received HI-Hx at day 1 for 15 minutes (flow rate 20.0 mL/h), subsequently
followed by saline for seven hours (Flow rate 5.0 mL/h), after which the cannula
was disconnected. At day 2, identical infusions in the same rat were carried out,
using native Hx. Urine samples collected every 30 minutes during the experiments
were monitored for protein content using standard methods. In the second set of
experiments, unilateral perfusion was done ex vivo in anesthetized rats with Hx
(N = 5) or HI-Hx (N = 3; 1.5 mg/mL; 4.0 mL during 6 min). After reconnection of
the circulation, urine samples of both kidneys were collected every 30 minutes
during five hours via ureter cannulation. Urinary protein (expressed as the
difference in excretion between perfused and nonperfused kidney) was calculated
in mg/24 h. In additional experiments, rats were sacrificed two hours after
perfusion of Hx or heat-inactivated (control) Hx (first set of experiments) or
after five hours (second set of experiments), and kidneys were processed for
immunohistochemical and ultrastructural examination. RESULTS: The results of
experiment 1 show a significant increase of proteinuria after Hx infusion versus
HI-Hx (means +/- SD, 41.91 +/- 16.01 mg/24 h vs. control, 21.22 +/- 5.69 mg/24 h;
P 10 mg/100 g) to high oxalate content due
to a faster analysis time and lower running costs, whereas IC may be better
suited for the analysis of foods with a low oxalate content. Accurate estimates
of the oxalate content of foods should permit the role of dietary oxalate in
urinary oxalate excretion and stone formation to be clarified. Other factors,
apart from the amount of oxalate ingested, appear to exert a major influence over
the amount of oxalate excreted in the urine.
PMID- 10760102
TI - Multistate outbreak of hemolysis in hemodialysis patients traced to faulty blood
tubing sets.
AB - BACKGROUND: Hemolysis associated with hemodialysis is rare. The most frequent
causes of hemodialysis-associated hemolysis are chemical contamination, heat, or
mechanical injury of erythrocytes from occluded or kinked hemodialysis blood
lines. When patients in three states developed hemolysis while undergoing
hemodialysis between May 13 and 23, 1998, an investigation was initiated.
METHODS: A case-patient was defined as any patient at healthcare facilities A
(Nebraska), B (Maryland), or C (Massachusetts) during May 13 through 23, 1998
(epidemic period), who had hemolysis diagnosed > or =48 hours after undergoing
hemodialysis. To identify case-patients and to determine background rates, the
medical records of patients from facilities A, B, and C who were undergoing
hemodialysis during the epidemic and pre-epidemic (that is, May 5 through 19,
1998) periods were reviewed. Experiments simulating hemodialysis with the same
lot numbers of hemodialysis blood tubing cartridge sets used on case- and control
patients were conducted. RESULTS: The rates of hemolysis among patients at
facilities A, B, and C were significantly higher during the epidemic than the pre
epidemic period (13 out of 118 vs. 0 out of 118, P < 0.001; 12 out of 298 vs. 0
out of 298, P = 0.001; and 5 out of 62 vs. 0/65, P = 0.03, respectively). All
case-patients had hemolysis. Twenty (66%) had hypertension. Eighteen (60%) had
abdominal pain, and 10 (36%) were admitted to an intensive care unit. There were
two deaths. The only commonality among the three outbreaks was the use of the
same lot of disposable hemodialysis blood tubing from one manufacturer.
Examination of the implicated hemodialysis blood tubing cartridge sets revealed
narrowing of an aperture through which blood was pumped before entering the
dialyzers. In vitro experiments with the hemodialysis blood tubing revealed that
hemolysis was caused by increased pressure on erythrocytes as they passed through
the partially occluded hemodialysis blood tubing. CONCLUSIONS: Our investigation
traced the multiple hemolysis outbreaks to partially occluded hemodialysis blood
tubing produced by a single manufacturer. On May 25, 1998, the manufacturer
issued a voluntary nationwide recall of the implicated lots of hemodialysis blood
tubing cartridge sets.
PMID- 10760103
TI - Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism.
AB - BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in
the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may
reduce the renal hemodynamic abnormalities following radiocontrast
administration. METHODS: One hundred fifty-eight patients with chronic renal
insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/-
92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive
either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All
patients received intravenous hydration with 0.45% saline before and after
radiocontrast administration. Serum creatinine concentrations were measured at
baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration.
The primary end point was the mean change in serum creatinine concentration from
baseline at 48 hours; the secondary end point was the incidence of radiocontrast
nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44
micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast
administration. RESULTS: The mean increase in serum creatinine 48 hours after
angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6
micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1
micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also
higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This
negative effect of SB 209670 was apparent in both diabetic and nondiabetic
patients. Adverse effects, especially hypotension or decreased blood pressure,
were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic
renal insufficiency who were undergoing cardiac angiography, endothelin receptor
antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast
nephrotoxicity compared with hydration alone.
PMID- 10760104
TI - Outcome and growth of infants with severe chronic renal failure.
AB - BACKGROUND: We aimed to assess the outcome and growth of infants with severe
chronic renal failure (CRF). One hundred and one children presented between
January 1, 1986, and December 12, 1998, with a glomerular filtration rate (GFR)
of <20 mL/min/1.73 m2. The median (range) age at presentation was 0.3 (0 to 1.5)
years, and follow-up was 7.6 (1.5 to 13) years. One- and five-year survival rates
were 87 and 78%, respectively. The growth of the 81 children who survived over
two years was evaluated. Eighty-one percent were enterally fed from age 0.7 (0 to
4.5) years for 1.9 (0.1 to 6.8) years. Forty-six percent had a gastrostomy, and
22% a Nissen fundoplication. Twenty-five were managed conservatively. Twenty were
transplanted without dialysis at age 4 (1.7 to 8.5) years, and 36 were dialyzed
at age 1.1 (0 to 9.8) before transplantation at age 2. 4 (1.3 to 10) years.
RESULTS: The mean (SD) height standard deviation score increased from -2.16
(1.34) at 6 months (N = 63) to -1.97 (1.37) at 1 year (N = 75), -1.79 (1.29) at 2
years (N = 75), -1.33 (1.29) at 3 years (N = 68, P = 0.0006), -1.27 (1.04) at 5
years (N = 47, P = 0.0001), and -0.85 (0.82) at 10 years (N = 18, P = 0.001). The
body mass index was in the normal range in the majority of patients. CONCLUSION:
Mortality in infants with CRF occurs mainly in the first year of life. With early
enteral feeding, the mean height standard deviation score is within the normal
range from one year of age.
PMID- 10760105
TI - Relationship between nutritional status and the glomerular filtration rate:
results from the MDRD study.
AB - BACKGROUND: The relationship between the protein-energy nutritional status and
renal function was assessed in 1785 clinically stable patients with moderate to
advanced chronic renal failure who were evaluated during the baseline phase of
the Modification of Diet in Renal Disease Study. Their mean +/- SD glomerular
filtration rate (GFR) was 39.8 +/- 21.1 mL/min/1.73 m2. METHODS: The GFR was
determined by 121I-iothalamate clearance and was correlated with dietary and
nutritional parameters estimated from diet records, biochemistry measurements,
and anthropometry. RESULTS: The following parameters correlated directly with the
GFR in both men and women: dietary protein intake estimated from the urea
nitrogen appearance, dietary protein and energy intake estimated from dietary
diaries, serum albumin, transferrin, percentage body fat, skinfold thickness, and
urine creatinine excretion. Serum total cholesterol, actual and relative body
weights, body mass index, and arm muscle area also correlated with the GFR in
men. The relationships generally persisted after statistically controlling for
reported efforts to restrict diets. Compared with patients with GFR > 37
mL/min/1.73 m2, the means of several nutritional parameters were significantly
lower for GFR between 21 and 37 mL/min/1.73 m2, and lower still for GFRs under 21
mL/min/1.73 m2. In multivariable regression analyses, the association of GFR with
several of the anthropometric and biochemical nutritional parameters was either
attenuated or eliminated completely after controlling for protein and energy
intakes, which were themselves strongly associated with many of the nutritional
parameters. On the other hand, few patients showed evidence for actual protein
energy malnutrition. CONCLUSIONS: These cross-sectional findings suggest that in
patients with chronic renal disease, dietary protein and energy intakes and serum
and anthropometric measures of protein-energy nutritional status progressively
decline as the GFR decreases. The reduced protein and energy intakes, as GFR
falls, may contribute to the decline in many of the nutritional measures.
PMID- 10760106
TI - Effect of peritonitis on peritoneal transport characteristics: glucose solution
versus polyglucose solution.
AB - BACKGROUND: Peritonitis is a common clinical problem and contributes to the high
rate of technique failure in continuous ambulatory peritoneal dialysis treatment.
The present study investigated the effect of peritonitis on peritoneal fluid and
solute transport characteristics using glucose and polyglucose (icodextrin)
solutions. METHODS: A four-hour dwell was performed in 32 Sprague-Dawley rats (8
rats in each group), with 131I albumin as an intraperitoneal volume marker.
Peritonitis was induced by an intraperitoneal injection of 2 mL
lipopolysaccharide (100 microg/mL phosphate-buffered saline) four hours before
the dwell. Each rat was intraperitoneally infused with 25 mL of 3.86% glucose
[glucose solution control group (Gcon) and glucose solution peritonitis group
(Gpts)] or 7.5% icodextrin solution [icodextrin solution control group (Pgcon)
and icodextrin peritonitis group (PGpts)]. RESULTS: Net ultrafiltration was
significantly lower (by 44%) in the Gpts as compared with the Gcon group, but was
significantly higher (by 138%) in the PGpts as compared with the PGcon group. The
peritoneal fluid absorption rate, including the direct lymphatic absorption rate,
was significantly increased (by 78%) in the Gpts group as compared with the Gcon
group. However, the total fluid absorption did not differ between the PGpts and
the PGcon groups. The dialysate osmolality decreased much faster in the Gpts
group as compared with the Gcon group, resulting in significantly lower (by 9%)
transcapillary ultrafiltration in the Gpts group. In contrast, the dialysate
osmolality increased faster in the PGpts group as compared with the PGcon group,
resulting in higher (by 40%) transcapillary ultrafiltration in the PGpts group.
The in vitro increase in dialysate osmolality was also higher in the PGpts group
as compared with the PGcon group. The solute diffusive transport rates were, in
general, increased in the two peritonitis groups as compared with their
respective control groups. CONCLUSIONS: Our results suggest the following: (1)
Peritonitis results in decreased net ultrafiltration using glucose solution
caused by (a) decreased transcapillary ultrafiltration and (b) increased
peritoneal fluid absorption. (2) Ultrafiltration induced by the icodextrin
solution appears to be related to the increase in dialysate osmolality (mainly
because of the degradation of icodextrin). (3) Peritonitis results in increased
degradation of icodextrin and a faster increase in dialysate osmolality and
therefore better ultrafiltration, whereas the fluid absorption rate does not
change. (4) Peritonitis results in increased peritoneal diffusive permeability.
PMID- 10760107
TI - Fat tissue accumulation during peritoneal dialysis is associated with a
polymorphism in uncoupling protein 2.
AB - BACKGROUND: Chronic treatment with peritoneal dialysis (PD) is a unique long-term
metabolic procedure entailing a continuous 24-hour supply of glucose absorbed
from the dialysis fluid. One common and important side effect of this treatment
is weight gain and accumulation of body fat stores. However, not all patients
accumulate body fat mass during PD, and the reason for this is not clear.
Recently, two new mitochondrial uncoupling proteins (UCP2 and UCP3) have been
found to have thermogenic properties that suggest involvement in the control of
metabolic efficiency in humans. Moreover, recent results suggest that a
polymorphism in the UCP2 gene may contribute to adipose tissue accumulation
through its effects on energy metabolism. It could therefore be speculated that
genetic differences in the metabolic rate might contribute to the differences in
the accumulation of fat tissue during PD. METHODS: Genotyping of a polymorphism
in the 3' untranslated region of exon 8 of UCP2 was performed in 41 patients (53
+/- 2 years) with chronic renal failure for whom we had prospective data on body
composition (as estimated by dual-energy x-ray absorptiometry) following PD. In
addition, indices of dialysis adequacy, peritoneal glucose absorption, and urea
kinetics were followed (3 to 6 times per year in each patient) during treatment
with PD. The degree of physical activity was assessed before the start of PD.
RESULTS: Twenty patients with the deletion/deletion UCP2 genotype had a
significant increase in body weight (3.0 +/- 0.8 vs. -1.0 +/- 1.1 kg, P < 0.01)
and body fat mass (3.8 +/- 0.9 vs. 0.8 +/- 1.0 kg, P < 0.05) during PD, compared
with 19 patients with an insertion/deletion UCP2 genotype. On the other hand, no
significant differences in indices of dialysis adequacy, peritoneal glucose
absorption, urea kinetic parameters, or degree of physical activity were observed
when comparing patients who accumulated or lost fat tissue during PD.
CONCLUSIONS: As most patients with the deletion/deletion UCP2 genotype acquired
fat tissue during PD, the present results suggest that the UCP2 polymorphism
contributes to variations in body composition. Thus, variations in UCP2
production or activity may be factors contributing to adipose tissue accumulation
in a subgroup of patients treated with PD. It is possible that the polymorphism
has a similar effect in the general population.
PMID- 10760108
TI - Comparative mortality of hemodialysis and peritoneal dialysis in Canada.
AB - BACKGROUND: Comparisons of mortality rates in patients on hemodialysis versus
those on peritoneal dialysis have been inconsistent. We hypothesized that
comorbidity has an important effect on differential survival in these two groups
of patients. METHODS: Eight hundred twenty-two consecutive patients at 11
Canadian institutions with irreversible renal failure had an extensive assessment
of comorbid illness collected prospectively, immediately prior to starting
dialysis therapy. The cohort was assembled between March 1993 and November 1994;
vital status was ascertained as of January 1, 1998. RESULTS: The mean follow-up
was 24 months. Thirty-four percent of patients at baseline, 50% at three months,
and 51% at six months used peritoneal dialysis. Values for a previously validated
comorbidity score were higher for patients on hemodialysis at baseline (4.0 vs.
3.1, P < 0.001), three months (3.7 vs. 3.2, P = 0.001), and six months (3.6 vs.
3.2, P = 0.005). The overall mortality was 41%. The unadjusted peritoneal
dialysis/hemodialysis mortality hazard ratios were 0.65 (95% CI, 0. 51 to 0.83, P
= 0.0005), 0.84 (95% CI, 0.66 to 1.06, P = NS), and 0. 83 (95% CI, 0.64 to 1.08,
P = NS) based on the modality of dialysis in use at baseline, three months, and
six months, respectively. When adjusted for age, sex, diabetes, cardiac failure,
myocardial infarction, peripheral vascular disease, malignancy, and acuity of
renal failure, the corresponding hazard ratios were 0.79 (95% CI, 0. 62 to 1.01,
P = NS), 1.00 (95% CI, 0.78 to 1.28, P = NS), and 0.95 (95% CI, 0.73 to 1.24, P =
NS). Adjustment for a previously validated comorbidity score resulted in hazard
ratios of 0.74 (95% CI, 0.58 to 0.94, P = 0.01), 0.94 (95% CI, 0.74 to 1.19, P =
NS), and 0.88 (95% CI, 0.68 to 1.13, P = NS) at baseline, three months, and six
months. There was no survival advantage for either modality in any of the major
subgroups defined by age, sex, or diabetic status. CONCLUSIONS: The apparent
survival advantage of peritoneal dialysis in Canada is due to lower comorbidity
and a lower burden of acute onset end-stage renal disease at the inception of
dialysis therapy. Hemodialysis and peritoneal dialysis, as practiced in Canada in
the 1990s, are associated with similar overall survival rates.
PMID- 10760109
TI - Hyperhomocysteinemia, nutritional status, and cardiovascular disease in
hemodialysis patients.
AB - BACKGROUND: Hyperhomocysteinemia, cardiovascular disease (CVD), and malnutrition
are common in patients with end-stage renal disease (ESRD). This study was
designed to assess possible relationships between total plasma homocysteine
(tHcy), nutritional status, and ischemic CVD. METHODS: We performed a cross
sectional study in 117 unselected patients on maintenance hemodialysis (HD)
treatment, among whom there was a high prevalence of malnutrition (56%), as
assessed by the subjective global nutritional assessment (SGNA), and a high
prevalence of CVD (60%), and prospectively, we followed-up the overall mortality
for four years. RESULTS: The level of tHcy was elevated in 95% of the HD
patients, and that of total plasma cysteine (tCys) was also significantly
elevated, while the plasma concentrations of methionine (Met), serine (Ser), and
taurine (Tau) were significantly lower than those in healthy controls. The 65
patients who were malnourished according to the SGNA score had significantly
lower levels of serum albumin (SAlb), plasma IFG-1 (p-IGF-1), tHcy, tCys, and Met
than the 52 patients with normal nutritional status, whereas the levels of Ser,
Tau, plasma folate, and vitamin B12 were similar in the two groups. The
prevalence of malnutrition was 30% in the 47 patients without CVD and was
significantly higher (70%, P < 0.001) in the 70 patients with CVD, who also had
lower tHcy, SAlb, plasma IGF-1, serum creatinine (SCr), and blood hemoglobin. The
tHcy levels were positively correlated with SAlb, Met, tCys, and SCr. Stepwise,
multiple-regression analysis showed that tCys, SAlb, and normalized protein
equivalent of nitrogen appearance (nPNA), an indicator of protein intake, were
independent predictors of tHcy. The patients with tHcy <24 micromol/L (median
value) had a significantly worse four-year survival than those with a higher tHcy
(> or =24 micromol/L). CONCLUSIONS: Our results demonstrate that most of HD
patients have grossly elevated tHcy levels, but that the absolute level appears
to be dependent on nutritional status, protein intake, and SAlb. The results also
suggest that the lower tHcy levels in patients with CVD than in those without CVD
may be related to the higher prevalence of malnutrition and hypoalbuminemia in
the CVD patients. This is also in accordance with our observation that the
patients with lower tHcy had a worse survival rate than those with higher tHcy,
considering that malnutrition is a strong risk factor for mortality and that CVD
is the most common cause of death in ESRD patients.
PMID- 10760111
TI - Analysis of the effects of increasing delivered dialysis treatment to
malnourished peritoneal dialysis patients.
AB - BACKGROUND: Poor nutrition is associated with a loss of residual renal function
and inferior clinical outcome in peritoneal dialysis (PD) patients. The value of
increasing the PD dose in these individuals is unclear. METHODS: An open,
prospective, longitudinal, "intention to treat" study was performed on a whole PD
population. All patients treated during an 18-month recruitment period underwent
nutritional assessment and were defined as malnourished if they had a subjective
global assessment (SGA) of B or C and were 5% or more below their desirable body
weight. These patients received an intended dialysis dose increase of 25% and
were reassessed after six months. Dialysis was not increased in the remaining
patients, unless dictated by uremic symptoms. RESULTS: Forty-eight of 153
patients were malnourished by the previously mentioned criteria. When compared
with well-nourished PD patients, they had evidence of declining nutrition over
the previous 12 months, as judged by a loss in body weight and mid-arm
circumference (MAC), a reduced creatinine appearance, a reduced appetite for
protein and calories, and low plasma albumin. They had been on treatment longer
and had less residual renal function, resulting in significantly poorer solute
clearances. Their peritoneal membrane function, plasma bicarbonate, comorbid,
Karnofsky, Hospital Anxiety and Depression (HAD) scores were not different.
Following intervention, their peritoneal Kt/Vurea was increased by 22.5%, and
their total Kt/Vurea by 18%, because of a continued loss of residual function.
There was also an increase in dialysis-derived calories. Weight and MAC
stabilized after an initial deterioration, and creatinine appearance increased.
There was no increase in protein intake, as judged by dietetic interview or
protein nitrogen appearance. Oral calorie intake improved, as did plasma albumin
after an initial decline. Both of these improvements were correlated with the
achieved increase in Kt/Vurea. Objective measures of improvement (plasma albumin
and protein nitrogen appearance) were significant in those patients without
comorbid disease. CONCLUSIONS: These results support the existing evidence that
malnutrition is acquired on PD in those patients who lose residual renal
function. It is feasible to increase the dialysis dose in these individuals
without a detrimental effect, and there is evidence of a modest benefit in
patients without comorbidity.
PMID- 10760110
TI - Increased protein loss during peritonitis associated with peritoneal dialysis is
neutrophil dependent.
AB - BACKGROUND: Peritonitis in peritoneal dialysis patients is accompanied by an
enhanced migration of neutrophils (PMNs) and increased protein loss into the
peritoneal cavity; however, the role of PMNs in governing increased protein loss
during peritonitis associated with peritoneal dialysis is unknown. METHODS: We
determined the importance of PMNs in governing changes in peritoneal permeability
to protein in New Zealand White rabbits in which acute peritonitis was induced by
adding 4 x 106 colony-forming units of Escherichia coli to 35 mL/kg of 0.9%
saline dialysate. The total leukocyte and PMN migration into the peritoneal
cavity was assessed by differential cell counts in the dialysate, and peritoneal
permeability to protein was evaluated by calculating the dialysate to plasma
concentration ratio for total protein as a function of time during a six- or
eight-hour dwell. In series 1 experiments, leukocytes were depleted from the
rabbit circulation by an intravenous injection of mustine (1.2 mg/kg) three days
before the experiment; in series 2 experiments, integrin-dependent PMN migration
into the peritoneal cavity was inhibited by an intravenous injection of
monoclonal antibody (mAb) 60.3 (2 mg/kg) directed against the integrin CD18 on
leukocytes five minutes before the experiment. RESULTS: In series 1 experiments,
mustine decreased circulating leukocytes by 82 +/- 5% (mean +/- SEM) and
circulating PMNs by 93 +/- 3%. Total leukocyte and PMN migration into the
peritoneal cavity and peritoneal permeability to protein were decreased in
mustine-treated rabbits after exposure to E. coli in the dialysate to levels
similar to those found in rabbits without bacterial peritonitis. In series 2
experiments, an intravenous injection of anti-CD18 antibody also abrogated both
the enhanced PMN migration into the peritoneal cavity and the increased
peritoneal permeability to protein after exposure to E. coli in the dialysate.
CONCLUSIONS: PMN migration into the peritoneal cavity is integrin dependent.
Increased protein loss during acute, gram-negative bacterial peritonitis in a
rabbit model of peritoneal dialysis is PMN dependent.
PMID- 10760112
TI - Influence of convection on small molecule clearances in online hemodiafiltration.
AB - BACKGROUND: Dialysis efficacy is mostly influenced by dialyzer clearance. Urea
clearance may be estimated in vitro by total ion clearance, which can be obtained
by conductivity measurements. We have previously used this approach to assess in
vitro clearances in a system mimicking predilutional and postdilutional online
hemodiafiltration with a wide range of QD, QB, and ultrafiltration rates. Our
current study elaborates on a formula that allows the prediction of the influence
of ultrafiltration on small molecule clearances, and validates the mathematical
approach both experimentally in vitro and clinically in vivo data. METHODS: Two
conductivimeters in the dialysate side of an E-2008 Fresenius machine were used.
HF80 and HF40 polysulfone dialyzers were used; reverse osmosis water and
dialysate were used for blood and dialysate compartments, respectively. Study
conditions included QB of 300 and 400 mL/min and QD of 500 and 590 mL/min, with a
range of ultrafiltration rate from 0 to 400 mL/min in postdilutional
hemodiafiltration and to 590 mL/min in predilutional hemodiafiltration. Urea
clearances were determined in the in vivo studies, which included 0, 50, 100, and
150 mL/min ultrafiltration rates. RESULTS: The ultrafiltration rate and clearance
were significantly correlated (R > 0.9, P < 0.001) and fitted a linear model (P <
0.001) in all of the experimental conditions. The following formula fitted the
experimental points with an error <2% for both postdilutional and predilutional
online diafiltration in vitro, respectively. K = K0 + [(QB - K0)/(QB)] x
ultrafiltration rateK = K0 + [((QD x QB)/(QB + QD) - K0)/QD] x ultrafiltration
rate where K is the clearance; K0 is the clearance with nil ultrafiltration rate;
QD is the total dialysate produced (in commercial HDF, QD = QDi + Qinf). Since
weight loss was maintained at 0, ultrafiltration rate = infusion flow. QB is the
"blood" line flow. The formula was also verified in vivo in clinical
postdilutional hemodiafiltration with a QB taking into account the cellular and
water compartments. DISCUSSION: In vitro, by simply determining the clearance in
conventional dialysis, the total clearance for any ultrafiltration rate may be
estimated in both predilutional and postdilutional online diafiltration with an
error of less than 2%. The same applies to in vivo postdilutional
hemodiafiltration when the formula takes into account the cellular and water
composition of blood.
PMID- 10760113
TI - Analysis of nanoliter samples of electrolytes using a flow-through
microfluorometer.
AB - Several techniques have been developed to study the transport properties of
nanoliter samples of renal tubule segments, such as continuous flow colorimetry
and continuous fluorometry. We have extended the capability of the NANOFLO, a
flow-through microfluorometer, designed for measurement of carbon dioxide, urea,
ammonia, glucose, lactate, etc., to analyze sodium, calcium and chloride ions,
using three commercially available fluorescent indicators for intracellular and
extracellular measurements. The selection of fluorescent indicator for each
electrolyte was dependent on the optimal match of the dissociation constant and
the analyte concentration range of interest. Using Fluo-3 dye we achieved a
detection limit for Ca2+ of 0.1 pmol and selectivity over Mg2+ of between 7:1 to
10:1. Using sodium green dye we achieved detection limit for Na+ of 12 pmol and a
selectivity over K+ of 40:1. The detection limit for Cl- using lucigenin dye was
10 pmol. This technique can be readily adapted for the measurement of other
physiologically important ultralow volume.
PMID- 10760114
TI - Polycystin: from structure to function.
PMID- 10760115
TI - Molecular basis of organic anion and cation transport.
PMID- 10760116
TI - Endothelin antagonists in renal disease.
PMID- 10760117
TI - Does a brief clerkship change Hong Kong medical students' ideas about general
practice?
AB - OBJECTIVES: This study examines the impact on students of a brief general
practice clerkship, during a curriculum that is otherwise almost entirely
hospital-based and in a practice environment that often does not encourage good
primary care. DESIGN: 15 focus group discussions were held with a total of 110
students, as part of an action research project. Student responses were
audiotaped, transcribed and then analysed for recurrent themes. SETTING: General
Practice Unit, University of Hong Kong. SUBJECTS: Medical students RESULTS: There
was evidence of pre-existing negative stereotypes of general practice, but in
many cases these were dispelled by the relationships students developed during
their attachment to general practitioners in the community. In an overcrowded
curriculum, students ration their time and energy, focusing their learning
pragmatically on subjects that have a high profile during examinations.
CONCLUSIONS: Even in healthcare and medical school systems that are specialist
dominated, and in which the circumstances of practice do not always encourage
high standards of care, the general practice clerkship can allow students to gain
an understanding of the importance of primary care, and of the significance of
the general practitioner's role in the healthcare system.
PMID- 10760118
TI - Views of junior doctors about their work: survey of qualifiers of 1993 and 1996
from United Kingdom medical schools.
AB - OBJECTIVE: To investigate the views of junior doctors about their work. DESIGN:
Postal questionnaire surveys. SETTING: United Kingdom. SUBJECTS: Doctors who
graduated from medical schools in the United Kingdom in 1996, surveyed at the end
of their preregistration year (2926 respondents), and graduates of 1993 surveyed
3 years after qualification (2541 respondents). RESULTS: Almost 70% of the 1996
qualifiers felt that they worked excessive hours and 80% felt that they undertook
too many routine non-clinical duties. Only 24% agreed that their postgraduate
training was of a high standard and 22% felt they were being asked to perform
clinical tasks with inadequate training. A total of 70% were dissatisfied with
arrangements for cover for absent doctors. Senior doctors and nurses were
regarded as supportive by most respondents, but hospital management was not.
Although 65% were satisfied with their future prospects, only 36% had been able
to obtain useful careers advice. Job enjoyment was reasonably high, with two
thirds scoring 6 or more on a scale from 1 (not enjoying at all) to 10 (greatly
enjoying), but 70% of respondents felt that they had insufficient time for family
and social activities. A briefer questionnaire sent to the 1993 qualifiers in
1996 showed similar results. CONCLUSIONS: More needs to be done to ensure that
junior doctors are trained appropriately for the tasks they undertake, to ensure
that they regard their training highly, to reduce excessive non-clinical work,
and to provide reasonable working hours and cover.
PMID- 10760119
TI - Views of UK medical graduates about flexible and part-time working in medicine: a
qualitative study.
AB - OBJECTIVES: To report on the views of doctors about flexible and part-time
working in medicine. DESIGN: As part of ongoing studies of doctors' careers,
postal questionnaires were sent in 1995 and 1996 to all doctors who qualified
from UK medical schools in 1977, 1988 and 1993. Structured questions about
recipients' careers were accompanied by a form which invited free-text comment.
Comments about flexible and part-time working were extracted for analysis.
SUBJECTS: All respondents who commented on flexible and part-time working.
RESULTS: Most doctors who commented believed there were insufficient
opportunities to meet demand. They also commonly commented that there was not
enough information about flexible training opportunities. Some men, as well as
women, expressed a wish to work part-time. The most frequently cited reasons for
part-time working were to balance career with family responsibilities, and to
reduce work-related stress. Cited disadvantages of part-time working were mainly
financial and included the problems of paying for childcare and professional
subscriptions when on a reduced income. Some respondents perceived negative
attitudes towards doctors in part-time jobs. DISCUSSION: It is well-recognised
that more flexible medical career structures are needed so that doctors can vary
their time commitment according to their needs at particular stages in their
lives. Until recently, needs have not been adequately met. Changes in
arrangements for flexible training accompanying the implementation of the
specialist registrar grade may have begun to alleviate some of the problems, but
others, such as negative attitudes towards part-time work, may take time to
change.
PMID- 10760120
TI - Defining competency - the role of standard setting.
AB - CONTEXT: The responsibility to determine just who is competent to practice
medicine, and at what standard, is great. Whilst there is still a period
available for potential remediation, examinations at the completion of year three
of the four-year Graduate Entry Medical Programme (GEMP) at Flinders University
of South Australia (FUSA) are high stakes and contain the majority of final
summative assessment for the certification of student to doctor. Therefore, the
medical school has recently examined its methods for certification, the clinical
practice standards sought in its programme and how to determine these standards.
DESIGN: For all assessments a standard was documented and methods employed to set
these standards using specific measures of performance. A modification of the
Angoff method was applied to the written examination and the Rothman method,
using two criteria, was used to determine competency in the objective structured
clinical examination (OSCE). These methods were used for the first time in 1998.
Both methods used trained 'experts' as standard setters and both methods used the
notion of the 'borderline candidate' to determine the passing standard. This
paper describes these two criterion-referenced standard-setting procedures as
used in this school and related examination performance. CONCLUSIONS: Whilst the
use of standard-setting procedures goes part way to defining and measuring
competence, it is time consuming and requires significant examiner training and
acceptance. Using 50% to determine who is and isn't competent is simpler but not
transparent, fair nor defensible.
PMID- 10760121
TI - The current status of senior house officer postgraduate education in a single
region.
AB - OBJECTIVE: To assess postgraduate education (PGE) for paediatric senior house
officers (SHOs) in a single region. METHODS: A survey of all paediatric SHOs in
the region was undertaken in the form of a questionnaire and telephone contact.
The standard set by the Committee of Postgraduate Medical Deans for SHO education
formed the basis for the questionnaire; there should be (i) a designated
educational supervisor for each SHO, (ii) regular work appraisal and counselling
and (iii) 4 h protected teaching per week. Supplementary questions were asked
regarding methods of teaching and study leave. RESULTS: There was a 92% response
rate from SHOs and 90% of SHOs contacted had a named educational supervisor. The
mean time for protected teaching per week was 2.14 h, although this varied widely
between centres. There were many different teaching methods used and 82% of SHOs
had no difficulty in obtaining study leave. There was a particular problem for
those who were working shifts or cross-covering. CONCLUSIONS: Our study has shown
that paediatric SHOs in Wales are reasonably satisfied with their postgraduate
education, although there is considerable variation between different units.
Several areas have been highlighted which need to be improved if we are to
provide SHOs with adequate preparation for the specialist registrar training
grade.
PMID- 10760122
TI - Recent changes in the workload and clinical experience of pre-registration house
officers: experiences over four years in south-west England.
AB - We aimed to measure changes in the training and workload of pre-registration
house officers using a postal questionnaire. Two hundred and six pre-registration
house officers in the south-western region of England were surveyed and asked to
report on the education, training and workload of their posts. Results were
compared with a survey conducted four years earlier. Since the previous survey,
the number of hours on duty had reduced from a median of 80 h week-1 in 1992/3 to
72 h week-1 in 1996/7 (P < 0.0001). There were no statistically significant
changes in the number of patients admitted or clerked in an average week, but
house officers' clinical experience had fallen. All but five of 26 marker
conditions showed a decline, which was statistically significant in seven cases.
House officers were keener to include four months of general practice in the pre
registration year and were less adverse to extending the pre-registration year to
two years. The reduction in hours of work for house officers has been accompanied
by a decline in their clinical exposure to common medical and surgical
emergencies. The long-term effects of these changes are unknown.
PMID- 10760123
TI - The impact of job stress and working conditions on mental health problems among
junior house officers. A nationwide Norwegian prospective cohort study.
AB - CONTEXT: Previous studies have shown that physicians have an increased risk of
mental health problems such as depression, suicide and substance abuse.
OBJECTIVES: To study the prevalence of mental health problems during the first
postgraduate year, and to investigate whether work-related factors in hospital
are linked to these, when we control for gender, previous mental health problems,
personality traits, stress in medical school and other possible predictors.
DESIGN: Nationwide and prospective postal questionnaire survey. SETTING:
University of Oslo. SUBJECTS: Medical students who answered questionnaires in
their graduating semester, and 1 year later when they were junior house officers
(n=371). RESULTS: Mental health problems (needing treatment) during internship
were reported by 11%, with no gender difference. Adjusted predictors of mental
health problems were: previous mental health problems, (odds ratio (OR)=5.1, 95%
confidence interval (CI) 1.7 to 15.8); being married/cohabitant (OR=0.2, CI 0.1
to 0.7); the personality trait 'vulnerability' (OR=1.5, CI 1.1 to 2.0); negative
life events during internship (OR=2.1, CI 1.2 to 3.5), and job stress as house
officer (OR=1.05, CI 1.01 to 1.10). The job stress factor of emotional
pressure/demands from patients was most important. Perceived study stress and
lack of skills at the end of medical school were univariately related to mental
health problems in internship, but not when other variables were adjusted.
Gender, weekly working hours and lack of sleep were not linked to having
problems. CONCLUSION: Job stress is related to mental health problems among young
doctors, even when the variables of previous mental health problems and
personality traits are controlled for. More support during internship is needed.
PMID- 10760124
TI - Primary care education for the new NHS: a discussion paper.
AB - CONTEXT: The White Paper, The New NHS: Modern, Dependable, once again heralds
change and new expectations of primary care in the UK. OBJECTIVES: This
discussion paper aims to encourage reflection on the implications for primary
care teams of current governmental strategy, and to address the pivotal role
which education can play in equipping practitioners for their roles. KEY AREAS:
The paper examines the opportunities and threats for primary care in the new NHS
developments, the strengths and weaknesses of the role that education currently
plays in primary care, and how recent innovations might be used to give a more
holistic approach to the needs of practitioners. The challenges for clinical
governance of lay engagement and ethical decision making are seen as two crucial
outcomes for an educational strategy which must be practice-led, and must
interface individual practitioner education with the needs of the team and the
community as a whole. I draw on a range of policy documents and educational
literature to alert the reader to the different choices which can be made when
thinking about appropriate educational models and methods; and offer a detailed
structure for a practical educational strategy that may effectively unite theory
and practice. The key elements are a three-tier link between practices, primary
care groups, and district-level resources for all educational and training
activity, and the aim of continuing multiprofessional development which will
underpin the new NHS.
PMID- 10760125
TI - Task-based learning: the answer to integration and problem-based learning in the
clinical years.
AB - INTRODUCTION: Integrated teaching and problem-based learning (PBL) are powerful
educational strategies. Difficulties arise, however, in their application in the
later years of the undergraduate medical curriculum, particularly in clinical
attachments. Two solutions have been proposed - the use of integrated clinical
teaching teams and time allocated during the week for PBL separate from the
clinical work. Both approaches have significant disadvantages. Task-based
learning (TBL) is a preferred strategy. In TBL, a range of tasks undertaken by a
doctor are identified, e.g. management of a patient with abdominal pain, and
these are used as the focus for learning. Students have responsibility for
integrating their learning round the tasks as they move through a range of
clinical attachments in different disciplines. They are assisted in this process
by study guides. METHOD: The implementation of TBL is described in one medical
school. One hundred and thirteen tasks, arranged in 16 groups, serve to integrate
the student learning as they rotate through 10 clinical attachments. RESULTS:
This trans-disciplinary approach to integration, which incorporates the
principles of PBL offers advantages to both teachers and students. It recognizes
that clinical attachments in individual disciplines can offer rich learning
opportunities and that such attachments can play a role in an integrated, as well
as in a traditional, curriculum. In TBL, the contributions of the clinical
attachments to the curriculum learning outcomes must be clearly defined and tasks
selected which will serve as a focus for the integration of the students'
learning over the range of attachments.
PMID- 10760126
TI - A review of a surgical ward round in a large paediatric hospital: does it achieve
its aims?
AB - The review which this paper outlines aimed to explore whether the ward round of
the surgical team at Birmingham Children's Hospital achieved its objectives and
to investigate the attitudes of medical and nursing staff, patients and their
parents towards the round. Initial open-ended interviews generated themes from
which questionnaires were constructed and administered to 16 members of the
surgical team, 30 nurses, 14 patients and 24 parents. The surgical team generally
felt that the round plays a valuable role whereas the nursing team expressed
dissatisfaction with many aspects of the round. The majority of the surgical and
nursing team thought that the round should change from its present form and a
number of suggestions were made as to how changes in the round could improve the
quality of the teaching experience and promote quality in patient care. Patients
tended to express rather neutral feelings towards the round although a
significant minority of parents expressed concerns over confidentiality and the
level of anxiety felt by children. It is hoped that the results of this review
will be used to inform changes in the way the round is carried out. A further
review will be initiated in the future to evaluate the efficacy of any such
changes.
PMID- 10760127
TI - Teaching patient wellness to first-year medical students: the impact on future
ability to perform the history of present illness.
AB - OBJECTIVES: Curriculum innovations to improve clinical skills have been
implemented at many American medical schools. A current curricular change at the
University of Connecticut School of Medicine involves teaching wellness to
students in the first year rather than the more traditional focus on disease
processes. It is unknown, however, if focusing on wellness detracts from
students' future ability to perform the history of present illness (HPI) which
requires students to focus on disease processes. DESIGN: The current study
examined this issue by comparing two cohorts' clinical skills (n=156), with one
class participating in a traditional curriculum during their first year and the
other in a revised curriculum teaching wellness during the first year. Each class
was evaluated at the beginning of their second year to determine their level of
clinical competence. SETTING: University of Connecticut School of Medicine
SUBJECTS: Second-year medical students. RESULTS: Analyses suggested that teaching
wellness did not detract from future ability to perform an HPI, and in fact
students taught wellness had significantly higher history-taking scores.
CONCLUSIONS: Curricular innovations which stress wellness and prevention early in
medical education do not detract from and may enhance students' ability to
perform the history of present illness later during medical training.
PMID- 10760128
TI - Impact of medical round on patients' and residents' perceptions at a university
hospital in Japan.
PMID- 10760129
TI - Athol kent
PMID- 10760130
TI - The mitochondrial protein targeting suppressor (mts1) mutation maps to the mRNA
binding domain of Npl3p and affects translation on cytoplasmic polysomes.
AB - In all eukaryotic organisms, messenger RNA (mRNA) is synthesized in the nucleus
and then exported to the cytoplasm for translation. The export reaction requires
the concerted action of a large number of protein components, including a set of
shuttle proteins that can exit and re-enter the nucleus through the nuclear pore
complex. Here, we show that, in Saccharomyces cerevisiae, the shuttle protein
Npl3p leaves the nuclear pore complex entirely and continues to function in the
cytoplasm. A mutation at position 219 in its RNA-binding domain leaves Npl3p
lingering in the cytoplasm associated with polysomes. Yeast cells expressing the
mutant Npl3(L-219S) protein show alterations in mRNA stability that can affect
protein synthesis. As a result, defects in nascent polypeptide targeting to
subcellular compartments such as the mitochondria are also suppressed.
PMID- 10760131
TI - The ClpP serine protease is essential for the intracellular parasitism and
virulence of Listeria monocytogenes.
AB - We identified the stress-induced ClpP of Listeria monocytogenes and demonstrated
its crucial role in intracellular survival of this pathogen. ClpP is a 21.6 kDa
protein belonging to a family of proteases highly conserved in prokaryotes and
eukaryotes. A clpP-deleted mutant enabled us to demonstrate that ClpP is involved
in proteolysis and is required for growth under stress conditions.
Intramacrophage survival of this mutant was strongly restricted, thus resulting
in loss of virulence for the mouse. The activity of listeriolysin O, a major
virulence factor implicated in bacterial escape from phagosomes of macrophages,
was much reduced in the clpP mutant under stress conditions. Direct evidence for
the role of ClpP in the intracellular parasitism was obtained by showing that
virulence and haemolytic activity were fully restored by complementation of the
mutant. These results suggest that ClpP is involved in the rapid adaptive
response of intracellular pathogens during the infectious process.
PMID- 10760133
TI - The role of tandem IS dimers in IS911 transposition.
AB - Using a combined in vivo and in vitro approach, we demonstrated that the
transposition products generated by IS911 from a dimeric donor plasmid are
different from those generated from a plasmid monomer. When carried by a
monomeric plasmid donor, free IS911 transposon circles are generated by intra-IS
recombination in which one IS end undergoes attack by the other. These represent
transposition intermediates that undergo integration using the abutted left (IRL)
and right (IRR) ends of the element, the active IRR-IRL junction, to generate
simple insertions. In contrast, the two IS911 copies carried by a dimeric donor
plasmid not only underwent intra-IS recombination to generate transposon circles
but additionally participated in inter-IS recombination. This also creates an
active IRR-IRL junction by generating a head-to-tail IS tandem dimer ([IS]2) in
which one of the original plasmid backbone copies is eliminated in the formation
of the junction. Both transposon circles and IS tandem dimers are generated from
an intermediate in which two transposon ends are retained by a single strand
joint to generate a figure 8 molecule. Inter-IS figure 8 molecules generated in
vitro could be resolved into the [IS]2 form following introduction into a host
strain by transformation. Resolution did not require IS911 transposase. The [IS]2
structure was stable in the absence of transposase but was highly unstable in its
presence both in vivo and in vitro. Previous studies had demonstrated that the
IRR-IRL junction promotes efficient intermolecular integration and intramolecular
deletions both in vivo and in vitro. Integration of the [IS]2 derivative would
result in a product that resembles a co-integrate structure. It is also shown
here that the IRR-IRL junction of the [IS]2 form and derivative structures can
specifically target one of the other ends in an intramolecular transposition
reaction to generate transposon circles in vitro. These results not only
demonstrate that IS911 (and presumably other members of the IS3 family) is
capable of generating a range of transposition products, it also provides a
mechanistic framework which explains the formation and activity of such
structures previously observed for several other unrelated IS elements. This
behaviour is probably characteristic of a large number of IS elements.
PMID- 10760132
TI - Low levels of Ypt protein prenylation cause vesicle polarization defects and
thermosensitive growth that can be suppressed by genes involved in cell wall
maintenance.
AB - The Rab/Ypt small G proteins are essential for intracellular vesicle trafficking
in mammals and yeast. The vesicle-docking process requires that Ypt proteins are
located in the vesicle membrane. C-terminal geranylgeranyl anchors mediate the
membrane attachment of these proteins. The Rab escort protein (REP) is essential
for the recognition of Rab/Ypt small G proteins by geranylgeranyltransferase II
(GGTase II) and for their delivery to acceptor membranes. What effect an
alteration in the levels of prenylated Rab/Ypt proteins has on vesicle transport
or other cellular processes is so far unknown. Here, we report the
characterization of a yeast REP mutant, mrs6-2, in which reduced prenylation of
Ypt proteins occurs even at the permissive temperature. A shift to the
restrictive temperature does not alter exponential growth during the first 3 h.
The amount of Sec4p, but not Ypt1p, bound to vesicle membranes is reduced 2.5 h
after the shift compared with wild-type or mrs6-2 cells incubated at 25 degrees
C. In addition, vesicles fail to be polarized towards the bud and small budded
binucleate cells accumulate at this time point. Growth in 1 M sorbitol or
overexpression of MLC1, encoding a myosin light chain able to bind the
unconventional type V myosin Myo2, or of genes involved in cell wall maintenance,
such as SLG1, GFA1 and LRE1, suppresses mrs6-2 thermosensitivity. Our data
suggest that, at least at high temperature, a critical minimal level of Ypt
protein prenylation is required for maintaining vesicle polarization.
PMID- 10760134
TI - The spliceosomal intron of the rolA gene of agrobacterium rhizogenes is a
prokaryotic promoter.
AB - Agrobacterium rhizogenes transfers DNA (T-DNA) from its Ri plasmid to plant
cells. All T-DNA genes are expressed in plant cells. The rolA gene is the only T
DNA gene that contains an intron in the untranslated leader region of its mRNA.
This paper shows that (i) the rolA gene is also transcribed in bacteria; (ii) the
85 bp corresponding to the spliceosomal intron drives prokaryotic gene expression
in agrobacteria, in free-living rhizobia and in bacteroids within root nodules;
and (iii) promoter activity is abolished by the deletion of 63 bp from its 5' end
and is reduced by mutations changing its sequence near the putative -10 region.
The expression pattern of a chimeric reporter gene shows that, in free-living
bacteria, gene expression takes place during the exponential phase of growth and
increases at the onset of the stationary phase. Within root nodules, reporter
gene expression occurs in the invasion, nitrogen fixing and senescent zones.
PMID- 10760135
TI - Evidence for donor strand complementation in the biogenesis of Haemophilus
influenzae haemagglutinating pili.
AB - Haemophilus influenzae haemagglutinating pili are surface appendages that promote
attachment to host cells and facilitate respiratory tract colonization, an
essential step in the pathogenesis of disease. In contrast to other well
characterized forms of pili, H. influenzae haemagglutinating pili are two
stranded helical structures. Nevertheless, haemagglutinating pili are assembled
by a pathway that involves a periplasmic chaperone and an outer membrane usher,
analogous to the prototype pathway involved in the biogenesis of Escherichia coli
P pili. In this study, we performed site-directed mutagenesis of the H.
influenzae HifB chaperone and HifA major pilus subunit at positions homologous to
sites important for chaperone-subunit interactions and subunit oligomerization in
P pili. Mutations at putative subunit binding pocket residues in HifB or at the
penultimate tyrosine in HifA abolished formation of HifB-HifA periplasmic
complexes, whereas mutations at the -14 glycine in HifA had no effect on HifB
HifA interactions but abrogated HifA oligomerization. To define further the
constraints of the interaction between HifA and HifB, we examined the
interchangeability of pilus gene cluster components from H. influenzae type b
strain Eagan (hifA-hifEEag) and the related H. influenzae biogroup aegyptius
strain F3031 (hifA-hifEF3031). Functional pili were assembled both with HifAEag
and the strain F3031 gene cluster and with HifAF3031 and the strain Eagan gene
cluster, underscoring the flexibility of the H. influenzae chaperone/usher
pathway in incorporating HifA subunits with significant sequence diversity. To
gain additional insight into the interactive surfaces of HifA and HifB, we
aligned HifA sequences from 20 different strains and then modelled the HifA
structure based on the recently crystallized PapD-PapK complex. Analysis of the
resulting structure revealed high levels of sequence conservation in regions
predicted to interact with HifB, and maximal sequence diversity in regions
potentially exposed on the surface of assembled pili. These results suggest broad
applicability of structure-function relationships identified in studies of P
pili, including the concepts of donor strand complementation and donor strand
exchange. In addition, they provide insight into the structure of HifA and
suggest a basis for antigenic variation in H. influenzae haemagglutinating pili.
PMID- 10760136
TI - The transfer region of IncI1 plasmid R64: similarities between R64 tra and
legionella icm/dot genes.
AB - The entire nucleotide sequence of the transfer region of IncI1 plasmid R64 was
determined together with previously reported sequences. Twenty-two transfer
genes, traE-Y and nuc, were newly identified in the present study. The protein
products of 17 genes were detected by maxicell experiments or by the T7 RNA
polymerase expression system. Mutagenesis experiments indicated that 16 genes
were indispensable for R64 transfer both in liquid and on surfaces. In summary,
the R64 transfer region located within an approximately 54 kb DNA segment was
shown to encode the most complex transfer system so far studied. It contains at
least 49 genes and may produce 58 different proteins as a result of shufflon DNA
rearrangement and overlapping genes. Among the 49 genes, 23 tra, trb and nik
genes have been shown to be indispensable for R64 conjugal transfer in liquid and
on surfaces. Twelve additional pil genes are required only for liquid matings.
The amino acid sequences of 10 R64 tra/trb products share similarity with those
of the icm/dot products of Legionella pneumophila that are responsible for its
virulence, suggesting that the R64 transfer and L. pneumophila icm/dot systems
have evolved from a common ancestral genetic system.
PMID- 10760137
TI - Escherichia coli DipZ: anatomy of a transmembrane protein disulphide reductase in
which three pairs of cysteine residues, one in each of three domains, contribute
differentially to function.
AB - DipZ is a bacterial cytoplasmic membrane protein that transfers reducing power
from the cytoplasm to the periplasm so as to facilitate the formation of correct
disulphide bonds and c-type cytochromes in the latter compartment. Topological
analysis using gene fusions between the Escherichia coli dipZ and either E. coli
phoA or lacZ shows that DipZ has a highly hydrophobic central domain comprising
eight transmembrane alpha-helices plus periplasmic globular N-terminal and C
terminal domains. The previously assigned translational start codon for the E.
coli DipZ was shown to be incorrect and the protein to be larger than previously
thought. The experimentally determined translational start position indicates
that an additional alpha-helix at the N-terminus acts as a cleavable signal
peptide so that the N-terminus of the mature protein is located in the periplasm.
The newly assigned 5' end of the dipZ gene was shown to be preceded by a
functional ribosome-binding site. The hydrophobic central domain and both of the
periplasmic globular domains each have a pair of highly conserved cysteine
residues, and it was shown by site directed mutagenesis that all six conserved
cysteine residues contribute to DipZ function.
PMID- 10760138
TI - A parallel intraphagosomal survival strategy shared by mycobacterium tuberculosis
and Salmonella enterica.
AB - Mycobacterium tuberculosis and Salmonella enterica cause very different diseases
and are only distantly related. However, growth within macrophages is crucial for
virulence in both of these intracellular pathogens. Here, we demonstrate that in
spite of the phylogenetic distance, M. tuberculosis and Salmonella employ a
parallel survival strategy for growth within macrophage phagosomes. Previous
studies established that the Salmonella mgtC gene is required for growth within
macrophages and for virulence in vivo. M. tuberculosis contains an open reading
frame exhibiting 38% amino acid identity with the Salmonella MgtC protein. Upon
inactivation of mgtC, the resulting M. tuberculosis mutant was attenuated for
virulence in cultured human macrophages and impaired for growth in the lungs and
spleens of mice. Replication of the mgtC mutant was inhibited in vitro by a
combination of low magnesium and mildly acidic pH suggesting that the M.
tuberculosis-containing phagosome has these characteristics. The similar
phenotypes displayed by the mgtC mutants of M. tuberculosis and Salmonella
suggest that the ability to acquire magnesium is essential for virulence in
intracellular pathogens that proliferate within macrophage phagosomes.
PMID- 10760139
TI - Characterization of the Lactococcus lactis transcription factor FlpA and
demonstration of an in vitro switch.
AB - The commercially important bacterium Lactococcus lactis contains two FNR-like
proteins (FlpA and FlpB) which have a high degree of identity to each other and
to the FLP of Lactobacillus casei. FlpA was isolated from a GST-FlpA fusion
protein produced in Escherichia coli. Like FLP, isolated FlpA is a homodimeric
protein containing both Zn and Cu. However, the properties of FlpA were more like
those of the E. coli oxygen-responsive transcription factor FNR than the FLP of
L. casei. As prepared FlpA recognized an FNR site (TTGAT-N4-ATCAA) but not an FLP
site (CCTGA-N4-TCAGG) in band-shift assays. In contrast to FLP, DNA binding by
FlpA did not require the formation of an intramolecular disulphide bond. However,
despite containing only two cysteine residues per monomer, FlpA was able to
acquire an FNR-like, oxygen-labile [4Fe 4S] cluster. But, whereas the
incorporation of a [4Fe 4S] cluster into FNR enhances interaction with target
DNA, it abolished DNA binding by FlpA. An FlpA variant (FlpA') with an N-terminal
region designed to be more FLP-like failed to incorporate an iron-sulphur cluster
but could now form an intramolecular disulphide. This simple example of protein
engineering, converting an oxygen-labile [4Fe 4S] containing FNR-like protein
into a dithiol-disulphide FLP-like redox sensor demonstrates the versatility of
the basic CRP structure. Attempts to demonstrate an FlpA-based aerobic-anaerobic
switch in the heterologous host E. coli were unsuccessful. However, studies with
a series of FNR-dependent lac reporter fusions in strains of E. coli expressing
flpA or flpB revealed that both homologues were able to activate expression of
FNR-dependent promoters in vivo but only when positioned 61 base pairs upstream
of the transcription start.
PMID- 10760140
TI - Mutational analysis of MarR, the negative regulator of marRAB expression in
Escherichia coli, suggests the presence of two regions required for DNA binding.
AB - MarR, the negative regulator of the Escherichia coli multiple antibiotic
resistance (marRAB) operon, is a member of a newly recognized family of
regulatory proteins. The amino acid sequences of these proteins do not display
any apparent homologies to the DNA binding domains of prokaryotic transcription
regulators and a DNA binding motif for any one of the MarR homologues is
currently unknown. In order to define regions of MarR required for DNA binding,
mutant repressors, selected based on their ability to interfere with (negatively
complement) the activity of wild-type MarR, were isolated. As determined using
gel mobility shift assays, 13 out of 14 negative complementing mutants tested
were unable to bind DNA in vitro. Three negative complementing alleles presumably
specify truncated repressors and one of these proteins, a 120 residue MarR, can
bind DNA in vitro. Most of the negative complementing mutations were clustered
within two areas of MarR with features related to a helix-turn-helix DNA binding
motif. These regions are presumed to be required for the DNA binding activity of
the repressor.
PMID- 10760141
TI - Homing of a bacterial group II intron with an intron-encoded protein lacking a
recognizable endonuclease domain.
AB - RmInt1 is a functional group II intron found in Sinorhizobium meliloti where it
interrupts a group of IS elements of the IS630-Tc1 family. In contrast to many
other group II introns, the intron-encoded protein (IEP) of RmInt1 lacks the
characteristic conserved part of the Zn domain associated with the IEP
endonuclease activity. Nevertheless, in this study, we show that RmInt1 is
capable of inserting into a vector containing the DNA spanning the RmInt1 target
site from the genome of S. meliloti. Efficient homing was also observed in the
absence of homologous recombination (RecA- strains). In addition, it is shown
that RmInt1 is able to move to its target in a heterologous host (S. medicae).
Homing of RmInt1 occurs very efficiently upon DNA target uptake
(conjugation/electroporation) by the host cell resulting in a proportion of
invaded target of 11-30%. Afterwards, the remaining intronless target DNA is
protected from intron invasion.
PMID- 10760142
TI - Escherichia coli response to hydrogen peroxide: a role for DNA supercoiling,
topoisomerase I and Fis.
AB - Bacterial cells respond to the deleterious effects of reactive oxygen species by
inducing the expression of antioxidant defence genes. Here we show that treatment
with hydrogen peroxide leads to a transient decrease in DNA negative
supercoiling. We also report that hydrogen peroxide activates topA P1 promoter
expression. The peroxide-dependent topA P1 activation is independent of oxyR, but
is mediated by Fis. This nucleoid-associated protein binds to the promoter region
of topA. We also show that a fis deficient mutant strain is extremely sensitive
to hydrogen peroxide. Our results suggest that topA activation by Fis is an
important component of the Escherichia coli response to oxidative stress.
PMID- 10760143
TI - Saccharomyces cerevisiae PAU genes are induced by anaerobiosis.
AB - Saccharomyces cerevisiae PAU genes constitute the largest multigene family in
yeast, with 23 members located mainly in subtelomeric regions. The role and
regulation of these genes were previously unknown. We detected PAU gene
expression during alcoholic fermentation. An analysis of PAU gene regulation
using PAU-lacZ fusions and Northern analyses revealed that they were regulated by
anaerobiosis. PAU genes display, however, different abilities to be induced by
anaerobiosis and this appears to be related to their chromosomal localization;
two subtelomeric copies are more weakly inducible than an interstitial one. We
show that PAU genes are negatively regulated by oxygen and repressed by haem.
Examination of PAU gene expression in rox1Delta and tup1Delta strains indicates
that PAU repression by oxygen is mediated by an unknown, haem-dependent pathway,
which does not involve the Rox1p anaerobic repressor but requires Tup1p. Given
the size of the gene family, PAU genes could be expected to be important during
yeast life and some of them probably help the yeast to cope with anaerobiosis.
PMID- 10760144
TI - Tyrosine phosphorylation of CpsD negatively regulates capsular polysaccharide
biosynthesis in streptococcus pneumoniae.
AB - In Streptococcus pneumoniae, the first four genes of the capsule locus (cpsA to
cpsD) are common to most serotypes. By analysis of various in-frame deletion and
site-directed mutants, the function of their gene products in capsular
polysaccharide (CPS) biosynthesis was investigated. We found that while CpsB, C
and D are essential for encapsulation, CpsA is not. CpsC and CpsD have similarity
to the amino-terminal and carboxy-terminal regions, respectively, of the
autophosphorylating protein-tyrosine kinase Wzc from Escherichia coli. Alignment
of CpsD with Wzc and other related proteins identified conserved Walker A and B
sequence motifs and a tyrosine rich domain close to the carboxy-terminus. We have
shown that CpsD is also an autophosphorylating protein-tyrosine kinase and that
point mutations in cpsD affecting either the ATP-binding domain (Walker A motif)
or the carboxy-terminal [YGX]4 repeat domain eliminated tyrosine phosphorylation
of CpsD. We describe, for the first time, the phenotypic impact of these two
mutations on polysaccharide production and show that they affect CPS production
differently. Whereas a mutation in the Walker A motif resulted in loss of
encapsulation, mutation of the tyrosines in the [YGX]4 repeat domain resulted in
an apparent increase in encapsulation and a mucoid phenotype. These data suggest
that autophosphorylation of CpsD at tyrosine attenuates its activity and reduces
the level of encapsulation. Additionally, we demonstrated that CpsC is required
for CpsD tyrosine phosphorylation and that CpsB influences dephosphorylation of
CpsD. These results are consistent with CpsD tyrosine phosphorylation acting to
negatively regulate CPS production. This has implications for the function of
CpsC/CpsD homologues in both Gram-positive and Gram-negative bacteria and
provides a mechanism to explain regulation of CPS production during pathogenesis.
PMID- 10760145
TI - Specific amino acid changes enhance the anti-recombination activity of the UmuD'C
complex.
AB - In addition to being an essential component of trans-lesion synthesis, the UmuD'C
complex is an antagonist of RecA-mediated homologous recombination. When
constitutively expressed at an elevated concentration, the UmuD'C complex
sensitizes recA+ bacteria to DNA damage, whereas it has no effect on bacteria
expressing a RecA [UmuR] protein that overcomes recombination inhibition. Using
as a genetic screen enhanced cell killing on mitomycin plates, we isolated novel
umuD' and umuC mutations that restored mitomycin sensitivity to recA D112G [UmuR]
bacteria overproducing the UmuD'C complex. The mutations were named [Rin++]
because a characterization in a recA+ as well in a recA D112G background showed
that they enhanced UmuD'C-promoted recombination inhibition in two assays,
conjugational recombination and recombinational repair of palindrome-containing
DNA. The [Rin++] mutations affect five amino acids, G25D, S28T, P29L, E35K, and
T95R, in UmuD' and seven, F10L, Y270C, K277E, F287L, F287S, K342Q and F351I, in
UmuC. These amino acids might play a key role in the UmuD'C anti-recombination
activity. None of the [Rin++] mutations enhanced UmuD'C-promoted mutagenic bypass
of UV lesions, in contrast, several lead to a defect in this process. In this
study, we discuss a few molecular mechanisms that could account for the
recombination and mutagenesis phenotypes of a mutant UmuD'C [Rin++] complex.
PMID- 10760146
TI - Manganese homeostasis in Bacillus subtilis is regulated by MntR, a bifunctional
regulator related to the diphtheria toxin repressor family of proteins.
AB - The Bacillus subtilis yqhN gene encodes a metalloregulatory protein distantly
related to the Corynebacterium diphtheriae diphtheria toxin repressor (DtxR).
While DtxR mediates the iron-dependent repression of iron uptake, we demonstrate
that yqhN (herein renamed mntR) encodes a manganese modulated regulator of
manganese transport. An mntR mutant strain is sensitive to both manganese and
cadmium, suggesting that the transport of these metals is derepressed. We
selected Tn10 insertions that suppress the Mn(II) sensitivity of the mntR mutant
or that increase the Cd(II) tolerance of wild-type cells, and in both cases we
recovered insertions in mntH (formerly ydaR). MntH is a member of the NRAMP
family of proton-coupled, metal ion transporters. MntR also regulates expression
of a Mn(II) ABC transporter (MntABCD). The MntH and MntABCD transporters are both
selectively repressed by Mn(II) and this regulation requires MntR. In high Mn(II)
conditions, MntR functions as a Mn(II)-dependent repressor of mntH transcription.
In contrast, MntR acts as a positive regulator of the mntABCD operon under low
Mn(II) growth conditions. Biochemical studies demonstrate that MntR binding to
the mntH control region requires Mn(II), while interaction with the mntABCD
control region does not depend on Mn(II).
PMID- 10760147
TI - Antisense RNA-mediated transcriptional attenuation: an in vitro study of plasmid
pT181.
AB - Antisense RNAs regulate plasmid replication by several different mechanisms. One
of these mechanisms, transcriptional attenuation, was first described for the
staphylococcal plasmid pT181, and later for the streptococcal plasmids pIP501 and
pAMbeta1. Previously, we performed detailed in vitro and in vivo analyses of the
pIP501 system. Here, we present an in vitro analysis of the antisense system of
plasmid pT181. The secondary structures of antisense and sense RNA species of
different lengths were determined. Binding rate constants for sense/antisense RNA
pairs were measured, and functional segments required for complex formation were
determined. A single-round transcription assay was used for in vitro analysis of
transcriptional attenuation. A comparison between pT181 and pIP501 revealed
several differences; whereas a truncated derivative of pIP501 antisense RNA was
sufficient for stable complex formation, both stem-loop structures of pT181-RNAI
were required. In contrast to the sense RNA of pIP501, which showed an intrinsic
propensity to terminate (30-50% in the absence of antisense RNA), the sense RNA
of pT181 required antisense RNA for induced termination. Rate constants of
formation of pT181 sense-antisense RNA complexes were similar to inhibition rate
constants, in striking contrast to pIP501, in which inhibition occurred at least
10-fold faster than stable binding.
PMID- 10760148
TI - The type III protein translocation system of enteropathogenic Escherichia coli
involves EspA-EspB protein interactions.
AB - Enteropathogenic Escherichia coli (EPEC), like many bacterial pathogens, use a
type III secretion system to deliver effector proteins across the bacterial cell
wall. In EPEC, four proteins, EspA, EspB, EspD and Tir are known to be exported
by a type III secretion system and to be essential for 'attaching and effacing'
(A/E) lesion formation, the hallmark of EPEC pathogenicity. EspA was recently
shown to be a structural protein and a major component of a large, transiently
expressed, filamentous surface organelle which forms a direct link between the
bacterium and the host cell. In contrast, EspB is translocated into the host cell
where it is localized to both membrane and cytosolic cell fractions. EspA and
EspB are required for translocation of Tir to the host cell membrane suggesting
that they may both be components of the translocation apparatus. In this study,
we show that EspB co-immunoprecipitates with the EspA filaments and that, during
EPEC infection of HEp-2 cells, EspB localizes closely with EspA. Using a number
of binding assays, we also show that EspB can bind and be copurified with EspA.
Nevertheless, binding of EspA filaments to the host cell membranes occurred even
in the absence of EspB. These results suggest that following initial attachment
of the EspA filaments to the target cells, EspB is delivered into the host cell
membrane and that the interaction between EspA and EspB may be important for
protein translocation.
PMID- 10760149
TI - The extremely halophilic archaeon Haloferax volcanii has two very different
dihydrofolate reductases.
AB - The gene encoding dihydrofolate reductase, hdrA, from the extremely halophilic
archaeon Haloferax volcanii was previously isolated from a spontaneous
trimethoprim-resistant mutant in a DNA sequence that had undergone amplification.
Here, we show that deletion of hdrA did not affect growth in minimal medium and
that the strain carrying the deletion remained sensitive to trimethoprim. A
spontaneous trimethoprim-resistant colony was isolated in the hdrA deletion
strain and found to possess a new DNA amplification. Sequencing of the
amplification revealed a second, substantially different, dihydrofolate reductase
gene, hdrB, which was found to be located immediately downstream of the
thymidylate synthase gene, hts. The physiological role of hDHFR-1 and hDHFR-2 was
determined by generating Haloferax volcanii strains in which each gene, hdrA or
hdrB, or both genes were deleted. It was found that hdrB alone can support growth
of Haloferax volcanii in minimal medium, whereas hdrA alone can support growth of
Haloferax volcanii in minimal medium only when the medium is supplemented with
thymidine. It was also shown that, in contrast to Escherichia coli, the
DeltahdrA, DeltahdrB double deletion mutant is viable in the presence of a
functional thymidylate synthase gene. The hdrB gene was overexpressed in
Escherichia coli and the enzyme purified to homogeneity. The biochemical
properties of the new enzyme (hDHFR-2) are markedly different from those of hDHFR
1. The use of the dihydrofolate reductase and thymidylate synthase genes as
stable selectable markers is described.
PMID- 10760150
TI - The ChiA (YheB) protein of Escherichia coli K-12 is an endochitinase whose gene
is negatively controlled by the nucleoid-structuring protein H-NS.
AB - The chromosome of Escherichia coli K-12 contains a putative gene, yheB (chiA), at
centisome 74.7, whose product shows sequence similarity with chitinases of
bacterial and viral origin. We cloned the chiA (yheB) gene and demonstrated that
it codes for a 94.5 kDa periplasmic protein with endochitinase/lysozyme activity.
Under standard laboratory growth conditions, chiA expression is very low, as
shown by the Lac- phenotype of a chiA transcriptional fusion to a promoterless
lacZ reporter. To identify factors that control chitinase gene expression, we
generated random Tn10 insertions in the chromosome of the fusion-containing
strain, selecting for a Lac+ phenotype. The majority of the mutations that caused
a Lac+ phenotype mapped to the hns gene, encoding the nucleoid-structuring
protein H-NS. Transcription of chiA in vivo is driven by a single sigma70
promoter and is derepressed in an hns mutant. Using a competitive gel retardation
assay, we demonstrated that H-NS binds directly and with high affinity to the
chiA promoter region. In addition to hns, other E. coli mutations causing defects
in global regulatory proteins, such as fis, crp or stpA in combination with hns,
increased chiA expression to different extents, as did decreasing the growth
temperature from 37 degrees C to 30 degrees C. A possible physiological function
of ChiA (YheB) endochitinase in E. coli K-12 is discussed.
PMID- 10760152
TI - Lewis X structures in the O antigen side-chain promote adhesion of Helicobacter
pylori to the gastric epithelium.
AB - Helicobacter pylori NCTC11637 expresses a lipopolysaccharide (LPS) that comprises
an O antigen side-chain with structural homology to the human blood group antigen
Lewis X (Le(x)). The role of this molecule in adhesion of H. pylori to gastric
epithelial cells was investigated. Mutants expressing truncated LPS structures
were generated through insertional mutagenesis of rfbM and galE; genes encode GDP
mannose pyrophosphorylase and galactose epimerase respectively. Compositional and
structural analysis revealed that the galE mutant expressed a rough LPS that
lacked an O antigen side-chain. In contrast, an O antigen side-chain was still
synthesized by the rfbM mutant, but it lacked fucose and no longer reacted with
anti-Le(x) monoclonal antibodies (Mabs). The ability of these mutants to bind to
paraffin-embedded sections from the antrum region of a human stomach was
assessed. Adhesion of the wild type was characterized by tropic binding to the
apical surface of mucosal epithelial cells and cells lining gastric pits. In
contrast, both the rfbM and galE mutants failed to demonstrate tropic binding and
adhered to the tissue surface in a haphazard manner. These results indicate that
LPS and, more specifically, Le(x) structures in the O antigen side-chain play an
important role in targeting H. pylori to specific cell lineages within the
gastric mucosa. The role of Le(x) in this interaction was confirmed by the tropic
binding of synthetic Le(x), conjugated to latex beads, to gastric tissue. The
observed pattern of adhesion was indistinguishable from that of wild-type H.
pylori.
PMID- 10760151
TI - Formate protects stationary-phase Escherichia coli and Salmonella cells from
killing by a cationic antimicrobial peptide.
AB - For a sustained infection, enteric bacterial pathogens must evade, resist or
tolerate a variety of antimicrobial host defence peptides and proteins. We report
here that specific organic acids protect stationary-phase Escherichia coli and
Salmonella cells from killing by a potent antimicrobial peptide derived from the
human bactericidal/permeability-increasing protein (BPI). BPI-derived peptide P2
rapidly halted oxygen consumption by stationary-phase cells preincubated with
glucose, pyruvate or malate and caused a 109-fold drop in cell viability within
90 min of addition. In marked contrast, O2 consumption and viability were not
significantly affected in stationary-phase cells preincubated with formate or
succinate. Experiments with fdhH, fdoG, fdnG, selC and sdhO mutants indicate that
protection by formate and succinate requires their oxidation by the Fdh-N formate
dehydrogenase and succinate dehydrogenase respectively. Protection was also
dependent on the BipA GTPase but did not require the RpoS sigma factor. We
conclude that the primary lesion caused by this cationic peptide is not gross
permeabilization of the bacterial cytoplasmic membrane but may involve specific
disruption of the respiratory chain. Because P2 shares sequence similarity with a
range of other antimicrobial peptides, its cytotoxic mechanism has broader
significance. Additionally, protective quantities of formate are secreted by E.
coli and Salmonella during growth suggesting that such compounds are important
determinants of bacterial survival in the host.
PMID- 10760153
TI - Death effector domain of a mammalian apoptosis mediator, FADD, induces bacterial
cell death.
AB - FADD is a mammalian pro-apoptotic mediator consisting of the N-terminal death
effector domain (DED) and the C-terminal death domain (DD). The N-terminal 88
residue fragment of murine FADD was defined as the stable structural unit of DED,
as determined by proteolytic digestion and conformational analysis. This domain
induced bacterial as well as mammalian cell death, whereas the full-length or DD
of FADD did not. The Escherichia coli cells expressing FADD-DED showed elongated
cell morphology and an increased level of nicked chromosomal DNA and mutation.
The lethality of FADD-DED was abolished by co-expression of thioredoxin and
superoxide dismutase or relieved by the addition of vitamin E as a reducing agent
and under anaerobic growth conditions. The toxicity of FADD-DED was genetically
suppressed by various oxidoreductases of E. coli. All these results suggest that
the death effector domain of mammalian FADD induced bacterial cell death by
enhancing cellular levels of reactive oxygen species (ROS).
PMID- 10760154
TI - Phosphorylcholine decoration of lipopolysaccharide differentiates commensal
Neisseriae from pathogenic strains: identification of licA-type genes in
commensal Neisseriae.
AB - Phosphorylcholine (ChoP) is a potential candidate for a plurispecific vaccine,
because it is present on surface components of many mucosal organisms, including
Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa. In
addition, ChoP has been detected on pili of Neisseria meningitidis and Neisseria
gonorrhoeae. In this study, we demonstrate the presence of the phosphorylcholine
epitope on the lipopolysaccharides (LPSs) of several species of commensal
Neisseriae (Cn), a property that differentiates commensal from the pathogenic
strains of Neisseriae. In an extended survey of 78 strains, we confirmed the
exclusive expression of the ChoP epitope on pili of pathogenic Neisseriae.
Despite the presence of pili on Cn, which are homologous to Class II pili of N.
meningitidis, they did not react with anti-ChoP antibody. This observation was
further supported by the fact that 14C-labelled choline was incorporated only in
the LPSs of Cn. Analysis of the LPS of N. lactamica strain NL4 revealed two
distinct and interconvertible molecular species of LPS with high and low levels
of reactivity with anti-ChoP antibody. In addition, on/off phase variation gave
rise to frequent modulation in the levels of antibody reactivity. A concurrent
modulation was also observed in the binding of C-reactive protein, CRP, a ChoP
binding reactant that is implicated in bacterial clearance. Genetic analysis
showed the presence of a gene in several Cn spp. with significant sequence
identity to H. influenzae licA. This gene encodes choline kinase and is also
involved in phase variation of the LPS-associated ChoP in H. influenzae. In
contrast, licA-like genes were not identified in the pathogenic Neisseria strains
tested. They are absent from N. meningitidis strain Z2491 genome database. These
data suggest that the genetic basis for ChoP incorporation in Cn LPS resembles
that in H. influenzae spp. and may be distinct from that generating the ChoP
epitope on pili of pathogenic Neisseriae. Further, the modulation of ChoP
expression on Cn LPS, and corresponding modulation of CRP binding, has the
potential to confer the property of immune avoidance and thus of persistence on
mucosa.
PMID- 10760155
TI - Identification of additional genes belonging to the LexA regulon in Escherichia
coli.
AB - Exposure of Escherichia coli to a variety of DNA-damaging agents results in the
induction of the global 'SOS response'. Expression of many of the genes in the
SOS regulon are controlled by the LexA protein. LexA acts as a transcriptional
repressor of these unlinked genes by binding to specific sequences (LexA boxes)
located within the promoter region of each LexA-regulated gene. Alignment of 20
LexA binding sites found in the E. coli chromosome reveals a consensus of 5'
TACTG(TA)5CAGTA-3'. DNA sequences that exhibit a close match to the consensus are
said to have a low heterology index and bind LexA tightly, whereas those that are
more diverged have a high heterology index and are not expected to bind LexA. By
using this heterology index, together with other search criteria, such as the
location of the putative LexA box relative to a gene or to promoter elements, we
have performed computational searches of the entire E. coli genome to identify
novel LexA-regulated genes. These searches identified a total of 69 potential
LexA-regulated genes/operons with a heterology index of <15 and included all
previously characterized LexA-regulated genes. Probes were made to the remaining
genes, and these were screened by Northern analysis for damage-inducible gene
expression in a wild-type lexA+ cell, constitutive expression in a lexA(Def) cell
and basal expression in a non-inducible lexA(Ind-) cell. These experiments have
allowed us to identify seven new LexA-regulated genes, thus bringing the present
number of genes in the E. coli LexA regulon to 31. The potential function of each
newly identified LexA-regulated gene is discussed.
PMID- 10760156
TI - NADP and NAD utilization in Haemophilus influenzae.
AB - Exogenous NAD utilization or pyridine nucleotide cycle metabolism is used by many
bacteria to maintain NAD turnover and to limit energy-dependent de novo NAD
synthesis. The genus Haemophilus includes several important pathogenic bacterial
species that require NAD as an essential growth factor. The molecular mechanisms
of NAD uptake and processing are understood only in part for Haemophilus. In this
report, we present data showing that the outer membrane lipoprotein e(P4),
encoded by the hel gene, and an exported 5'-nucleotidase (HI0206), assigned as
nadN, are necessary for NAD and NADP utilization. Lipoprotein e(P4) is
characterized as an acid phosphatase that uses NADP as substrate. Its phosphatase
activity is inhibited by compounds such as adenosine or NMN. The nadN gene
product was characterized as an NAD-nucleotidase, responsible for the hydrolysis
of NAD. H. influenzae hel and nadN mutants had defined growth deficiencies. For
growth, the uptake and processing of the essential cofactors NADP and NAD
required e(P4) and 5'-nucleotidase. In addition, adenosine was identified as a
potent growth inhibitor of wild-type H. influenzae strains, when NADP was used as
the sole source of nicotinamide-ribosyl.
PMID- 10760157
TI - Structural homology between MarA of the AraC family of transcriptional activators
and the integrase family of site-specific recombinases.
PMID- 10760158
TI - Developmental arrest of the human malaria parasite Plasmodium falciparum within
the mosquito midgut via CTRP gene disruption.
AB - Apicomplexan protozoa possess a family of micronemal and cell surface-associated
proteins, each comprised a combination of cell-adhesive vertebrate von Willebrand
factor (vWF)-like A domains and thrombospondin (TSP) type 1-like domains. The
human malaria parasite Plasmodium falciparum has in the extracellular portion of
the CS protein TRAP-related protein (CTRP) six tandemly arrayed A domains
followed by seven TSP type 1-like domains, whereas a second member of this
family, thrombospondin-related anonymous protein (TRAP), contains a single vWF
like A domain and a single TSP type 1-like domain. Here we show that CTRP
transcripts are present within the infected mosquito midgut and that CTRP protein
is expressed with a punctate distribution and a predominance at the apical end of
mosquito midgut-stage ookinetes. This expression pattern is analogous to
micronemal expression of TRAP in Plasmodium sporozoites. Disruption of the CTRP
gene by homologous recombination in cultures of the human malaria parasite P.
falciparum demonstrates that CTRP is essential for mosquito midgut development.
Oocyst formation was never observed following membrane feeds of CTRP disruptant
lines to Anopheline mosquitoes, despite the development of mature ookinetes. We
propose that CTRP is involved in essential recognition or motility processes at
the ookinete cell surface within the mosquito midgut.
PMID- 10760159
TI - AgfD, the checkpoint of multicellular and aggregative behaviour in Salmonella
typhimurium regulates at least two independent pathways.
AB - The regulatory programme of multicellular behaviour in Salmonella typhimurium is
determined by mutations in the agfD promoter. AgfD has already been identified to
regulate the extracellular matrix associated with the multicellular morphotype
composed of thin aggregative fimbriae (agf). To detect additional components
contributing to the multicellular morphotype in S. typhimurium, we constructed a
mutant in agfD, the positive transcriptional regulator of the agfBA(C) operon
encoding for fimbrial subunit proteins. The agfD mutant lacked any form of
multicellular behaviour as shown by analysis at the macroscopic and microscopic
level. In contrast, the agfBA mutant unable to form thin aggregative fimbriae
still maintained long-range intercellular adhesion. Promoter and expression
analysis revealed that the genes downstream of agfD agfEFG most likely did not
contribute to the remaining aggregative behaviour. Screening of transcriptional
fusions for agfD dependency uncovered adrA, a homologue of yaiC in Escherichia
coli. Environmental factors regulating adrA correspond to the regulation of thin
aggregative fimbriae. AdrA is a putative transmembrane protein with a C-terminal
GGDEF domain of unknown function although it is present in over 50 bacterial
proteins. AdrA mutant cells, which still formed thin aggregative fimbriae with
all binding characteristics, exhibited community behaviour but, unlike the wild
type, lacked long-range intercellular adhesion. An agfBA adrA double mutant
behaved like the agfD mutant. Therefore, it was concluded that agfD regulates at
least two independent pathways contributing to the multicellular morphotype in S.
typhimurium.
PMID- 10760160
TI - A monomeric histidine kinase derived from EnvZ, an Escherichia coli osmosensor.
AB - Histidine kinases function as dimers. The kinase domain of the osmosensing
histidine kinase EnvZ of Escherichia coli consists of two domains: domain A (67
residues) responsible for histidine phosphotransfer and dimerization, and domain
B (161 residues) responsible for the catalytic and ATP-binding function. The
individual structures of these two domains have been recently solved by NMR
spectroscopy. Here, we demonstrate that an enzymatically functional monomeric
histidine kinase can be constructed by fusing in tandem two domains A and one
domain B to produce a single polypeptide (A-A-B). We show that this protein,
EnvZc[AAB], is soluble and exists as a stable monomer. The autophosphorylation
and OmpR kinase activities of the monomeric EnvZc[AAB] are similar to that of the
wild-type EnvZ, while OmpR-binding and phosphatase functions are reduced. V8
protease digestion and mutational analyses indicate that His-243 of only the
amino proximal domain A is phosphorylated. Based on these results, molecular
models are proposed for the structures of EnvZc[AAB] and the kinase domain of
EnvZ. The present results demonstrate for the first time the construction of a
functional, monomeric histidine kinase, further structural studies of which may
provide important insights into the structure-function relationships of histidine
kinases.
PMID- 10760161
TI - Functional polarization of the Escherichia coli chromosome terminus: the dif site
acts in chromosome dimer resolution only when located between long stretches of
opposite polarity.
AB - In Escherichia coli, chromosome dimers are generated by recombination between
circular sister chromosomes. Dimers are lethal unless resolved by a system that
involves the XerC, XerD and FtsK proteins acting at a site (dif) in the terminus
region. Resolution fails if dif is moved from its normal position. To analyse
this positional requirement, dif was transplaced to a variety of positions, and
deletions and inversions of portions of the dif region were constructed.
Resolution occurs only when dif is located at the convergence of multiple,
oppositely polarized DNA sequence elements, inferred to lie in the terminus
region. These polar elements may position dif at the cell septum and be general
features of chromosome organization with a role in nucleoid dynamics.
PMID- 10760162
TI - The carbon metabolism-controlled Synechocystis gap2 gene harbours a conserved
enhancer element and a Gram-positive-like -16 promoter box retained in some
chloroplast genes.
AB - The two glyceraldehyde-3-phosphate dehydrogenase-encoding genes (gap) of
Synechocystis were shown to be expressed as monocistronic transcripts. Whereas
gap1 expression is slow and weak, gap2 gene induction is rapid and strong.
Transcription of the gap2 gene was shown to depend on functional photosynthetic
electron transport and on active carbon metabolism. The basal promoter of gap2
(P, -45 to +34, relative to the transcription start site) is controlled by three
cis-acting elements designated A (-443 to -45), B (+34 to +50, in the
untranslated leader region) and C (+50 to +167, in the coding region) that,
together, promote a 100-fold stimulation of P activity. Element B was found to
behave as a transcriptional enhancer, in that it was active regardless of its
position, orientation and distance relative to P. All three cis-acting
stimulatory elements exhibit a common 5'-agaTYAACg-3' nucleotide motif that
appears to be conserved in cyanobacteria and may be the target for a
transcriptional enhancer. We also report that gap2 transcription depends on a
Gram-positive-like -16 promoter box (5'-TRTG-3') that was obviously conserved
throughout the evolution of chloroplasts. This is the first report on the
occurrence of a -16 promoter element in photoautotrophic organisms.
PMID- 10760163
TI - Maturation and secretion of the non-typable Haemophilus influenzae HMW1 adhesin:
roles of the N-terminal and C-terminal domains.
AB - Non-typable Haemophilus influenzae is a common cause of human disease and
initiates infection by colonizing the upper respiratory tract. The non-typable H.
influenzae HMW1 and HMW2 adhesins mediate attachment to human epithelial cells,
an essential step in the process of colonization. HMW1 and HMW2 have an unusual N
terminus and undergo cleavage of a 441-amino-acid N-terminal fragment during the
course of their maturation. Following translocation across the outer membrane,
they remain loosely associated with the bacterial surface, except for a small
amount that is released extracellularly. In the present study, we localized the
signal sequence to the first 68 amino acids, which are characterized by a highly
charged region from amino acids 1-48, followed by a more typical signal peptide
with a predicted leader peptidase cleavage site after the amino acid at position
68. Additional experiments established that the SecA ATPase and the SecE
translocase are essential for normal export and demonstrated that maturation
involves cleavage first between residues 68 and 69, via leader peptidase, and
next between residues 441 and 442. Site-directed mutagenesis revealed that HMW1
processing, secretion and extracellular release are dependent on amino acids in
the region between residues 150 and 166 and suggested that this region interacts
with the HMW1B outer membrane translocator. Deletion of the C-terminal end of
HMW1 resulted in augmented extracellular release and elimination of HMW1-mediated
adherence, arguing that the C-terminus may serve to tether the adhesin to the
bacterial surface. These observations suggest that the HMW proteins are secreted
by a variant form of the general secretory pathway and provide insight into the
mechanisms of secretion of a growing family of Gram-negative bacterial
exoproteins.
PMID- 10760164
TI - Corynebacterium diphtheriae genes required for acquisition of iron from haemin
and haemoglobin are homologous to ABC haemin transporters.
AB - Corynebacterium diphtheriae and Corynebacterium ulcerans use haemin and
haemoglobin as essential sources of iron during growth in iron-depleted medium.
C. diphtheriae and C. ulcerans mutants defective in haemin iron utilization were
isolated and characterized. Four clones from a C. diphtheriae genomic library
complemented several of the Corynebacteria haemin utilization mutants. The
complementing plasmids shared an approximately 3 kb region, and the nucleotide
sequence of one of the plasmids revealed five open reading frames that appeared
to be organized in a single operon. The first three genes, which we have termed
hmuT, hmuU and hmuV, shared striking homology with genes that are known to be
required for haemin transport in Gram-negative bacteria and are proposed to be
part of an ABC (ATP-binding cassette) transport system. The hmuT gene encodes a
37 kDa lipoprotein that is associated with the cytoplasmic membrane when
expressed in Escherichi coli and C. diphtheriae. HmuT binds in vitro to haemin-
and haemoglobin-agarose, suggesting that it is capable of binding both haemin and
haemoglobin and may function as the haemin receptor in C. diphtheriae. This study
reports the first genetic characterization of a transport system that is involved
in the utilization of haemin and haemoglobin as iron sources by a Gram-positive
bacterium.
PMID- 10760165
TI - Antagonistic control of the Escherichia coli bgl promoter by FIS and CAP in
vitro.
AB - The wild-type Escherichia coli bgl promoter is silent in vivo but active in
vitro. Silencing in vivo is directed by silencer sequences that flank the
promoter, and requires nucleoid-associated protein H-NS and other unidentified
cellular factors. Here we show that the DNA bending protein FIS is a repressor of
the bgl promoter. Two FIS binding sites, centred at positions -52 and -27,
overlap the CAP binding site and the -35 box respectively. FIS efficiently
competes with CAP for binding to the wild-type promoter. However, FIS does not
prevent binding of RNA polymerase. It interferes with the formation of a heparin
resistant complex and represses transcription initiation up to 40-fold. The
presence of CAP has very little effect on the FIS-mediated repression of the wild
type bgl promoter in vitro. However, when a bgl promoter allele was tested that
carries an improved CAP binding site (which leads to activation in vivo) CAP
effectively counteracted repression by FIS in vitro. These results suggest that
FIS contributes to silencing of the wild-type bgl promoter in vivo, presumably in
the early exponential phase when FIS is predominantly expressed.
PMID- 10760166
TI - Genesis of BRO beta-lactamase-producing Moraxella catarrhalis: evidence for
transformation-mediated horizontal transfer.
AB - The dramatic rise in BRO-producing M. catarrhalis strains observed in the last
decades is without precedence. The aim of this study was to elucidate the events
that led to the emergence of BRO-1 and BRO-2 beta-lactamases. Previously, we
showed bro1 and bro2 to be >99% identical. Data presented here suggested that
bro2 was acquired by a fortuitous event and inserted between M. catarrhalis genes
orf1 and orf3. Subsequently, bro1 evolved from bro2. Promoter-up mutations
increased fitness of bro2, explaining its present predominance. The highly
conserved nature of bro compared with orf1 and orf3 suggested that acquisition
has occurred relatively recently. The random distribution of bro among M.
catarrhalis fingerprint types indicated that bro has spread by horizontal
transfer. Sequence analysis revealed that 80-200 bp is generally cotransferred
with bro, serving as regions of homology that target bro to the same chromosomal
locus. A region of 160 bases upstream of bro1 lacked polymorphism, indicating it
was derived from the original strain that acquired bro2. We observed that bro was
readily transferred by transformation between M. catarrhalis strains in vitro,
suggesting a mechanism by which bro has disseminated. In conclusion, we have been
able to reconstruct the steps that led to the emergence of BRO-producing M.
catarrhalis.
PMID- 10760167
TI - The gene for a halophilic beta-galactosidase (bgaH) of Haloferax alicantei as a
reporter gene for promoter analyses in Halobacterium salinarum.
AB - Investigations of transcriptional regulation and the characterization of
promoters in homologous expression systems are most easily performed using
suitable reporter genes. Presumably because of the high internal salt
concentration in halophilic Archaea, the successful application of the commonly
used reporter genes has not been reported so far. Recently, the gene for an
extremely halophilic beta-galactosidase (bgaH) from Haloferax alicantei has
become available. After transformation of Halobacterium salinarum with a vector
carrying bgaH, the enzyme activity in cell lysates could be readily determined by
a simple colorimetric assay and colonies could be screened for activity on plates
containing Xgal substrate. Expression of bgaH under the control of various
halobacterial promoters of known strength led to different specific beta
galactosidase activities in the lysates. Using Northern blot hybridization and
semiquantitative RT-PCR, it was shown that the bgaH transcript level corresponded
to the specific enzyme activity. Therefore, the bgaH gene of Haloferax alicantei
appears to be a useful tool for in vivo studies of gene expression in
Halobacterium salinarum and possibly other halophilic Archaea.
PMID- 10760168
TI - Sequence and expression of a halobacterial beta-galactosidase gene.
AB - Studies of gene expression in haloarchaea have been greatly hindered by the lack
of a convenient reporter gene. In a previous study, a beta-galactosidase from
Haloferax alicantei was purified and several peptide sequences determined. The
peptide sequences have now been used to clone the entire beta-galactosidase gene
(designated bgaH) along with some flanking chromosomal DNA. The deduced amino
acid sequence of BgaH was 665 amino acids (74 kDa) and showed greatest amino acid
similarity to members of glycosyl hydrolase family 42 [classification of
Henrissat, B., and Bairoch, A. (1993) New families in the classification of
glycosyl hydrolases based on amino acid sequence similarities. Biochem J 293: 781
788]. Within this family, BgaH was most similar (42-43% aa identity) to enzymes
from extremely thermophilic bacteria such as Thermotoga and Thermus. Family 42
enzymes are only distantly related to the Sulfolobus LacS and Escherichia coli
LacZ enzymes (families one and two respectively). Three open reading frames
(ORFs) upstream of bgaH were readily identified by database searches as glucose
fructose oxidoreductase, 2-dehydro-3-deoxyphosphogluconate aldolase and 2-keto-3
deoxygluconate kinase, enzymes that are also involved in carbohydrate metabolism.
Downstream of bgaH there was an ORF which contained a putative fibronectin III
motif. The bgaH gene was engineered into a halobacterial plasmid vector and
introduced into Haloferax volcanii, a widely used strain that lacks detectable
beta-galactosidase activity. Transformants were shown to express the enzyme;
colonies turned blue when sprayed with Xgal and enzyme activity could be easily
quantitated using a standard ONPG assay. In an accompanying publication, Patenge
et al. (2000) have demonstrated the utility of bgaH as a promoter reporter in
Halobacterium salinarum.
PMID- 10760169
TI - In vivo studies of upstream regulatory cis-acting elements of the alcR gene
encoding the transactivator of the ethanol regulon in Aspergillus nidulans.
AB - The alcR gene of Aspergillus nidulans, which encodes the specific transactivator
of the ethanol utilization pathway, is positively autoregulated and carbon
catabolite repressed. Regulation by these two circuits occurs at the
transcriptional level via the binding of the two regulators, AlcR and CreA, to
their cognate targets respectively. We demonstrate here that out of two clustered
putative AlcR repeated consensus sequences, only the palindromic target is
functional in vivo. Hence, it is solely responsible for the alcR positive
autogenous activation loop. Transcript mapping of the alcR gene showed that
transcription initiation can occur at 553 bp and at or near 86 bp upstream of the
start codon. These transcription start sites yield a transcript of 3.0 kb, which
appears only under induced growth conditions, and of 2.6 kb, which is present
under both induced and non-induced growth conditions respectively. Nine CreA
consensus sites are present in the alcR promoter but only two pairs of two sites
are functional in vivo. One of them is located in close proximity to the AlcR
functional target. Within this pair, both sites are necessary to mediate a
partial repression of alcR transcription. Disruption of either site results in an
overexpression of alcR due to the absence of direct competition between AlcR and
CreA for the same DNA region. The second functional pair of CreA sites is located
between the two transcription initiation sites. Disruption of either of the two
sites results in a totally derepressed alcR transcription, showing that they work
as a pair constituting the more efficient repression mechanism. Thus, CreA acts
by two different mechanisms: by competing with AlcR for the same DNA region and
by an efficient direct repression. The latter mechanism presumably interfers with
the general transcriptional machinery.
PMID- 10760170
TI - The aspartate chemoreceptor Tar is effectively methylated by binding to the
methyltransferase mainly through hydrophobic interaction.
AB - In the chemotaxis of Escherichia coli, adaptation requires the methylation and
demethylation of transmembrane receptors, which are catalysed by the
methyltransferase CheR and the methylesterase CheB respectively. CheR binds to
major chemoreceptors through their C-terminal motif NWETF, which is distinct from
the methylation sites. In this study, we carried out a systematic mutagenesis of
the pentapeptide sequence of Tar. Receptor methylation and adaptation were
severely impaired by the alanine substitution of residue W550 and, to a lesser
extent, by that of F553. Substitution of residues N549, E551 and T552 had only a
slight or little effect. The defects of the W550A and F553A mutations were
suppressed by high- and low-level overproduction of CheR respectively. Expression
of a fusion protein containing the NWETF sequence, but not its W550A and F553A
versions, inhibited chemotaxis of the Che+ strain. In an in vitro assay, CheR
bound to the wild-type version but not to the mutant versions. These results and
further mutagenesis suggest that the hydrophobicity and the size of residues W550
and F553 are critical in the interaction with CheR, a conclusion that is
consistent with the crystal structure of a CheR-NWETF complex. On the other hand,
the negatively charged side chain of E551 and the polar side chains of N549 and
T552 may not be strictly required, although the presence of a salt bridge and
hydrogen bonds between these residues and residues from CheR has been noted in
the co-crystal.
PMID- 10760172
TI - Localization of the histidine kinase PilS to the poles of Pseudomonas aeruginosa
and identification of a localization domain.
AB - Transcription of the type IV pilus subunit gene of Pseudomonas aeruginosa is
controlled by a two-component signal transduction system. PilS, the histidine
kinase, is membrane bound and PilR, its cognate response regulator, is
cytoplasmic. The signal that activates PilS is unknown. PilS has three domains:
(i) The N-terminus, predicted to form six transmembrane (TM) helices; (ii) a
central linker domain; and (iii) the C-terminal transmitter domain containing all
the conserved residues of sensor kinases. A translational fusion of the gfp gene
(green fluorescent protein) to the 3' end of pilS was used to determine the
position of PilS in the bacterial cell. Epifluorescence microscopy revealed that
PilS is retained to the poles of P. aeruginosa but is distributed evenly about
the membrane of Escherichia coli. Deletions of the PilS-GFP fusion revealed that
the TM domain was sufficient and necessary to bring GFP to the membrane of P.
aeruginosa and E. coli but was not sufficient to confine GFP to the poles.
Retention to the poles of P. aeruginosa required both the TM and linker domains.
Replacement of the PilS TM domain with an E. coli membrane protein, MalG, still
allowed polar localization. Therefore, the PilS TM domain positions the linker
domain close to the membrane allowing it to interact with the putative polar
anchor which is specific to P. aeruginosa.
PMID- 10760171
TI - Acid resistance of Helicobacter pylori depends on the UreI membrane protein and
an inner membrane proton barrier.
AB - ureI encodes an inner membrane protein of Helicobacter pylori. The role of the
bacterial inner membrane and UreI in acid protection and regulation of
cytoplasmic urease activity in the gastric microorganism was studied. The
irreversible inhibition of urease when the organism was exposed to a protonophore
(3,3',4', 5-tetrachlorsalicylanide; TCS) at acidic pH showed that the inner
membrane protected urease from acid. Isogenic ureI knockout mutants of several H.
pylori strains were constructed by replacing the ureI gene of the urease gene
cluster with a promoterless kanamycin resistance marker gene (kanR). Mutants
carrying the modified ureAB-kanR-EFGH operon all showed wild-type levels of
urease activity at neutral pH in vitro. The mutants resisted media of pH > 4.0
but not of pH < 4.0. Whereas wild-type bacteria showed high levels of urease
activity below pH 4.0, this ability was not retained in the ureI mutants,
resulting in inhibition of metabolism and cell death. Gene complementation
experiments with plasmid-derived H. pylori ureI restored wild-type properties.
The activation of urease activity found in structurally intact but permeabilized
bacteria treated with 0.01% detergent (polyoxy-ethylene-8-laurylether; C12E8),
suggested a membrane-limited access of urea to internal urease at neutral pH.
Measurement of 14C-urea uptake into Xenopus oocytes injected with ureI cRNA
showed acid activation of uptake only in injected oocytes. Acceleration of urea
uptake by UreI therefore mediates the increase of intracellular urease activity
seen under acidic conditions. This increase of urea permeability is essential for
H. pylori survival in environments below pH 4.0. ureI-independent urease activity
may be sufficient for maintenance of bacterial viability above pH 4.0.
PMID- 10760173
TI - The NC2 repressor is dispensable in yeast mutated for the Sin4p component of the
holoenzyme and plays roles similar to Mot1p in vivo.
AB - NC2 (Dr1/DRAP1) and Mot1p are global repressors of transcription that have been
isolated in both Saccharomyces cerevisiae and humans. NC2 is a dimeric histone
fold complex that represses RNA polymerase II transcription through binding to
TBP and inhibition of TFIIA and TFIIB. Mot1p is an ATPase that removes DNA-bound
TBP upon ATP hydrolysis. In this work, we studied the core promoter specificity
of NC2 in vivo using a strain that carries mutated NC2beta activity. We show that
NC2, like Mot1p, is required for transcription of the HIS3 and HIS4 TATA-less
core promoters. Furthermore, whereas neither Mot1p nor NC2 appear to function as
repressors of the HIS3 gene in cells growing exponentially in glucose, we find
that both are required for repression of the HIS3 TATA promoter when cells go
through the diauxic shift. Thus, the activity of these factors is similarly
regulated depending upon the physiological conditions, and it appears that core
promoters activated or repressed by them in vivo might be distinguishable by
whether or not they contain a canonical TATA sequence. Finally, although NC2 is
an essential factor for yeast viability, we isolated a mutation in a non
essential component of the holoenzyme, Sin4p, that bypasses the requirement for
NC2.
PMID- 10760174
TI - Identification of Escherichia coli K1 genes contributing to human brain
microvascular endothelial cell invasion by differential fluorescence induction.
AB - Most cases of Escherichia coli K1 meningitis arise as a result of haematogenous
spread, however there is a limited understanding of the mechanisms by which
circulating E. coli K1 cross the blood-brain barrier. We have previously shown
that environmental growth conditions both positively and negatively influence the
capabilities of E. coli K1 to invade brain microvascular endothelial cells
(BMEC), for example growth in media supplemented with 50% newborn bovine serum
(NBS) increased BMEC invasion, whereas growth in media supplemented with 0.2 M
NaCl repressed invasion in vitro and in vivo. In this study, differential
fluorescence induction (DFI) was used to identify E. coli K1 genes involved in
this differentially expressed invasion phenotype. E. coli K1 promoter libraries
were constructed and screened for gfp expression in a manner analogous to the
above growth conditions. Twenty-four clones were isolated that showed
fluorescence induction when grown under the invasion-enhancing condition (i.e.
NBS). Four of these clones also demonstrated repression or no induction of
fluorescence when grown under the invasion-repressing condition (i.e. 0.2 M
NaCl). One such clone, containing a ygdP promoter and an open reading frame
(ORF), showed significant homology to Bartonella bacilliformis IalA (invasion
associated locus). Among the other NBS-inducing loci, finPtraJ was identified as
well as several clones with no homology to other known genes. When ygdP, finPtraJ
and several of the unique loci were disrupted in E. coli K1, there was a
significant decrease in human BMEC (HBMEC) invasion. RNA transcript analysis
determined that these newly identified invasion loci were differentially
regulated at the transcriptional level. This is the first demonstration of using
DFI to identify E. coli K1 genes contributing to HBMEC invasion.
PMID- 10760175
TI - Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by
alternative drug interaction with domain II of 23S rRNA.
AB - The macrolide antibiotic erythromycin and its 6-O-methyl derivative
(clarithromycin) bind to bacterial ribosomes primarily through interactions with
nucleotides in domains II and V of 23S rRNA. The domain II interaction occurs
between nucleotide A752 and the macrolide 3-cladinose moiety. Removal of the
cladinose, and substitution of a 3-keto group (forming the ketolide RU 56006),
results in loss of the A752 interaction and an approximately 100-fold drop in
drug binding affinity. Within domain V, the key determinant of drug binding is
nucleotide A2058 and substitution of G at this position is the major cause of
drug resistance in some clinical pathogens. The 2058G mutation disrupts the drug
domain V contact and leads to a further > 25 000-fold decrease in the binding of
RU 56006. Drug binding to resistant ribosomes can be improved over 3000-fold by
forming an alternative and more effective contact to A752 via alkyl-aryl groups
linked to a carbamate at the drug 11/12 position (in the ketolide antibiotics HMR
3647 and HMR 3004). The data indicate that simultaneous drug interactions with
domains II and V strengthen binding and that the domain II contact is of
particular importance to achieve binding to the ribosomes of resistant pathogens
in which the domain V interaction is perturbed.
PMID- 10760176
TI - The Aspergillus niger transcriptional activator XlnR, which is involved in the
degradation of the polysaccharides xylan and cellulose, also regulates D-xylose
reductase gene expression.
AB - Screening of an Aspergillus niger differential cDNA library, constructed by
subtracting cDNA fragments of a xlnR loss-of-function mutant from wild-type cDNA
fragments, resulted in the cloning of the gene encoding D-xylose reductase
(xyrA). Northern blot analysis using an A. niger wild-type strain, a xlnR
multiple-copy strain and a xlnR loss-of-function mutant confirmed that the xyrA
gene is regulated by XlnR, the transcriptional activator of the xylanolytic
enzyme system in A. niger. D-xylose reductase catalyses the NADPH-dependent
reduction of D-xylose to xylitol, which is the first step in D-xylose catabolism
in fungi. Until now, XlnR was shown to control the transcription of genes
encoding extracellular hydrolytic enzymes involved in cellulose and xylan
degradation. In the present study, we show that A. niger is able to harmonize its
sugar metabolism and extracellular xylan degradation via XlnR by regulating the
expression of XyrA.
PMID- 10760177
TI - SC3 and SC4 hydrophobins have distinct roles in formation of aerial structures in
dikaryons of Schizophyllum commune.
AB - Two monokaryons of Schizophyllum commune can form a fertile dikaryon when the
mating-type genes differ. Monokaryons form sterile aerial hyphae, while dikaryons
also form fruiting bodies that function in sexual reproduction. The SC3
hydrophobin gene is expressed both in monokaryons and in dikaryons. The SC4
hydrophobin is dikaryon specific. In the monokaryon, SC3 lowers the water surface
tension, coats aerial hyphae with a hydrophobic layer and mediates attachment of
hyphae to hydrophobic surfaces. The SC4 protein lines gas channels within
fruiting bodies with a hydrophobic membrane. Using gene disruptions, in this
study, we show that in dikaryons SC3 fulfils the same roles as in monokaryons.
SC4, on the other hand, has a role within fruiting bodies. In contrast to gas
channels in fruiting bodies of the wild type, those of a DeltaSC4 strain easily
filled with water. Thus, SC4 prevents gas channels filling with water under wet
conditions, probably serving uninterrupted gas exchange. Other dikaryon-specific
hydrophobin genes, SC1 and SC6, apparently do not substitute for the SC4 gene. In
addition, by expressing the SC4 gene behind the SC3 promoter in a DeltaSC3
monokaryon, it was shown that SC4 cannot fully substitute for SC3, indicating
that both hydrophobins evolved to fulfil specific functions.
PMID- 10760178
TI - Transcription activation at the Escherichia coli melAB promoter: the role of MelR
and the cyclic AMP receptor protein.
AB - MelR is a melibiose-triggered transcription activator that belongs to the AraC
family of transcription factors. Using purified Escherichia coli RNA polymerase
and a cloned DNA fragment carrying the entire melibiose operon intergenic region,
we have demonstrated in vitro open complex formation and activation of
transcription initiation at the melAB promoter. This activation is dependent on
MelR and melibiose. These studies also show that the cyclic AMP receptor protein
(CRP) interacts with the melAB promoter and increases MelR-dependent
transcription activation. DNAase I footprinting has been exploited to investigate
the location of MelR-and CRP-binding sites at the melAB promoter. We showed
previously that MelR binds to two identical 18 bp target sequences centred at
position -100.5 (Site 1) and position -62.5 (Site 2). In this work, we show that
MelR additionally binds to two other related 18 bp sequences: Site 1', centred at
position -120.5, located immediately upstream of Site 1, and Site R, at position
238.5, which overlaps the transcription start site of the divergent melR
promoter. MelR can bind to Site 1', Site 1, Site 2 and Site R, in both the
absence and the presence of melibiose. However, in the presence of melibiose,
MelR also binds to a fifth site (Site 2', centred at position -42.5) located
immediately downstream of Site 2, and overlapping the -35 region of the melAB
promoter. Additionally, although CRP is unable to bind to the melAB promoter in
the absence of MelR, in the presence of MelR, it binds to a site located between
MelR binding Site 1 and Site 2. Thus, tandem-bound MelR recruits CRP to the MelR.
We propose that expression from the melAB promoter has an absolute requirement
for MelR binding to Site 2'. Optimal expression of the melAB promoter requires
Sites 1', Site 1, Site 2 and Site 2'; CRP acts as a 'bridge' between MelR bound
at Sites 1' and 1 and at Sites 2 and 2', increasing expression from the melAB
promoter. In support of this model, we show that improvement of the base sequence
of Site 2' removes the requirement for Site 1' and Site 1, and short circuits the
effects of CRP.
PMID- 10760179
TI - Repression of the Escherichia coli melR promoter by MelR: evidence that efficient
repression requires the formation of a repression loop.
AB - The Escherichia coli MelR protein is a transcription activator that, in the
presence of melibiose, activates expression of the melAB operon by binding to
four sites located just upstream of the melAB promoter. MelR is encoded by the
melR gene, which is expressed from a divergent transcript that starts 237 bp
upstream of the melAB promoter transcript start point. In a recent study, we have
identified a fifth DNA site for MelR that overlaps the melR promoter transcript
start and -10 region. Here we show that MelR binding to this site can
downregulate expression from the melR promoter; thus, MelR autoregulates its own
expression. Optimal repression of the melR promoter is observed in the absence of
melibiose and requires one of the four other DNA sites for MelR at the melAB
promoter. The two MelR binding sites required for this optimal repression are
separated by 177 bp. We suggest that, in the absence of melibiose, MelR forms a
loop between these two sites. We argue that, in the presence of melibiose, this
loop is broken as the melAB promoter is activated. However, in the presence of
melibiose, the melR promoter can still be partially repressed by MelR binding to
the site that overlaps the transcript start and -10 region. Parallels with the
Escherichia coli araC-araBAD regulatory region are discussed.
PMID- 10760180
TI - Agr-independent regulation of fibronectin-binding protein(s) by the regulatory
locus sar in Staphylococcus aureus.
AB - Fibronectin-binding proteins (FnBPs) are thought to be important for the
attachment of Staphylococcus aureus during infection. The regulation of the genes
fnbA and fnbB by the global regulatory loci sar and agr was examined using site
specific regulatory mutants of S. aureus strain Newman. The results from binding
assays using both aqueous and solid-phase fibronectin as well as ligand blotting
with biotinylated fibronectin showed that the expression of FnBPA is enhanced in
the agr mutant but inhibited in the sar mutant and the sar-agr double mutant. The
same regulatory pattern was observed in Northern blot analysis using fnbA
specific probes. The introduction of sar on a multicopy plasmid increased the
already enhanced fnbA transcription of the agr mutant. FnBPB was not detectable
by ligand blotting and the fnbB promoter activity in promoter fusion assays was
not affected by either sar or agr. The sequence encompassing ORF3 located
upstream of sarA was found to be essential for the activation of fnbA
transcription. We hypothesize that this sequence may modulate SarA expression
and/or activity on the post-transcriptional level. Gel shift assays demonstrated
that SarA binds to the fnbA promoter fragments, probably as a dimer. DNase I
footprinting assays with SarA revealed a protected area of 102 bp upstream of
fnbA.
PMID- 10760181
TI - Biological significance of a family of regularly spaced repeats in the genomes of
Archaea, Bacteria and mitochondria.
PMID- 10760182
TI - Vaccination against coccidiosis: host strain-dependent evocation of protective
and suppressive subsets of murine lymphocytes.
AB - BALB/c mice are normally more resistant than C57BL/6 (B6) mice to infection with
Eimeria vermiformis, but these phenotypes can be reversed by oral or parenteral
vaccination with a crude antigen prepared from the parasite. Treatment of mice
with antibodies specific for CD4+ or CD8+ T cells showed that the increased
susceptibility of vaccinated BALB/c mice was associated with the presence of CD4+
T cells. This finding was confirmed when the recipients of CD4+ T cells selected
from the mesenteric lymph nodes (MLN) of vaccinated BALB/c mice produced more
oocysts after challenge than the recipients of a similar population of cells from
sham-vaccinated mice. The residual population of cells (presumably enriched for
CD8+ T cells, 'CD8+'), on the other hand, conferred some protection and, in B6
mice, the findings were reversed. Thus, vaccination induced suppressive or
protective CD4+ cells and protective or suppressive 'CD8+' cells, depending upon
the normal resistance/susceptibility phenotype of the host. Examinations of the
isotypes (IgG1, IgG2a) of specific serum antibodies, and of the levels of IFN
gamma and IL-5 cytokines released by MLN cells stimulated ex vivo, did not allow
any further characterization of the mechanisms involved.
PMID- 10760183
TI - Cellular responses to Loa loa experimental infection in mandrills (Mandrillus
sphinx) vaccinated with irradiated infective larvae.
AB - In order to shed light on the mechanisms of antifilarial protective immunity, we
investigated the course of experimental loaiosis after vaccination in a nonhuman
primate host, Mandrillus sphinx. Six vaccinated (V) mandrills received 50
irradiated L3 while six nonvaccinated (NV) received saline solution on days -60,
30 and -15. All animals were challenged with 100 intact L3 (day 0).
Parasitological and immunological status were followed for 9 months. Vaccination
delayed the appearance and mean peak of microfilaraemia. Five mandrills (Mf-)
were never microfilaraemic (one V mandrill) or microfilaraemic on only one
occasion (2 V and 2 NV), the other seven having stable microfilaraemia (Mf+). The
cytokine response of peripheral blood mononuclear cells to L3 (L3 Ag) was Th2
dominated, while microfilariae (Mf Ag) elicited a Th0-like response. During
vaccination, Th2 cytokine production significantly increased in V mandrills
against L3 Ag, as well as Mf Ag, whereas Th1 cytokines decreased. On day 60
postinoculation, cellular proliferation was higher in V mandrills in response to
L3 and Mf Ags and PHA-L mitogen. At the end of prepatency (on day 130), mandrills
with delayed appearance of microfilaraemia exhibited a high, transient IL-2 and
IL-4 secretion in response to L3 Ag. Finally, high anti-Mf Th2 cytokine levels
characterized Mf-mandrills not only during prepatency, but also (for IL-5) before
immunization. However, the presence of a balanced Th1 anti-L3 response during
prepatency in the amicrofilaraemic mandrill suggests its importance in protective
immunity. Taken together, our data suggest that Th2 cells and also Th1 components
of the antifilarial response, especially to larval antigen, may contribute to
parasite elimination.
PMID- 10760184
TI - Differential immunoglobulin E and cytokine responses in BALB/c and C57Bl/6 mice
during repeated infections with blood-stage Plasmodium chabaudi malaria.
AB - Repeated blood-stage Plasmodium chabaudi chabaudi AS challenge infections in
BALB/c and C57Bl/6 mice result in increased serum immunoglobulin (Ig) E levels
and splenic cytokine production. The genetic background of the host influences
both the cytokine response as well as the development of IgE antibodies. BALB/c
mice showed high interleukin (IL)-4 secretion from splenocytes after in-vitro
stimulation with malaria antigen after repeated P. chabaudi challenges and this
was closely followed by higher levels of total IgE. Despite slightly elevated
serum IgE levels, splenocytes from C57Bl/6 mice did not secrete any detectable IL
4 but produced interferon (IFN)-gamma in response to malaria antigen-stimulation
in vitro. These data suggest that induction of IgE antibodies during murine
malaria infection is genetically regulated.
PMID- 10760185
TI - Cytoadherence of Plasmodium falciparum-infected erythrocytes in the human
placenta.
AB - In Plasmodium falciparum-parasitized pregnant women, erythrocytes infected by
mature stages of the parasite sequester into placental intervillous spaces. The
presence of parasites in the placenta causes maternal anaemia and low birth
weight of the infant. In-vitro studies suggest placental sequestration may
involve the cytoadherence of infected erythrocytes to chondroitin sulphate A
(CSA) and/or intercellular adhesion molecule 1 (ICAM-1) expressed by human
placental syncytiotrophoblast. We identified P. falciparum receptors expressed on
the surface of human syncytiotrophoblast using immunofluorescence of placental
biopsies from Cameroon, a malaria-endemic area. In all placentas, a strongly
positive staining was observed on the syncytiotrophoblast for CSA, but not for
ICAM-1, vascular endothelium cell adhesion molecule-1, E-selectin, nor CD36. The
cytoadherence ability of parasites from pregnant women and nonpregnant subjects
was assessed on in-vitro cultured syncytiotrophoblast. Parasites from pregnant
women bound to the trophoblast via CSA but not ICAM-1. Parasites from nonpregnant
hosts either did not bind to the trophoblast culture or bound using ICAM-1. Our
data support the idea that placental sequestration may result from cytoadherence
to placental trophoblast and that pregnant women are parasitized by parasites
that differ from parasites derived from nonpregnant host by their cytoadherence
ability.
PMID- 10760186
TI - Inhibition of the antiviral action of interferon by tick salivary gland extract.
AB - The saliva of haematophagous arthropods (e.g. mosquitoes, sandflies and ticks)
contains potent immunomodulatory activities that counter their hosts'
haemostatic, inflammatory and immune responses to facilitate blood-feeding. Such
effects are exploited by arthropod-transmitted pathogens to promote their
transmission. We investigated the ability of tick saliva to enhance arthropod
borne virus (arbovirus) transmission by determining its effect on the antiviral
action of murine interferon (IFN alpha/beta). Salivary gland extract (SGE) was
prepared from partially fed adult female Dermacentor reticulatus ticks that had
been feeding on mice for either 3 or 5 days (SGED3 and SGED5, respectively). We
demonstrated that SGE inhibits the antiviral effect of IFN as measured by a
biological assay using vesicular stomatitis virus (VSV), and by two-dimensional
electrophoretic analysis of the appearance of selected VSV proteins. The most
pronounced effect was observed when mouse L cells were treated with SGE prior to
IFN treatment. Following pretreatment with SGE, virus multiplication (which was
fully blocked by IFN treatment alone) achieved yields similar to those obtained
from infected cells not treated with IFN. Contemporaneous treatment, or treatment
with SGE after IFN, was less effective. In parallel with these findings,
formation of early viral proteins, N (nucleocapsid protein) and P
(phosphoprotein), which was blocked by IFN, was detectable following pretreatment
with SGE. The ability to inhibit the antiviral action of IFN was higher for SGED3
compared to SGED5. Demonstration that tick SGE can promote virus replication by
suppressing the action of IFN helps explain why ticks are such efficient vectors
of arboviruses.
PMID- 10760188
TI - Environmental health: responding to the call ellipsis
PMID- 10760187
TI - Anti-schistosome antibody responses in children coinfected with malaria.
AB - People residing in schistosome endemic areas are often infected with other
parasites. The interaction of the parasites in the host has important
implications in the development of acquired immunity to schistosomiasis, and
schistosome immuno-epidemiology. An analysis of specific anti-schistosome egg
responses in children coinfected with schistosomiasis and malaria shows that
malaria positive children produce significantly more anti-schistosome IgE and
IgG3 than schistosome infected children who are negative for malaria.
PMID- 10760189
TI - Public health nursing directors' perceptions regarding interagency collaboration
with community mental health agencies.
AB - Involvement in collaborative interagency relationships is crucial to the future
of public health nursing and public health agencies. The purpose of this study
was to describe public health nursing directors' perceptions regarding
relationships between public health agencies and mental health agencies in their
communities. A secondary analysis was conducted of textual responses to open
ended questions and unsolicited comments from 71 (55%) the of respondents to a
larger survey of nursing directors of all public health agencies in Ohio. Data
were analyzed inductively using content analysis for emergent themes and
patterns, which were organized and classified deductively according to a
community interagency collaboration framework. Public health nursing directors
described environmental, situational, task, and interagency factors that impact
collaboration between their agencies and local community mental health agencies.
These descriptions provide a context for understanding impediments to
collaboration between these two types of agencies, and have implications for
designing interventions to enhance public health nursing directors' skills at
marketing both their profession and their agencies. Collaborative relationships
between public health and mental health agencies could improve care for community
dwelling persons with severe mental disabilities and enhance the future of public
health nursing in a changing, competitive health care system.
PMID- 10760190
TI - Developing a caregiving tradition in opposition to one's past: lessons from a
longitudinal study of teenage mothers.
AB - Although teenage mothering has been exhaustively studied, the cross-sectional
designs and the deficit-finding focus of empirical-rational studies have
exaggerated the negative consequences of an early pregnancy and have obscured how
teenage mothering is often a rite of passage to adulthood, particularly in the
absence of middle-class resources and aspirations. In examining the experiences
of young mothers, an 8-year longitudinal study sought to understand how teenage
mothers extend and develop family caregiving traditions. The original sample
included 16 families and 39 subjects. Multiple individual and family interviews
were conducted once the teen's first-born infant reached 8 to 10 months of age,
and then 4 and 8 years later. Data from all three study periods were analyzed
using the interpretive method. The following analysis provides an in-depth
account of how young mothers with an oppressive past strive to become the parents
they want to be. In addition, the teen mother's difficulties and struggles of
creating a more positive maternal legacy and the role that positive and negative
examples of parenting play in fostering or hindering the development of a new
caregiving tradition are described. Study findings have implications for how
clinical practice and social policy can better assist mothers to become the
mothers they want to be.
PMID- 10760191
TI - Patient problems and advanced practice nurse interventions during transitional
care.
AB - This study is a secondary analysis of patient records written by advanced
practice nurses (APNs) as they provided discharge planning and 4 weeks of home
follow-up to elderly patients hospitalized with common medical and surgical
conditions. The purposes of this study were to examine the problems experienced
by elders who were hospitalized and discharged to home, the interventions used by
APNs as they cared for these patients, and the linkages between patient problems
and APN interventions. Care logs written by the APNs to document the patient
problems and nursing interventions were content analyzed and coded using the
Problem Classification Scheme and Intervention Scheme of the Omaha System. The
results provided a description of the 10 most frequent problems experienced by
the patients linked with the APN's interventions. The study provides a
description of the nature and complexity of patient problems as they transition
from hospital to home and increases our understanding of the contribution of APNs
to the care of elders.
PMID- 10760192
TI - What to do when the end is near: ethical issues in home health care nursing.
AB - As managed care shortens the length of hospital stays, home settings for the
practice of nursing will become increasingly important. In spite of community
health nursing's long tradition of family-centered care delivered in the home,
many discussions of the nurse/patient relationship in the medical ethics
literature assume the hospital setting for the practice of nursing and seem to
neglect the impact of family and significant others for the nurse/patient
relationship. Through a case-based analysis, this article highlights the special
ethical and legal issues encountered in caring for patients who are dying at
home. This analysis demonstrates that traditional frameworks for the
nurse/patient relationship are inadequate for capturing the richness of the
relationship the home health care nurse has with both patient and family. By
developing a new framework for the nurse/patient/family relationship that (a)
recognizes the patient's decision-making authority and autonomy, (b) allows the
exercise of the nurse's moral rights, and (c) recognizes the patient's
relationships to significant others, the authors attempt to resolve some
challenging legal and ethical questions concerning who should be allowed to
decide what to do when the end is near. The discussion details the implications
of this framework for nursing assessment in the home care setting.
PMID- 10760193
TI - Use of a Western theoretical model to investigate the relationships among
characteristics of pregnant women, utilization, and satisfaction with prenatal
care services in St. Petersburg, Russia.
AB - Few studies of utilization and satisfaction with prenatal care services have been
conducted internationally. In this study, utilization and satisfaction with
prenatal care services in St. Petersburg, Russia were examined using Aday and
Andersen's (1974) A Framework for the Study of Access to Medical Care. This study
was conducted under the auspices of the European Region, World Health
Organization (WHO) Healthy Cities Project, which promotes a community-based
intersectoral approach to meeting health needs. The convenience sample included
397 women with uncomplicated pregnancies and normal deliveries, representing an
86% response rate. Multiple regression and path analysis found significant
predictors of prenatal care utilization and satisfaction. They were different,
however, from those posited in the theoretical model. This indicates that Aday
and Andersen's health care services model is specific to the U. S. health care
system, where it originated. The Russian health care system has been and remains
different from that of the United States. If the reformed Russian health care
system takes on aspects of the U. S. health care system, the utility of Aday and
Andersen's theoretical model may change.
PMID- 10760194
TI - Enhancing low-income parents' capacities to promote their children's health:
education is not enough.
AB - In 1996 the Capital Heath Region in Edmonton, Alberta integrated a primary health
care component into Head Start programs. One aspect of the primary health care
component (PHC-HS) was a series of education sessions aimed at strengthening
parents' capacities to enhance their children's health. To make the education
sessions relevant, 10 focus groups with 65 parents of children who attended Head
Start were conducted prior to the sessions. Findings indicated that participants'
ability to enhance their children's health and manage their children's illnesses
was limited as much by low incomes, inadequate health care coverage, and lack of
transportation as it was by a lack of knowledge. Results provide evidence that
health education sessions alone are not adequate to significantly enhance low
income parents' capacities to promote their children's health. Efforts to
strengthen the abilities of low-income individuals and families to promote their
health will be most effective if health education is accompanied by policy
advocacy and social action strategies that challenge the socioeconomic and
political conditions that negatively affect health. Public health nursing's
commitment to social justice, as well as findings about the limitations that low
incomes, inadequate health care benefits, and lack of transportation placed on
participants' ability to enhance their children's health, underscore the need for
public health nurses (PHNs) to address structural conditions contributing to
health inequities. As such, an overview of literature that details strategies and
theoretical models for challenging socioeconomic and political conditions which
restrict the ability of low-income individuals and families to enhance their
health is provided.
PMID- 10760195
TI - Death and meaning in a storefront church.
AB - Nurses are often uncomfortable in addressing the needs of a spiritual family in
times of death and grieving. They frequently find that scientific explanations
and even emotional support fail to comfort individuals and families. This study,
based in a small Black storefront church, explores the meaning of death and the
experience of grieving among the deeply religious church members. Ethnographic
description and analysis of life history interviews were employed to analyze
these concepts. Church members had a particular way of managing the death of one
of their members or the death of a child. They made an attempt to "go on," and
they had a strong belief in an afterlife. Church members sometimes experienced
visions and visits from "the other side" that supported these beliefs. They had a
spiritual manner of comforting those left behind, speaking often of the
"homegoing" with acceptance, examining the purpose of the "journey" of one's
life, trying to inspire hope, and yet simultaneously preparing for death. Members
praised each other for doing all that they could for their loved one. The nurse
who cares for a spiritual family needs to carefully assess each family
individually, however, s/he may find that the approaches used by the church
members in caring for one another are helpful to incorporate into her/his care.
PMID- 10760196
TI - Teleform: a blessing or burden?
AB - Burgeoning technology has created numerous alternatives for even the most mundane
aspect of research, that is, data entry. Our research team is conducting a large
NIH NINR clinical trial, and data entry and management are important aspects of
this study. Our research team needed to decide whether to use manual data entry
or a scannable form of data entry. This article describes some of the advantages
and disadvantages related to our decision to use scannable data entry
Teleformtrade mark.
PMID- 10760197
TI - True HIV seroprevalence in Indian blood donors.
AB - The National AIDS Control Organization (NACO), the apex body for controlling AIDS
in India, projected that HIV seroprevalence would increase from 7/1000 in 1995 to
21.2/1000 in 1997. A high incidence (8.2%) of HIV was observed in blood donors.
This study was carried out to find out the true HIV positivity in Indian blood
donors. Blood donors from our centre were followed for more than 5 years to
determine the true HIV seroprevalence and our result was compared with similar
studies from India. Voluntary and relative blood donors who visited the SGPGIMS,
Lucknow, since 1993 to June 1998 were included. They were screened for HIV 1/2 by
ELISA kits (WHO approved). First-time HIV-positive samples were preserved frozen
for further study (stage-I). They were repeated in duplicate and retested with
other kits. If found positive, the sample was labelled as ELISA positive (stage
II). ELISA-positive samples were confirmed by Western Blot (WB) at stage-III. A
total of 65 288 donors were included and 834 (12.8/1000) were reactive at stage
I. But 1.1/1000 donors were found to be ELISA positive at stage-II, and 0.28/1000
donors were positive by WB at stage-III. The 'seropositivity' rate from the NACO
was significantly (P < 0.001) higher than our study. There were five similar
Indian studies and seropositivity rate varied from 0.72/1000 (using ELISA and WB)
to 5.5/1000 (using ELISA alone). The 'seropositivity' rate from the NACO was
significantly (P < 0.001) higher than all these studies. HIV seroprevalence in
the present study is lower (P < 0.001) than other Indian figures. The present and
other studies confirmed that the projected HIV seroprevalence (82/1000) in Indian
blood donors was high. The NACO result was based on one-time ELISA screening
reports from zonal blood testing centres which also receive samples from paid
donors donating in commercial blood banks. The HIV prevalence of blood donors
(and national prevalence) is to be reassessed.
PMID- 10760198
TI - The efficient organization of blood donation: what determines the number of
donors and donations?
AB - This study investigates the influence of socio-economic characteristics on the
number of donors in geographical areas in the North of Scotland as well as the
influence of panel-specific characteristics on the number of donations obtained
from each panel in the North of Scotland. Econometric models are applied to
establish the relationship between these variables. The main findings were that
there was no scope for identifying new areas in which to locate new panels or
extend the activities of existing panels because the number of donors in an area
was closely correlated with population. There was therefore little scope for
recruitment of donors by focusing on any particular area. It was found that
annual donations per panel are significantly influenced by the number of donors
invited, the number of opportunities to donate and the average length of
sessions. Combined with cost information, increasing the length of the session
appears to be the most cost-effective means of collecting higher volumes.
PMID- 10760199
TI - Haemodynamic response following a 10% topload infusion of HemolinkTM in
conscious, anaesthetized and treated spontaneously hypertensive rats.
AB - HemolinkTM (HLK), a haemoglobin-based oxygen carrier (HBOC), is currently
undergoing Phase II/III clinical trials in surgical patients. It causes some
blood pressure rise in animal and human tests. This study was designed to
investigate the systemic haemodynamic response to HemolinkTM in spontaneously
hypertensive rats (SHR rats). Conscious or anaesthetized SHR rats and control
Wistar Kyoto rats (WKY rats) received either HemolinkTM or homologous plasma as a
10% topload infusion. Some awake animals were pretreated with nifedipine and
followed by HLK infusion. In the conscious animal study, HLK induced a greater
pressure rise and less bradycardia in SHR rats than in WKY rats. In the
anaesthetized animal experiment, HLK-induced pressure rise and bradycardia were
similar in both strains and less pronounced than in the conscious animals. In the
nifedipine pretreated SHR rats, HLK-induced pressure rise was significantly
smaller than that observed in nontreated SHR rats and was not different from that
of nontreated WKY rats. The HLK-induced bradycardia was significantly smaller in
nifedipine-treated animals than in the nontreated SHR or WKY rats. This study
suggests that the pressor effect of HemolinkTM can be attenuated in hypertensive
animals with general anaesthesia or treatment with antihypertensive agents.
PMID- 10760200
TI - In vitro characteristics of red blood cell concentrates prepared from under- and
overcollected units of whole blood and from a paediatric blood bag system.
AB - The problem of how to deal with red blood cell concentrates (RBCs) prepared from
under- or overcollected units of whole blood (WB) and how to collect blood from
underweight persons arises in the context of autologous predeposit. To determine
the quality of RBCs stored in PAGGS-M additive solution prepared from under- and
overcollected units of whole blood and of PAGGS-M RBCs prepared from a paediatric
250-mL top outlet blood bag system we measured blood picture, haemolysis, K+, pH,
ATP and 2,3-DPG on days 0, 10, 20, 30, 40 and 49 of storage. The volume of WB
collected ranged from 150 to 600 mL in 50-mL increments (4 units per volume).
Haemolysis was under 0.8% on day 49 in all RBCs prepared from WB donations
between 200 mL and 600 mL. However, the day 49 haemolysis level of standard RBCs
prepared from 450 mL of WB (0.15 +/- 0.03%) was reached earlier in RBCs from
under- and overcollected units of whole blood. 2,3-DPG levels decreased rapidly
between days 10 and 20 in all RBCs studied. RBCs from 450-mL donations showed
acceptable ATP maintenance after 49 days (70.4% of day 0 value), while all other
RBC ATP levels were below 50% of the day 0 level on day 49. In vitro quality data
of RBCs prepared from a 250-mL donation in the paediatric blood bag system after
storage for about 25 days were comparable to those after 49 days of storage of
standard RBCs. Our results suggest that it is feasible to transfuse PAGGS-M RBCs
prepared from under- as well as overcollected units of WB in the autologous
setting. However, we strongly recommend shortening the storage period of such
RBCs to maintain the quality level of standard RBCs.
PMID- 10760201
TI - In vitro properties of red cells prepared from half-strength citrate CPD/RAS-2
(Erythro-sol) donations in PL-146 plastic.
AB - Whole blood donations were collected into 0.5CPD anticoagulant in PL-146 plastic.
This was shown to improve the stability of plasma FVIII levels when compared with
CPD. RAS-2 was used as additive and this improved the in vitro properties of the
red cells, such that post processing 2,3-DPG levels were maintained for 21 days
and ATP levels were maintained for 28 days. Whether or not such improvements in
red cell properties yield a benefit in clinical use remains to be established.
PMID- 10760202
TI - Quality assurance by a commercial flow cytometry method of leucodepletion of
whole blood donations: initial application of universal testing and proposals for
a batch-release sampling plan.
AB - We have used the Becton-Dickinson LeucoCOUNT test to monitor residual leucocytes
in whole blood by flow cytometry following leucodepletion filtration. This test
was found to be quick, robust and reliable, and allowed measurement of residual
leucocytes down to 2.25 x 104 leucocytes per unit, which was found to match
approximately the limit of filter proficiency. The results of testing > 1000
units showed a lognormal distribution with means between log(10) 4.864 (0.73 x
105) and log(10) 5.016 (1.04 x 105) leucocytes per unit in the three different
homogeneous groups of filtered units studied. The numbers of units with residual
leucocytes exceeding the 5 x 106 upper threshold were 1/577, 2/457 and 0/87 in
these groups. The filtration processes were validated according to the published
BEST working party guidelines and were well within the 99% confidence and 95%
tolerance target for the 5 x 106 upper threshold set for the UK. A sampling plan
based on British Standard BS 6001 with elimination of outliers by the extreme
studentized deviate (Grubbs' test) was evaluated on random samples from these
groups and has been adopted locally as a prospective batch-release criterion for
release of leucodepleted blood.
PMID- 10760203
TI - Differential leucocyte subpopulation analysis of leucodepleted red cell products.
AB - Donor leucocytes are responsible for many adverse transfusion effects. Clinical
reactions may be attributed to specific leucocyte subsets. In this study
leucocyte subpopulations were identified and quantified pre- and post
leucodepletion by integral filtration using novel Optipac(R) configurations
incorporating either WBF-1 (Pall Medsep) or RS2000 (Asahi) whole blood filters.
Leucocytes were analysed by flow cytometry using direct, four-colour, membrane
immunofluorescence with monoclonal antibodies specific for CD 3, 14, 16, 19 and
45. Filtration reduced the leucocyte load by 3-4 log10, consistently giving
products with < 2 cells microL-1. Subset distributions were also affected with
the proportion of neutrophils and monocytes increased and the lymphocyte/monocyte
ratio inverted. These effects were independent of the preprocessing hold
conditions, filter used and buffy coat (BC) removal. All filtered red cell
products contained 75-80% neutrophils, 16-20% monocytes and 2-7% lymphocytes.
Results presented here demonstrate that whole blood filtration, and BC removal,
significantly reduce the content and substantially alter the subpopulation
distribution of the donor leucocytes remaining in leucodepleted red cell
products.
PMID- 10760204
TI - Transfusion of platelet concentrates from pooled buffy-coats: comparison of
bedside vs. prestorage leukofiltration.
AB - Prestorage leucocyte filtration of platelet concentrates (PC) has been considered
to be superior to bedside filtration with regard to the incidence of
nonhaemolytic transfusion reactions (NHTR) or HLA-alloimmunization. It is
currently a matter of debate whether prestorage leucocyte filtration has an
impact on the storability of platelets and on the transfusion results of PC. In a
clinical retrospective study we investigated the transfusion results of PC from
pooled buffy-coats (PC-BC) in haematological patients without known
refractoriness to platelets, and compared bedside filtration (n = 228/36
patients) vs. prestorage filtration (n = 271/25 patients). Leukocyte and platelet
content of the PC, duration of storage, platelet count of the patient before
transfusion and 20 h after transfusion were determined and platelet increment and
corrected count increment (CCI) 20 h after transfusion were calculated. The mean
leucocyte content of the bedside filtered PC was 66 +/- 50 x 106 and < 0.1 x 106
for the prestorage filtered PC (P < 0.001). Mean platelet content of the PC (2.6
x 1011 vs. 2.7 x 1011) and the duration of PC storage (2.7 vs. 2.6 days) were
almost identical in both groups. The platelet increment after 20 h (14.6 x 109 L
1 vs. 14.9 x 109 L-1) was equal for both groups, but CCI values were
significantly higher for the bedside filtered PC (14.1 +/- 9.5 vs. 11.4 +/- 6.8)
(P = 0.008). Correlation with the storage time revealed that CCI levels were
higher for bedside filtered PC after short-term storage (< 36 h) (P = 0.014), but
declined more rapidly compared with prestorage filtered PC. A patient-based
analysis including fewer cases revealed superior but nonsignificant results for
bedside filtration. In conclusion, bedside filtered PC-BC resulted in better CCI
results after short-term storage, but values equalized with prestorage filtered
PC-BC after longer storage intervals. Prestorage-leucocyte filtration did not
improve platelet recovery in vivo, but CCI values decreased only moderately
throughout storage. Both preparations showed excellent transfusion results even
after a 5-day storage interval.
PMID- 10760205
TI - Quality assurance of progenitor cell content of apheresis products: a comparison
of clonogenic assays and CD34+ enumeration. The Canadian Apheresis Group and
Canadian Bone Marrow.
AB - The most common methods used for evaluation of the haematopoietic stem cell
content of peripheral blood apheresis products are the colony forming cell assay
and the enumeration of CD34+ cells by flow cytometry. The Canadian Apheresis
Group and the Canadian Bone Marrow Transplant Group established a multicentre
study to compare the reproducibility of colony forming cell assays and CD34+
enumeration by flow cytometry in six transplant centres routinely performing
haematopoietic stem cell apheresis. Over a 5-month period in 1996, 31 fresh
apheresis samples were shipped by overnight courier for testing at six centres to
perform CD34+ enumeration by flow cytometry and clonogenic assays. The mean
coefficient of variation and range for the following assays were: cell count 36%
(2.6-148%), CFU-GM 82% (46-123%), CD34+ absolute/kg 60% (14-174%) and CD34+ per
cent 42% (12-84%). The wide variation in cell count in this pilot study
highlights the difficulties related to provision of samples for quality
assessment programmes. Results showed poor interinstitutional reproducibility
even among selected samples with similar cell counts for both CFC and CD34+
assays demonstrating the need for development and implementation of an
interinstitutional quality assurance programme for haematopoietic stem cell
assessment. Provision of a reliable source of testing material will be a
necessary next step.
PMID- 10760206
TI - Platelet-specific antibodies in female blood donors after pregnancy.
AB - Sera of 500 female blood donors after pregnancy were tested for platelet-specific
antibodies (HPA-1, 3, 5) using the MAIPA assay. Twenty-one sera (4.2%) were found
to be positive: four anti-HPA-1a, one anti-HPA-5a and 16 anti-HPA-5b. Sera were
positive up to 30 years after the last pregnancy. All women with antibodies were
HLA-DR52 positive and 79% of the women with anti-HPA-5b were HLA-DR6 positive.
PMID- 10760207
TI - Neonatal thrombocytopenia in two of six human platelet alloantigen (HPA) 5a
positive children of an HPA-5a-immunized mother.
AB - We describe a human platelet alloantigen (HPA) 5a-alloimmunized HPA-5b5b mother.
The children were obligatory heterozygotes for HPA-5a but despite IgG class
maternal anti-HPA-5a antibodies only two (second and fifth) of the six children
developed neonatal thrombocytopenia. Throughout the 4-year follow-up the mother
had anti-HPA-5a antibodies (confirmed in the 8th Platelet serology workshop of
International Society of Blood Transfusion in 1996). Antibodies against
glycoproteins (GP) IIbIIIa or IbIX were not detected. Differences in the
children's HPA type (HPA-1, -2, -3, -5) did not correlate with thrombocytopenia.
We hypothesized that different expression of GPIaIIa recently associated with two
silent polymorphisms (C807T and G873A) of GPIa could explain the unpredictable
recurrence pattern of neonatal alloimmune thrombocytopenia (NAIT). Both parents
were homozygous for the silent polymorphisms (C807 and G873) associated with the
low expression of GP Ia. Thus, the inheritance pattern of the silent
polymorphisms (C807T and G873A) did not help in predicting the recurrence risk of
thrombocytopenia in the offspring. More detailed comprehension of the natural
history of NAIT would be necessary to enable directing fetal blood sampling to
the cases at the highest risk of thrombocytopenia.
PMID- 10760209
TI - The future is now
PMID- 10760208
TI - Severe haemolysis after an ABO unmatched kidney transplant - a nonsecretor
transplanted from a donor with high anti-A titre.
AB - A case of severe haemolysis following an ABO unmatched renal transplant is
reported in a group A nonsecretor who received a kidney from a group O living
related donor. Following the haemolytic episode, group A donor units were
incompatible and the patient was transfused with group O blood. Serological
investigation of the recipient revealed anti-A present in the serum and on the
red cells. Investigation of the donor revealed the presence of high-titre anti-A.
The association of such high-titre donor antibody with haemolysis in ABO
unmatched grafts has not been reported before. We discuss the risk factors for
developing haemolysis in an ABO unmatched organ transplant and explore the
possible relevance of such high donor antibody titre to recipients who are
nonsecretors.
PMID- 10760210
TI - Perspective article: the fate of collagen implants in tissue defects.
AB - The fate of collagen implants in a wound environment is determined by the host
response they elicit, their accommodation for cellular infiltration and their
susceptibility to proteolytic attack. Glutaraldehyde cross-linking is most
effective in delaying resorption and reducing an antibody response. The
proteolytic events reflect the sequence of cellular infiltration of inflammatory
cells during the proliferative phase of repair. The fibrous collagen implant is
initially degraded by matrix metalloproteinase-1 cleaving the triple helix into
3/4 and 1/4 helical fragments and by cathepsin cleavage of the telopeptide region
of the collagen molecule containing the intermolecular cross-links. The resulting
triple helical fragments denature at physiological temperature and the resulting
gelatin is rapidly degraded to amino acids by many proteases, primarily the
gelatinases (matrix metalloproteinase-2 and -9) and the cathepsins. A proportion
of the fiber fragments are phagocytosed and digested intracellularly by
cathepsins within the lysosomes. The collagen implant is ultimately degraded to
its constituent amino acids, which like all other protein metabolic products may
be re-utilized. The post-translational products, hydroxyproline and hydroxylysine
and the various cross-linking amino acids are excreted.
PMID- 10760211
TI - Mitogenic activity and cytokine levels in non-healing and healing chronic leg
ulcers.
AB - The cause of impaired healing in chronic leg ulcers is not known. However, recent
attempts to modify the healing process have focused on adding growth factors to
stimulate healing and have failed to produce dramatic improvements in healing.
This study used a unique model of chronic wound healing in humans to obtain wound
fluid samples from chronic venous leg ulcers that had changed from a nonhealing
to a healing phase. These samples were used to assess cytokine and growth factor
levels, and mitogenic activity in these nonhealing and healing chronic wounds.
The pro-inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis
factor-alphawere found to be present in significantly higher concentrations in
wound fluid from nonhealing compared to healing leg ulcers. There were detectable
levels but, no significant change in the levels of platelet derived growth
factor, epidermal growth factor, basic fibroblast growth factor or transforming
growth factor-betaas ulcers healed. Wound fluid was added to fibroblasts in vitro
to assess mitogenic activity. There was a significantly greater proliferative
response to healing wound fluid samples compared to nonhealing samples. These
results suggest that healing may be impaired by inflammatory mediators rather
than inhibited by a deficiency of growth factors in these chronic wounds.
PMID- 10760212
TI - Genetic modification of cultured skin substitutes by transduction of human
keratinocytes and fibroblasts with platelet-derived growth factor-A.
AB - Gene therapy promises the potential for improved treatment of cutaneous wounds.
This study evaluated whether genetically modified cultured skin substitutes can
act as vehicles for gene therapy in an athymic mouse model of wound healing.
Human keratinocytes and fibroblasts were genetically engineered by retroviral
transduction to overexpress human platelet-derived growth factor-A chain. Three
types of skin substitutes were prepared from collagen-glycosaminoglycan
substrates populated with fibroblasts and keratinocytes: HF-/HK-, containing both
unmodified fibroblasts and keratinocytes; HF-/HK+, containing unmodified
fibroblasts and modified keratinocytes; and HF+/HK-, containing modified
fibroblasts and unmodified keratinocytes. Skin substitutes were cultured for two
weeks before grafting to full-thickness wounds on athymic mice. The modified skin
substitutes secreted significantly elevated levels of platelet-derived growth
factor throughout the culture period. Expression of retroviral platelet-derived
growth factor-A mRNA was maintained after grafting to mice, and was detected in
all HF-/HK+ grafts and one HF+/HK- graft at two weeks after surgery. Although no
differences were seen between control and modified grafts, the results suggest
that genetically modified cultured skin substitutes can be a feasible mechanism
for cutaneous gene therapy. The cultured skin model used for these studies has
advantages over other skin analogs containing only epidermal cells; because it
contains both fibroblasts and keratinocytes, it therefore offers greater
opportunities for genetic modification and potential modulation of wound healing.
PMID- 10760213
TI - Adenoviral-mediated gene transfer in wound healing: acute inflammatory response
in human skin in the SCID mouse model.
AB - The use of an adenoviral vector as a means of therapeutic protein delivery for
the treatment of impaired wound healing is a potentially effective application of
current gene transfer techniques. This study was designed to investigate the
ability of adenovirus to mediate gene transfer in healing wounds in human skin in
vivo. The human skin/severe combined immunodeficient mouse chimera model was used
to study both the response of human tissue to adenoviral infection and the nature
of the acute inflammatory response. The effects of adenoviral infection and
transgene expression on the rate and quality of human wound healing were then
investigated. Cell- and species-specific monoclonal antibodies were used to
characterize the resident skin cell types participating in wound repair, the
inflammatory response, and the proliferative potential of adenovirus-treated
compared to control skin. Our studies show that, following wounding, normal skin
architecture is restored in the presence of adenoviral infection equivalent to
noninfected controls. Despite an increased acute inflammatory response after
adenovirus injection, no difference in the healing capabilities of wounded skin
was observed, suggesting that adenovirus-mediated gene transfer for growth factor
mediated acceleration of wound healing may be feasible.
PMID- 10760214
TI - Expression and localization of p53 and bcl-2 in healing wounds in diabetic and
nondiabetic mice.
AB - In a healing wound, inflammatory cells undergo apoptosis immediately beneath the
leading edge of migrating epithelium. A potential mediator of this apoptosis
pattern is p53, a protein with antiproliferative effects. Another protein, bcl-2,
is antagonistic to p53 and prevents apoptosis. The purpose of this study was to
determine the expression and location of p53 and bcl-2 mRNA and protein in
healing wounds of normal and genetically diabetic mice. At various time points,
full-thickness skin wounds from nondiabetic and diabetic mice were evaluated for
p53 and bcl-2 by immunohistochemistry and in situ hybridization. Apoptosis
patterns were also determined using the TUNEL method. Messenger RNA for p53 and
bcl-2 were quantitated by competitive reverse transcriptase-polymerase chain
reaction. Protein and mRNA for p53 were expressed in the leading edge of
migrating epithelium, with apoptosis patterns closely following those of p53
production. p53 mRNA levels decreased soon after wounding, but after a few days,
levels increased to greater than baseline. bcl-2 was localized to the wound
epithelium, but relative amounts tended to oppose levels of p53, i.e, when p53
increased, bcl-2 decreased and vice versa. Wounds in diabetic animals showed a
delayed onset of p53 mRNA expression but had persistently greater levels for
longer periods of time. bcl-2 mRNA expression was further delayed in diabetic
mice and did not develop to levels as high as p53. Production of both proteins
was delayed, consistent with the mRNA expression. Our data show that immediately
after wounding, bcl-2 increases and p53 decreases to allow for the cellular
proliferation that is required for tissue repair. Over time, bcl-2 levels
decrease while p53 levels increase to shut down the inflammatory process and down
regulate the proliferative response. Diabetic animals appear to lose the indirect
relationship between p53 and bcl-2. This loss may contribute to the altered
apoptosis patterns observed in diabetic healing.
PMID- 10760215
TI - Differential expression of hepatocyte growth factor and its receptor (c-Met) in a
rat artificial anus model.
AB - Hepatocyte growth factor is a multifunctional polypeptide that has been
implicated in cancer growth, tissue development and wound repair. It is mainly
synthesized in mesenchymal cells and acts on epithelial cells, where its actions
are dependent on binding to a specific cell-surface hepatocyte growth factor
receptor (c-Met). In an artificial anus, two different types of epithelial cells
(ductal cells of the colon and squamous cells of the skin) intermingle with each
other. In the present study, we examined the localization of hepatocyte growth
factor and c-Met during the process of repair in a rat artificial anus model, and
attempted to clarify the cell types that express hepatocyte growth factor or c
Met messenger RNA by in situ hybridization. Western blot analysis revealed
abundant localization of the mature form of hepatocyte growth factor in
artificial anal tissues. Moderate hepatocyte growth factor immunoreactivity was
noted in regenerated squamous cells in the skin and colonic ductal cells, and
strong expression in macrophages and fibroblasts. Moderate c-Met immunoreactivity
was present in regenerated epithelial cells in the skin and colon. Throughout the
repair process, hepatocyte growth factor and c-Met immunoreactivities were more
prominently localized in the squamous cells of the skin than in colonic ductal
cells. Competitive reverse transcription-polymerase chain reaction analysis
revealed that hepatocyte growth factor mRNA was maximal on day 14 after the
operation; however, c-Met mRNA expression had two peaks, on day 1 and day 7.
Hepatocyte growth factor mRNA was expressed more in the stromal fibroblasts,
macrophages and endothelial cells, and c-Met mRNA was predominant in regenerated
squamous cells of the skin. These findings suggest the possibility that
hepatocyte growth factor may act in a paracrine manner to mainly enhance the
growth of squamous cells of the skin and to a lesser extent the ductal cells of
the colon in the artificial anus.
PMID- 10760217
TI - Journal of WOCN: selected wound care article titles from journal of WOCN
PMID- 10760216
TI - Ischemia-reperfusion injury in chronic pressure ulcer formation: a skin model in
the rat.
AB - Most animal models of chronic pressure ulcers were designed to study only the
role of ischemic injury in wound formation, often using single applications of
constant pressure. The purpose of this study was to develop and characterize a
reproducible model of cyclic ischemia-reperfusion injury in the skin of small un
anesthetized animals using clinically relevant pressures and durations. Ischemia
reperfusion injury was created in a 9 cm2 region of dorsal skin in male rats by
periodically compressing skin under a pressure of 50 mm Hg using an implanted
metal plate and an overlying magnet. We varied the total number of ischemia
reperfusion cycles, examined the effect of varying the frequency and duration of
ischemic insult, and compared ischemia-induced injury to ischemia-reperfusion
induced injury with this model. Tissue injury increased with an increasing number
of total ischemia-reperfusion cycles, duration of ischemia, and frequency of
ischemia-reperfusion cycles. This model generates reproducible ischemia
reperfusion skin injury as characterized by tissue necrosis, wound thickness,
leukocyte infiltration, transcutaneous oxygen tension, and wound blood flow.
Using this model, the biological markers of ischemia-reperfusion-induced wound
development can be studied and therapeutic interventions can be evaluated in a
cost-effective manner.
PMID- 10760218
TI - Assessment of prolonged hospital stay attributable to surgical site infections
using appropriateness evaluation protocol.
AB - BACKGROUND: The accepted standard in estimating the stay prolongation
attributable to surgical site infections is the matched-cohort study method
(MCS), which is associated with selection bias. The Appropriateness Evaluation
Protocol (AEP) has been used to estimate stay prolongation attributable to
nosocomial infections but has not been validated specifically for surgical site
infections. AIM OF THE STUDY: To compare estimates of stay prolongation
attributable to surgical site infections after digestive surgery, obtained by AEP
and by MCS. METHODS: Sixty-five surgical site infections after digestive tract
surgery were analyzed by AEP and MCS. AEP stay prolongation was the number of
days judged specifically appropriate for the care of surgical site infections.
MCS stay prolongation was the difference of stay duration in surgical site
infection cases and two controls matched by age, sex, and diagnosis-related
groups. Sensitivity and specificity of AEP, and agreement between both methods,
were calculated. RESULTS: The mean AEP stay prolongation was 3.5 days vs 7.2 days
for MCS. The sensitivity of AEP was 58% and the specificity was 75%. The
agreement between the two methods was poor. CONCLUSION: Surgical site infections
after digestive tract surgery increased the hospital stay. Accurate estimations
of a prolongation of stay will vary according to the method selected.
PMID- 10760219
TI - Australian Infection Control Association members' use of skills and resources
that promote evidence-based infection control.
AB - BACKGROUND: To adopt an evidence-based approach, professionals must be able to
access, identify, interpret, and critically appraise best evidence. Critical
appraisal requires essential skills, such as computer literacy and an
understanding of research principles. These skills also are required for
professionals to contribute to evidence. METHODS: In 1996, members of the
Australian Infection Control Association were surveyed to establish a profile
including the extent to which they were reading infection control publications,
using specific documents for policy and guideline development, developing and
undertaking research, publishing research, and using computers. The relationships
between demographics, computer use, and research activity were examined. RESULTS:
The response rate was 63. 4% (630/993). The study group comprised mostly women
(96.1%), and most (66.4%) were older than 40 years of age. Median infection
control experience was 4 years (mean, 5.4 years; range, <12 months to 35 years).
When developing guidelines and policies (92.7%; 584/630), infection control
professionals reviewed State Health Department Infection Control Guidelines and
Regulations. Research relating to infection control was undertaken by 21.5%
(135/628) of the sample, and 27.6% (37/134) of this group published their
research findings. Of the respondents (51.1%; 318/622) who used a computer to
undertake infection control tasks, the majority (89.0%) used a personal computer
for word processing. CONCLUSION: Regardless of infection control experience,
Australian infection control professionals must be adequately prepared to
contribute to, access, appraise, and where appropriate, apply best evidence to
their practice. We suggest that computer literacy, an understanding of research
principles, and familiarity with infection control literature are three essential
skills that infection control professionals must possess and regularly exercise.
PMID- 10760220
TI - Enterobacterial repetitive intergenic consensus polymerase chain reaction typing
of isolates of Enterobacter cloacae from an outbreak of infection in a neonatal
intensive care unit.
AB - BACKGROUND: Enterobacter cloacae has become a common cause of nosocomial
infections. This study was designed to investigate the pattern of spread of E
cloacae during an outbreak in a neonatal intensive care unit. METHODS:
Enterobacterial repetitive intergenic consensus polymerase chain reaction was
used to examine 111 E cloacae isolates from 17 patients, including 81 from
surveillance cultures, 23 from endotracheal tubes, 3 from eyes, and 1 each from
blood, urine, skin, and throat. Antibiotic susceptibility profiles were also
obtained. RESULTS: Infection with E cloacae resulted from endogenous bacteria and
from horizontal transmission. One group of 61 isolates, a third of which were
obtained from clinical specimens, was uniformly susceptible to imipenem and
ciprofloxacin only. A second group of 50 isolates, only 18% of which were
obtained from clinical specimens, was susceptible to all antibiotics tested
except for aminopenicillins and first-generation cephalosporins. CONCLUSION:
These data indicate that (1) patient-to-patient spread is an important cause of E
cloacae infection in the neonatal intensive care unit and (2) highly antibiotic
resistant E cloacae may emerge during an outbreak.
PMID- 10760221
TI - A cluster of necrotizing enterocolitis in term infants undergoing open heart
surgery.
AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease
of unknown cause that predominantly affects premature infants, but it has been
reported in term infants with congenital heart disease. METHODS: In August and
September of 1997, 4 cases of NEC in term infants with congenital heart disease
were identified among 24 infants undergoing cardiac surgical procedures at our
institution. Because nosocomial NEC had not previously been identified among
infants in our pediatric intensive care unit, a case-control study was conducted
to identify risk factors for NEC. All infants less than 4 months old undergoing
cardiac surgery without development of NEC during the epidemic period were
selected as controls. RESULTS: The only significant risk factor associated with
case-infants was a higher mean temperature gradient (rectal/toe) during the
immediate 12-hour postoperative period (4.0 degrees C vs 2.0 degrees C, P <.01).
Urine output was higher in control-infants in this postoperative period, although
not statistically significant (11.9 mL/h vs 6.1 mL/h, P =.15). CONCLUSION:
Although an infectious etiology cannot be ruled out, the cases of NEC in infants
with congenital heart disease after cardiac procedures may have resulted from
mesenteric ischemia associated with a low perfusion state in the perioperative
period.
PMID- 10760222
TI - Improved tuberculosis infection control practices in Maryland acute care
hospitals.
AB - BACKGROUND: In 1992 and 1993, the Maryland Hospital Association and the Maryland
Department of Health and Mental Hygiene conducted 2 surveys of tuberculosis
prevention practices in Maryland hospitals that showed poor compliance with the
1990 Centers for Disease Control and Prevention's guidelines for preventing
transmission of tuberculosis in health care facilities. OBJECTIVE: The objective
of this study was to assess compliance in 1997 with the Centers for Disease
Control and Prevention's guidelines in Maryland acute care hospitals. METHODS: A
written questionnaire with 3 components-Infection Control, Employee Health, and
Microbiology Laboratory-was mailed to 56 Maryland acute care hospitals. RESULTS:
Seventy-three percent of the surveys were returned. One hundred percent of
responding hospitals with tuberculosis isolation rooms reported negative pressure
ventilation, 6 air exchanges per hour, and air exhausted to the outside or
through high-efficiency particulate air filters. One hundred percent of the
responding hospitals reported providing National Institute for Occupational
Safety and Health-approved respiratory protection for health care workers; this
compared with 24% in 1992 (P <.01). One hundred percent of the responding
hospitals reported performing at least annual tuberculin skin testing; this
compared with 50% in 1992 (P <. 01). CONCLUSIONS: The survey results demonstrate
excellent compliance with the 1994 Centers for Disease Control and Prevention
recommendations for tuberculosis control in Maryland acute care hospitals, even
in those facilities determined to be at minimal to low risk for tuberculosis
exposure. The proposed Occupational Safety and Health Administration regulations
are unlikely to further reduce the risk of tuberculosis exposure to health care
workers in Maryland acute care hospitals.
PMID- 10760223
TI - APIC guideline for infection prevention and control in flexible endoscopy.
Association for Professionals in Infection Control.
PMID- 10760224
TI - APIC state-of-the-Art report: the role of infection control during construction
in health care facilities.
AB - The Association for Professionals in Infection Control and Epidemiology, Inc
(APIC), is a multidisciplinary organization of more than 12,000 health care
professionals who practice infection control and epidemiology within a variety of
health care settings. This report reviews issues the infection control
professional should consider related to construction and renovation projects in
health care facilities. Preventing transmission of infectious agents to
vulnerable patient populations, health care workers, and visitors remains an
important component of infection control programs. Environmental dispersal of
microorganisms during construction, resulting in nosocomial infections, has been
described previously, and select examples are provided in Table I as a reminder
that there is a solid, scientific basis for these concerns. Environmental
airborne contaminants and infectious agents are closely related to water and
moisture-related conditions and figure prominently in construction activity.
Weems et al have established construction activity as an independent variable for
infectious risks in such circumstances. Construction-related outbreak literature
will not be revisited in detail; however, pertinent citations will identify
resources as appropriate.
PMID- 10760225
TI - APIC State-of-the-Art Report: the implications of service animals in health care
settings.
PMID- 10760226
TI - Enterobacter cloacae graft infection/bacteremia in a hemodialysis patient.
PMID- 10760227
TI - Triclosan: a review of effectiveness and safety in health care settings.
AB - Triclosan is a widely accepted antimicrobial ingredient because of its safety and
antimicrobial efficacy. Triclosan is a unique antimicrobial well suited for use
in the health care industry in which mildness is a necessity to protect the
health care worker during repeated use and antimicrobial activity is a necessity
to protect public health. Triclosan has demonstrated immediate, persistent, broad
spectrum antimicrobial effectiveness and utility in clinical health care
settings. This review highlights the utility and effectiveness of a 1% triclosan
formulation for use in high-risk, high-frequency handwashing.
PMID- 10760229
TI - Seminar promotes sound infection control practices in first-year residents.
PMID- 10760228
TI - Critical care bug team: a multidisciplinary team approach to reducing ventilator
associated pneumonia.
AB - BACKGROUND: Ventilator-associated pneumonia rates in the medical-surgical
intensive care unit first exceeded the 90th percentile in September 1997 and were
significantly (P <.05) higher than National Nosocomial Infections Surveillance
System pooled mean data. In January 1998, a multidisciplinary "Critical Care Bug
Team" was developed by the Infection Control Committee to review 1997 National
Nosocomial Infections Surveillance System data for four adult intensive care
units in a 583-bed tertiary care hospital. METHODS: Membership included clinical
nurse specialists, a dietitian, a pharmacist, a respiratory therapist, an
infection control professional, a research specialist, and a physician adviser.
Having the team report directly to the hospital's Infection Control and Adult
Critical Care Committees maximized support for recommendations and provided a
direct link from patient care to hospital administration. By identifying issues,
evaluating patient care processes, performing literature searches, and monitoring
compliance, the team implemented numerous interventions, including policy and
procedure changes, purchasing of equipment, and implementation of various
education tools. RESULTS: Each member of the Critical Care Bug Team contributed
to a synergized effort that may have produced the desired outcome of decreasing
ventilator-associated pneumonia rates. Except for August 1998, ventilator
associated pneumonia rates have been below the 75th percentile since May 1998.
CONCLUSION: This study illustrates the effectiveness of a multidisciplinary team
approach devised to reduce and stabilize ventilator-associated pneumonia rates in
a medical-surgical intensive care unit.
PMID- 10760230
TI - Use of ICD-9-CM coding as a case-finding method for sternal wound infections
after CABG procedures.
PMID- 10760231
TI - [Use of thrombolytic treatment in patients with acute myocardial infarction in
Spain. Observations from the PRIAMHO study].
AB - INTRODUCTION AND OBJECTIVES: Scarce information is actually available in our
country regarding the use of thrombolytic treatment in patients with acute
myocardial infarction and how consistently the recommendations of the clinical
guidelines are being implemented. METHODS: Cohort study with one year follow-up
of patients with acute myocardial infarction admitted in 24 Spanish hospitals in
1995. Differences in clinical characteristics and prognosis from patients treated
with or without thrombolysis were compared. RESULTS: 2,191 of the 5,242 patients
(42%) admitted with an acute myocardial infarction received thrombolytic therapy
(range: 23%-63%). Reasons for exclusion in the rest were the absence of ST
segment elevation (35%), contraindications (16%), prehospital delay >12 h (35%),
and other causes (15%). Thrombolysis treated patients were at lower risk in
general because they had shorter prehospital delays and were younger, more likely
to be male, less frequently diabetic, with less prior history of angina or
infarction. The average delay in administering therapy was of 3 hours while the
average in-hospital delay was 50 minutes and depended only on the hospital where
patients where admitted, as it was shorter in small centers. t-PA was
administered in 49% of patients, streptoquinase in 46% and other drugs in 5%.
Although t-PA was given more often to younger patients, smokers, anterior and Q
wave infarctions, and to patients with shorter prehospital delays, the
determinant factor was the admission hospital with a frequency ranging from 9% to
96%. Patients not treated with thrombolytics had more complications during the
acute phase, and required more invasive procedures. They also had a higher
mortality at 28 days (17% vs. 10%, p < 0.0001) and at one-year follow-up (27% vs.
15%, p < 0.0001). Furthermore, a correlation was observed between mortality and
delay of treatment application. In multivariate analysis, thrombolytic treatment
was an independent predictor of survival at one year, with an odds ratio for
mortality of 0.8 (95% CI: 0.66-0.96). CONCLUSIONS: Thrombolytic therapy in Spain
does not yet conform to the recommendations of the actual guidelines for the
treatment of patients with acute myocardial infarction because it is underused,
especially in high-risk patients, the prehospital and in-hospital delays are too
long, and a huge variability exists between hospitals in the frequency and delays
of administration and selection of the drug that are not sufficiently explained
by the characteristics of the patients. In spite of this, mortality of treated
patients was 20% lower in comparison to the non-treated patients, after adjusting
for the other clinical factors with demonstrated prognostic value.
PMID- 10760232
TI - Semiautomated method for determination of cystine concentration in
polymorphonuclear leukocytes.
PMID- 10760233
TI - Falsely low direct HDL-cholesterol results in a patient with
dysbetalipoproteinemia.
PMID- 10760235
TI - HSP101: a key component for the acquisition of thermotolerance in plants.
PMID- 10760236
TI - Parental contribution to plant embryos.
PMID- 10760237
TI - Microtubule stabilization leads to growth reorientation in Arabidopsis trichomes.
AB - The single-cell trichomes in wild-type Arabidopsis are either unbranched or have
two to five branches. Using transgenic Arabidopsis plants expressing a green
fluorescent protein-microtubule-associated protein4 fusion protein, which
decorates the microtubular cytoskeleton, we observed that during trichome
branching, microtubules reorient with respect to the longitudinal growth axis.
Considering branching to be a localized microtubule-dependent growth
reorientation event, we investigated the effects of microtubule-interacting drugs
on branch induction in trichomes. In unbranched trichomes of the mutant stichel,
a change in growth directionality, closely simulating branch initiation, could be
elicited by a short treatment with paclitaxel, a microtubule-stabilizing drug,
but not with microtubule-disrupting drugs. The growth reorientation appeared to
be linked to increased microtubule stabilization and to aster formation in the
treated trichomes. Taxol-induced microtubule stabilization also led to the
initiation of new branch points in the zwichel mutant of Arabidopsis, which is
defective in a kinesin-like microtubule motor protein and possesses trichomes
that are less branched. Our observations suggest that trichome cell branching in
Arabidopsis might be mediated by transiently stabilized microtubular structures,
which may form a component of a multiprotein complex required to reorient freshly
polymerizing microtubules into new growth directions.
PMID- 10760238
TI - Heat shock protein 101 plays a crucial role in thermotolerance in Arabidopsis.
AB - Plants are sessile organisms, and their ability to adapt to stress is crucial for
survival in natural environments. Many observations suggest a relationship
between stress tolerance and heat shock proteins (HSPs) in plants, but the roles
of individual HSPs are poorly characterized. We report that transgenic
Arabidopsis plants expressing less than usual amounts of HSP101, a result of
either antisense inhibition or cosuppression, grew at normal rates but had a
severely diminished capacity to acquire heat tolerance after mild conditioning
pretreatments. The naturally high tolerance of germinating seeds, which express
HSP101 as a result of developmental regulation, was also profoundly decreased.
Conversely, plants constitutively expressing HSP101 tolerated sudden shifts to
extreme temperatures better than did vector controls. We conclude that HSP101
plays a pivotal role in heat tolerance in Arabidopsis. Given the high
evolutionary conservation of this protein and the fact that altering HSP101
expression had no detrimental effects on normal growth or development, one should
be able to manipulate the stress tolerance of other plants by altering the
expression of this protein.
PMID- 10760239
TI - Structural requirements for ligand binding by a probable plant vacuolar sorting
receptor.
AB - How sorting receptors recognize amino acid determinants on polypeptide ligands
and respond to pH changes for ligand binding or release is unknown. The plant
vacuolar sorting receptor BP-80 binds polypeptide ligands with a central Asn-Pro
Ile-Arg (NPIR) motif. tBP-80, a soluble form of the receptor lacking
transmembrane and cytoplasmic sequences, binds the peptide SSSFADSNPIRPVTDRAASTYC
as a monomer with a specificity indistinguishable from that of BP-80. tBP-80
contains an N-terminal region homologous to ReMembR-H2 (RMR) protein lumenal
domains, a unique central region, and three C-terminal epidermal growth factor
(EGF) repeats. By protease digestion of purified secreted tBP-80, and from ligand
binding studies with a secreted protein lacking the EGF repeats, we defined three
protease-resistant structural domains: an N-terminal/RMR homology domain
connected to a central domain, which together determine the NPIR-specific ligand
binding site, and a C-terminal EGF repeat domain that alters the conformation of
the other two domains to enhance ligand binding. A fragment representing the
central domain plus the C-terminal domain could bind ligand but was not specific
for NPIR. These results indicate that two tBP-80 binding sites recognize two
separate ligand determinants: a non-NPIR site defined by the central domain-EGF
repeat domain structure and an NPIR-specific site contributed by the interaction
of the N-terminal/RMR homology domain and the central domain.
PMID- 10760240
TI - Auxin regulates the initiation and radial position of plant lateral organs.
AB - Leaves originate from the shoot apical meristem, a small mound of
undifferentiated tissue at the tip of the stem. Leaf formation begins with the
selection of a group of founder cells in the so-called peripheral zone at the
flank of the meristem, followed by the initiation of local growth and finally
morphogenesis of the resulting bulge into a differentiated leaf. Whereas the
mechanisms controlling the switch between meristem propagation and leaf
initiation are being identified by genetic and molecular analyses, the radial
positioning of leaves, known as phyllotaxis, remains poorly understood. Hormones,
especially auxin and gibberellin, are known to influence phyllotaxis, but their
specific role in the determination of organ position is not clear. We show that
inhibition of polar auxin transport blocks leaf formation at the vegetative
tomato meristem, resulting in pinlike naked stems with an intact meristem at the
tip. Microapplication of the natural auxin indole-3-acetic acid (IAA) to the apex
of such pins restores leaf formation. Similarly, exogenous IAA induces flower
formation on Arabidopsis pin-formed1-1 inflorescence apices, which are blocked in
flower formation because of a mutation in a putative auxin transport protein. Our
results show that auxin is required for and sufficient to induce organogenesis
both in the vegetative tomato meristem and in the Arabidopsis inflorescence
meristem. In this study, organogenesis always strictly coincided with the site of
IAA application in the radial dimension, whereas in the apical-basal dimension,
organ formation always occurred at a fixed distance from the summit of the
meristem. We propose that auxin determines the radial position and the size of
lateral organs but not the apical-basal position or the identity of the induced
structures.
PMID- 10760241
TI - A role for ectophosphatase in xenobiotic resistance.
AB - Xenobiotic resistance in animals, plants, yeast, and bacteria is known to involve
ATP binding cassette transporters that efflux invading toxins. We present data
from yeast and a higher plant indicating that xenobiotic resistance also involves
extracellular ATP degradation. Transgenic upregulation of ecto-ATPase alone
confers resistance to organisms that have had no previous exposure to toxins.
Similarly, cells that are deficient in extracellular ATPase activity are more
sensitive to xenobiotics. On the basis of these and other supporting data, we
hypothesize that the hydrolysis of extracellular ATP by phosphatases and ATPases
may be necessary for the resistance conferred by P-glycoprotein.
PMID- 10760242
TI - Cosuppression of a plasma membrane H(+)-ATPase isoform impairs sucrose
translocation, stomatal opening, plant growth, and male fertility.
AB - The plasma membrane H(+)-ATPase builds up a pH and potential gradient across the
plasma membrane, thus activating a series of secondary ion and metabolite
transporters. pma4 (for plasma membrane H(+)-ATPase 4), the most widely expressed
H(+)-ATPase isogene in Nicotiana plumbaginifolia, was overexpressed in tobacco.
Plants that overexpressed PMA4 showed no major changes in plant growth under
normal conditions. However, two transformants were identified by their stunted
growth, slow leaf initiation, delayed stem bolting and flowering, and male
sterility. Protein gel blot analysis showed that expression of the endogenous and
transgenic pma4 was cosuppressed. Cosuppression was developmentally regulated
because PMA4 was still present in developing leaves but was not detected in
mature leaves. The glucose and fructose content increased threefold, whereas the
sucrose content remained unchanged. The rate of sucrose exudation from mature
leaves was reduced threefold and the sugar content of apical buds was reduced
twofold, suggesting failure of sucrose loading and translocation to the sink
tissues. Cosuppression of PMA4 also affected the guard cells, stomatal opening,
and photosynthesis in mature leaves. These results show that a single H(+)-ATPase
isoform plays a major role in several transport-dependent physiological
processes.
PMID- 10760243
TI - eid1: a new Arabidopsis mutant hypersensitive in phytochrome A-dependent high
irradiance responses.
AB - To identify specific mutants for components of phytochrome A (phyA) signaling in
Arabidopsis, we established a light program consisting of multiple treatments
with alternating red and far-red light. In wild-type seedlings, irradiation with
multiple red light pulses can reduce the amount of phyA, which in turn decreases
the high-irradiance responses (HIRs) mediated by the subsequent treatments with
far-red light. Our mutants were able to avoid this red light-dependent reduction
of the HIR. Here, we describe eid1, a new recessive mutant with increased
sensitivity to far-red light. The eid1 mutation maps to the top of chromosome 4.
The mutants showed no change in phenotype in darkness or under continuous white
light, but they exhibited an increased sensitivity to red light and an increased
persistence of HIR during prolonged dark phases after multiple short pulses of
far-red light. The eid1 seedlings accumulated normal amounts of phytochrome and
showed no alterations in the degradation or de novo synthesis of phyA. The
expression of the Eid1 phenotype requires the presence of phyA. Our data provide
evidence that EID1 is a negatively acting component in the phyA-dependent HIR
signaling pathway.
PMID- 10760244
TI - yellow-in-the-dark mutants of Chlamydomonas lack the CHLL subunit of light
independent protochlorophyllide reductase.
AB - Light-independent protochlorophyllide reduction leading to chlorophyll formation
in the dark requires both chloroplast and nuclear gene expression in
Chlamydomonas reinhardtii. Mutations in any one of the plastid (chlL, chlN, and
chlB) or nuclear (y-1 to y-10) genes required for this process result in the
phenotype of the yellow-in-the-dark or y mutants. Analysis of the chlL, chlN, and
chlB transcript levels in both light- and dark-grown wild-type and y mutant cells
showed that the y mutations have no effect on the transcription of these plastid
genes. Protein gel blot analysis showed that the CHLN and CHLB proteins are
present in similar amounts in light- and dark-grown wild-type cells, whereas CHLL
is present only in wild-type cells grown in the dark or at light intensities < or
=15 micromol m(-2) sec(-1). Analysis of chlL transcript distribution on polysome
profiles and rates of protein turnover in chloramphenicol-treated cells suggested
that CHLL formation is most probably blocked at translation initiation or
elongation. Furthermore, treatment of cells with metabolic inhibitors and
uncouplers of photosynthetic electron transport showed that regulation of CHLL
formation is linked to the physiologic status of the chloroplast. Similar to wild
type cells, y mutants contain nearly identical amounts of CHLN and CHLB when
grown in either light or darkness. However, no CHLL is present in any of the y
mutants except y-7, which contains an immunoreactive CHLL smaller than the
expected size. Our findings indicate that CHLL translation is negatively
photoregulated by the energy state or redox potential within the chloroplast in
wild-type cells and that nuclear y genes are required for synthesis or
accumulation of the CHLL protein.
PMID- 10760245
TI - Arabidopsis RTM2 gene is necessary for specific restriction of tobacco etch virus
and encodes an unusual small heat shock-like protein.
AB - Arabidopsis plants have a system to specifically restrict the long-distance
movement of tobacco etch potyvirus (TEV) without involving either hypersensitive
cell death or systemic acquired resistance. At least two dominant genes, RTM1 and
RTM2, are necessary for this restriction. Through a series of coinfection
experiments with heterologous viruses, the RTM1/RTM2-mediated restriction was
shown to be highly specific for TEV. The RTM2 gene was isolated by a map-based
cloning strategy. Isolation of RTM2 was confirmed by transgenic complementation
and sequence analysis of wild-type and mutant alleles. The RTM2 gene product is a
multidomain protein containing an N-terminal region with high similarity to plant
small heat shock proteins (HSPs). Phylogenetic analysis revealed that the RTM2
small HSP-like domain is evolutionarily distinct from each of the five known
classes of plant small HSPs. Unlike most other plant genes encoding small HSPs,
expression of the RTM2 gene was not induced by high temperature and did not
contribute to thermotolerance of seedlings. The RTM2 gene product was also shown
to contain a large C-terminal region with multiple repeating sequences.
PMID- 10760246
TI - Maize profilin isoforms are functionally distinct.
AB - Profilin is an actin monomer binding protein that, depending on the conditions,
causes either polymerization or depolymerization of actin filaments. In plants,
profilins are encoded by multigene families. In this study, an analysis of native
and recombinant proteins from maize demonstrates the existence of two classes of
functionally distinct profilin isoforms. Class II profilins, including native
endosperm profilin and a new recombinant protein, ZmPRO5, have biochemical
properties that differ from those of class I profilins. Class II profilins had
higher affinity for poly-l-proline and sequestered more monomeric actin than did
class I profilins. Conversely, a class I profilin inhibited hydrolysis of
membrane phosphatidylinositol-4,5-bisphosphate by phospholipase C more strongly
than did a class II profilin. These biochemical properties correlated with the
ability of class II profilins to disrupt actin cytoplasmic architecture in live
cells more rapidly than did class I profilins. The actin-sequestering activity of
both maize profilin classes was found to be dependent on the concentration of
free calcium. We propose a model in which profilin alters cellular concentrations
of actin polymers in response to fluctuations in cytosolic calcium concentration.
These results provide strong evidence that the maize profilin gene family
consists of at least two classes, with distinct biochemical and live-cell
properties, implying that the maize profilin isoforms perform distinct functions
in the plant.
PMID- 10760247
TI - The Arabidopsis abscisic acid response gene ABI5 encodes a basic leucine zipper
transcription factor.
AB - The Arabidopsis abscisic acid (ABA)-insensitive abi5 mutants have pleiotropic
defects in ABA response, including decreased sensitivity to ABA inhibition of
germination and altered expression of some ABA-regulated genes. We isolated the
ABI5 gene by using a positional cloning approach and found that it encodes a
member of the basic leucine zipper transcription factor family. The previously
characterized abi5-1 allele encodes a protein that lacks the DNA binding and
dimerization domains required for ABI5 function. Analyses of ABI5 expression
provide evidence for ABA regulation, cross-regulation by other ABI genes, and
possibly autoregulation. Comparison of seed and ABA-inducible vegetative gene
expression in wild-type and abi5-1 plants indicates that ABI5 regulates a subset
of late embryogenesis-abundant genes during both developmental stages.
PMID- 10760248
TI - Thinking about p24 proteins and how transport vesicles select their cargo.
PMID- 10760249
TI - Mutant ion channel in cochlear hair cells causes deafness.
PMID- 10760250
TI - Identifying expressed genes.
PMID- 10760251
TI - Filling in the GAPs in the ADP-ribosylation factor story.
PMID- 10760252
TI - A topological invariant to predict the three-dimensional writhe of ideal
configurations of knots and links.
AB - We present herein a topological invariant of oriented alternating knots and links
that predicts the three-dimensional (3D) writhe of the ideal geometrical
configuration of the considered knot/link. The fact that we can correlate a
geometrical property of a given configuration with a topological invariant
supports the notion that the ideal configuration contains important information
about knots and links. The importance of the concept of ideal configuration was
already suggested by the good correlation between the 3D writhe of ideal knot
configurations and the ensemble average of the 3D writhe of random configurations
of the considered knots. The values of the new invariant are quantized: multiples
of 4/7 for links with an odd number of components (including knots) and 2/7 plus
multiples of 4/7 for links with an even number of components.
PMID- 10760253
TI - Characteristic length scale of the intermediate structure in zero-pressure
gradient boundary layer flow.
AB - In a turbulent boundary layer over a smooth flat plate with zero pressure
gradient, the intermediate structure between the viscous sublayer and the free
stream consists of two layers: one adjacent to the viscous sublayer and one
adjacent to the free stream. When the level of turbulence in the free stream is
low, the boundary between the two layers is sharp, and both have a self-similar
structure described by Reynolds-number-dependent scaling (power) laws. This
structure introduces two length scales: one-the wall-region thickness-determined
by the sharp boundary between the two intermediate layers and the second
determined by the condition that the velocity distribution in the first
intermediate layer be the one common to all wall-bounded flows and in particular
coincide with the scaling law previously determined for pipe flows. Using recent
experimental data, we determine both these length scales and show that they are
close. Our results disagree with the classical model of the "wake region."
PMID- 10760254
TI - Photo-control of helix content in a short peptide.
AB - The alpha-helix is a key structural element in a wide range of peptides and
proteins. We report here the design, synthesis, and characterization of a
modified peptide in which the helix content can be reversibly photoregulated. The
peptide contains two cysteine residues that are cross-linked by an azobenzene
derivative in an intramolecular fashion. In accordance with the design, the
photoisomerization of the azobenzene cross-linker from the trans to the cis form
causes a large increase in the helix content of the peptide, in water.
PMID- 10760255
TI - The human DINB1 gene encodes the DNA polymerase Poltheta.
AB - The human DINB1 gene shares a high degree of homology with the Escherichia coli
dinB gene. Here, we purify the hDINB1-encoded protein and show that it is a DNA
polymerase. Because hDinB1 is the eighth eukaryotic DNA polymerase to be
described, we have named it DNA polymerase (Pol) theta. hPoltheta is unable to
bypass a cis-syn thymine-thymine dimer, nor does it bypass a (6-4) photoproduct
or an abasic site. We also examine the fidelity of hPoltheta on nondamaged DNA
templates by steady-state kinetic analyses and find that hPoltheta
misincorporates deoxynucleotides with a frequency of about 10(-3) to 10(-4). We
discuss the relationship between the fidelity of hPoltheta and its inability to
bypass DNA damage.
PMID- 10760256
TI - Crystal structure of the cystine C-S lyase from Synechocystis: stabilization of
cysteine persulfide for FeS cluster biosynthesis.
AB - FeS clusters are versatile cofactors of a variety of proteins, but the mechanisms
of their biosynthesis are still unknown. The cystine C-S lyase from Synechocystis
has been identified as a participant in ferredoxin FeS cluster formation. Herein,
we report on the crystal structure of the lyase and of a complex with the
reaction products of cystine cleavage at 1.8- and 1.55-A resolution,
respectively. The sulfur-containing product was unequivocally identified as
cysteine persulfide. The reactive persulfide group is fixed by a hydrogen bond to
His-114 in the center of a hydrophobic pocket and is thereby shielded from the
solvent. Binding and stabilization of the cysteine persulfide represent an
alternative to the generation of a protein-bound persulfide by NifS-like proteins
and point to the general importance of persulfidic compounds for FeS cluster
assembly.
PMID- 10760257
TI - Targeted inhibition of transcription elongation in cells mediated by triplex
forming oligonucleotides.
AB - Triple-helix-forming oligonucleotides (TFOs) bind in the major groove of double
stranded DNA at oligopyrimidine small middle dotoligopurine sequences and
therefore are candidate molecules for artificial gene regulation, in vitro and in
vivo. We recently have described oligonucleotide analogues containing N3'-P5'
phosphoramidate (np) linkages that exhibited efficient inhibition of
transcription elongation in vitro. In the present work we provide conclusive
evidence that np-modified TFOs targeted to the HIV-1 polypurine tract (PPT)
sequence can inhibit transcriptional elongation in cells, either in transient or
stable expression systems. The same constructs were used in transient expression
assays (target sequence on transfected plasmid) and in the generation of stable
cell lines (target sequence integrated into cellular chromosomes). In both cases
the only distinguishable feature between the cellular systems is the presence of
an insert containing the wild-type PPT/HIV-1 sequence, a mutated version with two
mismatches, or the absence of the insert altogether. The inhibitory action
induced by np-TFOs was restricted to the cellular systems containing the
complementary wild-type PPT/HIV-1 target, and consequently can be attributed only
to a triple-helix-mediated mechanism. As a part of this study we also have
applied an imaging technique to quantitatively investigate the dynamics of TFO
mediated specific gene silencing in single cells.
PMID- 10760258
TI - Peptide nucleic acids rather than RNA may have been the first genetic molecule.
AB - Numerous problems exist with the current thinking of RNA as the first genetic
material. No plausible prebiotic processes have yet been demonstrated to produce
the nucleosides or nucleotides or for efficient two-way nonenzymatic replication.
Peptide nucleic acid (PNA) is a promising precursor to RNA, consisting of N-(2
aminoethyl)glycine (AEG) and the adenine, uracil, guanine, and cytosine-N-acetic
acids. However, PNA has not yet been demonstrated to be prebiotic. We show here
that AEG is produced directly in electric discharge reactions from CH(4), N(2),
NH(3), and H(2)O. Electric discharges also produce ethylenediamine, as do NH(4)CN
polymerizations. AEG is produced from the robust Strecker synthesis with
ethylenediamine. The NH(4)CN polymerization in the presence of glycine leads to
the adenine and guanine-N(9)-acetic acids, and the cytosine and uracil-N(1)
acetic acids are produced in high yield from the reaction of cyanoacetaldehyde
with hydantoic acid, rather than urea. Preliminary experiments suggest that AEG
may polymerize rapidly at 100 degrees C to give the polypeptide backbone of PNA.
The ease of synthesis of the components of PNA and possibility of polymerization
of AEG reinforce the possibility that PNA may have been the first genetic
material.
PMID- 10760259
TI - Using antibody catalysis to study the outcome of multiple evolutionary trials of
a chemical task.
AB - Catalytic aldolase antibodies generated by immunization with two different, but
structurally related, beta-diketone haptens were cloned and sequenced to study
similarities and differences between independently evolved catalysts. Kinetic and
sequence analysis coupled with mutagenesis, structural, and modeling studies
reveal that the defining event in the evolution of these catalysts was a somatic
mutation that placed a lysine residue in a deep, yet otherwise unrefined,
hydrophobic pocket. We suggest that covalent chemistries may be as readily
selected from the immune repertoire as the traditional noncovalent interactions
that have formed the basis of immunochemistry until this time. Further, we
believe that these experiments recapitulate the defining events in the evolution
of nature's enzymes, particularly as they relate to chemical mechanism, catalytic
promiscuity, and gene duplication.
PMID- 10760260
TI - Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype
in a tumor model.
AB - Among the earliest and most important stages during tumorigenesis is the
activation of the angiogenic process, an event that is termed the "switch to the
angiogenic phenotype." We have developed an in vivo system that can reliably
recapitulate the stages in tumor development that represent this transition.
Using this model, we have harvested and studied tumor nodules that can be
distinguished from each other on the basis of their degree of vascularization.
Angiogenic tumor nodules were characterized by the presence of capillary vessels
as determined by factor VIII immunohistochemistry, and both angiogenic and
proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid
of microvessels and showed little angiogenic or proteolytic activity in vitro.
Addition of a specific metalloproteinase inhibitor resulted in the abrogation of
both angiogenic and proteolytic activities of the angiogenic nodules in vitro.
Comparative substrate gel electrophoresis detected the presence of a prominent
matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the
preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides
in the vascular nodules resulted in the loss of angiogenic potential both in
vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this
suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in
vivo by approximately 70%. These results strongly implicate the activity of MMP-2
as a requirement for the switch to the angiogenic phenotype and validate this
model as a reliable and reproducible tool by which to study other cellular and
biochemical factors involved in the acquisition of the angiogenic phenotype.
PMID- 10760261
TI - Effects of saturation mutagenesis of the phage SP6 promoter on transcription
activity, presented by activity logos.
AB - A full set of SP6 promoter variants with all possible single substitutions at
positions -17 to +5 was constructed. Transcription activities of these variants
were individually measured in vivo and in vitro to determine the contribution of
each base pair to the promoter activity. The in vivo activity was measured
indirectly by transcriptional interference of the replication of promoter-bearing
plasmids. This activity depends most highly on residues -11, -9, -8, -7, and +1
(initiation site). All substitutions at -11, -9, -8, and -7 abolished formation
of closed complexes, except for A-8C. These residues are involved in base
specific interactions with the polymerase, and the substitutions exhibit the same
strong inhibition in vitro. In contrast, the in vitro activities of some other
variants, measured on linearized templates, were different from those in vivo.
Some variants at -13, -4, and -2, among others, showed exceptionally higher
activities in vivo than in vitro, supporting the possibility that these residues
are involved in postbinding steps, including template melting and bending. The A
3T variant showed much lower activity in vivo than in vitro, but it bound to the
polymerase 2-fold more than the consensus sequence and is possibly involved in
polymerase binding. A quantitative hierarchy of all the base pairs is graphically
displayed by activity logos, revealing the energetic contribution of each base
pair to the activity.
PMID- 10760262
TI - Leading and lagging strand DNA synthesis in vitro by a reconstituted herpes
simplex virus type 1 replisome.
AB - The synthesis of double-stranded DNA by a rolling circle mechanism was
reconstituted in vitro with a replisome consisting of the DNA polymerase-UL42
complex and the heterotrimeric helicase-primase encoded by herpes simplex virus
type 1. Okazaki fragments 3 kilobases in length and leading strands that may
exceed 10 kilobases are produced. Lagging strand synthesis is stimulated by
ribonucleoside triphosphates. DNA replication appears to be processive because it
resists competition with an excess of (dT)(150)/(dA)(20). The single-strand DNA
binding protein ICP8 is not required, and high concentrations of ICP8 can, in
fact, inhibit lagging strand synthesis. The inhibition can, however, be overcome
by the addition of an excess of the UL8 component of the helicase-primase.
Rolling circle replication by the herpesvirus and bacteriophage T7 replisomes
appears to proceed by a similar mechanism.
PMID- 10760263
TI - Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of
p65 with the basal transcription machinery, irrespective of coactivator levels in
the cell.
AB - Glucocorticoids (GCs) are used to combat inflammatory diseases. Their beneficial
effect relies mainly on the inhibition of NF-kappaB- and/or AP-1-driven
proinflammatory gene expression. Previously, we have shown that GCs repress tumor
necrosis factor-induced IL-6 gene expression by an NF-kappaB-dependent nuclear
mechanism without changing the DNA-binding capacity of NF-kappaB or the
expression levels of the cytoplasmic inhibitor of NF-kappaB (IkappaB-alpha). In
the present work, we investigate the effect of GC repression on different natural
and/or recombinant NF-kappaB-driven reporter gene constructs in the presence of
increasing amounts of various coactivator molecules, such as CREB-binding protein
(CBP), p300, and SRC-1. We found that GCs maintain their repressive capacities,
irrespective of the amount of cofactor present in the cell. Similar results were
obtained for the reciprocal transrepression of a GC receptor (GR) element-driven
reporter gene by p65. We demonstrate that neither the expression levels of p65
and CBP nor their physical association are affected by activated GR. Using Gal4
chimeras, we show that repression by GCs is specific for p65-mediated
transactivation, ruling out competition for limiting nuclear factors as the major
underlying mechanism of gene repression. In addition, the transactivation
potential of a point-mutated Gal4-p65 variant with a decreased CBP interaction
capability is still repressed by GR. Finally, we present evidence that the
specificity of GC repression on p65-driven gene expression is codetermined by the
TATA box context.
PMID- 10760264
TI - A stimulus-specific role for CREB-binding protein (CBP) in T cell receptor
activated tumor necrosis factor alpha gene expression.
AB - The cAMP response element binding protein (CREB)-binding protein (CBP)/p300
family of coactivator proteins regulates gene transcription through the
integration of multiple signal transduction pathways. Here, we show that
induction of tumor necrosis factor alpha (TNF-alpha) gene expression in T cells
stimulated by engagement of the T cell receptor (TCR) or by virus infection
requires CBP/p300. Strikingly, in mice lacking one copy of the CBP gene, TNF
alpha gene induction by TCR activation is inhibited, whereas virus induction of
the TNF-alpha gene is not affected. Consistent with these findings, the
transcriptional activity of CBP is strongly potentiated by TCR activation but not
by virus infection of T cells. Thus, CBP gene dosage and transcriptional activity
are critical in TCR-dependent TNF-alpha gene expression, demonstrating a stimulus
specific requirement for CBP in the regulation of a specific gene.
PMID- 10760265
TI - Activation of gene expression by small molecule transcription factors.
AB - Eukaryotic transcriptional activators are minimally comprised of a DNA binding
domain and a separable activation domain; most activator proteins also bear a
dimerization module. We have replaced these protein modules with synthetic
counterparts to create artificial transcription factors. One of these, at 4.2
kDa, mediates high levels of DNA site-specific transcriptional activation in
vitro. This molecule contains a sequence-specific DNA binding polyamide in place
of the typical DNA binding region and a nonprotein linker in place of the usual
dimerization peptide. Thus our activating region, a designed peptide, functions
outside of the archetypal protein context, as long as it is tethered to DNA.
Because synthetic polyamides can, in principle, be designed to recognize any
specific sequence, these results represent a key step toward the design of small
molecules that can up-regulate any specified gene.
PMID- 10760266
TI - The Escherichia coli signal transducers PII (GlnB) and GlnK form heterotrimers in
vivo: fine tuning the nitrogen signal cascade.
AB - The PII protein is Escherichia coli's cognate transducer of the nitrogen signal
to the NRII (NtrB)/NRI (NtrC) two-component system and to adenylyltransferase.
Through these two routes, PII regulates both amount and activity of glutamine
synthetase. GlnK is the recently discovered paralogue of PII, with a similar
trimeric x-ray structure. Here we show that PII and GlnK form heterotrimers, in
E. coli grown in nitrogen-poor medium. In vitro, fully uridylylated heterotrimers
of the two proteins stimulated the deadenylylation activity of
adenylyltransferase, albeit to a lower extent than homotrimeric PII-UMP. Fully
uridylylated GlnK did not stimulate, or hardly stimulated, the deadenylylation
activity. We propose that uridylylated PII/GlnK heterotrimers fine-regulate the
activation of glutamine synthetase. The PII/GlnK couple is a first example of
prokaryotic signal transducer that can form heterotrimers. Advantages of hetero
oligomer formation as molecular mechanism for fine-regulation of signal
transduction are discussed.
PMID- 10760267
TI - Reversal of charge selectivity in transmembrane protein pores by using
noncovalent molecular adapters.
AB - In this study, the charge selectivity of staphylococcal alpha-hemolysin
(alphaHL), a bacterial pore-forming toxin, is manipulated by using cyclodextrins
as noncovalent molecular adapters. Anion-selective versions of alphaHL, including
the wild-type pore and various mutants, become more anion selective when beta
cyclodextrin (betaCD) is lodged within the channel lumen. By contrast, the
negatively charged adapter, hepta-6-sulfato-beta-cyclodextrin (s(7)betaCD),
produces cation selectivity. The cyclodextrin adapters have similar effects when
placed in cation-selective mutant alphaHL pores. Most probably, hydrated Cl(-)
ions partition into the central cavity of betaCD more readily than K(+) ions,
whereas s(7)betaCD introduces a charged ring near the midpoint of the channel
lumen and confers cation selectivity through electrostatic interactions. The
molecular adapters generate permeability ratios (P(K+)/P(Cl-)) over a 200-fold
range and should be useful in the de novo design of membrane channels both for
basic studies of ion permeation and for applications in biotechnology.
PMID- 10760268
TI - The Holliday junction in an inverted repeat DNA sequence: sequence effects on the
structure of four-way junctions.
AB - Holliday junctions are important structural intermediates in recombination, viral
integration, and DNA repair. We present here the single-crystal structure of the
inverted repeat sequence d(CCGGTACCGG) as a Holliday junction at the nominal
resolution of 2. 1 A. Unlike the previous crystal structures, this DNA junction
has B-DNA arms with all standard Watson-Crick base pairs; it therefore represents
the intermediate proposed by Holliday as being involved in homologous
recombination. The junction is in the stacked-X conformation, with two
interconnected duplexes formed by coaxially stacked arms, and is crossed at an
angle of 41.4 degrees as a right-handed X. A sequence comparison with previous B
DNA and junction crystal structures shows that an ACC trinucleotide forms the
core of a stable junction in this system. The 3'-C x G base pair of this ACC core
forms direct and water-mediated hydrogen bonds to the phosphates at the crossover
strands. Interactions within this core define the conformation of the Holliday
junction, including the angle relating the stacked duplexes and how the base
pairs are stacked in the stable form of the junction.
PMID- 10760269
TI - A statistical mechanical method to optimize energy functions for protein folding.
AB - We present a method for deriving energy functions for protein folding by
maximizing the thermodynamic average of the overlap with the native state. The
method has been tested by using the pairwise contact approximation of the energy
function and generating alternative structures by threading sequences over a
database of 1, 169 structures. With the derived energy function, most native
structures: (i) have minimal energy and (ii) are thermodynamically rather stable,
and (iii) the corresponding energy landscapes are smooth. Precisely, 92% of the
1,013 x-ray structures are stabilized. Most failures can be attributed to the
neglect of interactions between chains forming polychain proteins and of
interactions with cofactors. When these are considered, only nine cases remain
unexplained. In contrast, 38% of NMR structures are not assigned properly.
PMID- 10760270
TI - Osmotic stress, crowding, preferential hydration, and binding: A comparison of
perspectives.
AB - There has been much confusion recently about the relative merits of different
approaches, osmotic stress, preferential interaction, and crowding, to describe
the indirect effect of solutes on macromolecular conformations and reactions. To
strengthen all interpretations of measurements and to forestall further
unnecessary conceptual or linguistic confusion, we show here how the different
perspectives all can be reconciled. Our approach is through the Gibbs-Duhem
relation, the universal constraint on the number of ways it is possible to change
the temperature, pressure, and chemical potentials of the several components in
any thermodynamically defined system. From this general Gibbs-Duhem equation, it
is possible to see the equivalence of the different perspectives and even to show
the precise identity of the more specialized equations that the different
approaches use.
PMID- 10760271
TI - Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)
expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the
human breast carcinoma cell line MDA-MB-468.
AB - PC-cell derived growth factor (PCDGF) is an 88-kDa growth factor originally
purified from the highly tumorigenic teratoma PC cell line and corresponds to the
epithelin/granulin precursor. In teratoma cells, PCDGF expression was shown to be
essential for tumorigenicity. We have reported that PCDGF was expressed in
estrogen receptor-positive (ER(+)) human mammary epithelial cells in an estrogen
dependent fashion. In this study, we have investigated PCDGF expression in human
mammary epithelial cell lines ranging from immortalized nontumorigenic cells to
ER(+) and ER(-) breast carcinoma cells. Northern and Western blot analyses
indicated that PCDGF mRNA and protein expression was low in nontumorigenic cells
and increased in human breast carcinomas cell lines in a positive correlation
with their tumorigenicity. Treatment of the ER(-) MDA-MB-468 cells with anti
PCDGF neutralizing antibody resulted in a dose-dependent inhibition of their
proliferation, suggesting that secreted PCDGF acted as an autocrine growth factor
for breast carcinoma cells. We then examined the in vitro and in vivo growth
properties of MDA-MB-468 cells, where PCDGF expression had been inhibited by
antisense PCDGF cDNA transfection. Inhibition of PCDGF expression resulted in a
reduced proliferation rate in vitro and a 60-80% reduction in colony formation.
Tumor formation in vivo was dramatically inhibited in antisense cells with a 90%
inhibition of tumor incidence and tumor weight. These results demonstrate the
importance of PCDGF overexpression for the proliferation and tumorigenicity of
ER(-) breast carcinomas and suggest that PCDGF overexpression may play an
important role in human breast cancer.
PMID- 10760272
TI - MIR16, a putative membrane glycerophosphodiester phosphodiesterase, interacts
with RGS16.
AB - We have identified the protein MIR16 (for Membrane Interacting protein of RGS16)
from a yeast two-hybrid screen by using RGS16 as bait. MIR16 shares strong
homology with bacterial glycerophosphodiester phosphodiesterases. It interacts
with RGS16 and, more weakly, with several other selected RGS proteins. Analysis
of deletion mutants showed that the N-terminal region of the RGS domain in RGS16
is required for its interaction with MIR16. MIR16 is an integral membrane
glycoprotein, because it remained associated with membrane fractions after
alkaline treatment and because, in some cells, it is sensitive to digestion with
endoglycosidase H. By immunofluorescence and immunoelectron microscopy, MIR16 was
localized on the plasma membrane in liver and kidney and on intracellular
membranes in rat pituitary and cultured pituitary cells. MIR16 represents the
only integral membrane protein identified thus far to interact with an RGS domain
and, to our knowledge, is the only mammalian glycerophosphodiester
phosphodiesterase that has been cloned. The putative enzymatic activity of MIR16
and its interaction with RGS16 suggest that it may play important roles in lipid
metabolism and in G protein signaling.
PMID- 10760273
TI - The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein
associated with the actin cytoskeleton.
AB - Despite the recent positional cloning of the PKD1 and PKD2 genes, which are
mutated in the great majority of patients with autosomal-dominant polycystic
kidney disease (PKD), the pathogenic mechanism for cyst formation is still
unclear. The finding, that the PKD1 and PKD2 proteins interact with each other
through their COOH termini, suggests that both proteins are part of the same
protein complex or signal transduction pathway. Using a yeast two-hybrid screen
with the PKD2 protein, we isolated the PKD2-interacting protein Hax-1. The
specificity of the interaction was demonstrated by the fact that PKD2L, a protein
closely related to PKD2, failed to interact with Hax-1. Immunofluorescence
experiments showed that in most cells PKD2 and Hax-1 colocalized in the cell
body, but in some cells PKD2 and Hax-1 also were sorted into cellular processes
and lamellipodia. Furthermore we demonstrated an association between Hax-1 and
the F-actin-binding protein cortactin, which suggests a link between PKD2 and the
actin cytoskeleton. We speculate that PKD2 is involved in the formation of cell
matrix contacts, which are dysfunctional without a wild-type PKD2 protein, thus
leading to cystic enlargement of tubular structures in the kidney, liver, and
pancreas.
PMID- 10760274
TI - Role of AMP-activated protein kinase in the regulation by glucose of islet beta
cell gene expression.
AB - Elevated glucose concentrations stimulate the transcription of the pre-proinsulin
(PPI), L-type pyruvate kinase (L-PK), and other genes in islet beta cells. In
liver cells, pharmacological activation by 5-amino-4-imidazolecarboxamide
riboside (AICAR) of AMP-activated protein kinase (AMPK), the mammalian homologue
of the yeast SNF1 kinase complex, inhibits the effects of glucose, suggesting a
key signaling role for this kinase. Here, we demonstrate that AMPK activity is
inhibited by elevated glucose concentrations in MIN6 beta cells and that
activation of the enzyme with AICAR prevents the activation of the L-PK gene by
elevated glucose. Furthermore, microinjection of antibodies to the alpha2-
(catalytic) or beta2-subunits of AMPK complex, but not to the alpha1-subunit or
extracellular stimulus-regulated kinase, mimics the effects of elevated glucose
on the L-PK and PPI promoter activities as assessed by single-cell imaging of
promoter luciferase constructs. In each case, injection of antibodies into the
nucleus and cytosol, but not the nucleus alone, was necessary, indicating the
importance of either a cytosolic phosphorylation event or the subcellular
localization of the alpha2-subunits. Incubation with AICAR diminished, but did
not abolish, the effect of glucose on PPI transcription. These data suggest that
glucose-induced changes in AMPK activity are necessary and sufficient for the
regulation of the L-PK gene by the sugar and also play an important role in the
regulation of the PPI promoter.
PMID- 10760275
TI - Membrane-associated GAIP is a phosphoprotein and can be phosphorylated by
clathrin-coated vesicles.
AB - GAIP (G alpha interacting protein) is a member of the RGS (regulators of G
protein signaling) family and accelerates the turnover of GTP bound to Galphai,
Galphaq, and Galpha13. There are two pools of GAIP-a soluble and a membrane
anchored pool. The membrane-anchored pool is found on clathrin-coated vesicles
(CCVs) and pits in rat liver and AtT-20 pituitary cells. By treatment of a GAIP
enriched rat liver fraction with alkaline phosphatase, we found that membrane
bound GAIP is phosphorylated. By immunoprecipitation carried out on
[(32)P]orthophosphate-labeled AtT-20 pituitary cells stably expressing GAIP,
(32)P-labeling was associated exclusively with the membrane pool of GAIP.
Phosphoamino acid analysis revealed that phosphorylation of GAIP occurred largely
on serine residues. Recombinant GAIP could be phosphorylated at its N terminus
with purified casein kinase 2 (CK2). It could also be phosphorylated by isolated
CCVs in vitro. Phosphorylation was Mn(2+)-dependent, using both purified CK2 and
CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results
establish that GAIP is phosphorylated and that only the membrane pool is
phosphorylated, suggesting that GAIP can be regulated by phosphorylation events
taking place at the level of clathrin-coated pits and vesicles.
PMID- 10760277
TI - Seed plant phylogeny inferred from all three plant genomes: monophyly of extant
gymnosperms and origin of Gnetales from conifers.
AB - Phylogenetic relationships among the five groups of extant seed plants are
presently quite unclear. For example, morphological studies consistently identify
the Gnetales as the extant sister group to angiosperms (the so-called
"anthophyte" hypothesis), whereas a number of molecular studies recover
gymnosperm monophyly, and few agree with the morphology-based placement of
Gnetales. To better resolve these and other unsettled issues, we have generated a
new molecular data set of mitochondrial small subunit rRNA sequences, and have
analyzed these data together with comparable data sets for the nuclear small
subunit rRNA gene and the chloroplast rbcL gene. All nuclear analyses strongly
ally Gnetales with a monophyletic conifers, whereas all mitochondrial analyses
and those chloroplast analyses that take into account saturation of third-codon
position transitions actually place Gnetales within conifers, as the sister group
to the Pinaceae. Combined analyses of all three genes strongly support this
latter relationship, which to our knowledge has never been suggested before. The
combined analyses also strongly support monophyly of extant gymnosperms, with
cycads identified as the basal-most group of gymnosperms, Ginkgo as the next
basal, and all conifers except for Pinaceae as sister to the Gnetales + Pinaceae
clade. According to these findings, the Gnetales may be viewed as extremely
divergent conifers, and the many morphological similarities between angiosperms
and Gnetales (e.g., double fertilization and flower-like reproductive structures)
arose independently.
PMID- 10760276
TI - Action of the Caenorhabditis elegans GATA factor END-1 in Xenopus suggests that
similar mechanisms initiate endoderm development in ecdysozoa and vertebrates.
AB - In ecdysozoan protostomes, including arthropods and nematodes, transcription
factors of the GATA family specify the endoderm: Drosophila dGATAb (ABF/Serpent)
and Caenorhabditis elegans END-1 play important roles in generating this primary
germ layer. end-1 is the earliest expressed endoderm-specific gene known in C.
elegans and appears to initiate the program of gene expression required for
endoderm differentiation, including a cascade of GATA factors required for
development and maintenance of the intestine. Among vertebrate GATA proteins, the
GATA-4/5/6 subfamily regulates aspects of late endoderm development, but a role
for GATA factors in establishing the endoderm is unknown. We show here that END-1
binds to the canonical target DNA sequence WGATAR with specificity similar to
that of vertebrate GATA-1 and GATA-4, and that it functions as a transcriptional
activator. We exploited this activity of END-1 to demonstrate that establishment
of the vertebrate endoderm, like that of invertebrate species, also appears to
involve GATA transcriptional activity. Like the known vertebrate endoderm
regulators Mixer and Sox17, END-1 is a potent activator of endoderm
differentiation in isolated Xenopus ectoderm. Moreover, a dominant inhibitory
GATA-binding fusion protein abrogates endoderm differentiation in intact embryos.
By examining these effects in conjunction with those of Mixer- and Sox17beta
activating and dominant inhibitory constructs, we further establish the likely
relationships between GATA activity and these regulators in early development of
the vertebrate endoderm. These results suggest that GATA factors may function
sequentially to regulate endoderm differentiation in both protostomes and
deuterostomes.
PMID- 10760278
TI - Phylogeny of seed plants based on all three genomic compartments: extant
gymnosperms are monophyletic and Gnetales' closest relatives are conifers.
AB - Efforts to resolve Darwin's "abominable mystery"-the origin of angiosperms-have
led to the conclusion that Gnetales and various fossil groups are sister to
angiosperms, forming the "anthophytes." Morphological homologies, however, are
difficult to interpret, and molecular data have not provided clear resolution of
relationships among major groups of seed plants. We introduce two sequence data
sets from slowly evolving mitochondrial genes, cox1 and atpA, which unambiguously
reject the anthophyte hypothesis, favoring instead a close relationship between
Gnetales and conifers. Parsimony- and likelihood-based analyses of plastid rbcL
and nuclear 18S rDNA alone and with cox1 and atpA also strongly support a
gnetophyte-conifer grouping. Surprisingly, three of four genes (all but nuclear
rDNA) and combined three-genome analyses also suggest or strongly support
Gnetales as derived conifers, sister to Pinaceae. Analyses with outgroups
screened to avoid long branches consistently identify all gymnosperms as a
monophyletic sister group to angiosperms. Combined three- and four-gene rooted
analyses resolve the branching order for the remaining major groups-cycads
separate from other gymnosperms first, followed by Ginkgo and then (Gnetales +
Pinaceae) sister to a monophyletic group with all other conifer families. The
molecular phylogeny strongly conflicts with current interpretations of seed plant
morphology, and implies that many similarities between gnetophytes and
angiosperms, such as "flower-like" reproductive structures and double
fertilization, were independently derived, whereas other characters could emerge
as synapomorphies for an expanded conifer group including Gnetales. An initial
angiosperm-gymnosperm split implies a long stem lineage preceding the explosive
Mesozoic radiation of flowering plants and suggests that angiosperm origins and
homologies should be sought among extinct seed plant groups.
PMID- 10760279
TI - A lower jaw of Pondaungia cotteri from the Late Middle Eocene Pondaung Formation
(Myanmar) confirms its anthropoid status.
AB - Pondaungia cotteri is the largest primate known from the Late Middle Eocene
Pondaung Formation, Myanmar. Its taxonomic status has been the subject of much
debate because of the fragmentary nature of its remains. Initially described as
an anthropoid, some authors recently have associated it with adapid primates.
These debates have been fueled not only by the incompleteness of the fossils
attributed to Pondaungia but also by the reticence of many authors to regard Asia
as an important evolutionary theater for Eocene anthropoids. During the November
1998 Myanmar-French Pondaung Expedition, a right lower jaw was discovered that
yields the most nearly complete dentition of Pondaungia cotteri ever found: it
shows the complete horizontal ramus, alveoli for the second incisor and canine,
three premolars, and three molars. The symphysis showed all characteristics of
anthropoids but was unfused. The canine root is large, the first premolar is
absent, and the second premolar is single-rooted, reduced, and oblique in the
tooth row, as in anthropoids. The premolars show a reduced mesio-distal length
compared with the tooth row, and their morphology is very similar to that of
Amphipithecus mogaungensis. Therefore, the two Pondaung taxa appear to be closely
related to each other, with Siamopithecus as their sister taxon.
PMID- 10760280
TI - Ecological character displacement in Plethodon: biomechanical differences found
from a geometric morphometric study.
AB - Ecological character displacement describes a pattern where morphological
differences between sympatric species are enhanced through interspecific
competition. Although widely considered a pervasive force in evolutionary
ecology, few clear-cut examples have been documented. Here we report a case of
ecological character displacement between two salamander species, Plethodon
cinereus and Plethodon hoffmani. Morphology was quantified by using linear
measurements and landmark-based geometric morphometric methods for specimens from
allopatric and sympatric populations from two geographic transects in south
central Pennsylvania, and stomach contents were assayed to quantify food resource
use. Morphological variation was also assessed in 13 additional allopatric
populations. In both transects, we found significant morphological
differentiation between sympatric populations that was associated with a
reduction in prey consumption in sympatry and a segregation of prey according to
prey size. No trophic morphological or resource use differences were found
between allopatric populations, and comparisons of sympatric populations with
randomly paired allopatric populations revealed that the observed sympatric
morphological differentiation was greater than expected by chance. The major
trophic anatomical differences between sympatric populations relates to
functional and biomechanical differences in jaw closure: sympatric P. hoffmani
have a faster closing jaw, whereas sympatric P. cinereus have a slower, stronger
jaw. Because salamanders immobilize prey of different sizes in different ways,
and because the observed sympatric biomechanical differences in jaw closure are
associated with the differences in prey consumption, the observed character
displacement has a functional ecological correlate, and we can link changes in
form with changes in function in this apparent example of character displacement.
PMID- 10760281
TI - Compositional genomes: prebiotic information transfer in mutually catalytic
noncovalent assemblies.
AB - Mutually catalytic sets of simple organic molecules have been suggested to be
capable of self-replication and rudimentary chemical evolution. Previous models
for the behavior of such sets have analyzed the global properties of short
biopolymer ensembles by using graph theory and a mean field approach. In
parallel, experimental studies with the autocatalytic formation of amphiphilic
assemblies (e.g., lipid vesicles or micelles) demonstrated self-replication
properties resembling those of living cells. Combining these approaches, we
analyze here the kinetic behavior of small heterogeneous assemblies of
spontaneously aggregating molecules, of the type that could form readily under
prebiotic conditions. A statistical formalism for mutual rate enhancement is used
to numerically simulate the detailed chemical kinetics within such assemblies. We
demonstrate that a straightforward set of assumptions about kinetically enhanced
recruitment of simple amphiphilic molecules, as well as about the spontaneous
growth and splitting of assemblies, results in a complex population behavior. The
assemblies manifest a significant degree of homeostasis, resembling the
previously predicted quasi-stationary states of biopolymer ensembles (Dyson, F.
J. (1982) J. Mol. Evol. 18, 344-350). Such emergent catalysis-driven,
compositionally biased entities may be viewed as having rudimentary
"compositional genomes." Our analysis addresses the question of how mutually
catalytic metabolic networks, devoid of sequence-based biopolymers, could exhibit
transfer of chemical information and might undergo selection and evolution. This
computed behavior may constitute a demonstration of natural selection in
populations of molecules without genetic apparatus, suggesting a pathway from
random molecular assemblies to a minimal protocell.
PMID- 10760282
TI - Are variations in cuticular hydrocarbons of queens and workers a reliable signal
of fertility in the ant Harpegnathos saltator?
AB - One of the key features of insect societies is the division of labor in
reproduction between one or a few fertile individuals and many sterile nestmates
that function as helpers. The behavioral and physiological mechanisms regulating
reproduction in ant societies are still not very well understood, especially in
species in which all colony members are reproductively totipotent. In the
ponerine ant Harpegnathos saltator, queen-worker dimorphism is very limited, and
a few mated workers reproduce ("gamergates") once the founding queen becomes
senescent. Worker oviposition is regulated by highly directed aggressive
interactions among nestmates, who can recognize different levels of ovarian
activity. We show that variations in cuticular hydrocarbons (CHC) correlate with
oogenesis, both for queens and workers. 13,23-Dimethylheptatriacontane is present
in egg-layers, but not in infertile workers and queens. Proportions of other CHCs
vary as well, resulting in clear separation of the ants in a multivariate
analysis. Egg-layers are characterized by an elongation of the chain length of
CHCs. We used solid-phase microextraction to measure CHCs in live ants that were
experimentally induced to start producing eggs. Over a period of 118 days, CHC
profiles of infertile workers changed completely to that of reproductives. The
effect of age can be excluded in this modification. This striking correlation of
ovarian activity with CHC variation and its correspondence with the observed
recognition behavior exhibited by the workers toward egg-laying nestmates
suggests that CHCs serve as a fertility signal in the ant H. saltator, a reliable
basis for regulating reproduction.
PMID- 10760283
TI - Screening poly(dA/dT)- cDNAs for gene identification.
AB - Many genes expressed in the human genome have not been identified despite
intensive efforts. We observed that the presence of long poly(dA/dT) sequences in
the 3' end of cDNA templates contributes significantly to this problem, because
the hybrids formed randomly between poly(dA) and poly(dT) sequences of unrelated
cDNA templates lead to loss of many templates in the normalization/subtraction
reactions. The low abundant copies, which account for the majority of the
expressed genes, are affected in particular by this phenomenon. We have developed
a strategy called screening poly(dA/dT)(-) cDNAs for gene identification to
overcome this obstacle. Applying this strategy can significantly enhance the
efficiency of genome-wide gene identification and should have an impact on many
functional genomic studies in the postgenome era.
PMID- 10760284
TI - High metastatic potential in mice inheriting a targeted p53 missense mutation.
AB - To understand the relevance of p53 missense mutations in vivo, we generated a
mouse containing an arg-to-his substitution at p53 amino acid 172, which
corresponds to the R175H hot-spot mutation in human tumors by homologous
recombination. Inadvertently, this mouse contains the additional deletion of a G
nucleotide at a splice junction that attenuates levels of mutant p53 to near wild
type levels. Mice heterozygous for the mutant allele differed from p53(+/-) mice
in tumor spectrum, with a significant increase in the number of carcinomas and a
slight decrease in the number of lymphomas. More importantly, the osteosarcomas
and carcinomas that developed in these mutant mice frequently metastasized (69%
and 40%, respectively). In contrast, metastasis is rare in osteosarcomas of
p53(+/-) mice. Loss of heterozygosity studies of tumors indicated loss of
heterozygosity in only 1 of 11 tumors. These data indicate clear differences
between a p53 missense mutation and a null allele in tumorigenesis in vivo and
suggest that the p53R172HDeltag mutant represents a gain-of-function allele.
PMID- 10760285
TI - Sox6 is a candidate gene for p100H myopathy, heart block, and sudden neonatal
death.
AB - The mouse p locus encodes a gene that functions in normal pigmentation. We have
characterized a radiation-induced mutant allele of the mouse p locus that is
associated with a failure-to-thrive syndrome, in addition to diminished
pigmentation. Mice homozygous for this mutant allele, p(100H), show delayed
growth and die within 2 wk after birth. We have discovered that the mutant mice
develop progressive atrioventricular heart block and significant ultrastructural
changes in both cardiac and skeletal muscle cells. These observations are common
characteristics described in human myopathies. The karyotype of p(100H)
chromosomes indicated that the mutation is associated with a chromosome 7
inversion. We demonstrate here that the p(100H) chromosomal inversion disrupts
both the p gene and the Sox6 gene. Normal Sox6 gene expression has been examined
by Northern blot analysis and was found most abundantly expressed in skeletal
muscle in adult mouse tissues, suggesting an involvement of Sox6 in muscle
maintenance. The p(100H) mutant is thus a useful animal model in the elucidation
of myopathies at the molecular level.
PMID- 10760286
TI - The function of the human homolog of Saccharomyces cerevisiae REV1 is required
for mutagenesis induced by UV light.
AB - In Saccharomyces cerevisiae, most mutations induced by a wide range of mutagens
arise during translesion replication employing the REV1 gene product and DNA
polymerase zeta. As part of an effort to investigate mammalian mutagenic
mechanisms, we have identified cDNA clones of the human homologs of the yeast REV
genes and examined their function in UV mutagenesis. Previously, we described the
isolation of a human homolog of yeast REV3, the catalytic subunit of pol zeta,
and here report the identification and sequence of a human homolog of yeast REV1.
This gene was isolated by identifying an expressed sequence tag encoding a
peptide with similarity to the C terminus of yeast Rev1p, followed by sequencing
of the clone and retrieval of the remaining cDNA by 5' rapid amplification of
cDNA ends. The human gene encodes an expected protein of 1,251 residues, compared
with 985 residues in the yeast protein. The proteins share two amino-terminal
regions of approximately 100 residues with 41% and 20% identity, a region of
approximately 320 residues with 31% identity, and a central motif in which 11 of
13 residues are identical. Human cells expressing high levels of an hREV1
antisense RNA grew normally, and were not more sensitive to the cytotoxic effect
of 254 nm UV radiation than cells lacking antisense RNA. However, the frequencies
of 6-thioguanine resistance mutants induced by UV in the cells expressing
antisense hREV1 RNA were significantly lower than in the control (P = 0.01),
suggesting that the human gene has a function similar to that of the yeast
homolog.
PMID- 10760287
TI - Serological identification of embryonic neural proteins as highly immunogenic
tumor antigens in small cell lung cancer.
AB - Serological analysis of expression cDNA libraries (SEREX) derived from two small
cell lung cancer (SCLC) cell lines using pooled sera of SCLC patients led to the
isolation of 14 genes, including 4 SOX group B genes (SOX1, SOX2, SOX3, and
SOX21) and ZIC2. SOX group B genes and ZIC2 encode DNA-binding proteins; SOX
group B proteins regulate transcription of target genes in the presence of
cofactors, whereas ZIC2 is also suspected to be a transcriptional regulator.
These genes are expressed at early developmental stages in the embryonic nervous
system, but are down-regulated in the adult. Although SOX2 mRNA can be detected
in some adult tissues, ZIC2 is expressed only in brain and testis, and SOX1,
SOX3, and SOX21 transcripts are not detectable in normal adult tissues. Of SCLC
cell lines tested, 80% expressed ZIC2 mRNA, and SOX1, SOX2, and SOX3 expression
was detected in 40%, 50%, and 10%, respectively. SOX group B and ZIC2 antigens
elicited serological responses in 30-40% of SCLC patients in this series, at
titers up to 1:10(6). In sera from 23 normal adults, no antibody was detected
against SOX group B or ZIC2 proteins except for one individual with low-titer
anti-SOX2 antibody. Seroreactivity against SOX1 and 2 was consistently higher
titered than SOX3 and 21 reactivity, suggesting SOX1 and/or SOX2 as the main
antigens eliciting anti-SOX responses. Although paraneoplastic neurological
syndromes have been associated with several SCLC antigens, neurological symptoms
have not been observed in patients with anti-SOX or anti-ZIC2 antibodies.
PMID- 10760288
TI - Relative contributions of distinct MHC class I-dependent cell populations in
protection to tuberculosis infection in mice.
AB - A necessary role for cytotoxic T lymphocytes in protection against Mycobacterium
tuberculosis (MTB) has been suggested by studies of the beta2-microglobulin
deficient mouse, which is unable to present antigens through MHC class I and
class I-like molecules and invariably succumbs early after infection. To identify
the relative contributions of distinct putative MHC class I-dependent cell
populations in protection against tuberculosis, we compared a variety of gene
disrupted mouse strains for susceptibility to MTB infection. Among the strains
tested, the most susceptible mice, as measured by survival time and bacterial
loads, were the beta2-microglobulin(-/-), followed by transporter associated with
antigen processing deficient (TAP1(-/-)), CD8alpha(-/-), perforin(-/-), and CD1d(
/-) mice. These findings indicated that (i) CD8(+) T cells contribute to
protection against MTB, and their protective activity is only partially dependent
on perforin; (ii) beta2-microglobulin-dependent T cell populations distinct from
CD8(+) T cells also contribute to anti-MTB immunity; and (iii) protective immune
mechanisms are predominantly TAP-dependent, although TAP-independent mechanisms
also contribute to protection. Because CD1d-deficient animals were fully
resistant to MTB, other TAP-independent mechanisms must contribute to protection.
We suggest here that both classical and nonclassical MHC class I-restricted T
cells, distinct from CD1d-restricted cells, may be involved in protective immune
responses against tuberculosis.
PMID- 10760289
TI - Conversion of alpha-lactalbumin to a protein inducing apoptosis.
AB - In this study alpha-lactalbumin was converted from the regular, native state to a
folding variant with altered biological function. The folding variant was shown
to induce apoptosis in tumor cells and immature cells, but healthy cells were
resistant to this effect. Conversion to HAMLET (human alpha-lactalbumin made
lethal to tumor cells) required partial unfolding of the protein and a specific
fatty acid, C18:1, as a necessary cofactor. Conversion was achieved with alpha
lactalbumin derived from human milk whey and with recombinant protein expressed
in Escherichia coli. We thus have identified the folding change and the fatty
acid as two key elements that define HAMLET, the apoptosis-inducing functional
state of alpha-lactalbumin. Although the environment in the mammary gland favors
the native conformation of alpha-lactalbumin that serves as a specifier in the
lactose synthase complex, the conditions under which HAMLET was formed resemble
those in the stomach of the nursing child. Low pH is known to release Ca(2+) from
the high-affinity Ca(2+)-binding site and to activate lipases that hydrolyze free
fatty acids from milk triglycerides. We propose that this single amino acid
polypeptide chain may perform vastly different biological functions depending on
its folding state and the in vivo environment. It may be speculated that
molecules like HAMLET can aid in lowering the incidence of cancer in breast-fed
children by purging of tumor cells from the gut of the neonate.
PMID- 10760290
TI - Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell
carcinogenesis in vivo.
AB - Field cancerization predisposes the upper aerodigestive tract mucosa to the
formation of multiple primary tumors, when exposed to environmental carcinogens.
Up-regulation of epidermal growth factor receptor occurs early in squamous cell
carcinogenesis and is critical for the loss of growth control in a variety of
human cancers, including head and neck squamous cell carcinomas. In these tumor
cells in culture, epidermal growth factor receptor stimulation initiates
signaling via persistent activation of selective STAT proteins. To determine the
timing of Stat3 activation in head and neck carcinogenesis, we studied the
expression and constitutive activation of Stat3 in tumors and normal mucosa from
patients with head and neck cancer compared with mucosa from controls without
cancer. Stat3 was up-regulated and constitutively activated in both primary human
head and neck tumors as well as in normal mucosa from these cancer patients
compared with control normal mucosa from patients without cancer. In vivo
liposome-mediated gene therapy with a Stat3 antisense plasmid efficiently
inhibited Stat3 activation, increased tumor cell apoptosis, and decreased Bcl
x(L) expression in a head and neck xenograft model. These findings provide
evidence that constitutively activated Stat3 is an early event in head and neck
carcinogenesis that contributes to the loss of growth control by an anti
apoptotic mechanism.
PMID- 10760291
TI - Evidence for regulation of the PTEN tumor suppressor by a membrane-localized
multi-PDZ domain containing scaffold protein MAGI-2.
AB - PTEN is a tumor suppressor gene mutated in human cancers. Although many mutations
target the phosphatase domain, others create a truncated protein lacking the C
terminal PDZ-binding motif or a protein that extends beyond the PDZ-binding
motif. Using the yeast two-hybrid system, we isolated a membrane-associated
guanylate kinase family protein with multiple PDZ domains [AIP-1 (atrophin
interacting protein 1), renamed MAGI-2 (membrane associated guanylate kinase
inverted-2)]. MAGI-2 contains eight potential protein-protein interaction domains
and is localized to tight junctions in the membrane of epithelial cells. PTEN
binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and
the second PDZ domain of MAGI-2. MAGI-2 enhances the ability of PTEN to suppress
Akt activation. Furthermore, certain PTEN mutants have reduced stability, which
is restored by adding the minimal PDZ-binding motif back to the truncated
protein. We propose that MAGI-2 improves the efficiency of PTEN signaling through
assembly of a multiprotein complex at the cell membrane.
PMID- 10760292
TI - High density lipoprotein deficiency and foam cell accumulation in mice with
targeted disruption of ATP-binding cassette transporter-1.
AB - Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been
demonstrated to be mutated in patients with Tangier disease. To investigate the
role of the ABC1 protein in an experimental in vivo model, we used gene targeting
in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of
the murine Abc1 gene was ablated by using a nonisogenic targeting construct that
deletes six exons coding for the first nucleotide-binding fold. Lipid profiles
from Abc1 knockout (-/-) mice revealed an approximately 70% reduction in
cholesterol, markedly reduced plasma phospholipids, and an almost complete lack
of high density lipoproteins (HDL) when compared with wild-type littermates
(+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in
HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low
density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also
significantly reduced in +/- and -/- compared with their littermate controls. The
inactivation of the Abc1 gene led to an increase in the absorption of cholesterol
in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic
examination of Abc1-/- mice at ages 7, 12, and 18 mo demonstrated a striking
accumulation of lipid-laden macrophages and type II pneumocytes in the lungs.
Taken together, these findings demonstrate that Abc1-/- mice display
pathophysiologic hallmarks similar to human Tangier disease and highlight the
capacity of ABC1 transporters to participate in the regulation of dietary
cholesterol absorption.
PMID- 10760293
TI - IMP and AMP deaminase in reperfusion injury down-regulates neutrophil
recruitment.
AB - We examined gene regulation in murine lungs after hind-limb vessel occlusion and
reperfusion. A rapid increase of transcript for the AMP deaminase 3 gene (AMPD3)
and its enzymatic activity (EC) generating inosine monophosphate (IMP) were
identified with transcripts located in bronchial and alveolar epithelium. AMP
deaminase inhibitor decreased IMP levels and significantly enhanced neutrophil
recruitment within lung tissue during reperfusion. In addition, IMP inhibited
cytokine-initiated neutrophil infiltration in vivo and selectively attenuated
neutrophil rolling by 90% in microvessels. We prepared labeled IMP and
demonstrated that IMP specifically binds to neutrophils. IMP also stimulated
binding of gamma-[(35)S]thio-GTP, suggesting that IMP is a potent regulator of
neutrophils. Taken together, these results elucidate a previously unrecognized
mechanism that protects tissues from the potentially deleterious consequences of
aberrant neutrophil accumulation. Moreover, they are relevant for new therapeutic
approaches to regulate neutrophil responses in inflammation and vascular disease.
PMID- 10760294
TI - Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the
DHEAge Study to a sociobiomedical issue.
AB - The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone
(DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the
question is posed whether administration of the steroid to compensate for the
decline counteracts defects associated with aging. The commercial availability of
DHEA outside the regular pharmaceutical-medical network in the United States
creates a real public health problem that may be resolved only by appropriate
long-term clinical trials in elderly men and women. Two hundred and eighty
healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or
placebo, orally, daily for a year in a double-blind, placebo-controlled study. No
potentially harmful accumulation of DHEAS and active steroids was recorded.
Besides the reestablishment of a "young" concentration of DHEAS, a small increase
of testosterone and estradiol was noted, particularly in women, and may be
involved in the significantly demonstrated physiological-clinical manifestations
here reported. Bone turnover improved selectively in women >70 years old, as
assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the
decrease of osteoclastic activity. A significant increase in most libido
parameters was also found in these older women. Improvement of the skin status
was observed, particularly in women, in terms of hydration, epidermal thickness,
sebum production, and pigmentation. A number of biological indices confirmed the
lack of harmful consequences of this 50 mg/day DHEA administration over one year,
also indicating that this kind of replacement therapy normalized some effects of
aging, but does not create "supermen/women" (doping).
PMID- 10760295
TI - Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for
carcinogenesis, senescence, and age-related diseases.
AB - Induction of cyclin-dependent kinase inhibitor p21(Waf1/Cip1/Sdi1) triggers cell
growth arrest associated with senescence and damage response. Overexpression of
p21 from an inducible promoter in a human cell line induces growth arrest and
phenotypic features of senescence. cDNA array hybridization showed that p21
expression selectively inhibits a set of genes involved in mitosis, DNA
replication, segregation, and repair. The kinetics of inhibition of these genes
on p21 induction parallels the onset of growth arrest, and their reexpression on
release from p21 precedes the reentry of cells into cell cycle, indicating that
inhibition of cell-cycle progression genes is a mechanism of p21-induced growth
arrest. p21 also up-regulates multiple genes that have been associated with
senescence or implicated in age-related diseases, including atherosclerosis,
Alzheimer's disease, amyloidosis, and arthritis. Most of the tested p21-induced
genes were not activated in cells that had been growth arrested by serum
starvation, but some genes were induced in both forms of growth arrest. Several
p21-induced genes encode secreted proteins with paracrine effects on cell growth
and apoptosis. In agreement with the overexpression of such proteins, conditioned
media from p21-induced cells were found to have antiapoptotic and mitogenic
activity. These results suggest that the effects of p21 induction on gene
expression in senescent cells may contribute to the pathogenesis of cancer and
age-related diseases.
PMID- 10760296
TI - Genetic evidence that the bacteriophage phi X174 lysis protein inhibits cell wall
synthesis.
AB - Protein E, a 91-residue membrane protein of phiX174, causes lysis of the host in
a growth-dependent manner reminiscent of cell wall antibiotics, suggesting E acts
by inhibiting peptidoglycan synthesis. In a search for the cellular target of E,
we previously have isolated recessive mutations in the host gene slyD
(sensitivity to lysis) that block the lytic effects of E. The role of slyD, which
encodes a FK506 binding protein-type peptidyl-prolyl cis-trans isomerase, is not
fully understood. However, E mutants referred to as Epos (plates on slyD) lack a
slyD requirement, indicating that slyD is not crucial for lysis. To identify the
gene encoding the cellular target, we selected for survivors of Epos. In this
study, we describe the isolation of dominant mutations in the essential host gene
mraY that result in a general lysis-defective phenotype. mraY encodes translocase
I, which catalyzes the formation of the first lipid-linked intermediate in cell
wall biosynthesis. The isolation of these lysis-defective mutants supports a
model in which translocase I is the cellular target of E and that inhibition of
cell wall synthesis is the mechanism of lysis.
PMID- 10760298
TI - Brain-derived neurotrophic factor restores long-term potentiation in polysialic
acid-neural cell adhesion molecule-deficient hippocampus.
AB - The neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM)
contribute to long-term potentiation (LTP) in the CA1 hippocampus. Here we report
that the deficient LTP found in slices prepared from NCAM knockout mice and in
organotypic slice cultures treated with Endo-N, an enzyme that cleaves the PSA
moiety of NCAM, can be rescued by brain-derived neurotrophic factor (BDNF). This
effect is not reproduced by nerve growth factor, but can be obtained with high
concentrations of NT4/5. The effect of BDNF cannot be accounted for by
modifications of N-methyl-D-aspartate receptor-dependent responses or of high
frequency bursts. PSA-NCAM, however, could directly interact with BDNF. Exogenous
application of PSA residues or recombinant PSA-NCAM also prevents LTP.
Furthermore trkB phosphorylation, and thus BDNF signaling, is reduced in both
NCAM knockout mice and Endo-N-treated slice cultures. These results suggest that
one action of PSA-NCAM could be to sensitize pyramidal neurons to BDNF, thereby
modulating activity-dependent synaptic plasticity.
PMID- 10760297
TI - Heteroduplex mobility assay-guided sequence discovery: elucidation of the small
subunit (18S) rDNA sequences of Pfiesteria piscicida and related dinoflagellates
from complex algal culture and environmental sample DNA pools.
AB - The newly described heterotrophic estuarine dinoflagellate Pfiesteria piscicida
has been linked with fish kills in field and laboratory settings, and with a
novel clinical syndrome of impaired cognition and memory disturbance among humans
after presumptive toxin exposure. As a result, there is a pressing need to better
characterize the organism and these associations. Advances in Pfiesteria research
have been hampered, however, by the absence of genomic sequence data. We employed
a sequencing strategy directed by heteroduplex mobility assay to detect
Pfiesteria piscicida 18S rDNA "signature" sequences in complex pools of DNA and
used those data as the basis for determination of the complete P. piscicida 18S
rDNA sequence. Specific PCR assays for P. piscicida and other estuarine
heterotrophic dinoflagellates were developed, permitting their detection in algal
cultures and in estuarine water samples collected during fish kill and fish
lesion events. These tools should enhance efforts to characterize these organisms
and their ecological relationships. Heteroduplex mobility assay-directed sequence
discovery is broadly applicable, and may be adapted for the detection of genomic
sequence data of other novel or nonculturable organisms in complex assemblages.
PMID- 10760300
TI - KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the
inner ear and the central auditory pathway.
AB - Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal
dominant form of progressive hearing loss in humans. In the mouse cochlea, the
transcript has been found exclusively in the outer hair cells. By using specific
antibodies, we now show that KCNQ4 is situated at the basal membrane of these
sensory cells. In the vestibular organs, KCNQ4 is restricted to the type I hair
cells and the afferent calyx-like nerve endings ensheathing these sensory cells.
Several lines of evidence suggest that KCNQ4 underlies the I(K,n) and g(K,L)
currents that have been described in the outer and type I hair cells,
respectively, and that are already open at resting potentials. KCNQ4 is also
expressed in neurons of many, but not all, nuclei of the central auditory
pathway, and is absent from most other brain regions. It is present, e.g., in the
cochlear nuclei, the nuclei of the lateral lemniscus, and the inferior
colliculus. This is the first ion channel shown to be specifically expressed in a
sensory pathway. Moreover, the expression pattern of KCNQ4 in the mouse auditory
system raises the possibility of a central component in the DFNA2 hearing loss.
PMID- 10760299
TI - Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects
on recovery of extinguished operant-responding and extracellular dopamine levels
in amygdala and nucleus accumbens.
AB - The conditioning of the pharmacological actions of cocaine with environmental
stimuli is thought to be a critical factor in the long-term addictive potential
of this drug. Cocaine-related stimuli may increase the likelihood of relapse by
evoking drug craving, and brain-imaging studies have identified the amygdala and
nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects
of cocaine cues. To study the significance of environmental stimuli in the
recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained
to associate discriminative stimuli (SDeltas) with response-contingent
availability of intravenous cocaine vs. saline. The rats then were subjected to
repeated extinction sessions during which cocaine, saline, and the respective
SDeltas were withheld until the animals reached an extinction criterion of 30% in both WT
and OD cells; further, in WT cells, H(2)O(2) restored K(+) current amplitude in
the presence of diphenylene iodonium. We conclude that NADPH oxidase acts as the
O(2) sensor in pulmonary airway chemoreceptors.
PMID- 10760305
TI - Mutants of Arabidopsis thaliana defective in the acquisition of tolerance to high
temperature stress.
AB - The ability of organisms to acquire thermotolerance to normally lethal high
temperatures is an ancient and conserved adaptive response. However, knowledge of
cellular factors essential to this response is limited. Acquisition of
thermotolerance is likely to be of particular importance to plants that
experience daily temperature fluctuations and are unable to escape to more
favorable environments. We developed a screen, based on hypocotyl elongation, for
mutants of Arabidopsis thaliana that are unable to acquire thermotolerance to
high-temperature stress and have defined four separate genetic loci, hot1-4,
required for this process. hot1 was found to have a mutation in the heat shock
protein 101 (Hsp101) gene, converting a conserved Glu residue in the second ATP
binding domain to a Lys residue, a mutation that is predicted to compromise
Hsp101 ATPase activity. In addition to exhibiting a thermotolerance defect as
assayed by hypocotyl elongation, 10-day-old hot1 seedlings were also unable to
acquire thermotolerance, and hot1 seeds had greatly reduced basal
thermotolerance. Complementation of hot1 plants by transformation with wild-type
Hsp101 genomic DNA restored hot1 plants to the wild-type phenotype. The hot
mutants are the first mutants defective in thermotolerance that have been
isolated in a higher eukaryote, and hot1 represents the first mutation in an Hsp
in any higher plant. The phenotype of hot1 also provides direct evidence that
Hsp101, which is required for thermotolerance in bacteria and yeast, is also
essential for thermotolerance in a complex eukaryote.
PMID- 10760306
TI - Intentionality detection and "mindreading": why does game form matter?
AB - By around the age of 4 years, children "can work out what people might know,
think or believe" based on what they say or do. This is called "mindreading,"
which builds upon the human ability to infer the intentions of others. Game
theory makes a strong assumption about what individual A can expect about B's
intentions and vice versa, viz. that each is a self-interested opponent of the
other and will reliably analyze games by using such basic principles as dominance
and backward induction, and behave as if the normal form of an extensive form
game is equivalent to the latter. But the extensive form allows intentions to be
detected from actual sequential play and is therefore not necessarily equivalent
psychologically to the normal form. We discuss Baron-Cohen's theory of the
mindreading system [Baron-Cohen, S. (1995) Mindblindness: An Essay on Autism and
Theory of Mind (MIT Press, Cambridge, MA)] to motivate the comparison of behavior
in an extensive form game with its corresponding normal form. As in the work of
Rapoport [Rapoport, A. (1997) Int. J. Game Theory 26, 113-136] and Schotter et
al. [Schotter, A., Wiegelt, K. & Wilson, C. (1994) Games Econ. Behav. 6, 445
468], we find consistent differences in behavior between the normal and extensive
forms. In particular, we observe attempts to cooperate, and in some treatments we
observe the achievement of cooperation, occurring more frequently in the
extensive form. Cooperation in this context requires reciprocity, which is more
difficult to achieve by means of intentionality detection in the normal as
opposed to the extensive form games we study.
PMID- 10760308
TI - Underlying causes and long-term survival in patients with initially unexplained
cardiomyopathy.
AB - BACKGROUND: Previous studies of the prognosis of patients with heart failure due
to cardiomyopathy categorized patients according to whether they had ischemic or
nonischemic disease. The prognostic value of identifying more specific underlying
causes of cardiomyopathy is unknown. METHODS: We evaluated the outcomes of 1230
patients with cardiomyopathy. The patients were grouped into the following
categories according to underlying cause: idiopathic cardiomyopathy (616
patients), peripartum cardiomyopathy (51); and cardiomyopathy due to myocarditis
(111), ischemic heart disease (91), infiltrative myocardial disease (59),
hypertension (49), human immunodeficiency virus (HIV) infection (45), connective
tissue disease (39), substance abuse (37), therapy with doxorubicin (15), and
other causes (117). Cox proportional-hazards analysis was used to assess the
association between the underlying cause of cardiomyopathy and survival. RESULTS:
During a mean follow-up of 4.4 years, 417 patients died and 57 underwent cardiac
transplantation. As compared with the patients with idiopathic cardiomyopathy,
the patients with peripartum cardiomyopathy had better survival (adjusted hazard
ratio for death, 0.31; 95 percent confidence interval, 0.09 to 0.98), and
survival was significantly worse among the patients with cardiomyopathy due to
infiltrative myocardial disease (adjusted hazard ratio, 4.40; 95 percent
confidence interval, 3.04 to 6.39), HIV infection (adjusted hazard ratio, 5.86;
95 percent confidence interval, 3.92 to 8.77), therapy with doxorubicin (adjusted
hazard ratio, 3.46; 95 percent confidence interval, 1.67 to 7.18), and ischemic
heart disease (adjusted hazard ratio, 1.52; 95 percent confidence interval, 1.07
to 2.17). CONCLUSIONS: The underlying cause of heart failure has prognostic value
in patients with unexplained cardiomyopathy. Patients with peripartum
cardiomyopathy appear to have a better prognosis than those with other forms of
cardiomyopathy. Patients with cardiomyopathy due to infiltrative myocardial
diseases, HIV infection, or doxorubicin therapy have an especially poor
prognosis.
PMID- 10760307
TI - Conventional-dose chemotherapy compared with high-dose chemotherapy plus
autologous hematopoietic stem-cell transplantation for metastatic breast cancer.
Philadelphia Bone Marrow Transplant Group.
AB - BACKGROUND: We conducted a randomized trial in which we compared high-dose
chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of
monthly conventional-dose chemotherapy in women with metastatic breast cancer.
METHODS: Women 18 to 60 years of age who had metastatic breast cancer received
four to six cycles of standard combination chemotherapy. Patients who had a
complete or partial response to induction chemotherapy were then randomly
assigned to receive either a single course of high doses of carboplatin,
thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic
stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil
in conventional doses. The primary end point was survival. RESULTS: The median
follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a
complete response to induction chemotherapy and 252 had a partial response. Of
these, 110 patients were assigned to receive high-dose chemotherapy plus
hematopoietic stem cells and 89 were assigned to receive conventional-dose
chemotherapy. In an intention-to-treat analysis, we found no significant
difference in survival overall at three years between the two treatment groups
(32 percent in the transplantation group and 38 percent in the conventional
chemotherapy group). There was no significant difference between the two
treatments in the median time to progression of the disease (9.6 months for high
dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional
dose chemotherapy). CONCLUSIONS: As compared with maintenance chemotherapy in
conventional doses, high-dose chemotherapy plus autologous stem-cell
transplantation soon after the induction of a complete or partial remission with
conventional-dose chemotherapy does not improve survival in women with metastatic
breast cancer.
PMID- 10760309
TI - Images in clinical medicine. Meningeal carcinomatosis in breast cancer.
PMID- 10760310
TI - Relation of race and sex to the use of reperfusion therapy in Medicare
beneficiaries with acute myocardial infarction.
AB - BACKGROUND: There are few reports describing the combined influence of the race
and sex of a patient on the use of reperfusion therapy for acute myocardial
infarction. METHODS: To determine the relation of race and sex to the receipt of
reperfusion therapy for myocardial infarction in the United States, we reviewed
the medical records of 234,769 Medicare patients with myocardial infarction. From
these records we identified 26,575 white or black patients who met strict
eligibility criteria for reperfusion therapy. We then performed bivariate and
multivariate analyses of prevalence ratios to determine predictors of the use of
reperfusion therapy in four subgroups of patients categorized according to race
and sex: white men, white women, black men, and black women. RESULTS: Among
eligible patients, white men received reperfusion therapy with the highest
frequency (59 percent), followed by white women (56 percent), black men (50
percent), and black women (44 percent). After adjustment for differences in
demographic and clinical characteristics, white women were as likely as white men
to receive reperfusion therapy (prevalence ratio, 1.00; 95 percent confidence
interval, 0.98 to 1.03). Likewise, black women were as likely as black men to
receive reperfusion therapy (prevalence ratio, 1.00; 95 percent confidence
interval, 0.89 to 1.13). However, black women were significantly less likely to
receive reperfusion therapy than white men (prevalence ratio, 0.90; 95 percent
confidence interval, 0.82 to 0.98), as were black men (prevalence ratio, 0.85; 95
percent confidence interval, 0.78 to 0.93). CONCLUSIONS: After adjustment for
differences in clinical and demographic characteristics and clinical
presentation, differences according to sex in the use of reperfusion therapy are
minimal. However, blacks, regardless of sex, are significantly less likely than
whites to receive this potentially lifesaving therapy.
PMID- 10760311
TI - Genetic causes of hearing loss.
PMID- 10760312
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 11-2000. A 74-year-old man with memory loss, language impairment,
and personality changes.
PMID- 10760313
TI - High-dose chemotherapy plus autologous bone marrow transplantation for metastatic
breast cancer.
PMID- 10760314
TI - Underlying causes and survival in patients with heart failure.
PMID- 10760315
TI - The Institute of Medicine report on medical errors--could it do harm?
PMID- 10760316
TI - The neurologic illness of Eugene O'Neill--a clinicopathological report.
PMID- 10760317
TI - Testicular metastases from solid tumors: an autopsy study.
AB - In a retrospective study of 738 consecutive autopsies of adult males with solid
malignant neoplasms, five (0.68%) were shown to have metastatic deposits within
the testis. These were metastases from bronchial carcinoma (three cases),
melanoma (one case), and pancreatic endocrine carcinoma (one case). The mean age
of the patients with solid tumors metastatic to the testis was 60 years (range,
32 to 83 years). The metastases from the solid tumors presented two patterns:
destructive and/or focal interstitial. The destructive pattern was characterized
by sheets of malignant cells that destroyed and replaced the seminiferous
tubules. The interstitial pattern was characterized by tumor cells within the
interstitium without involvement of the seminiferous tubules. All metastases
showing the destructive pattern were macroscopically evident. Approximately 40%
of the metastatic deposits were microscopic and showed a focal interstitial
pattern. These cases are not easily identified unless a sufficient number of
tissue blocks are sampled and carefully scrutinized. In 20% of the cases the
metastatic deposits were bilateral. Improved diagnostic skills and treatment
protocols in the last 11 years apparently have not significantly affected
incidence, distribution, or the pattern of metastatic spread of solid tumors to
the testis.
PMID- 10760318
TI - Quantitative thresholds for mitotic counts in histologic grading: confirmation in
nonfrozen samples of invasive ductal breast cancer.
AB - Increasing evidence in the medical literature suggests that freezing a sample
before fixation causes changes in the histologically observed mitotic activity.
In a recent study we determined quantitative thresholds for mitotic counts in
invasive ductal breast cancer in both nonfrozen and frozen formalin-fixed
specimens. Survival- and recurrence-based analyses of this study material
indicated grading thresholds of 17 and 32 mitoses/mm(2) for standardized mitotic
index (SMI) and 13 and 35 mitoses/10 high-power fields for mitotic activity index
(MAI). The purpose of the present study is to confirm and adjust the introduced
thresholds in only nonfrozen formalin-fixed samples. The SMI and MAI in 202 cases
of nonfrozen formalin-fixed samples were analyzed to determine optimal cutpoints
for prognostication of invasive breast cancer on the basis of mitotic activity.
The SMI thresholds were identical in both the present nonfrozen specimens and the
previous combined specimens. The optimal MAI thresholds in the nonfrozen material
changed to 11 and 37 mitoses/10 high-power field. The confirmation and adjustment
of the mitotic thresholds improved the prognostic significance of the method in
the nonfrozen material, which will contribute to the clinical applicability of a
morphometric grading system.
PMID- 10760319
TI - Quality control and sensitivity of polymerase chain reaction techniques for the
assessment of immunoglobulin heavy chain gene rearrangements from fixed- and
paraffin-embedded samples.
AB - Frozen tissue is considered the gold standard if DNA is to be extracted for
polymerase chain reaction (PCR) analysis. In molecular studies from paraffin
embedded material, only positive results are usually taken into account. Our goal
was to evaluate both the sensitivity and the specificity of PCR techniques for
immunoglobulin heavy chain (IgH) gene rearrangement according to various lengths
and types of fixative before paraffin embedding. One set of studies compared IgH
rearrangement in a case of mantle cell lymphoma tissue that had been fixed in 14
different ways before paraffin embedding and frozen tissue. Formalin fixation was
found not to be deleterious for DNA, amplification being possible up to 15 days
after fixation with good sensitivity. In contrast, the performance of PCR
decreased for samples fixed in Bouin's liquid for longer than 6 hours or after 48
hours of incubation in a vacuum infiltration processor (in which Bouin's liquid
fixed and formalin-fixed samples are mixed). In addition, we undertook a
retrospective study of 20 routinely processed B-cell lymphomas, with frozen
formalin-fixed and Bouin's liquid-fixed tissues for each case. Of the 14 positive
cases on frozen material, 13 were also clonal from paraffin-embedded tissues.
Whatever the IgH locus analyzed, each time the adapted control was positive,
results from paraffin-embedded material were identical to results obtained from
frozen tissue. In this study, we showed that the use of paraffin-embedded tissue
is efficient for the study of IgH gene rearrangement. Whenever adapted controls
are used, it is even possible to assess negative results.
PMID- 10760320
TI - Fine-needle aspiration diagnosis of synovial chondromatosis of the tibiofibular
joint.
AB - We report a case of synovial chondromatosis of the tibiofibular joint in a 25
year-old woman that was diagnosed by fine-needle aspiration (FNA). The patient
presented with pain in the left knee and a mass in the popliteal fossa. Synovial
chondromatosis usually presents with joint symptoms and is often associated with
intra-articular loose bodies, whereas presentation as a soft tissue mass is
unusual and may raise the clinical suspicion of malignant neoplasm. The diagnosis
is commonly confirmed by histopathologic examination of biopsy or excision of the
specimen. To the best of our knowledge, this is the first case of synovial
chondromatosis of a large joint successfully diagnosed by FNA. Two cases of
synovial chondromatosis of the temporomandibular joint have been reported in
which the diagnosis was suspected on the basis of FNA. In both these cases, the
final diagnosis was established by histopathology of the excised specimens.
PMID- 10760321
TI - Retroperitoneal peripheral hemangioblastoma: a case report and review of the
literature.
AB - Central nervous system hemangioblastomas are uncommon tumors of controversial
etiology that are usually found in the posterior fossa of the cranial cavity,
retina, and spinal cord. Peripheral involvement is rare; only isolated case
reports have been identified. We report an unusual case of hemangioblastoma
involving the retroperitoneum. A 47-year-old African-American man presented with
polycythemia on routine laboratory testing. Computed tomography revealed a large
retroperitoneal mass near the pancreas, in a left suprarenal location, without
adrenal involvement and without attachment to a nerve. Although hemangioblastoma
may be associated with the von Hippel-Lindau syndrome, this patient did not have
any of the stigmata of this disease. The histologic features included a highly
vascular tumor with cellular areas composed of plump, pleomorphic spindled and
epithelioid (stromal) cells with variable cytoplasmic lipid vacuoles and
hypocellular areas with inflammatory cells and collagenous fibrils.
Immunohistochemical staining showed that the tumor (stromal) cells were positive
for vimentin, calponin, S-100 protein, neuron-specific enolase, and CD57 and
negative for glial fibrillary acidic protein, cytokeratins, epithelial membrane
antigen, CD34, HMB-45, desmin, and the actins. These morphologic and
immunohistochemical findings are consistent with hemangioblastoma. To our
knowledge this is the first reported case of a hemangioblastoma in this location.
Based on this case we conclude that hemangioblastoma may occur in the
retroperitoneum and outside of the central nervous system in a patient without
von Hippel-Lindau syndrome. The immunoprofile of this case suggests that
hemangioblastomas are mesenchymal neoplasms exhibiting both neural and
myofibroblastic differentiation.
PMID- 10760322
TI - Epithelioid sarcoma of the penis: report of an unusual case and review of the
literature.
AB - Epithelioid sarcoma is a rare, slowly growing soft tissue tumor that uncommonly
involves the penis, with only 11 previously reported cases. We present a case of
penile epithelioid sarcoma in a 39-year-old man that mimicked Peyronie's disease,
which was diagnosed 13 years following initial presentation. Preoperative
magnetic resonance imaging showed multiple peripherally enhancing low signal
intensity nodules involving the corpora cavernosa bilaterally. Following
penectomy, histologic examination showed the typical features of epithelioid
sarcoma, with a prominent pseudogranulomatous pattern. Immunohistochemically, the
neoplastic cells demonstrated strong and diffuse staining for cytokeratins
(AE1/AE3 and CAM 5.2), vimentin, epithelial membrane antigen, and CD34. Stains
for S-100 protein, desmin, smooth muscle actin, and CD31 were negative. Electron
microscopy demonstrated abundant intracytoplasmic intermediate filaments,
scattered tonofilaments, and interdigitating filopodia. The present study is the
first to describe magnetic resonance imaging and comprehensive
immunohistochemical findings in penile epithelioid sarcoma. The majority of cases
reported in the literature have demonstrated features similar to those typically
found in epithelioid sarcoma involving the distal extremities. Consideration of
epithelioid sarcoma in the differential diagnosis of a penile nodule or
obstructive urinary symptoms may lead to early diagnosis and treatment.
PMID- 10760323
TI - Laparoscopic postmortem examination: a minimally invasive approach to the
autopsy.
AB - Laparoscopic and thoracoscopic autopsies have previously only been performed on
an experimental basis to determine their potential usefulness as a substitute for
a conventional postmortem examination. We present the case of a patient with an
unusual variant of malignant melanoma (diffuse melanosis) in whom the immediate
cause of death clinically was thought to be fulminant hepatic failure, the
etiology of which was unknown. The family was unwilling to consent to a
conventional autopsy, but would permit a postmortem examination limited to a 2-cm
abdominal incision and removal of a sample of liver. In view of the unanswered
clinical questions regarding the cause of the acute hepatic failure and its
possible relationship to the diagnosis of diffuse melanosis, we decided that more
extensive examination of the abdominal cavity, specifically the liver, was
required and that the only way that this could be accomplished was by
laparoscopic techniques. Laparoscopic examination of the abdominal cavity
revealed multiple melanotic nodules on the surface of the liver and studding the
omentum. Multiple liver samples were easily obtained; these revealed massive
diffuse necrosis of the liver parenchyma with scattered nodular deposits of dark
pigment consistent with melanin. We report the first known case in which a
laparoscopic autopsy was used to obtain valuable information that answered
clinically relevant questions. Laparoscopic autopsy can offer the a family that
is unwilling to consent to a conventional postmortem examination an alternative
that can potentially provide answers to clinical questions that otherwise would
have been unresolved.
PMID- 10760324
TI - Myxoma is not a single entity: a review of the concept of myxoma.
AB - Myxoid lesions can be subdivided into (1) mainstream myxomas of soft tissues, (2)
mainstream myxomas located outside the soft tissue, (3) inadequately
substantiated myxomas, (4) myxoid soft tissue tumors or lesions not regarded as
myxomas, (5) myxoid fatty conditions, (6) other soft tissue lesions and tumors
that are sometimes markedly myxoid, (7) other soft tissue tumors in which myxoid
foci may be seen, and (8) nonneoplastic myxoid conditions of soft tissue. More
than 60 such conditions are listed and the five entities regarded as mainstream
soft tissue myxomas (namely, intramuscular myxoma, juxta-articular myxoma,
superficial angiomyxoma, aggressive angiomyxoma, and myxoid neurothekeoma [myxoma
of nerve sheath]) are reviewed in detail. Intramuscular myxoma is exclusively
intramuscular, usually affects middle-aged women, is most commonly located in the
thigh, and does not recur after simple excision. Multiple intramuscular myxomas
are rare and are usually associated with monostotic or polyostotic fibrous
dysplasia and Albright's syndrome. Juxta-articular myxoma histologically
resembles an intramuscular myxoma, but involves periarticular tendons, ligaments,
joint capsules, muscles, and even the subcutis of adults. It may be associated
with osteoarthritis of the adjacent joint. Some 30% recur locally. Superficial
angiomyxoma also has been called cutaneous myxoma. It affects all ages, with a
peak incidence in the third and fourth decades; arises in the trunk, lower limb,
head, and neck regions; and usually measures less than 5 cm in diameter.
Epithelial components are present in approximately 25% of tumors. Approximately
one third recur locally, but there have been no metastases. Patients with
multiple lesions may have the Carney complex. Aggressive angiomyxoma usually
arises in the pelvic and perineal regions and affects females seven times as
often as males. Tumors usually measure 10 cm or more in diameter, invade
surrounding tissues, and recur in approximately 50% of cases. None have
metastasized. Myxoma of nerve sheath (the myxoid variant of neurothekeoma)
preferentially affects the dermis and subcutis of the cervicofacial areas and
shoulders of young women. Most patients are younger than 40 years; one third of
them are in the second decade of life. The majority of tumors measure between 0.5
and 1.5 cm. Only three of 102 cases compiled from the two largest published
series recurred; none metastasized. The different clinicopathologic features and
behavior of these five mainstream myxomas indicate that myxoma is not a single
entity.
PMID- 10760325
TI - Thomas Hodgkin: social activist.
AB - Thomas Hodgkin's discovery of a lymph gland disorder is merely one event in a
life of unusually varied public activities in the social reform and humanitarian
movements of the mid-19th century. He wrote pamphlets on medical care for the
working-class poor, public health, housing, sanitation, and the relief of cold,
hunger, and unemployment. Hodgkin wrote about the problems arising from urban
renewal and suburban development. His contributions to geographic explorations,
anthropology, ethnology, and foreign affairs are virtually unknown today.
Hodgkin's opposition to slavery and the slave trade involved him in the
development of settlements in Africa for freed slaves and disputes with the
abolitionists in America. He fought for social justice and human rights for
native populations being oppressed by British foreign policy in South Africa and
New Zealand. His criticism of the exploitation of Indians by the Hudson's Bay
Company's fur trade contributed to a professional conflict in the highly
politicized environment of Guy's Hospital and blocked advancement of his medical
career. Closer to home he advocated reform of medical education and practice and
sponsored adult education programs. As a member of its Senate, he helped in
establishing London University, the first nonsectarian institution of higher
learning in England. He lectured to working people on the means of preserving and
promoting health and advocated prepaid medical care for the working poor.
Concerned about unequal distribution of medical care, he opposed medical
contracts to the lowest bidder and price-determined government plans for health
care. He consistently maintained that the basic problems of the poor were not
medical but socioeconomic. Since charity leaves nothing behind in exchange,
Hodgkin was certain that greater benefits would result if charitable money was
used to provide jobs. He denounced the evils of tobacco, practices of trade
unions, and barbarous prize fights. On a trip to Jerusalem with Sir Moses
Montefiore in 1866, Hodgkin contracted dysentery and died. He is buried in a
protestant cemetery in Jaffa. His epitaph is fitting: "Nothing human was alien to
him."
PMID- 10760326
TI - Clarity on the diagnosis line
PMID- 10760327
TI - Gender differences in the management and outcome of acute myocardial infarction
in unselected patients in the thrombolytic era.
AB - This study compares the clinical features, management, and outcome in men and
women from a consecutive, unselected series of patients with acute myocardial
infarction (AMI) who were admitted to a university cardiac center over a 3-year
period. It is a retrospective observational study of 1,059 admissions with AMI
identified through the Hospital In-Patient Enquiry (HIPE) registry, validated
according to Minnesota Manual criteria, and followed for a period of up to 5
years (median 36 months). Women comprised 40% of all admissions, had a higher
hospital mortality (24% vs. 16%, p<0.001), and were less likely to receive
thrombolysis (23% vs. 33%, p<0.01), admission to coronary care (65% vs. 77%,
p<0.001), or subsequent invasive or noninvasive investigations (55% vs. 63%,
p<0.01). However, women with AMI were older than men with AMI (71 vs. 65 years,
p<0.001). After adjusting for age, differences that remained significant were
prevalence of hypertension (odds ratio [OR] 2.12, 95% confidence intervals [CI]
1.56 to 2.88) and cigarette smoking (OR 0.47, 95% CI 0.35 to 0.65), management in
coronary care (OR 0.66, 95% CI 0.49 to 0.88), and hospital mortality (OR 1.48,
95% CI 1.07 to 2.04). Excess mortality occurred predominantly in women <65 years
old (18% vs. 8%, OR [multivariate] 2.35, 95% CI 1.19 to 4.56), among whom
multivariate analysis demonstrated a significantly lower thrombolysis rate (OR
0.48, 95% CI 0.27 to 0.86). In this group, lack of thrombolysis independently
predicted hospital mortality (OR 5.37, 95% CI 1.45 to 19.82). Female gender was
not an independent predictor of mortality following AMI (OR 1.42, 95% CI 0.90 to
2.26). Thus, among unselected patients, female gender is associated with, but not
an independent predictor of, reduced survival after AMI. Gender differences in
mortality are greatest in younger patients, who are less likely to receive
thrombolysis and in whom lack of thrombolysis is independently associated with
mortality after AMI.
PMID- 10760328
TI - Relation between evolutionary ST segment and T-wave direction and
electrocardiographic prediction of mycardial infarct size and left ventricular
function among patients with anterior wall Q-wave acute myocardial infarction who
received reperfusion therapy.
AB - In the prethrombolytic era it was found that infarct size and left ventricular
ejection fraction could be predicted using the Selvester QRS score. We evaluated
whether infarct size and left ventricular ejection fraction could be predicted by
the predischarge QRS score in patients who had received reperfusion therapy and
whether considering the configuration of the ST segments and T waves would
increase the accuracy of these predictions. We evaluated 51 patients with first
anterior wall myocardial infarction who had received reperfusion therapy and
predischarge resting technetium-99m-sestamibi scan. The electrocardiograms
recorded on the same day of the scan were analyzed for the QRS score and were
divided into 3 groups: A, isoelectric ST and negative T waves; B, ST elevation (>
or =0.1 mV) and negative T waves; and C, ST elevation (> or =0.1 mV) and positive
T waves. Groups A, B, and C included 12, 23, and 16 patients, respectively. The
myocardial perfusion defect extent increased from groups A to C (median 21%, 37%,
and 43.5% in groups A, B, and C, respectively; p = 0.023). Similarly, left
ventricular ejection fraction decreased (44%, 38%, and 34%, respectively; p =
0.042) from groups A to C. Overall, the correlation between the QRS score and the
myocardial perfusion defect extent (rho 0.249; p = 0.08) and ejection fraction
(rho -0.229; p = 0.11) was poor. A statistically significant correlation between
myocardial perfusion defect size and QRS score was found only in group A (rho
0.599, p = 0.04). Among patients with anterior myocardial infarction who received
reperfusion therapy, the predischarge QRS score was predictive of infarct size
only in those in whom ST elevation resolved completely. In patients with residual
ST elevation there was no correlation between QRS score and infarct size.
PMID- 10760329
TI - Early diagnosis of right ventricular or posterior infarction associated with
inferior wall left ventricular acute myocardial infarction.
AB - Right ventricular (RV) or posterior infarction associated with inferior wall left
ventricular acute myocardial infarction (AMI) has important therapeutic and
prognostic implications. However, RV and posterior chest leads in addition to the
12-lead electrocardiogram are required for accurate detection. Body surface
mapping (BSM) has greater spatial sampling and may further improve inferior wall
AMI classification. Consecutive patients with chest pain lasting <12 hours were
assessed to identify those with AMI and > or =0.1 mV ST elevation in > or =2
contiguous inferior leads of the 12-lead electrocardiogram (bundle branch block
or left ventricular hypertrophy excluded). A 12-lead electrocardiogram, RV leads
(V(2)R, V(4)R), posterior chest leads (V(7), V(9)), and a BSM were recorded. From
each BSM, the 12 electrodes overlying the RV region (regional RV map) and 10
electrodes overlying the posterior wall (regional posterior map) were assessed
for ST elevation. Infarct size was estimated by serial cardiac enzymes. AMI
occurred in 173 of 479 patients. Of the 62 patients with inferior wall AMI, ST
elevation > or =0.1 mV occurred in 26 patients (42 in V(2)R or V(4)R compared
with 36 patients (58%) in > or =1 electrode on the regional RV map (p = 0.0019).
ST elevation > or =0.1 mV occurred in 1 patient (2%) in V(7) or V(9) compared
with 17 patients (27%) in > or =1 electrode on the regional posterior map (p =
0.00003). ST elevation > or =0.05 mV occurred in 6 patients (10%) in V(7) or V(9)
compared with 22 patients (36%) in > or =1 electrode on the regional posterior
map (p = 0.00003). Patients with ST elevation on regional RV and/or posterior
maps had a trend toward larger infarct size (mean peak creatine kinase 1,789+/
226 vs. 1,546+/-392 mmol/L; p = NS). Thus, BSM, when compared with RV or
posterior chest leads, provides improved classification of patients with inferior
wall AMI and RV or posterior wall involvement.
PMID- 10760330
TI - Prognostic significance of persistent right ventricular dysfunction as assessed
by radionuclide angiocardiography in patients with inferior wall acute myocardial
infarction.
AB - We evaluated cardiac hemodynamics and long-term prognosis in patients with right
ventricular (RV) acute myocardial infarction (AMI) using Fourier phase and
amplitude analysis of radionuclide angiocardiographic scanning. In 143 patients
with RV AMI, delayed phase and low amplitude in radionuclide RV images persisted
in 54 patients (persistent RV dysfunction group) 3 months after AMI, but
disappeared in the remaining 89 patients (improved RV function group). No
significant differences were present in RV dimensions, left ventricular (LV) wall
motion, LV ejection fraction, or RV ejection fraction between these groups during
the acute phase. At 3 months, RV dimension and LV and RV wall motion indexes were
significantly higher (p = 0.0292, p = 0.0124, p<0.0001, respectively), and LV and
RV ejection fractions were lower (p = 0. 0174 and p = 0.0008, respectively) in
the persistent RV dysfunction group. Percutaneous transluminal coronary
angioplasty in the acute phase was performed in a smaller group of patients (15%
vs. 34%, p = 0.0223), and the degree of residual stenosis in the proximal right
coronary artery was significantly greater in the persistent RV dysfunction group
than in the improved RV function group (82+/-22% vs. 53+/-30%, p<0.0001). The 8
year survival rate was significantly lower in the persistent RV dysfunction group
(p<0.0001). Persistent abnormality of phase and amplitude in radionuclide RV
images was a significant independent predictor of long-term survival (odds ratio
10.42; 95% confidence interval 3.65 to 29.71; p<0.0001). Radionuclide
angiocardiographic Fourier phase and amplitude scanning can detect persistent RV
dysfunction in patients with RV AMI and can predict patient outcome.
PMID- 10760331
TI - Prognostic value of coronary electron-beam computed tomography for coronary heart
disease events in asymptomatic populations.
AB - The predictive ability of electron-beam computed tomography (EBCT) for coronary
heart disease outcomes, particularly hard coronary outcomes (myocardial
infarction or death), has been questioned in asymptomatic populations. Our
objective was to synthesize data on the use of EBCT for determining
cardiovascular prognosis in asymptomatic populations. Studies were identified
using standard systematic review methods. The outcome of interest was relative
risk for myocardial infarction or sudden death, and combined events including
revascularization. Nine articles met the inclusion criteria, of which 5 were of
independent studies. Using meta-analytic techniques to synthesize prognostic
data, there was an increased risk (summary risk ratio 8.7, 95% confidence
interval 2.7 to 28.1) of a combined outcome of nonfatal myocardial infarction or
death or revascularization if the calcium score was above a median score.
Similarly, there was an increased risk for hard events: myocardial infarction or
death (summary risk ratio 4.2, 95% confidence interval 1.6 to 11.3). However,
there was significant heterogeneity in the studies' quality and patient
populations. Although EBCT appears to predict combined and hard coronary outcomes
similarly in high risk, asymptomatic populations, these results should be
interpreted with caution. Further study is needed on the incremental value of
EBCT over conventional risk prediction before this test is used in screening
asymptomatic populations.
PMID- 10760332
TI - Atherosclerotic changes of extracoronary arteries are associated with the extent
of coronary atherosclerosis.
AB - The aim of the present study was to examine the association between carotid and
femoral artery intima media thickness (IMT) and the extent and severity of
coronary artery disease (CAD) as well as the effects of traditional vascular risk
factors on the atherosclerotic changes in the carotid and femoral arteries. Two
hundred twenty-four patients who underwent coronary angiography for suspected CAD
were evaluated by B-mode ultrasound imaging of the common carotid, internal
carotid, carotid bifurcation, and femoral artery for measurement of IMT;
traditional vascular risk factors were also evaluated in these patients. CAD
extent was evaluated by the number of diseased vessels and by Gensini score. Age,
male gender, and diabetes were common risk factors for higher CAD extent and
higher carotid and femoral IMT. Insulin levels were correlated with femoral IMT
and CAD extent, whereas blood lipids were correlated predominantly with carotid
IMT. IMT from carotid and femoral arteries increased significantly with an
increase in CAD extent. Using multiple stepwise regression analysis, the
following parameters were found to be independent predictors of CAD extent: male
gender (p<0.0001), common femoral artery IMT (p = 0.0028), common carotid artery
IMT (p = 0.015), age (p = 0.02), diabetes mellitus (p = 0.035), and carotid
artery bulb IMT (p = 0.04). Common femoral IMT was the only independent parameter
for predicting Gensini score (p<0.0001). In conclusion, there are territorial
differences in the various arterial beds regarding their response to risk
factors. Femoral artery and carotid bulb are independent predictors of CAD extent
and the inclusion of these measurements would add information to that provided by
the common carotid artery.
PMID- 10760333
TI - Minimal heparinization in coronary angioplasty--how much heparin is really
warranted?
AB - The purpose of the study was to assess the results of percutaneous transluminal
coronary angioplasty (PTCA), performed with a single intravenous bolus of 2,500 U
of heparin, in a nonemergency PTCA cohort. Three hundred of 341 consecutive
patients (87.9%) undergoing PTCA were prospectively enrolled in the study. They
received heparin, 2,500-U intravenous bolus, before PTCA, with intention of no
additional heparin administration. Patient and lesion characteristics as well as
PTCA results were evaluated independently by 2 physicians. Patients were followed
up by structured telephone questionnaires at 1 and 6 months after PTCA. Mean
activated clotting time obtained 5 minutes after heparin administration was 185+/
19 seconds (range 157 to 238). There were 3 (1%) in-hospital major adverse
cardiovascular events: 2 deaths (0.66%), 1 (0.33%) Q-wave myocardial infarction.
Emergency coronary surgery and stroke were not reported. Six patients (2%)
experienced abrupt coronary occlusion within 14 days after PTCA, warranting
repeat target vessel revascularization. Angiographic and clinical success were
achieved in 96% and 93.3%, respectively. No bleeding or vascular complications
were recorded. Six-month follow-up (184 patients) revealed 3 cardiac deaths (1
arrhythmic, 2 after cardiac surgery), 1 Q-wave myocardial infarction, and 9.7%
repeat target vessel revascularization. This study suggests that very low doses
of heparin and reduced activated clotting time target values are safe in non
emergency PTCA, and can reduce bleeding complications, hospital stay, and costs.
Larger, randomized, double-blind heparin dose optimization studies need to
confirm this notion.
PMID- 10760334
TI - Balloon optimization versus stent study (BOSS): provisional stenting and early
recoil after balloon angioplasty.
AB - "Optimal" percutaneous transluminal coronary angioplasty (PTCA) may have a late
restenosis rate similar to stenting. We sought to assess short- and long-term
results of a provisional stenting/optimal PTCA approach compared with elective
stenting in a prospective, randomized study. A total of 97 patients with
discrete, de novo lesions in native coronary arteries > or =3 mm in diameter were
randomized 2:1 in PTCA with prolonged perfusion balloon inflation (n = 66) versus
elective stenting (n = 31). Recoil after PTCA was assessed by routine delayed
angiograms (5 and 20 minutes). Cross over to stent was allowed for an inadequate
result; there was no on-line quantitative angiography. An independent core
angiographic laboratory assessed all results and evaluated the adequacy of the
subjective interpretation. Within the PTCA arm, there were 24 (36%) crossovers to
stenting (5 of 24 [21%] due to recoil), whereas 2 stents could not be delivered
to the lesion and crossed over to PTCA. As assessed by quantitative angiography,
baseline reference vessel diameters were similar between the PTCA and stent
groups. The immediate lumen diameter achieved with PTCA was smaller than that
achieved with stenting (2.18+/-0.49 vs. 2.44+/-0.38 mm, respectively, p = 0.01).
There were no differences in angiographic results between elective and crossover
stenting and there were no in-hospital complications in any patient. Target
lesion revascularization at 8 months was 19% (n = 6) in the elective stent arm
versus 21% (n = 14) in the PTCA arm, p = NS; respective rates in PTCA alone and
crossed over-to-stent subsets were 23% (n = 10) versus 17% (n = 4), p = NS.
Angiographic restenosis was 47% after elective stenting versus 38% after PTCA
(intention to treat), p = NS. By received treatment, it was 41% (11 of 27) in the
group treated with the PTCA versus 33% (5 of 15) in the crossover-to-stent arm (p
= NS). Thus, provisional stenting can be safely performed in the treatment of
discrete, native de novo lesions. Early recoil after PTCA cannot be reliably
assessed without quantitative angiography.
PMID- 10760336
TI - Effectiveness of a low-fat vegetarian diet in altering serum lipids in healthy
premenopausal women.
AB - Few controlled trials have studied cholesterol-lowering diets in premenopausal
women. None has examined the cholesterol-lowering effect of a low-fat vegetarian
diet, which, in other population groups, leads to marked reductions in serum
cholesterol concentrations and, in combination with other life-style changes, a
regression of atherosclerosis. We tested the hypothesis that a low-fat,
vegetarian diet significantly reduces serum total and low-density lipoprotein
(LDL) cholesterol concentrations in premenopausal women. In a crossover design,
35 women, aged 22 to 48, followed a low-fat vegetarian diet deriving
approximately 10% of energy from fat for 2 menstrual cycles. For 2 additional
cycles, they followed their customary diet while also taking a "supplement"
(placebo) pill. Serum lipid concentrations were assessed at baseline and during
each intervention phase. Mean serum LDL, high-density lipoprotein (HDL), and
total cholesterol concentrations decreased 16. 9%, 16.5%, and 13.2%,
respectively, from baseline to the intervention diet phase (p<0.001), whereas
mean serum triacylglycerol concentration increased 18.7% (p<0.01). LDL/HDL ratio
remained unchanged. Thus, in healthy premenopausal women, a low-fat vegetarian
diet led to rapid and sizable reductions in serum total, LDL, and HDL cholesterol
concentrations.
PMID- 10760335
TI - Effect of statin therapy on restenosis after coronary stent implantation.
AB - The effect of statins on the development of restenosis and clinical outcome after
coronary stent implantation was assessed in a retrospective analysis of 525
consecutive patients. Baseline clinical, angiographic, and procedural
characteristics did not differ between 258 patients with and 267 patients without
statin therapy. Statin therapy was associated with a significantly (p<0.04)
improved survival free of myocardial infarction and a significant reduction in
repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05)
during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/
0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less
(0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased
(1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin
therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly
lower, with 25.4% in the statin group compared with 38% in the no-statin group
(p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal
lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02)
as independent predictors for subsequent restenosis development. Thus, statin
therapy is associated with reduced recurrence rates and improved clinical outcome
after coronary stent implantation.
PMID- 10760337
TI - Regulation of aldosterone secretion in patients with chronic congestive heart
failure by endothelins.
AB - We studied acute (day 1) and long-term (day 14) effects of endothelin (ET)
receptor blockade with the mixed ET(A/B) antagonist bosentan (1 g twice daily; n
= 18) or placebo (n = 12) on plasma angiotensin II and aldosterone in 30 patients
with symptomatic chronic heart failure taking angiotensin-converting enzyme
inhibitors, diuretics, and digoxin. Hormones were determined before and 3 hours
after morning doses of diuretics and digoxin and the double-blind study drug,
respectively, on days 1 and 14. On day 1, angiotensin II increased from 16.1+/
17.9 to 27.6+/-5.6 ng/L (p <0.05) with bosentan and similarly with placebo
(15.5+/-9.3 and 36.0+/-49.1 ng/L, p = 0.06) after the morning dose of diuretics
and digoxin. Aldosterone tended to increase from 322+/-239 to 362+/-254 pmol/L
(bosentan) and from 271+/-70 to 297+/-136 pmol/L (placebo). On day 14, before
drug intake, angiotensin II was unchanged compared with day 1 in both groups.
However, aldosterone was lower than on day 1 with bosentan (213+/-124 vs. 322+/
239 pmol/L, p<0.05) and remained below baseline values 3 hours after drug intake,
whereas it was unchanged with placebo. Thus, short-term ET(A/B) receptor
antagonism decreases basal aldosterone secretion independently of angiotensin II,
suggesting that ET participates in the regulation of aldosterone in patients
already treated with angiotensin-converting enzyme inhibitors and diuretics.
PMID- 10760338
TI - Inverse relation between aldosterone and venous capacitance in chronically
treated congestive heart failure.
AB - The purpose of this study was to examine if there is a relation between the
aldosterone escape phenomenon and venous capacitance of the upper and lower limbs
in patients with long-term congestive heart failure (CHF) receiving chronic
treatment with angiotensin-converting enzyme (ACE) inhibitors. The study group
consisted of 16 subjects with ischemic CHF in New York Heart Association
functional class II (age 59 +/-2 years, ejection fraction 24+/-4%), stabilized
under a constant drug regimen comprising furosemide, captopril 50 mg 3 times
daily, and digoxin for at least 3 months. Thirteen apparently healthy volunteers,
aged 50+/-4 years acted as controls. Forearm and calf venous capacitances were
measured simultaneously by venous occlusion plethysmography using mercury-in
silastic strain gauges. The equilibration technique was used to derive venous
capacitance from the recorded pressure-volume curves. Active renin, angiotensin
II, and aldosterone levels were determined on venous blood samples obtained in
the supine position. Angiotensin II (p<0.05) and aldosterone (p<0.01) were
statistically significantly higher in patients with CHF under long-term ACE
inhibition than in controls (aldosterone escape phenomenon). In CHF, forearm
venous capacitance was 2.19+/-0.18 ml/100 ml; calf venous capacitance was 2.83+/
0.27 ml/100 ml. Aldosterone significantly and inversely correlated with venous
capacitance in both upper (r = -0.586; p = 0.017) and lower (r = -0.625; p =
0.01) limbs. No correlations were found between forearm or calf venous
capacitance and renin or angiotensin II. In patients with heart failure
chronically treated with diuretics and full ACE inhibition, venous capacitance is
inversely correlated with aldosterone through the mechanism of aldosterone
escape, creating the potential for further deterioration of the CHF process.
PMID- 10760339
TI - Improved survival in patients with nonischemic advanced heart failure and syncope
treated with an implantable cardioverter-defibrillator.
AB - The purpose of this study was to assess whether in patients with syncope and
heart failure due to nonischemic cardiomyopathy, treatment with an implantable
cardioverter-defibrillator (ICD) compared with conventional medical therapy is
associated with a reduction in sudden death and total mortality. Patients with
advanced heart failure who have syncope have been shown to be at high risk for
sudden death. Further risk stratification has been difficult in patients with
nonischemic cardiomyopathy in whom inducibility on electrophysiologic study is
not predictive of future risk. Of 639 consecutive patients with nonischemic
cardiomyopathy referred for heart transplantation, 147 patients with history of
syncope and no prior history of sustained ventricular tachycardia or cardiac
arrest were identified. Outcomes were compared for the 25 patients managed with
an ICD and 122 patients managed with conventional medical therapy. There were no
differences in the baseline variables in the 2 groups of patients, including age,
ejection fraction, and medical treatments for heart failure, but patients
receiving an ICD were more likely to have had nonsustained ventricular
tachycardia (56% vs. 15%, p = 0.001). During a mean follow-up of 22 months, there
were 31 deaths, 18 sudden, in patients treated with conventional therapy, whereas
there were 2 deaths, none sudden, in patients treated with an ICD. An appropriate
shock occurred in 40% of the ICD patients. Actuarial survival at 2 years was
84.9% with ICD therapy and 66.9% with conventional therapy (p = 0.04). Thus, in
patients with nonischemic cardiomyopathy and syncope, therapy with an ICD is
associated with a reduction in sudden death and an improvement in overall
survival.
PMID- 10760341
TI - Sudden death in patients after transcatheter device implantation for congenital
heart disease.
AB - To explore whether transcatheter intracardiac devices increase risk for sudden
death, we analyzed patient and device-related variables with a case-control
design. Sudden death was defined as unexpected death with abrupt onset and rapid
deterioration. Cases included all patients known to have died suddenly after
device closure at our institution, using 3 large databases. Controls (2:1),
matched on year of procedure, were chosen randomly from the same databases. Data
were obtained from medical record review. Of 777 patients who received implants
between February 1989 and February 1999, 9 were known to have died suddenly
(1.2%). In 27 cases and controls, diverse defects were occluded: atrial (n = 16),
ventricular (n = 4), Fontan fenestration (n = 4), or other (n = 3). Cases were
more likely to have had a history of serious arrhythmias (p = 0.008), severe
valve regurgitation (p = 0.03), > or =1 cardiac surgery (p = 0.009), and multiple
devices (p = 0.03). Cases were somewhat more likely to have pulmonary
hypertension (p = 0.09), ventricular dysfunction (p = 0.09), and nonatrial septal
defects (p = 0.10). Patients were less likely to have device arm fractures (p =
0.05). The following were not related to sudden death: age, weight, gender, low
systemic cardiac index, end-diastolic pressure, major noncardiac disease, serious
adverse events, maximum device size, malposition, and residual leak. This study
suggests that sudden death was more likely to occur in device-implanted patients
who had severe underlying cardiac disease and/or multiple devices. No other
device-related variables were associated with sudden death.
PMID- 10760340
TI - Is the left atrial v. wave the determinant of peak pulmonary artery pressure in
patients with pure mitral stenosis?
AB - A large left atrial (LA) v. wave can be observed in patients with pure mitral
stenosis (MS) because of decreased LA compliance. Few data are available
regarding the relation between the magnitude of the LA v wave and pulmonary
artery pressure in MS. We hypothesized that pulmonary artery pressure may be
higher in patients with decreased LA compliance and thus a large v. wave. We
analyzed the right-sided cardiac and transseptal catheterization data in 113
patients (16 men and 97 women, mean age 39 years) with pure rheumatic MS in sinus
rhythm. Peak systolic, diastolic, and mean pulmonary artery pressures were
measured with right-sided cardiac catheterization. The magnitude of LA a and v.
waves were measured through transseptal catheterization. Two-dimensional and
Doppler echocardiography were also performed to measure LA size, mitral valve
area, mean mitral gradient, and valvular regurgitation. Multiple regression
analysis was performed to identify the most important factor in the determination
of pulmonary artery pressure. A large v wave, defined if peak v wave height
exceeded the mean LA pressure by > or =10 mm Hg, was observed in 43 of 113
patients (38%). Increased pulmonary artery systolic pressure (> or =50 mm Hg) was
observed in 38 patients (34%). Univariate analysis showed that the factors
associated with increased pulmonary artery systolic pressure were smaller mitral
valve area, higher mean mitral gradient, higher mean LA pressure, and higher LA
v. wave; among them, LA v wave (p <0. 001) and mean mitral gradient (p<0.001)
were significant independent factors for pulmonary artery systolic pressure in
multivariate analysis. In conclusion, in patients with pure MS and sinus rhythm,
the magnitude of the LA v. wave is strongly associated with pulmonary artery
pressure. This finding may suggest that LA compliance is a major contributing
factor determining pulmonary artery pressure in pure MS.
PMID- 10760342
TI - Comparison of cardiovascular adaptations to long-term arm and leg exercise in
wheelchair athletes versus long-distance runners.
AB - The effect of long-term arm exercise on cardiac morphology and function is
unknown. To study these effects, highly trained wheelchair athletes were compared
with long-distance runners and controls. In addition, the wheelchair athletes
were compared with the long-distance runners to determine if long-term leg
exercise confers a training effect during the performance of dynamic arm
exercise. The study included 31 male subjects (mean age of 33+/-5 years), who
comprised 3 groups matched for age and weight: wheelchair athletes (n = 9), long
distance runners (n = 12), and healthy controls (n = 10). All underwent
echocardiography at rest and arm ergometry exercise testing with expiratory gas
analysis. The peak work rate during arm exercise was highest among the wheelchair
athletes, and was significantly higher in both groups of trained athletes
compared with the control group (p<0.001). Runners demonstrated a significantly
lower submaximal heart rate response to arm exercise compared with wheelchair and
control subjects. Wheelchair athletes had increased left ventricular (LV) volume
and mass by echocardiography compared with controls, but not to the same degree
as that of runners. Although chamber dimensions and wall thickness did not differ
among the groups, the LV volume index tended to be largest in the runners.
Doppler indexes of diastolic LV filling were similar between the trained and
untrained subjects. These data demonstrate that both long-term arm and leg
exercise yield increases in LV volume and mass compared with untrained control
subjects, although to a lesser degree in arm-trained athletes. Runners
demonstrated a transfer of training effect in the performance of dynamic arm
exercise, as demonstrated by their ability to achieve a higher peak work rate
than controls, and showed a lower heart rate response to submaximal exercise than
the wheelchair athletes and control subjects.
PMID- 10760343
TI - Effects of 16 weeks of resistance training on left ventricular morphology and
systolic function in healthy men >60 years of age.
AB - Resistance training (RT) has gained popularity as an effective form of exercise
for older adults. However, the effects of RT on left ventricular (LV) morphology
and systolic function in older persons is not well known. The purpose of this
study was to assess the effects of 16 weeks of RT on LV morphology and systolic
function in healthy older men. Subjects were randomly assigned into a RT group (n
= 10; mean+/- SD age, 68 +/- 3 years) or a nonexercise control group (n = 10; age
68 +/- 4 years). RT was performed 3 times per week for 16 weeks at a mean
intensity between 60% and 80% of 1 repetition maximum. Leg and bench press 1
repetition maximum and 2-dimensional echocardiography were performed at baseline
and after 4, 8, 12, and 16 weeks of training in the RT group. Sixteen weeks of RT
was associated with an increase in leg press maximal strength (baseline, 285 +/-
48 kg; after 16 weeks, 367 +/- 47 kg; p <0.05) and bench press maximal strength
(baseline, 59 +/- 11 kg; after 16 weeks, 69 +/- 11 kg; p <0.05). No change in leg
press maximal strength (baseline, 291 +/- 59 kg; after 16 weeks, 290 +/- 53 kg; p
>0.05) or bench press maximal strength (baseline, 60 +/- 9 kg; after 16 weeks, 61
+/- 13 kg; p > .05) was found in control subjects during the same time. RT was
not associated with changes in LV cavity size, wall thickness, mass, or systolic
function after 4, 8, 12, and 16 weeks of exercise. Thus, 16 weeks of RT was
sufficient to increase leg press and bench press maximal strength but did not
alter the size or systolic function of the senescent left ventricle.
PMID- 10760344
TI - Methodology of head-up tilt testing potentiated with sublingual nitroglycerin in
unexplained syncope.
AB - Shortened head-up tilt testing (HUT) potentiated with sublingual nitroglycerin
(60 degrees passive standing for 20 minutes followed, if negative, by 400 microg
of sublingual nitroglycerin spray with the test continuing for another 20
minutes) differs from conventional nitroglycerin HUT for a shorter drug-free
phase (20 vs 45 minutes). To compare the positivity rate of the 2 protocols, both
tests were performed in a randomized sequence in 10 patients with unexplained
syncope (study 1), and another 42 patients were randomly assigned either to
conventional or to shortened nitroglycerin HUT (study 2). To evaluate the
reproducibility of the shortened nitroglycerin HUT, another 38 patients with
unexplained syncope underwent 2 consecutive tests within a 7+/-8 day interval
(study 3). Finally, to evaluate the specificity of the test, 47 control subjects
underwent shortened nitroglycerin HUT (study 4). Seven positive responses were
observed during shortened nitroglycerin HUT, and there were 8 positive responses
during conventional nitroglycerin HUT (p = NS) in the study 1 group. Fifteen
positive (71%) responses, 5 negative responses, and 1 exaggerated response were
observed during shortened nitroglycerin HUT; 16 positive (76%, p = NS vs.
shortened nitroglycerin HUT), 3 negative, and 2 exaggerated responses were
observed during conventional nitroglycerin HUT in the study 2 group. During the
first test, 21 patients (55%) had a positive, 15 patients had a negative, and 2
patients had an exaggerated response in study group 3. During the second test, 15
positive (39%), 19 negative, and 4 exaggerated responses were observed. Thus, the
reproducibility was 67% for a positive and 94% for a negative test. In control
subjects, 2 positive (4%) responses, 38 negative, and 7 exaggerated responses
were observed with a specificity of 96% in study group 4. In patients with
unexplained syncope, shortened nitroglycerin HUT allowed a positivity rate
similar to that of the conventional test. Moreover, the shortened test provided a
high specificity and adequate reproducibility for both the positive and the
negative responses.
PMID- 10760345
TI - Intrapericardial therapeutics and diagnostics.
PMID- 10760346
TI - Beyond the null hypothesis--do the HERS results disprove the estrogen/coronary
heart disease hypothesis?
PMID- 10760347
TI - Uric acid: is it a risk factor for cardiovascular disease?
PMID- 10760348
TI - Kligfield-Okin index: revisiting the correction of ST depression for delta heart
rate.
PMID- 10760349
TI - Comparison of major complication rates associated with four methods of arterial
closure.
PMID- 10760350
TI - Decline in the number of low-volume hospitals performing coronary angioplasty in
California, 1989 to 1996.
PMID- 10760351
TI - Evaluation of direct stent implantation without predilatation by intravascular
ultrasound.
AB - The present study shows that direct stent implantation without predilatation in
selected lesions provides angiographic and ultrasonographic results that could be
comparable to those expected with conventional stenting. These results may even
safely improve if a balloon-artery ratio of 1.1 to 1.2 is used in combination
with implantation pressures of 12 to 16 atm.
PMID- 10760352
TI - Efficacy and safety of intravenous dofetilide for rapid termination of atrial
fibrillation and atrial flutter.
PMID- 10760353
TI - Effect of warfarin versus aspirin on the incidence of new thromboembolic stroke
in older persons with chronic atrial fibrillation and abnormal and normal left
ventricular ejection fraction.
PMID- 10760354
TI - Comparison by real-time three-dimensional echocardiography of left ventricular
geometry in hypertrophic cardiomyopathy versus secondary left ventricular
hypertrophy.
PMID- 10760355
TI - Conservation of the ligand recognition site of metabotropic glutamate receptors
during evolution.
AB - Mammalian metabotropic glutamate receptors (mGluRs) are classified into 3 groups
based on their sequence similarity and ligand recognition selectivity. Recently,
we identified a Drosophila mGluR (DmGlu(A)R) which is about equidistant,
phylogenetically, from the 3 mGluR groups. However, both the G-protein coupling
selectivity and the pharmacological profile of DmGlu(A)R, as analysed with
mutated G-proteins and a few compounds, look similar to those of mammalian group
II mGluRs. In the present study we carefully examined the pharmacological profile
of DmGlu(A)R, and compared it to those of the rat mGlu(1a), mGlu(2) and mGlu(4a)
receptors, representative of group-I, II and III respectively. The
pharmacological profile of DmGlu(A)R was found to be similar to that of mGlu(2)R,
and only very small differences could be identified at the level of their
pharmacophore models. These data strongly suggest that the binding sites of these
two receptors are similar. To further document this idea, a 3D model of the
mGlu(2) binding domain was constructed based on the low sequence similarity with
periplasmic amino acid binding proteins, and was used to identify the residues
that possibly constitute the ligand recognition pocket. Interestingly, this
putative binding pocket was found to be very well conserved between DmGlu(A)R and
the mammalian group-II receptors. These data indicate that there has been a
strong selective pressure during evolution to maintain the ligand recognition
selectivity of mGluRs.
PMID- 10760356
TI - Behavioural evidence supporting a differential role for group I and II
metabotropic glutamate receptors in spinal nociceptive transmission.
AB - Metabotropic glutamate receptors (mGluRs) have been shown to contribute to
nociceptive processing in spinal cord. This study examined the effects of
intrathecal treatment with group I and II mGluR compounds on withdrawal
thresholds to noxious mechanical stimuli, in the absence of tissue damage or
inflammation, in adult female sheep. Both the group I/II mGluR agonist (+/-)-1
aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 5.2-520 nmol) and the
group II agonist (2S,1S, 2S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 620 nmol)
significantly increased mechanical withdrawal thresholds between 5-15 min post
injection. These anti-nociceptive effects were blocked by co-administration of
the mGluR antagonist (2S)-alpha-ethylglutamate (EGLU; 570 nmol; group II), but
not (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 450 nmol; group I).
Intrathecal administration of the group I-specific agonist (S)-3,5
dihydroxyphenylglycine ((S)-3,5-DHPG; 50 nmol) produced a significant reduction
in mechanical thresholds, which was blocked by co-administration of the group I
antagonist AIDA. In contrast, the highest dose of (S)-3,5-DHPG tested, 5
micromol, significantly elevated response thresholds. These results demonstrate
that both group I and II mGluRs play crucial, but contrasting roles in mediating
acute mechanical nociceptive events in spinal cord.
PMID- 10760357
TI - LY354740, a potent group II metabotropic glutamate receptor agonist prevents
lactate-induced panic-like response in panic-prone rats.
AB - LY354740 is a potent and selective agonist at the group II metabotropic glutamate
receptors and is shown to be an effective inhibitor of glutamate release with
significant anxiolytic and drug withdrawal alleviating properties in certain
animal models. Rats with chronic inhibition of GABA synthesis in the dorsomedial
hypothalamus (DMH) are highly anxious and exhibit panic-like responses to
peripheral lactate infusions similar to patients with panic disorder. Using these
panic-prone rats, we tested the efficacy of LY354740 in preventing the lactate
induced panic-like response, comparing it to alprazolam, a clinically effective
anti-panic drug. Rats were fitted with femoral arterial and venous catheters and
implanted with Alzet pumps infusing the GABA synthesis inhibitor L-allylglycine
into the DMH. After four days of recovery, they were confirmed to be panic-prone
to lactate infusions as indicated by increases in heart rate, blood pressure,
respiratory rate and "anxiety" measured in the social interaction test. Next,
they were pretreated with either vehicle, LY354740 (0.3 and 0.6 mg/kg) or
alprazolam (0.5 and 1.0 mg/kg) and re-challenged with lactate infusions. LY354740
treatment was equally efficacious as alprazolam in preventing lactate-induced
panic attacks in this model. These data suggest that LY354740 could be a novel
anti-panic drug, as effective as alprazolam in acute treatment.
PMID- 10760358
TI - CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and
injury induced c-fos expression and cortical spreading depression in rodents.
AB - (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP
101,606) is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors
containing the NR2B subunit. This compound was used to investigate the role of
NR2B containing receptors in three responses to NMDA receptor activation in vivo.
In mouse, CP-101,606 completely inhibited increases in fos-like immunoreactivity
in dentate gyrus caused by a subconvulsant intraperitoneal dose of NMDA. In rat,
the compound completely blocked cortical c-fos mRNA induction following focal
injury in parietal cortex and the initiation and propagation of electrically
induced cortical spreading depression. Inhibition of these responses by CP
101,606 indicates that c-fos induction and cortical spreading depression are
dependent on activation of NMDA receptors containing the NR2B subunit. Since NMDA
receptor dependent c-fos induction and cortical spreading depression may
contribute to neuron loss after focal CNS injury, inhibition of these responses
by CP-101,606 may contribute to the neuroprotective efficacy of the compound.
PMID- 10760359
TI - Purinergic modulation of [(3)H]GABA release from rat hippocampal nerve terminals.
AB - The hippocampal GABAergic system is assumed not to be a target for purine
modulation. We have now confirmed that neither adenosine A(1) and A(3) receptor
nor nucleotide P(2) or P(4) receptor activation modified the K(+)-evoked
[(3)H]GABA release from hippocampal synaptosomes. However, activation of
adenosine A(2A) receptors with CGS 21680 (10 nM) or HENECA (30 nM) facilitated
GABA release by 32% and 21%, respectively. These effects were prevented by the
A(2A) antagonist, ZM 241385 (20 nM). A(2A) receptors may activate adenylate
cyclase and protein kinase A since CGS 21680 (10 nM) facilitation was partially
prevented by 8-bromo-cAMP (1 mM), forskolin (10 microM) and HA-1004 (10 microM).
Protein kinase C may also be recruited, since chelerythrine (6 microM) and
phorbol-12, 13-didecanoate (250 nM) attenuated CGS 21680 (10 nM) facilitation of
[(3)H]GABA release. Omega-agatoxin-IVA (200 nM) occluded CGS 21680 facilitation
suggesting the involvement of P-type calcium channels. Thus, the adenosine A(2A)
receptor system appears to be one of the first presynaptic neuromodulatory
systems able to enhance the evoked release of GABA from hippocampal nerve
terminals.
PMID- 10760361
TI - Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone,
against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled
mice: comparison with diazepam and valproate.
AB - A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone,
is a 3beta-methylated analog of the naturally occurring neuroactive steroid
allopregnanolone. In the present study, ganaxolone was tested for its ability to
(1) suppress seizures (clonic and tonic) and lethality induced by
pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to
attenuate the development of sensitization to the convulsive and lethal effects
of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment
prior to each PTZ injection during kindling acquisition. Two classical
antiepileptic drugs, diazepam and valproate, were tested for comparison. All
three drugs dose-dependently suppressed tonic seizures and lethality induced by
PTZ in kindled mice; only ganaxolone was effective against clonic seizures.
Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of
kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of
PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and
lethality, but not clonic seizures; valproate was ineffective in preventing
development of any of these effects. Sensitivity to PTZ-induced seizures and
lethality was not affected in mice with a history of repeated treatment with
ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity
that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to
marked disruption (valproate). Taken together, the results of the present study
add to accumulating evidence of the unique anticonvulsive/behavioral profile of
neuroactive steroids.
PMID- 10760362
TI - PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5
HT(1A) agonist actions. I. Neurochemical effects.
AB - The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT)
5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for
human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)
K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771
showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat
hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed
at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A)
(K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures
of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in
CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23%
relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50)
of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD
158771 produced a dose-related decrease in DA synthesis in the striatum and
mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL),
indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD
158771 produced a dose-related decrease in DA synthesis and extracellular DA. A
decrease in 5-HT synthesis in several brain areas was observed consistent with an
agonist response. Further support for DA autoreceptor agonist action is that PD
158771 produced a partial inhibition of the firing of substantia nigra zona
compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771
exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT
agonist actions; and it could provide improved antipsychotic profile with minimal
side effects.
PMID- 10760360
TI - Differential modulatory actions of the volatile convulsant flurothyl and its
anesthetic isomer at inhibitory ligand-gated ion channels.
AB - A challenge for theories of general anesthesia is the existence of compounds
predicted to be anesthetics but which, instead, do not produce anesthesia and
often elicit other behavioral effects such as convulsions. This study focused on
flurothyl (bis[2,2, 2-trifluoroethyl] ether), a potent volatile convulsant, and
its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3, 3-hexafluoro-2
methoxypropane). The effects of flurothyl and iso-flurothyl were studied using
the whole-cell patch-clamp technique on agonist-activated chloride currents in
human GABA(A), glycine, and GABA(C) rho(1) receptors expressed in HEK 293 cells.
GABA(A) and glycine receptors are promising molecular targets for the actions of
inhaled ether general anesthetics. Flurothyl acted as a non-competitive
antagonist at GABA(A) alpha(2)beta(1) and alpha(2)beta(1)gamma(2s) receptors, but
had no effect at glycine alpha(1) receptors. Flurothyl had biphasic actions on
GABA responses at GABA(C) rho(1) receptors. In contrast, iso-flurothyl enhanced
('potentiated') submaximal agonist responses at GABA(A) and glycine receptors,
but had no effect on GABA responses at GABA(C) rho(1) receptors. Point mutations
in GABA(A) and glycine receptor subunits, which have been previously shown to
abolish potentiation of agonist responses by the ether anesthetics enflurane and
isoflurane, also ablated potentiation of agonist responses by iso-flurothyl.
These same mutations in the GABA(A) receptor had only modest effects on the
inhibitory actions of flurothyl. GABA(A) receptors with mutations conferring
insensitivity to antagonism by picrotoxin were still inhibited by flurothyl,
suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct
sites or mechanisms of action. In summary, antagonism of GABA(A) receptors is
likely to account for the convulsant effects of flurothyl, while the general
anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may
be related to positive modulation of GABA(A) and/or glycine receptors.
PMID- 10760363
TI - PD 158771, a potential antipsychotic agent with D2/D3 partial agonist and 5
HT(1A) agonist actions. II. Preclinical behavioral effects.
AB - PD 158771 has been described in receptor binding and biochemical tests as a
partial agonist at dopamine (DA) D2 and D3 receptors as well as an agonist at
serotonin (5-HT)(1A) receptors. The present studies describe the profile of PD
158771 in rodent and primate behavioral tests. PD 158771 reduced spontaneous
locomotor activity in mice (ED(50)=0.38 mg/kg, i.p.) and rats (ED(50) = 1.2
mg/kg, i.p. and 0.16 mg/kg, s.c.), and reduced amphetamine-stimulated locomotion
in mice (ED(50) = 0.13 mg/kg, i.p.). At relatively higher doses up to 3 mg/kg,
s.c. in rats, PD 158771 did not produce locomotor stimulation or induce
stereotypy, indicating a lack of postsynaptic DA agonist activity. PD 158771
reduced apomorphine stimulated locomotion in rats at a dose 4.6-fold greater than
those that reduced spontaneous locomotor activity, indicating weak postsynaptic
DA antagonist actions; results consistent with a partial agonist profile. PD
158771 produced anxiolytic-like effects in the water-lick (Vogel) conflict test,
effects possibly due to the 5-HT(1A) activity. However, PD 158771 was inactive in
the water wheel behavioral despair model in rats, indicating lack of
antidepressant properties. Similar to known antipsychotics, PD 158771 produced a
potent and long-lasting inhibition of conditioned avoidance responding in
squirrel monkeys. In contrast to standard antipsychotics, and similar to
clozapine, PD 158771 did not cause catalepsy in rats at a dose 20-fold higher
than the ED(50) dose for locomotor inhibition. PD 158771 also had a somewhat
lower liability than haloperidol to produce extrapyramidal dysfunction in
squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. The
data indicate that PD 158771 is a DA partial agonist with weak intrinsic activity
that selectively activates brain DA autoreceptors. PD 158771 produced behavioral
effects consistent with potential antipsychotic and anxiolytic efficacy, and has
an improved profile in the extrapyramidal side effect model when compared to
certain currently available antipsychotic agents.
PMID- 10760364
TI - Evidence for accelerated desensitisation of 5-HT(2C) receptors following combined
treatment with fluoxetine and the 5-HT(1A) receptor antagonist, WAY 100,635, in
the rat.
AB - Both pre-clinical and clinical studies suggest that additional treatment with 5
HT(1A) receptor antagonists may accelerate the antidepressant efficacy/onset of
selective serotonin re-uptake inhibitors (SSRIs). Given that chronic SSRI
treatment has been shown to desensitise 5-HT(2C) receptor mediated responses, we
have used the rat social interaction test to determine if combined treatment with
WAY 100,635, a selective 5-HT(1A) receptor antagonist, will accelerate this
effect. In pairs of unfamiliar rats, acute administration of the 5-HT(2C)
receptor agonist m-chlorophenylpiperazine (mCPP) or fluoxetine decreased the time
spent in social interaction, responses which were reversed by the 5-HT(2C/2B)
receptor antagonists SB 200646A and SB 221284. Similar reductions in social
interaction were observed in rats treated with fluoxetine (10 mg/kg, i.p. daily)
for 4, 7 and 14 days but was no longer apparent after 28 days of treatment. In
contrast, only 7 days of combined treatment with WAY 100,635 (1 mg/kg/s.c./day)
and fluoxetine were needed to reverse this response. The decrease in social
interaction induced by an acute challenge of mCPP (1 mg/kg, i. p.) was also
reduced after 6 days co-treatment with WAY 100,635 and fluoxetine. Thus, WAY
100,635 accelerates SSRI-induced desensitisation of 5-HT(2C) receptors,
suggesting that this response might contribute towards the therapeutic effects of
SSRIs in man.
PMID- 10760365
TI - Regional heterogeneity of serotonin(1A) receptor inactivation and turnover in the
aging female rat brain following EEDQ.
AB - The turnover of serotonin(1A) (5-HT(1A)) receptors was investigated in several
brain regions of young adult (3 months) and old (22 months) female Fischer 344
rats following irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2
dihydroquinoline (EEDQ). Equilibrium binding analyses for the 5-HT(1A) receptor
binding site incorporated [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin ([(3)H]8
OH-DPAT) and were conducted in the frontal cortex, amygdala and hippocampus at 1,
2, 7 and 14 days after treatment with EEDQ (6.0 mg/kg, s.c.) or vehicle. The
pattern of 5-HT(1A) receptor recovery following EEDQ treatment was found to be
age- and region-dependent. For example, in the hippocampus, receptor recovery
occurred at a faster rate in the old rats compared to young adult rats. While a
significant decrease in affinity for the 5-HT(1A) receptor was found in the
frontal cortex and amygdala in young adult and old rats following EEDQ, B(MAX)
values for [(3)H]8-OH-DPAT binding in these brain regions were unaltered by EEDQ
across age groups. In the frontal cortex and amygdala, significant age-dependent
decreases in affinity for the 5-HT(1A) receptor were revealed at day 1 following
EEDQ administration. The significance of the present findings is discussed in
terms of aging and a regionally-defined sensitivity of 5-HT(1A) receptors to the
irreversible inactivator EEDQ.
PMID- 10760366
TI - Inhibition of recombinant low-voltage-activated Ca(2+) channels by the
neuroprotective agent BW619C89 (Sipatrigine).
AB - T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK 293 cells stably
expressing recombinant low-voltage-activated Ca(2+) channel subunits. Current
voltage relationships revealed that these currents were low-voltage activated in
nature and could be reversibly antagonised by mibefradil, a known T-type channel
blocker. At a test potential of -25 mV alpha(1I)-mediated Ca(2+) currents were
rapidly and reversibly inhibited by 1-100 microM BW619C89 (IC(50)=14 microM, Hill
coefficient 1.3). In contrast to its actions on N-type Ca(2+) channels, a near
IC(50) dose (10 microM) of BW619C89 produced no alterations in either the
kinetics or voltage-dependence of T-type currents. In additional single dose
experiments, currents mediated by rat alpha(1G), human alpha(1H) or human
alpha(1I) channel subunits were also inhibited by BW619C89. Overall our data
indicate that T-type Ca(2+) channels are more potently blocked by BW619C89 than
either type-II Na(+) channels or N-type Ca(2+) channels. It seems, therefore,
that inhibition of low-voltage-activated Ca(2+) channels is likely to contribute
to the anticonvulsant and neuroprotective actions of this and related compounds.
PMID- 10760367
TI - Regulation of the calcium channel alpha(1G) subunit by divalent cations and
organic blockers.
AB - The pharmacological properties of the expressed murine T-type alpha(1G) channel
were characterized using the whole cell patch clamp configuration. Ba(2+) or
Ca(2+) were used as charge carriers. Both I(Ba) and I(Ca) were blocked by Ni(2+)
and Cd(2+) with IC(50) values of 0.47+/-0.04 and 1.13+/-0.06 mM (Ni(2+)) and
162+/-13 and 658+/-23 microM (Cd(2+)), respectively. Ni(2+), but not Cd(2+),
modified the gating of channel activation. Ni(2+) consistently accelerated
channel deactivation while Cd(2+) had a similar effect only on I(Ca). The
alpha(1G) channel was potently blocked by mibefradil in a dose- and voltage
dependent manner. I(Ba) was moderately blocked by phenytoin (IC(50) 73.9+/-1.9
microM) and was resistant to the block by valproate. Also 3 mM ethosuximide
blocked 20 and 35% of the I(Ba) at a HP of -100 and -60 mV, respectively, while 5
mM amiloride inhibited I(Ba) by 38% and significantly slowed current activation.
The alpha(1G) channel was not affected by 10 microM tetrodotoxin. Both 1 microM
(+)isradipine and 10 microM nifedipine inhibited 18 and 14% of I(Ba) amplitude at
a HP of -100 mV, and 23% and 29% of I(Ba) amplitude at a HP of -60 mV,
respectively. The alpha(1G) current was minimally activated by 1 microM Bay K
8644.
PMID- 10760368
TI - Allosteric modulation of [(3)H]gabapentin binding by ruthenium red.
AB - Gabapentin is an anticonvulsant with an unknown mechanism of action. However, it
has been proposed that gabapentin acts by binding to voltage-gated calcium
channels. To further characterize the interaction of gabapentin with its
endogenous binding site in cerebral cortex, we tested for competitive and
allosteric interactions between [(3)H]gabapentin and a variety of calcium channel
binding ligands. Most ligands for voltage- or ligand-gated calcium channels
(verapamil, the omega-conotoxins MVIIC and GVIA, ryanodine, caffeine, capsaicin,
MK-801) had no significant effect on [(3)H]gabapentin binding. However, ruthenium
red, a relatively nonselective calcium channel ligand, was found to robustly
modulate [(3)H]gabapentin binding. Ruthenium red slowed the association and
dissociation kinetics of [(3)H]gabapentin while increasing the number of
detectable binding sites. Spermine and MgCl(2), which also bind to calcium
channels and modulate [(3)H]gabapentin binding, were found to act in a similar
manner. These findings support the contention that the principal endogenous
binding site for gabapentin is a calcium channel; they characterize the nature of
the allosteric interaction of spermine, MgCl(2) and ruthenium red with this
binding site; and they suggest possible mechanisms by which gabapentin may
modulate calcium channel function and ultimately produce therapeutic actions.
PMID- 10760369
TI - A protein phosphatase is involved in the cholinergic suppression of the Ca(2+)
activated K(+) current sI(AHP) in hippocampal pyramidal neurons.
AB - The slow calcium-activated potassium current sI(AHP) underlies spike-frequency
adaptation and has a substantial impact on the excitability of hippocampal CA1
pyramidal neurons. Among other neuromodulatory substances, sI(AHP) is modulated
by acetylcholine acting via muscarinic receptors. The second-messenger systems
mediating the suppression of sI(AHP) by muscarinic agonists are largely unknown.
Both protein kinase C and A do not seem to be involved, whereas calcium
calmodulin kinase II has been shown to take part in the muscarinic action on
sI(AHP). We re-examined the mechanism of action of muscarinic agonists on sI(AHP)
combining whole-cell recordings with the use of specific inhibitors or activators
of putative constituents of the muscarinic pathway. Our results suggest that
activation of muscarinic receptors reduces sI(AHP) in a G-protein-mediated and
phospholipase C-independent manner. Furthermore, we obtained evidence for the
involvement of the cGMP-cGK pathway and of a protein phosphatase in the
cholinergic suppression of sI(AHP), whereas release of Ca(2+) from IP(3)
sensitive stores seems to be relevant neither for maintenance nor for modulation
of sI(AHP).
PMID- 10760370
TI - A bradycardiac agent ZD7288 blocks the hyperpolarization-activated current (I(h))
in retinal rod photoreceptors.
AB - Recently it has been reported that "I(f) channel blockers", which block the
hyperpolarization-activated inward current (I(f)) in heart sino atrial node
cells, also block the hyperpolarization-activated inward current (I(h)) in other
tissues. Here we compared the effects of one of these agents, ZD7288 [4-(N-ethyl
N-phenylamino)-1, 2-dimethyl-6-(methylamino) pyrimidinium chloride], with those
of Cs(+) on I(h) in amphibian rod photoreceptors using patch clamp and
intracellular recordings. ZD7288 strongly inhibited I(h) in newt rod
photoreceptors in a concentration-dependent manner (1-100 microM). ZD7288 exerted
a blocking action on the conductance of I(h) with no alteration of its gating
properties, and the blocking action of I(h) was not use-dependent. At
concentrations as low as 1 microM, ZD7288 markedly enhanced the hyperpolarizing
membrane responses of frog rod photoreceptors to bright light and delayed the
response recovery, indicating that ZD7288 is highly selective for I(h). The
apparent effect of the drug was slow in onset and irreversible, suggesting that
ZD7288 act at a cytosolic site on the I(h) channel. These observations also
confirm the involvement of I(h) in accelerating the response recovery process
from deep membrane hyperpolarization induced by bright light in rod cells.
PMID- 10760371
TI - Inhibition of amphetamine- and apomorphine-induced behavioural effects by
neuropeptide Y Y(1) receptor antagonist BIBO 3304.
AB - Neuropeptide Y (NPY) has an important role in the regulation of stress responses
and feeding behaviour. There is evidence that some effects elicited by NPY occur
due to modulation of action of regular neurotransmitters. The main objective of
the present study was to test behavioural effects of the novel neuropeptide Y
(NPY) Y(1) receptor antagonist (R)-N-[[4-(aminocarbonylaminomethyl)
phenyl]methyl]-N(2)-(diphe nylacetyl)-argininamide trifluoroacetate (BIBO 3304)
on dopamine-dependent behaviour. Intracerebroventricular administration of BIBO
3304 (1, 10, 50 nmol) had no effect on locomotor activity as measured by number
of rearings and number of squares visited in an open field test in rats, but at
50 nmol dose defecation was significantly increased. BIBO 3304 (10 nmol) reduced
amphetamine-induced increases in horizontal and vertical activity whereas its S
configurated enantiomer BIBO 3457 was inactive. In an open field test BIBO 3304
(10 nmol) inhibited purposeless running in rats sensitized to direct dopaminergic
agonist apomorphine (0.5 mg/kg, s.c.). BIBO 3304 (10 nmol but not 1 nmol, i.c.v.)
reduced fighting in apomorphine-induced aggression paradigm. Apomorphine-induced
aggression was reduced by another, structurally similar, but less potent NPY Y(1)
receptor antagonist BIBP 3226 (10 nmol, i.c.v.). A lower dose of BIBP 3226 (1
nmol, i.c.v.) was inactive. Concomitant administration of BIBO 3304 (10 nmol)
with low doses of apomorphine (0.5 mg/kg s.c.) over the course of 10 days failed
to prevent the development of apomorphine-induced aggressiveness. These data
demonstrate that behavioural response to indirectly (amphetamine) and directly
(apomorphine) acting dopaminergic stimulants is inhibited by NPY Y(1) receptor
antagonists and suggest that NPY Y(1) receptor activation might be important in
pathophysiology of disorders associated with hyperactivity of dopaminergic
pathways, such as psychosis, schizophrenia and drug abuse. We propose that the
effects of BIBO 3304 on amphetamine/apomorphine-induced locomotion and
apomorphine-induced aggressiveness are due to modulation of postsynaptic
dopaminergic responses rather than direct effects of NPY Y(1) receptor
antagonists on dopamine or NPY release.
PMID- 10760372
TI - Pituitary adenylate cyclase-activating polypeptide induces hyperthermia in the
rat.
AB - The effects of centrally administered pituitary adenylate cyclase-activating
polypeptide (PACAP-38) on body temperature were investigated in rats.
Intracerebroventricular (i.c.v.) administration of PACAP-38 in doses of 500 and
1000 ng induced a dose-related elevation in colon temperature 2, 3, 4, 5 and 6 h
after injection. The i.c.v. pretreatment of the animals with different dilutions
of PACAP-38 antiserum prevented the development of hyperthermia in PACAP-38
treated animals, whereas PACAP-38 antiserum alone did not modify the colon
temperature. An intramuscular injection of noraminophenazone (a cyclooxygenase
inhibitor) abolished the PACAP-38-induced hyperthermia. Our data indicate that
PACAP may induce hyperthermia via the central nervous system, and this
hyperthermic effect may be mediated via a cyclooxygenase-involved pathway.
PMID- 10760373
TI - Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose
deprivation in rat forebrain slices.
AB - Acetylsalicylic acid (ASA, Aspirin) is an anti-inflammatory drug with a wide
spectrum of pharmacological activities and multiple sites of action. Apart from
its preventive actions against stroke due to its antithrombotic properties,
recent data in the literature suggest that high concentrations of ASA also exert
direct neuroprotective effects. We have used an in vitro model of brain ischaemia
using rat forebrain slices deprived of oxygen and glucose to test ASA
neuroprotective properties. We have found that ASA inhibits neuronal damage at
concentrations lower than those previously reported (0.1-0.5 mM), and that these
effects correlate with the inhibition of excitatory amino acid release, of NF
kappaB translocation to the nucleus and iNOS expression caused by ASA. All of
these three mechanisms may mediate the neuroprotective effects of this drug. Our
results also show that the effects of ASA are independent of COX inhibition.
Taken together, our present findings show that ASA is neuroprotective in an in
vitro model of brain ischaemia at doses close to those recommended for its
antithrombotic effects.
PMID- 10760374
TI - Involvement of peroxynitrite and hydroxyradical generated from nitric oxide in
hypoxia/reoxygenation injury in rat cerebrocortical slices.
AB - The changes in nitric oxide (NO) formation during hypoxia and reoxygenation were
measured in slices of rat cerebral cortex, and the possible involvement of NO and
its decomposition products, including peroxynitrite and hydroxyradical, in the
hypoxia/reoxygenation injury was subsequently investigated. NO formation
estimated from cGMP accumulation in the extracellular fluids was enhanced during
hypoxia and to a lesser extent in the reoxygenation period. The mRNA for
inducible NO synthase (NOS) was detected 3-5 h after reoxygenation, although
neuronal NOS mRNA decreased after reoxygenation. Several NOS inhibitors such as
N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine blocked not only the NO
formation but also the hypoxia/reoxygenation injury as determined by lactate
dehydrogenase (LDH) leakage. The hypoxia/reoxygenation injury was prevented by
peroxynitrite scavengers including deferoxamine and uric acid, or several
hydroxyradical scavengers such as dimethylthiourea, 2-mercaptopropionylglycine
and D(-) mannitol. In addition, the hypoxia/reoxygenation injury was attenuated
by poly(ADP-ribose)synthetase inhibitors such as banzamide, 3-aminobenzamide and
1,5-isoquinolinediol. On the other hand, both N-morpholinosidnonimine, a
peroxynitrite generator, and hydroxyradical-liberating solution containing
FeCl(3)-ADP and dihydroxyfumarate caused a marked LDH leakage in normoxic slices.
These findings suggest that the enhanced formation of NO causes
hypoxia/reoxygenation injury after degradation to peroxynitrite and
hydroxyradical and the resultant activation of poly(ADP-ribose)synthetase.
PMID- 10760375
TI - Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP
dependent protein kinase activity in some rat brain regions.
AB - When Delta(9)-tetrahydrocannabinol (Delta(9)-THC,15 mg/kg) was injected
intraperitoneally twice a day for 6 days, tolerance to its analgesic effect
appeared to be complete. Chronic exposure to Delta(9)-THC caused a significant
reduction in CB1 receptor binding in all brain areas that contain this receptor.
Cannabinoid receptor density was markedly reduced in the cerebellum (52%),
hippocampus (40%) and globus pallidum (47%) compared to 30% in the cortex and
striatum. Chronic exposure enhanced the cAMP pathway, as shown by the significant
increase of cAMP levels and PKA activity in the areas with receptor down
regulation (cerebellum, striatum and cortex). We propose that the increase in
cAMP cascade is part of the biochemical basis of cannabinoid tolerance.
PMID- 10760376
TI - Effects of tryptophan depletion on carbon dioxide provoked panic in panic
disorder patients.
AB - Results of an earlier study in healthy volunteers suggest that the serotonergic
system is involved in anxiety-related mechanisms. We studied the influence of
tryptophan depletion on the response to a 35% carbon dioxide challenge. Twenty
four panic disorder patients received a mixture of amino acids, either with or
without tryptophan, under double-blind conditions. There was a significant
increase in anxiety as well as in neurovegetative symptoms in the depletion
group, compared to the placebo condition. Furthermore, when we compare the
results of the placebo group with earlier panic provocation studies, it also
seems that a balanced amino acid mixture might have a protective effect against a
panic provocation. We conclude that the panic-enhancing effect of tryptophan
depletion as well as the potential protective effect of tryptophan administration
in panic disorder patients can be explained by the Deakin-Graeff theory of
anxiety.
PMID- 10760377
TI - Prolactin response to D-fenfluramine and suicidal behavior in depressed patients.
AB - Previous studies of the prolactin response to D-fenfluramine in depressed
patients have yielded inconsistent results. This may be because they did not
address the question of suicidality. We carried out this study to test the
hypothesis that lower prolactin response to D-fenfluramine is more closely
associated with suicidal behavior than with depression itself. A D-fenfluramine
test was performed in a sample of 18 healthy control subjects and in 85 drug-free
inpatients with a DSM-III-R diagnosis of major depressive episode (49 with a
history of suicide attempt, 36 without). Depressed inpatients with a history of
suicide attempt showed a significantly lower prolactin response to D-fenfluramine
compared to depressed inpatients without such a history and compared to control
subjects. Healthy control subjects and depressed inpatients without a history of
suicide attempt showed comparable levels of prolactin after D-fenfluramine. Time
elapsed since suicide attempt did not influence prolactin level (baseline or post
stimulation). Results show that in our depressed drug-free inpatient sample,
prolactin response to D-fenfluramine seems to be a marker of suicidality, but not
of depression itself. We suggest that it is a trait marker of suicidality.
PMID- 10760378
TI - Serum iron and ferritin in acute neuroleptic akathisia.
AB - Acute akathisia is a common and disturbing side effect of classic antipsychotic
medication. Some evidence suggests a role for iron deficiency in chronic and
tardive akathisia. In acute akathisia, however, the data are contradictory. Serum
iron and ferritin levels of 33 inpatients with acute akathisia during classic
neuroleptic medication were compared with those of 23 patients on classic
neuroleptics without this side effect. Akathisia was rated by means of the
Hillside Akathisia Scale. The groups were balanced for age (mean 38.5+/-14.5),
medication (butyrophenone- and phenothiazine-derived neuroleptics) and diagnosis
(schizophrenia, schizoaffective disorder, psychotic affective disorder). Patients
with acute akathisia had significantly lower serum ferritin levels than the
patients in the control group. However, the ferritin (56. 94+/-39.54 ng/ml) and
iron (88.52+/-40.0 mg/dl) levels in these patients were within the normal range
(ferritin 30-300 ng/dl, iron 80-180 mg/dl). No correlations between serum iron or
ferritin and akathisia ratings could be found. Although some reduction in serum
ferritin was found in patients with acute akathisia compared to patients without
akathisia, the difference was small and the ferritin levels were within the range
of the normal population. These findings suggest a minor role for iron deficiency
in acute akathisia.
PMID- 10760379
TI - Loudness dependence of auditory evoked potentials in obsessive-compulsive
disorder: a pilot study.
AB - In recent years it has been suggested that a serotonergic dysfunction is involved
in the pathogenesis of obsessive-compulsive disorder (OCD). The loudness
dependence of auditory evoked potentials (AEPs) is one of the best validated
indicators of the activity of the serotonin system in humans. To explore the
validity of the hypothesis of a serotonergic dysfunction in OCD, the loudness
dependence of AEPs of 22 medication-free OCD patients were compared with those of
22 age- and gender-matched healthy subjects. Auditory evoked N1/P2 activity to
tones of increasing intensity was studied using dipole source analysis. Contrary
to the hypothesis, OCD patients and healthy controls did not differ in their
LDAEPs of the tangential dipole in particular, located in the primary auditory
cortex and closely related to central serotonergic activity. Furthermore, no
significant correlation was found between the severity of obsessive-compulsive or
depressive symptoms and the loudness dependence of AEPs. These findings do not
support the hypothesis of a serotonergic dysfunction in OCD patients.
PMID- 10760380
TI - Saliva level of free 3-methoxy-4-hydroxyphenylglycol (MHPG) as a biological index
of anxiety disorders.
AB - To access the saliva level of free 3-methoxy-4-hydroxyphenylglycol (MHPG) as a
biological index of anxiety disorders, gender- or age-dependent changes in saliva
MHPG level in patients with anxiety disorders were investigated. Saliva MHPG
levels in 196 normal volunteers (59 male, 137 female) and 42 outpatients with
anxiety disorders (20 male, 22 female) at the initial consultation to the
hospital were measured by gas chromatography-mass spectrometry. Saliva MHPG
levels in patients were higher than those in normal subjects. The increase in
saliva MHPG levels in male patients was greater than that in female patients. Age
associated increase in the saliva MHPG level was greater in patients than in
normal subjects. Especially, a significant interaction of age vs. patient effect
was found in female subjects (P=0.0005), but not in male subjects (P=0. 174).
These data indicate that the measurement of saliva MHPG would be valuable for
detecting pathological anxiety in male patients regardless of age and in older
female patients, but not in younger female patients.
PMID- 10760381
TI - Increased QT variability in patients with panic disorder and depression.
AB - This study investigated beat-to-beat QT variability in patients with panic
disorder and depression, and normal control subjects using an automated algorithm
to compute QT intervals. An increase in QT variability appears to be associated
with symptomatic patients with dilated cardiomyopathy and also with an increased
risk for sudden death. QT(vm) (QT variability normalized for mean QT interval)
and QT(vi) (a log ratio of QT variance normalized for mean QT over heart rate
variability normalized for mean heart rate) were significantly higher in patients
with panic disorder and depression in supine as well as standing postures
(P=0.002 and 0.0001 for QT(vm) and QT(vi), respectively). In another analysis,
QT(vi) was significantly higher in patients with panic disorder compared to
control subjects in supine as well as standing postures during spontaneous
breathing as well as 12, 15 and 20 per minute breathing (P=0.005). These findings
are important especially in view of the recent reports of increased risk for
cardiovascular mortality and sudden death in patients with anxiety and depression
and the utility of QT(vi) as a noninvasive measure of temporal repolarization
lability.
PMID- 10760382
TI - Social skills deficits in schizotypal personality disorder.
AB - Evidence of long-standing social difficulties has been well documented in persons
with schizophrenia. These deficits are often so rudimentary that a person with
schizophrenia may never have developed the skills necessary to present as
socially competent. Given the cognitive, biological, and neuroanatomical links
between schizophrenia and schizotypal personality disorder (SPD), a study of
social skills in persons with SPD may reveal a behavioral link. This study
examined persons with SPD and their ability to label emotions in a recognition
task, to display socially competent behaviors in a social role-play task, and to
select appropriate behaviors from a multiple choice measure of social behavior.
Results indicated that the performance of persons with SPD was similar to
previously published findings in persons with schizophrenia. In terms of emotion
recognition, the SPD group's ability to label positive emotions was significantly
worse than their ability to label other emotions. Persons with SPD performed
significantly worse than matched control participants on a social role-play task.
However, the groups were equivalent in their ability to select socially
appropriate behavior from a multiple choice measure. These results suggest that
persons with SPD display social skills which mirror those previously reported in
persons with schizophrenia.
PMID- 10760383
TI - Social functioning scale: new contributions concerning its psychometric
characteristics in a Spanish adaptation.
AB - The assessment of social functioning takes on special importance with the
development of promising new types of psychosocial intervention for the treatment
of schizophrenia. Nevertheless, there are still few satisfactorily reliable
instruments for the assessment of social functioning that are reasonably
applicable in terms of time. This scarcity is even more notable in the Spanish
language. The aim of this study is to validate a Spanish version of the Social
Functioning Scale (SFS) giving new data (test-retest stability and concurrent
validity) on the psychometric characteristics of the scale. One hundred and fifty
subjects with a diagnosis of functional psychosis according to the DSM-III-R
(codes 295-298) criteria - 105 (70%) of them schizophrenic patients - in an
outpatient regimen of the Community Mental Health Center were assessed using a
Spanish version of the Social Functioning Scale. The reliability and validity of
the scale were studied. Data on the reliability (internal consistency, item-total
correlation, test-retest and informant/self-report reliability) and validity (of
the construct, concurrent and the criterion group method) revealed a substantial
fulfillment of the basic psychometric criteria. The results corroborate the
favorable psychometric characteristics of the scales and support the worth of the
instrument for the assessment of the social functioning of psychotic patients
when there is reliable and feasible assessment of out-patients.
PMID- 10760384
TI - Sensitivity and specificity of DSM-IV atypical features for bipolar II disorder
diagnosis.
AB - The aim of the study was to find the sensitivity and the specificity of DSM-IV
atypical features (mood reactivity, weight gain, appetite increase, hypersomnia,
leaden paralysis, interpersonal rejection sensitivity) for the diagnosis of
bipolar II disorder. Consecutive 557 unipolar (54.9%) and bipolar II (45.0%)
major depressive episode (MDE) outpatients were interviewed with the Structured
Clinical Interview for DSM-IV and the Global Assessment of Functioning Scale.
Bipolar II was diagnosed broadly, with a minimum duration of hypomania of at
least some days, instead of the 4 days required by DSM-IV. MDE with atypical
features was significantly more common in bipolar II patients. For the diagnosis
of bipolar II disorder, MDE with atypical features, sensitivity was 0.45, and
specificity was 0. 74. Among individual atypical features, hypersomnia had the
best combination of sensitivity (0.35) and specificity (0.81). Combinations of
two and three features did not improve sensitivity and specificity. As the
diagnosis of past hypomania may not be very reliable from a patient's interview,
atypical features may be an important marker of bipolar II disorder.
PMID- 10760385
TI - Alexithymia and depression in eating disorders.
AB - We compared alexithymia and depression ratings for non-hospitalized women meeting
DSM-IV criteria for anorexia nervosa (n=32) and bulimia nervosa (n=32) to ratings
for healthy women (n=74). Alexithymia was evaluated by the Toronto Alexithymia
Scale (TAS-20) and depression by the Hospital Anxiety and Depression Scale (HAD).
TAS and HAD scores were significantly higher in anorexic compared to bulimic
patients, although these two scales were significantly and positively correlated
(r=0.53, P=0.001). After taking depression into account as a confounding
variable, rates of alexithymia did not vary according to the type of eating
disorder (anorexia or bulimia).
PMID- 10760386
TI - Immunological approaches to the control of tuberculosis in wildlife reservoirs.
AB - Attempts to eradicate tuberculosis from cattle and farmed deer in some countries
have been frustrated by the existence of wildlife reservoirs of Mycobacterium
bovis infection. Possum control programmes in New Zealand using poisons have
shown clearly that the brushtail possum is an important source of infection for
cattle and farmed deer, and the sum of evidence strongly suggests that badgers
serve as a source of infection for cattle in the UK. Bovine tuberculosis can only
be eradicated from these countries by controlling M. bovis infection in both
wildlife and domestic animals. The most promising options for control of M. bovis
infection in wildlife in the longer term include the development of a
tuberculosis vaccine for wildlife and a strategy for biological control of
possums. The aim of this review is to address the problems and approaches
involved in the control of wildlife tuberculosis from an immunological
perspective.
PMID- 10760387
TI - Immunohistology of the splenic compartments of the one humped camel (Camelus
dromedarius).
AB - The cellular composition of the different splenic compartments is well
characterized in several species, but the spleen of the camel has not been
studied due to the lack of specific antibodies detecting its leukocyte subsets.
Therefore, 5microm frozen sections from 15 camel spleens (0.5-15 years) were
studied for acid and alkaline phosphatases and for cross-reaction with antibodies
specific for bovine (n=181), swine (n=14) and human (n=6) leukocyte determinants.
Fifteen antibodies cross-reacted with camel spleen cells. These included 13 anti
bovine, two anti-human, but no anti-swine antibodies. The lymph follicles mainly
consisted of B cells. The germinal centers showed a strong alkaline phosphatase
activity. The periarterial lymphatic sheath harbored T lymphocytes. The marginal
zone contained gammadelta T cells, CD45R0+, MHC class II DR+, CD44+, IL-A 24+
cells and few macrophages. The red pulp contained B, T, MHC class II DR+, IL-A24+
and gammadelta T cells and few macrophages. The periarterial macrophage sheaths
contained many more macrophages than the marginal zone, so they may play a
central role in the phagocytosis of the blood born particles. The alkaline
phosphatase probably labeled activated B cells, but in contrast to other species
no positive cells were found in the marginal zone. In general, lymphocyte
compartmentalization in the camel spleen is similar to that in other species
except for lower numbers of macrophages and the absence of alkaline phosphatase
positive cells in the marginal zone. No age related differences were observed in
the splenic compartments.
PMID- 10760389
TI - IBDV-induced bursal T lymphocytes inhibit mitogenic response of normal
splenocytes.
AB - We examined the suppressive activity of bursal T cells induced by infectious
bursal disease virus (IBDV) in inbred (15x7) and outbred commercial specific
pathogen-free (SPF) chickens. The suppressive activity was measured by the
ability of bursal and splenic T cells from IBDV-infected chickens to inhibit
mitogenic responses of normal splenocytes. The bursacytes but not the splenocytes
of IBDV-infected chickens inhibited the mitogenic responses of normal
splenocytes. The mitogenic inhibition by the bursacytes of IBDV-infected chickens
was dose-dependent. The suppression was observed both in inbred and non-inbred
chickens, and thus, was non MHC-restricted. Cell-sorting experiments revealed
that both CD4(+) and CD8(+) cells from the bursa of IBDV-infected chickens, as
well as cell-culture supernatants conditioned by these cells, mediated
suppression. Suppressor T (Ts) cells may therefore be involved in the
immunosuppression induced by IBDV.
PMID- 10760388
TI - Cytokine mRNA expression in leukocytes of efferent lymph from stimulated lymph
nodes in pigs.
AB - To test the hypothesis that characteristic cytokine responses occur in stimulated
porcine lymph nodes (LNs), lymph node efferent ducts were surgically cannulated.
Efferent lymph (EL) leukocytes were collected before and after stimulation of LNs
with mitogens [bacterial lipopolysaccharide (LPS) or phytohemagglutinin-P(PHA-P)]
and antigens [hen egg white lysozyme (HEWL) or purified protein derivative of
tuberculin (PPD)]. Cytokine mRNA expression was evaluated by quantitative reverse
transcription polymerase chain reaction (Q-RT-PCR). Interleukin (IL)-1alpha was
predominantly produced after all stimuli except for HEWL after which tumour
necrosis factor (TNF)-alpha message was dominant. None of the stimuli induced
message for IL-2, IL-4 or IL-8. Other cytokine mRNAs were produced in variable
amounts and percentage of overall production of each cytokine message was in the
following descending rank: LPS: IL-1alpha, TNF-alpha, interferon (IFN)-gamma, IL
10, IL-12-p35, IL-6, IL-12-p40 and TNF-beta; PHA-P: IL-1alpha, TNF-alpha, IL-10,
IFN-gamma, IL-12-p40 and TNF-beta; HEWL: TNF-alpha, IL-1alpha, IFN-gamma, IL-10,
IL-6, IL-12-p40, TNF-beta and IL-12-p35 and PPD: IL-1alpha, IFN-gamma, TNF-alpha
and IL-10. Time course response of cytokines revealed early (IL-1alpha, 10, TNF
alpha) and intermediate (IL-12-p40, TNF-beta, IFN-gamma) responses for PHA-P and
early (IL-1alpha, 6, 10, IL-12-p35, IL-12-p40, TNF-alpha), intermediate (TNF
beta, IFN-gamma) and late (IL-1alpha, 6) for LPS. Cytokine mRNA response induced
by HEWL was early (IL-alpha, IFN-gamma), intermediate (IL-10, IL-12-p40, TNF
beta), late (IL-1alpha, IL-12-p35) and very late (IL-1alpha, 6, 10, IL-12-p40,
TNF-alpha). In Bacillus Calmette-Guerin (BCG) sensitized pigs, stimulation of LNs
with PPD induced message for IL-1alpha, 10, TNF-alpha and IFN-gamma which peaked
at 24h. Cytokine mRNAs varied by stimulus and differed for antibody and cell
mediated immune response.
PMID- 10760390
TI - The effect of ex vivo refrigerated storage and cell preservation solution (Cyto
Chex II) on CD11b expression and oxidative burst activity of dog neutrophils.
AB - The expression of CD11b and oxidative burst activity of dog neutrophils
undergoing ex vivo refrigerated storage was studied using flow-cytometry .
Additionally, the effect of a proprietary cell stabilization reagent (Cyto-Chex)
on the expression of CD11b and oxidative burst activity was studied. Expression
of CD11b was very high (>90% positive) on dog neutr ophils isolated from
peripheral blood. Dog neutrophils showed a rapid and sustained increase in CD11b
antigen density (P<0.01) during refrigerated storage, this increase was prevented
by treatment with Cyto-Chex but was not completely blocked on the first day.
There were no significant differences in mean antigen density between any days in
the non-preserved group or between Days 1 to 4 in the Cyto-Chex treated group.
The non-treated group showed significantly greater mean antigen density at all
time points when compared to the preservative treated group (P<0.0001). Treatment
with Cyto-Chex did not interfere with measurement of oxidative burst function on
the first 2 days. Alterations of both resting oxidative activity and stimulated
response were observed over time in both treated and untreated blood samples.
Cyto-Chex treated samples showed a dramatic, significant decline in stimulated
response after the third day of storage (P<0.001), while non-treated cells showed
steadily increasing, but non-significant differences in stimulated response. Cyto
Chex was demonstrated to be a useful reagent for stabilization of dog neutrophil
membrane antigens during storage, however this reagent is not recommended for
preservation of cells for functional assays.
PMID- 10760391
TI - Effects of human IL-8 isoforms on bovine neutrophil function in vitro.
AB - Interleukin 8 (IL-8) is a potent chemotactic and activating agent for human
neutrophils and bovine IL-8 is chemotactic for bovine neutrophils; however, it is
unclear whether IL-8 activates bovine neutrophils. Two isoforms of human
recombinant (hr) IL-8 protein (77 and 72 amino acid) were used to stimulate
bovine neutrophils in vitro. Bovine neutrophils exhibited significant migration
in the presence of 0.1, 0.5, 1.0 and 5.0ngml(-1) hr IL-8 when incubated for 30min
at 37 degrees C in a modified Boyden chamber assay. Both the 77 and 72 aa forms
were equally effective in inducing migration in this assay. At the highest doses
of IL-8 examined (1 and 5ngml(-1)), migration was similar to migration in the
presence of 20% zymosan-activated serum (ZAS) or 12h lipopolysaccharide (LPS)
stimulated blood monocyte supernatants (CM). Significant (p<0. 05) release of
alkaline phosphatase (ALK-P) (from specific granules) occurred but
myeloperoxidase (MPO) release and superoxide anion production were not enhanced
in bovine neutrophils by either form of hrIL-8 at any of the doses tested.
Significant (p<0.05) alkaline phosphatase release was observed in the presence of
10 and 100ngml(-1) for the 72 aa form of IL-8 and only at the higher dose for the
77 aa form of IL-8. The ZAS and CM significantly enhanced neutrophil
degranulation of ALK-P and MPO as well as inducing superoxide anion production.
These results suggest that IL-8 may play a role in both neutrophil recruitment
and activation during bovine inflammatory processes.
PMID- 10760392
TI - Distribution of MHC-II and CD1 molecules in the skin of lambs and changes during
experimentally-induced contact hypersensitivity.
AB - The presentation of antigen to specific T-cell populations is a crucial event
during the elicitation phase of contact hypersensitivity (CHS). Significant
changes in CD4(+) T-cell and gammadelta T-cell populations occur in the skin of
sheep 48h after re-exposure to dinitrochlorobenzene but the expression of antigen
presentation molecules such as MHC-II and CD1 at this stage of the
hypersensitivity response has not been investigated. In the present study, a
panel of monoclonal antibodies recognising CD1 and MHC-II subtypes was used in
combination with computer assisted morphometric analysis to estimate the
distribution of antigen presentation molecules in the superficial and deep dermis
of the ears of lambs during the elicitation phase of CHS. The MHC-II molecules
showed predominantly a perivascular and peri-appendageal distribution in the
dermis and there were scattered MHC-II(+) cells in the basal and suprabasal
layers of the epidermis. The CD1w2(+) (CD1b-like) molecules were present on
distinct cells that were scattered evenly through the dermis, whereas CD1w3(+)
(CD1c-like) molecules were almost exclusively detected on or in close association
with the vascular endothelium. There was a significant increase in the presence
of MHC-DQ(+) cells in the superficial dermis of dinitrochlorobenzene-treated
animals compared with both an untreated control group and a vehicle-treated
control group. However, MHC-DQ/DR(+) and CD1w3(+) cells only showed a significant
increase compared with the vehicle-treated control group. The present study shows
that the distribution of molecules involved in antigen presentation to CD4(+) T
cells and gammadelta T-cells changes during the elicitation phase of CHS in
sheep, and suggests a role for MHC-DQ molecules on antigen presenting cells.
However, the changes in distribution and expression of MHC-II and CD1 subtypes
argue against a prominent role for a CD1-dependent pathway for T-cell recognition
in the clinical cutaneous hypersensitivity response in sheep. Based on the
expression of MHC-II molecules and CD1c molecules, we also suggest a potential
role for endothelial cells in antigen presentation during the clinical dermatitis
reaction.
PMID- 10760393
TI - Flow cytometric analysis of an immunodeficiency disorder affecting juvenile
llamas.
AB - The present study was undertaken to characterize the immune system of llamas and
alpacas and establish the basis for an immunodeficiency disorder affecting
juvenile llamas. Flow cytometric (FC) analysis of the immune system with a panel
of monoclonal antibodies (mAbs) revealed the immune system of llamas and alpacas
is similar in leukocyte subset composition to that in ruminants. Peripheral blood
mononuclear cells in adults are comprised of surface immunoglobulin (sIg(+)) B
cells (31%+/-8 S.D.), alphabeta T-cells (27%+/-12 S.D.), WC1(+) gammadelta T
cells (16%+/-11 S.D.), and 5-16% monocytes. In contrast to cattle, goats, and
sheep, however, the frequency of WC1(+) gammadelta T-cells is not high in
juveniles but similar to the frequency in adults. Also, sIg(+) B-cells are
present in high concentration in juveniles (43%+/-11 S.D. ). Expression of major
histocompatibility class II molecules on resting T-cells was low or absent.
Comparative analysis of peripheral blood lymphocyte composition in normal
juvenile llamas and llamas presenting with the signs of the juvenile llama
immunodeficiency syndrome (JLIDS) revealed the concentration of B-cells is
extremely low (1-5%) in affected animals. The findings suggest JLIDS is
attributable to an autosomal recessive genetic defect in the development of B
cells.
PMID- 10760394
TI - A DNA vaccine coding for glycoprotein B of pseudorabies virus induces cell
mediated immunity in pigs and reduces virus excretion early after infection.
AB - Glycoproteins B (gB), gC and gD of pseudorabies virus (PRV) have been implicated
as important antigens in protective immunity against PRV infection. As cell
mediated immunity plays a major role in this protective immunity, we determined
the significance of these glycoproteins in the actual induction of cell-mediated
immunity. We vaccinated pigs with plasmid DNA constructs coding for gB, gC or gD
and challenged them with the virulent NIA-3 strain of pseudorabies virus.
Vaccination with plasmid DNA coding for gB induced the strongest cell-mediated
immune responses including cytotoxic T cell responses, whereas plasmid DNA coding
for gD induced the strongest virus neutralising antibody responses.
Interestingly, vaccination with gB-DNA reduced virus excretion early after
challenge infection while vaccination with gC-DNA or gD-DNA did not.This is the
first study to demonstrate that DNA vaccination induces cytotoxic T cell
responses in pigs and that cell-mediated immunity induced by vaccination with gB
DNA is important for the reduction of virus excretion early after challenge
infection.
PMID- 10760395
TI - Production of antibodies against chicken interferon-gamma: demonstration of
neutralizing activity and development of a quantitative ELISA.
AB - Four monoclonal antibodies (mAbs) specific for chicken interferon-gamma (ChIFN
gamma) were generated by gene gun immunization and were utilized to develop a mAb
based capture ELISA specific for ChIFN-gamma. Each mAb reacted specifically with
both baculovirus and Escherichia coli-derived recombinant ChIFN-gamma in ELISA
and Western Blot analysis or natural ChIFN-gamma in immunofluorescence
experiments. As determined by competition ELISAs, mAbs 3D5, 4C6 and 3A3
recognized the same or adjacent epitopes on the ChIFN-gamma molecule, whereas mAb
1E12 recognized a distant epitope. Moreover, this latter mAb was able to highly
neutralize the biological activities of both recombinant and natural ChIFN-gamma
as measured by inhibition of viral replication and macrophage activation. To
improve the detection of ChIFN-gamma, a capture ELISA was developed using mAb
1E12 as capture antibody and biotinylated mAb 4C6 as detection antibody. In
addition to being more rapid and easier to perform than classical cell-mediated
immunity tests, this ELISA has excellent sensitivity and improved specificity.
The use of a specific rabbit polyclonal serum as revealing antibody further
increased the sensitivity of the detection down to 0.5ng/ml of ChIFN-gamma. This
ELISA would provide a sensitive tool to measure the in vitro release of ChIFN
gamma by T-cells in response to specific recall antigen.
PMID- 10760396
TI - Effect of ascorbic acid supplementation on the immune response of chickens
vaccinated and challenged with infectious bursal disease virus.
AB - One-day-old chickens were divided into two groups and reared under similar
conditions. One group was fed a diet supplemented with 1000ppm ascorbic acid and
the other group was fed an identical diet, but not supplemented with ascorbic
acid. Both groups were vaccinated against infectious bursal disease (IBD) at 7
days of age and challenged orally with 4x10(5) of 50% embryo-lethal-dose IBDV 14
days later. The number of anti-IBDV antibody secreting cells, production of
interleukin-2 (IL-2) by splenocytes, number of CD4(+), CD8(+) and IgM(+) cells in
spleen and IgM(+) cells in bursa of Fabricius were compared between the two
groups at 7 days (prior to vaccination), 21 days (14 days post-vaccination and
prior to challenge) and 31 days (10 days post-challenge) of age. The number of
CD8(+) in spleen at 7 days of age and IgM(+) cells in bursa at 7, 21 and 31 days
of age were significantly higher in ascorbic acid supplemented group (P<0.05).
Production of IL-2 by splenocytes was higher as indicated by higher stimulation
indices in ascorbic acid supplemented group. The number of anti-IBDV IgG antibody
secreting cells in spleen at 21 and 31 days of age were significantly higher in
ascorbic acid supplemented group (P<0.05). Dietary supplementation of ascorbic
acid may ameliorate the immunosuppression caused by IBDV vaccination and improve
humoral and cellular immune responses.
PMID- 10760397
TI - Rabies seroprevalence of street dogs from Sao Paulo City, Brazil.
AB - A sample of 602 street dogs captured by the Sao Paulo zoonosis-control municipal
service was analyzed for the presence of serum antibodies against the rabies
virus and compared to a control sample of 37 dogs from the kennel of the police
of Sao Paulo. Data were stratified into 4 age intervals and the age from the
street-dog sample was estimated by general aspects and dental observation
according to standard techniques. We assumed that seropositivity was due to
previous vaccination (no sub-clinical infection). From the prevalence data, we
estimated the age-dependent incidence-density rate of vaccination by a simple
mathematical model, which also allowed the estimation of the period of antibody
protection given by the supposed vaccination. Crude seroprevalence in the street
dog sample was 16.5% and in the sample from the police-kennel dogs was 80%. The
average age of first vaccination calculated for the street-dog sample was 5 years
of age (if we assumed an average period of vaccine protection of 3 years) - but 5
months of age for the police-kennel sample.
PMID- 10760398
TI - A simulated surveillance program for bovine paratuberculosis in dairy herds in
Norway.
AB - Monte Carlo simulation models were used to evaluate the feasibility and potential
results of a proposed national survey of the prevalence of bovine
paratuberculosis (PTB) in dairy herds in Norway. The expected herd prevalence was
assumed to be 0.2% in the simulations. The low sensitivity of the ELISA test, the
assumed low herd prevalence, the typical low within-herd prevalence of PTB and
the small herd sizes all present problems in detection of the disease.
Simulations with 500, 1000, 2500 and 6000 herds tested were done. Our results
suggest that a national survey would not be feasible at present, due to the low
probability of detecting infected herds and because of the high number of false
positive reactions that would be expected to occur.
PMID- 10760399
TI - Risk factors for Marek's disease and mortality in white Leghorns in Norway.
AB - A prospective longitudinal field study was conducted in the period from January
1994 to January 1996 to analyse the relationship between some selected risk
factors in the growing and laying periods and (1) the flock-level occurrence of
Marek's disease (MD) during the period from 16 to 32 weeks of age and (2) the
cumulative mortality during the same period. A total of 171 layer flocks in 102
egg-production farms were included in the statistical analyses.A logistic
regression (with strain of layer and vaccination program against MD as fixed
effects) of flock-level MD-status during the first 16weeks of the laying period
was conducted. Of the risk factors investigated, "multi-age management" and
"housing system" were significantly associated at the rearing farm, and "number
of hens in each cage" at the egg-production farm. Flocks kept in single-age
facilities had a lower risk of MD than flocks housed in farms with multi-age
management. The odds of MD were larger for flocks housed on a litter floor in the
rearing farms compared to flocks housed in battery cages. At the egg-production
stage, flocks kept in battery cages housing more than three hens were at greater
risk of MD than those held in cages for three hens or less.A weighted least
squares regression (with strain of layer and flock-level MD-status as fixed
effects) of cumulative mortality during the period from 16 to 32weeks of age was
also run. The same risk factors (with the same directions of effects) and "size
of the rearing farm" were included in the final model of mortality. Chicks reared
in medium-sized farms were at higher risk of dying than those coming from either
small or large rearing farms. Our results confirm the importance of preventing
chicks from being exposed to MD-virus during the rearing period, to reduce the
risk of MD-outbreaks (and thereby, mortality losses) during the early stage of
the egg-laying period.
PMID- 10760400
TI - Risk factors for brucellosis seroprevalence of sheep and goat flocks in Spain.
AB - Risk factors for ovine and caprine brucellosis in the Avila region (center of
Spain) were evaluated using data from a cross-sectional study of the most
important diseases of small ruminants in this Spanish region between 1996 and
1997. Questionnaire data from 56 herds (35 ovine and 21 caprine) were used.
Sixteen (29%) flocks (3 caprine and 13 ovine) were brucellosis-seropositive.
Overall, 0.7% of sheep and 0.1% of goats were seropositive. Eleven risk factors
were studied at the group level by logistic regression using flock brucellosis
status as outcome, and by linear regression using percentage of brucellosis
seropositivity as outcome. Both final models contained the same variables:
contact with sheep and grazing in communal pastures as risk factors, and
frequency of disinfecting practices as a protective factor.
PMID- 10760401
TI - Prevalence of subclinical Salmonella enterica infection in Danish finishing pig
herds.
AB - Our aim was to determine the Salmonella enterica prevalence in 96 randomly
selected Danish pig herds, based on serological examination of blood samples and
bacteriological examination of faecal samples (collected simultaneously from the
same pens). For comparison, 39 high-seroprevalence herds were included in the
study. The representativeness of the selected herds was assessed, based on
descriptive statistics of herd size and type. Totals of 1330 pen samples and 6814
blood samples were examined.The results from the meat-juice screening in the
Danish S. enterica Control Programme were available for 3372 meat-juice samples
from 91 of the 96 randomly selected herds and 1195 meat-juice samples from 37 of
the 39 high-seroprevalence herds. Of the 96 randomly selected herds, 23 herds had
no positive pen samples (out of 10), no positive blood samples (out of 50) and no
positive meat-juice samples (out of approximately 30-40 samples in 6 months). Ten
herds had one or more positive meat-juice samples but were otherwise negative. S.
Typhimurium was isolated from 30 of the 39 high-seroprevalence herds. Our
conclusions were: (1) The within-herd seroprevalence among the 96 randomly
selected Danish pig herds was low (average within-herd seroprevalence=2%,
maximum=32%). (2) Among the 39 high-seroprevalence herds (recently assigned level
3 in the S. enterica Control Programme), S. enterica was isolated from 77% of the
herds when 10 pen samples were examined bacteriologically. (3) Seropositivity
tended to be related to the presence of S. Typhimurium.
PMID- 10760402
TI - Reproductive performance of farmed red deer (Cervus elaphus) in New Zealand: V.
Mob and individual-hind risk factors associated with calf rearing to weaning.
AB - A 2-year longitudinal observational study of 15 red deer farms was carried out in
New Zealand from March 1992. Both years combined, 3364 adult and 653 yearling
hinds were diagnosed pregnant in June by ultrasound scanning and monitored for
reproductive success up to weaning. At weaning, pre-rut at approximately 100 days
after calving, udders were palpated or observed by the farmer and hinds were
categorised as lactating (wet) indicating survival of calf, or not lactating
(dry). Farm management practices during calving and early lactation were
recorded. Analysis of risk factors associated with progeny survival was done
using path analysis (separately for adult and yearling hinds). Adult hinds >3
years old at calving, conceiving before 1 May and having a body-condition score
>2 in September had 2.8, 2.4 and 2.9 times significantly higher odds of rearing a
calf to weaning than other hinds, respectively. Adult hinds had about 5 times
lower odds of rearing a calf to weaning when they were mixed with mature stags
during calving. When farmers visited calving paddocks and checked for calving
problems, adult hinds had 1.7 times higher odds of rearing a calf to weaning.
When the farmer entered calving paddocks at least every second time they observed
the hinds, yearling hinds had a twice higher odds of rearing a calf up to
weaning. Sunny weather and high maximum temperatures were positively and
negatively associated, respectively, with the probability of an adult hind being
in lactation at weaning.
PMID- 10760404
TI - The effects of grit supplementation and feed type on steel-shot ingestion in
mallards.
AB - Lead poisoning by shot-pellet ingestion is an important cause of death in
waterfowl from wetlands that have high densities of lead-shot pellets and low
availabilities of grit in their sediments. To evaluate grit supplementation when
mixed with baited grain as a method of reducing shot ingestion in waterfowl, 24
mallards (Anas platyrhynchos) were kept in captivity to study the relationship
between steel-shot, grit and grain ingestion in four experiments. Steel-shot
ingestion was more related to seeking grit than to feeding on grain, and it did
not differ between two types of grain offered (rice or sorghum). Grit ingestion
increased with grit supplementation and shot ingestion was only slightly reduced.
Calcareous grit used in the experiments had a shorter half-life (1.4 days) in the
gizzard than values reported for siliceous grit (3.1 days).
PMID- 10760403
TI - Udder health and risk factors for subclinical mastitis in organic dairy farms in
Switzerland.
AB - 1+ were submitted for somatic cell counting (SCC), bacteriological examination
and to test for antibiotic susceptibility. The SCC and germ-cell counts of
monthly bulk-tank milk samples were available through Dairy Inspection and
Advisory Services and milk production data of 567 herd-book cows were available
from breeding associations. Possible individual and environmental predictors of
subclinical mastitis were identified using logistic models adjusted for
clustering of the data at herd and cow levels. Data were analyzed separately for
cows from 7 to 100 and from 101 to 305 days post partum. Prevalences of
subclinical mastitis at the quarter level were 21.2% for lactation period 7-100
days and 34.5% for 101-305 days post partum. The geometric mean SCC in bulk-tank
milk samples was 85.6x10(3)cells/ml. Samples at 7-100 and 101-305 days post
partum were positive for Staphylococcus aureus in 16.0 and 7.4%, for coagulase
negative Staphylococci in 51.5 and 50.6%, for Streptococcus agalactiae in 0.0 and
0.8%, for other Streptococci in 19.4 and 15.6%, for E. coli in 1.0 and 0.4%, and
for Corynebacterium bovis in 25.7 and 45.1%, respectively. Risks of subclinical
mastitis increased significantly with increasing days post partum and advancing
age of cow. Cows that were sampled when staying in alpine dairies had
considerably higher risks of subclinical mastitis than cows staying in home
barns. Significantly lower risks of subclinical mastitis were observed in farms
where CMT was performed regularly as a control measure. Bacteria in milk from
cows with mastitis exhibited antibiotic resistance at a comparable frequency as
found previously in conventional farms.
PMID- 10760405
TI - Financial analysis of animal trypanosomiasis control using cypermethrin pour-on
in Kenya.
AB - The financial impact of use of cypermethrin pour-on (Ectopor(R)) in control of
animal trypanosomiosis was determined in a trial undertaken by the Kenya
Trypanosomiasis Research Institute (KETRI). This trial started in December 1990
and ended in February 1992. It was undertaken in two adjacent ranches in the
coast province of Kenya. The trial site was in an area of high apparent density
(AD) of tsetse flies, and at the start of the trial no cattle were kept in this
area. Cypermethrin was applied fortnightly to the 1100 steers which were kept in
pour-on ranch 'A' while another 100 steers were kept in control ranch 'B' to act
as control sentinels. From the main pour-on group, 100 animals were identified as
the pour-on sentinels and compared to the control sentinels which received no
pour-on.Pour-on application led to a significant decrease in the tsetse AD in the
pour-on ranch A to 90% of the initial AD in some areas. The animals treated with
pour-on had a significantly higher mean packed-cell volume (PCV). The weekly
prevalence of trypanosome infections in animals treated with pour-on was <4% with
only one exception when it was <10%. In the control animals, the prevalence
ranged between 10 and 50% (with a few exceptions when it was <10%). The incidence
of tick-borne diseases was lower in the pour-on animals. The mean monthly weights
of the pour-on animals was significantly higher, and at the end of the trial the
pour-on animals had a mean weight gain of 136.70+/-16.7kg while the control
animals had gained 97.16+/-22.6kg. The financial net return of using cypermethrin
pour-on was positive and the financial rate of return of 122.6% indicated that
use of the pour-on was highly beneficial despite the high cost of the product.
PMID- 10760406
TI - Prevalence of subclinical coccidiosis in broiler-chicken farms in the
municipality of Mashhad, Khorasan, Iran.
AB - A survey of the prevalence of subclinical coccidiosis in broiler-chickens was
conducted in the municipality of Mashhad, Khorasan, Iran. Eighty-four chicken
farms were randomly selected; from each farm, five birds per 106th week of
age.6th week of age. The farm-level prevalence of subclinical coccidiosis was 38%
(95% CI: 48 .47%). Uni- and multi-variable associations were tested between each
va riable. An increased risk of infection in the broiler was associated wi th the
larger farm, with older chickens, and if the chicken farm were sa mpled in the
winter or spring, using coccidiostat in the food was not as sociated. The peak
oocyst score in the litter occurred at >6th week age . Most farms (97%) had E.
acervulina; (41%) had E. maxima and (12%) had E. tenella.
PMID- 10760407
TI - Seasonal dynamics of Anocentor nitens on horses in Brazil.
AB - Anocentor nitens is a widespread ectoparasite of horses in Brazil. A study of the
seasonal dynamics of the parasitic phase of this tick was made by regular census
of engorging females (>/=4mm) on free-ranging horses, fortnightly from July 1995
to July 1997, at Pedro Leopoldo, Minas Gerais. Twenty horses were divided into
four groups of five animals per group, each having a similar mix of resistant and
less resistant animals, based on initial infestation. Every 2 weeks, one of the
groups, in sequence, was treated with an acaricide to prevent excessive
infestations, and female ticks were censused 38 days later. The acaricide dips
did not interfere with the seasonal dynamics of the tick population, which
produced three major peaks of activity over a 12-month period. The first two
peaks were in the hot, wet season and the third in the cold dry season. Tick
numbers were similar for the two 12-month periods, decreasing from the spring and
summer to the autumn and winter. Infestation rates were not equal among different
horses. Twenty percent of the horses were responsible for 48% of the total
parasite load, while 30% accounted for only 2.5% of the total parasite load.
Principal predilection sites were; the ear (61%), mane (21%), and muzzle and face
(6%). Measures for the strategic control of A. nitens ticks are discussed.
PMID- 10760408
TI - Characterization of trypanosome isolates from naturally infected horses on a farm
in Kenya.
AB - Following an outbreak of trypanosomosis in horses on a farm in Kenya, 18
trypanosome isolates were collected from the infected animals over a period of
one and a half years and cryopreserved for characterization. The characterization
was done on the basis of morphology using Giemsa-stained blood and buffy coat
smears, infectivity to mice, recombinant DNA hybridization, and chromosome
separation by orthogonal field alternation gel electrophoresis (OFAGE).
Morphologically, all the trypanosome isolates were identified as belonging to the
subgenus Nannomonas, and a total of 16 out of the 18 isolates grew in mice. Using
the recombinant DNA hybridization technique, the isolates were further classified
as the 'savannah' type of Trypanosoma congolense. Furthermore, chromosome
separation by OFAGE, carried out on six clones derived from different isolates,
exhibited a profile characteristic of T. congolense, 'savannah' type. However,
there were differences in the number and positions of the medium-sized and
minichromosomes indicating a diversity of serodemes within the isolates. Hence
the infecting trypanosomes in this disease outbreak were T. congolense,
'savannah' type, and comprised several serodemes or strains.
PMID- 10760409
TI - Detection of Trypanosoma congolense antibodies with indirect ELISAs using antigen
precoated microtitre plates.
AB - The study reports the performance of four indirect enzyme-linked immunosorbent
assays (ELISAs) for antibody (AB) detection using microtitre plates which were
precoated with native or heat/detergent denatured antigens (AGs) from Trypanosoma
congolense (T.c.) and T. vivax (T.v.), and stored for between 1 to 206 days at
+37 degrees C. Bovine serum samples were obtained by sequential bleeding of 3
months old T.c.-infected bulls and their uninfected cohorts, as well as by a
single bleeding of uninfected adult cattle. The first day of AB detection, and
observations on samples after this (defined as estimated ELISA sensitivity),
depended on the cut-off value in the specific ELISAs. Cut-off values from pre-
and early post-infection samples of individual animals demonstrated a
seroconversion in all ELISAs on average after 10-15 days post-infection (dpi).
The AB detection was delayed in the T.c. native and denatured AG-based ELISAs
using cut-off points from uninfected cohort cattle (16.5 dpi, 19.3 dpi) and the
adult cattle population (22.1 dpi, 25.0 dpi). The T.v. AG-based ELISAs however
lacked crossreactiviy to T.c. ABs. The estimated sensitivity of each T.c. AG
based ELISA was above 96% throughout, but significantly lower for the T.c. native
AG-based ELISA (91.1%) when the adult cattle derived cut-off point was used
(p<0.01). The sensitivity of the phase contrast buffy coat technique was similar
to the T.c. AG-based ELISAs, but significantly lower when the T.c. denatured AG
based ELISA was used at the adult cattle derived cut-off point (p<0.05). The
implications of the results and future research aspects on ELISAs to detect
trypanosomal ABs and AGs are discussed.
PMID- 10760410
TI - Comparison of growth rates of Tritrichomonas foetus isolates from various
geographic regions using three different culture media.
AB - The growth rates of 16 isolates of Tritrichomonas foetus from three distinct
geographic regions were investigated in modified Diamond's medium, liver infusion
broth medium and a commercially available culture kit. While some differences in
growth characteristics were detected for different isolates and in the three
different media, all isolates grew. Trichomonads reached peak concentrations from
an initial concentration of 10(4) trichomonads/ml on Days 2, 3 and 4 in modified
Diamond's medium, on Days 2-6 (excluding CAPTF102) in the commercial culture kit
and on Days 2-7 in liver infusion broth medium. Viable parasites were detectable
for longer periods in liver infusion broth medium and the commercial culture kit
than in Diamond's medium. Peak concentrations for isolates tended to be higher in
modified Diamond's medium than in liver infusion broth medium or the commercial
culture kit. Results show that these three media are suitable for the growth of
all 16 T. foetus isolates from three continents and suggest that these media
could be used effectively throughout the world.
PMID- 10760411
TI - Effects of repeat fenbendazole treatment in dairy calves with giardiosis on cyst
excretion, clinical signs and production.
AB - In this 90-day study, 60 male Holstein dairy calves were experimentally infected
with Giardia duodenalis. Calves were randomly blocked by weight into treatment
(N=30) and placebo (N=30) groups. Beginning on study Day 0, calves in the
treatment group were administered an oral dose of 5mg/kg of fenbendazole once
daily for three consecutive days. Calves in the placebo group received a daily
oral treatment of 5 ml of saline for 3 days. These treatments were repeated on
Days 30 and 60 of the study. Fecal samples were collected from calves once per
week and examined for the presence of Giardia cysts. Calves were monitored daily
for clinical signs of intestinal disease and all episodes of diarrhea recorded.
Calves were weighed once per week and total feed intake, on a dry matter basis,
was calculated daily. Following each treatment, the number of calves shedding
Giardia cysts in the fenbendazole group was reduced (p<0.001) compared to the
saline group. Also, calves in the fenbendazole group had fewer cysts (p<0.05)
detected in their feces following treatment compared with calves that received
saline. Within 2 weeks post treatment, the number of infected animals and fecal
Giardia cysts returned to placebo levels. This pattern of reinfection was
consistent after every treatment period. Calves receiving fenbendazole had fewer
total days with diarrhea (p<0.01) and the average number of days each calf had
diarrhea was reduced (p<0.05), compared to the placebo group. There were no
differences in mean body weight, average daily gain, or feed intake between the
treatment or placebo groups. This study demonstrates that fenbendazole is an
effective treatment for giardiosis, resulting in a clinical benefit and reducing
the number of infective cysts shed by calves. However, this treatment regime had
no impact on production parameters and reinfection occurred rapidly in these
calves.
PMID- 10760412
TI - Efficacy of the nematophagous fungus Duddingtonia flagrans in reducing equine
cyathostome larvae on pasture in south Louisiana.
AB - The effectiveness of Duddingtonia flagrans in reducing the free living third
stage larvae (L(3)) of equine cyathostomes on pasture when fed to horses has been
demonstrated in cold temperate climates. The objective of this experiment was to
assess the efficacy of D. flagrans against equine cyathostomes in the subtropical
environment of southern Louisiana. Fecal pats were prepared by mixing feces
obtained from a parasite-free horse fed D. flagrans at a dose of approximately 2
x 10(6) spores kg(-1), with feces containing cyathostome eggs from a parasitized
horse. Control pats contained feces from a parasite-free horse mixed with feces
containing cyathostome eggs. The fecal pats were placed on pasture in six
replicates at 4-week intervals from March 1997 until January 1998. Comparison of
recoveries of L(3) from non-treated control pats in the field with non-treated
coprocultures maintained in the laboratory indicated that L(3) survival on
pasture was reduced during the months of May, June, July, August and September.
The efficacy of the fungus was determined by L(3) recovery from grass surrounding
the fecal pats of treated and control groups. D. flagrans significantly reduced
L(3) during the months of April, May, and October 1997 to January 1998 (range 66
99% reduction, p=0.0001), and for the year as a whole (p=0.0001).
PMID- 10760413
TI - Localisation and characterisation of ovine immunglobulin within the sheep scab
mite, Psoroptes ovis.
AB - Ovine IgG was detected in homogenates of repeatedly washed Psoroptes ovis. Some
of the immunoglobulin in the homogenates was fragmented although the host IgG
present in mite washings was largely intact. The host immunoglobulin was immuno
localised to the surface or cytoplasm of the gut cells of feeding stages of
freshly harvested P. ovis examined by cryosectioning. A similar distribution of
rabbit IgG was detected in P. cuniculi. The IgG demonstrated in the mite gut
represented partially digested as well as intact immunoglobulin. The presence of
intact host immunoglobulin suggests that P. ovis may be susceptible to
vaccination by the gut antigen approach, a method used successfully for blood
feeding ectoparasites like Boophilus microplus.
PMID- 10760414
TI - Detection of a new pathogenic Babesia microti-like species in dogs.
AB - Small babesiae in dogs are generally considered to belong to Babesia gibsoni.
Here we describe the genotypic characterisation of small piroplasms found in the
blood of a dog which suffered from clinical babesiosis. Pairwise identities as
well as distance, parsimony and maximum likelihood analyses of the 18S rDNA
clearly demonstrated that this isolate was only distantly related to the other
canine piroplasms characterised genetically so far, including B. gibsoni. It was
more closely related to B. microti, B. rodhaini, and Theileria equi. It is
concluded that the small canine piroplasms described in this study represent a
hitherto unknown species and that the fauna of piroplasms occurring in dogs is
more diverse than assumed so far.
PMID- 10760415
TI - Fractionated stereotactic radiotherapy (FSRT) for optic glioma.
AB - PURPOSE: To determine efficacy and toxicity of fractionated stereotactic
radiotherapy (FSRT) in patients with optic glioma. METHODS AND MATERIALS: Ten
patients suffering from optic glioma were treated by FSRT between December 1990
and December 1995 at the German Cancer Research Center (DKFZ) in Heidelberg.
Eight patients were treated for progressive recurrent tumor following partial
tumor resection and 2 patients were treated postoperatively. Dose distributions
were calculated by a 3D treatment planning system (Voxelplan, Heidelberg).
Patients were treated with a noninvasive repeatable stereotactic fixation system
using a manually driven midsize multileaf collimator attached to a linear
accelerator. We applied a median prescribed total dose to the isocenter of 52.4
Gy with a median daily fraction size of 1.8 Gy. RESULTS: All patients treated by
definitive radiotherapy remained free from local tumor progression during the
follow-up period (range 12-72 months) except the 1 patient treated for recurrence
after previous radiotherapy. A complete remission was achieved in 3 patients with
subsequent improvement of visual acuity. None of the patients with locally
controlled tumor experienced any further impairment of vision. One patient
developed new ACTH deficiency. No other clinically significant late effects
attributable to radiotherapy were observed. CONCLUSION: FSRT permits treatment of
optic glioma with excellent tumor control and without clinically relevant
morbidity. Compared to conventional techniques there is the potential of sparing
the pituitary gland in chiasmatic lesions.
PMID- 10760416
TI - Pediatric choroid plexus neoplasms.
AB - PURPOSE: Choroid plexus tumors (CPT) are rare childhood neoplasms. The relatively
small number of reported cases and the controversies surrounding the clinical and
pathological classification of these tumors have made it difficult to define a
standard of care for these patients. Our intention is to contribute to the body
of knowledge of these tumors and further define the role of adjuvant therapy.
METHODS AND MATERIALS: We performed a retrospective review of 14 children with
choroid plexus neoplasms referred to St. Jude Children's Research Hospital
between October 1985 and December 1987. Ten patients had choroid plexus carcinoma
(CPC) based on pathologic criteria and evidence of brain invasion at surgery or
leptomeningeal disease (M+); 4 patients had choroid plexus papilloma (CPP).
Patients with CPP were initially treated with surgery alone whereas patients with
CPC were generally treated with postoperative therapy that included chemotherapy
(CT) and/or craniospinal irradiation (CSI) with a focal boost to the primary
site. For most patients CT consisted of combinations of cyclophosphamide,
etoposide, vincristine, and a platinum agent. The median CSI dose was 35.2 Gy
(range 24-46.2 Gy). The median primary site dose was 55.2 Gy (range 49.6-64 Gy).
RESULTS: Seven of the 10 CPC cases presented with leptomeningeal dissemination;
two of these patients have succumbed to disease. Of the 3 patients with M0
status, all are alive with no evidence of disease (NED). The medial time to
relapse from the time of surgery was 5.3 mo (range 3-25 mo). Seven CPC patients
were treated with gross total resection (GTR). Three of these patients (2 M0, 1
M+) received CT without CSI and are currently NED (27, 69, and 60 mo
respectively). One M+ patient progressed on CT and has stable disease after CSI
(6 mo), one (M0) received CT and CSI and is NED (120 mo), one (M+) is currently
on CT with objective response (3 mo) and one (M+) died of progressive disease
(24.5 mo) despite CT and CSI. Three patients with CPC had subtotal resection
(STR). One of these patients (M+) received CT and CSI and is NED (23 mo), one
(M0) had an elective second resection GTR alone and is currently NED (153 mo),
and one (M+) developed progressive disease (13.5 mo) while on CT and died despite
CSI. Among the 4 CPP patients, GTR was performed in two; both were NED at 54 and
81 mo. Two patients with CPP (one with focal atypia) were treated with STR
initially; both transformed to CPC at 7 and 27 mo, respectively. Both were
currently NED following salvage with (1) GTR and CSI alone (98 mo) or (2) STR,
CT, and CSI (62 mo). Six of the 12 survivors in this series had significant
neuropsychological sequelae. CONCLUSION: The prognosis of CPP is good for
patients treated with GTR. Malignant transformation occurred in 2 CPP patients
with less than GTR. Patients with localized CPC who undergo GTR have had a
favorable outcome with the addition of chemotherapy or irradiation. CSI may not
be routinely indicated in M0 children following GTR. There is evidence that
salvage with radiation therapy may be successful following progression on
chemotherapy. For patients treated with STR, the use of CT and CSI appears to be
necessary.
PMID- 10760417
TI - The role of radiation therapy in the management of craniopharyngioma: a 25-year
experience and review of the literature.
AB - PURPOSE: To review the outcome and quality of life at 5 years and more of 37
children treated with radiation therapy combined or not with surgical resection
for a craniopharyngioma in a single institution. METHODS AND MATERIALS: From
January 1969 through December 1992, 37 children received external therapy at the
Institut Gustave Roussy (Villejuif, France). Age ranged between 1 and 15 years
(mean 7.4), M/F sex ratio was 0.76. In approximately one-half of the cases
(18/37), radiation therapy was applied in conjunction with a surgical resection,
and in almost one-half of the cases (18/37) as part of a salvage program
following local failure. Total dose ranged between 45 and 56 Gy (median 50) given
with a conventional fractionation in most children. Survival (S), event-free
survival (EFS) were computerized according to the Kaplan-Meier method and
prognostic factors for local failure and functional status analyzed. Functional
outcome was evaluated according to the Wen score in 4 grades (gr 1: normal
with/without hormonal replacement, gr 4: totally dependent, gr 2 and 3:
intermediate disabilities). RESULTS: At the time of analysis, 24 children (65%)
were alive with NED, 4 (11%) alive after failure, and 9 (24%) dead of various
causes. Following therapy, S and EFS regularly degraded and didn't seem to reach
a plateau before 9 years (5 and 10 year S and EFS, respectively, 91, 65, and 78
and 56.5%). This was due to the occurrence of late failures (5 and 8.5 years) and
late lethal complications (1 in-field glioblastoma multiforme at 9 years). A
significant gain on EFS followed the introduction of modern imaging (p = 0.03),
the association of surgical resection with RT (p = 0.01) and of higher doses of
radiation superior or equal to 55 Gy (p = 0.05); a similar gain on S was observed
in patients with a good initial performance status (p = 0.05). It is remarkable
that surgical salvage of local failures following RT could induce prolonged
remission in 4 children. Functional outcome was impaired in all but 5 children
out of 35 fully evaluable (86%) and related with the initial symptomatology
and/or therapy. Endocrinological, visual, neurological functions were affected in
97, 34, and 40%, respectively. It appeared correlated with the initial
performance status (p = 0.02) and possibly with a younger age at treatment (p =
0.07). CONCLUSIONS: Long-term follow-up beyond 5 years is warranted in
craniopharyngioma to assess tumor control and functional outcome after radiation
therapy. Although this therapeutical modality provides a high cure rate alone or
in combination with surgery and even though at the time of failure, further
strategies should aim to limit the severe toxicity (i.e., Wen gr 3 + 4) that was
observed in more than one-third of our patients.
PMID- 10760418
TI - Primary central nervous system lymphoma in Japan: a nationwide survey.
AB - PURPOSE: To analyze clinical features, treatment results, and prognostic factors
of primary central nervous system lymphoma (PCNSL) in Japan, we conducted a
nationwide survey. METHODS AND MATERIALS: We analyzed 466 patients with
histologically proven PCNSL treated between 1985 and 1994 at 62 institutions,
including 56 medical schools. RESULTS: Patient and tumor characteristics of the
466 patients were not greatly different from those reported previously, except
for the relatively high proportion of T-cell lymphoma (8.5%). The median survival
time of the 466 patients was 18 months, and the 5- and 10-year survival rates
were 15.2% and 8.2%, respectively. Complete response was observed in 63% of
evaluable patients, but 64% of the complete responders developed recurrence (77%
within the irradiated volume). Among patient- or tumor-related factors, higher
age, worse performance status, presence of B symptom, multiple lesions, presence
of meningeal dissemination, and elevated lactate dehydrogenase (LDH) level were
associated with poorer survival, whereas no significant difference was observed
in prognosis with respect to sex, T/B phenotype, or histological
subclassification. In 410 patients receiving at least 40 Gy to the tumor, there
was no difference in survival with respect to total radiation dose or field.
Patients receiving 2 or more cycles of systemic chemotherapy had a slightly
longer median survival time (22 months) and higher 5-year survival rate (20%)
than those receiving radiotherapy alone (18 months and 17%, respectively), but
the difference was not significant (p = 0.13). No chemotherapy protocol appeared
to be better than any other. CONCLUSIONS: In addition to age and performance
status, which are well-known prognostic factors, B symptom, tumor number,
presence of meningeal dissemination, and serum LDH level also seemed to influence
survival. Higher radiation dose was not associated with better prognosis. The
role of chemotherapy could not be clarified because of the use of various
protocols, but it seemed that the influence of various prognostic factors is
greater than the effect of chemotherapy.
PMID- 10760419
TI - The importance of local-regional radiotherapy with conventional or high-dose
chemotherapy in the management of breast cancer patients with > or = 10 positive
axillary nodes.
AB - PURPOSE: To assess the effect of local-regional radiotherapy (RT) on the outcome
of breast cancer patients with > or = 10 positive axillary lymph nodes who have
received modern conventional or high-dose systemic therapy. METHODS AND
MATERIALS: A total of 55 women with local-regionally confined breast cancer
involving 10 or more axillary nodes were treated between October 1983 and January
1996. Local-regional therapy consisted of modified radical mastectomy in 39 and
breast-conserving surgery in 16. Postoperative radiotherapy was given to 44 of
the 55 patients. Radiotherapy consisted of tangential fields to the chest wall or
intact breast to a median dose of 50.40 Gy. A total of 86% (38 of 44) received
regional nodal irradiation as follows: 35 patients received RT to the
supraclavicular (SC) region and axillary midplane to a median dose of 50.40 Gy
and 46.20 Gy, respectively; 3 patients received RT to the SC region without
inclusion of the axilla to a median dose of 50. 40 Gy. All patients received
adjuvant standard-dose systemic chemotherapy, 9 of whom received additional
intensification chemotherapy followed by autologous bone-marrow transplant (ABMT)
or peripheral blood stem-cell transplant (PBSC). Twenty-five patients received
adjuvant tamoxifen. RESULTS: With a median follow-up of 30 months, the crude
overall survival (OS) and disease-free survival (DFS) for the entire group were
67% and 53%, respectively. On univariate analysis of various clinical,
pathological, and therapy-related features, radiotherapy emerged as the most
important factor influencing the relapse rate. The addition of RT was
significantly associated with an improved DFS (p = 0.003), specifically by
prolonging the time to disease progression. The median time to failure was 61
months and 12.5 months with and without RT, respectively. Patients receiving RT
also appeared to survive longer; however, the groups were not statistically
different (p = 0.10). Analysis of the patterns of failure showed local-regional
recurrence (LRR) as the first site of failure in 12 (22%) of 55 and distant
failure in 20 (36%) of 55. Univariate results revealed both radiotherapy and
tamoxifen to be significantly associated with decreased LRR rates (p = 0.0001 and
p = 0.03, respectively); only RT remained independently significant on
multivariate analysis. CONCLUSION: Local-regional radiotherapy is an essential
component of the management of breast cancer patients with extensive nodal
involvement, despite the use of contemporary adjuvant chemotherapy including high
dose regimens with autologous rescue. In addition to the expected improvement in
LRR, radiotherapy is also associated with significantly prolonged DFS and a trend
for improvement in OS.
PMID- 10760420
TI - Incidence and time of occurrence of regional recurrence in stage I-II breast
cancer: value of adjuvant irradiation.
AB - PURPOSE: The value of adjuvant radiation therapy (RT) of the axilla and
supraclavicular fossa is controversial in early-stage breast cancer. This
retrospective study was undertaken to identify pathological risk factors that
would predict which subsets of patients would benefit from regional nodal
irradiation (RNI). METHODS AND MATERIALS: A total of 1309 women with Stage I/II
breast cancer underwent full axillary dissection and either mastectomy (n = 894)
or breast-conserving surgery (n = 415). Of these, 712 patients received RNI. The
median axilla/supraclavicular fossa dose was 50 Gy. RESULTS: The 10-year
actuarial rate of axillary failure (AXF) was 0. 5% in N0 and 2.8% in N1 patients
(p 5, also correlated with AXF; the respective rate was 4.3% vs. 1.2% (p =
0.0142). Neither the incidence of AXF nor the time to AXF was affected
significantly by the use of RNI, but in N1 patients with retrieved nodes < or =
5, the rate of AXF was 8.3% without RNI vs. 0% with RNI (p = 0.2340). The 10-year
actuarial rate of supraclavicular failure (SCF) was 1.2% in N0 and 6.3% in N1
patients (p = 0.0000). SCF was also associated with the extent of nodal
involvement (p = 0.0031). The incidence of SCF was not significantly affected by
the use of RNI. However, when the results of N1bii and N1biv patients were
evaluated as a single group, the effect of RNI was significant (p = 0.0358). The
rates of SCF without RNI were high in patients with N1bii or N1biv stage: 10% and
37.5% and, with RNI, 3.2% and 18.2%, respectively. These findings were reinforced
by the various combinations of T- and N1-stage. The mean time to SCF was 53.6
months in the irradiated and 24.9 months in the nonirradiated patients (p =
0.0007). CONCLUSIONS: After a complete axillary dissection, only N1 patients with
retrieved nodes < or = 5 may be considered for axillary RT. Elective
supraclavicular RT is suggested for patients with N1bii or N1biv stage.
Supraclavicular irradiation decreases the incidence and delays the appearance of
SCF.
PMID- 10760421
TI - Accelerated superfractionated radiotherapy for inflammatory breast carcinoma:
complete response predicts outcome and allows for breast conservation.
AB - PURPOSE: Chemotherapy and accelerated superfractionated radiotherapy were
prospectively applied for inflammatory breast carcinoma with the intent of breast
conservation. The efficacy, failure patterns, and patient tolerance utilizing
this approach were analyzed. METHODS AND MATERIALS: Between 1983 and 1996, 52
patients with inflammatory breast carcinoma presented to the Medical College of
Virginia Hospitals of VCU and the New England Medical Center. Thirty-eight of
these patients were jointly evaluated in multidisciplinary breast clinics and
managed according to a defined prospectively applied treatment policy. Patients
received induction chemotherapy, accelerated superfractionated radiotherapy,
selected use of mastectomy, and concluded with additional chemotherapy. The
majority were treated with 1.5 Gy twice daily to field arrangements covering the
entire breast and regional lymphatics. An additional 18-21 Gy was then delivered
to the breast and clinically involved nodal regions. Total dose to clinically
involved areas was 63-66 Gy. Following chemoradiotherapy, patients were evaluated
with physical examination, mammogram, and fine needle aspiration x 3. Mastectomy
was reserved for those patients with evidence of persistent or progressive
disease in the involved breast. All patients received additional chemotherapy.
RESULTS: Median age was 51 years. Median follow-up was 23.9 months (6-86) months.
The breast preservation rate at the time of last follow-up was 74%. The treated
breast or chest wall as the first site of failure occurred in only 13%, and the
ultimate local control rate with the selected use of mastectomy was 74%. Ten
patients underwent mastectomy, 2 of which had pathologically negative specimens
despite a clinically palpable residual mass. Response to chemotherapy was
predictive of treatment outcome. Of the 15 patients achieving a complete
response, 87% remain locoregionally controlled without the use of mastectomy.
Five-year overall survival for complete responders was 68%. This is in contrast
to the 14% 5-year overall survival observed with incomplete responders. The 5
year actuarial disease-free survival and overall survival for the entire patient
cohort was 11% and 33%, respectively. All patients tolerated irradiation with
limited acute effects, of which all were managed conservatively. CONCLUSION: Our
experience demonstrates that induction chemotherapy, accelerated
superfractionated radiotherapy, and the selected use of mastectomy results in
excellent locoregional control rates, is well tolerated, and optimizes breast
preservation. Based on our present results, we recommend that a patient's
response to induction chemotherapy guide the treatment approach used for
locoregional disease, such that mastectomy be reserved for incomplete responders
and avoided in those achieving a complete response.
PMID- 10760422
TI - Relationship between p21/WAF-1/CIP-1 and apoptosis in cervical cancer during
radiation therapy.
AB - PURPOSE: P21/WAF-1/CIP-1 was not considered to be involved in the regulation of
apoptosis, an important indicator of radiosensitivity. However, it has been
reported recently that apoptosis was suppressed when p21 expressed. The purpose
of this study was to clarify the relationship between p21 and apoptosis and to
evaluate the role of p21 in cervical cancer during radiation therapy (RT).
METHODS AND MATERIALS: Twenty-one patients with cervical cancer were treated by
RT. Tissue samples were obtained from cervical tumors of all patients before RT,
and 6 hours after the fifth dose of 1.8 Gy (5th Dose). Samples were subjected to
nick end labeling for apoptosis and immunohistochemical staining for p21 and p53
antigen expression. RESULTS: The mean apoptotic index, p21 labeling index and p53
labeling index were 0.27%, 9.24% and 6.60%, respectively, before RT and increased
significantly to 1.20%, 17.5% and 13.9%, respectively, after 5th Dose. The
apoptotic index at 5th Dose was inversely correlated with the p21 labeling index
(r = -0.50, p = 0.025). Furthermore, a positive correlation was observed between
the p21 and p53 labeling indices both before RT and at 5th Dose (r = 0.52, p = 0.
02; r = 0.63, p < 0.01, respectively). CONCLUSION: Our results demonstrate that
apoptosis and expression of p21 and p53 were induced in cervical cancer during
RT. p21 expression was dependent on p53 expression and moreover, it is suggested
that p21 might be a potential suppressor of radiation-induced apoptosis in
cervical cancer during RT.
PMID- 10760423
TI - Computed tomography findings of bony regeneration after radiotherapy for
nasopharyngeal carcinoma with skull base destruction: implications for local
control.
AB - PURPOSE: To evaluate the response of bony destruction (BD) of the skull base
following radiotherapy in nasopharyngeal carcinoma (NPC) and investigate the
implications of bony regeneration (BR) on local control and its related factors.
METHODS AND MATERIALS: Ninety patients with NPC with skull base destruction
clearly demonstrated on computed tomography (CT) were reviewed. These patients
have completed the prescribed treatment and received regular CT follow-up. A
total of 338 sets of CT images of the head and neck were reviewed. The tumor
response and the appearance of BR in the previous destructive part of the skull
base were recorded and analyzed. The tumor response was divided into complete,
partial, or no response. BR was defined as recalcification or sclerotic change
with partial or complete healing in the previous osteolytic bony defect. Local
failure was confirmed either by pathological or merely by imaging studies showing
progression of tumor in consecutive radiological pictures. RESULTS: The
distribution of specific sites of bony destruction (BD) in these patients
included the sphenoid bone (68%), paracavernous sinus area (48%), petrous apex
(47%), clivus (44%), pterygoid plates (20%), and others (7%). The CT showed 57
patients (63%) had BR. All were observed within 1 year after treatment. Sixty-two
patients (69%) had complete tumor response after treatment. Analyzed by logistic
regression method, tumor response after treatment was found to have a
statistically significant correlation with BR (p = 0.0004). Most BR (55/57) was
demonstrated in patients with complete tumor response. The 3-year actuarial local
control rate was 54 % in these patients. The local control was quite different in
the comparison of patients with BR versus those with persistent BD (77% vs. 21%,
p < 0.0001). Multivariate analysis showed that patients with complete tumor
response or with BR on imaging had statistically better local control than those
without either of the two findings (p < 0.05). CONCLUSION: Appearance of BR at
previous destructive skull base following radiotherapy for NPC patients could be
clearly demonstrated on CT. Bony regeneration significantly correlated with
treatment response and local control. Although the underlying significance of BR
was unknown, to predict the outcome after treatment, the appearance of BR shown
on CT may imply the complete eradication of tumor in this area.
PMID- 10760424
TI - A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy of
unrespectable head and neck cancer.
AB - PURPOSE: To determine the maximum tolerated dose (MTD) of paclitaxel given as a
96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy
schedule for the definitive treatment of advanced (nonmetastatic) unresectable
squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS:
Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70
72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed
by 1.6 Gy b.i.d. for 2 weeks, with no planned interruptions. Paclitaxel was
administered over a 96-hour continuous infusion during Weeks 1 and 5 of
radiotherapy at the following dose levels: Dose Level 1: 40 mg/m(2)/96-hours (3
patients); Dose Level 2: 80 mg/m(2)/96-hrs (5 patients); Dose Level 3: 120
mg/m(2)/96-hours (2 patients); and Dose Level 2A: 100 mg/m(2)/96-hours (3
patients). RESULTS: The MTD of Paclitaxel was 100 mg/m(2)/96-hours. All but one
patient (who experienced progressive disease after receiving 61 Gy and both
cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity
occurred in both patients enrolled at Dose Level 3, with one patient experiencing
Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4
mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose
limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis
occurred at all paclitaxel dose levels. There were no treatment-related deaths.
All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8
of 13 patients, 4 patients achieved partial responses, and 1 patient had no
response/progressive disease. CONCLUSIONS: Infusional paclitaxel over 96 hours
during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The
MTD of paclitaxel in this protocol was 100 mg/m(2)/96-hours. Dose-limiting
toxicities were primarily enhanced epithelial reactions, but febrile neutropenia
also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal
reactions, reflecting the high treatment intensity. This regimen merits further
investigation.
PMID- 10760425
TI - The utility of serial complete blood count monitoring in patients receiving
radiation therapy for localized prostate cancer.
AB - PURPOSE: It is standard practice in our department to monitor weekly complete
blood counts (CBCs) in patients receiving definitive radiation therapy for
prostate cancer. The clinical utility and cost effectiveness of this practice has
not been analyzed. METHODS AND MATERIALS: The charts of all prostate cancer
patients treated with radiation therapy between January 1994 and July 1996 at the
Veterans Administration Hospital, Philadelphia, PA were reviewed. CBC values were
available for 89 patients. Patients received a median dose of 68 Gy using a four
field box technique and megavoltage photons. Whole-pelvic radiotherapy followed
by a conedown to the prostate was administered to 29 patients. Fifty-nine
patients received radiation to the prostate alone or prostate and seminal
vesicles. Fifty-seven patients received concurrent hormonal therapy which
included luteinizing hormone-releasing hormone (LHRH) agonist, antiandrogens, or
both. RESULTS: No patient experienced a drop in their hemoglobin, white blood
cells (WBCs), or platelets below critical nadirs (defined as WBC < 2 counts x
1000/mm(3), hemoglobin < 8 g/dl, platelet < 50 counts x 1000/mm(3) 2 in WBCs. In
the urban area surrounding the Philadelphia Veterans Administration Medical
Center, the cost of obtaining a CBC is approximately $30. However, if staff time
is considered, the cost of obtaining a weekly CBC during prostate cancer
radiotherapy approached $400 per patient. CONCLUSION: These results suggest that
weekly monitoring of CBCs in prostate cancer patients undergoing definitive
radiotherapy may not be necessary. We recommend a baseline CBC be performed, and
if normal, no other monitoring unless clinically indicated. This strategy would
result in a cost savings approaching $30,000 per 100 treated patients. Further
research on the cost effectiveness and utility of serial blood tests in patients
receiving partial body radiation therapy is needed.
PMID- 10760426
TI - Follow-up costs after external radiation for low risk prostate cancer.
AB - PURPOSE: Some routine follow-up costs for external radiation for prostate cancer
might not be justifiable. To study this possibility, we reviewed the follow-up
costs and clinical course of 36 consecutive, unselected patients treated with
external beam radiation (EBRT) for low-risk prostate cancer at the University of
Washington. METHODS AND MATERIALS: Thirty-six consecutive patients with Stage
T1/T2 prostate cancer and pretreatment prostate specific antigen (PSA) < 10 ng/ml
were treated with EBRT with curative intent at the University of Washington from
1990 through 1996. All follow-up visits with each patient's urologist and
radiation oncologist, and all laboratory tests were tabulated. Charges quoted in
this report are based on University of Washington billing. RESULTS: A total of 8
patients demonstrated biochemical evidence of tumor progression/persistence, none
of whom has had any therapeutic intervention for progressive cancer. No patient
had local disease progression by physical examination. One patient experienced a
Radiation Therapy Oncology Group (RTOG) grade 3 bowel complication (obstruction),
not detected on routine follow-up. The average combined PSA and physician follow
up charges for the first 2 years after therapy was $1,013. CONCLUSION: The data
presented here suggests that for low-risk prostate cancer (PSA < 10 ng/ml),
frequent follow-up by physical examinations and PSAs during the first 2 years
after therapy is not warranted.
PMID- 10760427
TI - Interfraction interval does not affect survival of patients with non-small cell
lung cancer treated with chemotherapy and/or hyperfractionated radiotherapy: a
multivariate analysis of 1076 RTOG patients.
AB - PURPOSE: It was observed by Jeremic et al. that a shorter interfraction interval
(IFI) was associated with an improved survival in patients (pts) with locally
advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated
radiation therapy (HFX-RT), with or without chemotherapy (CT). Our analysis was
undertaken to verify this hypothesis. METHODS AND MATERIALS: Records of patients
treated on 5 Radiation Therapy Oncology Group (RTOG) studies were reviewed, and
an actual IFI, defined as a mean of all daily IFIs, was calculated. RT dose was
1.2 Gy BID to 69.6 Gy. The relationship between the length of IFI and the median
survival time and incidence of esophagitis was investigated. RESULTS: In 682 pts
eligible for this analysis, a full dose of RT was delivered and at least 90% of
all daily IFIs were available. The actual mean IFI was as follows: 4-4.9 h in 51%
of pts; 5-5.9 h in 17%; 6-6.9 h in 28% and 7-8 h in 4%. In multivariate analysis,
only lack of weight loss, use of CT, low nodal stage and good KPS, but not IFI (4
6 h vs. 6-8 h) were associated with an improved survival for all pts (p values:
<0.0001; <0.0001; 0.006; 0.006, and 0.73, respectively), as well as for HFX-RT
only pts. For the CT-HFX-RT pts, not enough data points are available for a
meaningful analysis. Length of IFI did not influence the incidence of Grade 3 or
higher esophagitis (p = 0.82), but use of CT was associated with a 12-fold
greater risk of developing severe esophagitis (p < 0.0001). CONCLUSION: Length of
IFI (4-6 h vs. 6-8 h) did not influence survival and acute complications
incidence in pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy.
Previously identified factors, such as use of CT, minimal weight loss, good KPS
and low nodal stage, were confirmed again to be associated with a favorable
prognosis in a multivariate analysis. Use of CT was associated with a 12-fold
greater risk of developing severe esophagitis than HFX-RT alone. It appears that
an IFI of 4-8 hr is acceptable in clinical practice for pts with NSCLC, treated
with HFX-RT.
PMID- 10760428
TI - Radiotherapy for lung cancer: target splitting by asymmetric collimation enables
reduction of radiation doses to normal tissues and dose escalation.
AB - PURPOSE: This study was performed to develop a method of reducing the radiation
doses to normal thoracic tissues, increasing the target dose, especially in the
primary radiotherapy of non-small cell lung cancer (NSCLC), and to evaluate
acute/subacute toxicity of dose escalation. METHODS AND MATERIALS: From December
1195 to March 1998, the technique of target splitting has been applied to 58
patients. In this period, 30 patients were treated with doses > 80 Gy (ICRU
specification, mean 85.1 Gy, range 80. 1-90.2 Gy). The target volume is split
into a cranial part (e.g., upper mediastinum) and a caudal part (e.g., primary
tumor and middle mediastinum). Both volumes are planned and treated
independently, using conformal irradiation techniques for both parts with half
collimated fields to prevent over- or underdosage in the junction plane. After
fine-adjustment of the jaws, a verification film, exposed in a
polymethylmethacrylate (PMMA) phantom, demonstrates the homogeneity of dose in
the entire target volume. For comparison with conventional techniques, planning
to identical doses is performed for 5 patients. Dose-volume histograms (DHVs) for
normal lung tissue are presented for both methods. RESULTS: The irradiated volume
of normal tissue of the ipsilateral lung can be lowered at dose levels > or = 65,
> or =45 Gy, and > or = 20 Gy to values of 37% (range 25-54%), 49% (range 46
54%), and 86% (range 55-117%), respectively. Other organs at risk, such as heart
or esophagus, can also be spared significantly. Only 1 patient showed a transient
grade 3 toxicity (pneumonitis), and there where no grade 4 acute/subacute side
effects. Two patients with Stage III A central tumors in close proximity to the
large vessels died due to a pulmonary hemorrhage 2 and 4 months after therapy,
respectively. No patient developed esophagitis. Antimycotic prophylaxis for
esophagitis and posttherapeutic steroid prophylaxis for pneumonitis for several
weeks were routinely used. CONCLUSION: The technique of target splitting by
asymmetric collimation helps to increase conformation, and thus enhances the
sparing of normal tissues. It can be used whenever there is a marked difference
in the shape of the planning target volume (PTV) in a cranio-caudal direction.
This technique can principally be handled with 2D-planning systems, because it is
coplanar. We consider target splitting as an important tool for dose escalation
in the primary radiotherapy of NSCLC, that should also be used for other lung
cancer patients necessitating moderate doses only.
PMID- 10760429
TI - A phase II study of concurrent accelerated hyperfractionated radiotherapy and
carboplatin/oral etoposide for elderly patients with stage III non-small-cell
lung cancer.
AB - PURPOSE: To investigate feasibility, toxicity, and efficacy of accelerated
hyperfractionated radiation therapy and concurrent carboplastin/oral etoposide in
elderly (> 70 years) patients with stage III non-small-cell lung cancer. METHODS
AND MATERIALS: Between January 1988 and June 1993, a total of 58 patients entered
a phase II study. Carboplatin (400 mg/m(2)) was given intravenously on days 1 and
29, and etoposide (50 mg/m(2)) was given orally on days 1-21 and 29-42.
Accelerated hyperfractionated radiotherapy was administered starting on day 1,
with a total dose of 51 Gy in 34 fractions over 3.5 weeks. RESULTS: In 55
evaluable patients, the complete response rate was 27% and the overall response
rate was 65%. For the 55 patients, the median survival time was 10 months, and
the 1-, 2-, and 5-year survival rates were 45%, 24%, and 9.1%, respectively. The
median time until relapse was 8 months and the 1-, 2-, and 5-year relapse-free
survival rates were 45%, 20%, and 9.1%, respectively. The median time to local
recurrence was 14 months and the 5-year local control rate was 13%; the median
time to distant metastasis was 18 months and the 5-year distant metastasis-free
rate was 15%. Hematological, esophageal, and bronchopulmonary acute grade 3 or 4
toxicities were observed in 22%, 7%, and 4% of the patients, respectively. There
was no grade 5 toxicity or late grade > or = 3 toxicity. CONCLUSION: Concurrent
accelerated hyperfractionated radiotherapy and carboplatin/oral etoposide
produced relatively low and acceptable toxicity. The survival results appeared to
be comparable to those obtained in nonelderly patients with stage III non-small
cell lung cancer treated by full-dose radiation.
PMID- 10760431
TI - Changes in the use of radiotherapy in Ontario 1984-1995.
AB - PURPOSE: To describe changes in the use of radiotherapy in the management of
cancer in Ontario between January 1, 1984 and December 31, 1995. METHODS: A
retrospective review of prospectively gathered electronic records of all
radiotherapy for cancer at nine provincial cancer treatment centres. RESULTS:
Over the 12 years of the study, the incidence of cancer increased by 33%. The
number of curative and adjuvant courses per incident case increased by 39.3% and
the number of palliative courses per incident case decreased by 15.8%. The mean
number of fractions per curative and adjuvant course increased by 13%, and the
mean number of fractions per palliative course decreased by 22%. The number of
curative fractions per incident case increased by 63%, and the number of
palliative fractions per incident case decreased by 32%. The increase in curative
workload was mainly due to an increase in the incidence of prostate cancer, to an
increase in the number of courses per incident case in breast and prostate
cancer, and to an increase in the number of fractions per curative course in
every disease group. The decrease in palliative workload was due to a decrease in
the number of courses per incident case in most disease groups, and to a decrease
in the number of fractions per course in most disease groups. CONCLUSIONS: In
Ontario, between 1984 and 1995, there was a large shift in workload from
palliative radiotherapy to curative radiotherapy. Potential causes for this
phenomenon are discussed.
PMID- 10760430
TI - Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent
radiation therapy in the treatment of refractory solid tumors.
AB - PURPOSE: Patients with refractory solid tumors were treated with the combination
of fractionated radiation therapy and multiple-dose intravenous tirapazamine to
determine the toxicities and maximum tolerated dose of tirapazamine when given
concurrently with radiation therapy. METHODS: Patients received radiation therapy
in accordance with standard treatment practice in relation to fraction size and
number of fractions for their particular cancer. In all cases, the course of
radiation therapy exceeded the time of tirapazamine administration. Initially,
tirapazamine was administered 5 days per week for 2 weeks for a total of 10
doses. After the first 8 patients, the schedule was changed to 3 times per week
(Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6
patients were treated at each dose level. RESULTS: A total of 43 patients were
treated in the study between 1991 and 1995. All patients were 18 years old or
older, had a Karnofsky performance status of > or = 60% and had adequate
hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose
and was increased using a modified Fibonacci schema. The maximum tolerated dose
was not reached and dose escalation was stopped at 260 mg/m(2) because of other
data that became available suggesting 330 mg/m(2) was associated with dose
limiting toxicity (1, 2). CONCLUSION: Tirapazamine in doses of up to 260 mg/m(2)
times 12 doses can be given safely with fractionated radiation therapy. This dose
appears to result in adequate plasma exposure (2) for radiation sensitization,
and this schedule is being tested in a Phase II trial by the Radiation Therapy
Oncology Group to determine if tirapazamine is a radiation enhancer in the
clinic.
PMID- 10760432
TI - Feasibility of external beam radiation for prevention of restenosis following
balloon angioplasty.
AB - PURPOSE: Brachytherapy has been shown to inhibit neointima formation after
vascular balloon injury. This study was done to test the feasibility of low dose
external radiation for prevention of restenosis in a non-stented balloon injury
model. MATERIALS AND METHODS: Twelve red Duroc swine underwent balloon
overdilation injury of both iliac arteries. Twelve Gy was delivered to one side
using a Theratron T-1000 Cobalt unit with the other side used as the control.
Twelve weeks post injury arteriograms were performed. The animals were then
sacrificed and iliac arteries explanted. Histomorphometric analysis of arterial
cross sections was performed. RESULTS: Neointima formation was observed in all
arteries. Unilateral thrombosis was noted in two animals. The mean neointimal
thickness in the radiated and control arteries was 0.63 +/- 0.17 mm and 0.72 +/-
0.31 mm, respectively. The differences in minimal luminal diameter and the
neointimal thickness between the two groups were not statistically significant.
Complications included superficial hair loss in the radiation port in 4 animals,
and 2 deaths prior to the completion date (1 of hemorrhagic enteritis possibly
related to the radiation, and 1 of iliac rupture). CONCLUSION: External radiation
at this low dose is not effective in preventing vascular restenosis following
balloon injury in this animal model.
PMID- 10760433
TI - The delta-TCP concept: a clinically useful measure of tumor control probability.
AB - PURPOSE: The aim of this article is to provide a quantitative tool to evaluate
the influence of the different dose regions in a non-uniformly irradiated tumour
upon the probability of controlling that tumor. METHODS AND MATERIALS: First, a
method to generate a distribution of the probability of controlling the cells in
a voxel (VCP) is explored and found not to be useful. Second, we introduce the
concept of delta-TCP, which represents the gain or loss in the overall TCP as a
result of each particular bin in a DVH not receiving the prescribed dose (the
same concept is applicable to dose cubes or to a fraction of the bin). The delta
TCP method presented here is based on the Poisson TCP model, but any other model
could also be used. Third, using this tool, with parameters appropriate to Stage
C prostate tumors, the consequences of "cold" and "hot" dose regions have been
explored. RESULTS: We show that TCP is affected by the minimum dose, even if it
is delivered to a very small volume (20% dose deficit to 5% of the volume makes
the TCP decrease by 18%), and that a hot region may be "wasted" unless the boost
is to the bulk of the volume. An example of the application of the delta-TCP
concept to a prostate radiotherapy plan is also given. CONCLUSION: The delta-TCP
distribution adds more objective information to the original DVH by enabling the
clinician or planner to directly evaluate the effects of a non-uniform dose
distribution on local control.
PMID- 10760434
TI - BED-time charts and their application to the problems of interruptions in
external beam radiotherapy treatments.
AB - PURPOSE: The use of radiobiological modelling to examine the likely consequences
of interruptions to radiotherapy schedules and to assess various compensatory
measures. METHODS AND MATERIALS: An effect-time graphical display, the BED-time
chart, has been developed using the linear-quadratic (LQ) model. This is used to
examine the effects on tumour and normal tissues of treatment interruption
scenarios representative of clinical situations. The mathematical criteria
governing successful salvage have also been drafted and applied to typical
situations. RESULTS: The successful salvage of an interrupted treatment is
dependent on a number of interacting factors and the method presented here can be
used to examine the trade-offs that exist. Although the mathematics may be
complex, it is shown that the dilemmas posed by an interrupted treatment may be
more easily appreciated with reference to BED-time charts. These may therefore
have a useful role as a teaching aid for portraying a wider variety of
radiotherapy problems and also in the documentation of interruptions to treatment
and the measures taken to compensate for them. CONCLUSIONS: Interruptions to
radiotherapy regimes are undesirable and compensatory measures need to be
initiated as soon as possible after the gap, with a view to completing the
amended treatment within the originally prescribed treatment time. Adequate
compensation is particularly difficult for long gaps and gaps which occur towards
the end of the scheduled treatment. Modelling exercises can help establish
guidelines on the available windows of opportunity.
PMID- 10760435
TI - Reoxygenation in quiescent and total intratumor cells following thermal neutron
irradiation with or without (10)B-compound-compared with that after gamma-ray
irradiation.
AB - PURPOSE: Reoxygenation in quiescent (Q) and total tumor cells within solid tumors
after thermal neutron irradiation with or without (10)B-compound was examined,
comparing with that following gamma-ray irradiation. METHODS AND MATERIALS:
C3H/He mice bearing SCC VII tumors received 5-bromo-2'-deoxyuridine (BrdU)
continuously for 5 days via implanted mini-osmotic pumps to label all
proliferating (P) cells. Thirty minutes after intraperitoneal injection of sodium
borocaptate-(10)B (BSH), or 3 h after oral administration of dl-p
boronophenylalanine-(10)B (BPA), the tumors were irradiated with thermal
neutrons, or those without (10)B-compounds were irradiated with thermal neutrons
alone or gamma-rays. At various time points after each treatment, a series of
test doses of gamma-rays were given to tumor-bearing mice while alive or after
being killed to obtain hypoxic fractions in the tumors. Immediately after
irradiation, the tumors were excised, minced, and trypsinized. Following
incubation of tumor cells with cytokinesis blocker, the micronucleus (MN)
frequency in cells without BrdU labeling ( = Q cells) was determined using
immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor
cells was determined from the tumors that were not pretreated with BrdU. The MN
frequency of BrdU-unlabeled cells was then used to calculate the surviving
fraction of the unlabeled cells from the regression line for the relationship
between the MN frequency and the surviving fraction of total tumor cells.
RESULTS: In both total and Q tumor cells, the hypoxic fractions immediately after
each treatment went up suddenly. Reoxygenation after each treatment occurred more
rapidly in total cells than in Q cells. In both cell populations, reoxygenation
appeared to be rapidly induced in the following order: neutron irradiation
without (10) gamma-ray irradiation. CONCLUSION: Based on our previous report that
total and Q cell fractions within these tumors have larger acutely and
chronically hypoxic fractions, respectively, acute hypoxic cells appeared to play
a larger role in reoxygenation. BSH was thought to have a potential to distribute
more homogeneously in solid tumors than BPA, because BSH induced the nearer
reoxygenation pattern to that following neutron irradiation alone than BPA.
PMID- 10760437
TI - Hyperthermia enhances the response of paclitaxel and radiation in a mouse
adenocarcinoma.
AB - PURPOSE: The aim of our study was to investigate if the efficacy of paclitaxel
and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia.
MATERIALS AND METHODS: Paclitaxel was administered i.p. in doses from 30 to 60
mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local
hyperthermia (41 degrees, 42 degrees, 43 degrees C) was carried out by immersing
tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90
Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD(50),
radiation dose needed to induce local tumor control in 50% of irradiated animals)
were the endpoints. RESULTS: A significant increase of dose-dependent growth
delay was observed in paclitaxel and 43 degrees C hyperthermia combined
treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg.
Combined treatments with hyperthermia at 41 degrees and 42 degrees C were less
effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min
and 4 h after hyperthermic treatments produced similar results (TGDs varying from
22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after
hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment
(paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD(50) of 14. 1 Gy, in
respect to the TCD(50) of 53.1 obtained with X-ray alone, was the most effective.
CONCLUSIONS: Hyperthermia enhanced the effectiveness of paclitaxel in all the
tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg
combined with a hyperthermic treatment of 1 h at 43 degrees C. Trimodality
treatment, evaluated in terms of percentage of cures, shows a very high
enhancement ratio.
PMID- 10760436
TI - Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition.
AB - PURPOSE: To test for in vitro radiopotentiation by the orally-administered
platinum (IV) complex, JM216; to compare these results to cisplatin and
carboplatin; and to investigate whether the mechanism of radiopotentiation
involves repair inhibition of radiation-induced DNA damage. METHODS AND
MATERIALS: H460 human lung carcinoma cells were incubated with the drugs for 1 h
at 37 degrees C, irradiated at room temperature, and returned to 37 degrees C for
20 min. Cells were then rinsed and colony forming ability was assessed. Wild-type
V79 Chinese hamster cells and radiosensitive, DNA repair-deficient mutant cells
(XR-V15B) were also studied along with H460 cells. Ku86 cDNA, which encodes part
of a protein involved in DNA repair, was transfected into XR-V15B cells as
previously described. The effect of JM216 on sublethal damage repair (SLDR) was
also assessed using split-dose recovery. RESULTS: Using equally cytotoxic doses
of JM216, cisplatin, and carboplatin, the radiation dose enhancement ratios (DER)
were 1.39, 1.31, and 1.20, respectively; the DER with 20 microM JM216 was 1.57.
JM216 (20 microM) did not significantly change the final slope of radiation
survival curves, but greatly reduced the survival curve shoulder. V79 cells also
showed radioenhancement using 20 microM JM216, but no enhancement occurred using
XR-V15B cells. Transfection of Ku86 cDNA into XR-V15B cells restored
radiopotentiation by JM216 to wild-type V79 levels. In addition, 20 microM JM216
completely inhibited sublethal damage repair in H460 cells. CONCLUSION: Our
results show that JM216 can potentiate the effects of radiation in human lung
cancer cells, and that the mechanism of this effect is probably inhibition of DNA
repair by JM216.
PMID- 10760438
TI - Association of increased radiocurability of murine carcinomas with low
constitutive expression of p21(WAF1/CIP1) protein.
AB - PURPOSE: The study investigated whether basal, constitutive levels of
p21(WAF1/CIP1) protein in murine carcinomas are related to in vivo tumor
radioresponse. The study is based on recent observations demonstrating that in
vitro cancer cell lines are resistant to cytotoxic drugs when they express high
basal levels of p21(WAF1/CIP1) protein, and that the loss of the p21 gene in the
HCT116 human colorectal cancer cell line results in increased radioresponse of
xenografts derived from that cell line. METHODS AND MATERIALS: Protein levels of
p21(WAF1/CIP1), p53, bax, and bcl-2 were determined in 8 carcinomas (3 mammary
carcinomas designated MCa-4, MCa-29, and MCa-35, 2 squamous cell carcinomas
designated SCC-IV and SCC-VII, ovarian adenocarcinoma OCa-I, hepatocarcinoma HCa
I, and adenosquamous carcinoma ACa-SG) syngeneic to C3Hf/Kam mice using Western
blot analysis. The tumors, growing in the right hind legs of mice, were 8 mm in
diameter at the time of analysis. These tumors greatly differ in their
radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation
induced apoptosis. RESULTS: Protein levels of these oncogenes varied among
tumors, with p21(WAF1/CIP1) showing the greatest variation: its mean
densitometric value ranged from 1 to 19. Bcl-2 levels also showed broad variation
in densitometric values, from 1 to 10. In comparison, bax and p53 (7 of 8 tumors
contained wild-type p53) varied much less among different tumor types; their
variation was within a 5-fold range, and the level of p53 was similar in 6 of 8
tumors. Tumor radioresponse correlated significantly (R = 0.77, p = 0.02) only
with the magnitude of p21(WAF1/CIP1)expression: tumors with high levels of
p21(WAF1/CIP1)were less radiocurable than those with lower levels. Tumor
radiocurability showed a significant positive correlation (p = 0.02) with the
extent of radiation-induced apoptosis, indicating that tumors that responded to
radiation with higher percentages of apoptosis were more curable by radiation.
Despite a strong trend to correlation, (p = 0.15), p21(WAF1/CIP1) expression did
not correlate significantly with radiation-induced apoptosis, which suggested
that p21(WAF1/CIP1) influenced tumor radioresponse by mechanisms beyond that of
apoptosis induction. CONCLUSION: Our findings showed that murine tumors exhibit
wide variation in constitutive levels of p21(WAF1/CIP1) which had a significant
relationship with tumor radioresponse: tumors with high levels of p21(WAF1/CIP1)
were less radiocurable than those with lower levels. These findings support the
concept that p21(WAF1/CIP1) is a major determinant of tumor radioresponse in
vivo, and may have important clinical implications. The pretreatment assessment
of p21(WAF1/CIP1) protein could serve as a useful predictor of radiotherapy
outcome and may assist in selecting an effective treatment modality.
PMID- 10760439
TI - Assessment of the uncertainties in dose delivery of a commercial system for linac
based stereotactic radiosurgery.
AB - PURPOSE: Linac-based stereotactic radiosurgery (SRS) was introduced in our
department in 1992, and since then, more than 200 patients have been treated with
this method. An in-house-developed algorithm for target localization and dose
calculation has recently been replaced with a commercially available system. In
this study, both systems have been compared, and positional accuracy, as well as
dose calculation, have been verified experimentally. METHODS AND MATERIALS: The
in-house-developed software for target localization and dose calculation is an
extension to George Sherouse's GRATIS(R) software for radiotherapy treatment
planning, and has been replaced by a commercial (BrainSCAN version 3.1; BrainLAB,
Germany) treatment planning system (TPS) for SRS. The positional accuracy for the
entire SRS procedure (from image acquisition to treatment) has been investigated
by treatment of simulated targets in the form of 0.2-cm lead beads inserted into
an anthropomorphic phantom. Both dose calculation algorithms have been verified
against manual calculations (based on basic beam data and CT data from phantom
and patients), and measurements with the anthropomorphic phantom applying
ionization chamber, thermoluminescent detectors, and radiographic film. This
analysis has been performed on a variety of experimental situations, starting
with static beams and simple one-arc treatments, to more complex and clinical
relevant applications. Finally, 11 patients have been evaluated with both TPS in
parallel for comparison and continuity of clinical experience. RESULTS: Phantom
studies evaluating the entire SRS procedure have shown that a target, localized
by CT, can be irradiated with a positional accuracy of 0.08 cm in any direction
with 95% confidence. Neglecting the influence of dose perturbation when the beam
passes through bone tissue or air cavities, the calculated dose values obtained
from both TPSs agreed within 1% (SD 1%) for phantom and patient studies. The
application of a one-dimensional path length correction for tissue heterogeneity
influences the treatment prescription 4% on average (SD 1%), which is in
compliance with theoretical predictions. The phantom measurements confirmed the
predicted dose at isocenter within uncertainty for the different treatment
schedules in this study. CONCLUSION: The full SRS procedure applied to an
anthropomorphic phantom has been used as a comprehensive method to assess the
uncertainties involved in dose delivery and target positioning. The results
obtained with both TPSs are in agreement with AAPM Report 54, TG 42 and clinical
continuity is assured. However, the use of a one-dimensional path length
correction will result in an increase of 4% in dose prescription, which is
slightly more than that predicted in the literature.
PMID- 10760440
TI - Design and development of new collimator cones for fractionated stereotactic
radiation therapy in Samsung Medical Center.
AB - PURPOSE: In stereotactic radiotherapy using X-Knife system, the commercially
supplied collimator cone system had a few mechanical limitations. The authors
have developed new collimator cones to overcome these limitations and named them
"SMC type" collimator cones. METHODS: We made use of cadmium-free cerrobend alloy
within the stainless steel cylinder housing. We made nine cones of relatively
larger sizes (3.0 cm to 7.0 cm in diameter) and of shorter length with bigger
clearance from the isocenter than the commercial cones. The cone housing and the
collimator cones were designed to insert into the wedge mount of the gantry head
to enable double-exposure linac-gram taking. RESULTS: The mechanical accuracy of
pointing to the isocenter was tested by ball test and cone rotation test, and the
dosimetric measurements were performed, all of which were with satisfactory
results. A new innovative quality assurance procedure using linac-grams on the
patients at the actual treatment setup was attempted after taking 10 sets of AP
and lateral linac-grams and the overall mechanical isocenter accuracy was
excellent (average error = 0.4 +/- 0.2 mm). CONCLUSIONS: We have developed the
SMC type collimator cone system mainly for fractionated stereotactic radiation
therapy use with our innovative ideas. The new cones' mechanical accuracy and
physical properties were satisfactory for clinical use, and the verification of
the isocenter accuracy on the actual treatment setup has become possible.
PMID- 10760441
TI - Practical considerations in using calculated healthy-tissue complication
probabilities for treatment-plan optimization.
AB - PURPOSE: Healthy and neoplastic tissues are generally exposed nonuniformly to
ionizing radiation. It is thus useful to develop algorithms that predict the
probability of tumor control or normal tissue complication probability (NTCP) for
any given spatial pattern of dose delivery. The questions addressed here concern:
(a) the sensitivity of the NTCP predictions to the actual model used for
extrapolation from uniform irradiation (where some clinical data exist) to
nonuniform exposures, (b) its dependence on tissue type, and (c) consequences for
treatment-plan optimization. METHODS AND MATERIALS: Two (of several possible)
NTCP formulations are used here: the Lyman model and a binomial equation. The
effective volume-reduction scheme of Kutcher and Burman is used to obtain the
NTCP for an arbitrary distribution of dose. NTCP was calculated for seven organs
by postulating a dose distribution of maximum nonuniformity. RESULTS: Both models
fit available NTCP data well, but have very different extrapolations for
exposures of small tissue volumes and very low values of NTCP (e.g., < 5%) where
no data exist. Organs with pronounced volume effects (lung, kidneys) show
substantial NTCP differences between the two models. Even in organs where the
volume effect is small (e.g., spinal cord, brain), differences in NTCP due to the
model selected may still have serious clinical consequences, as an actual example
(for the spinal cord) indicates. CONCLUSIONS: NTCP calculations based on
extrapolations to volume fractions and/or NTCP levels for which reliable data do
not exist depend on the model used to fit the data and the degree of dose
nonuniformity. If NTCP is to be used in treatment-plan optimization, the prudent
approach is to design plans that reproduce the conditions under which available
dose-volume data were taken (e. g., uniform dose distributions).
PMID- 10760442
TI - Beam intensity modulation for penumbra enhancement in the treatment of lung
cancer.
AB - PURPOSE: A treatment planning study was performed for patients with lung cancer
in order to investigate the extent to which doses to critical structures could be
reduced by penumbra enhancement at the superior and inferior field edges, using
beam intensity modulation (BIM) with a multileaf collimator. By applying two
independent published models for the prediction of the incidence of normal tissue
complications, the potential for dose escalation without increasing the incidence
of pneumonitis was estimated. METHODS AND MATERIALS: For 12 patients, the
standard treatment technique was compared with the BIM technique using the
Cadplan 3D planning system (Varian-Dosetek). Dose distributions in the healthy
lung tissue were evaluated by considering both lungs minus the tumor as one
functional unit. The following parameters were compared: (i) the average
normalized total dose (NTD), (ii) the lung volume receiving an NTD of more than
20 Gy, and (iii) the calculated normal tissue complication probability (NTCP).
RESULTS: Due to the applied BIM technique, the field lengths could be reduced by
1.4 cm for all patients, while achieving a minimum dose at the superior and
inferior parts of the target of 95% of the isocenter dose. Compared to the
standard technique, BIM reduced the patient mean of the average NTD for the
healthy lung tissue from 16.5 to 15.3 Gy. The volume of healthy lung tissue
receiving an NTD of 20 Gy or more was reduced by 9.7% (range 2.2 to 23.1%). The
calculated NTCP reduced from 10.7% to 7.6% on average. The length of the
esophagus that received a dose of 60 Gy or more could be reduced for 5 of the 6
stage III patients in this study. Based on equal lung NTCPs for the standard
technique and the BIM technique, a mean dose escalation of 5.7 Gy (range 1.1 to
16.0 Gy) was possible for the 12 patients in this study. Based on equal average
NTDs for the two techniques, the patient mean of the allowed dose escalation was
6.5 Gy (range 1.1 to 18.2 Gy). All dose escalations would be possible without
exceeding the spinal cord tolerance dose. CONCLUSIONS: The BIM technique reduced
the dose delivery to critical tissues. Two published methods for estimating the
incidence of pneumonitis both pointed to a potential for dose escalation of 6 to
7 Gy on average with the BIM technique, without increasing the incidence of
pneumonitis. For 2 of the 12 patients in this study the estimated allowed dose
escalation even exceeded 15 Gy.
PMID- 10760443
TI - A method of estimating fetal dose during brain radiation therapy.
AB - PURPOSE: To develop a simple method of estimating fetal dose during brain
radiation therapy. METHODS AND MATERIALS: An anthropomorphic phantom was modified
to simulate pregnancy at 12 and 24 weeks of gestation. Fetal dose measurements
were carried out using thermoluminescent dosimeters. Brain radiation therapy was
performed with two lateral and opposed fields using 6 MV photons. Three sheets of
lead, 5.1-cm-thick, were positioned over the phantom's abdomen to reduce fetal
exposure. Linear and nonlinear regression analysis was used to investigate the
dependence of radiation dose to an unshielded and/or shielded fetus upon field
size and distance from field isocenter. RESULTS: Formulas describing the
exponential decrease of radiation dose to an unshielded and/or shielded fetus
with distance from the field isocenter are presented. All fitted parameters of
the above formulas can be easily derived using a set of graphs showing their
correlation with field size. CONCLUSION: This study describes a method of
estimating fetal dose during brain radiotherapy, accounting for the effects of
gestational age, field size and distance from field isocenter. Accurate knowledge
of absorbed dose to the fetus before treatment course allows for the selection of
the proper irradiation technique in order to achieve the maximum patient benefit
with the least risk to the fetus.
PMID- 10760444
TI - Inhomogeneous target-dose distributions: a dimension more for optimization?
AB - PURPOSE: To evaluate if the use of inhomogeneous target-dose distributions,
obtained by 3D conformal radiotherapy plans with or without beam intensity
modulation, offers the possibility to decrease indices of toxicity to normal
tissues and/or increase indices of tumor control stage III non-small cell lung
cancer (NSCLC). METHODS AND MATERIALS: Ten patients with stage III NSCLC were
planned using a conventional 3D technique and a technique involving noncoplanar
beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined:
PTV1 included macroscopic tumor volume and PTV2 included macroscopic and
microscopic tumor volume. Virtual simulation defined the beam shapes and
incidences as well as the wedge orientations (3D) and segment outlines (BIM).
Weights of wedged beams, unwedged beams, and segments were determined by
optimization using an objective function with a biological and a physical
component. The biological component included tumor control probability (TCP) for
PTV1 (TCP1), PTV2 (TCP2), and normal tissue complication probability (NTCP) for
lung, spinal cord, and heart. The physical component included the maximum and
minimum dose as well as the standard deviation of the dose at PTV1. The most
inhomogeneous target-dose distributions were obtained by using only the
biological component of the objective function (biological optimization). By
enabling the physical component in addition to the biological component, PTV1
inhomogeneity was reduced (biophysical optimization). As indices for toxicity to
normal tissues, NTCP-values as well as maximum doses or dose levels to relevant
fractions of the organ's volume were used. As indices for tumor control, TCP
values as well as minimum doses to the PTVs were used. RESULTS: When optimization
was performed with the biophysical as compared to the biological objective
function, the PTV1 inhomogeneity decreased from 13 (8-23)% to 4 (2-9)% for the 3D
(p = 0.00009) and from 44 (33-56)% to 20 (9-34)% for the BIM plans (p < 0.
00001). Minimum PTV1 doses (expressed as the lowest voxel-dose) were similar for
both objective functions. The mean and maximum target doses were significantly
higher with biological optimization for 3D as well as for BIM (all p values <
0.001). Tumor control probability (estimated by TCP1 x TCP2) was 4.7% (3D) and
6.2% (BIM) higher for biological optimization (p = 0.01 and p = 0.00002
respectively). NTCP(lung) as well as the percentage of lung volume exceeding 20
Gy was higher with the use of the biophysical objective function. NTCP(heart) was
also higher with the use of the biophysical objective function. The percentage of
heart volume exceeding 40 Gy tended to be higher but the difference was not
significant. For spinal cord, the maximum dose as well as NTCP(cord) were similar
for 3D plans (D(max): p = 0.04; NTCP: p = 0.2) but were significantly lower for
BIM (D(max): p = 0.002; NTCP: p = 0.008) if the biophysical objective function
was used. CONCLUSIONS: When using conventional 3D techniques, inhomogeneous dose
distributions offer the potential to further increase the probability of
uncomplicated local control. When using techniques as BIM that would lead to
large escalation of the median and maximum target doses, it seems indicated to
limit target-dose inhomogeneity to avoid dose levels that are so high that the
safety becomes questionable.
PMID- 10760445
TI - Preface.
PMID- 10760446
TI - The history of the Dorper sheep.
AB - This short history of the Dorper sheep traces its background and the steps taken
to develop that breed in South Africa. The most important traits considered for
the developing of the Dorper are listed and the breeding system outlined. The
development of the White Dorper is also detailed and the breed improvement
programs are indicated.
PMID- 10760447
TI - The development of the Dorper, its nutrition and a perspective of the grazing
ruminant on veld.
AB - The development of the non-woolled Dorper sheep breed is briefly reviewed.
Despite the large number of Dorpers in South Africa, precious little research
results have been published on its nutrition under harsh, arid grazing
conditions, especially since this has been an objective for creating and
developing the breed. Results from the limited number of trials with free ranging
Dorpers on natural pasture (veld) regarding diet selection, voluntary feed intake
and rumen variables are used in conjunction with production data to create a
nutritional perspective of the free ranging ruminant.
PMID- 10760448
TI - Productive performance of Dorper sheep.
AB - The Dorper is a hardy South African composite breed, derived from a cross between
the Black-headed Persian and the Dorset Horn. Dorpers are regarded as early
maturing, and ewes lambed at an age of 1 year in one study. Age at first lambing
was higher in other literature sources cited. The fertility of Dorper ewes was
approximately 0.90 ewes that lambed per ewe mated, with a litter size ranging
from 1.45 to 1.60. The gestation length of Dorper ewes was approximately 147
days, while they were reported to start cycling as soon as 52 days after
parturition. The pre-weaning survival of Dorper lambs was cited at approximately
0.90. Overall reproduction rate of Dorpers ranged from 0.99 to 1.40 lambs weaned
per ewe mated, while it exceeded 1.40 lambs weaned per ewe mated per annum under
accelerated mating conditions. Dorper lambs gained from 0.24 to 0.28kg per day
under vastly different environmental conditions. When weaned early at 2-3 months
of age, post-weaning gains in excess of 0.18-0.20kg per day were recorded. At
slaughter, Dorper lambs had dressing percentages of approximately 50%. Two
divergent genotypes in the breed (with a hairy or a woolly fleece cover) were
evaluated under natural pasture conditions. No conclusive advantage in favour of
either genotype could be demonstrated as far as productive traits were concerned.
It was concluded that the breed adapts well to a wide variety of environmental
conditions. In view of the scarcity of estimates of genetic parameters for the
breed, the maintenance and expansion of datasets suitable for this purpose should
receive high priority.
PMID- 10760449
TI - A comparative assessment of Dorper sheep in different production environments and
systems.
AB - Performance of Dorper sheep was compared to other breeds in pure and cross
breeding evaluations under different production systems. The number of ewes
lambed per ewe joint (E(L)/E(J)) varied for the Dorper from 0.68 to 0.91 (average
0.81) and for other breeds and crosses from 0.65 to 0.91 (average 0.82). Average
litter size (L(B)/lambing) varied from 1.02 to 1.52 (average 1.28) and from 1.02
to 1.70 (average 1.30) for the two groups, respectively. In general, the Afrino
and Finnish composite lines were more prolific than the Dorper. Post-weaning
mortality rates in Kenya were high (49%) among Dorper lambs compared to the local
Red Maaisai breed, owing to a high susceptibility to gastrointestinal parasites.
Average weaning weights (WW) (100 days) were 12.4% heavier in the Dorper than in
the breeds it was compared to, but 31.7% heavier than the woolled breeds. Total
WW and efficiency of Dorper and Dorper crosses were higher than Merino, Afrino,
Dohne merino, South African Mutton Merino, but lower than in Finnish Landrace
composite lines. Both Dorper and Dorper cross-breeds reached target slaughter
weight of approx. 40kg earlier than Merino, Afrino, Suffolk and Ile de France
crosses. Average daily gain to slaughter was 44% higher in the Dorper than the
average of the groups it was compared to. It is concluded that the Dorper was
superior in reproductive and growth traits to woolled and other indigenous
breeds. However, there is a lack of information on the performance of the Dorper
in cross-breeding systems.
PMID- 10760450
TI - Grazing behaviour and diet selection by Dorper sheep.
AB - The grazing behaviour and diet selection by Dorper sheep, as well as other
related aspects (pasture intake, walking habits and trampling) is reviewed. It
was clear that Dorper sheep are less-selective grazers, compared to Merino-type
breeds. Dorpers utilised shrubs and bushes to a greater extent, but grass to a
lesser extent in relation to Merino sheep. The Dorper also utilised a larger
number of different plant species than Merinos. Dorpers walked less to select
food, or a suitable spot to graze, which consequently led to a shorter grazing
time and less separate grazing periods. Dorpers consumed less herbage per
metabolic size compared to Merino-type sheep. No uniform pattern in the walking
distance of Dorpers was observed when compared to other sheep breeds. The
relative trampling factor for Dorper sheep was less than that of evaluated Merino
type sheep. The review revealed a lack on information on the grazing behaviour
and diet selection of Dorper sheep under more intensive grazing conditions. There
is also a total lack of scientific information on other behaviour aspects of this
unique breed.
PMID- 10760451
TI - Status of Dorper sheep as hosts of ectoparasites.
AB - Seventeen ixodid tick species or subspecies have been collected from Dorper sheep
in South Africa. The diseases transmitted or the conditions caused by these ticks
in sheep are discussed. Although Dorper sheep may be infested with the scab mite,
Psoroptes ovis, this does not seem to cause production losses. These sheep may,
however, serve as a source of mite infestation for woolled sheep. The majority of
Dorper sheep are infested with the larvae of the nasal bot fly, Oestrus ovis,
they may also be subject to myiasis caused by the larvae of two calliphorid
flies. In certain regions of the country Dorper sheep are prone to serious fly
worry by female Simulium chutteri. Although Dorper sheep may be infested by
various louse species these do not seem to reach large numbers or cause
production losses.
PMID- 10760452
TI - The improved Boer goat.
AB - The history, origin and characteristics of the South African Boer breed of goats
are reviewed. The development was carried out by a handful of farmers in the
Eastern Cape, particularly in the district of Somerset East. The prototype for
the breed was selected from several existing breeds of goats in South Africa in
order to achieve the present functional characteristics and type. The Boer goat
is a hardy breed with great capacity for adaptation and an exceptional ability to
withstand and resist diseases. The Boer goat is highly fertile, conception rate
is about 90%, kidding rate about 189% and fecundity rate 210%. Weaning weight at
120 days averages 29kg. Boer doe produces enough milk to raise twins easily. Boer
goat yields flavoursome, succulent, tender and tasty lean meat of high quality,
particularly during the young stage. Boer goat is able to maintain a high level
of production up to 10 years of age. Details on breed standards of the Boer goat
are presented. Numerous countries had imported Boer goats from South Africa
including USA, New Zealand, Australia, Germany, Israel, France and more recently
China.
PMID- 10760453
TI - Reproduction traits in the Boer goat doe.
AB - The aim of this review is to give insight into the reproduction potential of the
Boer goat doe. Assessment of the reproduction traits in the Boer goat doe
demonstrates a mean body weight at puberty of between 30.6 and 27.5kg, depending
on the dietary energy level. Kids weaned during the natural breeding season
(April/May) exhibit oestrus or puberty earlier than those weaned outside the
natural breeding season. The mean age at the onset of puberty in the Boer goat
doe is 191.1 and 157.2 days for kids born in August (late winter) and January
(mid-summer). Although periods of complete anoestrus was not observed, the peak
of sexual activity occurred during autumn and the period of lowest sexual
activity from late spring to mid-summer. The duration of the oestrous cycle was
recorded as being 20.7+/-0.7 days, with the mean duration of the oestrous period
being 37.4+/-8.6h and the position of the LH peak (indicative of ovulation) being
8.0+/-1.5h following the onset of oestrus. The time of ovulation was recorded as
occurring 36.8h after the onset of oestrus, with a mean ovulation rate of 1.72+/
0.9 ovulations per doe. The mean gestation period is quoted as being 148.2+/-3.7
days, with multiple births having no significant effect on gestation length.
Involution of the Boer goat uterus is macroscopically complete by day 28 post
partum with the duration of the post-partum anoestrous period in the Boer goat
being 55.5+/-24.9 days. The mean interval from partus to conception recorded, was
62.0+/-20.2 days. To optimise the reproductive efficiency in the Boer goat doe,
it is essential that its reproductive potential be known and exploited.
PMID- 10760454
TI - Adaptation to various environments and resistance to disease of the Improved Boer
goat.
AB - The Improved Boer Goat is a remarkable small-stock ruminant that possesses
distinctive qualities enabling it to excel as an efficient red meat producer. It
is early maturing, reaching a mean maximum weight of approximately 62kg at 3.5
years of age on natural pasture under extensive grazing conditions. It boasts
high fecundity, with approximately 2.09 kids born per doe kidded. A relatively
large proportion of does ( approximately 33%) have triplets, whilst the
occurrence of kids born as quadruplets and quintuplets have also been documented.
The Boer goat is predominantly a browser, enabling it to convert shrub and bush
into red meat, thereby playing a supplementary role to other farm stock in
increasing meat production per unit area, rather than being in competition with
them. As a browser, the goat is also extremely useful and effective in combatting
undesirable bush encroachment. In addition, it appears to be fairly resistant
towards certain diseases which are normally contracted by other small stock, such
as sheep. Lastly, Boer goats produce red meat of high quality which is hardly
distinguishable from that of mutton or lamb as far as flavour is concerned,
provided animals are slaughtered at a relatively young age.
PMID- 10760455
TI - Growth of Spanish, BoerxAngora and BoerxSpanish goat kids fed milk replacer.
AB - Seventy-seven male kids were used to compare growth performance of Spanish (S,
n=26), BoerxAngora (BA, n=21) and BoerxSpanish (BS, n=30) kids during the
preweaning period. All kids were removed from does 3 days postpartum, moved
indoors and randomly allocated to individual cages. Kids received goat milk
fortified with milk replacer for approximately 1 week followed by 600ml of milk
replacer (23% CP, 30% crude fat) twice daily until weaning at 8 week. At 3 week
of age, all kids had ad libitum access to a commercial goat starter diet (20%
CP). Feed intake was measured daily and BW gain at 2-week intervals. There were
interactions (P<0.05) between breed and time or 2-week period in BW, BW gain and
feed efficiency. Boer crosses (i.e., BA and BS) were heavier than S kids at 2, 6
and 8 weeks of age (P<0.05), but there were no BW differences between Boer
crosses (P0.10). From Week 3-8, Boer crosses gained BW more rapidly (P=0.001)
than did S kids (60, 71 and 77g/day for S, BA and BS, respectively), although BW
gain of S in Week 3-4 was greater (P<0.05) than that of Boer crosses (60, 50 and
54g/day for S, BA and BS, respectively). Starter diet DM intake in Week 3-8 was
greatest for BS (S versus BA and BS, P=0.05; BA versus BS, P<0.01) (23, 24 and
37g/day for S, BA and BS, respectively). The ratio of BW gain to total DM intake
in Week 3-8 was greater (P=0.03) for BA and BS than for S (0.52, 0.59 and 0.58
for S, BA and BS, respectively). The incidence of scours was 17, 21 and 31% for
S, BA and BS kids, respectively (P0.10). These results reflect that crossbreeding
with Boer goats can improve growth of young kids and, thus, potentially increase
economic returns for goat producers.
PMID- 10760456
TI - Transcervical embryo collection in Boer goats.
AB - Two experiments were conducted, aimed at improving the practicability of the
method for transcervical embryo collection in Boer goats described by Pereira et
al. [Pereira, R.J.T.A., Sohnrey, B., Holtz, W., 1998. J. Anim. Sci. 76, 360-363].
Invention of a hammock-like restraining device, use of a wider-bore flushing
catheter and a modified flushing mode contributed toward this end. The importance
of a luteolytic prostaglandin F(2alpha)-treatment [Pereira et al., 1998] was
confirmed. In Experiment 1, administration of PGF(2alpha) 8h before does are
flushed, increased the recovery rate from 43 to 79% (P<0.05). Advancing the PG
F(2alpha)-treatment to 24h before flushing was instrumental in further enhancing
embryo recovery rate. The amount of time required for flushing was reduced by
about 20min (P<0.05) and the number of embryos recovered from the first 10 out of
30 flushes amounted to more than 80%, compared to 50% (P<0.05) when treating 8h
before flushing. Administration of 1IU of oxytocin at the onset of flushing did
not have any significant effect. When applying the findings of this
investigation, the time required for flushing may be reduced from about 4h
[Pereira et al., 1998] to less than 45min per doe and the required number of
person involved decreased from four to two persons.
PMID- 10760457
TI - Synchronization of oestrus in goats: dose effect of progestagen.
AB - A trial was conducted to test the efficiency of different doses of intravaginal
progestagen in the synchronization of different goat breeds, in the breeding
season. Sixty Multiparous Boer and 60 Indigenous feral does were allocated to
three treatment groups. The groups consisted of a control group (natural oestrus)
(n=20/breed); 60mg MAP sponge groups inserted for 14 days plus 300IU PMSG at
sponge withdrawal (n=20/breed) and halved 60mg MAP (+/-30mg) sponges inserted for
14 days plus 300IU PMSG at withdrawal (n=20/breed). The time from sponge
withdrawal to oestrus was not significantly different in the treatment groups
(whole and halved sponges), irrespective of breed. The duration of the oestrous
period was significantly (p<0.01) shorter in the control group (29.3+/-14.9h
versus 28.0+/-15.7h for the Indigenous and Boer goats, respectively), compared to
the induced period for the 60mg (31.1+/-14.7 and 31.5+/-15.9h) or 30mg (40.0+/
22.0h versus 34.3+/-21.7h) for the Boer and Indigenous goats, respectively. No
significant difference in pregnancy rate following AI was recorded (mean 74.2%).
The mean serum progesterone concentration for the observation period varied
between 0.01 and 6.19ng/ml for Indigenous and 0.01 and 9.05ng/ml for Boer goat
does. No significant correlation was recorded between the does pregnant and serum
progesterone levels. Mean serum LH concentration of the 60mg MAP groups (0.59+/
0.22ng/ml) was significantly (p<0.05) lower than the control (0.84+/-0.66ng/ml)
and the halved sponge (1.9+/-0.49ng/ml) groups. Dose of progestagen played no
role in the efficiency of synchronization, regardless of the breed. The mean
pregnancy rate achieved, is acceptable following fixed-time AI in both breeds and
at both doses progestagen.
PMID- 10760458
TI - Glucosylcaldarchaetidylglycerol, a minor phosphoglycolipid from Thermoplasma
acidophilum.
AB - A novel phosphoglycolipid (GPL-K) was isolated from Thermoplasma acidophilum
(ATCC 27658). The chemical components of GPL-K were analyzed by gas liquid
chromatography and GC-MS. The sugar moiety of GPL-K and its anomeric region were
analyzed by NMR assignment. The core lipid of GPL-K was caldarchaeol, and its
main hydrocarbon chains were acyclic and monocyclic C(40) biphytanyl. The polar
head groups were alpha-glucose and glycerophosphate. The negative FAB-MS spectrum
of GPL-K confirmed that the lipid peak of m/z 1614 consists of a caldarchaeol
(including one cyclopentane ring), a hexose sugar, and a glycerophosphate. We
have proposed the tentative structure of GPL-K.
PMID- 10760459
TI - The change in leukotrienes and lipoxins in activated mouse peritoneal
macrophages.
AB - The aim of this study was to investigate to what extent the generation of
leukotrienes (LTs) and lipoxins (LXs) was affected by the expression of definite
levels of macrophage activation. We used a system of murine peritoneal
macrophages at different states of activation consisting in resident macrophages
and FCS-, thioglycollate- or Corynebacterium parvum-elicited macrophages. The
profile of lipoxygenase metabolites in resident macrophages was characterized by
the presence of high levels of 12-HETE, followed by 15-HETE, 5-HETE, LTB(4) and 6
trans-LTB(4), 6-trans-12-epi-LTB(4). A comparable pattern was also found in FCS
elicited macrophages which appeared not to be responsive to the challenge with
interferon gamma plus LPS, as measured by the generation of NO and tumor necrosis
factor alpha. Resident as well as FCS-elicited macrophages also generated
appreciable quantities of LXs (A(4) and B(4)). Thioglycollate-elicited
macrophages, which expressed a state of 'responsive' macrophages, showed a block
of the LT and LX synthesis. This block was also present in C. parvum-elicited
macrophages which expressed a fully 'activated' phenotype, reflected by their
capacity of releasing NO and tumor necrosis factor alpha even though they were
not challenged. These results provide the first evidence that the level of
'responsive' as well as 'activated' macrophages was associated with of a
simultaneous block of LTB(4) and LXs.
PMID- 10760460
TI - Recent advances in the study of prenylated proteins.
AB - Post-translational modification of proteins with isoprenoids was first recognized
as a general phenomenon in 1984. In recent years, our understanding, including
mechanistic studies, of the enzymatic reactions associated with these
modifications and their physiological functions has increased dramatically. Of
particular functional interest is the role of prenylation in facilitating protein
protein interactions and membrane-associated protein trafficking. The loss of
proper localization of Ras proteins when their farnesylation is inhibited has
also permitted a new target for anti-malignancy pharmaceuticals. Recent advances
in the enzymology and function of protein prenylation are reviewed in this
article.
PMID- 10760462
TI - beta-oxidation - strategies for the metabolism of a wide variety of acyl-CoA
esters.
AB - Living organisms are exposed to a number of different fatty acids and their
various derivatives arising either via endogenous synthesis or from exogenous
sources. These hydrophobic compounds can play specific metabolic, structural or
endocrinic functions in the organisms before their elimination, which can be
metabolism to CO(2) or to more polar lipid metabolites allowing their excretion.
Quantitatively, one of the major pathways metabolizing fatty acids is beta
oxidation, which consists of a set of four reactions operating at the carbons 2
or 3 of acyl-CoA esters and shortening of the acyl-chain. To allow the beta
oxidation of acyl groups with various steric variants to proceed, different
strategies have been developed. These strategies include evolution of beta
oxidation enzymes as paralogues showing specificity with respect to either chain
length or modified acyl-chain, metabolic compartmentalization in eukaryotic
cells, controlling of substrate transport across membranes, development of
auxiliary enzyme systems, acquisition of enzymes with adaptive active sites and
recruiting and optimizing enzymes from non-homologous sources allowing them to
catalyze a parallel set of reactions with different substrate specificities.
PMID- 10760461
TI - Functions of a new family of sphingosine-1-phosphate receptors.
PMID- 10760463
TI - Interactions between metabolism and intracellular distribution of cholesterol and
sphingomyelin.
AB - There is ample evidence from experimental models and human metabolic disorders
indicating that cholesterol and sphingomyelin (SM) levels are coordinately
regulated. Generally it has been observed that altering the cellular content of
sphingomyelin or cholesterol results in corresponding changes in mass and/or
synthesis of the other lipid. In the case of cholesterol synthesis and
trafficking, SM regulates the capacity of membranes to absorb cholesterol and
thereby controls sterol flux between the plasma membrane and regulatory pathways
in the endoplasmic reticulum. This relationship exemplifies the importance of
cholesterol/sphingolipid-rich domains in cholesterol homeostasis, as well as
other aspects of cell signaling and transport. Evidence for regulation of
sphingomyelin metabolism by cholesterol is less convincing and dependent on the
model system under study. Sphingomyelin biosynthetic rates are not dramatically
affected by alterations in cholesterol balance suggesting that sphingomyelin or
its metabolites serve other indispensable functions in the cell. A notable
exception is the robust and specific regulation of both SM and cholesterol
synthesis by 25-hydroxycholesterol. This finding is reviewed in the context of
the role of oxysterol binding protein and its putative role in cholesterol and SM
trafficking between the plasma membrane and Golgi apparatus.
PMID- 10760464
TI - Sterols and inhibitors of sterol transport modulate the degradation and secretion
of macrophage ApoE: requirement for the C-terminal domain.
AB - Macrophage-derived apoE, produced in the vessel wall, may have important effects
during atherogenesis. The production of apoE by macrophages can be regulated at a
transcriptional level by cellular differentiation state, cytokines and sterol
loading. In addition, there are post-transcriptional and post-translational loci
for regulation. We have recently identified an intermediate density cell membrane
fraction in which the degradation of apoE can be modulated by sterols.
Suppressing degradation of apoE in this fraction by pre-incubating cells in
sterols led to enhanced apoE secretion. In this report we demonstrate that the
suppressive effect of sterols on the degradation of newly synthesized apoE in
this fraction depends on the presence on its C-terminal domain, by studying a
macrophage cell line transfected to express a mutant form of apoE in which amino
acids beyond amino acid 202 were deleted. In addition, two modulators of cellular
sterol transport, progesterone and U1866A, inhibited the degradation of full
length apoE. In contrast, incubation of cells in the acyl-CoA:cholesterol
acyltransferase inhibitor S58035 did not influence apoE degradation. As would be
predicted based on the results of degradation assays, U1866A, but not S58035,
increased the secretion of apoE from a cell line transfected to constitutively
express full-length apoE cDNA. The effect of U1866A on apoE degradation, like the
effect of sterol, required the presence of the apoE C-terminal domain. Our
results indicate that alteration of intracellular sterol homeostasis by pre
incubation in sterols or by drugs that modify the subcellular transport of
sterol, modulates the susceptibility of apoE to degradation and that this
modulation requires the presence of C-terminal lipid binding domains.
PMID- 10760465
TI - Membrane perturbation by mastoparan 7 elicits a broad alteration in lipid
composition of L1210 cells.
AB - Mastoparan 7 (Mas-7), an amphiphilic peptide possessing membrane perturbing
activity, has been known to selectively stimulate some lipases. To examine
changes in the lipid composition induced by Mas-7, we carried out systemic lipid
analysis of L1210 cells after Mas-7 treatment. The total lipid was determined by
HPLC, gas-liquid chromatography, and electrospray ionization mass spectrometry in
conjunction with differential radiolabelling with [(32)P]orthophosphate,
[(3)H]myristic acid, and [(3)H]arachidonic acid. The lipid analysis revealed
multiple changes in more than 10 lipid classes. Free fatty acids (FFAs) and
phosphatidylethanol (PEt), the phospholipase D product in the presence of
ethanol, were increased significantly and phosphatidylcholine (PC) was decreased.
Digitonin, a membrane permeabilizing reagent, similarly affected the lipid
composition of L1210. The FFA released showed a very broad distribution of
saturated, monounsaturated, and polyunsaturated fatty acids, implying that
phospholipase A(2) alone could not account for all of the FFAs released. By
comparing the molecular species of PEt with those of endogenous PC, we showed
that phospholipase D in L1210 cells appeared to act selectively on diacyl-PC. The
perturbation-induced alterations in the lipid composition brought about by Mas-7
might play a crucial role in the physiology of the affected cells.
PMID- 10760466
TI - Susceptibility of S49 lymphoma cell membranes to hydrolysis by secretory
phospholipase A(2) during early phase of apoptosis.
AB - During cell death, plasma membranes of cells become vulnerable to attack by
extracellular secretory phospholipase A(2). The purpose of this study was to
identify the timing of this phenomenon relative to other events that occur during
the process of cell death. Death was induced in S49 murine lymphoma cells by
treatment with dexamethasone, dibutyryl cAMP, ionomycin, thapsigargin, or heat
shock (1 h at 43 degrees C). The appearance of membrane susceptibility to
secretory phospholipase A(2) was compared to the following apoptotic events: loss
of mitochondrial membrane potential, phosphatidylserine exposure in the outer
leaflet of the cell membrane, early DNA damage assessed by the comet assay, and
changes in cell size and internal complexity assessed by flow cytometry. Each
inducer of death was distinct in the time course of events produced. Although
dead cells were susceptible to the action of phospholipase A(2), live cells
(impermeable to propidium iodide) also became vulnerable to the enzyme during
characteristic time courses after exposure to each inducer. In fact,
susceptibility to sPLA(2) was observed in each case prior to or concurrent with
the earliest of the markers of apoptosis. These results demonstrate that the
onset of susceptibility to sPLA(2) is an early event in apoptosis suggesting that
changes in membrane structure may be relevant to initial aspects of the apoptotic
process.
PMID- 10760467
TI - Identification and chromosomal localisation by fluorescence in situ hybridisation
of human gene of phosphoinositide-specific phospholipase C beta(1).
AB - Members of phosphoinositide-specific phospholipase C (PLC) families are central
intermediary in signal transduction in response to the occupancy of receptors by
many growth factors. Among PLC isoforms, the type beta(1) is of particular
interest because of its reported nuclear localisation in addition to its presence
at the plasma membrane. It has been previously shown that both the stimulation
and the inhibition of the nuclear PLCbeta(1) under different stimuli implicate
PLCbeta(1) as an important enzyme for mitogen-activated cell growth as well as
for murine erythroleukaemia cell differentiation. The above findings hinting at a
direct involvement of PLCbeta(1) in controlling the cell cycle in rodent cells,
and the previously reported mapping of its gene in rat chromosome band 3q35-36, a
region frequently rearranged in rat tumours induced by chemical carcinogenesis,
prompted us to identify its human homologue. By screening a human foetal brain
cDNA library with the rat PLCbeta(1) cDNA probe, we have identified a clone
homologous to a sequence in gene bank called KIAA 0581, which encodes a large
part of the human PLCbeta(1). By using this human cDNA in fluorescence in situ
hybridisation on human metaphases, it has been possible to map human PLCbeta(1)
on chromosome 20p12, confirming the synteny between rat chromosome 3 and human
chromosome 20 and providing a novel locus of homology between bands q35-36 in rat
and p12 in man. Since band 20p12 has been recently reported amplified and/or
deleted in several solid tumours, the identification and chromosome mapping of
human PLCbeta(1) could pave the way for further investigations on the role
exerted both in normal human cells and in human tumours by PLCbeta(1), which has
been shown to behave as a key signalling intermediate in the control of the cell
cycle.
PMID- 10760468
TI - Accumulation of unsaturated lipids in monocytes during early phase pyrogen
tolerance.
AB - This paper presents data that inspired a new explanation for the mechanism of
early phase endotoxin tolerance. Rabbits injected intravenously with LPS from
Salmonella abortus developed a two-phase fever (6 h) and monophasic
hyperlipidemia of very low density lipoproteins (two consecutive days). If during
these days rabbits were injected with the same dose of LPS at 24-h intervals, the
second phase of fever disappeared, i.e. early phase pyrogenic tolerance was
obtained. This was correlated with a decrease of lipoprotein hyperlipidemia
(measured 1.5 h after LPS injection) and an accumulation of lipids rich in double
bonds in monocytes (measured 3.5 h after LPS injection). Results showed that the
degree of unsaturation of acyl chains (AC) in monocytes (AC/DB, DB=double bonds)
is negatively correlated (r=-0.72) with fever response (fever index). The authors
maintain that a gradual increase in monocyte membrane fluidity is an adaptation
to repeated exposure of monocytes to lipid A and is responsible for the
progressive desensitization of monocytes to endotoxin. It is suggested that
disorders of this mechanism lead to an accumulation of abnormal quantities of
saturated lipids and cholesterol within macrophages, which, as foam cells, are
the starting point for atherosclerosis pathology.
PMID- 10760469
TI - Bacterial cell membrane hydrolysis by secreted phospholipases A(2): a major
physiological role of human group IIa sPLA(2) involving both bacterial cell wall
penetration and interfacial catalysis.
AB - The ability of human group IIa secreted phospholipase A(2) (human sPLA(2)) to
hydrolyse the phospholipid membrane of whole cell suspensions of Gram-positive
bacteria is demonstrated in real time using a continuous fluorescence
displacement assay. Micrococcus luteus is used as a model system and demonstrates
an almost absolute specificity for this human enzyme compared with porcine
pancreatic and Naja naja venom sPLA(2)s. This specificity is due to selective
penetration of the highly cationic human sPLA(2)50%) phospholipid hydrolysis was
observed and this was confirmed by electrospray mass spectrometry that allowed
the identification of several molecular species of phosphatidylglycerol as the
targets for hydrolysis. However, the bactericidal activity of the human enzyme
under these assay conditions was low, highlighting the capacity of the organism
to survive a major phospholipid insult. In addition to pure enzyme, the human
sPLA(2) activity in tears was demonstrated using M. luteus as substrate. In
comparison to M. luteus, cell suspensions of Staphylococcus aureus were highly
resistant to hydrolysis by human sPLA(2) as well as to the pancreatic and venom
enzymes. Treatment of this organism with the specific cell wall protease
lysostaphin resulted in a dramatic enhancement in cell membrane phospholipid
hydrolysis by all three sPLA(2)s. Overall, the results highlight the potential of
the human sPLA(2) as a selective antimicrobial agent against Gram-positive
bacteria in vivo because this enzyme is essentially inactive against mammalian
plasma membranes. However, the enzyme will be most effective in combination with
other antimicrobial agents that enhance the permeability of the bacterial cell
wall and where potentiation of the effectiveness of other antibiotics would be
expected.
PMID- 10760470
TI - Subcellular localization and PKC-dependent regulation of the human
lysophospholipase A/acyl-protein thioesterase in WISH cells.
AB - Lysophospholipases play essential roles in keeping their multi-functional
substrates, the lysophospholipids, at safe levels. Recently, a 25 kDa human
lysophospholipase A (hLysoPLA I) that is highly conserved among rat, mouse, human
and rabbit has been cloned, expressed and characterized and appears to hydrolyze
only lysophospholipids among the various lipid substrates. Interestingly, this
enzyme also displays acyl-protein thioesterase activity towards a G protein alpha
subunit. To target the subcellular location of this hLysoPLA I, we have carried
out immunocytochemical studies and report here that hLysoPLA I appears to be
associated with the endoplasmic reticulum (ER) and nuclear envelope in human
amnionic WISH cells and not the plasma membrane. In addition, we found that the
hLysoPLA I can be up-regulated by phorbol 12-myristate 13-acetate (PMA)
stimulation, a process in which phospholipase A(2) is activated and
lysophospholipids are generated in WISH cells. Furthermore, the PMA-induced
hLysoPLA I expression can be blocked by the protein kinase C (PKC) inhibitor
Go6976. The regulated expression of the LysoPLA/acyl-protein thioesterase by PKC
may have important implications for signal transduction processes.
PMID- 10760471
TI - Regulation of the expression of group IIA and group V secretory phospholipases
A(2) in rat mesangial cells.
AB - Rat mesangial cells synthesize and secrete a secretory phospholipase A(2) upon
stimulation of the cells with cytokines, like IL-1beta and TNF and with cAMP
elevating agents like forskolin. This enzyme was previously characterized to
belong to group IIA sPLA(2). The discovery of several other low molecular weight
phospholipases, like group IIC in murine testis and group V in human and rat
heart, prompted investigations on the presence of group IIC and group V sPLA(2)
in rat mesangial cells. This was done by isolating the RNA from stimulated cells
and performing RT-PCR, using primers specific for group IIC and V sPLA(2). The
results indicate that rat mesangial cells upon stimulation express next to group
IIA also group V sPLA(2). No indications were obtained for the expression of
group IIC sPLA(2). The regulation of the expression of group V sPLA(2) at the
mRNA level was further investigated by examining the time-dependent expression,
the influence of dexamethasone and the signaling route of the IL-1beta
stimulation. The results show that the IL-1beta induced expression of group V
sPLA(2) mRNA was time dependent and, similar to that of group IIA sPLA(2) mRNA,
involves activation of NF-kappaB. However, in contrast to the group IIA sPLA(2),
the expression of group V sPLA(2) was not influenced by the presence of
dexamethasone. The expression of both phospholipases was also examined at the
protein level in stimulated mesangial cells. Western blot analysis shows that
stimulated mesangial cells synthesize both group IIA and group V sPLA(2) protein
but the expression of group V is lower compared to that of group IIA sPLA(2). In
addition, the extent of secretion into the medium appears to be considerably
higher for group IIA than for group V sPLA(2).
PMID- 10760472
TI - The polar-lipid composition of the sphingolipid-producing bacterium
Flectobacillus major.
AB - Polar lipids comprise about 90% of the total chloroform-methanol extractable
lipids of the Gram-negative, fresh-water, ring-forming bacterium Flectobacillus
major FM and consist of at least 10 constituents. These are
aminophosphosphingolipids, 2-N-(2'-D-hydroxy-13'-methyltetradecanoyl)-15-methyl
4(E)-hexad ecasph ingenyl-1-phosphoethanolamine (36.8% of the total polar lipids)
and its 2'-deoxy derivative (3.7%); sulfonic-acid analogues of ceramide, 2-D-(2'
D-hydroxy-13'-methyltetradecanoyl)amino-3-D-hydroxy-15-met hyl hexadecane-1
sulfonic acid (18.1%) and its 2'-deoxy derivative (3. 5%); a lipoamino acid, N-[3
D-(15'-methylhexadecanoyloxy)-15-methylhexadecanoyl]-gl ycine (3. 7%); a
lipodipeptide, N-?N'-[3"-D-(15"'-methylhexadecanoyloxy)-15"-methylhexadecanoyl
]glycy l?-L-serine (7.8%); 1,2-diacyl-sn-glycero-3-phosphoethanolamine (7. 7%),
1,2-diacyl-3-alpha-D-galactopyranosyl-sn-glycerol (2.9%); ceramide phospho-myo
inositol (4.9%), and a previously described unusual glycosphingolipid, 7-deoxy-7
amino-D-manno-heptulosonopyranosyl (1-hydroxycarbonyl-6-deoxy-6-amino-alpha-D
mannopyranosyl) ceramide (10.9%); the last two lipids contain only 15-methyl-4(E)
hexadecasphingenine as a long-chain base. The sole structural type of amide-bound
fatty acids in the sphingolipids, including the sulfonic-acid analogues, is iso
15:0, either non-hydroxylated or hydroxylated at 2-C, whereas 15
methylhexadecanoic acid is the major ester-bound fatty acid in the remaining
lipids.
PMID- 10760473
TI - A marked stimulation of Fe(3+)-dependent lipid peroxidation in phospholipid
liposomes under acidic conditions.
AB - Lipid peroxidation in phosphatidylcholine liposomes induced by Fe(3+) alone,
assessed by thiobarbituric acid-reactive substances (TBARS) production, was
markedly enhanced as the solution pH was lowered from 7.4 to 5.5. On the other
hand, at physiological pH, TBARS production by Fe(3+) was almost negligible.
Results of the radical scavenger experiments with superoxide dismutase, catalase
and hydroxyl radical ((&z.rad;)OH) scavengers (sodium benzoate, mannitol and
dimethylthiourea), deoxyribose degradation and ESR spectrometry suggest that the
stimulation of Fe(3+)-dependent lipid peroxidation under acidic conditions is
involved in generation of superoxide anion (O(2)(&z.rad;-)), hydrogen peroxide
(H(2)O(2)) and (&z.rad;)OH during the reaction. The stimulation of Fe(3+)
dependent TBARS production by increasing the [H(+)] completely disappeared by
triphenylphosphine (TPP) treatment of the liposomes, but the reaction was
reversible with either incorporation of cumen hydroperoxide (CumOOH) into the TPP
treated liposomes or the addition of CumOOH to the treated liposomes. Incubation
of the CumOOH-incorporated TPP-treated liposomes with Fe(3+) at pH 5.5 also
resulted in (&z.rad;)OH generation. Based on these results, a possible mechanism
of stimulatory effect of Fe(3+) on lipid peroxidation under acidic conditions is
discussed.
PMID- 10760474
TI - Electrospray ionization mass spectrometric analyses of phospholipids from INS-1
insulinoma cells: comparison to pancreatic islets and effects of fatty acid
supplementation on phospholipid composition and insulin secretion.
AB - Insulin secretion by pancreatic islet beta-cells is impaired in diabetes
mellitus, and normal beta-cells are enriched in phospholipids with arachidonate
as sn-2 substituent. Such molecules may play structural roles in exocytotic
membrane fusion or serve as substrates for phospholipases activated by insulin
secretagogues. INS-1 insulinoma cells respond to secretagogues and permit the
study of effects of culture with free fatty acids on phospholipid composition and
secretion. INS-1 cell glycerophosphocholine (GPC) and glycerophosphoethanolamine
(GPE) lipids are demonstrated here by electrospray ionization mass spectrometry
to contain a lower fraction of molecules with arachidonate and a higher fraction
with oleate as sn-2 substituent than native islets. Palmitic acid supplementation
induces little change in these INS-1 cell lipids, but supplementation with
linoleate or arachidonate induces a large rise in the fraction of INS-1 cell GPC
species with polyunsaturated sn-2 substituents and a fall in oleate-containing
species to yield a GPC profile similar to native islets. The fraction of GPE
lipids comprised of plasmenylethanolamine species with polyunsaturated sn-2
substituents in early-passage INS-1 cells is similar to that of islets, but
declines on serial passage. Such molecules might participate in exocytotic
membrane fusion, and late-passage INS-1 cells have reduced insulin secretory
responses. Arachidonate supplementation induces a rise in the fraction of INS-1
cell GPE lipids with polyunsaturated sn-2 substituents and partially restores
responses to insulin secretagogues by late-passage INS-1 cells, but does not
further amplify secretion by early-passage cells. Effects of extracellular free
fatty acids on beta-cell phospholipid composition and secretory responses could
be involved in changes in beta-cell function during the period of hyper-free
fatty acidemia that precedes diabetes mellitus.
PMID- 10760475
TI - Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in
androgen metabolism.
AB - Human brain short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) has been
demonstrated to be a unique 3alpha-hydroxysteroid dehydrogenase (HSD) that can
convert 5alpha-androstane-3alpha, 17beta-diol (3alpha-adiol) to
dihydrotestosterone (DHT), whose affinity to the androgen receptor is 10(5)-fold
higher than that of 3alpha-adiol. The catalytic efficiency of human SCHAD for
this oxidative 3alpha-HSD reaction was estimated to be 164 min(-1) mM(-1), about
10-fold higher than that measured for the backward reaction. Thus, human brain
SCHAD may function in androgen metabolism as a new kind of 3alpha-HSD by
counteracting all other known 3alpha-HSDs, which would unidirectionally catalyze
the reduction of DHT to the almost inactive 3alpha-adiol. Human SCHAD is
identical to an amyloid-beta binding protein (ERAB) involved in Alzheimer's
disease, which was previously reported to be associated with the endoplasmic
reticulum. This protein is, in fact, localized in mitochondria, not endoplasmic
reticulum, as evidenced by immunocytochemical studies and its noncleavable
mitochondrial targeting sequence and lack of endoplasmic reticulum targeting
signals or transmembrane segments. These results prompt the suggestion that the
mitochondrion plays not only an essential role in the initial step of
steroidogenesis, but also important roles in the intracellular homeostasis of sex
steroid hormones. Northern blot analysis revealed that the human SCHAD gene is
expressed in both gonadal and peripheral tissues including the prostate whose
growth notably requires DHT, the most potent androgen. This study represents the
first report of a 3alpha-HSD that could act to generate DHT from 3alpha-adiol and
thereby maintain intracellular DHT levels. We propose that inhibitors of the
3alpha-HSD activity of human brain SCHAD could be useful for the treatment of
benign prostatic hyperplasia and other disorders involving DHT metabolism, in
combination with known inhibitors of steroid 5alpha-reductases.
PMID- 10760476
TI - Long chain fatty acids inhibit and medium chain fatty acids activate mammalian
cardiac hexokinase.
AB - We investigated the effect of non-esterified fatty acids (FAs) on bovine heart
hexokinase (type I: ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1). Long chain
FAs (C14 to C20) inhibited the enzyme in a way that correlated positively with
both the chain length and the degree of unsaturation. Medium chain FA with 12 or
less carbons activated hexokinase in a chain length dependent manner with the
greater activation shown by laurate. The activation constant of laurate was 91.5
microM with a maximal activation of 60.3%. Oleate caused a maximal decrease in
specific activity of 25% with an inhibition constant of 79 microM. Using the
fluorescent probe cis-parinarate, we found a saturable binding site with K(d) of
3.5 microM. Oleate competed the fluorescent probe from the protein with a K(d) of
1.4 microM. Medium chain FAs did not compete the probe from HK. The binding of
fatty acid to the protein appears to be entropically driven as indicated by an
Arrhenius analysis (DeltaS=+231.6 J mol(-1) deg(-1)). The presence of oleate
significantly increased the K(ATP)(m) from 0.47 mM to 0.89 mM while the
K(glucose)(m) in the presence of the FA (0.026+/-0.003 mM) was not significantly
different from the control (0.014+/-0.004 mM). A decrease in V(max) values in the
presence of oleate indicated that a mixed allosteric inhibition was operating.
PMID- 10760477
TI - Genetic evidence for a multi-subunit complex in the O-methyltransferase steps of
coenzyme Q biosynthesis.
AB - Coq3 O-methyltransferase carries out both O-methylation steps in coenzyme Q
(ubiquinone) biosynthesis. The degree to which Coq3 O-methyltransferase activity
and expression are dependent on the other seven COQ gene products has been
investigated. A panel of yeast mutant strains harboring null mutations in each of
the genes required for coenzyme Q biosynthesis (COQ1-COQ8) have been prepared.
Mitochondria have been isolated from each member of the yeast coq mutant
collection, from the wild-type parental strains and from respiratory deficient
mutants harboring deletions in ATP2 or COR1 genes. These latter strains
constitute Q-replete, respiratory deficient controls. Each of these mitochondrial
preparations has been analyzed for COQ3-encoded O-methyltransferase activity and
steady state levels of Coq3 polypeptide. The findings indicate that the presence
of the other COQ gene products is required to observe normal levels of O
methyltransferase activity and the Coq3 polypeptide. However, COQ3 steady state
RNA levels are not decreased in any of the coq mutants, relative to either wild
type or respiratory deficient control strains, suggesting either a decreased rate
of translation or a decreased stability of the Coq3 polypeptide. These data are
consistent with the involvement of the Coq polypeptides (or the Q-intermediates
formed by the Coq polypeptides) in a multi-subunit complex. It is our hypothesis
that a deficiency in any one of the COQ gene products results in a defective
complex in which the Coq3 polypeptide is rendered unstable.
PMID- 10760478
TI - 15-Lipoxygenation of leukotriene A(4). Studies Of 12- and 15-lipoxygenase
efficiency to catalyze lipoxin formation.
AB - The unstable epoxide leukotriene (LT) A(4) is a key intermediate in leukotriene
biosynthesis, but may also be transformed to lipoxins via a second lipoxygenation
at C-15. The capacity of various 12- and 15-lipoxygenases, including porcine
leukocyte 12-lipoxygenase, a human recombinant platelet 12-lipoxygenase
preparation, human platelet cytosolic fraction, rabbit reticulocyte 15
lipoxygenase, soybean 15-lipoxygenase and human eosinophil cytosolic fraction, to
catalyze conversion of LTA(4) to lipoxins was investigated and standardized
against the ability of the enzymes to transform arachidonic acid to 12- or 15
hydroxyeicosatetraenoic acids (HETE), respectively. The highest ratio between the
capacity to produce lipoxins and HETE (LX/HETE ratio) was obtained for porcine
leukocyte 12-lipoxygenase with an LX/HETE ratio of 0.3. In addition, the human
platelet 100000xg supernatant 12-lipoxygenase preparation and the human platelet
recombinant 12-lipoxygenase and human eosinophil 100000xg supernatant 15
lipoxygenase preparation possessed considerable capacity to produce lipoxins
(ratio 0.07, 0.01 and 0.02 respectively). In contrast, lipoxin formation by the
rabbit reticulocyte and soybean 15-lipoxygenases was much less pronounced
(LX/HETE ratios <0.002). Kinetic studies of the human lipoxygenases revealed
lower apparent K(m) for LTA(4) (9-27 microM), as compared to the other
lipoxygenases tested (58-83 microM). The recombinant human 12-lipoxygenase
demonstrated the lowest K(m) value for LTA(4) (9 microM) whereas the porcine
leukocyte 12-lipoxygenase had the highest V(max). The profile of products was
identical, irrespective of the lipoxygenase used. Thus, LXA(4) and 6S-LXA(4)
together with the all-trans LXA(4) and LXB(4) isomers were isolated. Production
of LXB(4) was not observed with any of the lipoxygenases. The lipoxygenase
inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate was considerably more
efficient to inhibit conversion of LTA(4) to lipoxins, as compared to the
inhibitory effect on 12-HETE formation from arachidonic acid (IC(50) 1 and 50
microM, respectively) in the human platelet cytosolic fraction.
PMID- 10760479
TI - Analysis of low-density lipoprotein catabolism by primary cultures of hepatic
cells from normal and low-density lipoprotein receptor knockout mice.
AB - Low-density lipoproteins (LDL) are taken up by LDL receptor (LDLr)-dependent and
independent pathways; the role and importance of the latest being less well
defined. We analyzed the importance of these pathways in the mouse by comparing
LDL binding to primary cultures of hepatocytes from LDLr knockout (LDLr KO) and
normal C57BL/6J mice. Saturation curve analysis shows that (125)I-LDL bind
specifically to normal and LDLr KO mouse hepatocytes with similar dissociation
constants (K(d)) (31.2 and 22.9 microg LDL-protein/ml, respectively). The maximal
binding capacity (B(max)) is, however, reduced by 48% in LDLr KO mouse
hepatocytes in comparison to normal hepatocytes. Conducting the assay in the
presence of a 200-fold excess of high-density lipoprotein-3 (HDL3) reduced by 39%
the binding of (125)I-LDL to normal hepatocytes and abolished the binding to the
LDLr KO mouse hepatocytes. These data indicate that in normal mouse hepatocytes,
the LDLr is responsible for approximately half of the LDL binding while a
lipoprotein binding site (LBS), interacting with both LDL and HDL3, is
responsible for the other half. It can also be deduced that both receptors/sites
have a similar affinity for LDL. The metabolism of LDL-protein and cholesteryl
esters (CE) was analyzed in both types of cells. (125)I-LDL-protein degradation
was reduced by 95% in LDLr KO hepatocytes compared to normal hepatocytes.
Comparing the association of (125)I-LDL and (3)H-CE-LDL revealed a CE-selective
uptake of 35.6- and 22-fold for normal and LDLr KO mouse hepatocytes,
respectively. Adding a 200-fold excess of HDL3 in the assay reduced by 71% the CE
selective uptake in LDLr KO hepatocytes and by 96% in normal hepatocytes. This
indicates that mouse hepatocytes are able to selectively take up CE from LDL by
the LBS. The comparison of LDL-CE association also showed that the LBS pathway
provides 5-fold more LDL-CE to the cell than the LDLr. Overall, our results
indicate that in mouse hepatocytes, LDLr is almost completely responsible for LDL
protein degradation while the LBS is responsible for the major part of LDL-CE
entry by a CE-selective uptake pathway.
PMID- 10760480
TI - Endogenously produced glycosaminoglycans affecting the release of lipoprotein
lipase from macrophages and the interaction with lipoproteins.
AB - Macrophages are intimately involved in the pathogenesis of atherosclerotic
diseases. A key feature of this process is their uptake of various lipoproteins
and subsequent transformation to foam cells. Since lipoprotein lipase (LPL) is
believed to play a role in foam cell formation, we investigated if endogenously
produced proteoglycans (PGs) affect the release of this enzyme from macrophages.
The human leukaemic cell line THP-1 which differentiates into macrophages by
treatment with phorbol ester (phorbol 12-myristate 13-acetate) served as a model.
The differentiation of THP-1 macrophages promoted the release of PGs into the
cell medium which caused the detachment of LPL activity from the cell surface,
and prevented LPL re-uptake and inactivation. These PGs were mainly composed of
chondroitin sulfate type and exerted a heparin-like effect on LPL release. LPL is
known to increase the cell association of lipoproteins by the well known bridging
function. Exogenous bovine LPL at a concentration of 1 microg/ml enhanced low
density lipoprotein (LDL)-binding 10-fold. Endogenously produced PGs reduced LPL
mediated binding of LDL. It is proposed that the differentiation-dependent
increase in the release of PGs interferes with binding of LPL and reduces
lipoprotein-binding to macrophages.
PMID- 10760482
TI - Chronic tooth pulp inflammation causes transient and persistent expression of Fos
in dynorphin-rich regions of rat brainstem.
AB - We have analyzed central Fos immunoreactivity (Fos-IR) brainstems of adult rats
after three clinically relevant dental injuries: filled dentin (DF) cavities that
cause mild pulp injury and heal within 1-2 weeks; open pulp exposures (PX) that
cause gradual pulp loss and subsequent periodontal lesions; and filled pulp
exposures (PXF). By 1 week after DF cavities, no Fos-IR remained except for sites
such as lateral-ventral periolivary nucleus (LVPO) that had Fos-IR in all rats
including controls. PX injury induced (1) a delayed transient expression of Fos
at 1-2 weeks at three loci (ipsilateral neurons in dorsomedial nucleus oralis,
paratrigeminal nucleus, and trigeminal tract), (2) persistent ipsilateral Fos for
at least 4 weeks after injury in dynorphin (Dyn)-rich regions (rostral lateral
solitary nucleus, periobex dorsal nucleus caudalis), and (3) late Fos-IR at 2-4
weeks (bilateral superficial cervical dorsal horn, contralateral dorsal nucleus
caudalis, contralateral rostral lateral solitary nucleus). Rats with PXF injury
were examined at 2 weeks, and they had greater numbers and more extensive rostro
caudal distribution of Fos neurons than the PX group. One week after PX injury,
Fos-IR neurons were found in regions with strong Dyn-IR central fibers. Co
expression of Dyn and Fos was found in some unusually large neurons of the
ipsilateral rostral lateral solitary nucleus, trigeminal tract, and dorsal
nucleus caudalis. Immunocytochemistry for the p75 low affinity neurotrophin
receptor (p75NTR) or for calcitonin gene-related peptide (CGRP) showed no
consistent change in trigeminal central endings in any Fos-reactive brainstem
areas, despite the extensive structural and cytochemical reorganization of the
peripheral endings of the dental neurons. The Fos responses of central neurons to
tooth injury have some unusual temporal and spatial patterns in adult rats
compared to other trigeminal injury models.
PMID- 10760483
TI - Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from
the spinal cord is mediated by nitric oxide but not by cyclic GMP.
AB - Recent data support a role for nitric oxide (NO) in pain processing at the level
of the spinal cord, possibly via regulation of neuropeptide release. The goal of
this study was to determine whether capsaicin, which selectively activates
primary afferent neurons and evokes neuropeptide release, acts in an NO-dependent
manner. Our results indicate that capsaicin (1 microM)-evoked release of
immunoreactive calcitonin gene-related peptide (iCGRP) is significantly reduced
in the presence of the NO synthase inhibitor, L-NAME (10-400 nM; F(3,45)=68.38;
P<0.001) and, the selective nNOS inhibitor, 3-bromo-7-nitroindazole (170-680 nM;
F(5,48)=56.2; P<0. 01). D-NAME (200 nM) had no effect on capsaicin-evoked iCGRP
release. Hemoglobin (an extracellular scavenger of NO; 3 mg/ml) significantly
reduced the effect of capsaicin on the release of iCGRP (F(1,8)=9.12; P<0.05).
The NOS substrate, L-arginine, effectively reversed the inhibitory effect of 3
bromo-7-nitroindazole on capsaicin-evoked iCGRP release. To determine whether the
NO-mediated release was NMDA-driven, we superfused spinal cord slices with
competitive and non-competitive NMDA antagonists in the presence and absence of
capsaicin. MK-801 (0. 1-10 microM; F(4,33)=8.49; P<0.0001) and AP-5 (0.01-10
microM; F(4, 38)=3.34; P<0.05) reduced capsaicin-evoked iCGRP release. CNQX, an
AMPA/kainate antagonist (10 nM-10 microM), significantly decreased capsaicin
evoked release of iCGRP (F(6,42)=8.76; P<0.01) in a dose-dependent fashion.
Additionally, our results demonstrate that while capsaicin-evoked release is
significantly reduced in the presence of LY-83583 (10 microM; F(2,18)=3.46;
P<0.01; a cyclic GMP lowering agent), there is no effect of ODQ (a potent and
selective inhibitor of guanylate cyclase). Moreover, the application of a cell
permeable analog of cyclic GMP (8-bromo-cGMP; 0.01-1000 microM) is without effect
on both basal and evoked iCGRP release. Finally, we observed no colocalization of
immunoreactive neuronal NOS (nNOS) with CGRP in the dorsal horn. In summary,
these data indicate that capsaicin evokes the release of iCGRP, in part, via the
production of NO which enters the extracellular space prior to having an effect.
Moreover, iCGRP and nNOS are produced in distinct populations of neurons within
the dorsal horn. We conclude that capsaicin-evoked release involves the
activation of the NMDA receptor but is also modified by the activation of AMPA or
kainate receptors. Finally, these data suggest that while capsaicin-evoked iCGRP
release is modified by NO, this release does not require the activation of
guanylate cyclase and subsequent production of cyclic GMP.
PMID- 10760484
TI - Examining the effects of lipopolysaccharide and cholecystokinin on water
ingestion: comparing intake and palatability.
AB - Lipopolysaccharide (LPS) and cholecystokinin (CCK) have been shown to have
anorectic properties in a variety of species. The present study examined the
effects of LPS and CCK, both alone and in combination, on two different aspects
of water ingestion, water intake and palatability. On test days, animals were
first injected intraperitoneally (i.p.) with either LPS (200 microg/kg) or NaCl
vehicle, and 2 h later received a second injection of either CCK (8 microg/kg) or
NaCl vehicle. In Experiment 1, water intake was monitored for 1 h on 3 separate
test days 72 h apart; while in Experiment 2, water palatability was assessed
using the taste reactivity test (TRT), on two separate test days 72 h apart. Both
LPS and CCK significantly (p<0.05) reduced water intake, with the effects of
combined LPS with CCK being more pronounced than either agent injected alone.
Rats developed a rapid tolerance to the effects of LPS on water intake on
subsequent exposures to LPS. Results from the TRT indicated that LPS enhanced
water palatability (p<0.05), as evidenced by a high level of ingestive
responding, whereas CCK produced a pattern of responding indicative of satiety.
LPS plus CCK reduced ingestive responding on the first test day, but these
responses were significantly increased on the second test day (p<0.05). These
results demonstrate that although LPS reduces water intake, it enhances water
palatability. The results further underscore the necessity for examining
palatability changes in addition to intake measures when studying the regulation
of feeding and drinking.
PMID- 10760485
TI - Temporal EEG dynamics of non-REM sleep episodes in humans.
AB - The process of the human non-rapid eye movement (non-REM) sleep period has not
been clarified. Time-based analysis on sleep EEG may provide an explanation. We
focused on chronological aspects of initiation and termination of non-REM
episodes, using spectral analysis of sleep EEG. The subjects were healthy male
volunteers (n14 Hz) and longer in lower frequency ranges (<14 Hz). There were
significant differences in the rise and decay latencies between low and high
sigma ranges, indicating that the whole frequency ranges were clearly separated
at the middle of the sigma range (14 Hz). The rise and decay latencies were
significantly different in lower frequency ranges. The clock time of the night
significantly affected only the rise latencies of the delta (0.78-3.9 Hz), alpha
(8.2-11.7 Hz) and low sigma (12.1-13.7 Hz) ranges. In conclusion, initiation and
termination of non-REM sleep was represented by higher frequency ranges, whereas
further evolution and devolution of non-REM sleep was represented by lower
frequency ranges, and only the evolution process was affected by the clock time
of the night.
PMID- 10760486
TI - Baroreceptive and somatosensory convergent thalamic neurons project to the
posterior insular cortex in the rat.
AB - Connectivity between the rat posterior insula and the ventrobasal thalamus has
been demonstrated anatomically. Neurons convergent for baroreceptor and
nociceptive input have also been identified in the homologous anterior insula of
the primate. Whether similar convergent cells exist in the ventrobasal thalamus
was investigated in 30 urethane anesthetized male Sprague--Dawley rats. Six
classes of cells were identified in the right ventrobasal thalamus: (a) 83/159
(52%) baroreceptive and nociceptive convergent units; (b) 2/159 (1%) convergent
cells responding to baroreceptor activation and light touch; (c) 44/159 (28%)
purely nociceptive units; (d)10/159 (6%) purely baroreceptive units; (e) 1/159
(0.6%) cells responding to brush alone and (f) 19/159 (12%) unresponsive units.
Of the viscerosomatic convergent cells, 66/85 (78%) were situated in the
ventroposterolateral nucleus (VPL), 6/85 (7%) in the ventroposterolateral
parvicellular nucleus (VPLpc), and 13/85 (15%) in the ventroposteromedial nucleus
(VPM). Fifteen right ventrobasal thalamic units were antidromically activated and
34 units orthodromically activated by right posterior insular microstimulation.
Cobalt injection into the right ventrobasal thalamus blocked the right insular
response to baroreceptor activation by >70%. These data indicate: (a)
baroreceptive and somatosensory nociceptive convergent units exist in the
ventrobasal thalamus; (b) thalamic convergent neurons project directly to the
ipsilateral posterior insula and receive reciprocal insulothalamic projections;
and (c) a significant proportion of baroreceptor input relays to the posterior
insula through the ipsilateral ventrobasal thalamus.
PMID- 10760488
TI - Spatio-temporal analyses of stimulus-evoked and spontaneous stochastic neural
activity observed by optical imaging in guinea pig auditory cortex.
AB - Stimulus-evoked response in the cortex involves random neural activity besides
the deterministic responses reproducible to the stimulus. Recently, we have
developed a new bright optical system that enables us to investigate the spatio
temporal patterns of such stochastic activity in the guinea pig auditory cortex
without averaging. We show that (1) the stochastic neural activity is evoked by a
tone-stimulus in addition to the deterministic response, and spontaneous
stochastic activity is also observed in a similar manner; (2) our statistical
estimation of optical responses such as variance showed that the evoked
stochastic activity was increased by the sound stimulus compared to the
spontaneous activity; (3) both types of stochastic activity mainly display
oscillatory behavior, in the frequency range of 5-11 Hz; (4) there are no
significant differences between the stimulus-induced and spontaneous stochastic
neural activity in our statistical analyses using the PSD (power-spectrum
density) and the spatial correlation function; (5) the spatial area of the evoked
stochastic activity is not strongly correlated with the tonotopical area of the
deterministic response that is mainly localized in the caudal area of field A of
the guinea pig auditory cortex. Thus, the stochastic neural activity existing in
the stimulus response and the spontaneous activity in the auditory cortex are
possibly generated by a common neural mechanism. These results were confirmed
statistically using 27 animals.
PMID- 10760487
TI - Gap junctions in the chicken pineal gland.
AB - The chicken pineal gland, which contains a heterogeneous cell population,
sustains a circadian rhythm of activity. Synchronization of cellular activity of
heterogeneous cells might be facilitated by gap junctional intercellular channels
which are permeable to ions and second messengers. To test this possibility, we
looked for morphologically identifiable gap junctions between the different
pineal cells, used antibodies and cDNA probes to screen for the presence of
connexins, and tested for functional intercellular coupling. By transmission
electron microscopy and immunocytochemistry, gap junctions and connexins were
observed between pinealocyte cell bodies, stromal cells, astrocytes, and
astrocyte and pinealocyte processes. Two gap junctional proteins, connexin43 and
connexin45, were detected by immunocytochemistry, immunoblotting and RNA blot
analysis. Functional intercellular coupling was observed in the gland by transfer
of low molecular weight dyes. Dye transferred between homologous and heterologous
cells. These data suggest that homologous and heterologous gap junctions may
provide a mechanism for coordination of the cellular responses of the elements of
the biological clock which are induced by lighting cues to produce the circadian
rhythm of pineal activity.
PMID- 10760489
TI - Brain lactate uptake increases at the site of impact after traumatic brain
injury.
AB - Although glucose is the main carbohydrate energy substrate for the normal brain,
several studies published over the last 10 years now challenge this assumption.
The activated brain increases its metabolism to meet increased energy demands by
glycolysis after injury. In vitro studies now show that lactate alone can serve
as an energy source to maintain synaptic function. In this study, we used 14C
lactate to test the hypothesis that blood lactate is acutely taken up by the
injured brain, after fluid percussion injury (FPI) in the rat. 50 microCi
radioactive lactate was injected i.v. immediately after FPI, in injured and sham
rats. After 30 min, the brain was removed, frozen, and cut into 20 microm
sections for autoradiography. Uptake of 14C-label was mainly concentrated at the
injury site (2.5 times greater) although uninjured brain also took up the 14C
label. This increased concentration of radioactive lactate at the injury site
suggests that the injured brain may use the lactate as an energy source.
PMID- 10760490
TI - Corticosterone delivery to the amygdala increases corticotropin-releasing factor
mRNA in the central amygdaloid nucleus and anxiety-like behavior.
AB - The present study examined the effects of stereotaxic delivery of corticosterone
to the amygdala on anxiety-like behavior and corticotropin-releasing factor (CRF)
mRNA level in the central nucleus of the amygdala (CeA). Micropellets (30 microg)
of crystalline corticosterone or cholesterol (control) were implanted bilaterally
at the dorsal margin of the CeA in Wistar rats. Seven days post-implantation,
anxiety-like behavior was accessed using an elevated plus-maze. CRF mRNA level in
the CeA was determined by in situ hybridization 4 h after being tested on the
elevated plus-maze. Corticosterone implants increased indices of anxiety on the
elevated plus-maze and produced a concomitant increase in both basal level of CRF
mRNA per neuron and the number of neurons with CRF hybridization signal in the
CeA. The plus-maze increased CRF mRNA levels in the CeA of cholesterol implanted
rats to the elevated basal levels observed in corticosterone treated animals.
Exposure to the plus-maze did not increase CRF mRNA level in the CeA of
corticosterone implanted rats beyond elevated basal levels. Taken together, these
findings support the involvement of the amygdala in anxiety-like behaviors in
response to chronically elevated corticosterone and suggests that elevated
glucocorticoids may increase anxiety by inducing CRF expression in the CeA.
PMID- 10760491
TI - Delta opioid receptors regulate calcium-dependent, amphetamine-evoked glutamate
levels in the rat striatum: an in vivo microdialysis study.
AB - Blockade of opioid receptors decreases amphetamine-induced behaviors and dopamine
release in the striatum. Use of selective opioid receptor ligands has indicated
that these effects are mediated by delta opioid receptors (DORs). However, the
site of action of delta receptors and the influence of delta receptor antagonists
on other neurotransmitters released by amphetamine are unknown. Therefore, the
effect of reverse microdialysis of the selective delta opioid antagonist,
naltrindole, on extracellular striatal glutamate levels evoked by amphetamine
(2.5 mg/kg, i.p.) was investigated. Naltrindole (10-100 microM) decreased
amphetamine-evoked glutamate levels in a concentration-dependent manner. The
selective delta agonist, [D-Pen(2,5)]-enkephalin (100, 500 microM), reversed the
effect of naltrindole, confirming that delta receptors mediated this effect. The
amphetamine-evoked increase in extracellular glutamate levels was determined to
be 39% calcium-sensitive by lowering the calcium concentration in the perfusate.
Under these conditions, naltrindole had no effect on the calcium-independent
component of amphetamine-evoked glutamate levels. These data indicate that
intrastriatal DORs modulate a calcium-dependent, amphetamine-evoked component of
extracellular glutamate levels that may depend on activation of a transsynaptic
basal ganglia-thalamo-cortical loop.
PMID- 10760492
TI - In vitro and in vivo m2 muscarinic subtype selectivity of some
dibenzodiazepinones and pyridobenzodiazepinones.
AB - Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1,
subtype receptors in cortical and hippocampal regions of the human brain.
Emission tomographic study of the loss of m2 receptors in AD has been limited by
the absence of available m2-selective radioligands, which can penetrate the blood
brain barrier. We now report on the in vitro and in vivo m2 muscarinic subtype
selectivity of a series of dibenzodiazepinones and pyridobenzodiazepinones
determined by competition studies against (R)-3-quinuclidinyl (S)-4-iodobenzilate
((R,S)-[125I]IQNB) or [3H]QNB. Of the compounds examined, three of the 5-[[4-[(4
dialkylamino)butyl]-1-piperidinyl]acetyl]-10, 11-dihydro-5-H
dibenzo[b,e][1,4]diazepin-11-ones (including DIBA) and three of the 11-[[4-[4
(dialkylamino)butyl]-1-phenyl]acetyl]-5, 11-dihydro-6H-pyrido [2,3
b][1,4]benzodiazepin-6-ones (including PBID) exhibited both high binding affinity
for the m2 subtype (/=10). In vivo rat
brain dissection studies of the competition of PBID or DIBD against
(R,S)[125I]IQNB or [3H]QNB exhibited a dose-dependent preferential decrease in
the binding of the radiotracer in brain regions that are enriched in the m2
muscarinic subtype. In vivo rat brain autoradiographic studies of the competition
of PBID, BIBN 99, or DIBD against (R,S)[125I]IQNB exhibited an insignificant
effect of BIBN 99 and confirmed the effect of PBID and DIBD in decreasing the
binding of (R,S)[125I]IQNB in brain regions that are enriched in the m2
muscarinic subtype. We conclude that PBID and DIBD are potentially useful parent
compounds from which in vivo m2 selective derivatives may be prepared for
potential use in positron emission tomographic (PET) study of the loss of m2
receptors in AD.
PMID- 10760493
TI - Characteristics of induced spreading depression after transient focal ischemia in
the rat.
AB - We examined characteristics of spreading depression (SD) induced on the rat
cortex 1 day after transient focal ischemia. Male Wistar rats (n=21) were
subjected to transient intraluminal thread occlusion of the right middle cerebral
artery for 75 min. Twenty-four hours after the reperfusion, cerebral blood flow
(CBF) was determined using laser Doppler flowmeter during multiple SDs elicited
on both non-stroke (left) and stroke (right) cortex by the topical application of
2 M KCl. We also examined CBF responses before and after the intravenous
administration of the nonspecific NOS inhibitor Nomega-nitro-L-arginine methyl
ester (L-NAME, 10 mg/kg) in normal and stroke cortex. Animals were divided into
two groups; Group 1 (n=12), animals with subcortical infarction and Group 2
(n=9), animals with subcortical plus cortical infarction. There were no
differences between non-stroke and stroke sides in the duration or amplitude of
the DC potential shifts in either group. The transient CBF hyperemia during SD
was not different between non-stroke (372+/-23% of baseline, mean+/-S.E.) and
stroke sides (383+/-30%) in Group 1. However, in Group 2, CBF was significantly
restricted on the stroke side (192+/-15% vs. non-stroke side, 374+/-33%). In four
normal animals without ischemia, there were no differences in CBF response
between both sides. L-NAME had no effect on the transient CBF hyperemia during SD
in any of the groups. These data suggest that the CBF responses during SD in the
peri-infarction area is restricted 1 day after the transient focal ischemia,
while CBF responses are intact in normal cortex overlapping a subcortical
infarct. Further, our results indicate that nitric oxide does not promote CBF
responses during SD in normal cortex or in tissue surrounding infarction.
PMID- 10760494
TI - Positive and negative modulation of the GABA(A) receptor and outcome after
traumatic brain injury in rats.
AB - Glutamate-mediated excitotoxicity has been shown to contribute to cellular
dysfunction following traumatic brain injury (TBI). Increasing inhibitory
function through stimulation of gamma-aminobutyric acid (GABA(A)) receptors may
attenuate excitotoxic effects and improve outcome. The present experiment
examined the effects of diazepam, a positive modulator at the GABA(A) receptor,
on survival and cognitive performance in traumatically brain-injured animals. In
experiment 1, 15 min prior to central fluid percussion brain injury, rats (n=8
per group) were injected (i.p.) with saline or diazepam (5 mg/kg or 10 mg/kg).
Additional rats (n=8) were surgically prepared but not injured (sham-injury).
Rats pre-treated with the 5 mg/kg dose of diazepam had significantly lower
mortality (0%) than injured, saline-treated rats (53%). Also, diazepam-treated (5
mg/kg) rats had significantly shorter latencies to reach the goal platform in the
Morris water maze test performed 11-15 days post-injury. In experiment 2, at 15
min post-injury, rats were given either saline (n=5) or 5 mg/kg diazepam (n=6).
Rats treated with diazepam did not differ in mortality from injured rats treated
with vehicle. However, rats treated with diazepam at 15 min post-injury had
significantly shorter latencies to reach the goal platform in the Morris water
maze than injured, vehicle-treated rats. In experiment 3, the post-injury
administration of bicuculline (1.5 mg/kg, n=8), a GABA(A) antagonist, increased
Morris water maze goal latencies compared to injured animals treated with saline
(n=8). These results suggest that enhancing inhibitory function during the acute
post-injury period produces beneficial effects on both survival and outcome
following experimental TBI.
PMID- 10760495
TI - Fos expression in the rat brain after exposure to gravito-inertial force changes.
AB - The immediate-early genes constitute useful neurobiological tools for mapping
brain functional activity after sensory stimulation. We immunohistochemically
investigated Fos protein expression in the brain of rats exposed to gravito
inertial force changes. Experiments were performed in hypergravity rats born and
housed for 60 days in terrestrian gravity (1xg) and thereafter exposed for 90 min
to 2xg or 4xg in a centrifuge, and in hypogravity rats born and housed for 60
days at 2xg and submitted for 90 min to 1xg. Data from these two experimental
groups were quantified by light microscopy and compared to those from two groups
of control rats born and permanently housed in either 1xg or 2xg environments
that never had to adapt to novel gravito-inertial environments. Results showed a
low basal Fos expression in the controls and a strong Fos staining in the
experimental rats. Only the hypergravity rats displayed Fos-positive cells in
vestibular-related brainstem regions (medial, inferior, and superior vestibular
nuclei (VN); group y; dorsomedial cell column (DMCC) of the inferior olive (IO)).
By contrast, many suprabulbar areas were strongly labeled in both the hyper- and
hypogravity rats, as shown by the numerous Fos-positive cells in mesencephalic
(colliculus, laterodorsal periaqueductal gray, autonomic nuclei), diencephalic
(hypothalamic and thalamic nuclei), and telencephalic (parietal, temporal,
entorhinal and visual cortices) structures. These spatial patterns of Fos
expression suggest that an increase in gravito-inertial force activates otolith
vestibulo-olivar pathways and various suprabulbar structures underlying the
corticovestibular interactions, which govern the multiple representations of
vestibular information in the cortex. A decrease in gravito-inertial force has
the opposite effects on the vestibulo-olivar structures as a result of otolith
system disfacilitation which, in turn, modifies the activity of complex neural
pathways. Exposure to both hyper- and hypogravity environments likely induces
neurovegetative and/or stress effects that could account for Fos labeling in
autonomic nuclei and in nervous structures involved in the hypothalamo-pituitary
adrenal axis.
PMID- 10760496
TI - Differential regulation of ciliary neurotrophic factor and its receptor in the
rat hippocampus following transient global ischemia.
AB - To investigate a potential role of ciliary neurotrophic factor (CNTF) in
transient global ischemia, we have studied the postischemic regulatory changes in
the expression of CNTF and its receptor, the ligand-binding alpha-subunit
(CNTFRalpha). Immunoblot analysis demonstrated CNTF levels were slightly
upregulated already during the first day after ischemia and then increased
markedly by more than 10-fold until 2 weeks postischemia. Immunoreactivity for
CNTF became detectable 1 day after ischemia and was localized in reactive
astrocytes. The intensity of the immunolabeling was maximal in CA1 during the
phase of neuronal cell death (days 3-7 postischemia) and in the deafferented
inner molecular layer of the dentate gyrus. Upregulation of CNTF expression was
less pronounced in CA3 and absent in the stratum lacunosum moleculare and the
outer molecular layer of the dentate gyrus and thus did not simply correlate with
astroliosis as represented by upregulation of glial fibrillary acidic protein
(GFAP). As shown by in situ hybridization, expression of CNTFRalpha mRNA was
restricted to neurons of the pyramidal cell and granule cell layers in control
animals. Following ischemia, reactive astrocytes, identified by double labeling
with antibodies to GFAP, transiently expressed CNTFRalpha mRNA with a maximum
around postischemic day 3. This astrocytic response was most pronounced in CA1
and in the hilar part of CA3. These results show that CNTF and its receptor are
differentially regulated in activated astrocytes of the postischemic hippocampus,
indicating that they are involved in the regulation of astrocytic responses and
the neuronal reorganizations occurring after an ischemic insult.
PMID- 10760497
TI - Evidence for the direct role of acetylcholinesterase in neurite outgrowth in
primary dorsal root ganglion neurons.
AB - Dorsal root ganglion (DRG) neurons show a transient peak expression of
acetylcholinesterase (AChE) during periods of axonal outgrowth prior to
synaptogenesis, suggesting that AChE has a non-enzymatic role during development.
We have previously shown that perturbation of cell surface AChE in cultured
embryonic rat DRG neurons results in decreased neurite outgrowth and neurite
detachment. In this report, we demonstrate a direct correlation between
endogenous AChE content and neurite outgrowth in primary DRG neurons. Adenoviral
vectors were constructed using full-length rat AChE(T) cDNA in either the sense
or antisense orientations to overexpress or knock down AChE expression,
respectively. Treatment with the sense-expressing vector produced a 2.5-fold
increase in AChE expression and a 2-fold increase in neurite length compared with
either untreated or null virus-treated control cells. Conversely, treatment with
the antisense-expressing vector reduced AChE expression by 40% and resulted in a
reduction in neurite length of similar magnitude. We also observed that
overexpression of AChE resulted in greater branching at the distal tips of each
primary neurite as well as an increase in cell body size. These findings further
indicate that AChE expressed on the axonal surface of developing DRG neurons may
modulate their adhesive properties and thereby support axonal development.
PMID- 10760498
TI - Activation of renal afferent pathways following furosemide treatment. I. Effects
Of survival time and renal denervation.
AB - Three experiments were performed to determine whether renal afferent pathways
were activated by the diuretic drug, furosemide. It was hypothesized that
activated neurons of the renal afferent pathway would express the protein product
Fos of the c-fos immediate early gene and be identified by immunocytochemical
staining for Fos in the cell nucleus. In the first two experiments, rats were
injected with either furosemide (5 mg) or vehicle solution (sterile isotonic
saline) and sacrificed either 1.75 h (short-survival experiment) or 3.5 h (long
survival experiment) after injection. In both experiments, the furosemide-treated
rats had significantly more Fos-positive cell nuclei than vehicle-treated rats in
the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT),
supraoptic nuclei (SON), and magnocellular region of the paraventricular nuclei
(PVN) - areas previously shown to be activated by hypovolemia or peripheral
angiotensin. In the short-survival experiment, the furosemide-treated rats had
more Fos-positive cell nuclei in the nucleus of the solitary tract (NTS) and in
the dorsal horn of the spinal cord at spinal levels T(11), T(12), and T(13). In
contrast, furosemide treatment did not produce more Fos-positive cell nuclei in
the NTS and dorsal horn of the spinal cord in the long-survival experiment. These
results suggest that the activation of the SFO, OVLT, SON and PVN may be via a
different mechanism than that of NTS or spinal cord dorsal horn. Based upon our
previous work, we hypothesized that the NTS and spinal cord dorsal horn labeling
was due to activation of sympathetic afferents originating in the kidney and
labeling in forebrain structures was due to stimulation by angiotensin generated
by renal renin release. To test this hypothesis, a third experiment was devised
that was identical to the short-survival experiment, except that all rats had
bilateral renal denervation surgery 1 week previously. In this experiment,
furosemide administration increased the number of Fos-positive cells in the SFO,
OVLT, SON and PVN, but not in the caudal thoracic spinal cord or NTS. These
results together with the results of first two experiments lend support to our
hypothesis that furosemide-induced neuronal activation in the thoracic spinal
cord and NTS is due to activation of second- and/or third-order neurons of a
renal sympathetic afferent pathway. Furosemide-induced activation in the SFO,
OVLT, SON and PVN does not depend on renal innervation. It is hypothesized that
activation in these forebrain regions depends on the action of angiotensin II
that is generated after furosemide treatment. Our results indicate that both a
hormonal pathway and a renal sympathetic afferent pathway conduct information
from the kidney to the central nervous system (CNS) after furosemide treatment.
PMID- 10760499
TI - Activation of renal afferent pathways following furosemide treatment. II. Effect
Of angiotensin blockade.
AB - The goal here and in the accompanying paper was to evaluate the two pathways used
by the kidney to provide information to the central nervous system (CNS); e.g.,
the indirect, hormonal route via activation of the renin-angiotensin system and
the direct pathway via activation of sympathetic afferents in the caudal thoracic
spinal cord. Here, three experiments were designed to evaluate the actions of
angiotensin elicited by subcutaneous injection of furosemide on neural activation
of the CNS. The number of neurons immunocytochemically staining for the protein
product (Fos) of the c-fos gene was used as an index of neuronal activation. In
the first experiment, furosemide injection was preceded by treatment with a dose
of Captopril, CAP, (an angiotensin-converting enzyme (ACE) inhibitor) that blocks
the peripheral but not the central formation of angiotensin II. In the second
experiment, furosemide injection was preceded by treatment with a higher dose of
CAP; this dosage blocks the peripheral and central formation of angiotensin II.
In the third experiment, furosemide injection was preceded by treatment with
Losartan, a competitive receptor antagonist of type I angiotensin II receptors at
a dose that would block central and peripheral angiotensin receptors. Control
animals in each experiment received injections of vehicle (sterile isotonic
saline) instead of furosemide. In each experiment, rats were sacrificed 1.75 h
following furosemide or saline injection by transcardial perfusion and tissues
were immunocytochemically processed for demonstration of Fos antigen. Rats
receiving furosemide plus the low CAP dose showed more Fos-positive cells than
control rats in the subfornical organ (SFO), organum vasculosum lamina terminalis
(OVLT), supraoptic nucleus (SON), magnocellular region of the paraventricular
nucleus, nucleus of the solitary tract (NTS), and caudal thoracic/rostral lumbar
spinal cord dorsal horn. Rats receiving furosemide plus Losartan or furosemide
plus the higher CAP dose did not show increased Fos immunoreactivity in any of
the abovementioned structures relative to their respective control animals. We
conclude that the receptor-mediated action of angiotensin II is in some way
involved in the activation of the pathway that occurs in the SFO, OVLT, SON, and
magnocellular region of the paraventricular nucleus (PVN) in response to
furosemide treatment. It is possible that the furosemide-induced activation in
the SON and PVN is not due to direct actions of angiotensin II on angiotensin
receptors in those structures, but instead occurs synaptically as a result of
inputs from the SFO and OVLT, which have themselves been activated directly by
angiotensin II. In the accompanying paper, furosemide-induced activation in the
NTS and caudal thoracic spinal cord is abolished by prior bilateral renal
denervation, meaning that these neurons are likely part of a renal afferent
pathway. Here, these structures did not elaborate Fos in animals injected with
furosemide plus the high CAP dose or furosemide plus Losartan. Thus, the present
results also suggest that the central blockade of the formation of angiotensin II
or blockade of the actions of angiotensin II prevents in some way the activation
of the renal afferent pathway mediated by the renal nerves (the direct pathway)
in response to the actions of furosemide. Therefore, these results suggest that
central angiotensin II is somehow involved in "priming" or increasing the
sensitivity of the direct renal afferent pathway. Taken together with the
accompanying paper, our results indicate that interruption of the direct pathway
via renal denervation did not interfere with the elaboration of Fos in the lamina
terminalis; in contrast, modification of the humoral renal afferent pathway can
affect the sensitivity of the direct pathway. These results may have important
implications for pathophysiological changes associated with fluid balance
disorders including renal hypertension.
PMID- 10760500
TI - Role of spinal muscarinic and nicotinic receptors in clonidine-induced nitric
oxide release in a rat model of neuropathic pain.
AB - Intrathecal administration of alpha(2) adrenergic agonists, such as clonidine, is
capable of alleviating neuropathic pain. Recent studies suggest that spinal
nitric oxide (NO) mediates the analgesic effect of intrathecal clonidine.
Furthermore, compared to nicotinic receptors, spinal muscarinic receptors play a
greater role in the analgesic effect of intrathecal clonidine. In the present
study, we tested a hypothesis that clonidine-evoked NO release is dependent
primarily on muscarinic receptors in the spinal cord after nerve injury. A rat
model of neuropathic pain was induced by ligation of the left L(5)/L(6) spinal
nerves. Using an in vitro spinal cord perfusion preparation, the effect of
muscarinic and nicotinic receptor antagonists on clonidine-evoked nitrite (a
stable product of NO) release was determined. Both muscarinic and nicotinic
antagonists dose-dependently attenuated clonidine-elicited nitrite release. In
spinal cords from the neuropathic rats, the inhibitory effect of muscarinic
receptor antagonists (atropine and scopolamine) on clonidine-elicited nitrite
release was more potent than that of nicotinic receptor antagonists (mecamylamine
and hexamethonium). However, in spinal cords obtained from sham animals, the
inhibitory effect of muscarinic and nicotinic antagonists did not differ
significantly. These results indicate that muscarinic, as well as nicotinic,
receptors mediate clonidine-induced NO release in the spinal cord. These data
also suggest that after nerve injury, the cascade of activation of alpha(2)
adrenergic receptors-muscarinic receptors-NO in the spinal cord likely plays a
predominant role in the analgesic effect of intrathecal clonidine on neuropathic
pain.
PMID- 10760501
TI - The SCG10-related gene family in the developing rat retina: persistent expression
of SCLIP and stathmin in mature ganglion cell layer.
AB - Neuronal growth-associated proteins (GAPs), such as GAP-43 and SCG10, are thought
to play crucial roles in both axonal and dendritic outgrowth during neural
development and regeneration, although the underlying mechanisms remain largely
unknown. The recent finding that SCG10 is a microtubule regulator and also the
identification of RB3 and SCLIP as two new SCG10-related members prompted us to
investigate the roles of SCG10-related family in neural development, using the
retina as a model system. We determined the temporal expression and the spatial
distribution of SCG10-related mRNAs in the developing rat retina.
Semiquantitative analysis by RT-PCR revealed that in prenatal retina, levels of
SCG10 and stathmin mRNAs were higher than those of RB3 and SCLIP. In the
postnatal retina, the level of SCLIP increased, whereas the level of RB3 remained
low. In situ hybridization revealed that GAP-43 and all of the SCG10-related
family mRNAs were present in the retinal ganglion cells (RGCs) at all stages of
retinal development, and that stathmin mRNA was present in mitotic neuroblastic
cells. Differential expression of SCG10 and other members of the family became
more evident as retinal development proceeded; SCG10 and RB3 expression were
relatively specific in the RGCs and amacrine cells, whereas SCLIP was also
evident in bipolar and horizontal cells. Stathmin mRNA was highly expressed both
in the RGCs and other interneurons. These results indicate that multiple SCG10
related proteins are expressed in single neurons including RGCs, and suggest that
these nGAPs play similar but distinct roles in differentiation and functional
maintenance of retinal neurons.
PMID- 10760502
TI - In vitro glucuronidation of kaempferol and quercetin by human UGT-1A9 microsomes.
AB - Flavonoids are important polyphenolic substances with widespread occurrence in
plants and therefore in the human diet. Although considerable work has been done
on the pharmacology of flavonoids, the understanding of their metabolism is still
incomplete. In this work, the in vitro glucuronidation of the common dietary
flavonoids quercetin and kaempferol by human UDP-glucuronosyltransferase
microsomes (UGT-1A9) was investigated using HPLC and LC-MS. The two flavonoids
were extensively metabolised by this enzyme with four monoglucuronides of
quercetin and two of kaempferol being detected after incubation. The presence of
a quercetin monoglucuronide in the urine of a volunteer after consumption of
Ginkgo biloba tablets was demonstrated.
PMID- 10760503
TI - Fine architecture of bacterial inclusion bodies.
AB - The molecular organisation of protein aggregates, formed under physiological
conditions, has been explored by in vitro trypsin treatment and electron
microscopy analysis of bacterially produced inclusion bodies (IBs). The kinetic
modelling of protein digestion has revealed variable proteolysis rates during
protease exposure that are not compatible with a surface-restricted erosion of
body particles but with a hyper-surfaced disintegration by selective enzymatic
attack. In addition, differently resistant species of the IB proteins coexist
within the particles, with half-lives that differ among them up to 50-fold.
During in vivo protein incorporation throughout IB growth, a progressive increase
of proteolytic resistance in all these species is observed, indicative of folding
transitions and dynamic reorganisations of the body structure. Both the
heterogeneity of the folding state and the time-dependent folding transitions
undergone by the aggregated polypeptides indicate that IBs are not mere deposits
of collapsed, inert molecules but plastic reservoirs of misfolded proteins that
would allow, at least up to a certain extent, their in vivo recovery and
transference to the soluble cell fraction.
PMID- 10760504
TI - Activation of rabbit blood platelets by anandamide through its cleavage into
arachidonic acid.
AB - Anandamide (ANA), a cannabinoid receptor ligand, stimulated platelet aggregation
at concentrations similar to those of arachidonic acid (AA). The aggregating
effect of ANA was inhibited by aspirin but not by SR-141716, a cannabinoid
receptor antagonist. In addition, HU-210, a cannabinoid receptor agonist, failed
to induce platelet activation. Radiolabelling experiments showed that exogenous
ANA was cleaved by platelets into AA through a phenylmethylsulfonyl fluoride
(PMSF)-sensitive pathway. In agreement, PMSF was shown to abolish the aggregating
effect of ANA. In conclusion, ANA is able to induce platelet activation via its
cleavage by a PMSF-sensitive amidase activity, leading to the release of AA which
in turn activates platelets.
PMID- 10760505
TI - An ARID family protein binds to the African swine fever virus encoded ubiquitin
conjugating enzyme, UBCv1.
AB - The NH(2)-terminal end of a protein, named SMCp, which contains an ARID (A/T rich
interaction domain) DNA binding domain and is similar to the mammalian SMCY/SMCX
proteins and retinoblastoma binding protein 2, was shown to bind the African
swine fever virus encoded ubiquitin conjugating enzyme (UBCv1) using the yeast
two hybrid system and in in vitro binding assays. Antisera raised against the
SMCp protein were used to show that the protein is present in the cell nucleus.
Immunofluorescence showed that although UBCv1 is present in the nucleus in most
cells, in some cells it is in the cytoplasm, suggesting that it shuttles between
the nucleus and cytoplasm. The interaction and co-localisation of UBCv1 with SMCp
suggest that SMCp may be a substrate in vivo for the enzyme.
PMID- 10760506
TI - Targeting of the 22 kDa integral peroxisomal membrane protein.
AB - Investigating targeting of the 22 kDa peroxisomal membrane protein (Pmp22p) to
the peroxisomal membrane we have confined the targeting signal to amino acid
residues 16-37 located in the N-terminal cytoplasmic tail. Comparison of Pmp22p
orthologous sequences revealed a conserved motif Y3xL3xP3x(KQN) which might
represent the core of this targeting signal not found so far in other Pmps.
Fusion of the Pmp22p N-terminal tail to the C-terminal portion of Pmp22p which
per se is not targeted to peroxisomes, conveys peroxisomal targeting. These data
suggest that Pmp22p is targeted to peroxisomes by a new membrane targeting signal
which is necessary and sufficient to target a polypeptide containing two
transmembrane spans to peroxisomes.
PMID- 10760507
TI - A CDE/CHR-like element mediates repression of transcription of the mouse RB2
(p130) gene.
AB - The bipartite repressor elements, termed cell cycle-dependent element (CDE)/cell
cycle regulatory element (CCRE)-cell cycle homology region (CHR) control the
growth-dependent transcription of the cyclin A, cdc25C, cdc2 genes. Here, we have
identified a functional element displaying the signature of the CDE-CHR in the
promoter of the mouse RB2 (p130) gene, encoding the retinoblastoma protein family
(pRB)-related protein p130. This element locates close to the major transcription
start site where it makes major groove contacts with proteins that can be
detected in a cellular context using in vivo genomic footprinting techniques.
Inactivation of either the CDE or CHR sequence strongly up-regulates the p130
promoter activity in exponentially growing cells, a situation where endogenous
p130 gene expression is almost undetectable. Electrophoretic mobility shift
assays suggest that two different protein complexes bind independently to the
p130 CDE and CHR elements, and that the protein(s) bound to the CDE might be
related to those bound on cyclin A and cdc2 promoters.
PMID- 10760508
TI - Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.
AB - The peroxisome proliferator-activated receptor alpha (PPARalpha) is a
transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty
acids and eicosanoids are natural PPARalpha ligands. Here, we show using
transient transfection assays that oxidized (oxLDL) but not native low-density
lipoproteins (LDL) dose-dependently activate PPARalpha in endothelial cells
without affecting PPARalpha protein expression. Fractioning of oxLDL lipids
followed by transactivation experiments demonstrated that the oxidized
phospholipid component in oxLDL is responsible for PPARalpha activation. Using
specific inhibitors, it is shown that oxLDL-mediated PPARalpha activation
requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13
HODE activate PPARalpha directly. Finally, we found that, similar to the
synthetic PPARalpha ligand Wy-14643, oxLDL induced expression of the fatty acid
transport protein-1 in human primary endothelial cells. Our findings define a
novel group of PPARalpha activators and provide a molecular basis for certain
effects of these biologically active phospholipids on gene transcription.
PMID- 10760509
TI - Regulatory role of the 3' untranslated region of luteinizing hormone receptor:
effect on mRNA stability.
AB - Posttranscriptional regulation of luteinizing hormone receptor (LHR) mRNA has a
significant role in regulating cell surface receptor expression during ovarian
cycle. In order to gain insight into the mechanism of posttranscriptional
regulation, the cis-acting elements in the 3' untranslated region (3' UTR) of LHR
mRNA were examined by transfection studies followed by measurements of the
receptor expression and receptor mRNA half-life. The results show that the
inhibitory effect exerted by the 3.51 kb 3' UTR of the LHR resides in the distal
1.98 kb region. Half-life measurement of LHR mRNA showed that the inhibitory
effect of the 3' UTR was due to a decrease in receptor mRNA stability. Deletion
studies revealed that the entire 1.98 kb region is required for LHR mRNA
destabilization. Although the 3.51 kb 3' UTR of LHR contains 11 AUUUA motifs,
their removal had no effect on mRNA stability or receptor expression. Thus,
although AUUUA motifs have been implicated in mRNA stability, these motifs do not
appear to play an inhibitory role in LHR expression. The 3' UTR of LHR was also
able to decrease the expression of a reporter gene indicating that the inhibitory
effect of 3' UTR is not unique to the open reading frame of LHR. The present
studies show that the distal 1.98 kb portion of the 3' UTR exerts an inhibitory
effect on the expression of LHR by decreasing the receptor mRNA half-life. The
inhibitory effect of 3' UTR might play a role in the maintenance of the steady
state levels of the receptor mRNA under different physiological states.
PMID- 10760510
TI - Genotype dependent and cigarette specific effects on endothelial nitric oxide
synthase gene expression and enzyme activity.
AB - We explored the interactive effects of endothelial nitric oxide synthase (eNOS)
genotypes and cigarette smoking on protein levels and enzyme activity in 33
postpartum placentas. Whilst the eNOS protein levels were lower in the rare
allele (0.48+/-0.11, n=9 vs. 1. 05+/-0.10, n=24, P<0.01), the eNOS enzyme
activity was about 7-fold higher in the rare allele (4556.2+/-255.4 vs. 621.8+/
180.5 cpm/mg/min, P<0.01). Smokers had lower eNOS protein levels (1.07+/-0. 09
vs. 0.50+/-0.19, P<0.05) in both alleles. It reduced the eNOS activities only in
the rare allele (non-smokers: 6143.8+/-251.2, n=5, smokers: 2968.5+/-259.4, n=4,
52% reduction, P<0.01). We conclude that associations between eNOS polymorphism
and protein levels and enzyme activities are modifiable by smoking, the effects
of smoking are dependent on the eNOS genotypes.
PMID- 10760511
TI - Green tea compounds inhibit tyrosine phosphorylation of PDGF beta-receptor and
transformation of A172 human glioblastoma.
AB - The effect of the green tea compounds 2-(3,4-dihydroxyphenyl)-3, 4-dihydro-2H-1
benzopyran-3,5,7-triol (catechin), epicathechin (EC), epigallocathechin-3 gallate
(EGCG), epicathechin-3 gallate (ECG) and catechin-3 gallate (CG) on the tyrosine
phosphorylation of PDGF beta-receptor (PDGF-Rbeta) and on the anchorage
independent growth of A172 glioblastoma cells in semisolid agar has been
investigated. Treatment of A172 glioblastoma with 50 microM CG, ECG, EGCG and 25
microM Tyrphostin 1296 resulted in an 82+/-17%, 77+/-21%, 75+/-8% and 55+/-11%,
respectively (mean+/-S.D., n=3) inhibition of the PDGF-BB-induced tyrosine
phosphorylation of PDGF-Rbeta. The PDGF-Rbeta downstream intracellular
transduction pathway including tyrosine phosphorylation of phospholipase C-gamma1
(PLC-gamma1) and phosphatidylinositol 3'-kinase (PI 3'-K) was also inhibited.
Spheroid formation was completely inhibited by 50 microM ECG, CG, EGCG and by 25
microM Tyrphostin 1296. We conclude that catechins of the green tea possessing
the gallate group in their chemical structure act as anticancer agents probably
partly via their ability to suppress the tyrosine kinase activity of the PDGF
Rbeta.
PMID- 10760512
TI - Ligand interaction with the purified serotonin transporter in solution and at the
air/water interface.
AB - The purified serotonin transporter (SERT) was spread at the air/water interface
and the effects both of its surface density and of the temperature on its
interfacial behavior were studied. The recorded isotherms evidenced the existence
of a stable monolayer undergoing a lengthy rearrangement. SERT/ligand
interactions appeared to be dependent on the nature of the studied molecules.
Whereas an unrelated drug (chlorcyclizine) did not bind to the spread SERT, it
interacted with its specific ligands. Compared to heterocyclic drugs, for which
binding appeared to be concentration-dependent, a 'two-site' mechanism was
evidenced for pinoline and imipramine.
PMID- 10760513
TI - Crystal structure of rat heme oxygenase-1 in complex with heme.
AB - Heme oxygenase catalyzes the oxidative cleavage of protoheme to biliverdin, the
first step of heme metabolism utilizing O(2) and NADPH. We determined the crystal
structures of rat heme oxygenase-1 (HO-1)-heme and selenomethionyl HO-1-heme
complexes. Heme is sandwiched between two helices with the delta-meso edge of the
heme being exposed to the surface. Gly143N forms a hydrogen bond to the distal
ligand of heme, OH(-). The distance between Gly143N and the ligand is shorter
than that in the human HO-1-heme complex. This difference may be related to a pH
dependent change of the distal ligand of heme. Flexibility of the distal helix
may control the stability of the coordination of the distal ligand to heme iron.
The possible role of Gly143 in the heme oxygenase reaction is discussed.
PMID- 10760514
TI - A plant defensive cystatin (soyacystatin) targets cathepsin L-like digestive
cysteine proteinases (DvCALs) in the larval midgut of western corn rootworm
(Diabrotica virgifera virgifera).
AB - Feeding bioassay results established that the soybean cysteine proteinase
inhibitor N (soyacystatin N, scN) substantially inhibits growth and development
of western corn rootworm (WCR), by attenuating digestive proteolysis [Zhao, Y. et
al. (1996) Plant Physiol. 111, 1299-1306]. Recombinant scN was more inhibitory
than the potent and broad specificity cysteine proteinase inhibitor E-64. WCR
digestive proteolytic activity was separated by mildly denaturing SDS-PAGE into
two fractions and in-gel assays confirmed that the proteinase activities of each
were largely scN-sensitive. Since binding affinity to the target proteinase
[Koiwa, H. et al. (1998) Plant J. 14, 371-380] governs the effectiveness of scN
as a proteinase inhibitor and an insecticide, five peptides (28-33 kDa) were
isolated from WCR gut extracts by scN affinity chromatographic separation.
Analysis of the N-terminal sequence of these peptides revealed similarity to a
cathepsin L-like cysteine proteinase (DvCAL1, Diabrotica virgifera virgifera
cathepsin L) encoded by a WCR cDNA. Our results indicate that cathepsin L
orthologs are pivotal digestive proteinases of WCR larvae, and are targets of
plant defensive cystatins (phytocystatins), like scN.
PMID- 10760515
TI - Chlorophyll fluorescence quenching in isolated light harvesting complexes induced
by zeaxanthin.
AB - Non-photochemical quenching of chlorophyll fluorescence in plants occurs in the
light harvesting antenna of photosystem II and is regulated by the xanthophyll
cycle. A new in vitro model for this process has been developed. Purified light
harvesting complexes above the detergent critical micelle concentration have a
stable high fluorescence yield but a rapidly inducible fluorescence quenching
occurs upon addition of zeaxanthin. Violaxanthin was without effect, lutein and
antheraxanthin induced a marginal response, whereas the violaxanthin analogue,
auroxanthin, induced strong quenching. Quenching was not caused by aggregation of
the complexes but was accompanied by a spectral broadening and red shift,
indicating a zeaxanthin-dependent alteration in the chlorophyll environment.
PMID- 10760516
TI - In vitro differentiation of human monocytes to macrophages results in depletion
of antioxidants and increase in n-3 fatty acids levels.
AB - The lipid composition and alpha-tocopherol content of human monocytes were
investigated before and after their differentiation to macrophages. The total
lipid and protein content per number of cells increased after the differentiation
of monocytes by approximately four-fold; a two-fold increase in docosahexaenoic
and docosapentaenoic acids and a two-fold decrease in linoleic acid were also
noted. As opposed to an initial monocytic vitamin E content of 4.75 pmol/10(6)
cells, macrophagic vitamin E levels were undetectable. Changes in vitamin E and
fatty acids contents in macrophages, with respect to monocytes, appear to reflect
the lipid composition of fetal calf serum, that is low in vitamin E and has a
proportionally higher docosahexaenoic acid content than adult human serum.
PMID- 10760517
TI - Human glutathione dependent prostaglandin E synthase: gene structure and
regulation.
AB - A P1 clone containing the gene for human glutathione dependent PGE synthase
(PGES) was isolated and characterized. The gene is divided into three exons,
spans 14.8 kb and was localized to chromosome 9q34. 3. In A549 cells, the protein
and activity levels of PGES were increased by interleukin-1beta. This increase
was prevented by phenobarbital. Reporter constructs containing the 5'-flanking
region of exon 1, which exhibited strong promoter activity, responded
accordingly, except that interleukin-1beta induced a transient increase followed
by a decrease. As cyclooxygenase 2 expression has been reported to respond in a
similar fashion, a transcriptional regulatory basis for the observed co
regulation with PGES is implied. The strong down-regulation by phenobarbital
raises important issues concerning its mechanisms of action.
PMID- 10760518
TI - Cytokine-mediated cPLA(2) phosphorylation is regulated by multiple MAPK family
members.
AB - Cytosolic phospholipase A(2) (cPLA(2)) plays a critical role in various
neutrophil functions including the generation of leukotrienes and platelet
activating factor release. Enzyme activity is regulated both by translocation to
the membrane in a Ca(2+)-dependent manner and serine phosphorylation by members
of the mitogen-activated protein kinase (MAPK) family. In this report, we have
investigated the role of granulocyte/macrophage colony-stimulating factor (GM
CSF)-mediated signalling pathways in the regulation of cPLA(2). GM-CSF-induced
cPLA(2) phosphorylation was not affected by pharmacological inhibition of p38
MAPK, phosphatidylinositol 3-kinase or Src. However, inhibition of extracellular
signal-regulated kinase (ERK) MAPK activation resulted in a partial inhibition of
cPLA(2) phosphorylation, revealed in a slower onset of phosphorylation. A cell
line stably transfected with the GM-CSF receptor was used to further analyze GM
CSF-mediated cPLA(2) phosphorylation. Mutation of tyrosine residues 577 and 612
resulted in a delayed cPLA(2) phosphorylation similar to the pharmacological ERK
inhibition. Furthermore, inhibition of p38 MAPK in cells bearing the double
mutant betac577/612 completely abrogated GM-CSF-induced cPLA(2) phosphorylation.
We conclude that GM-CSF can mediate cPLA(2) phosphorylation through the redundant
activation of both p38 and ERK MAP kinases.
PMID- 10760519
TI - Ultrafast excitation dynamics of low energy pigments in reconstituted peripheral
light-harvesting complexes of photosystem I.
AB - Ultrafast dynamics of a reconstituted Lhca4 subunit from the peripheral LHCI-730
antenna of photosystem I of higher plants were probed by femtosecond absorption
spectroscopy at 77 K. Intramonomeric energy transfer from chlorophyll (Chl) b to
Chl a and energy equilibration between Chl a molecules observed on the
subpicosecond time scale are largely similar to subpicosecond energy
equilibration processes within LHCII monomers. However, a 5 ps equilibration
process in Lhca4 involves unique low energy Chls in LHCI absorbing at 705 nm.
These pigments localize the excitation both in the Lhca4 subunit and in LHCI-730
heterodimers. An additional 30-50 ps equilibration process involving red pigments
of Lhca4 in the heterodimer, observed by transient absorption and picosecond
fluorescence spectroscopy, was ascribed to intersubunit energy transfer.
PMID- 10760520
TI - Failure of Bcl-2 to block cytochrome c redistribution during TRAIL-induced
apoptosis.
AB - Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a
member of the TNF family of cytokines that promotes apoptosis and NF-kappaB
activation. Here we show that recombinant hu-TRAIL initiates the activation of
multiple caspases, the loss of mitochondrial transmembrane potential, the
cleavage of BID and the redistribution of mitochondrial cytochrome c. However,
whereas Bcl-2 efficiently blocked UV radiation-induced cytochrome c release and
consequent apoptosis of CEM cells, it failed to do either in the context of TRAIL
treatment. Thus, TRAIL engages a death pathway that is at least partially routed
via the mitochondria, but in contrast with other stimuli that engage this
pathway, TRAIL-induced cytochrome c release is not regulated by Bcl-2.
PMID- 10760521
TI - Soluble P-type ATPase from an archaeon, Methanococcus jannaschii.
AB - MJ0968 has been proposed to be an ancestor of P-type ATPase, because its primary
structure is highly homologous to that of the core catalytic domain of P-type
ATPase. However it completely lacks amino acid sequences that possibly constitute
transmembrane domains. To examine if MJ0968 is indeed a P-type ATPase, it was
overexpressed in Escherichia coli and purified. It did show ATPase activity,
autophosphorylation and inhibition by vanadate. All these properties support the
idea that MJ0968 is indeed a soluble P-type ATPase.
PMID- 10760522
TI - Interaction between the critical aromatic amino acid residues Tyr(352) and
Phe(504) in the yeast Gal2 transporter.
AB - Three critical aromatic sites have been identified in the yeast galactose
transporter Gal2: Tyr(352) at the extracellular boundary of putative
transmembrane segment (TM) 7, Tyr(446) in the middle of TM10 and Phe(504) in the
middle of TM12. The relationship between these sites was investigated by random
mutagenesis of each combination of two of the three residues. Galactose transport
positive clones selected by plate assays encoded Tyr(446) and specific
combinations of aromatic residues at sites 352 and 504. Double-site mutants
containing aromatic residues at these latter two positions showed either
essentially full galactose transport activity (Phe(352)Trp(504) and
Trp(352)Trp(504)) or no significant activity (Phe(352)Tyr(504) and
Trp(352)Tyr(504)), whereas single-site mutants showed markedly reduced activity.
These results are indicative of a specific interaction between sites 352 and 504
of Gal2.
PMID- 10760523
TI - Long-chain fatty acid-promoted swelling of mitochondria: further evidence for the
protonophoric effect of fatty acids in the inner mitochondrial membrane.
AB - Swelling of non-respiring rat liver mitochondria suspended in isotonic potassium
acetate at pH 6.5-7.4 in the presence of valinomycin was promoted by long-chain
fatty acids, such as myristate, indicating a protonophoric mechanism. This
swelling was partly inhibited by inhibitors or substrates of mitochondrial anion
carriers. The results show that the fatty acid cycling mechanism responsible for
uncoupling of oxidative phosphorylation can also operate in the direction
opposite to that originally proposed [Skulachev, V.P. (1991) FEBS Lett. 294, 158
162], i.e. the inwardly directed transfer of the fatty acid anion accompanied by
outwardly directed free passage of undissociated fatty acid. They also extend the
list of mitochondrial anion carriers, that are involved in this process, over the
mono- and tricarboxylate transporters. At pH 8, myristate, but not the synthetic
protonophore, p-trifluoromethoxycarbonyl-cyanide phenylhydrazone, induced
mitochondrial swelling in both potassium acetate and KCl media, that did not
require the presence of valinomycin. This indicates that, at alkaline pH,
myristate facilitates permeation of the inner mitochondrial membrane to
monovalent cations and, possibly, activates the inner membrane anion channel.
PMID- 10760524
TI - The cytotoxic action of Bax on yeast cells does not require mitochondrial ADP/ATP
carrier but may be related to its import to the mitochondria.
AB - The effect of the expression of murine Bax protein on growth and vitality was
examined in Saccharomyces cerevisiae and compared with the effect of Bax in
mutant cells lacking functional mitochondria. The cytotoxic effect of Bax on
yeast does not require functional oxidative phosphorylation, respiration, or
mitochondrial proteins (ADP/ATP carriers) implicated in the formation of the
permeability transition pore in mammalian mitochondria. In the wild type S.
cerevisiae the expression of Bax does not result in a severe effect on
mitochondrial membrane potential and respiration. On the basis of Bax induced
differences in the fluorescence of green fluorescent protein fused to
mitochondrial proteins, it is proposed that Bax may interfere with one essential
cellular process in yeast: the mitochondrial protein import pathway that is
specific for the proteins of the mitochondrial carrier family.
PMID- 10760525
TI - Peroxisome proliferator-activated receptor activators modulate the osteoblastic
maturation of MC3T3-E1 preosteoblasts.
AB - The reduced bone mineral density (BMD) observed in osteoporosis results, in part,
from reduced activity of bone-forming osteoblasts. We examined the effect of
peroxisome proliferator-activated receptor (PPAR) activators on MC3T3-E1
preosteoblast maturation. Activators of PPARalpha, delta and gamma induced
alkaline phosphatase activity, matrix calcification and the expression of
osteoblast genes as determined by reverse transcriptase-polymerase chain
reaction. However, at relatively high concentrations of the specific PPARgamma
ligands, ciglitazone and troglitazone, maturation was inhibited. PPARalpha, delta
and gamma1 were expressed in MC3T3-E1 cells. PPARgamma1 mRNA and protein levels
were induced early during osteoblastic maturation. We speculate that endogenous
and pharmacological PPAR activators may affect BMD by modulating osteoblastic
maturation.
PMID- 10760526
TI - Frequency and significance of preterm delivery in twin pregnancies.
AB - OBJECTIVE: We investigated the frequency of preterm delivery and its influence on
the neonatal outcome in twin pregnancies at a perinatal center. Are there
differences in the course of twin pregnancies with preterm or term delivery?
METHOD: A retrospective investigation was carried out at the Department of
Obstetrics on 502 twin pregnancies and deliveries between 1978 and 1993.
Pregnancy history and clinical parameters were compared among preterm (<37+0
weeks) and term deliveries. RESULT: Median duration of all twin pregnancies was
36+3 weeks of gestation. In the preterm group, preterm labor was more frequent,
both, the first and the second neonate had lower birth weight and were more often
admitted to the neonatal intensive care unit (NICU) where they stayed longer than
full-term neonates needing intensive care. Perinatal deaths occurred only in the
preterm group. CONCLUSIONS: The incidence of preterm delivery is significantly
elevated in twin pregnancies and consequently the incidence of low- and very-low
birth-weight-infants and perinatal mortality. Preterm delivery is the main reason
why twin pregnancies are at a higher risk for an adverse neonatal outcome and
thereby cause considerable costs.
PMID- 10760527
TI - Early pregnancy nausea and vomiting in a high-altitude Andean population.
AB - OBJECTIVES: We examined the prevalence, risk factors, and maternal-neonatal
consequences of early pregnancy nausea and vomiting (NVP) in a high altitude
Ecuadorian Andean population. METHODS: Subjects were 1000 low-income urban
primigravidas who delivered full-term pregnancies. RESULTS: NVP prevalence was
67%. Decreased NVP risk was associated with higher altitude and increased risk
with less education, common law marriage, and white collar/professional
occupation. Lifestyle changes associated with NVP included decreased likelihood
of drinking and outside employment but increased probability of prenatal care,
supportive living arrangements, and dietary disturbances. NVP had no apparent
long-term effect on maternal nutritional status but was associated with increased
fetal subcutaneous fat reserves. CONCLUSIONS: NVP prevalence and timing was
similar to developed populations although some of the identified risk factors
were unique to the group. NVP did not appear to have a significant impact on
prenatal nutrition at term but was linked with increased fetal fat accumulation.
PMID- 10760528
TI - Total free radical trapping antioxidant potential in pre-eclampsia.
AB - OBJECTIVE: The aim of the present study was to measure serum urate, tocopherol
and ascorbate and to calculate total radical trapping antioxidant potential
(TRAP) in pre-eclampsia. METHODS: Study samples were taken from 25 pre-eclamptic,
25 normotensive pregnant and 25 non-pregnant healthy females for measuring uric
acid, vitamin C and E, total sulfhydryl group. Also lipid peroxidation product
malonaldehyde (MDA), the superoxide generation (NBT reduction) were estimated and
TRAP was calculated. Data were analyzed statistically using Student's t-test.
RESULT: Pre-eclamptic women had significantly increased MDA levels, superoxide
generation and uric acid levels as compared to control subjects (P<0.001).
Vitamin C and E and total thiols were lower in pre-eclampsia as compared to
control subjects (P<0.001). TRAP was significantly higher in pre-eclampsia.
CONCLUSION: TRAP provides a means of assessing the total capacity of the chain
breaking antioxidants to prevent lipid peroxidation in plasma.
PMID- 10760529
TI - Extraperitoneal pelvic lymphadenectomy to complement vaginal operations for
cervical and endometrial cancer.
AB - OBJECTIVE: The aim of the current study was to test the applicability of a
personal modification of Mitra extraperitoneal pelvic lymphadenectomy in
combination with radical vaginal operations for treatment of endometrial and
cervical cancer. METHOD: In a prospective series, 82 patients were submitted to
extraperitoneal pelvic lymphadenectomy. In 34 cases of stage I endometrial cancer
the procedure was combined with a class I vaginal hysterectomy and in 48 cases of
cervical cancer stage Ib-IIIb lymphadenectomy was associated with a class II or
III radical vaginal hysterectomy. Type of anesthesia, number of lymph nodes
removed, operating time, blood loss and postoperative complications were
recorded. RESULT: The operation was performed with spinal anesthesia in 43% of
the cases. Thirty-seven patients (45%) were high surgical risk because of
associated diseases. The median operative time for lymphadenectomy was 20 min for
each side; the vaginal procedures took a median of 25 min (class I) and 40 min
(class II-III). Blood transfusions were necessary in seven cases (8. 5%). A
median of 26 lymph nodes were removed from each patient. Lymphocyst occurred in
seven patients (8.5%), retroperitoneal hematoma in two and retroperitoneal
abscess in one. CONCLUSION: Extraperitoneal pelvic lymphadenectomy has proven to
be a safe and quick technique to complement vaginal operations for endometrial
and cervical cancer. Specific features of this approach are: (1) fast, timesaving
procedure; (2) possible use of spinal anesthesia; and (3) applicability in high
surgical risk patients.
PMID- 10760531
TI - Maternal deaths in Sagamu, Nigeria.
PMID- 10760530
TI - Characteristics of pregnant vs. non-pregnant women physicians: findings from the
women physicians' health study.
AB - OBJECTIVE: Many young physicians are women, and many are in their childbearing
years. Knowing pregnant physicians' status is useful for epidemiological and
workforce reasons, yet no studies have compared pregnant with same-age, non
pregnant physicians, an especially appropriate comparison group. STUDY DESIGN:
Data from the Women Physicians' Health Study, a national questionnaire-based
survey. We compare 87 pregnant with 1148 non-pregnant women physicians, ages 30
40. RESULTS: Pregnant physicians ate more fat, fruits and vegetables, and cheese,
but not more dairy than non-pregnant women physicians. While nearly half consumed
alcohol, they reported drinking an average of only 0.4 drinks/week, and none
smoked. Nearly all took vitamin supplements. Pregnant physicians exercised as
much as non-pregnant physicians, and pregnant physicians' self-reported health
status was better. Work amount, desire to work less, perceived work control,
career satisfaction, and work stress did not significantly differ by pregnancy
status. CONCLUSION: The prenatal period may be a time of especially healthy
habits and considerable productivity for female physicians.
PMID- 10760532
TI - Filaria associated hemolysis in pregnancy.
PMID- 10760533
TI - Polyhydramnios as a sign of fetal pseudohypoaldosteronism.
PMID- 10760534
TI - Putting an ear to the ground: where now with Quinacrine?
PMID- 10760535
TI - Prognostic factors associated with pressure sore development in the immediate
post-operative period.
AB - The purpose of this study was to identify variables associated with post
operative pressure sore incidence. The data were derived from a sequential,
double triangular, randomised, blinded, controlled trial of the intra-operative
use of a visco-elastic polymer pad conducted at two centres. Of 446 surgical
patients recruited the main endpoint was assessed for 416 patients of whom 65
(15.6%) had a post-operative pressure sore. Analysis determined that the
probability of a patient developing a pressure sore was associated with increased
number of hypotensive episodes and mean core temperature during surgery, and
reduced mobility Day 1 post-operatively. The development of a probability
equation illustrates the future potential of prognostic factor research in the
development of risk assessment tools and their application within clinical
settings.
PMID- 10760536
TI - Mothers' developmental expectations for young children in the Philippines.
AB - The purpose of the study was to investigate the developmental timetables of rural
and urban mothers in the Central Visayas, Philippines. Examined were mothers'
expectations for children's development (physical/perceptual-motor, cognitive,
and psychosocial) and mothers' child rearing practices, as influenced by four
selected variables (child's gender and ordinal position, mother's education, and
rural or urban residence). The total sample size was 303 mothers [153 of rural
residence and 150 urban] in two provinces. Mothers responded to a structured
questionnaire which was read to them aloud by trained interviewers who then
recorded the responses. All the mothers had children between 4-6 years old; equal
numbers of male and female children were included, and the entire economic and
educational ranges were represented. MANOVA results showed significant main
effects of all four variables on maternal expectations of child development and
on maternal child rearing practices. Also, significant interaction effects of
residential location and maternal education on mothers' expectations of
children's physical/perceptual motor development were found (F[2, 256]=3.05,
P=0.05). Significant interaction effects also were found of maternal education
and the child's ordinal position (F[4,256]=2. 95, P=0.02) on maternal
expectations of children's psychosocial development.
PMID- 10760537
TI - Attitudes toward patient expertise in chronic illness.
AB - Although it has become an accepted standard to acknowledge the patient as a full
partner in health care decisions, replacing traditional authoritative
relationships with those based on an emancipatory model, the experiences of
persons living with chronic illness confirm that this paradigm shift is not yet
apparent in many health care relationships. In this paper, the authors present a
qualitative secondary analysis of combined data sets from their research into
chronic illness experience with two quite different chronic diseases - Type I
Diabetes (a socially legitimized chronic disease) and Environmental Sensitivities
(a disease which is currently treated with considerable scepticism). Comparing
the experiences of individuals with diseases that are quite differently socially
constructed, it becomes possible to detect common underlying health professional
values and attitudes that powerfully influence the experience of living with and
negotiating health care for a chronic illness. In the discussion of findings from
this study, the authors examine the implications of the spiral of behaviors that
fuels mutual alienation in chronic illness care relationships if professionals
are unable to value patient expertise.
PMID- 10760538
TI - Validity and reliability of the braden scale and the influence of other risk
factors: a multi-centre prospective study.
AB - The Braden scale is one of the most intensively studied risk assessment scales
used in identifying the risk of developing pressure sores. However, not all
studies show that the sensitivity and specificity of this scale is sufficient.
This study, therefore, investigated whether adding new risk factors can enhance
the sensitivity and specificity of the Braden scale. The Braden scale was tested
in a prospective multi-centre design. The nurses of 11 wards filled in the Braden
scale every 5 days for each patient who was admitted without pressure sores and
who had a probable stay of at least 10 days. Based on a literature study and in
depth interviews with experts, the Braden scale was extended by the risk factor
blood circulation. In addition, other risk factors, which are more or less stable
patient characteristics, were measured during the admission of the patient.
Independent research assistants measured the presence of pressure sores twice a
week. As the external criterion for the risk of developing pressure sores, the
presence of pressure sores and/or the use of preventive activities was used.
Results showed that the original Braden scale was a reliable instrument and that
the sensitivity and specificity was sufficient. However, reformulating the
factors moisture and nutrition, and adding the risk factor age could enhance the
sensitivity and specificity. Furthermore, results showed that the factors sensory
perception, and friction and shear were especially important risk factors for the
Braden scale. In fact, using only the factors sensory perception, friction and
shear, moisture (a reformulated factor) and age give the highest explained
variance of the risk of developing pressure sores. The added risk factor blood
circulation, did not enhance the sensitivity and specificity of the original
Braden scale. Suggestions are given on how to use risk assessment scales in
practice.
PMID- 10760540
TI - Reflections on caring as a virtue ethic within an evidence-based culture.
PMID- 10760539
TI - "Is there a place for "care" within nursing?".
AB - This paper explores the assumption that care and nursing are both interchangeable
and symbiotic concepts, and argues through exploration of the literature on the
nature of care, its relationship to nursing, the socialisation process, and the
personal human difficulties nurses experience when carrying out their daily role,
that this assumption needs serious reconsideration. This has major implications
for the nursing profession when attempting to define its roles and boundaries, as
current views appear inconsistent with each other and in conflict with the actual
process of nursing, and need to be resolved to reflect the actual practice of
nursing and work of the nurse.
PMID- 10760541
TI - Evaluation of the role of the Parkinson's disease nurse specialist.
AB - A one year follow up study of 108 randomised patients with Parkinson's disease at
three centres was performed to investigate differences between care provided by
the hospital based Parkinson's disease nurse specialist (PDNS) compared with the
Consultant Neurologist (control). Only two (out of 22) differences were found
where physical functioning and general health improved more in the control group.
Provision of PDNS' for patients with Parkinson's disease cannot therefore be
recommended solely on cost-effectiveness grounds because of similar outcomes but
increased costs associated with the PDNS providing additional care. However
medical and nursing specialists valued their complimentary expertise, and patient
and carers responses to consultations also reflect that PDNS's have particular
contributions. Aspects of care most valued by patients and carers and
consultation interactions are discussed.
PMID- 10760542
TI - Her Majesty's coroners and home office forensic pathologists perception of the
nurses' role in the coroner's enquiry.
AB - A study was performed to elicit the perceived role of the registered nurse in the
coroner's enquiry from Her Majesty's coroners and Home Office forensic
pathologists viewpoint. A qualitative small sample study of unstructured
interviews was performed followed by a quantitative and qualitative survey of all
134 coroners and 44 forensic pathologists practising in England and Wales. 72
(53.5%) coroners and 26 (59.1%) forensic pathologists finally participated in the
study of which 51% perceived that there was a role for the nurse in the coroner's
enquiry. Roles identified included: actual i. e. keeping records, being
conversant with nursing policies and "knowing" ("Knowing" means having knowledge
about coroners' enquiries); potential i.e. resource provider, communicator,
supporter, presencing, evidence giver and stewardship; and future i. e.
certifying the fact of death and being an expert witness. Possible action by the
registered nurse to embrace the outcome of this study is put forward.
PMID- 10760543
TI - Ability for self-care among home dwelling elderly people in a health district in
Sweden.
AB - The aim of this study was to describe the ability for self-care among home
dwelling elderly in the community in a health district in western Sweden. Two
self-report instruments plus a number of self-care related questions were
distributed by mail to an age stratified random sample and finally completed by a
total of 125 subjects. Bivariate and multivariate statistical methods were used
in the analyses. The results showed that self-care ability and self-care agency
decreased for respondents 75+ years of age. Self-care ability was predicted by
three productive means for self-care and four risk factors.
PMID- 10760544
TI - Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine.
AB - The variability in the individual response to drugs may be due either to
interindividual variations in the pharmacokinetics of the drugs or to the
heterogeneity of the mechanism(s) underlying the diseases, or both. In both
cases, genetic heterogeneity is involved in the metabolism of cardiovascular
drugs and pathogenesis of inherited cardiovascular disorders. Molecular genetic
technologies can now provide sensitive and efficient genetic testing, not only to
identify polymorphic drug metabolism genes, but also to identify disease
associated genes for diagnosis and risk stratification of many hereditary
cardiovascular diseases. In this review, we discuss the polymorphic metabolism of
cardiovascular drugs and the molecular genetics of cardiovascular diseases in
relation to the genes determining the responsiveness to a given drug.
PMID- 10760545
TI - Extraneuronal cholinergic system in lymphocytes.
AB - Acetylcholine (ACh) is well known as a neurotransmitter in both the central and
peripheral nervous systems in mammalian species. Both muscarinic and nicotinic
ACh receptors have been identified in lymphocytes isolated from thymus, lymph
node, spleen, and peripheral blood, and their stimulation by muscarinic and
nicotinic agonists elicits a variety of functional and biochemical effects. On
the basis of these findings, it has been postulated that the parasympathetic
nervous system may play a role in immune-neurohumoral crosstalk. However, ACh
present in the blood of several species has been localized to lymphocytes from
various origins using radioimmunoassay. Moreover, using Northern blots or reverse
transcription-polymerase chain reaction, expression of choline acetyltransferase,
an ACh synthesizing enzyme, has been identified in human blood mononuclear
leukocytes, human leukemic T-cell lines, and rat lymphocytes. Stimulation of T
lymphocytes with phytohemagglutinin activates the lymphoid cholinergic system, as
evidenced by increased synthesis and release of ACh, increased
acetylcholinesterase activity, and the increased expression of mRNA encoding
choline acetyltransferase and ACh receptors. The observation that muscarinic
receptor stimulation by ACh or agonists increases in [Ca(2)+](i) and up-regulates
c-fos expression strongly argues that ACh synthesized and released from T
lymphocytes acts as an autocrine and/or paracrine factor regulating immune
function. In summary, these data present a compelling picture in which immune
function is not only regulated by the cytokine system, but is also under the
control of an independent, lymphoid cholinergic system.
PMID- 10760546
TI - Paracrine and autocrine effects of nitric oxide on myocardial function.
AB - Complex paracrine interactions exist between endothelial cells and cardiac
myocytes in the heart. Cardiac endothelial cells release (or metabolize) several
diffusible agents (e.g., nitric oxide [NO], endothelin-1, angiotensin II,
adenylpurines) that exert direct effects on myocyte function, independent of
changes in coronary flow. Some of these mediators are also generated by cardiac
myocytes, often under pathological conditions. This review focuses on the role of
NO in this paracrine/autocrine pathway. NO modulates several aspects of
"physiological" myocardial function (e.g., excitation-contraction coupling;
myocardial relaxation; diastolic function; the Frank-Starling response; heart
rate; beta-adrenergic inotropic response; and myocardial energetics and substrate
metabolism). The effects of NO are influenced by its cellular and enzymatic
source, the amount generated, the presence of reactive oxygen species,
interactions with neurohumoral and other stimuli, and the relative activation of
cyclic GMP-dependent and -independent signal transduction pathways. The relative
physiological importance of endothelium- and myocyte-derived NO remains to be
established. In pathological situations (e.g., ischemia-reperfusion, left
ventricular hypertrophy, heart failure, transplant vasculopathy and rejection,
myocarditis), NO can potentially exert beneficial or deleterious effects.
Beneficial effects of NO can result from endothelial-type nitric oxide synthase
derived NO or from spatially and temporally restricted expression of the
inducible isoform, inducible-type nitric oxide synthase. Deleterious effects may
result from (1) deficiency of NO or (2) excessive production, often inducible
type nitric oxide synthase-derived and usually with concurrent reactive oxygen
species production and peroxynitrite formation. The balance between beneficial
and deleterious effects of NO is of key importance with respect to its
pathophysiological role.
PMID- 10760547
TI - Regulation of coronary vasomotor tone under normal conditions and during acute
myocardial hypoperfusion.
AB - Ischemia generally has been assumed to cause maximal vasodilation of the coronary
resistance vessels. However, recent observations have demonstrated that during
ischemia, the coronary microvessels can retain some degree of vasodilator reserve
and remain responsive to vasoconstrictor stimuli. Traditional understanding of
coronary blood flow regulation envisioned an array of resistance vessels that
respond homogeneously to local myocardial metabolic needs. Although coronary
arterioles (<100 microm) do respond to myocardial metabolic activity, recent
studies have demonstrated that up to 40% of total coronary resistance resides in
small arteries 100-400 microm in diameter. Vasoconstriction of these small
arteries is capable of decreasing blood flow, but they are minimally responsive
to the metabolic effects of the resultant flow reduction. The lack of metabolic
vasoregulation of the resistance arteries explains, at least in part, the
observation that myocardial ischemia does not predictably cause maximal
resistance vessel dilation. In addition, vasoconstrictor influences can compete
with metabolic vasodilator activity in coronary arterioles. These findings
suggest that pharmacologic vasodilators acting at the microvascular level might
be therapeutically useful in patients with ischemic heart disease. Unfortunately,
when myocardial ischemia results from a flow-limiting coronary stenosis,
nonselective pharmacologic vasodilation of the resistance vessels can worsen
subendocardial ischemia by decreasing intravascular pressure to produce coronary
steal and by worsening of stenosis severity. Selective dilation of small arteries
in ischemic regions might have potential for enhancing blood flow. A critical
property of an effective agent is that it not interfere with metabolic
vasoregulation at the arteriole level, so that dilation of small arteries in
adequately perfused regions would be countered by compensatory vasoconstriction
of the arterioles to prevent coronary steal.
PMID- 10760548
TI - Development of the visual system of the chick. I. Cell differentiation and
histogenesis.
AB - This review summarizes present knowledge on the embryonic development of the
avian visual projections, based on the domestic chick as a model system. The
reductionist goal to understand formation and function of complex neuroanatomical
systems on a causal level requires a synthesis of classic developmental biology
with recent advances on the molecular mechanisms of cell differentiation and
histogenesis. It is the purpose of this article. We are discussing the processes
underlying patterning of the anterior neural tube, when the retina and optic
tectum are specified and their axial polarity is determined. Then the development
of these structures is described from the molecular to the anatomical level.
Following sections deal with the establishment of secondary visual connections,
and the developmental interactions between compartments of the retinotectal
system. Using this latter pathway, from the retina to the optic tectum, many
investigations aimed at mechanisms of axonal pathfinding and connectivity have
accumulated a vast body of research, which will be covered by a following review.
PMID- 10760549
TI - Ion channels in glial cells.
AB - Functional and molecular analysis of glial voltage- and ligand-gated ion channels
underwent tremendous boost over the last 15 years. The traditional image of the
glial cell as a passive, structural element of the nervous system was transformed
into the concept of a plastic cell, capable of expressing a large variety of ion
channels and neurotransmitter receptors. These molecules might enable glial cells
to sense neuronal activity and to integrate it within glial networks, e.g., by
means of spreading calcium waves. In this review we shall give a comprehensive
summary of the main functional properties of ion channels and ionotropic
receptors expressed by macroglial cells, i.e., by astrocytes, oligodendrocytes
and Schwann cells. In particular we will discuss in detail glial sodium,
potassium and anion channels, as well as glutamate, GABA and ATP activated
ionotropic receptors. A majority of available data was obtained from primary cell
culture, these results have been compared with corresponding studies that used
acute tissue slices or freshly isolated cells. In view of these data, an active
glial participation in information processing seems increasingly likely and a
physiological role for some of the glial channels and receptors is gradually
emerging.
PMID- 10760550
TI - Eye fields in the frontal lobes of primates.
AB - Two eye fields have been identified in the frontal lobes of primates: one is
situated dorsomedially within the frontal cortex and will be referred to as the
eye field within the dorsomedial frontal cortex (DMFC); the other resides
dorsolaterally within the frontal cortex and is commonly referred to as the
frontal eye field (FEF). This review documents the similarities and differences
between these eye fields. Although the DMFC and FEF are both active during the
execution of saccadic and smooth pursuit eye movements, the FEF is more dedicated
to these functions. Lesions of DMFC minimally affect the production of most types
of saccadic eye movements and have no effect on the execution of smooth pursuit
eye movements. In contrast, lesions of the FEF produce deficits in generating
saccades to briefly presented targets, in the production of saccades to two or
more sequentially presented targets, in the selection of simultaneously presented
targets, and in the execution of smooth pursuit eye movements. For the most part,
these deficits are prevalent in both monkeys and humans. Single-unit recording
experiments have shown that the DMFC contains neurons that mediate both limb and
eye movements, whereas the FEF seems to be involved in the execution of eye
movements only. Imaging experiments conducted on humans have corroborated these
findings. A feature that distinguishes the DMFC from the FEF is that the DMFC
contains a somatotopic map with eyes represented rostrally and hindlimbs
represented caudally; the FEF has no such topography. Furthermore, experiments
have revealed that the DMFC tends to contain a craniotopic (i.e., head-centered)
code for the execution of saccadic eye movements, whereas the FEF contains a
retinotopic (i.e., eye-centered) code for the elicitation of saccades. Imaging
and unit recording data suggest that the DMFC is more involved in the learning of
new tasks than is the FEF. Also with continued training on behavioural tasks the
responsivity of the DMFC tends to drop. Accordingly, the DMFC is more involved in
learning operations whereas the FEF is more specialized for the execution of
saccadic and smooth pursuit eye movements.
PMID- 10760551
TI - Lesch-Nyhan disease and the basal ganglia.
AB - The purpose of this review is to summarize emerging evidence that the
neurobehavioral features of Lesch-Nyhan disease (LND), a developmental disorder
caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine
phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal
ganglia. Affected individuals have severe motor disability described by prominent
extrapyramidal features that are characteristic of dysfunction of the motor
circuits of the basal ganglia. They also display disturbances of ocular motility,
cognition, and behavioral control that may reflect disruption of other circuits
of the basal ganglia. Though neuropathologic studies of autopsy specimens have
revealed no obvious neuroanatomical abnormalities in LND, neurochemical studies
have demonstrated 60-90% reductions in the dopamine content of the basal ganglia.
In addition, recent PET studies have documented significant reductions in
dopamine transporters and [18F]fluorodopa uptake in the basal ganglia. These
findings support the proposal that many of the neurobehavioral features of LND
might be related to dysfunction of the basal ganglia.
PMID- 10760552
TI - Roles of NMDA receptor activity and nitric oxide production in brain development.
AB - The concept that neural activity is important for brain maturation has focused
much research interest on the developmental role of the NMDA receptor, a key
mediator of experience-dependent synaptic plasticity. However, a mechanism able
to link spatial and temporal parameters of synaptic activity during development
emerged as a necessary condition to explain how axons segregate into a common
brain region and make specific synapses on neuronal sub-populations. To comply
with this developmental constraint, it was proposed that nitric oxide (NO), or
other substances having similar chemical and biological characteristics, could
act as short-lived, activity-dependent spatial signals, able to stabilize active
synapses by diffusing through a local volume of tissue. The present article
addresses this issue, by reviewing the experimental evidence for a correlated
role of the activity of the NMDA receptor and the production of NO in key steps
of neural development. Evidence for such a functional coupling emerges not only
concerning synaptogenesis and formation of neural maps, for which it was
originally proposed, but also for some earlier phases of neurogenesis, such as
neural cell proliferation and migration. Regarding synaptogenesis and neural map
formation in some cases, there is so far no conclusive experimental evidence for
a coupled functional role of NMDA receptor activation and NO production. Some
technical problems related to the use of inhibitors of NO formation and of gene
knockout animals are discussed. It is also suggested that other substances, known
to act as spatial signals in adult synaptic plasticity, could have a role in
developmental plasticity. Concerning the crucial developmental phase of neuronal
survival or elimination through programmed cell death, the well-documented
survival role related to NMDA receptor activation also starts to find evidence
for a concomitant requirement of downstream NO production. On the basis of the
reviewed literature, some of the major controversial issues are addressed and, in
some cases, suggestions for possible future experiments are proposed.
PMID- 10760553
TI - Lymphocyte proliferation among major depressive and dysthymic patients with
typical or atypical features.
AB - BACKGROUND: Depressive illness may be associated with immune and cytokine
alterations. However, data are unavailable concerning functional immune changes
associated with chronic, low-grade depression (dysthymia). Moreover, the
contribution of the neurovegetative features of depression (e.g., altered sleep,
eating) to the immune alterations remains to be determined. METHODS: Mitogen
stimulated cell proliferation was assessed in major depressive and dysthymic
patients exhibiting either typical or atypical features. In a subset of patients,
lymphocyte proliferation was also assessed before and after pharmacotherapy to
determine whether alleviation of symptoms would be accompanied by normalization
of immune functioning. RESULTS: Lymphocyte proliferation was reduced to a greater
extent among dysthymic than among major depressive patients. Among dysthymic
patients reduced cell proliferation was evident irrespective of symptom
typicality; however, among major depressive patients the contribution of
neurovegetative features varied with the specific mitogen used. Symptom
alleviation following antidepressant treatment was not accompanied by
normalization of cell proliferation. LIMITATIONS: Patients received 12 weeks of
antidepressant treatment, and more sustained therapy may be required for
normalization of immune activity. As well, conclusions concerning normalization
of immune functioning in drug-treated major depressive patients requires that a
greater number of patients be assessed. CONCLUSIONS: As the immune variations
were more pronounced in dysthymia than in major depression, chronicity of illness
may be a pertinent factor in promoting immune disturbances. This does not exclude
the possibility that depression is associated with immune activation, which then
provokes suppression of other aspects of immunity. As well, it is conceivable
that immune alterations indirectly contribute to the symptoms accompanying
depressive state, although it does not appear that variations of lymphocyte
proliferation are associated with neurovegetative status.
PMID- 10760554
TI - WFS1 gene mutation search in depressive patients: detection of five missense
polymorphisms but no association with depression or bipolar affective disorder.
AB - BACKGROUND: Wolfram syndrome (WFS) is an autosomal recessive neurodegenerative
disorder. Recently, the WFS1 gene was isolated, and approximately 80% of the
mutations responsible for WFS were found in exon 8 of WFS1. It has been noted
that heterozygous carriers of the WFS gene are 26-fold more likely to be
hospitalized for depression, and it has been estimated that approximately 25% of
all people hospitalized for depression may carry the WFS gene(s). METHODS: We
searched for mutations in exon 8 of WFS1 in 30 depressive patients with a history
of hospitalization and whose age at onset was under 40 years. We also examined 47
bipolar affective patients and 62 control subjects for an association. RESULTS: A
were detected. Four of the six were novel. No nonsense or frameshift mutation was
detected. Genotypic and allelic distributions were similar between the depressive
patients and the controls. No association with bipolar affective disorder was
suggested. LIMITATIONS: Because of the small sample size, the probability of
finding at least one patient with WFS-responsible mutation(s) was 70% if
depression is associated with WFS1 mutation(s) in 5% of patients. CONCLUSION: It
is not likely that WFS1 mutations are responsible for as much as 25% of
depressive illness.
PMID- 10760555
TI - Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta
analysis of efficacy and tolerability.
AB - BACKGROUND: A meta-analysis of the efficacy and tolerability of selective
serotonin reuptake inhibitors (SSRIs) against tricyclic antidepressants (TCAs) in
depressed patients was carried out. METHODS: Efficacy data from 102 randomised
controlled trials (10706 patients) were pooled to provide a summary variance
weighted effect size. Tolerability data from 95 studies (10553 patients) were
combined to give variance-weighted relative risk of drop out for all reasons and
for adverse effects from each study. The effect of age, treatment setting,
severity and TCA dose were examined as well as the performance of individual
SSRIs and TCAs where there were sufficient studies. RESULTS: There is no overall
difference in efficacy between SSRIs and TCAs (effect size -0.03, 95% confidence
interval -0.09 to 0.03). TCAs do appear more effective in in-patients (-0.23,
0.40 to -0.05) and amitriptyline is more effective than SSRI comparators (-0.14,
0.25 to -0.03) but publication bias cannot be excluded. The SSRIs are better
tolerated, with significantly lower rates of treatment discontinuations overall
(relative risk 0.88, 0.83 to 0.93; number needed to treat 26) and due to side
effects (0.73, 0.67 to 0.80; number needed to treat 33). Individual SSRIs show a
similar advantage except for fluvoxamine which does not differ from the TCAs.
Individual TCAs show a similar disadvantage in tolerability compared to SSRIs
except for dothiepin against which SSRI treatment results in more side-effect
related drop outs (2.64, 1.50 to 4.63; number needed to harm 12). LIMITATIONS:
The evidence is from short-term studies and subgroup analyses may result in
chance results. CONCLUSIONS: Overall efficacy between the two classes is
comparable but SSRIs are not proven to be as effective as TCAs in in-patients and
against amitriptyline. SSRIs have a modest advantage in terms of tolerability
against most TCAs.
PMID- 10760556
TI - Discontinuation of antidepressant drugs during electroconvulsive therapy: a
controlled study.
AB - BACKGROUND: The concurrent use of antidepressant drugs with ECT is recommended by
a recent ECT guideline. The study aimed to examine differential therapeutic and
side effect responses when antidepressants are discontinued or not during ECT.
METHODS: This study compared the effectiveness and side effect profile of
unilateral ECT with antidepressant drugs (Group-1) or unilateral ECT with drug
placebo (Group-2) in 30 major depressive disorder (DSM-IV) patients on
antidepressants using a prospective randomised trial. Hamilton Rating Scale for
Depression (HRSD), Montgomery Asberg Depression Rating Scale (MADRS), UKU scale,
Columbia ECT side effect check list were used. The assessments were carried out
before starting ECTs and at fixed intervals thereafter for four weeks. In
addition, at six weeks a follow-up assessment was carried out using HRSD. ECTs
were stopped after four weeks or earlier if patient obtained HRSD scores <8 and
remained so for one week. RESULTS: Continuation of antidepressant drugs with ECT
conferred no therapeutic advantage. Barring tricyclic antidepressant induced
anticholinergic side effects, no differential side effect profile was noted. At
follow-up none relapsed in Group-2 and the mean HRSD scores between the groups
did not differ. LIMITATION: The antidepressant treatment prior to ECT was
uncontrolled. In addition, the design was not strictly double-blind. CONCLUSION:
The study failed to support an advantage with antidepressant continuation during
an ECT course in major depressive disorder.
PMID- 10760557
TI - The development of agoraphobia in panic disorder: a predictable process?
AB - BACKGROUND: Panic attacks are conceptualized to be the central feature of both
panic disorder without (PDU) and with agoraphobia (PDA). As a sizeable percentage
of panic patients do not develop avoidance behavior, other factors than 'panic
attacks', in general, must influence the different courses of the disorder.
METHOD: We studied 84 outpatients suffering from PDU or PDA concerning different
factors which were hypothesized to influence the development of agoraphobia.
RESULTS: 'Earlier age of onset', 'fear of losing control' and 'chills or hot
flushes' turned out to correlate statistically significantly with PDA, while
'chest pain or discomfort' occurred more often in PDU. LIMITATIONS: The present
study used retrospective data. CONCLUSIONS: The results of this study suggest
that the development of agoraphobia in panic disorder is influenced by specific
variables and is not a purely coincidental process.
PMID- 10760558
TI - Linkage of mood disorders with D2, D3 and TH genes: a multicenter study.
AB - BACKGROUND: It has been suggested that the dopaminergic system is involved in the
pathophysiology of mood disorders. We conducted a multicenter study of families
with mood disorders, to investigate a possible linkage with genes coding for
dopamine receptor D2, dopamine receptor D3 and tyrosine hydroxylase (TH).
METHODS: Twenty three mood disorder pedigrees collected within the framework of
the European Collaborative Project on Affective Disorders were analyzed with
parametric and non-parametric linkage methods. Various potential phenotypes were
considered, from a narrow (only bipolar as affected) to a broad (bipolar+major
depressive+schizoaffective disorders) definition of affection status. RESULTS:
Parametric analyses excluded linkage for all the candidate genes, even though
small positive LOD (Limit of Detection) scores were observed for TH in three
families. Non-parametric analyses yielded negative results for all markers.
CONCLUSION: The D2 and D3 dopamine receptors were, therefore, not a major
liability factor for mood disorders in our sample, whereas TH may play a role in
a subgroup of patients.
PMID- 10760559
TI - Polyglutamine coding genes in bipolar disorder: lack of association with selected
candidate loci.
AB - BACKGROUND: Several studies have suggested that expanded trinucleotide repeats,
particularly CAG, may have a role in the etiology of BD. Results obtained with
the repeat expansion detection technique (RED) have indicated that bipolar
patients have an excess of expanded CAG repeats. However, it is not clear which
loci account for this difference. METHODS: Using lithium-responsive bipolar
patients in order to reduce heterogeneity, we investigated five loci that are
expressed in the brain and contain translated CAG repeats. A sample of 138 cases
and 108 controls was studied. Genotypes were coded quantitatively or
qualitatively and repeat distributions were compared. RESULTS: No difference was
found in allele distribution between cases and controls for any of the loci
studied. In one locus - L10378 - patients had a tendency to present shorter
alleles (28.1 versus 27.9 repeats; t=2.55, df=205, P=0.011), however, this
difference disappeared after correction for multiple testing. LIMITATIONS: The
study has limitations common to most candidate gene association studies, that is,
limited number of loci investigated and limited power to detect loci that account
for a small proportion of the total genetic variability. CONCLUSIONS: Our results
suggest that the loci investigated have no major role in the genetic
predisposition to bipolar disorder.
PMID- 10760560
TI - The in vitro immunosuppressive effects of moclobemide in healthy volunteers.
AB - BACKGROUND: Many studies have demonstrated that major depression is related to an
activation of the inflammatory response system (IRS) with an increased production
of proinflammatory cytokines. It has been shown that tricyclic antidepressants
and serotonin reuptake inhibitors suppress the activation of the IRS in
depression and have negative immunoregulatory effects in vitro. Little is known
on the immune effects of moclobemide, a reversible monoamine oxidase A inhibitor.
METHODS: We examined, in nine normal volunteers, the in vitro effects of
moclobemide on the production of interleukin-6 (IL-6), IL-8, tumor necrosis
factor-alpha (TNFalpha), interferon-gamma (IFNgamma), IL-10 and the IL-1 receptor
antagonist (IL-1RA) by diluted whole blood stimulated or not with
lipopolysaccharide (LPS)+phytohemagglutinin (PHA). RESULTS: Moclobemide 10(-3)
and 10(-5) M significantly suppressed the unstimulated production of TNFalpha and
IL-8, and significantly enhanced the stimulated-production of IL-10. The
production of IL-6, IL-1RA and IFNgamma was not significantly affected either in
the unstimulated or stimulated conditions. CONCLUSIONS: Moclobemide has negative
immunoregulatory capacities through inhibition of the production of
proinflammatory cytokines, i.e. TNFalpha and IL-8, and through enhancement of the
production of IL-10, an anti-inflammatory cytokine.
PMID- 10760561
TI - Variation in rates of electroconvulsive therapy use among consultant teams in
Edinburgh (1993-1996).
AB - BACKGROUND: Critics of electroconvulsive therapy (ECT) have expressed concern
about variations in ECT use among consultant teams within the same hospital. The
aim was to establish whether or not there was a significant variation in rates of
ECT use among consultant teams in the same hospital when in-patient workload was
taken into account. METHODS: A computerised database was used to calculate annual
and aggregate rates of ECT use by consultant team, expressed as the number of
individual in-patients treated per 100 in-patients discharged between 1993 and
1996. RESULTS: The variation in aggregate rates of ECT use varied approximately
18-fold among the 11 general adult psychiatric teams (P<0.001), and twofold among
the three sector old-age psychiatric teams (P<0.05). CONCLUSIONS: Substantial
variation in the rates of ECT use was confirmed, but only among general adult
psychiatric teams. LIMITATIONS: The extent to which findings from one teaching
hospital can be generalised was unknown. Possible explanations of the variations
were not assessed.
PMID- 10760562
TI - Social support and self-esteem predict changes in bipolar depression but not
mania.
AB - INTRODUCTION: Our own and other research has suggested that social support
predicts course of bipolar disorder, with particularly strong effects on
depressive symptoms. Within this paper, we examine which components of social
support appear most powerful. METHODS: Thirty-one individuals with Bipolar I
disorder were followed longitudinally for 9 months. Participants completed a
standardized symptom severity interview monthly, and at a 2-month follow-up, they
completed the Interpersonal Support Evaluation List. At a 6-month follow-up, they
completed the Rosenberg Self-Esteem Inventory. RESULTS: Self-esteem support
appeared to the most important predictor of change in depression across a 6-month
follow-up, and multiple regression analyses suggested that social support effects
were mediated through self-esteem. LIMITATIONS AND IMPLICATIONS: Although the
small sample size suggests a need for replication, current results highlight the
importance of psychosocial variables in the course of bipolar depression. Self
esteem may be a particularly important target for clinical interventions.
PMID- 10760563
TI - Growth-phase regulation of the Escherichia coli thioredoxin gene.
AB - The two promoters of Escherichia coli trxA gene were separately cloned into
pKO100 as well as pJEL170. Galactokinase expression in cells containing the
pKO100 derivatives was found to be negatively correlated with growth rate and was
6- to 20-fold higher in stationary cultures than in exponential cultures. The
expression of trxA-galK was induced by amino acid starvation in a RelA(+) strain
but not in an isogenic Rel(-) strain indicating that the control involves
guanosine 3',5'-bispyrophosphate (ppGpp). RpoS, which appears to be essential for
expression of most stationary phase expressed genes, is not required for trxA
expression. Increased expression of relA, which increases ppGpp concentration,
increases trxA expression.
PMID- 10760564
TI - Promoter elements involved in the expression of the Aspergillus parasiticus
aflatoxin biosynthesis pathway gene avnA.
AB - One of the early genes in aflatoxin biosynthesis, avnA, encodes a pathway
specific cytochrome P-450 monooxygenase that catalyzes the hydroxylation of the
polyketide anthraquinone, averantin. Based on beta-glucuronidase (GUS) reporter
and electrophoretic mobility shift assays, promoter sites upstream of -118 bp in
the 367-bp verB-avnA intergenic region are not required for avnA gene activity.
Therefore, only the -100 to -110 site of the four putative binding sites for
AFLR, the aflatoxin biosynthetic pathway transcription regulatory protein
(consensus binding sequence: 5'-TCGN(5)CGR-3') was required for elevated avnA
expression.
PMID- 10760565
TI - Differential regulation of constitutive and retinoic acid-induced galectin-1 gene
transcription in murine embryonal carcinoma and myoblastic cells.
AB - Galectin-1 (gal-1), a galactoside-binding lectin, is found in many vertebrate
tissues and its expression is regulated during development. We had found that gal
1 expression is increased in F9 murine embryonal carcinoma cells concurrently
with induction of differentiation by all-trans retinoic acid (RA). In contrast,
gal-1 expression was constitutively high in murine myoblastic C2C12 cells.
Therefore, we used these two cell types as models to begin to understand the
mechanisms underlying constitutive and RA-induced gal-1 expression. We
transfected transiently into F9 cells a series of reporter constructs containing
different deletions of the 5' upstream region of the gal-1 gene promoter placed
upstream of the chloramphenicol acetyltransferase reporter cDNA and evaluated the
activation of transcription by RA treatment. The results indicate that the
induction of gal-1 by RA is regulated at least partially at the level of
transcription. A strong RA responsiveness region was found within the sequence
from -1578 to -1448 upstream of the transcription start site (+1). In contrast,
the high constitutive gal-1 expression in C2C12 cells appeared to be mediated by
a sequence within the promoter region from -62 to +1, which contains an Sp1
consensus sequence. A gel electrophoretic mobility shift assay indicated that the
transcription factor SP1 bound to the gal-1 Sp1 site and mutagenesis of this Sp1
site abolished both the binding of nuclear proteins to the mutated Sp1 site and
the high constitutive expression of the gal-1 gene. The results demonstrate that
gal-1 expression is cell type-specific and suggest that different factors
regulate constitutive and RA-induced gal-1 expression.
PMID- 10760566
TI - P53 tumour suppressor modulates transcription of the TATA-less gene coding for
the tumour-associated carbonic anhydrase MN/CA IX in MaTu cells.
AB - MN/CA IX (MN) exhibits a strong association with tumours. Co-transfection
experiments revealed that in MaTu cells the activity of the (-173;+31) MN
promoter construct was repressed by the wild type p53 in a dose-responsive manner
and stimulated by the (143(Val-->Ala)) mutant. Upregulation of endogenous p53 by
mitomycin C treatment in MaTu cells also had a profound effect on MN expression
as well as the activity of MN promoter in a reporter construct. p53 can thus
modulate MN expression and at least in a subset of tumours the changed p53 status
might be responsible for MN positivity. Co-transfections with internally deleted
MN promoter constructs demonstrated that the wild type p53 exerts its repression
activity on the level of the basal transcriptional machinery and not on a
particular cis element within the MN promoter.
PMID- 10760567
TI - qBrain-2, a POU domain gene expressed in quail embryos.
AB - We isolated a quail class III POU domain gene, qBrain-2, which was cloned from a
cDNA library of E5 embryos. Northern blot and in situ hybridization analyses
showed that qBrain-2 was expressed in developing central nervous system and adult
brain. Moreover, qBrain-2 transcripts showed a dynamic distribution in embryonic
central nervous system. Its transcripts were dominantly detected in the
ventricular zone of the developing brain and spinal cord, but rarely in the
differentiated region of mantle zone as well as the non-neuronal roof plate and
floor plate. This suggests that qBrain-2 is involved in proliferation and
differentiation of the neuroepithelial cells of quail central nervous system.
PMID- 10760568
TI - Glucose starvation induces a drastic reduction in the rates of both transcription
and degradation of mRNA in yeast.
AB - Gradual depletion of essential nutrients in yeast cultures induces a complex
physiological response, leading initially to induction of pathways required for
the utilization of alternative nutrients and, when such sources are depleted, to
entry into stationary phase. Abrupt removal of sugar does not allow the proper
establishment of stationary phase. Here we report that abrupt removal of glucose
from the growth medium elicits a coordinated response in yeast cells that
resembles, in some aspects, the gradual passage to stationary phase.
Phosphorylation of RNA polymerase II at a subset of sites in the COOH-terminal
domain (CTD) is decreased. Transcription by RNA polymerases I and II is shut down
almost completely, whereas transcription by RNA polymerase III continues. In
parallel, the rate of mRNA degradation is drastically reduced, at a stage
preceding poly(A) shortening. This response is suited for conservation of scarce
resources while preserving the ability of cells to recover when nutrients become
available.
PMID- 10760569
TI - Allelic expression of the putative tumor suppressor gene p73 in human fetal
tissues and tumor specimens.
AB - p73, a proposed tumor suppressor, shares significant amino acid sequence homology
with p53. However, p73 is rarely mutated in tumors but it has been suggested that
p73 is monoallelically expressed in some tissues. This latter feature would
predispose p73 to gene inactivation because a single genetic 'hit' or the loss of
the expressed parental allele would leave the cell without p73 activity. We
examined the allelic expression of p73 in normal fetal tissues and in ovarian
cancer and Wilms' tumor. We found that p73 was biallelically expressed in all
fetal tissues, except in brain, where differential expression of the two parental
alleles was observed. Biallelic expression of p73 was also observed in paired
samples of ovary cancer and Wilms' tumor. Loss of heterozygosity of p73 occurred
at relatively low rates in tumors: one of 11 informative samples (9.1%) of
ovarian cancer and two of 19 (10.1%) Wilms' tumors. These data demonstrate that
p73 is biallelically expressed in most tissues, thus excluding genomic imprinting
as a molecular mechanism to predispose to allelic inactivation of p73 in human
tumors.
PMID- 10760570
TI - Promoter analysis of the human ubiquitin-conjugating enzyme gene family UBE2L1-4,
including UBE2L3 which encodes UbcH7.
AB - UbcH7 is a ubiquitin-conjugating enzyme mediating c-fos degradation,
transcription factor NF-kappaB maturation, human papilloma virus-mediated p53 and
Myc protein degradation, in vitro. Previously, we characterised a highly
dispersed gene family, UBE2L1-UBE2L4, whose members could potentially encode
different isoforms of the UbcH7 protein. UBE2L3, located at chromosome 22q11.2,
is the only identified family member with introns and encodes a polypeptide
sequence identical to that of UbcH7. Promoter characterisation of UBE2L1, UBE2L3
and UBE2L4 5'-upstream regions was performed to establish which are transcribed
under normal physiological conditions and after heat shock. Promoter activity was
observed only with the UBE2L3 construct, the minimal promoter lying within a
region 100 bp upstream of the transcriptional start site. No evidence for the
presence of UBE2L1 or UBE2L4 transcripts was observed in human or murine tissues
and cell lines. These data strongly suggest that UBE2L1 and UBE2L4 are likely to
encode pseudogenes. Sequencing revealed that the UBE2L3 promoter contained no
TATA or CCAAT boxes. Protein:DNA interaction studies confirmed the presence of
binding sites for the transcription factors AP2 and Sp1 in the UBE2L3 minimal
promoter. Deletion of these binding sites indicated that these factors are
crucial for transcription of this gene.
PMID- 10760571
TI - Expression and subcellular localization of cpn60 protein family members in
Leishmania donovani.
AB - We have identified two diverged members of the cpn60 gene family in Leishmania
donovani, causative agent of Indian Kala Azar. One of the genes, cpn60.1,
although actively transcribed, is not expressed to detectable levels of protein
in cultured L. donovani. The other gene, cpn60.2, which, compared with cpn60.1,
shows a higher sequence conservation with the hsp60 genes from Trypanosoma brucei
and Trypanosoma cruzi is expressed constitutively in cultured promastigotes. The
abundance of the gene product, Cpn60.2, increases by 2.5-fold under heat stress
and in axenic amastigotes of L. donovani. Cpn60.2 is also found enriched in
mitochondrial cell fractions and localizes to the mitochondrial matrix. We
conclude that Cpn60.2 is the major mitochondrial chaperonin in Leishmania.
PMID- 10760573
TI - Murine and human cathepsin Z: cDNA-cloning, characterization of the genes and
chromosomal localization.
AB - A novel murine cysteine protease from the family of papain-like cysteine
proteinases was identified by dbEST-database search. A 1. 4-kb full-length cDNA
encoding a predicted polypeptide of 306 amino acids was characterized. The new
protease, tentatively named cathepsin Z, exhibits all features characteristics of
a papain-like cysteine protease, including the highly conserved residues of the
'catalytic triad'. Cathepsin Z shares only 26-35% overall homology with
previously described mammalian papain-like cysteine peptidases and has an
unusually short propeptide, which may indicate that it is a member of a putative
new subfamily within the family of papain-like cysteine peptidases. Genomic
clones covering the murine and human cathepsin Z genes were isolated. They
comprise six exons and five introns spanning a 12-kb region of genomic DNA,
respectively. Murine cathepsin Z was mapped to chromosome 2, a region with
synteny homology to a region of human chromosome 20 to which human cathepsin Z
has been mapped previously. Northern blot analysis revealed ubiquitous expression
of murine cathepsin Z. Multiple transcriptional start sites were identified for
the murine cathepsin Z gene and together with the absence of a TATA box, a high
G+C content, a CpG island and the presence of several Sp1-binding sites in the
promoter region, murine cathepsin Z may be classified as a 'housekeeping' gene.
PMID- 10760572
TI - Genomic structure and expression profile of LPHH1, a 7TM gene variably expressed
in breast cancer cell lines.
AB - Gene identification studies, centred on a region of overlapping loss of
heterozygosity in breast tumours within band 1p31.1, lead to the characterisation
of LPHH1, a novel human 7TM gene. The coding sequence of LPHH1 extends over a 60
kb region and comprises in excess of 28 exons. Alternative splicing occurs
minimally at five positions, four of which are within the coding sequence. The
fifth region of alternative splicing occurs at the extreme 5' end of the
transcript. A clear tissue specific bias in alternative exon selection is
observed to some degree at all five positions, including the extreme 5' region,
which raises the possibility of multiple and perhaps tissue specific promoters.
One such putative promoter region, which appears to be utilised predominantly in
breast cancer cells, has been identified. LPHH1 is highly evolutionarily
conserved, with the simplest (19 exon) gene product being 95% identical between
human and rat. Comparison of the alternatively spliced exons between three
species, where data are available, has so far revealed 100% identity in the
encoded peptide sequences, suggesting conservation of a functional aspect of this
splicing. Gene expression has been observed in all tissues and cell lines tested,
with the exception of lymphoblastoid and multiple myeloma lines, where there
appears to be only a very low level of transcription. LPHH1 also appears to be
downregulated in human bone marrow. These data are consistent with a role for the
gene products in adhesion-mediated signalling. Analysis of a panel of breast
tumour cell lines revealed that a number apparently overexpressed the gene whilst
others showed very low levels of transcription. In one case, the overexpression
correlated with a low level increase in gene copy number in the tumour line. In
addition to differences in the overall levels of expression, LPHH1 mRNAs were
alternatively spliced to varying degrees with shifts in the major gene product to
truncated or altered forms in some lines. No somatic LPHH1 mutations were
detected through sequence analysis of four primary breast tumours that showed
loss of the adjacent 1p31.1 marker D1S207.
PMID- 10760574
TI - Liver cell-specific transcriptional regulation of connexin32.
AB - Gap junctional intercellular communication facilitates liver homeostasis and
growth control in the liver. The major gap junction protein expressed by
hepatocytes is connexin32 (Cx32) and non-parenchymal hepatic cells do not express
this gene. We investigated the regulation of Cx32 transcription by trans
activating factors in liver cells. Transient transfection assays using deletions
of the rat Cx32 promoter (nt -753 to -33) linked to the luciferase gene were
performed in MH1C1 rat hepatoma cells that express endogenous Cx32 compared with
WB-F344 rat liver epithelial cells that do not. The basal promoter element was
located within nt -134 to -33 and was 1.4-fold more active in MH1C1 cells than WB
F344 cells whereas the entire promoter fragment (nt -754 to -33) was four-fold
more active in MH1C1 cells. Specific nuclear protein-DNA complexes that bound to
Sp1 consensus sites within the basal promoter were formed using nuclear extracts
from both types of cells. Additional promoter sequences increased promoter
activity more strongly in MH1C1 cells than WB-F344 cells and this was correlated
with the binding of hepatocyte nuclear factor-1 (HNF-1) to two HNF-1 consensus
sites centered at -187 and -736. Expression of HNF-1 and binding to these
elements was only observed with MH1C1 cells. Other specific protein-DNA complexes
were formed, however, that included YY-1- and NF-1-containing complexes, but
these were not related to promoter activity. Dexamethasone increased Cx32
promoter activity and expression in MH1C1 cells, but had little effect in WB-F344
cells and did not alter protein-DNA complex formation. These data suggest that
Sp1 is responsible for Cx32 promoter basal activity, that HNF-1 determines the
cell-specific expression of Cx32, and that dexamethasone increases Cx32
expression through other mechanisms.
PMID- 10760576
TI - Expression of two vacuolar-type ATPase B subunit isoforms in swimbladder gas
gland cells of the European eel: nucleotide sequences and deduced amino acid
sequences.
AB - The poly(A)(+) RNA of swimbladder gas gland cells of the European eel Anguilla
anguilla was isolated and used for cDNA synthesis. Using a pair of degenerate PCR
primers directed towards the evolutionary highly conserved central part of the B
subunit of vacuolar type H(+)-ATPase (V-ATPase) a fragment of 388 bp was
amplified. By sequencing the cloned PCR products two different amplicons with a
sequence identity of about 86% were obtained. BLASTN searches revealed a high
degree of similarity of both to V-ATPase B subunits of other species. The
sequences were completed by performing rapid amplification of cDNA ends PCR,
subsequent cloning, and sequencing of the obtained products. The expression of
two different isoforms of the V-ATPase B subunit is already demonstrated for Homo
sapiens and Bos taurus. This is the first report that attributes the same
phenomenon to a non-mammalian species, A. anguilla. The first isoform found in
eel (vatB2) shows the highest degree of amino acid sequence homology with the
human brain isoform (98.2%), the second one (vatB1) with the B subunit sequence
of rainbow trout (Oncorhynchus mykiss) gill and kidney (98, 6%). The alignment of
the deduced amino acid sequences of vatB1 and vatB2 shows that the highest
sequence variation between these two isoforms is found at the amino-terminus,
where vatB1 is nine amino acids shorter than vatB2, while at the carboxy-terminus
it is two amino acids longer than vatB2. This has also been reported for the
human and bovine kidney isoforms when compared with the brain isoforms. Northern
blot analysis using specific hybridization probes revealed the expression of two
mRNA's with lengths of about 2.9 kb and 3.5 kb for vatB1 and vatB2, respectively.
For mammals, it is well known that V-ATPases containing the kidney isoforms of
the B subunit are responsible for the extrusion of protons across the plasma
membranes of several cell types. The fact that eel vatB1 seems to share
structural features with the kidney isoforms in mammals supports the hypothesis
that in gas gland cells a V-ATPase contributes to the acidification of the blood
in the swimbladder.
PMID- 10760575
TI - Expression of human prostatic acid phosphatase gene is regulated by upstream
negative and positive elements.
AB - Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific
differentiation antigen. To understand the regulation of expression of the PAcP
gene, we studied the cis-regulatory elements of its promoter. A DNA fragment from
-2899 to +87 base pairs (bp) of PAcP gene was fused to the chloramphenicol
acetyltransferase (CAT) reporter gene and introduced into PC-3 and LNCaP human
prostate cancer cells. The expression of the CAT gene driven by the PAcP promoter
was assessed in transient expression assays. Sequential 5' deletions of the
promoter were constructed and analyzed to reveal the positive and the negative
regulatory elements that are involved in regulating the transcription of the PAcP
gene. Our data showed that the proximal sequence -1305/+87 bp directs a high
level of the CAT activity in both cell lines. Deletion of the region from -1305
to -779 resulted in approximately a 10- and three-fold decrease of the PAcP
promoter activity in PC-3 and LNCaP cells, respectively. Interestingly, an
inverse correlation of the CAT activity with the cell growth was observed when
the reporter gene was driven by the -1305/+87 fragment, but not by the -779/+87
fragment. Two regions of transcriptional suppression were identified and located
in positions from -2899 to -2583, and from -2583 to -1305 bp. Furthermore, the
activity of the core promoter region from -779 to +87 bp can be activated by a SV
40 enhancer. The results, thus, clearly demonstrate the presence of positive and
negative cis-elements in the promoter region of the PAcP gene.
PMID- 10760577
TI - Molecular characterization of cDNAs encoding G protein alpha and beta subunits
and study of their temporal and spatial expression patterns in Nicotiana
plumbaginifolia Viv.
AB - We have isolated cDNA sequences encoding alpha and beta subunits of potential G
proteins from a cDNA library prepared from somatic embryos of Nicotiana
plumbaginifolia Viv. at early developmental stages. The predicted NPGPA1 and
NPGPB1 gene products are 75-98% identical to the known respective plant alpha and
beta subunits. Southern hybridizations indicate that NPGPA1 is probably a single
copy gene, whereas at least two copies of NPGPB1 exist in the N. plumbaginifolia
genome. Northern analyses reveal that both NPGPA1 and NPGPB1 mRNA are expressed
in all embryogenic stages and plant tissues examined and their expression is
obviously regulated by the plant hormone auxin. Immunohistological localization
of NPGPalpha1 and NPGPbeta1 preferentially on plasma and endoplasmic reticulum
membranes and their immunochemical detection exclusively in microsomal cell
fractions implicate membrane association of both proteins. The temporal and
spatial expression patterns of NPGPA1 and NPGPB1 show conformity as well as
differences. This could account for not only cooperative, but also individual
activities of both subunits during embryogenesis and plant development.
PMID- 10760578
TI - Novel roles for elongin C in yeast.
AB - Mammalian Elongin C is a 112-amino acid protein that binds to the von Hippel
Lindau (VHL) tumor suppressor and to Elongin A, the transcriptionally active
subunit of the RNA polymerase II elongation factor, SIII. It is conserved in
eukaryotic cells, as homologs have been identified in Saccharomyces cerevisiae,
Drosophila melanogaster and Caenorhabditis elegans. The mammalian protein is
thought to function as part of a ubiquitin targeting E3 ligase, yet the function
in yeast has not been determined. In this report we examine the role of Elongin C
in yeast and establish that yeast Elongin C may function in a mode distinct from
its role as an E3 ligase. The RNA is expressed ubiquitously, albeit at low
levels. Two hybrid analyses demonstrate that Elongin C in yeast interacts with a
specific set of proteins that are involved in the stress response. This suggests
a novel role for Elongin C and provides insights into additional potential
functions in mammalian cells.
PMID- 10760579
TI - Increased xylanase production in Streptomyces lividans after replacement of the
signal peptide: dependence on box and inverted repeat sequence.
AB - The signal peptide of the xylanase A gene of Streptomyces lividans was replaced
by the signal sequence of the cellulase A preceded by a 57 nucleotides (nt)
upstream sequence. This latter contains a 5 nt inverted repeat (5'
TGGGAACGCTCCCA). The 3'-end of the inverted repeat contains a 5 nt box (TCCCA),
which is complementary to the 16S rRNA of S. lividans. The effects on the
production of xylanase resulting from deletions in the inverted repeat and from
variations in the length of the box are shown. Removal of the inverted repeat and
box decreased the xylanase production by 75%. Increasing the complementarity of
the box with the 16S rRNA to 17 nt decreased the production by 90%. A reduction
in the length of the inverted repeat, and consequently in the box, from 5 to 4 nt
decreased the production by 40%. Preserving the 4 nt inverted repeat but
lengthening the box from 5 to 6 nt increased the production by 1.5-fold. Finally,
removing the inverted repeat but introducing an 8 nt box increased the xylanase
production by 1.9-fold which then averaged 2.3 g/l of xylanase. The most
efficient boxes contained 6-8 nt and were located between 14 and 19 nt downstream
from the first initiation codon.
PMID- 10760580
TI - Reiterative transcription initiation from galP2 promoter of Escherichia coli.
AB - The expression of gal operon in Escherichia coli is driven by two promoters, P1
and P2 separated by 5 bp. The transcription initiated from the P2 generates a
large amount of abortive transcripts to produce a comparable amount of full
length transcript as P1 in vitro. In this study, we investigated the source of
the abortive transcripts by employing a quantitative potassium permanganate
footprinting method that determines the extent of open promoter complex
formation. The extents of open promoter complex formation at the two gal
promoters were about the same during the given reaction time while the amount of
transcription initiation determined by in vitro transcription assay showed a
considerable difference: several hundred-fold more transcription initiation from
the P2 than the P1, most of which was abortive. Thus, it was concluded that the
abortive transcripts are generated reiteratively by a small fraction of RNA
polymerase. An in vitro transcription assay using an immobilized DNA template
revealed that the fraction of RNA polymerase generating abortive transcripts
never produces the full-length transcript and it remains bound to the promoter.
We concluded that there are two kinds of RNA polymerase-promoter complexes formed
at galP2, at least in vitro, productive complex and nonproductive complex; and,
the nonproductive complex is responsible for generating large amount of abortive
transcripts from the P2.
PMID- 10760581
TI - DRG represents a family of two closely related GTP-binding proteins.
AB - In a previous publication we identified a novel human GTP-binding protein that
was related to DRG, a developmentally regulated GTP-binding protein from the
central nervous system of mouse. Here we demonstrate that both the human and the
mouse genome possess two closely related drg genes, termed drg1 and drg2. The two
genes share 62% sequence identity at the nucleotide and 58% identity at the
protein level. The corresponding proteins appear to constitute a separate family
within the superfamily of the GTP-binding proteins. The DRG1 and the DRG2 mRNA
are widely expressed in human and mouse tissues and show a very similar
distribution pattern. The human drg1 gene is located on chromosome 22q12, the
human drg2 gene on chromosome 17p12. Distantly related species including
Caenorhabditis elegans, Schizosaccharomyces pombe and Saccharomyces cerevisiae
also possess two drg genes. In contrast, the genomes of archaebacteria (Halobium,
Methanococcus, Thermoplasma) harbor only one drg gene, while eubacteria do not
seem to contain any. The high conservation of the polypeptide sequences between
distantly related organisms indicates an important role for DRG1 and DRG2 in a
fundamental pathway.
PMID- 10760582
TI - Structural organization of the human microphthalmia-associated transcription
factor gene containing four alternative promoters.
AB - Microphthalmia-associated transcription factor (MITF) affects the development of
many types of cells, including melanocytes and retinal pigment epithelium (RPE).
MITF consists of at least three isoforms, MITF-A, MITF-H and MITF-M, differing at
their amino-termini and expression patterns. Here, we characterize the structural
organization of the human MITF gene. The gene contains at least four isoform
specific first exons, exons 1A, 1H, 1B and 1M in the 5' to 3' direction, each of
which encodes the unique amino-terminus of a given isoform, including newly
identified MITF-B. The 5'-flanking regions of these isoform-specific exons are
termed promoters A, H, B and M, respectively, which showed different promoter
activities, as judged by transient transfection assay. Promoter A directs the
expression of a reporter gene in RPE, cervical cancer and melanoma cells, whereas
promoter M is functional only in melanoma cells. Promoter H showed the
significant activity in RPE and cervical cancer cells but not in melanoma cells.
In contrast, the 1.7 kb 5'-flanking region of exon 1B showed no noticeable
promoter activity in these cell lines. Therefore, alternative promoters provide
the MITF gene with the diversity in transcriptional regulation and the capability
of generating structurally different protein isoforms.
PMID- 10760583
TI - 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression is regulated
by diet composition and ration size in liver of gilthead sea bream, Sparus
aurata.
AB - Modulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF-2-K/Fru
2,6-P(2)ase) gene expression by diet composition and ration size was studied in
the liver of gilthead sea bream, Sparus aurata. From five different types of diet
supplied to fish, those with either high carbohydrate/low protein or high
carbohydrate/low lipid content stimulated 6PF-2-K/Fru-2,6-P(2)ase expression at
the levels of mRNA, immunodetectable protein and kinase activity as well as
promoting higher fructose-2,6-bisphosphate (Fru-2,6-P(2)) values. The expression
of the bifunctional enzyme and Fru-2,6-P(2) levels showed also direct dependence
on the quantity of diet supplied. These findings demonstrate for the first time
nutritional regulation of 6PF-2-K/Fru-2,6-P(2)ase at mRNA level by diet
composition and ration size and suggest that the carnivorous fish S. aurata can
adapt its metabolism, by stimulation of liver glycolysis, to partial substitution
of protein by carbohydrate in the diet. In addition, the expression of 6PF-2
K/Fru-2,6-P(2)ase can be used as an indicator of nutritional condition.
PMID- 10760584
TI - Cloning, mapping and expression analysis of the sheep Wilson disease gene
homologue.
AB - Copper homeostasis in mammals is maintained by the balance of dietary intake and
copper excretion via the bile. Sheep have a variant copper phenotype and do not
efficiently excrete copper by this mechanism, often resulting in excessive copper
accumulation in the liver. The Wilson disease protein (ATP7B) is a copper
transporting P-type ATPase that is responsible for the efflux of hepatic copper
into the bile. To investigate the role of ATP7B in the sheep copper accumulation
phenotype, the cDNA encoding the ovine homologue of ATP7B was isolated and
sequenced and the gene was localised by fluorescence in situ hybridisation to
chromosome 10. The 6.3 kb cDNA encoded a predicted protein of 1444 amino acids
which included all of the functional domains characteristic of copper
transporting P-type ATPases. ATP7B mRNA was expressed primarily in the liver with
lower levels present in the intestine, hypothalamus and ovary. A splice variant
of ATP7B mRNA, which was expressed in the liver and comprised approximately 10%
of the total ATP7B mRNA pool, also was isolated. The results suggest that ATP7B
is produced in the sheep and that the tendency to accumulate copper in the liver
is not due to a gross alteration in the structure or expression of ATP7B.
PMID- 10760585
TI - Characterisation of the promoter region of the zebrafish six7 gene.
AB - The Drosophila homeobox gene sine oculis and its murine homologue Six3 have both
been shown to have regulatory functions in eye and brain development. In
zebrafish, three Six3-related genes with conserved expression during early eye
and head formation have been identified. One of these, six7, is first expressed
at the gastrula stage in the involuting axial mesoderm, and later in the
overlying neuroectoderm from which the forebrain and optic primordium develop. To
elucidate the mechanisms regulating six7 expression, we isolated a 2.7-kb
fragment of the 5'-flanking region. Three sequentially deleted fragments of this
upstream region were used to produce GFP reporter constructs for analysis of
tissue-specific expression in zebrafish embryos. The results show that a 625-bp
upstream fragment is sufficient to direct strong expression of the reporter
during gastrulation and early neurulation. The proximal part of the promoter
contains binding sites for various constitutive transcription factors and an
additional upstream element that was shown to be critical in directing expression
to the anterior region of the zebrafish brain.
PMID- 10760586
TI - Molecular cloning and sequencing of the sodB gene from a heterocystous
cyanobacterium Anabaena sp. PCC 7120.
AB - Superoxide dismutase (Sod) plays an important role in all aerobic organisms. The
sodB gene of a heterocystous cyanobacterium Anabaena sp. PCC 7120 was cloned and
sequenced. The Sod protein is predicted to have 199 amino acids and a molecular
mass of 22.5 kDa. Sequence comparison among SodB from cyanobacteria and
chloroplasts revealed that the sodB gene indeed encodes an iron-Sod. Northern
blot analysis showed that the sodB gene of Anabaena sp. PCC 7120 is transcribed
as a single gene and its expression was up-regulated when the cells were
subjected to a shift from a nitrogen repletion condition to a nitrogen depletion
condition.
PMID- 10760587
TI - Genomic organization and regulation of the vav proto-oncogene.
AB - Vav and vav2 are members of the dbl family of guanine nucleotide exchange factors
(GEF) for the rho/rac family of GTP binding proteins. Vav is expressed primarily
in hematopoietic cells, while vav2 has a wider tissue distribution. The genomic
structure of the human vav proto-oncogene was studied by identifying and
sequencing all 27 exons of the gene from overlapping P1 and cosmid clones. The
gene spans a 77-kb region on chromosome 19. In contrast, the coding region of
vav2 is distributed over 30 exons spanning 227-kb. The overall organization of
the exons which encode both proteins was found to be similar. In humans,
alternative splicing of exons 6, 16 and 28 generated at least two distinct vav2
mRNA species. Several differences from the original vav cDNA sequence were noted.
The most important difference was the identification of amino acid 718 as
isoleucine, rather than threonine. This change warrants the reclassification of
the vav SH2 domain as a type 3 SH2, instead of a type 2 SH2 as originally
proposed by Songyang et al. (Mol. Cell. Biol. 14 (1994) 2777-2785). A series of
vav promoter deletions were constructed using the enhanced green fluorescent
protein (EGFP) as a reporter gene. A 23-bp segment that included a potential
CBF/AML-1 binding site was found to be essential for EGFP expression in U937
cells. The same constructs were not active in HeLa cells, which do not express
vav. A potential c-myb DNA binding site within the vav promoter was not required
for EGFP expression.
PMID- 10760588
TI - Characterization of the Aspergillus parasiticus major nitrogen regulatory gene,
areA.
AB - The major nitrogen regulatory gene, areA, was cloned from Aspergillus
parasiticus. It encoded a polypeptide of 864 amino acids which contained a
nuclear localization signal (NLS), a highly acidic region from positions 497 to
542, a Cys-X(2)-Cys-X(17)-Cys-X(2)-Cys DNA-binding motif and a conserved carboxy
terminus. Electrophoretic mobility shift assays suggested that the A. parasiticus
AREA DNA-binding domain fusion protein bound cooperatively to single GATA
elements in the A. parasiticus niaD-niiA intergenic region. AREA also bound to
the aflR-aflJ intergenic region of the aflatoxin biosynthesis gene cluster.
Regions of areA were fused to a yeast GAL4 DNA-binding domain coding region to
localize putative transcription activation domain(s) of AREA based on activation
of the GAL1(p)::lacZ reporter gene expression. The portion between NLS and the
acidic domain demonstrated 16-20-fold higher activation activities than other
portions of AREA, which suggests that the transcription activation domain is
located in this region.
PMID- 10760589
TI - Molecular cloning of a cDNA encoding a novel Ca(2+)-dependent nuclease of
Arabidopsis that is similar to staphylococcal nuclease.
AB - We have isolated a cDNA from Arabidopsis thaliana for a protein consisting of 323
amino acids with similarity to an extracellular nuclease from Staphylococcus.
Nuclease assay using toluidine blue-DNA plates has demonstrated that the gene
product has nuclease activity dependent on Ca(2+) and inhibited by Zn(2+),
designated CAN (Ca(2+)-dependent nuclease). Differing from the staphylococcal
nuclease, CAN has neither a signal peptide nor any long hydrophobic regions,
suggesting that it is not a secreted protein.
PMID- 10760590
TI - cDNA cloning and expression analysis of a non-photosynthetic ferredoxin gene in
morning glory (Pharbitis nil).
AB - A full-length cDNA encoding a non-photosynthetic ferredoxin was isolated from
apical buds of morning glory (Pharbitis nil), a short-day plant, by differential
screening under flower-inducing and non-inducing conditions. Northern analysis
and in situ hybridization showed that the transcript was abundant in shoot apices
and root tips. The transcript level in the apical buds decreased with the flower
inducing light treatment.
PMID- 10760591
TI - Two novel first exons in the prolactin receptor gene are transcribed in a tissue
specific and sexual maturation-dependent manner to encode multiple 5'-truncated
transcripts in the testis of the chicken.
AB - Cloning and sequencing of the chicken prolactin receptor (PRLR) gene segment from
the transmembrane domain to the box 2 motif revealed the presence of the two
testis-specific first exons, TSE-1 and TSE-2, encoding the unique 5'-end
sequences of the reported and newly identified multiple 5'-truncated PRLR
transcripts containing only the cytoplasmic domain in the testis. TSE-1 was
located downstream of the exon encoding the transmembrane domain and TSE-2
presented downstream of the exon encoding the box 1 motif. These findings
indicate that the box 1-containing 5'-truncated transcripts are generated by the
utilization of TSE-1 as the first exon with distinct splicing donor sites to the
box 1-containing exon, and that the utilization of TSE-2 as the first exon and
its splicing to the box 2-containing exon results in the generation of the box 1
lacking transcript. Three transcription initiation sites for the box 1-containing
5'-truncated transcripts and two transcription initiation sites for the box 1
lacking transcript were detected by the RNase protection assays. Reverse
transcription-polymerase chain reaction analysis showed that the expression
levels of all these 5'-truncated PRLR transcripts are simultaneously increased
during sexual maturation, accompanying the decrease of the amount of the
canonical full-length transcript for PRLR.
PMID- 10760592
TI - The human RGL (RalGDS-like) gene: cloning, expression analysis and genomic
organization.
AB - Ral GDP dissociation stimulator (RalGDS) and its family members RGL, RLF and RGL2
are involved in Ras and Ral signaling pathways as downstream effector proteins.
Here we report the precise localization and cloning of two forms of human RGL
gene differing at the amino terminus. Transcript A, cloned from liver cDNA
libraries has the same amino terminus as the mouse RGL, whereas transcript B
cloned from brain has a substitution of 45 amino acids for the first nine amino
acids. At the genomic level, exon 1 of transcript A is replaced by two
alternative exons (1B1 and 1B2) in transcript B. Both forms share exons 2 through
18. The human RGL protein shares 94% amino acid identity with the mouse protein.
Northern blot analysis shows that human RGL is expressed in a wide variety of
tissues with strong expression being seen in the heart, brain, kidney, spleen and
testis.
PMID- 10760593
TI - Mouse cathepsin M, a placenta-specific lysosomal cysteine protease related to
cathepsins L and P.
AB - The complete nucleotide sequence of a novel cathepsin cDNA derived from mouse
placenta was determined and is termed cathepsin M. The predicted protein of 333
amino acid is a member of the family C1A proteases and is related to mouse
cathepsins L and P. Mouse cathepsin M is highly expressed in placenta, whereas no
detectable levels were found in lung, spleen, heart, brain, kidney, thymus,
testicle, liver, or embryo. Phylogenic analyses of the sequences of human and
mouse cathepsins show that cathepsin M is most closely related to cathepsins P
and L. However, the differences are sufficiently large to indicate that the
enzymes will be found in other species. This is in contrast to human cathepsins L
and V, which probably resulted from a gene duplication after divergence of
mammalian species.
PMID- 10760594
TI - Mouse hepatocyte growth factor activator gene: its expression not only in the
liver but also in the gastrointestinal tract.
AB - A cDNA encoding mouse hepatocyte growth factor activator (HGFA) has been cloned
by RT-PCR, based on the screening result from the database of expressed sequence
tags. Subsequently, its gene was cloned from a mouse genomic bacterial artificial
chromosome library using the cDNA as a probe. Sequencing analysis revealed that
mouse HGFA protein deduced from the cDNA, similar to its human and rat
counterparts, has two epidermal growth factor-like domains, type 1 and 2
fibronectin homology domains, a single kringle domain and a catalytic domain of
serine proteinase, and the gene consists of 14 exon spanning approximately 7.5
kb. Interestingly, mouse HGFA mRNA was detected not only in the liver but also in
the gastrointestinal tract by RNA blot analysis. Since hepatocyte growth factor
(HGF) is up-regulated in the damaged gastrointestinal mucosa, our present data
suggest that HGFA might activate proHGF directly in the gastrointestinal mucosa
and play an important role in wound repair throughout the gastrointestinal tract.
PMID- 10760595
TI - Structure and tissue distribution of chicken leptin receptor (cOb-R) mRNA.
AB - Chicken leptin receptor (cOb-R) cDNA has been cloned, sequenced and
characterized. The predicted cOb-R preprotein was composed of 1148 amino acids
showing approximately 60% sequence identity with the long isoform of mammalian
leptin receptor, and contained a putative signal peptide, a single transmembrane
domain and the conserved box 1, 2 and 3 motifs in the cytoplasmic region. High
levels of cOb-R mRNA expression were observed in ovary and brain, and less
abundant expression of the mRNA was detected in liver, kidney and intestine in
juvenile females and sexually matured hens. The expression levels of cOb-R mRNA
did not change during sexual maturation in most tissues, but the mRNA level in
the intestine was higher in matured hens than in juveniles. Estrogen treatment
was found to enhance the Ob-R mRNA expression in the intestine, but not in other
tissues.
PMID- 10760596
TI - Molecular cloning and characterization of maize Toc34, a regulatory component of
the protein import machinery of chloroplast.
AB - Several components of the chloroplast protein import machinery have been
identified mostly in the C3 dicot plant pea. We describe here two homologous cDNA
sequences of Toc34, a regulatory component of the import machinery, from maize, a
C4 monocot plant. The deduced amino acid sequences of two maize Toc34 proteins,
named ZmToc34-1 and ZmToc34-2, show 95% identity to each other and about 60% to
those of previously identified Toc34 proteins. The GTP-binding motif and the
presumed carboxyl terminal membrane anchor are also conserved in the ZmToc34
proteins. The maize Toc34, like that of pea, is tightly associated with the outer
envelope membrane of chloroplast and exposed to the cytosol.
PMID- 10760597
TI - Cloning and characterization of the gene encoding RNA polymerase sigma factor
sigma(54) of deep-sea piezophilic Shewanella violacea.
AB - We have recently reported that a sigma(54)-like factor recognizes a DNA element,
designated as region A, upstream of a pressure-regulated operon in piezophilic
Shewanella violacea strain DSS12 (Nakasone et al., FEMS Microbiology Lett. 176
(1999) 351-356). In this study, we isolated and characterized the rpoN gene of
this piezophilic bacterium. The rpoN gene was found to encode a putative protein
consisting of 492 amino acid residues with a predicted molecular mass of 55359
Da. Significant homology was evident comparing the rpoN sequence of S. violacea
with that of Escherichia coli (62.8% identity), Vibrio anguillarum (61.7%
identity) and Pseudomonas putida (57.0% identity). The DNA-binding domain at the
C-terminus of sigma(54) is well conserved in the case of the S. violacea rpoN
gene product and the helix-turn-helix motif and the RpoN box are also present. In
addition, the conserved glutamine-rich domain is present at the N-terminus.
sigma(54) in S. violacea was expressed at a relatively constant level under
various growth conditions as determined by both primer extension and Western
blotting analyses. By means of a recombinant plasmid, a hexahistidine-tagged
derivative of the sigma(54) from strain DSS12 was overexpressed in Escherichia
coli and purified to near homogeneity. An electrophoretic mobility shift assay
demonstrated that the purified sigma(54) protein specifically recognizes region A
in the above-mentioned pressure-regulated operon.
PMID- 10760598
TI - Molecular cloning and characterization of a novel human gene (NESCA) which
encodes a putative adapter protein containing SH3.
AB - A full-length cDNA encoding a novel protein was isolated and sequenced from a
human placental cDNA library. This cDNA consists of 1990 bp and has a predicted
open reading frame encoding 433 amino acids. It possesses an Src homology 3 (SH3)
motif, a leucine zipper motif and no catalytic domain, suggesting that it seems
to be an adapter protein. PCR-based mapping with both a monochromosomal hybrid
panel and radiation hybrid cell panels placed the gene to human chromosome 1q21
22.
PMID- 10760599
TI - Cloning and expression profile of chicken radixin.
AB - Radixin is a member of the ERM (ezrin/radixin/moesin) family of cytoskeletal
linkers. We have cloned chicken radixin as a 4.3 kb cDNA, which encodes an 80 kDa
protein that is more than 98% identical to radixin from evolutionarily diverse
species. High sequence homology (70-80%) also extends into the 3'-untranslated
region (UTR) of the radixin gene. The 3'-UTR of moesin, but not ezrin, was also
conserved, suggesting an essential, and possibly specific, regulatory function. A
distinct pattern of radixin expression is seen in chicken tissues, suggesting a
cell-type-specific function.
PMID- 10760600
TI - Molecular characterization of two soybean homologs of Arabidopsis thaliana
CLAVATA1 from the wild type and fasciation mutant.
AB - Arabidopsis thaliana CLAVATA1 (CLV1)-like genes were isolated from the wild type
and fasciation mutant of soybean (Glycine max). Two soybean homologs of CLV1,
designated GmCLV1A and GmCLV1B, are similar in sequence. No missense mutations in
GmCLV1A and GmCLV1B between the wild type and mutant were found. GmCLV1 was
mapped at 7. 1 cM from a restriction fragment length polymorphism marker on the
linkage group H of the soybean molecular map. DNA fingerprinting using bacterial
artificial chromosome clones identified two contigs indicating there are two loci
for GmCLV1 in the soybean genome. One locus contains GmCLV1A and the other locus
contains GmCLV1A and GmCLV1B. Relative multiplex quantitative reverse
transcriptase-polymerase chain reaction analysis indicates that the two genes are
transcribed in all organs and at higher levels in floral apices. Differential
expression patterns of the two genes suggest that the function of the two genes
is slightly different in different organs.
PMID- 10760601
TI - Sexual stage-specific expression of a third calcium-dependent protein kinase from
Plasmodium falciparum.
AB - A third calcium-dependent protein kinase (CDPK) gene has been isolated from the
human malaria parasite Plasmodium falciparum by vectorette technology. The gene
consists of five exons and four introns. The open reading frame resulting from
removal of the four introns encodes a protein of 562 amino acid residues with a
predicted molecular mass of 65.3 kDa. The encoded protein, termed PfCDPK3,
consists of four distinct domains characteristic of a member of the CDPK family
and displays the highest homology (46% identity and 69% similarity) to PfCDPK2,
the second CDPK of P. falciparum. The N-terminal variable domain is rich in
serine/threonine and lysine and contains multiple consensus phosphorylation sites
for a range of protein kinases. The catalytic domain possesses all conserved
motifs of the protein kinase family except for the highly conserved glutamic acid
residue in subdomain VIII, which is replaced by a glutamine residue. The sequence
of the junction domain comprising 31 amino acid residues is less conserved. The
calmodulin-like regulatory domain contains four EF-hand calcium-binding motifs,
each consisting of a loop of 12 amino acid residues which is flanked by two alpha
helices. Southern blotting of genomic DNA digests showed that the Pfcdpk3 gene is
present as a single copy per haploid genome. A 2900 nucleotide transcript of this
gene is expressed specifically in the sexual erythrocytic stage, indicating that
PfCDPK3 is involved in sexual stage-specific events. It is proposed that PfCDPK3
may serve as a link between calcium and gametogenesis of P. falciparum.
PMID- 10760602
TI - Alternative splicing of murine SorCS leads to two forms of the receptor that
differ completely in their cytoplasmic tails.
AB - We report the identification of a splice variant of SorCS, a member of the family
of VPS10 domain containing receptors. These type I transmembrane proteins share
the presence of internalization signals in their cytoplasmic tail as one common
characteristic. We show that an alternatively spliced transcript of SorCS is
generated by differential processing of a composite internal/terminal exon. This
splice variant encodes a protein with an N-terminal VPS10 domain followed by a
leucine-rich module and a transmembrane domain identical with the already
described SorCS protein, but a divergent cytoplasmic tail. In contrast to the
known intracellular regions of the related receptors, this splice variant
contains no internalization or sorting signals.
PMID- 10760603
TI - Characterization of JDP genes, an evolutionarily conserved J domain-only protein
family, from human and moths.
AB - We characterized evolutionarily conserved J domain containing protein (JDP) genes
from human, Bombyx mori, and Manduca sexta. Each of the JDP proteins contains a J
domain at its N-terminus and a highly conserved C-terminal domain. Southern blot
analysis revealed that the human JDP1 gene is present as a single copy in the
human genome. Expression was higher in brain, heart, and testis than in kidney or
stomach. Human JDP1 was mapped in silico to chromosome 10q21.1, which exhibits a
conserved synteny with the central region of mouse chromosome 10. Drosophila jdp
is located at 99F4-99F11 on the right arm of the third chromosome.
PMID- 10760604
TI - Sequence of the two operons encoding the four core subunits of the cytochrome
b(6)f complex from the thermophilic Cyanobacterium synechococcus elongatus.
AB - The genes encoding cytochrome f (petA), cytochrome b(6) (petB), the Rieske FeS
protein (petC), and subunit IV (petD) of the cytochrome b(6)f complex from the
thermophilic cyanobacterium Synechococcus elongatus were cloned and sequenced.
Similar to other cyanobacteria, the structural genes are arranged in two short,
single-copy operons, petC/petA and petB/petD, respectively. In addition, five
open reading frames with homology to known orfs from the cyanobacterium
Synechocystis PCC 6803 were identified in the immediate vicinity of these two
operons.
PMID- 10760605
TI - Y-receptor-like genes GPR72 and GPR73: molecular cloning, genomic organisation
and assignment to human chromosome 11q21.1 and 2p14 and mouse chromosome 9 and 6.
AB - Two novel G-protein-coupled receptors, one from human, GPR72, and one from mouse,
GPR73 have been isolated, sequenced and their genomic organisation determined.
Non-isotopic in situ hybridisation and radiation hybrid mapping have identified
GPR72 to be localised on human chromosome 11q21.1, and GPR73 on human chromosome
2p14. Interspecific mouse backcross mapping has localised the genes to mouse
chromosomes 9 and 6, respectively. Northern analysis reveals GPR72 mRNA
expression only in brain tissue. However, GPR73 mRNA can be found in heart,
skeletal muscle and pancreas. Both receptors are closely related with 36 and 33%
overall amino acid identity, respectively, to the Y-receptor family. However,
although successful cell surface expression in a heterologous expression system
can be achieved no specific binding to this ligand family can be detected,
indicating that perhaps additional factors are required for binding.
PMID- 10760606
TI - Molecular cloning and sequences of cDNAs encoding alpha (large) and beta (small)
isoforms of human pancreatic zymogen granule membrane-associated protein GP2.
AB - cDNA clones encoding two different (alpha and beta) forms of human pancreatic
zymogen granule membrane-associated protein glycoprotein 2 (GP2) (also referred
to as ZAP75), a critical component in regulated membrane trafficking along the
apical secretory pathway in pancreatic acinar cells, have been isolated.
Structural analysis of the clones revealed that the alpha and beta forms of GP2
consist of 527 and 380 amino acid (aa) residues, respectively. The beta form
lacks a 147 aa domain that corresponds to the 25-171 region of the alpha form,
suggesting that it is a product of an alternative splicing event. Expression of
both forms of GP2 in the human pancreas was confirmed. A unique isoform of GP2 is
reported for the first time in humans.
PMID- 10760607
TI - Treatment of separation anxiety in dogs with clomipramine: results from a
prospective, randomized, double-blind, placebo-controlled, parallel-group,
multicenter clinical trial.
AB - The efficacy and tolerability of clomipramine in the treatment of separation
anxiety in dogs was tested in a prospective, randomized, double-blind, placebo
controlled, parallel-group, international multicenter clinical trial. For a
diagnosis of separation anxiety, dogs had to exhibit at least one of the
following signs in the absence of their owner: destruction, defecation, urination
and/or vocalization, as well as the behaviour suggestive of "hyper-attachment" to
their owner. A total of 95 dogs were randomized to receive one of the three
treatments for 2-3 months: "standard-dose" clomipramine (1 to <2 mg/kg, PO, q. 12
h); "low-dose" clomipramine (0.5 to <1 mg/kg, PO, q. 12 h); and placebo (PO, q.
12 h). All dogs received behavioural therapy. Dogs were examined at four time
points (days 0, 28, 56 and 84) after the initiation of therapy. Improvement in
each dog's behaviour at days 28, 56 and 84 was evaluated in comparison to its
behaviour at day 0.The results showed that, compared to placebo, dogs receiving
standard-dose clomipramine were rated improved at least three times faster for
the signs destruction, defecation and urination. At most time points, more dogs
in the standard-dose clomipramine group were rated improved for the signs
destruction, defecation and urination, and in an owner's global assessment of the
dog's overall behaviour (p<0.05 at certain time points). However, there were no
statistically significant differences at any time point between the standard dose
and the placebo groups in the sign vocalization. The low-dose clomipramine group
produced no statistically significant effect when compared with placebo. Mild and
transient vomiting was noted as a side effect of clomipramine in a small number
of dogs.It is concluded that addition of standard-dose (1 to <2 mg/kg, PO, q. 12
h) clomipramine to conventional behavioural therapy for 2-3 months ameliorated
the signs of separation anxiety in dogs.
PMID- 10760608
TI - The effect of omitted milking on the behaviour of cows in the context of cluster
attachment failure during automatic milking.
AB - In robotic milking there is always a slight chance of failure to attach the
milking cluster. Attachment failure is most likely for cows whose udder
conformation is less convenient for robot attachment. In general, after milking
failure cows try to revisit the milking robot if they are not sent to a separate
area. Since it is difficult to estimate the effect of milking failure on such a
cow and her welfare in conditions of robotic milking, a specific 16-day trial was
conducted on 12 cows. These cows were milked in a milking parlour with six
milking stalls. Each afternoon milking, three cows were not milked. All the cows
were closely observed in the cubicle house for 1 h after the afternoon milking.
Thereafter, all cows were brought to the milking parlour the third time and the
three unmilked cows were milked. In total, each cow was observed 12 times after
milking and four times after omitted milking. The following behavioural traits
were registered: time budget for the 1 h, occurrence and time until eating,
drinking, lying, urination and defecation, and aggressive interactions. Milking
order was defined on the basis of how often a cow came to the milking parlour in
the first batch of six cows. Moreover, the data related to the milk yield and the
use of the automatic feeding installation with the complete diet were analysed.
After omitted milking, only the cows from the first batch stood longer in
cubicles (14.2 min of 1 h) and lay less (5.4 min of 1 h) than milked cows of the
same batch (respectively 7.0 min and 16.3 min for standing and lying in cubicles)
(P<0.01). After omitted milking, cows urinated earlier and more frequently
(64.5%) than milked cows (36.3%) (P<0.002) (both batches). There were no
statistically significant differences in eating time and feed intake after
milking and omitted milking. Milk yield per cow averaged 24.9 kg during days with
omitted (delayed by 1 h) milking and 25.3 kg during the days without omitted
milking (P<0.05). It was concluded that cows show some signs of discomfort after
omitted milking (urination); this discomfort seemed to be greater in cows coming
earlier to the milking parlour (afterwards they preferred to stand rather than to
lie). The 60% of cases of milk leakage found after omitted milking indicates that
failed cluster attachment can be accompanied by an extra risk factor for the
occurrence of mastitis. However, omitted milking as a treatment did not influence
feeding and aggressive behaviour or milking order when unmilked cows were brought
to the milking parlour the third time together with the milked cows. Our methods
and results can be useful for estimating the effects of robot milking failures on
a cow. Future studies should pay particular attention to high-yielding cows and
to longer periods of delayed milking.
PMID- 10760609
TI - The effect of exposure to oestrous ewes on rams' sexual behaviour, plasma
testosterone concentration and ability to stimulate ovulation in seasonally
anoestrous ewes.
AB - Previous research has shown that the proportion of seasonal anoestrous ewes that
ovulate in response to the introduction of rams ('ram effect') is dependent upon
pheromonal and sexual behavioural stimuli emitted by the rams. Close contact with
oestrous ewes is likely to increase the rams' libido and level of testosterone
secretion, which in turn has been suggested to positively influence the
production of pheromones. Thus, the sexual stimulation of rams could be used to
improve the efficacy of the 'ram effect'. In the present experiment, 272 ewes
were introduced (1) to rams without recent experience of oestrous ewes, (2) to
rams recently exposed to oestrous ewes, (3) and (4) to oestrous ewes and rams
with or without recent experience with oestrous ewes, or (5) remained isolated
from rams. Serum testosterone concentration of rams was elevated equally (P<0.05)
when oestrous or anoestrous were introduced. Exposure to oestrous ewes before or
after introduction increased (P<0.05) the various measures of ram sexual
behaviour directed towards anoestrous ewes. However, there was no statistical
evidence that increased sexual activity resulted in an improvement in the ability
of rams to stimulate ovulation in anoestrous ewes.
PMID- 10760610
TI - Space use and agonistic behaviour in relation to sex composition in large flocks
of laying hens.
AB - Some authors have found indications of subgroup formation when domestic fowl are
forced to live together in large flocks, while others have not. In this study
experiments were carried out to test the hypothesis that hens in large flocks
have home ranges in parts of the pen and that they form subgroups. We also
studied if this is influenced by males. In a tiered aviary system (density
averaged 16 hens/m(2) of floor area) eight flocks of 568+/-59 ISA Brown laying
hybrids were kept in pens. Half of the pens contained 1 male per on average 24
females (mixed flocks). At peak production (36-53 weeks of age) four females
roosting closely together for about 14 days and four females roosting far apart
from each other were taken out from each flock and put together in separate
groups in small pens. Their agonistic behaviour was studied for 2 days before
they were put back. This was repeated with new birds, resulting in 16 small
sample groups being studied. At 70 weeks, three groups of 10 females per flock
roosting closely together in different parts of the pen were dyed with different
colours and their locations were observed for 2 nights and 2 days.The incidence
of aggressive pecks during day 1 among birds that had been roosting close to each
other tended to be lower (P=0.05) than among birds that had been roosting far
apart. This effect was not significant among birds from all-female flocks, but
among birds from mixed flocks (P<0.05). However, this indicates a recognition of
roosting partners and possibly also a rebound effect of the males' reduction of
female aggressiveness towards strangers. Irrespective of sex composition in the
flocks, birds marked while roosting at the ends of the pens were significantly
more often observed within these areas than in other areas of the pen during
daytime and came back to the same roosting sites at night (P<0.05-P<0.001). This
was not the case for birds from the middle of the pens, where the distribution in
the pen in most cases did not differ from random. These results show that laying
hens in large groups are rather constant in their use of space, which indicate
the presence of home ranges. However, environmental features that facilitate
localisation may be important. In summary, we think that these findings indicate
the existence of subgroup formation.
PMID- 10760611
TI - The interaction of liveweight and the degree of competition on drinking behaviour
in growing pigs at different group sizes.
AB - The pattern of drinking behaviour in pigs, and the influence of social factors
such as competition on this behaviour, have been poorly documented. If
competition for access to a limited resource is substantial, access to that
resource may be allocated disproportionately to different members of a group.
Priority may be based on a dominance hierarchy, or on physical characteristics,
such as weight. The pattern of drinking behaviour was examined and the effect of
pig liveweight on drinking behaviour under conditions likely to produce different
levels of competition was investigated. Four replicates of a 2x2 factorial design
of two group sizes (20 vs. 60) and two drinker:pig ratios (1:10 vs. 1:20) used a
total of 640 growing pigs (start weight 36+/-5.0 kg). The drinking behaviour,
skin lesion score and performance of nine focal pigs (three each of heavy (41.9
S.E.M. 0.57 kg), medium (35.7 S.E.M. 0.51 kg) and light weight (30.9 S.E.M. 0.63
kg)) per pen were recorded. For all focal pigs, the maximum time spent at the
drinkers occurred between the 1800 and 1900 h and the minimum time between 0700
and 0800 h. The mean number of drinking bouts per pig per day was 30.9 S.E.M.
1.41, the median bout length was 21 s and the mean daily duration spent at the
drinkers was 832 s. The frequency of visits to the drinkers, drinking bout
duration and daily drinking time were affected by group size and drinker
allocation, but not by weight or the interaction of treatments and weight. The
diurnal spread of drinking was similar for each of the four treatment
combinations and each weight category. Heavy pigs had the greatest number of
lesions, and light weight pigs the least (13.2 vs. 8.8 S.E.D. 1.18, P<0.005), but
this was not affected by the four treatment combinations. Lesion score correlated
poorly with the parameters of drinking behaviour. The treatments, in isolation,
or in interaction with weight, did not affect performance. No treatment
encouraged sufficient competition to compromise the drinking behaviour, social
behaviour or performance of the lightest animals in the pen.
PMID- 10760612
TI - A note on possible link between behaviour and the occurrence of lameness in dairy
cows.
AB - Lameness in cattle is a major welfare problem and has important economic
implications. It is known that lameness has a multifactorial causation; however,
it is still not clear why some individuals are more susceptible than others to
present foot lesions under the same environment. Social and individual behaviour
is thought to play an important role. The aim of this study was to assess the
possible relationships between social behaviour, individual time budgets, and the
incidence of lameness in 40 dairy cows. The incidence of lameness in the group of
cows observed was 42%. There were no differences in the mean time standing
between low-, middle- and high-ranking cows. Low-ranking cows spent more time
standing still in passageways and standing half in the cubicles than middle- and
high-ranking cows. No differences were found in the mean time standing between
cows that got lame and cows that did not get lame. However, cows that got
clinically lame spent longer standing half in the cubicles and had a
significantly lower index of displacements than those cows that did not get lame.
This study may offer a starting point to better understand the relationships
between behaviour and the occurrence of lameness in dairy cows.
PMID- 10760620
TI - Finding the key to reform in end-of-life care.
PMID- 10760621
TI - Regulatory and educational initiatives fail to promote discussions regarding end
of-life care.
AB - We conducted an observational cohort study to determine if hospital-based,
reinforcing regulatory and educational interventions could encourage physicians
to discuss end-of-life (EOL) care with their patients. Specifically, we measured
the effect of (1) administrative prompts to encourage discussions about EOL care
and (2) a mandatory educational seminar focusing on EOL issues. Study subjects
were patients consecutively admitted to the medicine service who faced an
anticipated 3-year mortality rate of at least 50%. The main study endpoint was
the frequency of documented EOL discussions between physicians and patients. In
the inception cohort of 184 patients, physicians discussed EOL care with 64
patients (34. 8%), and in the follow-up cohort of 121 patients, 41 individuals
(33. 9%) had documented discussions regarding EOL issues (P = 0.90). Actual "Do
Not Resuscitate"(DNR) orders were written for 53 patients (28.8%) in the
inception cohort and for 33 persons (27.3%) in the follow-up cohort (P = 0.71).
We conclude that enhanced, mutually reinforcing regulatory and educational
efforts focusing on EOL care proved ineffectual at promoting either discussions
about EOL issues or the use of DNR orders.
PMID- 10760622
TI - Demographic, symptom, and medication profiles of cancer patients seen by a
palliative care consult team in a tertiary referral hospital.
AB - In this retrospective study, the charts of 100 consecutive cancer patients who
had been referred to a palliative care consult team within a tertiary acute care
hospital were reviewed. Demographic characteristics, including reason for
admission and disease status upon admission, length of stay, and discharge and
admission location, were recorded. Symptom acuity, cognitive status, and risk for
substance abuse were evaluated. Medications before and after the consult were
tabulated and compared to recommended medications; compliance with the
recommendations was assessed. Five patients were not palliative at the time of
the consult. Only 46/95 (48%) were known to have untreatable cancer at the time
of their admission. The CAGE questionnaire for alcoholism and the Mini-Mental
State Questionnaire (MMSQ) were abnormal in 19/78 (24%) and 40/91 (44%),
respectively. The most intense symptoms, as measured by the 100-mm scales of the
Edmonton Symptom Assessment Scale (ESAS) were fatigue (72 +/- 24), appetite (60
+/- 32), and well-being (50 +/- 29). Eighty-nine of the 95 patients were living
at home prior to admission and 34/95 were able to return home. Twenty died during
hospitalization, 23 were transferred to a palliative care unit, and the remaining
18 were discharged to another hospital or long-term care. The patient's physician
complied with the palliative care consult team's recommendation in 122/137 cases
(89%).
PMID- 10760623
TI - Transdermal fentanyl in opioid-naive cancer pain patients: an open trial using
transdermal fentanyl for the treatment of chronic cancer pain in opioid-naive
patients and a group using codeine.
AB - To treat cancer pain, physicians often decide to jump directly from step 1 of the
World Health Organization (WHO) analgesic ladder to step 3. The use of
transdermal fentanyl in patients with cancer pain who had either used no opioid
before, or only codeine, is evaluated in the present trial. Both opioid-naive (N
= 14) and codeine-using (N = 14) patients started with transdermal fentanyl in
the lowest available delivery rate (25 microg/hr). Immediate-release oral
morphine was present as "rescue" medication. Transdermal fentanyl provided good
to excellent pain relief in the majority (68%) of these patients. During the
study, 5 patients continued with 25 microg/hr, and the others used a higher dose.
Clinically relevant respiratory depression was not observed. The common side
effects of opioids were found; constipation was mentioned by 3 patients (11%).
Transdermal fentanyl appeared a safe analgesic in these opioid-naive cancer pain
patients. In this study, WHO step 2 could be skipped without untoward
complications.
PMID- 10760624
TI - A phase II trial of triamcinolone hexacetanide for symptomatic recurrent
malignant ascites.
AB - Ascites is a common complication of advanced cancer and frequently requires
paracentesis to reduce symptoms of pain, anorexia, and dyspnea. For many patients
repeat paracenteses are required at short intervals. We prospectively studied 15
patients with recurrent ascites of malignancy to determine if intraperitoneal
triamcinolone hexacetonide, a slowly metabolized corticosteroid, produced
objective and symptomatic responses. After biochemical, radiological, and symptom
assessment and the establishment of the interval between paracenteses, patients
underwent large-volume paracentesis followed by intraperitoneal triamcinolone
hexacetonide 10 mg/kg. Patients were followed after treatment for assessment of
symptoms and physical signs of ascites. Repeat paracentesis was performed when
symptomatic ascites recurred. Symptomatic ascites recurred in 13 of 15 patients,
but the interval between paracenteses was extended from 9.5 +/- 1.6 days to 17.5
days (P = 0.0086). Symptom questionnaire scores assessing well-being, nausea,
abdominal pain, dyspnea, appetite, appearance, and change in abdominal size on a
scale from 0 to 6 averaged 3.2 +/- 0.3 at entry and 2.5 +/- 0.2 at the 2-week
assessment (P = 0.026). Self-assessed symptoms, feeling of well-being, abdominal
distention, and physical appearance improved significantly. The mean serum
cortisol decreased from baseline, suggesting that some systemic corticosteroid
absorption occurred. Thirteen of 15 patients have died, with a median survival of
42 days. Potential adverse effects included 1 episode each of transient abdominal
pain, bacterial peritonitis, and localized herpes zoster infection. In patients
with ascites of malignancy, intraperitoneal triamcinolone hexacetonide appears to
postpone the requirement for repeat paracentesis and improve symptoms of
malignant ascites.
PMID- 10760625
TI - Effects of opioids on driving ability.
AB - Driving has been regarded as an activity of daily living that is important in
maintaining a person's independence in the community, access to employment, and
social activities. Many patients, however, using opioid medications on a regular
basis (Chronic Opioid Analgesic Therapy: COAT) to ameliorate their intractable
pain have been restricted from driving out of concern that skills would be
impaired and driving safety compromised by these medications. Yet there are no
driving studies which have explored the effects of using opioid analgesics for an
extended period of time. This pilot study was designed to determine the effects
of medically prescribed, stable opioid use on the driving abilities of patients
with persistent, nonmalignant pain. Sixteen patients with chronic nonmalignant
pain on COAT, who met criteria for participation in the study, underwent a
comprehensive off-road driving evaluation using measures which have been shown to
be sensitive in predicting on-road driving performance. The evaluation consisted
of a pre-driver evaluation (PDE), a simulator evaluation (SDE), and behavioral
observation during simulator performance. Patients in the COAT group were
compared to a historical control group of 327 cerebrally compromised patients
(CComp) who had undergone the same evaluation and then passed an on-road, behind
the-wheel evaluation (BTW Pass; n = 162) or failed (BTW Fail; n = 165). Results
revealed that COAT patients generally outperformed the CComp patients as a group
by equaling or exceeding PDE and SDE scores of the BTW Fail patients as well as
the BTW Pass patients on all measures that differentiated the groups. Notably,
COAT patients had a relatively poorer performance than CComp patients on specific
neuropsychometric tests in the PDE; however, the differences were not
statistically significant and did not imply a systematic pattern of scores that
reflected domain-specific deficits. Behaviorally, COAT patients were generally
superior to CComp patients, also; however, COAT patients had greater difficulty
in following instructions and as well as a tendency toward impulsivity, like the
BTW fail group. While there was general support for the notion that COAT did not
significantly impair the perception, cognition, coordination, and behavior
measured in off-road tests that have been regarded as requisite for on-road
driving, methodological problems may limit the generalizability of results and
recommendations are made for research beyond a pilot study.
PMID- 10760626
TI - A prospective study of catheter-related complications of intrathecal drug
delivery systems.
AB - Intrathecal drug administration via implanted pump is an effective treatment for
intractable pain and spasticity but can be compromised by catheter-related
complications. To determine the etiology of catheter-related complications, we
have conducted a multicenter, prospective study of the long-term performance of a
one-piece catheter system. Data pertaining to catheter-related complications were
collected at implant and at specified times during the follow-up period. Catheter
implantation characteristics that might affect complications were assessed. Two
hundred nine patients were studied at 22 participating centers, with 1764
cumulative patient-months of catheter experience. Forty-nine catheter system
complications occurred in 37 patients (7 complications related to the catheter
itself, and 42 complications related to the implantation procedure). The 9-month
complication-free "survival" rate was 78.9% overall (95.5% for the catheter
itself). No specific catheter implantation characteristics were associated with
the occurrence of complications. These data indicate that the incidence of
complications for a one-piece catheter system is similar to that of commercially
available two-piece systems, and highlight the need for careful surgical
technique during implantation.
PMID- 10760627
TI - Analysis of pain content in nursing textbooks.
AB - This paper reports on one goal of a project designed to improve end-of-life (EOL)
care in nursing education. The goal was to improve the content regarding pain and
EOL care included in major nursing textbooks. A descriptive study used content
analysis of 50 textbooks selected from a potential of over 700 texts used in
nursing education. The 50 texts included 45,683 pages. The text review was
conducted using an analysis framework and included content analysis as well as
quantification of the content present in the texts. While pain was the most
common topic in the texts, the 248 pages of pain content represents only 0.5% of
total text content. All nine areas of EOL content (902 pages) comprised only 2%
of overall text. Particular weaknesses in the review of pain content were
recognized in pharmacologic management of pain. In summary, nursing texts have
limited content on pain. Increased attention to this area is essential to prepare
nurses to care for patients at the end of life.
PMID- 10760628
TI - Managing addiction in advanced cancer patients: why bother?
AB - The management of addiction in patients with advanced cancer can be time
consuming, labor-intensive, and difficult. Some clinicians believe that it is not
worth the effort, due in part to a failure to appreciate the deleterious impact
of addiction on palliative care efforts and a view of addiction as intractable in
any case. Indeed, it is possible that some clinicians perceive addiction not only
fatalistically but, because of common misconceptions, believe that managing or
attempting to decrease the patient's use of alcohol or illicit substances would
be tantamount to depriving a dying patient of a source of pleasure. In this
paper, we argue that managing addiction is an essential aspect of palliative care
for chemically-dependent and alcoholic patients. The goal of such efforts is not
complete abstinence, but exerting enough control over illicit drug and alcohol
use to allow palliative care interventions to decrease suffering. To illustrate
this view, we describe two patients with chemical-dependency. We highlight the
impact of unchecked substance abuse on patients' perpetuation of their own
suffering, the complication of symptom management, the diagnosis and treatment of
mood/anxiety disorders, and the effect on the patients' family and caregivers.
PMID- 10760630
TI - Likelihood and clinical trials.
AB - The history of the application of statistical theory to the analysis of clinical
trials is reviewed. The current orthodoxy is a somewhat illogical hybrid of the
original theory of significance tests of Edgeworth, Karl Pearson, and Fisher, and
the subsequent decision theory approach of Neyman, Egon Pearson, and Wald. This
hegemony is under threat from Bayesian statisticians. A third approach is that of
likelihood, stemming from the work of Fisher and Barnard. This approach is
illustrated using hypothetical data from the Lancet articles by Bradford Hill,
which introduced clinicians to statistical theory.
PMID- 10760631
TI - Vital epidemiologic clues in heart failure.
AB - The epidemiologic investigation of heart failure evolution by the Framingham
Heart Study has provided vital clues concerning the pathogenesis, predisposing
conditions, other predictive risk factors, and indicators of deteriorating
ventricular function related to the disease. This information is important in the
early detection of those susceptible to heart failure who are candidates for
preventive measures-of importance because the prevalence of the disease has not
declined despite the recent therapeutic advances. Epidemiologic investigation has
identified useful indicators for the disease including a low or falling vital
capacity suggesting diastolic dysfunction, a rapid resting heart rate in
compensation for a decreased stroke volume, and cardiomegaly indicating
myocardial hypertrophy or dilatation. Hypertension and coronary disease remain
the leading causes of the disease, and heart failure due to myocardial infarction
has increased in prevalence. Hypertension and coronary disease often coexist in
individuals who develop heart failure so that correction and prevention of these
conditions deserve a high priority. Early detection and correction of insulin
resistance is important because a threefold increase in the prevalence of
diabetes in the general population has serious implications for the incidence of
heart failure. In patients with hypertension, the occurrence of a myocardial
infarction increases the risk of developing heart failure five to sixfold,
whereas angina increases it less than twofold. In these patients, the presence of
left ventricular hypertrophy increases the risk of developing heart failure two-
to threefold. Heart failure-related mortality remains unacceptably high, despite
improvements in treatment, indicating a need for early detection and treatment of
predisposing conditions.
PMID- 10760633
TI - Back pain and obesity in the 1958 British birth cohort. cause or effect?
AB - An association between obesity and back pain has been observed, but the
underlying causal direction is uncertain. We examined the temporal sequence among
back pain, BMI, and weight gain using data from the 1958 British birth cohort
followed to age 33 (4395 men and 4468 women). Heights and weights were measured
at ages 7 and 33, and self-reported at age 23. Back pain was classified as:
chronic, incident, early onset but recovered, and never. Those with chronic pain
gained more weight between ages 23 and 33 than those with no pain, significantly
for women (7.39 kg vs. 6.29 kg). Women who were obese at age 23 years had an
elevated risk of subsequent back pain onset (32-33 years) (adjusted OR = 1.78).
No significant relationships were found for men. The risk of pain onset among
women was evident in relation to BMI at baseline (age 23) and cannot therefore be
explained by an effect of back pain on adiposity.
PMID- 10760632
TI - The relation between fish consumption, death from all causes, and incidence of
coronary heart disease. the NHANES I Epidemiologic Follow-up Study.
AB - 1 time/week (adjusted relative risk 0.85, 95% CI 0.68-1.06). Similar but
nonsignificant trends were seen in white and black women, but not black men. In
white men, risk of noncardiovascular death but not cardiovascular death was also
significantly reduced in those consuming fish once or more a week. No consistent
association of fish consumption and coronary heart disease incidence or mortality
was seen. White men consuming fish once a week had significantly lower risk of
death over a 22-year follow-up than those never consuming fish. This was mostly
attributable to reductions in death from noncardiovascular causes. Similar
patterns, though not significant, were seen in women. Further studies are needed
to confirm these findings and to elucidate mechanisms for the effect of fish
consumption on noncardiovascular mortality.
PMID- 10760634
TI - Estimating risks for matching factors in case-control studies.
AB - Matching for factors such as age and sex is a convenient method for minimizing
confounding in case-control studies, but it does not allow inferences about the
effects of the matching factors unless case ascertainment is virtually complete
and the distribution of the matching factors in the source population is known.
When this is so, the effect of a particular factor can be estimated by comparing
the population distribution of that factor with what is observed in the case
series. Such a comparison, however, may itself be confounded by other factors
that are related to both the matching factors and the disease under
investigation. This article proposes a method for evaluating matching factors as
risk factors, which uses information on the distribution of potential confounders
in the reference series and exposure relative risk estimates to adjust the person
time proportionality constant in a Poisson regression model. The method is
particularly suited to data sets in which many of the elementary matching strata
contain few or no cases and/or controls. It makes use of standard analytic
procedures, but requires the estimation of an additional variance-covariance
component for the estimated Poisson regression coefficients. Further factors that
may confound the relationship between exposure and disease are easily
accommodated. The method is demonstrated in two examples: a matched case-control
study of drugs in relation to the rare blood dyscrasia, agranulocytosis, that was
conducted in Europe and Israel, and a case-control study of ovarian cancer in
Australia.
PMID- 10760635
TI - Health and functional capacity as predictors of community dwelling among elderly
people.
AB - The aim of this study was to identify factors that predict community dwelling
(i.e., nonuse of institutional bed-days) among elderly people. This was a
longitudinal study of institution use including both short-term and long-term use
of hospitals and nursing homes. The impact of health, functional performance, and
carrying out the activities of daily living on community dwelling was studied
using the method of path analysis. The participants were all the 75-year-old (N =
388) and 80-year-old (N = 291) men and women resident in the City of Jyvaskyla,
Finland. Predictor variables included disease severity, symptoms of illness,
cognitive capacity, walking speed, muscle strength, hearing, and ability to carry
out the activities of daily living. The outcome variable was community dwelling.
Over 70% of the elderly people had received institutional care during the 5-year
follow-up. The path analysis models showed that disease severity and symptoms of
illness had an effect on community dwelling: those with a more severe disease or
more symptoms needed more institutional care. The effect was also mediated
through limitations in physical performance and cognitive capacity and need for
assistance in activities of daily living. The explanatory power of these models
varied from 23% to 36%. The results of this study suggest that prevention,
treatment, and rehabilitation programs aimed at the promotion of community
dwelling in elderly people should focus on the severity of diseases, functional
performance, and the ability to carry out the activities of daily living.
PMID- 10760636
TI - The cross-cultural validity of self-reported use of health care: a comparison of
survey and registration data.
AB - Surveys are often used to obtain data on ethnic differences in health care
utilization. This study examines the cross-cultural validity of such data. Survey
data were linked to an insurance register, for 3054 residents of Amsterdam, the
Netherlands. Concordance was estimated using Cohen's kappa statistics (agreement
adjusted for chance agreement) and loglinear analyses regarding hospitalization,
ambulatory physiotherapy, and prescription drugs. Self-reports yield higher
utilization rates than registration, but irrespective of ethnicity and without
statistical significance. Concordance between self-report and registration is
fair [kappas (95% confidence interval): 0.77 (0.72-0.82), 0.71 (0.66-0.75), and
0. 58 (0.54-0.63) for hospitalization, physiotherapy, and prescription drugs].
Concordance is lower, though mostly without statistical significance, for
immigrants, especially from Morocco and Turkey. Health care utilization is
somewhat overestimated on the basis of self-report. This has no systematic impact
on estimates of ethnic differences in health care utilization but adds
measurement error to such comparisons.
PMID- 10760637
TI - Influence of question structure on the recall of self-reported drug use.
AB - Epidemiological studies often rely on self-reported information as a source of
drug exposure. Several studies have evaluated the accuracy of self-reported
information on drug use. The influence of question structure on the accuracy of
recall, however, has not been studied extensively in these studies. In this study
we examined the recall accuracy of questionnaire information on drug use in a
ongoing public health survey with special attention to the influence of question
structure on sensitivity of recall. A sample of 372 hypertensive subjects for
whom questionnaire information and pharmacy records were available was examined.
Self-reported information on drug use was obtained through questions about
medications used for a specific condition and one final open-ended question. This
information was compared with the pharmacy medication history. About 71% of all
drugs that were currently in use according to the pharmacy records were recalled
through the self-administered questionnaire, and 94% of all drugs mentioned in
the questionnaire could be traced in the pharmacy records. Recall sensitivity was
higher for questions about medications used for a specific indication (88%) than
for the open-ended question (41%). The type of drug that was used might have
caused part of this difference in recall. We conclude that questionnaire
structure might be of influence on the accuracy of recall of self-reported drug
use, and more attention should be paid to the structure of questions on drug use.
PMID- 10760638
TI - Identification of clinically important changes in health status using receiver
operating characteristic curves.
AB - Identification of criterion standards for clinically important changes for groups
of patients requires that judgments of the degree of change that represents a
clinically important change are consistent among patients. We demonstrate the use
of receiver operating characteristic (ROC) curves to test if patients' judgments
of clinically important changes are consistent. Twenty-three patients with
systemic lupus erythematosus (SLE) were examined prospectively every 2 weeks for
up to 40 weeks. At each assessment, each patient rated the activity of their SLE
on a visual analog scale, rated whether their SLE was more active, less active,
or unchanged over each 2-week interval, and rated the importance of any change in
SLE activity. One of three physician examiners completed similar assessments.
Each measured change in the patient global assessment was categorized according
to the patient's judgment of whether no change in SLE activity was noted or
whether the patient thought their SLE was more or less active during the
interval. ROC curves were constructed from these data. Areas under the ROC curve
that were significantly greater than 0.5 were considered evidence for consistent
ratings among patients of important changes in SLE activity. Patient assessments
of change were available for 383 of 392 2-week intervals (97.7%). Of these,
patients reported no change in SLE activity in 200 intervals, improvement in 72
intervals, and worsening in 111 intervals. Intervals of improvement could be
distinguished from intervals of no change by changes in the patient global
assessments [ROC area = 0.68; 95% confidence interval (CI) 0. 60, 0.76]. The
cutpoint with the greatest sensitivity and specificity for any improvement was a
decrease of 5 points or more (on a 0-100 scale) in patient global assessment.
Intervals of worsening could also be distinguished from intervals of no change
(ROC area = 0.80; 95% CI 0.74, 0.85), and the best cutpoint was an increase of 5
points or more in the patient global assessment. Group criteria for major
improvement or worsening and for relative changes in the patient global
assessment could also be determined, as could criteria for important changes in
physician global assessments. By testing the consistency of patients' judgments
of important changes, ROC curves provide a means to determine if group criteria
for clinically important change can be established.
PMID- 10760639
TI - Test of item-response bias in the CES-D scale. experience from the New Haven
EPESE study.
AB - We present results of item-response bias analyses of the exogenous variables age,
gender, and race for all items from the Center for Epidemiologic Studies
Depression (CES-D) scale using data (N = 2340) from the New Haven component of
the Established Populations for Epidemiologic Studies of the Elderly (EPESE). The
proportional odds of blacks responding higher on the CES-D items "people are
unfriendly" and "people dislike me" were 2.29 (95% confidence interval: 1.74,
3.02) and 2.96 (95% confidence interval: 2.15, 4.07) times that of whites matched
on overall depressive symptoms, respectively. In addition, the proportional odds
of women responding higher on the CES-D item "crying spells" were 2.14 (95%
confidence interval: 1.60, 2.82) times that of men matched on overall depressive
symptoms. Our data indicate the CES-D would have greater validity among this
diverse group of older men and women after removal of the crying item and two
interpersonal items.
PMID- 10760640
TI - Epidemiology of Dupuytren's disease: clinical, serological, and social
assessment. The Reykjavik Study.
AB - Dupuytren's disease or palmar fibromatosis is a common disabling hand disorder,
mainly confined to Caucasians of northwestern European origin. The prevalence of
Dupuytren's disease and possible risk factors related to the disease were
evaluated in a random sample of 1297 males and 868 females, aged 46 to 74 years.
Blood samples were collected and biochemical parameters were evaluated. The
possible relation between the disease and clinical, social, and biochemical
parameters were estimated with age-adjusted univariate logistic regression
analysis. Altogether 19.2% of the males and 4.4% of the female participants had
clinical signs of Dupuytren's disease. The prevalence increased with age, from
7.2% among males in the age group 45-49 years up to 39.5% in those 70-74 years
old. The more severe form of the disease, finger contractures, was found in 5.0%
of the men and 1.4% had required operation, while this was rarely seen among
women. In men elevated fasting blood glucose (P < 0.04), low body weight, and
body mass index were significantly correlated with the presence of the disease (P
< 0.001). Dupuytren's disease was common among heavy smokers (P = 0.02) and those
having manual labor as occupation (P = 0.018). These results show that
Dupuytren's disease is common in the Icelandic population and occupation and
lifestyle seem to be related to the disease.
PMID- 10760641
TI - The UK IBDQ-a British version of the inflammatory bowel disease questionnaire.
development and validation.
AB - Measurement of health-related quality of life (HRQL) is becoming more important
in studies of patients with inflammatory bowel disease. The McMaster IBDQ is the
most widely used HRQL instrument for these patients. However, its use with
patients in the United Kingdom has not been validated. This study develops and
validates a UK version of the McMaster IBDQ (UK IBDQ). The UK IBDQ was tested
with two samples of patients for its reliability, validity, reproducibility, and
responsiveness. The first sample consisted of 180 patients participating in a
randomized clinical trial. The second was recruited from members of the National
Association for Colitis and Crohns Disease. Reliability of the subscales and the
summary score of the UK IBDQ is demonstrated by Cronbach's alpha and item-total
correlations. Their validity is demonstrated by their correlations with SF-36
subscales and an empirical index of disease activity. Good intraclass
correlations and responsiveness ratios show their reproducibility and
responsiveness. The findings support the reliability, validity, reproducibility,
and responsiveness of the UK IBDQ and its acceptability to patients in UK.
PMID- 10760642
TI - Obesity, overweight and patterns of osteoarthritis: the Ulm Osteoarthritis Study.
AB - The objective of this study was to assess the association between obesity and
osteoarthritis (OA) of the knee, hip, and hand. OA patterns were studied in 809
patients with knee or hip joint replacement due to OA. Patients with OA were
categorized as having bilateral or generalized OA according to the presence of
radiographic OA in the contralateral joint or different finger joints, and as
normal weight, overweight, or obese according to their body mass index (BMI).
Odds ratios (OR) and 95% confidence intervals (CI) for relative weight and OA
patterns were estimated with multivariable logistic regression. Eighty-five
percent of participants had bilateral OA, 26% had generalized OA, and 31% were
obese. Obesity (BMI >/= 30 kg/m(2); OR = 8.1; 95% CI: 2.4-28) and overweight (BMI
>/= 25 kg/m(2); OR = 5.9; 95% CI: 2.0-18) were strongly associated with bilateral
knee OA. No association between obesity and bilateral hip OA (OR = 0.7; 95% CI:
0.3-1.7) nor generalized OA (OR = 1.1; 95% CI: 0.6-2.1) was observed. Obesity
seems to be a mechanical rather than a systemic risk factor for OA with the knee
joint being especially susceptible.
PMID- 10760643
TI - Physical activity and self-reported, physician-diagnosed osteoarthritis: is
physical activity a risk factor?
AB - This prospective study evaluated regular physical activity and self-reported
physician-diagnosed osteoarthritis of the knee and/or hip joints among 16,961
people, ages 20-87, examined at the Cooper Clinic between 1970 and 1995. Among
those aged 50 years and older, osteoarthritis incidence was higher among women
(7.0 per 1000 person-years) than among men (4.9 per 1000 person-years, P =
0.001), while among those under 50 years of age, osteoarthritis incidence was
similar between men (2.6) and women (2.7). High levels of physical activity
(running 20 or more miles per week) were associated with osteoarthritis among men
under age 50 after controlling for body mass index, smoking, and use of alcohol
or caffeine (hazard ratio = 2.4, 95% CI: 1.5, 3.9), while no relationship was
suggested among women or older men. These findings support the conclusion that
high levels of physical activity may be a risk factor for symptomatic
osteoarthritis among men under age 50.
PMID- 10760644
TI - Organochlorine exposure and breast cancer survival.
AB - Recent research suggests that exposure to organochlorines, such as dieldrin that
possess estrogenic properties, may increase the risk of breast cancer by
promoting growth of malignant cells. Whether this potential also affects
malignant cells not eradicated by treatment, and thereby survival, is unknown. To
evaluate this blood samples from female participants in the Copenhagen City Heart
Study, Denmark, were analyzed for organochlorines. A total of 195 breast cancer
cases, who each provided two blood samples that were taken in 1976-78 and 1981
83, respectively, were included in the survival analysis. Dieldrin had a
significant adverse effect on overall survival and breast cancer specific
survival (RR, 2.78, 95% CI, 1. 38-5.59, P trend < 0.01; RR, 2.61, 95% CI, 0.97
7.01, P trend < 0. 01). This association was strengthened when exposure was
assessed as the average serum concentration of the two measurements. These
findings suggest that past exposure to estrogenic organochlorines such as
dieldrin may not only affect the risk of developing breast cancer but also the
survival.
PMID- 10760645
TI - Telephone follow-up in a randomized controlled trial in a less developed country:
feasibility, validity and representativeness.
AB - Telephone follow-up would offer considerable advantages over other modes of
follow-up in less developed countries, if it were feasible and the findings were
valid and generalizable. Telephone follow-up was assessed in the context of a
randomized controlled trial of chest radiography in South African children.
Hospital-based clinical outcomes were measured from hospital records, and also by
telephone, in a subset of the same patients who offered a contact telephone
number. Of 398 subjects offering a telephone number 308 (77.4%) were followed to
recovery or for 28 days. Kappa statistics for a subsequent hospital visit,
hospital admission, and chest radiograph were 0.88, 0.83, and 0.56, respectively.
The effect of chest radiography did not differ significantly in participants
accessible and not accessible by telephone. Telephone follow-up was feasible and
produced valid and generalizable results at low cost.
PMID- 10760685
TI - Enhancer-promoter activity of human papillomavirus type 16 long control regions
isolated from cell lines SiHa and CaSki and cervical cancer biopsies.
AB - Expression of human papillomavirus 16 (HPV-16) oncogenes is markedly higher in
cervical cancer cells than in precancerous cells, and the elevated expression is
believed to be required for the malignant phenotypes. We compared cancer cell
lines CaSki (with 200 to 400 copies of HPV-16 DNA per cell) and SiHa (with one to
two copies of HPV-16 DNA per cell) for the E7 expression in cells and the
enhancer-promoter activity of the isolated viral long control region (LCR).
Although these parameters per cell were 10-fold higher in CaSki than in SiHa, the
levels of the E7 mRNA and protein per HPV DNA copy were 10- to 20-fold higher in
SiHa than in CaSki. Characterization of the isolated LCRs showed that, whereas
the LCR from CaSki resembled the prototype in structure and activity, the LCR
from SiHa, with a deletion of 38 base pairs, enhanced transcription from P97 as
assayed by using a plasmid capable of expressing luciferase. The upregulation
appeared to be due to removal of one of the silencer YY1-binding sites.
Furthermore, we isolated and characterized LCRs from 51 cervical cancer patients'
biopsies. Among them, one with a deletion including YY1-binding sites and the
other with a substitution in a YY1-motif were found to enhance the transcription.
These findings suggest that mutation affecting YY1-motifs in the LCR is one of
the mechanisms enhancing the viral oncogene expression in the course of
progression of cancer cells.
PMID- 10760686
TI - Microsatellite instability and k-ras, p53 mutations in thyroid lymphoma.
AB - Patho-epidemiological studies showed that thyroid lymphoma (TL) arises in
inflammatory lesions of chronic lymphocytic thyroiditis (CLTH). Replication error
(RER) is found in inflammatory lesions and associated cancer, suggesting that
chronic inflammation could be a risk factor for neoplastic development through
causing RER. To clarify whether RER is involved in the pathogenesis of TL, we
examined the microsatellite instability (MSI) in 9 cases with CLTH and 19 with
TL, including 10 diffuse large B-cell lymphoma (DLBL), 4 follicle center cell
lymphoma, 3 marginal zone B-cell lymphoma of extranodal (MALT) type, and 2
lymphoplasmacytic type. Sixteen distinct microsatellite repeats were analyzed.
Mutations of p53 and k-ras genes were also examined. When alterations at 2 or
more microsatellite loci were judged as positive, only 5 DLBL cases exhibited
MSI. The frequency of MSI in DLBL was significantly higher than that in other
types of TL and CLTH (P < 0.05). Four of 19 cases (21.1%) showed point mutation
of the k-ras gene. The k-ras mutations occurred in the cases with DLBL with RER,
and four of five cases with RER had a k-ras mutation, indicating a close
association between RER and k-ras mutation. p53 mutations were not found in the
CLTH. Two of 19 TL cases showed mutations of p53 gene. There was no significant
association between RER and p53 mutation. These findings indicate that genomic
instability contributes to the progression of TL from low grade to high grade,
but not to the development of low grade lymphoma in CLTH lesions.
PMID- 10760688
TI - Mapping of target regions of allelic loss in primary breast cancers to 1-cM
intervals on genomic contigs at 6q21 and 6q25.3.
AB - Allelic losses on the long arm of human chromosome 6 are frequently observed in
cancers of the ovary, prostate, and breast. To identify the locations of putative
tumor suppressor genes on 6q, we examined 192 primary breast cancers for patterns
of allelic loss at 16 polymorphic microsatellite loci distributed along this
chromosome arm. Allelic losses at one or more loci were observed in 105 (55%) of
the tumors examined. Detailed deletion mapping with appropriate yeast artificial
chromosome (YAC) contigs identified two distinct commonly deleted regions; one
was confined to a 1-cM interval at 6q21 flanked by D6S1040 and D6S262 and the
other to a 1-cM interval at 6q25.3 flanked by D6S305 and D6S411. Allelic losses
at 6q21 were more frequent in invasive solid tubular and scirrhous carcinomas
than in tumors of less aggressive histologic types (P = 0.0006). Allelic loss at
6q25.3 was associated with loss of progesterone receptor (P = 0.0256). Our
results suggest the presence of two tumor suppressor genes for breast cancer on
6q that are likely to be associated with tumor progression and / or loss of
hormonal dependency.
PMID- 10760687
TI - PTEN / MMAC1 mutation and frequent loss of heterozygosity identified in
chromosome 10q in a subset of hepatocellular carcinomas.
AB - Frequent allelic losses on chromosome 10q have been reported in several types of
cancers, suggesting the presence of a putative tumor suppressor gene(s) on the
chromosomal arm. We examined loss of heterozygosity (LOH) on chromosome 10q in 37
hepatocellular carcinomas (HCC) using eleven dinucleotide microsatellite markers,
spanning the entire chromosome arm of 10q. Twelve (32%) out of 37 informative
cases showed allelic losses of at least one locus on 10q and eight tumors showed
a partial deletion of 10q. Analysis of deletion mapping of these eight cases
identified two commonly deleted regions within the distal part of 10q (10q24
q26), a 20-cM interval flanked by D10S597 and D10S216 and a 24-cM interval
flanked by D10S216 and D10S590. Moreover, we detected a somatic missense mutation
(Met --> Val) of a candidate tumor suppressor gene PTEN / MMAC1, located at
10q23.3, in one HCC with LOH of 10q. Our findings indicated the presence of
putative tumor suppressor gene(s) in the distal region of 10q that might be
involved in the development and progression of HCC. Inactivation of PTEN / MMAC1
gene located outside the commonly deleted region of 10q might also play an
important role in a subset of HCCs.
PMID- 10760689
TI - Helicobacter pylori and the t(11;18)(q21;q21) translocation in gastric low-grade
B-cell lymphoma of mucosa-associated lymphoid tissue type.
AB - The reported regression of mucosa-associated lymphoid tissue (MALT) type gastric
low-grade B-cell lymphoma following treatment for Helicobacter pylori (H. pylori)
infection has not yet been comprehensively analyzed, especially in relation to
the recently identified c-IAP2-MALT1 / MLT gene alteration resulting from the
t(11;18)(q21;q21) chromosomal translocation found in MALT lymphoma. The
relationship between MALT lymphomas and H. pylori was investigated in 30 patients
who received an antibacterial treatment. Patients were followed up by means of
endoscopy and biopsy. Molecular genetic analyses focused on the presence or
absence of the immunoglobulin heavy chain (IgH) gene and / or MALT1 / MLT gene
alteration resulting from t(11;18)(q21;q21) translocation. H. pylori was positive
in 26 of the 30 patients. The overall success rate of cure of H. pylori infection
was 96% (25 / 26). Thirteen patients (52%) showed complete remission (CR) of
lymphoma, nine (36%) partial remission (PR), and three (12%) registered no change
(NC). Statistical analysis revealed significant differences between CR and PR /
NC patients in age ( < 60 or 60), in lymphoma location (single or multiple sites)
and in the presence or absence of gene rearrangement before eradication (P <
0.05). Endoscopy showed a cobblestone appearance only in PR cases and polypoid
features predominantly in NC cases. Two NC patients with polypoid gross
appearance showed rearrangements involving either c-IAP2 or MALT1 gene in
Southern blot analysis, while none of seven other resected patients with non
polypoid superficial gross appearance showed rearrangement. Gastric MALT lymphoma
could be pragmatically subdivided into three groups, CR (MALT-A), PR (MALT-B),
and NC (MALT-C) on the basis of the reaction to eradication of H. pylori. We
speculate that MALT-A may represent an incipient neoplasm or dysplasia, MALT-B a
neoplasm activated by antigenic stimulation of H. pylori, and MALT-C a lymphoma
independent of H. pylori. Polypoid lesions in MALT-C were associated with c-IAP2
MALT1 / MLT gene alteration resulting from t(11;18)(q21;q21). This classification
is thought to be clinically significant for deciding the most appropriate mode of
treatment of MALT-type lymphoproliferative disorders.
PMID- 10760690
TI - Expression of glutathione S-transferase alpha, P1-1 and T1-1 in the human
gastrointestinal tract.
AB - Glutathione S-transferases (GSTs) form a family of enzymes, which play an
important role in the prevention of cancer by detoxifying numerous potentially
carcinogenic compounds. GSTs catalyze the conjugation of glutathione to such
harmful molecules, and enable their secretion. Human GSTs can be divided into
five main classes. The theta class of isoenzymes was only recently identified and
limited (immunohistochemical) data on these enzymes are available. In the present
study, paraffin-embedded sections of different gastrointestinal tissues were
analyzed immunohistochemically for GSTalpha, GSTP1-1 and GSTT1-1 expression using
specific antibodies. GSTalpha, GSTP1-1 and GSTT1-1 were highly expressed in all
gastrointestinal tissues examined, with a unique cellular distribution. GSTT1-1
is the first GST isoenzyme demonstrated in duodenal Paneth cells and glands of
Brunner. The common expression of GSTalpha, GSTT1-1 and GSTP1-1 in many cell
types along the human gastrointestinal tract suggests an important role in the
protection against carcinogens and other xenobiotics.
PMID- 10760691
TI - Characterization of high-grade neuroendocrine tumors of the lung in relation to
menin mutations.
AB - It has been suggested that mutations in the menin gene play a role in the
development of multiple endocrine neoplasia type 1 (MEN1)-associated and of
sporadic forms of low- and intermediate-grade neuroendocrine tumors of the lung.
In the present study, eight tumor specimens of large cell neuroendocrine
carcinoma (LCNEC) and 13 of small cell lung cancer (SCLC), which represent a high
grade category of neuroendocrine tumors, were examined for the potential
involvement of menin alterations as well as for the expression of various
neuroendocrine markers and p53 and Rb abnormalities. All specimens expressed
multiple neuroendocrine markers as expected and almost invariably carried p53 and
Rb alterations. Unexpectedly, however, mutations in the menin gene were not
detected in any of the high-grade neuroendocrine tumors examined. We thus
conclude that menin mutations do not play a crucial role in the pathogenesis of
high-grade subsets, in contrast to their suggested significant role in the
development of low- and intermediate-grade subsets. Interestingly, loss of
heterozygosity (LOH) in the menin gene appeared to be more prevalent in LCNEC
(50%) than in SCLC (22%), suggesting a possible distinction between SCLC and
LCNEC.
PMID- 10760692
TI - Increased expression after X-irradiation of MUC1 in cultured human colon
carcinoma HT-29 cells.
AB - The effect of X-irradiation on production of MUC1 was studied with human colon
carcinoma HT-29 cells. As evaluated by immunocytochemical staining, the
percentages of MUC1-positive cells in cells at 4 days after 6 Gy irradiation and
in unirradiated control cells were 52 +/- 3.5% (n = 6) and 26 +/- 2.8% (n = 6),
respectively. Flow-cytometric analysis of living cells showed that MUC1 began to
rise from day 1, reaching a plateau by day 4 after 6 Gy irradiation. Western blot
analysis with monoclonal antibody MY.1E12 against glycosylated MUC1 (mature form)
showed dose-dependent increases of two bands (500 and 390 kDa) corresponding to
two polymorphic MUC1 alleles. Premature forms of MUC1 (350 and 240 kDa) were
detectable with monoclonal antibody HMFG-2 only in irradiated cells, suggesting
that new core protein synthesis had been induced. The transcriptional activity of
the MUC1 gene was analyzed in terms of transient expression of MUC1-CAT reporter
plasmids containing 5'-flanking sequences of the MUC1 gene fused to the bacterial
chloramphenicol acetyltransferase (CAT) gene. The results of CAT assay indicate
that enhanced expression of MUC1 in irradiated HT-29 cells was due to
upregulation of MUC1 transcription, and required the upstream promoter.
PMID- 10760693
TI - Significance of thymidine phosphorylase/platelet-derived endothelial cell growth
factor in carcinoma of the papilla of Vater.
AB - The expression of thymidine phosphorylase (TP) in carcinoma of the papilla of
Vater was studied to clarify its significance in tumor progression and in
determining prognosis. Fifty-nine cases of surgically resected carcinoma of the
papilla of Vater were studied. Immunohistochemical staining was performed to
evaluate the expression of TP, microvessel count and p53 overexpression. TP
expression was demonstrated in tumor cells in 62.7% (37/59) of the cases. A
higher frequency of regional lymph node metastasis was found in TP-positive
tumors than in TP-negative tumors (P = 0.006). TP-positive tumors were more
advanced than TP-negative tumors with regard to clinical stage (P = 0.035). TP
positive tumors had significantly higher microvessel density (27.6 +/- 10.1) than
TP-negative tumors (20.4 +/- 10.0, P = 0.01). Moreover, TP expression was
significantly correlated with a poor prognosis (P = 0. 02). These suggest that in
carcinoma of the papilla of Vater, TP production by tumor cells is correlated
with tumor progression through its regulatory effect on neovascularization.
PMID- 10760694
TI - Expression of SART3 tumor-rejection antigen in gastric cancers.
AB - We previously reported SART3 as a tumor-rejection antigen recognized by
histocompatibility leukocyte antigen (HLA)-A24-restricted cytotoxic T lymphocytes
(CTLs). In this study, we investigated the expression of the SART3 antigen in
gastric cancers, as a candidate for use in specific immunotherapy. The SART3
antigen was detected in 9 of 10 (90%) gastric cancer cell lines, 35 of 52 (67.3%)
gastric cancer tissues, and 0 of 20 non-tumorous gastric tissues. SART3-derived
peptides corresponding to positions 109- 118 and 315-323 induced HLA-A24
restricted and tumor-specific CTLs from peripheral blood mononuclear cells
(PBMCs) of gastric cancer patients. These peptide-induced CTLs recognized HLA
A24(+) SART3(+) gastric cancer cells, but not HLA-A24(+) SART3(-) or HLA-A24(-)
SART3(+) gastric cancer cells. Therefore, the SART3 peptides could be useful in
specific immunotherapy of gastric cancer patients.
PMID- 10760697
TI - [Suivre la mode ou s'adapter, telle est la question]
PMID- 10760695
TI - Selective inhibition of hepatoma cells using diphtheria toxin A under the control
of the promoter/enhancer region of the human alpha-fetoprotein gene.
AB - We constructed a plasmid containing human alpha-fetoprotein (AFP)
promoter/enhancer to direct the cell type-specific expression of diphtheria toxin
fragment A (DTA), designated as pAF-DTA, to AFP-producing hepatocellular
carcinoma cells. The transfection was carried out with cationic liposomes (DMRIE
C) and the expression of the DTA gene was confirmed by a northern blot analysis.
When pAF-DTA was transfected, the growth of AFP-positive HuH-7 cells was
inhibited, whereas growth inhibition was not observed in AFP-negative MKN45
cells. In this experiment, the secretion of AFP was similarly suppressed, but the
secretion of carcinoembryonic antigen from MKN45 was not altered. pAF-DTA could
also exert its growth inhibitory effect on PLC, a cell line with a low level of
AFP. However, no inhibitory effect of pAF-DTA was observed on the proliferation
of primary hepatocyte cells. Furthermore, transfection experiments in which HuH-7
and splenic stromal cells were co-cultured revealed the growth inhibition by pAF
DTA to be selective in HuH-7 cells. Finally, the growth of HuH-7 transplanted on
BALB/c nu/nu mice was inhibited by the direct injection of pAF-DTA/liposome
complex into a tumor mass. These results suggest that use of pAF-DTA may be
potentially useful as a novel approach for the selective treatment of tumor cells
producing AFP even at low levels, without affecting other types of cells.
PMID- 10760698
TI - [La SFBC sur le Net]
PMID- 10760696
TI - Practical utility of the revised European-American classification of lymphoid
neoplasms for Japanese non-Hodgkin's lymphomas.
AB - A clinicopathological study of 515 non-Hodgkin's lymphoma (NHL) cases was
performed using the revised European-American classification of lymphoid
neoplasms (REAL classification) in an HTLV1-nonendemic area of Japan. The
following characteristics were revealed: 1) frequency of extranodal lymphomas was
high (59%) with 79% B-cell lymphomas in this series, while the overall ratio of
B:T/NK lineage was 3.7:1; 2) the most common type was the diffuse large B-cell
lymphoma (46%), follicle center lymphomas occurred at an incidence lower (15%)
than that in European and American populations, and marginal zone B-cell
lymphomas accounted for as much as 12%; 3) peripheral T-cell lymphomas were
common (19%), with the unspecified type predominant (11%), while adult T-cell
lymphomas were present at a level equivalent to that among European and American
patients (1%). Clear segregation of survival curves was rated according to cell
lineage and B-cell lymphomas had a better prognosis than T / NK-cell lymphomas.
Furthermore, new subtypes in the REAL classification, such as marginal zone B
cell and mantle cell lymphomas, exhibited distinct curves. Taken altogether, the
REAL classification demonstrated advantages for assessment of Japanese NHL cases.
PMID- 10760699
TI - [40 years of blood gases and critical care analytes measurements].
AB - Drawing on his professional experience of fourty years, the author retraces the
history of the technological development of blood gases and other critical care
analytes measurements from the end of the fifties until today. He reviews the
various techniques now available and comments on the phases of their development
from test bench to hospital acceptance and market availability. Pulse oximetry is
noted as being of particular interest.
PMID- 10760700
TI - [Caveolae membrane domains, specialized transmembrane exchange zones implicated
in cell signalling].
AB - Caveolae are small pockets or invaginations localized at the plasma membrane.
They are enriched in glycosphingolipids, cholesterol, sphingomyelin and lipid
enchored membrane proteins, and they are characterized by a light buoyant density
and resistance to solubilization by Triton X-100 at 4 C. Caveolins are the
principal protein components of caveolae and play an important structural role in
the formation of caveolae membranes. Numerous molecules involved in cell
signalling have been identified in caveolae, suggesting that these structures may
serve to compartimentalize, modulate and integrate signalling events at the cell
surface. Depletion of membrane cholesterol disrupts the formation and function of
caveolae, suggesting that these membrane microdomains are involved in a range of
biological processes. Moreover, exposure of endothelial cells to high levels of
cholesterol upregulates the caveolin abundance in caveolae, and decreases nitric
oxide synthesis, suggesting that this may be an early event in atherogenesis.
Alteration in the expression of caveolin genes has also been implicated in human
diseases such as cancers, diabetes, Alzheimer's disease and muscular distrophy.
PMID- 10760701
TI - [Biology of malignant hyperthermia: a disease of the calcium channels of the
skeletal muscle].
AB - Malignant hyperthermia susceptibility (MHS), a skeletal muscle disorder, is
mostly inherited as an autosomal dominant trait. Exposure of susceptible
individuals to volatile halogenated anaesthetics can lead to a MH episode
resulting in irreversible tissue damages or to the patient's death if not
immediately reversed by dantrolene treatment. A MH episode is characterised by a
combination of hyperthermia, skeletal muscle rigidity and hypermetabolism.
Porcine stress syndrome has proved to be a valuable model for physiopathological
studies of MHS. Malignant hyperthermia syndrome is associated with a failure of
the calcium homeostasis in muscular fibres. Dysfunction of the calcium channels:
the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR), which are
involved in the release of the Ca2+ stored in sarcoplasmic reticulum has been
clearly demonstrated. A biochemical test based on the analysis of the in vitro
contracture response of muscular fibres to caffeine and halothane was developed
to define the MHS status of patients. Although the genetic analysis of MHS has
beneficiated from recent progresses, genetic testing is still far to answer to
all testing situations. If in swine, hyperthermia syndrome was always associated
with a unique mutation of the RyR1 gene, genetic analysis is far more complicated
in human: i) more than 20 different MHS mutations in the RyR1 gene have been
described; ii) a mutation of the gene encoding the dihydropyridine receptor has
been identified; iii) 4 other potential MHS loci have been reported.
PMID- 10760702
TI - [Current biological markers of cutaneous melanoma progression].
AB - Melanoma is the most agressive skin cancer in humans. The most important
prognostic factors are the histological features of the tumor, while the clinical
ones play a secondary role. Melanoma progression is characterized by the
metastatic process which directly threatens the patients life. Unfortunately,
routine imaging methods cannot estimate early enough this metastatic risk. Are
biologic markers of cancer progression more efficient than those applied in
everyday practice? Are they able to evaluate the metastatic risk and thus help
the therapeutic strategy? In this review, we analysed the analytical and the
clinical aspects of biologic markers of cutaneous melanoma currently available or
in development. At the present time it is very difficult to distinguish one
single marker of melanoma progression in the blood which correlates with the
stage and the prognosis of melanoma. The most specific and sensitive enough are
the melanoma associated antigens protein S-100, MIA (melanoma inhibiting
activity) and the melanin precursors 5-S-cysteinyldopa and the ratio L-dopa/L
tyrosine. Tyrosinase mRNA remains the best target for the detection of
circulating metastatic melanoma cells by RT-PCR. Simultaneous detection of
several markers might be useful if they are carefully selected. Despite the
progress in the field, more clinical studies should be performed for the
development of new techniques or improvements of the existing ones for the follow
up of cutaneous melanoma.
PMID- 10760703
TI - [Tamm-Horsfall protein].
AB - Human Tamm-Horsfall glycoprotein, the major urinary protein, is a glycosyl
phosphatidyl-inositol (GPI) - anchored membrane protein which mainly resides at
the luminal face of cells of the thick ascending limb of Henle's loop (TAL) and
early distal convoluted tubules of nephron. Tamm-Horsfall protein contains
exclusively N-linked glycans, mainly of polyantennary type largely sialylated and
fucosylated, but also high-mannose glycans. Only a portion of the Tamm-Horsfall
protein is released as soluble protein by the action of proteases and in a minor
amount by a cell-associated GPI-specific phospholipase. The physiological
function of Tamm-Horsfall glycoprotein has not been clarified to date. Since the
urinary Tamm-Horsfall protein has a high gel-forming tendency, it has been
postulated that it takes part in the water impermeability of TAL. It is also
proposed that the Tamm-Horsfall protein plays a protective role towards
pyelonephritogenic pathogens such as Escherichia coli. The Tamm-Horsfall protein
may inhibit the colonization of these pathogens in the renal mucosa in that the
soluble form competes with that exposed at the plasma membrane. Recently, urinary
Tamm-Horsfall protein has been implicated in tubulointerstitial nephritis.
PMID- 10760705
TI - [Role of isoelectric focusing of cerebrospinal fluid immunoglobulin G in the
early biological assessment of multiple sclerosis].
AB - A retrospective study was carried out at the Neurological and Neurosurgical
Hospital of Lyon in order to evaluate the interest of detecting IgG oligoclonal
bands by isoelectric focusing with IgG immunorevelation for the early diagnosis
of multiple sclerosis (MS). Patients have been grouped according to their
disorders: multiple sclerosis (281 cases), definite (182 cases) and possible (99
cases), others inflammatory neurological diseases (63 cases), various non
inflammatory neurological disorders (180 cases) and indefined neurological
disorders (664 cases). The following examinations were performed: CSF cell count
and cytology after concentration and cytocentrifugation, CSF and serum
determination of albumin and IgG with CSF/serum ratios, agarose gel
electrophoresis and isoelectric focusing of oligoclonal IgG. The technique used
was isoelectric focusing using agarose gel, transfer onto PVDF membrane and then
IgG immunorevelation with biotinylated anti-human IgG antibodies. Isoelectric
focusing with IgG immunorevelation is the most sensitive (94%) and specific (96%)
technique. Isoelectric focusing with immune detection can be recommended as the
most efficient test (gold standard) for the detection of chronic CNS
inflammation.
PMID- 10760704
TI - [Determination of plasma concentrations of antioxidants, antibodies against
oxidized LDL, and homocysteine in a population sample from Liege].
AB - A large number of epidemiological and clinical studies suggest that oxidative
stress plays an important role in the development of cardiovascular diseases. In
this way, following reference values in plasmatic antioxidants have been
determined in a group of 123 blood donors (94 males, 29 females; age: 21-64
years) living in the surroundings of Liege, Belgium: vitamin A (1.5-3.62 mmol/l),
vitamin C (3.68-75.21 mmol/l), vitamin E (16.98-46.46 mmol/l), ratio vitamin
E/cholesterol (3.92-8.32 mmol/mmol), selenium (0.66-1.26 mmol/l), sulphydryl
proteins (216-556 mmol/l), uric acid (174-477 mmol/l), superoxide dismutase (542
852 IU/g hemoglobine), glutathion peroxidase (39.55-91.83 IU/g hemoglobine). Only
a few number of subjects were found with values corresponding to high risk of
deficiency in antioxidants although low values in vitamin C (< 11.35 mmol/l) and
in selenium (< 0.75 mmol/l) were respectively observed in 5.69 and 10.5% of our
subjects. Autoantibodies against oxidized LDL, as marker of oxidative stress, and
homocysteine, as a risk factor of atherosclerosis involved in the development of
oxidative stress, have also been investigated. Approximatively 40% of the
population presented values higher than the superior limit mean value (20.3% >
650 IU/l in autoantibodies and 19.5% > 15.2 mmol/l in homocysteine) that are,
however, not correlated with age or low levels in antioxidants. The effect of
smoking (25% of the population) contributed to significantly decrease vitamin C,
selenium and glutathion peroxidase concentrations by 31.9 and 13% when compared
to nonsmokers. Intake of 1 to 4 fruits per day resulted in a significant increase
of 56.9% in vitamin C when compared to nonconsumers (26.8% of the population). In
contrast, homocysteine concentrations were significantly decreased by 21.4% in
fruits consumers. Thank to the development of methods allowing the routine dosage
of all these parameters, general practitioners can now easily establish the
oxidative stress status of their patients and, as fonction of getting patterns,
detect populations at risk of developing cardiovascular diseases.
PMID- 10760706
TI - [Exclusion of recent toxoplasmosis infections in pregnant women by the Toxo IgG
Vidas avidity test].
PMID- 10760707
TI - [Evaluation of the Bio-Rad Variant II analyzer for hemoglobin A1c determination].
PMID- 10760708
TI - [May-hegglin anomaly].
PMID- 10760711
TI - [4e Forum interdisciplinaire sur les Herpesviridae]
PMID- 10760709
TI - [Procalcitonin and C-reactive protein kinetics in neonates with group B
streptococcus infection].
PMID- 10760710
TI - [Homocysteine symposium. Nice, France, 15 October 1999. Abstracts].
PMID- 10760712
TI - [Implementation of a quality assurance manual at hospital laboratory].
PMID- 10760714
TI - [Nouvelles du comite scientifique et des groupes de travail]
PMID- 10760713
TI - [A new software for quality control at a laboratory].
PMID- 10760715
TI - [Assemblee generale de la Societe francaise de biologie clinique]
PMID- 10760716
TI - [Multimedia Review]
PMID- 10760717
TI - Topical corticosteroids and oral vesiculo-erosive disease: where's the beef???
PMID- 10760718
TI - In reply:
PMID- 10760719
TI - Is oral lichen planus premalignant?
PMID- 10760720
TI - Instrument for lateral release in temporomandibular joint hypomobility.
PMID- 10760721
TI - Early soft tissue pathosis associated with impacted third molars without
pericoronal radiolucency.
AB - OBJECTIVES: This study was performed to histologically evaluate soft tissue
pathosis in pericoronal tissues of impacted third molars that did not exhibit
pathologic pericoronal radiolucency. STUDY DESIGN: One hundred impacted third
molars without evidence of abnormal pericoronal radiolucency (follicular space
<2.0 mm) were removed for reasons other than participation in this study, and the
pericoronal tissues were submitted for histopathologic examination. Specimens
were fixed and processed routinely and were stained with hematoxylin and eosin
before independent evaluation by each of 2 oral pathologists. A subset of both
diseased and healthy tissues underwent additional evaluation for the presence of
proliferating cell nuclear antigen (PCNA) for assessment of cellular activity.
RESULTS: Of the specimens submitted, 34% showed squamous metaplasia suggestive of
cystic change equivalent to that found in dentigerous cysts. Soft tissue pathosis
was significantly higher in patients over 21 years of age (P =.001). Five of 8
diseased specimens demonstrated PCNA uptake, whereas none of 10 healthy specimens
were PCNA positive. CONCLUSIONS: These findings suggest that radiographic
appearance may not be a reliable indicator of the absence of disease within a
dental follicle. We conclude that the incidence of soft tissue pathologic
conditions is higher than generally assumed from radiographic examination alone.
PMID- 10760722
TI - Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5%
etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block.
AB - OBJECTIVE: The purpose of this study was to determine the anesthetic efficacy and
heart rate effects of an intraosseous (IO) injection of 1.5% etidocaine with
1:200,000 epinephrine after an inferior alveolar nerve block. STUDY DESIGN: In a
repeated-measures designed study, 48 subjects randomly received 2 combinations of
injections at 2 separate appointments. The combinations were an inferior alveolar
nerve (IAN) block (with 3% mepivacaine) + IO injection with 1.8 mL of 1.5%
etidocaine hydrochloride containing 1:200,000 epinephrine, and an IAN + mock IO
injection. The first molar was blindly tested with a pulp tester at 2-minute
cycles for 60 minutes after the injection. Anesthesia was considered successful
when 2 consecutive 80 readings (no subject response) were obtained. Heart rate
(pulse rate) was measured with a pulse oximeter. RESULTS: Lip numbness occurred
in 100% of the subjects with both the techniques. For the first molar, anesthetic
success for the IAN + mock IO and the IAN + IO etidocaine hydrochloride groups,
respectively, were 81% and 100%. The differences were significant (P <.05) when
the IAN + IO etidocaine hydrochloride technique was compared with the IAN + mock
IO. A mean increase in heart rate of 32 beats/min occurred in 90% of the subjects
with the IO injection of the etidocaine hydrochloride solution. In 89% of these
subjects, the heart rate returned to within 5 beats of baseline values 4 minutes
or less after solution deposition. CONCLUSIONS: The IO injection of 1.8 mL of
1.5% etidocaine hydrochloride with 1:200,000 epinephrine, when used to augment an
inferior alveolar nerve block, significantly increased anesthetic success in the
first molar. The majority of subjects receiving the IO injection of the
etidocaine hydrochloride solution had a transient increase in heart rate.
PMID- 10760723
TI - Descending necrotizing mediastinitis due to odontogenic infections.
AB - OBJECTIVE: Acute purulent mediastinitis caused by oropharyngeal infection is
termed descending necrotizing mediastinitis. Such infections usually have a
fulminate course, leading to sepsis and frequently to death. The purpose of this
study is to show the importance of early diagnosis, aggressive surgical
intervention, and optimal antibiotics chemotherapy in controlling this fatal
infectious disease. STUDY DESIGN: Two patients with descending necrotizing
mediastinitis due to odontogenic infection who were treated at our institution
are described. RESULTS: Both patients survived. CONCLUSIONS: From the patients,
23 different aerobic and anaerobic bacteria were isolated. All of the isolates
were susceptible to carbapenem. Early evaluation by means of cervicothoracic
computed tomography scanning was extremely useful for diagnosis and surgical
planning. Knowledge of anatomic pathways from the mouth to the mediastinum is
essential. We believe that tracheostomy is not always necessary. In both of the
cases presented, mediastinal drainage was completed through use of a
transcervical approach. However, a more aggressive drainage including
tracheostomy might be necessary when the infection extends below the carina.
PMID- 10760724
TI - The prevalence of calcified carotid artery atheromas on the panoramic radiographs
of patients with type 2 diabetes mellitus.
AB - OBJECTIVE: Type 2 diabetes mellitus, which afflicts 15 million Americans, is
associated with accelerated cervical carotid artery atherosclerosis and a
heightened risk of stroke. This study attempted to determine the prevalence of
calcified atherosclerotic lesions in a group of patients with type 2 diabetes
mellitus. STUDY DESIGN: The panoramic radiographs of 49 men (age range, 55 to 81;
mean age, 66.2 years) receiving routine dental treatment and insulin for diabetes
at a Department of Affairs Veterans clinic were evaluated for calcified
atheromas. Age-match controls, free of diabetes, were assessed in a like manner.
Statistical comparison of the atheroma prevalence rates was by means of the
Fisher exact test, and statistical comparison of atherogenic risk factors was by
means of t test with Bonferroni adjustment and, where necessary, the Mann-Whitney
U test. RESULTS: The radiographs of the diabetics (mean age, 66.9 years) revealed
that 20.4% had atheromas whereas those of the controls (mean age, 68.1 years)
demonstrated that 4% had atheromas (a statistically significant difference; P
=.0275). Also statistically significant was the prevalence of atherogenic risk
factors (plasma glucose, low-density lipoproteins, and serum triglycerides)
identified in the diabetic group. The radiographic appearance of the atheromas
manifested by both groups of individuals, however, was similar, with the lesions
located 1.5-2.5 cm inferior-posterior to angle of the mandible. CONCLUSIONS:
People with type 2 diabetes have a greater prevalence of calcified atheromas on
their panoramic radiographs than do nondiabetics.
PMID- 10760725
TI - Intraoral digital imaging documenting recurrent aphthous ulcer healing in 2-octyl
cyanoacrylate versus sham-treated lesions.
AB - OBJECTIVE: A device to standardize imaging was coupled with a digital intraoral
camera to investigate the efficacy of 2-octyl cyanoacrylate (OC) tissue adhesives
on the healing of minor aphthous ulcers. STUDY DESIGN: Forty-two subjects were
enrolled in a patient-blinded, sham-controlled study assessing the effects of 2
OC formulations on ulcer size and healing time. Daily images were made until
ulcers were healed. Ulcer image outlines were traced by using a mouse, and ulcer
areas were automatically calculated. RESULTS: A mean difference of -0.15 mm(2)
was seen between baseline and next-day measurements (P =.48). The cumulative
ulcer area was meaningfully reduced in one OC group compared with the sham group
(P =.04). Time to healing was reduced by 1.9 days in the same group compared with
the sham group (P =.02). CONCLUSIONS: The use of digital intraoral images with an
integrated measurement reference enhances the accuracy and reproducibility of
measurements. 2-OC adhesives hold promise as devices to promote healing of
recurrent aphthous ulcers.
PMID- 10760726
TI - Oral and systemic factors associated with increased levels of human
immunodeficiency virus type 1 RNA in saliva.
AB - OBJECTIVE: The purpose of this investigation was to quantify human
immunodeficiency virus type-1 (HIV-1) RNA in saliva and plasma and identify
factors associated with increased salivary viral load. STUDY DESIGN: Forty HIV-1
seropositive adults underwent oral examinations to assess mucosal and periodontal
health. Whole saliva was evaluated for HIV-1 RNA titer and occult blood. Plasma
viral load, CD4 cell count, HIV-1 staging, and antiretroviral therapy data were
obtained from medical records. Associations between salivary titers and
oral/systemic parameters were analyzed by means of t tests, Wilcoxon signed rank
tests, Pearson's correlation coefficient, and analysis of covariance. RESULTS:
Forty-two percent of the subjects had detectable salivary HIV-1 RNA. Oral titers
were highly correlated with plasma viral levels (r = 0.51, P <.01). HIV
associated periodontal disease (in particular, linear gingival erythema), severe
gingival inflammation, and absence of antiretroviral therapy were associated with
high salivary titers (P <.01). CONCLUSIONS: Substantial quantities of HIV-1 can
be shed in the oral cavity, particularly when inflammatory conditions are
present. Salivary titer may be a useful indicator of systemic viral burden.
PMID- 10760727
TI - Sanguinaria-associated oral leukoplakia: comparison with other benign and
dysplastic leukoplakic lesions.
AB - OBJECTIVE: This study was undertaken to compare and contrast biomarkers and
ploidy data from maxillary gingiva leukoplakias associated with dentifrices and
mouthrinses containing the herbal compound sanguinaria with other forms of oral
benign and premalignant mucosal keratosis. STUDY DESIGN: Representative archived
specimens of benign keratosis, sanguinaria-associated keratosis, and keratosis
with dysplasia were used for computerized image analysis and biomarker
immunohistochemical assays to assess ploidy, DNA content, and p53 and
proliferating cell nuclear antigen immunoreactivity of nuclei. RESULTS: DNA
content was significantly higher and higher numbers of cell populations with
hyperploid nuclei were encountered in the dysplastic group than in the other two
groups (P <.001). Sanguinaria-associated keratosis did not harbor significant
numbers of p53-expressing nuclei, yet it showed a significant elevation in
proliferating cell nuclear antigen-labeled nuclei in total, in the basal layer,
and in the spinous layer in comparison with benign keratoses (P <.001). In
addition, 1.5% of the sanguinaria-associated leukoplakia epithelial cell
population was characterized by nuclei with a greater than 4-fold increase in DNA
content. CONCLUSIONS: Sanguinaria-associated keratoses show some marker and image
analysis profiles similar to those of non-sanguinaria dysplastic lesions of the
lip and mucosa. Preparations containing sanguinaria should be avoided until the
risk for malignant transformation is determined.
PMID- 10760728
TI - Desmoplastic malignant melanoma of the palatal alveolar mucosa: sustained disease
free survival after surgery and postoperative radiotherapy.
AB - Aggressive surgical and radiotherapeutic management of a patient with
desmoplastic malignant melanoma arising from the mucosa of the oral cavity has
resulted in disease-free survival of more than 2(1/2) years after diagnosis. This
case represents only the tenth reported instance of desmoplastic malignant
melanoma arising from the oral cavity and only the third for which survival has
exceeded 2 years. Details of the clinical, histopathologic, and therapeutic
features of the case are provided to augment the paucity of literature available
to clinicians managing this rare disease.
PMID- 10760729
TI - Angiosarcoma of the mandible: a case report and review of the literature.
AB - Angiosarcoma is a rare malignancy that is characterized by endothelial cell
differentiation. In the head and neck area, most of these lesions arise in the
scalps of elderly individuals. Less commonly, angiosarcomas can be found within
bone. The purpose of this report is to describe an example of angiosarcoma
involving the floor of the mouth and right body of the mandible. The
histopathologic and immunopathologic features of these lesions are also reviewed.
PMID- 10760730
TI - A case of Sweet's syndrome (acute febrile neutrophilic dermatosis) with palatal
ulceration.
PMID- 10760731
TI - Immunolocalization of CD44 adhesion molecules in human periradicular lesions.
AB - OBJECTIVE: The hyaluronate receptor CD44 is a cell surface protein that is
involved in several functions. To elucidate whether CD44 plays a role in
periapical lesions, an immunohistochemical technique was used to study its
distribution. STUDY DESIGN: Twenty periapical lesions-16 periapical granulomas
and 4 radicular cysts-constituted the sample. Formalin-fixed/paraffin-embedded
tissue sections were studied by means of immunohistochemistry for the presence of
the standard CD44H form and its V3 splicing variant. RESULTS: Immunohistochemical
staining for CD44H and CD44V3 was observed on epithelial, endothelial, and
connective tissue cells. The cells of the fibrous lining around each granuloma
were positive, showing an immune reactive pattern directly correlated with the
dimension of the lesion. Epithelial rests of Malassez were strongly positive; the
reaction product was also evident in the epithelial lining of the cysts. Blood
vessels, mainly observed around the lesion, were immunoreactive for CD44.
CONCLUSIONS: Our findings demonstrate that CD44H and its V3 variant are expressed
in at least 3 different tissue types of periapical lesions. These glycoproteins
may be involved in different steps of periapical lesion pathogenesis and
evolution.
PMID- 10760732
TI - A comparison of the effects of two burs on endodontic access in all-ceramic high
lucite crowns.
AB - OBJECTIVE: The purpose of this study was to examine and compare the effects of
diamond and tungsten carbide burs with respect to the preparation of access
through all-ceramic crowns. STUDY DESIGN: Thirty extracted maxillary premolars
were restored with all-ceramic crowns. Each specimen was assigned to one of two
groups: (1) access opening prepared with a round diamond bur; (2) access opening
prepared with a carbide fissure bur. Access preparations were scanned by means of
scanning electron microscopy; observed were defects categorized as edge chipping,
microcracks, and fractures. RESULTS: Edge chipping around the access was
universal. Significant chipping (x > or = 0.1 m) was seen in 43% of access
peripheries. Eleven percent of the crowns fractured. chi(2) analysis (P <.05)
demonstrated no statistical difference between the bur groups. Results of a t
test revealed no statistical difference in edge chipping between the two bur
types. CONCLUSIONS: All-ceramic crowns bonded to extracted maxillary premolars
may experience edge chipping, microcracks, and fractures at equal rates whether
access is prepared with a round medium coarse diamond bur or a tungsten carbide
fissure bur.
PMID- 10760733
TI - Enamel pearls and cervical enamel projections on 2 maxillary molars with
localized periodontal disease: case report and histologic study.
AB - Presented here is an unusual case of teeth with aberrant enamel. One small and 3
large enamel pearls were identified in 2 maxillary third molars of a patient. One
long enamel projection was connected to one of the large enamel pearls, along
with 2 short cervical enamel projections. The ectopic enamel was associated with
advanced localized periodontal destruction. After extraction, the molars were
investigated radiographically and under the scanning electron microscope. The 3
large pearls contained distinct dentinal cones. The enamel of the pearls and the
long cervical projection exhibited most of the structural attributes of crown
enamel but were somewhat irregular, with variable shape and course of the prisms.
Morphologic considerations suggest that these enamel pearls were aberrations and
should not be regarded as attempts at new cusp or new tooth formation.
PMID- 10760734
TI - Quantitative dental radiography with a new photostimulable phosphor system.
AB - OBJECTIVE: The purposes of this report are to present a quantitative model for
digital oral radiography and to evaluate a new photostimulable phosphor system
for bone mass measurements. STUDY DESIGN: Noise, linearity, and precision were
measured from stepwedge images and blank images through use of a special least
squares calibration method. The model was used to estimate lower limits of
detection for observing small changes in bone mineral content. RESULTS: The
response was virtually linear, and the noise level of 2% to 3% is less than that
of digitized film images. The precision of measurements averaged over a region of
interest was generally better than 0.5%. CONCLUSIONS: If the scatter fraction is
measured for each patient, bone loss can be measured by using only extraoral
standards. Assuming a scatter fraction of 50% and considering only instrumental
errors, the detection limit is <0.02 g/cm(2) for large image areas (> or =7
mm(2)) and <0.3 mg over areas of 1 mm(2) or smaller.
PMID- 10760736
TI - A new, simple method of making a spacer in interstitial brachytherapy for mobile
tongue cancer.
AB - OBJECTIVES: This article demonstrates a new method of making a spacer that
increases the distance between the mandible and implanted radioactive sources in
interstitial brachytherapy for patients with mobile tongue cancer. STUDY DESIGN:
Fifty-three patients with mobile tongue cancer underwent interstitial
brachytherapy with spacers made by this new technique. RESULTS: Our spacer is not
difficult to create or to use. The spacer was made from a plastic splint by using
thermoforming techniques and quick self-curing resin, which did not need waxing,
wiring, or casting. The surface of the spacer, which comes in contact with the
tongue, is smooth because it is covered with tissue-conditioning material. There
were no complaints of pain from the patients. Osteoradionecrosis of the mandible
developed in only 1 (1.9%) of these patients. CONCLUSIONS: This spacer is simple
to make and prevented osteoradionecrosis.
PMID- 10760735
TI - Diagnostic imaging with newly developed ortho cubic super-high resolution
computed tomography (Ortho-CT).
AB - OBJECTIVE: Ortho cubic super-high resolution computed tomography (Ortho-CT),
which we have developed, is characterized by the small size of the unit and the
ability to produce 3-dimensional images of high resolution with low-radiation
doses. The purpose of this study was to investigate the clinical usefulness of
Ortho-CT for the diagnosis of diseases in the oral and maxillofacial region.
STUDY DESIGN: Ortho-CT has been used for the imaging diagnosis of a radicular
cyst of the upper first molar, mesiodense, tooth fractures in the upper anterior
region, a fracture of the condylar process, or presurgical evaluation for a
dental implant. The usefulness of 3-dimensional images obtained by Ortho-CT was
investigated in this study. RESULTS: Ortho-CT produced images of high resolution,
enabling identification of the extent of the lesions and the fracture line, the
condition of the impacted tooth, and the relationship with the maxillary sinus,
mandibular canal, and adjacent teeth. CONCLUSION: Because Ortho-CT can take high
resolution 3-dimensional images at any tomographic layer with only 1 exposure, it
is useful for the diagnosis of diseases in the oral and maxillofacial region.
PMID- 10760737
TI - The oblique radiographic technique for bone height measurements on edentulous
mandibles: a preclinical study and an introduction to the clinical use.
AB - OBJECTIVE: The aim of this study was to quantify the effect of mandibular
angulation, position, and shape of the edentulous mandible on the distortion of
its image on lateral oblique radiographs in a preclinical study. Suggestions for
the clinical use of this technique are made. STUDY DESIGN: Five edentulous dry
mandibles were used, varying in size from small to wide and equipped with metal
bars in and on top of the mandible. The mandibles were radiographed at 9
different positions by tilting the mandible around the intercondylar axis and by
using the oblique projection technique in a cephalostat. RESULTS: The length of
the images of the metal bars varied significantly when we tilted the mandibles
from 20 degrees to -20 degrees. As a result of the effects of magnification and
distortion, the image size varied from between 0.96% and 1.06% of the real size.
Neither the size of the mandible nor the position of the bars was related to the
degree of magnification. CONCLUSION: The oblique projection technique has limited
geometric errors in depicting the edentulous mandible. For evaluative bone height
measurements in patients with extremely resorbed mandibles treated with dental
implants, it is a promising technique if the patient (specifically the mandible)
can be positioned reproducibly in the apparatus.
PMID- 10760738
TI - Postnatal differentiation of efferent ductule epithelium in goats: a light
microscopic and ultrastructural study.
AB - Caprine efferent ductule epithelium contains ciliated and nonciliated cells. The
latter cells are divided into three types: type II cells contain PAS-positive
granules, type III cells contain PAS-negative vacuoles, and type I cells lack
both granules and vacuoles (Goyal and Williams, Anat. Rec. 220:58-67). The
objectives of this study are i) to determine when the epithelium differentiates
into ciliated and nonciliated cells, ii) to determine when nonciliated cells
acquire characteristics typical for type II and type III cells, and iii) to
relate developmental changes in the epithelium with those in the testis. Testes
and efferent ductules were examined at the light and electron microscopic levels
in goats from 1-25 weeks of age. Efferent ductule epithelium contained ciliated
and nonciliated cells as early as week 1. While ciliated cells were
differentiated at week 1, differentiation of nonciliated cells did not occur
until week > or =15. Differential features in ciliated cells included the
presence of cilia at the apical border and an aggregation of mitochondria in the
apical cytoplasm. Those in nonciliated cells included the presence of i) an
endocytotic apparatus at week > or =15, ii) PAS-positive granules at week > or
=15, and iii) PAS-negative vacuoles at week > or =25. The seminiferous tubules
developed lumens at 12-15 weeks. Hence, while differentiation of ciliated cells
occurred much before lumen formation in the seminiferous tubules, that of
nonciliated cells coincided with, or occurred soon after, lumen formation,
suggesting a role for testicular fluid contents in their differentiation. The
goat efferent ductules can be characterized morphologically mature by 25 weeks.
PMID- 10760739
TI - Disturbed enamel formation in wild boars (Sus scrofa L.) from fluoride polluted
areas in Central Europe.
AB - The pathological alterations of enamel structure in the teeth of wild boars from
fluoride polluted areas in N-Bohemia (Czech Republic) and S-Saxony (Germany) were
studied on a macroscopic and a microscopic level. Mandibular bone fluoride
concentration (mg F(-)/kg, dry wt; mean +/-SD, individuals <24 months of age) in
the specimens from N-Bohemia (754.3+/-149.6) and S-Saxony (490.8+/-135.1) was
significantly higher than that of controls (free of dental fluorosis),
originating from the western part of Germany (304.7+/-91.0). Fluoride content in
bulk enamel (mg F(-)/kg, ash wt) of fluorotic permanent teeth from N-Bohemia
(382.1+/-165.2) and S-Saxony (125.0+/-38.3) was likewise significantly increased
over that of non-fluorotic control teeth from W-Germany (33.6+/-26.7).
Macroscopically, fluorosed wild boar enamel exhibited opacity and discoloration
of varying extent, accentuated perikymata as well as hypoplastic and posteruptive
surface defects. Microradiographic and scanning electron microscopic analyses
revealed enamel subsurface hypomineralization, accentuated Retzius lines and
occurrence of broad, hypomineralized incremental bands of abnormal structure
underlying hypoplastic enamel surface defects. The presence of zones of
aprismatic enamel was associated with these bands. Incremental bands with altered
enamel structure and enamel surface hypoplasias, both denoting a severe
disturbance during the secretory stage of amelogenesis, have previously been
observed in rodents following acute parenteral fluoride dosing. It is concluded
that in the chronically fluoride exposed wild boars periods of especially
elevated plasma fluoride levels exerted an acute toxic effect on the secretory
ameloblasts. A feature not previously reported from fluorosed enamel was the
occurrence of canal-like structures that originated at the broad incremental
bands and extended into the external enamel. The presence of these canals
presumably results from a delay in the resumption of secretory activity by groups
of ameloblasts following a fluoride insult. Based on experimental evidence in
domestic pigs and in sheep, the overall subsurface hypomineralization of
fluorosed wild boar enamel is attributed to a disturbance of enamel maturation.
The distribution of fluorotic enamel changes within the dentition of the wild
boars could be related to the developmental sequence of tooth formation in the
species. Teeth whose crown formation took place prenatally (deciduous teeth) or
largely pre-weaning (permanent first molars) exhibited no or only moderate
fluorotic enamel alterations. Based on the extension of enamel surface
hypoplasias along the coronoapical axes of the tooth crowns, the timing of excess
fluoride exposure that caused a marked disruption of enamel matrix secretion was
estimated in specimens with a known date of death. The results indicate that the
wild boars had been exposed to a particularly severe fluoride impact during
autumn and winter of their first year of life.
PMID- 10760740
TI - Histology and ultrastructure of the chorioallantoic membrane of the mallard duck
(Anas platyrhynchos).
AB - The histology and fine structure of the chorioallantoic membrane of the mallard
duck (Anas platyrhynchos), and the density of vessels per millimeter of membrane
were assessed between days 12 and 24 of incubation. Light and transmission
electron microscopy of the chorioallantoic membrane of the mallard duck after
various days of incubation was carried out. Blood vessels within the mesoderm
were counted per millimeter of membrane by light microscopy (40x). The
chorioallantoic membrane had three distinct layers from day 12 to 24 of
incubation, the chorionic epithelium, the mesoderm, and the allantoic epithelium.
After day 12, chorionic epithelium consisted of two layers of flattened,
elongated epithelial cells interfaced by numerous desmosomes, and separated from
the underlying mesoderm by a basement membrane. At this stage, the allantoic
epithelium consisted of a single layer of flattened, overlapping cells. Blood
capillaries were observed in the mesoderm close to the chorionic epithelium on
days 12 and 13; by day 14, these capillaries were located within the chorionic
epithelium, forming a capillary sinus. Between days 14 and 16, the chorion
underwent cellular and cytological differentiation into three cell types:
capillary covering cells, villus cavity cells, and less differentiated basal
cells. The mesoderm was composed of a loose matrix of mesenchymal cells and
collagen fibrils through which coursed blood and lymphatic vessels. The vascular
density in the mesoderm increased rapidly from 4.2+/-0.6 vessels per mm (n = 12)
on day 12 to a maximum of 9.4+/-0.3 vessels per mm (n = 15) by day 16. From day
16, the allantoic epithelium had two to three layers of elongated and overlapping
cells. The luminal layer of allantoic epithelial cells had microvillus
projections and varying numbers of membrane-bound dense vesicles at all stages
from day 12 onward. The histologic and ultrastructural features of mallard duck
chorioallantoic membrane from day 12 to 24 of incubation were very similar to
those described in the chorioallantoic membrane of the chicken (Gallus gallus)
from day 8 to 20 of incubation. Much of the information available concerning the
CAM of the chicken also may apply to the CAM of the mallard, with timing adjusted
to match the developmental time-frame recorded here.
PMID- 10760741
TI - NPY immunoreactivity in endocrine cells of duck pancreas: an ontogenetic study.
AB - In the literature, neuropeptide Y (NPY) has been described in the brain and
peripheral nerves. More recently, it has also been detected in endocrine cells of
hamster, embryonic mouse, and rat pancreas. However, the presence of NPY in avian
embryos and the possible colocalization of this peptide with the other pancreatic
hormones have not been reported previously. In this study, NPY presence was
studied by immunocytochemical methods in the endocrine pancreas of domestic duck
during pre- and postnatal development. NPY immunoreactivity (IR) was detected in
embryos and adult animals. Around hatching the intensity of IR in endocrine cells
decreased. Double immunohistochemical staining revealed that: 1) NPY-IR is
extensively colocalized in small and mixed islets with insulin-IR both in embryos
and in adults; and 2) in early embryos NPY-IR occasionally colocalized with
glucagon and somatostatin. In early embryos, the colocalization of NPY-IR with
several pancreatic hormones could be related to the presence of multi-hormonal
progenitor cells. The close relation between insulin and NPY, both in embryos and
adults, led us to hypothesize a key role for NPY on insulin cells of duck
pancreas.
PMID- 10760742
TI - Diaphragm structure and function in the Florida manatee (Trichechus manatus
latirostris).
AB - Relative to many other mammals, little is known about the functional morphology
of the four extant species of the order Sirenia. In this study, 166 Florida
manatee (Trichechus manatus latirostris) carcasses fresh enough to collect
detailed anatomical information were examined to describe the gross anatomy of
the diaphragm. Our results show that the Florida manatee's diaphragm differs from
those of other mammals in that it: lies in a dorsal plane, rather than in the
more typical transverse plane; is located dorsal to the heart and does not attach
to the sternum; and attaches medially at the "I"-shaped central tendon to bony
projections extending ventrally from the vertebral bodies, forming two distinct
hemidiaphragms. The manatee's transverse septum is a separate structure that lies
at a right angle to the diaphragm and separates the heart from the liver and
other viscera. The extreme muscularity of the diaphragm and the ability of
manatees to adjust their position in the water column with minimal external
movement suggest that diaphragmatic contractions may change the volume of each
pleural cavity to affect buoyancy, roll, and pitch. We also hypothesize that such
contractions, in concert with contractions of powerful abdominal muscles, may
compress gas in the massive large intestine, and thereby also contribute to
buoyancy control.
PMID- 10760743
TI - Extracellular matrix (ECM) components in a very primitive multicellular animal,
the dicyemid mesozoan Kantharella antarctica.
AB - One of the most vital synapomorphic properties of metazoans is the presence of an
extracellular matrix (ECM), i.e., a complex of proteoglycans, adhesive
glycoproteins, and collagens. The genetically controlled ECM mediates between the
respective receptors morphogenesis and cell differentiation and is central to
gastrulation, i.e., the process which generates the embryonic germ layers, upon
which all metazoan body structures are based. However, the primitive metazoans
include a phylum, viz. the Dicyemida, which lacks any kind of typical metazoan
ECM structures including a basement membrane, and hence does not develop through
gastrulation. Since the ECM components fibronectin, laminin, and type IV
collagen, all of which are essential constituents of each basement membrane, have
been proved to be evolutionary ancient molecules from the lowest metazoans up to
vertebrates, antibodies against the respective vertebrate ECM components were
employed by electron microscopy to look for these molecules also in the dicyemid
mesozoan Kantharella antarctica. As a result, all three protein families showed
an immunolabel which was localized intracellularly and intimately associated with
the cell membranes as well as with the submembranously arranged delicate
filamentous network. The immunolabel was most intense in the fibronectin-like
protein, followed by the type IV collagen-like protein and weakest in the laminin
like protein. From an evolutionary point of view, this kind of distribution of
ECM components, primarily found in intracellular regions, seems to reflect a very
primitive situation of the structures of the respective ECM molecules having not
yet reached their definitive position outside the cell, thus generating the
complete biological function of typical ECM. Moreover, these results confirm the
long-standing presumption that the dicyemid mesozoan body structure might be the
missing link between the Protozoa and Metazoa.
PMID- 10760744
TI - Missing secretory granules, dilated endoplasmic reticulum, and nuclear
dislocation in the thyroid gland of rdw rats with hereditary dwarfism.
AB - Previous studies on the rdw rat have suggested that its dwarfism is caused
primarily by dysfunction of the thyroid gland. In this study, rat thyroid glands
were analyzed endocrinologically and morphologically to clarify the primary cause
of dwarfism in the rdw rat. The rdw rat showed lowered thyroid hormone (T4 and
T3) levels but elevated TSH in serum. The rdw thyroid gland was almost
proportional in size and it was not goiter in gross inspection. Our histological
investigation produced three results that may lend important evidence in
understanding the problem in the thyroid gland of rdw rats. First of all,
secretory granules could not be detected in the follicular epithelial cells of
the rdw. Secondly, thyroglobulin was found at very low levels in the follicular
lumen by immunohistochemical analysis. In contrast, it could be detected in a
substantial quantity inside the dilated rER and in the huge vacuoles that are
formed by swelling of the rough endoplasmic reticulum (rER) at the basal side of
the follicular epithelial cells. Additionally, the nucleus of the follicular
epithelial cells was pressed to the luminal side by the enlarged rER. These
morphological changes would indicate that the transport of thyroglobulin is
stopped at or before the formation of the secretory granules and thyroglobulin is
not secreted into the follicular lumen. The rdw characterization strongly
supports that rdw dwarfism is induced by hypothyroidism due to some defect(s) in
the thyroid gland.
PMID- 10760745
TI - Relationship in the chick of the developing pulmonary vein to the embryonic
systemic venous sinus.
AB - Previous studies have shown that the relationship of the systemic venous sinus
(sinus venosus) to the developing pulmonary vein are very similar in mice, rats,
and man, with the pulmonary vein gaining access to the heart through a persisting
segment of the dorsal mesocardium. It has been suggested that this process
differs in avian development, with the pulmonary vein being connected to the
systemic venous sinus with subsequent transfer to the left atrium. Here we have
investigated the anatomical sequence of events in the chick, using serial
histological sections and microdissection followed by scanning electron
microscopy. We examined a temporal series of chick embryos, ranging from
Hamburger and Hamilton stage 15 to stage 30. Although there are some differences
in detail, the development of the pulmonary venous connections in the chick was
found to be directly comparable to that already described in eutherian mammals.
In both mammals and the chick, the dorsal mesocardial connection, which connects
the primitive atrium to the posterior thoracic wall, forms a fixed point through
which the pulmonary vein gains access to the atrial compartment of the heart,
only varying if the connection itself is anomalous. The tributaries of the
systemic venous sinus and the primary atrial septal structures develop around the
dorsal connection.
PMID- 10760746
TI - Bone wound healing after maxillary molar extraction in ovariectomized aged rats:
quantitative backscattered electron image analysis.
AB - The processes of bone wound healing after maxillary molar extraction in
ovariectomized aged rats were examined by means of quantitative backscattered
electron image analysis and energy-dispersive X-ray microanalysis. Six-month-old
female rats were either sham-operated or underwent bilateral ovariectomy (OVX),
and 60 days postoperatively, the maxillary first molars were extracted. On post
extraction days 7, 30, and 60, the dissected and resin-embedded maxillae were
micromilled in the transverse direction through the extracted alveolar sockets,
and new bone formation on the buccal maxillary bone surface and within the
extracted alveolar sockets was examined. In both sham-operated control and OVX
rats, new bone formation was recognized on the buccal bone surface, as well as
within the extracted sockets, and increased daily through to day 60. In
comparison to sham-operated controls, new bone formation in OVX rats was
significantly decreased both on the buccal bone surface and within the extracted
sockets. Our results suggest that bone wound healing by new bone formation after
maxillary molar extraction is significantly decreased in OVX-induced
osteoporosis.
PMID- 10760747
TI - Intrinsic interrelation of lymphatic endothelia with nerve elements in the monkey
urinary bladder.
AB - Histochemical staining techniques for 5'-nucleotidase (5'-Nase) and
acetylcholinesterase (AChE) were undertaken to localize the lymphatic network and
nerve plexus in the monkey urinary bladder. Abundant 5'-Nase-positive lymphatic
networks were characterized by increased number of valve-like structures and
decreased calibre of blind-ends from the subepithelium to the subserosa. AChE
positive nerve fibers were visible throughout the vesical walls as fine plexuses,
the densest being the neuromuscular plexus among the detrusor muscle cells or in
each muscle bundle. AChE-positive nerve fibers or terminals were more frequently
discernible around blood vessels than around lymphatics, and showed more intimate
association with the lymphatics in the muscularis than those in the
subepithelium. The nerve terminals in the subepithelium were frequently separated
from attenuated lymphatic endothelium by the long processes of fibroblasts or
some connective tissue cells. An ultrastructural observation revealed that
unmyelinated nerve fibers with numerous neurofilaments and neurotubules run in
close apposition to the lymphatic endothelium. Noteworthily, fewer terminal
varicosities containing numerous small agranular vesicles (30-50 nm) and
mitochondria, partially or completely bare of their Schwann cell covering in the
vicinity of the lymphatic endothelium, were found in the subendothelium of
initial lymphatics than in collecting ones. These terminals were occasionally
identified at a distance of 120-350 nm from the subendothelial aspect of valve
originating roots, although no direct innervation of the vascular muscle cells
could be found. A loose fibro-elastic connective tissue was usually interlaced
between glial cell covering and lymphatic endothelium. The intrinsic
interrelation of the lymphatic wall with the nerve plexus implies that the
twisted subendothelial nerve terminals might be involved in intramural lymph
drainage of the bladder.
PMID- 10760748
TI - Osteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the
chick chorioallantoic membrane and synergizes with basic fibroblast growth factor
and transforming growth factor-beta1.
AB - Capillary invasion is a vital regulatory signal during bone morphogenesis that is
influenced by angiogenic molecules such as fibroblast growth factor (FGF) and
some members of the transforming growth factor-beta (TGF-beta) superfamily,
including TGF-betas themselves. Bone morphogenetic proteins (BMPs), which are
members of the TGF-beta superfamily, have previously not been shown to possess
direct angiogenic properties. Osteogenic protein-1 (OP-1; BMP-7) is a potent
regulator of cartilage and bone differentiation in vivo. The osteogenic and
angiogenic properties of OP-1 at both ortho- and heterotopic sites in adult
chacma baboons (Papio ursinus) are enhanced synergistically by the simultaneous
application of relatively low doses of TGF-beta1. The single application of
relatively high doses of TGF-beta1 (20 ng), and bFGF (500 ng) or relatively low
(100 ng) and high (1,000 ng) doses of OP-1 in the chick chorioallantoic membrane
(CAM) assay elicited a prominent and (for OP-1) dose-dependent angiogenic
response. The binary application of a relatively low dose of OP-1 (100 ng) with a
relatively low dose of bFGF (100 ng) or with a relatively low (5 ng) or high (20
ng) dose of TGF-beta1 resulted in a synergistic enhancement of the angiogenic
response. The angiogenic effect of the relatively low doses of the combined
morphogens was distinctly more pronounced than that of the single application of
the relatively high doses of the respective factors. The present findings suggest
that these morphogens may be deployed in binary combination in order to
accentuate experimental angiogenesis. The cooperative interaction of the
different morphogens in the CAM assay may provide important biological clues
towards the control of clinical angiogenesis.
PMID- 10760749
TI - The superiority of the new International Union Against Cancer and American Joint
Committee on Cancer TNM staging of gastric carcinoma.
PMID- 10760750
TI - Hail to the histologic grading of papillary thyroid carcinoma?
PMID- 10760751
TI - Bone marrow necrosis.
AB - BACKGROUND: In the medical community, little is known regarding bone marrow
necrosis (BMN) as a clinicopathologic entity, although to the authors' knowledge
it was described for the first time more than 50 years ago. To identify the rate
of prevalence, the symptoms and signs, the underlying disease associations, and
the usefulness of diagnostic procedures, an extensive literature search was made.
METHODS: Only cases identified as extensive necrosis and diagnosed during life
were selected. Two hundred forty cases met these criteria. RESULTS: Bone pain
(75%) and fever (68.5%) were the most important symptoms, whereas anemia (91%)
and thrombocytopenia (78%), associated with a leukoerythroblastic picture (51%),
were the most frequent hematologic abnormalities. Nearly 50% of patients showed
elevated lactate dehydrogenase and alkaline phosphatase levels. In 90% of the
patients an underlying malignancy was identified. CONCLUSIONS: Bone marrow
necrosis is caused by hypoxemia after failure of the microcirculation. Given the
high rate of malignancy as an underlying disease association, an extensive search
for neoplastic disease is justified whenever BMN is diagnosed. Pancytopenia and
embolic processes are major complications that should be managed with supportive
measures until effective treatment of the underlying disease has been
administered. When necrosis resolves, repopulation of the bone marrow cavity with
normal hematopoiesis is observed.
PMID- 10760752
TI - A prospective longitudinal study examining the quality of life of patients with
esophageal carcinoma.
AB - BACKGROUND: Quality of life (QL) measurement provides detailed information about
outcome from the patient's perspective. This study assessed the impact on short
and long term QL of esophagectomy and palliative treatment in patients with
esophageal carcinoma. METHODS: Consecutive patients undergoing potentially
curative esophagectomy or purely palliative treatment completed the European
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the
dysphagia scale from the EORTC QLQ-OES24 before treatment and at regular
intervals until death or for 3 postoperative years. Median scores were calculated
for patients surviving more than 2 years after surgery (n = 17), for patients
surviving less than 2 years after esophagectomy (n = 38), and for patients
undergoing palliative treatment (n = 37). RESULTS: Baseline functional and
symptom QL scores were similar in both groups of patients undergoing
esophagectomy, and these were better than scores from patients selected for
palliative treatment. Six weeks after esophagectomy, patients reported worse
functional, symptom, and global QL scores than before treatment. In patients who
survived at least 2 years, QL scores returned to preoperative levels within 9
months, but patients who died within 2 years of surgery never regained their
former QL. In both groups, dysphagia improved after surgery and the improvement
was maintained until death or for the duration of the study. Patients undergoing
palliative treatment reported gradual deterioration in most aspects of QL until
death. CONCLUSIONS: Esophagectomy has a negative impact on QL; this effect is
transient for patients who survive for 2 or more years. This finding should be
considered when selecting patients for surgery.
PMID- 10760753
TI - Endosonographic assessment of multimodality therapy predicts survival of
esophageal carcinoma patients.
AB - BACKGROUND: Standard endosonographic (EUS) staging criteria are unreliable for
staging esophageal carcinoma after neoadjuvant therapy; however, measurement of
tumor size reduction can identify patients who have achieved a pathologic
response. In the current study the authors prospectively compared survival
between patients classified as responders and those classified as nonresponders
by EUS. METHODS: The maximal transverse cross-sectional area of the tumor was
measured before and after neoadjuvant therapy in patients who were candidates for
multimodality treatment. Response was defined as a > or = 50% reduction in tumor
area. RESULTS: A total of 59 patients at 2 centers were followed for a median of
19 months. EUS assessed response in 34 patients (58%). Overall, responders had a
median survival of 17.6 months compared with 14.5 months for nonresponders (P <
0.005). Survival was significantly longer in responders compared with
nonresponders in the patient subgroup who underwent surgical resection (19.7
months vs. 14.6 months; P < 0. 005), the patient subgroup with adenocarcinoma
(21.4 months vs. 10.8 months; P < 0.005), and the patient subgroup initially
classified as having T3N1 disease (17.6 months vs. 14.1 months; P < 0.05).
Survival was not found to differ significantly between responders and
nonresponders in the subgroup of patients with squamous cell carcinoma. EUS
response was the only clinical variable that was associated with survival time in
a multivariate analysis (relative hazard = 0.27; P < 0.005). CONCLUSIONS:
Patients with esophageal carcinoma who respond to neoadjuvant treatment as
identified by EUS measurement of reduction in tumor size have a significantly
better prognosis than nonresponders.
PMID- 10760754
TI - Evaluation of the New International Union Against Cancer TNM staging for gastric
carcinoma.
AB - BACKGROUND: The lymph node (N) classification in the International Union Against
Cancer (UICC) TNM staging system for gastric adenocarcinoma has been revised. The
new classification is based on the number of positive regional lymph nodes
instead of the anatomic location of the regional lymph node metastasis. Both
classification systems were compared for prognostic significance. METHODS: A
total of 4362 gastric carcinoma patients who underwent resection between 1969 and
1990 were analyzed. RESULTS: Thirteen percent of patients could not be staged
according to the new system. Based on the previous classification, 647 patients
were classified as pN1 and 711 patients as pN2. When reclassified, 587 patients
remained pN1, 54 patients became pN2, and 6 patients became pN3. Of the 711 pN2
patients, 333 became pN1, 267 remained pN2, and 111 patients became pN3. Both
lymph node classification methods defined groups with widely differing prognoses.
The prognoses of patients classified as new pN2 were more homogeneous than those
of the group classified as old pN2. Survival of new pT4/pN1 patients was
significantly better than that of other subgroups in Stage IV. Nine potential
prognostic factors, including lymph node metastasis, were studied in multivariate
analysis. The hazard ratios were 1.38 (1.16-1.64) for pN1 and 2.55 (2.16-3.01)
for pN2, based on the old classification. They were 1.51 (1.29-78) for pN1, 3.11
(2.56-3.78) for pN2, and 3.88 (2.98-5.05) for pN3, based on the new
classification. CONCLUSIONS: The new N classification is superior as a prognostic
factor to the old N classification, although there is inadequacy in stage
grouping. [See editorial on pages 1763-5, this issue.]
PMID- 10760755
TI - Frequency of TPR-MET rearrangement in patients with gastric carcinoma and in
first-degree relatives.
AB - BACKGROUND: The activation of the c-met protooncogene through a rearrangement has
been detected previously in gastric carcinoma tissue and precancerous lesions. In
the current study the authors analyzed the rearrangement of TPR-MET in gastric
carcinoma patients and in first-degree relatives to evaluate the potential role
and timepoint of this genetic alteration in the process of gastric carcinogenesis
and its potential value in identifying those individuals with an increased risk
of developing gastric carcinoma. METHODS: The presence of TPR-MET mRNA was
determined in gastric tissue from 19 patients with gastric carcinoma and in the
gastric mucosa of 18 first-degree relatives without gastric carcinoma and in the
gastric mucosa of 18 first-degree relatives without gastric carcinoma using a
nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot
analysis. A 205-base pair (bp) cDNA fragment and a 70-bp cDNA fragment spanning
the breakpoint were amplified by nested PCR. Amplification products were
hybridized with an oligonucleotide labeled at the 3'-end with DIG-11-dUTP
spanning the breakpoint using Southern blot analysis. The MNNG-HOS cell line
served as a positive control. RESULTS: TPR-MET mRNA was detected in nine gastric
carcinoma patients (47%). Among these patients, TPR-MET mRNA was present in the
both tumor and tumor free tissues in 5 patients (26%), in the tumor tissue only
in 2 patients (11%), and in the tumor free gastric mucosa only in 2 patients
(11%). It is interesting to note that TPR-MET rearrangement also was detected in
the gastric corpus mucosa of 1 first-degree relative (6%), but in none of the
control subjects. CONCLUSIONS: The data from the current study indicate that TPR
MET activation may be an early event in gastric carcinogenesis and may be useful
for the identification of individuals with an increased risk of developing
gastric carcinoma.
PMID- 10760756
TI - Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients
with advanced colorectal carcinoma: results from a phase II study.
AB - BACKGROUND: The aim of this study was to confirm the activity and assess the
safety profile of multitargeted antifolate (MTA) for patients with metastatic
colorectal adenocarcinoma. METHODS: Forty-six patients were enrolled in the
study, 35 with colon and 11 with rectal carcinoma. Adjuvant therapy was allowed
if completed 1 year previously. Patients received MTA 600 mg/m(2) as a 10-minute
intravenous infusion once every 21 days. Blood samples were taken every cycle for
pharmacokinetic and vitamin metabolite assays. RESULTS: Among 39 patients
eligible for efficacy analysis, 1 complete response and 5 partial responses were
identified, for an overall response rate of 15.4% (95% confidence interval [CI],
4.1-26. 7%) for all patients. Fifteen patients had stable disease, with 9 living
longer than 1 year. The median survival was 16.2 months (95% CI, 10.5-17.0%); 65%
of patients were alive at 1 year, and the median time to progression was 4.4
months (range, 3.2-5.7 months). The main toxicities were hematologic, with common
toxicity criteria (CTC) Grades 3 or 4 noted as follows: thrombocytopenia (18%),
neutropenia (55%), and anemia (18%). Nonhematologic toxicities included Grade 2
or 3 skin reaction (53%), ameliorated by dexamethasone, and Grade 3 transaminases
(23%). Dose omissions were not required and 21% of doses were reduced.
CONCLUSIONS: MTA has clear activity in patients with colorectal carcinoma, and
encouraging survival times were noted. MTA was well tolerated in this patient
group, but myelosuppression was frequent. Toxicity may be increased with folate
deficiency.
PMID- 10760757
TI - p53 tumor suppressor gene mutations predict decreased survival of patients with
sporadic colorectal carcinoma.
AB - BACKGROUND: Mutations of the p53 tumor suppressor gene play an integral role in
sporadic colorectal carcinogenesis but prior studies have failed to show their
prognostic significance consistently. METHODS: Fifty-six consecutive sporadic
colorectal tumors were analyzed for their p53 status. Polymerase chain reaction
amplification with primers for exons 5-9 was conducted and these products were
subjected to single strand conformation polymorphism analysis. Suspected
mutations were confirmed with DNA sequencing. p53 status was entered into a
colorectal clinical database and these patients then were followed prospectively.
Patient status with regard to disease recurrence and survival was updated every 6
months. Survival and disease free survival were calculated according to the
method of Kaplan and Meier. The association between p53 status and clinical and
pathologic factors with survival and recurrence was statistically determined
using univariate analysis and the Cox proportional hazards model for multivariate
analysis. RESULTS: p53 mutations were detected in 28 of 56 patients (50%). The
median follow-up time was 45 months (range, 3-72 months). There were 33 patients
(59%) who were alive at last follow-up. Fifteen of the 23 patients who died (65%)
had p53 mutations and 8 (35%) had wild-type p53. Thirteen patients developed a
disease recurrence, 9 of whom (69%) had tumors with p53 mutations. Overall 4-year
survival rates for patients with wild-type p53 and mutant p53 were 71% and 54%,
respectively (P = 0.05). The 4-year disease free survival rates for patients with
wild-type p53 and mutant p53 were 83% and 62%, respectively (P = 0.09). p53
status and stage were found to be independent significant predictors for survival
(p53 negative: P = 0. 02; stage: P = 0.0002.) Stage was found to be the sole
significant predictor for disease free survival (P = 0.006). CONCLUSIONS: In this
group of colorectal carcinoma patients, p53 mutations were a significant negative
prognostic indicator for overall survival. This finding holds prognostic and
therapeutic implications for the management of colorectal carcinoma patients.
PMID- 10760758
TI - Implication of vascular endothelial growth factor and p53 status for angiogenesis
in noninvasive colorectal carcinoma.
AB - BACKGROUND: It still is unclear when angiogenic potential, which is believed to
be a prerequisite for tumor development, is acquired. The current study was
designed 1) to clarify when the phenotypic change of angiogenicity occurs during
the development of colon carcinoma and 2) to investigate the possible roles of
vascular endothelial growth factor (VEGF) and p53 in angiogenesis. METHODS: Colon
carcinomas were classified according to the following criteria: m carcinomas were
tumors in which carcinoma cells were observed within the mucosa (excluding
adenomas with severe atypia) according to the World Health Organization criteria.
sm carcinomas were defined by invasion into the submucosa but not into the
muscularis propria. Using 27 adenomas, 26 m carcinomas, and 20 sm carcinomas,
VEGF expression was analyzed with reverse transcriptase-polymerase chain reaction
and immunohistochemistry. Microvessel density, VEGF, and p53 status were
evaluated by immunohistochemistry. RESULTS: Neither VEGF mRNA nor VEGF protein
was detected in any of the mild-to-moderate dysplastic adenomas, whereas 16 of 26
m carcinomas (62%) and all sm carcinomas exhibited VEGF protein. The microvessel
density in adenomas, m carcinomas, and sm carcinomas was 3 +/- 0.55, 6.1 +/-
1.12, and 12 +/- 1.35 (0.739 mm(2) per field), respectively. In m carcinomas,
positive VEGF expression was coincident with the expression of p53, and
stainability for both VEGF and p53 was similar with regard to spatial
distribution in tumor tissues. In m and sm carcinomas, there was a statistically
significant correlation between the intensity of VEGF expression and microvessel
density. CONCLUSIONS: The results of the current study demonstrated that
angiogenesis develops in association with tumor progression from adenoma to
noninvasive colorectal carcinoma, at least in part due to VEGF, and suggested
that VEGF in m carcinomas is induced by mutant p53, although alternative
mechanisms of VEGF up-regulation may exist in sm carcinomas.
PMID- 10760759
TI - Gangliosides as targets for immunotherapy for pancreatic adenocarcinoma.
AB - BACKGROUND: Pancreatic adenocarcinoma cells express gangliosides and sialyl Lewis
(sLe) antigens. It is not known whether these carbohydrate antigens can be
targeted by immunotherapy. The authors measured the expression of GM(2) and sLe
antigens on the surface of pancreatic carcinoma cells and the serum levels of
total gangliosides, GM(2), and antiganglioside antibodies in patients with
pancreatic carcinoma. METHODS: Cell surface GM(2) and sLe antigens were measured
by cell suspension enzyme linked immunoadsorbent assay (ELISA) in four pancreatic
carcinoma cell lines. Sera from 20 pancreatic carcinoma patients and 20 age- and
gender-matched healthy volunteers were analyzed for antiganglioside and anti-sLe
immunoglobulin (Ig) M titers by ELISA. Serum levels of total gangliosides and
GM(2) also were measured. RESULTS: All cell lines expressed GM(2) and sLe
antigens. When compared with age- and gender-matched volunteers, patients had
significantly higher serum levels of total gangliosides (25.6 +/- 9.0 mg/dL vs.
15.6 +/- 2.7 mg/dL; P < 0.001), GM(2) (0.278 +/- 0.415 mg/dL vs. 0.013 +/- 0.018
mg/dL; P = 0.02), ELISA units of anti-GM(2) IgM antibody (368 +/- 95 vs. 155 +/-
25; P = 0.04) and anti-GD(1b) IgM antibody (351 +/- 91 vs. 138 +/- 26; P = 0.03),
but not anti-sLe(x) IgM (1389 +/- 345 vs. 1081 +/- 224; P = 0.46) or anti-sLe(a)
IgM antibody (1097 +/- 253 vs. 1200 +/- 315; P = 0.80). Patients with
unresectable tumors had higher serum levels of total gangliosides compared with
patients with resectable tumors, and a serum level > 25 mg/dL was found to
correlate significantly with poor overall survival (P < 0.02). CONCLUSIONS:
Increased serum levels of total gangliosides and GM(2) may reflect shedding or
release of gangliosides from the surface of tumor cells. Production of IgM
antibody against GM(2) and GD(1b) indicates that these gangliosides are
immunogenic antigens that may be potential targets for effective active
immunotherapy.
PMID- 10760760
TI - Adenocarcinoma of the lung in young patients: the M. D. Anderson experience.
AB - BACKGROUND: Surveillance, Epidemiology, and End Results (SEER) data for the years
1973-1992 documented that patients age < 50 years presented with more advanced
disease. Because of the increase in the incidence rate of lung adenocarcinoma in
the past few decades and the presentation of more advanced disease in young
patients, this study was performed to determine whether differences in survival
exist between younger and older patients with this disease. METHODS: The authors
reviewed the experience of the University of Texas M. D. Anderson Cancer Center
between 1985-1994, encompassing 157 patients age < 40 years of 4097 patients
registered with adenocarcinoma of the lung. For comparison, 157 patients age > 50
years with lung adenocarcinoma were selected; these patients were matched for
gender, stage of disease at presentation, and definitive therapy modality to
assess survival differences more accurately. Data regarding exposure to second
hand smoke were not collected secondary to lack of documentation in the charts
reviewed. RESULTS: There were no significant differences between the 2 groups
with regard to the overall survival rate (P = 0.34) or time to progression (P =
0.43). Smoking status (current vs. former vs. never-smoker) was not found to be
predictive of survival in either the younger group (P = 0.51) or the older group
(P = 0.92). CONCLUSIONS: The data from the current study indicate that overall
survival and disease free survival rates were not significantly different in
these two groups. Thus, the younger patient population should be treated
similarly to the older patient population. However, a surprisingly high
percentage of younger patients were female (45%) and had never smoked (27%),
suggesting that risk factors other than active smoking may be involved in lung
carcinogenesis in these patients.
PMID- 10760761
TI - Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and
therapeutic considerations.
AB - BACKGROUND: Merkel cell carcinoma is a primary small blue cell tumor of the skin
with a proclivity to metastasize. Surgery and radiation therapy have defined
roles in the primary treatment of Merkel cell carcinoma. Systemic chemotherapy
can produce good response rates but does not have a primary role in the
management of nondisseminated Merkel cell carcinoma patients. METHODS: Twenty-two
patients were identified over the last 10 years in a retrospective analysis of
tumor registries from the 6 hospitals of the ScrippsHealth facilities. Hospital
and clinic charts as well as pathology specimens were reviewed. RESULTS: Eight
patients underwent Mohs' surgery with permanent tissue technique. None of these
patients had a subsequent local recurrence. Six patients received adjuvant
radiation therapy, only one of whom developed a disease recurrence within a
radiation port. Systemic chemotherapy was given to seven patients. One patient
did not accept further treatment after a punch biopsy. CONCLUSIONS: Merkel cell
carcinoma is an aggressive primary neoplasm of the skin, the histologic diagnosis
of which can be difficult. Mohs' surgical technique combined with radiation
therapy provides excellent local control. Systemic treatment is associated with
high response rates, but to the authors' knowledge durable responses are
uncommon.
PMID- 10760762
TI - A decision analysis of the effect of avoiding axillary lymph node dissection in
low risk women with invasive breast carcinoma.
AB - BACKGROUND: Evidence that avoiding axillary lymph node dissection (AxD) strikes
an appropriate balance between morbidity and recurrence risk in patients with
invasive breast carcinoma generally is anecdotal and without a formally
quantified basis. The current study presents a decision analysis of the
difference in 5-year disease free survival (DFS) rate between treatment scenarios
with and without routine AxD. METHODS: To derive quantitative estimates of the
effect of avoiding AxD on 5-year DFS, the authors examined outcomes for women
undergoing 2 treatment scenarios: AxD or no AxD with adjuvant therapy decisions
based on risk factors in the primary tumor. Eligible patients belonged to 2 lymph
node metastases risk groups: low (patients without palpable lymph nodes and
lymphatic or vascular invasion [LVI] negative tumors < or = 0.5 cm in greatest
dimension) and moderate (patients with mammographically detected, LVI negative
tumors, between 0.6-2.0 cm in greatest dimension or patients with palpable LVI
negative tumors between 0.6-1.0 cm in greatest dimension with nonpalpable lymph
nodes). Along with observed data regarding treatment and recurrence, the authors
employed estimates of the efficacy of chemotherapy, tamoxifen, and regional
radiation therapy derived from published randomized trials to estimate the 5-year
DFS rate for treatment scenarios with and without AxD. RESULTS: Patients in the
low risk group had a 5% risk of lymph node metastases. In these women,
eliminating AxD and treating no patients with chemotherapy and/or tamoxifen
resulted in a < 1% decrease in the 5-year DFS rate. Patients in the moderate risk
group had a 10% risk of lymph node metastases. Eliminating AxD and treating only
those women with Grade 3 tumors > 1 cm in greatest dimension with chemotherapy
and/or tamoxifen resulted in a 1.8% decrease in the 5-year DFS rate. However, if
all patients in this group were treated with chemotherapy and/or tamoxifen and no
AxD, the 5-year DFS rate increased by 2.7%. CONCLUSIONS: In patients with a low
risk of lymph node metastases, it was estimated that eliminating AxD may result
in only minimal changes in the estimated 5-year DFS rate.
PMID- 10760763
TI - High response rate with a lower dose of paclitaxel in combination with cisplatin
in heavily pretreated patients with advanced breast carcinoma.
AB - BACKGROUND: Paclitaxel has been found to be efficacious in the treatment of
breast carcinoma either when administered alone or in combination with other
anticancer agents. Synergistic interaction between paclitaxel and cisplatin has
been demonstrated in vitro. METHODS: Thirty-two patients with breast carcinoma
that was resistant to anthracyclines and to several other antineoplastic agents
were selected to receive 80 mg/m(2) of paclitaxel on Day 1 and 80 mg/m(2) of
cisplatin on Day 2 with a 3-week interval between the courses. RESULTS: High
response rates were observed, with 3 complete responses (9.4%) and 13 partial
responses (40.6%) reported. Furthermore, the disease remained stable in 7
patients (21.9%) and progressed in only 9 patients (28.1%). CONCLUSIONS: The
results show that high response rates can be achieved with the combination of
paclitaxel and cisplatin, even in heavily pretreated breast carcinoma patients.
The combination of paclitaxel plus cisplatin was found to be highly efficacious
and well tolerated.
PMID- 10760764
TI - Recurrent squamous cell carcinoma of the vulva: clinicopathologic determinants
identifying low risk patients.
AB - BACKGROUND: The identification of prognostic factors in the recurrence of vulvar
squamous cell carcinoma is crucial for less invasive treatments. METHODS: The
authors studied 101 patients treated for primary invasive squamous cell carcinoma
of the vulva. Selected pathologic variables were observed in a standardized
manner during treatment, and their association with disease free survival was
investigated using the Cox model. Independent prognostic factors were selected by
a stepwise procedure. The absolute survival of patient groups determined on the
basis of such factors was computed by the product limit method. RESULTS: The
median follow-up was 3.1 years (range, 56 days to 15.5 years). Recurrences
developed in 33 patients. The independent recurrence predictors were as follows:
International Federation of Gynecology and Obstetrics (FIGO) Stage IVA (vs. IB,
II, or III) (risk ratio [RR]adjusted for other independent factors, 7.39), tumor
multifocality (RR, 4.10), lymphovascular space involvement (LVSI) (RR, 2.96), the
presence of associated vulvar intraepithelial neoplasia (VIN) Grade 2 or 3 (RR,
3.34), and the involvement of resection margins (RR, 4.88). By ignoring the FIGO
stage and lymph node status, the independent predictors were then as follows:
greatest tumor dimension < 2.5 cm, 2.5-4 cm (RR, 2.86), or > 4 cm (RR, 5.98);
tumor multifocality (RR, 3.36); LVSI (RR, 4.19); the presence of VIN 2 or 3 (RR,
3.06); and the involvement of surgical margins (RR, 2.78). No recurrences were
observed in 119 at-risk years among patients with unifocal tumors < 2.5 cm in
greatest dimension, free surgical margins, no LVSI, and no associated VIN 2 or 3.
CONCLUSIONS: The presence of associated VIN 2 or 3 was revealed to be a
previously unidentified independent prognostic factor for recurrence. Subjects at
low risk of recurrence could be identified even without consideration of lymph
node status.
PMID- 10760765
TI - Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility
of cervical carcinoma patients.
AB - BACKGROUND: Cervical carcinoma occurs frequently in young women who would like to
preserve their childbearing potential. For those with early stage invasive
lesions, the authors designed and performed radical trachelectomy, a surgical
procedure that preserves the functions of the uterus. METHODS: Radical
trachelectomy combines laparoscopic (for pelvic lymphadenectomy) and transvaginal
approaches. Between April 1987 and December 1996, 56 patients were scheduled for
this procedure, and 47 underwent it. The charts of these patients were
retrospectively reviewed for medical and obstetric history, characteristics and
complications of surgical procedures, pathologic findings, postoperative
obstetric results, and cancer recurrences. RESULTS: The mean durations of the
laparoscopic and vaginal steps of the procedure were 62 and 67 minutes,
respectively. One intraoperative complication (cystotomy) and seven postoperative
complications (drainage of pelvic collection) were observed. The pathologic tumor
classification was International Union Against Cancer (UICC) pT1a1 (International
Federation of Gynecology and Obstetrics [FIGO] Stage pIA1) in 5 cases, UICC pT1a2
(FIGO Stage pIA2) in 13 cases, UICC pT1b (FIGO Stage pIB) in 25 cases, UICC pT2a
(FIGO Stage pIA2) in 1 case, and UICC pT2b (FIGO pIIB) in 3 cases. The mean
follow-up was 52 months. Two recurrences (4%) were observed (one lateropelvic and
one distant), and one patient died of disease progression. Despite a 25% rate of
late miscarriages, 13 normal children were born after radical trachelectomy.
CONCLUSIONS: In young patients affected by early invasive cervical carcinoma,
radical trachelectomy does not appear to increase the rate of recurrence. It
carries a relative risk of infertility and late miscarriage but makes it possible
for some patients to become pregnant and give birth to normal newborns. Thus, it
seems reasonable to offer this procedure in selected cases, provided that each
patient is fully informed and the surgeon properly trained.
PMID- 10760766
TI - Extraperitoneal endosurgical aortic and common iliac dissection in the staging of
bulky or advanced cervical carcinomas.
AB - BACKGROUND: A pilot study of a new surgical technique for aortic dissection,
combining the advantages of extraperitoneal surgery and minimal invasive surgery,
was conducted. METHODS: Fifty-three patients underwent infrarenal aortic and
common iliac dissection for the staging of bulky or advanced cervical carcinomas.
The indication for extended lymph node staging was bulky early stage in 33
patients, International Federation of Gynecology and Obstetrics distal Stage IIB
or higher in 14 patients, nonbulky early stage with microscopic positive pelvic
lymph nodes in 1 patient, and central recurrence in 5 patients. The lymph node
dissection template included the common iliac lymph nodes, the inframesenteric
lymph nodes, and the preaortic and lateroaortic infrarenal lymph nodes. The
operation was performed using endoscopic techniques with CO(2) insufflation of
the extraperitoneal space. RESULTS: The procedure failed in two patients. Nine
patients had lymph node biopsy or selective removal of macroscopically positive
lymph nodes. For the 42 remaining patients, the average duration of the operation
was 125.9 +/- 31.8 minutes and the average number of lymph nodes was 20.7.
Overall, 17 patients had positive lymph nodes, in whom disease was macroscopic in
9 patients and microscopic in 8. Overall, the positivity rate was 32%. Five
complications occurred, four of them related to the extraperitoneal dissection
technique. An intraoperative complication occurred in one patient, in whom a
lateral injury to a fixed and dilated ureter was managed by stenting. A
postoperative complication occurred in another patient, in whom a retroperitoneal
hematoma causing ileus and compression of the upper ureter was managed
conservatively. Two symptomatic lymphocysts occurred; one of them required
drainage under ultrasound guidance. All patients but one had external radiation
therapy tailored according to the aortic lymph node status. After an average
follow-up of 18.9 months, 60% of lymph node positive patients and 15% of lymph
node negative patients died. Distant recurrence occurred in 53% of lymph node
positive patients and 9% of lymph node negative patients. No patient had
recurrence in the aortic or common iliac area. Two patients developed radiation
enteritis. CONCLUSIONS: This new technique deserves to be used as a tool to
identify lymph node positive patients who require extended-field radiation and/or
chemotherapy.
PMID- 10760767
TI - A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and
interleukin-2 for renal cell carcinoma patients with pulmonary metastases: a case
of fatal central nervous system thrombosis.
AB - BACKGROUND: Interleukin-2 (IL-2) and granulocyte-macrophage-colony stimulating
factor (GM-CSF) are cytokines with nonoverlapping pleiotropic effects. In a prior
Phase Ib study, this combination of agents exhibited antitumor effects in the
lungs of four of eight patients with renal cell carcinoma and pulmonary
metastases. We conducted this Phase Ib/II trial to determine the response rate of
renal cell carcinoma patients with pulmonary metastases treated with continuous
infusion IL-2 plus GM-CSF. METHODS: Patients with renal cell carcinoma and
pulmonary metastases were treated with 1.5, 2.25, or 4.5 x 10(6) IU/m(2)/day 96
hour continuous infusion IL-2 on Days 1-4, 8-11, and 15-18, and 1.25, 2.25, or
2.5 microg/kg/day GM-CSF on Days 8-19. RESULTS: Sixteen patients were treated per
protocol, 14 of whom could be evaluated for disease progression. None of these 14
patients had >50% shrinkage of either total tumor burden or pulmonary metastasis.
One patient developed Grade 5 neurotoxicity. Autopsy revealed acute multifocal
cerebral venous thrombosis as well as acute subdural and subarachnoid hemorrhage.
CONCLUSIONS: The combination of IL-2 and GM-CSF may be associated with marked
morbidity and, as in one case in this study, mortality. No significant antitumor
activity was appreciated. Thus, the combination of IL-2 and GM-CSF, when
administered at this dose and according to this schedule, does not appear to be
active in renal cell carcinoma and is associated with significant toxicities.
Further studies using this combination of agents should only be undertaken with
extreme caution and particular attention to neurotoxicity.
PMID- 10760768
TI - Prognostic significance of histologic grading compared with subclassification of
papillary thyroid carcinoma.
AB - BACKGROUND: Papillary thyroid carcinomas represent a diversity of morphologic
subtypes and variants, but to the authors' knowledge the prognostic significance
of subclassification is not clear. Therefore, the authors compared the value of
histologic classification with a combined assessment of histologic key features
such as marked nuclear atypia, tumor necrosis, and vascular invasion (i.e.,
histologic grade). METHODS: One hundred twenty-eight surgically treated patients
with papillary carcinoma > 10 mm were studied. The tumors were subclassified and
individual histologic features were examined and compared in univariate and
multivariate survival analyses. RESULTS: Of all the cases, 55% were of the usual
type, whereas 27% showed complex histologic features with different components
present and 18% represented specific subtypes. Tall cell differentiation showed
an increased frequency of tumor necrosis and vascular invasion, and tumors with
solid areas had an increased occurrence of mitotic figures and vascular invasion.
Patients with tall cell tumors tended to have reduced survival (P = 0.074), and
two patients with columnar cell features died of the disease. When combined, the
group of patients with all tumor subtypes had significantly reduced survival when
compared with the remainder of patients (P = 0.034), although the difference was
only minor. Histologic grade was highly significant (P = 0.0001) in survival
analysis, together with mitotic frequency (P = 0.028), S-phase (P = 0.015), and
G(2)M-phase fractions (P = 0.040). In multivariate analysis, tumor dimension (P =
0.019) and histologic grade (P = 0. 008) showed significant and independent
prognostic importance, whereas subclassification was not found to be significant.
CONCLUSIONS: Subclassification of papillary thyroid carcinomas had only a minor
prognostic impact, whereas histologic grade was a strong and independent
prognostic marker. The authors recommend that all papillary carcinomas be given a
histologic grade based on a combined examination of nuclear atypia, tumor
necrosis, and vascular invasion. [See editorial on pages 1766-68, this issue.]
PMID- 10760769
TI - Improved prediction of calcitonin normalization in medullary thyroid carcinoma
patients by quantitative lymph node analysis.
AB - BACKGROUND: The aim of this study was to identify better prognostic parameters
for normalization of serum calcitonin in medullary thyroid carcinoma (MTC)
patients. METHODS: In 73 patients who had undergone systematic lymph node
dissection for MTC between September 1995 and November 1998, preoperative (n =
29) and postoperative (n = 65) basal and stimulated serum calcitonin were
correlated with the pTNM classification and the number of positive regional lymph
nodes and compartments. RESULTS: In contrast to pT and M, there was a significant
correlation between postoperative calcitonin and the pN category. With rising
numbers of positive lymph nodes (0, 1-9, 10-19, and > or = 20), postoperative
basal and stimulated calcitonin increased exponentially, and gross distant
metastases (M1) occurred more frequently (0%, 4%, 13%, and 50%; P = 0.013).
Conversely, serum calcitonin was less often normalized (65%, 31%, 0%, and 0%; P =
0. 003). There was a close correlation between the number of positive lymph nodes
and the number of affected compartments (P < 0.001; r = 0.93). Irrespective of
location, involvement of 10 or more lymph nodes and more than 2 compartments
precluded normalization of serum calcitonin. CONCLUSIONS: Quantitative lymph node
analysis of MTC improves prediction of calcitonin normalization. When more than
two compartments are involved, normalization of serum calcitonin cannot be
attained. Surgery should then be less extensive and more directed at preventing
local complications.
PMID- 10760770
TI - Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and
survival time for dogs with lymphoma: a double-blind, randomized placebo
controlled study.
AB - BACKGROUND: Polyunsaturated n-3 fatty acids have been shown to inhibit the growth
and metastasis of tumors. This double-blind, randomized study was designed to
evaluate the hypothesis that polyunsaturated n-3 fatty acids can improve
metabolic parameters, decrease chemical indices of inflammation, enhance quality
of life, and extend disease free interval and survival time for dogs treated for
lymphoblastic lymphoma with doxorubicin chemotherapy. METHODS: Thirty-two dogs
with lymphoma were randomized to receive one of two diets supplemented with
menhaden fish oil and arginine (experimental diet) or an otherwise identical diet
supplemented with soybean oil (control diet). Diets were fed before and after
remission was attained with up to five dosages of doxorubicin. Parameters
examined included blood concentrations of glucose, lactic acid, and insulin in
response to glucose and diet tolerance tests; alpha-1 acid glycoprotein; tumor
necrosis factor; interleukin-6; body weight; amino acid profiles; resting energy
expenditure; disease free interval (DFI); survival time (ST); and clinical
performance scores. RESULTS: Dogs fed the experimental diet had significantly (P
< 0.05) higher mean serum levels of the n-3 fatty acids docosahexaenoic acid
(C22:6) and eicosapentaenoic acid (C20:5) compared with controls. Higher serum
levels of C22:6 and C20:5 were associated with lesser (P < 0.05) plasma lactic
acid responses to intravenous glucose and diet tolerance testing. Increasing
C22:6 levels were significantly (P < 0.05) associated with longer DFI and ST for
dogs with Stage III lymphoma fed the experimental diet. CONCLUSIONS: Fatty acids
of the n-3 series normalize elevated blood lactic acid in a dose-dependent
manner, resulting in an increase in DFI and ST for dogs with lymphoma.
PMID- 10760771
TI - Minority cancer patients and their providers: pain management attitudes and
practice.
AB - BACKGROUND: The goals of the current studies were: 1) to determine the pain
treatment needs of socioeconomically disadvantaged African-American and Hispanic
patients with recurrent or metastatic cancer and 2) to assess the attitudes of
health care professionals who treat them. METHODS: In the first study 108 African
American and Hispanic patients with metastatic or recurrent cancer and pain
completed a survey about their pain intensity, pain interference, and attitudes
toward analgesic medications. Physicians also rated their patients' pain and the
adequacy of the patients' current analgesic prescriptions was assessed. In the
second study 55 physicians and nurses who treat these patients completed a
questionnaire regarding cancer pain and its management in their practice
settings. RESULTS: Approximately 28% of the Hispanic and 31% of the African
American patients received analgesics of insufficient strength to manage their
pain. Although the majority of patients received appropriate analgesics, 65%
reported severe pain. Physicians underestimated pain severity for 64% of the
Hispanic and 74% of the African-American patients. Physicians were more likely to
underestimate the pain severity of female patients than male patients. Inadequate
pain assessment, patient reluctance to report pain, and lack of staff time were
perceived as barriers to pain management. CONCLUSIONS: Although the data suggest
recent improvements in analgesic prescribing practices for African-American and
Hispanic cancer patients, the majority of patients reported high levels of pain
and limited pain relief from analgesic medications. Inadequate pain assessment
remains a major barrier to optimal cancer pain treatment.
PMID- 10760772
TI - Good outcome of children with acute myeloid leukemia and t(8;21)(q22;q22), even
when associated with granulocytic sarcoma: a report from a single institution in
Argentina.
AB - BACKGROUND: The association between t(8;21) and granulocytic sarcoma (GS) is well
known, but to the authors' knowledge the prognostic significance of GS in these
patients has not been defined clearly. METHODS: Between January 1990 and July
1999 174 children with acute myeloid leukemia were admitted to the study
institution. Translocation (8;21) was identified in 20 patients (11.5%). Eighteen
patients were evaluable for the current study and 8 presented with GS at the time
of diagnosis (GS+). RESULTS: The authors defined two groups of patients: those
who were GS+ and those who were GS-. One patient in the GS+ group and two
patients in the GS- group died during the induction phase of the study. Complete
remission was achieved in seven patients in the GS+ group and eight patients in
the GS- group. Two patients developed a recurrence in the GS+ group as did one
patient in the GS- group. The event free-survival probability (the standard
error) was 58% (18%) in the GS+ group and 70% (14%) in the GS- group.
Localization of GS was in only one site in seven patients and at multiple sites
in one patient. Patients with an epidural mass received local radiotherapy (one
patient) or surgery (two patients). Two of these patients developed paraplegia as
sequelae: one patient after surgery and one patient after radiotherapy. One
patient with orbital GS received local radiotherapy because of progressive
proptosis. The remaining four patients had a complete resolution of the GS with
chemotherapy only. CONCLUSIONS: In the current study of patients with
t(8;21)(q22;q22), the presence of granulocytic sarcoma was not found to be an
adverse prognostic factor. However, careful attention should be paid, especially
to patients with an epidural site, to avoid sequelae. Chemotherapy appears to be
the optimum treatment for these children.
PMID- 10760773
TI - Prognostic significance of cytogenetic abnormalities of chromosome arm 12p in
childhood acute lymphoblastic leukemia: a report from the Children's Cancer
Group.
AB - BACKGROUND: The authors have determined the prognostic significance of
cytogenetically detectable 12p abnormalities, which are frequent in children with
acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk
adjusted protocols of the Children's Cancer Group (CCG). METHODS: The presence of
an abnormal 12p was identified among 1880 children with newly diagnosed ALL;
outcome was assessed by standard life table methods. RESULTS: A total of 174
cases (9%) had cytogenetically detectable 12p abnormalities; the majority of
cases had a balanced translocation, a del(12p), or an add(12p). In the overall
cohort, event free survival (EFS) at 6 years was similar for patients with or
without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P =
0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved
outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31
0.85). There was a trend for improved EFS for those with abnormalities in both
chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10-1.55) and
those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18-1.09).
Among T-lineage ALL patients, there was a trend for worse outcome for abnormal
versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78-4.93). There was
no difference in EFS for the 12 patients with a dic(9;12) compared with patients
lacking an abnormal 12p. CONCLUSIONS: These data suggest that although a
cytogenetically detectable 12p aberration is a favorable risk factor for children
with ALL and pseudodiploidy, it is not prognostic for the overall group of
pediatric ALL patients treated with contemporary therapies of the CCG.
PMID- 10760774
TI - Multifocal neuroblastoma: biologic behavior and surgical aspects.
AB - BACKGROUND: Although multifocal neuroblastoma is rare, its incidence has
increased because of recent improvements in diagnostic tools and the introduction
of mass screening. Among the 106 neuroblastoma cases treated at the authors'
hospital between 1984 and 1998, 8 were multifocal neuroblastoma. METHODS: The
authors examined clinicopathologic findings and biologic features, including MYCN
amplification, NTRK1 and Ha-ras p21 expression, cellular DNA content, and
telomerase activity in these 8 multifocal neuroblastoma cases. Moreover,
clinicopathologic findings were investigated with a review of 53 published cases
of multiple neuroblastoma in the literature published in English between 1966 and
1999. RESULTS: Among these eight cases, five were detected by mass screening and
three were incidental neuroblastomas. Histologically, all tumors were classified
as ganglioneuroma or favorable neuroblastoma except one advanced case. All tumors
lacked the MYCN gene amplification and expressed NTRAK1 mRNA and Ha-ras p21
protein. Cellular DNA content showed that half of these tumors were near
triploid, and the proliferative index (%S-phase) of all tumors was less than 25%.
High telomerase activity was detected in none of these cases. Four patients
underwent multistage operation and five patients with bilateral adrenal
neuroblastomas underwent tumor enucleation to preserve adrenal function.
Currently, all patients are disease free and none have required corticosteroid
replacement therapy. Among the previously reported 53 cases with multifocal
neuroblastoma, 25 were incidentally detected, 18 had familiar history, and most
patients without other major complications also had extremely good prognoses.
CONCLUSIONS: These findings suggested that most multifocal neuroblastomas have
favorable biologic features. Clinically, surgical approaches should be attempted
to preserve organ function, especially adrenal function, and minimal invasive
surgery should be performed. In cases of thoracoabdominal neuroblastoma,
multistage surgery is effective and safe.
PMID- 10760775
TI - Substituting dexamethasone for prednisone complicates remission induction in
children with acute lymphoblastic leukemia.
AB - BACKGROUND: The authors report the occurrence of fatal or near-fatal sepsis in 16
of 38 children with newly diagnosed acute lymphoblastic leukemia (ALL) treated
with a new induction regimen that differed from its predecessor by the
substitution of dexamethasone for prednisone. METHODS: The frequency of septic
deaths among 38 children who received multiagent remission induction therapy,
including dexamethasone (6 mg/m(2)) daily for 28 days (pilot protocol 91-01P),
was compared with the frequency of septic deaths among children previously
treated (protocol 87-01) and subsequently treated (protocol 91-01) in consecutive
Dana-Farber Cancer Institute (DFCI) ALL trials with induction therapy that
included 21 and 28 days of prednisone (40 mg/m(2)), respectively. Except for
dexamethasone in protocol 91-01P, the remission induction agents used were
identical in substance to those used in protocol 87-01. Protocol 91-01, the
successor 91-01P, was also similar, with the exception of the deletion of a
single dose of L-asparaginase. RESULTS: Sixteen of the 38 children (42%) treated
on the DFCI 91-01P had documented gram positive or gram negative sepsis (17
episodes) during remission induction, including 4 toxic deaths (11%). In
contrast, there were 4 induction deaths among 369 children (1%) treated on
protocol 87-01 (P = 0.0035) and 1 induction death among 377 children (<1%)
treated on protocol 91-01 (P = 0.0003). CONCLUSIONS: Substitution of
dexamethasone for prednisone or methylprednisolone in an otherwise intensive
conventional induction regimen for previously untreated children with ALL
resulted in an alarmingly high incidence of septic episodes and toxic deaths.
Awareness of this complication, considering that the substitution has no apparent
benefit in the efficacy of remission induction, argues against its routine use in
intensive induction regimens for children with ALL.
PMID- 10760776
TI - Hemophagocytosis by leukemic blasts in 7 acute myeloid leukemia cases with
t(16;21)(p11;q22): common morphologic characteristics for this type of leukemia.
AB - BACKGROUND: In a previous study of a case of acute megakaryoblastic leukemia with
t(16;21)(p11;q22), which displayed hemophagocytosis by leukemic blasts, the
authors mentioned that the same type of morphology had been cited in the
literature for 4 other cases of acute myeloid leukemia (AML) with the same
translocation. This observation prompted the authors to examine more cases of AML
with t(16;21)(p11;q22) for this morphology. METHODS: The authors reviewed bone
marrow smears for the presence of hemophagocytosis in 7 patients with AML
identified as having t(16;21)(p11;q22). RESULTS: The leukemias belonged to the
FAB-M1/M7 (n = 5), M5b (n = 2), and contained phagocytic blasts in various
percentages (< 0.2-36.7%). The blasts contained either single or multiple
cytoplasmic vacuoles, in some of which the phagosomes were visible. The engulfed
hemopoietic cells (red cells, erythroblasts, lymphocytes, and thrombocytes) were
also noted in their cytoplasm. These observations confirmed that hemophagocytosis
by leukemic blasts is a common and characteristic feature of this type of
leukemia. CONCLUSIONS: The study of 12 cases (the 7 cases described here and the
previous 5 cases) strongly supports the hypothesis that hemophagocytosis by
leukemic blasts is common and characteristic in this type of leukemia, which may
be related to the specific chromosome aberration of t(16;21)(p11;q22).
PMID- 10760777
TI - Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP)
eight-year update of protocol B-17: intraductal carcinoma.
PMID- 10760778
TI - Author reply
PMID- 10760779
TI - ["El Nino" - Leben fur die untergehende Pflanzenwelt der Atacama]
AB - Jeder Botaniker, der sich mit der Artenvielfalt beschaftigt, traumt davon, neue
Arten zu entdecken. Die Meinung, dies sei heute nur noch im Reichtum des
tropischen Regenwalds moglich, trugt. Auch die Trockengebiete der Erde bergen
noch eine Fulle unentdeckter Schatze, die allerdings nicht zu jeder Zeit sichtbar
sind.
PMID- 10760781
TI - [Uberleben in der Kalte - wie Pflanzen sich vor Froststress schutzen]
AB - Kalte ist sowohl ein direkt, als auch indirekt wirkender Umweltfaktor, der die
Produktivitat und die Verbreitung von Pflanzen erheblich einschrankt. Besondere
Schutzmechanismen ermoglichen es uberwinternden Pflanzen, Frosttemperaturen
wahrend der kalten Jahreszeit ohne grobetaere Schaden zu uberstehen. Wahrend der
Anpassung an tiefe Temperaturen kommt es zur Umstellung des pflanzlichen
Stoffwechsels und zu Veranderungen in der Ultrastruktur der Zelle.
PMID- 10760780
TI - [Kohlhernie - neue Ansatze zur Bekampfung der gefurchteten Kohlerkrankung]
AB - Durch Pflanzenkrankheiten entstehen weltweit hohe Ernteverluste. Eine der
haufigsten Infektionen in der Familie der Kreuzb&luml;tengewachse wird durch den
Pilz Plasmodiophora brassicae verursacht. Die Krankheit aubetaert sich in Form
von Wurzeltumoren, den "Kohlherniegallen". Da es auf verseuchten Boden zu hohen
Ernteausfallen kommt, besteht ein enormes Interesse an der Aufklarung der
Vorgange, die zu diesem Krankheitsbild fuhren.
PMID- 10760783
TI - [Selbstorganisation, Strukturbildung und Wahrnehmung - Versuche mit dem singenden
Rohr]
PMID- 10760782
TI - [Leben im Eismeer - Tauchuntersuchungen zur Biologie arktischer Meerespflanzen
und Meerestiere]
AB - Die Maske wird nochmals auf Dichtigkeit uberpruft, der Knoten der Sicherungsleine
mit zwei halben Schlagen fixiert, dann rutscht die Taucherin von der Eiskante in
das kalte Wasser. Eine halbe Stunde vergeht, bevor ihr Kopf wieder aus dem
Eisloch auftaucht und sie ein grobetaes Sammelnetz nach oben reicht, gefullt mit
verschiedenen Arten von Makroalgen. Obwohl noch grobetae Flachen des Kongsfjordes
im arktischen Spitzbergen zugefroren sind und das Festland von einer dicken
Schneedecke bedeckt ist, hat unter Wasser in den Algenwaldern bereits der Sommer
und damit die Saison der Meeresbiologen begonnen.
PMID- 10760784
TI - Systemic lupus erythematosus in mice, spontaneous and induced, is associated with
autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA.
AB - The tumor suppressor molecule p53 features a regulatory domain at the C terminus
that recognizes damaged DNA. Since damaged DNA might be involved in activating
anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53
might mark murine systemic lupus erythematosus (SLE). We now report that MRL /
MpJ-Fas(lpr) mice, which spontaneously develop SLE, produce antibodies both to
the C terminus of p53 and to a monoclonal antibody (PAb-421) that binds the p53 C
terminus. Anti-idiotypic antibodies to PAb-421 (sampled as monoclonal antibodies)
could also bind DNA. Thus, the PAb-421 antibody mimics DNA, and the anti
idiotypic antibody to PAb-421 mimics the p53 DNA-binding site. This mimicry was
functional; immunization of BALB / c mice to PAb-421 induced anti-DNA antibodies
and antibodies to the C terminus of p53, and most of the mice developed an SLE
like disease. Immunization of C57BL / 6 mice to PAb-421 induced antibodies to
p53, but not to its C-terminal domain. The C57BL / 6 mice also did not develop
anti-DNA antibodies or the SLE-like disease. Thus, network autoimmunity to the
domain of p53 that recognizes damaged DNA can be a pathogenic feature in SLE in
genetically susceptible strains of mice.
PMID- 10760785
TI - Selective induction of NK cell proliferation and cytotoxicity by activated NKT
cells.
AB - NK T cells produce cytokines when their semi-invariant TCR engages glycolipids
associated with CD1d. The physiological consequences of NKT cell activation
remain controversial, although they have been implicated in control of
autoimmunity, parasites and tumors. We show here that specific activation of NKT
cells in liver and spleen leads to a rapid induction of extensive NK cell
proliferation and cytotoxicity. This NK cell activation is dependent, at least in
part, on IFN-gamma production by NKT cells and IL-12 production by antigen
presenting cells. Remarkably, activation of NK cells by NKT cells is highly
selective, since bystander T and B lymphocytes show transient expression of
activation markers but almost no proliferation. Collectively our data suggest
that CD1d-dependent NKT cells regulate innate immunity by sampling blood-borne
glycolipid antigens and rapidly activating NK cells.
PMID- 10760786
TI - Preferential stimulation of human lymphocytes by oligodeoxynucleotides that copy
DNA CpG motifs present in virulent genes of group A streptococci.
AB - Immunostimulatory oligodeoxynucleotides (ODN) containing CpG dinucleotides have
been shown to stimulate murine and human lymphocytes. We investigated the
presence of stimulatory DNA motifs in specific group A streptococcal (GAS) genes
to elucidate the potential role of DNA in the immunopathogenesis of GAS
infections. Despite low GC content in GAS DNA, the emm1 gene encoding the
streptococcal M1 protein contained a relatively high frequency of TTCG(T/C),
TCGTCG and (G/A)TCGT motifs that preferentially stimulated human lymphocytes.
Interestingly, these motifs were also found in genes encoding M-like proteins of
group C and G streptococci. ODN copying the emm1 gene sequences harboring these
motifs induced the proliferation of human B cells and up-regulated the expression
of CD25 on their surface. T cells were not required for the response to the ODN,
indicating a direct effect of these motifs on B lymphocytes. Inter-individual
variations in responsiveness to ODN were observed, suggesting that host factors
potentiate these responses. The finding that GAS DNA contains stimulatory motifs
that induce activation of human B cells in a T cell-independent manner suggests
that this may be an important mechanism by which the bacteria can target the
innate arm of the immune system in the early stages of invasive infections.
PMID- 10760787
TI - Naive T lymphocytes traffic to inflamed central nervous system, but require
antigen recognition for activation.
AB - Organ-specific autoimmune diseases may be induced by infiltration of the target
tissue by CD4(+) T cells with specificity for self antigen(s). As disease
progresses, T cells of other specificities appear in the tissue. Traffic of
naive, antigen-inexperienced T cells to target tissues has not been shown,
although many studies have shown extravasation of activated or memory T cells. We
have used a novel experimental system to track naive T cells to the central
nervous system (CNS) in TCR transgenic mice with adoptively transferred
experimental autoimmune encephalomyelitis. Ovalbumin (OVA)-specific CD4(+) T
cells were equivalent in number to disease-inducing myelin basic protein (MBP)
specific T cells at disease onset. Furthermore, OVA-specific T cells retained a
naive phenotype and did not transcribe Th1 cytokines, in contrast to MBP-specific
T cells. These findings demonstrate that the T cell pool in the CNS of animals
with demyelinating disease contains potential recruits from the time of disease
onset, and that T cells require more than an inflammatory milieu for their
induction to the autoimmune attack.
PMID- 10760788
TI - The insulin-like growth factor-I receptor is regulated by CD28 and protects
activated T cells from apoptosis.
AB - Co-stimulatory signals through the CD28 receptor enhance the survival of T cells
that have their antigen receptor (TCR) engaged. Here we show that stimulation
through the CD28 receptor in the absence of TCR engagement with either an anti
CD28 cross-linking antibody or the CD80 ligand transiently increases expression
of the insulin-like growth factor-I receptor (IGF-IR) on T cells. Antibodies that
block signaling through the IGF-IR decrease the survival of T cells activated
through the TCR and CD28 in the presence of IL-2 by more than 50%, and also
enhance susceptibility to Fas-induced apoptosis. CD28 stimulation increases IGF
IR expression on Jurkat cells, and exogenously added IGF-I can protect these
cells from Fas-induced apoptosis. We conclude that CD28-mediated enhancement of
IGF-IR expression provides activated T cells with essential survival signals that
are independent of survival mediated by IL-2 and Bcl-xl.
PMID- 10760789
TI - Regulation of the promoter for human immunoglobulin gamma3 germ-line
transcription and its interaction with the 3'alpha enhancer.
AB - The mechanism underlying the differential regulation of switching to human IgG
subclasses is still largely unknown. We demonstrate that the region upstream of
the initiation sites for gamma3 germ-line (GL) transcripts contains a functional
promoter which is synergistically induced by IL-4, antibody to CD40 and phorbol
dibutyrate in transient transfection assays in the human DG75 cell line. Linker
scanning mutations identified multiple elements in the 3' half of the
evolutionarily conserved sequence that are required for inducibility.
Electrophoretic mobility shift assays showed that Stat6 and NF-kappaB p50 / p65
are induced after stimulation, and bind to specific sequence motifs within the
promoter. Overexpression of Stat6, NF-kappaB p50 / p65 and C / EBPgamma
synergistically induced the GL gamma3 promoter. Insertion of DNA segments from
the human 3' IgH regions, which may function as a locus control region for switch
recombination, greatly activated the promoter in an orientation-independent
manner. Duplication of the enhancer fragments resulted in a further increase of
promoter activity. The greater enhancement of the HS1,2 fragment from the 3'
alpha1 rather than the alpha2 locus may suggest a mechanistic explanation for the
differential expression of various isotypes.
PMID- 10760790
TI - Inhibition by IL-12 and IFN-alpha of I-309 and macrophage-derived chemokine
production upon TCR triggering of human Th1 cells.
AB - Th1 and Th2 cells, which produce distinct sets of cytokines, differentially
express several chemokine receptors that may regulate their tissue-specific
localization. Although the expression pattern and regulation of chemokines are
likely to play a critical role in many immunopathological processes, they remain
largely unknown. Here, we investigated the requirements for Th1 and Th2 cells to
produce the Th2 cell-attracting chemokines thymus and activation-regulated
chemokine (TARC), macrophage-derived chemokine (MDC) and I-309. TCR triggering of
Th1 and Th2 cells leads to production of MDC and I-309 (CCR4 and CCR8 ligands,
respectively), whereas TARC (CCR4 ligand) is selectively produced by Th2 cells.
Secretion of these chemokines appears to be independent of endogenous production
of IL-4 and IFN-gamma. IL-12 and IFN-alpha, cytokines that promote the
differentiation of human Th1 cells, selectively inhibit secretion and mRNA
expression of MDC and I-309 by Th1 cells. Suppression of I-309 secretion results
in a decreased chemotactic effect on L1.2 cells transfected with human CCR8,
indicating that IL-12 and IFN-alpha may inhibit the recruitment of CCR8
expressing cells such as Th2 cells. The inhibition of Th2 cell-attracting
chemokines MDC and I-309 illustrates a novel mechanism by which IL-12 and IFN
alpha could promote and maintain an ongoing Th1 response.
PMID- 10760791
TI - Molecular cloning and characterization of murine ICOS and identification of B7h
as ICOS ligand.
AB - Human ICOS (huICOS) is a T cell-specific molecule structurally related to CD28
and CTLA-4 with potent co-stimulatory activities on T cell proliferation,
cytokine induction and T cell help for B cells. We have now cloned and
characterized murine ICOS (muICOS). muICOS mRNA of 1.5 kb and 3.3 kb encodes a
protein with a deduced molecular mass of 20.3 kDa, which is 71.7 % identical to
huICOS. On the cell surface, muICOS is expressed as a disulfide-linked,
glycosylated homodimer of 47-57 kDa, with subunits of approximately 26 kDa. With
a panel of monoclonal antibodies we have determined the expression of muICOS in
vitro and in vivo. Following activation of splenic T cells via CD3, muICOS became
detectable at 12 h and reached a maximum of expression at around 48 h, thus
exhibiting expression kinetics similar to huICOS. In vivo, muICOS was found to be
substantially expressed in the thymic medulla and in the germinal centers and T
cell zones of lymph nodes and Peyer's patches. Non-lymphoid tissue was ICOS
negative. The muICOS gene was mapped to a region of chromosome 1 also harboring
the CD28 and CTLA-4 genes. Using recombinant chimeric muICOS-Ig we determined
that B7h, a recently cloned B7-like molecule, is a ligand for muICOS.
PMID- 10760792
TI - Culture of bone marrow cells in GM-CSF plus high doses of lipopolysaccharide
generates exclusively immature dendritic cells which induce alloantigen-specific
CD4 T cell anergy in vitro.
AB - Dendritic cells (DC) can be generated from mouse bone marrow (BM) in the presence
of granulocyte-macrophage colony-stimulating factor (GM-CSF). Bacterial stimuli
such as endotoxin / lipopolysaccharide (LPS) can induce their final maturation.
When BM-DC cultures were treated at day 6 or later with LPS, this final
maturation was induced in vitro within 24 h. Such mature DC exhibited high levels
of surface MHC II molecules and potent T cell sensitizing, but reduced
endocytosis capacity. In contrast, immature DC express only few MHC II molecules
and are weak T cell stimulators but highly endocytic. When BM-DC cultures in GM
CSF were treated with 1 microg / ml LPS at day 0 of the culture or throughout the
culture, only immature DC developed as defined by phenotype (MHC II low) and
function (high endocytosis, weak primary mixed lymphocyte reaction). Those early
LPS-treated immature DC induced alloantigen-specific anergy of CD4(+) T cells in
vitro. These findings might contribute to the understanding of reduced T cell
immunity in the course of septic shock and find application in DC-mediated
tolerogenic immunotherapy strategies.
PMID- 10760793
TI - Substantial in vivo proliferation of CD4(+) and CD8(+) T lymphocytes during
secondary Listeria monocytogenes infection.
AB - In mice Listeria monocytogenes infection induces a strong T cell response. In an
attempt to quantitatively analyze the magnitude and kinetics of the CD4(+) and
CD8(+) T cell response during L. monocytogenes infection in vivo we used a T cell
transfer system that is independent of in vitro cell culture techniques and
information about the identity of immunogenic T cell epitopes. Our results
demonstrate substantial expansion of the in vivo primed and transferred T cell
populations in response to L. monocytogenes. At the peak of response, transferred
T cells represented more than one third of the total CD4(+) and CD8(+) T cell
populations in blood and spleen of recipient mice. After stimulation in vitro, 40
% of these CD4(+) T cells responded to heat-killed listeriae with the production
of IFN-gamma. Thus, our results reveal that in addition to the large CD8(+) T
cell population an almost equally large population of Listeria-reactive CD4(+) T
cells is generated in response to L. monocytogenes infection.
PMID- 10760794
TI - Degree of ERK activation influences both positive and negative thymocyte
selection.
AB - Considerable evidence suggests that the ERK pathway is required for positive but
not negative thymocyte selection. Here, we report that ERK is highly activated in
double-positive (DP) thymocytes expressing an MHC class I-restricted TCR (P14) in
response to negatively selecting conditions, whereas ligands that trigger
positive selection induced weaker ERK activation. Biochemical evidence also shows
that death by neglect is associated with a further reduction in ERK activation.
These findings are consistent with the affinity / avidity model of thymocyte
selection. To further examine the role of ERK in negative selection we used the
MEK-1 inhitibor, PD98059, a specific pharmacological inhibitor of the ERK
pathway. Biochemical data demonstrated a reduction of ERK activity by PD98059 in
the presence of the negatively selecting ligand. Analysis of P14 TCR-transgenic
fetal thymic lobes cultured with PD98059 under negatively selecting conditions
showed impaired clonal deletion of DP thymocytes and a concomitant increase in
positive selection of functional mature, TCR(hi) transgenic T cells. This
demonstrates that altering ERK activity switched negative to positive selection.
Contrary to previous reports that show an exclusive role for ERK signaling in
positive selection, our data demonstrate that negative selection is also
sensitive to the degree of ERK activation.
PMID- 10760795
TI - Impaired up-regulation of CD86 in B cells of "type A" common variable
immunodeficiency patients.
AB - Common variable immunodeficiency (CVID) is characterized by defective B cell
maturation and antibody formation resulting in low serum antibody levels of most
or all Ig isotypes. A specific subgroup of patients ("type A") has normal numbers
of mature surface (s)IgM / sIgD- positive circulating B cells. However, since
these lymphocytes do not respond to in vitro stimulation by differentiation and
Ig synthesis, they seem to suffer from so far unknown intrinsic defects.
Analyzing the expression pattern of a large set of B cell activation-specific
surface markers, we found that type A CVID patients show a highly reduced
expression of the CD28 / CTLA-4 ligand CD86 (B7-2) and of the lymphocyte
activation marker CDw137 when compared to B cells of healthy donors and non-type
A CVID patients. The lowered CD86 expression levels were found to correlate with
reduced levels of CD86 mRNA. Since combined stimulation via B cell antigen
receptor and CD40 cross-linking did not rescue the defects in CD86 and CDw137
expression, B cells of CVID type A patients resemble functionally unresponsive
lymphocytes incapable of cooperating with T cells. The fact that these cells
accumulate in type A CVID patients suggests a causal relationship with the
pathogenesis of this disease.
PMID- 10760796
TI - CD59 cross-linking induces secretion of APO2 ligand in overactivated human T
cells.
AB - Jurkat cells and the derived TCR / CD3-defective subline, J.RT3.T3.5 undergo
activation induced cell death (AICD) when stimulated with phytohemagglutinin
(PHA). Since J.RT3.T3.5 cells do not express antigen receptor, we searched for
the molecules that could be ligated by PHA and induce AICD in this cell line. We
show here that the glycosylphosphatidylinositol linked CD59 molecule is expressed
at the surface of Jurkat and J.RT3.T3.5 cells, and when cross-linked by specific
antibodies can induce cell death. The toxicity of supernatants from PHA
stimulated Jurkat or J.RT3.T3.5 cells was prevented by a combination of the
blocking anti-Fas mAb SM1 / 23 and anti-APO2L / TRAIL mAb 5C2. However, toxicity
of supernatants from anti-CD59 stimulated cells was specifically prevented by the
anti-APO2L blocking antibody. Anti-CD59 cross-linking induced AICD also in normal
human T cell blasts, which secreted toxic molecules into the supernatant. The
toxicity of these supernatants on Jurkat cells was fully prevented by the anti
APO2L blocking antibody, showing that CD59 crosslinking induces the preferential
release of APO2L also in normal T cells. The possible physiological and / or
pathological consequences of this observation are discussed.
PMID- 10760797
TI - Innate and adaptive immunity to tumors: IL-12 is required for optimal responses.
AB - We have investigated the importance of endogenously produced IL-12 in innate and
adaptive immunity to tumor transplants. The immunogenic lymphoma RMA and its TAP
deficient variant RMA-S were tested for rejection responses by normal and IL-12
deficient mice. IL-12 was crucial for the immunity induced by one immunization
with irradiated RMA cells, as well as for in vivo priming of a CTL response in
mixed lymphocyte tumor cultures against this MHC class I-expressing tumor. The
defective in vivo response could be overcome by multiple immunizations. In
further studies of in vitro CTL responses, we found that IL-12 production from
either the antigen-pulsed dendritic cells or from host cells was necessary to
obtain strong CTL responses. In the complete absence of IL-12, no or only very
weak responses could be detected. NK cell-mediated innate resistance, as assessed
in non-immunized mice inoculated with a threshold dose of RMA-S cells, also
required IL-12. However, NK cells with reduced activity were present in IL-12
deficient mice and contributed to innate resistance, as demonstrated with lower
cell dose challenges. In conclusion, IL-12 is required for optimal adaptive and
innate responses against tumors.
PMID- 10760798
TI - Role of Qa-1(b)-binding receptors in the specificity of developing NK cells.
AB - NK cells acquire the ability to recognize MHC class I molecules during
development. Studies with Qa-1(b) tetramers (Qa-1 tetramers) showed that nearly
all NK1.1(+) cells from newborn C57BL/6 mice express Qa-1-binding receptors.
Cytotoxic activity of these cells is fully inhibited by Qa-1 ligands on target
cells. In contrast, neither receptors for H-2K(b) nor H-2D(b) were observed on
NK1.1(+) cells from newborn mice. After birth, frequencies of Qa-1 tetramer(+)/
NK1.1(+) cells gradually decrease as the number of Ly49(+) /NK1.1(+) cells
increases. Cell transfer studies showed that Qa-1 tetramer(+) cells from newborn
mice do not lose expression of Qa-1 receptors, but that they further acquire
expression of Ly49 molecules. Acquisition of Qa-1-binding receptors appears
largely independent of host MHC class I molecules, as observed in studies using
beta2-microglobulin-deficient (beta2m(-/-)) mice as well as K(b)/ D(b-/-) and
K(b)/D(b)/beta2m(-/-) mice. The present results suggest that Qa-1-binding
receptors play an important role in the specificity of developing NK cells, and
suggest that these cells rely mainly on inhibitory receptors specific for non
classical MHC class I molecules to maintain self tolerance during the first weeks
of life.
PMID- 10760799
TI - ATF and Jun transcription factors, acting through an Ets/CRE promoter module,
mediate lipopolysaccharide inducibility of the chemokine RANTES in monocytic Mono
Mac 6 cells.
AB - The chemokine RANTES is produced by a variety of tissues, including cells of the
monocyte/macrophage lineage. RANTES expression is rapidly and transiently up
regulated in primary monocytes and the monocytic cell line Mono Mac 6 in response
to stimulation by the bacterial product lipopolysaccharide (LPS). Transient
transfection of Mono Mac 6 cells with RANTES reporter-promoter deletion
constructs, in conjunction with DNase I footprinting and heterologous reporter
gene assays, allowed identification of an LPS-responsive region within the RANTES
promoter. Electrophoretic mobility shift assays (EMSA), methylation interference
and EMSA supershift experiments were used to characterize sequences and
transcription factors responsible for this LPS inducibility. The region, termed
RANTES site G [R(G)], contains consensus sites for Ets and CRE/AP-1-like
elements. Site-directed mutagenesis of the Ets site resulted in a loss of only 15
% of promoter activity, while mutation of the CRE/AP-1 site led to a loss of 40 %
of LPS-induced promoter activity. The Ets site constitutively binds the Ets
family member PU.1. LPS stimulation leads to an induction of ATF-3 and JunD
factor binding to the CRE/AP-1 site. Thus, LPS induction of RANTES transcription
is mediated, in part, through the activation and selective binding of ATF and Jun
nuclear factors to the R(G) promoter module.
PMID- 10760800
TI - The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma
production by resting T cells is IL-12 dependent and is mediated by up-regulation
of the IL-12 receptor beta2 subunit.
AB - IL-18 was originally described as a cytokine which induced IFN-gamma production
by established Th1 cells in an IL-12-independent manner. However, subsequent
studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive
Th1 differentiation of naive cells and induced IFN-gamma from established Th1
cells only in combination with IL-12. We have examined the role of endogenous IL
18 in controlling Th1 lineage commitment. When naive TCR-transgenic T cells were
stimulated with antigen, anti-IL-18 antibodies resulted in partial inhibition of
IFN-gamma production, but did not inhibit Th1 differentiation. To distinguish
whether the inhibitory effect of anti-IL-18 antibodies was mediated directly by
blocking IFN-gamma production or indirectly by blocking IL-12Rbeta2 up
regulation, naive T cells from IL-12 - / - mice were stimulated with anti-CD3 and
IL-18. These cells failed to produce IFN-gamma, but markedly up-regulated IL
12Rbeta2 expression. We propose that the major effect of IL-18 on Th1 development
is mediated by up-regulation of IL-12Rbeta2 expression, thereby enhancing IL-12
mediated signaling. The enhancement of IL-12Rbeta2 expression by IL-18 may be
particularly important for the differentiation of foreign antigen- or autoantigen
specific Th1 cells when the stimulatory concentration of IL-12 in the
microenvironment is just below the threshold required for Th1 development.
PMID- 10760801
TI - Highly stable oligomerization forms of HIV-1 Tat detected by monoclonal
antibodies and requirement of monomeric forms for the transactivating function on
the HIV-1 LTR.
AB - The use of newly generated murine monoclonal antibodies directed against distinct
epitopes of a functionally active, chemically synthesized HIV-1 Tat protein has
permitted the identification of several molecular forms including monomers,
dimers and trimers. Dimers and trimers are particularly stable and resistant to
strong reducing conditions. Through epitope mapping it has been possible to
demonstrate that the major immunodominant epitope is contained within the basic
region of the Tat protein and is lost after oligomerization of the molecule. In
contrast, N-terminal, C-terminal and conformation-dependent epitopes are still
accessible to mAb specific recognition after Tat oligomerization. Moreover, by
using a quantitative HIV-LTR transactivation assay depending upon exogenous Tat,
we could extrapolate the amount of functional Tat produced by cell lines stably
transfected with the viral transactivator. More importantly, we could show that
only the monomeric form of exogenous Tat is the relevant functional form acting
in cells harbouring the HIV-1 LTR promoter.
PMID- 10760802
TI - Antigen-presenting cells recruited by Brugia malayi induce Th2 differentiation of
naive CD4(+) T cells.
AB - A key feature of nematode infection is a bias towards a type 2 immune response.
To investigate the role that antigen-presenting cells (APC) may play in promoting
this bias, we used adherent peritoneal exudate cells (PEC) recruited in response
to the filarial nematode Brugia malayi, to stimulate naive T cells from pigeon
cytochrome c (PCC)-specific TCR transgenic (PCC-tg) mice. Although the
proliferation of PCC-tg T cells was inhibited by parasite- induced PEC during
primary stimulation, they proliferated normally upon secondary stimulation and
were not rendered anergic. However, PCC-tg T cells primed by suppressive APC
differentiated into IL-4-producing Th2 cells upon secondary stimulation instead
of IFN-gamma-producing Th1 cells, as has been previously described. Studies with
carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled cells indicated
that Th2 differentiation was associated with the inhibition of (or failure to
stimulate) IFN-gamma production during primary stimulation. Interestingly,
blocking antibodies against TGF-beta (but not IL-10) restored the differentiation
of IFN-gamma-producing Th1 cells. Identical results with CFSE-labeled cells were
obtained using purified IL-4-dependent F4/80(+) macrophages. These data indicate
that T cells exposed to parasite-induced alternatively activated macrophages are
driven towards Th2 differentiation. This may be an important factor in the Th2
bias that accompanies nematode infection.
PMID- 10760803
TI - CD28 and LFA-1 contribute to cyclosporin A-resistant T cell growth by stabilizing
the IL-2 mRNA through distinct signaling pathways.
AB - In clinical transplantation, the occurrence of cyclosporin A (CsA)-resistant
production of IL-2 in vitro correlates with graft rejection in vivo. In this
study we investigated the role of the costimulatory molecules CD28 and LFA-1 in
this process in the setting of TCR-induced proliferation of primary T lymphocytes
in vitro. Co-stimulation with ICAM-1 and B7.2 led to strong and CsA-resistant
proliferation, which was found to be largely IL-2 dependent. All of the known
calcineurin-dependent events, such as induction of NF-AT and NF-kappaB or stress
activated protein kinase activation, were markedly modulated by CsA independently
of costimulation. In contrast, both ICAM-1 and B7.2 enhanced the half-life of the
inducible IL-2 transcript in a CsA-resistant manner. LFA-1- but not CD28-induced
IL-2 mRNA stabilization required the integrity of the actin-based cytoskeleton,
suggesting that the two costimulatory molecules impact on qualitatively different
signaling pathways. This is further suggested by the demonstration that LFA-1 and
CD28 acted synergistically to confer CsA resistance in a model of co-stimulation
using superantigen-pulsed dendritic cells. We propose that IL-2 transcript
accumulation and subsequent T cell proliferation at the low transcriptional rate
imposed by CsA are the result of co-stimulation-dependent stabilization of IL-2
mRNA.
PMID- 10760804
TI - Quantification of thymic function by measuring T cell receptor excision circles
within peripheral blood and lymphoid tissues in monkeys.
AB - The thymus is the primary organ responsible for the production of mature TCR
alpha / beta T cells. Quantification of a DNA excision circle that is produced
during TCR rearrangement, termed a signal joint TCR rearrangement excision circle
(sjTREC) can be used as a measure of thymic function. Here sjTREC measurement has
been applied to two monkey species used as animal models of human disease, rhesus
macaques (Asian origin) and sooty mangabeys (African origin). Initial PCR
analysis determined that the TCR deltaRec-PsiJalpha rearrangement leading to
sjTREC formation occurs in both species. Primers to a DNA sequence conserved in
macaques, mangabeys and humans were used in a quantitative competitive PCR assay
to quantify sjTREC. We found that as in humans, sjTREC in these two monkey
species decline with age. sjTREC are first generated in thymocytes during the
early stages of TCR rearrangement. Lymph node CD4(+) and CD8(+) T cells contain
more sjTREC than peripheral blood T cell populations, suggesting that recent
thymic emigrants home to the lymphoid tissues. The sjTREC level is significantly
higher within the peripheral blood CD4(+) and CD8(+) T cells of mangabeys
compared to macaques. Removal of the thymus in four macaques led to a profound
decrease in peripheral blood sjTREC level by 1 year post-thymectomy, indicating
the lack of a significant extra-thymic source of peripheral naive T cells in
macaques. Our results indicate that production, trafficking, and proliferation of
recent thymic emigrants in these two monkey species represents a useful animal
model system for understanding human immunological disorders.
PMID- 10760805
TI - Steroid- and retinoid-mediated growth arrest and apoptosis in WEHI-231 cells:
role of NF-kappaB, c-Myc and CKI p27(Kip1).
AB - IgM cross-linking induces NF-kappaB inactivation, c-Myc down-regulation, and
cyclin kinase inhibitor p27(Kip1) accumulation in WEHI-231 murine B lymphoma
cells. p27(Kip1) up-regulation leads to a decreased cyclin-dependent kinase 2
activity, retinoblastoma protein hypophosphorylation, G1 arrest and apoptosis.
Similar to membrane (m) IgM cross-linking in B lymphoma cells, steroids and
retinoids down-regulate c-Myc (via NF-kappaB inactivation) and induce apoptosis
in T cell hybridomas and thymocytes. In this study, we determined if steroids and
retinoids have similar effects in WEHI-231 cells. Our results show that steroids
and retinoids induce NF-kappaB inactivation, c-Myc down-regulation, p27(Kip1) up
regulation, G1 arrest, and apoptosis. Importantly, these hormones enhance anti
IgM-induced apoptosis in WEHI-231 cells. Similar to mIgM signaling, all these
effects are prevented by treatment with CD40 ligand. Caspase inhibition, on the
other hand, rescues cells from steroid/retinoid-induced apoptosis, but has no
effect on growth arrest, p27(Kip1), and c-Myc. Together, these findings suggest
that steroids/retinoids and mIgM cross-linking share a common signal transduction
pathway leading to G1 arrest and cell death.
PMID- 10760806
TI - Monoclonal antibody screening of a phage-displayed random peptide library reveals
mimotopes of chemokine receptor CCR5: implications for the tertiary structure of
the receptor and for an N-terminal binding site for HIV-1 gp120.
AB - The chemokine receptor CCR5 contains seven transmembrane-spanning domains. It
binds chemokines and acts as co-receptor for macrophage (m)-tropic (or R5)
strains of HIV-1. Monoclonal antibodies (mAb) to CCR5, 3A9 and 5C7, were used for
biopanning a nonapeptide cysteine (C)-constrained phage-displayed random peptide
library to ascertain contact residues and define tertiary structures of possible
epitopes on CCR5. Reactivity of antibodies with phagotopes was established by
enzyme-linked immunosorbent assay (ELISA). mAb 3A9 identified a phagotope C
HASIYDFGS-C (3A9 / 1), and 5C7 most frequently identified C-PHWLRDLRV-C (5C7 /
1). Corresponding peptides were synthesized. Phagotopes and synthetic peptides
reacted in ELISA with corresponding antibodies and synthetic peptides inhibited
antibody binding to the phagotopes. Reactivity by immunofluorescence of 3A9 with
CCR5 was strongly inhibited by the corresponding peptide. Both mAb 3A9 and 5C7
reacted similarly with phagotopes and the corresponding peptide selected by the
alternative mAb. The sequences of peptide inserts of phagotopes could be aligned
as mimotopes of the sequence of CCR5. For phage 3A9 / 1, the motif SIYD aligned
to residues at the N terminus and FG to residues on the first extracellular loop;
for 5C7 / 1, residues at the N terminus, first extracellular loop, and possibly
the third extracellular loop could be aligned and so would contribute to the
mimotope. The synthetic peptides corresponding to the isolated phagotopes showed
a CD4-dependent reactivity with gp120 of a primary, m-tropic HIV-1 isolate. Thus
reactivity of antibodies raised to CCR5 against phage-displayed peptides defined
mimotopes that reflect binding sites for these antibodies and reveal a part of
the gp120 binding sites on CCR5.
PMID- 10760807
TI - A single naturally processed measles virus peptide fully dominates the HLA-A*0201
associated peptide display and is mutated at its anchor position in persistent
viral strains.
AB - We studied the natural MHC class I display of measles virus (MV) epitopes.
Peptide ligands associated with HLA-A*0201 were purified from a B lymphoblastoid
cell line prior to and after infection with MV. Infection-induced peptides were
revealed using microcapillary reversed phase high performance liquid
chromatography electrospray ionization/mass spectrometry (microLC-ESI/MS) by
subtraction of the "infected" and "uninfected" ion traces. Three naturally
processed viral epitopes derived from different MV proteins were identified
through tandem MS sequencing. These peptides were expressed at widely divergent
levels of HLA-peptide complexes, but had similar binding capacities to HLA
A*0201. The most abundant viral peptide species, identified as residues 84-92
(KLWESPQEI) of the MV nonstructural C protein, was expressed at an unprecedented
high density (> 10(5) copies per cell) and was immunogenic in HLA-A2/Kb
transgenic mice. Furthermore, natural mutants of this epitope, occurring in
persistent lethal MV strains, were shown to have lost their HLA-A*0201 binding
capacity. Thus, here we report for the first time the direct discovery through
microLC-ESI/MS of a uniquely dominant viral HLA class I ligand, KLWESPQEI, with
features eligible for immune selection pressure.
PMID- 10760808
TI - Abolition of anti-glomerular basement membrane antibody-mediated
glomerulonephritis in FcRgamma-deficient mice.
AB - Several recent studies have demonstrated the central role of Fc receptors (FcR)
rather than the complement system in triggering hypersensitivity reactions. We
investigated the role of FcR for IgG (FcgammaR) using a murine model of
accelerated anti-glomerular basement membrane (GBM) antibody-mediated
glomerulonephritis as a representative of type II hypersensitivity diseases.
Intravenous injection of rabbit anti-GBM antibody after preimmunization with
normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and
CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice.
Light microscopic findings revealed marked tissue damage in the glomeruli of wild
type C57BL/6 and CD40(+/-) mice. However, no tissue damage except
polymorphonuclear cell infiltration was observed in the glomeruli of FcRgamma(-/
) mice. The glomeruli of CD40(-/-) mice were almost normal. Immunohistochemistry
revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM
antibody. However, depositions of mouse IgG and complement to the glomeruli were
not observed in CD40(-/-) mice, and deposition of fibrin was not observed in
FcRgamma(-/-) or CD40(-/-) mice. These findings suggest that FcgammaR may
initiate anti-GBM antibody-mediated renal disease. We conclude that FcgammaR
rather than the complement system is critically involved in the development of
type II hypersensitivity diseases.
PMID- 10760809
TI - Role of MHC class I expression and CD8(+) T cells in the evolution of iodine
induced thyroiditis in NOD-H2(h4) and NOD mice.
AB - Dietary iodine has long been known to influence the development of human
autoimmune thyroid disease. In nonobese diabetic (NOD) and NOD-H2(h4) mice
elevated dietary iodine has been shown to induce autoimmune thyroid disease.
Immune responses to thyroid antigens can be detected in these mouse strains,
including T cell responses in the NOD-H2(h4) mouse to thyroid peroxidase. Cell
transfer studies and antibody depletion experiments reveal a requirement for both
CD4(+) T cells and CD8(+) T cells in the development of thyroid autoimmunity.
Histological analyses of the thyroids show that following 1 week of iodine
administration MHC class I expression is elevated on thyroid follicular cells and
CD4(+) and CD8(+) T cells have begun to infiltrate the gland. Although MHC class
II expression on thyroid epithelial cells was also elevated, the tempo of
expression was slower and the extent of expression was far less than that for MHC
class I. Depletion of CD8(+) T cells at early stages of disease induction
inhibited not only thyroid infiltration and autoantibody production but also
reduced the levels of MHC expression in the thyroid, suggesting that cytokine
production by infiltrating lymphocytes was responsible for the increased MHC
expression.
PMID- 10760810
TI - Increased efficiency of folding and peptide loading of mutant MHC class I
molecules.
AB - Class I molecules, encoded by diverse alleles at several loci of the major
histocompatibility complex (MHC) are assembled in the endoplasmic reticulum (ER)
from heavy chain, beta2 microglobulin and peptide in association with accessory
proteins of the peptide loading complex. We show here, that mutations in the
alpha2 domain (Q115A; D122A) of the human class I allele HLA-A2 cause a lack of
apparent association with the loading complex and a faster assembly. Despite the
drastically reduced association with the TAP loading complex, i. e. less than 20
% of HLA-A2 expressed in the cells can be co-precipitated with either TAP,
calreticulin or tapasin, the mutant proteins are expressed on the cell surface in
a stable conformation, and bind a complex set of peptides almost identical to
that of wild-type HLA-A2. Furthermore, the mutant class I molecules are more
rapidly exported from the ER than wild-type HLA-A2 and undergo faster maturation.
The mutation Q115A does not destroy a binding site for the loading complex as
this HLA-A2 mutant associates with the loading complex when peptide supply is
limited. The association of class I molecules with the TAP-associated loading
complex appears to be a reflection of how quickly the stable conformation is
gained.
PMID- 10760811
TI - Immunogenetic analysis of the immune response to pneumococcal polysaccharide.
AB - Pneumococcal serotype-specific anti-capsular polysaccharide antibodies protect
against invasive pneumococcal disease. Within an individual the diversity of
these antibodies is limited. To evaluate the repertoire of antibodies to
pneumococcus and determine whether oligoclonality is seen both between serotypes
and between individuals, we sampled the B cell repertoire induced by
polysaccharide and conjugate vaccine in adult volunteers. Fifteen hybridomas
secreting pneumococcus-specific monoclonal antibodies were generated from five
volunteers. Ten were isotype switched, six were IgG2 and four were IgA. These
included two isotype switch variants of the same clone. V(H)3 and V(kappa)2 were
used by 10/15 and 7/13 of the sequenced clones, respectively, with identical
genes, V(H)3-48 and V(kappa)2-A17 used by a number of volunteers to a variety of
serotypes. VDJ junctional characteristics and complementarity-determining region
(CDR) 3 length were variable. High levels of somatic mutation in CDR1 and 2,
inconsistent with a primary response, were found in 10/11 of the isotype-switched
antibodies, including those induced by plain polysaccharide antigens. These data
suggest that wild-type infection or nasopharyngeal carriage of Streptococcus
pneumoniae in adults may induce memory and the response to subsequent
immunization with plain polysaccharide or conjugate pneumococcal vaccines may
have the characteristics of a secondary response.
PMID- 10760812
TI - Monitoring gene expression of TNFR family members by beta-cells during
development of autoimmune diabetes.
AB - Autoimmune diabetes results from destruction of pancreatic beta-cells by islet
infiltrating leukocytes. Different molecular mechanisms seem to be involved in
this destruction but the results from many studies have not provided a clear
picture so far. Therefore, we have developed a multiplex single-cell reverse
transcription polymerase chain reaction to analyze the expression of genes of the
tumor necrosis factor receptor (TNFR) family in pancreatic beta-cells during the
development of autoimmune diabetes in a TCR-HA x INS-HA double transgenic as well
as a non-obese diabetic (NOD) animal model. To this end we have followed the
expression of cell surface receptors of the TNFR family in NOD mice as well as in
double transgenic mice that express in their T cells class II MHC-restricted TCR
specific for peptide 111 - 119 from influenza hemagglutinin (TCR-HA) as well as
hemagglutinin under the control of the rat insulin promoter (INS-HA). Both types
of mice develop insulitis and diabetes spontaneously. The data show a significant
increase in the expression of Fas and TNFR2 (p75) during the development of
insulitis, whereas TNFR1 (p55) is already expressed in beta-cells before the
onset of insulitis. As ligands for these receptors are already expressed at high
levels during the phase of insulitis, it is possible that beta-cell death is
regulated by intracellular inhibitors of apoptosis pathways.
PMID- 10760813
TI - Differential effects of corticosteroids during different stages of dendritic cell
maturation.
AB - Dendritic cell (DC) maturation is a complex process involving many cell
functions. We have studied how the exposure of DC to corticosteroids at different
stages of DC maturation affects priming and the expansion of different subsets of
CD4(+) T cells. Growth factor- dependent DC lines and fresh bone marrow-derived
DC were used. When exposed to inflammatory stimuli, immature DC previously
treated with dexamethasone were unable to undergo full maturation and were unable
to prime Th1 cells efficiently. There was specific and significant reduction in
the number of IFN-gamma-producing effector cell (shown by intracellular cytokine
staining) and also in the amount of IFN-gamma produced. Interestingly, the number
of IL-4-producing T cells and the amount of IL-4 synthesis was not significantly
altered. Furthermore, multiple restimulation of T cells with these DC gave rise
to a subpopulation of T regulatory cells (Tr1) which were negative for IFN-gamma
and IL-4 but were IL-10 positive. In contrast, when DC were activated with
lipopolysaccharide prior to dexamethasone treatment, the suppressive effect of
glucocorticoids was not significant. Thus, the stage of DC maturation influences
the inhibitory effect of corticosteroids. By arresting DC maturation,
corticosteroids strongly reduce cell-mediated Th1 responses and allow the
selective expansion of Tr1 cells.
PMID- 10760814
TI - Assessment of the interaction of human complement regulatory proteins with group
A Streptococcus. Identification of a high-affinity group A Streptococcus binding
site in FHL-1.
AB - Group A Streptococcus (GAS), the most frequent bacterial cause of suppurative
infections in humans, expresses on the cell surface M proteins with capacity to
bind factor H, FHL-1 and C4b binding protein (C4BP). This has been interpreted as
a mechanism developed by this pathogen to decrease phagocytosis by macrophages
and polymorphonuclear cells. We report the analysis of the capacity to bind
factor H, FHL-1 and C4BP of 69 clinical isolates from 19 different serotypes. We
show that strains binding complement regulators (30/69) belong to specific M
serotypes. Of these, M18 strains are relatively frequent and interact with all
three complement regulators simultaneously. However, the most virulent M1 and M3
strains did not bind complement regulators in our assays. The relevance of the
interaction between complement regulators and S. pyogenes was analyzed using
different approaches with the conclusion that under physiological conditions only
FHL-1 and C4BP bind to streptococci. We show that FHL-1 presents a higher binding
affinity for S. pyogenes than factor H because it carries a hydrophobic, high
affinity, GAS binding site in addition to the heparin binding site in SCR7. Using
synthetic peptides we provide evidence that the high-affinity GAS binding site in
FHL-1 involves the hydrophobic tail (Ser-Phe-Thr-Leu) that distinguishes FHL-1
from factor H.
PMID- 10760815
TI - Suppression of the tumorigenic growth of Burkitt's lymphoma cells in
immunodeficient mice by cytokine gene transfer using EBV-derived episomal
expression vectors.
AB - Epstein-Barr virus (EBV)-based expression vectors were tested for cytokine gene
transfer-mediated induction of an immune response against human lymphoma cells.
These vectors express the EBV latent gene EBNA 1 and carry the EBV latent origin
of replication (ori P) for episomal replication in transfected cells. In
addition, 3 human immunoglobulin light chain enhancer elements augment expression
in B-cells. The suitability of these vectors for expression of cytokine genes in
human lymphoma cells in vitro has been demonstrated. In order to extend these
experiments in vivo, highly tumorigenic Burkitt's lymphoma (BL) cells were
transfected with different cytokine genes of human and murine origin cloned into
the EBNA 1/ori P vectors. Tumorigenicity of the transfectants was measured after
inoculation into nude mice. No effect on tumorigenicity was observed after hIL 6
transfection and an inconsistent effect after hTNFalpha transfection. In
contrast, complete suppression of tumor outgrowth occurred in hIL 10
transfectants. This tumor suppressive effect, however, was restricted to the IL
10 transfectants themselves and not directed against non-transfected cells. By
comparison, mIL 4 transfected BL cells also were non-tumorigenic. However, co
inoculation of mIL 4 transfected and non transfected cells resulted in
suppression of the tumorigenicity of the non-transfected cells. Thus, highly
tumorigenic BL cells in nude mice are sensitive to immune effector mechanisms
triggered by cytokine expression. In this experimental model, EBNA 1/ori P
expression vectors are a suitable tool for cytokine gene transfer mediated
induction of an anti-lymphoma immune response of the host.
PMID- 10760816
TI - Overexpression of epidermal growth factor receptor in human head and neck
squamous carcinoma cell lines correlates with matrix metalloproteinase-9
expression and in vitro invasion.
AB - Numerous reports have shown an association between overexpression of the
epidermal growth factor receptor (EGFR), and poor prognosis in head and neck
squamous cell carcinomas (HNSCC), however, the underlying mechanisms are still
unclear. In the present study, we set out to determine whether EGFR expression
was associated with in vitro invasive capacity in a panel of four established and
ten newly derived HNSCC lines. Ten of the cell lines expressed high levels of
EGFR as determined by a ligand-binding assay and dot blot analysis, whereas the
remaining four showed weak overexpression or normal levels of EGFR. The ability
of cells to invade through Matrigel was found to be higher in the EGFR
overexpressing cell lines (p < 0. 0001). Expression levels of matrix
metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13,
MT1-MMP) and tissue inhibitors of MMP (TIMP-1, TIMP-2) were evaluated by
semiquantitative RT-PCR, substrate zymography and western blot. We found a strong
positive correlation between EGFR levels and the expression of MMP-9 mRNA (r(2) =
0.95; p < 0.0001), MMP-9 enzyme activity (r(2) = 0.8099; p < 0.0001) and an
inverse correlation with TIMP-1 (r(2) = 0.48; p = 0.0059). In six selected HNSCC
lines, in vitro invasion was assayed in the presence of an anti-EGFR monoclonal
antibody, ICR62. A significant reduction of invasion in four selected EGFR
overexpressing cell lines was found with 30 nM ICR62 (from 50% to 70%; p < 0.001)
but there was no effect in two cell lines with normal EGFR levels. Our results
show that the in vitro invasive phenotype of HNSCC lines correlates with high
EGFR and MMP-9 expression, and it is therefore suggested that the EGFR signaling
pathway might play an important role in the invasive behavior of HNSCC via
specific upregulation of MMP-9 and downregulation of TIMP-1.
PMID- 10760817
TI - Mutation analysis of replicative genes encoding the large subunits of DNA
polymerase alpha and replication factors A and C in human sporadic colorectal
cancers.
AB - We examined cDNAs of the catalytic subunit of DNA polymerase alpha (185 kDa), the
70 kDa subunit of replication protein A (single-stranded DNA-binding protein) and
the 140 kDa subunit of replication factor C for mutations. Surgical specimens
from 12 patients with sporadic colon cancer and normal mucosae from the same
patients were investigated. In addition, we analyzed 3 human colon cancer cell
lines that exhibited defects in mismatch repair (DLD-1, HCT116, SW48) and 3 colon
cancer cell lines without such a defect (HT29, SW480 and SW620). For detection of
mutations, we used reverse transcription of mRNA, amplification of cDNAs by PCR,
analysis of single-strand conformation polymorphism and DNA sequencing. Eleven
colon cancers and 6 colon cancer cell lines were analyzed for DNA polymerase
alpha. Only 2 silent point mutations were detected, in 1 colon carcinoma and in
cell line HCT116. Two sequence alterations of the 70 kDa subunit of replication
factor A were identified in 15 specimens (9 colon carcinomas and 6 cell lines).
Colon carcinomas from 2 patients (CC5MA and CC25HN) exhibited an ACA-->GCA
transition in codon 351, which caused a Thr-->Ala exchange. In carcinomas CC5MA
and CC8MA, a TCC-->TCT (Ser-->Ser) transition in codon 352 was observed. The
deviations in codons 351 and 352 occurred in both cancer tissues and normal
mucosae, suggesting a genetic polymorphism. No mutation was found in the 140 kDa
subunit of replication factor C from 16 specimens (10 tumors and 6 cell lines).
Point mutations were identified in the p53 tumor-suppressor gene in 4 of the 6
colon cancer cell lines and 3 of the 8 carcinoma specimens. We did not find tumor
associated DNA sequence alterations that resulted in amino acid changes in the
DNA replication genes analyzed. We infer that the scarcity of mutations found is
due to stringent selection, eliminating functionally impaired replication
proteins.
PMID- 10760818
TI - Altered expression of androgen-receptor isoforms in human colon-cancer tissues.
AB - Many groups have examined of androgen the effects on normal and neoplastic colon
tissues, but no clear picture has hitherto emerged. In particular, the presence
and the function of the androgen receptor (AR) has only partially been
investigated in the past. The present study reports analysis of expression of the
AR gene as messenger RNA and as protein in surgical samples of neoplastic colon
mucosa and of corresponding healthy surrounding tissue. Specific binding for DHT,
demonstrating the presence of AR, was observed in almost all the samples (2
samples out of 12 were negative). No significant difference was observed between
healthy and neoplastic mucosa, or between male and female patients. A further
characterization of AR was performed with Western blot, using 2 different primary
antibodies. Both AR isoforms, AR-B and AR-A, were detected in healthy mucosa,
while only AR-A, resolving at 87 kDa, was observed in neoplastic mucosa. RT-PCR
analysis revealed the transcript for AR in both healthy and neoplastic mucosa in
10 samples; no message was detectable in 2 samples (negative also for binding); 2
additional samples presented AR mRNA only in healthy colon mucosa, 2 others only
in neoplastic mucosa. In addition, a variant AR messenger RNA, probabily derived
from alternative splicing, was observed. We found that AR is expressed both in
healthy and in neoplastic colon mucosa, either as mRNA or as protein. Neoplastic
colon tissue shows a characteristic loss of expression of the AR-B isoform, while
AR-A expression is maintained. These findings underscore the possible role of
androgen and its receptor in colon carcinogenesis.
PMID- 10760819
TI - Loss of type VI collagen in experimental and most spontaneous human
fibrosarcomas.
AB - Expression of type VI collagen, an adhesive protein of mesenchymal tissues, is
significantly down-regulated upon viral transformation of fibroblasts. Likewise,
most cell lines derived from spontaneous mesenchymal tumors, including
fibrosarcomas, rhabdomyosarcomas, leiomyosarcomas, chondrosarcomas and
liposarcomas, do not synthesize type VI collagen because they are not capable of
expressing all 3 of the polypeptide chains required for the assembly of a
functional heterotrimeric molecule. When injected into nude mice, neither
fibrosarcoma cells (HT1080) nor rhabdomyosarcoma cells (A204) initiate the
synthesis of type VI collagen, suggesting that the inhibition is not caused by
deficiency of a paracrine factor. Immuno-histochemical studies further illustrate
that 15 of 17 spontaneous adult fibrosarcomas lack type VI collagen in the tumor
stroma. The absence of this important adhesion protein may contribute to
tumorigenicity, invasiveness and/or metastasis of mesenchymal tumor cells.
PMID- 10760820
TI - Increased expression of the transcription factors CCAAT-enhancer binding protein
beta (C/EBBeta) and C/EBzeta (CHOP) correlate with invasiveness of human
colorectal cancer.
AB - Regulation of cell differentiation is most often impaired in malignant tumors and
may represent a key mechanism for the progression of the disease. CCAAT-enhancer
binding protein (C/EBP) is a family of transcription factors involved in the
regulation of embryonic gut development in rodents, which has also been detected
in various malignancies, e.g., liposarcomas and breast and ovarian epithelial
tumors. We studied the relationship between C/EBP and tumor histology (Duke's
invasive stage and pathological grade) in colorectal cancer. Immunoblotting
techniques were used on microdissected fresh frozen tumor specimens, and
expression of C/EBPalpha, C/EBPbeta and C/EBPzeta (CHOP) was analyzed in addition
to that of the cell-cycle regulator p53 and the proliferation marker PCNA.
Expression of C/EBPbeta (LAP isoforms) was markedly increased in all tumors
compared with normal colon mucosa. Although the inter-patient variability was
large, we found that LIP, the isoform of C/EBPbeta known to inhibit
transcription, was expressed at higher levels in Duke's stage B tumors compared
with Duke's stage A, whereas Duke's C tumors had the lowest LIP expression. A
similar relationship was seen for CHOP. The cell-cycle regulator gene p53 was the
only factor that clearly correlated with pathological grade: a decrease in p53
expression was demonstrated. Our data suggest that genetic and cellular events
involving C/EBPbeta and CHOP are important for tumor invasion and that these
events do not appear to be related to the pathological grade of the tumor.
PMID- 10760821
TI - Non-random trisomies of chromosomes 5, 8 and 12 in the prolactinoma sub-type of
pituitary adenomas: conventional cytogenetics and interphase FISH study.
AB - Specimens from 53 pituitary adenomas (PAs), including 17 NFPA, 16 PRL-, 9 ACTH-,
9 GH- and 2 TSH-secreting tumors, underwent cytogenetic analysis by the direct
and short-term culture methods. Only 8 tumors (15%) appeared to have an abnormal
karyotype. To increase the resolution of cytogenetic analysis, direct
preparations from 31 PAs were investigated by interphase FISH with probes
specific for chromosomes 5, 8, 12 and X, for which gain in pituitary tumors has
been reported. Of these 31 PAs, 17 (54.8%) had an abnormal dosage of one or more
of the 4 chromosomes tested. Separate or combined trisomies of chromosomes 5, 8
and 12 were found in 10/10 prolactinomas and in 4/9 NFPA, whereas the combined
loss of chromosomes 5 and 8 was observed in 1/6 ACTH- and 1/6 GH-secreting PAs.
Present and earlier data on 23 PAs showed that tumors with the highest frequency
of abnormal karyotypes revealed by cytogenetics and/or interphase FISH were PRL
(78%), followed by NFPA (26%) and GH (18%). Recurrent structural rearrangements
affecting chromosomes 1, 3 and 12 were also identified in prolactinomas, which
therefore appear to be the only pituitary adenoma sub-type with a defined trend
of tumor-specific chromosomal changes. Cytogenetic and FISH analyses of different
pituitary tumor sub-types indicate that they may harbour genetically distinct
lesions.
PMID- 10760822
TI - Longitudinal follow-up of antibody response to selected antigens of human
papillomaviruses and herpesviruses in patients with invasive cervical carcinoma.
AB - A group of 21 cervical-carcinoma patients was followed longitudinally. All
patients had undergone intensive radiotherapy. In the course of a more than 5
year observation period, 2 patients died of cervical cancer, 1 from other causes,
3 were lost from follow-up, and 15 survived without any signs of the disease.
Sera taken before, up to 17 months after and more than 5 years after the start of
therapy, were tested by ELISA for IgG antibodies reactive with a broad spectrum
of HPV-derived antigens, glycoprotein G of HSV 2, whole virion antigen of HCMV,
and a synthetic peptide corresponding to the immuno-dominant region of EBNA 1.
The therapy was associated with a marked decrease in E2 and E7 antibodies in
nearly all patients possessing pre-existing antibodies; the changes in VLP
antibody levels in the treated women were more rare and less pronounced. In the
course of the observation period, seroconversion to gG HSV2 positivity was seen
in 5 patients, while, a marked increase in pre-existing gG HSV2 antibodies was
observed in 5 out of 7 originally seropositive patients. At enrollment, only 2
patients were free of HCMV antibody and only 1 was free of EBNA1 antibody; no
seroconversion relative to either antigen was seen during the observation period.
PMID- 10760823
TI - No direct role for Epstein-Barr virus in oral carcinogenesis: a study at the DNA,
RNA and protein levels.
AB - Reports on the association of EBV with oral squamous-cell carcinomas (OSCCs) are
scarce and inconclusive. To determine the potential role of EBV in oral
carcinogenesis, we investigated 36 EBV DNA PCR-positive OSCCs for the expression
of EBV transcripts and proteins. From these EBV DNA-positive OSCCs, 13 were
analysed for the presence of EBV products, either at RNA and/or protein level.
EBER transcripts were investigated by RNA in situ hybridisation. EBNA-1, EBNA-2,
LMP-1, LMP-2, BHRF1 and BARF0 transcripts were investigated by RT-PCR and/or
NASBA. EBNA-1, LMP-1 and ZEBRA protein expressions were investigated by
immunohistochemistry. All 36 OSCCs were positive for EBV DNA, using the highly
sensitive BamHI W PCR, and 18 of these (50%) were positive using the less
sensitive PCR, which targets BNLF-1. However, virtually all OSCCs tested failed
to reveal EBV transcripts, including EBERs and EBNA-1 transcripts. No ZEBRA and
LMP-1 proteins were found in the neoplastic or any other cells of the OSCCs
investigated. Immunohistochemistry using a monoclonal antibody (MAb) raised
against EBNA-1 (2B4) resulted in positive staining in some cases of OSCCs, but
these results were non-specific, since EBV-negative epithelial tissues showed
extensive non-specific staining and no EBNA-1-specific transcripts were detected
by RT-PCR or NASBA. The absence of expression of EBV encoded transcripts and
proteins indicate that, with the present knowledge on EBV, an active role in oral
carcinogenesis for this virus is unlikely.
PMID- 10760824
TI - Inactivation of phosphatidylethanolamine N-methyltransferase-2 in aflatoxin
induced liver cancer and partial reversion of the neoplastic phenotype by PEMT
transfection of hepatoma cells.
AB - Phosphatidylethanolamine N-methyltransferase(PEMT) is an enzyme in liver that
catalyzes the stepwise methylation of phosphatidylethanolamine to
phosphatidylcholine, in addition to the main pathway that synthesizes
phosphatidylcholine directly from choline. We have reported that PEMT is
permanently inactivated in liver cancer induced by the Solt and Farber model.
Here we studied, (i) whether similar changes also occur in the progression of
hepatocarcinoma triggered by aflatoxin B(1) (AFB(1)) in rats; (ii) whether the
hepatoma phenotype could be reversed by over-expression of PEMT2. We found that
PEMT2 protein decreased in pre-neoplastic nodules and virtually disappeared in
hepatocellular carcinoma induced by AFB(1) due to decreased levels of mRNA
without any deletion or mutation of the DNA sequence. PEMT activity, which
reflects the function of both PEMT1 and PEMT2, was lower in nodules and
negligible in the tumor, consistent with its regulation at the level of gene
transcription. McArdle hepatoma cells transfected with PEMT2 failed to form
anchorage-independent colonies in soft agar, while the vector-transfected control
line grew efficiently. Moreover, PEMT2-transfected cells were also poorly
tumorigenic in vivo in athymic mice, as shown by the lower tumor incidence, the
longer cancer-free-time and the lower tumor volume and weight. Together, these
data indicate that the loss of PEMT function may contribute to malignant
transformation of hepatocytes.
PMID- 10760825
TI - IL-12- and IL-2-induced tumor regression in a new murine model of oral squamous
cell carcinoma is promoted by expression of the CD80 co-stimulatory molecule and
interferon-gamma.
AB - Therapy with IL-12 or IL-2 induces tumor regression in only a few patients with
head-and-neck squamous cell carcinoma (SCC), and the factors promoting
responsiveness have not been well defined. In this study, we examined whether
combined IL-12 and IL-2 therapy can induce tumor regression in a new murine model
of oral SCC and determined if the anti-tumor response is promoted by expression
of the immune co-stimulatory molecule CD80 and cytokine IFN-gamma. In CD80
positive or -negative subclones of a BALB/c oral SCC line in syngeneic mice, we
showed that systemic rIL-12 alone was comparable in effectiveness to combined
therapy with IL-12 and peri-tumoral rIL-2, inducing complete regression of the
CD80(+) line B7E11-4scid. However, therapy with these cytokines had no effect on
growth of the CD80(-) subclone B7E3-4scid and did not induce complete regression
of the CD80(+) subclone B7E11-4scid in congenic BALB/c IFN-gamma knockout mice,
indicating that expression of the CD80 co-stimulatory molecule and IFN-gamma
contributes to tumor regression. In cytokine-treated mice that rejected the
CD80(+) SCC line, an increase in infiltrating CD4(+) lymphocytes and apoptotic
bodies within the tumor specimens was observed, and resistance to rechallenge
with the same tumor was detected in 50% of recipients, consistent with an immune
response. Our results provide evidence that regression of oral head-and-neck SCC
may be induced by therapy with systemic IL-12 and that expression of the CD80 co
stimulatory molecule by SCC and IFN-gamma by the host promote IL-12 induced
regression of SCC.
PMID- 10760826
TI - Retinoic acid induces persistent, RARalpha-mediated anti-proliferative responses
in Epstein-Barr virus-immortalized b lymphoblasts carrying an activated C-MYC
oncogene but not in Burkitt's lymphoma cell lines.
AB - We have previously demonstrated that 13-cis-retinoic acid (RA), 9-cis-RA and all
trans-RA (ATRA) powerfully inhibit the proliferation of Epstein-Barr virus
immortalized B-lymphoblastoid cell lines (LCLs). The aim of the present study was
to assess whether these compounds are effective at inhibiting the growth of B
cells at more advanced stages of lymphomagenesis, including fully transformed B
lymphocytes. To this end, c-myc-transfected LCLs (myc-LCLs) and Burkitt's
lymphoma (BL) cell lines were used. We report that 13-cis-RA, 9-cis-RA and ATRA
also markedly inhibit the proliferation of myc-LCLs by inducing G(0)/G(1) growth
arrest as well as enhancing rates of apoptosis. Conversely, all but 1 (DG75) of
the 8 BL cell lines investigated were poorly RA-responsive. Moreover, unlike LCLs
and myc-LCLs, RA-treated DG75 cells rapidly resumed proliferation upon drug
removal. Analysis of cell cycle-regulatory proteins showed that, as in LCLs,
strong up-regulation of p27(Kip-1) and increased levels of under-phosphorylated
pRb and p130 were detected in RA-treated DG75 cells. While the catalytic activity
of all 3 G(1)-associated CDKs (CDK2, CDK4 and CDK6) was strongly inhibited in RA
treated LCLs, only CDK2-associated kinase activity was reduced in DG75 cells
arrested in G(0)/G(1) by RA. Moreover, RA-treated DG75 cells failed to show the
down-regulation of cyclin D3 observed in LCLs. Use of receptor-selective agonists
and antagonists showed that in LCLs and RA-responsive BL cells, RA-induced growth
arrest is mainly mediated by RARalpha. The RARalpha-selective agonist Ro 40-6055
was also effective at very low concentrations (10(-10) M). Nevertheless,
comparable levels of RARalpha mRNA were found in RA-responsive and -resistant BL
cell lines, indicating that mechanisms different from transcriptional
deregulation of RARalpha probably underlie the differential responsiveness of BL
cells.
PMID- 10760827
TI - Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic
cells generated in vitro from CD34(+) hematopoietic progenitor cells.
AB - Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can
be used for vaccination purposes, to induce a specific T-cell response in vivo
against melanoma-associated antigens. We have shown that the sequential use of
early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6,
followed by differentiation with IL-4 and granulocyte-macrophage colony
stimulating factor allows the in vitro generation of large numbers of immature
DCs from CD34(+) peripheral blood progenitor cells. Maturation to interdigitating
DCs could specifically be induced within 24 hr by addition of TNF-alpha. Here, we
report on a phase I clinical vaccination trial in melanoma patients using peptide
pulsed DCs. Fourteen HLA-A1(+) or HLA-A2(+) patients received at least 4 i.v.
infusions of 5 x 10(6) to 5 x 10(7) DCs pulsed with a pool of peptides including
either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending
on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side
effects were mild and consisted of low-grade fever (WHO grade I-II). Clinical and
immunological responses consisted of anti-tumor responses in 2 patients,
increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4
patients, significant expansion of Melan-A- and gp100-specific cytotoxic T
lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination
and development of vitiligo in another HLA-A2(+) patient. Our data indicate that
the vaccination of peptide-pulsed DCs is capable of inducing clinical and
systemic tumor-specific immune responses without provoking major side effects.
PMID- 10760828
TI - Early and late deaths after elective end of therapies for childhood cancer in
Italy.
AB - The first cohort of subjects treated for cancer during childhood is now entering
adulthood, and it is necessary to determine whether treatment has been sufficient
to completely eradicate the neoplastic clone, and whether the cancer itself or
treatment-related toxicity may have increased the risk of premature death. For
these reasons, long-term survival and causes of death were evaluated in a cohort
of subjects treated for childhood cancer who reached the elective end of therapy
in continuous remission and were registered until 1992 in the Italian Registry of
off-therapy subjects (OTR). The vital status of OTR subjects was ascertained in
1996 by a postal survey through census bureaux; for deceased subjects, the cause
of death was defined and compared with the expected rates in the general
population. At follow-up, out of 6402 eligible and evaluable subjects, 890 were
found to have died; the estimated overall survival at 20 years was 80.7% (95% CI
79.3-82.1). Most of the patients (84.6%) died due to recurrence of the primary
cancer, usually within the first 5 years after the OT. The cumulative incidence
of death due to recurrence of the primary tumor was greater among subjects
treated for solid tumor than among those treated for leukemia/lymphoma (p =
0.0001); in contrast, OT subjects after leukemia and lymphoma were more likely to
die due to of medical complications of therapy (p < 0.02). Second cancers were
the second most frequent cause of death, with a 12-fold risk compared with the
general population; the figures were similar in the 2 cancer groups. Compared
with the general population, OT subjects were 32 times more likely than same-age
subjects to die. The SMR decreased to 6.1 when only non-cancer deaths were
considered. Deaths due to external or avoidable causes occurred among survivors
at a rate similar to that of the general population.
PMID- 10760829
TI - Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells.
AB - Pancreatic cancer cells are usually resistant to apoptosis induced by cytotoxic
drugs, by activation of surface receptors such as Fas and TNF receptor or by
serum or growth factor withdrawal. Actinomycin D (actD) is an inhibitor of RNA
synthesis and acts as a potent inducer of apoptosis in several cell lines. In the
present study, we investigated the effects of actD on PANC-1 pancreatic cancer
cells. ActD caused apoptosis in PANC-1 cells in a dose-dependent manner, as
determined by cell growth assays, DNA laddering and TUNEL assays. Induction of
apoptosis correlated with activation of the JNK/SAPK pathway and increased
expression of Bax but not Bad or p53. PANC-1 cells were completely resistant to
Fas antibody and TNF-alpha. In contrast, TRAIL decreased the growth of PANC-1
cells by 22%. Low concentrations of actD (10 ng/ml) enhanced the cytotoxic
effects of all 3 cytokines. EGF, FGF-2 and IGF-I did not protect PANC-1 cells
from actD-mediated apoptosis. ActD (10 ng/ml) also inhibited the growth of CAPAN
1 and T3M4 pancreatic cancer cells but not MiaPaCa-2 cells. Our observations
suggest that actD may act via JNK/SAPK and Bax to promote apoptosis in PANC-1
cells and that it may inhibit the growth of other pancreatic cancer cell lines.
PMID- 10760831
TI - Genistein attenuates peritoneal metastasis of azoxymethane-induced intestinal
adenocarcinomas in Wistar rats.
AB - The effects of the soybean isoflavonoid genistein on the development of bombesin
enhanced peritoneal metastasis from intestinal adenocarcinomas induced by
azoxymethane (AOM) were investigated in male inbred Wistar rats. From the
beginning of the experiment, rats were given 10 weekly s.c. injections of AOM
(7.4 mg/kg body weight) and s.c. injections of bombesin (40 microg/kg body
weight) every other day, and from week 16, s.c. injections of genistein (5 or 10
mg/kg body weight) every other day until the end of the experiment in week 45.
Bombesin significantly increased the incidence of intestinal tumors and of cancer
metastasis to the peritoneum. Although genistein administered at either dose had
little or no effect on the enhancement of intestinal carcinogenesis by bombesin
or on the location, histologic type, depth of involvement, labeling index, or
growth pattern of intestinal cancers, it significantly decreased the incidence of
cancer metastasis. Genistein also significantly decreased the incidence of
lymphatic vessel invasion of adenocarcinomas, which was enhanced by bombesin. Our
findings indicate that genistein attenuates cancer metastasis by inhibiting
cancer cell invasion into lymphatic vessels through activities that do not affect
the growth of intestinal cancers.
PMID- 10760830
TI - Randomized trial on the effect of radiotherapy in addition to 6 cycles CMF in
node-positive breast-cancer patients. The German Breast-Cancer Study Group.
AB - In 1984 the GBSG started a multicenter randomized trial to compare the
effectiveness of 6 cycles of cyclophosphamide, methotrexate and fluorouracil
(CMF) with or without radiotherapy (RT) as adjuvant treatment in node-positive
breast-cancer patients treated by mastectomy. During 5 years, 199 patients were
randomized. After a median follow-up of about 9 years, the treatment groups 6 x
CMF and 6 x CMF + RT were compared regarding time to recurrence and death. As the
first event of failure, we observed locoregional recurrence in 22 patients,
distant metastases in 66 patients, a secondary malignancy in 9 patients and death
without previous event in 5 patients. For event-free survival (EFS), no
significant difference was observed [relative risk (RR) 6 x CMF + RT vs. 6 x CMF
0.82, 95% confidence interval (CI) 0.55-1.21]. Event-specific analysis showed a
significant decreased risk after radiotherapy for locoregional recurrence. The
risk for distant metastases was estimated as slightly decreased and the risk for
secondary malignancy and for death without previous event was estimated as
increased in treatment group 6 x CMF + RT in comparison with treatment group 6 x
CMF, but these effects were not significant. For overall survival (OS) and breast
cancer-specific survival (BCS), no significant treatment effect could be
demonstrated. There is a beneficial effect of radiotherapy on locoregional
recurrence. For EFS and BCS, a tendency in favour of radiotherapy is observed,
but this is not significant; for OS, no difference can be demonstrated, but the
power of the study is too low to detect small treatment effects.
PMID- 10760832
TI - Comparison of lifestyle and risk factors among Japanese with and without gastric
cancer family history.
AB - To find specific risk factors of gastric cancer (GC) independent of GC family
history (GCFH), 2 studies were conducted using the database of the Hospital-based
Epidemiological Research Program at Aichi Cancer Center: (i) a comparison of
lifestyles between non-cancer cases with positive and negative GCFH status and
(ii) a case-reference investigation of subjects with and without GCFH, treated
separately. The first showed no significant variation of GCFH status with regard
to smoking, drinking and most food habits. Multivariate analyses in the case
referent studies revealed odds ratios (ORs) for GC associated with habitual
smoking of 2.78 (95% CI 1.22-6.28) for those with and 2.74 (95% CI 1.76-4.26) for
those without GCFH. In individuals with GCFH, an independently lowered OR (0.52,
95% CI 0.27-0.99) was evident for frequent consumption of raw vegetables, whereas
the opposite was noted for pickled vegetables (2. 39, 95% CI 1.28-4.45). No
statistically significant interaction was found between GCFH and selected
lifestyle items. In conclusion, our results suggest a limited influence of GCFH
on risk factors for GC.
PMID- 10760833
TI - Red meat intake and cancer risk: a study in Italy.
AB - Meat intake has been positively associated with risk of digestive tract cancers
in several epidemiological studies, while data on the relation of meat intake
with cancer risk at most other sites are inconsistent. The overall data set,
derived from an integrated series of case-control studies conducted in northern
Italy between 1983 and 1996, included the following incident, histologically
confirmed neoplasms: oral cavity, pharynx and esophagus (n = 497), stomach (n =
745), colon (n = 828), rectum (n = 498), liver (n = 428), gallbladder (n = 60),
pancreas (n = 362), larynx (n = 242), breast (n = 3,412), endometrium (n = 750),
ovary (n = 971), prostate (n = 127), bladder (n = 431), kidney (n = 190), thyroid
(n = 208), Hodgkin's disease (n = 80), non-Hodgkin's lymphomas (n = 200) and
multiple myelomas (n = 120). Controls were 7,990 patients admitted to hospital
for acute, non-neoplastic conditions unrelated to long-term modifications in
diet. The multivariate odds ratios (ORs) for the highest tertile of red meat
intake (>/=7 times/week) compared with the lowest (0.05) with CYP2C8 activity. Collectively, these findings suggest
that CYP2B6 is a major contributor towards residual 3-methoxymorphinan activity,
while CYP2C8 and 2C18 are either minor contributors or do not contribute to this
metabolic process.
PMID- 10760843
TI - Dissolution rate-limited absorption and complete bioavailability of roquinimex in
man.
AB - In order to investigate the bioavailability and the rate-limiting step of the
absorption of roquinimex, an oral solution and a tablet formulation (Linomide(R))
were given to healthy volunteers. The study was conducted as a randomized three
period crossover study in seven male and seven female healthy volunteers. The
subjects received an intravenous infusion, an oral solution and an oral tablet
formulation, each of 5 mg (about 0.07 mg kg(-1)), as single doses after an
overnight fast on three occasions, with a wash-out period of 3 weeks in between.
Venous blood samples were taken over 7 days and the plasma concentrations of
roquinimex were determined by high-performance liquid chromatography (HPLC) with
ultraviolet (UV)-detection. The pharmacokinetics of roquinimex was characterized
by a low plasma clearance, 4.9 mL h(-1) kg(-1) and a small volume of
distribution, 0.22 L kg(-1). The oral bioavailability of the drug was complete
for both the solution and the tablet formulation. The absorption rate was faster
for the solution than for the tablet. The disposition of roquinimex was biphasic,
with a terminal disposition half-life of 32 h. Between 4 and 8 hours after
dosing, a secondary plasma peak was observed, indicating enterohepatic
circulation of the drug. No major sex differences were shown in the
pharmacokinetics of roquinimex. In conclusion, dissolution rate-limited
absorption of roquinimex was shown, which demonstrates that disintegration and
dissolution of the tablet play a major role in the absorption process of
roquinimex. Despite the delayed absorption after administration of the tablet,
the extent of absorption was complete.
PMID- 10760844
TI - Stability, blood partition and plasma protein binding of ipriflavone, an
isoflavone derivative.
AB - It is generally recognized that the partition between plasma and blood cells, the
immediate centrifugation of blood samples after collection for the measurement of
'true' in vivo concentrations and free drug concentrations in plasma are
important determinants of the pharmacokinetics and/or pharmacodynamics of drugs.
Therefore, the stability, blood partition between plasma and blood cells, and
factors influencing the binding of ipriflavone to 4% human serum albumin (HSA)
using an equilibrium dialysis technique were evaluated. Ipriflavone was unstable
in rat liver homogenate and various pH solutions ranging from 1 to 13, except pH
8, rat blood and plasma and human plasma when incubated in a water-bath shaker
for 24 h kept at 37 degrees C and at a rate of 50 oscillations/min. The
recoveries of spiked amounts of ipriflavone at 24 h pH solutions ranging from 1
to 12 were 67.0, 78.1, 87.9, 89.6, 84.2, 87.4, 85.5, 99.3, 88.0, 76. 6, 79.4 and
81.5%, respectively. Ipriflavone was very unstable in pH 13 solution; only 0.814%
of ipriflavone was recovered after 30 min incubation. Ipriflavone was stable for
up to 3 h incubation in human gastric juices. Ipriflavone reached equilibrium
fast (within 30 s of being mixed manually) between plasma and blood cells and the
equilibrium plasma/blood cells partition ratios were independent of the initial
rabbit blood concentrations of ipriflavone: 0.2, 2, and 10 microg/mL; the values
were in the range of 0.900-2.45. The binding of ipriflavone to 4% HSA was 96.6+/
0.407% at ipriflavone concentrations ranging from 2 to 100 microg/mL, but it was
dependent on HSA concentrations (0.5-6%), incubation temperature (4, 22 and 37
degrees C), 'the buffer' pHs (5.8, 6.4, 7.0, 7.4 and 8.0), and addition of
salicylic acid (150-300 microg/mL) and sulphisoxazole (100-300 microg/mL).
However, the binding was independent of buffers containing various concentrations
of chloride ion (0-0.546%), glucose (0 and 5%), alpha-1-acid glycoprotein (0
0.32%) and heparin (0-40 U/mL), and addition of its metabolites (M1 and M5, 5
microg/mL).
PMID- 10760845
TI - Polyanionic Clusters and Networks of the Early p-Element Metals in the Solid
State: Beyond the Zintl Boundary.
AB - Reduction of p-element (post-transition) metals and metalloids by alkali metals
leads to many salts containing polyatomic clusters or network anions of these
elements. The earliest solvated examples were referred to as Zintl ions.
Synthetic explorations have now established that many of the clusters can in fact
be obtained from neat (solvent free) high-temperature reactions of binary to
quaternary systems, particularly for the heavier tetrel (group 14) and triel
(group 13) elements. Some synthetic tricks have also proven useful. Electronic
guidelines such as Wade's rules, known to account well for other types of
electron-deficient cluster bonding, are widely applicable to these compounds, but
numerous hypoelectronic (electron-poor) trielide salts have also been discovered.
These developments also extend to related infinite network structures and Zintl
(valence) compounds. The Zintl boundary designation traditionally delineated the
tetrel elements that form salts with the active metals from those of the triel
and earlier elements that were once thought to generate only intermetallic
phases. The distinction no longer seems appropriate, at least with regard to some
alkali-metal compounds of the triel elements.
PMID- 10760846
TI - New Results of Chemical Transport as a Method for the Preparation and
Thermochemical Investigation of Solids.
AB - Chemical transport experiments are a valuable aid of great potential in the
synthesis and thermochemical characterization of solids. Compounds of interest
can often only be crystallized by this method. The use of a transport balance
allows very detailed observations, particularly of the course of the experiment
over time (simultaneous or sequential deposition of multiple-phase solids). The
computer program CVTRANS enables a quantitative thermochemical description of the
experiment based on the cooperative transport model. A compilation of recent
results illustrates the development and efficiency of the method. The transport
of phosphides, anhydrous phosphates and sulfates, and rare-earth oxide and
oxohalide compounds are treated in detail.
PMID- 10760847
TI - Water Clusters: Towards an Understanding Based on First Principles of Their
Static and Dynamic Properties.
PMID- 10760848
TI - Unusual Alkylation Reactions in the Biosynthesis of Natural Products and
Elucidation of Their Reaction Mechanisms.
PMID- 10760850
TI - Diastereoselective Pinacol Coupling Reactions of alpha-Ketoamides Mediated by
SmI(2): Synthesis of Enantiomerically Pure R and S Quaternary Tartaric Acids.
PMID- 10760849
TI - Synthesis of Highly Functionalized Cyclooctenes by Ring-Closing Metathesis:
Unexpected Formation of a trans Isomer.
PMID- 10760851
TI - An Expedient Construction of Seven-Membered Rings Adjoining Aromatic Systems.
PMID- 10760852
TI - Selenium-Based Solid-Phase Synthesis of Benzopyrans I: Applications to
Combinatorial Synthesis of Natural Products.
PMID- 10760853
TI - Selenium-Based Solid-Phase Synthesis of Benzopyrans II: Applications to
Combinatorial Synthesis of Medicinally Relevant Small Organic Molecules.
PMID- 10760854
TI - Hydrogen-Transfer Catalysis with Pincer-Aryl Ruthenium(II) Complexes.
PMID- 10760855
TI - Synthesis and Characterization of an Open-Framework Antimony(III) Phosphate:
PMID- 10760856
TI - A p(O(2))-Responsive MRI Contrast Agent Based on the Redox Switch of Manganese(II
/ III) - Porphyrin Complexes.
PMID- 10760857
TI - Electrophilic Aromatic Substitution Reactions of a Metallabenzene: Nitration and
Halogenation of the Osmabenzene
PMID- 10760858
TI - Highly Regio- and Stereoselective Cycloreductions of 1,6- and 1,7-Enynes
Activated with a Carbonyl Functionality.
PMID- 10760859
TI - Guest-Templated Selection and Amplification of a Receptor by Noncovalent
Combinatorial Synthesis.
PMID- 10760860
TI - Rigid Amphiphiles for Membrane Protein Manipulation.
PMID- 10760862
TI - Self-Assembled Porphyrin Polymers.
PMID- 10760861
TI - The Total Synthesis of Frondosin B.
PMID- 10760863
TI - Dinuclear pi Complexes of Yttrium and Lutetium with Sandwiched Naphthalene and
Anthracene Ligands: Evidence for Rapid Intramolecular Inter-Ring Rearrangements.
PMID- 10760864
TI - Solid-Supported Hydrazine Substrate For Labeling Estradiol Ligands with Rhenium.
PMID- 10760865
TI - Regioselective Lactonization of Tetrasialic Acid.
PMID- 10760866
TI - Octahedral Coordination of an Iodide Ion in an Electrophilic Sandwich.
PMID- 10760867
TI - Medium-Controlled Intramolecular Catalysis in the Direct Synthesis of 5'-O
Protected Ribonucleoside 2'- and 3'-Dialkylphosphates.
PMID- 10760869
TI - Intracellular Degradation of Diorganomercury Compounds by Biological Thiols
Insights from Model Reactions.
PMID- 10760868
TI - Iron-Mediated Diastereoselective Spiroannelations with Vinylogous Urethanes - A
Novel Access to Spiroannelated Carbo- and Heterocycles.
PMID- 10760870
TI - An Unprecedented
PMID- 10760871
TI - Dialkylaminoethyl-Functionalized ansa-Zirconocene Dichlorides: Precatalysts for
the Regulation of the Molecular Weight Distribution of Polyethylene.
PMID- 10760872
TI - Real Space Observation of a Chiral Phase Transition in a Two-Dimensional Organic
Layer.
PMID- 10760873
TI - The Novel Hybrid Antitumor Compound Premithramycinone H Provides Indirect
Evidence for a Tricyclic Intermediate of the Biosynthesis of the Aureolic Acid
Antibiotic Mithramycin.
PMID- 10760874
TI - A Metalloid Al(14) Cluster with the Structure of a "Nano-Wheel"
PMID- 10760875
TI - Palladium-Catalyzed Allylic Alkylations without Isomerization-Dream or Reality?
PMID- 10760876
TI - A Stable, Conspicuously Active, Water-Soluble Pd Catalyst for the Alternating
Copolymerization of Ethene and CO in Water.
PMID- 10760877
TI - Generation-Dependent Intramolecular CT Complexation in a Dendrimer Electron
Sponge Consisting of a Viologen Skeleton.
PMID- 10760878
TI - A Redox-Controlled Molecular Switch Based on the Reversible C-C Bond Formation in
Octamethoxytetraphenylene.
PMID- 10760879
TI - From the Laboratory to the Clinic: A Retrospective on Fully Synthetic
Carbohydrate-Based Anticancer Vaccines Frequently used abbreviations are listed
in the appendix.
AB - This review provides an account of our explorations into oligosaccharide and
glycoconjugate construction for the creation and evaluation of vaccines based on
carbohydrate-centered tumor antigens. Our starting point was the known tendency
of transformed cells to express selective carbohydrate motifs in the form of
glycoproteins or glycolipids. Anticancer vaccines derived from carbohydrate-based
antigens could be effective targets for immune recognition and attack. Obtaining
significant quantities of such structures from natural sources is, however,
extremely difficult. With the total synthesis of tumor-associated carbohydrate
antigens accomplished, we began to evaluate at the clinical level whether the
human immune system can respond to such fully synthetic antigens in a focused and
useful way. Toward this goal, we have merged the resources of chemistry and
immunology in an attack on the problem. The synthesis and immunoconjugation of
various tumor-associated carbohydrate antigens and the results of such constructs
in mice vaccinations will be described. For fashioning an effective vaccine,
conjugation to a suitable immunogenic carrier was necessary and conjugates of KLH
(keyhole limpet cyanin) have consistently demonstrated the relevant
immunogenicity. Preclinical and clinical studies with synthetic conjugate
carbohydrate vaccines show induction of IgM- and IgG-antibody responses. Another
approach to anticancer vaccines involves the use of clustered glycopeptides as
targets for immune attack. Initial attention has been directed to mucin related O
linked glycopeptides. Synthetic trimeric clusters of glycoepitopes derived from
the Tn-, TF- and Lewis(y)-antigens, appropriately bioconjugated, have been
demonstrated to be immunogenic. The hope is that patients immunized in an
adjuvant manner with synthetic carbohydrate vaccines would produce antibodies
reactive with cancer cells and that the production of such antibodies would
mitigate against tumor spread, thereby enabling a more favorable survival and
"quality of life" prognosis.
PMID- 10760881
TI - Parallel Kinetic Resolutions.
PMID- 10760880
TI - Dendronized Polymers: Synthesis, Characterization, Assembly at Interfaces, and
Manipulation.
AB - Dendrimers are presently one of the most intensely studied classes of compounds
because of their unusual structure. They can be described as a jungle of
entangled branches traversed by winding trails which lead to sweet fruits and
bright blossoms. On these trails one can reach the thicket's interior as well as
find a way out. Expressed less lyrically, this thicket stands for regularly
branched, densely packed structures, and the trails represent voids and channels
not filled by bent back branches but by solvent. The fruit and blossoms are
photochemically, electrochemically, or synthetically addressable units,
catalytically active sites, etc., and the back and forth on the trails stands for
transport processes. In a mathematical sense dendrimers are enveloped by an
interface, which defines what is either in or out. This interface is shaped like
a sphere if the trails are filled to bursting. Otherwise dendrimers are more
flattened like amoeba, especially if in contact with a surface. The high density
of the functional groups, the expansion of these compounds to a range of several
nanometers, the existence of usable "surface" and transport possibilities in and
with them have made dendrimers interesting candidates for many applications. This
review describes how dendrimer construction and polymer synthesis were combined
and used to move from fully or flattened spherical shapes to cylindrical ones.
The shape-inducing influence of dendritic substituents can be driven to create
nanoobjects with a cylindrical shape, which not only considerably widens the
range of applications for the dendrimer class but also opens up new perspectives
for supramolecular and polymer chemistry. Because of the sheer size of the
described objects and complexity of shape-related properties, research in this
area must necessarily be interdisciplinary. This article tries to mirror this by
giving special attention not only to synthesis but also the characterization and
behavior of these compounds in bulk and at interfaces. Furthermore, potential
application fields are described.
PMID- 10760882
TI - Selective Oxidations of Linear Alkanes with Molecular Oxygen on Molecular Sieve
Catalysts-A Breakthrough?
PMID- 10760883
TI - On the Surprising Kinetic Stability of Carbonic Acid (H(2)CO(3)) The work was
supported in part by grants of the Austrian Academy of Sciences (T.L.) and the
Austrian Science Fund (P13930-PHY).
PMID- 10760884
TI - Are beta-Turn Mimetics Mimics of beta-Turns?
PMID- 10760885
TI - Novel Type of Thermostable Channel Clathrate Hydrate Formed by Heptakis(2,6-di-O
methyl)-beta-cyclodextrin small middle dot15 H(2)O-A Paradigm of the Hydrophobic
Effect Topography of Cyclodextrin Inclusion Complexes, Part 47. This work was
financed by a scholarship under the Development and Promotion of Science and
Technology Talents Project (DPST) by the Royal Thai Government Agencies and the
Institute for the Promotion of Teaching Science and Technology (IPST) to T. Aree,
by the Deutsche Forschungsgemeinschaft, and by Fonds der Chemischen Industrie. We
are grateful to Prof. Dr. H. Hartl for the DSC measurements. For Part 46, see T.
Aree, H. Hoier, B. Schulz, G. Reck, W. Saenger, Carbohydr. Res. 1999, 320, 120 -
128.
PMID- 10760886
TI - Synthesis and Functional Studies of a Membrane-Bound THF-Gramicidin Cation
Channel This work was supported by the Deutschen Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, the Volkswagenstiftung, Schering AG, and the
Pinguin Foundation.
PMID- 10760887
TI - Simple Synthesis of Tetra-Acceptor-Substituted Alkenes by the Formal
Dehydrodimerization of Malonates This work was supported by the Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft (SFB 347 "Selective
Reactions of Metal-Activated Molecules").
PMID- 10760888
TI - Direct Evidence for Trivalent Cationic Conduction in Nd(3+)-beta"-Al(2)O(3) The
fully ion exchanged Nd(3+)-beta"-Al(2)O(3) crystals were prepared at the
Universitat Hannover. The electrochemical investigations were conducted at Osaka
University. J.K. gratefully acknowledges the financial support for his
postdoctoral fellowship for foreign researchers in Japan by the Japan Society for
the Promotion of Science (JSPS).
PMID- 10760889
TI - Extremely Strong s(2) - s(2) Closed-Shell Interactions This work was supported by
the Auckland University Research Committee, the Deutsche Forschungsgemeinschaft
(DFG), and the Marsden Fund managed by the Royal Society of New Zealand. We are
grateful to Prof. W. H. E. Schwarz (Siegen) for his critical and most valuable
comments.
PMID- 10760890
TI - A General Approach to L-(+)-Furanomycin and Some Stereoisomers and Analogues
Using Furoisoxazoline Intermediates Syntheses via Isoxazolines, Part 24. Part of
the planned dissertation of P. J. Zimmermann. We thank the Volkswagen-Stiftung,
Hannover, the Fonds der Chemischen Industrie, the Landesgraduiertenforderung
Baden-Wurttemberg (doctoral fellowship to P.J.Z.), and Bayer AG, Wuppertal, for
financial support of this work. I.B. gratefully acknowledges a grant from the
Volkswagen-Stiftung for a research stay at Stuttgart. We thank Dr. W. Frey for
the X-ray crystal structure determinations. This work was presented at the 17th
ICHC, Vienna, in August 1999, Book of Abstracts OP-61. Part 23: ref. 1.
PMID- 10760891
TI - Spontaneous Assembly of a Schiff Base Tetramacrocycle We thank Professor D.
Sellmann and Priv.-Doz. Dr. T. Clark (Universitat Erlangen-Nurnberg) for generous
suppport of this work. We also thank Professor R. Robson (University of
Melbourne, Parkville, Victoria, Australia) for his interest in the results
presented here. Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
PMID- 10760892
TI - Discovery of a New Efficient Chiral Ligand for Copper-Catalyzed Enantioselective
Michael Additions by High-Throughput Screening of a Parallel Library We thank the
Commission of the European Union (TMR Network grant "Combinatorial catalysts" ERB
FMR XCT 96-0011) for financial support and a postdoctoral fellowship to I.
Chataigner. We are grateful to Mr. Andrea Stevenazzi and Ms. Chiara Monti
(Universita di Milano) for technical assistance. Part of this work was presented
as a plenary lecture (C. Gennari) at 11th European Symposium on Organic Chemistry
(ESOC 11, Goteborg, Sweden, July 23 - 28, 1999).
PMID- 10760893
TI - The Melting Point Alternation in alpha,omega-Alkanediols and alpha,omega
Alkanediamines: Interplay between Hydrogen Bonding and Hydrophobic Interactions
The Melting Point Alternation in n-Alkanes and Derivatives, Part 2. This work was
supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie. V.R.T. thanks the Alexander von Humboldt Foundation for a postdoctoral
fellowship. Part 1: ref. 6.
PMID- 10760894
TI - Bridged Cyclic Oligoribonucleotides as Model Compounds for Codon - Anticodon
Pairing R.M. acknowledges the Austrian Academy of Science for an APART fellowship
(Austrian Programme for Advanced Research and Technology). This work was
supported by the Austrian Science Fund, Vienna (P13216-CHE). R.M. is obliged to
Prof. Eschenmoser (Zurich) and Prof. Falk (Linz) for generous hospitality in
their laboratories. We thank Dr. Krishnamurthy (Scripps Institute, La Jolla,
California) for mass analyses and Dr. Weiss (Xeragon AG, Zurich) for 2'-O-TOM
phosphoramidites of standard bases.
PMID- 10760895
TI - A Convenient and General Tin-Free Procedure for Radical Conjugate Addition
Organoboranes in Radical Reactions. Part 4. This work was generously supported by
the Fonds National Suisse de la Recherche Scientifique. We thank Valery Weber for
performing some preliminary experiments. Parts 1 - 3: see ref. 5.
PMID- 10760896
TI - "Naked" Phosphorus as a Bent Bridging Ligand This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
PMID- 10760898
TI - Copper Chalcogenolate Complexes as Precursors to Ternary Nanoclusters: Synthesis
and Characterization of
PMID- 10760897
TI - A Quadruply Stranded, Alkaline Earth Metal Containing Helical Catenate: A Charge
Neutral Heterotopic Homodinuclear
PMID- 10760899
TI - Stereocontrol in Pinacol Ring-Contraction of Cyclopeptidyl Glycols: The
Diazonamide C(10) Problem We thank Mr. Imran Alibhai and Dr. Jing Li for
invaluable experimental assistance. Financial support provided by the Advanced
Research Program of the Texas Higher Education Coordinating Board and The Robert
A. Welch Foundation, and junior faculty awards administered through the Howard
Hughes Medical Institute and the University of Texas Southwestern Medical Center
are gratefully acknowledged.
PMID- 10760900
TI - Electrochemical Transduction of Liposome-Amplified DNA Sensing This research was
supported by the Israel Ministry of Science as an infrastructure project in
biomicroelectronics.
PMID- 10760901
TI - Alkylation of Nitroaromatics with Trialkylborane The authors would like to thank
Dr. S. Levinger and Dr. Y. Zeitlyn for their assistance.
PMID- 10760902
TI - Metal Ions as Allosteric Inhibitors in Hydrogen-Bonding Receptors This work was
supported by a grant from the Natural Sciences and Engineering Research Council
of Canada and by Research Corporation (Research Innovation Award).
PMID- 10760903
TI - A Base-Stabilized Terminal Borylene Complex of Osmium Derived from Reaction
between a Dichloroboryl Complex and 8-Aminoquinoline This work was supported by
the Marsden Fund administered by The Royal Society of New Zealand.
PMID- 10760905
TI - Addition of Enantioenriched gamma-Oxygenated Allylic Stannanes to N-Acyl Iminium
Intermediates: A New Synthesis of syn-Amino Alcohol Derivatives This research was
supported by the National Institute of Allergy and Infectious Diseases (grant R01
AI31422).
PMID- 10760904
TI - Orientation-Controlled Monolayer Assembly of Zeolite Crystals on Glass and Mica
by Covalent Linkage of Surface-Bound Epoxide and Amine Groups We thank the
Ministry of Science and Technology, Korea, for financial support through the
Creative Research Initiatives Program.
PMID- 10760906
TI - Sterically Controlled Pathways in the Reaction of 2,4,6
Tris(isopropyl)benzenesulfonyl Azide and
PMID- 10760907
TI - Formation of the Azadisulfite Dianion
PMID- 10760908
TI - Controllable Orientation of Helical Poly(L-glutamic acid) Rods through
Macrodipole Interaction on Gold Surfaces and Vectorial Electron Transfer.
PMID- 10760910
TI - Mimicking the Structure and Function of DNA: Insights into DNA Stability and
Replication.
AB - The physical and chemical factors that allow DNA to perform its functions in the
cell have been studied for several decades. Recent advances in the synthesis and
manipulation of DNA have allowed this field to move ahead especially rapidly
during the past fifteen years. One of the most common chemical approaches to the
study of interactions involving DNA has been the use of DNA base analogues in
which functional groups are added, deleted, blocked, or rearranged. Here we
describe a different strategy, in which the polar natural DNA bases are replaced
by nonpolar aromatic molecules of the same size and shape. This allows the
evaluation of polar interactions (such as hydrogen bonding) with little or no
interference from steric effects. We have used these nonpolar nucleoside
isosteres as probes of noncovalent interactions such as DNA base pairing and
protein - DNA recognition. We have found that, while base-pairing selectivity
does depend on Watson - Crick hydrogen bonding in the natural pairs, it is
possible to design new bases that pair selectively and stably in the absence of
hydrogen bonds. In addition, studies have been carried out with DNA polymerase
enzymes to investigate the importance of Watson - Crick hydrogen bonding in
enzymatic DNA replication. Surprisingly, this hydrogen bonding is not necessary
for efficient enzymatic synthesis of a base pair, and significant levels of
selectivity can arise from steric effects alone. These results may have
significant impact both on the study of basic biomolecular interactions and in
the design of new, functionally active biomolecules.
PMID- 10760911
TI - Amidocarbonylation-An Efficient Route to Amino Acid Derivatives.
AB - Atom efficient, multicomponent reactions that lead to high-value products from
inexpensive starting materials are of both economic and ecological interest for
industrial organic synthesis. alpha-Amino acids are amongst the most important
compounds in chemistry and biology. As well as their biochemical significance as
building blocks of peptides and proteins, alpha-amino acids are also becoming
increasingly interesting as fine chemicals. Possibly one of the key reactions in
the preparation of these compounds is transition metal catalyzed
amidocarbonylation, where the alpha-amino acid framework is constructed in a
single step from an aldehyde, an amide, and carbon monoxide. This article gives a
current overview of transition metal catalyzed amidocarbonylation reactions used
in the synthesis of alpha-amino acids derivatives. A classification and summary
of the significant features of this three component reaction is first presented
together, with an historical introduction. This section is followed by two
sections on cobalt- and palladium-catalyzed amidocarbonylation. A discussion of
the mechanism of each of the different amidocarbonylation variants form an
introduction. Overviews on further synthetic development of the methodology, such
as the domino reaction with an amidocarbonylation step and the expansion of the
range of starting materials, form the main topics of both variants. The potential
of the method is demonstrated with the help of examples of special synthetic
utility (for example, the preparation of arylglycines). Finally, possibilities
for future developments in transition metal catalyzed amidocarbonylation
reactions are proposed on the basis of the current state of knowledge.
PMID- 10760912
TI - Small Neutral P(n) Molecules.
PMID- 10760913
TI - Imprinted Polymers with Memory for Small Molecules, Proteins, or Crystals The
author is grateful to Dr. Andrew Hall and Dr. Gunter Buchel for linguistic
advice.
PMID- 10760914
TI - Sequestration of Trace Metals Using Water-Soluble and Fluorous Phase-Soluble
Polymers Support of this work by the National Science Foundation and the Robert
A. Welch Foundation is gratefully acknowledged.
PMID- 10760915
TI - pi-Allylpalladium-Mediated Catalytic Synthesis of Functionalized Allenes This
work was supported by the "Research for the Future" Program, the Japan Society
for the Promotion of Science, and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Japan.
PMID- 10760916
TI - A New Route to Fused Aromatic Compounds by Using a Palladium-Catalyzed Alkylation
- Alkenylation Sequence This work was supported by the NSERC (Canada) and the
University of Toronto. S.P. thanks the Fondation Bettencourt - Schueller for a
postdoctoral fellowship.
PMID- 10760917
TI - Towards the Design of Open-Framework Cluster Materials: A Novel Layered Niobium
Oxochloride with a Honeycomblike Structure The authors are grateful to Dr. Peter
White from the University of North Carolina at Chapel Hill, USA, for crystal data
collection, and Prof. Hanno zur Loye, University of South Carolina, USA, for
magnetic susceptibility measurements. Wake Forest University supported this
research through a grant from the Research and Creativity Fund.
PMID- 10760918
TI - Molecular Beacons: A Novel Approach to Detect Protein - DNA Interactions This
work was partially supported by a U.S. NSF Career Award (CHE-9733650) and by a
U.S. Office of Naval Research Young Investigator Award (N00014-98-1-0621).
PMID- 10760919
TI - Novel Zinc Fluorescent Probes Excitable with Visible Light for Biological
Applications We thank Prof. E. Kimura and Prof. T. Koike for advice on the
chemistry of macrocyclic polyamines.
PMID- 10760920
TI - Calixphyrins: Novel Macrocycles at the Intersection between Porphyrins and
Calixpyrroles This work was supported by the National Institutes of Health (CA
68682, GM-58907, and TW-00682 to J.L.S.), the National Science Foundation (CHE
9725399 to J.L.S. and CHE-9807702 to V.L. for the purchase of the Nonius Kappa
CCD), the Howard Hughes Foundation (V.K. and J.L.S.), the Grant Agency of the
Czech Republic (No. 203/97/1099 to V.K.), the Ministry of Education (No. VS-97135
and Project CEZ: J19/98: 223400008 to V.K.), and the Howard Hughes Medical
Institute (74195-541101 to V.K.).
PMID- 10760921
TI - Synthesis of Geometrically Well Defined, Molecularly Thin Polymer Films This work
was supported by the National Institutes of Health (GM30376). A.D.S is supported
by a NIH Molecular Biophysics Training Grant (GM08313-10).
PMID- 10760922
TI - Surface-Enhanced Resonance Raman Scattering as a Novel Method of DNA
Discrimination The authors wish to thank the BBSRC for the award of a David
Phillips Fellowship to D.G., Zeneca Diagnostics for funding to B.J.M., and the
OSWEL DNA unit, University of Southampton (UK), for supplying the modified
oligonucleotides.
PMID- 10760923
TI - alpha-Oxymethyl Ketone Enolates for the Asymmetric Mannich Reaction. From
Acetylene and N-Alkoxycarbonylimines to beta-Amino Acids This work was supported
by the University of the Basque Country, the Basque Government (Projects UPV
170.215-G47/98, EX-1998-124) and in part by M. E. C. (Project PB 98-0549). Grants
to A.S. and M.C.G. from the Basque Government, and to C.L. from the Government of
Navarra and M.E.C. are acknowledged.
PMID- 10760924
TI - Facile Synthesis of beta-Derivatized Porphyrins-Structural Characterization of a
beta - beta-Bis-Porphyrin Financial support for this work was provided by the
National Institutes of Health (GM 47274). The authors would like to thank William
Cieslik from Hamamatsu Corporation for providing a C4334-0 Streak Camera for
luminescence lifetime measurements and Alan Heyduk for assistance with the X-ray
crystal structure determination.
PMID- 10760925
TI - One-Pot Synthesis of Antigen-Bearing, Lysine-Based Cluster Mannosides Using Two
Orthogonal Chemoselective Ligation Reactions This work was financially supported
by the ANRS and the Fondation pour la Recherche Medicale (Sidaction grant to CG).
We are grateful to B. Coddeville and G. Montagne for recording ES-MS and NMR
spectra, respectively, and also to Dr. S. Brooks for proofreading the manuscript.
PMID- 10760926
TI - The Tetraaza
PMID- 10760927
TI - Nanoscale Container Structures and Their Host - Guest Properties We are grateful
for financial support from the Skaggs Research Foundation and the National
Institutes of Health. Dr. Laura Pasternack and Dr. Takeharu Haino are sincerely
acknowledged for assistance with the 2D NMR experiments and experimental advise,
respectively.
PMID- 10760928
TI - Design of Small Molecules That Recognize RNA: Development of Aminoglycosides as
Potential Antitumor Agents That Target Oncogenic RNA Sequences This work was
supported by the NIH. We thank Professor Peter Voght for his suggestion of the
oncogenic RNA sequences as targets.
PMID- 10760929
TI - New Selenium-Based Safety-Catch Linkers: Solid-Phase Semisynthesis of Vancomycin
We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass
spectrometric assistance, respectively. This work was financially supported by
the National Institutes of Health (USA), The Skaggs Institute for Chemical
Biology, a fellowship from the George Hewitt Foundation (N. W.), and grants from
Schering Plough, Pfizer, Glaxo, Merck, Hoffmann-La Roche, DuPont, and Abbott
Laboratories.
PMID- 10760930
TI - 1,2-Seleno Migrations in Carbohydrate Chemistry: Solution and Solid-Phase
Synthesis of 2-Deoxy Glycosides, Orthoesters, and Allyl Orthoesters We thank Drs.
D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric
assistance, respectively. We gratefully thank Nicolas Winssinger for helpful
discussions and preparation of the selenium bromide resin. This work was
financially supported by the Skaggs Institute for Chemical Biology, the National
Institutes of Health (USA), postdoctoral fellowships from M.E.C., Spain (R.M.R.,
Fullbright), the Japan Society for the Promotion of Science (H.S.), the George
Hewitt Foundation (K.C.F.), and grants from Schering Plough, Pfizer, Glaxo,
Merck, Hoffmann - La Roche, DuPont, Abbott Laboratories, and Boehringer -
Ingelheim.
PMID- 10760931
TI - Solution and Solid-Phase Synthesis of Functionalized 3-Arylbenzofurans by a Novel
Cyclofragmentation - Release Pathway Financial support for this work was provided
by The Skaggs Institute for Chemical Biology, the National Institutes of Health
(USA), doctoral fellowships from the National Science Foundation (S.A.S.) and the
Department of Defense (J.A.P.), and grants from Abbott, Amgen, Boehringer -
Ingelheim, Glaxo, Hoffmann - La Roche, DuPont, Merck, Novartis, Pfizer, and
Schering Plough.
PMID- 10760932
TI - Novel Ruthenium Building Blocks for the Efficient Modular Construction of
Heterobimetallic Molecular Squares of Porphyrins This work was supported by the
Italian MURST. We thank Prof. L. G. Marzilli (Emory University, Atlanta, USA) for
helpful discussions, and Johnson Matthey for a loan of RuCl(3) small middle dotx
H(2)O. The CNR staff at ELETTRA is acknoweldged for help in the use of the
facility supported by CNR and Elettra Scientific Division.
PMID- 10760933
TI - Furan-Based Porphyrins: Tetraoxa
PMID- 10760934
TI - Porphyrinoids with 26 pi Electrons: Molecules with Exceptional Spectroscopic
Properties This work was supported by the Fonds der Chemischen Industrie.
PMID- 10760935
TI - Tin-Free Radical Cyclization Reactions Using the Persistent Radical Effect I am
grateful to Prof. Dieter Seebach for generous financial support and to Prof.
Hanns Fischer for helpful discussions. Dr. Sylvain Marque is acknowledged for
conducting the ESR experiments, and Dr. Volker Gramlich for carrying out the X
ray analysis. I also thank Christian Wetter and Elisabeth Baier for conducting
some experiments.
PMID- 10760936
TI - Pseudoprolines: Targeting a cis Conformation in a Mimetic of the gp120 V3 Loop of
HIV-1 We are grateful to Dipl.-Biol. Raymond Jacquet for helpful advice. This
work was supported by the Swiss National Science Foundation.
PMID- 10760937
TI - A Triangular Mixed-Valent Cu(II)Cu(I)Cu(I) Cluster Supported by the Tripod Ligand
2-Quinolyl-2,2'-dipyrrolylmethane This work was supported by a Grant-in-Aid for
Scientific Research (No. 11136230) from the Ministry of Education, Science,
Sports, and Culture, Japan. We are grateful to S. Nomura (IMS, Okazaki) for FABMS
analysis, and to M. Nishinaka (Kobe University) for microanalysis.
PMID- 10760938
TI - 1,2,4,6-Cycloheptatetraene: Room-Temperature Stabilization inside a Hemicarcerand
This work was supported by the Petroleum Research Fund administered by the
American Chemical Society, by Kansas State University, and by KSU Center for
Basic Cancer Research (undergraduate fellowship to M.A.M.).
PMID- 10760939
TI - Thioxylation as One-Atom-Substitution Generates a Photoswitchable Element within
the Peptide Backbone We thank Dr. Peter Bayer for the NMR investigations and Dirk
Wildemann for his assistance with the peptide syntheses. This work was supported
by the Deutsche Forschungsgemeinschaft, the Fond der Chemischen Industrie, the
Boehringer-Ingelheim-Stiftung, and the Land Sachsen-Anhalt.
PMID- 10760940
TI - On the Unusual Electrochemical Stability of Nanofabricated Copper Clusters This
work was supported by the Deutsche Forschungsgemeinschaft through grant No. Ko
576/10-2. One of us (G.E.E.) gratefully acknowledges receipt of a stipend from
the Fonds der Chemischen Industrie. We acknowledge helpful discussions with Prof.
Jacek Lipkowski, Guelph, and Prof. Uwe Kreibig, Aachen.
PMID- 10760941
TI - Synthesis of the (9S,18R) Diastereomer of Cyclamenol A This research was
supported by the Bayer AG and the Fonds der chemischen Industrie.
PMID- 10760942
TI - Crossed Condensation of Two Different Hydrosulfido-Bridged Dinuclear Complexes:
Structures and Reactivities of TiRu(3)S(4) Cubane-Type Sulfido Clusters This work
was supported by a Grant-in-Aid for Specially Promoted Research (09102004) from
the Ministry of Education, Science, Sports, and Culture of Japan.
PMID- 10760943
TI - Synthesis of Mixed-Metal High-Nuclearity Clusters by Fusion of Anionic Ruthenium
Carbido Clusters through Palladium Units.
PMID- 10760944
TI - High levels of intracellular polyamines promote histone acetyltransferase
activity resulting in chromatin hyperacetylation.
AB - Polyamines stimulate expression of a variety of genes, including many implicated
in cell proliferation. Indeed, aberrant expression of ornithine decarboxylase
(ODC), a rate-limiting enzyme in polyamine biosynthesis, plays a causal role in
tumorigenesis. Gene activity is influenced by dynamic changes in acetylation of
nucleosomal histones. Although polyamines influence the histone acetyltransferase
and deacetylase activities in cell-free systems, their ability to modulate these
enzymes in live cells has never been established. To examine the effects of
elevated intracellular levels of ODC and polyamines on gene transcription and
histone acetylation, cells were infected with a retrovirus containing a cDNA for
ODC. ODC overexpression potentiated the stimulatory effects of histone
deacetylase inhibitors on reporter gene expression beyond that promoted by ODC or
inhibitor treatment alone. Indeed, elevated intracellular levels of ODC promoted
hyperacetylation of histones in several epidermal and fibroblast cell types. The
ODC-mediated increase in acetylated histones was abrogated when cells were
treated with alpha-difluoromethylornithine, a specific inhibitor of ODC activity,
implying a distinct role for polyamines. Specifically, polyamines were found to
enhance the action of histone acetyltransferases either directly or indirectly.
Our studies document effects of elevated intracellular polyamine levels on
histone acetylation in proliferating cells, suggesting a mechanism by which
altered polyamine biosynthesis contributes to aberrant expression of genes,
facilitating tumor growth. In addition, these studies may have implications for
the development of drugs designed to regulate enzymes that modify the acetylation
status of histones.
PMID- 10760945
TI - Amphotericin B both inhibits and enhances T-cell proliferation: inhibitory effect
is mediated through H(2)O(2) production via cyclooxygenase pathway by
macrophages.
AB - Amphotericin B (AmB) has been shown to have both immunosuppressive and -enhancing
effects, making its precise nature of action enigmatic. In the present study, we
found that AmB inhibited concanavalin A (Con A)-induced T cell proliferation if
added within first 30 min of stimulation, after which inhibition began to
diminish rapidly. However, AmB did not inhibit T-cell proliferation induced by a
combination of PMA and ionomycin. AmB inhibition of Con A-induced proliferation
was completely overcome by cyclooxygenase inhibitor ibuprofen ([alpha-methyl-4
(isobutyl)phenylacetic acid]) and H(2)O(2) scavenger catalase. In fact, in the
presence of ibuprofen and catalase, AmB enhanced, instead of suppressing, Con A
induced proliferation in a dose-dependent way. The effect of catalase was limited
to the removal of extracellular H(2)O(2) only, as the enzyme did not enter the
cells. AmB stimulated H(2)O(2) production by macrophages, but not by a lymphocyte
population, which was inhibited by ibuprofen. Our T-cell preparation contained
about 3% macrophages, and AmB inhibition of proliferation was further pronounced
by increasing the macrophage number by as little as 1%. Finally, AmB inhibition
of Con A-induced T-cell proliferation was completely overcome by 2
mercaptoethanol. On the basis of these results, we suggest that AmB stimulates
H(2)O(2) production by macrophages through the activation of the cyclooxygenase
pathway of arachidonate metabolism. H(2)O(2) then inhibits Con A-induced T-cell
proliferation by interfering with an early step of the T-cell receptor signaling
pathway through the oxidative modification of some signaling proteins. Our
results also show that AmB enhances T-cell proliferation, which can be seen only
after blocking its inhibitory effect.
PMID- 10760946
TI - DNA methyltransferase levels and altered CpG methylation in the total genome and
in the GSTP1 gene in human glioma cells transfected with sense and antisense DNA
methyltransferase cDNA.
AB - This study examines the efficacy of using plasmid expression vectors containing
sense and antisense DNA MTase cDNA to both up- and downregulate intracellular DNA
MTase levels in human glioma cells. The effects of the changes in MTase levels on
global genomic DNA methylation and on the methylation status of CpG dinucleotides
in the GSTP1 gene were determined in a glioma cell line that overexpresses the
GSTP1 gene. In cells transfected with sense DNA MTase cDNA, MTase gene
transcripts increased to a maximum of 2. 5-fold at 24 h, while MTase activity
increased to a maximum of 3. 6-fold at 48 h. The effects of antisense MTase cDNA
transfections were less pronounced, and levels of MTase gene transcripts and
enzyme activity in transfectants were decreased to only, approximately, one-half
the levels of controls. The alterations in DNA MTase expression were associated
with corresponding changes in the level of global DNA methylation and in the
methylation of the GSTP1 gene in the cells, however, with no detectable
morphological or cytotoxic effects on the cells. No significant changes in GSTP1
gene expression were detected after the transfections, presumably because of the
high levels of basal GSTP1 expression in the cells. Consequently, the p16 gene,
known to be repressed transcriptionally by DNA methylation, was examined for the
functional effects of the altered MTase levels. The results showed a 2-fold
decrease in p16 gene transcripts with the sense MTase transfectants, while in the
MTase antisense-transfected cells p16 transcript levels increased by 30%.
Together, these results demonstrate the feasibility of using both sense and
antisense DNA MTase expression vectors to regulate DNA MTase levels in glioma
cells and that, over relatively short periods of time, the alterations in MTase
activities are not deleterious to the cells. The system provides a model with
which the role of DNA methylation in critical genes and DNA sequences can be
investigated in glioma cells.
PMID- 10760947
TI - Cholesterol inhibits the nuclear entry of estrogen receptor activation factor (E
RAF) and its dimerization with the nonactivated estrogen receptor (naER) in goat
uterus.
AB - An alternative form of estrogen receptor isolated from goat uterus, the
nonactivated estrogen receptor (naER), has no DNA-binding function, although it
is closely similar to the classical estrogen receptor (ER) in its hormone binding
affinity and specificity. The naER dimerizes with a DNA binding protein, estrogen
receptor activation factor (E-RAF). The heterodimer binds to the DNA. Assays
carried out during the purification of E-RAF showed that an endogenous inhibitor
that is heat stable and dialyzable bound to the E-RAF and prevented the formation
of the heterodimer. The inhibitor has been isolated and purified. GC-MS analysis
identifies this molecule to be cholesterol. Circular dichroism measurement has
shown that the high-affinity binding of cholesterol to E-RAF results in subtle
changes in the secondary and the tertiary structure of the protein. The E-RAF
with altered conformation fails to dimerize with the naER. Instead of
facilitating E-RAF entry into the nucleus, dimerization with the naER prevents
it. Similarly, cholesterol binding blocks the nuclear entry of the protein,
showing that E-RAF with altered conformation is incapable of interaction with the
nuclear pore complex/membrane proteins. The naER-E-RAF heterodimer remains at the
nuclear periphery, incapable of further transport. These results indicate the
possibility that the dimerization between naER and the E-RAF takes place only
within the nuclear compartment. The observation that cholesterol binding prevents
nuclear entry of the E-RAF reflects the similarity of E-RAF with the sterol
regulatory element (SRE) binding protein that enters the nucleus and binds to SRE
only when the intracellular level of cholesterol remains low.
PMID- 10760948
TI - Stress protein GRP78 prevents apoptosis induced by calcium ionophore, ionomycin,
but not by glycosylation inhibitor, tunicamycin, in human prostate cancer cells.
AB - GRP78 induction has recently been shown to play a critical role in maintaining
cell viability against several kinds of stress, including depletion of
endoplasmic reticulum Ca(2+) and accumulation of unglycosylated proteins, under
specific experimental conditions. However, the functional significance of GRP78
induction after stressful treatment has not been well defined. This article
characterizes the different biological features associated with GRP78 induction
by two kinds of stress agents, calcium ionophore, ionomycin (IM), and
glycosylation inhibitor, tunicamycin (TM), focusing on the association with
apoptosis in human prostate cancer cells. Both IM and TM treatment resulted in
marked induction of GRP78 transcription in androgen-dependent prostate cancer
LNCaP cells maintained in medium without androgen, but not in medium containing
androgen, as measured by Northern blotting and nuclear run-off assays. After
pretreatment with tumor necrosis factor-alpha, which has potent cytotoxic effects
on LNCaP cells, both IM and TM could induce substantial increases in GRP78
transcription in LNCaP cells, even in medium containing androgen. Under both
experimental conditions described, DNA fragmentation assays showed a direct
correlation between the onset of apoptosis in LNCaP cells after IM treatment and
the initiation of GRP78 transcript induction, while induction of GRP78 expression
preceded TM-induced apoptosis. To elucidate the functional differences of GRP78
induction by IM and TM, an antisense oligodeoxynucleotide (ODN) targeted against
the grp78 gene was designed to reduce GRP78 expression in a sequence-specific and
dose-dependent manner. Antisense GRP78 ODN treatment substantially enhanced
apoptosis of LNCaP cells induced by IM compared with mismatch control ODN
treatment, whereas no marked differences were observed in apoptotic features
induced by TM with antisense GRP78 and mismatch control ODN treatment. Studies of
additional androgen-independent prostate cancer PC3 cells also demonstrated a
correlation between GRP78 induction and resistance to apoptosis after IM
treatment, but not after TM treatment. These findings suggest that there are at
least two GRP78 signaling pathways, which play different roles in resistance
against stress-induced apoptosis.
PMID- 10760949
TI - Rapid identification of antigenic T-cell epitopes by extracellular acidification
rate signals.
AB - We used a silicon-based biosensor, a microphysiometer, to measure real-time
extracellular acidification rate signals associated with T lymphocyte responses
to peptide ligands interacting with the T-cell receptor (TCR). We compared these
effector responses with those of interferon-gamma (IFN-gamma) production, and T
cell proliferation. Within minutes, major histocompatibility complex (MHC)-bound
peptides on antigen-presenting cells (APCs) engaged the TCR to increase
acidification rates of the extracellular media was measured by microphysiometer.
We exposed two myelin peptide-specific human T-cell clones, MSF132E11 (DRB1*1501
restricted) and TOM3A6 (DRB5*0101 restricted), to truncated analogues of the
parent MBP 84-102 peptide, in the presence of MHC restricted human antigen
presenting cells, and measured the extracellular acidification rate signal
changes, IFN-gamma production and T-cell proliferation. The core epitopes
recognized by these clones were identified by microphysiometer and found to be
MBP 88-100 and MBP 91-100, respectively. These epitopes were identical to those
identified by the IFN-gamma and proliferation assays. We conclude that
measurement of real-time extracellular acidification rate signals by the
microphysiometer may facilitate rapid identification of human T-cell epitopes
involved in immune disorders and the development of specific T-cell antagonists.
PMID- 10760950
TI - Identification and characterisation of transcript and protein of a new short N
terminal utrophin isoform.
AB - Dystrophin and utrophin are known to link the intracellular cytoskeleton to the
extracellular matrix via a transmembraneous glycoprotein complex. Four short C
terminal isoforms (Dp71, Dp116, Dp140, and Dp260) are described for dystrophin
and three for utrophin (Up71, Up113, and Up140). We describe here for the first
time the existence of a 3.7-kb transcript and a 62-kDa protein in C6 glioma cells
representing a short N-terminal isoform unique for utrophin (N-utrophin). More
than 20 clones covering the entire coding region of utrophin were isolated from a
rat C6 glioma cell cDNA library. Two clones were found to code for a protein with
539 amino acids. Its sequence is identical to that of the full-length utrophin,
except for the last residue where Cys is replaced by Val. This isoform contains
the actin binding domain (consisting of two calponin homology subdomains),
followed by two spectrin-like repeats. A recombinant fragment corresponding to N
utrophin binds to F-actin in vitro with an equilibrium constant (affinity) K of
4.5 x 10(5) M(-1) and a stoichiometry of one fragment per around five actin
monomers. Immunocytochemical staining of C6 glioma cells with antisera specific
for different utrophin regions localised full-length utrophin in the
submembraneous cortical actin layer as revealed by confocal microscopy. A
distinct staining pattern for the N-utrophin was not detectable, although it was
expected to localise at the actin stress fibers. It is assumed that it co
localises via the two spectrin-like repeats with the full-length utrophin at the
cell membrane.
PMID- 10760951
TI - Insulin-induced gene 33 mRNA expression in Chinese hamster ovary cells is insulin
receptor dependent.
AB - Gene 33 (g33) is a non-tissue-specific gene regulated in rat liver and hepatoma
cells by insulin and other agents. It is thought to participate in the transition
from quiescence to proliferation in mitogen-treated cells. The mechanism(s) by
which insulin exerts its action on g33 are not totally understood; it is unclear
whether a functional insulin receptor is required for this action. In this study,
we evaluate the mechanism for insulin induction of g33 mRNA in Chinese hamster
ovary (CHO) cells transfected with the neomycin-resistant plasmid (CHONeoB),
human insulin receptor (CHONewIRa), and a kinase-defective insulin receptor
mutated at the ATP-binding site (CHOK1018A). Transfected cells had higher levels
of insulin binding than that of CHONeoB cells; insulin-induced phosphorylation of
the insulin receptor and its intracellular substrates were impaired in CHOK1018A
cells. Maximal insulin induction of mRNA(g33) occurred 3 h after hormonal
exposure in all cell lines. The degree of insulin stimulation of g33 mRNA levels
was four- to sixfold higher in CHONewIRa than in CHONeoB or CHOK1018A cells,
which had minimal levels of insulin-stimulated g33 mRNA levels. Half-maximal
stimulation of g33 mRNA levels was observed at 0.06 +/- 0.01 nM in CHONewIRa
cells, consistent with insulin interaction with its own receptor. Wortmannin, an
inhibitor of phosphatidyl inositol 3-kinase (PI3K), had some effects on insulin
stimulation of g33 mRNA in CHO NewIRa cells. PD98059, an inhibitor of mitogen
activated kinase kinase (MAPKK), and rapamycin, a p70 S6 kinase inhibitor, had
minimal effect on insulin stimulation of g33 mRNA in all cells tested. By
contrast, hydroxy-2-naphthalenylmethyl)phosphonic acid triacetoxymethyl ester
(HNMPA(AM)(3), a selective inhibitor of the insulin receptor tyrosine kinase,
caused complete inhibition of insulin stimulation of g33 mRNA levels. These data
indicate that the insulin receptor with intact kinase activity is required for
insulin stimulation of g33 mRNA levels. They also suggest that AKT, a PI 3-kinase
downstream effector molecule, could mediate insulin stimulation of g33 mRNA. The
mechanism(s) of insulin regulation of g33 expression downstream of receptor do
not seem to rely entirely on the classic insulin receptor transduction pathway,
as a minor effect was observed upon inhibition of MAPKK, suggesting that multiple
pathways may be involved.
PMID- 10760952
TI - Phosphatase activity in rat adipocytes: effects of insulin and insulin
resistance.
AB - Insulin regulates the activity of both protein kinases and phosphatases. Little
is known concerning the subcellular effects of insulin on phosphatase activity
and how it is affected by insulin resistance. The purpose of this study was to
determine insulin-stimulated subcellular changes in phosphatase activity and how
they are affected by insulin resistance. We used an in vitro fatty acid
(palmitate) induced insulin resistance model, differential centrifugation to
fractionate rat adipocytes, and a malachite green phosphatase assay using peptide
substrates to measure enzyme activity. Overall, insulin alone had no effect on
adipocyte tyrosine phosphatase activity; however, subcellularly, insulin
increased plasma membrane adipocyte tyrosine phosphatase activity 78 +/- 26% (n =
4, P < 0.007), and decreased high-density microsome adipocyte tyrosine
phosphatase activity 42 +/- 13% (n = 4, P < 0.005). Although insulin resistance
induced specific changes in basal tyrosine phosphatase activity, insulin
stimulated changes were not significantly altered by insulin resistance. Insulin
stimulated overall serine/threonine phosphatase activity by 16 +/- 5% (n = 4, P <
0.005), which was blocked in insulin resistance. Subcellularly, insulin increased
plasma membrane and crude nuclear fraction serine/threonine phosphatase
activities by 59 +/- 19% (n = 4, P < 0. 005) and 21 +/- 7% (n = 4, P < 0.007),
respectively. This increase in plasma membrane fractions was inhibited 23 +/- 7%
(n = 4, P < 0. 05) by palmitate. Furthermore, insulin increased cytosolic protein
phosphatase-1 (PP-1) activity 160 +/- 50% (n = 3, P < 0.015), and palmitate did
not significantly reduce this activity. However, palmitate did reduce insulin
treated low-density microsome protein phosphatase-1 activity by 28 +/- 6% (n = 3,
P < 0.04). Insulin completely inhibited protein phosphatase-2A activity in the
cytosol and increased crude nuclear fraction protein phosphatase-2A activity 70
+/- 29% (n = 3, P < 0.038). Thus, the major effects of insulin on phosphatase
activity in adipocytes are to increase plasma membrane tyrosine and
serine/threonine phosphatase, crude nuclear fraction protein phosphatase-2A, and
cytosolic protein phosphatase-1 activities, while inhibiting cytosolic protein
phosphatase-2A. Insulin resistance was characterized by reduced insulin
stimulated serine/threonine phosphatase activity in the plasma membrane and low
density microsomes. Specific changes in phosphatase activity may be related to
the development of insulin resistance.
PMID- 10760953
TI - Ethanol inhibits prolactin- and tumor necrosis factor-alpha-, but not gamma
interferon-induced expression of intercellular adhesion molecule-1 in human
astrocytoma cells.
AB - In humans, alcohol consumption has multiple effects on the immune system. Despite
an increase in our understanding of the effects of alcohol on the immune system,
little is known about the effect of alcohol on the neuroimmune response. In the
central nervous system (CNS), astrocytes and microglial function as immune
effector cells. In response to infection of injury, astrocytes increase in number
and size, express several proinflammatory cytokines, MHC class I and II antigens,
and several adhesion molecules, including intercellular adhesion molecule-1 (ICAM
1). Interactions between ICAM-1 and its counter-receptors play an important role
in the regulation of neuroimmune response. In this study, cultured human
astrocytoma cells were used to examine the effect of ethanol on ICAM-1
expression. Western blot analyses show that quiescent astrocytes express, at
least, four immunoreactive ICAM-1 proteins with apparent molecular weights 55,
67, 82, and 90 kDa. Incubation of human astrocytoma cells with tumor necrosis
factor-alpha (TNF-alpha) or prolactin (PRL) resulted in marked increases in all
four immunoreactive ICAM-1 proteins. In the presence of ethanol, however, PRL-
and TNF-alpha-induced increases in all four immunoreactive ICAM-1 proteins were
markedly inhibited. ICAM-1 is a cell surface transmembrane glycoprotein. Using a
cell surface specific ICAM-1 adhesion assay we found that in human astrocytoma
cells TNF-alpha, interferongamma (IFN-gamma) and PRL increased cell surface ICAM
1 expression. Consistent with our Western blot analyses, ethanol significantly
inhibited TNF-alpha- and PRL-induced cell surface ICAM-1 expression. By contrast,
IFN-gamma-induced ICAM-1 expression was not inhibited by exposure of the cells to
ethanol. Expression of ICAM-1 is regulated predominantly at the transcriptional
level. In the present report, we show that TNF-alpha increased ICAM-1 mRNA levels
in human astrocytoma cells and that ethanol markedly blocked TNF-alpha-induced
increases in ICAM-1 mRNA levels. Further, we found that PRL-induced ICAM-1
expression was, at least in part, due to a PRL-induced increase in TNF-alpha
syntheses and secretion. Our results clearly indicate that ethanol has a
pronounced effect on ICAM-1 expression in human astrocytoma cells, thus
suggesting that ETOH exposure may impair the immune response in the CNS by
blocking leukocytes adhesion and migration into the CNS in response to injury or
infection.
PMID- 10760954
TI - Selective inhibition of endothelial cell proliferation by fumagillin is not due
to differential expression of methionine aminopeptidases.
AB - The angiogenesis inhibitors fumagillin and TNP-470 selectively inhibit the
proliferation of endothelial cells, as compared with most other cell types. The
mechanism of this selective inhibition remains uncertain, although methionine
aminopeptidase-2 (MetAP2) has recently been found to be a target for fumagillin
or TNP-470, which inactivates MetAP2 enzyme activity through covalent
modification. Primary cultures of human endothelial cells and six other non
endothelial cell types were treated with fumagillin to determine its effect on
cell proliferation. Only the growth of endothelial cells was completely inhibited
at low concentrations of fumagillin. MetAP1 and MetAP2 levels in these cells were
investigated to determine whether differential enzyme expression plays a role in
the selective action of fumagillin. Western blot analysis and RT-PCR data showed
that MetAP1 and MetAP2 were both expressed in these different types of cells,
thus, ruling out differential expression of MetAP1 and MetAP2 as an explanation
for the cell specificity of fumagillin. Expression of MetAP2, but not of MetAP1,
is regulated. Treatment of human microvascular endothelial cells (HMVEC) with
fumagillin resulted in threefold increases of MetAP2 protein in the cells, while
MetAP1 remained constant. Similar upregulation of MetAP2 by exposure to
fumagillin was also observed in non-endothelial cells, eliminating this response
as an explanation for cell specificity. Taken together, these results indicate
that while MetAP2 plays a critical role in the effect of fumagillin on
endothelial cell proliferation, differential endogenous expression or fumagillin
induced upregulation of methionine aminopeptidases is not responsible for this
observed selective inhibition.
PMID- 10760955
TI - A NF-kappaB p65 subunit is indispensable for activating manganese superoxide:
dismutase gene transcription mediated by tumor necrosis factor-alpha.
AB - Expression of the manganese superoxide dismutase (Mn-SOD) is induced by tumor
necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and lipopolysaccharide
(LPS). Recently, a TNF-responsive element (TNFRE) was identified within the
second intron of the murine Mn-SOD gene. The 5' CCAAT/enhancer binding protein
(C/EBP)-related region within the TNFRE was responsive to TNF, whereas the 3' NF
kappaB-related region alone was not. This report describes the minimal promoter
region of the Mn-SOD gene and investigates the cis-acting elements and trans
acting factors responsible for TNF-alpha-induced Mn-SOD gene expression. Reporter
plasmid transfection studies demonstrated that inducible transcription factors
enhanced the transcriptional activity of the Mn-SOD gene through the intronic
enhancer region. Electrophoretic mobility shift assays demonstrated that after
TNF-alpha stimulation, p50 and p65 NF-kappaB subunits bound specifically to the
newly identified NF-kappaB transcription factor-binding site, distinct from the
previously described NF-kappaB site, within the intronic enhancer region. In
addition, site-directed mutagenesis and cotransfection studies demonstrated that
the NF-kappaB p65 subunit enhanced the transcriptional activity of the Mn-SOD
gene through the newly identified NF-kappaB site. These results show that a NF
kappaB p65 subunit is mainly involved in the molecular mechanisms controlling TNF
alpha-mediated Mn-SOD gene transcription.
PMID- 10760956
TI - Antibodies to different peptides in osteopontin reveal complexities in the
various secreted forms.
AB - We have generated synthetic peptides corresponding to various portions of human
osteopontin (OPN) and have immunized rabbits and mice with these peptides to
generate polyclonal and monoclonal antibodies specific to human OPN. We then
generated six distinct sandwich enzyme-linked immunoabsorbent assay (ELISA)
systems by using different pairs of polyclonal and monoclonal antibodies against
human OPN. These systems allowed us to detect not only various isoforms and
truncated forms of recombinant OPN, but also the glycosylated form of native
urinary OPN. Most importantly, tumor-derived OPN was differentially detected by
the six ELISA systems. The ELISA systems that we have developed will be useful
for clarifying the functional roles for OPN in vivo in various physiologic and
pathologic conditions.
PMID- 10760957
TI - Differential regulation of cadherins by dexamethasone in human osteoblastic
cells.
AB - Human osteoblasts express a repertoire of cadherins, including N-cadherin (N
cad), cadherin-11 (C11), and cadherin-4 (C4). We have previously shown that
direct cell-cell adhesion via cadherins is critical for BMP-2-induced osteoblast
differentiation. In this study, we have analyzed the regulation of cadherin
expression in normal human trabecular bone osteoblasts (HOB), and osteoprogenitor
marrow stromal cells (BMC), during exposure to dexamethasone, another inducer of
human bone cell differentiation. Dexamethasone inhibited the expression of both
C11 and N-cad mRNA in both BMC and HOB, although the effect was much more
pronounced on N-cad than on C11. This action of the steroid was dose dependent,
was maximal at 10(-7) M concentration, and occurred as early as after 1 day of
incubation. By contrast, expression of C4 mRNA and protein was strongly induced
by dexamethasone in BMC and was stimulated in HOB. This stimulatory effect lasted
for at least 2 weeks of incubation. A cadherin inhibitor, HAV-containing
decapeptide only partially ( approximately 50%) prevented dexamethasone-induced
stimulation of alkaline phosphatase activity by BMC, which instead was not
altered by incubation with a neutralizing antibody against C4. Therefore, the
pattern of cadherin regulation by dexamethasone radically differs form that
observed with BMP-2. Dexamethasone effects on certain osteoblast differentiated
features, such as induction of alkaline phosphatase activity are not strictly
dependent on cadherin function.
PMID- 10760958
TI - Recognition and binding of the human selenocysteine insertion sequence by
nucleolin.
AB - Prokaryotic and eukaryotic cells cotranslationally incorporate the unusual amino
acid selenocysteine at a UGA codon, which conventionally serves as a termination
signal. Translation of selenoprotein gene transcripts in eukaryotes depends upon
a "selenocysteine insertion sequence" in the 3'-untranslated region. We have
previously shown that DNA-binding protein B specifically binds this sequence
element. We now report the identification of nucleolin as a partner in the
selenoprotein translation complex. In RNA electromobility shift assays, nucleolin
binds the selenocysteine insertion sequence from the human cellular glutathione
peroxidase gene, competes with binding activity from COS cells, and shows
diminished affinity for probes with mutations in functionally important,
conserved sequence elements. Antibody to nucleolin interferes with the gel shift
activity of COS cell extract. Antibody to DNA-binding protein B co-extracts
nucleolin from HeLa cell cytosol, and the two proteins co-sediment in glycerol
gradient fractions of ribosomal high salt extracts. Thus, nucleolin appears to
join DNA-binding protein B and possibly other partners to form a large complex
that links the selenocysteine insertion sequence in the 3'-untranslated region to
other elements in the coding region and ribosome to translate the UGA "stop"
codon as selenocysteine.
PMID- 10760959
TI - Atrial fibrillation: part I.
PMID- 10760960
TI - The heart is a fast learner.
PMID- 10760961
TI - Resistance training for people with heart disease.
PMID- 10760962
TI - Heart lines. Snoring: a heart disease risk factor for women.
PMID- 10760963
TI - Ask the doctor. I am 83 years old and have coronary artery disease that causes
angina everyday with activities like climbing stairs. My doctor thinks I am going
to need bypass surgery to get some freedom from my symptoms. Isn't it too risky
at my age?
PMID- 10760964
TI - Memory loss. You can remember this--even as time goes by.
PMID- 10760965
TI - Near-death experiences. Gentle into that good night.
PMID- 10760966
TI - General anesthesia. Awake during surgery.
PMID- 10760967
TI - Osteopathy. Is there a D.O. in the house?
PMID- 10760968
TI - Xerostomia. Absence makes the mouth get drier.
PMID- 10760969
TI - By the way, doctor. I've read about private companies putting patents on genes.
That seems strange to me. Why do they have the right to patent part of the human
body?
PMID- 10760970
TI - Treatment of alcoholism -- part I.
PMID- 10760971
TI - An alternative approach to ADHD.
PMID- 10760972
TI - Long grieving.
PMID- 10760973
TI - Forum. What are the current treatments for panic disorder?
PMID- 10760974
TI - Bad fats, good fats: new insights into diet and health.
PMID- 10760975
TI - Liniments.
PMID- 10760976
TI - Submissiveness and survival.
PMID- 10760977
TI - On call. I am 62 years old and I've always been very healthy. At my last annual
checkup, however, my blood pressure was 166/96. My doctor told me to cut down on
drinking to lower my pressure. I usually have a cocktail or two before dinner and
two or three glasses of wine with my meal. Is my doctor right?
PMID- 10760978
TI - Tobacco smoke and women: a special vulnerability?
PMID- 10760979
TI - Cancer. Progress report on ovarian cancer.
PMID- 10760980
TI - Supplements. Glucosamine for osteoarthritis.
PMID- 10760981
TI - New treatment for actinic keratosis.
PMID- 10760982
TI - Caution monitoring bone mineral density.
PMID- 10760983
TI - By the way, doctor. I've been reading a lot about the increasing number of
chronically ill adults who are cared for at home. There are so many benefits to
staying at home, but it seems to exact a toll on the caregiver. Can you suggest
ways to reduce the emotional and physical stresses involved in giving this kind
of care?
PMID- 10760996
TI - Ionizing radiation-induced mitogen-activated protein (MAP) kinase activation in
DU145 prostate carcinoma cells: MAP kinase inhibition enhances radiation-induced
cell killing and G2/M-phase arrest.
AB - These studies examine the role(s) played by the mitogen-activated protein kinase
(MAPK) pathway after exposure of DU145 prostate carcinoma cells to radiation.
Radiation (2 Gy) was found to cause both immediate primary (0-30 min) and
prolonged secondary activations (90-1440 min) of the MAPK pathway. These
activations of the MAPK pathway were abolished by inhibition of epidermal growth
factor receptor (EGFR) function. The secondary activation was also abolished by
addition of a neutralizing monoclonal antibody against transforming growth factor
alpha (TGFA). Activation of the MAPK pathway could be induced in nonirradiated
cells by the transfer of medium from irradiated cultures. Neutralizing antibody
to TGFA blocked this effect, indicating that radiation causes secondary
activation of the MAPK pathway by release of TGFA in DU145 cells. Radiation
induced a transient G(2)/M-phase growth arrest that was prolonged for up to 24 h
by inhibition of the MAPK pathway. Inhibition of the MAPK pathway significantly
increased the ability of radiation to cause apoptosis 24 h after exposure. The
ability of DU145 cells to proliferate after irradiation became dependent on MAPK
signaling. When cells were subjected to single doses or fractionated radiation
exposure, continuous inhibition of the MAPK pathway significantly decreased
clonogenic survival. Only a small fraction of this cell killing could be
accounted for by apoptosis within the first 96 h. Thus inhibition of the MAPK
pathway increased radiation-induced cell killing likely by both apoptotic and
nonapoptotic mechanisms. Collectively, our findings indicate that disruption of
the TGFA/EGFR/MAPK pathway may represent a strategy that could be exploited to
manipulate prostate carcinoma growth and cell survival after irradiation.
PMID- 10760997
TI - Enhancement of radiation effects in vitro by the estrogen metabolite 2
methoxyestradiol.
AB - 2-Methoxyestradiol. 2-Methoxyestradiol (2-ME) is an endogenous estradiol
metabolite that disrupts microtubule function, suppresses murine tumors, and
inhibits angiogenesis. Since some microtubule inhibitors have been shown to alter
radiosensitivity, we have evaluated 2-ME as a radiation enhancer in vitro. H460
human lung cancer cells were plated, treated with 2-ME for 24 h, and irradiated;
then colony-forming ability was assessed. The radiation dose enhancement ratios
(DERs) using this protocol were 1.3, 1.8 and 2.1 for 1, 1.5 and 2 microM 2-ME,
respectively. Using a single-cell plating protocol, the respective DERs were 1.2,
1.5 and 1.8. The parent compound of 2-ME, beta-estradiol, did not enhance
radiation effects at equally cytotoxic doses. Isobologram analysis showed that 1
microM 2-ME was additive with radiation, but that 1.5 and 2 microM were
synergistic. Cell cycle analysis showed a dose-dependent increase in the
percentage of cells in the radiosensitive G(2)/M phase after a 24-h treatment
with 2-ME; a threefold increase in the percentage of cells in G(2)/M phase was
observed using 2 microM 2-ME. Treatment with 2 microM 2-ME almost completely
inhibited repair of sublethal damage (SLD) as shown using split-dose recovery.
Radiosensitive, repair-deficient murine SCID (severe combined immunodeficient)
cells did not show enhancement of radiation effects with 2 microM 2-ME, but
enhancement was observed in the wild-type parental cells (CB-17). SCID cells
complemented with human DNA-dependent protein kinase restored radioenhancement by
2-ME. In addition, MCF-7 breast cancer cells were also radiosensitized by 2
microM 2-ME (DER = 2.1). These data suggest that 2-ME is a potential radiation
sensitizer, in addition to its previously reported antitumor and antiangiogenic
properties. We have verified the antiangiogenic activity of 2-ME in vitro using
human endothelial cells. Based on these results, we hypothesize that the
mechanism of radiation enhancement may involve redistribution of cells into
G(2)/M phase by 2-ME, and that the resulting population of cells is repair
deficient and thus radiosensitive.
PMID- 10760998
TI - Increased expression of intracisternal A-particle RNA in regenerated myeloid
cells after X irradiation in C3H/He inbred mice.
AB - Myeloid Cells after X Irradiation in C3H/He Inbred Mice. Myeloid leukemia cells
were derived from regenerated hematopoietic cells damaged by sublethal doses of X
radiation in C3H/He inbred mice. We previously found that within the genome of
the myeloid leukemia cells, a retrotransposon, the intracisternal A-particle
(IAP) element, is integrated. Levels of IAP RNA, the source of cDNA for the
integration, were analyzed quantitatively in C3H mice. Higher levels of IAP
transcripts were observed in normal cells, particularly in hematopoietic cells,
from C3H/He mice, than in those from C57BL/6J and STS/A mice. In the C3H/He mice,
an approximately twofold increase in IAP RNA was found in the regenerated spleen
and bone marrow cells at 5 days and from 12 to 90 days after whole-body X
irradiation. In addition, an increased level of IAP RNA was observed in all the
myeloid leukemia cells derived from C3H/He mice. This suggests that the elevated
levels of IAP RNA in the regenerated hematopoietic cells after irradiation
contribute to the increase in retrotransposition of IAP found in myeloid leukemia
cells from C3H/He mice.
PMID- 10760999
TI - Changes in blood perfusion and hypoxia after irradiation of a human squamous cell
carcinoma xenograft tumor line.
AB - The effect of irradiation depends on the oxygenation status of the tissue, while
irradiation itself also changes the oxygenation and perfusion status of tissues.
A better understanding of the changes in tumor oxygenation and perfusion over
time after irradiation will allow a better planning of fractionated radiotherapy
in combination with modifiers of blood flow and oxygenation. Vascular
architecture (endothelial marker), perfusion (Hoechst 33342) and oxygenation
(pimonidazole) were studied in a human laryngeal squamous cell carcinoma tumor
line grown as xenografts in nude mice. The effect of a single dose of 10 Gy X
rays on these parameters was evaluated from 2 h to 11 days after irradiation.
Shortly after irradiation, there was an 8% increase in perfused blood vessels
(from 57% to 65%) followed by a significant decrease, with a minimum value of 42%
at 26 h after irradiation, and a subsequent increase to control levels at 7 to 11
days after irradiation. The hypoxic fraction showed a decrease at 7 h after
treatment from 13% to 5% with an increase to 19% at 11 days after irradiation.
These experiments show that irradiation causes rapid changes in oxygenation and
perfusion which may have consequences for the optimal timing of radiotherapy
schedules employing multiple fractions per day and the introduction of
oxygenation- and perfusion-modifying drugs.
PMID- 10761000
TI - Can angiotensin-converting enzyme inhibitors protect against symptomatic
radiation pneumonitis?
AB - This study was designed to determine whether patients taking angiotensin
converting enzyme (ACE) inhibitors while receiving radiation therapy for lung
cancer are protected from developing symptomatic radiation pneumonitis. The
records of 213 eligible patients receiving thoracic irradiation for lung cancer
with curative intent at Duke University Medical Center from 1994-1997 were
reviewed. Of the 213 patients, 26 (12.2%) were on ACE inhibitors (usually for the
management of hypertension) during radiotherapy (group 1); the remaining 187
patients (group 2) were not. Patients were irradiated, with fields shaped to
protect normal tissues, with total doses of 50-80 Gy. After treatment, patients
were generally followed every 3 months for 2 years, then every 6 months
thereafter. Symptomatic radiation pneumonitis was scored according to modified
National Cancer Institute Common Toxicity Criteria (i.e., radiographic changes
alone were not sufficient for the diagnosis of pneumonitis). There was no
difference in the incidence of pneumonitis between the two groups (P = 0.75).
Fifteen percent of the patients on ACE inhibitors (group 1) developed symptomatic
radiation-induced lung injury compared to 12% of the patients not receiving these
drugs (group 2). Although patients in group 1 tended to develop pneumonitis
slightly sooner than did patients in group 2, this difference also was not
significant (P = 0. 8). Within the dose range prescribed for treating
hypertension, ACE inhibitors do not appear to either decrease the incidence or
delay the onset of symptomatic radiation pneumonitis among lung cancer patients
receiving thoracic irradiation.
PMID- 10761001
TI - N2 laser-induced oxidation of hemoproteins in red blood cell lysate.
AB - Irradiation of red blood cell lysate with a N(2) laser (337 nm) was observed to
induce oxidation of hemoproteins. This process showed a strong dependence on the
concentration of red blood cell lysate and the dose of radiation. Studies of
mechanisms and experiments with deoxygenated red blood cell lysate rule out
involvement of any reactive oxygen species and suggest that the process is not a
photodynamic reaction.
PMID- 10761002
TI - Protection by DMSO against cell death caused by intracellularly localized iodine
125, iodine-131 and polonium-210.
AB - The mechanisms by which DNA-incorporated radionuclides impart lethal damage to
mammalian cells were investigated by examining the capacity of dimethyl sulfoxide
(DMSO) to protect against lethal damage to Chinese hamster V79 cells caused by
unbound tritium ((3)H(2)O), DNA-incorporated (125)I- and (131)I-iododeoxyuridine
((125)IdU, (131)IdU), and cytoplasmically localized (210)Po citrate. The
radionuclides (3)H and (131)I emit low- and medium-energy beta particles,
respectively, (125)I is a prolific Auger electron emitter, and (210)Po emits 5.3
MeV alpha particles. Cells were radiolabeled and maintained at 10.5 degrees C for
72 h in the presence of different concentrations of DMSO (5-12.5% v/v), and the
surviving fraction compared to that of unlabeled controls was determined. DMSO
afforded no protection against the lethal effects of the high-LET alpha particles
emitted by (210)Po. Protection against lethal damage caused by unbound (3)H,
(131)IdU and (125)IdU depended on the concentration of DMSO in the culture
medium. Ten percent DMSO provided maximum protection in all cases. The dose
modification factors obtained at 10% DMSO for (3)H(2)O, (131)IdU, (125)IdU and
(210)Po citrate were 2.9 +/- 0.01, 2.3 +/- 0.5, 2.6 +/- 0.2 and 0.95 +/- 0.07,
respectively. These results indicate that the toxicity of Auger electron and beta
particle emitters incorporated into the DNA of mammalian cells is largely radical
mediated and is therefore indirect in nature. This is also the case for the low
energy beta particles emitted by (3)H(2)O. In contrast, alpha particles impart
lethal damage largely by direct effects. Finally, calculations of cellular
absorbed doses indicate that beta-particle emitters are substantially more toxic
when incorporated into the DNA of mammalian cells than when they are localized
extracellularly.
PMID- 10761003
TI - Paradoxical effects of iodine-125 decays in parent and daughter DNA: a new target
model for radiation damage.
AB - Chinese hamster ovary cells were synchronized at the G(1)/S-phase boundary of the
cell cycle and were pulse-labeled with (125)I-iododeoxyuridine 30 min after they
entered the S phase. Cell samples were harvested and frozen for accumulation of
(125)I decays during the first and second G(2) phase after labeling. Cell
aliquots that had accumulated the desired number of decays were thawed and plated
for evaluation micronucleus formation and cell death. Cells subjected to (125)I
decays during the first G(2) phase after labeling exhibited single-hit kinetics
of cell killing (n = 1, D(0) 41 decays/cell). In contrast, decays accumulated
during the second G(2) phase killed cells with dual-hit kinetics (n = 1.9, D(0)
81 decays/cell). A similar divergence in the action of (125)I was noted for
micronucleus formation. These findings indicate that the effects of (125)I varied
depending on whether the decays occurred in daughter DNA (first G(2) phase) or
parent DNA (second G(2) phase). Control studies with external X rays showed no
such divergence of the action of radiation. To account for this paradox, a model
is proposed that invokes higher-order chromatin structures as radiation targets.
This model implies differential spatial arrangements for parent and daughter DNA
in the genome, with DNA strands organized such that a single (125)I decay
originating in daughter DNA damages two targets during the first G(2) phase, but
identical decays occurring during the second G(2) phase damage only one of the
targets.
PMID- 10761004
TI - Direct radiation damage to crystalline DNA: what is the source of unaltered base
release?
AB - The radiation chemical yields of unaltered base release have been measured in
three crystalline double-stranded DNA oligomers after X irradiation at 4 K. The
yields of released bases are between 10 and 20% of the total free radical yields
measured at 4 K. Using these numbers, we estimate that the yield of DNA strand
breaks due to the direct effect is about 0.1 micromol J(-1). The damage
responsible for base release is independent of the base type (C, G, A or T) and
is not scavenged by anthracycline drugs intercalated in the DNA. For these
reasons, reactions initiated by the hydroxyl radical have been ruled out as the
source of base release. Since the intercalated anthracycline scavenges electrons
and holes completely but does not inhibit base release, the possibility for
damage transfer from the bases to the sugars can also be ruled out. The results
are consistent with a model in which primary radical cations formed directly on
the sugar-phosphate backbone react by two competing pathways: deprotonation,
which localizes the damage on the sugar, and hole tunneling, which transfers the
damage to the base stack. Quantitative estimates indicate that these two
processes are approximately equally efficient.
PMID- 10761005
TI - Double base lesions in DNA X-irradiated in the presence or absence of oxygen.
AB - Previously, double lesions in which two adjacent bases are modified were
identified in DNA oligomers exposed in solution to ionizing radiation. However,
the formation of such lesions in polymer DNA had not been demonstrated. Using
reference oligomer containing a specific double lesion and employing liquid
chromatography-mass spectrometry (LC-MS), it was possible to show directly that
double lesions are formed in irradiated calf thymus DNA. The double lesion in
which a pyrimidine base is degraded to a formamido remnant and an adjacent
guanine base is oxidized to 8-oxoguanine was detected in DNA X-irradiated in
oxygenated aqueous solution. The double lesion in which the methyl carbon atom of
a thymine base is covalently linked to carbon at the 8-position of an adjacent
guanine base was detected in DNA irradiated in a deoxygenated environment.
PMID- 10761006
TI - DMPO-Alkyl radical spin trapping: an in situ radiolysis steady-state ESR study.
AB - Short-lived free radicals formed in the reaction of 11 substrates and
radiolytically produced hydroxyl radicals were trapped successfully with 5, 5
dimethyl-1-pyrroline-N-oxide (DMPO) in dilute aqueous solution. The in situ
radiolysis steady-state ESR spectra of the spin adducts were analyzed to
determine accurate ESR parameters for these spin adducts in a uniform
environment. Parent alkyl radicals include methyl, ethyl, 1-propyl and 2-propyl
(1-methylethyl). Hydroxyalkyl parent radicals were hydroxymethyl, hydroxyethyl, 2
hydroxy-2-propyl (1-methyl-1-hydroxyethyl), 1-hydroxypropyl and 2-hydroxy-2
methylpropyl. Carboxyl radical (carbon dioxide anion, formate radical) and
sulfite anion radical were the sigma radicals studied. The DMPO spin adduct of 1
propyl was identified for the first time. For most spin adducts, g factors were
also determined for the first time. In DMPO spin adducts of hydroxyalkyl
radicals, nitrogen and C(2)-proton hyperfine coupling constants are smaller than
those of alkyl radical adducts; the hydroxyalkyl spin adducts possess larger g
values than their unsubstituted counterparts. These changes are ascribed to the
spread of pi conjugation to include the hydroxyl group. Strong evidence of spin
addend-aminoxyl group interaction can be seen in the asymmetrical line shapes in
the hydroxyethyl and the hydroxypropyl spin adducts.
PMID- 10761007
TI - Strand break induction by photoabsorption in DNA-bound molecules.
AB - Dried samples of a DNA-chloroterpyridine platinum complex were irradiated with
monochromatic X rays tuned to the photoabsorption resonance of the L(III) inner
shell of the platinum atom. The number of single- and double-strand breaks (SSBs
and DSBs) triggered by the Auger effect in supercoiled DNA plasmids was measured
by the production of circular nicked and linear forms. To probe the specific
contribution of the L(III) inner-shell excitation of the platinum atom, photon
wavelengths were tuned on the resonance energy (on peak) and below (off peak).
The quantum yields of the resonance radiation were typically found to be 11 for
the SSBs and 1 for the DSBs. The DSB-to-SSB ratio increased by 20% when switching
from off-resonance to on-resonance irradiation.
PMID- 10761008
TI - Model for radial dependence of frequency distributions for energy imparted in
nanometer volumes from HZE particles.
AB - This paper develops a deterministic model of frequency distributions for energy
imparted (total energy deposition) in small volumes similar to DNA molecules from
high-energy ions of interest for space radiation protection and cancer therapy.
Frequency distributions for energy imparted are useful for considering radiation
quality and for modeling biological damage produced by ionizing radiation. For
high-energy ions, secondary electron (delta-ray) tracks originating from a
primary ion track make dominant contributions to energy deposition events in
small volumes. Our method uses the distribution of electrons produced about an
ion's path and incorporates results from Monte Carlo simulation of electron
tracks to predict frequency distributions for ions, including their dependence on
radial distance. The contribution from primary ion events is treated using an
impact parameter formalism of spatially restricted linear energy transfer (LET)
and energy-transfer straggling. We validate our model by comparing it directly to
results from Monte Carlo simulations for proton and alpha-particle tracks. We
show for the first time frequency distributions of energy imparted in DNA
structures by several high-energy ions such as cosmic-ray iron ions. Our
comparison with results from Monte Carlo simulations at low energies indicates
the accuracy of the method.
PMID- 10761009
TI - Stochastic radial dose distributions and track structure theory.
AB - Measured single-event distributions of the specific energy deposited in
cylindrical volumes with simulated diameters down to 150 nm for (4)He and (12)C
ions with energies of 25 MeV/nucleon and (16)O ions with 21 MeV/nucleon and
radial distances up to 12 microm are presented. The mean specific energy per ion
, the mean specific energy per target hit z(1)(r), and the relative
frequency of target hits nu(r) as a function of radial distance are evaluated and
compared with the corresponding quantities of the track structure model of Kiefer
and Straaten (Phys. Med. Biol. 31, 1201-1209, 1986). Though there are some
discrepancies in the absolute values, the radial dependence of , z(1)(r)
and v(r) for (12)C and (16)O ions is reproduced satisfactorily. The model fails
to describe the data for (4)He ions. A more detailed comparison of the radial
shape of the mean specific energies calculated from the experimental data from
the present work and data from the literature reveals a significant projectile
charge dependence which is not included in track structure models.
PMID- 10761010
TI - Primary DNA damage in human blood lymphocytes exposed in vitro to 2450 MHz
radiofrequency radiation.
AB - Human peripheral blood samples collected from three healthy human volunteers were
exposed in vitro to pulsed-wave 2450 MHz radiofrequency (RF) radiation for 2 h.
The RF radiation was generated with a net forward power of 21 W and transmitted
from a standard gain rectangular antenna horn in a vertically downward direction.
The average power density at the position of the cells in the flask was 5
mW/cm(2). The mean specific absorption rate, calculated by finite difference time
domain analysis, was 2.135 (+/-0.005 SE) W/kg. Aliquots of whole blood that were
sham-exposed or exposed in vitro to 50 cGy of ionizing radiation from a (137)Cs
gamma-ray source were used as controls. The lymphocytes were examined to
determine the extent of primary DNA damage (single-strand breaks and alkali
labile lesions) using the alkaline comet assay with three different slide
processing schedules. The assay was performed on the cells immediately after the
exposures and at 4 h after incubation of the exposed blood at 37 +/- 1 degrees C
to allow time for rejoining of any strand breaks present immediately after
exposure, i.e. to assess the capacity of the lymphocytes to repair this type of
DNA damage. At either time, the data indicated no significant differences between
RF-radiation- and sham-exposed lymphocytes with respect to the comet tail length,
fluorescence intensity of the migrated DNA in the tail, and tail moment. The
conclusions were similar for each of the three different comet assay slide
processing schedules examined. In contrast, the response of lymphocytes exposed
to ionizing radiation was significantly different from RF-radiation- and sham
exposed cells. Thus, under the experimental conditions tested, there is no
evidence for induction of DNA single-strand breaks and alkali-labile lesions in
human blood lymphocytes exposed in vitro to pulsed-wave 2450 MHz radiofrequency
radiation, either immediately or at 4 h after exposure.
PMID- 10761011
TI - Chronic T-cell Leukemia/Lymphoma.
PMID- 10761012
TI - Cutaneous T-cell Lymphoma.
AB - BACKGROUND: Cutaneous T-cell lymphoma (CTCL) represents a spectrum of diseases
composed of malignant helper T lymphocytes. An accurate diagnosis of early CTCL
is difficult because of the varied clinical and histologic expressions of the
disease. METHODS: The authors review the epidemiology, possible risk factors,
clinical manifestations, diagnostic techniques, staging, prognosis, and treatment
options for CTCL. RESULTS: The varied and often nonspecific clinical and
histologic presentations of CTCL may delay diagnosis and staging, thus
necessitating further studies such as immunophenotyping, flow cytometry, and T
cell receptor gene rearrangement analysis. CONCLUSIONS: A multidisciplinary
approach to the diagnosis, staging, and treatment of CTCL assists in optimizing
outcomes from management of patients with this disease.
PMID- 10761013
TI - T-cell Prolymphocytic Leukemia.
AB - BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a post-thymic T-cell
malignancy with aggressive clinical course. Although T-PLL has been referred to
under different designations, it is a distinct clinico-biological entity and
should be distinguished from other T-cell disorders. METHODS: The literature on T
PLL is reviewed. Experience on the clinical and laboratory features, differential
diagnosis, and therapy on a large series of T-PLL patients is presented. RESULTS:
T-PLL affects adults and occurs more frequently in men. The principal disease
characteristics are organomegaly, skin lesions, and a raised lymphocyte count.
Immunological markers show a post-thymic T-cell phenotype (TdT- CD2+ CD5+ CD3n)
with strong expression of CD7. A CD4+ CD8- phenotype is seen in two thirds of
cases. CD4 and CD8 are coexpressed in 25%, and a CD4- CD8+ phenotype is rare.
Cytogenetics show a recurrent abnormality inv(14)(q11;q32) that is always
associated to other aberrations (particularly iso8q or trisomy 8). Differential
diagnosis between T-PLL and other T-cell malignancies is based on a constellation
of clinical and laboratory features. Generally, T-PLL patients are refractory to
the therapy used in lymphoid disorders. Median survival is short but is improving
with the use of 2'-deoxycoformycin and the humanized monoclonal antibody, anti
CDw52 (Campath-1H). CONCLUSIONS: T-PLL is a distinct T-cell disorder with
characteristic clinical and laboratory features and a poor prognosis. A precise
diagnosis of this disease is important in determining patient management and
treatment.
PMID- 10761014
TI - Large Granular Lymphocyte Leukemia.
AB - BACKGROUND: Clonal diseases of large granular lymphocyte (LGL) disorders can
arise from a CD3+ T-cell lineage or from a CD3- NK-cell lineage. CD3+ LGL
leukemia is the most frequent form of LGL leukemia and is a distinct entity by
FAB and REAL classifications. METHODS: The clinical course, biological features,
and recent data on pathogenesis of CD3+ LGL leukemia are reviewed. The spectrum
of differential diagnosis is described. RESULTS: T-LGL leukemia affects elderly
people. Approximately 60% of patients are symptomatic; recurrent infections
secondary to chronic neutropenia, anemia, and rheumatoid arthritis are the main
clinical features. The most common phenotype is CD3+, CD8+, CD57+. Clonality is
detected by clonal rearrangement of the T-cell receptor gene. Clinical and
molecular remission can be obtained with oral low-dose methotrexate. Serologic
findings show frequent reactivity to the BA21 epitope of HTLV-I env p21e,
suggesting that a cellular or retroviral protein with homology to BA21 may be
important in pathogenesis. Clonal expansion may be facilitated by IL-12 and IL-15
lymphokines. Constitutive expression of Fas ligand by leukemic LGLs support the
hypothesis that leukemic cells arise from antigen-activated cytotoxic T cells.
Leukemic LGLs express a multidrug-resistance phenotype that could partly explain
the chemoresistance observed in aggressive cases. CONCLUSIONS: CD3+ LGL leukemia
is a distinct lymphoproliferative T-cell disorder with specific clinicobiological
aspects. The clinical spectrum of LGL proliferations is wide and
immunophenotypic, and genotypic studies are needed to establish the diagnosis.
PMID- 10761015
TI - Progress in the Systemic Treatment of Advanced Soft-Tissue Sarcomas.
AB - BACKGROUND: Despite the plethora of chemotherapeutic remedies for advanced soft
tissue sarcomas, little evidence has developed to indicate that these efforts
have been curative. No controlled comparison has yet proven that patients
receiving multidrug regimens survive longer than those receiving doxorubicin
alone. METHODS: The authors review current systemic treatments and then discuss
some investigational efforts now in progress. Also, they seek to demonstrate how
the therapies currently available can be integrated with surgery and radiation
therapy to accomplish more than might be anticipated from chemotherapy alone.
RESULTS: While working to develop better systemic therapies for advanced soft
tissue sarcomas, the integrated use of our best chemotherapy regimens in
combination with selected surgical and radiotherapy efforts may provide patients
with the best available therapy. Some recent observations involving the use of
molgramostim plus chemotherapy have been intriguing. CONCLUSIONS: Progress in the
systemic treatment of advanced soft-tissue sarcomas may be gradual, but it is
real. Our daily challenge is to be certain that we offer each patient the best
available multimodality treatment applicable to his or her clinical situation.
Molgramostim should be made available for further study with chemotherapy in
controlled clinical trials.
PMID- 10761016
TI - The Pleural Tent.
PMID- 10761017
TI - The Role of Immunohistochemistry in the Differential Diagnosis of Soft-Tissue
Tumors.
PMID- 10761018
TI - Disseminated Nocardia Brasiliensis Infection in an Immunocompromised Patient.
PMID- 10761019
TI - Digital Mammography: From Theory to Practice.
PMID- 10761020
TI - Brain Tumor Therapy: New Lights on the Horizon.
PMID- 10761021
TI - The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Organization,
Objectives, and Activities.
AB - BACKGROUND: Despite advances in neuro-imaging, neurosurgery, radiation therapy,
and chemotherapy, limited progress has been made in the treatment of patients
with high-grade astrocytomas. The National Cancer Institute has attempted to
speed advances in this field by funding CNS consortia to conduct innovative
clinical trials in this patient population since 1994. METHODS: The NABTT CNS
Consortium is composed of a consortium headquarters and nine member institutions
with outstanding multidisciplinary expertise, clinical and laboratory research
capabilities, and access to large numbers of patients with brain tumors. RESULTS:
The objectives of the NABTT Consortium are to improve the therapeutic outcome for
adults with primary brain tumors, to conduct basic science and clinical research,
and to improve the care and quality of life of adults with primary brain tumors.
NABTT's clinical studies have discovered important drug interactions between
anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and
9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation
strategy for brain tumor trials, and established new protocol "classes" to
expedite and standardize clinical research in this field. CONCLUSIONS:
Significant progress in the care of patients with primary brain tumors is likely
to result from the highly focused and multidisciplinary efforts of the NIH-funded
CNS consortia.
PMID- 10761022
TI - Perfusion Magnetic Resonance Imaging to Assess Brain Tumor Responses to New
Therapies.
AB - BACKGROUND: Although magnetic resonance imaging (MRI) is effective in detecting
the location of intracranial tumors, new imaging techniques have been studied
that may enhance the specificity for the prediction of histologic grade of tumor
and for the distinction between recurrence and tumor necrosis associated with
cancer therapy. METHODS: The authors review their experience and that of others
on the use of perfusion magnetic resonance imaging to evaluate responses of brain
tumors to new therapies. RESULTS: Functional imaging techniques that can
distinguish tumor from normal brain tissue using physiological parameters. These
new approaches provide maps of tumor perfusion to monitor the effects of novel
compounds that restrict tumor angiogenesis. CONCLUSIONS: Perfusion MRI not only
may be as effective as radionuclide-based techniques in sensitivity and
specificity in assessing brain tumor responses to new therapies, but also may
offer higher resolution and convenient co-registration with conventional MRI, as
well as time- and cost-effectiveness. Further study is needed to determine the
role of perfusion MRI in assessing brain tumor responses to new therapies.
PMID- 10761023
TI - Management of Cerebral Metastases: The Role of Surgery.
AB - BACKGROUND: Metastatic brain tumors represent the most common neurological
complication in patients with systemic cancer. They are predominantly cerebrally
located and constitute a significant source of morbidity and mortality. The
overall incidence of brain metastases exceeds that of all other intracranial
tumors, and as improved systemic cancer treatments have extended patients' lives,
this number is rising. METHODS: The role of surgery in the management of cerebral
metastases is reviewed by considering patient selection criteria, surgical
approaches to metastases, intraoperative adjuncts, whole-brain irradiation as a
postoperative adjuvant, resection of multiple vs single metastases, and the
relative roles of stereotactic radiosurgery and conventional surgery. RESULTS:
Surgical resection of single or multiple metastases can be effective management
for patients with otherwise good prognoses, providing all the known metastases
can be removed without producing significant neurologic deficit. Radiosurgery, an
alternate approach, can be used for smaller or inaccessible tumors. CONCLUSIONS:
The presence of multiple brain metastases does not automatically contraindicate
surgery because in properly selected patients, resection of multiple metastases
can extend survival and enhance the quality of life. An awareness of how the
modalities of open craniotomy, whole-brain radiotherapy, and stereotactic
radiosurgery best complement each other will result in the best outcomes.
PMID- 10761024
TI - Implantable Slow-Release Chemotherapeutic Polymers for the Treatment of Malignant
Brain Tumors.
AB - BACKGROUND: Despite significant advances in neurosurgery, radiation therapy, and
chemotherapy, the prognosis for patients with malignant brain tumors remains
dismal. In an effort to improve control of local disease, we have developed a
biodegradable, controlled-release polymer that is implanted directly at the tumor
site. METHODS: The preclinical and clinical development of the polymeric delivery
of chemotherapeutic agents for treatment of patients with malignant gliomas is
reviewed. RESULTS: Carmustine (BCNU)-impregnated biodegradable polymer is the
first new therapy approved by the FDA for patients with gliomas in 23 years. This
delivery system provides high local concentration of drug with minimal systemic
toxicity and obviates the need for drug to cross the blood-brain barrier.
Randomized, multi-institutional, double-blinded, placebo-controlled studies have
shown improved survival in patients treated for gliomas both at initial
presentation and at recurrence. Several clinical principles have emerged from the
use of this polymer system, and further applications are currently being
investigated. CONCLUSIONS: Local delivery of therapeutic agents via biodegradable
polymers may play an increasing role in patients with brain tumors.
PMID- 10761025
TI - Current Concepts in the Management of Tumors of the Skull Base.
AB - BACKGROUND: Due to their involvement with critical neurovascular structures,
tumors located in the cranial base present challenges to neurosurgeons and are
associated with high morbidity and mortality. METHODS: Rates of tumor control,
complications, patient outcomes, and recurrences were extracted and summarized
from two decades of our surgical and radiological treatment follow-up and review
of the medical literature. RESULTS: Recent advances in surgical techniques
involving cranial base approaches have made surgical intervention safer and
curative resection more likely. In managing benign tumors, surgical resection is
the gold standard for treatment. While immediate complications are still
significant, long-term outcomes in most cases are excellent. Focused radiosurgery
using a gamma knife or linear accelerator has produced favorable outcomes, and it
improves the management of small or minimally symptomatic cranial base tumors.
For slow-growing malignant tumors, extensive surgery followed by radiotherapy
achieves the best outcome. In managing highly malignant tumors, outcome is
determined by the effects of chemotherapy and radiotherapy. On some occasions,
surgery is needed to obtain greater control of highly malignant tumors.
CONCLUSIONS: Skull base tumors are relatively common, and management of these
tumors is rapidly evolving. The combination of surgical excision using cranial
base techniques, radiosurgery, fractionated radiotherapy, and chemotherapy should
be individually tailored based on the location and pathological aggressiveness of
the tumor and the symptomatology of the patient.
PMID- 10761026
TI - Cytostatic Agents in the Management of Malignant Gliomas.
AB - BACKGROUND: Cytotoxic therapy for malignant gliomas is limited by poor delivery
and drug resistance, and local therapy is ineffective in managing migratory
cells. However, recent developments in malignant glioma therapy involve trials of
cytostatic rather than conventional cytotoxic agents. METHODS: The biology of the
brain extracellular matrix, tumor invasion, and angiogenesis are reviewed, and
the cytostatic agents that inhibit matrix metalloproteinases, angiogenesis, cell
proliferation, and signal transduction are discussed, as well as studies of the
angiogenic and migratory capacity of malignant brain tumors. RESULTS: Two
specific and interrelated areas, anti-invasion (migration) and anti-angiogenesis,
are potential areas to develop new treatment strategies. Tumor invasion and
angiogenesis are important components of the spread and biologic effects of
malignant gliomas. Several proteinase inhibitors are in clinical trial, as well
as anti-angiogenic agents and signal transduction cascade inhibitors.
CONCLUSIONS: Biologic control of brain tumor cell populations may offer a new
management approach to add to currently available management options for
malignant brain tumors.
PMID- 10761027
TI - Antisense Oligodeoxynucleotide Technology: Potential Use for the Treatment of
Malignant Brain Tumors.
AB - BACKGROUND: Antisense oligodeoxynucleotides (ODNs) have been proposed as a new
therapy for patients with cancer, including malignant brain tumors. Antisense
ODNs are taken up by tumor cells and selectively block gene expression. Use of
ODNs for brain tumors is attractive due to their theoretical specificity,
relative ease of production and, to date, paucity of reported adverse effects.
This article presents current information regarding antisense ODNs and their
possible future use for the treatment of brain tumors. METHODS: The available
published experimental and clinical information regarding antisense ODN treatment
of glioblastoma cells and administration into the central nervous system (CNS)
was reviewed. Other clinically relevant information pertaining to the molecular
biology of antisense ODNs was also collected and summarized. RESULTS: Targets for
antisense ODN therapy in malignant glioma cells have included c-myc, c-myb, c
sis, c-erb B, CD44, p34cdc2, bFGF, PDGF, TGF-beta, IGF-1, PKC-alpha tumor
necrosis factor, urokinase, and S100beta protein. Few in vivo studies of ODN
treatment of brain tumors have yet been reported. Systemically administered ODNs
enter the brain only in extremely small quantities; therefore, microinfusion into
the brain has been recommended. CONCLUSIONS: Antisense ODNs have been used
successfully to block glioblastoma gene expression in vitro and expression of
multiple genes within the CNS of experimental animals. Upcoming clinical trials
will address the safety of antisense ODN use against malignant brain tumors.
PMID- 10761028
TI - Peripherally Enhancing Liver Mass.
PMID- 10761030
TI - Recurrent Cellulitis With Group G Streptococcus Bacteremia in a Cancer Patient: A
Case Report.
PMID- 10761029
TI - Papillary Squamous Cell Carcinoma.
PMID- 10761048
TI - Ontogeny of the extraembryonic membranes of the oviparous lizard, Eumeces
fasciatus (Squamata: scincidae).
AB - Oviposited eggs of Eumeces fasciatus contain embryos in the limb bud stage.
Amniogenesis is complete and two yolk sac membranes, vascular trilaminar
omphalopleure (choriovitelline membrane) and bilaminar omphalopleure, enclose the
yolk vesicle. A small allantoic vesicle contacts the chorion. The choriovitelline
membrane is the primary vascular system. Blood islands, sites of hematopoiesis,
are associated with omphalomesenteric vessels of the choriovitelline membrane.
The bilaminar omphalopleure, which contacts the eggshell over the abembryonic
hemisphere of the egg, lies external to an isolated yolk mass and yolk cleft and
is not vascularized. The definitive yolk sac (splanchnopleure) is formed when the
extraembryonic coelom and allantoic vesicle intrude into the choriovitelline
membrane. Omphalomesenteric vessels are retained with the yolk sac
splanchnopleure and the associated hematopoietic sites are present throughout
incubation. The chorioallantoic membrane reaches the equator of the egg, entirely
supplanting the choriovitelline membrane, after 25% of incubation is completed.
Further growth of the allantois is stalled until 65% of incubation is completed
when rapid expansion of the allantoic vesicle, in conjunction with resorption of
the isolated yolk mass, supplants the bilaminar omphalopleure. As a result, the
chorioallantoic membrane completely envelopes the egg for the final 35% of
incubation. This developmental event is coincident with published reports for the
timing of increased growth and metabolism of embryos. As the isolated yolk mass
regresses, intravitelline cells associated with the yolk cleft invade and resorb
the yolk to form a large cavity. The wall of this cavity is a germinal epithelium
that produces cells that fill the cavity. This structure appears to be a site of
hematopoiesis previously undescribed in vertebrates.
PMID- 10761049
TI - Anatomy and histochemistry of flight muscles in a wing-propelled diving bird, the
Atlantic puffin, Fratercula arctica.
AB - Twenty-three species within the avian family Alcidae are capable of wing
propelled flight in the air and underwater. Alcids have been viewed as Northern
Hemisphere parallels to penguins, and have often been studied to see if their
underwater flight comes at a cost, compromising their aerial flying ability. We
examined the anatomy and histochemistry of select wing muscles (Mm. pectoralis,
supracoracoideus, latissimus dorsi caudalis, coracobrachialis caudalis, triceps
scapularis, and scapulohumeralis caudalis) from Atlantic puffins (Fratercula
arctica) to assess if the muscle fiber types reveal the existence of a compromise
associated with "dual-medium" flight. Pectoralis was found to be proportional in
size with that of nondiving species, although the supracoracoideus was
proportionally larger in puffins. Muscle fiber types were largely aerobic in both
muscles, with two distinct fast-twitch types demonstrable: a smaller, aerobic,
moderately glycolytic population (FOg), and a larger, moderately aerobic,
glycolytic population (FoG). The presence of these two fiber types in the primary
flight muscles of puffins suggests that aerial and underwater flight necessitate
a largely aerobic fiber complement. We suggest that alcids do not represent an
adaptive compromise, but a stable adaptation for wing-propelled locomotion both
in the air and underwater.
PMID- 10761050
TI - Morphology and function of the feeding apparatus of Pelusios castaneus (Chelonia;
Pleurodira).
AB - Feeding mechanics of vertebrates depend on physical constraints of the
surrounding media, water or air. Such functions are inseparably combined with
form. The aim of this study is to show this linkage for the pleurodiran
freshwater turtle Pelusios castaneus and, additionally, to point out the major
functional and biomechanical distinctions between aquatic and terrestrial feeding
turtles as well as several intermediate forms. Gross morphological investigations
of skull, hyoid, tongue, and connected musculature, as well as scanning electron
microscopy of the tongue surface, show typical features of an aquatic feeder,
e.g., strongly developed hyoid apparatus vs. a small tongue with only moderate
papillae, and massive jaw and hyoid musculature. Additionally, the special
function of the esophagus during feeding is investigated to elucidate the
problems of a bidirectional feeder. The esophagus is highly distensible in order
to store the excess water sucked in during feeding until the prey is fixed by the
jaws. The distension is probably achieved by a coincidence of active (branchial
horn) as well as passive (water) components. P. castaneus is a feeding
generalist, and is well adapted to the aquatic medium in terms of its functional
as well as morphological features.
PMID- 10761051
TI - Morphology of the Harderian gland of the Gecko, Tarentola mauritanica.
AB - The Harderian gland of the gecko, Tarentola mauritanica, was studied at the
histological, histochemical, and ultrastructural levels. It is a nonlobate
compound acinar gland surrounded by a thin capsule of connective tissue. Numerous
connective tissue-type mast cells, ultrastructurally similar to those described
in other higher vertebrates, were identified in the interstitial tissue between
the acini. Pyramidal or columnar-shaped secretory glandular cells were observed
in the acini. In the glandular cells, two types of structures could be
distinguished on the basis of their high or low electron density. Lipid droplets
were found in the cytoplasm of the Harderian gland of both sexes. Histochemical
tests showed that the Harderian gland of the gecko is a seromucous gland. The
secretion is essentially merocrine, although an apocrine type of secretion is
sometimes observed.
PMID- 10761052
TI - Comparative ultrastructure of Clara cells in neonatal and older cattle.
AB - Calf lungs were fixed with glutaraldehyde and examined by scanning (SEM) and
transmission (TEM) electron microscopy to compare the ultrastructure of Clara
cells in terminal bronchioles of neonatal calves and older cattle. In the
neonatal calf, SEM revealed numerous smooth-surfaced Clara cells protruding above
a similar number of ciliated cells, whereas in older animals the surface of Clara
cells was lobulated. Thin sections examined by TEM revealed numerous cuboidal to
columnar Clara cells with indented nuclei and a pale cytoplasm filled with
faintly granular glycogen in the neonatal calf. Some cells were characterized by
apical dense and/or pale membrane-bound granules or secretory droplets. Many
cells had an apical tubular network of cisternae that were partly smooth and
partly decorated with ribosomes. Ultrastructural comparison of Clara cells in a 2
day-old calf with those of 14- and 19-day-old, 4- and 5. 5-month-old, and 3.5
year-old cattle revealed a striking reduction in the amount of glycogen per cell
after 14 days. The number of cells with apical granules was small at all ages,
and the density of the secretory granules varied greatly in different cells. A
variable amount of smooth endoplasmic reticulum (SER) was present but was less
prominent than cisternae of ribosomal endoplasmic reticulum (RER). In older
cattle, the limited amount of SER compared to the RER and secretory granules
suggests that bovine Clara cells are more likely to be secretory than
detoxifying.
PMID- 10761053
TI - Overview of the Advances in the Treatment of Multiple Myeloma.
PMID- 10761054
TI - Biology of the Transition of Monoclonal Gammopathy of Undetermined Significance
(MGUS) to Multiple Myeloma.
AB - BACKGROUND: Approximately 25% of patients with monoclonal gammopathy of
undetermined significance (MGUS) eventually develop multiple myeloma (MM) or a
related plasma cell disorder that is universally fatal. In this report, we
examine the changes that occur in the clonal plasma cell that are likely to be
important in the progression of MGUS to active myeloma. METHODS: Studies that
investigate the mechanisms involved in the multistep pathogenesis of monoclonal
gammopathies are reviewed. Cytokines such as IL-6 and IL-1-beta, adhesion
molecules, viruses, and oncogenes including ras, bcl-2, Rb, and p53 are
discussed. RESULTS: IL-1-beta is produced by plasma cells from virtually all MM
patients but is undetectable in most MGUS patients. IL-1-beta has potent
osteoclast activating factor activity, can increase the expression of adhesion
molecules, and can induce paracrine IL-6 production. The increased production of
adhesion molecules could explain why myeloma cells are found predominantly in the
bone marrow. Subsequently, these "fixed" monoclonal plasma cells could now
stimulate osteoclasts through the production of IL-1-beta and paracrine
generation of IL-6 resulting in osteolytic disease. With continued progression of
the myeloma, the monoclonal plasma cells may later acquire the ability to produce
IL-6 in an autocrine fashion that will be manifested clinically by an elevated
labeling index. CONCLUSIONS: A better understanding of the progression of MGUS to
myeloma may lead to novel therapeutic strategies to prevent the development of
MM.
PMID- 10761055
TI - Management of Myeloma: Current and Future Approaches.
AB - BACKGROUND: The treatment of multiple myeloma, relatively stagnant for many
years, appears to be entering a promising era for improvement. This paper reviews
treatment interventions available for patients with multiple myeloma to indicate
a standard approach and to evaluate the spectrum of current standard therapy.
METHODS: The author reviews published literature on the treatment of multiple
myeloma. Both journal articles and papers presented at national and international
meetings are utilized. RESULTS: Intensive combination chemotherapy offers
relatively modest improvement over standard melphalan plus prednisone, but the
use of interferon for maintenance therapy lengthens response duration and
possibly survival. High-dose chemotherapy with stem-cell transplantation is a
relatively safe and effective treatment modality for patients under 70 years of
age at first relapse. Studies in progress will determine its role in first
response consolidation. Use of hematopoietic growth factors, prophylactic
antibiotics, and bisphosphonate treatment of lytic bone disease has diminished
disease morbidity. CONCLUSIONS: While cure of multiple myeloma remains elusive
and 10-year survival is still uncommon, newer treatment approaches offer better
control of disease manifestations and perhaps a real opportunity to prolong
functional life. Future treatments that will address minimal residual disease may
improve long-term survival.
PMID- 10761056
TI - Interferon in the Treatment of Multiple Myeloma.
AB - BACKGROUND: The role of interferon (IFN) in the treatment of multiple myeloma has
been investigated for nearly two decades. The mechanisms underlying antitumor
activity of IFN may be mediated by antiproliferative and immunomodulatory
effects. The benefits of treatment remain controversial, and guidelines for the
use of IFN in myeloma are needed. This review evaluates available data on the
impact of IFN therapy on multiple myeloma. METHODS: A MEDLINE search of published
prospective, randomized trials of IFN in multiple myeloma provided the data
included in this review, as well as selected abstracts presented at international
meetings. RESULTS: IFN has complex and pleiotropic effects on human myeloma lines
and ex vivo myeloma cells. An antiproliferative effect with disruption of the IL
6-mediated growth loop may be crucial, but biologic heterogeneity in myeloma may
have important clinical implications for response to IFN. IFN has demonstrable
antitumor activity in multiple myeloma but appears to have a modest effect on
overall survival when combined with chemotherapy during induction or when used as
maintenance therapy. Most studies have shown a prolongation of the plateau phase
of disease with IFN of variable duration of between four and 12 months.
CONCLUSIONS: A reliable estimate of the benefit of IFN in the overall population
of patients with myeloma is difficult to determine with discordant results from
different trials. Possible sources of heterogeneity in randomized trials need to
be identified, and recognition of subsets of patients who may benefit is
important. Cost-benefit analyses with integration of quality-of-life data are
essential for developing guidelines for the use of IFN in myeloma.
PMID- 10761057
TI - Hematopoietic Cell Transplantation for Multiple Myeloma.
AB - BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disorder with a
median survival of three years. Despite the development of numerous conventional
chemotherapy regimens and interferons, there has been little progress in
improving the survival of patients with MM. Very high-dose chemoradiotherapy and
autologous or allogeneic hematopoietic stem cell transplantation (HSCT) can
result in high complete remission rates, even in patients with advanced disease.
METHODS: A prospective, randomized study has shown that autologous HSCT results
in superior response rates, progression-free survival, and disease-free survival
compared with conventional chemotherapy. This is the first real advance in the
treatment of this disease in 30 years. Unfortunately, few, if any, patients with
MM who receive autologous HSCT are cured. RESULTS: Allogeneic HSCT can be
curative for a fraction of patients with MM. However, very high transplant
related morbidity and mortality limit the application of allografts to younger
patients with compatible donors. CONCLUSIONS: Challenges for the future include
the development of less intensive or more disease-specific chemotherapy regimens
that preserve the antitumor activity but are less toxic, improvement in the
control of graft-vs-host disease in the case of allografts and, for autologous
graft recipients, the development of vaccines and cytotoxic lymphocytes to
augment a graft vs myeloma effect.
PMID- 10761058
TI - Contracting With a Medicare HMO.
PMID- 10761060
TI - Sternoclavicular Joint Septic Arthritis.
PMID- 10761059
TI - Thallium Imaging of the Brain.
PMID- 10761061
TI - The Generalist Finds a Niche in a Comprehensive Cancer Center: A Decade of Growth
at the University of Texas M.D. Anderson Cancer Center.
PMID- 10761078
TI - Welcome to the World of Ocular Oncology.
PMID- 10761079
TI - Uveal Melanoma.
AB - BACKGROUND: Malignant melanoma of the uveal tract is a rare malignancy but a
significant cause of mortality and visual loss. Approximately 50% of patients
diagnosed with a melanoma of the choroid or ciliary body will die of the disease
within 15 years of enucleation. METHODS: The author reviewed the current
literature on the clinical findings, epidemiology, and treatment of uveal
melanoma. RESULTS: Methods of diagnosis have improved substantially in the past
several years, although clinical diagnosis by an experienced examiner remains the
standard in eyes with clear media. Ultrasound is the most useful adjunctive
technique. While enucleation has been the mainstay of therapeutic intervention,
alternative therapies - especially different types of irradiation - offer hope
for tumor control and vision preservation. The Collaborative Ocular Melanoma
Study, a multicenter national trial, is designed to provide long-term data on the
natural history as well as therapeutic intervention. CONCLUSIONS: Malignant
melanoma of the uveal tract can be diagnosed clinically with more confidence than
ever before. It is also possible in many cases to retain the eye and functional
vision while controlling the tumor. However, unanswered questions remain about
the natural history and optimal therapy of uveal melanoma.
PMID- 10761080
TI - Retinoblastoma.
AB - BACKGROUND: Retinoblastoma is the most common intraocular malignancy of infants
and children. With early diagnosis and treatment, survival is greater than 90%;
however, patients with a germline retinoblastoma mutation have a substantial risk
of having a second high-grade malignancy. METHODS: The recent developments in the
diagnosis and treatment of retinoblastoma are reviewed. RESULTS: Identification
of the retinoblastoma germline mutation is now possible with the discovery of the
retinoblastoma gene. Patients with the germline mutation have a 51% cumulative
risk over 50 years of developing a second malignancy. Several pilot studies using
primary chemotherapy for retinoblastoma have shown promising results.
CONCLUSIONS: Risk assessment and genetic counseling have become more precise with
the development of laboratory methods to identify the retinoblastoma gene. The
development of primary chemotherapy regimens to reduce the size of retinoblastoma
tumors may decrease the need for radiation therapy and thereby reduce the risk of
radiation-related malignancies in patients with the germline mutation.
PMID- 10761081
TI - Intraocular Lymphoma.
AB - BACKGROUND: Primary ocular lymphoma is a distinct subtype of intraocular
lymphoma. Its clinical presentation can mimic benign conditions. Diagnosis is
often based on obtaining an intraocular biopsy. Optimal management is not yet
realized. METHODS: This report combines the experience of the author with a
review of the current literature pertaining to intraocular lymphoma. RESULTS:
Primary ocular lymphoma, a subtype of primary central nervous system (CNS)
lymphoma, has a variable clinical course and frequently mimics benign
inflammatory disease. Even when suspected, diagnosis can be elusive.
Chemoradiation is the most effective treatment, but significant ocular and
cerebral morbidity is associated with its use. Novel treatment regimens may
reduce or eliminate side effects while preserving life, vision, and CNS function.
CONCLUSIONS: Primary CNS lymphoma with ocular involvement should be considered in
patients with refractory uveitis, yellow-white choroidal masses, and CNS
lymphoma. Aggressiveness in making the diagnosis should be tempered by the
potential complications of the diagnostic process and advanced by the life
threatening nature of the disease. Treatment should attempt to maximize efficacy
while incorporating considerations such as extent of disease and the patient's
age, health, and mental state.
PMID- 10761082
TI - Management of Ocular Metastasis.
AB - BACKGROUND: Intraocular metastasis is a significant clinical problem in patients
with metastatic cancer. The frequency of intraocular metastasis in all patients
dying of cancer is approximately 12%, but in breast cancer patients, the
frequency can be as high as 37%. METHODS: A review of pertinent literature and
the author's experience are used to describe the epidemiology, diagnosis, and
management of metastatic tumors of the eye. RESULTS: Intraocular metastases occur
frequently and are diagnosed by ophthalmologic examination. Radiotherapy remains
the cornerstone of therapy and allows the majority of patients to maintain useful
vision for the remainder of their lives. CONCLUSIONS: The recognition and
treatment of intraocular metastasis are important clinical oncologic issues. With
proper management, patients with ocular metastasis can maintain vision and thus
maximize quality of life.
PMID- 10761083
TI - A Short Atlas of Intraocular Tumors.
AB - The evaluation of intraocular tumors differs from almost all other oncologic
evaluations because there is little reliance on tissue diagnosis. Definitive
therapies such as enucleation and radiation are usually based on the results of
ophthalmoscopy and a limited number of ancillary studies without the aid of
biopsy. Although biopsies can be performed on most intraocular tumors, the ocular
morbidity associated with these procedures is usually not worth the added benefit
of a tissue diagnosis. The limited role of intraocular biopsy reflects the high
degree of confidence that exists with interpretation of clinical findings. The
single most important diagnostic study is visual inspection of the tumor with the
slit lamp and/or ophthalmoscope. For this reason, representative illustrations of
the most common intraocular tumors are presented.
PMID- 10761084
TI - Breast Cancer Care: Developments in 1998.
AB - BACKGROUND: Breast cancer is a significant cause of mortality and morbidity
worldwide, although death rates in the United States and some other countries are
beginning to fall. METHODS: Several sources of information in 1998, including
publications and presentations at the 1998 meeting of the American Society of
Clinical Oncology, are pertinent to contemporary breast cancer care. RESULTS: It
is now possible to prescribe hormonal therapy that will reduce the incidence of
breast cancer. Methods are available to reduce the morbidity from axillary node
dissection, and improvements in adjuvant therapy and management of metastatic
breast cancer are now at hand. CONCLUSIONS: The information presented provides a
broad-based platform for new standards of care for breast cancer that will serve
as a sound base for further progress in this important disease.
PMID- 10761085
TI - Cancer Care in the Elderly: Cost and Quality-of-Life Considerations.
PMID- 10761086
TI - Campylobacter Jejuni Bacteremia in an HIV-Positive Patient With Non-Hodgkin's
Lymphoma.
PMID- 10761087
TI - High-Dose Therapy and Stem Cell Transplantation.
PMID- 10761088
TI - Manipulating the Immunologic Characteristics of Both Graft and Host to Improve
Transplant Outcome.
AB - BACKGROUND: Several critical outcomes of allogeneic stem cell transplantation for
hematologic malignancies such as engraftment, incidence of graft-vs-host disease
(GVHD) and disease-free survival depend on a balance between residual host and
infused donor T cells and on chemosensitivity of the underlying disorder.
Manipulating cell compartments of the allograft does affect long-term outcome.
METHODS: The authors review investigations on the effect of blood and marrow
graft components, treatment regimens, and immunologic interventions on eventual
transplant outcome, an approach termed "graft engineering." Results: Major
advances in graft engineering over the last decade are presented as a series of
related developments or levels that derive from the goals of reducing GVHD and
minimal residual disease. CONCLUSIONS: Morbidity and mortality of GVHD have
decreased markedly by methods of T-cell depletion but at the expense of recurrent
disease. Cellular therapy and immunotherapy show promise in potentially
eradicating residual disease posttransplant.
PMID- 10761089
TI - High-Dose Chemotherapy in the Adjuvant Treatment of Breast Cancer: Benefit/Risk
Analysis.
AB - BACKGROUND: High-dose chemotherapy (HDRx) may improve the prognosis of patients
with high-risk breast cancer but at the expense of increased toxicity. However,
no randomized, controlled trials have been published that clearly demonstrate the
superiority of HDRx over conventional adjuvant chemotherapy. METHODS: We
developed a simple model to compare benefits and risks of HDRx with conventional
adjuvant chemotherapy (SDRx). The model integrates data on efficacy and risks of
two competing treatment strategies into a single decision rule. RESULTS AND
CONCLUSIONS: Using data from phase II studies, we show that if a disease-free
survival is considered to be the most important outcome, HDRx should be
administered when the probability of breast cancer relapse at five years exceeds
54% to 71% for patients with 4 to 9 positive nodes and exceeds 29% to 40% for
patients with >9 positive nodes. If the endpoint of interest is five-year overall
survival, then the treatment should be administered when the probability of
relapse exceeds 77% to 83% for patients with 4 to 9 nodes involved and 22% to 31%
for those with >9 lymph nodes involved. While awaiting results of randomized,
controlled trials to definitively establish the efficacy rate of HDRx, we also
found that HDRx could be considered in the management of high-risk breast cancer
if its efficacy rate is at least 54% to 60% superior to SDRx in reducing relapse
risk in breast cancer patients with 4 to 9 nodes and at least 31% to 38% for >9
positive nodes. If survival data are used instead of disease-free survival
outcomes, HDRx efficacy should be at least 47% to 48% superior to SDRx in
reducing death risk in breast cancer patients with 4 to 9 nodes and at least 27%
to 30% superior for >9 positive nodes to consider its use in the adjuvant
setting.
PMID- 10761090
TI - Minimal Residual Cancer Detection in Hematopoietic Stem Cell Products and Its
Prognostic Significance in Patients With Breast Cancer, Lymphoma, or Multiple
Myeloma.
AB - BACKGROUND: Despite the initial success of high-dose therapy and bone marrow
transplant, the major reason for posttransplant failure is relapse of disease.
Reinfusion of tumor cells may contribute to relapse in autologous stem cell
transplants. We now have ultra-sensitive methods of tumor cell detection that can
determine the presence of minimal residual cancer (MRC) in marrow and peripheral
blood stem cells. METHODS: The author has conducted a critical review of the
literature on this issue. Results: The factors that are associated with an
increase in contamination of the graft include (1) the number of cycles of
induction therapy, (2) the type of mobilization regimen used, (3) the presence of
tumor cells in the marrow, and (4) the number of phereses. A number of studies
show that the presence of occult breast cancer in the marrow and/or stem cell
product predicts for a poor posttransplant clinical outcome. The presence of
clonogenic breast cancer or lymphoma cells in the graft is also associated with a
very poor outcome. Published data regarding contamination in graft and outcome
for patients with myeloma are limited. CONCLUSIONS: Testing for minimal MRC in
the oncology patient provides prognostic information that may be useful to the
transplant physician.
PMID- 10761091
TI - Pharmacoeconomics of Cancer Therapy.
AB - BACKGROUND: In 1990, annual costs of the diagnosis and treatment of cancer
reached nearly $100 billion and currently constitutes approximately 10% of health
care expenditures in the United States. As new and often more expensive therapies
for cancer treatment become available, the health care decision-maker must
consider the cost effectiveness of the therapy. METHODS: Key principles of
economic analyses and the inherent differences among these analyses are reviewed.
Results: While pharmacoeconomic analyses are increasingly being used in treatment
decision-making, several issues relating to study design, data collection, and
research methods are controversial. CONCLUSIONS: Pharmacoeconomics analyses are
necessary in the current health care environment, but the assumptions used within
the analyses warrant careful evaluation.
PMID- 10761092
TI - Radiation-Induced Sarcoma Following Treatment of Breast Cancer.
AB - BACKGROUND: Radiation therapy (XRT) is an important modality in the treatment of
cancer, and XRT is now commonly utilized in the treatment of early-stage breast
cancer. However, its use has occasionally resulted in the development of
secondary malignancies. We present a critical review of radiation-induced sarcoma
(RIS) that develops after irradiation for the treatment of breast cancer.
METHODS: The case of a patient who developed sarcoma after radiation for breast
cancer is presented, and current literature on RIS is reviewed. The role of XRT
in the development of RIS is examined, and the evaluation and treatment of these
malignancies are reviewed. Results: RIS occurs in 0.2% of patients following
treatment of breast cancer. The role of radiation in the development of RIS has
been clearly demonstrated. Clinical presentation varies, and diagnosis is
commonly delayed. Treatment consists of wide surgical excision. The role of
chemotherapy is controversial. CONCLUSIONS: The occurrence of RIS following
treatment of breast cancer is rare. Its development has an average latency of
over 10 years and likely correlates with the dose and technique of the radiation
treatment. The prognosis of patients with RIS following treatment for breast
cancer is poor predominantly due to a delay in diagnosis. However, the benefit
derived by breast cancer patients from XRT far outweighs the risk of RIS and
should not affect the decision to treat these patients with this modality.
PMID- 10761094
TI - The Use of Lipid Formulations of Amphotericin B in Cancer Patients.
PMID- 10761093
TI - Dysphagia Secondary to a Solitary Plasmacytoma.
PMID- 10761095
TI - Newer Imaging Modalities.
PMID- 10761096
TI - Prostate Cancer: Of Turtles, Birds, and Rabbits.
PMID- 10761097
TI - Clinical Applications of Radioimmunoscintigraphy With Prostate-Specific
Antibodies for Prostate Cancer.
AB - BACKGROUND: The presence of metastasis is the most important prognostic indicator
in patients with prostate carcinoma and is the predominant determinant of
therapeutic choices. Current tools for detection of recurrence or metastasis are
less than optimal. Recent clinical trials with radiolabeled monoclonal antibodies
appear to provide more precise localization of prostate cancer in these clinical
circumstances. METHODS: Multicenter national trials of patients at relatively
high risk for metastasis at diagnosis and patients with biochemical evidence of
recurrence after prostatectomy underwent radioimmunoscintigraphy with capromab
pendetide. RESULTS: Tissue confirmation of scan results demonstrated a 15-fold
and 4-fold increase in sensitivity over computed tomography and magnetic
resonance imaging, respectively, for newly diagnosed patients. Preliminary data
have shown a 3- to 4-fold increase in durable complete response to radiation
therapy in patients with biochemical failure following radical prostatectomy.
CONCLUSIONS: Patients at relatively high risk for metastasis at diagnosis and
those with biochemical evidence of recurrence after prostatectomy may benefit
from radioimmunoscintigraphy.
PMID- 10761098
TI - The Current Status of the Pathology of Prostate Cancer.
AB - BACKGROUND: The pathology of prostate cancer in modern day medicine cannot be
understood simply in terms of tissue patterns or genetic abnormalities. Efforts
to accommodate changes in patient care delivery and reimbursement, combined with
an explosion in information, have wrought major changes in pathology. METHODS:
The author summarizes the current status of the pathology of prostate cancer in
light of these influences. The detection of prostate cancer in needle biopsies,
the diagnostic interpretations that tend to confuse clinicians, the prognostic
factors in prostate cancer, and the effects of radiotherapy and hormone therapy
on prostatic tissue are discussed. RESULTS: Collegial associations are difficult
to maintain when consultants are spatially separated and patients are shuttled
between primary care and specialty centers. Economic forces cannot be ignored,
regardless of the level of altruism of individual practitioners. A medical
environment governed by judgment and wisdom is difficult to maintain when
external forces and even patients themselves demand application of the latest
information to each case. CONCLUSIONS: Current trends in medicine offer almost as
many pitfalls as promises. Information gathering and transfer tend to marginalize
anatomic pathologists from patient care. Current pathology is affected by the
influences of medicolegal and economic forces.
PMID- 10761099
TI - Circulating Prostate Cancer Cells Detected by Reverse Transcription-Polymerase
Chain Reaction (RT-PCR): What Do They Mean?
AB - BACKGROUND: Molecular techniques have been developed recently to assess for
circulating tumor cells. This "molecular staging" of prostate cancer uses the
reverse transcription-polymerase chain reaction (RT-PCR) to detect cells that
contain PSA or PSMA in the bloodstream. Currently, the clinical application of
this concept is controversial. METHODS: The authors discuss the current status of
molecular biologic methods to detect circulating prostate cancer cells. They
report on the limitations of the technology and the advances that will allow the
quantification of these circulating cells. RESULTS: Studies generally indicate an
increasing level of PSA RT-PCR positivity as disease advances. However, reports
have been significantly diverse, and there is no clear explanation for this
disparity. CONCLUSIONS: The determination of the "circulating prostate cancer
cell load" by RT-PCR or other techniques may prove to be useful in the management
of patients with prostate cancer, but questions remain to be answered before we
can develop and assess new therapeutic strategies that will advance the treatment
of prostate cancer before metastasis becomes evident. A better understanding of
the biology of tumor cells present in the circulatory system is also needed.
PMID- 10761100
TI - Management of Hormone-Sensitive and Hormone-Refractory Metastatic Prostate
Cancer.
AB - BACKGROUND: Prostate cancer is a significant health problem in the United States
and is the focus of increasing attention in our society. With the aging of the US
population, it is likely that prostate cancer will continue to grow in
importance. The options for systemic therapy of metastatic prostate cancer should
be familiar to physicians, including nonspecialists, whose patients seek their
advice and counsel. METHODS: Past and recent literature was surveyed to provide
an understanding of the systemic treatment of advanced prostate cancer. The
author presents a review of the systemic treatment of metastatic prostate cancer
in different clinical circumstances and addresses the current status of
chemotherapy in the management of advanced prostate cancer. RESULTS: Early
androgen deprivation used over prolonged periods appears to be modestly superior
to delayed androgen deprivation with a small potential survival advantage and an
advantage in delaying disease progression in advanced prostate cancer. Patients
with hormone-refractory prostate cancer may benefit from secondary hormonal
therapy (eg, adrenal enzyme inhibitors, antiandrogens, glucocorticoids) and
chemotherapy. CONCLUSIONS: The choices of therapy for metastatic prostate cancer
depend on individual patient preference. Patients and physicians should be aware
of the possible side effects associated with the therapeutics options for
treatment of metastatic prostate cancer.
PMID- 10761101
TI - The Current Status of Gene Therapy for Prostate Cancer.
AB - BACKGROUND: Due to limitations of local and systemic therapies for prostate
cancer, interest has continued in the development of new treatment modalities.
Gene therapy has emerged as a new approach that may prevent or treat disease by
using the therapeutic information encoded in DNA sequences. Several institutions
are actively experimenting with this approach. METHODS: The authors review the
most common genetic alterations in prostate cancer, the principles of gene
therapy, and gene delivery including both viral and nonviral vectors. Treatment
strategies for both cytoreductive gene therapy as well as corrective gene therapy
are described, and the available protocols to date with gene therapy for the
treatment of prostate cancer are presented. RESULTS AND CONCLUSIONS: More than
150 active protocols are ongoing to evaluate gene therapy in the treatment of
cancer, with 13 of these open for patients with prostate cancer. The future of
gene therapy as applicable to prostate cancer depends on additional development
of vector systems and a better understanding of the genes involved in tumor
induction and proliferation. Although gene therapy is clearly in its infancy, it
is in an explosive growth phase and holds tremendous promise as a treatment
modality for prostate cancer.
PMID- 10761102
TI - The Evolving Arena of Bone Marrow/Peripheral Blood Stem Cell Transplantation.
PMID- 10761103
TI - Prostate Cancer Imaging.
PMID- 10761104
TI - The Role of Immunohistochemistry in the Diagnosis of Primary Tumors of the Bone.
PMID- 10761105
TI - Development of an insulated reporter system to search for cis-acting DNA
sequences required for dosage compensation in Drosophila.
AB - Dosage compensation (equalization of X-linked gene products) occurs in Drosophila
melanogaster by a two-fold transcriptional increase of X-linked gene expression
in the male. The cis-acting X-linked DNA sequences required for dosage
compensation (called DCREs) remain elusive, despite numerous attempts to identify
them. We have developed an insulated reporter system to minimise problems
previously encountered with identifying these elements. The system consists of
the constitutive autosomal armadillo promoter fused to the lacZ reporter gene
(called arm-lacZ) which was flanked by SCS insulator elements to block potential
repressive effects of an autosomal chromatin environment. Seven X-linked DNA
fragments, totaling 62.7 kb, were each inserted between the SCS element and the
armadillo promoter. If an X-linked fragment contains a DCRE, then transgenic
males carrying an autosomal insert of the construct should produce twice the beta
galactosidase activity of females. However, in all cases, males and females
expressed the same level of lacZ. Thus, it's likely that none of the X-linked
fragments contained a DCRE, suggesting these elements may be rarer than
previously thought. The insulated reporter system was also used to test the
hypothesis that some genes may be dosage compensated due to repression by Sex
lethal (Sxl) in females. A fragment from the runt gene containing three Sxl
binding sites was inserted into the 3' untranslated region of arm-lacZ.
Transgenic males carrying an autosomal insert of the construct had on average
1.31-1.46 times the level of beta-galactosidase than females, suggesting that
some genes could be compensated, at least partially, by Sxl repression in
females.
PMID- 10761106
TI - Limited genetic variation in Lacerta mixta and its parthenogenetic daughter
species: evidence from cytochrome b and ATPase 6 gene DNA sequences.
AB - Little mtDNA variation was observed among populations of the bisexual Caucasian
rock lizard Lacerta mixta and unisexual L. dahli and L. armeniaca. Three
haplotypes were detected in L. mixta and the maximum pairwise difference among
the samples was 0.67%. No intra- and interspecific variation was found among
populations of either L. armeniaca or L. dahli. Moreover, both unisexual species
were identical to one of the three haplotypes of L. mixta. The limited variation
in L. mixta is likely the result of bottleneck effect, although the small sample
size may also be responsible. The lack of variation in the unisexual was
attributed to the restricted variation among the maternal parents, limited
involvement of females in the hybridization, and recent origin.
PMID- 10761107
TI - A sequence similar to bacterial transposable IS elements present in the 5'
untranslated region of the bovine butanediol dehydrogenase cDNA.
AB - A sequence similar to prokaryotic transposable elements was identified in the
long 5' untranslated region (5'UTR) of the butanediol dehydrogenase cDNA isolated
from a bovine brain lambda gt11 library. Several observations suggested that this
sequence could be related to bacterial IS elements: (a) 58% nucleotide sequence
identity, (b) 56% amino acid sequence identity, and (c) the presence of inverted
terminal repeats. However, nucleotide sequence analyses of the 5'UTR bovine cDNA
showed the presence of chain-terminating nucleotide substitutions that would
render it incapable of encoding a functional transposase. Finally, it was
observed that different vertebrate genomes have sequences related to this
putative transposable element.
PMID- 10761108
TI - Structural instability of 297 element in Drosophila melanogaster.
AB - 297 element Southern pattern modifications previously detected in mutation
accumulation lines of Drosophila melanogaster were further investigated by in
situ hybridisation, Southern blotting with different combinations of genomic
digest-probe, and PCR. Only one out of the nine pattern modifications studied
could be interpreted as an excision and was detectable by in situ hybridisation
to polytene chromosomes. Results were consistent with most pattern modifications
being small rearrangements within the body of the element. In agreement with the
existence of spontaneous rearrangements of this kind is the observation that many
genomic copies of element 297 are defective and these are not limited to
heterochromatin. These findings have important implications for the models of
transposable element (TE) number regulation as well as for the study of genome
evolution.
PMID- 10761109
TI - Microspatial genetic differentiation for tolerance and utilization of various
alcohols and acetic acid in Drosophila species from India.
AB - In five Indian localities, it was possible to collect D. melanogaster in two
different types of habitats, namely ordinary domestic and alcohol rich ones.
Tolerance and utilization capacity of several alcohols and of acetic acid were
analyzed in a total of 10 local populations. Results on two other species (D.
repleta and D. immigrans) were also available from one place. In each locality,
the population from alcohol rich habitat proved to be more tolerant to all the
investigated products and also to be more capable of using them as a resource.
Alcohols toxicity increased with increasing carbon chain length and secondary
alcohols were more toxic than primary ones. Utilization capacity of all products
was relatively independent of their toxicity. Especially acetic acid, the
toxicity of which was low and similar to that of ethanol, was always a fairly
poor resource. From a genetic point of view, tolerance and utilization capacity
appeared as two relatively independent traits. Natural selection, which is
responsible for the genetic differentiation of local populations, is likely to
act simultaneously on both traits.
PMID- 10761110
TI - The distribution of the P-M hybrid dysgenesis system in Drosophila melanogaster
strains from Brazil.
AB - Wild-caught flies of Drosophila melanogaster from seven natural populations of
extreme regions of Brazil (Sao Luis, MA; Teresina, PI; Rio Cipo, MG; Maringa, PR;
Sao Jose do Rio Preto, SP; Joinville, SC; and Porto Alegre, RS) were studied with
the purpose of evaluating hybrid dysgenesis due to mobilization of P elements and
the regulatory capacity of the strains' cytotypes. Diagnostic crosses were made
and the strains classified according to their P-M phenotypes. Four strains were
classified as moderate P (MA, MG, PI, and SP), two as Q (PR and RS) and one as M'
(SC). Females of southern strains (PR, SC, and RS) presented in A crosses lower
degrees of gonadal dysgenesis scores than those from northern strains (MA and
PI).
PMID- 10761111
TI - Multipoint genetic mapping of quantitative trait loci with dominant markers in
outbred populations.
AB - We present a multipoint algorithm for mapping quantitative trait loci (QTLs)
using dominant markers. The algorithm is designed for outbred populations and is
particularly suited for large families. The algorithm works with either
codominant or dominant markers, either of which may be interspersed within the
same linkage map. Concurrently, the algorithm also partitions dominance variance
at the QTL. Computer simulations show that with large families, QTL mapping with
dominant markers can be almost as powerful as with bi-allelic, codominant
markers. Yet despite this, other situations show a large standard deviation in
the estimate of the QTL position, thus making QTL mapping with dominant markers
in outbred populations a useful detection tool, albeit limited in its resolution.
PMID- 10761112
TI - Banded karyotype of spined loach Cobitis taenia and triploid Cobitis from Poland.
AB - The present work provides new data on the banding pattern of diploid Cobitis
taenia and its triploid hybrid females, which belong to the diploid-polyploid
complex in the Vistula River tributary. C-banding, silver-staining (Ag), and
fluorescent staining with chromomycin A3 techniques were used to describe the
diploid and triploid karyotype. The karyotype of Cobitis taenia of 2n = 48 was
characterised by one pair of NOR-bearing subtelocentric chromosomes and at least
four chromosomes with CMA3-positive sites. The C-positive heterochromatin was
present in the centromeres of almost all chromosomes and the pericentromeric
regions of several metacentric and submetacentric chromosomes. The triploid
females of 3n = 74 had two pairs of chromosomes with active NORs. The NORs-sites
were located terminally on two biarmed and two uniarmed chromosomes. The CMA3
staining revealed at least six A3-positive sites. The C-banded and A3-stained
triploid karyotype was composed of haploid set of Cobitis taenia and diploid set
of unidentified species, so heterochromatin pattern confirmed the possibility of
their hybrid origin. The characteristics of banded diploid and triploid
karyotype, and the hypothetical karyotype of an unknown species of 2n = 50 is
discussed.
PMID- 10761113
TI - NOR polymorphism in the Iberian species Chondrostoma lusitanicum (Pisces:
Cyprinidae)--re-examination by FISH.
AB - Chromosomal polymorphism regarding the number of chromosomal NOR sites in the
cyprinid fish Chondrostoma lusitanicum reported previously (Rodrigues & Collares
Pereira, 1996) was re-examined using fluorescence in situ hybridization (FISH)
with a ribosomal DNA (rDNA) probe. All positive CMA3-bands contained ribosomal
DNA documented by either two or four FISH positive signals in the respective
karyotypes. This polymorphism suggests the occurrence of structural
rearrangements of translocation type in rDNA region from one ancestral NOR
bearing chromosome pair ubiquitous among leuciscine cyprinid fishes to another
pair. The absence of individuals heterozygous for this polymorphism is discussed.
PMID- 10761114
TI - Factors controlling lineage specification in the neural crest.
AB - The neural crest is a transitory tissue of the vertebrate embryo that originates
in the neural folds, populates the embryo, and gives rise to many different cell
types and tissues of the adult organism. When neural crest cells initiate their
migration, a large fraction of them are still pluripotent, that is, capable of
generating progeny that consists of two or more distinct phenotypes. To elucidate
the cellular and molecular mechanisms by which neural crest cells become
committed to a particular lineage is therefore crucial to the understanding of
neural crest development and represents a major challenge in current neural crest
research. This chapter discusses selected aspects of neural crest cell
differentiation into components of the peripheral nervous system. Topics include
sympathetic neurons, the adrenal medulla, primary sensory neurons of the spinal
ganglia, some of their mechanoreceptive and proprioceptive end organs, and the
enteric nervous system.
PMID- 10761115
TI - Phospholipid transfer proteins and physiological functions.
AB - Issues of how cells generate and maintain unique lipid compositions in distinct
intracellular membrane systems remain the subject of much study. A ubiquitous
class of soluble proteins capable of transporting phospholipid monomers from
membrane to membrane across an aqueous milieu has been thought to define part of
the mechanism by which lipids are sorted in cells. Progress in the study of these
phospholipid transfer proteins (PLTPs) raises questions regarding their
physiological functions in cells and the mechanisms by which these proteins
execute them. It is now clear that across the eukaryotic kingdom, members of this
protein family exert essential roles in the regulation of phospholipid metabolism
and central aspects of phospholipid-mediated signaling. Indeed, it is now known
that dysfunction of specific PLTPs defines the basis of inherited diseases in
mammals, and this list is expected to grow. Phospholipid transfer proteins, their
biochemical properties, and the emerging clues regarding their physiological
functions are reviewed.
PMID- 10761116
TI - Dendritic cell dynamics in the liver and hepatic lymph.
AB - Dendritic cells (DC) are bone-marrow-derived cells that function as professional
antigen-presenting cells (APC). Liver is an essential organ for a host defense.
It not only is armed with a powerful macrophage system but also is constantly
surveyed by a heavy traffic of DC and lymphocytes. In case of emergency, such as
infection and inflammation, DC traffic in the liver is accelerated. DC in the
liver (interstitial DC) capture and process antigens, enter the draining lymph
(DC in hepatic lymph) and accumulate in the T-cell area of hepatic lymph nodes
(LN). DC in the LN present antigens to T and B cells to initiate immune
responses. In accelerated states, DC precursors are recruited to the liver and
soon translocate to hepatic lymph. Even mature lymph DC can undergo a blood-lymph
translocation from the liver to hepatic LN after i.v. injection into normal rats.
Rat Kupffer cells in the hepatic sinusoids are capable of selectively trapping DC
from the blood in vivo and in vitro, suggesting involvement of certain adhesion
molecules. Kupffer cells presumably elaborate chemokines to attract and trap the
recruited DC via selective adhesion, leading to DC extravasation. The accelerated
traffic and the presence of blood-lymph translocation would induce rapid and
efficient immune responses and thus contribute to the local defense to antigens
within liver tissues as well as systemic defense to blood-borne antigens. DC
progenitors are also present in the liver, and these may play an important role
in tolerance induction in liver transplantation.
PMID- 10761117
TI - Protooncogenes as mediators of apoptosis.
AB - Apoptosis has been well established as a vital biological phenomenon that is
important in the maintenance of cellular homeostasis. Three major protooncogene
families and their encoded proteins function as mediators of apoptosis in various
cell types and are the subject of this chapter. Protooncogenic proteins such as c
Myc/Max, c-Fos/c-Jun, and Bcl-2/Bax utilize a synergetic effect to enhance their
roles in the pro- or antiapoptotic action. These family members activate and
repress the expression of their target genes, control cell cycle progression, and
execute programmed cell death. Repression or overproduction of these
protooncogenic proteins induces apoptosis, which may vary as a result of either
cell type specificity or the nature of the apoptotic stimuli. The proapoptotic
and antiapoptotic proteins exert their effects in the membrane of cellular
organelles. Here they generate cell-type-specific signals that activate the
caspase family of proteases and their regulators for the execution of apoptosis.
PMID- 10761119
TI - The characterization of chemical structures using molecular properties. A survey
PMID- 10761118
TI - Glial cells as targets and producers of neurotrophins.
AB - Glial cells fulfill important tasks within the neural network of the central and
peripheral nervous systems. The synthesis and secretion of various polypeptidic
factors (cytokines) and a number of receptors, with which glial cells are
equipped, allow them to communicate with their environment. Evidence has
accumulated during recent years that neurotrophins play an important role not
only for neurons but also for glial cells. This brief update of some
morphological, immunocytochemical, and biochemical characteristics of glial cell
lineages conveys our present knowledge about glial cells as targets and producers
of neurotrophins under normal and pathological conditions. The chapter discusses
the presence of neurotrophin receptors on glial cells, glial cells as producers
of neurotrophins, signaling pathways downstream Trk and p75NTR, and the
significance of neurotrophins and their receptors for glial cells during
development, in cell death and survival, and in neurological disorders.
PMID- 10761120
TI - Bit-string methods for selective compound acquisition
AB - Selective compound acquisition programs need to ensure that the compounds that
are chosen do not contain undesirable functionality. This is easy to achieve if a
supplier is prepared to provide unambiguous structure representations for the
compounds that they have available: this paper discusses selection techniques
that can be used when a supplier is prepared to make available only fragment bit
string representations for the compounds in their catalog. Experiments with three
databases and three types of bit-string show that a simple k-nearest-neighbor
searching method provides a surprisingly effective, although far from perfect,
way of selecting compounds when only bit-string representations are available. A
second approach, based on the use of a fragment weighting scheme analogous to
those used in substructural analysis studies, proved to be noticeably less
effective in operation.
PMID- 10761121
TI - Sensitivity analysis and other improvements to tailored combinatorial library
design
AB - "Tailoring" combinatorial libraries was developed several years ago as a very
general and intuitive method to design diverse compound collections while
controlling the profile of other pharmaceutically relevant properties. The
candidate substituents were assigned to "categorical bins" according to their
properties, and successive steps of D-optimal design were performed to generate
diverse substituent sets consistent with required membership quotas from each
bin. This serial algorithm was expedient to implement from existing D-optimal
design codes, but was order-dependent and did not generally locate the very best
possible design. A new "parallel" Fedorov search algorithm has now been
implemented that can find the most diverse property-tailored design. An ambiguous
mass penalty has been added, whereby most duplicate masses can be eliminated with
little loss of library diversity. Sensitivity analysis has also been added to
quantitatively explore the diversity trade-offs due to increasing or decreasing
each specific kind of bias.
PMID- 10761122
TI - Prediction of organic reaction products: determining the best reaction conditions
AB - We describe some of our most recent achievements concerning the selection of the
best set of reaction conditions for a specific reaction. In particular, we will
concentrate on the selection of the best solvent to minimize side reactions. The
solvent should favor a kinetically controlled reaction if it is a good solvent
for the transition state and a bad solvent for the ground state, decreasing the
activation energy. Consequently, we need the descriptions of the transition state
and of the state solvation. We generally apply the principle of "similarity in
solvation"; i.e., we calculate an approximate similarity between reactants,
transition states, and solvent molecules. The more the former are similar to the
latter, the more they are solvated. This permits the selection and the ordering
of the solvents. We considered other aspects of reaction conditions that will be
briefly commented on. Some results will be presented to illustrate the power of
the method.
PMID- 10761123
TI - Universal organic solvent-water partition coefficient model
AB - A method that permits a semiquantitative estimate of the partitioning of any
solute between any two media is presented. As an example, the organic solvent
water partition coefficients P are calculated. Program GSCAP is written as a
version of Pascal's SCAP program. The only needed parameters are the dielectric
constant and molecular volume of the organic solvent. The log P results are
compared with the Pomona database. The average absolute deviation is 1.48 log
units and the standard deviation is 1.66 log units.
PMID- 10761124
TI - CerBeruS: a system supporting the sequential screening process
AB - This paper describes the general design and application of CerBeruS, a computer
based system for supporting the process of sequential screening. CerBeruS stands
for cluster-based selection, with cluster analysis forming the pivotal part of
the system. CerBeruS uses the Ward's clustering method for partitioning the data
set to be screened into smaller, more homogeneous subsets. One representative is
picked from each subset and suggested as a screening candidate. Although the
number of compounds submitted to screening is most often driven by the capacity
of the assay, CerBeruS provides a statistical measure that computes the optimal
number of clusters in the data set. This measure forms a point of reference for
all screening experiments. Different hierarchies of subsets are stored in an
Oracle database. Information about the size and content of a cluster can be
retrieved from this database via a Visual Basic application. How these components
work together in the CerBeruS system is demonstrated on a large data set. In
addition, we show that, using the statistical measure, one can find an optimal
trade-off between screening effort and number of hits.
PMID- 10761125
TI - Flexsim-X: a method for the detection of molecules with similar biological
activity
AB - We describe the development of the method Flexsim-X, which can be used to detect
molecules with similar biological activity. This procedure is based on comparing
virtual affinity fingerprints made up from docking scores of the molecules with
respect to a reference set of binding sites. Using a test data set consisting of
ligands from five different activity classes and randomly chosen compounds, the
reference panel of binding sites was optimized in terms of size and composition.
Systematic approaches as well as genetic algorithm based (GA) optimization
procedures have been evaluated. Additionally, the effectiveness of the method is
illustrated.
PMID- 10761126
TI - New approach to molecular docking and its application to virtual screening of
chemical databases
AB - This paper describes the validation of a molecular docking method and its
application to virtual database screening. The code flexibly docks ligand
molecules into rigid receptor structures using a tabu search methodology driven
by an empirically derived function for estimating the binding affinity of a
protein-ligand complex. The docking method has been tested on 70 ligand-receptor
complexes for which the experimental binding affinity and binding geometry are
known. The lowest energy geometry produced by the docking protocol is within 2.0
A root mean square of the experimental binding mode for 79% of the complexes. The
method has been applied to the problem of virtual database screening to identify
known ligands for thrombin, factor Xa, and the estrogen receptor. A database of
10,000 randomly chosen "druglike" molecules has been docked into the three
receptor structures. In each case known receptor ligands were included in the
study. The results showed good separation between the predicted binding
affinities of the known ligand set and the database subset.
PMID- 10761127
TI - Enhancing the hit-to-lead properties of lead optimization libraries
AB - In this paper we address several issues in the design of lead optimization
libraries. Multipharmacophore descriptors were first developed in the context of
designing diverse compound libraries. One reason for favoring such descriptors is
the importance of the pharmacophore hypothesis in understanding the interaction
of a compound with a protein target. Allied to this is the proposal that sampling
over all potential pharmacophores leads to diversity in a biologically relevant
space. We present results in support of this argument and also demonstrate that
such methods are applicable to the design of focused libraries where the aim is
to design the library toward a known lead or leads. This portability is important
because it means that the same descriptors can be used for diverse library
design, screening set selection, and focused library design, giving a consistent
approach. We also examine the question of designing libraries with improved
pharmacokinetic properties and show that it is possible to derive simple and
rapidly computable descriptors applicable to the prediction of drug transport
properties. Furthermore, these can be applied in the context of library design,
although it may be necessary to synthesize libraries in a noncombinatorial manner
to obtain the best results. To address this problem, we describe a Monte Carlo
search procedure that allows the selection of a near-combinatorial subset in
which all library members satisfy the design criteria. We present an example from
our own work that illustrates how consideration of calculated log P, molecular
weight, and polar surface area in the design of a combinatorial library can lead
to compounds with improved absorption characteristics as determined by
experimental Caco-2 measurements.
PMID- 10761128
TI - Graph-theoretic techniques for macromolecular docking
AB - We propose a solution to the problem of docking two macromolecules. We represent
each of two proteins as a set of potential hydrogen bond donors and acceptors and
use a clique-detection algorithm to find maximally complementary sets of
donor/acceptor pairs. Preliminary results are presented which demonstrate the
feasibility of the method.
PMID- 10761129
TI - Potential drugs and nondrugs: prediction and identification of important
structural features
AB - Using decision trees, a model to discriminate between potential drugs and
nondrugs has been developed. Compounds from the Available Chemical Directory and
the World Drug Index databases were used as training set; the molecular
structures were represented using extended atom types. The error rate on an
independent validation data set is 17.4%. The number of false negatives can be
reduced by penalizing the misclassification of drugs so that 92 out of 100
potential drugs are correctly recognized. At the same time, 34 out of 100
nondrugs are classified as potential drugs. The predictions of the model can be
used to guide the purchase or selection of compounds for biological screening or
the design of combinatorial libraries. The visualization of the generated models
in the form of colored trees allowed us to identify a few, surprisingly simple
features that explain the most significant differences between drugs and nondrugs
in the training set: Just by testing the presence of hydroxyl, tertiary or
secondary amino, carboxyl, phenol, or enol groups, already three quarters of all
drugs could be correctly recognized. The nondrugs, on the other hand, are
characterized by their aromatic nature with a low content of functional groups
besides halogens. The general applicability of the model is shown by the
predictions made for several Organon databases.
PMID- 10761130
TI - How to add chemical abstracts service registry numbers and structures to
databases via chemical names comparison
AB - For the conversion of nonstructural chemical databases to structure databases, a
series of algorithms to find the closest match between existing names to names in
a reference database are described. On the basis of the best match, new fields
such as the Chemical Abstracts Service Registry Number (CASRN) or structures were
added to the database.
PMID- 10761131
TI - Similarity searching in files of three-dimensional chemical structures: analysis
of the BIOSTER database using two-dimensional fingerprints and molecular field
descriptors
AB - This paper compares the effectiveness of similarity measures based on two
dimensional fingerprints and on molecular fields for identifying pairs of
bioisosteric molecules in the BIOSTER database. The results suggest that the two
types of descriptor are complementary in nature, each finding some bioisosteric
pairs that are not found by the other. This conclusion is confirmed by studies of
groups of BIOSTER molecules that share the same activity characteristics, and by
experiments that involve combining the two types of similarity measure.
PMID- 10761132
TI - Substructure isomorphism matrix
AB - A substructure isomorphism matrix n x p contains binary elements describing which
of the given p query structures (substructures) are part of the given n target
structures (molecular structures). Such a matrix can be used to investigate the
diversity of the target structures and allows the characterization and comparison
of structural libraries. A quadratic substructure isomorphism matrix n x n is
obtained if the same structures are used as molecular structures and as
substructures; this matrix contains full information about the topological
hierarchy of the n structures. A hierarchical arrangement of chemical structures
is useful for the evaluation of results obtained from searches in structure
databases.
PMID- 10761134
TI - JChem: Java applets and modules supporting chemical database handling from web
browsers
AB - A Java based development tool for building portable chemical information systems
is presented. The system contains applets for constructing web-based interfaces
and classes that add structure handling to relational databases. Custom
applications built with JChem can combine SQL and structural queries.
PMID- 10761133
TI - Diversity measures for enhancing ADME admissibility of combinatorial libraries.
AB - For general screening libraries, structural diversity descriptors and drug
likeness indicators still do not guarantee the in vivo bioavailability for the
candidates, which is considered a major bottleneck in drug development. Early
prediction of pharmacokinetics (log P, log D), metabolism, and toxicity makes it
possible to deal with ADME (adsorption, distribution, metabolism, excretion)
related diversity as an extension to the classical diversity concepts. It opens
several new possibilities for optimization of a discovery library before doing
any experimental screening. This new diversity concept is demonstrated on a
subset of MeDiverse, which is a diverse collection of pharmacologically relevant
compounds selected from our in-house library. From consideration of the ADME
interface in living systems, virtual secondary libraries of metabolites and
retrometabolites (prodrugs) can be generated. These additional libraries readily
enhance both the structural and ADME related diversity. This new opportunity in
library design can substantially improve the success rate for in vivo lead
generation from in vitro hits.
PMID- 10761135
TI - Fuzzy definition of molecular fragments in chemical structures
AB - This paper presents a methodology for seeking the relationships between chemical
substructures (molecular fragments) and spectral parameters using a computer
collection data of molecular spectra. To establish the spectrum-structure
correlations, the program has to search the chemical structure base in order to
find compounds containing a given molecular fragment in the molecule. There
exists no sole definition of a substructure, as it always depends on the type of
problem dealt with. In the problem of structural identification, fuzzy
definitions of substructures are applied, and their forms are imposed by the
spectral methods used.
PMID- 10761136
TI - Automatic generation of knowledge base from infrared spectral database for
substructure recognition
AB - This paper presents a new methodology of chemical substructure recognition by
interpretation of an infrared spectrum. The approach in spectrum interpretation
is based on the determination of functional groups, which may be present or
absent in compounds whose structure is unknown. The process of searching for
spectrum-substructure correlation is realized by application of a statistical
algorithm. In this method, correlations are generalized and condensed into a set
of interpretation rules which are applied to the interpretation of an unknown
compound's spectrum in order to predict whether the respective substructures are
present or absent in the unknown molecule.
PMID- 10761137
TI - Novel treatment of conformational flexibility using interval analysis
AB - A revolutionary new flexible conformational search technique is presented
together with its application to geometrical docking. The algorithm is guaranteed
to find all (even an infinite number of) solutions in a continuous manner.
Examples are given using 2-(4'-amidinophenyl)pyruvate (APPA) docked to trypsin.
Other potential applications are briefly discussed.
PMID- 10761138
TI - Expert system assisted pharmacophore identification
AB - An expert system for automatic perception of pharmacophoric groups is presented.
Important features include consideration of the protonation state at
physiological pH and detection of potential tautomerism. This perception
information is used in the generation of pharmacophores using clique detection.
PMID- 10761139
TI - Correlating the molecular electrostatic potentials of some organic peroxides with
their antimalarial activities.
AB - The molecular electrostatic potentials (MEPs) of artemisinin (also known as
qinghaosu), yingzhaosu A, and some synthetic analogues have been calculated and
studied as a means of distinguishing between high and low antimalarial activity.
To facilitate comparison, the dimensionality of the MEP was reduced by Kohonen
Neural Network transforms. The reduction revealed that peroxides exhibiting high
antimalarial activity are characterized by a continuous strip of negative
electric potential surrounding the molecule, whereas peroxides of lesser activity
show a broken strip.
PMID- 10761140
TI - Thermochemical database of Halomethanes, Halosilanes, Halophosphines, and
Haloamines
AB - An accurate thermochemical database for 28 halides of carbon, silicon, nitrogen,
and phosphorus is presented. The database provides improved standard enthalpies
of formation for several compounds of ecological importance (CH3F, CF2Cl2, CFCl3)
together with enthalpies of other compounds which are not known due to
experimental difficulties in measuring their enthalpies. We also present a
comparison of the latest ab initio methods (CBS-QB3 and G3) which are used for
thermochemical predictions. The comparison shows that the G3 method consistently
underestimates delta H degree f by 1-2 kJ/mol (relative to CBS-QB3).
PMID- 10761141
TI - Isomer generation: semantic rules for detection of isomorphism
AB - The problem of exhaustive generation of a nonredundant set of structural formulas
(graphs) of acyclic alkanes was considered. A technique based on the compressed
adjacency matrix (CAM) was proposed. The algorithm generates CAMs, which encode
trees numbered according to the Morgan naming algorithm. Out of this set of CAMs
those corresponding to the maximal Morgan codes--which in fact are the CAMs of
canonically numbered isomers--must be found. CAMs are conceived as "sentences" of
a primitive language. Sentences violating the syntactic and semantic rules of
this language have to be discarded. In this paper three semantic rules have been
proposed. The algorithm devised is efficient, and the decision to retain or to
reject the actual structure does not involve any comparison with other
structures. It was proved that several subsets of CAMs will not contain any
maximal CAM and therefore it is not necessary to generate them. The whole
procedure was illustrated by generating CAMs of all acyclic graphs containing
nine vertices.
PMID- 10761143
TI - Duplications among reaction databases
AB - We have examined the extent of duplication in 16 reaction databases from four
commercial sources, totaling nearly a million reactions, by converting them to a
common format for comparison. The overlap is surprisingly small, less than 3%.
PMID- 10761142
TI - Mining and visualizing large anticancer drug discovery databases.
AB - In order to find more effective anticancer drugs, the U.S. National Cancer
Institute (NCI) screens a large number of compounds in vitro against 60 human
cancer cell lines from different organs of origin. About 70,000 compounds have
been tested in the program since 1990, and each tested compound can be
characterized by a vector (i.e., "fingerprint") of 60 anticancer activity, or
[log(GI50)], values. GI50 is the concentration required to inhibit cell growth by
50% compared with untreated controls. Although cell growth inhibitory activity
for a single cell line is not very informative, activity patterns across the 60
cell lines can provide incisive information on the mechanisms of action of
screened compounds and also on molecular targets and modulators of activity
within the cancer cells. Various statistical and artificial intelligence methods,
including principal component analysis, hierarchical cluster analysis, stepwise
linear regression, multidimensional scaling, neural network modeling, and genetic
function approximation, among others, can be used to analyze this large activity
database. Mining the database can provide useful information: (a) for the
development of anticancer drugs; (b) for a better understanding of the molecular
pharmacology of cancer; and (c) for improvement of the drug discovery process.
PMID- 10761144
TI - Coverage of Indian leather patents in chemical abstracts
AB - Patent information is increasingly becoming important in the current context of
international trade and commerce. The printed version of Chemical Abstracts still
continues to be used heavily, and it was evaluated as the source of information
on Indian patents using leather patents as a case study. The results of the study
are given.
PMID- 10761145
TI - Regarding enumeration of molecular isomers
AB - In this paper, a simple theoretical approach to counting of substitution isomers
is described. It is based on Polya's theorem and on point groups as recently
described by us [Baraldi, I.; Fiori, C.; Vanossi, D. J. Math. Chem. 1999, 25, 23
30] and extended in this paper. Several applications are developed that range
from molecules without symmetry to molecules with icosahedral symmetry (Ih). The
problem of the appearance of stereoisomers is also analyzed.
PMID- 10761146
TI - A novel quantum-topology index
AB - By modifying the delta values of molecular connectivity indexes, new quantum
topology descriptors are presented in this paper. Their ability to describe
molecular structure, both geometric and electronic, is established by correlating
them with the bonding energy (E), force constant (kappa), and radius (R) of a
heterogeneous set of monohydrides, as well as with the solubility in water -log
S, hydrophobic constants -log P, and molecular volumes of halogenobenzenes and
the standard heat of formation of SiXn (n = 1-4, X = F, Cl, Br, I). Moreover, it
is clearly demonstrated that this ability is greater than that shown by the chi
connectivity indexes.
PMID- 10761147
TI - Nonlinear multivariate regression outperforms several concisely designed neural
networks on three QSPR data sets
AB - Neural networks (NNs) are accepted as the most powerful nonlinear technique in
QSAR and QSPR modeling. However, the NN models are often very robust, containing
a large number of parameters optimized during the training procedure. We have
recently found (J. Chem. Inf. Comput. Sci. 1999, 39, 121-132) that the simpler
nonlinear multiregression (MR) models are significantly better than the robust
NNs, according to the same statistical parameters. In the present paper we
investigated whether the nonlinear MR models are also better than the concisely
designed NN models. Nonlinear MR models were generated in the following way.
First, nonlinear terms, the 2-fold and 3-fold cross-products of initial
descriptors, were calculated and added to initial descriptors. Then, the
combination of two powerful techniques for descriptor selection (CROMRsel for
"the best" selection and CROMRiisel for approximative, "i by i" stepwise
selection) were used to detect the most important descriptors in MR models. For
boiling points (BPs) of 150 alkanes the 20-descriptor MR model produced the cross
validated (CV) standard error of 2.88 K, and the best NN model (with 70-80
adjusted weights) had 3.60 K. Prediction of BPs of 50 compounds using the 17
descriptor MR model (obtained on 100 compounds) gave the standard error of 3.58
K. In the case of modeling of 243 chemical shifts CV standard errors were (in
ppm) 0.89 and 1.19 with 15- and 9-descriptor MR models, respectively. The best NN
models adjusted 60-90 weights and achieved 1.42 ppm. The standard error in
predicting the 83 chemical shifts using the 10-descriptor MR model obtained on
160 samples was 1.25 ppm. It is also shown in this data set that the model
quality depends on the scaling procedure used for transformation of the initial
descriptors. In modeling the sublimation enthalpy the CV correlation coefficient
was 0.97 using the best 4-descriptor MR model versus 0.93 obtained using NN with
approximately 50 adjusted weights. The CV correlation coefficient in predicting
the sublimation enthalpies for 21 compounds using the 4-descriptor MR model was
0.98. This is, to our knowledge, the first unambiguous result which shows a way
for obtaining nonlinear MR models having better fitted, cross-validated, and
predictive performances than the corresponding NN models. Moreover, the nonlinear
MR models are significantly simpler than the NN models, which allows one to
establish the functional relationships between the modeled property/activity and
descriptors.
PMID- 10761148
TI - Molecular dataset diversity indices and their applications to comparison of
chemical databases and QSAR analysis
AB - A new mutual molecular dataset diversity index (MMDDI), individual molecular
dataset diversity index (IMDDI), and volume ratio (VR) are proposed to assess
molecular dataset diversity. MMDDI and IMDDI can serve as valuable instruments
for selecting monomer pools for combinatorial synthesis and in decision making
about acquiring new databases. MMDDI can also be used as one of the criteria to
estimate the quality of quantitative structure-activity relationship (QSAR)
models aimed at the prediction of biological activities. The indices can be
calculated directly from molecular descriptor values. The procedures applied for
MMDDI and IMDDI calculations allow one to automatically compile lists of
compounds, which can simplify molecular diversity analyses and database
searching. The information can also be used for forming training and test sets in
QSAR analysis.
PMID- 10761149
TI - Combinatorial enumeration of nonrigid isomers with given ligand symmetries on the
basis of promolecules with a subsymmetry of D infinity h
AB - To enumerate nonrigid isomers with given ligand symmetries on the basis of a D
infinity h skeleton, the concept of extended partial cycle indices (extended
PCIs) proposed newly has been combined with the concept of promolecules proposed
previously. The infinite nature of the D infinity h-group is concealed by
adopting the factor group of finite order, D infinity h/C infinity (= K). Thus,
the partial cycle indices with chirality fittingness (PCI-CFs) for the factor
group K are calculated and combined with the PCIs for ligand symmetries so as to
give the extended PCIs for various itemized enumurations. This method has been
successfully applied to the enumeration of ethane derivatives, where the full
enumeration based on K has been compared with partial enumerations based on K as
well as with those based on the factor group C infinity h/C infinity (= K3
[symbol: see text] K). Each term of the resulting generating functions has been
factorized into a pair of factors to represent ligand constitutions. Thereby, the
depiction of resulting molecules can be conducted systematically so as to provide
the maps of ethane derivatives corresponding to all of the substitution types.
PMID- 10761150
TI - Chemometrics: an important tool for the modern chemist, an example from wood
processing chemistry
AB - This study briefly outlines the idea of principal component analysis and cross
correlation calculations (applied chemometrics) and presents an illustrative
example from wood-processing chemistry. The applicability of chemometric data
analysis was demonstrated by investigating the various structural changes that
take place in dissolved and degraded lignin ("kraft lignin") during laboratory
scale kraft pulping of Scots pine (Pinus sylvestris) and silver birch (Betula
pendula). The structural data (31P NMR and size exclusion chromatographic data)
on kraft lignin were further processed by chemometric multivariate techniques
(PCA and 2DCC), confirming, for example, that the cleavage of beta-aryl ether
structures, the most prominent linkages between monomeric units, is directly
related to the decrease in the average molecular mass of lignin.
PMID- 10761151
TI - Fast similarity search in three-dimensional structure databases
AB - Given a database D of three-dimensional (3D) molecular structures and a target
molecule Q, the similarity search problem is to find the molecules O in D that
match Q after allowing for an arbitrary number of whole-structure rotations and
translations as well as a certain number of edit operations. The edit operations
include relabeling an atom, deleting an atom, and inserting an atom. This search
operation arises in many biochemical applications. In this paper we study the
similarity search problem and a class of related queries. We present a computer
vision based technique, called geometric hashing, for processing these queries.
Experimental results on a database of 3D molecular structures obtained from the
National Cancer Institute indicate the good performance of the presented
technique.
PMID- 10761152
TI - Nonparametric regression applied to quantitative structure-activity relationships
AB - Several nonparametric regressors have been applied to modeling quantitative
structure-activity relationship (QSAR) data. The simplest regressor, the Nadaraya
Watson, was assessed in a genuine multivariate setting. Other regressors, the
local linear and the shifted Nadaraya-Watson, were implemented within additive
models--a computationally more expedient approach, better suited for low-density
designs. Performances were benchmarked against the nonlinear method of smoothing
splines. A linear reference point was provided by multilinear regression (MLR).
Variable selection was explored using systematic combinations of different
variables and combinations of principal components. For the data set examined, 47
inhibitors of dopamine beta-hydroxylase, the additive nonparametric regressors
have greater predictive accuracy (as measured by the mean absolute error of the
predictions or the Pearson correlation in cross-validation trails) than MLR. The
use of principal components did not improve the performance of the nonparametric
regressors over use of the original descriptors, since the original descriptors
are not strongly correlated. It remains to be seen if the nonparametric
regressors can be successfully coupled with better variable selection and
dimensionality reduction in the context of high-dimensional QSARs.
PMID- 10761153
TI - Stochastic similarity selections from large combinatorial libraries
AB - A stochastic procedure for similarity searching in large virtual combinatorial
libraries is presented. The method avoids explicit enumeration and calculation of
descriptors for every virtual compound, yet provides an optimal or nearly optimal
similarity selection in a reasonable time frame. It is based on the principle of
probability sampling and the recognition that each reagent is represented in a
combinatorial library by multiple products. The method proceeds in three stages.
First, a small fraction of the products is selected at random and ranked
according to their similarity against the query structure. The top-ranking
compounds are then identified and deconvoluted into a list of "preferred"
reagents. Finally, all the cross-products of these preferred reagents are
enumerated in an exhaustive manner, and systematically compared to the target to
obtain the final selection. This procedure has been applied to produce similarity
selections from several virtual combinatorial libraries, and the dependency of
the quality of the selections on several selection parameters has been analyzed.
PMID- 10761154
TI - Mean Wiener numbers and other mean extensions for alkane trees
AB - The "Wiener number" (the sum over intersite graph distances of a structure) as
averaged over all alkane structural isomers of a fixed number N of carbon atoms
is considered. This and several other measures of average graphical "extension"
of N-site alkanes are computed for N up to 90 (where there are over 10(35) such
isomers). Fits are then made for several surmised or derived asymptotic forms,
and a heuristic argument is made relating these results to geometric extensions
of a random mix of (N-site) alkanes.
PMID- 10761155
TI - Simulation of organic reactions: from the degradation of chemicals to
combinatorial synthesis
AB - Organic reactions can be run under a variety of conditions, from laboratory
experiments, through technical processes, to combinatorial chemistry. The scope
is further extended when the metabolism of compounds and the reactions in the
mass spectrometer are included. We present here several concepts: reactors,
phases, and modes, which, together with a kinetic modeling, allow the treatment
of such a broad scope of organic reactions. These concepts have been implemented
in a knowledge-based system, EROS. Several applications of this system to the
wide world of organic reactions are given.
PMID- 10761156
TI - Multiple flexible alignment with SEAL: a study of molecules acting on the
colchicine binding site.
AB - An extension of the steric and electrostatic alignment alignment (SEAL) method
(MultiSEAL) is described that allows the overlay of multiple molecules and
conformations. The method is well-suited for the systematic study of possible
alignments, also revealing information about the conformational energies
associated with a given overlay. It has been tested on three examples:
angiotensin II antagonists, 5-HT3 antagonists, and dopaminergic compounds. The
utility of the method is further demonstrated in an analysis of molecules that
putatively bind to the colchicine site of tubulin. On the basis of its overlay
with colchicine, allocolchicine, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone,
and combretastatin A-4, it appears that 2-methoxyestradiol (2-ME) is unlikely to
fit the colchine site properly. The weak antimitotic activity of 2-ME may be
explained by its partial fit in the site.
PMID- 10761157
TI - Partial molecular alignment via local structure analysis
AB - Molecular alignment remains as one of the most problematic aspects of molecular
design. A technique is introduced that facilitates the alignment of a range of
structures that could not be handled easily using existing alignment procedures.
The flexibility of the method is illustrated with a series of test sets. First,
an alignment is performed on a series of molecules from a typical 3D-quantitative
structure-activity relationship data set. The results of this test show the
technique to outperform many existing alignment methodologies based upon the
optimization of molecular similarity of molecular overlaps. This test set is then
extended to consider the alignment of more structurally diverse inhibitors of HIV
1 reverse transcriptase and HIV-1 protease. Finally, in the most challenging
test, a large protein-based inhibitor is matched with a small-molecule mimic. It
is believed that the existence of such a versatile alignment technique will prove
invaluable in the fields of molecular design and chemical information handling.
PMID- 10761158
TI - Prospective allometric scaling: does the emperor have clothes?
AB - We are not suggesting that an allometric relationship between pharmacokinetic
parameters in animals and humans does not exist; we believe that it does. We are
suggesting that using prospective AS to select doses in an FTIM study may lead to
a false sense of security given the large publication bias in the literature.
There are a number of unrecognized pitfalls to this approach, including (1)
prediction intervals so wide as to be of limited use, (2) prediction error is
often no better than arbitrarily chosen constants, and (3) it is not possible to
determine which drugs will fail a priori. We encourage journals to publish
studies in which prospective AS has failed so as scientists we may begin to see
what makes these compounds different, with a goal toward better prediction of
human pharmacokinetics.
PMID- 10761159
TI - Critique of prospective allometric scaling: does the emperor have clothes?
PMID- 10761160
TI - Rebuttal to Mahmood
PMID- 10761161
TI - Prokinetic effects of erythromycin after antimotion sickness drugs.
AB - Motion sickness and the antimotion sickness drugs scopolamine (SCP) and
promethazine (PMZ) inhibit gastric emptying (GE). This study was conducted to
determine if erythromycin would exert its well-known prokinetic effects in normal
and motion-sick subjects given antimotion sickness drugs. Fifteen fasted
volunteers (11 males, 4 females) participated in the study. In control tests, 8
subjects were given intramuscular (i.m.) saline (SAL, 0.5 ml), SCP (0.1 mg), or
PMZ (25 mg). GE of liquid (300 ml) containing 1 mCi of Tc 99m
diethylenetriaminepentaacetic acid (DTPA) was measured by sequential gastric
scintigraphy 30 minutes after i.m. treatments. In other tests, GE was measured in
8 subjects after each i.m. treatment, followed 10 minutes later by 200 mg of
erythromycin ethylsuccinate (ESS) suspension given orally. In a third group of
tests, 7 subjects received an i.m. treatment, oral EES 10 minutes later, and were
then brought to an advanced level of motion sickness short of vomiting. To induce
motion sickness, blindfolded subjects made timed head movements while seated in a
rotating chair. GE was measured immediately after rotation. GE half-life, rate
constant, area under the curve (AUC), and lag time were calculated using
conventional mathematical methods for analyzing exponential rate processes. GE
parameters calculated for normal and motion-sick subjects given antimotion
sickness drugs and EES were compared with those from subjects given i.m.
treatments (control) only. In normal subjects, EES significantly (p < 0.05)
increased the GE rate constant for all i.m. treatments and reduced the AUC for
SAL, SCP, and PMZ by 49% (p < 0.05), 44% (p < 0.05), and 69% (p < 0.01),
respectively. In motion-sick subjects, lag time was significantly (p < 0.05)
increased, and the rate constant and AUC values were unchanged from control for
all i.m. treatments. The authors conclude that oral EES reverses the gastrostatic
actions of the antimotion sickness drugs but does not affect the inhibition of
gastric emptying associated with motion sickness. The results suggest that motion
sickness and antimotion sickness drugs reduce GE through different mechanisms.
PMID- 10761162
TI - Pharmacokinetics of ketoprofen syrup in small children.
AB - Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti
inflammatory, and antipyretic properties. Its pharmacokinetics has not been
determined in small children. The objective here was to determine the
pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children.
Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and
Group 2 was from ages 2 to 7 years. Venous blood samples were collected before
drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC
method was used to determine plasma levels of ketoprofen. The lower limit of
quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed
rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3
micrograms/ml. The pharmacokinetics was similar between the two groups of
children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group
2, was similar to that reported in adults.
PMID- 10761163
TI - Acetaminophen controlled-release sprinkles versus acetaminophen immediate-release
elixir in febrile children.
AB - Current acetaminophen (APAP) formulations approved for antipyretic use in
children require up to five doses/day, which compromise compliance and risk
breakthrough fever over 4 hours after dosing. A total of 112 evaluable febrile
children received oral APAP-equivalent doses of either one dose of APAP
controlled release (CR) as sprinkles on applesauce or one dose q 4 hours x 2 of
APAP immediate-release (IR) elixir in an 8-hour, double-blind, double-dummy,
randomized, multicenter study. Prior or concurrent antibiotic use did not
significantly affect either the magnitude or the pattern of temperature reduction
during the 8-hour observation period. Significantly greater aural temperature
reductions were found with APAP-CR than with APAP-IR at 4 and 5 hours. However,
the 8-hour AUCs of temperature reduction were not significantly different between
treatments. Pharmacokinetic/pharmacodynamic modeling of APAP was performed in 8
patients with values in both treatments similar to previous results, except for
expected differences in AUC0-infinity. Similar 8-hour temperature reduction for
APAP-CR (one dose) and APAP-IR (two doses) demonstrates the efficacy of APAP-CR
as an antipyretic in children 2 to 11 years of age. A decrease in the number of
APAP daily doses and the prolonged antipyretic effect of APAP-CR may assist those
who care for febrile children at home.
PMID- 10761164
TI - Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen
1000 mg compared to tablet acetaminophen 1000 mg in postoperative dental pain: a
single-dose, double-blind, randomized, placebo-controlled study.
AB - This randomized, double-blind, placebo-controlled study compared the time to
onset of analgesia and the analgesic efficacy of two formulations of
acetaminophen 1000 mg--an effervescent solution and tablet--in 242 patients with
moderate or severe pain following dental surgery. Onset of analgesia was
determined using a two-stopwatch procedure. Analgesia was assessed over a 4-hour
period. Treatments were compared using standard indexes of pain intensity and
pain relief and summary measures. Both acetaminophen formulations were
significantly more effective than their corresponding placebo for all efficacy
assessments. The median time to onset of analgesia was significantly shorter with
effervescent acetaminophen (20 minutes) compared to tablet acetaminophen (45
minutes). During the first 45 minutes after administration, effervescent
acetaminophen was significantly more effective at each scheduled assessment time
than tablet acetaminophen. The median time to meaningful pain relief was
significantly shorter with effervescent acetaminophen (45 minutes) compared to
tablet acetaminophen (60 minutes). At 4 hours after administration, the pain
relief was significantly better with tablet acetaminophen than with effervescent
acetaminophen. No other significant differences were observed between the active
treatments. In conclusion, effervescent acetaminophen produces a significantly
faster onset of analgesia than tablet acetaminophen.
PMID- 10761165
TI - Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic
controlled-release OROS (methylphenidate HCl) formulation.
AB - Methylphenidate is used for the treatment of attention deficit hyperactivity
disorder (ADHD). OROS (methylphenidate HCl) is an osmotic controlled-release
delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS
(methylphenidate HCl) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd,
and the immediate-release (IR) formulation given as three 5 mg doses every 4
hours (tid) were compared in adults. In addition, the single- and multiple-dose
pharmacokinetics of the OROS formulation were studied. Following OROS
(methylphenidate HCl), there was a gradual increase in the mean methylphenidate
plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR
formulation, peak plasma concentrations were noted at approximately 4 hours.
Following the IR regimen, methylphenidate plasma concentrations fluctuated in
tandem with oral dosing; peak concentrations were noted at 6.5 hours. The
terminal half-life of methylphenidate was similar for the three formulations. The
dose-normalized methylphenidate Cmax for OROS (methylphenidate HCl) was
significantly lower than for IR and SR methylphenidate. The bioavailability of
methylphenidate and PPA from OROS (methylphenidate HCl) relative to the IR and SR
formulations was complete. Mean methylphenidate AUC and terminal half-life were
similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2
ng.h/mL and 3.9 hours) of OROS (methylphenidate HCl).
PMID- 10761166
TI - The pharmacokinetics and pharmacodynamics of losartan in continuous ambulatory
peritoneal dialysis.
AB - The pharmacokinetics and pharmacodynamics of losartan and its active metabolite,
E-3174, were studied in 8 stable, hypertensive continuous ambulatory peritoneal
dialysis (CAPD) patients. Following a 1-week washout period, subjects received
100 mg of losartan orally for 7 days. On Days 1 and 7, hemodynamic and hormonal
responses were determined, as were PK parameters on Day 7. Peritoneal
equilibration testing was performed pre-Day 1 and on Day 7. AUC0-24 and t1/2 for
losartan and E-3174 were 95 +/- 49.9 micrograms.min/mL and 176 +/- 82.1
micrograms.min/mL and 172.5 +/- 86.7 minutes and 628 +/- 575 minutes,
respectively. These values are similar to those of normal subjects and subjects
on hemodialysis. Peritoneal clearance of losartan and E-3174 was negligible. All
subjects demonstrated a substantial reduction in blood pressure with at least a
10 mmHg drop in diastolic BP. Plasma renin activity (PRA) values increased, but
aldosterone, endothelin, norepinephrine, and epinephrine values did not change
following 7 days of losartan. Losartan was well tolerated in all study subjects.
PMID- 10761167
TI - Cirrhosis does not affect the pharmacokinetics and pharmacodynamics of
clopidogrel.
AB - Clopidogrel, a new platelet ADP receptor antagonist used for the prevention of
vascular ischemic events, is converted to an active metabolite via the cytochrome
P450 system. Patients with cirrhosis may not metabolize drugs normally and may,
in addition, have a number of defects in the coagulation system. To assess the
effect of cirrhosis on the pharmacokinetics and pharmacodynamics of clopidogrel,
the authors performed an open-label, parallel-group study of 12 patients with
Child-Pugh Class A or B cirrhosis and 12 matched controls. All 24 subjects
received clopidogrel 75 mg PO QD for 10 days. Pharmacokinetics of clopidogrel and
the major metabolite SR 26334 were analyzed on Days 1 and 10; pharmacodynamics
were assessed by the inhibition of ADP-induced platelet aggregation and by
bleeding time prolongation factor. Pharmacokinetic analysis of clopidogrel was
limited due to low plasma concentrations arising from rapid hydrolysis to SR
26334. The Cmax at SS for clopidogrel was higher in cirrhotics than in normals.
However, exposures to the metabolite SR 26334, as measured by AUC(tau), were
comparable. At Day 10, there was not a statistically significant difference in
mean inhibition of platelet aggregation (49.2% +/- 38.6% in cirrhotics vs. 66.7%
+/- 7.5% in normals) or in bleeding time prolongation factor (1.64 +/- 0.49 in
cirrhotics vs. 1.54 +/- 0.87 in normals) between groups. No significant adverse
events, including bleeding events, were reported. In conclusion, there were no
significant differences in the pharmacokinetics and pharmacodynamics of
clopidogrel in this group of subjects with cirrhosis and matched normals.
Therefore, no dosage adjustment of clopidogrel is required in patients with Child
Pugh Class A or B cirrhosis.
PMID- 10761168
TI - Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR)
in patients with chronic spinal cord injury.
AB - Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently
being investigated for its therapeutic efficacy in ameliorating central
conduction deficits due to demyelination in patients with spinal cord injury
(SCI). The present open-label pharmacokinetic trial examined the absorption
characteristics of a sustained-release form of the drug in 25 SCI subjects with
chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL
occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For
paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly
less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in
the initial rate and extent of absorption, but not in total 4-AP bioavailability
over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/-
0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear
correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax.
These results confirm and extend previous observations of different rates of drug
absorption among SCI patients with lesions above and below the sympathetic
outflow (T6) and provide evidence of the absorption characteristics of this
sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.
PMID- 10761169
TI - Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside
phosphorylase inhibitor, following single and multiple oral doses in healthy
volunteers.
AB - The pharmacokinetic parameters of peldesine (BCX-34) were investigated after
single and multiple oral doses in two groups of healthy adult volunteers. The
pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was
simultaneously monitored. The first group of 8 subjects received an intravenous
dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A
second group of 12 subjects received 160 mg/m2 in four and in six divided doses
orally. Serial blood samples and total urine outputs were collected during dosing
and for at least 24 hours after the last dose was administered. One set of
samples was analyzed using high-pressure liquid chromatography/ultraviolet
(LC/UV) methods, validated for intact drug in human plasma and urine samples.
Another set of samples was analyzed for the biomarkers, inosine and 2'
deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or
electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine
and 2'-deoxyguanosine were calculated using noncompartmental methods and
correlated against the pharmacokinetic parameters of BCX-34. For the single-dose
study, the results exhibited linear pharmacokinetics over the dose range from 30
to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the
absolute bioavailability of the oral formulation was approximately 51%. Analysis
of urine in the first 24 hours of collection accounted for approximately 82% of
the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics
indicated that steady-state blood concentrations were achieved by 24 hours when
the drug was administered four or six times a day. A drug dose-related elevation
of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with
plasma inosine levels. However, analysis of urine samples showed an increase in
inosine output with an increase in the drug dose. The calculated terminal half
life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h,
respectively.
PMID- 10761170
TI - Flow cytometric assessment of effects of fluvastatin on low-density lipoprotein
receptor activity in stimulated T-lymphocytes from patients with heterozygous
familial hypercholesterolemia.
AB - To test the effects of fluvastatin on low-density lipoprotein (LDL) receptor
activity in patients with heterozygous familial hypercholesterolemia, the authors
measured LDL receptor activity in stimulated T-lymphocytes prepared from 34
patients before and after treatment with 40 mg fluvastatin daily for 12 weeks.
Maximally induced pretreatment LDL receptor activities did not correlate with
pretreatment plasma cholesterol levels or with changes in plasma cholesterol
levels during treatment, and there were no significant changes in LDL receptor
activity during treatment. Barring methodological problems, two explanations are
possible. Insofar that LDL receptor activity in lymphocytes reflects LDL receptor
activity in the liver, the results suggest that the primary response to treatment
with fluvastatin in heterozygous familial hypercholesterolemia (FH) patients is
not enhanced LDL receptor activity. Alternatively, fluvastatin increases LDL
receptor activity in hepatocytes but has little effect on receptor-dependent
lipoprotein catabolism in extrahepatic tissues in vivo.
PMID- 10761171
TI - Trauma exposure and psychological reactions to genocide among Rwandan children.
AB - A total of 3030 children age 8-19 years from Rwanda was interviewed about their
war experiences and reactions approximately 13 months after the genocide that
started in April 1994. Rwandan children had been exposed to extreme levels of
violence in the form of witnessing the death of close family members and others
in massacres, as well as other violent acts. A majority of these children (90%)
believed that they would die; most had to hide to survive, and 15% had to hide
under dead bodies to survive. A shortened form of the Impact of Event Scale used
in a group of 1830 of these children documented high levels of intrusion and
avoidance. While children living in shelters were exposed to more trauma, they
evidenced less posttraumatic reactions. Analyses showed that reactions were
associated with loss, violence exposure, and, most importantly, feeling their
life was in danger.
PMID- 10761172
TI - Coping with technological disaster: an application of the conservation of
resources model to the Exxon Valdez oil spill.
AB - One hundred twenty-five commercial fishers in Cordova, Alaska, completed a mailed
survey regarding current mental health functioning 6 years after the Exxon Valdez
oil spill. Economic and social impacts of the oil spill and coping and
psychological functioning (modified Coping Strategies Scales, Symptom Checklist
90-R) were measured. Multiple regression was used to test the utility of the
Conservation of Resources stress model for explaining observed psychological
symptoms. Current symptoms of depression, anxiety, and Posttraumatic Stress
Disorder were associated with conditions resource loss and avoidant coping
strategies. The Conservation of Resources model provided a framework for
explaining psychological impacts of the oil spill. Future research is needed to
identify factors related to recovery.
PMID- 10761173
TI - An investigation of the impact of posttraumatic stress disorder on physical
health.
AB - In a large sample of Gulf War veterans (N = 2301) we examined the relations
between PTSD symptoms assessed immediately upon returning from the Gulf War and
self-reported health problems assessed 18-24 months later. PTSD symptomatology
was predictive of self-reported health problems over time for both men and women
veterans, even after the effects of combat exposure were removed from the
analysis. Female veterans reported significantly more health problems than male
veterans, however, there was no interactive effect of gender and PTSD on health
problems. These findings provide further support for the theory that
psychological response to stressors impacts health outcome.
PMID- 10761174
TI - What parts of PTSD are normal: intrusion, avoidance, or arousal? Data from the
Northridge, California, earthquake.
AB - The incidence and comorbidity of posttraumatic stress disorder (PTSD) are
addressed in a study of 130 Northridge, California, earthquake survivors
interviewed 3 months post-disaster. Only 13% of the sample met full PTSD
criteria, but 48% met both the re-experiencing and the arousal symptom criteria,
without meeting the avoidance and numbing symptom criterion. Psychiatric
comorbidity was associated mostly with avoidance and numbing symptoms. For
moderately severe traumatic events, re-experiencing and arousal symptoms may be
the most "normal," and survivors with a history of psychiatric problems may be
those most likely to develop full PTSD. A system that considers people who meet
all three symptom criteria to have a psychiatric disorder yet recognizes the
distress of other symptomatic survivors may best serve traumatized populations.
PMID- 10761175
TI - An examination of bias in volunteer subject selection: findings from an in-depth
child abuse study.
AB - Remarkably few reported studies tested the assumption that a research sample can
be constructed which is representative of the population of interest. In order to
investigate potential volunteer bias in abuse research, we utilized a database
assembled for an NIMH funded study investigating the relationship among
adolescent physical abuse, suicidal behavior, and psychopathology. Extensive
information was available concerning the nonparticipant pool from which this
sample was assembled, allowing for a comprehensive assessment of possible sample
bias. The volunteer sample of 99 abused families who agreed to participate in our
study was compared on a large number of variables with a random sample of 99
abused families who declined to participate. Comparisons of the two groups did
not support the hypothesis that the non-participating families represented a more
dysfunctional population. The two groups were far more similar to, than disparate
from, each other.
PMID- 10761176
TI - Anger, dissociation, and posttraumatic stress disorder among female assault
victims.
AB - The goal of the present study was to explore the relationship between anger and
dissociation and their relationship to symptoms of post-trauma pathology. One
hundred four female assault victims were assessed prospectively 2, 4, and 12
weeks post-assault. Measures of posttraumatic stress disorder (PTSD) severity,
social functioning, anger, and dissociation were obtained at all assessments.
Results revealed that differentiation between symptoms that predict later PTSD
and impaired social functioning first becomes evident at 4 weeks post-assault. At
4 weeks post-assault, anger expression was predictive of later PTSD severity,
whereas dissociation was predictive of poorer later functioning.
PMID- 10761177
TI - Psychometric evaluation of Horowitz's Impact of Event Scale: a review.
AB - Despite being developed before the formal introduction of posttraumatic stress
disorder (PTSD) within the diagnostic literature, the Impact of Event Scale
(Horowitz, Wilner, & Alvarez, 1979) remains one of the most widely used self
report measures of posttraumatic stress. This paper presents an overview of
research using the IES in an attempt to assess its psychometric status. It is
concluded that the psychometric properties of the IES are satisfactory (although
not as a PTSD diagnostic measure) and that continued use of the IES as a measure
of intrusive and avoidant processes is warranted.
PMID- 10761178
TI - Relationships among trauma exposure, chronic posttraumatic stress disorder
symptoms, and self-reported health in women: replication and extension.
AB - Fifty-two women who served during the Vietnam era were assessed for war-zone
exposure, traumatic life events, post-traumatic stress disorder (PTSD), and self
reported health status. Symptoms of PTSD were examined as mediators in the
relationship between traumatic exposure and subsequent reports of health
problems. Results showed that PTSD symptoms accounted significantly for variance
in health problems reported by women with prior traumatic stressor exposure. When
the cardinal symptom domains of PTSD (re-experiencing, numbing, avoidance, hyper
arousal) were analyzed separately, the symptom cluster representing hyper-arousal
accounted uniquely for the variance associated with health complaints, beyond
that contributed by other symptom clusters. Discussion of the results focuses on
mechanisms underlying the relationship between specific symptoms of PTSD and self
reported health. Implications for intervention within the medical system are also
considered.
PMID- 10761179
TI - "Amnesia" for summer camps and high school graduation: memory work increases
reports of prior periods of remembering less.
AB - Claims regarding amnesia for childhood sexual abuse have often been based on
studies of adults' responses to questions of the form, "Was there ever a period
of time when you remembered less of the abuse than you do now?" In this
experiment, 43 adult (mean age = 42) participants rated their current and prior
memories of several nontraumatic childhood/adolescent events. Reports of prior
periods of less memory were fairly common. Participants then engaged in
"reminiscence" or "enhanced" retrieval activities directed toward remembering
more about a selected target event. Following retrieval, 35% of the reminiscence
condition participants reported prior poor memory for the target event, as did
70% of the enhanced condition. These results highlight the need for appropriate
control conditions in retrospective studies of amnesia for childhood trauma.
PMID- 10761180
TI - Dimensionality and reliability of the Civilian Mississippi Scale for PTSD in a
postearthquake community.
AB - This study examines psychometric properties of the Civilian Mississippi Scale for
posttraumatic stress disorder when administered in a community survey of 656
persons following the 1989 Loma Prieta earthquake. Internal consistency was lower
(Cronbach's alpha = .73) than for previous analyses of civilian and combat
versions of the Mississippi Scale. The analysis produced one strong factor
composed of 25 items with regular wording and a second, weaker factor composed of
10 items with reversed wording. Internal consistency was higher when the 10
reversed items were removed (Cronbach's alpha = .86); the two factors were
negatively correlated. Traumatic experiences and psychological distress measures
explained more variance in the 25-item factor than in the 35-item scale. Further
studies should focus on content analysis and performance of the reversed items.
PMID- 10761181
TI - Relations between coercive strategies and MMPI-2 scale elevations among women
survivors of childhood sexual abuse.
AB - The relationship between coercion strategies used by perpetrators of childhood
sexual abuse (CSA) and elevations of CSA survivors on the Minnesota Multiphasic
Personality Inventory-2 (MMPI-2) was investigated. Participants were 151 women
survivors of CSA in outpatient treatment at a university-based community mental
health center. Scores on the MMPI-2 clinical scales and the Keane posttraumatic
stress disorder (PTSD) scale were examined. Main effects were found for promised
or received rewards on several clinical scales and the PTSD scale of the MMPI-2,
independent of the presence of force. Specifically, the presence of such rewards
was associated with significantly higher levels of symptomatology on Paranoia
(Pa), Psychasthenia (Pt), Schizophrenia (Sc), and PTSD (Pk). There were no main
or interaction effects noted for the presence of actual or threatened force on
any of the scales.
PMID- 10761182
TI - Health monitoring of non-human primate colonies. Recommendations of the
Federation of European Laboratory Animal Science Associations (FELASA) Working
Group on non-human primate health accepted by the FELASA Board of Management, 21
November 1998.
PMID- 10761183
TI - FELASA guidance paper for the accreditation of laboratory animal diagnostic
laboratories. Report of the Federation of European Laboratory Animal Science
Associations (FELASA) Working Group on Accreditation of Diagnostic Laboratories.
PMID- 10761184
TI - Implications of infectious agents on results of animal experiments. Report of the
Working Group on Hygiene of the Gesellschaft fur Versuchstierkunde--Society for
Laboratory Animal Science (GV-SOLAS).
PMID- 10761185
TI - Comparison of the distribution of magnesium in plasma determined by size
exclusion chromatography and 31P NMR spectroscopy.
AB - The distribution of magnesium in plasma, bound to proteins (pMg), complexed to
low molecular weight anions (cMg) and ionized (iMg), was compared by size
exclusion chromatography and an approach using a combination of atomic absorption
spectroscopy, ion selective electrodes and 31P nuclear magnetic resonance
spectroscopy. The distribution of pMg:cMg:iMg was 28:13:59 as determined by
chromatography and 26:14:60 as determined by the latter methodology. These
results are consistent with the hypothesis that plasma proteins and weak
complexing anions correspond to high and low affinity magnesium binding ligands
in plasma, respectively.
PMID- 10761186
TI - Low extracellular Mg2+ concentrations suppress phagocytosis in vitro by alveolar
macrophages from rats.
AB - The aim of this study was to assess the effects of extracellular Mg2+
concentrations on phagocytosis in vitro by alveolar macrophages from rats.
Phagocytosis was suppressed in the presence of low, but not high, Mg2+
concentrations. Vanadate, a Mg(2+)-ATPase inhibitor, suppressed phagocytosis. In
the presence of a low Mg2+ concentration or vanadate, the cytosolic free Ca2+
concentration ([Ca2+]i) increased, but the cytosolic free Mg2+ concentration did
not. These results suggest that low extracellular Mg2+ concentrations and
vanadate suppress phagocytosis by rat alveolar macrophages by increasing [Ca2+]i.
PMID- 10761187
TI - Magnesium deficiency in the rat: effects of fructose, boron and copper.
AB - Magnesium (Mg) participates in many biochemical reactions which involve a variety
of other nutrients. To elucidate some nutrient interactions, fructose (FR) and
starch (ST) were compared as carbohydrate sources, and boron (B) and copper (Cu)
were added to low-Mg diets for young male rats. Lack of Mg always caused
characteristic deficiency symptoms. FR resembled Mg deficiency in effects on
body, liver, and kidney weights and on plasma cholesterol level, but did not
affect serum Mg or calcium (Ca). FR effects apparently were not mediated by
changes in plasma Mg and Ca concentrations and were not prevented by adding Cu. B
appeared to lessen effects of a low-Mg diet on body growth, serum cholesterol,
and ash concentration in bone, but exacerbated deficiency symptoms, without
affecting the concentration of Mg or Ca in serum. Results suggest that increased
FR intake and marginal B might adversely affect individuals whose Mg status is
suboptimal.
PMID- 10761188
TI - Alterations in magnesium and oxidative status during chronic emotional stress.
AB - Magnesium and oxidative status were investigated in young volunteers exposed to
chronic stress (political intolerance, awareness of potential military attacks,
permanent stand-by duty and reduced holidays more than 10 years) or subchronic
stress consisting of everyday mortal danger in military actions lasting more than
3 months. Significant decreases in plasma ionized Mg2+, total Mg and ionized Ca2+
concentrations were found in both groups. Similarly, both study groups exhibited
oxidative stress as assessed by increased plasma superoxide anions and
malondialdehyde and modified antioxidant defense. There were no significant
differences between the two stress groups. A negative correlation between
magnesium balance and oxidative stress was observed suggesting that the same
etiological factor (chronic stress) initiate decreases in both free and total
magnesium concentrations and simultaneously increase oxidative stress intensity.
These findings support the need for magnesium supplementation with antioxidant
vitamins for people living in conditions of chronic stress.
PMID- 10761189
TI - Magnesium and calcium concentration in the abdominal aorta of patients deceased
by ischemic heart disease.
AB - Magnesium (Mg) and calcium (Ca) concentrations were determined in the abdominal
aorta of 28 patients who died by acute myocardial infarction (AMI), of 52 by
ischemic heart disease (IHD) and of 26 subjects deceased by accidents or from
causes other than atherosclerosis. Mg concentration in the fibrous and calcareous
plaques, was significantly lower than in controls. The lowest Mg values were
found in those who died by AMI. Calcium concentration, especially in the
calcareous plaques, was enormous as against the controls. The four-seven times
decreases of Mg/Ca ratio compared with the controls imply an alteration of the
arterial wall cells. Magnesium deficit in the arterial wall probably plays a
certain role in this process.
PMID- 10761190
TI - [Intronic genes].
PMID- 10761191
TI - [Participation of viral and cellular IAP proteins in regulation of apoptosis and
cell survival].
PMID- 10761192
TI - [Is annexin VI, a protein that binds calcium and phospholipids, a G protein?].
PMID- 10761193
TI - [Can mutation of the AMPD1 gene encoding human deaminase muscle muscle isozyme
AMP be a prognostic marker of primary dilated cardiomyopathy?].
PMID- 10761194
TI - [The role of myosin light chains in regulation of myocardial contraction].
PMID- 10761195
TI - [Endothelins--one decade after their discovery].
PMID- 10761196
TI - [Various effects of protein kinase A action].
PMID- 10761197
TI - [Synapsins--intracellular ATP receptors in the neurotransmitter release process].
PMID- 10761198
TI - [Disorders of leptin receptor structure and function--one of the causes of
obesity?].
PMID- 10761199
TI - Breast cancer patterns and lifetime risk of developing breast cancer among Puerto
Rican females.
AB - OBJECTIVES: The purpose of this study was to evaluate the epidemiologic patterns
of breast cancer and to estimate the lifetime risk probability of developing
breast cancer among Hispanic females using cancer data from Puerto Rico.
BACKGROUND: The age-adjusted breast cancer incidence rate (per 100,000) in Puerto
Rico increased from 15.3 in 1960-1964 to 43.3 in 1985-1989. The age-adjusted
breast cancer mortality rate (per 100,000) increased from 5.7 to 10.6 comparing
the same two time periods (1960-1964 vs 1985-1989). Nevertheless, in 1985-1989
breast cancer incidence rate was higher in US White females (110.8 per 100,000)
compared to Puerto Rican females (51.4 per 100,000; age-adjusted to the 1970 US
standard population). The breast cancer mortality rate was also higher in US
White females (27.4 per 100,000) than in Puerto Rican females (15.1 per 100,000;
age-adjusted to the 1970 US standard population) during 1985-1989. METHODS: A
multiple decrement life table was constructed applying age-specific incidence and
mortality rates from cross-sectional data sets (1980-1984 and 1985-1989 data for
Puerto Rican females and 1987-1989 SEER data sets for US White and Black females)
to a hypothetical cohort of 10,000,000 women. The probability of developing
invasive breast cancer was computed for the three groups using the long version
of DEVCAN: Probability of DEVeloping CANcer software, version 3.3. RESULTS: The
lifetime risk of developing breast cancer was 5.4% for Puerto Rican females,
compared to 8.8% for US Black females and 13.0% for US White females. Lifetime
risk for Puerto Rican females increased from 4.5% in 1980-1984 to 5.4% in 1985
1989. CONCLUSIONS: Lifetime risk of breast cancer appears to be increasing in
Puerto Rico, but remains lower than the probability for US White females.
Therefore, the application of lifetime probability of developing invasive breast
cancer estimated for the US female population will overestimate the risk for the
Puerto Rican female population.
PMID- 10761200
TI - Treatment of childhood acute immune thrombocytopenic purpura with high-dose
methylprednisolone, intravenous immunoglobulin, or the combination of both.
AB - OBJECTIVE: To compare the effectiveness of intravenous immunoglobulin (IVIG)
alone, high dose methylprednisolone (HDMP) alone and the combination of IVIG and
HDMP in the treatment of childhood immune thrombocytopenic purpura (ITP).
BACKGROUND: Acute ITP in children is a self-limited disease with a benign course
and low mortality rate. Patients with platelet count less than 20,000 x 10(9)/L
are at increased risk of bleeding complications, making them candidates for
treatment. METHOD: A 4 year retrospective study of 148 patients hospitalized with
acute ITP was conducted to compare the effectiveness of HDMP vs IVIG vs the
combination of IVIG/HDMP. Statistical methods used were descriptive statistics
and variance analysis utilizing F distribution. RESULTS: The IVIG and the HDMP
combination demonstrated to be superior to HDMP alone in raising the platelet
count within the first 24 hours. The HDMP and IVIG combination was statistically
a superior modality of treatment for patients with platelet count greater than
10,000 x 10(9)/L than was IVIG or HDMP alone. Intravenous immunoglobulin had the
least effectiveness in patients with platelet count less then 10,000 x 10(9)/L
within the first 24 hours. CONCLUSIONS: IVIG followed by the combination of HDMP
and IVIG is the most effective therapeutic modality in rapidly increasing the
platelet count to safe levels in children with acute ITP when compared to HDMP
alone within the first 24 hours. For borderline low platelet count (> 10,000 x
10(9)/L) HDMP and IVIG was superior to IVIG alone.
PMID- 10761201
TI - Intracellular studies of the nucleoside reverse transcriptase inhibitor active
metabolites: a review.
AB - Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not
correlate with clinical efficacy or toxicity. These agents need to be
phosphorylated to become active against HIV-infection. Thus, the characterization
of the NRTIs intracellular metabolite pharmacological parameters will provide a
better understanding that could lead to the development of more rational dose
regimens in the HIV-infected population. Furthermore, intracellular measurements
of NRTIs may provide a better marker with respect to clinical efficacy and
toxicity than plasma concentrations. Thus, in this article we review the latest
information regarding the intracellular pharmacological parameters of zidovudine
(ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including
the results from our recent clinical studies. We will start the discussion with
ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We
will then discuss the in vitro and in vivo intracellular studies with particular
emphasis in the method development to measure these metabolites and we will
conclude with the most current data from our clinical trials.
PMID- 10761202
TI - Mother-to-child HIV-1 transmission: state of the art and implications for public
policy.
AB - During the past five years there have been significant advances in the knowledge
of the factors that affect mother-to-infant HIV-1 transmission. Diverse
interventions have been designed and proven effective in reducing the risk of
such transmission. In reviewing the pivotal literature in such respect
implications for public policy are also analyzed. Because of the constant
evolution of the interventions, the public policies also need constant revisions.
The impact of viral load assessment during pregnancy and its relationship to
transmission risks is discussed, as well as the effectiveness of elective
Caesarean delivery. The latter has both positive and negative aspects which merit
consideration. Newer approaches, such as highly active anti retroviral therapies
(HAART), which have shown to decrease the AIDS mortality, have also shown zero
transmission in small cohorts. Shorter and cheaper interventions are also
somewhat effective and are good alternatives to resource poor countries.
PMID- 10761203
TI - Nutrition-related problems of pediatric patients with neuromuscular disorders.
AB - Children with neuromuscular disorders have special health needs that place them
at risk of nutritional problems. These needs may have detrimental effects on
their development, immune and respiratory system. Identified nutrition-related
problems are malnutrition, obesity, food intolerance, food allergies, drug
nutrient interactions, constipation and reflux. In order to improve the
nutritional status of these patients, a nutritional assessment is recommended
which should include anthropometric measurements and laboratory tests.
PMID- 10761205
TI - [Bailey K. Ashford, more in his remembrance].
AB - The military physician Bailey K. Ashford (Washington, D. C., September 18, 1873-
San Juan, Puerto Rico, November 1, 1934) is mostly remembered for having
identified in 1899 the cause of fatal anemia prevalent among Puertorican
peasants, but he was also a distinguished investigator of other diseases, and
organizer of mass medical services, in peace and in war. In spite of Ashford's
own sober statements, the great influence of his scientific work in Puerto Rico
and the impact of his personality in patients and colleagues have helped cast him
as a mythical figure. His personal archives (kept at the library of the
University of Puerto Rico's Medical Sciences Campus) make clear that his
autobiography presents only a selection among the episodes that would form a
complete biography.
PMID- 10761204
TI - [Descriptive study of animal attacks and bites in the municipality of San Juan,
Puerto Rico, 1996-1998].
AB - The present study described the frequency of animal bites and attacks in the
municipality of San Juan, Puerto Rico between the fiscal years 1996 through 1998.
A total of 275 cases were reported to the San Juan Local Office of Environmental
Health. The distribution of cases by gender was equal, and persons aged 18 years
or older had the highest frequency of animal bites and attacks (52.9%). The
animal species reported to be involved in the majority of animal bites was the
dog (81.1%). Upper extremities were involved in 43% of these injuries. Animal
bites caused by dogs were more often reported among male victims (87.4%) (p =
0.031). Approximately 41% of dog bites and attacks and 75% of bites and attacks
caused by other animal species were documented as provoked (p = 0.002). More than
75% of the injuries in the head, face or neck involved children < 13 years
whereas 65.9% of the injuries in the upper extremities involved adults (> 18
years) (p = 0.001). Animal bites and attacks in the upper extremities were more
prominent among injuries caused by an animal species different to the dog (71%)
(p < 0.001). We conclude that animal bites and attacks is a public health concern
in light of the increasing pet population. Therefore, educational strategies
towards the general population must stress careful supervision of the human
animal interaction as well as the general procedures to follow in case of an
injury.
PMID- 10761207
TI - Sexual behavior among Puerto Rican adolescents.
AB - OBJECTIVE: The objective of this study is to compare the prevalence of several
types of sexual behaviors among Puerto Rican adolescents living in New York City
and in the Greater San Juan Metropolitan Area of Puerto Rico. BACKGROUND: There
is a scarcity of literature about sexual behaviors among Hispanic adolescents.
The available literature has several limitations. METHODS: The data for the
analysis was collected through personal interviews in two high schools, one in
Puerto Rico and the other in New York City as part of multi-site Centers for
Disease Control (CDC) study. RESULTS: To test whether the adolescent sexual
behavior varied by site and more specifically to determine whether the Puerto
Rican youngsters surveyed in New York are more sexually experienced, as measured
by a sexual involvement scale, a set-wise hierarchical multiple
regression/correlation (MRC) analysis was done. It showed that the sexual
involvement behavior of Puerto Rican students in N.Y. was higher that the
involvement of students surveyed in Puerto Rico even when controlling by gender,
age, mother's education and household composition. CONCLUSION: Variations in the
sexual behavior of Puerto Rican adolescents living in two socio-cultural
environments (New York City and Greater San Juan in Puerto Rico) were documented.
Differences were observed both in the patterns of sexual experiences reported in
the two sites in the higher levels of sexual experience reported in the New York
sample. The documented differences have important implications for the
development of interventions for HIV/STD prevention strategies.
PMID- 10761208
TI - [Theater of Life: theory, method and practice].
AB - Theater of Life is an educational model that integrate theater theories and
techniques as a strategy for health education. Theater as an educational
technique has become a useful tool for the health context. In this work the
author discuss the role of social change as an important element in health
education and suggests the use of theatrical techniques for it's promotion. Also
offers information about the different approaches of popular theatre and popular
education incorporated in this model, Theatre of the Oppressed by A. Boal,
Popular Education by P. Freire, Poor Theater by J. Grotowoski and Education for
Peace by C. Beristain and P. Cascon and explain the basic principles of each one
of them. In the methodology section the author explains the different steps for
implementing the strategy: solidarity and connection games, story telling
technique and script development, presentation and forum. In the practice section
the author shares the process of model development and the significance events
that had contribute to their elaboration.
PMID- 10761209
TI - [Professional identity and ethical compromise at the time of "managed care"].
PMID- 10761206
TI - The sixth Carlos E. Rubio Memorial Lecture. Prevention and treatment of variceal
hemorrhage.
AB - The medical treatment of portal hypertension has experienced a marked progress in
the past decade due to the introduction of effective portal hypotensive therapy.
This has been possible because of the better understanding of the
pathophysiological mechanisms leading to portal hypertension. A major step
forward was the introduction of beta-blockers for the prevention of bleeding and
rebleeding from gastroesophageal varices. Effective therapy requires the
reduction of the hepatic venous pressure gradient (HVPG) to 12 mmHg or below, or
at least by 20% of baseline values. Unfortunately, this is only achieved in 1/3
to 1/2 of patients. Combination therapy, associating isosorbide-5-mononitrate and
propranolol or nadolol administration enhances the reduction in portal pressure
and increases the number of patients in whom HVPG decreases by more than 20% of
baseline values and below 12 mmHg. Randomized clinical trials (RCT's) do support
the concept that combination therapy is more effective than propranolol or
nadolol alone, significantly better than sclerotherapy, and probably than
endoscopic banding ligation. Therapy may be complemented by the association of
spironolactone. The main inconvenience of pharmacological therapy is that there
is no non-invasive method available to detect non-responders to treatment.
Failures of drug therapy should be managed endoscopically. Failures of endoscopic
treatment require 'rescue' by means of TIPS or shunt surgery. Patients with
advanced liver failure should be considered for orthotopic liver transplantation,
and put into a waiting list if eligible. In the treatment of acute variceal
bleeding pharmacological therapy offer the unique advantage of allowing to
provide specific therapy immediately after arrival to hospital, or even during
transferral to hospital by ambulance, since it does not require sophisticated
equipment and highly qualified medical staff. Vasopressin has been abandoned
because of its toxicity, although this can be reduced by the combined
administration of transdermal nitroglycerin. Terlipressin has longer effects and
is more effective and safer than vasopressin alone or in combination with
nitroglycerin. It has proved to be effective and to decrease mortality from
bleeding in double-blind studies. RCT's have shown that this drug is as effective
and safer than emergency sclerotherapy. Therapy should be maintained for five
days to prevent early rebleeding. Somatostatin is probably as effective as
terlipressin. Octreotide is probably useful after endoscopic therapy but can not
be recommended as first line treatment. Endoscopic injection sclerotherapy and
endoscopic banding ligation are very effective, but require well trained medical
staff. There is an increasing trend for initiating therapy with a pharmacological
agent, followed by semi-emergency endoscopic therapy as soon as a well trained
endoscopist is available (within 12-24 hours), while maintaining drug therapy for
5 days. Failures of medical therapy may be treated by a second session of
endoscopic treatment, but if this fails TIPS of emergency surgery should be done.
In high-risk situations, such as bleeding from gastric varices or in patients
with advanced liver failure, the decision for TIPS or surgery should be done
earlier, after failure of the initial treatment.
PMID- 10761210
TI - [Functional role of vitamin K].
AB - Three basic functions of vitamin K in organism are considered. Besides (vitamin K
dependent) posttranslational modification of Ca-binding proteins, this vitamin
can operate via vitamin D hormonal system, and can directly influence membranes.
PMID- 10761211
TI - [Combined tumor chemotherapy/gene therapy based on the activation of
antineoplastic agents by genetic constructions of cytochromes p450].
AB - This article generally reviews new original two-stage approach to an effective
treatment of solid cancers by killing tumour cells by the activation of a prodrug
after the gene encoding for an activating enzyme has been targeted to the
malignant cell. The experimental data concerning gene therapy for malignant
tumours by using oxazaphosphorines and cytochrome P450 in a novel combined
chemotherapy/cancer gene therapy strategy discussed.
PMID- 10761213
TI - [The effect of gamma-L-glutamyl histamine on the severity of experimental
anaphylactic reaction, hormonal status and liver cytochrome p-450].
AB - gamma-L-Glutamyl-histamine (gamma-GluHA) was synthesized at Department of the
chemistry and technology of fine organic compounds M. V. Lomonosov Moscow state
academy of fine chemical technology. It was investigated the influence of gamma-L
glutamyl-histamine on the severity of experimental anaphylactic reaction,
hormonal content in blood plasma and liver cytochrome P-450. The induction of
liver cytochrome P-450, the elevation of hormonal content (thyroxine and
glucocorticoids) in blood plasma and decrease of the severity of experimental
anaphylactic reaction are observed.
PMID- 10761212
TI - [Changes in the activity of neutral and acidic isoforms of sphingomyelinase in
hepatoma-22, regenerating and ischemic liver].
AB - Activity of neutral and acidic sphingomyelinases (N- and A-SMases) were studied
in regenerating liver after partial hepatectomy (during 48 hrs after operation),
in ischemic liver during 15, 30 min and 1 and 2 hrs ischemia and during following
reperfusion (from 5 min up to 2 hrs), in hepatoma- 22 after 15 days of
transplantation and in liver of tumor bearing animals. It was shown that activity
of N-SMase is increased in hepatoma-22 and in regenerating liver and it is
decreased in ischemic liver. Following reperfusion of ischemic liver area
activity of enzyme was found to have returned to baseline in dependence on time
of ischemia and reperfusion. Activity of A-SMase is decreased in tumor, is not
changed in regenerating liver and increased after long time of ischemia. It was
supposed that N-SMase is involved in cell proliferation, but A-SMase is connected
with cell damage.
PMID- 10761214
TI - [Ethanol inhibits platelet monoamine oxidase type B activity in patients with
alcoholism].
AB - The influence of 400 mM ethanol on the activity of monoamine oxidase type B (MAO
B) of blood platelets has been studied in vitro in 30 alcoholic patients and 30
healthy volunteers. Benzylamine was used as a substrate for MAO-B. MAO-B
inhibition by ethanol was higher in alcoholics compared to healthy volunteers.
The higher vulnerability of MAO-B of alcoholics inhibiting action to of ethanol
may be one of the mechanisms underlying some symptoms of alcoholism.
PMID- 10761215
TI - [The dynamic of biochemical stress reaction inductors in various tactics for
surgical treatment of patients with a combined trauma of cranium and lower limbs
].
AB - In 31 patients after a craniocerebral trauma combined with a trauma of locomotor
system (CCCT), and in 28 patients with only a limb fractures a time course (1, 3,
7, and 14 days) of biochemical stress reaction inductors (cortisol, serotonin,
histamine, lipid peroxidation products) in various tactics of surgical treatment
was studied. It was established that CCCT in a significantly stronger degree
increases cortisol and lipid peroxidation products' levels than an isolated
locomotor system trauma. An early postponed surgical intervention in lower
extremities in CCCT results in the same increase in the biochemical stress
reaction inductors as a late postpone surgical intervention in the lower
extremities. In an early postponed osteosynthesis in CCCT patients, a mean term
of hospital stay was 67 days, and in a late postponed one 117 days. The
disability period was correspondingly 200 vs 315 days.
PMID- 10761217
TI - [Intensity of free radical process and antioxidant enzymes activity in human
saliva and plasma under emotional stress].
AB - The intensity of free radical processes (FRP) and the activity of antioxidant
(AO) systems in human blood plasma and saliva were studied under physiological
emotional strain and depressive pathologies (before and after treatment). The
significant alterations in the dynamics of investigative indexes under different
emotional strain were revealed. These alterations in saliva were more intensive
than in blood plasma. The treatment led to the stabilization of FRP intensity and
the activity of AO protection. The correlation between saliva and blood plasma
parametres allows to use saliva for the estimation of emotional strain and of the
efficiency of therapeutics under depressive pathologies.
PMID- 10761216
TI - [Lipid peroxidation, peroxyl radical-scavenging system of plasma and liver and
heart pathology in adolescence heroin users].
AB - Chronic opiate intoxication has been shown to cause various pathologic changes in
the liver almost in 100% of cases. Earlier it has been demonstrated that acute or
chronic morphine intoxication evokes activation of lipid peroxidation in the
liver, heart, and brain cells. The aim of the present work was to assess
parameters reflecting cytolysis in the liver and heart, and the plasma content of
factors contributing to the peroxyl radical-scavenging system of the blood of
teenagers using heroin. Blood samples were obtained from 20 male patients from 14
to 16 years old, with a mean duration of regular heroin use of 1.7 years. The
control group included 13 healthy teenagers which denied the previous drug use.
Mean plasma ALT and myocardial isoform of LDH activities were significantly
higher (1.7- and 1.4-times respectively) in the heroin users than in the control
group. The mean plasma level of lipid peroxides in the heroin users is increased
by 20% compared to the control individuals. In teenagers using heroin a high
level of correlation was observed between the plasma content of lipid peroxides
and myocardial LDH activity (r = 0.76; P < 0.01). The effect of heroin use on the
content of the plasma peroxyl radical-scavenging factors--vitamin E, ascorbic
acid, and protein SH-groups--was not found. It has been concluded that heart
injury during heroin use in teenagers may be associated with activation of lipid
peroxidation reactions in the myocardium.
PMID- 10761218
TI - [Common properties of pharmacological agonists and antagonists of surface
membrane receptors].
AB - Using experimental transcription model in vitro, and method of electron
topological calculations the elements of pharmacological and structural community
have been found in the groups of physiologically active compounds (PAC), blocking
and activating external cellular receptors. This finding confirms the necessity
of subdivision special groups of bio-substrates blockators and activators for
hierarchical classification, of PAC.
PMID- 10761219
TI - [Protection of mice by carbamates cholinesterase inhibitors against poisoning by
armin and its dependence on certain physico-chemical indicators].
AB - A series of aminostigmin derivatives with various substituents at nitrogen in the
second position of the pyridine ring, has been tested. The efficacy of preventing
the death of mice poisoned by armine in five of the seven substances correlates
with the constant of the rate of carbamylation of acetylcholinesterase in the in
vitro experiments and with the hydrophobic nature. It is suggested that the
phenomenon of protection of animals against the toxic effect of organophosphorous
compounds involves the "leaving portion" of the molecule of carbamates.
PMID- 10761220
TI - [The use of ion-selective field transistors (ISFT) with photopolymerizable
polyurethane membranes in nephrology for determination of potassium concentration
(activity)].
AB - The applicability is examined of ion selective field transistors with
photocurable polyurethane membranes to control of the electrolytic composition of
dialyzing solutions used in artificial kidney apparatus, and also of plasma in
patient treated by chronic hemodialysis. The short- and long-time characteristics
of the efficiency of K(+)-selective field transistors in continuous contact with
solutions. Comparative testing of such transistors and other sensing systems is
made. It is demonstrated that a sufficient reliability of measurements in the
range of physiological concentrations in combination with low cost provide the
possibility of using K(+)-selective field transistors for monitoring of the
potassium concentration both in dialyzing solutions and plasma in patients on
chronic hemodialysis treatment.
PMID- 10761221
TI - [Diagnosis of intra-abdominal abscess using various imaging techniques].
AB - Basing on the material of 24 patients with intra-abdominal abscesses an analysis
was performed of the diagnostic value of different imaging techniques. It has
been shown that in acute conditions without focal changes CT is the technique of
choice since it covers the whole abdominal cavity. Ultrasound, however, is a
method mainly useful in monitoring the dynamics of the disease course.
PMID- 10761222
TI - The dimensions of the superior and inferior colliculi of the tectal lamina in
people aged 18-91 years.
PMID- 10761223
TI - The cords of the brachial plexus in postnatal life in man.
AB - The cords of the brachial plexus--lateral, medial and the posterior one, which
belong to its structure have been known for a long time (3, 4, 15), but there is
a lack of publications concerning their internal structure in available
literature. The investigation and comparison of some features of the internal
structure of brachial plexus cords gave interesting results, which are collected
in this paper.
PMID- 10761224
TI - [Personal observations in diagnosis of changes after compound fracture of the
knee joint using 2D and 3D computer tomography].
AB - Basing on the material comprising 26 patients with compound fractures of the knee
joint the authors analysed the diagnostic value of sections and two-dimensional
reconstructions (2D CT). It has been shown that spatial reconstructions (3D CT)
localize bone fragments, their displacements and degree of torsion by visualising
spatial depth. Besides, they make possible the assessment of injuries of cruciate
ligaments.
PMID- 10761225
TI - Traumatic injuries to permanent teeth in children treated in Department of
Pedodontics, Medical Academy in Lublin.
AB - The traumatic dental injuries in children represent the second, after dental
caries, most common reason of attending the dental surgeries. The paper presents
the statistical analysis of the patients attending the Department of Pedodontics,
Medical Academy in Lublin due to the traumatic dental injuries.
PMID- 10761226
TI - Dimensions of the pons, the medulla oblongata and the fourth ventricle fundus in
people aged 18-91 years.
AB - The structure of human central nervous system has not been fully known yet. There
were studies concerning the anatomical structure of the human brain and
anatomical and experimental studies performed in animals (4, 7, 10, 18). The new
methods of CT and MRI (15) enable the intravital studies of CNS which cause no
visible side-effects in patients. The present paper reports the anatomical
studies of the human brain stem in autopsy material.
PMID- 10761227
TI - [[Orbital wall fractures in 3D computer tomographic imaging].
AB - Assessment of diagnostic value of three-dimensional reconstruction of
computerised tomography pictures was performed on 26 patients with compound
fractures of orbital and craniofacial bony structures. There were carried out
examinations in the patients in standard axial or frontal sections and then three
dimensional reconstructions were obtained with bony threshold. Rotational ability
of the reconstructed picture was used by performing cranial rotations in any axis
and at any angle. 3-D reconstructions have distinctly revealed bony fragments
displaced towards the orbital lumen from the vault to the maxillary sinus in
fractures of the fundus and depressions of the medial wall to the ethmoid.
Compound fractures of orbital walls tightening the superior orbital fissure,
canal of the optic nerve and the apical region have revealed reconstructions with
cut off screening structures combined with rotations of the obtained picture.
Manipulations with the picture reveals the dimension of spatial depth allowing
the assessment of distance and showing the course of fissures of multiplanar
fractures branching off towards the environment.
PMID- 10761228
TI - [A fortuitous diagnosis of familial Albers Schoenberg disease].
AB - An accidentally diagnosed family benign form of Alberts-Schonberg disease has
been presented. Generalised bone sclerose was differentiated from other forms of
bone dysplasia. There was emphasised the value of chest examinations in revealing
abnormalities of the costal (bone) structure during routine-periodic chest-X
rays.
PMID- 10761229
TI - [The effect of lithium chloride on the rat behavior after short-term oligemic
hypoxia].
AB - The experiments were carried out on male Wistar rats. The influence of brain
oligemic hypoxia and lithium chloride (LiCl) on some behavioural parameters was
investigated. Reduction of brain blood supply was performed by surgical clamping
of both carotid arteries for 60 min in general anaesthesia induced by brietal
(Methoxitone sodium, 10 mg/kg i.p.). Control animals had their vessels separated,
but not clamped (sham operated). 6 days after surgery animals received LiCl (2.5
mEq/kg i.p.). Behavioral experiments were performed 24 h and 7 days after lithium
administration. Experimental groups consisted of 12 animals. It was found that
oligemic hypoxia reduced inconsiderably spontaneous locomotor and exploratory
activity in rats. Similar influence of LiCl was observed. But LiCl administered
to animals after oligemic hypoxia prevented them against locomotor and
exploratory impairment. In addition, LiCl strongly enhanced amphetamine-induced
hyperactivity and diminished haloperidol-induced catalepsy in hypoxic animals.
These effects were not observed in sham operated animals. The above results could
be connected with antidepressive action of LiCl and the model of moderate
oligemic hypoxia used in present work could be a useful model for investigation
of new antidepressive compounds.
PMID- 10761231
TI - Central action of some cytostatics--methotrexate (MTX) and doxorubicin (DXR). II.
The influence on the seizure activity and the learning and memory processes in
mice.
PMID- 10761230
TI - Central action of some cytostatics--methotrexate (MTX) and doxorubicin (DXR). I.
Long-term influence on the pain sensitivity and activity of brain dopaminergic
system in mice.
PMID- 10761232
TI - The influence of the ACTH-derived short regulatory peptide on the rabbit
behaviour.
PMID- 10761233
TI - [Epidemiologic and clinical tests of patients suffering from laryngeal cancer in
the Lublin macro-region in the years 1991-1995].
AB - The study of registered morbidity of patients suffering from laryngeal cancer in
the Lublin macro-region in the years 1991-95 was carried out. Morbidity rates in
the population in consecutive years of investigated 5-year age groups were
examined. In clinical investigations the conditions of clinical advancement of
the disease in particular organs was determined and environmental factors and
occupation were also revealed.
PMID- 10761234
TI - The influence of normobaric hyperoxide process on antioxidant enzymes activity
and on lipid peroxidation processes in the rat's liver.
PMID- 10761235
TI - The influence of normobaric hyperoxide process on antioxidant enzymes activity
and on lipid peroxidation processes in the rat's pancreas.
PMID- 10761236
TI - Surgical treatment of squamous cell carcinoma of the thoracic oesophagus.
PMID- 10761237
TI - Oesophageal surgical anatomy.
PMID- 10761238
TI - Lysosomal enzyme activity of iliac arterial walls in rabbits.
PMID- 10761239
TI - Lysosomal enzyme activity of internal and middle layers of renal arterial wall in
rabbits.
PMID- 10761240
TI - The ultrastructure of thyroid in the course of the experimental diabetes.
PMID- 10761242
TI - [Epidermal lipids in psoriasis].
AB - The authors have reviewed the bibliography on the behaviour of epidermis lipids
in the course of psoriasis. In individual papers the researchers have reported
numerous irregularities concerning epidermal lipids in psoriasis.
PMID- 10761241
TI - [Convulsive status epilepticus--clinical analysis of patients treated iin the
Neurological Clinics, Medical Academy in Lublin in the years 1986-1995].
AB - The authors reviewed clinical records of 57 consecutive adults (age: 17-78, 63%-
men) treated in the intensive care unit to convulsive SE that was refractory to
first-line medication (BDZ,PB). They were divided into three groups: up to 30
(mean 21 years, 28%), between 31-50 (43 y, 32%) and above 50 (59 y, 40%), 58% had
previously had epilepsy with prevalence in the youngest (85%). Among the oldest
in whom epilepsy occurred de novo as much as 42% experienced it in the form of
convulsive SE. Generalized SE was observed in 83% of cases; exclusively in
patients up to 50 and in 61% of the oldest. The identifiable precipitating causes
of SE were determined in 72% cases but in 25% there were two or more of them.
Among previously epileptics leading etiologies for SE were: alcohol abuse,
infection or drug withdrawal. Recent brain injury (stroke, neuro-infection,
trauma) accelerated refractory seizures in epilepsy-free cases. Time to recovery
varied from 0.5-2 (6%) to 2-6 or above 6 hrs (46% each) after continuous i.v.
administration of BZD or chlormethiazole (53%) when ineffective. No side effects
were noted. The commonest complications during SE were hyperthermia and transient
dysregulation of circulatory or/and respiratory systems. Everyone was led out of
SE. Overall mortality amounted to 12%. Among the deceased 71% were in the oldest
group and everyone with recent brain lesion. This study highlights differences in
the course of convulsive SE according to age and underlying etiology and the
importance of intense care in therapeutic schedule. A more common chlormethiazole
administration, a useful therapeutic tool in management of convulsive SE in
adults had been discussed.
PMID- 10761243
TI - [Levels of LDL,HDL and total phospholipids in blood serum of male patients with
psoriasis].
AB - The levels of LDL and HDL phospholipids as well as concentrations of total
phospholipids were determined in the blood serum of 38 patients with generalized
form of psoriasis (PG) and in 35 healthy volunteers of the control group (C).
Patients with psoriasis were divided into two groups according to age at the
onset of the disease. Group I (PG I, No = 11) were patients in whom the onset of
psoriasis was observed before the age of 14.5, whereas group II (PGII; No = 27)
were those in whom the first symptoms of the disease manifested themselves over
the age of 15. A statistically insignificant tendency was noted towards a slight
decrease in the concentration of total lipids, and towards an increase in the
level of LDL phospholipids, whereas a statistically significant decrease was
observed in the concentration of HDL phospholipids.
PMID- 10761244
TI - Changes in the digestive system in patients suffering from psoriasis.
AB - Literature published in the recent years provides more evidence for psoriasis
being a disease which involves the whole organism. In the course of the disease
not only the skin, but also numerous cells and internal organs are affected (1,
2, 3, 6-12, 15, 17, 20). Despite long effort of many research teams, the
etiopathogenesis of the disease has remained unknown. Among many suppositions
about the cause of psoriasis the one put forward at the Third Psoriatic Congress
in Stanford deserves special attention. It suggests that the starting point of
the disease are kinetic disturbances of the digestive system (15). This system
takes part in decomposition, modifications and synthesis of many organic
compounds, including lipids, and disturbances of its function can be reflected in
all the metabolic routes. In psoriatic patients structural and functional
abnormalities of the digestive system were found in nearly all its segments (1-4,
6-8, 10, 12, 15, 17, 20). However, changes revealed in the alimentary tract by
means of accessory examinations were hardly ever accompanied by any complications
of the system. Long-term observations of a big group of psoriatics carried out in
our clinics confirm the absence of subjective symptoms in these patients. The
most common anatomopathologic abnormalities in psoriasis are prelipidophilia and
palatal lipidophilia, inflammatory changes in the mucous membrane of the stomach
and duodenum (gastritis chronica superficialis and duodentis chronica nature), as
well as changes in the structure of the hepatic lobule and intestinal villi (1,
2, 3, 10, 12, 15, 17, 20).
PMID- 10761245
TI - [Treatment of experimental broncho-pleural fistula with myoplasty].
AB - Surgical experiment of closing broncho-pleural fistula by muscle flap from the
chest wall was conducted on the sheep model. The procedure was completed in two
stages. During the first thoracotomy the middle lobe of the right lung was
removed. In the second stage the vascularised muscle flap of the latissimus dorsi
was inserted in the pleural space and stitched onto the bronchi stump closing
broncho-pleural fistula. Microscopic investigation of lung, bronchus and muscle
tissue performed after each step of procedure showed the inflammatory process
primarily and the regression of it after the second stage. Well vascularised
muscle flap is the best tissue for repair of broncho-pleural fistula.
PMID- 10761246
TI - [Iatrogenic foreign bodies within the maxillofacial region].
AB - Five hundred different X-ray pictures of the maxillofacial region were analysed.
Foreign bodies such as dental filling materials and instruments were found. It
was stated that most often the excess of endodontic material was observed in the
region of a treated tooth. The second site where iatrogenic foreign bodies were
found was the maxillary sinus. The reason of these complications was the lack of
proper radiological and endometric diagnosis before the beginning of the
endodontic treatment.
PMID- 10761247
TI - [The applicability of phleboscintigraphy in diagnosis and treatment result
evaluation of patients with disorders of leg venous circulation].
AB - The aim of the paper was the applicability of phleboscintigraphy in the diagnosis
and monitoring of the treatment in patients with various disorders of venous
circulation in lower extremities. The study comprised eighty-eight patients with
the suspicion of deep veins impatience. The examination was performed using DTPA
99mTc by means of a gamma camera connected with a computer. The radioisotope was
injected into the foot dorsal veins. The dose was 185 MBq. Its activity was
monitoring continuously for 1 min. The estimation of the results was performed by
scintigraphy imaging and curves of activity changes of chosen regions over deep
veins. Phleboscintigraphy was found out to be of a great value in the diagnostics
and assessment of treatment results in thrombotic-embolic disease, extra
thrombotic syndromes and in qualification of patients with lower legs varices for
surgical procedures. Because of easy performance, possibility of repeating, small
invasiveness and rather low cost, the method can be recommended as an
introductory examination in patients with above mentioned diseases.
PMID- 10761248
TI - The influence of certain arachidonic acid pathway inhibitors on central nervous
system catecholamine level in rats administered with ethanol.
PMID- 10761249
TI - The influence of prolonged administration of high doses of hydrocortisone and
salmon calcitonin on cortical bone strength in young adult rats.
PMID- 10761250
TI - Radiologist workforce issues.
PMID- 10761251
TI - Workforce requirements in radiation oncology: a complex issue.
PMID- 10761252
TI - Radiology of the nasopharynx: pictorial essay.
AB - The nasopharynx, located just below the central skull base, is a difficult area
to evaluate clinically. Endoscopic examination provides useful information but
cannot delineate submucosal disease. Benign lesions of the nasopharynx are
relatively uncommon. They include Thornwaldt cyst, juvenile angiofibroma,
haemangioma, haemangiopericytoma, Kimura's disease, branchial cleft cyst,
oncocytoma, amyloidoma, and non-ossifying fibromyxoid tumours. The most common
malignant lesions are carcinomas and lymphomas. Other malignant neoplasms such as
adenocystic carcinomas are rarely seen. The purpose of the present pictorial
review is to highlight the salient normal anatomy of the nasopharynx and the
spectrum of pathological anatomy.
PMID- 10761253
TI - Symptomatic ossification of the posterior longitudinal ligament of the cervical
spine: pictorial essay.
AB - Symptomatic ossification of the posterior longitudinal ligament (OPLL) of the
cervical spine is a rare but well-documented condition. It is the causative
factor in up to 5% of cases presenting with cervical radiculopathy or myelopathy.
Computed tomography is the modality of choice in showing the distinctive
characteristics and extent of the disease. Magnetic resonance imaging (MRI) is
sensitive in detecting cord compression and its attendant complications. Cervical
OPLL commonly affects those of middle and advanced age, and the condition is
noted to be particularly common in Japanese, although other racial groups are
also affected. A 'mushroom' or 'hill' shape on axial CT typifies OPLL. A sharp
radiolucent line separating the posterior vertebral margin from the superficial
component of the ossified ligament is a characteristic feature.
PMID- 10761254
TI - Radiological classification of meniscocapsular tears of the anterolateral portion
of the lateral meniscus of the knee.
AB - In an arthroscopic-MRI correlation study of acute injuries to the knee it was
found that anterolateral meniscocapsular separations of the lateral aspect of the
knee were missed on MRI reporting. Eighty sports-related injuries of the knee
were seen by experienced orthopaedic surgeons at the University of Malaya Medical
Centre and at the National Sports Centre, Malaysia from January 1996 to July
1997. Fifty of the patients were suspected to have meniscal tears that were
either lateral or medial on clinical examination and they were sent for MRI. Many
of these patients were tertiary referrals. Magnetic resonance imaging
examinations in 27 of the 50 patients were reported as not showing any
intrasubstance or obvious meniscocapsular tears, but arthroscopy performed on
them revealed anterolateral meniscocapsular tears of the lateral meniscus of
varying degrees in nine of these patients. In retrospect the tears could be seen
on MRI, and a pattern to the tears was noted and classified as follows. Type 0,
normal; type 1, torn inferior or superior meniscocapsular attachment; type 2,
both meniscofemoral and meniscotibial ligaments torn but with minimal separation
of meniscus and capsule by fluid or synovitis; and type 3, marked separation of
meniscus and capsule by fluid (> 3 mm). Ten patients who did not undergo
arthroscopy for various personal and financial reasons underwent MRI which showed
type 1 and type 2 tears, and were treated conservatively. These patients were all
asymptomatic after 4-6 weeks with regard to clinical signs, suggesting a lateral
meniscal tear. Magnetic resonance imaging therefore does reveal minor degrees of
meniscocapsular tears anterolaterally when one understands the normal anatomy in
this region.
PMID- 10761255
TI - Meningeal infiltration in recurrent nasopharyngeal carcinoma.
AB - Permeative infiltration of the meninges appears to be a distinct form of
recurrent nasopharyngeal carcinoma (NPC). The present report of eight patients
with recurrent NPC illustrates meningeal infiltration following basal foramina
extension. Seven of the eight patients (88%) showed jugular foramen involvement.
Three patients had concomitant infiltration of the foramen magnum. There was one
patient showing spread through the foramen lacerum. Only four (50%) of these
patients had clinically detectable tumour in the nasopharynx, while the other
half showed deep submucosal recurrence with endoscopically unremarkable findings.
Permeative meningeal infiltration appears to be a distinct form of NPC
recurrence. It is important to recognize this phenomenon so as to optimize the
treatment options.
PMID- 10761256
TI - Early experience in the use of Levovist ultrasound contrast in the evaluation of
liver masses.
AB - The aim of the present paper was to assess the utility of Levovist in defining
the pathology of liver masses. Levovist is a new ultrasound contrast agent
consisting of galactose microparticles, air bubbles and palmitic acid.
Prospective studies were performed in patients referred for further evaluation of
known liver masses. Levovist was peripherally injected and colour Doppler
ultrasound studies were performed. Findings were correlated with clinicopathology
and three other imaging modalities: biphasic spiral CT, CT arterial portography
and contrast MRI. Twenty-five patients were studied (15 male and 10 female) in
the age range 25-74 years. Liver masses ranged from 0.5 to 7 cm in maximum
diameter. Thirteen lesions were benign and 12 were malignant (four hepatomas
(HCC) and eight metastases). Levovist enhancement occurred in 18 lesions. Of
these, six were benign (four focal nodular hyperplasias (FNH) and two
haemangiomas). All 12 malignant lesions demonstrated enhancement. The HCC showed
a mosaic pattern of central and peripheral enhancement, and the FNH demonstrated
a spoke-wheel pattern. It was not possible to distinguish between haemangiomas
and malignant lesions. Non-enhancing lesions may well be benign, with all
malignancies showing some enhancement. Characteristic enhancement patterns were
found for HCC (mosaic) and FNH (spoke-wheel). It was not possible to distinguish
between metastases and benign lesions (haemangiomas) when the pattern of
enhancement was peripheral.
PMID- 10761257
TI - Acceptable levels of digital image compression in chest radiology.
AB - The introduction of picture archival and communications systems (PACS) and
teleradiology has prompted an examination of techniques that optimize the storage
capacity and speed of digital storage and distribution networks. The general
acceptance of the move to replace conventional screen-film capture with computed
radiography (CR) is an indication that clinicians within the radiology community
are willing to accept images that have been 'compressed'. The question to be
answered, therefore, is what level of compression is acceptable. The purpose of
the present study is to provide an assessment of the ability of a group of
imaging professionals to determine whether an image has been compressed. To
undertake this study a single mobile chest image, selected for the presence of
some subtle pathology in the form of a number of septal lines in both costphrenic
angles, was compressed to levels of 10:1, 20:1 and 30:1. These images were
randomly ordered and shown to the observers for interpretation. Analysis of the
responses indicates that in general it was not possible to distinguish the
original image from its compressed counterparts. Furthermore, a preference
appeared to be shown for images that have undergone low levels of compression.
This preference can most likely be attributed to the 'de-noising' effect of the
compression algorithm at low levels.
PMID- 10761258
TI - Doppler ultrasound (pre- and post-contrast enhancement) for detection of
recurrent stenosis in stented renal arteries: preliminary results.
AB - The purpose of the present paper was to assess whether conventional renal Doppler
ultrasound and the commonly used parameters of peak systolic velocity and renal
aortic ratio may be an appropriate modality for the follow-up of renal artery
stents. A total of 19 arteries in 15 patients was examined with both renal
Doppler ultrasound and angiography for the presence or absence of recurrent renal
artery stenosis. Disease was considered present on angiography if the arterial
diameter was more than 60% stenotic. Doppler criteria for stenosis were either a
peak systolic velocity of > 180 cm/s or a renal aortic ratio of > 3.0. Echo
enhancement with Levovist (Schering, Berlin, Germany) was used if studies were
technically unsuccessful or to improve diagnostic confidence. Renal Doppler
ultrasound detected 100% of renal artery stenoses. The specificity was 75%, the
positive predictive value was 67% and the negative predictive value was 100%.
Echo enhancement improved the technical success rate from 89 to 95% and also
increased diagnostic confidence in six examinations. The present limited study
suggests that similar renal Doppler parameters as used for the study of unstented
renal arteries may be applied to the examination of renal arteries with renal
stents in situ. It therefore suggests that Doppler ultrasound may provide an
adequate non-invasive means of renal artery stent follow-up, particularly when
combined with echo-enhancing agents. Further study is warranted to confirm these
initial conclusions.
PMID- 10761259
TI - 1998 Australian radiology workforce report.
AB - The 1998 Australian Radiologist Workforce Survey findings form the basis of the
present report, prepared by the Workforce Committee of the Royal Australian and
New Zealand College of Radiologists (RANZCR). A more detailed report can be
accessed through the RANZCR web site (http:@www.ranzcr.edu.au). This follows
similar previously published reports by the Workforce Committee in the 1990s. The
issues of radiologist workforce supply and demand are examined, and benchmarks
again reviewed. One of the conclusions of the present report is a possible
upcoming shortage of radiologists in Australia, due to several factors, including
a possible increase in the attrition rate of an ageing radiologist population,
increasing female participation in the workforce, and increasing medical imaging
utilization rates. In comparison with other Organization for Economic Cooperation
and Development (OECD) nations, Australia had a mid-range supply of radiologists,
and also medical imaging utilization, although there has been an increase in the
latter. Australian radiologist annual workloads appear to be increasing.
PMID- 10761260
TI - Early glottic carcinoma: results of treatment by radiotherapy.
AB - The purpose of the present paper was to review the results of treating early
(stages T1-2N0) glottic, squamous cell carcinoma by radiotherapy in the
Department of Radiation Oncology, Prince of Wales Hospital, Sydney. A
retrospective review was carried out of all patients seen in the department from
1967 to 1994, inclusive. To be eligible, patients had to have newly diagnosed
cancer and to have been treated with curative intent by radiotherapy alone. Three
hundred and sixty-nine patients satisfied the eligibility requirements. The mean
follow-up time was 12.2 years (maximum: 28 years). At 5 years the actuarial local
control rate was 80% (84% for stage T1 and 72% for T2). The ultimate local
control rate was 96%. The overall survival rates at 5 and 10 years were 73% and
52%, respectively. The risk of nodal recurrence was much higher after persisting
disease or local recurrence. Our results confirm the high cure rates achieved
with this modality of treatment and are comparable with those reported in the
literature.
PMID- 10761261
TI - The rate of breast-conserving surgery in early breast cancer: an audit of
surgical practice at St Vincent's campus, NSW in 1990 and 1994.
AB - An audit was undertaken to document the use of breast-conserving surgery (BCS) in
the management of early breast cancer (EBC) at St Vincent's campus during two
time periods, the calendar years 1990 and 1994. The medical records of all women
diagnosed with a new primary breast cancer at St Vincent's Public and Private
Hospitals initially treated during 1990 and 1994 were reviewed to document
patient, tumour and treatment characteristics. Comparisons were made with data on
BCS in EBC from the Australian medical literature. A total of 228 patients was
managed with a definitive surgical procedure in the years 1990 and 1994. There
were no major differences in the manner of presentation, the tumour subtypes or
the treatment techniques between the two years. There was an apparent increase in
the number of tumours < 2 cm managed in 1994 but no major difference in the use
of BCS. The BCS rates for the two years were 33 and 36%, respectively. There were
wide variations in the rate of BCS between surgeons, and for the same surgeon,
between the two calendar years. These data from a major teaching hospital serving
a largely non-mammographically screened population would suggest that BCS rates
for EBC are lower than expected. The data on BCS rates for EBC in Australia are
limited and the optimal rate of BCS in current practice is unknown.
PMID- 10761262
TI - A quality assurance audit: phase III trial of maximal androgen deprivation in
prostate cancer (TROG 96.01).
AB - In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality
assurance (QA) audit of its phase III randomized clinical trial investigating the
effectiveness of different durations of maximal androgen deprivation prior to and
during definitive radiation therapy for locally advanced carcinoma of the
prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres
across Australia and New Zealand. In addition to verification of technical
adherence to the protocol, the audit also incorporated a survey of centre
planning techniques and a QA time/cost analysis. The present report builds on
TROG's first technical audit conducted in 1996 for the phase III accelerated head
and neck trial (TROG 91.01) and highlights the significant progress TROG has made
in the interim period. The audit provides a strong validation of the results of
the 96.01 trial, as well as valuable budgeting and treatment planning information
for future trials. Overall improvements were detected in data quality and
quantity, and in protocol compliance, with a reduction in the rate of
unacceptable protocol violations from 10 to 4%. Audit design, staff education and
increased data management resources were identified as the main contributing
factors to these improvements. In addition, a budget estimate of $100 per patient
has been proposed for conducting similar technical audits. The next major QA
project to be undertaken by TROG during the period 1998-1999 is an intercentre
dosimetry study. Trial funding and staff education have been targeted as the key
major issues essential to the continued success and expansion of TROG's QA
programme.
PMID- 10761263
TI - Decision-making models in the analysis of portal films: a clinical pilot study.
AB - Portal films continue to play an important role in the verification of
radiotherapy treatment. There is still some discussion, however, as to what
action should be taken after a port film has shown a radiation field deviation
from the prescribed volume. It was the aim of the present pilot study to
investigate the performance of three decision-making models ('Amsterdam',
'Quebec' and 'Newcastle') and an expert panel basing their decision on intuition
rather than formal rules after portal film acquisition in a clinical setting.
Portal films were acquired on every day during the first week of treatment for
five head and neck and five prostate cancer patients (diagnostic phase). If
required, the field position was modified according to our normal practice
following the recommendation of the expert panel. In order to analyse the results
of the models, however, additional port films were taken in the following 3
treatment weeks with the patient moved as required by the different models
(intervention phase). The portal films were taken over 4 consecutive days,
positioning the patient according to each of the different models on one day
each. None of the models diagnosed a field misplacement in the head and neck
patients, while the 'Amsterdam' and 'Quebec' models predicted a move in one
prostate patient. The 'Newcastle' model, which is based on Hotelling's T2
statistic, proved to be more sensitive and diagnosed a systematic displacement
for three prostate patients. The intervention phase confirmed the diagnosis of
the model, even if the three portal films taken with the patient position
adjusted as required by the model proved to be insufficient to demonstrate an
improvement. The 'Newcastle' model does not rely on assumptions about the random
movement of patients and requires five portal films before a decision can be
reached. This approach lends itself well to incorporation into electronic portal
imaging 'packages', where repeated image acquisitions present no logistical
difficulty.
PMID- 10761264
TI - A study of concurrent radiochemotherapy with paclitaxel in glioblastoma
multiforme.
AB - Despite advances in neurosurgery and radiotherapy, the prognosis of patients with
glioblastoma multiforme remains poor. Reports in the literature about the
radiosensitizing properties of paclitaxel stimulated the authors to conduct a
study using paclitaxel concurrently with radiation in a group of 18 patients who
had residual disease postoperatively. Paclitaxel was delivered weekly as an
intravenous infusion in a dose of 60 mg/m2 along with radiation to the primary
lesion. A total of 108 cycles of paclitaxel was given. All the patients tolerated
the treatment well. The main side effects were haematological, and neuropathy
which was self-limiting. The overall 1-year survival rate was 70%, with 12
patients alive at 13 months. The median survival has not yet been reached
although it is more than 13 months. Thus, paclitaxel can be safely delivered
concomitantly with radiation in patients with glioblastoma multiforme. Larger,
randomized trials are required to establish the comparative efficacy of
paclitaxel as a radiosensitizer in glioblastoma multiforme.
PMID- 10761265
TI - Projected requirements for radiation oncologists and trainees in Australia and
New Zealand to 2007.
AB - Workloads in radiation oncology facilities in Australia and New Zealand have been
increasing steadily for many years and it is anticipated that this trend will
continue. In the present paper the projected number of radiation oncologists
required to meet this demand to the year 2007 are estimated, along with the
number of trainees required. The estimates are based on data from regular surveys
by the Royal Australian and New Zealand College of Radiologists (RANZCR) for the
years 1988-97 (inclusive). From these surveys profiles of numbers, age and gender
of specialists and trainees are documented together with increases from the
training programme and losses from retirement. It is concluded that if the
current trainee numbers are increased by 12 in Australia and two in New Zealand,
there will be approximately 10 radiation oncologists per million of population by
the year 2007. This number is considered appropriate considering the anticipated
increase in demands and complexity of treatment. Because projections too far
forward are unreliable, careful monitoring of progress is essential to obtain the
appropriate balance between requirement and supply. Comparisons are made with
other estimates of needs including the 1998 Australian Medical Workforce Advisory
Committee (AMWAC) Report and the New Zealand Clinical Agency Workforce Project
Report in 1997.
PMID- 10761266
TI - Magnetic resonance imaging features of subacute idiopathic brachial neuritis.
AB - A 60-year-old man presented with sudden onset of left shoulder pain followed 2
weeks later by the development of left shoulder girdle weakness. A clinical and
electrophysiological diagnosis of subacute idiopathic brachial neuritis was made.
The MRI features of subacute muscular denervation in this patient are discussed
and the relevant literature reviewed.
PMID- 10761267
TI - Isolated optic nerve pseudotumour.
AB - Isolated optic nerve involvement by the idiopathic inflammatory process is a rare
finding and very few reports are available. Here a case of an isolated optic
nerve inflammatory pseudotumour presenting with gradually progressive unilateral
loss of vision is described. It showed dramatic response to a trial of steroids
and its differential diagnoses are discussed.
PMID- 10761268
TI - Craniofacial mucormycosis following assault: an unusual presentation of an
unusual disease.
AB - A case of craniofacial mucormycosis following assault is discussed. A female
diabetic developed peri-orbital cellulitis adjacent to a scalp wound which
progressed to a necrotizing fasciitis. This did not respond to treatment.
Subsequently the patient developed a hemiparesis, with CT imaging showing peri
orbital and paranasal sinus inflammatory changes, evidence of cavernous sinus
invasion and development of a middle cerebral artery territory infarction. The
patient died shortly afterwards. The imaging findings and their relationship to
the pathological spread of mucor infection are discussed.
PMID- 10761269
TI - Twin ectopic pregnancy 10 years after permanent sterilization.
AB - An ectopic twin pregnancy was reported in a 37-year-old woman with a history of
tubectomy for permanent sterilization 10 years earlier. Ectopic pregnancy is
common, but twin ectopic pregnancy is a rarer case.
PMID- 10761270
TI - Mesenteric Castleman's disease: ultrasound, computed tomography and angiographic
appearance.
AB - The localized form of Castleman's disease is rare, and a mesenteric location is
particularly unusual. A case of an asymptomatic young woman having the hyaline
vascular type is presented and the ultrasound, CT and angiographic features of
the condition are demonstrated.
PMID- 10761271
TI - Unusual extra-axial central nervous system involvement of non-Hodgkin's lymphoma:
magnetic resonance imaging.
AB - The MR imaging findings in a patient with non-Hodgkin's lymphoma with unusual
involvement of the sella, pituitary stalk and left parasellar region are reported
here. On the basis of the MR imaging findings, the initial differential diagnosis
included invasive pituitary adenoma, a granulomatous lesion and en plaque
meningioma. Trans-sphenoidal biopsy of the sellar mass showed chronic
inflammatory changes and the patient was initially treated for tuberculosis.
Because follow-up imaging showed the lesion to be progressive, a biopsy was done
of an enlarged right inguinal lymph node. This revealed non-Hodgkin's lymphoma.
PMID- 10761273
TI - Multiple calvarial haemangiomas.
AB - Calvarial haemangiomas are rare benign tumours that may be suspected by their
characteristic expansile 'sunburst' appearance. It is important to recognize them
as such and to make the surgeon aware of haemorrhage after biopsy or resection.
PMID- 10761272
TI - Cerebellopontine angle Hodgkin's disease.
AB - Intracranial Hodgkin's disease is a rare site of involvement, and even more rare
is its presentation as a cerebellopontine angle mass. The imaging findings are
non-specific but the rapid response to therapy may provide a clue to diagnosis.
PMID- 10761274
TI - Functional entrapment of the popliteal artery.
AB - A case of functional entrapment missed at the initial angiogram is presented. The
imaging of popliteal artery entrapment syndrome and functional entrapment is
discussed. The importance of appropriate imaging is emphasized. The
classification of popliteal artery entrapment syndrome is discussed and it is
proposed that functional entrapment is added to the existing classification in
the interest of consistent reporting.
PMID- 10761275
TI - Spontaneous rupture of the renal pelvis.
AB - The object of the case report is to present a case of spontaneous rupture of the
renal pelvis with no underlying pathological condition to account for the
rupture, a very rare and unusual occurrence. The patient was a 46-year-old Korean
who presented with severe left loin pain and vomiting. The diagnosis was
suspected on intravenous urography and confirmed by CT. Treatment was by ureteral
stenting. The patient made a complete recovery. The differential diagnosis of
this condition is discussed and the literature is reviewed.
PMID- 10761276
TI - The value of narrow CT window settings in the recognition of subtle acute aortic
intramural haematoma.
AB - Four patients with acute aortic intramural haematoma are presented. In all
patients the typical crescentic hyperdense rim within the aortic wall was not
obvious on unenhanced CT when reviewed on standard mediastinal windows, but the
hyperdense crescentic rim was well seen on narrow window settings. The findings
suggest that all patients with a typical clinical presentation of acute thoracic
aortic dissection who do not have a classical dissection on contrast-enhanced CT
or a hyperdense intramural haematoma on standard mediastinal settings, should
have the non-contrast scans reviewed on narrow window settings.
PMID- 10761277
TI - Simulated bone metastases: a case study of two patients with breast cancer:
comment.
PMID- 10761278
TI - Basic treatment equivalent is better, but not perfect.
PMID- 10761279
TI - A cognitive model of posttraumatic stress disorder.
AB - Posttraumatic stress disorder (PTSD) is a common reaction to traumatic events.
Many people recover in the ensuing months, but in a significant subgroup the
symptoms persist, often for years. A cognitive model of persistence of PTSD is
proposed. It is suggested that PTSD becomes persistent when individuals process
the trauma in a way that leads to a sense of serious, current threat. The sense
of threat arises as a consequence of: (1) excessively negative appraisals of the
trauma and/or its sequelae and (2) a disturbance of autobiographical memory
characterised by poor elaboration and contextualization, strong associative
memory and strong perceptual priming. Change in the negative appraisals and the
trauma memory are prevented by a series of problematic behavioural and cognitive
strategies. The model is consistent with the main clinical features of PTSD,
helps explain several apparently puzzling phenomena and provides a framework for
treatment by identifying three key targets for change. Recent studies have
provided preliminary support for several aspects of the model.
PMID- 10761280
TI - Responsibility attitudes and interpretations are characteristic of obsessive
compulsive disorder.
AB - The cognitive-behavioural theory of Obsessive Compulsive Disorder (OCD) proposes
that a key factor influencing obsessional behaviour is the way in which the
intrusive cognitions are interpreted. The present paper reports an investigation
of links between clinical symptoms (of anxiety, depression and obsessionality)
and responsibility beliefs. These beliefs include not only measures of general
responsibility attitudes (assumptions) but also more specific responsibility
appraisals consequent on intrusive cognitions. The characteristics of two new
questionnaires specifically designed to measure these beliefs were assessed in
patients suffering from Obsessive Compulsive Disorder, in patients suffering from
other anxiety disorders and in non-clinical controls. The scales measuring
negative beliefs about responsibility were found to have good reliability and
internal consistency. Comparisons between criterion groups indicate considerable
specificity for both assumptions and appraisals with respect to OCD. There was
also good evidence of specificity in the association between responsibility
cognitions and obsessional symptoms across groups, and that this association was
not a consequence of links with anxiety or depressive symptoms. Although the two
measures were correlated, they each made unique contributions to the prediction
of obsessional symptoms. Overall, the results are consistent with the hypothesis
that responsibility beliefs are important in the experience of obsessional
problems.
PMID- 10761281
TI - The facilitative effects of heart-rate feedback in the emotional processing of
claustrophobic fear.
AB - This study examines predictions derived from Foa and Kozak's theory of emotional
processing. We hypothesized that the provision of heart-rate feedback would
facilitate emotional processing through a fuller activation of the participant's
fear structure, and by focusing participants' attention on information that is
incompatible with the fear structure, i.e., the interoceptive pattern of
habituation. Nonclinical students (N = 54) showing marked claustrophobic fear
received 30 min of self-directed exposure to a claustrophobic chamber. Three
exposure conditions (heart-rate feedback, paced-tone control, and exposure only
control) were examined across six 5-min exposure trials. Participants receiving
heart-rate feedback displayed greater between-trial habituation across treatment
trials and lower levels of fear at post-treatment. Treatment process findings
failed to support the fear activation hypothesis. Implications of the findings
for theories of fear reduction are discussed.
PMID- 10761282
TI - The effects of 'non-directive' questioning on an anticipated decision whether to
undergo predictive testing for heart disease: an experimental study.
AB - This study investigates how individuals can be helped to make decisions about
predictive genetic testing. Participants (n = 120) rated how likely they would be
to opt for predictive testing for heart disease if it were available, and other
variables such as anxiety about heart disease. They received information on
predictive testing for heart disease and ratings were repeated. Participants were
then randomly allocated to one of three groups and focused on the personal
relevance of positive issues or negative issues which had been mentioned as part
of the standardised information previously given. The third group focused on
issues irrelevant to testing for heart disease. The form of questioning used in
this focusing manipulation was intended to model the processes involved in non
directive questioning. Results showed a significant increase in likelihood of
testing in the positive group, and a significant decrease in the negative group.
There was also a significant decrease in rated anxiety about heart disease and
perceived severity of an increased susceptibility to heart disease of the
negative group relative to the positive and control groups. The results may have
implications for the ways in which pre-test counselling is carried out.
PMID- 10761283
TI - Patterns of anxious arousal during exposure to feared situations in individuals
with social phobia.
AB - Behavioral assessment tests (BATs) are commonly used in studies of social phobia
(SP). While previous studies have examined subjective anxiety during BATs, they
have usually reported only mean or peak ratings. The current study examined
whether there are different patterns of anxious arousal in anticipation of, and
during exposure to, feared situations among individuals seeking treatment for SP
(N = 153). A four cluster solution was judged to best describe the data, and the
four clusters were labeled 'high anxiety,' 'increasing/high anxiety', 'moderate
anxiety' and 'mild anxiety'. Before treatment, the cluster groups did not differ
on person characteristics, subtype of social phobia, or levels of depressive
symptoms. However, they did differ in terms of the severity of social phobia
symptoms and the emotional valence of thoughts reported at the conclusion of the
BAT. While members of all clusters benefited from cognitive-behavioral group
therapy for social phobia, the clusters showed some differential response in
amount of symptom reduction and likelihood of continuing to meet diagnostic
criteria following treatment. The different emotional experiences of clients in
the various clusters are explored and implications for cognitive-behavioral
therapy are proposed. Finally, limitations of this study and future directions
are discussed.
PMID- 10761284
TI - [Telemetric impedance analysis of the liver: evaluation of a noninvasive device
for diagnosis of acute graft rejection after experimental liver transplantation].
AB - Allograft rejection and its differentiation from other causes of organ
dysfunction remains a diagnostic problem in liver transplant patients. Currently,
acute rejection can be prevented only by a combination of diagnostic and
therapeutic modalities. The diagnostic potential of a novel implantable
telemetric rejection monitoring device has been assessed on the basis of the
noninvasive impedance analysis in normal and liver transplanted pigs. The
electric impedance data were correlated with biochemical and histological
parameters. Acute rejection was correctly predicted in n = 4, and correctly
excluded in n = 32, biopsy-related impedance recordings (p = 0.004). A
correlation between impedance measurements and severity of histological findings
r = 0.84; p = 0.0001) was confirmed. Only the biochemical parameters SGLDH and
serum bilirubin revealed a comparable correlation. Impedance gradient analysis
revealed evidence of a physiological relationship between liver function and the
electrical properties of the organ. Telemetric impedance analysis would appear a
promising means of assessing acute rejection noninvasively.
PMID- 10761285
TI - [Characterization of mechanical in vitro hemolysis and sub-hemolysis. 2:
Variables of state and dimensionless characteristic values of hemolysis].
AB - Blood damaging effects of artificial perfusion devices such as assist devices,
heart valve prostheses, for example, must be evaluated in vitro before being used
in the clinical setting. For this purpose, mainly animal blood has been used, and
a number of associated problems are currently being discussed. Differences in the
use of the term hemolysis--meaning breakdown of erythrocytes or increased plasma
hemoglobin, result in incompatibility among different authors. In addition,
subhemolytic damage and its quantification has not been investigated to any
extent. Another problem are the differences in the mechanical fragility of
erythrocytes from different animal species, and the question of transferability
to the in vivo situation. Furthermore, the variability of mechanical stability
within a given species is often greater than the differences between one species
and another. International efforts are now being made to standardize haemolytic
test conditions and the present study is meant as a contribution to this. In the
first part we describe an extension of our LYSE number model. Characteristically,
the model uses dimensionless similarity numbers, LY and MY, thus making the
results obtained under different test conditions comparable with one another. The
LY number reflects the breakdown of cells (decreasing hematocrit), the MY number
an increase in plasma hemoglobin. Differences between LY and MY are an indication
of subhemolytic events.
PMID- 10761286
TI - A simple, PC-dedicated, implanted digital PIM radiotelemetric system.
AB - The short-distance, PC-dedicated implanted telemetry system is described.
Schematic drawings of the transmitter and Centronics port interface are given and
the main problems of the controlling program are discussed. The interface can be
easily converted to serve as an analog output and the method of adaptation is
demonstrated. The whole system was tested in animal experiments with two
different amplifiers and the examples of resulting direct ECG and both direct and
integrated intestinal EMG recordings are included.
PMID- 10761287
TI - [Semi-automatic generation of finite element meshes fo dental preparations].
AB - The mechanical properties and elastic behaviour of periodontal tissue are a
decisive factor in understanding initial tooth mobility and bone remodelling
processes in orthodontics. An experimental set-up was designed to precisely
determine a tooth's elastic response to different loading conditions. Segments of
pig's maxilla bearing separated molars were used, and their mechanical response
to loading was recorded. Subsequently, finite element analysis (FEA) was
performed on the basis of the experimental data. The combination of experimental
and numerical methods was used to determine the material properties of the
periodontal ligament (PDL). The geometries of the preparations were reconstructed
and FE meshes generated semi-automatically with the aid of the special computer
program, CAGOG (Computer Aided Generator for Orthodontic Geometries) to optimally
match the experimental geometry. Nonlinear material parameters were determined
for the PDL and verified by comparing experimental and numerical results obtained
in other specimens with an error of about 10%. This good correlation indicates
that the selected method of mesh generation is appropriate for creating realistic
FE models that can be compared with experimental results.
PMID- 10761288
TI - Osteodensitometry in uncemented total hip arthroplasty using computertomography.
AB - The aim of this investigation was to evaluate a new method developed for the
measurement of bone mineral density and bone remodelling phenomena after total
hip arthroplasty using computer tomography. Computertomography is a radiological
technique to examine bone structures in high resolution. Using an extended scale
it is possible to investigate bone scans and implants with fewer metal artifacts.
For osteodensitometry measurement a special software (IMPact HIP) for the
analysis of the data was used. The measured parameters were the overall bone
mineral density (mg Calcium-Hydroxyapatite/ml) and the cortical bone structure. A
standard scan mode enable to compare the computertomography scans at follow-up.
Nineteen total hip arthroplasty patients (20 hips) with a mean age of 58 years
(31-70) were operated on using an uncemented titanium alloy stem with a tapered
design. The periprosthetic bone was assessed using computertomography-assisted
osteodensitometry two weeks and one year after surgery. We observed a decrease of
the overall bone mineral density (15%) and of the cortical bone structure (20%)
one year after insertion of the stem in the proximal part of the femur. The area
corresponds to the Gruen zones 1 and 7. On the other hand, a decrease of mineral
density of 5% for the overall bone and of 3% for the cortical bone was found at
the level of the tip of the stem, which corresponds to the Gruen zones 3, 4 and
5. Computertomography-assisted osteodensitometry allows to investigate the bone
remodelling after total hip arthroplasty by separating the analysis of the
overall bone mineral density and of the cortical structure. The present method is
a reliable tool for quality-control in total hip arthroplasty.
PMID- 10761289
TI - [Additive effect of pilocarpine and Timoptol on pupillary diameter and
intraocular pressure in healthy rabbits].
AB - In the submitted paper experimental results are interpreted comparing the
administration of two fundamental anti-glaucomatous drugs into the conjunctival
sac of healthy rabbits of the Chinchilla strain. The authors administered 2%
pilocarpine and 0.25% Timoptol (Timololi maleas, Leciva) alone, as combined
consecutive administration and concurrent administration. The greatest effect on
the width of the pupil and on IOP was exerted before 60 minutes by administration
of pilocarpine, then Timoptol resp. And after 60 minutes the mixture of the two
substances was most effective. This effect is explained by the additive action
via substances produced by interaction (metabolites). Pilocarpine being a
cholinergic substance promotes formation of the vitreous fluid and thus also an
increased supply of free amino acids into ciliary body processes and the vitreous
fluid. Timoptol then interacts with the increased amount of free amino acids and
thus a greater and longer reduction of VOT occurs than after the action of newly
formed cholinergic or newly formed adrenergic substances alone.
PMID- 10761290
TI - [The idiopathic uveal effusion syndrome].
AB - The authors describe two cases of idiopathic uveal effusion syndrome, in one
instance affecting consecutively both eyes, in the second patient the finding is
unilateral so far. In the female patient with the bilateral finding reattachment
of the retina and improvement of the visual acuity developed only after surgery
(sclerotomy). The second patient, where the disease was detected only
accidentally, is so far only under observation. The authors discuss the causes of
this rare disease, the variability of clinical symptoms, diagnostic and
therapeutic possibilities.
PMID- 10761291
TI - [Glaucoma after surgery for idiopathic macular holes].
AB - The objective of the prospective randomized study is to evaluate the effect of
surgery of an idiopathic macular hole (IMH) on intraocular pressure (IOP). The
study comprised 60 primary pars plana vitrectomies (PPV) on account of IMH using
16% perfluoropropane (C3F8). Stage III according to Gass predominated in 65% and
stage IV in 28.3%. Furthermore the authors enlisted in the study 15 secondary PPV
on account of a patent IMH. A total of 75 primary and secondary PPV were
performed. In 43 PPV an autologous thrombocyte concentrate (ATC) was used. With
regard to the IOP after PPV the patients were subdivided into the following
groups. Group A: IOP under 24 mm Hg was recorded throughout the investigation
period in 24 of 75 PPV (32%). The total mean value of IOP in group A was 17.4 mm
Hg. Group B: Early increase of IOP during the first week after surgery was
recorded in 51 of 75 PPV (68.0%) This group was divided into two sub-groups
according to the maximum postoperative deviation of IOP during that period. Sub
group B1 comprised a total of 34 PPV (45.3%) where the maximum postoperative
deviation of IOP was between 25-35 mm Hg. The total mean value of IOP in sub
group B1 was 23.5 mm Hg. In sub-group B2 there was a total of 17 PPV (22.7%) and
the maximum postoperative deviation of IOP was above 35 mm Hg. The total mean
value of IOP in sub-group B2 was 28.6 mm Hg. Moreover the authors investigated
the effect of ATC administration on the IOP after primary and secondary PPV. They
did not reveal a significant relationship between administration of ATC and
postoperative glaucoma. CONCLUSION: 1. Glaucoma after PPV in IMH can in
individual cases cause deterioration of the functional results of the operation.
PPV in IMH has an increased risk: a) in a monoculus, b) in advanced primary
glaucoma with an open angle, c) in primary glaucoma with a narrow angle.
PMID- 10761292
TI - [Visual function after pars plana lensectomy and intraocular lens implantation in
dislocation of the lens into the vitreous body].
AB - The authors evaluate the functional result of the surgery solving luxation of
lenses into the vitreous body cavity with helping of pars plana lensectomia with
implantation of intraocular lenses, they have been performed in The Department of
Ophthalmology of The Teaching Hospital of The Charles University in Hradec
Kralove between February 1995 to February 1999. Our group consisted of 11
patients (11 eyes), 8 males and 3 females in the age from 28 to 81 years, with
average age of 60 years, the patients were divided into 3 units. 1st unit is
represented by 5 patients with traumatic luxation of lens into vitreous body
cavity after its contusion with developing of the secondary glaucoma, in the 2nd
unit there are 5 patients with this complication as a consequence of operation of
cataract, the 3rd unit includes only 1 patient with the Marfan syndrome. Study
proved the fact that due to using of new surgical methods it is possible to keep
a satisfactory visual functions in patients with a serious eye complications.
PMID- 10761293
TI - [Results of implantation of endocapsular distance rings].
AB - Endocapsular distance ring increases possibilities of extraction subluxated
cataract. Its importance consists of stabilisation of capsular bag and with the
possibility of implantation posterior intraocular lens. In the group there are 20
patients with implanted 21 distance rings. The period of follow up was 4-24
months. We used of a polymethyl methacrylate distance ring from firms Erilens,
Morcher and IOLTechnology. Indication for the implantation of a distance ring was
dialysis less than 2 quadrants, it depends on size and type of distance ring. The
authors evaluate complications during the operation and early and later results
after operation.
PMID- 10761294
TI - [Phacoemulsification in chronic closed-angle decompensated glaucoma].
AB - The author followed up the medium-term results of cataract operations in five
patients with decompensated closed angle glaucoma. From the results ensues that
in patients with an intraocular pressure of less than 30 mm Hg surgery of
cataract alone has a positive effect on the compensation of glaucoma. An
advantage is also the standard surgical technique. The operation is made on an
eye with a narrower pupil and requires an experienced ophthalmosurgeon.
PMID- 10761295
TI - [Frequency of secondary cataracts in patients with AcrySof MA30BA and MA60BM
lenses].
AB - The authors present an account on the incidence of secondary cataract in AcrySof
lenses MA30BA and MA60BM in a group of 65 eyes. The authors selected as criterium
for evaluation of secondary cataract the transparency of the posterior capsule in
correlation with deterioration of visual acuity and the number of performed
Nd:YAG posterior capsulotomies. The follow-up period was 6 to 32 months. The
incidence of secondary cataract in AcrySof lenses was 13.8%, the number of
performed capsulotomies was 0. These results were compared with the incidence of
secondary cataract in PMMA and silicone lenses. The incidence of secondary
cataract in eyes with PMMA lenses was recorded in 58.5% and in eyes with a
silicone lens in 46.2%. In eyes with a PMMA lens Nd:YAG posterior capsulotomy was
performed in 32% and in eyes with a silicone lens in 26%.
PMID- 10761296
TI - [Clinical results in implantation of 150 MemoryLens lenses].
AB - The authors present results of prospective clinical study of 150 foldable
hydroacrylate intraocular lenses MemoryLens (CIBA Vision). There were 75 women
(52.82%) and 67 men (47.18%), altogether 142 patients (150 eyes). All lenses were
implanted through 3.5 mm clear-cornea tunnel incision. Best corrected visual
acuity was 6/9 or better in 119 eyes (79.3%) on the first postoperative day and
in 136 eyes (90.6%) one year after surgery. Induced astigmatism was below 0.5 D
in 59 eyes (39.3%) on the first postoperative day and in 140 eyes (93.3%) one
year after surgery. Capsular opacification rate was 3.3% (5 eyes) one year after
surgery. We have not seen any serious complications. Excellent postoperative
results enable us to suggest MemoryLens for routine use after phaco surgery.
PMID- 10761297
TI - [Standards of ultrasonography of the ocular bulb. Principles of standardised
ultrasonography and the examination technique].
PMID- 10761298
TI - [Histochemical analysis of enzymes in the rabbit cornea after LASIK surgery].
AB - The first experience with histochemistry of rabbit corneas after the operation
LASIK is presented in this study. Activity of the following enzymes was assessed:
alkalic phosphatase, acid phosphatase and dipeptidylpeptidase IV. No pathological
activity of assessed enzymes was found in comparison with control corneas.
PMID- 10761299
TI - [Choroid cysts--laser therapy].
AB - The author presents the survey of cysts of choroid classification. He covers a
case of serous cyst of iris of a young man. The cyst caused the vision disorder
because of pressure on the front capsule of lens. The successful therapeutical
method was a laser photocoagulation. There was not find any recurrent disease
during the six years of monitoring.
PMID- 10761300
TI - [Fluorescence angiography in Stargardt's disease].
AB - The author submits information on Stargardt's disease, and based on a case-report
he mentions actual steps which led to the establishment of the diagnosis of the
disease. Stargardt's disease is one of the forms of juvenile macular degeneration
which affects the retinal pigmented epithelium. It is a relatively rare
hereditary, slowly progressing, usually bilateral disease leading to
deterioration of vision. In the majority the heredity is autosomal recessive. The
majority of ophthalmologists do not encounter the disease in their practice but
it has to be taken into consideration.
PMID- 10761301
TI - [Corneal transplantation].
PMID- 10761302
TI - Ultrastructural analysis of human eosinophils.
PMID- 10761303
TI - Differentiation of human eosinophils. Role in allergic inflammation.
PMID- 10761304
TI - The surface phenotype of human eosinophils.
PMID- 10761305
TI - IgE receptors on human eosinophils.
PMID- 10761306
TI - Metabolism of lipid mediators in human eosinophils.
PMID- 10761307
TI - Inflammatory cell activation by eosinophil granule proteins.
PMID- 10761308
TI - Immunological interactions between human eosinophils and cardiac mast cells.
PMID- 10761309
TI - Eosinophil cytokines.
PMID- 10761310
TI - Expression of eosinophil-specific chemokines by human epithelial cells.
PMID- 10761311
TI - Activation of human eosinophils by chemokines.
PMID- 10761312
TI - Hypereosinophilic syndromes.
PMID- 10761313
TI - Eosinophilic diseases of the skin.
PMID- 10761314
TI - Increased transmission of syphilis in Manchester.
PMID- 10761316
TI - HIV/AIDS infection.
PMID- 10761315
TI - Orthodontic training.
PMID- 10761317
TI - Amalgam.
PMID- 10761318
TI - A multidisciplinary approach to pre-operative implant diagnostics.
PMID- 10761319
TI - Facilitating clinical oral research in Canada.
PMID- 10761320
TI - "Think globally, act locally".
PMID- 10761322
TI - Safeguard your practice against losses.
PMID- 10761321
TI - Sociodemographic and workload characteristics of dentists who participated in
national survey, 1995.
AB - Comprehensive, standardized data on the sociodemographic characteristics and
workload of dentists in different provinces and territories in Canada are not
available. The authors mailed a survey to a stratified random sample of dentists
(n = 6,444) with three follow-up attempts. The response rate was 66.4%.
Significant provincial and territorial differences in sociodemographic
characteristics included gender, age, years since graduation, marital status,
population size of town or city where primary practice is located and patient
load. There was considerable variation in dentists' workload: more than 10% of
dentists from New Brunswick and Prince Edward Island reported seeing > or = 30
patients per day. The majority of respondents reported seeing patients for 25 to
40 hours per week. British Columbia, Ontario, Saskatchewan and Newfoundland had a
greater proportion of respondents > or = 60 years of age compared with other
provinces/territories, indicating that there may be more opportunities in these
provinces for younger dentists as a result of retirements.
PMID- 10761323
TI - New method to prevent bladder dysfunction after radical hysterectomy for uterine
cervical cancer.
AB - OBJECTIVE: The purpose was to improve the surgical procedures to prevent bladder
dysfunction after radical hysterectomy. METHODS: Twelve patients with stage Ib
cervical cancer underwent intraoperative electrical stimulation to identify the
vesical branches of the pelvic nerves. Autonomic nerve localization in the
vesicouterine ligament was examined in 10 patients immunohistochemically.
According to the results of the above studies a new method to preserve the
vesical branches was developed. Grades of postoperative bladder dysfunction were
compared between new (n = 19) and conventional methods (n = 18). RESULTS:
Electrical stimulation on the outer surface of the posterior sheath of the
vesicouterine ligament caused the increase of intravesical pressure. S-100
protein localized also on this area. Postoperative compliance of the detrusor in
cases with the new method demonstrated less decrement from preoperative values
than in cases with the conventional method. The new method required significantly
fewer days to achieve residual urine volumes less than 50 ml after surgery.
CONCLUSIONS: The new method significantly reduces bladder dysfunction after
radical hysterectomy.
PMID- 10761324
TI - An earlier menopause as clinical manifestation of granulosa-cell tumor: a case
report.
AB - We present a case of a granulosa-cell tumor, which can cause menopause at an
earlier than normal age. The hormonal profiles were characterized by undetectable
FSH levels associated with an estradiol level compatible with the level seen in
perimenopausal women and by a significant increase in the inhibin level.
PMID- 10761325
TI - Intrapartum common peroneal nerve compression resulted in foot drop: a case
report.
AB - This case report is to illustrate a case of a 24-year-old Jordanian woman,
gravida 1, para 0 who developed intrapartum foot drop due to compression injury
of the common peroneal nerve behind the head of fibula. Diagnosis was based on
history, clinical examination and electrophysiological studies. Treatment
included daily sessions of physiotherapy. Complete recovery of the condition took
place within 2 months.
PMID- 10761326
TI - Contraception in diabetic women: comparative metabolic study of Norplant, depot
medroxyprogesterone acetate, low dose oral contraceptive pill and CuT380A.
AB - OBJECTIVE: To evaluate the long-term intake of Norplant, depot
medroxyprogesterone acetate (DMPA) and low dose oral contraceptive pill (OCs) on
glycemic control, lipoprotein metabolism and coagulation profile in diabetic
women. METHODS: Prospective comparative study including 80 uncomplicated
controlled diabetic women. Twenty women allocated to each group. Clinical,
metabolic and coagulation status were followed up at 3, 6 and 9 months' visits.
RESULTS: Fasting blood sugar increased in OCs and DMPA users. Total cholesterol
(TC) and LDL-cholesterol (LDL-C) decreased in all groups except DMPA where it
increased. Triglyceride (TG) only increased in OCs group. HDL-cholesterol (HDL-C)
increased with OCs and decreased with Norplant and DMPA. Compared to IUD users,
significantly higher percentage TG and HDL-C and lower LDL-C were observed in OCs
users, while DMPA users had significantly higher TC and LDL-C and lower HDL-C.
Partial thromboplastin time was prolonged in Norplant users. CONCLUSION: In
diabetics, Norplant results in minimal metabolic alterations followed by OCs
while DMPA has unfavorable outcome.
PMID- 10761327
TI - Maternal and perinatal outcome of pregnancies after the age of 45.
AB - OBJECTIVE: To describe the maternal and perinatal outcome of pregnancies in women
aged 45 years or more at the time of delivery and to compare them with
pregnancies in women aged between 20 and 29 years. METHODS: A retrospective
review of hospital deliveries after 28 weeks gestation was performed at the
Princess Badeea Teaching Hospital in North Jordan for patients delivered between
1st April 1994 and 31st December 1997. We compared the maternal and perinatal
outcome of pregnancies in women aged of 45 years or more (study group, n = 114)
with women aged between 20-29 years (control group, n = 121) delivered at the
same hospital during the same period. RESULTS: The incidence of pregnant women
aged 45 years or more was 3.3 per 1,000 births. The median maternal age was 45
years. The majority of women (81.6%) were 45 to 46 years old. Gravidity and
parity was significantly higher in the study group (p < 0.0001), also antenatal
and medical complications as pre-eclampsia and diabetes mellitus were higher in
the study group. Caesarean section rate, incidences of placental abruption and
placenta previa were more common in older patients compared with young patients
(32.4 vs 10.7%, 6.1 vs 0.8% and 4.4 vs 1.6%, respectively). There were no
differences in the incidences of neonatal deaths, lethal malformations and fetal
weight between the 2 groups. CONCLUSION: Women aged 45 years or more at delivery
may expect a good pregnancy outcome but should expect a higher incidences of
placental abruption, placenta previa, preeclampsia and caesarean delivery.
PMID- 10761328
TI - Asymptomatic uterine incarceration at term gestation: a case report.
AB - Uterine incarceration is a rare event complicating pregnancy. Herein, we present
a unique case of an asymptomatic term pregnancy with uterine incarceration; this
patient had had an anterior myomectomy 3 years earlier. She had an asymptomatic
antenatal course and incidental identification of uterine incarceration during
cesarean section. We also address the importance of early recognition and
appropriate management regarding this circumstance.
PMID- 10761329
TI - A case of a sclerosing stromal ovarian tumor that expresses VEGF.
AB - A case of a sclerosing stromal tumor (SST) of the ovary is presented. One of the
tumor's characteristics was its high vascularity. On immunohistochemical
staining, the vascular endothelial growth factor (VEGF) was positive for both
cellular and edematous areas in the tumor. VEGF was thought to be a factor that
affected the clinicopathological features of this tumor.
PMID- 10761330
TI - B-cell-type malignant lymphoma with placental involvement.
AB - We present here a case of B-cell-type mediastinal malignant lymphoma during
pregnancy complicated by placental involvement. In this case, some nodular high
echo patterns were recognized in the placenta by ultrasonography. A cesarean
section and resection of the mediastinal tumor were performed at 33 weeks and 6
days of gestation due to the deterioration of the dyspnea. A female infant
weighing 1,868 g was delivered and she is now a healthy 2-year-old. The mother,
however, died of the disease 1 month after surgery, due to progression of the
tumor. The placenta showed numerous white firm nodules varying from 3 mm to 3 cm
in diameter. The pathologic findings of both the mediastinal tumor and the
placenta indicated primary mediastinal (thymic) B-cell lymphoma.
PMID- 10761331
TI - Primary peritoneal pregnancy: a case report.
AB - A 22-year-old primipara using intrauterine contraceptive device was diagnosed to
be in haemorrhagic shock due to acute ruptured ectopic pregnancy. At laparotomy,
both tubes and ovaries were normal and products of conception were found to be
implanted on the posterior surface of uterus near the attachment of right
uterosacral ligament producing a haemoperitoneum of more than 2 l. This is the
fourth case report of primary abdominal pregnancy associated with intrauterine
contraceptive device (IUCD).
PMID- 10761332
TI - Influence of female age on pregnancy outcome in in vitro fertilization and embryo
transfer patients undergoing intracytoplasmic sperm injection.
AB - PURPOSE: To determine the influence of female age on the outcomes of ICSI in IVF
ET patients. METHODS: One hundred and seventy-five couples underwent 352 cycles
of ICSI. The quality of oocytes and embryos, fertilization rate, and pregnancy
outcomes were retrospectively evaluated according to female age; < 30 years in
Group A (49 cycles), 30-34 in Group B (177 cycles), 35-39 in Group C (97 cycles),
and > or = 40 in Group D (29 cycles). RESULTS: The fertilization rates were not
significantly different among the age groups. Significant negative linear
correlations were observed between female age and the numbers of oocytes
retrieved and embryos transferred, and cumulative embryo score. Clinical
pregnancy rates were significantly decreased and spontaneous abortion rate
increased with advancing age. CONCLUSIONS: Female age may be a prognostic
indicator in ICSI program.
PMID- 10761333
TI - Clinical usefulness of basal FSH as a prognostic factor in patients undergoing
intracytoplasmic sperm injection.
AB - OBJECTIVE: To determine if basal serum follicle stimulating hormone (FSH) level
could be a prognostic factor of the clinical outcome in intracytoplasmic sperm
injection (ICSI) cycles in the couples with male factor infertility. MATERIALS
AND METHODS: From December 1995 to March 1998, total 118 patients underwent in
vitro fertilization and embryo transfer (IVF-ET) with ICSI due to male factor
infertility were included in this study. Patients were allocated to the low basal
FSH group (< 8.5 mIU/ml) and the high basal FSH group (> or = 8.5 mIU/ml). The
basal levels of FSH were measured in the 3rd day of menstrual cycle preceding
ovarian stimulation cycle in total IVF cycles by immunoradiometric assay (IRMA).
Statistical analysis was performed using Student's t-test, Fisher's exact test,
and chi 2 test as appropriate. Statistical significance was defined as p < 0.05.
RESULTS: The total dose of exogeneous gonadotropin required in the high basal FSH
group was significantly higher than that in the low basal FSH group. The numbers
of retrieved oocytes and oocytes with grade I, II were significantly higher in
the low basal FSH group. The clinical pregnancy rate per cycle in the low basal
FSH group (16.2%) was significantly higher than that in the high basal FSH group
(4.0%). CONCLUSION: These results suggested that the basal serum FSH levels could
be predictive of pregnancy outcome and the results of controlled ovarian
hyperstimulation (COH) in ICSI cycles.
PMID- 10761334
TI - Effect of labour and delivery on plasma hepatic enzymes in the newborn.
AB - OBJECTIVE: To study the relationship between cord blood hepatic enzymes and
obstetric and neonatal outcome in a Chinese population. MATERIALS AND METHODS:
The study group consisted of 288 low-risk Chinese women with singleton term
pregnancies. The following enzymes were assayed in cord blood: lactate
dehydrogenase (LDH), glutamyl transferase (GGT), aspartate aminotransferase (AST)
and alanine transferase (ALT). These were correlated to maternal and neonatal
characteristics. RESULTS: A strong correlation was noted between cord blood AST
and LDH (R = 0.582, p < 0.01), which was absent amongst those infants delivered
by elective cesarean section. LDH, AST and ALT were negatively correlated with
cord arterial pH and base excess (BE). GGT was inversely related only to
gestational age (R = -0.18, p < 0.01). Both LDH and AST were weakly correlated
with the duration of the first and second stages of labour. LDH was most closely
linked to arterial pH, whereas AST was related to both arterial BE and duration
of the second stage. CONCLUSIONS: The reference values are comparable to those
published for Caucasian populations. There are moderate elevations in LDH and AST
associated with the onset of labour and changes in acid-base status.
PMID- 10761335
TI - The fimbrio-ovarian relation and its role on ovum picking in unexplained
infertility: the fimbrio-ovarian accessibility tests.
AB - OBJECTIVE: To study the ovum pickup mechanism and the fimbrio-ovarian relation in
fertile women and cases of unexplained infertility and to design a method for
investigation and anticipation of the state of ovum pickup. DESIGN: Prospective
clinical study. SETTING: Department of Obstetrics and gynecology Kasr El Aini
Hospital, Cairo University, Egypt. PATIENTS: Fifty fertile and 25 cases of
unexplained infertility. INTERVENTIONS: In all of cases the fimbrio-ovarian
relation is studied by determining the length of the free ovarian border between
the ovarian ligament and the fimbria ovarica that contains the corpus luteum (the
ovulation border), the site of ovulation on that border and the length of the
fimbria ovarica. It is also determined by a simple test "The fimbrio-ovarian
accessibility test." The fimbriae are held by non-traumatizing grasper and their
ability to reach and/or to cover the ovulation site are taken as a prove for
successful ovum pickup. In addition, cases having suspected failed ovum picking
are treated by controlled superovulation, also by drilling of the ovary at an
accessible site to the fimbria ovarica and by freeing short fimbria ovarica with
or without its advancement on the ovulation border. RESULTS: The ovulation site
is found to be usually accessible to the fimbrial end of the tube (94%) in the
fertile cases and not accessible (92%) in the infertile cases. Correction of the
fimbrio-ovarian relation in the infertile cases was associated with a cumulative
ongoing pregnancy rate of 68%. CONCLUSION: Failed ovum pickup should be
considered one of the important causes of unexplained infertility. The suggested
"fimbrio-ovarian accessibility" test may be useful for the elucidation of the
state of ovum pickup in infertile cases. Correction of the fimbrio-ovarian
relation, to make ovum pickup possible, should be considered a method for
treating such cases.
PMID- 10761336
TI - Transvaginal hysterosalpingo-contrast sonography (HyCoSy) compared with
chromolaparoscopy.
AB - OBJECTIVE: To compare the efficacy and safety of HyCoSy with chromolaparoscopy
for the diagnosis of tubal occlusion and uterine abnormalities. METHODS: Sixty
infertile women in whom the cause of infertility was thought to be tubal
occlusion or uterine abnormalities and who satisfied the inclusion and exclusion
criteria as specified in the study protocol were included. HyCoSy was performed
during the first half of the menstrual cycle at least 24 hours prior to
chromolaparoscopy. The results from both HyCoSy and chromolaparoscopy were
compared in assessing tubal occlusion and uterine pathology. RESULTS: For the
evaluation of fallopian tubes, we found corresponding results between HyCoSy and
chromolaparoscopy in 80.0%. The agreement between both procedures in assessing
the uterine pathology was 80.4%. Twenty-two women experienced adverse events. The
most common complaint was pelvic pain. Other events encountered were: nausea (3
women) and vaginal bleeding (2 women). All events were thought to be not related
to the study drug. CONCLUSION: HyCoSy showed good diagnostic performance in the
evaluation of the fallopian tubes and uterus in infertile women. The adverse
events reported in this study are minor and procedure-related (catheter
insertion) rather than the trial substance.
PMID- 10761337
TI - Pediatric psychopharmacology.
PMID- 10761338
TI - Fragile X syndrome.
PMID- 10761339
TI - Central auditory processing disorder and ADHD.
PMID- 10761340
TI - Cannabis use by French adolescents.
PMID- 10761341
TI - School consultation: a review of research on issues unique to the school
environment.
AB - OBJECTIVE: To provide clinicians with current information to assist in their
consultations to schools on 4 major topics that are unique to the school
environment and of serious concern to educators: absenteeism, disciplinary
referrals, retention (non-promotion), and dropping out. METHOD: Computer
literature searches and the major journals of the various school disciplines were
used to identify empirically based articles with sound methodology. Information
on each of the 4 issues is presented as general characteristics, characteristics
of psychopathology, prevention and treatment, and implications for consultation.
RESULTS: Findings are largely general, with little specific information on level
of intelligence, learning disorders, psychopathology, or family stressors.
Students under each topic have varied presentations. However, many pupils with
absenteeism, disciplinary referrals, or retention appear to be characterized by
chronic and serious academic and/or behavior problems, all of which can predate
dropping out. CONCLUSIONS: Considerable research is still needed on all 4 school
issues, especially psychopathology. Nevertheless, consultants can reasonably
first help schools to identify students at risk for the 4 outcomes, followed by
appropriate screening/evaluation to indicate more clearly their true intervention
needs. The ongoing process can further educate school staff about psychiatric
disorders in their most problematic students.
PMID- 10761342
TI - Therapeutic changes in children, parents, and families resulting from treatment
of children with conduct problems.
AB - OBJECTIVE: To examine changes in child, parent, and family functioning over the
course of child therapy among children who completed outpatient treatment.
METHOD: Children (N = 250, ages 2-14 years) referred for oppositional,
aggressive, and antisocial behavior received variations of cognitive-behavioral
treatments. Outcome was evaluated by changes in the children (multiple symptom
domains), parents (symptoms, stress), and family (relationships, family
functioning, support, marital satisfaction). RESULTS: Child, parent, and family
functioning improved significantly over the course of therapy. The magnitude of
these changes indicated large improvements for child outcome measures and smaller
improvements for parent and family outcome measures. Improvements in children,
parents, and family measures were significantly and moderately correlated.
Finally, the pattern of predictors varied among child, parent, and family
outcomes. CONCLUSIONS: The benefits of child therapy extended to parent and
family functioning, even though these were not focused on directly. The broad
changes have significant implications for evaluating the effectiveness of
treatment and the benefits and costs of delivering services to children.
PMID- 10761343
TI - Physical fighting in childhood as a risk factor for later mental health problems.
AB - OBJECTIVE: The prevalence, persistence, and desistance of boys' physical fighting
was examined over a 7-year period. The importance of persistent physical fighting
compared with other risk factors in the prediction of later mental health
problems was explored. METHOD: One hundred seventy-seven boys, aged 7 to 12
years, who had been referred to clinics for mental health problems were followed
up annually for 7 years, with the boys, their parents, and teachers as
informants. RESULTS: Agreement among different informants about the boys'
fighting tended to be low. The prevalence of fighting over time remained quite
similar for different age cohorts. Almost 9 of 10 fighters in year 1 continued to
fight in one or more successive years, and about one third of the boys could be
classified as persistent fighters. Only 13.1% of the boys desisted in fighting.
Boys who desisted, compared with those who persisted, had higher intelligence and
their mothers scored lower on measures of antisocial personality disorder. At
year 7, persistent fighting was significantly associated with impairment. The
prevalence of psychiatric diagnoses in year 7 was 3 times higher for persistent
fighters than for nonfighters. Using regression analyses with several control
variables, conduct disorder was best predicted by earlier oppositional defiant
disorder in year 1 and persistent fighting. Global impairment was best predicted
by oppositional defiant disorder in year 1, persistent fighting, and low IQ.
Finally, the number of diagnoses at year 7 was best predicted by persistent
fighting. CONCLUSION: Physical fighting constitutes a significant mental health
risk in referred boys.
PMID- 10761344
TI - Parents' reactions to adolescents' suicide attempts.
AB - OBJECTIVES: To examine parents' emotional and verbal reactions to adolescents'
suicide attempts and to test models of the interpersonal functions of suicide
attempts. METHOD: Thirty-four mothers and fathers of 23 adolescent suicide
attempters were assessed shortly after the attempt regarding their emotional
reactions the day before, upon discovering, and the day after the suicide
attempt, using both open-ended and structured interviews. RESULTS: Feelings of
caring, sadness, and anxiety increased from before the attempt to the point of
discovery, and for mothers they remained higher through the following day.
Hostile feelings were present in approximately 50% of mothers across the time
points; however, upon discovering the suicide attempt, parents were less likely
to verbalize hostility than they were to verbalize support and to be careful what
they said. CONCLUSIONS: The findings have implications for clinical interventions
with parents of recent suicide attempters.
PMID- 10761345
TI - Suicide-bereaved children and adolescents: II. Parental and family functioning.
AB - OBJECTIVE: The current study extends the authors' earlier examination of suicide
bereaved (SB) children from the Grief Research Study, a longitudinal study of
childhood bereavement after parental death, by examining the children's family
history of psychopathology and family environment before and after death. METHOD:
Twenty-six SB children, aged 5 to 17 years, and their 15 surviving parents were
compared with 332 children bereaved from parental death not caused by suicide
(NSB) and their 201 surviving parents in interviews 1, 6, 13, and 25 months after
the death. RESULTS: Suicide completers evidenced more psychopathology than
parents who died from reasons other than suicide. Contrary to expectations,
surviving SB parents were not more impaired than NSB parents. Before the death,
SB families were less stable than NSB families and relationships with the
decreased SB parent were compromised. However, no differences were detected
between groups in children's relationships with their surviving parents.
Likewise, few differences were found in social support or changes in religious
beliefs. CONCLUSIONS: SB children generally come from families with a history of
psychopathology and substantial family disruption. However, surviving SB parents
do not exhibit higher rates of psychopathology than other bereaved parents and
many have positive relationships with their children.
PMID- 10761346
TI - Assessment of life stress in adolescents: self-report versus interview methods.
AB - OBJECTIVE: To compare the investigator-based Life Events and Difficulties
Schedule (LEDS) with a self-report measure (Life Events Checklist [LEC]) for the
purpose of measuring life stress in adolescents with and without a diagnosis of
major depressive disorder (MDD). METHOD: Adolescents (aged 13-18 years) with a
recent episode of MDD based on DSM-III-R (n = 35) and normal controls free of any
Axis I lifetime psychiatric disorder (n = 35) were assessed using both the LEC
and the LEDS. RESULTS: Both measures predicted membership in the depressed and
nondepressed groups of adolescents. Adolescents in the depressed group were more
likely to report a severe event on the LEDS (97%) than adolescents in the
nondepressed group (66%) (p = .001). Similarly, subjects in the depressed group
endorsed a greater number of negative events (mean = 8.1) on the LEC than
subjects in the nondepressed group (mean = 3.0) (p = .0001). An examination of
potential provoking agents for episodes of major depression revealed that the LEC
captured only 32% of preonset severe events and 36% of preonset major
difficulties identified by the LEDS. CONCLUSIONS: Interpreted in light of
relative advantages and disadvantages, the results suggest that checklist and
interview measures each have distinct advantages depending on the purpose for
which they are being used.
PMID- 10761347
TI - Psychiatric phenomenology of child and adolescent bipolar offspring.
AB - OBJECTIVE: To establish prodromal signs of and risk factors for childhood bipolar
disorder (BD) by characterizing youths at high risk for BD. METHOD: Structured
diagnostic interviews were performed on 60 biological offspring of at least one
parent with BD. Demographics, family histories, and parental history of childhood
disruptive behavioral disorders were also assessed. RESULTS: Fifty-one percent of
bipolar offspring had a psychiatric disorder, most commonly attention
deficit/hyperactivity disorder (ADHD), major depression or dysthymia, and BD. BD
in offspring tended to be associated with earlier parental symptom onset when
compared with offspring without a psychiatric diagnosis. Bipolar parents with a
history of childhood ADHD were more likely to have children with BD, but not
ADHD. Offspring with bilineal risk had increased severity of depressed and
irritable mood, lack of mood reactivity, and rejection sensitivity, while
severity of grandiosity, euphoric mood, and decreased need for sleep were not
preferentially associated with such offspring. CONCLUSIONS: Bipolar offspring
have high levels of psychopathology. Parental history of early-onset BD and/or
childhood ADHD may increase the risk that their offspring will develop BD.
Prodromal symptoms of childhood BD may include more subtle presentations of mood
regulation difficulties and less presence of classic manic symptoms.
PMID- 10761348
TI - Does shy-inhibited temperament in childhood lead to anxiety problems in
adolescence?
AB - OBJECTIVE: To assess the relationships between shy-inhibited temperament in
childhood and anxiety problems in early adolescence using a prospective,
longitudinal data set from a large community sample. METHOD: Relationships
between shyness ratings on age-appropriate temperament scales and anxiety
problems were analyzed, looking both forward and backward in time from infancy to
adolescence. RESULTS: Forty-two percent of children rated as shy on 6 or more
occasions over 8 surveys in childhood had anxiety problems in adolescence,
compared with 11% who were never shy. Persistence of shyness and its presence in
middle childhood increased risk for anxiety. A highly reactive temperament added
to shyness did not increase the risk for anxiety. Few children with an anxiety
diagnosis in early adolescence had a history of shyness. CONCLUSIONS: Prediction
from childhood shyness to adolescent anxiety disorder is modest but clinically
meaningful in a community sample. However, most shy children did not develop an
anxiety disorder and most adolescents with anxiety disorders had not been
especially shy.
PMID- 10761349
TI - A twin study of inattentive, aggressive, and anxious/depressed behaviors.
AB - OBJECTIVE: To estimate genetic, environmental, and rater contrast influences on
parental report of Attention Problems (AP), Aggressive (Agg), and
Anxious/Depressed (AxD) behaviors of 492 twin pairs assessed with the Child
Behavior Checklist. METHOD: A parent (92% mothers) of twins aged 8 to 12 years
completed the Child Behavior Checklist. Genetic, shared and unique environmental,
and rater bias effects were estimated for the AP, Agg, and AxD syndromes. Data on
boys and girls were analyzed separately. Results were compared to prior research
on related DSM disorders. RESULTS: Estimates of genetic influences on AP (60%
68%), Agg (70%-77%), and AxD (61%-65%) were high for both sexes, but lower for AP
than prior findings using DSM attention-deficit hyperactivity disorder (ADHD).
However, unlike equivalent analyses of DSM ADHD based on parental report, there
was no evidence of rater bias. CONCLUSIONS: Estimates of genetic influence on
these common child psychopathological domains were high. There was no evidence of
rater contrast effects. These findings have implications for diagnosis,
particularly when assessing families with multiple children.
PMID- 10761350
TI - Using MRI to examine brain-behavior relationships in males with attention deficit
disorder with hyperactivity.
AB - OBJECTIVE: The relationship between neuropsychological measures of inhibition and
sustained attention and structural brain differences in the regions of the
caudate and the frontal region was examined in males with attention deficit
disorder with hyperactivity (ADD/H). METHOD: Ten males with ADD/H (aged 8-17) and
11 male controls (aged 9-18) participated in a neuropsychological evaluation and
had a magnetic resonance imaging scan. RESULTS: As had been reported previously
by these authors, the children with ADD/H were found to have reversed asymmetry
of the head of the caudate, smaller volume of the left caudate head, and smaller
volume of the white matter of the right frontal lobe. Children with ADD/H were
found to score more poorly on measures of inhibition and sustained attention but
not on measures of IQ, achievement, or motor speed. Comparison of
neuropsychological measures and brain structure measures indicated a significant
relationship between reversed caudate asymmetry and measures of inhibition and
externalizing behavior; i.e., children with reversed caudate asymmetry performed
more poorly on measures of inhibition regardless of group membership. Poorer
performance on sustained attention tasks was related to smaller volume of the
right-hemispheric white matter. CONCLUSIONS: There is emerging evidence that
compromised brain morphology of selected regions is related to behavioral
measures of inhibition and attention.
PMID- 10761351
TI - Phonological processing, not inhibitory control, differentiates ADHD and reading
disability.
AB - OBJECTIVE: To test for the distinctiveness of attention-deficit hyperactivity
disorder (ADHD) and reading disability (RD) and the independence of the cognitive
domains, inhibition and phonological processing, which are proposed as central to
ADHD and RD, respectively, using a classic double dissociation design. METHOD: A
2 (ADHD versus no ADHD) x 2 (RD versus no RD) model was used to examine the
cognitive profile of 4 groups of children, aged 7 to 11 years. Two measures of
inhibitory control and 3 phonological processing measures were used. RESULTS: The
2 RD groups (RD, ADHD + RD) were significantly impaired relative to the 2 non-RD
groups (controls, ADHD) on all phonological processing measures. The 2 ADHD
groups were significantly impaired on simple go-task responding relative to the
non-ADHD groups and in inhibition. Contrary to predictions, an RD effect on
inhibitory control was found on one inhibition measure. The comorbid group (ADHD
+ RD) generally exhibited the deficits of both single groups in an additive
fashion. CONCLUSIONS: These findings question the role of inhibitory control as a
unique cognitive marker for ADHD and suggest true comorbidity for children with
both ADHD and RD.
PMID- 10761352
TI - Instability of sleep patterns in children with attention-deficit/hyperactivity
disorder.
AB - OBJECTIVE: To compare the stability of the sleep-wake system of children with
attention-deficit/hyperactivity disorder (ADHD) and controls by objective and
subjective measures. METHOD: Thirty-eight school-age boys with diagnosed ADHD and
64 control school-age boys were examined using actigraphic monitoring and sleep
diaries, over 5 consecutive nights. RESULTS: Increased instability in sleep
onset, sleep duration, and true sleep were found in the ADHD group compared with
the control group. Discriminant analysis revealed that children's classification
(ADHD versus control) could be significantly predicted on the basis of their
sleep measures. CONCLUSIONS: The findings support the hypothesis that instability
of the sleep-wake system is a characteristic of children with ADHD. Given the
potential negative effects of disturbed or unstable sleep on daytime functioning,
it is recommended that a thorough sleep assessment be conducted when a sleep
disturbance is suspected or when symptoms associated with daytime sleepiness or
decreased arousal level are present.
PMID- 10761353
TI - Sleep and psychiatric symptoms in school-age children.
AB - OBJECTIVE: To assess associations between the quantity and quality of children's
sleep and parent- and teacher-reported psychiatric symptoms. METHOD: Forty-nine
physically healthy 7- to 12-year-old children from normal classes participated.
They were monitored for 72 consecutive hours with belt-worn activity monitors
(actigraphs) to obtain objective data on their daytime and nighttime activity and
sleep. In addition, Child Behavior Checklists and Teacher's Report Forms were
filled out by the parents and teachers, respectively. RESULTS: Quantity of sleep
was significantly associated with total symptom score on the Teacher's Report
Form. The highest associations were found between low true sleep time and teacher
reported externalizing symptoms such as aggressive and delinquent behavior and
attention and social problems. Sleep parameters were not associated with parent
reported psychiatric symptoms, except for the association found between delayed
sleep latency and aggressive, delinquent behavior. CONCLUSIONS: The objectively
measured amount of school-age children's sleep was associated with teacher
reported psychiatric symptoms. Parents may be unaware of their child's sleep
deficiencies as the behavioral problems may be more evident at school than at
home. Sensitive and objective measurements are needed to rule out the possibility
of inadequate sleep underlying behavioral problems.
PMID- 10761354
TI - A double-blind pilot study of risperidone in the treatment of conduct disorder.
AB - OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment
of youths with conduct disorder. METHOD: This was a 10-week, randomized, double
blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly
assigned to receive placebo and 10 youths were randomly assigned to receive
risperidone. Patients were seen weekly throughout the trial. Medications could be
increased at weekly intervals during the first 6 weeks of the study from an
initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight.
Patients weighing less than 50 kg had a maximum total daily dose of risperidone
of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of
risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression
Against People and/or Property Scale. RESULTS: Risperidone was superior to
placebo in ameliorating aggression on most measures. Risperidone was reasonably
well tolerated, with none of the risperidone-treated patients developing
extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence
that risperidone may have efficacy in the treatment of youths with conduct
disorder. Because of the small sample size and the brief length of this study,
further research is necessary to confirm these findings.
PMID- 10761356
TI - Case study: bipolar disorder after head injury.
AB - A case of bipolar disorder subsequent to a mild head injury in a 15-year-old girl
is reported. Review of the literature indicates that this is an extremely rare
outcome. Lack of adequate follow-up studies makes it difficult to accurately
predict type and severity of psychiatric outcome. Assessment and management
involves ongoing consideration of both organic and psychosocial factors even
after initial negative investigations.
PMID- 10761355
TI - Predictors of adult height and weight in boys treated with methylphenidate for
childhood behavior problems.
AB - OBJECTIVE: To examine associations between childhood treatment with
methylphenidate (MPH) and adult height and weight. METHOD: Subjects were 97 boys,
aged 4 to 12 years, with behavior problems who were (1) referred to a child
psychiatry outpatient clinic, (2) treated clinically with MPH for an average of
36 months, and (3) reevaluated between ages 21 and 23 years. Hierarchical
analyses predicted adult height and weight from sets of non-medication and
medication-related variables. RESULTS: Medicated subjects' age, height, and
parental socioeconomic status (SES) at referral predicted 44.8% of variation in
adult height. Medicated subjects' birth weight, age, height and weight at
referral, and parental SES predicted 61.8% of variation in adult weight. With
these non-medication variables held constant, initial nausea and vomiting side
effects predicted 4.4% incremental variation in adult height, and MPH maintenance
dose predicted 3.2% incremental variation in adult weight. CONCLUSIONS: Medicated
individuals who had attained their final stature did not differ in average height
or weight from family, community, or unmedicated controls. Most aspects of
medication were not associated with adult height or weight. In some individuals,
nausea and vomiting side effects and treatment with higher doses of MPH were
associated with adult growth decrements.
PMID- 10761357
TI - Internal validity.
PMID- 10761358
TI - Genetics of childhood disorders: XIII. Genomic imprinting: the indelible mark of
the gamete.
PMID- 10761359
TI - Against all odds. Medical providers keep watch as jockeys bet their health on
winning rides.
PMID- 10761360
TI - Raising HDL-C to prevent atherosclerotic events.
PMID- 10761361
TI - Cholesterol treatment with statins and/or Benecol.
PMID- 10761362
TI - Frequency and duration of inattentive behavior after traumatic brain injury:
effects of distraction, task, and practice.
AB - Traumatic brain injury (TBI) is associated with impairments of attention, most
typically measured through tests of information processing, or by subjective
symptom endorsement by patients, families, and clinicians. We have previously
shown increased rates of off-task behavior among patients with TBI versus
controls as defined by videotaped records of independent work in distracting
environments. In this research, we report on a more detailed method of coding
such videotaped records which allows measurement of the precise number of off
task behaviors, their durations, and their relationship to distracting events.
Using this method, we studied 20 patients with recent moderate-to-severe TBI and
20 demographically comparable controls as they performed independent work tasks
while being subjected to controlled distracting events. This research confirms
that patients are markedly less attentive than controls both in the presence of
distractions and in their absence, that distractions have an influence on off
task behavior in both groups, and that the disruptive impact of distractors wanes
relatively quickly for controls but not for patients. The duration of distraction
produced by various classes of distracting events appeared similar for patients
and controls, although the power to detect differences in behavioral duration
between groups was limited. The pattern of inattentiveness among patients showed
minimal relationship to measures of injury severity within this sample.
PMID- 10761363
TI - Alcoholics' initial organizational and problem-solving skills predict learning
and memory performance on the Rey-Osterrieth Complex Figure.
AB - This study was undertaken to investigate whether alcoholics differ qualitatively
from controls in their organizational approach to the Rey-Osterrieth Complex
Figure (ROCF) and to examine the effects of problem-solving and organizational
ability on learning and retention. Data were collected on 3 groups of
neuromedically healthy, middle-aged men: 29 recently detoxified alcoholics (RDA)
abstinent at least 2 weeks, 29 long-term abstinent alcoholics (LTA) abstinent at
least 18 months, and 29 nonalcoholic controls (NAC). Groups were comparable in
age, education, WAIS-R Vocabulary score, and ANART IQ. Three indices of problem
solving approach were used to score how participants produce the ROCF during the
copy condition: perceptual clustering, organization, and constructional accuracy.
Learning and retention were measured by immediate recall, 20-min delayed recall,
and recognition performance. RDAs had significantly impaired immediate recall,
delayed recall, and recognition scores compared to NACs. RDAs also had
significantly lower perceptual clustering, organization, and constructional
accuracy scores than their long-term abstinent and nonalcoholic counterparts.
Multiple regression analyses revealed that problem-solving ability at copy
accounted for a significant proportion of the variance in immediate recall,
delayed recall, and recognition. Further investigation of memory performance
using a repeated measures design revealed that across the 3 groups, little
forgetting occurred between immediate and delayed recall, while performance
improved significantly on the recognition trial. Use of less efficient problem
solving strategies appears to affect RDAs' ability to learn and retrieve complex
figural information.
PMID- 10761364
TI - Cognitive decline in patients with Cushing's syndrome.
AB - Chronic exposure to elevated glucocorticoid levels in Cushing's syndrome (CS), is
associated with deficits in cognitive function and in emotion. The hippocampus
plays a crucial role in the behavioral manifestations of the syndrome as it is
richest in glucocorticoid receptors and is thus particularly vulnerable to
glucocorticoid excess. The wide distribution of glucocorticoid receptors
throughout the cerebral cortex, however, suggests that several cognitive
functions can also be affected by the dysregulation of glucocorticoids. In this
study, we investigated how an excess of glucocorticoid hormones affects cognitive
processes. Nineteen patients with chronic hypercortisolemia due to CS were
compared to healthy controls matched for age, sex, education, and occupation in
tests of processing of visual and spatial information, memory, reasoning and
concept formation, language and verbal functions, and attention. Multivariate and
univariate analyses revealed overall differences in tests of treatment of visual
and spatial information, reasoning and concept formation as well as in verbal and
language performance, with poorer performance from CS patients. Differences were
also observed in nonverbal aspects of memory and in attention tasks. The results
suggest that chronic exposure to elevated levels of cortisol is associated with
deficits in several areas of cognition, particularly those involving processing
of selective attention and visual components. This study also shows that hormones
play an important role in the modulation of cognitive function and that their
influence on cerebral structure and function merits closer scrutiny.
PMID- 10761365
TI - Accelerated age-related decline in processing resources in schizophrenia:
evidence from pupillary responses recorded during the span of apprehension task.
AB - Cognitive impairment in schizophrenia may be related to reduced availability of
information-processing resources (resource limitations hypothesis). An abnormally
accelerated age-related decline in processing resource availability may also
occur in older patients with schizophrenia (neurodegeneration hypothesis). To
test these hypotheses, pupillary responses were recorded as an index of
processing resource availability during performance of the span of apprehension
(SOA) task in 33 middle-aged and older patients with schizophrenia and 37 age
comparable nonpsychiatric participants. Consistent with the resource-limitations
hypothesis, the patients with schizophrenia showed impaired detection accuracy
and abnormally small pupillary responses (reduced resource allocation) only in
the higher processing load SOA conditions. This pattern of results suggests that
the patients depleted their available processing resources at lower processing
loads than the nonpsychiatric participants. Consistent with the neurodegeneration
hypothesis, cross-sectional analyses showed abnormally accelerated rates of age
related decline in SOA performance and pupillary responses in the patients with
schizophrenia relative to age-comparable normal participants.
PMID- 10761366
TI - Long-term retention of transient news events.
AB - Many retrospective analyses of remote memory have demonstrated recency effects in
that memory for events proximal to the time of testing is superior to memory for
events from remote time periods. However, the rate at which information decays
over time and the specific pattern of forgetting may vary depending upon the
distinct attributes of stimuli used as indices of memory. Studies examining long
term forgetting of well rehearsed, conceptually integrated information underscore
preservation of remote events, some of which are thought to be permanently stored
in memory. A different pattern of forgetting emerges in relation to recall of
discrete facts whereby recall declines according to a negatively accelerated
decay curve. In the current study long-term retention of transient news events
was examined. Results were examined in relation to the effects of age and sex.
All age groups demonstrated recency effects in that events from the recent past
were recalled better than remote events. Age did not exert a negative influence
on recall of remote or recent events with the exception of younger participants
who did not recall items predating their dates of birth. Older female
participants were less adept at recalling very old events than their male
counterparts.
PMID- 10761367
TI - Elucidating the contributions of processing speed, executive ability, and frontal
lobe volume to normal age-related differences in fluid intelligence.
AB - One theory of normal cognitive aging asserts that decreases in simple processing
speed mediate the age-related decline of fluid intelligence. Another possibility
is that age-related atrophic changes in frontal brain structures undermine the
functioning of executive abilities, thereby producing the same decline. In this
study, we used principal components analysis to derive a measure of fluid-spatial
intelligence in 197 normal adults between 20 and 92 years of age. Measures of
perceptual comparison speed, working memory, and executive ability, as well as
regional brain volumes based on high resolution magnetic resonance imaging were
obtained from a subsample of 112 participants. We then conducted a series of
hierarchical multiple regression analyses to test whether (1) the processing
speed theory, (2) frontal-executive theory, or (3) some combination of these best
accounted for age-related variation in fluid intelligence. The results showed
that perceptual comparison speed, executive ability, and frontal lobe volume each
made significant contributions to a regression equation that explained 57% of the
variance in fluid intelligence. These findings suggest that both the processing
speed and frontal-executive theory of cognitive aging are partially correct and
complement one another.
PMID- 10761368
TI - The CyberCruiser: an investigation of development of prospective memory in
children.
AB - Prospective memory can be defined as the timely execution of a previously formed
intention, and is critical in daily life because of its inherent involvement in
goal-directed behavior. Cognitive systems involved in prospective memory have
been hypothesized as involving the frontal cortex, and in adults, associated with
working memory and executive functions. This study introduces a new computerized
measure of prospective memory designed for children. In this study prospective
memory is examined in a driving game task called the CyberCruiser. In a sample of
80 children ages 6-12 years, variables from this task demonstrated a significant
age effect and were significantly correlated with other well known measures of
executive function, even after controlling for chronological age. Performance on
this task also demonstrated the anticipated pattern of strategic monitoring that
has been demonstrated in other studies of prospective memory.
PMID- 10761369
TI - Limb and hemispatial hypometria.
AB - In a previous study, we demonstrated that unilateral cerebral lesions produce
hypometric limb movements of the contralateral arm and hemispatial (i.e.,
directional) hypometria for movements towards contralateral hemispace. In the
present study, we investigated 10 patients with right cerebral lesions and 25
healthy controls using a task to uncouple deficits in sensory perceptual systems
and motor-action output systems on directional hypometria. This task required
participants, with their eyes closed, to reproduce lateral and medial horizontal
displacements (15-27 cm) with each arm. Each participant was seated at a waist
high table and had their hand placed at an origin point aligned with the axillary
fold on the same side. Their hand was moved by the investigator from the origin
point to a target point and brought back to the point of origin (input
displacement). The participant was then asked to return their hand to either the
same target point or to an equidistant target point in the opposite direction.
Healthy dextral participants were significantly more hypometric with their right
arm, but patients with right cerebral lesions exhibited an opposite pattern with
overall left arm hypometria. In addition, patients were significantly more
hypometric for movements when output displacements were toward left hemispace. No
effect was found for direction of sensory input. The results suggest that the
directional hypometria is predominantly produced by hemispatial output deficits.
PMID- 10761370
TI - Exploring the relationship between age, executive abilities, and psychomotor
speed.
AB - Age-related declines in executive abilities have been widely reported and are
thought to result from neuropathological changes in the prefrontal cortex. Some
investigators have suggested that age-related changes in cognition may be the
result of slowed information processing speed rather than declines in specific
cognitive abilities. We examined the relationships among age, executive
abilities, and psychomotor speed in 40 older adults and 46 young adults. Both
verbal and nonverbal tasks were administered that measured 2 aspects of executive
ability: set formation and set shifting. Executive and psychomotor speed tasks
were paired based on similarities in basic task demands. Our results revealed
that poorer executive performance was associated with increasing age. Further,
although psychomotor speed attenuated the relationship, age accounted for a
unique and significant proportion of variance in executive performance after
controlling for psychomotor speed. These results suggest that age has an effect
on prefrontally mediated executive abilities that cannot be explained solely in
terms of psychomotor slowing.
PMID- 10761371
TI - MR spectroscopy in HIV and stimulant dependence HNRC Group. HIV Neurobehavioral
Research Center.
PMID- 10761372
TI - Neuropsychological and neuropathological sequelae of cerebral anoxia: a critical
review.
AB - Fifty-eight studies of the neuropathological and neuropsychological outcomes of
cerebral anoxia were reviewed. Neuropathological reports were examined for the
variety, extent, and specificity of lesions resulting from an anoxic event. While
most attention has focused on damage to the hippocampus following anoxic brain
injury, the review indicated that watershed cerebral cortex and the basal ganglia
were both more frequently damaged than the hippocampus. The hippocampus was the
sole affected structure in only 18% of reported cases. Neurological,
neuropsychological and psychiatric studies were analyzed. Of 67 individual case
reports, a memory disturbance was documented in 36 (54%), but a memory
disturbance without report of additional cognitive deficits occurred in only 13
(19.4%). Changes in personality and behavior were noted in 31 (46.2%).
Visuospatial or, less frequently, visual recognition problems were noted in 21
individual cases (31.3%) reviewed. Memory deficits were found in all 14 group
studies reviewed, while in 9 papers changes in behavior or personality were also
documented. Six studies also reported visuospatial deficits. Careful reading of
the literature reveals a range of cognitive and behavioral changes that reflect
very well the neuropathological outcomes of anoxic episodes.
PMID- 10761373
TI - [liver portion transplantation from living donor: pilot clinical experience].
AB - The unique in Russia experience of 35 liver transplantations since 1990 has
revealed benefits of the method and quite encouraging results with 81% survival
of the recipients. But the extreme shortage of cadaveric donor organs followed by
more than 60 per cent mortality in waiting list and absence of any real
facilities to improve the situation dictate the living related donation to become
a considerable alternative. Totally 12 living related liver transplant procedures
were performed with no morbidity in donors. In 7 donors the routine surgical
technique of harvesting were used to get left lateral segment in five and whole
left lobe in two cases. The unique twin-to-twin liver left lobe donation with no
consequent immunosuppression was observed in this series. New special technique
of living donor surgery was successfully developed for liver right lobe
harvesting. The living related liver right lobe replacement was used in 5 cases
and appeared to become a real compensation of donor organs shortage for elder
children with body weight more than 20 kg and adults.
PMID- 10761374
TI - [Diverticuli of duodenal papillar region and their role in development of
choledocholithiasis and strictures of bile and pancreatic ducts].
AB - Up to present time there is no common view on the role of diverticuli of the
papillar region of the duodenum (DPRD) in development of the strictures of
terminal parts of the common bile duct and major pancreatic duct. The main method
for the diagnosis of DPRD is fibroduodenoscopy (FDS). Relaxational FDS is the
most informative method for detailed examination of diverticulum and for
assessment of its interrelations with longitudinal crease and the major duodenal
papilla (MDP). During the last 2 years all patients with DPRD underwent ERCPG,
which helped to obtain more complete information of the presence and the
character of the strictures of terminal parts of the common bile duct and the
pancreatic duct. DPR has been revealed in 5% of patients with calculous
cholecystitis and in 9.5% of patients with choledocholithiasis. Of the patients,
admitted to the Institute for postcholecystectomy syndrome from 1994 to 1999,
DPRD were revealed in 30% of cases. The patients with DPR and chronic
pancreatitis of nonalcoholic and nonlithogenic etiology, made up 9% of all
patients with DPR and chronic pancreatitis. In 87 patients with DPR, suffering
from various surgical diseases, following changes of bile and pancreatic ducts
were revealed: choledocholithiasis (47%), stenosis of the large bile duct (15%),
strictures of terminal parts of the large bile duct and major pancreatic duct
(10%). There is evidence, that para- and peripapillary diverticuli deteriorate
evacuatory function of the bile and pancreatic tracts due to compression of
terminal parts of the choledochus and the pancreatic ducts with strictures
formation, which promote disturbances of the bile and pancreatic juice passage.
Biliary stasis and pancreatic juice passage disturbances create favorable
conditions for lithogenesis and promote development of cholangitis, mechanical
jaundice and chronic pancreatitis. Patients with choledochal and major pancreatic
duct strictures and stenoses of the papilla in DPR underwent EPST with favorable
initial and long-term results. The authors suggest, that DPR are an important
etiopathogenetic link in the development of many diseases of the organs of
hepatobiliary region, associated with biliary and pancreatic hypertension.
PMID- 10761375
TI - [Hepatoprotective action of phosphogliv in surgery of patients with chronic
calculous cholecystitis].
AB - 32 patients with chronic calculous cholecystitis were treated by a new
preparation. Phosphogliv (on the base of polyunsaturated phospholipids)--5 days
before planned surgery and 5 days after. The increase of alanine and asparagine
aminotransferases activities and of bilirubin concentration (2-2.5 fold) was
observed in all the patients, cirespective of the drug treatment. However, the
essential difference between treated and untreated patients was revealed in the
course of post-operative period. In the control group asparagine aminotransferase
activity and bilirubin level remained high, and alanine aminotransferases
activity even more increased. In contrast, both two aminotransferases activities
and bilirubin level fell substantially in Phosphogliv group, that may show more
active liver regeneration after surgery. Besides, in this group operation did not
result even in short-time changes of plasma protein fractions ratios--opposite to
control. It may testify on some protective action of Phosphogliv on liver protein
synthesis system. The observed action of new phospholipid preparation
Phosphogliv, together with the absence of side effects, allows to recommend it as
an adjuvant in the surgery of patients with chronic calculous cholecystitis.
Besides, the above results broaden usage field of polyunsaturated
phosphatidylcholine as cell membranes repair agent: it appears to be effective
not only for liver diseases treatment, but also for soonest overcome of post
surgery liver changes.
PMID- 10761376
TI - [Follow-up results of splenic artery embolization in liver cirrhosis].
AB - Long-term results of splenic artery embolization (SAE) were compared with those
of surgical splenectomy and medical therapy for liver cirrhosis complicated by
hypersplenism (50, 20 and 46 patients, respectively). Lethality and complication
occurrence (AFTER) SAE were as high as 18% and 12% vs 10% and 5% after
splenectomy. In long-term period correction of hypersplenism persisted only in
16%. However, clinical outcomes and survival of patients treated conservatively,
did not significantly differ from results of transcatheter and surgical
treatment. This investigation evidences that SAE has a high rate of complications
and low effectiveness. Both SAE and splenectomy did not improve the survival if
compared with medical therapy and therefore they should not be routinely used in
clinical practice.
PMID- 10761377
TI - [Treatment of gastroduodenal ulcer hemorrhages].
AB - The results of treatment of 901 patients with acute ulcerogenic gastroduodenal
bleedings in 1986 to 1997 are analysed. The tactics of the treatment, developed
in the clinic, combines active diagnostic and curative measures with
differentiated determination of the indications for urgent operative treatment.
Improvements of the method for urgent operative treatment, wide implementation of
the organ-saving and mini-invasive surgical procedures, usage of new methods for
nonoperative (endoscopical) hemostasis, as well as an improvement of the complex
for intensive and anti-ulcerogenic therapy enabled in the last group of patients
(1994-1997 years) to decrease the postoperative lethality up to 5.9%, and general
lethality--to 6.4%.
PMID- 10761378
TI - [Transanal resection of rectum with mesorectumectomy].
AB - The possibility of sparing resection of the rectum in cancer is considered. The
results of treatment in 27 patients with cancer of rectal lower ampulla (T1-10
patients, T2-12, T3-5) by transanal resection of distal part of the rectum are
presented. The technique of operation, which provides the removal of all layers
of rectal wall with surrounded tissues, e.g.--mesorectumectomy is described. The
indications for this operation are formulated.
PMID- 10761379
TI - [Laparostomy in treatment of diffuse peritonitis].
AB - Two methods for laparostomy were used in peritonitis: programmed sanitation and
variant of N.S. Makokha method (68.8 and 31.2% of patients respectively). 215
patients with diffuse peritonitis have been under control for the period from
1989 to 1997, beginning with the method of Makokha for laparostomy and then
converting to programmed sanitation. Lethality rate in 1989-1992 made up 67.6%,
in 1993-1997--35.4%. Among the patients, in whom for performing elective
sanitation "ventrophiles" were fixed during the initial operation, lethality made
up 25.7% and if it was done during the second and later procedures, lethality
made up 45.7%.
PMID- 10761380
TI - [Morphological examinations of infected burn wounds].
AB - Electron microscopical and electron radioautographic methods have been used for
morphological examination. This allowed to raise sensitivity of the tests
facilitating detection of living solitary bacterial cells (by intensive mark
above them). Radioautography showed functional status of wound bacteria (the
intensity of the metabolism and reproduction). It was determined that in living
tissues, not damaged by the burn and unchanged morphologically bacteria do not
penetrate. Especially massive accumulations of the microorganisms are found in
necrotic tissues, under the scab, at the external border of demarcation
protuberance, and they represent colonization of the wound. When modern methods
of treatment and early necrectomy are used, morphological examination usually
does not reveal pathogenic microorganisms. Only inflammatory reaction of the
wound tissues could be seen: oedema, hyperemia, hemorrhages, cellular
infiltrates. The development of granulation tissue indicated cessation of wound
infection. Especially favourable feature, demonstrating healing of the wound, was
appearance and reproduction of young cells of fat tissue (indusion of labelled
thymidine). The results of the study have confirmed the advantage of new
electronic methods for microscopy in infected burn wounds.
PMID- 10761381
TI - [Early diagnosis and differentiated treatment of thyroid cancer].
AB - Cancer of the thyroid gland is an entity characterised by progressive rise of
morbidity. The study is based on the results of surgical treatment of 237
patients with various forms of thyroid cancer for the period of 11 years from
1987 to 1998. Absolute majority of malignant thyroid tumors are differentiated
(94%). The study of morphological peculiarities of the tumors has shown the
prevalence of an incapsulated type of cancer (84%). Such features of "biological
aggression" as growth through the capsule of cancer node, vascular invasion,
multicentricity and other high increase probability of regional metastasizing
even in the initial forms of cancer and could be considered as a prognostic
factor. Long-term result (5-year survival--98.9%, 10-year--96.8%), evidence for
feasibility of organ-saving operations in differentiated cancer of the thyroid-
e.g. saving of its intact lobe.
PMID- 10761383
TI - [Surgical sepsis (discussion aspects, problems)].
PMID- 10761382
TI - [Prolonged epidural anesthesia in the treatment of frostbite].
AB - A comparative analysis of efficiency of prolonged epidural anesthesia with
lidocain in a complex of medical measures has been presented in 91 patients with
cold damage of the lower extremities (9 of 3-4 degrees). Application of the
method of prolonged epidural anesthesia by lidocain in a combined treatment of
frost-bites has allowed to improve clinical course of the disease and hospital
stay of the patients 2.5 times, and in 100% of cases to avoid invalidating
surgery.
PMID- 10761384
TI - [Use of "Angiojet" system for thrombectomy from arterial anastomosis in patients
with tetralogy of Fallot].
PMID- 10761385
TI - [Transanal removal of foreing bodies from rectum and sigmoid].
PMID- 10761386
TI - [Evolution in treatment of inguinal hernias].
PMID- 10761387
TI - [Lymphadenectomy in rectal cancer].
PMID- 10761388
TI - [Prophylaxis and treatment of DIC syndrome in surgery of gastrointestinal
neoplasms].
PMID- 10761389
TI - [Complications of balloon tissue distention].
PMID- 10761390
TI - Distribution of proteoglycans in the human trabecular meshwork: histochemical
electron microscopic findings with cuprolinic blue.
AB - The distribution of sulfated proteoglycans (PGs) in the normal human trabecular
meshwork was studied by histochemical electron microscopy using the cationic dye,
cuprolinic blue (CB).. The trabecular meshwork was obtained from human enucleated
eyes and incubated for three days. After incubation, they were stained with 0.2%
CB at a critical electrolyte concentration and prepared for histochemical
electron microscopy. Ultrastructurally, PG-CB complexes were found as small
punctate or filamentous structures, and were associated with collagen fibrils in
the cores of the trabecular beams and the basal laminae of trabecular endothelial
cells. In addition, large filamentous PG-CB complexes were mainly associated with
areas of amorphous extracellular matrix between the collagen fiber bundles and in
the fine fibrillar material near the basal laminae of endothelial cells of
Schlemm's canal. This investigation resulted in an illustration of the
ultrastructural distribution of PGs in the human trabecular meshwork. Further
studies will be needed to specify the nature of PGs and their role in the aqueous
outflow system.
PMID- 10761391
TI - Mitomycin C-induced apoptosis in cultured human Tenon's capsule fibroblasts.
AB - To investigate the mitomycin C-induced apoptotic cell death of fibroblasts, the
primarily cultured human Tenon's capsule fibroblasts were exposed to a clinically
used dosage of 0.4 mg/ml of mitomycin C for 5 minutes. TUNEL (TdT-mediated dUTP
biotin nick end labeling) assay and electron microscopic studies were performed
to determine the extent of mitomycin C-induced apoptosis. A flow cytometric study
was performed to quantify the apoptotic cell population over time. The TUNEL
stains were positive and electron microscopy showed features of apoptotic cell
death in some fibroblasts 3 and 5 days after treatment. Flow cytometric analysis
using Annexin V-propidium iodide double staining detected apoptotic cells 3 days
after treatment. These apoptotic cell populations increased at 4 days and were
sustained for one week. This study revealed that the clinical effects of
mitomycin C on fibroblasts may be mediated not only by antiproliferative but also
apoptotic cell death to some degree. Therefore, the apoptotic cell death of
fibroblasts induced by mitomycin C should be considered to properly understand
the mechanism of wound healing after trabeculectomy with adjunctive mitomycin C.
PMID- 10761392
TI - Synthesized TGF-beta s in RPE regulates cellular proliferation.
AB - Retinal pigment epithelial (RPE) cells transdifferentiate in culture, a
transition which is accompanied by a shift in biological activity. The present
study investigates whether transforming growth factor (TGF)-beta has the same
effects on morphologically transformed RPE cells that it has on primary RPE
cells. It also evaluates the autocrine and paracrine activities of TGF-beta s
synthesized by RPE cells as well as the anti-TGF-beta effect of mannose-6
phosphate (M-6-P). RPE cells were subcultured at the sixth passage to induce
morphological change. The effect of second passaged RPE-conditioned medium (CM)
on DNA synthesis was evaluated by the incorporation of 3H-thymidine in rabbit
subconjunctival fibroblasts (SCFs) and primary RPE cells. The presence of TGF
beta in RPE-CM was determined using immunoblotting analysis. And the inhibitory
effect of M-6-P on cell proliferation mediated by RPE-CM was also analyzed using
3H-thymidine incorporation into DNA. TGF-beta 1, TGF-beta 2, and TGF-beta 3
inhibited the proliferation of the primary cultures of RPE cells in a dose
dependent manner, but the spindle-shaped sixth passaged RPE cells were not
inhibited by these growth factors. The medium conditioned by RPE cells stimulated
the proliferation of SCFs and inhibited the proliferation of primary RPE cells,
in a manner similar to TGF-beta. When this medium was precipitated with either
anti-TGF-beta 1, anti-TGF-beta 2, or anti-TGF-beta 3 antibodies, all three TGF
beta s, with an apparent molecular size of 25 kDa, were detected. Mannose-6
phosphate significantly blocked the effect of RPE-CM on cell proliferation. These
findings indicate that RPE cells produce biologically functional TGF-beta s and
that M-6-P can block the inhibitory effect of RPE-CM on cell proliferation.
PMID- 10761393
TI - Changes in refraction and axial length according to the viscosity of intraocular
silicone oil.
AB - We performed this study to evaluate the changes in refraction and axial length
induced by intraocular silicone oil, and to compare with various clinical
parameters between 1,000 and 5,000 cSt silicone oil. The refraction length was
measured with an autorefractometer, and the axial length was measured with A-scan
ultrasonography. These measurements were performed before and after removal of
the silicone oil, using a clear cornea technique in which the silicone oil was
injected in combination with pars plana vitrectomy. The mean age of the 25
patients was 38.73 years. On average the intraocular retention after the removal
of the silicone oil lasted 5.13 months, and the follow-up time following silicone
oil removal was 4.37 months. The changes in refraction and axial length were 6.32
diopters and 12.02 mm, respectively. Eyes injected with 5,000 cSt (11 eyes)
tended to have higher changes in the refraction (5.84 vs 6.86 diopters) and axial
length (11.70 vs 12.34 mm) than did eyes injected with 1,000 cSt silicone oil (14
eyes). Statistically significant differences were shown for the changes in
refraction (p = 0.010) and intraocular pressure (0.63 vs 2.00 mmHg; p = 0.006),
whereas but not for the changes in axial length (p = 0.306) and visual acuity
(14/100 vs 15/100; p = 0.125). Intraocular silicone oil induced changes in
refraction and axial length, and these changes seemed to vary with different
viscosities.
PMID- 10761394
TI - Surgical treatment of subretinal neovascular membrane.
AB - The visual results of laser photocoagulation for subfoveal choroidal neovascular
membrane (CNVM) has not always been satisfactory. The surgical removal of the
neovascular membrane may be another treatment option. To investigate the
prognosis and risk factors of this surgery, we analyzed the results of surgical
removal of subfoveal CNVM (23 eyes), subfoveal hemorrhage with CNVM (6 eyes), and
subfoveal hemorrhage alone (6 eyes). The mean follow-up period was 17.7 months
(range 2 to 47 months). The mean preoperative membrane size was 0.89 disc
diameter and the mean postoperative retinal pigment epithelial (RPE) defect size
was 1.33 disc diameter. Visual improvement was observed in 13 out of the 23 eyes
(56.5%) with sufoveal CNVM, four out of the six eyes (66.6%) with subretinal
hemorrhage and CNVM, and five out of the six eyes (83.3%) with subretinal
hemorrhage only. The visual outcome of subfoveal CNVM surgery was related to the
presence of a subfoveal RPE defect (p = 0.005) rather than to the size of the RPE
defect. No recurrence of neovascular membrane was observed during the follow up
period. In conclusion, surgical removal may be a good alternative treatment for
subfoveal CNVM.
PMID- 10761395
TI - Continued lodging of retinal emboli in a patient with internal carotid artery and
ophthalmic artery occlusions.
AB - Internal carotid artery or ophthalmic artery occlusions are devastating
ophthalmological events which lead to severe impairment of vision. A case of
multiple branch retinal artery occlusions in a 63-year-old male with internal
carotid artery and ophthalmic artery occlusions on brain angiography is
presented. Emboli lodging in branches of the retinal arteries were bright,
glistening, yellow or orange in appearance. Such a distinctive ophthalmoscopic
appearance led to the diagnosis of cholesterol emboli. Fluorescein and
indocyanine green angiography disclosed delayed filling of the retinal vessels
and choroid, and showed multiple hypofluorescence distal to the vessels in which
the emboli were lodged. At the time of initial examination, the number of emboli
lodged in retinal arteries was estimated at more than 20. As time passed, a few
of the previous emboli disappeared and new emboli appeared in other sites on
fundus examination. We think that the lodging of new emboli in other sites is due
to the continued break-up of atheromatous tissue through the collateral
circulation associated with the occlusion of the internal carotid and ophthalmic
arteries.
PMID- 10761396
TI - An unusual type of cancer-associated retinopathy in a patient with ovarian
cancer.
AB - We studied a case of unusual retinopathy in a 35-year-old woman who presented
with bilateral visual deterioration due to retinal pigmentary mottling and serous
elevation in the posterior pole. Two years before, she had undergone hysterectomy
and bilateral salphingo-oophorectomy for ovarian cancer. Her electroretinogram
became subnormal, and her fluorescein angiogram exhibited multiple deep retinal
pigment epithelial leakages and subretinal dye pooling in both eyes.
Corticosteroid therapy failed to prevent visual loss. She was found to possess
antibodies against retinal 45 kd protein. This led to a diagnosis of cancer
associated retinopathy with atypical protein profile. We report a rare variety of
cancer-associated retinopathy in a patient with-ovarian cancer.
PMID- 10761397
TI - Scleral perforation after scleral buckling surgery for retinopathy of
prematurity.
AB - Scleral perforation occurred as a result of using a silicone band during scleral
buckling surgery for subtotal retinal detachment in retinopathy of prematurity
(ROP). The patient was initially treated by cryotherapy and scleral buckling
surgery for ROP, and was later referred due to a dark bluish mass in the
superotemporal quadrant of the eyeball. After removing the overlying whitish
membrane, uveal tissue prolapsed through the melted scleral wound (5 mm x 5 mm).
A silicone encircling band had passed through the wound and was exposed
subconjunctivally around the temporal and the inferior limbus. The band was
removed and a scleral allograft was performed. After three years, follow up
revealed the eyeball was slightly microphthalmic. Though scleral bucking surgery
is helpful for the treatment of advanced ROP, a scleral perforation may develop
as a disastrous complication.
PMID- 10761398
TI - Clinical effect of low vision aids.
AB - The number of patients with low vision is increasing as life expectancy
increases. In addition, the interest and demand for low vision aids are also
increasing with improved socioeconomic status and the development of mass media.
Therefore, it is imperative to recognize the importance of low vision aids. We
reviewed the clinical records of 118 patients who visited our low vision clinic
more than twice. According to the data analyzed, optic nerve atrophy, retinal
degeneration, diabetic retinopathy and age-related macular degeneration were the
most common causes of low vision in these patients. The best corrected visual
acuities without low vision aids were less than 0.3, but with the help of low
vision aids, vision improved to more than 0.4 in 87% of the patients for near
vision, and 56% for distant vision. The patients had complained that they could
not read books, see a blackboard, recognize a person at a distance, and had other
problems because of low vision. However, with the use of low vision aids their
satisfaction with their vision rose to 70%. Hand magnifiers, high-powered
spectacle lenses, and stand magnifiers were the low vision aids commonly used by
people for near vision, while the Galilean telescope and Keplerian telescope were
the most popular devices used for distant vision. In conclusion, low vision aids
are very helpful devices to patients with low vision.
PMID- 10761399
TI - Stimulation of macrophage function by interphotoreceptor retinoid-binding
protein: production of nitric oxide.
AB - In this study, we investigated whether retinal soluble proteins, such as
interphotoreceptor retinoid-binding protein(IRBP), play a role in the induction
of nitric oxide by macrophages in vitro. Cells from the murine macrophage cell
line RAW 264.7 and rat and rabbit peritoneal macrophages were incubated in the
presence of retinal soluble protein. The nitrite level in the cultured
supernatant was evaluated for nitric oxide production using the Griess reaction.
IRBP induced significant, dose-dependent nitrite production in both RAW 264.7 and
rat peritoneal macrophages. Induction of inducible nitric oxide synthase (iNOS)
by retinal proteins was inhibited by the iNOS-specific inhibitor, aminoguanidine,
and the tyrosine inhibitor, genistein. These results show that soluble retinal
proteins significantly induce nitric acid production by macrophages. Increased
production of reactive oxygen species by macrophages in the presence of this
soluble retinal protein in vivo may accelerate photoreceptor degeneration in
uveitis.
PMID- 10761400
TI - Experimental preretinal neovascularization by laser-induced thrombosis in albino
rats.
AB - The primary objective of this study was to develop a simple experimental model of
angiogenesis by photodynamic thrombosis of the retinal veins in Sprague-Dawley
rats. After a tail vein injection of rose bengal (40 mg/kg), all major retinal
veins adjacent to the optic nerve head were photocoagulated with an argon green
laser. The eyes were examined regularly for the following eight weeks. A grading
system was devised using fluorescein angiograms and ADPase staining to describe
the progression of the new vessels. Nine out of ten eyes showed development of
the preretinal new vessels by day 14. Seven weeks after laser coagulation, 2 of 5
eyes developed localized tractional retinal detachment. Regression of the
neovascularization was not noted in any of the animals during the follow-up
period. The authors were able to establish an experimental model for preretinal
neovascularization by vein occlusion. This model may be applied in study of the
pathogenesis and treatment of retinal neovascularization.
PMID- 10761401
TI - Effect of FK 506 on the cornea: use of topical FK 506 in corneal transplantation
in a guinea pig-rat model.
AB - To evaluate the effect of different concentrations 0.03%, 0.1% and 0.3% of FK 506
on xenograft corneal rejection, guinea pig corneas were transplanted into rats.
FK 506 was then applied topically four times a day for 21 days. The grafts were
inspected and scored according to opacity, edema, and graft protrusion. All
grafts in the control group were rejected by the 14th postoperative day, and
grafts in the FK 506 treated groups began to be rejected by the 17th
postoperative day. Inflammatory cell infiltration was less dense in the FK 506
treated grafts than in the control group. Higher concentrations of FK 506
appeared to be more effective in preventing and decreasing the severity of the
graft rejection. Topical FK 506 can delay the development of xenograft corneal
rejection and decrease its severity in this animal model.
PMID- 10761402
TI - The efficacy of 0.2% brimonidine for preventing intraocular pressure rise
following argon laser trabeculoplasty.
AB - Brimonidine tartrate of 0.5% was identified as the most effective and safe dose
for acute intraocular pressure (IOP) lowering. The efficacy of brimonidine
tartrate 0.2% in preventing IOP elevation after an argon laser trabeculoplasty
(ALT) was evaluated. Eighty patients were selected for a randomized, prospective
study. Each patient was assigned to one of four treatment regimens: (1)
brimonidine before and after ALT(B/B), (2) brimonidine before and placebo after
ALT(B/P), (3) placebo before and brimonidine after ALT(P/B), (4) placebo before
and after ALT(P/P). IOP elevation of 5 mmHg or greater occurred in 3.3% (2/60) of
brimonidine-treated patients and in 30% (6/20) of placebo-treated patients. There
was a mean decrease of IOP from baseline during the first 3 hours after ALT in
all brimonidine-treated groups (7.1 +/- 3.4, 6.2 +/- 4.4, 3.5 +/- 2.9 mmHg for
the B/B, B/P, P/B groups), but no change of mean IOP in the Placebo-treated
group. Only one drop of brimonidine tartrate of 0.2% installed either before or
after ALT was sufficient to prevent post-ALT IOP spike and minimize the undesired
systemic adverse effects that two drop installation can produce.
PMID- 10761403
TI - Midterm follow-up of necrotic bleb excision and advancement of the fornical
conjunctiva.
AB - Mitomycin C has improved the success rate of glaucoma filtering surgery in
patients at high risk for surgical failure. However chronic hypotony is marked by
decreased vision and a late-onset leaking bleb after filtration surgery using
mitomycin C. Bleb excision and conjunctival advancement is the method of choice
to repair bleb leakage and chronic hypotony. Five eyes from five patients were
received glaucoma filtration surgery with topical mitomycin C. All of the
patients' blebs were avascular and transparent. The reasons for bleb excision
were two spontaneous bleb leaks, two traumatic bleb leaks and one case of severe
irritation. The mean follow-up period was 18.4 +/- 8.3 months (ten to 29 months).
Cataract surgery was combined in one eye. Postoperative intraocular pressure
(IOP) increased from 2.3 +/- 1.5 mmHg to 9.5 +/- 3.7 mmHg at nine months
postoperatively in four eyes. It went from 28 mmHg to 40 mmHg in one patient with
uveitis, for whom a second trabeculectomy with mitomycin C; 0.4 mg/ml for 3
minutes, was performed. After surgery, IOP decreased to 4 mmHg in three months.
Postoperative visual acuity improved four snellen lines in three eyes. A
partially avascular bleb recurred in three eyes, a corneal bleb in one eye and
blepharoptosis, which disappeared spontaneously at four months postoperatively,
in one eye. Necrotic bleb excision and advancement of fornical conjunctiva were
useful methods to increase IOP and to improve visual acuity for the patient
experiencing irritation symptoms, and for leaking blebs, and hypotonic
maculopathy.
PMID- 10761404
TI - Wide-angle fluorescein angiographic scanning with high resolution using a
scanning laser ophthalmoscope through a mirror image fixation target.
AB - Internal and moving targets of scanning laser ophthalmoscopes are not capable of
observing the fundus beyond a field of more than 80 degrees with high resolution.
The authors enabled wide-angle fundus examination with high resolution through a
modification of the target. Mirror image fixation targets(MIFT), which fixated
the opposite side of the examined eye onto the mirror image of five lamps placed
1.5 m away from the patient, were used to observe the fundus during fluorescein
angiography in five diabetic retinopathy patients. In three of them, the ranges
of the fundus examinations were measured using conventional internal fixation
targets. The mean ranges of the fundus examinations when using MIFT (77.2 +/- 2.5
degrees horizontally, 67.9 +/- 2.1 degrees vertically) were significantly wider
than when using internal fixation targets (65.5 +/- 2.6 degrees horizontally,
44.4 +/- 2.8 degrees vertically). MIFT provided a wide angle fundus view with
high resolution equal to that of 40 degrees angle images using a scanning laser
ophthalmoscope.
PMID- 10761405
TI - Fluorescein angiographic features of choroidal insufficiency in anterior ischemic
optic neuropathy.
AB - Anterior ischemic optic neuropathy(AION) is known to be caused by circulatory
disturbance in the anterior optic nerve(AON). Because the AON shares blood supply
from the paraoptic short posterior ciliary artery with peripapillary choroid, the
authors investigated the angiographic evidences of combined choroidal
insufficiency in patients with acute AION. Fundus fluorescein angiograms from 30
eyes from 28 patients with acute AION were enrolled in this study. The diagnosis
of acute AION was based primarily on angiographic evidences of filling delay of
optic nerve head and the various clinical features, such as decreased visual
acuity, visual field defects, afferent pupillary defect, and optic disc swelling.
Angiographic evidences of combined choroidal filling delay were as follows: 1)
circular or localized filling delay of peripapillary choroid in 15 eyes (50%), 2)
generalized filling delay of posterior pole in 11 eyes (36.7%), 3) filling delay
of unilateral choroid divided by watershed zone in 5 eyes (16.7%), and 4)
choriocapillary filling delay in 10 eyes (33.3%). In this study, various types of
choroidal insufficiency in patients with AION were observed, which helped us to
differentiate AION from the other various diseases of the anterior optic nerve.
PMID- 10761406
TI - Two cases of late postoperative capsular block syndrome.
AB - Two cases of late postoperative capsular block syndrome that occurred 4 and 8.5
years, respectively, were encountered. One case underwent phacoemulsification
after continuous curvilinear capsulorhexis in his left eye. The other case had a
can opener type capsulorhexis and underwent extracapsular cataract extraction
with trabeculectomy. One-piece posterior chamber lenses were implanted in both
cases. Upon slit-lamp examination, the posterior capsules were found distorted
posteriorly; the capsular openings were apparently sealed by the lens optic. A
whitish material existed between the intraocular lens optic and posterior
capsule, with thick aggregation in a lower fifth space in case 1. After Nd:YAG
laser anterior capsulotomy in case 1, the thick aggregate spread diffusely on the
posterior capsule which was sunken completely for 4 weeks. After Nd:YAG
capsulotomy, the distorted posterior capsule disappeared and the best corrected
visual acuity was restored to 20/20 in both cases.
PMID- 10761407
TI - Central retinal vein occlusion combined with cilioretinal artery occlusion.
AB - A healthy 65-year-old man with sudden profound visual loss in his right eye
presented with clinical signs of central retinal venous occlusion and retinal
whitening, indicative of a cilioretinal arterial obstruction. He had been
diagnosed with cilioretinal artery occlusion at a private ophthalmology clinic
three days before being referred to our department. On fluorescein angiogram of
the affected eye, the proximal portion of the retinal arteries filled with dye
27.3 seconds after injection, indicating a delay in retinal arterial filling.
Moreover, the cilioretinal artery did not fill at that phase, but went on to fill
45.1 seconds after injection. Over 63.4 seconds after the filling of the retinal
arteries, the laminar flow of the retinal venous vessels appeared. This was not
until 90.7 seconds after injection. This patient was elderly, had no systemic
diseases, and showed non-ischemic CRVO, prolonged retinal arterial filling on
fluorescein angiography, and poor prognosis in visual acuity. His clinical course
seemed to favor the pathogenetic hypothesis of a primary arterial affection.
PMID- 10761408
TI - A case of presumed ocular toxocariasis in a 28-year old woman.
AB - This is a case of presumed ocular toxocariasis in a 28-year old woman complaining
of a sudden onset of nasal side field defect of the right eye. The patient had
been suffering from uveitis for ten months. Fundoscopic examination of the right
eye showed a rhegmatogenous retinal detachment. Furthermore, a retinochoroidal
granulomatous lesion was observed nearby the tear site. Scleral buckling,
cryotherapy, and gas injection(SF6, pure gas, 0.7 cc) were conducted. Mebendazole
was prescribed for one month at 25 mg/kg per body weight daily. Even though the
interventions resulted in the recovery of the field defect, anti-Toxocara IgG and
IgE titer levels did not decrease when checked three months after the treatment
ended. This is the first confirmed serological ocular toxocariasis case in Korea.
Uveitis may be a clinical presentation prior to retinal detachment of a person
with toxocariasis.
PMID- 10761409
TI - A case of optic neuropathy treated by percutaneous trans-coronary angiography.
AB - There are many risk factors involved in the development of ischemic optic
neuropathy such as diabetes mellitus, hypertension, arteriosclerosis, and
vascular incompetence. Therefore, the treatment of ischemic optic neuropathy
should not be solely based on proper diagnosis but should also involve a thorough
and systemic investigation to identify those multifactorial possibilities, which
may contribute to the pathogenesis of the disease. We report upon a patient who
developed non-arteritic ischemic optic neuropathy following treatment of a
sphenoethmoid mucocele, which lead to recovered vision and a satisfactory
improvement of visual field defects, after percutaneous trans-coronary
angiography with stent insertion of the coronary arteries.
PMID- 10761410
TI - Reoperation in acquired involutional ptosis.
AB - Postoperative upper lid asymmetry is a common problem following ptosis surgery.
Recently we performed multiple ptosis operative procedures to correct lid
asymmetry in the management of a patient with bilateral acquired upper eyelid
ptosis. The patient's eyelids were corrected successfully after five procedures.
We retrospectively reviewed the treatment of this patient with unsatisfactory
results. The medical literature was reviewed for further insight into the common
problem of reoperation after ptosis surgery.
PMID- 10761411
TI - Orbitocranial injury caused by wood.
AB - A rare case of a patient with orbitocranial injury by a wooden foreign body is
reported. Penetrating periorbital wound by a wooden stick with entry site at the
right upper eyelid was related to the invasion into the temporal lobe.
Fortunately, the anterior and posterior segments of eye were unharmed, but right
ocular motility was markedly restricted mechanically in all directions. Forced
duction test was strong positive, especially the dextroversion of the right eye.
Computed tomography scan showed a well-delineated low density from the orbital
wall into the temporal lobe. The wooden foreign body was subsequently removed
from the orbit and the temporal lobe, through the neurosurgical frontotemporal
approach. After the wooden foreign body was removed, the ocular movement of the
right eye fully recovered without any intracranial or ocular complications.
PMID- 10761412
TI - Phakomatous choristoma of the eyelid.
AB - This article describes the first report of phakomatous choristoma of the eyelid
in Korea. A six-month-old boy underwent excision of a congenital inferonasal
orbital mass arising from the left lower lid. A dermoid cyst was suspected,
however a diagnosis of phakomatous choristoma was made following conventional
histology. An immunohistochemical study of this rare benign congenital tumor was
conducted. The cuboidal epithelial cells comprising this choristoma showed
strongly positive cytoplasmic staining with S-100 protein and vimentin. They also
showed focally positive staining with a neuron-specific enolase, while they
showed no immunoreactivity to cytokeratin or epithelial membrane antigen. The
results of the immunohistochemical study support the conclusion that this tumor
is of lenticular anlage origin.
PMID- 10761413
TI - Palpebral myiasis.
AB - Myiasis is most prevalent in Mexico, central and south America, tropical Africa,
and the southwestern United States. Although dermal myiasis is rare in most of
the United States, it is a disorder that may be seen in international travelers.
In the United States, external myiasis is usually caused by the cattle botfly. We
report here a case of ophthalmomyiasis involving the left upper eyelid of a
child. We examined a six-year-old boy who presented to the Massachusetts Eye and
Ear Infirmary (MEEI) in September 1998. He complained of persistent swelling of
his left upper eyelid for the previous ten days. The edema and erythema were
unresponsive to warm compresses and oral antibiotics. Ocular examination revealed
a mild preseptal cellulitis of the left upper eyelid with a small draining
fistula. On slit-lamp examination, we found one larva protruding intermittently
from the fistula site. The larva was extracted with forceps, wrapped in a moist
towel and sent in a jar to the parasitology laboratory. The specimen was
identified as a Cuterebra larva by a parasitologist at the Harvard School of
Public Health. One week later, the patient's eyelid edema and erythema had
completely resolved.
PMID- 10761414
TI - Births: final data for 1998.
AB - OBJECTIVES: This report presents 1998 data on U.S. births according to a wide
variety of characteristics. Data are presented for maternal demographic
characteristics including age, live-birth order, race, Hispanic origin, marital
status, and educational attainment; maternal lifestyle and health characteristics
(medical risk factors, weight gain, and tobacco and alcohol use); medical care
utilization by pregnant women (prenatal care, obstetric procedures, complications
of labor and/or delivery, attendant at birth, and method of delivery); and infant
health characteristics (period of gestation, birthweight, Apgar score, abnormal
conditions, congenital anomalies, and multiple births). Also presented are birth
and fertility rates by age, live-birth order, race, Hispanic origin, and marital
status. Selected data by mother's State of residence are shown including teenage
birth rates and total fertility rates, as well as data on month and day of birth,
sex ratio, and age of father. Trends in fertility patterns and maternal and
infant characteristics are described and interpreted. METHODS: Descriptive
tabulations of data reported on the birth certificates of the 3.94 million births
that occurred in 1998 are presented. RESULTS: Birth and fertility rates increased
in 1998 by about 1 percent, the first increase since 1990. Birth rates for
teenagers fell 2-5 percent. Rates for women in their twenties increased 1-2
percent each, whereas rates for women in their thirties rose 2-4 percent. All
measures of childbearing by unmarried women increased in 1998; the number of
births rose 3 percent, the birth rate increased about 1 percent while the percent
of births that were to unmarried women rose to 32.8 percent. Smoking by pregnant
women overall dropped again in 1998, but continued to increase among teenagers.
Improvements in prenatal care utilization continued. The cesarean delivery rate
increased for the second year after declining for 7 consecutive years. The
proportion of multiple births continued to rise; higher order multiple births
(e.g., triplets, quadruplets) rose by 13 percent in 1998, following a 14 percent
rise from 1996 to 1997. Key measures of birth outcome--the percents of low
birthweight and preterm births--increased. These changes are in large part the
result of increases in multiple births.
PMID- 10761415
TI - [Physician and state, public health and law].
PMID- 10761416
TI - [Medical, ecological, social and labor adaptation of the indigenous population of
the North-Eastern regions of Russia].
AB - Social and economic status of the indigenous population of the Extreme North-East
is critical; fundamentals of vital activity and health status of aborigines
drastically deteriorated in recent years. The proposed measures will decrease the
social strain, provide rational nutrition, and introduce into practical public
health new approaches to medical ecological prophylaxis of many diseases.
PMID- 10761417
TI - [Morbidity of young people in the rural population].
AB - The morbidity of rural young people is analyzed from the rate of consultations at
treatment-and-prophylaxis institutions and data of comprehensive medical check
ups. The aggravation index was estimated for patients with chronic diseases in
the studied population, which provided additional information. The age/sex
aggravation indexes of the population extend the current methodological
approaches to complex evaluation of population health and serve as additional
information in evaluation of the need in different types of care.
PMID- 10761418
TI - [Approaches to formation of a territorial logopedic service].
AB - The incidence of speech disorders in children and adolescents of the Ryazan
region in 1993-1998 is analyzed. Speech abnormalities became highly prevalent
among children in recent years, particularly among preschool children, and hence
specialized service for subjects with speech disorders is to be formed, which
should pay the priority attention to children. Approaches to creation of
logopedic service of a territory are outlined.
PMID- 10761419
TI - [Medical and social studies of sex behavior of adolescents].
AB - Due to economic and social causes, risky reproductive behavior of adolescents in
modern Russia is characterized by a clear-cut tendency to an increasing
discrepancy between physical, social, and psychological maturing of young people.
The necessity of alteration of the sexual behavioral style of adolescents is
dictated by necessity of retaining their reproductive health. Preventive
educational programs can become one of the methods for attaining this purpose.
However, a truly effective program determining the forms and methods of
permissible effects on the adolescents can be developed only after profound
studies of their knowledge in the sphere of sexual behavior. Such studies were
carried out in 1994-1998 in Novosibirsk and its region by the Juventus Municipal
Consultation and Diagnosis Center for Children and Adolescents. The detected
tendencies are presented in the paper.
PMID- 10761420
TI - [Methodology of studying health based on population register].
AB - Morbidity among the Moscow population receiving medical care at clinical hospital
No. 85 and among workers, particularly those occupationally exposed to harmful
factors, has been studied using an original system of automated processing of
medical statistical information. The structure and incidence of the major groups
of diseases has been studied in comparison with the mean data for Moscow. Total
morbidity of adults and adolescents in 1998 was 1408/1000, which is close to the
level for the whole Moscow (1396/1000). Morbidity among men was 1249/1000, which
is lower than among women (1595/1000), while the incidence of diseases with
temporary disability, primary invalidity, and mortality are higher among men.
Population health is better in a relatively closed and socially protected
population attached to a single institution in Moscow than in Russia in general;
specifically, the incidence of infectious diseases and injuries is lower.
PMID- 10761421
TI - [Problems in reforming health care centers].
AB - Reformation of therapeutic and prophylactic institutions attached to various
institutions and ministries is and important problem of public health at the
modern stage of its development. A model developed and tried in Magnitogorsk can
serve as a perspective trend of such reforms. A medical institution with mixed
form of property has been created. The institution was set up by administration
of the territory and a plant (Magnitogorsk metallurgical plant). Creation of a
new health center as a non-commercial institution promoted its integration in the
municipal public health system; the institution possesses all the potentialities
of a budget organization and retains close contact with the plant. Such a
solution of the problem improved the financial status of the health center and
promoted its adaptation to marketing conditions. Attraction of additional
finances from industry to municipal public health allowed the administration of
the health center start and carry out internal restructuring aimed at priority
development of outpatient care, restructuring of the bed fund, technological
updating, and, in general, more rational utilization of the available resources.
PMID- 10761422
TI - [Role of teaching practices in the training of nurses for primary health care
centers].
AB - The role of "training practice" in the formation of teams of specialists of the
reformed primary health care is discussed. Innovation models of a "general
practitioner" ("family doctor"), "family office manager", "general practice
nurse" are mastered at "experimental" sites of an organization experiment. The
philosophy of a tutor in general practice, individual requirements of students,
and regulations of training are defined. Scheme of information of all interested
persons and organizations on the alterations is presented. Prospects in
development of primary health and social care of the family are outlined on the
basis of general practices in the Samara region.
PMID- 10761423
TI - [Current problems in reforming of dental care services].
AB - Orientation to priority utilization of economic and medical legal approaches to
reformation of dental service is an obligatory condition for effective solution
of the problems of Russian dentistry. The priority tasks are: creation of
economic and legal models of a dental profession and improvement of its normative
and legal basis; development and realization of general Russian and regional
programs of transformation of state dental centers into other than state ones and
privatization of dental institutions; practical reformation of economic
mechanisms of dental service; development of methods for state regulation of
dental activities during the transition period; determination of directions and
choice of social measures to modify dentistry service; creation of a system of
guarantee of high quality of dental care; improvement of legally-based
professional protection of dentists.
PMID- 10761424
TI - [Comprehensive assessment of the work of physicians of the therapeutics profile].
AB - A system for comprehensive evaluation of the work of hospital therapists, based
on the qualimetric principles and methods, is presented. Comparative quantitative
analysis of data characterizing the physical activity of a physician and the
normative standard parameters are used. The work is evaluated by its chief
characteristics: quantity, complexity, and quality. Other signs of labor,
significant for its type and results, are taken into consideration. The system is
relatively easy to use and optimizes the management of labor.
PMID- 10761425
TI - [Role of statistics in municipal public health system].
AB - Five-year experience of information service of filing and analyzing medical care
volume is summarized. The service has been set up on the basis of regional
medical information analytical center in the Voskresensk district of the Moscow
region for solving the problems of management.
PMID- 10761426
TI - [Medical and social aspects of causes of neglected lung cancer at the primary
health care level].
AB - A technology of managing the treatment- and diagnostic process, based on
automation and algorithms for adopting decisions, has been introduced at
outpatient center No. 9 in Barnaul.
PMID- 10761427
TI - [Approaches to improving drug supply to the population].
AB - The official record system has been introduced at public health institutions of
the Novgorod region 3 years ago. It helped regulate the drug supply at medical
institutions and in the region at large.
PMID- 10761428
TI - [Current state of medical rehabilitation in the Republic of Byelarus].
AB - Problems in the modern status of medical rehabilitation (MR) service in the
Republic of Belarus, prerequisites for its creation, and prospects for
development are discussed. The service is set up on the basis of laws of the
Republic and normative acts of the Ministry of Health. Main aspects of these laws
and acts are presented and their significance for the formation of MR service is
discussed. Main stages in organization support of the service are characterized:
evaluation of the disease consequences before rehabilitation measures, evaluation
of the rehabilitation potential, rehabilitative measures proper, and assessment
of their efficacy. Approaches to practical rehabilitation in Belarus and in
foreign countries are presented in accordance with published reports. Economic
efficiency of MR is discussed. Trends of research of MR service are outlined.
PMID- 10761429
TI - [Teaching of pathological anatomy at the Moscow University in the 1st half of the
19th century. 3].
PMID- 10761430
TI - [History of the pre-revolutionary period if the development of public health in
West Siberia].
PMID- 10761431
TI - [Public health of Byelarus during the First World War].
PMID- 10761432
TI - [Stages in improvement of extraction instruments in dentistry].
PMID- 10761433
TI - [Concentration of attention and learning processes in patients with schizophrenic
psychosis. Part I. Attention disorders].
AB - Test of the ability to focus attention on the task at hand revealed attention
deficits in each group of patients under study. The decision taking time in
simple reaction test was longest in schizophrenic patients, significantly longer
then in patients with affective disorder. It was also fund that chronic
schizophrenics performed relatively better in the vigilance test then patients
hospitalized for the first time.
PMID- 10761434
TI - [Concentration of attention and learning processes in patients with schizophrenic
psychosis. Part II. Process of acquisition of verbal material].
AB - All examined patient groups did worse in tests of auditory acquisition of new
verbal material than healthy controls. Long term schizophrenic patients scored
lower in these tests than those hospitalized for the first time.
PMID- 10761435
TI - [Seeking the mechanisms of disorders of cognitive deficits in dementia,
depression and aging. Part I].
AB - The article includes research review in cognitive functions (orientation, memory,
learning and visuo-spatial function) in dementia, depression and old age. This
paper focuses on neuropsychological and anatomical mechanism progress of
cognitive deficits. With reference to the quoted research we depict trends and
dynamics of the distinguished cognitive functions.
PMID- 10761436
TI - [Seeking the mechanisms of disorders of cognitive deficits in dementia,
depression and aging. Part II].
AB - The article includes research review in cognitive functions (attention, solving
problems and language function) in dementia, depression and ageing. This paper
focuses on neuropsychological and anatomical mechanism of progress of cognitive
deficits. With reference to the quoted research we depict trends and dynamics of
the distinguished cognitive functions.
PMID- 10761437
TI - [Clinical picture and duration of prodromal period of schizophrenia in
adolescents].
AB - The aim of study was retrospective estimation of clinical picture and duration of
prodromal period in 150 adolescents with the first episode of schizophrenia.
PMID- 10761438
TI - [Presentation of the scales for the diagnosis and evaluation of therapy results
in catatonia].
AB - A new concept of diagnostic and rating scales as well as a model of standardized
examination in catatonia treatment are presented.
PMID- 10761439
TI - [Psychotic realization of the "myth of return": a case study involving delusional
misidentification].
AB - Case study of a Polish man who for many years was treated in hospitals in Great
Britain, whose psychopathology forms at the same time a psychotic return to the
fatherland.
PMID- 10761440
TI - [Depressive symptoms in the preclinical period of dementia of the Alzheimer's
type].
AB - Five-year observation performed on 204 persons indicates that depressive symptoms
very often appear in the preclinical period of dementia of the Alzheimer type.
PMID- 10761441
TI - [The costs of Alzheimer's disease treatment: the rationale of
acetylcholinesterase inhibitors use?].
AB - The costs of Alzheimer's disease treatment in the era of acetylcholinesterase
inhibitors use are critically discussed.
PMID- 10761442
TI - [Transsexualism. Definition, classifications, symptomatology of the phenomenon].
AB - The main objective of this paper is to show different definitions and
classifications of transsexualism, as well as changing the diagnostic criteria of
this phenomenon according to DSM-III, DSM-III-R, DSM-IV, ICD-10.
PMID- 10761443
TI - [Etiology of transsexualism].
AB - The paper is devoted to the topic of the aetiology of transsexualism, different
theoretical approaches to this issue are presented, being supported by numerous
empirical evidence.
PMID- 10761444
TI - Mesocosms in ecotoxicology (1): Outdoor aquatic systems.
AB - Mesocosms have been used in aquatic ecotoxicology for approximately 20 years and
were sometimes claimed to be essential tools, especially for regulatory purposes.
The term aquatic mesocosm currently describes indoor and outdoor artificial
streams or experimental ponds and enclosures. The use of mesocosms refines the
classical methods of ecotoxicological risk assessment because mesocosms provide
conditions for a better understanding of environmentally relevant effects of
chemicals. They make it possible to assess effects of contaminants by looking at
the parts (individuals, populations, communities) and the whole (ecosystems)
simultaneously. Ecotoxicological investigations in mesocosms will not entirely
replace the use of laboratory animals. However, they allow tests to be performed
on species that are not of major societal concern, but which play key roles in
the structure and function of ecosystems. In this respect, mesocosms allow
nondestructive measurements of integrated endpoints. They also appear as potent
tools to predict changes at the highest levels of organization (population,
community, and ecosystem) from measurements of individual endpoints. However,
after a period of extensive use, regulatory studies using large-scale mesocosms
were more or less abandoned at the beginning of the 1990s, mainly because their
cost-effectiveness was questionable. This review covers key features of outdoor
aquatic mesocosms that can be critical for their use in environmental risk
assessment of chemicals and emphasizes the optimization of their use for such
purpose. The originality of mesocosms is mainly based on the combination of
ecological realism, achieved by introduction of the basic components of natural
ecosystems, and facilitated access to a number of physicochemical, biological,
and toxicological parameters that can be controlled to some extent. This
characteristic determines various features of the systems such as the minimal
size required, initial physicochemical and biological composition, or choice of
model species for ecotoxicological investigations. Ecological maturity of
mesocosms affects the degree of variability of both physicochemical and
biological parameters used to investigate the impact of contaminants. Adequate
time is required to establish a number of interacting functional groups. The
choice of appropriate time scales must be considered in the selection of both
study duration and sampling frequency. Whatever the system used, duration of
experiments should be sufficient to identify both direct and indirect effects on
populations and communities. The choice of the experimental design should be
based on the objectives of the study rather than on theoretical considerations.
In addition to classical parametric statistical methods, nonparametric approaches
and multivariate analysis may significantly improve data processing. Realism,
representativity, and replicability of mesocosms are critical for evaluating
their usefulness in both risk and impact assessment procedures. Each natural
ecosystem is unique because its structure and function mainly depend on local
factors. Therefore, there is a conceptual opposition between realism and
replicability when applied to mesocosms. Considering the objectives of most
mesocosm studies, replicability should be preferred to realism. Replicability may
be achieved, in part, by a relative simplification of the systems. Reconstituted
systems do not need to exactly simulate natural conditions at all levels, but key
features at both structural and functional levels should be preserved as they
ensure ecological representativity. Reliability of information on
ecotoxicological effects of chemicals tested in aquatic mesocosms closely depends
on the representativity of biological processes or structures that are likely to
be affected. Extrapolation from small experimental systems to the real world
seems generally more problematic than the use of larger systems in which more
complex interacti
PMID- 10761445
TI - Lizard contaminant data for ecological risk assessment.
AB - This review is the most comprehensive currently available of the effects and
accumulation of environmental contaminants on lizards. The importance of lizards
was emphasized in hope that they be included in ecological risk assessments as
well as any study on environmental contamination. Some studies presented here
indicated that lizards are ideal bioindicators. They are important as a component
of biodiversity, and many species are listed as threatened or endangered. In
addition, lizards are a significant part of many ecosystems as well as an
important link in many food chains. There are large gaps in data for many
environmental contaminants, particularly data on lizards. Ecotoxicological
studies on a wide variety of lizard species are needed; both laboratory and field
studies would provide useful information. Because the majority of lizards are
insectivores, studies of the effects and accumulation of pesticides are
essential. A few current studies are available from Africa and Australia, but
most, especially those conducted in the U.S., were not current. Studies are
needed on the effects and accumulation of ubiquitous contaminants, such as heavy
metals and PCBs. Because of the many contaminated sites and the significant waste
disposal problem, studies are needed on the effects and accumulation of
radionuclides on lizards. Furthermore, effects of multiple stressors must be
studied. Last, studies are needed linking the effects of contaminants to tissue
residues. It is hoped that the convenience of having the vast majority of lizard
environmental contaminant data available in one document will encourage its use.
PMID- 10761446
TI - Biomarkers in earthworms.
AB - Earthworms are believed to be so-called key species within ecosystems and are
often exposed to a wide range of anthropogenic compounds released to the
terrestrial environment. As a consequence, they may suffer from the toxicity of
these compounds. For these and other reasons, earthworms have been used
extensively in ecotoxicological studies. In recent years the use of other
biological responses (biomarkers) to estimate either exposure or resultant
effects of chemicals has received increased attention. Biomarkers address the
question of bioavailability by only responding to the bioactive fraction. They
may incorporate effects following exposure to a mixture of chemicals. Biomarkers
may also reduce extrapolation of results from the laboratory to the field, as
they may be applicable under both conditions. The present review has drawn
together current knowledge on potential biomarkers in earthworms and appraised
them in relation to basic requirements needed for supplying information relevant
to devising satisfactory risk assessment. A wide range of potential biomarkers
have been measured in earthworms, including DNA alteration, induction of metal
binding proteins (MTs and MBP), depression of ChE activity and other enzymatic
responses, energy reserve responses, responses in neural impulse conductivity,
lysosomal membrane stability, immunological responses, changes in sperm numbers,
histopathological changes, and behavioral changes. Both organic and inorganic
compounds have been included; however, for each biomarker the main emphasis
historically has been placed on only a few chemicals. Dose-response relationships
were in some cases observed. Little information is available on the linkage of
the biomarker response to effects at population or community levels. The
influence of other factors, biotic and abiotic, on the biomarker responses and
their temporal duration have been only sporadically reported.
PMID- 10761447
TI - Hepatitis C, iron, and hemochromatosis gene mutations. A meaningful relationship
or simple cohabitation?
PMID- 10761448
TI - Noninvasive blood cell measurements by imaging of the microcirculation.
PMID- 10761449
TI - Hepatosplenic gamma-delta T-cell lymphoma as a late-onset posttransplant
lymphoproliferative disorder in renal transplant recipients.
AB - We report 2 cases of renal transplant recipients in whom hepatosplenic gamma
delta T-cell lymphoma (gamma-delta HSTCL) developed 5 and 10 years after
transplantation. Both patients had marked hepatosplenomegaly, B symptoms (weight
loss, fever, and night sweats), and abnormal peripheral blood findings, including
anemia in both, thrombocytopenia and leukoerythroblastic changes in 1, and
leukocytosis in the other. Markedly atypical lymphoid infiltrate of intermediate
to large cells was observed in the spleen, liver, and bone marrow. The malignant
cells showed typical immunophenotype of gamma-delta T cells (CD2+, CD3+, CD4-,
CD8-, CD7+, gamma-delta T-cell receptor-positive, and alpha-beta T-cell receptor
negative) with clonal T-cell receptor gene rearrangement and were of the V-delta
1 subset. In addition, the cells contained a cytolytic granule-associated
protein, TIA-1, and Fas ligand, indicating cytotoxic T-cell differentiation. The
malignant T cells in both cases were of host tissue origin. Both cases were
negative for Epstein-Barr virus genome using Southern blot analysis. The patients
did not respond to reduction of immunosuppression. Despite initial response to
chemotherapy, both patients died within 6 months of diagnosis. Our findings
indicate that gamma-delta HSTCL can occur as a late complication in transplant
recipients.
PMID- 10761450
TI - Evaluation of the Abbott CELL-DYN 4000 hematology analyzer.
AB - A new generation hematology analyzer, Abbott CELL-DYN 4000 (CD 4000), capable of
providing 26 parameters, including fully automated reticulocyte, nucleated RBC,
blast, band, and immature granulocyte, and variant lymphocyte counts, was
evaluated by using the National Committee for Clinical Laboratory Standards H20-A
protocol and compared with the Bayer-Technicon H-2 analyzer, which is used
routinely in our laboratory. A lipid interference experiment and a sample aging
study also were performed. Linearity, carryover, and precision were within the
limits established by the manufacturer, and satisfactory agreement was found with
the H-2 analyzer. The evaluation of leukocyte differential counts indicated an
excellent correlation with the manual reference method for neutrophils and
lymphocytes, a good correlation for monocytes and eosinophils, and a poor
correlation for basophils in samples with low counts; for basophil counts of 2%
or higher, we found an improvement of the correlation coefficient. In the lipid
interference experiment, only hemoglobin determination was influenced
significantly on the CD 4000, but by using a new Abbott hemoglobin reagent, the
interference was eliminated. The CBC and differential counts were stable and
reportable up to at least 24 hours. Intrasample viability information on
leukocytes provided a quality check on each individual specimen.
PMID- 10761451
TI - von Willebrand factor is the most reliable immunohistochemical marker for
megakaryocytes of myelodysplastic syndrome and chronic myeloproliferative
disorders.
AB - To find the best immunohistochemical marker for megakaryocytes in normal marrow,
myelodysplastic syndrome (MDS), and chronic myeloproliferative disorders (CMPD),
57 marrow biopsy specimens were studied semiquantitatively with
immunohistochemical methods using a panel of 7 antibodies. The staining intensity
was graded 0 to 3 for scoring 100 consecutive megakaryocytes in each stained
section. The final score for each stain was the sum of these 100 megakaryocytes
individually multiplied by their corresponding grade. In normal marrow (11
cases), the average scores for antivon Willebrand factor (vWF) and Ulex europaeus
agglutinin-1 (UEA-1) were 177.1 and 195.1, respectively. The scores for the other
5 markers, including anti-platelet-derived growth factor-BB, 2 anti-transforming
growth factor-beta 3, anti-CD61, and anti-CD79a ranged from 96.1 to 124.1. In MDS
(27 cases), the scores were 200.8 (vWF), 152.6 (UEA-1), and 28.7 to 98.5
(others). In CMPD (19 cases), the scores were 220.5 (vWF), 179.2 (UAE-1), and
64.8 to 101.2 (others). These results show that vWF and UEA-1 are good
immunohistochemical markers for megakaryocytes in normal marrow, and vWF is the
best marker in MDS and CMPD. For routine practice, vWF is the most reliable
marker for identifying atypical megakaryocytes, especially in the cases of 5q
syndrome and agnogenic myeloid metaplasia.
PMID- 10761452
TI - Expression of c-Myc and p53 correlates with clinical outcome in diffuse large B
cell lymphomas.
AB - We performed a retrospective immunohistochemical study of the relationships
between clinical manifestations and outcomes of diffuse large B-cell lymphoma
(DLBCL) and expression of oncogenic proteins in 21 cases of DLBCL at various
clinical stages. Cases of nodal origin expressed p53 more often and presented
with high clinical stage more frequently than those of extranodal origin.
Expression of c-Myc or p53, but not Bcl-6, Bcl-2, or Bcl-1, showed a
statistically significant positive correlation with high clinical stage at
presentation and with high or high-intermediate risk. Coexpression of c-Myc and
p53 occurred in 7 of 12 patients with high clinical stage but was absent in
patients with low clinical stage; coexpression was more frequent in patients with
high or high-intermediate risk than in patients with low or low-intermediate
risk. Four patients with this coexpression pattern demonstrated an unusually
aggressive clinical course (median survival, 7 months). Coexpression of c-Myc and
p53 seems to be a better indicator than the MIB1 proliferative index for
identification of a cohort of aggressive disease in patients with DLBCL.
PMID- 10761453
TI - Variability of laboratory test results.
AB - Variabilities of serum total cholesterol and potassium results provided to 11
medical clinics were assessed using an audit sample-split specimen design. This
involved collection of 3 tubes of blood from each of 302 patients, with 1 split
specimen divided into 3 audit samples: 1 was sent to the original participating
laboratory, another to a commercial referral laboratory, and the third to an
academic referee laboratory. Two methods were used to assess variability of test
results. Method 1 was based on result pairs corresponding to the split specimen
and its corresponding audit sample. Method 2 was based on audit sample results
only. The 2 methods provided comparable results for total cholesterol; the
estimated coefficient of variation was 1.0% to 3.7%. However, method 1
consistently provided higher estimates of variability for potassium; the
estimated SD was 0.096 to 0.168 mmol/L for method 1, while it was 0.035 to 0.090
mmol/L for method 2. Method 1 is more practical, but method 2 can provide a more
accurate assessment of analytic variability.
PMID- 10761454
TI - A new method of quantitative fecal fat microscopy and its correlation with
chemically measured fecal fat output.
AB - Fecal fat microscopy using the Sudan stain has suffered from a relative lack of
specificity, and results are "qualitative." Therefore, we developed a
quantitative fecal fat microscopic method with hopes of improving diagnostic
accuracy. One hundred eighty patients with chronic diarrhea collected stools for
1 to 3 days, and fecal fat output was measured by a standard chemical method, and
microscopy was performed by the old qualitative and new quantitative methods.
There was a highly statistically significant linear correlation between
quantitative fecal fat microscopy and chemically measured fecal fat output. The
quantitative microscopic method had a sensitivity of 94% and a specificity of
95%; the traditional method had a sensitivity and specificity of 76% and 99%,
respectively. Fecal fat Sudan microscopy performed by a dedicated approach to
counting and size measurement of fat globules can yield a quantitative result
that correlates well with chemically measured fecal fat output and has a high
diagnostic accuracy.
PMID- 10761455
TI - Apolipoprotein E allele distribution in trisomy 13, 18, and 21 conceptuses in a
Hungarian population.
AB - Reports documented a higher frequency of apolipoprotein E (apoE) allele epsilon 4
among mothers of children diagnosed with Down syndrome. We studied the prevalence
of apoE alleles among 56 conceptuses with trisomy 13, trisomy 18, or trisomy 21.
The presence of the 3 most common apoE alleles (epsilon 2, epsilon 3, epsilon 4)
was determined by polymerase chain reaction-restriction fragment length
polymorphism, and trisomy status was detected by fluorescent polymerase chain
reaction followed by DNA fragment analysis and by conventional cytologic methods.
We found no significant difference in the distribution of apoE alleles in the
group of trisomy 21 fetuses compared with samples from healthy blood donors. The
odds of having trisomy 18 for the apoE epsilon 4 group was 3-fold as high as for
apoE epsilon 3 allele compared with the healthy control group. Furthermore, a
statistically significant association was found for those with trisomy 18 and
apoE epsilon 4, while for those with trisomy 13 and apoE epsilon 4, the test
showed no significant association. The observed apoE allele epsilon 3 frequencies
among patients with Down syndrome and healthy control subjects may help explain
and support previous work that did not find high rates of atherosclerosis among
these persons. The role of apoE alleles in the development of trisomies needs
further study.
PMID- 10761456
TI - Diabetic mastopathy. A clinicopathologic review.
AB - Diabetic mastopathy, an uncommon form of lymphocytic mastitis and stromal
fibrosis, typically occurs in longstanding type 1 diabetes. Nineteen cases
meeting predetermined histopathologic criteria for diabetic mastopathy were
correlated as to clinical history and disease recurrence. Physical examination
revealed palpable discrete masses or diffuse nodularity, both predominantly in
the subareolar region. One nonpalpable lesion was detected incidentally during
reduction mammoplasty. All cases contained lymphocytic ductitis and lobulitis
with varying degrees of keloidal fibrosis, vasculitis, epithelioid fibroblasts,
and lymphoid nodule formation. Single mammary lesions were found in 11 patients
with type 1 diabetes, 1 with type 2 diabetes, and 3 without diabetes. Four cases
were bilateral (3 patients with type 1 and 1 patient with type 2 diabetes). Six
of 19 cases recurred (3 ipsilateral, 2 contralateral, and 1 bilateral). We
confirm the histopathologic constellation for diabetic mastopathy. However, we
question the specificity of these features because of identical findings in
patients with type 2 diabetes and nondiabetic patients. We found diabetic
mastopathy in men and women, as a solitary mass or bilateral disease, and
recurrence in either breast, sometimes multiple. Recognition of potential
recurrence is important because it might spare patients with documented diabetic
mastopathy from repeated breast biopsies.
PMID- 10761457
TI - Iron deposition and progression of disease in chronic hepatitis C. Role of
interface hepatitis, portal inflammation, and HFE missense mutations.
AB - Histologically detectable iron (HDI) and HFE mutations were searched for in liver
biopsy specimens from 58 Italian patients with chronic hepatitis C, and
morphologic features were compared to examine their reciprocal relation and their
contribution to disease progression. HDI was evident in 48% of cases with
features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI
increased with stage; grade was related to all iron scores because of the
contribution of portal inflammation and interface hepatitis. HFE mutations were
seen in 47% of patients with chronic hepatitis C and in 28% of control subjects;
they were related to stage and the His63Asp mutation to portal HDI. On
multivariate analysis, grade but not stage or HFE mutations was associated with
HDI in all sites. Interface hepatitis with its sequelae (sinusoidal
capillarization and microshunting) represents a major factor in iron deposition
in chronic hepatitis C and justifies the features of HDI. HFE mutations are not
responsible for HDI deposition but could favor the progression of virus-induced
damage independently from interference with iron metabolism.
PMID- 10761459
TI - Fine-needle aspiration cytology of lymphoproliferative lesions involving the
major salivary glands.
AB - Fine-needle aspiration biopsy (FNA) is an accurate and cost-effective procedure
for evaluating salivary gland lesions. Lymphoproliferative lesions may manifest
as salivary gland enlargement. We report our experience with 43 cases of reactive
and neoplastic lymphoproliferative lesions of the salivary glands evaluated by
FNA, including 23 cases of reactive lymphoid hyperplasia and 20 neoplastic
lymphoproliferative processes. The latter included 2 multiple myelomas and 18 non
Hodgkin lymphomas (small lymphocytic lymphoma/chronic lymphocytic leukemia, 1;
small cleaved cell lymphoma, 1; lympho-plasmacytoid lymphoma, 1; mucosa
associated lymphoid tissue lymphoma, 2; mixed cell lymphoma, 4; lymphoblastic
lymphoma, 1; and large cell lymphoma, 8). There were no false-negative diagnoses.
Aspiration smears from 3 patients with reactive lymphoid hyperplasia and 4
patients with malignant lymphoma initially were interpreted as atypical lymphoid
proliferations or as suggestive of malignant lymphoma. Thus, FNA had a
sensitivity of 100% and a specificity of 87%. The majority of patients were
treated medically without surgical intervention. Among the patients who underwent
surgical resection of the salivary gland, 7 had an equivocal cytologic diagnosis
and 2 had a benign cytologic diagnosis, but their parotid swelling failed to
regress despite medical treatment. In most instances, FNA provides useful
information for subsequent disease management and obviates surgical intervention.
PMID- 10761458
TI - Microvessel density as a predictor of PSA recurrence after radical prostatectomy.
A comparison of CD34 and CD31.
AB - Whether prostate cancer recurrence can be predicted by microvessel density (MVD)
measurements is controversial. One reason for the lack of agreement may be the
differing antibodies used to determine MVD. We evaluated MVD using 2 different
antibodies against endothelial cells, CD31 and CD34, on 102 patients who
underwent radical prostatectomy without adjuvant hormonal therapy. The tumors
from these cases were identified, and areas with the highest Gleason pattern were
immunostained. Average MVD determined by CD31 (MVD/CD31) staining was
significantly lower than that obtained by MVD/CD34 staining (60.1 vs 80.3). By
using Kaplan-Meier analysis, prostate-specific antigen (PSA) recurrence was
correlated with MVD/CD31 and MVD/CD34. MVD/CD34 and MVD/CD31 were associated
strongly with PSA recurrence on a univariate level. However, only MVD/CD34 was an
independent predictor of PSA failure. Therefore, some of the confusion about MVD
value as a prognostic indicator may be due to the antibodies used.
PMID- 10761460
TI - Extramammary Paget disease is characterized by the consistent lack of estrogen
and progesterone receptors but frequently expresses androgen receptor.
AB - Extramammary Paget disease (EPD) is an uncommon cutaneous malignant neoplasm that
arises in areas rich in apocrine glands (perineum, vulva, and axilla). Apocrine
gland origin or apocrine differentiation of cells of EPD has been suggested.
Estrongen, progesterone, and androgen hormone receptors have been reported to
exhibit a characteristic pattern of expression in mammary apocrine type
carcinomas; however, their expression in EPD has not been elucidated fully. By
using immunohistochemical methods, we studied the expression of steroid receptors
in EPD on formalin-fixed paraffin-embedded tissue samples from 28 patients with
EPD without associated visceral malignant neoplasms or adnexal carcinoma.
Androgen receptor (AR) was identified in 15 of 28 cases. The proportion of AR
positive cells varied from 1% to more than 75%; 8 cases expressed AR in more than
10% of cells. Strong AR expression also was seen in the invasive carcinoma
arising from 1 case of EPD. All cases lacked immunohistochemically detectable
estrogen and progesterone receptors. The immunophenotype characteristic of
apocrine carcinomas (AR-positive, estrogen receptor-negative, progesterone
receptor-negative) was seen in a substantial proportion of EPD cases. Results
suggest that AR expression is a factor in pathogenesis of EPD. This may be
important for the therapy of recurrent or invasive disease.
PMID- 10761461
TI - Cytokeratin expression in seminoma of the human testis.
AB - We studied cytokeratin (CK) expression immunohistochemically in 64 seminomas
using a panel of commercially available antikeratin antibodies and tested for
association of CK expression with patient age, tumor size, stage, and outcome.
Seventeen embryonal carcinomas were compared with seminoma. CK7, CAM 5.2,
AEI/AEIII, and wide-spectrum screening keratin (WSK) were positive in 41%, 30%,
36%, and 36% of the seminomas, respectively. CK20 and high-molecular-weight
keratin (HMWK) were negative in all cases. CD30, placental alkaline phosphatase
(PLAP), and epithelial membrane antigen (EMA) were positive in 6%, 100%, and 2%
of cases, respectively. There were no differences in patient age, stage, tumor
size, or outcome between CK-positive and CK-negative seminomas. CK7, CAM 5.2,
AEI/AEIII, and WSK were positive in 100%, 88%, 94%, and 88% of embryonal
carcinomas, respectively. CK20 and HMWK were negative in all cases. CD30, EMA,
and PLAP were positive in 100%, 12%, and 76%, respectively. CKs are present in
seminoma, and their presence is not associated with a difference in patient age,
stage, or outcome. In cases such as small needle biopsy specimens, CK and CD30
stains may be useful in separating seminoma from embryonal carcinoma.
PMID- 10761462
TI - Suspected myocardial infarction.
PMID- 10761463
TI - Adenomatous hyperplasia.
PMID- 10761464
TI - Further "teleconsultation" called for.
PMID- 10761465
TI - An overlooked factor VLeiden autopsy study.
PMID- 10761466
TI - Flow cytometry defended.
PMID- 10761467
TI - A new form of T-cell PTLD.
PMID- 10761468
TI - Another type of PLGA tumor.
PMID- 10761469
TI - Concurrent primary large cell lymphoma and carcinoid tumor of the small bowel.
PMID- 10761470
TI - [Cancer--the unsolved challenge].
PMID- 10761471
TI - [Public opinion on active euthanasia. The results of a pilot project].
AB - BACKGROUND AND OBJECTIVE: Despite eager public interest there have been few
significant studies about the views of the German population on active
euthanasia. It was our purpose to investigate, before undertaking a
representative enquiry about this controversial and ethically sensitive topic, to
what extent public opinion and the underlying norms, values and preferences can
be adequately obtained by standardized data collection. COHORT AND METHODS: An
interdisciplinary project group established a standardized written form of
enquiry for measuring public opinion about active euthanasia. The test was
performed on an anonymized convenience [corrected] sample of 110 persons living
in North Germany. The questionnaires consisted of ten hypothetical cases, 11
potentially relevant viewpoints on likely decisions and eight frequently
expressed arguments used in the debate for and against euthanasia. RESULTS: The
reply rate to the questionnaire was 89% (n = 98; 37 men and 59 women, average age
39.5 [21-81] years). Agreement with active euthanasia in the various case
examples ranged, according to context, from 85 to 93%. Active euthanasia was
accepted by a clear majority, if preconditions of a voluntary decision by a
mentally sound person and incurable, terminal disease (cancer) are cumulatively
fulfilled. Otherwise it was rejected by most respondents. To a clear majority,
active euthanasia implied both the chance that suffering would be shortened, but
also the danger of misuse. Among the persons questioned those with professional
experience of euthanasia were clearly more sceptical about active euthanasia than
those without such experience. CONCLUSIONS: The standardized written
questionnaire made it possible to obtain a differentiated picture of public
opinion on active euthanasia. However, these data represent only a moment in the
dynamic process of a norm being established within a society and must on no
account be used as legitimizing active euthanasia by plebiscite.
PMID- 10761472
TI - [Whole-body hyperthermia: global warming in tumor therapy?].
PMID- 10761473
TI - [Chemotherapy in combination with whole-body hyperthermia in advanced malignant
pleural mesothelioma].
AB - HISTORY AND CLINICAL FINDINGS: A 57-year-old man presented with dyspnoea, cough,
fatigue and weight loss. He had been exposed to asbestos 30 years ago. Physical
examination was unremarkable apart from a suspected pleural effusion.
INVESTIGATIONS: Computed tomography (CT) of the thorax showed multiple pleural
masses with pleural effusion on the left side. CT of the abdomen and bronchoscopy
were normal. The patient underwent explorative thoracoscopy; biopsies were taken,
and diffuse malignant pleural mesothelioma was demonstrated. TREATMENT AND
COURSE: The patient was evaluated at the University Hospital Lubeck for Phase II
experimental therapy with whole-body hyperthermia (WBH). The pretreatment
evaluation revealed normal cardiorespiratory function and a normal contrast
enhanced CT of the brain. The patient's haematologic profile and electrolytes
were normal. The WBH-radiant heat device (RHD) used for therapy was Aquatherm
provided by the Cancer Research Institute (CRI, New York, USA). The patient
received ifosfamide (5 g/m2, day 1), carboplatin (300 mg/m2, day 1), etoposide
(150 mg/m2, days 2-3) combined with WBH at 41.8 degrees C (for 60 minutes). Two
cycles were applied without complications and a partial remission of the disease
was observed. CONCLUSION: Radiant heat whole body hyperthermia, in conjunction
with a defined anticancer treatment and pharmacological approach to sedation, was
a safe and effective palliative treatment in this patient.
PMID- 10761474
TI - [A therapeutic study of hepatocellular carcinoma using octreotide (HECTOR).
Hepatocellular Carcinoma: Treatment with Octreotide].
PMID- 10761475
TI - [Diagnosis and staging in gastric carcinoma].
PMID- 10761476
TI - [The therapy of testicular tumors 2 decades after the introduction of cisplatin].
PMID- 10761477
TI - [The refusal of life-sustaining therapeutic measures in moribund patients].
PMID- 10761478
TI - [The refusal of life-sustaining therapeutic measures in moribund patients].
PMID- 10761479
TI - [The evaluation of therapeutic results as exemplified by the adjuvant
chemotherapy of breast carcinoma].
PMID- 10761480
TI - Paul Karrer--research on vitamins.
PMID- 10761481
TI - Mayo Clinic Proceedings: from internal newsletter to international journal.
PMID- 10761482
TI - Mayo Clinic Proceedings celebrates its 75th year of service.
PMID- 10761483
TI - Mayo Foundation at the turn of the 21st century: adapting to change but
consistent in values.
PMID- 10761484
TI - Education in the 21st century: challenges and opportunities.
PMID- 10761485
TI - Biomedical research at Mayo Clinic: a tradition of collaboration and a vision for
year 2000 and beyond.
PMID- 10761486
TI - Reflections from past editors.
PMID- 10761487
TI - Benefits of laparoscopic-assisted colectomy for colon polyps: a case-matched
series.
AB - OBJECTIVE: To clarify the true benefits of laparoscopic-assisted colectomy by
comparing clinical outcomes from a series of laparoscopic right colectomies with
matched open colectomies, all performed for the singular indication of polyp not
amenable to colonoscopic removal. PATIENTS AND METHODS: A retrospective case
matched study was performed of consecutive patients undergoing laparoscopic
assisted right hemicolectomy for polyps between January 1992 and July 1997. Each
case was matched to a control undergoing the equivalent open procedure for the
same indication during the same time period. RESULTS: Thirty-eight patients
undergoing laparoscopic-assisted right hemicolectomy for polyps were identified,
and matches were found. The conversion rate was 18.4% (7/38), 21.4% early in the
series and 10% in later experience. Operative times were longer for laparoscopic
associated colectomy (median, 208 minutes vs 150 minutes, P < .001). Laparoscopic
assisted colectomy resulted in shorter postoperative ileus (time to flatus, 3.0
vs 4.0 days, P < .001; time to bowel movement, 3.5 vs 5.0 days, P < .001) and in
earlier tolerance of regular diet (3.5 vs 6.0 days, P < .001). Fewer days of
narcotic administration were required by the laparoscopic group (3.0 vs 4.5 days,
P < .001). This resulted in a significantly shorter length of hospital stay (4.0
vs 7.0 days, P < .001). There was no significant difference in the incidence of
postoperative complications. CONCLUSIONS: Laparoscopic right hemicolectomy has
significant patient benefits. These benefits are apparent when procedures of
equal complexity and equivalent indications are compared. Laparoscopic-assisted
resection has become our preferred approach for polyps not amenable to
colonoscopic polypectomy.
PMID- 10761489
TI - Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis
C virus infection.
AB - OBJECTIVES: To investigate whether patients with chronic hepatitis C virus (HCV)
infection without evidence of cirrhosis have an increased risk of diabetes
mellitus (DM) and to evaluate possible risk factors for diabetes in this group.
PATIENTS AND METHODS: We conducted a case-control study of 45 consecutive
eligible patients with HCV infection and no clinical, scintigraphic, or
histological evidence of cirrhosis, and a control group of 90 subjects without
liver disease matched by age, sex, and body mass index and similar in their
origin distribution. Eighty-eight patients with chronic hepatitis B virus (HBV)
infection with no evidence of cirrhosis were also evaluated. The diagnosis of
diabetes was based on the 1997 American Diabetes Association criteria. RESULTS:
Fifteen patients (33%) with HCV infection were found to have type 2 diabetes
compared with 5.6% in the control group without liver disease (P < .001) and 12%
in the group with HBV infection (P = .004). Comparison of the patients with and
without diabetes revealed that positive family history of diabetes, HCV 1b
genotype, and a more severe liver histology were significantly associated with
DM. CONCLUSIONS: Patients with chronic HCV infection have an increased prevalence
of type 2 diabetes, and this prevalence is independent of cirrhosis. The
pathogenesis is intriguing, appears to be unique to HCV, and requires further
study.
PMID- 10761488
TI - Asphyxiation by laryngeal edema in patients with hereditary angioedema.
AB - OBJECTIVE: To describe the occurrence of fatal laryngeal edema in patients with
hereditary angioedema due to C1 esterase inhibitor deficiency. PATIENTS AND
METHODS: We describe 6 patients from various regions of Germany who died from
laryngeal edema within the last 10 years. Furthermore, we conducted a
retrospective survey of 58 patients with hereditary angioedema, originating from
46 affected families. The data were obtained from the attending physicians and
from the patients' relatives. RESULTS: Among the 6 reported patients, aged 9 to
78 years, hereditary angioedema had been diagnosed in 3 and was undiagnosed in 3.
None of them had an emergency cricothyrotomy or received C1 inhibitor
concentrate. The interval between onset of the laryngeal edema and asphyxiation
was 20 minutes in a 9-year-old boy, and in the other patients, the interval was 1
to 14 hours (mean for all, 7 hours). The retrospective survey of 58 patients with
hereditary angioedema revealed 23 deaths by asphyxiation (40%). The average age
of all 29 patients at the time of asphyxiation was 39 years. CONCLUSION:
Laryngeal edema in hereditary angioedema may be fatal. Most of the patients
asphyxiated between their 20th and 50th years of life, but asphyxiation can occur
even in children. The possibility that the first episode of laryngeal edema may
be fatal must be emphasized to the relatives, and attending physicians must have
a high degree of awareness.
PMID- 10761490
TI - Acute pancreatitis in the postpartum period: a population-based case-control
study.
AB - OBJECTIVE: To determine relationships among pregnancy (during and postpartum),
acute pancreatitis, and gallstones. PATIENTS AND METHODS: In this retrospective
population-based case-control study, we identified all 12- to 50-year-old
Rochester, Minn, females diagnosed between 1976 and 1991 as having acute
pancreatitis (cases). For each case, we matched 4 women of the same age (+/- 6
years) with no history of acute pancreatitis (controls). Acute pancreatitis was
defined as associated with pregnancy if it occurred from 10 months prior to
delivery to delivery and with the postpartum period if it occurred within 10
months of the date of delivery. Logistic regression was used to assess
associations between pregnancy-related acute pancreatitis, age, gallstone
occurrence, and alcohol use. RESULTS: In a cohort of 61 women who developed acute
pancreatitis and 244 controls, the relative risk for acute pancreatitis
associated with pregnancy was 1.43 (95% confidence interval, 0.61-3.40). All 10
cases of acute pancreatitis associated with pregnancy occurred in the postpartum
period. Gallstones were present in 6 of them compared with 13 of 51 women with
non-pregnancy-related acute pancreatitis (P < .05). Women with postpartum-related
pancreatitis were younger than those with non-pregnancy-related pancreatitis
(mean, 28 vs 36 years; P < .05). Alcohol was not associated with pregnancy
related pancreatitis. CONCLUSIONS: Acute pancreatitis during the postpartum
period is not directly related to pregnancy but is associated with gallstones and
occurs in younger women.
PMID- 10761491
TI - Telemedicine applications in primary care: a geriatric patient pilot project.
AB - OBJECTIVE: To determine patient satisfaction with telemedicine technology.
SUBJECTS AND METHODS: In this pilot study, 20 generally healthy elderly residents
(mean age, 77.3 years) of a Florida retirement community consulted weekly by
"Electronic House Call" with a primary care physician to record their vital signs
and discuss their condition. At the end of the 8-week study period, they were
asked to complete a survey indicating their satisfaction with the telemedicine
experience. RESULTS: Eighteen of the 20 participants completed the survey. Eleven
respondents (61%) reported they were comfortable using the computer system
without assistance. Most (13/18; 72%) believed the computer system correctly
recorded vital signs. Almost all (17/18; 94%) reported the computer system did
not have a negative impact on their relationship with their primary health care
provider, and 11 (61%) thought that the system had a positive effect.
CONCLUSIONS: The participants in this small pilot study were pleased with the
experience they had with telemedicine. Large-scale studies are needed to
determine the widespread utility of telemedicine technology.
PMID- 10761493
TI - Clinical preventive medicine in primary care: background and practice: 3.
Delivering preventive screening services.
AB - The first article in this 3-part review on clinical preventive medicine described
background information, supportive evidence, and current practices in preventive
medicine. The second article discussed incorporating primary preventive
activities including health promotion and immunizations into primary care
practice. This third and final article in the series focuses on secondary
prevention, i.e., screening, and examines the evidence and recommendations for
various screening tests and procedures. Screening for hyperlipidemia and
hypertension, 2 areas in which national programs are in place, are discussed.
Wider incorporation of currently underutilized preventive services into primary
care has a great potential to improve morbidity, mortality, and the quality of
life in the general population.
PMID- 10761492
TI - Novel risk factors for atherosclerosis.
AB - In the past several years, evidence has accumulated that factors other than
conventional risk factors may contribute to the development of atherosclerosis.
Conventional risk factors predict less than one half of future cardiovascular
events. Furthermore, conventional risk factors may not have the same causal
effect in different ethnic groups in whom novel risk factors may have a role.
These newer risk factors for atherosclerosis include homocysteine, fibrinogen,
impaired fibrinolysis, increased platelet reactivity, hypercoagulability,
lipoprotein(a), small dense low-density lipoprotein cholesterol, and inflammatory
infectious markers. Identification of other markers associated with an increased
risk of atherosclerotic vascular disease may allow better insight into the
pathobiology of atherosclerosis and facilitate the development of preventive and
therapeutic measures. In this review, we discuss the evidence associating these
factors in the pathogenesis of atherosclerosis, the mechanism of risk, and the
clinical implications of this knowledge.
PMID- 10761494
TI - Treatment guidelines for HIV-associated wasting.
AB - Patients with acquired immunodeficiency syndrome (AIDS) often suffer from weight
loss manifested by a loss of body cell mass (BCM). The causes of human
immunodeficiency virus (HIV)-associated wasting may include anorexia,
malabsorption, and a variety of altered metabolic states. Malabsorption and
diarrhea may result from gastrointestinal tract opportunistic infections or from
direct effects of HIV on the gastrointestinal tract. Infection with HIV may
produce metabolic derangements that alter nutrient utilization, resulting in loss
of BCM. Nutritional assessment of the patient with AIDS should include an
evaluation of BCM and physical and psychosocial functioning. Antiretroviral
therapy and eradication of opportunistic infections do not always reverse
wasting. Treatment should include nutritional counseling. Total parenteral
nutrition is sometimes of benefit, particularly in patients with damaged
gastrointestinal tracts. Dronabinol and megestrol acetate may promote weight
gain; however, dronabinol may have adverse effects, and most of the gain with
megestrol acetate is in fat rather than BCM. If gonadal dysfunction is present,
testosterone replacement therapy should be included in the treatment plan. Some
studies suggest that oral anabolic steroids may improve muscle strength and body
composition. In randomized, placebo-controlled trials, mammalian-derived human
growth hormone (rhGH[m]) has produced sustained weight and BCM gains in AIDS
patients. If a patient continues to lose BCM after the above factors have been
addressed and corrected, a 12-week course of rhGH[m] is indicated. Halting the
progression of HIV-associated wasting may improve survival, enhance physical and
social functioning, and enrich quality of life.
PMID- 10761495
TI - Management of abdominal aortic aneurysms.
AB - Rupture of an abdominal aortic aneurysm (AAA) remains a common vascular
catastrophe in all emergency departments. Currently, the natural history of AAAs
indicates that risk of rupture increases considerably when the aneurysm is
greater than 5 cm in diameter. Appropriate management of aneurysms is elective
repair for patients with a good operative risk whose aneurysm is between 5 and 6
cm. For patients with a serious medical comorbidity, the threshold for AAA repair
is usually 6 cm. Surgical management is generally safe with extraordinarily
durable results. Another current option is an investigational endovascular stent
graft, but the long-term outcome for these new devices remains unknown. In
addition, optimal medical management should include careful control of
hypertension and smoking cessation. The current prognosis for healthy patients
who undergo elective aneurysm repair is excellent.
PMID- 10761496
TI - Physostigmine in the treatment of gamma-hydroxybutyric acid overdose.
AB - The widespread abuse of the recreational drug gamma-hydroxybutyric acid has
resulted in several reports of overdose leading to coma. The use of a short
acting anticholinesterase agent such as physostigmine as a potential reversal
agent has been proposed previously. We report 2 cases of gamma-hydroxybutyric
acid-induced coma that rapidly reversed with intravenous administration of
physostigmine.
PMID- 10761497
TI - Meningoencephalitis due to Blastomyces dermatitidis: case report and literature
review.
AB - Infection of the central nervous system by Blastomyces dermatitidis is a rare
cause of meningoencephalitis. The existence of exclusive clinical infection of
the meninges in the absence of pulmonary or other foci of infection has been
debated. We describe a 20-year-old man presenting with meningoencephalitis caused
by B dermatitidis. Blastomycotic infection was confirmed by isolation of the
organism from brain tissue obtained at biopsy. Magnetic resonance imaging
demonstrated progressive enhancement of basal meninges with involvement of
bilateral basal ganglia and thalami. Treatment with amphotericin B arrested
further neurologic decline. However, clinical and radiographic follow-up
suggested damage to diencephalic structures. The diagnosis of blastomycotic
meningoencephalitis is difficult to establish because no sensitive serologic test
exists, and attempts to isolate the organism in cerebrospinal fluid obtained by
lumbar puncture generally fail. A biopsy specimen of brain tissue is frequently
necessary for the diagnosis. Survival is possible with timely initiation of
therapy.
PMID- 10761498
TI - Neurologic disorders masquerading as carpal tunnel syndrome: 12 cases of failed
carpal tunnel release.
AB - We describe 12 patients with a diagnosis of carpal tunnel syndrome in whom carpal
tunnel release was unsuccessful and another neurologic disorder was diagnosed
subsequently. Final diagnoses included polyneuropathy, radiculopathy, motor
neuron disease, spondylotic myelopathy, syringomyelia, and multiple sclerosis.
Sources of error by the electromyographer and treating physician were identified.
Care must be taken to avoid an inappropriate carpal tunnel operation when
clinical or electrodiagnostic features are atypical.
PMID- 10761499
TI - Position-dependent ventricular tachycardia related to a peripherally inserted
central catheter.
AB - Recently, peripherally inserted central venous catheters (PICCs) have been widely
used for venous access. Advantages of a PICC over centrally inserted central
catheters include the virtual elimination of the risk of pneumothorax,
hemothorax, and arterial puncture, along with a reduced risk of bleeding.
However, the PICC has associated risks. We present 2 cases of body position
dependent ventricular tachycardia related to PICCs. These events occurred in
patients with no prior history of cardiac arrhythmia and were corrected by
repositioning of the PICC. They serve to identify a potentially serious cardiac
complication of the PICC that, to our knowledge, has not been described
previously.
PMID- 10761500
TI - 52-year-old man with shortness of breath.
PMID- 10761501
TI - Deliver us from our embarrassments.
PMID- 10761502
TI - Use of likelihood ratio computation to standardize the predictive power of
noninvasive cardiovascular tests.
PMID- 10761503
TI - Childhood immunizations 2000. Introduction.
PMID- 10761504
TI - Pneumococcal vaccine.
AB - Streptococcus pneumoniae or pneumococcus is a major pathogen causing meningitis,
pneumonia, other invasive infections, and the common infections acute otitis
media and sinusitis. The major virulence factor is the polysaccharide capsule,
present as one of approximately 90 serotypes. Anticapsular antibodies protect
against infection. In 1977 and 1997, vaccines composed of purified capsular
polysaccharide from 14- and 23-capsular types, respectively, were licensed for
use in those children 2 years of age or older who are at increased risk for
invasive pneumococcal infection. These vaccines have limited immunogenicity in
infants and young children. Pneumococcal conjugate vaccines in which capsular
polysaccharides from a limited number of serotypes are covalently linked to a
protein carrier have recently been developed. In preliminary reports of
randomized, double-blind control studies, a heptavalent vaccine administered as a
series of infections to normal infants was efficacious in the prevention of
invasive infections, episodes of lobar pneumonia, and acute otitis media caused
by vaccine serotypes.
PMID- 10761505
TI - Poliovirus vaccines. Progress toward global poliomyelitis eradication and
changing routine immunization recommendations in the United States.
AB - Poliomyelitis prevention in the United States has relied virtually exclusively on
OPV during the past 30 years. Starting in 1997, a major change in the
poliomyelitis vaccination policy occurred, facilitated by substantial progress
toward worldwide poliomyelitis eradication. A sequential schedule of IPV followed
by OPV became the preferred means to prevent poliomyelitis, although an all-OPV
and an all-IPV schedule were considered acceptable alternatives. In 1999, two
doses of IPV were recommended to start the primary series, followed by two doses
of either poliovirus vaccine. As of January 2000, an all-IPV schedule is
currently being implemented in the United States for routine childhood
vaccination. Several unusual features are associated with the major public health
policy change from an all-OPV to a sequential schedule, including (1) the process
of involving a neutral party (i.e., the IOM); (2) the perceived concerns
expressed before the change in policy with regard to provider and parent
compliance, which could affect the hard-earned gains in raising immunization
coverage rates; (3) the ethical issues surrounding the change (e.g., societal
versus individual protection) and the influence that a single case of VAPP may
have on national policy; (4) the relative lack of importance of cost
effectiveness data; and (5) the weight of progress in the global polio
eradication initiative spurring the change in the United States and,
increasingly, in other industrialized countries. The IOM assisted in the
evaluation of the national poliomyelitis vaccination policy in 1977 and again in
1988. The 1988 review recommended that a sequential IPV-OPV schedule be
considered at such time that a combination vaccine becomes available. Also, the
IOM raised several important questions. Extensive research to address the
questions raised by the IOM had been conducted so that, in 1996, more data were
available for the decision-making process. The primary reasons for the change in
vaccination policy were (1) the continued occurrence of VAPP in the absence of
indigenously acquired wildtype poliovirus-associated paralytic disease, (2) the
reduced risk for importation and spread of wild-type poliovirus caused by the
progress of the global polio eradication initiative, (3) evidence from vaccine
trials that combined IPV-OPV schedules are safe and immunogenic, and (4)
maintenance of high levels of population immunity to poliovirus. The global
effect of a national change in poliomyelitis vaccination policy was also
considered in this policy-making process. Some members of the public health and
medical communities raised objections that an increased reliance on IPV in the
United States could lead other countries, especially developing countries, to
inappropriately abandon OPV and increase reliance on IPV for routine vaccination.
Experience from the global smallpox eradication campaign indicated that this
scenario was unlikely. The United States ceased vaccinating against smallpox in
1971, 6 years before smallpox was eliminated from the world, without jeopardizing
the global smallpox campaign. Subsequently, the effect on the global eradication
initiative has been negligible. This article illustrates the potential
discrepancy between expressed theoretic concerns about the number of injections
and the actual practice once vaccination policy recommendations become the
standard of care and that appropriate training and education can overcome these
initial concerns. The authors found that compliance with the recommended use of
IPV for the first and second doses as part of the sequential schedule was high,
independent of socioeconomic status and ethnicity. The need for additional
injections did not present a barrier to completion of the recommended childhood
immunization schedule. (ABSTRACT TRUNCATED)
PMID- 10761506
TI - Acellular pertussis vaccines.
AB - Although whole-cell pertussis vaccines have been highly effective in preventing
whooping cough, their common and burdensome adverse reactions have spurred the
development of safer alternatives. Seven acellular vaccines are licensed in one
or more countries; four have been licensed thus far in the United States, and
more may follow. Although the licensed acellular pertussis vaccines differ in
their immunogenicity, adverse reactions, and efficacy, all are effective and,
compared with whole-cell vaccine, are associated with markedly fewer and milder
adverse reactions.
PMID- 10761507
TI - Update on Haemophilus influenzae serotype b and meningococcal vaccines.
AB - Use of conjugate Haemophilus influenzae type b (Hib) vaccines has resulted in the
near elimination of Hib invasive disease among infants in the United States in
only 10 years, which places this intervention among the most notable public
health achievements of the past decade. This has radically altered our perception
of the major causes of bacterial meningitis and invasive bacterial disease among
children, increasing the prominence of meningococcal disease as an important
cause of childhood and adult meningitis and leading researchers to apply the same
conjugate technology to the development of improved vaccines for Neisseria
meningitidis. Use of conjugated meningococcal vaccines against serogroups A, C,
Y, and W-135 are expected to offer the possibility of better control of sporadic
disease and outbreaks throughout developed and developing countries within the
next 5 years.
PMID- 10761508
TI - Influenza and respiratory syncytial virus. Update on infection, management, and
prevention.
AB - This article is an overview of the epidemiology and spectrum of clinical disease
attributed to influenza and respiratory syncytial virus in children. It
separately discusses the pathogenesis of the two diseases and the host responses
to the viruses to emphasize each infection's significance and need for a vaccine.
Updates on current preventive measures and a preview of potential future vaccine
developments are presented.
PMID- 10761509
TI - Varicella vaccine.
AB - Varicella vaccine is safe, effective, and cost-effective in healthy children,
adolescents, and adults. Breakthrough cases of MVLS are significantly milder than
wild-type varicella infection. No severe adverse events have been reported
following vaccination, and the incidence of herpes zoster is less in vaccinees
than in individuals who have had natural varicella infections. To date, there is
no evidence waning immunity following vaccination. "New and improved" varicella
vaccines that may be more effective than the current vaccine and can be stored at
refrigerator temperatures may soon become available in the United States.
PMID- 10761510
TI - Current update of pediatric hepatitis vaccine use.
AB - Vaccines are now available for the prevention of hepatitis A and hepatitis B. In
this article, biologics are reviewed with special attention to their use in the
pediatric patient. Special attention is paid to issues that developed in 1999.
For hepatitis A vaccine, it is the change in US recommendations regarding
increased use in higher-risk US locations. For hepatitis B vaccine, it is the
concern about toxicity, real or imagined.
PMID- 10761511
TI - New combination vaccines.
AB - Physicians can achieve full vaccination at each of the recommended visits by
administering three or four injections, but for infants, four injections seem to
be a maximum in light of the size of the infant thigh, which is the preferred
injection site. Thus, physicians must make room for all of the new vaccines on
the horizon. To accomplish that task, combinations will be necessary. Progress
toward that goal is occurring.
PMID- 10761512
TI - Pediatric vaccine compliance.
AB - Immunization programs have produced a significant trend toward reducing the
occurrence of disease in the United States. The resurgence of vaccine-preventable
diseases, however, is a reminder that many goals have not yet been achieved. The
methods discussed in this article may be useful in delivering vaccines to the
pediatric population.
PMID- 10761513
TI - Immunization for children traveling abroad.
AB - More children are travelling these days, often to underdeveloped countries with
high prevalence of vaccine-preventable vector-borne, food-borne, zoonotic, and
other infections. The pretravel office visit involves consideration of routine
and travel vaccines. Epidemiology of typhoid fever, rabies, yellow fever,
Japanese encephalitis, vaccines against them, and their recommended use are
reviewed.
PMID- 10761514
TI - A step ahead. Infant protection through maternal immunization.
AB - The concept of maternal immunization to prevent infectious diseases during a
period of increased vulnerability in infants is not new and is supported by
historical experience and carefully conducted studies of various viral and
bacterial vaccines. Candidate vaccines should be minimally reactogenic,
immunogenic, and safe for maternal immunization to be considered as a disease
prevention strategy. The possibilities increase as more potential candidate
vaccines for use during pregnancy become available, including conjugate
meningococcal vaccines, parainfluenza virus type 3 purified subunit vaccines,
herpes simplex virus, cytomegalovirus, and HIV vaccines. Additional research on
the safety and efficacy of maternal immunization must continue to effect the
development of infectious diseases in neonates and infants.
PMID- 10761515
TI - Pediatric immunization for the future. Lyme disease vaccine and beyond.
AB - This article highlights some of the exciting new developments in pediatric
immunization. Starting with the newly licensed Lyme disease vaccine, which is not
yet approved for children younger than 15 years of age, the article discusses
potential vaccines for severe allergy and cocaine abuse and stresses some of the
new techniques in needleless vaccination, including the edible plant technology.
PMID- 10761516
TI - [Medical treatment of cystinuria: evaluation of long-term results in 30
patients].
AB - OBJECTIVE: Because urinary hyper-excretion of cystine is permanent in homozygous
cystinuric patients, stone recurrence is frequent and may alter renal function.
Identification of factors predictive of success of medical treatment (no further
urological procedure required) is therefore needed to improve patient management.
PATIENTS AND METHODS: Thirty adult patients with homozygous cystinuria and
urolithiasis were referred to the nephrology department of the Necker Hospital
from 1963 to 1999, with a mean follow-up of medical therapy of 10.5 +/- 8.4
years. The basal treatment schedule was hyperdiuresis and alkalinization with
thiol derivative (D-penicillamine or tiopronine) added when needed. RESULTS:
Overall incidence of urological procedures decreased from 0.33/pt-year in the
pretherapeutic period to 0.15 on treatment (p < 0.01), a 55% reduction. Sixteen
patients (53%) did not require any urological procedure during follow-up. The
only significant difference between those patients and the other 14 in whom
medical therapy failed was the daily urine volume (3.2 l/day in the former
compared with 2.4 l/day in the latter, p < 0.001). CONCLUSION: Regular medical
therapy was able to stop stone disease activity in the long term in more than
half of the patients. Sustained hyperdiuresis, with a daily urine volume > 3
liters, appears as a major factor of therapeutic success, even in patients
treated with thiols.
PMID- 10761518
TI - [Mycobacterium xenopi osteoarthritis of the ankle in a patient followed for
psoriatic rheumatism].
AB - BACKGROUND: Mycobacterium xenopi is an uncommon cause of osteoarticular sepsis.
However, a recent series of M. xenopi spondylodiscitis emphasizes the potential
risk after invasive procedures. CASE REPORT: A 33-year-old woman was followed for
psoriasis rheumatoid arthritis. She had undergone several exploratory procedures
including arthroscopy of the left ankle for invalidating joint disease. In 1999,
M. xenopi arthritis and osteomyelitis was diagnosis in this joint. DISCUSSION:
Sterilization and maintenance of surgical instruments must abide by rigorously
controlled strict protocols. The benefit/risk ratio of invasive procedures in
debilitated joints should be more precisely evaluated. Specific and repeated
sample cultures should be performed to search for mycobacteria in all bone and
joint infections, particularly in case of prior invasive procedures.
PMID- 10761517
TI - [Efficacy and tolerance of trimetazidine, a metabolic antianginal, in combination
with a hemodynamic antianginal in stable exertion angina. TRIMPOL I, a
multicenter study].
AB - OBJECTIVE: Assess the antianginal and anti-ischemic effect of trimetazidine in
patients with stable exercise-induced angina insufficiently controlled with
conventional antianginal drugs. PATIENTS AND METHODS: The study population
included patients with coronarographically documented stable exercise-induced
angina and no other serious concomitant condition. For inclusion, patients had to
have two comparably positive treadmill exercise tests. Conventional antiangina
drugs (long-acting nitrate derivatives, beta-blockers or calcium antagonists)
were continued as was any other therapy having no effect on the ECG ST segment.
The patients were given a 4-week regimen of trimetazidine (20 mg t.i.d.) after
the second positive treadmill test and final inclusion. At the end of this
period, a final exercise test was performed. The study population included 700
patients (mean age 54 +/- 8.4 years, range 32-71 years, 615 men, 85 women) who
completed the entire treatment protocol. RESULTS: The main findings observed
after 4 weeks of treatment with trimetazidine were: significant lengthening of
the total duration of exercise (486.6 s versus 443.7 s, p < 0.01)), increase in
total work (10.6 METS versus 9.4 METS, p < 0.01), significant lengthening of
delay to 1 mm ST depression (389.9 s versus 337.8 s, p < 0.01) and of the delay
to onset of angina (450.3 s versus 251.7 s, p < 0.01). The other results were a
significant reduction in the number of daily episodes of angina (2.47 versus
3.66, p < 0.01) and a reduction in mean use of complementary trinitrine (1.8
versus 2.94, p < 0.01). CONCLUSIONS: Four weeks of treatment with trimetazidine
in combination with conventional antiangina drugs leads to a longer delay to
development of 1 mm ST depression (ischemia threshold), significant lengthening
of total duration of treadmill exercise, increased total work, and longer delay
to angina theshold. Clinically, there was a reduction in the mean number of
episodes of angina and a reduction in the use of trinitrine.
PMID- 10761519
TI - [Asymptomatic nodular thyroiditis].
PMID- 10761520
TI - [Obstetric sacral plexus lesions. 19 cases].
PMID- 10761521
TI - [Analysis of a circulating anticoagulant in the course of treatment with an
antivitamin K. Importance in a febrile patient].
PMID- 10761522
TI - [What dose of acetylsalicylic acid to use after carotid endarterectomy?].
PMID- 10761523
TI - [Medications: good practice and recommendations].
PMID- 10761524
TI - [The drama of blood contamination in France. An approach to public health].
AB - The tragic HIV contamination of hemophilics and transfusion recipients between
1980 and 1985 in France led to low court proceeding the same events. In addition,
last June a state minister was arraigned for not recalling transfused patients
before 1985. This involves later events and announces other court actions. France
is the only country where these dramatic events have take on the dimension of a
major political scandal. Based on the scientific elements (reactions and articles
in the international medical literature) and an analysis of the decisions made by
France, a chronological examination of the disease and the risks for hemophiliacs
and transfusion recipients offers helpful insight into possible options for
reducing these risks. The interval between these the court proceeding allows time
for further thought focusing on a serious deviation of public health in France.
PMID- 10761525
TI - [Obesity: the crimes they commit in thy name].
PMID- 10761526
TI - [Psychological approaches to the obese].
AB - AN ESSENTIAL ELEMENT: Interest in psychological factors of obesity has been
clearly on the decline over the last thirty years. Despite this fact, the
psychological approach to obese subjects is a fundamental element both in
understanding the causal mechanisms but also to follow therapeutic effects in the
long run. However, everything cannot be explained by the fact that many
nutritionists lack a formation in psychology and many psychiatrists lack interest
for corporal diseases. What is missing is a theoretical background allowing each
participant to find his/her role in this multifactorial condition which requires
a multidisciplinary management. COLLABORATIVE CARE: The nutritionist-psychiatrist
pair would appear to be the best choice for a large number of obese subjects who
may or may not have eating habit disorders. The type of psychological help will
depend on many factors: the subject's background, environment, demands, and most
importantly, capacity for mentalization. There are many possibilities for simple
supportive care: psychoanalytic approach, behavioral therapy, cognitive therapy,
etc. The choice of a therapeutic method depends on the clinician's competence and
on the subject's characteristics. An emphatic active attitude is indispensable
for those patients whose demand for psychological help is often buried in the
somatic condition.
PMID- 10761527
TI - Genetics of obesity: towards the understanding of a complex syndrome.
AB - GENETICS AND ENVIRONMENT: Obesity is a multifactorial disease combining the
effects of genetic predisposition with very powerful environmental risk factors.
Recent genetic studies have demonstrated that there is a continuum between
different forms of human obesity. SINGLE GENE FACTORS: In certain cases, mainly
cases of very severe obesity with childhood onset, a single gene would play a
permissive role allowing environmental factors to have major impact. Rare
mutations of the leptin gene and its receptor, proopiomelanocortin, or more
frequently, melanocortin receptor 4 mutations, are evidence of the existence of
an obesity gene. Inactivity of this gene would be sufficient to produce early
onset anomalous eating habits. COMMON OBESITY: The more common forms of obesity
are however polygenic. The strong environmental pressure exceeds the capacity for
homeostatic adaptation of genetically predisposed persons, leading to an energy
imbalance favoring fat storage. WHICH GENES? Certain candidate genes, such as
decoupling genes, beta-3 adrenergic receptor genes, or regulator regions of the
leptin gene, play a minor role in the constitution or aggravation of overweight.
Recently, "whole genome" explorations in obese families have localized major
obesity genes on chromosomes 2, 5, 10, 11, and 20. Identification of these genes
with positional cloning and functional genomic techniques will be helpful in
better understanding the molecular determinants of obesity and better defining
targets for new therapies.
PMID- 10761528
TI - [Obesity in the child].
AB - The prevalence of childhood obesity increases dramatically in all industrialized
countries. As in adults, it is defined by an increase in fat mass. The United
States seem to be facing the most difficult situation. However, rapid changes in
the way of life leads to consider that, in a near future, as much as 25% of the
children in Europe could be concerned as well. A new epidemiological tool
designed by the International Obesity Task Force takes as reference criteria the
body mass index and will allow comparisons between countries as well as it will
take into account the physiological variations of fat mass during growth.
GENETICS AND ENVIRONMENT: A NEW PUZZLE: Inactivity seems to account as much as
increased or unbalanced food intakes. While genetics account for a part of the
disease at the population level, its role remains unclear in individuals. Most
complications occur early in life, in a silent and progressive way. All these
aspects do not only open fields of research but also provide new understanding
and therapeutic basis for clinicians. PREVENTION: A PUBLIC HEALTH PRIORITY:
Prevention has become a priority which should be based on early individual
surveillance and Health Policy programs based on "National Recommendations for
the diagnosis, prevention and treatment of obesity". All professionals dealing in
one way or another with children lifestyle are concerned as well as do the
families.
PMID- 10761529
TI - [Spontaneous intra-aortic contrast].
PMID- 10761530
TI - Mobilization of peripheral blood stem cells by granulocyte-colony stimulating
factors: comparison of a standard dose of glycosylated and mutated granulocyte
colony stimulating factor in non-Hodgkin's lymphoma patients following CHOP
therapy.
AB - The effects of granulocyte-colony stimulating factor (G-CSF) have been studied in
several clinical settings. G-CSFs are widely used to stimulate the production of
granulocytes and are well known to mobilize peripheral blood stem cells (PBSCs).
However, very few studies have examined differences among G-CSFs. The aim of this
study was to compare the mobilization of PBSCs induced by a standard dose of two
G-CSFs following biweekly cyclophosphamide, doxorubicin, vincristine and
prednisone (CHOP) therapy. Using a standard dose of G-CSF, we conducted a
randomized, crossover trial that compared the efficacy of two kinds of G-CSF,
glycosylated [lenograstim (2 micrograms/kg)] and mutated [nartograstim (1
microgram/kg)], on PBSC mobilization in 10 patients with non-Hodgkin's lymphoma
after biweekly CHOP chemotherapy. Lenograstim (2 micrograms/kg) was more
effective in shortening the duration of neutropenia than nartograstim (1
microgram/kg) (3.8 days vs. 5.0 days, p < 0.05, the number of days for the
neutrophil count to reach 5 x 10(9)/l from nadir). The number of CD34+ cells and
granulocyte-macrophage colony forming units (GM-CFU) was higher for lenograstim
but no statistically significant difference between the two groups was found.
Glycosylated G-CSF is more effective than mutated G-CSF in shortening the
duration of neutropenia. As for the mobilization of CD34+ cells and the number of
CFU-GM, there was a tendency to increase in the lenograstim group but no
statistically significant differences were found.
PMID- 10761531
TI - Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence
syndrome in rats.
AB - The effect of acetyl-L-carnitine on alcohol consumption and its possible ability
to alleviate all symptomatology of ethanol withdrawal syndrome has been
investigated in rats. Alcohol-dependence was induced in animals (9-15 g/kg
ethanol solution at 20% for a period of 4 days) in order to measure the effects
of acetyl-L-carnitine on ethanol abstinence syndrome. The ethanol dependence
phase was characterized by the onset of signs and responses of progressive
severity: hyperactivity, tremors, spastic rigidity and spontaneous convulsive
seizures. After 4 days, 8 h after the last ethanol administration, two groups of
animals received acetyl-L-carnitine (125 mg/kg and 250 mg/kg intraperitoneally,
respectively) and the intensity of the withdrawal syndrome was assessed on the
basis of the appearance of tremors. The effect of acetyl-L-carnitine on voluntary
alcohol consumption was investigated in a rat line selected for innate ethanol
preference. For 15 days the animals could freely choose both water and/or a
hydroalcoholic solution (10% p:v). Acetyl-L-carnitine was given intraperitoneally
at a dose of 200 mg/kg twice daily. The water and the hydroalcoholic solution
levels were checked at the same time daily. Acetyl-L-carnitine treatment
significantly reduced the onset of tremors in ethanol withdrawal syndrome as well
as the level of ethanol intake in alcohol-preferring rats. These results suggest
a possible pharmacological role of acetyl-L-carnitine in the treatment of alcohol
dependence.
PMID- 10761532
TI - Comparative study of D-002 versus sulfasalazine on acetic acid-induced colitis in
rats.
AB - D-002 is a natural mixture of higher aliphatic primary alcohols purified from
beeswax and has experimentally proven mild antiinflammatory and effective
antiulcer effects. It reduces leukotrienes in the exudate of carrageenan-induced
pleurisy and has a protective effect on the preulcerative phase of carrageenan
induced colonic ulceration in the guinea pig. This study was conducted to compare
the effect of D-002 and sulfasalazine on acetic acid-induced colitis in rats
administered at 1, 5.25 and 100 mg kg-1, 24 h before colitis induction.
Significant reductions in wet weight, macroscopic injury, polymorphonuclear
infiltration and wall thickness were observed in the colonic mucosa of D-002 and
sulfasalazine-treated animals compared with controls, except at the dose of 1 mg
kg-1. It was concluded that the effects of D-002 and sulfasalazine were
comparable in this experimental model.
PMID- 10761533
TI - Six-month prospective study to monitor the treatment of rheumatic diseases with
sustained-release flurbiprofen.
AB - Nonsteroidal antiinflammatory drugs (NSAIDs) are used in the therapy of both
inflammatory and degenerative diseases of the locomotor system. Due to the
relatively high occurrence of adverse effects, mainly on the gastrointestinal
tract, NSAID therapy often has to be discontinued. Studies focusing on long-term
NSAID therapy end points are rare. Two hundred patients presenting with classic
rheumatic diseases (osteoarthritis, n = 50; rheumatoid arthritis, n = 130;
ankylosing spondylitis, n = 20) were given a daily dose of 200 mg sustained
release flurbiprofen (flurbiprofen SR). The aim of the study was to assess the
results of a 6-month treatment. This open therapeutic study was carried out in 10
rheumatological outpatient departments in the Slovak Republic with 20 patients
from each department. The patients were monitored monthly during the 6 months of
treatment. The group comprised 71% females with an average age of 52.7 years
(range 22-72 years). The degree of the disease activity was assessed at the start
of the study as moderate (68%) for all groups. Average disease duration was 10.4
years (0.4-35 years). Most patients had previously been treated with other
NSAIDs. A total of 151 patients (75.5%) successfully completed the 6-month
therapy with flurbiprofen; 49 patients (24.5%) withdrew from the treatment
prematurely, most of them at an early stage (23 during the first month, 11 during
the second month, five during the third and fourth months each, three during the
fifth month and two during the sixth month). The reasons were lack of efficacy in
10 patients and adverse effects (mostly mild to moderate gastrointestinal
intolerance) in 26. The remaining 13 patients gave other reasons for withdrawal.
No predictive factors could be identified on comparing the basic demographic data
of patients who completed the course of treatment with those who withdrew from
therapy. In conclusion, flurbiprofen SR given in a single daily dose of 200 mg is
an effective and relatively well tolerated NSAID, which is suitable for the long
term treatment of most patients with chronic arthritic conditions.
PMID- 10761534
TI - Intravenous clodronate for acute pain induced by osteoporotic vertebral fracture.
AB - Even though newly developed drugs may in the future preserve bone mass and reduce
the risk of fracture, patients with osteoporosis will continue to suffer from
episodes of painful vertebral fracture for many years to come. For this reason,
the treatment of acute pain induced by this pathology is still a clinically
important issue. The aim of this study was to assess the effect of intravenous
disodium clodronate (300 mg) on three pain conditions (at rest, on pressure and
on motion) associated with recent osteoporotic vertebral fractures. The effects
of disodium clodronate were compared with those of paracetamol in 30 patients
during a 30-day observation period. The results showed higher pain remission rate
in patients receiving disodium clodronate intravenously than in those receiving
paracetamol. The rapid onset of analgesic activity produced by intravenous
administration of disodium clodronate after vertebral fracture represents a
definite clinical indication.
PMID- 10761535
TI - Serum pharmacokinetics of antimycobacterial drugs in patients with multidrug
resistant tuberculosis during therapy.
AB - Serum samples of 13 patients with multidrug-resistant tuberculosis were taken 0,
1, 2, 4, 8 h after administration of antimycobacterial drugs for assay of levels
in order to gain further insight into their basic pharmacokinetics. The drugs
assessed were amikacin, kanamycin, ofloxacin, levofloxacin, para-aminosalicylic
acid, prothionamide, cycloserine, pyrazinamide and ethambutol. Techniques used
for assay were reversephase high-performance liquid chromatography, gas liquid
chromatography and fluorescent polarization immunoassay. The results from 12
patients were evaluated. These provided new pharmacokinetic data on high-dose
levofloxacin, cycloserine and prothionamide given once daily, and could be useful
in guiding the scheduling of drugs. The data obtained might also lead to insights
into the development of therapeutic drug monitoring in multidrug-resistant
tuberculosis.
PMID- 10761537
TI - Evaluation of metronidazole toxicity: a prospective study.
AB - Metronidazole is an antimicrobial, antiprotozoal agent that has been widely used
in the treatment of a variety of infections. Some therapeutic indications
necessitate prolonged treatment with metronidazole. Peripheral neuropathy is a
potential metronidazole-induced toxicity, which has been reported in only a few
isolated retrospective studies. This prospective study was designed to determine
the toxic profile of metronidazole in patients undergoing long-term treatment
with this drug. In the present study, 17 patients of both sexes, aged between 20
and 50 years, with body weights ranging from 46 to 62 kg and who were suffering
from various medical ailments were recruited. The patients received 400 mg t.i.d.
oral metronidazole in a total dose of 16.8-39.6 g for 2-4 weeks. It was found
that patients usually suffered from some of the toxic symptoms of metallic taste,
headache and dry mouth and to a lesser extent nausea, glossitis, urticaria,
pruritus, urethral burning and dark colored urine. Symptoms were irrespective of
sex and directly proportional to duration of therapy. Deep tendon ankle jerks
were maximally reduced in four patients and sense of vibration at the level of
olecranon and patella was affected in two patients. Distal latency and velocity
of the sural and posterior tibial nerves were significantly affected (p < 0.01)
compared with control values. These results indicate possible motor-sensory
neurotoxicity involving the lower limbs due to long-term metronidazole therapy.
PMID- 10761536
TI - Pharmacokinetic and pharmacodynamic interactions of mefloquine and quinine.
AB - This study was carried out to investigate the pharmacokinetic and pharmacodynamic
interactions between two antimalarial drugs, mefloquine and quinine. A
randomized, comparative, three-way crossover study was performed in seven healthy
male Thais after the administration of three drug regimens on three occasions
i.e., a single oral dose of quinine sulfate (600 mg), mefloquine (750 mg) alone,
or the combination of mefloquine (750 mg) and quinine (600 mg given 24 h after
mefloquine). QTc interval was significantly prolonged in subjects following the
combination regimen (at 2.5, 3, 4, 6, 8, 12, 18, 24 h after the quinine dose) but
no abnormal clinical signs or symptoms were found. There were no significant
changes in vital signs or routine laboratory values in any of the subjects. The
pharmacokinetics of mefloquine and quinine were influenced by the presence of the
other drug. Greater blood schizonticidal activities were collected from the sera
of subjects on the combination regimen than from the sera of subjects the quinine
or mefloquine regimens. The minimum inhibitory concentrations (MICs) of the
equivalent concentrations (Eqs) of quinine or mefloquine, which completely
inhibited the growth of the K1 strain of Plasmodium falciparum in vitro (MICs of
quinine Eq and mefloquine Eq) were significantly lower in the sera of subjects on
the combination regimens, than in the sera of subjects on mefloquine or quinine
alone [MICs of quinine Eq: 41.2 (21.25-73.5) vs. 135 (118-150) ng/ml; MICs of
mefloquine Eq: 18.2 (17-19.2) vs. 25.2 (24.4-26.8) ng/ml].
PMID- 10761538
TI - Effects of a standardized ginseng extract on quality of life and physiological
parameters in symptomatic postmenopausal women: a double-blind, placebo
controlled trial. Swedish Alternative Medicine Group.
AB - A randomized, multicenter, double-blind, parallel group study was performed to
assess the effects of a standardized ginseng extract compared with those of a
placebo on quality of life (QoL) and on physiological parameters in symptomatic
postmenopausal women. Validated questionnaires [Psychological General Well-Being
(PGWB) index, Women's Health Questionnaire (WHQ)] and Visual Analogue (VA) scales
were used to assess the effects of the extract on QoL at baseline and after 16
weeks' treatment with either the ginseng extract or placebo. To assess the
efficacy of ginseng on postmenopausal symptoms, physiological parameters
[follicle-stimulating hormone (FSH) and estradiol levels, endometrial thickness,
maturity index and vaginal pH] were recorded at the same time points. Of the 384
randomized patients (mean age 53.5 +/- 4.0 years), the questionnaires were
completed by 193 women treated with ginseng and 191 treated with placebo. With
regard to the primary endpoint (total score of the PGWB index) the extract showed
only a tendency for a slightly better overall symptomatic relief (p < 0.1).
Exploratory analysis of PGWB subsets, however, reported p-values < 0.05 for
depression, well-being and health subscales in favor of ginseng compared with
placebo. No statistically significant effects were seen for the WHQ and the VA
scales or the physiological parameters, including vasomotor symptoms (hot
flushes). The positive effects of ginseng on health-related QoL in menopausal
women should be further investigated. This study shows, however, that the
beneficial effects of ginseng are most likely not mediated by hormone replacement
like effects, as physiological parameters such as FSH and estradiol levels,
endometrial thickness, maturity index and vaginal pH were not affected by the
treatment.
PMID- 10761539
TI - Resveratrol, a natural stilbene in grapes and wine, enhances intraphagocytosis in
human promonocytes: a co-factor in antiinflammatory and anticancer
chemopreventive activity.
AB - Trans-resveratrol, a natural stilbene present in wine and grapes, has been
studied mainly for its antiinflammatory and anticancer activities. In this study
the activity of resveratrol on proliferative immunological parameters
(differentiation, apoptosis, phagocytosis and intracellular killing) was studied
using a U937 human promonocytic cell line in comparison with another polyphenol,
quercetin. After incubation of the pathogen, Candida albicans, intracellular
killing by macrophage-like cells was decreased by quercetin and resveratrol 10
microM but was enhanced by resveratrol 1 microM after 20 h of treatment.
Phagocytosis rate, expressed as phagocytosis frequency, (i.e., percentage number
of phagocytosing cells/total cells) at 20 h was highest with resveratrol 10
microM and was higher with quercetin 10 microM than with resveratrol 1 microM.
The phagocytosis index exhibited the same trend. While both polyphenols
demonstrated cytostatic activity on U937 growth, a prointraphagocytic effect for
resveratrol 10 microM-treated cells at 10 min, resveratrol 1 microM-treated cells
at 20 h and resveratrol 10 microM-treated cells at 48 h was observed.
Morphological examination with optic microscopy demonstrated both apoptotic and
differentiating cells, even after 10 min treatment. Resveratrol-induced apoptosis
(following 4 h treatment) was confirmed by flow cytometry at concentrations as
low as 1 microM and 100 nM in the assay for detection of membrane
phosphatidylserine. Resveratrol- or quercetin-treated, but unstimulated cells,
did not produce tumor necrosis factor-alpha protein. As phosphatidylserine
externalization triggers specific recognition by monocytes and macrophages,
removal of intact apoptotic cells is important a) in cell population selection
and differentiation for antiblastic therapy, and b) in preventing the release of
toxic inflammatory substances such as reactive oxygen substances and proteolytic
enzymes by dying cells. This observation suggests that wine polyphenols, at the
same concentrations as those found in plasma after moderate wine consumption, are
important cofactors in antiinfective, antiinflammatory and anticancer nonspecific
immune reactions.
PMID- 10761540
TI - Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant
arthritis.
AB - Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism
of drug effects have enabled the use of new drugs and drug combinations in
rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme
therapy and combined therapy with cyclosporin in rats with adjuvant arthritis.
Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5
or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice
daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for
a period of 40 days from the adjuvant application. Levels of serum albumin,
changes in hind paw swelling and bone erosions were measured in rats as variables
of inflammation and arthritis-associated destructive changes. Treatment with 5 mg
of cyclosporin A, as well as with the combination therapy with cyclosporin A plus
PHL, significantly inhibited both the inflammation and destructive arthritis
associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited
these disease markers, although to a lesser extent and at a later stage of
arthritis development. The results show the inhibitory effect of enzyme therapy
on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A
given in combination with enzyme therapy, which may be useful in the treatment of
rheumatoid arthritis.
PMID- 10761541
TI - Colony stimulating factors regulate nitric oxide and prostaglandin E2 production
in rat cartilage chondrocytes.
AB - Colony stimulating factors (CSFs) are now widely used in cancer treatment and
immunological disease therapy. Both granulocyte CSF (G-CSF) and granulocyte
macrophage CSF (GM-CSF) are used to increase neutrophil counts in Felty syndrome.
In the present study, the effects of macrophage CSF (M-CSF), G-CSF, GM-CSF and
interleukin-3 (IL-3) (10 ng/ml) on the production of nitric oxide and
prostaglandin E2 (PGE2) by cartilage explants were examined over 24 and 48 h. The
effects of these CSFs were also measured in combination with IL-1 beta (10
ng/ml). M-CSF, GM-CSF and IL-3 had no effect on nitrite production. However, both
IL-1 beta and G-CSF caused a significant increase (p < 0.05) in nitrite levels at
48 h. NG-L-arginine-methyl-ester was used to inhibit nitrite production induced
by G-CSF and this implicated nitric oxide synthase activity. When G-CSF and IL-1
beta were used in a combined treatment, nitrite levels were significantly
increased (p < 0.05) at both 24 and 48 h. Both IL-3 alone and in combination with
IL-1 beta caused elevated PGE2 production in this model. PGE2 levels were also
significantly increased by stimulation with GM-CSF and IL-3 combined with IL-1
beta. These findings demonstrate that GM-CSF, G-CSF and IL-3 may induce changes
in the production of inflammatory mediators such nitric oxide and PGE2 in
cartilage chondrocytes. Hence, CSFs may play a vital role in influencing
cartilage metabolism in rheumatoid and osteoarthritis.
PMID- 10761542
TI - Quantitative ultrasound of the proximal phalanges: reproducibility in erosive and
nodal osteoarthritis of the hands.
AB - The aims of the study were to evaluate the reproducibility of quantitative
ultrasound (QUS) densitometry of the hands and to verify whether this method is
sensitive to phalangeal bone changes occurring in osteoarthritis patients and in
erosive osteoarthritis patients. We studied 60 postmenopausal women (aged 63.8 +/
3.2): 20 had osteoarthritis, 20 had erosive osteoarthritis, 20 were
postmenopausal without local pathology of the hand and eight were premenopausal
(aged 23.5 +/- 3.4). The patients were evaluated by means of a DBM Sonic 1200
which is able to evaluate ultrasound transmission velocity (amplitude-dependent
speed of sound). The results indicated good intra- and interoperator
reproducibility (coefficient of variation = 0.99% and 1.04%) in the premenopausal
group. The ultrasound device was able to discriminate between the different
groups and detected differences between the QUS values of erosive osteoarthritis
patients, osteoarthritis patients and control subjects. QUS densitometry is
reproducible and sensitive to bone changes occurring in patients with
osteoarthritis and as well as in those with erosive osteoarthritis.
PMID- 10761543
TI - [Diagnostic significance of antinuclear antibodies].
AB - In three patients, women of 17, 25 and 15 years, suffering from arthralgia and in
whom the existence of antinuclear antibodies (ANA) was established, the diagnosis
'systemic lupus erythematosus' was made or considered. Upon reevaluation, the ANA
results could not be confirmed. The conclusion was drawn that in patients, who
lack one or more clinical signs of a connective tissue disease (CTD), no
indication is present for determination of ANA. Literature data indicate that the
positive predictive value of ANA for the presence of CTD is 5-10%. Conversely, a
negative ANA result does not rule out that CTD is present (negative predictive
value: 98.5-99.3%). In addition, the question is raised if a hospital laboratory,
lacking experience or routine in ANA assays could reliably perform these assays.
PMID- 10761544
TI - [Screening of hearing in children up to 18 months of age].
AB - In the Netherlands the hearing screening of young children is carried out at the
age of nine months by the Ewing or 'Compact Amsterdam paedo-audiometric screener'
(CAPAS) test. These screening tests do not always lead to the necessary follow-up
diagnostics, mainly because the different disciplines disagree. Recently a
consensus concerning the follow-up of children with a poor test result was
reached by the Youth Health Care institutions, general practitioners,
paediatricians, ENT physicians and audiologic centres. Each party has its own
responsibilities and commits itself to complete the diagnostics before the age of
18 months. Until new screening methods have been validated it is advised to refer
all children with poor screening test results for special diagnostics, if
necessary after they have been treated for otitis media with effusion. Currently
the most appropriate method for final diagnosis is the measurement of oto
acoustic emissions.
PMID- 10761546
TI - [Youth Health Care Services guideline 'Early screening for hearing impairment, 0
19 years'].
AB - The Youth Health Care guideline 'Early screening for hearing impairment, ages 0
19 years' draws the attention of all parties involved to the case finding of,
notably, perceptive hearing loss; it helps workers in the Youth Health Care argue
their referrals and improve the next steps in the process. Referrals always aim
at ruling out perceptive hearing impairment. It is essential to diagnose and
subsequently treat children with perceptive hearing impairment. It is important
to keep track of the process after the referral. Screening methods are the Ewing
test, the 'Compacte Amsterdamse paedo-audiometrische screener' (CAPAS) test and
audiograms. Each age category has groups at risk for hearing impairment. Problems
in neonates are a low specificity of the Ewing/CAPAS tests, treatment of middle
ear disease without ruling out perceptive hearing impairment and absence of
interdisciplinary agreements regarding the steps to be taken and the necessary
feedback. Children with perceptive hearing loss should be diagnosed before 18
months of age. In the near future neonatal screening may detect congenital
perceptive hearing impairment, but hearing impairment may still develop after the
screening. Alertness with respect to hearing impairment will remain necessary in
every consultation of a child.
PMID- 10761545
TI - [Neonatal hearing screening].
AB - Approximately 1 to 2 per thousand live-born infants suffer from a serious
perceptive hearing loss. Normal hearing from birth is essential for optimal human
development (language and speech, social and emotional development, communicative
skills and learning). The earlier the hearing loss is diagnosed the better the
prognosis for the infant with a hearing impairment. Suitable methods are now
available for neonatal hearing screening: automated measurement of auditory brain
stem response and measurement of oto-acoustic emissions. Screening must be viewed
as only the first step in a program of diagnosis, treatment and habilitation of
these children. The ultimate goal of the implementation of neonatal hearing
screening is: identification of bilateral hearing losses before the age of 3
months and start of therapy and counselling before the age of 6 months.
PMID- 10761547
TI - [Substantial increase in gonorrhea and syphilis among clients of Amsterdam
Sexually Transmitted Diseases Clinic].
AB - In the Sexually Transmitted Diseases (STD) clinic of the Amsterdam Municipal
Health Service standardized data are collected about all visitors, which makes it
possible to gain insight into the STD trends. In 1999, 706 new cases of
gonorrhoea and 76 new cases of infectious syphilis were diagnosed, increases of
46% and 111% respectively compared with 1998. The largest increase was seen among
men who had sex with men. In this group the number of diagnosed cases of
anorectal gonorrhoea in 1999 was twice as high as in 1998 (186 versus 94) and the
number of infectious syphilis cases four times as high (40 versus 9). These data
indicate an increase in unsafe sexual behaviour, possibly because of a change in
attitudes about AIDS, now that effective antiretroviral treatment is available.
PMID- 10761548
TI - [Transposition of the tendon of M. tibialis posterior an effective treatment of
drop foot; retrospective study with follow-up in 12 patients].
AB - OBJECTIVE: To evaluate the results of transposition of the tendon of the M.
tibialis posterior in patients with a drop foot. DESIGN: Descriptive,
retrospective and follow-up investigation. METHODS: Surgical treatment was
carried out in 12 patients with a drop foot (9 women and 3 men, with an average
age of 37 years) in the period 1986-1998. The aetiology of the drop foot was a
traumatic or iatrogenic lesion of the peroneal nerve or sciatic nerve in 9
patients and in 3 patients spina bifida occulta, leprosy and a herniation of a
lumbar disc respectively. None of the patients had important comorbidity.
Treatment consisted of lengthening the Achilles tendon according to Huckstep,
transposition of the tibial posterior tendon in two tails to the dorsomedial and
dorsolateral side of the foot, and six weeks of immobilisation in plaster of
Paris. RESULTS: The postoperative period was without complications. The treatment
improved the heel-toe steppage gait in all patients. None of the 10 patients who
had used an orthosis preoperatively still used it at the time of the follow up.
Fifty per cent of the patients acquired a dorsiflexion of the foot of more than 0
degree. The results were in accordance with those in the literature. CONCLUSION:
Transposition of the tibial posterior tendon is a worthwhile alternative for
those patients with a drop foot (and without important comorbidity) who cannot
walk satisfactorily with an ankle-foot orthosis.
PMID- 10761549
TI - [Sexually transmitted diseases in Limburg in 1997; prevalence according to a
survey of family practitioners and specialists and according to reports from
microbiological laboratories].
AB - OBJECTIVE: To determine the incidence of sexually transmitted diseases (STDs) and
to compare data reported by general practitioners (GPs) and specialists with
those reported by microbiological laboratories. DESIGN: Retrospective. METHOD:
All 593 GPs and gynaecologists, dermatologists and urologists in Limburg, the
Netherlands, in 1998 were asked to fill in a questionnaire about the number of
cases of Chlamydia trachomatis, condylomata acuminata, genital herpes and
gonorrhoea in 1997, by sex, age and diagnostic test. Data were compared with
information gathered from the six laboratories of medical microbiology. For
gonorrhoea the results were compared with those from a study in 1985. RESULTS:
The response to the enquiry amounted to 75%. A total of 2730 cases were reported
(32 per 10,000 of the population. Infection with C. trachomatis was the most
frequent sexually transmitted disease (46%), followed by condylomata acuminata
(28%), genital herpes (17%) and gonorrhoea (8%). Of the diseases 84% occurred in
persons younger than 35 years of age and 66% in women. The GPs saw 79% of the
STDs, they diagnosed 'gonorrhoea' in 25% of the cases merely on the basis of the
clinical picture. Compared to 1985 the number of gonorrhoea cases was decimated
in Limburg in 1997. Of those who answered the questions about warning the partner
(approximately 50% of those concerned), 87% reported that they had let the
partner know. It appears from the data of the six laboratories that the incidence
of C. trachomatis infection was 3.2 and that of gonorrhoea 0.6 per 10,000 of the
population. For the diagnosis of infection with C. trachomatis the GPs and
specialists use a culture in 50% of the cases, as against 2% of the laboratories,
for the ligase chain reaction and polymerase chain reaction tests these
proportions were 20 and 78%.
PMID- 10761550
TI - [Proctocolectomy with an ileal pouch-anal anastomosis; results from 100
consecutive patients in the Academic Medical Center at Amsterdam, 1994-1999].
AB - OBJECTIVE: To evaluate the results of proctocolectomy with creation of an ileac
pouch anal anastomosis (IPAA). DESIGN: Retrospective. METHOD: Of the 100 patients
in whom an IPAA procedure was performed in the period 1994/'99 in the Department
of Surgery of the Academic Medical Centre, Amsterdam, the Netherlands, data were
collected on the complications: in the patients with a follow-up of over 12
months the functional results were studied. RESULTS: The group comprised 48 males
and 52 females with a mean age of 36.3 years (range: 15-62). Preoperative
diagnoses were ulcerative colitis (n = 84), familial polyposis coli (12), slow
transit obstipation (2), Hirschsprung's disease (1) and Muir-Torre syndrome (1).
Median operating time was 2.3 h, peroperative blood and fluid loss 500 ml and
median hospital stay 15 days. There was no mortality. Ten patients had a loop
ileostomy formation, in 6 because of postoperative complications. A total of 30
patients developed postoperative complications, peroperatively or during follow
up 10 of those patients needed a relaparotomy. After 12 months 1 pouch had to be
excised and 2 patients still had a loop ileostomy due to postoperative
complications. In 56 patients with at least 12 months follow-up, median 24-hour
stool frequency was 6. Eighty-nine per cent of these patients were satisfied or
highly satisfied with the overall outcome. CONCLUSION: A proctocolectomy with
IPAA formation is a safe procedure with good functional results.
PMID- 10761551
TI - [Pulmonary hemorrhage with respiratory insufficiency in Henoch- Schoenlein
purpura].
AB - A 20-year-old woman presented with abdominal pain, purpura on the extremities,
and arthralgia. The diagnosis of Henoch-Schonlein purpura was made based on
granular IgA deposits in the vessels in a skin biopsy. Three weeks after onset of
these symptoms, she developed glomerulonephritis and diffuse alveolar
haemorrhage; she developed respiratory failure and needed mechanical ventilation.
She recovered upon treatment with corticosteroids. Diffuse alveolar bleeding has
occasionally been reported in adults with Henoch-Schonlein purpura; this is the
first report from the Netherlands.
PMID- 10761552
TI - ['Medical technology assessment'; more than just efficacy].
AB - 'Medical technology assessment' means investigating the developments, costs and
effects of medical technologies. Practising physicians increasingly are
confronted with consequences of management based on such research results. In
order to follow and participate in the discussion they should be aware of this
and know the jargon. In policy problems, measures of effect in natural units
(e.g. cardiovascular mortality) offer advantages over measures of clinical
findings (e.g. decrease of the serum cholesterol levels). Survival in various
health states and disorders can be compared by multiplying the number of life
years gained by a factor for the quality of life in those years. Costs are
usually expressed in monetary terms. These may be calculated as direct medical
costs on the basis of fees or actual costs for society. The latter is the case
when the balancing is based on a societal perspective. The societal perspective
enables a more objective assessment of health effects than when a patient
perspective is used. 'Incremental cost effectiveness' expresses where extra
expenditures will have maximum effect, and bears higher relevance for policy
decisions than mean costs per unit of effect. Immaterial matters are more
difficult to assess, but should nevertheless be considered in selecting the
policy to be implemented.
PMID- 10761553
TI - [Acute abdomen: consider also the thorax].
PMID- 10761554
TI - [Critical review of anti-influenza drugs].
PMID- 10761555
TI - Host-parasite interactions in Acanthocephala: a morphological approach.
AB - In this review recent morphological and histochemical descriptions have been
compiled of (mainly outer) features of all developmental stages of the
Acanthocephala as well as what is known about the host's defence measures
directed against these worms. From acanthors, for instance, it is documented how
they escape melanization inside the haemocoel of a suitable intermediate host
after they have been activated and released from their eggshell enclosure in the
gut of the arthropod. Acanthors possess a complex set of eggshell-envelopes and
interstices that fulfil different tasks. While the sequence of events inside the
intermediate host's haemocoel is rather well known, what happens in paratenic
hosts has been little studied. In final hosts the host-parasite interactions
depend on the systematic affiliation of the parasite as well as the host and on
the depth of penetration of each acanthocephalan species in the intestinal wall
of the host. The mode of attachment also influences the microhabitat preference
inside the gut. Mammals often reveal symptoms of high morbidity when infected
with acanthocephalans, while fish seem to tolerate high intensities of worms
deeply penetrating into their intestinal wall without showing pronounced symptoms
of disease. The review also treats the subjects of host specificity, nutrient
uptake and metabolism of the worms as well as their absorbance of metals and
other elements. The high absorbance capacity for heavy metals suggests the
usefulness of acanthocephalans as bioindicators.
PMID- 10761556
TI - Eicosanoids in parasites and parasitic infections.
AB - Eicosanoids are lipid mediators with multiple functions in vertebrate tissues and
invertebrate organisms. In this review the roles of eicosanoids--mostly
prostaglandins (PGs), thromboxanes and leukotrienes--in parasite physiology and
host-parasite interactions are discussed. PGs are present in the saliva of blood
sucking arthropods facilitating feeding by increasing local blood flow and
prolonged attachment of ticks by immune suppression. Release of various
eicosanoids has also been demonstrated for a number of protozoan and metazoan
endoparasites. These substances appear to play a role in penetration, immune
suppression, inflammation or modulation of haemostasis, enabling parasite
invasion and establishment. Moreover, endogenous eicosanoids serve various
functions in parasite metabolism and physiology. In many parasitic infections
eicosanoids are involved in host pathology, e.g. granuloma formation,
coagulopathy, secretory diarrhoea, or fever. Immune suppression by induction of
PG release, in particular PGE2, by host defence cells appears to be a common
feature of many parasitic infections and is though to be important for parasite
establishment. Contradictory results have been obtained for gastrointestinal
nematode infections, which probably reflect the considerable differences between
the various models employed. Although most of the available studies indicate an
important role for eicosanoids in parasites and parasitic infections, our current
knowledge is still fragmentary and more data are urgently needed.
PMID- 10761557
TI - [Erysipelas. A retrospective series of 92 patients in a department of internal
medicine].
AB - Erysipleas, also known as Saint Anthony's fire, is an acute infection of the skin
caused, in most of cases, by group A streptococci. In the past, the most common
site of involvement was the face and, in the pre-antibiotic era, mortality was
high. In this retrospective study, we highlight the clinical and bacteriological
features and report follow-up in 92 patients hospitalized in an internal medicine
unit between 1st March 1992 and 31st December 1996 for 94 episodes of erysipelas.
The involvement of the lower limbs predominated as involvement of the face is
becoming very rare. Streptococci from others groups and Staphylococcus aureus
have been implicated on occasions. Recovery is usual even if this infection may
greatly weaken these often fragilized patients. In this paper, antibiotic
treatment as well as the place of anticoagulants and Doppler ultrasound are
discussed. Hospitalization is often necessary but it must not be systematic.
PMID- 10761558
TI - [Drug-induced gynecomastia].
AB - Drugs are a very common cause of gynecomastia and should always be entertained as
the possible causal agent of such a condition. This drug side-effect is due to an
impaired balance in the serum estrogen/serum androgen ratio, whatever the
mechanism, or a rise in prolactin level. Sex hormones, antiandrogens, are
frequently involved as well as spironolactone, cimetidine, verapamil and cancer
chemotherapy (especially alkylating agents). Diazepam, tricyclic antidepressants,
neuroleptics, calcium channel blockers, captopril, digitalis glycosides,
omeprazole, some antibiotics and growth hormone are all possibly, but less often,
the responsible agent. Criteria of the French method for determining drug
causality are discussed.
PMID- 10761559
TI - Mixed cryoglobulinemia in hepatitis C patients. GERMIVIC.
AB - Cryoglobulins are immunoglobulins that persist in the serum, precipitate with
cold temperature and resolubilize when rewarmed. Types II and III are mixed
cryoglobulins (MC), composed of different immunoglobulins, with a monoclonal
component in type II and only polyclonal immunoglobulins in type III. Mixed
cryoglobulins are associated with connective-tissue disease, malignant
hematological disorder (type B lymphoproliferation) or obvious infectious
process. Mixed cryoglobulinemia syndrome is characterized by the clinical triad
of purpura, arthralgia and asthenia associated with type II or type III MC. The
disorder is the consequence of an immune-complex-type vasculitis as supported by
clinical features, analysis of the cryoglobulins, the usually depressed level of
complement during the active phase of the disease, and the deposition of
immunoglobulins and complement in the lesions. Such cryoglobulinemia vasculitis
may involve numerous organs, particularly the peripheral nervous system and the
kidneys. MC is frequently associated with clinical and biological evidence of
liver disease. There has been some controversy about which comes first, MC or
chronic liver disease, but it seems fairly clear that MC is often a manifestation
of underlying chronic active or persistent hepatitis. In MC patients, the
hepatotropic antigen(s) capable of triggering production of antibodies which can
later form immune complexes has been sought for many years. In the last ten
years, numerous studies have demonstrated that infection with hepatitis C virus
is involved in the pathogenesis of most mixed cryoglobulinemia. This review
analyzes the main published data on hepatitis C virus-mixed cryoglobulinemia, the
role of liver alterations, the predictive factors associated with MC production
in HCV patients and its symptomatic nature or not, and the different types of
vasculitis associated with HCV chronic infection.
PMID- 10761560
TI - The rheumatoid factor response in the etiology of mixed cryoglobulins associated
with hepatitis C virus infection.
AB - Studies of mixed cryoglobulins (MC) from patients infected with hepatitis C virus
(HCV) show that the principal constituents in cryoprecipitate are IgM rheumatoid
factors (RF), polyclonal IgG anti-HCV antibodies, and HCV RNA. The HCV-induced RF
response is biased to produce IgM RF encoded by a restricted set of Ig V genes,
predominantly the VH/VL gene pair 51p1/kv325. The propensity of such IgM RF to
cryoprecipitate is likely a coincidental property of their V region sequences,
but the clinical effect of this bias is increased by the persistence of
circulating HCV-IgG immune complexes. These complexes might induce production of
cryoprecipitable IgM RF and furnish multi-molecular structures that favor binding
by cryoprecipitable IgM RF. The V gene sequences of HCV-induced IgM RF have
features seen in other RF responses, suggesting a common immunological mechanism
that is independent of HCV. B cell proliferation is probably enhanced by HCV
specific properties, however, including the ability of HCV proteins to bind to
CD81 on the B cell surface, and to influence intracellular regulatory functions
following viral entry into B cells. The V gene bias in HCV-induced RF is most
apparent among the B cells in monoclonal expansions responsible for type II
cryoglobulins, but it might originate early the polyclonal RF response, before MC
are detectable. Monoclonal B cell expansions and lymphomatoid bone marrow
infiltrates in HCV+ patients predominantly involve CD5-negative IgM RF B cells.
Non-RF B cells can also be expanded, including producers of IgG1 and IgG3 that
are likely anti-HCV antibodies. The initial site of B cell clonal expansion may
be in the liver, where lymphoid aggregates are abundant and RF are produced.
Sorting out how MC formation is influenced by properties that are inherent to the
RF response, or specific to HCV infection, will be a challenge to future HCV
research.
PMID- 10761561
TI - Renal manifestations associated with hepatitis C virus.
AB - Among the several types of chronic glomerulonephritis (GN) described in
association with hepatitis C virus (HCV) infection, cryoglobulinemic
glomerulonephritis is by far the most frequent. It is usually associated with
type II cryoglobulinemia with IgM k rheumatoid factor. It is a
membranoproliferative GN, which shows some distinctive histologic features
(intraglomerular monocyte infiltration, intraluminal thrombi due to massive
precipitation of cryoglobulins, renal vasculitis), has a chronic course with
acute recurrent episodes that can be controlled by corticosteroids more than by
antiviral therapy (interferon alpha). More controversial is the association with
type I non-cryoglobulinemic membranoproliferative GN, which has been found in
some series from the USA and Japan but not in others. The demonstration of HCV
antibodies and/or HCV-RNA in other types of chronic glomerulonephritis is usually
reported in a small minority of cases suggesting the possibility of a
coincidental finding more than an etiologic factor.
PMID- 10761562
TI - Cutaneous disorders associated with hepatitis C virus infection.
AB - Since the discovery of hepatitis C virus (HCV) in 1989, many cutaneous disorders
have been observed in patients suffering from chronic HCV infection. The
relationship between HCV infection and cryoglobulinemia or porphyria cutanea
tarda (PCT) is now clearly established, but the link between HCV and other
dermatoses is still controversial. This review of the main dermatologic
disorders, directly or indirectly related to HCV infection, lead to conclude that
HCV markers have to be investigated systematically in case of cryoglobulinemia,
PCT or pruritus. In other dermatologic disorders, HCV serology will be necessary
only in case of risk factors for HCV infection, or presence of abnormal liver
function tests.
PMID- 10761563
TI - Lymphoproliferative diseases and hepatitis C virus infection.
AB - The putative role of hepatitis C virus (HCV) infection in the pathophysiology of
lymphoproliferative diseases (LPD) is supported by north-American and south
European studies reporting high HCV seroprevalence in patients with B-cell-non
Hodgkin lymphoma (NHL). However, controversial data were reported from other
areas. The review of available reports to data on HCV-associated LPD points to
some features: predominance of low-grade malignant lymphoma, frequent involvement
of extranodal sites, absence of particular HCV genotype distribution (except in
Italy for genotype 2), important geographical seroprevalence discrepancies. In
our experience in 43 cases of HCV-associated LPD in France, we noted a
predominance of B-cell NHL (31/43 cases), and the frequency of LPD among HCV
infected patients approximates 2.5%. Pathophysiology hypotheses are discussed,
particularly in view of the lympho tropism of HCV. HCV is frequently associated
with type II mixed cryoglobulinemia, a benign monoclonal lymphoproliferation
which sometimes evolves to overt B-cell lymphoma. The recent finding of HCV
binding on CD81, a surface-expressed protein present on lymphocyte membrane,
enhances the putative role of HCV in lymphomagenesis. Further investigations are
needed to characterize interaction between B lymphocytes and HCV, and to
determine putative cofactors involved in the multistep process leading to clonal
lymphoproliferation in HCV patients.
PMID- 10761564
TI - Treatment of autoimmune and extra-hepatic manifestations of HCV infection.
AB - Hepatitis C virus (HCV) infects mononuclear cells and may, like other viruses,
cause immunological disorders. Immunological abnormalities observed in HCV
infections are usually nonspecific (e.g. cryoglobulinemia, immune complex
deposits, autoantibodies). There is a clear association between cryoglobulinemia
and hepatitis C and cryoglobulinemia related symptoms are usually improved by
treatment with interferon alpha, although patients usually relapse after
treatment end. The relationships between hepatitis C and other immunological
abnormalities are unclear. The association between chronic hepatitis C and anti
smooth muscle or anti-nuclear antibodies does not appear to be significantly
different from that in other hepatic disorders, particularly hepatitis B.
Conversely, patients with hepatitis C have significantly more often anti-liver
kidney microsomal (LKM1) antibodies than patients with other causes of liver
diseases. When clinical, histological and biological findings are indicative of
HCV infection with chronic hepatitis, interferon alpha or combination therapy
with ribavirin are treatments options. Conversely, when clinical context and
results of laboratory tests are in favor of an autoimmune disorder or of overlap
syndromes (i.e. both autoimmune and viral hepatitis), interferon should not be
given in first intention, since revelation or exacerbation of autoimmune
hepatitis have been reported under interferon. An important prevalence of anti
HCV antibodies has also been reported in patients with sialadenitis, lichen
planus and thyroiditis. It has been clearly demonstrated that interferon may
induce or worsen such immunological diseases, but there are very few studies
showing improvement of these manifestations under interferon. In conclusion,
interferon may be appropriate in patients with HCV infection and extrahepatic
manifestations linked to immune complex deposition, whereas, in other cases,
careful assessment of patients with autoimmune processes is necessary before
choosing any treatment strategy.
PMID- 10761565
TI - [Aneurysm of the sinus of Valsalva. Apropos of a case of right intra-atrial
rupture].
AB - An unusual systolo-diastolic heart murmur was discovered fortuitously in a 39
year-old man undergoing a routine check-up. Transesophageal echocardiography gave
the diagnosis of Valsalva sinus aneurysm ruptured into the right atrium. Cardiac
surgery was successful. We reviewed the literature on this unusual condition,
focusing on the pathophysiological, clinical, diagnostic and therapeutic aspects.
Transesophageal echocardiography provides the diagnosis.
PMID- 10761566
TI - [Hemolytic-uremic syndrome caused by mitomycin c: long-term management].
AB - We describe the case of a 51-year-old woman who developed a hemolytic uremic
syndrome nine weeks after the end of chemotherapy with mitomycin C for cancer of
the anus. Episodes of hemolytic uremic syndrome recurred within a period of up to
six months. They were treated with plasma infusion and exchange, antiplatelet
agents and rigorous control of blood pressure. The patient was followed for eight
years. Her blood pressure has been normal without the use of antihypertensive
agents and the renal function has remained stable with serum creatinine at 110
mumol/1. The tumor has remained in remission. This case suggests that recovery
from the acute phase of hemolytic uremic syndrome leads to good long-term
prognosis.
PMID- 10761567
TI - [Cardiac amyloidosis: a restrictive cardiopathy with no single prognosis].
AB - Cardiac amyloidosis is expressed as a restrictive myocardiopathy.
Echocardiography suggests the diagnosis. There is a great difference between the
prognosis of senile cardiac amyloidosis and "AL" amyloidosis. We illustrate this
point with two case reports.
PMID- 10761568
TI - [Nephrotic syndrome and oligo-anuria complicating treatment with diclofenac].
PMID- 10761569
TI - The current state of insect molecular systematics: a thriving Tower of Babel.
AB - Insect molecular systematics has undergone remarkable recent growth. Advances in
methods of data generation and analysis have led to the accumulation of large
amounts of DNA sequence data from most major insect groups. In addition to
reviewing theoretical and methodological advances, we have compiled information
on the taxa and regions sequenced from all available phylogenetic studies of
insects. It is evident that investigators have not usually coordinated their
efforts. The genes and regions that have been sequenced differ substantially
among studies and the whole of our efforts is thus little greater than the sum of
its parts. The cytochrome oxidase I, 16S, 18S, and elongation factor-1 alpha
genes have been widely used and are informative across a broad range of
divergences in insects. We advocate their use as standards for insect
phylogenetics. Insect molecular systematics has complemented and enhanced the
value of morphological and ecological data, making substantial contributions to
evolutionary biology in the process. A more coordinated approach focused on
gathering homologous sequence data will greatly facilitate such efforts.
PMID- 10761570
TI - Medicinal maggots: an ancient remedy for some contemporary afflictions.
AB - Certain fly larvae can infest corpses or the wounds of live hosts. Those which
are least invasive on live hosts have been used therapeutically, to remove dead
tissue from wounds, and promote healing. This medicinal use of maggots is
increasing around the world, due to its efficacy, safety and simplicity. Given
our low cultural esteem for maggots, the increasing use and popularity of maggot
therapy is evidence of its utility. Maggot therapy has successfully treated many
types of chronic wounds, but much clinical and basic research is needed still. In
this review, the biology of myiasis and the history of maggot therapy are
presented, the current status of our understanding and clinical use of medicinal
maggots is discussed, and opportunities for future research and applications are
proposed.
PMID- 10761571
TI - Life history and production of stream insects.
AB - Studies of the production of stream insects are now numerous, and general factors
controlling the secondary production of stream communities are becoming evident.
In this review we focus on how life-history attributes influence the production
dynamics of stream insects and other macroinvertebrates. Annual production of
macroinvertebrate communities in streams world-wide ranges from approximately
10(0) to 10(3) g dry mass m-2. High levels are reported for communities dominated
by filter feeders in temperate streams. Filter feeding enables the accrual and
support of high biomass, which drives the very highest production. Frequently
disturbed communities in warm-temperate streams are also highly productive.
Biomass accrual by macroinvertebrates is limited in these streams, and production
is driven by rapid growth rates rather than high biomass. The lowest production,
reported for macroinvertebrate communities of cool-temperate and arctic streams,
is due to the constraints of low seasonal temperatures and nutrient or food
limitation. Geographical bias, paucity of community-wide studies, and limited
knowledge of the effects of biotic interactions limit current understanding of
mechanisms controlling stream productivity.
PMID- 10761572
TI - Amino acid transport in insects.
AB - Most insect cell membranes seem to contain uniporters that facilitate the
diffusion of amino acids into and out of the cells. In addition to these passive
diffusion systems, all but one of the insect tissues studied to date seem to
contain at least one amino acid-cation symport system that allows their cells to
accumulate certain amino acids from the extracellular medium. cDNAs encoding
three such symporters have very recently been cloned and sequenced. The deduced
amino acid sequence of each insect symporter was determined to be homologous to
that of symporters mediating the transport of the same or related substrates in
mammalian tissues.
PMID- 10761573
TI - Social wasp (Hymenoptera: Vespidae) foraging behavior.
AB - Social wasps (Hymenoptera: Vespidae) forage for water, pulp, carbohydrates, and
animal protein. When hunting, social wasps are opportunistic generalists and use
a variety of mechanisms to locate and choose prey. Individual foragers are
influenced by past foraging experience and by the presence of other foragers on
resources. A forager's ability to learn odors and landmarks, which direct its
return to foraging sites, and to associate cues such as odor or leaf damage with
resource availability provide the behavioral foundation for facultative
specialization by individual foragers. Social wasps, by virtue of their behavior
and numbers, have a large impact on other organisms by consuming them directly.
Indirect effects such as disruption of prey and resource depletion may also be
important. Community-level impacts are particularly apparent when wasps feed upon
clumped prey vulnerable to depredation by returning foragers, or when species
with large, long-lived colonies are introduced into island communities. A clearer
understanding of these relationships may provide insight into impacts of
generalist predators on the evolution of their prey.
PMID- 10761574
TI - Blood barriers of the insect.
AB - The blood-brain barrier (BBB) ensures brain function in vertebrates and insects
by maintaining ionic integrity of the neuronal bathing fluid. Without this
barrier, paralysis and death ensue. The structural analogs of the BBB are
occlusive (pleated-sheet) septate and tight junctions between perineurial cells,
glia and perineurial cells, and possibly between glia. Immature Diptera have such
septate junctions (without tight junctions) while both junctional types are found
in the imago. Genetic and molecular biology of these junctions are discussed,
namely tight (occludin) and pleated-sheet septate (neurexin IV). A temporal
succession of blood barriers form in immature Diptera. The first barrier forms in
the peripheral nervous system where pleated-sheet septate junctions bond cells of
the nascent (embryonic) chordotonal organs in early neurogenesis. At the end of
embryonic life, the central nervous system is fully vested with a blood-brain
barrier. A blood-eye barrier arises in early pupal life. Future prospects in
blood-barrier research are discussed.
PMID- 10761575
TI - Habitat management to conserve natural enemies of arthropod pests in agriculture.
AB - Many agroecosystems are unfavorable environments for natural enemies due to high
levels of disturbance. Habitat management, a form of conservation biological
control, is an ecologically based approach aimed at favoring natural enemies and
enhancing biological control in agricultural systems. The goal of habitat
management is to create a suitable ecological infrastructure within the
agricultural landscape to provide resources such as food for adult natural
enemies, alternative prey or hosts, and shelter from adverse conditions. These
resources must be integrated into the landscape in a way that is spatially and
temporally favorable to natural enemies and practical for producers to implement.
The rapidly expanding literature on habitat management is reviewed with attention
to practices for favoring predators and parasitoids, implementation of habitat
management, and the contributions of modeling and ecological theory to this
developing area of conservation biological control. The potential to integrate
the goals of habitat management for natural enemies and nature conservation is
discussed.
PMID- 10761576
TI - Function and morphology of the antennal lobe: new developments.
AB - The antennal lobe of insects has emerged as an excellent model for olfactory
processing in the CNS. In the present review we compile data from areas where
substantial progress has been made during recent years: structure-function
relationships within the glomerular array, integration and blend specificity,
time coding and the effects of neuroactive substances and hormones on antennal
lobe processing.
PMID- 10761578
TI - Entomology in the twentieth century.
AB - A number of landmark events in applied entomology are listed together with some
insect-related studies that have had a major impact on biology in general. In
large part, however, advances in our understanding of insects have depended on
technological advances, especially in the second half of the century. The
exponential increase in the ease and extent of communication has been critical.
Sometimes, as in the field of insect/plant relations, the ideas of a few
individuals have been critical with technological advances having a facilitating
role. Elsewhere, as in the study of olfaction, major changes in understanding
have been directly dependent on new technology. Very brief accounts of the
impacts on insect-related science of developments in the fields of radio,
radioactivity, immunology, imaging techniques, and chemical analysis are given.
Despite the importance of technology, the lovers of their insects continue to
have a key role.
PMID- 10761577
TI - Lipid transport biochemistry and its role in energy production.
AB - Recent advances on the biochemistry of flight-related lipid mobilization,
transport, and metabolism are reviewed. The synthesis and release of adipokinetic
hormones and their function in activation of fat body triacylglycerol lipase to
produce diacylglycerol is discussed. The dynamics of reversible lipoprotein
conversions and the structural properties and role of the exchangeable
apolipoprotein, apolipophorin III, in this process is presented. The nature and
structure of hemolymph lipid transfer particle and the potential role of a
recently discovered lipoprotein receptor of the low-density lipoprotein receptor
family, in lipophorin metabolism and lipid transport is reviewed.
PMID- 10761579
TI - Control of insect pests with entomopathogenic nematodes: the impact of molecular
biology and phylogenetic reconstruction.
AB - Entomopathogenic nematodes are excellent biological control agents. Utilization
of these nematodes is developing rapidly with almost a doubling of newly
described species in the past five years. Advances in molecular biology and
phylogenetic reconstruction have revolutionized understanding of population
structure, identification, genetic improvement, systematics, and the symbiosis
between entomopathogenic nematodes and their bacteria. Population structure
provides the most fundamental information for reliable identification of species
and unique genetic variants. Such information could be further assessed for
nematode potential as biological control agents. Phylogenetic reconstruction is
an important approach for understanding multitrophic interactions among
entomopathogenic nematodes, symbiotic bacteria, and their insect hosts.
Phylogenetic reconstruction is also important for the development of a natural
and stable type of systematics, which can provide guidelines for selecting
appropriate entomopathogenic nematode species for particular biological control
programs.
PMID- 10761580
TI - Culicoides biting midges: their role as arbovirus vectors.
AB - Culicoides biting midges are among the most abundant of haematophagous insects,
and occur throughout most of the inhabited world. Across this broad range they
transmit a great number of assorted pathogens of human, and domestic and wild
animals, but it is as vectors of arboviruses, and particularly arboviruses of
domestic livestock, that they achieve their prime importance. To date, more than
50 such viruses have been isolated from Culicoides spp. and some of these cause
diseases of such international significance that they have been allocated Office
International des Epizooties (OIE) List A status. Culicoides are world players in
the epidemiology of many important arboviral diseases. In this context this paper
deals with those aspects of midge biology facilitating disease transmission,
describes the factors controlling insect-virus interactions at the individual
insect and population level, and illustrates the far-reaching effects that
certain components of climate have upon the midges and, hence, transmission
potential.
PMID- 10761581
TI - Evolutionary ecology of progeny size in arthropods.
AB - Most models of optimal progeny size assume that there is a trade-off between
progeny size and number, and that progeny fitness increases with increasing
investment per young. We find that both assumptions are supported by empirical
studies but that the trade-off is less apparent when organisms are iteroparous,
use adult-acquired resources for reproduction, or provide parental care. We then
review patterns of variation in progeny size among species, among populations
within species, among individuals within populations, and among progeny produced
by a single female. We argue that much of the variation in progeny size among
species, and among populations within species, is likely due to variation in
natural selection. However, few studies have manipulated progeny environments and
demonstrated that the relationship between progeny size and fitness actually
differs among environments, and fewer still have demonstrated why selection
favors different sized progeny in different environments. We argue that much of
the variation in progeny size among females within populations, and among progeny
produced by a single female, is probably nonadaptive. However, some species of
arthropods exhibit plasticity in progeny size in response to several
environmental factors, and much of this plasticity is likely adaptive. We
conclude that advances in theory have substantially outpaced empirical data. We
hope that this review will stimulate researchers to examine the specific factors
that result in variation in selection on progeny size within and among
populations, and how this variation in selection influences the evolution of the
patterns we observe.
PMID- 10761582
TI - Insecticide resistance in insect vectors of human disease.
AB - Insecticide resistance is an increasing problem in many insect vectors of
disease. Our knowledge of the basic mechanisms underlying resistance to commonly
used insecticides is well established. Molecular techniques have recently allowed
us to start and dissect most of these mechanisms at the DNA level. The next major
challenge will be to use this molecular understanding of resistance to develop
novel strategies with which we can truly manage resistance. State-of-the-art
information on resistance in insect vectors of disease is reviewed in this
context.
PMID- 10761583
TI - Applications of tagging and mapping insect resistance loci in plants.
AB - This review examines how molecular markers can be used to increase our
understanding of the mechanisms of plant resistance to insects and develop insect
resistant crops. We provide a brief description of the types of molecular markers
currently being employed, and describe how they can be applied to identify and
track genes of interest in a marker-assisted breeding program. A summary of the
work reported in this field of study, with examples in which molecular markers
have been applied to increase understanding of the mechanistic and biochemical
bases of resistance in potato and maize plant/pest systems, is provided. We also
describe how molecular markers can be applied to develop more durable insect
resistant crops. Finally, we identify key areas in molecular genetics that we
believe will provide exciting and productive research opportunities for those
working to develop insect-resistant crops.
PMID- 10761584
TI - Ovarian dynamics and host use.
AB - Oviposition behavior in herbivorous and frugivorous insects and parasitoids is
dynamic at the level of the individual, responding to variation in host quality
and availability. Patterns of variation in egg load in response to host presence
and quality suggest that ovarian development also responds to variation in the
host environment. Ovarian dynamics are mediated by feedback from oviposition, by
host feeding, and by sensory input from the host. The last of these mechanisms,
host sensory cuing, is known to occur in three major orders and provides strong
evidence that ovarian dynamics are adaptive by design. Conditions favoring host
effects on ovarian development include trade-offs between egg production and
either survival or dispersal, uncertainty in the host environment, and a
correlation in host conditions between the time that oogenesis is initiated and
the time that eggs are laid. Some host defenses block ovarian development,
suggesting that ovarian dynamics in host-specific insects should be viewed from a
coevolutionary perspective.
PMID- 10761585
TI - Cyclodiene insecticide resistance: from molecular to population genetics.
AB - This review follows progress in the analysis of cyclodiene insecticide resistance
from the initial isolation of the mutant, through cloning of the resistance gene,
to an examination of the distribution of resistance alleles in natural
populations. Emphasis is given to the use of a resistant Drosophila mutant as an
entry point to cloning the associated gamma-aminobutyric acid (GABA) receptor
subunit gene, Resistance to dieldrin. Resistance is associated with replacements
of a single amino acid (alanine302) in the chloride ion channel pore of the
protein. Replacements of alanine302 not only directly affect the drug binding
site but also allosterically destabilize the drug preferred conformation of the
receptor. Resistance is thus conferred by a unique dual mechanism associated with
alanine302, which is the only residue replaced in a wide range of different
resistant insects. The underlying mutations appear either to have arisen once, or
multiply, depending on the population biology of the pest insect. Although
resistance frequencies decline in the absence of selection, resistance alleles
can persist at relatively high frequency and may cause problems for compounds to
which cross-resistance is observed, such as the novel fipronils.
PMID- 10761586
TI - Life systems of polyphagous arthropod pests in temporally unstable cropping
systems.
AB - Annual cropping systems consist of a shifting mosaic of habitats that vary
through time in their availability and suitability to insect pests. Agroecosystem
instability results from changes that occur within a season with crop planting,
development, and harvest. Further instability results from continuous alterations
in biotic and abiotic insect life system components and from agricultural inputs.
Changes to agroecosystems occur across seasons with changing agricultural
practices, changing cropping patterns, and technological innovations. Much of
this instability is a result of events unconnected with pest management. The
abilities of polyphagous pest species to move among and utilize different habitat
patches in response to changes in suitability enable the pests to exploit
unstable cropping systems. These pest characteristics determine the location and
timing of damaging populations. Habitat suitability is influenced by plant
species and cultivar, crop phenology, and agricultural inputs. Pest movement is
affected by a suite of intrinsic factors, such as population age structure and
mobility, and extrinsic factors, including weather systems and habitat
distribution. The life systems of three selected polyphagous pests are presented
to demonstrate how an understanding of such systems in agricultural ecosystems
improves our ability to predict and hence manage these populations.
PMID- 10761587
TI - Accessory pulsatile organs: evolutionary innovations in insects.
AB - In addition to the dorsal vessel ("heart"), insects have accessory pulsatile
organs ("auxiliary hearts") that supply body appendages with hemolymph. They are
indispensable in the open circulatory system for hemolymph exchange in antennae,
long mouthparts, legs, wings, and abdominal appendages. This review deals with
the great diversity in the functional morphology and the evolution of these
accessory pulsatile organs. In primitive insects, hemolymph is supplied to
antennae and cerci by arteries connected to the dorsal vessel. In higher insects,
however, these arteries were decoupled and associated with autonomous pumps that
entered their body plan as evolutionary innovations. To ensure hemolymph supply
to legs, wings, and some other appendages, completely new accessory pulsatile
organs evolved. The muscular components of these pulsatile organs and their
elastic antagonists were recruited from various organ systems and assembled to
new functional units. In general, it seems that the evolution of accessory
pulsatile organs has been determined by developmental and spatial constraints
imposed by other organ systems rather than by changes in circulatory demands.
PMID- 10761588
TI - Parasitic mites of honey bees: life history, implications, and impact.
AB - The hive of the honey bee is a suitable habitat for diverse mites (Acari),
including nonparasitic, omnivorous, and pollen-feeding species, and parasites.
The biology and damage of the three main pest species Acarapis woodi, Varroa
jacobsoni, and Tropilaelaps clareae is reviewed, along with detection and control
methods. The hypothesis that Acarapis woodi is a recently evolved species is
rejected. Mite-associated bee pathologies (mostly viral) also cause increasing
losses to apiaries. Future studies on bee mites are beset by three main problems:
(a) The recent discovery of several new honey bee species and new bee
parasitizing mite species (along with the probability that several species are
masquerading under the name Varroa jacobsoni) may bring about new bee-mite
associations and increase damage to beekeeping; (b) methods for studying bee
pathologies caused by viruses are still largely lacking; (c) few bee- and
consumer-friendly methods for controlling bee mites in large apiaries are
available.
PMID- 10761589
TI - Insect pest management in tropical Asian irrigated rice.
AB - Abundant natural enemies in tropical Asian irrigated rice usually prevent
significant insect pest problems. Integrated pest management (IPM) extension
education of depth and quality is required to discourage unnecessary insecticide
use that upsets this natural balance, and to empower farmers as expert managers
of a healthy paddy ecosystem. Farmers' skill and collaboration will be
particularly important for sustainable exploitation of the potential of new,
higher-yielding and pest-resistant rice. IPM "technology transfer" through
training and visit (T&V) extension systems failed, although mass media campaigns
encouraging farmer participatory research can reduce insecticide use. The "farmer
first" approach of participatory nonformal education in farmer field schools,
followed by community IPM activities emphasizing farmer-training-farmer and
research by farmers, has had greater success in achieving IPM implementation.
Extension challenges are a key topic for rice IPM research, and new pest
management technology must promote, rather than endanger, ecological balance in
rice paddies.
PMID- 10761590
TI - Polyene hydrocarbons and epoxides: a second major class of lepidopteran sex
attractant pheromones.
AB - Polyene hydrocarbons and epoxides are used as pheromone components and sex
attractants by four macrolepidopteran families: the Geometridae, Noctuidae,
Arctiidae, and Lymantriidae. They constitute a second major class of lepidopteran
pheromones, different from the C10-C18 acetates, alcohols, and aldehydes commonly
found in other species. They are biosynthesized from diet-derived linoleic or
linolenic acids and are characterized by C17-C23 straight chains, 1-3 cis double
bonds separated by methylene groups, and 0, 1, or 2 epoxide functions. Pheromone
blends are created from components with different chain lengths, numbers of
double bonds, and functional groups, or from mixtures of epoxide regioisomers or
enantiomers, with several examples of synergism between enantiomers. Behavioral
antagonists also limit interspecific attraction, with numerous examples of
antagonism by enantiomers. This review summarizes the taxonomic distribution,
mechanisms used to generate unique pheromone blends, and the identification,
synthesis, and biosynthesis of these compounds.
PMID- 10761591
TI - Insect parapheromones in olfaction research and semiochemical-based pest control
strategies.
AB - The possibility of disrupting the chemical communication of insect pests has
initiated the development of new semiochemicals, parapheromones, which are
anthropogenic compounds structurally related to natural pheromone components.
Modification at the chain and/or at the polar group, isosteric replacements,
halogenation or introduction of labeled atoms have been the most common
modifications of the pheromone structure. Parapheromones have shown a large
variety of effects, and accordingly have been called agonists, pheromone mimics,
synergists and hyperagonists, or else pheromone antagonists, antipheromones and
inhibitors. Pheromone analogues have been used in quantitative structure-activity
relationship studies of insect olfaction, and from a practical point of view they
can replace pheromones when these are costly to prepare or unstable under field
conditions.
PMID- 10761592
TI - Pest management strategies in traditional agriculture: an African perspective.
AB - African agriculture is largely traditional--characterized by a large number of
smallholdings of no more than one ha per household. Crop production takes place
under extremely variable agro-ecological conditions, with annual rainfall ranging
from 250 to 750 mm in the Sahel in the northwest and in the semi-arid east and
south, to 1500 to 4000 mm in the forest zones in the central west. Farmers often
select well-adapted, stable crop varieties, and cropping systems are such that
two or more crops are grown in the same field at the same time. These diverse
traditional systems enhance natural enemy abundance and generally keep pest
numbers at low levels. Pest management practice in traditional agriculture is a
built-in process in the overall crop production system rather than a separate
well-defined activity. Increased population pressure and the resulting demand for
increased crop production in Africa have necessitated agricultural expansion with
the concomitant decline in the overall biodiversity. Increases in plant material
movement in turn facilitated the accidental introduction of foreign pests. At
present about two dozen arthropod pests, both introduced and native, are
recognized as one of the major constraints to agricultural production and
productivity in Africa. Although yield losses of 0% to 100% have been observed on
station, the economic significance of the majority of pests under farmers'
production conditions is not adequately understood. Economic and social
constraints have kept pesticide use in Africa the lowest among all the world
regions. The bulk of pesticides are applied mostly against pests of commercial
crops such as cotton, vegetables, coffee, and cocoa, and to some extent for
combating outbreaks of migratory pests such as the locusts. The majority of
African farmers still rely on indigenous pest management approaches to manage
pest problems, although many government extension programs encourage the use of
pesticides. The current pest management research activities carried out by
national or international agricultural research programs in Africa focus on
classical biological control and host plant resistance breeding. With the
exception of classical biological control of the cassava mealybug, research
results have not been widely adopted. This could be due to African farmers facing
heterogeneous conditions, not needing fixed prescriptions or one ideal variety
but a number of options and genotypes to choose from. Indigenous pest management
knowledge is site-specific and should be the basis for developing integrated pest
management (IPM) techniques. Farmers often lack the biological and ecological
information necessary to develop better pest management through experimentation.
Formal research should be instrumental in providing the input necessary to
facilitate participatory technology development such as that done by Farmer Field
Schools, an approach now emerging in different parts of Africa.
PMID- 10761593
TI - The development and evolution of exaggerated morphologies in insects.
AB - We discuss a framework for studying the evolution of morphology in insects, based
on the concepts of "phenotypic plasticity" and "reaction norms." We illustrate
this approach with the evolution of some of the most extreme morphologies in
insects: exaggerated, sexually selected male ornaments and weapons, and elaborate
social insect soldier castes. Most of these traits scale with body size, and
these scaling relationships are often nonlinear. We argue that scaling
relationships are best viewed as reaction norms, and that the evolution of
exaggerated morphological traits results from genetic changes in the slope and/or
shape of these scaling relationships. After reviewing literature on sexually
selected and caste-specific structures, we suggest two possible routes to the
evolution of exaggerated trait dimensions: (a) the evolution of steeper scaling
relationship slopes and (b) the evolution of sigmoid or discontinuous scaling
relationship shapes. We discuss evolutionary implications of these two routes to
exaggeration and suggest why so many of the most exaggerated insect structures
scale nonlinearly with body size. Finally, we review literature on insect
development to provide a comprehensive picture of how scaling relationships arise
and to suggest how they may be modified through evolution.
PMID- 10761594
TI - Phylogenetic system and zoogeography of the Plecoptera.
AB - Information about the phylogenetic relationships of Plecoptera is summarized. The
few characters supporting monophyly of the order are outlined. Several characters
of possible significance for the search for the closest relatives of the
stoneflies are discussed, but the sister-group of the order remains unknown.
Numerous characters supporting the presently recognized phylogenetic system of
Plecoptera are presented, alternative classifications are discussed, and
suggestions for future studies are made. Notes on zoogeography are appended. The
order as such is old (Permian fossils), but phylogenetic relationships and global
distribution patterns suggest that evolution of the extant suborders started with
the breakup of Pangaea. There is evidence of extensive recent speciation in all
parts of the world.
PMID- 10761595
TI - Impact of the Internet on entomology teaching and research.
AB - The Internet is affecting entomology teaching and research. Internet tools help
students communicate and easily find and access information. Entomology
instructors who adopt these tools may discover they are surprisingly time
consuming to implement. Requiring students to use the Internet teaches them to
glean from the glut of available information and to communicate electronically,
both vital skills in today's workplace. The Internet helps meet the growing need
for distance education by providing a medium that allows students to conveniently
access course materials and to communicate with the instructor and other
students. Researchers benefit from using the Internet for one-to-one and one-to
many communication and from access to large cooperative databases, for example,
in molecular biology and systematics. Perhaps the greatest impact on research
will be the migration to the Web of journals and other specialized research
literature. This may permit free access and will change the content and format of
journal articles. In the online version of this chapter, the hyperlinks in the
Literature Cited section are active.
PMID- 10761596
TI - Molecular mechanism and cellular distribution of insect circadian clocks.
AB - Circadian clocks are endogenous timing mechanisms that control molecular,
cellular, physiological, and behavioral rhythms in all organisms from
unicellulars to humans. Circadian rhythms influence many aspects of insect
biology, finetuning life functions to the light and temperature cycles associated
with the solar day. Genetic studies in the fruit fly Drosophila melanogaster have
led to the cloning and characterization of several genes involved in the
mechanism of the circadian clock. Periodic transcription and translation of these
clock genes form the basis of a molecular feedback loop that has a "circa" 24
hour period. Rhythmic expression of clock genes in specific brain neurons appears
to control behavioral rhythms in adult flies. However, clock genes are also
expressed in other tissues, both within and outside of the nervous system. These
observations prompted chronobiologists to investigate whether nonneural tissues
possess intrinsic circadian clocks, what role they may be playing, and what the
relationships are between clocks in the nervous system and those in peripheral
tissues. Answers to those questions are providing important insights into the
overall organization of the circadian system in insects.
PMID- 10761597
TI - [Acetaminophen should remain the first choice drug for the treatment of fever in
children].
PMID- 10761598
TI - [Lamotrigine therapy in children. Retrospective study of 32 children].
AB - BACKGROUND: Lamotrigine is one of the new anti-epileptic drugs, which is a
phenyltriazine derivative. It is considered to act via an inhibitory effect on
voltage-sensitive sodium channels and to have no GABAergic action. PATIENTS AND
METHOD: We studied its efficiency in 32 children with refractory epilepsy after a
treatment of at least one year with other anti-epileptic drugs. We then compared
our results with other publications. RESULTS: Good efficiency (at least 50%
reduction of crises) has been demonstrated for lamotrigine in children with
generalized epilepsy (62.5% good results), particularly with absence epilepsy and
Lennox-Gastaut syndrome. Results are encouraging for our few patients with
epilepsy with continuous spike waves during slow-wave sleep. On the other hand,
more precise indications are needed in partial epilepsy. CONCLUSION: Seizure
control was generally maintained during one year of lamotrigine treatment.
Association to sodium valproate is relevant for most of the authors. Adverse
effects are uncommon, and we did not observe any skin rash. Lastly, improvement
of behaviour and cognitive functions represents another important benefit of
lamotrigine.
PMID- 10761599
TI - [Congenital malarial disease due to Plasmodium falciparum in high-infection-risk
newborn].
AB - The aim of this work was to differentiate in an endemic area congenital malaria
diseases (CMD) from congenital malaria infestations (CMI) or other maternal-fetal
infections. METHODS: Four hundred and seventy-five newborn (0-7 d) suspected of
infection were prospectively studied. CMD was diagnosed when clinical
manifestations were associated with positive thick and thin blood films in a
mother and her newborn. The diagnosis of CMI was retained when despite positive
parasitemia, no clinical manifestations were observed. RESULTS: Forty newborns
(1.7% of the cases of maternal malaria) were diagnosed as CMD and ninety-one (19%
of live births) were considered as CMI. The main clinical manifestations were
related to cerebral (100%), respiratory (95%) and hemodynamic (90%) systems.
Hematologic signs were present in 95% of cases. The level of parasitemia varied
from 700 to 3,000 parasites/mL in CMD and from 360 to 870 parasites/mL in CMI.
Death occurred in ten cases (25%) of CMD. CONCLUSION: In this malaria-endemic
area, neither clinical manifestions nor parasitemia allow one to distinguish CMD
from CMI associated with bacterial materno-fetal infections. Studying placental
or systemic immunity and antimalaria IgM in the newborn could be of interest to
clarify this problem.
PMID- 10761600
TI - [Prevention of sickle cell crises with multiple phlebotomies].
AB - OBJECTIVES: Sickle cell disease patients suffering from frequent painful crises
were submitted to phlebotomies in order to reduce hospitalization days due to
pain, through hemoglobin (Hb) level reduction and iron deficiency in patients
with an hemoglobin level equal to or above 9.5 g/dL. PATIENTS: Seven sickle cell
disease patients (four SC, three SS), aged four to 24 years, were submitted to
sequential phlebotomies during periods from 18 months to four years. METHODS: The
number of hospitalization days for crises was considered. The volumes and
frequencies of phlebotomies were adjusted according to the patients ages, the
hemoglobin concentrations and the serum ferritin levels. RESULTS: One hundred and
forty-four hospitalization days were recorded in the seven patients in the year
preceding the treatment. During the study period, the annual numbers of
hospitalization days were respectively 20, five, six and one. Mean hemoglobin
concentration was 10.7 g/dL before phlebotomies and 8.8 to 9.2 g/dL during the
four years of treatment. Mean corpuscular volume, mean corpuscular hemoglobin
concentration and serum ferritin were also reduced. The volume of phlebotomies
was 116 to 39 mL/kg/year according to the patients. COMMENTS AND CONCLUSION: The
striking decrease of the number of hospitalization days for all the patients
suggests a closed relationship between therapy and clinical improvement. The
mechanism of this effect is probably multifactorial: a) the concentration of Hb
level is known to influence the blood viscosity and its decrease always improved
rheology in sickle cell disease patients; b) the mean corpuscular hemoglobin
concentration is a critical factor concerning the HbS molecule polymerization in
sickle cell disease, and its slight reduction may have an important biological
effect. We observed these two biological modifications in our patients and
suggest that they mediate the clinical effects. The iron deficiency induced by
phlebotomies has no evident deleterious consequence either on height and weight
in the children or on intellectual performance in any patients.
PMID- 10761601
TI - [The characteristics of sleep-wake rhythm in adolescents aged 15-20 years. A
survey made at school during ten consecutive days].
AB - Adolescents' fatigue is a worrying subject. PATIENTS AND METHOD: A survey was
carried out over a period of ten days (a school week between two weekends).
Through a daily questionnaire, 386 adolescents aged 15-20 years were asked about
sleep onset and offset, time delay of sleep onset, quality of sleep, daytime
sleepiness and naps. RESULTS: The results confirmed that the length of sleep was
lessened during weekdays. This duration was one hour shorter than on Saturday
nights or during holidays. However, a significant delay occurs in sleep onset on
Saturday nights and sleep offset on Sunday mornings, which represents the main
irregularity in the sleep schedule. Poor quality of sleep is due to difficulties
in sleep onset (16%) and night awakenings (39%). Daytime sleepiness is reported
by 38% of the adolescents, and many of them have a nap on Sundays, or other days
of the week. Daytime activities (out-of-school sports, particularly) and evening
activities were studied as well as the use of hypnotics and stimulants.
CONCLUSION: This work stresses sleep insufficiency during the week at school,
changes in sleeping patterns during weekends, and sometimes poor quality of
sleep. Similar facts have already been found in children, and this may explain
the consequences on the life and behaviour of adolescents. The population has to
be informed about the effects of sleep on health.
PMID- 10761602
TI - [Neonatal myasthenia gravis].
AB - BACKGROUND: Myasthenia gravis, an autoimmune disease of young women, is due to
the dysfunction of neuromuscular transmission. The newborn of a myasthenic mother
inconstantly presents a transitory neonatal myasthenic syndrome. Maternal
aggravation, or even myasthenic crisis with respiratory failure, can occur in the
first three months post-partum. CASE REPORT: Mrs. S., para two without
appreciable medical history, delivered normally a boy weighing 4 kg with an Apgar
score of 10/10. At 3 h of life the newborn was admitted to the neonatal care unit
for grunting and axial hypotonia. Diagnoses of maternal-fetal infection and fetal
distress were excluded. The dissociated pattern of neurological disorders
(refusal to drink, axial hypotonia, hypomimia, but good contact and normal
alertness) led to search for neuromuscular causes or poison. Myasthenia gravis
was then considered and confirmed by maternal electromyography, allowing the
diagnosis of transient neonatal myasthenia gravis and early diagnosis and
treatment of the maternal myasthenic crisis in a specialized care unit. The
outcome of both mother and child was favorable under treatment. CONCLUSION: Lack
of maternal myasthenia gravis history should not result in excluding the
diagnosis of transitory neonatal myasthenia gravis when evocative neonatal
neurological signs are present. The symptomatology in the newborn may indeed
reveal maternal myasthenia gravis, allowing an early diagnosis in both the mother
and the newborn.
PMID- 10761603
TI - [Intravascular rupture of a central venous catheter in a premature infant:
retrieval by a nonsurgical technique].
AB - Central venous access is a frequent procedure in pediatric intensive care and
neonatology. Catheter fracture with migration of the distal portion into the
vessels is rare but may have side effects such as thrombosis. CASE REPORT: We
report the case of a premature infant who had at three weeks of age a retained
central venous catheter fragment in the pulmonary artery. The fragment was
successfully retrieved by a percutaneous endovascular technique. No complication
was observed during the procedure and afterward. CONCLUSION: This technique has
avoided either delicate surgery or thrombotic risk due to a persistent
intravascular foreign body. The authors prompted this interventional procedure
within 36 hours after catheter migration in a center experienced in neonatal
interventional catheterization.
PMID- 10761604
TI - [Hereditary neuropathy with tendency to pressure palsies (HNPP) in a child:
clinical and biological diagnosis. A case report].
AB - HNPP occurs rarely but not exceptionally during childhood. CASE REPORT: Jose M.,
seven years old, presented an isolated radial nerve palsy of progressive onset
with no other clinical feature. There was no family history of neurological
disorder. The electromyogram (EMG) showed a 'mosaic-like' pattern of extended
sensitive and motor alterations, with diminished conduction velocities and
amplitudes and increased distal latencies. HNPP was considered through the
association of an isolated radial nerve palsy with an asymptomatic
polyneuropathy, and was confirmed by molecular biology. CONCLUSION: HNPP is
generally considered on clinical features, heredity and EMG findings. Molecular
biology confirms the diagnosis in most of the cases, even in apparently sporadic
patients, and is of great interest in atypical cases.
PMID- 10761605
TI - [Cheilitis granulomatosa in a child].
AB - Granulomatous cheilitis is a rare disorder characterized by intermittent swelling
of one or both lips, which may become persistent. We report a case occurring in a
child, which improved with minocycline treatment. CASE REPORT: An eight year-old
girl was seen for the swelling of her upper lip, which persisted for more than
one year. There was no history of applied irritants, local trauma or atopy. On
examination, the upper lip was swollen, indurated, erythematous and fissured with
a bilateral perleche. The tongue and gums were normal. There was no facial palsy.
The girl was in good health and did not take any drugs. Blood investigations were
normal. Patch tests were negative. Antibiotic treatment or local steroids
provided only temporary improvement. A biopsy showed extravascular epithelioid
and gigantocellular non-caseating granulomas with lymphoid infiltrates. There was
no sign of sarcoidosis or Crohn's disease. Treatment with hydroxychloroquine for
three months, then with oral metronidazole, did not improve the symptoms.
Minocycline (100 mg/d) was effective. CONCLUSION: Granulomatous cheilitis should
be considered in children as well and differentiated from infectious, allergic or
factitious dermatoses. Granulomatous cheilitis can be associated with Crohn's
disease or sarcoidosis, and could precede these disorders from several months or
years, thus requiring a long-term follow-up.
PMID- 10761606
TI - [Reactive hemophagocytic syndrome in children].
AB - Reactive haemophagocytic syndrome is characterized by activation and uncontrolled
non-malignant proliferation of T lymphocytes and macrophages, leading to a
cytokine overproduction, which accounts for the main biological signs. Children
usually present with an acute febrile illness, fulminant pancytopenia and
hepatosplenomegaly, posing a problem of differential diagnosis with severe
sepsis. Hemopoietic cells are actively ingested by monocytes/macrophages in
various organs, including lymph nodes, bone marrow, liver and spleen. This
exarcerbation of the histiocytic system is currently classified among the
reactional histiocytoses. It reflects an inappropriate host immune response. Most
patients have a known underlying disease (hemopathy, lupus, systemic juvenile
arthritis, HIV infection). In the few cases that occur in the apparent absence of
any risk factors, investigations should be made to look for predisposing
inherited diseases, such as familial lymphohistiocytosis or Purtilo's disease in
boys. The treatment rests on immunosuppressive agents, followed by bone marrow
transplantation, which can provide a definitive cure in genetic forms.
PMID- 10761607
TI - [Pulmonary cystic images as a presentation of a pleuropulmonary blastoma].
AB - A five-month-old infant presented with a sudden choking cough and mild dyspnea.
Bilateral cystic pulmonary images were found on a chest X-ray, leading to
exploratory surgery. A pleuropulmonary blastoma, a rare malignant embryonic tumor
of childhood, was diagnosed on histologic examination. This case illustrates the
necessity of performing surgical resection and histologic evaluation of any
pulmonary cystic malformations, particularly when bilateral.
PMID- 10761608
TI - [Autopsy practices in cases of sudden infant death syndrome in the French
speaking community of Belgium and comparison with other European countries].
AB - This work summarises the current difficulties encountered in performing autopsies
in cases of sudden unexplained infant deaths in Belgium. Over the last few years,
the incidence of postneonatal deaths in most European countries has significantly
decreased, probably due to prevention campaigns. However, there are still many
difficulties encountered in systematically including autopsies in the general
strategy for managing this public health problem. The analysis of autopsy
practices in Belgium in cases of unexplained infants' deaths and their comparison
with other European countries' practices give us the opportunity to propose
changes in order to improve policies and the overall understanding of these
unexplained deaths.
PMID- 10761609
TI - [Inhaled antiasthmatics in children. How to choose?].
AB - An optimal combination of anti-asthmatic drugs and delivery devices produces the
best short- and long-term control in asthmatic children. Various inhalation
devices can be used: nebulizer, metered dose inhaler with or without spacer
devices, dry powder inhaler. Their use will depend on age, asthma severity, acute
or long-term treatment and the child's preference. Explanation and control of
inhalation techniques are essential for a good compliance.
PMID- 10761610
TI - [Use of infant formulas with reduced antigenic content. Committee on Nutrition of
the French Pediatrics Society].
AB - Three types of infant formulas with reduced antigenic content are presently
available: formulas with partially hydrolyzed proteins (hypoallergenic formulas),
formulas with extensively hydrolyzed proteins, and amino-acids mixtures. There
respective indications for preventing, postponing or treating allergic
manifestations are presented, recalling that breast milk remains the best
recommendation. Patent cow milk allergy requires extensively hydrolyzed proteins
formulas.
PMID- 10761611
TI - [Children, television and violence].
AB - The relationships between children and television are a source of heated debate.
Several studies, mainly conducted in North America, have found a correlation
between television violence viewing and aggressive behavior, preadolescents
appearing as the most vulnerable. However, in France opinions are more nuanced
and one generally considers that television-induced violence in children mainly
depends upon individual and educative socio-familial factors.
PMID- 10761612
TI - [Cellular therapy in osteogenesis imperfecta].
PMID- 10761613
TI - [Peroneal nerve palsy in anorexia nervosa: three cases].
PMID- 10761614
TI - [A report of drowning in an infant].
PMID- 10761615
TI - [Emla cream in pediatric emergency cases by using selection criteria. Feasibility
study].
PMID- 10761616
TI - [How to improve the management of children allergic to foods in the school
cafeteria?].
PMID- 10761617
TI - [Dysfunction of the vocal cords simulating asthma].
PMID- 10761618
TI - Serum ferritin levels in subjects at high risk of atherosclerosis.
AB - Serum ferritin levels were determined in a group of 148 subjects drawn from a
community study who were found to be at high risk of atherosclerosis (evaluated
on the basis of the following data: levels of non-HDL cholesterol, arterial
pressure, smoking status, cardiovascular or cerebrovascular disease in a
subject's history, diabetes mellitus, a positive family predisposition to, or
accumulation of the above factors) and compared with the levels obtained in a
control group of 148 examined age- and sex-matched subjects from the same
community with non-significant risk factors. Mean serum ferritin levels were
higher in the whole risk group and in the subgroups of risk men and
postmenopausal women than in the corresponding controls (the whole risk group:
263.4 +/- 218.5 micrograms/l vs. 198.3 +/- 179.5 micrograms/l, p < 0.05; the
subgroup of men 361.8 +/- 235.7 micrograms/l vs. 286.4 +/- 194.6 micrograms/l, p
< 0.05 and the subgroup of postmenopausal women 184.1 +/- 143.1 vs. 126.7 +/-
108.4 micrograms/l, p < 0.05).
PMID- 10761619
TI - Nutrition, nutritional behavior, and obesity.
AB - THE PURPOSE: Of this investigation is to explore the effect of several alimentary
factors--such as diet, nutritional habits, and personal preferences--upon the
occurrence of obesity. SUBJECTS: Of the study were 264 workers (203 men and 61
women) from the ammonium production department of a fertilizer plant, divided
into two age groups: under 30 years and over 30 years. METHODS: The data are
collected by means of a questionnaire about daily nutrition, including the types
and average quantity of food (Food Frequency Questionnaires--FFQ). All collected
information is analyzed by means of a computer program with a database that
includes the chemical structure of food products and takes into account the
losses in their nutritional value that occurs in the course of preservation and
thermal processing. The nutritional status is assessed on the basis of a Body
Mass Index (BMI): group I--normal body mass--BMI 18.5-25 kg/m2; group II-
overweight--BMI 25.1-30 kg/m2; group III--obesity--BMI > 30 kg/m2. RESULTS: The
assessment of the individual energy intake shows that hyper-energetic nutrition
is typical for 67% of the individuals examined. There is no significant age
and/or gender difference. This is the result of extra-intake of fat (over 30 E%),
which is observed for 87.9% of all workers, and over 40 E% for almost half of the
women examined. All age and gender groups display hyper-protein nutrition with
pronounced cellulose (fiber) deficit, high daily intake of sodium, and disbalance
of mineral salts as well as a relative deficit of vitamin A, B1, and PP. The
frequency of overweight individuals is 43.9%, while that of obese individuals is
23.1%. The majority of workers (70.1% of group I, 63.2% of group II, and 79% of
group III) have three meals a day. For 43% of group III individuals dinner is the
largest meal. A significantly higher percentage of group III individuals (21.3%)
think that they overeat. CONCLUSIONS: Hyper-energetic, disbalanced nutrition, and
incorrect nutritional-behavioral model are factors that determine the prevalence
of overweight and obesity among the workers examined.
PMID- 10761620
TI - Risk assessment of the occupational contact with ammonium.
AB - The aim of the cohort retrospective study was to analyze and evaluate the
influence of certain factors (age, profession, smoking) on the characteristics
and the incidence rate of the upper respiratory tract diseases (URTDs) in the
occupational contact with ammonium. Subjects were 180 men, divided into 3
professional groups. The average shift concentrations of ammonium were measured
in the permanent work places and individually by personal passive dosemeters. The
URTDs were classified into 15 groups according to localization and the stage of
the inflammatory process. The relationships "time-response" and "dose
(concentration)-response" were determined. The factor "cumulative exposure" was
used in order to evaluate the actual noxious effect of NH3 on the mucose of the
upper respiratory tract (URT). There was a statistically reliable difference
found in the incidence rate of atrophic rhinitis, hypertrophic pharyngitis and
laryngitis, and neoplasms of the URT in the workers with the highest cumulative
exposure. For this group relative risk was 4.00, 2.22, 3.20 and 4.00,
respectively, with 95% Cl. The "cumulative exposure" factor gives the best proofs
for the toxic effect of ammonium and a possibility for assessment of the relative
risk.
PMID- 10761621
TI - Production of slime by staphylococcal isolates from blood cultures.
AB - The aim was to examine the ability of staphylococci isolated from blood cultures
to produce slime and to compare the slime production of strains considered
clinically significant and of strains considered mere contaminants. The ability
to produce slime was examined in 359 staphylococcal isolates from blood cultures
by the congo red agar method. The clinical significance of an isolate was
estimated according to the frequency of its occurrence in a series of blood
cultures. Only strains isolated at least twice from the series of two or more
blood cultures were considered significant. The slime production was detected in
18 of 32 strains (56.2%) of Staphylococcus aureus, in 61 of 231 strains (26.4%)
of S. epidermidis and in 14 of 101 strains (14.6%) of the remaining seven
species. Out of 80 strains considered significant, 33 strains (41.2%) produced
slime, out of 132 strains considered contaminants, 24 strains (18.2%) were slime
producers. The significance of the remaining isolates was non-evaluable. We
conclude that the staphylococcal isolates from blood cultures considered
clinically significant produced slime more often than the isolates considered
mere contaminants.
PMID- 10761622
TI - Growth and development of school children.
AB - With the support of the Internal Grant Agency of the Ministry of Health of the
Czech Republic in 1997-1999 work proceeded on the grant "Semi-longitudinal study
of the somatic growth of school children in the Czech Republic". The objective of
this project is to assess the growth rate of the basic bodily characteristics in
children and youth aged 6 to 14 years, to confirm the positive secular trend in
height and body weight or its slowing or stagnation, and also to evaluate the
growth and development of children under the new socio-economic conditions. In
addition to thirty somatic characteristics which are assessed repeatedly every
six months, in 1,925 children some supplementary data were obtained from parents.
From hitherto assembled data ensues that there was no significant change of the
mean length at birth nor of the birth weight as compared with 1989. The increase
in height up to adolescence continues, in the higher age groups probably
stagnation occurs. Despite a slight increase of mean body weight values since
1981, a gradual decline of the BMI values was observed. In boys this tendency is
less marked than in girls, in particular in the oldest age groups. This trend was
confirmed also by the results of the present investigation. As compared with the
results of the 5th Nationwide Anthropological Survey in 1991 the group of
overweight children, i.e. those above the 90th percentile of BMI comprises 6.9%
boys and 8.9% girls from a total of almost 2,000 children, as compared with the
expected 10%.
PMID- 10761623
TI - The first occurrence of a multi-drug resistant tuberculosis epidemic in the Czech
Republic caused by genetically closely related Mycobacterium tuberculosis
strains.
AB - DNA fingerprinting based on the detection of the insertion sequence IS6110 in
Pvull restriction fragments was applied to M. tuberculosis isolates originating
in the first microepidemic of multidrug resistant tuberculosis recorded in the
Czech Republic. Their disseminators were 21 individuals living in--or roaming
between three distant areas. The age of 17 males ranged from 36 to 64 years
(average 45 years) and of 4 females aged from 38 to 52 years. The index person
was most probably a former male prisoner, aged 49 years, who disseminated
multidrug resistant M. tuberculosis over a period of 28 months. In ten of the
patients the following risk factors for tuberculosis were found: imprisonment,
homelessness, immigration and previous stay in asylum--or in a psychiatric ward.
In six cases, M. kansasii infection preceded tuberculosis. Four out of the 21
patients died. The RFLP analysis separated the patients into two distinct groups:
group A comprising 14 members of which M. tuberculosis strains were isolated with
six IS6110 copies, whereas the isolates of seven individuals of the group B, the
RFLP profile displayed highly similar RFLP patterns compared to the isolates of
group A, but with two additional IS6110 copies. In one patient, both A and B
patterns were found: the first one in a M. tuberculosis strain isolated in 1993
and the second one in the isolate isolated two years later. Both the appearance
of pattern B among the isolates of a part of patients and the switch from A to B
pattern in one of patients can be plausibly explained by the unstability of DNA
genotypes caused by transposition of IS6110 elements.
PMID- 10761624
TI - Health risk assessment for inhalation exposure to arsenic.
AB - Health risk assessment was used as the formal process to estimate the likelihood
and magnitude of the health effects occurring in humans as a result of
environmental and occupational exposure to polluting agents. This study was
focused at estimating the human health risk of the general and working population
living in the region polluted by arsenic for more than 40 years, from combustion
of coal with high arsenic content in the power plant. The exposure to arsenic
from inhalation was under investigation. A study period of 40 years (1973-1993)
was chosen. The study period was defined taking into account, besides the
availability of data, the temporal patterns of the technological processes and
the trends over time of environmental concentrations. The results from the
arsenic risk assessment study were used for the evaluation of the health risk for
different population groups in the polluted areas and for different professions
of workers exposed to As in a power plant. The results are applicable for the
evaluation of risk in real conditions, for health surveillance and for remedial
changes and a potential suggestion on technological improvement.
PMID- 10761625
TI - Environmental respiratory health in central and eastern Europe.
AB - The main objective of the paper was to discuss the environmental issues in the
countries of central and eastern Europe (CEE) and to show their significance for
respiratory health. Many epidemiologic studies carried out in the region have
documented an association between air pollution and adverse health effects in the
respiratory tract. Short-term exposure to ambient air pollution has been related
to an increase in mortality and hospital admissions for diseases of respiratory
tract. Effects of long-term exposure was implicated in the rising trends of lower
respiratory tract diseases, such as asthma and bronchitis, in both children and
adults. Recent evidence indicates that the prevalence of allergic sensitization
in the CEE countries is higher in urban than in rural areas, however, it is not
clear to what extent ambient air pollution has contributed to this difference. It
is difficult to estimate the toll of adverse health effects caused by air
pollution in the CEE countries because of insufficient data on exposure. However,
it is evident that significant positive effects would occur if air pollution
concentrations in the region were reduced along with the WHO guidelines.
PMID- 10761626
TI - Influence of cadmium on the immune system. Description of stimulating reactions.
AB - Allergic diseases, atopy, bronchial asthma and chronic obstructive bronchitis are
diseases which can directly or indirectly be traced to changes in the function of
the immune system. Epidemiological studies have shown that these allergic
diseases have increased in the course of time and that the incidence of
obstruction of the respiratory system is clearly higher in polluted regions than
in comparable control areas. These diseases are mainly the result of a
comprehensive influence on the immune system. The present study describes the
influence of pollutants on the behavior of cytokines which cannot be directly
traced to an allergen or antigen in order to be able to explain various
immunological or pseudo-allergic processes. We have isolated and cultivated PBMC
from six donors and exposed them to different concentrations (5, 25, 50 and 100
mumol) of cadmium chloride. After incubation of cells with cadmium, different
genes of cytokines were detected on the basis of mRNA by RT-PCR. Hsp70 can be
detected in a relatively brief period following stress and there is an excellent
correlation between heavy metal dose (stress) and expression of hsp70. In the
case of IL-1, and TNF-alpha low concentrations of cadmium chloride increase the
expression of these genes, whereas this effect is less noticeable with higher
amounts of cadmium. After only one hour of exposure to heavy metals, large
volumes of mRNA of IL-6 have been detected. IFN-gamma only reacts at high
concentrations of cadmium. Heavy metals may influence immunocompetent cells so
that they release several cytokines which may act on a large variety of cells in
terms of a proinflammatory reaction. The influence of cytokines as well as the
pollutants themselves on fibroblasts, endothelial cells as well as macrophages
explains a number of processes which cannot be explained by allergical reactions.
At low concentrations, cadmium is able to stimulate the immune system, while at
higher concentrations inhibitory and suppressive reactions were observed.
PMID- 10761627
TI - Caries experience, oral health status and urine fluoride excretion in children in
some localities in the Czech Republic.
AB - Two studies on caries experience and oral health status in 12-year-old-children
were conducted in a five year period (1993-1998). The examination was completed
by analysing the urinary fluoride excretion of the examined children. The DMFT
was recorded. The F-selective electrode was used for the analysis of the urinary
fluoride concentration. The percentage of caries-free children decreased between
1993-1998. Caries experience rose in most of the localities. The highest caries
experience expressed by DMFT was found in Tabor where it reached 5 per person.
The urinary fluoride excretion ranged from the lowest level, found in Strakonice
(0.478 mg/l), to the highest which was in Ostrava (0.660 mg/l) in 1998. F
concentrations in all other localities were between these extremes (both in 1993
and 1998). Oral health and fluoride exposure from the environment varied
considerably which implies the necessity to implement individual precautions in
oral care and prevention at a local level.
PMID- 10761628
TI - Occupational diseases in the Czech Republic in the year 1998. The need for
unifying European standards/criteria for all occupational diseases.
AB - In the Czech Republic, the Clinics and Departments for Occupational Medicine
according to the legislation have the right to recognise occupational diseases.
The diagnosis must correspond to the Czech list of occupational diseases, which
is similar to the European list of occupational diseases. The exposure,
sufficient enough to cause certain occupational disease, must be confirmed by
regional industrial hygienists, responsible for hygienic control of the
workplace. It is evident that the number of diseases is very much dependent upon
the standards/criteria used to recognise occupational diseases. In the Czech
Republic, the patients suffering from occupational diseases are given
considerable financial compensations, which creates a great motivation for them
to apply for occupational diseases. The article presents the overview of
occupational diseases in the Czech Republic in the year 1998. The total number of
diseases was 2111, the incidence per 100,000 employees was 45.8. It is necessary
to present and discuss unifying criteria for occupational diseases in European
countries, as well as the minimum level of the damage, that could be called an
occupational disease. The criteria should be co-ordinated, because in a unified
Europe, there will be many more possibilities for change in the workplace.
PMID- 10761629
TI - Soil pollution and soil limit values.
AB - One of the tools for preventing soil pollution and thus protection of public
health is the application of appropriate limit values. Policies on soil
protection in relation to soil pollution include two basic strategies: a
preventive approach and a remediation or cleanup approach. Preventive,
multifunctional limit values are independent from present or future land use.
Remediation limit values are connected with land use--these are functional limit
values. Both types of limit values are applied in Hungary. Determination of soil
limit values demands long-term field investigations, but to estimate allowable
concentration for a given site reverse risk assessment methods are well
applicable. A comparison and evaluation of the calculated data and the
measurement results obtained at the use of the area is indispensable. Further
investigations are needed for establishment of combined limit values when more
polluting components are present simultaneously in the soil.
PMID- 10761630
TI - The concentrations of mixed populations of fungi in indoor air: rooms with and
without mould problems; rooms with and without health complaints.
AB - The aim of this study was to establish the concentrations of mixed populations of
fungi in indoor air and to attempt to correlate these concentrations and health
complaints of residents. We investigated 68 rooms. These were divided into four
groups: rooms without moulds on the walls and with/or without complaints; rooms
without moulds on the walls and with/or without complaints. Health problems were
noted by those living in the rooms and these were non-specific symptoms such as
cough, headache, rhinitis and sore throat. The total concentrations of airborne
fungi (monitored by aeroscop) were much higher in mouldy rooms than in the
reference rooms. Even if health complaints did not correlate with the total
concentrations of airborne fungi, all occupants of rooms where the average
concentrations was 2,476 cfu/m3 reported health complaints. Concentration of
fungi in indoor air above 2,000 cfu/m3 can be considered to be a serious risk
factor for health of occupants.
PMID- 10761631
TI - International Quit and Win: successful global action for smoking cessation.
AB - Quit and Win has rapidly grown in popularity as a practical international smoking
cessation activity. This is likely to be due to Quit and Win's unique, positive
approach to a problem that is receiving increasing attention worldwide as a major
health threat. The campaign is also a concrete channel for large international
health collaboration, which is necessary considering the global nature of
marketing efforts of the tobacco industry. Based on encouraging experiences of
three previous international campaigns in 1994, 1996 and 1998, the next
International Quit and Win will be organized in 2000. It will be larger than ever
and support the new WHO Tobacco-Free Initiative.
PMID- 10761632
TI - Interaction between cells and elastin, the elastin-receptor.
AB - This article dedicated to Ines Mandl at her 80th birthday is a short review of
the recent work of our team on the elastin receptor. Our studies started in the
early nineteen eighties aimed at the understanding of cell-elastin interactions.
The first experiments reviewed demonstrated the inducible interaction of cells-
smooth muscle cells, fibroblasts--with elastic fibers. Their strong adhesion was
accelerated and amplified by elastin peptides and cell adhesion to elastin needed
protein neosynthesis. The demonstration of the presence of the elastin receptor
on leukocytes facilitated the detailed description of the transmission pathway
from receptor to the intracellular sites activated by the receptor: modifications
of ion fluxes, increase of elastase production and excretion of reactive oxygen
species, superoxide and NO*. The calcium transients triggered by elastin peptides
acting on the receptor decrease with age, the receptor appears to be uncoupled
from the G-proteins, but superoxide release is increased. As circulating blood
was shown to contain elastin peptides at concentrations saturating for the
receptor (microg/ml conc-s for a Kd in the nanomolar range), the receptor on
cells in contact with excess agonists is constantly overstimulated. The
continuous release of lytic enzymes and free radicals might well be involved in
cell damage. This was demonstrated with human lymphocytes undergoing cell death
by necrosis and apoptosis in presence of higher concentrations of elastin
peptides.
PMID- 10761633
TI - The role of the carboxy terminus of tropoelastin in its assembly into the elastic
fiber.
AB - Tropoelastin, the soluble precursor protein of insoluble amorphous elastin,
contains repeating segments that are important for the characteristic elasticity
and crosslinking sites of mature elastin. In addition, there is a unique carboxy
terminal domain that is encoded by exon 36 of the elastin gene, and it has been
suggested that this region may play a role in the process of insolubilization.
The contribution of exon 36 to the maturation of tropoelastin into insoluble
elastin was probed in these studies. Neonatal rat aortic smooth muscle cells were
cultured and the fate of [3H] Lys labeled human recombinant tropoelastin (hrTE)
molecules added to the cultures was monitored. In comparison to the hrTE
containing the region encoded by exon 36, hrTE molecules lacking this domain were
less efficiently incorporated into elastin, as evidenced by a decrease in NaOH
insoluble radioactivity. Specific residues within the domain encoded by exon 36
were targeted for further study in experiments in which the two Cys residues were
reduced and alkylated, and/or the four basic Arg-Lys-Arg-Lys residues at the
carboxy terminus were removed. Both of these modifications resulted in decreased
incorporation into elastin equivalent to the complete removal of the carboxy
terminus. Prior treatment of the cell layer with elastase reduced the efficiency
of insolubilization of hrTE containing the domain encoded by exon 36, but had no
effect on the processing of molecules lacking this region. These data suggest
that exon 36 of the elastin gene contributes to normal efficient incorporation of
tropoelastin into the elastin fiber.
PMID- 10761634
TI - The pulmonary matrix, glycosaminoglycans and pulmonary emphysema.
AB - This paper reviews recent evidence of the effect of intratracheal hyaluronan (HA)
to limit the induction of experimental emphysema in hamsters. Experimental
emphysema was induced by both neutrophil and pancreatic elastase instilled
intratracheally. Emphysema was quantified anatomically by measurement of alveolar
mean linear intercept. Hyaluronidase, instilled intratracheally, enhanced the
induction of experimental emphysema. Air-space size measured one week after
intratracheal instillation of elastase showed that administration of 1 mg HA
immediately following elastase administration resulted in a marked reduction in
air-space enlargement (82 microM vs 122 microM, p < 0.01). Similarly, animals
given either 1 or 2 mg HA 2 h before elastase or 2mg HA 1 h after elastase showed
a significant decrease in air-space enlargement compared to controls (96 microM,
88 microM vs 120 microM and 66 microM vs 104 microM, respectively; p < 0.05.
Experimental emphysema induced by neutrophil elastase was also limited by the
administration of 1 or 4 mg of HA, administered 2 h prior to elastase (57 and 59
microM, respectively vs 64 for controls, p < 0.05). Characterization of
administered HA showed a mean molecular weight of 104,800 Da, less than 5%
protein and a uronic acid/hexosamine ratio of 1, which is characteristic of HA.
Studies using fluorescein-labeled hyaluronan (HA) showed fluorescence associated
with interstitial, pleural and vascular elastic fibers. The mechanism of
attachment of the administered HA to elastin remains unknown. Fluorescein
labeling of elastin was visible for at least 4 h post-instillation. These studies
indicate a protective effect of hyaluronan against elastase degradation of
pulmonary elastin in vivo by both pancreatic and neutrophil elastases. The
anatomical studies further suggest a mechanism of protective coating of
hyaluronan which may limit access to pulmonary elastin from neutrophils and
alveolar macrophages. Results also suggest that a reduction in pulmonary
hyaluronan content increases the susceptibility of elastin to degradation by
elastases. These studies provide evidence for an antielastase effect of
hyaluronan which is not dependent upon enzyme inhibition but on anatomical
protection of pulmonary elastin by other mechanisms.
PMID- 10761635
TI - The zebrafish swimbladder: A simple model for lung elastin injury and repair.
AB - In this communication we offer data to suggest that the zebrafish swimbladder may
provide a simple model of elastin injury and repair which is amenable to genetic
analysis and pertinent to lung physiology. In situ hybridization of zebrafish
embryos illustrated that elastin gene expression is evident in the developing gut
tract prior to swimbladder morphogenesis. Northern blot analysis demonstrated
that the major zebrafish elastin mRNA is 2.0 kb which is significantly smaller
than its higher vertebrate counterpart. Amino acid analysis of alkali-resistant
protein from the anterior chamber of the adult zebrafish swimbladder showed a
composition similar to higher vertebrate elastins including significant amounts
of desmosine crosslinks. Electron microscopic investigations of the swimbladder
wall indicate a simple structure with an inner layer of elastin fibers. Elastase
delivery to the swimbladder in vitro resulted in significant fragmentation of
elastin in the anterior chamber providing an environment for studying elastin
repair within the tissue.
PMID- 10761636
TI - Remodeling of elastic fiber components in scleroderma skin.
AB - The skin of patients with scleroderma is characterized by an excess accumulation
of collagen in the extracellular matrix of the fibrotic reticular dermis. Elastic
fibers are also disrupted in this disease, however, in contrast to collagen,
relatively few studies have provided information concerning the changes that
occur to elastic fiber components in scleroderma. In the present study, the
extracellular matrix in scleroderma skin was examined with a specific focus on
the integrity of elastic fibers. Electron microscopic observations confirmed an
excess of 10 nm microfibrils present in small bundles independent of amorphous
elastin in the fibrotic reticular dermis. In the same area, a population of
stellate-shaped fibroblasts was identified in close association with the dermal
elastic fibers. In contrast to the uniform black appearance of the elastic fibers
seen in the papillary dermis and in areas of the reticular dermis not infiltrated
by these cells, the elastic fibers apposed to the cells were mottled in density
and often almost electron-lucent. These observations suggest that the elastic
fibers in the reticular dermis were being actively degraded. Results from this
study provide evidence for disintegration of elastic fibers in the skin of
scleroderma patients and suggest the possibility that degradation products from
the elastic matrix in the diseased tissues may act as a feedback signal for
increased matrix production.
PMID- 10761637
TI - Proteins secreted by vascular smooth muscle cells as substrates of lysyl oxidase.
AB - The mixture of proteins secreted by neonatal rat aorta smooth muscle cells
cultured in the presence of beta-aminopropionitrile was readily oxidized and
polymerized upon incubation with purified or crude preparations of lysyl oxidase.
Western blot analysis indicated that these substrates included 30-60kDa protein
bands reactive with anti-elastin, presumed to be fragments derived from
tropoelastin. Thus, truncated, elastin-like as well as other proteins accumulate
in the media of these cultures which, in toto, can serve as a conveniently
prepared, highly efficient substrate for the routine assay of lysyl oxidase
activity.
PMID- 10761638
TI - The effect of caloric restriction on the aortic tissue of aging rats.
AB - Connective tissue shows peculiar and complex age-related modifications, which can
be, at least in part, responsible for altered functions and increased
susceptibility to diseases. Food restriction has long been known to prolong life
in rodents, having antiaging effects on a variety of physiologic and pathologic
processes. Therefore, the aorta has been investigated in rats fed normal or
hypocaloric diet, from weaning to senescence. Compared with controls, caloric
restricted animals showed less pronounced age-dependent alterations such as
elastic fiber degradation, collagen accumulation and cellular modifications.
Immunocytochemical analyses revealed that elastic fibers were positively labelled
for biglycan, decorin, ApoB100 (LDL), ApoA1 (HDL) and elastase and that the
intensity of the reactions was time- and diet-dependent. With age, the major
changes affecting aortic elastic fibers were increased positivity for decorin,
LDL and elastase. Compared with age-matched normal fed rats, caloric restricted
animals revealed lower content of LDL, decorin and elastase and higher positivity
for HDL. These data suggest that a caloric restricted diet might influence the
aging process of the arterial wall in rats, delaying the appearance of age
related degenerative features, such as structural alterations of cells and matrix
and modified interactions of elastin with cells and with other extracellular
matrix molecules.
PMID- 10761639
TI - Elastin gene expression is upregulated during pulmonary fibrosis.
AB - Elastin is a chief component of lung interstitium, and it is central to lung
morphology and function. Efforts to understand the pathogenesis of pulmonary
fibrosis have focused primarily upon collagen turnover in the lung; few studies
have focused on elastin. In this study, we examined steady-state elastin mRNA
levels after lung injury in the mouse induced by (1) butylated hydroxytoluene
(BHT) which causes acute lung injury with recovery, (2) BHT + 70% O2 (fibrosis),
or (3) 70% O2. Total lung elastin mRNA increased 70-80-fold on d10-14 after
BHT/O2, but was unchanged after BHT or O2 alone. In situ hybridization studies
localized elastin mRNA to cells in the muscularis of conducting airways and to
scattered interstitial cells in fibrotic foci. Elastic fiber morphology was
markedly distorted after BHT/O2. Thus, marked upregulation of elastin gene
expression is correlated with the histopathology of fibrotic lung disease.
PMID- 10761640
TI - Expression of the elastin promoter in novel tissue sites in transgenic mouse
embryos.
AB - We have previously shown in a transgenic mouse line, in which 5.2 kb of the
elastin promoter was linked to the reporter enzyme chloramphenicol
acetyltransferase (CAT), that the highest levels of expression were found in
embryonic lungs and aorta, while lower levels were detected in other elastin
containing tissues. Furthermore, in general, expression of the transgene showed
developmental regulation similar to that of the endogenous gene. However, the
precise location of cellular expression could not be determined in this model. To
overcome this limitation, we have developed a similar model, but replaced CAT
with the reporter enzyme beta-galactosidase. Enzyme activity was readily detected
in the transgenic mouse embryos in expected regions of tissue forming elastic
fibers, including the dermis and elastic cartilage. Of considerable interest,
however, was the novel finding of expression in specific areas of neuroepithelium
of the brain and in the perichondrium surrounding areas destined to form hyaline
cartilage in endochondral bone formation. These latter areas included all the
bones of the limbs, the spine and rib cage. It appeared that these segments of
elastin expression demarcated the border between the developing cartilage and the
surrounding mesenchymal tissue. Elastin promoter expression was also found in
developing somites, in the mesenchymal layer of the forming cornea of the eye, in
the genital tubercle and in the epithelium destined to form the olfactory
epithelium. These findings indicate that the elastin promoter is activated during
embryonic development in a variety of tissues, suggesting that elastin gene
expression may play a role in organizing cutaneous, skeletal and neural
structures.
PMID- 10761641
TI - Tailoring new gene delivery designs for specific targets.
AB - Advancing biotechnology spurs the development of new pharmaceutically engineered
gene delivery vehicles with the capability to target specific cell types. The low
density lipoprotein (LDL) element of the terplex gene carrier is shown to be
efficient in delivery to smooth muscle cells as well as inducing minimal toxicity
to A7R5 cells in culture. The terplex system condensed plasmid DNA into polyplex
sizes ranging from 100 to 400 nm. Terplex demonstrated higher transfection
efficacy than Lipofectin. Lactose was conjugated through a poly(ethyl glycol)
(PEG) spacer to poly(L-lysine) (PLL) to tailor a gene carrier capable of
condensing plasmid DNA. This cationic polymer targeted Hep G2 cells
preferentially in culture. The inclusion of a lactose targeting moiety greatly
increased the efficacy of the gene carrier over PEG-PLL and Lipofectin. A
biodegradable nanoparticle gene carrier, polysaccharide-graft-PLL and poly(D,L
lactic acid), was synthesized and characterized. The nanoparticle size was
controllable by changing the copolymer concentration, where the particles could
be as small as 60 nm. When polysaccharide was used in the copolymer, the
nanoparticle became more DNA adsorbent. The JLI mAb was linked to PLL. This gene
carrier targets the antigen confined to stage II immature cortical thymocytes for
leukemia therapy. A 20,000 mw PLL backbone was sufficient for compaction of DNA.
Folic acid linked to PLL through a PEG spacer is currently being studied for DNA
condensation and delivery to membrane associated folate binding protein positive
endothelial cancer cells.
PMID- 10761642
TI - Structure and structure-function studies of lipid/plasmid DNA complexes.
AB - Recent synchrotron-based X-ray diffraction studies have enabled us to
comprehensively solve the self-assembled structures in mixtures of cationic
liposomes (CLs) complexed with linear lambda-DNA. In one case the CL-DNA
complexes were found to consist of a higher ordered multilamellar structure
(labeled L(alpha)C with DNA sandwiched between cationic bilayer membranes. The
membrane charge density is found to control the DNA interaxial spacing with high
densities leading to high DNA compaction between lipid bilayers. A second self
assembled structure (labeled H(II)C) consists of linear DNA strands coated by
cationic lipid monolayers and arranged on a 2D hexagonal lattice. In this paper
we report on a combined X-ray diffraction and optical microscopy study of CLs
complexed with functional supercoiled plasmid DNA. We describe the self-assembled
structures in cell culture medium for both a high transfectant complex
(DOTAP/DOPE, phiDOPE = 0.72) and a low transfectant complex (DOTAP/DOPC, (phiDOPC
= 0.72). Fluorescence optica microscopy shows two distinct interactions between
these two types of complexes and mouse fibroblast L-cells, demonstrating the
existence of a correlation between structure and transfection efficiency.
PMID- 10761643
TI - Pharmacokinetics and in vivo gene transfer of plasmid DNA complexed with
mannosylated poly(L-lysine) in mice.
AB - To achieve mannose receptor-mediated, cell-specific, in vivo gene transfer by
intravenous injection of plasmid DNA, mannosylated poly(L-lysine) (Man-PLL) was
synthesized as a carrier molecule, and mixed with a plasmid DNA encoding
chloramphenicol acetyltransferase (CAT) gene to form DNA/Man-PLL complex. The
particle size and zeta potential of DNA/Man-PLL (prepared at 1:0.7 on a weight
basis) were determined to be 220 nm and +12 mV, respectively. The
pharmacokinetics of the DNA/Man-PLL complex was assessed in mice using 32P
labeled DNA ([32P]DNA). After intravenous injection of [32P]DNA/Man-PLL, the
radioactivity in plasma fell rapidly and was recovered mainly in the liver
nonparenchymal cells. The amount in the liver reached more than 80% of the dose.
Radioactivity observed in kidney, lung, and spleen was very low compared to that
in the liver. Then, the in vivo gene expression after intravenous injection of
DNA/Man-PLL was examined by a CAT assay. Highest CAT activity was detected in the
liver, but no activity was detected in the lung, kidney, and spleen. These
results clearly indicate that a cell-specific gene delivery system can be
developed by regulating the biodistribution of DNA/carrier complex through the
control of its physicochemical properties.
PMID- 10761644
TI - Tissue distribution and persistence in mice of plasmid DNA encapsulated in a PLGA
based microsphere delivery vehicle.
AB - Information regarding the distribution and persistence of DNA encapsulated in
poly-(lactide co-glycolide) microspheres was collected to provide additional
information regarding the safety of DNA vaccines and to support the clinical
testing of this new delivery system for DNA. Plasmid DNA was encapsulated in
poly(lactide co-glycolide) microspheres and the distribution and persistence of
plasmid in murine tissues resulting from parenteral administration were examined
by a sensitive PCR assay. Encapsulated DNA delivered by intramuscular or
subcutaneous injection can be detected for 100 days post-injection and is
distributed primarily at the site of injection and the lymphoid organs.
Intravenous administration results in more widespread dissemination with long
term persistence limited to the lymphoid organs and those of the
reticuloendothelial system. Specific cellular uptake of DNA by professional
antigen presenting cells (APCs) following injection suggests the utility of
microspheres as DNA delivery agents. Distribution and persistence studies support
the safety of encapsulated DNA and the specific cellular uptake of DNA by
professional APCs following injection suggests the utility of microspheres as DNA
delivery agents.
PMID- 10761645
TI - Effects of physicochemical characteristics of poly(2-(dimethylamino)ethyl
methacrylate)-based polyplexes on cellular association and internalization.
AB - The cationic polymer poly(2-(dimethylamino)ethyl methacrylate) (p(DMAEMA)) is
able to efficiently bind and condense DNA and to mediate transfection of a
variety of cell types. In this study, fluorescence activated cell sorting (FACS),
confocal laser fluorescence microscopy (CSLM) and electron microscopy (EM)
techniques were used to investigate in vitro the cellular interaction of
p(DMAEMA)-based polyplexes with human ovarian carcinoma cells (OVCAR-3). Cellular
association and subsequent internalization only occurred when the polyplexes
exhibited a positive zeta potential. Small-sized polyplexes have an advantage
over large-sized complexes regarding cellular entry. The effect of the presence
of tertiary amine groups versus the presence of quatenary amine groups was
evaluated by comparing p(DMAEMA) with its quaternary ammonium analogue poly(2
(trimethylamino)ethyl methacrylate) (p(TMAEMA)). The combined cellular
interaction and transfection results suggest that the latter polymer does not
have an intrinsic endosomal escape property, in contrast to the 'proton sponge'
effect proposed for p(DMAEMA). PEGylation of p(DMAEMA) effectively shielded the
surface charge and yielded a notably lower degree of cellular interaction. Data
on the effects of the presence of endocytosis inhibitors and an endosome
disruptive peptide in the culture medium on the cellular interaction and
transfection activity of p(DMAEMA)-based polyplexes support endocytosis as being
the principal pathway for intracellular delivery of plasmid. Both the CLSM and EM
studies did not reveal the presence of polyplexes or plasmid outside the
endocytic vesicles or within the nucleus, suggesting that intracellular
trafficking from the endosomes to the nucleus is a very inefficient process.
PMID- 10761646
TI - Extradural neural axis compartment.
AB - The lengthy, continuous, slender extradural neural axis compartment (EDNAC),
which extends from the coccyx to the orbit, has been not so much discovered as
recognized. Through this compartment run arteries, myelinated and unmyelinated
nerves, and valveless veins. Adipose tissue is abundant in the orbital and spinal
segments, possibly due to movement requirements, although it is very sparse in
the skull base segment, the last segment to be recognized as a continuation of
the EDNAC, which connects Breschet's veins to the orbit. The lateral sellar
compartment (in older terminology, the cavernous sinus) is an enlarged segment of
this EDNAC along the skull base connecting the orbit with the extradural space
through the superior orbital fissure and down the dorsum to Breschet's veins of
the basilar process of the occipital bone. Understanding the continuity of the
EDNAC should help the student understand any segment, particularly the skull
base. As Batson noted, "Living anatomy is slowly editing and replacing the
anatomy of the dead room."
PMID- 10761647
TI - Correspondence between functional magnetic resonance imaging somatotopy and
individual brain anatomy of the central region: comparison with intraoperative
stimulation in patients with brain tumors.
AB - OBJECT: The goal of this study was to determine the somatotopical structure
function relationships of the primary motor cortex in individual patients by
using functional magnetic resonance (fMR) imaging. This was done to assess
whether there is a displacement of functional areas compared with anatomical
landmarks in patients harboring brain tumors close to the central region, and to
validate these findings with intraoperative cortical stimulation. METHODS: One
hundred twenty hemispheres in 60 patients were studied by obtaining blood oxygen
level-dependent fMR images in patients while they performed movements of the
foot, hand, and face on both sides. There was a good correspondence between
anatomical landmarks in the deep portion of the central sulcus on axial slices
and the somatotopical organization of primary motor areas. Pixels activated
during hand movements were centered on a small characteristic digitation; those
activated during movements in the face and foot areas were located in the lower
portion of the central sulcus (lateral to the hand area) and around the
termination of the central sulcus, respectively. In diseased hemispheres, signal
intensity changes were still observed in the projection of the expected
anatomical area. The fMR imaging data mapped intraoperative electrical
stimulation in 92% of positive sites. CONCLUSIONS: There was a high
correspondence between the somatotopical anatomy and function in the central
sulcus, which was similar in normal and diseased hemispheres. The fMR imaging and
electrical stimulation data were highly concordant. These findings may enable the
neurosurgeon to locate primary motor areas more easily during surgery.
PMID- 10761648
TI - In vivo assessment of the window of barrier opening after osmotic blood-brain
barrier disruption in humans.
AB - OBJECT: Osmotic blood-brain barrier (BBB) disruption induced by intraarterial
infusion of mannitol is used in conjunction with chemotherapy to treat human
brain tumors. The time course to barrier closure, or the so-called therapeutic
window, has been examined in animals but little information is available in
humans. The authors, therefore assessed the time course to barrier closure after
osmotic BBB disruption in humans. METHODS: Disruption of the BBB was demonstrated
using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography
(SPECT) scanning in 12 patients who were treated monthly with combination
chemotherapy in conjunction with BBB disruption. The primary diagnosis was
primary central nervous system lymphoma in seven patients and primitive
neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480
minute intervals after osmotic BBB disruption, and patients underwent SPECT
scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent
BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was
seen in the other nine studies. The TcGH indices correlated with the degree of
BBB disruption as measured postprocedure on contrast-enhanced CT scans (r =
0.852). Mean baseline TcGH indices were 1.02+/-0.07. For the group of patients
with good-to-excellent disruptions the mean indices at 1 minute postdisruption
measured 2.19+/-0.18. After 40 minutes no significant change was noted (mean
index 2.13+/-0.2). Then the indices declined more steeply and at 120 minutes
after the disruption the index was 1.36+/-0.02. A very slow decline was noted
between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier
was still open for all good-to-excellent disruptions (index 1.33+/-0.08) but at
480 minutes the mean indices had returned to the baseline level. CONCLUSIONS:
Results of these in vivo human studies indicate that the time course to closure
of the disrupted BBB for low-molecular-weight complexes is longer than previously
estimated. The barrier is widely open during the first 40 minutes after osmotic
BBB disruption and returns to baseline levels only after 6 to 8 hours following
the induction of good or excellent disruption. These findings have important
clinical implications for the design of therapeutic protocols.
PMID- 10761649
TI - Is cerebral perfusion pressure a major determinant of cerebral blood flow during
head elevation in comatose patients with severe intracranial lesions?
AB - OBJECT: Head elevation as a treatment for lower intracranial pressure (ICP) in
patients with intracranial hypertension has been challenged in recent years.
Therefore, the authors studied the effect of head position on cerebral
hemodynamics in patients with severe head injury. METHODS: The effect of 0
degrees, 15 degrees, 30 degrees, and 45 degrees head elevation on ICP, cerebral
blood flow (CBF), systemic arterial (PsaMonro) and jugular bulb (Pj) pressures
calibrated to the level of the foramen of Monro, cerebral perfusion pressure
(CPP), and the arteriovenous pressure gradient (PsaMonro - Pj) was studied in 37
patients who were comatose due to severe intracranial lesions. The CBF decreased
gradually with head elevation from 0 to 45 degrees, from 46.3+/-4.8 to 28.7+/-2.3
ml x min(-1) x 100 g(-1) (mean +/- standard error, p<0.01), and the PsaMonro - Pj
from 80+/-3 to 73+/-3 mm Hg (p< 0.01). The CPP remained stable between 0 degrees
and 30 degrees of head elevation, at 62+/-3 mm Hg, and decreased from 62+/-3 to
57+/-4 mm Hg between 30 degrees and 45 degrees (p<0.05). A simulation showed that
the 38% decrease in CBF between 0 degrees and 45 degrees resulted from PsaMonro -
Pj changes for 19% of the decrease, from a diversion of the venous drainage from
the internal jugular veins to vertebral venous plexus for 15%, and from CPP
changes for 4%. CONCLUSIONS: During head elevation the arteriovenous pressure
gradient is the major determinant of CBF. The influence of CPP on CBF decreases
from 0 to 45 degrees of head elevation.
PMID- 10761650
TI - Bilateral subthalamic stimulation for Parkinson's disease by using three
dimensional stereotactic magnetic resonance imaging and electrophysiological
guidance.
AB - OBJECT: Several methods are used for stereotactically guided implantation of
electrodes into the subthalamic nucleus (STN) for continuous high-frequency
stimulation in the treatment of Parkinson's disease (PD). The authors present a
stereotactic magnetic resonance (MR) method relying on three-dimensional (3D) T1
weighted images for surgical planning and multiplanar T2-weighted images for
direct visualization of the STN, coupled with electrophysiological recording and
stimulation guidance. METHODS: Twelve patients with advanced PD were enrolled in
this study of bilateral STN implantation. Both STNs were visible as 3D ovoid
biconvex hypointense structures located in the upper mesencephalon. The
coordinates of the centers of the STNs were determined with reference to the
patient's anterior commissure-posterior commissure line by using a new landmark,
the anterior border of the red nucleus. Electrophysiological monitoring through
five parallel tracks was performed simultaneously to define the functional target
accurately. Microelectrode recording identified high-frequency, spontaneous,
movement-related activity and tremor-related cells within the STNs. Acute STN
macrostimulation improved contralateral rigidity and akinesia, suppressed tremor
when present, and could induce dyskinesias. The central track, which was directed
at the predetermined target by using MR imaging, was selected for implantation of
19 of 24 electrodes. No surgical complications were noted. CONCLUSIONS: At
evaluation 6 months after surgery, continuous STN stimulation was shown to have
improved parkinsonian motor disability by 64% and 78% in the "off' and "on"
medication states, respectively. Antiparkinsonian drug treatment was reduced by
70% in 10 patients and withdrawn in two patients. The severity of levodopa
induced dyskinesias was reduced by 83% and motor fluctuations by 88%. Continuous
high-frequency stimulation of the STN applied through electrodes implanted with
the aid of 3D MR imaging and electrophysiological guidance is a safe and
effective therapy for patients suffering from severe, advanced levodopa
responsive PD.
PMID- 10761651
TI - Tethered cord syndrome in children with anorectal malformations.
AB - OBJECT: Anorectal malformations are known to be associated with neurological
deficits, which may contribute to the disability suffered by patients with these
malformations. This study was undertaken to determine the incidence and pattern
of sacral abnormalities in children with anorectal malformations, the incidence
and nature of the neurological deficits, and the incidence and nature of operable
intraspinal abnormalities in patients with this condition. METHODS: Neurological
evaluation was performed in 81 children with anorectal malformations. Plain x-ray
films were obtained to identify the presence of sacral abnormalities. The
patients with neurological deficits were evaluated for the presence of operable
intraspinal anomalies, and when such anomalies were identified, correction of the
same was undertaken. In 21% of these children radiographic evidence of sacral
abnormalities was shown. Fifteen percent of patients harbored neurological
deficits, and 10% harbored operable intraspinal anomalies. In addition, one
patient had split notochord syndrome. Patients with operable intraspinal
anomalies underwent surgical correction, with resultant neurological improvement.
CONCLUSIONS: Bone abnormalities of the sacrum, neurological deficits, and
operable intraspinal lesions are not uncommon in children with anorectal
malformations. Because the neurological deficits can contribute to the disability
suffered by these individuals, we recommend routine screening of patients with
anorectal malformations and neurological deficits and/or sacral abnormalities for
the early identification and treatment of potentially correctable intraspinal
lesions.
PMID- 10761652
TI - Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal synostosis:
clinical spectrum, prevalence, and surgical outcome.
AB - OBJECT: A recurrent point mutation in the fibroblast growth factor receptor 3
gene that converts proline 250 into arginine has been reported recently in cases
of apparently nonsyndromic coronal craniosynostosis. The goal of the present
study was to examine the phenotype of patients in whom this mutation was present,
to determine the prevalence of the condition, and to assess the functional and
the morphological outcome of the surgically treated patients. METHODS: A DNA
analysis was performed in 103 children suffering from apparently isolated coronal
synostosis, 41 of whom had bilateral and 62 of whom had unilateral disease. There
were 31 boys and 72 girls in the study group. Sixty cases were sporadic and 43
were familial; the 43 familial cases arose in 33 unrelated families. The mutation
was found in seven (12%) of 60 sporadic cases and in 24 (73%) of the 33 families.
The functional and morphological results were assessed in all surgically treated
patients who had at least 1 year of follow up and who were at least 3 years of
age at the time of assessment. A comparison was made between patients with the
mutation and those without. CONCLUSIONS: The most typical presentation was seen
in girls and consisted of a bicoronal synostosis resulting in a severe
brachycephaly associated with mild hypertelorism and marked bulging of the
temporal fossae, which resulted in a huge enlargement of the upper part of the
face. The most frequently associated extracranial anomaly was brachydactyly,
identified either clinically or radiologically. Based on the proportion of
bilateral and unilateral coronal synostoses, the present data indicate that the
mutation is associated with more severe cases and that girls with the mutation
are more severely affected than boys. The functional and morphological results
were worse in patients in whom the mutation was present as compared with those in
whom it was not.
PMID- 10761653
TI - Neuroscience education of undergraduate medical students. Part I: role of
neurosurgeons as educators.
AB - OBJECT: Economic, demographic, and political pressures have mandated that medical
schools increase the number of primary care physicians. The goal of this study
was to determine the nature of the average medical student's exposure to
neurosurgical issues. METHODS: Surveys were sent to every neurosurgical program
director in the United States and to the dean of every medical school in North
America, querying the extent of neurosurgical involvement in medical student
education. Specifically, the respondents were asked how medical students were
educated about the management of low-back pain and radiculopathy, carotid artery
disease, head and spine trauma, and headache. Survey results were obtained from
65 (67%) of 97 neurosurgery program directors and from 57 (40%) of 143 medical
school deans. Only one program in North America reported having a required
neurosurgical rotation for all medical students, and just over 50% (29 of 57
deans and 34 of 65 program directors) reported that neurosurgery was an option in
a required neuroscience or surgical subspecialty course. Neurosurgeons were not
listed among the top three sources for medical student education in the topics of
low-back pain and radiculopathy or carotid artery disease. Neurosurgeons were the
most frequently cited source of education regarding head and spinal injuries,
despite the fact that the majority of medical schools do not have any required
medical student exposure to neurosurgery. CONCLUSIONS: With rare exceptions,
neurosurgeons are not significantly involved in the education of medical students
concerning the management of common neurosurgical issues. As a result, most
emerging primary care physicians are taught about these issues by other
specialists or not at all. The implications of this situation are discussed.
PMID- 10761654
TI - Neuroscience education of undergraduate medical students. Part II: outcome
improvement.
AB - OBJECT: Because of political and economic pressures, primary care physicians are
now charged with greater responsibility for the care of patients with disease
processes definitively managed by neurosurgeons. The goal of this study was to
establish the feasibility and efficacy of a neurosurgical curriculum designed to
teach future primary care physicians about these diseases. METHODS: A compact,
seven-lecture curriculum was developed to teach 3rd-year medical students about
degenerative spine disease, stroke, tumor- and hydrocephalus-related raised
intracranial pressure, head and spine injury, and subarachnoid hemorrhage. This
curriculum was given as part of a 6-week pilot course that included neurology,
neurosurgery, ophthalmology, and rehabilitation medicine components. This course
was administered to two groups of 18 medical students, and an examination was
administered at the end of the pilot course. The same examination was
administered to an additional 19 students immediately after their completion of
the neurology course currently required. Students enrolled in the pilot
neuroscience course performed significantly better (p<0.001) on the examination
than those who had completed the standard neurology course. Striking improvements
were noted in the recognition and management of head injury, hydrocephalus, and
radiculopathy. CONCLUSIONS: Inclusion of a short neurosurgery-related curriculum
in a combined neuroscience course significantly improved student performance on
an examination focusing on the recognition and management of common neurosurgical
disorders. Because primary care physicians are responsible for the initial
recognition and management of these disorders, the knowledge gained may lead to
improved patient care.
PMID- 10761655
TI - Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model
of transient focal ischemia.
AB - OBJECT: The use of thrombolytic agents in the treatment of stroke has yielded
surprisingly modest success, possibly because of reperfusion injury mediated by
reactive oxygen species (ROS). Therefore, scavenging ROS may be of therapeutic
value in the treatment of stroke. Nitroxides are low-weight superoxide dismutase
mimics, which allows them to act as cell-permeable antioxidants. In this study
the nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempol) is
investigated to determine its ability to reduce reperfusion injury. METHODS: Male
Sprague-Dawley rats weighing between 280 g and 350 g underwent middle cerebral
artery occlusion with an intraluminal suture for 60 minutes. Regional cerebral
blood flow, blood pressure, cerebral temperature, and rectal temperature were
monitored during the procedure. After reperfusion, the animals were randomized to
groups receiving blinded intravenous administration of either Tempol (10 mg/kg;
eight animals) or vehicle (eight animals) over the first 20 minutes of
reperfusion (Study I). In a second study to determine dose dependency, animals
were randomized to groups receiving Tempol (20 mg/kg; eight animals), low-dose
Tempol (5 mg/kg; eight animals), or vehicle (eight animals; Study II). The rats
were killed after 4 hours of reperfusion, and brain sections were stained with
2,3,5 triphenyltetrazolium chloride. Infarct volumes were measured using digital
imaging. Animals receiving Tempol had significantly reduced infarct volumes at
doses of 20 mg/kg and 10 mg/kg compared with controls (49.01+/-18.22% reduction
[p = 0.003] and 47.47+/-34.57 [p = 0.02], respectively). No significant
differences in the physiological variables measured were observed between groups.
CONCLUSIONS: Tempol provides significant neuroprotection after reperfusion in a
rat model of transient focal ischemia. These results support the importance of
ROS in reperfusion injury and encourage further study of this molecule as a
therapeutic agent following thrombolysis.
PMID- 10761656
TI - Genetic reflection of glioblastoma biopsy material in xenografts:
characterization of 11 glioblastoma xenograft lines by comparative genomic
hybridization.
AB - OBJECT: Human tumors implanted as subcutaneous xenografts in nude mice are widely
used for the study of tumor biology and therapy. Validation of these models
requires knowledge of the genetic makeup of the xenografts. The aim of this study
was to establish whether chromosomal imbalances in 11 xenograft lines derived
from human glioblastomas multiforme (x-GBMs) are similar to those found in GBM
biopsy samples. The authors also studied genetic stability during serial
passaging of three xenograft lines. METHODS: Chromosomal imbalances in x-GBMs
were detected using comparative genomic hybridization (CGH). The authors compared
the CGH results in x-GBMs with those in the original GBMs (o-GBMs) that were used
to establish three of the xenograft lines and with the GBM biopsy results
reported in the literature (1-GBMs). In three xenograft lines two different
passages were analyzed. CONCLUSIONS: The results show that the chromosomal
imbalances in x-GBMs are similar to those in o-GBMs and 1-GBMs, indicating that
the GBM xenograft lines used were valid models from a genetic point of view. The
CGH analysis of two different passages of three xenograft lines indicates that x
GBMs (like 1-GBMs) show intratumoral genetic heterogeneity and do not acquire
chromosomal imbalances as a result of serial passaging.
PMID- 10761657
TI - Promotion of survival and regeneration of nigral dopamine neurons in a rat model
of Parkinson's disease after implantation of embryonal carcinoma-derived neurons
genetically engineered to produce glial cell line-derived neurotrophic factor.
AB - OBJECT: The P19 embryonal carcinoma-derived cell line consists of
undifferentiated multipotential cells, which irreversibly differentiate into
mature neurons after exposure to retinoic acid (RA). In the present study, the
authors genetically engineered P19 cells to produce glial cell line-derived
neurotrophic factor (GDNF), and grafted the cells in a rat model that had been
rendered parkinsonian. METHODS: Undifferentiated P19 cells were grown in vitro
and transduced with GDNF complementary DNA. The level of GDNF released from the
transduced cells was measured using an enzyme-linked immunosorbent assay, and its
neurotrophic activities were assessed by testing the effects on rat embryonic
dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours
and allowed to differentiate into postmitotic neurons, the GDNF gene-transduced
cells were implanted into the midbrain of immunosuppressed rats. A unilateral
nigrostriatal lesion was then induced by intrastriatal infusions of 6
hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting
revealed that the GDNF-producing cells expressed several neuronal markers without
evidence of overgrowth. The grafts expressed GDNF protein and prevented the death
of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks
after nigrostriatal lesions restored the expression of tyrosine hydroxylase in
injured DA neurons and induced their dendritic sprouting. CONCLUSIONS: The
results indicate that the P19 cell line transduced with the GDNF gene can stably
secrete functional levels of GDNF, even after being converted to postmitotic
neurons. Because it is has been established that GDNF exerts trophic effects on
DA neurons, the means currently used to deliver GDNF into the brain could be a
viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's
disease.
PMID- 10761658
TI - Pretreatment with continuous-wave ultraviolet irradiation to prevent the
development of delayed vasospasm in the rabbit common carotid artery model.
AB - OBJECT: Ultraviolet (UV) light irradiation can lead to immunomodulation. The
purpose of this study was to determine the preventive effect of UV light on
cerebral vasospasm by using a rabbit common carotid artery (CCA) model. METHODS:
Rabbit CCAs were constricted for a long period by application of autologous blood
within a silicon sheath. Before immersion in blood, the CCAs were adventitiously
exposed to UV light emitted from a helium-cadmium laser (wavelength 325 nm)
yielding an irradiation energy of 10 mJ/mm2. The occurrence of vasospasm was
evaluated using angiography 48 hours after blood exposure in this model. The UV
light treatment significantly reduced the degree of vasospasm. Compared with
luminal diameters measured on Day 0, prior to treatment, the luminal diameters of
UV light-treated arteries (six animals) decreased by only 6%, whereas that of the
sham-treated arteries (eight animals) significantly decreased by 26% (p<0.001).
Histological examination of UV light-treated CCAs revealed no endothelial damage
and extended smooth-muscle cells, in which some fragmented nuclei were confirmed
by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick
end labeling. Twenty-eight days after blood exposure, examination of UV light
treated CCAs revealed only myointimal proliferation, similar to that of the sham
treated CCAs. CONCLUSIONS: These results are the first to provide evidence of a
prophylactic effect of UV light on vasospasm and are suggestive of involvement of
apoptosis in the mechanism of this effect.
PMID- 10761659
TI - Arteries of the insula.
AB - OBJECT: The insula is located at the base of the sylvian fissure and is a
potential site for pathological processes such as tumors and vascular
malformations. Knowledge of insular anatomy and vascularization is essential to
perform accurate microsurgical procedures in this region. METHODS: Arterial
vascularization of the insula was studied in 20 human cadaver brains (40
hemispheres). The cerebral arteries were perfused with red latex to enhance their
visibility, and they were dissected with the aid of an operating microscope.
Arteries supplying the insula numbered an average of 96 (range 77-112). Their
mean diameter measured 0.23 mm (range 0.1-0.8 mm), and the origin of each artery
could be traced to the middle cerebral artery (MCA), predominantly the M2
segment. In 22 hemispheres (55%), one to six insular arteries arose from the M1
segment of the MCA and supplied the region of the limen insulae. In an additional
10 hemispheres (25%), one or two insular arteries arose from the M3 segment of
the MCA and supplied the region of either the superior or inferior periinsular
sulcus. The insular arteries primarily supply the insular cortex, extreme
capsule, and, occasionally, the claustrum and external capsule, but not the
putamen, globus pallidus, or internal capsule, which are vascularized by the
lateral lenticulostriate arteries (LLAs). However, an average of 9.9 (range four
14) insular arteries in each hemisphere, mostly in the posterior insular region,
were similar to perforating arteries and some of these supplied the corona
radiata. Larger, more prominent insular arteries (insuloopercular arteries) were
also observed (an average of 3.5 per hemisphere, range one-seven). These coursed
across the surface of the insula and then looped laterally, extending branches to
the medial surfaces of the opercula. CONCLUSIONS: Complete comprehension of the
intricate vascularization patterns associated with the insula, as well as
proficiency in insular anatomy, are prerequisites to accomplishing appropriate
surgical planning and, ultimately, to completing successful exploration and
removal of pathological lesions in this region.
PMID- 10761660
TI - Central nervous system leiomyosarcoma in patients with acquired immunodeficiency
syndrome. Report of two cases.
AB - Leiomyosarcomas (LMSs) of the central nervous system are extremely rare; however,
they are becoming more prevalent in immunocompromised patients. The authors
present the cases of two patients with acquired immunodeficiency syndrome: one
with LMS of the thoracic vertebral body and the other with LMS originating from
the region of the cavernous sinus. The epidemiological and histological
characteristics of LMS and its association with latent Epstein-Barr virus are
discussed, as well as the treatments for this neoplasm.
PMID- 10761661
TI - Bilateral median nerve compression at the level of Struthers' ligament. Case
report.
AB - Struthers' ligament syndrome is a rare cause of median nerve entrapment.
Bilateral compression of the median nerve is even more rare. It presents with
pain, sensory disturbance, and/or motor function loss at the median nerve's
dermatomal area. The authors present the case of a 21-year-old woman with
bilateral median nerve compression caused by Struthers' ligament. She underwent
surgical decompression of the nerve on both sides. To the authors' knowledge,
this case is the first reported bilateral compression of the median nerve caused
by Struthers' ligament. The presentation and symptomatology of Struthers'
ligament syndrome must be differentiated from median nerve compression arising
from other causes.
PMID- 10761662
TI - A giant intracranial mucocele associated with an orbitoethmoidal osteoma. Case
report.
AB - The authors present a rare case of a giant intracranial mucocele associated with
an orbitoethmoidal osteoma in a patient suffering from a generalized convulsive
disorder. The broad pedicle of the osteoma had penetrated the cribriform plate
and extended intracranially to form a nodular mass in the olfactory groove. The
intracranial portion of the osteoma was surrounded by a mucocele. Both the cyst
wall and multilayered intracystic septations of the mucocele were indented by
layers of the osteoma. Although the extracranial portion adhered to the mucosa of
the ethmoidal sinus, there were no signs of sinus obstruction. No direct
communication other than the osteoma was identified between the mucocele and the
ethmoidal mucosa. The large cerebral defect, which the mucocele occupied,
communicated directly with the lateral ventricle without any intervening
membranous structures. A frontal craniotomy is recommended for exposure of the
lesion and plastic repair of the dural defect.
PMID- 10761663
TI - Right temporal lobe glioblastoma presenting in the left orbit. Case report.
AB - Dissemination of gliomas outside the central nervous system without preceding
neurosurgery is a rare phenomenon. Glial neoplasms presenting as bone lesions are
even more rare. A case of glioblastoma multiforme (GBM) with initial presentation
in the orbit following a single generalized seizure is described. Signs of
intracranial hypertension resulted from subarachnoid tumor invasion. The patient
was treated with whole-dose radiation therapy but survived for only 6 months
following the initial presentation. An autopsy revealed a right temporal GBM with
extensive subarachnoid spread and invasion in the left orbit and skull base. The
literature on dissemination of primary tumors of the brain is reviewed.
PMID- 10761664
TI - Intraparenchymal meningioma originating from underlying meningioangiomatosis.
Case report and review of the literature.
AB - The authors present the case of a 20-year-old woman with right-sided temporal
intraparenchymal meningioma originating from underlying meningioangiomatosis. The
patient manifested temporal-type seizures as the initial symptom. She had no
stigmata of neurofibromatosis Type 2. Neuroradiological studies revealed an
intraaxial, contrast-enhancing lesion in the right temporal lobe. After gross
total removal of the tumor, histological examination revealed a transitional
meningioma with surrounding neural parenchyma and features of
meningioangiomatosis. Although there were no signs of anaplasia, necrosis, or
increased mitosis, tumor islands were observed in the adjacent neuropil. The rare
association of meningioangiomatosis and meningioma is discussed, along with
radiological and surgical findings.
PMID- 10761665
TI - Magnetic resonance appearance of multiple intracranial epidermoid cysts:
intrathecal seeding of the cysts? Case report.
AB - A 44-year-old man presented to the hospital with multiple intracranial epidermoid
cysts. The clinical manifestations of his disease included chronic headaches and
one seizurelike episode. Findings determined by magnetic resonance (MR) imaging,
surgery, and histological analysis indicated intrathecal and intraventricular
seeding of the cysts. Spontaneous (nontraumatic) seeding of multiple daughter
cysts from intracranial epidermoid cysts is still very rare and their multiple
appearances on MR imaging should be distinguished from the simple scattering of
oily contents due to cyst rupture.
PMID- 10761666
TI - Microvascular decompression for trigeminal neuralgia in Charcot-Marie-Tooth
disease.
AB - The authors report on three patients suffering from coexistent trigeminal
neuralgia (TGN) and Charcot-Marie-Tooth disease who, based on preoperative
magnetic resonance tomographic angiography findings, underwent microvascular
decompression. All patients had demonstrable neural compression and all
experienced immediate postoperative pain relief. Symptoms recurred in one patient
and required a second procedure in the form of a neurotomy. Two patients suffered
from bilateral TGN. When a patient with TGN suffers coexistent neurological
disease and experiences bilateral symptoms, preoperative imaging and subsequent
decompressive surgery may avoid the unacceptable risk of morbidity associated
with bilateral ablative procedures.
PMID- 10761667
TI - Thalamic stimulation for choreiform movement disorders in children. Report of two
cases.
AB - Surgery for movement disorders is most commonly performed in patients with
dyskinesia and tremor associated with Parkinson's disease or in those with
essential tremor. The role of ablative surgery or deep brain stimulation in
patients with choreiform movements is poorly defined. The authors placed thalamic
stimulation systems in two children with disabling choreiform disorders due to
intracerebral hemorrhage or cerebral palsy. Each patient displayed choreiform
movements in the upper extremities both at rest and with intention, which
interfered with daily activities and socialization. Both children obtained
significant improvement in their choreiform movements, and their upper extremity
function improved with no incidence of morbidity. Thalamic stimulation appears to
be a promising and nonablative approach for children with choreiform movement
disorders.
PMID- 10761668
TI - Malignant transformation of a dysembryoplastic neuroepithelial tumor. Case
report.
AB - A 29-year-old man presented in 1984 with a recent onset of partial seizures
marked by speech arrest. Electroencephalography identified a left frontotemporal
dysrhythmia. Computerized tomography (CT) scanning revealed a superficial
hypodense nonenhancing lesion in the midleft frontal convexity, with some
remodeling of the overlying skull. The patient was transferred to the London
Health Sciences Centre for subtotal resection of what was diagnosed as a
"fibrillary astrocytoma (microcystic)." He received no chemotherapy or radiation
therapy and remained well for 11 years. The patient presented again in late 1995
with progressive seizure activity. Both CT and magnetic resonance imaging
demonstrated a recurrent enhancing partly cystic lesion. A Grade IV astrocytoma
was resected, and within the malignant tumor was a superficial area reminiscent
of a dysembryoplastic neuroepithelial tumor (DNT). Data on the lesion that had
been resected in 1984 were reviewed, and in retrospect the lesion was identified
as a DNT of the complex form. It was bordered by cortical dysplasia and contained
glial nodules, in addition to the specific glioneuronal element. The glial
nodules were significant for moderate pleomorphism and rare mitotic figures. The
Ki67 labeling index averaged 0.3% in the glial nodules and up to 4% focally.
Cells were rarely Ki67 positive within the glioneuronal component. This case is
the first documented example of malignant transformation of a DNT. It serves as a
warning of the potential for malignant transformation in this entity, which has
been traditionally accepted as benign. This warning may be especially warranted
when confronted with complex forms of DNT. The completeness of resection in the
benign state is of paramount importance.
PMID- 10761670
TI - Scintigraphic pitfall: delayed radionecrosis. Case illustration.
PMID- 10761669
TI - Gamma knife radiosurgery for hypothalamic hamartomas in patients with medically
intractable epilepsy and precocious puberty. Report of two cases.
AB - Hamartoma of the hypothalamus represents a well-known but rare cause of central
precocious puberty and gelastic epilepsy. Due to the delicate site in which the
tumor is located, surgery is often unsuccessful and associated with considerable
risks. In the two cases presented, gamma knife radiosurgery was applied as a safe
and noninvasive alternative to obtain seizure control. Two patients, a 13-year
old boy and a 6-year-old girl, presented with medically intractable gelastic
epilepsy and increasing episodes of secondary generalized seizures. Abnormal
behavior and precocious puberty were also evident. Magnetic resonance (MR)
imaging revealed hypothalamic hamartomas measuring 13 and 11 mm, respectively.
After general anesthesia had been induced in the patients, radiosurgical
treatment was performed with margin doses of 12 Gy to 90% and 60% of isodose
areas, covering volumes of 700 and 500 mm3, respectively. After follow-up periods
of 54 months in the boy and 36 months in the girl, progressive decrease in both
seizure frequency and intensity was noted (Engel outcome scores IIa and IIIa,
respectively). Both patients are currently able to attend public school. Follow
up MR imaging has not revealed significant changes in the sizes of the lesions.
Gamma knife radiosurgery can be an effective and safe treatment modality for
achieving good seizure control in patients with hypothalamic hamartomas.
PMID- 10761671
TI - False-positive findings on magnetic resonance imaging mimicking vestibular
schwannoma. Case illustration.
PMID- 10761672
TI - Brain tissue oxygenation.
PMID- 10761673
TI - Undergraduate neuroscience education.
PMID- 10761674
TI - Posttraumatic stress disorder: the burden to the individual and to society.
AB - BACKGROUND: Little is known about the total population prevalence and societal
costs of posttraumatic stress disorder (PTSD); this report reviews relevant
literature on these topics. METHOD: A literature search of computerized databases
for published reports on trauma and PTSD was conducted. This literature was
reviewed to find data on general population exposure to trauma, conditional risk
of PTSD among those exposed to trauma both in focused samples of trauma victims
and in general population samples, and the adverse consequences of PTSD. RESULTS:
PTSD was found to be a commonly occurring disorder that often has a duration of
many years and is frequently associated with exposure to multiple traumas. The
impairment associated with PTSD in U.S. samples, where the majority of research
on these consequences has been carried out, is comparable to, or greater than,
that of other seriously impairing mental disorders. Risk of suicide attempts is
particularly high among people with PTSD. Available evidence suggests that the
prevalence of PTSD and the adverse emotional and psychological consequences of
PTSD are much greater in the many countries around the world that are in the
midst of armed conflicts involving political, racial, or ethnic violence.
CONCLUSION: PTSD is a highly prevalent and impairing condition. Only a minority
of people with PTSD obtain treatment. Early and aggressive outreach to treat
people with PTSD could help reduce the enormous societal costs of this disorder.
PMID- 10761675
TI - Posttraumatic stress disorder: a model of the longitudinal course and the role of
risk factors.
AB - Posttraumatic stress disorder (PTSD) differs from other anxiety disorders in that
experience of a traumatic event is necessary for the onset of the disorder. The
condition runs a longitudinal course, involving a series of transitional states,
with progressive modification occurring with time. Notably, only a small
percentage of people that experience trauma will develop PTSD. Risk factors, such
as prior trauma, prior psychiatric history, family psychiatric history,
peritraumatic dissociation, acute stress symptoms, the nature of the biological
response, and autonomic hyperarousal, need to be considered when setting up
models to predict the course of the condition. These risk factors influence
vulnerability to the onset of PTSD and its spontaneous remission. In the majority
of cases, PTSD is accompanied by another condition, such as major depression, an
anxiety disorder, or substance abuse. This comorbidity can also complicate the
course of the disorder and raises questions about the role of PTSD in other
psychiatric conditions. This article reviews what is known about the emergence of
PTSD following exposure to a traumatic event using data from clinical studies.
PMID- 10761676
TI - The psychobiology of posttraumatic stress disorder.
AB - Posttraumatic stress disorder (PTSD) develops after exposure to events that are
threatening and/or intensely distressing. Accumulating evidence suggests that
intense psychological trauma can cause long-standing alterations in the
neurobiological response to stress. These alterations translate into a number of
symptoms commonly experienced by patients with PTSD. Current treatments for this
disorder are only partially effective in managing the disease, and patients have
to endure unpleasant symptoms associated with hyperarousal. As a result, they
often withdraw from social interaction and increase the use of central nervous
system depressants. Data suggest that biological dysregulation of the
glutamatergic, amine neurotransmitter (noradrenergic and serotonergic), and
neuroendocrine pathways plays a fundamental part in the pathology of PTSD and may
cause brain structural as well as functional abnormalities. Knowledge of these
pathologic changes in PTSD provides direction for the development of new
treatments that will offer more comprehensive management of PTSD and enable
patients to enjoy a much improved quality of life. This article reviews current
knowledge regarding the psychobiology of PTSD and considers specific agents that
are emerging as key modulators of this pathological process.
PMID- 10761677
TI - Measuring outcome in posttraumatic stress disorder.
AB - This article summarizes the features of posttraumatic stress disorder (PTSD) that
may affect treatment outcome and discusses the areas in which treatment outcome
can be productively evaluated. PTSD is a complex psychiatric condition that tends
to run a chronic course. Measurement of treatment outcome in PTSD is confounded
by multiple factors, including a high prevalence of comorbid disorders,
reactivation of the syndrome by ongoing environmental stressors, spontaneous
recovery of the early disorder, and a fluctuating course of the chronic disorder.
Four principal domains of treatment outcome may be evaluated in PTSD: core
symptom severity, comorbid conditions (particularly depression), adverse
practices (e.g., violence or alcohol consumption), and social/vocational
disability. To gain an accurate assessment of these domains, a comprehensive
assessment battery is needed. The relevant instruments and their yield in studies
of PTSD are reviewed.
PMID- 10761678
TI - Psychosocial treatment of posttraumatic stress disorder.
AB - This article reviews empirically validated psychosocial treatments for
posttraumatic stress disorder (PTSD) and considers factors associated with
successful therapy outcome. Most of the treatments whose efficacy was studied
empirically fall within the broad category of cognitive-behavioral therapy. These
include exposure therapy, anxiety management programs, and cognitive therapy.
These therapy modalities have been developed to modify conditioned fear and
erroneous cognitions that are thought to underlie PTSD. Exposure therapy has the
most empirical support because it was found to be effective across different
populations of trauma victims with PTSD. Combinations of therapies have also been
used, and the value of these is discussed. In addition, this article presents
recent evidence about the efficacy of eye movement and desensitization
reprocessing. A growing body of evidence supports the use of psychosocial
treatments for PTSD, but not all patients benefit. Future research should develop
programs that increase the motivation of patients to take advantage of these
efficacious treatments.
PMID- 10761679
TI - Pharmacotherapy of posttraumatic stress disorder: treatment options, long-term
follow-up, and predictors of outcome.
AB - Posttraumatic stress disorder (PTSD) is a prevalent and disabling condition.
Treatment is essential to reduce symptoms, increase the patient's functioning and
well-being, and reduce comorbidity with other psychological disorders. Evidence
suggests that psychopharmacologic therapy can be effective in PTSD. This article
considers clinical data for various pharmacologic treatment options for PTSD; in
particular, several recent studies of selective serotonin reuptake inhibitors are
examined. The long-term effects of pharmacotherapy and issues concerning patient
management are also discussed.
PMID- 10761680
TI - Consensus statement on posttraumatic stress disorder from the International
Consensus Group on Depression and Anxiety.
AB - OBJECTIVE: To provide primary care clinicians with a better understanding of
management issues in posttraumatic stress disorder (PTSD) and guide clinical
practice with recommendations on the appropriate management strategy.
PARTICIPANTS: The 4 members of the International Consensus Group on Depression
and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves
Lecrubier, and David J. Nutt. Other faculty invited by the chair were Edna B.
Foa, Ronald C. Kessler, Alexander C. McFarlane, and Arieh Y. Shalev. EVIDENCE:
The consensus statement is based on the 6 review articles that are published in
this supplement and the scientific literature relevant to the issues reviewed in
these articles. CONSENSUS PROCESS: Group meetings were held over a 2-day period.
On day 1, the group discussed the review articles and the chair identified key
issues for further debate. On day 2, the group discussed these issues to arrive
at a consensus view. After the group meetings, the consensus statement was
drafted by the chair and approved by all attendees. CONCLUSION: PTSD is often a
chronic and recurring condition associated with an increased risk of developing
secondary comorbid disorders, such as depression. Selective serotonin reuptake
inhibitors are generally the most appropriate choice of first-line medication for
PTSD, and effective therapy should be continued for 12 months or longer. The most
appropriate psychotherapy is exposure therapy, and it should be continued for 6
months, with follow-up therapy as needed.
PMID- 10761681
TI - Histamine H3 receptors in the guinea pig ileum: evidence for a postjunctional
location.
AB - The effect of the selective histamine H3 receptor agonists (R)alpha
methylhistamine, (R)MHA and immepip (IMM) on intestinal smooth muscle
contractility was investigated on isolated cells from the longitudinal muscle of
the guinea pig ileum. (R)MHA (10(-13)-10(-8) M) and IMM (10(-13)-10(-8) M) did
not significantly modify the basal length of intestinal cells; in contrast both
agonists (10(-15)-10(-11) M) prevented the contraction produced by acetylcholine
(10(-7) M). The (S)-isomer of alpha-methylhistamine, (S)MHA, was inactive both on
basal contractility and on acetylcholine-induced contractions. The relaxant
effect of (R)MHA was not modified by famotidine (10(-7) M), but totally prevented
by the selective H3 receptor antagonist clobenpropit (10(-8) M), which per se did
not modify either basal contractility or the contractile response to
acetylcholine. These data indicate that inhibitory histamine H3 receptors are
present on smooth muscle cells of the guinea pig ileum and can be activated by
very low concentrations of selective agonists. It is not clear, however, whether
they can have a functional importance in the regulation of intestinal
contractility in an intact system.
PMID- 10761682
TI - Antisecretory and gastroprotective activities of compounds endowed with H2
antagonistic and nitric oxide (NO) donor properties.
AB - In spite of the well recognized gastric antisecretory activity, the
gastroprotective potential of histamine H2 receptor antagonists is controversial.
Most clinical studies in fact indicate that these drugs do not substantially
protect the gastric mucosa from aggressive factors. Nitric oxide (NO) has been
recently recognized as a fundamental mediator in gastric defence mechanisms, due
to its ability to increase gastric mucosal blood flow and mucus production and to
inhibit neutrophils adherence to endothelial cells. The aim of this study was to
investigate the gastroprotective and H2 receptor antagonistic activity of a
series of lamtidine analogues which contain different NO-releasing moieties
(furoxan, nitroxy and nitrosothiol). These compounds were tested, in comparison
with related H2 antagonists devoid of NO-donor structures, in different H2
receptor assays and in the conscious rat against 0.6 N HCl-induced gastric
lesions. All the compounds tested were able to antagonize histamine-mediated
responses at cardiac and gastric H2 receptors; however, furoxan and nitroxy
derivatives were 10-fold less potent than the analogues devoid of NO-donor
properties. By contrast, NO-donor compounds were more active than reference H2
antagonists as gastroprotective agents against mucosal injury induced by 0.6 N
HCl. Among the different NO-donor moieties, the furoxan group conferred to the H2
antagonist molecule the highest gastroprotective potential; this finding closely
correlates with the characteristics of NO release. In conclusions, lamtidine
analogue H2 antagonists combined with NO-donor moieties are endowed with gastric
antisecretory and protective activity and could be the prototypes of a new class
of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most
favourable among the different moieties tested.
PMID- 10761683
TI - Gastric acid secretion in streptozotocin-diabetic rats--different responses to
various secretagogues.
AB - We compared gastric acid secretion in response to various stimuli in normal and
streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the
alteration of acid secretory response in diabetic conditions. Animals were
injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood
glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted
on an ex vivo chamber, perfused with saline and acid secretion was measured at pH
7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was
stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)),
pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(
1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin
releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In
normal rats, gastric acid secretion was increased in response to either
histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In
STZ diabetic rats, however, changes in acid secretion varied depending on the
stimuli; the acid secretory responses to histamine remained unchanged, those to
YM-14673 and vagal electrical stimulation significantly decreased, but the
responses to both pentagastrin and carbachol were significantly enhanced as
compared to normal rats. Luminal release of histamine in response to both
pentagastrin and carbachol was increased in STZ-diabetic rats as compared to
normal animals. The altered acid secretory responses in STZ diabetic rats were
partially reversed by daily injection of insulin with amelioration of high blood
glucose levels. These results suggest that STZ-diabetic rats showed different
changes in gastric acid secretory responses to various stimuli; no change in
response to histamine, a decrease to both YM-14673 and vagal electrical
stimulation and an increase to both pentagastrin and carbachol. The increased
acid secretory response may be associated with an enhanced release of mucosal
histamine, while the decreased response may be due to vagal neuropathy.
PMID- 10761684
TI - Comparison of five antisecretory agents acting via gastric H+/K+-ATPase.
AB - Lansoprazole(L), pantoprazole (P), rabeprazole and RO-18-5364 (RO) are new
benzimidazole derivatives which rival omeprazole (O) as proton pump inhibitors
(PPIs) for treatment of ulcer disease. In this study, we compared the effects of
these compounds on acid secretion and determined their relative potencies in
relation to their effect on [14C]-aminopyrine (AP) accumulation in isolated
gastric glands. Inhibition of AP (1.2 microCi x mL(-1)) accumulation was measured
in rabbit isolated gastric glands. dbcAMP (1 mmol; stimulant of acid secretion)
and Ro 20-1724 (0.1 mmol; a phosphodiasterase inhibitor) were added to the
Eppendorf tubes containing the PPIs and AP and dose-response curves were done for
each drug after incubating for 5, 10 and 20 min at 37 degrees C and AP
accumulation was determined using a scintillation counter. All the PPIs
significantly (P < 0.001) inhibited acid secretion as demonstrated by the
inhibition of AP accumulation in the isolated gastric glands. Minimum inhibition
occurred at a concentration of 0.001 micromol for lansoprazole and omeprazole,
0.01 micromol for rabeprazole and RO 18-5364 and 0.02 micromol for pantoprazole.
No differences were observed between PPIs with regards to the maximum inhibition
they produce. When expressed as a percentage inhibition of control at 10-min
incubation and at concentrations of 1 micromol, L showed 85.6 +/- 0.5, O 87 +/-
0.5, P 83.2 +/- 1.1, R 86.4 +/- 1.1 and RO 87.8 +/- 1.9 inhibition respectively.
When comparing the IC50 values, their relative potencies were different. Maximum
potency was shown by L (0.007 micromol) > O (0.012 micromol) > R (0.018 micromol)
> RO (0.034 micromol) > P (0.050 micromol). All the new PPIs showed different
potencies as inhibitors of acid secretion as evident from their IC50s. Extensive
ulcer healing trials demonstrated comparable efficacy with a number of studies
indicating that symptoms relief are more rapid with P and L, while in this study
L appeared to be the most potent in inhibiting AP accumulation in the isolated
gastric glands.
PMID- 10761685
TI - Stimulatory effect of dibutyryl cyclic GMP on acid secretion in mouse isolated
stomach and on histamine release in gastric mucosal cells.
AB - We previously reported that endogenous nitric oxide (NO) is involved in the
peripheral control of gastric acid secretion induced by some secretagogues, and
that endogenous NO is involved in the acid secretion process via histamine
release from histamine-containing cells. However, the stimulus-secretion coupling
in the cells remains to be clarified. In the present study, we investigated the
effect of dibutyryl cyclic GMP on gastric acid secretion in mouse isolated
stomach and on histamine release in gastric mucosal cells, in comparison with
those of dibutyryl cyclic AMP. Dibutyryl cyclic GMP (300 microM) produced a
slight but significant increase of gastric acid secretion, which was completely
inhibited by the histamine-H2 receptor antagonist famotidine. In contrast,
dibutyryl cyclic GMP (1 mM) markedly inhibited histamine-induced acid secretion.
Dibutyryl cyclic AMP (100 microM) produced a sustained increase of gastric acid
secretion. The pretreatment with famotidine partially inhibited dibutyryl cyclic
AMP-induced gastric acid secretion. Dibutyryl cyclic GMP and dibutyryl cyclic AMP
significantly increased the histamine release from gastric mucosal cells. These
results suggest that both intracellular cyclic GMP and cyclic AMP act as second
messengers for histamine release in the histamine-containing cells, probably ECL
cells. On the other hand, in gastric parietal cells, cyclic AMP has a stimulatory
effect on gastric acid secretion, whereas cyclic GMP has an inhibitory effect.
PMID- 10761686
TI - Diverse effects of phytohaemagglutinin on gastrointestinal secretions in rats.
AB - Kidney bean lectin phytohaemagglutinin (PHA) is known for its binding capacity to
the small intestinal surface inducing marked hyperplasia and hypertrophy and an
increased pancreatic function. Recent observations indicate that PHA is able to
attach to gastric mucosal and parietal cells. Therefore, we compared the effects
of PHA on gastric acid secretion, and pancreatic amylase secretion in rats. To
study gastric secretion in conscious animals, rats were surgically prepared with
chronic stainless steel gastric cannula and with indwelling polyethylene jugular
vein catheter. Acid secretion was determined by titration of the collected
gastric juice to pH 7.0. Similar studies were performed to investigate the effect
of PHA on pancreatic enzyme secretion in conscious rats supplied with pancreatic
cannula. Pancreatic enzyme secretion was also studied in rats anesthetized with
either halothane or urethane. In conscious rats PHA significantly inhibited basal
acid secretion when compared to vehicle-treated controls. The effect was dose
dependent and reversible. On the other hand, given in the same doses as in the
acid-secretory studies, PHA stimulated pancreatic amylase secretion in rats
prepared with chronic pancreatic cannula. This effect was blocked by devazepide,
a CCK-A receptor antagonist. In halothane-anesthetized rats PHA administration
increased pancreatic amylase secretion, too. During urethane anesthesia, however,
the stimulatory effect of PHA was not observed. These results provide evidence
that intragastric PHA treatment induces opposite effects on gastric acid
secretion and pancreatic enzyme secretion: it is a potent inhibitor of acid
output, and a stimulator of pancreatic enzyme discharge. Our data also show that
the stimulatory effect of PHA on pancreatic enzyme secretion can be blocked by
urethane, an anaesthetic that is known to turn off the negative pancreatic
feedback control of pancreatic function in rats.
PMID- 10761687
TI - Antisecretory effects of galanin and its putative antagonists M15, M35 and C7 in
the rat stomach.
AB - The neuropeptide galanin has been reported to have a wide range of biological
actions both in the central nervous system and in the gastrointestinal tract.
Recent works led to the discovery of selective galanin receptor antagonists
including M15 (galanin(1-12)-Pro-substanceP(5-11)-amide), M35 (galanin(1-12)-Pro
bradykinin(2-9)-amide) and C7 (galanin(1-12)-Pro-spantide-amide). These
antagonists were shown to competitively inhibit actions of galanin in the central
nervous system. The present study was designed to investigate the effect of
galanin, M15, M35 and C7 on gastric acid secretion and gastric emptying.
Pentagastrin-stimulated gastric acid secretion was inhibited by galanin (0.1-9
nmol x kg(-1) x h(-1), i.v.) in a dose-dependent manner (ID50 = 1.8 +/- 0.3 nmol
x kg(-1) x h(-1)). When 9 nmol x kg(-1) x h(-1) galanin infusion was given,
inhibition became almost complete. M15, M35 and C7 (1-9 nmol x kg(-1) x h(-1))
did not modify responses of the stomach to galanin, but acted as agonists of
galanin on acid secretion. Neither galanin nor its putative antagonists affected
the emptying of non-caloric liquids from the stomach. In conclusion, galanin may
play an antisecretory role in the regulation of gastric acid secretion but not in
the control of gastric emptying of liquids in rats. Its antisecretory action on
the stomach is mediated by galanin receptors that are distinct from those in the
central nervous system.
PMID- 10761688
TI - The pathogenesis of L-arginine-induced acute necrotizing pancreatitis:
inflammatory mediators and endogenous cholecystokinin.
AB - This study was aimed at an assessment of the role of oxygen-derived free
radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L
arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of
malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide
dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor
necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and CCK, and evaluated
the protective effect of the xanthine oxidase inhibitor allopurinol and a novel
CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar
rats by injecting 2x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h
interval, as a 20% solution in 0.15 M NaCl. Control rats received the same
quantity of glycine. 200 mg x kg(-1) allopurinol 30 min before the first Arg
treatment or 50 mg x kg(-1) KSG-504 30 min before and 6, 18 and 36 h after the
first Arg injection was administered subcutaneously. Rats were killed at 6, 12,
24 and 48 h following Arg administration, and acute pancreatitis was confirmed by
a serum amylase level elevation and typical inflammatory features observed
microscopically. The serum level of amylase reached the peak level at 24 h after
the Arg injection (30,800 +/- 3,813 versus 6,382 +/- 184 U x L(-1) in the
control) and normalized at 48 h. The tissue concentration of MDA was
significantly elevated at 24 h, and reached the peak value at 48 h (5.00 +/- 1.75
versus 0.28 +/- 0.05 nM x mg(-1) protein in the control). The catalase and Mn-SOD
activities were significantly decreased throughout the study, while the GPx
activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was
significantly lower at 12 h after the Arg injection as compared with the
controls. Both the TNF-alpha and the IL-6 levels were already elevated
significantly at 12 h and peak at 24 h versus the controls (19.1 +/- 7.9 U x mL(
1) and 57.6 +/- 11.2 pg x mL(-1) versus 3.1 +/- 0.8 U x mL(-1) and 15.2 +/- 3.1
pg x mL(-1), respectively). No significant changes in plasma CCK levels were
observed. Allopurinol treatment markedly reduced the serum amylase elevation
(12.631 +/- 2.257 U x L(-1) at 24 h), prevented the increase in tissue MDA
concentration (0.55 +/- 0.09 nM x mg(-1) protein at 48 h) and significantly
ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg
administration. KSG-504 administration did not exert any beneficial effect on the
development of histopathological changes neither modified the serum amylase or
cytokine levels. Oxygen-derived free radicals and cytokines are involved, while
endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced
acute pancreatitis.
PMID- 10761689
TI - Recovery of exocrine pancreas six months following pancreatitis induction with L
arginine in streptozotocin-diabetic rats.
AB - The aim of the present work was to investigate the laboratory and morphologic
alterations in the pancreas 6 months after pancreatitis induction with L-arginine
(Arg) in normal and streptozotocin (STZ)-diabetic rats. The amylase content of
the pancreas was significantly decreased in the Arg-treated groups vs. the
control group. No significant changes were observed in the DNA, soluble protein
and lipase contents of the pancreas. In the STZ-treated groups, the serum glucose
level was significantly elevated, whereas the serum immunoreactive insulin (IRI)
level was significantly decreased vs. the control group. In these treated groups,
the amylase content of the pancreas was also significantly decreased, but that of
trypsinogen was significantly elevated vs. the control group. Histologic sections
revealed periductal fibroses, adipose tissue and tubular complexes in the Arg
treated rats, but centroacinar hyperplasia was not observed in these groups. No
alterations were observed on histological examination in the diabetic rats vs.
normal rats 6 months following pancreatitis induction. In conclusion, a major
restitution of the pancreatic enzyme content, but moderate histologic alterations
were detected 6 months following pancreatitis induction with Arg. The diabetic
state appeared to shift the normal pancreatic enzyme content (decreased amylase
and increased trypsinogen) in this long-term study, but not to modify the
recovery of the exocrine pancreas 6 months following Arg-induced pancreatitis.
PMID- 10761690
TI - Inhibitory effect of a long-acting somatostatin analogue on EGF-stimulated cell
proliferation in Capan-2 cells.
AB - Numerous studies have reported diverse effects of gut-derived regulatory peptides
on growth of the normal pancreas, pancreatic neoplasms induced experimentally in
animals, and pancreatic cancer cell lines, but the results of these
investigations are rather controversial. The stimulatory effect of epidermal
growth factor (EGF) on cell proliferation of pancreatic cell lines is well
established. Whether this action can be modulated by somatostatin is not clear.
Furthermore, it is not certain whether another regulatory peptide,
cholecystokinin (CCK), affects the proliferation of these cells. In the present
study we investigated the presence of CCK-A and CCK-B, as well as somatostatin-2
(SSTR2) receptors by RT-PCR, and studied the actions of EGF, CCK and octreotide
on DNA synthesis in the human pancreatic adenocarcinoma cell line Capan-2.
Octreotide, a long-acting somatostatin analogue was used as somatostatin agonist.
Cells were cultured in RPMI-1640 medium. They were incubated in serum free medium
containing 0.2% BSA in the absence (control) or the presence of the peptides.
[3H]-thymidine incorporation into DNA was measured after 48 h of incubation. By
means of RT-PCR analysis we were able to demonstrate SSTR2 expression, but not
CCK-A or CCK-B receptor mRNA in Capan-2 cells. DNA synthesis evaluated by [3H]
thymidine incorporation was found to be increased by 45.2 +/- 5.6% in response to
EGF (10(-8) M) and decreased by 11.7 +/- 2.6% to octreotide (10(-8) M) compared
to controls (P < 0.01). The increase in [3H]-thymidine incorporation was
significantly lower when EGF treatment was combined with octreotide
administration (10.1 +/- 2.5% over control). In the concentration range of 10(
11)-10(-8) M, CCK did not alter significantly the incorporation of [3H]-thymidine
into DNA in Capan-2 cells. In conclusion, these data support a role for EGF as a
growth factor for the human pancreatic cancer cell Capan-2. Somatostatin may play
an important role in regulating cell proliferation in Capan-2 cells both under
basal, and growth factor-stimulated conditions. Our results suggest, however,
that CCK receptors are not expressed, and CCK does not affect cell proliferation
in this transformed pancreatic cell line.
PMID- 10761691
TI - Vasopressin deficiency decreases the frequency of gastroduodenal ulceration in
humans.
AB - Vasopressin is a stress hormone released from the posterior pituitary. In humans
suffering from central diabetes insipidus, this release of vasopressin is
diminished. It was shown previously that the congenitally vasopressin-deficient
Brattleboro homozygous rat is less sensitive to various ulcerogenic stimuli. In
this study, we investigated the incidence of gastroduodenal ulceration in
vasopressin deficient patients. Data on patients aged 20-70, hospitalized in
Hungary between 1992 and 1995 were compared with those on the total population in
this age group (6,681,020 in 1994). Subjects with central diabetes insipidus were
selected separately (815 cases). Gastroduodenal ulceration was compared in
subjects with an intact vasopressin release and vasopressin-deficient patients.
The frequencies of gastroduodenal ulceration were also examined separately in
male and female subjects. In the total population, the frequency of
gastroduodenal ulceration was lower in vasopressin-deficient cases (2.22% versus
0.61%; P < 0.005). Among normal-vasopressin subjects, males have a higher risk of
gastroduodenal ulceration than females (3.04% versus 1.46%, respectively; P <
0.001). Among vasopressin-deficient subjects, a similar male:female ratio was
observed, but it was not significant (P = 0.36). In comparison to the normal
vasopressin population, the incidence of gastroduodenal ulceration was reduced
among vasopressin-deficient males and females by 77% (P < 0.01) and by 82% (P <
0.05), respectively. In conclusion, endogenous vasopressin has a significant
harmful action towards the human gastroduodenal mucosa. Peptide and non-peptide
vasopressin receptor antagonists might have a potential therapeutic benefit in
the treatment (as an adjuvant) and prevention of gastroduodenal ulceration.
PMID- 10761692
TI - Evidence for the involvement of oxygen free radicals in the ethanol-induced late
cellular injury in mouse myeloma cells.
AB - In this study, we analysed the ethanol-induced long term cell injury on a general
cell model (Sp2/0-Ag14 cell line). Cells were incubated in 1, 5, 10, 15 and 20%
of ethanol (EtOH) for 5 min. After washing cell viability was tested by the
Trypan Blue exclusion test in 5, 60 min, 4 and 24 h after EtOH exposure. Free
radicals were monitored every 30 min by electron spin resonance (ESR) with alpha
phenyl-N-tert-butylnitrone (PBN) spin trapping technique. Scavenger compounds
such as glutathione (GSH), dimethyl sulfoxide (DMSO) and 5,5-dimethyl-1-pyrroline
N-oxide (DMPO) were applied for 24 h incubation after EtOH exposure. EtOH
concentration dependently decreased the cell viability immediately after 5 min
exposure, but with 4 and 24 h, a secondary cell destruction was found. Using ESR
spin trapping technique, an increased free radical activity could be detected.
DMPO, DMSO and GSH significantly, but in different period protected the cells
against free-radical induced cellular damage. EtOH produces an early (immediately
after EtOH exposure) and a late (in about 4 h) cellular damage on Sp2/0-Ag14
cells. The oxygen free radicals can be detected in a short time after EtOH
exposure, its biological effect manifested as a secondary cell destruction at 4
and 24 h. This phenomenon can be prevented by scavenger compounds.
PMID- 10761693
TI - Gastrin and pentagastrin enhance the tumour proliferation of human stable
cultured gastric adenocarcinoma cells.
AB - The effect of gastrin on stimulating tumour proliferation has been evaluated on
human pancreas cancer cells in culture and in tumours transplanted to nude mice.
The presence of CCK-B/gastrin-like receptor responsible for that effect of
gastrin has been proved in colonic (WiDr, HT-29, YAMC) and pancreatic (PANC-1,
BON) cell lines. The aim of our study was to examine the stimulating effect of
gastrin and pentagastrin on the growth of human gastric adenocarcinoma cell line.
The human gastric adenocarcinoma cell line (AGS, CRL-1739) was purchased from
ATCC (Rockville, MA, USA). Gastrin-17 was purchased from Sigma-Aldrich (Budapest,
Hungary), pentagastrin was from Zeneca Limited (Macclasfield, UK). The cells were
incubated in DMEM containing 10% FCS on 96-well culturing plate with 10(4)
cells/well starting cell number at 37 degrees C with 5% CO2. The proliferation
rates were detected: by the measurements of the metabolically active cells with
Owen's reagent and the determination of protein content, and by cell counting in
a haemocytometer at several incubation times. As a result, we detected similar
proliferation rates using gastrin-17 or pentagastrin in the incubation medium.
The stimulating effect of gastrin/pentagastrin on cell line proliferation was in
correlation with its concentration. Our results proved that pentagastrin is a 10
times less effective stimulator of proliferation of gastric cancer than gastrin
17, and that AGS human adenocarcinoma cell line might be CCK receptor positive.
PMID- 10761694
TI - Integrins: regulators of embryogenesis.
AB - Integrins are heterodimeric transmembrane glycoproteins involved in cell-cell and
cell-extracellular matrix adhesion. They also participate in cytoskeletal
rearrangements, co-regulation of growth factor activities and activation of
signal transductions. This review describes experimental approaches that have
given new insights into the integrin functions during embryogenesis. Using anti
functional antibodies, peptide inhibitors of integrin-ligand interactions and
genetic ablation of integrins results, this review will show that integrins are
key molecules during early development of both invertebrates and vertebrates.
PMID- 10761695
TI - Identification, cloning and characterization of a novel nuclear protein, HA95,
homologous to A-kinase anchoring protein 95.
AB - Previously, we have identified and characterized nuclear AKAP95 from man which
targets cyclic AMP (cAMP)-dependent protein kinase (PKA)-type II to the condensed
chromatin/spindle region at mitosis. Here we report the cloning of a novel
nuclear protein with an apparent molecular mass of 95 kDa that is similar to
AKAP95 and is designated HA95 (homologous to AKAP95). HA95 cDNA sequence encodes
a protein of 646 amino acids that shows 61% homology to the deduced amino acid
sequence of AKAP95. The HA95 gene is located on chromosome 19p13.1 immediately
upstream of the AKAP95 gene. Both HA95 and AKAP95 genes contain 14 exons encoding
similar regions of the respective proteins, indicating a previous gene
duplication event as the origin of the two tandem genes. Despite their apparent
similarity, HA95 does not bind RII in vitro. HA95 contains a putative nuclear
localization signal in its N-terminal domain. It is localized exclusively into
the nucleus as demonstrated in cells transfected with HA95 fused to either green
fluorescence protein or the c-myc epitope. In the nucleus, the HA95 protein is
found as complexes directly associated with each other or indirectly associated
via other nuclear proteins. In interphase, HA95 is co-localized with AKAP95, but
the two proteins are not biochemically associated. At metaphase, both proteins co
localize with condensed chromosomes. The similarity in sequence and localization
of HA95 and AKAP95 suggests that the two molecules constitute a novel family of
nuclear proteins that may exhibit related functions.
PMID- 10761696
TI - Biochemical and ultrastructural changes in Herpetomonas roitmani related to the
energy metabolism.
AB - Herpetomonas roitmani, a non-pathogenic trypanosomatid was grown in chemically
defined media either containing proline or glucose as carbon source. Using
transmission electron microscopy we observed that cells grown in the presence of
proline present more lipid inclusions, and a larger mitochondrion with more
cristae and higher activity of succinate cytochrome c reductase. On the other
hand, cells grown with glucose as carbon source had more glycosomes, which were
preferentially located close to the bacterium endosymbiont, and a much higher
activity of hexokinase, a typical glycosome marker. Three-dimensional
reconstruction and morphometrical analysis confirm these observations. The number
of promastigotes of H. roitmani increased in the presence of proline. Taken
together these results indicate that the growth conditions markedly influenced
the ultrastructure and the metabolism of H. roitmani.
PMID- 10761697
TI - Nuclear localisation of wild type and mutant galectin-3 in transfected cells.
AB - Galectin-3, a member of a family of carbohydrate-binding proteins, is present
generally in the cytoplasm of cells. However, galectin 3 can also be located in
nuclei under certain conditions although it lacks any known nuclear localisation
signal and the mechanism by which the protein is sequestered in nuclei is
unknown. Here we describe that Cos-7 cells or rabbit smooth muscle Rb-1 cells
transfected with cDNA encoding hamster galectin-3 sequester the protein in nuclei
whereas untransfected BHK cells expressing the endogenous hamster lectin or
transfected BHK cells over-expressing the protein, do not. Confocal
immunofluorescence microscopy of Cos-7 cells or rabbit smooth muscle Rb-1 cells
transfected with cDNAs encoding mutants of hamster galectin-3 containing N
terminal or internal deletions shows that nuclear localisation does not require
the first 103 amino acid residues of the protein. Further deletion of residues
104-110 dramatically prevents sequestration in nuclei. However, the sequence
A104PTGALT110 by itself is not obligatory for nuclear localisation and can be
substituted by other unrelated sequences. A truncated galectin-3 protein, that is
blocked in nuclear expression, retains carbohydrate-binding activity, making less
likely the possibility that severe N-terminal truncations of galectin-3 induce
mis-folding leading to aggregation and cytoplasmic sequestration and an
incidental effect on nuclear trafficking. These studies indicate that nuclear
import and retention of galectin-3 is a property of the CRD domain and is
independent of N-terminal domains that others have shown to contain binding
domains for various nuclear components.
PMID- 10761698
TI - High resolution detection of rRNA and rDNA in plant nucleoli with different
activities by in situ hybridization.
AB - In the present work we perform in situ hybridization with probes to different
stretches of rDNA and electron microscopy of nucleoli with different activities,
to gain insight into the ultrastructural organization of transcription and
processing in the plant nucleolus. The main ultrastructural nucleolar components:
fibrillar centers (FC), dense fibrillar component (DFC), and granular component
(GC), are arranged in different ways depending on nucleolar activity.
Heterogeneous FCs containing RNP fibrils and nucleolar perichromatin granules are
frequently seen in nucleoli in the process of activation. DNA-RNA in situ
hybridization with biotinylated probes spanning different sequences of the rDNA
unit followed by immunogold detection of biotin, demonstrated the localization of
the ribosomal transcripts in DFC, mainly in the zones around the FCs, in GC, and
in the periphery of pale FC. The internal region of the heterogeneous FCs is
labeled only in cells in the process of activation of transcription after
dormancy. The distribution of the U3 probe indicates that the processing of the
rRNA takes place in the DFC and inside the heterogeneous FCs, in which
transcription occurs. DNA-DNA hybridization demonstrates the presence of rDNA in
the compact and extended chromatin located in the interior and at the periphery
of FCs and in nucleolar associated chromatin. Our results support the view that
the plant nucleolus has a highly dynamic morphological and functional
organization composed of a bipartite domain formed by FCs surrounded by DFC,
which is associated with rRNA transcription and processing, and the GC
representing a store of preribosomal particles.
PMID- 10761699
TI - New evidence that Lacandonia granules are ultrastructurally related to
perichromatin and Balbiani ring granules.
AB - Lacandonia granules are abundant non-typical extranucleolar ribonucleoprotein
particles found in the nucleus of Lacandonia schismatica, a rare plant showing
spatial inversion of sex organs. In the present study, changes in the number of
Lacandonia granules during flower development, and the presence of SR proteins
and poly(A)+ RNA in the nuclei of L. schismatica were analyzed by electron
microscopy, immunoelectron microscopy and ultrastructural in situ hybridization.
Our results show an important reduction in the number of Lacandonia granules in
the nuclei of cells of opened (post-anthesis) in relation to unopened (pre
anthesis) flowers, where granules are very abundant. The SR family of splicing
factors and poly(A)+ RNA are present in both perichromatin fibers and Lacandonia
granules. The developmental behavior, the presence of SR proteins, recently
involved in post-splicing events, poly(A)+ RNA and the reported absence of snRNPs
splicing factors in Lacandonia granules, suggest that these particles are
involved in postranscriptional events as storage and/or transport of mRNAs. A
similar situation is present in other nuclear RNP as perichromatin granules
present in mammals and Balbiani ring granules of salivary glands of Chironomus.
Based on similarities in morphological, developmental behavior,
immunocytochemistry and in situ hybridization results, we conclude that
Lacandonia, perichromatin and Balbiani ring granules may be also functionally
similar structures.
PMID- 10761700
TI - Renal carcinogenicity of concurrently administered fish meal and sodium nitrite
in F344 rats.
AB - The effects of long-term concurrent administration of powdered fish meal and
sodium nitrite were examined in F344 rats. A total of 600, 6-week-old rats were
divided into 6 male and 6 female groups, each consisting of 50 animals. Rats in
groups 1-3 and 7-9 were respectively fed diets supplemented with 64%, 32% and 8%
(basal diet) fish meal, and simultaneously given 0.12% sodium nitrite in their
drinking water. Groups 4-6 and 10-12 were respectively given 64%, 32% and 8% fish
meal and tap water. At the 104th week, all surviving animals were killed and
examined histopathologically. Treatment with fish meal dose-dependently increased
the incidences and multiplicities of atypical tubules, adenomas and renal cell
carcinomas in sodium nitrite-treated males. Females were less susceptible than
males for renal tumor induction. In males given the 64% fish meal diet alone, the
incidence and multiplicity of atypical tubules were also significantly increased
as compared with the 8% fish meal alone case. Nephropathy was apparent in fish
meal-treated groups in a clear dose-dependent manner, irrespective of the sodium
nitrite treatment, and was more prominent in males than in females.
Dimethylnitrosamine was found in the stomach contents after 4-week treatment with
64% fish meal plus 0.12% sodium nitrite, at a level twice that in the 8% fish
meal plus 0.12% sodium nitrite group. The results clearly indicate that
concurrent administration of fish meal and sodium nitrite induces renal
epithelial tumors. Further studies are required to elucidate how nephropathy and
nitrosamines produced in stomach contents may contribute to the observed renal
tumor induction.
PMID- 10761701
TI - Suppression of N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis by
dietary feeding of 1'-acetoxychavicol acetate.
AB - The modifying effects of 1'-acetoxychavicol acetate (ACA) on N
nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis were
investigated in male F344 rats. At 5 weeks of age, all test animals, except those
given the test chemical alone, and the control rats received s.c. injections of
NMBA (0.5 mg/kg body weight/injection, three times per week) for 5 weeks. At the
termination of the study (20 weeks), 75% of rats treated with NMBA alone had
esophageal neoplasms (papillomas). However, the groups given a dose of 500 ppm
ACA during the initiation phase developed a significantly reduced incidence of
tumors (29%; P<0.01). Exposure to ACA (500 ppm) during the post-initiation phase
also decreased the frequency of the tumors (38%; P<0.05). A reduction of the
incidence of preneoplastic lesions (hyperplasia or dysplasia) was obtained when
ACA was administered in the initiation phase (P<0.01). Cell proliferation in the
esophageal epithelium, determined by assay of proliferating cell nuclear antigen
(PCNA), was lowered by ACA (P<0.05). Blood polyamine contents in rats given NMBA
and the test compound were also smaller than those of rats given the carcinogen
(P<0.05). These findings suggest that dietary ACA is effective in inhibiting the
development of esophageal tumors by NMBA when given during the initiation or post
initiation phase, and such inhibition is related to suppression of cell
proliferation in the esophageal epithelium.
PMID- 10761702
TI - Molecular cytogenetic analysis of 17 renal cancer cell lines: increased copy
number at 5q31-33 in cell lines from nonpapillary carcinomas.
AB - Comparative genomic hybridization (CGH) was used to screen for genomic imbalances
in cell lines derived from 13 nonpapillary renal-cell carcinomas (RCCs), two
papillary RCCs, one renal squamous-cell carcinoma, and one transitional-cell
carcinoma of the renal pelvis. Aberrations were found in all 17 lines. The most
frequent changes in nonpapillary RCC cell lines were gains of 5q (85%), 7q (69%),
8q (69%) and 1q (54%) and losses of 3p (92%), 8p (77%), 4q (62%) and 14q (54%).
High-level gains (HLGs) were detected at 4q12, 5p, 5q23-33, 7q22-qter, 8q23-24,
10q21-qter, 12p and 12q13-22. By means of fluorescence in situ hybridization
(FISH) we narrowed the smallest common region involving 5q gains to the genomic
segment between D5S642 and D5S673, and found that the HLG at 4q12 possibly
involved amplifications of c-kit and PDGFRA. Two papillary RCC cell lines showed
gains of entire chromosomes 7, 12 and 17. The CGH data reported here should help
to facilitate the choice of individual renal-tumor cell lines for exploring
target genes in regions of interest.
PMID- 10761703
TI - p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M
arrest by the isoflavone genistein in human prostate carcinoma cells.
AB - Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein
tyrosine kinase and DNA topoisomerase II activities. Genistein has been shown to
have anticancer proliferation, differentiation and chemopreventive effects. In
the present study, we have addressed the mechanism of action by which genistein
suppressed the proliferation of p53-null human prostate carcinoma cells.
Genistein significantly inhibited the cell growth, which effect was reversible,
and induced dendrite-like structure. The inhibitory effects of genistein on cell
growth proliferation were associated with a G2/M arrest in cell cycle progression
concomitant with a marked inhibition of cyclin B1 and an induction of Cdk
inhibitor p21 (WAF1/CIP1) in a p53-independent manner. Following genistein
treatment of cells, an increased binding of p21 with Cdk2 and Cdc2 paralleled a
significant decrease in Cdc2 and Cdk2 kinase activity with no change in Cdk2 and
Cdc2 expression. Genistein also induced the activation of a p21 promoter reporter
construct, utilizing a sequence distinct from the p53-binding site. Analysis of
deletion constructs of the p21 promoter indicated that the response to genistein
could be localized to the 300 base pairs proximal to the transcription start
site. These data suggest that genistein may exert a strong anticarcinogenic
effect, and that this effect possibly involves an induction of p21, which
inhibits the threshold kinase activities of Cdks and associated cyclins, leading
to a G2/M arrest in the cell cycle progression.
PMID- 10761704
TI - Adenovirus-mediated transfer of p53-related genes induces apoptosis of human
cancer cells.
AB - Two p53-related genes, p73 and p51, were recently identified as structural
homologues of the p53 tumor suppressor gene, suggesting that the roles of these
two genes may be similar to those of p53, including growth suppression and
induction of apoptosis. Here we show that introduction of p73 or p51 cDNAs into
cultured human cancer cells suppressed colony formation in the presence of G418.
We then examined the ability of various isoforms of p73 and p51 to activate
transcription of a reporter gene. This assay showed that p73beta and p51A
activated transcription through a consensus p53 binding sequence, while p73alpha
and p51B isoforms minimally transactivated the p53 reporter gene. To characterize
further the biological functions of the p53-related genes, we constructed
recombinant adenoviruses containing the p73 and p51 cDNAs. Ad-p73beta and Ad-p51A
induced endogenous p21 gene expression more effectively than Ad-p73alpha and Ad
p51B, respectively. To evaluate the mode of cell death induced by p53-related
genes, Ad-p73 and Ad-p51 were used to infect human cancer cells. Infection of Ad
p73beta, Ad-p51A or Ad-p51B resulted in DNA fragmentation in a subset of cancer
cell lines more efficiently than did infection of Ad-p53. We then examined the
combined effect of each p53-related gene and the E1A oncogene in the induction of
apoptosis. The E1A oncogene cooperated with p51 as well as p53 to induce
apoptosis, while p73 resulted in a weak induction of apoptosis by E1A. Overall,
apoptosis induction by p51B and p73alpha isoforms may be due to mechanisms other
than transcriptional activation of p53-target genes. Our results suggest that p53
related genes are both similar to and different from p53 in their pathways
leading to growth suppression.
PMID- 10761705
TI - p53 status in multiple human urothelial cancers: assessment for clonality by the
yeast p53 functional assay in combination with p53 immunohistochemistry.
AB - Multifocal synchronous or metachronous tumor development is a common observation
in human urothelial cancer cases. However, the underlying mechanism has remained
obscure. We have employed a new tool to investigate the p53 gene status, the
yeast p53 functional assay, in combination with immunohistochemistry in a total
of 50 tumor samples from 32 cases with urothelial cancers, including 8 with
multiple synchronous tumor development and 2 demonstrating metachronous tumors.
p53 mutations were found in 13 cases (9 with missense mutations, 3 with deletion,
1 with splicing mutation) by the yeast p53 functional assay. p53 protein
overexpression was seen in all 9 cases with missense mutations, but in only one
of the 4 cases with nonsense mutations. Two tumors without p53 mutation also
showed positive p53 immunoreactivity. Overall, p53 abnormalities including
mutations and/or protein overexpression were found in 15 (47%) cases. p53
abnormalities were significantly more frequent in non-papillary and in high grade
tumors. Loss of the wild type allele in addition to a p53 mutation was suggested
in 8 of the 15 (53%) cases. All 4 cases with mutations in multiple synchronous
tumors had identical p53 mutations in the separate urothelial cancers, strongly
suggestive of monoclonality. The one case with multiple metachronous tumors, in
contrast, was characterized by variation in the p53 status, indicative of
different clonal origins. In conclusion, combined assessment for p53 status as
used here (yeast p53 functional assay plus immunohistochemistry) may provide
insights into the molecular mechanisms of urothelial carcinogenesis.
PMID- 10761706
TI - Mutations in zinc-binding domains of p53 as a prognostic marker of esophageal
cancer patients.
AB - Some investigators have suggested that mutations of the p53 gene may be molecular
markers for poor prognosis of cancer patients, although others have reported
conflicting results. We examined esophageal cancers from 138 patients to
investigate whether mutational status of p53 could be correlated either with
prognosis or with response to chemotherapy or radiation. We detected p53
mutations in the tumors of 78 (56.5%) patients. Kaplan-Meier analysis showed that
these 78 patients tended to have shorter survival times and greater resistance to
either form of therapy than patients whose tumors carried two wild-type p53
alleles. The difference became more evident when we focused on mutations in zinc
binding domains of p53 (L2 and L3); the prognosis was significantly poorer among
the 29 patients with tumors in this category than among patients whose tumors had
no p53 mutations, or p53 mutations outside L2 or L3 (P=0.0060). Moreover, those
tumors as a group were more resistant to chemotherapy or radiation than the
others (P=0.0105). Our results underscore the importance of the zinc-binding
domains of p53 with respect to clinical prognosis for patients with esophageal
carcinomas.
PMID- 10761707
TI - L-myc restriction fragment length polymorphism in Japanese patients with
esophageal cancer.
AB - L-myc polymorphism is a representative genetic trait related to an individual's
susceptibility to several cancers. However, there have been no reports concerning
the association between esophageal cancer and L-myc polymorphism. To analyze the
distribution of polymorphism in Japanese patients with esophageal cancer, a
molecular genotyping method using a polymerase chain reaction-based restriction
fragment length polymorphism (PCR-RFLP) was used. Based on an analysis of 65
Japanese patients with esophageal cancer and 107 healthy control subjects, a
significant difference was observed in either the distribution of genotypes
(P=0.012) or of allele frequencies between the two groups (P=0.004). The relative
risk of esophageal cancer for genotypes including the shorter allele was 2.9
compared to the longer allele homozygote. Furthermore, the patients with S-allele
had a tendency for poor prognosis among those with three genotypes. A significant
difference between the distribution of genotypes and the incidence of lymph node
metastasis was found based on the clinicopathological features of the cancers.
These results suggest that L-myc polymorphism may be implicated as a genetic
trait affecting an individual's susceptibility to esophageal cancer, at least
among Japanese patients.
PMID- 10761708
TI - Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan:
an extended study of 77 families.
AB - We have previously reported on the analysis of germ-line mutations in Japanese
von Hippel-Lindau disease (VHL) patients and found mutations in 26 families. We
have now extended these studies to include an additional 41 VHL families. Germ
line mutation of the VHL gene was screened by DNA-SSCP, direct sequencing, and
Southern blot analysis. To summarize all of the data we have studied in this and
our previous report, germ-line mutations have been detected in 55 of 77 (73%)
(type 1: 41/62 (66%) and type 2: 14/15 (93%)) families. We found similarities in
the nature of germ-line mutations including mutational incidence, location, and
DNA substitution patterns between Japanese and Western VHL. These similarities
may reflect the predominance of endogenous mutational processes. We also found
several interesting characteristics in Japanese VHL. Twenty of 41 (49%)
intragenic mutations were unique and not reported in the Western VHL. Four
mutations (Arg113Stop, Gln132Stop, Leu158Val, and Cys162Tyr) previously
characterized as type 1 mutations were identified in the type 2 (with
pheochromocytoma) Japanese families. Genotype-phenotype correlation study
suggested non-missense mutations predicted to result in the loss of VHL function
were associated with the occurrence of renal cell carcinoma, as in sporadic
tumors. Our data add to the diversity of VHL germ-line mutations and provide a
better understanding of VHL disease in terms of both clinical management and
molecular pathogenesis.
PMID- 10761709
TI - Interrelationships between cellular nucleotide excision repair, cisplatin
cytotoxicity, HER-2/neu gene expression, and epidermal growth factor receptor
level in non-small cell lung cancer cells.
AB - Nucleotide excision repair (NER) is a major repair mechanism for DNA lesions
induced by cisplatin. Overexpressions of epidermal growth factor receptor (EGFR)
and HER-2/neu have been reported to affect the sensitivity of certain human
cancer cells to cisplatin, presumably by modification of DNA repair activity
through interference with NER. Using an in vitro repair assay, we investigated
NER activity of cisplatin-induced DNA lesions in a panel of 16 non-small cell
lung cancer (NSCLC) cell lines. The interrelationships between NER activity,
cisplatin sensitivity, HER-2/neu expression and EGFR level, were also analyzed.
The results showed that high NER activity was closely correlated with cisplatin
resistance and high levels of HER-2/neu expression (P<0.05). Analysis of the
relationships between EGFR level and each of the other three parameters revealed
no statistically significant correlations (all P values were >0.05 by Spearman
rank correlation), but a trend of association (all the values of proportion of
accordance were > or =62.5% by using a 2x2 contingency table). These results
suggest that NER activity may play an important role in the cisplatin resistance
of NSCLC cells and there may be an association between enhanced NER activity and
high levels of p185neu and probably EGFR in NSCLC cells. The finding that high
levels of EGFR showed very little influence on the relationship between p185neu
and cisplatin resistance suggests that EGFR may be a less crucial factor in
modulating the chemoresistance of NSCLC cells when compared with HER-2/neu.
PMID- 10761710
TI - Transforming growth factor-alpha induces the differentiation of sarcomatoid
cholangiocarcinoma cells.
AB - A sarcomatoid cholangiocarcinoma cell line, ETK-1, was established from a
patient. Phenotypically, the cells corresponded to immature biliary epithelial
cells. Because a small number of ETK-1 cells appeared to differentiate
spontaneously along a biliary epithelial lineage in continuous culture, we
examined the factors that initiate and/or promote the differentiation of the
cells. Transforming growth factor-alpha (TGFalpha) induced significant changes in
ETK-1 cells. After stimulation with the factor, ETK-1 cells displayed morphologic
transformation at a much higher frequency, with the appearance of many large
cells with intracytoplasmic vacuoles, and the production of mucinous substances.
These morphologically transformed cells were phenotypically similar to well
differentiated adenocarcinoma cells. The expression pattern of integrins after
TGFalpha treatment also supported the maturation of the ETK-1 cells. The antibody
against the receptor of TGFalpha inhibited these changes by TGFalpha. Moreover,
the proliferation rate of ETK-1 cells was suppressed by TGFalpha. Our data
suggest that TGFalpha can act as a differentiation factor along a biliary
epithelial lineage.
PMID- 10761711
TI - Molecular identification of a human carcinoma-associated glycoprotein antigen
recognized by mouse monoclonal antibody FU-MK-1.
AB - Mouse monoclonal antibody FU-MK-1, raised against a human gastric adenocarcinoma,
recognizes an antigen (termed MK-1 antigen) present on the majority of
carcinomas. The present study aimed to identify the MK-1 molecule and to
establish its relationship to other carcinoma antigens. Immunoprecipitation
studies of human tumor cell lines revealed that FU-MK-1 recognizes a monomeric
membrane glycoprotein with two forms, 40 kDa (major form) and 42 kDa (minor
form), and with a molecular mass of 35 kDa following treatment with the N
glycosylation inhibitor tunicamycin. The partial amino acid sequence of a main
fragment of the MK-1 molecule obtained by spontaneous cleavage under hypotonic
conditions was examined, and the 17 contiguous NH2-terminal amino acids were
found to be identical with residues 81-97 of the 314-residue GA733-2 protein
[Szala et al.; Proc. Natl. Acad. Sci. USA, 87, 3542-3546 (1990)]. Hence, the
GA733-2 cDNA was cloned and the specificity of FU-MK-1 was confirmed using four
recombinant forms of the GA733-2 antigen expressed in COS-1 cells.
Immunoprecipitation with FU-MK-1 of the cell lysate transfected with the full
length GA733-2 cDNA revealed two bands corresponding to those obtained from the
tumor cell lines. FU-MK-1 also precipitated three other recombinant proteins
consisting of amino acids 1-265, 1-201, and 1-139 of the GA733-2 protein,
respectively. Furthermore, immunoblotting analysis indicated that FU-MK-1 binds
to a small fragment (6 kDa) generated from a tumor cell line under hypotonic
conditions, suggesting that the FU-MK-1 epitope exists on the distal 6-kDa
peptide of the extracellular domain of the GA733-2 molecule. We thus conclude
that the MK-1 antigen is the GA733-2 antigen, which is currently being used as a
target in clinical trials with monoclonal antibodies.
PMID- 10761712
TI - Mouse homologue of the human SART3 gene encoding tumor-rejection antigen.
AB - We recently isolated a human SART3 (hSART3) gene encoding a tumor-rejection
antigen recognized by HLA-A2402-restricted cytotoxic T lymphocytes (CTLs). The
hSART3 was also found to exist as an RNA-binding nuclear protein of unknown
biological function. In this study, we cloned and analyzed the homologous mouse
SART3 (mSART3) gene in order to understand better the function of hSART3, and to
aid in establishing animal models of specific immunotherapy. The cloned 3586-bp
cDNA encoded a 962-amino acid polypeptide with high homology to hSART3 (80% or
86% identity at the nucleotide or protein level, respectively). Nonapeptides
recognized by the HLA-A2402-restricted CTLs and all of the RNA-binding motifs
were conserved between hSART3 and mSART3. The mSART3 mRNA was ubiquitously
expressed in normal tissues, with low level expression in the liver, heart, and
skeletal muscle. It was widely expressed in various organs from as early as day 7
of gestation. mSART3 was mapped to chromosome 5, a syntenic region for human
chromosome 12q23-24, and its genomic DNA extended over 28-kb and consisted of 19
exons. This information should be important for studies of the biological
functions of the SART3 protein and for the establishment of animal models of
specific cancer immunotherapy.
PMID- 10761713
TI - The novel anticancer drug KRN5500 interacts with, but is hardly transported by,
human P-glycoprotein.
AB - The interaction of the novel anticancer drug KRN5500, a spicamycin derivative,
with human P-glycoprotein (P-gp) was analyzed from the viewpoint of cellular
pharmacokinetics, i.e. by means of [3H]azidopine photoaffinity labeling, cellular
accumulation and transcellular transport experiments. In this study, P-gp
overexpressing LLC-GA5-COL150 cells, porcine kidney epithelial LLC-PK1 cells
transformed with human MDR1 cDNA, were used, since this cell line constructs
monolayers with tight junctions, and would provide sufficient information for
analyzing the cellular pharmacokinetics. 3-(4,5-Dimethylthiazol-2-yl)-2,5
diphenyltetrazolium bromide (MTT) assay revealed that the growth-inhibitory
effect of KRN5500 in LLC-GA5-COL150 cells was comparable to that in LLC-PK1 cells
(IC50 = 79.4 and 72.7 nM, respectively), but the inhibition of [3H]azidopine
binding by KRN5500 was concentration-dependent in the membrane fraction of LLC
GA5-COL150 cells. The cellular accumulation of [14C]KRN5500 after its basal
application in LLC-GA5-COL150 cells was slightly lower than that in LLC-PK1
cells, and was restored by the multidrug resistance (MDR) modulator SDZ PSC 833.
The basal-to-apical transport of [14C]KRN5500 in LLC-GA5-COL150 cells was also
slightly higher than that in LLC-PK1 cells, and was inhibited by SDZ PSC 833.
However, the basal-to-apical transport of [14C]KRN5500 in LLC-GA5-COL150 cells
was only a little higher than the apical-to-basal transport. Consequently, these
results demonstrated that KRN5500 interacted with, but was hardly transported
via, P-gp. These observations suggested that KRN5500 may be useful even for the
treatment of tumors exhibiting P-gp-mediated MDR.
PMID- 10761714
TI - Sonodynamically induced antitumor effect of 4-formyloximethylidene-3-hydroxy-2
vinyl-deuterio-porphynyl(IX)-6,7-dia spartic acid (ATX-S10).
AB - The sonodynamically induced antitumor effect of 4-formyloximethylidene-3-hydroxy
2-vinyl-deuterio-porphyn yl(IX)-6,7-diaspartic acid (ATX-S10) was investigated.
Both in vitro and in vivo antitumor effects were tested in combination with
ultrasound at 2 MHz. The rate of ultrasonically induced damage to isolated
sarcoma 180 cells in air-saturated suspension was enhanced two-fold with 80
microM ATX-S10. This enhancement was significantly inhibited by histidine, which
may suggest that it was mediated by ultrasonically induced oxidation. The
coadministraion of 25 mg/kg ATX-S10 followed by ultrasonic exposure at 2 MHz
stopped the growth of implanted colon 26 tumors at an intensity at which
ultrasound alone showed only a slight antitumor effect.
PMID- 10761715
TI - Tumor-selective blood flow decrease induced by an angiotensin converting enzyme
inhibitor, temocapril hydrochloride.
AB - To enhance chemotherapeutic efficacy against cancer, it is important to deliver
anticancer drugs preferentially to cancer cells and to retain the drugs there for
a prolonged time. The in vivo prolongation of the exposure time of anticancer
drugs in tumors can be accomplished by decreasing tumor tissue blood flow (tBF)
after anticancer drug administration. The present study demonstrated that
temocapril hydrochloride, an angiotensin converting enzyme inhibitor, decreases
tumor tBF markedly in LY80 tumor, a subline of Yoshida sarcoma in the rat,
without affecting the blood flow in liver, kidney, bone marrow, and brain. In
tumor areas with flow of above 20 ml/min/100 g, the tBF decreased by
approximately 50% due to temocapril. In tumor areas with tBF of about 20
ml/min/100 g, it became less than 3 ml/min/100 g with temocapril and did not
recover during the 2 h experiment. These findings were obtained not only in large
tumors, but also in microfoci growing within a transparent chamber. Furthermore,
even when temocapril was administered under the condition of increased tumor tBF
by administering angiotensin II, tumor tBF decreased immediately. Using this
technique, it should be possible to trap anticancer drugs selectively in tumor
tissue for an extended period of time.
PMID- 10761716
TI - Comparison of the prevalence of IgG antibodies to hepatitis E virus and hepatitis
A virus in members of households in the Mekong delta region of Vietnam.
PMID- 10761717
TI - Chloroquine enhances viral replication and murine disease.
PMID- 10761718
TI - National progress in dengue vector control in Vietnam: survey for Mesocyclops
(Copepoda), Micronecta (Corixidae), and fish as biological control agents.
AB - This paper describes the process of expanding a successful dengue control program
in 3 provinces in northern Vietnam into a national one and demonstrates the
presence of a rich, low-cost resource that could have similar applicability to
other countries in the region. The cornerstone of the preventive strategy is
larval control of Aedes aegypti (L.), the major vector, using predators such as
copepods, Mesocyclops spp., aided by the corixid bug Micronecta quadristrigata
Bredd, and fish in large water storage containers. From 1989 to 1998, 9 species
of Mesocyclops (M. woutersi Van de Velde, M. aspericornis (Daday), M. ruttneri
Kiefer, M. thermocyclopoides Harada, M. affinis Van de Velde, M. ogunnus
Onabamiro, M. yenae Holynska, M. cf. pehpeiensis Hu, and M. dissimilis Defaye and
Kawabata) were found in natural and artificial habitats in 26 provinces
throughout Vietnam. The predatory capacities of 6 of these were evaluated in the
laboratory. This indicated that daily consumption/killing averaged between 16 and
41 Ae. aegypti larvae per copepod. From detailed evaluations in 9 provinces,
Mesocyclops spp. were surprisingly common in 8,413 artificial containers
(concrete tanks, wells, ornamental ponds and in the south, large jars). Because
of existing practices for washing and water transfer from ponds and lakes in Ha
Tay and Ha Bac, Mesocyclops spp. already occurred in 60-100% of the water storage
containers. When the relationship between the presence or absence of Mesocyclops
and Aedes larvae in 5,111 containers was analyzed by the chi-square test, their
distributions were significantly related, indicating control (odds ratio = 0.56).
When 3,426 containers that did not contain Mesocyclops or fish were analyzed in
relation to the distribution of Aedes larvae, those with Micronecta also had
significantly less Aedes (odds ratio = 0.43). Therefore, this study demonstrates
that there is an abundance of local Mesocyclops spp. in Vietnam that can be
incorporated into specifically designed community-based control programs aided by
Micronecta and fish.
PMID- 10761719
TI - Transmission thresholds for dengue in terms of Aedes aegypti pupae per person
with discussion of their utility in source reduction efforts.
AB - The expense and ineffectiveness of drift-based insecticide aerosols to control
dengue epidemics has led to suppression strategies based on eliminating larval
breeding sites. With the notable but short-lived exceptions of Cuba and
Singapore, these source reduction efforts have met with little documented
success; failure has chiefly been attributed to inadequate participation of the
communities involved. The present work attempts to estimate transmission
thresholds for dengue based on an easily-derived statistic, the standing crop of
Aedes aegypti pupae per person in the environment. We have developed these
thresholds for use in the assessment of risk of transmission and to provide
targets for the actual degree of suppression required to prevent or eliminate
transmission in source reduction programs. The notion of thresholds is based on 2
concepts: the mass action principal-the course of an epidemic is dependent on the
rate of contact between susceptible hosts and infectious vectors, and threshold
theory-the introduction of a few infectious individuals into a community of
susceptible individuals will not give rise to an outbreak unless the density of
vectors exceeds a certain critical level. We use validated transmission models to
estimate thresholds as a function of levels of pre-existing antibody levels in
human populations, ambient air temperatures, and size and frequency of viral
introduction. Threshold levels were estimated to range between about 0.5 and 1.5
Ae. aegypti pupae per person for ambient air temperatures of 28 degrees C and
initial seroprevalences ranging between 0% to 67%. Surprisingly, the size of the
viral introduction used in these studies, ranging between 1 and 12 infectious
individuals per year, was not seen to significantly influence the magnitude of
the threshold. From a control perspective, these results are not particularly
encouraging. The ratio of Ae. aegypti pupae to human density has been observed in
limited field studies to range between 0.3 and >60 in 25 sites in dengue-endemic
or dengue-susceptible areas in the Caribbean, Central America, and Southeast
Asia. If, for purposes of illustration, we assume an initial seroprevalence of
33%, the degree of suppression required to essentially eliminate the possibility
of summertime transmission in Puerto Rico, Honduras, and Bangkok, Thailand was
estimated to range between 10% and 83%; however in Mexico and Trinidad,
reductions of >90% would be required. A clearer picture of the actual magnitude
of the reductions required to eliminate the threat of transmission is provided by
the ratio of the observed standing crop of Ae. aegypti pupae per person and the
threshold. For example, in a site in Mayaguez, Puerto Rico, the ratio of observed
and threshold was 1.7, meaning roughly that about 7 of every 17 breeding
containers would have to be eliminated. For Reynosa, Mexico, with a ratio of
approximately 10, 9 of every 10 containers would have to be eliminated. For sites
in Trinidad with ratios averaging approximately 25, the elimination of 24 of
every 25 would be required. With the exceptions of Cuba and Singapore, no
published reports of sustained source reduction efforts have achieved anything
near these levels of reductions in breeding containers. Practical advice on the
use of thresholds is provided for operational control projects.
PMID- 10761720
TI - Quantitative assessment of eosinophiluria in Schistosoma haematobium infections:
a new marker of infection and bladder morbidity.
AB - Eosinophiluria, as quantified by measuring eosinophil cationic protein (ECP) in
urinary extracts, microhematuria, egg excretion, and ultrasound-detectable
bladder pathology were recorded in Schistosoma haematobium-infected Tanzanian
school children at a baseline survey and during an 18-month post-treatment follow
up study. Significant correlations were seen between urinary ECP levels,
intensity of infection, and bladder pathology. Treatment resulted in a marked
reduction in prevalence and intensity of infection, in a delayed and less marked
reduction in ECP levels, and in a resolution of pathology. The overall diagnostic
efficiency of the ECP test (cut-off value for the ECP > or =5 ng/ml) in relation
to infection was comparable with that of egg count and microhematuria, but with a
better sensitivity than a single egg count. In relation to bladder pathology, the
diagnostic performance of the ECP test (cut-off value for the ECP > or =25 ng/ml)
exceeded that of a single egg count. In addition, the ECP was better in
discriminating between different grades of bladder pathology. The present study
points to the ECP as a useful marker of both S. haematobium infection and of
associated bladder morbidity reflecting the inflammatory status of the bladder
wall.
PMID- 10761721
TI - Comparative pathology, and immunohistology associated with clinical illness after
Ehrlichia phagocytophila-group infections.
AB - The Ehrlichia phagocytophila-group also includes E. equi and the human
granulocytic ehrlichiosis (HGE) agent that are probably a single species. Disease
is mild to severe illness in ruminants, horses, and humans, but the comparative
pathology and ehrlichial distribution in tissues is poorly described. We compared
pathology and ehrlichial distribution in humans with HGE, horses with E. equi
infection, and a sheep with E. phagocytophila infection. Frequent findings
included splenic lymphoid depletion, small macrophage aggregates and apoptoses in
liver, and paracortical hyperplasia in lymph nodes. Bone marrow was normocellular
or hypercellular. Only the spleen was frequently infected; other organs with
infected cells included lung, liver, heart, and kidney, but lesions were present
in lung and liver only. Most infected cells were neutrophils. Ehrlichia
phagocytophila-group infections are associated with moderate tissue damage. While
the pathogenesis of granulocytic ehrlichiosis is not clear, pathologic studies
suggest that the process is initiated by ehrlichia-infected cells but may result
from host-mediated injury and immunosuppression.
PMID- 10761722
TI - Cytoadherence characteristics of Plasmodium falciparum isolates in Thailand using
an in vitro human lung endothelial cells model.
AB - Using an in vitro model of human lung endothelial cells, we studied different
characteristics of Plasmodium falciparum isolates as potential factors for
malaria severity in 2 Thai patient groups: 27 with complicated malaria and 42
with uncomplicated malaria. In regard to binding properties, no association
existed between cytoadherence and rosette phenotypes (P = 0.1) and
hypothrombocytemia increased the cytoadherence level (P = 0.007). Cytoadherence
was significantly associated with malaria severity (P = 0.05) in contrast to
rosette formation (P = 0.9). Intercellular adhesion molecule-1 and chondroitin-4
sulfate were major receptors of cytoadherence in those with complicated malaria
compared with those with uncomplicated malaria (P < 10(-4)). Chondroitin-4
sulfate could act as a putative receptor for malaria complications in non
pregnant women. CD36 was the main receptor in patients with uncomplicated malaria
(P < 10(-3)). Vascular cell adhesion molecule-1 and E-selectin played a minor
role in 2 groups (P = 0.6). Qinghaosu derivatives were more efficient than other
antimalarial drugs, but a positive correlation was observed between the 50%
inhibitory concentrations of halofantrine and quinine and the number of adhesive
parasitized red blood cells, suggesting their influence on cytoadherence.
PMID- 10761723
TI - Tissue responses in experimental schistosomiasis japonica in the pig: a
histopathologic study of different stages of single low- or high-dose infections.
AB - The tissue responses of pigs exposed to either 100 or 2,000 Schistosoma japonicum
cercariae were examined at 4, 11, 17, and 24 weeks postinfection (PI) to explore
the pig as an animal model for pathologic aspects of human schistosomiasis
japonica. Egg granulomas were present in the liver, intestine, and occasionally
in the lungs from 11 weeks PI. There were also many free eggs and early exudative
reactions to eggs in the intestine. At 11 weeks PI, pigs in the higher dose group
showed marked periportal and septal fibrosis with minimal parenchymal
destruction. Thereafter, lesions regressed spontaneously as the pigs underwent a
self-cure. The lower dose group showed only mild lesions throughout the study.
The degree of hepatic fibrosis was correlated with the density of eggs and
granulomas in liver tissue. The results indicate that the pig would be
particularly useful for studies of the development and resolution of schistosomal
hepatic fibrosis, and also for investigations of the mechanisms behind the self
cure phenomenon.
PMID- 10761724
TI - Susceptibility and resistance to Schistosoma mansoni reinfection: parallel
cellular and isotypic immunologic assessment.
AB - Cellular and humoral immune responses to Schistosoma mansoni antigen preparations
were evaluated in individuals presumed to be susceptible or resistant to
reinfection after chemotherapeutic cure. A consistent proliferative increase in
the response to soluble egg antigen (SEA) was observed post-treatment in both the
susceptible and resistant groups. However, this change was not related to
resistance. Isotype studies showed that IgM antibody levels to soluble worm
antigen preparation (SWAP) and cercariae antigens were significantly higher in
the resistant group than in the susceptible group. Post-treatment, an increase in
IgE anti-SWAP and anti-schistosomular tegument (STEG) responses and a decrease in
IgG4 anti-SEA and anti-STEG responses were observed in the resistant group. These
finding are similar to those we have reported previously for a putative resistant
group termed endemic normals, and are compatible with immunologic studies in
different endemic areas. Together, these findings indicate that even on the
population level, high IgE specificities coupled with low IgG4 specificities
correlate well with documented resistance to reinfection.
PMID- 10761725
TI - A case-control auditory evaluation of patients treated with artemisinin
derivatives for multidrug-resistant Plasmodium falciparum malaria.
AB - The artemisinin derivatives are now used widely in areas with multidrug-resistant
Plasmodium falciparum malaria such as Southeast Asia, but concerns remain over
their potential for neurotoxicity. Mice, rats, dogs, and monkeys treated with
high doses of intramuscular artemether or arteether develop an unusual pattern of
focal damage to brain stem nuclei (particularly those involved in auditory
processing). To investigate whether a similar toxic effect occurs in patients
treated with these compounds, clinical neurologic evaluation, audiometry and
early latency auditory evoked responses were measured in a single-blind
comparison of 79 patients who had been treated with > or =2 courses of oral
artemether or artesunate within the previous 3 years, and 79 age- and sex-matched
controls living in a malaria-endemic area on the northwestern border of Thailand.
There were no consistent differences in any of these test results between the
cases and controls. This study failed to detect any evidence of significant
neurotoxicity in patients treated previously with oral artemether or artesunate
for acute malaria.
PMID- 10761726
TI - Short report: possible Cryptosporidium muris infection in humans.
AB - Oocysts of cryptosporidia whose morphology resembled that of Cryptosporidium
muris were found in the stool of 2 healthy girls in Surabaya, Indonesia. The
oocysts were predominantly oval and measured 7.75+/-0.17 x 5.55+/-0.13 microm
(mean+/-SD). The number of oocysts excreted were more than 10(5) per gram of
stool. The oocysts were well stained with fluorescein-conjugated monoclonal
antibody to Cryptosporidium. The specimens from both girls containing the oocysts
showed a positive result by the polymerase chain reaction (PCR) using primers
specific for the genus Cryptosporidium, but a negative result by the PCR using
primers specific for C. parvum. The 2 girls passed oocysts for 5 and 6 days,
respectively. They did not complain of any symptoms during the passage of
oocysts.
PMID- 10761727
TI - Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin
combination against Toxoplasma gondii.
AB - The effect of artesunate and its metabolite dihydroartemisinin against the
cerebral cysts of Toxoplasma gondii was studied. In vitro experiments were
performed with the THP-1 cell line and showed an inhibition of parasite growth of
approximately 70% with 0.1-0.5 microg/ml of dihydroartemisinin for 96 hr.
However, with artesunate, dihydroartemisinin, or a combination (50:50) of them,
the number of tachyzoites decreased approximately 40-50% and they appeared
motionless. Fifty-eight to 72 hr after washing of the tachyzoites and THP-1 cells
in culture, parasitized cells reappeared. In vivo, the 50:50 artesunate
dihydroartemisinin combination produced a decrease in cerebral cysts of
approximately 40% after only 5 days of treatment. However, transplantations into
naive mice using brains of treated mice gave positive results.
PMID- 10761728
TI - Xanthones as antimalarial agents: stage specificity.
AB - The erythrocytic development of Plasmodium falciparum is divided into the ring,
trophozoite, and schizont stages based on morphologic assessment. Using highly
synchronous ring and trophozoite cultures of P. falciparum, we observed
considerable differences in their sensitivity to hydroxyxanthones: trophozoites
were much more sensitive to the drugs than ring-stage parasites. Trophozoites
treated with a prototypic xanthone, the 2,3,4,5,6-pentahydroxy derivative (X5),
were arrested in their development and became degenerate in appearance within 24
hr of drug exposure. These morphologic changes appeared to reflect the cytotoxic
nature of the action of the drug against the parasite, since daughter ring-stage
forms were not observed following addition of the drug. That X5 was more active
against parasites in the later stages of intraerythrocytic development is
consistent with the proposed mode of action, inhibition of heme polymerization.
Knowledge of the structure-activity relationships for xanthones as antimalarial
agents has also been expanded. Xanthones with a hydroxyl group in the peri
position exhibited decreased antimalarial activity, possibly due to
intramolecular hydrogen bonding with the carbonyl and consequent reduced affinity
for heme. Paired hydroxyls attached to the lower half of the xanthone greatly
enhanced drug potency.
PMID- 10761730
TI - Pharmacokinetics of UMF-078, a candidate antifilarial drug, in infected dogs.
AB - The pharmacokinetics of the filaricidal benzimidazole compounds UMF-078 and UMF
289 were evaluated in beagle dogs experimentally infected with Brugia pahangi.
Twenty-four infected microfilaremic beagles were selected and randomly allocated
into 4 treatment groups of 6 dogs each: oral (PO) UMF-078, PO UMF-289 (the HCl
salt form of UMF-078), intramuscular (IM) UMF-078, and untreated controls.
Equivalent doses of 50 mg/kg of the free base were given twice a day for 3 days
to the 3 groups of treated dogs. Oral absorption is rapid compared with IM
dosing; the absorption half-life (K01-HL) for the IM treatment is approximately
14 hr compared with 1 and 2 hr for the PO regimen of salt and free base forms,
respectively. The elimination half-lives (K10-HL) for the PO regimens are 13 and
15 hr for the salt and free base forms, respectively. Because of sustained
absorption following IM dosing, the K10-HL is prolonged. In contrast to oral
administration, IM dosing of UMF-078 provides sustained, relatively low plasma
drug levels, with good tolerance and efficacy.
PMID- 10761729
TI - Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro
activity of doxycycline against Senegalese isolates.
AB - The in vitro activities of doxycycline, chloroquine, quinine, amodiaquine,
artemether, pyrimethamine, and cycloguanil were evaluated against Plasmodium
falciparum isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro,
drug susceptibility test. The 71-50% inhibitory concentration (IC50) values for
doxycycline ranged from 0.7 to 108.0 microM and the geometric mean IC50 for the
71 isolates was 11.3 microM (95% confidence interval = 9.5-13.4 microM). The
activity of doxycycline did not differ significantly (P = 0.0858) between the
chloroquine-susceptible isolates and the chloroquine-resistant isolates. There
was no in vitro correlation between the responses to doxycycline and those to
artemether, chloroquine, quinine, amodiaquine, pyrimethamine, and cycloguanil,
suggesting no in vitro cross-resistance among these drugs. Potency was increased
by prolonged exposure. In 96-hr incubations, the activity of doxycycline was 4-5
fold more increased than in 48-hr incubations. The in vitro activity of
doxycycline against intraerythrocytic stages of multidrug-resistant P.
falciparum, its action against the preerythrocytic forms, the lack of correlation
between the responses in vitro of P. falciparum to doxycycline and the other
antimalarial drugs, and its original potential site of action are factors that
favor its use as antimalarial drug.
PMID- 10761731
TI - Genotypic analysis of hepatitis C virus in blood donors in Indonesia.
AB - A study was conducted to describe the genetic diversity of hepatitis C virus
(HCV) in a population of positive blood donors from throughout Indonesia. Repeat
analysis by reverse transcription-polymerase chain reaction (RT-PCR) of 102 anti
HCV positive samples showed that 67 gave HCV-specific positive signals by the PCR
for the 5'-untranslated genomic region of HCV. Further genotypic analysis on 64
HCV RNA-positive samples indicated that 57 belonged to the following individual
genotypes: 1a, 1b, 2a, 2b, and 3b. The predominant HCV genotypes in this donor
population were 1b (57.8%), 2a (17.2%), and 3b (10.9%). The core sequences of the
4 indeterminate samples when aligned with published sequences of various HCV
genotypes showed a range of homology from 16.16% to 78.67%. Comparative analysis
of genotypic representation from other anti-HCV-positive study populations,
including polytransfused pediatric and adult renal dialysis groups, is now being
carried out to determine the potential genotypic association with mechanistic HCV
spread.
PMID- 10761732
TI - SALP16, a gene induced in Ixodes scapularis salivary glands during tick feeding.
AB - Guinea pigs infested with Ixodes scapularis acquire antibody-mediated resistance
to tick bites, a phenomenon known as tick-immunity. An I. scapularis salivary
gland cDNA expression library was therefore probed with sera from tick-immune
guinea pigs to identify antigens that elicit humoral responses in the host. Sera
from sensitized guinea pigs strongly recognized 3 of 4,500 library clones in an
initial screening. The open reading frames of all 3 clones encoded a putative
16.4-kD acidic protein, designated Salp16, with an N-terminal signal sequence and
signal peptidase cleavage sites specific for secretory proteins. The salp16 mRNA
and Salp16 protein were detected in the salivary glands of engorged, but not
unfed, nymphal and adult ticks, and Salp16 was also found in the saliva of
engorged ticks. Immunization with recombinant Salp16 induced high antibody titers
in guinea pigs, but did not elicit tick-immunity. Salp16 is the first feeding
inducible gene that has been cloned from L. scapularis. Molecular
characterization of I. scapularis salivary antigens that are induced upon tick
feeding should help to facilitate our understanding of tick-host interactions.
PMID- 10761733
TI - Serologic evidence of Puumala virus infection in wild moose in northern Sweden.
AB - Puumala (PUU) virus is the causative agent of nephropathia epidemica, the
Scandinavian form of hemorrhagic fever with renal syndrome. The infection is
acquired by airborne transmission of PUU virus from its rodent reservoir, the
bank vole. Besides serologic data indicating that the virus may spread also to
heterologous rodents, there is little information on the susceptibility of wild
living animals to PUU virus. We studied the occurrence of antibodies to PUU virus
in serum samples from 427 wild-living moose, of which 260 originated from the PUU
virus-endemic northern and central parts of Sweden and 167 originated from the
southern, nonendemic part of Sweden. Samples from 5 animals showed reactivity in
an ELISA for recombinant PUU virus nucleocapsid protein, an immunofluorescent
assay, and a neutralization test. These 5 animals all originated from the PUU
virus-endemic northern part of Sweden. In conclusion, 5 of 260 moose from the
endemic region showed convincing serologic evidence of past PUU virus infection.
The seroprevalence was low, suggesting that the moose is subjected to endstage
infection rather than being part of an enzootic transmission cycle.
PMID- 10761734
TI - Detection of dengue infection in patients investigated for leptospirosis in
Barbados.
AB - The annual incidence of leptospirosis in Barbados is approximately 13 severe
cases/100,000. The peak incidence occurs in October to December of each year,
coinciding with the months of heaviest rainfall. During the second half of 1995,
an epidemic of dengue type 1 infection produced almost 1,000 laboratory-confirmed
cases. During the same period, leptospirosis mortality was twice the average,
suggesting that some cases of leptospirosis were being misdiagnosed and treated
inappropriately. Sera from patients investigated for dengue or leptospirosis were
analyzed retrospectively to determine the extent of misdiagnosis. During 1995 and
1996, 31 of 139 and 29 of 93 patients, respectively, were confirmed as having
leptospirosis. Sera from the remaining leptospirosis-negative patients were
tested for IgM antibodies to dengue virus. During 1995 and 1996, 48 of 108
patients and 21 of 64 patients, respectively, were found to have dengue. In 1997,
sera from all patients investigated for leptospirosis were also tested
prospectively for IgM antibodies to dengue: 38 of 92 leptospirosis-negative
patients (41%) were dengue IgM-positive, while 2 of 25 leptospirosis cases also
had serologic evidence suggesting acute dengue infection. A second large outbreak
of dengue caused by serotype 2 occurred in 1997. During the 1995 and 1997 dengue
epidemics in Barbados, dengue cases outnumbered leptospirosis cases investigated
in the leptospirosis diagnostic protocol. During 1997, patients investigated but
negative for dengue were also tested for anti-leptospiral IgM: 7.3% (19 of 262)
were IgM-positive. Substantial misdiagnosis of both dengue and leptospirosis can
occur and greater public awareness and clinical suspicion of the similar
presentations of these two diseases are necessary.
PMID- 10761736
TI - Different prevalences of Plasmodium vivax phenotypes VK210 and VK247 associated
with the distribution of Anopheles albimanus and Anopheles pseudopunctipennis in
Mexico.
AB - The geographic distribution of Plasmodium vivax circumsporozoite protein
phenotypes from patient blood used to infect colonized Anopheles albimanus and
An. pseudopunctipennis was investigated in southern Mexico. Parasite phenotype
types were determined in blood samples by a polymerase chain reaction and
oligoprobe hybridization or by immunofluorescent assay of sporozoites. The
proportion of infected mosquitoes and the number of oocysts per mosquito
confirmed previous in vitro observations indicating that An. albimanus is more
susceptible to VK210 and that An. pseudopunctipennis is more susceptible to
VK247. All patients living on the coast were infected with VK210 and most
patients living above 170 meters above sea level had VK247. Both phenotypes
infected patients from intermediate altitudes. These results concur with the
distribution of the anophelines, indicating that An. albimanus is the main vector
of the phenotype VK210, but that An. pseudopunctipennis transmits both
phenotypes. These conditions have direct implications on parasite transmission
rates and malaria epidemiology in Mexico.
PMID- 10761735
TI - Malaria, intestinal parasites, and schistosomiasis among Barawan Somali refugees
resettling to the United States: a strategy to reduce morbidity and decrease the
risk of imported infections.
AB - In 1997, enhanced health assessments were performed for 390 (10%) of
approximately 4,000 Barawan refugees resettling to the United States. Of the
refugees who received enhanced assessments, 26 (7%) had malaria parasitemia and
128 (38%) had intestinal parasites, while only 2 (2%) had Schistosoma haematobium
eggs in the urine. Mass therapy for malaria (a single oral dose of 25 mg/kg of
sulfadoxine-pyrimethamine) was given to all Barawan refugees 1-2 days before
resettlement. Refugees >2 years of age and nonpregnant women received a single
oral dose of 600 mg albendazole for intestinal parasite therapy. If mass therapy
had not been provided, upon arrival in the United States an estimated 280 (7%)
refugees would have had malaria infections and 1,500 (38%) would have had
intestinal parasites. We conclude that enhanced health assessments provided rapid
on-site assessment of parasite prevalence and helped decrease morbidity among
Barawan refugees, as well as, the risk of imported infections.
PMID- 10761737
TI - Short report: occurrence of Leishmania donovani DNA in donated blood from
seroreactive Brazilian blood donors.
AB - Human visceral leishmaniasis (kala-azar) transmitted by blood transfusion has
been described in previous reports. Seroprevalence of antibodies to Leishmania
donovani was shown to be related to prior blood transfusions in multiply
transfused hemodialysis patients in Natal, Rio Grande do Norte, Brazil. In this
study, a possible correlation between seroreactivity and the presence of L.
donovani DNA was investigated in asymptomatic healthy blood donors. Sera were
tested using the fucose mannose ligand (FML) ELISA, which was shown to have a
sensitivity of 100%, a specificity of 96-100%, reliability, and diagnostic and
prognostic potential for the detection of human and canine kala-azar,
respectively. Leishmanial DNA was assessed by the polymerase chain reaction (PCR)
and dot-blot hybridization techniques in blood and bone marrow samples. Among 21
FML-seroreactive asymptomatic blood donors, 5 (24%) were positive by the PCR and
9 (43%) were positive in a dot-blot assay of blood samples, showing a significant
correlation (chi2 = 14.24, P < 0.01). No Leishmania DNA was detected in 20 FML
non-reactive blood donors. Our results point to the need for control of
transmission of kala-azar by blood transfusion in areas endemic for this disease.
PMID- 10761738
TI - Epidemiologic tools for malaria surveillance in an urban setting of low
endemicity along the Colombian Pacific coast.
AB - An evaluation of 3 different methods for malaria diagnosis was carried out in an
urban area of low endemicity on the Pacific coast of Colombia. Samples were
collected from 833 symptomatic patients at a malaria clinic and examined by the
polymerase chain reaction (PCR), quantitative buffy coat (QBC; Becton Dickinson,
Franklin Lakes, NJ) method, and the traditional thick blood smear. The prevalence
of Plasmodium falciparum malaria was 5.88% by thick blood smear, 7.34% by the QBC
method, and 21.87% by PCR. The agreement between microscopists was 99.5%. The
agreement between the QBC method and thick blood smear was 96.13% (n = 745).
Samples positive by PCR but negative by thick blood smear or conversely negative
by PCR and positive by thick blood smear were usually of low-level parasitemias.
All 3 methods showed agreement in 76.3% of the samples. Sixty-nine (18.8%)
samples were positive by PCR but negative by the other 2 methods. Ten samples
were positive by both the QBC method and thick blood smear but negative by PCR;
most of them had low-level parasitemias. The use of malaria diagnostic methods
for epidemiologic surveillance is discussed.
PMID- 10761739
TI - Seroprevalence of hepatitis C virus in the general population of northwest
Tanzania.
AB - Sera from 516 participants enrolled in a population-based cross-sectional study
in northwest Tanzania were tested for antibodies to hepatitis C virus (HCV). The
mean age of study subjects was 29 years (range = 16-49 years); 43% were men, 6%
reported a history of blood transfusion, and 4% were infected with human
immunodeficiency virus-1 (HIV-1). Although 53 of 516 sera (10.3%, 95% confidence
interval [CI] = 7.8-13.2%) were repeatedly reactive by a third-generation enzyme
immunoassay (EIA-3), only 6 of the 53 were positive when tested with a third
generation recombinant immunoblot assay (confirmed HCV seroprevalence = 1.2%, 95%
CI = 0.4-2.5%). The positive predictive value of the HCV EIA-3 in this population
was 18.8% (95% CI = 7.0-36.4%). False positivity was not correlated with EIA-3
optical density values, age, sex, infection with HIV-1, or a history of blood
transfusion, but it was marginally associated with increased serum IgG levels. We
conclude that the prevalence of HCV is low in this region and that the HCV EIA-3
has a higher false-positivity rate in this population than has been reported
among U.S. blood donors.
PMID- 10761740
TI - Short report: isolation and identification of two spotted fever group rickettsial
strains from patients in Catalonia, Spain.
AB - Two rickettsial strains, 16B (previously isolated) and FB1, were isolated from
blood from patients with Mediterranean spotted fever in Catalonia, Spain. These
are the only 2 human rickettsial isolates of the spotted fever group obtained so
far in Spain. These strains were identified by the polymerase chain reaction and
sequence analysis of a fragment of the outer membrane protein A (ompA) gene. The
partial ompA sequence was found to be 100% identical with that of Rickettsia
conorii (Malish 7 strain) for both strains. These results confirm the presence of
R. conorii in Catalonia, despite the fact that in a previous study, no R. conorii
were isolated, but a new rickettsial strain of the spotted fever group (Bar29)
was isolated from dog ticks (Rhipicephalus sanguineus) in Catalonia. Further
studies are necessary to get a better knowledge of the epidemiology of
rickettsiae in Catalonia.
PMID- 10761742
TI - Vertical transmission of the yellow fever virus by Aedes aegypti (Diptera,
Culicidae): dynamics of infection in F1 adult progeny of orally infected females.
AB - Vertical transmission of yellow fever virus from orally infected females to their
progeny was experimentally demonstrated in 2 Aedes aegypti colonies from the
Dakar and Koungheul regions in Senegal. A total of 10,530 F1 adult mosquito
progeny were tested. The overall vertical transmission rate was 0.97%, with no
significant difference between the Dakar and Koungheul colonies. The infection
rates were significantly higher in females (1.15%) than in males (0.74%) in both
colonies. The virus was not isolated from the progeny of the first oviposition
cycle (OVC1). The true infection rates were 0.27% and 1.99%, respectively, for
the OVC2 and OVC3 progeny in the Dakar colony, and 1.1% and 1.48%, respectively,
for the OVC2 and OVC3 progeny in the Koungheul colony. The infection rates
increased with extrinsic incubation in both male and female offspring of the 2
colonies, reaching 5.2% in 20-day-old OVC3 female progeny in the Dakar colony.
The epidemiologic consequences of these results are discussed.
PMID- 10761741
TI - Adenosine, AMP, and protein phosphatase activity in sandfly saliva.
AB - As they probe the skin for blood, sand flies inject saliva that prevents
hemostasis. Sand fly saliva also promotes leishmaniasis by suppressing
immunologic functions of macrophages. Saliva of Phlebotomus papatasi, the vector
of Old World cutaneous leishmaniasis, contains adenosine and AMP. We show that
Ph. papatasi saliva as well as pure adenosine down-regulate the expression of the
inducible nitric oxide (NO) synthase gene in activated macrophages. In addition
Ph. papatasi, but not Lutzomyia longipalpis, saliva inhibits the production of
NO. Taken together, these data suggest that salivary adenosine is responsible for
the down-regulation of NO synthesis. Saliva of both genera Phlebotomus and
Lutzomyia contains significant levels of endogenous protein phosphatase-1/2A-like
activity that is heat labile, inhibitable by okadaic acid and calyculine a, and
does not require divalent cations.
PMID- 10761743
TI - Identification of morphologically similar Rhodnius species (Hemiptera:
Reduviidae: Triatominae) by electrophoresis of salivary heme proteins.
AB - We examined intraspecific variability in the genus Rhodnius using starch gel
electrophoresis of salivary heme proteins. Salivary protein profiles of 8
Rhodnius species (R. prolixus, R. robustus, R. neglectus, R. nasutus, R.
ecuadoriensis, R. pallescens, R. pictipes, and R. domesticus) were compared. All
species could be distinguished by this technique. The greatest protein
polymorphism was found in R. ecuadoriensis, R. nasutus, R. robustus, and R.
pictipes, followed by R. prolixus, R. neglectus, R. pallescens, and R.
domesticus. This approach was able to distinguish R. prolixus from R. robustus
and R. neglectus from R. nasutus, species with extreme phenotypical similarity.
PMID- 10761744
TI - New drugs meeting in Washington: too demanding for clinicians?
PMID- 10761745
TI - Amid growing inequalities, an invitation to act.
PMID- 10761746
TI - The prognosis of prognostic factors in phase I clinical trials.
PMID- 10761747
TI - Is one cycle every three or four weeks' obsolete? A critical review of dose-dense
chemotherapy in solid neoplasms.
AB - BACKGROUND: Shortening the interval between cycles is one means of increasing the
dose intensity of chemotherapy, and can be supported by biological and
mathematical rationales. Our objective was to assess the clinical relevance of
the rapid repetition of regimens (so-called 'dose-dense chemotherapy') in various
solid neoplasms. DESIGN: The medical literature was reviewed in accord with
Mulrow's recommendations. Randomised studies comparing frequently-repeated
chemotherapy to standard regimens as well as open studies are described and
critically examined. RESULTS: Dose-dense regimens were widely found to be
feasible. In small-cell lung cancer, survival of patients receiving dose-dense
regimens was better than that of patients treated by standard chemotherapy in
three trials, two of which reached significance, when these intensive regimens
allowed better dose intensity. In poor-prognosis germ-cell tumors, a dose-dense
regimen was not better than standard therapy, perhaps because of an excessively
high toxicity-related death rate. However, recent phase II studies have provided
encouraging results. In early breast cancer, the one published randomized study
in the adjuvant setting showed only a trend towards better disease-free survival
in node-positive women receiving a weekly-repeated regimen. Two randomized trials
failed to show any benefit in the neoadjuvant setting with a dose-dense regimen.
No evidence of a benefit was provided in metastatic breast cancer. In advanced
colorectal cancer, evidence of an improvement in survival with weekly or bi
weekly 5-FU-leucovorin compared to a classic monthly schedule has recently been
shown in two randomized trials, and dose-dense regimens are recognized as
standard therapy in many countries. Phase II studies of dose-dense regimens have
also shown high response rates and long survival in many neoplasms, including
Ewing's sarcoma, gestational trophoblastic disease, ovarian carcinoma and gastric
cancer. CONCLUSIONS: A considerable amount of experience has been gained with
frequently-repeated regimens. A few randomized trials have demonstrated a benefit
for survival on standard chemotherapy in small-cell lung cancer and advanced
colorectal cancer. However, this benefit appears to be weak. The combination of
dose-dense chemotherapy regimens with new anti-cancer strategies based on our
insights into the mechanisms of oncogenesis is a challenge on the eve of the
millennium.
PMID- 10761748
TI - Multivariable analysis of prognostic factors for toxicity and survival for
patients enrolled in phase I clinical trials.
AB - BACKGROUND: Patients with advanced solid tumors may be included in phase I
clinical trials. In such studies, the benefit expected is generally lower than
the likelihood of toxicity and may even be non-existent if the patient's life
expectancy is too short. This study was performed to identify prognostic
variables for toxicity and survival in patients who participate in phase I
clinical trials. PATIENTS AND METHODS: One hundred fifty-four patients treated on
a phase I clinical trial in our institute were evaluated retrospectively.
Univariable and multivariable analyses of patients' characteristics were
undertaken to determine their effects on the probability of grade 3 and 4
toxicity and on survival. RESULTS: Grade 3 or 4 toxicity was experienced by 56
patients (36%): dosage level at entry (P < 0.001) and age over 65 years (P =
0.03) were independently associated with the risk of toxicity. Median overall
survival was 5 months. The multivariable analysis identified performance status 2
or 3 (P < 0.001) and lactate dehydrogenase levels greater than 600 UI (P < 0.001)
as independent adverse prognostic variables for overall survival. Using these two
parameters, we determined a prognostic index which allowed us to discriminate
three risk groups of patients with an observed median survival of 8.5, 4.5 and
1.5 months, respectively. CONCLUSIONS: Subgroups with different survival
expectancy can be identified among patients who are eligible for phase I clinical
trials. If confirmed, the proposed prognostic model may be useful for therapeutic
decision making in palliative oncology.
PMID- 10761749
TI - Cost-effectiveness of second-line treatment with irinotecan or infusional 5
fluorouracil in metastatic colorectal cancer.
AB - BACKGROUND: It has been shown that irinotecan is superior to infusional 5
fluorouracil (5-FU) in patients with advanced colorectal cancer after 5-FU
failure. In a recent trial, median survival was 10.8 months for patients treated
with irinotecan, compared to 8.5 months in patients receiving infusional 5-FU.
Considering the statistically significant but clinically relatively small
advantage of irinotecan over 5-FU, cost effectiveness should also be part of
treatment decision. PURPOSE: To relate the costs of each management approach to
overall survival in patients with metastatic colorectal cancer. PATIENTS AND
METHODS: The healthcare costs and medical benefits (treatment-added survival) of
second-line chemotherapy in patients (infusional 5-FU: 129, irinotecan: 127) were
compared. Data on overall survival were drawn from a multicenter randomised trial
that compared infusional 5-FU (continuous infusion, AIO, or LV5-FU2 regimens) to
irinotecan alone. Costs were derived from the accounting system in two university
hospitals in Paris, France. RESULTS: The range in total healthcare costs was
14,135 to 12,192 US$ patient between management approaches, with irinotecan
chemotherapy costing most and 5-FU-continuous infusion least. If survival was
included as a treatment benefit, the cost-effectiveness ratio of irinotecan over
5-FU ranged from 9,344 to 10,137 US$ per year of added survival. CONCLUSIONS: The
least expensive management for metastatic colorectal was 5-FU infusion but the
additional cost of irinotecan was balanced by the added months of survival, with
a cost-effectiveness ratio close to that of other cancer treatments.
PMID- 10761750
TI - Second-line chemotherapy with weekly oxaliplatin and high-dose 5-fluorouracil
with folinic acid in metastatic colorectal carcinoma: a Hellenic Cooperative
Oncology Group (HeCOG) phase II feasibility study.
AB - BACKGROUND: Oxaliplatin is a novel platinum derivative, which, combined with 5
fluorouracil (5-FU), and folinic acid (FA), demonstrates synergistic activity in
metastatic colorectal cancer (MCC). The HeCOG performed a multicenter phase II
study of a weekly oxaliplatin administration schedule in patients with previously
treated MCC to evaluate the antitumor efficacy and toxicity of this combination.
PATIENTS AND METHODS: Eligible patients included those who relapsed after or
during chemotherapy with 5-FU and FA and/or irinotecan. Prior radiotherapy was
accepted provided that measurable disease was outside the radiation fields. Other
eligibility criteria included written informed consent, a WHO performance status
< or = 2 and adequate bone marrow, liver and renal function. Treatment consisted
of Oxaliplatin 50 mg/m2 by two-hour intravenous (i.v.) infusion followed by FA
500 mg/m2 (two-hour i.v. infusion) and 5-FU 2,500 mg/m2 (24-hour continuous i.v.
infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every 50 days.
RESULTS: Thirty-two patients (Median age 61 years, range 25-76) entered the
trial. The majority (75%) had progressed after receiving first-line chemotherapy.
Diarrhea was the main non-hematologic toxicity. More than half of the patients
(53%) developed grades 3 or 4 diarrhea. Due to this side effect only 29% of
cycles were given with at least 90% of the planned dose of 5-FU. Hematologic
toxicity included grade 3 neutropenia and thrombocytopenia (10% for each), and
grade 4 thrombocytopenia (3%). Two patients (6%) died of sepsis, one related to
neutropenia and one due to urinary tract sepsis. Sixteen patients (50%) developed
grades 1 and 2 neurotoxicity in the form of sensory neuropathy, which was mild
and transient. The objective response rate was 13% (95% CI: 3%-29%). All four
responses were partial. Twelve patients (38%) had stable disease and 8 (25%)
progressive disease. The median time to progression was three months and the
median survival was nine months from the start of therapy. The Kaplan-Meier
estimated probability of one-year survival for the group as a whole was 32%.
CONCLUSIONS: The weekly administration of oxaliplatin with 5-FU and FA was
associated with considerably less neurotoxicity than other schedules. However,
the high percentage of diarrhea suggests that a dose reduction of 5-FU in this
regimen may result in better therapeutic synergy.
PMID- 10761751
TI - A feasibility study evaluating docetaxel-based sequential and combination
regimens in the adjuvant therapy of node-positive breast cancer.
AB - BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of
metastatic breast cancer. We evaluated the feasibility of docetaxel-based
sequential and combination regimens as adjuvant therapies for patients with node
positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of
patients with node-positive breast cancer or locally-advanced disease, aged < or
= 70 years, received one of the following regimens: a) sequential A-->T-->CMF:
doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x
3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T
->CMF: A and T were administered at the same doses q 2 weeks; c) combination
therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF
x 4. When indicated, radiotherapy was administered during or after CMF, and
tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been
treated. Median age was 48 years. A 30% rate of early treatment discontinuation
was observed in patients receiving the sequential accelerated therapy (23% during
A-->T), due principally to severe skin toxicity. Median relative dose-intensity
was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by
treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis
a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c:
48%. After a median follow-up of 18 months, no late toxicity has been reported.
CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due
to an excess of skin toxicity. The sequential non accelerated and the combination
regimens are feasible and under evaluation in a phase III trial of adjuvant
therapy.
PMID- 10761752
TI - Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory'
prostate cancer.
AB - BACKGROUND: Although not clearly defined, 'hormone refractory' prostate cancer
implies disease progression after orchiectomy +/- antiandrogens. Patients in this
setting are usually offered chemotherapy protocols which often lead to
significant toxicity and expense. In search of a well-tolerated, active, third
line treatment, we have attempted to prolong hormonal maneuvers by using low-dose
estrogen therapy. DESIGN: Thirty-eight patients with evidence of disease
progression (as indicated by 2 consecutively rising PSA determinations) after >
or = 2 hormonal treatments (including surgical or chemical orchiectomy and a
median of 3 prior treatment lines) received fosfestrol 100 mg t.i.d. per os in a
continuous schedule until the appearance of progressive disease or excessive
toxicity. Response was assessed by serial PSA levels. Complete response (CR) was
defined as normalisation and partial response (PR) as a > or = 50 decrease of PSA
levels for longer than one month. The median duration of prior treatment was 20
months and the median PSA at fosfestrol start was 126 ng/ml (range 8-12,800);
symptoms (pain) were present in 73% of patients. RESULTS: CR + PR were observed
in 79% (95% confidence interval: 66%-92%). The median time to progression was
seven months. Pain remained stable or improved in 34% and 53%, respectively, of
symptomatic patients with PSA response. Toxicity included worsening of
gynecomastia, peripheral edema, and deep vein thrombosis (8%). No treatment
related deaths occurred. Uni- and multivariate analyses failed to identify
predictive factors for response. PSA response was associated with significantly
longer survival (13 vs. 7 months, P < 0.05 by Mantel-Haentzel). CONCLUSIONS: FOSF
produces high rates of PSA-determined and symptomatic response in 'hormone
refractory' prostate cancer. Toxicity and ease of administration compare
favorably with those reported for CHT regimens used in this setting. The role of
estrogens in prostate cancer should be redefined.
PMID- 10761753
TI - Response and palliation in a phase II trial of gemcitabine in hormone-refractory
metastatic prostatic carcinoma. Swiss Group for Clinical Cancer Research (SAKK).
AB - BACKGROUND: In a phase II trial, 43 patients with hormone-refractory prostate
cancer were treated with gemcitabine at a dose of 1,200 mg/m2 over 2 hours (later
decreased to 1,000 mg/m2 due to hematological toxicity) on days 1, 8 and 15 of a
28 day cycle. PATIENTS AND METHODS: Inclusion criteria were proven tumor
progression after hormonal treatment and increased PSA levels, a WHO PS < or = 2,
adequate bone marrow reserve, liver and renal function and age < or =, 80 years.
Response criteria were based on PSA levels (CR: normalization of PSA, PR: > 50%
decrease). Quality of life (QL) was assessed with the EORTC QLQ-C30 on day 1 of
each treatment cycle and on day 8 of the first cycle (range of scales 0-100).
Physician-rated pain intensity and use of pain medication were assessed at the
same timepoints. RESULTS: Hematological toxicity of gemcitabine led to a dose
reduction in 48% of all cycles. Three of forty-three patients (RR = 7%) showed a
PSA response: one CR and three PR with time to treatment failure of 8.7, 6.6 and
> or = 9.3 months. Seven patients (16%) had stable disease (NC) for a median
duration of 7.1 months (range 6.1-11.7 months). There was one case with objective
regression of lymph node metastases. Patients reported a considerably impaired
health status/QL (n = 41, median = 50) and severe fatigue (n = 41, median = 55.6)
at baseline, with no change under treatment. Pain (QLQ-C30) was also severe at
baseline (N=41, median=50) but was improved at the end of cycles 1 (n = 33,
median change = -16.7, P = 0.0002), 2 (n = 19, median change = -33.3, P =
0.0006), 3 (n = 14, median change = -16.7, P = 0.06) and 4 (n = 9, median change
= -33.3, P = 0.04). Patient-rated pain and use of analgesics as combined endpoint
yielded palliation for at least 8 weeks in 14 patients (32%). Nine of these
patients showed at least stable disease (CR/PR or NC by PSA level), five
indicated a benefit in spite of progressive disease. CONCLUSIONS: Gemcitabine in
the dose and schedule indicated above has a significant beneficial impact on pain
in patients with hormone-refractory prostatic carcinoma despite its limited
activity in terms of PSA response and considerable, especially hematological,
toxicity.
PMID- 10761754
TI - L-asparagine depletion and L-asparaginase activity in children with acute
lymphoblastic leukemia receiving i.m. or i.v. Erwinia C. or E. coli L
asparaginase as first exposure.
AB - PURPOSE: The present study was aimed at investigating L-asparaginase (L-ASE)
activity (in plasma) and L-asparagine (L-ASN) depletion (in plasma and CSF) in
children with newly diagnosed acute lymphoblastic leukemia (ALL) exposed for the
first time to different L-ASE products. PATIENTS AND METHODS: During the
induction treatment of the AIEOP ALL 95 study, 62 patients were treated with
either Erwinase (n = 15), or E. coli medac (n = 47) L-ASE products, given either
i.m. or i.v., at the standard dosage of 10,000 IU/m2, q 3 days x 8 (first
exposure). RESULTS: Plasma and CSF L-ASN trough levels were undetectable in all
cases, including those with L-ASE trough activity < 50 mU/ml. L-ASE trough
activity during the administration of medac was however significantly higher when
compared with that of Erwinase. CONCLUSIONS: L-ASN depletion after a first
exposure to standard doses of Erwinase or medac is obtained in virtually all
patients. No differences are seen between the I.M. or I.V. administration routes
but the medac product is associated with a significantly higher enzyme activity
in respect of Erwinase. L-ASN levels may be undetectable also in patients with L
ASE trough activity levels < 50 mU/ml, challenging the current opinion that an
activity level of 100 mU/ml is needed to obtain L-ASN depletion.
PMID- 10761755
TI - Acute myelogenous leukaemia and myelomonocytic blast crisis following
polycythemia vera in HIV positive patients: report of cases and review of the
literature.
AB - BACKGROUND: Acute myelogenous leukaemia (AML) and myeloproliferative diseases are
rare in HIV-infected individuals and optimal treatment has not been defined.
PATIENTS AND METHODS: We report on the cases of two HIV-infected men, one with
AML and one with myeloid blast crisis after polycythaemia vera (PV). A
comprehensive review of the available literature will be presented. RESULTS:
Patient 1, a 57-year-old bisexual man known to be HIV seropositive for more than
four years (CDC-category A1), presented with a pulmonary infiltrate. On admission
WBC showed leukocytes 5.6 x 10(9)/l and the differential revealed 80% blasts. A
diagnosis of AML FAB M0 was made. Pneumonia resolved under antibiotic treatment
and the patient received induction chemotherapy. However, he once more developed
multiple pulmonary infiltrates and died of respiratory failure despite broad
spectrum antibiotic and antimycotic therapy. Autopsy revealed pulmonary
aspergillosis. Patient 2 was a 63-year old HIV-positive hemophiliac (CDC A3) with
a 10-year history of PV. On admission his white cell count showed leukocytes
256.6 x 10(9)/l with 82% blasts. Cytochemistry revealed myelomonocytic
differentiation. The patient died of tumor lysis syndrome with renal and cardio
pulmonary failure two days later. CONCLUSIONS: This is the first report of an HIV
infected individual with AML M0. The literature describes the cases of 39 HIV+
patients with AML and only one further case with PV. The association of both,
myeloproliferative disease and AML with HIV infection is coincidental. However,
the proportion of FAB type M4/5 appears to be higher than in the general
population. Despite a high risk of treatment associated mortality durable
remissions can be achieved in a small proportion of HIV-infected patients with
AML.
PMID- 10761756
TI - Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in
advanced non-small-cell lung cancer and mesothelioma.
AB - BACKGROUND: A randomised phase II study was performed to compare standard
combination chemotherapy containing cisplatin and etoposide with infusional
carboplatin. PATIENTS AND METHODS: One hundred twenty patients with locally
advanced/metastatic non-small-cell lung cancer or mesothelioma were enrolled. All
were chemotherapy-naive and had a Karnofsky performance status of > or = 50.
Patients were randomised to either four cycles of bolus therapy of cisplatin 80
mg/m2 day 1, etoposide 120 mg/m2 day 1-3, or continuous infusion of carboplatin
100/mg/m2/week for six weeks. RESULTS: No patients on infusional therapy incurred
grade 3-4 toxicity while in the bolus arm, grade 3 and grade 4 leucopenia
occurred in 17% and 35% of patients, respectively. Grade 4 thrombocytopenia
occurred in 8% of patients and there were two instances of grade 3 renal
toxicity. No responses occurred in the pump arm. Eight of forty-six patients with
non-small-cell lung cancer responded to treatment (response rate 17.3%) with two
complete responses and six partial responses. Only one patient with mesothelioma
responded to bolus therapy. There was no difference in survival for the subset of
NSCLC patients. Survival for mesothelioma patients in the pump arm was superior
but this was likely to be a result of early deaths in the bolus arm. CONCLUSIONS:
The pump arm was well-tolerated but not active, whilst combination platinum-based
therapy demonstrated activity but significantly more toxicity than the pump arm.
Further studies of infusional carboplatin with this schedule are not warranted.
PMID- 10761757
TI - Second-line treatment of small-cell lung cancer with the camptothecin-derivative
GI147211: a study of the EORTC Early Clinical Studies Group (ECSG).
AB - BACKGROUND: GI147211, a 10,11-ethylenedioxy substituted analogue of camptothecin
(CPT), was brought into clinical development because of its higher water
solubility and greater potency as compared to topotecan (TPT). The antitumor
activity of GI147211 as second-line therapy in small-cell lung cancer (SCLC) was
assessed after stratification of patients in refractory (no response to initial
treatment or relapse within three months from last cycle) and chemosensitive
(relapse more than three months from last cycle). PATIENTS AND METHODS: Sixty
seven patients were entered in the study and sixty-two were evaluable for
response, twenty-eight in the refractory and thirty-four in the chemosensitive
group. All patients had received 1 line of chemotherapy; radiation had also been
given in 29 cases, 6 in the refractory and 23 in the chemosensitive group.
GI147211 was administered at 1.2 mg/m2/day as 30-min infusion for five
consecutive days every three weeks. RESULTS: The overall response rate was 16.6%
(11 of 66 patients; 95% confidence interval (95% CI): 8.5%-27.5%), 10.3% (3 of 29
patients; 95% CI: 2.2%-27%) in the refractory and 21.1% (8 of 37 patients; 95%
CI: 9.5%-37%) in the chemosensitive group. Only partial responses (PR) were
observed with a median duration of PR of 4.8 months (5.7 months in the refractory
and 5.2 in the chemosensitive group). Hematological toxicity consisted mainly of
neutropenia (grades 3-4 in 25% of cycles) and thrombocytopenia (grades 3-4 in 23%
of cycles); non-hematological toxicity was mild to moderate and consisted of
nausea (22% of cycles), vomiting (11%), malaise (34%). CONCLUSIONS: At the dose
and schedule tested GI147211 is an active new agent for second-line treatment of
SCLC; the antitumor activity and toxicity profile are comparable to those
observed with TPT which remains the leading CPT analogue for salvage treatment.
Interest has been renewed in the clinical development of GI147211 by preclinical
data with the liposomal formulation showing an increased therapeutic index.
PMID- 10761758
TI - Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin
or carboplatin.
AB - PURPOSE: To evaluate the toxicity, response rate and short-term survival
associated with the chemotherapy combinations of docetaxel plus cisplatin or
carboplatin when used for the treatment of patients with metastatic carcinoma of
unknown primary site. PATIENTS AND METHODS: Twenty-six patients were treated with
docetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every three weeks
(study A) and subsequently, 47 patients were treated with docetaxel 65 mg/m2 and
carboplatin (AUC dose = 6) every three weeks (study B). Stable or responding
patients received a maximum of eight courses of therapy. Patients who were known
to be in treatable subset groups were excluded from these trials. The majority of
patients had two or more sites of metastasis; about 45% had adenocarcinoma and
50% poorly differentiated carcinoma. RESULTS: In study A, 6 of 23 (26%)
assessable patients had a major response to therapy. The median survival was
eight months and one-year survival 42%. Seven patients were removed from the
study early for grade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable
patients (22%) had a major response to therapy. Median survival was eight months
and one-year survival 29%. Toxicity associated with this regimen was
predominantly myelosuppression. Comparisons of the two sequential trials showed
no differences in response rates or survivals (P = 0.75). CONCLUSIONS: Docetaxel
and cisplatin (study A) is an active combination in carcinoma of unknown primary
site, but associated with substantial gastrointestinal toxicity. A combination of
docetaxel plus carboplatin (study B) is better tolerated and produced a similar
response rate, median survival and one-year survival. Comparative phase III
trials will be necessary to unequivically prove a survival advantage for any form
of therapy in these patients. However, the survival for patients with carcinoma
of unknown primary site receiving docetaxel-based chemotherapy is comparable to
the survivals for several other groups of advanced cancer patients, such as non
small cell lung cancer, receiving various types of chemotherapy.
PMID- 10761759
TI - Guillain-Barre syndrome in a patient with non-Hodgkin's lymphoma.
AB - We describe a case of Guillain-Barre syndrome (GBS) in a patient with non
Hodgkin's lymphoma (NHL). A 21-year-old woman with a newly diagnosed stage IV
high-grade lymphoma (precursor T-cell NHL according to the R.E.A.L.
Classification) developed flaccid quadriparesis and bilateral facial diplegia
after three weeks of treatment with vincristine, daunorubicin, L-asparaginase and
prednisolone. The clinical course and neurological examination were consistent
with GBS. Despite treatment with intravenous immunoglobulins her neurological
symptoms progressed. Plasmapheresis was therefore initiated followed by
intravenous immunoglobulins. After partial remission of neurologic symptoms,
induction chemotherapy with cyclophosphamide and cytarabine was continued without
any further complication. Three months later, the lymphoma was in complete
remission. GBS has been described in Hodgkin's disease and after bone marrow
transplantation but is rare in NHL. In patients with NHL who develop neurological
symptoms, drug toxicity and nervous system infiltration are the leading cause of
neuropathology, but GBS should be considered in the differential diagnosis.
PMID- 10761760
TI - Reversibility of paraneoplastic bilateral diaphragmatic paralysis after
nephrectomy for renal cell carcinoma.
AB - Bilateral diaphragmatic paralysis is usually caused by anatomic lesions of both
phrenic nerves (e.g., after cardiothoracic surgery), generalized neurologic
diseases (e.g., primary motor neuron disease, amyotrophic lateral sclerosis) or
is without a known cause (idiopathic). We report a case of a patient with renal
cell carcinoma complicated by an isolated bilateral diaphragmatic paralysis
without clinical or electromyographic signs of other muscle or nerve involvement.
There has been progressive, though till now partial, recovery of his vital
capacity rising from 44% to 72% of predicted values, and maximal inspiratory
pressures during the two years following the curative resection of his renal cell
carcinoma. We believe this is the first report of a paraneoplastic bilateral
diaphragmatic paralysis with actual recovery after tumour therapy.
PMID- 10761761
TI - Phase II study of dolastatin-10 in patients with advanced non-small-cell lung
cancer.
PMID- 10761762
TI - Dose-finding study of oral idarubicin and cyclophosphamide in first-line
treatment of elderly patients with metastatic breast cancer.
PMID- 10761763
TI - Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin's
lymphoma: a phase II randomized study.
AB - BACKGROUND: It is unclear whether the purine analogs fludarabine (Flu) and
cladribine (CdA) are non-resistant. PATIENTS AND METHODS: Sixty patients with
relapsed or refractory low-grade NHL were randomly allocated to initial treatment
with either Flu 25 mg/m2, or CdA 0.14 mg/kg, each for five consecutive days every
four weeks. Upon treatment failure, eligible patients were crossed over to the
other study drug. RESULTS: Overall response and CR were 68% and 48% with Flu, and
72% and 38% with CdA, respectively. For responders, actuarial three-year
progression-free survival was 58% with Flu and 52% with CdA. Treatment with both
drugs was well tolerated, with toxic effects primarily hematological. Two
patients (8%) in the Flu group and 15 patients (47%, P = 0.001) in the CdA group
were taken off study because of persistent hematological toxicity. After cross
over, none of seven refractory patients responded, while eight of nine previously
responsive patients achieved second responses. CONCLUSIONS: Our study confirms
that Flu and CdA have similar response rates and durations. However, further
studies are required to optimize the CdA schedule and dosage in order to
ameliorate its toxic profile while maintaining antitumor activity. The two drugs
appear to be cross-resistant.
PMID- 10761764
TI - Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU
resistant colorectal cancer.
AB - BACKGROUND: MF (protracted infusion 5-fluorouracil (5-FU), 300 mg/m2/24 hours
plus bolus mitomycin, 7 mg/m2 every 6 weeks, maximum 4 doses), was recently shown
in a randomised trial to be superior to protracted 5-FU alone, as first-line
chemotherapy for metastatic colorectal cancer (Ross et al. Ann Oncol 1997; 8: 995
1001 [5]). We have examined the same regimen in patients with 5-FU-resistant
disease. PATIENTS AND METHODS: MF was given to 24 patients with metastatic
colorectal cancer, median age 63 years. Two had progressed within four months of
adjuvant 5-FU; the rest had already received palliative 5-FU, with progression
during (11 patients), within four months (5 patients) or after four months of
completion (6 patients). The prior 5-FU regimens were bolus 5-FU/FA (8 patients);
48 hour bolus + infusion 5-FU/FA (18 patients) or protracted 5-FU alone (3
patients). Five patients had received more than one prior 5-FU regimen. RESULTS:
Three patients, 12.5%, achieved WHO partial response; seven others had minor
response or stable disease (SD or better = 42%, 95% confidence interval (95% CI):
22%-64%). Median failure-free survival (FFS) was 15 weeks; median overall
survival was 9.0 months. No grade 3 or 4 drug toxicity occurred, but dose
reduction and/or interruption for persistent grade 2 toxicity was required in
eight patients (33%). Three patients (12.5%) had venous line problems (2
thrombosis; 1 dislodged). There were no toxic deaths. 12 patients (50%) went on
to receive third-line therapy after MF, including irinotecan or oxaliplatin.
CONCLUSIONS: MF is a low-cost, well-tolerated regimen in second-line treatment of
metastatic colorectal cancer. The response rate and FFS obtained in this small
group are similar to those reported for single agent irinotecan. Half our
patients obtained a useful period of control with MF before moving on to further
treatment with new agents such as irinotecan and oxaliplatin.
PMID- 10761765
TI - Open label, multi-centre phase II study of raltitrexed ('Tomudex') in patients
with inoperable squamous-cell carcinoma of head and neck.
AB - BACKGROUND: Raltitrexed ('Tomudex') is a folate based inhibitor of thymidylate
synthase which has been registered in Europe and Australia for the treatment of
advanced colorectal cancer. In a European phase I trial of raltitrexed anti
tumour activity was seen in two patients with head and neck cancer, prompting the
current study. PATIENTS AND METHODS: From November 1996 to December 1998, 24
patients with metastatic or recurrent squamous-cell carcinoma of the head and
neck from 7 Australian centres received raltitrexed, 3 mg/m2 given intravenously
over 15 minutes every 3 weeks, for a maximum of 6 cycles. Patients were required
to be chemotherapy naive and have measurable disease, age > 18 years, WHO
performance status initially < or = 2, no significant intercurrent illness or
organ dysfunction and a life expectancy > 12 weeks. RESULTS: Twenty-two men and
two women, median age 65 years, median performance status 1 were enrolled.
Fifteen patients (63%) had received both prior surgery and radiotherapy. In 15
patients (63%) there was recurrent locoregional disease only. Twelve patients
(50%) received one cycle of treatment with only four patients (17%) receiving
four or more cycles of treatment. No patient achieved a complete or partial
response, although 5 patients experienced stable disease which lasted a median of
188 days (range 61-436). The median survival for the whole group was 101 days
(range 20436). Raltitrexed was generally well tolerated with minimal
antiproliferative toxicity. CONCLUSIONS: Single-agent raltitrexed does not
demonstrate significant anti-tumour response rates in patients with predominantly
locally recurrent head and neck cancer.
PMID- 10761767
TI - Sequential development of liver cirrhosis, hepatocellular carcinoma, essential
mixed cryoglobulinemia, and non-Hodgkin's lymphoma in a hepatitis C-positive
subject.
PMID- 10761766
TI - Recommendation for surgical treatment of colorectal liver metastases.
PMID- 10761768
TI - Emerging trends at the threshold of a new millennium.
PMID- 10761769
TI - A robotic system for blood sampling.
AB - A robotic system to take blood samples autonomously from the forearm is presented
and preliminary results are discussed which demonstrate its feasibility.
Force/position profiles, while pressing a flat-headed probe against the surface
of the skin, enable the determination of a vein's location to within 1 mm on a
phantom. When a needle is inserted, the characteristic force/position profile, on
puncturing the vein wall, is distinctive enough to implement automatic needle
withdrawal to prevent overshoot. Future developments of the project are presented
that provide both an autonomous blood sampling robot and a force-feedback
surgical trainer.
PMID- 10761770
TI - A novel mechatronic tool for computer-assisted arthroscopy.
AB - This paper describes a novel mechatronic tool for arthroscopy, which is at the
same time a smart tool for traditional arthroscopy and the main component of a
system for computer-assisted arthroscopy. The mechatronic arthroscope has a cable
actuated servomotor-driven multi-joint mechanical structure, is equipped with a
position sensor measuring the orientation of the tip and with a force sensor
detecting possible contact with delicate tissues in the knee, and incorporates an
embedded microcontroller for sensor signal processing, motor driving and
interfacing with the surgeon and/or the system control unit. When used manually,
the mechatronic arthroscope enhances the surgeon's capabilities by enabling
him/her to easily control tip motion and to prevent undesired contacts. When the
tool is integrated in a complete system for computer-assisted arthroscopy, the
trajectory of the arthroscope is reconstructed in real time by an optical
tracking system using infrared emitters located in the handle, providing
advantages in terms of improved intervention accuracy. The computer-assisted
arthroscopy system comprises an image processing module for segmentation and
three-dimensional reconstruction of preoperative computer tomography or magnetic
resonance images, a registration module for measuring the position of the knee
joint, tracking the trajectory of the operating tools, and matching preoperative
and intra-operative images, and a human-machine interface that displays the
enhanced reality scenario and data from the mechatronic arthroscope in a friendly
and intuitive manner. By integrating preoperative and intra-operative images and
information provided by the mechatronic arthroscope, the system allows virtual
navigation in the knee joint during the planning phase and computer guidance by
augmented reality during the intervention. This paper describes in detail the
characteristics of the mechatronic arthroscope and of the system for computer
assisted arthroscopy and discusses experimental results obtained with a
preliminary version of the tool and of the system.
PMID- 10761771
TI - Schemes for the identification of tissue types and boundaries at the tool point
for surgical needles.
AB - Precise control of automated invasive surgical tools requires real-time
identification of tissue types and their deformation. At the focus of this paper
is the epidural puncture, for which it is shown that the tissue type and
deformation can respectively be determined from laser-based spectroscopy and the
change in force required to push the needle through the various tissues. Studies
have shown that physiological variations from one patient to another are too
great to allow absolute values to be reliably used to indicate the position of
the needle tip. However, the pattern of force variation during penetration is
shown to be similar between specimens. Interpretation of this information in
conjunction with spectroscopic techniques can be used to discriminate between
tissues and tissue structure at the needle tip. This paper describes results from
an investigation on automatic techniques for interpreting the type and
deformation of tissues under tool action.
PMID- 10761772
TI - Home telecare system using cable television plants--an experimental field trial.
AB - To solve the inconvenience of routine transportation of chronically ill and
handicapped patients, this paper proposes a platform based on a hybrid fiber
coaxial (HFC) network in Taiwan designed to make a home telecare system feasible.
The aim of this home telecare system is to combine biomedical data, including
three-channel electrocardiogram (ECG) and blood pressure (BP), video, and audio
into a National Television Standard Committee (NTSC) channel for communication
between the patient and healthcare provider. Digitized biomedical data and output
from medical devices can be further modulated to a second audio program (SAP)
subchannel which can be used for second-language audio in NTSC television
signals. For long-distance transmission, we translate the digital biomedical data
into the frequency domain using frequency shift key (FSK) technology and insert
this signal into an SAP band. The whole system has been implemented and tested.
The results obtained using this system clearly demonstrated that real-time video,
audio, and biomedical data transmission are very clear with a carrier-to-noise
ratio up to 43 dB.
PMID- 10761773
TI - A virtual-reality-based telerehabilitation system with force feedback.
AB - A PC-based orthopedic rehabilitation system was developed for use at home, while
allowing remote monitoring from the clinic. The home rehabilitation station has a
Pentium II PC with graphics accelerator, a Polhemus tracker, and a multipurpose
haptic control interface. This novel interface is used to sample a patient's hand
positions and to provide resistive forces using the Rutgers Master II (RMII)
glove. A library of virtual rehabilitation routines was developed using
WorldToolKit software. At the present time, it consists of three physical therapy
exercises (DigiKey, ball, and power putty) and two functional rehabilitation
exercises (peg board and ball game). These virtual reality exercises allow
automatic and transparent patient data collection into an Oracle database. A
remote Pentium II PC is connected with the home-based PC over the Internet and an
additional video conferencing connection. The remote computer is running an
Oracle server to maintain the patient database, monitor progress, and change the
exercise level of difficulty. This allows for patient progress monitoring and
repeat evaluations over time. The telerehabilitation system is in clinical trails
at Stanford Medical School (CA), with progress being monitored from Rutgers
University (NJ). Other haptic interfaces currently under development include
devices for elbow and knee rehabilitation connected to the same system.
PMID- 10761774
TI - DataFoundry: information management for scientific data.
AB - Data warehouses and data marts have been successfully applied to a multitude of
commercial business applications. They have proven to be invaluable tools by
integrating information from distributed, heterogeneous sources and summarizing
this data for use throughout the enterprise. Although the need for information
dissemination is as vital in science as in business, working warehouses in this
community are scarce because traditional warehousing techniques do not transfer
to scientific environments. There are two primary reasons for this difficulty.
First, schema integration is more difficult for scientific databases than for
business sources, because of the complexity of the concepts and the associated
relationships. While this difference has not yet been fully explored, it is an
important consideration when determining how to integrate autonomous sources.
Second, scientific data sources have highly dynamic data representations
(schemata). When a data source participating in a warehouse changes its schema,
both the mediator transferring data to the warehouse and the warehouse itself
need to be updated to reflect these modifications. The cost of repeatedly
performing these updates in a traditional warehouse, as is required in a dynamic
environment, is prohibitive. This paper discusses these issues within the context
of the DataFoundry project, an ongoing research effort at Lawrence Livermore
National Laboratory. DataFoundry utilizes a unique integration strategy to
identify corresponding instances while maintaining differences between data from
different sources, and a novel architecture and an extensive meta-data
infrastructure, which reduce the cost of maintaining a warehouse.
PMID- 10761775
TI - Combining high-performance computing and networking for advanced 3-D cardiac
imaging.
AB - This paper deals with the integration of a powerful parallel computer-based image
analysis and visualization system for cardiology into a hospital information
system. Further services are remote access to the hospital Web server through an
internet network. The visualization system includes dynamic three-dimensional
representation of two types of medical images (e.g., magnetic resonance and
nuclear medicine) as well as two images in the same modality (e.g., basal versus
stress images). A series of software tools for quantitative image analysis
developed for supporting diagnosis of cardiac disease are also available,
including automated image segmentation and quantitative time evaluation of left
ventricular volumes and related indices during cardiac cycle, myocardial mass,
and myocardial perfusion indices. The system has been tested both at a
specialized cardiologic center and for remote consultation in diagnosis of
cardiac disease by using anatomical and perfusion magnetic resonance images.
PMID- 10761776
TI - Laryngeal pathology detection by means of class-specific neural maps.
AB - Most of the existing systems and methods for laryngeal pathology detection are
characterized by a classification error. One of the basic problems is the
approximation and estimation of the probability density functions of the given
classes. In order to increase the accuracy of laryngeal pathology detection and
to eliminate the most dangerous error--classification of a patient with laryngeal
disease as a normal speaker--here an approach based on modeling of the
probability density functions (pdf's) of the input vectors of the normal and
pathological speakers by means of two prototype distribution maps (PDM),
respectively, is proposed. The pdf of the input vectors of an unknown normal or
pathological speaker is also modeled by such a prototype distribution neural map-
PDM(X)--and the pathology detection is done by means of a ratio of specific
similarities rather than by a direct comparison of some type of
distance/similarity with a threshold. The experiments show an increased
classification accuracy and that the proposed method can be used for screening
the laryngeal diseases. The method is applied in a consulting system for clinical
practice.
PMID- 10761777
TI - An architecture for the automatic acquisition of vital signs by clinical
information systems.
AB - An architecture is presented which provides clinical information systems with
access to vital sign information from medical devices. Middleware components
encapsulate details of communicating with devices whilst adoption of de facto and
international standards maximizes interoperability with client software. An
application in routine clinical use is described.
PMID- 10761778
TI - A software data generator for radiographic imaging investigations.
AB - A software data generation tool, intended to be used in radiographic
applications, has been developed. The application integrates a phantom design
module and an imaging simulator. Phantoms can be described as a set of either
geometrical objects or voxels, or contours drawn on multiple tomographic slices.
Radiographic projections of the phantoms are formed on the basis of a simulated
irradiation process, with selectable imaging parameters. Comparison between
actual projection images from a physical and a simulated phantom shows good
correspondence. The application was used for digital tomosynthesis (DTS)
investigations and has proven to be a useful tool in the study of tomographic
noise. Further development is expected to expand the use of the application to
more areas of radiological imaging research.
PMID- 10761779
TI - Development of an interactive multimedia training simulator for responding to
abortion clinic bomb threats.
AB - This paper describes the development of an interactive multimedia computer
program to provide realistic training for responding to bomb threats targeted at
abortion clinics. Because the simulator is computer-based, clinic administrators
can receive training that might not otherwise be possible due to time, cost, or
operational limitations.
PMID- 10761780
TI - Emerging evidence for a survival benefit associated with regional lymph node
dissection for melanoma.
PMID- 10761781
TI - Mechanisms of radiocolloid localization in sentinel node biopsy.
PMID- 10761782
TI - Laparoscopic radiofrequency.
PMID- 10761783
TI - Regional nodal surgery for melanoma impacts recurrence rates and survival.
PMID- 10761785
TI - Total rectal resection.
PMID- 10761784
TI - Is intraoperative lymph node mapping and sentinel lymph node biopsy for
colorectal carcinoma necessary?
PMID- 10761786
TI - Long-term results of a multi-institutional randomized trial comparing prognostic
factors and surgical results for intermediate thickness melanomas (1.0 to 4.0
mm). Intergroup Melanoma Surgical Trial.
AB - BACKGROUND: Ten- to 15-year survival results were analyzed from a prospective
multi-institutional randomized surgical trial that involved 740 stages I and II
melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and
compared elective (immediate) lymph node dissection (ELND) with clinical
observation of the lymph nodes as well as prognostic factors that independently
predict outcomes. METHODS: Eligible patients were stratified according to tumor
thickness, anatomical site, and ulceration, and then prerandomized to either ELND
or nodal observation. By using Cox stepwise multivariate regression analysis, the
independent predictors of outcome were tumor thickness (P < .001), the presence
of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than
60 years (P = .01). RESULTS: Overall 10-year survival was not significantly
different for patients who received ELND or nodal observation (77% vs. 73%; P =
.12). Among the prospectively stratified subgroups of patients, 10-year survival
rates favored those patients with ELND, with a 30% reduction in mortality rate
for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30%
reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to
2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385
patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the
presence or absence of ulceration should be the key factor for making treatment
recommendations with regard to ELND for patients with intermediate thickness
melanomas. CONCLUSIONS: These long-term survival rates from patients treated at
77 institutions demonstrate that ulceration and tumor thickness are dominant
predictive factors that should be used in the staging of stages I and II
melanomas, and confer a survival advantage for these subgroups of prospectively
defined melanoma patients.
PMID- 10761787
TI - Active macromolecule uptake by lymph node antigen-presenting cells: a novel
mechanism in determining sentinel lymph node status.
AB - BACKGROUND: Although sentinel lymph node (SLN) biopsy is a powerful staging tool
for patients with melanoma and breast cancer, controversy remains regarding
specific aspects of technique. We examined particle uptake by antigen-presenting
cells (APCs) to determine if this mechanism is responsible for the differential
retention of radioactivity in SLNs relative to nonsentinel lymph nodes (NSLNs).
METHODS: Mapping was conducted in pigs injected with vital blue dye, fluoroscein
isothiocyanate-labeled human serum albumin (FITC-HSA), and one of two
99mtechnetium-labeled tracers, i.e., human serum albumin, a small macromolecule,
or unfiltered sulfur colloid, a mixture of small and large particles.
Macromolecule uptake by APCs was studied in vitro by using FITC-HSA and measured
by fluorescence-activated cell sorting (FACS). SLNs and NSLNs were analyzed by
fluorescence microscopy or FACS, with counterstaining for leukocyte cell surface
markers. RESULTS: Both radiotracers were effective. Cultured APCs rapidly took up
FITC-HSA. Microscopy showed FITC-HSA in the subcapsular sinus of SLNs shortly
after injection and subsequent distribution to interfollicular areas. FACS
revealed increasing amounts of FITC-HSA in SLNs over time. Cells responsible for
uptake were APCs, expressing major histocompatibility (locus) class II.
CONCLUSIONS: This report establishes active macromolecule uptake as a mechanism
that determines SLN status. This mechanism has important implications for
performing SLN biopsy.
PMID- 10761788
TI - Local recurrence after laparoscopic radiofrequency thermal ablation of hepatic
tumors.
AB - BACKGROUND: Since we first described laparoscopic radiofrequency ablation (LRFA)
of liver tumors, several reports have documented technical and safety aspects of
this procedure. Little is known, however, about the long-term follow-up of such
patients. METHODS: From January 1996 to February 1999, we performed LRFA on 250
liver tumors in 66 patients. Triphasic spiral computed tomographic scanning was
obtained preoperatively and at 1 week, and every 3 months postoperatively. Lesion
diameter was measured in the x- and y-axes and the volume estimated; 181 lesions
in 43 patients for whom computed tomographic scans available were included in the
study. The tumor types were as follows: 64 metastatic adenocarcinomas, 79
neuroendocrine metastases, 27 other metastases, and 11 primary liver tumors.
RESULTS: One week postoperatively, the ablated zone was larger than the original
tumor in 178 of 181 lesions, which suggests ablation of the tumor and a margin of
normal liver tissue. A progressive decline in lesion size was seen in 156 (88%)
of 178 lesions, followed for at least 3 months (mean, 13.9 months; range, 4.9
37.8 months), which suggests resorption of the ablated tissue. Fourteen definite
local treatment failures were apparent by increase in size and change in computed
tomographic scan appearance, and eight lesions were scored as failures because of
multifocal recurrence that encroached on ablated foci (22 total recurrences).
Predictors of failure include lack of increased lesion size at 1 week (2 of 3
such lesions failed), adenocarcinoma or sarcoma (18 of 22 failures; P < .05),
larger tumors (failures, M = 18 cm3 vs. successes, M = 7 cm3; P < .005) and
vascular invasion on laparoscopic ultrasonography. By size criteria, 17 of 22
failures were apparent by 6 months. Energy delivered per gram of tissue was not
significantly different (P = .45). CONCLUSIONS: LRFA has a 12% local failure
rate, with larger adenocarcinomas and sarcomas at greatest risk. Failures occur
early in follow-up, with most occurring by 6 months. LRFA seems to be a safe and
effective treatment technique for patients with primary and metastatic liver
malignancies.
PMID- 10761789
TI - Can elective lymph node dissection decrease the frequency and mortality rate of
late melanoma recurrences?
AB - BACKGROUND: Although more than 90% of the morbidity and mortality from localized
cutaneous melanoma occurs in the first decade after initial surgical treatment,
melanoma can recur after a 10-year disease-free interval (DFI) with fatal
consequences. We reviewed our melanoma data base of more than 8,500 prospectively
acquired patients to identify clinicopathological factors that affect the type,
rate of occurrence, and outcome of disease recurring 10 years or more after
surgical treatment of primary cutaneous melanoma. METHODS: From 1971 to 1997,
1907 melanoma patients treated at our cancer center reached or presented with a
DFI of 10 years or more after surgical treatment of clinically localized
melanoma. Of these, 217 (11%) patients had recurrences (mean DFI, 182 months).
The sites of recurrence were local/in-transit in 26 (12%) patients, regional
lymph nodes in 101 (47%) patients, and distant sites in 90 (41%) patients.
RESULTS: Univariate and multivariate analysis, using patient age and sex, type of
initial treatment, and the site, Breslow thickness, and Clark level of the
initial tumor, showed that the type of treatment for the primary tumor was a
significant (P = .0005) prognostic factor in the development of late nodal
recurrence. Of the 217 patients who had recurrences, 172 (79%) had undergone wide
local excision for their primary melanoma, and 45 (21%) had undergone wide local
excision plus elective lymph node dissection (ELND). The rates of nodal
recurrence were 53% (92 of 172) and 20% (9 of 45), respectively, a significant (P
= .0001) difference. When all patients with a DFI of 10 years or more were
stratified by type of initial treatment, the ELND group demonstrated a
significant improvement in disease-free survival and overall survival.
CONCLUSIONS: The risk of late-recurring nodal disease increases and the chance of
long-term survival decreases when wide local excision is performed without ELND.
With the advent of sentinel lymphadenectomy, ELND can be selectively performed
only for those nodal basins with occult tumor cells, thereby decreasing operative
morbidity but allowing identification and early removal of nodal micrometastases.
PMID- 10761790
TI - Technical details of sentinel lymph node mapping in colorectal cancer and its
impact on staging.
AB - BACKGROUND: Sentinel lymph node (SLN) mapping for melanoma and breast cancer has
greatly enhanced the identification of micrometastases in many patients, thereby
upstaging a subset of these patients. The purpose of this study was to see if SLN
mapping technique could be used to identify SLNs in colorectal cancer and to
assess its impact on pathological staging and treatment. METHODS: At the time of
surgery, 1 ml of Lymphazurin 1% was injected subserosally around the tumor
without injecting into the lumen. The first to fourth blue nodes identified were
considered the SLNs, which have the highest probability to contain metastases. A
standard oncological resection of the bowel was then performed. Multilevel
microsections of the SLNs, including a detailed pathological examination of the
entire specimen, was performed. RESULTS: SLN was successfully identified in 85
(98.8%) of 86 patients. In 85 patients, there were 1,367 (16 per patient) lymph
nodes examined, of which 140 (1.6 per patient) were identified as SLNs. In 53
(95%) of 56, of whom the SLNs were without metastases (negative), all other non
SLNs also were negative. In 29 (34% of 85) patients, SLNs were positive for
metastases; in 14 of the 29 patients, other non-SLNs also were positive in
addition to the SLNs. In the other 15 of the 29 patients (18% of 85 patients),
SLNs were the only site of metastases, and all other non-SLNs were negative. In 7
patients (8.2% of 85 patients), micrometastases were identified only in 1 or 2 of
the 10 sections of a single SLN. In five of seven patients, such micrometastases
were detected by hematoxylin and eosin staining and immunohistochemistry; in the
other two patients, it was detected only by immunohistochemistry. In patients
with negative SLNs, the rate of occurrence of micrometastases in non-SLNs was 5
(0.4%) of 1,184 lymph nodes. CONCLUSIONS: SLN mapping can be performed easily in
colorectal cancer patients, with an accuracy of more than 95%. The identification
of submicroscopic lymph node metastases by this technique may have upstaged these
patients (18%) from stage I/II to stage III disease, who may then benefit from
further adjuvant chemotherapy.
PMID- 10761791
TI - Total rectal resection and complete mesorectum excision followed by coloendoanal
anastomosis as the optimal treatment for low rectal cancer: the experience of the
National Cancer Institute of Milano.
AB - BACKGROUND: At present, abdominoperineal resection remains the most diffuse
method of treatment of very low rectal cancer. Today, we can avoid this method in
some patients by using a sphincter-saving procedure. METHODS: From March 1990 to
January 1999, 273 consecutive total rectal resections and coloendoanal
anastomoses were performed at our Institute; this study concerns 141 consecutive
patients treated for a primary adenocarcinoma of the distal rectum, from 3.5 to 8
cm from the anal verge. Patient stratification, based on definitive pathological
report, was 31 Dukes' stage A (T2N0), 44 stage B (T3N0), and 66 stage C (T2N+
T3N+). RESULTS: Overall recurrence rate was 9.2%; postoperative morbidity
attributable to the procedure was low. A perfect continence was documented in 61%
of cases. The only pathological factor related to local recurrence rate is
peritumoral lymphocytic reaction inside and around the tumor (P = .0005 and .031)
independently from the number of metastatic lymph nodes, depth of fatty tissue
infiltration, and lymphatic and venous neoplastic emboli. The minimum follow-up
time is 12 months. CONCLUSIONS: Our data, in accordance with other authors, seem
to highlight the relevant role that a well-practiced surgery, together with
accurate information on the spreading of this disease, has in achieving an
optimal local control of cancer.
PMID- 10761792
TI - Interleukin-6 blood level is associated with circulating carcinoembryonic antigen
and prognosis in patients with colorectal cancer.
AB - BACKGROUND: Interleukin-6 (IL-6) is an important proinflammatory cytokine that
has multiple effects on stimulating inflammation and cell growth. Experimental
data suggest that carcinoembryonic antigen (CEA) induces the systemic production
of IL-6 and that IL-6 may stimulate tumor cell growth at metastatic sites. We
tested the hypothesis that blood concentrations of IL-6 are associated with the
amount of circulating CEA and with prognosis in patients with colorectal cancer.
METHODS: CEA and IL-6 concentrations were measured by using enzyme immunoassay in
preoperative serum samples from 208 patients with stages I through IV colorectal
cancer. RESULTS: Linear regression analysis showed a significant association
between serum values of CEA and IL-6 (r = .544; R2 = .296; P < .001). Patients
with stage III and stage IV disease had a significantly higher IL-6 serum
concentration than those with stage I and stage II disease. In patients with
stages I through III, 5-year survival was 83% in cases with concentrations of IL
6 at 10 pg/ml or less (n = 94) and 56% in cases with IL-6 concentrations of more
than 10 pg/ml (n = 54; P = .001; median follow-up time, 46 months). By using
multivariate analysis, an IL-6 concentration of more than 10 pg/ml was an
independent prognostic factor of survival (relative risk = 1.820; P = .020).
CONCLUSIONS: In patients with colorectal cancer, blood concentration of IL-6 is
associated with high circulating CEA and advanced stage. Furthermore, an IL-6
concentration of more than 10 pg/ml is an independent negative prognostic marker
of survival.
PMID- 10761793
TI - Outcome of patients with proximal gastric cancer depends on extent of resection
and number of resected lymph nodes.
AB - BACKGROUND: Studies have shown that the survival of patients with gastric
adenocarcinoma is related to the number of regional lymph nodes with metastases.
The probability of identifying node-positive cancers increases with the number of
lymph nodes resected and examined. It has been recommended that at least 15 lymph
nodes be removed and examined for adequate staging. Prospective randomized
studies have shown the lymph node yield is much greater with the D2 resection
than the D1. This study evaluated the relative contribution of both the number of
resected lymph nodes and the extent of gastric resection (D1/D2) on the outcome
of patients with proximal gastric cancer. METHODS: The medical records of 114
patients with adenocarcinoma of the proximal stomach, who underwent a curative
gastric resection, were reviewed. Patients were stratified into four groups,
i.e., two groups, D1/D1.5 and D2/D2.5, based on the extent of resection, and two
groups based on the number of lymph nodes removed, fewer than 15 lymph nodes and
15 or more lymph nodes. Survival was determined by the method of Kaplan-Meier and
differences compared by the log-rank test. Multivariate analysis was performed by
using the Cox model. RESULTS: The number of resected lymph nodes had no effect on
the survival of the group as a whole. A significant improvement in survival was
noted for patients with a D2 or greater resection. The median survival of
patients with 15 or more lymph nodes resected improved from 25 months to 42
months when treated with an extended resection, (D2 or D2.5). Resection of 15 or
more lymph nodes alone, or combined with an extended resection, resulted in a
statistically significant improvement in survival for patients in American Joint
Committee on Cancer Staging (AJCC) stage II. CONCLUSIONS: Both resection of 15 or
more lymph nodes and extended lymphadenectomy contributed to the survival
advantage observed in patients with AJCC stage II gastric cancer. The D2 gastric
resection prolonged the median survival time and improved the 5-year survival
rate for patients with 15 or more resected lymph nodes.
PMID- 10761794
TI - Preoperative paclitaxel and radiotherapy for locally advanced breast cancer:
surgical aspects.
AB - INTRODUCTION: Approximately 15% of breast cancer patients present with large
tumors that involve the skin, the chest wall, or the regional lymph nodes.
Multimodality therapy is required, to provide the best chance for long-term
survival. We have developed a regimen of paclitaxel, with concomitant radiation,
as a primary therapy in patients with locally advanced breast cancer. METHODS:
Eligible patients had locally advanced breast cancer (stage IIB or III). After
obtaining informed consent, patients received paclitaxel (30 mg/m2 during 1 hour)
twice per week for 8 weeks and radiotherapy to 45 Gy (25 fractions, at 180
cGy/fraction, to the breast and regional nodes). Patients then underwent modified
radical mastectomy followed by postoperative polychemotherapy. RESULTS: Twenty
nine patients were enrolled. Of these, 28 were assessable for clinical response
and toxicity, and 27 were assessable for pathological response. Objective
clinical response was achieved in 89%. At the time of surgery, 33% had no or
minimal microscopic residual disease. Chemoradiation-related acute toxicity was
limited; however, surgical complications occurred in 41% of patients.
CONCLUSIONS: Preoperative paclitaxel with radiotherapy is well tolerated and
provides significant pathological response, in up to 33% of patients with locally
advanced breast cancer, but with a significant postoperative morbidity rate.
PMID- 10761795
TI - Women's regrets after bilateral prophylactic mastectomy.
AB - BACKGROUND: Primary prevention strategies such as chemopreventive agents (e.g.,
tamoxifen) and bilateral prophylactic mastectomy (PM) have received increasingly
more attention as management options for women at high risk of developing breast
cancer. METHODS: A total of 370 women, who had registered in the Memorial Sloan
Kettering Cancer Center National Prophylactic Mastectomy Registry, reported
having undergone a bilateral PM. Twenty-one of these women expressed regrets
about their decision to have a PM. A psychiatrist and psychologist interviewed 19
of the women about their experiences with the PM. RESULTS: A physician-initiated
rather than patient-initiated discussion about the PM represented the most common
factor in these women. Psychological distress and the unavailability of
psychological and rehabilitative support throughout the process were the most
commonly reported regrets. Additional regrets about the PM related to cosmesis,
perceived difficulty of detecting breast cancer in the remaining breast tissue,
surgical complications, residual pain, lack of education about the procedure,
concerns about consequent body image, and sexual dysfunction. CONCLUSIONS:
Although a PM statistically reduces the chances of a woman developing breast
cancer, the possibility of significant physical and psychological sequelae
remains. Careful evaluation, education, and support both before and after the
procedure will potentially reduce the level of distress and dissatisfaction in
these women. We discuss recommendations for the appropriate surgical and
psychiatric evaluation of women who are considering a PM as risk-reducing
surgery.
PMID- 10761796
TI - Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and
melphalan in advanced soft-tissue sarcomas: histopathological considerations.
AB - BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha
and melphalan was used as induction treatment in locally advanced extremity soft
tissue sarcomas for limb sparing surgery. The typical histopathological changes
that occur in these tumoral masses are described in a series of 30 patients.
METHODS: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas
and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks
after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus
melphalan. The specimens were studied for surgical margins, extent and type of
tumor necrosis, lymph node involvement, perineural and vascular invasion, and the
effects on adjacent normal tissues such as nerves, muscles, and blood vessels.
RESULTS: The typical histological changes were central cystic hemorrhagic
necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted
in the soft tissues around the mass. In eight cases, more than 90% necrosis was
found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in
4 of 17 cases). In five cases, less than 60% necrosis was noted. The best
responses (>90% necrosis) were observed in distally located tumors. The
responsive types were malignant fibrous histiocytoma, followed by myxoid
liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high
grade sarcomas. Vascular invasion was observed in two cases and intralesional
venous thrombosis in one case. No perineural invasion or lymph nodes involvement
were observed. The soft tissues adjacent to the tumor bed did not show major
morphological changes. No correlation was found between the histological changes
and each of the following: the anatomical (upper vs. lower limb) or compartmental
location of the tumor; whether the tumor was primary or recurrent; and the types
of previous treatment (systemic chemotherapy or radiotherapy) and tumor size.
CONCLUSIONS: This is the first serial histological description of the effects of
tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated
limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small
number of specimens and, especially, the variability of tumors preclude definite
conclusions. Larger numbers and more homogeneity are needed in future studies.
PMID- 10761798
TI - The modern treatment of heart failure: how many drugs are enough?
PMID- 10761797
TI - Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick
(> or = 4 mm) primary melanoma.
AB - BACKGROUND: Historically, patients with thick (> or =4 mm) primary melanoma have
not been considered candidates for elective lymph node dissection, because their
risk for occult distant disease is significant. Sentinel lymph node (SLN) biopsy
offers an alternative approach to assess disease in the regional nodal basin, but
no studies have specifically addressed the role for this technique in patients
with thick melanoma. Although adjuvant therapy benefits patients who develop
nodal metastases, data that supports its routine use in all patients with thick
melanoma is both limited and controversial. This study was performed to determine
whether pathological status of the SLN is an important risk factor in this
heterogeneous group and, thus, provides a rationale for SLN biopsy. METHODS: The
records of 131 patients with primary cutaneous melanoma whose primary tumors were
at least 4 mm thick and who underwent lymphatic mapping and SLN biopsy were
reviewed. Several known prognostic factors, i.e., tumor thickness, ulceration,
Clark level, location, sex, as well as SLN pathological status were analyzed with
respect to disease-free and overall survival. RESULTS: Lymphatic mapping and SLN
biopsy was successful in 126 (96%) of 131 patients who underwent the procedure.
In 49 patients (39%), the SLN biopsy was positive by conventional histology,
although it was negative in 77 patients (61%). The median follow-up was 3 years.
Although presence of ulceration and SLN status were independent prognostic
factors with respect to disease-free and overall survival, SLN status was the
most powerful predictor of overall survival by univariate and multivariate
analyses. CONCLUSIONS: Lymphatic mapping and SLN biopsy is a highly accurate
method of staging lymph node basins at risk for regional metastases in patients
with thick melanoma and identifies those patients who may benefit from earlier
lymphadenectomy as well as patients with a more favorable prognosis. Pathological
status of the SLN in these patients with clinically negative nodes is the most
important prognostic factor for survival and is essential to establish
stratification criteria for future adjuvant trials in this high-risk group.
PMID- 10761799
TI - Aortic valve replacement for patients with mild to moderate aortic stenosis
undergoing coronary artery bypass surgery.
AB - Aortic valve replacement (AVR) is not normally recommended in asymptomatic
patients, even if aortic stenosis is severe. However, as the population ages, an
increasing number of patients with mild or moderate aortic stenosis will require
coronary artery bypass grafting (CABG). In these cases, risk of "prophylactic"
AVR needs to be weighed against risks of subsequent worsening of the mildly or
moderately diseased aortic valve. If unoperated, aortic stenosis will worsen at
an average of 6-8 mmHg per year (-0.1 cm2/year valve area), and one-quarter of
such patients will require late AVR with a high operative mortality (14-24%). If
AVR is performed at the time of CABG, operative risk is increased only slightly
(from 1-3% to 2-6%), as are late mortality (1-2% per year) and morbidity (1-2%
per year), mainly from hemorrhagic complications. Intrinsic gradients of most
prosthetic valves are sufficiently low that even patients with low aortic valve
gradients are likely to derive hemodynamic benefit from AVR. Thus, if there is a
measurable (>20-25 mmHg) gradient across the aortic valve in a patient who
requires CABG, the patient is at considerable risk for developing symptomatic
aortic stenosis prior to reaching the end of expected benefit from CABG; in this
case AVR should be considered. It may be reasonable in patients with very mild
gradients (<25 mmHg) to defer aortic valve surgery; however, it should be noted
that aortic stenosis progression is generally more rapid when the initial
gradient is small.
PMID- 10761800
TI - Echocardiography of the coronary sinus in adults.
AB - The coronary sinus (CS) is a small tubular structure just above the posterior
left atrioventricular junction. The CS can be imaged in several different
echocardiographic views. Using zoom M-mode recordings of the CS in apical two
chamber view, CS caliber can be sharply imaged and easily measured during
different phases of the cardiac cycle. We have recently shown that the CS narrows
during atrial contraction in persons with sinus rhythm, but does not narrow at
all if atrial fibrillation is present. Attenuation of CS narrowing occurs in
patients with congestive heart failure and inferior vena cava plethora. Maximal
CS caliber occurs during ventricular systole. Patients with poor left ventricular
systolic function show mild CS dilatation. Greater CS dilatation is present in
patients with persistent left superior vena cava, and huge dilatation when this
anomaly is accompanied by absence of a right superior vena cava. Injection of
sonicated saline into a left and then a right arm vein is diagnostically useful
in confirming these two venous anomalies. Pulsed-wave Doppler of the CS can be
recorded in the parasternal right heart inflow view. From this and from the CS
cross-section area it may be possible to estimate coronary blood flow.
PMID- 10761801
TI - Atrial fibrillation independently prolongs hospital stay after coronary artery
bypass surgery.
AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia occurring in
patients after coronary artery bypass surgery (CABG). HYPOTHESIS: The purpose of
this study was to determine whether AF independently prolonged postoperative
length of stay (LOS). METHODS: Consecutive patients undergoing elective CABG were
identified. Baseline clinical variables, postoperative course including the
development of AF, and postoperative LOS were recorded. RESULTS: In all, 216
patients (aged 61 +/- 13 years) were examined. Postoperative LOS was 11.3 +/- 6.4
days (median LOS = 9 days). Fifty-five patients (25%) developed AF. Among 16
variables examined, the univariate predictors of LOS included age (p < 0.001),
preoperative left ventricular ejection fraction (p < 0.001), absence of a prior
smoking history (p < 0.05), bypass limited to venous conduits (p < 0.001),
postoperative AF (p < 0.001), and the occurrence of a postoperative event (p <
0.001). Length of stay for patients who developed AF was significantly longer
than that for patients who did not (15.1 +/- 9.0 vs. 10.0 +/- 4.6 days, p <
0.001). After adjusting for other significant variables, the occurrence of AF
after CABG independently prolonged LOS: patients who developed AF stayed 3.2 +/-
1.7 days longer than patients who did not (p < 0.001). CONCLUSIONS: Atrial
fibrillation lengthens hospital stay after CABG, and its effect is independent of
other important variables. Identification of patients who are at risk for AF and
successful treatment to prevent AF will likely contribute to major reductions in
consumption of health care resources in patients with CABG.
PMID- 10761802
TI - The role of strict metabolic control by insulin infusion on fibrinolytic profile
during an acute coronary event in diabetic patients.
AB - BACKGROUND: Many clinical and laboratory observations give support to the
hypothesis that strict metabolic control by insulin infusion during acute
coronary events may improve the ischemic damage and prognosis. HYPOTHESIS: We
investigated the impact of intensive insulin treatment on fibrinolytic parameters
during an acute ischemic myocardial event (unstable angina or acute myocardial
infarction) in patients with type 2 diabetes mellitus. METHODS: The study group
consisted of 48 type 2 diabetic patients, of whom 24 were randomized to
conventional therapy plus intensive insulin treatment (Group 1) and 24 to
conventional therapy only (Group 2). The two groups were comparable according to
gender, age, body mass index, waist:hip ratio, duration of diabetes, previous
antidiabetic treatment, type of ischemic events, concomitant therapy, and the
classic risk factors for coronary disease. Insulin-treated patients were excluded
from the study. Plasma levels of fibrinogen, tissue plasminogen activator (t-PA),
and plasminogen activator inhibitor-1 (PAI-1) were measured on admission and
discharge. Fibrinogen (fibr) was measured using the photometric method. PAI-1 and
t-PA were measured by enzyme-linked immunosorbent assays. RESULTS: T-PA increased
in both groups during hospitalization (t-PA(admission) vs. t-PA(discharge): Group
1: 15.42 +/- 4.4 ng x ml(-1) vs. 21.2 +/- 5.74 ng x ml(-1), p = 0.000037; Group
2: 14.47 +/- 6.31 ng x ml(-1) vs. 19.18 +/- 6.88 ng x ml(-1), p = 0.001). On the
other hand, fibr and PAI-1 levels increased remarkably in controls (Group 2,
fibr(admission) vs. fibr(discharge): 2.98 +/- 1.04 g x l(-1) vs. 3.59 +/- 1.01 g
x l(-1), p = 0.002, and PAI-1admission vs. PAI-1 discharge: 30.6 +/- 17.34 ng x
ml(-1) vs. 40.62 +/- 23.48 ng x ml(-1), p = 0.003). This finding was not observed
in the intensive insulin treatment group (Group 1, fibr(admission) vs.
fibr(discharge): 2.87 +/- 0.73 g x l(-1) vs. 2.67 +/- 0.72 g x l(-1), p = 0.101,
and PAI-1 admission vs. PAI-1 discharge: 30.75 +/- 15.81 ng x ml(-1) vs. 27.75 +/
6.43 ng x ml(-1), p = 0.484). CONCLUSION: Intensive insulin treatment during an
acute coronary event improves fibrinolytic profile in patients with diabetes
mellitus. This is a possible mechanism for the reduced short- and long-term
mortality in diabetic patients treated with intensive insulin treatment protocol.
PMID- 10761803
TI - Intensity of antianginal therapy in patients referred for coronary angiography: a
comparison of fee-for-service and health maintenance organization therapeutic
strategies.
AB - BACKGROUND: No formal criteria have been developed to guide medical therapy for
angina prior to revascularization, and no comparisons have been made between
health maintenance organization (HMO) and fee-for-service (FFS) hospitals with
respect to angina treatment. HYPOTHESIS: Using a literature-based measure of
medical intensity, we tested the hypothesis that there is no difference in
anginal medical therapeutic intensity between HMO and FFS systems. METHODS: For
each antianginal drug, we developed a model from which an intensity score between
0 and 100 could be calculated. Average and maximal daily doses of drug were fit
to a sigmoid curve such that they represented scores of 50 and 99, respectively.
Overall intensity scores were obtained by weighted and unweighted averaging of
three scores from nitrates, calcium-channel blockers, and beta blockers. This
model was applied to 199 patients undergoing angiography at an FFS and an HMO
hospital. RESULTS: HMO patients were taking more classes of antianginal drug (1.9
vs. 1.0, p < 0.001). Overall unweighted (17.7 vs. 11.7, p = 0.02) and weighted
(27.3 vs. 16.9, p = 0.003) intensity scores for both HMO and FFS patients were
low. HMO intensity scores for the use of beta blockers were greater than FFS
scores (19.2 vs. 9.6, p = 0.002). The intensity scores for the use of nitrates
and calcium blockers were similar. CONCLUSIONS: Models for the measurement of
anginal medical therapy intensity can provide important information regarding
medical therapy prior to revascularization. The overall intensity of medical
therapy was low in both health care systems. These findings have important
implications for patient management, guideline development, and national
healthcare policy.
PMID- 10761804
TI - Electropharmacologic effect of a standard dose of intravenous procainamide in
patients with sustained ventricular tachycardia.
AB - BACKGROUND: Patients with inducible sustained ventricular tachycardia (VT)
sometimes receive intravenous procainamide during electrophysiologic testing.
Unfortunately, the responses to intravenous and subsequent oral drug therapy are
variable and may be discordant. HYPOTHESIS: It was the aim of this study to
determine whether this variability might be explained by heterogeneity in the
electropharmacologic response, even in a homogeneous population. METHODS: We
studied 42 patients who had spontaneous malignant ventricular arrhythmia and were
inducible to sustained monomorphous VT during electrophysiologic testing. Each
received 15 mg/kg of intravenous procainamide followed by a 2 mg/min infusion.
Serum levels were drawn immediately following programmed stimulation. The mean
procainamide level was 6.7 +/- 1.4 mcg/ml with an N-acetyl procainamide level of
1.0 +/- 0.5 mcg/ml. The 14 procainamide responders (5 of whom were noninducible
and 9 whose VT cycle length increased > 100 ms) and the 28 nonresponders had
similar procainamide and NAPA levels (6.5 +/- 1.4 vs. 6.7 +/- 1.4 mcg/ml).
RESULTS: There was no significant difference in baseline clinical parameters, His
to ventricular electrogram (HV) interval, effective refractory period, or VT
cycle length. Prolongation of the effective refractory period and infra His
conduction time occurred to a similar extent in responders and nonresponders.
CONCLUSION: We conclude that procainamide has a consistent dose-response
relationship with respect to refractoriness and conduction in patients with
malignant arrhythmias. However, acute antiarrhythmic efficacy of procainamide
cannot be predicted by clinical factors, drug levels, or drug-induced changes in
common electrophysiologic parameters.
PMID- 10761805
TI - Severity of residual stenosis of infarct-related lesion and left ventricular
function after single-vessel anterior wall myocardial infarction: implication of
ST-segment elevation in lead aVL of the admission electrocardiograms.
AB - BACKGROUND: The relationship between the severity of chronic-phase stenosis of
infarct-related lesions (IRLs) and chronic left ventricular function in anterior
acute myocardial infarctions (AMI) has not been adequately investigated.
HYPOTHESIS: This study investigated whether ST elevation in lead aVL of admission
electrocardiogram (ECG) would be a determinant factor of the relationship between
the severity of stenosis of the IRL and chronic left ventricular function after
anterior wall AMI. METHODS: One month after AMI, the IRL was evaluated by
coronary angiography in 98 patients with anterior AMI, and left ventricular
ejection fraction (LVEF) was determined using multigated radionuclide
angiocardiography. Patients were classified according to the severity of the IRL:
patients with 100% occlusion (Group O), patients with 90 to 99% stenosis (Group
H), and patients with < or =75% stenosis (Group L). Patients with ST elevation >
or =0.1 mV in the aVL lead on their admission ECG were included in the ST
elevation group, and those with ST elevation <0.1 mV were included in the non-ST
elevation group. RESULTS: The LVEF was greater in the non-ST-elevation group than
in the ST-elevation group (p<0.0001), and the LVEF in a whole group as follows:
Group L LVEF>Group H LVEF>Group O LVEF (p = 0.0160). In the ST-elevation group,
LVEF was higher in Group L than in the other groups (p = 0.0251). There were
three independent predictors of a reduced LVEF: ST-elevation in aVL [odds ratio
(OR): 3.38, p = 0.0044], IRL stenosis > or =90% (OR: 2.90, p = 0.0044), and the
IRL occurring in the left anterior descending artery proximal to the first
diagonal branch (OR: 6.31, p = 0.0024). CONCLUSION: Left ventricular function was
preserved, regardless of the severity of residual stenosis, in patients without
ST elevation in aVL if the IRL was not totally occluded. In patients with ST
elevation in aVL, LVEF was lower in patients with more severe stenosis, even if
the IRL was patent.
PMID- 10761806
TI - Changes of QT dispersion in patients with coronary artery disease dependent on
different methods of stress induction.
AB - BACKGROUND: Episodes of stress-induced myocardial ischemia in patients with
coronary artery disease (CAD) may cause increases of QT dispersion (QTd).
HYPOTHESIS: Aim of this study was to analyze the effect of increasing heart rates
on QTd and to compare the effect of different methods of stress induction in
patients with varying degrees of CAD when estimating QTd. METHODS: We studied 58
patients, 22 with prior myocardial infarction (MI), 25 without MI or wall motion
disturbances at rest, and 11 patients without evidence of CAD. Prior to coronary
angiography, standard 12-lead ECGs were obtained at rest as well as during
dynamic exercise and pharmacologic stress using arbutamine simultaneously with
echocardiography. QTd was determined at each stress level by subtracting minimal
from maximal QT interval duration. RESULTS: QTd values at rest were not
consistently higher in the patients with CAD. At maximal heart rate, QTd was
statistically significantly higher in patients with CAD with a better
discrimination between groups for pharmacologic stress (p < 0.005 for exercise, p
< 0.0001 for arbutamine). Patients after MI had higher QTd values under all
conditions than did the groups without MI. As in patients with CAD, the values of
this group changed more radically as a result of pharmacologic stress.
CONCLUSION: Patients with CAD can be identified on the basis of QTd under stress.
These changes were not as marked in patients with MI as their rest values were
already increased. Overall, drug-induced stress produced greater differences than
dynamic exercise, suggesting that the ischemic threshold might be lower in the
former.
PMID- 10761808
TI - Implantable cardioverter defibrillator discharge rates in patients with
unexplained syncope, structural heart disease, and inducible ventricular
tachycardia at electrophysiologic study.
AB - BACKGROUND AND HYPOTHESIS: The implantable cardioverter defibrillator (ICD) is
the best available strategy to protect patients from life-threatening ventricular
arrhythmia. Although unproven, it is commonly utilized to treat subjects with
syncope, a negative clinical workup, structural heart disease, and inducible
sustained monomorphic ventricular tachycardia (VT) on programmed
electrophysiologic stimulation (EPS). The purpose of this paper was to validate
this approach. METHODS: We retrospectively identified 36 subjects who received
primary ICD therapy for syncope in the setting of structural heart disease with
inducible sustained monomorphic VT on EPS. The cohort was predominantly male
(32/36) with underlying coronary artery disease (29/36). The mean left
ventricular ejection fraction was 31 +/- 12%, and a third of the patients (12/36)
had undergone bypass surgery. RESULTS: The study group was followed for a mean of
23 +/- 15 months (range 3-81 months) and experienced an ICD event rate of 22% at
3 months, which increased to 55% at 36 months. This event rate was comparable
with the 66% event rate seen in a group of patients with primary ICD therapy for
spontaneous life-threatening VT treated during the same time period. No future
predictors of ICD events in the study group could be identified. CONCLUSION:
Syncope patients with negative workup, structural heart disease, and sustained
monomorphic VT at EPS are at high risk for future tachyarrhythmic events. Based
on present evidence, primary ICD therapy in this group appears warranted and
justified.
PMID- 10761807
TI - Clinical and demographic determinants of heart rate variability in patients post
myocardial infarction: insights from the cardiac arrhythmia suppression trial
(CAST).
AB - BACKGROUND: Clinical and demographic determinants of heart rate variability
(HRV), an almost universal predictor of increased mortality, have not been
systematically investigated in patients post myocardial infarction (MI).
HYPOTHESIS: The study was undertaken to evaluate the relationship between
pretreatment clinical and demographic variables and HRV in the Cardiac Arrhythmia
Suppression Trial (CAST). METHODS: CAST patients were post MI and had > or =6
ventricular premature complexes/h on pretreatment recording. Patients in this
substudy (n = 769) had usable pretreatment and suppression tapes and were
successfully randomized on the first antiarrhythmic treatment. Tapes were
rescanned; only time domain HRV was reported because many tapes lacked the
calibrated timing signal needed for accurate frequency domain analysis.
Independent predictors of HRV were determined by stepwise selection. RESULTS:
Coronary artery bypass graft surgery (CABG) after the qualifying MI was the
strongest determinant of HRV. The markedly decreased HRV associated with CABG was
not associated with increased mortality. Ejection fraction and diabetes were also
independent predictors of HRV. Other predictors for some indices of HRV included
beta-blocker use, gender, time from MI to Holter, history of CABG before the
qualifying MI, and systolic blood pressure. Decreased HRV did not predict
mortality for the entire group. For patients without CABG or diabetes, decreased
standard deviation of all NN intervals (SDANN) predicted mortality. Clinical and
demographic factors accounted for 31% of the variance in the average of normal-to
normal intervals (AVGNN) and 13-26% of the variance in other HRV indices.
CONCLUSIONS: Heart rate variability post MI is largely independent of clinical
and demographic factors. Antecedent CABG dramatically reduces HRV. Recognition of
this is necessary to prevent misclassification of risk in patients post infarct.
PMID- 10761809
TI - Stability of the noninvasive baroreflex sensitivity assessment using cross
spectral analysis of heart rate and arterial blood pressure variabilities.
AB - BACKGROUND: Depressed baroreflex sensitivity (BRS), usually estimated using the
invasive phenylephrine method or the nitroprusside test, is significantly and
independently associated with an increased risk of malignant ventricular
arrhythmias and sudden cardiac death in patients surviving acute myocardial
infarction. Several investigators have compared the standard phenylephrine test
and different noninvasive methods. HYPOTHESIS: This study evaluated the influence
of different body positions with different breathing regimes on cross-spectral
baroreflex indices (coherence between the spectral densities of blood pressure
and cardiac cycle variabilities) in both low- and high-frequency bands. METHODS:
The data were obtained in 103 patients (73 males, aged 53 +/- 12 years) with
coronary artery disease and/or hypertension. Simultaneous electrocardiographic
and noninvasive blood pressure recordings were obtained in each subject in both
supine and sitting positions during both spontaneous and slow and fast controlled
respiration (0.1 and 0.33 Hz). RESULTS: The results show a significant bias and
disagreement between noninvasive baroreflex sensitivity (BRS) indices. The mean
values of the baroreflex in low frequency ranged from 5.0 +/- 5.3 to 10.1 +/- 7.9
ms/mmHg, while in high frequency, the mean values ranged from 6.6 +/- 6.1 to 10.1
+/- 7.9 ms/mmHg. The limits of agreement ranged from +/-1.7 to +/-4.1 ms/mmHg
with bias from -1.0 to +0.7 ms/mmHg. CONCLUSION: A comprehensive comparison of
different methods shows that BRS estimated in low-frequency band in sitting
position during spontaneous respiration is the most representative part of the
global baroreflex gain.
PMID- 10761810
TI - L-arginine reduces heart rate and improves hemodynamics in severe congestive
heart failure.
AB - BACKGROUND: Stimulated endothelium-derived relaxing factor-mediated vasodilation
and conduit artery distensibility are impaired in congestive heart failure (CHF).
L-arginine could have a potentially beneficial role in CHF, acting through the
nitric oxide (NO)-L-arginine pathway or by growth hormone increment. HYPOTHESIS:
This study was undertaken to investigate the effects of L-arginine on heart rate,
hemodynamics, and left ventricular (LV) function in CHF. METHODS: In seven
patients (aged 39 +/- 8 years) with CHF, we obtained the following parameters
using echocardiography and an LV Millar Mikro-Tip catheter simultaneously under
four conditions: basal, during NO inhalation (40 ppm), in basal condition before
L-arginine infusion, and after L-arginine intravenous infusion (mean dose 30.4 +/
1.9 g). RESULTS: Nitric oxide inhalation increased pulmonary capillary wedge
pressure from 25 +/- 9 to 31 +/- 7 mmHg (p < 0.05), but did not change
echocardiographic variables or LV contractility by elastance determination. L
arginine decreased heart rate (from 88 +/- 15 to 80 +/- 16 beats/min, p<0.005),
mean systemic arterial pressure (from 84 +/- 17 to 70 +/- 18 mmHg, p < 0.007),
and systemic vascular resistance (from 24 +/- 8 to 15 +/- 6 Wood units, p<0.003).
L-arginine increased right atrial pressure (from 7 +/- 2 to 10 +/- 3 mmHg,
p<0.04), cardiac output (from 3.4 +/- 0.7 to 4.1 +/- 0.8 l/min, p < 0.009), and
stroke volume (from 40 +/- 9 to 54 +/- 14 ml, p < 0.008). The ratios of pulmonary
vascular resistance to systemic vascular resistance at baseline and during NO
inhalation were 0.09 and 0.075, respectively, and with L-arginine this increased
from 0.09 to 0.12. CONCLUSION: L-arginine exerted no effect on contractility;
however, by acting on systemic vascular resistance it improved cardiac
performance. L-arginine showed a negative chronotropic effect. The possible
beneficial effect of L-arginine on reversing endothelial dysfunction in CHF
without changing LV contractility should be the subject of further
investigations.
PMID- 10761811
TI - Images in cardiology. Wolff-Parkinson-White syndrome associated with a coronary
sinus diverticulum.
PMID- 10761812
TI - Images in cardiology. Acute severe mitral regurgitation due to unusual detachment
of bioprosthetic valve leaflet.
PMID- 10761813
TI - Images in cardiology. Multiple ecchymotic lesions on the torso of a patient with
unstable angina.
PMID- 10761814
TI - Images in cardiology. Cabrol perfusion graft.
PMID- 10761815
TI - Paroxysmal atrial fibrillation and insidious neck pain.
AB - Paroxysmal atrial fibrillation (AF) is an arrhythmia usually secondary to
autonomic imbalance, and it may occur in the absence of any structural heart
disease. The case of a patient with paroxysmal AF, in whom the arrhythmia may
have been a presenting symptom of a later diagnosed cervical schwannoma, is
reported.
PMID- 10761816
TI - Acetylcholine- and ergonovine-induced coronary microvascular spasm reflected by
increased coronary vascular resistance and myocardial lactate production.
AB - Diagnosis of coronary microvascular spasm remains largely speculative because it
has been mostly based on chest pain and electrocardiographic ST-segment shift
with slow filling of contrast medium into the coronary artery. A patient with
resting chest pain and normal coronary angiograms underwent provocative tests
with intracoronary acetylcholine (ACh) and ergonovine. During the tests, coronary
diameter and flow velocity in the left anterior descending (LAD) coronary artery
were measured with quantitative coronary angiography and intracoronary Doppler
guide wire, respectively. Vascular resistance of the LAD and lactate production
were determined separately. With injections of 100 microg of ACh and 20 microg of
ergonovine, chest pain occurred with ST-segment elevation in the precordial leads
in the absence of epicardial coronary spasm. Coronary vascular resistance
increased by 2.2- and 1.6-fold of the baseline value with ACh and ergonovine,
respectively. Myocardial lactate production was noted during the ST-segment
elevation. Coronary microvascular spasm was verified by the increment in coronary
vascular resistance and myocardial lactate production with concomitant ST-segment
elevation in the presence of normal coronary angiograms.
PMID- 10761817
TI - Evaluation of coronary subclavian steal syndrome using sestamibi imaging and
duplex scanning with observed vertebral subclavian steal.
AB - Coronary subclavian steal is defined as retrograde blood flow from the myocardium
through the internal mammary artery graft, secondary to a proximal subclavian
artery stenosis. The incidence of this syndrome in patients undergoing internal
mammary artery grafts for coronary artery bypass is estimated to be 0.44%.
Angiography remains the definitive diagnostic test for confirming this condition.
We describe a noninvasive method for evaluating coronary subclavian steal
syndrome in a 57-year-old man, with a 50-55% subclavian stenosis confirmed by
angiography. Noninvasive evaluation using duplex scanning demonstrated normal
vertebral artery blood flow. Technetium 99m-sestamibi (99mTc) imaging confirmed a
fixed anterolateral defect. When left-arm isometric exercise was employed,
retrograde vertebral artery blood flow was observed by Doppler imaging. A repeat
99mTc-sestamibi study documented an increase in tracer distribution in the
anterolateral defect confirming reperfusion of the myocardium through the left
internal mammary artery graft. The use of duplex scanning and 99mTc-sestamibi may
serve as an adjunct in evaluating coronary subclavian steal syndrome as well as
documenting transient vertebral subclavian steal in this patient population.
PMID- 10761818
TI - James Bryan Herrick.
PMID- 10761819
TI - Critical evaluation of the effect of valerian extract on sleep structure and
sleep quality.
AB - A carefully designed study assessed the short-term (single dose) and long-term
(14 days with multiple dosage) effects of a valerian extract on both objective
and subjective sleep parameters. The investigation was performed as a randomised,
double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12
female) with previously established psychophysiological insomnia (ICSD-code
1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the
study. The main inclusion criteria were reported primary insomnia according to
ICSD criteria, which was confirmed by polysomnographic recording, and the absence
of acute diseases. During the study, the patients underwent 8 polysomnographic
recordings: i.e., 2 recordings (baseline and study night) at each time point at
which the short and long-term effects of placebo and valerian were tested. The
target variable of the study was sleep efficiency. Other parameters describing
objective sleep structure were the usual features of sleep-stage analysis, based
on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored
according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective
parameters such as sleep quality, morning feeling, daytime performance,
subjectively perceived duration of sleep latency, and sleep period time were
assessed by means of questionnaires. After a single dose of valerian, no effects
on sleep structure and subjective sleep assessment were observed. After multiple
dose treatment, sleep efficiency showed a significant increase for both the
placebo and the valerian condition in comparison with baseline polysomnography.
We confirmed significant differences between valerian and placebo for parameters
describing slow-wave sleep. In comparison with the placebo, slow-wave sleep
latency was reduced after administration of valerian (21.3 vs. 13.5 min
respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased
after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1%
respectively, p<0.05). At the same time point, a tendency for shorter subjective
sleep latency, as well as a higher correlation coefficient between subjective and
objective sleep latencies, were observed under valerian treatment. Other
improvements in sleep structure - such as an increase in REM percentage and a
decrease in NREM1 percentage - took place simultaneously under placebo and
valerian treatment. A remarkable finding of the study was the extremely low
number of adverse events during the valerian treatment periods (3 vs. 18 in the
placebo period). In conclusion, treatment with a herbal extract of radix
valerianae demonstrated positive effects on sleep structure and sleep perception
of insomnia patients, and can therefore be recommended for the treatment of
patients with mild psychophysiological insomnia.
PMID- 10761820
TI - Influence of methodology on outcomes of randomised clozapine trials.
AB - The aim of this study was to clarify the impact of various methodological quality
factors on reported outcome of randomised clozapine trials. Trials comparing the
atypical antipsychotic clozapine with other antipsychotic drugs were identified
in extensive electronic searches. Two independent reviewers extracted data on
methodology and primary outcomes, and assessed trial quality by use of three sets
of criteria (Cochrane, Delphi, and Jadad). There was no association between trial
quality, as measured by any of the criteria sets, and primary measures of
outcome. Trials with the best score for randomisation and concealment according
to the Delphi scale had a significantly lower relative risk for relapse in
clozapine-treated groups, and studies with well reported random order generation
according to Jadad criteria tended to have better odds ratios for clinical
improvement on clozapine. These findings strengthen the evidence of true
clozapine superiority in these aspects. No other quality items correlated to the
primary outcomes. Inadequate randomisation techniques may be a source of bias in
clozapine studies, but much more research is needed on the connections between
trial quality and trial outcome.
PMID- 10761821
TI - Effect of the Hypericum perforatum extract on serotonin turnover in the mouse
brain.
AB - St. John's Wort, a traditional herbal medicine obtained from the extract of
Hypericum perforatum, has been used in the treatment of mild depression. Its
mechanism of action remains to be established. The present study confirmed that
Hypericum extract exhibited very weak inhibitory activities towards MAO. Mouse
brain MAO activities was unchanged following either acute or chronic treatment
with Hypericum extract. 5-HIAA levels were found to be significantly increased in
the cerebral cortex, hypothalamus, hippocampus and caudate 3 h after treatment
with the Hypericum extract at a dose as low as 10 mg/Kg. An increase of 5-HT
levels was also observed in hypothalamus and hippocampus. The increase of brain 5
HIAA was not further enhanced following chronic administration of the herb. The
Hypericum extract significantly reduced the plasma tryptophan levels, the
precursor of 5-HT. The action of Hypericum extract is consistent with the notion
that serotonergic system is involved. The effect of Hypericum extract on the
brain 5-HIAA and 5-FIT levels appeared to be quite different from the effect of
classical 5-HT re-uptake blockers.
PMID- 10761822
TI - Choosing antipsychotic maintenance therapy--a naturalistic study.
AB - Antipsychotic maintenance treatment is essential for preventing relapses of
schizophrenia, but the variety of available antipsychotics may complicate the
choice of drug. The aim of our naturalistic one-year follow-up study was to find
out the factors predicting the choice of antipsychotics in discharged patients
with schizophrenia or schizoaffective disorder and the predictors of one-year
rehospitalization. The patients were receiving oral or depot classical
antipsychotics or atypical agents clozapine or risperidone. Symptoms were
assessed with Present State Examination. Included were 447 patients (202 males
and 245 females) with a mean age of 39.1 years and 5.9 previous hospitalizations.
The majority of patients (n = 322) were receiving depot antipsychotics and 43
were prescribed atypical agents. Two predictive models were built using the
logistic regression analysis. Previously prescribed depot antipsychotics were
positively related to further depot use, while patients who left the hospital
against medical advice and those with slowness of speech at admission were less
likely to receive depot drugs. On the other hand, previously used atypical
antipsychotics and longer hospitalization predicted further use of atypical
agents while patients discharged to community care facilities or nursing homes
and those with more frequent previous hospitalizations were less likely to
receive atypical agents. The Cox survival analysis showed the following one-year
rehospitalization risk factors: diagnosis of schizoaffective disorder, frequent
previous hospitalizations, inappropriate behavior, and oral classical
antipsychotics versus depot or atypical agents. This study may yield some insight
into the decision-making process in everyday clinical work regarding the choice
of antipsychotic maintenance medication and its influence on rehospitalization
rate.
PMID- 10761823
TI - Schizophrenic psychosis: a contraindication for treatment of hepatitis C with
interferon alpha?
AB - Depressive or psychotic symptoms are a well known side-effect of interferon alpha
(INF-alpha). Therefore, the questions arises whether a chronic psychosis should
be considered a contraindication for the treatment of active hepatitis C with INF
alpha. We report on a 38-year-old woman with a chronic schizophrenic psychosis,
who acquired chronic aggressive hepatitis C. Considering the young age of the
woman, the potential risk of developing a hepatocellular carcinoma and the result
of the liver biopsy, treatment with interferon alpha 2 b (3x5 million IU/week)
was started. The patient was seen three times a week, her psychiatric condition
was monitored using the positive and negative symptoms score (PANSS). No signs of
psychotic or depressive symptoms appeared during INF-alpha therapy. During the
first 6 months the liver enzymes dropped slowly but the virus load was
increasing. After adding ribavirin to the therapy, the liver enzymes dropped
again, and the PCR carried out 9 months after initiation and 6 months after the
end of the 12 months INF-alpha treatment did not detect any virus RNA. This
positive result should encourage prospective studies including patients with
these two diagnoses on whether patients benefit from INF-alpha.
PMID- 10761824
TI - Are low basal serum levels of the thyroid stimulating hormone (b-TSH) a risk
factor for switches into states of expansive syndromes (known in Germany as
"maniform syndromes" in bipolar I depression?
AB - Switching over from depression into states known an "maniform" in Germany
("expansive syndromes") been frequently, observed and appears to be partially
related to the type of antidepressive medication. Apart from the medication, some
evidence suggests that additional factors such as thyroid function may be
relevant for the switchover. With this background, the aim of the present study
was to evaluate the hypothesis that depressed bipolar patients with lower basal
TSH serum levels (b-TSH) on admission at the hospital as inpatients are at a
higher risk of switching from depression into "maniform" states than depressed
bipolar patients with higher b-TSH. From a total of 158 bipolar depressed
patients, 16 patients developed mania during their hospital stay. After dividing
the sample of patients at the median b-TSH into one group with lower b-TSH (N =
78) and another group with higher b-TSH (N = 79), we found that the switchover
rate to mania was significantly higher in the group of patients with lower b-TSH
(15.4%) than in the group of patients with higher b-TSH (5.1 %). These findings
suggest that lower b-TSH may be a risk factor for switching over from depression
into "maniform" states in bipolar depressed patients.
PMID- 10761825
TI - Healthy outcome under olanzapine treatment in a pregnant woman.
AB - Our report focuses on the case of a pregnant women with recurrent, paranoid
schizophrenia. The patient was treated with Olanzapine from the 18th gestational
week until delivery and during breast-feeding. No adverse events occurred during
pregnancy, and the outcome was healthy. After delivery, the plasma level of
olanzapine in the infant was one-third of the maternal plasma level, and during
breast-feeding, it decreased to an undetectable limit.
PMID- 10761826
TI - The neurological complications of achondroplasia.
AB - The genetics of achondroplasia are discussed, and then the clinical features. The
respiratory complications are only considered when related to the neurological
ones which are the concern of this paper; and their effects on morbidity and
mortality. Cervicomedullary compression can cause pain, ataxia, incontinence,
apnea, and respiratory arrest. One of the signs can be progressive quadriparesis
which can be a presenting symptom; and may be caused by a vascular lesion as well
as by cord compression. Also nerve root compression in the neural foramina can
cause symptoms and signs in the limbs. Enlargement of the head is a feature of
achondroplasia. This may be due to subdural haematoma related to the wide
subarachnoid spaces, and to trauma. Hydrocephalus is common, and may be non
communicating and due to aqueduct stenosis, but is much more often communicating
and the result of raised intracranial venous pressure. Shunting may be necessary,
but surgery directed towards relieving the venous pressure may be more logical.
Otitis media often affects these children, and can cause deafness and
subsequently delayed language development. Sleep disturbances can be the result
of both neurological and respiratory complications. Apart from the treatment for
hydrocephalus the most important decision is often the question of operating on
the cervical medullary compression. Risk factors such as brisk reflexes, small
foramen magnum, and central hypopnea, can be an indication for surgery; but
timing can be difficult as the cord compression can resolve spontaneously. The
intelligence levels of these children are usually normal, and studies have shown
a surprisingly high level of satisfaction with the services provided.
PMID- 10761827
TI - Restoration of biochemical function of the peroxisome in the temperature
sensitive mild forms of peroxisome biogenesis disorder in humans.
AB - We have found that peroxisome assembly is temperature-sensitive (ts) in mild
forms of peroxisome biogenesis disorders (PBDs), that is all infantile Refsum
disease (IRD) patients and a few neonatal adrenoleukodystrophy patients of
several complementation groups. The number of peroxisomes increased daily in
incubation at 30 degrees C in the ts cells. Oxidation of very long-chain fatty
acids, processing of acyl-CoA oxidase and dihydroxyacetonephosphate
acyltransferase activity also improved after 8 days incubation at 30 degrees C in
the IRD fibroblasts. These biochemical functions of the peroxisome did not change
at 30 degrees C in Zellweger fibroblasts. Number of peroxisomes gradually
decreased after 4 days when the temperature shifted from 30 to 37 degrees C in
the ts cells. These results indicate that the biochemical functions of peroxisome
are also restored by incubation at 30 degrees C in the mild and ts phenotype of
PBDs, and the results will aid to predict the severity and the prognosis of
affected children.
PMID- 10761828
TI - Reading of kana (phonetic symbols for syllables) in Japanese children with
spastic diplegia and periventricular leukomalacia.
AB - In 31 Japanese children with spastic diplegia and periventricular leukomalacia
(PVL), the age at which they could read Hiragana (phonetic symbols for syllables)
and psychometric data were examined. Reading of Hiragana was achieved between 2
and 8 years of age in all subjects except one. Four children could read Hiragana
at 2 to 3 years of age, an age which is considered early among Japanese children.
Performance IQs of the Wechsler Scale were lower than Verbal IQs in 18 of 19
children who were administered this test, and DQs of the cognitive adaptive (C-A)
area of the K-form developmental test (a popular test in Japan) were lower than
those of the language social area in all 12 children taking this test. Among
eight children having performance IQs or DQs of C-A less than 50, seven acquired
reading ability of Hiragana at 8 years of age or below. A visuoperceptual
disorder manifested by diplegic children with PVL does not affect the acquisition
of Kana-reading ability.
PMID- 10761829
TI - The perfusion defect seen with SPECT in West syndrome is not correlated with
seizure prognosis or developmental outcome.
AB - We used interictal single photon emission computed tomography (SPECT) on 40
patients with West syndrome to determine whether cortical perfusion abnormalities
are closely related to the development of West syndrome and whether they are
correlated with the long-term seizure prognosis or the developmental outcome.
Localized cortical perfusion abnormalities were seen in 24 patients (60%), while
15 patients (38%) were classified as normal. The remaining patient showed
hyperperfusion of the basal ganglia bilaterally. Of 24 patients with localized
perfusion abnormalities, unifocal cortical hypoperfusion was present in 11,
multifocal hypoperfusion in 10, multiple cortical hypo- and hyperperfusion in
one, hyperperfusion of the bilateral frontal cortices and brain stem in one, and
focal hyperperfusion in the residual frontal cortex in one. For statistical
analysis, we focused on 26 patients (cryptogenic; 10, symptomatic; 16), who were
followed for more than 2 years after the onset of tonic spasms (mean 5.0 years).
The results showed that focal cortical perfusion abnormalities were not
correlated with the long-term seizure prognosis, the developmental outcome, or
the response to ACTH therapy. In agreement with previous reports, the results of
interictal SPECT suggested that focal cortical lesions play an important role in
the development of West syndrome. However, statistical analysis showed that the
existence of cortical dysfunction as defined by SPECT did not predict the seizure
prognosis or the developmental outcome.
PMID- 10761830
TI - A neurodegenerative disorder with early myoclonic encephalopathy, retinal
pigmentary degeneration and nephronophthisis.
AB - A female case of developmental arrest, early-onset seizures, retinal pigmentary
degeneration, progressive central nervous symptoms and peripheral neuropathy,
associated with progressive renal dysfunction, anemia and nephrotic syndrome, was
presented. Her epileptic syndrome was possibly an early myoclonic encephalopathy,
though neonatal seizures were not evident. Serial cranial MRIs showed progressive
brain atrophy and a white matter change. Neuropathological examination revealed a
neurodegenerative disease mainly involving the white matter with
olivopontocerebellar degeneration. She also had the nephronophthisis-medullary
cystic disease complex and an early stage of focal segmental glomerulosclerosis.
Her grandaunts had renal diseases, one of whom died of renal failure in
adolescence, and her father showed cerebellar symptoms since the middle age. All
possible metabolic studies were negative. This case is similar to Senior-Loken
syndrome, but distinct in terms of the severe and progressive neurological
symptoms, suggestive of a new malignant syndrome with some inherent metabolic
derangement affecting both the nervous system and the kidneys.
PMID- 10761831
TI - Mental retardation subsequent to refractory partial seizures in infancy.
AB - Whether seizures are the direct cause of cognitive deterioration in epileptic
children is undetermined. This retrospective study aimed to delineate a subgroup
of pediatric patients with cognitive deterioration and refractory seizures in the
absence of recognized causes for mental retardation. Of the 80 children
identified as having mental retardation and refractory seizure disorder, seven
(8.7%) had normal cognitive development until at least 1 year of age. Their
metabolic status was normal. Five of them suffered repeated frequent partial
seizures with onset in the first year of life and two had repeated episodes of
status epilepticus. All seven had similar characteristics of early onset partial
seizures, six of them had partial seizures secondarily generalized and one had
complex partial seizures. The time of peak cognitive deterioration correlated
with increases in seizure frequency during that period. Evaluation revealed a
well-defined epileptic focus in the absence of neuroimaging abnormality except
for hippocampal atrophy in the two children with complex partial seizures and a
small vascular malformation in one child. Uncontrolled partial seizures in the
first months of life may result in cognitive deterioration.
PMID- 10761833
TI - Developmental changes of distortion product and transient evoked otoacoustic
emissions in different age groups.
AB - The developmental changes of distortion product otoacoustic emissions (DPOAEs)
and transient evoked otoacoustic emissions (TEOAEs) were evaluated in 275 normal
subjects aged from 1 month to 39 years. The DP-grams showed an M-shaped pattern
with peaks at 1587 Hz and 5042 Hz for all age groups. In subjects younger than 3
years, low frequency DPOAEs did not rise above the noise floor. The DP levels at
high frequency (5042 Hz) did not change much from infancy to young adulthood
(12.9-16.5 dB SPL), however, those at low and middle frequency significantly
decreased with age. Total echo power (TEP) of TEOAE was greatest in early
infancy, decreased rapidly before 6-7 years old, and then decreased gradually
(TEP = 16.6 - 1.9 X ln (age)). Wave reproducibility was constant across age. The
frequency area peak power (FAPP) to middle and high frequency sounds changed
little with age, however, FAPP at low frequency sounds dramatically increased
with age. FAPP at 5000 Hz was relatively depressed levels at each age. The TEOAE
value was more prominent at middle and low frequencies while DPOAE was
predominant at high frequencies. These two measurements may reflect different
functions of outer hair cells in the developing cochlea.
PMID- 10761832
TI - Phenytoin administration in the newborn and infant.
AB - To evaluate the efficacy and safety of phenytoin (PHT) in the treatment of
situation-related seizures and epilepsies in the newborn and infant; the clinical
histories of 82 patients were retrospectively reviewed. Sixty patients received
for status epilepticus (SE), intravenous PHT followed by long-term oral
administration for 27 of them. The other 22 patients had oral treatment only.
Intravenous administration made 55% of these patients seizure-free, whereas oral
administration produced lasting seizure control in only 9.1%. During chronic oral
treatment, it was most difficult to obtain adequate plasma concentrations in
69.1% of the patients, and 43.6% had side effects, most of which were related to
very high plasma concentrations. In conclusion, in the first 2 years of life,
intravenous administration of PHT is useful for SE, but oral treatment is poorly
effective with difficulty to achieve appropriate and stable therapeutic plasma
concentrations, and with frequent side effects.
PMID- 10761834
TI - A case of chronic infantile type of fucosidosis: clinical and magnetic resonance
image findings.
AB - Fucosidosis is a rare autosomal recessive disorder resulting from a deficiency of
alpha-L-fucosidase. In this report, we describe clinical and magnetic resonance
image (MRI) findings of a chronic infantile type patient heterozygous for a
nonsense mutation and a large deletion. The disease onset occurred at 2-3 years
of age. She was bound to a wheelchair at 6 years of age, and developed dystonia
at the age of 13 years. Brain MRI at 13 years of age showed marked cerebral and
cerebellar atrophy, high intensities in the white matter of the frontal and
occipital lobes, and low intensities of the bilateral thalamus, striatum,
substantia nigra, red nucleus and mamillary bodies on T2-weighted images. The low
intensities of basal ganglia on T2-weighted images seems characteristic of
lesions in fucosidosis.
PMID- 10761835
TI - Transient seizure disappearance due to bilateral striatal necrosis in a patient
with intractable epilepsy.
AB - An 8-year-old girl had suffered from intractable epilepsy due to cortical
dysplasia. She developed mycoplasma pneumonia with massive pleural effusion.
Fever continued for 3 weeks. Four weeks after the onset of this infection, she
suddenly developed horizontal nystagmus, ataxia, choreoathetotic movements and
confusion. CT disclosed swelling and low density of the heads of the caudate
nuclei and putamina bilaterally. MRI revealed areas of symmetrical high intensity
in the striatum on T2-weighted imaging. These lesions were thought to comprise
bilateral striatal necrosis (BSN) mediated by the mycoplasma infection or
Wernicke encephalopathy. Six months later, she had completely recovered
clinically. During the 6 months after BSN, she did not have any epileptic
seizures. Her epileptic seizures reappeared thereafter at a lower frequency. The
striatum may be involved in the propagation pathway for epileptic seizure
activity in this patient.
PMID- 10761836
TI - Successful control with bromide of two patients with malignant migrating partial
seizures in infancy.
AB - A 3-month-old male and a 4-month-old female infant with intractable seizures were
diagnosed as having malignant migrating partial seizures in infancy (MMPSI) with
developmental arrest on the basis of characteristics of symptoms, clinical
courses and EEGs. We treated these two patients with potassium bromide (80 mg/kg)
after conventional antiepileptic drugs failed to adequately control the seizures.
The potassium bromide therapy resulted in complete control of seizures in one
patient, and more than 95% reduction in seizure frequency in the other.
PMID- 10761837
TI - Chronic fatigue syndrome in childhood.
AB - Chronic fatigue occurring in previously healthy children and adolescents is one
of the most vexing problems encountered by pediatric practitioners. We report
three cases, 11, 12 and 13-year-old children, with chronic fatigue syndrome
(CFS). They initially developed a low grade fever and generalized fatigue,
followed by sleep disturbance and psychosomatic symptoms, and their performance
ability deteriorated. They were diagnosed as having CFS on the basis of criteria.
To investigate the brain function in CFS patients, we examined the regional
cerebral blood flow by single-photon emission-computed tomography (SPECT) with
111 MBq [123I]-iodoamphetamine (123I-IMP) or xenon-computed tomography (Xe-CT),
and brain metabolic levels by MR spectroscopy (MRS). Blood flow, expressed as the
corticocerebellar ratio (CCR), in the left temporal and occipital lobes was
markedly lower in cases 2 and 3 than that in healthy subjects reported by another
investigator. In case 1, however, blood flow in the left basal ganglia and
thalamus was markedly higher than in healthy subjects. The MR spectroscopy (MRS)
study revealed remarkable elevation of the choline/creatine ratio in the patients
with CFS. None of our patients exhibited evidence of focal structural
abnormalities on MRI. These findings suggest that the various clinical symptoms
in CFS patients may be closely related to an abnormal brain function.
PMID- 10761839
TI - The recent development of development in Britain.
PMID- 10761838
TI - Perturbation in dystrophin-associated glycoprotein complex in a boy with Becker
muscular dystrophy.
AB - We report on a boy with a BMD phenotype presenting with a deletion of exons 45-49
in the DMD gene. Immunofluorescence and Western blot analysis of a skeletal
muscle sample revealed, as expected, truncated dystrophin with loss in the
central rod domain, but with an unusual severe deficiency in the sarcoglycan
complex, as in severe DMD. We discuss possible neighboring between dystrophin and
associated proteins within their complex organization at the muscle membrane.
PMID- 10761840
TI - Biographical memoir on Joseph Needham (1900-1995).
PMID- 10761841
TI - Conrad H. Waddington's contributions to avian and mammalian development, 1930
1940.
PMID- 10761842
TI - Michael Abercrombie (1912-1979).
PMID- 10761843
TI - Embryonic development of heads, skeletons and amphioxus: Edwin S. Goodrich
revisited.
PMID- 10761844
TI - Development at the edge of multi-cellularity: Dictyostelium discoideum.
PMID- 10761845
TI - Worm tales.
PMID- 10761846
TI - The introduction of Xenopus laevis into developmental biology: of empire,
pregnancy testing and ribosomal genes.
PMID- 10761847
TI - Mammalian development in the UK (1950-1995).
PMID- 10761848
TI - A UK-centric history of studies on the mouse t-complex.
PMID- 10761849
TI - Developmental genetics in Sheffield: a meeting point for Hedgehog researchers.
PMID- 10761850
TI - A brief history of developmental biology at the National Institute for Medical
Research.
PMID- 10761851
TI - A short history of the British Society for Developmental Biology.
PMID- 10761852
TI - From engineering to positional information to public understanding. An interview
with Lewis Wolpert. Interview by James C Smith.
PMID- 10761853
TI - Not a total waste of time. An interview with John Gurdon. Interview by James C
Smith.
PMID- 10761854
TI - Limb development: an international model for vertebrate pattern formation.
AB - Limb development is an excellent model for studying how patterns of
differentiated cells and tissues are generated in vertebrate embryos. The cell
interactions that mediate patterning have been discovered and, more recently,
some of the molecules involved in these interactions have been identified. This
has provided a direct link to genetics and thus to genes that cause human
congenital limb defects.
PMID- 10761855
TI - Evolutionary shifts of vertebrate structures and Hox expression up and down the
axial series of segments: a consideration of possible mechanisms.
AB - The term 'transposition' describes how, during vertebrate evolution, anatomical
structures have shifted up or down the axial series of segments. For example, the
neck/thorax junction and the position of the forelimb in the chicken have shifted
posteriorly, relative to mouse, by a distance of seven somites or vertebrae. By
examining the expression boundaries of some chick Hox genes not previously
described, we provide new evidence that axial shifts in anatomical structures
correspond with shifts in Hox expression domains. These shifts occur both in
mesodermal components (somites, vertebrae, and lateral plate mesoderm) and neural
components (spinal ganglia). We discuss morphogen gradient, timing, spreading,
and growth models for the setting of Hoxexpression boundaries, and consider how
evolutionary shifts in boundary positions might have been effected in terms of
these models.
PMID- 10761856
TI - Orienting axon growth: spinal nerve segmentation and surround-repulsion.
AB - The study of spinal nerve trajectories in higher vertebrate embryos has revealed
an inherent polarity within somites along the antero-posterior axis, and provides
a simple system in which to study the factors that influence axon pathfinding. We
argue that the orientation of spinal axons is determined by the simultaneous
operation of two distinct guidance mechanisms, contact repulsion and
chemorepulsion. Motor and sensory axons traverse the anterior half of each somite
because they are excluded by contact repulsion from the posterior half-somite,
and the molecular nature of several candidate contact repellents is reviewed. In
contrast, we find that the dorsoventral trajectory of primary sensory axons is
oriented by diffusible repellents originating from the notochord medially and
dermamyotome laterally. In this system, therefore, repulsion by surrounding
tissues ('surround-repulsion') is the main force directing axon growth in three
dimensions.
PMID- 10761857
TI - Effects of follistatin and BMP4 proteins on early dorso-ventral patterning in
chick.
AB - In Xenopus and zebrafish certain bone morphognetic proteins (BMPs), and proteins
that antagonise these by preventing their interaction with receptors, constitute
a morphogen system in primary dorso-ventral patterning. This system may be
directly involved in the parallel processes, within mesoderm and ectoderm,
whereby the boundaries of the dorsal (paraxial) mesoderm and the neural plate are
established. The bird blastoderm, amenable to grafting techniques and to direct
exposure to specific proteins, has provided an opportunity to explore the
phylogenetic conservation of such antagonistic system. We have grafted the
gastrular organiser (node) into hosts, testing the effects of prior exposure of
either grafted or host tissue to Follistatin (a known antagonist of TGFbeta
superfamily ligands including BMP4) or to BMP4 protein. Strong, converse effects
are seen from the two agents, the most consistent being on the sizes of new
dorsalised areas (second neural plates) induced in host epiblast. Follistatin
also enhances extension movements due to grafts, though without clear effect upon
the rostro-caudal completeness of new patterns. Neural induction in chick
epiblast by grafted mouse nodes are also more extensive, after their pre
incubation in Follistatin. Follistatin potentiates other, unknown but distinctive
signals coming from the node, being unable to convert other non-inducing pieces
of blastoderm into organisers on grafting. Pre-incubation of early blastoderms in
BMP4 has such profound effects on normal dorsal axial development that host
responsiveness of these blastoderms as hosts to node grafts is difficult to
assess. Follistatin has no such overt effect on host development, but greatly
enhances the competence of host epiblast to grafts of untreated nodes. Early
chick BMP4 and BMP7 expressions are consistent with the proposed roles, though
Follistatin is probably an experimental tool only in the present study.
PMID- 10761858
TI - Expression pattern of BXR suggests a role for benzoate ligand-mediated signalling
in hatching gland function.
AB - The Xenopus laevis nuclear receptor BXR has recently been shown to be activated
by a class of endogenous benzoate metabolites, indicating the presence of a novel
and unsuspected benzoate ligand-dependent signalling pathway. The receptor is
expressed ubiquitously in blastula and gastrula stage embryos, and its expression
declines during neurula stages. In order to examine further this novel vertebrate
signalling system, we have examined the expression of the BXR gene in tailbud
stage embryos and adults. We show here that in Xenopus tailbud stage embryos
expression is restricted to the hatching gland, suggesting a role in hatching
gland function. Neither BXR nor a BXR-VP16 fusion is sufficient to specify
hatching gland in neurally-induced tissue. In adults, BXR expression is abundant
in the brain and gonads. This expression pattern in adults is distinct from any
of the putative mammalian homologues. A nuclear receptor that mediates benzoate
signalling has yet to be found in mammals.
PMID- 10761859
TI - Igf2 imprinting in development and disease.
AB - Igf2 is one of the first imprinted genes discovered and occupies a centre stage
in the study of imprinting. This is because it has dramatic effects on the
control of fetal growth, it is involved in growth disorders and in cancer, it
interacts with products of other imprinted genes, and its imprinting status is
under complex regulation in a cluster of tightly linked imprinted genes. Here we
review briefly the key features of Igf2 imprinting in normal development and in
disease, and hope to show what a fascinating subject of study this gene and its
biology provides.
PMID- 10761860
TI - Abnormalities of somite development in the absence of retinoic acid.
AB - We describe the effects of an absence of retinoic acid (RA) on the development of
somites in the quail embryo. RA was removed by generating vitamin A deficient
quail embryos whereupon the resulting defects in the embryos can be analysed. The
effect on the somites is threefold. Firstly, they are half the size of normal,
but the total number of somites is the same as normal. There has therefore been
some global regulation event. Secondly, by TUNEL staining and TEM we show that
the lateral halves of all of the somites undergo apoptosis between stages 11 and
14. This effect is confined to the sclerotome of the somites. Thirdly, some of
the genes involved in somite differentiation are down-regulated such as fgf-4,
fgf-8, engrailed and myogenin whereas others we examined such as cek-8, Delta,
follistatin and myf5 are not affected. These studies reveal remarkably specific
effects of RA on developmental gene pathways in the embryo.
PMID- 10761861
TI - Studies of the mechanism of amniotic sac puncture-induced limb abnormalities in
mice.
AB - The principal advantage of chorionic villus sampling (cvs) over amniocentesis for
the determination of the genetic constitution of the embryo is that it may be
undertaken earlier in pregnancy. If carried out too early in pregnancy, it has
the risk of inducing craniofacial and limb abnormalities, a condition termed the
oromandibulofacial limb hypogenesis (OMFL) syndrome in genetically normal
infants. It is believed that the defects observed have a vascular origin,
possibly due to anoxia of tissues due to fetal blood loss or thrombus formation
at the site of biopsy with distal embolization. We believe that this does not
adequately explain the findings from the experimental animal literature involving
amniotic sac puncture (ASP). Based on these experimental findings, we have
hypothesised that (i) the defects observed following cvs may result from the
consequences of oligohydramnios following the inadvertent puncturing of the
amniotic sac during this procedure, and (ii) that cleft palate and the postural
limb defects observed (e.g., clubfoot and clubhand) are secondary to
embryonic/fetal compression. Our experimental studies shed new light on the
mechanism of induction of the limb defects seen, but particularly syndactyly.
Evidence of hypoperfusion of the peripheral part of the developing limb bud is
observed, which interferes with apoptosis that occurs in the digital interzones,
or induces an abnormal degree of cellular proliferation and/or tissue
regeneration in these sites, possibly because of over-expression of critical
genes involved in limb pattern specification. Cleft palate, tail abnormalities
and abnormalities of sternal ossification are also observed in our model.
PMID- 10761862
TI - The aetiology of Type I diabetes.
AB - The aetiology of Type I diabetes involves both genetic and environmental factors.
The genes implicated are 'susceptibility genes', which modify risk. Individual
susceptibility genes may not be required and are not sufficient for disease
development. The strongest genetic risk component is encoded within the major
histocompatibility complex (MHC) and is designated IDDM I. The HLA-DQ genes
contribute to the risk, but so may other MHC-encoded genes. The susceptibility
encoded by IDDM2 refers to a variable number of tandem repeats in the insulin
gene region. Many other genomic regions have been designated as susceptibility
intervals potentially containing candidate genes. Environmental factors appear to
be important in disease expression in either a causative or a protective role.
Epidemiological data indicate that such factors operate from early in life. Viral
infection(s) may have a disease-initiating and/ or accelerating effect. A
potential diabetogenic role for cows' milk protein remains unconfirmed. Further
research is necessary to elucidate fully the aetiological factors involved and
how they interact.
PMID- 10761863
TI - The epidemiology of Type 2 diabetes and its current measurement.
AB - Type 2 diabetes is globally increasing in prevalence and is widely recognized as
a major cause of morbidity and mortality, as well as being a burden to the health
care services. Planning for current and future diabetes services requires up-to
date prevalence information. The enumeration of Type 2 diabetes is, however,
surprisingly difficult. Large numbers of people are undiagnosed, and those known
cases have variable loci of care. Traditional techniques include cross-sectional
diagnostic surveys, postal or house-to-house surveys and cohort surveys. All are
time-consuming and expensive, and may potentially undercount. The use of multiple
patient lists (e.g. hospital clinic data, general practitioner (GP) lists,
prescribing information, etc.) can, however, increase accuracy and, if the data
are computerized, may be rapid and inexpensive. A new and potentially exciting
tool to utilize multiple lists in Type 2 diabetes prevalence assessment is known
as 'capture-recapture'. In this, statistical models are used to estimate
prevalence from the degree of overlap between lists. Capture-recapture is
emerging as a valuable tool in the epidemiological assessment of Type 2 diabetes.
PMID- 10761864
TI - Obesity and diabetes.
AB - Obesity, particularly truncal obesity, is closely correlated to the prevalence of
diabetes and cardiovascular disease. Plasma leptin, tumour necrosis factor-alpha
and non-esterified fatty acid levels are all elevated in obesity and play a role
in causing insulin resistance. Diabetic glycaemic control and insulin resistance
improve with reductions in obesity, but the treatment of obesity is difficult,
and sustained weight reduction rarely occurs with dietary management alone.
Hypocaloric diets should be combined with education and low-impact exercise, as
well as behavioural techniques used to encourage long-term changes. Weight
reducing drugs have a role in the management of obesity but only as part of such
a total package. Newer anti-obesity drugs such as orlistat and sibutramine are
well tolerated and have been shown to improve glycaemic control in diabetes. It
is probable that drugs developed in the future will act at different sites in the
pathways regulating body weight, but they may have to be used in combination.
PMID- 10761865
TI - Diabetic nephropathy.
AB - Diabetic nephropathy remains a leading cause of end-stage renal disease (ESRD) in
western societies, accounting for over one-third of all patients beginning renal
replacement therapy. Patients with Type 2 diabetes comprise the largest and
fastest-growing single disease group requiring renal support therapy. In addition
to the high risk of progression to ESRD, diabetic nephropathy is associated with
a very high risk of cardiovascular morbidity and mortality, which is not
abolished by dialysis and renal transplantation. While the prognosis of patients
with diabetic nephropathy has considerably improved, a greater focus has recently
been placed on treating diabetic patients early in order to prevent future organ
failure. Microalbuminuria is an important intermediary end-point that correlates
strongly with future advanced renal disease and cardiovascular mortality. Recent
evidence indicates that optimum glycaemic control, tight blood pressure control,
and the regular screening for and early treatment of microalbuminuria are
necessary to prevent the development and progression of diabetic renal disease.
By utilizing such strategies, the challenge is to reduce the cumulative incidence
of overt nephropathy, with its associated increase in cardiovascular mortality,
and the requirement for renal support therapy. Over the next 5-10 years, the
patient with Type 2 diabetes will need to be the specific focus of such
preventive treatment modalities.
PMID- 10761866
TI - Diabetic dyslipidaemia.
AB - The risk of coronary heart disease and atherosclerosis is increased in both Type
2 and Type I diabetes mellitus. The dyslipidaemia of Type 2 diabetes consists of
hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)
cholesterol. In Type I diabetes, hypertriglyceridaemia is also present, but when
glycaemic control is good, HDL cholesterol levels may be normal or even
increased. In both types of diabetes, nephropathy is associated with an
exacerbation of hypertriglyceridaemia, a decline in HDL cholesterol level and an
increase in serum cholesterol. In the absence of nephropathy, serum cholesterol
levels are typically similar to those of the background non-diabetic population.
The risk of coronary heart disease (CHD) associated with serum cholesterol is,
however, considerably higher in diabetics than in non-diabetic people, and is
much less in diabetic populations living in countries where the average
cholesterol level is low, even when hypertension is present. Currently, the
strongest evidence that lipid-lowering drug therapy will decrease the risk of
CHD, particularly in secondary prevention, comes from trials of statins that
lower cholesterol. There is growing experimental and observational evidence that
hypertriglyceridaemia, because of its effects on cholesteryl ester transfer,
leading to the formation of a small low-density lipoprotein susceptible to
oxidation, compounds the risk of serum cholesterol in diabetes. Both fibrates and
statins can decrease this cholesteryl ester transfer. Further studies of fibrates
with clinical end-points should clarify their role in the prevention of CHD. In
the meantime, statins should be part of routine diabetic clinical practice,
fibrates having a more limited role when hypertriglyceridaemia is extreme.
PMID- 10761867
TI - Diabetic hypoglycaemia.
AB - Hypoglycaemia is a major factor preventing insulin-treated patients from
achieving normoglycaemia. This reflects the inadequacy of current insulin
treatment, which causes high insulin concentrations in the post-absorptive
period. Physiological defences to hypoglycaemia include autonomic activation,
which limits the fall in glucose level and causes symptoms, alerting patients to
an impending episode. Many patients develop defective responses and hypoglycaemia
unawareness after longstanding disease or with tight glycaemic control and are
then prone to severe attacks. This may be the result of repeated hypoglycaemic
episodes, which by altering cerebral glucose uptake, disturb the mechanisms that
activate the central response to hypoglycaemia. Preventing further hypoglycaemia
can partially reverse these defects and restore symptomatic awareness. Clinical
hypoglycaemia has also been implicated in the 'dead in bed' syndrome and in
chronic cognitive impairment. The problem of hypoglycaemia will eventually be
solved by better insulin delivery and non-invasive glucose meters, but until
then, more focused education may have a more substantial impact.
PMID- 10761868
TI - Painful diabetic neuropathy.
AB - Chronic painful diabetic neuropathy can cause a variety of challenges,
particularly in successful treatment. The pain, which can last for years, can
severely impair quality of life. Management is difficult, although the careful
use of drugs can be significantly beneficial. Tricyclic and anticonvulsant drugs
may be effective, with a variety of drugs available as second line agents. Newer
non-drug systems such as electrical spinal cord stimulation represent exciting
possibilities for the future management of this most difficult diabetic syndrome.
PMID- 10761870
TI - Diabetes and myocardial infarction.
AB - Myocardial infarction (MI) is a common cause of mortality in people with
diabetes. The case fatality from MI is high and may be reduced by thrombolysis
and treatment with aspirin, beta-blockers and angiotensin-converting enzyme
inhibitors. Poor metabolic control is common among diabetic patients with MI, but
the importance of controlling blood glucose during and following an MI is
debatable. Treatment with statins reduces cardiovascular end-points in diabetic
patients with previous MI (secondary prevention). Large studies in diabetic
patients without existing heart disease have shown statistically insignificant
reductions in heart disease and MI with improved glycaemic control of the
diabetes (primary prevention). The treatment of hypertension in people with
diabetes prevents cardiovascular end-points, and studies on whether the treatment
of hyperlipidaemia reduces heart disease and MI are proceeding.
PMID- 10761869
TI - New agents for Type 2 diabetes.
AB - Current agents for the treatment of Type 2 diabetes mellitus improve the
metabolic profile but do not reinstate normality. They also reduce chronic
diabetic complications, but they do not eliminate them. Thus, new agents with
novel actions are required to complement and extend the capabilities of existing
treatments. Insulin resistance and beta-cell failure, which are crucial
components in the pathogenesis of Type 2 diabetes, remain the underlying targets
for new drugs. Recently introduced agents include a short-acting non
sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion
with meal digestion in order to reduce post-prandial hyperglycaemia. The
thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a
new class of agonists for the nuclear receptor peroxisome proliferator-activated
receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain
insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal
lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight
reducing agents that may benefit glycaemic control in obese Type 2 diabetes
patients. Several further new insulin-releasing agents, and agents to retard
carbohydrate digestion and modify lipid metabolism stand poised to enter the
market. The extent to which they will benefit glycaemic control remains to be
seen. However, the prospect of permanently arresting or reversing the progressive
deterioration of Type 2 diabetes continues to evade therapeutic capture.
PMID- 10761871
TI - A histological and electron-microscopic study of the architecture and
ultrastructure of human periodontal tissues.
AB - The structure of periodontal tissues is still far less understood than their
clinical relevance would demand. Here the periodontal ligament and radicular
cementum in healthy human teeth were studied by light microscopy, transmission
and scanning electron microscopy. These observations showed that the
extracellular matrix of periodontal ligament is composed of a loose plexus of
wavy collagen fibrils immersed in a highly hydrated interfibrillar matrix. Only
close to their cemental insertion do these fibrils gather in thick, parallel
fascicles (Sharpey's fibres). As these cross the mineralization front, they
become infiltrated by the mineral phase and continue directly with the cementum
matrix. Sharpey's fibres, "extrinsic" and "intrinsic" fibres all appear to be the
same fibres, which bend and branch repeatedly during their course within the
thickness of the cementum. Because of its physical continuity with the cementum,
a limited portion of the periodontal ligament approximately corresponding to the
length of Sharpey's fibres remains unaffected by enzymatic digestion of the
interfibrillar matrix while the rest of the ligament is completely dissolved. The
findings here indicate that the periodontal ligament and dental cementum join by
a continuity rather than a contiguity of structures; that the collagen-mineral
relation in cementum has distinctive features in comparison to other hard
tissues; that extrinsic and intrinsic fibres of cementum and the adjoining
portion of periodontal ligament form a structural, mechanical and metabolic unit
distinct from the central, more metabolically active portion of the periodontal
ligament.
PMID- 10761872
TI - The effect of sucrose diet of rat dams on the dentine apposition and dental
caries of their pups.
AB - The purpose was to examine whether a sucrose diet in rat dams reduces dentine
apposition and enhances dental caries in their pups. Sprague-Dawley rat pups were
randomized into four groups on the day of birth. During the lactation period
three dams received a standard rodent diet and three a diet containing 41%
sucrose. At the age of 3 weeks the pups were weaned and given an intraperitoneal
injection of oxytetracycline hydrochloride. During the experimental period, half
of the pups of control dams received a sucrose diet (Cnt-Suc pups) and half of
the pups of sucrose dams received a standard diet (Suc-Cnt pups). The pups in the
other halves received the same diet as given to their dams during lactation (Cnt
Cnt and Suc-Suc pups). Urine samples were collected from dams and pups during the
test periods. After 4 weeks the pups were killed, their blood was collected and
their jaws sectioned sagittally. Dentine apposition was determined
planimetrically and dental caries using Schiffs staining. Ca, K and Na of serum
and urine were measured flame photometrically and P using an ultraviolet method.
The lactational sucrose diet was associated with decreased P and Na excretion in
the dams, and also with reduced dentine apposition in their pups. Reduced dentine
apposition and induced Ca excretion with decreased P, K and Na excretions were
observed in Suc-Suc pups and Cnt-Suc pups during the experiment period. Fewer
intact teeth with more enamel and dentinal caries lesions occurred in sucrose
exposed groups (Suc-Cnt, Cnt-Suc and Suc-Suc pups). It was concluded that the
sucrose diet given to dams during lactation changed the function of the pulp
dentine complex of their pups leading to reduced dentinogenesis, but also
predisposed to a reduction of dentinogenesis in pups during the experimental
period and enhanced the occurrence of dental caries.
PMID- 10761873
TI - The effect of hormone replacement therapy on salivary calcium concentrations in
menopausal women.
AB - Hormone replacement therapy in menopausal women is known to affect the general
calcium turnover of the body. No information is available about the effects of
hormone therapy on salivary electrolytes and on calcium in particular. A group of
16 healthy peri- and postmenopausal women, all recommended to start hormone
replacement therapy, were studied longitudinally for 5 months. Paraffin
stimulated whole saliva was collected at baseline, at 3 and at 5 months after the
onset of therapy, and analysed for calcium, sodium and potassium concentrations.
In response to hormone replacement therapy, calcium concentration decreased (p =
0.037), that of sodium increased (p = 0.019), while no change was observed in the
potassium concentrations during the follow-up period.
PMID- 10761874
TI - Gene expression and immunolocalization of amelogenin in enamel hypoplasia induced
by successive injections of bisphosphonate in rat incisors.
AB - Successive injections of 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) in rats
induce enamel hypoplasia. To elucidate the pathogenesis of this hypoplasia, male
Wistar rats were daily injected with HEBP or physiological saline for 7 days.
After the last injection, they were killed under anaesthesia and their maxillary
incisors were examined using an in situ hybridization technique and
immunohistochemical staining to detect the gene expression and localization of
amelogenin protein, respectively. In the HEBP-injected rats, several islets of
partially mineralized enamel were present along crown-analogous surface of the
incisor in the secretory stage of amelogenesis and enamel-free zones existed
between these islets. In situ hybridization demonstrated amelogenin gene
expression over the ameloblasts facing the islets of the matrix enamel as well as
over those of the enamel-free zones. Immunohistochemical studies using rabbit
antiamelogenin antibody revealed positive reaction both in the enamel matrix of
the control group and in the islets of enamel matrix of the HEBP-injected group.
Some small granules immunoreactive to amelogenin antibody were found in the
distal portions of the ameloblasts in the HEBP-injected rats. The results
indicate that HEBP does not alter amelogenin gene expression over ameloblasts, or
the protein's existence in enamel matrix. There appeared to be some accumulation
of amelogenin in the HEBP-treated ameloblasts. It is therefore suggested that the
enamel hypoplasia in this experiment may not be due to a disturbance in
amelogenin synthesis but to a disturbance in a later process, presumably of
protein secretion.
PMID- 10761875
TI - Crown components of mandibular molar teeth in 45,X females (Turner syndrome).
AB - This study was designed to determine the possible effect of one X-chromosome
constitution on components of the human permanent and primary molar teeth.
Enamel, dentine, pulp and crown dimensions were measured on radiographs of first
and second permanent and second primary mandibular molars of 49 Finnish 45,X
females (Turner syndrome), their 46 first-degree male and female relatives and 50
non-related males and females. In permanent first and second molars of the 45,X
females, crown width and the dimensions of tooth components were less than those
of normal females and males. Reduction in size affected first more than second
molars, and in both teeth the enamel was relatively as well as absolutely thinner
than in the controls. No differences were found in tooth components between
normal relatives and unrelated controls. These data agree with previous studies
which have demonstrated that the X chromosome promotes enamel apposition and that
both X chromosomes in normal females are active in amelogenesis, while the Y
chromosome influences both dentine and enamel growth. The relative reduction in
"dentine" or the estimated mesiodistal width of the tooth germ in the 45,X
females indicates that their tooth development is affected at an early stage of
morphogenesis. Taken together with the results already reported for anterior
teeth, the present results suggest that there is an inverse correlation between
the duration of crown formation and the severity of size reduction.
PMID- 10761876
TI - Expression of connexin 32 and 43 in developing rat submandibular salivary glands.
AB - The expression of the gap-junction proteins connexin 32 and 43 in the developing
rat submandibular gland was determined using reverse transcription-polymerase
chain reaction and immunohistochemistry. Sprague-Dawley rats from the 17th
gestational day through to the 28th postnatal day were used. Connexin 43 gene
expression was detected on the 17th gestational day. Connexin 32 gene expression
was also detected on the 17th gestational day but less intensely. Immunolabelling
for connexin 43 was also found in the developing submandibular gland from the
17th gestational day. Prenatally the most immunoreactive areas for connexin 43
were located in the periphery of terminal tubules, but some staining was
discernible between the cells in terminal buds. In the postnatal period, reactive
areas were located at both the periphery of acinus-like structures and around the
intercalated duct. This is consistent with the known association of connexin 43
with myoepithelial cells. Connexin 32 immunostaining was first detected in the
developing submandibular glands on the 18th day of prenatal development. Positive
staining was present on the lateral side of the proacinar and mature acinar
cells. The number of immunoreactive areas per cell increased during early
development followed by a significant decrease perinatally. During postnatal
development the density of areas again showed a pattern of increase. These
results suggest that connexin 43 is associated with growth and differentiation in
the pre- and perinatal periods and also with the contractile function of
myoepithelial cells in the postnatal period of the developing submandibular
gland. It is also implied that the number of connexin 32-positive areas may
correspond to an increase or decrease in the number of proacinar and mature
acinar cells.
PMID- 10761877
TI - Distribution of plasma-membrane Ca2+ pump in mandibular condyles from growing and
adult rabbits.
AB - Chondrocytes may control the mineralization of the extracellular matrix of
condylar cartilage by several mechanisms including the release of microvesicles
involved in the initial nucleation, the creation or modification of the local
matrix to help propagate or restrict mineralization, and the regulation of the
ionic environment at the calcifying foci within the matrix. The plasma membrane
Ca2+-Mg2+ ATPase (Ca2+ pump) is known to play a part in the vectorial efflux of
calcium in a variety of cells including chondrocytes. The purpose here was to
study the distribution of Ca2+-pump protein in mandibular condyles from growing
and adult rabbits, and compare the expression of that protein in progressively
differentiating chondrocytes whose final stage is associated with a mineralized
extracellular matrix. Ca2+-pump antigen was identified immunohistochemically in
six growing and six adult rabbit mandibular condyles with a Ca2+ pump-specific
monoclonal antibody. The presence of Ca2+-pump antigen was established in
hypertrophic chondrocytes, and in osteoblasts and osteoclasts of subchondral
bone. Slot-blot analysis of nitrocellulose-immobilized chondrocyte homogenates
showed that the amount of Ca2+ pump in growing cartilage was more than twice that
in adult cartilage (p < 0.05). The demonstration of Ca2+-pump antigen in the
hypertrophic chondrocytes of growing rabbit condyles is consistent with a role
for the plasma-membrane Ca2+ pump in the calcification of mandibular condylar
cartilage.
PMID- 10761878
TI - Magnetic resonance imaging of human mandibular elevator muscles after repetitive
maximal clenching exercise.
AB - Exercise can enhance the signal intensity (SI) of skeletal limb muscles on T2
weighted magnetic resonance imaging (MRI). The purpose here was to evaluate the
effects of repetitive maximal clenching exercises involving the mandibular
elevator muscles with T2-weighted MRI. Seven normal volunteers were imaged before
and immediately after performing repetitive maximal clenching and at 3, 6, 9, 12,
15, 20 min after the exercise in a 1.5 T GE magnet with spin-echo sequences. SI
in the masseter, medial pterygoid and temporalis increased significantly (p <
0.001) and the cross-sectional area (CSA) of masseter increased 10.11% on T2
weighted MRI after exercise. The increased SI and CSA declined approximately to
the pre-exercise level in about 20 min after exercise. No SI and CSA changes were
found in the inactive neck muscle and no SI changes in the mandibular bone marrow
(p > 0.05). The findings suggest that the use of exercise-enhanced MRI might be
helpful in the study of the function and dysfunction of muscles in the orofacial
region.
PMID- 10761880
TI - A squandered opportunity
PMID- 10761879
TI - Fluoride content in khat (Catha edulis) chewing leaves.
AB - Khat (qat) leaves are chewed for their psychostimulative effects; there is an
unconfirmed suggestion that they contain a high concentration of fluoride (F).
Khat samples from Yemen were suspended in deionized water, spun, and the
supernatants exposed to a chelator that decomplexes F, which was assayed with an
F(-)-electrode coupled to an ion analyser. F released into whole saliva after
chewing khat for 15 min and from khat suspended in stimulated whole saliva for
1.5 h in vitro was measured also. Total F in dried khat leaves and their ash was
assayed by the acid-hexamethyldisiloxane microdiffusion method. All methods
demonstrated negligible amounts of F in or from khat leaves (<0.02 microg F/ml
leached into water or saliva; 0.06 microg F/ml in saliva after chewing; 0.93
microg total F/g in dried leaf, 2.07 microg total F/g in ash).
PMID- 10761881
TI - Safety concerns force NASA to condemn satellite to fiery end
PMID- 10761882
TI - Balance is returning after US biotechnology shares scare.
PMID- 10761883
TI - The worm's turn to claim Internet fame.
PMID- 10761884
TI - Radical changes urged for Spanish universities
PMID- 10761885
TI - Is starting simple the path to complexity?
PMID- 10761886
TI - India and US bring collaboration out of the freezer.
PMID- 10761887
TI - Chemists 'volunteered for nerve gas tests'.
PMID- 10761888
TI - Local farmers would be able to feed Africa if they were given the chance.
PMID- 10761890
TI - No pie in the sky, thanks
PMID- 10761889
TI - Ancient Chinese had their fingers on the pulse.
PMID- 10761892
TI - Eternal verities, eternal questions
PMID- 10761891
TI - The Big Bang and the genetic code.
PMID- 10761893
TI - Survival of the clearest.
PMID- 10761894
TI - A view of mount Drosophila.
PMID- 10761895
TI - Peeking into the obscured universe
PMID- 10761897
TI - Nuclear physics. Doubly magic nickel
PMID- 10761896
TI - Bats about the Arctic.
PMID- 10761899
TI - Superfluidity. A new twist to an old story
PMID- 10761898
TI - Enzymology. Not just an active site.
PMID- 10761901
TI - Particle physics. Backyard exotica
PMID- 10761900
TI - ABC of meningococcal diversity.
PMID- 10761902
TI - Neanderthal population genetics.
PMID- 10761903
TI - Finger-length ratios and sexual orientation.
PMID- 10761905
TI - Colour mixing in wing scales of a butterfly.
PMID- 10761904
TI - A unique circadian-rhythm photoreceptor.
PMID- 10761906
TI - Resolving the extragalactic hard X-ray background
AB - The origin of the hard (2-10 keV) X-ray background has been a mystery for over 35
years. Most of the soft X-ray background has been resolved into individual
sources (mainly quasars), but these sources do not have the spectral energy
distribution required to match the spectrum of the X-ray background as a whole.
Here we report the results of a deep survey, using the Chandra satellite, in
which the detected hard X-ray sources account for at least 75 per cent of the
hard X-ray background. The mean X-ray spectral energy distribution of these
sources is in good agreement with that of the background. Moreover, most of those
hard X-ray sources are associated unambiguously with either the nuclei of
otherwise normal bright galaxies, or with optically faint sources. The latter
could be active nuclei in dust-enshrouded galaxies or a population of quasars at
extremely high redshift.
PMID- 10761908
TI - Double-quantum vortex in superfluid 3He-A
AB - Linear defects are generic in continuous media. In quantum systems they appear as
topological line defects which are associated with a circulating persistent
current. In relativistic quantum field theories they are known as cosmic strings,
in superconductors as quantized flux lines, and in superfluids and low-density
Bose-Einstein condensates as quantized vortex lines. A conventional quantized
vortex line consists of a central core around which the phase of the order
parameter winds by 27(pi)n, while within the core the order parameter vanishes or
is depleted from the bulk value. Usually vortices are singly quantized (that is,
have n = 1). But it has been theoretically predicted that, in superfluid 3He-A,
vortex lines are possible that have n = 2 and continuous structure, so that the
orientation of the multicomponent order parameter changes smoothly throughout the
vortex while the amplitude remains constant. Here we report direct proof, based
on high-resolution nuclear magnetic resonance measurements, that the most common
vortex line in 3He-A has n = 2. One vortex line after another is observed to form
in a regular periodic process, similar to a phase-slip in the Josephson effect.
PMID- 10761907
TI - Peptide exosite inhibitors of factor VIIa as anticoagulants.
AB - Potent anticoagulants have been derived by targeting the tissue factor-factor
VIIa complex with naive peptide libraries displayed on M13 phage. The peptides
specifically block the activation of factor X with a median inhibitory
concentration of 1 nM and selectively inhibit tissue-factor-dependent clotting.
The peptides do not bind to the active site of factor VIIa; rather, they work by
binding to an exosite on the factor VIIa protease domain, and non-competitively
inhibit activation of factor X and amidolytic activity. One such peptide (E-76)
has a well defined structure in solution determined by NMR spectroscopy that is
similar to the X-ray crystal structure when complexed with factor VIIa. These
structural and functional studies indicate an allosteric 'switch' mechanism of
inhibition involving an activation loop of factor VIIa and represent a new
framework for developing inhibitors of serine proteases.
PMID- 10761909
TI - Imaging of localized electronic states in the quantum Hall regime
AB - The concept of electron localization has long been accepted to be essential to
the physics of the quantum Hall effect in a two-dimensional electron gas. The
exact quantization of the Hall resistance and the zero of the diagonal resistance
over a range of filling factors close to integral are attributed to the
localization of electronic states at the Fermi level in the interior of the gas.
As the electron density is changed, charging of the individual localized states
may occur by single-electron jumps, causing associated oscillations in the local
electrostatic potential. Here we search for such a manifestation of localized
states in the quantum Hall regime, using a scanning electrometer probe. We
observe localized potential signals, at numerous locations, that oscillate with
changing electron density. In general, the corresponding spatial patterns are
complex, but well-defined objects are often seen which evidently arise from
individual localized states. These objects interact, and at times form a lattice
like arrangement.
PMID- 10761910
TI - Anisotropic spinodal dewetting as a route to self-assembly of patterned surfaces
AB - The ability to pattern surfaces on a microscopic length scale is of importance
for technological applications such as the fabrication of microelectronic
circuits and digital storage media. Devices fabricated entirely from polymers are
now available, opening up the possibility of adapting polymer processing
technologies to fabricate cheap, large-area devices using non-lithographic
techniques--for example, by exploiting dewetting and phase separation in thin
films. But the final pattern adopted by the polymer film using such approaches
requires a template printed onto the substrate by optical lithography,
microcontact printing or vapour deposition. Here we describe a simple process for
patterning surfaces that does not require a template. Our method involves the
spinodal dewetting of a polymer surface by a thin polymer film, in which a liquid
film breaks up owing to the amplification of thermal fluctuations in film
thickness induced by dispersion forces. A preferred orientation is imposed on the
dewetting process simply by rubbing the substrate, and this gives rise to
patterns of remarkably well-aligned polymer lines. The width of these lines is
well-defined, and is controlled by the magnitude of the dispersion forces at the
interface, which in turn can be varied by varying the thickness of the polymer
substrate. We expect that further work will make it possible to optimize the
degree of order in the final morphology.
PMID- 10761911
TI - A soluble and air-stable organic semiconductor with high electron mobility
AB - Electronic devices based on organic semiconductors offer an attractive
alternative to conventional inorganic devices due to potentially lower costs,
simpler packaging and compatibility with flexible substrates. As is the case for
silicon-based microelectronics, the use of complementary logic elements-requiring
n- and p-type semiconductors whose majority charge carriers are electrons and
holes, respectively-is expected to be crucial to achieving low-power, high-speed
performance. Similarly, the electron-segregating domains of photovoltaic
assemblies require both n- and p-type semiconductors. Stable organic p-type
semiconductors are known, but practically useful n-type semiconductor materials
have proved difficult to develop, reflecting the unfavourable electrochemical
properties of known, electron-demanding polymers. Although high electron
mobilities have been obtained for organic materials, these values are usually
obtained for single crystals at low temperatures, whereas practically useful
field-effect transistors (FETs) will have to be made of polycrystalline films
that remain functional at room temperature. A few organic n-type semiconductors
that can be used in FETs are known, but these suffer from low electron mobility,
poor stability in air and/or demanding processing conditions. Here we report a
crystallographically engineered naphthalenetetracarboxylic diimide derivative
that allows us to fabricate solution-cast n-channel FETs with promising
performance at ambient conditions. By integrating our n-channel FETs with
solution-deposited p-channel FETs, we are able to produce a complementary
inverter circuit whose active layers are deposited entirely from the liquid
phase. We expect that other complementary circuit designs can be realized by this
approach as well.
PMID- 10761912
TI - Molecular-scale interface engineering for polymer light-emitting diodes
AB - Achieving balanced electron-hole injection and perfect recombination of the
charge carriers is central to the design of efficient polymer light-emitting
diodes (LEDs). A number of approaches have focused on modification of the
injection contacts, for example by incorporating an additional conducting-polymer
layer at the indium-tin oxide (ITO) anode. Recently, the layer-by-layer
polyelectrolyte deposition route has been developed for the fabrication of
ultrathin polymer layers. Using this route, we previously incorporated ultrathin
(<100 A) charge-injection interfacial layers in polymer LEDs. Here we show how
molecular-scale engineering of these interlayers to form stepped and graded
electronic profiles can lead to remarkably efficient single-layer polymer LEDs.
These devices exhibit nearly balanced injection, near-perfect recombination, and
greatly reduced pre-turn-on leakage currents. A green-emitting LED comprising a
poly(p-phenylene vinylene) derivative sandwiched between a calcium cathode and
the modified ITO anode yields an external forward efficiency of 6.0 per cent
(estimated internal efficiency, 15-20 per cent) at a luminance of 1,600 candelas
per m2 at 5 V.
PMID- 10761913
TI - Effect of climate change relative to ozone depletion on UV exposure in subarctic
lakes.
AB - The effect of stratospheric ozone depletion on increases in ambient levels of
solar ultraviolet (UV) radiation in high-latitude regions' has raised concerns
about the response of northern ecosystems to environmental change. The
concentration of coloured dissolved organic material, which is derived from
terrestrial vegetation and acts as a screen for ultraviolet radiation, is low in
high-latitude lakes. The underwater light environment in these lakes is therefore
likely to be sensitive to small variations in the supply of this material, in
addition to the effects of ozone depletion. Here we use fossil diatom assemblages
in combination with bio-optical models to estimate the magnitude of past
variations in the underwater light regime of a lake at the boreal tree line. We
find large shifts in underwater UV-B, UV-A and photosynthetically available
radiation associated with changes in the input of coloured dissolved organic
material into subarctic lakes during the Holocene. The inferred changes in
biological exposure to UV radiation were at least two orders of magnitude greater
than those associated with moderate (30%) ozone depletion. Our findings indicate
that freshwater ecosystems at present located across vegetation gradients will
experience significant shifts in underwater spectral irradiance through the
effects of climate change on catchment vegetation and the export of coloured
dissolved organic material.
PMID- 10761914
TI - Hf-Nd isotope evidence for a transient dynamic regime in the early terrestrial
mantle
AB - Modern basalts have seemingly lost all 'memory' of the primitive Earth's mantle
except for an ambiguous isotopic signal observed in some rare gases. Although the
Earth is expected to have reached a thermal steady state within several hundred
million years of accretion, it is not known how and when the initial chemical
fractionations left over from planetary accretion (and perhaps a stage involving
a magma ocean) were overshadowed by fractionations imposed by modern-style
geodynamics. Because of the lack of samples older than 4 Gyr, this early dynamic
regime of the Earth is poorly understood. Here we compare published Hf-Nd isotope
data on supracrustals from Isua, Greenland, with similar data on lunar rocks and
the SNC (martian) meteorites, and show that, about 3.8 Gyr ago, the geochemical
signature of the Archaean mantle was partly inherited from the initial
differentiation of the Earth. The observed features seem to indicate that the
planet at that time was still losing a substantial amount of primordial heat. The
survival of remnants from an early layering in the modern deep mantle may account
for some unexplained seismological, thermal and geochemical characteristics of
the Earth as observed today.
PMID- 10761915
TI - Molecular analysis of Neanderthal DNA from the northern Caucasus.
AB - The expansion of premodern humans into western and eastern Europe approximately
40,000 years before the present led to the eventual replacement of the
Neanderthals by modern humans approximately 28,000 years ago. Here we report the
second mitochondrial DNA (mtDNA) analysis of a Neanderthal, and the first such
analysis on clearly dated Neanderthal remains. The specimen is from one of the
eastern-most Neanderthal populations, recovered from Mezmaiskaya Cave in the
northern Caucasus. Radiocarbon dating estimated the specimen to be approximately
29,000 years old and therefore from one of the latest living Neanderthals. The
sequence shows 3.48% divergence from the Feldhofer Neanderthal. Phylogenetic
analysis places the two Neanderthals from the Caucasus and western Germany
together in a clade that is distinct from modern humans, suggesting that their
mtDNA types have not contributed to the modern human mtDNA pool. Comparison with
modern populations provides no evidence for the multiregional hypothesis of
modern human evolution.
PMID- 10761916
TI - Pervasive density-dependent recruitment enhances seedling diversity in a tropical
forest.
AB - Negative density-dependent recruitment of seedlings, that is, seeds of a given
species are less likely to become established seedlings if the density of that
species is high, has been proposed to be an important mechanism contributing to
the extraordinary diversity of tropical tree communities because it can
potentially prevent any particular species from usurping all available space,
either in close proximity to seed sources or at relatively larger spatial scales.
However, density-dependent recruitment does not necessarily enhance community
diversity. Furthermore, although density-dependent effects have been found at
some life stages in some species, no study has shown that density-dependent
recruitment affects community diversity. Here we report the results of
observations in a lowland, moist forest in the Republic of Panama in which the
species identities of 386,027 seeds that arrived at 200 seed traps were compared
with the species identities of 13,068 seedlings that recruited into adjacent
plots over a 4-year period. Across the 200 sites, recruit seedling diversity was
significantly higher than seed diversity. Part of this difference was explained
by interspecies differences in average recruitment success. Even after accounting
for these differences, however, negative density-dependent recruitment
contributes significantly to the increase in diversity from seeds to seedling
recruits.
PMID- 10761917
TI - The evolution of syntactic communication.
AB - Animal communication is typically non-syntactic, which means that signals refer
to whole situations. Human language is syntactic, and signals consist of discrete
components that have their own meanings. Syntax is a prerequisite for taking
advantage of combinatorics, that is, "making infinite use of finite means. The
vast expressive power of human language would be impossible without syntax, and
the transition from non-syntactic to syntactic communication was an essential
step in the evolution of human language. We aim to understand the evolutionary
dynamics of this transition and to analyse how natural selection can guide it.
Here we present a model for the population dynamics of language evolution, define
the basic reproductive ratio of words and calculate the maximum size of a
lexicon. Syntax allows larger repertoires and the possibility to formulate
messages that have not been learned beforehand. Nevertheless, according to our
model natural selection can only favour the emergence of syntax if the number of
required signals exceeds a threshold value. This result might explain why only
humans evolved syntactic communication and hence complex language.
PMID- 10761918
TI - Glutamate spillover suppresses inhibition by activating presynaptic mGluRs.
AB - Metabotropic glutamate receptors (mGluRs) found on synaptic terminals throughout
the brain are thought to be important in modulating neurotransmission. Activation
of mGluRs by synaptically released glutamate depresses glutamate release from
excitatory terminals but the physiological role of mGluRs on inhibitory terminals
is unclear. We have investigated activation of mGluRs on inhibitory terminals
within the cerebellar glomerulus, a structure in which GABA (gamma-aminobutyric
acid)-releasing inhibitory terminals and glutamatergic excitatory terminals are
in close apposition and make axo-dendritic synapses onto granule cells. Here we
show that 'spillover' of glutamate, which is released from excitatory mossy
fibres, inhibits GABA release from Golgi cell terminals by activating presynaptic
mGluRs under physiological conditions. The magnitude of the depression of the
inhibitory postsynaptic current is dependent on the frequency of mossy fibre
stimulation, reaching 50% at 100 Hz. Furthermore, the duration of inhibitory
postsynaptic current depression mirrors the time course of mossy fibre activity.
Our results establish that mGluRs on inhibitory interneuron axons sense the
activity of neighbouring excitatory synapses. This heterosynaptic mechanism is
likely to boost the efficacy of active excitatory fibres by locally reducing the
level of inhibition.
PMID- 10761919
TI - Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491.
AB - Neisseria meningitidis causes bacterial meningitis and is therefore responsible
for considerable morbidity and mortality in both the developed and the developing
world. Meningococci are opportunistic pathogens that colonize the nasopharynges
and oropharynges of asymptomatic carriers. For reasons that are still mostly
unknown, they occasionally gain access to the blood, and subsequently to the
cerebrospinal fluid, to cause septicaemia and meningitis. N. meningitidis strains
are divided into a number of serogroups on the basis of the immunochemistry of
their capsular polysaccharides; serogroup A strains are responsible for major
epidemics and pandemics of meningococcal disease, and therefore most of the
morbidity and mortality associated with this disease. Here we have determined the
complete genome sequence of a serogroup A strain of Neisseria meningitidis,
Z2491. The sequence is 2,184,406 base pairs in length, with an overall G+C
content of 51.8%, and contains 2,121 predicted coding sequences. The most notable
feature of the genome is the presence of many hundreds of repetitive elements,
ranging from short repeats, positioned either singly or in large multiple arrays,
to insertion sequences and gene duplications of one kilobase or more. Many of
these repeats appear to be involved in genome fluidity and antigenic variation in
this important human pathogen.
PMID- 10761920
TI - The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell
lineage fate.
AB - Signals elicited by binding of the T-cell antigen receptor and the CD4/CD8 co
receptor to major histocompatibility complex (MHC) molecules control the
generation of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors
that initially express both co-receptor proteins. These precursors have unique,
clonally distributed T-cell receptors with unpredictable specificity for the self
MHC molecules involved in this differentiation process. However, the mature T
cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC class I
binding) co-receptor that complements the MHC class-specificity of the T-cell
receptor. How this matching of co-receptor-defined lineage and T-cell-receptor
specificity is achieved remains unknown, as does whether signalling by the T-cell
receptors, co-receptors and/or general cell-fate regulators such as Notch-1
contributes to initial lineage choice, to subsequent differentiation processes or
to both. Here we show that the CD4 versus CD8 lineage fate of immature thymocytes
is controlled by the co-receptor-influenced duration of initial T-cell receptor
dependent signalling. Notch-1 does not appear to be essential for this fate
determination, but it is selectively required for CD8+ T-cell maturation after
commitment directed by T-cell receptors. This indicates that the signals
constraining CD4 versus CD8 lineage decisions are distinct from those that
support subsequent differentiation events such as silencing of co-receptor loci.
PMID- 10761921
TI - DNA repair protein Ku80 suppresses chromosomal aberrations and malignant
transformation.
AB - Cancer susceptibility genes have been classified into two groups: gatekeepers and
caretakers. Gatekeepers are genes that control cell proliferation and death,
whereas caretakers are DNA repair genes whose inactivation leads to genetic
instability. Abrogation of both caretaker and gatekeeper function markedly
increases cancer susceptibility. Although the importance of Ku80 in DNA double
strand break repair is well established, neither Ku80 nor other components of the
non-homologous end-joining pathway are known to have a caretaker role in
maintaining genomic stability. Here we show that mouse cells deficient for Ku80
display a marked increase in chromosomal aberrations, including breakage,
translocations and aneuploidy. Despite the observed chromosome instabilities,
Ku80-/- mice have only a slightly earlier onset of cancer. Loss of p53 synergizes
with Ku80 to promote tumorigenesis such that all Ku80-/- p53-/- mice succumb to
disseminated pro-B-cell lymphoma before three months of age. Tumours result from
a specific set of chromosomal translocations and gene amplifications involving
IgH and c-Myc, reminiscent of Burkitt's lymphoma. We conclude that Ku80 is a
caretaker gene that maintains the integrity of the genome by a mechanism
involving the suppression of chromosomal rearrangements.
PMID- 10761922
TI - Yeast Sm-like proteins function in mRNA decapping and decay.
AB - One of the main mechanisms of messenger RNA degradation in eukaryotes occurs by
deadenylation-dependent decapping which leads to 5'-to-3' decay. A family of Sm
like (Lsm) proteins has been identified, members of which contain the 'Sm'
sequence motif, form a complex with U6 small nuclear RNA and are required for pre
mRNA splicing. Here we show that mutations in seven yeast Lsm proteins (Lsm1
Lsm7) also lead to inhibition of mRNA decapping. In addition, the Lsm1-Lsm7
proteins co-immunoprecipitate with the mRNA decapping enzyme (Dcp1), a decapping
activator (Pat1/Mrt1) and with mRNA. This indicates that the Lsm proteins may
promote decapping by interactions with the mRNA and the decapping machinery. In
addition, the Lsm complex that functions in mRNA decay appears to be distinct
from the U6-associated Lsm complex, indicating that Lsm proteins form specific
complexes that affect different aspects of mRNA metabolism.
PMID- 10761923
TI - Structural basis for the anticoagulant activity of the thrombin-thrombomodulin
complex.
AB - The serine proteinase alpha-thrombin causes blood clotting through proteolytic
cleavage of fibrinogen and protease-activated receptors and amplifies its own
generation by activating the essential clotting factors V and VIII.
Thrombomodulin, a transmembrane thrombin receptor with six contiguous epidermal
growth factor-like domains (TME1-6), profoundly alters the substrate specificity
of thrombin from pro- to anticoagulant by activating protein C. Activated protein
C then deactivates the coagulation cascade by degrading activated factors V and
VIII. The thrombin-thrombomodulin complex inhibits fibrinolysis by activating the
procarboxypeptidase thrombin-activatable fibrinolysis inhibitor. Here we present
the 2.3 A crystal structure of human alpha-thrombin bound to the smallest
thrombomodulin fragment required for full protein-C co-factor activity, TME456.
The Y-shaped thrombomodulin fragment binds to thrombin's anion-binding exosite-I,
preventing binding of procoagulant substrates. Thrombomodulin binding does not
seem to induce marked allosteric structural rearrangements at the thrombin active
site. Rather, docking of a protein C model to thrombin-TME456 indicates that
TME45 may bind substrates in such a manner that their zymogen-activation cleavage
sites are presented optimally to the unaltered thrombin active site.
PMID- 10761924
TI - Polarity in cell division: what frames thy fearful asymmetry?
PMID- 10761925
TI - PIP2 and PIP3: complex roles at the cell surface.
PMID- 10761926
TI - The physiology of taste, vintage 2000.
PMID- 10761927
TI - The molecular architecture of odor and pheromone sensing in mammals.
PMID- 10761928
TI - Establishing biorientation occurs with precocious separation of the sister
kinetochores, but not the arms, in the early spindle of budding yeast.
AB - Sister kinetochores are bioriented toward the spindle poles in higher eukaryotic
prometaphase before chromosome segregation. We show that, in budding yeast, the
sister kinetochores are separated in the very early spindle, while the sister
arms remain associated. Biorientation of the separated kinetochores is achieved
already after replication. Mtw1p, a homolog of fission yeast Mis12 required for
biorientation, locates at the centromeres in an Ndc10p-dependent manner. Mtw1p
and the sequences 1.8 and 3.8 kb from CEN3 and CEN15, respectively, behave like
the precociously separated kinetochores, whereas the sequences 23 and 35 kb
distant from CEN3 and CEN5 previously used as the centromere markers behave like
a part of the arm. Mtw1p and Ndc10p are identically located except for additional
spindle localization of Ndc10p. A model explaining small centromeres and early
spindle formation in budding yeast is proposed.
PMID- 10761929
TI - The stem cell population of Arabidopsis shoot meristems in maintained by a
regulatory loop between the CLAVATA and WUSCHEL genes.
AB - The higher-plant shoot meristem is a dynamic structure whose maintenance depends
on the coordination of two antagonistic processes, organ initiation and self
renewal of the stem cell population. In Arabidopsis shoot and floral meristems,
the WUSCHEL (WUS) gene is required for stem cell identity, whereas the CLAVATA1,
2, and 3 (CLV) genes promote organ initiation. Our analysis of the interactions
between these key regulators indicates that (1) the CLV genes repress WUS at the
transcript level and that (2) WUS expression is sufficient to induce meristem
cell identity and the expression of the stem cell marker CLV3. Our data suggest
that the shoot meristem has properties of a self-regulatory system in which
WUS/CLV interactions establish a feedback loop between the stem cells and the
underlying organizing center.
PMID- 10761930
TI - Targeted overactivity of beta cell K(ATP) channels induces profound neonatal
diabetes.
AB - A paradigm for control of insulin secretion is that glucose metabolism elevates
cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing
depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of
K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased
insulin secretion and diabetes. To test this critical prediction, we generated
transgenic mice expressing beta cell K(ATP) channels with reduced ATP
sensitivity. Animals develop severe hyperglycemia, hypoinsulinemia, and
ketoacidosis within 2 days and typically die within 5. Nevertheless, islet
morphology, insulin localization, and alpha and beta cell distributions were
normal (before day 3), pointing to reduced insulin secretion as causal. The data
indicate that normal K(ATP) channel activity is critical for maintenance of
euglycemia and that overactivity can cause diabetes by inhibiting insulin
secretion.
PMID- 10761931
TI - A novel transcription factor, T-bet, directs Th1 lineage commitment.
AB - Naive T helper cells differentiate into two subsets, Th1 and Th2, each with
distinct functions and cytokine profiles. Here, we report the isolation of T-bet,
a Th1-specific T box transcription factor that controls the expression of the
hallmark Th1 cytokine, IFNgamma. T-bet expression correlates with IFNgamma
expression in Th1 and NK cells. Ectopic expression of T-bet both transactivates
the IFNgamma gene and induces endogenous IFNgamma production. Remarkably,
retroviral gene transduction of T-bet into polarized Th2 and Tc2 primary T cells
redirects them into Th1 and Tc1 cells, respectively, as evidenced by the
simultaneous induction of IFNgamma and repression of IL-4 and IL-5. Thus, T-bet
initiates Th1 lineage development from naive Thp cells both by activating Th1
genetic programs and by repressing the opposing Th2 programs.
PMID- 10761932
TI - Decoding of sorting signals by coatomer through a GTPase switch in the COPI coat
complex.
AB - Sorting signals on cargo proteins are recognized by coatomer for selective uptake
into COPI (coatomer)-coated vesicles. This study shows that coatomer couples
sorting signal recognition to the GTP hydrolysis reaction on ARF1. Coatomer
responds differently to different signals. The cytoplasmic signal sequence of
hp24a inhibits coatomer-dependent GTP hydrolysis. By contrast, the dilysine
retrieval signal, which competes for the same binding site on coatomer, has no
effect on GTPase activity. It is inferred that, in vivo, sorting signal selection
is under kinetic control, with coatomer governing a GTPase discard pathway that
excludes dilysine-tagged proteins from one class of COPI-coated vesicles. The
concept of competing sets of sorting signals that act positively and negatively
during vesicle budding through a GTPase switch in the COPI coat complex suggests
mechanisms for cargo segregation in which specificity is conferred by GTP
hydrolysis.
PMID- 10761933
TI - The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1:
implications for Chk1 regulation.
AB - The checkpoint kinase Chk1 is an important mediator of cell cycle arrest
following DNA damage. The 1.7 A resolution crystal structures of the human Chk1
kinase domain and its binary complex with an ATP analog has revealed an identical
open kinase conformation. The secondary structure and side chain interactions
stabilize the activation loop of Chk1 and enable kinase activity without
phosphorylation of the catalytic domain. Molecular modeling of the interaction of
a Cdc25C peptide with Chk1 has uncovered several conserved residues that are
important for substrate selectivity. In addition, we found that the less
conserved C-terminal region negatively impacts Chk1 kinase activity.
PMID- 10761934
TI - A novel family of mammalian taste receptors.
AB - In mammals, taste perception is a major mode of sensory input. We have identified
a novel family of 40-80 human and rodent G protein-coupled receptors expressed in
subsets of taste receptor cells of the tongue and palate epithelia. These
candidate taste receptors (T2Rs) are organized in the genome in clusters and are
genetically linked to loci that influence bitter perception in mice and humans.
Notably, a single taste receptor cell expresses a large repertoire of T2Rs,
suggesting that each cell may be capable of recognizing multiple tastants. T2Rs
are exclusively expressed in taste receptor cells that contain the G protein
alpha subunit gustducin, implying that they function as gustducin-linked
receptors. In the accompanying paper, we demonstrate that T2Rs couple to
gustducin in vitro, and respond to bitter tastants in a functional expression
assay.
PMID- 10761935
TI - T2Rs function as bitter taste receptors.
AB - Bitter taste perception provides animals with critical protection against
ingestion of poisonous compounds. In the accompanying paper, we report the
characterization of a large family of putative mammalian taste receptors (T2Rs).
Here we use a heterologous expression system to show that specific T2Rs function
as bitter taste receptors. A mouse T2R (mT2R-5) responds to the bitter tastant
cycloheximide, and a human and a mouse receptor (hT2R-4 and mT2R-8) responded to
denatonium and 6-n-propyl-2-thiouracil. Mice strains deficient in their ability
to detect cycloheximide have amino acid substitutions in the mT2R-5 gene; these
changes render the receptor significantly less responsive to cycloheximide. We
also expressed mT2R-5 in insect cells and demonstrate specific tastant-dependent
activation of gustducin, a G protein implicated in bitter signaling. Since a
single taste receptor cell expresses a large repertoire of T2Rs, these findings
provide a plausible explanation for the uniform bitter taste that is evoked by
many structurally unrelated toxic compounds.
PMID- 10761936
TI - A potential concern in total joint arthroplasty: systemic dissemination of wear
debris.
PMID- 10761937
TI - Dissemination of wear particles to the liver, spleen, and abdominal lymph nodes
of patients with hip or knee replacement.
AB - BACKGROUND: The importance of particles generated by wear and corrosion of joint
replacement prostheses has been understood primarily in the context of the local
effects of particle-induced periprosthetic osteolysis and aseptic loosening. We
studied dissemination of wear particles in patients with total hip and knee
replacement to determine the prevalence of and the histopathological response to
prosthetic wear debris in the liver, spleen, and abdominal para-aortic lymph
nodes. METHODS: Postmortem specimens from twenty-nine patients and biopsy
specimens from two living patients with a failed replacement were analyzed.
Specimens of tissue obtained from the cadavera of fifteen patients who had not
had a joint replacement served as controls. The concentration of particles and
the associated tissue response were characterized with the use of light
microscopy of stained histological sections. Metallic particles were identified
by electron microprobe analysis. Polyethylene particles were studied with the use
of oil-red-O stain and polarized light microscopy. The composition of
polyethylene particles was confirmed in selected cases by Fourier transform
infrared spectroscopy and hot-stage thermal analysis. Twenty-one of the patients
studied post mortem had had a primary total joint replacement. Eleven of them had
had a hip prosthesis for a mean of sixty-nine months (range, forty-three to 171
months), and ten had had a knee replacement for a mean of eighty-four months
(range, thirty-one to 179 months). The other eight patients studied post mortem
had had a hip replacement in which one or more components had loosened and had
been revised. The mean time between the initial arthroplasty and the time of
death was 174 months (range, forty-seven to 292 months), and the mean time
between the last revision procedure and the time of death was seventy-one months
(range, one to 130 months). RESULTS: Metallic wear particles in the liver or
spleen were more prevalent in patients who had had a failed hip arthroplasty
(seven of eight) than in patients who had had a primary hip (two of eleven) or
knee replacement (two of ten). The principal source of wear particles in the
majority of these patients involved secondary nonbearing surfaces rather than
wear between the two primary bearing surfaces as intended. In one living patient,
dissemination of titanium alloy particles from a hip prosthesis with mechanical
failure was associated with a visceral granulomatous reaction and
hepatosplenomegaly, which required operative and medical treatment. Metallic wear
particles were detected in the paraaortic lymph nodes in 68 percent (nineteen) of
the twenty-eight patients with an implant from whom lymph nodes were available
for study. In 38 percent (eleven) of all twenty-nine patients with an implant who
were studied post mortem, metallic particles had been further disseminated to the
liver or spleen, where they were usually found within small aggregates of
macrophages occurring as infiltrates without apparent pathological importance.
Polyethylene particles elicited a similar response. They were identified in the
paraaortic lymph nodes of 68 percent (nineteen) of the twenty-eight patients and
the liver or spleen of 14 percent (four) of the twenty-nine patients. The
majority of the disseminated wear particles were less than one micrometer in
size. Currently available methods lack the sensitivity and specificity necessary
to detect very low concentrations of submicrometer polyethylene particles and
probably underestimated the prevalence of polyethylene wear debris in the liver
and spleen. CONCLUSIONS: In this study, systemic distribution of metallic and
polyethylene wear particles was a common finding, both in patients with a
previously failed implant and in those with a primary total joint prosthesis. The
prevalence of particles in the liver or spleen was greater after reconstructions
with mechanical failure. (ABSTRACT TRUNCATED)
PMID- 10761938
TI - Functional bracing for the treatment of fractures of the humeral diaphysis.
AB - BACKGROUND: Nonoperatively treated fractures of the humeral diaphysis have a high
rate of union with good functional results. However, there are clinical
situations in which operative treatment is more appropriate, and, though interest
in plate osteosynthesis has decreased, intramedullary nailing has gained
popularity in recent years. We report the results of treating fractures of the
humeral diaphysis with a prefabricated brace that permits full motion of all
joints and progressive use of the injured extremity. METHODS: Between 1978 and
1990, 922 patients who had a fracture of the humeral diaphysis were treated with
a prefabricated brace that permitted motion of adjacent joints. The injured
extremities were initially stabilized in an above-the-elbow cast or a coaptation
splint for an average of nine days (range, zero to thirty-five days) prior to the
application of the prefabricated brace. Orthopaedic residents, supervised by
teaching staff, provided follow-up care in a special outpatient clinic.
Radiographs were made at each follow-up visit until the fracture healed. RESULTS:
We were able to follow 620 (67 percent) of the 922 patients. Four hundred and
sixty-five (75 percent) of the fractures were closed, and 155 (25 percent) were
open. Nine patients (6 percent) who had an open fracture and seven (less than 2
percent) who had a closed fracture had a nonunion after bracing. In 87 percent of
the 565 patients for whom anteroposterior radiographs were available, the
fracture healed in less than 16 degrees of varus angulation, and in 81 percent of
the 546 for whom lateral radiographs were available, it healed in less than 16
degrees of anterior angulation. At the time of brace removal, 98 percent of the
patients had limitation of shoulder motion of 25 degrees or less. We were unable
to follow most of the patients long-term, as they did not return to the clinic
once the fracture had united and use of the brace had been discontinued.
CONCLUSIONS: Functional bracing for the treatment of fractures of the humeral
diaphysis is associated with a high rate of union, particularly when used for
closed fractures. The residual angular deformities are usually functionally and
aesthetically acceptable. The present study illustrates the difficulties
encountered in carrying out long-term follow-up of indigent patients treated in
charity hospitals that are affiliated with teaching institutions. These
difficulties are also becoming common with patients insured under managed-care
organizations and are frequent in our peripatetic population.
PMID- 10761939
TI - Charnley total hip arthroplasty with cement. Minimum twenty-five-year follow-up.
AB - BACKGROUND: This report presents the results of the senior author's initial
twenty-five-year experience with the use of Charnley total hip arthroplasty with
cement. The purpose of this paper was to evaluate the long-term results of total
hip arthroplasty. METHODS: Between July 1970 and April 1972, the senior author
(R. C. J.) performed 330 Charnley total hip replacements with cement using a hand
packing cement technique in 262 patients. Fifty-one patients (sixty-two hips) who
were alive at least twenty-five years post-operatively were evaluated from a
clinical standpoint with use of a standard-terminology questionnaire. The average
age of this group at the time of surgery was fifty-six years (range, thirty-five
to seventy-one years) compared with sixty-five years (range, twenty-one to eighty
nine years) for the entire group. All patients were evaluated for radiographic
changes at the time of their most recent follow-up. Of the fifty-one patients
(sixty-two hips) who were alive at least twenty-five years postoperatively,
thirty-one (thirty-six hips) had a follow-up radiograph made at a minimum of
twenty-five years after the surgery. The average duration of radiographic follow
up for the fifty-one patients was 22.7 years (range, two to twenty-seven years).
RESULTS: Of the sixty-two hips in the fifty-one patients who were alive at least
twenty-five years postoperatively, fourteen (23 percent) had been revised. Three
(5 percent) had the revision because of loosening with infection; eleven (18
percent), because of aseptic loosening; and none, because of dislocation. The
prevalence of revision due to aseptic loosening of the acetabular component in
all 316 hips (excluding those that were lost to follow-up or that were revised
for infection or dislocation) was 6 percent (eighteen hips), whereas the
prevalence in the fifty-nine hips (excluding the three revised for infection) in
the patients who were alive at least twenty-five years after the arthroplasty was
15 percent (nine hips). The prevalence of revision because of aseptic loosening
of the femoral component in all 316 hips was 3 percent (nine hips), and the
prevalence in the fifty-nine hips in the living patients was 7 percent (four
hips). In the group of living patients, osteolysis occurred in Gruen zone 1 or 7
in thirty-three hips and in Gruen zones 2 through 6 in two hips. Ballooning
acetabular osteolysis occurred in five hips. Of the 327 hips for which the
outcome was known after a minimum of twenty-five years, 295 (90 percent) had
retained the original implants until the patient died or until the most recent
follow-up examination. Of the sixty-two hips in patients who lived for at least
twenty-five years after the surgery, forty-eight (77 percent) had retained the
original prosthesis. CONCLUSIONS: Our follow-up study at twenty-five years
following Charnley total hip arthroplasty with cement demonstrates the durability
of the results of the procedure. These results should provide a means for
comparison with the results of newer cementing techniques as well as those
associated with newer cemented and cementless hip designs.
PMID- 10761940
TI - Ultrasonography of the rotator cuff. A comparison of ultrasonographic and
arthroscopic findings in one hundred consecutive cases.
AB - BACKGROUND: There has been limited acceptance of shoulder ultrasonography by
orthopaedic surgeons in the United States. The purpose of this retrospective
study was to determine the diagnostic performance of high-resolution
ultrasonography compared with arthroscopic examination for the detection and
characterization of rotator cuff tears. METHODS: One hundred consecutive
shoulders in ninety-eight patients with shoulder pain who had undergone
preoperative ultrasonography and subsequent arthroscopy were identified. The
arthroscopic diagnosis was a full-thickness rotator cuff tear in sixty-five
shoulders, a partial-thickness tear in fifteen, rotator cuff tendinitis in
twelve, frozen shoulder in four, arthrosis of the acromioclavicular joint in two,
and a superior labral tear and calcific bursitis in one shoulder each. All
ultrasonographic reports were reviewed for the presence or absence of a rotator
cuff tear and a biceps tendon rupture or dislocation. All arthroscopic
examinations were performed according to a standardized operative procedure. The
size and extent of the tear and the status of the biceps tendon were recorded for
all shoulders. The findings on ultrasonography and arthroscopy then were compared
for each parameter. RESULTS: Ultrasonography correctly identified all sixty-five
full-thickness rotator cuff tears (a sensitivity of 100 percent). There were
seventeen true-negative and three false-positive ultrasonograms (a specificity of
85 percent). The overall accuracy was 96 percent. The size of the tear on
transverse measurement was correctly predicted in 86 percent of the shoulders
with a full-thickness tear. Ultrasonography detected a tear in ten of fifteen
shoulders with a partial-thickness tear that was diagnosed on arthroscopy. Five
of six dislocations and seven of eleven ruptures of the biceps tendon were
identified correctly. CONCLUSIONS: Ultrasonography was highly accurate for
detecting full-thickness rotator cuff tears, characterizing their extent, and
visualizing dislocations of the biceps tendon. It was less sensitive for
detecting partial-thickness rotator cuff tears and ruptures of the biceps tendon.
PMID- 10761941
TI - The results of repair of massive tears of the rotator cuff.
AB - BACKGROUND: Massive tears of the tendons of the rotator cuff cause atrophy and
fatty degeneration of the rotator cuff muscles and painful loss of function of
the shoulder. Repair of massive rotator cuff tears is often followed by retears
of the tendons, additional muscular degeneration, and a poor clinical outcome.
The purposes of this study were to determine whether a new method of repair of
rotator cuff tendons can yield a lower retear rate and a better clinical outcome
than previously reported methods, to assess the muscular changes following repair
of massive tears of the musculotendinous units, and to correlate findings on
magnetic resonance imaging with the clinical results. METHODS: Twenty-nine
massive rotator cuff tears involving complete detachment of at least two tendons
were repaired operatively with use of a new laboratory-tested technique in a
prospective study. At least two years (average, thirty-seven months; range,
twenty-four to sixty-one months) postoperatively, twenty-seven patients were
evaluated clinically and with magnetic resonance imaging to determine the
clinical outcome, the integrity of the repair, and the condition of the rotator
cuff muscles. RESULTS: The age and gender-adjusted Constant score improved from
an average of 49 percent preoperatively to an average of 85 percent
postoperatively, corresponding to a subjective shoulder value of 78 percent of
that of a normal shoulder. Pain-free flexion improved from an average of 92
degrees to an average of 142 degrees, and abduction improved from an average of
82 degrees to an average of 137 degrees. Pain decreased and performance of
activities of daily living improved significantly (p < 0.05). The seventeen
patients who had a structurally successful repair all had an excellent clinical
outcome. Muscle atrophy could not be reversed except in successfully repaired
supraspinatus musculotendinous units. Fatty degeneration increased in all
muscles. CONCLUSIONS: The method of repair of massive rotator cuff tears that was
used in this study yielded a comparatively low retear rate and good-to-excellent
clinical results; however, the repair did not result in substantial reversal of
muscular atrophy and fatty degeneration. Retears occurred more often in patients
who had had a shorter interval between the onset of the symptoms and the
operation (p < 0.05). Patients who had a retear had improvement of the shoulder
compared with the preoperative state, but they had less improvement than did
those who had a successful repair.
PMID- 10761942
TI - Clinical results of modular polyethylene insert exchange with retention of total
knee arthroplasty components.
AB - BACKGROUND: Modular polyethylene inserts have enabled surgeons to perform an
isolated tibial insert exchange while retaining well fixed components. The
purpose of this study was to review the results of insert revision and to clarify
the role of this option compared with that of revision total knee arthroplasty.
METHODS: Fifty-six patients (sixty-three knees) were managed with revision of a
tibial polyethylene insert and retention of well aligned and stable femoral and
tibial components. The implants had been in situ for an average of fifty-nine
months (range, two to 108 months) at the time of the insert exchange. The inserts
that were removed at the time of exchange were evaluated with regard to wear of
the articular surface according to the classification system of Hood et al. and
with regard to undersurface wear according to the method described by Wasielewski
et al. Forty-eight knees were followed for an average of 7.4 years (range, 3.0 to
12.2 years) after the insert exchange. Knees that did not require an additional
operation were considered to have had a successful exchange. RESULTS: Seven of
the forty-eight exchanges failed, at an average of fifty-four months, because of
accelerated wear of the new insert. All seven knees required complete revision of
all components. Of the twenty-two exchanges that were performed because of severe
wear of the primary insert, six (27 percent) failed at an average of less than
five years; thus, knees in which the exchange was performed because of advanced
wear were more likely to fail again (p < 0.05). In addition, primary inserts that
were removed from knees in which the exchange procedure subsequently failed had
higher delamination scores than those that were removed from knees in which the
exchange was successful (p < 0.05). Most of the primary inserts had substantial
undersurface wear at the time of the exchange procedure. Metallosis (thirty
knees) and osteolysis (nineteen knees) were unrelated to failure of the exchange.
CONCLUSIONS: An isolated revision of the tibial polyethylene insert should not be
performed when there is accelerated wear of the insert with severe delamination
and grade-3 or 4 undersurface wear within ten years after the primary procedure.
Because a variety of patient-related, implant-related, and technical factors
influence polyethylene wear, the orthopaedist must consider multiple variables
whenever contemplating a limited revision.
PMID- 10761943
TI - The safety and efficacy of Isola-Galveston instrumentation and arthrodesis in the
treatment of neuromuscular spinal deformities.
AB - BACKGROUND: Implant systems that realign and stabilize a deformed spine continue
to evolve. The purpose of the study of this case series was to determine the
safety and effectiveness of a system designed to integrate hook, wire, screw, and
post anchors for the treatment of a wide spectrum of neuromuscular disorders
associated with pelvic deformity or the potential for deformity. METHODS: Forty
seven consecutive patients who had a spinal deformity that was due to cerebral
palsy or an upper motor-neuron cerebral palsy-like disease (thirty-one patients),
myelomeningocele (nine), Duchenne muscular dystrophy (four), or other disorders
(three) were managed with Isola-Galveston instrumentation and arthrodesis. The
average age at the time of the operation was fourteen years and three months
(range, five years and four months to twenty-three years and nine months). Eight
patients (17 percent) had an additional anterior discectomy and arthrodesis
without instrumentation, and three (6 percent) had an additional decancellation
egg-shell osteotomy. The forty-seven patients were followed for an average of
forty-seven months (range, twenty-four to 100 months). The complications were
tabulated to assess the safety of the procedure, and the correction of each
deformity was calculated to determine the efficacy. RESULTS: There were no
deaths, acute wound infections, or serious neurological problems. Reoperation was
necessary in five patients (11 percent). One reoperation was performed because of
a delayed deep wound infection; one, because of delayed sterile drainage; and
one, for a pseudarthrosis repair. The remaining two reoperations were done for
removal of an implant because the cephalad portion had become prominent. In
addition to the pseudarthrosis that required a reoperation, there were three
possible pseudarthroses that did not require a reoperation (overall prevalence of
pseudarthrosis, 9 percent). Postoperative bracing was used for eleven patients
(23 percent); it did not influence the rate of pseudarthrosis or possible
pseudarthrosis. The average preoperative scoliosis of 70 degrees was corrected to
24 degrees (a 66 percent correction) at the time of the latest follow-up, and the
average preoperative pelvic obliquity of 27 degrees was corrected to 5 degrees
(an 81 percent correction). A survey of the patients, parents, and caregivers
indicated that 96 percent of them were satisfied or very satisfied with the
result of the operation. CONCLUSIONS: Isola-Galveston instrumentation seems as
safe and effective as other types of instrumentation that have been studied in
comparable series in the literature. Isola-Galveston instrumentation is probably
more effective for the correction of pelvic obliquity and the maintenance of
correction. Only a posterior procedure is used, and the instrumentation appears
to decrease the need for an additional anterior approach. Spinal hook, wire,
screw, and post anchors have been successfully integrated into one posterior
spinal implant system.
PMID- 10761944
TI - Vascularized free fibular transfer combined with autografting for the management
of fracture nonunions associated with radiation therapy.
AB - BACKGROUND: The purpose of this study was to evaluate the functional results,
rates of union, and complications associated with vascularized free fibular
transfer combined with autografting for the treatment of nonunions in previously
irradiated bone. METHODS: Seventeen patients who had had eighteen vascularized
free fibular transfers combined with autografting for the treatment of nonunion
of a fracture in previously irradiated bone were included in this study. There
were eleven female patients and six male patients. Eight patients had a bone
neoplasm and nine, a soft-tissue neoplasm. The diagnosis was Ewing sarcoma in
four patients; lymphoma, malignant fibrous histiocytoma, and rhabdomyosarcoma in
two patients each; and cavernous hemangioma, metastatic breast carcinoma,
reticulum-cell sarcoma, myxosarcoma, hemangiopericytoma, and fibrosarcoma in one
patient each. The remaining patient had a soft-tissue tumor for which the
diagnosis was not known. All patients received radiation therapy. The average
dose was 5564 centigray. There were no recurrent tumors. The average interval
between the radiation therapy and the original fracture was 111 months. The
fracture was in the femur in thirteen patients, in the humerus in three, and in
the tibia in one. All patients had operative or nonoperative treatment, or both,
of the initial fracture, and two had iliac-crest bone-grafting after the initial
open reduction and internal fixation procedure. The ages of the patients ranged
from thirteen to eighty-two years at the time of the vascularized free fibular
transfer. All fibular transfers were applied as onlay grafts because no nonunion
was associated with a large segmental defect. Cancellous autogenous bone graft
from the iliac crest was used as an additional graft at the proximal and distal
junctions of the graft with the bone and at the fracture site in all patients.
The average duration of follow-up after the vascularized free fibular transfer
was fifty-seven months (range, twenty-eight to 112 months). RESULTS: Sixteen of
the eighteen fracture sites united, after an average of 9.4 months (range, three
to twenty-four months). Thirteen patients had an excellent result, one had a good
result, two had a fair result, and one had a failure of treatment. Four patients
had an infection, including one who continued to have a nonunion. The other three
patients had union after treatment with antibiotics, debridement, and removal of
the hardware. Another patient who had a recalcitrant nonunion eventually required
an above-the-knee amputation. CONCLUSIONS: On the basis of this review, we
suggest that microvascular fibular transfer combined with autografting is an
appropriate treatment option for difficult nonunions associated with previously
irradiated bone.
PMID- 10761945
TI - Posterolateral dislocation of the elbow joint. Relationship to medial
instability.
AB - BACKGROUND: Dislocation of the elbow joint is the second most common dislocation
in the upper extremity, dislocation of the shoulder being the most common. It has
been reported that uncomplicated dislocation of the elbow joint may be associated
with a decreased range of motion, degenerative changes in the elbow joint,
ectopic calcification, or neurological deficits. As the medial collateral
ligament complex can be completely disrupted during dislocation, we evaluated the
association between the long-term results of treatment of simple posterolateral
dislocation of the elbow and the presence of persistent medial or valgus elbow
instability. METHODS: Fifty patients who had a mean age of thirty-three years
(range, eighteen to fifty-eight years) had closed reduction of a posterolateral
dislocation of the elbow without associated fractures. The extremity was
immobilized in an above-the-elbow plaster cast for three weeks. After a mean
duration of follow-up of nine years (range, six to thirteen years), forty-one
patients were evaluated with an interview, a physical examination, and
radiographs made while a valgus load was applied to the elbow. RESULTS: The
average score according to the system of The Hospital for Special Surgery was 91
points (range, 49 to 100 points), and thirty-one patients described their elbow
function as good or excellent. Twenty-four patients had evidence of medial
instability on radiographs made while a valgus load was applied to the elbow.
Twenty-one patients had signs of degeneration of the joint, and twenty-five
patients had ectopic ossification. Magnetic resonance imaging combined with
arthrography was performed for the first twenty patients; eight had evidence of
rupture of the medial collateral ligament, seven had generalized degenerative
changes of the cartilage, and four had a chondral defect of the capitellum. (The
study could not be completed for the remaining patient.) Medial instability on
radiographs was correlated with signs of degeneration (p = 0.001), ectopic
ossification (p = 0.01), a worse score according to the system of The Hospital
for Special Surgery (p = 0.002), and persistent pain (p = 0.04). CONCLUSIONS:
Posterolateral dislocation of the elbow joint can lead to persistent valgus
instability that is associated with a worse overall clinical and radiographic
result.
PMID- 10761946
TI - Gait and function after intra-articular arthrodesis of the hip in adolescents.
AB - BACKGROUND: Patients who have had a hip arthrodesis have been reported to have
pain in the back and the knee due to an altered gait. There is little information
about the specific compensatory mechanisms that are adopted when walking. The
purpose of this study was to objectively define gait adaptations after an
arthrodesis of the hip and to correlate the kinematic findings with pain and
other patient outcomes. METHODS: Nine patients who had had an arthrodesis of the
hip at an average age of thirteen years and five months (range, ten years and
nine months to sixteen years and eleven months) were evaluated with gait analysis
and muscle strength-testing and completed a questionnaire related to pain and
function. The average duration of follow-up was eight years and ten months
(range, two years and one month to thirteen years and ten months). The frequency
of the postoperative visits varied. Seven patients were adults at the time of the
study and were called back specifically for the study. RESULTS: All patients had
decreased cadence and step lengths. The kinematic findings included decreased
dorsiflexion of the ipsilateral ankle, hyperextension of the ipsilateral knee
during the stance phase, and a tendency toward increased genu valgum during gait.
In normal gait, there is no genu varum or valgum during the stance phase. The
patients had an average (and standard deviation) of 7 +/- 4 degrees of genu
valgum. Pelvic and lumbar motion in the sagittal plane was excessive in all
patients. Strength-testing revealed clinically relevant weakness in the
ipsilateral quadriceps in all patients, with a difference of more than 20 percent
between the two extremities in six patients. The gastrocnemius. soleus muscle was
stronger on the side with the fused hip in six patients. The questionnaire,
designed by Harris in 1969 and completed by the patients at the time of the gait
analysis, revealed back pain in seven patients. The questionnaire was
administered only once. The functional outcome as measured with use of the same
questionnaire worsened as the duration of follow-up increased. CONCLUSIONS: The
gait analysis showed excessive motion in the lumbar spine and the ipsilateral
knee in all nine patients. This abnormal motion led to pain as the duration of
follow-up increased, and all patients who had been followed for four or more
years after the arthrodesis complained of back pain. We hypothesized that
excessive motion for an extended duration can lead to back pain. The preferred
position of the hip for the arthrodesis was 20 to 25 degrees of flexion, neutral
abduction-adduction, and neutral rotation.
PMID- 10761947
TI - Spinal instability secondary to metastatic cancer.
PMID- 10761948
TI - Topics in medical economics: lessons of the prisoner's dilemma.
PMID- 10761949
TI - Acute renal failure.
PMID- 10761950
TI - Spinoglenoid ligament.
PMID- 10761951
TI - Conversations with a cab driver.
PMID- 10761952
TI - The quality of anticoagulation management.
PMID- 10761954
TI - Intensive care unit syndrome: a dangerous misnomer.
AB - The terms intensive care unit (ICU) syndrome and ICU psychosis have been used
interchangeably to describe a cluster of psychiatric symptoms that are unique to
the ICU environment. It is often postulated that aspects of the ICU, such as
sleep deprivation and sensory overload or monotony, are causes of the syndrome.
This article reviews the empirical support for these propositions. We conclude
that ICU syndrome does not differ from delirium and that ICU syndrome is caused
exclusively by organic stressors on the central nervous system. We argue further
that the term ICU syndrome is dangerous because it impedes standardized
communication and research and may reduce the vigilance necessary to promptly
investigate and reverse the medical cause of the delirium. Directions for future
research are suggested.
PMID- 10761953
TI - Overweight, obesity, and health risk.
AB - More than half of adult Americans are overweight or obese, and public health
recommendations call for weight loss in those who are overweight with associated
medical conditions or who are obese. However, some controversy exists in the lay
press and in the medical literature about the health risks of obesity. We review
briefly the large body of evidence indicating that higher levels of body weight
and body fat are associated with an increased risk for the development of
numerous adverse health consequences. Efforts to prevent further weight gain in
adults at risk for overweight and obesity are essential. For those whose present
or future health is at risk because of their obesity and who are motivated to
make lifestyle changes, a recommendation for weight loss is appropriate.
PMID- 10761955
TI - Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes
and disease.
AB - Originally suggested to function mainly in inflammatory situations, recent data
have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive
biologic processes, renal and neurologic function, and the antithrombotic
activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have
recently become available as analgesic and anti-inflammatory drugs, a
comprehensive view of this rapidly evolving field is necessary to anticipate both
the potential therapeutic benefits and toxic effects associated with these
agents.
PMID- 10761956
TI - Self-selected posttrial aspirin use and subsequent cardiovascular disease and
mortality in the physicians' health study.
AB - BACKGROUND: The randomized aspirin component of the Physicians' Health Study
(PHS) was terminated early, after 5 years, primarily because of the emergence of
a statistically extreme (P<.00001) 44% reduction of first myocardial infarction
(MI) among those assigned to aspirin. As a result, there were insufficient
numbers of strokes or cardiovascular disease (CVD)-related deaths to evaluate
these end points definitively. METHODS: Data on self-selected aspirin use were
collected until the beta carotene component ended as scheduled after 12 years.
Posttrial use of aspirin was assessed at the 7-year follow-up among 18 496
participants with no previous reported CVD. Randomized and posttrial
observational results in the PHS were compared, and differences between those
self-selecting aspirin and those not were examined. RESULTS: At 7 years, 59.5% of
participants without CVD reported self-selected aspirin use for at least 180 d/y,
and 20.8% for 0 to 13 d/y. Use was significantly associated with family history
of MI, hypertension, elevated cholesterol levels, body mass index, alcohol
consumption, exercise, and use of vitamin E supplements. In multivariate
analyses, self-selected aspirin use for at least 180 vs 0 to 13 d/y was
associated with lower risk for subsequent MI (relative risk [RR], 0.72; 95%
confidence interval [CI], 0.55-0.95), no relation with stroke (RR, 1.02; 95% CI,
0.74-1.39), and significant reductions in CVD-related (RR, 0.65; CI, 0.47-0.89)
and total mortality (RR, 0.64; CI, 0.54-0.77). CONCLUSION: These associations
between self-selected aspirin use and CVD risk factors increase the likelihood of
residual confounding and emphasize the need for large-scale randomized trials,
such as the ongoing Women's Health Study, to detect reliably the most plausible
small to moderate effects of aspirin in the primary prevention of stroke and CVD
related death.
PMID- 10761957
TI - Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third
National Health and Nutrition Examination Survey (NHANES III).
AB - BACKGROUND: Ascorbic acid-deficient guinea pigs frequently develop gallstones,
and ascorbic acid status may also affect the risk of gallbladder disease in
humans. To examine the relationship of ascorbic acid, an antioxidant nutrient
involved in cholesterol catabolism, to gallbladder disease, we analyzed data
collected from a probability sample of US adults. METHODS: Analyses of data from
7042 women and 6088 men enrolled in the Third National Health and Nutrition
Examination Survey, 1988-1994, were performed. Multiple logistic regression
models stratified by sex were examined, controlling for the effects of age, race,
diet, body mass index, and other potential confounders. RESULTS: A total of 761
women (11%) and 235 men (4%) reported a history of clinical gallbladder disease
(symptomatic gallstones or cholecystectomy). Of the 9650 participants without a
history of clinical gallbladder disease or abdominal pain consistent with
gallbladder disease, and with valid abdominal ultrasonography, 408 (8%) of 4863
women and 274 (6%) of 4787 men had asymptomatic gallstones. Serum ascorbic acid
level was inversely related to prevalence of clinical and asymptomatic
gallbladder disease among women, but not among men. Among women, each SD (27
micromol/L) increase in serum ascorbic acid level was independently associated
with a 13% lower prevalence of clinical gallbladder disease (P = .006) and
asymptomatic gallstones (P = .048). CONCLUSION: Ascorbic acid, which affects the
catabolism of cholesterol to bile acids and, in turn, the development of
gallbladder disease in experimental animals, may affect the risk of gallbladder
disease among women.
PMID- 10761958
TI - Effect of smoking cessation on mortality after myocardial infarction: meta
analysis of cohort studies.
AB - OBJECTIVE: To determine the effect of smoking cessation on mortality after
myocardial infarction. DATA SOURCES: English- and non-English-language articles
published from 1966 through 1996 retrieved using keyword searches of MEDLINE and
EMBASE supplemented by letters to authors and searching bibliographies of
reviews. STUDY SELECTION: Selection of relevant abstracts and articles was
performed by 2 independent reviewers. Articles were chosen that reported the
results of cohort studies examining mortality in patients who quit vs continued
smoking after myocardial infarction. DATA EXTRACTION: Mortality data were
extracted from the selected articles by 2 independent reviewers. DATA SYNTHESIS:
Twelve studies were included containing data on 5878 patients. The studies took
place in 6 countries between 1949 and 1988. Duration of follow-up ranged from 2
to 10 years. All studies showed a mortality benefit associated with smoking
cessation. The combined odds ratio based on a random effects model for death
after myocardial infarction in those who quit smoking was 0.54 (95% confidence
interval, 0.46-0.62). Relative risk reductions across studies ranged from 15% to
61%. The number needed to quit smoking to save 1 life is 13 assuming a mortality
rate of 20% in continuing smokers. The mortality benefit was consistent
regardless of sex, duration of follow-up, study site, and time period.
CONCLUSION: Results of several cohort studies suggest that smoking cessation
after myocardial infarction is associated with a significant decrease in
mortality.
PMID- 10761959
TI - Are beta-blockers effective in elderly patients who undergo coronary
revascularization after acute myocardial infarction?
AB - BACKGROUND: Although randomized clinical trials have demonstrated that beta
blocker therapy is effective in reducing mortality after acute myocardial
infarction (AMI), many of these studies excluded patients who undergo coronary
revascularization. However, the clinical practice guidelines established by the
American College of Cardiology and the American Heart Association recommend that
beta-blocker therapy be considered for patients who underwent successful
revascularization after AMI. METHODS: Using data from the Cooperative
Cardiovascular Project, we compared the initiation of beta-blocker therapy at
discharge in patients aged 65 years or older who underwent coronary artery bypass
surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA) during
their hospitalization for AMI with that of patients who did not undergo
revascularization. We then examined whether beta-blocker therapy was associated
with lower 1-year mortality between revascularized and nonrevascularized groups.
RESULTS: After excluding patients with contraindications to beta-blocker therapy,
84 457 patients remained in the study sample. Of these, 8482 patients underwent
CABG, and 13 997 patients underwent PTCA. After adjusting for demographic and
clinical factors, we found that these patients were less likely to initiate beta
blocker therapy after CABG (odds ratio [OR], 0.44; 95% confidence interval [CI],
0.41-0.47) or PTCA (OR, 0.89; 95% CI, 0.85-0.93) relative to the
nonrevascularized group. After adjusting for potential confounders, beta-blockers
were significantly associated with lower 1-year mortality in patients who
underwent CABG (hazard ratio [HR], 0.70; 95% CI, 0.55-0.89) or PTCA (HR, 0.86;
95% CI, 0.74-1.00), similar to that of the non-revascularized group (HR, 0.83;
95% CI, 0.80-0.87). CONCLUSIONS: Therapy after AMI with beta-blockers appears to
be as effective in reducing 1-year mortality for elderly patients who have
undergone CABG or PTCA as for a nonrevascularized group. Our findings suggest
that routine use of beta-blockers should be considered for patients who undergo
revascularization after AMI.
PMID- 10761960
TI - Mortality among women with ductal carcinoma in situ of the breast in the
population-based surveillance, epidemiology and end results program.
AB - BACKGROUND: Over 14% of breast cancers diagnosed in the United States annually
are ductal carcinomas in situ (DCIS). There are no published population-based
reports of the likelihood of breast cancer death among US women with DCIS.
METHODS: We used data from the Surveillance, Epidemiology and End Results program
to determine the likelihood of breast cancer death at 5 and 10 years among US
women aged 40 and older diagnosed with DCIS from 1978 to 1983 (before screening
mammography was common; n = 1525) and from 1984 to 1989 (when screening
mammography became common; n = 5547). We also calculated standardized mortality
ratios (SMRs) to compare observed deaths from breast cancer, cardiovascular
disease, and all causes combined among women with DCIS with deaths expected based
on general population mortality rates. RESULTS: Among women diagnosed with DCIS
from 1978 to 1983, 1.5% died of breast cancer within 5 years and 3.4% within 10
years. Among women diagnosed from 1984 to 1989, 0.7% died of breast cancer within
5 years and 1.9% within 10 years. Relative to the general population, risk of
breast cancer death was greater for women diagnosed from 1978 to 1983 (SMR, 3.4;
95% confidence interval [CI], 2.5-4.5) than for women diagnosed from 1984 to 1989
(10-year SMR, 1.9; 95% CI, 1.5-2.3). Women diagnosed from 1984 to 1989 were
significantly less likely than women in the general population to have died of
cardiovascular diseases (10-year SMR, 0.6; 95% CI, 0.5-0.7) or of all causes
combined (SMR, 0.8; 95% CI, 0.7-0.8). CONCLUSIONS: Among women diagnosed with
DCIS, risk of death from breast cancer was low, at least within the 10 years
following diagnosis. This may reflect the effectiveness of treatment for DCIS,
the "benign" nature of DCIS, or both. At 10 years, women diagnosed from 1984 to
1989 were less likely than women diagnosed from 1978 to 1983 to have died of
breast cancer, and their risk of dying of all causes combined was lower than that
in the general population.
PMID- 10761961
TI - Hyperhomocyst(e)inemia and the increased risk of venous thromboembolism: more
evidence from a case-control study.
AB - BACKGROUND: Elevation of plasma homocyst(e)ine level is an independent risk
factor for arterial and venous thrombosis. We studied the degree to which
hyperhomocyst(e)inemia contributes to the development of venous thromboembolism,
using a retrospective case-control study design. METHODS: Cases were individuals
with objectively confirmed venous thromboembolism and no history of
atherosclerosis seen at the Toronto Hospital Thrombosis Clinic, Toronto, Ontario,
between January 1, 1996, and July 31, 1998. Three controls were matched for every
case according to sex and age within 5 years and were derived from a large
community cohort. All subjects underwent assessment for fasting plasma
homocyst(e)ine levels. Hyperhomocyst(e)inemia was defined as a fasting total
homocyst(e)ine concentration above the 95th percentile control value. RESULTS:
Seventy cases and 210 matched controls were included. Men and women were equally
represented, and most were younger than 60 years. Among cases with venous
thromboembolism, the mean (+/- SD) plasma homocyst(e)ine level was significantly
higher than in controls (13.0 +/- 6.9 micromol/L vs 9.0 +/- 4.8 micromol/L,
respectively; P<.001). Sixteen (23%) of 70 cases had hyperhomocyst(e)inemia
compared with 10 (5%) of 210 controls (odds ratio, 5.9; 95% confidence interval
[CI], 2.5-13.8). Among subjects aged 60 years or younger, the odds ratio was 4.9
(95% CI, 1.4-16.4), while for those aged 60 years or older, it was 7.3 (95% CI,
2.2-24.0). Even with the exclusion of cases showing abnormal renal function or
low serum vitamin B12 or folate levels, the odds ratio remained significantly
elevated at 3.3 (95% CI, 1.1-10.0). CONCLUSIONS: We found that fasting
hyperhomocyst(e)inemia is a significant risk factor for venous thromboembolic
disease in patients at a thrombosis clinic. Given the magnitude of effect and
consistency across these studies, it is likely that homocyst(e)ine plays a
causative role in the development of venous thrombosis, and it should be
considered in the workup for venous thromboembolism.
PMID- 10761962
TI - Quality of anticoagulation management among patients with atrial fibrillation:
results of a review of medical records from 2 communities.
AB - BACKGROUND: Most treatment of patients at risk for stroke is provided in the
ambulatory setting. Although many studies have addressed the proportion of
eligible patients with atrial fibrillation (AF) receiving warfarin sodium, few
have addressed the quality of their anticoagulation management. OBJECTIVE: As a
comprehensive assessment of quality, we analyzed the proportion of eligible
patients receiving warfarin, the proportion of time their international
normalized ratios (INRs) were within the target range, and, when an out-of-target
range INR value occurred, the time until the next INR measurement was made.
METHODS: Retrospective review of the medical records of 660 patients with AF
managed by general internists and family practitioners in Rochester, NY, and the
Research Triangle area of North Carolina. RESULTS: Only 34.7% of eligible
patients with AF received warfarin. The INR values were out of the target range
approximately half the time, and the response to these values was not always
timely. For all the measures considered, both Rochester practices with access to
an anticoagulation service had higher (albeit not ideal) quality of warfarin
management than the remaining practices. CONCLUSIONS: We found significant
deficiencies in the practice of warfarin management and suggestive evidence that
anticoagulation services can partially ameliorate these deficiencies. More
research is needed to describe the quality of anticoagulation management in
typical practice and how this management can be improved.
PMID- 10761963
TI - A randomized trial of in-home visits for disability prevention in community
dwelling older people at low and high risk for nursing home admission.
AB - BACKGROUND: In-home preventive visits with multidimensional geriatric assessments
can delay the onset of disabilities in older people. METHODS: This was a
stratified randomized trial. There were 791 participants, community-dwelling
people in Bern, Switzerland, older than 75 years. The participants' risk status
was based on 6 baseline predictors of functional deterioration. The intervention
consisted of annual multidimensional assessments and quarterly follow-up in-home
visits by 3 public health nurses (nurses A, B, and C), who, in collaboration with
geriatricians, evaluated problems, gave recommendations, facilitated adherence
with recommendations, and provided health education. Each nurse was responsible
for conducting the home visits in 1 ZIP code area. RESULTS: After 3 years,
surviving participants at low baseline risk in the intervention group were less
dependent in instrumental activities of daily living (ADL) compared with controls
(odds ratio, 0.6; 95% confidence interval, 0.3-1.0; P = .04). Among subjects at
high baseline risk, there were no favorable intervention effects on ADL and an
unfavorable increase in nursing home admissions (P= .02). Despite the similar
health status of subjects, nurse C identified fewer problems in the subjects who
were visited compared with those assessed by nurses A and B. Subgroup analysis
revealed that among low-risk subjects visited by nurses A and B, the intervention
had favorable effects on instrumental ADL (P = .005) and basic ADL (P = .009),
reduced nursing home admissions (P = .004), and resulted in net cost savings in
the third year (US $1403 per person per year). Among low-risk subjects visited by
nurse C, the intervention had no favorable effects. CONCLUSIONS: These data
suggest that this intervention can reduce disabilities among elderly people at
low risk but not among those at high risk for functional impairment, and that
these effects are likely related to the home visitor's performance in conducting
the visits.
PMID- 10761964
TI - Relationship between persistence of abdominal symptoms and successful outcome
after cholecystectomy.
AB - BACKGROUND: Patients frequently have persistent abdominal symptoms after
undergoing cholecystectomy. The relationship between abdominal symptoms and
biliary dysfunction is often unclear. OBJECTIVES: To describe the persistence
rate of abdominal symptoms in a large cohort of patients after elective
cholecystectomy, to identify predictors of symptom persistence and operative
success, to understand which symptoms improve after cholecystectomy, and to
describe the important determinants of an unsuccessful operation. METHODS:
Secondary analysis of a prospective, multisite cohort study of 2481 patients
undergoing elective cholecystectomy. RESULTS: The mean +/- SD number of abdominal
symptoms per patient decreased from 3.1 +/- 2.0 to 1.1 +/- 1.3; 27% of patients
who identified a symptom as most bothersome before surgery still had the symptom
6 months after surgery. Symptom persistence rates ranged from 5.6% (vomiting) to
40.2% (gas/flatulence). A balance score that quantified the abdominal symptom mix
between dyspeptic and biliary symptoms shifted after surgery to the dyspeptic
category. Predictors of persistence of a most bothersome symptom were dyspeptic
symptom category, worse operative risk and self-rated health status, symptom
duration longer than 6 months, and no previous episodes of acute cholecystitis.
The major correlate of not achieving a very successful outcome (15.2% of
patients) was the presence of postoperative abdominal pain. Other predictors
included worse self-rated health status and physical functioning, symptom
duration longer than 6 months before surgery, and no previous episodes of acute
cholecystitis. CONCLUSIONS: Symptoms categorized as dyspeptic were more likely to
persist than were biliary symptoms, although all symptoms showed a decrease in
prevalence after cholecystectomy. More attention to the rationale for gallbladder
removal and clarification of patient expectations for symptom relief might be
necessary to improve outcomes after elective cholecystectomy.
PMID- 10761965
TI - The educational value of autopsy in a residency training program.
AB - BACKGROUND: Historically, the autopsy has been an indispensable educational tool.
Over the past several decades, however, the national autopsy rate has declined
and the educational role of autopsy in modern medicine is being questioned.
OBJECTIVE: To assess the educational value of autopsy attendance in an internal
medicine residency program. METHODS: We performed a retrospective review of all
autopsies performed on the general internal medicine teaching service between
October 1996 and September 1998. Premortem and postmortem diagnoses were
determined and compared and attending physician surveys were reviewed. RESULTS:
Eighty-eight deaths occurred during the study period. Twenty-nine (33%) patients
underwent autopsy. All autopsies were observed by the primary team and the
attending physician completed an autopsy survey on each patient. An unexpected
pathological diagnosis directly contributing to death was detected in 10 (34%)
patients at autopsy. Additional unexpected pathological diagnoses were discovered
in 23 (79%) cases. Attending physician surveys revealed that all 10 unexpected
diagnoses contributing to death were observed by the primary team at the time of
autopsy. Autopsy attendance was rated as a valuable educational experience in 27
cases (93%). CONCLUSION: Autopsy is a valuable educational tool and autopsy
attendance should remain an integral part of internal medicine residency
training.
PMID- 10761966
TI - Predicting methicillin resistance and the effect of inadequate empiric therapy on
survival in patients with Staphylococcus aureus bacteremia.
AB - BACKGROUND: The restriction of vancomycin hydrochloride use is recommended as a
measure to decrease the emergence of vancomycin resistance in gram-positive
organisms; however, vancomycin also is the treatment of choice for methicillin
resistant Staphylococcus aureus (MRSA) infections. If vancomycin use is
restricted to patients with documented infections due to methicillin-resistant
organisms, then patients with MRSA infections may not initially receive
vancomycin. This study was performed to determine factors that predict MRSA
bacteremia and if ineffective empiric antibiotic therapy increased the risk of
death in patients with S aureus bacteremia. METHODS: We conducted a retrospective
cohort study of all patients with clinically significant S aureus bacteremia (132
episodes in 128 patients) diagnosed between October 1, 1995, and January 1, 1998,
at an urban acute care Veterans Affairs medical center (approximately 200 acute
care beds) in Baltimore, Md. During the study period, vancomycin was a restricted
antibiotic. Empiric use had to be approved by an attending physician specializing
in infectious diseases. RESULTS: Compared with patients who had methicillin
sensitive S aureus bacteremia, patients with MRSA bacteremia were significantly
older (70 vs 58 years; P<.01), more likely to have a history of MRSA (47% vs 6%;
P<.01) and a nosocomial infection (76% vs 50%; P<.01), and less likely to use
injection drugs (8% vs 32%; P<.01). In addition, compared with patients who had
methicillin-sensitive S aureus bacteremia, patients with MRSA bacteremia were
significantly less likely (45% vs 98%; P<.01) to receive effective antibiotic
therapy during the first 48 hours of hospitalization. However, the risk of death
due to ineffective empiric therapy was less than 1 (relative risk, 0.82; 95%
confidence interval, 0.36-1.88) and did not change significantly when adjusted
for age, occurrence of sepsis, or nosocomial infection. CONCLUSIONS: The results
of this study support the safety of the restriction of vancomycin use in patients
with clinically significant S aureus bacteremia. However, patients with a history
of MRSA are more likely to have future MRSA infections and should receive empiric
therapy using vancomycin for possible S aureus infections, particularly for
nosocomial infections.
PMID- 10761967
TI - American ginseng (Panax quinquefolius L) reduces postprandial glycemia in
nondiabetic subjects and subjects with type 2 diabetes mellitus.
AB - BACKGROUND: Despite a lack of medical evidence to support its therapeutic
efficacy, the use of herbal medicine has increased considerably. Ginseng, one of
the most widely used herbs, is hypothesized to play a role in carbohydrate
metabolism and diabetes mellitus. We therefore undertook a preliminary short-term
clinical study to assess whether American ginseng (Panax quinquefolius L) affects
postprandial glycemia in humans. DESIGN: On 4 separate occasions, 10 nondiabetic
subjects (mean [+/-SD] age, 34+/-7 years; mean [+/-SD] body mass index [BMI],
25.6 +/- 3 kg/m2) and 9 subjects with type 2 diabetes mellitus (mean [+/-SD] age,
62 +/- 7 years; mean [+/-SD] BMI, 29 +/- 5 kg/m2; mean [+/-SD] glycosylated
hemoglobin A1c, 0.08+/-0.005) were randomized to receive 3-g ginseng or placebo
capsules, either 40 minutes before or together with a 25-g oral glucose
challenge. The placebo capsules contained com flour, in which the quantity of
carbohydrate and appearance matched the ginseng capsules. A capillary blood
sample was taken fasting and then at 15, 30, 45, 60, 90, and 120 (only for
subjects with type 2 diabetes mellitus ) minutes after the glucose challenge.
RESULTS: In nondiabetic subjects, no differences were found in postprandial
glycemia between placebo and ginseng when administered together with the glucose
challenge. When ginseng was taken 40 minutes before the glucose challenge,
significant reductions were observed (P<.05). In subjects with type 2 diabetes
mellitus, the same was true whether capsules were taken before or together with
the glucose challenge (P<.05). Reductions in area under the glycemic curve were
18%+/-31% for nondiabetic subjects and 19+/-22% and 22+/-17% for subjects with
type 2 diabetes mellitus administered before or together with the glucose
challenge, respectively. CONCLUSIONS: American ginseng attenuated postprandial
glycemia in both study groups. For nondiabetic subjects, to prevent unintended
hypoglycemia it may be important that the American ginseng be taken with the
meal.
PMID- 10761968
TI - Handwashing compliance by health care workers: The impact of introducing an
accessible, alcohol-based hand antiseptic.
AB - CONTEXT: Under routine hospital conditions handwashing compliance of health care
workers including nurses, physicians, and others (eg, physical therapists and
radiologic technicians) is unacceptably low. OBJECTIVES: To investigate the
efficacy of an education/ feedback intervention and patient awareness program
(cognitive approach) on handwashing compliance of health care workers; and to
compare the acceptance of a new and increasingly accessible alcohol-based
waterless hand disinfectant (technical approach) with the standard sink/soap
combination. DESIGN: A 6-month, prospective, observational study. SETTING: One
medical intensive care unit (ICU), 1 cardiac surgery ICU, and 1 general medical
ward located in a 728-bed, tertiary care, teaching facility. PARTICIPANTS:
Medical caregivers in each of the above settings. INTERVENTIONS: Implementation
of an education/ feedback intervention program (6 in-service sessions per each
ICU) and patient awareness program, followed by a new, increasingly accessible,
alcohol-based, waterless hand antiseptic agent, initially available at a ratio of
1 dispenser for every 4 patients and subsequently 1 for each patient. MAIN
OUTCOME MEASURE: Direct observation of hand-washing for 1575 potential
opportunities monitored over 120 hours randomized for both time of day and bed
locations. RESULTS: Baseline handwashing compliance before and after defined
events was 9% and 22% for health care workers in the medical ICU and 3% and 13%
for health care workers in the cardiac surgery ICU, respectively. After the
education/feedback intervention program, handwashing compliance changed little
(medical ICU, 14% [before] and 25% [after]; cardiac surgery ICU, 6% [before] and
13% [after]). Observations after introduction of the new, increasingly
accessible, alcohol-based, waterless hand antiseptic revealed significantly
higher handwashing rates (P<.05), and handwashing compliance improved as
accessibility was enhanced-before 19% and after 41% with 1 dispenser per 4 beds;
and before 23% and after 48% with 1 dispenser for each bed. CONCLUSIONS:
Education/feedback intervention and patient awareness programs failed to improve
handwashing compliance. However, introduction of easily accessible dispensers
with an alcohol-based waterless handwashing antiseptic led to significantly
higher handwashing rates among health care workers.
PMID- 10761969
TI - Alcohol consumption and risk of type 2 diabetes mellitus among US male
physicians.
AB - OBJECTIVE: To examine the association between low to moderate alcohol consumption
and the incidence of type 2 diabetes mellitus (DM) in men. DESIGN: Prospective
cohort study. SUBJECTS AND METHODS: Over an average period of 12.1 years, we
evaluated 20 951 participants in the Physicians' Health Study between ages 40 and
84 years who were free of cardiovascular disease, cancer, and diabetes and
provided data on alcohol consumption at baseline. MAIN OUTCOME MEASURE: Type 2 DM
diagnosed after randomization. RESULTS: Among 20 951 physicians, 766 cases of
incident DM were reported over an average follow-up period of 12.1 years. After
adjustment for age, randomized treatment assignment, smoking, physical activity,
and body mass index, the relative risk estimates and 95% confidence intervals for
those reporting alcohol use of rarely/ never, 1 to 3 drinks per month, 1 drink
per week, 2 to 4 drinks per week, 5 to 6 drinks per week, and 1 or more drinks
per day were 1.00 (referent), 1.03 (0.80-1.33), 0.89 (0.70-1.14), 0.74 (0.59
0.93), 0.67 (0.51-0.89), and 0.57 (0.45-0.73), respectively (linear trend,
P<.001). Additional adjustment for baseline history of hypertension, high
cholesterol level, or parental history of myocardial infarction or family history
of diabetes (data collected at 9 years) did not materially alter the results.
These associations persisted in analyses stratified by age, smoking status, body
mass index, physical activity, and family history of DM. CONCLUSION: These data
indicate that apparently healthy men who self-select for light to moderate
alcohol consumption have a decreased subsequent risk of type 2 DM.
PMID- 10761970
TI - Idiopathic adulthood ductopenia: case report and review of the literature.
AB - The clinical and pathological findings of idiopathic ductopenia were studied in a
30-year-old woman who initially manifested jaundice and pruritus. Serum
biochemical tests of liver function indicated severe and progressive cholestasis.
Viral hepatitis markers and circulating autoantibodies were absent. The patient
had a normal cholangiogram and lacked evidence of inflammatory bowel disease.
Histological examination of a liver specimen showed severe cholestasis and
absence of interlobular bile ducts. Severe jaundice and intractable pruritus
developed in the patient and served as the indications for liver transplantation
4 months after initial examination. Transplantation resulted in prompt and
complete resolution of the jaundice and pruritus. Two types of idiopathic
adulthood ductopenia associated with different prognoses are recognized. Patients
with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms
of cholestatic liver disease. They tend to have less destruction of the
intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges
from spontaneous improvement to progression to biliary cirrhosis. In contrast,
patients with type 2 idiopathic adulthood ductopenia generally manifest initial
symptoms of decompensated biliary cirrhosis, have extensive destruction of the
intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver
transplantation.
PMID- 10761971
TI - Fibromyalgia: is recovery impeded by the internet?
PMID- 10761972
TI - Gabapentin vs amitriptyline for the treatment of peripheral neuropathy.
PMID- 10761973
TI - A pregnant woman with influenza A encephalopathy in whom influenza A/Hong Kong
virus (H3) was isolated from cerebrospinal fluid.
PMID- 10761974
TI - Atypical SCH23390 binding sites are present on bovine adrenal medullary
membranes.
AB - D1-selective dopamine receptor agonists inhibit secretagogue-stimulated
catecholamine secretion from bovine adrenal chromaffin cells. The purpose of the
studies reported here was to use the radiolabeled D1-selective dopamine receptor
antagonist, SCH23390, to characterize putative D1-like dopamine receptors
responsible for this effect. Characterization of SCH23390 binding sites
demonstrated an unusual pharmacological profile inconsistent with classical D1
like receptors. [125I]SCH23390 bound to adrenal medullary membranes was competed
for by nonradioactive iodo-SCH23390 (Kd = 490 +/- 50 nM), but not by
(+)butaclamol. Other classical D1 antagonists had little, if any, effect.
Competition with dopamine receptor agonists demonstrated a relative rank order of
potency profile characteristic of D1-like dopamine receptors, however, K(i)s were
higher than those found in other tissues. The K(i)s for competition of
[125I]SCH23390 binding by Cl-APB and SKF38393 (16 and 118 microM, respectively)
are nearly identical to the IC(50)s previously observed for inhibition of
secretion (9 and 100 microM, respectively). Combined these data suggest that
adrenal medullary membranes contain a novel SCH23390 binding site involved in the
inhibition of secretion by D1-selective agonists.
PMID- 10761975
TI - C-fos mRNA induction in the central and peripheral nervous systems of diisopropyl
phosphorofluoridate (DFP)-treated hens.
AB - A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP produces mild ataxia in
hens in 7-14 days, which develops into severe ataxia or paralysis as the disease
progresses. Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase II (CaM kinase
II) alpha-subunit, tau, tubulin, neurofilament (NF) protein, vimentin, GFAP) as
well as their mRNAs (e.g., NF, CaM kinase II alpha-subunit), we determined the
effect of a single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured by Northern
hybridization in cerebrum, cerebellum, brainstem, midbrain, spinal cord, and the
sciatic nerves of hens at 0.5 hr, 1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days
after a single 1.7 mg/kg, sc. injection of DFP. All the tissues (cerebrum, 52%;
cerebellum, 55%; brainstem, 49%; midbrain, 23%; spinal cord, 80%; sciatic nerve,
157%) showed significant increase in c-fos expression in 30 min and this elevated
level persisted at least up to 2 hr. Expressions of beta-actin mRNA and 18S RNA
were used as internal controls. The significant increase in c-fos expression in
DFP-treated hens suggests that c-fos may be one of the IEGs involved in the
development of OPIDN.
PMID- 10761976
TI - Calcium/calmodulin inhibits the binding of specific [125I]omega-conotoxin GVIA to
chick brain membranes.
AB - The effect of Ca2+/calmodulin (CaM) on the specific binding of [125I]omega
conotoxin GVIA (125I-omega-CTX) to crude membranes from chick brain was
investigated. When we examined the effects of the activation of various
endogenous protein kinases on specific [125I]omega-CTX binding to crude
membranes, we observed that Ca2+/CaM had an inhibitory effect regardless of
whether or not the standard medium contained ATP (0.5 mM). Ca2+/CaM also had an
inhibitory effect in a simple binding-assay medium containing HEPES-HCl buffer,
BSA, Ca2+ and CaM, and this effect was dependent on the concentration of Ca2+.
The effect of Ca2+/CaM was attenuated by the CaM antagonists W-7 and CaM-kinase
II fragment (290-309). An experiment with modified ELISA using purified anti
omega-CTX antibody indicated that Ca2+/CaM did not affect the direct binding of
[125I]omega-CTX and CaM. These results suggest that Ca2+/CaM either directly or
indirectly affects specific [125I]omega-CTX binding sites, probably N-type Ca2+
channels in crude membranes from chick whole brain.
PMID- 10761978
TI - Calcium antagonist isradipine reduces metabolic alterations in acute cerebral
ischemia in spontaneously hypertensive rats.
AB - The present study was designed to examine the effect of a calcium antagonist
isradipine (PN200-110: PN) on local cerebral blood flow and brain tissue
metabolism after 1-hour supratentorial ischemia induced by bilateral carotid
artery ligation (BCL) in spontaneously hypertensive rats (SHR). PN, dissolved in
ethanol plus polyethylene glycol 400, diluted with saline to make the final
concentration of 0.25mg/ml and 2.5mg/ml, was administered subcutaneously either
30 min prior to BCL or just after the induction of incomplete cerebral ischemia
(n = 7 in each group). Vehicle injection was served as a control group (n = 7).
Cerebral blood flow in the parietal cortex (CBF) and the cerebellar cortex (CeBF)
was measured by hydrogen clearance technique, and the supra- and infratentorial
metabolites of the brain frozen in situ were determined by the enzymatic method.
Blood pressure was lowered, but CBF was increased by PN administration in pre-BCL
treatment study. After 1 hour of BCL, CBF decreased to around 10% or less of the
resting value, being insignificant among the groups. Brain adenosine triphosphate
was better preserved in PN-administered groups. The increase in lactate level
tended to reduce dose dependently by PN treatment. PN also reduced the metabolic
alterations in brain tissue with significance, even when administered just after
the induction of forebrain ischemia. It is considered that pre- as well as post
BCL administration of PN is beneficial to attenuate the metabolic alterations in
incomplete forebrain ischemia in SHR.
PMID- 10761977
TI - Role of heat shock proteins in the effect of NMDA and KCl on cerebellar granule
cells survival.
AB - Cerebellar granule cells (CGC) die apoptotically after five days in culture (DIV)
at physiological concentrations of potassium (5 mM; K5). When CGC are depolarized
(K25) or treated with NMDA (150 microM) cell survival is increased. CGC changed
from K25 to K5 die after 24-48 h. It is known that heat shock protein (HSP) may
protect from cell death. Here, we found that cells in K5 showed an increase in
HSP-70 levels after 3 DIV. Similarly, in cells changed from K25 to K5, HSP-70
levels were increased after 6 h. Neither NMDA nor K25 treatment affected HSP-70
levels from 2-7 DIV. Ethanol or thermal stress induced HSP-70, but cell survival
was not affected in K5 medium. These results suggest that HSP, particularly HSP
70, are not involved in the mechanisms by which NMDA and KCl promote cell
survival.
PMID- 10761979
TI - In vivo indomethacin treatment causes microglial activation in adult mice.
AB - The current study was undertaken to study the role of prostaglandins in
regulating microglial activation. Mice were treated with indomethacin (2
microg/ml) in their drinking water to selectively inhibit cyclooxygenase
activity. After 4-8 days, the effect of inhibiting prostaglandin synthesis on
microglial activity was evaluated. This was accomplished by analyzing microglial
expression of Mac-1 (C3 complement receptor) as an indicator of activation. Mac-1
expression was assessed by immunohistochemistry of fixed brain cryosections, and
by flow cytometric analysis of immunostained single cell suspensions. Both
methods demonstrated that compared to age-matched, untreated controls, brains of
indomethacin-treated mice had increased levels of Mac-1 expression, suggesting an
increase in the state of microglial activation. These results demonstrate the
importance of prostaglandins in down regulating microglial activity, and that
inhibition of prostaglandin synthesis with indomethacin may act to increase the
reactivity of the brain's immune system.
PMID- 10761980
TI - Inhibition of dopamine biosynthesis by protoberberine alkaloids in PC12 cells.
AB - Berberine and palmatine exhibit a mild and competitive inhibition on bovine
adrenal tyrosine hydroxylase (EC 1.14.16.2; TH). In this study, the inhibitory
effects of protoberberine alkaloids (such as berberine, palmatine and coptisine)
on dopamine biosynthesis in PC12 cells were investigated. Treatment with
berberine and palmatine showed 53.7% and 61.0% inhibition of dopamine content in
PC12 cells at a concentration of 20 microM for 24 hr, respectively. However,
coptisine did not reduce dopamine content. The IC50 values of berberine and
palmatine were 18.6 microM and 7.9 microM. Dopamine content was lowered at 6 hr
and reached the minimal level at 24 hr after exposure to berberine and palmatine
at 20 microM. The decreased dopamine level was maintained up to 48 hr, and then
recovered to the control level at about 72 hr. TH activity was inhibited at 6 hr
following treatment with berberine and palmatine, and was maintained at a reduced
level up to 36 hr in PC12 cells (21-27% inhibition at 20 microM), whereas TH mRNA
level was not found to alter for 24 hr. However, the intracellular Ca2+
concentration decreased by treatment with berberine and palmatine at 20 microM by
22-26% inhibition relative to the control level in PC12 cells. These results give
evidence that berberine and palmatine lead to decreased dopamine content by
inhibition of TH activity but not by regulation of TH gene expression in PC12
cells.
PMID- 10761981
TI - Effect of selective brain hypothermia on regional cerebral blood flow and tissue
metabolism using brain thermo-regulator in spontaneously hypertensive rats.
AB - To investigate the effect of selective hypothermia of the brain (brain cooling)
on regional cerebral blood flow and tissue metabolism, we have developed a brain
thermo-regulator. Brain temperature was modulated by a water-cooled metallic
plate placed on the surface of the rats' scalp to get the appropriate brain
temperature precisely with ease. Regional cerebral blood flow and brain
temperature were measured simultaneously using a Teflon-coated platinum electrode
and thermocouple probe inserted stereotaxically into the parietal cortex and
thalamus in spontaneously hypertensive rats. Experimental forebrain ischemia was
induced by the occlusion of bilateral common carotid artery under normo- and
hypothermic brain condition, and the supratentorial brain tissue metabolites were
measured enzymatically after 60 min of forebrain ischemia. When cortical
temperature was set to hypothermia, cortical blood flow was significantly lowered
by 40% at 30 degree C and 20% at 33 degree C as compared with that at 36 degree C
(p < 0.0001 and p < 0.05, respectively). Thalamic blood flow was also
significantly reduced by 20% when cortical temperature was set to 30 degree C as
compared with 36 degree C (p < 0.05). There were no significant differences in
arterial blood pressure and gas parameters throughout these experiments. In the
rats with selective brain hypothermia (30 degree C) immediately after the
induction of cerebral ischemia, the level of brain ATP concentration after 60 min
of ischemia was significantly higher than that in normothermia rats (36 degree C)
(p < 0.05). Our findings indicate that: 1) the metallic plate brain thermo
regulator is useful in small animal experiments; 2) regional brain temperature
regulates regional cerebral blood flow; and 3) selective brain hypothermia, even
started after the forebrain ischemia, ameliorates the derangement of brain
metabolism, suggesting its effectiveness as a cytoprotective strategy.
PMID- 10761982
TI - Acetylcholine secretion enhanced by glutamate in rat embryonic spinal
motoneurons: respective involvement of NMDA and AMPA receptors.
AB - The spontaneous acetylcholine secretion and endogenous acetylcholine content were
measured by means of chemiluminescent assay from isolated embryonic rat spinal
motoneurons. The sensitivity of the detection allows to study the kinetics of the
acetylcholine secretion with short time intervals. Following the demonstration of
the presence of acetylcholine and glutamate in embryonic motoneurons, the aim of
this work was to study the characteristics of acetylcholine secretion and the
effect of glutamate in its modulation. The involvement of NMDA and AMPA
glutamatergic receptors was mainly studied. Our data show that spontaneously
acetylcholine secretion, is not calcium-dependent and is significantly enhanced
by glutamate (1 mM). Pharmacological approaches show that glutamate effect on
acetylcholine secretion is decreased in presence of APV (50 microM and 100
microM), or in presence of GYKI 53655 (10 microM), demonstrating that both NMDA
and AMPA receptors are present at the membrane of embryonic spinal motoneurons
and involved in the modulation of acetylcholine secretion. Presence of glutamate
in the embryonic motoneuron and secretion may represent a mechanism of control of
extracellular acetylcholine concentration, which was shown to control neuritic
growth at early embryonic stage.
PMID- 10761983
TI - The Na+-Ca2+ exchange inhibitor KB-R7943 inhibits high K+-induced increases in
intracellular Ca2+ concentration and [3H]noradrenaline release in the human
neuroblastoma SH-SY5Y.
AB - The effects of the Na+-Ca2+ exchange inhibitor 2-[2-[4-(4
nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943) on
depolarization-induced Ca2+ signal and [3H]noradrenaline release were examined in
SH-SY5Y cells. KB-R7943 at 10 microM significantly inhibited high K+-induced
increase in intracellular Ca2+ concentration. KB-R7943 also inhibited high K+
evoked release of [3H]noradrenaline from the cells. These findings suggest that
the Na+-Ca2+ exchanger in the reverse mode is involved at least partly in
depolarization-induced transmitter release.
PMID- 10761984
TI - Reduction of brain antioxidant defense upon treatment with butylated
hydroxyanisole (BHA) and Sudan III in Syrian golden hamster.
AB - Treatment with the antioxidant butylated hydroxyanisole (BHA) or the azo dye
Sudan III during two weeks led to changes in the brain enzymatic antioxidant
defense of Syrian golden hamsters. BHA was able to induce liver superoxide
dismutase (SOD) 2-fold but had no effect on the brain SOD activity, whereas SOD
activity was reduced to 50% in brain and remained unchanged in liver with Sudan
III. These two substances are known inducers of DT-diaphorase and in fact this
enzymatic activity was induced 4- and 6-fold in liver with BHA and Sudan III,
respectively. However, BHA promoted a significant 40% reduction, whereas no
change was observed with Sudan III in brain DT-diaphorase activity.
Glutathione(GSH)-related enzymatic activities were also assayed in brain and
liver. No induction was observed with BHA or Sudan III for any of the activities
tested in hamster brain: GSH S-transferase (GST), GSH peroxidase (GSH-Px) and
glutathione disulfide (GSSG) reductase (GR). Only 1.3- and 1.4-fold increases of
GST and GR activities were observed in liver and no change in any of these
enzymatic activities in brain with BHA; a partial limitation of permeability to
BHA of the blood-brain barrier may explain this results. Furthermore, Sudan III
promoted reductions in all these GSH-related enzymatic activities in brain and
liver. The possible explanations for these results are discussed.
PMID- 10761985
TI - Effect of long-term feeding with acetyl-L-carnitine on the age-related changes in
rat brain lipid composition: a study by 31P NMR spectroscopy.
AB - Changes in brain lipid composition have been determined in 24 months-old Fischer
rats with respect to 6 months-old ones. The cerebral levels of sphingomyelin and
cholesterol were found to be significantly increased in aged rats, whereas the
amount of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,
phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging.
Long-term feeding with acetyl-L-carnitine was able to reduce the age-dependent
increase of both sphingomyelin and cholesterol cerebral levels with no effect on
the other measured phospholipids. These findings shown that changes in membrane
lipid metabolism and/or composition represent one of the alterations occurring in
rat brain with aging, and that long-term feeding with acetyl-L-carnitine can be
useful in normalizing these age-dependent disturbances.
PMID- 10761986
TI - IDPN-induced monoamine and hydroxyl radical changes in the rat brain.
AB - beta-beta'-iminodipropionitrile (IDPN)-induced monoamine and hydroxyl radical
changes in the rat brains were studied. IDPN caused decreases in 5-HT and 5-HIAA
levels in all brain regions, strongly indicating that IDPN's neurotoxicity
primarily affects 5-HT containing neurons. Dopamine and its metabolites' levels
decreased in the some regions, most likely due to depression of dopamine
metabolic turnover. Our results more clearly demonstrate IDPN-induced monoamine
alterations in the rat brain more than previous reports. To clarify one of the
pathogenesis of IDPN-induced neurological disorders, we measured hydroxyl radical
levels. 2,3-DHBA increased at 1st day, and decreased in some regions at 7th days
after discontinuing IDPN. We conclude, hydroxyl radical formation causes neuronal
damage, and monoamine changes contribute to IDPN-induced neurological disorder.
PMID- 10761987
TI - Effect of AMPA on cerebral cortical oxygen balance of ischemic rat brain.
AB - We tested the hypothesis that the excitatory neurotransmitter receptor agonist,
alpha amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), would worsen
cerebral cortical oxygen supply/consumption balance during focal ischemia. In
this study, we compared regional cerebral blood flow, arterial and venous O2
saturation, O2 extraction and oxygen consumption of ischemic and AMPA treated
ischemic and control regions of rat brain. Ischemia was induced by middle
cerebral artery (MCA) occlusion in isoflurane (1.4%) anesthetized Wistar rats.
Twenty minutes after MCA occlusion, 10(-5) M AMPA was applied to the ischemic
cortex (IC) for a period of 40 min; the fluid was changed every 10 min. After 1
hr of ischemia, animals were sacrificed and regional cerebral blood flow (rCBF)
was determined using the C14-iodoantipyrine autoradiographic technique. Regional
arterial and venous oxygen saturation were determined
microspectrophotometrically. In control, the cerebral blood flow and oxygen
consumption of the IC were significantly lower than the contralateral cortex
(rCBF: 46 +/- 20 vs. 81 +/- 39 ml/min/100g, O2 consumption: 2.8 +/- 1.4 vs. 3.6
+/- 1.4 ml O2/min/100g). 10(-5) M AMPA did not significantly alter regional
cerebral blood flow and oxygen consumption of the IC, but did decrease the
average venous O2 saturation of the IC from 50.2 +/- 3.9% to 46.7 +/- 1.6%. AMPA
also significantly increased the frequency of small veins with less than 45% O2
saturation in the IC (8 out of 56 veins in IC vs. 18 out of 56 veins in AMPA
treated IC). Thus, topical application of 10(-5) M AMPA to the ischemic area
worsens cerebral O2 balance and suggests that excitatory amino acids contribute
to the degree of cerebral ischemia.
PMID- 10761988
TI - Cerebrospinal fluid concentrations of tryptophan and 5-hydroxyindoleacetic acid
in Macaca mulatta: diurnal variations and response to chronic changes in dietary
protein intake.
AB - In rats, dietary protein is known to influence brain tryptophan (TRP)
concentrations and serotonin (5HT) synthesis. However, few studies have examined
this relationship in primates (including humans). We therefore studied the effect
in monkeys of changes in chronic protein intake on plasma and cerebrospinal fluid
(CSF) concentrations of TRP and 5-hydroxyindoleacetic acid (5HIAA), the principal
5HT metabolite. Juvenile male monkeys (Macacca mulatta) consumed for sequential 4
week periods diets differing in protein content (approximately 23%-
>approximately 16%--> approximately 10%-->approximately 6% protein [%
energy/day]). Each day, food was presented as a morning meal of fruit, and an
afternoon meal consisting of a pelleted, commercial diet and fruit. During week 4
on each diet, blood and CSF were sampled diurnally via indwelling catheters.
Plasma and CSF TRP varied diurnally and with dietary protein content. On all
diets, CSF TRP declined modestly in the morning, and increased in the afternoon;
the magnitude of the increments varied directly with dietary protein content.
Diurnal variations were absent for CSF 5HIAA; however, CSF 5HIAA varied directly
with chronic dietary protein content. We conclude that dietary protein content
can chronically influence CSF TRP concentrations in monkeys. The variation in CSF
5HIAA suggests chronic protein intake may influence serotonin synthesis and
turnover, perhaps via changes in TRP concentrations.
PMID- 10761989
TI - Interaction of amyloid beta-protein with anionic phospholipids: possible
involvement of Lys28 and C-terminus aliphatic amino acids.
AB - Fibrillar amyloid beta-protein (Abeta) is the major protein of amyloid plaques in
the brains of patients with Alzheimer's disease (AD). The mechanism by which
normally produced soluble Abeta gets fibrillized in AD is not clear. We studied
the effect of neutral, zwitterionic, and anionic lipids on the fibrillization of
Abeta 1-40. We report here that acidic phospholipids such as phosphatidic acid,
phosphatidylserine, phosphatidylinositol (PI), PI 4-phosphate, PI 4,5-P2 and
cardiolipin can increase the fibrillization of Abeta, while the neutral lipids
(diacylglycerol, cholesterol, cerebrosides), zwitterionic lipids
(phosphatidylcholine, phosphatidylethanolamine, sphingomyelin) and anionic lipids
lacking phosphate groups (sulfatides, gangliosides) do not affect Abeta
fibrillization. Abeta was found to increase the fluorescence of 1-acyl-2-[12-[(7
nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphate (NBD
PA) in a concentration-dependent manner, while no change was observed with 1-acyl
2- [12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3
phosphoethanolamine (NBD-PE). Under similar conditions, other proteins such as
apolipoprotein E, gelsolin and polyglutamic acid did not interact with NBD-PA.
The order of interaction of amyloid beta-peptides with NBD-PA was Abeta 1-43 =
Abeta 1-42 = Abeta 17-42 > Abeta 1-40 = Abeta 17-40. Other Abeta peptides such as
Abeta 1-11, Abeta 1-16, Abeta 1-28, Abeta 1-38, Abeta 12-28, Abeta 22-35, Abeta
25-35, and Abeta 31-35 did not increase the NBD-PA fluorescence. These results
suggest that phosphate groups, fatty acids, and aliphatic amino acids at the C
terminus end of Abeta 1-40/Abeta 1-42 are essential for the interaction of Abeta
with anionic phospholipids, while hydrophilic Abeta segment from 1-16 amino acids
does not participate in this interaction. Since positively charged amino acids in
Abeta are necessary for the interaction with negatively charged phosphate groups
of phospholipids, it is suggested that Lys28 of Abeta may provide anchor for the
phosphate groups of lipids, while aliphatic amino acids (Val-Val-Ile-Ala) at the
C-terminus of Abeta interact with fatty acids of phospholipids.
PMID- 10761990
TI - The regulation of normal melanocyte proliferation.
AB - In vitro, normal human melanocytes require synergistic mitogens, in addition to
the common growth factors present in serum, in order to proliferate. The peptide
growth factors that confer stimulation are fibroblast growth factors (such as
bFGF/FGF2), hepatocyte growth factor/scatter factor (HGF/SF), mast/stem cell
factor (M/SCF), endothelins (such as ET-1) and melanotropin (MSH). The proper
function of these factors and their cognate receptors is likely to be important
in vivo, as all five ligands are produced in the skin, and disruption of their
normal function, by elimination due to deletions or mutations, or overproduction
due to ectopic expression, disrupts the normal distribution of melanocytes. The
synergistic growth factors activate intracellular signal transduction cascades
and maintain the intermediate effectors at optimal levels and duration required
for nuclear translocation and modification of transcription factors. The
consequent induction of immediate-early response genes, such as cyclins, and
subsequent activation of cyclin-dependent kinases (CDK4, CDK6 and CDK2)
inactivates the retinoblastoma family of proteins (pRb, p107 and p130, together
termed pocket proteins), and releases their suppressive association with E2F
transcription factors. Molecular events that disrupt this tight control of pocket
proteins and cause their inactivation, increase E2F transcriptional activity and
confer autonomous growth on melanocytes.
PMID- 10761991
TI - Hermansky-Pudlak syndrome and pale ear: melanosome-making for the millennium.
AB - Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder
characterized principally by oculocutaneous albinism, a bleeding tendency, and a
ceroid-lipofuscin lysosomal storage disease. These clinical manifestations of HPS
are associated with defects of multiple cytoplasmic organelles--melanosomes,
platelet granules, and lysosomes--suggesting that the HPS gene product is
involved in some shared feature of the biogenesis or functions of these diverse
organelles. The HPS gene has been cloned, and a number of pathologic mutations of
the gene have been identified. Functional studies indicate that the HPS protein
is part of a high-molecular weight complex involved in the biogenesis of early
melanosomes. Additional disorders with similarities to HPS have been identified
in man, mouse, flies, and yeast, and it is rapidly becoming clear that
understanding these disorders will shed new light on the mechanisms by which
cells traffic newly synthesized proteins through the cytoplasm to assemble
functional organelles.
PMID- 10761992
TI - Gene expression analysis.
AB - The response of cells to extracellular signals usually requires altered
expression of many genes, possibly including several distinct metabolic pathways.
In some cases, only a subset of genes involved in such responses are known, which
requires techniques to analyze changes in the expression of multiple genes, both
known and unknown. Three techniques, two-dimensional gel electrophoresis,
differential display, and gene discovery arrays, provide opportunities for
measuring changes in gene expression levels, as well as for identifying novel
gene products.
PMID- 10761993
TI - Higher plasma catecholamine and metabolite levels in the early phase of
nonsegmental vitiligo.
AB - The etiology of vitiligo is still being debated, although neural factors seem to
play a pivotal role in its pathogenesis. In our search for a link between
vitiligo and the activity of monoaminergic systems, we used high-pressure liquid
chromatography and electrochemical detector (HPLC-ED) methods to measure the
plasma levels of the following substances in 35 healthy subjects and in 70
patients suffering from nonsegmental vitiligo at the different stages of the
disease: catecholamines [norepinephrine (NE), epinephrine (E), and dopamine
(DA)], their precursor 3,4-dihydroxyphenylalanine (DOPA), their metabolites [3
methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NMN), metanephrine (MN),
and homovanillic acid (HVA)], and 5-hydroxyindolacetic acid (5-HIAA) as the major
metabolite of serotonin. We found that the levels of NE, E, NMN, MN, HVA, and 5
HIAA were significantly higher in patients compared to controls. The patients at
an active phase of the disease (n = 49/70) showed significantly higher levels of
NE, NMN, MHPG, and HVA than ones at a stable phase. The patients with progressive
vitiligo and at its more recent onset (< 1 year) showed significantly increased
levels of E, NE, and MN in comparison with longer-term sufferers. No significant
differences were observed when the patients were subdivided according to the type
of vitiligo or their age at its onset. The higher catecholamine and metabolite
levels in the early phase of the disease may reflect increased activity by
monoaminergic systems, probably due to stressful events, including the onset of
vitiligo itself.
PMID- 10761994
TI - Tyrosinase-mediated formation of a reactive quinone from the depigmenting agents,
4-tert-butylphenol and 4-tert-butylcatechol.
AB - Exposure of the skin to certain phenols or catechols such as 4-tert-butylphenol
(TBP) and 4-tert-butylcatechol (TBC) may cause leukoderma. These substances are
used in the polymer industry and numerous cases have been reported. Several
theories of the mechanism for chemical leukoderma have been suggested. In the
present study, TBP and TBC are shown to be oxidised by tyrosinase. The oxidation
of TBC yields a quinone that is further investigated on its reactions with
cysteine or glutathione (GSH). The products formed are isolated and identified by
mass spectrometry and nuclear magnetic resonance as being 4-tert-butyl-6-S
cysteinylcatechol (cys-TBC) and 4-tert-butyl-6-S-glutathionylcatechol (GS-TBC).
The reactive quinone is a strongly electrophilic substance that rapidly reacts
with GSH. A depletion of the GSH defence system may give conditions where the
quinone lives long enough to effect its toxic properties. The influence of the
reactive tert-butylquinone on enzymatic activities is demonstrated by the
inhibition of glyceraldehyde-3-phosphate dehydrogenase.
PMID- 10761995
TI - The study of cutaneous melanomas in Camargue-type gray-skinned horses (1):
clinical-pathological characterization.
AB - The clinical and pathological characteristics of cutaneous melanomas occurring in
Camargue-type gray-skinned horses are reported. Examination of 83 tumor-bearing
horses revealed that the tumors occurred most frequently underneath the tail
(93.9%) and at high rates in the peri-anal region (43.0%), the lips (33.0%), and
the eyelids (24.0%), but rarely in the vulva (3.8%). Tumorous lesions were
characterized by the presence of either hemispheric nodules or large infiltrated
plaques, or their combinations. Microscopic examination indicated that tumorous
lesions were composed mostly of melanocytes and numerous melanophages and that
component cells manifested a remarkable cellular atypia with anisocytosis and
anisokarinosis. Pathological examination of lesions corresponding to earlier
stages of the tumors disclosed that tumor formation and its related melanogenesis
occurred in close topographical association with apocrine sweat glands, but not
at the dermal-epidermal junction. Larger nodules of the tumors were often
composed of a concentric deposition of cell layers, each being separated by
dermal components from the epidermis. Because of the absence of their tropism
toward the epidermis and their multiloculation, horse melanomas are considered to
be different in their pathological characteristics from human melanomas.
PMID- 10761996
TI - The study of cutaneous melanomas in Camargue-type gray-skinned horses (2):
epidemiological survey.
AB - An epidemiological survey was made on cutaneous melanomas occurring in Camargue
type, gray-skinned horses in southern France. The population investigated was
composed of 264 horses, which were selected from the Camargue horse stud registry
and were allowed to be examined by the owners. The presence of tumors was
inspected macroscopically according to the standardized protocols of veterinary
medicine specialists, and some tumors were subjected to macroscopic
histopathological examination. The results indicated that: 1) the prevalence of
melanomas in the overall population was 31.4%; 2) the odds ratio was obtained for
an age class of 5-9 years, in which most melanomas were presumed to occur; 3) the
incidence of melanomas was significantly correlated with age, giving a prevalence
of 67% at ages > 15 years; 4) the size and number of tumorous lesions were
significantly related to age; 5) little correlation was observed between melanoma
incidence and gender; and 6) the most frequently occurring body site of these
tumors was underneath the tail. Because of their frequent occurrence in shaded
body regions, sun exposure was not likely to be a risk factor for melanoma
formation in these horses. In view of the slightly darker skin pigmentation in
these horses at younger ages, the unique characteristics of their melanocytes may
be associated with melanoma formation.
PMID- 10761997
TI - CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates.
AB - To assess the effects of Ile359 to Leu359 change on CYP2C9-mediated metabolism,
we performed site-directed mutagenesis and cDNA expression in yeast for CYP2C9
and examined in detail the kinetics of seven metabolic reactions by wild-type
CYP2C9 (Ile359) and its Leu359 variant. For the metabolism of all the substrates
studied, the Leu359 variant exhibited smaller Vmax/Km values than did the wild
type. The differences in the Vmax/Km values between the wild-type and the Leu359
variant varied from 3.4-fold to 26.9-fold. The Leu359 variant had higher Km
values than did the wild-type for all the reactions studied. Among the seven
reactions studied, the greatest difference in the Vmax values between the wild
type and the Leu359 variant was for piroxicam 5'-hydroxylation (408 versus 19
pmol/min/nmol P450), whereas there were no differences in the Vmax values between
the wild-type and the Leu359 variant for diclofenac 4'-hydroxylation and
tolbutamide methylhydroxylation. These results indicate that the Ile359 to Leu359
change significantly decreases the catalytic activity of all the CYP2C9-mediated
metabolisms studied, whereas the extent of the reduction in activity and changes
of the kinetic parameters varies between substrates. Moreover, the amino acid
substitution decreased the enantiomeric excess in the formation of 5-(4
hydroxyphenyl)-5-phenylhydantoin from phenytoin.
PMID- 10761998
TI - CYP1A1 polymorphisms and lung cancer risk: a meta-analysis.
AB - To examine the risk of lung cancer associated with the MspI-restriction fragment
length polymorphism and Exon7-Val polymorphisms of CYP1A1, a meta-analysis of
published case-control studies was undertaken using a random effects model. The
principal outcome measure was the odds ratio for the risk of lung cancer, using
homozygosity of the 'wild-type allele' as the reference group. Fifteen reports
detailing the relationship between the lung cancer and the MspI and Ile-Val
polymorphisms of CYP1A1 were identified. The odds ratio of lung cancer associated
with the MspI combined variant and homozygous genotypes were 1.09 (0.94-1.25) and
1.27 (0.91-1.77), respectively. The odds ratio of lung cancer associated with the
Ile-Val combined variant and homozygous genotypes were 1.16 (0.92-1.48) and 1.62
(0.93-2.82), respectively. The hypothesis that the modulation of carcinogen
metabolism is under genetic control is a plausible and attractive mechanism for
explaining inter-individual susceptibility of lung cancer. However, the results
from this analysis provide little support for the role of variation in the CYP1A1
gene defined by either polymorphisms represents as lung cancer risk factor.
Additional well-designed studies based on sample sizes commensurate with the
detection of small genotypic risks may allow a more definitive conclusion.
PMID- 10761999
TI - NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control
studies conducted in the general population.
AB - The NAT2 gene is involved in phase II detoxification of aromatic monoamines, a
class of known bladder carcinogens. Certain allelic combinations result in the
slow acetylation phenotype, which is thought to increase bladder cancer risk. We
conducted a meta-analysis of all identifiable published case-control studies
conducted in the general population that had examined the relationship of
acetylation status and bladder cancer risk (22 studies, 2496 cases, 3340
controls). Using meta-analysis techniques that employed weighting based on
individual-study variation, slow acetylators had an approximately 40% increase in
risk compared with rapid acetylators [odds ratio (OR) 1.4, 95% confidence
interval (CI) 1.2-1.6]. Statistical tests indicated, however, that pooling of all
studies, or of studies conducted in Caucasian populations, hid potentially
important heterogeneity in the individual study results, and suggested that the
relationship of NAT2 slow acetylation and bladder cancer risk might differ by
geographical region. Studies conducted in Asia generated a summary OR of 2.1 (CI
1.2-3.8), in Europe, a summary OR of 1.4 (CI 1.2-1.6), and in the USA, a summary
OR of 0.9 (CI 0.7-1.3). Among European studies, the relationship between NAT2
slow acetylation and bladder cancer risk did not differ by method used to assess
acetylation status (older drug-based phenotyping methods: 10 studies, OR 1.5, CI
1.2-1.8; more recent NAT2 genotyping methods: four studies, OR 1.4, CI 1.1-1.7).
Our results suggest that in most populations studied to date, NAT2 slow
acetylation status is associated with a modest increase in bladder cancer risk.
PMID- 10762000
TI - Comparison of GSTM polymorphisms and risk for oral cancer between African
Americans and Caucasians.
AB - Two members of the mu class of glutathione S-transferase (GST) genes, GSTM1 and
GSTM3, have polymorphic alleles which have been associated with altered levels of
GST mu protein expression and may be linked to increased risk for several tobacco
related cancers. Oral cancer is a tobacco-related disease that affects African
American men at a significantly higher incidence than Caucasian men. To examine
the potential role of GSTM polymorphisms in risk for oral cancer in African
Americans and Caucasians, the prevalences of the GSTM1 null and GSTM3 intron 6
polymorphisms were examined in 63 African-American and 101 Caucasian patients
with histologically confirmed primary oral cancer, as well as in 133 African
American and 213 Caucasian matched control subjects. In African-Americans, the
odds ratio for oral cancer associated with the GSTM1 (0/0) genotype was 3.1 [95%
confidence interval (CI) = 1.1-8.5], with the association between the GSTM1 (0/0)
genotype and oral cancer risk strongest in heavy smokers [i.e. > 24 pack-years;
odds ratio (OR) = 5.4, 95% CI = 1.2-24]. Using the potentially most protective
GSTM1 [+]/GSTM3 (B/B) genotype as the reference group, increased risk for oral
cancer was observed in African-Americans with the GSTM1 [+]/GSTM3 [(A/A) + (A/B)]
(OR = 2.2, 95% CI = 0.82-6.0), GSTM1 (0/0)/GSTM3 (B/B) (OR = 4.3, 95% CI = 1.1
16), and GSTM1 (0/0)/GSTM3 [(A/A) + (A/B)] (OR = 6.6, 95% CI = 1.2-38) genotypes
(P < 0.01, trend test). No significant associations were observed between GSTM
genotype and oral cancer risk in Caucasians. These results suggest that the GSTM1
null and GSTM3 intron 6 polymorphisms play an important role in risk for oral
cancer among African-Americans and implicates the mu class of GSTs as important
tobacco carcinogen detoxifying enzymes in this population.
PMID- 10762001
TI - High CA repeat numbers in intron 13 of the endothelial nitric oxide synthase gene
and increased risk of coronary artery disease.
AB - Endothelial nitric oxide synthase (eNOS) plays a key role in vascular
homeostasis. Because its product, nitric oxide, possesses vasodilatory and
antiatherogenic properties, an altered eNOS function might promote
atherosclerosis. We investigated the association between variations in CA repeat
copy number [(CA), polymorphism] in intron 13 of the eNOS gene and the risk of
coronary artery disease. (CA), polymorphism was investigated in 1000 consecutive
patients with angiographically confirmed coronary artery disease and 1000 age-
and gender-matched control subjects by a PCR-based fragment length calculation.
Twenty-eight different alleles were identified containing 17-44 CA repeats. The
presence of one allele containing > or = 38 repeats was associated with an excess
risk of coronary artery disease (odds ratio 1.94, 95% confidence interval 1.31
2.86, P = 0.001). Carriers of alleles containing > or = 38 CA repeats were, in
particular, overrepresented in the subgroup without common cardiovascular risk
factors (odds ratio 3.39, 95% confidence interval 1.30-8.86, P = 0.009). Logistic
regression analysis revealed that the (CA), polymorphism proved to be an
independent risk factor (relative risk 2.17, 95% confidence interval 1.44-3.27, P
= 0.0002). Our findings indicate that high numbers of CA repeats in intron 13 of
the eNOS gene are associated with an excess risk of coronary artery disease.
PMID- 10762002
TI - Refining the mouse chromosomal location of Cdm, the major gene associated with
susceptibility to cadmium-induced testicular necrosis.
AB - Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC
'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may
be involved clinically in cardiovascular disease and osteoporosis. Genetic
differences in sensitivity to cadmium toxicity have been noted in humans,
whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance
to cadmium-induced testicular damage was reported in 1973 to be associated with a
single major recessive gene, named Cdm, which has now been localized to mouse
chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative
histological parameters, we have corroborated the original 1973 data concerning
mendelian inheritance and have further refined the region containing the Cdm gene
from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26
recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2,
sensitive) inbred mice, and determined that the Cdm gene maps between
microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy
metals is well known, virtually no molecular mechanisms have yet been uncovered
either in humans or laboratory animals. Identification and characterization of
the mouse Cdm gene should enhance our understanding of heavy metal toxicity by
identifying and characterizing, for the first time, a major mammalian gene
responsible for susceptibility to diseases caused by heavy metal toxicity.
PMID- 10762003
TI - Influence of genetic polymorphisms in the beta2-adrenoceptor on desensitization
in human lung mast cells.
AB - The beta-adrenoceptor agonist, isoprenaline, inhibited the immunoglobulin E
mediated release of histamine from human lung mast cells (HLMC). Long-term (24 h)
exposure of HLMC to isoprenaline reduced the subsequent effectiveness of
isoprenaline to inhibit histamine release. The extent of this functional
desensitization was variable with some HLMC preparations resistant and others
highly susceptible. We sought to determine whether the variability in the degree
of functional desensitization was influenced by genetic polymorphisms in the
beta2-adrenoceptor. HLMC preparations were genotyped at two polymorphic loci,
positions 16 (arg to gly) and 27 (gln to glu), and the effect of desensitizing
conditions (24 h with 10(-6) M isoprenaline) on the subsequent ability of
isoprenaline (10(-7) M) to inhibit histamine release from HLMC was determined (n
= 72). In HLMC preparations expressing beta2-adrenoceptors with arg (wild-type)
or gly (mutant) at position 16, desensitization was 71 +/- 5% (n = 18) or 43 +/-
5%, (n = 26), respectively, whereas the desensitization was 59 +/- 6% (n = 28)
for heterozygotes at this position. In HLMC preparations expressing beta2
adrenoceptors with gln (wild-type) or glu (mutant) at position 27,
desensitization was 65 +/- 5% (n = 25) or 28 +/- 7% (n = 17), respectively,
whereas the desensitization was 61 +/- 5% (n = 30) for heterozygotes at this
position. These data suggest that mutant (gly16 and glu27) forms of the receptor
are resistant to desensitization compared to wild-type (arg16 and gln27) forms.
However, analyses to determine the relative contributions of positions 16 and 27
suggest that position 27 is more important in influencing the degree of
functional desensitization.
PMID- 10762004
TI - Association between functional genetic polymorphisms of human sulfotransferases
1A1 and 1A2.
AB - Three human phenol sulfotransferases, provisionally named SULT1A1, 1A2 and 1A3,
show 91-96% homology of their amino acid sequences and are encoded by
neighbouring gene loci. Functional genetic polymorphisms are known for two of
these sulfotransferases. In SULT1A1, a G to A transition leads to an Arg213 to
His exchange and eliminates a Bsp143II restriction site. SULT1A1*His shows lower
enzyme activity and thermostability than SULT1A1*Arg. In SULT1A2, an A to C
transversion causes an Asn235 to Thr exchange and introduces a BpiI restriction
site. Enzyme SULT1A2*Thr is less active than SULT1A2*Asn. These substitutions
were detected by restriction fragment length polymorphism analyses of genomic
sequences amplified by polymerase chain reaction. Despite the high similarity
between the different human SULT1A genes, it was possible to amplify specifically
the polymorphic parts of either SULT1A1 or 1A2, but not the homologous sequences
of the other SULT, by setting the forward primer into intron 6. DNA from 300
adult male Caucasian subjects was analysed. Allele frequencies were 0.63 and 0.37
for SULT1A1*Arg and *His, and 0.62 and 0.38 for SULT1A2*Asn and *Thr,
respectively. The frequency of the haplotype SULT1A1*Arg/SULT1A2*Asn (0.61) was
nearly as high as the allele frequencies of its components. The same was observed
for the haplotype SULT1A1*His/SULT1A2*Thr, whose frequency was 0.35. In contrast,
haplotypes 1A1*Arg/1A2*Thr and 1A1*His/1A2*Asn were very rare. Their frequencies
(0.02 each) were less than 10% of the figures expected in an independent
distribution. The results demonstrate a strong association of the alleles
producing the more active enzyme variants (SULT1A1*Arg and SULT1A2*Asn) and of
those encoding the less active variants (SULT1A1*His and SULT1A2*Thr).
PMID- 10762005
TI - Acetylator phenotype and genotype in patients infected with HIV: discordance
between methods for phenotype determination and genotype.
AB - The acetylator phenotype and genotype of AIDS patients, with and without an acute
illness, was compared with that of healthy control subjects (30 per group). Two
probe drugs, caffeine and dapsone, were used to determine the phenotype in the
acutely ill cohort. Polymerase chain reaction amplification and restriction
fragment length polymorphism analysis served to distinguish between the 26 known
NAT2 alleles and the 21 most common NAT1 alleles. The distribution (%) of
slow:rapid acetylator phenotype seen among acutely ill AIDS patients differed
with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone.
Phenotype assignment differed considerably between the two methods and there were
numerous discrepancies between phenotype and genotype. The NAT2 genotype
distribution was 45:55 slow:rapid. Control subjects, phenotyped only with
caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients,
phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically.
Following resolution of their acute infections, 12 of the acutely ill subjects
were rephenotyped with dapsone. Phenotype assignment remained unchanged in all
cases. The distribution of NAT1 alleles was similar in all three groups. It is
evident from the amount of discordance between caffeine phenotype and dapsone
phenotype or genotype that caution should be exercised in the use of caffeine as
a probe for NAT2 in acutely ill patients. It is also clear that meaningful study
of the acetylation polymorphism requires both phenotypic and genotypic data.
PMID- 10762006
TI - Role of NAT2 deficiency in susceptibility to lung cancer among asbestos-exposed
individuals.
PMID- 10762007
TI - Hormonal approach to breast cancer prevention.
AB - Breast cancer is more frequent in nulliparous women, while its incidence is
significantly reduced by full-term pregnancy. The fact that the protection
conferred by pregnancy is observed in women from different countries and ethnic
groups, regardless of the endogenous incidence of this malignancy, indicates that
this protection does not result from extrinsic factors specific to a particular
environmental, genetic, or socioeconomic setting, but rather from an intrinsic
effect of parity on the biology of the breast. Using an experimental system we
have shown that treatment of young virgin rats with human chorionic gonadotropin
(hCG), like full-term pregnancy, efficiently inhibits the initiation and
progression of chemically induced mammary carcinomas. Treatment of young virgin
rats with hCG induced a profuse lobular development of the mammary gland, reduced
the proliferative activity of the mammary epithelium, and induced the synthesis
of inhibin, a secreted protein with tumor-suppressor activity. HCG treatment also
increased the expression of the programmed cell death (PCD) genes testosterone
repressed prostate message 2 (TRPM2), interleukin 1-beta-converting enzyme (ICE),
p53, c-myc, and bcl-XS, induced apoptosis, and downregulated cyclins. PCD genes
were activated through a p53-dependent process, modulated by c-myc, and with
partial dependence on the bcl-2 family-related genes. The possibility that this
hormonal treatment activates known or new genes was tested by differential
display technique. We have identified a series of new genes, hormone-induced-1
(HI-1) among them. The characterization of their functional role will contribute
to clarify the mechanisms through which hCG inhibits the initiation and
progression of mammary cancer. Of great significance was the observation that PCD
genes remained activated even after lobular formations had regressed due to the
cessation of hormone administration. We postulate that this mechanism plays a
major role in the long-lasting protection exerted by hCG from chemically induced
carcinogenesis, and might be also involved in the lifetime reduction in breast
cancer risk induced in women by full-term pregnancy. The implications of these
observations are two-fold: on one hand, they indicate that hCG, as pregnancy, may
induce early genomic changes that control the progression of the differentiation
pathway, and on the other, that these changes are permanently imprinted in the
genome, regulating the long-lasting refractoriness to carcinogenesis. The
permanence of these changes, in turn, makes them ideal surrogate markers of hCG
effect in the evaluation of this hormone as a breast cancer preventive agent.
PMID- 10762008
TI - Breast cancer chemoprevention trials using the fine-needle aspiration model.
AB - Selection of surrogate endpoint biomarkers (SEBs) and appropriate study design
are two of the main challenges in evaluating potential chemopreventive agents. In
a prospective random fine-needle aspiration (FNA) study of women at high risk of
development of breast cancer, we previously demonstrated that cytologic evidence
of epithelial hyperplasia with or without atypia, as well as abnormalities of
several cellular biomarkers (DNA ploidy; immunocytochemical expression of p53,
EGFR, ER, and/or Her-2/neu), were more prevalent in high-risk women than in low
risk controls. We also demonstrated that the subsequent development of breast
cancer was best predicted by an initial presentation of hyperplasia with atypia,
as well as by multiple biomarker abnormalities. These findings indicate that FNA
cytology and biomarkers can be used to identify women who are appropriate
subjects for chemoprevention trials, and can then be used as surrogate endpoint
biomarkers to monitor efficacy of potential agents. An example of this use in an
ongoing single-agent phase II trial is provided. Several options for study design
of possible multi-agent breast cancer chemoprevention trials are discussed,
depending upon the existing preclinical and clinical data, the questions being
asked, and the number of eligible subjects available.
PMID- 10762009
TI - BRCA1 and BRCA2 mutation carriers as potential candidates for chemoprevention
trials.
AB - The identification of cancer susceptibility genes offers new avenues for
selecting high-risk individuals as subjects for chemoprevention trials. Because
carriers of predisposing mutations are at high risk, they are more likely to
enroll and comply with chemoprevention trials, and meaningful results can be
achieved with smaller numbers of participants and shorter periods of follow-up.
Such studies have immediate benefits for carriers themselves, but they are also
likely to result in effective chemopreventive strategies for the general
population. In this review, we discuss BRCA1 and BRCA2 carriers as potential
candidates for breast and ovarian cancer chemoprevention trials. The existence of
a large population with a high frequency of easily identifiable BRCA1/2 mutations
can provide ample opportunity for such studies. However, the possibility that
tumor characteristics and hormonal profile of BRCA1/BRCA2 related cancers are not
completely equivalent to cancers in the general population should be borne in
mind.
PMID- 10762010
TI - Genetic syndromes as potential targets for chemoprevention of colorectal
neoplasia.
AB - Colorectal cancer is the second leading cause of cancer death in the United
States (Landis et al. [1998] CA 48:6-29) and is the most common cancer in Israel
(Muir et al. [1997] International Agency for Research on Cancer, Lyon, France).
In the United States, it is estimated that 130,000 individuals will be diagnosed
with colorectal cancer in 1999 and that 57,000 individuals will die from this
disease. In Israel, approximately 2,000 individuals are diagnosed with colorectal
cancer each year (Landis et al. [1998] CA 48:6-29). The incidence rate varies
considerably in different population groups, viz. 21.1/100,000 among Jews born in
Europe or North America, 19.3/100,000 in Jews born in Israel, 12.1/100,000 among
Jews born in Africa or Asia (Muir et al. [1997] International Agency for Research
on Cancer, Lyon, France).
PMID- 10762011
TI - Implications of low COX-2 expression in colorectal neoplasms with defective DNA
mismatch repair.
AB - Most colorectal adenomas and carcinomas arise in the setting of chromosomal
instability and progressive loss of heterozygosity. Approximately 15-20% of
colorectal neoplasms arise through a distinct genetic pathway characterized by
microsatellite instability (MSI) and frequent loss of expression of one of the
DNA mismatch repair enzymes, most often hMLH1 or hMSH2. These distinct genetic
pathways are reflected by differences in tumor histopathology, distribution in
the colon, prognosis, and dwell time required for progression from adenoma to
carcinoma. The molecular and clinical distinctions between these tumors suggest
that they are biologically distinct and may respond differently to therapeutic
and chemopreventive agents. Recently, we showed that expression of a putative
chemopreventive target, COX-2, is significantly reduced in colorectal cancers
with defective mismatch repair as assessed by MSI and absent staining for hMLH1
and/or hMSH2. The mechanisms responsible for low COX-2 expression in tumors with
MSI remain unknown, but they may be linked to molecular events giving rise to MSI
tumors. Although the clinical implications of these observations are unknown, the
presence of MSI should be considered an important variable when assessing the
efficacy of COX-2 inhibitors in chemoprevention trials.
PMID- 10762012
TI - Potential roles of genetic biomarkers in colorectal cancer chemoprevention.
AB - Colorectal cancer is a significant cause of morbidity and mortality in
industrialized societies and the second most frequent cause of cancer death in
the United States. Surrogate endpoint biomarkers are gaining wide acceptance in
early diagnosis and short-term cancer chemoprevention trials in place of cancer
endpoints. Molecular genetic biomarkers can be useful tools in identifying
subjects at risk of developing cancer and screening for early cancers amenable to
complete cure. They may be useful both in predicting and assessing response to a
given therapy and in determining prognosis after an initial diagnosis has been
made. Ideally, biomarkers should fulfill some, if not all, of the following
criteria: variability of expression between phases of carcinogenesis, association
with cancer risk, ability to undergo modification in response to a
chemopreventive agent, and finally, permit ease of measurement. In consideration
of colorectal cancer chemoprevention, several genetic biomarkers seem to meet
many of these criteria, as they do exhibit distinct variability of expression at
different phases of carcinogenesis, are often strongly associated with increased
cancer risk (especially the hereditary/familial syndromes), are generally able to
be measured relatively easily through peripheral blood sampling (germline
mutations) or by colonic mucosal sampling by endoscopic techniques (somatic
mutations). In some cases, genetic biomarkers have also been demonstrated to
undergo modification in response to a chemopreventive agent. With further
understanding of the genetic and molecular changes involved in sporadic and
familial colorectal carcinogenesis, genetic biomarkers appear to hold great
potential for the identification of subjects at high risk of developing
colorectal cancer, as well as the development of novel chemopreventive approaches
and form a promising area for further research.
PMID- 10762013
TI - Utilization of K-ras mutations identified in stool DNA for the early detection of
colorectal cancer.
AB - Colorectal cancer is one of the most common malignancies in the western world.
About 60,000 Americans die of colorectal cancer each year. The annual incidence
rate in Israel is 40 per 100,000 persons, namely a total of 2,000 new cases each
year. An important step in the progression of colorectal cancer includes
induction of activating mutations in the proto-oncogene K-ras. The mutations in K
ras appear early during tumorigenesis, at the intermediate adenoma stage, and
thus can be used as a biomarker for early detection in about 40% of colonic
tumors. A large yet unknown number of mutated cells are shed from the developing
tumor during its progression. Indeed, K-ras mutations were detected in DNA
isolated from stool obtained from symptomatic and asymptomatic patients with
colorectal cancer, suggesting a novel approach for a noninvasive screening
procedure. However, severe difficulties in obtaining reproducible yields of
amplifiable DNA from stool, and usage of nonquantitative, time-consuming
procedures, hampered further progress in the utilization of K-ras mutations for
the early detection of colorectal cancer. Apparently a novel protocol is required
that provides reproducible output of amplifiable DNA from small amounts of stool,
detects if K-ras mutated DNA is present, and determines the quantity of K-ras
mutated cells in the stool sample. In addition, this protocol should be simple,
robotics compatible, and thus suitable for cost-effective, large-scale mutation
screening. Molecular assays for detecting K-ras mutations and additional
biomarkers in stool DNA promise to be highly sensitive, specific, and cost
effective. As such they should be very effective when used in chemoprevention
studies and screening protocols for colorectal cancer.
PMID- 10762014
TI - The ubiquitin-mediated proteolytic pathway: mode of action and clinical
implications.
AB - Proteolysis via the ubiquitin system plays important roles in a variety of basic
cellular processes. Among these are regulation of cell cycle and division,
modulation of the immune and inflammatory responses, and development and
differentiation. In all cases studied, these complex processes are mediated via
degradation or processing of a single or a subset of specific proteins. Ubiquitin
mediated degradation of a protein involves two discrete and successive steps: (1)
conjugation of multiple moieties of ubiquitin to the protein, and (2) degradation
of the conjugated protein by the 26S proteasome complex with the release of free
and reutilizable ubiquitin. In a few cases, it has been reported that
ubiquitination targets membrane-anchored proteins to degradation in the
lysosome/vacuole. An important yet largely unresolved problem involves the
mechanisms that endow the system with the high degree specificity and selectivity
toward its many substrates. These are determined by a large family of ubiquitin
protein ligases that recognize different primary and/or secondary/post
translational motifs in the different substrates and by a wide array of modifying
enzymes, such as protein kinases, and ancillary proteins, such as molecular
chaperones, that render them susceptible for recognition by the ligases via
modification or association with protein substrates. With the broad spectrum of
protein substrates and the complex enzymatic machinery involved in targeting
them, it is not surprising that the system was recently implicated in the
pathogenesis of several important diseases. In addition, genetic studies in
animals underscore the role of the system in normal development. We briefly
review the enzymatic cascade involved in ubiquitin-mediated degradation, describe
some of the structural motifs identified by the conjugating machinery, and
summarize recent developments in the involvement of the system in the
pathogenesis of selected disease states.
PMID- 10762015
TI - The ErbB/HER family of receptor tyrosine kinases: A potential target for
chemoprevention of epithelial neoplasms.
AB - Cancer chemoprevention trials can be directed at targeting established molecular
mechanisms which contribute to neoplasia. One potential target is the ErbB/HER
family of growth factor receptors with intrinsic tyrosine kinase activity. This
group of four receptors mediates the action of multiple stromal ligands of the
EGF/neuregulin family on the adjacent epithelium. Aberrant autocrine loops and
overexpression of certain receptors, especially ErbB-2 (also called HER2 or Neu),
play a role in fixation and propagation of oncogenic mutations. Here we
concentrate on ErbB-2 and epithelial cancer and discuss current and future
therapeutic strategies that may limit cancer, particularly in patients who are at
high risk after removal of the primary tumor. Because ErbB-2 acts as a shared co
receptor, and its heterodimers are relatively potent receptor combinations, it
offers selectivity that spares other routes of signal transduction.
Immunotherapy, as well as gene therapy and tyrosine kinase inhibitors specific to
ErbB-2 may join the ranks of effective chemopreventive agents.
PMID- 10762016
TI - Differential expression of genes by tumor cells of a low or a high malignancy
phenotype: the case of murine and human Ly-6 proteins.
AB - Progression of tumor cells toward a high malignancy phenotype and metastasis is a
multi-event cascade involving inter alia alterations in the expression of various
genes. The focus of our laboratory is on genes whose altered expression may lead,
directly or indirectly, to an increased malignancy phenotype. The identification
of such genes and the evaluation of the consequences of their altered expression
is essential for attempts to halt tumor progression and prevent metastasis
formation. Published work originating in our laboratory showed that members of
the murine Ly-6 supergene family are involved in the progression of certain mouse
tumors. The expression level of several members of this family was higher on
highly malignant cells than on tumor cells expressing a lower malignancy
phenotype. Sorting by flow cytometry of tumor cells to subpopulations expressing
either high or low levels of Ly-6E.1 yielded correspondingly cells expressing a
high or a low malignancy phenotype. The high malignancy, high Ly-6E.1-expressing
cells also expressed high levels of the receptor for urokinase plasminogen
activator (uPAR), whereas low malignancy, low Ly-6E.1-expressing cells also
expressed low levels of uPAR. Transfection studies indicated that uPAR was
causally involved in conferring a high malignancy phenotype upon tumor cells
expressing high levels of Ly-6E.1. E48 is a human homologue of the murine ThB
protein, a member of the Ly-6 supergene family (but distinct from the Ly-6E.1
protein mentioned above) and expressed on head and neck squamous carcinoma cells.
Experiments currently in progress are aimed to find out whether E48 is involved
in the progression of such cancer cells. Using the differential display
technology, it was shown that ligation of E48 on tumor cells by the corresponding
antibodies (serving as a surrogate for an as yet unidentified E48 ligand)
upregulates an enzyme (FX) involved in the biosynthesis of GDP-L-fucose. Fucose
is an essential component of certain selectin ligands.
PMID- 10762017
TI - Endpoint markers for cancer chemoprevention trials derived from the lesion of
precancer (intraepithelial neoplasia) measured by computer-assisted quantitative
image analysis.
AB - Endpoint markers for cancer chemoprevention clinical trials are described that
are developed from the morphological properties of the precancerous lesion of
intraepithelial neoplasia itself, as measured by computer-assisted quantitative
image analysis. The markers include increased proliferative fraction (percentage
MIB-1 positive nuclear area); nuclear DNA content (DNA ploidy), including DNA
content exceeding fivefold the haploid amount (5C-exceeding rate);
nuclear/nucleolar morphometry; and disorganization of nuclear chromatin pattern
as characterized by Markovian parameters and other functions. A significant new
advance in image analysis is the process of "tiling," in which hundreds of full
monitor image fields of a given histological section at x40 magnification are
reduced in size and fused seamlessly to produce a single image of the
histological section at x1.25 magnification. The operator may review the low
power image and retrieve x40 magnification of any desired area by point/clicking
with a mouse.
PMID- 10762018
TI - Quality control for HPLC assay and surrogate end point biomarkers from the
fenretinide (4-HPR) breast cancer prevention trial.
AB - The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical
trial designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at
a dose of 200 mg per os every day for 5 years, in reducing the incidence of
contralateral breast cancer in patients previously operated on for T1-T2 N-M0
breast cancer. During the trial, blood samples were collected at baseline and on
a yearly basis from most of the patients. Evaluation of drug and retinol
concentrations by HPLC assay has been performed for all the samples to obtain 4
HPR pharmacokinetic information as well as information on the effect of 4-HPR in
lowering retinol plasma levels. The most important criteria for validation and
quality control of the HPLC assay are summarized in order to provide a guide and
practical recommendations for analytical procedures to be performed during
prevention trials. Studies have been performed on subsets of patients
participating in the trial in order to identify circulating biomarkers predictive
of breast cancer. Evidence has been obtained on a lowering effect of 4-HPR on
biologically active IGF-I only in premenopausal women. This was due to a decrease
of IGF-I, associated with a trend to an increase in IGF-I binding protein 3
(IGFBP-3). An interim analysis of the ongoing trial indicates that 4-HPR reduces
the incidence of contralateral breast cancer only in premenopausal women.
Analyses of total and unbound IGF-I are being performed on plasma samples
collected at baseline and during intervention from women < or = 50 years old. The
relationship between the incidence of a second breast cancer and the changes in
IGF-I plasma levels will be assessed in order to validate IGF-I as a surrogate
end point of contralateral breast cancer. The preliminary results of other
studies on the effects of 4-HPR on tissue plasminogen activator (t-PA),
plasminogen activator inhibitor-1 (PAI-1), and urokinase plasminogen activator
(uk-PA) and on the relevance of circulating p53 antibodies with relapse will be
also presented.
PMID- 10762019
TI - Recruiting subjects in cancer prevention and control studies.
AB - Recruitment of subjects is a critical aspect of prevention trials that is often
overlooked by investigators. As a consequence, accrual time is often extended,
workloads may become heavy, and resource utilization is increased in an effort to
complete projects. Recruitment of healthy subjects in cancer prevention and
control studies presents unique issues that need to be considered. The barriers
to recruitment include participant issues, physician variables, features of the
study design, and characteristics of the health care system in the United States.
The authors provide their experience in overcoming these difficulties.
PMID- 10762020
TI - Chemoprevention of breast cancer: the Italian experience.
AB - The activity of our group is focused on the conduction of chemoprevention
clinical trials of breast cancer in at-risk subjects, among which we include
women on hormone replacement therapy (HRT). The role of the insulin-like growth
factor (IGF) system and of mammographic breast density as surrogate biomarkers
for breast cancer prevention is also being investigated. The IGF system is
involved in human carcinogenesis of several solid tumors. IGF-I is a potent
mitogen for breast cancer cells; elevated circulating IGF-I levels have been
associated with a higher risk of premenopausal breast cancer, prostate and
colorectal cancer in prospective studies. Both tamoxifen and the synthetic
retinoid fenretinide (4-HPR) have been shown to decrease plasma IGF-I levels. A
trial of their combination is ongoing in premenopausal women with increased risk
for breast cancer. Mammographic breast density has also been associated with an
increased risk of breast cancer in several prospective studies. In this article,
we discuss the rationale for selection of appropriate cohorts, candidate agents,
and putative surrogate biomarkers in our breast cancer prevention trials.
Moreover, updated results of the secondary prevention trial of 4-H PR and of the
primary prevention trial of tamoxifen are presented. Finally, the rationale for a
reduction of tamoxifen dose in future prevention trials is provided.
PMID- 10762021
TI - COX-2 and colon cancer: potential targets for chemoprevention.
AB - Evidence derived from several lines of investigation suggest that prostaglandins,
metabolites of arachidonic acid, play an important role in colon cancer
development. Elevated prostaglandin levels are found in colon cancers and their
precursor lesions, adenomatous polyps. Agents such as aspirin and NSAIDs, which
inhibit the generation of these arachidonic acid metabolites, are associated with
a decreased risk of developing or dying from colon cancer. Both the amount of the
agent used and the duration of exposure seem to be important variables. In
animals, NSAIDs are among the most potent agents discovered for the reduction of
tumors in both genetic and carcinogen-induced models. Data from human trials also
suggests that NSAIDs such as sulindac can reduce the size and number of polyps in
individuals with familial adenomatous polyposis (FAP). In parallel with the above
findings, it is now understood that at least two forms of the enzyme responsible
for the metabolism of arachidonic acid exist. One of these forms, COX-1, is
generally considered a constitutive form that is responsible for maintaining
normal physiologic function. Inhibition of COX-1 leads to many of the clinically
undesirable side effects associated with NSAID use. The other known form of the
enzyme, COX-2, is an inducible form that is found in increased levels in
inflammatory states and in many cancers and their associated pre-malignant
lesions. Levels of COX-2 are increased by exposure to mitogens and growth
factors. Agents that specifically inhibit COX-2 are now in clinical development
and appear to be well-tolerated and effective for the treatment of osteoarthritis
and rheumatoid arthritis. The potential for use of COX-2 specific NSAIDs in the
prevention of colon cancer is suggested from the distribution of COX-2 in
adenomatous polyps and colon cancer and the effectiveness of these agents in
genetic and carcinogen-induced animal models of colon cancer. The development of
these agents for the prevention of colon cancer will be discussed.
PMID- 10762022
TI - Clinical development of estrogen modulators for breast cancer chemoprevention in
premenopausal vs. postmenopausal women.
AB - Tamoxifen has proven to be beneficial in the chemoprevention of breast cancer in
women at increased risk for the disease. Other compounds that mediate the
estrogen pathway remain to be tested for clinical efficacy. The mechanism of
action, efficacy, and dose response of the estrogen modulators is determined by
the hormonal milieu of the host which should be considered in the early clinical
trials for dose range finding studies and surrogate endpoint biomarker (SEB)
evaluation. This review presents the hormonal effects to consider in the clinical
testing of an agent in premenopausal vs. postmenopausal cohorts. Recommended SEBs
that may be evaluated in Phase I/II clinical trials of estrogen modulators for
breast cancer chemoprevention are presented.
PMID- 10762023
TI - Criteria for implementation of large and multiagent clinical chemoprevention
trials.
AB - If one were to wait for the perfect set of experimental results before launching
a multi-agent chemoprevention or large risk reduction study, the trial would
never be launched. On the other hand, non-scientific considerations have led to
the premature launching of at least three prominent studies (CARET, Carotene and
Retinol Efficacy Trial; ATBC, Apha Tocopherol Beta Carotene; PCPT, Prostate
Cancer Prevention Trial) and the much delayed start-up of another, BCPT, the
Breast Cancer Prevention Trial. Strong epidemiologic data by itself should not be
adequate to justify starting a large trial; experimental and/or clinical data
should be developed. On the other hand fear of secondary adverse events that are
of low incidence should not be enough to delay a trial if the overall health
benefit could be high. The development of multiagent chemoprevention trials
requires that each agent is active and additively or synergistically so in
combination in preclinical models. Additionally, side effects of each agent
should be non-overlapping and low to non-existent, preferably a feature
determined in formal phase IIa and IIb trials. These principles will be discussed
in the context of prior (CARET, ATBC) and ongoing (EUROSCAN,
acetylcysteine/retinol), as well as proposed future trials
(difluromethyl/sulindac).
PMID- 10762024
TI - Multiagent chemopreventive agent combinations.
AB - Cancer chemoprevention is a new discipline whose foundation rests upon
epidemiologic evidence suggesting that dietary components such as beta-carotene,
vitamin E, calcium and selenium may be inhibitors of carcinogenesis. Over the
last decade, as molecular and biochemical mechanisms of the carcinogenesis
process have been elucidated, the rationale of combining chemopreventive agents
to target multiple pathways has strengthened. The process of identifying
potential synergistic combinations of chemoprevention agents should be based upon
a systematic process of preclinical development in vitro followed by testing in
animal models of carcinogenesis. Surrogates of anticarcinogenesis effects might
include biochemical, molecular and pathologic assessment of tissue from animal
carcinogenesis models. If evidence of chemopreventive effect is found in animal
models, systematic studies in humans are indicated. These studies should include
a careful Phase I trial to describe optimal chemoprevention doses for all agents
being tested in combination followed by Phase II trials to assess efficacy upon
carcinogenesis biological and pathological surrogates.
PMID- 10762025
TI - Recommendations from NIH/NSF sponsored workshop, "What is sleep? What is it good
for"?
PMID- 10762026
TI - What can the chronobiologist do to help the shift worker?
AB - This article is composed of a review of how the increasing numbers of people
working abnormal hours (referred to as "shift workers") can best be helped by the
science of chronobiology. While recognizing that chronobiologists can give much
general advice regarding such things as diet, sleep hygiene, cardiovascular
health, and the need to address social and domestic tensions, this article will
focus specifically on the advice that can be given to employers and employees,
which is directly rooted in our knowledge of chronobiology.
PMID- 10762027
TI - Fos in the suprachiasmatic nucleus of house mouse lines that reveal a different
phase-delay response to the same light pulse.
AB - Increased light intensity of a 5-min light pulse is positively correlated with
Fos mRNA and Fos protein levels in the suprachiasmatic nucleus (SCN) of hamsters.
These findings suggest that the level of Fos activation is proportional to the
light intensity and that the magnitude of the phase-shift response depends on the
level of Fos activation. However, to what extent different phase-delay responses
to the same light pulse are mediated by differential Fos activation is unknown.
To elucidate this, the authors used selected house mouse lines that reveal an
almost threefold difference in phase-delay responses in constant darkness (DD)
between circadian time (CT) 16 and CT 20 to the same light pulse. The authors
measured wheel-running activity and subjected male mice of these lines to a 15
min light pulse at CT 16 after 2 weeks in DD. The behavioral response was
measured and 10 to 12 days later the animals were again subjected to the same
light pulse at CT 16. One hour after the start of the second light pulse, the
animals were sacrificed for Fos immunocytochemistry. Results indicate a
significant difference between the lines in the phase-delay response (F2,26 =
5.112, p < 0.017) and the level of Fos activation (F2,26 = 27.15, p < 0.0001)
after a 15-min light pulse at CT 16. These findings support the hypothesis that
the magnitude of the phase-delay response is proportional to the number of cells
in the SCN that exhibit Fos induction after the same 15-min light pulse at CT 16
in DD. It also indicates a possible difference in the input pathways among the
lines.
PMID- 10762028
TI - Retinal innervation of calbindin-D28K cells in the hamster suprachiasmatic
nucleus: ultrastructural characterization.
AB - The authors have described a subregion of the hamster hypothalamic
suprachiasmatic nucleus (SCN) containing cells that are immunopositive for the
cytosolic calcium-binding protein, Calbindin-D28K (CaBP). Several lines of
evidence indicate that this region may constitute the site of the pacemaker cells
that are responsible for the regulation of circadian locomotor rhythms. First,
79% of the CaBP-immunoreactive (ir) neurons express Fos in response to photic
stimulation, indicating that they are close to or part of the input pathway to
pacemakers. Second, at the light microscopy level, retinal terminals innervate
the CaBP subnucleus. Finally, destruction of this subnucleus renders animals
arrhythmic in locomotor activity. In this study, the authors examined the
ultrastructural relationship between cholera toxin (CTbeta) labeled retinal
fibers and the CaBP-ir subregion within the hamster SCN. CTbeta-ir retinal
terminals make primarily axo-somatic, symmetric, synaptic contacts with CaBP-ir
perikarya. In addition, retinal terminals form synapses with CaBP processes as
well as with unidentified profiles. There are also complex interactions between
retinal terminals, CaBP perikarya, and unidentified profiles. Given that axo
somatic synaptic input has a more potent influence on a cell's electrical
activity than does axo-dendritic synaptic input, cells of the CaBP subregion of
the SCN are ideally suited to respond rapidly to photic stimulation to reset
circadian pacemakers.
PMID- 10762029
TI - The effects of melatonin and L-DOPA on the diurnal rhythms of free amino acids
content in the rat retina.
AB - The effects of melatonin and dopamine precursor L-3,4-dihydroxyphenylalanine (L
DOPA) intraperitoneal administration on the rhythms of free amino acids content
in the retina of rats were studied. The authors found that the levels of those
amino acids, which are protein constituents but not neurotransmitters in the rat
retina, change diurnally with maximum at 3-6 h after light onset. Diurnal changes
of Ala, Arg, Asn, Ile, Met, Ser, Trp, and Val content persisted in the retina of
rats maintained at constant darkness. This fact confirms the true circadian
nature of these rhythms. Constant lighting abolished diurnal changes of the
content of all amino acids with the exception of Trp. Daytime but not nighttime
administration of melatonin decreased the levels of Ala, Asn, Gln, Ile, Met, and
Ser down to nocturnal values. Diurnal changes of amino acids content vanished in
melatonin-injected rats. The effect of melatonin administration disappeared when
the protein synthesis was inhibited by cycloheximide. The effect of
intraperitoneal administration of L-DOPA on the levels of free amino acids was
opposite the effect of melatonin administration. L-DOPA increased nocturnal
levels of Gly, Thr, Trp, and Val but had no effect on the daytime amino acids
content. As in the case of melatonin administration, significant diurnal changes
of amino acid levels disappeared in L-DOPA-injected rats. The authors hypothesize
that melatonin and dopamine can serve as zeitgebers-antagonists of amino acids
content rhythms in the rat retina.
PMID- 10762030
TI - Evidence of an annual rhythm in a small proportion of Siberian hamsters exposed
to chronic short days.
AB - Siberian hamsters are photoperiodic seasonally breeding rodents. To date, there
has been no evidence that Siberian hamsters exhibit an annual rhythm in
reproductive, thermoregulatory, molt, or body mass changes. However, given that
the termination of their winter cycle is under endogenous control, the authors
thought it possible that under particular conditions, other aspects of their
seasonal cycle may be endogenously mediated. Consequently, the authors monitored
the reproductive condition, body mass, and molt of hamsters chronically exposed
to short days (LD 9:15) for up to 2 years. All animals were taken from previous
experiments and had exhibited gonadal regression, followed by refractoriness to
shorts days and spontaneous gonadal growth, as well as a complete cycle of body
mass and molt changes. Although some hamsters died during the study, the authors
continued to monitor some animals for up to 106 weeks of short-day exposure. Of
the 57 animals monitored, 4 (7.02%) exhibited a second cycle of reproductive
regression and recrudescence. Furthermore, the timing of the second regression
was similar in the 4 animals, occurring about 1 year after the initial short-day
exposure (50.5 +/- 1.71 weeks). However, the timing of the second bout of
recrudescence was more variable, occurring at about week 80 (79.5 +/- 8.01
weeks). Hamsters exhibited regressed gonads for about 7 months (29.0 +/- 8.02
weeks). Although the body mass of the 4 hamsters declined at the time of the
second cycle of gonadal regression, it never recovered. No hamster exhibited a
second molt cycle. These observations indicate that a small percentage of
Siberian hamsters chronically exposed to short days can exhibit an annual cycle
of reproduction.
PMID- 10762031
TI - Photic entrainment of circannual rhythms in golden-mantled ground squirrels: role
of the pineal gland.
AB - Entrainment of circannual rhythms of body mass and reproduction was monitored for
3 years in female golden-mantled ground squirrels maintained in a simulated
natural photoperiod. Both pinealectomized and pineal-intact squirrels generated
circannual rhythms of body mass and estrus, but only the intact animals entrained
these rhythms to a period of 365 days. In the second and third years after
treatment, the period of the body mass rhythm was significantly shorter than 365
days for pinealectomized squirrels, and variance in tau among these animals was
significantly greater than for intact squirrels. A similar pattern was evident in
the rhythm of reproduction, which was phase-disrupted in pinealectomized
squirrels but entrained in intacts. Seasonal changes in duration of nocturnal
melatonin secretion by the pineal appear to be necessary to produce phase-delays
required to entrain the circannual clock to a period of 12 months.
PMID- 10762032
TI - Differential control of morning and evening components in the activity rhythm of
Drosophila melanogaster--sex-specific differences suggest a different quality of
activity.
AB - The rhythms of locomotor activity of male and virgin or mated female flies were
compared in the Drosophila melanogaster wild-type strains CantonS, Berlin, and
OregonR. Under light-dark conditions, most flies showed a bimodal activity
pattern with a morning peak around lights-on and an evening peak before lights
off. For all strains, a distinct sexual dimorphism was observed in the phase of
the morning peak. Males had a significantly earlier morning peak than females and
consequently a larger phase angle between morning and evening peak (psi(m, e)).
Under constant dark conditions, the morning component merged with the evening
component to a unimodal activity band in about half of the flies. In those flies
who maintained bimodality, the sex-specific difference in psi(m, e) disappeared.
Other sex-specific differences were now apparent: Males showed a shorter free
running period than females, and in two of the three strains, females were more
active than males. Morning and evening components seem to contribute to the free
running period. Spontaneous or externally provoked change in psi(m, e) were
correlated with period changes. In some flies, the morning and the evening
components showed splitting, indicating that they are the output of two different
oscillators. The sexual dimorphism in the phase of the morning peak under LD
conditions suggests that the function of activity during morning and evening peak
might be different, for example, during the morning peak, males are active to
find females. Overall, the results underline the multioscillatory nature of
Drosophila's circadian system.
PMID- 10762033
TI - A novel mechanism for the control of circadian clock period by light.
AB - The free-running period expressed by circadian clocks in constant environmental
conditions is history dependent, and one effect of entrainment of circadian
clocks by light cycles is to cause long-lasting changes in the free-running
period that are termed aftereffects. It has been suggested that aftereffects are
a consequence of the particular phase relationships among constituent oscillators
of the circadian system that are established by the entrainment. In a test of
this hypothesis, it is shown that aftereffects of entrainment of the free-running
rhythm of nerve impulse activity from the eye of Bulla gouldiana are completely
unaffected by treatment with 12-, 24-, or 48-h pulses of the translation
inhibitor cycloheximide or with 24-h pulses of the transcription inhibitor DRB
(5,6-dichlorobenzimidazole riboside). These treatments reset the phase of
circadian oscillators generally and those in the eye of B. gouldiana
specifically. The absence of any effect of the treatments indicates that
aftereffects are independent of oscillator phase. These results suggest that
history-dependent changes in period result from a novel, long-lasting, and
previously unrecognized mechanism of action of light on the circadian pacemaking
system. Furthermore, the data indicate that aftereffects can persist in the
absence of translation, transcription, or the continued cycling of the circadian
system.
PMID- 10762034
TI - Circadian rhythm of ERG in Iguana iguana: role of the pineal.
AB - In green iguanas, the pineal controls the circadian rhythm of body temperature
but not the rhythm of locomotor activity. As part of a program to investigate the
characteristics of this multioscillator circadian system, the authors studied the
circadian rhythms of the electroretinographic response (ERG) and asked whether
the pineal gland is necessary for the expression of this rhythm. ERGs from a
total of 24 anesthetized juvenile iguanas were recorded under four different
conditions: (a) complete darkness (DD), (b) dim light-dark cycles (dLD), (c)
constant dim light (dLL), and (d) pinealectomized in DD. Results demonstrate that
the b-wave component of the ERG shows a very clear circadian rhythm in DD and
that this rhythm persists in dLL and entrains to dLD cycles. The ERG response is
maximally sensitive during the subjective day. Pinealectomy does not abolish the
circadian rhythm in ERG, demonstrating that the oscillator responsible for the
ERG rhythm is located elsewhere.
PMID- 10762035
TI - Circadian ovulatory rhythms in Japanese quail: role of ocular and extraocular
pacemakers.
AB - Previous studies have shown that the circadian system of Japanese quail is
composed of multiple photic inputs and multiple oscillators. Among these are
extraretinal photoreceptors that mediate both circadian and photoperiodic
responses and circadian pacemakers in the eyes that, via neural and hormonal
outputs, help to maintain rhythmicity of central circadian clocks (presumably
located in the suprachiasmatic area of the hypothalamus). Furthermore, a
component of the central circadian system is influenced by reproductive hormones.
Under certain conditions, the circadian system of female quail can be induced to
split into two circadian components: one driven by ocular pacemakers and one
driven by feedback from reproductive hormones. Importantly, ovulation is either
inhibited or permitted as these two oscillators (or sets of oscillators)
constantly change internal phase relationships with each other, suggesting an
"internal coincidence" mechanism in the control of ovulation. The oviposition
patterns of quail in light-dark (LD) cycles also support an internal coincidence
mechanism. The authors tested the hypothesis that the ocular pacemakers are an
important component of an internal coincidence mechanism controlling ovulation by
examinig the effects of blinding by complete eye removal (EX), and the effects of
eye-patching, on the body temperature and oviposition patterns of quail exposed
to 24-h LD cycles. They also examined the effects of EX on quail exposed to
continuous light (LL) and to continuous darkness (DD). Neither EX nor eye
patching affected the oviposition patterns of birds in LD. Furthermore, robust
body temperature and oviposition rhythms continued in EX birds in LL, but body
temperature became arrhythmic in DD with the cessation of ovulation. The results
do not show a role for ocular pacemakers in the control of ovulation, but they do
support the hypotheses that (1) entrainment of the central oscillators by
extraretinally perceived light is sufficient to preserve a normal ovulatory
pattern in LD in the absence of the ocular pacemakers, and (2) in LL, feedback of
reproductive hormones onto the central oscillators is sufficient to organize the
circadian system even in the absence of the ocular pacemakers. Whether or not the
ocular pacemakers are normally involved in the control of ovulation is still an
open question.
PMID- 10762036
TI - Design and synthesis of anticonvulsive agents as gamma-vinyl GABA-based potential
dual acting prodrugs and their biological activities.
AB - For the development of new anticonvulsive agents, gamma-vinyl GABA (vigabatrin)
and GABA mimetics derivatives were covalently coupled as potential dual acting
prodrugs and evaluated for their anticonvulsive activities. Among the prepared
compounds, 11 showed the most potent anticonvulsive activity, a shorter onset
time and a broader spectrum compared to vigabatrin.
PMID- 10762037
TI - Synthesis of a novel class of cdc25A inhibitors from vitamin D3.
AB - We have developed a novel class of cdc25A inhibitors by drastic modification of
the hydrophobic and hydrophilic substructures of dysidiolide. The unsaturated
derivative 3b strongly inhibited cdc25A (IC50 = 7.7 microM) and caused GI arrest
of HL60 cells.
PMID- 10762038
TI - Novel retinoic acid receptor alpha agonists: syntheses and evaluation of pyrazole
derivatives.
AB - We have designed and synthesized a series of pyrazole derivatives as candidate
retinoic acid receptor (RAR) agonists. One of them, 4-[5-(1, 5-diisopropyl-1H-3
pyrazolyl)-1H-2-pyrrolyl]benzoic acid (11b), which possesses a 2,5-disubstituted
pyrrole moiety, showed selective transactivation activity for the RAR alpha
receptor, and had highly potent cell-differentiating activity on HL-60 cells.
PMID- 10762039
TI - Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as
potent and selective retinoic acid receptor alpha agonists.
AB - Synthesis and structure activity relationships (SAR) of RAR alpha-selective
agonists are discussed. 4-[5-(5,8-Dimethyl-2H-3-chromenyl)-1H-2-pyrrolyl]benzoic
acid (12a), which possesses a flat structural moiety and an oxygen atom at the
hydrophobic part, showed highly selective transactivation activity at the RAR
alpha receptor.
PMID- 10762040
TI - Yohimbine dimers exhibiting binding selectivities for human alpha2a- versus
alpha2b-adrenergic receptors.
AB - A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and
alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO)
cells. All dimers display higher binding selectivities for alpha2a versus alpha2b
subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the most
potent and alpha2a versus alpha2b-AR selective ligands identified so far.
PMID- 10762041
TI - Parallel synthesis of a library of 1,4-naphthoquinones and automated screening of
potential inhibitors of trypanothione reductase from Trypanosoma cruzi.
AB - Solid- and solution-phase parallel syntheses of 1,4-naphthoquinones (1,4-NQ) are
described. A library of 1360 amides was constructed from the combination of 12
newly synthesised 1,4-NQ carboxylic acid and 120 amines, and was screened for
inhibition of trypanothione reductase (TR) from Trypanosoma cruzi. The most
active hits from a primary screening were re-synthesised and confirmed. This
approach proves that it is possible to design potent and highly specific TcTR
inhibitors deriving from menadione, juglone and plumbagin.
PMID- 10762042
TI - Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity
relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium
salts.
AB - The syntheses, the anticholinesterase activities and structure-activity
relationships of homodimeric (3a-c) and heterodimeric (6a-c) alkylene linked bis
galanthamine are reported. Compounds 6b-c were found to be more potent than
galanthamine and tacrine in inhibiting AChE.
PMID- 10762044
TI - Synthesis and antiviral activity of acyclovir-5'-(phenyl methoxy alaninyl)
phosphate as a possible membrane-soluble nucleotide prodrug.
AB - We describe a synthesis of acyclovir-5'-(phenyl methoxy alaninyl) phosphate (2)
from acyclovir (1). This compound was designed to act as a lipophilic, membrane
soluble prodrug of the free nucleotide. However, the biological activities of
this derivative against a range of viruses indicated poor intracellular phosphate
delivery, in marked contrast to the earlier successful delivery of several
dideoxy anti-HIV nucleotides.
PMID- 10762043
TI - Synthesis and biological evaluation of enantiopure thionitrites: the solid-phase
synthesis and nitrosation of D-glutathione as a molecular probe.
AB - The D-isomer of the naturally-occurring tripeptide glutathione (gamma-L-Glu-L-Cys
Gly, L-GSH) has been synthesised using the Fmoc solid phase peptide synthesis
strategy. The D-GSH obtained has been nitrosated to give the D-isomer of the
bioactive thionitrite, S-nitroso-L-glutathione. The biological activity of both
enantiomers of S-nitrosoglutathione has been studied and compared to the activity
of the D- and L-isomers of N-acetyl-S-nitrosopenicillamine (SNAP) and S
nitrosocysteine (CysNO).
PMID- 10762045
TI - The solid phase synthesis of tetrahydroisoquinolines having cdc25B inhibitory
activity.
AB - A solid phase synthesis of substituted tetrahydroisoquinolines was developed and
used to prepare directed libraries of compounds for screening against the protein
phosphatase, CDC25B. From these libraries, a compound was found having
approximately a 4-fold improvement in activity.
PMID- 10762046
TI - Diacylglycerols with lipophilically equivalent branched acyl chains display high
affinity for protein kinase C (PK-C). A direct measure of the effect of
constraining the glycerol backbone in DAG lactones.
AB - New synthetic diacylglycerols (DAGs) with equivalent branched acyl chains were
compared with commercially available DAGs as PK-C ligands. The results support
the view that there is a minimal lipophilic requirement provided by the
equivalent acyl groups that results in high binding affinity. Locking the
glycerol backbone of the most potent DAG into a five-member lactone resulted in a
10-fold increase in potency.
PMID- 10762047
TI - Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in
vitro activity. Part 9.
AB - Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent
Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and
nickel(II) 3 octahedral complexes of stoichiometry [MeL2(H2O)2]. Their
antimycobacterial in vitro activity was evaluated against Mycobacterium
tuberculosis H37Rv in comparison with the ligands. Complexes 2a, 2b, 2f, 3b, 3d
and 3g displayed MIC values < or = 0.2 microg/mL.
PMID- 10762048
TI - Eryloside F, a novel penasterol disaccharide possessing potent thrombin receptor
antagonist activity.
AB - We report the discovery of Eryloside F, a novel disaccharide of the steroidal
carboxylic acid penasterol, isolated from an extract of the marine sponge Erylus
formosus. The compound is a potent thrombin receptor antagonist, and furthermore
inhibits human platelet aggregation in vitro.
PMID- 10762049
TI - Synthesis of 19-[(2-azido-5-iodo)-benzoyloxy]-LTA4 and enzymatic conversion to
the LTC4 analogue.
AB - New photoaffinity probes based on C-19 position of leukotriene A4 has been
synthesized from 19-hydroxy-LTA4 methyl ester. Enzymatic conversion into the LTC4
analogue yielded a potential tool for the study of cys-LT2 receptors.
PMID- 10762050
TI - Inhibition of the ras-dependent mitogenic pathway by phosphopeptide prodrugs with
antiproliferative properties.
AB - Phosphopeptide prodrugs bearing two S-acyl-2-thioethyl (SATE) biolabile phosphate
protections were developed. They are capable to inhibit the Shc/Grb2 interaction
and MAP kinases (ERK1 and ERK2) phosphorylation in cellular assay. The S-acetyl-2
thioethyl (MeSATE) analogue showed an IC50 of 1 microM in the inhibition of the
colony formation of tumor cell line NIH3T3/HER2.
PMID- 10762051
TI - Carbonic anhydrase inhibitors: topical sulfonamide antiglaucoma agents
incorporating secondary amine moieties.
AB - Reaction of aromatic/heterocyclic sulfonamides possessing free amino, imino or
hydrazino moieties with 7-chloro-4-chloromethylcoumarin afforded a series of N
[(7-chloro-4-coumarinyl)-methyl]- derivatives which showed effective inhibition
of three carbonic anhydrase (CA) isozymes. Topical application within the rabbit
eye of some of these compounds led to effective intraocular pressure lowering due
to CA inhibition within the ocular tissues, and reduced aqueous humor production.
PMID- 10762052
TI - Beta-cyclodextrin/epoxysuccinyl peptide conjugates: a new drug targeting system
for tumor cells.
AB - Beta-cyclodextrin is known to form inclusion complexes with hydrophobic drugs.
Several tumor cell lines are known to secrete and/or contain membrane-associated
cathepsin B which is possibly involved in invasion and metastasis. Based on these
information, our recently developed endo-epoxysuccinyl peptide inhibitor MeO-Gly
Gly-Leu-(2S,3S)-tEps-Leu-Pro-OH for cathepsin B was conjugated with beta
cyclodextrin to obtain a site-directed drug carrier system. Furthermore, the
conjugate, was shown to form an inclusion complex with the cytotoxic drug
methotrexate.
PMID- 10762053
TI - Synthesis of conformationally constrained analogues of KN62, a potent antagonist
of the P2X7-receptor.
AB - Conformationally constrained analogues of KN62 containing 1,2,3,4-tetrahydro-7
hydroxyisoquinoline-3-carboxylic acid with S configuration in position 3 were
synthesized and their antagonist activities were tested on human macrophage
cells. While KN62 is a potent antagonist of the P2X7 receptor, these analogues
were inactive as antagonists and only one compound showed appreciable activity as
P2X7 antagonist, which was 30 times weaker than that reported for KN62.
PMID- 10762054
TI - Quantitative characterization of reversible macromolecular associations via
sedimentation equilibrium: an introduction.
AB - The measurement and analysis of sedimentation equilibrium provides one of the
most powerful and widely applicable methods for the characterization of
reversible associations of macromolecules in solution. Recent developments in
instrumentation, experimental design, and data analysis have substantially
broadened the range of systems to which this technique may be applied, simplified
its application, and reduced the cost of acquiring analytical capability.
PMID- 10762055
TI - The new genotypic human calicivirus isolated in Seoul.
AB - A new type of human calicivirus (HuCV) showing the classic cup-shaped surface
morphology was identified in the stool sample from a child with symptoms of acute
gastroenteritis in Seoul, Korea (SK virus). Genomic RNA was extracted directly
from the stool sample, and the nucleotide sequence of 3.2 kb of the 3' end of SK
virus was determined from cDNA. This region spanned sequences from the RNA
dependent RNA polymerase (RDRP) region in the open reading frame 1 (ORF1) to the
3' poly A tail. The non-structural and capsid protein coding sequences were fused
in a single ORF as observed in Manchester type (Genogroup III). However, ORF2 of
Manchester virus was missing in SK virus. In RDRP region, SK virus showed amino
acid and nucleotide identities of 74-75% and 68-69% respectively, with those of
Manchester virus, while showed 34-46% and 55-60% identities respectively with
those of other human caliciviruses. However, capsid protein of SK virus showed a
partial (29-46%) amino acid identity with those of other caliciviruses including
Manchester type. The closest resemblance in amino acid (97-99%) and nucleotide
sequence (85-86%) identities were found in RDRP region with Vanderbijlpark and
Pretoria isolates recently found in South Africa. These results suggest that SK
virus together with Vanderbijlpark and Pretoria isolates belong to a new type
different from Manchester virus.
PMID- 10762056
TI - Protective mechanism of glucose against alloxan-induced beta-cell damage: pivotal
role of ATP.
AB - Glucose prevents the development of diabetes induced by alloxan. In the present
study, the protective mechanism of glucose against alloxan-induced beta-cell
damage was investigated using HIT-T 15 cell, a Syrian hamster transformed beta
cell line. Alloxan caused beta-cell damages with DNA fragmentation, inhibition of
glucose-stimulated insulin release, and decrease of cellular ATP level, but all
of these beta-cell damages by alloxan were prevented by the presence of 20 mM
glucose. Oligomycin, a specific inhibitor of ATP synthase, completely abolished
the protective effects of glucose against alloxan-induced cell damage.
Furthermore, treatment of nuclei isolated from HIT-T15 cells with ATP
significantly prevented the DNA fragmentation induced by Ca2+. The results
indicate that ATP produced during glucose metabolism plays a pivotal role in the
protection of glucose against alloxan-induced beta-cell damage.
PMID- 10762057
TI - Cross-linking of CD4 induces cytoskeletal association of CD4 and p56lck.
AB - A membrane glycoprotein CD4 functions as a co-receptor of a T lymphocyte. The co
receptor function has been attributed to a protein tyrosine kinase, p56lck, which
is activated upon CD4 binding to MHC molecule. In this study, we present
evidences that one of the pathways through which CD4 transmits its signal is
cytoskeleton association of p56lck tyrosine kinase as well as CD4 itself.
Cytoskeletal association of both proteins is inhibited by a tyrosine kinase
inhibitor, genistein, indicating that tyrosine protein kinase activation is
important for cytoskeletal association of CD4 and p56lck. Cytoskeletal
association of these proteins by CD4 cross-linking is not affected by inhibitors
of protein kinase C nor PI3-kinase. Taken together, these results suggest that
CD4 cross-linking activates a tyrosine kinase which then induces the simultaneous
association of CD4 and p56lck with cytoskeleton.
PMID- 10762058
TI - Enhanced induction of Bax gene expression in H460 and H1299 cells with the
combined treatment of cisplatin and adenovirus mediated wt-p53 gene transfer.
AB - Cytotoxic effect of either cisplatin or p53 gene transfection of lung cancer
cells may be different depending on the p53 status of cells. We investigated
cytotoxic effects on the combined treatment of cisplatin and adenovirus mediated
p53 gene transfer (Avp53) in both H460 and H1299 cells in vitro. The results
showed the highest numbers of apoptotic cells in both H460 and H1299 cells
following the combined treatment regardless of p53 status in comparison with
either cisplatin or Avp53 alone. The expression levels of p53, p21, Bax and ICE
were examined to understand a possible cellular signal path of the combined
treatment. In western analyses, the patterns of phosphorylated p53 protein were
different between Avp53 and combined treatment. The expressions of p21 and Bax
were increased in combined treatment, whereas the cleaved form of ICE (20 kD) was
not detected. These results suggest that cisplatin induced p53 protein
phosphorylation and may activate the downstream of p53 gene expression such as
p21 and Bax. The enhanced apoptosis of lung cancer cells by the combined
treatment may be useful in the development of clinical therapeutic modality of
lung tumors.
PMID- 10762059
TI - Dedifferentiation of conditionally immortalized hepatocytes with long-term in
vitro passage.
AB - The rat hepatocytes were immortalized using a temperature-sensitive mutant of
SV40 large T antigen (tsT) to develop as a possible substitute for primary
hepatocytes. Four rat hepatocyte lines that have been developed and maintained
more than passage 50, were characterized for their cellular morphology, T antigen
and p53 expression, chromosomes, liver-specific differentiation, telomerase
activity and anchorage independent growth. All of four cell lines showed a
typical epithelial cell morphology, but the population-doubling time became short
with passage: 18 to 60%. T antigen expression was increased with passage about 3
to 65 times at permissive temperature but decreased significantly at non
permissive temperature. The expression level of p53 unchanged during passages was
also decreased at non-permissive temperature. The distribution of chromosome
number changed somewhat with passage. The production levels of albumin and urea
in four cell lines were 2.4 to 13.0% and 7.5 to 19.9% of those produced in
primary hepatocytes, respectively and were decreased to an undetectable level
with passage. Telomerase activity was increased 10 fold following immortalization
of cells, but anchorage independent growth of cells did not develop. These
results indicate that conditionally immortalized hepatocytes become
dedifferentiated with in vitro passage, which may be caused by marked chromosomal
damages that occur with compulsive and continuous replications by the increment
of T antigen content with passage and its sequential inhibition of p53 function.
PMID- 10762060
TI - Detection of cryptic Y chromosome mosaicism by coamplification PCR with archived
cytogenetic slides of suspected Turner syndrome.
AB - Turner syndrome is one of the most common cytogenetic abnormalities. It is known
that the Y chromosome or Y derived material is present in 6-9% of TS patient and
it may develop a high risk of gonadoblastoma in 15-25%. So it is crucial to carry
out cyto genetic analysis and Y-specific probe studies for all persons with
gonadal dysgenesis to rule out mosaicism with Y-bearing cell line; eg 45,X/46,XY.
In this study, 26 archival slides previously analyzed cytogenetically as 45,X,
45,X/46,X,i(X), 45,X/46,X,r(X), and 45,X/46,XX were examined. Coamplification
PCR, having the advantage of providing rapid result and confirming PCR failure,
was performed with the slide samples in the regions of dystrophin gene in Xp21and
DYZ3 in the Y centromeric region. All of archived slides were positive for X
specific gene and one slide of 45,X was found to have the cryptic Y chromosome
material. Our result suggests that the archived cytogenetic slides could be
applied for the detection of Y chromosome rapidly and efficiently in TS patients.
PMID- 10762061
TI - Regulation of bcl-2 family in hydrogen peroxide-induced apoptosis in human
leukemia HL-60 cells.
AB - Numerous types of cells have been shown to undergo apoptosis when exposed to
oxidant agent such as hydrogen peroxide. In order to understand the functional
relationship between the anti- and pro-apoptotic regulatory proteins in the cells
under oxidant stress, we have studied the level of expression of apoptosis
regulatory proteins, bcl-2 and bax, in human leukemia HL-60 cells. The exposure
of HL-60 cells to different concentrations of H2O2 for 6 h resulted in a typical
apoptosis of the cells as characterized by flow cytometry, cell cycle analysis,
and DNA fragmantation. There was a block in G1 to S transition and apoptotic
cells were mainly derived from S and G2 cells. Kinetic study demonstrated that
the levels of both bcl-2-mRNA and -protein expression were decreased with the
progression of cellular apoptosis whereas the level of bax-mRNA was unchanged but
the expressed bax-protein was not detectable. Cycloheximide, a nonspecific
translation inhibitor, did not prevent the hydrogen peroxide-mediated apoptosis
in HL-60 cells. These results suggest that the regulation of bcl-2, but not of
bax are important factor in the oxidative stress-induced apoptosis in HL-60
cells.
PMID- 10762062
TI - Regulation of chicken protein tyrosine phosphatase 1 and human protein tyrosine
phosphatase 1B activity by casein kinase II- and p56lck-mediated phosphorylation.
AB - Protein tyrosine phosphorylation and dephosphorylation are important in the
regulation of cell proliferation and signaling cascade. In order to examine
whether phosphatase activity of CPTP1 and HPTP1B, typical nontransmembrane
protein tyrosine phosphatase, could be controlled by phosphorylation, affinity
purified PTPs were phosphorylated by CKII and p56lck in vitro. Phosphoamino acid
analysis revealed that CPTP1 was phosphorylated on both serine and threonine
residues by CKII, and tyrosine residue by p56lck. Phosphatase activity of CPTP1
was gradually increased by three-fold concomitant with phosporylation by CKII.
Phosphorylation of HPTP1B by CKII resulted in quick two-fold enhancement of its
phosphatase activity within 5 min of incubation and remained in that state. In
the presence of CKII inhibitor, heparin or poly(Glu.Tyr), both phosphorylation
and enhancement of phosphatase activity of CPTP1 and HPTP1B were mostly blocked.
p56lck catalyzed tyrosine phosphorylation of CPTP1 and HPTP1B was only observed
by inhibiting the intrinsic tyrosine phosphatase activity. Taken together, these
results indicate that CPTP1 or HPTP1B possesses a capability to regulate its
phosphatase activity through phosphorylation processes and may participate in the
cellular signal cascades.
PMID- 10762063
TI - Homocysteine.
AB - Homocysteine does not occur in the diet but it is an essential intermediate in
normal mammalian metabolism of methionine. Each compound, methionine or
homocysteine, is the precursor of the other. Similarly, the synthesis of one is
the mechanism for the detoxification of the other. The ubiquitous methionine
cycle is the metabolic basis for this relationship. In some tissues the
transsulfuration pathway diverts homocysteine from the cycle and provides a means
for the synthesis of cysteine and its derivatives. Methionine, (or homocysteine)
metabolism is regulated by the disposition of homocysteine between these
competing sequences. Both pathways require vitamin-derived cofactors, pyridoxine
for transsulfuration and both folate and cobalamin in the methionine cycle. The
clinical consequences of disruption of these pathways was apparent first in rare
inborn errors of metabolism that cause homocystinuria, but recent studies focus
on "hyperhomocysteinemia"--a lesser metabolic impairment that may result from
genetic variations, acquired pathology, toxicity and nutritional inadequacy.
Hyperhomocysteinemia is an independent risk factor for thrombovascular diseases
however it is not clear whether the minimally increased concentration of the
amino acid is the causative agent or merely a marker for the pathology. Until we
resolve that question we cannot predict the potential efficacy of therapies based
on folate administration with or without additional cobalamin and pyridoxine.
PMID- 10762064
TI - S-Adenosylmethionine.
AB - S-Adenosyl-Lmethionine (SAM) is an important molecule in normal cell function and
survival. SAM is utilized by three key metabolic pathways: transmethylation;
transsulfuration; and polyamine synthesis. In transmethylation reactions, the
methyl group of SAM is donated to a large variety of acceptor substrates
including DNA, phospholipids and proteins. Thus, interference of these reactions
can affect a wide spectrum of processes ranging from gene expression to membrane
fluidity. In transsulfuration, the sulfur atom of the SAM is converted via a
series of enzymatic steps to cysteine, a precursor of taurine and glutathione, a
major cellular anti-oxidant. Polyamines are required for normal cell growth.
Given the importance of SAM in tissue function, it is not surprising that this
molecule is being investigated as a possible therapeutic agent for the treatment
of various clinical disorders.
PMID- 10762065
TI - DNA methylation and histone acetylation of rat methionine adenosyltransferase 1A
and 2A genes is tissue-specific.
AB - Methionine adenosyltransferase (MAT) catalyzes the biosynthesis of S
adenosylmethionine (AdoMet). In mammals MAT activity derives from two separate
genes which display a tissue-specific pattern of expression. While MAT1A is
expressed only in the adult liver, MAT2A is expressed in non-hepatic tissues. The
mechanisms behind the selective expression of these two genes are not fully
understood. In the present report we have evaluated MAT1A and MAT2A methylation
in liver and in other tissues, such as kidney, by methylation-sensitive
restriction enzyme digestion of genomic DNA. Our data indicate that MAT1A is
hypomethylated in liver and hypermethylated in non-expressing tissues. The
opposite situation is found for MAT2A. Additionally, histones associated to MAT1A
and MAT2A genes showed enhanced levels of acetylation in expressing tissues (two
fold for MAT1A and 3.5-fold for MAT2A liver and kidney respectively). These
observations support a role for chromatin structure and its modification in the
tissue-specific expression of both MAT genes.
PMID- 10762066
TI - Molecular organization, catalytic mechanism and function of serine
hydroxymethyltransferase--a potential target for cancer chemotherapy.
AB - Serine hydroxymethyltransferase, a pyridoxal-5'-phosphate dependent enzyme,
catalyzes the retro-aldol cleavage of serine to yield glycine and the
hydroxymethyl group is transferred to 5,6,7,8-tetrahydrofolate to generate 5,10
methylene-H4-folate. The enzyme plays a pivotal role in channeling metabolites
between amino acid and nucleotide metabolism. Dihydrofolate reductase and
thymidylate synthase have been favorite targets for the development of anticancer
drugs. However, development of resistance to drugs, due to a variety of reasons,
has necessitated the identification of alternate targets for cancer chemotherapy
and serine hydroxymethyltransferase is one such potential target. A detailed
study of the kinetics of interaction of serine and folate analogs with this
enzyme revealed several unique features that can be exploited for the design of
new chemotherapeutic agents. The pathways for the reversible unfolding of the
dimeric Escherichia coli and the tetrameric sheep liver enzyme, although
different, revealed a requirement for the cofactor in the final step for
generating an active enzyme. The gly A gene of Escherichia coli has been shown to
code for this enzyme. Analysis of available gene sequences indicate that serine
hydroxymethyltransferase is one of the most highly conserved proteins. The
isolation of the cDNA clones for the enzyme and their overexpression in
heterologous systems has enabled the probing of the molecular mechanisms of
catalysis and the role of lysine, arginine and histidine in cofactor,
substrate(s) binding and in maintaining the structure of the protein. Recently,
the three-dimensional structure of the human liver serine
hydroxymethyltransferase has been published. This, along with the information
already available, provides a framework for the rational design of drugs targeted
specifically towards this enzyme.
PMID- 10762067
TI - Analysis of expressed sequence tags of retinal pigment epithelium: cystatin C is
an abundant transcript.
AB - In order to identify genes that are expressed in the retinal pigment epithelium
(RPE), randomly chosen clones of a cDNA library of cultured human foetal RPE
cells were analyzed by sequencing. Of 164 informative expressed sequence tags
(ESTs), 88 matched the sequences of 74 genes for proteins of known or presumed
function. Approximately a third of these represented genes with involvement in
gene/protein expression, with a major subcategory concerned with protein
turnover. In particular, the gene coding for precursor cystatin C was represented
by 3 independent ESTs, and plaque hybridization estimated the frequency of
cystatin C clones in the library to be 1.3%. Cystatin C mRNA in cultured RPE
cells was confirmed by Northern blotting and by reverse transcription polymerase
chain reaction (RT-PCR) with identification of the cystatin C sequence as the
product of the reaction. The survey also revealed 25 novel human sequences
representing genes that are active in RPE. One of these was localized near a
recently identified, new autosomal recessive retinitis pigmentosa locus. In
conclusion, the findings specifically demonstrate the unexpected presence of
cystatin C mRNA at fairly high abundance in cultured human RPE cells, and, more
generally, serve as a model study establishing the usefulness of the EST approach
for further characterizing the molecular basis of the activities of the RPE.
PMID- 10762068
TI - Purification and partial characterization of creatine kinase from electric organ
of Electrophorus electricus (L.).
AB - The present investigation deals with the purification and the partial
characterization of the soluble creatine kinase (CK) isoenzyme, isolated from the
electric organ electrocyte of Electrophorus electricus (L.). Purification was
performed by precipitation of the enzyme in the crude extract with ammonium
sulfate (80%). The precipitate obtained was analyzed on an ion exchange column of
diethylaminoethyl cellulose-52 (DEAE) followed by gel filtration on Superose 12
in a Fast Protein Liquid Chromatography (FPLC) system. Electrophoretic mobility
of the active peak confirmed previous results identifying the hybrid isoenzyme MB
in the electrocyte cytoplasm. Electrocyte CK is a dimeric enzyme with two
identical subunits of approximately 40 kDa as estimated by sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE). The sequence analysis of the N
terminal peptide (14 amino acids) of the 40 kDa subunit showed homology with
other CK enzymes from electric fish (Torpedo) and human muscle type CK.
PMID- 10762069
TI - Tyrosine phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase
correlates with high proliferation rates in sublines derived from the Jurkat
leukemia.
AB - A prominent tyrosine phosphorylated protein of 85 kDa (p85) was detected in
highly proliferative sublines derived from the Jurkat T cell leukemia. We
undertook a study to characterize the identity of this protein and its possible
role in the hyperproliferative phenotypes observed. Using immunoblot and
immunoprecipitation techniques, this protein was characterized as the p85
regulatory subunit of phosphatidylinositol 3-kinase. Cell proliferation and p85
tyrosine phosphorylation was not affected by tyrphostin AG-490, an inhibitor of
Jak kinases, wortmannin or LY294002, inhibitors of the activity of the catalytic
phosphatidylinositol 3-kinase subunit. Herbimycin-A and PPI, inhibitors of src
like protein tyrosine kinases, and genistein, a general tyrosine kinase
inhibitor, inhibited p85 tyrosine phosphorylation and induced cell death in the
sublines. PD98059, an inhibitor of Mek, inhibited cell growth of the sublines,
but not that of the parental cells. It was concluded that tyrosine
phosphorylation of p85 is associated with highly proliferative tumoral
phenotypes, at least in T cell leukemias, independent of the phosphatidylinositol
3-kinase activity of the catalytic subunit.
PMID- 10762070
TI - Ribose 1,5-bisphosphate is a putative regulator of fructose 6-phosphate/fructose
1,6-bisphosphate cycle in liver.
AB - 6-Phosphofructo-1-kinase and fructose-1,6-bisphosphatase are rate-limiting
enzymes for glycolysis and gluconeogenesis respectively, in the fructose 6
phosphate/fructose 1,6-bisphosphate cycle in the liver. The effect of ribose 1,5
bisphosphate on the enzymes was investigated. Ribose 1,5-bisphosphate
synergistically relieved the ATP inhibition and increased the affinity of liver 6
phosphofructo-1-kinase for fructose 6-phosphate in the presence of AMP. Ribose
1,5-bisphosphate synergistically inhibited fructose-1,6-bisphosphatase in the
presence of AMP. The activating effect on 6-phosphofructo-1-kinase and the
inhibitory effect on fructose-1,6-bisphosphatase suggest ribose 1,5-bisphosphate
is a potent regulator of the fructose 6-phosphate/fructose 1,6-bisphosphate cycle
in the liver.
PMID- 10762071
TI - An endogenous proteinacious inhibitor in porcine liver for S-adenosyl-L
methionine dependent methylation reactions: identification as oligosaccharide
linked acyl carrier protein.
AB - A proteinacious inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent
transmethylation reactions was purified to homogeneity from porcine liver by size
exclusion chromatography and FPLC. The molecular weight of the inhibitor was
12,222 Da. A 7400 Da polypeptide fragment of the purified inhibitor was sequenced
by matrix-associated laser desorption ionization; time-of-flight MS, and was
found to be identical with the known sequence of spinach acyl carrier protein
(ACP). Although the remainder of the molecule was not clearly defined, 1H and H-H
correlation of spectroscopy (COSY) NMR analysis revealed the presence of an
oligosaccharide with alpha-glycosidic linkage. The purified oligosaccharide
linked ACP inhibited several AdoMet-dependent transmethylation reactions such as
protein methylase I and II. S-farnesylcysteine O-methyltransferase, DNA
methyltransferase and phospholipid methyltransferase. Protein methylase II was
inhibited with a Ki value of 2.4 x 10(-3) M in a mixed inhibition pattern,
whereas a well-known competitive product inhibitor S-adenosyl-L-homocysteine
(AdoHcy) had Ki value of 6.3 x 10(-6) M. Commercially available active ACP
fragments (65-74) and ACP from Escherichia coli had less inhibitory activity
toward S-farnesylcysteine O-methyltransferase than the purified inhibitor. The
biological significance of this oligosaccharide-linked ACP which has two
seemingly unrelated functions (inhibitor for transmethylation and fatty acid
biosynthesis) remains to be elucidated.
PMID- 10762072
TI - Rhodanese as a thioredoxin oxidase.
AB - A major catalytic difference between the two most common isoforms of bovine liver
mitochondrial rhodanese (thiosulfate: cyanide sulfurtransferase, EC 2.8.1.1) has
been observed. Both isoforms were shown to be capable of using reduced
thioredoxin as a sulfur-acceptor substrate. However, only the less negative form
in common with the recombinant mammalian rhodanese expressed in E. coli, can also
catalyze the direct oxidation of reduced thioredoxin evidently by reactive oxygen
species. These activities are understood in terms of the established persulfide
structure (R-S-SH) of the covalently substituted rhodanese in the
sulfurtransferase reaction and an analogous sulfenic acid structure (R-S-OH) when
the enzyme acts as a thioredoxin oxidase. The observations suggest a role for one
rhodanese isoform in the detoxication of intramitochondrial oxygen free radicals.
PMID- 10762073
TI - Viral double-stranded RNA, cytokines, and the flu.
AB - The symptoms of the flu, such as fever, drowsiness, and malaise, are the sole
means by which this common clinical syndrome is defined. The syndrome is usually
the first clinical manifestation of both acute bacterial and viral infections. In
the case of acute bacterial infections, several proinflammatory cytokines induced
by bacterial products have been implicated as the causative agents of the flu
syndrome. Viruses induce similar cytokines to bacteria, plus substantial amounts
of interferon-alpha (IFN-alpha), although the direct association of these
cytokines with the viral flu syndrome is less clear. Furthermore, the viral
inducer(s) of cytokines has not been defined. The best candidate cytokine inducer
associated with a majority of viral infections is virus-associated double
stranded RNA (dsRNA). This review examines the essential physical properties of
toxic dsRNA, the cytokines induced by it, its viral and cellular sources,
evidence for its presence in infected cells, its quantities in normal and
infected cells, its cytotoxic mechanisms, and its cell-penetration properties.
Toxic effects of viruses and dsRNA are compared. Energetics and extraction
artifact issues are also discussed. Whereas most research on dsRNA toxicity has
employed synthetic dsRNA, studies with virus-associated dsRNA are featured when
available. Finally, a model for how viral dsRNA might initiate systemic disease
is presented.
PMID- 10762074
TI - Induction of transforming growth factor-beta 1 production in human cells by
herpes simplex virus.
AB - Transforming growth factor-beta (TGF-beta) is a cytokine of particular interest
in human retrovirus infections because it can abrogate antigen-specific cellular
activation. Although TGF-beta production has been observed in HIV infections,
there is no evidence that herpes simplex virus (HSV)-stimulated human cells
produce this cytokine. Here we present evidence, for the first time, that in
vitro infection of human mononuclear cells with HSV type 1 (HSV-1) induced the
release of TGF-beta1 protein. The production of this cytokine was time dependent
and was found highly significant (p < 0.001) after 48 h. In addition, we observed
that the secretion of TGF-beta1 was dependent on the concentration of human
cells. It was found that virus needs to replicate in human cells for the
production of TGF-beta1, as UV-inactivated virus did not induce significant
production of cytokine protein. Interestingly, increased HSV-1-induced TGF-beta1
production in cultures containing antiinterleukin (IL)-12 or antiinterferon (IFN)
gamma antibodies was observed, whereas an irrelevant antibody had no effect on
the production of this cytokine. Taken together, these findings indicate that
human cells synthetize TGF-beta1 in response to HSV-1 and at the same time
suggest that HSV-1-induced TGF-beta1 production may be one of the mechanisms by
which HSV can at least partly evade activation of the host immune system.
PMID- 10762075
TI - Tunicamycin enhances the anticellular activity of interferon by inhibiting G1/S
phase progression in 3T3 cells.
AB - We have shown earlier that the cell growth inhibitory activity of interferon
(IFN) is significantly enhanced by tunicamycin (TM) (Maheshwari et al., Science
219, 1339-1341, 1983). In this report, we investigated various regulatory points
of synergistic action between TM and IFN-alpha/beta that inhibit cell growth in
NIH 3T3 cells. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium
bromide) viability assays showed a dose-dependent increase in percentage
inhibition of the cells when treated with either TM or IFN. When doses of TM and
IFN that had no significant inhibition on cell viability were used in
combination, there was a pronounced suppression of DNA synthesis (tritiated
thymidine incorporation). Flow cytometry studies revealed that individual
treatments with either IFN or TM that did not alter the cell cycle profile, when
combined, resulted in an impaired cell cycle by inhibiting G1/S progression. The
blockage of G1/S transition was associated with reduction of cyclin-dependent
kinase (CDK4) activity. The mRNA (analyzed by ribonuclease protection assay) and
protein levels (assayed by Western blotting) of cyclins D1, D3, and CDK4 were
downregulated by combined treatment with IFN and TM. An increase in the
expression of p27/kipl, an inhibitor of CDK4, was observed in cells that were
treated with both IFN and TM. These studies suggest that insufficient formation
of the active cyclin/CDK complex could possibly be deferring the cells from
normal cycling and may be responsible for the ability of TM to enhance cell
growth inhibition induced by IFN.
PMID- 10762076
TI - Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by
prostaglandin E2: the role of p38 mitogen-activated protein kinase.
AB - Prostaglandin E2 (PGE2) regulates production of a wide array of cytokines. We
have found that PGE2 can upregulate the levels of both interleukin-10 (IL-10) and
IL-6 produced by activated murine macrophages, but the molecular pathways leading
to their augmentation differ. Synthesis of IL-10 in response to PGE2 is dependent
on p38 MAP kinase activity, whereas synthesis of IL-6 is not. Evidence to support
this derives from two experimental approaches. First, we established that PGE2 is
effective in elevating IL-10 levels only when it is added to cells in which p38
kinase has been activated. In contrast, PGE2 can augment IL-6 levels regardless
of whether or not p38 kinase is active. Second, we showed that inhibitors that
are selective for p38 kinase prevent the IL-10 response to PGE2 but not the IL-6
response. We found that p38 kinase inhibitors are able to inhibit IL-6 production
in activated macrophages, but this occurs primarily as a result of their
concurrent inhibition of cyclooxygenase-2 and endogenous PGE2 synthesis. These
results indicate that macrophage IL-10 and IL-6 expression is differentially
regulated by PGE2 and p38 MAP kinase in murine inflammatory macrophages.
PMID- 10762077
TI - Interleukin-4 and IFN-gamma differentially stimulate macrophage chemoattractant
protein-1 (MCP-1) and eotaxin production by intestinal epithelial cells.
AB - When the intestine becomes infected by pathogenic organisms, intestinal
epithelial cells (IEC) respond with the production of chemokines, which then
attract and activate specific subsets of leukocytes. During chronic inflammation,
the panel of IEC chemokines produced likely represents the net effect of a
plethora of mediators present in the milieu, including cytokines from activated T
lymphocytes. To explore the influence of T lymphocyte cytokines, we treated IEC
18 cells with interferon-y (IFN-gamma) and interleukin-4 (IL-4) and measured the
effect on production of the CC chemokines, monocyte chemoattractant protein-1
(MCP-1) and eotaxin, and the CXC chemokine, macrophage inflammatory protein-2
(MIP-2). Both IFN-gamma and IL-4 enhanced MCP-1 mRNA levels but with different
kinetics. IFN-gamma stimulated a transient increase in MCP-1 mRNA levels, which
peaked at 2 h, whereas IL-4-stimulated MCP-1 mRNA levels were markedly increased
at 1 h and remained elevated at all time points studied. With each stimulus, the
increase in MCP-1 mRNA levels was accompanied by a steady time-dependent increase
in MCP-1 secretion. In addition, treatment with IFN-gamma or IL-4 enhanced IL
1beta-stimulated MCP-1 mRNA production and protein secretion. Eotaxin mRNA was
detectable in unstimulated IEC-18 cells, and IL-4 but not IFN-gamma caused a
rapid enhancement in levels, which remained elevated for 24 h after treatment.
Finally, IL-1beta but not IFN-gamma or IL-4 enhanced MIP-2 mRNA levels. Knowledge
gained from studying the outcome of T lymphocyte-derived stimuli will help
understand the complex sequence of events during chronic intestinal inflammation.
PMID- 10762078
TI - Interleukin-6 levels in tears of contact lens wearers.
AB - The purpose of this study was to evaluate the presence of interleukin-6 (IL-6) in
basal tears of contact lens wearers (n = 18) and nonlens wearers (n = 25).
Samples (5 microl) were collected with a microcapillary pipette and evaluated
using PAGE electrophoresis and immunoblot analysis. Contact lens-wearing patients
had a mean IL-6 level of 43.8 +/- 5.3 pg/5 microl compared with nondetectable IL
6 levels throughout the noncontact lens-wearing population. IL-6 in several
patients removed from contact lens wear for 6 days became nondetectable. When
these patients were returned to wearing lenses, IL-6 levels increased to their
original levels within 24 h. The data presented indicate that an ocular medical
device may stimulate IL-6 production.
PMID- 10762079
TI - Coimmunization with IFN-gamma or IL-2, but not IL-13 or IL-4 cDNA can enhance Th1
type DNA vaccine-induced immune responses in vivo.
AB - As we explore the potential improvements to the current DNA vaccine strategies,
it may be desirable to investigate methods to improve the level of resulting
immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants
for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of
expression plasmid encoding for cytokines with DNA vaccine constructs is an
effective method to modulate the magnitude and direction (humoral or cellular) of
the immune responses. We have previously reported on the immunomodulatory effects
of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for
DNA-based vaccines. In this report, we extend these finding and compare the
immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl
type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed
that distinct antigen-specific immune modulation can be achieved by the
coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed
that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in
contrast to previous reports on their similarities in biologic activities, IL-13
and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses
differently in this model. Overall, these results further support the potential
utility of this strategy as an important tool for the development of vaccines and
immune therapies.
PMID- 10762080
TI - Cell wall components of Staphylococcus aureus induce interleukin-5 production in
patients with atopic dermatitis.
AB - Lipoteichoic acid (LTA) and peptidoglycan (PEG) from Staphylococcus aureus
induced interleukin-5 (IL-5) production in human peripheral blood mononuclear
cells (PBMC) from patients with atopic dermatitis (AD) but not in PBMC from
healthy donors. The production of IL-5 induced by LTA or PEG was correlated with
the expression of IL-5 mRNA in PBMC. Furthermore, the level of IL-5 production
induced by treatment with both LTA and PEG from S. aureus was higher than that
induced by the addition of each alone. These results suggest that LTA and PEG
have an additive effect on IL-5 production in PBMC from AD patients and may
explain the role of colonization with nontoxin-producing strains of S. aureus in
these patients.
PMID- 10762081
TI - Interaction between interleukin-6 and the natural anticoagulant system in acute
stroke.
AB - Inflammatory reactions mediated by cytokines are involved in the pathogenesis of
acute stroke. Decrease in circulating levels of protein C (PC) and protein S (PS)
induced by inflammatory cytokines has been postulated as a potential mechanism
for a procoagulant tendency during acute stroke. The procoagulant state
associated with impairments in natural anticoagulants may induce microvascular
obstruction leading to a tissue perfusion reduction that worsens cerebral
ischemia. Interleukin-6 (IL-6) regulate the synthesis of C4b-binding protein
(C4BP), an acute-phase protein that also regulates PS plasma levels. We measured
IL-6, C4BP, erythrocyte sedimentation rate (ESR), total and free PS and PC in 44
patients with acute ischemic stroke to determine if IL-6 decreases circulating
levels of natural anticoagulants through the C4BP pathway and if these acute
changes in natural anticoagulants may have clinical implications. Patients with
higher levels of IL-6 had more severe neurologic deficits on admission, greater
infarct size, higher levels of acute-phase reactants, and lower levels of free
PS. IL-6 was significantly correlated with C4BP, ESR, and free PS levels. PC
levels were also lower in the group of patients with greater IL-6, but
differences were not statistically significant. No correlations were found
between C4BP and natural anticoagulants. Severe neurologic deficit, greater
infarct volume, atrial fibrillation, increased levels of inflammatory parameters
(ESR and IL-6), and reduced levels of free PS were associated with disabling
stroke at 3 months, but only neurologic severity and ESR remained as independent
predictors of stroke disability on multiple regression analysis. Inflammatory
reactions mediated by IL-6 during the acute phase of stroke influence the
modulation of free PS. However, variations in free PS levels do not have
implications for clinical outcome in stroke patients. The link between
proinflammatory cytokines and free PS in the acute phase of stroke is not related
to the C4BP pathway.
PMID- 10762082
TI - Detection of porcine interleukin-18 by sandwich ELISA and immunohistochemical
staining using its monoclonal antibodies.
AB - We describe here the development of sandwich enzyme-linked immunosorbent assay
(sandwich ELISA) and immunohistochemical staining for porcine interleukin-18
(PoIL-18) and their application to detection of PoIL-18 in vivo. Ten anti-PoIL-18
monoclonal antibodies (mAb), all of which were reactive with recombinant PoIL-18
by Western blotting, were established. Four (2-C-4, 9-H-6, 11-H-5, and 12-C-12)
of 10 neutralized the biologic activity of PoIL-18 to induce interferon-y (IFN
gamma) from porcine peripheral blood mononuclear cells (PBMC). Four (2-C-4, 5-F
6, 9-H-6, and 12-C-12) of 10 were shown to be useful in immunohistochemical
staining and detected PoIL-18 in Kupffer cells and macrophages in hepatic focal
necrosis and macrophages in interstitial pneumonia in piglets with experimental
endotoxemia using formalin-fixed, paraffin-embedded sections. A sandwich ELISA
was developed using mAb 7-G-8 as a capture antibody and biotinylated mAb 5-C-5 as
a detection antibody. This ELISA detected PoIL-18 with a minimum detectable
concentration of 20 pg/ml and did not show cross-reactivity against PoIL-1beta,
IL-8, IL-12, and IFN-gamma or murine and human IL-18. Using this ELISA, PoIL-18
was detected in the plasma and the bronchoalveolar lavage fluid (BALF) of pigs
experimentally infected with Actinobacillus pleuropneumoniae. The availability of
this ELISA and immunohistochemical staining for PoIL-18 may contribute to a
further understanding of the role of this cytokine in various porcine immune
responses and diseases.
PMID- 10762083
TI - Effects of specific mutations in active site motifs of 2',5'-oligoadenylate
synthetase on enzymatic activity.
AB - 2',5'-Oligoadenylate synthetase (2',5'-OAS) is a double-stranded RNA-dependent
nucleotidyl-transferase induced by interferon (IFN). Several 2',5'-OAS cDNA have
been cloned from human, pig, rat, mouse, and chicken. A P-loop motif followed by
an Asp-containing sequence (referred to as D-box) and a region with a high
content of Lys and Arg (KR-rich region) are well conserved in 2',5'-OAS. The
sequence 196DFLKQR201 of 40-kDa human 2',5'-OAS, to which 8-azido-ATP binds (N.
Kon and R.J. Suhadolnik, J. Biol. Chem. 271, 19983-19990, 1996), is included in
the KR-rich region. We introduced several site-directed mutations into these
active motifs of 42-kDa murine 2',5'-OAS. Each mutant enzyme studied bound to
poly(I):poly(C) to the same extent as wild-type enzyme. Both K67R, a P-loop
mutant, and K200R, a KR-rich region mutant, exhibited a reduced but considerable
rate of enzymatic activities. The activity of the double mutant K67R/K200R was
about 10% of the wild type. On the other hand, the activities of both K67M and
K200M were not more than 2% of the wild-type enzyme, and no activity was detected
in another P-loop mutant, G62A/G63A. The binding of Mg2+ to a D-box mutant
D76N/D78N was markedly reduced, and only a very low level of enzymatic activity
was detected in this mutant. These results demonstrate that the P-loop, the D-box
that binds Mg2+, and the KR-rich region are important for the enzymatic
activities of 2',5'-OAS.
PMID- 10762084
TI - Reversible depolarization of in situ mitochondria by oxidative stress parallels a
decrease in NAD(P)H level in nerve terminals.
AB - We have reported recently (Chinopoulos et al., 1999 J. Neurochem. 73, 220 228)
that mitochondrial membrane potential (delta(psi)m) in isolated nerve terminals
is markedly reduced by H2O2 in the absence of F0F1-ATPase working as a proton
pump. Here we demonstrate that delta(psi)m reduced by H2O2 (0.5 mM) in the
presence of oligomycin (10 mM), an inhibitor of the F0F1-ATPase, was able to
recover by the addition of catalase (2000 U). Similarly, a decrease in the
NAD(P)H level due to H2O2 can be reversed by catalase. In addition, H2O2
decreased the ATP level and the [ATP]:[ADP] ratio measured in the presence of
oligomycin reflecting an inhibition of glycolysis by H2O2, but this effect was
not reversible. The effect of H2O2 on delta(psi)m in the presence of the complex
I inhibitor, rotenone, was also unaltered by addition of catalase. These results
provide circumstantial evidence for a relationship between the decreased NAD(P)H
level and the inability of mitochondria to maintain delta(psi)m during oxidative
stress.
PMID- 10762085
TI - Effect of 1-methyl-4-phenylpyridinium on glutathione in rat pheochromocytoma PC
12 cells.
AB - We investigated the effect of the selective dopaminergic neurotoxin 1-methyl-4
phenylpyridinium (MPP+) on glutathione redox status and the generation of
reactive oxygen intermediates (ROI) in rat pheochromocytoma PC 12 cells in vitro.
Treatment with MPP+ (250 microM) led to a 63% increase of reduced glutathione
(GSH) after 24 h, while a 10-fold higher concentration of MPP+ (2.5 mM) depleted
cellular GSH to 12.5% of control levels within that time. Similarly, the complex
I-inhibitor rotenone induced a time-dependent loss of GSH at 1 and 10 microM,
whereas treatment with lower concentrations of rotenone (0.1, 0.01 microM)
increased cellular GSH. Both MPP+ and rotenone increased cellular levels of
oxidised glutathione (GSSG) and the higher concentrations of both compounds led
to an elevated ratio of oxidised glutathione (GSSG) vs total glutathione (GSH +
GSSG) indicating a shift in cellular redox balance. MPP+ or rotenone did not
induce the generation of ROI or significant elevation of intracellular levels of
thiobabituric acid reactive substances (TBARS) for up to 48 h. Our data suggest
that MPP+ has differential effects on glutathione homeostasis depending on the
degree of complex I-inhibition and that inhibition of complex I is not sufficient
to generate ROI in this paradigm.
PMID- 10762086
TI - Endogenous phosphorylation of the GABA(A) receptor protein is counteracted by a
membrane-associated phosphatase.
AB - Incubation of bovine brain membranes with [gamma-33P]ATP phosphorylated mainly a
51-kDa band. Electrophoretic co-migration was observed for 33P- and
[3H]flunitrazepam-labeled bands in both membrane fractions and in affinity
purified GABA(A) receptor (GABAA-R) preparations. An alpha-subunit monoclonal
antibody adsorbed most of the radiolabeled-band, suggesting that the labeled
membrane polypeptide corresponds to the GABA(A)-R alpha1-subunit, which is the
only GABA(A)-R subunit with a molecular weight of 51 kDa. The phosphorylation
rate was much faster in membranes than in purified receptor. Dephosphorylation
was detected in membranes only. The membrane-bound phosphatase was potently
inhibited by vanadate and Zn2+>>Mn2+ , but was insensitive to okadaic acid (a
phosphatase 1, 2 and 2B inhibitor), cyclosporin (specific calcineurin inhibitor)
and phosphatase-1 inhibitor. Endogenous kinase was activated by divalent cations
including calcium (Mg2- > Mn2+ > Ca2+), whilst dephosphorylation did not require
the presence of Ca2+ ions. This suggests that at least one membrane-bound
phosphatase counteracts the endogenous phosphorylation of the GABA(A)-R: the lack
of dephosphorylation in the purified receptor preparation indicates that, in
contrast to the endogenous kinase, no phosphatase is closely associated with the
receptor protein complex.
PMID- 10762087
TI - 7alpha-Hydroperoxycholesterol causes CNS neuronal cell death.
AB - Brain cholesterol, which is synthesized in the central nervous system and also
partly taken up from lipoproteins via the blood-brain barrier, is a major
component of neuronal membranes. Oxidation of cholesterol leads to the formation
of oxysterols, which have been shown to act cytotoxic. The influence of 7alpha
hydroperoxycholesterol, was investigated using the human neuroblastoma cell line
SH-SY5Y. 7alpha-Hydroperoxycholesterol caused neuronal cell death; this
neurotoxic effect was dose-dependent, within 48 h 10 microM led to 50%, 50 microM
to 92% loss of cell viability, which was detected by cell morphology and Trypan
blue exclusion. DNA-fragmentation or caspase-3 activity were not detectable, LDH
release occurred rapidly and reactive oxygen species (ROS) were generated.
Therefore we infer that 7alpha-hydroperoxycholesterol, apart from its role in
atherosclerosis, leads to necrosis of neuronal cells.
PMID- 10762088
TI - Kinetic and pharmacological analysis of L-[35S]cystine transport into rat brain
synaptosomes.
AB - The synaptosomal transport of L-[35S]cystine occurs by three mechanisms that are
distinguishable on the basis of their ionic dependence, kinetics of transport and
the specificity of inhibitors. They are (a) low affinity sodium-dependent
transport (Km 463 +/- 86 microM, Vmax 185 +/- 20 nmol mg protein-1 min-1), (b)
high affinity sodium-independent transport (Km 6.90 +/- 2.1 microM, Vmax 0.485 +/
0.060 nmol mg protein(-1) min(-1)) and (c) low affinity sodium-independent
transport (Km 327 +/- 29 microM, Vmax 4.18 +/- 0.25 nmol mg protein(-1) min(-1)).
The sodium-dependent transport of L-cystine was mediated by the X(AG)- family of
glutamate transporters, and accounted for almost 90% of the total quantity of L
[35S]cystine accumulated into synaptosomes. L-glutamate (Ki 11.2 +/- 1.3 microM)
was a non-competitive inhibitor of this transporter, and at 100 microM L
glutamate, the Vmax for L-[35S]cystine transport was reduced to 10% of control. L
cystine did not inhibit the high-affinity sodium-dependent transport of D
[3H]aspartate into synaptosomes. L-histidine and glutathione were the most potent
inhibitors of the low affinity sodium-independent transport of L-[35S]cystine. L
homocysteate, L-cysteine sulphinate and L-homocysteine sulphinate were also
effective inhibitors. 1 mM L-glutamate reduced the sodium-independent transport
of L-cystine to 63% of control. These results suggest that the vast majority of
the L-cystine transported into synaptosomes occurs by the high-affinity glutamate
transporters, but that L-cystine may bind to a site that is distinct from that to
which L-glutamate binds. The uptake of L-cystine by this mechanism is sensitive
to inhibition by increased extracellular concentrations of L-glutamate. The
importance of these results for understanding the mechanism of glutamate-mediated
neurotoxicity is discussed.
PMID- 10762089
TI - Differential effect of beta-N-oxalylamino-L-alanine, the Lathyrus sativus
neurotoxin, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on the
excitatory amino acid and taurine levels in the brain of freely moving rats.
AB - We studied the effect of beta-oxalylamino-L-alanine, a glutamate analog present
in Lathyrus sativus seeds and implicated in the etiopathogenesis of
neurolathyrism, and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on
the extracellular levels of aspartate, glutamate and taurine in the primary motor
cortex of freely moving rats. We found that while both neurotoxins increase the
level of aspartate and glutamate, only (+/-)-alpha(-amino-3-hydroxy-5
methylisoxazole-4-propionate is able to modulate the level of taurine. GYKI
52466, a non-competitive non-NMDA antagonist, inhibited beta-oxalylamino-L
alanine-induced increase of aspartate, but not that of glutamate. Conversely,
this antagonist proved to be very efficient in blocking the stimulating effect of
(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate on all three amino
acids. We suggest that beta-oxalylamino-L-alanine increases the level of
glutamate in vivo by a mechanism not connected to its effect on the non-NMDA
receptors, which might involve the inhibition of glutamate transport. This would
allow the excitatory neurotransmitter to reach a concentration sufficient to
stimulate the non-NMDA receptors, which in their turn mediate the specific
release of aspartate. Although the role of aspartate as a neurotransmitter is
still under discussion, it might indeed amplify the excitotoxic cascade through
its action on NMDA receptors. We speculate that this sequence of events might
represent an important step in the molecular cascade leading to the appearance of
the selective motoneuron degeneration in neurolathyrism.
PMID- 10762090
TI - Glial glutamate transporter GLT-1 down-regulation precedes delayed neuronal death
in gerbil hippocampus following transient global cerebral ischemia.
AB - Glial (GLT-1 and GLAST) and neuronal (EAAC1) high-affinity transporters mediate
the sodium dependent glutamate reuptake in mammalian brain. Their dysfunction
leads to neuronal damage by allowing glutamate to remain in the synaptic cleft
for a longer duration. The purpose of the present study is to understand their
contribution to the ischemic delayed neuronal death seen in gerbil hippocampus
following transient global cerebral ischemia. The protein levels of these three
transporters were studied by immunoblotting as a function of reperfusion time (6
h to 7 days) following a 10 min occlusion of bilateral common carotid arteries in
gerbils. In the vulnerable hippocampus, there was a significant decrease in the
protein levels of GLT-1 (by 36-46%, P < 0.05; between 1 and 3 days of
reperfusion) and EAAC1 (by 42-68%, P < 0.05; between 1 and 7 days of
reperfusion). Histopathological evaluation showed no neuronal loss up to 2 days
of reperfusion but an extensive neuronal loss (by approximately 84%, P < 0.01) at
7 days of reperfusion in the hippocampal CA1 region. The time frame of GLT-1
dysfunction (1-3 days of reperfusion) precedes the initiation of delayed neuronal
death (2-3 days of reperfusion). This suggests GLT-1 dysfunction as a
contributing factor for the hippocampal neuronal death following transient global
cerebral ischemia. Furthermore, decreased EAAC1 levels may contribute to
GABAergic dysfunction and excitatory/inhibitory imbalance following transient
global ischemia.
PMID- 10762091
TI - Evidence for a zinc/proton antiporter in rat brain.
AB - The data presented in this paper are consistent with the existence of a plasma
membrane zinc/proton antiport activity in rat brain. Experiments were performed
using purified plasma membrane vesicles isolated from whole rat brain. Incubating
vesicles in the presence of various concentrations of 65Zn2+ resulted in a rapid
accumulation of 65Zn2+. Hill plot analysis demonstrated a lack of cooperativity
in zinc activation of 65Zn2+ uptake. Zinc uptake was inhibited in the presence of
1 mM Ni2+, Cd2+, or CO2+. Calcium (1 mM) was less effective at inhibiting 65Zn2+
uptake and Mg2+ and Mn2+ had no effect. The initial rate of vesicular 65Zn2+
uptake was inhibited by increasing extravesicular H+ concentration. Vesicles
preloaded with 65Zn2+ could be induced to release 65Zn2+ by increasing
extravesicular H+ or addition of 1 mM nonradioactive Zn2+. Hill plot analysis
showed a lack of cooperativity in H+ activation of 65Zn2+ release. Based on the
Hill analyses, the stoichiometry of transport may include Zn2+/Zn2+ exchange and
Zn2+/H+ antiport, the latter being potentially electrogenic. Zinc/proton antiport
may be an important mode of zinc uptake into neurons and contribute to the
reuptake of zinc to replenish presynaptic vesicle stores after stimulation.
PMID- 10762092
TI - Serum endothelial adhesion molecules levels correlate with lesion burden in
multiple sclerosis patients treated with interferon beta-1b.
AB - The levels of serum-soluble intracellular adhesion molecule-1 and soluble
endothelial-leukocyte adhesion molecule-1, and the Gadolinium-enhanced T1
weighted MRI were studied in a group of patients with relapsing-remitting
multiple sclerosis treated with interferon beta-1b and compared to a non-treated
control group. The levels of serum-soluble intracellular adhesion molecule-1 and
soluble endothelial-leukocyte adhesion molecule-1 increased, after three months
treatment, as compared to baseline and the non-treated MS patients. A significant
correlation was found in the treated group between serum-soluble endothelial
leukocyte adhesion molecule-1 and the lesion area in the Gadolinium-enhancing (T2
weighted scan) MRI.
PMID- 10762093
TI - Effect of dietary zinc deficiency on brain metallothionein-I and -III mRNA levels
during stress and inflammation.
AB - Zinc is an essential heavy metal for the normal function of the central nervous
system (CNS), but the knowledge of its metabolism and functions is scarce. In
this report we have studied the effect of a zinc deficient diet on the regulation
of brain metallothioneins (MTs). In situ hybridization analysis revealed that
brain MT-I induction by restraint stress was significantly blunted in some but
not all brain areas in the mice fed the zinc deficient diet compared to normally
fed mice. In contrast, brain MT-I induction by the administration of bacterial
lipopolysaccharide (LPS) was not significantly lower in the mice fed the zinc
deficient diet. In contrast to MT-I, MT-III mRNA levels were minimally affected
by either stress or LPS. Yet, significant decreasing effects of the zinc
deficient diet were observed in areas such as the neocortex, CA1-CA3 neuronal
layer and dentate gyrus of the hippocampus, and the Purkinje neuronal layer of
the cerebellum. These results demonstrate that dietary zinc deficiency impairs
the response of brain MTs during both stress and LPS-elicited inflammatory
response in a highly specific manner.
PMID- 10762094
TI - Group support interventions for women with breast cancer: who benefits from what?
AB - Research on the benefits of social support groups has been inconclusive. One
reason is that individual differences in intervention responses have rarely been
examined. The authors determined the extent to which individual difference
variables moderated the effects of an information-based educational group and an
emotion-focused peer discussion group on the mental and physical functioning of
women with breast cancer (n = 230). The authors administered the SF-36 (S.E.
Ware, K.K. Snow, M. Kosinski, & B. Gandek, 1993), a multidimensional quality of
life instrument, pre- and postintervention. Educational groups showed greater
benefits on the physical functioning of women who started the study with more
difficulties compared with less difficulties (e.g., lacked support or fewer
personal resources). Peer discussion groups were helpful for women who lacked
support from their partners or physicians but harmful for women who had high
levels of support. Implications of these results for clinical interventions are
discussed.
PMID- 10762095
TI - The relation between risk factors for binge eating and bulimia nervosa: a
population-based female twin study.
AB - This study investigated the differential risk factors for the initiation of binge
eating and the transition from binge eating to bulimia nervosa. Women from a
population-based twin registry (850 complete pairs) were assessed with respect to
specific measured variables (including demographics, religiosity, lifetime
psychopathology, current symptomatology, and personality) and latent genetic and
environmental variables. Because of the relative rarity of bulimia nervosa,
statistical power was low, but findings suggested considerable overlap between
the genetic risk factors for the development of binge eating and the genetic risk
factors for the transition from binge eating to bulimia nervosa. Genetic risk
factors for binge eating and bulimia nervosa may be largely similar, whereas
nonshared environment may be important in influencing the risk for bulimia
nervosa once binge eating is initiated.
PMID- 10762096
TI - Patterns, correlates, and barriers to medication adherence among persons
prescribed new treatments for HIV disease.
AB - New treatments for HIV can improve immune functioning and decrease mortality.
However, lapses in adherence may render these complex regimens ineffective. Sixty
three men and 9 women on highly active antiretroviral therapy completed measures
of medication adherence, psychological characteristics, and barriers to
adherence. HIV viral load, a health outcome measure of virus amount present in
blood, was also obtained. The sample was 36% African American and 56% Caucasian,
with 35% reporting disability. Nearly one third of patients had missed medication
doses in the past 5 days, and 18% had missed doses weekly over the past 3 months.
Frequency of missed doses was strongly related to detectable HIV viral loads.
Depression, side-effect severity, self-efficacy, and social support distinguished
patients with good and poor adherence. Barriers also varied with adherence level.
Implications for interventions promoting HIV treatment adherence are discussed.
PMID- 10762097
TI - Impact of combination therapies on HIV risk perceptions and sexual risk among HIV
positive and HIV-negative gay and bisexual men.
AB - The availability of improved HIV treatments may prompt reduced concern about HIV
and sexual risk. Gay and bisexual men (N = 554, 17% HIV-positive) completed
measures of treatment attitudes, sexual risk, and assumptions regarding the
infectiousness of sexual partners. A substantial minority reported reduced HIV
concern related to treatment advances. Reduced HIV concern was an independent
predictor of sexual risk, particularly among HIV-positive men. In response to
hypothetical scenarios describing sex with an HIV-positive partner, participants
rated the risk of unprotected sex to be lower if the partner was taking
combination treatments and had an undetectable viral load, relative to scenarios
with a seropositive partner not taking combination treatments. Prevention efforts
must address attitudinal shifts prompted by recent treatment successes, stressing
the continued importance of safer sex, and that an undetectable viral load does
not eliminate infection risks.
PMID- 10762098
TI - Perceptual style and behavioral pattern of individuals with functional
gastrointestinal disorders.
AB - The present research examined the perceptual style and coping pattern
characterizing individuals with functional gastrointestinal disorders. A matched
case-control design was adopted to compare differences among the target group of
individuals with functional gastrointestinal disorders (n = 40), a pain control
group of individuals with rheumatism (n = 40), and the community control group of
healthy individuals (n = 40). Perceptual style was measured by both monitoring
and blunting responses to hypothetical stressful situations, and coping pattern
was measured by the use of coping strategies in real-life stressful events.
Results revealed that participants with functional gastrointestinal disorders
differed from their healthy and rheumatic counterparts in having higher
monitoring and lower blunting scores and using action-oriented coping strategies
regardless of the controllability of stressful situations.
PMID- 10762100
TI - Matched and mismatched interventions with young adult smokers: testing a stage
theory.
AB - This experiment tested the transtheoretical model (J.O. Prochaska & C.C.
DiClemente, 1983) of smoking cessation by matching or mismatching interventions
to smokers in a particular stage. The interventions were tested against a no
intervention condition with 92 college-aged daily smokers in the precontemplation
stage of change. The stage-matched intervention asked smokers to think more about
quitting smoking; the stage-mismatched intervention provided action-oriented
activities typically used for those ready to quit smoking. The results failed to
support the value of matching interventions to a smoker's stage of change.
Instead, more smokers who received the action intervention tried to quit smoking.
Matching interventions to an individual's current stage may be less important
than the transtheoretical model suggests.
PMID- 10762099
TI - Perceived control, coping efficacy, and avoidance coping as mediators between
spouses' unsupportive behaviors and cancer patients' psychological distress.
AB - This study examined whether avoidance, coping efficacy, and perceived control
mediate the effects of spouses' unsupportive behaviors on patient psychological
distress among 191 married individuals enrolled in cancer treatment. Results of
the structural equation analyses suggested that avoidance and coping efficacy
mediated the relationship between spouses' unsupportive behaviors and patient
psychological distress. Perceived control of emotional aspects of the illness,
including emotional responses and relationships with family and friends, and
perceived control of the medical course of the cancer did not mediate the
relationship between spouses' unsupportive behaviors and patient psychological
distress. These findings suggest 2 mechanisms to explain why unsupportive
responses from spouses may be associated with psychological distress among cancer
patients.
PMID- 10762101
TI - Integrating stage and continuum models to explain processing of exercise messages
and exercise initiation among sedentary college students.
AB - Concepts from the transtheoretical model (J.O. Prochaska, C.C. DiClemente, & J.C.
Norcross, 1992), theory of planned behavior (I. Ajzen, 1985), and the elaboration
likelihood model (R.E. Petty & J.T. Cacioppo, 1986b) were used to examine how
exercise readiness impacted processing of exercise messages and exercise
initiation. Sedentary college students (n = 147) were assessed for exercise
attitude, intent, behavior, and stage of change. Students also listed their
thoughts after reading messages with either strong or weak arguments for
exercise. Attitude predicted depth of message processing, but stage of change did
not. Stage of change and intent at baseline predicted exercise adoption at 1- to
3-month follow-up (n = 134), with baseline activity moderating the effect of
intent. Tailoring messages to recipients' depth of processing and interactive
effects of intent and behavior on exercise adoption should be considered in
future research.
PMID- 10762102
TI - The effect of nondirective questioning on women's decisions whether to undergo
bone density screening: an experimental study.
AB - This study investigated the effects of nondirective counseling on health
screening decisions. Ninety women (mean age = 51 years) received information
about bone density screening and osteoporosis. They were then randomly allocated
to 1 of 4 groups and were encouraged to focus on positive issues about bone
density screening (positive group), on negative issues (negative group), on both
positive and negative issues (all-focusing group), or on issues relating to the
common cold (control group). Women were asked to rate how likely they would be to
opt for bone density screening if they saw it available. After being informed
that they could have bone density screening, actual uptake was assessed. It was
found that the issues on which individuals focused significantly influenced their
rate likelihood of opting for the scan. Rated likelihood of testing was
significantly associated with whether individuals actually did opt for testing
when it was subsequently offered to them.
PMID- 10762103
TI - The role of patients' ability to pay, gender, and smoking history on public
attitudes toward cardiac transplant allocation: an experimental investigation.
AB - This study assessed public attitudes toward organ allocation through vignettes
that were varied by patient's ability to pay (insured or uninsured), gender, and
smoking history (current, former, or never). Participants were 681 adults
contacted at a state driver's license office who read a vignette about a heart
transplant candidate and subsequently rated their likelihood and priority of
offering transplantation. Results revealed main effects for patient smoking
history exclusively. Post hoc analyses for likelihood of offering transplantation
revealed that participants gave higher ratings for never smokers than current
smokers. For priority of transplantation, analyses revealed higher ratings for
never smokers than for both former smokers and current smokers. Results suggest
that public opinion about organ allocation may include the consideration of
smoking history but not ability to pay or gender.
PMID- 10762104
TI - Introduction to the mini-review series on emerging infectious diseases.
PMID- 10762105
TI - Emerging and re-emerging infectious diseases.
AB - Microbial pathogens discovered as aetiological agents of human disease over the
last 25 years are reviewed. Strengthening of laboratory and public health
surveillance is of paramount importance for early detection and management of
emerging infectious diseases.
PMID- 10762106
TI - Ebola haemorrhagic fever--a review.
PMID- 10762107
TI - Infection hazards of xenotransplantation.
PMID- 10762108
TI - Optimal management of central venous catheter-related infections--what is the
evidence?
PMID- 10762109
TI - Pelvic inflammatory disease--an evidence-based approach to diagnosis.
PMID- 10762110
TI - Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor
zanamivir in the treatment of influenza: a randomized, double-blind, placebo
controlled European study.
AB - OBJECTIVES: To assess the clinical efficacy and safety of orally inhaled
zanamivir in the treatment of influenza in a European primary care setting.
METHODS: This was a randomized, double-blind, placebo-controlled trial in primary
care and hospital clinics in 11 European countries. Patients aged > or = 12 years
were recruited within 2 days of onset of typical influenza symptoms and received
orally inhaled zanamivir 10 mg via a Diskhaler twice daily for 5 days or matching
placebo. Influenza symptoms and temperature were recorded daily for 14 days. The
primary endpoint was time to alleviation of clinically significant symptoms of
influenza. Other endpoints included symptom severity, use of relief medications,
time to return to normal activities, complications and investigator's assessment
of symptoms. RESULTS: A total of 356 patients were recruited; 277 (78%) had
laboratory-confirmed influenza and 32 (9%) were considered high-risk (i.e.
elderly or with underlying medical conditions). Zanamivir significantly reduced
the time to alleviation of symptoms versus placebo (median 5 days versus 7.5
days, P<0.001), a 33% reduction in duration of illness. Zanamivir significantly
reduced the severity of several symptoms; improvements versus placebo were
discernible after approximately 24 h. The proportion of patients who were
afebrile after 24 h increased by 46% versus placebo. Similar treatment benefits
were observed in the high-risk patients. Zanamivir was well tolerated, with an
adverse event profile similar to that of placebo. CONCLUSIONS: Zanamivir is
effective in reducing the duration and severity of influenza illness and is well
tolerated. Zanamivir should therefore be a clinically valuable intervention in
the management of influenza.
PMID- 10762111
TI - Comparison of clarithromycin-sensitive and clarithromycin-resistant Mycobacterium
avium strains isolated from AIDS patients during therapy regimens including
clarithromycin.
AB - OBJECTIVES: Sixteen Mycobacterium avium strains were isolated from the blood of
eight AIDS patients over a period of months. All the patients were on combination
therapies including clarithromycin, and all had treatment failure and relapses of
M.avium bacteremia. Paired clarithromycin-sensitive and resistant M.avium strains
isolated at the beginning of treatment and at the first relapse of bacteremia
were compared. METHODS: The M.avium isolates were identified after hybridization
with DNA probes specific for M.avium rRNA and typed epidemiologically with random
amplified polymorphic DNA analyses using three arbitrary primers. The rate of
intracellular cell entry or the tumour necrosis factor alpha induction by the
M.avium isolates were studied in human monocytes and J774 cells. RESULTS: When
the M.avium isolates were hybridized with the rRNA probes, we obtained lower
hybridization values with clarithromycin-resistant isolates than with
clarithromycin-sensitive isolates. This appeared to be due to smaller amounts of
rRNA available for hybridization than to mutation of the 23S rRNA sequences in
clarithromycin-resistant strains. The RAPD analyses showed that the
clarithromycin-resistant isolates were clonally related to the clarithromycin
sensitive strains in six of the eight patients. The other two patients had a RAPD
profile, suggesting a re-infection and/or polyclonal infection. The M.avium
isolates obtained on day 0 and after the emergence of resistance to
clarithromycin did not differ in terms of their intracellular entry rate, or in
terms of tumour necrosis factor alpha induction. CONCLUSIONS: We infer that
M.avium strains isolated during bacteraemic relapses on combination therapies
including clarithromycin are epidemiologically related to the initial strain and
do not show changes in the rate of intracellular cell entry and in terms of
tumour necrosis factor alpha induction. Re-infections and/or polyclonal
infections however, although less frequent, can also occur.
PMID- 10762112
TI - Clinical distinction between human granulocytic ehrlichiosis and the initial
phase of tick-borne encephalitis.
AB - OBJECTIVES: The aim of our study was to establish clinical and laboratory
differences between patients with acute human granulocytic ehrlichiosis (HGE) and
patients with the initial phase of tick-borne encephalitis (TBE). METHODS:
Clinical features and laboratory results of four patients with acute HGE
(established by the presence of the specific DNA sequences of the HGE agent in
whole blood by polymerase chain reaction and/or by seroconversion to the HGE
agent by indirect immunofluorescence assay) and 12 patients with the initial
phase of TBE (demonstrated by the presence of serum IgM antibodies to TBE virus)
were compared. All these patients were uncovered at the Department of Infectious
Diseases, University Medical Centre, Ljubljana, Slovenia, during 1995-1996, in a
prospective study on the aetiology of febrile illnesses occurring within 6 weeks
after a tick bite. RESULTS: Findings were similar for the majority of the
examined parameters including severity of illness, level and duration of fever,
presence of headache, leukopenia, thrombocytopenia, and liver - function test
abnormalities. Statistically significant differences were found only for
arthralgia (P=0.026) and elevated concentration of C-reactive protein (P=0.003);
both variables were found more often in patients with acute HGE. CONCLUSIONS: In
a patient residing in the central part of Slovenia, who reports a tick bite
followed by a febrile illness with leukopenia and/or thrombocytopenia, the
presence of arthralgias and/or an elevated C-reactive protein value directs
toward the diagnosis of acute HGE and against the initial phase of TBE.
PMID- 10762113
TI - Brucella bacteraemia: clinical and laboratory observations in 160 patients.
AB - OBJECTIVES: To describe the clinical, serological, and prognostic features of
bacteraemic brucellosis in an endemic region. METHODS: Retrospective case series
of 160 patients admitted from 1983 to 1995 to a hospital providing secondary and
tertiary level medical care in Saudi Arabia. All patients had positive blood
cultures for Brucella species, predominantly Brucella melitensis. RESULTS:
Bacteraemia was documented in 38% of 545 cases of brucellosis admitted to our
institution during the study period. The main clinical syndromes were febrile
illness alone (44%) or fever with arthritis (42%). Of 68 isolates that were
speciated, 93% were Brucella melitensis. Initial agglutinating antibody titre was
> or =1:320 in 96% of the patients. Antimicrobial resistance of B.melitensis
isolates was: co-trimoxazole, 29%; rifampicin, 3.5%; streptomycin, 0.6%; and
tetracycline, 0.6%. No increase in resistance was noted over the 13-year study
period. Commonly used antimicrobial regimens consisted of streptomycin plus
tetracycline or rifampicin plus doxycycline given for 6 weeks. Seven patients
(5%) had relapse of their symptoms after antimicrobial therapy. Three of these
had infective endocarditis with repeated bacteraemia. These patients required
aortic valve replacement and recovered after surgery. The remaining four patients
responded to a second course of therapy. CONCLUSIONS: Brucella bacteraemia is an
acute febrile disease often associated with rheumatologic complaints. Most
patients have an agglutinating antibody titre > or =1:320 and respond well to
standard chemotherapy regimens with low mortality.
PMID- 10762114
TI - Analysis of antibody response to Cryptococcus neoformans in five patients with
AIDS and cryptococcosis by immunoblotting.
AB - OBJECTIVES: The serological response of five patients with AIDS and
cryptococcosis to non capsular antigens from Cryptococcus neoformans var.
neoformans has been investigated. METHODS: Pressates of different isolates of C.
neoformans were used as antigenic preparation for immunoblotting of patient
samples. RESULTS: Multiple sera and cerebrospinal fluids sequentially collected
from five AIDS patients with cryptococcosis showed a wide heterogeneity in
antibody response with bands at 48. 43, 38 and 26 kD being present in all
clinical samples of all five patients. The variation in banding patterns of the
sequential samples from three patients was correlated with a decrease of the
antigen titre and with an amelioration of the cryptococcal infection.
CONCLUSIONS: We identified antibodies to four immunodominant non-capsular
antigens, which might represent major target molecules of the humoral response of
patients with cryptococcosis.
PMID- 10762115
TI - Aeromonas infection in acute suppurative cholangitis: review of 30 cases.
AB - OBJECTIVES: Aeromonads, though not common pathogens in biliary sepsis, caused
substantial mortality in patients with impaired hepatobiliary function. Our aim
was to study the pathogenic role of Aeromonas in acute suppurative cholangitis.
METHODS: Between 1996 and 1998, the medical records of patients with a diagnosis
of biliary sepsis were reviewed. Those who fulfilled the diagnostic criteria for
acute suppurative cholangitis and had positive bile or blood cultures for
Aeromonas species were studied. RESULTS: One thousand and forty-five patients
were confirmed to have acute suppurative cholangitis. Of these, 30 patients
(2.9%) had Aeromonas species isolated from bile; four were complicated by
aeromonas septicaemia with simultaneous recovery of the bacteria from blood. All
except two isolates were A. hydrophila. Twenty-four patients (80%) had bile duct
stones, four (13%) had cholangiocarcinoma and two (7%) pancreatic cancer. Twenty
five cases (83%) had previous exploration of the biliary tract. There was
substantial resistance to piperacillin (58%), ceftazidime (30%) and imipenem
(15%). Most patients improved after biliary decompression. Only three patients
(10%) died, two had terminal malignancy and one had end-stage liver failure. No
excess mortality was attributable to Aeromonas infection in biliary sepsis.
CONCLUSIONS: Previous instrumentation facilitated ascending Aeromonas infection
of the biliary tract from the gastrointestinal tract. Unlike early reports, our
results showed that aeromonads did not adversely affect the clinical outcome of
acute suppurative cholangitis with successful drainage of biliary obstruction.
PMID- 10762116
TI - Clinical features, laboratory findings and management of meningococcal meningitis
in England and Wales: report of a 1997 survey. Meningococcal meningitis: 1997
survey report.
AB - OBJECTIVES: To describe the epidemiological, clinical and laboratory features of
meningococcal meningitis and the effects of antibiotics on laboratory
investigations under current clinical practices in England and Wales. METHODS:
Using a telephone questionnaire, information was gathered on 103 cases with a
clinical diagnosis of meningococcal meningitis. Included were cases with samples
submitted to the Public Health Laboratory Service (PHLS), Meningococcal Reference
Unit (MRU) over a 5-month period in 1997. Tests included microscopic examination,
latex agglutination and culture for Neisseria meningitidis, and at MRU
confirmation of identification and characterization of isolates and meningococcal
polymerase chain reaction (PCR) analysis on blood and cerebrospinal fluids (CSF).
RESULTS: Clinically 45% of the cases had predominantly meningitis and 55% had
septicaemia and meningitis. Only 29% of the cases received pre-admission
benzylpenicillin, and 66% were given antibiotics within an hour of hospital
attendance. Microbiological confirmation was achieved in 97 cases, 46 (44%) by
traditional tests and 92 (89%) by PCR assay, including some with both. The blood
culture positive rate was 23 (22%), but in predominant meningitis the rate was
only 10% (5/46). PCR was the sole method of confirmation in 48 cases. Seventy
percent of the plasma samples referred were reactive by PCR assay, but all
samples taken more than 24 h after hospital antibiotics were non-reactive. PCR
based techniques increased the overall number of cases with a serogroup
identified by 44%. Lumbar punctures were performed in 73 of the cases and
microbiological confirmation was achieved in 67 (92%) of these cases, compared to
26/30 without lumbar puncture (LP). Eighty-nine percent of the CSF samples
referred were reactive by PCR; 50% of the CSF samples taken more than 24 h after
hospital antibiotics were reactive, whilst none were positive by culture or
microscopy. CONCLUSION: Due to variable clinical manifestations, early diagnosis
and treatment was difficult. Laboratory confirmation has been improved by the
introduction of PCR-based techniques. Meningococcal DNA was detected by molecular
methods in CSF samples taken up to 72 h after commencement of antibiotics. During
this period patients could be stabilized and the chances of complications
attendant upon early LP reduced. In addition to providing accurate
epidemiological information, confirming the diagnosis may alter the extent and
length of follow-up.
PMID- 10762117
TI - Epidemiological aspects of human papillomavirus infection and cervical cancer in
Brazil.
AB - OBJECTIVES: A study was conducted to determine the prevalence of HPV infection in
cervical lesions of Brazilian women and to search for specific risk factors
associated to progression to malignancy. METHODS: Five hundred and fourteen
paraffin-embedded biopsies obtained from female cervical lesions were classified
according to the Bethesda System in low grade squamous intraepithelial lesion
(LSIL), high grade SIL (HSIL) and squamous cell carcinoma (SCC). Specimens were
tested for the presence of human papillomavirus (HPV) types 6/11,16/18 and
31/33/35 DNA using non-isotopic in situ hybridization. RESULTS: HPV prevalence
ranged from 85.6% in LSIL to 55.2% in SCC. Patients were analysed through an 8
year period: 27. 1% of the lesions spontaneously regressed while 43.6% persisted
and 29.3% progressed to carcinoma. High risk types were present in 80.5% (Crude
OR 13.8, P=0.0003) of the progressive lesions. Possible co-factors have also been
evaluated: history of other sexually transmitted diseases, mainly syphilis,
showed to be positively related to progression (Adjusted OR 13.0, P=0.0003) while
oral contraceptive use and tobacco smoking were not significantly related to it
(P>O.1). Association of two or more co-factors also proved to be related to
progression. CONCLUSIONS: Oncogenic HPV types 16 and 18 and history of other
concurrent sexually transmitted diseases were found to be significantly
associated with progression to cancer. Smoking and the use of oral contraceptives
did not show a relation to cancer establishment, but when they were associated a
significant co-operative role in progression was demonstrated. Our study
indicated that HPV and other risk factors for cancer can act together,
corroborating the observation of a poor prognosis for Brazilian women presenting
SILs.
PMID- 10762118
TI - Case report of three Candida albicans infections detected at delivery.
AB - We report three similar cases of Candida albicans infections in neonates, at
delivery. A retrospective study of the isolates was conducted to define the
diversity of infective strains and their susceptibility to amphotericin B and
fluconazole. Three neonates with fever, 'not doing well' at delivery had positive
cultures for C. albicans. Samples were then taken from the mothers who did not
exhibit any clinical symptoms of infection. Candida albicans strains isolated
from both neonates and mothers were cultured, six colonies of each were typed by
multilocus enzyme electrophoresis. The E-test method was used to determine the
susceptibility of each colony to the two antifungals commonly used in this unit:
amphotericin B and fluconazole. The initial isolates were composed of different
types of strains. In the three cases, one of the mother types was found in the
neonate isolates, leading us to suggest a vertical transmission of strains. All
of the other types were distinct. All of the types were susceptible to
amphotericin B, although three of them, one type isolated from a neonate and two
types isolated from the mother, were resistant to fluconazole. The diversity of
infective strains remains alarming and encourages the consideration of several
colonies per isolate or several isolates, when it is possible, per infection
case. This study also points out the need to survey the susceptibility of
infective strains, since some of them appear soon to be resistant to fluconazole.
PMID- 10762119
TI - Successful treatment of Castleman's disease with HAART in two HIV-infected
patients.
AB - Castleman's disease is a heterogeneous group of lymphoproliferative disorders of
unknown aetiology. Recently, human herpesvirus type 8 (HHV-8) has been associated
with various diseases in individuals with HIV infection, including Kaposi's
sarcoma, B cell non Hodgkin's lymphomas, and Castleman's disease. In Castleman's
disease it has been hypothesized that HHV-8, encoding a number of various
virokines, can be responsible for clinical manifestations of the
disease.Previously, two reports have described a clinical recovery from HIV
associated Castleman's disease: by administration of a monoclonal antibody
neutralizing human IL-6 in one case, and in another case by treatment with highly
antiretroviral therapy and anti-herpesvirus therapy, following splenectomy. We
report two cases where HAART alone led to clinical recovery from Castleman's
disease. In both the cases reported here, although follow-up biopsy was not
performed, it is likely that the inhibition of HHV-8 replication and of virokine
release, through the restoration of immunity by HAART, was the basis for the
disappearance of the clinical symptoms.
PMID- 10762120
TI - Successful treatment of Candida glabrata endophthalmitis with amphotericin B
lipid complex (ABLC).
AB - We report a case of Candida (Torulopsis) glabrata endophthalmitis which occurred
2 months following urological surgery. The patient was treated successfully with
intravenous amphotericin B lipid complex (ABLC) and flucytosine. Diagnosis and
management of this condition are discussed.
PMID- 10762121
TI - Long-term remission of human immunodeficiency virus-associated visceral
leishmaniasis after initiation of potent combination antiretroviral treatment:
report of two cases.
AB - We describe two cases of human immunodeficiency virus-infected patients with
visceral leishmaniasis in whom no clinical and parasitological disease relapses
were observed after liposomal amphotericin B therapy combined with potent
antiretroviral treatment.
PMID- 10762122
TI - Pasteurella multocida infection following cat bites in humans.
PMID- 10762123
TI - Bone and prosthetic joint infection with Staphylococcus lugdunensis.
PMID- 10762124
TI - Epidemiology of infective endocarditis.
PMID- 10762125
TI - Fatal course of HIV-associated progressive multifocal leukoencephalopathy despite
successful highly active antiretroviral therapy.
PMID- 10762126
TI - Haemorrhagic cystitis and renal dysfunction associated with high dose
benzylpenicillin.
PMID- 10762127
TI - The spectrum of levodopa-induced dyskinesias.
AB - The most common types of levodopa-induced dyskinesias in patients with
Parkinson's disease (PD) are chorea and dystonia, and often the two types are
intermixed. Myoclonus is a far less common problem. The dyskinesias tend to
develop over time, not usually being encountered at the initiation of levodopa
therapy. Eventually, they affect more than 50% of patients on long-term levodopa
treatment. Once they appear, they are difficult to eliminate. Substituting weaker
dopaminergic agents for levodopa often fails to eliminate the dyskinesias. Most
of the dyskinesias occur at the time of the highest brain concentration of
levodopa and its product, dopamine--so-called peak-dose dyskinesias. Chorea and
dystonia, usually in the legs, occur less commonly at the beginning and end of
dosing, and these are called diphasic dyskinesias. Dystonia can also occur during
the 'off' state, i.e. when the levodopa concentration is low. These 'off'
dystonias are often painful and must be distinguished from peak-dose dystonia and
from dystonia that may be a feature of PD itself.
PMID- 10762128
TI - Dopamine receptors and locomotor responses: molecular aspects.
AB - The responses obtained with drugs acting as dopamine receptors depend on the
spectrum of receptors activated and the neuronal signal transduction pathways
that are activated. Drugs that reliably discriminate among the various cloned
dopamine receptors are not yet available. Therefore, elucidating the role of
these receptors has largely relied on molecular genetic approaches, including
heterologous receptor expression in cell lines and manipulation of receptor
expression in animal models. The current understanding of the molecular, cellular
and systemic consequences of dopaminergic activation of the different cloned
dopamine receptors is reviewed.
PMID- 10762129
TI - Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems
with the current model.
AB - The anatomical and physiological basis of levodopa-induced dyskinesias (LIDs) in
patients with Parkinson's disease (PD) is reviewed in the light of the current
model for the organization of the basal ganglia. This model, which was developed
in the late 1980s, works relatively well in explaining the motor features of PD
but, for example, it does not account for why tremor, rigidity, bradykinesia,
gait dysfunction and postural instability present to differing degrees in
different patients, and may respond differently to levodopa treatment or surgical
procedures. Recent information suggests that LIDs develop as a consequence of
pulsatile stimulation of dopamine receptors, with consequent dysregulation of
genes and proteins in downstream neurons resulting in changes in neuronal firing
patterns. A modified model of the basal ganglia in PD patients with LID is
proposed, which incorporates more recent clinical and experimental data.
PMID- 10762130
TI - Physiologic basis of dyskinesia.
AB - The current functional model of the basal ganglia suggests that dyskinesia
results from abnormally low activity at the output of the system. This view
appears incomplete. The recent literature suggests other factors. Thus,
dyskinesia may result from disturbance of surround inhibition: a physiologic
mechanism to select neuronal responses. A major criterion for selection in the
basal ganglia is prediction of reward, materialized by release of dopamine.
However, much of this release is independent of impulse flow, and controlled
presynaptically, at a myriad of terminals, whose presence is then essential.
Thus, levodopa in parkinsonism is likely to exaggerate imbalance between regions
of the basal ganglia more or less deprived of dopaminergic terminals. The cortex
and thalamus may be viewed as equally important afferents to the basal ganglia.
Each of them appears to influence preponderantly its own half of striatal
projection neurons. Those of the indirect pathway would be part of a mainly
transcortical loop, specialized for the precise weighing, and selection of
cortical information. Those of the direct pathway would be part of a
predominantly subcortical loop, more likely concerned by changes in alertness and
attention. Dyskinesia could thus result from imbalance between cortical and
thalamic functions, between selection and attention.
PMID- 10762131
TI - Dopamine-mediated gene regulation in models of Parkinson's disease.
AB - The normal functioning of the basal ganglia is dependent on dopamine maintaining
a balance between the two major output pathways of the striatum, through the D1
and D2 dopamine receptors, which have opposing effects on these pathways. Lesions
of the dopamine system, such as occur in Parkinson's disease (PD), disrupt this
balance. Gene regulation studies provide a measure of the cellular and molecular
effects of dopamine on striatal neurons in animal models of PD. Dopamine
agonists, involving selective or mixed D1 and D2 agonists, such as levodopa, are
able to reverse many of the homeostatic changes induced by striatal dopamine
depletion. However, following dopamine depletion, a supersensitive responsiveness
of D1 striatal neurons to dopamine agonists develops, indicated by the induction
of immediate early genes. The molecular and cellular mechanisms underlying the
irreversibility of this supersensitive response with long-term dopamine agonist
treatments may provide insights into dyskinesias that develop with long-term
levodopa therapy in the treatment of PD.
PMID- 10762132
TI - Patterns of gene expression and behavior induced by chronic dopamine treatments.
AB - Chronic administration of drugs that increase dopaminergic neurotransmission
produces long-lasting changes in gene regulation and behavior. Evidence suggests
that several conditions in which the serial ordering and coordination of motor
actions are disrupted following dopaminergic treatment share common underlying
neurobiological mechanisms. The induction of high-intensity motor stereotypies by
dopamine D1- and D2-class receptor agonists, the sensitized behavioral
responsiveness to psychostimulant drugs in normal animals, and the progressive
sensitization of dyskinesias after intermittent treatment with dopamine agonists
following dopamine depletion are all correlated with persistent changes in gene
induction in the striatum. These changes, as measured by the induction of
immediate-early genes, consist of a relative enhancement in the autoregulatory
activity of the striosomal pathway and the disinhibitory activity of the direct
output pathway. We hypothesize that long-term modifications in the activity of
these pathways result in persistent adaptations in striatum-centered motor loops
linking the basal ganglia and cortex, as well as long-lasting disruption of the
timing and segmentation of motor behavior.
PMID- 10762133
TI - Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?
AB - The pathogenesis of the alterations in motor response that complicate levodopa
therapy of Parkinson's disease remains obscure. Several experimental and clinical
observations strongly suggest that changes in striatal activity may be crucial
for this physiopathological condition. Accordingly, it has been postulated that
dyskinesia might be due to abnormal activity of the corticostriatal pathway.
Here, we review the physiological and pharmacological mechanisms underlying
glutamatergic regulation of striatal neurons by the corticostriatal projection.
In particular, we discuss the role of both (RS)-alpha-amino-3-hydroxy-5-methyl-4
isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate
receptors in the control of the short- and long-term efficacy of corticostriatal
transmission. Indeed, repetitive cortical activation can generate either long
term depression or long-term potentiation (LTP) at corticostriatal synapses
depending on the subtype of glutamate receptor activated during the induction
phase of these forms of synaptic plasticity. Dopamine plays an important function
in the regulation of both forms of synaptic plasticity. Dopamine denervation
abolishes the physiological corticostriatal plasticity by producing biochemical
and morphological changes within the striatum. We have recently observed a
'pathological' form of LTP at the corticostriatal synapse during energy
deprivation. We speculate that this 'pathological' LTP, depending on the
activation of NMDA glutamate receptors located on spiny striatal neurons, might
play a role in the generation of levodopa-induced dyskinesia.
PMID- 10762134
TI - Molecular basis of levodopa-induced dyskinesias.
AB - A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding
the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this
model by de novo treatment with levodopa, or selective D1 or D2 agonists,
provided the drugs are short acting and administered in the pulsatile mode.
Biochemical analysis of the brains revealed several alterations in dopamine
receptor-binding and messenger RNA message following denervation and dopaminergic
treatment, but none that clearly correlated with the presence of dyskinesias. On
the other hand, gamma-aminobutyric acid (GABA)A binding was increased in the
internal segment of the globus pallidus of dyskinetic MPTP monkeys. This was
observed consistently and could be associated with an exaggerated response to
GABAergic inhibitory inputs in this strategic structure. Increased
preproenkephalin message was also found to correlate with dyskinesias and may be
linked to changes in GABA receptors. Treatments that caused dyskinesias induced,
in the striatum, chronic Fos proteins of the deltaFosB family which, when coupled
with Jun-D, form AP-1 complexes that can affect several genes, including
enkephalin and N-methyl-D-aspartate receptor. We suggest that levodopa-induced
dyskinesias represent a form of pathological learning, which results from
deficient gating of glutamatergic inputs to the striatum by dopamine.
PMID- 10762135
TI - Investigating levodopa-induced dyskinesias in the parkinsonian primate.
AB - Research into the cause of dyskinesias arising from levodopa treatment has been
vexingly limited, partly due to the lack of an inexpensive and widely available
animal model. Rodents do not develop levodopa-induced dyskinesias in a clinically
recognizable form. However, nonhuman primates with 1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine (MPTP)-induced parkinsonism readily develop levodopa-induced
dyskinesias that are virtually indistinguishable from those seen in patients with
Parkinson's disease. We have developed and validated a five-point Global Primate
Dyskinesia Rating Scale to accurately measure these dyskinesias. Monkeys with
MPTP-induced parkinsonism were then investigated to evaluate the relationship
between dyskinesias, parkinsonism and severity of the nigrostriatal lesion. All
parkinsonian animals were responsive to levodopa, and developed dyskinesias
within 2-3 days of levodopa administration. Monkeys treated with only a single
injection of MPTP also developed dyskinesias, even though they were not
parkinsonian. It would appear that there is a different threshold of striatal
dopamine depletion for parkinsonism and dyskinesias in the monkey. Finally, three
hypotheses, put forward to explain the genesis of dyskinesias, are reviewed, and
various experimental approaches suggested for each.
PMID- 10762136
TI - Factors influencing the onset and persistence of dyskinesia in MPTP-treated
primates.
AB - The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate model of
Parkinson's disease provides a unique opportunity to study factors influencing
the onset and persistence of dyskinesia induced by levodopa or dopamine agonist
treatment. Contrary to popular belief, denervation is not essential for the
induction of dyskinesia, and both D1 and D2 dopamine agonist drugs are able to
initiate dyskinetic movements. However, their ability to do so is currently
attributed to their pharmacokinetic and pharmacodynamic properties rather than to
their receptor selectivity, although this view is challenged in this article.
Short-acting pulsatile dopamine agonists are more likely to induce dyskinesia
than drugs that have a long duration of effect and produce continuous receptor
stimulation. The induction of dyskinesia does not seem to be associated with any
obvious change in the number or sensitivity of post-synaptic dopamine receptors,
but rather to downstream events associated with the indirect and direct output
pathways. Currently, there is evidence for the involvement of both pathways in
the genesis of dyskinesia and so there is no clear explanation for the onset of
involuntary movements or for the priming process that initiates dyskinesia.
However, a variety of therapeutic strategies primarily related to the use of non
dopaminergic agents may be able to prevent dyskinesia from occurring, and the
actions of neurotropic factors, such as glial-derived neurotropic factor, may be
effective in reversing established involuntary movements.
PMID- 10762137
TI - The neural mechanisms underlying levodopa-induced dyskinesia in Parkinson's
disease.
AB - Treatment-related dyskinesias are the major limitation of dopamine replacement
therapies such as levodopa in Parkinson's disease (PD). Recent studies in
parkinsonian, nonhuman primates have highlighted abnormalities in neural
functioning that might underlie the generation of dyskinetic symptoms in patients
with PD who have received prolonged dopaminergic therapy. This article reviews
studies on metabolic activity in subregions of the basal ganglia which suggest
that profound abnormalities in basal ganglia output may underlie levodopa-induced
dyskinesia. Such abnormalities may result from changes within basal ganglia
circuitry and may include either overt changes in average firing rate or
modulation of the pattern of cell-cell communication within subregions of the
basal ganglia circuitry. An appreciation of abnormalities in the mechanisms
responsible for modulating synaptic transmission in the basal ganglia may suggest
novel therapeutic approaches to the problem of dyskinesia.
PMID- 10762138
TI - Nigrostriatal system plasticity in Parkinson's disease: effect of dopaminergic
denervation and treatment.
AB - Clinical studies suggest that the appearance of levodopa-induced dyskinesias may
be partly related to changes in the dopaminergic system. This article reviews
data on biochemical and morphological changes induced by treatment, the lesion,
or both, in dopaminergic neurons themselves, postsynaptic striatal tissue, and
afferent fibers to dopaminergic neurons in the substantia nigra. Recent studies
on dopaminergic neurons suggest that levodopa therapy can induce sprouting of
surviving dopaminergic neurons at their terminals in the striatum. At the
postsynaptic level, treatment may trigger induction of D3 dopamine receptors and
internalization of D1 receptors. Furthermore, dopaminergic denervation has been
shown to be involved in plastic changes in the striatum associated with
hyperactivity of glutamatergic fibers making synapses with the head of the spines
of gamma-aminobutyric acidergic neurons. At the level of the dendrites of
dopaminergic neurons, plasticity of excitatory cholinergic afferent fibers
targeting dopaminergic neurons and an involution of noncholinergic afferent
fibers have been observed. Taken together, these data suggest that dopaminergic
denervation and treatment induce profound plastic changes in the nigrostriatal
system. Whether such changes participate in side-effects of treatment and, in
particular, the appearance of dyskinesias remains to be determined.
PMID- 10762139
TI - Striatal mechanisms and pathogenesis of parkinsonian signs and motor
complications.
AB - Recent studies suggest that motor dysfunction associated with the chronic
nonphysiologic stimulation of dopaminergic receptors on striatal spiny neurons
alters the sensitivity of nearby glutamatergic receptors, especially those of the
N-methyl-D-aspartate (NMDA) subtype. Lesioning the nigrostriatal dopamine system
of rats or nonhuman primates induces parkinsonian signs; subsequent once- or
twice-daily treatment with levodopa produces many of the features of the human
motor complication syndrome. Some drugs that block NMDA receptors palliate
parkinsonian signs in these animal models, as well as in patients with
Parkinson's disease. Certain NMDA receptor antagonists injected into the striatum
or given systemically also have the ability to act palliatively or
prophylactically to alleviate levodopa-induced response alterations. These
observations support the view that sensitization of striatal NMDA receptors
contributes to the pathogenesis of motor dysfunction in Parkinson's disease.
Since protein phosphorylation serves as an important regulatory mechanism for
NMDA receptors, differential increases in the phosphorylation state of tyrosine
and serine residues, observed as a result of nigrostriatal system destruction as
well as response alteration induction, could account for the apparent
augmentation in synaptic efficacy. Current evidence thus suggests that the
intermittent stimulation of dopaminergic receptors activates signal transduction
pathways in striatal neurons, which augment phosphorylation of NMDA receptors and
thus their sensitivity to cortical glutamatergic input. As a result, striatal
output changes in ways that favor the appearance of parkinsonian signs and motor
complications.
PMID- 10762140
TI - Physiology of hypokinetic and hyperkinetic movement disorders: model for
dyskinesia.
AB - Although the basal ganglia have been implicated in the development of movement
disorders since the 1940s, the exact role played by these structures has remained
elusive. The development of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
monkey model of parkinsonism, and the recent resurgence of surgical therapy for
the treatment of hypokinetic and hyperkinetic movement disorders has, however,
led to an improved understanding of the pathophysiological mechanisms that
underlie their development. In this article, we review the functional
organization and examine the changes in neuronal activity that occur in the basal
ganglia thalamocortical 'motor' circuit in these disorders. An alternative to the
classic 'rate' model for Parkinson's disease is presented that incorporates the
observed changes in neuronal activity, as well as additional neuronal pathways
that contribute to these changes. Based on studies in animal models and humans
with hyperkinetic movement disorders, it is postulated that dyskinesias develop
as the result of a combination of excessive reductions in the mean discharge
rate, altered patterns and increased synchronization of neurons in the internal
segment of the globus pallidus. It is further postulated that the particular type
of involuntary movement which develops also depends on the relative change in
neuronal activity in the direct, indirect and alternative pathways. Support for
these postulates is examined, and models for drug-induced dyskinesia,
hemiballismus and dystonia are proposed.
PMID- 10762141
TI - Neuronal recordings in Parkinson's disease patients with dyskinesias induced by
apomorphine.
AB - Dopaminergic agents reverse parkinsonism but commonly induce dyskinesia in
patients with Parkinson's disease (PD) on long-term levodopa therapy. The aim of
this study was to determine the neurophysiologic correlates of the amelioration
of parkinsonism and the involuntary movements produced by the dopamine agonist
apomorphine. Seventeen PD patients were given apomorphine (2-6 mg) before
surgery. Neural activity was recorded for individual neurons and for populations
of neurons before and after apomorphine. Both internal (GPi) and external (GPe)
segments of the globus pallidus were sampled in patients undergoing pallidal
surgery. The subthalamic nucleus (STN) was sampled in STN surgery patients.
Results suggest that dopaminergic agents act by decreasing GPi and STN activity,
and increasing GPe activity, and that drug-induced dyskinesias results from a
large reduction in GPi firing.
PMID- 10762142
TI - Clinical physiology of dopa dyskinesia.
AB - Levodopa-induced dyskinesias are clinically heterogeneous, both in appearance and
timing with respect to dose. Electromyogram observations indicate that levodopa
induced dyskinesias are comprised of irregular bursts of either synchronous or
asynchronous neuronal firing in antagonist muscles. Studies of the blink reflex
and spontaneous blinking have provided useful neurophysiologic information on
brainstem function that is sensitive to changes in brain dopamine concentrations.
The blink rate is reduced in Parkinson's disease (PD) and increased with dopamine
treatment. The blink rate in patients with levodopa-induced dyskinesias, however,
has been shown to be faster than that in optimally treated PD patients and normal
individuals. These results suggest that dyskinesias are associated with a
relative hyperdopaminergic state. However, there appears to be no correlation of
dopaminergic benefit to the parkinsonian symptoms, indicating perhaps that there
are several dopaminergic systems, including one responsible for motor function
and one for dyskinesia. Alternatively, it may be that the pattern of neural
firing influences dyskinesias, while the average firing rate may be responsible
for motor benefits.
PMID- 10762143
TI - Neuroimaging of dyskinesia.
AB - Dyskinesias are observed in the majority of Parkinson's disease (PD) patients who
have been chronically exposed to levodopa, and these may result from
supersensitivity of postsynaptic striatal dopamine D1 and D2 receptors following
loss of nigral dopaminergic projections. Dyskinetic and nondyskinetic PD patients
were studied using 11C-SCH23390 and 11C-raclopride positron emission tomography
(PET). No difference in mean putamen or caudate D1 or D2 receptor binding between
the two patient subgroups was found, suggesting that dyskinesias are unlikely to
arise from a primary disturbance of dopamine receptor availability. When
dyskinetic and nondyskinetic patients were studied with 11C-diprenorphine PET,
the former showed a significant reduction (p < 0.05) in striatal and thalamic
opioid site availability, compatible with the presence of raised levels of
endogenous opioid peptides. H2(15)O PET activation studies of patients with focal
limb dyskinesias showed that resting levels of regional cerebral blood flow after
oral levodopa were increased during dyskinesias in lentiform nuclei, motor,
premotor and dorsal prefrontal cortex. These results suggest that dyskinesias are
associated with derangement of basal ganglia opioid transmission, resulting in
overactivity of basal ganglia-frontal projections.
PMID- 10762144
TI - Clinical pharmacology of levodopa-induced dyskinesia.
AB - Levodopa-induced dyskinesia (LID) is a major impediment to the successful therapy
of Parkinson's disease. The development of LID is facilitated by dopaminergic
denervation but may not require denervation. Repeated levodopa dosing is
necessary to induce dyskinesia, implying the development of sensitization to
levodopa. There is inconclusive evidence on whether repeated dosing lowers the
threshold (shifts the levodopa-dyskinesia response curve to the left), increases
the severity of dyskinesia (increases the maximum effect that is initially zero)
or induces more complex changes in the dose-response curve. Once a patient
develops LID, the severity of LID is not dose responsive, but the duration of
dyskinesia is. Clinically, it is very difficult to separate the antiparkinsonian
and dyskinetic effects of levodopa. Whether this separation is possible with more
selective agonists with antiparkinsonian effects that are equipotent to levodopa
is unknown. The fact that selective stimulation of the pallidum does not separate
antiparkinsonian and dyskinetic actions implies that they are closely related
anatomically and physiologically.
PMID- 10762145
TI - Preventing levodopa-induced dyskinesias.
AB - The precise cause of levodopa-induced dyskinesias is unknown. Current evidence
indicates that dyskinesias develop in response to pulsatile stimulation of
striatal dopamine receptors. The half-life of the dopaminergic agent employed and
disease severity are thought to affect the occurrence of pulsatile stimulation.
Dyskinesias are not seen or are attenuated with continuous delivery of levodopa
or short-acting agonists, or with the use of long-acting agonists. In advanced
disease, there are fewer striatal dopamine terminals and reduced buffering
capacity; fluctuations in plasma levodopa concentration are more likely to cause
fluctuations in striatal dopamine concentration and pulsatile stimulation of
dopamine receptors. Pulsatile stimulation is thought to induce postsynaptic gene
and protein changes that result in alterations in the patterns of neuronal
communication, with the emergence of dyskinetic movements. Thus, strategies
preventing pulsatile stimulation may prevent the development of dyskinesias.
These could include the use of dopaminergic agents with a relatively long half
life, neuroprotective therapies that prevent the loss of dopamine neurons, and
transplantation strategies or trophic factors that increase the number of
dopamine terminals capable of buffering fluctuations in striatal dopamine.
Alternatively, approaches that interfere with or compensate for postsynaptic
molecular and neurophysiologic changes that ensue in downstream neurons might
provide antidyskinetic benefits.
PMID- 10762146
TI - Medical treatment of levodopa-induced dyskinesias.
AB - Clinicians can presently choose from three main pharmacological strategies to
medically treat levodopa-induced dyskinesias (LIDs): prevent the occurrence of
the priming phenomenon, which generates dyskinesias; reverse, once primed, the
changes that occurred in the basal ganglia to induce dyskinesias; or avoid the
expression of dyskinesias in an already primed brain. To prevent, at least
partly, priming for dyskinesias can be attempted by delaying the need for
levodopa, and/or reducing the cumulative dose of levodopa, using, for example,
dopamine D2 agonists at the early stages of treatment. The question of
reversibility of dyskinesia priming remains a matter of controversy. Any
improvement gained from a drug holiday can be short lived, and the re
introduction of levodopa can re-prime the patient. Reducing the dose of levodopa
and using other drugs as an adjunct has proved inconsistent. High-frequency deep
brain stimulation of the subthalamic nuclei and mesencephalic embryonic cell
grafts have shown potential in small numbers of patients. To avoid the expression
of dyskinesias in already primed patients, agents that act on either the dopamine
or nondopaminergic receptors have been used. For example, amantadine, given as an
adjuvant to levodopa, has been shown to improve dyskinesias, but larger,
controlled studies are required.
PMID- 10762147
TI - Dyskinesias and the subthalamic nucleus.
AB - Severe dyskinesias or ballism can occur following hemorrhagic events in the
subthalamic nucleus (STN), and it has recently been established that the STN
plays a major role in the pathophysiology of the motor dysfunction of Parkinson's
disease (PD) and that STN inhibition improves parkinsonian dysfunction. Deep
brain stimulation of the STN in PD patients is therefore currently being
evaluated as a therapy. High-frequency stimulation of the STN in PD patients can
induce intense dyskinesias that are similar to those induced by levodopa. These
may occur with a variable latency and resemble all types of levodopa-induced
dyskinesias (LIDs). They can be decreased by reducing the levodopa dosage, which
is permitted by the antiparkinsonian effect of stimulating the STN. STN
stimulation has been shown to improve all types of LIDs, with the most dramatic
effect being that on off-period dystonia. The improvement in LIDs may relate to
the decrease in drug dosage, while the off-period dystonia is likely improved by
the simultaneous administration of levodopa and STN stimulation. It is thought
that the STN is an important node in a network, which can produce dyskinesias
when disturbed by a lesion, and is particularly sensitive for the induction of
these abnormal movements.
PMID- 10762148
TI - Surgery for levodopa-induced dyskinesias.
AB - The effects of surgical interventions for levodopa-induced dyskinesias (LIDs) in
Parkinson's disease are reviewed. Since the introduction of levodopa, thalamotomy
has been reported to have variable effects on LIDs. Striking benefit has been
demonstrated, and efficacy is probably dependent on the size and location of the
lesion. However, it remains unclear whether it is an effective treatment for all
types of LIDs. Currently, pallidotomy is probably the most reliable and effective
surgical treatment for LIDs, and will continue to play an important role in its
management until other treatments become more widely available. Deep brain
stimulation is an extremely exciting mode of therapy, particularly in the
subthalamic nucleus and the globus pallidus, and early results of its use in the
treatment of LIDs are promising. The effects of cerebral transplantation, still
an experimental technique, on LIDs are inconsistent and controversial, and there
is little reliable evidence that gamma knife radiosurgery can be safely applied
to parkinsonian patients for the treatment of LIDs.
PMID- 10762149
TI - "Missing" tau mutation identified.
PMID- 10762150
TI - Mere forgetfulness or early Alzheimer's disease?
PMID- 10762151
TI - Where in the brain does Alzheimer's disease begin?
PMID- 10762152
TI - A novel mutation at position +12 in the intron following exon 10 of the tau gene
in familial frontotemporal dementia (FTD-Kumamoto)
AB - Exonic and intronic mutations in the tau gene cause familial frontotemporal
dementia and parkinsonism linked to chromosome 17. Here, we describe a new
mutation, consisting of a C-to-T transition at position +12 of the intron
following exon 10 of the tau gene in the Kumamoto pedigree, showing
frontotemporal dementia. The mutation caused a marked reduction in melting
temperature of the tau exon 10-splicing regulatory element RNA and a large
increase in exon 10-containing transcripts. Brain tissue from affected
individuals showed an abnormal preponderance of exon 10-containing transcripts
that was reflected at the protein level by an overproduction of tau isoforms with
four microtubule-binding repeats. Immunostaining revealed the presence of tau
aggregates in degenerating neurons and glial cells. Isolated tau filaments had a
twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat
tau isoforms. The additional mutation located dose to the splice-donor site of
the intron following exon 10 of the tau gene supports the view that intronic
mutations exercize their pathogenic effect by destabilizing RNA secondary
structure.
PMID- 10762153
TI - Use of structural magnetic resonance imaging to predict who will get Alzheimer's
disease.
AB - We used magnetic resonance imaging (MRI) measurements to determine whether
persons in the prodromal phase of Alzheimer's disease (AD) could be accurately
identified before they developed clinically diagnosed dementia. Normal subjects
(n = 24) and those with mild memory difficulty (n = 79) received an MRI scan at
baseline and were then followed annually for 3 years to determine which
individuals subsequently met clinical criteria for AD. Patients with mild AD at
baseline were also evaluated (n = 16). Nineteen of the 79 subjects with mild
memory difficulty "converted" to a diagnosis of probable AD after 3 years of
follow-up. Baseline MRI measures of the entorhinal cortex, the banks of the
superior temporal sulcus, and the anterior cingulate were most useful in
discriminating the status of the subjects on follow-up examination. The accuracy
of discrimination was related to the clinical similarity between groups. One
hundred percent (100%) of normal subjects and patients with mild AD could be
discriminated from one another based on these MRI measures. When the normals were
compared with the individuals with memory impairments who ultimately developed AD
(the converters), the accuracy of discrimination was 93%, based on the MRI
measures at baseline (sensitivity = 0.95; specificity = 0.90). The discrimination
of the normal subjects and the individuals with mild memory problems who did not
progress to the point where they met clinical criteria for probable AD over the 3
years of follow-up (the "questionables") was 85% and the discrimination of the
questionables and converters was 75%. The apolipoprotein E genotype did not
improve the accuracy of discrimination. The specific regions selected for each of
these discriminations provides information concerning the hierarchical fashion in
which the pathology of AD may affect the brain during its prodromal phase.
PMID- 10762154
TI - Neural consequences of competing stimuli in both visual hemifields: a
physiological basis for visual extinction.
AB - We used positron emission tomography in healthy volunteers to test hemispheric
rivalry theories for normal and pathological spatial attention, which provide an
influential account of contralesional extinction on bilateral stimulation after
unilateral brain injury. Subjects reported visual characters presented either
unilaterally or bilaterally. An extinction-like pattern was found behaviorally,
with characters in one hemifield reported less accurately when competing
characters appeared in the other hemifield. Differences in neural activity for
unilateral minus bilateral conditions revealed greater activation of striate and
extrastriate areas for stimuli presented without competing stimuli in the other
hemifield. Thus, simultaneous bilateral stimulation led to a significant
reduction in response by spatiotopic visual cortex contralateral to a particular
stimulus. These data provide physiological support for interhemispheric rivalry
in the intact human brain, and demonstrate that such competition impacts at early
levels of perceptual processing.
PMID- 10762155
TI - Partial deficiency of manganese superoxide dismutase exacerbates a transgenic
mouse model of amyotrophic lateral sclerosis.
AB - The pathogenesis of neuronal cell death as a consequence of mutations in
copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic
lateral sclerosis may involve oxidative damage and mitochondrial dysfunction. We
examined whether crossing transgenic mice with the G93A SOD1 mutation with
transgenic mice with a partial depletion of manganese superoxide dismutase (SOD2)
would affect the disease phenotype. Compared with G93A mice alone, the mice with
partial deficiency of SOD2 and the G93A SOD1 mutation showed a significant
decrease in survival and an exacerbation of motor deficits detected by rotorod
testing. There was a significant exacerbation of loss of motor neurons and
substantia nigra dopaminergic neurons in the G93A mice with a partial deficiency
of SOD2 compared with G93A mice at 110 days. Microvesiculation of large motor
neurons was more prominent in the G93A mice with a partial deficiency of SOD2
compared with G93A mice at 90 days. These findings provide further evidence that
both oxidative damage and mitochondrial dysfunction may play a role in the
pathogenesis of motor neuron death associated with mutations in SOD1.
PMID- 10762156
TI - Movement-related electroencephalographic desynchronization in patients with hand
cramps: evidence for motor cortical involvement in focal dystonia.
AB - We studied the dynamic changes in the amplitude of scalp electroencephalographic
(EEG) oscillations to self-paced simple index finger abduction movements in
patients with writer's cramp and compared them with those of normal aged-matched
controls. The changes in EEG oscillations were measured in predefined frequency
bands (8-10, 10-12, 12-20, and 20-30 Hz) by using the event-related
desynchronization technique. Movements of the affected and unaffected hand in
patients with writer's cramp showed significantly less reduction in 20- to 30-Hz
power compared with controls. The differences in movement-related EEG power
decline were apparent over the contralateral central and midline regions before
and after electromyographic onset. Because EEG beta rhythm in the sensorimotor
region likely emanates from the motor cortex and is related to ongoing muscle
activity, this abnormality could be a manifestation of the abnormal motor command
at the cortical level.
PMID- 10762157
TI - Thrombolytic reversal of acute human cerebral ischemic injury shown by
diffusion/perfusion magnetic resonance imaging.
AB - Diffusion magnetic resonance imaging provides an early marker of acute cerebral
ischemic injury. Thrombolytic reversal of diffusion abnormalities has not
previously been demonstrated in humans. Serial diffusion and perfusion imaging
studies were acquired in patients experiencing acute hemispheric cerebral
ischemia treated with intra-arterial thrombolytic therapy within 6 hours of
symptom onset. Seven patients met inclusion criteria of prethrombolysis and
postthrombolysis magnetic resonance studies, presence of large artery anterior
circulation occlusion at angiography, and achievement of vessel recanalization.
Mean diffusion-weighted imaging lesion volume at baseline was 23 cm3 (95%
confidence interval [95% CI], 8-38 cm3) and decreased to 10 cm3 (95% CI, 3-17
cm3) 2.5 to 9.5 hours after thrombolysis. Mean apparent diffusion coefficient
lesion volume decreased from 9 cm3 (95% CI, 2-16 cm3) at baseline to 1 cm3 (95%
CI, 0.4-2 cm3) early after thrombolysis. A secondary increase in diffusion
volumes was seen in 3 of 6 patients at day 7. In all 4 patients in whom perfusion
imaging was obtained before and after treatment, complete resolution of the
perfusion deficit was shown. Diffusion magnetic resonance signatures of early
tissue ischemic injury can be reversed in humans by prompt thrombolytic vessel
recanalization. The ischemic penumbra includes not only the region of
diffusion/perfusion mismatch, but also portions of the region of initial
diffusion abnormality.
PMID- 10762158
TI - Verbal fluency activates the left medial temporal lobe: a functional magnetic
resonance imaging study.
AB - Verbal fluency tests (VFTs) are suggested to assess frontal lobe function. This
view is supported by functional imaging studies that report left frontal
activation during VFTs. VFTs require retrieval of semantically associated words
from long-term memory storage. The neural networks that participate in this
process, however, are largely unknown. These neural networks are of interest,
given that patients with early Alzheimer's disease, typically without frontal
pathology, are often impaired in VFTs. In the present study, functional magnetic
resonance imaging was performed to determine brain activation areas during VFTs
in young subjects. In the activation task, category fluency was contrasted with
orderly listing of numbers. As judged from using this comparison, there was
activation in the left medial temporal lobe, in the inferior frontal and
retrosplenial cortices bilaterally, and in the left superior parietal lobule.
Left medial temporal lobe activation was present in 13 of the 14 study subjects
either in the hippocampal formation (11 of 14) or in the posterior
parahippocampal gyrus (12 of 14). These results suggest that the medial temporal
lobe is required for the process of retrieval by category. Functional magnetic
resonance imaging combined with a category fluency task may provide a new method
to study patients with early Alzheimer's disease.
PMID- 10762159
TI - Thalamic involvement in neurofibromatosis type 1: evaluation with proton magnetic
resonance spectroscopic imaging.
AB - Neurofibromatosis type 1 is a common autosomal dominant disorder associated with
learning disabilities. In addition to gliomas and other tumors, T2 hyperintense
lesions (unidentified bright objects or UBOs) are frequently found in the globus
pallidus, cerebellum, and white matter regions. To better characterize
supratentorial UBO functional significance, we studied by quantitative magnetic
resonance spectroscopic imaging (MRSI) 9 male subjects with neurofibromatosis
type 1 (age, 6-19 years) and 9 age-matched and sex-matched controls. Maps of the
anatomical distribution of the metabolites choline (Cho), N-acetylaspartate
(NAA), and creatine were calculated in four axial 15-mm slices. Absolute
metabolite concentrations within UBOs, unaffected globus pallidus, and thalami
demonstrated an age-related pattern, characterized by elevated Cho and relatively
preserved NAA in younger subjects (<10 years) and reduced NAA and normal Cho in
older subjects. These changes were found in both UBOs and thalami but were only
significant for NAA, NAA/creatine, and NAA/Cho in the latter region. Decreases in
NAA ratios were most severe in the thalami of subjects with UBOs in the globus
pallidus, whereas UBOs showed similar but milder abnormalities than those in the
thalamus. We speculate that the MRSI metabolic abnormality may represent a more
generalized phenomenon, without a T2 signal counterpart in the affected brain
regions. Based on the neuropathological study by DiPaolo and colleagues (1995),
we postulate that Cho elevations reflect increased myelin turnover in areas of
intramyelinic edema, which is followed by neuropil injury (reduced NAA). Temporal
progression and behavioral correlates of these MRSI changes deserve further
exploration.
PMID- 10762160
TI - Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy
metabolism, blood flow, and steady potential.
AB - The effect of focal ischemia on tissue pH was studied at various times up to 6
hours after permanent middle cerebral artery occlusion in rats. Tissue pH was
imaged by using umbelliferone fluorescence and correlated with cerebral blood
flow, ATP content, and recordings of the steady potential. Circumscribed foci of
allalosis (pH 7.32+/-0.11) were detected with increasing frequency in penumbral
regions having near-to-normal ATP concentrations and cerebral blood flow values
between 20% and 40% of control. Both the infarct core, defined by ATP loss and
cerebral blood flow values of less than 20% of control, and the inner peri
infarct rim were consistently acidic (pH 6.03+/-0.36 and 6.53+/-0.24,
respectively). Treatment with the glutamate antagonist dizocilpine (MK-801)
suppressed negative shifts of the steady potential and reduced significantly the
occurrence of alkalosis observed in 90% of untreated but only in 44% of treated
animals. Penumbral alkalosis appeared to be a time-dependent event occurring 30
to 60 minutes after the passage of peri-infarct depolarizations. The diversity of
penumbral pH changes reflects the local disturbance of pH regulation and,
possibly, the differential fate of penumbral subareas.
PMID- 10762161
TI - In vivo positron emission tomographic evidence for compensatory changes in
presynaptic dopaminergic nerve terminals in Parkinson's disease.
AB - Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA)
neuronal loss reaches a symptomatic threshold. To explore the mechanisms of
functional compensation that occur in presynaptic DA nerve terminals in PD, we
compared striatal positron emission tomographic (PET) measurements by using
[11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine
transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA
transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three
consecutive PET scans were performed in three-dimensional mode by using each
tracer on 35 patients and 16 age-matched, normal controls. PET measurements by
the three tracers were compared between subgroups of earlier and later stages of
PD, between drug-naive and drug-treated subgroups of PD, and between subregions
of the parkinsonian striatum. The quantitative relationships of [18F]dopa and
[11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD
and the normal control subjects. We found that [18F]dopa Ki was reduced less than
the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum,
whereas the [11C]methylphenidate binding potential was reduced more than
[11C]DTBZ binding potential. These observations suggest that the activity of
aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane
DA transporter is down-regulated in the striatum of patients with PD.
PMID- 10762162
TI - IgG from "seronegative" myasthenia gravis patients binds to a muscle cell line,
TE671, but not to human acetylcholine receptor.
AB - Antibodies to acetylcholine receptor (AChR) are found in 85% of patients with
myasthenia gravis (seropositive MG [SPMG]) and are thought to be pathogenic; but
in 15% of MG patients, the standard immunoprecipitation test for anti-AChR is
negative (seronegative MG [SNMG]). Here, we used a novel approach, fluorescence
activated cell sorting analysis, to measure binding of SPMG and SNMG IgG
antibodies to rhabdomyosarcoma cell lines that express human adult (TE671
epsilon) or fetal (TE671-gamma) AChR, and to human embryonic kidney (HEK)
fibroblasts that express adult human AChR (HEK-AChR). We found that whereas most
SPMG antibodies bind to all three cell lines, IgG from 8 of 15 SNMG sera/plasmas
bind to the surface of both TE671 cell lines but not to HEK-AChR cells. These
results indicate that SNMG antibodies bind to a muscle surface antigen that is
not the AChR, which strongly supports previous studies that suggest that SNMG
should be considered a distinct subtype of MG.
PMID- 10762163
TI - Reversible brain creatine deficiency in two sisters with normal blood creatine
level.
AB - We describe a new creatine metabolism disorder in 2 young sisters who suffered
from mental retardation and severe language delay. Blood examination,
investigation of the most common neurometabolic disorders, and brain magnetic
resonance imaging were normal. Diagnosis was established only by means of in vivo
proton magnetic resonance spectroscopy, which disclosed generalized depletion of
creatine in the brain. Creatine monohydrate oral administration led to almost
complete brain creatine level restoration along with improvement of the patients'
disabilities.
PMID- 10762164
TI - Sonic hedgehog signal peptide mutation in a patient with holoprosencephaly.
AB - We investigated the molecular basis of holoprosencephaly in a sporadic patient
and identified a novel missense mutation in the signal sequence of the sonic
hedgehog (Shh) gene. Magnetic resonance imaging of the head showed a lobar type
of holoprosencephaly and partial agenesis of the anterior corpus callosum. He was
treated for craniosynostosis at 7 months of age. All three exons of the Shh gene
were amplified by polymerase chain reaction from genomic DNA of the patient and
controls. Sequencing analysis of the polymerase chain reaction fragments,
screened by single-strand conformation polymorphism analysis, revealed a
heterozygous mutation of a T-to-C substitution at nucleotide position 50. This
mutation predicted an amino acid replacement of leucine to proline at codon 17
located in the signal peptide of SHH protein. It probably disturbs the
translocation of the protein into the endoplasmic reticulum and may lead to
holoprosencephaly because of haploinsufficiency of Shh.
PMID- 10762165
TI - Dopa-responsive dystonia due to a large deletion in the GTP cyclohydrolase I
gene.
AB - Although it is assumed that most patients with autosomal dominant dopa-responsive
dystonia (DRD) have a GTP cyclohydrolase I dysfunction, conventional genomic DNA
sequencing of the gene (GCH1) coding for this enzyme fails to reveal any
mutations in about 40% of DRD patients, which makes molecular genetic diagnosis
difficult. We found a large heterozygous GCH1 deletion, which cannot be detected
by the usual genomic DNA sequence analysis, in a three-generation DRD family and
conclude that a large genomic deletion in GCH1 may account for some "mutation
negative" patients with dominantly inherited DRD.
PMID- 10762166
TI - Synphilin-1 is present in Lewy bodies in Parkinson's disease.
AB - Alpha-synuclein is believed to play an important role in Parkinson's disease
(PD). Mutations in the alpha-synuclein gene are responsible for familial forms of
PD and alpha-synuclein protein is a major component of Lewy bodies in patients
with sporadic PD. Synphilin-1 is a novel protein that we have previously found to
associate in vivo with alpha-synuclein. We now show that synphilin-1 is present
in Lewy bodies of patients with PD. Our data suggest that synphilin-1 could play
a role in Lewy body formation and the pathogenesis of PD.
PMID- 10762167
TI - Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker
for peroxynitrite-mediated oxidative stress in neurodegenerative diseases.
AB - Peroxynitrite can nitrate tyrosine residues of proteins. We examined
nitrotyrosine-containing proteins in cerebrospinal fluid of 66 patients with
neurogenic disease by immunoblot analysis. Nitrated tyrosine residue-containing
protein was observed in the cerebrospinal fluid and was concluded to be manganese
superoxide dismutase (Mn-SOD). The nitrated Mn-SOD level was strikingly elevated
in amyotrophic lateral sclerosis patients and was slightly increased in
Alzheimer's and Parkinson's disease patients, whereas an elevated Mn-SOD level
was observed only in progressive supranuclear palsy group.
PMID- 10762168
TI - A single nucleotide polymorphism of dopamine transporter gene is associated with
Parkinson's disease.
AB - We identified two polymorphisms out of all coding regions of the dopamine
transporter gene. One existed in exon 9 (1215A/G) and another in exon 15
(1898T/C). The 1215G was significantly less frequent among patients with
Parkinson's disease than the controls. Although the polymorphism caused no amino
acid substitution, we concluded that it was associated with decreasing the
susceptibility to Parkinson's disease through mechanisms other than the protein
function of dopamine transporter.
PMID- 10762169
TI - A novel congenital myopathy with apoptotic changes.
AB - We report on a female child with congenital myopathy with delayed developmental
milestones and mental retardation. The most striking pathological finding was the
presence of many condensed to fragmented myonuclei. DNA fragmentation was
confirmed by the TUNEL method and supported by the ultrastructural
characteristics of apoptotic nuclear changes. We also demonstrated
immunohistochemically the activation of caspase-3 and caspase-9. This appears to
be the first reported case of congenital myopathy with apoptotic process.
PMID- 10762170
TI - Novel missense mutations in the glycogen-branching enzyme gene in adult
polyglucosan body disease.
AB - We describe the first non-Ashkenazi patient with adult polyglucosan body disease
and decreased glycogen-branching enzyme (GBE) activity in leukocytes. Gene
analysis revealed compound heterozygosity for two novel missense mutations
Arg515His and Arg524Gln in the GBE gene. Both missense mutations are predicted to
impair GBE activity. This is the first identification of GBE mutations underlying
adult polyglucosan body disease in a non-Ashkenazi family, and confirms that
adult glycogen storage disease type IV can manifest clinically as adult
polyglucosan body disease.
PMID- 10762171
TI - Mental retardation and behavioral problems as presenting signs of a creatine
synthesis defect.
AB - Recently, 3 patients with a creatine synthesis defect have been described. They
presented with developmental regression, extrapyramidal movement abnormalities,
and intractable epilepsy, and they improved with treatment of creatine
monohydrate. We report 2 unrelated boys with a creatine synthesis defect and
nonspecific presenting signs of psychomotor retardation, behavioral problems,
and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all
metabolites, expressed as millimoles per mole of creatinine, which suggests
decreased creatinine excretion. This finding led to the correct diagnosis. We
propose to include the assessment of the overall concentrations of amino acids
and organic acids relative to creatinine in routine metabolic urine screening.
PMID- 10762172
TI - Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and
transthyretin Val122Ile allele.
AB - Typical of sporadic inclusion body myositis muscle biopsies are vacuolated muscle
fibers containing intracellular amyloid deposits and accumulations of "Alzheimer
characteristic" proteins. There is no muscle blood vessel or cardiac amyloidosis.
We report on a 70-year-old African-American man homozygous for the transthyretin
Val122Ile allele who has both sporadic inclusion body myositis and cardiac
amyloidosis. His unique pathological features included transthyretin
immunoreactivity in prominent muscle blood vessel amyloid and congophilic amyloid
deposits within vacuolated muscle fibers.
PMID- 10762173
TI - Neuronal intranuclear inclusions in spinocerebellar ataxia type 2.
PMID- 10762174
TI - Valproate for girls with epilepsy.
PMID- 10762175
TI - Simvastatin and plasma very-long-chain fatty acids in X-linked
adrenoleukodystrophy.
PMID- 10762176
TI - Mirror agnosia: the ramachandran sign.
PMID- 10762177
TI - Aspects of the failed back syndrome: role of litigation.
AB - OBJECTIVE: A review that attempts to identify the mechanism and causation of
persistent or recurring low back pain. DESIGN: A personal assessment of clinical
features with a selective review of the literature. RESULTS: Thirty to forty per
cent of our population aged 10-65 years report that back trouble occurs on a
monthly basis and in 1% to 8% this interferes with work. A definite patho
anatomical cause for the pain is demonstrable in only a minority. It can be
deduced that psychosocial factors, including insurance benefits are of importance
for this variation. CONCLUSIONS: Neither non-operative nor surgical procedures
have a major impact on the capacity for work in this substantial minority of
backache sufferers. The main risk factors identified are: Wrong diagnosis,
repeated medical certificates for sickness benefits, failed surgery, symptoms
incongruous with signs or imaging, multiple spinal procedures, poor social
support and poor motivation, psychological illness, clinical depression before or
after injury or operation. Pending compensation and delays in settlement are
important additional features in claimants for compensation. For patients with
unproven diagnostic labels such as 'pain-behaviour', no evidence exists that any
type of surgery is cost effective.
PMID- 10762178
TI - Pharmacological therapy of spinal cord injury during the acute phase.
AB - STUDY DESIGN: Prospective, randomized clinical trial. SETTING: France.
OBJECTIVES: To evaluate the safety and effect on neurological outcome of
nimodipine, methylprednisolone, or both versus no medical treatment in spinal
cord injury during the acute phase. METHOD: One hundred and six patients who had
spinal trauma (including 48 with paraplegia and 58 with tetraplegia) were
randomly separated into four groups: M=methylprednisolone (30 mg x kg(-1) over 1
h, followed by 5.4 mg x kg(-1) x h(-1) for 23 h), N=nimodipine (0.015 mg x kg(-1)
x h(-1) for 2 h followed by 0.03 mg x kg(-1)h(-1) for 7 days), MN (both agents)
or P (neither medication). Neurological assessment (ASIA score) was performed by
a blinded senior neurologist before treatment and at 1-year follow-up. Early
spinal decompression and stabilization was performed as soon as possible after
injury. RESULTS: One hundred patients were reassessed at 1 year. Neurological
improvement was seen in each group (P<0.0001), however no additional neurological
benefit from treatment was observed. Infectious complications occurred more often
in patients treated with M. Early surgery (49 patients underwent surgery within 8
h of their accident) did not influence the neurological outcome. The only
predictor of the latter was the extent of the spinal injury (complete or
incomplete lesion). CONCLUSION: The present study confirms the absence of benefit
of pharmacological therapy in this indication. Because of the paucity of clinical
studies that demonstrate the efficacy of pharmacological treatment in spinal
injury during the acute phase, systematic use of pharmaceutical agents should be
reconsidered.
PMID- 10762180
TI - Subjective health in spinal cord injury after outpatient healthcare follow-up.
AB - OBJECTIVE: To compare self-reported health, independence, and depression in two
samples of people with spinal cord injury (SCI), one which receives regular,
comprehensive outpatient health care follow-up and one that does not. DESIGN:
Exploratory study of self-reported secondary conditions in 235 individuals with
SCI who received health care follow-up using post hoc quasi-experimental
comparisons with a group of 136 people with SCI who had no health care follow-up.
SETTING: Outpatients at a Veterans Affairs Health Care System SCI Center. MAIN
OUTCOME MEASURES: The Check Your Health Instrument surveyed three self-report
measures: overall health, independence, and depression. The Secondary Conditions
Screening Instrument (SCSI) addressed 40 secondary conditions that may have been
experienced in the prior year. RESULTS: Study participants who receive ongoing
SCI health care reported higher subjective health, independence, and absence of
depression scores compared to those that did not receive regular SCI health care
follow-up. Results on the SCSI showed similar secondary conditions in the two
groups, but higher frequency and severity in the no follow-up group. CONCLUSION:
SCI outpatient health care follow-up is associated with higher subjective health,
independence, and absence of depression.
PMID- 10762179
TI - Aging after spinal cord injury: an exploratory study.
AB - OBJECTIVE: To identify the relationship between two aspects of aging (age at
injury onset and years since injury onset) with the post-injury prevalence of six
classes of secondary conditions among a sample of participants with spinal cord
injury (SCI). DESIGN: A cross-sectional study to identify the relationship
between the two aging variables and secondary conditions after spinal cord
injury. SETTING: A large southeastern rehabilitation hospital, with the
collaboration of two midwestern hospitals. PARTICIPANTS: Three hundred and forty
seven participants, all of whom had traumatic SCI of an average duration of 18.2
years. MAIN OUTCOME MEASURES: The Secondary Conditions Questionnaire (SCQ), a 50
item self-report screening measure for secondary conditions after SCI, was used
to measure the post-injury prevalence of six classes of secondary conditions.
RESULTS: There was a significantly greater odds of kidney stones, non-urinary
related infections, and three types of musculoskeletal conditions (ie, curvature
of the spine, contractures, and fractures) among participant cohorts who were 20
29 years post-injury and 30 or more years post-injury. The odds of heart problems
and bowel obstructions were higher with a greater age at injury onset, whereas
the odds of seven other conditions decreased among older cohorts at injury. Among
these seven conditions, the most dramatic findings were for kidney stones, where
individuals who were less than 18 at injury had over 30 times the odds of having
had the condition since injury than those who were injured at 40 or older.
CONCLUSIONS: Although the study was cross-sectional in nature, the results point
to secondary conditions which may be problematic with increasing years since
injury, as well as those conditions which are more or less likely to occur among
individuals injured at different points in their lives.
PMID- 10762181
TI - Hemilaminectomy for the removal of the spinal lesions.
AB - OBJECTIVE: We evaluated 20 patients with spinal lesions with respect to the value
of unilateral hemilaminectomy at the Department of Neurosurgery, Erciyes
University, Medical Faculty, Kayseri, Turkey. The operative technique of the
limited approach for spinal lesions is described. METHODS: The study is based on
20 prospective consecutive patients with spinal lesions who had unilateral
hemilaminectomy. There were 12 women and eight men. Age ranged from 17 to 63
years mean (42 years) with a slight preponderance of women patients (60%). Spinal
lesions were cervical in three cases, lumbar in five cases, and thoracic in 12
cases. Hemilaminectomy was performed by using a high speed drill. RESULTS:
Postoperative neurological status was unchanged in six cases, improved in 11
cases, and worsened in three cases. We only observed two cases of wound
infections that were not related to our surgical approach. At the follow-up
evaluation, which occurred approximately 25 months after surgery none of the
patients showed spinal deformity or spinal instability. CONCLUSION: The rationale
of attempting unilateral approach is to avoid damage to the dorsal static
structures of the vertebral column. With the precise preoperative definition of
the relationship of tumor to the surface of the spinal cord by contrast enhanced
MRI, unilateral approaches might be more applicable to spinal lesions except
invasive extradural lesions.
PMID- 10762182
TI - Evaluation of the use of Urocath-Gel catheters for intermittent self
catheterization by male patients using conventional catheters for a long time.
AB - STUDY DESIGN: Prospective study of intermittent self-catheterization (CIC) with
change from conventional catheter to low-friction Urocath-Gel catheter.
OBJECTIVES: To evaluate if such catheters are well accepted and to evaluate their
practical use. METHODS: Thirty-nine male patients, between 19 and 74 years old,
performing clean intermittent self-catheterization with conventional catheters
for a neuropathic bladder for many years were included in this study after
written informed consent. Exclusion criteria were clinical urinary tract
infection, acute infection of urethra, prostate or epididymis, untreated urethral
strictures and false passages or severe urethral bleeding occurring within the
last month. During 1 month they changed to the use of the Urocath-Gel catheter.
Complications were noted. Satisfaction was evaluated by a visual analogue scale
and by questioning. RESULTS: Four patients did not complete the study, two for
side effects, two for difficulties with the catheterization technique. Time
needed for CIC was not different with both techniques. Difficult introduction or
difficult retreat of the catheter were not different in frequency. Impossibility
to introduce the catheter was less frequent. Urethritis and urethral bleeding
were less frequent than during the use of conventional catheters. Satisfaction
was better with the low friction catheters. Negative satisfaction was mainly
related to the availability and the use of water to lubricate the catheter,
difficulty of manipulation and fear for cost. CONCLUSION: The hydrophilic
catheter Urocath-Gel proved as easy to use as conventional catheters but was
better tolerated. Satisfaction was better especially in patients who experienced
problems with conventional catheters. Some patients were unsatisfied for reasons
of practical use or for economical reasons.
PMID- 10762183
TI - Bacterial contamination of bath-water from spinal cord lesioned patients with
pressure ulcers exercising in the water.
AB - AIM: To evaluate the bacterial contamination of the water from the microflora of
pressure ulcers in para- and tetraplegic patients, when they were exercising in
water at 36 degrees C for half an hour. MATERIAL: Twelve spinal cord lesioned
(SCL) patients with ulcers participated, and six of the 12 SCL patients with
healed ulcers constituted a control group. METHODS: The evaluation was performed
both with and without the ulcer covered with a moisture reactive occlusive
dressing, DuoDERM. Bacterial samples were taken from the bath-water before and
after the exercise programmes and additionally specimens were obtained from the
ulcer, the patients skin and urine, and from the skin of the physiotherapist who
exercised the patient. A similar procedure was carried out in the controls.
RESULTS: The bacteriologic analyses showed no significant difference in the
contamination of the bath-water after exercising with or without DuoDERM covering
the ulcers. In half of the patients DuoDERM loosened. After all exercise
programmes with or without DuoDERM dressing the water was contaminated with
facultative aerobic intestinal bacteria, ie E. faecalis and Enterobacteriaceae
(E. coli, Klebsiella species, Proteus species, Enterobacter species). In nearly
one-third of the exercise sessions the bath-water was contaminated with P.
aeruginosa before starting, and after the exercise programmes one fourth of the
ulcers were colonized with these pathogens. CONCLUSION: The water specimen showed
the bacteria from the intestine to be much more prominent than the bacteria
coming from the ulcers. Thus the pressure ulcers were of minor importance for the
bath-water and ought not to prohibit patients from the potential benefits of
water exercise, but chlorination of the water in the training pool seems
appropriate.
PMID- 10762184
TI - Screening for bacteriuria in patients with spinal cord lesion: dipstick test,
microscopic examination and urine culture.
AB - AIM: To investigate the positive and negative predictive values for bacteriuria
of a rapid chemical dipstick procedure for leukocytes and nitrite, and a
microscopic examination for leukocytes and bacteria with a urine culture being
the reference in patients with spinal cord lesion (SCL). METHODS: A prospective
study. Significant bacteriuria was defined as > or = 10(5) CFU/mL. The
microscopic examination for leukocytes was divided in four different cut-off
limits for positive results. MATERIAL: A total of 256 consecutive early morning
urine samples were collected from 143 SCL patients admitted to our in-patient
facility. RESULTS: One hundred and twenty-eight urine cultures revealed
significant bacteriuria. Eighty-seven were infected by only one microorganism, 41
samples contained significant growth of more than one species. A total of 186
microorganisms in significant growth were identified. CONCLUSION: Three or more
leukocytes should be considered as a positive result. The dipstick and microscopy
tests are equally valuable, considering the single tests as well as the
combinations evaluated.
PMID- 10762185
TI - Midodrine hydrochloride and the treatment of orthostatic hypotension in
tetraplegia: two cases and a review of the literature.
AB - STUDY DESIGN: A report of two cases of orthostatic hypotension in acute
tetraplegia that were resistant to classic treatment interventions. OBJECTIVE: To
discuss the use of midodrine hydrochloride for the treatment of orthostatic
hypotension in early tetraplegia. SETTING: Department of Rehabilitation Medicine,
The University of Texas Health Science Center at San Antonio, Texas, USA.
METHODS: Presentation of two cases. RESULTS: Midodrine hydrochloride successfully
treated two cases of orthostatic hypotension that had been refractory to classic
treatment interventions. CONCLUSION: Midodrine hydrochloride should be included
in the armamentarium of the physician treating orthostatic hypotension in spinal
cord injury.
PMID- 10762186
TI - Femoral head disintegration in a paraplegic patient: loose bodies in neuropathic
joints.
AB - A case report of potential loose body formation in a hip joint of a paraplegic
patient is presented. The case is used to discuss why loose bodies do not persist
in neuropathic joints, although they might be expected to be common when this
type of joint pathology exists.
PMID- 10762187
TI - Odontoid fracture complicating ankylosing spondylitis.
AB - Patients with ankylosing spondylitis are prone to fractures. We describe a 32
year-old male patient with an odontoid fracture and anterior dislocation of C1
vertebra relative to C2 complicating ankylosing spondylitis. The importance and
difficulties of the rehabilitation program are stressed. The role of magnetic
resonance imaging and three-dimensional computerized tomography in diagnosis is
emphasized.
PMID- 10762188
TI - Cruciate paralysis, hypothesis for injury and recovery.
AB - STUDY DESIGN: Case report and review of the literature. OBJECTIVES: Discuss a
case of cruciate paralysis, a review of the literature and the hypotheses
regarding the pathogenesis and recovery in spinal cord injuries that cause
disproportionate weakness of the upper extremities. SETTING: Thomas Jefferson
University Hospital, Philadelphia, PA, USA. METHODS: Case report. RESULTS: A case
of cruciate paralysis is presented involving a 59-year-old female who experienced
a gunshot wound to the face. Initial motor exams revealed mild lower limb
weakness and absent upper limb function with an upper limb modified American
Spinal Injury Association motor score of 0/50 (a modified impairment scale using
half point muscle grades). Spinal imaging revealed fractures of the C1 anterior
ring and the odontoid process, both associated with multiple bullet fragments. No
spinal surgery was performed and she was placed in halo fixation. By 3 weeks she
had regained enough upper limb function to manipulate large objects with her left
hand and move her right hand. At that time, her upper limb ASIA score was 16/50.
By 5 weeks, her upper limb modified ASIA motor score had improved to 31.5/50 and
she began manipulating feeding utensils, writing legibly, and brushing her teeth
with her left hand. CONCLUSIONS: In this case report we present a patient's motor
and functional recovery. We also discuss the hypothesis that the acute central
cord syndrome and cruciate paralysis are a likely result of similar pathologic
mechanisms and that good functional outcome resulted from an initially disabling
trauma.
PMID- 10762189
TI - Pseudomonas aeruginosa infection in an intrathecal baclofen pump: successful
treatment with adjunct intra-reservoir gentamicin.
AB - OBJECTIVE: To describe the use of intra-reservoir gentamicin for the treatment of
a Pseudomonas aeruginosa infected baclofen pump. SETTING: Regional Spinal
Injuries Centre, Hexham, Northumberland, England. SUBJECT: Male patient aged 32
years with progressive multiple sclerosis and severe bilateral spasticity.
RESULTS: Intra-reservoir gentamicin proved successful in treating infection with
Pseudomonas aeruginosa. CONCLUSION: Intra-reservoir gentamicin may be successful
in treating pump infection with Pseudomonas aeruginosa without the need for pump
removal.
PMID- 10762190
TI - Spinal cord injury without radiographic abnormality in adults. SK Gupta et al.,
Spinal Cord 1999; 37: 726-729.
PMID- 10762191
TI - Spinal cord injury and partner relationships.
AB - INTRODUCTION: Among the many issues confronting a newly spinal cord injured (SCI)
person are apprehension about the potential impact of the acquired disability on
present or future intimate relationships. OBJECTIVE: To summarize the research
regarding partner relationships and SCI. METHOD: Medline, Psychlit and Cinahl
database researches were undertaken. RESULTS: Several studies have focused on the
issue of marital status before and after the onset of the injury. The results of
the studies carried out on the prevalence of divorce are conflicting. Divorce
rates have been reported to be anywhere from 8% to 48%. It appears that divorce
rates tend to decline to the normal rate for the general population after the
initial high risk period. Some studies have shown that marital status is a
powerful predictor of independent-living outcome variables. Thus, marital
stability is a concern in SCI care. The study investigating why able-bodied women
might choose to marry men with a permanent physical disability, such as a SCI,
showed a substantial overlap with existing models of courtship. It was also shown
that a SCI person who strives to minimise the impact of the disability on a
potential partner makes a more attractive candidate for a long-term relationship
than an individual who has come to rely on others. CONCLUSION: Partner
relationships seem to be affected by a SCI, although not as much as is widely
believed. There are, however, problems interpreting the varying results of the
studies due to culture differences, changes in family life in society in general
and the different methodologies used. Systematic research that puts the patients'
and partners' problems into perspective is necessary. Uniformity in measurement
instruments would facilitate comparisons of studies.
PMID- 10762192
TI - Intravenous infusion of 4-AP in chronic spinal cord injured subjects.
AB - STUDY DESIGN: A prospective double blind cross over trial of intravenous 4
Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the
treatment of spinal cord injured (SCI) patients for neurologic impairment, pain
and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care
acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double
blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams
of 4-AP or placebo were administered over a 2 h period. Patients were serially
examined during and after the infusion clinically for pain, sensorimotor
function, hypertonicity and motor control using electromyography (EMG). Samples
of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals.
RESULTS: Despite penetration of 4-AP into the CSF, no significant differences
were noted in the clinical and EMG parameters at the times measured. Individual
changes in sensory function were reported by some patients in both the placebo
and 4-AP trials, however mean values were not robust. Frequently, patients
complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The
intravenous route may not be the best way to administer this drug as no short
term benefits were observed.
PMID- 10762193
TI - Influence of lesion level on the cardioventilatory adaptations in paraplegic
wheelchair athletes during muscular exercise.
AB - OBJECTIVES: To characterize the influence of neurological lesion level on the
cardiorespiratory and ventilatory responses of two groups of paraplegic athletes
during incremental exercise on a treadmill and in the usual conditions for
wheelchair exercise. METHODS: Cardioventilatory responses evaluated in two groups
of paraplegic wheelchair sportsmen designated as high paraplegic athletes (HPA)
and low paraplegic athletes (LPA). After 2 min of data collection at rest and 3
min of warm-up at 4 km x h(-1), treadmill speed was increased by 1 km x h(-1)
every minute until exhaustion. During this test, ventilation and its components,
as well as respiratory exchanges, were measured breath by breath (C.P.X. Medical
Graphics) every minute by taking the mean of the last 20 s of each increment.
RESULTS: Spirometric values presented no significant differences between groups.
At rest, no significant difference was observed between the two groups for all
cardiorespiratory and ventilatory values obtained during the treadmill test. At
submaximal exercise, all variables increased with the augmentation in workload.
With the exception of R, there were no significant differences in the classic
cardiorespiratory parameters (VO2, VCO2, HR, VE) between the two groups of
paraplegics. For the ventilatory parameters, we observed significant differences
between the two groups, with values of f and It/Trf significantly higher
(0.010.05) and 12 months after SCI
(radius 28% less, P<0.01; ulna 15% less, P<0.05). The cortical bone density was
significantly reduced 12 months after SCI (radius 3% less, P<0.05; ulna 4% less,
P<0.05). No changes in BMD of trabecular or cortical bone of radius and ulna were
detected in subjects with paraplegia. The trabecular BMD of tibia was
significantly reduced 6 months (5% less, P<0.05) and 12 months after SCI (15%
less, P<0.05) in all subjects with SCI. The cortical bone density of the tibia
only was decreased after a year following SCI (7% less, P<0.05). No significant
difference between both groups, subjects with paraplegia and subjects with
tetraplegia was found for tibia cortical or trabecular BMD. There was no
significant influence for the physical activity level or the degree of spasticity
on bone mineral density in all subjects with SCI. CONCLUSIONS: Twelve months
after SCI a significant decrease of BMD was found in trabecular bone in radius
and in tibia of subjects with tetraplegia. In subjects paraplegia, a decrease
only in tibia BMD occurred. Intensity of physical activity did not significantly
influence the loss of BMD in all subjects with para- and tetraplegia. However, in
some subjects regular intensive loading exercise activity in early rehabilitation
(tilt table, standing) can possibly attenuate the decrease of BMD of tibia. No
influence was found for the degree of spasticity on the bone loss in all subjects
with SCI.
PMID- 10762195
TI - Radiotherapy as a local treatment option for heterotopic ossifications in
patients with spinal cord injury.
AB - OBJECTIVE: Heterotopic ossifications (HO) occur in about 20% of patients with
spinal cord injury and may seriously compromise the rehabilitation process. The
aim of the present study was to ascertain whether radiotherapy (RT) administered
early in the course of the disease prevents the manifestation of HO and whether
in patients, whose HO have been resected, recurrence can be avoided. METHODS:
Thirty-six patients (46 joints) were irradiated; 33 patients were evaluable. Mean
follow up was 23.6 months. In 27 patients RT was performed as primary treatment
in the inflammatory phase of soft tissue swelling that precedes manifest HO.
Eleven patients were treated after resection of manifest HO, while two had
primary and postoperative RT in different joints. The dose was 10 Gy in fractions
of 2-2.5 Gy in 25 patients. Four patients were treated with total doses between
7.5 and 20 Gy. Seven patients received single dose irradiation with 8 Gy. RT was
performed with 8 MV photons after simulation on the basis of CT scans. RESULTS:
The mean duration of follow up was 23.6 months. Thirty of the 36 irradiated
patients showed no progression of HO. In three patients reossifications after
therapy caused a moderate decrease in joint mobility. No relevant adverse effects
were observed. CONCLUSION: These results suggest that RT is a safe and effective
local treatment option for spinal cord injury patients with HO.
PMID- 10762196
TI - Paraplegic adaptation to assisted-walking: energy expenditure during wheelchair
versus orthosis use.
AB - STUDY DESIGN: To study the energy cost of locomotion during ambulation with
different orthoses (HIP Guidance Orthosis Orlau Parawalker (PW), n=4;
Reciprocating Gait Orthosis (RGO), n=6; RGO + FNS, n=4). OBJECTIVES: Since high
energy costs of locomotion have been proposed as a major reason for early
rejection of orthotic use, our aims were (a) to evaluate the impact of functional
neuromuscular stimulation (FNS) on energy expenditure during orthosis-assisted
ambulation; (b) to study whether energy expenditure data can predict the poor
long-term patients' compliance and (c) to assess selection criteria for the
assignment of the different types of orthosis. SETTING: The study was completed
at the Center of Sports Medicine and Center of Bioengineering, don C. Gnocchi
Foundation, IRCCS, Milan, Italy. METHODS: The HR/VO2 relationship and the energy
cost of locomotion (C) were studied in 14 patients (lesion level C7-T11) during
wheelchair (WHCH) use at various speeds and during locomotion with different
orthotic devices. Patients' short- and long-term compliance were assessed by
questionnaires evaluating duration of and problems related to orthotic use.
RESULTS: (a) In patients using RGO + FNS the slope difference of HR/VO2 curves
(deltaslHR/VO2) between WHCH and orthosis was significantly lower than in other
groups (-3 beats l(-1) in RGO + FNS vs 43 and 52 beats l(-1) in RGO and PW,
respectively); (b) neither C, nor VO2 peak, or deltaslHR/VO2 correlated with
orthosis duration of use; (c) in the RGO + FNS group, C was lower at maximal
walking speed, which linearly correlated with maximal WHCH speed. CONCLUSION: (a)
Electrical stimulation seems to improve locomotion, as a consequence of
hemodynamic effects, but does not decrease energy expenditure, which remains
high; (b) the poor long-term compliance to orthosis use cannot be predicted by
the energy expenditure parameters; (c) the subjects who can reach high speeds by
WHCH seem to be the most appropriate for RGO + FNS locomotion.
PMID- 10762197
TI - The importance of osmolality for intermittent catheterization of the urethra.
AB - OBJECTIVES: The urethral trauma after catheterization with intermittent catheters
was studied histologically using unconscious rabbits. SETTING: The study was
performed at Astra Hassle, Molndal, Sweden. MATERIALS AND METHODS: Fifteen
rabbits were randomized into five groups (three rabbits in each group), one
control group and four groups catheterized with four different LoFric catheters
(Astra Tech, Molndal, Sweden): (1) control (not catheterized); (2) salt coated
(i.e. high osmolality catheters) with drainage eyes; (3) without salt (i.e. low
osmolality catheters) and with eyes; (4) with salt coating but without drainage
eyes; and (5) without neither salt coating nor drainage eyes. The urethral
injuries were evaluated using a four graded histological scale. RESULTS: The
results showed that salt coated LoFric catheters gave less urethral trauma than
LoFric catheters without salt. This was also supported by the significantly lower
removal friction measured during withdrawal of the high osmolality catheters. No
significant differences either in removal friction or in urethral trauma could be
observed between LoFric catheters with or without drainage eyes. CONCLUSION: It
may be concluded that osmolality is one important factor (there might be others,
like e.g. water binding ability) when comparing different hydrophilic catheters,
in regards to removal friction and urethral trauma. Furthermore it is suggested
that there is no difference in urethral trauma between catheters with eyes or
without eyes. To minimize the risk of urethral trauma, high osmolality catheters
are recommended, especially when the catheterization times are a few minutes or
more.
PMID- 10762198
TI - Return to work after spinal cord injury.
AB - OBJECTIVE: To describe predictors of return to work after spinal cord injury
(SCI), in particular the physical intensity of the pre-injury job. STUDY DESIGN:
Survey. SETTING: Patients' home. METHODS: We interviewed 234 persons with a
spinal cord injury (SCI) between 18 and 65 years of age and who were gainfully
employed at the time of the injury. Possible predictors were tested with logistic
regression analyses. RESULTS: After the SCI, only 37% of the persons were
gainfully employed. People with heavy and strenuous physical work pre-injury
regained work in only 25%, respectively 21%. Being male (Odds Ratio (OR) 3.70),
light to moderate physical job pre-injury (OR 3.16), high Barthel Index (OR
2.76), high educational level (OR 2.12) and education post-injury (OR 2.14) were
significant predictors for returning to gainful work after injury. Many
unemployed persons thought they were capable of working. CONCLUSIONS: Only a
minority returned to gainful employment after SCI even to a physically less
demanding job. In addition to intensive inpatient re-education, long-term support
in job seeking is very important, including switching to a less demanding job.
PMID- 10762199
TI - Spinal subdural tuberculous abscess.
AB - OBJECTIVES: Spinal subdural abscess is rare and only 48 cases have been described
to date. In this report, we present an additional spinal subdural tuberculous
abscess. METHOD: Tuberculous meningitis was diagnosed with clinical and
laboratory findings in a 45-year-old man. A spinal subdural abscess was
demonstrated using MRI. Presence of the abscess was revealed by surgical
intervention. The diagnosis was confirmed by pathological examination. RESULTS:
The patient had been treated for tuberculous meningitis 2 years previously. The
disease recurred when anti-tuberculous therapy was prematurely discontinued.
During the second treatment, the patient also underwent a ventriculo-peritoneal
shunt operation for hydrocephalus. Dizziness and weakness of both legs developed
after the postoperative period. Spinal MRI showed a spinal subdural abscess as a
iso-intense mass with spinal cord in the T1 and T2 weighted images, ring like
enhancement and compression on the spinal cord at T3-T4 level. The patient
underwent surgery and the abscess was drained. CONCLUSION: Tuberculosis may cause
a spinal subdural abscess and although it is a rare disorder, when encountered
MRI is very useful in the diagnosis.
PMID- 10762200
TI - Laparoscopic bladder auto-augmentation in an incomplete traumatic spinal cord
injury.
AB - OBJECTIVES: To assess the urodynamic and clinical outcome of a laparoscopic auto
augmentated bladder. METHODS: Laparoscopic bladder autoaugmentation in a 27-year
old woman with an incomplete spinal cord injury at T12 level with urge
incontinence caused by a hyperreflexic bladder. RESULTS: Six months later the
patient voids by Valsalva's manoeuvre every 3 h and remains dry day and night.
The radio-urodynamic study, performed 2 months later, revealed an intact bladder
with a diverticulum of anterior wall and a capacity of 510 ml with filling rate
of 100 ml/min without evidence of leakage of infusion water. CONCLUSION:
Laparoscopic retropubic auto-augmentation allows a brief hospital stay and minor
postoperative discomfort. Moreover the laparoscopic approach should not
complicate or preclude subsequent enterocystoplasty if necessary.
PMID- 10762201
TI - Peptide-mediated non-viral gene transfer for transplantation.
PMID- 10762202
TI - Graft-specific inhibition of complement activation after xenotransplantation;
genetically modified pig organs versus systemic anticomplement strategies.
PMID- 10762203
TI - Hyperacute rejection: fact or fancy.
PMID- 10762204
TI - Posttransplant cataract.
PMID- 10762205
TI - Pathology makes the difference.
PMID- 10762206
TI - Tissue-binding properties of a synthetic peptide DNA vector targeted to cell
membrane integrins: a possible universal nonviral vector for organ and tissue
transplantation.
AB - BACKGROUND: Gene delivery through a nonviral, receptor-mediated system widely
expressed in transplanted tissue would have important advantages in
transplantation, where gene delivery is performed ex vivo. Integrins are widely
expressed cell surface receptors and can be targeted for gene delivery. METHODS:
A synthetic 31 amino acid DNA vector (polylysine-molossin) comprising a 15-amino
acid moiety for targeting cellular integrins (derived from the snake venom,
molossin) and a 16-amino acid polylysine moiety for DNA-binding, has been
evaluated. The 31-amino acid vector, as well as its separate 15-amino acid
integrin-binding and (lys)16 components, were individually synthesized, and a
monoclonal antibody was raised to the molossin peptide for these studies. Binding
to cell lines and tissue sections and capacity for gene delivery were examined.
RESULTS: Flow cytometric studies with the ECV304 cell line demonstrated that the
binding of polylysine-molossin and polylysine-molossin/DNA complexes involved
both electrostatic and integrin-mediated interactions with the cells, with the
electrostatic binding being sufficient for maximal binding. However, binding to
cellular integrins was essential for successful gene transfer. Binding studies on
frozen tissue sections of the rat and pig demonstrated that the molossin peptide
bound to many cell types of interest in transplantation, but not to all. Among
the negative tissues were vascular endothelium and pancreatic islets. Small
species differences in tissue binding were noted between the rat and pig.
CONCLUSIONS: This study defines the cooperative nature of the binding of this
vector system to target cells and establishes the cell types most likely to be
effectively targeted for DNA transfer.
PMID- 10762207
TI - Delivery of Cu/Zn-superoxide dismutase genes with a viral vector minimizes liver
injury and improves survival after liver transplantation in the rat.
AB - BACKGROUND: Oxygen-derived free radicals play a central role in pathomechanisms
of reperfusion injury after organ transplantation. Endogenous radical scavenger
systems such as superoxide dismutase (SOD) degrade toxic radicals; however, SOD
is degraded rapidly when given exogenously. Therefore, the hypothesis that
treatment of the donor liver with an adenoviral vector encoding the Cu/Zn-SOD
gene (Ad-SOD1) would lead to permanent gene expression and therefore protect the
organ against injury and increase survival in a rat model of liver
transplantation was tested. METHODS: Some donors were infected with Ad-SOD1,
whereas untreated grafts and livers infected with the indicator gene lacZ
encoding bacterial beta-galactosidase (Ad-lacZ) served as controls. After
orthotopic liver transplantation, survival, serum transaminases, and
histopathology were evaluated. RESULTS: Approximately 80% of hepatocytes
expressed beta-galactosidase 72 hr after injection of Ad-lacZ. Moreover, SOD1
gene expression and activity were increased 3- and 10-fold in the Ad-SOD1 group,
respectively. After transplantation, 20-25% of rats treated with Ad-lacZ
survived. In contrast, all SOD1-treated animals survived. Transaminases measured
8 hr after transplantation in Ad-SOD1 rats were only 40% of those in controls,
which increased 40-fold above normal values. Approximately 20% of hepatocytes in
untreated and Ad-lacZ-infected organs were necrotic 8 hr after reperfusion,
whereas necrosis was nearly undetectable in grafts from rats treated with Ad
SOD1. CONCLUSIONS: This study provides clear evidence for the first time that
gene therapy with Ad-SOD1 increases survival and decreases hepatic injury after
liver transplantation. Genetic modification of the liver represents a future
approach to protect organs against injury where oxygen-derived free radicals are
involved.
PMID- 10762208
TI - Tolerance of rat liver allografts induced by short-term selective
immunosuppression combining monoclonal antibodies directed against CD25 and CD54
with subtherapeutic cyclosporine.
AB - BACKGROUND: Our purpose was to develop and evaluate protocols for selective
immunosuppression after liver transplantation using the monoclonal antibodies
(mAbs) NDS-61, directed against the interleukin-2 receptor (CD25), and 1A29,
directed against the intercellular adhesion molecule-1 (CD54), in combination
with subtherapeutic cyclosporine (CsA). METHODS: Orthotopic rat liver
transplantation (ORLT) was performed in a DA-to-LEW strain combination.
Immunosuppression was administered from day 0 to +13. Functional parameters such
as survival time, body weight, and serum bilirubin levels were measured and the
liver grafts were evaluated histologically. RESULTS: A stepwise tapering of CsA
from 3 to 0.25 mg/kg/day reduced the long-term survival rate. All animals died at
a CsA dosage of 0.25 mg/kg/day, which was therefore defined as subtherapeutic.
Monotherapy with the anti-CD25 mAb was performed at dosages of 600 and 1800
microg/kg/day. The lower mAb dosage resulted in a long-term survival rate of 12%
and was defined as subtherapeutic. The combination therapy of CsA (0.25
mg/kg/day) and anti-CD25 mAb (600 microg/kg/day) produced a synergistic effect
and led to a long-term survival rate of 84%. This survival rate was significantly
higher than those after either CsA (P<0.005) or anti-CD25 mAb (P<0.001)
monotherapy. Both dosages (10 and 30 microg/kg/day) of anti-CD54 mAb monotherapy
as well as anti-CD54 mAb combined with a subtherapeutic dosage of CsA were
ineffective in preventing acute allograft rejection. The addition of anti-CD54
mAb (30 microg/kg/day) to combined CsA plus anti-CD25 mAb therapy (triple
therapy), however, increased the long-term survival rate to 100%. In the triple
therapy group there was no rejection process in the liver allografts at any time,
and donor-specific tolerance could be shown by donor-specific and third-party
heterotopic heart transplantation. CONCLUSIONS: The synergistic action of
subtherapeutic CsA plus anti-CD25 mAb NDS-60 could be demonstrated, whereas anti
CD54 mAb only had a positive effect in a triple therapy group. Triple therapy
prevented both acute and chronic rejection and induced donor-specific tolerance.
PMID- 10762209
TI - Optimization of ex vivo pressure mediated delivery of antisense
oligodeoxynucleotides to ICAM-1 reduces reperfusion injury in rat cardiac
allografts.
AB - BACKGROUND: Our purpose was to optimize hyperbaric pressure as a vector for ex
vivo transfection of antisense oligodeoxynucleotides (AS-ODN) to intercellular
adhesion molecule-1 to limit reperfusion injury (RI) in cardiac allografts. We
investigated the effects of increased pressure, incubation time, and AS-ODN
concentrations on transfection efficiency and toxicity. METHODS AND RESULTS: PVG
(RT1c) donor hearts were heterotopically transplanted to ACI (RT1a) recipients.
Donor hearts were harvested and the various groups were treated at: (1) different
pressure (1-9 atm) for 45 min with 80 micromol/liter AS-ODN; (2) different
incubation times (15 min to 6 hr) at 5 atm with 80 micromol/liter AS-ODN; 3)
different AS-ODN concentrations (80-240 micromol/liter) at 5 atm for 45 min.
Hearts were procured 24 or 72 hr after transplantation. Transfection efficiency
was determined with fluorescein-labeled AS-ODN. The degree of RI was determined
with biochemical and histological analysis. Increasing pressure from ambient (1
atm) pressure to pressures as high as 9 atm leads to a increase in transfection
efficiency from 1.7+/-.5 to 62+/-3.9% and a reduction in RI. Increased incubation
time up to 45 min increased transfection efficiency and reduced RI, but longer
incubation times induced significant toxicity to the allograft. Increased AS-ODN
concentrations improved transfection and reduced RI. CONCLUSIONS: Hyperbaric
pressure is a safe and effective vector for the ex vivo delivery of AS-ICAM-1-ODN
to rodent cardiac allografts and results in a reduction in reperfusion injury.
PMID- 10762210
TI - Murine xenogeneic immune responses to the human testis: a presumed immune
privileged tissue.
AB - INTRODUCTION: Immune privilege provides a natural paradigm for potentially down
regulating allogeneic and xenogeneic inflammatory immune responses. Fas ligand
has been suggested as a general underlying mechanism of immune privilege; the
human Fas ligand has been shown to ligate murine Fas in vitro. METHODS: In this
study, we examined whether the human testicular xenograft, a presumed immune
privileged tissue would have prolonged survival in mice. In addition, in vitro
and in vivo murine xenogeneic immune responses to the human testicular xenografts
were characterized using MHC class I, MHC class II, CD4, CD8, CD4/8 knockout
mice. RESULTS: Unlike in rodent testis, Fas ligand mRNA is not expressed and Fas
is highly expressed in human testis. Human testicular xenografts are immunogenic,
and do not induce any preferential pattern of recipient systemic Th1 or Th2
cytokine bias. Interestingly, an indefinite survival of the human testicular
xenografts is observed in murine MHC class II knockout mice, whereas the human
skin xenografts were rejected without a delay. In vivo murine immune responses to
human testicular xenografts require a recipient MHC class II-dependent CD4 T cell
mediated process that appears to depend on B7-1/B7-2 costimulatory signals.
CONCLUSIONS: Our results demonstrate that the concept of immune privilege, as
defined by the expression of Fas ligand and prolonged survival after
transplantation, cannot be extended to human testis. The stringent restriction of
murine xenogeneic immune responses to discordant human testicular xenografts to
the indirect MHC class II-dependent CD4 T cell-mediated pathway suggests a
potential venue for immune modulation to induce tolerance across a discordant
species barrier.
PMID- 10762211
TI - Microencapsulation of neonatal porcine islets: protection from human
antibody/complement-mediated cytolysis in vitro and long-term reversal of
diabetes in nude mice.
AB - BACKGROUND: Recently, we have developed a simple and reliable method to
efficiently isolate large numbers of neonatal porcine islets (NPI). We and others
have shown that NPI are susceptible to cytolysis by the activation of human
complement in vitro. Microencapsulation of islets may be one strategy to protect
NPI from this form of rejection. We examined whether microencapsulation can
prevent lysis of NPI induced by human antibody and complement in vitro and also
assessed their ability to reverse hyperglycemia in diabetic nude mice. METHODS:
NPI were microencapsulated with purified alginate, cultured for 2 days, then
tested for sensitivity to fresh human serum using an established in vitro
cytotoxicity assay or transplanted into alloxan-induced diabetic nude mice.
RESULTS: Incubation of nonencapsulated NPI for 24 hr in the presence of fresh
human serum resulted in a 53% loss of cellular insulin content, a 51% reduction
in recoverable DNA content, and a marked reduction of insulin secretory
responsiveness when compared with controls cultured in heat-inactivated human
serum. In contrast, exposure of encapsulated islets to fresh human serum had no
cytotoxic effect on the islets. Transplantation of 2000 encapsulated NPI i.p.
into diabetic nude mice (n=16) corrected hyperglycemia in all mice within 8
weeks. Similar results were obtained when 2000 nonencapsulated NPI were implanted
under the kidney capsule (n=10); however recipients of nonencapsulated NPI placed
i.p. failed to obtain euglycemia and survived for only 3 weeks
posttransplantation. CONCLUSION: Microencapsulation protects NPI from the
cytotoxic effects of human antibody and complement and allows for long-term
reversal of diabetes in nude mice.
PMID- 10762212
TI - fas-fas-ligand antigen expression and its relationship to increased apoptosis in
acute renal transplant rejection.
AB - BACKGROUND: To examine the role of fas-fas-ligand interaction and apoptosis in
acute transplant rejection. METHODS: Pre- and posttransplant renal allograft
biopsies were stained by in situ 3-end labeling of DNA for detection of apoptotic
cells (TUNEL) and immunohistochemistry techniques were used for demonstration of
fas and fas-ligand antigen expression. RESULTS: Posttransplantation apoptosis was
significantly increased in acute rejection and acute tubular necrosis (P<0.0001)
compared to preimplantation biopsies and biopsies taken from grafts showing
dysfunction not attributed to rejection. Fas and fas-ligand expression was
demonstrated predominantly in the tubular epithelium. In preimplant biopsies fas
was expressed in 11% (4/37) of cases; posttransplantation expression increased
to: 44% (8/18) acute rejection, 63% (5/8) acute tubular necrosis, and 38% (5/13)
dysfunction without evidence of rejection. Fas-ligand was expressed by 30%
(11/37) of preimplant biopsies, posttransplantation expression was reduced in all
groups: 17% (3/18) acute rejection, 13% (1/8) acute tubular necrosis, delayed
xenograft rejection and 15% (2/13) dysfunction without evidence of rejection. A
correlation with fas-1 expression preimplantation and a subsequent absence of
acute rejection post transplant was noted (P<0.001). CONCLUSIONS: Apoptosis is a
feature of acute rejection and acute tubular necrosis. Fas expression is uncommon
preimplantation and increases non-specifically post transplant. Fas-1 was
expressed by a third of preimplantation biopsies and expression was lost non
specifically post transplant. The expression of fas-ligand preimplantation
correlated with an absence of acute rejection episodes posttransplant, suggesting
some degree of immune privilege. These data suggest that the fas-fas-1 mediated
pathway does not play a specific role in apoptosis during acute rejection. We
were unable to find any evidence that the fas-fas-1-mediated pathway has a role
in the increased apoptosis seen during acute rejection.
PMID- 10762213
TI - Immunohistochemical characterization of coronary thrombi in allograft vascular
disease.
AB - BACKGROUND: Coronary thrombosis is a frequent complication of allograft vascular
disease (AVD) in cardiac transplant recipients. No data are available on thrombus
composition in these hearts. METHODS: The present study aimed at characterizing
thrombus components in coronary arteries from transplanted hearts with AVD, using
single and double immunostain with anti-gpIIb-IIIa, anti-fibrin, and anti
endothelial antibodies. The pathologic series consists of 55 grafts survived
longer than 2 months, and obtained from 55 patients deceased (n=44) or undergone
repeat transplantation (n=11). RESULTS: Mural thrombi were found in multiple
segments of 75 of 440 total coronary vessels (17%) (recent in 33, organizing in
28, and organized in 14), whereas occlusive thrombi were found in 19 vessels (8
recent and 11 with multichannel pattern of organization). Recent and thin mural
thrombi were mostly constituted of CD41a- and CD61-positive platelets; the amount
of fibrin progressively increased with the increase of thrombus size. In
organizing mural thrombi, gpIIb-IIIa immunostain was still present. Fibrin was
the only identifiable thrombus component in old mural thrombi embedded within the
intimal lesions. Recent occlusive thrombi immunoreacted both with anti-CD41a and
anti-CD61 and with anti-fibrin antibodies, whereas organized occlusive thrombi
with multichannel pattern exclusively immunoreacted with anti-fibrin antibodies.
Double immunostain showed that mural thrombi were stratified on de-endothelized
arterial segments. CONCLUSIONS: Thrombus composition is related to both type and
"age" of thrombus, with platelets as the early and major components of mural
microthrombi at one end of the spectrum, and fibrin as the dominant component of
occlusive thrombi at the other end.
PMID- 10762214
TI - Immunomodulatory effect of pentoxifylline during human allograft rejection:
involvement of tumor necrosis factor-alpha and adhesion molecules.
AB - BACKGROUND: Pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor,
is poorly active as an immunosuppressant but prevents the synthesis of
proinflammatory cytokines. In a randomized double-blind study comparing PTX
versus placebo in 140 patients receiving cadaveric kidney grafts under
cyclosporine and prednisone, we have shown that PTX weakened the consequences of
rejection on graft survival. To assess the mechanism underlying the beneficial
effect recorded during this trial, we analyzed the impact of PTX on tumor
necrosis factor (TNF-alpha) production and expression of cell adhesion molecules.
METHODS: Plasma levels of TNF-alpha and its soluble receptors (sTNF-RI, sTNF-RII)
and of soluble vascular cell adhesion molecule 1 (sVCAM-1) were monitored over
the 6 months postgraft period when PTX or placebo were administered. Expression
of VCAM-1 and intercellular cell adhesion molecule 1 was scored by
immunohistochemical staining of biopsy specimens from patients who underwent
rejection crisis. Lymphocyte subset composition was analyzed longitudinally
during cytomegalovirus (CMV) infections. RESULTS: Plasma TNF-alpha levels were
significantly reduced in the PTX-treated group over the 6 months of
administration, and specifically during isolated rejection episodes and during
CMV infections. Plasma levels of sTNFR-I, sTNFR-II, and sVCAM-1 did not differ
between the two groups of patients, but a decrease in renal tubular VCAM-1
expression was observed in the PTX group. During CMV infections, CD8
lymphocytosis and expansion of CD57+ (CD28-) CD8+ T cells were similar in the two
groups. CONCLUSION: The data collected during this double-blind study point to an
immunomodulatory role of PTX, the beneficial effect on graft survival resulting
from a restraining effect of the drug on the inflammatory conditions involved in
acute graft rejection.
PMID- 10762215
TI - Posttransplant cataract: lessons from kidney-pancreas transplantation.
AB - INTRODUCTION: Cataract is a major cause of visual disturbance after
transplantation. Although corticosteroid therapy has been linked with posterior
subcapsular cataract, its natural history in the cyclosporine era is not well
understood. METHODS: Baseline and regular postoperative slit-lamp biomicroscopy
and ophthalmic examinations (n=432) were performed in 108 eyes of simultaneous
kidney/pancreas (SPK) recipients (n=54) for up to 10 years after transplantation.
Triple therapy immunosuppression of cyclosporine, azathioprine, and prednisolone
was used. RESULTS: Cataract was present in 40% of eyes at simultaneous
kidney/pancreas associated with duration of diabetes, lower insulin dose, and the
use of pretransplant hemodialysis (P<0.05-0.01). Cataract became increasing more
common 2 years after simultaneous kidney/pancreas, and lens abnormalities were
virtually universal at 6-10 years by slit lamp biomicrosopy. The instantaneous
hazard rate for new cataract formation was highest within the first 2 years and
remained abnormal for the study duration. Nuclear and posterior subcapsular
cataract increased significantly after transplantation (P<0.05) and were the
predominant types of cataract presenting late. Risk factors for posttransplant
cataract formation included older age and high-dose pulse methylprednisolone
dose. Visual acuity was reduced by severity of cataract grade, presence of
combined nuclear and subcapsular cataract, retinal hemorrhage and underlying
diabetic retinopathy (P<0.05-0.001). Cataract formation imposed significant
additional impairment of visual acuity above that of diabetic retinopathy.
Cataract surgery was undertaken in 14% of eyes, improving visual acuity from mean
decimalized score of 0.28 to 0.43, P<0.01 but did not normalize it to the
noncataract level of 0.72. CONCLUSION: Transplantation substantially increases
all types of cataract, and is highly prevalent by slit lamp examination. High
risk patients are older and diabetic, and received hemodialysis and pulse
corticosteroid therapy. In contrast to older studies using high-dose
corticosteroid and azathioprine, the pattern of cataract in the cyclosporine era
is different with broader cataract types, a weaker association with
corticosteroids and a progressive course. Regular screening of visual acuity and
appropriate surgery for posterior subcapsular or severe cataract are recommended.
PMID- 10762216
TI - Human islet transplantation: lessons from 13 autologous and 13 allogeneic
transplantations.
AB - BACKGROUND: A series of 13 islet autotransplantations and 13 islet
allotransplantations performed between 1992 and 1999 at the University Hospital
of Geneva are presented. Factors affecting the outcome are analyzed. METHODS:
Islet autotransplantation has been performed in seven patients with chronic
pancreatitis and in six patients with benign tumors undergoing extensive
pancreatectomy. Islet allografts were performed in C-peptide-negative patients
simultaneously or after a kidney or lung transplantation. Each recipient received
islets from one to four donors. Panel-reactive antibodies were monitored by
microlymphocytotoxicity test. RESULTS: Eleven of 13 patients who underwent
autotransplantation maintained insulin independence for 6 months to 5 years. Two
years after autologous islet transplantation, five of nine patients were insulin
independent with an glycosylated hemoglobin of 5.9%. Three late islet failures
occurred in patients with chronic pancreatitis. Islet yield was significantly
lower in patients with chronic pancreatitis than in patients with benign tumors
(2044 equivalent islet number/gram resected pancreas versus 5184 equivalent islet
number/gram; P=0.037). In islet allotransplantation, no early graft loss was
found. All 13 patients who underwent allotransplantation had basal C-peptide
levels above 0.3 nmol/L for 3 months to 5 years. Mean glycosylated hemoglobin
decreased from 9.1% before transplantation to 5.5% at month 3. Insulin
independence was achieved in two type I diabetic patients. In four of six
patients with graft failure, the graft had induced panel-reactive antibodies.
CONCLUSIONS: In islet autotransplantation, the reduced number of islets that can
be isolated from fibrotic pancreata may be the major limiting factor. In islet
allotransplantation, early graft function can now be consistently achieved. Islet
allografts seem to be highly immunogenic, and chronic islet failure cannot be
prevented consistently by conventional immunosuppression.
PMID- 10762217
TI - Impact of the Banff '97 classification for histological diagnosis of rejection on
clinical outcome and renal function parameters after kidney transplantation.
AB - BACKGROUND: Data on a systematic correlation of specific pathomorphologic lesions
in renal allograft biopsy specimens with clinical outcome parameters are crucial
to determine the relevance of kidney biopsy findings after transplantation for
graft prognosis. Specific histologic lesions of the revised Banff '97
classification were correlated with clinical follow-up data. METHODS: The
analysis was done on a series of 48 consecutive renal allograft biopsy specimens.
Logistic regression was used to compare for response to rejection treatment
dependent on histologic grading. Cox regression was applied to analyze the impact
of the histologic findings on graft failure during ongoing follow-up. RESULTS:
Severity of acute rejection was statistically associated with unresponsiveness to
antirejection treatment (odds ratio 2.39, 95% confidence interval 1.13-5.03) and
predicted an increased risk of graft failure (hazard ratio 2.16, 95% confidence
interval 1.48-3.14). Intimal arteritis (hazard ratio 1.85, 95% confidence
interval 1.40-2.45) was the only determinate of a poor survival prognosis. Mean
serum creatinine level and the need for antihypertensive drugs were significantly
higher in the Banff I-III graded groups after 1 and 2 years of follow-up, whereas
patients with borderline rejection were not significantly different from the
control group. CONCLUSION: We confirmed a significant association between the
revised Banff '97 classification and graft outcome. Intimal arteritis was the
only significant predictor of a poor survival probability. The distinction of
borderline rejection and Banff grade I rejection seems to be important from a
prognostic point of view.
PMID- 10762218
TI - Inhibition of hyperacute transplant rejection by soluble proteins with the
functional domains of CD46 and FcgammaRII.
AB - BACKGROUND: Recombinant soluble forms of complement regulatory molecules,
including the human complement regulatory protein CD46 (rsCD46), have been shown
to inhibit hyperacute transplant rejection (HAR) and protect against complement
mediated inflammatory tissue damage. Similarly, recombinant soluble forms of the
immunoglobulin receptor FcgammaRII (rsFcgammaRII) can attenuate antibody-mediated
inflammatory responses. We have produced and tested the function of novel
recombinant chimeric proteins that incorporate the functional domains of both
CD46 (membrane cofactor protein, MCP) and the low affinity human IgG receptor
FcgammaRII (CD32). METHODS: Two recombinant soluble chimeric proteins (CD46:FcR
and FcR:CD46) were designed and produced using a human cell expression system.
Their ability to protect cells against complement-mediated lysis (through the
CD46 domain) and bind human IgG (through the Fc receptor domain) was assessed in
vitro. They were also tested in vivo in the rat reverse passive Arthus reaction
and a murine model of hyperacute cardiac transplant rejection. RESULTS: In vitro,
the functional domains of the chimeric proteins each retained their activity. In
vivo, the serum half-life of the recombinant chimeric proteins in mice was more
than either rsCD46 or rsFcgammaRII. In the rat reverse passive Arthus reaction,
intradermal injection of each recombinant protein substantially reduced
inflammatory skin edema (>50%) and polymorphonuclear neutrophil infiltration
(>90%). In the hyperacute rejection model, i.v. treatment with FcR:CD46 prevented
complement-mediated rejection, macroscopic bruising, edema, and thrombosis more
effectively than rsCD46. CONCLUSIONS: CD46/FcgammaRII bifunctional proteins have
an improved ability to control complement-mediated hyperacute graft rejection and
have therapeutic potential in other conditions involving antibody-mediated
inflammation.
PMID- 10762219
TI - Prolongation of xenograft survival using monoclonal antibody CD45RB and
cyclophosphamide in rat-to-mouse kidney and heart transplant models.
AB - BACKGROUND: Intrigued by the finding that a monoclonal antibody (mAb) directed
against the B exon of restricted CD45 (CD45RB mAb) induced renal allograft
tolerance in the mouse model, we hypothesized that CD45RB mAb may prevent
xenograft rejection. We explored the role of CD45RB mAb in preventing xenograft
rejection in rat-to-mouse kidney and heart transplant models. METHODS: Mice with
rat kidney and heart xenografts were treated with a short course of mAb,
cyclosporine, cyclophosphamide, or mAb + cyclophosphamide combination therapy.
Untreated heart and kidney xenografts served as controls. RESULTS: Untreated
controls developed acute vascular and cellular rejection rapidly with a median
survival time of only 6 days. Long-term kidney (median survival time = 70 days)
and heart xenograft survival (median survival time = 65 days) was achieved using
the combination therapy of mAb + cyclophosphamide. One-third of the kidney
recipients with combination therapy survived 100 days. Immunohistochemistry and
xenospecific-antibody analysis demonstrated that combination therapy remarkably
reduced IgG and IgM deposition and also inhibited CD4+, CD8+, and Mac-1+ cell
infiltration at early stages. This therapy, however, did not induce tolerance in
this model as evoked xenoreactive antibodies and cellular responses may be the
cause of late xenograft failure. CONCLUSION: A short course of CD45RB mAb
combined with cyclophosphamide effectively inhibits cellular and humoral
immunoresponses and remarkably prolongs xenograft survival in rat-to-mouse heart
and kidney transplant models.
PMID- 10762220
TI - Early expression of interferon-gamma inducible protein 10 and monokine induced by
interferon-gamma in cardiac allografts is mediated by CD8+ T cells.
AB - BACKGROUND: Our goal was to test the intragraft mRNA expression and production of
two chemokines that are potent chemoattractants for antigen-primed T cells,
interferon-gamma inducible protein 10 (IP-10) and monokine-induced by IFN-gamma,
(Mig), in allogeneic heart grafts. METHODS: Syngeneic or allogeneic A/J (H-2a)
hearts were heterotopically transplanted to wild-type, CD4-/-, CD8alpha-/-, or
IFN-gamma-/- C57BL/6 (H-2b) recipients. To test expression of IP-10 and Mig,
grafts were removed 1-8 days posttransplant for RNA isolation and Northern blot
analysis. To test the potential recipient leukocyte populations mediating
intraallograft expression of IP-10 and Mig, recipients were treated with anti-NK
1.1, anti-CD4, and/or anti-CD8 monoclonal antibodies before transplantation.
RESULTS: Allogeneic heart grafts transplanted to wild-type, but not IFN-gamma-/-,
recipients expressed IP-10 and Mig at day +2 posttransplant that increased
thereafter until rejection was completed. Expression of IP-10 and Mig in
isografts was low or undetectable. Cardiac allografts from CD8+ T cell depleted,
but not NK cell or CD4+ T cell depleted, recipients had low to undetectable
expression of IP-10 and Mig on day +2 posttransplant. Similarly, cardiac
allografts from CD8-/-, but not CD4-/-, recipients had low to undetectable
expression of IP-10 and Mig on day +2 posttransplant. CONCLUSIONS: Early
intraallograft expression of Mig and IP-10 during primary rejection of cardiac
allografts is dependent on the activities of recipient CD8+ T cells.
PMID- 10762221
TI - Influence of cold ischemia time, pretransplant anti-porcine antibodies, and
donor/recipient size matching on hyperacute graft rejection after discordant
porcine to cynomolgus kidney transplantation.
AB - Organs transplanted between phylogenetically disparate species, such as from the
pig into the primate, are subject to hyperacute rejection (HAR). This form of
xenograft rejection is mediated by preformed natural antibodies and is believed
to occur invariably in discordant xenografts thus leading to rapid destruction
and complete thrombosis of the graft. Recent data, however, have shown that in
the porcine to cynomolgus monkey setting, HAR is not inevitably seen after
porcine kidney transplantation. The influence of preoperative antiporcine
antibody levels in the recipient, cold ischemia time, and donor organ weight on
the onset of HAR was investigated by using unmodified large white pigs (aged 3-12
weeks) as organ donors and adult cynomolgus monkeys (aged 1.5-3.5 years) as
recipients. Porcine kidney xenotransplantation was performed in either a non-life
supporting model (n=7) or in a life-supporting model (n=8). In both models, no
correlation was found between cold ischemia time and HAR. When preoperative anti
porcine antibody levels were investigated, a significant increase in incidence of
HAR was observed in animals with elevated anti-porcine IgM (P<0.05) but not IgG
levels (P=NS). Interestingly, although 5 of 12 grafts with an organ weight of
less than 50 g underwent HAR, none of three grafts with a donor organ weight of
more than 70 g showed signs of HAR. In addition, all three larger grafts showed
intraoperative and postoperative urine production, although only in 1 (48 g) of
the 12 grafts weighing less than 50 g primary graft function was observed. In one
animal, a second porcine kidney (23 g) was successfully transplanted (without
HAR) immediately after HAR and subsequent removal of a first porcine kidney (20
g). These results indicate that in the porcine to cynomolgus monkey setting anti
porcine IgM rather than IgG anti-porcine antibody levels seem to be of
predominant importance for the induction of HAR. By increasing the donor organ
size and weight the frequency of the onset of HAR can be at least reduced. This
is most likely due to immunoabsorption of the recipients preformed antibodies in
the porcine kidney without lethal damage for the graft.
PMID- 10762222
TI - Cytomegalovirus infection of vascular cells induces expression of pro
inflammatory adhesion molecules by paracrine action of secreted interleukin
1beta.
AB - BACKGROUND: Infection with human cytomegalovirus (HCMV) has been associated with
vascular disease processes such as vascular allograft rejection, transplantation
vasculopathy, restenosis after angioplasty, and native atherosclerosis. To
elucidate underlying pathomechanisms, the effect of acute HCMV infection on the
expression of pro-inflammatory adhesion molecules on human umbilical vein
endothelial cells (HUVEC) and human vascular smooth muscle cells (hvSMC) was
examined. METHODS AND RESULTS: Cells were infected in vitro with clinical strains
of HCMV and the resulting changes in adhesion molecule expression were quantified
by histology and flow cytometric analysis. On HUVEC, surface expression of
vascular cell adhesion molecule-1 and E-selectin was induced de novo on HCMV
infection and intercellular adhesion molecule-1 expression was increased by
>200%. On hvSMC, intercellular adhesion molecule-1 surface expression induced de
novo, although vascular cell adhesion molecule-1 and E-selectin were not changed.
Expression of major histocompatibility complex (MHC) class II, lymphocyte
function associated antigen 3 (LFA-3; CD58), and CD40 was not altered by HCMV
infection in either cell type. In partially infected cultures, up-regulation of
surface molecules also occurred on noninfected cells, suggesting a paracrine
mechanism via a soluble factor. Expression of surface molecules could be enhanced
in noninfected HUVEC and hvSMC by incubation with virus-free conditioned
supernatant from HCMV-infected cells or by coincubation in transwells with
infected cells. The responsible agent could be identified as IL- interleukin-
(IL) 1beta by detection of de novo secretion of IL-1beta by HCMV-infected cells
and by prevention of adhesion molecule up-regulation after addition of an IL-1
converting enzyme inhibitor or IL-1 receptor antagonist. Surface molecule up
regulation could be suppressed by UV inactivation of virus, but not by treatment
of cell cultures with inhibitors of viral replication (ganciclovir). CONCLUSION:
We propose that HCMV infection induces IL-1beta release and subsequent up
regulation of pro-inflammatory adhesion molecules on noninfected neighboring
cells through a paracrine mechanism. This may lead to local potentiation of the
inflammatory effects of HCMV infection, not amenable to current therapeutic
antiviral strategies.
PMID- 10762223
TI - In vitro investigation of factors important for the delivery of an integrin
targeted nonviral DNA vector in organ transplantation.
AB - BACKGROUND: Polylysine-molossin is a 31 amino acid synthetic peptide that has
previously been demonstrated to function as a DNA vector in vitro for cell lines
and for the cornea. It incorporates the 15 amino acid integrin-binding domain of
the venom of the American pit viper, Crotalus molossus molossus as the targeting
moiety and a chain of 16 lysines as the DNA-binding moiety. The objective of this
study was to evaluate several parameters of importance for in vivo applications.
METHODS: Binding and tissue distribution of the vector/DNA complexes were
followed by a monoclonal antibody to the vector, or by the use of fluorescein
labeled DNA. Standard in vitro transfections were used to monitor effective gene
transfer. RESULTS: (1) Optimal DNA/vector concentration. Saturation of vector/DNA
binding sites on the ECV304 cell line occurred at 6 microg/ml of DNA. The
concentration of vector/DNA complexes required for optimal gene transfection was
found to be 2-8 microg/ml of DNA, corresponding to the concentration needed for
saturation binding. (2) Optimal target cell exposure time. Vector/ DNA complexes
saturated target cell binding sites within 5 min of incubation. However, lengthy
exposure times (>2-3 hr) to the transfection medium were essential for
substantial gene transfer. This was a consequence of two complementary factors.
First, it was important that target cells be exposed to vector/DNA complexes for
approximately 1 hr at 37 degrees C. Saturation of target sites at 4 degrees C and
then removal of the transfection medium was much less effective. Second, exposure
to chloroquine for 8-10 hr after uptake of vector/DNA complexes was essential for
optimal gene transfer. (3) Inhibitory effects of serum. Exposure of complexes to
even 1% serum before transfection, markedly inhibited gene transfer. However,
target cells previously saturated with vector/DNA complexes and then exposed to
10% serum showed substantial gene transfer. (4) Extravasation and binding
stability in vivo. Cold ex vivo perfusion of rat hearts with vector/DNA complexes
demonstrated that little, if any, complex moved out of the vascular system. After
transplantation of the heart, most of the complex bound to the vasculature was
lost within 30 min of reestablishing the blood circulation. CONCLUSIONS: Careful
attention to several parameters of little importance in vitro need to be paid for
optimal in vivo application of DNA vector systems.
PMID- 10762225
TI - Endothelial nitric oxide synthase protects aortic allografts from the development
of transplant arteriosclerosis.
AB - BACKGROUND: Inducible nitric oxide synthase (iNOS) is up-regulated in rejecting
allografts and is protective against allograft arteriosclerosis; it suppresses
neointimal smooth muscle cell accumulation and inhibits adhesion of platelets and
leukocytes to the endothelium. However, the functional importance of endothelial
NOS (eNOS) in the rejecting allografts remains unclear. METHODS: We examined the
effects of selective eNOS deficiency in aortic allografts in a murine chronic
rejection model using grafts from eNOS knockout (KO) mice (C57BL/6 background;
H2b) and normal C3H (H2K) as recipients. Grafts from wild-type C57BL/6 mice
served as controls. Grafts from iNOS KO mice served as a second group of controls
where the contribution from iNOS was eliminated but eNOS was preserved. Aortic
grafts were harvested and analyzed at days 10-14, 18-22, and 26-30 after
transplantation. RESULTS: Endothelial NOS-deficient grafts showed significantly
increased intima/media ratios at days 26-30 compared to controls. Immunostaining
demonstrated that in eNOS KO grafts, eNOS was not detectable whereas iNOS was
expressed prominently in infiltrating recipient mononuclear cells. In control
grafts, eNOS expression was preserved in the endothelium even by day 30, and
associated with a decrease in intimal thickening. We further demonstrated that
early overexpression of iNOS by ex vivo gene transfer completely prevented the
development of arteriosclerosis associated with eNOS deficiency. CONCLUSIONS: We
found that eNOS plays a protective role in allografts, and that in eNOS-deficient
allografts, early overexpression of iNOS is capable of preventing the development
of allograft arteriosclerosis. In allografts with dysfunctional vascular
endothelium and impaired eNOS activity as a result of ischemia or native
arteriosclerotic disease, iNOS gene therapy may serve to improve their long-term
survival and function.
PMID- 10762224
TI - Pancreatic islet xenograft tolerance after short-term costimulation blockade is
associated with increased CD4+ T cell apoptosis but not immune deviation.
AB - BACKGROUND: Our purpose was to determine if short-term inhibition of the
CD40/CD40L and CD28/B7 costimulatory pathways was capable of inducing specific
unresponsiveness to pancreatic islet xenografts and to ascertain the mechanism of
tolerance induction. METHODS: Diabetic B6AF1 mice were transplanted with Wistar
or DA rat islets and were treated short term with CTLA4-Fc and anti-CD40L mAb
(MR1). RESULTS: Coadministration of CTLA4-Fc with MR1, resulted in indefinite rat
islet xenograft survival in mice. Tolerance was species but not strain specific
as long-term surviving recipients rejected third party BALB/c islet allografts
but accepted a second rat islet xenograft from the same or different donor
strain. Tolerance induction was associated with a large leukocyte infiltrate that
did not exhibit features of immune deviation as intragraft T cell-specific
cytokine gene expression was globally reduced. In particular, interleukin-4 gene
expression was markedly suppressed. There was a complete inhibition of anti-donor
IgG, IgG1, and IgM antibody in the serum of CTLA4-Fc/MR1- treated animals.
Tolerance induction was associated with increased CD4+ T cell apoptosis as there
was an increased proportion of annexin-V staining and Fas expressing CD4+ T cells
and a decrease in CD4+ T cell Bcl-2 expression in the grafts and draining lymph
nodes of CTLA4-Fc/MR1-treated recipients. CONCLUSION: Combined costimulatory
blockade was capable of producing tolerance to pancreatic islet xenografts. The
induction of this tolerant state was associated with increased T cell apoptosis,
whereas the maintenance phase of tolerance was associated with the accumulation
of a large number of inactive lymphocytes within the graft.
PMID- 10762226
TI - Induction of anti-Forssman antibodies in the hamster-to-rat xenotransplantation
model.
AB - BACKGROUND: In the hamster-to-rat heart xenotransplantation model, the serum
response of the host contributes to determine whether the xenograft is
accommodated or rejected. METHODS: To further characterize the serum response in
this model, we compared anti-hamster antibodies found in naive LEW-1A rats, or in
LEW-1A rats rejecting or accommodating a hamster heart, using a combination of
cobra venom factor (CVF) and cyclosporin A (CsA) given for 10 days, and then CsA
alone. RESULTS: Hamster hearts grafted into rat recipients contained IgG and IgA
deposits to the same extent whether the xenograft was rejected or accommodated.
Only immunoglobulins of the IgM isotype were found to be more abundant in
recipients rejecting their graft. A significant part of this IgM response was
directed toward the Forssman antigen, a sphingolipid present in the hamster but
not in the rat. However, although anti-Forssman antibodies bind in situ to
hamster tissues, this binding was not able to induce hyperacute rejection after
antibody transfer. Furthermore, depletion of anti-Forssman antibodies from a
rejecting serum did not modify its rejection properties. CONCLUSION: Unlike the
pig-to-primate discordant xenotransplantation model, in which preexisting anti
carbohydrate antibodies are directly responsible for hyperacute rejection, in the
concordant hamster-to-rat situation, the evoked IgM anti-Forssman carbohydrate
antibodies do not appear to be the main cause of the vascular rejection.
PMID- 10762227
TI - Cytomegalovirus induces sialyl Lewis(x) and Lewis(x) on human endothelial cells.
AB - BACKGROUND: Cytomegalovirus (CMV) is the primary viral cause of complications in
transplant recipients. We sought to understand the mechanisms of its
dissemination and induction of vascular disease, which may lead to transplant
complications. Sialyl Lewis(x) (sLe(x)) and Lewis(x) (Le(x)) are known for their
roles in mediating cell adhesion and as tumor-associated carbohydrate antigens.
Herein we explore whether CMV induces surface expression of these important
molecules in endothelial cells (EC). METHODS: Flow cytometry was used to detect
surface expression of sLe(x) and Le(x) on CMV-infected human umbilical vein
endothelial cells (HUVEC), with or without ultraviolet inactivation of the virus.
To elucidate mechanisms of CMV-mediated induction, mRNA coding for predominant
HUVEC sialyltransferases (ST) and fucosyltransferases (FT), key enzymes in sLe(x)
and Le(x) synthesis, was analyzed by Northern blot. Dual immunohistochemical
staining for sLe(x) and Le(x) expression of human colon and placental tissue was
performed to investigate in vivo relevance. RESULTS: sLe(x) expression on CMV
infected HUVEC was strongly up-regulated by 8 days after inoculation. Le(x)
expression was detectable earlier and increased steadily over time. In contrast,
ultraviolet-inactivated CMV did not induce expression of these molecules.
Northern blot assays demonstrated higher levels of important EC
glycosyltransferases ST-IV, FT-III, and FT-IV in CMV-infected EC. Finally, high
levels of sLe(x) and Le(x) were expressed in CMV-infected EC in vivo.
CONCLUSIONS: Given the known biologic functions of sLe(x) and Le(x), we suggest
that CMV induction of these molecules may have widespread consequences ranging
from CMV dissemination to induction of CMV-associated vascular disease, including
thrombosis.
PMID- 10762228
TI - Programmed cell death signaling via cell-surface expression of a single-chain
antibody transgene.
AB - BACKGROUND: The monoclonal antibody, 5H7, is specific for a monomorphic
determinant on the a3 domain of human class I MHC (A, B, C). Immobilized 5H7
delivers programmed cell death (PCD) signals to human lymphoid tumor cells as
well as peripheral blood mononuclear cells. METHODS: The potential clinical
utility of 5H7 was addressed by design of a single-chain variable antibody
(scFv), termed 5H7scFv, which was coupled to glycophosphotidylinostitol (GPI),
thereby providing membrane expression of the 5H7 idiotype (5H7scFv-GPI). Membrane
expression of 5H7scFv-GPI conferred PCD-inducing properties to cells that do not
normally have the capability to process and express whole antibody molecules. The
initial construction was undertaken in a bacterial expression system, and
appropriate protein folding was determined by binding to class I MHC-expressing
cells. RESULTS: 5H7scFv-GPI-transfected Chinese hamster ovary cells demonstrated
reconstitution of the 5H7 idiotype and binding to soluble HLA-A2. Cross-linking
of class I MHC, via membrane expression of the scFv, provided effective PCD
signaling in B and T lymphocyte tumor cells. Peripheral blood mononuclear cells
were susceptible to 5H7scFv-GPI-induced PCD, and augmentation of PCD signals was
noted with anti-CD3 and anti-CD28 preactivation. Responder cells demonstrated
typical histologic features of PCD and Annexin V-fluorescein isothiocyanate
binding. CONCLUSIONS: Cell surface anchorage of scFv thus provides effective
delivery of immune modulatory signals, which may be manipulated for various
therapeutic strategies.
PMID- 10762229
TI - The effect of conversion from cyclosporine to tacrolimus on gingival hyperplasia,
hirsutism and cholesterol.
AB - The use of cyclosporine for immunosuppression in renal transplantation allograft
recipients is associated with hypertrichosis, gingival hyperplasia, and
hypercholesterolemia. Conversion of patients to tacrolimus may lead to an
improvement in these effects with minimal risk of rejection or allograft
dysfunction. METHODS: Sixteen renal transplant recipients were prospectively
converted from CsA to tacrolimus and followed for 1 year. Gingival hyperplasia
index, total cholesterol, and blood pressure were recorded at the outset, 4-, 8-,
and 12-month intervals. Glomerular filtration rate was checked before conversion
and 1 year later. Photographs documenting hypertrichosis were taken before
conversion and 1 year later. Adverse effects from tacrolimus were recorded at 4,
8, and 12 months. RESULTS: Twelve patients with hypertrichosis noted rapid
improvement. Mean gingival hyperplasia index decreased from 24 to 6; mean total
cholesterol decreased from 237 to 195. Glomerular filtration rate was essentially
unchanged (56 to 54). One episode of rejection occurred, three patients developed
diarrhea, three noted headaches, and one had a tremor. CONCLUSION: If carefully
monitored, patients suffering adverse effects secondary to cyclosporine may be
converted to tacrolimus with minimal risk of allograft dysfunction or rejection.
PMID- 10762230
TI - Transplantation and 2-year follow-up of kidneys procured from a cadaver donor
with a history of lupus nephritis.
AB - BACKGROUND: Two patients underwent cadaver transplantation with kidneys from a
donor with a history of World Health Organization Class IV/V lupus nephritis, and
we report their clinical and pathological outcome. METHODS: The donor had a
diagnosis of lupus nephritis made by renal biopsy 5 years before donation. At the
time of donation, a biopsy was performed on the donor and on one of the
recipients at 2 months and 1 year after the transplant. RESULTS: Both recipients
underwent uneventful renal transplantation. On the first postoperative day, the
donor's final pathological results became available. Although the frozen section
seemed to be quite benign, the permanent sections revealed World Health
Organization Class II/V lupus nephritis, with full house immunofluorescence and
multiple electron dense deposits. Biopsies were performed on recipient #2 at 8
weeks and 1 year after the transplant. These revealed marked diminution followed
by complete resolution of all tubular reticular structures and deposits as well
as immunofluorescent activity. Both recipients remain with normal renal function
and urinalysis at 3 years after the transplant. CONCLUSION: Although a history of
clinically significant renal disease has been considered an absolute
contraindication to kidney donation, with appropriate workup and caution, select
patients may still be considered, which would increase the potential donor pool.
PMID- 10762231
TI - Successful transplant of a liver from a kidney transplant recipient 11 years
after transplantation.
PMID- 10762232
TI - Molecular control of expression of penicillin biosynthesis genes in fungi:
regulatory proteins interact with a bidirectional promoter region.
PMID- 10762233
TI - Genetic analysis of functions involved in adhesion of Pseudomonas putida to
seeds.
AB - Many agricultural uses of bacteria require the establishment of efficient
bacterial populations in the rhizosphere, for which colonization of plant seeds
often constitutes a critical first step. Pseudomonas putida KT2440 is a strain
that colonizes the rhizosphere of a number of agronomically important plants at
high population densities. To identify the functions involved in initial seed
colonization by P. putida KT2440, we subjected this strain to transposon
mutagenesis and screened for mutants defective in attachment to corn seeds. Eight
different mutants were isolated and characterized. While all of them showed
reduced attachment to seeds, only two had strong defects in their adhesion to
abiotic surfaces (glass and different plastics). Sequences of the loci affected
in all eight mutants were obtained. None of the isolated genes had previously
been described in P. putida, although four of them showed clear similarities with
genes of known functions in other organisms. They corresponded to putative
surface and membrane proteins, including a calcium-binding protein, a hemolysin,
a peptide transporter, and a potential multidrug efflux pump. One other showed
limited similarities with surface proteins, while the remaining three presented
no obvious similarities with known genes, indicating that this study has
disclosed novel functions.
PMID- 10762234
TI - Functional expression in Escherichia coli and membrane topology of porin HopE, a
member of a large family of conserved proteins in Helicobacter pylori.
AB - HopE is one of the smallest members of a family of 31 outer membrane proteins in
Helicobacter pylori and has been shown to function as a porin. In this study it
was cloned into Escherichia coli where it was expressed in the outer membrane, as
confirmed by indirect immunofluorescence using HopE-specific antibodies. HopE
purified from E. coli reconstituted channels in planar bilayer membranes that
were the same size as those formed by HopE purified from H. pylori. A model of
the membrane topology of HopE was constructed and indicated that this protein
formed a beta-barrel with 16 transmembrane amphipathic beta-strands. The accuracy
of this model was tested by linker insertion mutagenesis, assuming that, like
other porins, amino acid insertions were not tolerated in the transmembrane beta
strands but were tolerated in the adjoining loop regions. Generally, the results
obtained with a series of 12 insertions of the sequence RSKDV and two
substitutions were consistent with the topological model. The preponderance of
amino acids that were conserved in the extended family of HopE paralogs were
predicted to be within the membrane and comprised 45% of all residues in the
membrane.
PMID- 10762235
TI - A rac homolog is required for induction of hyphal growth in the dimorphic yeast
Yarrowia lipolytica.
AB - Dimorphism in fungi is believed to constitute a mechanism of response to adverse
conditions and represents an important attribute for the development of virulence
by a number of pathogenic fungal species. We have isolated YlRAC1, a gene
encoding a 192-amino-acid protein that is essential for hyphal growth in the
dimorphic yeast Yarrowia lipolytica and which represents the first Rac homolog
described for fungi. YlRAC1 is not an essential gene, and its deletion does not
affect the ability to mate or impair actin polarization in Y. lipolytica.
However, strains lacking functional YlRAC1 show alterations in cell morphology,
suggesting that the function of YlRAC1 may be related to some aspect of the
polarization of cell growth. Northern blot analysis showed that transcription of
YlRAC1 increases steadily during the yeast-to-hypha transition, while Southern
blot analysis of genomic DNA suggested the presence of several RAC family members
in Y. lipolytica. Interestingly, strains lacking functional YlRAC1 are still able
to grow as the pseudohyphal form and to invade agar, thus pointing to a function
for YlRAC1 downstream of MHY1, a previously isolated gene encoding a C(2)H(2)
type zinc finger protein with the ability to bind putative stress response
elements and whose activity is essential for both hyphal and pseudohyphal growth
in Y. lipolytica.
PMID- 10762236
TI - A new IS4 family insertion sequence, IS4Bsu1, responsible for genetic instability
of poly-gamma-glutamic acid production in Bacillus subtilis.
AB - Certain Bacillus subtilis strains, such as B. subtilis (natto) starter strains
for the manufacture of natto (fermented soybeans), produce capsular poly-gamma
glutamate (gammaPGA). In B. subtilis (natto), gammaPGA synthesis is controlled by
the ComP-ComA two-component regulatory system and thereby induced at the
beginning of the stationary growth phase. We have found a new insertion sequence
(IS), designated IS4Bsu1, in the comP gene of a spontaneous gammaPGA-negative
mutant of B. subtilis (natto) NAF4. IS4Bsu1 (1,406 bp), the first IS discovered
in B. subtilis, encodes a putative transposase (Tpase) with a predicted M(r) of
34,895 (374 residues) which displays similarity to the Tpases of IS4 family
members. Southern blot analyses have identified 6 to 11 copies of IS4Bsu1, among
which 6 copies were at the same loci, in the chromosomes of B. subtilis (natto)
strains, including NAF4, three commercial starters, and another three gammaPGA
producing B. subtilis (natto) strains. All of the eight spontaneous gammaPGA(-)
mutants, which were derived from five independent NAF4 cultures, had a new
additional IS4Bsu1 copy in comP at six different positions within 600 bp of the
5'-terminal region. The target sites of IS4Bsu1 were determined to be AT-rich 9
bp sequences by sequencing the flanking regions of IS4Bsu1 in mutant comP genes.
These results indicate that IS4Bsu1 transposes by the replicative mechanism, in
contrast to other IS4 members that use the conservative mechanism, and that most,
if not all, of spontaneous gammaPGA(-) mutants appear to have resulted from the
insertion of IS4Bsu1 exclusively into comP. The presence of insertion hot spots
in comP, which is essential for gammaPGA synthesis, as well as high transposition
activity, would account for the high frequency of spontaneous gammaPGA(-)
mutation by IS4Bsu1 in B. subtilis (natto).
PMID- 10762237
TI - Genetic variation and evolutionary origin of the direct repeat locus of
Mycobacterium tuberculosis complex bacteria.
AB - The direct repeat region in Mycobacterium tuberculosis complex strains is
composed of multiple direct variant repeats (DVRs), each of which is composed of
a 36-bp direct repeat (DR) plus a nonrepetitive spacer sequence of similar size.
It has been shown previously that clinical isolates show extensive polymorphism
in the DR region by the variable presence of DVRs, and this polymorphism has been
used in the epidemiology of tuberculosis. In an attempt to better understand the
evolutionary scenario leading to polymorphic DR loci and to improve strain
differentiation by spoligotyping, we characterized and compared the DNA sequences
of the complete DR region and its flanking DNA of M. tuberculosis complex
strains. We identified 94 different spacer sequences among 26 M. tuberculosis
complex strains. No sequence homology was found between any of these spacers and
M. tuberculosis DNA outside of the DR region or with any other known bacterial
sequence. Although strains differed extensively in the presence or absence of
DVRs, the order of the spacers in the DR locus was found to be well conserved.
The data strongly suggest that the polymorphism in clinical isolates is the
result of successive deletions of single discrete DVRs or of multiple contiguous
DVRs from a primordial DR region containing many more DVRs than seen in present
day isolates and that virtually no scrambling of DVRs took place during
evolution. Because the majority of the novel spacer sequences identified in this
study were confined to isolates of the rare Mycobacterium canettii taxon, the use
of the novel spacers in spoligotyping led only to a slight improvement of strain
differentiation by spoligotyping.
PMID- 10762238
TI - Insertion mutagenesis and membrane topology model of the Pseudomonas aeruginosa
outer membrane protein OprM.
AB - Pseudomonas aeruginosa OprM is a protein involved in multiple-antibiotic
resistance as the outer membrane component for the MexA-MexB-OprM efflux system.
Planar lipid bilayer experiments showed that OprM had channel-forming activity
with an average single-channel conductance of only about 80 pS in 1 M KCl. The
gene encoding OprM was subjected to insertion mutagenesis by cloning of a foreign
epitope from the circumsporozoite form of the malarial parasite Plasmodium
falciparum into 11 sites. In Escherichia coli, 8 of the 11 insertion mutant genes
expressed proteins at levels comparable to those obtained with the wild-type gene
and the inserted malarial epitopes were surface accessible as assessed by
indirect immunofluorescence. When moved to a P. aeruginosa OprM-deficient strain,
seven of the insertion mutant genes expressed proteins at variable levels
comparable to that of wild-type OprM and three of these reconstituted MIC
profiles resembling those of the wild-type protein, while the other mutant forms
showed variable MIC results. Utilizing the data from these experiments, in
conjunction with multiple sequence alignments and structure predictions, an OprM
topology model with 16 beta strands was proposed.
PMID- 10762239
TI - Natural genetic competence in Bacillus subtilis natto OK2.
AB - We isolated a Bacillus subtilis natto strain, designated OK2, from a lot of
commercial fermented soybean natto and studied its ability to undergo natural
competence development using a comG-lacZ fusion at the amyE locus. Although
transcription of the late competence genes was not detected in the B. subtilis
natto strain OK2 during competence development, these genes were constitutively
transcribed in the OK2 strain carrying either the mecA or the clpC mutation
derived from B. subtilis 168. In addition, both OK2 mutants exhibited high
transformation frequencies, comparable with that observed for B. subtilis 168.
Moreover, as expected from these results, overproduction of ComK derived from
strain 168 in strain OK2 resulted in a high transformation frequency as well as
in induction of the late competence genes. These results clearly indicated that
ComK produced in both the mecA and clpC mutants of strain OK2 (ComK(OK2)) could
activate the transcription of the whole set of late competence genes and
suggested that ComK(OK2) was not activated in strain OK2 during competence
development. We therefore sequenced the comS gene of OK2 and compared it with
that of 168. The comS(OK2) had a single-base change, resulting in the replacement
of Ser (strain 168) by Cys (strain OK2) at position 11.
PMID- 10762240
TI - The stability region of the large virulence plasmid of Shigella flexneri encodes
an efficient postsegregational killing system.
AB - The large virulence plasmid pMYSH6000 of Shigella flexneri contains a determinant
that is highly effective in stabilizing otherwise unstable plasmids in
Escherichia coli. Expression of two small contiguous genes, mvpA and mvpT
(formerly termed STBORF1 and STBORF2), was shown to be sufficient for stability.
Mutations in mvpT abolished plasmid stability, and plasmids expressing only mvpT
killed the cells unless mvpA was supplied from a separate plasmid or from the
host chromosome. When replication of a plasmid carrying the minimal mvp region
was blocked, growth of the culture stopped after a short lag and virtually all of
the surviving cells retained the plasmid. Thus, the mvp system stabilizes by a
highly efficient postsegregational killing (PSK) mechanism, with mvpT encoding a
cell toxin and mvpA encoding an antidote. The regions that surround the mvp genes
in their original context have an inhibitory effect that attenuates plasmid
stabilization and PSK. The region encompassing the mvp genes also appears to
contain an additional element that can aid propagation of a pSC101-based plasmid
under conditions where replication initiation is marginal. However, this appears
to be a relatively nonspecific effect of DNA insertion into the plasmid vector.
PMID- 10762241
TI - Action of RNase II and polynucleotide phosphorylase against RNAs containing stem
loops of defined structure.
AB - The 3'-->5' exoribonucleases, RNase II and polynucleotide phosphorylase (PNPase),
play an essential role in degrading fragments of mRNA generated by prior
cleavages by endonucleases. We have assessed the ability of small RNA substrates
containing defined stem-loop structures and variable 3' extensions to impede the
exonucleolytic activity of these enzymes. We find that stem-loops containing five
G-C base pairs do not block either enzyme; in contrast, more stable stem-loops of
7, 9, or 11 bp block the processive action of both enzymes. Under conditions
where enzyme activity is limiting, both enzymes stall and dissociate from their
substrates six to nine residues, on average, from the base of a stable stem-loop
structure. Our data provide a clear mechanistic explanation for the previous
observation that RNase II and PNPase behave as functionally redundant.
PMID- 10762242
TI - Calcofluor antifungal action depends on chitin and a functional high-osmolarity
glycerol response (HOG) pathway: evidence for a physiological role of the
Saccharomyces cerevisiae HOG pathway under noninducing conditions.
AB - We have isolated several Saccharomyces cerevisiae mutants resistant to calcofluor
that contain mutations in the PBS2 or HOG1 genes, which encode the mitogen
activated protein kinase (MAPK) and MAP kinases, respectively, of the high
osmolarity glycerol response (HOG) pathway. We report that blockage of either of
the two activation branches of the pathway, namely, SHO1 and SLN1, leads to
partial resistance to calcofluor, while simultaneous disruption significantly
increases resistance. However, chitin biosynthesis is independent of the HOG
pathway. Calcofluor treatment also induces an increase in salt tolerance and
glycerol accumulation, although no activation of the HOG pathway is detected. Our
results indicate that the antifungal effect of calcofluor depends on its binding
to cell wall chitin but also on the presence of a functional HOG pathway.
Characterization of one of the mutants isolated, pbs2-14, revealed that
resistance to calcofluor and HOG-dependent osmoadaptation are two different
physiological processes. Sensitivity to calcofluor depends on the constitutive
functionality of the HOG pathway; when this is altered, the cells become
calcofluor resistant but also show very low levels of basal salt tolerance.
Characterization of some multicopy suppressors of the calcofluor resistance
phenotype indicated that constitutive HOG functionality participates in the
maintenance of cell wall architecture, a conclusion supported by the antagonism
observed between the protein kinase and HOG signal transduction pathways.
PMID- 10762243
TI - A sigma(54) activator protein necessary for spore differentiation within the
fruiting body of Myxococcus xanthus.
AB - Insertion of an internal DNA fragment into the act1 gene, which encodes one of
several sigma(54)-activator proteins in Myxococcus xanthus, produced a mutant
defective in fruiting body development. While fruiting-body aggregation appears
normal in the mutant, it fails to sporulate (<10(-6) the wild-type number of
viable spores). The A and C intercellular signals, which are required for
sporulation, are produced by the mutant. But, while it produces A-factor at
levels as high as that of the wild type, the mutant produces much less C-signal
than normal, as measured either by C-factor bioassay or by the total amount of C
factor protein detected with specific antibody. Expression of three C-factor
dependent reporters is altered in the mutant: the level of expression of
Omega4414 is about 15% of normal, and Omega4459 and Omega4403 have alterations in
their time course. Finally, the methylation of FrzCD protein is below normal in
the mutant. It is proposed that Act1 protein responds to C-signal reception by
increasing the expression of the csgA gene. This C-signal-dependent increase
constitutes a positive feedback in the wild type. The act1 mutant, unable to
raise the level of csgA expression, carries out only those developmental steps
for which a low level of C-signaling is adequate.
PMID- 10762244
TI - Efficient targeted mutagenesis in Borrelia burgdorferi.
AB - Genetic studies in Borrelia burgdorferi have been hindered by the lack of a
nonborrelial selectable marker. Currently, the only selectable marker is gyrB(r),
a mutated form of the chromosomal gyrB gene that encodes the B subunit of DNA
gyrase and confers resistance to the antibiotic coumermycin A(1). The utility of
the coumermycin-resistant gyrB(r) gene for targeted gene disruption is limited by
a high frequency of recombination with the endogenous gyrB gene. A kanamycin
resistance gene (kan) was introduced into B. burgdorferi, and its use as a
selectable marker was explored in an effort to improve the genetic manipulation
of this pathogen. B. burgdorferi transformants with the kan gene expressed from
its native promoter were susceptible to kanamycin. In striking contrast,
transformants with the kan gene expressed from either the B. burgdorferi flaB or
flgB promoter were resistant to high levels of kanamycin. The kanamycin
resistance marker allows efficient direct selection of mutants in B. burgdorferi
and hence is a significant improvement in the ability to construct isogenic
mutant strains in this pathogen.
PMID- 10762245
TI - Probing the CD lumenal loop region of the D2 protein of photosystem II in
Synechocystis sp. strain PCC 6803 by combinatorial mutagenesis.
AB - The CD lumenal loop region of the photosystem II reaction center protein D2
contains residues involved in oxygen evolution. Since detailed structural
information about this region is unavailable, an M13-based combinatorial
mutagenesis approach was used to investigate structure-function relationships in
this vital region of D2 in Synechocystis sp. strain PCC 6803. The CD loop coding
region contains close to 100 nucleotides, and for effective mutagenesis, it was
subdivided into four regions of seven to eight codons. A gain-of-function
selection protocol was employed such that all mutants that were selected
contained a functional D2 protein. In this way, conservation patterns of residues
along with numbers and types of amino acid substitutions accommodated at each
position for each set of mutants would indicate which residues in the CD loop may
play important structural and functional roles. Results of this study have
substantiated the importance of residues previously studied by site-directed
mutagenesis such as Arg180 and His189 and have identified other previously
unremarkable residues in the CD loop (such as Ser166, Phe169, and Ala170) that
cannot be replaced by many other residues. In addition, the pliability of the CD
loop was further tested using deletion and D1-D2 substitution constructs in M13.
This showed that the length of the loop was important to its function, and in two
cases, D2 could accommodate homologous sequences from D1, which forms a
heterodimer with D2 in photosystem II, but not the other way around. This study
of the CD loop in D2 provides valuable clues regarding the structural and
functional requirements of the region.
PMID- 10762246
TI - Dimers of pi protein bind the A+T-rich region of the R6K gamma origin near the
leading-strand synthesis start sites: regulatory implications.
AB - The replication of gamma origin, a minimal replicon derived from plasmid R6K, is
controlled by the Rep protein pi. At low intracellular concentrations, pi
activates the gamma origin, while it inhibits replication at elevated
concentrations. Additionally, pi acts as a transcription factor (auto)repressing
its own synthesis. These varied regulatory functions depend on pi binding to
reiterated DNA sequences bearing a TGAGNG motif. However, pi also binds to a "non
iteron" site (i.e., not TGAGNG) that resides in the A+T-rich region adjacent to
the iterons. This positioning places the non-iteron site near the start sites for
leading-strand synthesis that also occur in the A+T-rich region of gamma origin.
We have hypothesized that origin activation (at low pi levels) would require the
binding of pi monomers to iterons, while the binding of pi dimers to the non
iteron site (at high pi levels) would be required to inhibit priming. Although
monomers as well as dimers can bind to an iteron, we demonstrate that only dimers
bind to the non-iteron site. Two additional pieces of data support the hypothesis
of negative replication control by pi binding to the non-iteron site. First, pi
binds to the non-iteron site about eight times less well than it binds to a
single iteron. Second, hyperactive variants of pi protein (called copy-up) either
do not bind to the non-iteron site or bind to it less well than wild-type pi. We
propose a replication control mechanism whereby pi would directly inhibit primer
formation.
PMID- 10762247
TI - Regions of RNase E important for 5'-end-dependent RNA cleavage and autoregulated
synthesis.
AB - RNase E is an important regulatory enzyme that plays a key role in RNA processing
and degradation in Escherichia coli. Internal cleavage by this endonuclease is
accelerated by the presence of a monophosphate at the RNA 5' end. Here we show
that the preference of E. coli RNase E for 5'-monophosphorylated substrates is an
intrinsic property of the catalytically active amino-terminal half of the enzyme
and does not require the carboxy-terminal region. This property is shared by the
related E. coli ribonuclease CafA (RNase G) and by a cyanobacterial RNase E
homolog derived from Synechocystis, indicating that the 5'-end dependence of
RNase E is a general characteristic of members of this ribonuclease family,
including those from evolutionarily distant species. Although it is dispensable
for 5'-end-dependent RNA cleavage, the carboxy-terminal half of RNase E
significantly enhances the ability of this ribonuclease to autoregulate its
synthesis in E. coli. Despite similarities in amino acid sequence and substrate
specificity, CafA is unable to replace RNase E in sustaining E. coli cell growth
or in regulating RNase E production, even when overproduced sixfold relative to
wild-type RNase E levels.
PMID- 10762248
TI - Distribution of twelve linear extrachromosomal DNAs in natural isolates of Lyme
disease spirochetes.
AB - We have analyzed a panel of independent North American isolates of the Lyme
disease agent spirochete, Borrelia burgdorferi (sensu stricto), for the presence
of linear plasmids with sequence similarities to the 12 linear plasmids present
in the B. burgdorferi type strain, isolate B31. The frequency of similarities to
probes from each of the 12 B31 plasmids varied from 13 to 100% in the strain
panel examined, and these similarities usually reside on plasmids similar in size
to the cognate B31 plasmid. Sequences similar to 5 of the 12 B31 plasmids were
found in all of the isolates examined, and >66% of the panel members hybridized
to probes from 4 other plasmids. Sequences similar to most of the B. burgdorferi
B31 plasmid-derived DNA probes used were also found on linear plasmids in the
related Eurasian Lyme agents Borrelia garinii and Borrelia afzelii; however, some
of these plasmids had uniform but substantially different sizes from their B.
burgdorferi counterparts.
PMID- 10762250
TI - An n-alkane-responsive promoter element found in the gene encoding the
peroxisomal protein of Candida tropicalis does not contain a C(6) zinc cluster
DNA-binding motif.
AB - When an asporogenic diploid yeast, Candida tropicalis, is cultivated on n-alkane,
the expression of the genes encoding enzymes of the peroxisomal beta-oxidation
pathway is highly induced. An upstream activation sequence (UAS) which can induce
transcription in response to n-alkane (UAS(ALK)) was identified on the promoter
region of the peroxisomal 3-ketoacyl coenzyme A (CoA) thiolase gene of C.
tropicalis (CT-T3A). The 29-bp region (from -289 to -261) present upstream of the
TATA sequence was sufficient to induce n-alkane-dependent expression of a
reporter gene. Besides n-alkane, UAS(ALK)-dependent gene expression also occurred
in the cells grown on oleic acid. Several kinds of mutant UAS(ALK) were
constructed and tested for their UAS activity. It was clarified that the
important nucleotides for UAS(ALK) activity were located within 10-bp region from
-273 to -264 (5'-TCCTGCACAC-3'). This region did not contain a CGG triplet and
therefore differed from the sequence of the oleate-response element (ORE), which
is a UAS found on the promoter region of 3-ketoacyl-CoA thiolase gene of
Saccharomyces cerevisiae. Similar sequences to UAS(ALK) were also found on
several peroxisomal enzyme-encoding genes of C. tropicalis.
PMID- 10762249
TI - Genome plasticity among related ++Lactococcus strains: identification of genetic
events associated with macrorestriction polymorphisms.
AB - The genomic diversity of nine strains of the Lactococcus lactis subsp. cremoris
(NCDO712, NCDO505, NCDO2031, NCDO763, MMS36, C2, LM0230, LM2301, and MG1363) was
studied by macrorestriction enzyme analysis using pulsed-field gel
electrophoresis. These strains were considered adequate for the investigation of
genomic plasticity because they have been described as belonging to the same
genetic lineage. Comparison of ApaI and SmaI genome fingerprints of each strain
revealed the presence of several macrorestriction fragment length polymorphisms
(RFLPs), despite a high degree of similarity of the generated restriction
patterns. The physical map of the MG1363 chromosome was used to establish a
genome map of the other strains and allocate the RFLPs to five regions. Southern
hybridization analysis correlated the polymorphic regions with genetic events
such as chromosomal inversion, integration of prophage DNA, and location of the
transposon-like structures carrying conjugative factor or oligopeptide transport
system.
PMID- 10762251
TI - Effects of bfp mutations on biogenesis of functional enteropathogenic Escherichia
coli type IV pili.
AB - Enteropathogenic Escherichia coli expresses a type IV fimbria known as the bundle
forming pilus (BFP) that is required for autoaggregation and localized adherence
(LA) to host cells. A cluster of 14 genes is sufficient to reconstitute BFP
biogenesis in a laboratory strain of E. coli. We have undertaken a systematic
mutagenesis of the individual genes to determine the effect of each mutation on
BFP biogenesis and LA. Here we report the construction and analysis of nonpolar
mutations in six genes of the bfp cluster, bfpG, bfpB, bfpC, bfpD, bfpP, and
bfpH, as well as the further analysis of a previously described bfpA mutant
strain that is unable to express bundlin, the pilin protein. We found that
mutations in bfpB, which encodes an outer membrane protein; bfpD, which encodes a
putative nucleotide-binding protein; and bfpG and bfpC, which do not have
sequence homologues in other type IV pilus systems, do not affect prebundlin
expression or processing but block both BFP biogenesis and LA. The mutation in
bfpP, the prepilin peptidase gene, does not affect prebundlin expression but
blocks signal sequence cleavage of prebundlin, BFP biogenesis, and LA. The
mutation in bfpH, which is predicted to encode a lytic transglycosylase, has no
effect on prebundlin expression, prebundlin processing, BFP biogenesis, or LA.
For each mutant for which altered phenotypes were detected, complementation with
a plasmid containing the corresponding wild-type allele restored the wild-type
phenotypes. We also found that association of prebundlin or bundlin with sucrose
density flotation gradient fractions containing both inner and outer membrane
proteins does not require any accessory proteins. These studies indicate that
many bfp gene products are required for biogenesis of functional type IV pili but
that mutations in the individual genes do not lead to the identification of new
phases of pilus assembly.
PMID- 10762252
TI - Evidence for Na(+) influx via the NtpJ protein of the KtrII K(+) uptake system in
Enterococcus hirae.
AB - The ntpJ gene, a cistron located at the tail end of the vacuolar-type Na(+)
ATPase (ntp) operon of Enterococcus hirae, encodes a transporter of the KtrII
K(+) uptake system. We found that K(+) accumulation in the ntpJ-disrupted mutant
JEM2 was markedly enhanced by addition of valinomycin at pH 10. Studies of the
membrane potential (DeltaPsi; inside negative) by 3, 3'-dihexyloxacarbocyanine
iodide fluorescence revealed that the DeltaPsi was hyperpolarized at pH 10 in
JEM2; the DeltaPsi values of the parent strain ATCC 9790 and JEM2, estimated by
determining the equilibrium distribution of K(+) or Rb(+) in the presence of
valinomycin, were -118 and -160 mV, respectively. DeltaPsi generation at pH 10
was accomplished by an electrogenic Na(+) efflux via the Na(+)-ATPase, whose
levels in the two strains were quite similar. Na(+) uptake driven by an
artificially imposed DeltaPsi (inside negative) was missing in JEM2, suggesting
that NtpJ mediates Na(+) movement in addition to K(+) movement. Finally, the
growth of JEM2 arrested in K(+)-limited high-Na(+) medium at pH 10 was restored
by addition of valinomycin. These results suggest that NtpJ mediates electrogenic
transport of K(+) as well as Na(+), that it likely mediates K(+) and Na(+)
cotransport, and that Na(+) movement via NtpJ is the major Na(+) reentry pathway
at high pH values.
PMID- 10762253
TI - Role of ger proteins in nutrient and nonnutrient triggering of spore germination
in Bacillus subtilis.
AB - Dormant Bacillus subtilis spores germinate in the presence of particular
nutrients called germinants. The spores are thought to recognize germinants
through receptor proteins encoded by the gerA family of operons, which includes
gerA, gerB, and gerK. We sought to substantiate this putative function of the
GerA family proteins by characterizing spore germination in a mutant strain that
contained deletions at all known gerA-like loci. As expected, the mutant spores
germinated very poorly in a variety of rich media. In contrast, they germinated
like wild-type spores in a chemical germinant, a 1-1 chelate of Ca(2+) and
dipicolinic acid (DPA). These observations showed that proteins encoded by gerA
family members are required for nutrient-induced germination but not for chemical
triggered germination, supporting the hypothesis that the GerA family encodes
receptors for nutrient germinants. Further characterization of Ca(2+)-DPA-induced
germination showed that the effect of Ca(2+)-DPA on spore germination was
saturated at 60 mM and had a K(m) of 30 mM. We also found that decoating spores
abolished their ability to germinate in Ca(2+)-DPA but not in nutrient
germinants, indicating that Ca(2+)-DPA and nutrient germinants probably act
through parallel arms of the germination pathway.
PMID- 10762254
TI - The trimethylamine methyltransferase gene and multiple dimethylamine
methyltransferase genes of Methanosarcina barkeri contain in-frame and read
through amber codons.
AB - Three different methyltransferases initiate methanogenesis from trimethylamine
(TMA), dimethylamine (DMA) or monomethylamine (MMA) by methylating different
cognate corrinoid proteins that are subsequently used to methylate coenzyme M
(CoM). Here, genes encoding the DMA and TMA methyltransferases are characterized
for the first time. A single copy of mttB, the TMA methyltransferase gene, was
cotranscribed with a copy of the DMA methyltransferase gene, mtbB1. However, two
other nearly identical copies of mtbB1, designated mtbB2 and mtbB3, were also
found in the genome. A 6.8-kb transcript was detected with probes to mttB and
mtbB1, as well as to mtbC and mttC, encoding the cognate corrinoid proteins for
DMA:CoM and TMA:CoM methyl transfer, respectively, and with probes to mttP,
encoding a putative membrane protein which might function as a methylamine
permease. These results indicate that these genes, found on the chromosome in the
order mtbC, mttB, mttC, mttP, and mtbB1, form a single transcriptional unit. A
transcriptional start site was detected 303 or 304 bp upstream of the
translational start of mtbC. The MMA, DMA, and TMA methyltransferases are not
homologs; however, like the MMA methyltransferase gene, the genes encoding the
DMA and TMA methyltransferases each contain a single in-frame amber codon. Each
of the three DMA methyltransferase gene copies from Methanosarcina barkeri
contained an amber codon at the same position, followed by a downstream UAA or
UGA codon. The C-terminal residues of DMA methyltransferase purified from TMA
grown cells matched the residues predicted for the gene products of mtbB1, mtbB2,
or mtbB3 if termination occurred at the UAA or UGA codon rather than the in-frame
amber codon. The mttB gene from Methanosarcina thermophila contained a UAG codon
at the same position as the M. barkeri mttB gene. The UAG codon is also present
in mttB transcripts. Thus, the genes encoding the three types of
methyltransferases that initiate methanogenesis from methylamine contain in-frame
amber codons that are suppressed during expression of the characterized
methyltransferases.
PMID- 10762255
TI - Kinetics and substrate specificity of membrane-reconstituted peptide transporter
DtpT of Lactococcus lactis.
AB - The peptide transport protein DtpT of Lactococcus lactis was purified and
reconstituted into detergent-destabilized liposomes. The kinetics and substrate
specificity of the transporter in the proteoliposomal system were determined,
using Pro-[(14)C]Ala as a reporter peptide in the presence of various peptides or
peptide mimetics. The DtpT protein appears to be specific for di- and
tripeptides, with the highest affinities for peptides with at least one
hydrophobic residue. The effect of the hydrophobicity, size, or charge of the
amino acid was different for the amino- and carboxyl-terminal positions of
dipeptides. Free amino acids, omega-amino fatty acid compounds, or peptides with
more than three amino acid residues do not interact with DtpT. For high-affinity
interaction with DtpT, the peptides need to have free amino and carboxyl termini,
amino acids in the L configuration, and trans-peptide bonds. Comparison of the
specificity of DtpT with that of the eukaryotic homologues PepT(1) and PepT(2)
shows that the bacterial transporter is more restrictive in its substrate
recognition.
PMID- 10762256
TI - Peptidase E, a peptidase specific for N-terminal aspartic dipeptides, is a serine
hydrolase.
AB - Salmonella enterica serovar Typhimurium peptidase E (PepE) is an N-terminal Asp
specific dipeptidase. PepE is not inhibited by any of the classical peptidase
inhibitors, and its amino acid sequence does not place it in any of the known
peptidase structural classes. A comparison of the amino acid sequence of PepE
with a number of related sequences has allowed us to define the amino acid
residues that are strongly conserved in this family. To ensure the validity of
this comparison, we have expressed one of the most distantly related relatives
(Xenopus) in Escherichia coli and have shown that it is indeed an Asp-specific
dipeptidase with properties very similar to those of serovar Typhimurium PepE.
The sequence comparison suggests that PepE is a serine hydrolase. We have used
site-directed mutagenesis to change all of the conserved Ser, His, and Asp
residues and have found that Ser120, His157, and Asp135 are all required for
activity. Conversion of Ser120 to Cys leads to severely reduced (10(4)-fold) but
still detectable activity, and this activity but not that of the parent is
inhibited by thiol reagents; these results confirm that this residue is likely to
be the catalytic nucleophile. These results suggest that PepE is the prototype of
a new family of serine peptidases. The phylogenetic distribution of the family is
unusual, since representatives are found in eubacteria, an insect (Drosophila),
and a vertebrate (Xenopus) but not in the Archaea or in any of the other
eukaryotes for which genome sequences are available.
PMID- 10762257
TI - Osmotic and chill activation of glycine betaine porter II in Listeria
monocytogenes membrane vesicles.
AB - Listeria monocytogenes is a foodborne pathogen known for its tolerance to
conditions of osmotic and chill stress. Accumulation of glycine betaine has been
found to be important in the organism's tolerance to both of these stresses. A
procedure was developed for the purification of membranes from L. monocytogenes
cells in which the putative ATP-driven glycine betaine permease glycine betaine
porter II (Gbu) is functional. As is the case for the L. monocytogenes sodium
driven glycine betaine uptake system (glycine betaine porter I), uptake in this
vesicle system was dependent on energization by ascorbate-phenazine methosulfate.
Vesicles lacking the gbu gene product had no uptake activity. Transport by this
porter did not require sodium ion and could be driven only weakly by artificial
gradients. Uptake rates could be manipulated under conditions not affecting
secondary transport but known to affect ATPase activity. The system was shown to
be both osmotically activated and cryoactivated. Under conditions of osmotic
activation, the system exhibited Arrhenius-type behavior although the uptake
rates were profoundly affected by the physical state of the membrane, with breaks
in Arrhenius curves at approximately 10 and 18 degrees C. In the absence of
osmotic activation, the permease could be activated by decreasing temperature
within the range of 15 to 4 degrees C. Kinetic analyses of the permease at 30
degrees C revealed K(m) values for glycine betaine of 1.2 and 2.9 microM with
V(max) values of 2,200 and 3,700 pmol/min. mg of protein under conditions of
optimal osmotic activation as mediated by KCl and sucrose, respectively.
PMID- 10762258
TI - The ++Sinorhizobium meliloti lon protease is involved in regulating
exopolysaccharide synthesis and is required for nodulation of alfalfa.
AB - While screening for Sinorhizobium meliloti Pho regulatory mutants, a transposon
mutant was isolated that constitutively expressed higher levels of acid and
alkaline phosphatase enzymes. This mutant was also found to form pseudonodules on
alfalfa that were delayed in appearance relative to those formed by the wild-type
strain, it contained few bacteroids, and it did not fix nitrogen. Sequence
analysis of the transposon insertion site revealed the affected gene to have high
homology to Lon proteases from a number of organisms. In minimal succinate
medium, the mutant strain was found to grow more slowly, reach lower maximal
optical density, and produce more extracellular polysaccharide (EPS) than the
wild-type strain. The mutant fluoresced brightly on minimal succinate agar
containing calcofluor (which binds to EPSI, a constitutively expressed
succinoglycan), and gas chromotographic analysis of purified total EPS showed
that the glucose-to-galactose ratio in the lon mutant total EPS was 5.0 +/- 0.2
(mean +/- standard error), whereas the glucose-to-galactose ratio in the wild
type strain was 7.1 +/- 0.5. These data suggested that in addition to EPSI, the
lon mutant also constitutively synthesized EPSII, a galactoglucan which is the
second major EPS known to be produced by S. meliloti, but typically is expressed
only under conditions of phosphate limitation. (13)C nuclear magnetic resonance
analysis showed no major differences between EPS purified from the mutant and
wild-type strains. Normal growth, EPS production, and the symbiotic phenotype
were restored in the mutant strain when the wild-type lon gene was present in
trans. The results of this study suggest that the S. meliloti Lon protease is
important for controlling turnover of a constitutively expressed protein(s) that,
when unregulated, disrupts normal nodule formation and normal growth.
PMID- 10762259
TI - Purification and characterization of the alanine aminotransferase from the
hyperthermophilic Archaeon pyrococcus furiosus and its role in alanine
production.
AB - Alanine aminotransferase (AlaAT) was purified from cell extracts of the
hyperthermophilic archaeon Pyrococcus furiosus by multistep chromatography. The
enzyme has an apparent molecular mass of 93.5 kDa, as estimated by gel
filtration, and consists of two identical subunits of 46 kDa, as deduced by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the gene sequence.
The AlaAT displayed a broader substrate specificity than AlaATs from eukaryal
sources and exhibited significant activity with alanine, glutamate, and aspartate
with either 2-oxoglutarate or pyruvate as the amino acceptor. Optimal activity
was found in the pH range of 6. 5 to 7.8 and at a temperature of over 95 degrees
C. The N-terminal amino acid sequence of the purified AlaAT was determined and
enabled the identification of the gene encoding AlaAT (aat) in the P. furiosus
genome database. The gene was expressed in Escherichia coli, and the recombinant
enzyme was purified. The pH and temperature dependence, molecular mass, and
kinetic parameters of the recombinant were indistinguishable from those of the
native enzyme from P. furiosus. The k(cat)/K(m) values for alanine and pyruvate
formation were 41 and 33 s(-1) mM(-1), respectively, suggesting that the enzyme
is not biased toward either the formation of pyruvate, or alanine. Northern
analysis identified a single 1.2-kb transcript for the aat gene. In addition,
both the aat and gdh (encoding the glutamate dehydrogenase) transcripts appear to
be coregulated at the transcriptional level, because the expression of both genes
was induced when the cells were grown on pyruvate. The coordinated control found
for the aat and gdh genes is in good agreement with these enzymes acting in a
concerted manner to form an electron sink in P. furiosus.
PMID- 10762260
TI - A single amino acid substitution in a mannosyltransferase, WbdA, converts the
Escherichia coli O9 polysaccharide into O9a: generation of a new O-serotype
group.
AB - wbdA is a mannosyltransferase gene that is involved in synthesis of the
Escherichia coli O9a polysaccharide, a mannose homopolymer with a repeating unit
of 2-alphaMan-1,2-alphaMan-1,3-alphaMan-1, 3-alphaMan-1. The equivalent
structural O polysaccharide in the E. coli O9 and Klebsiella O3 strains is 2
alphaMan-1,2-alphaMan-1, 2-alphaMan-1,3-alphaMan-1,3-alphaMan-1, with an excess
of one mannose in the 1,2 linkage. We have cloned wbdA genes from these O9 and O3
strains and shown by genetic and functional studies that wbdA is the only gene
determining the O-polysaccharide structure of O9 or O9a. Based on functional
analysis of chimeric genes and site-directed mutagenesis, we showed that a single
amino acid substitution, C55R, in WbdA of E. coli O9 converts the O9
polysaccharide into O9a. DNA sequencing revealed the substitution to be conserved
in other E. coli O9a strains. The reverse substitution, R55C, in WbdA of E. coli
O9a resulted in lipopolysaccharide synthesis showing no ladder profile instead of
the conversion of O9a to O9. This suggests that more than one amino acid
substitution in WbdA is required for conversion from O9a to O9.
PMID- 10762261
TI - High spontaneous mutation rate in the hyperthermophilic archaeon Sulfolobus
solfataricus is mediated by transposable elements.
AB - We have isolated uracil-auxotrophic mutants of the hyperthermophilic archaeon
Sulfolobus solfataricus in order to explore the genomic stability and mutational
frequencies of this organism and to identify complementable recipients for a
selectable genetic transformation system. Positive selection of spontaneous
mutants resistant to 5-fluoroorotate yielded uracil auxotrophs with frequencies
of between 10(-4) and 10(-5) per sensitive, viable cell. Four different,
nonhomologous insertion sequences (ISs) were identified at different positions
within the chromosomal pyrEF locus of these mutants. They ranged in size from
1,058 to 1,439 bp and possessed properties typical of known transposable
elements, i.e., terminal inverted repeats, flanking duplicated target sequences,
and putative transposase genes encoding motifs that are indicative of the IS4-IS5
IS element families. Between 12 and 25 copies of each IS element were found in
chromosomal DNAs by Southern analyses. While characteristic fingerprint patterns
created by IS element-specific probes were observed with genomic DNA of different
S. solfataricus strains, no homologous sequences were identified in DNA of other
well-characterized strains of the order Sulfolobales.
PMID- 10762263
TI - Mutation of ndh genes leads to inhibition of CO(2) uptake rather than HCO(3)(-)
uptake in Synechocystis sp. strain PCC 6803.
AB - Six mutants (B1 to B6) that grew poorly in air on BG11 agar plates buffered at pH
8.0 were rescued after mutations were introduced into ndhB of wild-type (WT)
Synechocystis sp. strain PCC 6803. In these mutants and a mutant (M55) lacking
ndhB, CO(2) uptake was much more strongly inhibited than HCO(3)(-) uptake, i.e.,
the activities of CO(2) and HCO(3)(-) uptake in B1 were 9 and 85% of those in the
WT, respectively. Most of the mutants grew very slowly or did not grow at all at
pH 6.5 or 7.0 in air, and their ability to grow under these conditions was
correlated with CO(2) uptake capacity. Detailed studies of B1 and M55 indicated
that the mutants grew as fast as the WT in liquid at pH 8.0 under air, although
they grew poorly on agar plates. The contribution of CO(2) uptake appears to be
larger on solid medium. Five mutants were constructed by inactivating each of the
five ndhD genes in Synechocystis sp. strain PCC 6803. The mutant lacking ndhD3
grew much more slowly than the WT at pH 6.5 under 50 ppm CO(2), although other
ndhD mutants grew like the WT under these conditions and showed low affinity for
CO(2) uptake. These results indicated the presence of multiple NAD(P)H
dehydrogenase type I complexes with specific roles.
PMID- 10762262
TI - Phosphorylation of HPr by the bifunctional HPr Kinase/P-ser-HPr phosphatase from
Lactobacillus casei controls catabolite repression and inducer exclusion but not
inducer expulsion.
AB - We have cloned and sequenced the Lactobacillus casei hprK gene encoding the
bifunctional enzyme HPr kinase/P-Ser-HPr phosphatase (HprK/P). Purified
recombinant L. casei HprK/P catalyzes the ATP-dependent phosphorylation of HPr, a
phosphocarrier protein of the phosphoenolpyruvate:carbohydrate phosphotransferase
system at the regulatory Ser-46 as well as the dephosphorylation of seryl
phosphorylated HPr (P-Ser-HPr). The two opposing activities of HprK/P were
regulated by fructose-1,6-bisphosphate, which stimulated HPr phosphorylation, and
by inorganic phosphate, which stimulated the P-Ser-HPr phosphatase activity. A
mutant producing truncated HprK/P was found to be devoid of both HPr kinase and P
Ser-HPr phosphatase activities. When hprK was inactivated, carbon catabolite
repression of N-acetylglucosaminidase disappeared, and the lag phase observed
during diauxic growth of the wild-type strain on media containing glucose plus
either lactose or maltose was strongly diminished. In addition, inducer exclusion
exerted by the presence of glucose on maltose transport in the wild-type strain
was abolished in the hprK mutant. However, inducer expulsion of methyl beta-D
thiogalactoside triggered by rapidly metabolizable carbon sources was still
operative in ptsH mutants altered at Ser-46 of HPr and the hprK mutant,
suggesting that, in contrast to the model proposed for inducer expulsion in gram
positive bacteria, P-Ser-HPr might not be involved in this regulatory process.
PMID- 10762264
TI - ADP-Ribosylation of variants of Azotobacter vinelandii dinitrogenase reductase by
Rhodospirillum rubrum dinitrogenase reductase ADP-ribosyltransferase.
AB - In a number of nitrogen-fixing bacteria, nitrogenase is posttranslationally
regulated by reversible ADP-ribosylation of dinitrogenase reductase. The
structure of the dinitrogenase reductase from Azotobacter vinelandii is known. In
this study, mutant forms of dinitrogenase reductase from A. vinelandii that are
affected in various protein activities were tested for their ability to be ADP
ribosylated or to form a complex with dinitrogenase reductase ADP
ribosyltransferase (DRAT) from Rhodospirillum rubrum. R140Q dinitrogenase
reductase could not be ADP-ribosylated by DRAT, although it still formed a cross
linkable complex with DRAT. Thus, the Arg 140 residue of dinitrogenase reductase
plays a critical role in the ADP-ribosylation reaction. Conformational changes in
dinitrogenase reductase induced by an F135Y substitution or by removal of the
Fe(4)S(4) cluster resulted in dinitrogenase reductase not being a substrate for
ADP-ribosylation. Through cross-linking studies it was also shown that these
changes decreased the ability of dinitrogenase reductase to form a cross-linkable
complex with DRAT. Substitution of D129E or deletion of Leu 127, which result in
altered nucleotide binding regions of these dinitrogenase reductases, did not
significantly change the interaction between dinitrogenase reductase and DRAT.
Previous results showed that changing Lys 143 to Gln decreased the binding
between dinitrogenase reductase and dinitrogenase (L. C. Seefeldt, Protein Sci.
3:2073-2081, 1994); however, this change did not have a substantial effect on the
interaction between dinitrogenase reductase and DRAT.
PMID- 10762265
TI - DnaA, the initiator of Escherichia coli chromosomal replication, is located at
the cell membrane.
AB - Given the lack of a nucleus in prokaryotic cells, the significance of spatial
organization in bacterial chromosome replication is only beginning to be fully
appreciated. DnaA protein, the initiator of chromosomal replication in
Escherichia coli, is purified as a soluble protein, and in vitro it efficiently
initiates replication of minichromosomes in membrane-free DNA synthesis
reactions. However, its conversion from a replicatively inactive to an active
form in vitro occurs through its association with acidic phospholipids in a lipid
bilayer. To determine whether the in situ residence of DnaA protein is
cytoplasmic, membrane associated, or both, we examined the cellular location of
DnaA using immunogold cryothin-section electron microscopy and
immunofluorescence. Both of these methods revealed that DnaA is localized at the
cell membrane, further suggesting that initiation of chromosomal replication in
E. coli is a membrane-affiliated event.
PMID- 10762266
TI - Generation of dominant selectable markers for resistance to pseudomonic acid by
cloning and mutagenesis of the ileS gene from the archaeon Methanosarcina barkeri
fusaro.
AB - Currently, only one selectable marker is available for genetic studies in the
archaeal genus Methanosarcina. Here we report the generation of selectable
markers that encode resistance to pseudomonic acid (PA(r)) in Methanosarcina
species by mutagenesis of the isoleucyl-tRNA synthetase gene (ileS) from
Methanosarcina barkeri Fusaro. The M. barkeri ileS gene was obtained by screening
of a genomic library for hybridization to a PCR fragment. The complete 3,787-bp
DNA sequence surrounding and including the ileS gene was determined. As expected,
M. barkeri IleS is phylogenetically related to other archaeal IleS proteins. The
ileS gene was cloned into a Methanosarcina-Escherichia coli shuttle vector and
mutagenized with hydroxylamine. Nine independent PA(r) clones were isolated after
transformation of Methanosarcina acetivorans C2A with the mutagenized plasmids.
Seven of these clones carry multiple changes from the wild-type sequence. Most
mutations that confer PA(r) were shown to alter amino acid residues near the
KMSKS consensus sequence of class I aminoacyl-tRNA synthetases. One particular
mutation (G594E) was present in all but one of the PA(r) clones. The MIC of
pseudomonic acid for M. acetivorans transformed with a plasmid carrying this
single mutation is 70 microgram/ml of medium (for the wild type, the MIC is 12
microgram/ml). The highest MICs (560 microgram/ml) were observed with two triple
mutants, A440V/A482T/G594E and A440V/G593D/G594E. Plasmid shuttle vectors and
insertion cassettes that encode PA(r) based on the mutant ileS alleles are
described. Finally, the implications of the specific mutations we isolated with
respect to binding of pseudomonic acid by IleS are discussed.
PMID- 10762267
TI - Structural modeling and site-directed mutagenesis of the actinorhodin beta
ketoacyl-acyl carrier protein synthase.
AB - A three-dimensional model of the Streptomyces coelicolor actinorhodin beta
ketoacyl synthase (Act KS) was constructed based on the X-ray crystal structure
of the related Escherichia coli fatty acid synthase condensing enzyme beta
ketoacyl synthase II, revealing a similar catalytic active site organization in
these two enzymes. The model was assessed by site-directed mutagenesis of five
conserved amino acid residues in Act KS that are in close proximity to the Cys169
active site. Three substitutions completely abrogated polyketide biosynthesis,
while two replacements resulted in significant reduction in polyketide
production. (3)H-cerulenin labeling of the various Act KS mutant proteins
demonstrated that none of the amino acid replacements affected the formation of
the active site nucleophile.
PMID- 10762268
TI - The GacS sensor kinase regulates alginate and poly-beta-hydroxybutyrate
production in Azotobacter vinelandii.
AB - Azotobacter vinelandii produces two polymers: the extracellular polysaccharide
alginate and the intracellular polyester poly-beta-hydroxybutyrate (PHB). A
cosmid clone (pSMU588) from an A. vinelandii gene library diminished alginate
production by A. vinelandii mucoid strain ATCC 9046. The nucleotide sequence and
predicted amino acid sequence of the locus responsible for the mucoidy
suppression revealed 65% identity to Pseudomonas GacS, a transmembrane sensor
kinase of the two-component regulators, whose cognate response regulator, GacA,
is a global activator regulating several products and virulence factors. Plasmid
pMC15, harboring gacS, and a strain carrying a gacS nonpolar mutation were
constructed. Either pMC15 or the gacS mutation significantly reduced alginate
production and transcription of algD, the gene coding for the key enzyme GDP
mannose dehydrogenase of the alginate biosynthetic pathway. We found that the
gacS mutation also reduced PHB accumulation and impaired encystment. Taken
together, these data indicate that in A. vinelandii the gacSA global system
regulates polymer synthesis.
PMID- 10762269
TI - Heterologous expression of bacterial Epoxyalkane:Coenzyme M transferase and
inducible coenzyme M biosynthesis in Xanthobacter strain Py2 and Rhodococcus
rhodochrous B276.
AB - Coenzyme M (CoM) (2-mercaptoethanesulfonic acid) biosynthesis is shown to be
coordinately regulated with the expression of the enzymes of alkene and epoxide
metabolism in the propylene-oxidizing bacteria Xanthobacter strain Py2 and
Rhodococcus rhodochrous strain B276. These results provide the first evidence for
the involvement of CoM in propylene metabolism by R. rhodochrous and demonstrate
for the first time the inducible nature of eubacterial CoM biosynthesis.
PMID- 10762270
TI - Site-specific serine incorporation by Lif and Epr into positions 3 and 5 of the
Staphylococcal peptidoglycan interpeptide bridge.
AB - The FemAB-like factors Lif and Epr confer resistance to glycylglycine
endopeptidases lysostaphin and Ale-1, respectively, by incorporating serine
residues into the staphylococcal peptidoglycan interpeptide bridges specifically
at positions 3 and 5. This required the presence of FemA and/or FemB, in contrast
to earlier postulations.
PMID- 10762271
TI - The yvaJ gene of Bacillus subtilis encodes a 3'-to-5' exoribonuclease and is not
essential in a strain lacking polynucleotide phosphorylase.
AB - Studies of Bacillus subtilis RNases that are involved in mRNA degradation reveal
a different pattern from that of Escherichia coli. A strain lacking
polynucleotide phosphorylase, the major 3'-to-5' exoribonuclease activity in cell
extracts, is viable. Here, we show that the B. subtilis yvaJ gene encodes a
second 3'-to-5' exoribonuclease. A strain lacking both of these RNases grows
slowly but is viable. The existence of another, as yet unknown, 3'-to-5'
exoribonuclease in B. subtilis is suggested.
PMID- 10762272
TI - A C-terminal disulfide bridge in pediocin-like bacteriocins renders bacteriocin
activity less temperature dependent and is a major determinant of the
antimicrobial spectrum.
AB - Several lactic acid bacteria produce so-called pediocin-like bacteriocins that
share sequence characteristics, but differ in activity and target cell
specificity. The significance of a C-terminal disulfide bridge present in only a
few of these bacteriocins was studied by site-directed mutagenesis of pediocin PA
1 (which naturally contains the bridge) and sakacin P (which lacks the bridge).
Introduction of the C-terminal bridge into sakacin P broadened the target cell
specificity of this bacteriocin, as illustrated by the fact that the mutants were
10 to 20 times more potent than the wild-type toward certain indicator strains,
whereas the potency toward other indicator strains remained essentially
unchanged. Like pediocin PA-1, disulfide-containing sakacin P mutants had the
same potency at 20 and 37 degrees C, whereas wild-type sakacin P was
approximately 10 times less potent at 37 degrees C than at 20 degrees C.
Reciprocal effects on target cell specificity and the temperature dependence of
potency were observed upon studying the effect of removing the C-terminal
disulfide bridge from pediocin PA-1 by Cys-->Ser mutations. These results clearly
show that a C-terminal disulfide bridge in pediocin-like bacteriocins contributes
to widening of the antimicrobial spectrum as well as to higher potency at
elevated temperatures. Interestingly, the differences between sakacin P and
pediocin PA-1 in terms of the temperature dependency of their activities
correlated well with the optimal temperatures for bacteriocin production and
growth of the bacteriocin-producing strain.
PMID- 10762273
TI - H-NS is a repressor of the Proteus mirabilis urease transcriptional activator
gene ureR.
AB - Expression of Proteus mirabilis urease is governed by UreR, an AraC-like positive
transcriptional activator. A poly(A) tract nucleotide sequence, consisting of
A(6)TA(2)CA(2)TGGTA(5)GA(6)TGA(5), is located 16 bp upstream of the sigma(70)
like ureR promoter P2. Since poly(A) tracts of DNA serve as binding sites for the
gene repressor histone-like nucleoid structuring protein (H-NS), we measured beta
galactosidase activity of wild-type Escherichia coli MC4100 (H-NS(+)) and its
isogenic derivative ATM121 (hns::Tn10) (H-NS(-)) harboring a ureR-lacZ operon
fusion plasmid (pLC9801). beta-Galactosidase activity in the H-NS(-) host strain
was constitutive and sevenfold greater (P < 0.0001) than that in the H-NS(+)
host. A recombinant plasmid containing cloned P. mirabilis hns was able to
complement and restore repression of the ureR promoter in the H-NS(-) host when
provided in trans. Deletion of the poly(A) tract nucleotide sequence from pLC9801
resulted in an increase in beta-galactosidase activity in the H-NS(+) host to
nearly the same levels as that observed for wild-type pLC9801 harbored by the H
NS(-) host. Urease activity in strains harboring the recombinant plasmid pMID1010
(encoding the entire urease gene cluster of P. mirabilis) was equivalent in both
the H-NS(-) background and the H-NS(+) background in the presence of urea but was
eightfold greater (P = 0.0001) in the H-NS(-) background in the absence of urea.
We conclude that H-NS represses ureR expression in the absence of urea induction.
PMID- 10762275
TI - A novel sphingoglycolipid containing galacturonic acid and 2-hydroxy fatty acid
in cellular lipids of Sphingomonas yanoikuyae.
AB - A novel sphingoglycolipid was isolated from Sphingomonas yanoikuyae, and its
structure was identified as a galacturonosyl-beta (1-->1)-ceramide. This was a
characteristic sphingoglycolipid present in S. yanoikuyae and certain other
species of Sphingomonas, such as Sphingomonas mali, Sphingomonas terrae, and
Sphingomonas macrogoltabidus, but not in the type species of Sphingomonas,
Sphingomonas paucimobilis.
PMID- 10762274
TI - Negative regulation of expression of the Bacillus megaterium bmlP1 gene by the
bmlP1 3' flanking region.
AB - We report that the expression of the Bacillus megaterium bmlP1 gene is subject to
negative regulation by the bmlP1 3' flanking region. This repression occurred
both in B. megaterium and in Escherichia coli. When the bmlP1 promoter was
replaced with a heterologous promoter or when the orientation of the bmlP1 3'
flanking region was reversed, the inhibitory effect was still observed. However,
the bmlP1 3' flanking region was unable to exert repression on a heterologous
gene when fused downstream in either orientation, and it was incapable of acting
in trans. Dot blot and Northern blot analyses revealed that the repression
occurred at the RNA level. Deletion analysis showed that the regulatory site
responsible for the repression is located within a 116-bp region immediately
following the bmlP1 gene. Possible mechanisms for this repression are discussed.
PMID- 10762276
TI - Expression of UGA-containing Mycoplasma genes in Bacillus subtilis.
AB - We used Bacillus subtilis to express UGA-containing Mycoplasma genes encoding the
P30 adhesin (one UGA) of Mycoplasma pneumoniae and methionine sulfoxide reductase
(two UGAs) of Mycoplasma genitalium. Due to natural UGA suppression, these
Mycoplasma genes were expressed as full-length protein products, but at
relatively low efficiency, in recombinant wild-type Bacillus. The B. subtilis
expressed Mycoplasma proteins appeared as single bands and not as multiple bands
compared to expression in recombinant Escherichia coli. Bacillus mutants carrying
mutations in the structural gene (prfB) for release factor 2 markedly enhanced
the level of readthrough of UGA-containing Mycoplasma genes.
PMID- 10762277
TI - Equivalence of lauric acid and glycerol monolaurate as inhibitors of signal
transduction in Staphylococcus aureus.
AB - Glycerol monolaurate (GML) inhibits the expression of virulence factors in
Staphylococus aureus and the induction of vancomycin resistance in Enterococcus
faecalis, presumably by blocking signal transduction. Although GML is rapidly
hydrolyzed by bacteria, one of the products, lauric acid, has identical
inhibitory activity and is metabolized much more slowly. At least four distinct
GML-hydrolyzing activities are identified in S. aureus: the secreted Geh lipase,
residual supernatant activity in a geh-null mutant strain, a novel membrane-bound
esterase, and a cytoplasmic activity.
PMID- 10762278
TI - A common regulator for the operons encoding the enzymes involved in D
galactarate, D-glucarate, and D-glycerate utilization in Escherichia coli.
AB - Genes for D-galactarate (gar) and D-glucarate (gud) metabolism in Escherichia
coli are organized in three transcriptional units: garD, garPLRK, and gudPD. Two
observations suggested a common regulator for the three operons. (i) Their
expression was triggered by D-galactarate, D-glucarate, and D-glycerate. (ii)
Metabolism of the three compounds was impaired by a single Tn5 insertion mapped
in the yaeG gene (proposed name, sdaR), outside the D-galactarate and D-glucarate
systems. Expression of the sdaR gene is autogenously regulated.
PMID- 10762279
TI - Is monoclonality in pituitary adenomas synonymous with neoplasia?
PMID- 10762280
TI - Genes, mice and the internet: is WT1 the shape of things to come?
PMID- 10762281
TI - How will we know if 11beta-hydroxysteroid dehydrogenases are important in common
diseases.
PMID- 10762282
TI - Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and
insulin sensitivity in the basal state and after 24h of insulin infusion in
healthy subjects and type 2 diabetic patients.
AB - OBJECTIVES: To test whether insulin resistance in type 2 diabetes mellitus is
associated with an altered overall setpoint of the 11beta-hydroxysteroid
dehydrogenase (11betaHSD) mediated cortisol to cortisone interconversion towards
cortisol, and to evaluate whether changes in insulin sensitivity induced by
antecedent hyperinsulinaemia are related to changes in the 11betaHSD setpoint.
PATIENTS AND MEASUREMENTS: The urinary ratio of (tetrahydrocortisol + allo
tetrahydrocortisol)/tetrahydrocortisone ((THF + allo-THF)/THE) and of free
cortisol/free cortisone (UFF/UFE), as well as the plasma cortisol/cortisone ratio
were measured in 8 male type 2 diabetic patients and 8 healthy male subjects
without and after 24 h of insulin infusion. Insulin was infused at a rate of 30
mU/kg/h with blood glucose being clamped at euglycaemic levels in healthy
subjects and at isoglycaemic levels in diabetic patients. Insulin sensitivity was
assessed by measurement of whole body glucose uptake (M-value) during a 3-4 h
euglycaemic clamp, directly after the 24 h insulin infusion and compared to the M
value on a control day, at least 1 week apart from the 24 h insulin infusion.
RESULTS: Despite impaired insulin sensitivity (M-value, 11.6 +/- 7.7 vs. 28.5 +/-
11.6 micromol/kg/minutes, in type 2 diabetic and healthy subjects, respectively,
P < 0.05), urinary (THF + allo-THF)/THE ratio and baseline plasma
cortisol/cortisone ratio at 0800 h were similar in type 2 diabetic patients (0.82
+/- 0.07 and 3. 77 +/- 0.70, respectively) and healthy subjects (0.76 +/- 0.14
and 3. 81 +/- 0.88, respectively, ns). Insulin sensitivity was not correlated
with urinary (THF + allo-THF)/THE ratio nor with baseline plasma cortisol/
cortisone. In type 2 diabetic patients, insulin sensitivity was further impaired
by antecedent hyperinsulinaemia (P < 0.05), but the urinary (THF + allo-THF)/THE
ratio (0.80 +/- 0.14, ns) and the plasma cortisol/cortisone at 0800 h (3.66 +/-
0.72, ns) did not change. In healthy subjects, insulin sensitivity did not change
significantly (M-value, 22.5 +/- 9.7 micromol/kg/minutes, ns), although the
urinary (THF + allo-THF)/THE ratio (0.92 +/- 0.25, P < 0.05) and the plasma
cortisol/cortisone (4.59 +/- 0.63, P < 0.05) increased. Insulin did not affect
the UFF/UFE ratio in either group. CONCLUSION: The present study does not support
the hypothesis that insulin resistance in type 2 diabetes mellitus is associated
with an overall change in the 11betaHSD set point towards cortisol. In view of
the stimulatory effects of insulin and cortisol on adipogenesis, long-term
stimulation of 11betaHSD reductase activity by insulin could aggravate visceral
obesity.
PMID- 10762283
TI - alpha2-adrenoceptor regulation of the hypothalamic-pituitary-adrenocortical axis
in obesity.
AB - BACKGROUND: Abdominal obesity is associated with hyper-responsiveness of the
hypothalamic-pituitary-adrenocortical (HPA) axis to stimulatory neuropeptides and
to stress. Catecholamines are involved in the regulation of the HPA axis,
particularly during stress, via alpha-adrenoceptor modulation. DESIGN: In this
study, we investigated the effects of pre-treatment with an alpha2-adrenoceptor
agonist, clonidine (2 microg/kg over 10 minutes) and antagonist, yohimbine (0.125
mg/kg bolus, followed by 0. 001 mg/kg/minutes per 90 minutes infusion) on the HPA
axis, measured by ACTH and cortisol response to combined CRH (human, 100 microg)
plus AVP (0.3 IU) administration, and on noradrenalin (NA) and adrenalin (A)
blood levels, in a group of obese women with abdominal (A-BFD) or peripheral (P
BFD) body fat distribution and in nonobese controls. RESULTS: During the control
CRH + AVP test the ACTH but not the cortisol response was higher (P < 0.05) in
obese A-BFD women than in controls, with minor and transient variations of NA
levels. Neither the control test nor clonidine or yohimbine influenced basal or
post CRH + AVP A concentrations. Clonidine pretreatment similarly and
significantly decreased NA levels in all women and, compared to the control test,
marginally influenced the ACTH response to CRH + AVP. Conversely, during
yohimbine infusion NA levels steadily and similarly increased to values more or
less double baseline values in all groups. Compared to the control test, however,
the ACTH response to the CRH + AVP test performed during yohimbine infusion
significantly decreased in the control subjects whereas a tendency to a further
increase occurred in the obese groups and, specifically, in the A-BFD group
significantly (P < 0.05) more than in the P-BFD group. CONCLUSIONS: This study
shows that alpha2-adrenoceptor regulation of the HPA axis is different in obese
and nonobese women, particularly in stressed conditions. We suggest that the
abnormal ACTH response to CRH + AVP challenge with increased noradrenergic tone
may represent a specific pathophysiological aspect of the abnormal response to
stress or to other specific stimulatory factors in obese women, particularly
those with abdominal body fat distribution.
PMID- 10762284
TI - The emergence of salivary cortisol circadian rhythm and its relationship to sleep
activity in preterm infants.
AB - OBJECTIVE: The circadian rhythm of cortisol is established at between 8 and 12
postnatal weeks in term infants. However, there is limited information about the
effect of prematurity on this rhythm. We evaluated the emergence of the salivary
cortisol circadian rhythm in premature infants and its relationship to the onset
of sleep daily rhythm. DESIGN AND PATIENTS: A longitudinal study of a group of
nine premature infants (gestational age 31-34 weeks) was performed. Salivary
samples were obtained in the morning and at night at 2, 4, 8, 12, 16, 20 and 24
postnatal weeks and the babies' sleeping periods were recorded by their mothers.
MEASUREMENTS: Cortisol was determined by RIA in 25-microl salivary samples. Two
techniques based on assay coefficients of variation were used to characterize the
circadian pattern of cortisol. RESULTS: Five infants (55%) established and
maintained their cortisol rhythm at 2 and 8 postnatal weeks. In the remaining
four infants the age of appearance was 12 and 16 weeks. This rhythm emerged in
the group as a whole between 8 and 12 postnatal weeks. The circadian rhythm of
sleep was detected starting from the eighth postnatal week. CONCLUSIONS: Our data
suggest that in this group of premature infants the circadian maturation of the
hypothalamic-pituitary-adrenal axis occurred at the same postnatal age as
reported for term infants and that there was a parallelism between the appearance
of such rhythm and the onset of sleep rhythm.
PMID- 10762285
TI - Treatment of pituitary-dependent Cushing's syndrome: long-term results of
unilateral adrenalectomy followed by external pituitary irradiation compared to
transsphenoidal pituitary surgery.
AB - BACKGROUND: The preferred treatment of Cushing's disease (CD) nowadays is
transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden
University Medical Centre were treated by unilateral adrenalectomy followed by
external pituitary irradiation (UAPI). We report on long-term results of both
UAPI and TPS and compare remission, relapse rates, and complications. PATIENTS
AND METHODS: A retrospective study was carried out on 130 patients with CD.
Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients
underwent UAPI and TPS, respectively. Of these patients, 85 and 41 were evaluable
for long-term results. RESULTS: Remission following UAPI and TPS was identical at
64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and
22% (6/27), respectively, - for UAPI and TPS, although the mean follow-up periods
were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free
survival curves after UAPI and TPS are identical until 5 years of follow-up, but
diverge thereafter indicating more sustained remissions following UAPI (P = 0.17,
Wilcoxon statistic). Pituitary dysfunction following UAPI (36%) and pituitary
surgery (55%) likewise did not differ significantly. However, pituitary
dysfunction was an immediate event after TPS, whereas it developed after a mean
interval of 17.8 years following UAPI.Low-dose dexamethasone testing during
follow-up had no value in predicting therapeutic outcome. CONCLUSIONS: The
results of unilateral adrenalectomy followed by external pituitary irradiation do
not justify that this therapy is totally abandoned in favour of transsphenoidal
pituitary surgery. Unilateral adrenalectomy followed by external pituitary
irradiation is a valid therapeutic modality for the treatment of Cushing's
disease, and could be considered as alternative to bilateral adrenalectomy and
under some circumstances to transsphenoidal pituitary surgery.
PMID- 10762286
TI - Hormone levels and tumour size response to quinagolide and cabergoline in
patients with prolactin-secreting and clinically non-functioning pituitary
adenomas: predictive value of pituitary scintigraphy with 123I-methoxybenzamide.
AB - BACKGROUND: Dopamine agonists are indicated as primary therapy for PRL-secreting
pituitary adenomas, while controversial results have been reported in
nonfunctioning adenomas (NFA). OBJECTIVE: To evaluate whether the in vivo
visualization of dopamine D2 receptor expression detected by pituitary
scintigraphy using 123I-methoxybenzamide (123I-IBZM) was correlated with the
response to chronic treatment with quinagolide or cabergoline. PATIENTS: 10
patients affected with NFA (5 men and 5 women, age ranging between 25 and 50
years), and 10 with PRL-secreting naive macroadenomas (3 men and 7 women, age
ranging between 22 and 59 years), serving as control. STUDY DESIGN: All patients
underwent an acute test with quinagolide: at 3-day intervals and in random order
all patients received the drug (0.075 mg at 0800 h), or placebo. Blood samples
were taken 15 and 5 minutes before and every 30 minutes for 6 h after drug or
placebo administration. The test was considered positive when PRL and/or alpha
subunit levels decreased >/=50% as compared to baseline levels. After 6 months of
treatment, 10 patients were randomised to continue the treatment with quinagolide
and the remaining 10 received cabergoline for the remaining 6 months. The doses
of quinagolide and cabergoline ranged from 0.075 to 0.6 mg/day and from 0.5 to 3
mg/week, respectively. At study entry, a magnetic resonance imaging (MR) study of
the pituitary region and 123I-IBZM pituitary scintigraphy were performed. MR was
repeated after 12 months of treatment to evaluate tumour shrinkage: reduction of
tumour volume = 80% in prolactinomas and = 50% in NFA was considered significant.
Basal PRL levels were 9495.0 +/- 1131.6 mU/l in prolactinomas and 602.4 +/- 50.5
mU/l in NFA. RESULTS: The scintigraphy was negative in 6 out of 10 patients with
NFA. Moderate uptake was observed in 3 patients with prolactinoma and 2 patients
with NFA whereas intense uptake was observed in the remaining 7 patients with
prolactinoma and 2 patients with NFA. Among the 8 patients with NFA and high
circulating alpha-subunit levels, the acute test was negative in 5 while it was
positive in the remaining 3 patients. The acute test was positive in all 10
patients with prolactinoma. After 12 months of treatment with quinagolide and
cabergoline, circulating PRL levels were decreased in all 10 patients with
prolactinoma (571.8 +/- 255.9 mU/l), being normalized in 7 patients. Suppression
of PRL levels was found in all 10 patients with NFA (89.5 +/- 2.3 mU/l). A
significant reduction of alpha-subunit levels was obtained in 9 out of 10
patients with NFA: in 4 out of 8 patients alpha-subunit levels were normalized.
Significant adenoma shrinkage was recorded in 4 patients with prolactinoma among
the 7 with intense pituitary uptake of 123I-IBZM. Significant adenoma shrinkage
was recorded only in the 2 out of 10 patients with NFA with intense pituitary
uptake of 123I-IBZM. A significant positive correlation was found between the
degree of uptake (considered as score) and the response to quinagolide or
cabergoline treatment (considered as percent hormone suppression) either in
patients affected with PRL-secreting adenoma (r = 0.856, P < 0.005) or in those
affected with NFA (r = 0.787, P < 0.05). CONCLUSIONS: An intense 123I-IBZM uptake
in patients with non-functioning adenomas was predictive of a good response to a
chronic treatment with quinagolide and cabergoline. This result suggests that a
pituitary 123I-IBZM scintigraphy could be considered in selected patients with
non-functioning adenomas before starting medical treatment with dopamine
agonists.
PMID- 10762287
TI - Does the age of onset of growth hormone deficiency affect cardiac performance? A
radionuclide angiography study.
AB - BACKGROUND: GH and IGF-I seem to play a relevant role in cardiac development and
performance. Long-standing GH deficiency (GHD) causes several abnormalities in
cardiac structure and performance which ultimately determine an increased
cardiovascular morbidity and mortality. OBJECTIVE: To investigate whether the age
of onset of GHD plays a role in determining the negative effects on the heart.
DESIGN: Open cross-sectional PATIENTS: 55 patients with adulthood-onset GHD and
36 healthy sex- and age-matched controls. Patients and controls were divided into
2 groups in line with age: 32 patients and 16 controls, were aged 0.40 from baseline; P > 0.80 from change with placebo). In the extension
study, overall crypt LI was also unchanged in those patients who received GH
after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9,
P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate
evaluation of the LI at the basal, mid and luminal portions of the colonic crypts
also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS:
Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into
the (high) physiological range, does not adversely affect colonic epithelial cell
proliferation as a biomarker for the risk of development of colorectal cancer.
PMID- 10762289
TI - Analysis of the intracellular signalling domain of the human growth hormone
receptor in children with idiopathic short stature.
AB - OBJECTIVE: To investigate the hypothesis that intracellular, dominant-negative
mutations of the growth hormone receptor (GHR) exist in children with idiopathic
short stature (ISS) and partial growth hormone insensitivity (GHI). SUBJECTS: We
studied 31 children aged 4.55-13.14 years with ISS (height CATHis) was found in one patient. A missense mutation in codon 12 of
PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25
non-diabetic, non-obese control individuals. The patient with the Pro12Ala
variant had the highest steady state glucose infusion rate (SSGIR) and most
marked suppression of hepatic glucose production rate (HGPR) of all of the
patients studied. CONCLUSIONS: Mutations in the PPARgamma gene are unlikely to be
major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may
correlate with a lesser degree of insulin resistance in these patients.
PMID- 10762292
TI - Raised plasminogen activator inhibitor-1 (PAI-1) is not an independent risk
factor in the polycystic ovary syndrome (PCOS).
AB - BACKGROUND: It has been postulated that an insulin-driven increase in plasminogen
activator inhibitor-1 (PAI-1) levels may link insulin resistance to anovulatory
infertility in women with PCOS and that it may place them at increased risk of
thromboembolic disease. However, previous studies have been conflicting because
many have failed to control for body mass index (BMI) which may affect PAI-1. The
aim of this study was to investigate PAI-1 activity in women with PCOS and to
compare it with unaffected controls of a similar BMI. DESIGN AND PATIENTS: 41
women with PCOS and 25 weight-matched controls participated in this cross
sectional study. Patients were evaluated clinically and by pelvic ultrasound and
fasting blood samples were taken for haematological and biochemical tests.
MEASUREMENTS: PAI-1 activity, insulin, glucose, triglycerides, total cholesterol,
LDL cholesterol, HDL cholesterol, FSH, LH, PRL, testosterone, SHBG, 17
hydroxyprogesterone, plasminogen, fibrinogen (alpha2 antiplasmin, blood pressure
and insulin sensitivity with a homeostasis model assessment (HOMA) computer
programme. RESULTS: There was no significant difference in BMI or in (log) PAI-1
activity in women with PCOS compared with controls (BMI 29.5 +/- 5.6 vs. 28.4 +/-
6.3 kg/m2, P = 0.25 and PAI-1 2.56 (SD 0.85) vs. 2.14 (SD 0.98) au/ml, P = 0.07).
The median fasting insulin level was significantly higher (17 (4.6-134.5) vs. 9.6
(3.7-41.5) mU/l, P < 0.01), and insulin sensitivity significantly lower in the
PCOS group, ( 43.17% (5. 48-160) vs. 82.8% (21.8-193), P < 0.01). Women with PCOS
also had a significantly higher free androgen index, LH/FSH ratio and a lower
HDL/total cholesterol ratio. However blood pressure and all other lipid and
haematological measurements were not significantly different between both groups.
There were significant positive correlations between (log) PAI-1 activity and BMI
(rho = 0.61), triglycerides (rho = 0.49) and fasting insulin (rho = 0.60) and a
negative correlation with HDL cholesterol (rho = - 0.46). Triglyceride
concentrations showed the most significant relationship with (log) PAI-1 activity
on multiple regression. 29% of PCO women (12/41) gave a positive family history
of thrombosis compared to 8% (2/25) in the control group. CONCLUSION: Plasminogen
activator inhibitor-1 activity is not raised in women with PCOS independent of
obesity and these results do not support the hypothesis that it may contribute to
their anovulatory infertility, or increase their risk of thrombosis. The only
significant metabolic features of the PCOS independent of obesity are insulin
resistance, hyperinsulinaemia and lower HDL/total cholesterol ratio. The higher
frequency of a positive family history of thrombosis in these women nevertheless
requires further explanation.
PMID- 10762293
TI - The negative association between serum free testosterone and leptin is dependent
on insulin-like growth factor-binding protein 1 in healthy young and middle-aged
men.
AB - OBJECTIVE: Previous studies have shown that serum levels of testosterone
correlate negatively with leptin and positively with insulin-like growth factor
binding protein 1 (IGFBP-1). The present study examined whether these
associations are linked. DESIGN AND PATIENTS: The association between serum
levels of IGFBP-1, free testosterone and insulin on one hand and leptin on the
other hand were investigated in 38 healthy men with a median age of 48 years
(range 23-62 years). RESULTS: Univariate analyses revealed that serum levels of
leptin correlated negatively with serum free testosterone (r = - 0.42, P = 0.008)
and with serum IGFBP-1 (r = - 0. 45, P = 0.005) and positively with body mass
index (BMI; r = 0.46, P = 0.003) and serum insulin (r = 0.45, P = 0.004). Serum
free testosterone correlated with IGFBP-1 (r = 0.42, P = 0.008) but not with
serum insulin (r = - 0.08, ns). The correlations between leptin and free
testosterone and between leptin and IGFBP-1 remained significant after
adjustement for the influences of BMI and insulin. Forward stepwise multiple
regression when BMI, insulin, testosterone and IGFBP-1 were entered in a model as
independent variables and leptin as the dependent variable showed that BMI and
IGFBP-1 were independent predictors of circulating leptin. These two parameters
yielded an r 2 of 0.38, thereby together explaining approximately 40% of serum
leptin. CONCLUSION: Serum levels of free testosterone and IGFBP-1 correlate
negatively with serum leptin in healthy nonobese men but this influence is
dependent on the influence of IGFBP-1. The study therefore suggests an important
impact of IGFBP-1 on the regulation of circulating leptin in young and middle
aged men.
PMID- 10762294
TI - The development of a sialic acid specific lectin-immunoassay for the measurement
of human chorionic gonadotrophin glycoforms in serum and its application in
normal and Down's syndrome pregnancies.
AB - OBJECTIVE: We have developed and validated a lectin-immunoassay for the
recognition of sialic acid residues on hCG glycoforms in serum. DESIGN: This
assay employs a hCG specific capture antibody and a sialic acid specific lectin
(Wheat Germ Agglutinin) labelled with horse radish peroxidase. RESULTS: The
standard curve covered hCG concentrations of 0-4000 IU/l (3rd IS for hCG, 75/537)
with an analytical sensitivity of 1.0 IU/l. The within and between batch
coefficient of variation was < 7% for all doses. Cross-reactivity of < 1% with
TSH, LH, FSH, hCGalpha, hCGbeta and desialylated hCG confirmed assay specificity.
Dilutions of serum of < 10% final concentration were parallel to the standard
curve (within and between batch CV, < 6%). The assay working range was 100 - >
500 000 IU/l and the recovery of hCG from serum was in the range of 94.5% to
115.4%, with a mean value of 102.1%. The assay detected a time dependent change
in hCG sialylation during normal pregnancy with the relative abundance of
sialylated hCG declining after week 9 and increasing after week 15 of gestation.
In addition preliminary studies showed that maternal serum hCG concentrations
measured with the lectin-immunoassay were elevated in high risk Down's
pregnancies (as defined by conventional screening tests between weeks 16-18
gestation, median multiple of median, 3.14; range 1.81-19.12, P < 0. 001) and low
risk (1.57, 0.49-6.14, P = 0.034) compared to normal (1. 00, 0.32-3.20)
pregnancies. Furthermore, the lectin immunoassay had greater discriminatory power
compared to conventional immunoassay of hCG and hCGbeta between normal and both
low and high risk Down's pregnancies. CONCLUSION: This assay will allow analysis
of serum samples for the investigation of sialylated variants of hCG glycoforms
in various pathological and physiological situations.
PMID- 10762295
TI - Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without
germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1.
AB - OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a familial tumour
syndrome of endocrine tumours involving parathyroids, anterior pituitary and
enteropancreatic neuroendocrine tissues, and is inherited in an autosomal
dominant manner with high penetrance. Recently, the gene responsible for this
syndrome, MEN1, was positionally cloned from chromosome 11q13. PATIENTS: To
characterize sporadic MEN1 patients, we analysed the MEN1 gene by direct
sequencing of the entire open reading frame from 20 individuals. RESULTS: We
identified heterozygous germline mutations of the MEN1 gene in 8 of 20 (40%)
cases. Seven were novel MEN1 germline mutations. Three mutations were splicing
abnormalities, and all were confirmed to be splicing defects by RT-PCR. The
clinical significance of detecting germline MEN1 mutations, not only in familial
MEN1 but also in sporadic MEN1, was confirmed by the finding of asymptomatic
mutant carriers among family members of the sporadic MEN1 patients. Seven of 8
cases with MEN1 mutations had enteropancreatic lesions in contrast to 4 of 12 (P
< 0.018) in those cases with no mutation. Ten of the 12 cases without MEN1
mutation were more than 50-year-old. Six of these 10 cases had the same clinical
features; primary hyperparathyroidism and a GH-secreting pituitary tumour.
CONCLUSIONS: It is likely that the six cases without mutations were MEN1
phenocopies due to (i) two kinds of tumours with high natural incidence in older
subjects developed by chance (ii) another familial tumour syndrome with low
penetrance, e. g. familial acromegaly with primary hyperparathyroidism by
mutation of another gene, or (iii) somatic mutation during early embryonic
stages.
PMID- 10762296
TI - Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene
associated disorder of intersex and nephropathy?
AB - Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for
normal development and function of the urogenital tract, can result in both
tumourigenesis [corrected] and urogenital abnormalities. The association of WT1
gene mutations with most cases of Denys-Drash syndrome is well described. More
recently WT1 mutations have also been described in a related condition, Frasier
syndrome. We report a case where genetic analysis showed a WT1 mutation typically
associated with Frasier syndrome: a 1228 + 5 guanine to adenine substitution at
the 3' alternative splice donor site in intron 9. The case provides a focus for
the discussion of recent evidence that Denys Drash and Frasier syndrome form two
ends of a spectrum of disorders. In addition, it illustrates the increasing
significance of genetic investigation within clinical practice for diagnostic,
prognostic and therapeutic purposes and the importance of karyotype analysis in
phenotypically normal girls with renal disease.
PMID- 10762297
TI - Genomic screening for blood-borne viruses in transfusion settings.
AB - The residual risk of post-transfusion human immunodeficiency virus (HIV)
infection is low but slightly higher for hepatitis B virus (HBV) and hepatitis C
virus (HCV), the main reason being viraemia during the window period preceding
antibody or antigen detection by enzyme immunoassays. Immunosilent-infected
individuals and carriers of distant viral variants also play an unquantifiable
role. Multiple techniques, e.g. reverse transcription-polymerase chain reaction
(RT-PCR), PCR, ligase-chain reaction, nucleic acid sequence-based amplification
(NASBA) and transcription-mediated amplification (TMA) have been developed to
amplify and detect viral genomes as single or multiplex assays. Equipment
providing various degrees of automation has been adapted to these techniques.
Applying nucleic acid amplification techniques (NAT) to blood screening, two main
approaches have been advocated: plasma pool and single-donation testing. Pool
testing presents the advantage of lower cost and readily available equipment
although it is prone to false negative and positive reactions. The time required
to identify infected donations is incompatible with blood component release, and
may lead to product waste. Single-unit testing, although appealing, is not yet
fully automated and potentially very costly unless a systematic multiplex
approach is taken. Although technically feasible, NAT applied to the blood supply
needs to be clinically evaluated and its cost efficiency assessed in the general
public health context. However, pool NAT is currently implemented in continental
Europe and the USA.
PMID- 10762298
TI - Haemolytic uraemic syndrome: prognostic factors.
AB - Haemolytic uraemic syndrome (HUS) associated with Escherichia coli O157:H7 is the
commonest cause of acute renal failure (ARF) in childhood. Production of
verotoxin by the organism is pivotal in the pathogenesis of the disease.
Verotoxin binds to a receptor on blood and endothelial cells, expressed as the P1
blood group antigen on red blood cells. A protective effect of the P1 phenotype
has been proposed in this disease. This study investigates prognostic factors and
the relationship between outcome and P1 phenotype in 27 cases of diarrhoea
associated HUS. A poor outcome as defined by the presence of chronic renal
failure (CRF), hypertension or proteinuria on 6 month follow-up was associated
with the age of the patient at presentation and with the following clinical
markers: maximum WBC and duration of raised WBC, duration of anuria and duration
of need for dialysis. None of these outcome measures or prognostic factors, and
no extra-renal manifestations of the disease were associated with P1 phenotype.
PMID- 10762299
TI - Interferon-alpha treatment decreases serum cross-linked C-terminal telopeptide of
type I collagen in haematological diseases.
AB - Interferon-alpha (IFN-alpha) is used in the treatment of many haematological
diseases and it is known that IFN-alpha may affect bone turnover. The effect of
IFN-alpha on bone metabolism was studied in 10 haematological patients. The mean
duration of the treatment was 4 (range: 2.8-7.2) months. Besides the usual
markers of bone metabolism, levels of the cross-linked C-terminal telopeptide of
type I collagen (ICTP), the N-terminal propeptide of type I procollagen (PINP)
and the bone-specific alkaline phosphatase were measured. The bone mineral
density was measured by computed tomography. During IFN-alpha treatment, serum
ICTP decreased from a mean of 5.4 (range: 1.8-12.4) to 3.6 (range: 1.4-8.8)
microg/l (P = 0.017). All other variables reflecting bone metabolism remained
unaltered during IFN-alpha treatment. The bone mineral density remained
unchanged. It was concluded that the observed decrease in ICTP may be an
indicator of a beneficial therapeutic effect of IFN-alpha on bone turnover,
resulting in decreased bone resorption. However, it is possible that elevated
pretreatment ICTP values reflected disease of the bone marrow.
PMID- 10762300
TI - Storage pool defect in pooled buffy coat platelet concentrates within the shelf
life period.
AB - Platelet concentrate (PC) transfusions are useful for maintaining haemostasis in
a variety of clinical situations. The function of transfused platelets is of
critical importance, and changes on storage of buffy coat-prepared PC may
influence their haemostatic potential. Total platelet adenine nucleotide content
and platelet aggregation responses were studied, serially, in pooled buffy coat
derived PCs (n = 7), stored under UK recommended blood bank conditions, over the
stipulated shelf-life of 5 days. Mean platelet volume (MPV), platelet counts and
platelet distribution width (PDW) were also quantified. Total platelet ADP
content decreased from 4.45+/-0.78 to 3.71+/-0.69 nmol/108 platelets (P<0.01, day
1 versus day 5, mean +/- SEM) over the shelf-life period. This was associated
with reduced aggregatory responses: responses (expressed as percentage of maximum
height) to 5 and 10 microM ADP decreased from 10.8+/-2.8% to 1.0+/-1.0% (P<0.005,
5 microM, day 1 versus day 5) and from 18.0+/-5.4% to 4.7+/-2.2% (P<0.02, 10
microM, day 1 versus day 5) while the decreased responsiveness was more
pronounced for 4 microg/ml of collagen: 49.0+/-13.3% to 7.2+/-7.1% (P<0.01, day 1
versus day 4) and 49.9 +/-13.3% to 2.1+/-1.9% (P<0.001, day 1 versus day 5).
These data indicate an acquired storage pool defect that is maximal by day 4 or 5
and accompanied by decreased platelet function, characterized by significant
decreases in platelet aggregation responses. Addition of freeze-thawed plasma
(autologous day 1) to PCs on days 2, 3, 4 and 5 did not alter the responses to
ADP and collagen.
PMID- 10762301
TI - Evaluation of the von Willebrand factor antigen (vWF-Ag) assay using an immuno
turbidimetric method (STA Liatest vWF) automated on the MDA 180 coagulometer.
AB - The standard enzyme-linked immunosorbent assay (ELISA) test for von Willebrand
factor antigen (vWF-Ag), though sensitive and specific, does not deliver the
flexibility to handle single sample assessments economically or provide rapid,
emergency testing capability. The present study examined the performance
characteristics of an immuno-turbidimetric assay kit (STA Liatest) modified for
automation on the MDA(R)180 coagulation analyser using a supplied protocol. One
hundred and sixteen patient samples were assessed by both the standard and the
modified method. The correlation coefficient was 0.98 across the range of values
1-487 IU/dl. Above 200 IU/dl, where specimen dilution was indicated, there was
greater diversity (r = 0.86) between the techniques. Plotting the difference
between methods against the mean of both showed excellent agreement between
methods below 100 IU/dl vWF. The intra-assay and interassay coefficients of
variation were less than 3% at both low and normal range levels. The MDA(R)180
automated vWF assay merits consideration as an alternative to ELISA testing that
provides random access and result availability within 30 min.
PMID- 10762302
TI - Anti-coagulant monitoring service delivery: a comparison of costs of hospital and
community outreach clinics.
AB - Anti-coagulated patients are monitored at regular intervals to ensure that their
warfarin dosage is appropriate for their target International Normalized Ratio.
The traditional setting for this monitoring has been the hospital clinic.
Technological advances allow-- and with growing numbers of anti-coagulated
patients, are leading to-- greater provision of monitoring clinics outside the
hospital, at a more convenient location nearer patients' homes. This paper
discusses the differences in organization between a hospital clinic and one set
in the community (although provided by the hospital), and compares their costs.
The comparison demonstrates the greater average cost per appointment in outreach
of pound sterling 13.12 under current arrangements. Estimates are presented of
incremental cost per appointment of pound sterling 3.93 and pound sterling 15.88
for a 10% increase in weekly patient numbers put through hospital and outreach
clinics, respectively. Cost estimates are also presented for suggested
alterations to hospital clinics that may reduce patient inconvenience, and the
conditions under which outreach provision might be expanded at comparable cost to
hospital provision are also examined.
PMID- 10762303
TI - Gastrointestinal mucormycosis complicated by arterio-enteric fistula in a patient
with non-Hodgkin's lymphoma.
AB - Gastrointestinal mucormycosis is a rare, often fatal, systemic infection found
predominantly in immunocompromised patients. We report a case of gastrointestinal
mucormycosis in a 53-year-old female with non-Hodgkin's lymphoma. Following her
first course of chemotherapy, bowel obstruction developed as a result of
mucormycosis. Despite treatment with antifungal therapy, she required a
laparotomy owing to severe haemorrhage caused by mucormycosal invasion of her
iliac artery. With continued antifungal treatment and further chemotherapy, she
ultimately underwent reversal of her Hartmann's procedure and remains disease
free.
PMID- 10762304
TI - Relapsing polychondritis and myelodysplasia: a report of two cases and review of
the current literature.
AB - Relapsing polychondritis (RP) is a rare multisystem disorder. We describe two
case reports of patients with RP, one of whom developed myelodysplasia subtype
refractory anaemia (RA) and the other, refractory anaemia with ringed
sideroblasts (RARS). We also review the literature of association between RP and
haematological disorders.
PMID- 10762305
TI - Simultaneous occurrence of the 5q- syndrome and multiple myeloma.
AB - We report a case of the 5q- syndrome with simultaneous occurrence of multiple
myeloma, characterized by a very complicated course. To the best of our
knowledge, this is the first report of such an association.
PMID- 10762306
TI - Pure red cell aplasia in a patient with chronic granulocytic leukaemia treated
with interferon-alpha.
AB - Interferon-alpha has been shown to improve survival in patients with chronic
granulocytic leukaemia, therefore it is increasingly becoming part of the
standard treatment of this condition. Interferon has a wide variety of side
effects. Pure red cell aplasia has been reported in a few cases of chronic
granulocytic leukaemia but this usually heralds the onset of the transformation
to the acute phase. This paper reports a possible, and not previously reported,
side-effect of interferon-alpha in a patient with chronic granulocytic leukaemia.
PMID- 10762307
TI - Gq protein alpha subunits Galphaq and Galpha11 are localized at postsynaptic
extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal
cells.
AB - Following cell surface receptor activation, the alpha subunit of the Gq subclass
of GTP-binding proteins activates the phosphoinositide signalling pathway. Here
we examined the expression and localization of Gq protein alpha subunits in the
adult mouse brain by in situ hybridization and immunohistochemistry. Of the four
members of the Gq protein alpha subunits, Galphaq and Galpha11 were transcribed
predominantly in the brain. The highest transcriptional level of Galphaq was
observed in cerebellar Purkinje cells (PCs) and hippocampal pyramidal cells,
while that of Galpha11 was noted in hippocampal pyramidal cells. Antibody against
the C-terminal peptide common to Galphaq and Galpha11 strongly labelled the
cerebellar molecular layer and hippocampal neuropil layers. In these regions,
immunogold preferentially labelled the cytoplasmic face of postsynaptic cell
membrane of PCs and pyramidal cells. Immunoparticles were distributed along the
extra-junctional cell membrane of spines, dendrites and somata, but were almost
excluded from the junctional membrane. By double immunofluorescence,
Galphaq/Galpha11 was extensively colocalized with metabotropic glutamate receptor
mGluR1alpha in dendritic spines of PCs and with mGluR5 in those of hippocampal
pyramidal cells. Together with concentrated localization of mGluR1alpha and
mGluR5 in a peri-junctional annulus on PC and pyramidal cell synapses (Baude et
al. 1993, Neuron, 11, 771-787; Lujan et al. 1996, Eur. J. Neurosci., 8, 1488
1500), the present molecular-anatomical findings suggest that peri-junctional
stimulation of the group I metabotropic glutamate receptors is mediated by
Galphaq and/or Galpha11, leading to the activation of the intracellular effector,
phospholipase Cbeta.
PMID- 10762308
TI - Galanin knockout mice reveal nociceptive deficits following peripheral nerve
injury.
AB - The neuropeptide galanin has been identified as a potential
neurotransmitter/neuromodulator within the central nervous system. In the present
study, the role of endogenous galanin in nociceptive processing in the nervous
system has been analysed by using mice carrying a targeted mutation in the
galanin gene. Supporting this, the effect of chronic administration of exogenous
galanin on nociceptive sensory inputs has been assayed in adult rats. In the
absence of peripheral nerve injury, the sensitivity to threshold noxious stimuli
is significantly higher in galanin mutant mice than wild-type controls. Following
peripheral nerve injury, in conditions under which endogenous galanin levels are
elevated, spontaneous and evoked neuropathic pain behaviours are compromised in
mutant mice. Conversely, chronic intrathecal delivery of exogenous galanin to
nerve-intact adult rats is associated with persistent behavioural
hypersensitivity, a significant increase in c-fos expression and an increase in
PKCgamma immunoreactivity within the spinal cord dorsal horn. The present results
demonstrate that a relationship exists between the degree of nerve injury-induced
galanin expression and the degree of behavioural hypersensitivity, and show that
galanin may play a role in nociceptive processing in the spinal cord, with
interrelated inhibitory and excitatory effects.
PMID- 10762309
TI - GABAB receptors mediate frequency-dependent depression of excitatory potentials
in rat perirhinal cortex in vitro.
AB - Excitatory synaptic transmission in the perirhinal cortex exhibits marked
homosynaptic paired pulse depression (PPD) at inter-pulse intervals between 100
and 1000 ms, being maximal at 200 ms. Additionally, there is greater PPD with
stimulation of the pathway from the temporal cortex side than with stimulation of
the pathway from the entorhinal cortex side. We establish that this frequency
dependent depression relies on the activation of GABAB (gamma-aminobutyric acid)
receptors. PPD in both temporal and entorhinal pathways is abolished by either of
the selective GABAB receptor antagonists, 3-N[1-(S)-(3, 4
dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid
(CGP55845A) or 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP35348). Barium
which blocks G-protein-coupled, inwardly rectifying potassium channels, does not
block PPD. Heterosynaptic depression mediated by GABAB receptors was also
observed. The depression of the entorhinal pathway by stimulation of the temporal
pathway is greater than depression of the temporal pathway by stimulation of the
entorhinal pathway. Moreover, PPD increases with stimulus strength and the
depression is enhanced by short trains of stimuli, consistent with stronger
stimulation resulting in more GABA reaching GABAB receptors on excitatory
glutamatergic synapses. Synaptic activation of GABAB receptors may be important
in regulating excitability in a frequency-dependent manner with maximal
depression occurring at approximately 5 Hz, which approximates to the theta
rhythm. That homosynaptic and heterosynaptic depression by stimulation of the
temporal pathway is greater than by stimulation of the entorhinal pathway
suggests that activation of temporal feedforward connections to the perirhinal
cortex can dominate the GABAergic control of synaptic activity within the
perirhinal cortex.
PMID- 10762310
TI - Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy.
AB - The degree of postsynaptic type A gamma-aminobutyric acid receptor (GABAA
receptor) occupancy was investigated by using the benzodiazepine agonist
zolpidem. This drug increases the affinity of GABAA receptors for gamma
aminobutyric acid (GABA) at room temperature (Perrais & Ropert 1999, J.
Neurosci., 19, 578) leading to an enhancement of synaptic current amplitudes if
receptors are not fully occupied by the released transmitter. We recorded
miniature inhibitory postsynaptic currents (mIPSCs) from eight different cell
types in three brain regions of rats and mice. Receptors in every cell type were
benzodiazepine sensitive, as 10-20 microM zolpidem prolonged the decays of mIPSCs
(151-184% of control). The amplitude of the GABAA receptor-mediated events was
significantly enhanced in dentate granule cells, CA1 pyramidal cells, hippocampal
GABAergic interneurons, cortical layer V pyramidal cells, cortical layer V
interneurons, and in cortical layer II/III interneurons. An incomplete
postsynaptic GABAA receptor occupancy is thus predicted in these cells. In
contrast, zolpidem induced no significant change in mIPSC amplitudes recorded
from layer II/III pyramidal cells, suggesting full GABAA receptor occupancy.
Moreover, different degrees of receptor occupancy could be found at distinct
GABAergic synapses on a given cell. For example, of the two distinct populations
of zolpidem-sensitive mIPSCs recorded in olfactory bulb granule cells, the
amplitude of only one type was significantly enhanced by the drug. Thus, at
synapses that generate mIPSCs, postsynaptic receptor occupancy is cell type and
synapse specific, reflecting local differences in the number of receptors or in
the transmitter concentration in the synaptic cleft.
PMID- 10762311
TI - Differences in bcl-2- and bax-independent function in regulating apoptosis in
sensory neuron populations.
AB - Bcl-2 and Bax are cytoplasmic proteins that have antagonistic actions on
apoptosis. To investigate the extent to which these proteins function
independently in regulating neuronal apoptosis, we studied the in vivo and in
vitro development of two populations of sensory neurons of mouse embryos that
lack one or both proteins. Absence of Bcl-2 increased neuronal apoptosis and
reduced the number of neurons in both the trigeminal and nodose ganglia during
the period of naturally occurring neuronal death. Absence of Bax reduced neuronal
apoptosis and increased the number of surviving neurons in these ganglia and
promoted sustained neuronal survival in neurotrophin-free cultures. In contrast,
the elimination of both Bcl-2 and Bax had different consequences for these
populations of neurons. In nodose ganglia, apoptosis was suppressed just as
effectively in embryos lacking both proteins as in embryos lacking Bax alone, and
neurons that lacked both proteins survived just as effectively in neurotrophin
free medium as Bax-deficient neurons. This suggests that for nodose neurons, the
suppression of apoptosis by Bcl-2 is entirely dependent on the presence of Bax.
In trigeminal ganglia, although neuronal apoptosis was reduced in embryos lacking
both proteins compared with wild-type embryos, there were significantly more
apoptotic neurons and significantly fewer surviving neurons in embryos lacking
both proteins compared with Bax-deficient embryos, and significantly fewer
trigeminal neurons from embryos lacking both proteins survived in neurotrophin
free medium compared with trigeminal neurons that lacked Bax alone. This suggests
that for trigeminal neurons, Bcl-2 functions partly independently of Bax in
regulating survival. Our results therefore suggest that the relative independence
of Bcl-2 and Bax in regulating neuronal survival differs from one population of
neurons to another.
PMID- 10762312
TI - Perineuronal nets ensheath fast spiking, parvalbumin-immunoreactive neurons in
the medial septum/diagonal band complex.
AB - Perineuronal nets, composed of extracellular matrix material, have previously
been associated with parvalbumin-immunoreactive neurons in the medial
septum/diagonal band (MS/DB) complex of the rat. The aim of this study was to
correlate the presence of perineuronal nets with electrophysiological properties
and parvalbumin immunoreactivity in MS/DB neurons. Intracellular recordings were
made from cells in a brain slice preparation maintained in vitro, and neurons
were characterized into four populations: (i) slow-firing neurons, (ii) burst
firing neurons, (iii) fast spiking neurons with narrow action potentials and a
small degree of spike frequency adaptation, and (iv) regular spiking neurons with
broader action potentials and a high degree of spike frequency adaptation.
Following electrophysiological characterization, neurons were filled with
biocytin, processed for parvalbumin immunoreactivity and stained for perineuronal
nets using Wisteria floribunda lectin. The three substances were viewed with
triple fluorescence. Fast spiking, nonadapting neurons, shown previously to
contain parvalbumin immunoreactivity, were nearly all ensheathed by perineuronal
nets. There was a population of small parvalbumin-immunoreactive neurons which
did not possess perineuronal nets, and which were not encountered with the
intracellular electrodes. The other three neuron types in the MS/DB did not
contain parvalbumin immunoreactivity or perineuronal nets. In keeping with this
neurochemical profile for electrophysiologically identified neurons, burst-firing
neurons had action potential parameters more similar to those of regular spiking
than of fast spiking neurons. We conclude that fast spiking neurons, presumed to
be GABAergic septohippocampal projection neurons, are surrounded by supportive
structures to enable the high level of neuronal discharge required for producing
disinhibition of hippocampal pyramidal neurons.
PMID- 10762313
TI - Location of calcium transporters at presynaptic terminals.
AB - The plasma membrane ATP-driven Ca2+ pump (PMCA) and the Na+/Ca2+ exchanger (NCX)
are the major means of Ca2+ extrusion at presynaptic nerve terminals, but little
is know about the location of these transporters relative to the major sites of
Ca2+ influx, the transmitter release sites. We used immunocytochemistry to
identify these transport proteins in a calyx-type presynaptic nerve terminal from
the ciliary ganglion of the chick. The PMCA clusters were localized to the
transmitter release sites, as identified by staining for the secretory vesicle
specific protein synaptotagmin I. This colocalization was not due to the presence
of the pump on the secretory vesicle itself because membrane fractionation of
chick brain synaptosomes demonstrated comigration of the pump with surface
membrane and not vesicle markers. In contrast, the NCX did not colocalize with
synaptotagmin but tended to be located at nonsynaptic regions of the terminal.
The PMCA location, near the transmitter release sites, suggests that it plays a
role in priming the release site by maintaining a low free Ca2+ level,
facilitating the dissociation of the ion from its binding sites. The PMCA may
also replenish external Ca2+ in the synaptic cleft following periods of synaptic
activity. In contrast, the NCX location suggests a role in the rapid emptying of
cytoplasmic Ca2+ uptake organelles which serve as the main line of defence
against high free Ca2+.
PMID- 10762314
TI - Physiological role of group III metabotropic glutamate receptors in visually
responsive neurons of the rat superficial superior colliculus.
AB - There is evidence from immunohistochemical and in situ hybridization studies for
the presence of Group I, II and III metabotropic glutamate receptors (mGluRs) in
the rat superficial superior colliculus (SSC). The purpose of this study was to
investigate if manipulation of Group III mGluRs affects visual responses in the
SSC. Drugs were applied by iontophoresis and single neuron activity was recorded
extracellularly. L-AP4 (Group III agonist) resulted in a reduction of visual
responses in most neurons, but also a potentiation in others. The effect of L-AP4
is drug- and stereospecific in that application of D-AP4 did not significantly
affect visual responses. L-AP4 application also resulted in a potentiation of the
response to iontophoretically applied NMDA. The effects of MPPG and CPPG (Group
III antagonists) were compared with the effect of L-AP4 in the same neuron and
were found to produce the opposite effect to L-AP4. Furthermore, the effect of L
AP4 could be blocked by coapplication of MPPG or CPPG. Presynaptic depression of
glutamate release is a possible mechanism by which L-AP4 could reduce visual
responses in the SSC whereas the potentiation of visual responses by L-AP4 could
be due to a reduction of GABAergic inhibition. The finding that MPPG and CPPG, as
well as antagonizing the L-AP4 effect, have a direct effect on visual responses
suggests that Group III mGluRs are activated by endogenous transmitter released
during visual stimulation.
PMID- 10762315
TI - Metabolic coupling between glia and neurons is necessary for maintaining
respiratory activity in transverse medullary slices of neonatal mouse.
AB - The respiratory rhythm is generated and regulated by a neuronal network within
the lower brainstem. While the neuronal mechanisms of rhythm generation have been
extensively investigated, the contribution of glial cells remains to be
determined. Here we report the effect of specific blockade of the glial Krebs
cycle and glutamine synthetase on the neuronal activity of the respiratory
network. Application of 5 mM fluoroacetate, which selectively blocks the glial
Krebs cycle, suppressed rhythmic respiratory burst activity. Substitution of
either the Krebs cycle substrate isocitrate (3 mM) or glutamine (3 mM) restored
rhythmic network activity. Blockade of glutamine synthetase by methionine
sulfoximine (0.5 mM) suppressed rhythmic burst activity as well. Resubstitution
of glutamine (3 mM) was able to restore rhythmic activity in the presence of
methionine sulfoximine. This data demonstrates that the glutamate-glutamine cycle
in astrocytes and their supply of glutamine to neuronal glutamatergic terminals
is essential for the rhythm generation in the respiratory centre.
PMID- 10762316
TI - Differential effects of NT-3 on reinnervation of the fast extensor digitorum
longus (EDL) and the slow soleus muscle of rat.
AB - Previous studies of gastrocnemius muscle reinnervation showed specific
normalization of the proportion and diameter of fast type 2b muscle fibres
following NT-3 delivery to the proximal stump of the cut sciatic nerve. Here, we
investigate if normalization was related to greater improvement of muscle
reinnervation of fast (extensor digitorum longus; EDL) than slow (soleus) motor
units. NT-3-impregnated (NT-3 group) or plain fibronectin (FN group) mats were
inserted into a sciatic nerve gap. Neuromuscular junctions (NMJs) labelled with
TRITC-alpha-bungarotoxin were colabelled with calcitonin gene-related peptide
(CGRP) or 4E2 antisera and imaged using confocal microscopy. CGRP and 4E2 were
used as markers for newly reinnervated and structurally mature NMJs,
respectively. At 40 days postsurgery, denervated NMJs in EDL and soleus muscles
of both groups presented a 50% decrease of surface area due to decreased width.
At day 80 in EDL, more NMJs were reinnervated by CGRP-immunoreactive terminals in
the NT-3 (7.1%) than in the FN group (4.2%); there was no difference between
groups for soleus. At 120 days, 4E2-immunoreactive NMJs were more numerous in EDL
of the NT-3 (40.0%) than in the FN group (7.3%), unlike in soleus (NT-3, 1. 6%;
FN, 1.8%), and presented a partial size recovery. These results indicate that NT
3 preferentially improves reinnervation of fast muscles over slow muscle,
although the mechanism of this improvement is still unclear.
PMID- 10762317
TI - Developmental and adult expression of rat calcium-sensing receptor transcripts in
neurons and oligodendrocytes.
AB - The calcium-sensing receptor (CaSR) is a member of a growing family of
heptahelical receptors with an unusually large extracellular domain. To further
delineate its functions in neurons and glia, we have investigated the expression
pattern of CaSR transcripts in the postnatal and adult rat brain, spinal cord and
dorsal root ganglia by in situ hybridization. CaSR-expressing cells were
spatially and temporally regulated in myelinated structures with a caudo-rostral
pattern that paralleled that of myelin basic protein, a marker of myelination,
with a downregulation observed in the adult. Double-labelling studies
demonstrated that CaSR mRNA colocalizes with myelin basic protein-expressing
cells within fibre tracts, suggesting that CaSR is expressed by mature
oligodendrocytes. In cultured rat oligodendrocytes, Ca2+ induced stimulation of
phosphatidylinositol hydrolysis with an EC50 of 1.4 mM and increased
intracellular calcium. NPS R-568 (1 microM), a calcimimetic, significantly
stimulates the inositol phosphate response, whereas a less potent stereoisomer,
NPS S-568 (1 microM), was without effect. These data suggest that a functional
CaSR is expressed in mature oligodendrocytes with a potential role in
myelination. CaSR expression was also developmentally regulated in neurons of the
orbital cortex and in the CA2 region of the hippocampus, and present in olfactory
nuclei, hypothalamic areas and in the area postrema through postnatal days to
adulthood. This expression is consistent with a role of CaSR in olfactory or
gustatory signal integration, and with the regulation of fluid and mineral
homeostasis. CaSR expression in a subpopulation of small cells in dorsal root
ganglia suggests additional roles for extracellular Ca2+ in sensory nerves.
PMID- 10762318
TI - Enlarged cholinergic forebrain neurons and improved spatial learning in p75
knockout mice.
AB - The p75 low affinity neurotrophin receptor (p75) can induce apoptosis in various
neuronal and glial cell types. Because p75 is expressed in the cholinergic
neurons of the basal forebrain, p75 knockout mice may be expected to show an
increased number of neurons in this region. Previous studies, however, have
produced conflicting results, suggesting that genetic background and choice of
control mice are critical. To try to clarify the conflicting results from
previous reports, we undertook a further study of the basal forebrain in p75
knockout mice, paying particular attention to the use of genetically valid
controls. The genetic backgrounds of p75 knockout and control mice used in this
study were identical at 95% of loci. There was a small decrease in the number of
cholinergic basal forebrain neurons in p75 knockout mice at four months of age
compared with controls. This difference was no longer apparent at 15 months due
to a reduction in numbers in control mice between the ages of 4 and 15 months.
Cholinergic cell size in the basal forebrain was markedly increased in p75
knockout mice compared with controls. Spatial learning performance was
consistently better in p75 knockout mice than in controls, and did not show any
deterioration with age. The results indicate that p75 exerts a negative influence
on the size of cholinergic forebrain neurons, but little effect on neuronal
numbers. The markedly better spatial learning suggests that the function, as well
as the size, of cholinergic neurons is negatively modulated by p75.
PMID- 10762319
TI - Acidic motif responsible for plasma membrane association of the voltage-dependent
calcium channel beta1b subunit.
AB - Voltage-dependent calcium channels consist of a pore-forming transmembrane alpha1
subunit, which is known to associate with a number of accessory subunits,
including alpha2-delta- and beta-subunits. The beta-subunits, of which four have
been identified (beta1-4), are intracellular proteins that have marked effects on
calcium channel trafficking and function. In a previous study, we observed that
the beta1b-subunit showed selective plasma membrane association when expressed
alone in COS7 cells, whereas beta3 and beta4 did not. In this study, we have
examined the basis for this, and have identified, by making chimeric beta
subunits, that the C-terminal region, which shows most diversity between beta
subunits, of beta1b is responsible for its plasma membrane association.
Furthermore we have identified, by deletion mutations, an 11-amino acid motif
present in the C terminus of beta1b but not in beta3 (amino acids 547-556 of
beta1b, WEEEEDYEEE), which when deleted, reduces membrane association of beta1b.
Future research aims to identify what is binding to this sequence in beta1b to
promote membrane association of this calcium channel subunit. It is possible that
such membrane association is important for the selective localization or
clustering of particular calcium channels with which beta1b is associated.
PMID- 10762320
TI - Formation of hippocampal synapses on patterned substrates of a laminin-derived
synthetic peptide.
AB - We created a new culture system which provides simple, stereotyped neuronal
circuitries suitable for investigating synaptic events between mammalian central
neurons. We used surface chemistry and laser-lithography to produce geometrical
patterns of neuron-compatible substrate spaced by less neuron-compatible
surfaces. The patterned substrates were composed of a laminin-derived synthetic
peptide, PA22-2, and the spacing surfaces of either decyldimethylsilane (DDMS) or
trimethylsilane (TMS). Dissociated rat hippocampal neurons survived on the
patterned substrates for several days without the aid of glia and extended their
neurites along the substrates. The TMS spacing surfaces appeared more favourable
for the excitability development and axonal differentiation of the hippocampal
neurons, but less favourable for the development of the resting conductance than
the DDMS spacing surfaces. Furthermore, neurons grown on the patterned substrates
frequently made synaptophysin-positive contacts with one another. Spontaneous
post-synaptic currents recorded from such neurons suggest that these contacts
were indeed functional synapses. When hippocampal neurons were plated at a very
low density, they often formed circuitries consisting of only two neurons on the
patterned substrate. Such a simple circuitry allowed us to analyse synaptic
transmission in a single neuronal pair without the influence of the third
neurons. With the clarity of analysis and the readiness of manipulation, our
culture system would offer a powerful tool for studying development and functions
of mammalian central synapses.
PMID- 10762321
TI - Cyclooxygenase-1 is a marker for a subpopulation of putative nociceptive neurons
in rat dorsal root ganglia.
AB - Immunocytochemical and morphometric techniques were used to quantify the
distribution of cyclooxygenase (cox)-containing neurons in rat L5 dorsal root
ganglia (DRG). Cox-1 immunolabelling was almost exclusively restricted to small
diameter DRG neurons (< 1000 microm2), and was extensively colocalized with
calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4). Cox-1 was present
in 65% and 70% of CGRP- and IB4-labelled neurons, respectively. Cox-1 labelling
was also found in neurons expressing the sensory neuron-specific (SNS) Na+
channel. Cox-2 labelling was absent in DRG from normal rats. In the Freund's
adjuvant model of monoarthritis, the proportion of cox-1-positive DRG neurons was
unchanged and no neurons were found to be labelled for cox-2. In primary tissue
culture, cox-1 immunolabelling persisted in vitro for up to 9 days and was
present in morphologically identical neurons. The selective expression of cox-1
in peripheral ganglia was confirmed by the small number of nodose ganglion
neurons and superior cervical ganglion (SCG) neurons labelled for cox-1. These
data suggest that cox-1 is a marker for a subpopulation of putative nociceptive
neurons in vitro and in vivo, and suggests that the prostaglandins synthesized by
these neurons may be important for nociceptor function. These data may have
important implications for the mode and mechanism of action of non-steroidal anti
inflammatory drugs (NSAIDs).
PMID- 10762322
TI - Cell death is prevented in thalamic fields but not in injured neocortical areas
after permanent focal ischaemia in mice overexpressing the anti-apoptotic protein
Bcl-2.
AB - Previous studies have suggested that various apoptotic-related proteins could be
involved in the death process induced by cerebral ischaemia. In order to further
clarify their role and examine how the anti-apoptotic protein Bcl-2 could
influence this process, the time-course of mRNA expression of various cell death
genes was studied from 1 to 14 days following permanent occlusion of the middle
cerebral artery in wild-type (WT) and Bcl-2 transgenic mice, within and outside
the area of infarction. No differences of the infarct sizes were observed between
the two groups of mice, showing that the extent of neuronal injury could not have
been lowered by the Bcl-2 transgene. Seven days after the ischaemic insult, the
mRNA expression of the cell death gene effector cpp32 was dramatically
upregulated in the penumbra of WT and Bcl-2 transgenic mice. Interestingly, the
cpp32 transcript was markedly induced from 3 days in the ipsilateral thalamus of
the two groups of mice. However, apoptotic bodies were observed in the thalamic
field of WT but not transgenic mice. This suggests that cpp32 mRNA may be induced
in an attempt to kill the injured cells and, in contrast to the penumbra, cell
death in the thalamus may be prevented in Bcl-2 transgenic mice. Based on these
results, the pathophysiological mechanisms that underly neuronal damage following
ischaemia need consideration in order to evaluate the extent of neuroprotection
that may be afforded by the Bcl-2 anti-apoptotic protein. Although the present
study does not confirm previous data showing a protective role of Bcl-2 in
neocortical infarcted areas, it suggests that anti-apoptotic therapies may
constitute a possible treatment for areas of the brain remote from those directly
affected by ischaemia.
PMID- 10762323
TI - Inhibition of delayed rectifier K+ conductance in cultured rat cerebellar granule
neurons by activation of calcium-permeable AMPA receptors.
AB - Activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
receptors in cerebellar granule cells during perforated-patch whole-cell
recordings activated an inward current at negative voltages which was followed,
after a delay, by the inhibition of an outward potassium current at voltages
positive to -20 mV. The activated inward current was inwardly rectifying
suggesting that the AMPA receptors were Ca2+-permeable. This was confirmed by
direct measurements of intracellular calcium where Ca2+ rises were seen following
AMPA receptor activation in Na+-free external solution. Ca2+ rises were equally
large in the presence of 100 microM Cd2+ to block voltage-gated Ca2+ channels.
Specific voltage-protocols, allowing selective activation of the delayed
rectifier potassium current (KV) and the transient A current (KA), showed that
kainate inhibited KV, but not to any great extent KA. The inhibition of KV was
blocked by the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3
dione) and was no longer observed when the KV current was abolished with high
concentrations of Ba2+. The responses to kainate were not altered by pre-treating
the cells with pertussis toxin, suggesting that the AMPA receptor stimulation of
the G-protein Gi cannot account for the effects observed. Replacing extracellular
Na+ with choline did not alter the inhibition of KV by kainate, however, removing
extracellular Ca2+ reduced the kainate response. The inhibition of KV by kainate
was unaffected by the presence of 100 microM Cd2+. The guanylyl cyclase
inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), did not alter
kainate inhibition of KV. It is concluded that ion influx (particularly Ca2+
ions) through AMPA receptor channels following receptor activation leads to an
inhibition of KV currents in cerebellar granule neurons.
PMID- 10762324
TI - Alterations in Purkinje cell spines of calbindin D-28 k and parvalbumin knock-out
mice.
AB - The second messenger Ca2+ is known to act in a broad spectrum of fundamental cell
processes, including modifications of cell shape and motility, through the
intermediary of intracellular calcium-binding proteins. The possible impact of
the lack of the intracellular soluble Ca2+-binding proteins parvalbumin (PV) and
calbindin D-28 k (CB) was tested on spine morphology and topology in Purkinje
cell dendrites of genetically modified mice. Three different genotypes were
studied, i.e. PV or CB single knock-out (PV-/-, CB-/-) and PV and CB double knock
out mice (PV-/-CB-/-). Purkinje cells were microinjected with Lucifer Yellow and
terminal dendrites scanned at high resolution with a confocal laser microscope
followed by three-dimensional (3-D) reconstruction. The absence of PV had no
significant effect on spine morphology, whereas the absence of CB resulted in a
slight increase of various spine parameters, most notably spine length. In double
knock-out mice, the absence of both PV and CB entailed a doubling of spine
length, an increase in spine volume and spine surface, a higher spine density
along the dendrites, as well as a more clustered spine distribution. In all three
genotypes, a reduction in the number of stubby spines was observed compared with
wild-type animals. These results suggest a morphological compensation for the
lack of the soluble calcium buffers in the cytoplasm of Purkinje cell dendritic
spines. The increase in various spine parameters, particularly volume, may
counteract the lack of the calcium buffers, such as to adjust Ca2+-transients at
the transitional zone between spines and dendrites.
PMID- 10762325
TI - Molecular and functional properties of synaptically activated NMDA receptors in
neonatal motoneurons in rat spinal cord slices.
AB - The functional properties of N-methyl-D-aspartate (NMDA) receptor-mediated
excitatory postsynaptic currents (EPSC) were studied in fluorescence-labelled
motoneurons in thin spinal cord slices. The deactivation of NMDA receptor EPSCs
in motoneurons voltage-clamped at +40 mV was independent of intensity or location
of stimulation and of postnatal age [taufast = 28.5 +/- 4.6 ms (63.6 +/- 8.8%)
and tauslow = 165.6 +/- 49.6 ms]. In the presence of 1 mM Mg2+ the amplitude of
NMDA receptor EPSCs was voltage-dependent. Boltzmann analysis of the relationship
between peak NMDA receptor EPSC amplitude and membrane potential suggested an
apparent Kd of Mg2+ (at 0 mV) of 0.87 mM. Nonstationary variance analysis of NMDA
receptor EPSCs gave an estimated single-channel conductance of 59 +/- 14 pS.
Direct measurement of the NMDA receptor channel openings in outside-out patches
isolated from motoneurons indicated the presence of single-channel conductance
levels of 21.8 +/- 2.8 pS, 37. 1 +/- 3.2 pS, 49.6 +/- 5.1 pS and 69.6 +/- 4.2 pS.
Single-cell RT-PCR analysis of mRNA revealed that NR1, NR2A-D and NR3A
transcripts were expressed in motoneurons. These results suggest that specific
assembly of NMDA receptor subunits in motoneurons determines the functional and
pharmacological properties of the receptors in these cells.
PMID- 10762326
TI - Transcription factor dynamics and neuroendocrine signalling in the mouse pineal
gland: a comparative analysis of melatonin-deficient C57BL mice and melatonin
proficient C3H mice.
AB - In rodents, the nocturnal rise and fall of arylalkylamine N-acetyltransferase
(AANAT) activity controls the rhythmic synthesis of melatonin, the hormone of the
pineal gland. This rhythm involves the transcriptional regulation of the AANAT by
two norepinephrine (NE)-inducible transcription factors, e.g. the activator pCREB
(phosphorylated Ca2+/cAMP-response element binding protein) and the inhibitor
ICER (inducible cAMP early repressor). Most inbred mouse strains do not produce
melatonin under standard laboratory light/dark conditions. As melatonin-deficient
mice are often the founders for transgenic animals used for chronobiological
experimentations, molecular components of neuroendocrine signalling in the pineal
gland as an integral part of clock entrainment mechanisms have to be deciphered.
We therefore compared calcium signalling, transcriptional events and melatonin
synthesis in the melatonin-deficient C57BL mouse and the melatonin-proficient C3H
mouse. Pineal glands and primary pinealocytes were cultured and stimulated with
NE or were collected at various times of the light/dark (LD) cycle. Changes in
intracellular calcium concentrations, the phosphorylation of CREB, and ICER
protein levels follow similar dynamics in the pineal glands of both mouse
strains. pCREB levels are high during the early night and ICER protein shows
elevated levels during the late night. In the C57BL pineal gland, a low but
significant increase in melatonin synthesis could be observed upon NE
stimulation, and, notably, also when animals were exposed to long nights. We
conclude that the commonly used C57BL mouse is not completely melatonin-deficient
and that this melatonin-deficiency does not affect molecular details involved in
regulating transcriptional events of melatonin synthesis.
PMID- 10762327
TI - The dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is
hormone-dependent.
AB - The dopaminergic projection to the shell of the nucleus accumbens is the most
reactive to stress, reward and drugs of abuse and this subregion of the nucleus
accumbens is also considered a target of therapeutic effects of atypical
antipsychotic drugs (APD). In this report we show, by means of in vivo
microdialysis and Fos immunohistochemistry, that the hyper-responsiveness which
characterizes the dopaminergic transmission to the shell is dependent on
glucocorticoid hormones. In Sprague-Dawley rats, after suppression of endogenous
glucocorticoids by adrenalectomy, extracellular dopamine levels selectively
decreased in the shell, whilst they remained unchanged in the core. This effect
was observed in basal conditions, after a mild stress (vehicle injection), as
well as after subcutaneous administration of morphine (2 mg/kg, s.c. ) or
intraperitoneal injection of cocaine (15 mg/kg, i.p.). The decrease in dopamine
observed in the shell had a postsynaptic impact, as shown by less induction of
Fos-like proteins selectively in the shell in response to cocaine. However, the
induction of Fos-like proteins by the full D1 agonist SKF82958 (1.5 mg/kg, i.p.)
remained unchanged after adrenalectomy, suggesting that the changes in Fos
expression after cocaine injection were likely to depend on changes in
extracellular dopamine levels rather than on changes in postsynaptic sensitivity
to dopamine. The effects of adrenalectomy were glucocorticoid-specific given that
they were prevented by corticosterone treatment. This anatomical specificity in
the control of neuronal activity by a hormonal input highlights the role of
steroid hormones in shaping the functional activity of the brain.
PMID- 10762328
TI - Effect of nitric oxide and NO synthase inhibition on nonquantal acetylcholine
release in the rat diaphragm.
AB - After anticholinesterase treatment, the postsynaptic muscle membrane is
depolarized by about 5 mV due to nonquantal release of acetylcholine (ACh) from
the motor nerve terminal. This can be demonstrated by the hyperpolarization
produced by the addition of curare (H-effect). The magnitude of the H-effect was
decreased significantly to 3 mV when the nitric oxide (NO) donors, sodium
nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) were applied to
the muscle, or when NO production was elevated by adding L-arginine, but not D
arginine, as a substrate. The H-effect was increased to 8-9 mV by inhibition of
NO synthase by L-nitroarginine methylester (L-NAME), or by guanylyl cyclase
inhibition by methylene blue and 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one
(ODQ). ODQ increased the H-effect to 7.3 +/- 0.2 mV and diminished the SNP
induced decrease of the H-effect when applied together with SNP. The effects of
NO donors and L-arginine were eliminated by adding reduced haemoglobin, an
extracellular NO scavenger. The present results, together with earlier evidence
for the presence of NO synthase in muscle fibres, indicate that nonquantal
release of ACh is modulated by NO production in the postsynaptic cell.
PMID- 10762329
TI - The retrograde inhibition of IPSCs in rat cerebellar purkinje cells is highly
sensitive to intracellular Ca2+.
AB - The Ca2+-dependent retrograde inhibition of inhibitory postsynaptic currents
(depolarization-induced-suppression of inhibition; DSI) was investigated using
fura-2 Ca2+ measurements and whole-cell patch-clamp recordings in rat cerebellar
Purkinje cells. DSI was studied in cells loaded with different concentrations of
the Ca2+ chelators BAPTA and EGTA. A concentration of 40 mM BAPTA was required to
significantly interfere with DSI, whereas 10 mM BAPTA was almost ineffective. 40
mM EGTA reduced DSI, but was less effective than 40 mM BAPTA. Ratiometric Ca2+
measurements indicated that the extent of DSI depended critically on the changes
in intracellular calcium ([Ca2+]i). The relationship between DSI and peak
Delta[Ca2+]i could be approximated by a hyperbolic function, with apparent half
saturation concentrations of 200 and 40 nM for dendritic and somatic [Ca2+]i,
respectively. It is suggested that DSI is due to somatodendritic exocytosis of a
retrograde messenger, and that this exocytosis is highly sensitive to [Ca2+]i.
PMID- 10762330
TI - Glycine receptors containing the alpha4 subunit in the embryonic sympathetic
nervous system, spinal cord and male genital ridge.
AB - Inhibitory glycine receptors (GlyRs) are known to mediate postsynaptic inhibition
in spinal cord, brain stem and some higher brain regions. Several developmentally
and regionally regulated GlyR isoforms exist, which result from a differential
expression of the GlyR alpha (alpha1-alpha4) and beta subunit genes. Currently,
very little is known about GlyRs containing the alpha4 subunit, whose existence
was predicted from a partial genomic sequence. Here, we describe the isolation of
complementary DNA (cDNA) sequences for the mouse and chick GlyR alpha4 subunits.
We show that a mouse GlyR alpha4 subunit full-length cDNA directs the formation
of functional homo-oligomeric strychnine-sensitive GlyRs in Xenopus laevis
oocytes and mammalian cells, and that these resemble GlyRs composed of the alpha1
subunit in pharmacological profile and single-channel properties. In situ
hybridization reveals high levels of GlyR alpha4 subunit transcripts in the
embryonic (E13) chick spinal cord, lumbosacral sympathetic ganglia and dorsal
root ganglia. The avian GlyR alpha4 subunit gene also shows male-specific
expression in the developing genital ridge. The pharmacological profile of alpha4
subunit-containing receptors and deduced location of the avian GlyR alpha4
subunit are consistent with it being a component of the embryonic excitatory
GlyRs previously identified in sympathetic neurons. Our data also suggest a novel
role for GlyRs in the maturation of reproductive organs.
PMID- 10762332
TI - Depolarizing stimulation upregulates GA-binding protein in neurons: a
transcription factor involved in the bigenomic expression of cytochrome oxidase
subunits.
AB - Neurons are unique in having dendrites that extend far away from their cell
bodies. Mitochondria located in the dendrites can be separated from the nucleus
for long distances. The mechanism of bigenomic coordination is of particular
importance to cytochrome oxidase (CO), which has subunits that are encoded in
both the nuclear and mitochondrial DNA. GA-binding protein (GABP) is a
transcription factor that is required for the promoter activity of mitochondrial
transcription factor A as well as several nuclear-encoded CO subunits. Thus, GABP
may play a key role in coordinating the transcription of both mitochondrial and
nuclear-encoded subunits of CO. The goal of the present study was to determine if
GABP was expressed in neurons and whether and how it responded to increased
neuronal activity. Using primary neuronal cultures, the beta-subunit of GABP was
localized immunocytochemically to both the cytoplasm and the nucleus, whereas the
alpha-subunit was expressed mainly in the nucleus. In KCl-treated cultures,
immunoreactivity for both alpha- and beta-subunits was significantly increased in
the nucleus compared with untreated sister cultures. The induction of GABP
preceded that of CO gene expression from the two genomes, which, in turn,
preceded that of CO activity. Thus, our data suggest that neuronal activity
regulates subunit concentrations of GABP in the nucleus, and GABP may be a
critical sensor of changes in neuronal activity. Our data are also consistent
with the postulated role of GABP as a coordinator of both mitochondrial and
nuclear transcription for subunits of CO in neurons.
PMID- 10762331
TI - Tissue plasminogen activator controls multiple forms of synaptic plasticity and
memory.
AB - Induction of long-term depression (LTD) in rat striatal slices revealed that this
form of synaptic plasticity is coupled to an increased expression of tissue
plasminogen activator (t-PA) mRNA, as detected by the mRNA differential display
technique. To further investigate the involvement of this gene in synaptic
remodelling following striatal LTD, we recorded electrical activity from mice
lacking the gene encoding t-PA (t-PA-KO) and from wild-type (WT) mice. Tetanic
stimulation induced LTD in the large majority of striatal neurons recorded from
WT mice. Conversely, LTD was absent in a significant proportion of striatal
neurons obtained from mice lacking t-PA. Electrophysiological recordings obtained
from hippocampal slices in the CA1 area showed that mainly the late phase of long
term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related
behavioural abnormalities were also found in these transgenic mice. Disruption of
the t-PA gene, in fact, altered both the context conditioning test, a hippocampus
related behavioural task, and the two-way active avoidance, a striatum-dependent
task. In an open field object exploration task, t-PA-KO mice expressed deficits
in habituation and reactivity to spatial change that are consistent with an
altered hippocampal function. Nevertheless, decreased rearing and poor initial
object exploration were also observed, further suggesting an altered striatal
function. These data indicate that t-PA plays a critical role in the formation of
various forms of synaptic plasticity and memory.
PMID- 10762333
TI - Outgrowth-promoting molecules in the adult hippocampus after perforant path
lesion.
AB - Lesion-induced neuronal plasticity in the adult central nervous system of higher
vertebrates appears to be controlled by region- and layer-specific molecules. In
this study we demonstrate that membrane-bound hippocampal outgrowth-promoting
molecules, as present during the development of the entorhino-hippocampal system
and absent or masked in the adult hippocampus, appear 10 days after transection
of the perforant pathway. We used an outgrowth preference assay to analyse the
outgrowth preference of axons from postnatal entorhinal explants on alternating
membrane lanes obtained from hippocampus deafferented from its entorhinal input
taken 4, 10, 20, 30 and 80 days post-lesion and from adult control hippocampus.
Neurites from the entorhinal cortex preferred to extend axons on hippocampal
membranes disconnected from their entorhinal input for 10 days in comparison with
membranes obtained from unlesioned adult animals. Membranes obtained from
hippocampi disconnected from their entorhinal input for 10 days were equally as
attractive for growing entorhinal cortex (EC) axons as membranes from early
postnatal hippocampi. Further analysis of membrane properties in an outgrowth
length assay showed that entorhinal axons extended significantly longer on
stripes of lesioned hippocampal membranes in comparison with unlesioned
hippocampal membranes. This effect was most prominent 10 days after lesion, a
time point at which axonal sprouting and reactive synaptogenesis are at their
peak. Phospholipase treatment of membranes obtained from unlesioned hippocampi of
adult animals strongly promoted the outgrowth length of entorhinal axons on these
membranes but did not affect their outgrowth preference for deafferented
hippocampal membranes. Our results indicate that membrane-bound outgrowth
promoting molecules are reactivated in the adult hippocampus following
transection of the perforant pathway, and that neonatal entorhinal axons are able
to respond to these molecules. These findings support the hypothesis of a
temporal accessibility of membrane-bound factors governing the layer-specific
sprouting of remaining axons following perforant path lesion in vivo.
PMID- 10762334
TI - Bicuculline injections into the rostral and caudal motor thalamus of the monkey
induce different types of dystonia.
AB - The pathophysiology of dystonia remains unclear in comparison with other movement
disorders. Recent data suggest that there may exist in dystonia an increased
thalamic drive to the mesial premotor cortex. To test this hypothesis, we induced
overactivity of the motor thalamus by injecting a GABA-A (gamma-aminobutyric
acid) antagonist (bicuculline) into the rostral (pallidal) and caudal
(cerebellar) ventrolateral nuclei of the thalamus in both hemispheres of one
monkey. Dystonic postures were observed in the contralateral limbs and axis.
Electromyographic recordings revealed bursts of muscular activation with co
contractions during spontaneous dystonic movements and alterations in muscular
patterns during sequential visually guided arm movements. The type of dystonia
depended on the site of injections. Rostral thalamic injections induced more
severe dystonic postures, whereas myoclonic jerks predominated following caudal
injections. We conclude that these two distinct clinical patterns, which are
frequently associated in humans, are probably due to a dysfunctioning of
segregated thalamic projections to the supplementary motor area (from the rostral
part) and to the primary motor cortex (from the caudal part).
PMID- 10762335
TI - Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum.
AB - Region-specific up-regulation of the cyclic AMP pathway is considered an
important molecular mechanism in the origin of the somatic manifestations of the
withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a
withdrawal syndrome after prolonged cannabinoid administration has long been a
controversial issue. Recent studies, in different species, have shown that
withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid
antagonist SR141716A is characterized by physical signs underlying impairment of
motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an
increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the
functional role of the cyclic AMP pathway in the cerebellum in the establishment
of cannabinoid withdrawal. We show that after SR141716A precipitation of
cannabinoid withdrawal, basal and calcium-calmodulin-stimulated adenylyl cyclase
activities as well as active PKA in the cerebellum increase in a transient manner
with a temporal profile which matches that of the somatic expression of
abstinence. Selectively blocking the up-regulation of the cyclic AMP pathway in
the cerebellum, by microinfusing the cyclic AMP blocker Rp-8Br-cAMPS in this
region, markedly reduced both PKA activation and the somatic expression of
cannabinoid withdrawal. Our results (i) directly link the behavioural
manifestations of cannabinoid withdrawal with the up-regulation of the cyclic AMP
pathway in the cerebellum, pointing towards common molecular adaptive mechanisms
for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular
role for the cerebellum as a major neurobiological substrate for cannabinoid
withdrawal.
PMID- 10762336
TI - Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to
maternal glucocorticoids, permanently programs amygdala GR mRNA expression and
anxiety-like behaviour in the offspring.
AB - Glucocorticoids may underlie the association between prenatal stress, low birth
weight and adult stress-associated disorders, e.g. hypertension and type 2
diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective
dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)
rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus
acting as a 'barrier' to maternal steroids. We investigated the effect of
inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on
subsequent HPA activity and regulation and stress-induced behaviour in adult
offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle
daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring
of CBX-treated dams had persistently reduced body weight, increased basal
corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and
reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular
nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA
expression were unaltered. In addition, these animals showed less grooming and
rearing in an open field and reduced immobility in a forced swim test, and had
increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial
(MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that
disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids
reduces birth and body weight, and produces permanent alterations of the HPA axis
and anxiety-like behaviour in aversive situations. The behavioural and HPA
effects may reflect GR gene programming in amygdala and hypothalamus,
respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress
or reduced activity of foeto-placental 11beta-HSD) may represent a common link
between the prenatal environment, foetal growth and adult neuroendocrine and
affective disorders.
PMID- 10762337
TI - Role of basal ganglia and ectostriatum in the context-dependent properties of the
optocollic reflex (OCR) in the pigeon (Columba livia): a lesion study.
AB - The possible participation of basal ganglia and associated structures [dorsal
striato-pallidum, nucleus spiriformis lateralis (SpL), ectostriatum] in the
elaboration of the optocollic reflex (OCR) was investigated by making bilateral
chemical lesions (ibotenic acid). Previous data have shown that both the slow and
fast phases of the OCR are dependent on the behavioural context. The slow phase
velocity (SPV) and the peak velocity of fast phases obtained in non-flying
pigeons ('resting condition') were enhanced in pigeons in which a flying posture
was experimentally provoked ('flying condition'). Therefore, the effect of
lesions was analysed in pigeons standing in the 'resting' or 'flying' condition.
In the 'resting' as in the 'flying' condition, all the lesions provoked a
decrease in SPV, which augmented with the stimulation velocity. Velocity step
stimuli revealed greater OCR deficits than velocity ramp stimuli. Extensive
lesions (including the striato-pallidum, ectostriatum and a part of the
neostriatum), as well as SpL lesions, provoked a greater SPV decrease over a
longer time than lesions restricted to the striato-pallidum or the ectostriatum.
The peak velocity of fast phases was only reduced by the 'extensive lesion' in
the 'flying condition'. The present data show that the basal ganglia system is
involved in the elaboration of optokinetic responses and suggest that, to work in
an optimal range, the optokinetic centres need to receive integrated information
from basal ganglia in addition to direct visual input.
PMID- 10762338
TI - Chronic psychosocial stress reduces the density of dopamine transporters.
AB - The effect of different types of physical stress on brain dopaminergic function
has been well established in rodents; however, the role of the dopaminergic
system in more naturalistic stress situations is poorly understood. Therefore,
the aim of the current study was to investigate the effect of chronic
psychosocial stress on the dopamine transporter, which is an important component
in the regulation of dopaminergic neurotransmission. For this purpose, we used
the well-characterized paradigm of subordination stress in male tree shrews
(Tupaia belangeri). In the present study, the animals were subjected to
psychosocial stress for 28 days. Animals were daily videotaped and locomotor
activity was quantified. In subordinate animals, urinary cortisol and
noradrenaline, as well as adrenal weight, were increased, whereas body weight,
locomotor activity and testicular function were decreased. Brain dopamine
transporter binding sites were quantified by in vitro autoradiography using [3H]
WIN 35,428 as ligand. Chronic stress reduced the number of binding sites (Bmax)
in the caudate nucleus and the putamen without affecting the affinity (Kd).
Stress did not influence the binding parameters in the nucleus accumbens, the
substantia nigra or the ventral tegmental area. Furthermore, we found a positive
correlation between locomotor activity and the Bmax values for [3H] WIN 35,428
binding in the caudate nucleus, the putamen and the nucleus accumbens. The
present study shows that a naturalistic stressor, such as chronic psychosocial
conflict, decreases dopamine transporter binding sites in motor-related brain
areas, suggesting that the reduction in locomotor activity in subordinate tree
shrews is related to the downregulation of dopamine transporter binding sites.
PMID- 10762339
TI - Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic,
but not serotonergic, transmission by blockade of alpha2-adrenergic and
serotonin2C receptors: a comparison with citalopram.
AB - Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR)
receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine
5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine
showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it
abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist
properties were revealed in vivo by blockade of UK-14,304-induced
antinociception, while antagonist actions at 5-HT2C receptors were demonstrated
by blockade of Ro 60 0175-induced penile erections and discriminative stimulus
properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in
contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving
rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and
striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA)
and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA
and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing
rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic
neurons in the ventral tegmental area, nor adrenergic neurons in the locus
coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and
adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the
facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5
HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT
versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and
mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In
conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical
dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission.
These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors.
PMID- 10762340
TI - Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not
preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys
chronically treated with L-DOPA.
AB - Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's
disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated
monkeys, but is not thought to do so in normal humans or primates. However, we
have shown that chronic oral high dose L-DOPA administration, with the peripheral
decarboxylase inhibitor, carbidopa and with or without the peripherally acting
catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque
monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the
present study, in situ hybridization histochemistry was used to investigate the
effect of chronic L-DOPA administration on the activity of the direct and
indirect striatal output pathways by measuring striatal preprotachykinin (PPT),
preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in
these monkeys. Overall there was no significant difference in striatal PPT, PPE-A
and A2a receptor mRNA levels between normal animals and all L-DOPA (plus
carbidopa and/or entacapone)-treated animals irrespective of whether or not
dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was
analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA
(plus carbidopa with or without entacapone) treatment, there was a significant
increase in PPE-A and A2a receptor mRNA message levels in the striatum compared
with animals receiving identical treatment, but displaying few or no involuntary
movements, and compared with normal controls. There was no difference in striatal
PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those
showing little or no dyskinesia after L-DOPA treatment or to normal controls.
These results suggest that prolonged L-DOPA treatment alone has no consistent
effect on either the direct or indirect pathways, as judged by striatal PPT, PPE
A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting
marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is
detected in the indirect striato-pallidal output pathway, as judged by striatal
PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct
and indirect striatal pathway which may explain the emergence of dyskinesia in
these animals.
PMID- 10762341
TI - Induction of integrin-associated protein (IAP) mRNA expression during memory
consolidation in rat hippocampus.
AB - We have previously demonstrated that hippocampal integrin-associated protein
(IAP) gene expression is associated with memory formation in a one-way inhibitory
avoidance learning in rats. In the present study, we further investigated the
role and mechanism of IAP involved in memory consolidation in rats. Because of
the minute amount of IAP present in the brain, we have adopted the quantitative
reverse transcription-polymerase chain reaction (RT-PCR) method. Our results
revealed that hippocampal IAP mRNA expression is approximately fourfold higher in
rats showing good memory retention (GM, retention score of 600 s) at 3 h, but not
at other time points, after training when compared with the poor memory rats
(retention score < 80 s). On the other hand, integrin alphav mRNA level was
markedly increased ( approximately twofold), while integrin beta3 mRNA level was
decreased ( approximately 50%) at 1 h post-training. Further, separate sets of RT
PCR analysis revealed that IAP5 and IAP6 mRNA expressions, but not that of IAP7,
were markedly increased in GM rats 3 h post-training. Moreover, regional
distribution studies revealed that different isoforms of the IAP gene are
similarly distributed in different brain areas, while IAP7 has been the
predominant form present in astrocyte cells. These results together suggest that
IAP mRNA expression is indeed induced upon training, rather than that the GM rats
have constitutively higher levels of IAP. The unparallel change of IAP and
integrin mRNA expressions as far as time-course is concerned suggests that they
are possibly involved in different forms and stages of memory processing.
Further, IAP5 and IAP6 are more closely associated with memory consolidation,
while IAP7 may constitute the major isotype for signal transduction in astrocyte
cells.
PMID- 10762342
TI - Red nucleus lesions impair overground locomotion in rats: a kinetic analysis.
AB - The red nucleus is a prominent brainstem nucleus in mammals which is thought to
be involved in production of skilled limb movements. The presence of the red
nucleus and associated rubrospinal tract in animals that do not produce skilled
limb movements, however, suggests that these structures might also be involved in
control of more general limb actions, such as those occurring during locomotion.
The present study investigates this question by measuring the three-dimensional
ground reaction forces produced by locomoting rats with unilateral excitotoxic
lesions of the red nucleus. Twenty-four to 48 h after the lesion, rats moved with
an asymmetric gait during which abnormal braking and propulsive forces were
produced during the dual contact time of the forelimb contralateral to the lesion
and the ipsilateral hindlimb. Rats did not recover normal symmetrical locomotion
within the 55-day duration of the study. The persistent asymmetry produced by red
nucleus ablation provides the first unequivocal demonstration that the red
nucleus plays a role in ongoing overground locomotion in the rat. Species
differences in phylogeny and connectivity of the red nucleus are discussed, as
well as the possibility that there is a general compensatory response to
unilateral CNS injury in the rat.
PMID- 10762343
TI - The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein.
AB - We used reverse transcriptase polymerase chain reaction to detect the expression
of the central and peripheral cannabinoid receptors (CB1 and CB2, respectively)
mRNA, and Western blotting to show the presence of the CB1 protein in subregions
of the human eye. CB2 mRNA transcripts were undetectable, while levels of CB1
mRNA were significantly expressed in the human retina (25.8 +/- 2.46%), ciliary
body (210 +/- 11.55%) and iris (62.7 +/- 5.94%) when compared with those of the
normalizing reference gene beta2 microglobulin. The CB1 gene encodes a functional
protein which is detected in its glycosylated (63 kDa) and unglycosylated (54
kDa) form in the same areas by a specific purified antibody raised against the
amino terminus (residues 1-77) of the CB1 receptor. These results further support
the proposed role of the CB1 receptor in controlling intraocular pressure,
helping to explain the antiglaucoma properties of marijuana.
PMID- 10762344
TI - Long-term potentiation of primary afferent neurotransmission at trigeminal
synapses of juvenile rats.
AB - Primary afferent monosynaptic and polysynaptic excitatory postsynaptic currents
(EPSCs) were recorded from brainstem trigeminal neurons by stimulation of the
mandibular nerve attached to the brainstem preparation of juvenile rats. A high
frequency conditioning stimulus induced long-term potentiation (LTP) of high
threshold EPSCs in the majority of trigeminal caudal neurons in substantia
gelatinosa, where both A- and C-fibres terminate. However, the same conditioning
stimulus did not potentiate low-threshold EPSCs in caudal neurons or EPSCs
recorded from neurons in the middle part of trigeminal interpolar nucleus, where
C-fibres rarely terminate. LTP in caudal neurons could be induced after blocking
N-methyl-D-aspartate (NMDA) receptors with D(-)-2-amino-5-phosphonopentanoic acid
(D-AP5, 50 microM), after postsynaptic loading of the Ca2+ chelator BAPTA (10
mM), or even after completely blocking excitatory transmission with kynurenic
acid during conditioning. However, LTP was blocked by the metabotropic glutamate
receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (1 mM). We suggest
that LTP of the trigeminal primary afferent EPSCs is induced preferentially in
the C-fibre inputs and that the induction mechanism involves metabotropic
glutamate receptors, possibly at the presynaptic terminals.
PMID- 10762345
TI - Visual response augmentation in cat (and macaque) LGN: potentiation by
corticofugally mediated gain control in the temporal domain.
AB - Visual responses of neurons are dependent on the context of a stimulus, not only
in spatial terms but also temporally, although evidence for temporally separate
visual influences is meagre, based mainly on studies in the higher cortex. Here
we demonstrate temporally induced elevation of visual responsiveness in cells in
the lateral geniculate nucleus (LGN) of cat and monkey following a period of high
intensity (elevated contrast) stimulation. This augmentation is seen in 40-70%
(monkey-cat) of cells tested and of all subtypes. Peaking at approximately 3 min
following the period of intense stimulation, it can last for 10-12 min and can be
repeated and summed in time. Furthermore, it is dependent on corticofugal input,
is seen even when high contrast stimuli of orthogonal orientation are used and
therefore results from a/any prior increase in activity in the retino-geniculo
striate pathway. We suggest that this reflects a general mechanism for control of
visual responsiveness; both a flexible and dynamic means of changing
effectiveness of thalamic activity as visual input changes, but also a mechanism
which is an emergent property of the thalamo-cortico-thalamic loop.
PMID- 10762346
TI - Evidence for functional compartmentalization of trigeminal muscle spindle
afferents during fictive mastication in the rabbit.
AB - Primary afferent neurons innervating muscle spindles in jaw-closing muscles have
cell bodies in the trigeminal mesencephalic nucleus (NVmes) that are electrically
coupled and receive synapses. Each stem axon gives rise to a peripheral branch
and a descending central branch. It was previously shown that some spikes
generated by constant muscle stretch fail to enter the soma during fictive
mastication. The present study examines whether the central axon is similarly
controlled. These axons were functionally identified in anaesthetized and
paralysed rabbits, and tonic afferent firing was elicited by muscle stretch. For
the purpose of comparison, responses were recorded extracellularly both from the
somatic region and from the central axon in the lateral brainstem. Two types of
fictive masticatory movement patterns were induced by repetitive stimulation of
the masticatory cortex and monitored from the trigeminal motor nucleus. Field
potentials generated by spike-triggered averaging of action potentials from the
spindle afferents were employed to determine their postsynaptic effects on jaw
closing motoneurons. Tonic firing of 32% NVmes units was inhibited during the jaw
opening phase, but spike frequency during closing was almost equal to the control
rate during both types of fictive mastication. A similar inhibition occurred
during opening in 83% of the units recorded along the central branch. However,
firing frequency in these was significantly increased during closing in 94%,
probably because of the addition of antidromic action potentials generated by
presynaptic depolarization of terminals of the central branch. These additional
spikes do not reach the soma, but do appear to excite motoneurons. The data also
show that the duration and/or frequency of firing during the bursts varied from
one pattern of fictive mastication to another. We conclude that the central axons
of trigeminal muscle spindle afferents are functionally decoupled from their stem
axons during the jaw-closing phase of mastication. During this phase, it appears
that antidromic impulses in the central axons provide one of the inputs from the
masticatory central pattern generator (CPG) to trigeminal motoneurons.
PMID- 10762347
TI - Localization of the A kinase anchoring protein AKAP79 in the human hippocampus.
AB - The phosphorylation state of the proteins, regulated by phosphatases and kinases,
plays an important role in signal transduction and long-term changes in neuronal
excitability. In neurons, cAMP-dependent protein kinase (PKA), protein kinase C
(PKC) and calcineurin (CN) are attached to a scaffold protein, A kinase anchoring
protein (AKAP), thought to anchor these three enzymes to specific sites of
action. However, the localization of AKAP, and the predicted sites of linked
phosphatase and kinase activities, are still unknown at the fine structural
level. In the present study, we investigated the distribution of AKAP79 in the
hippocampus from postmortem human brains and lobectomy samples from patients with
intractable epilepsy, using preembedding immunoperoxidase and immunogold
histochemical methods. AKAP79 was found in the CA1, presubicular and subicular
regions, mostly in pyramidal cell dendrites, whereas pyramidal cells in the CA3,
CA2 regions and dentate granule cells were negative both in postmortem and in
surgical samples. In some epileptic cases, the dentate molecular layer and hilar
interneurons also became immunoreactive. At the subcellular level, AKAP79
immunoreactivity was present in postsynaptic profiles near, but not attached to,
the postsynaptic density of asymmetrical (presumed excitatory) synapses. We
conclude that the spatial selectivity for the action of certain kinases and
phosphatases regulating various ligand- and voltage-gated channels may be ensured
by the selective presence of their anchoring protein, AKAP79, at the majority of
glutamatergic synapses in the CA1, but not in the CA2/CA3 regions, suggesting
profound differences in signal transduction and long-term synaptic plasticity
between these regions of the human hippocampus.
PMID- 10762348
TI - Peripheral but not central axotomy induces changes in Janus kinases (JAK) and
signal transducers and activators of transcription (STAT).
AB - Nerve injury leads to the release of a number of cytokines which have been shown
to play an important role in cellular activation after peripheral nerve injury.
The members of the signal transducer and activator of transcription (STAT) gene
family are the main mediators in the signal transduction pathway of cytokines.
After phosphorylation, STAT proteins are transported into the nucleus and exhibit
transcriptional activity. Following axotomy in rat regenerating facial and
hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3
and STAT5 was detected using in situ hybridization and semi-quantitative
polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3
protein was significantly increased. In addition, activation of STAT3 by
phosphorylation on position Tyr705 and enhanced nuclear translocation was found
within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine
phosphorylation was obvious for more than 3 months. In contrast, none of these
changes was found in response to axotomy of non-regenerating Clarke's nucleus
neurons, although all the investigated models express c-Jun and growth-associated
protein-43 (GAP-43) in response to axonal injury. Increased expression of Janus
kinase (JAK) and STAT molecules after peripheral nerve transection suggests
changes in the responsiveness of the neurons to signalling molecules. STAT3 as a
transcription factor, which is expressed early and is activated persistently
until the time of reinnervation, might be involved in the switch from the
physiological gene expression to an 'alternative program' activated only after
peripheral nerve injury.
PMID- 10762349
TI - Expression of neuronal nitric oxide synthase/NADPH-diaphorase during olfactory
deafferentation and regeneration.
AB - Neuronal nitric oxide synthase (nNOS) expression can be regulated under natural
or experimental conditions. This work aims at elucidating whether the expression
of nNOS or its related NADPH-diaphorase (ND) activity are modified by
manipulation of the normal inputs to neurons. We used the olfactory bulbs from
two mouse strains, BALB and CD1, because they show divergences in their synapse
patterns, and these differences affect periglomerular cells, interneurons
expressing tyrosine hydroxylase or nNOS/ND. The olfactory inputs to these neurons
can be disrupted by inhalation of methyl bromide. The effect of this gas on
olfactory axons, as well as the synaptic features in both mouse strains, were
studied using electron microscopy. The changes in expression were analysed
qualitatively and quantitatively at different times after lesion to nine
topographical regions of the olfactory bulb. Methyl bromide inhalation induced a
degeneration of olfactory axons in both strains, but had different effects on the
expression of nNOS/ND and tyrosine hydroxylase. In BALB mice, where
periglomerular cells do not receive direct inputs from olfactory axons, no
changes were detected in tyrosine hydroxylase or in ND expression. In CD1
periglomerular cells, where olfactory axons establish direct synapses, a
significant down-regulation of both markers was observed. These changes were
observed differentially across the olfactory bulb, being more pronounced in
rostral regions and more acute for ND than for tyrosine hydroxylase. Our results
indicate that the synaptic inputs influence the expression of ND activity related
to nNOS and that the activation of the enzyme is more severely affected than its
protein expression.
PMID- 10762350
TI - The distribution of the mRNA and protein products of the melanin-concentrating
hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat.
AB - Melanin-concentrating hormone (MCH), a 19 amino acid cyclic peptide, is largely
expressed in the hypothalamus. It is implicated in the control of general arousal
and goal-orientated behaviours in mammals, and appears to be a key messenger in
the regulation of food intake. An understanding of the biological actions of MCH
has been so far hampered by the lack of information about its receptor(s) and
their location in the brain. We recently identified the orphan G-protein-coupled
receptor SLC-1 as a receptor for the neuropeptide MCH. We used in situ
hybridization histochemistry and immunohistochemistry to determine the
distribution of SLC-1 mRNA and its protein product in the rat brain and spinal
cord. SLC-1 mRNA and protein were found to be widely and strongly expressed
throughout the brain. Immunoreactivity was observed in areas that largely
overlapped with regions mapping positive for mRNA. SLC-1 signals were observed in
the cerebral cortex, caudate-putamen, hippocampal formation, amygdala,
hypothalamus and thalamus, as well as in various nuclei of the mesencephalon and
rhombencephalon. The distribution of the receptor mRNA and immunolabelling was in
good general agreement with the previously reported distribution of MCH itself.
Our data are consistent with the known biological effects of MCH in the brain,
e.g. modulation of the stress response, sexual behaviour, anxiety, learning,
seizure production, grooming and sensory gating, and with a role for SLC-1 in
mediating these physiological actions.
PMID- 10762351
TI - Neuronal distribution and functional characterization of the calcium channel
alpha2delta-2 subunit.
AB - The auxiliary calcium channel alpha2delta subunit comprises a family of three
genes, alpha2delta-1 to 3, which are expressed in a tissue-specific manner.
alpha2delta-2 mRNA is found in the heart, skeletal muscle, brain, kidney, liver
and pancreas. We report here for the first time the identification and functional
characterization of alpha2delta-2 splice variants and their mRNA distribution in
the mouse brain. The splice variants differ in the alpha2 and delta protein by
eight and three amino acid residues, respectively, and are differentially
expressed in cardiac tissue and human medullary thyroid carcinoma (hMTC) cells.
In situ hybridization of mouse brain sections revealed the highest expression of
alpha2delta-2 mRNA in the Purkinje cell layer of the cerebellum, habenulae and
septal nuclei, and a lower expression in the cerebral cortex, olfactory bulb,
thalamic and hypothalamic nuclei, as well as the inferior and superior
colliculus. As the in situ data did not suggest a specific colocalization with
any alpha1 subunit, coexpression studies of alpha2delta-2 were carried out either
with the high-voltage-gated calcium channels, alpha1C, alpha1E or alpha1A, or
with the low-voltage-gated calcium channel, alpha1G. Coexpression of alpha2delta
2 increased the current density, shifted the voltage dependence of channel
activation and inactivation of alpha1C, alpha1E and alpha1A subunits in a
hyperpolarizing direction, and accelerated the decay and shifted the steady-state
inactivation of the alpha1G current.
PMID- 10762352
TI - Acetylcholine stimulates cortical precursor cell proliferation in vitro via
muscarinic receptor activation and MAP kinase phosphorylation.
AB - Increasing evidence has shown that some neurotransmitters act as growth
regulatory signals during brain development. Here we report a role for the
classical neurotransmitter acetylcholine (ACh) to stimulate proliferation of
neural stem cells and stem cell-derived progenitor cells during neural cell
lineage progression in vitro. Neuroepithelial cells in the ventricular zone of
the embryonic rat cortex were found to express the m2 subtype of the muscarinic
receptor. Neural precursor cells dissociated from the embryonic rat cortical
neuroepithelium were expanded in culture with basic fibroblast growth factor
(bFGF). reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the
presence of m2, m3 and m4 muscarinic receptor subtype transcripts, while
immunocytochemistry demonstrated m2 protein. ACh and carbachol induced an
increase in cytosolic Ca2+ and membrane currents in proliferating (BrdU+) cells,
both of which were abolished by atropine. Exposure of bFGF-deprived precursor
cells to muscarinic agonists not only increased both cell number and DNA
synthesis, but also enhanced differentiation of neurons. These effects were
blocked by atropine, indicating the involvement of muscarinic ACh receptors. The
growth-stimulating effects were also antagonized by a panel of inhibitors of
second messengers, including 1,2-bis-(O-aminophenoxy)-ethane-N,N,N', N'
tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, EGTA to complex
extracellular Ca2+, pertussis toxin, which uncouples certain G-proteins, the
protein kinase C inhibitor H7 and the mitogen-activated protein kinase (MAPK)
inhibitor PD98059. Muscarinic agonists activated MAPK, which was significantly
inhibited by atropine and the same panel of inhibitors. Thus, muscarinic
receptors expressed by neural precursors transduce a growth-regulatory signal
during neurogenesis via pathways involving pertussis toxin-sensitive G-proteins,
Ca2+ signalling, protein kinase C activation, MAPK phosphorylation and DNA
synthesis.
PMID- 10762353
TI - Interleukin-6 inhibits neurotransmitter release and the spread of excitation in
the rat cerebral cortex.
AB - Cytokines are extracellular mediators that have been reported to affect
neurotransmitter release and synaptic plasticity phenomena when applied in vitro.
Most of these effects occur rapidly after the application of the cytokines and
are presumably mediated through the activation of protein phosphorylation
processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6)
has been found to have a neuroprotective effect against ischaemia lesions and
glutamate excitotoxicity, and to increase neuronal survival in a variety of
experimental conditions. In this paper, the functional effects of IL-6 on the
spread of excitation visualized by dark-field/infrared videomicroscopy in rat
cortical slices and on glutamate release from cortical synaptosomes were analysed
and correlated with the activation of the STAT3, mitogen-activated protein kinase
ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase
(SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation
and evoked glutamate release in the cerebral cortex, and that these effects are
accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of
MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK
substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6
were effectively counteracted by treatment of the cortical slices with the
tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on
glutamate release and on the spread of excitation in the rat cerebral cortex
indicate that the protective effect of IL-6 on neuronal survival could be
mediated by a downregulation of neuronal activity, release of excitatory
neurotransmitters and MAPK/ERK activity.
PMID- 10762354
TI - Dynorphins directly inhibit neuronal nicotinic acetylcholine receptors in PC12
cells.
AB - The authors have previously reported that dynorphin A (1-17), an endogenous kappa
opioid agonist, inhibits the current mediated through neuronal nicotinic
acetylcholine receptors (nAChRs) without the involvement of opioid receptors or G
proteins. We have further characterized this action to elucidate the mechanisms.
The nicotine-induced current was studied in PC12 cells using patch-clamp
techniques. In the whole-cell configuration, four kinds of dynorphins with
different lengths, dynorphin A (1-17) (1-13) (2-13) and (1-8), similarly
inhibited the nicotine-induced inward current at 1 microM and accelerated the
current decay. The inhibition by dynorphin A (1-17) was not antagonized by the
increasing concentrations of nicotine. The current-voltage relationship revealed
that dynorphin's inhibition was voltage independent at the membrane potentials
from -30 to -70 mV. The inhibition was not affected by pretreatment with
pertussis toxin (PTX) or inclusion of staurosporine into the pipette solution.
The inhibitory effect of dynorphin A (1-17) was well preserved in the outside-out
patch configuration. Analysis of the nicotine-induced noise and single-channel
kinetics revealed that dynorphin A(1-17) reduced open time without changing the
amplitude of the unitary current. We found that the inhibitory effect on neuronal
nAChRs is shared by all four dynorphins studied. The inhibition appears to be non
competitive and voltage independent. The outside-out recording together with
other experiments indicated that a major part of this inhibition is not mediated
through cytoplasmic messengers, but based on the direct action of dynorphins on
neuronal nAChRs leading to the reduction of open time.
PMID- 10762355
TI - Age-dependent changes in projections from locus coeruleus to hippocampus dentate
gyrus and frontal cortex.
AB - Age-dependent changes in noradrenergic innervations of the hippocampal dentate
gyrus (DG) and the frontal cortex (FC) have been studied in male F344 rats. The
projections from the nucleus locus coeruleus (LC) to DG or FC with advancing age
(from 7 to 27 months) in rats have been quantified by electrophysiological and
immunohistochemical methods. In the electrophysiological study, we observed that
the percentage of LC neurons activated antidromically by electrical stimulation
(P-index) of DG or FC decreased with age. We found that the percentage of LC
neurons showing multiple antidromic latencies (M-index), which suggests axonal
branching of individual LC neurons, increased markedly between 15 and 17 months
in DG or FC. In DG, the M-index increased steadily between 15 and 24 months. In
contrast, the increased M-index in FC was maintained until 24 months. The
increased M-index in both targets declined at 27 months. These results suggest
that LC neurons give rise to axonal branching following the loss of projections
to DG or FC with age. In the immunohistochemical study, the density of dopamine
beta-hydroxylase-positive axonal varicosities was measured in molecular, granule
cell and polymorphic layers of DG. The density in the polymorphic layer
significantly decreased in the earlier stage of ageing (7-19 months), whilst the
density in the molecular and granule cell layers decreased in the later stage (27
months). These findings suggested that a layer-specific decline occurred with age
in the noradrenergic axon terminals in DG.
PMID- 10762356
TI - Serotoninergic and noradrenergic axonal contacts associated with premotor
interneurons in spinal pathways from group II muscle afferents.
AB - We investigated the possibility that monoaminergic axons make contacts with
spinal interneurons which project to motor nuclei and are monosynaptically
activated by group II muscle afferents. Interneurons in midlumbar spinal segments
of adult cats were characterized electrophysiologically and intracellularly
labelled with tetramethylrhodamine dextran. Serotoninergic and noradrenergic
axons were identified with immunofluorescence in sections containing labelled
cells. Contacts between monoaminergic axons and interneurons were investigated
with three-colour confocal laser scanning microscopy and analysed with a computer
reconstruction program. Cell bodies and dendritic trees of five cells were
reconstructed and putative contacts were plotted. The average number of contacts
formed by serotoninergic axons was 140 and the average number of noradrenergic
contacts was 38. The majority (95%) of contacts were formed with dendrites; these
were distributed over the entire dendritic tree, even on the most distal
branches. These findings provide a morphological basis for the modulatory actions
of monoamines on premotor spinal interneurons in pathways from group II muscle
afferents.
PMID- 10762358
TI - Synaptotagmin I and IV define distinct populations of neuronal transport
vesicles.
AB - Mammalian synaptotagmins constitute a multigene family of at least 11 membrane
proteins. We have characterized synaptotagmin IV using antibodies directed
against the C2A domain of the protein. Antibodies reacted specifically with a
protein band that migrated as a 41-44 kDa doublet. Synaptotagmin IV expression
was regulated throughout development. A strong decrease in the amount detected by
Western blotting occurred between postnatal day 5 and adulthood, in agreement
with studies on the expression of synaptotagmin IV transcripts. In subcellular
fractionation, synaptotagmin IV was not detected in the synaptic vesicle-enriched
fraction. Immunofluorescence microscopy was concordant with this finding. In 6
day-old rat cerebellum and cultured hippocampal neurons the subcellular
distribution of synaptotagmin IV was clearly different from that of synaptotagmin
I. Synaptotagmin IV displayed a punctate non-polarized distribution on neuronal
extensions, whereas synaptotagmin I staining was essentially synaptic.
Synaptotagmin IV staining was also observed in the soma in strong perinuclear
fluorescent puncta superimposed on that of Golgi/TGN markers. Furthermore,
synaptotagmin IV was seen in the proximal part of the growth cone domain and not
in the microfilament-rich region which includes filopodia. Co-localizations with
the adhesion molecules vinculin and zyxin at the proximal part of growth cones
were observed. Synaptotagmin IV may thus be involved in the regulation of
specific membrane-trafficking pathways during brain development.
PMID- 10762357
TI - Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron
precursors in vitro: differential impact of mu and delta receptor activation on
proliferation and neurite elongation.
AB - Although opioids are known to affect neurogenesis in vivo, it is uncertain the
extent to which opioids directly or indirectly affect the proliferation,
differentiation or death of neuronal precursors. To address these questions, the
intrinsic role of the opioid system in neurogenesis was systematically explored
in cerebellar external granular layer (EGL) neuronal precursors isolated from
postnatal mice and maintained in vitro. Isolated neuronal precursors expressed
proenkephalin-derived peptides, as well as specific mu and delta, but negligible
kappa, opioid receptors. The developmental effects of opioids were highly
selective. Morphine-induced mu receptor activation inhibited DNA synthesis, while
a preferential delta2-receptor agonist ([D-Ala2]-deltorphin II) or Met
enkephalin, but not the delta1 agonist [D-Pen2, D-Pen5]-enkephalin, inhibited
differentiation within the same neuronal population. If similar patterns occur in
the developing cerebellum, spatiotemporal differences in endogenous mu and delta
opioid ligand-receptor interactions may coordinate distinct aspects of granule
neuron maturation. The data additionally suggest that perinatal exposure to
opiate drugs of abuse directly interfere with cerebellar maturation by disrupting
normal opioid signalling and inhibiting the proliferation of granule neuron
precursors.
PMID- 10762359
TI - Evidence for nonvesicular nitric oxide release evoked by nerve activation.
AB - The gaseous nature of nitric oxide (NO) has led to the general assumption that
its release from neurons during nerve stimulation is independent of vesicular
storage. However, recent findings have shown that NO can exist intracellularly as
part of more stable bioactive molecules, suggesting that the role of vesicular
exocytosis for NO release cannot be excluded simply based on the chemical nature
of NO itself. We have used botulinum toxin B (BTX B) to directly address the role
of vesicular exocytosis for NO release. BTX B cleaves the synaptic vesicle
protein synaptobrevin/VAMP, and by this inhibits Ca++-mediated exocytic release
of neurotransmitters. As a target organ we used the guinea-pig enteric nervous
system, which innervates the gastrointestinal tract, and in which both classical
neurotransmitters as well as NO are released and influence smooth muscle
activity. As expected, BTX B (0.1 microM) blocked the nerve stimulation-induced
cholinergic and tachykininergic smooth muscle contractions, and markedly
inhibited the nerve stimulation-evoked release of [3H]-choline. In contrast, BTX
B (0.1 microM) had no effect on nerve stimulation-evoked relaxations, which were
equally inhibited by an NO-synthase inhibitor as well as by a selective inhibitor
of soluble guanylyl cyclase. In addition, nerve stimulation-evoked NO synthase
dependent outflow of NO/NO2- was unaffected by BTX B (0.1 microM). These findings
suggest that the neuronal release of endogenous NO is independent of intact
synaptobrevin/VAMP, and therefore provide further evidence that nerve-mediated
release of further NO is nonvesicular.
PMID- 10762360
TI - (+)-MCPG induces PKCepsilon translocation in cortical synaptosomes through a PLD
coupled mGluR.
AB - We have tested whether different agonists of metabotropic glutamate receptors
could induce translocation of selective protein kinase C isozymes in nerve
terminals. In rat cortical synaptosomes 1S, 3R-1-aminocyclopentane-1,3
dicarboxylic acid (1S,3R-ACPD; 100 microM) induced an increase in translocation
to 124.6 +/- 5.7% of basal unstimulated conditions of the Ca++-independent
protein kinase Cepsilon, but not of the Ca++-dependent isozyme beta. This effect
was counteracted by 1-aminoindan-1,5-dicarboxylic acid (100 microM), an
antagonist of metabotropic glutamate receptor 1. On the other hand, (+)-alpha
methyl-4-carboxyphenylglycine [(+)-MCPG], an antagonist of metabotropic glutamate
receptors group I and II, did not antagonize the effect of 1S,3R-ACPD, and per se
induced a translocation of protein kinase Cepsilon of 164 +/- 17.7% of basal
unstimulated conditions. Because the (+)-MCPG induction of protein kinase
Cepsilon translocation was not antagonized by 1-aminoindan-1, 5-dicarboxylic
acid, it is suggested that 1S,3R-ACPD and (+)-MCPG activate this signal
transduction pathway through distinct membrane receptors. Indeed (2-[2"-carboxy
3'-phenylcyclopropyl]glycine)-13 (300 nM), a new compound known to antagonize
metabotropic glutamate receptors coupled to phospholipase D, was able to
antagonize protein kinase Cepsilon translocation induced by (+)-MCPG. Moreover
(+)-MCPG directly induced phospholipase D activity, measured as
[3H]phosphoethanol production in cortical synaptosomes. These data suggest that
in cortical nerve terminals (i) distinct metabotropic glutamate receptors,
coupled to different signal transduction pathways, are present, (ii) (+)-MCPG is
able to induce protein kinase Cepsilon translocation, and that (iii) a
metabotropic glutamate receptor associated to phospholipase D might influence
translocation of protein kinase C in a calcium-independent manner.
PMID- 10762361
TI - Association of neuropeptide Y Y1 receptors with glutamate-positive and NPY
positive neurons in rat hippocampal cultures.
AB - The hippocampus is particularly enriched with neuropeptide tyrosine (NPY) and NPY
receptors including the Y1, Y2 and Y5 subtypes. We have previously reported on
the enrichment of cultured rat hippocampal neurons in specific [125I][Leu31,
Pro34]PYY/BIBP3226-sensitive (Y1) binding sites and Y1 receptor mRNAs [St-Pierre
et al. (1998) Br. J. Pharmacol., 123, p183]. We have now identified which cell
types express the Y1 receptor. The majority of Y1 receptors, visualized using
either the radiolabeled probe [125I][Leu31,Pro34]PYY or two antibodies directed
against distinct domains of the Y1 receptor, was expressed in neurons as revealed
by neuron-specific enolase (NSE) immunostaining. One antibody was directed
against the second extracelllular loop of the Y1 receptor (amino acids 185-203)
whereas the second was directed against the intracellular C-terminal loop (amino
acids 355-382). The labelling was evident over both perikarya and processes.
Neurons labelled by the various Y1 receptor probes were mostly glutamate-positive
as revealed by double immunostaining. Most interestingly, a number of NPY
positive cultured hippocampal neurons were also enriched with the Y1 receptor,
suggesting that this subtype may act as an autoreceptor to regulate NPY release
in the hippocampus. These results thus provide an anatomical basis for the
modulation of glutamate and NPY release by the Y1 receptor in the hippocampus.
PMID- 10762362
TI - Developmental changes in astrocyte density in the macaque perifoveal region.
AB - We studied astrocyte density both in the perifoveal region and in extrafoveal
regions within the same distance of the optic disc (OD) over a time period from
foveal pit formation (embryonic day E112) until 2 months after birth. The study
was prompted by earlier observations that the adult macaque displays an almost
astrocyte-free region around the fovea which, however, at birth is occupied by
astrocytes. Thus, we wanted to determine if the perifoveal region is invaded by
astrocytes during early development to the same degree as other regions in the
central retina, and how the reduction in density can be explained. From the
earliest age we studied (embryonic day 112), less astrocytes were found in the
perifovea than in other regions equidistant from the OD. In addition, the number
of astrocytes steadily declined both in the perifovea and outside until birth.
During the first week after birth, there was a further dramatic decline in
perifoveal astrocyte density. Double-labelling with glial fibrillary acidic
protein (GFAP) immunocytochemistry and the TUNEL method showed that during the
whole observation period astrocytes undergo DNA fragmentation and presumably die.
However, the rate of TUNEL-positive astrocytes did not significantly differ
between perifovea and other regions equidistant to the OD, and at no time did we
find a significant peak of apoptosis rate. Thus, the reduction in perifoveal
astrocyte density cannot be explained by missing invasion or by selectively
elevated apoptosis rates in the foveal and perifoveal regions. Alternative
hypotheses are discussed.
PMID- 10762363
TI - Neurite morphogenesis of identified visual interneurons and its relationship to
photoreceptor synaptogenesis in the flies, Musca domestica and Drosophila
melanogaster.
AB - The first neuropile, or lamina, of the fly's optic lobe comprises a model set of
identified neurons that are arrayed in cylindrical modules, called cartridges.
The cartridge acquires adult form only in the second half of the fly's pupal
life. All cells are by then correctly located within each of the lamina's
cartridges (Drosophila, Musca), becoming invested by glial cells after 75% of
pupal development (P + 75%). In adult cartridges, two lamina cells, L1 and L2,
receive input from photoreceptor terminals R1-R6, at so-called tetrad synapses
that form in the pupa when these cells' dendrites contact R1-R6. Single-section
electron microscopy (EM, Drosophila) and serial-EM reconstructions of L1 and L2
(Musca) reveal relationships between the morphogenesis of L1/L2 dendrites and the
formation of tetrads. Neurite outgrowth is initially (P + 55%) random and
neurites are unbranched; many neurites invaginate surrounding terminals of R1-R6
but, later, embrace the outer surfaces of these. The maximum profusion of
neurites at P + 74% coincides with peak numbers of nascent tetrads; neurites then
branch vertically, in the lamina's depth. Later, neurites failing to reach R1
R6's outer surfaces regress. Down the length of their axons, L1 and L2's neurites
initially form a random sequence, L1 partnering L1 as often as L2, etc., but
beginning at P + 74%, L1 partners L2, and L2 partners L1, with progressive
strictness. L1 has more neurites overall than L2. These observations are
consistent with the following hypotheses: a neurite only survives if it contacts
a presynaptic site; a synapse only survives if it progressively acquires the
appropriate number and combination of postsynaptic neurites, culminating in a
tetrad; an interaction exists between the neurites of L1 and L2, so that the
growth of one respects the pattern of growth of the other.
PMID- 10762364
TI - Correlation between gene functions and developmental expression patterns in the
mouse cerebellum.
AB - Quantitative changes of 419 gene transcripts during postnatal mouse cerebellar
development were accurately determined with a novel polymerase chain reaction
(PCR)-based technique. About 70% of the genes showed differences in expression
levels, and the magnitude of difference was relatively small. By hierarchic
cluster analysis of developmental expression patterns, the genes were categorized
into 19 clusters, which were subsequently assembled into four major groups: group
1, with elevation of gene expression throughout the time course; group 2, with
relatively unchanged levels; group 3, with transiently high expression at
approximately 12 days; and group 4, with highest expression at approximately 4
days. Genes related to brain functions were segregated into several clusters of
group 1 and group 3: the same clusters in which cerebellum-specific genes were
also segregated. Genes for protein synthesis belonged to group 4. Genes with
housekeeping functions belonged to group 2. Western blotting analysis of
representative protein products of each group revealed correlation with the mRNA
level for those belonging to group 1 and group 4, but not necessarily in the
other groups. The close correlation of algorithmically categorized temporal
expression patterns of genes with their functions will be useful for estimating
the functions of thousands of novel genes.
PMID- 10762365
TI - NFI in the development of the olfactory neuroepithelium and the regulation of
olfactory marker protein gene expression.
AB - Nuclear factor I (NFI) proteins are DNA-binding transcription factors that
participate in the tissue specific expression of various genes. They are encoded
by four different genes (NFI-A, B, C, and X) each of which generates multiple
isoforms by alternative RNA splicing. NFI-like binding sites have been identified
in several genes preferentially expressed in olfactory receptor neurons. Our
prior demonstration that NFI binds to these elements led to the hypothesis that
NFI is involved in the regulation of these genes. To analyse the role of NFI in
the regulation of olfactory neuron gene expression we have performed transient
transfection experiments in HEK 293 cells using constructs that place luciferase
expression under the control of an olfactory marker protein (OMP)-promoter
fragment containing the NFI binding site. In vitro mutagenesis of this site
revealed a negative modulation of luciferase expression by endogenous NFI
proteins in HEK 293 cells. In addition, we have used in situ hybridization to
analyse the tissue and cellular distribution of the four NFI gene transcripts
during pre- and postnatal mouse development. We have simultaneously characterized
the expression of Pax-6, and O/E-1, transcription factors known to regulate the
phenotype of olfactory receptor neurons. We demonstrate that all of these
transcription factors vary in specific spatio-temporal patterns during the
development of the olfactory system. These data on NFI activity, and on
transcription factor expression, provide a basis to understand the role of NFI in
regulating gene expression in olfactory receptor neurons.
PMID- 10762366
TI - MDMA ('ecstasy') enhances basal acetylcholine release in brain slices of the rat
striatum.
AB - The pharmacological basis of acute (+/-)-MDMA (3, 4
methylenedioxymethamphetamine) intoxication still awaits full characterization.
According to present knowledge, MDMA enhances the release of serotonin and
dopamine in striatal slices and interacts with different types of receptors such
as 5-HT2 (5-hydroxytryptamine or serotonin), M1 and M2 muscarinic acetylcholine
(ACh), and histamine H1 receptors. Currently, no information is available about
the influence of (+/-)-MDMA on striatal cholinergic neurotransmission. In the
present study, we used the in vitro perfusion technique to investigate the effect
of (+/-)-MDMA on ACh release in rat striatal slices. Perfusions with (+/-)-MDMA
(10-300 microM) resulted in a dose-dependent increase of spontaneous ACh release
(EC50 approximately 30 microM). The effect was reversible and Ca++- and
tetrodotoxin-sensitive. To determine the neurochemical pathways underlying this
response, we perfused with (+/-)-MDMA in the presence of various inhibitors of
neurotransmitter receptors. Blockade of glutamate or muscarinic ACh receptors as
well as 5-HT1, 5-HT2, 5-HT3C or dopamine D2 receptors did not modulate (+/-)-MDMA
induced ACh release. However, the presence of histamine H1 receptor antagonists
in the perfusion medium abolished (+/-)-MDMA-induced ACh release. The present
data clearly demonstrate that (+/-)-MDMA enhances the activity of striatal
cholinergic neurons and suggest an involvement of histamine H1 receptors. The
effect is not mediated by glutamate and does not involve the activation of
receptors of dopamine D2, 5-HT1, 5-HT2, 5-HT3C or muscarinic ACh. Considering the
relatively high affinity of (+/-)-MDMA for the H1 histamine receptor (Ki 6
microM), a direct activation of this type of receptor might represent a plausible
mechanism for (+/-)-MDMA-induced ACh release.
PMID- 10762367
TI - The serotonin 5-HT2 receptor-phospholipase C system inhibits the induction of
long-term potentiation in the rat visual cortex.
AB - The effect of serotonin 5-HT2 receptor stimulation on long-term potentiation
(LTP) in the primary visual cortex was investigated by using rat brain slices in
vitro. Field potentials evoked by stimulation of layer IV were recorded in layer
II/III. The 5-HT2 receptor agonist 1-(2,5-dimethyl-4-iodophenyl)-2-aminopropane
(DOI) did not affect baseline synaptic potentials evoked by single-pulse test
stimulation, but significantly inhibited the induction of LTP in a concentration
dependent manner (0.1-10 microM). The LTP-inhibiting effect of DOI (10 microM)
was blocked by the 5-HT2,7 receptor antagonist ritanserin (10 microM), but not by
the 5-HT1A receptor antagonist NAN-190 (10 microM) nor by the 5-HT3,4 receptor
antagonist MDL72222 (10 microM). The inhibitory effect of DOI was also blocked by
the phospholipase C inhibitor U73122, but not by its inactive analogue U73343.
These results suggest that visual cortex LTP is inhibited by activation of the 5
HT2 receptor-phospholipase C system. In addition, the LTP-inhibiting effect of
DOI was abolished by the presence of the GABAA receptor antagonist bicuculline
(10 microM), suggesting that 5-HT2 receptor-mediated inhibition of visual cortex
LTP is dependent on GABAergic inhibition.
PMID- 10762368
TI - Differential c-fos expression in the rhinencephalon and striatum after enhanced
sleep-wake states in the cat.
AB - In order to delimit the supra-brainstem structures that are activated during the
sleep-waking cycle, we have examined c-fos immunoreactivity in four groups of
polygraphically recorded cats killed after 3 h of prolonged waking (W), slow-wave
sleep (SWS), or paradoxical sleep (PS), following microinjection of muscimol (a
gamma-aminobutyric acid, GABA agonist) into the periaqueductal grey matter and
adjacent areas [Sastre et al. (1996), Neuroscience, 74, 415-426]. Our results
demonstrate that there was a direct relationship between a significant increase
in c-fos labelling and the amount of PS in the laterodorsalis tegmenti in the
pons, supramamillary nucleus, septum, hippocampus, gyrus cingulate, amygdala,
stria terminalis and the accumbens nuclei. Moreover, in all these structures, the
number of Fos-like immunoreactive neurons in the PS group was significantly
higher (three to 30-fold) than in the SWS and W groups. We suggest that the dense
expression of the immediate-early gene c-fos in the rhinencephalon and striatum
may be considered as a tonic component of PS at the molecular level and that,
during PS, the rhinencephalon and striatum are the main targets of an excitatory
system originating in the pons.
PMID- 10762369
TI - Trk B signalling controls LTP but not LTD expression in the developing rat visual
cortex.
AB - Neurotrophins have been suggested to act as liaison molecules between activity
dependent synaptic plasticity and the establishment of patterns of synaptic
connectivity during postnatal developmental in different brain areas, including
the visual cortex. In particular, recent studies have shown that Trk B ligands
are involved in the formation of the ocular dominance columns during postnatal
development. Here, we examined the contribution of endogenous Trk B activation to
the regulation of different forms of synaptic plasticity including long-term
potentiation (LTP), long-term depression (LTD) and LTP after LTD in the
developing visual cortex. Rat cortical slices were incubated with a soluble form
of Trk B receptor (TrkB IgG) preventing Trk B activation by endogenous ligands.
LTP expression was also studied at P23 (postnatal), when the expression of brain
derived neurotrophic factor (BDNF) reaches a peak and the LTP expression is
normally downregulated. The present results demonstrate that Trk B activation is
required for the long-term maintenance, > 30 min, of both LTP and LTP after LTD
at P17. At P23, a higher concentration of TrkB IgG was necessary to impair LTP.
In contrast, neither amplitude nor duration of LTD were affected by Trk B ligands
blockade. Taken together, these results indicate that endogenous Trk B ligands
are necessary for the expression of LTP but not LTD at a critical time during
postnatal cortical development.
PMID- 10762370
TI - Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK-801)
injures pyramidal neurons in rat retrosplenial cortex.
AB - Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, ketamine,
phencyclidine (PCP) and dizocilpine (MK-801), produce psychosis in people. In
rodents they produce cytoplasmic vacuoles in injured retrosplenial cortical
neurons that express HSP70 heat shock protein. This study examined possible
circuits and receptors that mediate this neuronal injury. Bilateral, but not
unilateral, injection of dizocilpine (5, 10, 15, 20 microg/microL per side) into
the anterior thalamus induced HSP70 protein in pyramidal neurons in deep layer
III of rat retrosplenial cortex 24 h later. In contrast, bilateral dizocilpine
injections (5, 10, 15, 20 microg/microL per side) into the retrosplenial cortex
or into the diagonal band of Broca did not induce HSP70. Bilateral injections of
muscimol (0.1, 1, 10 microg/microL per side), a GABAA (gamma-aminobutyric acid)
agonist, into the anterior thalamus blocked HSP70 induction in the retrosplenial
cortex produced by systemic dizocilpine (1 mg/kg). Bilateral thalamic injections
of baclofen (0.1, 1, 10 microg/microL per side), a GABAB agonist, were
ineffective. Anterograde tracer studies confirmed that neurons in the anterior
thalamus project to superficial layer III of the retrosplenial cortex where the
dendrites of HSP70-immunostained neurons in deep layer III reside. Bilateral
blockade of NMDA receptors on GABA neurons in the reticular nuclei of the
thalamus is proposed to decrease GABA neuronal firing, decrease GABA release and
decrease activation of GABAA receptors. This activates thalamic projection
neurons that damage retrosplenial cortical neurons presumably via unblocked
cortical glutamate alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)
and kainate receptors. The increases of blood flow that occur in the thalamus and
retrosplenial cortex of people that have psychosis produced by NMDA antagonists
could be related to thalamic excitation of the retrosplenial cortex produced by
these drugs.
PMID- 10762371
TI - Free radical production correlates with cell death in an in vitro model of
epilepsy.
AB - Free radical (FR) production, a major step in calcium-dependent
neurodegeneration, has been linked to the generation of epileptiform activity and
seizure-induced cell death. However, direct evidence of FR production in neurons
during seizures has never been presented. Using hippocampal cultured slices we
demonstrate that FRs are produced in CA3 but not CA1 pyramidal neurons during the
rhythmic synchronous activity induced by the GABAA receptor antagonist
bicuculline. The production of FRs (measured as changes in the fluorescence
emission of dihydrorhodamine 123) was correlated with an increase in the baseline
levels of intracellular calcium ([Ca2+]i) estimated by fluo-3 injected into
individual neurons via a patch pipette. [Ca2+]i increased during spike bursting
and returned to baseline levels after the burst termination in CA1, but not in
CA3, pyramidal neurons where 'interburst' calcium concentrations progressively
increased. Measurement of cell death, performed with propidium iodide 48 h after
a 30-min exposure to bicuculline, revealed most prominent degeneration of
pyramidal neurons in the CA3 pyramidal layer. The FR scavengers vitamin E and
glutathione significantly reduced the seizure-induced neurodegeneration without
supressing spontaneous epileptiform activity. These observations indicate that FR
overproduction is related to seizure-induced neuronal death.
PMID- 10762372
TI - Relationships between image structure and gamma oscillations and synchronization
in visual cortex of cats.
AB - The relationships between visual object configurations and interneuronal spike
synchronization and gamma oscillations are examined in the present investigation.
Cells were initially stimulated with moving, optimally oriented, single 20
degrees -long bars of light, centred on the compound receptive field of a pool of
cortical neurons. When this kind of stimulus evoked intrinsic gamma oscillations
and/or synchronization, we gradually fractured the original target. In addition,
colinearity was ruptured by forming L- and T-shaped configurations. All fractures
and discontinuities were introduced well outside the excitatory receptive field.
Multiunit activity in the visual cortex (areas 17 and 18) was recorded in
anaesthetized cats. Recording sites were separated by 0.4-1.2 mm. The data
analysis indicates that gamma oscillations follow a rule by which unfractured
bars yielded the highest S/N ratios. Synchronization strength, as revealed by the
central peak in cross-correlograms, also seemed to depend upon stimulus
configuration. However, the magnitude of the central peak failed to follow a
consistent trend. For instance, the greatest magnitude of the central peak
occurred for both colinear and orthogonal types of target. Our results support
the notion that both gamma oscillations and neuronal synchronization are stimulus
dependent.
PMID- 10762373
TI - Fast oscillations display sharper orientation tuning than slower components of
the same recordings in striate cortex of the awake monkey.
AB - We wanted to know whether fast oscillations ( approximately 30-80 Hz) in striate
cortex of awake monkeys show sharper orientation selectivity than (i) slower
components, including spike rate modulations, and (ii) broad-band signals of the
same recordings. As fast oscillations are probably of cortical origin this may
further clarify whether cortical network mechanisms are substantially involved in
generating orientation selectivity. We recorded multi unit activity (MUA) and
local field potentials (LFP, 1-140 Hz) by the same microelectrodes from upper
layers of macaque striate cortex during visual stimulation with grating textures
of different orientations. An orientation index (OI) was derived from the
cortical responses in three frequency ranges (low, 0-11.7 Hz; medium, 11.7-31.3
Hz; and fast oscillations, 31.3-62.5 Hz) and for the broad-band LFP and MUA
power. (i) Both LFP and MUA fast oscillations reveal a higher orientation index
than signal components in the low and medium frequency ranges. (ii) For MUA the
orientation index was significantly higher with fast oscillations than for the
lower frequency ranges and the initial broad-band transient responses. (iii) LFPs
show a significantly higher orientation index only for the fast oscillations
during sustained activation compared with their broad-band power during the
transient responses. Thus, our main result is the sharper orientation tuning of
fast oscillations in spike activities of local populations compared with slower
components of the same broad-band recordings. As fast oscillations occur
synchronized in the awake monkey's striate cortex we assume that they have
enhanced probability of activating successive stages of visual processing and
hence contribute to the perception of orientation.
PMID- 10762374
TI - Functional coupling shows stronger stimulus dependency for fast oscillations than
for low-frequency components in striate cortex of awake monkey.
AB - It has been argued that coupling among the neural signals activated by a visual
object supports binding of local features into a coherent object perception.
During visual stimulation by a grating texture we studied functional coupling by
calculating spectral coherence among pairs of signals recorded in the striate
cortex of awake monkeys. Multiple unit activity (MUA) and local field potentials
(LFP, 1-140 Hz) were extracted from seven parallel broad band recordings.
Spectral coherence was dominated by high-frequency oscillations in the range 35
50 Hz and often by additional low-frequency components (0-12 Hz). Functional
coupling among separate cortical sites was more stimulus specific for MUA than
for LFP: MUA coherence at high and low frequencies depended highly significantly
on: (i) the similarity of the preferred orientations at the two sites - the more
similar the higher the coherence; (ii) the orientation of the stimulus grating -
with highest coherence at half angle between the preferred orientations at the
two sites; (iii) cortical distance - coherence decreases to noise levels at
approximately 3 mm (MUA) and 6 mm (LFP). Coherence of fast oscillations did not
depend on the degree of coaxiality of the orientation-sensitive receptive fields,
whereas low frequencies showed significant dependency. This indicates that
different frequency components can engage different coupling networks in the
striate cortex which probably support different coding tasks. Changes in average
oscillation frequency with stimulus orientation were highly significant for fast
oscillations while there was no dependency for low frequencies. Finally, stimulus
related spectral power and coherence of fast oscillations were considerably
higher than of low frequency components. Fast oscillations may therefore
contribute more to feature binding and coding of object continuity than low
frequency components, at least for texture surfaces as analysed here.
PMID- 10762375
TI - Neuropsin regulates an early phase of schaffer-collateral long-term potentiation
in the murine hippocampus.
AB - We found that neuropsin, an extracellular matrix serine protease, has a
regulatory effect on Schaffer-collateral long-term potentiation (LTP) in the
mouse hippocampus. Bath application of 1-170 nM recombinant neuropsin modulated
early phase LTP in the Schaffer-collateral pathway with a 'bell-shape' dose
response curve. The maximum enhancing activity (134% of control LTP) was found at
approximately 2.5 nM. Bath application of a neutralizing antibody against
neuropsin in the hippocampal slice resulted in a marked inhibition of the tetanus
induced early phase of LTP. The in vivo continuous intraventricular infusion of
an antisense oligonucleotide against neuropsin significantly reduced the
amplitude of the tetanus-induced early phase of LTP in vitro. Neuropsin did not
directly change the N-methyl D-aspartate (NMDA) current. Thus, neuropsin appears
to act as a regulatory molecule in the early phase of LTP via its proteolytic
function on extracellular matrix rather than affecting NMDA receptor-mediated
calcium increase.
PMID- 10762376
TI - Ageing alters intrahypothalamic release patterns of vasopressin and oxytocin in
rats.
AB - The ageing process has been shown to have a profound impact on the hypothalamo
neurohypophysial system (HNS) and the hypothalamo-pituitary-adrenocortical (HPA)
axis in humans as well as in rodents. Therefore, in this study, the intracerebral
and peripheral release patterns of both vasopressin and oxytocin have been
studied in aged male Wistar rats under basal conditions and in response to
ethologically relevant stressors, using intracerebral microdialysis and chronic
blood sampling techniques, respectively. Approximately a twofold higher basal
release of arginine vasopressin (AVP) within the hypothalamic paraventricular
nucleus (PVN), but not within the supraoptic nucleus (SON), was found in aged
rats, whereas basal oxytocin (OXT) release did not differ in comparison with
young rats. With increasing age the rise in intra-PVN release of both AVP and OXT
was blunted in response to forced swimming. In contrast, the intra-SON release of
AVP was unrelated to age. Simultaneously recorded basal secretion of both AVP and
OXT from the neurohypophysis into blood was increased in aged rats, with a
blunted OXT response to swim stress. Opposed to that, plasma AVP levels remained
unchanged in both groups. Basal plasma levels of corticotropin (ACTH) and
corticosterone were elevated in aged rats, whereas stress-elicited ACTH and
corticosterone responses were indistinguishable. These results indicate age
related changes in the HNS and HPA axis with an enhanced basal activity opposed
to a blunted response to stressors with increasing age. The increased basal
release of AVP within the PVN suggests a role of intracerebral AVP in age
associated alterations of HPA axis regulation.
PMID- 10762377
TI - Lack of glucocorticoids attenuates the self-stimulation-induced increase in the
in vivo synthesis rate of dopamine but not serotonin in the rat nucleus
accumbens.
AB - Our previous study demonstrated that intracranial self-stimulation of the medial
forebrain bundle can increase the in vivo synthesis turnover rate of dopamine
(DA) and serotonin (5-HT) in the nucleus accumbens of adrenal-intact rats. The
present study examined using microdialysis whether such increases in DA and 5-HT
syntheses are influenced by adrenal hormones, which are also activated following
intracranial self-stimulation. A decarboxylase inhibitor, NSD-1015, was perfused
through reversed microdialysis which enabled the simultaneous measurement of 3,4
dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) as an index of the
in vivo turnover rate of DA and 5-HT syntheses. Adrenalectomy (ADX) attenuated
significantly the self-stimulation-induced increase in dialysate levels of DOPA
but not 5-HTP. Corticosterone (Cort) replacement reversed the attenuation in DOPA
levels in adrenalectomized rats. The finding indicates that activation of DA
synthesis in vivo in the nucleus accumbens during intracranial self-stimulation
is dependent on, whereas that of 5-HT synthesis is independent of glucocorticoid
modulation.
PMID- 10762378
TI - Previous experience of withdrawal from chronic diazepam ameliorates the
aversiveness of precipitated withdrawal and reduces withdrawal-induced c-fos
expression in nucleus accumbens.
AB - Flumazenil (20 mg/kg, i.p.)-precipitated withdrawal from chronic treatment with
diazepam (DZP, 15 mg/kg, s.c. in sesame oil for 21 days) resulted in a decreased
seizure threshold to the convulsant, pentylenetetrazole (PTZ), infused into the
tail vein; withdrawal from 21-day chronic diazepam treatment, interspersed with
two periods of drug withdrawal, resulted in a greater decrease in convulsant
threshold. A separate experiment showed that consumption of a sucrose solution
immediately prior to precipitated withdrawal resulted in a decreased subsequent
consumption of the sucrose solution; no such evidence of a conditioned taste
aversion (CTA) was seen in mice given prior experience of withdrawal. Thus, prior
experience of withdrawal enhanced the effects of a subsequent precipitated
withdrawal in increasing seizure sensitivity, but weakened the ability of this
withdrawal to serve as an aversive unconditioned stimulus (US). The weakening of
the aversive properties of precipitated withdrawal may reflect habituation to the
withdrawal stimulus, and was accompanied by a loss of the ability of withdrawal
to induce c-fos expression in the shell of the nucleus accumbens, an area
sensitive to both novel, and stressful, as well as rewarding stimuli.
PMID- 10762379
TI - Repeated long-term potentiation induces mossy fibre sprouting and changes the
sensibility of hippocampal granule cells to subconvulsive doses of
pentylenetetrazol.
AB - Electrical and chemical kindling induces sprouting of the mossy fibre system and
potentiation of evoked field potentials in the dentate gyrus. It has been
postulated that such changes may also be induced by repeated induction of long
term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP
was induced in rats chronically implanted with stimulation electrodes in the
ipsilateral and contralateral angular bundles and with a recording electrode in
the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10
consecutive days but with different tetanization strengths. Sprouting of the
mossy fibres terminating in the CA3 region was significantly induced only in the
group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized
animals, or in low-frequency stimulated animals. Additionally, a novel form of
potentiation which was previously found in pentylenetetrazol (PTZ)-kindled
animals was also observed in the group of 'strongly' and 'weakly' tetanized rats.
Differences in duration of this potentiation were found between the two groups of
animals tetanized with different strengths. The results further demonstrate that
morphological and functional changes in the hippocampus, similar to those seen
after kindling, can also occur in an activation paradigm leading to long-lasting
synaptic plasticity but not accompanied by seizure activity.
PMID- 10762380
TI - Layer-specific immunocytochemical localization of GABA(B)R1a and GABA(B)R1b
receptors in the rat piriform cortex.
AB - A peculiar, layer-segregated immunoreactive distribution of GABABR1a and GABABR1b
receptor antibodies is present in the piriform cortex of adult rats. The GABABR1a
antibody selectively marked the neuropile in layer Ia, where afferent olfactory
fibres and intrinsic GABAergic (gamma-aminobutyric acid) axons terminate on the
distal apical dendrites of pyramidal neurons. The GABABR1b antibody was detected
in the soma and the large basal dendrites of layer II and III neurons. The
pattern of distribution observed supports the hypothesis that (presynaptic)
GABABR1a receptors in the superficial molecular layer modulate neurotransmitter
release in a feedforward synaptic circuit, whereas GABABR1b (postsynaptic)
receptors mediate feedback inhibitory potentials on principal cells.
PMID- 10762381
TI - Nitric oxide released by gastric mechanoreceptors modulates nicotinic activation
of coeliac plexus neurons in the rabbit.
AB - The effects on the nicotinic activation of the coeliac plexus neurons of nitric
oxide (NO) released within the coeliac plexus by gastric mechanoreceptors, in
particular during gastroduodenal inhibitory reflex, were assessed. This study was
performed in the rabbit on an in vitro preparation of the coeliac plexus
connected to the stomach and the duodenum. The electrical activity of ganglionic
neurons was recorded with intracellular recording techniques. Water-filled
balloons were used for gastric distensions and recording of duodenal motility.
When a 10-s train of pulses (20-40Hz) of supramaximal intensity was applied to
the splanchnic nerves, gradual depression of nicotinic activation occurred.
Gastric distension (50 mL, 7.5 min) modulated this depression phenomenon by
inhibiting or facilitating the nicotinic activation. In the neurons impaled
during the recording of duodenal motility, gastric distension triggered an
inhibition of nicotinic activation concomitantly with a gastroduodenal inhibitory
reflex organized by the coeliac plexus. If the gastric distensions were performed
while the coeliac plexus was superfused by a NO scavenger, the nicotinic
activation was unaffected and the gastroduodenal inhibitory reflex was abolished.
Moreover, when the coeliac plexus was superfused with an inhibitor of nitric
oxide synthase, gastric distensions were without effect on the nicotinic
activation. These results demonstrate that NO released within the coeliac plexus
by gastric mechanoreceptors, in particular during the gastroduodenal inhibitory
reflex, modulates the central nicotinic activation of coeliac plexus neurons, so
NO released within a prevertebral ganglion by gastric afferent fibres, in
particular during the organization by this ganglion of a reflex regulating the
gastrointestinal tract motility, also exerts a gating of the central inputs to
the ganglionic neurons.
PMID- 10762382
TI - The evolution of the G matrix: selection or drift?
AB - The evolution of quantitative characters can be described by the equation
Deltaz=GP-1S where Deltaz is the vector of mean responses, G is the matrix of
additive genetic variances and covariances, P is the matrix of phenotypic
variances and covariances and S is the vector of selection differentials. This
equation can be used to predict changes in trait values or to retrospectively
estimate the selection gradient and is thus a central equation of evolutionary
quantitative genetics. Genetic variances and covariances will be reduced by
stabilizing selection, directional selection and drift, and increased by
mutation. Changes in trait values resulting from directional selection that are
comparable with differences observed among species are readily obtainable in
short geological time spans (<5000 generations) with selection intensities so
small that they would have an insignificant effect on the G matrix (of course it
is possible that such changes came about by strong selection over a few
generations, followed by long periods of stasis; there is insufficient evidence
to presently distinguish these two possibilities). On the other hand, observed
effective population sizes are sufficiently small that considerable changes in G
can be expected from drift alone. The action of drift can be distinguished from
selection because the former produces a proportional change in G whereas the
latter, in general, will not. A survey of studies examining variation in G
suggests that the null hypothesis that most of the variation can be attributed to
drift rather than selection cannot be rejected. However, more research on the
predicted statistical distribution of G as a result of selection and/or drift is
required and further development of statistical tests to distinguish these two
forces needs to be made.
PMID- 10762383
TI - Microsatellite analysis of the regeneration process of Magnolia obovata Thunb.
AB - We analysed the regeneration process of Magnolia obovata using polymorphic
microsatellite markers. Eighty-three adult trees standing in a watershed covering
an area of 69 ha, and saplings collected from a smaller research plot (6 ha)
located at the centre of the watershed were genotyped using microsatellite
markers. Among 91 saplings analysed, 24 (26%) had both parents, 31 (34%) had one
parent and 36 (40%) had no parent within the watershed. The proportion of genes
in saplings inherited from the adults within the watershed was 43%, and therefore
57% were from outside the site, indicating active gene exchange across the
watershed area. Average distance between parents and saplings (264.6 +/- 135.3
(SD) m) was significantly smaller than that of pairs randomly chosen between
adults and saplings (436.7 +/- 203.0 (SD) m). The distance of pollen movement
inferred from the distance between the two parents of each sapling ranged from
3.2 m to 540 m with an average of 131.1 m +/- 121.1 m (SD). Because 34% ( =
31/91) of saplings had only one parent within the watershed, the estimate of
average pollen movement must be smaller than the actual one. Long-distance seed
dispersal by birds, inbreeding depression and limitation in acceptance of pollen
because of the difference of phenology in each individual flower were considered
to be the probable causes of large gene exchange across the watershed.
PMID- 10762384
TI - The evolutionary dynamics of male-killers and their hosts.
AB - Male-killing bacteria are cytoplasmic sex-ratio distorters that are transmitted
vertically through females of their insect hosts. The killing of male hosts by
their bacteria is thought to be an adaptive bacterial trait because it augments
the fitness of female hosts carrying clonal relatives of those bacteria. Here we
attempt to explain observations of multiple male-killers in natural host
populations. First we show that such male-killer polymorphism cannot be explained
by a classical model of male-killing. We then show that more complicated models
incorporating the evolution of resistance in hosts can explain male-killer
polymorphism. However, this is only likely if resistance genes are very costly.
We also consider the long-term evolutionary dynamics of male-killers, and show
that evolution towards progressively more 'efficient' male-killers can be
thwarted by the appearance of host resistance. The presence of a resistance gene
can allow a less efficient male-killer to outcompete its rival and hence reverse
the trend towards more efficient transmission and reduced metabolic load on the
host.
PMID- 10762385
TI - Persistence of asexuality through mixed reproduction in Eucypris virens
(Crustacea, Ostracoda).
AB - The ostracod species Eucypris virens exhibits geographical parthenogenesis, with
rare sexual populations in southern Europe and widespread asexual populations
elsewhere. DNA sequence data from the nuclear ITS1 and mitochondrial COI regions
have been used to estimate genetic variabilities and reconstruct phylogenies. The
observed divergence was exceptionally high, with intraspecific maxima of 10.3%
(ITS1) and 20.9% (COI) among European lineages, levels reported for interspecific
comparisons of other taxa. Phylogenetic reconstructions reveal multiple origins
of asexual clones from sexual populations. However, we argue that such data can
only provide a lower limit on the number of origins of asexual reproduction, and
an upper limit on the age of asexual lineages. Congruence between gene trees for
different loci can provide support for the inference of long-term apomictic
reproduction. Nuclear and mitochondrial data differ in their placement of some
asexual clones, possibly indicating that genetic exchange has taken place between
sexual and asexual lineages. Such intraspecific hybridization is one route to
combine the benefits of both reproductive modes, and it might explain how
asexuality managed to persist in E. virens even in long, evolutionary terms.
PMID- 10762386
TI - Clonal and spatial genetic structure in Eurya emarginata (Theaceae).
AB - Eurya emarginata (Thunb.) Makino (Theaceae) is a dioecious, insect-pollinated
tree, which combines sexual reproduction and clonal spread. It is narrowly
distributed in coastal areas from southern China, along southern Korea, and
extending to central and southern Japan. We used allozyme loci and spatial
autocorrelation statistics to examine the clonal structure and the spatial
distribution of allozyme polymorphisms of sexually reproduced individuals in a
study population (70 m x 120 m area) in Korea. The population maintains moderate
levels of allozyme variability (mean He=0.133), and multilocus genotypic
diversity is high (mean DG=0. 992). The frequency of clones was 0.377 (90/239),
and the mean clone-pair distance was very large (35.06 m +/- 1.91 m [SE]),
indicating that clones can form at long distances away from their ancestors. In
addition, it was found that genetic patch width was at least 24 m. However, join
count statistics for the total number of unlike joins showed that, contrary to
expectation for such species, clonal reproduction does not contribute
substantially to genetic isolation by distance neither among the sexually
reproduced individuals nor the whole population. In contrast, limits to seed and
pollen dispersal create substantial levels of genetic structure.
PMID- 10762387
TI - Spatial distribution of allozyme polymorphisms following clonal and sexual
reproduction in populations of Rhus javanica (Anacardiaceae).
AB - Rhus javanica L. (Anacardiaceae), a dioecious tree with both sexual reproduction
and clonal growth, is widely distributed in warm temperate, subtropical, and
tropical regions in east Asia. We used allozyme loci and spatial autocorrelation
statistics to examine clonal structure and the spatial distribution of allozyme
polymorphisms in two Korean populations. Populations of the species maintain
moderate levels of allozyme variability (mean He=0.175, GST=0.060), and high
levels of multilocus genotypic diversity (mean DG=0.971). Clone-pair distances
ranged from 1.4 m to 57.4 m, and had high mean values of 24.0 m and 25.6 m in the
two study populations. Approximate genetic patch widths were inferred to be 23-25
m. The results indicated that within populations there is moderate (one study
population) or no (other study population) spatial genetic structure among
sexually reproduced individuals, and vegetatively reproduced genotypes also are
almost randomly distributed. The spatial genetic structure among sexually
reproduced trees in the one case is probably caused by limited pollen dispersal
in that population, and the lack of structure in the other probably results from
the short time elapsed since founding. It appears that clonal reproduction also
does not contribute substantially to genetic isolation by distance neither among
the sexually reproduced individuals nor the total population. Ramets often
establish long distances from their progenitors and thus do not substantially
increase the degree of local consanguineous matings.
PMID- 10762388
TI - The evolution of haplodiploidy under inbreeding.
AB - Although haplodiploid organisms tend to be inbred, previous models of the
evolution of haplodiploidy have assumed outbred populations. Here a model for the
evolution of haplodiploidy is developed which incorporates sib mating,
deleterious mutations generated by mutation, and fitness differences between
haploids and diploids. Simulations of the model allow an assessment of the effect
of inbreeding on the deleterious mutation and maternal transmission theories for
the evolution of haplodiploidy. As expected from intuitive arguments, inbreeding
favours haplodiploidy under the deleterious mutation hypothesis but disfavours
haplodiploidy under the maternal transmission hypothesis. It appears that the
effect of inbreeding is greater on the maternal transmission theory, and thus
inbreeding may restrict the evolution of haplodiploidy.
PMID- 10762389
TI - A quantitative genetic analysis of phenotypic plasticity of diapause induction in
the cricket Allonemobius socius.
AB - Although numerous studies have indicated that diapause is heritable and
phenotypically plastic, none of them has examined the quantitative genetic basis
of this plasticity. In this paper we report such an analysis for egg diapause in
the cricket Allonemobius socius, the induction of which appears to be largely
determined by the mother. We analysed the quantitative genetic basis of the
phenotypically plastic response of female A. socius to age and environmental
conditions. We measured the production of diapause eggs on four occasions over a
16-day period, and in two environments; one mimicking an 'early' period of the
year and another mimicking a 'late' period. We analysed genetic variation in
phenotypic plasticity using the character-state approach. Diapause proportion was
heritable (h2 ranged from 0.17 to 0.49, being larger in the 'early' environment),
and the genetic correlation between ages in proportion of diapausing eggs was
close to 1 but showed a decrease with increased difference between ages. There
were significant genetic correlations between environments for all ages. Because
of the reduction in genetic correlation as the difference in ages increases,
selection will be more effective at changing the overall shape of the reaction
norm than causing local changes. Furthermore, the high genetic correlations may
constrain the evolution of the reaction norm. When the two environments are
converted into the estimated days in the year the two reaction norms form
approximately a single curve as predicted from previous theoretical analysis of
the optimal reaction norm.
PMID- 10762390
TI - Evolutionary implications of the relationship between genome size and body size
in flatworms and copepods.
AB - Genome and body sizes were measured in 38 species of turbellarian flatworms and
16 species of copepod crustaceans. Significant positive relationships existed
between genome size and body size in both groups. The slopes of these regressions
indicated that increases in cell volume are reinforced by increased cell numbers,
or that cell volumes show positive allometric variation with genome size. Genome
sizes appear to vary in a discontinuous fashion among congeneric species in both
groups, indicating that such changes have occurred rapidly, and with potentially
profound effects on important morphological characters.
PMID- 10762391
TI - Analysis of the phenotypic effects of B chromosomes in a natural population of
Metagagrella tenuipes (Arachnida: Opiliones).
AB - Phenotypic effects of B chromosomes in a natural population of Metagagrella
tenuipes (Arachnida: Opiliones) were studied. Mean number of Bs per individual in
the population studied was 6.0, and remained stable during two successive summers
of 1997 and 1998. In contrast to the number of B chromosomes, ratios between
individuals possessing odd and those possessing even numbers of Bs changed during
both collection seasons: the proportion of harvestmen with an even number of Bs
decreased from June-July to October-November. A possible reason for this may be a
difference in susceptibility to parasites between B-odd and B-even harvestmen. In
the group of B-even individuals the percentage of infected harvestmen in the June
July samples was much higher compared to the B-odd group. In addition, the
infection rate in the B-even group decreased more sharply than among B-odd
harvestmen. In the group of B-even harvestmen infection was associated with
reduced body size, whereas no such association was found among B-odd harvestmen.
In the group of B-even individuals there was a U-shaped relationship between
number of Bs and the probability of being infected by parasites, and an inverted
U-shaped relationship between body size and number of Bs. No such associations
were found in the group of B-odd harvestmen. Seasonal selection is suggested to
be a main factor contributing to the B-chromosome polymorphism in M. tenuipes.
PMID- 10762392
TI - Effects of specialization on genetic differentiation in sister species of bark
beetles.
AB - We investigated the relative importance of resource use and geography on genetic
differentiation in the sister-species pair of generalist and specialist bark
beetles: Dendroctonus ponderosae and D. jeffreyi (Coleoptera: Scolytidae). In two
regions, where the distributions of these species overlap, we collected specimens
of the generalist from multiple host species and specimens of the specialist from
its single host species. Using allozyme techniques, we uncovered genetic
differentiation between generalist populations on different host species in the
same region (one locus in each region). However, a much stronger pattern of
differentiation was found between specialist populations in the two distantly
separated regions (three loci). With mtDNA, we found no significant
differentiation between regions in the specialist, or among host species in the
generalist, although there was some differentiation between regions in the
generalist (AMOVA, P < 0.05). Overall, the generalist populations maintained
approximately 10 times the genetic variation in mtDNA as the specialist
populations, which suggests that the specialist either has generally smaller
population sizes than the generalist, or has experienced a historical population
bottleneck.
PMID- 10762393
TI - Monogenic inheritance of apomixis in two Hieracium species with distinct
developmental mechanisms.
AB - Apomixis, the asexual formation of seed, has been known in angiosperms for more
than a century yet the genetic mechanisms that control this trait remain poorly
understood. Most members of the genus Hieracium are apomicts, forming
predominantly asexual seed. Some purely sexual forms, however, also exist. In
this paper we present a study of the inheritance of apomixis using two apomictic
species of Hieracium which utilize very different forms of megagametogenesis. In
both cases the progeny inherited apomixis as a monogenic, dominant trait that
could be transferred by both haploid and diploid male gametes. In common with
observations from other systems, no diploid apomictic progeny were recovered from
these crosses. This appears to have been caused by selection against the survival
of diploid zygotes, rather than against the mediation of haploid gametes as has
been noted in other systems. Crosses between the two apomicts showed that the
dominant determinants in the two forms examined were closely linked, possibly
allelic. The significance of these data is discussed with respect to current
theories on the associative link between gametophytic apomixis and polyploidy.
PMID- 10762394
TI - Low among-population genetic differentiation in Chinese bisexual Artemia
populations.
AB - We studied the population genetic structure of nine bisexual Artemia sinica
populations from the provinces of Inner Mongolia, Shanxi and Qinghai in China,
using variation at nine allozyme loci (cellulose acetate electrophoresis). There
is a clear-cut tendency for an increase in genetic variation, as measured by
heterozygosity, with increasing habitat size. Although we observe a positive
relationship between genetic differentiation and geographical distance, overall
FST values are low: populations separated by approximately 1000 km show average
FST values of 0.05-0.1, whereas populations separated by 100 km show no genetic
differentiation at all.
PMID- 10762395
TI - Populations of the south-west Pacific malaria vector Anopheles farauti s.s.
revealed by ribosomal DNA transcribed spacer polymorphisms.
AB - Malaria in the south-west Pacific is transmitted by members of the Anopheles
punctulatus group which comprises 12 cryptic species with overlapping morphology.
The most widely distributed species of the group is Anopheles farauti s.s. (An.
farauti 1) found throughout northern Australia, Papua New Guinea, eastern
Indonesia, the Solomon Islands and Vanuatu. A study of the population structure
of this species using PCR-RFLP analysis on the ribosomal DNA internal transcribed
spacer 1 reveals five genotypes which had distinct geographical distributions.
Where these distributions overlap, genotype hybrids can be identified.
Heteroduplex analysis of the ITS2 region reveals combinations of nonhomogenized
ITS2 sequences and subsequently seven identifiable genotypes, reflecting the ITS1
distribution. Sequence analysis of these ITS2 polymorphisms reveals a minimum of
13 ITS2 sequence types present in heterogeneous combinations in individual
mosquitoes. It appears that there are different levels of evolution occurring
within the ITS1 and ITS2 regions. These data suggest that An. farauti s.s. may
contain multiple loci for the rDNA gene family or that the homogenization of
these regions is relatively slow and can be used in genetic studies of population
distribution and structure.
PMID- 10762396
TI - High diversity of structurally heterozygous karyotypes and rDNA arrays in
parthenogenetic aphids of the genus Trama (Aphididae: Lachninae).
AB - Karyotypes of permanently parthenogenetic aphids of three species of the genus
Trama show great diversity, particularly in the number and distribution of
chromosomal elements containing highly repetitive sequences. Sampling at only a
few sites in southern England, chromosome number varied from 14 to 23 in T.
troglodytes, 9-12 in T. caudata and 10-14 in T. maritima, with some colonies
having individuals of more than one karyotype. This variation was paralleled by
differences in the number and distribution of rDNA arrays revealed by in situ
hybridization. This high intraspecific karyotype diversity contrasts with very
low genetic diversity in the same populations, suggesting rapid karyotype
evolution. Although T. troglodytes feeds on many species of composite plants
there was no evidence of any karyotype-associated host race formation.
PMID- 10762397
TI - Microsatellite analysis of Pinus taeda L. in Zimbabwe.
AB - Deducing the origin of early 20th century introductions of Pinus taeda into
Zimbabwe is possible given microsatellite markers and clear population
differentiation in ancestral U.S. populations. This study was designed to
determine whether P. taeda introductions into Zimbabwe came from one U.S. region
or whether the present-day population is an admixture of introductions from east
and west of the Mississippi River Valley. Principal components analysis, Cavalli
Sforza and Edwards' chord distances and presence of diagnostic alleles each
indicate that the Zimbabwe population is an admixture. There were five novel
alleles in the Zimbabwe population not represented in the indigenous U.S.
populations, possibly because of de novo mutation, introgression with other
introduced North American pines or sampling error.
PMID- 10762398
TI - Inbreeding and outbreeding depression in male courtship song characters in
Drosophila montana.
AB - In Drosophila montana, male courtship song frequency is closely associated with
male courtship success and offspring survival. Other pulse characters (pulse
length and cycle number) may also affect female mate choice, whereas pulse train
characters (interpulse interval, pulse number and pulse train length) are not
associated with these male fitness components. Inbreeding depression in these
song characters was investigated by comparing the songs of inbred and outbred fly
strains. The average change in most song characters as a result of inbreeding was
only a few percent. However, in male song frequency the average inbreeding
depression was about 14%, suggesting that this song character is associated with
fitness. Outbreeding depression and the genetic architecture of song characters
were investigated with interpopulation crosses and joint scaling tests. For pulse
train characters the generation means show only evidence of additivity, and the
existence of dominance or epistasis in these characters was strongly rejected in
each case. In pulse characters the means of the F1 males were lower than the
average of the parental generations. In pulse length and cycle number this
difference was attributable to dominance alone. In frequency there was
outbreeding depression also in the F2 generation, suggesting a break-up of
favourable epistatic gene combinations. The outbreeding depression in this
character in the F1 generation was caused by dominance, and in the F2 also by
duplicate epistasis between dominant decreasers. The possible role of outbreeding
depression and epistasis in speciation is discussed.
PMID- 10762399
TI - Inbreeding depression and mating systems in two species of Linanthus
(Polemoniaceae).
AB - Theory predicts that, at equilibrium, the magnitude of inbreeding depression
caused by recessive alleles should decrease as the level of self-fertilization
increases, facilitating the evolution of even higher selfing rates. Data are
presented on mating systems and inbreeding depression in multiple populations of
two annual species in the genus Linanthus (Polemoniaceae). Outcrossing rates were
found to be less than 0.075 in populations of a small-flowered species, L.
bicolor, and ranged from 0.104 to 0.300 in populations of a larger-flowered
species, L. jepsonii. Inbreeding depression for both species was low for all life
history stages, with cumulative inbreeding depression less than 0.23 in all
populations. Significant inbreeding depression for pollen fertility was found in
L. jepsonii populations and may contribute substantially to total inbreeding
depression. A competitive treatment had no significant effect on the expression
of inbreeding depression for above-ground dry mass. In accordance with
theoretical expectations, the magnitude of inbreeding depression was lower in L.
bicolor, the more highly selfing species. The magnitude of inbreeding depression
in L. jepsonii, although greater than that of L. bicolor, is not sufficient to
prevent evolution of increased selfing rates in this species, according to some
theoretical models of mating system evolution.
PMID- 10762400
TI - Population dynamics of the symbiotic mushroom Hebeloma cylindrosporum: mycelial
persistence and inbreeding.
AB - The pattern of colonization of a forest site by the ectomycorrhizal basidiomycete
fungus Hebeloma cylindrosporum Romagnesi was followed from 1993 until 1997. Fruit
bodies of this tetrapolar heterothallic species were mapped, collected and
propagated as pure mycelial cultures. Isolates were analysed for their mating
types and molecular markers (rDNA polymorphism and RAPD). Dedikaryotization of
the 26 isolates collected in 1993 and the separate analysis of each individual
haploid nucleus established that two fully compatible genets, which occupied two
nonoverlapping territories, were present. Isolates belonging to the same genet
could nevertheless be distinguished from each other based on Southern
hybridization using hyperpolymorphic DNA probes. A majority of the 143 isolates
collected from 1994 to 1997 belonged to either of the two genets identified in
1993, whose territories extended at a rate of about 0. 45-0.60 m per year.
Selfing of the two 1993 genets, rather than outcrossing, was the most likely
explanation for the origin of additional genotypes identified between 1995 and
1997. The spatial distribution of fruit-bodies and genets of H. cylindrosporum
suggested that only a fraction of the sampled area was favourable to colonization
and that genetic diversification through meiospore dispersal may be inhibited by
the presence of resident genets, possibly via a somatic incompatibility system.
PMID- 10762401
TI - Gene flow and mode of pollination in a dry-grassland species, Filipendula
vulgaris (Rosaceae).
AB - Filipendula vulgaris is a characteristic species of dry nonacidic grasslands in
Denmark. This habitat type occurs only on marginal areas not suitable for
agriculture or urbanization and that are by their nature fragmented. The
population genetic structure of F. vulgaris was investigated in 17 populations
within two regions of Denmark, using isozyme electrophoresis. Small populations
were found to have significantly fewer polymorphic loci than larger populations,
but all populations maintained the same common allelic variants. The degree of
isolation of individual populations did not affect the amount of genetic
variation. Offspring arrays revealed a very high outcrossing rate (0.96). The
field study demonstrated a very high level of gene flow between populations
considering that small insects are thought to be the main pollinators of this
species. An experiment to verify whether pollen transport by wind could explain
the results from the field study demonstrated long-distance transport from
isolated plants to bagged plants. Filipendula vulgaris pollen grains are very
small and this explains why outcrossed progeny were found using pollination bags
with small pore sizes. We conclude that wind pollination is indeed possible and
together with insect pollination is causing the observed patterns of genetic
variation. The substantial gene flow between populations may be reducing the
effects of genetic drift in the small fragmented populations of F. vulgaris.
PMID- 10762402
TI - Transglobal comparisons of nuclear and mitochondrial genetic structure in a
marine polyploid clam (Lasaea, Lasaeidae).
AB - Existing genetic studies have proposed that the intertidal clam, Lasaea, is one
of a few animal groups with asexual lineages that has persisted for an
evolutionarily significant time. This proposal is based on the exceptional
mitochondrial genetic divergence between studied sexual and asexual lineages.
Nevertheless, a conclusion of long-lived asexuality awaits a more comprehensive
sampling of the collective global range of this taxon. We assessed the breeding
system and phylogeography of geographically divergent Lasaea populations using
nuclear and mtDNA genetic markers. The allozyme genetic structure of five
populations (from Japan, New Zealand, South Africa, Florida and Bermuda) showed
marked deviation from expected random mating patterns (within and among loci),
frequent fixed heterozygosity, and reduced genotypic diversity. This pattern and
the finding of multiple asymmetric allozymic heterozygotes, indicated a clonal
structure consistent with allopolyploid origins for each population. Spatial
analysis of mtDNA and allozyme markers revealed strong geographical structure and
yielded no cosmopolitan clonal lineages. Australian sexual species formed sister
taxa to a minority of the clonal lineages, but pronounced mitochondrial genetic
divergence levels and developmental differences precluded their identification as
convincing parental species to any of the clones. A majority of asexual lineages
may have originated in areas where no sexual congeners are presently known. The
observed nuclear and mtDNA genetic structure is consistent with Lasaea clonal
diversity being enriched by local mutational derivatives but infrequent
recombination cannot be ruled out.
PMID- 10762403
TI - Population structure of Aedes albopictus (Skuse): the mosquito which is
colonizing Mediterranean countries.
AB - Multilocus electrophoresis analysis has been used to study the genetic structure
of 18 populations of Aedes albopictus newly introduced to Italy, in comparison
with two populations in the United States, four in Japan, and four in Indonesia.
Allozyme analysis revealed that 15 out of the 18 studied loci were polymorphic
among the 28 populations. No significant deviations from Hardy-Weinberg
equilibrium were found at polymorphic loci. High genetic affinity was observed
between the Italian populations and those from the United States and Japan. The
analysis of variance in allele frequencies showed that variance among
subpopulations accounted for most of the total variance, suggesting that
isolation of the Italian populations is not related to distance. Analysis of
linkage disequilibrium using Ohta's method shows that the variance in the
frequency of allele combinations could be explained by the action of the genetic
drift which accompanies the establishment of new populations. The colonization
process of Ae. albopictus in Italy is following a trend similar to that
previously observed in the U.S. A., probably because both infestations derive
from several successive introductions, each with large numbers of individuals.
PMID- 10762404
TI - Cellular basis of wing size variation in Drosophila melanogaster: a comparison of
latitudinal clines on two continents.
AB - We investigated the cellular basis of two extensive, continuous, latitudinal,
genetic, body size clines of Drosophila melanogaster by measuring wing area and
cell size in the wing blade of adult flies reared under standard, laboratory
conditions. We report that the contribution of cell size to an Australian cline
is much smaller than that to a South American cline. The data suggest that
neither cell size nor cell number were the targets of selection, but rather wing
area itself, or a trait closely related to it. We hypothesize that the
differences between the continents were caused by differences in the initial
pattern of genetic variation for the cell traits and/or by the direction of
selection on the source populations of the clines. Despite large differences
between continents in the cellular basis of the latitudinal variation, multiple
regression analysis, using the individual variation within populations, showed
that the relationship between cell size and cell number was changed with latitude
in the same way in the two clines. The relative contribution of cell number to
wing area variation increased with latitude, probably because of compensatory
interactions with cell size as a consequence of the latitudinal increase in cell
number. Our findings are discussed in relation to the cellular basis of
evolutionary change in laboratory thermal selection lines and natural populations
along latitudinal clines.
PMID- 10762405
TI - Paternity and gene dispersal in limber pine (Pinus flexilis James).
AB - This study provides empirical information on intrapopulation gene dispersal via
pollen, the size of genetic 'neighbourhoods', and interpopulation gene flow in a
long-lived conifer, limber pine (Pinus flexilis). We used allozyme loci for a
paternity analysis of 518 seeds produced in an isolated population of limber pine
located in north-eastern Colorado, U.S.A., separated by 2 km from the nearest
conspecific trees and nearly 100 km from populations in the Rocky Mountains. We
also used indirect techniques (FST analyses) to estimate gene flow rates among
subdivisions of the study population and among five widely separated populations.
Within the main study population limber pine exhibited a polymorphism level of
50%, observed heterozygosity of 0.159, and 2.36 alleles per polymorphic locus.
Mountain populations were slightly more variable. The main study population
showed significant differentiation in allozymes among neighbouring
subpopulations. The mean FST was 0.031 and the gene flow rate among
subpopulations was estimated as 7.8 migrants per generation. Among widely
separated populations the mean FST was 0.035 and the gene flow rate was estimated
as 6.9 migrants per generation. The paternity analysis indicated a best estimate
of 6.5% pollen immigration (minimum 1.1%) from populations 2 km to 100+ km away.
For 4% of the seeds examined, paternity could be ascribed to a single tree in the
study population. Fractional paternity and likelihood methods were used to
estimate pollen dispersal distances for the remainder of the seeds. Mean pollen
dispersal distance was estimated at 140 m using the fractional method, similar to
results from the other techniques. This compares with a mean distance of 172 m
between potential mates. These results suggest near-panmictic pollen dispersal
over this population, which covers about 15 ha. The observed allozyme differences
and surprisingly low estimates of among-subpopulation gene flow are ascribed to a
probable restriction of gene dispersal by seeds.
PMID- 10762406
TI - Mitochondrial DNA variation, phylogeography and population structure of the Asian
elephant.
AB - We report the first genetic analysis of free-ranging Asian elephants (Elephas
maximus). We sampled 118 elephants from Sri Lanka, Bhutan/North India, and
Laos/Vietnam by extracting DNA from dung, PCR amplifying and sequencing 630
nucleotides of mitochondrial DNA, including part of the variable left domain of
the control region. Comparison with African elephant (Loxodonta africana)
sequences indicated a relatively slow molecular clock in the Proboscidea with a
sequence divergence of approximately 1%/Myr. Genetic diversity within Asian
elephants was low, suggesting a small long-term effective population size.
Seventeen haplotypes were identified within Asian elephants, which clustered into
two well-differentiated assemblages with an estimated Pliocene divergence of 2.5
3.5 million years ago. The two assemblages showed incomplete geographical
partitioning, suggesting allopatric divergence and secondary admixture. On the
mainland, little genetic differentiation was observed between elephant
populations of Bhutan and India or Laos and Vietnam. A significant difference in
haplotype frequencies but relatively weak subdivision was observed between the
regions Bhutan-India and Laos-Vietnam. Significant genetic differentiation was
observed between the mainland and Sri Lanka, and between northern, mid-latitude
and southern regions in Sri Lanka.
PMID- 10762407
TI - Estimating multilocus linkage disequilibria.
AB - The state of a diploid population segregating for two alleles at each of n loci
is described by 22n genotype frequencies, or equivalently, by allele frequencies
and by multilocus moments or cumulants of various orders. These measures of
linkage disequilibrium cannot usually be determined, both because one cannot tell
whether a gene came from the maternal or paternal gamete, and because such a
large number of parameters cannot be estimated even from large samples.
Simplifying assumptions must therefore be made. This paper sets out methods for
estimating multilocus genotype frequencies which are appropriate for unlinked
neutral loci, and for populations that are ultimately derived by mixing of two
source populations. In such a hybrid population, all multilocus associations
depend primarily on the number of loci involved that derive from the maternal
genome, and the number derived from the paternal genome. Allele frequencies may
differ across loci, and the contribution of each locus to multilocus associations
may be scaled by the difference in allele frequency between source populations
for that locus (deltap 5 ng/mL (0.2 x 10-9 M) to medium containing both insulin and
DHT, inhibited the expected increase in overall size of BUGs, epithelial area and
ductal branching in a dose-dependent manner. TGF-beta1 also decreased [3H]
thymidine labelling indices of both epithelium and mesenchyme. TGF-beta1 at 10
ng/mL elicited these inhibitory effects on BUGs cultured in medium containing DHT
alone. Addition of All-trans-RA (10-8 to 10-6 M) to the medium containing DHT
plus insulin, or DHT alone did not exert significant effects on either overall
size of BUGs or epithelial growth and ductal branching. All-trans-RA at 10-6 M
decreased the [3H]-thymidine labelling index of mesenchyme of BUGs cultured in
medium with DHT plus insulin or DHT alone, but did not decrease the [3H]
thymidine labelling index of epithelium. The present results indicate that TGF
beta1 inhibits androgen-induced epithelial and mesenchymal growth as well as
epithelial morphogenesis of BUGs from neonatal mice. Such an inhibitory effect of
TGF-beta1 is not mimicked by All-trans-RA at physiological concentrations.
PMID- 10762432
TI - Sperm number and condition affect the number of basal cells and their expression
of macrophage antigen in the murine epididymis.
AB - Unilateral ligation of the mid-corpus epididymis, the proximal vas deferens and
imposition of an abdominal temperature for 6 days as well as bilateral castration
for 3, 6 or 14 days, resulted in a change in epithelial composition of the adult
murine epididymis with regard to the number and antigen expression of basal
cells. There were fewer basal cells per tubule cross-section with fewer
expressing F4/80 antigen when spermatozoa were absent from the proximal lumen
following short-term castration. Conversely, more basal cells with more of them
demonstrating macrophage antigen expression were evident when more or damaged
spermatozoa were in the proximal lumen after corpus ligation and exposure to
abdominal temperature or in the cauda after long-term withdrawal of androgen
support. By contrast, ligation of the vas deferens did not lead to tubule
distension, and hence sperm accumulation, and did not alter the basal cell
population in the cauda epididymis. The data suggest that epididymal basal cells
respond in number and macrophage antigen expression to the presence of sperm
autoantigens in the lumen with little dependence on circulating androgens. These
changes may represent responses to minimise the interaction of sperm autoantigens
with the immune system and the risk of immunological infertility.
PMID- 10762433
TI - Objective evaluation of the morphology of human epididymal sperm heads.
AB - Spermatozoa were obtained from nine epididymal regions of six epididymides taken
from five men undergoing castration for prostatic carcinoma (53-76 years) and
from one man with testicular cancer (38 years). Spermatozoa were obtained by
mincing tissue in phosphate-buffered saline, making air dried smears and staining
with Hemacolor. The percentage of sperm heads categorised subjectively as normal
(of uniform shape) or otherwise was calculated for each region. This confirmed
that grossly swollen sperm heads (previously shown to be artefacts) were only
present in proximal regions of the duct. A computer-aided sperm morphology
analyser (Sperm Class Analyzer(R)) was used to provide objective measurements of
sperm head area, perimeter, length and width of the uniform sperm heads and
revealed that there was a gradual and statistically significant decline in sperm
head size upon maturation, as occurs in other species. There was no significant
difference between the morphometric parameters of spermatozoa obtained from the
distal cauda epididymis and those obtained from the ejaculates of young
normozoospermic patients.
PMID- 10762434
TI - Spermatogenic disturbance induced by di-(2-ethylhexyl) phthalate is significantly
prevented by treatment with antioxidant vitamins in the rat.
AB - Phthalate esters, now regarded as endocrine disruptors, are widely used in the
plastics industry. In particular, di-(2-ethylhexyl) phthalate (DEHP) is produced
in large quantities, and is used in blood storage bags, catheters and
haemodialysis instruments. Previous studies have demonstrated that treatment of
rats with DEHP induces testicular atrophy with liver enlargement, although the
precise nature and mechanism of the action of DEHP on these organs remains
unclear. In the present study, we produced an experimental model of DEHP-induced
spermatogenic disturbance in rats by feeding them a DEHP-containing diet. Liver
enlargement occurred in rats fed either a 1 or 2% DEHP-containing diet. However,
testicular atrophy accompanied by aspermatogenesis was induced by feeding with
the 2% but not with the 1% DEHP-containing diet. This suggests that the critical
DEHP dose for gonadotoxicity is higher than that for hepatotoxicity. Using the 2%
DEHP-dose, the effect of simultaneous administration of antioxidant vitamins (=
vitamins C and E) was next examined. It was found that the vitamin
supplementation significantly prevented the testicular injury. The results
suggest that antioxidant vitamins can protect the testes from DEHP-toxicity.
PMID- 10762435
TI - Evaluation of the ability of levonorgestrel butanoate alone, or in combination
with testosterone buciclate, to suppress spermatogenesis in the bonnet monkey
(Macaca radiata).
AB - Levonorgestrel butanoate, 0.25, 1.0 and 2.5 mg/kg, administered as two injections
60 days apart (groups II, III, IV), failed to suppress spermatogenesis
consistently and uniformly in adult bonnet monkeys (group size, n=6) compared to
controls (group I). Levonorgestrel butanoate at the same doses combined with two
simultaneous injections of 40 mg testosterone buciclate (groups V, VI, VII),
consistently suppressed spermatogenesis in the period 60-240 days and in most
animals to azoospermia or severe oligozoospermia (<5 x 106/mL) during days 90
210. The degree and duration of suppression were greatest in group VI. Sperm
motility declined in all treated animals and spermatozoa in the semen of animals
from groups V and VI lost all progressive motility in the period 60-150 and 60
210 days, respectively. The changes in testosterone levels were similar in groups
V and VI, increasing within 24 h after the combined injection to reach a peak by
day 28 followed by a sharp decrease until day 67. The second injection increased
testosterone levels by a lesser degree to peak levels on day 81. In group VII,
testosterone levels decreased until day 59 after the first injection but
increased to a maximum on day 81 after the second injection followed by a gradual
decrease until day 150 to below baseline values. Peak levels of serum
levonorgestrel were observed 1-7 days after injection of levonorgestrel butanoate
alone. Clearance of the drug was slow, being detectable in the circulation until
day 330 of the 360 day study period in the high dose group. Dose-response
increases to peak levels of levonorgestrel were attained on day 7 in groups V, VI
and VII, after the first injection. After the second injection, peak levels were
seen on day 61 in groups V and VI and on day 81 in group VII. Levonorgestrel was
no longer detectable in blood in groups V and VI by days 210 and 300,
respectively, but small circulating amounts remained in group VII at the
conclusion of the study on day 360. This study indicates that when levonorgestrel
butanoate is combined with a long-acting androgen and injected at two-monthly
intervals, effective and reversible suppression of spermatogenesis is achieved.
PMID- 10762436
TI - Ultracytochemical localization of 5'-nucleotidase activity in human ejaculated
spermatozoa.
AB - 5'-nucleotidase, an adenosine producing enzyme with a
glycosylphosphatidylinositol-anchored structure, was localized in human
ejaculated spermatozoa. The poly-L-lysine-coated dish method was used to prepare
the specimens, and the cerium method was employed for electron-microscopic enzyme
localization. Precipitates indicating enzyme activity were detected on the outer
side of the external plasma membrane of the acrosomal region. This enzyme may
play a role in sperm motility and male infertility.
PMID- 10762437
TI - Decapitated and decaudated spermatozoa in man, and pathogenesis based on the
ultrastructure.
AB - The ultrastructure of decapitated tails and decaudated heads of ejaculated
spermatozoa from an infertile man were investigated. The decaudated heads had the
nucleus and acrosome, but neither the implantation fossa nor the basal plate were
observed at the caudal pole of the nucleus. The nuclear membrane at this portion
showed numerous nuclear pores. The decapitated tails contained the proximal
centriole at the proximal end. In addition, most decapitated tails had segmented
columns, outer coarse fibres, axoneme, mitochondrial sheath and fibrous sheath in
the normal position. The ultrastructure reflects the high motility of the
decapitated tails of the spermatozoa. Drastic abnormalities were found in the
developing spermatids in the biopsied testes. In spermatids later than the Golgi
phase, the pair of centrioles were floating in the cytoplasm of the spermatid,
but the distal centriole elongated the flagellum. Neither the implantation fossa
nor the basal plate were observed at the caudal pole of the nucleus. It is
concluded that the tail might be separated from the head before or after
completion of tail formation in spermatids. The explanation for why the proximal
centriole failed to connect to the nucleus is unknown.
PMID- 10762438
TI - Impact of a deep saturation dive on semen quality.
AB - The demonstration dive 'Aurora' has provided an opportunity to study the impact
of extreme hyperbaric conditions on male fertility. This operation involved a 33
day diving programme during which divers were exposed to a maximum pressure of
4.6 Mega Pascals (Mpa) for 7 days. At days - 4, + 27, + 34, + 82 and + 263
relative to the initiation of the dive, semen samples were analysed to determine
the quality of spermatogenesis and the functional competence of the spermatozoa.
A dramatic fall in semen quality was observed in association with the dive and by
day + 82 the potential fertility of the men was seriously compromised as
evidenced by oligoasthenoteratozoospermic semen profiles and the poor fertilizing
potential of the spermatozoa. These studies indicate, for the first time, that
the severe hyperbaric conditions associated with deep saturation dives have a
profound effect on male reproductive function.
PMID- 10762443
TI - Cytokine expression by cultured osteoblasts from patients with osteoporotic
fractures.
AB - Human osteoblasts were derived in culture from explants of bone from patients who
had recently suffered osteoporotic fractures and from patients with no evidence
of osteoporosis. The expression of cytokine mRNA in these osteoblasts was
subsequently determined by reverse transcriptase-linked polymerase chain reaction
(RT-PCR). We have detected mRNA for IL-1beta, IL-3, IL-6, IL-8, TNF-alpha and
beta, and the three TGF-beta isoforms in the cells. The profile of cytokines
expressed by osteoblasts derived from patients with osteoporotic fractures was
consistent with profiles observed in osteoblasts derived from patients with no
evidence of reduced bone mass--the latter included children undergoing corrective
surgery and adult subjects ranging from 31 to 80 years undergoing elective
surgery for osteoarthritis and other bone pathologies.
PMID- 10762442
TI - Animal models of acute hepatic failure.
AB - The understanding and treatment of acute hepatic failure has developed rapidly
over the last 40 years reducing morbidity and mortality from this syndrome.
Progress has been made by the study of animal models that reflect the clinical,
biochemical and histological pattern of the syndrome seen in man. This is of
increasing importance with the use of therapeutic intervention, liver
transplantation and the use of extra-corporeal liver support devices. This review
examines and critically appraises the various approaches to the study of acute
hepatic failure in animal models, including both surgical and pharmacological
approaches.
PMID- 10762444
TI - Antiviral effect of nitric oxide during Japanese encephalitis virus infection.
AB - The ability of Japanese encephalitis virus (JEV) and JEV-induced macrophage
derived neutrophil chemotactic factor (MDF) to produce nitric oxide (NO), and the
possible antiviral effect of NO during JEV infection, was investigated. Splenic
macrophages of JEV infected mice produced maximum NO in vivo at day 7 post
infection, and in vitro at 24 h after JEV stimulation. MDF-induced NO production
was dose dependent and maximal at 60 min after MDF treatment. The response was
sensitive to anti-MDF antibody treatment and the nitric oxide synthase inhibitor
NG-monomethyl-L-arginine (L-NMMA). Pretreatment of mice with L-NMMA increased the
mortality to 100% in JEV infected mice in vivo and inhibited NO production in
vitro, while MDF stimulated macrophages inhibited virus replication with high
levels of NO production. MDF treatment increased the survival rate of JEV
infected mice. The findings thus demonstrate that MDF induces production of NO
during JEV infection, which has an antiviral effect. This may be one of the
important mechanisms of natural immunity in controlling the initial stages of JEV
infection.
PMID- 10762439
TI - The mechanisms of coronary restenosis: insights from experimental models.
AB - Since its introduction into clinical practice, more than 20 years ago,
percutaneous transluminal coronary angioplasty (PTCA) has proven to be an
effective, minimally invasive alternative to coronary artery bypass grafting
(CABG). During this time there have been great improvements in the design of
balloon catheters, operative procedures and adjuvant drug therapy, and this has
resulted in low rates of primary failure and short-term complications. However,
the potential benefits of angioplasty are diminished by the high rate of
recurrent disease. Up to 40% of patients undergoing angioplasty develop
clinically significant restenosis within a year of the procedure. Although the
deployment of endovascular stents at the time of angioplasty improves the short
term outcome, 'in-stent' stenosis remains an enduring problem. In order to gain
an insight into the mechanisms of restenosis, several experimental models of
angioplasty have been developed. These have been used together with the tools
provided by recent advances in molecular biology and catheter design to
investigate restenosis in detail. It is now possible to deliver highly specific
molecular antagonists, such as antisense gene sequences, to the site of injury.
The knowledge provided by these studies may ultimately lead to novel forms of
intervention. The present review is a synopsis of our current understanding of
the pathological mechanisms of restenosis.
PMID- 10762441
TI - Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages,
proliferative units and cancer.
AB - Gastrointestinal stem cells are shown to be pluripotential and to give rise to
all cell lineages in the epithelium. After damage, gut stem cells produce
reparative cell lineages that produce a wide range of peptides with important
actions on cell proliferation and migration, and promote regeneration and
healing. Increase in stem cell number is considered to induce crypt fission, and
lead to increases in the number of crypts, even in the adult; it is also the mode
of spread of mutated clones in the colorectal mucosa. Stem cell repertoire is
defined by both intrinsic programming of the stem cell itself, but signalling
from the mesenchyme is also vitally important for defining both stem cell progeny
and proliferation. Carcinogenesis in the colon occurs through sequential
mutations, possibly occurring in a single cell. A case is made for this being the
stem cell, but recent studies indicate that several stem cells may need to be so
involved, since early lesions appear to be polyclonal in derivation.
PMID- 10762445
TI - Globalization, coca-colonization and the chronic disease epidemic: can the
Doomsday scenario be averted?
AB - There are at present approximately 110 million people with diabetes in the world
but this number will reach over 220 million by the year 2010, the majority of
them with type 2 diabetes. Thus there is an urgent need for strategies to prevent
the emerging global epidemic of type 2 diabetes to be implemented. Tackling
diabetes must be part of an integrated program that addresses lifestyle related
disorders. The prevention and control of type 2 diabetes and the other major
noncommunicable diseases (NCDs) can be cost- and health-effective through an
integrated (i.e. horizontal) approach to noncommunicable diseases disease
prevention and control. With the re-emergence of devastating communicable
diseases including AIDS, the Ebola virus and tuberculosis, the pressure is on
international and regional agencies to see that the noncommunicable disease
epidemic is addressed. The international diabetes and public health communities
need to adopt a more pragmatic view of the epidemic of type 2 diabetes and other
noncommunicable diseases. The current situation is a symptom of globalization
with respect to its social, cultural, economic and political significance. Type 2
diabetes will not be prevented by traditional medical approaches; what is
required are major and dramatic changes in the socio-economic and cultural status
of people in developing countries and the disadvantaged, minority groups in
developed nations. The international diabetes and public health communities must
lobby and mobilize politicians, other international agencies such as UNDP,
UNICEF, and the World Bank as well as other international nongovernmental
agencies dealing with the noncommunicable diseases to address the socio-economic,
behavioural, nutritional and public health issues that have led to the type 2
diabetes and noncommunicable diseases epidemic. A multidisciplinary Task Force
representing all parties which can contribute to a reversal of the underlying
socio-economic causes of the problem is an urgent priority.
PMID- 10762446
TI - Physicians' use of plasma methylmalonic acid as a diagnostic tool.
AB - OBJECTIVES: To investigate physicians' reasons for requesting plasma
methylmalonic acid and their reactions to an increased concentration of plasma
methylmalonic acid. DESIGN: Study of medical records. SETTING: Three somatic
district hospitals in Denmark. SUBJECTS: Medical records of 198 patients with a
plasma methylmalonic acid measurement above the reference interval. Information
on diagnostic decisions was available for 177 patients. MAIN OUTCOME MEASURES:
Reasons for requesting plasma methylmalonic acid and the reactions to the finding
of elevated plasma methylmalonic acid. RESULTS: An explicit reason for requesting
plasma methylmalonic acid was stated in 57% of 198 examined medical records,
known or suspected anaemia being the most frequent reason. No further action was
taken in 109 (62%) of the 177 cases available for follow-up. Amongst the
remaining 68 patients, the finding of an increased plasma methylmalonic acid led
to diagnosis of cobalamin deficiency in 46 patients. Six patients with a markedly
increased plasma methylmalonic acid (above 0.99 micromol L-1) and clearly
decreased plasma cobalamins (below 200 pmol L-1) were not recognized as having
cobalamin deficiency. CONCLUSIONS: This lack of response to an increased plasma
methylmalonic acid raises an important question. Is the clinical response
inadequate, or is the connection between an increased level of plasma
methylmalonic acid and signs of clinical significant cobalamin deficiency less
clear?
PMID- 10762447
TI - Dietary and other non-pharmacological treatments in patients with drug-treated
hypertension and control subjects.
AB - OBJECTIVE: To study the nutrient intakes and other lifestyle patterns of drug
treated hypertensives and control subjects. DESIGN: A cross-sectional population
based epidemiological study. SETTING: The participating study subjects visited
the research laboratory of the Department of Internal Medicine of the University
of Oulu, Oulu, Finland. PARTICIPANTS: A total of 1045 Finnish men and women aged
40-60 years, of whom 716 (69%) completed 7-day food records. MAIN OUTCOME
MEASURES: Intakes of energy, protein, total fat, saturated, monounsaturated and
polyunsaturated fatty acids, carbohydrate, alcohol, fibre, calcium, magnesium,
potassium and sodium were assessed from 7-day food records. The study also
included measurements of blood pressure, blood glucose and plasma lipids, and
anthropometric variables. Information about alcohol consumption, smoking habits
and physical activity was collected by interviewing. RESULTS: Obesity was common
amongst the hypertensive subjects, whose body mass indices were significantly
higher than those of the control subjects. Only minor differences existed in the
energy intake levels and nutrient intakes of the hypertensive and control
cohorts, but the control subjects performed more physical activity than the
hypertensive subjects. The dietary recommendations concerning the intakes of
total and saturated fats, carbohydrate and fibre were poorly met by both the
hypertensive and the control subjects. Alcohol consumption was high amongst the
hypertensive men, especially amongst the smokers. CONCLUSIONS: Non
pharmacological treatment, including dietary management, of hypertensive patients
at high risk for cardiovascular complications seems still to be inadequate.
Additional well-focused efforts are needed to intensify the dietary treatment as
well as to reduce alcohol consumption and smoking amongst hypertensives.
PMID- 10762440
TI - The clonal origin and clonal evolution of epithelial tumours.
AB - While the origin of tumours, whether from one cell or many, has been a source of
fascination for experimental oncologists for some time, in recent years there has
been a veritable explosion of information about the clonal architecture of
tumours and their antecedents, stimulated, in the main, by the ready
accessibility of new molecular techniques. While most of these new results have
apparently confirmed the monoclonal origin of human epithelial (and other)
tumours, there are a significant number of studies in which this conclusion just
cannot be made. Moreover, analysis of many articles show that the potential
impact of such considerations as patch size and clonal evolution on
determinations of clonality have largely been ignored, with the result that a
number of these studies are confounded. However, the clonal architecture of
preneoplastic lesions provide some interesting insights --many lesions which
might have been hitherto regarded as hyperplasias are apparently clonal in
derivation. If this is indeed true, it calls into some question our hopeful
corollary that a monoclonal origin presages a neoplastic habitus. Finally, it is
clear, for many reasons, that methods of analysis which involve the
disaggregation of tissues, albeit microdissected, are far from ideal and we
should be putting more effort into techniques where the clonal architecture of
normal tissues, preneoplastic and preinvasive lesions and their derivative
tumours can be directly visualized in situ.
PMID- 10762448
TI - Bone mineral density and blood pressure in patients with asymptomatic
hyperparathyroidism. The Tromso Study.
AB - OBJECTIVE: To evaluate bone mineral density and blood pressure in asymptomatic
hyperparathyroidism. DESIGN: A case-control study. SETTING: The participants
obtained from an epidemiological survey in Tromso 1994-95, that included more
than 27 000 subjects. The re-examination in 1998 was performed at the University
Hospital of Tromso, Norway. Participants. Thirty-nine subjects with
hyperparathyroidism and 72 control subjects were studied. MAIN OUTCOME MEASURES:
Bone mineral density measurements of the lumbar spine and the proximal femur
(femoral neck, Ward's triangle, and trochanter). Systolic and diastolic blood
pressure. RESULTS: In the hyperparathyroidism group bone mineral density was
significantly lower measured at the lumbar spine (1.000 +/- 0.181 vs. 1.079 +/-
0. 194 g cm-2, mean +/- SD, P < 0.01) and at the femoral neck (0.806 +/- 0.121
vs. 0.852 +/- 0.141 g cm-2, P < 0.05). In the females, but not in the males,
blood pressure was significantly higher in the hyperparathyroidism group than in
the control group [systolic blood pressure 146.7 +/- 18.6 vs. 137.4 +/- 23.0 mmHg
(P < 0.05) and diastolic blood pressure 88.1 +/- 11.8 vs. 82.2 +/- 10.6 mmHg (P <
0. 05)]. In the females the number of subjects on antihypertensive medication was
significantly higher in the hyperparathyroidism group than in the control group
(32.1% and 16.6%, respectively, P < 0.01). CONCLUSIONS: Subjects with
asymptomatic hyperparathyroidism have moderately reduced bone mineral density. In
females with hyperparathyroidism there is an increase in blood pressure.
PMID- 10762449
TI - Does immigration contribute to decreasing CHD incidence? Coronary risk factors
among immigrants in Goteborg, Sweden.
AB - OBJECTIVES: To investigate if an increasing proportion of immigrants may have
contributed to the decreasing trend in coronary heart disease (CHD) in Sweden
during the last few decades and to analyse the cardiovascular risk factor pattern
in immigrants compared to Swedish-born subjects. POPULATION AND METHODS: CVD risk
factors were investigated within the framework of the WHO MONICA project. A
random sample of 1618 men and women aged 25-64 years responded to the invitation
to a screening procedure including questionnaires and physical and laboratory
examination. Data on myocardial infarctions (MI) were collected from the Goteborg
Myocardial Infarction Register. Data from the City Council secretariat were used
to estimate the number of immigrants in the total population. RESULTS: In 1995,
immigrants constituted 22.4% of the population between 25 and 64 years of age in
Goteborg. The incidence of MI in immigrants, 21.7%, was similar to that in
Swedish-born subjects. Non-Finnish immigrants reported more unemployment, low
physical activity during leisure time and psychological stress than Swedish
subjects. Immigrant men also smoked more. BMI and WHR were significantly higher
in immigrant women and Finnish immigrants had higher blood pressure than Swedes.
Total- and LDL-cholesterol were higher in Finnish men. HDL-cholesterol was
significantly lower and s-triglycerides significantly higher in non-Finnish
immigrants of both genders. CONCLUSION: The decreasing trend in CHD in Sweden
during the last few decades is not due to an increasing number of immigrants from
'low-risk countries'. On the contrary, the immigrants in the present study seem
to have a worse CVD risk factor profile than Swedes.
PMID- 10762451
TI - Introduction
PMID- 10762450
TI - The association between C-reactive protein on admission and mortality in patients
with acute myocardial infarction.
AB - OBJECTIVE: In patients presenting with acute myocardial infarction the
pathophysiologic and prognostic value of serum C-reactive protein is not well
defined. This study assessed the association between serum C-reactive protein
levels on admission and mortality in patients admitted because of acute
myocardial infarction. DESIGN: Retrospective cohort study. SETTING: Tertiary care
centre. PATIENTS: A total of 729 patients with acute myocardial infarction
admitted within a period of 3 years. MAIN OUTCOME MEASURES: C-reactive protein
levels on admission, cardiovascular risk factors and survival within the
observational period. RESULTS: Within the 3-year observational period, 118
patients died of a cardiovascular cause. With increasing serum C-reactive protein
levels (<0.5, 0.5 to <2, 2 to <5, 5-10 and >10 mg dL-1) mortality also increased
(14%, 19%, 20%, 39% and 28%, respectively). When controlling for the confounding
effect of age, thrombolytic treatment, the time interval between onset of pain
and admission, smoking, diabetes mellitus, hypercholesterolemia, hypertension,
and elevated creatine kinase on admission in a multivariate Cox regression model,
there was only a weak and nonsignificant association between increased serum C
reactive protein and the risk of death. CONCLUSIONS: Patients with elevated
concentrations of serum C-reactive protein admitted to the hospital because of
acute myocardial infarction are at an increased risk of dying. This association
is however, largely explained by other baseline variables, in particular by an
estimate of the duration of myocardial ischaemia. If C-reactive protein measured
by means of an ultra-sensitive assay is more suitable for risk stratification of
unselected patients with acute myocardial infarction, needs further study.
PMID- 10762452
TI - Changing concepts of atherogenesis.
AB - This review discusses three stages in the life history of an atheroma:
initiation, progression and complication. Recruitment of mononuclear leucocytes
to the intima characterizes initiation of the atherosclerotic lesion. Specific
adhesion molecules expressed on the surface of vascular endothelial cells mediate
leucocyte adhesion: the selectins and members of the immunoglobulin superfamily
such as vascular cell adhesion molecule-1 (VCAM-1). Once adherent, the leucocytes
enter the artery wall directed by chemoattractant chemokines such as macrophage
chemoattractant protein-1 (MCP-1). Modified lipoproteins contain oxidized
phospholipids which can elicit expression of adhesion molecule and cytokines
implicated in early atherogenesis. Progression of atheroma involves accumulation
of smooth muscle cells which elaborate extracellular matrix macromolecules. These
processes appear to result from an eventual net positive balance of growth
stimulatory versus growth inhibitory stimuli, including proteins (cytokines and
growth factors) and small molecules (e.g. prostanoids and nitric oxide). The
clinically important complications of atheroma usually involve thrombosis.
Arterial stenoses by themselves seldom cause acute unstable angina or acute
myocardial infarction. Indeed, sizeable atheroma may remain silent for decades or
produce only stable symptoms such as angina pectoris precipitated by increased
demand. Recent research has furnished new insight into the molecular mechanisms
that cause transition from the chronic to the acute phase of atherosclerosis.
Thrombus formation usually occurs because of a physical disruption of
atherosclerotic plaque. The majority of coronary thromboses result from a rupture
of the plaque's protective fibrous cap, which permits contact between blood and
the highly thrombogenic material located in the lesion's lipid core, e.g. tissue
factor. Interstitial collagen accounts for most of the tensile strength of the
plaque's fibrous cap. The amount of collagen in the lesion's fibrous cap depends
upon its rate of biosynthesis stimulated by factors released from platelets (e.g.
transforming growth factor beta or platelet-derived growth factor), but inhibited
by gamma interferon, a product of activated T cells found in plaques. Degradation
by specialized enzymes (matrix metalloproteinases) also influences the level of
collagen in the plaque's fibrous cap. Such studies illustrate how the application
of cellular and molecular approaches has fostered a deeper understanding of the
pathogenesis of atherosclerosis. This increased knowledge of the basic mechanisms
enables us to understand how current therapies for atherosclerosis may act.
Moreover, the insights derived from recent scientific advances should aid the
discovery of new therapeutic targets that would stimulate development of novel
treatments. Such new treatments could further reduce the considerable burden of
morbidity and mortality due to this modern scourge, and reduce reliance on costly
technologies that address the symptoms rather than the cause of atherosclerosis.
PMID- 10762453
TI - Modified LDL - trigger of atherosclerosis and inflammation in the arterial
intima.
AB - Atherosclerosis is characterized by chronic inflammation of an injured intima.
The pathological processes are initiated by accumulation of morphologically
distinct, modified forms of LDL, and followed by cellular infiltration and foam
cell formation. Activated intimal cells secrete enzymes and agents capable of
modifying LDL, and the modified lipids of LDL, in turn, are able to activate
intimal cells and to trigger various inflammatory signals. These processes can
initiate and maintain a vicious circle in the intima and lead to lesion
progression. In this review, we focus on the LDL modifications relevant to the
initial lipid accumulation and discuss their pro-inflammatory effects.
PMID- 10762454
TI - Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the
development of atherosclerosis.
AB - Extensive evidence suggests that humoral and cellular immune responses against
lipid peroxidation products occur in vivo and that they modulate the progression
of atherosclerosis. The biological significance of these immune responses is the
focus of this review. Lipid peroxidation generates reactive aldehydes and
oxidized phospholipids which form complex, immunogenic adducts with proteins or
other phospholipids. Autoantibodies against oxidative neoepitopes are present in
humans and other species and their titre may be an indicator of the extent of
atherosclerosis. Interventions boosting immune responses to oxidized LDL reduce
the progression of atherosclerosis in animal models. However, other interventions
inhibiting immune cells or signalling factors enhance atherogenesis, suggesting
that different elements of the immune system exert opposite effects. Evaluation
of the role of immune mechanisms in atherosclerosis is further complicated by the
fact that other chronic inflammatory conditions induce similar humoral immune
responses to oxidative neoepitopes, in particular oxidized phospholipids.
Naturally occurring antibodies cloned from atherosclerotic mice provide insights
into the nature of antigens formed in vivo and on biological effects of some
antibody populations. For example, antibodies to oxidized phospholipid adducts
inhibit macrophage uptake of oxidized LDL by blocking scavenger receptors.
Antibodies to oxidation-specific epitopes may also be suitable for non-invasive
diagnosis of atherosclerosis.
PMID- 10762455
TI - Autoantibodies to modified LDLs and other phospholipid-protein complexes as
markers of cardiovascular diseases.
AB - Recent studies have suggested that antiphospholipid antibodies contribute to the
development of atherothrombosis by enhancing atherogenesis and/or by interfering
with blood coagulation. The antigenic targets of antiphospholipid antibodies are
cardiolipin, oxidized LDL, beta2-glycoprotein I, or prothrombin. Oxidized LDL and
beta2-glycoprotein I are found in the atherosclerotic plaque and antibodies to
these proteins enhance in vitro the accumulation of modified LDL into
macrophages. Autoantibodies binding to modified LDL, cardiolipin and prothrombin
have been associated with atherosclerosis and its thrombotic complications in
sero-epidemiological studies. These autoantibodies can be used as markers of
atherosclerosis but their possible pathogenic role in the athero- and
thrombogenesis needs further studies.
PMID- 10762456
TI - Heterogeneity of autoantibodies against cardiolipin and oxidatively modified LDLs
revealed by human monoclonal antibodies.
AB - Human monoclonal antibodies against cardiolipin, native and oxidatively modified
LDL and against apoB100 were obtained by Epstein-Barr virus transformation of
peripheral blood mononuclear cells followed by cloning. The antibodies were used
to analyse the cross-reactivity between monoclonals with different specificities
and to study the repertoire of antibodies present in sera from patients.
Monoclonal antibodies selected for binding to cardiolipin were the least cross
reactive, whereas antibodies against different modifications of LDL frequently
also reacted with other modifications. Inhibition studies showed that serum
antibodies against cardiolipin and against oxidatively modified LDL were to a
different extent inhibited by the different monoclonal antibodies and thus
markedly heterogeneous.
PMID- 10762457
TI - Chlamydia pneumoniae in atherosclerosis.
AB - Chlamydia pneumoniae is currently the infectious agent most often associated with
the inflammation found in atherosclerosis. The seroepidemiological association
and the actual presence of pathogen in lesions has been confirmed in numerous
studies, in which technical difficulties seem to be the only limitation. Besides
animal experiments and intervention trials, we need information of possible
pathogenic mechanisms. Recently, several studies have suggested mechanisms by
which C. pneumoniae infection could participate in the development of
atherosclerosis.
PMID- 10762458
TI - Immunomodulation of atherosclerosis: myth and reality.
AB - Atherosclerosis is an inflammatory disease which displays features of immune
activation both locally and systemically. In the present review, we discuss the
evidence for immune activation in human disease and experimental models, and
survey candidate antigens associated with atherosclerosis. Studies of
atherosclerosis in genetic models of immunodeficiency are analysed, as well as
immunomodulating therapies and immunization protocols. Based on recent research,
it is concluded that immunomodulation represents an interesting approach to the
development of new prevention and treatment methods for atherosclerosis.
PMID- 10762459
TI - Could attacks of abdominal pain in cases of acute intermittent porphyria be due
to intestinal angina?
AB - Abdominal pain is by far the most serious symptom in attacks of acute
intermittent porphyria. Its cause is unknown. This case study suggests visceral
ischaemia as a possible cause of the abdominal pain. A 31-year-old woman with
recurrent bouts died during an attack; the autopsy revealed a 20-cm necrotic
gangrene in the ileum. A protracted intestinal vasospasm could have been the
immediate cause of death. It is discussed whether intestinal angina could be the
cause of the abdominal pain in acute intermittent porphyria.
PMID- 10762460
TI - Hematopoietic Abnormalities in Patients With Cancer.
PMID- 10762461
TI - Laboratory and Bone Marrow Evaluation in Patients With Cancer.
PMID- 10762462
TI - Anemia of Aging: A Model of Erythropoiesis in Cancer Patients.
PMID- 10762463
TI - The Physiologic Basis for the Pharmacologic Use of Recombinant Erythropoietin.
PMID- 10762464
TI - Erythropoietin and the Management of Anemia in Patients With Lung Cancer.
PMID- 10762466
TI - Diagnosis and Management of Anemia in Patients With the Myelodysplastic Syndrome.
PMID- 10762465
TI - The Use of Erythropoietin in Radiation Oncology.
PMID- 10762467
TI - Anemia in Multiple Myeloma and Its Management.
PMID- 10762468
TI - Anemia in Lymphoproliferative Disorders.
PMID- 10762469
TI - Tumor Susceptibility Genes.
PMID- 10762470
TI - Host-Tumor Interactions.
PMID- 10762471
TI - Signal Transduction Pathways in Growth Control and Oncogenesis.
PMID- 10762473
TI - The Epidemiology of Cancer in Florida.
PMID- 10762472
TI - Novel Natural Products and Other Anticancer Therapeutics: 1998.
PMID- 10762474
TI - Screening and Detection of Colorectal Cancer.
PMID- 10762475
TI - The Role of Specialized Genetic Counseling for the Patient at Risk for Breast
Cancer.
PMID- 10762476
TI - Efficacy of Detection Methods for Metastatic Gastrointestinal Cancers.
PMID- 10762477
TI - Preoperative Chemoradiation Therapy for Rectal Cancer.
PMID- 10762479
TI - Management of Hepatic Metastases.
PMID- 10762478
TI - Chemotherapy of Gastrointestinal Malignancies.
PMID- 10762480
TI - Hepatobiliary Cancer.
PMID- 10762481
TI - Gastric Cancer.
PMID- 10762482
TI - Esophageal Cancer.
PMID- 10762483
TI - Nursing Issues in Managing Skin Cancer in the Year 2000.
PMID- 10762484
TI - The Nurse's Role in Prostate Cancer Education: Prevention, Treatment, and
Rehabilitation.
PMID- 10762485
TI - Symptom Management in the Geriatric Patient.
PMID- 10762486
TI - Lung Cancer: The Nursing Challenge for the Next Millennium.
PMID- 10762487
TI - The Emerging Acceptance and Importance of Alternative Medical Therapies.
PMID- 10762488
TI - Diffusion-weighted MRI as an evolving standard of care in acute stroke.
PMID- 10762489
TI - Testing a test: a report card for DWI in acute stroke.
PMID- 10762490
TI - Weighing the evidence on DWI: caveat emptor.
PMID- 10762491
TI - Multispecialty consensus on diagnosis and treatment of headache.
PMID- 10762492
TI - The Websters' dictionary: the binification of medical and neurologic education.
PMID- 10762493
TI - Comparison of diffusion-weighted MRI and CT in acute stroke.
AB - OBJECTIVE: To compare diffusion-weighted MRI (DWI) and CT with respect to
accuracy of localizing acute cerebral infarction; sensitivity, specificity, and
interrater reliability for identifying more than one-third middle cerebral artery
(MCA) territory involvement; and correlation of acute lesion volume with final
infarct volume. METHOD: Nineteen consecutive stroke patients underwent CT and DWI
within 7 hours of stroke onset and a follow-up DWI examination 36 hours after
symptom onset, which served as the "gold standard" for lesion location and extent
of MCA involvement. Each scan was evaluated for acute ischemic lesions by two
experienced observers. After 30 days, T2-weighted MRI was obtained for assessment
of the final infarct volume. RESULTS: The acute CT and DWI scans were obtained on
average 2.6 and 5.1 hours after symptom onset. On DWI the acute lesion was
identified correctly in all instances and on CT it was identified correctly in 42
to 63% of patients. Sensitivity for detection of more than 33% MCA involvement
was better for DWI (57 to 86%) than for CT (14 to 43%), whereas specificity was
excellent for both. Interrater reliability was moderately good for both (kappa,
0.6 for DWI; 0.5 for CT). A positive correlation (r = 0.79; p = 0.001) existed
between lesion volume on acute DWI and final infarct volume, whereas no
correlation was found between CT volume and final infarct volume. CONCLUSION:
When compared with CT, DWI was more accurate for identifying acute infarction and
more sensitive for detection of more than 33% MCA involvement. In addition,
lesion volume on acute DWI, but not on acute CT, correlated strongly with final
infarct volume. Additional studies are required to demonstrate whether these
advantages of DWI are clinically relevant in the management of patients with
acute stroke.
PMID- 10762494
TI - Yield of diffusion-weighted MRI for detection of potentially relevant findings in
stroke patients.
AB - OBJECTIVE: To determine whether diffusion-weighted imaging (DWI) could identify
potentially clinically relevant findings in patients presenting more than 6 hours
after stroke onset when compared with conventional MRI. METHODS: MRI with both
conventional (T2 and proton density images) and echoplanar imaging (DWI and
apparent diffusion coefficient maps) was performed 6 to 48 hours after symptom
onset (mean, 27 hours) in 40 consecutive patients with acute stroke. All acute
lesions were identified first on conventional images, then on DWI, by a
neuroradiologist who was provided with the suspected lesion location, based on a
neurologist's examination before imaging. Abnormalities were rated as potentially
clinically relevant if they were detected only on DWI and 1) confirmed the acute
symptomatic lesion to be in a different vascular territory than suspected
clinically, 2) revealed multiple lesions in different vascular territories
suggestive of a proximal source of embolism, or 3) clarified that a lesion,
thought to be acute on conventional imaging, was not acute. RESULTS: The initial
clinical impression of lesion localization was incorrect in 12 patients (30%).
Clinically significant findings were detected by DWI alone in 19 patients (48%).
DWI demonstrated the symptomatic lesion in a different vascular territory than
suspected clinically or by conventional MRI in 7 patients (18%) and showed acute
lesions in multiple vascular distributions in 5 patients (13%). In 8 patients
(20%), DWI clarified that lesions thought to be acute on conventional MRI were
actually old. CONCLUSION: In patients imaged 6 to 48 hours after stroke onset,
DWI frequently provided potentially clinically relevant findings that were not
apparent on conventional MRI.
PMID- 10762495
TI - Body iron stores and early neurologic deterioration in acute cerebral infarction.
AB - BACKGROUND: Iron-dependent free radicals formation has been related to greater
damage in cerebral ischemia. The authors analyzed whether increased body iron
stores were associated with early neurologic worsening and excitatory amino acid
release in patients with acute ischemic stroke. METHODS: Ferritin, total iron,
and glutamate concentrations in plasma and CSF were measured on admission in 100
consecutive patients with a cerebral infarction of <24 hours' duration. The
authors diagnosed progressing stroke when the Canadian Stroke Scale score
decreased one or more points between admission and 48 hours. Cranial CT was
performed on admission and repeated on days 4 to 7 of hospitalization. RESULTS:
Ferritin concentrations in plasma (median 391, range 119 to 500 versus 148, 21 to
399 ng/mL) and in CSF (17.4, 6.8 to 82, versus 4.8, 0.6 to 14 ng/mL) were
significantly higher in the 45 patients with subsequent progressing stroke than
in those with nonprogressing stroke (p < 0.001). There was a positive correlation
between ferritin and glutamate concentrations in plasma (r = 0.81, p < 0.001) and
CSF (r = 0.64, p < 0.001). Plasma ferritin concentrations >275 ng/mL in plasma
(OR, 33.5; 95% CI, 4.7 to 235) and >11 ng/mL in CSF (OR, 11.4; 95% CI, 3. 1 to
41) were independently and significantly related to early neurologic worsening.
The effect was reduced by >60% after controlling for glutamate concentrations,
but remained significant. CONCLUSIONS: High plasma and CSF ferritin
concentrations within the first 24 hours from the onset of ischemic stroke are
associated with early neurologic deterioration. Increased body iron stores may
contribute to stroke progression by enhancing the cytotoxic mechanisms in
cerebral ischemia.
PMID- 10762496
TI - From spinal shock to spasticity: neuronal adaptations to a spinal cord injury.
AB - OBJECTIVE: To investigate the adaptational changes in excitability of spinal
neuronal circuits below the level of lesion from spinal shock to spasticity in
patients with spinal cord injury (SCI). METHODS: More than 6 months after an
acute SCI, clinical follow-up examinations were paralleled by electrophysiologic
recordings with tibial nerve stimulation (M-wave, F-wave, H-reflex, and flexor
reflex). RESULTS: During spinal shock, the loss of tendon tap reflexes and
flaccid muscle tone were associated with low persistence of F-waves and loss of
flexor reflexes, whereas H-reflexes were already elicitable. During the
transition to spasticity, the reappearance of tendon tap reflexes and muscle tone
and the occurrence of spasms was associated with the recovery of F-waves and
flexor reflex excitability, whereas the H-to-M ratio remained about stable over
months. At later stages (2 to 6 months after SCI) when clinical signs of
spasticity became established, the electrophysiologic measures showed little
change. In paraplegic patients, in contrast to tetraplegic patients, M-wave and
flexor reflex amplitudes even decreased. CONCLUSIONS: The late decrease in M-wave
and flexor reflex amplitude in paraplegic patients suggests a secondary
impairment/degeneration of premotoneuronal circuits and of motoneurons. The
divergent course of clinical signs of spasticity and their probable neuronal
correlates indicates the occurrence of non-neuronal changes contributing to
spasticity.
PMID- 10762497
TI - A multicenter randomized controlled trial of remacemide hydrochloride as
monotherapy for PD. Parkinson Study Group.
AB - BACKGROUND: Preclinical evidence suggests that manipulation of the glutamatergic
system may provide an alternative strategy for therapeutic intervention in PD.
Remacemide hydrochloride is a low affinity NMDA channel blocker that might
improve parkinsonian symptoms by modulating glutamatergic overactivity in the
basal ganglia or slow worsening by decreasing excitotoxicity. METHODS: The
authors performed a multicenter, randomized, double-blind, placebo-controlled,
parallel-group, dose-ranging study of remacemide in patients with early PD who
were not yet receiving levodopa or dopamine agonists. The primary objective was
to assess the short-term tolerability and safety of three dosage levels of
remacemide. Two hundred patients were randomized to receive either remacemide 150
mg, 300 mg, or 600 mg, or matching placebo daily for 5 weeks. RESULTS:
Significantly fewer patients receiving remacemide 600 mg daily were able to
tolerate 5 weeks of their assigned treatment on a BID schedule compared with
patients receiving placebo (64% versus 94%, p = 0.0002). Most patients who
experienced intolerable side effects on the BID schedule, however, could tolerate
the same daily dosage on a QID schedule. The most common adverse events were
dizziness and nausea. There were no serious adverse events or clinically
significant treatment-related changes in vital signs, laboratory values, or
electrocardiograms. There was no evidence of improvement in PD signs or symptoms
associated with remacemide monotherapy. CONCLUSION: Remacemide was generally well
tolerated and safe in this 5-week trial. There was no evidence for a symptomatic
effect of remacemide monotherapy in patients with early PD. Based on its
favorable safety profile and several animal studies, further studies of
remacemide are warranted as symptomatic therapy in levodopa-treated patients and
as a neuroprotective agent.
PMID- 10762498
TI - AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.
AB - OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole
proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian
signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and
dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA
subtype. The possible role of AMPA receptors, however, has not yet been examined.
METHODS: The authors compared the ability of an AMPA agonist (CX516) and a
noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and
levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated
parkinsonian monkeys received rising doses of each drug, first in monotherapy and
then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516
alone, as well as when combined with low-dose levodopa, did not affect motor
activity but induced dyskinesia. Moreover, following injection of the higher
doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p <
0.05). LY300164 potentiated the motor activating effects of low-dose levodopa,
increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose
levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa
induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor
upregulation may contribute to the expression of levodopa-induced dyskinesia.
Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or
in combination with NMDA antagonists, in the treatment of PD, by enhancing the
antiparkinsonian effects of levodopa without increasing and possibly even
decreasing levodopa-induced dyskinesia.
PMID- 10762500
TI - Access www.neurology.org now for full-text articles
PMID- 10762499
TI - A 10-year study of the incidence of and factors predicting dementia in
Parkinson's disease.
AB - OBJECTIVE: To compare the incidence of dementia in PD with that of a control
group without PD, and to assess the relationship between dementia and other
features of PD. METHODS: The authors recruited 83 patients with PD and 50
controls, all without dementia at initial assessment, and assessed them at
regular intervals over a maximum period of 122 months. Dementia was diagnosed
according to objective criteria, and included a judgment by researchers masked to
subject group and to variables putatively associated with dementia. RESULTS:
Seventeen patients fulfilled dementia criteria; no controls did so. The
cumulative proportion of PD patients becoming demented by 112 months was 0.38
(95% CI 0.20 to 0.55), or 42.6 cases per 1000 years of observation. Univariate
analyses showed that incident dementia in patients with PD was associated with
older age at entry into the study, greater severity of neurologic symptoms,
longer duration of PD, greater disability, and male sex. The association of age
at onset of PD with incident dementia was of only borderline significance.
Multivariate analysis found that age at entry into the study and severity of
motor symptoms were significant predictors of dementia but duration of PD and age
at onset of PD were not. CONCLUSIONS: Dementia in PD is likely to reflect
interaction of the neuropathology of the basal ganglia and age-related pathology.
The findings do not support the division of PD into early and late-onset cases.
PMID- 10762501
TI - Clinical and genetic study of familial Parkinson's disease in Tunisia.
AB - OBJECTIVE: To determine inheritance patterns and clinical characteristics of
familial PD (F-PD) in Tunisia. METHODS: Twenty-one index patients were selected
on the basis of typical PD and a family history of PD. The 21 families of the
index patients were visited at home, and clinical assessment of all available
relatives, a total of 133 individuals, was made. Extensive pedigree data detected
67 additional cases. We ascertained medical history, age, age at onset, first
sign at onset, course of the disease, dosage and duration of levodopa (LD)
treatment, and associated diseases. One patient from each family was hospitalized
to confirm response to LD by evaluation of untreated and treated Unified
Parkinson's Disease Rating Scale scores. The sex ratio, transmission pattern,
ancestral secondary cases, and segregation ratio (SR) were determined by pedigree
analysis. RESULTS: Eighty-eight patients were analyzed (44 men and 44 women; mean
age at onset, 39.8 +/- 14.4 years). Pedigree analysis showed 10 single-generation
(SG) families (i.e., all affected members belonging to 1 generation) and 11
multigenerational (MG) families (i.e., affected members spanning >1 generation).
Parental consanguinity was more frequent in SG families than in MG families. The
SR in SG families was 0.23 +/- 0.05, compatible with autosomal recessive (AR)
inheritance. Analysis of MG pedigrees showed autosomal dominant (AD) inheritance
with reduced penetrance in 9 of 10 families. Age at onset was younger than in
sporadic PD. Intrafamilial variability of age at onset, symptom of onset, and
clinical course was observed. There was no difference in clinical characteristics
between SG and MG families apart from dystonic foot at onset, which was more
frequent in SG families. CONCLUSIONS: First, F-PD is clinically similar to
sporadic PD apart from younger age at onset. Second, there is intrafamilial and
interfamilial variability of all clinical features. Third, F-PD in Tunisia is
genetically heterogenous with at least two inheritance patterns: AD and AR.
PMID- 10762502
TI - Periodic limb movements in sleep: state-dependent excitability of the spinal
flexor reflex.
AB - OBJECTIVE: To test the hypothesis that periodic limb movements (PLMs) are related
to spinal flexor reflexes (FRs), the authors compared the state-dependent changes
in FR excitability in 10 patients with restless legs syndrome (RLS) and PLMs with
those from matched controls. BACKGROUND: PLM is a disorder of motor control
during sleep, frequently occurring in RLS. Clinically, PLMs resemble spinal FRs.
METHODS: FRs were obtained by electrically stimulating the medial plantar nerve
and recording from antagonist leg and thigh muscles bilaterally. RESULTS:
Compared with controls, patients had significantly increased spinal cord
excitability, as indicated by lower threshold and greater spatial spread of the
FR, which was more prominent during sleep. Multiple late responses were seen
during sleep in all patients and in some controls at higher threshold. The most
prominent of these responses had a very long duration and a latency range of 250
to 800 msec, and because of its close temporal relationship to the FR stimulus,
the authors considered it was a late, high-threshold component of the FR (FR3).
The authors also found a similarity between the pattern of muscle recruitment and
spatial spread of late components of the FR and those of spontaneous PLMs.
CONCLUSIONS: The results support the hypothesis that PLMs in RLS and FRs share
common spinal mechanisms and suggest that PLMs may result from enhanced spinal
cord excitability in RLS patients. Because dopaminergic mechanisms are involved
in spinal FR control, the results are consistent with the current view that RLS
is a disorder of dopaminergic function.
PMID- 10762503
TI - Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and
vascular dementia.
AB - BACKGROUND: Case reports and clinical observations suggest that fluctuating
cognition (FC) is common in the major dementias, particularly dementia with Lewy
bodies (DLB), where it is one of three core clinical diagnostic features.
OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of
FC in dementia using clinical, attentional, and EEG markers. METHOD: - A total of
155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35
elderly controls) received clinical evaluation for FC using a semiquantified
measure applied by experienced clinicians and 90-second cognitive choice reaction
time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also
received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients
with DLB had a greater prevalence and severity of FC than did patients with AD or
VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive
and EEG trials demonstrated that FC occurs on a second-to-second basis in
patients with DLB. Patients with VaD had a higher prevalence of FC than did those
with AD, although the profile of FC was different from that expressed by DLB
cases. Optimal cutoff values on the clinical scale achieved good discrimination
between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD;
sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity
77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that
FC is significantly more common and severe in DLB than in other major dementias.
The periodicity of FC is different in DLB and VaD cases, with important
implications for the underlying causal mechanisms and for differential diagnosis.
PMID- 10762504
TI - Functional MR evaluation of temporal and frontal language dominance compared with
the Wada test.
AB - OBJECTIVE: To evaluate the reliability of temporal and frontal functional MRI
(fMRI) activation for the assessment of language dominance, as compared with the
Wada test. PATIENTS AND METHODS: Ten patients with temporal lobe epilepsy were
studied using blood oxygen level dependent fMRI and echoplanar imaging (1.5-T).
Three tasks were used: semantic verbal fluency, covert sentence repetition, and
story listening. Data were analyzed using pixel by pixel autocorrelation and
cross-correlation. fMRI laterality indices were defined for several regions of
interest as the ratio (L - R)/(L + R), L being the number of activated voxels in
the left hemisphere and R in the right hemisphere. Wada laterality indices were
defined as the difference in the percentages of errors in language tests between
left and right carotid injections. RESULTS: Semantic verbal fluency: The
asymmetry of frontal activation was correlated with Wada laterality indices. The
strongest correlation was observed in the precentral/middle frontal
gyrus/inferior frontal sulcus area. Story listening: The asymmetry of frontal,
but not temporal, activation was correlated with Wada laterality indices. Covert
sentence repetition: No correlation was observed. CONCLUSIONS: There was a good
congruence between hemispheric dominance for language as assessed with the Wada
test and fMRI laterality indices in the frontal but not in the temporal lobes.
The story listening and the covert sentence repetition tasks increased the
sensitivity of detection of posterior language sites that may be useful for brain
lesion surgery.
PMID- 10762505
TI - Sleep reactivity during acute nasal CPAP in obstructive sleep apnea syndrome.
AB - OBJECTIVE: To measure the readjustments of sleep macro- and microstructure in
patients with obstructive sleep apnea syndrome (OSAS) after acute nasal
continuous positive airway pressure (NCPAP) treatment. BACKGROUND: The
conventional polysomnographic analysis (macrostructure of sleep) does not
necessarily provide the best measures of sleep disruption associated with OSAS.
In contrast, microstructural methods of analyzing sleep (i.e., arousals and
cyclic alternating pattern) may improve evaluation of patients with OSAS. METHOD:
- Ten patients with OSAS were monitored polygraphically before and during the
first night of NCPAP therapy. The results were compared with those of 10 age- and
sex-matched controls without sleep-related breathing disorders. Each nocturnal
recording was followed by daytime observation using the multiple sleep latency
test and Visual Analogue Scale (VAS). RESULTS: The first night of ventilatory
therapy was characterized by a remarkable expansion of stages 3 and 4 and of REM
sleep. In addition, NCPAP suppressed the presence of cyclic alternating pattern
(CAP) in REM sleep and induced an impressive rebound of arousals and of certain
CAP variables-i.e., CAP rate, CAP time, number of CAP cycles-which dropped well
below the physiologic values expressed by controls. A normal duration of phases A
and B was re-established starting the first treatment night. When we matched
sleep variables with the indices of daytime function, a significant correlation
emerged only between the variations of CAP rate and VAS scores. In particular,
improvement of daytime sleepiness was less evident when the ventilatory-induced
drop of CAP rate was more pronounced. CONCLUSIONS: The application of CAP
variables to the microstructural analysis of sleep may expand our knowledge
regarding sleep and respiration.
PMID- 10762506
TI - Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of
PrP gene.
AB - OBJECTIVES: To determine the contribution of methionine/valine (Met/Val)
polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic
pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob
disease. BACKGROUND: Creutzfeldt-Jakob disease is a transmissible spongiform
encephalopathy characterized by a conformational change of PrP and a variety of
PrP deposits in the brain, some of which aggregate into amyloid plaques. METHODS:
The authors semiquantitatively assessed neuropathologic lesions and performed PrP
immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died
in France between 1994 and 1998. RESULTS: Met/Met cases (mild lesions mostly
involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits,
no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in
the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with
Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and
distinct neuropathology: severe lesions heavily involving the hippocampal
formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits,
rare amyloid plaques). The course of Val/Val patients younger than age 55 was
particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the
pathology, suggesting a distinct variety. CONCLUSIONS: Polymorphism at codon 129
modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype
enhances the production of proteinase-resistant PrP, and the Met/Val genotype
facilitates its aggregation into amyloid plaques.
PMID- 10762507
TI - Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1
in children.
AB - BACKGROUND: "Unidentified bright objects" (UBOs) have been observed as areas of
increased T2-weighted signal intensity on MRI in 43% to 93% of children with
neurofibromatosis 1 (NF1). Because of this high frequency and the fact that the
NIH diagnostic criteria often do not permit diagnosis of NF1 in early childhood,
UBOs have been proposed as an additional diagnostic criterion. METHODS: The
authors examined the sensitivity and specificity of UBOs for NF1 in 19 affected
children and 19 age-matched controls. Eleven of the control patients had CNS
pathology that might be classified as UBOs on MRI scan. The authors measured the
agreement in recognition of UBOs between two pediatric neuroradiologists who
independently examined the MRI studies of these patients. They also assessed the
effect of adding UBOs to the NIH diagnostic criteria on ability to diagnose NF1
in young patients. RESULTS: Sensitivity and specificity of UBOs for NF1 averaged
97% and 79%, respectively. Agreement between the two radiologists was 84%
overall, but varied greatly from one brain region to another. Adding UBOs as a
diagnostic criterion permitted the diagnosis of 30% of young patients with NF1
mutations who do not meet the existing NIH diagnostic criteria for NF1. The value
of including UBOs is less in older patients because a larger proportion of them
meet the existing diagnostic criteria. CONCLUSIONS: UBOs are difficult to
identify with certainty and occur in children with suspected CNS disorders who do
not have NF1, but they tend to occur in different brain regions. UBOs may be more
useful for diagnosis of NF1 in young children if they can be defined precisely
and if only the cerebellum, brainstem, and basal ganglia are considered.
PMID- 10762508
TI - Neuropsychological testing may predict early progression of asymptomatic
adrenoleukodystrophy.
AB - OBJECTIVES: To investigate the correlation between neuropsychological and MRI
findings in children with the childhood cerebral (CCALD) and asymptomatic forms
of X-linked adrenoleukodystrophy (ALD) and to identify early cognitive markers
that may predict disease progression in asymptomatic children with ALD.
BACKGROUND: The few published neuropsychological studies on CCALD suggest a
correlation between the pattern of cognitive deficit and lesion site; however,
neuropsychological performance in asymptomatic children with ALD has not been
investigated. METHODS: The authors assessed cognitive function and cerebral MRI
findings in seven CCALD and eight asymptomatic ALD children. RESULTS: The CCALD
children's cognitive skills were severely compromised, especially Wechsler and
executive functions. Visual perception, short-term memory, and language were
generally preserved, except that naming was severely impaired. All had extensive
posterior white matter deterioration. The asymptomatic children had relatively
intact neuropsychological performance, but their verbal fluency was compromised
and naming severely impaired. All except one had mild white matter alterations.
For all the children, the majority of neuropsychological test performance
correlated significantly with extent of white matter lesions. CONCLUSIONS: The
pattern of cognitive deterioration in children with CCALD and the significant
correlation of neuropsychological test performance with extent of white matter
lesions indicate a white matter dementia similar to that observed in adults with
demyelinating diseases. The deficits found in asymptomatic children, despite
their normal intelligence, suggest that careful neuropsychological investigation
can identify early signs of malfunction. These may be markers of disease
progression useful for selecting children for bone marrow transplant, although
this will require confirmation by prospective longitudinal studies.
PMID- 10762509
TI - Lack of anticipatory gaze-orienting responses in patients with right brain
damage.
AB - OBJECTIVE: To study eye movements during cervical proprioceptive stimulation by
passive body rotation in darkness, with the head held stationary, in patients
with right brain damage and hemineglect. BACKGROUND: At very low frequency, this
stimulation is reported to produce an illusion of head turning in space and eye
deviations directed opposite to trunk rotation (in the direction of the illusory
head rotation). METHODS: Ten normal subjects and seven patients with unilateral
cerebral lesions (five right brain-damaged patients with mild to moderate
visuospatial neglect, two left brain-damaged patients without neglect) were
included in the study. Subjects were seated on a rotating chair. Stimuli
consisted of slow sinusoidal passive trunk rotations (+/-30 degrees, 0.01 Hz)
while the head was fixed in space. RESULTS: Eye movements directed opposite to
trunk rotation were typical for normal subjects and for left brain-damaged
patients. In contrast, all right brain-damaged patients showed either eye
movements in the direction of trunk rotation or no eye deviations at all.
CONCLUSION: This result could characterize a lack of anticipatory coordinating
gaze behavior in patients with right brain damage.
PMID- 10762510
TI - IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barre
syndrome.
AB - OBJECTIVE: Guillain-Barre syndrome (GBS) is characterized by nerve infiltration
of leukocytes and autoantibodies of the immunoglobulin G (IgG) isotype directed
against nerve constituents. Leukocyte receptors for IgG (FcgammaR) constitute an
important link between the humoral and cellular parts of the immune system and
confer potent cellular effector functions to myelin-directed antibodies. Three
FcgammaR subclasses exhibit genetically determined biallelic functional
polymorphisms (FcgammaRIIa: R131 versus H131; FcgammaRIIIa: 158V versus 158F;
FcgammaRIIIb: NA1 versus NA2) that determine efficacy of the cellular immune
response. To study the relevance of these polymorphisms for susceptibility and
severity of GBS, we compared FcgammaR genotype distributions in GBS patients with
those in controls. METHODS: Genomic DNA was isolated from whole blood of 31
randomly selected patients with GBS and 187 healthy blood donors. Genotypes of
the three polymorphic FcgammaR genes were determined by PCR. RESULTS: FcgammaRIIa
H131 homozygosity was significantly increased in patients as compared with
healthy controls (OR 2.45; 95% CI 1.12 to 5.36; p = 0.037). Furthermore,
FcgammaRIIa-H131 homozygous GBS patients had a higher risk for severe disease
than did patients with other genotypes (OR 18.57; 95% CI 1.95 to 176.49; p =
0.007). CONCLUSION: FcgammaRIIa allotypes capable of initiating efficient
cellular effector functions are associated with increased risk for GBS and a more
severe disease course. FcgammaR alleles may constitute novel genetic risk markers
for GBS.
PMID- 10762511
TI - The muscle mitogen-activated protein kinase is altered in sporadic inclusion body
myositis.
AB - OBJECTIVE: To examine the origin of hyperphosphorylated proteins within the
vacuolated myofibers in sporadic inclusion body myositis (s-IBM) and search for
dysregulated intracellular protein phosphorylation. BACKGROUND: s-IBM is
morphologically characterized by primary endomysial inflammation and vacuolated
myofibers containing tubulofilaments that originate from cytoskeletal proteins.
Mitogen-activated protein kinases (MAPKs) play a role in regulating
phosphorylation and maintaining the stability of the cytoskeletal architecture.
METHODS: Muscle biopsies from seven patients with s-IBM and 15 controls were
examined for the expression of the active components of the various MAPKs,
including p44/42MAPK, p38MAPK, p46JNK1, p54JNK2, and p54JNK3, using
immunocytochemistry and Western blot analysis. The expression of selected
phosphorylated components was also examined in the same specimens. RESULTS: In s
IBM, but not the disease controls, the vacuolated muscle fibers express active
p42MAPK but not JNK or p38MAPK. Western blots of cell lysates confirmed the
hyperexpression of p42MAPK and demonstrated a novel 35 kD phosphoprotein.
Antibodies against phosphoepitopes of the 35 kD protein preferentially
immunostained antigens within the vacuolated muscle fibers of s-IBM but not
disease controls. CONCLUSION: In s-IBM, there is increased p42MAPK activation and
abnormal intracellular protein phosphorylation with selective accumulation of a
35 kD phosphoprotein within the vacuolated fibers. Although the hyperexpression
of 35kD protein may represent cytoskeletal by-products due to heightened p42MAPK
activation, its abundant expression only in s-IBM implies that
hyperphosphorylated myofibrillar proteins may be involved in the primary disease
process.
PMID- 10762512
TI - Vascular endothelial growth factor in CSF: a biological marker for carcinomatous
meningitis.
AB - OBJECTIVE: To determine the value of vascular endothelial growth factor (VEGF) in
CSF as a marker for carcinomatous meningitis (CM). METHODS: The concentration of
VEGF was measured by ELISA in matched samples of CSF and serum collected from 162
patients. These included patients with solid tumors with CM (n = 11) or brain
metastases without concomitant CM (n = 12), paraneoplastic neurologic syndromes
(n = 4), viral (n = 15) and bacterial (n = 20) meningitis, and a variety of non
neoplastic and noninfectious neurologic diseases (n = 100). Using CSF/serum
albumin ratios, the VEGF index was calculated to estimate the proportion of
intrathecally produced VEGF. Immunohistochemical staining for VEGF was performed
in a brain metastasis from a mammary carcinoma associated with CM. RESULTS: High
VEGF levels (median 6,794.8 pg/mL) were found in CSF of all patients with CM,
whereas VEGF levels in matched sera were comparable to other disease groups. In
patients with CM, the concentration of VEGF in CSF decreased significantly
following antineoplastic treatment. In CSF samples from patients with brain
metastases without concomitant CM, VEGF was not detectable. Median VEGF
concentration in CSF from patients with acute bacterial meningitis was 38.6
pg/mL, with only 9 of these 17 patients showing detectable VEGF levels in CSF.
The VEGF indices in patients with bacterial meningitis were significantly lower
than in tumor patients with CM (<22.8 versus >62.3), suggesting that the
proportion of intrathecally produced VEGF is much higher in patients with CM as
compared with patients with bacterial meningitis. Patients without neoplastic or
infectious neurologic disorders consistently showed VEGF levels in CSF below the
assay detection limit of 25 pg/mL. Immunohistochemistry revealed strong
cytoplasmic staining for VEGF in a metastatic lesion from breast cancer
infiltrating the meninges. CONCLUSION: In patients with carcinomatous meningitis,
significant amounts of VEGF are released into CSF. This study yields preliminary
evidence that VEGF in CSF may be a useful biologic marker for both the diagnosis
and evaluation of treatment response in carcinomatous meningitis.
PMID- 10762514
TI - Activate your online subscription
PMID- 10762513
TI - Rapid immunologic diagnosis of classic late infantile neuronal ceroid
lipofuscinosis.
AB - OBJECTIVE: To establish a new method for rapid diagnosis of late infantile
neuronal ceroid lipofuscinosis (LINCL, CLN2) using specific polyclonal antibodies
against the CLN2 gene product. METHODS: Cells and tissues were obtained from five
patients with LINCL, two with variant type NCL, three with other lysosomal
storage diseases, and eight control subjects. Two antibodies were raised against
N- and C-terminal peptide fragments of the normal product of the CLN2 gene. The
authors examined the possibility of diagnosis of LINCL with immunostaining and
immunoblotting using specific antibodies made of the recently identified
defective gene in LINCL. RESULTS: Immunoreactivity with these antibodies showed
the absence or marked reduction of CLN2 immunoreactivity in the lymphocytes,
lymphoblasts, and fibroblasts of all five patients with LINCL examined.
CONCLUSIONS: These results indicate the usefulness of this diagnostic method
based on the changes in CLN2 immunoreactivity. This relatively simple, specific,
and cost-effective method is a promising diagnostic tool for this disease,
although additional studies are necessary.
PMID- 10762515
TI - Clinical characteristics of pathologically proved cholesterol emboli to the
brain.
AB - Cholesterol emboli (CE) to the brain are an important but often unrecognized
cause of stroke. The authors reviewed 29 cases of brain CE identified on autopsy.
Most patients were elderly (mean age, 74 years) and presented with encephalopathy
and acute renal failure. Ten patients developed symptoms spontaneously, 19 after
a procedure involving manipulation of the aorta. Brain imaging revealed multiple,
small ischemic lesions and border zone infarcts in 11 of 17 patients. Pathology
in most patients demonstrated multiple CE mixed with emboli of other types.
PMID- 10762516
TI - Intra-arterial thrombolysis for the treatment of perioperative childhood
cardioembolic stroke.
AB - Local intra-arterial lysis using recombinant tissue plasminogen activator (rTPA)
was performed in a 6 and 2/3-year-old patient with major cardioembolic ischemic
stroke 48 hours after intracardiac surgery. Selective application of 2.5 mg rTPA
(0.11 mg/kg body weight) resulted in recanalization of the occluded cerebral
vasculature with good neurologic recovery.
PMID- 10762517
TI - Long-term outcome of cognition and functional health after cerebral venous sinus
thrombosis.
AB - The authors examined cognition and functional health of 57 patients with sinus
thrombosis 1 year or more after enrollment in a randomized trial of anticoagulant
treatment or placebo. Eight patients died and two declined participation. Of the
remaining 47 patients, 16 (35%) had cognitive impairments, 3 (6%) were dependent,
19 (40%) had symptoms that led to restrictions in lifestyle, and 19 (40%) could
not resume their previous level of economic activity. Outcome after sinus
thrombosis may be less favorable than reported previously, and was not
significantly influenced by treatment.
PMID- 10762518
TI - Detection of ventricular enlargement in patients at the earliest clinical stage
of MS.
AB - The aim of this study was to determine whether atrophy could be detected at the
earliest clinical stages of MS. Patients were selected from a 1-year follow-up
MRI study of clinically isolated syndromes. Nine patients who developed MS were
compared with eight matched patients who had no further symptoms. Significant
ventricular enlargement occurred in the group that developed MS but not in the
other group. Our findings show that atrophy, albeit mild, can be detected early
in the course of MS.
PMID- 10762519
TI - Emotional outbursts and post-traumatic stress disorder during intracarotid
amobarbital procedure.
AB - Severe emotional outbursts (SEOs) during intracarotid amobarbital procedures
(IAP) rarely jeopardize preoperative language and memory testing. Four of four
patients (100%) with outbursts had experienced significant emotional trauma
(three were raped and one witnessed a decapitation), compared with 26 of 546
patients (4.8%) without outbursts (chi2 = 69.8, p < 0. 0001). Evocative
injections were ipsilateral to seizure focus. IAP may disrupt emotional balance
in some traumatized patients. Counseling may prevent SEOs.
PMID- 10762520
TI - A new mtDNA mutation associated with a progressive encephalopathy and cytochrome
c oxidase deficiency.
AB - The authors describe a novel pathogenic G5540A transition in the mitochondrial
transfer RNA (tRNA)Trp gene of a sporadic encephalomyopathy characterized by
spinocerebellar ataxia. Clinical features also included neurosensorial deafness,
peripheral neuropathy, and dementia. Biochemistry revealed a severe reduction of
cytochrome c oxidase (COX) activity. Single-fiber PCR demonstrated higher levels
of mutant genomes in COX-negative ragged red fibers than in normal fibers. These
findings confirm that COX is more susceptible than other respiratory chain
complexes to mutations in the mitochondrial tRNATrp gene.
PMID- 10762521
TI - Cranial nerve involvement in CMT disease type 1 due to early growth response 2
gene mutation.
AB - Mutations in the gene coding for the Schwann cell transcription factor early
growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain
development, have been observed in few cases of inherited neuropathy. The authors
describe a unique combination of cranial nerve deficits in one member of a
Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding
further supports the role of EGR2 in cranial nerve development.
PMID- 10762522
TI - Abnormalities in CSF concentrations of ferritin and transferrin in restless legs
syndrome.
AB - CSF and serum were obtained from 16 patients with idiopathic restless legs
syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had
lower CSF ferritin levels (1. 11 +/- 0.25 ng/mL versus 3.50 +/- 0.55 ng/mL; p =
0.0002) and higher CSF transferrin levels (26.4 +/- 5.1 mg/L versus 6.71 +/- 1.6
mg/L; p = 0.018) compared with control subjects. There was no difference in serum
ferritin and transferrin levels between groups. The presence of reduced ferritin
and elevated transferrin levels in CSF is indicative of low brain iron in
patients with idiopathic RLS.
PMID- 10762523
TI - Septo-optic dysplasia plus: a spectrum of malformations of cortical development.
AB - The authors describe three children with septo-optic dysplasia (SOD)-plus: SOD
and an associated malformation of cortical development. All three children had
developmental delay, and two of the children had significant associated motor
deficits. The associated cortical malformations with SOD include a spectrum of
disorders of neuronal organization, not limited, as previously described, to
schizencephaly. SOD-plus should be suspected in children with SOD and
developmental delay.
PMID- 10762525
TI - CNS demyelination from zinc toxicity?
PMID- 10762524
TI - Early and severe presentation of autosomal dominant Emery-Dreifuss muscular
dystrophy (EMD2).
PMID- 10762526
TI - gamma-hydroxybutyric acid for alcohol-sensitive myoclonus with dystonia.
PMID- 10762527
TI - PCV salvage chemotherapy for recurrent primary CNS lymphoma.
PMID- 10762528
TI - Consent issues in the management of cerebrovascular diseases.
PMID- 10762529
TI - Fatigue in MS: cross-sectional correlation with brain MRI.
PMID- 10762530
TI - Ibuprofen treatment versus gradual introduction of interferon beta-1b in patients
with MS.
PMID- 10762531
TI - Parkinson's disease in twins.
PMID- 10762532
TI - Catalepsy after stroke.
PMID- 10762533
TI - Ask the doctor. I had a heart attack last year, and afterwards learned that my
homocysteine level is elevated. I wanted to start taking vitamins to lower it,
but before I make myself swallow another two or three pills per day, is there any
proof vitamins will make me live longer?
PMID- 10762534
TI - Ask the doctor. I read in the paper about a manufacturer that recalled some heart
valves. I had surgery a year ago to replace my mitral valve. How can I tell if
this is a problem for me?
PMID- 10762535
TI - The season of suicide.
PMID- 10762536
TI - Prostate cancer: events before birth may affect lifelong risk.
PMID- 10762537
TI - C-reactive protein and heart attack risk.
PMID- 10762538
TI - Disruption of a novel imprinted zinc-finger gene, ZNF215, in Beckwith-Wiedemann
syndrome.
AB - The genetics of Beckwith-Wiedemann syndrome (BWS) is complex and is thought to
involve multiple genes. It is known that three regions on chromosome 11p15
(BWSCR1, BWSCR2, and BWSCR3) may play a role in the development of BWS. BWSCR2 is
defined by two BWS breakpoints. Here we describe the cloning and sequence
analysis of 73 kb containing BWSCR2. Within this region, we detected a novel zinc
finger gene, ZNF215. We show that two of its five alternatively spliced
transcripts are disrupted by both BWSCR2 breakpoints. Parts of the 3' end of
these splice forms are transcribed from the antisense strand of a second zinc
finger gene, ZNF214. We show that ZNF215 is imprinted in a tissue-specific
manner.
PMID- 10762540
TI - Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10
truncating mutations and expression in developing brain.
AB - Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a
rare neurocristopathy that results from the absence of melanocytes and intrinsic
ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal
recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an
autosomal dominant condition when SOX10 mutations are involved. We report on
three unrelated WS4 patients with growth retardation and an as-yet-unreported
neurological phenotype with impairment of both the central and autonomous nervous
systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three
patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients
and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype
is relevant to the brain expression of SOX10 during human embryonic and fetal
development. Indeed, the expression of SOX10 in human embryo was not restricted
to neural-crest-derived cells but also involved fetal brain cells, most likely of
glial origin. These data emphasize the important role of SOX10 in early
development of both neural-crest-derived tissues, namely melanocytes, autonomic
and enteric nervous systems, and glial cells of the central nervous system.
PMID- 10762539
TI - Effects of cystic fibrosis and congenital bilateral absence of the vas deferens
associated mutations on cystic fibrosis transmembrane conductance regulator
mediated regulation of separate channels.
AB - The protein defective in cystic fibrosis (CF), the CF transmembrane-conductance
regulator (CFTR), functions as an epithelial chloride channel and as a regulator
of separate ion channels. Although the consequences that disease-causing
mutations have on the chloride-channel function have been studied extensively,
little is known about the effects that mutations have on the regulatory function.
To address this issue, we transiently expressed CFTR-bearing mutations associated
with CF or its milder phenotype, congenital bilateral absence of the vas
deferens, and determined whether mutant CFTR could regulate outwardly rectifying
chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first
nucleotide-binding domain (NBD1), DeltaF508, functioned as a chloride channel but
did not regulate ORCCs. However, CFTR bearing disease-associated mutations in
other domains retained both functions, regardless of the associated phenotype.
Thus, a relationship between loss of CFTR regulatory function and disease
severity is evident for NBD1, a region of CFTR that appears important for
regulation of separate channels.
PMID- 10762541
TI - Coding and noncoding variation of the human calcium-channel beta4-subunit gene
CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.
AB - Inactivation of the beta4 subunit of the calcium channel in the mouse
neurological mutant lethargic results in a complex neurological disorder that
includes absence epilepsy and ataxia. To determine the role of the calcium
channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human
disorders, we screened for mutations in small pedigrees with familial epilepsy
and ataxia. The premature-termination mutation R482X was identified in a patient
with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino
acids containing part of an interaction domain for the alpha1 subunit. The
missense mutation C104F was identified both in a German family with generalized
epilepsy and praxis-induced seizures and in a French Canadian family with
episodic ataxia. These coding mutations were not detected in 255 unaffected
control individuals (510 chromosomes), and they may be considered candidate
disease mutations. The results of functional tests of the truncated protein R482X
in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant
for inactivation of the cotransfected alpha1 subunit. Further studies will be
required to evaluate the in vivo consequences of these mutations. We also
describe eight noncoding single-nucleotide substitutions, two of which are
present at polymorphic frequency, and a previously unrecognized first intron of
CACNB4 that interrupts exon 1 at codon 21.
PMID- 10762542
TI - Localization of the Fanconi anemia complementation group D gene to a 200-kb
region on chromosome 3p25.3.
AB - Fanconi anemia (FA) is a rare autosomal recessive disease manifested by bone
marrow failure and an elevated incidence of cancer. Cells taken from patients
exhibit spontaneous chromosomal breaks and rearrangements. These breaks and
rearrangements are greatly elevated by treatment of FA cells with the use of DNA
cross-linking agents. The FA complementation group D gene (FANCD) has previously
been localized to chromosome 3p22-26, by use of microcell-mediated chromosome
transfer. Here we describe the use of noncomplemented microcell hybrids to
identify small overlapping deletions that narrow the FANCD critical region. A 1.2
Mb bacterial-artificial-chromosome (BAC)/P1 contig was constructed, bounded by
the marker D3S3691 distally and by the gene ATP2B2 proximally. The contig
contains at least 36 genes, including the oxytocin receptor (OXTR), hOGG1, the
von Hippel-Lindau tumor-suppressor gene (VHL), and IRAK-2. Both hOGG1 and IRAK-2
were excluded as candidates for FANCD. BACs were then used as probes for FISH
analyses, to map the extent of the deletions in four of the noncomplemented
microcell hybrid cell lines. A narrow region of common overlapping deletions
limits the FANCD critical region to approximately 200 kb. The three candidate
genes in this region are TIGR-A004X28, SGC34603, and AA609512.
PMID- 10762544
TI - Characteristics and frequency of germline mutations at microsatellite loci from
the human Y chromosome, as revealed by direct observation in father/son pairs.
AB - A number of applications of analysis of human Y-chromosome microsatellite loci to
human evolution and forensic science require reliable estimates of the mutation
rate and knowledge of the mutational mechanism. We therefore screened a total of
4,999 meioses from father/son pairs with confirmed paternity (probability >/=99.
9%) at 15 Y-chromosomal microsatellite loci and identified 14 mutations. The
locus-specific mutation-rate estimates were 0-8. 58x10-3, and the average
mutation rate estimates were 3.17x10-3 (95% confidence interval [CI] 1.89-4.94x10
3) across 8 tetranucleotide microsatellites and 2.80x10-3 (95% CI 1.72-4.27x10-3)
across all 15 Y-chromosomal microsatellites studied. Our data show a mutational
bias toward length increase, on the basis of observation of more repeat gains
than losses (10:4). The data are in almost complete agreement with the stepwise
mutation model, with 13 single-repeat changes and 1 double-repeat change.
Sequence analysis revealed that all mutations occurred in uninterrupted
homogenous arrays of >/=11 repeats. We conclude that mutation rates and
characteristics of human Y-chromosomal microsatellites are consistent with those
of autosomal microsatellites. This indicates that the general mutational
mechanism of microsatellites is independent of recombination.
PMID- 10762543
TI - Association between the surfactant protein A (SP-A) gene locus and respiratory
distress syndrome in the Finnish population.
AB - Respiratory-distress syndrome (RDS) in the newborn is a major cause of neonatal
mortality and morbidity. Although prematurity is the most-important risk factor
for RDS, the syndrome does not develop in many premature infants. The main cause
of RDS is a deficiency of pulmonary surfactant, which consists of phospholipids
and specific proteins. The genes underlying susceptibility to RDS are
insufficiently known. The candidate-gene approach was used to study the
association between the surfactant protein A (SP-A) gene locus and RDS in the
genetically homogeneous Finnish population. In the present study, 88 infants with
RDS and 88 control infants that were matched for degree of prematurity, prenatal
glucocorticoid therapy, and sex were analyzed for SP-A genotypes. We show that
certain SP-A1 alleles (6A2 and 6A3) and an SP-A1/SP-A2 haplotype (6A2/1A0) were
associated with RDS. The 6A2 allele was overrepresented and the 6A3 allele was
underrepresented in infants with RDS. These associations were particularly strong
among small premature infants born at gestational age <32 wk. In infants
protected from RDS (those that had no RDS, despite extreme prematurity and lack
of glucocorticoid therapy), compared with infants that had RDS develop despite
having received glucocorticoid therapy, the frequencies of 6A2 (.22 vs.71), 6A3
(.72 vs.17), 6A2/1A0 (.17 vs.68), 6A3/1A1 (.39 vs.10), and 6A3/1A2 (.28 vs.06) in
the two groups, respectively, were strikingly different. According to the results
of conditional logistic-regression analysis, diseases associated with premature
birth did not explain the association between the odds of a particular homozygous
SP-A1 genotype (6A2/6A2 and 6A3/6A3) and RDS. In the population evaluated in the
present study, SP-B intron 4 variant frequencies were low and had no detectable
association with RDS. We conclude that the SP-A gene locus is an important
determinant for predisposition to RDS in premature infants.
PMID- 10762545
TI - Persistent heteroplasmy of a mutation in the human mtDNA control region:
hypermutation as an apparent consequence of simple-repeat expansion/contraction.
AB - In the genealogical and phylogenetic analyses that are reported here, we obtained
evidence for an unusual pattern of mutation/reversion in the human mitochondrial
genome. The cumulative results indicate that, when there is a T-->C polymorphism
at nt 16189 and a C-->T substitution at nt 16192, there is an extremely high rate
of reversion (hypermutation) at the latter site. The apparent reversion rate is
sufficiently high that there is persistent heteroplasmy at nt 16192 in maternal
lineages and at the phylogenetic level, a situation that is similar to that
observed for the rapid expansion/contraction of simple repeats within the control
region. This is the first specific instance in which the mutation frequency at
one site in the D-loop is markedly influenced by the local sequence "context."
The 16189 T-->C polymorphism lengthens a (C:G)n simple repeat, which then
undergoes expansion and contraction, probably through replication slippage. This
proclivity toward expansion/contraction is more pronounced when there is a C
residue, rather than a T, at nt 16192. The high T-->C reversion frequency at nt
16192 apparently is the result of polymerase misincorporation or slippage during
replication, the same mechanism that also causes the expansion/contraction of
this simple-repeat sequence. In addition to the first analysis of this
mitochondrial hypermutation process, these results also yield mechanistic
insights into the expansion/contraction of simple-repeat sequences in mtDNA.
PMID- 10762546
TI - Equivalence of single- and multilocus markers: power to detect linkage with
composite markers derived from biallelic loci.
AB - The reintroduction of biallelic markers, now in the form of single-nucleotide
polymorphisms (SNPs), has again raised concerns about the practicality of the use
of markers with low heterozygosity for genomic screening for complex traits, even
if thousands of such markers are available. Like the early blood-group markers
(e.g., Rh and MNS), tightly linked biallelic SNPs can be combined into composite
markers with heterozygosity similar to that of short-tandem-repeat polymorphisms.
The assumptions that underlie the equivalence between single-locus multiallelic
and composite markers are presented. We used computer simulation to determine the
power of the Haseman-Elston test for linkage with composite markers when not all
of these assumptions hold. The Genometric Analysis Simulation Program was used to
simulate continuous and discrete traits, one single-locus four-allele marker, and
six biallelic markers. We studied composite markers created from pairs, trios,
and quartets of biallelic markers in nuclear families and in independent sib
pairs. The power to detect linkage with a two-point approach for composite
markers and with a multipoint approach that incorporated all six biallelic
markers was compared with that for a single-locus, four-allele reference marker.
Although the power to detect linkage with a single biallelic marker was
considerably less than that of the reference marker, the power to detect linkage
with two- and three-locus composite markers was quite similar to that of the
reference marker. The power to detect linkage with four-locus composite markers
was similar to that of a multipoint approach.
PMID- 10762547
TI - Power of linkage versus association analysis of quantitative traits, by use of
variance-components models, for sibship data.
AB - Optimal design of quantitative-trait loci (QTL) mapping studies requires a
precise understanding of the power of QTL linkage versus QTL association
analysis, under a range of different conditions. In this article, we investigate
the power of QTL linkage and association analyses for simple random sibship
samples, under the variance-components model proposed by Fulker et al. After a
brief description of an extension of this variance-components model, we show that
the powers of both linkage and association analyses are crucially dependent on
the proportion of phenotypic variance attributable to the QTL. The main
difference between the two tests is that, whereas the power of association is
directly related to the QTL heritability, the power of linkage is related more
closely to the square of the QTL heritability. We also describe both how the
power of linkage is attenuated by incomplete linkage and incomplete marker
information and how the power of association is attenuated by incomplete linkage
disequilibrium.
PMID- 10762548
TI - A unified sampling approach for multipoint analysis of qualitative and
quantitative traits in sib pairs.
AB - Recent advances in molecular biology have enhanced the opportunity to conduct
multipoint mapping for complex diseases. Concurrently, one sees a growing
interest in the use of quantitative traits in linkage studies. Here, we present a
multipoint sib-pair approach to locate the map position (tau) of a trait locus
that controls the observed phenotype (qualitative or quantitative), along with a
measure of statistical uncertainty. This method builds on a parametric
representation for the expected identical-by-descent statistic at an arbitrary
locus, conditional on an event reflecting the sampling scheme, such as affected
sib pairs, for qualitative traits, or extreme discordant (ED) sib pairs, for
quantitative traits. Our results suggest that the variance about tau&d4;, the
estimator of tau, can be reduced by as much as 60%-70% by reducing the length of
intervals between markers by one half. For quantitative traits, we examine the
precision gain (measured by the variance reduction in tau&d4;) by genotyping
extremely concordant (EC) sib pairs and including them along with ED sib pairs in
the statistical analysis. The precision gain depends heavily on the residual
correlation of the quantitative trait for sib pairs but considerably less on the
allele frequency and exact genetic mechanism. Since complex traits involve
multiple loci and, hence, the residual correlation cannot be ignored, our finding
strongly suggests that one should incorporate EC sib pairs along with ED sib
pairs, in both design and analysis. Finally, we empirically establish a simple
linear relationship between the magnitude of precision gain and the ratio of the
number of ED pairs to the number of EC pairs. This relationship allows
investigators to address issues of cost effectiveness that are due to the need
for phenotyping and genotyping subjects.
PMID- 10762549
TI - Composite statistics for QTL mapping with moderately discordant sibling pairs.
AB - Extreme discordant sibling-pair (EDSP) designs have been shown in theory to be
very powerful for mapping quantitative-trait loci (QTLs) in humans. However,
their practical applicability has been somewhat limited by the need to phenotype
very large populations to find enough pairs that are extremely discordant. In
this paper, we demonstrate that there is also substantial power in pairs that are
only moderately discordant, and that designs using moderately discordant pairs
can yield a more practical balance between phenotyping and genotyping efforts.
The power we demonstrate for moderately discordant pairs stems from a new
statistical result. Statistical analysis in discordant-pair studies is generally
done by testing for reduced identity by descent (IBD) sharing in the pairs. By
contrast, the most commonly-used statistical methods for more standard QTL
mapping are Haseman-Elston regression and variance-components analysis. Both of
these use statistics that are functions of the trait values given IBD information
for the pedigree. We show that IBD sharing statistics and "trait value given IBD"
statistics contribute complementary rather than redundant information, and thus
that statistics of the two types can be combined to form more powerful tests of
linkage. We propose a simple composite statistic, and test it with simulation
studies. The simulation results show that our composite statistic increases power
only minimally for extremely discordant pairs. However, it boosts the power of
moderately discordant pairs substantially and makes them a very practical
alternative. Our composite statistic is straightforward to calculate with
existing software; we give a practical example of its use by applying it to a
Genetic Analysis Workshop (GAW) data set.
PMID- 10762550
TI - Power comparison of parametric and nonparametric linkage tests in small
pedigrees.
AB - When the mode of inheritance of a disease is unknown, the LOD-score method of
linkage analysis must take into account uncertainties in model parameters. We
have previously proposed a parametric linkage test called "MFLOD," which does not
require specification of disease model parameters. In the present study, we
introduce two new model-free parametric linkage tests, known as "MLOD" and
"MALOD." These tests are defined, respectively, as the LOD score and the
admixture LOD score, maximized (subject to the same constraints as MFLOD) over
disease-model parameters. We compared the power of these three parametric linkage
tests and that of two nonparametric linkage tests, NPLall and NPLpairs, which are
implemented in GENEHUNTER. With the use of small pedigrees and a fully
informative marker, we found the powers of MLOD, NPLall, and NPLpairs to be
almost equivalent to each other and not far below that of a LOD-score analysis
performed under the assumption the correct genetic parameters. Thus, linkage
analysis is not much hindered by uncertain mode of inheritance. The results also
suggest that both parametric and nonparametric methods are suitable for linkage
analysis of complex disorders in small pedigrees. However, whether these results
apply to large pedigrees remains to be answered.
PMID- 10762551
TI - Detection of the signature of natural selection in humans: evidence from the
Duffy blood group locus.
AB - The Duffy blood group locus, which encodes a chemokine receptor, is characterized
by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O allele, which
corresponds to the absence of Fy antigen on red blood cells, is at or near
fixation in most sub-Saharan African populations but is very rare outside Africa.
The FST value for the FY*O allele is the highest observed for any allele in
humans, providing strong evidence for the action of natural selection at this
locus. Homozygosity for the FY*O allele confers complete resistance to vivax
malaria, suggesting that this allele has been the target of selection by
Plasmodium vivax or some other infectious agent. To characterize the signature of
directional selection at this locus, we surveyed DNA sequence variation, both in
a 1.9-kb region centered on the FY*O mutation site and in a 1-kb region 5-6 kb
away from it, in 17 Italians and in a total of 24 individuals from five sub
Saharan African populations. The level of variation across both regions is two-
to threefold lower in the Africans than in the Italians. As a result, the pooled
African sample shows a significant departure from the neutral expectation for the
number of segregating sites, whereas the Italian sample does not. The FY*O allele
occurs on two major haplotypes in three of the five African populations. This
finding could be due to recombination, recurrent mutation, population structure,
and/or mutation accumulation and drift. Although we are unable to distinguish
among these alternative hypotheses, it is likely that the two major haplotypes
originated prior to selection on the FY*O mutation.
PMID- 10762552
TI - An optimized probe set for the detection of small interchromosomal aberrations by
use of 24-color FISH.
AB - The rapid spread of the use of new 24-color karyotyping techniques has preceded
their standardization. This is best documented by the fact that the exact
resolution limits have not yet been defined. Indeed, it is shown here that a
substantial proportion of interchromosomal aberrations will be missed by all
multicolor karyotyping systems currently in use. We demonstrate that both the
sensitivity and the specificity of 24-color karyotyping critically depend on the
fluorochrome composition of chromosomes involved in an interchromosomal
rearrangement. As a solution, we introduce a conceptual change in probe labeling.
Seven-fluorochrome sets that overcome many of the current limitations are
described, and examples of their applications are shown. The criteria presented
here for an optimized probe-set design and for the estimation of resolution
limits should have important consequences for pre- and postnatal diagnostics and
for research applications.
PMID- 10762553
TI - Linkage of a gene for familial hypobetalipoproteinemia to chromosome 3p21.1-22.
AB - Familial hypobetalipoproteinemia (FHBL) is an apparently autosomal dominant
disorder of lipid metabolism characterized by less than fifth percentile age- and
sex-specific levels of apolipoprotein beta (apobeta) and low-density lipoprotein
cholesterol. In a minority of cases, FHBL is due to truncation-producing
mutations in the apobeta gene on chromosome 2p23-24. Previously, we reported on a
four-generation FHBL kindred in which we had ruled out linkage of the trait to
the apobeta gene. To locate other loci containing genes for low apobeta levels in
the kindred, a genomewide search was conducted. Regions on 3p21.1-22 with two
point LOD scores >1.5 were identified. Additional markers were typed in the
region of these signals. Two-point LOD scores in the region of D3S2407 increased
to 3.35 at O = 0. GENEHUNTER confirmed this finding with an nonparametric
multipoint LOD score of 7.5 (P=.0004). Additional model-free analyses were
conducted with the square root of the apobeta level as the phenotype. Results
from the Loki and SOLAR programs further confirmed linkage of FHBL to 3p21.1-22.
Weaker linkage to a region near D19S916 was also indicated by Loki and SOLAR.
Thus, a heretofore unidentified genetic susceptibility locus for FHBL may reside
on chromosome 3.
PMID- 10762554
TI - The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1.
AB - We studied a large consanguineous Anatolian family with children who exhibited
hydranencephaly associated with microcephaly. The children were severely
affected. This novel genetic disorder is autosomal recessive. We used
autozygosity mapping to identify a locus at chromosome 16p13.3-12.1; it has a LOD
score of 4.11. The gene locus is within a maximal 11-cM interval between markers
D16S497 and D16S672 and within a minimal critical region of 8 cM between markers
D16S748 and D16S490.
PMID- 10762555
TI - Evidence for a new Graves disease susceptibility locus at chromosome 18q21.
AB - Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as
a complex multigenic trait. By using a single microsatellite marker at each
locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and
IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This
showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6
marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the
investigation of the IDDM6 locus was extended by genotyping 11 microsatellite
markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with
autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib
pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker
D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak
NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type
1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which
suggests that this locus may have a role in several forms of autoimmunity.
PMID- 10762556
TI - Genomewide search and genetic localization of a second gene associated with
autosomal dominant branchio-oto-renal syndrome: clinical and genetic
implications.
AB - Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical
fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder
with variable clinical manifestations. The most common features of BOR syndrome
are branchial, hearing, and renal anomalies. However, many affected subjects have
been observed with branchial-cleft anomalies and hearing loss but without renal
anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to
question whether the BOR and BO syndromes are allelic or whether they represent
distinct genetic entities. We identified a very large extended family whose
members had branchial and hearing anomalies associated with commissural lip pits
that segregated in an autosomal dominant fashion. Using a genomewide search
strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at
recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757
in the genetic region of chromosome 1q31. This is the first report of linkage for
a second gene associated with BOR syndrome. The findings have important clinical
implications and will provide insight into the genetic basis of BOR syndrome.
PMID- 10762557
TI - Complement factor H gene mutation associated with autosomal recessive atypical
hemolytic uremic syndrome.
PMID- 10762559
TI - Evolution of hepatitis B virus polymerase gene sequence during famciclovir
therapy for chronic hepatitis B.
AB - Prolonged administration of nucleoside analogues for chronic hepatitis B may
result in the emergence of hepatitis B viral polymerase mutants. To gain insight
into the mechanism involved in the virus's resistance to famciclovir, the amino
acid sequences of the terminal protein and reverse-transcriptase (RT) domains of
the viral polymerase were determined during therapy among 28 patients. The
antiviral response was independent of viral genotypes, and nonresponse to
famciclovir was associated with a complex variability of the RT domain. No
mutation in the YMDD motif was observed, whereas an L528M mutation was clearly
selected by famciclovir treatment in 2 patients, as well as 14 novel mutations in
7 patients. Clone sequence analysis of the RT domains of patients undergoing
retreatment with famciclovir and/or lamivudine showed the selection of a
preexisting drug-resistant mutant in one case and indicated that sequential
antiviral therapy may allow the rapid selection of resistant strains.
PMID- 10762560
TI - Use of herpes simplex virus (HSV) type 1 ISCOMS 703 vaccine for prophylactic and
therapeutic treatment of primary and recurrent HSV-2 infection in guinea pigs.
AB - The effect of subunit vaccination on the incidence and severity of primary and
recurrent genital herpes was investigated in the female guinea pig model of
herpes simplex virus (HSV) type 2 genital infection. After prophylactic
immunization with zwitterionic detergent-solubilized HSV-1 glycoproteins
formulated with alhydrogel or as immunostimulating complex particles, significant
reductions in the incidence and severity of primary herpetic illness were
observed in both vaccinated groups compared with immunization-naive controls.
There was a significant reduction in the incidence of spontaneous herpetic
recurrences after administration of HSV-1 antigens formulated as
immunostimulatory complexes to guinea pigs in a prophylactic mode (P<.01).
Increased levels of both postimmunization and postchallenge ELISA and
neutralizing antibodies were significant correlates of protection against primary
herpetic disease in a prophylactic scenario. However, no correlation was observed
between elevated ELISA or neutralizing antibody levels and protection against
recurrent disease following prophylactic or therapeutic administration of HSV-1
subunit vaccines.
PMID- 10762561
TI - The relationship between T cell proliferative responses and plasma viremia during
treatment of human immunodeficiency virus type 1 infection with combination
antiretroviral therapy.
AB - The relationship between human immunodeficiency virus (HIV) type 1 replication
and CD4+ T cell function was examined. T lymphocyte proliferation in response to
both HIV-1 antigens and recall antigens was measured in HIV-1-infected
individuals before and after they received highly active antiretroviral therapy
(HAART). No correlation was observed between baseline viral load or CD4+ T cell
count and the T cell proliferative response to HIV-1 Gag. Suppression of viremia
was not associated with an increase in T cell proliferative responses. Emergence
of viral replication during short periods of intermittent therapy promoted
generalized activation of T helper lymphocytes, manifested by increased T cell
proliferative responses to HIV-1 Gag and recall antigens. Recovery of CD4+ T cell
responses occurred in some individuals who initiated HAART years after infection
and who were intermittently adherent to drug treatment. Thus, CD4+ T cell
responses can sometimes be regenerated if viral load is suppressed to allow some
immune recovery and if antigenic stimulation is later provided.
PMID- 10762562
TI - Clarithromycin or rifabutin alone or in combination for primary prophylaxis of
Mycobacterium avium complex disease in patients with AIDS: A randomized, double
blind, placebo-controlled trial. The AIDS Clinical Trials Group 196/Terry Beirn
Community Programs for Clinical Research on AIDS 009 Protocol Team.
AB - The efficacy and safety of clarithromycin and rifabutin alone and in combination
for prevention of Mycobacterium avium complex (MAC) disease were compared in 1178
patients with AIDS who had < or =100 CD4 T cells/microL in a randomized, double
blind, placebo-controlled trial. MAC disease occurred in 9%, 15%, and 7% of those
randomized to clarithromycin or rifabutin alone or in combination, respectively;
time-adjusted event rates per 100 patient-years (95% confidence interval [CI])
were 6.3 (4.2-8.3), 10.5 (7.8-13.2), and 4. 7 (2.9-6.5). Risk of MAC disease was
reduced by 44% with clarithromycin (risk ratio [RR], 0.56; 95% CI, 0.37-0.84;
P=.005) and by 57% with combination therapy (RR, 0.43; 95% CI, 0.27-0.69; P=.
0003), versus rifabutin. Combination therapy was not more effective than
clarithromycin (RR, 0.79; 95% CI, 0.48-1.31; P=.36). Of those in whom
clarithromycin or combination therapy failed, 29% and 27% of MAC isolates,
respectively, were resistant to clarithromycin. There were no survival
differences. Clarithromycin and combination therapy were more effective than
rifabutin for prevention of MAC disease, but combination therapy was associated
with more adverse effects (31%; P<.001).
PMID- 10762563
TI - A pneumococcal capsular polysaccharide vaccine induces a repertoire shift with
increased VH3 expression in peripheral B cells from human immunodeficiency virus
(HIV)-uninfected but not HIV-infected persons.
AB - The molecular mechanism of pneumococcal vaccine failure in human immunodeficiency
virus (HIV)-infected persons is not fully understood. A polymerase chain reaction
ELISA was used to determine the proportion of peripheral IgG, IgA, and IgM CD19
positive B cells expressing 6 immunoglobulin heavy-chain variable region (VH)
subgroups before and 7 days after pneumococcal vaccination of 12 HIV-infected and
12 HIV-uninfected subjects. Significant postvaccination increases in the
expression of the VH3 subgroup by IgG and IgA and a greater serologic response to
vaccination were observed in the HIV-uninfected group. In contrast, the HIV
infected group had reduced prevaccination IgG VH3 and a postvaccination increase
in IgG VH5. These results demonstrate that pneumococcal vaccination changes the
pattern of B cell VH gene expression and support the concept that aberrant VH3
expression may translate into a poor antipneumococcal response in the setting of
HIV infection.
PMID- 10762564
TI - A pneumococcal protein that elicits interleukin-8 from pulmonary epithelial
cells.
AB - To understand how neutrophils are recruited to the lung in pneumococcal
pneumonia, the ability of pneumococcal components to elicit the chemokine
interleukin (IL)-8 from monolayers of cultured human type II cells was assessed.
Heat-killed clinical and laboratory strains of Streptococcus pneumoniae and
secreted proteins from exponentially growing pneumococci elicited significant
quantities of IL-8 from A549 cells. All strains that elicited IL-8 production
secreted a protein ( approximately 90 kDa) that comigrated on SDS-PAGE with a C3
binding protein previously identified in S. pneumoniae. As little as 7 pmol of
the purified 90-kDa protein readily elicited levels of IL-8 production equivalent
to those obtained with 1 U of IL-1alpha. Supernatant proteins and heat-killed
cells of an isogenic mutant that failed to produce the C3-binding protein
elicited significantly less IL-8 than did supernatant proteins or heat-killed
cells of the parent strain. These results implicate the C3-binding protein of S.
pneumoniae in a novel pathway of pulmonary inflammation.
PMID- 10762565
TI - Biomaterial-associated persistence of Staphylococcus epidermidis in pericatheter
macrophages.
AB - Biomaterial surfaces may be modified to reduce bacterial adhesion. The
susceptibility in mice to Staphylococcus epidermidis infection in tissue
surrounding the commonly used catheter materials-silicon elastomer (SE),
polyamide (PA), and their surface-modified polyvinylpyrrolidone (PVP)-grafted
derivatives, SE-PVP and PA-PVP, respectively-was assessed. Abscesses developed
around SE-PVP. Around SE, PA, and PA-PVP catheters, no signs of infection were
observed, although mice carrying PA-PVP developed septicemia after 14-21 days. S.
epidermidis was cultured from the tissue surrounding PA-PVP segments. Cells
around PA-PVP segments containing large numbers of bacteria were identified as
macrophages by use of immunohistochemistry and electron microscopy. This
persistence of intracellular bacteria was also observed around SE-PVP, SE, and PA
catheters, although to a lesser extent. The cytokine profiles around the 4
materials were different. Implanted biomaterial induces an inflammatory response
favorable to the persistence of S. epidermidis. Intracellular persistence of
bacteria inside macrophages may be a pivotal process in the pathogenesis of
biomaterial-associated infection.
PMID- 10762566
TI - Morphine increases susceptibility to oral Salmonella typhimurium infection.
AB - This study examined the effect of morphine on oral infection with virulent
Salmonella typhimurium. Animals were treated with a 75-mg slow-release morphine
pellet followed by inoculation with salmonellae. Morphine markedly sensitized
mice to oral infection, as assessed by survival, mean survival time, and colony
culture. By 24 h after Salmonella inoculation, morphine-treated mice had a 105
fold difference in number of organisms in the Peyer's patches, compared with
controls. The opioid antagonist naltrexone significantly blocked Salmonella
colonization in Peyer's patches and reduced Salmonella burden in other organs,
indicating that morphine acts at least in part via an opioid receptor-mediated
pathway. The data show that morphine markedly potentiates Salmonella infection at
the gastrointestinal portal of entry and enhances subsequent dissemination of
Salmonella organisms. The results have implications for potentiating
gastrointestinal opportunistic infections in intravenous drug abusers and in
opioid-medicated postsurgical patients.
PMID- 10762567
TI - Seroprevalence and ethnic differences in Helicobacter pylori infection among
adults in the United States.
AB - The seroprevalence of Helicobacter pylori infection was examined in the adult US
population and among different ethnic groups. Stored sera from 7465 adult
participants in the first phase of the third National Health and Nutritional
Examination Survey (1988-1991) were tested with a sensitive and specific IgG
ELISA, to diagnose infection. Seroprevalence of H. pylori among all participants
was 32. 5%. This increased with age, from 16.7% for persons 20-29 years old to
56.9% for those > or =70 years old. Age-adjusted prevalence was substantially
higher among non-Hispanic blacks (52.7%) and Mexican Americans (61.6%) than among
non-Hispanic whites (26.2%). After controlling for age and other associated
factors, the odds ratios relative to non-Hispanic whites decreased for non
Hispanic blacks, from 3.9 (95% confidence interval [CI], 3.1-4.9) to 3.3 (95% CI,
2. 6-4.2), and for Mexican Americans, from 6.3 (95% CI, 4.8-8.3) to 2.3 (95% CI,
1.6-3.5). The high prevalence of H. pylori infection among non-Hispanic blacks
and Mexican Americans is partially explained by other factors associated with
infection.
PMID- 10762568
TI - cagE is a virulence factor associated with Helicobacter pylori-induced duodenal
ulceration in children.
AB - This study was undertaken to determine whether infection with Helicobacter pylori
strains that contain the cagE gene was associated with duodenal ulceration in
children. The presence of flaA, cagA, and cagE genes was determined by polymerase
chain reaction in H. pylori previously cultured from 29 children. Twelve (92%) of
13 children with duodenal ulcers were infected with cagE-positive isolates,
compared with only 5 (31%) of 16 with gastritis alone (P<.01). Infection of
gastric cells in tissue culture by cagE-positive H. pylori resulted in greater
increments in interleukin-8 levels compared with cagE-negative strains (2.3+/-0.1
vs. 1.3+/-0.2 ng/mL in AGS cells [P<.005]; 1.5+/-0.3 vs. 0.5+/-0.2 ng/mL in KATO
III cells [P<.05]). H. pylori-containing cagE was associated with the presence of
duodenal ulceration in children. Enhanced chemokine production after infection
with cagE-positive H. pylori could affect disease outcome.
PMID- 10762569
TI - Analysis of Moraxella catarrhalis by DNA typing: evidence for a distinct
subpopulation associated with virulence traits.
AB - Two DNA typing methods, probe-generated restriction fragment length polymorphism
analysis and single-adapter amplified fragment length polymorphism analysis, were
used to study the genetic relationships among 90 Moraxella catarrhalis strains.
Both methods were found to be highly concordant, generating a dendrogram with 2
main branches. The division of the M. catarrhalis population into 2 subspecies
was supported by analysis of the 16S rRNA sequences. Both beta-lactamase-positive
and beta-lactamase-negative strains were found in all main branches, suggesting
horizontal transfer of the beta-lactamase gene. In contrast, 2 virulence traits,
complement resistance and adherence to epithelial cells, were strongly associated
with 1 of the 2 subspecies. The branch depth suggested that complement-resistant
adherent strains diverged from a common ancestor more recently than did
complement-sensitive nonadherent strains. These findings suggest the existence of
subpopulations of M. catarrhalis that differ in virulence, and they may have
implications for vaccine development.
PMID- 10762570
TI - Aberrantly low transferrin receptor expression on human monocytes is associated
with nonpermissiveness for Legionella pneumophila growth.
AB - Growth of Legionella pneumophila within human monocytes is iron dependent. A
person with monocytes uniquely nonpermissive to L. pneumophila growth was
identified whose monocytes expressed an abnormally low number of transferrin
receptors in the nonactivated state, similar to the typically low level expressed
in the interferon-gamma-activated state. The monocytes failed to up-regulate
transferrin receptor expression appropriately in response to iron-transferrin.
After treatment for chronic periodontal disease, the subject's monocytes
converted to a permissive state. In contrast to the nonpermissive state, the
permissive monocytes had normal transferrin receptor expression and up-regulated
transferrin receptor expression appropriately in response to iron-transferrin.
Thus, a nonpermissive state for L. pneumophila intracellular multiplication is
associated with low levels of transferrin receptor expression in nonactivated
monocytes and with an inability to up-regulate transferrin receptor expression in
response to iron-transferrin. This nonpermissive state may be related to chronic
inflammatory conditions such as periodontal disease.
PMID- 10762571
TI - Opsonic potential, protective capacity, and sequence conservation of the
Treponema pallidum subspecies pallidum Tp92.
AB - By means of a differential screening technique, a 92-kDa antigen, designated
Tp92, was identified from Treponema pallidum subspecies pallidum. This protein is
similar in sequence to the protective surface antigens D15 from Haemophilus
influenzae and Oma87 from Pasteurella multocida. Amino acid sequence analyses
revealed a cleavable N-terminal signal sequence and predicted the outer membrane
location for Tp92. In support of this, antiserum raised against recombinant Tp92
promotes opsonization and phagocytosis of T. pallidum by rabbit macrophages, and
anti-Tp92 reactivity is absent from washed treponemal preparations presumed to be
lacking outer membranes. The Tp92 amino acid sequence is 95.5%-100% conserved
among 11 strains representing 4 pathogenic treponemes, and immunization with
recombinant Tp92 partially protected rabbits from subsequent T. pallidum
challenge. These results demonstrate that Tp92 is an invariant, immunoprotective
antigen that may be present on the surface of T. pallidum and may represent a
potential vaccine candidate for syphilis.
PMID- 10762572
TI - A hospital-based prevalence survey of bloodstream infections in febrile patients
in Malawi: implications for diagnosis and therapy.
AB - The etiology of bloodstream infections (BSIs) in febrile (> or =37.5 degrees C)
adults (> or =18 years old) in one Malawi hospital were determined during August
and September 1997. After clinical evaluation, blood was drawn for comprehensive
culture, human immunodeficiency virus (HIV) type 1 testing, and malaria smear. Of
233 patients, 173 (74%) were HIV-1 infected, and 70 (30%) had BSI. BSI pathogens
included 25 (33%) Streptococcus pneumoniae and 21 (28%) Mycobacterium
tuberculosis. Nine patients (4%) had malaria parasitemia. BSIs were more likely
in HIV-1-positive than in -negative patients (62/173 vs. 8/60, P<.01). Clinical
predictors of BSI included HIV-1 infection and altered mental status. Mortality
among inpatients with BSI was higher than among those without BSI (P<.001). In
conclusion, S. pneumoniae and M. tuberculosis are frequent causes of BSI in
febrile adults. Similar surveys, performed periodically in developing countries,
may assist in the identification of clinical predictors of BSI and in planning
appropriate therapy.
PMID- 10762573
TI - Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment
failure.
AB - In vitro susceptibility testing and genotyping were done on urogenital isolates
of Chlamydia trachomatis from 3 patients, 2 of whom showed evidence of clinical
treatment failure with azithromycin and one of whom was the wife of a patient.
All 3 isolates demonstrated multidrug resistance to doxycycline, azithromycin,
and ofloxacin at concentrations >4.0 microg/mL. Recurrent disease due to
relapsing infection with the same resistant isolate was documented on the basis
of identical genotypes of both organisms. This first report of clinically
significant multidrug-resistant C. trachomatis causing relapsing or persistent
infection may portend an emerging problem to clinicians and public health
officials.
PMID- 10762574
TI - Estrogen effects on Candida albicans: a potential virulence-regulating mechanism.
AB - Three Candida albicans strains were tested in the presence of 17-beta-estradiol
(10-6 M and 10-9 M) for increased growth and for enhanced survival during
incubation at nonpermissive temperatures. All 3 test organisms showed increased
growth in the presence of estradiol compared with estrogen-free controls.
Likewise, all 3 strains, when treated with estradiol, survived incubation at 48
degrees C better than did controls. Cytoplasmic extracts were probed with an anti
hsp90 antibody, and results suggested that intracellular hsp90 was up-regulated
in the presence of 10-9 M 17-beta-estradiol. The results were confirmed by
reverse-transcriptase polymerase chain reaction with primers specific for C.
albicans hsp90. A kinetic study revealed that peak hsp90 expression occurred
within 2 h of exposure to 17-beta-estradiol. In addition, estrogen increased the
amount of cdr1 (Candida multidrug resistance) mRNA compared with cells not
treated with estrogen. Coumarin and phenol also up-regulated hsp90 and cdr1
mRNAs, indicating that the estrogen-sensing and -response systems in C. albicans
may lack specificity.
PMID- 10762575
TI - Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver
transplant recipients.
AB - Human herpesvirus-6 (HHV-6) may be a risk factor for cytomegalovirus (CMV)
disease in posttransplant patients, possibly through a direct interaction or
through a general immunomodulatory effect. To examine this possibility, 88 liver
transplant recipients were monitored with serial HHV-6 polymerase chain reaction
(PCR), CMV antigenemia, and CMV plasma viral load. HHV-6 infection was defined by
a positive PCR of peripheral blood lymphocytes. Forty-eight (54.4%) of 88
patients had at least 1 positive HHV-6 PCR. CMV recurrence was significantly more
common in patients with HHV-6 infection (38/48 patients [79. 2%]), compared with
recurrence in those without HHV-6 infection (18/40 patients [45%]; P=.001). Peak
CMV viral load was 24, 147+/-6799 copies/mL in patients with HHV-6 infection
versus 8391+/-4598 copies/mL in patients without HHV-6 infection (P=.001).
Symptomatic CMV disease was more common in patients with HHV-6 infection than it
was in those without infection (15/48 patients [31. 3%] vs. 4/10 patients
[10.0%]; P=.013). In a multivariate analysis including other risk factors for
CMV, HHV-6 infection remained an independent risk factor for CMV disease (P=.013;
odds ratio, 7.26; 95% confidence interval, 1.52-34.72). HHV-6 is associated with
CMV infection and disease, thus supporting an interaction between these viruses.
PMID- 10762576
TI - Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance
and prevention.
AB - This study compared characteristics of patients who had herpes simplex virus
(HSV) type 1 with characteristics of patients who had HSV-2, by use of data from
a cross-sectional analysis. Data were collected in an urban sexually transmitted
diseases clinic from patients who had positive genital HSV cultures. Overall,
17.1% (95% confidence interval [CI], 14.9%-19.3%) of 1145 genital HSV isolates
obtained during 1993-1997 were HSV-1. The proportion of HSV-1 among initial
genital herpes infections was higher among men who had sex with men (46.9%) than
among women (21.4%) and was lowest among heterosexual men (14.6%). White race
(odds ratio [OR], 3.7; 95% CI, 2.3-5.9) and receptive oral sex in the preceding 2
months (OR, 2.8; 95% CI, 1.9-4.3) significantly increased the odds that initial
infections were HSV-1 rather than HSV-2. Genital HSV-1 may often be acquired
through contact with a partner's mouth. These data suggest that seroprevalence
studies based solely on HSV-2 type-specific assays underestimate overall
prevalence of genital HSV infection.
PMID- 10762577
TI - Characterization of an acyclovir-resistant herpes simplex virus type 2 strain
isolated from a premature neonate.
AB - Acyclovir resistance is not a recognized problem among neonates with perinatal
herpes simplex virus (HSV) infection. A premature newborn with neurocutaneous HSV
infection was treated for 21 days with acyclovir. Disseminated disease recurred 8
days later. A recurrent isolate was resistant to acyclovir and lacked thymidine
kinase activity on the basis of a frameshift mutation in the thymidine kinase
(tk) gene. Compared with the sensitive isolate obtained during primary infection,
replication of the resistant isolate was reduced on primary and permanent cells
and even further impaired on cells deleted for cellular tk. The resistant isolate
lacked virulence in a murine model of genital infection. Acyclovir-resistant HSV
2 mutants can develop rapidly in neonatal infection and cause clinically
significant disease, despite decreased replication in vitro and attenuated
virulence in an animal model.
PMID- 10762578
TI - Epidemiology of herpesvirus papio infection in a large captive baboon colony:
similarities to Epstein-Barr virus infection in humans.
AB - The epidemiology of herpesvirus papio, a lymphocryptovirus similar to Epstein
Barr virus (EBV), was studied in a captive colony of >1900 baboons. Herpesvirus
papio IgG antibody titers were measured by IFA. In total, 438 specimens from 296
baboons were assessed, including 116 serial specimens from 52 juveniles and 6
infants studied monthly for 1 year following birth and at age 18 months.
Maternally derived antibody reached a nadir at 4 months of age. About 75% of
animals at 12 months of age and >95% of animals after age 24 months demonstrated
serologic evidence of herpesvirus papio infection. After age 3 years, the
geometric mean titer was 1:60-75. The epidemiology of herpesvirus papio infection
in baboons closely parallels that of EBV infection in humans. An animal model of
lymphocryptovirus infection will facilitate investigations of human
lymphocryptovirus biology.
PMID- 10762579
TI - Rapid antiviral effect of inhaled zanamivir in the treatment of naturally
occurring influenza in otherwise healthy adults.
AB - The antiviral and clinical effects of inhaled zanamivir (10 mg twice daily for 5
days, started within the first or second day of a flulike illness) were evaluated
in a randomized, placebo-controlled trial during the 1997-1998 influenza season
in Canada. Pharyngeal secretions were collected with swabs every 12 h during 6
days, and symptoms were self-evaluated twice daily during 14 days. After only 12
h of treatment (1 dose), median virus titers decreased by 1.0 log10 TCID50/mL in
the zanamivir group (n=17), compared with a 0. 42-log10 increase in the placebo
group (n=10; P=.08). This was associated with a 4.5-day (47.4%) reduction in the
median time to alleviation of all significant flu symptoms in the zanamivir
recipients (P=.03 after adjusting for the initial virus titer and the time
between onset of symptoms and treatment). Resistance to zanamivir was not
detected in virus isolates by either phenotypic or genotypic assays.
PMID- 10762580
TI - Effect of HIV on thymic function before and after antiretroviral therapy in
children.
AB - Studies were undertaken to investigate the role of the thymus in T cell
reconstitution in human immunodeficiency virus (HIV)-infected children treated
with antiretroviral therapy. Nine pediatric patients who acquired HIV perinatally
were treated with multidrug combinations of antiretroviral agents. Plasma virus
load and CD4+ and CD8+ T cell subsets were measured, and thymus function was
measured by quantifying T cell receptor rearrangement excision circles in
peripheral blood. Patients with virus loads remaining >400 RNA copies/mL plasma
were classified as virologic nonresponders. Thymus function was initially
decreased in all subjects. After antiretrovirus therapy, peripheral CD4+ T cells
increased in all subjects. Thymus function was restored in 4 of 5 virologic
responders but in only 1 of 4 virologic nonresponders. This suggests that HIV has
an adverse effect upon thymic function in pediatric HIV infection. Potent
antiretroviral therapy restores thymic function but is affected by the degree to
which virus suppression is achieved.
PMID- 10762581
TI - Haptoglobin polymorphism in human immunodeficiency virus infection: Hp0 phenotype
limits depletion of CD4 cell counts in HIV-1-seropositive individuals.
AB - Patients seropositive for human immunodeficiency virus (HIV) type 1 and
seronegative control subjects were categorized by their haptoglobin phenotypes,
which were determined by electrophoresis of hemoglobin-supplemented plasma
samples followed by benzidine staining. The CD4 cell counts, determined by flow
cytometry from peripheral blood mononuclear cells according to subject
categories, were severely diminished in seropositive patients with the Hp2-2
phenotype (P<.025). In contrast, the CD4 cell counts for patients with the Hp0
phenotype remained relatively high (P<.025), compared with those of the controls.
In seronegative patients, CD4 cell counts were generally high (P<.005), but they
were more elevated in subjects with Hp2-2 and Hp1-1, although the differences
were not significant. Thus, the Hp2-2 phenotype is associated with poor outcome
in HIV-1 infection, whereas the Hp0 phenotype is associated with a better
prognosis once the patient is infected with HIV-1. Haptoglobin polymorphism plays
a significant role in HIV-1 infection and transmission.
PMID- 10762582
TI - Effects of Mycobacterium avium complex-infection treatment on cytokine expression
in human immunodeficiency virus-infected persons: results of AIDS clinical trials
group protocol 853.
AB - Human immunodeficiency virus (HIV) type 1-infected persons with newly diagnosed
Mycobacterium avium complex (MAC) bacteremia were enrolled in an 8-week study to
determine whether treatment of MAC infection is associated with decreases in
plasma tumor necrosis factor (TNF)-alpha levels. Blood specimens were obtained
for quantitative MAC cultures and to determine plasma levels of HIV RNA, TNF
alpha, and other proinflammatory cytokines. MAC levels decreased by 1.75 log at
week 4 (P=.008) and by 2.48 log at week 8 (P=.001). Plasma TNF-alpha decreased by
0.15 log at week 4 (P=.042) and by 0. 40 log at week 8 (P=.027). Plasma
interleukin (IL)-6 decreased by 0. 56 log at week 8 (P=.039). There were
nonsignificant trends (P<.10) for plasma levels of IL-1beta and HIV RNA to
decrease at week 8. Nonsignificant decreases in plasma levels of TNF-alpha, IL
1beta, IL-6, and HIV RNA were also seen in those individuals who remained on
stable antiretroviral therapy throughout the 8 weeks of the study.
PMID- 10762584
TI - Intimin-mediated tissue specificity in enteropathogenic Escherichia coli
interaction with human intestinal organ cultures.
AB - The hallmark of enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E.
coli (EPEC) adhesion to cultured human host cells is intimate attachment and the
formation of attaching and effacing (A/E) lesions. Recently, EHEC O157:H7 was
shown to induce A/E lesions on human intestinal explants. Unlike EPEC, which
colonized the small intestine, EHEC adhesion was restricted to follicle
associated epithelium (FAE) of ileal Peyer's patches. This study tested the
hypothesis that the bacterial adhesin intimin contributes to tissue specificity.
Complementing the eae gene mutation in CVD206 (derived from EPEC strain E2348/69)
with EPEC eaealpha (encoding intimin-alpha) restored the ability to colonize
small intestinal mucosa like the parent strain. In contrast, complementing with
EHEC eaegamma (encoding intimin-gamma) resulted in the strain adhering and
inducing A/E lesion on Peyer's patches, similar to EHEC. An intimin-gamma
positive O55:H7 EPEC also targeted FAE. Thus, intimin contributes to the tissue
specificity of A/E lesion-forming microbial pathogens.
PMID- 10762583
TI - Traveler's diarrhea at sea: three outbreaks of waterborne enterotoxigenic
Escherichia coli on cruise ships.
AB - Enterotoxigenic Escherichia coli (ETEC) has become the leading bacterial cause of
gastroenteritis outbreaks on cruise ships. Investigation of recent outbreaks of
ETEC gastroenteritis on 3 cruise ships indicated that all were associated with
consuming beverages with ice cubes on board the ship (relative risk [RR], 1.4,
95% confidence interval [CI], 1.0-1.9, P=.02; RR, 1.9, 95% CI, 1.3-2. 9, P<.001;
and RR, 1.3, 95% CI, 1.0-1.6, P<.01), and 2 were associated with drinking
unbottled water (RR, 2.7, 95% CI, 1.8-4.1, P<.001; RR, 1.7, 95% CI, 1.3-2.3,
P<.001). Multiple ETEC serotypes were detected in patients' stool specimens in
each of the 3 outbreaks, and 12 (38%) of 32 isolates were resistant to > or =3
antimicrobial agents. ETEC appears to be emerging as a waterborne pathogen on
cruise ships. Water bunkered in overseas ports was the likely source of ETEC
infection in these outbreaks. To ensure passenger safety, cruise ships that take
on water in foreign ports must ensure that water treatment and monitoring systems
function properly.
PMID- 10762585
TI - Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus
pneumoniae in Malawian children after treatment for malaria with
sulfadoxine/pyrimethamine.
AB - Treatment of malaria with sulfadoxine/pyrimethamine and of presumed bacterial
infections with trimethoprim/sulfamethoxazole (cotrimoxazole) was assessed to see
if either increases the carriage of cotrimoxazole-resistant Streptococcus
pneumoniae in Malawian children. Children <5 years old treated with
sulfadoxine/pyrimethamine, cotrimoxazole, or no antimicrobial agent were enrolled
in a prospective observational study. Nasopharyngeal swabs were taken before
treatment and 1 and 4 weeks later. Pneumococci were tested for antibiotic
susceptibility by broth microdilution. In sulfadoxine/pyrimethamine-treated
children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci
increased from 38.1% at the initial visit to 44.1% at the 4-week follow-up visit
(P=.048). For cotrimoxazole-treated children, the proportion colonized with
cotrimoxazole-nonsusceptible pneumococci increased from 41.5% at the initial
visit to 52% at the 1-week follow-up visit (P=.0017) and returned to 41.7% at the
4-week follow-up. Expanding use of sulfadoxine/pyrimethamine to treat chloroquine
resistant malaria may have implications for national pneumonia programs in
developing countries where cotrimoxazole is widely used.
PMID- 10762586
TI - Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages: early
membrane modifications and intracellular mycobacterial viability.
AB - Apoptosis has been observed in monocytes/macrophages in the course of in vivo and
in vitro Mycobacterium tuberculosis (MTB) infection. In order to define the early
events of MTB-induced apoptosis, membrane CD14 expression and the exposure of
Annexin V-binding sites in MTB-infected monocytes/macrophages have been
monitored. Moreover, the role of MTB-induced apoptosis was further analyzed in
vitro in terms of mycobacterial viability. Results show that monocyte/macrophage
apoptosis is a very early event that is strictly dependent on the MTB amount, and
this apoptosis is associated with a selective down-regulation of surface CD14
expression. Furthermore, no statistically significant decrease in mycobacterial
viability was observed, which indicates that the apoptotic pathway triggered by
high doses of MTB is associated with parasite survival rather than with killing
of the parasite.
PMID- 10762587
TI - Influence of hemoglobin E trait on the antimalarial effect of artemisinin
derivatives.
AB - To determine whether hemoglobin E trait influences the antimalarial effect of
artemisinin derivatives, we retrospectively compared 32 case patients with
hemoglobin E trait to 32 control patients who did not have hemoglobin E, beta
thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia
trait on the basis of a mean corpuscular volume > or =78 femtoliters. All
patients were admitted to the Hospital for Tropical Diseases in Bangkok,
Thailand, with acute falciparum malaria. Control patients were matched to case
patients with hemoglobin E trait by treatment with artemisinin derivatives versus
other antimalarial drugs, by ethnic group, and by parasite count. Among 38
patients treated with artemisinin derivatives, the presence of hemoglobin E trait
was associated with significantly faster parasite clearance (2.9-fold; 95%
confidence interval [CI], 1.4-6.3; P=.006). Among 26 patients treated only with
other antimalarial drugs, hemoglobin E trait did not significantly enhance
parasite clearance (hazards ratio, 1.1; 95% CI, 0.5-2.5; P=. 8). Hemoglobin E
trait may potentiate the antimalarial effect of artemisinin derivatives.
PMID- 10762588
TI - Effects of famciclovir and valacyclovir on herpes simplex virus type 1 infection,
latency, and reactivation in mice: how dissimilar are study results?
PMID- 10762589
TI - Questions about results reported with potent antiretroviral therapy for human
immunodeficiency virus type 1 infection.
PMID- 10762590
TI - Reply
PMID- 10762591
TI - Reply
PMID- 10762592
TI - Cell-cycle dysregulation and the molecular mechanisms of prostate cancer.
AB - Prostate cancer is the most common cause of non-cutaneous cancer in men and
although frequently latent is the second commonest cause of death. Screening for
the disease was historically based on symptoms of urethral obstruction, clinical
examination of the prostate gland and serum measurements of prostate specific
antigen. As prostate cancer growth in the early stages is enhanced by androgens,
the mainstay of therapy has been androgen ablation by pharmaco-therapeutic or
surgical means. The subsequent development of androgen therapy resistant prostate
cancer in many patients, for whom therapeutic options remain limited, has led
researchers to focus attention on understanding the molecular genetics of
prostate cancer. The array of genetic abnormalities observed in prostate tumors,
which include changes in components of the cell cycle, suggest the disease is
quite heterogeneous and may require further sub-classification based on genetic
markers. Such analyses may lead to identification of relevant new prognostic and
therapeutic indicators. The advent of transgenic mouse models of prostate cancer
may provide a critical tool for the implementation of rational genetic based
therapeutics and alternate drug design.
PMID- 10762593
TI - Protein kinase C-mediated regulation of the cell cycle.
AB - Members of the protein kinase C (PKC) family of signal transduction molecules
have been widely implicated in regulation of cell growth/cell cycle progression
and differentiation. Increasing evidence from studies using in vitro and in vivo
systems points to PKC as a key regulator of critical cell cycle transitions,
including cell cycle entry and exit and the G1 and G2 checkpoints. PKC-mediated
control of these transitions can be negative or positive, depending on the timing
of PKC activation during the cell cycle and on the specific PKC isozymes
involved. Most of the mechanistic information available relates to the
involvement of this enzyme family in negative regulation of these transitions.
Accumulating data indicate that a major target for PKC-mediated inhibition of
cell cycle progression is the Cip/Kip cyclin-dependent kinase (cdk) inhibitor
p21waf1/cip1. Increased expression of p21waf1/cip1 blocks cdk2 activity in G1
phase, leading to hypophosphorylation of the retinoblastoma protein and
inhibition of cell cycle progression into S phase. In G2, p21waf1/cip1 expression
blocks cdc2/cyclin B activity, likely through an indirect mechanism involving
inhibition of the cdk2/cyclin A complex, and prevents progression into M phase.
PKC signaling can also activate a coordinated program of pocket protein
regulation leading to cell cycle withdrawal into G0. The molecular events
underlying positive regulation of cell cycle progression by PKC signaling remain
poorly understood, although there is evidence for a role of the enzyme in
promoting G2(r)M progression by phosphorylating lamin B at sites involved in
nuclear lamina disassembly. Understanding of the mechanisms underlying PKC
mediated control of the cell cycle is beginning to provide important insight into
its role in uncontrolled cell growth and transformation.
PMID- 10762594
TI - BETA 2 integrin signaling in leukocytes.
AB - Members of the beta 2 integrin family are the dominating integrins expressed on
leukocytes, and they play a major role in leukocyte cell-cell and cell-matrix
adhesions during inflammation and other immune responses. Beta 2 integrins are
signaling receptors, but they are also targets of and are functionally affected
by intracellular signals. Accordingly, researchers usually discuss two types of
signaling by beta 2 integrins (and integrins in general): transmission of signals
into the cell following binding of ligands or counter-receptors to the integrins
(outside-in signaling), and regulation of the avidity and conformation of
integrins by signals generated by other receptors within the cell (inside-out
signaling). In this review, our aim is to summarize what is known about the
capacity of beta 2 integrins to generate outside-in signaling in leukocytes, in
particular polymorphonuclear neutrophils. Results in the literature clearly
demonstrate that one of the earliest events in beta 2 integrin signaling is
activation of non-receptor tyrosine kinases, which in turn triggers downstream
activation of various signaling pathways that affect different functional
responses of the cell. We also discuss molecules of potential importance in beta
2 integrin signaling.
PMID- 10762595
TI - Role of endoscopic ultrasound in the diagnosis and staging of pancreatic cancer.
AB - Endoscopic Ultrasound (EUS) is a relatively new modality. Its high resolution
makes it possible to detect tumors of 5mm in diameter otherwise missed by other
imaging modalities. It is more accurate than computerized tomography (CT) scan,
Transabdominal Ultrasound (US) and Magnetic Resonance Imaging (MRI) in diagnosing
pancreatic lesions, especially those less than 20mm in diameter. EUS can be used
to obtain pancreatic and nodal tissue using ultrasound- guided fine needle
aspiration increasing the diagnostic yield and helping determining further
management. It can also determine vascular involvement by pancreatic cancer with
a sensitivity of more than 90%. The current indications for EUS in the diagnosis
and management of pancreatic cancer will be reviewed.
PMID- 10762596
TI - The neurobiology of attention-deficit hyperactivity disorder.
AB - Attention-deficit hyperactivity disorder is a childhood psychiatric disorder
characterized by inattention, impulsivity, and overactivity. Considerable
research has focused on the neurobiological substrates of this disorder. Although
the specific nature of the brain dysfunction remains elusive, progress has been
made and several models of the underlying pathophysiology have been suggested.
Research in the fields of neuropsychology, neuroimaging, neurochemistry, and
molecular genetics, which points to a multifactorial etiology for the disorder,
is reviewed. While several inconsistencies exist across studies, evidence
supports dysfunction of fronto-striatal dopaminergic and noradrenergic circuits
with resultant executive deficits in cognitive functioning.
PMID- 10762597
TI - Reprogramming erythroleuekmia cells to terminal differentiation and terminal cell
division.
AB - In vitro differentiation of murine erythroleuekemia cells recapitulates many
aspects of the erythroid terminal differentiation program, including hemoglobin
synthesis and proliferation arrest. It also provides an opportunity to study the
changes occurring during reprogramming of tumor cells into their normal
differentiation program. This review is focused on the recent progress made in
understanding the key events occurring during the reprogramming of
erythroleukemia cells. We discuss the contributions of PU.1 to the block to
terminal differentiation exhibited by the erythroleukemia cells as well as the
role of GATA-1 in restoring normal differentiation. We also discuss the role of
certain cell cycle regulators in the decision to resume normal differentiation
and in the resulting terminal cell divisions and arrest.
PMID- 10762598
TI - Cell cycle molecules and diseases of the cardiovascular system.
AB - Injury to the cardiovascular system causes an elevated expression of endothelin-1
(ET-1) and activation of several important signaling pathways including the
mitogen-activated kinase (MAPK) cascade. The activation of these pathways has
been implicated in the pathogenesis of cardiovascular disease caused by hypoxia,
infections, and ischemia /reperfusion injury, cardiomyopathy and restenosis after
balloon angioplasty. Important downstream targets of the MAPK and ET-1 pathways
are the cell cycle regulatory molecules (cyclins, cyclin-dependent kinases, and
cyclin-dependent kinase inhibitors). Regulation of these molecules contributes to
remodeling throughout the cardiovascular system. In addition, cell cycle
molecules are important in the regulation of angiogenesis. These new data have
led to the development of potential therapeutic modalities targeting these
regulatory molecules in order to ameliorate various cardiovascular disease
states.
PMID- 10762599
TI - Mechanisms of interferon-induced cell cycle arrest.
AB - The interferons (IFNs) are a group of cytokines, which in addition to their
antiviral activity are capable of modulating a variety of cellular responses. One
such prominent effect of IFNs is their potent antimitogenic action, which can be
observed both on malignant and non-malignant cells of many different origins.
IFNs are also used in the clinic, mainly in malignant and viral diseases, and
their cell growth -inhibitory effect has been suggested to be of major importance
in their antitumour and antiviral action. The aim of the present review is to
provide insight into the molecular mechanisms by which IFNs modulate cell cycle
progression in various cell types. With the recent progress in our understanding
of how the cell cycle is regulated at the molecular level, it has become possible
to delineate intracellular effectors of IFN in this respect. Understanding the
antiproliferative effects of IFN may not only help in understanding its
antineoplastic and antiviral activities, but may also provide an insight into
cell cycle regulation in general and aid in making IFNs a more useful tool in
treating disease.
PMID- 10762600
TI - Tumor suppressor p53: regulation and function.
AB - The p53 protein is a transcription factor involved in maintaining genomic
integrity by controlling cell cycle progression and cell survival. Mutations in
p53 are the most frequently seen genetic alterations in human cancer. The
function of p53 is critical to the way many cancer treatments kill cells because
radiotherapy and chemotherapy act in part by triggering programmed cell death in
response to DNA damage. Consequently, tumors which bear p53 mutations, are often
difficult to treat and their prognosis is poor. Since the underlying feature of
tumors with p53 mutations is the absence of functional p53, gene replacement
therapy with wild-type p53 gene is being considered as an approach for treating a
variety of cancers. In recent years, more information has been obtained regarding
various pathways leading to the activation of p53, particularly those involving
post-translational modifications of p53. Several new target genes of p53 have
been identified. This review will summarize current knowledge on the structure,
mechanism of activation and effectors of p53 function.
PMID- 10762603
TI - Pathobiology of visceral pain: molecular mechanisms and therapeutic implications.
II. Genetic approaches to pain therapy.
AB - New analgesic drugs are necessary because a number of pain states are
untreatable. Genetic approaches to the identification of analgesic drug targets
include mapping genes involved in human pain perception (e.g., trkA involved in
hereditary neuropathies), identifying regulators of sensory neuron function in
simple multicellular organisms and then investigating the activity of their
mammalian homologs (e.g., POU domain transcription factors that specify sensory
cell fate), as well as difference, expression, and homology cloning of receptors,
ion channels, and transcription factors present in sensory neurons. After target
validation through the construction of null mutant mice, high-throughput cell
based screens can be used to identify potential drug candidates. As a result of
these approaches, a number of receptors and ion channels present in sensory
neurons such as voltage-gated sodium channels [sensory neuron specific (SNS) and
Na channel novel] and ATP-gated (P2X3), capsaicin-gated [vanilloid receptor
1(VR1)], and proton-gated [acid-sensing ion channel (ASIC)] channels are now
under investigation as potential new analgesic drug targets.
PMID- 10762602
TI - X. Trefoil peptide and EGF receptor/ligand transgenic mice.
AB - The use of genetically engineered mice with both gain-of-function and loss-of
function mutations has been particularly informative about the normal and
pathophysiological actions of a number of regulatory peptides of the
gastrointestinal tract. This review highlights some of the major findings
pertinent to the epidermal growth factor (EGF) receptor and its ligands,
particularly the major gut ligand transforming growth factor-alpha, as well as
the trefoil peptides. Both of these peptide families have important local actions
in maintaining tissue homeostasis and repair after injury, and when mechanisms
governing their regulation are disrupted they may contribute to disease
progression. Future applications of transgenic technology to these areas are
likely to be productive in furthering our understanding of the biology of these
peptides in health and disease.
PMID- 10762601
TI - The development and biology of bradyzoites of Toxoplasma gondii.
AB - Toxoplasma gondii is a protozoan parasite of mammals and birds that is an
important human pathogen. Infection with this Apicomplexan parasite results in
its dissemination throughout its host via the tachyzoite life-stage. After
dissemination these tachyzoites differentiate into bradyzoites within cysts that
remain latent. These bradyzoites can transform back into tachyzoites and in
immunosupressed individuals this often results in symptomatic disease. Both
tachyzoites and bradyzoites develop in tissue culture and thus this crucial
differentiation event can be studied. Recent advances in the genetic manipulation
of T. gondii have expanded the molecular tools that can be applied to studies on
bradyzoite differentiation. Evidence is accumulating that this differentiation
event is stress mediated and may share common pathways with other stress-induced
differentiation events in other eukaryotic organisms. Study of the stress
response and signaling pathways are areas of active research in this organism. In
addition, characterization of unique bradyzoite-specific structures, such as the
cyst wall, should lead to a further understanding of T. gondii biology. This
review focuses on the biology and development of bradyzoites and current
approaches to the study of the tachyzoite to bradyzoite differentiation process.
PMID- 10762604
TI - TIEG proteins join the Smads as TGF-beta-regulated transcription factors that
control pancreatic cell growth.
AB - The control of epithelial cell proliferation, differentiation, and apoptosis
requires a balance between signaling and transcriptional regulation. Recent
developments in pancreatic cell research have revealed that transforming growth
factor-beta (TGF-beta) signaling is important for the regulation of each of these
phenomena. More importantly, perturbations in this pathway are associated with
pancreatic cancer. A chief example of these alterations is the mutation in the
TGF-beta-regulated transcription factor Smad4/DPC4 that is found in a large
percentage of pancreatic tumors. Surprisingly, studies on transcription factors
have remained an underrepresented area of pancreatic research. However, the
discovery of Smad4/DPC4 as a transcription factor fueled further studies aimed at
characterizing transcription factors involved in normal and neoplastic pancreatic
cell growth. Our laboratory recently described the existence of a novel family of
zinc finger transcription factors, TGF-beta-inducible early-response gene (TIEG)1
and TIEG2, from the exocrine pancreas that, similarly to Smads, participate in
the TGF-beta response and inhibit epithelial cell proliferation. This review
therefore focuses on describing the structure and function of these two families
of transcription factor proteins that are becoming key players in the regulation
of pancreatic cell growth.
PMID- 10762605
TI - MRP2, a human conjugate export pump, is present and transports fluo 3 into apical
vacuoles of Hep G2 cells.
AB - The multidrug resistance protein 2 (MRP2, symbol ABCC2) transports anionic
conjugates and certain amphiphilic anions across the apical membrane of polarized
cells. Human hepatoma Hep G2 cells retain hepatic polarity and form apical
vacuoles into which cholephilic substances are secreted. Immunofluorescence
microscopy showed that human MRP2 was expressed in the apical vacuole membrane of
polarized Hep G2 cells, whereas the isoform MRP3 was localized to the lateral
membrane. Expression of both MRP2 and MRP3 was confirmed by immunoblotting and
reverse transcription PCR. Fluo 3 secretion into the apical vacuoles was
inhibited by cyclosporin A but not by selective inhibitors of multidrug
resistance 1 P-glycoprotein. In addition, carboxyfluorescein, rhodamine 123, and
the fluorescent bile salt derivatives ursodeoxycholyl-(Nepsilon
nitrobenzoxadiazolyl)-lysine and cholylglycylamido-fluorescein were secreted into
the apical vacuoles; the latter two probably via the bile salt export pump. We
conclude that MRP2 mediates fluo 3 secretion into the apical vacuoles of
polarized Hep G2 cells. Thus the function of human MRP2 and the action of
inhibitors can be analyzed by the secretion of fluorescent anions such as fluo 3.
PMID- 10762606
TI - Hepatic glutamine transporter activation in burn injury: role of amino acids and
phosphatidylinositol-3-kinase.
AB - Burn injury elicits a marked, sustained hypermetabolic state in patients
characterized by accelerated hepatic amino acid metabolism and negative nitrogen
balance. The transport of glutamine, a key substrate in gluconeogenesis and
ureagenesis, was examined in hepatocytes isolated from the livers of rats after a
20% total burn surface area full-thickness scald injury. A latent and profound
two- to threefold increase in glutamine transporter system N activity was first
observed after 48 h in hepatocytes from injured rats compared with controls,
persisted for 9 days, and waned toward control values after 18 days,
corresponding with convalescence. Further studies showed that the profound
increase was fully attributable to rapid posttranslational transporter activation
by amino acid-induced cell swelling and that this form of regulation may be
elicited in part by glucagon. The phosphatidylinositol-3-kinase (PI3K) inhibitors
wortmannin and LY-294002 each significantly attenuated transporter stimulation by
amino acids. The data suggest that PI3K-dependent system N activation by amino
acids may play an important role in fueling accelerated hepatic nitrogen
metabolism after burn injury.
PMID- 10762607
TI - Differential lobular induction in rat liver of glutathione S-transferase A1/A2 by
phenobarbital.
AB - Phenobarbital and other xenobiotics induce drug-metabolizing enzymes, including
glutathione S-transferase A1/A2 (rGSTA1/A2). We examined the mechanism of
induction of rGSTA1/A2 in rat livers after phenobarbital treatment. The induction
of rGSTA1/A2 was not uniform across the hepatic lobule; steady-state transcript
levels were threefold higher in perivenous hepatocytes relative to periportal
hepatocytes when examined by in situ hybridization 12 h after a single dose of
phenobarbital. Administration of a second dose of phenobarbital 12 or 24 h after
the first dose did not equalize the induction of rGSTA1/A2 across the lobule. The
transcriptional activity of the rGSTA1/A2 gene was increased 3.5- to 5.5-fold in
whole liver by phenobarbital, but activities were the same in enriched periportal
and perivenous subpopulations of hepatocytes from phenobarbital-treated animals.
The half-life of rGSTA1/A2 mRNA in control animals was 3.6 h, whereas it was 10.2
h in phenobarbital-treated animals. We conclude that phenobarbital induces
rGSTA1/A2 expression by increasing transcriptional activity across the lobule but
induction of rGSTA1/A2 is greater in perivenous hepatocytes due to localized
stabilization of mRNA transcripts.
PMID- 10762609
TI - Role of GRPergic neurons in secretin-evoked exocrine secretion in isolated rat
pancreas.
AB - Effects of intrapancreatic gastrin-releasing peptide (GRP)-containing neurons on
secretin-induced pancreatic secretion were investigated in the totally isolated
perfused rat pancreas. Electrical field stimulation (EFS) increased secretin (12
pM)-induced pancreatic secretions of fluid and amylase. EFS induced a twofold
increase in GRP concentration in portal effluent, which was completely inhibited
by tetrodotoxin but not modified by atropine. An anti-GRP antiserum inhibited the
EFS-enhanced secretin-induced secretions of fluid and amylase by 12 and 43%,
respectively, whereas a simultaneous infusion of the antiserum and atropine
completely abolished them. Exogenous GRP dose-dependently increased the secretin
induced pancreatic secretion with an additive effect on fluid secretion and a
potentiating effect on amylase secretion, which was not affected by atropine. In
conclusion, excitation by EFS of GRPergic neurons in the isolated rat pancreas
results in the release of GRP, which exerts an additive effect on fluid secretion
and a potentiating effect on amylase secretion stimulated by secretin. The
release and action of GRP in the rat pancreas are independent of cholinergic
tone.
PMID- 10762608
TI - Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat
mesentery in vivo.
AB - Physiological roles of endogenous nitric oxide (NO) in the lymphatic pump
activity of rat mesenteries in vivo were evaluated using an intravital video
microscope system. Changes in the pumping frequency (F), the end diastolic
diameter (EDD), and the end systolic diameter (ESD) of the mesenteric lymph
microvessels were measured with the microscope system and then the pump flow
index (PFI) was calculated. A 15-min superfusion of 30 microM N(omega)-nitro-L
arginine methyl ester (L-NAME) in the mesenteries caused significant increases of
F and PFI and a significant decrease of the EDD and ESD. Simultaneous superfusion
of 1 mM L-arginine with 30 microM L-NAME produced a significant reversal of the L
NAME-mediated increase of F and decrease of ESD. A 15-min superfusion of 100
microM aminoguanidine caused no significant effects on F, EDD, and ESD of the
mesenteric lymph vessels in vivo. These findings suggest that endogenous NO has
physiologically modulated the lymphatic pump activity in rat mesentery in vivo
and that the production and release of NO may be mediated by constitutive NO
synthase but not by inducible NO synthase.
PMID- 10762610
TI - Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco
2 cells.
AB - Substrate specificity and pH dependence of the transport system for
diphenhydramine were investigated in Caco-2 cell monolayers. Diphenhydramine
uptake was not affected by any typical substrate for the renal organic cation
transport system except procainamide. Along with procainamide, tertiary amine
compounds with N-dimethyl or N-diethyl moieties in their structures inhibited the
diphenhydramine uptake. Moreover, accumulation of diphenhydramine was stimulated
by preloading the Caco-2 cells with these tertiary amines (trans-stimulation
effect), indicating the existence of the specific transport system for tertiary
amines with N-dimethyl or N-diethyl moieties. Efflux of diphenhydramine from
monolayers was enhanced by medium acidification. In addition, intracellular
acidification resulted in marked stimulation of diphenhydramine accumulation. ATP
depletion of the cells caused an enhancement of diphenhydramine accumulation,
suggesting the involvement of an active secretory pathway. However, P
glycoprotein did not mediate the diphenhydramine transport. These findings
indicate that a novel pH-dependent tertiary amine transport system that
recognizes N-dimethyl or N-diethyl moieties is involved in diphenhydramine
transport in Caco-2 cells.
PMID- 10762611
TI - Mechanism of glucocorticoid-mediated reversal of inhibition of Cl(-)/HCO(-)(3)
exchange during chronic ileitis.
AB - In the normal ileum, coupled NaCl absorption occurs via the dual operation of
Na(+)/H(+) and Cl(-)/HCO(-)(3) exchange on the brush-border membrane (BBM) of
villus cells. In a rabbit model of chronic small intestinal inflammation we
determined the cellular mechanism of inhibition of NaCl absorption and the effect
of steroids on this inhibition. Cl(-)/HCO(-)(3) but not Na(+)/H(+) exchange was
reduced in the BBM of villus cells during chronic ileitis. Cl(-)/HCO(-)(3)
exchange was inhibited secondary to a decrease in the affinity for Cl(-) rather
than an alteration in the maximal rate of uptake of Cl(-) (V(max)).
Methylprednisolone (MP) stimulated Cl(-)/HCO(-)(3) exchange in the normal ileum
by increasing the V(max) of Cl(-) uptake rather than altering affinity for Cl(-).
MP reversed the inhibition of Cl(-)/HCO(-)(3) exchange in rabbits with chronic
ileitis. However, MP alleviated the Cl(-)/HCO(-)(3) exchange inhibition by
restoring the affinity for Cl(-) rather than altering the V(max) of Cl(-) uptake.
These data suggest that glucocorticoids mediate the alleviation of Cl(-)/HCO(
)(3) exchange inhibition in chronically inflamed ileum by reversing the same
mechanism that was responsible for inhibition of this transporter rather than
exerting a direct effect on the transporter itself, as was the case in normal
ileum.
PMID- 10762612
TI - Modulation by colonic fermentation of LES function in humans.
AB - Colonic fermentation of carbohydrate has been shown to influence gastric and
intestinal motility. Our aim was to investigate the effects of colonic infusion
of lactose and short-chain fatty acids (SCFAs) on lower esophageal sphincter
(LES) function in humans. LES pressure (LESP), transient relaxations of LES
(TLESRs), and esophageal pH were monitored over 6 h on 4 different days in 7
healthy volunteers. After 1 h of baseline recording, the effects of different
colonic infusions (270 ml of isotonic or hypertonic saline, 30 g lactose, or 135
mmol SCFAs) were tested in fasting conditions and after a standard meal. Peptide
YY (PYY) and oxyntomodulin (OLI) were also measured in plasma. Both lactose and
SCFA infusions increased the number of TLESRs as well as the proportion of TLESRs
associated with acid reflux episodes, but saline solutions did not. The
postprandial fall of LESP was enhanced by previous SCFA infusion. Plasma PYY and
OLI increased similarly after all colonic infusions. Colonic fermentation of
lactose markedly affected LES function, and this effect was reproduced by SCFA
infusion. Whether the mechanisms of this feedback phenomenon are of hormonal
nature, neural nature, or both remains to be determined.
PMID- 10762613
TI - Effect of chronic inflammation on ileal short-chain fatty acid/bicarbonate
exchange.
AB - Short-chain fatty acids (SCFA) have been demonstrated to at least partially
ameliorate chronic intestinal inflammation. However, whether and how intestinal
SCFA absorption may be altered during chronic intestinal inflammation is unknown.
A rabbit model of chronic ileitis produced by coccidia was used to determine the
effect of chronic inflammation on ileal SCFA/HCO(-)(3) exchange. SCFA/HCO(-)(3)
exchange was present in the brush-border membrane (BBM) of villus but not crypt
cells from normal rabbit ileum. An anion-exchange inhibitor, DIDS, significantly
inhibited SCFA/HCO(-)(3) exchange. Extravesicular Cl(-) did not alter the uptake
of SCFA, suggesting that SCFA/HCO(-)(3) exchange is a transport process distinct
from Cl(-)/HCO(-)(3) exchange. In chronically inflamed ileum, SCFA/HCO(-)(3)
exchange was also present only in BBM of villus cells. The exchanger was
sensitive to DIDS and was unaffected by extravesicular Cl(-). However, SCFA/HCO(
)(3) exchange was significantly reduced in villus cell BBM vesicles (BBMV) from
chronically inflamed ileum. Kinetic studies demonstrated that the maximal rate of
uptake of SCFA, but not the affinity for SCFA, was reduced in chronically
inflamed rabbit ileum. These data demonstrate that a distinct SCFA/HCO(-)(3)
exchange is present on BBMV of villus but not crypt cells in normal rabbit ileum.
SCFA/HCO(-)(3) exchange is inhibited in chronically inflamed rabbit ileum. The
mechanism of inhibition is most likely secondary to a reduction in transporter
numbers rather than altered affinity for SCFA.
PMID- 10762614
TI - Regulation of the human Na(+)-glucose cotransporter gene, SGLT1, by HNF-1 and
Sp1.
AB - The Na(+)-glucose cotransporter (SGLT1) is expressed primarily by small
intestinal epithelial cells and transports the monosaccharides glucose and
galactose across the apical membrane. Here we describe the isolation and
characterization of 5.3 kb of the 5'-flanking region of the SGLT1 gene by
transiently transfecting reporter constructs into a variety of epithelial cell
lines. A fragment (nt -235 to +22) of the promoter showed strong activity in the
intestinal cell line Caco-2 but was inactive in a nonintestinal epithelial cell
line (Chinese hamster ovary). Within this region, three cis-elements, a
hepatocyte nuclear factor-1 (HNF-1) and two GC box sites are critical for
maintaining the gene's basal level of expression. The two GC boxes bind to
several members of the Sp1 family of transcription factors and, in the presence
of HNF-1, synergistically upregulate transactivation of the promoter. A novel 16
bp element just downstream of one GC box was also shown to influence the
interaction of Sp1 to its binding site. In summary, we report the identification
and characterization of the human SGLT1 minimal promoter and the critical role
that HNF-1 and Sp1-multigene members have in enhancing the basal level of its
transcription in Caco-2 cells.
PMID- 10762615
TI - Relative contributions of "pressure pump" and "peristaltic pump" to gastric
emptying.
AB - The relative contributions to gastric emptying from common cavity antroduodenal
pressure difference ("pressure pump") vs. propagating high-pressure waves in the
distal antrum ("peristaltic pump") were analyzed in humans by high-resolution
manometry concurrently with time-resolved three-dimensional magnetic resonance
imaging during intraduodenal nutrient infusion at 2 kcal/min. Gastric volume,
space-time pressure, and contraction wave histories in the antropyloroduodenal
region were measured in seven healthy subjects. The subjects fell into two
distinct groups with an order of magnitude difference in levels of antral
pressure activity. However, there was no significant difference in average rate
of gastric emptying between the two groups. Antral pressure history was separated
into "propagating high-pressure events" (HPE), "nonpropagating HPEs," and
"quiescent periods." Quiescent periods dominated, and average pressure during
quiescent periods remained unchanged with decreasing gastric volume, suggesting
that common cavity pressure levels were maintained by increasing wall muscle tone
with decreasing volume. When propagating HPEs moved to within 2-3 cm of the
pylorus, pyloric resistance was found statistically to increase with decreasing
distance between peristaltic waves and the pylorus. We conclude that transpyloric
flow tends to be blocked when antral contraction waves are within a "zone of
influence" proximal to the pylorus, suggesting physiological coordination between
pyloric and antral contractile activity. We further conclude that gastric
emptying of nutrient liquids is primarily through the "pressure pump" mechanism
controlled by pyloric opening during periods of relative quiescence in antral
contractile wave activity.
PMID- 10762616
TI - Defective cholinergic Cl(-) secretion and detection of K(+) secretion in rectal
biopsies from cystic fibrosis patients.
AB - Rectal biopsies from cystic fibrosis (CF) patients show defective cAMP-activated
Cl(-) secretion and an inverse response of the short-circuit current (I(sc))
toward stimulation with carbachol (CCh). Alternative Cl(-) channels are found in
airway epithelia and have been attributed to residual Cl(-) secretion in CF
colon. The aim of the present study was to investigate ion conductances causing
reversed I(sc) upon cholinergic stimulation. Furthermore, the putative role of an
alternative Ca(2+)-dependent Cl(-) conductance in human distal colon was
examined. Cholinergic ion secretion was assessed in the absence and presence of
cAMP-dependent stimulation. Transepithelial voltage and I(sc) were measured in
rectal biopsies from non-CF and CF individuals by means of a perfused micro
Ussing chamber. Under baseline conditions, CCh induced a positive I(sc) in CF
rectal biopsies but caused a negative I(sc) in non-CF subjects. The CCh-induced
negative I(sc) in non-CF biopsies was gradually reversed to a positive response
by incubating the biopsies in indomethacin. The positive I(sc) was significantly
enhanced in CF and was caused by activation of a luminal K(+) conductance, as
shown by the use of the K(+) channel blockers Ba(2+) and tetraethylammonium.
Moreover, a cAMP-dependent luminal K(+) conductance was detected in CF
individuals. We conclude that the cystic fibrosis transmembrane conductance
regulator is the predominant Cl(-) channel in human distal colon. Unlike human
airways, no evidence was found for an alternative Cl(-) conductance in native
tissues from CF patients. Furthermore, we demonstrated that both Ca(2+)- and cAMP
dependent K(+) secretion are present in human distal colon, which are unmasked in
rectal biopsies from CF patients.
PMID- 10762617
TI - Mode of action of ANG II on ion transport in guinea pig distal colon.
AB - The effect of ANG II on mucosal ion transport and localization of ANG type 1
receptor (AT(1)R) in the guinea pig distal colon was investigated.
Submucosal/mucosal segments were mounted in Ussing flux chambers, and short
circuit current (I(sc)) was measured as an index of ion transport. Serosal
addition of ANG II produced a concentration-dependent (10(-9)-10(-5) M) increase
in I(sc). The maximal response was observed at 10(-6) M; the increase in I(sc)
was 164.4 +/- 11.8 microA/cm(2). The ANG II (10(-6) M)-evoked response was mainly
due to Cl(-) secretion. Tetrodotoxin, atropine, the neurokinin type 1 receptor
antagonist FK-888, and piroxicam significantly reduced the ANG II (10(-6) M)
evoked response to 28, 45, 58, and 16% of control, respectively. Pretreatment
with prostaglandin E(2) (10(-5) M) resulted in a threefold increase in the ANG II
evoked response. The AT(1)R antagonist FR-130739 completely blocked ANG II (10(
6) M)-evoked responses, whereas the ANG type 2 receptor antagonist PD-123319 had
no effect. Localization of AT(1)R was determined by immunohistochemistry. In the
immunohistochemical study, AT(1)R-immunopositive cells were distributed clearly
in enteric nerves and moderately in surface epithelial cells. These results
suggest that ANG II-evoked electrogenic Cl(-) secretion may involve submucosal
cholinergic and tachykinergic neurons and prostanoid synthesis pathways through
AT(1)R on the submucosal plexus and surface epithelial cells in guinea pig distal
colon.
PMID- 10762618
TI - Upregulation of HGF activator inhibitor type 1 but not type 2 along with
regeneration of intestinal mucosa.
AB - Hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1) and type 2 (HAI
2) are new Kunitz-type serine protease inhibitors that were recently purified and
cloned from the human stomach cancer cell line MKN45 as specific inhibitors
against HGF activator. Both proteins contain two Kunitz inhibitor domains and are
expressed abundantly throughout the gastrointestinal tract, in addition to the
placenta, pancreas, and kidney. In this study, to assess the possible roles of
HAI-1 and HAI-2 in the intestinal mucosa, we examined the expression of HAI-1 and
HAI-2 during regeneration of the intestinal mucosa. Immunohistochemical studies
revealed that HAI-1 but not HAI-2 was detected more strongly in regenerative
epithelium than in normal epithelium, although both proteins were detected
throughout the human gastrointestinal tract. During the course of acetic acid
induced experimental colitis in an in vivo mouse model, HAI-1 but not HAI-2 was
upregulated in the recovery phase, suggesting that HAI-1 but not HAI-2 is
associated with the regeneration of damaged colonic mucosa. Upregulation of HAI-1
may serve to downregulate the proliferative response after initial activation of
MET receptor by HGF/scatter factor after an injury.
PMID- 10762619
TI - Patch-clamp study of neurons and glial cells in isolated myenteric ganglia.
AB - Most of the physiological information on the enteric nervous system has been
obtained from studies on preparations of the myenteric ganglia attached to the
longitudinal muscle layer. This preparation has a number of disadvantages, e.g.,
the inability to make patch-clamp recordings and the occurrence of muscle
movements. To overcome these limitations we used isolated myenteric ganglia from
the guinea pig small intestine. In this preparation movement was eliminated
because muscle was completely absent, gigaseals were obtained, and whole cell
recordings were made from neurons and glial cells. The morphological identity of
cells was verified by injecting a fluorescent dye by micropipette. Neurons
displayed voltage-gated inactivating inward Na(+) and Ca(2+) currents as well as
delayed-rectifier K(+) currents. Immunohistochemical staining confirmed that most
neurons have Na(+) channels. Neurons responded to GABA, indicating that membrane
receptors were retained. Glial cells displayed hyperpolarization-induced K(+)
inward currents and depolarization-induced K(+) outward currents. Glia showed
large "passive" currents that were suppressed by octanol, consistent with
coupling by gap junctions among these cells. These results demonstrate the
advantages of isolated ganglia for studying myenteric neurons and glial cells.
PMID- 10762620
TI - Gender differences in early alcohol-induced liver injury: role of CD14, NF
kappaB, and TNF-alpha.
AB - The purpose of this study was to determine whether early alcohol-induced liver
injury (ALI) in females is associated with changes in CD14 on Kupffer cells,
activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor
necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat
control or ethanol-containing diets for 4 wk using the intragastric enteral
protocol. Physiological parameters were similar in both genders. Ethanol was
increased as tolerance developed with higher blood levels than previously
observed, resulting in a fourfold increase in aspartate aminotransferase (males
389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more
rapidly and was nearly twofold greater and endotoxin levels were significantly
higher in females after ethanol. Also, expression of CD14 on Kupffer cells was
1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear
extracts and TNF-alpha mRNA expression were threefold greater in females. These
data are consistent with the hypothesis that elevated endotoxin after ethanol
triggers more activation of Kupffer cells via enhanced CD14 expression in
females. NF-kappaB is activated in this process, leading to increases in TNF
alpha mRNA expression in the liver and more severe liver injury in females. It is
concluded that gender differences in ALI are dependent on endotoxin and a
signaling cascade leading to TNF-alpha.
PMID- 10762621
TI - Transgenic animal models of human papillomavirus-dependent disease (Review).
AB - Human papillomaviruses (HPVs) are DNA tumor viruses that induce
hyperproliferative lesions in cutaneous and mucosal epithelia. A wide variety of
studies implicate the viral E6 and E7 oncoproteins as cell immortalizing agents,
and show that these proteins work, respectively, by interfering with the function
of the p53 and pRb tumor suppressor genes. Most of these studies have been
performed using cell culture models. However, recently, a variety of in vivo
mouse model systems have been developed for the study of HPV-dependent disease.
These models use tissue-specific promoters to deliver HPV oncoprotein expression
to specific body sites. Using this strategy, mouse models have been designed for
the study of cancer progression in epithelia, and additional models have been
designed to use E6 and E7, respectively, to probe the role of p53 and pRb on
tissue differentiation and function. In the present report, we summarize the
literature describing these systems, and highlight some of the important findings
derived from these studies.
PMID- 10762622
TI - Cell cycle control as a basis for cancer drug development (Review).
AB - Normal cell cycle progression relies on the cell's ability to translate
extracellular signals such as mitogenic stimuli and intact extracellular matrices
in order to efficiently replicate DNA and divide. Cyclin dependent kinases (cdks)
respond to these signals and are largely responsible for positively pushing cells
through the cell cycle. Due to their pivotal role in cell division, nature has
evolved elaborate mechanisms to regulate the kinase activity of cdks. Cyclins are
cdk binding partners which are required for kinase activity and their protein
levels are intimately linked to the cell cycle stage. A variety of other cdk
regulators such as phosphorylation events, natural inhibitors and complex
stability are discussed. Phosphorylation of various cdk substrates results in
diverse outcomes such as changes in gene expression, formation of prereplicative
complexes and breakdown of the nuclear envelope. Cancer cells evolve in part by
over-riding normal cell cycle regulation. Abnormal cdk activity is accomplished
by cyclin amplification, cdk or substrate mutation as well as inactivation of
inhibitors. The selective growth advantage of cancer cells also stems from
amplification of positive growth signals, mutation of checkpoint and surveillance
genes as well as deregulation of programmed cell death or apoptosis. The full
potential of cancer therapies, such as small molecule inhibitors and gene therapy
among others, focusing on our knowledge of cell cycle regulation has yet to be
reached.
PMID- 10762623
TI - Induction of apoptosis by hexamethylene bisacetamide is p53-dependent associated
with telomerase activity but not with terminal differentiation.
AB - The present study investigated the relationships amongst apoptosis, terminal
differentiation and telomerase activity in human colon carcinoma cells. We found
that hexamethylene bisacetamide (HMBA) induced apoptosis in human colon carcinoma
LoVo cells harbouring wild-type p53 but not in SW1116 cells harbouring mutant
p53. HMBA reduced telomerase activity in both colon carcinoma cells but it did
not induce differentiation in the colon carcinoma cells. Taken together, our
results suggest that HMBA can induce apoptosis via a p53-dependent pathway, but
apoptosis and terminal differentiation may be separately regulated in LoVo cells.
Inhibition of telomerase activity may activate apoptosis through a p53-dependent
mechanism.
PMID- 10762624
TI - Establishment of a visible peritoneal micrometastatic model from a gastric
adenocarcinoma cell line by green fluorescent protein.
AB - To establish a visible peritoneal micrometastatic model, an enhanced green
fluorescent protein (EGFP) expressing plasmid vector was transfected into the
gastric cancer cell line, MKN-45. Highly expressing EGFP cells were injected into
the peritoneal cavity of nude mice. Then, the peritoneum and abdominal organs
were harvested and observed on days 1, 4 and 7. Fluorescence stereomicroscopy
identified peritoneal micrometastases that had been undetected by
stereomicroscopy. Micrometastases as small as a single cell are detectable in
this model. This peritoneal micrometastatic model should be a useful tool for
research on metastasis of gastric cancer.
PMID- 10762625
TI - Gene delivery with optimized electroporation parameters shows potential for
treatment of gliomas.
AB - Electroporation, a standard laboratory method of introducing exogenous molecules
into cells, has been gaining importance as a very effective non-viral physical
technique of gene delivery. In this study, we have used subcutaneous model of the
C6 rat glioma cells and established an optimal condition to obtain very high gene
expression in tumor tissues using both reporter and functional genes. Tumors
grown on the flanks of Wistar rats are exposed and directly injected with plasmid
DNA having the constructs of luciferase, green fluorescent protein and, the
fragment of the diphtheria toxin, DT-A. The tumors are then subjected to square
wave pulses from an electroporator. Gene expression is found to be several orders
of magnitude higher when the tumors are pulsed with the optimized electrical
parameters compared to the controls. For luciferase, the enhancement is
approximately 135-fold, for the green fluorescent protein, gene expression is
seen over a wide area within the sections examined, as contrast to a few punctate
dots in the control specimens, and finally, DT-A shows massive death in the tumor
tissue. A special circular array of six needles through which pulses are
delivered with rotating electric field is found to be highly efficient in
transferring genes inside the tumor. Direct injection of plasmid DNA followed by
electroporation allows very high in vivo gene transfer and its subsequent
expression into tumor tissues. This method may be applicable to any solid tumor.
PMID- 10762626
TI - Identification of the full-length KIAA0591 gene encoding a novel kinesin-related
protein which is mapped to the neuroblastoma suppressor gene locus at 1p36.2.
AB - The distal region of a short arm of chromosome 1p is frequently deleted in many
human cancers including neuroblastoma (NBL), in which it has been narrowed down
to the smallest region of overlap between D1S244 and D1S214 (approximately 7 cM).
During the search for the candidate tumor suppressor genes mapped within the
region, we found the KIAA0591 gene which encoded a new human kinesin-related
protein with a homology to human axonal transporter of synaptic vesicles (ATSV).
The kinesin is an intracellular motor protein and often associated with neuronal
differentiation and survival. Here we identified a complete open reading frame of
the KIAA0591 gene by screening a cDNA library derived from human substantia
nigra. The KIAA0591 protein contains a possible pleckstrin homology (PH) domain
at its carboxy-terminus. However, it did not possess a force-generating motor
domain which is well conserved among kinesin superfamily members (KIFs). Northern
blot analysis demonstrated that KIAA0591 mRNA was preferentially expressed in
both adult and fetal brains, kidney, skeletal muscle and pancreas. KIAA0591 was
expressed in favorable NBLs at higher levels than in unfavorable NBLs, although
RT-PCR SSCP analysis showed no mutation within the coding region of the KIAA0591
gene, when 8 neuroblastoma tissues and 15 neuroblastoma-derived cell lines were
examined. Thus, the full-length KIAA0591 gene may be a novel member of human KIF
superfamily which lacks motor domain and might function as a tumor suppressor in
an epigenetic but not a classic Knudson's manner.
PMID- 10762627
TI - Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer
cell line is associated with TRAIL resistance.
AB - The family of tumor necrosis factor related apoptosis inducing ligand (TRAIL)
receptors, including the pro-apoptotic DR4 and p53-regulated KILLER/DR5, as well
as the decoys TRID and TRUNDD, are all located on human chromosome 8p21-22. This
region of the genome is frequently altered in head and neck cancer. We previously
reported that KILLER/DR5 can be mutationally inactivated in head and neck cancer.
Here, we report that the FaDu nasopharyngeal cancer cell line contains an
abnormal chromosome 8p21-22 region. In addition, there appears to be a homozygous
deletion involving DR4 but not KILLER/DR5 in FaDu cells. The homozygous loss
within the DR4 gene encompasses its death domain, which is required for apoptotic
signaling. The deletion of DR4 in FaDu cells is associated with resistance to the
cytotoxic effects of TRAIL. Re-introduction of wild-type DR4 leads to apoptosis
and restores TRAIL sensitivity of FaDu cells. These observations suggest that the
death inducing DR4 receptor gene may be a rare target for inactivation in human
cancer and that DR4 loss may contribute to resistance to TRAIL therapy.
PMID- 10762628
TI - Pit pattern diagnosis of early colorectal carcinoma by magnifying colonoscopy:
clinical and histological implications.
AB - The relation between subclassification of V type pit pattern and histopathologic
features, particularly, in regards to the invasion depth, was examined in 75
cases of early colorectal carcinoma. After we classified two grades (VA, VN) of V
type pit pattern, we subclassified VN type pit pattern into three subtypes (Grade
A, B, and C) according to the degree of appearance of VN pit pattern. V type pit
pattern subclassification was diagnosed with use of a magnifying colonoscope.
There were 37 VA type lesions, 8 VN.Grade A type, 16 VN.Grade B type, and 14
VN.Grade C type lesions. The incidence of submucosal massive invasion (sm2, sm3)
rates was 5 (14%) of the 37 VA type lesions, 3 (38%) of the 8 VN.Grade A type, 15
(94%) of the 16 VN.Grade B type and 14 (100%) of the 14 VN.Grade C type lesions,
respectively. The incidence of desmoplastic reaction (++) levels in VN.Grade B
and C type lesions was significantly higher than that in VA type lesions
(P<0.01), and that in VN.Grade C type lesions was significantly higher than that
in VN.Grade A type lesions (P<0.05). The incidence of pit disorder or destruction
(+) and (++) levels in VN.Grade B and C type lesions was significantly higher
than that in VA type lesions (P<0.01), and that in VN.Grade C type lesions was
significantly higher than that in VN.Grade A type lesions (P<0.01). The incidence
of high grade carcinoma in VN.Grade B and C type lesions was significantly higher
than that in VA type lesions (P<0.01), and that in VN.Grade C type lesions was
significantly higher than that in VN.Grade A type lesions (P<0.05). These
findings indicate that V type pit pattern subclassification, including our new
subtype, is useful for predicting the detail invasion depth of early colorectal
carcinoma. These V pit pattern subtypes are based on the degrees of desmoplastic
reaction, pit disorder or destruction, and histologic grade of carcinoma.
PMID- 10762629
TI - Neonatal estradiol exposure alters mouse mammary estrogen receptor alpha
expression.
AB - The rate of prepubertal ductal morphogenesis as well as the incidence of
hyperplastic growth in the adult mouse mammary gland is enhanced by 5 days of
neonatal estradiol exposure. It is unknown whether estradiol acts through its
nuclear receptor to affect growth in the neonatal gland. Immunohistochemical
analysis indicates that estrogen receptor alpha (ER) is present in both the
mammary epithelium and stroma before estradiol exposure is initiated at day 1. By
7 days of age, the frequency of ER-positive epithelial and stromal cells is
significantly reduced in mammary glands of estradiol-exposed mice compared to
controls. Coincident with this decrease in mammary ER is growth inhibition of the
estradiol-exposed gland. At day 21, the exposed glands exhibit precocious
epithelial outgrowth while significantly fewer stromal cells express ER compared
to controls. By day 35, the exposed epithelium fills the fat pad while the
exposed stromal cells express significantly more ER. To study the function of
mammary ER, we have established mammary epithelial cell lines from oil and
estradiol treated mice. Two cell lines from oil-treated and two from estradiol
exposed glands maintain ER expression in culture. Transient transfection of these
ER-positive cell lines with a reporter vector containing an estrogen response
element (ERE) demonstrates that the immunodetected ER is functional as a
transcription factor in response to 100 nM estradiol. The in vitro
transcriptional activity in response to estradiol is anti-estrogen sensitive,
requires the presence of the ERE, and is independent of neonatal treatment in
vivo. Our data indicate that neonatal estradiol exposure alters ER expression and
mammary growth, but does not alter ER function.
PMID- 10762630
TI - Patched 2, located in 1p32-34, is not mutated in high stage neuroblastoma tumors.
AB - Neuroblastoma is a childhood malignancy originating from cells of the sympathetic
nervous system, exhibiting a marked diversity in outcome, with spontaneous
regression at one end of the spectrum and severe disease and death at the other
end. Features associated with frequent recurrence, a poor prognosis, and high
tumor stage are loss of heterozygosity in the distal region of chromosome 1p and
amplification of the N-myc gene. Patched 2 is a novel homologue to the tumor
suppressor gene Patched 1, and has been mapped to 1p32-34, a part of chromosome 1
frequently deleted in high stage neuroblastoma tumors. RT-PCR analysis of 9
neuroblastoma cell lines showed expression of both Patched 1 and 2. We analyzed
14, mainly high stage, neuroblastoma tumors for mutations in the Patched 2 gene
with denaturing HPLC using the Wave DNA fragment analysis system. In four tumor
samples variations were detected within the coding sequence, and two of them gave
rise to amino-acid substitutions. These variations were, however, also detected
in normal DNA from the respective patients. We conclude that Patched 2 is
expressed, but not frequently mutated, in high stage neuroblastomas and is
therefore not likely to be involved in the genesis of this tumor.
PMID- 10762631
TI - p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non
small cell lung cancer.
AB - p21 (p21WAF1/CIP1) is involved in cell cycle regulation, as an inhibitor of
cyclin dependent kinases (CDK2, CDK4 and CDK6). However, subsequent in vitro
studies have suggested that p21 may influence this process by an additional
mechanism, in particular through the regulation of cyclin D1 subcellular
localisation. This study of primary resectable non-small cell lung cancer (NSCLC)
was designed to examine p21 functions in association with the expression of
cyclin D1 (including its subcellular localisation), p16INK4a and pRb. p21
expression was examined in 50 NSCLC (stage I-IIIA) and in several normal lung
samples all of which had previously been studied for cyclin D1 (DNA, RT-PCR,
immunostaining), p16INK4a (DNA, RT-PCR, immunostaining), and pRb
(immunostaining). As assessed by immunoblotting and immunostaining, p21 was
expressed at low levels in normal lung tissue with immunoreactivity seen in a
small number of bronchial epithelial cells only. In NSCLC, p21 expression (> or
=10% of positive cells) was observed in 42% (21/50) of cases. High p21 expression
was associated with well differentiated tumours (p = 0.01) and cyclin D1 nuclear
staining (p = 0.02). Furthermore, we found an inverse correlation with p16INK4a
(p = 0.004) and a direct correlation with pRb expression (p = 0.02). Risk of
relapse was associated with p16INK4a and p21 status with no relapse in patients
with normal p16INK4a and p21. Our results confirm that a large number of NSCLC
have a low level of p21 expression. The associations of p21 and nuclear cyclin
D1, pRb, p16INK4a support the relevance of pathways linked to lung carcinogenesis
that involve p21 but may act in addition to direct CDK inhibition.
PMID- 10762632
TI - Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs,
into MRP-overexpressing drug resistant cells.
AB - Multidrug resistance associated protein (MRP) is one of drug transport membranes
that confer multidrug resistance in cancer cells. Multidrug resistance has been
known to be associated with resistance to apoptosis. In this study, using MRP
overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the
expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs
between drug sensitive KB and its resistant KB/7D cells. We also examined whether
the introduction of apoptosis related gene could increase the sensitivity to
anticancer drugs in association with apoptotic cell death. The relative
resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6,
61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and
vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells
was associated with the attenuation of internucleosomal DNA ladder formation in
apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was
decreased in one-fourth as compared to that of KB cells among the apoptosis
genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl
Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA
expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo
cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP
16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in
KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS,
respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on
the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in
KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells.
Collectively, these results indicated that the mechanism(s) of drug resistance in
KB/7D cells could be explained at least by two factors: a) reduced drug
accumulation mediated by MRP; b) resistance to apoptosis due to the decreased
expression of the bcl-Xs gene. These results also indicated that the multidrug
resistance mediated by MRP might be partially overcome by introducing apoptosis
gene into drug resistant cells without modulation of MRP function in drug
accumulation.
PMID- 10762633
TI - Structure-activity relationships for G2 checkpoint inhibition by caffeine
analogs.
AB - Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the
toxicity of DNA-damaging agents towards p53-defective cancer cells. The
relationship between structure and G2 checkpoint inhibition was determined for 56
caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in
loss of activity, while replacement at position 1 by ethyl or propyl increased
activity slightly. 8-Substituted caffeines retained activity, but were relatively
insoluble. The structure-activity profile did not resemble those for other known
pharmacological activities of caffeine. The active analogs also potentiated the
killing of p53-defective cells by ionizing radiation, but none was as effective
as caffeine.
PMID- 10762635
TI - Enhanced radiation killing by 5-fluorouracil of biliary tract cancer cell lines.
AB - Despite the frequent clinical use of 5-fluorouracil (5-FU) in combination with
radiotherapy for patients with biliary tract cancers, data remain scarce
concerning specifically the influence of 5-FU on the sensitivity of these cancer
cells to radiation. The present study was carried out to evaluate the effects of
concomitant treatment with 5-FU on radiation-induced cell killing in two
established human biliary tract cancer cell lines (Mz-ChA-2 and SK-ChA-1 cells).
These lines were chosen as we have previously shown that SK-ChA-1 cells are
significantly more resistant to both radiation and 5-FU than Mz-ChA-2 cells.
Clonogenic survival was employed as the end-point for cell killing.
Administration of 5-FU at LD50 doses to each cell line significantly enhanced
radiation-induced cell killing. The enhancement ratio (ER) was obtained by
dividing the radiation dose required to decrease the cell survival fraction to
37% (D0) by the dose to decrease cell survival to the same level when the cells
were also treated with 5-FU. The ER in each of the cell lines was greater when
they were incubated with 5-FU after radiation rather than prior to radiation.
Longer exposure times with 5-FU resulted in enhanced radiation killing. The ER
was significantly higher in the radioresistant cell line than in the
radiosensitive line. These findings suggest that therapy with radiation and 5-FU
may be of value as components of multidisciplinary treatment for biliary tract
cancer. Protracted low dose exposure to 5-FU may prove to be most efficacious in
enhancing the effects of radiation therapy.
PMID- 10762634
TI - Electrochemotherapy can eradicate established colorectal carcinoma and leaves a
systemic protective memory in mice.
AB - Mice bearing subcutaneously established colorectal carcinoma (CRC) were given
intratumoral, intravenous or intraperitoneal injection of various doses of
bleomycin (BLM), followed by the delivery of direct current, square wave electric
pulses to the tumor. Approximately 50% of animals treated with
electrochemotherapy with BLM had completely eradicated established CRC tumors.
Importantly, it was shown that CRC-specific cytotoxic T lymphocytes were elicited
in the spleens of cured animals, resulting in the protection of the rechallenge
with CRC. These results indicate that electrochemotherapy with BLM is promising
for the treatment of metastatic CRC as well as the original lesion.
PMID- 10762636
TI - Telomerase activity and telomere length in human ovarian cancer and melanoma cell
lines: correlation with sensitivity to DNA damaging agents.
AB - Since telomerase plays a role in cellular resistance to apoptosis, which is the
primary mode of cell death induced by several drugs, telomerase could be involved
in determining the chemosensitivity profile of tumor cells. Thus, we investigated
the relationship between telomerase activity, telomere length and
chemosensitivity to effective antitumor agents in a panel of human melanoma and
ovarian cancer cell lines. Telomerase activity, as detected by the telomeric
repeat amplification protocol, ranged from 0.58 to 1.10 arbitrary units in
individual cell lines, with similar median values for melanoma and ovarian
carcinoma cell lines (0.80 vs. 0.90). Telomeres were generally longer in melanoma
than in ovarian carcinoma cell lines, with a more than 2-fold median telomere
restriction fragment length (7.74 vs. 3.82 kb). No significant correlation was
evidenced between the two telomere-related parameters and cell population
doubling time, DNA index or TP53 gene status. No precise relation was found
between telomerase activity and cellular sensitivity to different DNA damaging
agents including doxorubicin, cisplatin and the multinuclear platinum compound
BBR 3464. In contrast, longer telomeres were associated to resistance to the
drugs, even though the association reached statistical significance only for
cisplatin. Since platinum compounds may have affinity for telomere sequences, it
is conceivable that the interaction is relevant for drug sensitivity/resistance
status depending on telomere length.
PMID- 10762637
TI - Accumulation of intracellular platinum is correlated with intrinsic cisplatin
resistance in human bladder cancer cell lines.
AB - We investigated the mechanism of intrinsic resistance to cisplatin in human
transitional cell cancer (TCC) using 7 human bladder cancer cell lines, which
were derived from untreated TCC of the urinary bladder. The sensitivity to
cisplatin was different from cell line to cell line, and a 15-fold difference was
observed between the most sensitive line and the most resistant line. No
significant correlation was observed between the content of intracellular
glutathione and the resistance to cisplatin. In contrast, a positive correlation
was seen between intracellular cisplatin accumulation and cisplatin resistance.
The expression of drug resistance-related genes including glutathione S
transferase pi, gamma-glutamyl-cysteine synthetase, multidrug resistance-1,
multidrug resistance-associated protein, DNA topoisomerase I, topoisomerase II,
human canalicular multispecific organic anion transporter, and thioredoxin was
not significantly related to cisplatin resistance. These data suggest that
intracellular cisplatin may contribute to intrinsic cisplatin resistance and may
therefore be a useful biomarker to predict cisplatin sensitivity in human
untreated TCC.
PMID- 10762638
TI - Luteinizing hormone-releasing hormone as an autocrine growth factor in ES-2
ovarian cancer cell line.
AB - Agonistic and antagonistic analogs of luteinizing hormone-releasing hormone
(LHRH) inhibit the growth of various cancers in vivo. This effect is mainly
exerted through the suppression of the pituitary-gonadal axis and the creation of
a state of sex steroid deprivation. In addition, much evidence has been
accumulated in the past few years that LHRH analogs can also have direct effects
on tumor growth mediated by specific LHRH receptors (-R) on tumor cells. Although
an involvement of LHRH in the proliferation of some cancer cells has been
postulated, it is still not clear at present whether LHRH produced locally has a
stimulatory or inhibitory effect. In the present study we investigated whether
LHRH can function as an autocrine growth factor in ovarian cancer. ES-2 human
ovarian cancer cell line expresses mRNA for LHRH, which is apparently translated
into peptide LHRH and then secreted by the cells, as demonstrated for the first
time by the detection of LHRH-like immunoreactivity in conditioned media from the
cells cultured in vitro. ES-2 cells also express mRNA for LHRH receptors. [D
Trp6]LHRH agonist at 10 ng/ml stimulates the proliferation of ES-2 in vitro after
48 h, but is inhibitory after 72 h and at concentrations of 1000 ng/ml. LHRH
antagonist Cetrorelix inhibits growth of ES-2 cell line only at 1000 ng/ml. The
incubation of ES-2 ovarian cancer cells in vitro with an LHRH antibody inhibited
cell proliferation in a time and concentration-dependent manner. Collectively,
our results suggest that LHRH may function as an autocrine growth factor in
ovarian cancer.
PMID- 10762639
TI - Virulizin-2gamma, a novel immunotherapeutic agent, in treatment of human
pancreatic cancer xenografts.
AB - Virulizin-2gamma, a novel biological response modifier extracted from bovine
bile, has shown in clinical studies a significant antitumor activity against
pancreatic cancer. We report here the results of preclinical evaluation of
Virulizin-2gamma in treatment of human pancreatic cancer xenograft in nude mice.
In this in vivo study, 14 daily bolus intraperitoneal administrations of
Virulizin-2gamma (0.2 ml/mouse/day) significantly inhibited the growth of BxPC-3
human pancreatic tumor xenografts, with T/C value of 60%. Virulizin-2gamma also
potentiated the antitumor activity of gemcitabine (120 mg/kg x4, q3d) in this
tumor model. The combination therapy resulted in T/C values of 26% compared to
gemcitabine alone (T/C 33%). In addition, based on body weight observation, no
signs of toxicity related to treatment with Virulizin-2gamma, either as a single
agent or when combined with gemcitabine were found. Virulizin-2gamma was well
tolerated by the mice. The data from in vitro studies revealed that Virulizin
2gamma did not have direct cytotoxicity against cultured tumor cell lines,
indicating that the in vivo antitumor activity is likely due to its
immunomodulating effects on host immune cells. These preclinical results
supported the safety and efficacy observed in clinical studies and indicated that
Virulizin-2gamma is a promising immunotherapeutic agent for treatment of
pancreatic cancer and worthy of further clinical evaluation.
PMID- 10762640
TI - A phase III randomized study comparing oral doxifluridine and oral 5-fluorouracil
after curative resection of gastric cancer.
AB - To investigate the usefulness of oral doxifluridine (5'-DFUR), an active
intermediate metabolite of capecitabine (XELODA), in gastric cancer patients
after curative resection, we conducted a phase III randomized controlled study to
compare oral 5'-DFUR and oral 5-fluorouracil (5-FU). 485 gastric cancer patients
with Stage II or III operative findings at curative resection were registered and
administered 5'-DFUR (460 mg/m2/day, daily, for two years) or 5-FU (115
mg/m2/day, daily, for the same period). Although no differences in overall
survival or disease-free survival were detected, subset analysis showed 5'-DFUR
was more effective in reducing peritoneal recurrence than 5-FU (p = 0.047), and
in patients with Stage III or stage IIIb (histologic findings) in the 5'-DFUR
group had more favorable disease-free survival curves and survival curves than
the 5-FU group with similar stages.
PMID- 10762641
TI - Anti-tumor effects of 25-hydroxycholesterol and low-dose recombinant tumor
necrosis factor-alpha on rat liver tumorigenesis: modulated differentiation
therapy for hepatocellular carcinoma.
AB - Previously, we have demonstrated that treatment of rat AH136B ascites hepatoma
cells with 25-hydroxycholesterol (25-OH) induces apoptosis. In this study, to
elucidate whether modulated differentiation therapy may be useful in treating
patients with hepatoma, we assayed the effects of 25-OH and/or tumor necrosis
factor-alpha (TNF) on rat AH136B ascites hepatoma cells in vivo. Here we show
that a high concentration of TNF (250 U/ml) mediated a stronger cytocidal effect
than a low concentration of TNF (25 U/ml) in vitro. Flow cytometric DNA analysis
also showed that treatment of cells with the high concentration of TNF (250 U/ml)
increased the percentage of AH136B cells in the G0/G1 phase, while 25 U/ml of TNF
did not cause any marked change in cell kinetics. In in vivo experiments, 25-OH
(80 microg/rat) and TNF (500 U/rat) were administered after transplanting AH136B
cells into Donryu rats intraperitoneally. We found that tumor development was
completely inhibited by this treatment in 3 of 9 rats, and their 40-day survival
rate was 44%; in contrast, rats administered 25-OH (80 microg/rat) alone or TNF
(500 U/ml) alone developed peritonitis carcinomatosa, and died within 13 days of
inoculation. These findings suggest that local combined treatment with 25
hydroxycholesterol and low-dose TNF can induce synergistic anti-tumor effects.
PMID- 10762642
TI - Tyrosine phosphorylation of an erbB-2 related p90 protein induced by estrogen in
human breast epithelial cells.
AB - Estrogen induced erbB-2 tyrosine kinase activity in human breast epithelial cells
irrespective of estrogen receptor expression. MCF10A is an immortal normal human
breast epithelial cell line which does not express estrogen receptor. After
treatment of MCF10A cells with estradiol-17beta (E2), a phosphorylated 90 kDa
protein which co-immunoprecipitates with p185erbB-2 is detected. The response is
transient, detected after 1-5 min exposure to E2, and dose dependent, occurring
at 10-10 M E2. A similar response was observed for MCF10A cells transfected with
an estrogen receptor, estrogen receptor expressing MCF-7 cells, and estrogen
receptor-negative MDA-MB-435 cells but at 10-11 M E2. Overexpression of c-erbB-2
in MCF10A cells prolonged the phosphorylated p90 response to E2.
PMID- 10762643
TI - Proto-oncogene ras GTPase-linked induction of glutathione-S-transferase by growth
factors in PC12 cells.
AB - This report provides evidence linking activation of Ras GTPase by growth factors
and induction of glutathione-S-transferase isozymes in PC12 cells. Ras GTPase was
activated by EGF, NGF, insulin and phorbolester in PC12 cells. Activation of Ras
GTPase was found to be associated with induction of the expression of GST mu and
pi isoenzymes while there was no detectable induction of GST alpha expression.
GST pi was found to be induced by all the Ras GTPase activating agents tested
while activation of Ras by phorbolester and insulin induced expression of GST mu
only. These results suggest a role of Ras, at least in part, in controlling the
expression of GST and that there might be independent signalling pathways for the
expression of different GST isoenzymes. GST activity was found to be very high (4
fold) in the lysate obtained from retinoic acid treated PC12 cells when compared
with untreated cells. Induction of GST expression was found to be initiated
within 30 min of retinoic acid treatment in PC12 cells reaching a maximum level
at 4 h. However, immunoblot analysis showed that retinoic acid (RA), unlike
mitogens/growth factors, weakly induced the expression of GST pi but not the
expression of alpha, mu and microsomal GSTs. Overxpression of inhibitory
polypeptides that block signals generated from Ras and Cdc42 was found to reverse
the retinoic acid activation-dependent induction of GST expression in PC12 cells.
These results provide evidence for the first time suggesting a novel role of Ras
GTPase in the regulation of GST expression which might have a significant
implication in developing drug resistance and/or growth of cancer cells.
PMID- 10762644
TI - Identification and characterization of amino acid starvation-induced CD24 gene in
MCF-7 human breast cancer cells.
AB - Amino acid starvation is a pathophysiological condition that results in protein
deprivation due to cancer cachexia. Using the method of differential display of
reverse transcription PCR (DDRT-PCR), we isolated a cDNA fragment in MCF-7 human
breast cancer cells in response to amino acid starvation, which was identical
with human CD24 gene. Northern blot results showed that CD24 mRNA in MCF-7 cells
was constitutively expressed and significantly upregulated upon amino acid
starvation. This stimulation was time-dependent and the maximal response was at
24 h. The expression of the amino acid starvation-induced CD24 mRNA decreased
when starved cells were returned to a medium supplemented with amino acids. This
repressive response was also time-dependent. Amino acid starvation-induced CD24
mRNA expression in MCF-7 cells was completely blocked by actinomycin D, which
suggested that the regulation of CD24 mRNA by amino acid availability occurred at
transcriptional level. When amino acid-starved cells were refed with amino acids
for 8 h, the expression of CD24 mRNA declined to the basal levels confirming that
CD24 mRNA expression could be stimulated by amino acid starvation. Interestingly,
CD24 mRNA was poorly detected in MCF-10 cells, a benign human breast epithelial
cell line. In conclusion, CD24 mRNA expression in MCF-7 cells was upregulated
upon amino acid starvation. This amino acid starvation-induced upregulation of
CD24 mRNA occurred at transcriptional level. The regulation of CD24 mRNA in MCF-7
cells by amino acid availability may play an important role in the progression
and metastasis of human breast cancer.
PMID- 10762645
TI - PAR, a novel androgen regulated gene, ubiquitously expressed in normal and
malignant cells.
AB - During our work on the mechanism of hormone resistance of prostatic carcinomas, a
novel gene that we called PAR (prostate androgen regulated) was isolated from an
androgen resistant subline (LNCaP-OM) using a modified representational
difference analysis. The complete sequence of the gene cDNA has 1029 nucleotides
with a continuous reading frame of 438 bases encoding for 146 amino acids. Its
deduced amino acid sequence has motifs for myristoylation and phosphorylation by
protein kinase C. The PAR gene was overexpressed in all prostatic carcinoma cell
lines studied (LNCaP, DU145, PC3 and LNCaP-OM) compared to the normal prostatic
tissue. Furthermore, its expression was higher in androgen resistant prostate
cancer lines DU145, PC3 and LNCaP-OM, in comparison to androgen sensitive LNCaP
cells. The expression of this gene was down regulated by androgens in androgen
sensitive prostate cells, but not in the hormone resistant cell lines. The PAR
mRNA was detected in all 29 normal human tissues studied and overexpressed in
most (67%) of their malignant counterparts. The PAR expression was higher in MCF7
and T47D breast cancer cell lines, as well as in all primary breast tumors
studied compared to their normal tissue counterparts. The biological function of
this gene is still unknown, but its ubiquitous expression in normal tissues and
its overexpression in some malignancies suggest the PAR involvement in certain
basic cellular processes and possibly, in malignant transformation.
PMID- 10762646
TI - Signaling pathways induced by vascular endothelial growth factor (review).
AB - Vasculogenesis and angiogenesis are the mechanisms responsible for the
development of the blood vessels. Angiogenesis refers to the formation of
capillaries from pre-existing vessels in the embryo and adult organism, while
vasculogenesis is the development of new blood vessels from the differentiation
of endothelial precursors (angioblasts) in situ. Vascular endothelial growth
factor (VEGF) family members are major mediators of vasculogenesis and
angiogenesis both during development and in pathological conditions. VEGF has a
variety of effects on vascular endothelium, including the ability to promote
endothelial cell viability, mitogenesis, chemotaxis, and vascular permeability.
It mediates its activity mainly via two tyrosine kinase receptors, VEGFR-1 (flt
1) and VEGFR-2 (flk-1/KDR), although other receptors, such as neuropilin-1 and
2, can also bind VEGF. Another tyrosine kinase receptor, VEGFR-3 (flt-4) binds
VEGF-C and VEGF-D and is more important in the development of lymphatic vessels.
While the functional effects of VEGF on endothelial cells has been well studied,
not as much is known about VEGF signaling. This review summarizes the different
pathways known to be involved in VEGF signal transduction and the biological
responses triggered by the VEGF signaling cascade.
PMID- 10762647
TI - Mechanism of hepatocellular dysfunction during sepsis: the role of gut-derived
norepinephrine (review).
AB - Despite major advances in the management of trauma victims, the incidence of
sepsis has increased significantly over the past two decades. The increasingly
high morbidity and mortality associated with sepsis could be attributed to the
fact that early alterations of cellular functions are not recognized, thereby
leading to delayed or inadequate treatment of the septic patient. In this regard,
studies have demonstrated that hepatocellular function is depressed early after
the onset of sepsis. Due to its major role in metabolism and host defense
mechanisms, it is becoming increasingly evident that the liver is an important
organ in the development of multiple organ dysfunction during sepsis. Mediators
which are released from the gut have been implicated in initiating hepatocellular
dysfunction via the release of inflammatory cytokines such as TNF-alpha by
Kupffer cells, the resident macrophages present in the hepatic sinusoids. Kupffer
cells, by virtue of their location in the mainstream of splanchnic blood flow,
are positioned to receive a constant exposure to gut-derived mediators known to
activate macrophages. In this review article, we will first describe the animal
model of cecal ligation and puncture which has led to our understanding of the
consequences of sepsis. We will then discuss the occurrence of hepatocellular
dysfunction during early sepsis. The mechanism responsible for such a deleterious
alteration in organ function, focusing especially on the role of gut-derived
norepinephrine and its effect on TNF-alpha release by Kupffer cells, will be
specifically discussed. Moreover, we will discuss potential approaches for
modulating Kupffer cell inflammatory cytokine release and improving
hepatocellular function during sepsis.
PMID- 10762648
TI - nPKCdelta a new therapeutic marker for melanoma metastasis? (Review).
AB - Melanoma metastasis is almost uniformly fatal. The identification of signal
transduction as crucial effectors for tumorigenesis suggests modalities of gene
therapy as well as design of specific drugs. the possible use of nPKCdelta as a
therapeutic target is reviewed and discussed. Motivated by recent results, we
propose a model in which nPKCdelta modulates melanin synthesis as well as
metastasis.
PMID- 10762649
TI - Frequent expression of soluble Fas and Fas ligand in Chinese stomach cancer and
its preneoplastic lesions.
AB - To investigate the frequency and pattern of Fas and FasL expression in the
gastric mucosa at different stages of gastrocarcinogenesis, the combined
examinations of pathology, immunocytochemistry and Western blot hybridisation
were performed on the cancer specimens as well as their preneoplastic and non
cancerous counterparts. The frequencies of Fas and FasL expression were found to
be 6.3% (1/16) and 62.5% (10/16) in non-cancerous mucosa, 60% (6/10) and 80%
(8/10) in atrophic gastritis, 75% (9/12) and 83% (10/12) in intestinal
metaplasia, 100% in both dysplasia Grades II (20/20) and Grade III (15/15) and 4
types of gastric carcinomas (74/74). Two forms of FasL protein in 37 kDa and 26
kDa were detected in all FasL+ cases. Soluble Fas (30 kDa) but not the membrane
type (43 kDa) is predominantly expressed in the Fas+ cases. Our data thus suggest
a close correlation of soluble Fas with stomach tumour progression P<0.01. The
sFas protein, together with the tumor-derived soluble and membrane FasL, may
confer on the transforming and transformed gastric epithelial cells an immune
advantage enabling escape from endogenous and exogenous suicide signal(s).
PMID- 10762650
TI - Characterization of the nuclear localization signal in the DNA helicase
responsible for Bloom syndrome.
AB - Bloom syndrome (BS) is a rare genetic disorder characterized by small body size,
photosensitivity, immunodeficiency and a high predisposition to various types of
cancer. BLM was identified as the causative gene for BS. The BLM protein is
homologous to DNA helicase and has two basic amino acid clusters in its C
terminal region. Previously, we reported that the distal arm of these basic amino
acids clusters in the BLM protein functioned as the nuclear localization signal
(NLS) of the protein. In this study, we generated plasmid constructs for
expression of enhanced green fluorescent protein (EGFP) fused with various BLM
protein variants having a mutation with deletions or substitutions in the basic
amino acid and analyzed the subcellular localization of the expressed proteins.
The EGFP-fused protein containing the basic amino acid cluster region proximal to
the C-terminus of BLM helicase was localized exclusively in the nucleus. However,
the EGFP-BLM proteins that lacked either Arg1344 or Lys1346 distributed in both
the cytoplasm and the nucleus equally. Deletion of Arg1347 also resulted in
localization in both the nucleus and cytoplasm, and substitution of Arg1344,
Lys1346, Arg1347 or Arg1348 with non-basic amino acids reduced the nuclear
localization of BLM protein. Mouse BLM protein which also migrate to the nucleus
has two basic amino acid clusters in the C-terminus and the basic amino acids
(Lys1346-Pro1347-Lys1348-Arg1349-Arg1350) proximal to the C-terminus are
conserved between mouse and human. These findings suggest that the Arg1344
Ser1345-Lys1346-Arg1347 sequence at the C-terminus of the human BLM protein is
essential for nuclear localization of this protein.
PMID- 10762651
TI - New chromosomal breakpoints in non-Hodgkin's lymphomas revealed by spectral
karyotyping and G-banding.
AB - Chromosomal rearrangements in short term cultures from nine cases of non
Hodgkin's lymphomas (NHL) were characterized by G-banding, spectral karyotyping
(SKY), and fluorescence in situ hybridization (FISH). Eight of the nine cases
showed complex karyotypes with chromosomal aberrations which, in most cases,
could not be fully characterized by traditional G-banding analysis alone.
Karyotypic abnormalities of special interest were marker chromosomes and
chromosomes with added unidentified chromosomal material, as previously non
identified chromosomal translocations were hidden behind these aberrations. SKY
and FISH analysis, as a complement to banding analysis, significantly improved
the karyotypes in seven of the nine cases and unveiled 21 previously unidentified
rearrangements with novel translocation breakpoints. Traditional G-banding alone
revealed seven new rearrangements, which were all confirmed by SKY. None of these
new aberrations occurred as single clonal rearrangements but as parts of complex
karyotypes. Nevertheless, the chromosomal break-point regions identified should
be considered as potential hot spots for genes involved in the tumorigenesis of
the malignancy.
PMID- 10762652
TI - Possible role of diadenosine polyphosphates in glucose-stimulated insulin
release: effects of NaF upon metabolic and functional variables in rat isolated
islets.
AB - Diadenosine polyphosphates, such as diadenosine triphosphate (A2P3) and
diadenosine tetraphosphate (A2P4), were recently proposed to participate in the
stimulus-secretion coupling for nutrient-stimulated insulin release. Since NaF,
an inhibitor of inorganic pyrophosphatase, was reported to lower A2P3 and A2P4
content in glucose-stimulated pancreatic islets, its effects upon metabolic,
cationic, biosynthetic and secretory variables in rat pancreatic islets were
investigated in the present study. Up to a concentration close to 0.1 mM, NaF
failed to affect most of these variables, except for a decrease in 45Ca net
uptake. Much higher concentrations of NaF (e.g. 5.0 mM) were required to cause
inhibition of the metabolic, ionic, biosynthetic and secretory responses of the
islets to nutrient secretagogues. Yet, even at this high concentration, NaF
failed to lower the islet content in tritiated A2P3 and A2P4 in islets
prelabelled with [2,8-3H]adenosine and failed to prevent the glucose-induced
increase in such a content. It is concluded, therefore, that NaF may not
represent a suitable tool to assess the participation of diadenosine
polyphosphates in the process of nutrient-induced insulin secretion.
PMID- 10762653
TI - Clinical significance of tenascin-C expression in osteosarcoma: tenascin-C
promotes distant metastases of osteosarcoma.
AB - Tenascin-C (TN-C) is one of extracellular matrix glycoproteins. We have
immunohistochemically examined the TN-C expression of 33 primary osteosarcoma
paraffin-embedded samples. The TN-C expression of the patient group with
metastases was higher than that of the group without metastases at significant
difference, and the survival curves show a tendency for poor outcome in the high
grade staining group. Moreover, the supplemental TN-C had an effect of easier
migration of a human osteosarcoma cell line (HOS) in vitro. The results may
suggest that TN-C help osteosarcoma cells to migrate and to metastasize.
PMID- 10762654
TI - Free DNA induces modification on the protein synthesis profile of human
peripheral blood mononuclear cells of healthy donors.
AB - Understanding how free DNA might act as a signal between cells is important for
knowing how DNA orchestrates immune responses and for optimizing the therapeutic
of cancer, infection and immunologic diseases. This communication demonstrates
that DNAs from different origins (bacteria, T. cruzi, HeLa cells) and synthetic
oligonucleotide containing an unmethylated CpG motif are capable of inducing
alterations in the protein profile of normal human leukocytes. As far as we know
there have been no similar studies regarding the comparative effects of different
free DNAs on early protein synthesis of human peripheral blood mononuclear cells.
PMID- 10762655
TI - Anabolic effect of genistein in osteoblastic MC3T3-E1 cells.
AB - Genistein is a natural isoflavone found in Leguminosae. The effect of genistein
on osteoblastic MC3T3-E1 cells was investigated. Cells were cultured for 48 h in
the presence of genistein (10(-7)-10(-5) M). Genistein (10(-6) and 10(-5) M)
caused a significant elevation of protein content, alkaline phosphatase activity,
and deoxyriboncleic acid (DNA) content in the cells. The effect of genistein (10
5 M) in increasing protein content, alkaline phosphatase activity and DNA content
in the cells was completely prevented by the presence of cycloheximide (10(-6)
M), an inhibitor of protein synthesis, suggesting that the isoflavone's effect
results from a newly synthesized protein component. The effect of genistein (10(
5) M) in elevating cellular protein content and alkaline phosphatase activity was
completely inhibited by the presence of trifluo-perazine (10(-5) M),
staurosporine (10(-7) M) or vanadate (10(-6) M), various protein kinase
inhibitors. Moreover, genistein (10(-5) M)-increased protein content and alkaline
phosphatase activity in the cells was clearly abolished by the presence of anti
estrogen tamoxifen (10(-6) M). The effect of 17beta-estradiol (10(-9) M) in
elevating protein and alkaline phosphatase activity in the cells was not enhanced
by the presence of genistein (10(-5) M). Genistein's effect might be partly
involved in estrogen action. The present study demonstrates that genistein has an
anabolic effect on osteoblastic MC3T3-E1 cells.
PMID- 10762656
TI - Preferentially deleted chromosome region 9p21 in large hepatocellular carcinomas.
AB - The role of somatic deletions in chromosome 9 and chromosome 22 loci in
hepatocellular carcinomas (HCC) was studied. Twenty-one paired HCC and adjacent
tumor-free liver tissue samples were examined for loss of heterozygosity at six
chromosome 9 and ten chromosome 22 loci. Among informative cases, the highest LOH
rates were observed at 9p21 (40% or 4/10 at IFNA) and 9q23 (23% or 3/13 at
D9S318). Our observed LOH rate at 9p21 was significantly higher than the
background level previously reported for the same tumor type. Clinical data
indicate that chromosome 9p21 deletions occurred preferentially in larger tumors
(>5 cm diameter). However, a sequence analysis of the MTS1 gene coding region in
cases of 9p21 LOH did not reveal any change, suggesting another tumor suppressor
gene as the LOH target.
PMID- 10762657
TI - Fate of 2-deoxy-2-[18F]fluoro-D-glucose in control and diabetic rats.
AB - Recent experiments conducted in vitro have documented a marked difference in the
time course for D-[U-14C]glucose net uptake by pieces of pancreatic tissue versus
isolated pancreatic islets. The present study aimed, therefore, at assessing
whether the endocrine pancreas contributes to a detectable extent to the overall
net uptake of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) by the pancreatic gland. For
this purpose, the radioactive content of the pancreas was compared to that of
plasma, erythrocytes, liver, brain, hypophysis and parotid gland 3 min, 15 min
and 240 min after the intravenous injection of FDG to both control rats and
animals injected with streptozotocin and later treated with insulin or not. In
the control rats, the radioactive content (cpm/mg wet wt.) of erythrocytes was
always lower than that of liver. In other organs, it displayed the following
hierarchy pancreas < parotid < hypophysis < brain, the absolute values being
either lower (3 min) or much higher (240 min) than in liver. In the diabetic
rats, whether treated with insulin or not, the radioactive content of
erythrocytes, pancreas, brain, hypophysis and parotid gland, relative to the
paired value found in liver, was equal or lower than that of control rats when
the animals were hyperglycemic and equal or higher than that of control rats when
the animals became hypoglycemic as the result of intensive insulin treatment.
Even only 3 min after the injection of FDG, and despite persistent hyperglycemia
in the streptozotocin-injected and insulin-treated rats, the pancreas/ liver
paired ratio in radioactive content failed to be significantly lower in the
diabetic animals than in control rats. These findings indicate that 2-deoxy-2
[18F]fluoro-D-glucose is not a suitable tool to detect any preferential labelling
of insulin-producing cells, relative to acinar cells, at least when considering
only the total radioactive content of the pancreatic gland.
PMID- 10762658
TI - Activation of topoisomerase I by poly [ADP-ribose] polymerase.
AB - Poly(ADP-ribose) polymerase (PARP I) and Topoisomerase I (Topo I) were reisolated
from calf thymus to eliminate cross contamination as tested by immunotransblots.
The specific activity of Topo I was greatly increased by added PARP I, following
saturation kinetics. Recombinant PARP I and isolated PARP I at final purity were
indistinguishable in terms of their activation of Topo I. There was a coincidence
of experimentally obtained binding constants and computer generated values based
on the kinetic model, indicating that the association of PARP I and Topo I is
rate limiting in the catalytic activation of Topo I by PARP I. Polypeptide
domains of PARP I that are required for protein-protein binding and protein-DNA
binding also activate Topo I. Fluorescence resonance energy transfer between
fluorophor-labeled PARP I and Topo I was demonstrated. The binding of Topo I to
circular SV40 DNA, assayed either by the formation of a) the sum of non
covalently and covalently attached Topo I to DNA or b) by the covalently bound
transient intermediate in the presence of camptothecin, was augmented when PARP I
protein was bound to SV40 DNA. These binding experiments provide a molecular
basis for the kinetic activation of Topo I by PARP I inasmuch as the increased
superhelicity of SV40 DNA induced by PARP I may facilitate the formation of a
more Topo I-DNA complex that increases the rate of the DNA
breakage-reunion cycle of Topo I catalysis.
PMID- 10762659
TI - Inhibition of growth and stimulation of apoptosis by beta-sitosterol treatment of
MDA-MB-231 human breast cancer cells in culture.
AB - Epidemiological and experimental studies have suggested a protective role of
phytosterols (PS) in the development of some types of cancer such as colon and
prostate cancer. No work has been reported on the role of PS in the development
of breast cancer, the second leading cancer in woman. The present study was
designed to examine the effect of the two most common dietary PS, beta-sitosterol
(SIT) and campesterol, as compared to cholesterol, the main sterol in the Western
diet, on growth, apoptosis and cytotoxicity of MDA-MB-231 human breast cancer
cells in culture. In addition, we investigated the possible role of protein
phosphatase 2A (PP2A), an enzyme that has been shown to regulate growth and
apoptosis in tumor parameters studied. Breast cancer cell growth was found to be
inhibited by 66% after 3 days and 80% after 5 days with 16 microM SIT. Both
campesterol and cholesterol sustained tumor growth at levels comparable to that
of the vehicle control. None of the sterols tested at this level (16 microM)
induced cytotoxicity as measured by lactic dehydrogenase release. SIT
supplementation for 3 days at 16 microM resulted in a 6-fold increase in
apoptosis in cells when compared to cholesterol treated cells. SIT treatment was
found to have no effect on the level and content of tumor cell PP2A. It is
concluded that SIT, by a still unknown mechanism, may offer protection from
breast cancer by inhibiting growth and stimulating apoptosis.
PMID- 10762660
TI - Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients.
AB - Previously, a specific angiogenesis inhibitor, angiostatin, discovered in urine
and serum of tumor-bearing mice, was reported to potently block tumor growth and
metastasis in animal models. Detection of angiostatin and its precursor proteins
in urine from cancer patients has not been reported. Now, we report the
development of an antibody-based analysis system that allows us to detect
angiostatin and plasminogen/plasmin (Pgn/plasmin) in the urine of cancer
patients. The detection system is a combination of a novel lysine-ELISA assay and
Western immunoblot analysis using a specific antibody to human angiostatin and
Pgn/plasmin. High levels of Pgn/plasmin were detected in the urine from various
cancer patients, whereas healthy individuals showed relatively low levels of
urine Pgn/plasmin. Of interest, angiostatin is detectable in urine samples of
patients with various cancers, including acute lymphoblastic leukemia, suggesting
that angiogenesis may play an important role in the development and progression
of leukemia. Our data for the first time show that angiostatin and Pgn/plasmin
are present at relatively high levels in the urine of human cancer patients.
Detection of urine angiostatin in cancer patients helps us not only to understand
the role of this angiogenesis inhibitor in cancer development and progression but
also allows us to develop tools of cancer diagnosis and prognosis. Thus
angiostatin has both therapeutic and diagnostic implications in cancer disease.
PMID- 10762661
TI - A new region of synteny between human chromosome 1p22 and mouse chromosome 5.
AB - By constructing a physical map of the p22 region of human chromosome 1 we have
been able to show the relative orientation of four genes; GFI1, NB4S/EVI5, RPL5
and DR1. Analysis of the mouse physical map shows that the murine orthologs of
these genes are located on mouse chromosome 5. Through this analysis we have
established a new region of synteny between mouse chromosome 5 and human
chromosome region 1p22.
PMID- 10762662
TI - beta-amyloid peptide-induced death of PC 12 cells and cerebellar granule cell
neurons is inhibited by long-term lithium treatment.
AB - Treatment of rat pheochromocytoma cells (PC 12) cells with beta-amyloid peptide
(1-42) for 24 h induced a concentration-dependent decrease in cellular redox
activity in the dose range of 1 to 20 microM. These effects were markedly
attenuated by pretreatment with 2 mM LiCl for 7 days, whereas 1-day pretreatment
was ineffective. Measurements of live and dead cells by double-staining with
fluorescein diacetate and propidium iodide, respectively revealed that protracted
lithium pretreatment attenuated PC 12 cell death induced by beta-amyloid-(1-42)
and cerebellar granule cell death induced by beta-amyloid-(25-35). Preceding PC
12 cell death, beta-amyloid peptide elicited a slight decrease in protein levels
of Bcl-2. Conversely, 7-day pretreatment with lithium resulted in an approximate
doubling of Bcl-2 protein levels in cells treated with or without beta-amyloid
peptide-(1-42). Lithium-induced Bcl-2 upregulation was temporally associated with
the cytoprotective effects of this drug. Thus, lithium protection against beta
amyloid peptide neurotoxicity might involve Bcl-2 overexpression, and lithium
treatment for Alzheimer's disease should be reexamined.
PMID- 10762663
TI - Pharmacology of quinpirole-stimulated [35S]GTPgammaS binding: discrepancy with
receptor binding profile.
AB - Functional consequences of receptor stimulation by quinpirole, a dopamine D(2)
like receptor agonist, were assessed using agonist-stimulated [35S]GTPgammaS
binding in rat striatal membranes. Dopamine receptor antagonists inhibited
quinpirole-stimulated [35SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl
2,3,4, 5-tetrahydro-1H-3-benzazepine), consistent with a dopamine D(2)-like
profile. In contrast, the monoamine oxidase inhibitors Ro 41-1049 (N-(2
aminoethyl)-5-(3-fluorophenyl)-4-thiazolecarboxemide), and (+)- and (-)-deprenyl,
which inhibit [3H]quinpirole binding, had no effect on agonist-independent or
quinpirole-stimulated [35S]GTPgammaS binding. Clorgyline inhibited [35S]GTPgammaS
binding by a non-dopamine D(2) receptor-mediated mechanism. These findings
demonstrate a notable discrepancy between the pharmacological profile of
[3H]quinpirole binding and quinpirole-stimulated [35S]GTPgammaS binding.
PMID- 10762664
TI - Effect of methylene methylimino linkage of antisense oligonucleotide to the
platelet-derived growth factor A-chain on growth of vascular smooth muscle cells
from spontaneously hypertensive rats.
AB - Spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells show
exaggerated growth and increased expression of platelet-derived growth factor
(PDGF) A-chain mRNA. We examined the effect of methylene methylimino linkage of
antisense oligodeoxynucleotide, a novel modification of antisense
oligodeoxynucleotide designed to increase nuclease resistance, to PDGF A-chain on
the exaggerated growth of vascular smooth muscle cells from SHR. Methylene
methylimino-linked oligodeoxynucleotide provided complete resistance against S1
nuclease. Methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF
A-chain resulted in a rapid inhibition of basal DNA synthesis of vascular smooth
muscle cells from SHR. This inhibition was much greater than that produced by
phosphorothioate linkage of antisense oligodeoxynucleotide to PDGF A-chain. The
methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF A-chain
may prove useful in the treatment of arterial proliferative diseases including
hypertension.
PMID- 10762666
TI - High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic
pimozide.
AB - Pimozide is an antipsychotic agent also used to treat facial tics. Pimozide can
cause acquired long QT syndrome and ventricular arrhythmias. To elucidate the
mechanism behind these clinical findings, we examined the effects of pimozide on
the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene;
rapid component of delayed rectifier), Kv1.5 (ultra-rapid delayed rectifier) and
KvLQT1/minK (slow component of delayed rectifier). Using patch clamp
electrophysiology, we found that pimozide was a potent inhibitor of HERG
displaying an IC(50) value of 18 nM. In contrast, pimozide (10 microM) was a weak
inhibitor of KvLQT1/minK and Kv1.5. We conclude that pimozide is a specific, high
affinity antagonist of HERG, and that this interaction leads to prolongation of
cardiac repolarization.
PMID- 10762665
TI - Biphasic effects of dithiocarbamates on the activity of nuclear factor-kappaB.
AB - Dithiocarbamates are well-known antioxidants and nuclear factor-kappaB (NF
kappaB) inhibitors. Recently, they have been characterized as zinc ionophores.
Concentration-dependent biphasic effects of dithiocarbamates on NF-kappaB
activity have been widely reported. We studied the mechanism of this phenomenon
in relation to Zn(2+) influx. Two dithiocarbamates, pyrrolidine dithiocarbamate
and diethyldithiocarbamate, showed concentration-dependent biphasic effects in
inhibiting NF-kappaB activation in cerebral endothelial cells. These unique
effects of dithiocarbamates on NF-kappaB were tightly linked to their ability to
elevate intracellular Zn(2+)500 microM), dithiocarbamates started to lose their
ability to promote Zn(2+) influx and to inhibit NF-kappaB activation. These
results might provide insight into the appropriate use of dithiocarbamates in
various disorders.
PMID- 10762667
TI - Activation of cGMP-dependent protein kinase Ialpha is required for N-methyl-D
aspartate- or nitric oxide-produced spinal thermal hyperalgesia.
AB - The effect of a selective cyclic guanocine 3',5'-monophosphate (cGMP)-dependent
protein kinase Ialpha inhibitor, Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine
(Rp-8-p-CPT-CGMPS), on either N-methyl-D-aspartate (NMDA)- or N-ethyl-2-(1-ethyl
2-hydroxy-2-nitrosohydrazino)ethanamine (NOC-12, a nitric oxide (NO) donor)
produced thermal hyperalgesia was examined in the rat. Intrathecal administration
of NMDA (15 pg/10 microl) or NOC-12 (10, 20 and 30 microg/10 microl) produced a
marked curtailment of the tail-flick latency. Maximal NMDA- or NOC-12-produced
facilitation of the tail-flick reflex was significantly and dose-dependently
blocked by intrathecal pretreatment with Rp-8-p-CPT-CGMPS (7.5, 15 and 30
microg/10 microl). Rp-8-p-CPT-CGMPS given alone did not markedly alter baseline
tail-flick latency. These results suggest that the activation of cGMP-dependent
protein kinase Ialpha is required for NMDA- or NO-produced facilitation of
thermal hyperalgesia at the spinal cord level.
PMID- 10762668
TI - Low dose anandamide affects food intake, cognitive function, neurotransmitter and
corticosterone levels in diet-restricted mice.
AB - This investigation reports the possible role of the endocannabinoid anandamide on
modulating the behavioral and neurochemical consequences of semi-starvation. We
studied the effect of very low dose anandamide (0.001 mg/kg) administration on
food intake, cognitive function and catecholaminergic and serotonergic pathways
in two murine brain areas concerned with appetite (hypothalamus) and learning
(hippocampus), and the peripheral corticosterone response to the stress of 40%
diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during
1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly
increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5
hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased
significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001).
Diet restriction was accompanied in both areas by a significant decrease in all
neurotransmitter concentrations that were partially restored by anandamide for
dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction,
anandamide significantly improved impaired maze performance. Norepinephrine
turnover and plasma corticosterone levels were also raised significantly by
anandamide. The fact that low dose anandamide improved food intake, cognitive
function and reversed some of the neurotransmitter changes caused by diet
restriction, might have implications for the treatment of cachexia associated
with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes
sometimes associated with dieting, and in the extreme case, of patients with
anorexia.
PMID- 10762669
TI - Analysis of sex and gonadectomy differences in beta-endorphin antinociception
elicited from the ventrolateral periaqueductal gray in rats.
AB - Male rats exhibit significantly greater antinociception following central
administration of morphine than female rats. The present study examined potential
differences in beta-endorphin (5.2-26 microg) antinociception elicited from the
ventrolateral periaqueductal gray in adult sham-operated and gonadectomized male
and female rats. Male rats displayed significantly greater peak (30 min) tail
flick latencies across the entire range of beta-endorphin doses administered into
the ventrolateral periaqueductal gray than female rats tested during the estrous
phase of the estrous cycle. Adult gonadectomy failed to appreciably change the
pattern of this effect in either males of females. Thus, antinociception elicited
from the ventrolateral periaqueductal gray by beta-endorphin, like morphine, is
sensitive to sex differences.
PMID- 10762670
TI - Time course of changes in endothelium-dependent and -independent relaxation of
chronically diabetic aorta: role of reactive oxygen species.
AB - In the present study, the role of reactive oxygen species and the contribution of
antioxidant defence in the time course of changes in acetylcholine-stimulated
endothelium-dependent and sodium nitroprusside-stimulated endothelium-independent
relaxation were investigated in aortic rings isolated from 6-month streptozotocin
diabetic and age-matched control rats. Although there were no significant
differences in the degree of the peak relaxations produced by a single
administration of acetylcholine (1 microM) or sodium nitroprusside (0.01 microM)
between control and diabetic rings, the endothelium-dependent and -independent
relaxant responses were more transient and the time required to reach a peak
relaxation after addition of acetylcholine was shorter in diabetic vessels.
Pretreatment of diabetic vessels with superoxide dismutase (100 U/ml) normalized
the recovery phases of endothelium-dependent and -independent relaxations, but
had no effect on the peak responses to acetylcholine and sodium nitroprusside. In
the presence of diethyldithiocarbamate (5 mM), an inhibitor of superoxide
dismutase, the transient nature of the relaxant response to acetylcholine or
sodium nitroprusside was more marked and the peak relaxations were inhibited;
these effects of diethyldithiocarbamate were more pronounced in diabetic than in
control rings. Catalase, 160 U/ml, decreased the peak relaxant response to
acetylcholine and accelerated fading of the relaxation in diabetic aorta. Similar
results were obtained for control aorta with a higher concentration of catalase
(550 U/ml). Pretreatment with 3-amino-1,2,4 triazole (5 mM), a catalase
inhibitor, inhibited the peak relaxant response to acetylcholine in diabetic
rings. The combination of superoxide dismutase (100 U/ml) plus 3-amino-1,2,4
triazole (5 mM) produced an increase of the transient nature of endothelium
dependent relaxation of diabetic rings greater than that with 3-amino-1,2,4
triazole alone. Neither catalase nor 3-amino-1,2,4 triazole affected the
characteristics of sodium nitroprusside-induced relaxation. Desferrioxamine, an
inhibitor of hydroxyl radical (.OH) production, or mannitol, a.OH scavenger, had
no effect on the characteristics of either acetylcholine- or sodium nitroprusside
induced relaxation in control and diabetic rings. Biochemical measurements
revealed an inhibited superoxide dismutase activity in diabetic aorta together
with activated catalase. Our findings suggest that, during the chronic phase of
streptozotocin-diabetes, excess superoxide (O(2)(. -)) is responsible for the
enhanced transient nature of endothelium-dependent and -independent relaxation of
aorta via a reduction in bioavailable concentrations of nitric oxide (NO).
However, the involvement of hydrogen peroxide (H(2)O(2)) in the establishment of
acetylcholine-stimulated relaxation may be increased, which is likely to account
for the maintenance of the relaxant effect of acetylcholine in chronically
diabetic vessels.
PMID- 10762671
TI - Tumor necrosis factor-alpha augments contraction and cytosolic Ca(2+) sensitivity
through phospholipase A(2) in bovine tracheal smooth muscle.
AB - To elucidate the effects of tumor necrosis factor-alpha (TNF-alpha) on tracheal
smooth muscle contraction, we simultaneously measured isometric tension and
intracellular Ca(2+) ([Ca(2+)](i)) in fura 2-loaded muscle strips. Smooth muscle
force generation was evaluated in a high potassium (K(+); 20.0-80.0 mM) solution
and with acetylcholine (3 nM-10 microM ). TNF-alpha (1-100 ng/ml) did not
directly contract muscle strips. The contractile response to acetylcholine was
enhanced after application of 10 ng/ml of TNF-alpha for 30 min but not the
response of [Ca(2+)](i). The contractile response and the response of [Ca(2+)](i)
to a high K(+) solution were not altered after application of TNF-alpha. The
[Ca(2+)](i)-tension curve indicated that TNF-alpha enhanced the responsiveness of
tracheal smooth muscle through the acetylcholine-mediated Ca(2+) sensitivity of
intracellular contractile elements. The augmentation of the acetylcholine
concentration-response curves for muscle tension in the presence of TNF-alpha (10
ng/ml) was inhibited in part after application of manoalide, a phospholipase A(2)
inhibitor. We conclude that a low concentration of TNF-alpha enhances smooth
muscle responsiveness to acetylcholine by agonist-mediated Ca(2+) sensitivity
facilitated by phospholipase A(2).
PMID- 10762672
TI - Evidence for the involvement of ATP, but not of VIP/PACAP or nitric oxide, in the
excitatory effect of capsaicin in the small intestine.
AB - The contractile effect of capsaicin in the guinea-pig small intestine involves an
activation of enteric cholinergic neurons. Our present data show that the P(2)
purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid
(PPADS, 30 microM) significantly reduces the contractile response to capsaicin (2
microM) in the presence, but not in the absence, of the tachykinin receptor
antagonists [O-Pro(9), (Spiro-gamma-lactam)Leu(10), Trp(11)]physalaemin (1-11)
(GR 82334; 3 microM) and (S)-(N)-(1-(3-(1-benzoyl-3-(3, 4
dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidine-4-yl)-N -methylacetamide
(SR 142804: 100 nM) (for blocking tachykinin NK1 and NK3 receptors,
respectively). PPADS (30 microM) fails to influence submaximal cholinergic
contractions evoked by cholecystokinin octapeptide (CCK-8; 2-3 nM) or senktide (1
nM), or the direct smooth muscle-contracting effect of histamine (100-200 nM). A
higher concentration (300 microM) of PPADS is also without effect against the
stimulatory action of cholecystokinin octapeptide. This means that PPADS can
probably be safely used as a purinoceptor antagonist in intestinal preparations.
The putative pituitary adenylate cyclase activating peptide (PACAP) receptor
antagonist PACAP-(6-38) (3 microM) significantly reduces the contractile effect
of PACAP-(1-38) (10 nM) and abolishes that of vasoactive intestinal polypeptide
(VIP; 10 nM). PACAP-(6-38) (3 microM) fails to influence the effect of capsaicin
(2 microM) both in the absence and in the presence of tachykinin receptor
antagonists. The nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L
NOARG; 100 microM) also fails to inhibit the capsaicin-induced motor response. We
conclude that an endogenous ligand of PPADS-sensitive P(2) purinoceptors
(possibly ATP), but not a VIP/PACAP-like peptide or NO, is involved in the
nontachykininergic activation of cholinergic neurons in the course of the
capsaicin-induced contraction.
PMID- 10762673
TI - The role of fractalkine in the recruitment of monocytes to the endothelium.
AB - Recombinant fractalkine possesses both chemoattractive and adhesive properties in
vitro. Previous studies have demonstrated an upregulation of this molecule on the
membranes of activated human endothelial cells and hypothesised that fractalkine
plays a role in the recruitment and adherence of monocytes to the activated
endothelium. Here we present data analysing both the adhesive and chemoattractive
properties of this chemokine expressed by activated human umbilical vein
endothelial cells. We demonstrate that both recombinant fractalkine and
endogenously produced fractalkine function as adhesion molecules, tethering
monocytes to the endothelium. However, our data demonstrate that although
recombinant fractalkine has the potential to function as a potent monocyte
chemoattractant, the endogenous fractalkine cleaved from activated human
umbilical vein endothelial cells is not responsible for the observed chemotaxis
in this model. Instead, we show that monocyte chemoattractant protein-1 (MCP-1),
secreted from the activated human umbilical vein endothelial cells, is
responsible for the chemotaxis of these monocytes.
PMID- 10762674
TI - The role of the G protein gamma(2) subunit in opioid antinociception in mice.
AB - We examined the role of the gamma(2) subunit of G proteins (Ggamma(2)) in the
antinociception produced by c[D-Pen(2), D-Pen(5)]enkephalin (DPDPE) in mice.
DPDPE produced 84.0+/-9.0% antinociception in vehicle-treated mice. After
intracerebroventricular (i.c.v.) treatment with an antisense phosphorothioate
oligodeoxynucleotide to the Ggamma(2) subunit, DPDPE-mediated antinociception
decreased to 24.4+/-7.4%. The mismatch phosphorothioate oligodeoxynucleotide
treated mice showed 65.1+/-10.3% antinociception, while the missense
phosphorothioate oligodeoxynucleotide-treated mice showed 76.4+/-23.6%
antinociception by DPDPE. The reduction of analgesia in antisense
phosphorothioate oligodeoxynucleotide-treated mice was significant in comparison
with vehicle-treated (P<0.001), mismatch phosphorothioate oligodeoxynucleotide
treated (P<0.01) and missense phosphorothioate oligodeoxynucleotide-treated
(P<0.05) mice. These results suggest that the G protein gamma(2) subunit is
involved in the transduction pathway leading to antinociception by DPDPE.
PMID- 10762675
TI - Experimental design of FPD made of all-ceramics and fibre-reinforced composite.
AB - OBJECTIVES: This study was carried out to combine flexural properties of FRC
materials with aesthetic values of ceramics. METHODS: The bonding strength of
fibre-reinforced composite to ceramic was determined. Afterwards, 8 three unit
and 8 four unit FPDs (fixed partial dentures) were manufactured based on the
experimental design and were then adhesively luted onto human molars. After
thermal cycling and mechanical loading in an artificial environment, the fracture
strength and marginal adaptation was determined. FPDs made of FRC (fibre
reinforced composite) materials were used as a control. RESULTS: The most
reliable bonding strength of ceramic to FRC material was achieved using acid
etching in combination with adhesive luting techniques. Median fracture strength
values of 575 N for three unit FPD and 876 N for four unit FPD were established.
More than 85% of the experimental FPDs showed a perfect margin while less than
15% revealed a marginal gap, even after thermal cycling and mechanical loading
(TCML). The strongest influence of TCML on the marginal adaptation of the
experimental design FPD was determined within the four unit system showing
approximately a 10% change in marginal gap and perfect margin. SIGNIFICANCE:
Assuming an improvement in adhesive bonding between the ceramic and the FRC
material and, in addition, an enhancement of the contact surface between pontic
and abutment, the hybrid technique could represent an interesting procedure for
further investigations and, eventually, clinical implication.
PMID- 10762676
TI - Fluoride release from glass ionomer cements and resin composites coated with a
dentin adhesive.
AB - OBJECTIVES: This laboratory study compared the effect of surface coatings on
patterns and amounts of fluoride released from four glass ionomer cements and two
fluoride-containing resin composites. METHODS: Twelve cylinders of each material
were prepared in a polyethylene mold. The experimental groups (n = 6) were coated
with one layer of an adhesive resin (3M Scotchbond Multipurpose Adhesive), while
the control groups (n = 6) remained uncoated. Cumulative fluoride release into
deionized water was measured on days 1, 2, 3, 7, 14, 21 and 28 using an ion
analyzer. Total fluoride release after 28 days was analyzed for significant
differences among materials using one-way ANOVA and Student-Newman-Keuls test (p
< 0.05). RESULTS: The total amounts of fluoride release from the coated samples
were found to be significantly less than the uncoated samples for all materials,
except Solitaire. The uncoated samples released a total amount of fluoride of
between 2.3 and 85.4 ppm, while the coated samples released a total amount of
fluoride of between < 0.2 and 24.1 ppm. Similar patterns of fluoride release were
found in coated and uncoated samples. SIGNIFICANCE: The results indicated that
the application of a dentin adhesive coating did not completely prevent fluoride
release from glass ionomer cements and fluoridated resin composites, although the
amounts were significantly less. Clinically, it suggests that a continued release
of fluoride from glass ionomer cements and fluoridated resin composites is
possible after placing a thin layer of resin adhesive. The clinical significance
of these findings is not known.
PMID- 10762677
TI - Release of methacrylic acid from dental composites.
AB - OBJECTIVE: The aim of this study was to investigate the release of methacrylic
acid from four commercial dental composite restoratives (Silux Plus (3M), Z100
(3M), Ariston pHc (Vivadent) and Surefil (Dentsply)). METHODS: Three specimen
disks (10(0.2) mm in diameter and 2(0.2) mm thick), were prepared for each
material using custom-made molds. Each disk was placed in artificial saliva for
24 h at 37 degrees C, rinsed and subsequently immersed in 1.5 ml of deionised
water in an airtight glass container. The container was continuously shaken at a
speed of 80 rpm for 24 h at 37 degrees C in an orbital incubator. After 24 h (Day
1), the water was removed and analyzed. The specimen disk was then re-immersed
into another 1.5 ml of fresh deionised water. The procedure of removing and
refilling of the water was repeated for a total of 7 days. The sample solutions
were filtered and injected into the capillary electrophoresis system for analysis
immediately after collection. Statistical analysis was performed by ANOVA and
Scheffe's test. RESULTS: For Days 1-7, methacrylic acid released in water at 37
degrees C by Ariston was significantly greater than that of the other composites.
Ranking from least to greatest total (cumulative over 7 days) methacrylic acid
release was as follows: Z100 (5.66 ppm) < Silux (8.81 ppm) < Surefil (20.21 ppm)
< Ariston (519.04 ppm). Methacrylic acid release was greatest at Day 1 for all
materials and generally decreased with time. SIGNIFICANCE: Some composites may
release high levels of methacrylic acid. The biological effects of such high
levels of methacrylic acid is not known and warrant further in vivo and in vitro
investigations.
PMID- 10762678
TI - Microtensile bond strengths of seven dentin adhesive systems.
AB - OBJECTIVES: The purpose of this study was to evaluate the microtensile bond
strengths of seven dentin adhesive systems (Solid Bond, EBS-Multi, PermaQuik, One
Coat Bond, Gluma One Bond, Prime & Bond NT/NRC and Clearfil Liner Bond 2V) and
their respective fracture modes. METHODS: Superficial occlusal dentin of
extracted human molars was exposed, finished with wet 600-grit silicon carbide
paper, and a block of resin composite bonded with the above adhesives according
to the manufacturers' instructions. The teeth were kept in tap water for 24 h at
37 degrees C, sectioned to obtain three or four bar-shaped specimens, which were
then shaped to an hour-glass form of 1.2 +/- 0.02 mm diameter. The specimens were
stressed at a crosshead speed of 1 mm/min until rupture of the bond. The mean
bond strengths were compared using one-way ANOVA and LSD tests. The frequency of
fracture modes was compared using Kruskal-Wallis and Mann-Whitney U-tests.
RESULTS: Mean microtensile bond strengths ranged from (17.8 +/- 7.0) MPa for
Solid Bond to (36.0 +/- 8.1) MPa for Clearfil Liner Bond 2V. The bond strength of
Clearfil Liner Bond 2V and PermaQuik (30.8 +/- 8.5 MPa) were not significantly
different, and were higher than all other materials. Bond strengths of Solid Bond
(17.8 +/- 7.0) MPa, EBS-Multi (18.7 +/- 5.0) MPa, One Coat Bond (21.9 +/- 5.6)
MPa, and Gluma One Bond (23.4 +/- 5.2) MPa were not significantly different. SEM
examination indicated that Solid Bond, EBS-Multi and One Coat Bond showed no
significant difference in failure modes but were significantly different from
PermaQuik, Prime & Bond NT/NRC and Clearfil Liner Bond 2V. SIGNIFICANCE: The self
etching primer system, Clearfil Liner Bond 2V, provided the simplest bonding
technique, and together with PermaQuik exhibited greatest bond strength to
dentin.
PMID- 10762679
TI - Current status of pulp capping with dentin adhesive systems: a review.
AB - Several studies have assessed the morphology and thickness of hybrid layer, the
dentin bond strengths as well as sealing ability of dentin adhesive systems.
However, few in vivo studies have evaluated the biocompatibility of the adhesive
systems following application to deep dentin or directly to the pulp of human
teeth. Many studies performed in non-human primate teeth or teeth of rats have
reported pulp healing and dentin bridging following pulp capping with bonding
agents. In addition, a few clinical and radiographical reports of the success of
resin pulp capping have been described in the dental literature. OBJECTIVES: The
aim of this review was to evaluate the literature on pulp responses following
total acid etching and application of adhesive resins on deep cavities or pulp
exposures. In addition, the clinical/radiographical evidence for the apparent
success of vital pulp therapy and results obtained from animal and human studies
were compared and discussed. SIGNIFICANCE AND CONCLUSIONS: The self-etching
adhesive systems may be useful and safe when applied on dentin. In contrast,
persistent inflammatory reactions as well as delay in pulpal healing and failure
of dentin bridging were seen in human pulps capped with bonding agents. The
results observed in animal teeth cannot be directly extrapolated to human
clinical conditions. Consequently, vital pulp therapy using acidic agents and
adhesive resins seems to be contraindicated.
PMID- 10762680
TI - The influence of luting cement on the probabilities of survival and modes of
failure of cast full-coverage crowns.
AB - OBJECTIVES: This study compares the probabilities of survival and modes of
failure of cast full-coverage crowns bonded with five cements when subjected to
tensile pull-off testing. METHODS: Five groups of 25 sound human premolar teeth
were prepared for full-coverage crowns, impressions recorded and customized
castings fabricated in Ni-Cr-Mb bonding alloy. The cements tested were zinc
phosphate, a hand-mixed and capsulated conventional glass-ionomer cement, a resin
modified glass-ionomer cement and a resin composite luting cement. The cemented
crowns were stored in water at 37 degrees C for 24 h prior to application of a
tensile pull-off force at a strain rate of 10 mm/min. The loads at failure were
ranked and modelled by derived Weibull functions each describing the probability
of a given specimen failing under a given load. Non-parametric statistical
analysis was also applied to the results. RESULTS: There were no significant
differences between the loads at failure of zinc phosphate cement, the hand-mixed
or the capsulated glass-ionomer cements. The resin-modified glass-ionomer cement
and the resin composite cement failed at significantly higher loads than the
other three cements, but were not significantly different from each other. The
Weibull modulus ranking for each cement from highest to lowest was resin
composite = zinc phosphate, resin-modified glass-ionomer, hand-mixed conventional
glass-ionomer and capsulated conventional glass-ionomer cement. SIGNIFICANCE:
Weibull analysis allows dentists to compare the probability of survival of a
crown bonded with different cements at a chosen load giving an indication of
cement reliability.
PMID- 10762682
TI - Effect of sub-lethal concentrations of HEMA (2-hydroxyethyl methacrylate) on THP
1 human monocyte-macrophages, in vitro.
AB - OBJECTIVE: Resin monomers such as HEMA (2-hydroxyethyl methacrylate) can be
released from restorative materials and diffuse into the tooth pulp over long
periods of time. Although the short-term toxicity of resin monomers has been well
documented, little is known about the risk for chronic toxicity resulting from
low concentrations of resins. Thus, the hypothesis tested in this study was that
sub-lethal concentrations of HEMA alter the functions of macrophages after long
term exposure. METHODS: Human THP-1 monocyte-macrophages were exposed to
concentrations of HEMA between 0 and 1.5 mmol/l for up to 6 weeks. Cellular
proliferation was measured by a hemocytometer with trypan-blue dye exclusion.
Mitochondrial activity was measured by the MTT assay, and total cellular protein
was measured using the bicinchoninic acid assay. RESULTS: Macrophage
proliferation was inhibited 40-50% (significant, p < 0.05) by as little as 0.75
mmol/l after 1 week of exposure. Inhibition of proliferation remained constant
after 1 week. The total protein per cell increased by as much as 80%
(significant, p < 0.05) after 2 weeks and remained elevated through 6 weeks.
Mitochondrial activity per cell increased 60-80% (significant, p < 0.05) after 2
weeks, then decreased. However, mitochondrial activity remained significantly
elevated above controls through 6 weeks. SIGNIFICANCE: Findings from the current
study indicate that 6-week exposures of monocytes to HEMA alter their
proliferation and other activities at concentrations substantially lower than
previously reported. This is particularly relevant in light of evidence that such
concentrations have been previously shown to come through dentin by diffusion.
PMID- 10762681
TI - Cytotoxicity of nickel-chromium alloys: bulk alloys compared to multiple ion salt
solutions.
AB - OBJECTIVE: Nickel-based alloys have been in use since the 1930s; however, there
are concerns regarding the biocompatibility of the metallic ions released from
these alloys to surrounding tissues. The objective of this study was to better
understand nickel-based alloy cytotoxicity as well as determine if multiple ion
salt solutions can be used to model the cytotoxic effects of bulk implant alloys.
METHODS: This study evaluated cellular morphology, viability, membrane integrity,
and alterations in metabolic activity, including DNA synthesis, RNA synthesis,
protein synthesis, oxygen consumption, intracellular ATP levels, and glucose-6
phosphate dehydrogenase in response to bulk alloys and multiple ion salt
solutions. RESULTS: Over a 24- or 72-h exposure time, the nickel-based alloys
released a total ion concentration in the parts per billion range and caused
alterations in DNA, RNA, and protein synthesis, intracellular ATP levels, and
glucose-6-phosphate dehydrogenase activity. Interestingly, cellular responses to
the salt solutions representing the ions released from the alloys were not
consistently significantly similar to those elicited from the alloys.
SIGNIFICANCE: From these studies, it was shown that a number of cellular
functions are altered in response to ions released from these implant alloys.
However, cellular functions were not similarly altered in response to salt
solutions representing the ions released from the alloys. These results
demonstrated salt solutions cannot be easily used to represent alloy
cytotoxicity, and ionic release from alloys is a complex process dependent on
variables including ion chemistry, ion valence, and dose-time dependence. This
study provides a better understanding of the metabolic response of fibroblasts to
ions released from dental alloys; and is a good first step towards developing a
more reliable cell culture model of cytotoxicity.
PMID- 10762683
TI - A new method to quantify wear using implant supported restorations.
AB - OBJECTIVES: To design a novel technique to assess the wear of prosthodontic
veneering materials. Further to determine whether accurate transfer between the
oral cavity and the measuring device is achievable and assess the reproducibility
of the coordinates generated by the measuring system. METHODS: The system is
based on the repositioning capacity of an octagonal connector of the ITI implant
system. The same type of connector was screwed onto the clinical implants that
supported the experimental restorations and secured to the x-y table of the
measuring device. The measuring setup also comprised a z-axis LVDT displacement
gauge that allowed the entire surface of the restorations to be profiled and
digitized. The system was under the control of a PC equipped with custom-made
software that set the position of the stepping motors, lifted and lowered the z
axis probe, and registered and wrote the x-, y- and z-axis coordinates. Final
numerical adjustments and analyses were performed using a commercial array
oriented software package. Validation procedures were performed using a specially
designed calibration surface. RESULTS: On repeated profile tracings, the
measurement error was less than 2 microns. When the calibration surface was
removed between measurements as during clinical trials, the measurement error
increased to ca. 5 microns. SIGNIFICANCE: The measurement error of the testing
procedure including transfer to and from the mouth is +/- 5 microns.
PMID- 10762684
TI - Mechanical property evaluation of pressable restorative ceramics.
AB - OBJECTIVE: The aim of this study was to evaluate the flexure strength under
static and cyclic loading and the fracture toughness under static loading of six
restorative ceramic materials. Specifically the intent was to compare four
leucite (K2O.Al2O(3).4SiO2) strengthened feldspathic (pressable) porcelains (OA,
OI, E, and FP) to a low fusing feldspathic porcelain (F) and an experimental (EC)
lithium disilicate containing ceramic. METHODS: All materials were tested as a
control in air and distilled water (without aging) and after three months aging
in air or distilled water to determine flexure strength and fracture toughness. A
staircase approach was used to determine the cyclic flexure strength. EDS and SEM
analysis were conducted on the polished and fracture surfaces. RESULTS: The mean
flexure strength for the controls in air and water (without aging or cyclic
loading) ranged from 67 to 99 MPa, except the experimental ceramic that was twice
as strong with a mean flexure strength of 191-205 MPa. For the mean fracture
toughness, the range was 1.1-1.9 MPa/m0.5 with the experimental ceramic being 2.7
MPa/m0.5. The effect of testing in water and aging for three months caused a
moderate reduction in the mean flexure strength (6-17%), and a moderate to severe
reduction in the mean fracture toughness (5-39%). The largest decrease (15-60%)
in mean flexure strength was observed when the samples were subjected to cyclic
loading. SIGNIFICANCE: The lithium disilicate containing ceramic had a
significantly higher flexure strength and fracture toughness when compared to the
four pressable leucite strengthened ceramics and the low fusing conventional
porcelain. All of the leucite containing pressable ceramics did provide an
increase in mean flexure strength (17-19%) and mean fracture toughness (3-64%)
over the conventional feldspathic porcelain. Further, the influence of testing
environment and loading conditions implies that these ceramic materials in the
oral cavity might be susceptible to cyclic fatigue, resulting in a significant
decrease in the survival time of all-ceramic restorations.
PMID- 10762685
TI - Picture recognition in animals and humans.
AB - The question of object-picture recognition has received relatively little
attention in both human and comparative psychology; a paradoxical situation given
the important use of image technology (e. g. slides, digitised pictures) made by
neuroscientists in their experimental investigation of visual cognition. The
present review examines the relevant literature pertaining to the question of the
correspondence between and/or equivalence of real objects and their pictorial
representations in animals and humans. Two classes of reactions towards pictures
will be considered in turn: acquired responses in picture recognition experiments
and spontaneous responses to pictures of biologically relevant objects (e.g. prey
or conspecifics). Our survey will lead to the conclusion that humans show
evidence of picture recognition from an early age; this recognition is, however,
facilitated by prior exposure to pictures. This same exposure or training effect
appears also to be necessary in nonhuman primates as well as in other mammals and
in birds. Other factors are also identified as playing a role in the acquired
responses to pictures: familiarity with and nature of the stimulus objects,
presence of motion in the image, etc. Spontaneous and adapted reactions to
pictures are a wide phenomenon present in different phyla including invertebrates
but in most instances, this phenomenon is more likely to express confusion
between objects and pictures than discrimination and active correspondence
between the two. Finally, given the nature of a picture (e.g. bi-dimensionality,
reduction of cues related to depth), it is suggested that object-picture
recognition be envisioned in various levels, with true equivalence being a
limited case, rarely observed in the behaviour of animals and even humans.
PMID- 10762686
TI - The effect of brachium conjunctivum transection on a conditioned limb response in
the cat.
AB - Seven cats were trained to perform a forelimb conditioned response to a paired
tone conditioned stimulus (CS)/shock unconditioned stimulus (UCS). Brachium
conjunctivum section ipsilateral to the trained limb was carried out following
criterion conditioned response (CR) performance. Lesion sites were identified
histologically and further confirmed by observation of cellular changes in the
dentate and interpositus nuclei ipsilateral to the section. The brachium
conjunctivum was found to have been sectioned in four of the seven subjects. Each
of these animals demonstrated a total or near-total loss of the CR. Extended
postoperative training resulted in no increase in CR performance levels. The
unconditioned response (UCR) remained unaffected, as did limb placing, accuracy
of striking at moving objects, grooming, running and walking. The results are
discussed in the context of an earlier report by McCormick et al. [Bull Psychonom
Soc 1981;18:103-5], in which section of the superior cerebellar peduncle was
found to abolish a conditioned nictitating membrane response in the rabbit. Taken
together, they support the contention of Lavond [Annu Rev Psychol 1993;44:317
42], Thompson [In: Sprague JM, Epstein AN, editors. Progress in Psychobiology and
Physiological Psychology. New York: Academic Press 1983, pp. 167-96], Yeo et al.
[Behav Brain Res 1984;13:261-66; Exp Brain Res 1985;60:87-98; Exp Brain Res
1985;60:99-113; Exp Brain Res 1992;88:623-38.] and others that the cerebellum
represents a critical site for acquisition and retention of a conditioned memory
trace.
PMID- 10762687
TI - A volumetric MRI study of the hippocampus in type 1 and 2 alcoholism.
AB - In recent years, magnetic resonance imaging (MRI) of the hippocampus has been
extensively studied on neurological and psychiatric disorders. Particularly in
studies on schizophrenia and mood disorders, findings regarding the hippocampal
involvement have been most controversial. Previously, minor volume loss of the
hippocampus in alcoholism, a major comorbidity alongside psychiatric disorders,
has been reported but no data exist on the hippocampal volumes in subtypes of
alcoholism. In this study, MRI was used to measure volumes of the hippocampus in
late-onset type 1 alcoholics and early-onset type 2 alcoholics. The type 2
alcoholic subjects were also violent offenders with antisocial personality
disorder, derived from a forensic psychiatric sample. All were non-psychotic and
legally competent. Normal volunteers, representing a wide age range, served as a
controls group. Compared to the controls, the right, but not left, hippocampi
were significantly smaller in both alcoholic groups. While there was no
correlation between the hippocampal volumes with age in the control subjects,
there was tendency towards decreased volumes with aging and also with the
duration of alcoholism in the type 1 alcoholic subjects. Surprisingly, there was
a significant positive correlation between the right hippocampal volume and age
in the type 2 alcoholics. This study provides further in vivo evidence that type
1 alcoholism, in general, is associated with a minor loss in hippocampal volume.
It is suggested that type 2 alcoholism, in general, similarly displays a minor
decrease in hippocampal volume, but this decrease is unevenly distributed within
the type 2 category, being weighted towards the younger subjects. These effects
suggest differences between the two alcoholic groups, and raise the possibility
that the observed effects within the type 2 category are due to other factors
than the cumulative acquired effects related to alcohol abuse, such as primary
personality psychopathology.
PMID- 10762688
TI - Effects of serotoninergic drugs on tremor induced by physostigmine in rats.
AB - We investigated the effects of various serotoninergic drugs and serotonin (5-HT)
depletion on physostigmine-induced visible tremor in rats. Physostigmine (0.25
1.5 mg/kg) caused dose-dependent tremor, initiated at 3-5 min (latency decreases
as dose increases) and lasted for 30-35 min. Serotonin agonists, 8-hydroxy-2-(di
n-propylamino) tetralin (2.5 mg/kg) and buspirone (5 mg/kg) augmented the tremor
response caused by physostigmine. The 5-HT(1)/5-HT(2) receptor antagonist,
metergoline (1 mg/kg), and 5-HT(2) blocker, cyproheptadine (10 mg/kg)
significantly decreased the duration (40%) as well as intensity (45-50%) of
physostigmine-tremor. The 5-HT(2a)/5-HT(2c) antagonist ritanserin (5 mg/kg)
significantly reduced the duration (60%) without affecting the intensity of the
tremor. In 5-HT depleted rats (p-chlorophenylalanine; 300 mg/kg, for 3 days),
physostigmine failed to produce tremor. Interestingly, in these animals,
administration of a non-specific 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine,
caused high intensity tremor. These results suggest that presence of 5-HT at the
pre-synaptic terminals is needed for the tremor response by physostigmine and the
response is greatly mediated via post-synaptic 5-HT receptors. The overall data
indicated a direct involvement of central 5-HT system in the cholinergic tremor
induced by physostigmine.
PMID- 10762689
TI - Involvement of the hippocampus and associative parietal cortex in the use of
proximal and distal landmarks for navigation.
AB - Rats with dorsal hippocampus or associative parietal cortex (APC) lesions and
sham-operated controls were trained on variants of the Morris water maze
navigation task. In the 'proximal landmark condition', the rats had to localize
the hidden platform solely on the basis of three salient object landmarks placed
directly in the swimming pool. In the 'distal landmark condition', rats could
rely only on distal landmarks (room cues) to locate the platform. In the 'beacon
condition', the platform location was signaled by a salient cue directly attached
to it. Rats with hippocampal lesions were impaired in the distal and to a less
extent in the proximal landmark condition whereas rats with parietal lesions were
impaired only in the proximal landmark condition. None of the lesioned groups was
impaired in the beacon condition. These results suggest that the processing of
information related to proximal, distal landmarks or associated beacon are
mediated by different neural systems. The hippocampus would contribute to both
proximal and distal landmark processing whereas the APC would be involved in the
processing of proximal landmarks only. Navigation relying on a cued-platform
would not require participation of the hippocampus nor the APC. Assuming that the
processing of proximal landmarks heavily depends on the integration of
visuospatial and idiothetic information, these results are consistent with the
hypothesis that the APC plays a role in the combination of multiple sensory
information and contributes to the formation of an allocentric spatial
representation.
PMID- 10762690
TI - Sex differences in catalepsy: evidence for hormone-dependent postural mechanisms
in haloperidol-treated rats.
AB - Catalepsy, a symptom of Parkinson's disease and related disorders can be produced
in rats and other laboratory animals by the blockade of nigrostriatal dopamine
using dopaminergic antagonists such as haloperidol. When haloperidol-induced
cataleptic rats are placed facing downward on an inclined plane, they will brace
against the resulting downward force by pushing backwards, and if they lose
postural stability, or their position on the inclined plane, they will jump
forward. Females, however, jump from the inclined plane at a significantly lower
angle than do males. Frame-by-frame analysis of the jumping sequences revealed
that females and males use a different combination of postural adjustments to
maintain their position on the inclined plane prior to jumping. Furthermore,
gonadal hormone manipulations at birth and in adulthood reveal that these sex
differences in postural adjustments are dependent on the organizational effects
of gonadal hormones in the perinatal period. These results provide evidence for
sex differences in postural support mechanisms and suggest that the sex of
subjects, or their hormonal state, must be considered when studying the
behavioral aspects of neurological disorders such as Parkinson's disease which
include a postural component.
PMID- 10762691
TI - Individual hemispheric asymmetry in vocal fold control of the squirrel monkey.
AB - In ten squirrel monkeys (Saimiri sciureus), electrodes were implanted into the
left and right facial motor cortex at sites producing bilateral vocal fold
adduction when electrically stimulated. All animals, in addition, had electrodes
in the periaqueductal grey of the midbrain (PAG) at sites producing vocalization
when electrically stimulated. In eight out of ten animals, motorcortical
stimulation during periaqueductally elicited vocalization caused a change in
vocal output. This change, in four cases, was more severe with left-sided
ipsilateral motor cortex/PAG stimulation than with right-sided ipsilateral
stimulation. In the other four cases, right-sided stimulation was more effective
than left-sided stimulation. It is concluded that the majority of squirrel
monkeys show a hemispheric asymmetry in vocal fold control with left- and right
sided dominance distributed about equally in the population.
PMID- 10762692
TI - Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity
in multiple behavioral tasks.
AB - Genetic redundancy is a problem in gene targeting studies because functionally
relevant sister proteins can compensate for the lack of protein product of a
targeted gene. A molecular system is chosen in which it is hoped to demonstrate
both the lack and presence of compensation after disruption of particular single
genes. Mammals may not be able to compensate for the lack of heregulin, a single
ligand for multiple ErbB receptors, however, compensation is expected when a
single ErbB receptor is knocked out. To investigate this the heregulin-1, ErbB2,
or ErbB3 locus was disrupted in a targeted manner and mice heterozygous for the
mutation were analyzed. Heregulin and its receptors were shown to be involved in
embryonic brain development and, more recently, in plastic changes associated
with adult brain function in rodents. Although they have never been shown to play
roles in mammalian behavior, it was decided to characterize the mice behaviorally
using a battery of simple tests. Heregulin mutant mice exhibited elevated
activity levels in the open field, showed improved rotorod performance, and
finished T-maze spontaneous alternation task faster compared to control wild type
littermates, findings that suggest a consistent hyperactivity across tests. ErbB2
and ErbB3 mutant mice, whose strain origin was identical to that of heregulin
mutants, showed no sign of the behavioral alterations. It is suggested that the
abnormalities seen in heregulin mutant mice are due to mutation at that locus and
the lack of alterations seen in ErbB2 and ErbB3 mutant mice is the result of
compensation by unaltered sister receptors.
PMID- 10762693
TI - Concurrent modulation of anxiety and memory.
AB - We have previously shown that the ventromedial prefrontal cortex (vmPFC) is
involved in spontaneous working memory and anxiety-related behaviour in CD-1
mice. Specifically, pretrial microinjection of the kappa(1) agonist, U-69,593, in
the infralimbic (IL) area of the vmPFC produced a robust anxiolytic behavioural
profile in the elevated plus-maze and enhanced spontaneous working memory in the
Y-maze. In the present study we sought to determine whether these effects were
specific to IL kappa receptors. We hypothesized that microinjection of the kappa
antagonist, norBNI, in the IL cortex would influence anxiety and spontaneous
memory in an opposite direction to the effects produced by the kappa(1) agonist.
In week 1, transfer-latency reference memory and anxiety were tested in the
elevated plus-maze in two separate trials with an intertrial interval of 24 h. In
week 2, spontaneous working memory was tested in the Y-maze followed immediately
by defensive/withdrawal anxiety in the open field for one half of the animals in
each group, and the other half was tested in reverse order. Pretreatment with one
injection of vehicle, 1, 5 or 10 nmol/0.5 microl norBNI in the IL cortex dose
dependently reduced transfer-latencies and produced an anxiogenic behavioural
profile in the first elevated plus-maze trial. Following a 24 h delay, transfer
latency reference memory was not influenced, but a robust anxiogenic behavioural
profile was observed in the second no-injection anxiety trial in the elevated
plus-maze relative to control animals. In week 2, the same groups of mice were
again pretreated with one injection of the same doses of norBNI in the IL cortex
and tested in the open field and Y-maze. NorBNI pretreatment was anxiogenic in
the defensive/withdrawal anxiety test and disrupted spontaneous working memory
regardless of testing order. The present results show the influence of kappa
receptor modulation on anxiety induction and spontaneous working memory. These
results also support the hypothesis that immediate memory processing may modulate
the induction of anxiety-related behaviours.
PMID- 10762694
TI - Distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamus, midbrain
and temporal lobe of spayed macaque: continued expression with hormone
replacement.
AB - This study used in situ hybridization (ISH) to examine the distribution of
estrogen receptor beta (ERbeta) mRNA in hypothalamic, limbic, and midbrain
regions of monkey brain and its regulation by estrogen (E) and progesterone (P).
Monkey-specific ERbeta cDNAs were developed with human primers and reverse
transcription and polymerase chain reaction (RT-PCR) using mRNA extracted from a
rhesus monkey prostate gland. ERbeta 5' (262 bases) and 3' (205 bases) riboprobes
were used in combination for ISH. Ovariectomized and hysterectomized (spayed)
pigtail macaques (Macaca nemestrina; four per treatment group) were either
untreated spayed-controls, treated with E (28 days), or treated with E plus P (14
days E+14 days E and P). Dense ERbeta hybridization signal was seen in the
preoptic area, paraventricular nucleus, and ventromedial nucleus of the
hypothalamus; the substantia nigra, caudal linear, dorsal raphe, and pontine
nuclei of the midbrain; the dentate gyrus, CA1, CA2, CA3, CA4, and the
prosubiculum/subiculum areas of the hippocampus. Expression in the
suprachiasmatic region, supraoptic nucleus, arcuate nucleus, and amygdala was
less intense. Image analysis of the dense areas showed no significant difference
in the hybridization signal in individual regions of the hypothalamus, midbrain,
or hippocampus between any of the treatment groups. However, P treatment
decreased overall ERbeta signal in the hypothalamus and hippocampus when several
different subregions were combined. The localization of ERbeta in monkey brain by
ISH is in general agreement with that previously described in rodents. The
presence of monkey ERbeta mRNA in brain regions that lack ERalpha should help to
clarify the molecular mechanisms by which E acts in the central nervous system to
influence hormone secretion, mood disorders, cognition, and neuroprotection.
PMID- 10762695
TI - Evidence for P2X(3), P2X(4), P2X(5) but not for P2X(7) containing purinergic
receptors in Muller cells of the rat retina.
AB - P2X receptors are ligand-gated ion channels activated by ATP. They are expressed
in a broad variety of tissues. To date, eight P2X receptor subunits (P2X(1)
P2X(7), P2XM) have been cloned. In spite of the considerable evidence of
signaling by extracellular nucleotides in other sensory systems, only few studies
have been undertaken in the retina. In earlier studies, we have demonstrated that
there is mRNA expression of the P2X(2-5) and P2X(7) subunits in the rat retina.
In the present study, molecular biological methods were used to investigate
expression of P2X receptor mRNA in freshly isolated Muller cells (MCs) of the
adult rat retina (Brown Norway). A total of 36 MCs was analyzed, employing the
single-cell RT-PCR. A positive amplification signal of 11/14 for P2X(3)-mRNA,
5/10 for P2X(4)-mRNA, 3/10 for P2X(5)-mRNA and 0/8 for P2X(7)-mRNA was revealed.
Additionally, the astroglial identity of the cells under studied was confirmed in
10 cases by simultaneous amplification of RT-PCR products of glutamine synthetase
(GS)- and P2X-mRNA. We conclude that MCs of rat retina express ionotropic P2
receptors, which, in addition to other functions, may play a key role within the
recently described long range calcium signaling and the fast direct glia-neuron
interactions in the rat retina.
PMID- 10762696
TI - Increased neuronal excitability after long-term O(2) deprivation is mediated
mainly by sodium channels.
AB - We have previously observed that prolonged O(2) deprivation alters membrane
protein expression and membrane properties in the central nervous system. In this
work, we studied the effect of prolonged O(2) deprivation on the electrical
activity of rat cortical and hippocampal neurons during postnatal development and
its relationship to Na(+) channels. Rats were raised in low O(2) environment
(inspired O(2) concentration = 9.5+/-0.5%) for 3-4 weeks, starting at an early
age (2-3 days old). Using electrophysiologic recordings in brain slices, RNA
analysis (northern and slot blots) and saxitoxin (a specific ligand for Na(+)
channels) binding autoradiography, we addressed two questions: (1) does long-term
O(2) deprivation alter neuronal excitability in the neocortical and hippocampal
neurons during postnatal development? and (2) if so, what are the main mechanisms
responsible for the change in excitability in the exposed brain? Our results show
that (i) baseline membrane properties of cortical and hippocampal CA1 neurons
from rats chronically exposed to hypoxia were not substantially different from
those of naive neurons; (ii) acute stress (e.g., hypoxia) elicited a markedly
exaggerated response in the exposed neurons as compared to naive ones; (iii)
chronic hypoxia tended to increase Na(+) channel mRNA and saxitoxin binding
density in the cortex and hippocampus as compared to control ones; and (iv) the
enhanced neuronal response to acute hypoxia in the exposed cortical and CA1
neurons was considerably attenuated by applying tetrodotoxin, a voltage-sensitive
Na(+) channel blocker, in a dose-dependent manner. We conclude that prolonged
O(2) deprivation can lead to major electrophysiological disturbances, especially
when exposed neurons are stressed acutely, which renders the chronically exposed
neurons more vulnerable to subsequent micro-environmental stress. We suggest that
this Na(+) channel-related over-excitability is likely to constitute a molecular
mechanism for some neurological sequelae, such as epilepsy, resulting from
perinatal hypoxic encephalopathy.
PMID- 10762697
TI - Opioid receptor endocytosis and activation of MAP kinase pathway.
AB - Opioid receptors, members of the G-protein coupled receptor (GPCR) super family,
bind to endogenous opioid peptides or opiate drugs and induce a wide variety of
signal transduction processes by inhibiting adenylyl cyclase, modulating cation
channels, and activating the mitogen-activated protein (MAP) kinases. Similar to
other GPCRs, agonist binding causes rapid internalization and down-regulation of
opioid receptors. The interdependence between receptor endocytosis and activation
of MAP kinase pathway are increasingly being examined. We have examined these
using ligands that exhibit differential extent of endocytosis as well as mutants
of mu and delta opioid receptors that are unable to internalize. We find that
ligands, including morphine, that do not induce receptor internalization are able
to stimulate MAP kinase phosphorylation not only in heterologous cells but also
in neuronal cell lines that express endogenous mu and delta receptors. Moreover,
mutant receptors that fail to undergo agonist-mediated internalization are able
to efficiently phosphorylate MAP kinases. Taken together, these data are
consistent with the notion that the activation of MAP kinase pathway is an
internalization independent phenomenon in the case of opioid receptors and that
GPCR internalization and activation of MAP kinase are governed by complex
regulatory mechanisms.
PMID- 10762698
TI - Cdk5 and MAPK are associated with complexes of cytoskeletal proteins in rat
brain.
AB - Neurofilament proteins, the major cytoskeletal components of large myelinated
axons, are highly phosphorylated by second messenger-dependent and -independent
kinases. These kinases, together with tubulins and other cytoskeletal proteins,
have been shown to bind to neurofilament preparations. Cdk5 and Erk2, proline
directed kinases in neuronal tissues, phosphorylate the Lys-Ser-Pro (KSP) repeats
in tail domains of NF-H, NF-M, and other axonal proteins such as tau and
synapsin. In neurofilament and microtubule preparations from rat brain, we
demonstrated by Western blot analysis that cdk5, a neuronal cyclin dependent
kinase and Erk1/2 were associated with complexes of NF proteins, tubulins and
tau. Using P13(suc1) affinity chromatography, a procedure known to bind cdc2-like
kinases in proliferating cells with high affinity, we obtained a P13 complex from
a rat brain extract exhibiting the same profiles of cdk5 and Erk2 bound to
cytoskeletal proteins. The phosphorylation activities of these preparations and
the effect of the cdk5 inhibitor, butyrolactone, were consistent with the
presence of active kinases. Finally, during a column fractionation and
purification of Erk kinases from rat brain extracts, fractions enriched in Erk
kinase activity also exhibited co-elution of phosphorylated NF-H, tubulin, tau
and cdk5. We suggest that in mammalian brain, different kinases, their regulators
and phosphatases form multimeric complexes with cytoskeletal proteins and
regulate multisite phosphorylation from synthesis in the cell body to transport
and assembly in the axon.
PMID- 10762699
TI - Proenkephalin A-derived peptides in invertebrate innate immune processes.
AB - Lipopolysaccharides (LPS) injection into the coelomic fluid of the leech
Theromyzon tessulatum stimulates release of proenkephalin A (PEA)-derived
peptides as determined by immunoprecipitation and Western blot analyses. This
release occurs in the first 15 min after LPS exposure and yields a 5.3-kDa
peptide fragment corresponding to the C-terminal part of the precursor. This
fragment is then cleaved to free an antibacterial peptide related to mammals
arginine phenylalanine extended enkelytin: the peptide B. These PEA processing
peptides were characterized using a combination of techniques including reversed
phase HPLC, microsequencing and mass spectrometry. The isolated invertebrate
peptide B presents a high sequence homology with the bovine's and the same
activity against Gram+bacteria. Titrations revealed the simultaneous appearance
of Methionine-enkephalin (ME) and peptide B in invertebrates after stimulation by
LPS (in a dose-dependent manner), surgical trauma or electrical stimulations to
neural tissues of the mussel. Furthermore, peptide B processing in vitro yields
Methionine-enkephalin arginine phenylalanine (MERF), which exhibits via the delta
receptors, immunocyte excitatory properties, i.e., movement and conformational
changes, but no antibacterial activity. We surmise that this unified response to
the various stimuli is a survival strategy for organism by providing immediate
antibacterial activity and immunocyte stimulation, thereby reducing any immune
latency period needed for an adequate immune response.
PMID- 10762700
TI - Calcium/calmodulin-dependent protein kinase II containing a nuclear localizing
signal is altered in retinal neurons exposed to N-methyl-D-aspartate.
AB - This study investigated N-methyl-D-aspartate (NMDA) mediated cell death and its
possible regulation by calcium/calmodulin-dependent protein kinase II (CaMKII) in
the adult rat retina. To investigate cell death, the terminal
deoxyribonucleotidyltransferase (TdT)-mediated biotin-16-dUTP nick-end labelling
(TUNEL) method was used to detect fragmented DNA in fixed tissue sections of rat
retina. The TUNEL assay confirmed that apoptosis occurs in the inner nuclear
layer (INL) and ganglion cell layer (GCL) following NMDA injection. The level of
antibody binding to CaMKII-alpha, the activity of CaMKII, and the mRNA level for
the alpha(B) subunit of CaMKII were found to be elevated for short time periods
(30 min, 2 h) after a single intravitreal injection of NMDA. In contrast to this,
there was a decrease in CaMKII activity and in the CaMKII-alpha(B) mRNA levels at
longer time periods (24 h) following injection of NMDA. These effects were
specific for the mRNA for the alpha(B) subunit, an alternatively spliced product
of the CaMKII-alpha gene, that contains a nuclear localizing signal (NLS) known
to target this protein to the nucleus. It is suggested that regulated expression
of CaMKII-alpha(B) could be involved in the NMDA-mediated cell death in retinal
neurons.
PMID- 10762701
TI - Electroconvulsive shock in rats: changes in superoxide dismutase and glutathione
peroxidase activity.
AB - Seizures trigger a variety of biochemical processes including an influx of
extracellular Ca(2+), activation of membrane phospholipases, liberation of free
fatty acids, diacylglycerols, eicosanoids, lipid peroxides and free radicals.
These lipid metabolites along with abnormal ion homeostasis may be involved in
cell injury and cell death. The aim of this study was to determine brain
antioxidant enzyme activities in rats with electroconvulsive shock (ECS)-induced
seizures. ECS, single or repeated, induced a decrease in superoxide dismutase
(SOD) and glutathione peroxidase (GPX) activities in various brain regions. The
most prominent changes of enzymatic activities were observed in rats that
received five ECSs with 24-h recovery period between them. Decreased SOD activity
was observed in the frontal cortex of all treated animals except those sacrificed
24 h after single ECS, in the cerebellum of the animals that received repeated
ECSs, in the hippocampus of animals that were decapitated 2 h after a single ECS
and in the pons-medulla region of rats that received five daily ECSs. Decreased
GPX activity was found in all examined brain regions of the rats that received
five ECSs, the cortex and hippocampus of rats that were decapitated 2 h after
single ECS and the cortex of those that received 10 ECSs with 48 h between them.
The results show that neither 24-h nor 48-h recovery period was sufficient for
the normalisation of antioxidative enzyme activities after repeated ECS
treatment.
PMID- 10762702
TI - Singular subsets of locus coeruleus neurons may recover tyrosine hydroxylase
phenotype transiently expressed during development.
AB - The number of tyrosine hydroxylase (TH)-expressing neurons appears to be
precisely determined in basal conditions within the noradrenergic pontine nucleus
locus coeruleus (LC). However, additional neurons exhibiting TH phenotype have
been observed in the adult rat LC following a single administration of RU 24722,
a potent inducer of TH expression specific to the LC. The neurons acquiring TH
phenotype following treatment had a topographical localization similar to that of
the neurons, which transiently expressed TH during postnatal development and lost
TH phenotype during the third postnatal week. The idea that the fluctuation of TH
phenotype in singular subsets of LC neurons during development may be selectively
restored in adults is of particular interest. The present study attempted to
determine whether the cells in which TH expression was repressed during the third
postnatal week could correspond to those which exhibited TH phenotype in response
to RU 24722 treatment in adults. We first verified that no massive cell death
occurred in the LC during the period ranging from days 13 to 30. Then, we
observed that both cell populations exhibited the same altered steady-state
concentration of TH-mRNA as compared to cells that permanently expressed TH.
Finally, we demonstrated the presence of TH-negative neurons expressing the
homeodomain transcription factor Phox2a, specific for the determination of
noradrenergic phenotype, providing further evidence that "resting-noradrenergic"
neurons exist in the adult rat LC under basal conditions. These neurons provide
interesting prospective for gain of noradrenergic function when classical
noradrenergic LC neurons are impaired.
PMID- 10762703
TI - Expression of antinociception in response to a signal for shock is blocked after
selective downregulation of mu-opioid receptors in the rostral ventromedial
medulla.
AB - Prior work has shown that release of endogenous ligands for mu-opioid receptors
in the rostral ventromedial medulla (RVM) is critical for the modulation of
spinal nociceptive reflexes observed during stress. In the present study, we used
antisense oligodeoxynucleotides (AS ODN) to suppress synthesis of mu-opioid
receptors in the RVM prior to activating descending antinociceptive systems with
a signal for foot shock. Five groups of rats with RVM cannulae were trained with
paired or unpaired exposures to white noise (WN) and foot shock. Over several
days, they received RVM infusions of an AS ODN probe targeting exon 1 of the
cloned MOR-1 receptor, an inactive missense (MS) ODN with the same base
composition in which the sequence for four bases was changed, an AS ODN probe
targeting exon 4, or saline. Tail-flick latencies (TFLs) were measured before,
during, and after presentation of the auditory signal for shock. Rats given
paired training and saline injections displayed longer TFLs than saline control
rats given unpaired exposures to WN and shock, confirming the ability of the
conditional stimuli (CS) to elicit antinociception. Expression of this
conditional hypoalgesia (CHA) was attenuated by pretreatment with the AS ODN
probe targeting exon 1, but was unaffected by pretreatment with AS ODN probe
targeting exon 4 or MS ODN sequence for exon 1. However, pretreatment with the AS
ODN probe targeting exon 1 did not affect expression of conditional freezing to
other shock-associated cues. Testing of the same animals several days after the
ODN injections showed that the attenuating effect on expression of CHA were
reversible. These results support the idea that mu-opioid receptors in the RVM
are critically involved in mediating expression of hypoalgesia following stress.
They also provide further evidence for dissociation in the mechanisms mediating
expression of aversive conditional responses.
PMID- 10762704
TI - Immunohistochemical localization of adenylyl cyclase isoforms in the lateral wall
of the rat cochlea.
AB - The enzymatic activity of adenylyl cyclase (AC) is attributable to nine isoforms
with individual pharmacology and tissue distribution. Polyclonal antibodies for
AC isoforms I-IV, VII and VIII were applied to sections of cochlear lateral wall,
a tissue involved in ion transport contributing to the unique ion content of
endolymph and electrical potential of scala media. Within the stria vascularis,
immunoreactivity primarily to Ca(2+)/calmodulin-independent isoforms II, IV and
VII was localized to sites consistent in position to the basolateral extensions
of marginal cells. Little immunoreactivity was observed in the stria vascularis
for Ca(2+)/calmodulin-dependent isoforms I, III and VIII. Within the spiral
ligament, type II and type IV fibrocytes exhibited moderate staining for ACII, IV
and VII, less staining for VIII and little for I and III. Immunoreactivity to
ACII, IV, VII and VIII was observed in type I fibrocytes. The outer sulcus cells
and root processes were highly immunoreactive for isoforms I and VIII, but not
for III or the Ca(2+)/calmodulin-independent isoforms. The differential pattern
of immunoreactivity in the lateral wall overall appears to reflect subfamily
specific expression with Ca(2+)/calmodulin-independent isoforms expressed in the
stria vascularis and Ca(2+)/calmodulin-dependent isoforms expressed in the outer
sulcus cells and root processes. cAMP-mediated modulation of ion transport by
marginal cells is predicted to exhibit, in the microenvironment of basolateral
membrane infoldings, pharmacological characteristics of the AC type II subfamily
(II, IV and VII), including activation by protein kinase C (II and VII).
PMID- 10762705
TI - Hippocampal expression of N-methyl-D-aspartate receptor (NMDAR1) subunit splice
variant mRNA is altered by developmental exposure to Pb(2+).
AB - N-methyl-D-aspartate receptors (NMDAR) play an important role in synaptic
plasticity and brain development. We have previously shown that NR1-pan mRNA is
significantly increased in the hippocampus of rats chronically exposed to low
levels of lead (Pb(2+)) during development [T.R. Guilarte, J.L. McGlothan,
Hippocampal NMDA receptor mRNA undergoes subunit specific changes during
developmental lead exposure, Brain Res., 790 (1998) 98-107]. It is not known
whether this Pb(2+)-induced increase in NR1-pan mRNA is associated with changes
in specific splice isoforms. To study this effect, we used in situ hybridization
of oligonucleotides to probe for the NR1-a, NR1-b, NR1-1, NR1-2, and NR1-4
isoforms which are most abundantly expressed in the rat hippocampus.
Developmental exposure to increasing levels of Pb(2+) resulted in significant
increases in NR1-a mRNA throughout the pyramidal and granule cell layers of the
rat hippocampus at postnatal day 14 (PN14). NR1-b mRNA was increased in the
pyramidal cell layer of Pb(2+)-exposed rats at PN21. Splicing of the C-terminus
cassettes was also regulated by developmental exposure to Pb(2+). NR1-2 mRNA was
increased in CA4 pyramidal cells and in dentate granule cells of PN21 Pb(2+)
exposed rats. Notably, expression of NR1-4 mRNA in CA3 pyramidal cells was
increased in Pb(2+)-exposed rats at PN14 and decreased at PN21. No significant
Pb(2+) effect was measured for NR1-1 mRNA expression. These data indicate that
alternative splicing of the NR1 gene shows selective anatomical and temporal
regulation by Pb(2+) in the developing rat hippocampus. This study provides
further support to the hypothesis that NMDARs are important targets for Pb(2+)
induced neurotoxicity.
PMID- 10762706
TI - Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic
denervation in the rat striatum.
AB - Degeneration of serotonergic fibers in the rat striatum was produced by local
administration of the serotonergic neurotoxin 5, 7-dihydroxytryptamine (5,7-DHT)
or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which is
also toxic to serotonergic neurons. One week before neurotoxin administration,
fibroblasts engineered to express the human BDNF gene were grafted into the
mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts
expressing the LacZ gene were used as controls, as well as sham-operated animals
(not injected with any neurotoxin). After a survival period of 1 week, the
serotonergic innervation of the striatum was assessed by measuring serotonin (5
HT) content and by immunohistochemical detection of 5-HT positive fibers. BDNF
producing cells prevented the striatal 5-HT loss induced by local administration
of either 5,7-DHT or MPP(+), as well as the striatal dopamine (DA) loss induced
by the latter neurotoxin. Grafting of fibroblasts carrying the BDNF or the Lac-Z
gene did not modify striatal 5-HT or DA content in sham-operated animals. In 5, 7
DHT-lesioned rats, implanted or not with control Lac-Z fibroblasts, a striking
reduction in the density of 5-HT immunoreactive fibers was observed. By contrast,
the density of 5-HT fibers was similar in rats implanted with BDNF-producing
fibroblasts as compared to sham-operated controls. The protective effect of BDNF
on the damage to serotonergic terminals induced by the two neurotoxins suggests
the interest of this neurotrophin in the treatment of behavioral disorders
associated to neurodegenerative diseases.
PMID- 10762707
TI - Depletion of a fatty acid-binding protein impairs neurite outgrowth in PC12
cells.
AB - Epithelial fatty acid-binding protein (E-FABP) is up-regulated in rat dorsal root
ganglia after sciatic nerve crush and in differentiating neurons during
development. The present study investigates the role of E-FABP during nerve
growth factor (NGF)-mediated neurite outgrowth in PC12 cells. Undifferentiated
PC12 cells express low levels of E-FABP, while NGF triggers a 6- and 8-fold
induction of E-FABP mRNA and protein, respectively. Up-regulation of E-FABP mRNA
occurs as early as 24 h after NGF treatment and remains highly expressed over the
course of several days, corresponding to NGF-mediated neurite outgrowth.
Withdrawal of NGF leads to down-regulation of E-FABP mRNA and retraction of
neurites. Immunofluorescence microscopy reveals E-FABP immunoreactivity in the
perinuclear cytoplasm, neurites and growth cones of NGF-differentiated cells. To
examine the role of E-FABP during neurite outgrowth, PC12 cells were transfected
with a constitutive antisense E-FABP vector to create the E-FABP-deficient line
PC12-AS. By morphometric analysis, PC12-AS cells treated for 2, 4, and 7 days
with NGF exhibited significantly decreased neurite expression relative to control
(mock-transfected) cells. Taken together, these data indicate that E-FABP is
important in normal NGF-mediated neurite outgrowth in PC12 cells, a finding that
is consistent with a potential role in axonal development and regeneration.
PMID- 10762708
TI - Changes in mRNA for post-synaptic density-95 (PSD-95) and carboxy-terminal PDZ
ligand of neuronal nitric oxide synthase following facial nerve transection.
AB - When the axon of motoneurons is transected, the number of synaptic boutons
contacting the cell body is decreased, and the recovery of synapses depends on
muscle reinnervation. Post-synaptic density-95 (PSD-95) is a protein which is
located at the post-synaptic density (PSD) and it plays a pivotal role in
regulating synaptic plasticity and synaptogenesis. In addition, PSD-95 binds with
neuronal nitric oxide synthase (nNOS), which is competitively inhibited by
carboxy-terminal PDZ ligand of nNOS (CAPON) and, thereby, nNOS activity is
thought to be regulated by PSD-95 and CAPON. We investigated the changes in mRNA
for PSD-95, CAPON and nNOS in the facial motor nucleus of adult rats following
axotomy, by in situ hybridization, in combination with the time course of muscle
reinnervation, by retrograde tracing and nNOS protein expression, by examining
nicotinamide adenine nucleotide phosphate diaphorase (NADPH-d) activity. Signals
of mRNA for PSD-95 and CAPON were initially expressed in the facial motoneurons,
transiently decreased following axotomy and gradually recovered to the control
level. When reinnervation of the axotomized nerve into muscle was observed, mRNA
expression of PSD-95 and CAPON started to recover in the facial motoneurons. It
was also found that mRNA and protein expression of nNOS started to increase in
the axotomized facial motoneurons just prior to the recovery of mRNA expression
of PSD-95 and CAPON. These results suggest that PSD-95 and CAPON are involved in
synaptogenesis and/or recovery of synaptic function in motoneurons after axotomy.
PMID- 10762709
TI - Dopamine D-5 receptor modulates hippocampal acetylcholine release.
AB - Dopamine is intimately involved in cognitive processes in the brain. Of the
several subtypes of dopamine receptors, the possible role of dopamine D1-like
receptors in brain functions, especially in learning and memory, has recently
generated much interest. However, molecularly the D1-like receptors are comprised
of at least two subtypes, namely D-1 and D-5, and it has not been possible to
ascertain which of these two receptor classes is responsible for these functions
due to the lack of selective ligands. In the present study, utilizing a combined
antisense-in vivo dialysis approach, we show that the D-5 subtype is the dopamine
D1-like receptor involved in modulating hippocampal acetylcholine (ACh) release,
a transmitter implicated in a variety of cognitive processes. This is one of the
first evidence for a functional role for the D-5 receptor.
PMID- 10762710
TI - Retinal lesions induce differential changes in the expression of flip and flop
isoforms of the glutamate receptor subunit GluR1 in the chick optic tectum.
AB - A sensitive RNase protection assay was employed to determine the levels of mRNA
encoding the GluR1 subunit flip and flop isoforms in the chick optic tectum and
forebrain. We found that the flip GluR1 mRNA predominates in the forebrain,
whereas the flop variant is more strongly expressed in the optic tectum. A
temporal analysis of GluR1 variants in the embryonic and adult chick brain
revealed that the flip isoform is more highly expressed at E12 than at P15-21,
whereas mRNA levels of the flop isoform are higher at P15-21 than at E12. To
study the effect of deafferentation on GluR1 expression, unilateral retinal
lesions were performed. Two days later the mRNA levels of GluR1 flip and flop
variants were decreased in the deafferented tectum, especially for the flop
isoform. However, 7 days after the lesion, the mRNA levels of both GluR1 isoforms
were increased, especially for the flip isoform. These results reveal an
important control of the retinal input upon the expression of the different GluR1
isoforms. Furthermore, they indicate a differential spatial and temporal
regulation of the flip and flop splice variants, suggesting the existence of a
mechanism regulating differential splicing or possibly differential RNA
stability.
PMID- 10762711
TI - Quantitation of BDNF mRNA in human parietal cortex by competitive reverse
transcription-polymerase chain reaction: decreased levels in Alzheimer's disease.
AB - Alzheimer's disease is a progressive neurodegenerative disorder of the central
nervous system. One pathological characteristic is excessive neuronal loss in
specific regions of the brain. Among the areas most severely affected are the
basal forebrain cholinergic neurons and their projection regions, the hippocampus
and cortex. Neurotrophic factors, particularly the neurotrophins nerve growth
factor and brain-derived neurotrophic factor, play an important role in the
development, regulation and survival of basal forebrain cholinergic neurons.
Furthermore, brain-derived neurotrophic factor regulates the function of
hippocampal and cortical neurons. Neurotrophins are synthesized in hippocampus
and cortex and retrogradely transported to the basal forebrain. Decreased levels
of neurotrophic factors are suspected to be involved in the neurodegenerative
changes observed in Alzheimer's disease. We examined autopsied parietal cortex
samples from age- and gender-matched Alzheimer's diseased and neurologically non
impaired individuals using the quantitative technique of competitive RT-PCR. We
demonstrate a 3.4-fold decrease in brain-derived neurotrophic factor mRNA levels
in the parietal cortex of patients with Alzheimer's disease compared to controls
(p<0.004). A decrease in brain-derived neurotrophic factor synthesis could have
detrimental effects on hippocampal, cortical and basal forebrain cholinergic
neurons and may account for their selective vulnerability in Alzheimer's disease.
PMID- 10762712
TI - Chronic repetitive transcranial magnetic stimulation enhances c-fos in the
parietal cortex and hippocampus.
AB - Repetitive transcranial magnetic stimulation (rTMS) is a novel non-invasive
method with anti-depressant properties. However, the mechanism of activation on
the cellular level is unknown. Twelve hours after the last chronic rTMS treatment
(14 days, once per day, 20 Hz, 10 s, 75% machine output, the transcription factor
c-fos was markedly increased in neurons in layers I-IV and VI of the parietal
cortex and in few scattered neurons in the hippocampus of Sprague-Dawley rats.
The cortical activation was not blocked by the NMDA antagonist MK-801. The
increase of c-fos was not paralleled by an increased glial response and
activation of cortical growth factors. Thus, it is concluded that chronic rTMS
differentially activates parietal cortical layers and this might be involved in
mediating anti-depressant activity in other brain areas.
PMID- 10762713
TI - Poly (ADP-ribose) polymerase induction is an early signal of apoptosis in human
neuroblastoma.
AB - Poly (ADP-ribose) polymerase (PARP) is an abundant chromatin associated protein
important in DNA repair, maintenance of chromosomal stability and programmed cell
death. Here we report that an increase in caspase 3-activity and cleavage of PARP
serves as an early execution phase signal in human neuroblastoma. Human
neuroblastoma SK-N-SH cells were exposed to a protein kinase inhibitor,
staurosporine, or a topoisomerase II inhibitor, etoposide, at various
concentrations and time points. Cells exposed to staurosporine (0.1 microM) for
30 min showed an increase in caspase 3-activity and by 1 h an increase in PARP
116-kDa band and an 85-kDa cleavage product, which further increased in density
with time after treatment. Quantitative analysis for condensed chromatin material
using bisbenzimide, and DNA fragmentation enzyme immunoassays showed a
significant increase in apoptosis 5 h after staurosporine treatment. This was
further confirmed with a Klenow fragment of DNA polymerase I assay which
primarily detects single-stranded DNA breaks. A significant decrease in
mitochondrial metabolism occurred within 8-12 h after treatment. Studies using
Trypan Blue exclusion, and lactic dehydrogenase (LDH) release revealed a
significant increase in membrane permeability 8 h after staurosporine (0.1
microM) or etoposide (10 microM) treatments. Cleavage of lamin B1, a protein
important in maintaining the nuclear envelope integrity was observed 12 h after
staurosporine treatment. Our results show that activation of caspase 3 followed
by PARP cleavage occur at much earlier time point than any other morphological or
biochemical parameters of apoptosis or cytotoxicity.
PMID- 10762714
TI - Alternative splicing of the NMDAR1 glutamate receptor subunit in human temporal
lobe epilepsy.
AB - It has been demonstrated in animal models that chronic epilepsy is associated
with increased excitability which may result from abnormal glutamatergic
transmission involving altered properties of N-methyl-D-aspartate (NMDA)
receptors. We have investigated whether human temporal lobe epilepsy is
associated with changes in the NMDA receptor at the molecular level by assessing
the relative expression of mRNAs of the different splice variants at the N
terminal (exon 5) and C-terminal (exon 21) position for the NMDAR1 subunit.
Specimens of hippocampus and temporal lobe cortex from patients with refractory
epilepsy were obtained during neurosurgical operations and analyzed by means of
the reverse transcription reaction followed by polymerase chain reaction. Non
epileptic control specimens obtained at autopsy exhibited a relatively high level
in expression of exon 5-lacking (hippocampus: 0.87; cortex: 0.81) and exon 21
containing (hippocampus: 0.95; cortex: 0.93) transcripts. The ratio for these
alternatively spliced transcripts was not significantly changed in epileptic
hippocampal and cortical tissues relative to the corresponding non-epileptic
samples. These results did not support a potential role for NMDAR1 splice
variants in the pathophysiology of epilepsy.
PMID- 10762715
TI - Quantitative assessment of nicotinic acetylcholine receptor proteins in the
cerebral cortex of Alzheimer patients.
AB - Cholinergic transmission has for long been known to be one of the most severely
affected systems in Alzheimer's disease (AD), resulting clinically in massive
cognitive deficits. The molecular basis of this dysfunction--on both the pre- and
the postsynaptic sites--is still a matter of ongoing investigations. Here, we
report on the quantitative assessment of nicotinic acetylcholine receptor isoform
expression in AD vs. control cortices. For both subunit proteins assessed, the
alpha4 and the alpha7 isoform, highly significant decreases in diseased vs.
normal cortices were observed. Both alpha4 and alpha7 subunits are known to be
important constituents in hetero- (alpha4beta2) and homooligomeric (alpha7)
receptor subtypes. Their decreased expression may contribute to the decreased
nicotinic binding known to be accompanied by AD and severe cognitive deficits.
The quantitative assessment of nicotinic acetylcholine receptor expression will
help to determine those subunits suited as targets for pharmacological
stimulation.
PMID- 10762716
TI - Beta-amyloid-induced calcium influx induces apoptosis in culture by oxidative
stress rather than tau phosphorylation.
AB - Beta-amyloid (betaA) toxicity in culture is accompanied by multiple events
culminating in apoptosis. Calcium influx may represent the initial event, since
calcium chelation prevents all subsequent events, while subsequent events include
increased generation of reactive oxygen species (ROS) and hyperphosphorylation of
tau. In the present study, we undertook to determine whether ROS generation or
tau hyperphosphorylation mediate betaA-induced apoptosis. The anti-oxidant
vitamin E or the kinase inhibitor N-(6-aminohexyl)-5-chloro-1
naphthalenslfonamide (W7) was added following brief treatment of differentiated
SH-SY-5Y human neuroblastoma cells with 22 microM betaA. Under these conditions,
vitamin E prevented ROS generation and apoptosis, but did not prevent
intracellular calcium accumulation or tau phosphorylation. W7 prevented tau
phosphorylation but did not block betaA-induced calcium influx, ROS generation or
apoptosis. While these studies do not address the long-term consequences of PHF
formation, they indicate that ROS generation, rather than tau
hyperphosphorylation, leads to apoptosis following betaA-induced calcium influx
into cultured cells.
PMID- 10762717
TI - Stimulation of astrocyte-enriched culture with arachidonic acid increases
proenkephalin mRNA: involvement of proto-oncoprotein and mitogen activated
protein kinases.
AB - In astrocyte-enriched cultures, arachidonic acid (AA, 100 microM) significantly
increased the proenkephalin (proENK) mRNA level (4. 9-fold at 8 h). In addition,
AA also increased several AP-1 proteins, such as c-Fos, Fra-1, Fra-2, JunB, JunD,
and c-Jun, or AP-1 and ENKCRE-2 DNA-binding activity. As well as AP-1 proteins
and their DNA-binding activities, proENK mRNA level induced by AA was reduced by
the pretreatment with 15 microM of cycloheximide (CHX; 1.6-fold). AA-dependent
increase of proENK mRNA is not mediated by cyclooxygenase- or lipoxygenase
dependent metabolites, or free radicals, because the AA-induced increase of
proENK mRNA levels was not affected by indomethacin (10 microM),
nordihydroguaiaretic acid (10 microM), or N-acetylcysteine. However, as well as
proto-oncoprotein levels, such as Fra-1, Fra-2, c-Jun, JunB, but not JunD, AA
induced increase of proENK mRNA was significantly reduced by the pretreatment
with 10 microM of PD98059 (1.3-fold) or 10 microM of SB203580 (1.8-fold). These
results strongly suggest that AA rather than one of its metabolites is involved
in the increase of proENK mRNA. In addition, the activation of both the p38 and
ERK pathways appears to be involved in the AA-induced increase of proENK mRNA via
activating the expression of proto-oncoprotein, such as Fra-1, Fra-2, c-Jun, and
JunB.
PMID- 10762718
TI - S100beta inhibits the phosphorylation of the L-MAG cytoplasmic domain by PKA.
AB - The myelin-associated glycoprotein (MAG) is a cell adhesion molecule expressed by
myelinating glia, existing as two isoforms that differ only by their cytoplasmic
domains. We have studied the in vitro phosphorylation of recombinant rat MAG
cytoplasmic domains by three kinases for which consensus sequences exist within
this domain, revealing phosphorylation of the L-MAG-specific domain by protein
kinase A (PKA). Phosphorylation of the L-MAG cytoplasmic domain by PKA was
decreased in the presence of S100beta, providing a functional significance to the
interaction between L-MAG and S100beta, and further indicating that L-MAG may
play a role in myelinating glial cell signalling processes.
PMID- 10762719
TI - Altered phosphofructokinase mRNA levels but unchanged isoenzyme pattern in brains
from patients with Alzheimer's disease.
AB - In order to find out whether the increased phosphofructokinase (PFK) activities
observed in brains from Alzheimer's disease (AD) patients are associated with
alterations in PFK mRNA levels, we determined total PFK mRNA and the three
different PFK isoenzyme mRNAs in AD and control patients by ribonuclease
protection assay (RPA) and quantitative RT-PCR. PFK mRNA levels were found
increased in some brain areas in AD patients. While all three PFK isoenzyme mRNAs
were detectable in every studied brain sample, no changes of the PFK isoenzyme
pattern were observed in patients with AD.
PMID- 10762720
TI - Expression of purinergic receptors in bipolar cells of the rat retina.
AB - P2X receptors are ligand-gated ion channels which are activated by excitatory
neurotransmitter ATP. Despite considerable evidence of signaling by extracellular
nucleotides in other sensory systems, P2X receptors in the visual system have
only rarely been studied, and almost nothing is known about their functional
significance in the retina. To determine whether ATP plays a role in the
modulation of vertical retinal signal pathways, we examined the expression of P2X
receptor mRNA in freshly isolated bipolar cells of the rat retina (Brown Norway,
P25) using the single-cell RT-PCR technique. Positive amplification signals were
found in about 33% of the bipolar cells for P2X(3), P2X(4) and P2X(5) but not for
P2X(7) mRNA. We conclude that at least a subpopulation of bipolar cells in the
rat retina expresses ionotropic P2 receptors of the P2X type and that these
possibly exert a neuromodulatory influence on information processing in the
retina.
PMID- 10762721
TI - Mechanisms of arachidonic acid induced glial swelling.
AB - Accumulation of arachidonic acid (AA) in the brain during ischaemia may
contribute to development of brain oedema. In this study we investigated the
effect of selected drugs on AA-induced cytotoxic brain oedema in C6 glioma cells.
Suspended C6 glioma cells were preincubated with drugs and AA (0.1 mM) was added.
When no drug was administered cell volume increased immediately after the
addition of AA with a maximum cell swelling of 13.1+/-1.9% at 15 min (mean +/-
S.E. M.). Preincubation of cells with BW 755C, a dual inhibitor of cyclo- and
lipoxygenases, showed no reduction in cell swelling from AA, whereas superoxide
dismutase, amiloride and the protein kinase inhibitor H-9370 led to a significant
attenuation of volume increase (p<0.05). The role of Na(+) ions during cell
swelling from AA was evaluated after pretreatment of C6 glioma cells with
ouabain. This resulted in a reversal of cell swelling (p<0.01). We conclude that
there is potential involvement of free radicals, signal transduction systems and
intracellular accumulation of Na(+) ions in glial cell swelling from AA.
PMID- 10762722
TI - Structure and expression of the Aplysia polyubiquitin gene.
AB - The ubiquitin-proteasome pathway, which is up-regulated in response to
sensitizing treatments with serotonin (5-HT), plays a critical role in inducing
long-term facilitation (LTF) of sensory-to-motor synapses in Aplysia. We
characterized the structure of the polyubiquitin gene of Aplysia and studied its
expression. At least six ubiquitin coding units exist in tandem, one of which
encodes a protein with an amino acid sequence identical to human ubiquitin.
Although the synthesis of polyubiquitin is induced by strong stimuli in many
organisms, we found that the expression of ubiquitin in Aplysia is not affected
by protocols that produce LTF.
PMID- 10762723
TI - Glutamate transporter GLT-1 is highly expressed in activated microglia following
facial nerve axotomy.
AB - Glutamate transporters play an important role in the re-uptake of glutamate after
its release from glutamatergic synapses. So far five of such transporters
subtypes have been cloned from rodent and human brains. The densities of
glutamate transporters are recognised to be developmentally regulated, but the
role of glutamate transporters in the mechanisms underlying the occurrence of
neuronal traumatic injury has not been widely studied. In the present study
quantitative Western blotting and immunohistochemical technique were employed to
study the expression of GLT-1/EAAT2 in the facial nuclei of adult rats following
unilateral facial nerve axotomy. The total content of GLT-1 protein decreased in
the ipsilateral axotomised rat facial nucleus. However, activated microglia
surrounding motoneurons showed high expression of GLT-1 after facial nerve
axotomy. Parallel studies revealed that primary cultured microglial cells also
showed GLT-1-immunoreactivity. To our knowledge, this is the first direct
demonstration of the expression of GLT-1 protein in activated microglial cells,
suggesting a neuroprotective role of microglia against glutamate excitotoxicity
following nerve axotomy.
PMID- 10762724
TI - Formation and inhibition of heterocyclic aromatic amines in fried ground beef
patties.
AB - The effect of vitamin E and oleoresin rosemary on heterocyclic aromatic amine
(HAA) formation in fried ground beef patties was studied. Patties were fried at
three temperatures (175 degrees C, 200 degrees C, 225 degrees C) for 6 and 10
min/side to determine the conditions for optimum HAA formation. HAAs were
isolated by solid phase extraction and quantitated by HPLC. Greatest
concentrations were generated when patties were fried at 225 degrees C for 10
min/side, 31.4 ng/g 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and
5.8 ng/g 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Vitamin E, when
used at two concentrations (1% and 10% based on fat content) and added directly
to the ground beef patties, reduced PhIP concentrations in the cooked patties by
69% and 72%, respectively. Smaller but more variable reductions were achieved for
MeIQx. Comparable inhibition of HAA formation was achieved by the direct addition
of vitamin E (1% based on fat content) to the surface of the patties before
frying. Concentrations of five HAAs studied were all significantly reduced
(P<0.006), with average reductions ranging from 45% to 75%. Oleoresin rosemary,
when used at two concentrations (1% and 10% based on fat content), reduced PhIP
formation by 44%.
PMID- 10762725
TI - Lack of effect of coumarin on unscheduled DNA synthesis in the in vivo rat
hepatocyte DNA repair assay.
AB - The ability of coumarin to induce UDS in male Sprague-Dawley CD rat hepatocytes
in vivo was assessed using the unscheduled DNA synthesis (UDS) assay. From a
preliminary toxicity study the oral maximum tolerated dose (MTD) of coumarin was
determined to be 320 mg/kg body weight. For the UDS studies, rats were treated
with 0 (corn oil control), 32 (one-tenth the MTD), 107 (one-third the MTD) and
320 (MTD) mg/kg coumarin via oral gavage. Rats were also treated with 20mg/kg
body weight dimethylnitrosamine (DMN) or 50mg/kg body weight 2
acetylaminofluorene (2-AAF) as positive controls for the 2-4 hr and 12-16 hr
expression of UDS, respectively. Hepatocytes were isolated by liver perfusion
either 2-4 hr or 12-16 hr after treatment and cultured in medium containing
[methyl-(3)H]thymidine for 4 hr and assessed for UDS by grain counting of
autoradiographs. Coumarin treatment at doses of 32-320 mg/kg body weight had no
statistically significant or dose-related effect on UDS in rat hepatocytes either
2-4 hr or 12-16 hr after dosing. In contrast, both DMN 2-4 hr after dosing and 2
AAF 12-16 hr after dosing produced significant increases in UDS assessed as the
net nuclear grain count. Both genotoxins also increased the percentage of
hepatocyte nuclei with greater than 5 net grains. Treatment with coumarin, DMN
and 2-AAF had no statistically significant effect on the proportion of rat
hepatocytes undergoing replicative DNA synthesis. In summary, this study
demonstrates that coumarin does not induce UDS in hepatocytes of male Sprague
Dawley CD rats after oral administration at doses up to the MTD of 320 mg/kg. The
responsiveness of the animals used in this study to genotoxic agents was
demonstrated by the clear induction of DNA repair after treatment with DMN and 2
AAF.
PMID- 10762726
TI - Protective effect of Hibiscus anthocyanins against tert-butyl hydroperoxide
induced hepatic toxicity in rats.
AB - Hibiscus anthocyanins (HAs), a group of natural pigments occurring in the dried
flowers of Hibiscus sabdariffa L., which is a local soft drink material and
medical herb, were studied for antioxidant bioactivity. The preliminary study
showed that HAs were able to quench the free radicals of 1,1-diphenyl-2
picrylhydrazyl. This antioxidant bioactivitiy was further evaluated using the
model of tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity in rat primary
hepatocytes and hepatotoxicity in rats. The results demonstrated that HAs, at the
concentrations of 0.10 and 0.20 mg/ml, significantly decreased the leakage of
lactate dehydrogenase and the formation of malondialdehyde induced by a 30-min
treatment of t-BHP (1.5 mM). The in vivo investigation showed that the oral
pretreatment of HAs (100 and 200 mg/kg) for 5 days before a single dose of t-BHP
(0.2 mmol/kg, ip) significantly lowered the serum levels of hepatic enzyme
markers (alanine and aspartate aminotransferase) and reduced oxidative liver
damage. The histopathological evaluation of the liver revealed that Hibiscus
pigments reduced the incidence of liver lesions including inflammatory, leucocyte
infiltration, and necrosis induced by t-BHP in rats. Based on the results
described above, we speculate that Hibiscus pigments may play a role in the
prevention of oxidative damage in living systems.
PMID- 10762727
TI - Thyroid peroxidase inhibition by Kalanchoe brasiliensis aqueous extract.
AB - Flavonoids are known inhibitors of thyroid peroxidase (TPO) and some are
components of Kalanchoe brasiliensis, a plant used in popular medicine to treat
tissue injuries, enlarged ganglia and peptic ulcer. As K. brasiliensis extract is
currently used, the present study was designed to evaluate the effects of K.
brasiliensis aqueous extract on TPO activity. We show here that TPO iodide
oxidation activity was significantly inhibited by K. brasiliensis aqueous extract
and that TPO inhibition seems to be competitive, since the enzyme V(max) was
unchanged and K(m) for iodide was significantly increased in the presence of the
plant extract. Furthermore, TPO inhibitory activity produced by K. brasiliensis
extract was unchanged after boiling or by incubation with hepatic enzymes
(activated S9 fraction), suggesting that at least the antithyroid component of
this plant infusion could probably reach systemic circulation. We also report
that K. brasiliensis aqueous extract is able to scavenge H(2)O(2), in vitro. As
H(2)O(2) is an essential TPO cofactor, it is possible that the H(2)O(2) trapping
effect of K. brasiliensis may be responsible, at least in part, for the
inhibition of the iodide-oxidation reaction catalysed by this enzyme. Thus, K.
brasiliensis aqueous extract has antithyroid effects in vitro, suggesting that
its chronic consumption could contribute to the development of goitre and
hypothyroidism, mainly in areas of low iodine intake.
PMID- 10762728
TI - Effect of decaglycerol monooleate on phagocytosis and respiratory burst activity
of human neutrophils: an in vitro study.
AB - Decaglycerol monooleate (DGMO), a type of polyglycerol esters of fatty acids
(PGEF), was evaluated for its in vitro effect on phagocytosis and respiratory
burst activity of isolated human neutrophils using flow cytometric assay.
Opsonized zymosan particles labelled with FITC (FITC-OZ) were employed as an
indicator of phagocytosis. Fluorescence of FITC-OZ attached on to the surface of
neutrophils was quenched by addition of trypan blue solution. After 10 minutes of
incubation with DGMO up to a concentration of 10 mg/ml, neutrophil phagocytosis
was not affected markedly. At the same time, the DGMO emulsion left little
influence on complement receptor type three (CR3) that is associated with
phagocytosis. On the other hand, oxidation of hydroethidine, which was used as an
indicator of intracellular generation of reactive oxygen species (mainly for
superoxide anion), was significantly inhibited by DGMO over 1 mg/ml. However,
this phenomenon was not seen in DGMO-treated neutrophils when DGMO was removed
after incubation. The present data suggest that DGMO does not affect phagocytosis
of human neutrophils but down-regulates respiratory burst activity.
PMID- 10762729
TI - Toxicity and mutagenicity studies of DN-50000((R)) and RP-1((R)) enzymes.
AB - Improved yields of 5'-nucleotides from yeast extract for food flavouring purposes
is possible through use of microbial nucleotidases, which will be available to
food processors as the flavour enhancer Aromild. The safety of these enzymes, 5'
phosphodiesterase (RP-1) and the 5'-adenylic deaminase (DN-50000) was
investigated in male and female rats. Feeding rats a diet admixed with 500, 2000
and 8000 mg/kg body weight of DN-50000 for 35 days resulted in no significant
dose-related changes in body weight, water consumption, urinalysis,
haematological profiles, blood chemistry or histopathological profiles of either
male or female rats from consumption of the enzyme preparation. There was an
increase in the absolute and/or relative organ weights of the submaxillary
(salivary) glands in both sexes at 8000 mg/kg. The no-observed-effect level
(NOEL) for DN-50000 was clearly evident at 2000 mg/kg. Consumption of RP-1 enzyme
for 35 days at dietary levels of 500, 2000 and 8000 mg/kg body weight resulted in
no significant changes in the above mentioned parameters, which could be directly
attributed to a dose-related effect, with the exception of an increase in the
absolute and relative weights of submaxillary glands of both male and female rats
in the 2000 and 8000 mg/kg groups. The increase in weight of the submaxillary
glands was associated with histological evidence of acinar cell hypertrophy. The
NOEL for dietary consumption of RP-1 was clearly evident at 500 mg/kg. In a
follow-up study in which rats were gavaged with 2000 mg/kg RP-1, submaxillary
gland hypertrophy did not occur. These studies suggest that DN-50000 and RP-1
exert an action on submaxillary glands similar to that which has been previously
reported for the enzyme pancreatin. Neither DN-50000 nor RP-1 were mutagenic in
the Ames assay using Salmonella typhimurium strains TA100, TA1535, TA98, TA1537
or Escherichia coli strain WP2uvrA, in the presence or absence of S9 mix.
PMID- 10762730
TI - Influence of dietary ginger (Zingiber officinales Rosc) on oxidative stress
induced by malathion in rats.
AB - Pesticide chemicals may induce oxidative stress leading to generation of free
radicals and alterations in antioxidants or oxygen free radical (OFR) scavenging
enzymes. Hence, the effect of subchronic malathion (O,O-dimethyl-S-1,2, bis
ethoxy carbonyl ethyl phosphorodithioate) exposure was evaluated on lipid
peroxidation, glutathione and related enzymes and OFR scavenging enzymes in
albino rats. Administration of malathion (20 ppm) for 4 weeks increased the
malondialdehyde (MDA) levels in serum, activities of superoxide dismutase (SOD),
catalase (CAT) and glutathione peroxidase (GPx) in erythrocytes and glutathione
reductase (GR) and glutathione S-transferase (GST) in serum. However, it
decreased the glutathione (GSH) level in whole blood. Concomitant dietary feeding
of Zingiber officinales Rosc (ginger 1%, w/w) significantly attenuated malathion
induced lipid peroxidation and oxidative stress in these rats. These results
indicate the possible involvement of free radicals in organophosphate-induced
toxicity and highlight the protective action of ginger, an indigenous medicinal
plant product.
PMID- 10762731
TI - Use of rat liver slices for the study of oxidative DNA damage in comparison with
isolated rat liver nuclei and HepG2 human hepatoma cells.
AB - Tissue slices are a useful biological system for lipid peroxidation studies but
their use for DNA damage studies is not well characterized. Hence, the present
study investigates DNA damage in rat liver slices, in comparison with isolated
rat liver nuclei and HepG2 human hepatoma cells, incubated with ferric
nitrilotriacetate (Fe(III)-NTA), bromotrichloromethane (BrCCl(3)), bromobenzene
(BrB) or 2-nitropropane (2-NP) at 37 degrees C for 2 hr. DNA damage was measured
in slices, cells or nuclei after centrifugation as formation of as 8-hydroxy-2'
deoxyguanosine (8-OH-dGu) and loss of double-stranded (dsDNA) due to strand
breakage using a fluorometric analysis of DNA unwinding (FADU). Lipid
peroxidation was measured as thiobarbituric acid-reactive substances (TBARS)
released into the medium. The results show that in liver slices and isolated
nuclei, Fe/NTA (1 mM/4 mM) induced high levels of TBARS but low levels of 8-OH
dGu, whereas the oxidant induced low levels of TBARS and no formation of 8-OH-dGu
in HepG2 cells. In all three systems, inclusion of ascorbate caused dose
dependent formation of 8-OH-dGu, and the levels were similar between liver slices
and HepG2 cells but were far higher in isolated nuclei. In liver slices the FADU
assay was not applicable due to limited solubilization of DNA from the slice,
whereas the assay detected significant loss of dsDNA in HepG2 cells and slight
loss in isolated nuclei induced by Fe/NTA with or without ascorbate. Liver slices
incubated with 1 mm BrCCl(3), BrB or 2-NP had elevated TBARS but had little or no
formation of 8-OH-dGu; none of these oxidants induced lipid peroxidation or DNA
damage in HepG2 cells. When liver slices obtained from rats injected with
diethylmaleate (to deplete GSH) were incubated with BrCCl(3), BrB or 2-NP, levels
of TBARS and 8-OH-dGu increased markedly. Similarly, HepG2 cells with decreased
GSH showed marked elevation of TBARS and loss of dsDNA induced by these oxidants,
although no formation of 8-OH-dGu was detected. The present study demonstrates
the usefulness and limitations of liver slices for DNA damage studies and the
importance of cellular GSH in the protection of DNA against environmental
toxicants.
PMID- 10762732
TI - Evaluation of the prenatal developmental toxicity of orally administered arsenic
trioxide in rats.
AB - A thorough review of the literature revealed no published repeated-dose oral
developmental toxicity studies of inorganic arsenic in rats. In the present
study, which was conducted according to modern regulatory guidelines, arsenic
trioxide was administered orally beginning 14 days prior to mating and continuing
through mating and gestation until gestational day 19. Exposures began prior to
mating in an attempt to achieve a steady state of arsenic in the bloodstream of
dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats
received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these
dose levels was based on a preliminary range-finding study, in which excessive
post-implantation loss and markedly decreased foetal weight occurred at doses of
15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in
the 10mg/kg/day group was evidenced by decreased food consumption and decreased
net body weight gain during gestation, increased liver and kidney weights, and
stomach abnormalities (adhesions and eroded areas). Transient decreases in food
consumption in the 5mg/kg/day group caused the maternal no-observed-adverse
effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters
were unaffected by arsenic trioxide. No treatment-related foetal malformations
were noted in any dose group. Increased skeletal variations at 10mg/kg/day were
attributed to reduced foetal weight at that dose level. The developmental NOAEL
was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide
cannot be considered to be a selective developmental toxicant (i.e. it is not
more toxic to the conceptus than to the maternal organism), nor does it exhibit
any propensity to cause neural tube defects, even at maternally toxic dose
levels.
PMID- 10762733
TI - Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8
hydroxydeoxyguanosine formation in vitro and in a rat carcinogenesis model.
AB - Various plant extracts, such as carrot, burdock (gobou), apricot and prune,
showed inhibitory effects in an in vitro assay of lipid peroxide-induced 8
hydroxydeoxyguanosine (8-OH-dG) formation. The major inhibitor purified from
various plants extracts was identified as chlorogenic acid (CA), on the basis of
UV- and mass-spectra and comparison with a standard sample. To examine whether CA
also inhibits 8-OH-dG formation in animal organs, an oxygen radical-forming
carcinogen, 4-nitroquinoline-1-oxide, was administered to rats, with or without
CA. The 8-OH-dG level in the DNA of the rat tongue, the target organ, was
significantly reduced in the CA-treated group.
PMID- 10762734
TI - Towards a neurobiology of dysfunctional arousal in depression: the relationship
between beta EEG power and regional cerebral glucose metabolism during NREM
sleep.
AB - This study sought to clarify the neurobiological basis of variations in one
aspect of central nervous system 'arousal' in depression by characterizing the
functional neuroanatomic correlates of beta electroencephalographic (EEG) power
density during non-rapid eye movement (NREM) sleep. First, nine healthy (n=9)
subjects underwent concurrent EEG sleep studies and [18F]2-fluoro-2-deoxy-D
glucose ([18F]FDG) positron emission tomography (PET) scans during their first
NREM period of sleep in order to generate hypotheses about specific brain
structures that show a relationship between increased beta power and increased
relative glucose metabolism. Second, brain structures identified in the healthy
subjects were then used as a priori regions of interest in similar analyses from
identical studies in 12 depressed subjects. Statistical parametric mapping was
used to identify the relationship between beta power and relative regional
cerebral glucose metabolism (rCMRglu) during NREM sleep. Regions that
demonstrated significant correlations between beta power and relative cerebral
glucose metabolism in both the healthy and depressed subjects included the
ventromedial prefrontal cortex and the right lateral inferior occipital cortex.
During a baseline night of sleep, depressed patients demonstrated a trend toward
greater beta power in relation to a separate age- and gender-matched healthy
control group. In both healthy and depressed subjects, beta power negatively
correlated with subjective sleep quality. Finally, in the depressed group, there
was a trend for beta power to correlate with an indirect measure of absolute
whole brain metabolism during NREM sleep. This study demonstrates a similar
relationship between electrophysiological arousal and glucose metabolism in the
ventromedial prefrontal cortex in depressed and healthy subjects. Given the
increased electrophysiological arousal in some depressed patients and the known
anatomical relations between the ventromedial prefrontal cortex and brain
activating structures, this study raises the possibility that the ventromedial
prefrontal cortex plays a significant role in mediating one aspect of
dysfunctional arousal found in more severely aroused depressed patients.
PMID- 10762735
TI - Age-related brain volume reductions in amphetamine and cocaine addicts and normal
controls: implications for addiction research.
AB - The study evaluated the relationship between age and frontal and temporal lobe
volumes in young cohorts of cocaine-dependent (CD), amphetamine-dependent (Am),
and normal control subjects. Ten CD, nine Am, and 16 age- and gender-matched
control subjects underwent magnetic resonance imaging (MRI). The volume of the
frontal and temporal lobes was measured from an identically positioned slab of
seven contiguous 3-mm-thick coronal images. Follow-up measures of the gray and
white matter subcomponents of these volumes were also obtained. Both CD and Am
groups had a significantly smaller temporal lobe volumes, but only the CD group
demonstrated a significantly greater decline in temporal lobe volume with age
(intracranial volume, education, and race were controlled for in all statistical
analyses). Segmenting the brain regions into gray and white matter revealed that
the negative correlation between age and temporal lobe volume of CD patients was
mostly due to a significant age-related decline in the gray matter subcomponent.
Negative trends between age and gray matter volumes were also observed in the Am
and normal groups. In the frontal lobes, age was negatively correlated with gray
matter volume in the control, CD, and Am groups. Unlike the consistent decreases
in gray matter volumes, white matter showed non-significant increases in volume
with age. The data suggest that CD patients may have an accelerated age-related
decline in temporal lobe gray matter volume and a smaller temporal lobe volume
compared to normal controls. In the frontal lobe, age-related gray matter volume
reductions occur in all three groups. These age-related cortical gray matter
volume reductions may be a biological marker for the risk of addictive behavior,
which also decreases with age.
PMID- 10762736
TI - Measurement of the planum temporale (PT) on magnetic resonance imaging scans:
temporal PT alone and with parietal extension.
AB - The planum temporale (PT) has been of interest because of (1) its consistent left
greater than right asymmetry among right-handed and most left-handed normal
individuals; and (2) its relation to language, another variable shown to be
highly left-lateralized in normal subjects. Individuals with neurodevelopmental
disorders have been reported to show abnormal PT asymmetry (either reversed or
absent asymmetry). Several studies have been conducted measuring the PT on MRI
scans, although the results do not always concur. We review some of these studies
and discuss methodological differences between them. Additionally, we propose a
method that has proved to be highly reliable for the measurement of both temporal
PT and its parietal extension (PT+).
PMID- 10762737
TI - Qualitative MRI findings in patients with schizophrenia: a controlled study.
AB - A variety of brain structural abnormalities, which can be identified only by
qualitative methods, have been shown to correlate with clinical presentation and
course of schizophrenia. In the present study, MRI scans of 122 patients with DSM
IV schizophrenia and 81 non-psychiatric controls were evaluated. Among males, the
frequency of CNS developmental abnormalities (CDAs) was higher in patients than
in controls. Lateral ventricular enlargement (LVE) was more frequent in patients
than in controls; when subjects were grouped in three age classes, LVE was more
frequent in patients than in controls in the youngest and the oldest age group.
Patients with LVE or third VE were older than those without these abnormalities.
Schizophrenic patients with LVE or cortical atrophy (CA) had a longer duration of
illness than those without these abnormalities. Both patients with LVE and those
with third VE had a poorer outcome than those without these abnormalities. CDA
findings add to the evidence of a higher frequency of neurodevelopmental
abnormalities in male schizophrenic patients. Results concerning LVE suggest that
both developmental and degenerative processes underlie this abnormality. The
association of LVE and third VE with a poor outcome indicates that qualitative
MRI evaluation might be of clinical relevance.
PMID- 10762738
TI - Brain perfusion and neuropsychological changes in schizophrenic patients after
cognitive rehabilitation.
AB - The role of cognitive variables was compared in two single cases of schizophrenia
hypofrontality. SPECT procedures and neuropsychological tests were used to study
frontal brain function. After cognitive rehabilitation, neuropsychological
performance were enhanced in both patients, but only one of them showed enhanced
the frontal blood flow. The brain perfusion changes after cognitive
rehabilitation could be associated with the cognitive-dependent hypofrontality.
PMID- 10762739
TI - Soft tissue sarcoma of high grade--a primary systemic disease?
PMID- 10762740
TI - Positron emission tomography (PET) in diagnostic oncology: is it a necessary tool
today?
PMID- 10762741
TI - Recent advances in cancer chemoprevention, with emphasis on breast and colorectal
cancer.
AB - Chemoprevention is a recently introduced and rapidly growing area of oncology
that is identifying agents with a potentially preventive role in cancer. Several
clinical trials have recently shown the feasibility of this approach in reducing
the risk of major human cancers. In the USA, a large trial that demonstrated a
reduction of approximately 50% in the risk of developing breast cancer led to
Food and Drug Administration (FDA) approval of tamoxifen as a preventive agent in
women at increased risk. Although the results could not be reproduced in two
smaller European trials, further investigations into this agent are clearly
warranted. Raloxifene, another selective oestrogen receptor modulator which has
reduced the risk of breast cancer in a trial in women with osteoporosis, is being
compared with tamoxifen in a large primary prevention trial in at-risk women.
Retinoids are a group of compounds that have proved especially effective in
reducing the occurrence of second primary tumours in subjects with skin, head and
neck or liver cancer. Fenretinide, a synthetic retinoic acid derivative, has
recently been shown to decrease the occurrence of a second breast malignancy in
premenopausal women. Results with non-steroidal anti-inflammatory drugs (NSAIDs)
have proved consistently encouraging in epidemiological studies in lowering the
incidence of colorectal cancer. Clinical trials with selective cyclo-oxygenase
inhibitors potentially devoid of gastrointestinal (GI) toxicity are currently
underway in at-risk subjects. Calcium and selenium have also received much
attention as chemopreventive agents. Originally investigated against skin cancer,
selenium showed efficacy in reducing prostate, lung and colon cancer incidence.
Similarly, vitamin E was effective in reducing prostate cancer incidence and
mortality in a lung cancer prevention trial in heavy smokers. The challenges of
conducting well-designed and unequivocal chemoprevention trials are considerable,
but advances in techniques of identification of at-risk subjects and establishing
surrogate endpoint biomarkers should contribute greatly to future studies.
Current knowledge suggests that a pharmacological approach to preventing cancer,
using natural or synthetic agents, could become an important way forward.
PMID- 10762742
TI - Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559
surgically-treated patients from the Scandinavian Sarcoma Group Register.
AB - The prognostic importance of surgical margins on local recurrence rates and
metastasis-free survival (MFS) was studied in 559 patients with soft tissue
sarcoma of the extremities and trunk wall. The patients were all surgically
treated, but received no adjuvant treatment. The median follow-up for the
survivors was 7.4 (range: 0.1 - 12.5) years. Independent prognostic factors for
MFS were analysed by Cox models. The overall 5-year MFS was 0.72 (95% confidence
intervals (CI) 0.68 - 0.76). High histopathological malignancy grade (relative
risk (RR) 3.0; 95% CI 1.5 - 6.3) and an inadequate surgical margin (RR 2.9; 95%
CI 1.8 - 4.6) were independent risk factors for local recurrence. High
histopathological malignancy grade and large tumour size (> 7 cm) were the most
important risk factors for metastasis. Local recurrence was associated with an
increased risk of metastasis (RR 4. 4; 95% CI 2.9-6.8), but an inadequate
surgical margin was not a risk factor for metastasis (RR 1.1; 95% CI 0.8-1.7).
This study confirms that, as regards metastasis, tumour-related risk factors
(malignancy grade and tumour size) are more important risk factors than treatment
related factors. Local recurrence was associated with an increased metastasis
rate, whereas inadequate surgical margin was a risk factor for local recurrence
but not for metastasis. Hence, the proposed causal association between local
recurrence and metastasis is doubtful, and if it exists is a weak association.
PMID- 10762743
TI - Molecular detection of cancer cells in bone marrow and peripheral blood of
patients with operable breast cancer. Comparison of CK19, MUC1 and CEA using RT
PCR.
AB - We have compared three different RT-PCR procedures to measure cytokeratin 19
(CK19), carcinoembryonic antigen (CEA) and mucin MUC1 gene expression in order to
determine their diagnostic value in detecting tumour cells in bone marrow
aspirates of patients with operable breast cancer. In an experimental model, the
best sensitivity was observed for CK19 and MUC1 RT-PCR assays, although only the
CEA and CK19 assays showed good specificity. The study of 42 patients showed that
a 'CK19 positive/CEA positive' RT-PCR assay in bone marrow correlated positively
with a positive axillary lymph node status (N(0) versus N(1-3), P<0.05). Both
assays were also positive in 17% of node negative patients. RT-PCR assays were
more sensitive in bone marrow than in peripheral blood. Our results suggest that
CK19 and CEA RT-PCR assays are powerful methods for detecting disseminated breast
cancer cells. A larger study with long-term follow-up is required in order to
clarify their clinical usefulness.
PMID- 10762744
TI - Estimates of the lifetime costs of breast cancer treatment in Canada.
AB - A comprehensive understanding of the cost components of common illnesses is a
necessary first step towards ensuring optimal use of scarce healthcare resources.
Since breast cancer is the commonest malignancy affecting Canadian women, we
estimated the direct healthcare costs associated with the lifetime management of
a cohort of 17700 women diagnosed in 1995. Using a multiplicity of data sources,
treatment algorithms, follow-up and disease progression patterns were determined
by age (<50; >/=50 years) for all four stages of breast cancer at diagnosis, as
well as for the management of local and distant recurrence. Statistics Canada's
Population Health Model (POHEM) was used to integrate the data from the different
sources and to estimate the lifetime costs, discounted at 0, 3 and 5% rates. The
average undiscounted lifetime cost per case of treating women diagnosed with
breast cancer varied by stage, from $36,340 for stage IV or metastatic disease,
to $23,275 for stage I patients. The total cost of treatment for the cohort
diagnosed in 1995 was estimated to be over 454 million Canadian dollars.
Hospitalisation (mainly for initial treatment and terminal care) represented 63%
of the lifetime costs of care delivery. Disease costing models are valuable tools
for optimising the use of scare resources without compromising the health status
of individual patients. The breast cancer costing model has recently been used to
assess the cost impact and cost-effectiveness of providing radiotherapy to all
patients undergoing breast surgery, and of performing outpatient breast surgery.
PMID- 10762745
TI - A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with
recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy.
AB - The aim of this study was to evaluate the efficacy and toxicity of ifosfamide, 5
fluorouracil (5-FU) and leucovorin (IFL) as a second-line chemotherapy regimen in
patients with recurrent undifferentiated nasopharyngeal carcinoma (NPC)
previously treated with platinum/5-FU. Between June 1997 and February 1999, 18
patients were entered into the study. 3 patients had loco-regional recurrence, 12
had distant metastases and 3 had both loco-regional recurrence and distant
metastases. All patients had previously received platinum/5-FU as adjuvant or
palliative treatments. The IFL regimen consisting of ifosfamide 1.2 g/m(2) (with
mesna), 5-FU 375 mg/m(2) and leucovorin 20 mg/m(2) for 5 days and was repeated
every 21 days. The dose of ifosfamide was escalated to 1.4 and 1.6 g/m(2) in
subsequent cycles according to the bone marrow toxicity, and the dose of 5-FU to
450 and 525 mg/m(2) according to the severity of mucositis. Patients received a
median of 3 cycles of IFL (range: 2-6), with a median total ifosfamide dose of 21
g/m(2) (range: 13-46) and a median total 5-FU dose of 6.75 g/m(2) (range: 4.1
14.7). The median follow-up was 10 months (range: 4-25). 9 patients (50%)
achieved a partial response and 1 patient (6%) achieved a complete response, with
an overall response rate of 56% (95% confidence interval (CI): 32-80%). For those
patients who responded to IFL, 8 had subsequent disease progression on follow-up,
with a median response duration of 7.1 months (95% CI: 5.3-8.9). The median time
to progression for all patients was 6.5 months (95% CI: 4.2-8.7). 12 patients are
still alive with an estimated 1-year survival probability rate of 51%. Treatments
were well tolerated, only 1 patient had grade 3 emesis. None of the patients had
grade 3/4 anaemia, leucopenia or thrombocytopenia, although IFL was discontinued
in 1 patient because of persisting thrombocytopenia. IFL is an effective second
line regimen in patients with recurrent NPC and is well tolerated with mild
toxicity. Combining platinum and IFL in chemonaive patients may further improve
the overall response rate and duration and is worth investigating in future
trials.
PMID- 10762746
TI - Docetaxel in combination with carboplatin for the treatment of advanced non-small
cell lung carcinoma: a multicentre phase I study.
AB - Docetaxel and carboplatin have shown in vitro and in vivo activity against non
small cell lung cancer (NSCLC). A phase I study was conducted in order to
determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses
(MTDs) of their combination. Chemotherapy-naive patients with stage IIIB and IV
NSCLC, age<75 years old, performance status (WHO) 0-2, with adequate bone marrow,
renal, liver and cardiac function, were treated with docetaxel and carboplatin.
Docetaxel was given at escalated doses starting from 70 mg/m(2) with increments
of 10 mg/m(2) followed by carboplatin also administered at escalated doses
starting from AUC 5 to 7 AUC (mg/ml. min); the regimen was administered every 3
weeks. No colony-stimulating factor or intrapatient escalation was allowed. The
toxicity of the regimen was assessed during the first chemotherapy cycle. 35
enrolled patients received a total of 114 chemotherapy cycles (median 3
cycles/patient; range: 1-8). All patients were assessable for toxicity.
Neutropenia was the main dose-limiting toxicity of the regimen; overall, grade
3/4 neutropenia occurred in 16 (14%) cycles; six (5%) neutropenic episodes were
complicated with fever but there was no septic death. Grade 3/4 thrombocytopenia
was uncommon (two cycles; 2%). Grade 3/4 diarrhoea occurred in 5 (14%) patients
whilst neurotoxicity, fatigue and mucositis were extremely uncommon. Two MTDs
were defined: the MTD(1) was docetaxel 80 mg/m(2) and carboplatin AUC 7 mg/ml x
min whilst MTD(2) was docetaxel 100 mg/m(2) and carboplatin AUC 6 mg/ml x min.
The combination of docetaxel and carboplatin is a feasible and well-tolerated
outpatient regimen for the treatment of patients with locally advanced and
metastatic NSCLC. This regimen merits further investigation in phase II trials.
PMID- 10762747
TI - Prognostic value of vascular endothelial growth factor expression in colorectal
cancer patients.
AB - Solid tumours require neovascularisation for growth and metastasis. Vascular
endothelial growth factor (VEGF) has been shown to be an important regulator of
tumour angiogenesis. To examine the relevance of VEGF in the neoplastic
transformation of human colon, we analysed protein expression in a total 30
polyps and 145 colorectal carcinomas by immunohistochemistry. All adenoma
specimens, regardless of histological differentiation, and normal colonic mucosa
did not express VEGF. Amongst 90 patients with non-metastatic colorectal cancer,
VEGF expression was observed in 43 (48%) cases, whilst 29 of the 55 patients
(53%) with metastases expressed the angiogenic factor. Both the proportion and
intensity of VEGF expression were positively associated with the progression of
colon carcinogenesis. Tumours with the highest VEGF expression tended to
correlate with patients' survival, although VEGF expression did not emerge as an
independent risk factor in a multivariate analysis. After exclusion of the
patients with distant metastases, both univariate and multivariate analysis did
not indicate any prognostic value for the tissues with the highest VEGF
expression. Our results suggest that VEGF may play a role in the progression of
colon cancer, although evaluation of this angiogenic phenotype did not provide
additional prognostic information compared with that obtained from Dukes' staging
of the tumours.
PMID- 10762748
TI - Treatment of HIV-associated invasive anal cancer with combined chemoradiation.
AB - There is an increased frequency of invasive anal cancer in HIV-seropositive men.
Early treatment strategies in this patient group employed reduced dosages of
chemotherapy or radiotherapy alone to reduce toxicity. Since 1989 we have used
combined modality treatment consisting of chemotherapy 5-fluorouracil (5-FU) and
mitomycin C, and concomitant radical radiotherapy to the pelvis (38-51 Gy in 20
30 fractions), with most patients receiving a perineal boost (10-18 Gy). 12
homosexual HIV-positive men have been treated. The median CD4 count at diagnosis
of anal cancer was 209 cells/microl (range: 29-380 cells/microl), 5 had prior
AIDS defining diagnoses. No patients had metastatic disease. Complete remissions
were obtained in 9/11 evaluable patients and in 1 further patient following
surgery. 2 patients relapsed both within 6 months of diagnosis. At a median
follow-up of 4.8 years (range: 0.4-10 years), 4 patients have died (2 from anal
cancer, 1 from treatment-related consequences and 1 from opportunistic infection
in remission). Actuarial 2-year survival is 60% (95% confidence interval (CI): 29
91%). Grade 3 haematological toxicity was recorded in 3 patients, grade 4 and 5
gastrointestinal toxicity in 1 patient each and grade 3 skin toxicity in 1
patient. Radical chemoradiation may be given safely at conventional doses in HIV
positive patients, with a high complete response rate.
PMID- 10762749
TI - Report on the quality of life analysis from the phase III trial of pion versus
photon radiotherapy in locally advanced prostate cancer.
AB - This report examines the quality of life (QOL) of 215 patients entered into a
randomised trial between pion and photon radiotherapy for prostate cancer at a
single institution. The survival and local control results of the trial were
equivalent in both arms. A modification of the Rotterdam Symptom Checklist (RSCL)
was used to assess QOL. Global QOL, toxicity and physical scores were found to be
worse in pion-treated patients at the end of treatment (P<0.001, P<0.001, and
P=0.02 respectively). There are no long-term differences in the QOL of pion-
versus photon-treated patients. Sexual function was a concern for patients even
at baseline. There was a progressive loss of sexual interest and erectile
function. There was a significant impact from hormonal therapy at relapse.
Hormonal treatment produced a stepwise significant worsening in global QOL,
particularly for physical and psychological domains.
PMID- 10762750
TI - Prevention of chemotherapy-induced alopecia using an effective scalp cooling
system.
AB - Alopecia is a distressing side-effect of cancer treatment. Taxanes (TX),
anthracyclines (ANR) and etoposide (ET) have been consistently associated with
significant alopecia. We studied an effective scalp cooling system, the Penguin
Cold Cap system, for the prevention of chemotherapy-induced alopecia in 70
patients receiving chemotherapy, including one of the following major alopecia
causing agents: Group A, TX-based regimes (without ANR); Group B, TX+ANR; Group
C, ANR-based regimes (without TX); Group D, ET-based regimes. Protection from
hair loss was achieved by maintaining scalp temperatures below 15 degrees C
before, during and after chemotherapy by frequent changing of the caps.
Assessment was carried out using a grading system from 0 to 4. Grades 0-2 were
considered as satisfactory hair protection, whilst Grades 3-4 were considered
failures. 57 patients were evaluable for assessment. An overall 81% protection
was achieved. In groups C and D 11 of 12 patients (92%) had no alopecia, whilst
30 of 34 patients (88%) treated with taxanes had adequate hair protection. In
Group B, 4 of 11 patients (36%) had adequate hair protection. The system was well
tolerated and is a very effective method for protection from hair loss caused by
TX, ANR and ET. Our results are comparable with and, in most cases, better than
those reported in other studies using various alopecia preventive methods.
PMID- 10762751
TI - Familial predisposition to breast cancer in a British population: implications
for prevention.
AB - The aims of this study were to estimate the familial relative risk of breast
cancer according to the age of the at risk individual and the age at which the
relative was affected, and to estimate the proportion of the general population
in several breast cancer risk categories because of a family history and, thus
estimate the potential to reduce the overall breast cancer burden using
interventions targeted at women at increased risk because of family history.
Familial relative risks were computed by comparing breast cancer incidence in
relatives of 2809 breast cancer cases from a population based case series with
that expected from general population incidence rates. The proportion of the
general population in different categories of risk according to family history
was estimated from the relative risk of breast cancer for that category and the
proportion of cases in that category. 389 (13.8%) cases had at least 1 first
degree relative with breast cancer. The relative risk of breast cancer in sisters
of index cases was 1.90 (95% confidence interval (CI) 1.63-2.36) and that in
mothers 1.73 (1.52-1. 97). The risk to mothers of cases diagnosed under 50 years
of age tended to decrease in older mothers, but no age effect was seen for
mothers of cases diagnosed >/=50 years of age. There was no evidence that
relative risk to sisters declined with age. For women with 2 affected first
degree relatives the relative risk was 2.85 (2.12-3. 76). From these data, we
estimate that in the general population 6. 8% of women under the age of 50 years
and 9.7% of women aged 50-65 years have at least 1 first degree relative affected
with breast cancer. Two per cent of women under 50 years have a family history
which confers an increased risk of at least 2.5-fold. An intervention targeted at
this group that reduced breast cancer morbidity by 20% would reduce the total
burden of breast cancer in this age group by 1.1% at most. A family history of
breast cancer is quite common in the general population, but preventive
interventions targeted at women at high risk of breast cancer because of family
history will have limited impact on breast cancer morbidity as a whole.
PMID- 10762752
TI - Induction of differentiation by 1alpha-hydroxyvitamin D(5) in T47D human breast
cancer cells and its interaction with vitamin D receptors.
AB - The role of the active metabolite of vitamin D, 1,25 dihydroxyvitamin D(3)
(1,25(OH)(2)D(3)), in cell differentiation is well established. However, its use
as a differentiating agent in a clinical setting is precluded due to its
hypercalcaemic activity. Recently, we synthesised a relatively non-calcaemic
analogue of vitamin D(5), 1alpha-hydroxyvitamin D(5) (1alpha(OH)D(5)), which
inhibited the development of carcinogen-induced mammary lesions in culture and
suppressed the incidence of chemically induced mammary carcinogmas in rats. In
the present study, we determined the differentiating effects of 1alpha-(OH)D(5)
in T47D human breast cancer cells and compared its effects with 1,25(OH)(2)D(3).
Cells incubated with either 10 or 100 nM of the analogues inhibited cell
proliferation in a dose-dependent manner, as measured by the dimethylthiazolyl
2,5-diphenyltetrazolium bromide (MTT) assay. Similar growth-inhibitory effects
were also observed for MCF10(neo) cells. Both vitamin D analogues induced cell
differentiation, as determined by induction of casein expression and lipid
production. However, MCF10(neo) cells failed to respond to either vitamin D
analogue and did not undergo cell differentiation. Since the cell differentiating
effect of vitamin D is considered to be mediated via the vitamin D receptor
(VDR), we examined the induction of VDR using reverse transcriptase-polymerase
chain reaction (RT-PCR) in both cells. The results showed that, in T47D cells,
both 1,25(OH)(2)D(3) and 1alpha(OH)D(5) induced VDR in a dose-dependent manner.
Moreover, both analogues of vitamin D upregulated the expression of vitamin D
response element-chloramphenicol acetyl transferase (VDRE-CAT). These results
collectively indicate that 1alpha-(OH)D(5) may mediate its cell-differentiating
action via VDR in a manner similar to that of 1,25(OH)(2)D(3).
PMID- 10762753
TI - Antisense RNA inhibition of cathepsin L expression reduces tumorigenicity of
malignant cells.
AB - Several tumour-forming cell lines are known to overproduce the lysosomal cysteine
peptidase cathepsin L. We have used an antisense approach to investigate whether
inhibition of cathepsin L overexpression in two malignant cell lines (myeloma SP
cells and L cells) reduces their tumorigenic potential. Two different cDNA
fragments of murine cathepsin L were inserted in the antisense direction into the
pcDNA3 vector, and SP and L cells were stably transfected with these plasmid
constructs. Several of the selected clones expressing the antisense transcript
showed specific reduction of the mRNA level and the intracellular activity of
cathepsin L, and a greatly diminished amount of secreted procathepsin L. When
tested in Balb/c nu/nu mice, the cell lines with low cathepsin L activity
exhibited a significantly decreased potential for tumour growth when compared
with control cells expressing wild-type levels of cathepsin L activity. This
observation suggests that cathepsin L is a critical factor in tumour growth.
PMID- 10762754
TI - Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon
cancer cells.
AB - The present study was undertaken to determine if (a) genistein induces topo II
mediated DNA damage in HT-29 colon cancer cells; and (b) if this damage is
required to induce apoptosis. DNA damage was evaluated using the comet assay.
Apoptosis was determined by the ethidium bromide/acridine orange staining
technique. DNA breakage was noted within 1 h of treatment. Apoptosis was only
induced with high concentrations (>/=60 microM) of genistein. Marked inhibition
of HT-29 cell growth was evident at concentrations ranging from 60 to 150 microM.
This was associated with a cell cycle arrest at G(2)/M. Similar findings were
obtained in SW-620 and SW-1116 colon cancer cell lines. Aclarubicin, a topo II
antagonist, reduced genistein-induced DNA breaks but did not reduce apoptosis.
These data suggest that, in colon cancer cells, topo II serves as the enzymatic
target of genistein. Furthermore, topo II-mediated DNA cleavage is not required
for the induction of apoptosis.
PMID- 10762755
TI - Antitumour activity of suramin analogues in human tumour cell lines and primary
cultures of tumour cells from patients.
AB - Suramin has shown promising antitumour activity against several tumour types,
both in vitro and in vivo, but the clinical utility of this compound is hampered
by its unfavourable toxicity profile. In the present study, the semi-automated
fluorometric microculture cytotoxicity assay (FMCA) was employed for evaluation
of the cytotoxicity of seven suramin analogues in vitro in a panel of human
tumour cell lines and in primary cultures of tumour cells from patients. Like
suramin, the analogues showed little sensitivity to resistance mechanisms
involving P-glycoprotein, topoisomerase II, multidrug resistance associated
protein and glutathione-mediated drug resistance. In the cell line panel, NF067
and FCE 26644 showed activity comparable with suramin. All analogues were less
potent than suramin in patient cells except for FCE 26644. Correlation to suramin
activity patterns in the cell line panel was highest for NF037 and low to
moderate for the remaining analogues. In patient cells, high correlation
coefficients were obtained for FCE 26644, NF110, NF031 and NF037. The results
indicate that the cytotoxic activity of suramin on patient tumour cells is shared
by the analogues with FCE 26644 being the most active. The pharmacophore for
cytotoxicity in patient cells may be different from that observed in the cell
lines.
PMID- 10762756
TI - A history of the Pan American Society for Clinical Virology.
PMID- 10762757
TI - Detection of Restenosis After Percutaneous Transluminal Coronary Angioplasty by
an Angiographic Score.
AB - BACKGROUND: Restenosis, or OAchilles heelO of balloon angioplasty, remains in a
range near 30% and cannot be predicted with certainty. To find adequate methods
for its foresight is a challenge. OBJECTIVES: To determine risk factors and an
angiographic score to predict the appearance of restenosis after one-site
percutaneous transluminal coronary angioplasty (PTCA). METHODS: We restudied
prospectively 315 (239 men, 76 women, age range from 29 to 78, 53.6 +/- 9.5
years) of 360 patients who underwent PTCA to a native coronary artery. The study
didnOt include patients with left main disease, total occlusion, side-branch
involvement, ostial stenosis, acute phase of myocardial infarction or those who
repeat PTCA. Two-hundred twenty-eight patients underwent PTCA of the left
anterior descending artery, 56 of the right coronary artery and 31 of the left
circumflex artery. RESULTS: Restenosis, defined as a luminal renarrowing > 50% at
follow-up, was present in 82 (26%) patients between 1 and 8 months after the
procedure. Univariate and multivariate analysis revealed four vascular factors
related to restenosis (p < 0.05): a) lesion length and; b) irregularity of the
lesion borders before PTCA; c) perivascular and/or endovascular haziness and; d)
intensity of residual stenosis after PTCA. To construct the score, a zero was
given to a lesion length < 8 mm; to smooth lesion borders; to residual stenosis
up to 20%; and to absence of haziness after PTCA. A one was given to a lesion
length between 8 and 10 mm; and to a lesion with irregular borders. A two was
given to a lesion length > 10 mm. A three was given to a residual stenosis > 20%;
and to the presence of haziness after PTCA. The sum of all terms was considered
the final score. So, it could oscillate from 0 to 9. Calculated score from 0 to >
5 showed respective restenosis rates of (%): 5.2; 15.1; 24.0; 39.4; 44.8; 60.8;
and 84.2. The calculated correlation coefficient (0.98) among the scored values
and the correspondent restenosis rates was highly significant (p < 0.001).
CONCLUSIONS: It is concluded that restenosis is primarily a multifactorial
problem based on vascular factors and may be predicted with a high degree of
probability by the proposed score.
PMID- 10762758
TI - Initial Clinical Experience of a Novel Device (the OFriend CatheterO) for Local
Anesthetic Delivery Around Indwelling Arterial Sheaths.
AB - The removal of femoral arterial sheaths, particularly after they have been in
place for some hours, is a source of pain for patients undergoing invasiveive
cardiac procedures. Methods of reducing this pain include systemic sedatives,
analgesics and local anesthetic. We tested a new disposable plastic device,
called the OFriend,O designed to reduce pain associated with sheath removal. The
Friend wraps around a standard 8 Fr sheath allowing local anesthetic infiltration
through side holes into local tissue. METHODS: Seventy-two patients undergoing
interventional procedures were randomized to 3 groups for anesthetic
administration just prior to sheath removal. Group 1 (control) received no local
anesthetic. Group 2 (local) received 10 ml of lignocaine directly infiltrated
with syringe and needle around the sheath. Group 3 (Friend) had the Friend
inserted with the sheath and 10 ml of lignocaine was delivered via the device.
Pain around the sheath was assessed prior to, during and just after, sheath
removal using a 5 point verbal scale. RESULTS: Sixty-two patients completed the
study. There were no serious complications related to the Friend device. The
Friend group patients had significantly less pain associated with sheath removal
than the control group. (Mean pain difference 1.28 vs. 0.34, p = 0.04). Pain
scores in group 2 (local) did not differ significantly from the control group.
The additional estimated cost involved in using the Friend was $16.93 per
patient. CONCLUSIONS: The Friend device is a new, inexpensive and safe method of
reducing pain associated with removal of arterial sheaths after cardiac
interventional procedures.
PMID- 10762759
TI - Three-Dimensional Intravascular Ultrasound Analysis of Coronary Stent Deployment
and In-Stent Neointimal Volume: Current Clinical Practice and the Concepts of
TRAPIST, ERASER, and ITALICS.
AB - Intravascular ultrasound (IVUS) permits the detailed examination of coronary
stent apposition and expansion in vivo. IVUS assessment of the extent and
distribution of in-stent neointima at follow-up is an ideal model for the
evaluation of new antiproliferative drugs that aim at a reduced in-stent
neointimal hyperplasia. Recently, automated systems for three-dimensional
reconstruction and analysis of IVUS images have been developed. This manuscript
illustrates the methodology and clinical use of automated three-dimensional IVUS
analysis systems during coronary stenting, and highlights the first randomized
trials to apply such a technique for the assessment of in-stent neointima.
PMID- 10762760
TI - Dissection During Restenotic Lesion Balloon Angioplasty: Comparison with Initial
Angioplasty.
AB - The aim of this study was to assess the frequency and severity of dissection
during repeat angioplasty for restenosis, to correlate the occurrence of this
event with the lesion characteristics and the procedure-related factors and to
examine if dissection during initial angioplasty predisposes to dissection during
the repeat procedure. Sixty-nine significant lesions in native coronary arteries
were treated with balloon angioplasty (A"PTCA) and retreated for restenosis with
balloon angioplasty (B"PTCA). Dissection was detected less frequently during
B"PTCA (7/69 vs. 18/69, p < 0.05). Anatomic variables did not differ
significantly between A" and B"PTCA. Balloon to artery ratio (B/A ratio) was
slightly but significantly higher during B"PTCA (1.03 +/- 0.13 vs. 0.97 +/- 0.14,
p < 0.05) and duration of inflation was shorter (377 +/- 218 vs. 473 +/- 305 sec,
p < 0.05). In 17 out of the 18 lesions which were dissected during A"PTCA,
dissection did not occur during B"PTCA, despite the application of a higher B/A
ratio (1.05 +/- 0.13 vs. 0.97 +/- 0.17, p < 0.05). Duration of inflation was
shorter during B"PTCA (390 +/- 227 vs. 639 +/- 394 sec, p < 0.05). Six out of
seven lesions which were dissected during B"PTCA had not been dissected during
A"PTCA. In this subgroup, lesion characteristics did not differ between the two
interventions and duration of inflation was shorter during B"PTCA (340 +/- 101
vs. 458 +/- 128, p < 0.05). CONCLUSIONS: Dissection occurred less frequently
during restenotic lesion PTCA. Dissection during A"PTCA did not predispose to
dissection during B"PTCA. These findings may be ascribed to the proliferative
nature of the restenotic process.
PMID- 10762761
TI - Treatment of Bifurcation Stenosis with the Multi-Link Coronary Stent.
PMID- 10762762
TI - Monoclonal Antibodies Against the IIb/IIIa Platelet Receptor to Treat Acute
Thrombotic Occlusion of a Coronary Stent.
PMID- 10762764
TI - The Effects of QT Dispersion During Head-Up Tilt Table Testing.
PMID- 10762763
TI - Entrapment and Removal of a Broken Angioplasty Balloon from a Chronically
Occluded Coronary Artery.
PMID- 10762766
TI - Surgery: Effects Upon Renal Function, Hypertension and Patient Survival.
PMID- 10762765
TI - Long-Term Effects of Stent Revascularization Upon Blood Pressure Management Renal
Function and Patient Survival.
PMID- 10762767
TI - Surgery: Indications and Variables that Affect Procedural Outcome, as well as
Morbidity and Mortality.
PMID- 10762768
TI - Experimental Evaluation of a New Single Wire Tantalum Coil Coronary Stent (Wiktor
ia).
AB - To improve scaffolding properties, a new more densely woven Wiktor stent, the
Wiktor-ia stent, was developed. Although the metal coverage remains still low
compared to other stents, increased metal/vessel area raises the concern of
increased thrombogenicity and neointimal hyperplasia. In this study we evaluated
the Wiktor-i stent in a porcine peripheral and coronary model and compared the
thrombogenicity and neointimal hyperplasia with the Wiktor-GX coronary stent. In
a first study, a Wiktor-i and a Wiktor-GX coronary stent were implanted
symmetrically in a preselected side branch of the right and left iliac artery of
10 healthy pigs. Quantitative vessel analysis showed comparable data before,
immediately after and at follow-up. Hyperplasia measured by morphometry was also
comparable in both groups (Wiktor-GX: 1.43 mm2 vs. Wiktor-i: 1.17 mm2, NS). Also,
area stenosis was very similar (Wiktor-GX: 32% vs. Wiktor-i: 29%, NS). In a
second study, 20 Wiktor (Wiktor-i: n=10, Wiktor-GX: n=10) coronary stents were
implanted in the right coronary artery of 20 healthy pigs. Quantitative coronary
analysis before, immediately after and at follow-up was comparable in both
stents. The hyperplasia measured morphometrically was also comparable in both
stents. (Wiktor-GX: 1.51 +/- 0.47 mm2 vs. Wiktor-i: 1.46 +/- 0.66 mm2, NS). Also
the area stenosis was not significantly different (Wiktor-GX: 31% vs. Wiktor-i:
35%). In conclusion, this study shows that the increased metal/vessel area of the
Wiktor-i stent does not result in an increased neointimal hyperplasia. Both
stents show to be very biocompatible when implanted in porcine coronary and
peripheral vessels.
PMID- 10762769
TI - Comparison of Angiographic and Clinical Outcome After Cutting Balloon and
Conventional Balloon Angioplasty in Vessels Smaller than 3 mm in Diameter: A
Randomized Trial.
AB - OBJECTIVES: The purpose of the study was to evaluate and compare the immediate
and six month follow-up angiographic and clinical outcome of cutting balloon
angioplasty and conventional balloon angioplasty in small vessels (less than 3 mm
in diameter). METHODS AND RESULTS: Between August 1995 and August 1996 a total of
71 eligible symptomatic patients with angiographically proven significant lesions
in their coronary arteries smaller than 3 mm and requiring revascularization,
were randomized to receive treatment by either cutting balloon angioplasty (CB)
or conventional balloon angioplasty (BA). OStand-aloneO CB was performed on 51
lesions in 36 patients and BA on 47 lesions in 35 patients. Basic angiographic
and clinical characteristics were similar in both groups. The overall procedural
success rates for CB and BA groups were 92% and 97%, respectively. The immediate
post-procedural minimal luminal diameter, residual stenosis and acute gain were
similar in the CB and BA cohorts (1.93 +/- 0.36 mm, 24 +/- 12%, 1.18 +/- 0.45 mm
vs. 2.01 +/- 0.34 mm, 22 +/- 9%, 1.26 +/- 0.35 mm, respectively). Total
dissection rate and C-F dissections were fewer in the CB group (37%, 6% vs. 51%,
19%, respectively, p < 0.05). Six month follow-up angiographic restenosis rate
was lower in the CB group (27% vs. 47%, p < 0.05). We also detected a significant
difference of total number of all events at nine month clinical follow up (28%
vs. 51%, p < 0.05). CONCLUSION: CB angioplasty can be performed with a comparable
success rate to conventional BA in small vessels. Fewer bail-out procedures are
needed as CB causes fewer and less severe dissections. There is also a
significant reduction in six month restenosis rate. We suggest that CB might be a
better option for revascularizing vessels smaller than 3 mm in diameter which are
inherently more prone to immediate complications and late restenosis with BA.
PMID- 10762770
TI - Initial Experience with the ACS Multi-Link Stent: Serial Angiographic Follow-Up
and Comparison with the Palmaz-Schatz Stent in Matched Lesions.
AB - To evaluate the efficacy of the more flexible ACS Multi-Link stent, a prospective
angiographic follow-up study was performed. Implantation of the ACS Multi-Link
stent was attempted in 70 consecutive patients with 79 coronary lesions from
April to November 1995. Clinical success defined as final % diameter stenosis of
< 50% without death, bypass surgery or Q-wave myocardial infarction was achieved
in 95% of the patients. There was 1 in-hospital death due to acute pulmonary
embolism. In-hospital subacute stent occlusion occurred in 2 cases. Follow-up
angiograms were obtained in 62 (83%) eligible lesions. The minimal luminal
diameter improved from 0.97 +/- 0.41 to 2.72 +/- 0.30 mm, but started to decrease
at 1 month (2.38 +/- 0.42 mm), and continued to decrease throughout the 6 months
(1.96 +/- 0.41 mm). Angiographic restenosis (stenosis 3 50%) occurred in 16% of
the lesions, a rate smaller though not significantly different from the 25% with
the Palmaz-Schatz stent. A revascularization procedure of the target lesion was
required in 6% of the patients. Multivariate analysis identified lack of post
dilatation, type of lesion, lesion length and pre-procedural reference diameter
to be predictors of angiographic restenosis. In conclusion, the ACS Multi-Link
stent can be implanted successfully with a low complication rate and a clinical
outcome at least comparable to the Palmaz-Schatz stent.
PMID- 10762771
TI - High-Pressure Bail-out Coronary Stenting Without Anticoagulation: Early Outcome
and Follow-up Results.
AB - PURPOSE:The purpose of this study is to assess the immediate outcome and long
term results of high pressure bail-out coronary stenting without subsequent
anticoagulation. PATIENTS AND METHODS: Between June 1994 and September 1996, 32
consecutive patients (males 24, mean age 55 +/- 9.3 years) underwent bail-out
stenting at a mean deployment pressure of 15.5 +/- 2.3 mmHg because of
complicated PTCA. A total of 54 stents (Palmaz-Schatz, Micro, Gianturco Roubin
and Wiktor) were implanted, from one to four stents into each vessel. After the
procedure all patients were treated with ticlopidine 500 mg/day and
acetylosalicylic acid 300 mg/day only. RESULTS: Stents were successfully
delivered in all patients. In the cath lab procedural success was 96.9%. During
the in-hospital phase, there was one (3.1%) acute stent thrombosis followed by
urgent bypass surgery (CABG). Four (12.5%) non-Q wave myocardial infarctions
occurred. There were no subacute stent thrombosis or hemorrhagic complications.
Six month angiographic restudy in 28 patients showed restenosis in 13 (46.4%): 9
patients were treated successfully by rePTCA. At one year 13 (40.6%) major
adverse cardiac events occurred: eleven (34.4%) target lesion revascularizations
(9 PTCA, 2 CABG), one (3.1%) elective CABG surgery and one (3.1%) late cardiac
death. Event-free survival was 93.8% at one month, 65.6% at six months, and 59.4%
at one year. CONCLUSIONS: High pressure bail-out coronary stenting with
antiplatelet regimen is an effective and safe procedure for treating complicated
PTCA. Although the restenosis rate is high, in most cases in-stent restenosis can
be treated by rePTCA. In 60% of patients clinical course at one year was
uneventful.
PMID- 10762772
TI - Treatment of In-Stent Restenosis in Saphenous Vein Grafts by Rotablator
Atherectomy.
PMID- 10762773
TI - Coronary Stent Entrapment on the Aortic Valve After Stent Loss.
PMID- 10762774
TI - Coronary Stenting for Refractory Coronary Vasospasm of Proximal Left Anterior
Descending Artery.
PMID- 10762775
TI - Delayed Coronary Perforation After the Use of High-Speed Rotational Atherectomy.
PMID- 10762777
TI - Procedural Indications and Variables that Affect Acute Outcome.
PMID- 10762776
TI - Recurrent Congestive Heart Failure, Flash Pulmonary Edema.
PMID- 10762779
TI - Review of the Angio-Seala Hemostatic Puncture Closure Device.
PMID- 10762778
TI - Is Survival Different for Renal Artery Stenosis Patients on Dialysis Compared to
Others with End Stage Renal Disease?
PMID- 10762780
TI - The Use of Standard Management Reports in a Cardiology Practice.
PMID- 10762781
TI - Clinical Practice N Building the True Insider Edge.
PMID- 10762782
TI - QT Dispersion in Inferior Wall Myocardial Infarction: Relation to Right
Ventricular Injury.
PMID- 10762783
TI - Percutaneous Application of Fibrin Sealant to Achieve Hemostasis Following
Arterial Catheterization.
AB - OBJECTIVES: The present study sought to investigate the safety and efficacy of a
new fibrin sealant using percutaneous delivery techniques. BACKGROUND: The
femoral approach has become the preferred means of access for percutaneous
diagnostic and interventional procedures. Control of access site bleeding
following catheterization, however, remains a significant problem in
interventional cardiology. METHODS: Adult mongrel dogs were used in this study.
Series 1 compared the effectiveness of fibrin sealant vs. manual compression
alone in the presence of anticoagulants, thrombolytic, and antiplatelet agents.
Series 2 assessed fibrin sealant safety. Series 3 examined fibrin sealant
performance under elevated blood pressure levels. RESULTS: Series 1: Hemostasis
was achieved in all fibrin sealant sites in significantly less time (8.5 +/- 4.3
min) with no major complications compared to manual compression sites (65.2 +/-
19.3 min) accompanied by serious complications. For all adjunctive agents
employed, hemostasis was achieved in fibrin sealant sites in significantly less
time (warfarin 9.9 +/-.2, urokinase 11.2 +/- 5.6, ReoProa 10.5 +/- 6.3 min) than
for manual compression sites (warfarin 86.5 +/- 21.4, urokinase 89.8 +/- 36.3,
ReoPro 77.9 +/- 26.5 min). Series 2: I25 iodine-labeled fibrinogen sealant was
applied to puncture sites with no traces of circulating radioactivity observed
over a one-hour period. Series 3: hemostasis was achieved under elevated blood
pressure conditions in all animals. Histologic studies showed complete re
absorption of fibrin sealant 28 days post-procedure with no evidence of foreign
body reaction. CONCLUSIONS: Percutaneous application of fibrin sealant to achieve
hemostasis following catheterization appears to be a simple, safe, and highly
effective procedure in a canine model.
PMID- 10762784
TI - Design-Dependent Variations in Coronary Stent Stenosis Measured as Precisely by
Angiography as by Histology.
AB - BACKGROUND: Coronary stent restenosis is a growing clinical concern which,
because restenosis may vary with stent design, requires a validated, accurate,
and sensitive method of evaluation as new stents are developed. Histologic
analysis of arterial cross sections, a highly accurate tool in animal models, has
limited applicability in humans. Quantitative coronary angiography, while
commonly used in the clinical evaluation of coronary interventions, has a
controversial role as an adequate measure of restenosis, and few studies have
validated quantitative angiography in diseased arteries. We tested the hypothesis
that in-stent stenosis could be assessed as accurately by pre-mortem angiography
as by post-mortem histology, allowing angiographic discrimination of variable
late luminal loss provoked by stents of different designs. METHODS AND RESULTS:
Stent stenosis in porcine coronary arteries was assessed by quantitative coronary
angiography and histology at 3, 28 and 56 days. Four stainless steel stent
designs were studied: a slotted tube configuration with or without a polymer wrap
and a corrugated ring configuration with or without a polymer coating. Although
acute luminal gain (mean stent:artery ratio 1.07 +/- 0.01) and stent recoil (mean
stent diameter at follow-up 2.65 +/- 0.02 mm) were similar for all designs and
time points, significant differences in late luminal loss were observed and were
detected as accurately by angiography as by histology. At 28 days, the polymer
wrapped slotted tube design resulted in a nearly two-fold greater late loss than
its bare metal counterpart (1.40 +/- 0.09 mm vs. 0.80 +/- 0.12 mm, p <.001 by
angiography; 1.33 +/- 0.10 mm vs. 0.67 +/- 0.06 mm, p <.0001 by histology), while
there was no significant difference in 28 day late loss between the polymer
coated and bare metal corrugated ring designs (p = NS by angiography or
histology). Time point differences were also observed both angiographically and
histologically, with marked progression of lumen loss between 3 and 28 days and
slower but persistent progression between 28 and 56 days. Overall comparison of
individual lumen diameter measurements for all stented arteries independent of
design or duration of follow-up demonstrated a precise correlation between
angiography and histology (y = 0.96x +0.25, p <.0001, r2 = 0.82). CONCLUSIONS:
Coronary stents of varied designs provoke markedly different degrees of late
luminal loss, and these differences can be measured as accurately by quantitative
angiography as by histologic analysis of arterial cross sections. This may be due
to optimization of angiographic measurements by the concentric nature of intimal
thickening in stented arteries, and to structural rigidity imparted by the stent,
preserving arterial lumen size for histologic analysis. Quantitative angiography,
therefore, may represent an adequate endpoint in clinical trials comparing stent
designs.
PMID- 10762785
TI - Stent Deployment Pressure Defines the Stent/Vessel Wall Relationship and has
Important Implications for Early and Late Outcome.
AB - OBJECTIVE: This study evaluates the effect of stent deployment pressure on stent
deployment, coronary vessel injury, subacute reclosure and foreign body reaction
in a porcine coronary model. METHODS: Stainless steel coil stents were deployed
in the right coronary artery of 30 pigs either using a deployment pressure of 4
atm (group I), 8 atm (group II), or 14 atm (group III). Serial quantitative
angiographic studies together with morphometric analysis of the stented vessels
were performed. RESULTS: Three pigs died within 48 hours due to subacute
thrombosis (group I: n = 1, group II: n = 0, group III: n = 2). Another 4 stents
were found occluded at day 7 (group I: n = 3, group II: n = 0, group III: n = 1).
Imperfect stent alignment was found in 8 coronary arteries (group I: n = 7, group
II: n = 1, group III: n = 0). Deep protrusion of stent filaments was found in 7
coronary arteries (group I: n = 0, group II: n = 1, group III: n = 6). Area
stenosis at 6 weeks of the patent vessels was as follows: 75.7 +/- 15.2% in group
I, 31.8 +/- 12.3% in group II, and 66.9 +/- 21.4% in group III, p < 0.001).
CONCLUSION: In a porcine coronary model, stent deployment pressure resulting in
an optimal alignment and a minimal coronary vessel injury leads to minimal
neointimal hyperplasia.
PMID- 10762786
TI - Primary Stenting for Coronary Artery Lesions 15D18 mm in Length: A Preliminary
Experience with the Long (18 mm) Palmaz-Schatz Stent.
AB - BACKGROUND: Currently little data exists on the use of single intracoronary
stents for the treatment of long coronary artery lesions. The aim of this study
was to evaluate the 18 mm Palmaz-Schatz stent (PS no. 204C) for the primary
treatment of native coronary lesions between 15 mm and 18 mm in length. METHODS:
A consecutive group of 17 patients were included in this study over a 3 month
period. Each patient selected was felt suitable for elective treatment with an
intracoronary stent and had a coronary artery lesion of >15 mm in length.
Coronary arteriograms recorded just before PTCA, after full stent deployment and
electively at 4 months after stent deployment were analyzed using semi
quantitative coronary angiography. RESULTS: Mean lesion length treated was 16.9
mm. The primary success rate for stent delivery was 16 out of 17 lesions. One
patient required immediate coronary artery bypass surgery for extensive
dissection of the right coronary artery. There were no out of hospital
complications and no patient suffered acute or subacute stent thrombosis. All
patients had an improvement in their Canadian Cardiovascular Angina Class: Three
patients (21%) had asymptomatic restenosis (stenosis 50%) at follow-up
angiography. CONCLUSION: This study shows the 18mm Palmaz-Schatz stent is
relatively successful for the elective treatment of long coronary artery
stenoses. Although the mean lesion length of 16.9 mm in this study is
significantly greater than that of the BENESTENT and STRESS studies, the 21%
restenosis rate is comparable.
PMID- 10762787
TI - Patient-Related and Angiographic Predictors of Restenosis After Excimer Laser
Coronary Angioplasty.
AB - Excimer laser coronary angioplasty (ELCA) is a useful technique for the treatment
of selected complex coronary lesions. However, this technology has been limited
by significant restenosis and, to date, predictors of restenosis after use of
this device are not clearly defined. In order to determine predictors of
restenosis after ELCA, 43 lesions presenting with restenosis (> 50% diameter
stenosis) at angiographic follow-up were compared to 46 lesions without
restenosis, based on patient-related, qualitative and quantitative angiographic
parameters. Univariate analysis revealed 9 variables with at least a borderline
(p < 0.15) significant relation to restenosis: (1) age (p = 0.0759), (2) proximal
left anterior descending site (p = 0.074), (3) presence of a restenotic lesion (p
= 0.104), (4) lesion length (p = 0.0034), (5) reference diameter of the treated
vessel (p = 0.0076), (6) post laser minimal luminal diameter (MLD) (p = 0.1160),
(7) post-procedural MLD (p = 0.0001), (8) post-procedural stenosis (p = 0.0250)
and (9) total procedural gain (p = 0.0051). After entering stepwise logistic
regression analysis, only 3 variables emerged as independent predictors of
restenosis: treatment of a restenotic lesion (p = 0.0255), lesion length (p =
0.0291) and post-procedural MLD (p = 0.0007). Based on these data, we conclude
that post-procedural MLD is the most important predictor of restenosis after
ELCA. Lesion length and the treatment of restenotic lesions are also
independently associated with an increased risk of restenosis after ELCA.
Therefore, achieving the best possible luminal result at the time of the first
intervention should be the goal of the procedure, especially when treating high
restenosis risk lesions.
PMID- 10762788
TI - Rotational Atherectomy: A New Treatment Modality for Ostial Stenoses of OStent
JailedO Side Branches.
PMID- 10762789
TI - High-Dose Abciximab During Coronary Angioplasty in a Patient with Essential
Thrombocytosis.
PMID- 10762790
TI - Restenosis After Coronary Stenting Presenting a ODouble LumenO Morphology: Value
of Intravascular Ultrasound to Recognize the True Lumen and Guide Coronary
Intervention.
PMID- 10762791
TI - Stenting of Bifurcation Lesions with the Wiktor Stent.
PMID- 10762792
TI - Rotational Atherectomy of a Side Branch Through a Palmaz-Schatz Stent: Is Stent
Jail Impenetrable to Rotational Atherectomy?
PMID- 10762793
TI - The Prevalence of Atherosclerotic Renal Artery Stenosis and Clinical Clues to the
Diagnosis.
PMID- 10762794
TI - Is There A Role for Medical Therapy in Management of Atherosclerotic Renal Artery
Stenosis?
PMID- 10762795
TI - Transient Increase in ST-segment Changes at Time of Reperfusion in Acute
Myocardial Infarction Treated by Coronary Angioplasty.
AB - PURPOSE: The clinical significance of early ST-segment re-elevation, a so called
Oreperfusion peakO in patients with acute myocardial infarction (AMI) treated
with thrombolysis is unclear. We examined the incidence and significance of early
ST-segment re-elevation immediately upon reperfusion in patients undergoing
percutaneous transluminal coronary angioplasty (PTCA) where the time of
reperfusion can be precisely established. METHODS: Thirty-two patients (6 women,
26 men, age 61.5 +/- 10.2 years) with an AMI, admitted less than four hours after
the onset of chest pain, were included. Twenty-four patients were treated with
primary PTCA and eight with rescue PTCA. Computerized on-line vectorcardiography
was used for continuous ischemia monitoring. A reperfusion peak was defined as an
increase in ST-vector magnitude (ST-VM) of > 50 uV, starting within two minutes
after the re-opening of the infarct-related coronary artery and followed by an
immediate decrease in the ST segment. RESULTS: Primary success was achieved in
all treated patients. Twenty of the patients (63%) developed a reperfusion peak.
ST-VM before coronary angiography was significantly larger (p = 0.004) and peak
enzyme levels were higher (p = 0.014) in patients who developed a reperfusion
peak. Thrombolytic treatment prior to rescue angioplasty, time to reperfusion,
target vessel, presence of collaterals or medication on admission did not differ
significantly between the groups. CONCLUSION: The occurrence of a reperfusion
peak during the minutes after the onset of reperfusion is a common finding in
patients with AMI treated at an early stage with angioplasty. There is a
relationship with the occurrence of a reperfusion peak and the extent of the
initial ST deviation (presumably reflecting the myocardium at risk) and peak
enzyme levels. The importance of a reperfusion peak for clinical outcome and
prognosis is so far not known.
PMID- 10762796
TI - Intravascular Ultrasound During Transcatheter Coil Closure of Patent Ductus
Arteriosus: Comparison with Angiography.
AB - Precise delineation of the size and shape of the ductus arteriosus may help in
catheter closure. The use of Intravascular Ultra Sound (IVUS) to study the
diameter of patent ductus arteriosus (PDA) has not been reported. We
prospectively evaluated the use of IVUS and compared it to angiography in
determining the size and shape of PDA and to assess the degree of coil protrusion
into the descending aorta and the clinical relevance after coil closure. Twenty
six patients (17 female, 9 male) underwent transcatheter closure of PDA using
single or multiple Gianturco coils. The median age of the patients was 1.7 yr
(range, 2 monthsD34 yr) and the median weight was 10.9 kg (range 4.2D80 kg). A
good quality IVUS image was obtained in all patients using 3.8 Fr, 30 MHz
catheters. The median PDA diameter measured by angiography was 2.8 mm (range
1.6D5.7 mm) and by IVUS was 3.2 mm (range 1.7D5.7). There was excellent agreement
between IVUS and angiography (D IVUS = 0.25+0.97*D angio, r = 0.90, (D: diameter
in mm). After closure, coils could be seen protruding into the aorta with a
median percent coil protrusion of 17.3% (range 0.0D47%). Only one patient had the
coil protruding into more than 1/2 the aorta. This coil was retrieved and another
coil was placed successfully. On follow-up at a median interval of 2.4 yr. (range
1.1D3.2 yr), there has been no clinical evidence for thromboembolic events. We
conclude that IVUS use to assess the size of PDA is accurate. On mid-term follow
up, coil protrusion into the aorta seems to be benign. Further follow-up is
needed.
PMID- 10762797
TI - Silicon Carbide Coating N A Semiconducting Hybrid Design of Coronary Stents N A
Feasibility Study.
AB - OBJECTIVE: To determine the rates of subacute and acute thrombotic stent
occlusion in patients with normal and high risk for stent thrombosis and to
assess the 6 month follow-up with respect to in-stent restenosis, using a new
principle of semiconductor coating (active passivating as metallic hybrid
design). DESIGN: Open, non-randomized, prospective, observational, feasibility
study. PATIENTS: One hundred sixty-five patients (215 stents) were scheduled
consecutively with respect to lesions suitable for slotted tube stent
implantation. Two subgroups of patients (stents) were identified based on the
local thrombotic risk (common indications for stent implantation N group I;
lesions with high(er) risk for stent implantation (group II). A closed clinical
3D12 (mean 6.5 +/- 2.3) months follow-up was done in 126 (92.6%) eligible
patients [164 (97.6%) stents]. Angiographic and/or IVUS data were available in 96
of 136 eligible patients (70.6%) after stenting 6.0 +/- 2.1 months). STENT
MATERIAL/MEDICATION: Balloon expandable tantalum three segment slotted tube
stents which were coated with silicon carbide, diameter ranged from 2.5 to 4.0 mm
were used. Stent deployment was limited by inflation pressure (12D16 Bar). Apart
from patients with acute myocardial infarction (n = 15 stents) patients received
heparin loading dose during the procedure only, no oral anticoagulation except
aspirin (300 mg p.d.) and ticlopidine (250D500mg p.d.) given over 1 month.
RESULTS: Acute complications. No in-hospital mortality occurred, stent-related
myocardial infarction was 1.9%; major bleedings 0.5% of implanted stents. Acute
stent thrombosis 1.4%, subacute stent thrombosis occurred in 0.5% (no significant
difference between group I and II). Late events: From 136 eligible patients
(range 15 daysD14 months) (187 stents) 92 patients (67.6%) with 142 stents
(75.9%) were event-free. In-stent restenosis. Thirty-six percent (biased group of
patients with events) resp. 26.8% (including negative clinical events) of the
implanted stents were restenosed. An inverse relationship between vessel size and
in-stent (re)stenosis was observed. CONCLUSIONS: Silicon-carbide coated coronary
stents are suitable in standard as well as in high-risk situations. The rates for
acute or subacute stent thrombosis are acceptably low even when using post
procedural conventional (aspirin/ticlopidine) anti-thrombotic medication in
patients who are at high risk for stent thrombosis. An inverse relationship
exists between stent-restenosis rate and the size of the reference segment of the
implanted vessel.
PMID- 10762798
TI - Intravascular Low Power Red Laser Light as an Adjunct to Coronary Stent
Implantation Evaluated in a Porcine Coronary Model.
AB - BACKGROUND: It is believed that restenosis following coronary interventions is
the result of endothelial denudation that leads to thrombus formation, vascular
remodeling, and smooth muscle cell proliferation. We previously demonstrated that
low power red laser light (LPRLL) irradiation enhances endothelial cell growth in
vitro and in vivo and reduces restenosis in a small animal model. The present
study investigated the effectiveness of intravascular LPRLL therapy in the
reduction of restenosis following stenting in a porcine model. METHODS AND
RESULTS: Stents were placed in the right coronary artery of domestic cross-bred
pigs. After stent deployment, an additional inflation was performed with the
laser-balloon. In group I (n = 18) no LPRLL was used; group II (n = 10) received
LPRLL dosage of 10 mW for 1 minute; group III (n = 10) received LPRLL dosage of
34 mW for 1 minute. Quantitative coronary analysis of the stented vessel was
performed before, immediately after stenting, and at 6 weeks. The pigs were
sacrificed and histologic and planimetric analysis conducted. At 6 weeks, minimal
luminal stent diameter was significantly narrower in the control group compared
to the higher dose group (p < 0.05), late loss correlated inversely proportional
to the dose used (r = 0.9; p < 0.03), these results were confirmed by
morphometric analysis. Neointimal area was also significantly decreased in the
higher dose group. CONCLUSIONS: Intravascular LPRLL contributes to reduction of
angiographic restenosis and hyperplastic reaction in this animal model and seems
to be dose dependent.
PMID- 10762799
TI - Stent Under-Expansion Refractory to Balloon Dilatation: A Novel Solution with
Excimer Laser.
PMID- 10762800
TI - Spontaneous Coronary Artery Dissection Presenting as Unstable Angina.
PMID- 10762801
TI - Treatment of Distal Right Coronary Artery Spasm During Coronary Angiography.
PMID- 10762802
TI - Carotid Intervention: A NeurosurgeonOs Perspective.
PMID- 10762803
TI - Is the Direct Cervical Approach a Reasonable Option for Endovascular Intervention
in the Carotid Artery?
PMID- 10762804
TI - Intracranial Angioplasty.
PMID- 10762805
TI - Carotid Interventions in Argentina N Our Results and Perspectives.
PMID- 10762806
TI - Carotid Stenting in 350 Vessels: Problems Faced and Solved.
PMID- 10762807
TI - The Effect of Body Weight and Body Surface Area Correction on the Distribution of
the ACT Response to Bolus Doses of Heparin for PTCA.
AB - Considerable controversy exists as to the appropriate dosing of heparin for PTCA.
We retrospectively reviewed records of 335 patients undergoing PTCA to determine:
1) the effects of correcting for weight and body surface area (BSA) on the
heparin dose-response distribution; and 2) the average dose of heparin (standard,
weight-based, and BSA-based) required to achieve an activated clotting time (ACT)
of 300 seconds. For each patient, height, weight, BSA, baseline ACT (HemoTec),
bolus heparin dose, and post-heparin ACT were recorded and the heparin response
calculated. There were no significant differences in the distributions of
standard (SD =.017 +/- 006 sec/U, 34% of mean), weight-based (SD = 1.41 +/- 0.46
sec/U/kg, 33% of mean), and BSA-based (SD = 0.033 +/- 0.011 sec/U/m2, 32% of
mean) heparin response. There were slight, but significant correlations between
heparin response and weight (r = 0.37) and heparin response and BSA (r = 0.36).
The estimated doses of heparin to achieve a HemoTec ACT of 300 seconds were
10,650 +/- 1270 U, 130 +/- 15 U/kg, and 5390 +/- 640 U/m2. CONCLUSIONS: There are
slight but significant correlations between heparin response and both weight and
BSA. The distributions of weight- and BSA-corrected heparin response are similar
to that of standard heparin dosing. Thus, weight adjusted heparin dosing would
not appear to be likely to provide a more reliable ACT response to bolus doses of
heparin.
PMID- 10762808
TI - Persistent High Restenosis After Local Intrawall Delivery of Long-Acting Steroids
Before Coronary Stent Implantation.
AB - OBJECTIVE: This pilot study was performed to evaluate the feasibility and safety
of intrawall delivery of long acting steroids before stent implantation, testing
the efficacy of this treatment in reducing intimal hyperplasia in lesions at high
risk for restenosis. METHODS: In 24 patients (40 lesions) local intrawall drug
delivery of methylprednisolone acetate, using a new catheter device, was
attempted before elective stent implantation. Treated lesions were compared to a
matched control group. RESULTS: Lesions were classified AHA/ACC type C in 47% of
cases, had a mean lesion length of 13.6 +/- 9.1 mm, and a mean vessel diameter of
2.85 +/- 0.44 mm. In 9 cases (25%) chronic total occlusions were treated.
Methylprednisolone acetate (mean 60 +/- 23 mg) was delivered in 36 lesions (21
patients; delivery success 90%) in the remaining 4 lesions (10%) the delivery
device did not cross the lesion. After drug delivery 46 stents were implanted
(1.2 stent/lesion; stented segment length 30.1 +/- 18.8 mm) using high pressure
for stent expansion (mean 16.4 +/- 3.1 atm). Intracoronary ultrasound guidance
was used in 64% of cases. Procedural and in-hospital complications were: Two non
Q wave myocardial infarctions (8%) and one (3%) subacute stent thrombosis.
Angiographic follow-up was obtained in all 36 treated lesions (100%) and the
angiographic restenosis rate (3 50% diameter stenosis) was 39%. A reduction of
the incidence of restenosis compared to the matched control group was not
observed. CONCLUSIONS: Long acting steroids could be delivered locally with high
success and low complication rates. The restenosis rate remained high in a subset
of unfavorable lesions with high risk for restenosis.
PMID- 10762809
TI - Ultrasound Appearances of Coronary Stents as Obtained by Three-Dimensional
Intracoronary Ultrasound Imaging In Vitro.
AB - Intracoronary ultrasound (ICUS) is an imaging technique which can provide a cross
sectional image of coronary arteries and implanted stents. Different stents may
have individual ICUS imaging characteristics. To investigate the imaging
characteristics and three-dimensional (3-D) reconstruction of different coronary
stent designs, we examined 26 different stents using ICUS in vitro. All stents
could be well visualized with planar ICUS. In 18 stents, 3-D imaging succeeded in
reconstructing the spatial stent architecture. This was not possible in the other
8 stents, most probably because of predominantly transversally-orientated strut
architecture, the small size of the strut wire width, the limited ICUS lateral
catheter resolution, and the smoothing and interpolation algorithms applied for 3
D reconstruction. ICUS in vitro provides a means of identifying coronary stent
structures which may be applicable in vivo. Three-D reconstruction of the entire
stent architecture in vitro can be achieved in stents with mesh or slotted tube
design, while stents with coil design and thin strut wires can only be partially
reconstructed.
PMID- 10762810
TI - Stenting of an Unprotected Bifurcating (Left Main, Circumflex) Lesion.
PMID- 10762811
TI - Coronary Stenting of an Anomalous Right Coronary Artery.
PMID- 10762812
TI - Severe Spasm of Subclavian Vein: Cannulation by a New Technique.
PMID- 10762814
TI - News from NASPE: Highlights of the 19th Annual Scientific Session of the North
American Society of Pacing and Electrophysiology.
PMID- 10762813
TI - Antegrade Guide Wire Crossing of Stenosed Aortic Valve During Balloon
Valvuloplasty: Use of a Steerable Catheter.
PMID- 10762815
TI - Intravascular Sonography of Vessels and the Aorta: When its Usefulness can be
Achieved.
PMID- 10762816
TI - The Relationship of U.S. Healthcare Policy to Decision Making in Vascular
Intervention: Do 960 Patients Really Have to Die?
PMID- 10762817
TI - Cost-Effectiveness Studies in Interventional Cardiology.
PMID- 10762818
TI - WhatOs Love Got to Do With It?
PMID- 10762819
TI - Coronary Pseudoaneurysm Following Stent Implantation Treated by New Stenting.
PMID- 10762820
TI - Intravascular Ultrasound-Guided Rotational Atherectomy and Stent Implant in a
Previously Undilatable Saphenous Vein Graft Lesion.
PMID- 10762821
TI - A Pitfall in the Diagnosis of Left Main Coronary Obstruction Due to Aortic
Dissection.
PMID- 10762822
TI - The MUST Trial: Acute Results and Six-Month Clinical Follow-up.
AB - Coronary stenting is now an established technique which is associated with
improved acute and long-term results and prevents restenosis in comparison to
balloon angioplasty in selected patients. However, subacute thrombosis and
vascular complications associated with conventional anticoagulant therapy
(warfarin for one month, with 4D5 days of IV heparin) remain of concern. By means
of a prospective, multi-center registry, we sought to demonstrate that the use of
ticlopidine and aspirin as the sole post-stenting treatment was safe by reducing
bleeding complications without increasing the risk of major cardiac events. A
total of 260 patients with stable and unstable angina and a short, single de novo
lesion were enrolled in this registry. Successful stent deployment without
ultrasound guidance was achieved in 259 patients. All patients were treated with
aspirin 3 100 mg daily for 6 months and ticlopidine 250 to 500 mg daily according
to body weight for 1 month. The primary endpoint was safety, defined by the
occurrence of death, myocardial infarction (MI), coronary bypass surgery (CABG)
or repeat angioplasty (PTCA) within 30 days of the procedure, in addition to
subacute stent thrombosis and bleeding and vascular complications within 30 days
of the intervention. During hospital stay there were no deaths; 8 patients
experienced MI, 1 patient underwent urgent CABG and 4 patients had repeat PTCA.
Therefore, the clinical success rate was 96.0%. Bleeding complications requiring
blood transfusion or vascular repair occurred in 2 patients. Treatment was
discontinued in one patient because of mild reversible leucopenia. At 6 months,
event-free survival was 90.3%. Major events involved CABG in 4 patients and a
second PTCA at the same site in 14 patients. The target vessel revascularization
rate at 6 months was 6.2%. This study demonstrates that Palmaz-Schatz stenting of
single de novo lesions with length < 15 mm, without ultrasound guidance but with
the routine use of high-pressure balloon dilatation, and with ticlopidine and
aspirin as the sole treatment post intervention, is feasible and safe both in
terms of clinical outcome and hematologic adverse side-effects. This registry
demonstrates that six-month event-free survival exceeding 90% can be achieved.
PMID- 10762823
TI - Femoral Arterial Hemostasis using the Angio-Seala System after Coronary and
Vascular Percutaneous Angioplasty and Stenting.
AB - The procedures of left cardiac catheterization and revascularization by
angioplasty are associated with a substantial risk of hemorrhagic complications.
This risk increases clearly in patients with an intravascular stent who require
early high doses of anticoagulant therapy. The first purpose of our study was to
evaluate the effectiveness of a mechanical system of femoral hemostasis (Angio
Seala, Sherwood Davis & Geck, St. Louis, Missouri) deployed in a group of 411
consecutive patients (302 males, 109 females, mean age 59 +/- 15) who
successfully underwent percutaneous angioplasty (PA) and application of an
intravascular stent (378 coronary, 33 vascular). The arterial closure system
consists of a small absorbable anchor and a collagen pad connected to a suture
thread which, at the end of the procedure, is positioned by percutaneous
introduction at the site of the femoral puncture. All the patients studied
received long-term platelet anti-aggregant therapy (ticlopidine 500 mg/day and
ASA 150 mg/day) for 3D4 days before and for one month after the procedure, and an
anticoagulant regimen of heparin sodium administered via intravenous bolus
(10,000 IU) during the procedure, followed by subcutaneous heparin calcium
(12,500 IU/day) for 21 days. Thirteen patients were treated intravenously with 10
mg abciximab and seven received pre-procedure coumadin. The ACT when the
hemostasis system was positioned was 355 +/- 43 seconds. Successful hemostasis
was reached in more than 95% of the patients (394/411 pts., 95.86%). In 17
(4.14%) of the 411 patients studied, the system failed; nine (2.19%) of these
were attributed by the operator to a failure of the positioning device procedure,
and the remaining 8 (1.95%) were attributed to a malfunction of the system.
Overall complications were observed in 23/411 (5.6%) of the patients (pts)
studied; eighteen were minor non-surgical hemorrhagic complications (bleeding
and/or hematoma) which occurred primarily in the first 4 hours. In 4 cases (1%)
vascular surgery was necessary for femoral pseudoaneurysm repair (2 pts) and
femoral hematoma (2 pts). One patient (0.24%) complained of severe claudication
related to a severe stenosis in the femoral artery caused by a malpositioning of
the anchor. This patient was successfully treated with balloon angioplasty and
stenting of the femoral artery. The average time to early mobilization was 9
hours, and all the patients without complications were completely mobile within
12 hours after the procedure; 380/411 (92.46%) of the patients were discharged
18D24 hours after percutaneous angioplasty. The second purpose of our study was
to compare data from 411 consecutive patients treated with the Angio-Seala device
after coronary and vascular angioplasty and stenting (Angio-Seal group), to a
group of 387 consecutive patients where the femoral arterial hemostasis was
obtained using manual compression after coronary angioplasty and stenting (manual
compression group). We found significant differences (p < 0.01) in the most
important elements concerning general patient management after the interventional
procedure, with excellent improvements using the Angio-Seal device, including:
successful hemostasis (95.86% vs. 88.37%); reduction of non-surgical hematomas
(1.22% vs. 4.65%); reduction of surgical hematomas (0.49% vs. 2.84%);
mobilization time (9 +/- 3 hours vs. 19 +/- 8 hours); and discharge within 18D24
hours (92.46% vs. 0.00%).
PMID- 10762824
TI - Local Delivery of TGF-b Antibodies to Prevent Neointima Formation after Balloon
Injury in a Pig Coronary Artery Model.
AB - BACKGROUND: The formation of neointima after vessel injury results from smooth
muscle cell proliferation and extracellular matrix secretion. This process is
activated by multiple growth factor release. Among these, Transforming Growth
Factor-b (TGF-b) has been shown to play an important role. We hypothesized that
local delivery of TGF-b antibodies could reduce neointima formation after balloon
angioplasty. METHODS AND RESULTS: Using autoperfusion double-balloon catheters
(Baxter, Irvine, California), we infused polyclonal TGF-b antibodies in 30
minutes, immediately after oversized balloon angioplasty in pig coronary
arteries. Eleven coronary arteries received 100 m anti-TGF-b and thirteen served
as controls. Animals were sacrificed 10 weeks later; coronary segments were
harvested and processed for histologic quantitative assessment of the neointima.
The extent of injury was similar in treated versus control vessels (39% +/- 5%
vs. 30% +/- 4%) and there was no difference in intimal thickening (0.63 +/- 0.19
mm for treated vs. 0.52 +/- 0.12 mm for controls). A previously validated
restenosis injury index (ratio of neointimal area to total wall area over extent
of injury) was also similar in both groups, 1.46 +/- 0.15 for treated versus 1.55
+/- 0.14 for controls. CONCLUSION: Local delivery of a single dose of TGF-b
antibodies failed to demonstrate a benefit on neointima formation in a pig
coronary artery model.
PMID- 10762826
TI - Contact Capitation in Cardiology.
PMID- 10762825
TI - Are Current Cardiovascular Stents MRI Safe?
AB - The number of coronary stents may be over half a million world-wide. The
neurologist and radiologist are frequently confronted with cardiac patients who
have had a recent carotid or coronary stent implanted and present with an acute
and unrelated stroke for which an MRI is recommended. We have reviewed and
classified all the major stents currently available world-wide and discussed
their interaction with MRI through their ferro-magneticity. All current stents
are MRI safe and MRI can be done anytime.
PMID- 10762827
TI - Happy Hunting or Adventure on the Run.
PMID- 10762829
TI - Evolution of the Society of Thoracic Surgeons National Cardiac Surgery Database.
PMID- 10762828
TI - How to Collect and Use Clinical Data to Enhance the Quality of Patient Care.
PMID- 10762830
TI - Development of the American College of Cardiology National Cardiovascular Data
Registry.
PMID- 10762831
TI - Identifying Data Reporting Needs.
PMID- 10762832
TI - Daughters of Charity National Health System: A System Approach.
PMID- 10762833
TI - A OWheel and SpokeO Network for Medical Records: The Emory Heart Center
Experience.
PMID- 10762834
TI - Gene Therapy for Restenosis: Progress or Frustration?
AB - No systemic pharmacological treatment has been shown to convincingly reduce the
incidence of restenosis after angioplasty in patients. The lack of success of
many pharmaceutical agents in reducing restenosis rates post-angioplasty and
following stent-implementation shown in dozens of clinical trials has encouraged
the development of new technological approaches as treatment. Gene therapy has
the potential to prevent some of the sequelae after arterial injury, particularly
cell proliferation. Mechanical methods of preventing restenosis, such as
sophisticated local drug delivery strategies and biodegradable stents using new
materials in combination with gene therapy, may be of use to maximize safety and
efficiency.
PMID- 10762835
TI - Insights into Coronary Restenosis: Lessons for Peripheral Vessels?
PMID- 10762836
TI - Is Bigger Always Better in Arterial Intervention?
PMID- 10762837
TI - Local Drug Delivery for Restenosis and Thrombosis N Progress?
AB - Platelet activation, inflammation, recoil, tissue hyperplasia and remodeling are
pivotal pathophysiologic factors in acute myocardial ischemia and restenosis
development after angioplasty. Even after the rising use of stents, the
tremendous amount of resulting tissue hyperplasia remains a therapeutic problem.
It has been suggested that short duration of effective drug levels and poor
efficiency of systemic drug administration account for the failure of therapy in
clinical trials. A rational effective therapy for angina and restenosis should
therefore be locally administered at the site of vascular obliteration. Special
local drug delivery devices could be used to administer sufficient drug amounts
at the site that needs to be treated. Local drug delivery systems using modified
balloon systems, stent systems or newly designed catheters have been developed.
In experimental studies, different effects can be demonstrated by using
endoluminal and adventitial substance delivery. Endoluminal application usually
resulted in < 1% effective drug delivery in the arterial wall and short lasting
deposition. Adventitial deposition led to higher mural concentrations; the drug
was detectable for up to 21 days. In media, the maximum is still comparable to
the maximum obtained after systemic application. Experimental studies indicate
positive therapeutic effects in restenosis models. Feasibility has been proven in
clinical studies of unstable angina with anticoagulants or antithrombotics.
Further preclinical and preliminary clinical studies are needed to clarify
regional drug distribution, regional wash-out, adverse effects and evaluation of
long-term therapeutic effects. Recent developments in catheter techniques might
enable effective local drug application in angina and restenosis prophylaxis with
a reduction in systemic adverse effects. (Supported by DFG Go 739/1-1).
PMID- 10762838
TI - Intravascular Red Light Therapy after Coronary Stenting N Angiographic and
Clinical Follow-up Study in Humans.
AB - In animal models of coronary restenosis, intravascular red light therapy (IRLT)
using a diode laser source has been shown to reduce neointimal hyperplasia
following balloon-induced injury and coronary stenting. We studied the safety and
efficacy of catheter-based IRLT for preventing restenosis after coronary stenting
in 22 patients with angina pectoris. IRLT was performed using a diode laser (650
nm) at an energy level of 10 megawatts delivered through a rapid exchange balloon
system containing the fiberoptics. The procedure was successful in all patients,
with no procedural or in-hospital complications. Two patients with recurrence of
symptoms had angiography at 3 and 4.1 months respectively. Angiographic follow-up
was also done after 6 months in the 20 remaining asymptomatic patients. The mean
minimal lumen diameter (MLD) for the whole group at 6 months follow-up was 2.57
+/- 0.62 mm. The calculated late lumen loss was 0.49 +/- 1.12 mm with a late loss
index of 0.21 +/- 0.54. Four patients (2 symptomatic and 2 asymptomatic) in the
series developed angiographic restenosis. Clinical events at follow-up of 10.9 +/
3.5 months were repeat angioplasty in 2 patients for symptomatic restenosis with
a 91% event free survival. These preliminary results demonstrate that IRLT after
coronary artery stenting is safe and feasible; it is associated with low rates of
angiographic indices of restenosis.
PMID- 10762839
TI - Experimental Evaluation of a New Tubular Coronary Stent (V-Flexa).
AB - The safety, efficacy, angiographic and histological effects of a new 316 L, SS
seamless stainless steel tubular stent (V-Flexa, Global Therapeutics, Broomfield,
Colorado) was evaluated in a porcine coronary and peripheral artery model.
Implantation in the right coronary artery was successful in all 16 pigs. Eight
pigs were angiographically controlled after 6 weeks and then sacrificed for
morphometric analysis. All stented coronary vessels were widely patent at this
moment and morphometric analysis showed only a mild fibromuscular neointimal
hyperplasia resulting in a neointimal hyperplasia of 1.15 +/- 0.38 mm2. The
remaining 8 pigs were controlled and sacrificed at 12 weeks. At that time, all
stented vessels were patent and neointimal hyperplasia was 1.22 +/- 0.34 mm2.
Comparison with the Palmaz-Schatza coronary stent (Cordis, Miami, Florida) in a
porcine peripheral artery model demonstrated significantly less neointimal
hyperplasia at 6 weeks (1.11 +/- 0.73 vs. 2.40 +/- 0.36, p = 0.001) and at 12
weeks (1.53 +/- 0.42 vs. 2.47 +/- 0.63, p = 0.003) for the V-Flex stent. In
conclusion, V-Flex coronary stent implantation in a porcine coronary and
peripheral arteries results in a high procedural success rate without subacute
thrombotic occlusions, despite no further anticoagulation nor antiplatelet
therapy. Six and 12 week histopathological and morphometric evaluation
demonstrated only a mild fibromuscular neointimal hyperplasia. Comparison with
the Palmaz-Schatz coronary stent in a peripheral artery model showed
significantly less neointimal hyperplasia in the V-Flex stent.
PMID- 10762840
TI - The Feasibility of Using Patent Foramen Ovale During Mitral Balloon
Valvuloplasty.
AB - This study was undertaken to examine the feasibility of searching and finding
probe patency during mitral balloon valvuloplasty and whether the duration of
procedure and/or the incidence and severity of iatrogenic atrial septal defect
decreased in this patient population. Sixty consecutive patients treated with
mitral balloon valvuloplasty (MBV) were studied; data from 55 patients were
analyzed. Fifteen patients out of 55 (27.3%) had probe patency. The duration of
the procedure was shorter (26.2 +/- 7.0 vs. 35.6 +/- 10.1 min; p < 0.01),
incidence of atrial septal defect was lower (40% vs. 72.5%, p < 0.01), and the
severity of atrial septal defect as measured by the jet area was smaller (1.68 +/
0.23 vs 2.6 +/- 1.3 cm2; p < 0.01) in the probe patency group compared to
patients without probe patency. At 6 month follow-up, all of the atrial septal
defects present in the probe patency group disappeared, but 4 (10.2%) persisted
in patients without probe patency. It was concluded that searching probe patency
during mitral balloon valvuloplasty was feasible and worthwhile, would not unduly
prolong the procedure, and would decrease the incidence and severity of
complicating atrial septal defect.
PMID- 10762841
TI - Vertical Approach N A Modified Method in Balloon Crossing of Mitral Valve in
Inoue Balloon Mitral Valvuloplasty.
AB - Recently, the shape of the J-tipped stylet used in Inoue balloon mitral
valvuloplasty has been altered to form a tighter loop. Consequently, the distal
balloon catheter tends to take a more vertical orientation when the stylet is
inserted into the catheter during manipulation of the balloon catheter across the
mitral valve. We describe a modified method N a vertical approach N to facilitate
and expedite crossing of the mitral valve during Inoue balloon mitral
valvuloplasty.
PMID- 10762844
TI - The Use of Abciximab in the Treatment of Subacute Stent Thrombosis.
PMID- 10762843
TI - Primary Stenting Without Predilatation, OStent Alone,O at the Origin of a Left
Internal Mammary Artery Graft Equivalent to a Left Main Coronary Artery.
PMID- 10762842
TI - Acquired Coronary Artery-Cameral Fistula in Rheumatic Mitral Stenosis with Left
Atrial Thrombus.
PMID- 10762845
TI - Legal Implications of Gain-Sharing/Cost-Savings Programs.
PMID- 10762847
TI - Endovascular Therapy: The Mother of All Turf Wars.
PMID- 10762846
TI - Gain Sharing and Other Contrivances: Reckless Dithering or Watershed Opportunity?
PMID- 10762848
TI - Interventional MRI: The Way to the Future.
PMID- 10762849
TI - A New Approach to Plaque Removal: The Redha-Cut Device.
AB - PURPOSE: To prospectively determine the safety, feasibility and efficacy of a new
atherectomy device. Methods. Seventy patients with 93 symptomatic femoro
popliteal lesions underwent percutaneous atherectomy with Redha-cut, a metallic,
flexible catheter. The device works on pull-back with two umbrella-like blades
and enables cutting, retaining and removing of material. Quantitative analysis of
the angiograms was performed. RESULTS: Obtaining of atherectomized samples was
successful in all cases. The mean atherectomy time was 5 +/- 2 minutes. The
stenoses were reduced from 74 +/- 2.3% before to 26 +/- 2% after atherectomy (p <
0.001). Subsequent PTA, which was performed to optimize the results, further
decreased the degree of stenosis to 17% (p > 0.5). No perforations, acute closure
or early re-thrombosis occurred. Cumulative patency rates according to the
findings of non-invasiveive examinations were 83% at 6 months and 66% at 12
months. Conclusions. The Redha-cut device is a simple, safe and efficacious tool
for biopsy sampling and atherectomy. Further studies randomizing patients either
to balloon or atherectomy are planned to compare this technique with others in
regard to long-term patency.
PMID- 10762850
TI - Endovascular Aortic Aneurysm Repair N Five Years Down the Road: Where to Now?
PMID- 10762852
TI - Foreward: Mechanical Reperfusion in AMI.
PMID- 10762851
TI - Introduction to Our New Series on Vascular Brachytherapy: Why is it So Important?
PMID- 10762853
TI - Lessons from the Pooled Outcome of the PAMI, ZWOLLE and Mayo Clinic Randomized
Trials of Primary Angioplasty Versus Thrombolytic Therapy of Acute Myocardial
Infarction.
PMID- 10762854
TI - Cost-Effectiveness of Primary PTCA Versus Thrombolysis.
PMID- 10762855
TI - Stenting in Acute Myocardial Infarction: Observational Studies and Randomized
Trials N 1998.
PMID- 10762856
TI - Platelet Glycoprotein IIb/IIIa Integrin Blockade: Focus on Acute Myocardial
Infarction.
PMID- 10762857
TI - Management of Patients with Cardiogenic Shock.
PMID- 10762858
TI - Mechanical Thrombectomy in Acute Ischemic Syndromes: Cutters, Suckers and
Busters.
PMID- 10762859
TI - Technical Aspects of a Regional Primary PTCA Program.
PMID- 10762860
TI - Combination enoxaparin-abciximab therapy during coronary intervention: the next
standard of care?
PMID- 10762861
TI - Prolonged therapy with low-molecular-weight heparin after PCI.
PMID- 10762862
TI - Monitoring anticoagulation.
PMID- 10762863
TI - Use of low-molecular-weight heparin in percutaneous intervention.
PMID- 10762864
TI - Use of enoxaparin in a patient with unstable angina.
PMID- 10762865
TI - Emergency Coronary Stenting with Wiktor Stent N Immediate and Late Results.
AB - In case of failed angioplasty, coronary stenting has gradually emerged as a non
surgical method to restore vessel patency and optimize coronary blood flow. There
is still little clinical and angiographic information on the use of radiopaque
single loose interdigitating wire stents in angioplasty complicated by threatened
or acute closure. Seventy-one patients received Wiktor stents after threatened
vessel closure in 53 cases and acute closure in 18 cases. Stent delivery was
successful in 98%. In-hospital death occurred in 1 case (1.4%). Stents occlusion
were faced in 10 cases (14%), of which 6 presented early and 4 late after the
procedure. Urgent bypass surgery was needed in 9 cases (12%) and 7 patients (10%)
developed acute myocardial infarction. Serious bleeding complications occurred in
7 cases (10%) and vascular repair was performed in 4 patients (5%). During a
follow-up of 20 +/- 10 months, 2 patients died, no myocardial infarction was
observed and recurrence of angina was noted in 17 patients (24%). Angiographic
analysis showed an acute gain in minimal lumen diameter of 1.71 +/- 0.22 mm and a
late loss of 0.63 +/- 0.17 mm. Angiographic restenosis (diameter stenosis > 50%)
presented in 20% of patients. Therefore, Wiktor stenting yields similar results
than currently used stents in acute closure and strictly defined threatened
vessel closure following angioplasty.
PMID- 10762866
TI - Success and Procedural Outcome of Excimer Laser Coronary Angioplasty Compared to
Conventional Balloon Angioplasty.
AB - BACKGROUND: Coronary excimer laser angioplasty was suggested to be superior for
treatment of lesions with complex lesion morphology. METHODS: In this study, 134
consecutive patients undergoing excimer laser angioplasty (ELCA) were compared to
203 patients treated with conventional balloon angioplasty (PTCA) in the same
study period. Baseline characteristics did not differ between both groups except
the distribution of target vessel (LAD: ELCA 72% vs. PTCA 50%). RESULTS: In the
ELCA group, 64 of 139 lesions required adjunctive balloon angioplasty. Overall
procedural success was achieved in 80% of patients treated with PTCA and in 78%
of patients treated with ELCA (NS), as defined by a reduction of at least 20% of
the luminal narrowing and 2 50% residual stenosis, and no in-hospital
complication. Complications included acute vessel closure (ELCA: 23.7%, PTCA
6.9%; NS), myocardial infarction (ELCA: 3.6%, PTCA 1.7%; NS), emergency bypass
surgery (ELCA: 0%, PTCA 0.5%; NS), and death (ELCA: 2.2%, PTCA: 0.5%; NS). No
significant difference was found between the acute success rates and major
complications in either A, B1, B2 and C lesions (modified ACC/AHA Task Force
classification) treated with ELCA as compared to PTCA. A trend toward increased
success rates were documented for ELCA of total and functional occlusion (ELCA:
86% vs. PTCA: 57%; NS) and bifurcational or ostial lesions (ELCA: 95% vs. PTCA
78%). CONCLUSIONS: Further randomized trials are needed to compare the acute
success of excimer laser treatment with balloon angioplasty for these selected
lesion types.
PMID- 10762867
TI - Effects of Whole Blood Viscosity on Atherogenesis.
AB - There is a high correlation between high whole blood viscosity and the well known
risk factors for arterial occlusive disease: hypertension, hyperlipidemia,
diabetes, male sex, age, smoking, and obesity. These risk factors increase whole
blood viscosity, whereas the preventive factors of arterial occlusive disease
such as fish oil, aspirin, alcohol, and exercise probably tend to reduce whole
blood viscosity. The protective adaptation theory recently presented by Kensey
and Cho1 proposed high whole blood viscosity as one of the major factors that
make up the mechanical injury possibly inducing arterial occlusive disease. New
diagnostic and prophylactic treatments for arterial occlusive disease are
suggested. An accurate, convenient, and cost-effective blood viscometer that can
be used in a clinical environment might become a useful diagnostic screening
device for patients at risk for arterial occlusive disease, and it would help
discover new prophylactic treatments.
PMID- 10762868
TI - Failure of Fluoroscopy and Success of Intravascular Ultrasound to Locate an
Intracoronary Embolized Palmaz-Schatz Stent.
AB - We describe a patient in whom one half (disarticulated) Palmaz-Schatz stent was
lost during a failed stenting procedure of an ostial left anterior coronary
artery (LAD) stenosis. The embolized stent could not be located by fluoroscopy
and was found in the left main coronary artery by intravascular ultrasound. The
stent could not be removed using a retrieval device and was successfully deployed
in the left main coronary artery by high-pressure balloon dilatation.
Subsequently, LAD stenosis was successfully treated with deployment of two
additional half Palmaz-Schatz stents.
PMID- 10762869
TI - Active Guidewire Technique: Using Guidewire Bias to Assist in Rotational
Atherectomy.
PMID- 10762870
TI - Provocation of Transvalvular Pressure Gradients in Rheumatic Tricuspid Stenosis
by Passive Leg Raising.
PMID- 10762871
TI - Balloon Coarctation Angioplasty: A New Approach Using Inoue Balloon.
PMID- 10762872
TI - QT Dispersion N A Simple and Cheap Method for Predicting Ventricular Tachycardia
Susceptibility.
PMID- 10762873
TI - Intravenous Procainamide for Predicting the Response of Sustained Ventricular
Tachycardia to Type III Antiarrhythmic Drugs.
AB - The use of serial electrophysiology studies to guide antiarrhythmic drug therapy
in patients with ventricular tachycardia is both costly and time consuming.
Intravenous procainamide administered during of the initial electrophysiology
study has previously been shown to be useful in predicting the efficacy of oral
antiarrhythmic medications (type I and III). The purpose of this study is to
confirm that ventricular tachycardia suppression after intravenous procainamide
correlates with suppression on oral class III antiarrhythmic medications
(amiodarone and sotalol). This study included all patients with sustained
ventricular tachycardia who underwent an initial electrophysiology study
including an acute suppression trial with intravenous procainamide and a
subsequent restudy on oral amiodarone or sotalol. The response to intravenous
procainamide was then compared with these type III antiarrhythmic medications.
Between January 1993 and May 1995, 360 patients underwent electrophysiology
studies for suspected or documented ventricular arrhythmias. One hundred patients
(28%) had an inducible sustained ventricular tachycardia, and 26 patients
received both intravenous procainamide and subsequently oral amiodarone or
sotalol. Acute infusion of procainamide provided a highly specific method for
predicting suppression of oral amiodarone and sotalol (82% and 100%
respectively). However, several patients who were not suppressed by intravenous
procainamide were suppressed by oral sotalol resulting in lower overall
predictive accuracy 12/15 (80%) for amiodarone vs. 5/11 (45%) for sotalol treated
group. We conclude that the acute infusion of procainamide may help to predict
ventricular tachycardia suppression after oral amiodarone and sotalol. A larger
prospective trial is warranted to confirm this finding.
PMID- 10762874
TI - Intravenous Procainamide for Predicting the Response of Sustained Ventricular
Tachycardia to Type III Antiarrhythmic Drugs.
PMID- 10762875
TI - Deal Mania N All the Rage Perhaps Some Folly!
PMID- 10762876
TI - Chronic Coronary Occlusion N Treatment Options and Results.
AB - Indications for chronic coronary occlusion angioplasty are based on the projected
benefit and technical difficulties. With current indications, primary success is
around 60% and complications are rare. In successful cases, the main benefits are
improvement of symptoms and obviation of the need for bypass surgery. Late
improvement of left ventricular function can also occur. Recurrences are
frequent, but reocclusions occur only in about 20% of cases. Several techniques
have been advocated to improve the success rate. It is obvious that the stiffer
the instrument used the higher the crossing rate, but also the risk for
perforation. While the laser wire aims at high crossing success, the Magnum wire
aims at high safety. In about 800 cases using the Magnum wire, the success rate
was 64% before, and 66% after crossover to another technique. Complications were
comparable to those of routine coronary angioplasty. Chronic total occlusions are
a major reason for selecting bypass surgery over angioplasty. The technical
success with angioplasty leaves room for improvement. However, safety should not
be compromised and there are limits to the investment in terms of time and
material because the clinical yield is relatively small, albeit uncontested.
PMID- 10762878
TI - High-Risk Coronary Intervention in Severe Left Ventricular Dysfunction.
PMID- 10762877
TI - Catheter-Based Therapy for Saphenous Vein Bypass Graft Disease.
AB - Improved patient survival and the limitations of repeat coronary artery surgery
have generated a growing population of patients referred for catheter-based
treatment of vein graft lesions. In this subject review, the current state of
knowledge regarding therapeutic options for these difficult lesions is discussed.
Despite improvements in technique and materials, risks of treatment with balloon
angioplasty remain higher than for other lesion types. The underlying lesion
pathology determines therapeutic risk to a large degree. Newer therapeutic
alternatives appear to offer advantages over balloon angioplasty, but improved
clinical outcomes have not been demonstrated in appropriate trials for most new
devices and treatment strategies. On-going studies will clarify the utility of
some new devices, and other studies are needed.
PMID- 10762879
TI - Rescue Angioplasty in Failed Thrombolysis in Acute Myocardial Infarction: A
Community Hospital Experience.
AB - OBJECTIVES: To determine the success and survival rate of patients undergoing
rescue angioplasty in failed thrombolysis in acute myocardial infarction, in the
private practice setting of a tertiary care community hospital. METHODS: Between
January 1990, and March 1995 we treated 125 patients with rescue angioplasty
after failed thrombolysis for acute myocardial infarction. All patients were
brought to the catheterization laboratory and studied if there was no evidence of
reperfusion, and rescue angioplasty was performed if the infarct related artery
showed TIMI 0D1 flow. Their records were reviewed for the results of the
angioplasty, presence of congestive heart failure, and survival during the
hospitalization. RESULTS: One hundred and one men and 24 women (ages 21 to 79)
were studied, of whom 48 had anterior infarcts, 8 lateral infarcts, and 69
inferior infarcts. Of the 109 patients with successful procedures (87.2%) three
died (2.8%). Of the 16 patients with failed procedures, six (37.5%) died (p =
0.00011). Eight of the nine patients who died were in extremis upon entering, or
soon after entering the hospital, and would have been expected to die. However,
one patient initially successfully recanalized and stabilized, rapidly
deteriorated and died when his artery reoccluded and could not be reopened.
Patients with congestive heart failure, documented by x-ray, had a higher
mortality rate (21.1%) than patients who were free of failure (3.3%, p = 0.017).
CONCLUSION: Patients who have a successful rescue angioplasty after failed
thrombolysis in acute myocardial infarction have a higher survival rate than
those who fail a rescue procedure. Most patients who die are in extremis upon
admission.
PMID- 10762880
TI - European Experience with the Self-Expanding Nitinol Coil: Pilot Phase Evaluation
in Cardiovascular Applications.
AB - BACKGROUND: The Cardiocoil (InStent) is a self-expanding nitinol coil that is
restrained on a delivery catheter in a compressed state and deployed by a wire
based release mechanism. We provide the initial data on the acute results of the
use of this stent in a multi-center study in Europe. We also briefly review the
other non-coronary applications of this stent. METHODS: One-hundred two stents
were implanted in 76 patients for suboptimal results or dissections. There were
39 LAD lesions, 28 RCA lesions and 9 Circumflex lesions. There were eight total
occlusions. Lesions were short in 41% (< 10 mm), tubular (between 10 and 20 mm)
in 37%, and diffuse (> 20%) in 22%. Stent deployment included predilatation to
the reference arterial side and post dilatation after stent deployment. RESULTS:
Stent deployment was successful in all cases in which lesions could be crossed.
In cases where the stent did not cross the lesion (n=3) it was removed
uneventfully. There were no stent losses. Complications included subacute
thrombosis in 4/76 (5.3%) patients (1- a long total RCA lesion, 2- diffuse
proximal LAD diseases). There were no late acute events after stenting and no
stent related mortality. Angiographic quantitative analysis showed that the stent
expands by both its intrinsic self-expanding properties and by post deployment
balloon assistance. CONCLUSIONS: The self-expanding coil stent for cardiovascular
interventions is safe and effective in treating a variety of complex lesions. It
provides adequate support to the arterial wall, preventing acute recoil and
tacking dissections to the arterial wall. The long-term efficiency of this stent
awaits further clinical testing.
PMID- 10762881
TI - Permanent Electronic Storage of Angiographic Images in the Catheterization
Laboratory: High-Resolution and Real-Time Acquisition on Optical Laserdiscs.
AB - The use of electronic OfilmlessO media for long-term archiving of coronary
angiograms has been impeded by the problems of image storage and data transfer
among institutions. Although long-term analogue storage of the images is
presently feasible, and much less costly than digital storage, processing has
been limited to a 625 lines video format, not optimal for high quality images. We
developed a bi-directional 1249/625 lines converter, able to store and to replay
high resolution (1249 lines) video images, from Component Record Video (CRV)
Optical Laser (Analogue) Videodisks. Image quality and medical relevance were
evaluated five ways: 1) Outside experts compared 593 static images stored on CRV
discs to the same images stored in a high-resolution digital format blinded to
source of image. The four experts found no visual or medical difference in 98% of
evaluated images and minor differences in the remainder. The differences in the
remaining images were not consistent among experts. 2) Two of the experts also
compared the enhanced CRV optically stored image to the image obtained on
simultaneously recorded 35mm cine film, and found the enhanced CRV stored image
to be superior or similar, but never inferior to the film image. 3) 90
representatives from 63 outside institutions compared images from both a digital
hard drive and the enhanced CRV optical (analogue) storage displayed at a Windows
based digital workstation. During the test they were blinded as to the source of
the images. The representatives found no difference in image resolution, quality,
diagnostic accuracy, and medical relevance. 4) We evaluated quantitative coronary
angiography (QCA) on standard coronary test phantoms using enhanced CRV stored
images digitally processed. The correlation of the enhanced CRV image to the
actual size of the phantom vessels was similar to the results obtained in the
literature from digitally stored images. 5) 78 arterial measurements ranging 0.65
to 4.85 mm were evaluated both from the digital hard disc (D) and the CRV optical
disc (CRV), using the same QCA analytical package. The correlation coefficient
and the Standard Error of the Estimate between D and CRV values were respectively
0.997 and 0.076, no systematic over or underestimation occurred, and the mean
variability was inferior to 0.1 mm. CONCLUSION: High-Resolution CRV-optical
storage represents a cost-effective solution for excellent image quality
equivalent to digitally stored images, permitting permanent electronic archiving
inside the cath-lab, and allowing digital image processing and digital image
communication.
PMID- 10762882
TI - Tissue Plasminogen Activator (t-PA) Induced Compartment Syndrome and Dopamine
Infiltration N Is There a Connection?
PMID- 10762883
TI - Aortic Dissection Due to Complete Detachment of the Left Coronary Ostium During
Percutaneous Transluminal Coronary Angioplasty.
PMID- 10762884
TI - Percutaneous Combined Balloon Dilatation of Mitral Valve Stenosis and Discrete
Subaortic Stenosis.
PMID- 10762885
TI - Prevention of Groin Vascular Complications Associated with Percutaneous
Procedures.
AB - Groin vascular complications are frequent problems associated with percutaneous
interventions. The potential for these problems may increase as more potent
antiplatelet and anticoagulant regimens are tested and become more widely used.
Prevention of these complications involves consideration of several factors
including 1) technical factors of arterial entry; 2) early sheath removal; 3)
careful monitoring of the patient after sheath removal; and 4) measurement of
activated clotting time and 5) consideration of weight adjustment of heparin in
selected patients in whom adjunctive medications are given. If local bleeding
occurs, prompt evaluation is required to assess the site of bleeding, the reason
for bleeding, and magnitude of hemodynamic compromise. Often local vascular
complications can be treated without need for other invasiveive procedures.
Prevention of vascular complications is essential to optimize the outcome of
interventional cardiology care.
PMID- 10762886
TI - Evaluation of New Cardiovascular Therapies N Conceptual and Regulatory Hurdles.
PMID- 10762887
TI - An Introduction to Clinical Databases.
PMID- 10762889
TI - Advances in Technology N Charging Ahead into the Future.
PMID- 10762888
TI - The Potential World Market for Cardiovascular and Medical Devices.
PMID- 10762890
TI - Changes in Left Ventricular Function After Coronary Recanalization by
Percutaneous Transluminal Coronary Angioplasty (PTCA).
AB - Forty-six patients (21 with stable angina and 25 with chronic myocardial
infarction, 37 men) with a total chronic proximal coronary occlusion and
collateral vessels to the distal part of the occluded artery (30 LAD, 10 RCA and
6 CX properly distributed in both groups) were studied angiographically before
and 2 to 8 months (mean 6) after balloon angioplasty. The patients were divided
in six subgroups: A) Angina pectoris no matter the result of recanalization (n =
21); B) Myocardial infarction no matter the result of recanalization (n = 25); C)
Angina pectoris with successful recanalization and open coronary (O.C.) > 50% at
follow-up (n = 13); D) Angina pectoris with unsuccessful recanalization and/or
restenosis or closed coronary (C.C.) at follow-up (n = 8); E) Myocardial
infarction with successful recanalization and O.C. > 50% at follow-up (n = 8); F)
Myocardial infarction with unsuccessful recanalization and/or restenosis or C.C.
at follow-up (n = 17). No subgroup showed statistical differences (p > 0.05) in
LVEDP before (B) and at follow-up (FU). On the other hand, several measurements
were statistically different in the subgroup A at B and at FU: Ejection fraction
(EF) [57.3 +/- 12.3 and 64.2 +/- 19.4%; p = 0.02]; Regional wall motion (RWM)
measured in the region of the affected coronary [18.7 +/- 9.6 and 23.6 +/- 11.8%;
p = 0.05]; Minimal wall motion (MWM) measured in the site of lesser parietal
movement [14.3 +/- 13.1 and 25.8 +/- 26.2%; p = 0.02]. In the subgroup C the
following differences were observed: EF [58.4 +/- 12.3 and 69.0 +/- 12.4%; p =
0.003]; RWM [16.3 +/- 8.4 and 25.4 +/- 8.2%; p = 0.005]; MWM [14.7 +/- 15.1 and
27.9 +/- 18.0%; p = 0.0001]. In the other considered subgroups we did not reach
significant differences (p > 0.05) in these measurements. We conclude that
recanalization of a chronic coronary occlusion improves left ventricular
contractile function in the presence of viable myocardium and that MSF is the
most sensitive among the studied variables to separate anginal patients from the
patients without viable myocardium after successful recanalization.
PMID- 10762891
TI - New Horizons in InterVentional Cardiology.
PMID- 10762892
TI - Back to the Future.
PMID- 10762893
TI - Flow Capacity, How Much is Enough, Do We Have it, Do We Need More?
PMID- 10762894
TI - High Pressure Coronary Stenting: Efficacy and Safety of Aspirin Versus Coumadin
Plus Aspirin N Preliminary Results of a Randomized Study.
AB - The efficacy and safety of treatment after coronary stenting was examined with
aspirin alone, 100 mg daily, as compared to coumadin plus aspirin. Data from the
first 101 patients, 73 men and 28 women, aged 59.2 +/- 9.3 years, of a
prospective randomized study are presented in this preliminary report. Forty
eight patients suffered from one-vessel disease, 32 had two- and 21 three-vessel
disease. Indications for stenting were stable angina in 65 patients, unstable
angina in 16, threatening myocardial infarction in 4 and restenosis in 16
patients. The stents were implanted by high pressure balloon inflation (14.5 +/-
2.2 atm), 55 of them were Palmaz-Schatz, 31 Micro, 10 Gianturco-Roubin, 2 Wiktor
and 3 combined stents. Intravascular ultrasonographic guidance was not performed.
The primary end point was defined as the absence of the following events: death,
subacute coronary artery closure, acute myocardial infarction, emergency coronary
bypass surgery, repeated PTCA, major bleeding or arterio-venous aneurysms needing
transfusion or surgery. Eighty out of 101 patients (79.2%), 41 out of 47 (87.2%)
in the aspirin group and 39 out of 54 (72.2%) in the coumadin plus aspirin group
(p = 0.06) were free of events during hospitalization (9.5 +/- 5.7 days, median:
8 days). Forty-five out of 47 patients (95.7%) in the aspirin and 51 out of 54
(94.4%) in the coumadin plus aspirin group (p = 0.8) were without subacute
closure. One death occurred in the aspirin group due to stent abscess two weeks
after an angiographically successful stent recanalization. All 7 arterio-venous
aneurysms with surgical interventions occurred in the coumadin group (p = 0.01).
No emergency bypass surgery had to be performed. If these preliminary results
will be confirmed by the final analysis, the combination of coumadin with aspirin
does not show more efficacy or safety as compared with aspirin alone in the
treatment after high-pressure coronary stenting during the hospital stay.
PMID- 10762895
TI - Management of Coronary Restenosis via the Radial Artery: An Elegant Approach to
the AchillesO Heel of PTCA.
AB - In spite of many efforts, the most effective treatment for restenosis after
coronary angioplasty remains repeat angioplasty. Although the second procedure is
known to be at lower risk, it is usually performed by the same technique, thus
requiring hospitalization. In such a group of patients, the feasibility of using
the radial route for repeat coronary angiography and angioplasty when needed and
the safety of early discharge were evaluated prospectively. Coronary angiography
via the radial artery was attempted in 51 patients referred within 6 months of
initial coronary angioplasty with the clinical suspicion of restenosis.
Successful cannulation of the radial artery was possible in 48 (94%). Following
placement of a 4 Fr arterial sheath, coronary angiography was completed
successfully in all but one patient. Restenosis was confirmed angiographically in
25 patients (one via the femoral route) and a new lesion was observed in 3.
Repeat angioplasty was attempted via the radial route (25 patients) or via the
femoral route (one patient) using a fixed-wire balloon catheter through the 4 Fr
diagnostic catheter (n=22). Angioplasty via the radial route including elective
stent implantation (5 patients) was a technical success in 92% of the patients.
Immediate arterial sheath withdrawal and mechanical compression of the radial
artery provided satisfactory hemostasis after 186 +/- 126 minutes. The radial
pulse was absent post-procedure without clinical consequence in 3 patients (6%).
Of the 46 patients without a femoral artery puncture, 39 (85%) were discharged
the same day without any cardiac or local complications. Thus, early discharge
after repeat coronary angiography and angioplasty for restenosis is feasible and
safe using the transradial route in the majority of patients.
PMID- 10762896
TI - The Radial Approach to Selective Carotid Artery Angiogram.
AB - Selective carotid artery angiography via either radial artery was performed in 12
patients, mostly in combination with other diagnostic procedures. No failures to
cannulate either the radial or carotid arteries were encountered. Extra-cranial
angiography through a radial approach is safe, feasible and comparable to other
accepted ports of entry.
PMID- 10762897
TI - Percutaneous Transvenous Mitral Commissurotomy Following Carpentier Ring
Annuloplasty.
PMID- 10762898
TI - Coronary Angioplasty of a Single Coronary Artery with an Anomalous Origin in the
Ascending Aorta.
PMID- 10762899
TI - Successful Unplanned Palmaz-Schatz Stenting of a Compromised Side Branch Through
a Previously Deployed Palmaz-Schatz Stent.
PMID- 10762900
TI - Management of Coronary Artery Dissection and Perforation Following Coronary
Angioplasty by Intra Coronary Stent.
PMID- 10762901
TI - The Multicenter Automatic Defibrillator Implantation Trial (MADIT) Revisited: The
First in a Series of Prophylactic Defibrillator Trials.
PMID- 10762902
TI - Comparative Analysis of Coronary Surgery Risk Stratification Models.
AB - BACKGROUND: Preoperative risk assessment models for coronary bypass surgery
(CABG) have been proposed, but comparison of them using independent databases
needs to be done. METHODS: Models of CABG hospital mortality were tested on a set
of 3,443 patients who underwent CABG including a subset of 3,237 patients who had
isolated CABG (no valve procedures), in our database since 1991. Four models
previously described were designated as Parsonnet (PS), Cleveland (CL), and
Society of Thoracic Surgeons version 1 (ST1) and version 2 (ST2). We developed
our own Bayesian (BA) and logistic regression (LR) models and calibrated the PS
and CL models on 2,842 patients operated on prior to 1991. Models were compared
with respect to 1) mean predicted mortality, 2) correlation of predicted to
observed mortality, 3) Brier mean probability score, 4) descriptive statistics,
4) the C-Index (area beneath the receiver operating characteristic curve), and 5)
predictive efficiency. Since the ST1 and ST2 models were developed for use only
with isolated CABG patients, these models were compared with the others using an
isolated CABG subset. RESULTS: Observed mortality for all 3,443 CABG patients was
4.0%. For this group, the mean mortality predicted by PS, CL, BA, LR, was 9.0 +/-
8.0, 6.0 +/- 6.0, 7.6 +/- 15.6, and 5.1 +/- 7.7 (mean +/- standard deviation)
respectively. C-Indexes were.80 +/-.02,.80 +/-.02,.83 +/-.02, and.80 +/-.02 (C
Index +/- standard error) respectively. Observed mortality for 3,237 isolated
CABG patients was 3.7%. For this subgroup, the mean mortality predicted by PS,
CL, BA, LR, ST1, and ST2 was 8.4 +/- 7.4, 5.7 +/- 5.9, 6.5 +/- 13.9, 4.5 +/- 6.5,
9.6 +/- 9.1, and 3.0 +/- 3.3 respectively. C-Indexes were.80 +/-.03,.80 +/
.03,.83 +/-.02,.79 +/-.03,.77 +/-.03, and.81 +/-.02 respectively. CONCLUSIONS:
Existing CABG models can accurately discriminate outcome about 80 percent of the
time. Models developed on a national database and those from non-local databases
appear to have validity for our local data set. Predictions can vary widely
between models and existing methods for comparing models appear to be inadequate.
The methodology presented here is applicable for use with patients undergoing
interventions in the cardiac catheterization laboratory.
PMID- 10762903
TI - Downsizing, Upsizing, Rightsizing and Strategic Alliances.
PMID- 10762905
TI - Femoro-Popliteal Interventions: Immediate Results and Long-Term Follow-Up.
PMID- 10762904
TI - Endoluminal Stent Grafts: Overview.
PMID- 10762907
TI - Radiation Exposure of Patients Having PTCA N Causes/Consequences of WHO Report.
PMID- 10762906
TI - The Active Guide Catheter: A Lost Art Form or Obsolete Technology?
PMID- 10762908
TI - Thermal Effects In Vivo from Holmium: YAG Lasing in the Intracoronary Setting.
AB - While the thermal effect of laser energy does ablate atheromatous plaque, thermal
injury to adjacent tissue produces high rates of arterial thrombosis and spasm.
Holmium:YAG lasers use a pulsed laser source to maximize photoblative effects
while minimizing thermal effects. These lasers have been utilized clinically to
ablate thousands of complex coronary lesions with low rates of spasm and
thrombosis, suggesting that little or no thermal injury occurs with these
devices. However, we have been able to detect thermal injury in patients
angioscopically in coronary arteries after holmium:YAG lasing. Here we report the
use of directional coronary atherectomy (DCA) to ObiopsyO arteries in patients
following holmium:YAG laser treatment, allowing direct histologic examination of
lased tissue. Thirty such lased DCA samples were matched for patient age, gender,
target vessel, and lesion characteristics with thirty control DCA samples
obtained from patients undergoing DCA without prior lasing. Blinded pathologic
examination correctly identified 27/30 control samples but only 18/30 lased
samples. Subsequent unblinded analysis, sometimes with recutting and restaining
of tissue blocks, resulted in the detection of thermal effects in 27/30 lased
samples. The thermal effects seen included edge disruption, charring, coagulation
necrosis, and most commonly, vacuolization. We conclude that holmium:YAG lasing
does produce detectable thermal effects in tissue in most patients. These effects
can be quite subtle or can be extensive, but do not predict poor patient outcome.
PMID- 10762909
TI - Coronary Stenting in Clinical Practice: Patient Profile, Immediate Outcome,
Clinical and Angiographic Follow-up in 243 Consecutive Patients.
AB - The purpose of this study is to assess immediate outcome and long term results in
unselected consecutive patients (pts) representing a spectrum of clinical and
angiographic subgroups and stent designs. RESULTS: From first implantation in
November 1989 through to October 1995, 243 pts underwent coronary stent insertion
(307 stents, males n=188, females n=55, mean age 57.8 years. Palmaz-Schatz stents
were implanted in 210 pts, Wiktor in 30 pts, both in 3. Bailout stenting was
performed in 11 patients. Overall procedural success was 97%. Complete
revascularization was achieved in 155 (64%) patients. Stenting of an infarct
related artery within 6 hours of an acute myocardial infarction was performed in
6 patients, and for unstable angina in 107. Pre-procedure 223 (92%) pts had class
III/IV angina. Stenting of 11 vein grafts and 5 left main arteries was performed.
Subacute stent thrombosis occurred in 13 (5%) pts while 6 (2.5%) pts died in
hospital, and 8 (3%) had a Q-wave myocardial infarction. At a mean (SD) 7.3
(12.9) months follow-up 233 (96%) pts were alive, 213 (91%) had no or mild
angina. Angiographic follow-up in 201 (83%) pts at 19 (30) weeks showed a 13% in
stent restenosis rate. CONCLUSIONS: In an unselected, consecutive series of
patients undergoing coronary stenting, mortality was low, procedural success was
high and late clinical and angiographic results were satisfactory. Subacute stent
thrombosis, though uncommon remains a challenge.
PMID- 10762910
TI - Extraction Atherectomy for Recently Occluded Saphenous Vein Grafts: A
Retrospective Study.
AB - BACKGROUND: Over 300,000 coronary artery bypass operations are performed annually
in the U.S., in which saphenous vein grafts remain the most often utilized
conduit for myocardial revascularization. Still, the relatively short life-span
of reverse saphenous vein grafts (SVG) demands that revascularization techniques
be developed for SVG occlusions. Extraction atherectomy (EA) as a pre-treatment
to percutaneous transluminal coronary angioplasty (PTCA) may offer advantages to
PTCA alone in the treatment of these lesions. While a randomized study would best
define the potential advantages of this treatment strategy, a retrospective
comparison to historical data may provide some practical insights. PATIENTS AND
METHODS: One hundred and six patients treated with EA + PTCA (Group 1) were
retrospectively compared to a historical subset of 101 patients treated with PTCA
alone (Group 2). Both groups presented with similar clinical profiles with
respect to gender, age, graft age, percent diameter stenosis, and location of the
target lesion. However, Group 1 had a significantly higher incidence of pre
procedure class III-IV angina than did Group 2 (92.4% vs. 70.3%, p < 0.002), and
more recent occlusions. Both groups were compared at one year for the presence of
angina, myocardial infarction, and death. Chi-square analysis was performed on
the categorical variables. RESULTS: At one-year follow-up, 62.1% of the Group 1
patients were free from cardiac events (defined as absence of angina, myocardial
infarction or death) and 58.9% of the Group 2 patients were event free (p =
0.78). A total of 27.0% of the Group 1 patients suffered from class I or Il
angina compared to 35.9% of the Group 2 patients (p = 0.40). A total of 10.8% of
the Group 1 patients had suffered a myocardial infarction compared to 28.2% of
the Group 2 patients (p = 0.06). A total of 2.7% of the Group 1 patients had died
compared to 10.5% of the Group 2 patients (p = 0.16). CONCLUSIONS: Patients with
recently occluded SVGs (within 3 months) and refractory angina (class III or IV)
treated with EA + PTCA have a similar clinical outcome at 1 year follow-up to a
historical population treated with PTCA alone, despite the higher incidence of
class III-IV angina, and more recent occlusions upon presentation. However, 1
year follow-up results reveal a trend towards less frequent myocardial
infarctions for patients treated with EA + PTCA than the historical group of
patients treated with PTCA alone (p = 0.06).
PMID- 10762911
TI - Pretreatment with Intracoronary Diltiazem Reduces Non-Q-Wave Myocardial
Infarction Following Directional Atherectomy.
AB - The Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) reported a
greater risk of non-Q-wave myocardial infarction (MI) with directional
atherectomy (DCA), although the specific mechanism was unclear. To assess the
possible role of microvascular spasm in creatinine phosphokinase (CPK) elevation
(> 2x normal) following DCA, 193 consecutive patients were given intracoronary
diltiazem (2-6 mg) prior to DCA. These patients were compared with a
retrospective control group of 400 consecutive patients who underwent DCA without
diltiazem (all 593 procedures performed by a single operator). The groups were
similar with respect to age, gender, clinical presentation and lesion morphology.
Comparative analysis revealed that clinical success and the need for emergency
bypass surgery was similar for each cohort. For patients who received
intracoronary diltiazem prior to DCA, there was a significant decrease in the
incidence of non-Q-wave myocardial infarction (2.7 vs. 6.8%, p =.04) and abrupt
closure (2.5 vs. 6.2%, p = 0.05). These findings suggest that intracoronary
diltiazem prior to DCA may result in a significant decrease in the rate of abrupt
closure and non-Q-wave MI. Adjunctive intracoronary diltiazem should be
considered in patients undergoing DCA.
PMID- 10762912
TI - A Case of Ehlers-Danlos Syndrome Type IV with Dilated Coronary Sclerosis and
Myocardial Infarction in a Young Man.
PMID- 10762913
TI - Coronary Angioplasty of Chronic Total Occlusions Using a New 0.014in. Nitinol
Glidewire with Platinum Coil.
PMID- 10762914
TI - New Stenosis of Left Circumflex Ostium Occurring Subsequent to Ostial Left
Anterior Descending Coronary Artery Stenting.
PMID- 10762915
TI - Left Anterior Descending Coronary Artery Angioplasty in a Seven-year-old Boy with
a Diffuse Idiopathic Dysplastic Arteriopathy.
PMID- 10762916
TI - The X Factor N Think About It.
PMID- 10762917
TI - The Histopathology of Angiographic Chronic Total Coronary Artery Occlusions N
Changes in Neovascular Pattern and Intimal Plaque Composition Associated with
Progressive Occlusion Duration.
AB - The current study describes the histopathology of angiographic chronic total
occlusions including residual lumen patency, intimal plaque composition, patterns
of neovascular channel formation, intimal plaque calcification, and cellular
inflammation, analyzed according to occlusion duration and intimal plaque type
(fibrocalcific vs. lipid laden vs. mixed). Histologic findings are related to
previously described clinical and angiographic predictors of successful chronic
total occlusion revascularization.
PMID- 10762918
TI - Intravascular Ultrasound Assessment of the Mechanisms and Predictors of
Restenosis Following Coronary Angioplasty.
AB - Restenosis occurs after 30% to 50% of transcatheter coronary procedures; its
mechanisms remain incompletely understood. Intravascular ultrasound (IVUS)
studies were analyzed in 360 nonstented native coronary artery lesions in which
follow-up quantitative angiographic and/or IVUS data was available. Pre
intervention, post-intervention, and follow-up, the external elastic membrane
(EEM) and lumen cross-sectional areas (CSA) were measured; plaque+media (P+M=EEM
D lumen CSA), and cross-sectional narrowing (CSN=P+M/EEM CSA) were calculated.
The anatomic slice selected for serial analysis had an axial location within the
lesion at the smallest follow-up lumen CSA. At follow-up, 73% of the decrease in
lumen CSA was due to a decrease in EEM CSA; 27% was due to an increase in P+M
CSA. The change in lumen CSA correlated more strongly with the change in EEM CSA
than with the change in P+M CSA. The change in EEM CSA was bidirectional; 47
lesions (22%) showed an increase in EEM CSA. Despite a greater increase in P+M
CSA, lesions exhibiting an increase in EEM CSA had (1) no change in lumen CSA,
(2) decreased restenosis, and (3) a 49% frequency of late lumen gain. The
independent clinical, angiographic, and IVUS predictors of angiographic
restenosis (3 50% diameter stenosis at follow-up) were the IVUS reference lumen
CSA, angiographic pre-intervention diameter stenosis, and post-intervention IVUS
CSN. Restenosis appeared to be determined primarily by the direction and
magnitude of the change in EEM CSA. An increase in EEM CSA was adaptive while a
decrease in EEM CSA contributed to restenosis. The most powerful predictor of
restenosis was the IVUS post-procedural CSN. The importance of the post
procedural CSN was related to the change in EEM CSA as a mechanism of restenosis.
PMID- 10762919
TI - Advances in Brachiocephalic Angioplasty.
PMID- 10762920
TI - Direct Angioplasty for Myocardial Infarction: One-Year Experience in a Center
with Surgical Back-up 220 Miles Away.
AB - AIMS: To report the outcome of patients undergoing angioplasty for myocardial
infarction in a general hospital in a city without cardiac surgery serving an
extended population of 500,000. The nearest cardiac surgical facilities are 220
miles away. METHODS AND RESULTS: Consecutive, unselected patients with myocardial
infarction associated/complicated by: cardiogenic shock (n=10), a
contraindication to thrombolysis (n=16), anterior site (n=27), stent or vein
graft thrombosis (n=7) or failed thrombolysis (n=11) comprised the study group
(n=71) who underwent angioplasty as a reperfusion strategy. In patients
presenting without cardiogenic shock, the primary procedural success rate
(absence of complications, TIMI 3 flow and a residual diameter stenosis <50%) was
93.4%. In those presenting in cardiogenic shock (CGS) the procedural success rate
was 40%. Seven patients (6 with CGS) died prior to hospital discharge for reasons
unrelated to the angioplasty procedure (6 progressive shock, one neurological
sequelae because of delayed resuscitation). Four additional patients had
recurrent infarctions, all were successfully treated by repeat PTCA. Two patients
were transferred emergently, by air, to the regional cardiothoracic unit in a
stable state in case surgery was required. In neither instance was this the
result of a direct complication of angioplasty. CONCLUSIONS: Direct angioplasty
for myocardial infarction may be safely performed by trained operators in centers
without nearby surgical backup.
PMID- 10762921
TI - Percutaneous Revascularization of Lower Extremity Arterial Disease in Females
Compared to Males.
AB - The outcome of percutaneous transluminal angioplasty (PTA) of lower extremity
peripheral arterial disease (PAD) in females is not well documented. Between June
1988 and June 1994, 206 patients underwent 293 PTA procedures for symptomatic
PAD. Females (63 patients, 97 PTA procedures) and males (143 patients, 196 PTA
procedures) were analyzed and compared. Female patients were older than male
patients, had lower prevalence of coronary artery disease and were more often
hypertensive. Both groups had similar prevalence of diabetes, hyperlipidemia and
cigarette smoking. Success rate in females was 98% versus 96% in males for all
lesions (p = NS), and 96% versus 81% (p < 0.003) for occluded vessels.
Complication rates were low and did not differ significantly between groups, with
the exception of the need for blood transfusions (3% versus 0%, p < 0.05, females
versus males). At a mean follow-up of 25 +/- 20 months, 60% of female patients
and 77% of male patients claimed symptomatic improvement (p < 0.05). There was no
gender-related difference in the subsequent PTA or bypass surgery. We conclude
that PTA appears to be an effective treatment modality for symptomatic PAD in
female patients which can be performed at very low risk.
PMID- 10762922
TI - The AVE Micro Coronary Stent as a Bailout Device.
AB - Vessel closure following percutaneous transluminal coronary angioplasty (PTCA)
remains an important source of morbidity and mortality. In this study we have
evaluated the AVE Micro stent in the management of the bailout situation
following angioplasty. All patients with abrupt vessel closure or threatened
abrupt vessel closure managed with this device were included in the study
population. Between January 1995 and January 1996, 86 consecutive patients with
abrupt or threatened abrupt vessel closure following PTCA were managed with the
AVE Micro coronary stent. Fifty-seven patients were male, the mean age was 60
years (range 32-76). Three patients had acute myocardial infarction and 58 had
unstable angina. Six had a left ventricular ejection fraction of less than 30%. A
total of 109 stents were implanted in 86 patients. There was one procedural
failure. One patient died following emergency CABG. Emergency CABG was required
in an additional two cases, both had a significant rise in CK (MB). Non-Q-wave
myocardial infarction occurred in an additional five patients (6%). Subacute
stent thrombosis occurred in six cases (7%). Major vascular complications
occurred in three patients (4%), necessitating surgical repair of the femoral
artery in two. Sixty-one patients (72%) had a 30 day event-free survival. The
mean duration of hospital admission was 7 days (range 4-30 days). In conclusion,
the AVE Micro coronary stent is an effective device in the management of abrupt
and threatened abrupt vessel closure following PTCA. Its use is associated with a
high procedural success rate and a relatively low complication rate.
PMID- 10762923
TI - Balloon Angioplasty for Native Coarctation of the Aorta: Acute and Mid-Term
Results.
AB - BACKGROUND: Balloon angioplasty is an accepted treatment for recurrent
coarctation of the aorta. Application of this technique to patients with native
coarctation is controversial. OBJECTIVE: To report on the immediate and mid-term
results of this procedure in patients with native coarctation, including infants
<6 months of age. METHODS AND RESULTS: Twenty-four children underwent balloon
angioplasty of their coarctation at a median age of 2 yr. (range 2 weeksD14.7
yr.) and median weight of 13 kg (range 3D64 kg). The mean peak systolic gradient
across the coarctation decreased from 40 +/- 14 to 9 +/- 6 mmHg (p < 0.001) and
the mean diameter of the narrowest area improved from 4.1 +/- 2.1 to 7.5 +/- 2.5
mm (p < 0.001). Four patients had recurrence of their coarctation, 3 of whom were
< 3 months of age. Two of these patients had successful repeat dilation. At a
mean follow-up interval of 2.4 +/- 1.7 years, one patient (4%) developed an
aneurysm. Three patients underwent surgical repair (two for recurrence and one
for resection of the aneurysm). The remaining patients (87.5%) are normotensive
with mean peak systolic gradient between the right arm and the lower extremity of
4 +/- 9 mmHg. CONCLUSION: Balloon angioplasty for native coarctation is an
effective and safe method for most patients with coarctation. Repeat dilation is
possible and surgical repair of an aneurysm is safe.
PMID- 10762924
TI - Rotablator Guide Wire Thrombosis Due to Inadequate Anticoagulation.
PMID- 10762925
TI - Reversible Severe Mitral Regurgitation Provoked by Reversible Myocardial Ischemia
N Abolition by Coronary Artery Stenting.
PMID- 10762926
TI - Thrombotic Occlusion of Coronary Stents after Prolonged Balloon Inflation Outside
the Stent.
PMID- 10762927
TI - Acute Coronary Intervention in a Young Patient with a Massive Thrombus in a Giant
Coronary Aneurysm Due to Kawasaki Disease.
PMID- 10762928
TI - Newer Stents: Materials and Designs.
AB - We aim to present here the experience with newer stents for coronary and
peripheral interventions. Specifically, the design and technical considerations
of the self-expanding nitinol coil stents for coronary and vascular indications,
as well as the design and clinical experience with the tubular stainless steel
balloon-expandable serpentine stents for coronary and peripheral interventions
are discussed. The animal and clinical experience with both types of stent have
shown that the mechanisms of deployment and expansion are different for these
inherently different stents. The self-expanding coil stent, providing adequate
scaffolding in various types of coronary lesions is deployed by self expansion,
aided to a significant extent by balloon expansion. Long-term outside pressure on
the wall may lead to further stent expansion as has been shown with this stent,
which may be an important parameter in the restenosis process. The tubular
balloon-expandable serpentine stent does not have the feature of long-term
expansion, however, is characterized by superior scaffolding properties and
unique features that allow its safe use in the most complex coronary diseases.
Long-term clinical results are pending for these two families of stents.
PMID- 10762930
TI - Applied Cerebrovascular Anatomy/Pathology.
PMID- 10762929
TI - Initial and Long-Term Results of Treatment of Brachiocephalic Arterial Stenoses
and Occlusions with Balloon Angioplasty, Thrombolysis, Stents.
PMID- 10762931
TI - Reduced Anticoagulation with Antiplatelet Therapy Alone is Safe and Effective
after "Bail-Out" Stenting for Failed Angioplasty.
AB - The aim of this retrospective study was to compare the safety and efficacy of
antiplatelet therapy alone with conventional anticoagulation with warfarin after
Obail-outO coronary stenting for failed balloon angioplasty at a tertiary
referral centre. Eighty-two consecutive patients undergoing Obail-outO stenting
over a 22-month-period were studied. Forty patients received antiplatelet therapy
alone with aspirin and ticlopidine and 42 patients received anticoagulation with
warfarin for 30 days. The main outcome measures examined were death, myocardial
infarction, coronary artery bypass surgery, repeat angioplasty, and significant
vascular complications. The angiographic procedural success rate was 100% in both
groups. At six weeks there were no deaths and no patient required emergency
coronary artery bypass surgery in either group. There were three (7.1%, p = NS)
stent thromboses and two (4.8%, p = NS) Q-wave myocardial infarctions in the
warfarin group as compared to none in the antiplatelet group. There was a
significantly higher incidence of vascular complications in the warfarin group
(21.4% vs. 0%, p = 0.004). The length of hospital stay was significantly shorter
in the antiplatelet group [3.4 (2.0) vs. 7.8 (2.6) days, p < 0.001]. This study
suggests that reduced anticoagulation with antiplatelet therapy alone after Obail
outO stenting is an effective and safe strategy which reduces vascular
complications and hospital stay without increasing the rate of stent thrombosis.
PMID- 10762932
TI - The Varying Behavior of Stent Thrombosis in Native Coronary Arteries Versus Aorto
Coronary Saphenous Vein Bypass Grafts.
AB - Out-of-lab closure due to stent thrombosis is a major limitation of stent
implantation. In this report, the incidence of stent thrombosis in native
coronary arteries is compared to saphenous vein bypass grafts. Elective stent
placement was performed in 1,782 patients. Overall, stent thrombosis occurred in
64 (3.6%) of patients. There was a significantly higher incidence of stent
thrombosis in native coronary arteries (56/1153, 4.9%) compared with venous
bypass grafts (8/629, 1.3%), (p < 0.0001). Multivariate analysis demonstrated
vessel size to be the most important predictor of stent thrombosis. We conclude
that stent thrombosis occurs less frequently in vein bypass grafts and that the
risk in the native circulation is inversely related to vessel size.
PMID- 10762933
TI - Thrombin Generation and Activity During Coronary Angioplasty: Influence of
Angiographic Lesion Morphology.
AB - OBJECTIVE: To investigate the relationships between coronary atherosclerotic
plaque injury, lesion morphology, and activation of the coagulation cascade.
BACKGROUND: Balloon angioplasty of coronary lesions may result in intracoronary
thrombin generation and activity. It is unknown whether the angiographic
morphology of the lesion prior to intervention, an indicator of the presence of
thrombus in the lesion, is a determinant of the degree of coagulation cascade
activation. METHODS AND RESULTS: Biochemical markers of thrombin generation
(prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A; FPA) were
measured in coronary blood before, 1 and 10 minutes after percutaneous
transluminal coronary angioplasty (PTCA) in 24 patients with an angiographically
complex lesion morphology and 24 patients with an angiographically simple lesion
morphology. Using previously defined criteria, 18 of the 48 patients (38%)
demonstrated a significant rise in coronary plasma F1+2; 8 of these 18 (44%) had
simple and 10 of 18 (55%) had complex angiographic lesion morphologies (p=NS).
With respect to thrombin activity, 15 of the 48 patients (31%) demonstrated a
significant rise in coronary plasma FPA; 7 of these 15 patients (47%) had a
simple lesion morphology and 8 (53%) had a complex morphology (p=NS). When
analyzed as a group, patients with complex lesion morphologies demonstrated a
small elevation in coronary plasma levels of FPA 10 minutes post-PTCA (median 3.2
ng/ml, 95% CI 2.4D5.8 ng/ml) in comparison to the levels measured proximal to the
lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.6D3.5 ng/ml; p=0.05). In contrast, in
the group of patients with simple lesion morphologies, the plasma FPA levels
proximal to the lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.5 to 3.9 ng/ml) were
similar to those measured 10 minutes after the procedure (median 2.0 ng/ml, 95%
CI 1.5 to 6.3 ng/ml; p=NS). CONCLUSIONS: In comparison to patients with
angiographically complex lesions, patients with angiographically simple lesions
demonstrate a similar incidence (~33%) of elevated coronary plasma thrombin
generation (F1+2) and activity (FPA) after PTCA. As a group, patients with
angiographically complex lesions (irregular borders, overhanging edges, filling
defects) demonstrate a slightly greater increase in thrombin activity in
comparison to patients with simple lesion morphologies. Percutaneous coronary
interventions of lesions with a wide variety of angiographic morphologies are
prone to result in activation of the coagulation cascade.
PMID- 10762935
TI - Three Vessel Coronary Revascularization as a Single Percutaneous Procedure.
PMID- 10762934
TI - Improvement of Left Ventricular Function and Wall Motion Abnormalities after
Recanalization of Total Occlusion of Left Anterior Descending Coronary Artery by
Percutaneous Transluminal Coronary Angioplasty.
AB - PTCA was performed in 262 consecutive patients (pts) with total LAD occlusion.
TIMI 3 flow was established in 164 pts (success rate was 62.6%). After 4D6 months
a follow-up angiography of 72 pts showed restenosis in 39 pts (restenosis rate
was 54.2%). In 33 pts without restenosis there was a significant increase in
ejection fraction (EF) (54.6 +/- 15 versus 59.8 +/- 18.1 before and after PTCA
respectively, p = 0.02). Improvement of wall motion abnormalities (WMA) in 12 of
26 pts was observed. Anterolateral-apical (AL-A) aneurysm disappeared in 6 pts
and limited to apex in 2 pts. AL-A hypokinesia in 3 and akinesia in 1 reversed to
normal wall motion (NWM). There was not a significant change in EF in either of
the groups of pts with reocclusion (24 pts) or restenosis (15 pts) (p > 0.05).
However, AL-A aneurysm disappeared in 2 of 12 pts with WMA before PTCA although
there was restenosis (but TIMI 3 flow) on follow-up coronary angiogram. In 3 pts
with restenosis but not reocclusion AL-A hypokinesia, akinesia and apical
dyskinesia returned to NWM. No significant changes were observed in the left
ventricular end diastolic pressures (LVEDP) in both pt groups with or without
improvement of WMA(p > 0.05). Filling fractions (FF) did not change in patients
with or without restenosis. CONCLUSION: The observations in patients with
successful total LAD occlusion angioplasty and no restenosis are as follows: 1)
There was a significant increase in EF; 2) There was no significant decrease in
LVEDP and no increase in FF; 3) The rate of improvement of WMA was 46.2%; 4)
There was no relation between improvement of WMA and the age of occlusion, the
grade of coronary collateral vessels and involvement of other coronary arteries.
However, it has been emphasized that in 11 of 12 pts (91.6%) with improvement of
WMA the age of occlusion was < 3 months, in 10 (83.3%) the grade of coronary
collateral vessels was 2 or 3 and in 10 (83.3%) the other coronary arteries were
normal. The improvement of WMA in 41.6% of pts. who had also subtotal restenosis
but not reocclusion was observed. Finally in 72 pts with follow-up coronary
angiography, the rate of improvement of wall motion was 23.5 %.
PMID- 10762936
TI - Occlusion of a Large Coronary to Pulmonary Communication with Coil Embolization
Technique.
PMID- 10762937
TI - Crimped Stent-Induced Pin Hole Rupture of Balloon Resulting in Extensive Coronary
Dissection.
PMID- 10762938
TI - Emergency Stenting for Complete Thrombosis of an Unprotected Left Main Coronary
Artery in Evolving Myocardial Infarction.
PMID- 10762939
TI - Implantable Cardioverter-Defibrillator Implantation in the Electrophysiology
Laboratory by Electrophysiologists.
AB - Recent developments in implantable cardioverter-defibrillator (ICD) technology
have helped simplify the surgical implantation technique of these devices. There
has been a marked reduction in the size of these devices making them easier to
implant pectorally. In addition ICDs have enhanced longevity and a more facile
transvenous lead system. Surgical implantation is almost identical to the
procedure used for permanent pacemaker implantation in conjunction with the
performance of a short electrophysiologic/arrhythmia induction protocol. In
general, the average implant time is approximately one hour and in our series
minimal morbidity and no mortality was identified. In conclusion, ICDs can be
safely and effectively implanted in the electrophysiology laboratory by
electrophysiologists in a timely and cost-effective manner. These implant
procedures can help to shorten the length of stay and improve the operating room
utilization for more critical procedures.
PMID- 10762941
TI - The Last Physician? OThe Parable of the Last PhysicianO
PMID- 10762940
TI - First Person Singular N Me Thinks Thou Protests Not Enough.
PMID- 10762942
TI - Experimental Results with the Multi-Linka Stent in a Porcine Model.
AB - OBJECTIVES: The purpose of this study was to assess the delivery characteristics
and the vascular response to placement of the Multi-Linka stent in normal porcine
coronary arteries. BACKGROUND: The Multi-Link stent is a balloon expandable
stainless steel stent with an interconnected corrugated ring structure designed
to provide a high degree of compressive resistance while preserving longitudinal
flexibility. The placement characteristics and vascular response to this stent in
normal porcine coronary arteries has not been characterized. METHODS: We tested
the delivery characteristics and vascular response to the Multi-Link stent in 19
normolipemic miniature swine. Quantitative coronary angiography was used to
define stent performance characteristics such as stent expansion and recoil.
Histologic assessment of the stented arteries was used to evaluate the acute and
chronic vascular response to stent placement. RESULTS: Thirty-five of thirty-five
stents (100%) were successfully implanted in the left anterior descending (n =
14), left circumflex (n = 8) or right (n = 13) coronary arteries of nineteen
swine. The baseline angiographic mean lumen diameter of the stented coronary
segment was 3.41 +/- 0.32 mm and increased to 3.53 +/- 0.33 mm (p < 0.001) after
stent placement. The balloon inflated stent diameter was 3.61 +/- 0.36 mm with
minimal recoil to a final minimal lumen diameter of 3.53 +/- 0.33 mm after
implant (p = 0.001). Linear regression analysis revealed that the percent stent
recoil had a significant positive correlation with the stent to artery ratio or
the degree of stent over-sizing (r = 0.67; p < 0.0001). Angiographic and
histologic follow-up at 72 hours (n = 9), 14 days (n = 12) and 56 days (n = 12)
demonstrated that all stents were patent without evidence of migration,
intraluminal filling defect or side-branch occlusion. On histology, there was
rare evidence of stent-induced deep arterial wall injury such as rupture of the
internal elastic lamina and medial laceration. There was no significant
difference in the mean injury score observed on day 3 (0.23 +/- 0.22), 14 (0.35
+/- 0.28) or 56 (0.36 +/- 0.27) after implant (p = 0.27). On day 3, the mean
thrombus thickness overlying the stent wires was 70 +/- 98u. The mean neointimal
area was similar at 14 and 56 days after implant (1.63 +/- 1.25 mm2 versus 1.78
+/- 0.68 mm2, p = 0.54). CONCLUSIONS: The MULTI-LINK stent easily tracked the
coronary arteries and deployed reliably in this experimental model. The multiple
interconnected ring geometry of the stent provides adequate compressive
resistance, longitudinal flexibility and uniform coverage of the arterial wall
throughout the length of the endoprothesis. The stent has acceptable blood and
tissue biocompatibility in normal porcine coronary arteries. Oversizing this
stent (>10 percent) may have a theoretical disadvantage resulting in a
proportionally higher degree of stent recoil. The results of clinical trials will
determine if the design features of the Multi-Link stent favorably impact on
procedural outcome or long-term patency.
PMID- 10762943
TI - Diagnostic Brachial Coronary Arteriography Using a Power-Assisted Injector and 4
French Catheters with New Shapes.
AB - BACKGROUND: Right brachial access in diagnostic coronary arteriography (CAG) has
demonstrated advantages over femoral approaches, including earlier ambulation and
more predictable hemostasis, particularly when small diameter catheters were
used. Poor results from some earlier reports of brachial CAG have been due
partially to the need to use large diameter catheters for positional control.
Technical advances in catheters and contrast injection may increase the utility
of brachial access CAG. PURPOSE AND STUDY DESIGN: We evaluated three 4 French
(Fr) catheters with new shapes and with a large internal to external diameter
ratio that were designed to overcome previous limitations to brachial CAG.
Contrast agent was delivered with a novel power injector (CAG-20) intended for
arteriography using small catheters. Routine right brachial access CAG and left
ventriculography (LVG) were evaluated in 2663 (69%) of 3880 consecutive patients
admitted for examination from 1991 to 1995. The study population included 128
patients (5%) with left main trunk disease, 819 (21%) with old myocardial
infarctions and 1747 (66%) with more than one vessel disease. For this trial,
1217 patients with valvular disease, ischemia associated with aortic or
peripheral vascular disease, congenital cardiac disease and post-surgical and
emergency catheterization were excluded because femoral access or a larger
catheter (> 4 Fr) were required in those cases. RESULTS: A total of 2573 (97%)
diagnostic quality CAG (> grade 3/5) were obtained solely with 4 Fr catheters
placed via the right brachial artery. Of the other 66 examinations, 50 were
completed through the brachial route but with alternate size or shape catheters
and 16 cases required the femoral JudkinOs technique. Useful LVG (> grade 2/4)
were obtained from 2604 patients (98%). Overall, 2536 (95%) of cases provided
clinically valuable images for both CAG and LVG from brachial access. We
experienced one semi-emergency bypass operation and one emergency stent
implantation caused by coronary dissection. There were no deaths, acute
myocardial infarctions, loss of pulse or nerve injuries. CONCLUSION: Power
injector assisted, brachial 4 Fr CAG and LVG proved to be safe and cost
effective. Brachial access has the potential to become a routine method for out
patient cardiac opacification.
PMID- 10762945
TI - Stenting of an Unprotected Ulcerated Left Main Coronary Artery in the Setting of
Acute Myocardial Infarction.
PMID- 10762946
TI - Dual Left Anterior Descending Arteries with a Right Coronary Artery Origin.
PMID- 10762944
TI - Late Clinical Outcome after Intracoronary Palmaz-Schatz Stenting with High
Pressure Balloon Dilation without Anticoagulation.
AB - In recent studies, the technique of high pressure balloon dilation for stent
optimization has been shown to improve procedural success and to reduce subacute
closure after stenting. The late clinical outcome, however, is still uncertain
after stenting with high pressure balloon dilation. Therefore, we evaluated the
effect of high pressure balloon dilation on the subsequent clinical course in
patients after intracoronary stenting. One-hundred ninety patients with 197
lesions were treated with Palmaz-Schatz stent implantation. Intracoronary
stenting without high pressure balloon dilation and with anticoagulation was
performed in 55 patients with 55 lesions (phase 1), whereas intracoronary
stenting with high pressure balloon dilation, without anticoagulation was done in
135 patients with 142 lesions (phase 2). We compared the angiographic and
clinical results immediately and at follow-up in both phase 1 and phase 2.
Coronary angiography was repeated at 6 months in 147 patients (79%) and 150
lesions (77%). The overall incidence of angiographic restenosis was 24% (31% in
phase 1 and 21% in phase 2). Angiographic restenosis occurred in 18% of elective
stenting on de novo lesions (23% in phase 1 and 15% in phase 2). The target
lesion revascularization rate was 19% (26% in phase 1 and 16% in phase 2). The
restenosis rate was significantly reduced with high pressure balloon dilation in
the infarct-related artery and for a stent size of 3 4.0 mm (p < 0.05). In
conclusion, intracoronary stenting using high pressure balloon dilation technique
without anticoagulation has good immediate results, negligible stent thrombosis
and may have a tendency towards lower rates of restenosis.
PMID- 10762947
TI - Treatment of a Long Segment of Symptomatic Myocardial Bridging with Multiple
Coronary Stents.
PMID- 10762948
TI - Atherosclerotic Renovascular Disease: Prevalence, Natural History, Noninvasiveive
Diagnosis and Endovascular Therapy Using Palmaz Stents.
AB - Atherosclerotic renovascular disease (RVD) occurs with a high prevalence in older
patients who have severe hypertension and other vascular disease. Natural history
studies of RVD have demonstrated progression with risk for occlusion. RVD leading
to ischemic nephropathy and renal failure accounts for up to 14 % of all patients
over the age of 50 years who are beginning dialysis. A number of clinical
variables are helpful in identifying patients with a high likelihood of RVD. In
addition, screening with noninvasiveive studies including renal artery duplex
exam, as well as with abdominal aortography at the time of coronary angiography,
may be warranted in patients at high risk for RVD. Balloon angioplasty for ostial
RVD has produced disappointing results, and surgical bypass has been associated
with significant morbidity and mortality risks, especially in elderly patients
with generalized atherosclerosis. The recent use of Palmaz stents as primary
therapy for ostial RVD has resulted in restenosis rates as low as 8 %, with
markedly reduced risks compared to surgery. Suggested guidelines for screening
for RVD by performing abdominal aortography at the time of coronary angiography
are outlined, along with a review of the preliminary data available regarding the
use of Palmaz stents for ostial RVD.
PMID- 10762949
TI - Exercise-Induced Atrioventricular Block Revisited: Case Report and Review.
AB - Exercise causes enhanced sympathetic discharge and results in physiologic
tachycardia. However, in certain patients with a diseased conduction system,
exercise can precipitate heart block. The sinus and atrioventricular nodes are
innervated by the autonomic nervous systems. The His-Purkinje system is
relatively devoid of autonomic nerve supply. Hence the former and not the latter
is influenced more by autonomic stimulation. During exercise, conduction improves
across the atrioventricular node which can stress the His-Purkinje system and
lead to heart block in those with significant His-Purkinje disease. In this
report, we discuss a recent case of exercise-induced heart block confirmed by
electrophysiology study and briefly review this subject.
PMID- 10762950
TI - Results of a Meta-Analysis of Trapidil, a PDGF Inhibitor N A Sufficient Reason
for a Second Look to the Pharmacological Approach to Restenosis.
AB - Restenosis in 30%D40% of patients remains the major limitation to the long-term
success of balloon angioplasty (PTCA) in patients with coronary artery disease.
So far, only coronary stent implantation has established its role as an effective
strategy to prevent restenosis after PTCA. In contrast to numerous
pharmacological strategies that all have failed to demonstrate a convincing
reduction in the rate of restenosis, trapidil, a PDGF inhibitor, has shown
promising and conclusive results in animal models as well as in three human
trials published between 1992 and 1994. Although the results of the human trials
showed trapidil to be capable of reducing restenosis after PTCA by 40%D53%
compared to control patients, the compound is not well known and little used in
interventional cardiology. Possible explanations for this situation may include
trapidilOs non-availability in the United States and most European countries, the
small number of trapidil trials and treated patients, as well as a probable
perception of the medical community that a pharmacological approach to restenosis
prevention is unlikely to work. Additionally, clinical expert behavior has often
shown not to be synchronized with accumulating evidence of efficacy. The results
of this meta-analysis, however, demonstrate trapidilOs efficacy. The rate of per
patient restenosis in the trapidil group was more than halved as compared to
controls (odds ratio 0.44, 95% confidence interval 0.29D0.66). Tolerability with
trapidil was good, and the rare adverse events observed included gastric
intolerance, thrombocytopenia, headache, and increased serum AST and ALT levels
which were transient or subsided with cessation of treatment.
PMID- 10762951
TI - Total Endovascular Reconstruction of Occluded Saphenous Vein Grafts Using
Coronary or Peripheral Wallstents.
AB - Degeneration of saphenous vein grafts (SVG) resulting in severe stenosis and,
ultimately, occlusion is common. Re-do bypass grafting is less successful than
the original operation. Intervention with balloon angioplasty alone has poor long
term results, and although improved long-term benefit has been demonstrated with
stenting, most stents are limited by their diameter and length. The self
expanding Wallstent has a number of properties that make it particularly suitable
for this purpose. We reviewed 26 patients, mean age 64.9 years, 24 males, who had
Wallstents deployed in totally occluded or severely obstructed SVG. Seven
patients had total graft occlusion, all patients had severe diffuse graft body
disease. The mean length of Wallstent used was 54.1 mm. Routine anti-coagulation
protocol was used. There were 2 major initial adverse events and no further in
hospital complications. Mean follow-up was 18.8 months. A total of 3 major late
clinical events were identified. We conclude that coronary or peripheral
Wallstents should be considered for the management of these patients.
PMID- 10762952
TI - The Radial Artery: An Applicable Approach to Complex Coronary Angioplasty.
AB - The purpose of this study was to assess the clinical value of the transradial
approach (TRA) in coronary angioplasty. During the 18Dmonth period from June 1994
to December 1995, 250 patients (mean age 61 +/- 11) underwent coronary
angioplasty using the transradial approach. In 7 (2.8%) radial puncture was
unsuccessful and in 6 (2.4%) additional femoral access was needed to complete the
procedure. Ninety patients (36%) had angioplasty of two or three vessels and
49.5% had type B2 or C lesions. Sixty-five patients (22%) had additional
procedures: stent implantations in 50 (16%) and rotational ablation in 15 (6%).
Angiographic success was 97% and there were no deaths. Major procedural
complications included: Q-wave myocardial infarction in 2 (0.8%), non-Q-wave
myocardial infarction in 5 (2.0%), urgent coronary artery bypass grafting in 2
(0.8%) and CVA in 2 (0.8%). Local vascular complication included: compartment
syndrome necessitating fasciotomy in 1 patient (0.4%), mild hematoma in 6 (2.4%)
and a small pseudo-aneurysm treated by local compression in 4 (1.6%). Radial
pulse was palpated in 93% before discharge and in 3% adequate flow could be heard
with Doppler. No patient suffered from ischemia of the hand. Complex coronary
angioplasty can be performed safely using the TRA with few vascular
complications.
PMID- 10762954
TI - Stenting of Myocardial Bridging.
PMID- 10762953
TI - The Falcona Eccentric Coronary Balloon Angioplasty Catheter: A Randomized Safety
and Efficacy Study.
AB - Percutaneous coronary angioplasty (PTCA) is usually performed using concentric
shaped balloon catheters with the guidewire passing through the center of the
shaft. The Falcona balloon catheter features a guide wire lumen on the outside of
the balloon so that an eccentric balloon catheter profile is obtained
concentrating the dilating force on the wire supported side, allowing lower
inflation pressures and potentially causing less vessel injury. The aim of this
study was to evaluate the safety and efficacy of this new balloon catheter in
patients with stable and unstable angina. In 95 prospectively randomized
patients, 57 lesions were dilated with a concentric balloon and 51 with the
eccentric balloon. Technical success in the two groups was similar (73.3% vs.
74.5% control vs. Falcon respectively). Procedural success was 96.5% vs. 96.1% in
the control and Falcon groups respectively. The mean increase in minimum luminal
diameter (MLD) was 1.01 +/- 0.41 mm in the control vs 0.85 +/- 0.45 mm in Falcon
(p = 0.053). There was an increase in type A dissections in the Falcon group 18
(36.75%) vs. 10 (19.23%) in the control group (p = 0.07) with no difference in
stent implantation, myocardial infarction, CABG or death between the two groups.
All patients with a technically successful PTCA were followed up. Seventeen
(43.6%) in the control and 11 (32.4%) in the Falcon had repeat coronary
angiography (p = 0.38), 12 (30.8%) vs. 7 (20.6%) had repeat PTCA (p = 0.37) and
time to PTCA was 116 +/- 70 days vs. 154 +/- 103 days respectively (p = 0.36).
The Falcon performed technically as well as the concentric balloons. Despite a
smaller MLD and increase in Type A dissections there was no associated increase
in complications or reintervention for restenosis. Further investigation is
required to evaluate the role of this mechanism of dilatation in restenosis.
PMID- 10762955
TI - Stent Implantation for Coronary Artery Stenosis after Kawasaki Disease.
PMID- 10762956
TI - Percutaneous Stent Treatment for a Spontaneous Coronary Pseudoaneurysm.
PMID- 10762958
TI - Legal Ramifications of Physician-Hospital Equity Ventures.
PMID- 10762957
TI - Unexpected Progressive Opacification of the Ascending Aorta During Coronary
Angioplasty: Diagnostic and Therapeutic Sequelae.
PMID- 10762959
TI - Tiptoeing Through the Legal Tulips N Our Collective Character.
PMID- 10762960
TI - Why Are We (or OWire WeO) Doing This? A Modern Electrophysiology Case.
PMID- 10762961
TI - Clinical and Angiographic Results with the Multi-Linka Coronary Stent System N
The West European Stent Trial (WEST).
AB - BACKGROUND: The objectives for the West European Stent Trial (WEST) were to
assess the safety and efficacy of the new ACS Multi-Linka coronary stent system
with regards to bleedings and vascular complications and incidence of major
adverse cardiac events during 12 months follow-up. METHODS AND RESULTS: The
balloon-expandable Multi-Link stent is made from a single hypotube and is
composed of 316 L stainless steel. In an open, non-randomized, multicenter
registry, 102 patients with angina pectoris to be treated with this stent were
recruited from 7 European centers. Following stent implantation, patients were
given heparin infusion and oral coumadin treatment was maintained for 3 months.
Procedural success was achieved in 100 of the 102 patients (98%). One patient had
subacute stent thrombosis and 6 patients had major bleeds during the hospital
stay. All patients were alive at 12 months and 85% were free of angina pectoris.
Nineteen patients (19%) reached a primary clinical endpoint; four patients
underwent bypass surgery (two in connection with the stent procedure), four
patients suffered an acute myocardial infarction and 11 had a repeat angioplasty
of the target vessel. Quantitative angiography showed that the minimum lumen
diameter had decreased from 2.66 +/- 0.34 mm after stent deployment to 2.02 +/-
0.58 mm at 6 months and the percent diameter stenosis had increased from 18 +/-
7% to 33 +/- 16%. The in-stent restenosis rate was 12% and appearance of a
stenosis in the target vessel outside the stent occurred in an additional 5%.
CONCLUSION: The WEST study has demonstrated a high degree of safety and efficacy
of the Multi-Link stent with a low incidence of complications and clinical events
during follow-up. The results compare favorably with data from other stents.
PMID- 10762962
TI - Transradial Coronary Stenting: A United States Experience.
AB - Coronary stenting is associated with increased vascular complications and
prolonged length of stay compared to balloon angioplasty. One strategy to address
these concerns is performing the coronary stent procedure via the radial artery
access site. The current study reviews the results of transradial coronary
stenting in 300 patients in a United States hospital setting. All patients who
underwent transradial coronary stent implantation at our center were included in
the study. Procedural success, clinical events, vascular complications, post
procedure length of stay, and hospital charges were evaluated. Transradial
coronary stenting was successfully performed in 283 of 300 patients (95%),
although a significant learning curve was present. Nine complications occurred in
the first 100 patients with only two in the last 100 patients. Unsuccessful
procedures were due to inability to cross lesion in 3 patients (1%), emergency
CABG in 6 patients (2%), stent embolization in 7 patients (2.3%), and 1 death
(0.3%). Only one minor vascular complication occurred. The study confirms that
transradial coronary stenting is feasible and safe, although new operators should
be aware of potentially serious complications of the bare stent technique.
Findings support the use of this alternative access site for coronary stenting in
selected patients.
PMID- 10762963
TI - Percutaneous Transvenous Mitral Commissurotomy Without Heparin.
AB - Six-hundred twenty-nine patients with rheumatic mitral stenosis in normal sinus
rhythm underwent percutaneous transvenous mitral commissurotomy (PTMC) by the
standard Inoue balloon technique. All patients underwent transthoracic
echocardiography, when necessary, transesophageal echocardiogram was done before
PTMC to exclude left atrial clot. In all cases, the PTMC procedure was completed
without administration of heparin. There was no incidence of embolism either in
the immediate post-procedure period or at a median follow-up of 3 months. There
were no femoral artery or venous complications in any of the cases. We conclude
that the conventional use of heparin during PTMC may not be required in patients
with sinus rhythm and no left atrial clot.
PMID- 10762964
TI - Cardiopulmonary Resuscitation and Direct Cardiac Injury: Evidence of Fractured
Coronary Arteries and HIS Bundle Hemorrhage.
AB - The heart is believed to escape serious direct injury during the administration
of closed chest cardiopulmonary resuscitation (CPR). However, no comprehensive
histologic studies of the coronary arteries or the atrioventricular conduction
system have been performed to determine whether these structures might be injured
by CPR. This report includes a retrospective review of 105 human hearts
extensively studied at autopsy after the injection of a colored barium gelatin
mass into the coronary arteries. The study group, 83 males and 22 females,
included 63 patients (60%) who died in the hospital. Eighty patients (76%)
received CPR immediately prior to death. Evidence consistent with direct blunt
injury to the coronary arteries and/or the His Bundle was found in 35 (44%)
patients who received CPR. These structural changes were characterized by
fracture and disruption of the coronary artery wall and/or hemorrhage into the
region of the branching His Bundle. Females were significantly older and showed a
significantly higher frequency of these lesions than males. Injuries were not
related to the site where CPR was administered, in- or out-of-hospital, nor to
the duration of CPR. We conclude that CPR is associated with evidence of direct
blunt injury to the coronary arteries and/or the His Bundle and proximal bundle
branches; and that these lesions may influence the outcome of resuscitative
efforts as well as ultimate prognosis.
PMID- 10762965
TI - Isolated Right Ventricular Infarction Following Right Coronary Artery Stent
Implantation in Patients with Recent Inferior Myocardial Infarction.
PMID- 10762966
TI - Bailout Bifurcation Stenting Involving AngioStent Through the Struts of AVE
MicroStenta
PMID- 10762967
TI - The Evolving Picture of High Risk Coronary Artery Intervention.
PMID- 10762968
TI - Head-Up Tilt Test (HUTT) in Patients with Episodic Bradycardia and Hypotension
Following Percutaneous Coronary Interventions.
AB - We investigated the possible association of post catheterization
hypotension/bradycardia and neurocardiogenic syncope. Head up tilt test (HUTT)
was performed in 12 consecutive patients (age 32D65 years) who developed
transient hypotension (systolic blood pressure < 80 mmHg) and/or bradycardia
(heart rate < 50/min) with or without syncope following a percutaneous coronary
intervention. Ten patients had undergone percutaneous transluminal coronary
angioplasty (PTCA) with stent implantation and one each PTCA alone and diagnostic
coronary angiography. This event occurred at the time of sheath removal in 7
patients (58%). HUTT was performed with and without intravenous edrophonium (10
mg intravenous). The tilt test was negative in all patients. Post-catheterization
hypotension/bradycardia responds promptly to conservative measures and it is
unclear whether this is related to neurocardiogenic syncope.
PMID- 10762970
TI - The Need for a New Way of Doing Practice N Really? The Power of N = 1 Revisited.
PMID- 10762969
TI - To Tilt or Not to Tilt, That is the Question?
PMID- 10762971
TI - A Critical Appraisal of Decision Analytic Models to Evaluate the Cost
Effectiveness of Stenting.
PMID- 10762972
TI - New Perspectives on the Cost-Effectiveness of Palmaz-Schatza Coronary Stenting,
Balloon Angioplasty, and Coronary Artery Bypass Surgery N A Decision Model
Analysis.
AB - We developed an outcomes model to compare both the clinical effects and cost
effectiveness of the following strategies for treating patients with single (SVD)
and multi-vessel (MVD) coronary artery disease: coronary stent implantation
(CSI), balloon angioplasty (PTCA), and coronary artery bypass surgery (CABG).
These analyses have been carried out in five European countries: France, Germany,
Italy, The Netherlands, and Spain, accounting for approximately 75% of
revascularization procedures performed in Europe. This paper describes the
methodology, details the model, discusses input data, and reports on clinical
outcomes. Country-specific data and findings are reported in five OsatelliteO
papers to this communication. The clinical outcomes predicted in our model are
different from those of earlier studies in that we have found stenting to be
clinically more superior to PTCA in terms of improving event-free survival than
previously reported in SVD (89% vs. 75% at 1 year; 82% vs. 68% at 3 years). This
is due to the clinical input data and expert estimates used, which consider the
most recent advances in stent technology: heparin-coated stents, high-pressure
post-stent dilatation, the replacement of anticoagulation with antiplatelet
therapy, and a shortened length of hospital stay due to reduced complications. In
MVD, CABG is the superior treatment strategy, with a predicted event-free
survival of 90% at 3-years. MVD stenting is predicted to markedly improve patient
outcomes as compared to PTCA, and is not far behind CABG (76% at 3 years).
PMID- 10762973
TI - Cost-Effectiveness of Palmaz-Schatza Stenting for Patients with Coronary Artery
Disease in France.
AB - The increasing use of stent implantation in coronary artery disease raises
economic concerns for health care decision-makers. This model analysis, which
applies to the French health care system and uses the latest clinical and
economic data, demonstrates coronary stent implantation (CSI) in single-vessel
disease (SVD) to be clinically and economically superior to conventional balloon
angioplasty (PTCA). Although the procedural cost for CSI remains higher than for
PTCA (FF 19,500 vs. FF 12,400), this cost difference in the cath lab is decreased
to approximately FF 4,800 during the in-hospital period due to avoided procedural
complications and associated bail-out treatments. By the end of year one, the
incremental cost of CSI is virtually recouped through savings in
revascularization procedures (cost difference FF 150), and the result is
maintained over subsequent years. this favorable cost outcome, combined with a
higher rate of event-free patients, also improves the cost-effectiveness of CSI
which has a 29.4%, 30.5% and 32.2% lower cost per event-free survivor than PTCA
at the 1D, 2D and 3Dyear follow-ups, respectively. In multi-vessel disease, CSI
also appears to be a cost-effective alternative to CABG.
PMID- 10762974
TI - Cost-Effectiveness of Palmaz-Schatza Stenting in Patients with Coronary Artery
Disease in Germany.
AB - The increasing use of stent implantation in coronary artery disease raises
economic concerns for health care decision-makers. This model analysis, applying
to the German health care system and using the latest clinical and economic data,
demonstrates coronary stent implantation (CSI) in single-vessel disease (SVD) to
be superior to conventional balloon angioplasty (PTCA). Although the procedural
cost for CSI remains higher than for PTCA (DM 6,776 vs. DM 5,117), this cost
difference in the cath lab is decreased to approximately DM 800 during the in
hospital period due to avoided procedural complications and associated bail-out
treatments. By the end of year one, the incremental cost of CSI is more than
recouped through savings in revascularization procedures, and the result is
maintained over subsequent years. This favorable cost outcome, combined with a
higher rate of event-free patients, also improves the cost-effectiveness of CSI,
which has a 34.6%, 35.4%, and 36.8% lower cost per event-free survivor than PTCA
at the 1-, 2-, and 3-year follow-ups, respectively. In multi-vessel disease, CSI
also appears to be a cost-effective alternative to CABG.
PMID- 10762975
TI - Cost-Effectiveness of Palmaz-Schatza Stenting for Patients with Coronary Artery
Disease in Italy.
AB - The increasing use of stent implantation in coronary artery disease raises
economic concerns for health care decision-makers. This model analysis, which
applies to the Italian health care system and uses the latest clinical and
economic data, demonstrates coronary stent implantation (CSI) in single-vessel
disease (SVD) to be clinically and economically superior to conventional balloon
angioplasty (PTCA). Although the procedural cost for CSI remains higher than for
PTCA (Lit. 7.5 million vs. Lit. 4.9 million), this cost difference in the cath
lab is decreased to approximately Lit. 1.7 million during the in-hospital period
due to avoided procedural complications and associated bail-out treatments. By
the end of year one, the incremental cost of CSI is totally recouped through
savings in revascularization procedures, and the result is maintained over
subsequent years. This favorable cost outcome, combined with a higher rate of
event-free patients, also improves the cost-effectiveness of CSI, which has a
30.2%, 31.2%, and 32.9% lower cost per event-free survivor than PTCA at the 1-, 2
, and 3-year follow-ups, respectively. In multi-vessel disease, CSI also appears
to be a cost-effective alternative to CABG.
PMID- 10762976
TI - Cost-Effectiveness of Palmaz-Schatza Stenting in Patients with Coronary Artery
Disease in The Netherlands.
AB - The increasing use of stent implantation in coronary artery disease raises
economic concerns for health care decision-makers. This model analysis, applying
to the Dutch health care system and using the latest clinical and economic data,
demonstrates coronary stent implantation (CSI) in single-vessel disease (SVD) to
be clinically and economically superior to conventional balloon angioplasty
(PTCA). Although the procedural cost for CSI remains over NLG 3,300 higher than
for PTCA (NLG 8,871 vs. NLG 5,510), this cost difference in the cath lab is
decreased to approximately NLG 2,200 during the in-hospital period due to avoided
procedural complications and associated bail-out treatments. By the end of year
one, the incremental cost of CSI is virtually recouped (by over 90%) through
savings in revascularization procedures, and this result is maintained over
subsequent years. Combined with a higher rate of event-free patients, this
virtual cost-equality improves the cost-effectiveness of CSI, which has a 27.8%,
29.4%, and 31.5% lower cost per event-free survivor than PTCA at the 1-, 2-, and
3-year follow-ups, respectively. In multi-vessel disease, CSI also appears to be
a cost-effective alternative to CABG.
PMID- 10762977
TI - Cost-Effectiveness of Palmaz-Schatza Stenting for Patients with Coronary Artery
Disease in Spain.
AB - The increasing use of stent implantation in coronary artery disease raises
economic concerns for health care decision-makers. This model analysis, applying
to the Spanish health care system and using the latest clinical and economic
data, demonstrates coronary stent implantation (CSI) in single-vessel disease
(SVD) to be clinically and economically superior to conventional balloon
angioplasty (PTCA). Although the procedural cost for CSI remains higher than for
PTCA (Ptas. 677,000 vs. Ptas. 436,000), this cost difference in the cath lab is
decreased to approximately Ptas. 150,000 during the in-hospital period due to
avoided procedural complications and associated bail-out treatments. By the end
of year one, the incremental cost of CSI is more than recouped through savings in
revascularization procedures, and this result is maintained over subsequent
years. Combined with a higher rate of event-free patients, this cost-savings
clearly improves the cost-effectiveness of CSI, which has a 31.1%, 32.0%, and
33.6% lower cost per event-free survivor than PTCA at the one-, two-, and three
year follow-ups, respectively. In multi-vessel disease, CSI also appears to be a
cost-effective alternative to PTCA and perhaps CABG.
PMID- 10762978
TI - New Perspectives on the Cost-Effectiveness of Palmaz-Schatza Coronary Stenting,
Balloon Angioplasty, and Coronary Artery Bypass Surgery.
PMID- 10762979
TI - Primary Angioplasty is the Treatment of Choice for Acute Myocardial Infarction.
PMID- 10762980
TI - Transfer of High-Risk Myocardial Infarction Patients for Primary PTCA.
PMID- 10762981
TI - PTCA in Centers without Surgical Backup N Outcome, Logistics and Technical
Aspects.
PMID- 10762982
TI - Primary Stenting in Acute Myocardial Infarction: Design and Interim Results of
the PAMI Stent Pilot Trial.
PMID- 10762983
TI - Program Operation and Technical Aspects of a Regional Primary PTCA Program.
AB - In this section of the symposium, we will divide the discussion into two parts:
the hypothesis, and the background and operation of a regional primary
angioplasty program with review of the results in our location in West Texas. A
brief discussion of the technical aspects in the performance of primary
angioplasty will be detailed. We will review the practical aspects of the
performance of primary percutaneous transluminal coronary angioplasty with
outlines for implementation of the angiogram, conducting angioplasty, giving
adjunctive mechanical and chemical therapies, care of the patient after the
intervention and the potential need for subsequent coronary bypass surgery.
Guidelines regarding initiation of a regional approach to triage acute myocardial
infarction patients will be discussed. The rationale for risk stratification with
angiography, order and technical aspects of the performance of percutaneous
transluminal coronary angioplasty, need for adjunctive medical therapy,
delineation of coronary bypass classification and details of after care will be
fundamentally outlined.
PMID- 10762984
TI - Establishing a Program and Performance of Primary PTCA N The PAMI Way.
PMID- 10762985
TI - The Burden of Coronary Revascularizations in Europe: Epidemiology Today and in
the Year 2010.
PMID- 10762986
TI - Gold Standards in Interventional Cardiology for the Management of Coronary Artery
Disease.
PMID- 10762987
TI - Current Research and Future Trends in Interventional Cardiology.
PMID- 10762988
TI - Lesser Invasiveive CABG: Media-Driven, Industry-Driven or Evidence-Driven?
PMID- 10762989
TI - The Pharmacologic Approach to Restenosis: Recent Experiences and Trends.
PMID- 10762990
TI - Understanding and Evaluating the Cost-Effectiveness of New Coronary
Interventions.
PMID- 10762992
TI - Current and Emerging Anti-Thrombotic Therapies for Acute Coronary Syndromes.
PMID- 10762991
TI - Healthcare Policy and its Impact on Interventional Cardiology: Reimbursement,
Budgets and Future Developments.
PMID- 10762993
TI - The Role of Platelet-Targeted Strategies in Managing the Spectrum of Unstable
Angina and Non-Q Wave Myocardial Infarction: Clinical Trials with Glycoprotein
IIb/IIIa Inhibitors.
PMID- 10762994
TI - Targeting Therapy in Unstable Angina.
AB - Patients presenting to hospital with unstable angina should be risk profiled on
admission and categorized as low, intermediate or high risk based on
demographics, the presence and duration of ischemia, electrocardiographic changes
and biochemical markers such as troponins T and I. Patients categorized as low
risk can be assessed as outpatients for confirmation of the diagnosis,
institution of therapy, non-invasiveive testing for inducible ischemia, and
modification of risk factors. Patients categorized as intermediate risk should be
admitted and treated with antithrombotic therapy and glycoprotein IIb/IIIa
receptor antagonists while undergoing careful monitoring for ischemia. If any
high-risk features occur during this period, the patient should be recategorized
as high risk. Alternatively, if the symptoms and signs of ischemia settle, they
can be recategorized as low risk and undergo noninvasiveive testing before
discharge. Patients categorized as high risk should be treated with
antithrombotic therapy and IIb/IIIa receptor antagonists with a plan to perform
expeditious angiography and revascularization (if appropriate) before early
discharge. Further studies are required comparing this approach in high-risk
patients with one of IIb/IIIa receptor antagonist therapy without
revascularization. The increased risk of cardiac events continues beyond the
acute phase, and long-term strategies, including administration of either low
molecular weight heparin or oral IIb/IIIa receptor antagonists, are being tested
in ongoing clinical trials.
PMID- 10762995
TI - Coronary Revascularization in Patients with Acute Coronary Syndromes.
AB - Non-Q wave myocardial infarction and unstable angina remain major causes of
morbidity and mortality in patients with atherosclerotic coronary artery disease.
Judicious use of cardiac catheterization and coronary revascularization may
further improve the prognosis of patients with these acute coronary syndromes
(ACS). Patients with ACS at high risk for further cardiac events include those
patients with electrocardiographic ST-segment depression, left bundle branch
block, and, to a lesser extent, T-wave inversion, and those patients with
recurrent pain, cardiac enzyme elevation, or exercise-induced ischemia after
hospitalization. While these patient subgroups may benefit from early cardiac
catheterization and revascularization, the role of routine coronary
revascularization is less well established. Whereas one study has demonstrated
reduced recurrent hospitalizations in patients treated with routine invasiveive
strategy, another has suggested that outcomes are not different with the two
approaches. Pending the results of a third ongoing study N the Thrombolysis in
Myocardial Infarction (TIMI)-18 trial N a judicious approach to revascularization
in patients presenting with ACS is warranted.
PMID- 10762996
TI - Conventional Versus New Therapies: Case Study Review.
PMID- 10762997
TI - The Endocrine Surgeon and Endocrine Neoplasms.
PMID- 10762998
TI - Hurthle Cell Carcinoma.
AB - BACKGROUND: Hurthle cell carcinoma represents approximately 3% of all
differentiated thyroid cancers. The terminology is often confusing, and
discrimination between Hurthle cell carcinoma and benign Hurthle cell tumors can
be unclear. Thus, optimal treatment of patients with these diseases remains
unsettled. METHODS: The authors reviewed published evidence on the presentation,
biologic behavior, and treatment outcomes for this disease. In addition, they
summarized their experience involving a series of 14 patients with Hurthle cell
carcinoma. RESULTS: Hurthle cell carcinoma generally produces thyroglobulin and
rarely takes up radioactive iodine. It is frequently bilateral or multifocal
within the thyroid gland and often presents with local invasion. Hurthle cell
carcinoma is associated with a high rate of locoregional recurrence and
significant mortality. CONCLUSIONS: The authors advocate total thyroidectomy with
central neck dissection as the therapy of choice for patients with Hurthle cell
carcinoma.
PMID- 10762999
TI - Carcinoid Tumors of the Gut.
AB - BACKGROUND: Carcinoid tumors are the most frequently encountered endocrine tumors
of the gastrointestinal tract. They are most often found in the appendix,
although they can arise in any location of the gut. Carcinoid tumors may secrete
a variety of bioactive substances, which can cause the complex of symptoms
associated with the carcinoid syndrome. METHODS: The authors reviewed the
pathology, clinical presentation, and management of carcinoid tumors with an
emphasis on the surgical management. RESULTS: The primary treatment for a
carcinoid tumor located anywhere in the gut is surgical. Those who have widely
metastatic disease or who are anatomically unresectable may undergo cytoreductive
surgical debulking and/or hepatic arterial embolization followed by palliation of
symptoms with octreotide, the long-acting somatostatin analog. CONCLUSIONS: The
prognosis for patients with carcinoid tumors that are fully resected is
excellent. Those with hepatic metastases and the carcinoid syndrome have a less
favorable prognosis.
PMID- 10763000
TI - Medullary Thyroid Cancer.
AB - BACKGROUND: Medullary thyroid cancer, a tumor of the parafollicular C cells,
accounts for approximately 10% of all thyroid malignancies. An estimated 75% of
cases are sporadic, and the remaining 25% are familial. METHODS: The author
reviews the clinical features and diagnostic tests for this entity, as well as
the surgical treatment of recurrent or persistent medullary carcinoma. RESULTS:
Sporadic medullary thyroid cancer typically presents as an isolated unilateral
mass. Familial tumors tend to be multifocal and bilateral. In patients with
multiple endocrine neoplasia type 2A, pheochromocytomas and parathyroid
hyperplasia also may develop. Care is taken to avoid operating on a patient with
occult pheochromocytoma. Total thyroidectomy and central lymph node dissection
are the keys for successful surgical treatment. CONCLUSIONS: Surgery is the
cornerstone of treatment for medullary carcinoma of the thyroid. Genetic testing
using the ret oncogene allows identification of individuals who are at risk for
the disease or those with early-stage disease.
PMID- 10763001
TI - Gastrinoma: State of the Art.
AB - BACKGROUND: The Zollinger-Ellison syndrome, implicating a gastrinoma, was first
recognized as a disease entity in 1955. At that time, total gastrectomy was the
most common treatment approach. Advances in several aspects of the disease have
occurred since that time. METHODS: The authors reviewed the changes that have
developed since 1955 in the diagnosis, imaging studies, operative and
nonoperative management, and follow-up of patients with this disease. RESULTS:
The presence of a gastrinoma can be confirmed by a secretin stimulation test. A
variable number of patients have hyperparathyroidism as part of the multiple
endocrine neoplasm syndrome type 1 (MEN 1). Localization of the primary
gastrinoma has been assisted by selective angiography, endoscopic
ultrasonography, and the octreotide scan. H2-blockers or omeprazole, sometimes at
high doses, usually controls acid secretion. Surgical removal of the primary
gastrinoma is performed when feasible, and parathyroidectomy is indicated in
those patients with hyperparathyroidism in the MEN 1 syndrome. Follow-up is
facilitated by measurement of fasting serum gastrin levels. CONCLUSIONS: Several
innovations have improved our capability to diagnose and effectively manage
patients with gastrinoma.
PMID- 10763002
TI - Localization of Neuroendocrine Tumors Using Somatostatin Receptor Imaging With
Indium-111-Pentetreotide (OctreoScan).
AB - BACKGROUND: Many imaging methods have been used to detect neuroendocrine tumors
of the gastrointestinal system. There is no gold standard for identifying the
location of primary tumors and their potential metastases, and most conventional
imaging techniques cannot detect tumors less than 1.0 cm in size. METHODS: The
authors have investigated the use of 111-In-pentetreotide as an imaging agent for
abdominal neuroendocrine tumors. RESULTS: The agent is cleared rapidly by the
kidneys and is primarily excreted intact with a biologic half-life of six hours.
The largest radiation burden is to the spleen and kidneys. A nine-center study
conducted in Europe involved 365 patients with gastroenteropancreatic
neuroendocrine tumors that were also imaged by other methods. The results of 111
In-pentetreotide were in agreement with those obtained by other methods for 79%
of tumor locations. An additional 110 tumor localizations were detected that were
not seen with conventional methods. The smallest gastrinoma imaged by 111-In
pentetreotide was a 4-mm duodenal tumor. CONCLUSIONS: Scintigraphy with 111-In
pentetreotide is effective in visualizing various somatostatin receptors
characteristic of neuroendocrine tumors of the gastrointestinal tract.
Insulinomas, however, are not well imaged. Concurrent computed tomography
scanning is advised to minimize the risk of missing liver metastases.
PMID- 10763003
TI - Imaging of Abdominal Pain.
PMID- 10763004
TI - Clinical Practice Guidelines for Melanoma.
PMID- 10763006
TI - Highlights of the NSABP Breast Cancer Prevention Trial.
PMID- 10763005
TI - Human Herpesvirus 8 DNA in Visceral Kaposi's Sarcoma of AIDS and Other
Immunocompromised Patients in Hungary.
PMID- 10763007
TI - Cancer Prevention: Perspectives and Implications.
PMID- 10763008
TI - Intermediate Markers and Molecular Genetics of Lung Carcinogenesis.
AB - BACKGROUND: Various options are available for the local control of cancer in the
breast - mastectomy, conservation therapy, and mastectomy with reconstruction.
METHODS: To evaluate the benefits and drawbacks of the available management
options, the authors combine their extensive experience with a review of the
literature on outcomes from these approaches. RESULTS: Conservation therapy
provides survival outcomes similar to those from mastectomy. Differences in local
recurrence rates can be minimized by close adherence to guidelines for patient
selection, operative approach, and radiation technique. CONCLUSIONS: The role of
the physician in selecting a local therapy for breast cancer has changed from one
of informing the patient of the treatment to assessing the presence of medical
contraindications to any of the treatments, educating the patients on each
treatment approach, providing access to multidisciplinary consultation, and
allowing the patient to choose an appropriate treatment approach.
PMID- 10763009
TI - Cancer Prevention: The Roles of Diet and Chemoprevention.
AB - BACKGROUND: Reduction of cancer risk by either preventing carcinogenesis or
stopping carcinogenesis in its early stages is a logical approach for reducing
the cancer burden, both for high-risk individuals and for the general population.
The areas of dietary modification and chemoprevention show considerable promise
as effective approaches for cancer prevention and are a focus of research
efforts. RESULTS: Diet and cancer studies show that, generally, vegetables and
fruits, dietary fiber, and certain nutrients seem to be protective against
cancer, whereas fat, excessive calories, and alcohol seem to increase cancer
risk. Chemoprevention research is closely linked to diet and cancer research and
represents a logical research progression. CONCLUSIONS: Dietary epidemiologic
studies have helped to identify many naturally occurring chemopreventive agents.
Currently, randomized clinical prevention trials sponsored by the NCI include
dietary interventions (eg, low-fat and/or high-fiber vegetables and fruits)
targeting breast and colorectal cancer, chemoprevention trials using
micronutrients (eg, vitamin E, calcium, vitamin D) aimed at lung and colorectal
cancer, and chemoprevention trials testing the effectiveness of pharmaceutical
agents (eg, tamoxifen, finasteride, aspirin) for breast, prostate, and colorectal
cancer.
PMID- 10763010
TI - Head and Neck Chemoprevention: Recent Advances.
AB - BACKGROUND: Head and neck cancers are important to human life and health in both
developed and underdeveloped countries. Management of established cancers is
difficult, and there is great interest in evaluating methods to prevent these
tumors from developing. METHODS: The biology of carcinogenesis, including field
carcinogenesis, is reviewed, together with the biology and pharmacology of the
retinoids. Intervention studies of premalignant lesions have led to prospective
clinical trials of the capability of various retinoids to reduce the incidence of
new second cancers. RESULTS: High-dose 13-cis-retinoic acid (13cRA) has
significant activity in reversing oral leukoplakia but at a cost of substantial
toxicity, and relapses occur early. An ongoing intergroup trial is underway to
evaluate the capacity of low-dose (30 mg/d) 13cRA given for three years to reduce
the incidence of second primary tumors in patients with "cured" squamous head and
neck cancers. CONCLUSIONS: Molecular studies of loss of heterozygosity and p53
gene mutations are advancing our understanding of field carcinogenesis and the
biology, pharmacology, and effects of the retinoids used in cancer prevention.
Translation of early clinical trials into large-scale intervention trials to
prevent second cancers are now underway.
PMID- 10763011
TI - Chemoprevention of Bladder and Prostate Carcinoma.
AB - BACKGROUND: The incidence of bladder and prostate cancer continues to rise, with
little accompanying improvement in management strategies. Opportunities exist for
testing various types of chemopreventive interventions. METHODS: The authors
review the biology of progression to invasive disease for cancers of the bladder
and the prostate and identify intermediate disease and surrogate endpoint
markers. Candidate interventions and initial clinical trial results are
described. RESULTS: Markers of cellular proliferation and differentiation, as
well as antigens such as Le(x), M344, DD23, and bladder tumor antigen, are
promising for bladder cancer. Testing with prostate-specific antigen and prostate
specific membrane antigen is promising for prostate cancer. Several prevention
intervention trials are in progress for both cancers. CONCLUSIONS: Vitamins,
polyamine synthesis inhibitors, and oltipraz are undergoing clinical tests for
chemopreventive effects in bladder cancer, and a large trial of finasteride to
prevent prostate cancer is completing accrual. Results from these studies will
direct future research.
PMID- 10763012
TI - Ethical Issues of Chemoprevention Clinical Trials.
AB - BACKGROUND: Chemoprevention of malignancy is a new concept in clinical medicine,
and little is written about the ethics of identifying and enrolling eligible
subjects in chemoprevention clinical trials. METHODS: The authors identify the
ethical issues raised in the conduct of clinical chemoprevention trials and
review the ethical considerations that should guide clinical researchers in the
design and conduct of this new type of clinical trial. RESULTS: The ethics of
chemoprevention clinical trials are complicated because (1) chemoprevention lies
at the intersection of disease management and health promotion, (2) there are
conflicting interests competing in these trials, and (3) multiple values play a
role in determining the nature and magnitude of the risks and benefits of
chemoprevention of cancer. Ethical questions related to these trials concern the
enrollment of healthy individuals rather than cancer patients, confidentiality in
recruitment, the enrollment of "high-risk" subjects, randomization, informed
consent, trial monitoring, and competing outcomes and toxicities. CONCLUSIONS:
These issues will be resolved with the accumulating clinical experience and
ethical deliberations that accompany ongoing clinical chemoprevention research
studies.
PMID- 10763014
TI - Pathology of Early Colonic Neoplasia: Clinical and Pathologic Features of
Precursor Lesions and Minimal Carcinomas.
PMID- 10763013
TI - Management of Bone Pain Secondary to Metastatic Disease.
PMID- 10763015
TI - Mucormycosis Associated With Deferoxamine Therapy After allogeneic Bone Marrow
Transplantation.
PMID- 10763016
TI - Talc: Rationale and Use in Malignant Pleural Effusions.
PMID- 10763017
TI - Cancer Risk Behaviors of Adolescents: Youth Risk Behavior Survey Data.
PMID- 10763018
TI - Breast Cancer, 1997.
PMID- 10763019
TI - Local Management of Primary Breast Cancer.
AB - BACKGROUND: Various options are available for the local control of cancer in the
breast -- mastectomy, conservation therapy, and mastectomy with reconstruction.
METHODS: To evaluate the benefits and drawbacks of the available management
options, the authors combine their extensive experience with a review of the
literature on outcomes from these approaches. RESULTS: Conservation therapy
provides survival outcomes similar to those from mastectomy. Differences in local
recurrence rates can be minimized by close adherence to guidelines for patient
selection, operative approach, and radiation technique. CONCLUSIONS: The role of
the physician in selecting a local therapy for breast cancer has changed from one
of informing the patient of the treatment to assessing the presence of medical
contraindications to any of the treatments, educating the patients on each
treatment approach, providing access to multidisciplinary consultation, and
allowing the patient to choose an appropriate treatment approach.
PMID- 10763020
TI - The Role of Selective Lymphadenectomy in Breast Cancer.
AB - BACKGROUND: Axillary node dissection is considered a standard staging procedure
in patients with breast cancer. The procedure is associated with significant
morbidity and provides pathologists with many lymph nodes to evaluate. METHODS: A
total of 174 women participated in a trial that included preoperative
lymphoscintigraphy and intraoperative lymphatic mapping using a combination of a
vital blue dye and radiocolloid mapping. RESULTS: The intraoperative lymphatic
mapping correctly identified a sentinel lymph node (SLN) in 160 (92%) of 174
patients. One skip metastasis (0.7%) occurred in 136 women who had a subsequent
complete node dissection. CONCLUSIONS: Lymphatic mapping and SLN biopsy using a
combination of mapping techniques provide accurate nodal staging for women with
breast cancer. With this technique, approximately 70% to 80% of women with no
axillary metastases could be spared the morbidity of a complete node dissection.
PMID- 10763021
TI - Conservation Therapy of the Breast: Optimizing Long-term Results.
AB - BACKGROUND: Radiation therapy is a key component of breast conservation therapy
for breast cancer. There is great interest in safety and long-term outcome issues
for this still underutilized approach. METHODS: The author reviews a series of
factors that may affect the end results of conservation therapy and highlights
those that are likely to be of clinical significance. RESULTS: Daily dose
fractions are usually less than 2 Gy and a homogeneous whole-breast dose is used.
Care is needed with patients with collagen vascular diseases, large breasts,
breast trauma, and prior infections, but these factors are not absolute
contraindications to breast conservation therapy. Acute skin reactions are not
predictive of long-term complications. CONCLUSIONS: With adherence to proper
surgical and radiation techniques, most patients presenting with localized breast
cancer can be managed safely and effectively with breast conservation.
PMID- 10763022
TI - Controversies in Breast Cancer.
AB - BACKGROUND: A large number of controversies about the management of breast cancer
produce uncertainties for patients and physicians alike. In addition, questions
are constantly raised about the true value of new approaches or treatments.
METHODS: The authors have conducted a critical review of the literature on
several of these issues, and they present a balanced view that can be useful for
clinical decision making. RESULTS: Although new staging systems for ductal
carcinoma in situ have been proposed, a consensus has not yet been reached
regarding the criteria to allow tumor excision alone. The extent of benefit of
the main adjuvant therapies is becoming better established, and improvement in
outcomes may accrue from dose-intensive treatments and autologous stem cell or
hematopoietic growth factor support. CONCLUSIONS: Progress in breast cancer
management continues to evolve. Several new approaches either reduce morbidity or
improve outcomes.
PMID- 10763023
TI - Malignancy and Rheumatic Disease.
AB - BACKGROUND: A wide variety of clinically significant interactions occur between
neoplastic and rheumatic diseases, and many are clinically significant. METHODS:
The types of interactions between rheumatologic and neoplastic diseases and their
clinical manifestations are reviewed and described. RESULTS: Several diseases
included in the classic definition of rheumatology are associated with an
increased incidence of specific neoplasms. Conversely, many neoplasms, by a
variety of mechanisms, can cause or simulate many rheumatic diseases.
CONCLUSIONS: Knowledge of the increased propensity for neoplasia in certain
conditions and of the possibility that cancer may be the cause of specific
rheumatologic syndromes will assist the physician in providing optimal clinical
care to affected patients.
PMID- 10763024
TI - Primary Gastric Lymphoma.
AB - BACKGROUND: Gastric lymphoma is a common presentation of non-Hodgkin's lymphoma.
Controversy reigns about many aspects of its classification and management,
especially regarding roles for surgical resection. METHODS: The authors review
the clinical features, staging, pathology, prognosis, and management issues with
an emphasis on the role of surgical resection. RESULTS: Staging usually can be
completed using noninvasive techniques. Those with a low-grade B-cell MALT type
lymphoma with Helicobacter pylori infection may be treated with antibiotics and
close follow-up. Patients with stage I or II disease may be treated with
chemotherapy and radiation. Surgery is indicated for those with perforation or
uncontrolled bleeding. CONCLUSIONS: Gastric lymphoma, primarily a B-cell tumor,
can be diagnosed and managed effectively with various approaches. Few
prospective, randomized trials of alternative approaches have been performed.
PMID- 10763025
TI - Dilemma of the Contemporary Physician: The Nobel Prize or the Business Prize?
PMID- 10763026
TI - A Chest CT Abnormality in an Immunocompromised Patient.
PMID- 10763027
TI - Successful Therapy of Postneurosurgical Meningitis Caused by a Resistant Strain
of Enterobacter Aerogenes.
PMID- 10763028
TI - What Is the Role and Impact of the Sentinel Node Sampling Technique in Breast
Cancer Staging?
PMID- 10763029
TI - What Is the Optimum Duration of Tamoxifen Adjuvant Therapy?
PMID- 10763031
TI - Can Metastatic Breast Cancer Be Cured or Controlled by hemotherapy?
PMID- 10763030
TI - What Is the Role of High-dose Chemotherapy and Autologous Marrow Support for
Patients With Breast Cancer?
PMID- 10763032
TI - What are the Roles of the Taxanes in Breast Cancer.
PMID- 10763033
TI - What New Drugs, Biologics, and Treatment Approaches Show Promise in Breast
Cancer?
PMID- 10763034
TI - Improving Our Management of Non-Small Cell Lung Cancer and Mesothelioma.
PMID- 10763035
TI - Postoperative and Preoperative Chemotherapy for Non-Small Cell Lung Cancer.
AB - BACKGROUND: Few randomized trials of preoperative and postoperative adjuvant
systemic therapy have been performed in patients with non-small-cell lung cancer
(NSCLC). METHODS: The authors reviewed the recent literature on comparative
trials and meta-analyses to determine the current status of adjuvant therapy for
patients with NSCLC. RESULTS: Postoperative adjuvant therapy with cisplatin
containing regimens reduces the risk of death by 3% at two years and by 5% at
five years. Preoperative therapy can clear tumor in the resected specimen in
approximately 15% of cases, and two small trials report substantial survival
benefit. CONCLUSIONS: The development of new and more active regimens for NSCLC
may provide the biologic basis for clinical trials to demonstrate more pronounced
benefit for adjuvant systemic therapy.
PMID- 10763036
TI - Management Issues for Stage IV Non-Small Cell Lung Cancer.
AB - BACKGROUND:The management of stage IV non-small-cell lung cancer (NSCLC) has been
a controversial subject over the past several decades. Data from randomized
trials and from phase II trials on new cancer agents are changing physician
attitudes and treatment practices. METHODS: The literature on the management of
metastatic lung cancer was reviewed and interpreted. RESULTS: There is good
evidence from randomized controlled trials and meta-analyses that chemotherapy
provides a modest survival benefit in stage IV NSCLC. There is indirect evidence
of improvement in quality of life, as systemic chemotherapy palliates cancer
related symptoms in the majority of patients. New drug combinations are likely to
improve recent treatment results with less morbidity than older chemotherapy
regimens. Despite the relatively high cost of these treatments, chemotherapy is
cost effective in the Canadian health care environment relative to other accepted
medical interventions. CONCLUSIONS: Chemotherapy will play an increasing role in
the management of patients with advanced NSCLC.
PMID- 10763037
TI - New Agents in the Management of Non-Small Cell Lung Cancer.
AB - BACKGROUND: Non-small-cell carcinoma of the lung has long been considered a
chemotherapeutically resistant neoplasm. Newer agents and combinations are being
tested. METHODS: The authors have reviewed data on recent and active phase I and
phase II trials of several new agents and combinations. RESULTS: New drugs that
affect both response rates and survival include vinorelbine, paclitaxel,
docetaxel, gemcitabine, topotecan, and irinotecan. CONCLUSIONS: The advent of
several relatively well-tolerated agents that alone have beneficial effects in
advanced non-small-cell lung cancer provides reasonable hope that more effective
drug combinations will soon be available for this disease.
PMID- 10763038
TI - Current Therapy for Mesothelioma.
AB - BACKGROUND: Diffuse malignant pleural mesotheliomas (DMPMs) are highly lethal
tumors that are becoming more common. Standard management approaches have
provided limited effectiveness. METHODS: The literature on management has been
revised, and the authors present their data on outcomes for 120 patients treated
with an aggressive trimodality approach. RESULTS: An aggressive trimodality
approach including extrapleural pneumonectomy followed by chemoradiation produces
low mortality and acceptable morbidity. The five-year survival rate in patients
with epithelial histology and negative nodes approaches 40%. CONCLUSIONS: Nodal
status and histologic subtype are major predictors for survival in patients with
early DMPM. A uniformly accepted staging system would allow comparison of
treatment approaches from various institutions. More effective management
interventions are required.
PMID- 10763039
TI - Menopausal Status and the Impact of Early Recurrence on Breast Cancer Survival.
AB - BACKGROUND: Breast cancer represents the leading form of invasive cancer among
American women, killing nearly 50,000 annually. Several prognostic factors that
are associated with survival include age, race, menopausal status, and the stage
of disease at presentation. METHODS: Patient characteristics were collected based
on a systematic chart audit of demographic features and medical, family, and
social histories. We studied the survival of 220 patients with recurrent disease
out of 1,429 consecutive patients with breast cancer seen over a 15-year period.
RESULTS: Patients with a disease-free interval following diagnosis of less than
24 months were more frequently premenopausal and hormone receptor-negative than
those with a disease-free interval of 24 months or greater. Patients with early
recurrence had a shorter survival than patients with late recurrence. Menopausal
status, nodal involvement, receptor status, and the site of recurrent disease
were independent predictors of survival following recurrence. CONCLUSIONS:
Premenopausal women with early recurrence of breast cancer experience a
significantly shorter survival than those with late recurrence, even after
adjustment for hormone receptor status and site of recurrence. This effect was
not seen in postmenopausal women.
PMID- 10763040
TI - Hospitals: What's Happening to Their Cancer Programs?
PMID- 10763041
TI - Neuroendocrine Carcinoma of the Skin.
PMID- 10763043
TI - Brunner's Gland Hamartoma: Is It Just a Morphologic Curiosity?
PMID- 10763044
TI - Blood Transfusions in the Home Sweet Home: How to Avoid a Sour Outcome.
PMID- 10763042
TI - A Liver Abnormality in a Patient With Mesothelioma.
PMID- 10763045
TI - Leukemia: A Transition From Basic Science to Clinical Practice.
PMID- 10763046
TI - Cytogenetic and Molecular Evaluation in Myelodysplastic Syndrome and in Acute and
Chronic Leukemia.
AB - BACKGROUND: The majority of the presently known nonrandom chromosome changes in
hematologic malignancy were described during the 1970s and 1980s. The last 10
years have been devoted to the location of oncogenes and tumor suppressor genes
altered as a consequence of those changes. New molecular methodology has helped
speed this process, which has resulted in DNA sequencing of many of the genes
involved, permitting molecular detection of abnormal clones. METHODS: This review
examines the most common alteration-based subgroups of cytogenetics and molecular
genetics in hematologic disorders with the exclusion of lymphoma. Prognosis has
been updated to reflect improving treatment protocols. RESULTS: The versatility
of cytogenetics for delineating genetic changes is difficult to match by
molecular testing. Once a clonal anomaly is identified, molecular methodology can
detect residual disease with far greater sensitivity than cytogenetics, but
relies on translocation junction targets that exclude clones characterized by
deletion or trisomy. CONCLUSIONS: Cytogenetic and molecular testing offers
independent diagnostic and prognostic evaluation for most patients with
hematologic malignancy.
PMID- 10763047
TI - Therapeutic Options in the Management of Acute Myelogenous Leukemia in Adults.
AB - BACKGROUND: The treatment of acute myelogenous leukemia has evolved in recent
years due to advances in supportive care, the identification of prognostic
factors, and the careful evaluation of chemotherapeutic modalities in randomized
clinical trials. METHODS: The classification and prognostic features are
reviewed, and the results from clinical trials have been evaluated with an
emphasis on randomized trials and on both remission induction and postremission
phases of management. RESULTS: The combination of an anthracycline and standard
dose Ara-C form the basis of remission induction. High-dose Ara-C has greater
toxicity. For postremission therapy, high-dose Ara-C improves results in those
with good risk features or normal cytogenetics. Acute promyelocytic leukemia
management includes all-trans-retinoic acid. CONCLUSIONS: Once a patient relapses
from a nontransplant approach, high-dose therapy and allogeneic marrow
transplantation are considered. Autologous stem cell transplantation cures some
patients who do not have a donor.
PMID- 10763048
TI - Leukemia Support Groups: How Are They Doing?
AB - BACKGROUND: Support groups help their participants to cope with the emotional and
practical impact of their illnesses. METHODS: The effectiveness of the Leukemia
Society of America support groups in enhancing the quality of life for their
participants is reviewed. The groundwork, purpose, and structure of such groups,
as well as alternate sources of support, are presented. Evaluation and future
directions for oncology groupwork are discussed. RESULTS: Support groups
complement the therapies provided by clinical practitioners and scientists by
addressing the additional needs of cancer patients over the course of illness and
survival. CONCLUSIONS: New concepts and methods that address the needs of
specific age-groups and incorporate the newly generated data on cancer treatments
will further enhance the benefits provided by support groups.
PMID- 10763049
TI - A Primer for Evaluating Clinical Trials.
AB - BACKGROUND: Evidence-based medicine demands the use of information from clinical
trials to direct medical care. Knowledge of the principles of trial design and
conduct is important to assess the validity of results. METHODS: The authors
review the key principles behind clinical study design and conduct, and they
summarize important biases and confounding issues. RESULTS: Clear hypotheses, a
well-described study population, precise measurements, freedom from bias, and
consideration of any interactions are attributes of good clinical trials.
CONCLUSIONS: The greatest level of evidence in support of a difference in outcome
is associated with randomized, controlled clinical trials, particularly when
combined with other randomized trials in a systematic fashion (meta-analysis).
PMID- 10763050
TI - Polypharmacy in the Older Patient With Cancer.
AB - BACKGROUND: Elderly patients -- those aged 65 years and over -- use more
medications than their younger counterparts and experience higher risks for
polypharmacy, drug interactions, adverse drug reactions, and noncompliance for
this age-group. METHODS: The data on polypharmacy in the aged is reviewed,
supplemented with preliminary information from studies performed on elderly
patients with cancer at our institution. RESULTS: Polypharmacy occurs in
ambulatory, extended care, and institutional settings. Over-the-counter
medications are underreported. The number of potential drug-related problems is
related to the total number of prescriptions. Methods for evaluating the extent
of polypharmacy include the "brown-bag" technique and careful medication
histories. CONCLUSIONS: The risks of polypharmacy may be reduced with patient and
physician education, intervention, and drug monitoring. Further pharmacokinetic
investigations of anticancer medications are needed to recognize the potential
for harmful drug interactions, to understand their toxicity profiles, and to
avoid the clinical implications of drug interactions.
PMID- 10763051
TI - Gallium Scanning as a Prognostic Indicator in Lymphoma.
PMID- 10763052
TI - Enhancing Cancer Care and Clinical Trials: New Paradigms for Success.
PMID- 10763053
TI - Toxoplasmic Lymphadenopathy Clinically Presenting as Lymphoma.
PMID- 10763054
TI - Diagnostic Pitfalls in Aspiration Biopsy Cytology of Papillary Breast Lesions.
PMID- 10763055
TI - The Next Revolution in General Surgery.
PMID- 10763056
TI - Lymphatic Mapping for Melanoma: Long-term Results of Regional Nodal Sampling With
Radioguided Surgery.
AB - BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy are new
techniques used in the surgical treatment of patients with malignant melanoma.
These procedures have the potential to change the surgical treatment of the
disease to provide a more rational approach to adjuvant therapy. METHODS: A
prospective database of melanoma patients undergoing lymphatic mapping and SLN
biopsy was reviewed to identify prognostic factors for overall and disease-free
survival in this patient population. RESULTS: Five-year overall and disease-free
survival was 92.3% and 79.0%, with a median follow-up of 17 months. The number of
histologically positive SLNs was the most powerful predictor of overall and
disease-free survival. Patients with no histologically positive SLNs had a five
year overall and disease-free survival of 97.9% and 93.3%, respectively. Tumor
ulceration and Clark level greater than or equal to III were the significant
prognostic factors for survival. CONCLUSIONS: The use of lymphatic mapping and
SLN biopsy effectively stages patients with primary cutaneous melanoma.
Additionally, the presence of histologically positive SLNs is the most powerful
indicator of overall and disease-free survival for these patients.
PMID- 10763057
TI - A Multidisciplinary Approach to Locoregional Management of the Axilla for Primary
Operable Breast Cancer.
AB - BACKGROUND: Lymph node metastasis is the single most important factor in
assessing breast cancer prognosis and planning systemic therapy. However, lymph
node dissection portends significant morbidity, with little or no therapeutic
benefit if the nodes prove to be negative for cancer. METHODS: The authors review
indications for avoiding axillary dissection, and they analyze the results from
lower-level axillary lymphadenectomy together with the morbidity from full
axillary dissection. RESULTS: Limited level I dissection depends on surgical
technique and limits prognostic information. Three approaches have evolved to
identify the sentinel node in breast cancer: perilesional breast injection of
radiocolloid alone, blue dye alone, or a combination of radiocolloid and blue
dye. These techniques provide high diagnostic accuracy, few false-negative
results, and less morbidity. CONCLUSIONS: Knowledge of axillary status is
critical to current breast cancer management and cannot be foregone in the
preponderance of patients with advanced breast cancer. Results from lymphatic
mapping and sentinel node biopsy are highly encouraging.
PMID- 10763058
TI - The Technique of Intraoperative Nuclear Mapping to Facilitate Minimally Invasive
Parathyroidectomy.
AB - BACKGROUND: Despite the fact that primary hyperparathyroidism (HPTH) is the
result of a single adenoma in 85% to 92% of cases and is cured following the
removal of this one gland, many surgeons continue to perform a complete bilateral
neck exploration for patients with primary HPTH. The advent of the sestamibi scan
now enables the identification of patients with a single adenoma. METHODS: The
use of preoperative sestamibi scanning followed immediately by minimally invasive
parathyroidectomy using intraoperative nuclear mapping allows cure for primary
HPTH in properly selected patients. RESULTS: Reports have shown that preoperative
sestamibi scanning has a sensitivity of approximately 90% and a specificity of
almost 100% in identifying patients with a single adenoma. Intraoperative mapping
allows a limited dissection to be performed under local anesthesia in an
outpatient setting in approximately 80% of all patients with primary
hyperparathyroidism. The details of this new technique - patient selection,
timing, use of the intraoperative nuclear probe, and surgical exploration - are
described. CONCLUSIONS: When selected appropriately, most patients with primary
HPTH can be successfully treated through a minimally invasive technique.
PMID- 10763059
TI - Radioimmunoguided Surgery for Gastrointestinal Malignancies: An Analysis of 14
Years of Clinical Experience.
AB - BACKGROUND: The identification of all sites of intra-abdominal adenocarcinoma is
key to optimal surgical resection and tumor staging. Conventional imaging methods
and direct visualization and palpation have limited sensitivity and specificity.
Radioimmunoguided surgery (RIGS) has a potential to improve these parameters.
METHODS: The development of the RIGS concept is presented, and the studies of
tumor localization, detection of disseminated disease, staging, and survival are
correlated with the tumor biopsy of gastrointestinal carcinoma, particularly
colorectal carcinoma. RESULTS: RIGS can detect clinically and histologically
occult neoplasm. Also, by providing immediate intraoperative information, the
RIGS approach improves surgical staging, impacts on surgical and medical care,
and affects patient prognosis. CONCLUSIONS: RIGS may become the standard of care
for the surgical staging and treatment of colorectal cancer and other
gastrointestinal malignancies.
PMID- 10763060
TI - Radioisotope-Guided Surgical Biopsy of Suspected Osseous Metastases.
AB - BACKGROUND: Radioisotope bone scanning is frequently used to stage patients with
suspected or proven malignancies. Since false-positive results are common,
especially in the ribs, open biopsy is often necessary. The conventional approach
of visual inspection of the bone scan image to guide the surgeon usually requires
excision of a large area of one or two ribs to assure that the biopsy was
performed on the correct rib. A more precise method to guide the biopsy is
desirable. METHODS: One technique to localize the suspicious area of bone
intraoperatively for accurate biopsy involves percutaneous injection of the bone
abnormality with a radioisotope followed by injection of methylene blue into the
periosteum and subsequent open surgical biopsy. A more recent technique uses a
hand-held gamma probe in a sterile sleeve in the operating room to locate the
bone "hot spot" directly in the wound to guide the biopsy. RESULTS: Both
techniques are effective in pinpointing the bone scan abnormality, but use of the
gamma probe is less cumbersome and consumes less time and fewer resources. In one
series of 10 patients undergoing gamma probe-guided biopsies of 13 rib and 1
sternal bone scan lesions, this technique showed a sensitivity of 100% in
locating the area of abnormal radioisotope uptake. All biopsies yielded an
abnormal diagnosis to account for the bone scan abnormality, but only 4 of 14
(29%) demonstrated metastatic tumor. CONCLUSIONS: Techniques described for
radioisotope-guided localization of areas of increased tracer uptake in
asymptomatic suspected bone metastases are accurate, sensitive guides to the open
biopsy of these bony abnormalities. Due to the high false-positive rates in these
asymptomatic but suspicious bone scan abnormalities, a diagnosis should be
histologically confirmed.
PMID- 10763061
TI - Breast Lymphoscintigraphy.
PMID- 10763062
TI - Identifying Sources and Reducing the Potential for Chemotherapy-Related Errors:
Mission Impossible?
PMID- 10763063
TI - Leiomyoblastoma of the Omentum Presenting as Hemoperitoneum: Report of a Case and
Review of the English Literature.
PMID- 10763064
TI - Diagnostic Dilemmas With Herpes Simplex Encephalitis.
PMID- 10763065
TI - A hairy situation.
PMID- 10763066
TI - Difficult mask ventilation.
PMID- 10763067
TI - Aerosolization of lidocaine.
PMID- 10763068
TI - Methods used to interpret the 12-lead electrocardiogram: pattern memorization
versus the use of vector concepts.
PMID- 10763069
TI - Spontaneous coronary artery dissection: favorable outcome illustrated by
angiographic data.
PMID- 10763070
TI - Current status of stress echocardiography.
AB - Stress echocardiography is a widely applied technique for the evaluation of
individuals with known or suspected coronary artery disease. The technique
combines echocardiographic imaging with exercise testing or pharmacologic stress.
Advances in digital image acquisition and harmonic imaging have substantially
improved the quality of echocardiographic images, and have therefore increased
general applicability of stress echocardiography.
PMID- 10763071
TI - Risk factors related to the occurrence of silent myocardial ischemia in Mexicans.
AB - BACKGROUND: Silent myocardial ischemia is a growing world health problem. It has
been related to factors that promote an increase in myocardial oxygen demand or
affect coronary vasomotor tone. Coronary artery disease has shown an increasing
trend in Mexico in this century. HYPOTHESIS: The aim of the study was to estimate
the strength of the association between some risk factors and the occurrence of
silent myocardial ischemia. METHODS: A cross-sectional study was conducted and
249 individuals were screened by 24-h Holter electrocardiogram. Silent myocardial
ischemia was diagnosed in patients with painless transient ST-segment depression.
All subjects were interviewed for coronary risk factors and total serum
cholesterol was measured. RESULTS: Silent ischemia was diagnosed in 115 patients
(46%), who were older (59 +/- 9 vs. 57 +/- 11 years; p = 0.01). In a logistic
regression analysis, a lower risk for silent ischemia was found in patients with
thrombolysis [odds ratio (OR) 0.28; 95% confidence interval (CI 95%) 0.14-0.53],
or those who followed their medical treatment (OR 0.16; CI 95% 0.04-0.68). The
major risk factors were hypercholesterolemia (OR 1.6; CI 95% 0.9-2.9) and more
severe coronary artery disease (OR 2.5; CI 95% 1.1-5.7). CONCLUSIONS: Some
coronary risk factors are related to silent ischemia. It is still important to
diagnose this entity, but modification of its related risk factors should be kept
in mind to diminish its occurrence and its severe consequences.
PMID- 10763072
TI - Long-term prognosis of patients with angina treated with enhanced external
counterpulsation: five-year follow-up study.
AB - BACKGROUND: Enhanced external counterpulsation (EECP) is a noninvasive treatment
for coronary artery disease (CAD) that has been used successfully in patients not
responding to medical and/or surgical therapy. HYPOTHESIS: The study was
undertaken to evaluate the effect of EECP on long-term prognosis in such
patients. METHODS: Major adverse cardiovascular events (MACE) were tracked in 33
patients with CAD treated with EECP. Patients were subgrouped based on whether or
not they demonstrated an early improvement in radionuclide stress perfusion
imaging (Responders vs. Nonresponders) and followed for MACE over a mean follow
up of 5 years. Patient population characteristics included 73% with multivessel
disease; 45% with prior myocardial infarction(s); and 61% who had undergone
either coronary artery bypass grafting (CABG) or percutaneous transluminal
coronary angioplasty (PTCA), or both. RESULTS: There were 26 of 33 (79%)
Responders, and 7 of 33 (21%) Nonresponders. Subsequent MACE over the 5-year
follow-up included four deaths and eight patients with cardiovascular events
[acute myocardial infarct (4), new CABG or PTCA (6), valve replacement (1),
unstable angina (1)]. Nonresponders had significantly (p < 0.01) more MACE (6/7
or 86%) than Responders (6/26 or 23%). Overall, 21 of the 33 (64%) patients
remained alive and without MACE and the need for revascularization 5 years post
EECP treatment. CONCLUSION: This study suggests that, particularly for the
majority of patients demonstrating improvement in radionuclide stress perfusion
post treatment, EECP may be an effective long-term therapy.
PMID- 10763073
TI - Plasma big-endothelin levels, cardiac autonomic neuropathy, and cardiac functions
in patients with insulin-dependent diabetes mellitus.
AB - BACKGROUND: The alteration of endothelin (ET) levels in diabetic patients with
cardiac autonomic neuropathy (CAN) has not been studied extensively and its
correlation with cardiac function parameters has not been discussed. HYPOTHESIS:
The aim of the present study was to discuss the correlation between the degree of
cardiac autonomic neuropathy, plasma big-ET levels, and cardiac functions in
diabetic patients who were clinically free of cardiovascular disease. METHODS:
Twenty subjects (32.1 +/- 7.8 years, 11 men, 9 women) with insulin-dependent
diabetes mellitus (IDDM) were studied to evaluate the relationship between
circulating big-endothelin (big-ET1) levels, CAN, and cardiac functions. The
severity of CAN was scored according to Ewing's criteria. Cardiac functions were
assessed using Doppler echocardiography. RESULTS: Left ventricular systolic
function in the patient group was within normal limits and comparable with the
values of the control group (n = 10). The mean E/A values of diabetics with CAN
(1.15 +/- 0.33, p = 0.004) and without CAN (1.34 +/- 0.17) were significantly
lower than those of controls (1.57 +/- 0.27). Diabetics with CAN had
significantly higher big-ET1 values (81.1 +/- 94 pg/ml) compared with others
(12.4 +/- 5.9 and 21.1 +/- 17.7 pg/ml, p = 0.04). Circulating big-ET1 levels
showed a significant correlation with E/A values in the control group (p = 0.01,
r = -0.7) and with peak A values (p = 0.003, r = 0.64) in diabetics. The CAN
score correlated negatively with E/A values (p = 0.01, r = 0.54). CONCLUSIONS:
High big-ET levels might have an important role in the pathogenesis or
consequences of diastolic dysfunction in diabetics with CAN. Their role in
cardiac autonomic neuropathy and diastolic dysfunction should be investigated
further.
PMID- 10763074
TI - Acute management of atrial fibrillation and atrial flutter in the critical care
unit: should it be ibutilide?
AB - BACKGROUND: Ibutilide is currently indicated for the rapid conversion of atrial
fibrillation (Afb) or atrial flutter (Afl) of recent onset but limited to
patients who are hemodynamically stable and without symptomatic cardiovascular
conditions. HYPOTHESIS: The study was undertaken to assess the efficacy and
safety of ibutilide in patients with Afb or Afl associated with acute
cardiovascular-medical disorders and in patients receiving prior selective
antiarrhythmic drug therapy. METHODS: The study included 34 patients, mean age 75
+/- 16.3 years, with Afb (n = 25) or Afl (n = 9) having a variety of disorders,
for example, congestive heart failure, unstable angina, borderline hypotension,
respiratory failure, and chronic renal failure. Prior antiarrhythmic drugs
consisted of propafenone (n = 5) or amiodarone (n = 3). Eligibility for
cardioversion was established with appropriate anticoagulation or transesophageal
echocardiography findings. Ibutilide was given as up to two 10 min infusions of 1
mg separated by 10 min. RESULTS: The overall conversion rate after ibutilide was
79.4% (27/34 patients): 80% for Afb and 78% for Afl. More than 90% converted
within 1 h of treatment. A high conversion rate of 92% resulted in those with an
arrhythmia duration of < or = 1 week. All eight patients with prior
antiarrhythmic therapy converted to sinus rhythm. The average baseline QTc
interval for all patients increased 17.1% (397 +/- 63.3 to 465 +/- 60.2 ms) at 30
min. For eight patients (including four who received prior antiarrhythmic drugs),
QTc interval prolongation > or = 500 ms was associated with nearly half the
entire incidence of arrhythmic events. Proarrhythmia, the exclusive adverse
effect, consisted of ventricular extrasystoles (n = 10) and nonsustained
monomorphic ventricular tachycardia (VT) (n = 2) managed with intravenous MgSO4,
and sustained polymorphic VT (n = 1) requiring electrical cardioversion.
CONCLUSION: Ibutilide is an effective and well tolerated drug for the rapid
termination of Afb or Afl of recent onset associated with symptomatic and/or
hemodynamically unstable disorders, and it is most efficacious (> or = 90%) when
the atrial arrhythmia is < or = 1 week in duration. Proarrhythmic events are
readily manageable in a monitored unit with access to appropriate treatment.
PMID- 10763075
TI - Potential reduction of costs and hospital emergency department visits resulting
from prehospital transtelephonic triage--the Shahal experience in Israel.
AB - BACKGROUND: The rising cost of services provided by hospital emergency
departments is of major concern. Attempts to reduce the costs of emergency
cardiac care have thus far focused primarily on medical and administrative
management in the hospital. The role of the patient in appropriate prehospital
decision-making has been generally ignored. HYPOTHESIS: Membership in "Shahal"
(an integrative telemedicine system) may have beneficial effects on patient
decision-making and national health costs. METHODS: During a 6-month period, a
random group of subscribers who had called for medical assistance during the
previous 24 h were asked what action they would have taken had they not been
Shahal subscribers. All study patients were followed for at least 7 days.
RESULTS: In all, 1,608 subscribers (age 71 +/- 13 years) were included. Of these,
514 replied that they "would have waited," 363 "would have contacted their
physicians," and 731 "would have sought emergency department care." Of the
presenting medical problems, 86% were resolved without utilizing hospital
facilities. A mobile intensive care unit was dispatched in 412 (26%) cases. A
cost estimate of abuse indicated that the service resulted in a savings to the
national economy of approximately $830,000 per 10,000 members per year.
CONCLUSIONS: This study demonstrated that Shahal membership can reduce costs of
medical care and the number of hospital emergency department visits.
PMID- 10763076
TI - Enhanced detection of ischemic but viable myocardium by QT interval dispersion on
treadmill exercise electrocardiograms of patients with healed anterior wall
myocardial infarcts.
AB - BACKGROUND: The presence of ischemic but viable myocardium in infarcted areas is
an important indication for coronary revascularization, but is often difficult to
detect with the use of treadmill exercise electrocardiography (ECG). HYPOTHESIS:
QT interval dispersion (QTd) is a sensitive method for detecting myocardial
ischemia and may improve the accuracy of treadmill exercise ECG testing for
detecting ischemic but viable myocardium in infarcted areas. METHODS: Forty-five
patients with Q-wave anterior wall myocardial infarctions who underwent treadmill
exercise ECG, exercise reinjection thallium-201 (201Tl) scintigraphy,
radionuclide angiocardiography, and coronary angiography 1 month after infarction
were enrolled in this study. The presence of viable myocardium in the infarct
area was determined by exercise reinjection 201Tl scintigraphy. Patients who had
no redistribution in the infarct area after reinjection were included in Group 1,
and those with redistribution were included in Group 2. RESULTS: QTd immediately
after exercise, and the difference between QTd before and immediately after
exercise, were significantly greater in Group 2 than in Group 1. The sensitivity,
specificity, and accuracy of conventional ST-segment depression criteria for
detecting viable myocardium in the infarct area were 48, 64, and 56%,
respectively. The measurement of QTd immediately after exercise (abnormal: > or =
70 ms; normal: < 70 ms) improved the sensitivity, specificity, and accuracy to
78, 82, and 80%, respectively. CONCLUSIONS: This novel diagnostic method using
QTd-based criteria significantly improves the clinical usefulness of treadmill
exercise ECG testing for detecting ischemic but viable myocardium in infarct
areas in patients with healed Q-wave anterior wall myocardial infarctions.
PMID- 10763077
TI - Brain natriuretic peptide increases acutely and much more prominently than atrial
natriuretic peptide during coronary angioplasty.
AB - BACKGROUND: Increased levels of plasma brain natriuretic peptide (BNP) are
observed in patients with congestive heart failure, hypertension, left
ventricular hypertrophy, and acute myocardial infarction. However, there are no
data on serial changes in plasma levels of BNP in patients undergoing coronary
angioplasty. HYPOTHESIS: The study was undertaken to examine plasma
concentrations of BNP together with those of atrial natriuretic peptide (ANP) in
patients undergoing percutaneous transluminal coronary angioplasty (PTCA).
METHODS: Plasma concentrations of BNP and ANP were examined in 13 patients with
stable angina pectoris and good left ventricular function undergoing PTCA. Blood
samples were taken from the femoral vein at baseline, after the first balloon
inflation, after the end of the procedure, and 4 h thereafter. RESULTS: Plasma
BNP levels were 14 +/- 4 at baseline, 22 +/- 10 after the first balloon
inflation, 28 +/- 12 at the end of the procedure, and 15 +/- 4 pgr/ml 4 h
thereafter (F = 13.05, p < 0.00001). Plasma ANP levels were 80 +/- 15, 86 +/- 14,
90 +/- 24, and 75 +/- 6 fmol/l (F = 5.95, p = 0.002), respectively. The increase
of BNP at the end of the procedure was related to the increase of ANP (r = 0.78,
p = 0.002). CONCLUSION: Plasma BNP levels increase acutely and much more
prominently than those of plasma ANP during coronary angioplasty; however, plasma
BNP levels return to baseline values shortly after the end of the procedure.
PMID- 10763078
TI - Early recurrence of angina pectoris after aortocoronary bypass surgery.
PMID- 10763079
TI - "Vegetation plop"--auscultatory findings in large mitral valve vegetation.
PMID- 10763080
TI - Takayasu's pulseless disease.
PMID- 10763081
TI - Ortner's syndrome in association with mitral valve prolapse.
AB - The case of an 83-year-old woman with a history of hypertension, valvular heart
disease, atrial fibrillation, and cardiomegaly is presented. The patient also had
progressive hoarseness of her voice and intermittent dysphagia. Ear, nose, and
throat examination revealed left vocal cord paralysis. Echocardiography revealed
severely dilated left (LA) and right atria (RA), moderate mitral regurgitation,
severe tricuspid regurgitation, and prolapse of both these valves. A review of
literature of Ortner's or cardiovocal syndrome is presented. Ortner's syndrome
due to mitral valve prolapse has not been reported previously.
PMID- 10763082
TI - Myocardial stunning in hyperthyroidism.
AB - The cases of two patients with hyperthyroidism and acute left ventricular (LV)
dysfunction with segmental wall motion abnormalities resulting in heart failure
are reported. Both had electrocardiographic changes mimicking ischemic coronary
artery disease. Treatment with antithyroid medications, beta blockers, and
angiotensin-converting enzyme inhibitors rapidly restored LV function. The rapid
reversibility suggests a role for myocardial stunning, an important entity to
recognize in hyperthyroidism since this form of LV dysfunction can be reversed
with appropriate treatment.
PMID- 10763083
TI - Tricuspid valve group B streptococcal endocarditis after an elective termination
of pregnancy.
AB - A patient developed fever, chills, and shortness of breath after an elective
first trimester dilation and curettage. Blood cultures grew Group B
streptococcus, and a transesophageal echocardiogram revealed a 2 x 2 cm
vegetation on the tricuspid valve and global left ventricular hypokinesis. A 6
week course of parenteral antibiotics and vasodilator therapy resulted in
resolution of the valvular vegetation as well as of the left ventricular
dysfunction.
PMID- 10763084
TI - High-output heart failure resulting from a remote traumatic aorto-caval fistula:
diagnosis by echocardiography.
AB - Congestive heart failure (CHF) due to high output states is known to occur in a
variety of systemic illnesses and in patients with arterial-venous fistulas. This
paper reports the case of a 45-year-old man admitted to the emergency room with a
diagnosis of new onset atrial fibrillation and CHF, whose past medical history
was not significant except for a gunshot wound to his abdomen 22 years
previously. The etiology of his CHF together with the cardiomegaly and
hyperdynamic left ventricular systolic function was unknown. A subcostal view
routinely done during transthoracic echocardiography revealed a severely dilated
inferior vena cava and the presence of an aorto-caval fistula by color doppler.
The patient underwent successful corrective repair with dramatic improvement in
symptoms and resolution of the atrial fibrillation, and cardiac size returned to
normal. This rare case emphasizes that patients with refractory CHF must be
closely examined with particular attention to palpation and auscultation over all
scars, irrespective of the duration since any traumatic or surgical event.
PMID- 10763085
TI - Augustus Desire Waller.
PMID- 10763086
TI - Who's smoking now? The epidemiology of tobacco use in the United States and
abroad.
AB - Numerous epidemiological studies have linked tobacco use with a wide variety of
diseases. Strong government-supported anti-smoking campaigns have decreased the
prevalence of smoking in many developed countries, including the United States.
However, it remains a major public health pariah. In developing countries, such
as China, cigarette smoking and other forms of tobacco use continue to increase.
If unchecked this will eventually lead to 10 million deaths per year worldwide.
Even in the United States, the prevalence of smoking is rising in crucial
population groups such as adolescents. Recent advances have made physicians more
able to help patients quit smoking, but organized campaigns must be further
strengthened to prevent the initiation of tobacco use, especially in the young.
PMID- 10763087
TI - The pathology of smoking-related lung diseases.
AB - A broad range of non-neoplastic pulmonary lesions is associated with cigarette
smoking including airway diseases with airflow limitation, vascular alterations
and interstitial lung diseases characterized by diffuse radiographic
abnormalities and restricted lung volumes. This article focuses on the pathology
of smoking-related emphysema, alterations of large airways, alterations of
pulmonary vessels, respiratory bronchiolitis associated interstitial lung disease
(RB-ILD), desquamative interstitial pneumonia (DIP), and eosinophilic granuloma
(EG).
PMID- 10763088
TI - Smoking and pediatric respiratory health.
AB - Many children are exposed to smoking both prenatally and postnatally. Prenatal
exposure to mainstream smoke from the mother and even to environmental tobacco
smoke (ETS) from the mother in utero has been shown to change fetal lung
development and cause airflow obstruction and airway hyperresponsiveness.
Children exposed to ETS postnatally have more symptoms of cough, wheeze,
respiratory illnesses, decreases in lung function, and increases in airway
responsiveness. Smoke exposure is associated with the early development of
asthma, increased severity of asthma, and the development of allergy. Finally
smoke exposure is associated with sudden infant death and airway obstruction.
This article reviews the spectrum of effects of cigarette smoke exposure on the
respiratory health of infants and children and highlights basic science research
exploring the mechanisms of these effects.
PMID- 10763089
TI - Cigarette smoking and women's respiratory health.
AB - Cigarette smoking is claiming an increasing health toll among women, with rising
morbidity and mortality related to lung cancer and COPD. Whether women are more
susceptible to the effects of cigarettes with regard to carcinogenesis and
development of COPD remains controversial. Gender differences clearly exist in
certain aspects of cigarette-related disease, including histologic distribution
of lung cancer and the ability of smokers to quit. It is likely that gender
differences also exist in the reasons that individuals choose to smoke.
Understanding those reasons will be important in developing targeted programs for
smoking cessation and in addressing the challenge of the prevention of smoking
initiation in women.
PMID- 10763090
TI - Smoking and chronic obstructive pulmonary disease.
AB - Smoking is overwhelmingly the major cause of chronic bronchitis and emphysema
worldwide. Additional risk factors for developing COPD are presented, along with
the variables that govern cigarette smoke deposition in the lung. Major paradigms
for the pathogenesis of COPD, including the protease-antiprotease and oxidant
antioxidant theories are described, and evidence for impaired reparative
mechanisms in the causation of emphysema is noted. A description of the natural
history of declining lung function in smokers and in the susceptible subset of
smokers that ultimately develop smoking-induced COPD is accompanied by a
discussion of the effects of smoking cessation on preservation of lung health.
The disordered ventilation and gas-exchange physiology in the cigarette smoke
damaged lung is explained on the basis of the observed morphological changes.
PMID- 10763091
TI - Smoking and the molecular epidemiology of lung cancer.
AB - Lung carcinogenesis in humans requires exposure to environmental agents,
including the inhalation of tobacco smoke, radioactive compounds, asbestos, heavy
metals, and petrochemicals. Tobacco smoking is the risk factor with the highest
attributable lung cancer risk worldwide. This article discusses occupational
carcinogen exposure and exposure from tobacco use, and the lung-cancer risk
associated with these types of exposure.
PMID- 10763092
TI - Diagnosis and staging of lung cancer.
AB - Lung cancer is the biggest cancer killer among men and women in the United
States. Lung cancer can present in a myriad of ways and the goal of prompt
diagnosis and staging requires that the clinician be able to knowledgeably choose
from a variety of tools available for such purpose. Review of some of these tools
and general strategies with regard to staging is provided. Many new technologies
are becoming available and much evaluation needs to be done before their proper
roles become well defined. Little has changed with regard to staging of small
cell lung cancer in recent years. The International System for Staging Non-Small
Cell Lung Cancer was revised for a second time in 1997. Although the revisions
have largely corrected the shortcomings of the 1985 version, some controversies
persist. Whenever possible, a multidisciplinary approach to diagnosis, staging,
and therapy should be utilized. This should include incorporating the services of
the pulmonologist, the thoracic surgeon, the medical oncologist, the radiologist,
the radiation therapist, the pathologist, the respiratory therapist, and the
social worker.
PMID- 10763093
TI - Evidence-based medicine in the treatment of non-small-cell lung cancer.
AB - Treatment decisions for non-small-cell lung cancer require accurate initial
staging of patients. Typically surgical resection is recommended for early stage
disease, while chemotherapy in conjunction with radiotherapy and possibly
surgical resection is recommended for selected patients with locally advanced
disease. Chemotherapy clearly has been demonstrated to improve survival and
quality of life in metastatic disease. Surgical, chemotherapeutic, and
radiotherapy treatment options as well as the role of multi-modality therapy will
be discussed focusing on the evidence for various stages of non-small-cell lung
cancer.
PMID- 10763094
TI - Other smoking-affected pulmonary diseases.
AB - Cigarette smoking is the leading cause of preventable death in the United States.
Smoking adversely affects many organ systems, but especially the lung. Carcinoma
of the lung and chronic obstructive pulmonary disease account for most smoking
associated respiratory morbidity and mortality, and their association with
smoking is both well established and widely recognized. Cigarette smoking also is
associated with differences in the incidence, severity, or natural history of a
broad array of other respiratory illnesses, ranging from the common cold to
pneumothorax, pulmonary hemorrhage, and various interstitial lung diseases.
Interestingly, while the general effect of smoking on respiratory diseases is
adverse, in the cases of sarcoidosis and hypersensitivity pneumonitis smoking may
actually be associated with a decrease in the incidence of disease. In this
article, the author briefly discusses some of the pulmonary and systemic effects
of smoking that might mediate its effects on an array of lung diseases, then
comprehensively reviews less common or less well-recognized smoking-affected lung
diseases such as pulmonary infections, spontaneous pneumothorax, Goodpasture's
syndrome, eosinophilic granuloma and other interstitial lung diseases, and
pulmonary metastatic disease.
PMID- 10763095
TI - Smoking and postoperative pulmonary complications. An evidence-based review of
the recent literature.
AB - Postoperative pulmonary complications (PPC) lead to significant morbidity after
both thoracic and non-thoracic surgical procedures. The role of smoking as an
independent risk factor is controversial, though recent level III and IV studies
suggest that it may indeed be significant. In addition, the role and timing of
pre-operative smoking cessation is not clear. Although some studies suggest that
abstinence too soon prior to operation may actually increase the risk of PPC, it
still appears that aggressive counseling for smoking cessation prior to any
elective procedure is the best overall course of action.
PMID- 10763096
TI - Upper airway complications of smoking.
AB - Tobacco smoke has a myriad of acute and chronic effects on the upper airway.
These problems can range from aggravating inflammatory reactions to life
threatening malignancies. Cessation of smoking is the key to successful
resolution of many upper airway complaints. An increased awareness of these
disease processes can improve early diagnosis and appropriate treatment. A better
awareness of these processes may facilitate physicians in counseling patients
about smoking.
PMID- 10763097
TI - Smoking and cardiovascular disease.
AB - Mainstream and ETS exposure are strong risk factors for cardiovascular disease in
men and women. The relationships between smoking and cardiovascular disease
result from multiple mechanisms that interact to contribute to atherosclerosis,
vascular injury, thrombosis, and vascular dysfunction. We are only now beginning
to understand how smoking contributes to the genesis and progression of
cardiovascular disease. Because of the complexity of the interactions between
nicotine and the components of MSS, ETS, and sidestream smoke with the
vasculature, it will take a great deal of time and effort to fully unravel the
mechanisms by which smoking contributes to cardiovascular disease. In addition,
cardiovascular risk in female smokers is complicated by hormonal variables that
may contribute to greater relative risk. It is important that health care
providers, educators, and policy makers recognize the changing patterns of
smoking and the impact of smoking on cardiovascular disease, and continue
campaigns aimed at enhancing smoking cessation in the general population and in
teens. Rigorous research is needed on the changing cultural, psychosocial, and
environmental factors that influence tobacco use to improve our understanding of
racial/ethnic smoking patterns, and identify strategic tobacco control
opportunities. The capacity of tobacco control efforts to keep pace with patterns
of tobacco use and cessation depends on timely recognition of emerging prevalence
and cessation patterns and the resulting development of appropriate community
based programs to address the factors involved. Smoking trends today will
determine how heavy the health burden of cardiovascular disease and others will
be among communities tomorrow. Programs that aim at early intervention and
reflect cultural diversity will be the cornerstone in the battle against tobacco
use. Continued interest in research, educational, and prevention efforts are
needed to help curb the risk of cardiovascular disease from smoking in men and
women.
PMID- 10763098
TI - Tobacco-related diseases. Is there a role for antioxidant micronutrient
supplementation?
AB - It is clear that smoking causes an increase in free radicals, reactive nitrogen
and oxygen species (RNS and ROS, respectively), and that cigarette smoking is
associated with increases in the incidence and severity of several diseases
including atherosclerosis, cancer, and chronic obstructive lung disease. Although
there is still no unequivocal evidence that oxidative stress is a contributor to
these diseases or that an increased intake of antioxidant nutrients is
beneficial, the observation that smokers have lower circulating levels of some of
these nutrients, raises concern. This article discusses the possible links
between the observed oxidant-induced damage related to tobacco smoking, effects
on cellular mechanisms, and their potential involvement in the causation and
enhancement of disease processes.
PMID- 10763099
TI - The human and financial costs of smoking.
AB - Smoking causes about 20% of United States adult deaths and numerous diseases.
Health care for cancer, cardiovascular, and pulmonary diseases from smoking costs
tens of billions of dollars per year. Yet those costs are likely far exceeded by
costs from bereavement, lost productivity, pain and suffering, and health care
for debilities from smoking. Though sometimes more difficult to precisely
quantify than costs for fatalities, the lost productivity, suffering, or familial
costs of smoking are often much larger, more immediate, and more understandable
threats to smokers, their families, and society. This article summarizes
qualitative and quantitative human and financial tolls from smoking. The tolls
range from cigarette burns, to cigarette ignited fire disasters, to caring for
dying smokers and replacing their financial and social contributions to their
spouses, children, grandchildren, and the tax base. In the face of such costs,
smoking cessation and prevention services are likely to be highly cost-effective.
PMID- 10763100
TI - Smoking cessation. Techniques and benefits.
AB - Tobacco dependency syndrome is an organic disease caused by chronic use of
inhaled tobacco smoke. It is occasionally controlled by willpower alone, but
often requires pharmacotherapy in conjunction with various techniques to manage
the psychological manifestations. The two effective drugs are bupropion, which is
an oral antidepressant, and nicotine, which can be administered by several
modalities, including a skin patch, an oral inhalant, a nasal spray, and a
chewable oral preparation. Successful therapy may require both drugs, and
multiple simultaneous nicotine modalities. High-dose nicotine therapy may achieve
an abstinence rate of 80% during therapy, but maintaining drug-free abstinence at
such high levels over long periods is less successful, possibly because the
tobacco smoke-induced changes in brain structure and function are not easily
reversed.
PMID- 10763101
TI - [A phase study of the glutamate-dependent EEG effects in the alpha- and beta
frequency ranges during the acute and subchronic administration of piracetam to
rats].
AB - The glutamatergic component of the piracetam effect upon the EEG frequency
spectrum was studied in wakeful rats with electrodes implanted into somatosensory
cortex and hippocampus and a cannula in the lateral ventricle. Piracetam at a
dose of 400 mg/kg enhanced the EEG activity in the range of 10.4-16.4 Hz in two
phases: early (10-40 min) and late (above 50 min). Only the late phase was
retained against the background of the NMDA receptor antagonist CPP (0.1 nmole).
This stage was also retained upon the subchronic administration of piracetam. The
AMPA-receptor agonist quisqualate (5 nmole) enhanced the EEG power in the range
of 1.5-5 Hz and decreased the activity at 10.4-16.4 Hz. The AMPA-receptor
antagonist glutamate diethyl ester (1 mumole) leveled the agonist effect, but
enhanced the piracetam action in the late phase at frequencies in the alpha
range.
PMID- 10763102
TI - [The search for selective blockers of NMDA and AMPA/kainate receptors in a series
of bis-ammonium compounds with adamantyl radicals].
AB - Two groups of substances capable of selectively blocking the NMDA and
AMPA/kainate receptors in experiments on intact animals were found in a series of
bis-ammonium compounds with adamantyl radicals. The selective NMDA receptor
blockers (IEM-1754, IEM-1755, IEM-1752), as well as the reference agents MK-801
and memantine, produced anticonvulsant, anti-ischemic, and antihypoxant effects
and prevented the loss of experimental animals from toxic doses of NMDA. The
selective AMPA/kainate receptor blockers (IEM-1553, IEM-1751, IEM-1592, and
DNQX)) also produced the anticonvulsant, anti-ischemic, and antihypoxant effects,
but did not prevent from the loss of animals caused by the toxic doses of NMDA.
The maximum activity was observed for IEM-1754, the activity of which exceeded
that of MK-801 (by a factor of 5-10) and memantine (by a factor of 300-800) in
all the test objects.
PMID- 10763103
TI - [The neurochemical profile of the caudate nucleus in the anxiolytic action of
benzodiazepine and nonbenzodiazepine tranquilizers on different models of
anxiety].
AB - In the experiments on rats in avoidance response to "eliminated area" and
"threatening situation" it is found that the microinjection of monoamines and
amino-acids of mediator action, adreno- and dophaminemimetics, their antagonists,
and blocker of GABAA receptors picrotoxine into dorsal and ventral sections of
caudate nucleus elucidates different functional value and neurochemical special
features of examined neostriatum specimens in realization of anxiety states of
different origin. Local injection of chlordiazepoxide, phenibutum, indoterum,
campirone and campironine into aforementioned sections of the caudate nucleus
reduces the state of anxiety in "eliminated area" and/or "threatening situation"
response tests thus revealing the similarity with well-known effects of GABA and
serotonin and substantial difference in the effects of catecholamines and
glutamine acid. It is found that anti-anxious effect of benzodiazepine and
nonbenzodiazepine anxiolytics can be mediated through participation of neuron
matrices of dorsal and ventral sections of the caudate nucleus having
functionally ambiguous neurochemical profile.
PMID- 10763104
TI - [The effect of GABA-positive agents on the formation of morphine dependence and
on the manifestations of a withdrawal syndrome].
AB - Experiments on mice showed that the GABA-positive preparations (THIP, baclofen,
fenibut, valproate sodium) intraperitoneally injected in the course of the
morphine addiction development (double daily subcutaneous injections at a dose
increasing from 10 to 100 mg/kg over a period of 8 days) and, to a greater
extent, upon cessation of the morphine injections, partly reduce manifestations
of the naloxone-enhanced (0.1 mg/kg, s.c.) daily abstinence, as evaluated by the
hopping activity and pair interaction tests.
PMID- 10763105
TI - [The affinity of m-cholinomimetics for the m-cholinoreceptors in different
tissues].
AB - The affinities of some cholinomimetics (acetylcholine, methacholine, carbachol,
oxotremorine, aceclidine and pilocarpine) for muscarinic acetylcholine receptors
of various isolated tissues (rat spontaneously beating atria, rat electrically
stimulated left atrium, segment of rat aorta precontracted by PGF2 alpha, rat
trachea and guinea pig trachea) was estimated in functional experiments. It was
established that each of full agonists (acetylcholine, methacholine, carbachol,
oxotremorine and aceclidine) has lower affinities for muscarinic M2 receptors of
rat atria as compared with its affinity for muscarinic M3 receptors of rat aorta.
The partial agonist pilocarpine has similar affinities for muscarinic receptors
of rat atria and rat aorta. It was shown that contractile response of guinea pig
tracheal smooth muscle is two-staged. It was found that rat and guinea pig
tracheal smooth muscle contractions are mediated primarily by muscarinic M3
cholinoceptors and partially by M2 cholinoceptors.
PMID- 10763106
TI - [The efficacy of different salt diets and the modulation of the protective action
of cerebrolysin in an experimental disturbance of the cerebral circulation].
AB - Experiments on rats showed that long-term excess sodium chloride feeding
increased the loss of animals as a result of the common carotid artery ligation.
The effect is related to maximum decrease in the local cerebral blood flow and
sharply pronounced brain swelling. The sodium chloride substitute giposol reduced
the extent of cerebral ischemia and produced antiswelling effect. On the
background of the hyper-sodium-chloride diet, the protective action of
cerebrolysine was less pronounced as manifested by decreasing survival of the
test animals. In contrast, the administration of giposol increased the efficacy
of cerebrolysine with respect to the carotid artery occlusion.
PMID- 10763107
TI - [The effect of bromantane on the cardiovascular and sympathetic-adrenal systems
in animals].
AB - Bromantan administration markedly increases the stroke and minute blood volume at
a reduced heart rate and peripheral resistance in anaesthetized rats, while the
systemic arterial pressure exhibits an insignificant short-time increase.
Bromantan also weakly increases the pressor effects of adrenaline and
noradrenaline. In anaesthetized cats, bromantan modifies the shape of the
amplitude-frequency characteristic of EEG measured in the upper cervical
ganglion, reducing (against the initial level) the induced potential in the
frequency range of the preganglionic fiber stimulation (1-10 and 25-30 Hz). In
freely moving rats, capable of well-learnt Sidman's [correction of Seedman's]
operant activity, bromantan showed a reliable tendency to decrease the rate of
noradrenaline and adrenaline excretion with urine.
PMID- 10763108
TI - [The action of a new taurine derivative in different variants of hypoxic states].
AB - A new N-phenylalkyl derivative of taurin was tested. The results show that this
compound exhibits a pronounced general antihypoxant activity and is capable of
increasing the stability of heart with respect to hypoxia and anoxia, protecting
heart against the ischemic damage, and facilitating the adaptation capacity of
myocardium.
PMID- 10763109
TI - [The effect of semax and mexidol on the course of acute pancreatitis in rats].
AB - The effect of semax and mexidol on the course of acute pancreatitis in rats was
studied in comparison with the action of contrical, fluorouracil, and dibunol. It
was established that a single intraductal or intraperitoneal administration of
semax or mexidol markedly reduces the loss of experimental animals (to 10-13%),
decreases hyperfermentemia, lipid peroxidation activation, and vascular
permeability, improves microcirculation, and accelerates healing of the damaged
pancreatic zones by substitutional repair of pancreatic acini not accompanied by
coarse fibrous changes in the parenchyma. Upon the intraductal administration,
semax and mexidol were more effective than contrical, fluorouracil, and dibunol.
PMID- 10763110
TI - [The effect of the new Russian concentrate of n-3 polyunsaturated fatty acids
epaden on thrombocyte functional activity in vitro].
AB - Epaden, the new domestic concentrate of n-3 polyunsaturated fatty acids (PUFA),
is capable of inhibiting in vitro the human thrombocyte aggregation induced by
ADP, collagen, and thrombin. It was established that the effect can hardly be
related to the action of cyclooxygenase metabolites of eicosapentadienoic acid
(entering into the epaden composition). The activity of epaden is probably
explained by the effect of lipoxygenase metabolites of the n-3 polyunsaturated
fatty acids or by the ligand properties of polyene acids entering into epaden. In
addition, epaden is capable of reducing the release of thrombocyte factor 4 and
tissue type plasminogen activator inhibitor from activated thrombocytes.
PMID- 10763111
TI - [The use of the DiaMorf (Russia) computer-programmed unit for evaluating the
effect of steroids and cytostatic agents on cultured cells].
AB - The effect of some steroid hormones and their synthetic analogs--dexamethasone,
estradiol, progesterone, testosterone, and cytostatics--on the fibroblast nuclei
in a monolayer culture was studied. Their proliferation was studied at the same
time by the radioindicator method. The method of computerized morphodensitometry
with the use of the apparatus-programmer complex DiaMorf (Russia) showed that the
compounds under study induce reorganization of interphase chromatin of fibroblast
nuclei over the molecules, the amount of which may be recorded by means of the
computer system of analysis of cell and tissue images.
PMID- 10763112
TI - [An acute toxicity study of bromantane].
AB - The toxicity of bromantan was evaluated by conventional acute tests (according to
Belen'kii) and by the behavioral activity data (according to Irvin). A method of
integral graphical representation of the behavioral activity data is suggested,
according to which the results are plotted as a "dose trajectory." Using the dose
trajectory constructed for bromantan, the levels of therapeutic, toxic, and
lethal doses were calculated. It was established that catecholaminergic effects
account for the mechanism of therapeutic action of bromantan, while cholinergic
effects determine the drug action in toxic doses.
PMID- 10763113
TI - [A toxicological study of a phytopreparation made from an extract of alfalfa
(Medicago sativa)].
AB - A phytopreparation from lucerne (Medicago sativa) was studied with respect to the
acute and chronic toxicity and the action upon the cellular genetic mechanism. It
was found that the preparation belongs to the group of practically nontoxic
properties.
PMID- 10763114
TI - [A chamber for evaluating the free choice by laboratory rats and mice of a space
containing tobacco smoke].
AB - An original experimental setup has been designed that allows evaluation of the
free preference of space containing tobacco smoke by small laboratory animals.
For the laboratory mice (C57B1/6 and BALB/c) and rats (MNRA and MR) placed every
day into this box, no emotional-stress reaction (ESR) caused by the environment
novelty was observed on the 19th day of experiment. A difference in the free
preference of space containing tobacco smoke was observed between inbred animals
with active and passive ESR phenotypes.
PMID- 10763115
TI - [The effect of drugs on free-radical oxidation].
AB - Data available in the literature and the results of original investigations of
the effect of drugs on the free-radical oxidation process are summarized. It is
pointed out that the character of drug influence on the on the free-radical
oxidation process must be taken into account in selecting drugs for the treatment
of particular diseases.
PMID- 10763116
TI - [The effect of the preparation rodakson on the psychophysiological and physical
adaptation of students to an academic load].
AB - The effect of rhodaxon, an adaptogen preparation based on the Rhodiola rosea
extract, upon the physical and intellectual working capacity and psychoemotional
state of foreign students during their study in a Russian high school was
evaluated. It was established that rhodaxon administration provided increase in
the amount of veloergometric work accomplished and reliably increased the
kinesthesiometric sensitivity. The drug also lead to marked increased in the
general condition and a decrease in the level of psychic fatigue and situational
anxiety. On the whole, the pharmacological properties of the rhodaxon preparation
studied coincided with those reported for the gold root extract. The fact that
the rhodaxon preparation contains no ethyl alcohol extends possibilities of the
clinical administration of the new preparation.
PMID- 10763117
TI - Effect of progesterone and oestradiol on expression of connexin43 in cultured
human myometrium cells.
AB - In human myometrium, the formation of gap junctions at various stages of labour
and in correlation with the concentration of progesterone and oestradiol in
maternal blood was described previously by electron microscopy and laser confocal
microscopy of immunohistochemically stained myometrial sections. The present
investigation focused on the effect of continuous exposure of isolated myometrial
tissue to progesterone and oestradiol on the number of gap junction plaques in
human myometrium cells in vitro. The presence of gap junctions was evaluated by
immunocytochemistry with antibodies against gap junction protein, connexin43
(Cx43). Human myometrial cells were isolated from biopsies obtained from term
pregnant women who had an elective caesarean operation in the 37th or 40th week
of pregnancy. The dispersed myometrial cells that were obtained by limited
enzymatic digestion of the myometrial samples were maintained in monolayer
culture for 1, 3 and 6 days in the presence of medium that contained foetal
bovine serum and the steroids at different concentration. In primary culture, as
well as after several passages, the characteristics of these cells were
morphologically and biochemically similar to those of smooth muscle cells and
myometrial tissue. The obtained results showed that the cells in culture
responded synchronously to the increased concentrations of
oestradiol/progesterone mixtures. The number of gap junctions increased
significantly on days 1, 3 and 6 in culture and showed positive correlation (p <
0.05) with the cell number when the concentration of oestradiol was raised to 1
microgram/mL in the progesterone ratio (1.0 microgram/0.5 microgram/mL). No
significant correlation, however, in connexin43 gap junction number versus cell
number was observed between the six experimental groups treated with progesterone
only.
PMID- 10763118
TI - Rhodanese activity and total sulfur content in frog and mouse liver.
AB - The activity of rhodanese was histochemically tested in cryostat sections of the
frog (Rana temporaria) and mouse liver. The activity levels were evaluated in
sections, and the results were expressed as the ratio of the area of all
granules, products of the enzymatic test, to the total analyzed area (area
fraction). The present study confirmed the biochemically detected activity of
rhodanese, and showed a large pool of endogenous sulfane sulfur donors,
substrates for rhodanese, in the frog liver. The area of a single granule
corresponded to the size of the mitochondrium, what suggests enzyme localization
in this organelle. In view of this it should be considered whether the rhodanese
activity, biochemically detected in the cytosolic fraction of the frog liver,
results from the enzyme action. The total content of sulfur in cryostat sections
of the mouse and frog liver was calculated and compared on the basis of the
Energy Dispersion Spectrum (EDS) obtained by a scanning microscope. These studies
showed higher total sulfur content in the frog liver than in the mouse liver. The
high total content of sulfur in the frog liver in autumn might be associated with
sulfur storing for protein biosynthesis during the period of hibernation.
PMID- 10763119
TI - A receptor-type protein tyrosine phosphatase PTP zeta is expressed in human
cutaneous melanomas.
AB - We describe the expression of a receptor-type protein tyrosine phosphatase PTP
zeta (or RPTP beta) in human cutaneous melanomas as detected by means of
immunohistochemistry. The expression of PTP zeta has been described to be
restricted to the central nervous system. In developing mice brain high levels of
PTP zeta have been detected indicating its developmental importance; PTP zeta is
also expressed in glioblastoma and neuroblastoma. By the use of
immunohistochemistry we detected PTP zeta in human primary and metastatic
melanomas. The melanocytes of healthy skin remained negative. Due to the
developmental origin of the melanocytes from neural crest, this represents a
further example for transformed cells switching back to express molecules related
to their ontogenetic history. These promising initial results have to be verified
in larger scaled studies; the inclusion of nevi will be necessary to further
elucidate the role of PTP zeta in melanocyte transformation and melanoma
development.
PMID- 10763120
TI - Differential expression of chemokine receptor CXCR4 in Th1 and Th2 subtypes of
CD4+ lymphocytes.
AB - Different cytokine profiles allow to divide the CD4+ lymphocytes into Th1, Th2
and Th0 subtypes. It has been observed that the Th2 cells are more efficient
supporters for HIV-1 replication than the Th1 cells. The Th1 and the Th2 cells
were isolated from peripheral blood lymphocytes of HIV-1 seronegative individuals
and the density of CXCR4 receptors was determined by flow cytometry using
antibodies directed against the CXCR4 receptor. Flow cytometric analysis revealed
higher expression of the HIV-1 co-receptor CXCR4 on Th2 cells than on the Th1,
which might explain better replication of HIV-1 viruses in the Th2 cells.
PMID- 10763121
TI - Antioxidative activity of flavonoids in stimulated human neutrophils.
AB - The release and production of oxidative products generated by the respiratory
burst under the influence of natural flavonoids: quercetin, kaempferol and
isorhamnetin derivatives have been studied in the polymorphonuclear neutrophils
(PMNs) from healthy human donors. Flavonoids were tested in vitro at
concentration range 1-100 microM. The antioxidative potential of flavonoids was
compared to the activity of a food preservative, butylated hydroxyanisole. Two
methods were applied to the measurement of the PMNs respiratory burst: flow
cytometry using dichlorofluorescein diacetate and luminol-dependent
chemiluminescence. It was found that the studied products decreased the
neutrophil hydrogen peroxide production in concentration-dependent manner. The
highest degree of inhibition was registered for concentration of 100 microM,
although in the chemiluminescence method the metabolic activity inhibition was
more prominent. Antioxidative activity of flavonoids depended on the number of
hydroxyl groups. These results provide useful data for establishing methods used
to assess the respiratory burst in phagocytic cells.
PMID- 10763122
TI - Peripheral blood reticulocytes and their reference range values for percentage,
absolute count, and immature fraction in children, measured with flow cytometry.
AB - Reticulocyte count by manual method has been the assay traditionally used to
evaluate the status of erythropoiesis in hematological disorders with
disturbances in erythropoietic activity. However, due to its variability, it is
rather a semiquantitative method. Automated reticulocyte counting based on flow
cytometry has provided more objective and exact measure of reticulocytes. Besides
traditional parameters, such as percentage and absolute number of reticulocytes,
automatic reticulocyte counters can detect differences in the amounts of cellular
RNA present in immature erythrocytes that reflect their maturational stages and
evaluate indices of reticulocyte maturation such as RMI, HFR, IRF. These
parameters can be used as the earliest signs of marrow engraftment after
autologous or allogeneic bone marrow transplantation. Currently there is no
strict agreement between various automated methods of reticulocyte evaluation.
Additionally, lack of standardization and quality control materials for this
assay compels determination of own, interlaboratory ranges of reference values
for new proposed parameters. A group of 102 children aged from 3 months to 18
years with normal hematological parameters was examined. Samples of blood stained
supravitally with thiazole orange were analyzed in a flow cytometer. Results for
percentage, absolute number and immature reticulocyte fraction expressed as a
mean +/- 2SD were: 2.00 +/- 1.56%, 88.8 +/- 68.94 x 10(3)/microliter, and 0.22 +/
0.16, respectively. A poor correlation was found between IRF and other
parameters, suggesting its independent role as a marker of erythropoietic
activity. Automated reticulocyte counting will probably improve the diagnosis and
monitoring of many hematological diseases.
PMID- 10763123
TI - Cell cycle and apoptosis in tumours of oral cavity estimated by image cytometry.
AB - The aim of investigations was to examine whether diploid and aneuploid tumours of
oral cavity differ in frequencies of occurrence of individual phases of cell
cycle and of apoptosis. Investigations were carried out on 53 tumours using
techniques of image cytometry. The studies were performed on properly isolated
cells of tumours, which were stained using Feulgen method and analysed by image
cytometry. Using a suitable computer programme, the percentages of cells present
in individual phases of cell cycle and in apoptosis were estimated. No respective
differences could be disclosed between diploid and aneuploid tumours. In
addition, the ratios of the fraction of cells in S phase of the cell cycle and
those in apoptosis were calculated and were found to carry certain prognostic
significance in patients with squamous cell carcinomas of oral cavity.
PMID- 10763124
TI - Flow cytometric estimation of the plasma membrane diversity of transplantable
melanomas, using annexin V.
AB - Using a recently described flow cytometric assay probing for cell surface
exposure of phosphatidylserine with fluoresceine-labeled annexin V, we attempted
to establish if there existed any differences in the phospholipid bilayer of the
plasma membranes of melanoma cells isolated from two lines of a hamster
transplantable melanoma characterized by a common origin but differing in many
biological features. In contrast to control nonstaining cells, the cells of both
melanoma lines bound annexin V, but at a different rate: 88% of melanotic and 94%
of amelanotic melanoma cells were annexin V positive. Among cells of the native
melanotic melanoma line we distinguished only one cell population binding annexin
but in some experiments with the amelanotic melanoma we observed two annexin V
positive cell populations with a different fluorescence intensity. It is possible
that these differences in annexin V binding to melanoma cell membranes reflect
some changes in the phospholipid bilayer, associated with the progression of
these tumors.
PMID- 10763125
TI - [Ischemic contractures of the forearm and hand].
AB - This article gives an overview of anatomy, pathophysiology, aetiology, and
diagnosis of the compartment syndrome and the resulting ischaemic necrosis of the
upper extremity. The relation between compartment syndrome and infection is
pointed out. Whereas the therapy of a manifest compartment syndrome is rather
uniform consisting in decompression of the involved fascial compartment, the
treatment of the ischaemic muscle necrosis is manifold. It depends upon severity
and location of the disease. Only the mildest involvement can be treated by
nonoperative measures. Surgically, neurolysis, excision of necrotic musculature
and scar, muscular slide, elongating tenotomy, tendon transposition and free
vascularized muscle transplantation have to be considered. Only the availability
of all treatment options gives the surgeon the choice of treatment that fits the
demands of the individual patient best.
PMID- 10763126
TI - [Non-traumatically-induced paralysis of the ramus profundus nervi radialis.
Aspects of a rare disease picture].
AB - Both radial tunnel syndrome and posterior interosseous nerve compression syndrome
are caused by compression of the posterior interosseous nerve. Posterior
interosseous nerve (PIN) compression syndrome is a rare condition--less than 10
percent of our cases of PIN-compression showed signs of palsy--and must be
differentiated from tendinous lesions. From 1992 to 1997, we decompressed the PIN
using an anterior approach in nine cases because of palsy without a history of
trauma. Only one patient was lost to follow-up. Our study indicates that the
results of operative decompression of the PIN depend on the time interval between
first symptoms of palsy and operation. On the other hand, some cases of posterior
interosseous nerve compression syndrome show spontaneous recovery. We recommend
operative decompression of the PIN if incomplete palsy worsens or if complete
palsy persists for more than 12 weeks.
PMID- 10763127
TI - [Preoperative intermittent pneumatic extension treatment stage III and IV
Dupuytren contracture].
AB - BACKGROUND: The purpose of this study was the development of a non-invasive
preoperative soft-tissue extension device for the treatment of patients with
Dupuytren's contracture grade III and IV according to the classification of
Tubiana, based on the experience of continuous extension treatment using the
external fixator of Messina. METHODS: Intermittent pneumatic distraction (IPD) of
soft tissue using a pneumatic extension device was employed for three weeks
preoperatively on ten patients. RESULTS: After three weeks the active and passive
extension deficit was reduced by 30.02% and 44.64% respectively. Eight months
postoperatively an increase of extension on average of 110 degrees was attained.
In contrast, a second group of ten patients with Dupuytren's contracture grade
III and IV (Tubiana) without preliminary treatment was listed. In these patients,
three times a skin graft was needed; in addition, the stay in hospital and time
of rehabilitation was longer. CONCLUSIONS: The preoperative reduction of
contracture simplifies the surgical treatment and reduces the complication rate.
We present a new non-invasive technique for preoperative continuous extension of
Dupuytren's contracture yielding at least equal results to the method introduced
by Messina. Comparing the two groups of patients, the patients with preliminary
treatment had a shorter stay in the hospital and a shorter time of
rehabilitation.
PMID- 10763128
TI - [Effect of surgical laser on collagen-rich tissue].
AB - The goal of this ex-vivo study was a controlled macroscopical and microscopical
comparison of the immediate effects of surgical lasers on dense collagenous
tissues. The investigation of the exact denaturizing effects following tissue
interaction between lasers and collagenous fibers are of importance for a better
understanding of the observed and described healing process. Partial tenotomies
were performed ex vivo on sixty tendons of the flexor digitorum profundus muscle
of New Zealand White Rabbits using four surgical lasers (Holmium:YAG-, Erbium:YAG
, Neodym:YAG-, and CO2-Laser). The tendons were evaluated macroscopically,
histologically and observations were made on the surgical handling of the lasers
during the procedure. The choice of lasers allowed the comparison of a wide
spectrum of wavelengths (gamma = 1.0 to 10.6 microns). In addition, beam delivery
modalities were compared to each other (focus vs. contact). The pulse (frequency
and power) was varied within each laser. Other parameters including focus size,
absorption, dispersion, and thermal tissue conductivity were maintained constant
in this test arrangement in order to allow a later comparison between the
observed areas of denaturated collagen. The macroscopical and histological
results showed great differences in the effects of the four lasers. Even within
each single laser group, the results varied greatly with the choice of variable
parameters. Holmium:YAG- and CO2-Laser can produce similar areas of collagen
denaturation. When comparing specimens with similar areas of collagen
denaturation induced by different laser types, different amounts of charring were
observed. Erbium:YAG-Laser tenotomies showed generally inhomogeneous denaturation
areas, while tenotomies with Neodym: YAG-Laser used in continuous mode resulted
in significant charring and tissue retraction in the area of interaction. These
observations help in defining the combination of parameters with which
Holmium:YAG-, Erbium:YAG-, and CO2-Lasers can be used for transsection of dense
collagenous tissues. In addition, these histological results as well as already
published observations on healing patterns following laser surgery allow for the
formulation of a hypothesis on the effects of laser in the wound healing process.
PMID- 10763129
TI - [Experiences with the alloplastic joint prosthesis of the interphalangeal joint].
AB - The replacement of finger joints, especially of the proximal interphalangeal
joint (PIP), remains an unsolved problem. Long-term results of conventional
reconstructive procedures as well as previously available artificial joint
implants have been disappointing. In a controlled study, 12 PIP-joints were
replaced by a new type of total endoprosthesis as an alternative to joint fusion.
The cementless prosthesis is unhinged and consists of metal joint surfaces. After
a follow-up of 18 months, implantation of this metal prosthesis resulted in
almost complete pain relief and an active range of movement of 58 degrees. The
absolute gain in mobility, however, was only 6 degrees. A swan-neck deformity was
found in nine out of 12 cases but corrective surgery was not required. The
proximal half of the implant had to be exchanged in two cases due to loosening.
All patients were satisfied with the result. The disparity between subjective
acceptance by the patients, who clearly prefer joint replacement to fusion, and
objective results demonstrates the necessity for further development in this
field. The type of prosthesis used in this study seems to be a useful baseline
tool which could be turned into a ingenious PIP-joint replacement by further
development aiming at reduced abrasion, increased initial stability, a more
individual configuration, to name just a few goals.
PMID- 10763130
TI - [Resection of the head of the ulna in patients with rheumatoid arthritis].
AB - PURPOSE: The purpose of the study was to investigate value and effect of distal
ulna resection (Darrach procedure) on the wrist in rheumatoid arthritis. CLINICAL
MATERIAL: From 1985 to 1995, resection of the distal ulna was performed in 47
patients (54 hands) with rheumatoid arthritis. 38 patients (6 men, 32 women, 43
hands) had an average clinical and radiological follow up of 4.7 years (range 3
to 13 years). RESULTS: 15 of the cases with rheumatoid arthritis were pain-free,
19 complained about pain after severe stress, seven complained about pain after
mild stress and two about continuous pain. 85% of the patients had a range of
motion (pro- and supination) of more than 120 degrees. 75% of the patients had a
good or very good wrist function. In 32 cases, the patients were absolutely
satisfied with the operative outcome, in five cases, they had expected more
improvement. Six reported, that there was no change due to the operation.
CONCLUSION: The results demonstrate that the main indication for the resection of
the distal ulna is rheumatoid arthritis. This operation does not influence the
progress of rheumatoid arthritis. Preoperative radiological changes (Larsen's
classification) have the main prognostic value. In Larsen's II and higher, a
partial arthrodesis is recommended.
PMID- 10763131
TI - [Follow-up of scaphoid pseudarthroses and scaphoid fractures after Herbert screw
implantation in the extremities--MRI (low-field MRI)].
AB - From January 1993 to September 1996, 59 patients with a scaphoid nonunion (38
times mid/distal third, 21 times proximal third) and 21 patients with a scaphoid
fracture (17 times mid/distal third, four proximal third) underwent surgery in
our clinic. Fractures of the scaphoid were treated by Herbert screw fixation. The
operative treatment of nonunions of the scaphoid included the transplantation of
an iliac crest graft and Herbert screw fixation. In all cases, an MRI of the
carpus in a low-field MRI was carried out pre-operatively in addition to standard
X-ray examination. Post-operatively, all patients were again controlled by MRI
within defined intervals. The signal intensities of the MRI in the fragments of
the scaphoid were determined qualitatively and quantitatively by computer
calculation, comparing the pre- and post-operative results with one another. It
was possible to depict the entire scaphoid and to determine the signal
intensities of the proximal and distal fragments after Herbert screw fixation due
to reduced artefacts on T1-weighted images in all cases. 41 patients with
scaphoid nonunion and five patients with a scaphoid fracture showed a pre
operative diminishing of the signal in the proximal fragment compared to the
distal fragment. For these patients, the fusion rate was lower than in patients
without pre-operative signal reduction.
PMID- 10763132
TI - [Results of different incisions in treatment of carpal tunnel syndrome].
AB - Various surgical techniques are used to treat the carpal tunnel syndrome. Besides
the endoscopic technique, the "open-standard-technique" and the "Millesi
technique" are very common. The success and the complication rate of all these
techniques are discussed controversially. However, the aim of the current
prospective study was to investigate the various open techniques to find the most
successful method with the least complications. Therefore, 64 patients (20 male,
44 female) were examined after surgery. 23 patients were operated with an "Open
Standard-Technique" (OST) including long incision, 22 patients were treated
according to the "Millesi-Technique", and 19 patients with the "Short-Incision
Technique" (SIT). All patients were evaluated using a prospectively designed
examination check-list. Comparing these various techniques, the OST and the SIT
yielded the best results with regard to complications, the SIT seems to be the
most successful technique.
PMID- 10763133
TI - DNA chips: the future of biomarkers.
AB - DNA chips are small, solid supports such as microscope slides onto which
thousands of cDNAs or oligonucleotides are arrayed, representing known genes or
simply EST clones, or covering the entire sequence of a gene with all its
possible mutations. Fluorescently labeled DNA or RNA extracted from tissues is
hybridized to the array. Laser scanning of the chip permits quantitative
evaluation of each individual complementary sequence present in the sample. DNA
chip technology is currently being proposed for qualitative and quantitative
applications, firstly for the detection of point mutations, small deletions and
insertions in genes involved in human diseases or affected during cancer
progression; secondly, to determine on a genome-wide basis the pattern of gene
expression in tumors, as well as in a number of experimental situations. The
extraordinary power of DNA chips will have a strong impact on medicine in the
near future, both in the molecular characterization of tumors and genetic
diseases and in drug discovery and evaluation. Quantitative applications will
soon spread through all fields of biology.
PMID- 10763134
TI - Poly(A) polymerase specifically implicated in the mechanism of chemotherapeutic
drug action during cell apoptosis.
AB - It has recently been established that most anticancer drugs act through the
mechanism of apoptosis. It has also been clinically confirmed that drug
combinations are more effective than single drugs and various chemotherapeutic
strategies have therefore been developed. The experiments described here concern
the induction of apoptosis with dimethylsulfoxide (DMSO), a substance with
multiple activity especially as an inducer of differentiation, and interferon
(IFN), a cytokine well known for its antiviral and antineoplastic effects; they
are used alone or in combination. Apoptosis may be regulated at all levels of
gene expression including the addition of the poly(A) tail to the 3' end of
mRNAs. Poly(A) polymerase (PAP) [EC.2.7.7.19], the enzyme that catalyzes the
addition of the poly(A) tail to mRNAs, changes in the process of development,
differentiation, transformation and apoptosis. In the present study the induction
of HeLa cells to apoptosis (65%) with a DMSO/rIFN-alpha combination resulted in
pronounced PAP dephosphorylation and activity reduction. HeLa cells induced to
apoptosis (35%) with DMSO gave lower levels of PAP dephosphorylation and
reduction of activity and cells induced to apoptosis (18%) with rIFN-alpha gave
only limited PAP dephosphorylation and reduction of activity. The implications of
these observations for chemotherapeutic drug action at the level of mRNA
polyadenylation point to the possible use of PAP as a biological marker for the
evaluation of this action.
PMID- 10763135
TI - Significance of soluble endothelial molecule E-selectin in patients with breast
cancer.
AB - Increasing evidence suggests that endothelial cells are involved in tumor growth
and metastasis. E-selectin, an adhesion molecule specifically expressed or
secreted by activated endothelial cells, may enhance tumor angiogenesis and the
adhesion of tumor cells to endothelial cells at distant sites. The aim of this
study was to assess the relationship between concentrations of circulating
soluble E-selectin and clinical, pathological and biological features in patients
with breast cancer (BC). sE-selectin concentrations were analyzed by an ELISA
method in sera from 113 patients with metastatic BC, 30 patients with primary
inflammatory BC, 105 patients with primary non-inflammatory BC, 456 patients with
node-negative BC, and 42 healthy controls. sE-selectin in the metastatic BC group
was significantly higher than in the healthy control group. In metastatic BC, sE
selectin was significantly higher in patients with liver metastases than in
patients without liver metastases. In patients with primary non-inflammatory BC,
a negative correlation was found between sE-selectin concentrations and tumoral
microvessel count. In overall and disease-free survival studies performed in the
node-negative population (median follow-up duration 7.5 years), multivariate
analyses demonstrated a prognostic value of sE-selectin and tumor size. This
study suggests that endothelial activation might play a role in the development
of BC. This role seems not to be related to angiogenesis.
PMID- 10763136
TI - Circulating immature and mature dendritic cells in relation to lymphocyte subsets
in patients with gastrointestinal tract cancer.
AB - Cancer-related deficiency in circulating dendritic cells (DC), whose important
anticancer role is well established, has been proven to be associated with
lymphocytopenia. This study was performed to evaluate which lymphocyte subset is
most markedly related to the failure of the DC system. The study included 30
patients with gastrointestinal tract cancer, 10 of whom had distant organ
metastases. Immature and mature DCs were measured by FACS and monoclonal
antibodies against CD123 and CD11c antigens, respectively. Low levels of immature
and mature DCs were observed in 63% and 43% of patients, respectively. Patients
with low levels of circulating mature DCs had significantly lower values of T
lymphocytes, T helper lymphocytes and NK cells than those with normal mature DC
levels. In contrast, no significant difference was seen between patients with
normal or abnormally low values of immature DCs. Conversely, patients with a
decreased number of T lymphocytes, T helper lymphocytes and NK cells showed
significantly lower values of circulating mature DCs than those with lymphocyte
subsets within the normal range, whereas no difference was seen in immature DC
amounts. This study suggests that only mature DC deficiency may be associated
with important lymphocyte subset alterations in cancer patients, whereas
deficiency in immature DCs does not seem to be related to other immune cell
disorders.
PMID- 10763137
TI - The expression of SEL1L and TAN-1 in normal and neoplastic cells.
AB - We have previously reported on the isolation and chromosomal mapping of a novel
human gene (SEL1L), which shows sequence similarity to sel-1, an extragenic
suppressor of C. elegans. sel-1 functions as a negative regulator of lin-12
activity, the latter being implicated in the control of diverse cellular
differentiation events. In the present study we compare the expression patterns
of SEL1L and TAN-1, the human ortholog of lin-12 in normal and neoplastic cells.
We found that, whereas both genes are expressed in fetal tissues at similar
levels, they are differentially expressed in normal adult and neoplastic cells.
In normal adult cells SEL1L is generally present at very low levels; only in the
cells of the pancreas does it show maximum expression. By contrast, SEL1L is
generally well represented in most neoplastic cells but not in those of
pancreatic and gastric carcinomas, where transcription is either downregulated or
completely repressed. TAN-1 on the other hand is well represented in almost all
normal and neoplastic cells, with very few exceptions. Our observations suggest
that SEL1L is presumably implicated in pancreatic and gastric carcinogenesis and
that, along with TAN-1, it is very important for normal cell function.
Alterations in the expression of SEL1L may be used as a prognostic marker for
gastric and pancreatic cancers.
PMID- 10763138
TI - A new specific method for measuring S-100B in serum.
AB - The S-100 family of proteins are acidic calcium and zinc binding low molecular
weight proteins mainly present in astrocytes and in a population of
oligodendrocytes of the CNS. S100b, an acidic low weight and zinc binding
protein, has attracted considerable interest due to its release into the
cerebrospinal fluid and blood from brain tissue following brain damage and from
malignant melanomas. A new simple two-step incubation assay has now been
elaborated in which two catcher and one tracer monoclonal antibodies are used.
The specificity of this assay is high because all the MAbs used bind exclusively
to S-100B, as shown by real-time biospecific interaction analyses. Moreover, the
working range of the assay is 0.2-60 micrograms/L with a CV of less than 10%; the
resulting high sensitivity has been confirmed by clinical studies. Time
dependence, shaking conditions, lower limit of detection limits, effects of
dilution, hook effect, recovery, impression as intra- and interassay variations,
and crossreactivities with S-100A1 were tested in order to obtain a highly
reproducible assay. Sera from healthy blood donors and patients undergoing
cardiopulmonary bypass operations were tested with the assay. Several of the
patients undergoing open heart surgery presented measurable values in this IRMA S
100 assay, indicating cerebral effects of open heart surgery. The test may be
used for postoperative monitoring of these patients.
PMID- 10763139
TI - Illegitimate villin transcripts in normal bone marrow precludes detection of
colon cancer micrometastases.
AB - Villin is a specific marker for normal and tumoral colon tissue. We have
developed a highly sensitive assay using reverse transcription (RT) and real-time
PCR to detect villin transcripts. The sensitivity of detection is one colon
cancer cell. However, high levels of illegitimate villin transcripts were
observed in normal bone marrow, precluding the use of villin RT-PCR for routine
detection of colon cancer cells in bone marrow of patients with colon cancer.
PMID- 10763140
TI - Tissue-type plasminogen activator (tPA) content in colorectal cancer and in
surrounding mucosa: relationship with clinicopathologic parameters and prognostic
significance.
AB - The aim of this study was to evaluate the cytosolic tissue-type plasminogen
activator (tPA) content in colorectal cancer, its possible relationship with the
clinicopathologic parameters of tumors, and its prognostic significance. We have
therefore examined by immunoenzymatic assay the cytosolic tPA content in tumors
and paired surrounding normal mucosa samples from 162 colorectal cancer patients.
Cytosolic tPA levels were significantly higher in surrounding normal mucosa
samples than in neoplastic tissues (4.01 +/- 5.07 vs 2.63 +/- 5.82 ng/mg protein;
p < 0.0001). By contrast, no significant correlation was found between tPA
content and clinicopathologic tumor parameters such as location, Dukes' stage,
histologic grade, and DNA content or S-phase fraction. However, the results
indicated that a high cytosolic tPA content (> 0.75 ng/mg protein) in tumors
predicted for a shorter relapse-free and overall survival (both p < 0.05) in 123
resectable colorectal cancer patients who were prospectively evaluated during a
mean follow-up period of 32.2 months. This suggests that tPA may give additional
information to that provided by other biochemical markers currently used in
colorectal cancer.
PMID- 10763141
TI - Prognostic significance of CEA and CA 19-9 in colorectal cancer in Kuwait.
AB - Preoperative CEA and CA 19-9 levels have been used in the past as prognostic
indicators in colorectal cancer, but Dukes' stage is still considered to be the
most important prognostic factor. Recent survival estimates may have been
influenced by the fact that in the last decade adjuvant chemotherapy and
postoperative irradiation have been included in the routine management of
advanced-stage disease. In a heterogeneous Kuwaiti population higher reference
levels (95th percentile) of CEA and CA 19-9 have been found than those usually
employed. In the present study 62 patients with Dukes' stage B + C could be
analyzed for two-year disease-free survival (DFS). Relapse was observed in 19
patients, 28 patients were disease free and 15 patients with censored
observations were included. No significant difference in DFS was observed in
Dukes' B (69%) versus Dukes' C (48%) patients (p = 0.09). On the other hand,
Dukes' stage B + C patients with elevated preoperative levels of CEA or CA 19-9
had a significantly poorer DFS than patients with normal levels. For CEA levels
below or above the cutoff the DFS was 74% versus 23% (p = 0.003); for CA 19-9
levels below or above the cutoff the DFS was 71% versus 33% (p = 0.004). In 54
patients with Dukes' stage B + C for whom preoperative levels of both CEA and CA
19-9 were available multivariate analysis revealed a decreasing risk of relapse
in the following order: CEA and/or CA 19-9 elevated (chi-square 7.09; p = 0.008),
CA 19-9 elevated (chi-square 6.27; p = 0.01), CEA elevated (chi-square 5.47; p =
0.02), and Dukes' C (chi-square 2.08; p = 0.15 n.s.). Hence, novel treatment
protocols may have improved the disease-free survival, but the use of adjuvant
chemotherapy and/or radiotherapy is of questionable benefit in patients who have
elevated levels of CEA and/or CA 19-9 prior to treatment.
PMID- 10763142
TI - Effects of oncological surgery on endothelin-1 secretion in patients with
operable gastric cancer.
PMID- 10763143
TI - EORTC external quality assurance program for ER and PgR measurements: trial
1998/1999. European Organisation for Research and Treatment of Cancer.
AB - Steroid receptor assays have clinical relevance in selecting women who would
benefit from endocrine intervention. As the degree of benefit from endocrine
therapy is directly related to the quantity of receptor present in the tumour,
the quality of the steroid receptor assays is important. Moreover, since patients
entered in multi-centre trials often include stratification based on the receptor
status, receptor assays should be comparable between different institutes. ER-
and PgR-assays have been evaluated in quality assessment studies for almost 20
years by the EORTC Receptor and Biomarker Study Group. During the QA trial
1998/1999 results were reported by 42 participants performing the Ligand Binding
Assay (LBA) and by 39 participants using the Enzyme Immuno-Assay (EIA) kit. Each
participant received a set of 12 QA vials to be analysed two at a time at two
monthly intervals. The between-laboratory CVs of ER LBA and EIA amounted to 40
50%. For PgR the between-lab CVs for the EIA method are lower as compared with
LBA but still are approx. 30%. Notwithstanding the high deviation in reported
values and the high between-lab CVs, the consistency of the participants over the
year is acceptable, which pave the way for calibration. Indeed, after
normalization of assay results the mean between-lab CVs dropped to 11% for ER
LBA, 14% for ER EIA, 9% for PgR LBA and 11% for PgR EIA. Such a reduction of
between-laboratory CVs is an essential requirement for the use of steroid
receptor data in multicentre clinical studies.
PMID- 10763144
TI - Pooled analysis of uPA and PAI-1 for prognosis in primary breast cancer patients.
EORTC Receptor and Biomarker Study Group.
PMID- 10763145
TI - Tumor-biological factors uPA and PAI-1 as stratification criteria of a
multicenter adjuvant chemotherapy trial in node-negative breast cancer.
AB - In axillary node-negative primary breast cancer, 70% of the patients will be
cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is
only needed for those 30% of node-negative patients who will relapse after
primary therapy and eventually die of metastases. Traditional histomorphological
and clinical factors do not provide sufficient information to allow accurate risk
group assessment in order to identify node-negative patients who might benefit
from adjuvant systemic therapy. In the last decade various groups have reported a
strong and statistically independent prognostic impact of the serine protease uPA
(urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen
activator inhibitor type 1) in node-negative breast cancer patients. Based on
these data, a prospective multicenter therapy trial in node-negative breast
cancer patients was started in Germany in June 1993, supported by the German
Research Association (DFG). Axillary node-negative breast cancer patients with
high levels of either or both proteolytic factors in the tumor tissue were
randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was
continued until the end of 1998, by which time 684 patients had been enrolled.
Since then, patients have been followed up in order to assess the value of uPA
and PAI-1 determination as an adequate selection criterion for adjuvant
chemotherapy in node-negative breast cancer patients. This paper reports on the
rationale and design of this prospective multicenter clinical trial, which may
have an impact on future policies in prognosis-oriented treatment strategies.
PMID- 10763146
TI - Long-term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in
primary breast cancer.
AB - After long-term follow-up, the prognostic impact of the following proteolytic
factors associated with tumor invasion and metastasis was evaluated in 276
primary breast cancer patients: uPA (urokinase-type plasminogen activator), PAI-1
(uPA inhibitor type 1), and cathepsins B, D and L. The median follow-up of
patients still alive at the time of analysis was 109 months. To date 119 patients
(43%) have relapsed and 117 (42%) have died. Antigen levels of uPA and PAI-1 were
determined by ELISA in detergent extracts; cathepsin B, D, and L content was
determined in cytosol fractions of the primary tumor: cathepsin D by ELSA and
cathepsin B and L by ELISA. In multivariate analysis (Cox model) for disease-free
survival (DFS), lymph node status (p < 0.001; RR = 3.8), cathepsin L (p < 0.001;
RR = 2.6) and PAI-1 (p = 0.027; RR = 1.7) were significant factors in all
patients. In addition to these factors, grading was significant for overall
survival (OS). In another multivariate approach, CART (Classification And
Regression Trees) analysis, lymph node status (p < 0.001) turned out to be the
strongest discriminator for patients at high risk of relapse. In the node
negative patient subset, PAI-1 was the strongest risk group discriminator (p <
0.001): in this subset, patients with low levels of both PAI-1 and cathepsin D
had a very low relapse rate of only 3.2% compared to 39% in the remaining node
negative patients. In node-positive patients cathepsin L gave the best risk group
assessment (p = 0.001). In conclusion, tumor-associated PAI-1 and cathepsins D
and L provide significant, statistically independent prognostic information for
DFS and OS in primary breast cancer, even after a median follow-up period of
almost 10 years.
PMID- 10763147
TI - Cysteine proteinases and their inhibitors in extracellular fluids: markers for
diagnosis and prognosis in cancer.
AB - Cathepsins B, H and L have been shown to participate in processes of tumor
growth, vascularization, invasion and metastasis. Their levels in tumor tissue
extracts can provide useful clinical information to predict disease-free and
overall survival in breast, lung, colorectal, brain and head and neck cancer
patients. Recently we have found that both cysteine cathepsins and their
endogenous protein inhibitors stefins and cystatin C can also predict prognosis
when measured extracellularly. In melanoma and colorectal cancer patients high
serum levels of cathepsins B and H correlated with shorter survival. Similarly,
increased extracellular levels of stefins A and B and cystatin C correlated
significantly with high risk of adverse outcome in cancer patients. However, the
cathepsin B/cystatin C complex was found to be less abundant in sera of patients
with malignant tumors than in those with benign diseases or in healthy controls,
suggesting an imbalance between the enzyme and its inhibitor in cancer patients.
PMID- 10763148
TI - Clinical and experimental studies of cysteine cathepsins and their inhibitors in
human brain tumors.
PMID- 10763149
TI - Independent prognostication and therapy monitoring of breast cancer patients by
DNA/RNA typing of minimal residual cancer cells.
AB - Clinical relevance, purification techniques and molecular characterization of
minimal residual cancer cells (MRCC) is a controversial topic in the literature.
An analytical concept including a novel isolation procedure and a panel of tests
for DNA and RNA typing of MRCCs is described and clinically evaluated in this
paper. The purification procedure exploiting the physical characteristics of
MRCCs shows superior performance leading to > 50% pure and viable tumor cells.
Proof of the presence and purity of MRCCs in an isolated sample is given by
multiparametric DNA typing (amplifications, mutations, losses of heterozygosity).
On the basis of the proven presence of MRCCs tumor-relevant mRNAs can be
adequately analyzed by normalized quantitative real-time RT-PCR. The molecular
characterization of MRCCs isolated from blood of breast cancer patients could
have a strong clinical impact on prognostication, drug targeting and therapy
monitoring.
PMID- 10763150
TI - A new approach to phenotyping disseminated tumor cells: methodological advances
and clinical implications.
AB - At the time of primary therapy (surgery, systemic chemotherapy and/or radiation),
disseminated tumor cells in the bone marrow can be found in almost one-third of
patients with cancer of the breast, ovary, esophagus, stomach, colon, and other
solid tumors. Whereas the prognostic impact of the mere presence of these cells
is still a matter of debate, it has been shown that expression of tumor
associated antigens in disseminated tumor cells is linked to more aggressive
disease. Therefore, further characterization of disseminated tumor cells at the
protein and gene level has become increasingly important. To date, the most
common detection method for disseminated tumor cells in the bone marrow is an
immunocytochemical approach using cytokeratin-directed antibodies for detection
of epithelial cells and the APAAP system for their visualization. We have
established a new double immunofluorescence technique enabling simultaneous
detection, phenotyping, and antigen quantification of disseminated tumor cells.
Mononuclear cells from bone marrow are enriched by Ficoll gradient centrifugation
and cytospins are prepared. Double immunofluorescence is performed using
antibodies against cytokeratins 8/18/19 (mAb A45B/B3) and the uPA receptor CD87
(pAb HU277). CD87 expression is recorded by confocal laser scanning microscopy
(CLSM) using fluorescence labeled latex beads as the reference; staining
intensities of all the scans are then summed and quantified (extended focus).
This protocol, originally designed for disseminated tumor cells in bone marrow,
can also be applied to disseminated tumor cells in blood, to leukapheresis cells
or to cells present in malignant ascites or other malignant effusions. The tumor
cells detected may be used for gene and mRNA analyses. Furthermore, disseminated
tumor cells also represent interesting targets for clinical studies on patient
prognosis or prediction of therapy response as well as for specific tumor
biological therapies.
PMID- 10763151
TI - Modulation of EGFR gene transcription by a polymorphic repetitive sequence--a
link between genetics and epigenetics.
AB - The epidermal growth factor receptor (EGFR) plays a crucial role in growth,
differentiation and motility of normal as well as tumor cells. The transduction
of extracellular signals to the cytoplasm via the receptor not only depends on
ligand binding, but is also determined by the receptor density on the cell
surface. Therefore, with regard to cancer diagnosis and therapeutic approaches
targeting EGFR it is important to know how the expression level of EGFR is
controlled. We found that transcription activity declines with increasing numbers
of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the
epidermal growth factor receptor gene. In vivo data from cultured cell lines
support these findings, although other regulation mechanisms can compensate this
effect. In addition, we showed that RNA elongation terminates at a site closely
downstream of the simple sequence repeat (SSR) and that there are two separate
major transcription start sites. Model calculations for the helical DNA
conformation revealed a high bendability in the EGFR polymorphic region,
especially if the CA stretch is extended. These data suggest that the CA-SSR can
act like a joint, bringing the promoter in proximity to a putative repressor
protein bound downstream of the CA-SSR. The data indicate that this polymorphism
may be a marker for cancer, linking genetic and epigenetic risk factors.
Furthermore, in breast cancer, heterozygous tumors with short CA-SSR showed an
elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with
loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression
if the longer allele was lost. Moreover, decreased EGFR gene levels were
significantly correlated with poor prognosis in breast cancer.
PMID- 10763152
TI - Blood-borne cancer cells--quo vadis?
AB - The detection of blood-borne cancer cells may help in clinical staging and
further understanding of cancer metastasis. We developed a cytokeratin-based
immunomagnetic method to isolate epithelium-derived cells from the circulating
blood of patients. The number of cell clusters positive for cytokeratin/prostate
specific antigen (PSA) from the peripheral blood of prostate cancer patients and
cytokeratin/p185c-erbB-2 from the peripheral blood of breast cancer patients has
been related to stage of the disease. Breast cancer patients who presented
cytokeratin/p185c-erbB-2-positive cell clusters showed a decrease in such cells
under adriamycin adjuvant therapy with Further molecular characterization by a
highly sensitive microsatellite multiplex-PCR enabled reproducible detection of
microsatellite alterations. The impact of these individually targeted results may
contribute to an individual diagnostic and therapeutic strategy.
PMID- 10763153
TI - Detection of estrogen receptor-beta mRNA in breast cancer using RT-PCR.
AB - The estrogen receptor (ER) is the most useful marker currently available for
breast cancer, being used both to predict response to therapy and assess
prognosis. Recently, a new form of the ER, known as ER-beta, was identified. In
this preliminary study we show that ER-beta mRNA was expressed less frequently in
breast cancers than ER-alpha. ER-alpha but not ER-beta levels correlated with ER
protein as determined by ELISA. We conclude that ER-beta is expressed in
approximately 50% of breast cancers but it does not appear to be detected by a
widely available ELISA.
PMID- 10763154
TI - Neural network analysis of follow-up data in primary breast cancer.
AB - This paper reports on the performance of a recently developed neural network
environment incorporating likelihood-based optimization and complexity reduction
techniques in the analysis of breast cancer follow-up data with the goal of
building up a clinical decision support system. The inputs to the neural network
include classical factors such as grading, age, tumor size, estrogen and
progesterone receptor measurements, as well as tumor biological markers such as
PAI-1 and uPA. The network learns the structural relationship between these
factors and the follow-up data. Examples of neural models for relapse-free
survival are presented, which are based on data from 784 breast cancer patients
who received their primary therapy at the Department of Obstetrics and
Gynecology, Technische Universitat Munchen, Germany. The performance of the
neural analysis as quantified by various indicators (likelihood, Kaplan-Meier
curves, log-rank tests) was very high. For example, dividing the patients into
two equally sized groups based on the neural score (i.e., cutoff = median score)
leads to an estimated difference in relapse-free survival of 40% or better (80%
vs. 40%) after 10 years in Kaplan-Meier analysis. Evidence for factor
interactions as well as for time-varying impacts is presented. The neural network
weights included in the models are significant at the 5% level. The use of neural
network analysis and scoring in combination with strong tumor biological factors
such as uPA and PAI-1 appears to result in a very effective risk group
discrimination. Considerable additional comparison of data from different patient
series will be required to establish the generalization capability more firmly.
Nonetheless, the improvement of risk group discrimination represents an important
step toward the use of neural networks for decision support in a clinical
framework and in making the most of biological markers.
PMID- 10763155
TI - Evaluating and understanding performance testing in COPD patients.
AB - PURPOSE: There is increasing interest in the use of performance tests to assess
physical function among patients with debilitating diseases. The purpose of this
study was to describe the measurement properties of a performance test battery
used in the Reconditioning Exercise and Chronic Obstructive Pulmonary Disease
Trial and to explore how well-selected physiologic and psychosocial measures
explained test performance. METHODS: To assess test-retest reliability of the
performance tests, older patients with chronic obstructive pulmonary disease (n =
30) completed, on two different occasions, a 6-minute walk for distance, a timed
stair climb, and a timed elevated-arm task. In addition, stepwise regression
analyses were conducted on a larger sample (n = 209) to examine how effective
conceptually relevant physiologic and psychosocial variables were at explaining
variation in task performance. RESULTS: Results showed that all three performance
tasks had good test-retest reliability (all coefficients > 0.80) and shared
variance in expected directions with VO2peak, forced expiratory volume in 1
second (FEV1), and self-reported disability. Regression analyses suggest that
VO2peak, FEV1, self-efficacy, and self-reported disability are important
variables to consider in attempts to understand performance-related disability in
patients with chronic obstructive pulmonary disease (COPD). CONCLUSIONS: The
physical performance test battery appears to be a reliable means of assessing
physical functioning in older patients with COPD. Furthermore, findings support
the important role that VO2peak plays in task performance and suggest that
patients' perceptions should be given careful consideration when attempting to
understand physical decline in clinical settings.
PMID- 10763156
TI - The effects of exercise training on the pharmacokinetics of digoxin.
AB - BACKGROUND: Studies have shown that digoxin binds to the working muscles during
an acute bout of exercise, with a concomitant decrease in serum digoxin
concentration. This study investigated the effects of 16 weeks of endurance
exercise training on the pharmacokinetics of digoxin in old and young adults.
METHODS: Twelve subjects, aged 68.5 +/- 4.5 years, and six subjects, aged 30.3 +/
3.8 years, completed the study. All subjects were healthy, sedentary, and taking
no cardiovascular medications. After initial testing and maximum oxygen
consumption (VO2max) measurements, subjects were hospitalized for 28 hours for
renal function testing and digoxin clearance studies and then randomly assigned
to an exercise (EG) or control (CG) group. The EG completed 16 weeks (three 1
hour bouts/week) of aerobic training at 75% to 85% of maximum capacity. The CG
did not exercise. All tests were repeated at the end of the 16-week study period.
RESULTS: In the older EG subjects, VO2max increased by 3.4 ml/kg/min, or
approximately 16% (P = 0.0002). VO2max increased in the younger EG subjects by
1.1 ml/kg/min, but the increase was not significant (P > 0.05). There were no
significant changes in body composition, renal function, or time of onset, peak
concentration, or elimination phase half-life of digoxin in either the old or
young exercise or control groups (P > 0.05 for all variables). CONCLUSION:
Although 16 weeks of endurance exercise training improves cardiorespiratory
fitness, the pharmacokinetics of digoxin are neither improved nor adversely
affected in healthy old and young adults.
PMID- 10763157
TI - Obesity, body fat distribution, and coronary artery disease.
AB - Obesity is an independent risk factor for the development of coronary artery
disease (CAD). Obesity also increases risk for CAD indirectly through its
association with insulin resistance, hyperlipidemia, and hypertension. An
increased accumulation of fat in the intraabdominal cavity, termed visceral
adiposity, is highly correlated with an adverse coronary risk profile. In
patients at risk for coronary artery disease, the treatment of obesity results in
an improved coronary risk profile. The prevalence of obesity is extremely high in
coronary populations, yet the effect of weight loss on cardiovascular outcomes in
CAD patients has received relatively little attention. Observational studies in
the cardiac rehabilitation setting showed that patients who lose weight and
exercise show an improvement in coronary risk profile. Further research is needed
to better define the clinical effectiveness of weight loss programs and their
benefits in coronary patients.
PMID- 10763158
TI - Supportive communication with implantable cardioverter defibrillator patients:
seven principles to facilitate psychosocial adjustment.
AB - METHODS: This article incorporates known findings from the psychological
literature regarding health behaviors and adjustment to cardiac illness with
identified psychosocial needs of implantable cardioverter defibrillator (ICD)
patients. An emphasis is placed on healthcare providers' unique ability to
facilitate adjustment during routine patient contacts. RESULTS: Seven principles
of supportive communication are presented to enhance healthcare providers'
awareness of the psychosocial needs of ICD patients. A table of "quotes"
representing each principle is provided to show how each form of supportive
communication may be delivered to optimize health outcomes for ICD patients.
CONCLUSIONS: Brief, routine communication between healthcare providers and ICD
patients about psychosocial issues can facilitate patient adjustment. Although
not sufficient to meet the needs of all ICD patients, supportive communication
bolsters problem-solving and coping strategies of most ICD patients. For patients
with more severe psychological adjustment difficulties, supportive communication
may lead to better identification of patients who would benefit from referrals to
mental health professionals.
PMID- 10763159
TI - Impact of duration in a cardiac rehabilitation program on coronary risk profile
and health-related quality of life outcomes.
AB - BACKGROUND: Optimal cardiac rehabilitation (CR) program length and the time
course of changes in relevant outcomes are unknown. The purpose of this study was
to assess changes in coronary risk factors and health-related quality of life
(HRQoL) after 3 months and 6 months of cardiac rehabilitation. METHODS: This is
an observational study of a cohort of 126 consecutive cardiac rehabilitation
patients who completed baseline, 3-month, and 6-month evaluations of coronary
risk factors and HRQoL. The coronary risk factors included lipid profile, blood
pressure, body mass index (BMI), and physical activity level. HRQoL was assessed
using the Short Form-36 questionnaire (SF-36) comprising eight health concepts
and two component scales (physical [PCS] and mental [MCS]). RESULTS: There was
significant improvement in all coronary risk factors and HRQoL measures, except
BMI, over the 6-month period (P < 0.001). Significant changes in blood pressure,
physical activity, PCS, and high-density lipoprotein cholesterol (HDL-C) were
apparent at 3 months, and no additional significant changes in these variables
occurred between 3 and 6 months. For total cholesterol (TC), low-density
lipoprotein cholesterol (LDL-C), and MCS, significant change was achieved between
3 and 6 months but not between baseline and 3 months. CONCLUSIONS: Secondary
prevention and HRQoL outcomes improved at variable rates. Physical activity and
physical function peaked at 3 months and were maintained at program completion.
Significant improvements occurred in mental health recovery beyond the
traditional 12-week CR program length. Outcomes furthest from normative values
showed the most rapid improvement. Optimal duration of participation may vary
according to the outcome of interest.
PMID- 10763160
TI - Symptomatic hypotension during arm cycle ergometry exercise: a report of five
cases.
AB - We report five cases of vasovagal and vasodepressor syncope or near-syncope that
occurred during arm cycle ergometry. In each case, arm exercise in the seated
position had been performed immediately after dynamic leg exercise. A likely
mechanism involves a decrease in preload from venous pooling of blood in the
lower extremities after leg exercise, and excessive stimulation of ventricular
mechanoreceptors with resultant sympatho-inhibition and enhanced vagal tone. Four
of the cases occurred early in the course of the exercise program, between the
8th and 10th sessions. The single case of true syncope occurred in a patient not
receiving a beta-receptor blocking medication. No further events occurred when
the exercise regimen was changed such that arm cycle ergometry was performed
before leg exercise. We recommend that when arm ergometry is incorporated into an
exercise program: (1) a cool-down period of exercise is performed after dynamic
leg exercise, or (2) arm exercise is performed before dynamic leg exercise. These
maneuvers may preclude the occurrence of symptomatic hypotension.
PMID- 10763161
TI - Home resistance training in an elderly woman with coronary heart disease.
AB - In the current report, a home-based resistive exercise training program was
designed for an older woman with coronary artery disease and chronic heart
failure, who was unable to participate in a center-based program. With
intermittent on-site instruction, the patient was able to learn and perform the
designed exercise program. After 6 months of exercise, muscle strength (handgrip
and leg extension) and lean body mass were increased, and indicators of physical
functional performance were improved. We conclude that a home resistive-based
exercise program, with intermittent on-site exercise counseling, may be an
effective method for physical training in older coronary patients unable to
travel to a rehabilitation center. Further study of this intervention in a
controlled clinical trial appears warranted.
PMID- 10763162
TI - Problems and our solutions for implementing telemedicine systems.
AB - There are several problems on the practical use of telemedicine, for example, the
difficulties involved in promoting communication between medical facilities,
uncooperative clinicians, and the absence of high-speed circuits and high
resolution CRT. From the Japanese point of view, we suggest ways to resolve these
problems. We will analyze and propose scenarios for realizing successful
communications among medical institutions, medical communication and its
characteristics, barriers to the promotion of communications among medical
institutions, second-opinion centers, and separate satellites and separate
circuits. We also mention the World Wide Web for teleconsultation, provision of
assistance to people with data handicaps via a communications satellite, and
assistance to programs designed for training telemedicine specialists. Using a
communication satellite, we offer programs that explain preventive medicine,
support activities for nursing at home, explain the risks of fast food, and
support activities for the handicapped and women in a simple manner to computer
illiterates.
PMID- 10763163
TI - Introducing the theme in a qualitative interview using a visual starter.
AB - Community involvement implies conscientious citizen engagement, not as passive
recipients but active contributors. Insufficient understanding of concepts of
health outcome in a socioeconomic deprived context with unemployment'as a major
feature was identified as a hindrance to intervention. This communication gives a
report of a "visual starter" used as a cognitive instrument for qualitative
research on concepts of joblessness and health. Health education and behavioral
change efforts are often insufficient in reaching empowerment on individual or
community levels. It is suggested that understanding different categories of
thinking using a phenomenographic method could contribute to strategies for
community involvement. The "visual starter" uses pictures to introduce the theme
as well as for associative purposes in the interview.
PMID- 10763164
TI - Assessment of psychosocial work environment in primary care--development of a
questionnaire.
AB - Recent studies have indicated deteriorated working conditions of health care
personnel. To have an efficient health care organization requires good working
conditions and the well-being of the personnel. Today there are no "gold
standard" assessment tools measuring psychosocial working conditions. The aim of
this study was to develop two valid and reliable questionnaires, one generic and
one specific, measuring psychosocial working conditions for general practitioners
(GPs) and district nurses (DNs) in Sweden, with a special emphasis on
organizational changes. The construction of the questionnaires were made after a
stepwise developing phase including literature review, interviews, and a pilot
study. The pilot study included GPs n = 42 and DNs n = 39. The questionnaires
were later on used in a main study (GPs n = 465, DNs n = 465). A factor analysis
was carried out and showed that there were fewer items in the main study that had
factor loading > or = 0.40 in more than one factor, compared to the pilot study.
The factors from the main study were easier to label and had good correspondence
with other studies. After this stepwise development phase good construct validity
and internal consistency were established for the questionnaire.
PMID- 10763165
TI - Face and contents validity, and feasibility of Healthometer: a Delphi study.
AB - Our recent descriptive report in this journal of "Healthometer", an interactive
instrument for self-mediated health counseling, was well received in the medical
systems research and development community. Suitable for paper as well as
electronic mediation and covering both screening, processing/storage, and
advisory tasks in a positively reinforcing and confidential way, it has on the
whole been considered to be an interesting model in the advancing "information
society technologies" perspective; however, a closer scientific and operative
evaluation is warranted. Because the power of the instrument in addition to the
hardware is critically dependent upon the wet- and software quality, the present
study aims at examining in the same forefront forum some basic aspects of all
these modalities, with emphasis on face and content validity, feasibility, and
users' attitudes and opinions. It can be summarized, quite briefly, that all of
them were satisfactory.
PMID- 10763166
TI - Analysis of integrated healthcare networks' performance: a contingency-strategic
management perspective.
AB - Few empirical analyses have been done in the organizational researches of
integrated healthcare networks (IHNs) or integrated healthcare delivery systems.
Using a contingency derived contact-process-performance model, this study
attempts to explore the relationships among an IHN's strategic direction,
structural design, and performance. A cross-sectional analysis of 100 IHNs
suggests that certain contextual factors such as market competition and network
age and tax status have statistically significant effects on the implementation
of an IHN's service differentiation strategy, which addresses coordination and
control in the market. An IHN's service differentiation strategy is positively
related to its integrated structural design, which is characterized as
integration of administration, patient care, and information system across
different settings. However, no evidence supports that the development of
integrated structural design may benefit an IHN's performance in terms of
clinical efficiency and financial viability.
PMID- 10763167
TI - The relationship between business process re-engineering and Internet usage:
survey of acute care hospitals in the United States.
AB - The data from a national survey of acute care hospitals was used for analysis.
Hatcher discusses the complete questionnaire, data collection procedure, and
sample selection. The relationship between business process re-engineering, total
quality management, innovation system approaches, and Internet usage and
potential usage will be reported and discussed.
PMID- 10763168
TI - [Immunohistochemical detection of humoral autoantibodies in patients with hearing
loss in the last hearing ear].
AB - BACKGROUND: An autoimmune etiology similar to the sympathetic ophthalmia has been
discussed for sensorineural hearing loss on the last hearing ear following
deafness in the first ear. In sympathetic cochleolabyrinthitis inner ear proteins
are thought to be released after laterobasal fracture, which may induce an
autoimmune process in the last hearing ear. Animal models have failed to clearly
demonstrate the location of the target in the labyrinth, attacked by immunologic
processes. Furthermore, it is unclear whether the humoral or cellular pathway is
initiating this process. METHODS AND PATIENTS: Serum was acquired from 15
patients with traumatic or post-inflammatory unilateral deafness and slowly
progressive or sudden sensorineural hearing loss on the last hearing ear.
Deparaffinized sections of rat temporal bones were incubated with patient serum
and subjected to immunohistochemical examination. RESULTS: A specific but
heterogeneous binding pattern of the labyrinth was found in 14 of 15 patients.
CONCLUSION: Our results indicate different autoantibodies in the patient serum,
which may be the cause of the hearing loss. Therefore, in patients with
sensorineural hearing loss on the last hearing ear, we recommend a therapeutic
trial with corticosteroids.
PMID- 10763169
TI - [Functional and morphological defects of the mucociliary system in secretory
otitis media].
AB - BACKGROUND: One of the main functions of the ciliated cells of the middle ear
mucosa is the continuous drainage of fluids from the middle ear cavity to the
Eustachian tube. Impaired mucociliary clearance is related to disturbed clearance
of middle ear secretions and results in otitis media with effusion. The aim of
this study was to evaluate the ciliary beat frequency (CBF) and the
ultrastructure of cilia in young patients suffering from otitis media with
effusion (OME). METHODS: CBF and ciliary ultrastructure were studied in 36
patients with OME and 10 normal subjects without any history of middle ear
effusion. RESULTS: The CBF was significantly decreased in the study group (6.59
Hz, +/- 1.83) compared to the controls (10.68 Hz, +/- 1.87) and the incidence of
ultrastructural defects was higher than in controls. The most common defect were
compound cilia, random orientation of the ciliary axes, and defects of the
central microtubules. Defects of the dynein arms were not observed.
PMID- 10763170
TI - [Reconstruction of the ossicular chain with titanium implants. Results of a
multicenter study].
AB - BACKGROUND: For decades, oto-surgeons have been trying to find suitable
alloplastic materials for replacing ossicles in the case of morphological and
functional disorders in the middle ear. The focus of attention has been on tissue
tolerance and functionality. PATIENTS: A retrospective analysis of the
implantation of titanium prostheses is presented (Type "Duesseldorf", Heinz Kurz
GmbH, Dusslingen, Germany) in 528 patients operated in 14 ENT hospitals. The
hospitals involved are ENT hospitals with different fields of specialization
presenting a representative cross-section of surgical ENT treatment. Evaluated
were healing results, hearing gain and surgical handling of the implants.
RESULTS: Despite pathological middle ear conditions, the tissue-implant healing
rate was very high. In 4.4% of the patients the implants were rejected. In the
case of partial ossicular reconstruction, an average hearing gain between 10 and
20 dB was achieved. Total reconstruction of the ossicular chain showed even
better audiological results (15 to 20 dB on average). CONCLUSION: Due to the good
morphological and functional results achieved, titanium implants have proven
their worth for middle ear micro-surgery. Their advantages are their light weight
and delicate structure, facilitating very good micro-surgical handling. It is
advisable to place a thin layer of cartilage between the prosthesis headplate and
the tympanic membrane. In this manner, the number of material extrusions can be
safely reduced, however, extrusions cannot completely be avoided.
PMID- 10763171
TI - [Electron microscopy studies of innervation of nasal mucosa glands in humans].
AB - BACKGROUND: Seromucous glands are one of the main components of human nasal
mucosa. The innervation pattern is important to understand the control of the
different physiological glandular functions. In addition to light-microscopical
findings electronmicroscopic investigations were performed to get more detailed
information on the innervation of nasal glands. PATIENTS AND METHODS: Tissue
samples of 16 human inferior turbinates were taken during nasal surgery and
preserved in Unicryl or 3.5% phosphate-buffered glutaraldehyde. After fixation
ultrathin sections were cut. Electron microscopical structures were
photodocumented by using a transmission-electron microscope (EM 902 A Zeiss).
RESULTS: Few axons were found in the periglandular tissue. No myo- or glandular
neural tight junctions could be identified. Unmyelinated nerve fibers showed
typical components such as neurofilaments, neurotubules and mitochondria in their
cytoplasm. An additional control of the glandular secretion by the vascular tone
of the fenestrated capillary vessels will be discussed. CONCLUSIONS: Based on
these ultramorphological findings further immunoelectron microscopical
investigations will follow to demonstrate the various neurotransmitters and their
distribution in periglandular axons.
PMID- 10763172
TI - [Improving wound healing after nose surgery by combined administration of
xylometazoline and dexpanthenol].
AB - BACKGROUND: The aim of this study was the examination of efficacy and
tolerability of an application-form of the new combination of Xylometazoline with
Dexpanthenol (Nasic) versus Xylometazoline alone. PATIENTS AND METHODS:
Randomized verum controlled parallel-group-comparison of two weeks treatment of a
nasal-spray. 61 inpatients with the diagnosis Rhinitis following nasal operation
were included in this study and 30 patients were treated with verum and placebo
each. The assessment of nasal-breathing-resistance according to scores was
defined as target-parameter. Confirmatory statistical analysis was carried out
according to Wilcoxon-Mann-Whitney-U two-sided at alpha < or = 0.05. MAIN OUTCOME
MEASURE: The superiority of the combination of Xylometazoline-Dexpanthenol nasal
spray versus Xylometazoline nasal spray could be proven for the target-parameter
as clinically relevant and statistically significant. The clinically proven
efficacy is emphasized by good tolerability of both treatments. Due to easy
handling of the nasal-spray a good compliance was confirmed. CONCLUSION: Distinct
improvement of symptoms in patients following nasal operations underlines the
efficacy of both medications. With respect to the tolerability therapy with the
combination is more beneficial in comparison to the alternative therapy. The
result of this controlled clinical study confirms that the combination
Xylometazoline-Dexpanthenol is an enlargement and improvement of effective
medicinal treatment of rhinitis following nasal operation in comparison to
therapy with Xylometazoline alone.
PMID- 10763173
TI - [Autologous rib cartilage harvesting: operative procedure and postoperative pain
reduction].
AB - INTRODUCTION: In reconstructive surgery there is a growing demand for cartilage
grafts. For small amounts of autologous tissue, cartilage from the nasal septum
or ear concha is a sufficient and reliable tissue, but in cases of extensive
defects or higher mechanical load autologous rib cartilage is a commonly used
transplant. Nevertheless, a serious donor-site morbidity, especially
postoperative pain, has to be taken into consideration. We present a modified
technique for harvesting rib cartilage with a consecutive local pain therapy.
TECHNIQUE: In contrast to the commonly used incision through all layers of tissue
the described technique follows the anatomical structures of skin tension-lines,
the fascial and muscle fibers and tissue sliding-planes. Starting with a
transversal skin incisions 1.5 cm above the costal arch, longitudinal splitting
of the rectus abdominis fascia and muscle, the rib cartilage of the ribs 6 to 8
can be exposed. Grafts in the size of at least 3 to 8 cm can be harvested under
preservation of the perichondrium. This technique causes a high degree of
stability and good function of the abdominal wall. POSTOPERATIVE PAIN THERAPY:
After harvesting rib cartilage most patients complain about extensive
postoperative pain. For adequate treatment the local application of a long
lasting anesthetic substance close to the intercostal nerves is helpful. The
introduction of a peridural catheter opens the feasibility of continuously
applying a local anesthetic for 3 to 4 days directly into the donor-site. This
procedure reduces the need for general anesthetics dramatically and prevents
further complications. DISCUSSION: This modified technique for harvesting rib
cartilage diminishes the donor-site morbidity by reducing the risk of
pneumothorax, hernias and functional deficits. Moreover, the local pain therapy
assures postoperative wellness and mobility.
PMID- 10763174
TI - [Growth of human respiratory epithelium on collagen foil].
AB - BACKGROUND: Clinical application of bioartificial tracheal prosthesis must still
be regarded as an experimental concept because restoration of a functional
respiratory epithelium outlining the prosthesis is still not possible. Tissue
engineering as a relatively new biotechnological discipline may offer new methods
in expanding differentiated respiratory epithelium in vitro. In this study we
compare two different cell and tissue culture procedures for growing human nasal
mucosa on commercially available collagen foil. MATERIAL AND METHODS: Harvested
specimens of human nasal mucosa (n = 6, 4 x 4 cm) were placed on collagen foil
and incubated as tissue cultures for 4, 6 and 8 weeks. A suspension of
enzymatically dispersed nasal epithelium seeded on collagen foil (5 x 10(5)
cells) served as control. Cell growth and ciliary beat were monitored through an
inverted microscope with Hoffman's modulation contrast and video set-up.
Histological examination was performed after 4, 6 and 8 weeks. RESULTS: In the
tissue cultures, the collagen foil was initially covered with fibroblasts growing
from the mucosa specimen before epithelial cells spread out. The epithelial layer
showed mostly ciliated cells which developed metachronous ciliary beat after 4
weeks in vitro. Ciliary activity was observed until the end of the experiments in
8 weeks. New cells on the suspension cultures were mesenchymal and did not
exhibit any ciliary activity. CONCLUSIONS: Mucosa specimens seem to be more
appropriate for tissue engineering of respiratory epithelium than cell
suspensions from nasal epithelium. Collagen foil as tissue scaffold initiates
epithelial-mesenchymal interaction and may play an important role in epithelial
differentiation of new respiratory epithelium.
PMID- 10763175
TI - [Self-expanding nitinol stents in proximal tracheal stenosis].
AB - The use of silicone- or metal stents in stenosis of the distal trachea and the
bronchial system is a customary procedure [1-4], for example after tumor invasion
or cicatricial stenosis after transplantation. In the proximal part of the
trachea, on smaller, short and soft strictures we try to stabilise the trachea by
the implantation of rings. Other methods are tracheal plasty or transverse
tracheal resectomy [5-7]. In the case of longer or nearer subglottal stenoses the
positioning of self-expanding nitinol stents has proven a simple, gentle and well
tolerated alternative procedure even in very serious disorders [1, 8, 9]. METHOD:
These stents can be placed in short narcosis under endoscopic control without
great strain on the patient. RESULTS: We placed nitinol-stents in the proximal
part of the trachea in eleven cases. In five cases dyspnoea caused by a tracheal
collapse improved. In two further cases a tracheal stenosis with massive
granulation tissue and cicatricial pull under an inlaid tracheal cannula was
removed and the tracheostoma was closed. In four cases a solid, scarred and
cartilaginous stenosis in the area of the cricoid and the upper tracheal rings
was widened with laser and later on stented. CONCLUSION: Over an observation time
of two years no complications showed safe one case in which a directly
postoperative dislocation was repositioned quickly. The patients live without
restrictions through the tracheal stenosis or a tracheostoma. In the best
possible case epithelialization over the metal meshes develops so that a nearly
normal mucus transportation is possible [1, 10-12].
PMID- 10763176
TI - [Infection of deep soft tissues of the neck in intravenous drug abuse].
AB - BACKGROUND: Despite the availability of antibiotics deep neck space infections
with anaerobic germs (Ludwig's angina) still carry the potential for significant
morbidity and mortality with delayed treatment. Usually, odontogenic infections
with involvement of the submandibular space are the source of deep neck space
infections in adults, whereas in the pediatric population the most common cause
is acute tonsillitis with involvement of the peritonsillar space. During the
second half of this century intravenous drug abusers appeared as a new group of
patients at risk for deep neck space infections. When peripheral veins sclerosis
the addicts feel it necessary to either inject subcutaneously or use the major
vessels of the neck and groin. Intravenous drug abusers injecting the major
vessels of the neck risk delayed diagnosis because of dissimulation of their
injection practices. Dangerous complications of deep neck space infections may be
the result. CASE: We report a clinical case with delayed diagnosis and fatal
outcome. CONCLUSION: Intravenous drug abuse is a rare cause for deep neck space
infections but should be considered when swelling of the neck soft tissue of
uncertain cause is presented. The search for the diagnose should not keep from
taking quick therapeutic steps.
PMID- 10763177
TI - [Differential diagnosis of parapharyngeal mass].
AB - BACKGROUND: Parapharyngeal lesions are rare. Tumors arising in the parapharyngeal
space can be silent clinically for a long period of time. Physical findings like
dislocation of the pharyngeal walls or cervical swelling are often recognized by
chance. MATERIAL AND METHODS: Representing three cases of parapharyngeal tumors
the differential diagnosis of parapharyngeal masses and the importance of the
magnetic resonance imaging will be shown. CONCLUSIONS: Mostly, parapharyngeal
masses are represented by salivary gland tumors (40%-50%). The second most common
tumors in the parapharyngeal space are neurogenic tumors (17%-25%).
Paragangliomas are the third group of common parapharyngeal lesions (10%-15%). A
mixed group of lesions like branchial cleft cysts, lymph nodes and hematogenic
tumors represent the remaining part of the parapharyngeal masses (10%-33%). Most
of the lesions (80%) are benign. Because of the magnetic response imaging a
reliable preoperative diagnosis is possible in more than 80% of the tumors. The
surgical management may also be influenced by the location of the tumor shown in
the magnetic resonance imaging.
PMID- 10763178
TI - [Diagnosis and therapy of primary snoring].
AB - Snoring, excessive daytime sleepiness and nocturnal apnoea are among the leading
symptoms of the obstructive sleep apnoea syndrome (OSAS). Primary snoring without
upper airway obstruction is a more common and normal phenomenon in sleep and has
to be distinguished from OSAS. Patients with primary snoring are often suffering
and complain of great distress and social embarrassment and therefore request
professional help. Therefore, the otorhinolaryngologist has to be aware of the
different treatment options that are possible and sensible. Apart from behavioral
changes and general measures (weight loss, reduction of alcohol consumption,
sleep position training), there are different conservative and surgical treatment
options. In this article, the pathophysiology, diagnosis and treatment of primary
snoring will be discussed.
PMID- 10763179
TI - [The interesting case No. 32. Secondary cricopharyngeal achalasia in underlying
mitochondrial myopathy].
PMID- 10763180
TI - [Animal experiments and cell culture studies on stapes reconstruction with
diverse biomaterials].
PMID- 10763181
TI - [Trachea surgery. Chronic stenoses].
PMID- 10763182
TI - [Should we consider hyperhomocysteinemia as a vascular risk factor?].
PMID- 10763183
TI - [Extra-ocular etiologic factors in retinal vein occlusion. Retrospective study of
24 patients].
AB - PURPOSE: Retinal vein occlusion has several causes. Cardiovascular risk factors,
particularly systemic hypertension; as well as thrombophilia appear to be
involved in the development of retinal vein occlusion. METHODS: In a
retrospective study we analyzed these factors in 24 patients, admitted for
retinal vein occlusion and isovolaemic hemodilution in an internal medicine unit.
RESULTS: In patients over 50 years of age, cardiovascular risk factors
predominate; while in patients under 50, one patient out of two has biological
features indicating a risk for thrombosis. CONCLUSION: Serological abnormalities
could be involved in the physiopathology of retinal vein occlusion in young
patients.
PMID- 10763185
TI - [Imported malaria in Moselle: 75 cases in three years].
AB - PURPOSE: Imported malaria frequency is increasing in France. Moselle, a north
east French county, with high concentration of servicemen going in endemic areas,
follows the same trend. METHODS: Clinical, epidemiological aspects and treatment
of all malaria attacks diagnosed over 3 years (from 1st january 1996 to 31st
january 1999) were studied. Data pertaining to antimalaria prophylaxis and the
reasons for prophylaxis failure were analyzed. RESULTS: Seventy-five patients
developed a paroxysmal episode of malaria. No severe malaria and no death were
noted. Ninety-six percent of the patients came from Africa (96%), 64% of them
coming from western Africa (Ivory coast, Senegal, and Togo). Plasmodium
falciparum was responsible for 90% of the cases. Giemsa staining, quantitative
buffy coat diagnosis system and parasight rapid dipstick antigen capture assay
help guide diagnosis. Halofantrine (64%) and quinine (28.6%) were used as
curative treatment. Investigation about prophylactic means showed than 37.9% of
interviewed patients did not comply with the preventive treatment. The primary
prophylaxis (avoiding bites) was in existent or badly done. CONCLUSION: Although
the best choice for chemoprophylaxis is still debated, travelers going to endemic
areas should be aware of the risks for malaria and persuaded to take a preventive
treatment, even though its efficacy may not be complete. They also should wear
insecticide-treated clothes in order to decrease the number of potentially
infective mosquito bites.
PMID- 10763184
TI - [Polyclonal B lymphocytosis and hyper-IgM: immunodeficiency and/or benign
lymphoid proliferation associated with tobacco?].
AB - PURPOSE: To study the association of polyclonal B-cell lymphocytosis with
binucleated lymphocytes with clinical manifestations suggesting the existence of
an immunodeficiency, to evaluate the effect of cigarette smoking on this 'benign
lymphoid proliferation', to analyze the clonality of lymphocytes, to determine
the levels of immunoglobulins (Ig) G, A, M. METHODS: Description and analysis of
the results obtained in four patients and literature review. RESULTS: Polyclonal
B-cell lymphocytosis is associated with both a decrease in IgA and IgG and an
increase in IgM. Recurrent infectious episodes (bronchitis) were observed in two
patients. Transient smoking cessation allowed a decrease in lymphocytosis and IgM
levels in two patients. No hematological malignancy occurred during the follow
up, while biological abnormalities persisted. CONCLUSION: Persistent polyclonal B
cell lymphocytosis may be associated with minor clinical features of
immunodeficiency. Smoking cessation may sometimes lead to a decrease in
lymphocytosis and IgM.
PMID- 10763186
TI - [Treatments for amyloidosis beyond symptomatic care].
AB - INTRODUCTION: Amyloid syndromes are pathogenetically different, each of the
various amyloid diseases requiring specific treatment. Unfortunately, those
treatments are often preventive and symptomatic, some efficient therapies being
limited to particular types of amyloidosis. CURRENT KNOWLEDGE AND KEY POINTS:
Colchicine is effective in the prevention of amyloidosis due to familial
Mediterranean fever but is less or not effective in other situations. Cytotoxic
agents are useful in the treatment of AL amyloidosis with or without hemopoietic
stem cell transplantation. Liver transplantation is indicated for familial
polyneuropathy and kidney transplantation for dialysis-related beta 2
microglobulin amyloidosis. FUTURE PROSPECTS AND PROJECTS: In vivo binding of
serum amyloid P (SAP) (component shared by all amyloid deposits) to amyloid
fibril, is a new avenue in the therapeutic approach. Development of radiolabeled
SAP scintigraphy allows assessment of the disease outcome and evaluation of
treatment-related effects. The various treatments that were assessed until now
with the objective of curing the disease are reviewed.
PMID- 10763187
TI - [Secondary infections after pacemaker implantation].
AB - INTRODUCTION: Infectious complications following pacemaker implantation are not
common but may be particularly severe. Localized wound infections at the site of
implantation have been reported in 0.5% of the cases in the most recent series,
with an average of about 2%. The incidence of septicemia and infectious
endocarditis is lower, about 0.5% of the cases. The operator's experience, the
duration of the procedure and repeat procedures are considered to be predisposing
factors. CURRENT KNOWLEDGE AND KEY POINTS: The main cause of these infections has
been recently demonstrated to be local contamination during implantation. The
commonest causal organism is Staphylococcus (75 to 92% of the cases),
Staphylococcus aureus being the cause of acute infections (less than 6 weeks),
whereas Staphylococcus epidermidis is associated with cases of secondary
infection (more than 2 months). The usual clinical presentation is infection at
the site of the pacemaker but other forms such as abscess, endocarditis,
rejection of the implanted material, septic emboli or phlebitis have been
described. The diagnosis is confirmed by local and systemic biological
investigations and by echocardiography (especially transesophageal
echocardiography) in cases of right heart endocarditis. There are two axes of
treatment: bactericidal double antibiotherapy and surgical ablation of the
infected material either percutaneously or by cardiotomy. FUTURE PROSPECTS AND
PROJECTS: A recent meta-analysis supported the role of systematic, preoperative,
prophylactic antibiotic therapy in the prevention of these complications. These
data should be confirmed by suitably powered clinical trials.
PMID- 10763188
TI - [Venous thromboembolism and cancer].
AB - INTRODUCTION: Thromboembolic venous disease, which includes both peripheral
venous thrombosis and pulmonary embolism, is a frequent disorder in patients with
cancer. Although thromboembolic manifestations may precede the diagnosis of
cancer, the value of extensive clinical search for potential underlying cancer
when faced with venous thromboembolic manifestations has not been demonstrated.
CURRENT KNOWLEDGE AND KEY POINTS: Clinical and biological studies have
demonstrated that acquired abnormalities in blood hemostasis, especially
procoagulant factors, account for the onset of thromboembolic manifestations in
patients with cancer. Classical anticoagulant therapy is associated with low
efficacy and tolerance in patience with cancer who are at high risk for
hemorrhagic complications and recurrence of thromboembolic disease. FUTURE
PROSPECTS AND PROJECTS: Recent data suggest the value of anticoagulant therapy
using either low molecular weight heparin or warfarin at low doses (INR < 2)
according to the specific surgical or medical context.
PMID- 10763189
TI - [Olfactory esthesioneuroma manifesting as Schwartz-Bartter syndrome].
AB - INTRODUCTION: Olfactory esthesioneuroblastoma is an uncommon neuroectodermal
tumor originating from the olfactory epithelium, which is rarely associated with
hormone excess syndrome. EXEGESIS: Asymptomatic olfactory esthesioneuroblastoma
was diagnosed in a 22-year-old man who presented a syndrome of inappropriate
antidiuretic hormone secretion. Following surgery, the immunohistochemical
analysis demonstrated the existence of neurophysin hormone in tumoral cells.
CONCLUSION: This case provides evidence that olfactory esthesioneuroblastoma can
be uncovered by inappropriate antidiuretic hormone secretion.
PMID- 10763190
TI - [Venlafaxine withdrawal syndrome: report of six cases and review of the
literature].
AB - INTRODUCTION: Venlafaxine is an antidepressant that selectively inhibits
serotonin reuptake and is a norepinephrine inhibitor. Withdrawal syndromes can
occur after abrupt drug discontinuation of long-term regimens. EXEGESIS: We
report six cases of withdrawal symptoms after venlafaxine discontinuation.
CONCLUSION: Physicians must be aware of the frequency, rapidity and potent
severity of these withdrawal syndromes.
PMID- 10763192
TI - [Malignant non-Hodgkins B lymphoma related to Epstein-Barr virus and chronic
natural killer lymphocytosis in a immunocompromised patient].
AB - INTRODUCTION: Immunocompromised patients are at high risk of Epstein-Barr virus
(EBV)-related lymphoproliferative disorders. The lymphoproliferation affects B,
T, and natural killer (NK) cells. EXEGESIS: We report the case of a woman
suffering from systemic lupus erythematous. She developed an opportunistic
pneumonia while immunodepressed during long-term corticotherapy aimed at curing
her auto-immune disease. Chronic lymphocytosis was also diagnosed at this time.
Several months later, non-Hodgkin's lymphoma was diagnosed. Genomic amplification
of the Epstein-Barr virus in the patient's blood and positive EBV latent membrane
protein 1 on the lymph nodes provided evidence for a strong correlation between
EBV reactivation and lymphoma. CONCLUSION: Two distinct lymphoid diseases
occurred during the immunosuppressive therapy for the auto-immune disease. PCR
monitoring of Epstein-Barr virus allows for early screening of
lymphoproliferative disorders in immunocompromised patients, leading to earlier
and more efficient treatment.
PMID- 10763191
TI - [Schnitzler syndrome: a rare cause of systemic urticaria].
AB - INTRODUCTION: The Schnitzler's syndrome first described in 1972, associates
urticaria, bone pain, and monoclonal IgM gammapathy. EXEGESIS: A 50-year-old man
presented symptoms of urticaria restricted to the trunk and lower members, with
episodes of fever accompanied by inflammatory pain in the knees and legs. Slight
deterioration of his general condition was also observed. Biological findings
showed the existence of an inflammatory syndrome. Electrophoresis and
immunoelectrophoresis provided evidence for the existence of underlying IgM
gammapathy. Bone X-ray demonstrated the presence of tibial and peroneal
metaphysis thickening, with hyperfixation on bone scintigraphy. The patient's
condition improved after cortisone and colchicine treatment, allowing decrease in
coricosteroid doses. Two years later, except for urticaria, clinical features
have disappeared and no hematological disorder has been observed.
PMID- 10763193
TI - [Ear cartilage calcification].
PMID- 10763194
TI - [The heart in air].
PMID- 10763195
TI - [Cutaneous porphyria cure in a patient infected with human immunodeficiency virus
treated with triple therapy].
PMID- 10763197
TI - [Lymphocytic lymphoma and regenerative liver nodular hyperplasia in systemic
scleroderma].
PMID- 10763196
TI - [Hyponatremia and sertraline].
PMID- 10763198
TI - [Isoprostanes: new markers of oxidative stress. Fundamental and clinical
aspects].
AB - A novel family of prostaglandin F2 isomers, called F2-isoprostanes, produced in
large quantities in vivo by a free radical peroxidation of arachidonic acid, has
recently been described. The quantification of the two major isoforms
(isoprostaglandin F2alpha type-III and VI) in biological fluids and tissues as
markers of lipid peroxidation appears to be an important advance in our ability
to explore the role of free radicals in the pathogenesis of human disease. In
addition, F2-isoporstanes quantification seems promising as intermediate
endpoints for clinical studies of antioxidant therapies.
PMID- 10763199
TI - [Immortal aspirin....].
PMID- 10763200
TI - [Aspirin throughout the ages: a historical review].
AB - Even at the beginning of the next millennium, aspirin will still offer surprises.
Its relatively young pharmacological history compares with the early use of
salicylate-containing plants since antiquity. The Assyrians and the Egyptians
were aware of the analgesic effects of a decoction of myrtle or willow leaves for
joint pains. Hippocrates recommended chewing willow leaves for analgesia in
childbirth and the Reverend Edward Stones is acknowledged as the first person to
scientifically define the beneficial antipyretic effects of willow bark. At the
beginning of the 19th century salicin was extracted from willow bark and
purified. Although a French chemist, Charles Gerhardt, was the first to
synthesize aspirin in a crude form, the compound was ignored, and later studied
by Felix Hoffmann. He reportedly tested the rediscovered agent on himself and on
his father, who suffered from chronic arthritis--a legend was born and Bayer
Laboratories rose to the heights of the pharmacological world. First used for its
potent analgesic, antipyretic and anti-inflammatory properties, aspirin was
successfully used as an antithrombotic agent. Sir John Vane elucidated aspirin's
active mechanism as an inhibitor of prostaglandin synthetase and received the
Nobel Price in Medicine for this work in 1982. Two isoform of cyclooxygenase (COX
1 and COX-2) have now been identified, each possessing similar activities, but
differing in characteristic tissue expression. The cox enzyme is now a target of
drug interventions against the inflammatory process. After two centuries of
evaluation, aspirin remains topical, and new therapeutic indications are
increasingly being studied.
PMID- 10763201
TI - [Pharmacology of aspirin].
AB - Aspirin (acetylsalicylic acid) is the best-known salicylate and belongs to the
non steroid anti-inflammatory drug class. Despite wide use being made since more
than 100 years, knowledge about mechanism of action and therapeutic issues
continually evolves. The main mechanism of action is prostaglandin synthesis
inhibition. This is achieved through inhibition of prostaglandin endoperoxide
synthase (PGHS) or cyclooxygenase (COX) synthesis. Most of the therapeutic uses
of aspirin are explained by this mechanism. Nevertheless aspirin uses change as
time goes by: if the main one during the first fifty years was an analgesic, anti
pyretic and anti-inflammatory one, the last fifty years saw aspirin being used
mainly as an anti-thrombotic agent, in primary and secondary thrombo-embolic
prevention. Better knowledge of mechanism of action points today at, on one hand,
more selective and therefore better tolerated molecules, and, on the other hand,
at new therapeutic applications, such as anti-cancer and neurodegenerative
diseases prevention.
PMID- 10763202
TI - [Aspirin and hemostasis].
AB - Aspirin is one hundred years old, though its use has clearly evolved during the
last 25 years. Identifying its action mechanism has allowed us to better
understand the antithrombotic impact. Prostaglandin H synthetase (PGHS) is a
bifunctional enzyme with cyclooxygenase and peroxydase activities. There are two
isoforms: constitutive PGHS-1 and inducible PGHS-2. Aspirin irreversive
acetylates the platelet cyclooxygenase involved in the formation of thromboxane
A2, a powerful proaggregating agent and vasoconstrictor. More than 95% of
inhibition of this synthesis takes place in two to three days using very weak
doses of aspirin, on the order of 30 to 50 mg per day. Under some circumstances,
this inhibition requires higher dosages. Certain clinical and biological
circumstances could lead to a resistance to aspirin, making a readjustment of
doses and sometimes complementary explorations necessary. The ISIS 2 study showed
in an apparently irrefutable way the entry of aspirin into the antithrombotics
arsenal, with a significant risk reduction of vascular death and recurrence of
infarctus. Numerous studies have confirmed this efficacy. Consensus studies are
based on information showing total coherence between the dose necessary to
acetylate the enzyme to inhibit thromboxane A2 platelet production and the
clinical antithrombotic effect. Aspirin seems to have a secure place, and it
begins the third millennium in relative peace with new extra-platelet
potentialities outside the framework of hemostasis and thrombosis.
PMID- 10763203
TI - [Aspirin and prevention of cardiovascular risk].
AB - PURPOSE: Aspirin, a potent platelet inhibitor, is widely used in patients with
cardiovascular diseases. Platelet aggregation is the cornerstone of acute
atherothrombotic complications. ACTUALITIES: Aspirin showed significant benefits
when administered in patients with acute myocardial infarction or unstable
angina, and also when used for secondary prevention in patients with known
coronary artery disease. Aspirin has been evaluated in primary prevention, with
interesting results in high-risk patients. Finally, aspirin can be used in some
patients with supraventricular arrhythmias or with mechanical valves.
PERSPECTIVES: Further investigation concerning the exact role of aspirin in
primary prevention is currently being done. The association of aspirin with new
antiplatelet agents in patients with acute coronary syndromes has shown
interesting results.
PMID- 10763204
TI - [Aspirin and cerebral ischemic accidents].
AB - At the acute phase of cerebral infarction, two recent large studies found that
the use of aspirin reduces both mortality and the risk of the recurrence of
stroke. In primary prevention, aspirin nearly halves the risk of myocardial
infarction but does not reduce that of stroke. Concerning the secondary
prevention of atherothrombotic brain infarcts, aspirin has been the most
extensively studied drug, and is efficient between 50 mg and 1.3 g. In spite of
the efficacy of other antiplatelets in this indication--ticlopidine (500 mg),
clopidogrel (75 mg) and dipyridamole (400 mg)--aspirin remains the most cost
effective, doses between 100 and 300 mg being the most widely used. Cardiac
diseases with a high embolic risk require the use of oral anticoagulation. In
nonvalvular atrial fibrillation, the choice of antithrombotic drugs depends on
risk stratification: oral anticoagulants are indicated in high-risk subjects,
whereas aspirin is recommended in low-risk subjects and when oral anticoagulants
are contraindicated. Studies with associations of aspirin and other antiplatelets
are required to increase the yield of this medication in high-risk subjects, in
parallel with efforts to detect and to treat the vascular risk factors.
PMID- 10763205
TI - [Digestive complications of aspirin].
AB - INTRODUCTION: This review focuses on aspirin-related gastrointestinal side
effects and the mechanism by which aspirin causes gastrointestinal damage.
CURRENT KNOWLEDGE AND KEY POINTS: Aspirin causes direct gastric damage by topical
irritant effects and indirect damage via systemic inhibition of cyclooxygenase
synthesis and microcirculation injury. The question of a possible synergistic
relation between the presence of Helicobacter pylori infection and aspirin use on
gastric damage is not resolved. The pathogenesis of small intestinal and colonic
damage is less well understood; an increase in intestinal permeability and free
radical synthesis are suggested. Gastric damage predominates. Gastroduodenal
lesions from aspirin have been documented in endoscopy studies. The lesions occur
rapidly, even for low-dose aspirin. The association of aspirin consumption with
upper gastrointestinal bleeding has been well established. The main risk factors
are advanced age, concomitant use of nonsteroidal antiinflammatory drugs and
history of ulcer. Low-dose aspirin are associated with increased risk of
gastrointestinal bleeding and this risk is dose-dependant. Chronic aspirin
consumption can cause iron deficiency anaemia. Uncomplicated gastric ulcer (but
not uncomplicated duodenal ulcer) is associated with aspirin use, with relative
risk 3. Other upper gastrointestinal complications have been reported: stenosis
and perforation. Aspirin can also damage other areas of the gastrointestinal
tract. Oesophageal injuries (oesophagitis and stricture) have been reported.
Aspirin is associated with variceal bleeding episodes in patients with cirrhosis.
The adverse effects of aspirin on the small bowel are perforation, bleeding,
increasing permeability. The adverse effects of aspirin on the large intestine
are perforation, bleeding, collagenous colitis and anorectal stenosis with
suppositories containing aspirin. Direct clinical data regarding prophylaxis with
co-administration of a protective drug are not yet available for aspirin. FUTURE
PROSPECTS AND PROJECTS: Patients should be made aware of adverse gastrointestinal
effects due to aspirin. Further studies regarding prophylactic therapy of low
dose aspirin induced gastroduodenal lesions, which identify a subset of patients
who may be at higher risk than the low-dose aspirin population as a whole, are
warranted.
PMID- 10763206
TI - [Aspirin against cancer].
AB - PURPOSE: That aspirin as an anti-aggregative and anti-inflammatory compound might
prevent tumor spread is an old concept that is still not of clinical relevance.
To date, aspirin has been shown in several epidemiologic studies to be linked
with a reduction of colorectal cancer incidence, as well as the incidence of lung
and breast cancer. In this issue, we have summarized the mechanisms that support
this hypothesis, and we have analysed the main clinical studies. RESULTS: Only
case-control studies and most of the prospective cohort studies showed a
reduction of colorectal cancer incidence in regular aspirin users. Nevertheless,
the minimum effective doses of aspirin and the duration of therapy remain
unclear. To date, only one prospective randomized trial has evaluated the
influence of aspirin in the prevention of colorectal cancer. Despite the
inclusion of 22,000 subjects and a five-year follow-up, aspirin failed to show
any protection. The mechanism of the potential role of aspirin in preventing
cancer, primarily supposed to rely on the antiprostaglandin effect, is now under
debate. Few studies have evaluated the prevention of other cancers, such as
breast or lung cancers, by aspirin. Data remain too sparse to allow any
conclusion. CONCLUSION: The role of aspirin in the prevention of colorectal
cancer still needs further studies, such as a prospective randomized study, which
should be conducted in a high-risk population.
PMID- 10763207
TI - [Aspirin and prevention of pre-eclampsia].
AB - Aspirin is used in pregnant women in order to obviate the imbalance of
prostanoids caused by a defective placentation, and also to counteract the
widespread thrombotic tendency related to endothelial dysfunction. After a series
of controlled trials which showed a very consistent effect of aspirin t prevent
preeclampsia and fetal growth retardation, several recent large trials have cast
the doubt, and even unbelief. Their results are analyzed in an explicative way.
Discrepancies seem largely related to either studying very low-risk populations,
or strong differences in aspirin dosage and/or term of introduction. In the last
few years, several works have shown the critical importance of an early
treatment, and also of a measurable biologic effect, which requires larger
dosages than those used in the most recent trials. The doubt largely remains as
for the adequate indications of this treatment. New data in the physiology of
placentation suggest that it would be logical to give aspirin as early as the
first wave of throphoblastic invasion. The effect of so an early treatment need
to be evaluated. The search for early markers should be pursued. The combination
of aspirin and heparin is under investigation. Finally, other ways of prevention,
such as anti-oxidants, are also being studied.
PMID- 10763208
TI - [Aspirin: allergy or intolerance].
AB - PURPOSE: The paper describes the clinical characteristics of patients with
aspirin-induced asthma and/or urticaria, angioedema, shock, the results of the
challenge tests and the evolution of this disease. MAIN POINT: The authors
present the different arguments supporting the physiopathological mechanisms from
genetics to the inhibition of cyclooxugenase or the leukotriene hypothesis.
PROSPECTIVES: Finally, they recall the methodology to be used for a good clinical
practice on this controversial field of research.
PMID- 10763209
TI - [Aspirin and antiphospholipid syndrome].
AB - INTRODUCTION: Antiphospholipid syndrome is the most frequent cause of acquired
thrombophilia. Aspirin may have some indications. CURRENT KONWLEDGE AND KEY
POINTS: The usefulness of low doses of aspirin is now well demonstrated in the
prevention of obstetric complications associated with antiphospholipid antibodies
(especially pregnancy loss). When heparin is combined with low-dose aspirin, the
recurrent rate of fetal loss is lower than 30%. In patients with arterial or
venous thrombosis, there is a high rate of recurrence during the two first years
except if high-dose warfarin was used (i.e., INR > or = 3). The association
warfarin-aspirin in secondary prevention of thrombosis may be evaluated in
prospective studies. It is not so clear in the literature and in our experience
that warfarin is superior to aspirin in stroke recurrence prevention in patients
with antiphospholipid antibodies, except in Sneddon's syndrome. There are no
guidelines in primary thrombosis prevention in patients with antiphospholipid
antibodies. In lupus patients, aspirin may not be sufficient after many years of
follow-up in preventing a first episode of thrombosis. Prospective studies may be
undertaken. Atherosclerotic patients with antiphospholipid antibodies are
particularly exposed to the risk of thrombosis after revascularisation or
angioplasty and stent implantation. Aspirin may have a place in those patients
but these must be evaluated. FUTUR PROSPECTS AND PROJECTS: Except in prevention
of obstetric complications, the usefulness of aspirin in patients with
antiphospholipid antibodies must be evaluated in prospective studies.
PMID- 10763210
TI - [Aspirin, pain and inflammation].
AB - SUBJECT: Acetylsalicylic acid (ASA) is among the most commonly analgesic,
antipyretic and anti-inflammatory used drugs. The anti-inflammatory effects of
ASA are mediated by the inhibition of cyclooxygenase enzymes with the subsequent
decrease of prostaglandin synthesis. NEW DATA: However, since this discovery of
Vane in 1971, much of other mechanisms of anti-inflammatory action, without
relation with cyclooxygenases, have been proposed. ASA has peripheric analgesic
properties by reducing prostaglandin biosynthesis. But there is evidence that the
analgesic effects could be mediated by central mechanisms with changes in the
monoaminergic and opioid systems. ASA is essentially used in moderate pains with
an inflammatory component (rheumatological disorders, headaches, dental and
postoperative pains). PERSPECTIVES: The clinical use of ASA at anti-inflammatory
dose is less frequent because the other non steroidal anti-inflammatory drugs are
as effective as ASA, but they are associated with less side effects.
Nevertheless, the synergism of ASA and morphine association and the possible
involvement of the central serotonergic and opiatergic systems in the
antinociceptive activity of ASA could confer a greater role of ASA in pain
management.
PMID- 10763211
TI - [Epidemiology of chronic hepatitis B and C among dialysis patients in
Switzerland].
AB - BACKGROUND: Among patients with renal insufficiency undergoing chronic dialysis
treatment, chronic hepatitis due to infection with viruses of the hepatitis B
(HBV) or hepatitis C (HCV) type represents a serious medical problem. In contrast
to other countries, detailed statistics on the prevalence of HBV and HCV
infection are not available for dialysed patients in Switzerland. METHODS: The
present study is based on a nationwide survey among the Swiss dialysis population
which evaluated the prevalence of patients positive for either the HBs antigen
(reflecting HBV infection) or anti-HCV antibodies (reflecting HCV infection) in
1999. From our survey we collected data on 1713 haemodialysis and 226 peritoneal
dialysis patients, representing 92 and 65% of the respective dialysis populations
in Switzerland. RESULTS: Of all patients (haemodialysis and peritoneal dialysis),
6.59% were HBV or HCV marker positive (HBV: 1.44%, HCV: 5.05%). In haemodialysis
patients the prevalence was clearly higher for HBV (1.63%) and HCV (5.72%)
compared to patients undergoing peritoneal dialysis (0.88 and 3.09%
respectively). Laboratory parameters of hepatitis--as evidenced by an increase in
liver transaminases--were present in 4% of the entire dialysis cohort, 0.6%
having an increase in ALAT beyond 1.5 times the normal range. Patients undergoing
treatment in haemodialysis units which do not implement additional precautions to
prevent the spread of HCV among patients were more likely to be HCV marker
positive with laboratory signs of hepatitis. A similar correlation was observed
between HBV or HCV marker positivity and the number of patients treated per
haemodialysis unit. Finally, the percentage of HBV/HCV marker positive patients
on the Swiss kidney transplant list is comparable with that of HBV/HCV marker
positive patients in the entire dialysis population.
PMID- 10763212
TI - [Vaccination against influenza in the hospital milieu and by family physicians in
Fribourg in 1997: facts and opinions].
AB - The influenza vaccine was underused in Switzerland in 1996, as less than half of
people at risk for the disease were vaccinated. We performed this study in 1997
to determine (1) the immunisation rate in the patients admitted to the internal
medicine ward of the Cantonal Hospital, Fribourg and in those seen by family
physicians, (2) the reasons underlying the decision of the physician to vaccinate
their patients or not, (3) the physicians' opinion of the vaccination. The study
was retrospective and included 383 patients hospitalised in the medicine ward
between October 15 and November 25, 1997. 249 of them (65%) had an indication for
vaccination against influenza according to the recommendations of the Federal
Office of Public Health. Only 20 patients (8%) were vaccinated during their
hospital stay. 86 family physicians (83%) answered the questionnaire concerning
141 patients (57%) whom they examined after their hospital discharge. Of these
patients, 77 (55%) were vaccinated by the family physician. The main reason for
not vaccinating the patients was the patient's refusal (33%). The effectiveness
of the vaccine was considered to be very good (effectiveness > 80%) by 40% of the
family physicians and good (effectiveness 60-80%) by 50%. The local and systemic
side effects were reported to be rare (incidence < 5%) by 55% and 71% of family
physicians respectively. The cost and the route of administration were not felt
to have any effect on acceptance of the vaccine. In decreasing importance the
family physicians considered the recommendations of the Federal Office of Public
Health useful for (1) chronic pulmonary disease, (2) immunosuppression, (3)
chronic cardiac disease, (4) chronic renal insufficiency and residency in homes
or institutions, (5) diabetes, (6) age over 64, (7) health care workers. In
conclusion, the influenza immunisation rate in Fribourg was very low at the
hospital but was higher than the Swiss figures for the family physicians.
Patient's refusal was the main reason for non-vaccination. The family physicians
have a favourable opinion of the effectiveness and tolerance of the influenza
vaccine.
PMID- 10763213
TI - [A new drug reaches Switzerland: coma after intake of gamma-hydroxybutyrate
(GHB)].
AB - The new recreational drug, gamma-hydroxybutyrate (GHB, "liquid ecstasy"), reached
Switzerland in 1998. We describe two cases from the city of Zurich. In both of
them the subjects were profoundly unconscious and needed hospitalization after
intake of a colourless liquid. Both patients recovered after a few hours, rapidly
and without after-effects. Gamma-hydoxybutyrate is abused mainly for its
euphorigenic and sedative properties by young people in discos, at raves, or on
the drug scene. It is also taken as an alleged anabolic agent among bodybuilders.
Criminals use it to narcotise potential victims. We summarise its effects,
adverse effects, diagnosis, treatment, toxicology, pharmacology, and medical
applications.
PMID- 10763214
TI - [Hereditary cancer syndromes in gynecology: what the practitioner needs to
know!].
AB - During the last 5 years progress in molecular genetics has offered the
possibility of genetic testing for inherited mutations of cancer-predisposing
genes. The exact cellular function and carcinogenic potential of these genes is
yet not completely understood. Only in 5-20% of all cancers inherited genetic
mutations play an important role in the polygenic and multifactorial nature of
the disease. Identification of inherited cancer syndromes, predictive genetic
testing, and counselling of women and family members at increased risk is of
clinical importance. The debate surrounding presymptomatic diagnostic testing and
adequate programmes for early cancer detection, prevention or clinical follow-up
continues.
PMID- 10763215
TI - [Chest pain in the influenza season].
PMID- 10763216
TI - Quality management data--the feedback challenge.
PMID- 10763217
TI - Commentary: why quality improvement efforts in health care fail and what can be
done about it.
AB - When you scratch below the surface, there is a palpable frustration in the field
of quality improvement. More often than not, these disappointments are rooted in
the slow pace of progress seen with improvement initiatives. Little is written
about the shortcomings of quality improvement in health care. Medicine, in
general, shuns from publicly discussing its failures. This article will focus on
10 features of failing quality improvement efforts.
PMID- 10763218
TI - Quality assessment in nursing home facilities: measuring customer satisfaction.
AB - A national study designed to assess the reliability and validity of a nursing
home customer satisfaction survey is summarized. One hundred fifty-nine
facilities participated, each responsible for the distribution and collection of
200 questionnaires randomly sent to the home of the resident's responsible party.
A total of 9053 completed questionnaires were returned, for an average adjusted
response rate of 53%. The factor analysis identified 4 scales: Comfort and
Cleanliness, Nursing, Food Services, and Facility Care and Services, each with
high reliability. Based on a multiple regression analysis, the scales were shown
to have good criterion-related validity, accounting for 64% of the variance in
overall quality ratings. Comparisons based on select characteristics indicated
significantly different satisfaction ratings among facilities. The results are
interpreted as providing evidence for the construct validity of a
multidimensional customer satisfaction scale with measured reliability and
criterion-related validity. Moreover, the scale can be used to differentiate
satisfaction levels among facilities.
PMID- 10763219
TI - Implications for clinical performance measurement of interlaboratory variability
in methods for glycosylated hemoglobin testing.
AB - In order to evaluate interlaboratory variation in glycosylated hemoglobin (GHb)
testing in the context of quality assessment and performance measurement systems,
we conducted a telephone survey of laboratories in Washington state. The survey
focused on GHb testing methods, analytes measured, reference ranges, awareness of
and adherence to the National Glycohemoglobin Standardization Program (NGSP)
standards, and recent changes in methods. We contacted 30 (81%) of 37
laboratories known to conduct GHb testing. Among the 25 laboratories using 1 or
more test methods in-house, 5 (20%) reported only total GHb levels rather than
HbA1C. There was considerable variability in test methods used and in reported
high and low reference ranges within and across methods. Eight (30%) of 27
individual methods used by the laboratories were not certified by the NGSP. From
January 1997 through August 1998, 11 of 25 laboratories (44%) made changes in
testing methods. Despite national efforts to decrease variability in GHb testing
methods, substantial variability remained in Washington state in 1997. In
addition to hindering management of individual patients, this variability poses
challenges for clinical performance measurement systems such as the Health Plan
and Employer Data Information Set that attempt to compare the adequacy of
glycemic control among health systems. However, the high frequency of recent
changes in testing methods may indicate an improving trend in test methods.
PMID- 10763220
TI - Improving outpatient diabetes management through a collaboration of six
competing, capitated Medicare managed care plans.
AB - This report addresses diabetes care in the managed care setting and improvement
in care brought about by collaboration between 6 Medicare managed care plans
(MCPs) and a Peer Review Organization (PRO). The objective was to improve the
quality of care of outpatient diabetes patients provided by primary care
physicians through the mutual collaboration of 6 Medicare managed care plans and
a Medicare Peer Review Organization. The design involved pre-post intervention
trial based on 2 random samples, a baseline sample drawn in 1995 and a
remeasurement sample drawn in 1996. Medical records of patients in both samples
were reviewed by the PRO to determine provision of 14 quality indicator services
over a 1-year period. The setting was 6 Arizona Medicare managed care plans
comprising approximately 40% of the Arizona Medicare population. Two random
samples were drawn from type 2 diabetes patients continuously enrolled in the
same managed care plan for at least 1 year. The intervention was comparative
feedback of baseline data by the PRO, enabling each plan to compare itself to any
other plan on any or all indicators. Each plan developed and implemented its own
intervention in response to the 1995 baseline results. The main outcome measures
were mean HbA1c, the proportion of HbA1c values below 8%, and positive change in
provision of 14 quality indicator services. At postintervention remeasurement,
mean HbA1c values fell from 8.9 +/- 2.2 to 7.9% +/- 2.1, and the proportion of
patients with HbA1c values below 8.0% rose from 40% to 61.6%. The proportion of
the 14 indicator services provided to patients rose from 35% to 55%. The mean
number of physician office visits fell 13% and the number of services provided
per visit doubled. We conclude that improving the process of care improves
glycemic control. Better outpatient diabetes management in competing, capitated
managed care plans is an attainable goal when mediated through a neutral third
party such as a PRO.
PMID- 10763222
TI - Chin up, chest out!
PMID- 10763221
TI - Use of continuous quality improvement to identify barriers in the management of
hypertension.
AB - We have made great strides in understanding the pathophysiology and medical
management of hypertension, yet barriers to effective blood pressure control
remain. The process of identifying the barriers within the health care system may
be as important as the barriers themselves. Our primary purpose was to apply the
widely accepted tool, Continuous Quality Improvement (CQI), to identify barriers
to the management of hypertension. We wanted to identify the most important
factors and (or) persons in effective blood pressure control and to compare
costs, satisfaction, and blood pressure control among subgroups of patients to
identify those most likely to benefit from interventions. We recruited patients
with essential hypertension who came to a university-based clinic staffed by
family physicians and residents; 181 patients with hypertension were identified
and asked at the time of their visit to complete a questionnaire relating to the
management of their blood pressure. Twenty-five physicians and 8 medical
assistants were also asked to complete a similar questionnaire regarding their
perceptions of barriers to blood pressure management. All other information came
from the patients' medical records. Blood pressure control was based on a reading
taken on the date the questionnaire was completed. Student's t test was used to
determine if statistically significant differences existed in blood pressure
control, patient satisfaction, and total costs for certain subgroups; regression
analysis was used to determine correlations. We had completed questionnaires from
91 patients, 89 physicians, and 79 staff. The physicians and staff were of course
involved; however, we found that the patients' gestalt was extremely important in
blood pressure control. Our patients perceived that lifestyle modifications such
as exercise and weight loss were the greatest barrier to better blood pressure
control. The cost of certain antihypertensive drugs was an obstacle for some
patients. African Americans had poorer blood pressure control, and their
satisfaction of care was significantly lower than that of other races. Our
patients taught us that the 2 major barriers to blood pressure control were
changes in lifestyle and reducing the cost of medications. We also found that our
African American patients showed the poorest blood pressure control and the
greatest dissatisfaction with their care. We surmise that the greatest benefit of
any intervention would be expected in this population. We demonstrated that CQI
can be used to identify barriers to hypertension management and subgroups of
patients likely to benefit from interventions.
PMID- 10763223
TI - Down under in wine country
PMID- 10763225
TI - Women in analytical chemistry speak
PMID- 10763224
TI - Split-flow thin fractionation
PMID- 10763226
TI - Combining multispectral image information using color
PMID- 10763227
TI - New choices for SPR
PMID- 10763228
TI - Cooperative student activities as learning devices
PMID- 10763229
TI - Fabrication of an interdigitated array electrode on ZnSe and its application to
electrooptical measurements using FT-IR spectroscopy
AB - An interdigitated array electrode (IDA) is fabricated on an IR-transparent
substrate for use in electrooptical measurements using Fourier transform infrared
(FT-IR) spectroscopy. The fabrication of the IDA and its unique sampling geometry
for transmission spectroscopy is detailed. The gold IDA was patterned on the ZnSe
substrate using a photolithographically defined liftoff process. An IR flow cell
was modified to enable the substrate containing the IDA to be used for
electrooptical measurements in transmission. The utility of the electrooptical
cell is demonstrated by application to two model systems. In the first, changes
in the conductivity and spectral features of a receptor membrane (Nafion) upon
dehydration are measured. In the second, the measurement of the electric-field
induced orientation of a liquid-crystalline film of 4-n-pentyl-4'-cyanobiphenyl
was conducted in a new experimental geometry, with IR transmission normal to the
direction of the applied electric field. Difference spectroscopy facilitated the
observation of the change in orientation of the liquid crystal with applied
potential. These systems demonstrate the general utility of the fabrication
scheme described here. It also illustrates its facile adaptation to infrared
difference spectroscopy as a means of studying complex phenomena in
electrochemical and electrooptical systems.
PMID- 10763230
TI - New nucleophilic catalysts for bright and fast peroxyoxalate chemiluminescence
AB - Miniaturized detection applications based on chemiluminescence require fast
reaction kinetics for optimum performance. In this work, high-intensity light
from the analytically useful peroxyoxalate chemiluminescence reaction has been
generated at high rates by employing both single-component and dual-component
nucleophilic catalysis. 4-(Dimethylamine)pyridine and its derivatives were
superior to all other bases in terms of reaction speed and intensity of the
generated light and outshone imidazole, which hitherto has been considered as the
best catalyst. The light intensity was related to the difference in pKa between
the 4-aminopyridine catalyst and the leaving group of the reagent, and the
optimum delta pKa was found to be close to 0. Similarly, high light intensities
were obtained when mixtures of the imidazole analogue 1,2,4-triazole and the
strong, nonnucleophilic base 1,2,2,6,6-pentamethylpiperidine acted as catalysts.
The mechanism behind this was concluded to be a "base-induced nucleophilic
catalysis", where the ancillary strong base assisted the production of the highly
nucleophilic 1,2,4-triazolate anion, which as the actual catalyst then
participated in the formation of a more reactive transient reagent. All the
investigated catalysts reduced the light yield of the reaction due to base
catalyzed breakdown reactions of the reagents and/or intermediates. The intensity
peak maximums of these bright and fast reactions typically appeared after less
than 10 ms, whereafter the light decayed to darkness within a few seconds. These
reaction characteristics are especially advantageous for sensitive detection
applications where the observation volumes and times are limited, e.g., peaks
emerging from a capillary-based separation process.
PMID- 10763231
TI - Principal component analysis of dynamical features in the peroxidase-oxidase
reaction
AB - Inherent variance due to oscillations in the peroxidase-oxidase (PO) reaction was
studied using principal component analysis (PCA). The substrates were oxygen and
reduced nicotinamide adenine dinucleotide (NADH). Horseradish peroxidase (HRP)
catalyzed the reaction. The concentration of a cofactor, methylene blue (MB), was
varied, and 2,4-dichlorophenol was kept constant. Increase in the NADH influx was
used to change the reaction dynamics from periodic to chaotic. The reaction space
was abstracted to the most significant, mutually independent, pairs of absorption
and kinetic basis vectors (principal components). Typically, two significant
principal components were extracted from the periodic time series and three from
the chaotic data. The PCA models accounted for 70-97% of experimental variance.
The greatest fraction of the total variance was accounted for in experiments
exhibiting periodic dynamics and less than 25 nM MB. More MB induced an increased
contribution of NADH to the PO oscillator variance, as did increased NADH influx.
A simulated absorption time series, computed from a mass-action model of the
chemistry, was analyzed by PCA as well. The comparison of simulation with
experiment indicates that the chemical model renders the time series for HRP
oxidation forms with fidelity, but incompletely represents NADH chemistry and
other salient processes underlying the observed dynamics.
PMID- 10763232
TI - Applicability of the alkylation chemistry for chemical C-terminal protein
sequence analysis.
AB - We have evaluated the alkylation chemistry first described some years ago by Boyd
et al. which is now routinely applied in a commercial instrument. We have found
that the low repetitive yields observed during these analyses are due to the
formation of a major side product when alkylating the C-terminal thiohydantoin.
This side product, resistant to the chemical cleavage methods currently used, was
characterized by NMR experiments in solution. We further demonstrate that
chemical C-terminal sequence analysis of proteins using the alkylation chemistry
is feasable with low picomole amounts of material. High-sensitivity C-terminal
sequencing allows a complementary approach by which a protein is first subjected
to N-terminal Edman degradation followed by C-terminal sequence analysis,
limiting the amount of material necessary for the characterization of the protein
under study. This limited C-terminal sequence information is often sufficient to
solve problems that cannot be solved by applying any other analytical method
commonly used today.
PMID- 10763233
TI - Gas chromatographic simulated distillation-mass spectrometry for the
determination of the boiling point distributions of crude oils
AB - The coupling of gas chromatographic simulated distillation with mass spectrometry
for the determination of the distillation profiles of crude oils is reported. The
method provides the boiling point distributions of both weight and volume percent
amounts. The weight percent distribution is obtained from the measured total ion
current signal. The total ion current signal is converted to weight percent
amount by calibration with a reference crude oil of a known distillation profile.
Knowledge of the chemical composition of the crude oil across the boiling range
permits the determination of the volume percent distribution. The long-term
repeatability is equivalent to or better than the short-term repeatability of the
currently available American Society for Testing and Materials (ASTM) gas
chromatographic method for simulated distillation. Results obtained by the mass
spectrometric method are in very good agreement with results obtained by
conventional methods of physical distillation. The compositional information
supplied by the method can be used to extensively characterize crude oils.
PMID- 10763234
TI - Probing the stoichiometry and oxidation states of metal centers in iron-sulfur
proteins using electrospray FTICR mass spectrometry.
AB - Electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass
spectrometry is used to determine the stoichiometry and oxidation states of the
metal centers in several iron-sulfur proteins. Samples are introduced into the
ESI source under nondenaturing conditions in order to observe intact metal
containing protein ions. The stoichiometry and oxidation state of the metal or
metal-sulfur cluster in the protein ion can be derived from the mass spectrum.
Mononuclear metal-containing proteins and [4Fe-4S] centers are very stable and
yield the molecular ion with little or no fragmentation. Proteins that contain
[2Fe-2S] clusters are less stable and yield loss of one or two sulfur atoms from
the molecular species, although the molecular ion is more abundant than the
fragment peaks. [3Fe-4S]-containing proteins are the least stable of the species
investigated, yielding abundant peaks corresponding to the loss of one to four
sulfur atoms in addition to a peak representing the molecular ion. Isotope
labeling experiments show that the sulfur loss originates from the [3Fe-4S]
center. Negative ion mode mass spectra were obtained and found to produce much
more stable [3Fe-4S]-containing ions than obtained in positive ion mode. ESI
analysis of the same proteins under denaturing conditions yields mass spectra of
the apo form of the proteins. Disulfide bonds are observed in the apoprotein mass
spectra that are not present in the holoprotein. These result from oxidative
coupling of the cysteinyl sulfur atoms that are responsible for binding the metal
center. In addition, inorganic sulfide is found to incorporate itself into the
apoprotein by forming sulfur bridges between cysteine residues.
PMID- 10763235
TI - Selection of anionic dopant for quantifying desialylation reactions with MALDI
FTMS.
AB - Alkylsulfonates are examined as anion dopants for the matrix-assisted laser
desorption/ionization-mass spectrometry (MALDI-MS) of neutral oligosaccharides.
The anion dopants allow neutral oligosaccharides to be examined in the same
mixture as acidic oligosaccharides. The alkylsulfonate dopants interact strongly
with the oligosaccharide to produce a quasimolecular ion composed of the
oligosaccharides and the deprotonated alkylsulfonates. Compounds as small as
disaccharides to large branched oligosaccharides can all be examined. The new
series of alkylsulfonates works as well as HSO4- in terms of signal-to-noise
ratio, sensitivity, and ease of preparation in the negative ion mode. The
alkylsulfonates are used to construct a calibration curve for obtaining the
relative amounts of varying neutral and acidic oligosaccharide mixtures. With the
anion dopants, the MALDI-FTMS signals are shown to have a linear relationship
with the molar ratios of the neutral and sialylated oligosaccharides. The method
is also used to monitor the product of a desialylation reaction by acid
hydrolysis.
PMID- 10763236
TI - Modulations in the abundance of salt clusters in electrosprays
AB - The abundance of tetraheptylammonium bromide clusters produced from formamide
solutions by electrospray ionization (ESI) is investigated. It exhibits a wavy
pattern when plotted as a function of cluster size, successive waves being
ordered according to the initial cluster charge z. This structure confirms the
ion evaporation mechanism of Iribarne and Thomson and simplifies drastically the
determination of the distribution of cluster charge z and radius R, from which
the kinetics of ion evaporation from charged drops can be inferred.
PMID- 10763237
TI - Broad spectrum analysis of 109 priority compounds listed in the 76/464/CEE
Council Directive using solid-phase extraction and GC/EI/MS
AB - A single multiresidue method was developed to determine 109 priority organic
compounds included in the 76/464/EEC Council Directive on Pollution of the
European Union. Such Directive includes 132 priority pollutants with a broad
spectrum of polarities to be analyzed in drinking and surface waters, with the
aim to protect water quality. From this list, the compounds analyzed included
benzidines, chloroanilines, chloronitrobenzenes, chloronitrotoluenes,
chlorophenols, chloronitrotoluidines, PAHs, PCBs, pesticides, phenylurea, and
triazine herbicides. The method was developed in four steps. First, automated off
line solid-phase extraction using polymeric sorbent Oasis 60 mg cartridges was
optimized to trap 109 compounds. Second, gas chromatography coupled to mass
spectrometry with electron impact ionization (GC/EI/MS) was used in selected ion
monitoring (SIM) mode for tentative identification of target analytes. Third,
GC/EI/MS under full scan conditions was used for spectrum identification and
analyte confirmation. Last, quantification was performed from SIM chromatogram
using surrogates and internal standard. This method offered excellent sensitivity
and selectivity, and the preconcentration of 200 mL permitted the achievement of
limits of detection at the low nanogram/liter level and recoveries between 70 and
120%. Such methodology was applied to determine 109 organic compounds in French
surface waters, and several pollutants were detected at levels from ppt to ppb.
This multiresidue method developed was highly reproducible and robust and
permitted a high sample throughput.
PMID- 10763238
TI - A fluorescence detection scheme for capillary electrophoresis of N
methylcarbamates with on-column thermal decomposition and derivatization
AB - This paper describes a fluorescence detection method for N-methylcarbamate (NMC)
pesticides in micellar electrokinetic chromatography (MEKC) separation.
Fulfillment of the fluorescence detection hinged on the discovery that quaternary
ammonium surfactants (particularly cetyltrimethylammonium bromide, CTAB), besides
serving as hydrophobic pseudophases in MEKC, are also capable of catalyzing the
thermal decomposition of NMCs to liberate methylamine. Thus, a multifunctional
MEKC medium consisting of borate buffer, CTAB, and derivatizing components (o
phthaldialdehyde/2-mercaptoethanol) was formulated, which allowed first normal
MEKC separation, subsequent thermal decomposition, and finally in situ
derivatization of NMCs. With careful optimization of the operation conditions,
fluorescence detection of 10 NMC compounds was achieved, with column efficiencies
typically higher than 50,000 and detection limits better than 0.5 ppm. The
present work represents an unprecedented effort in capillary electrophoresis
(CE), in which an intact capillary was consecutively utilized as chambers for
separation, decomposition, derivatization, and detection, without involving any
interfacing features. The success in the implementation of such a detection
system resulted in strikingly simple instrumentation as compared with the
traditional postcolumn fluorescence determination of NMCs by reversed-phase HPLC.
Similar protocols should be workable in the determination of a wide range of
pesticides and pharmaceuticals in CE formats.
PMID- 10763239
TI - Plastic microchip electrophoresis with analyte velocity modulation. Application
to fluorescence background rejection.
AB - Fluorescence background interference from the device is inherent in plastic
microchips, particularly with blue or UV excitation. Conventionally, microchip
background has been reduced with confocal optics or circumvented with specialized
long-wavelength fluorophores. We show that microchip background can be rejected
with analyte velocity modulation. In this scheme, the driving voltage is
modulated at low frequency, typically in the range of 7-20 Hz. Consequently,
migration velocities and analyte signals are modulated at the same frequency.
Microchip fluorescence is unmodulated, so that lock-in detection (synchronous
demodulation) easily separates the analyte signal from background. The technique
does not require a laser source. In our implementation, a blue (485 nm) LED is
the light source. Simple optics are used to shape the source and focus it to a
spot approximately 50 microns in diameter inside a microchip. Photomultiplier
detection is employed, and a lock-in amplifier is used to demodulate the signal.
Apertures in the system generate a derivative response, which can be converted to
conventional bands by integration. Fluorescence rejection provided by our current
system lowers detection limits by approximately 1 order of magnitude compared to
dc measurements with the same optical train.
PMID- 10763240
TI - A probe for the versatile analysis and characterization of N-linked
oligosaccharides.
AB - A novel fluorescent probe, 3-(acetylamino)-6-aminoacridine (AA-Ac), has been
synthesized and its applicability to the analysis of picomole levels of N-linked
glycans investigated. AA-Ac was found to be an excellent derivatization reagent
for N-linked glycans, giving at least twice the intensity of fluorescence as its
predecessor 2-aminoacridone. AA-Ac-labeled glycans were analyzed by both normal
and reversed-phase HPLC. They were also amenable to enzymatic sequencing and
analysis by MALDI-TOF mass spectrometry, free zone capillary electrophoresis, and
capillary electrophoresis/electrospray ionization mass spectrometry.
PMID- 10763241
TI - Stepwise mobilization of focused proteins in capillary isoelectric focusing mass
spectrometry.
AB - A stepwise mobilization strategy has been developed for the elution of complex
protein mixtures, separated by capillary isoelectric focusing (CIEF) for
detection using on-line electrospray ionization mass spectrometry (ESI-MS).
Carrier polyampholytes are used to establish a pH gradient as well as to control
the electroosmotic flow arising from the use of uncoated fused-silica
capillaries. Elution of focused protein zones is achieved by controlling the
mobilization pressure and voltage, leaving the remaining protein zones focused
inside the capillary. Protein zones are stepwise eluted from the capillary by
changing the mobilization conditions. Stepwise mobilization improves separation
resolution and simplifies coupling with multistage MS (i.e., MSn) analysis since
it allows more effective temporal control of protein elution from the CIEF
capillary. We also describe a modified configuration for coupling CIEF with ESI
MS using a coaxial sheath flow interface that facilitate the automation of on
line CIEF-ESI-MS analyses. The stepwise mobilization strategy is demonstrated for
the analysis of standard protein mixtures and soluble E. coli lysate proteins
using CIEF-ESI-MS. These results indicate that inlet pressure or voltage
programming to control the elution of the protein zones from the capillary (i.e.,
gradient mobilization) may allow for the optimization of the mobilization
conditions and provide higher resolution for CIEF separation of complex mixtures
with on-line MS.
PMID- 10763242
TI - Analysis of oligosaccharides by microbore high-performance liquid chromatography.
AB - A 1-mm microbore hydrophilic interaction column has been used for the separation
of 2-aminoacridone (2-AMAC)-derivatized glycan mixtures, released from naturally
occurring and recombinant proteins. Primary structure identification of the 2
AMAC glycan derivatives was carried out by HPLC using fluorescence and mass
spectrometric detection. In some cases, enzymatic digestion of the 2-AMAC glycans
was applied to confirm glycan structure. This strategy is considerably more rapid
than methods normally used in glycan analysis, which involves manual collection
of separated oligosaccharide derivatives and analysis of individual fractions by
mass spectrometry.
PMID- 10763243
TI - Restricted diffusion model for surface diffusion in reversed-phase liquid
chromatography
AB - The analysis of experimental results in reversed-phase liquid chromatography
(RPLC) allows further discussion of the restricted diffusion model of surface
diffusion formulated on the basis of the absolute rate theory. Chromatographic
data were acquired on different RPLC systems with two series of homologous
compounds, several stationary phases having different alkyl ligand densities and
ligands of various lengths, and methanol/water mobile phases of different
compositions. The enthalpy-entropy compensation observed and the linear free
energy relationships found for surface diffusion suggest that the surface
diffusion mechanism remains probably the same in all RPLC conditions studied.
Whereas the isosteric heat of adsorption approaches zero with decreasing
retention, the activation energy of surface diffusion tends toward a finite limit
and the surface diffusion coefficient tends toward a value near the corresponding
molecular diffusivity. These results support the validity of the restricted
diffusion model. The influence of different factors on the validity of this model
(i.e., the activation energy and the frequency factor of surface diffusion, and
the surface tortuosity) was also considered.
PMID- 10763244
TI - Recycling foam countercurrent chromatography
AB - A new sample injection method for foam countercurrent chromatography (CCC), named
the "recycle injection system", has been developed. In this system, the effluent
from the liquid outlet is directly returned into the column through the sample
feed line so that the sample solution is continuously recycled for repetitive
foam fractionation. The utility of this system was demonstrated in the
separations of microcystin extract and bacitracin complex from large volumes of
sample solution. Microcystins were separated and enriched in decreasing order of
hydrophobicity. Bacitracin A, a hydrophobic major component, in the bacitracin
complex was highly enriched in the foam fraction and almost completely isolated
from other components. This recycling foam CCC method may be effectively applied
for separation and enrichment of various foam-active components from crude
natural products.
PMID- 10763245
TI - High-concentration band profiles and system peaks for a ternary solute system
AB - High-concentration HPLC band profiles of single solutes and the individual band
profiles of the components of binary and ternary mixtures are reported for benzyl
alcohol, 2-phenylethanol, and 2-methylbenzyl alcohol. These solutes were eluted
from a C18 column by a binary mobile phase (MeOH:H2O = 1:1, v/v). High
concentration system peaks were obtained using mixtures of benzyl alcohol and 2
phenylethanol at different relative concentrations as the feed and 2-methylbenzyl
alcohol as the strong mobile phase additive. Band profiles and system peak
profiles were calculated using the equilibrium-dispersive model of
chromatography. The adsorption equilibrium in the multicomponent system was
characterized by the competitive Langmuir model. Excellent quantitative agreement
was found between the experimental and the calculated profiles. This work
confirms that extremely unusual system peak profiles can be obtained even when
the adsorption behavior is quite simple. Under certain circumstances, the use of
a properly chosen additive could markedly increase the separation between bands
and hence the production rate, the recovery yield, and/or the purity of the
fractions.
PMID- 10763246
TI - Identification and quantification of flavonoids in human urine samples by column
switching liquid chromatography coupled to atmospheric pressure chemical
ionization mass spectrometry.
AB - A rapid and sensitive high-performance liquid chromatographic mass spectrometric
(HPLC-MS) method is described for the determination and quantification of 12
dietary flavonoid glycosides and aglycons in human urine samples. Chromatographic
separation of the analytes of interest was achieved by column-switching, using
the first column (a Zorbax 300SB C-3 column) for sample cleanup and eluting the
heart-cut flavonoid fraction onto the second column (a Zorbax SB C-18 column) for
separation and detection by ultraviolet and atmospheric pressure chemical
ionization MS using single ion monitoring in negative mode. The fragmentor
voltage was optimized with regard to maximum abundance of the molecular ion and
qualifier ions of the analytes. Calibration graphs were prepared for urine, and
good linearity was achieved over a dynamic range of 2.5-1000 ng/mL. The inter-
and intraassay coefficients of variation for the analysis of the 12 different
flavonoids in quality control urine samples were 12.3% on average (range 11.0
13.7%, n = 24, reproducibility) and the repeatability of the assay were 5.0%
(mean, range 0.1-14.8%, n = 12). A subset of 10 urine samples from a human
dietary intervention study with high and low flavonoid content was analyzed, and
the results are reported.
PMID- 10763247
TI - Speciation of inorganic lead and ionic alkyllead compounds by GC/MS in
prescreened rainwaters
AB - A simple and novel screening method for lead compounds in environmental waters is
proposed. The analytes, in an acetic medium, are sorbed on a C60 fullerene column
as diethyldithiocarbamate complexes and subsequently eluted with isobutyl methyl
ketone (IBMK), the lead being determined by flame atomic absorption spectrometry.
The screening method acts as filter and indicates whether the target analytes are
present above or below the detection limit of the method (0.5 ng/mL), giving no
false positives. Positive samples were speciated by GC/MS, using a flow system
similar to that of the screening method. Lead(II) and ionic di- and trialkyllead
are derivatized with a Grignard reagent. Both methods use similar chemical and
flow variables except for the eluent, IBMK in the screening method and n-hexane
in the speciation method. The GC/MS speciation method is very sensitive; it
exhibits a linear range of 0.02-5 ng/mL, and detection limits of 1-4 ng/L are
achieved. Also, its repeatibility, as RSD, is less than 6%. The method was
applied to the speciation of Pb2+ and di- and trialkyllead in positive
prescreened rainwater samples from three different urban areas.
PMID- 10763248
TI - Analysis of poly(ethyl methacrylate)s by on-line hyphenation of liquid
chromatography at the critical adsorption point and nuclear magnetic resonance
spectroscopy
AB - Liquid chromatography at the critical adsorption point (LC CAP) with on-line NMR
detection (on-line LC CAP NMR) was utilized for analysis of tacticity
distribution of stereo-regular poly(ethyl methacrylate)s (PEMAs). The separation
of a model PEMA sample composed of four constituents with similar molar masses
(Mw = (14-16) x 10(3) g mol-1) differing in their tacticity (rr triad content =
0, 33, 68, and 89%) was achieved by LC CAP with a mixed eluent composed of
acetone, acetone-d6, and cyclohexane. The tacticity composition within each peak
eluted from the LC CAP column was directly determined by a 750-MHz 1H NMR
spectrometer that was used as a real-time detector in the continuous-flow mode.
Tacticity distribution in a particular PEMA sample with mm/mr/rr = 2/45/53 and
narrow molar mass distribution of Mw/Mn = 1.05 has been revealed by the LC CAP
NMR technique.
PMID- 10763249
TI - Adsorptions of plasma proteins and their elutabilities from a polysiloxane
surface studied by an on-line acoustic wave sensor.
AB - Gold electrodes of thickness-shear mode acoustic wave sensors were modified with
poly[(mercaptopropyl)methylsiloxane]. The flow-through adsorption of three major
plasma proteins (human serum albumin, fibrinogen, and immunoglobulin G) was
detected by acoustic network analysis. The elution of fibrinogen and albumin from
coated and unmodified gold surfaces by sodium dodecyl sulfate was studied with
respect to different adsorption times and protein concentrations. Both sequential
and competitive adsorptions of the three proteins on polymer-modified surfaces of
sensors were examined as were simultaneous adsorptions from binary and ternary
mixtures. The experimental results confirm that the competitive behaviors of
proteins in terms of adsorptive processes are explained by factors other than
displacement phenomena.
PMID- 10763250
TI - Differentiation of chemical components in a binary solvent vapor mixture using
carbon/polymer composite-based chemiresistors
AB - We demonstrate a "universal solvent sensor" constructed from a small array of
carbon/polymer composite chemiresistors that respond to solvents spanning a wide
range of Hildebrand solubility parameters. Conductive carbon particles provide
electrical continuity in these composite films. When the polymer matrix absorbs
solvent vapors, the composite film swells, the average separation between carbon
particles increases, and an increase in film resistance results, as some of the
conduction pathways are broken. The adverse effects of contact resistance at high
solvent concentrations are reported. Solvent vapors including isooctane, ethanol,
diisopropylmethylphosphonate (DIMP), and water are correctly identified
("classified") using three chemiresistors, their composite coatings chosen to
span the full range of solubility parameters. With the same three sensors, binary
mixtures of solvent vapor and water vapor are correctly classified; following
classification, two sensors suffice to determine the concentrations of both vapor
components. Poly(ethylenevinyl acetate) and poly(vinyl alcohol) (PVA) are two
such polymers that are used to classify binary mixtures of DIMP with water vapor;
the PVA/carbon particle composite films are sensitive to less than 0.25% relative
humidity. The Sandia-developed visual-empirical region of influence (VERI)
technique is used as a method of pattern recognition to classify the solvents and
mixtures and to distinguish them from water vapor. In many cases, the response of
a given composite sensing film to a binary mixture deviates significantly from
the sum of the responses to the isolated vapor components at the same
concentrations. While these nonlinearities pose significant difficulty for
(primarily) linear methods such as principal component analysis, VERI handles
both linear and nonlinear data with equal ease. In the present study, the maximum
speciation accuracy is achieved by an array containing three or four sensor
elements, with the addition of more sensors resulting in a measurable accuracy
decrease.
PMID- 10763251
TI - In situ adsorption studies at silica/solution interfaces by attenuated total
internal reflection fourier transform infrared spectroscopy: examination of
adsorption models in normal-phase liquid chromatography
AB - ATR-FT-IR spectroscopy was employed to the study the adsorption of ethyl acetate
and 2-propanol to the surface of thin silica sol-gel films in contact with n
heptane solutions. In situ vibrational spectra of silica-adsorbed species
provided information regarding the mechanisms of solute retention and elution in
normal-phase chromatography. Previous normal-phase chromatographic studies of
ethyl acetate adsorption revealed nonlinear isotherms which were explained by
both bilayer and adsorbate delocalization models. Infrared spectra of ethyl
acetate at the silica surface versus concentration showed that nonlinear
adsorption can be attributed to site heterogeneity, where adsorption to free
silanols and surface-adsorbed water can be distinguished. Least-squares modeling
of the data produced resolved spectra for the two sites and adsorption
equilibrium constants that differed by about an order of magnitude. Adsorption of
2-propanol was best modeled by a single Langmuir isotherm showing no significant
difference in adsorption energy for the two sites; 2-propanol was shown to easily
displace ethyl acetate from the silica surface. Ethyl acetate could also displace
2-propanol from the silica, and least-squares modeling again revealed two
adsorbed-component spectra for ethyl acetate that were indistinguishable from
spectra obtained when ethyl acetate adsorbed directly onto the surface.
PMID- 10763252
TI - Theoretical investigation of the spatial progression of temporal statistical
moments in linear chromatography.
AB - Migration and dispersion in chromatography are modeled by analogy to an effective
eddy diffusion process. On the basis of this model, the spatial rates of temporal
statistical moment change are derived for general chromatography in linear media.
In most practical cases, these equations can be simplified so that temporal
statistical moments can be calculated by solving a system of ordinary
differential equations that depend only on the local HETP, solute velocity, and
initial values of the temporal statistical moments. The calculations of temporal
centroid, temporal variance, temporal skew, and temporal excess are demonstrated
for the case of linear solvent strength gradients. It is shown for the case of
temporally invariant separation environments, such as isocratic liquid
chromatographic systems and isothermal gas chromatographic systems, that temporal
variance contributions are spatially additive and that the temporal third
normalized central moment is unaffected by spatial variations in the medium. A
refined explanation is given for how peak symmetry is improved in gradient forms
of chromatography.
PMID- 10763253
TI - Transport of low molecular weight anions through a Nafion lonomer membrane:
application to kraft cooking liquors
AB - The permeation of low molecular weight anions from liquors having high ionic
strengths through a Nafion 811 membrane in Na+ form has been studied. The
penetration of solutes through the membrane was monitored using UV-visible
spectrometry. A relation between penetration and ionic size has been established.
The influence of the presence of other ions on the permeation has also been
investigated. The results show that the membrane has great potential as part of a
selective interface in applications where the concentration of small anions is to
be monitored in media with high ionic strengths. In light of the new results, we
have validated a previously developed system for monitoring the concentrations of
hydrogen sulfide ion and dissolved lignin in a laboratory-scale kraft cooking
system.
PMID- 10763255
TI - Nanostructured carbon fiber disk electrodes for sensitive determinations of
adenosine and uric acid
AB - Nanostructured carbon fiber microdisk electrodes were prepared by a combination
of mechanical polishing and electrolytic treatment, where the latter involved
moderate oxidation of the surface, followed by a reduction. A high density of
surface defects contributed to a high capacitance of the nanostructured
electrodes. Facilitated proton transfer was observed at the nanostructured
surface and was associated with cation-exchanged oxide defects. The
nanostructured surfaces intercalated uric acid and adenosine and engaged in fast
electron/proton transfer in the oxidation of both analytes. As a result,
electrolytic treatment followed by fast-scan voltammetry determinations led to a
sensitive response to both analytes in physiological buffers. The nanostructured
electrodes showed remarkable stability and could be easily regenerated and
reused. With long use, electrode activity decreased. Kinetic discrimination of
the surface-mediated reaction of ascorbate was achieved at high scan rates.
PMID- 10763254
TI - Optical detection in microscopic domains. 1. Monitoring chemical manipulations
with absorption microspectrometry.
AB - In this research, we test whether optical detection techniques, such as
absorption microspectrometry, fluorescence detection, and inner filter effects,
show different characteristics in microscopic domains (nano-, pico- and
femtoliter range) with respect to usual solution volumes. In this part 1,
characterization of absorption microspectrometry is facilitated by the use of a
novel microscopic tool, the diffusional microburet (DMB), suitable for fine
chemical manipulations of microscopic liquid samples. Since diffusional delivery
of substances will not induce appreciable changes in volume and shape of the
sample, a DMB makes it possible to obtain spectral recordings and a reference
spectrum from the same microscopic droplet. Thus, good quantitative spectra of
microscopic domains can be assessed. With this approach, despite the curvature of
the sample boundaries, the large surface-to-volume ratios, and microscopic
optical path lengths, both Beer-Lambert's law and the law of superposition were
found to be directly applicable in microscopic domains without any corrections
for absorption at sample boundaries. Use of a combination of microspectrometry
and chemical manipulations by DMBs made it possible for the first time to record
in real time, in truly microscopic domains, spectral evolution upon addition or
subtraction of chemicals, as well as monitor the progress of chemical reactions.
This approach is expected to contribute to the optical exploration of
microchemistry and microanalysis.
PMID- 10763256
TI - Triangle-programmed coulometric nanotitrations completed by continuous flow with
potentiometric detection
AB - Coulometric nanotitrations were realized in a microchannel system using a
continuous-flow titration technique with a triangle current-time profile. Redox
and acid-base titrations were carried out on Fe(II) and nitric acid samples,
respectively, with the same nanotitrator device. A linear relation between the
concentration and the coulometric current transferred to the solution was found.
The advantages of this universally applicable nanotitrator are fast response, low
sample volume, high sensitivity, and high reproducibility as well as the
convenience of handling an automated analyzer of the flow-through type.
PMID- 10763257
TI - Redox hydrogel-based amperometric bienzyme electrodes for fish freshness
monitoring
AB - This work presents the design and optimization of amperometric biosensors for the
determination of biogenic amines (e.g., histamine, putrescine, cadaverine,
tyramine, cystamine, agmatine, spermidine), commonly present in food products,
and their application for monitoring of freshness in fish samples. The biosensors
were used as the working electrodes of a three-electrode electrochemical cell of
wall-jet type, operated at -50 mV vs Ag/AgCl, in a flow injection system. Two
different bienzyme electrode designs were considered, one based on the two
enzymes [a newly isolated and purified amine oxidase (AO) and horseradish
peroxidase (HRP)] simply adsorbed onto graphite electrodes, and one when they
were cross-linked to an Os-based redox polymer. The redox hydrogel-based
biosensors showed better biosensors characteristics, i.e., sensitivity of 0.194 A
M-1 cm-2 for putrescine and 0.073 A M-1 cm-2 for histamine, and detection limits
(calculated as three times the signal-to-noise ratio) of 0.17 microM for
putrescine and 0.33 microM for histamine. The optimized redox hydrogel-based
biosensors were evaluated in terms of stability and selectivity, and were used
for the determination of total amine content in fish samples kept for 10 days in
different conditions.
PMID- 10763258
TI - Open circuit reactions complicating the electroprecipitation of
poly(vinylferricinium) films from methylene chloride
AB - We describe an electrochemical quartz crystal microbalance interfacial
gravimetric study of the electroprecipitation and dissolution of PVF+ClO4- (PVF =
poly(vinylferrocene)) films exposed to methylene chloride solutions. Film
deposition is diffusion controlled by the supply of PVF from the solution. Film
solvent content is markedly dependent upon the deposition potential. The self
exchange process between surface-bound ferricinium sites and solution-phase
ferrocene sites, which is responsible for film deposition under conditions of
positive applied potential, is also responsible for film dissolution under open
circuit conditions. Dependent upon the deposition potential, releasing the
electrode from potential control may (not) result in transient deposition
processes that temporarily increase surface coverage. Under all conditions,
opening the circuit ultimately leads to reductive stripping of the film by
solution-phase PVF. The dissolution rate is independent of applied potential, and
is not limited by electron transfer at the outer film interface or by electron
(and coupled ion) transport within the film; we speculate that polymer-based
processes, such as chain disentanglement, are rate limiting.
PMID- 10763259
TI - Uranyl-selective electrode based on a new bifunctional derivative combining the
synergistic properties of phosphine oxide and ester of phosphoric acid
AB - Ion-selective electrodes based on the bifunctional chelating agent O
methyldihexylphosphine oxide O'-hexyl-2-ethylphosphoric acid (HL) incorporated
into a poly(vinyl chloride) membrane were developed. This new derivative is
proposed as a single molecular unit combining the overall properties of the
synergistic single components, di-2-ethylhexylphosphoric acid and
trioctylphosphine oxide. Two different ionophores, HL and its uranyl complex
(UO2L2), were studied. The response of the electrodes to uranyl ion was Nernstian
for UO2L2 and super-Nernstian for HL ionophores, with detection limits of 3.0 x
10(-6) and 2.0 x 10(-5) M, respectively. Results indicate a more effective
interaction with the analyte in the case of having a unique molecule
incorporating the two functional groups immobilized into a polymeric membrane,
rather than the separated two synergistic ligands. Flow-through tubular
electrodes based on both ionophores were also used as potentiometric detectors in
flow injection techniques.
PMID- 10763260
TI - Amperometric detection of Escherichia coli heat-labile enterotoxin by redox
diacetylenic vesicles on a sol-gel thin-film electrode.
AB - Supramolecular assemblies (bilayer vesicles) prepared from ferrocenic diacetylene
lipid and the cell surface receptor ganglioside GM1 are utilized to construct an
amperometric biosensor for Escherichia coli heat-labile enterotoxin on a sol-gel
thin-film electrode. The bilayer vesicles adsorbed on the sol-gel film provide an
open platform for molecular recognition, while the electrochemical communication
between the incorporated redox lipids and the electrode is influenced by the
binding of the toxin. Cyclic voltammetric studies suggest a facile redox reaction
for the adsorbed supramolecular assembly, which allows the sensor to detect
enterotoxin up to 3 ppm (3.6 x 10(-8) M) concentration. The apparent diffusion
coefficients for the redox lipids in the assembly were observed to be in the
range of 4.73 x 10(-8) -2.30 x 10(-8) cm/s2. A mechanism of lateral electron
transport of redox lipids controlled by biomolecular recognition is proposed.
PMID- 10763261
TI - Cationic or anionic sites? Selectivity optimization of ion-selective electrodes
based on charged ionophores
AB - The influence of ionic sites on the selectivities of ionophore-based ion
selective electrodes (ISEs) is described on the basis of a phase boundary
potential model. The discussion presented here is significantly more general than
previous ones. It is formulated for primary and interfering ions of any charges
and it is valid for ISEs based on electrically charged or neutral ionophores.
Furthermore, it also applies to membranes that contain more than one type of
complex of the primary or interfering ion. It has been believed thus far that
only ionic sites of the same charge sign as the primary ion improve the
selectivities of ISEs based on charged ionophores. However, it is shown here that
the charge sign of the ionic sites that give the highest potentiometric
selectivities depends on the charge number of the primary and interfering ions
and on the stoichiometry of their complexes with the ionophore. The validity of
our model was confirmed experimentally with three ISEs based on different charged
ionophores. ISEs based on lasalocid or 1-(N,N-dicyclohexylcarbamoyl)-2- (N,N
dioctadecylcarbamoyl)ethylphosphonic acid monomethyl ester (ETH 5639) as the
ionophore responded selectively to Sr2+ or Mg2+, respectively, and discriminated
well against other alkaline earth cations when their membranes contained anionic
sites. These two electrodes are the first examples of ISEs based on charged
ionophores for which maximum selectivities are obtained with membranes containing
ionic sites with a charge sign opposite to that of the primary ion. On the other
hand, the experimental F- selectivities of membranes based on oxo(5,10,15,20
tetraphenylporphyrinato)molybdenum-(V) improved gradually when the concentration
of anionic sites was increased from 0 to 75 mol%. The selectivity-modifying
influence of ionic sites for these three types of ISEs can be explained by
considering the different stabilities of the 1:2 ion-ionophore complexes of the
primary and of the interfering ions.
PMID- 10763263
TI - Correction of temperature-induced spectral variation by continuous piecewise
direct standardization
AB - In process analytical applications it is not always possible to keep the
measurement conditions constant. However, fluctuations in external variables such
as temperature can have a strong influence on measurement results. For example,
nonlinear temperature effects on near-infrared (NIR) spectra may lead to a
strongly biased prediction result from multivariate calibration models such as
PLS. A new method, called Continuous Piecewise Direct Standardization (CPDS) has
been developed for the correction of such external influences. It represents a
generalization of the discrete PDS calibration transfer method and is able to
adjust for continuous nonlinear influences such as the temperature effects on
spectra. It was applied to shortwave NIR spectra of ethanol/water/2-propanol
mixtures measured at different temperatures in the range 30-70 degrees C. The
method was able to remove, almost completely, the temperature effects on the
spectra, and prediction of the mole fractions of the chemical components was
close to the results obtained at constant temperature.
PMID- 10763262
TI - Electrochemical oxidation of histamine and serotonin at highly boron-doped
diamond electrodes.
AB - The electrochemistry of histamine and serotonin in neutral aqueous media (pH 7.2)
was investigated using polycrystalline, boron-doped diamond thin-film electrodes.
Cyclic voltammetry, hydrodynamic voltammetry, and flow injection analysis (FIA)
with amperometric detection were used to study the oxidation reactions.
Comparison experiments were carried out using polished glassy carbon (GC)
electrodes. At diamond electrodes, highly reproducible and well-defined cyclic
voltammograms were obtained for histamine with a peak potential at 1.40 V vs SCE.
The voltammetric signal-to-background ratios obtained at diamond were 1 order of
magnitude higher than those obtained for GC electrodes at and above 100 microM
analyte concentrations. A linear dynamic range of 3-4 orders of magnitude and a
detection limit of 1 microM were observed in the voltammetric measurements. Well
defined sweep rate-dependent voltammograms were also obtained for 5
hydroxytryptamine (5-HT). The characteristics of the voltammogram indicated lack
of adsorption of its oxidation products on the surface. No fouling or
deactivation of the electrode was observed within the experimental time of
several hours. A detection limit of 0.5 microM (signal-to-noise ratio 13.8) for
histamine was obtained by use of the FIA technique with a diamond electrode. A
remarkably low detection limit (10 nM) was obtained for 5-HT on diamond by the
same method. Diamond electrodes exhibited a linear dynamic range from 10 nM to
100 microM for 5-HT determination and a range of 0.5-100 microM for histamine
determination. The FIA response was very reproducible from film to film, and the
response variability was below 7% at the actual detection limits.
PMID- 10763264
TI - Mid-infrared quantum cascade lasers for flow injection analysis
AB - A Fabry-Perot quantum cascade laser (QCL) was used as a powerful light source for
mid infrared (MIR) detection in flow injection analysis. The QCL lased at several
wavelengths close to each other within a few wavenumbers (990-1010 cm-1), hence
fitting well to the broad absorption bands of molecules in liquid phase. As
compared with that of a state-of-the-art Fourier transform spectrometer, the
signal-to-noise ratio could be improved by a factor of 50. Additionally, by using
a QCL as the light source, optical path lengths of more than 100 microns could be
used even in aqueous matrixes which reduced the danger of cell clogging. In the
example shown here phosphate was determined in Diet Coke samples. The flow
injection system used allowed the measurement of the sample at two pH values (5
and 13) at which the analyte was present as H2PO4- and PO4(3-), respectively. As
the analytical readout the difference in IR absorption of H2PO4- and PO4(3-) at
the laser wavelengths was taken. The FIA-QCL measurements were corroborated by
ion chromatography which was used as a reference method.
PMID- 10763266
TI - Development of a robust calibration model for nonlinear in-line process data
AB - A comparative study involving a global linear method (partial least squares), a
local linear method (locally weighted regression), and a nonlinear method (neural
networks) has been performed in order to implement a calibration model on an
industrial process. The models were designed to predict the water content in a
reactor during a distillation process, using in-line measurements from a near
infrared analyzer. Curved effects due to changes in temperature and variations
between the different batches make the problem particularly challenging. The
influence of spectral range selection and data preprocessing has been studied.
With each calibration method, specific procedures have been applied to promote
model robustness. In particular, the use of a monitoring set with neural networks
does not always prevent overfitting. Therefore, we developed a model selection
criterion based on the determination of the median of monitoring error over
replicate trials. The back-propagation neural network models selected were found
to outperform the other methods on independent test data.
PMID- 10763265
TI - Investigation of the hydrolysis of single DNA molecules using fluorescence video
microscopy.
AB - We developed a method of studying the hydrolysis of single DNA molecules by
exonuclease (exo) III using fluorescence video microscopy. A single DNA molecule
immobilized at one end on a coverslip and labeled with a fluorescent bead at the
other end confined the motion of a bead to a two-dimensional projected circular
area determined by the contour length of DNA. The radius of this area decreased
with time after the addition of exo III, Mg2+, or a single-stranded DNA-binding
protein (SSB), which caused the single-stranded (ss) DNA to twist around itself.
However, the radius was relatively constant over time in the absence of Mg2+,
which is a cofactor in exo III activity, even when exo III and SSB were both
present. These observations indicated that the decrease in the radius was due to
hydrolysis of DNA by exo III. We then evaluated the rate of exo III hydrolysis of
single DNA molecules by monitoring the decrease in the radius.
PMID- 10763267
TI - UV resonance Raman detection and quantitation of domoic acid in phytoplankton.
AB - Cultures of the phytoplankton diatom, Pseudonitzschia multiseries, have been
harvested under controlled growth conditions ranging from late logarithmic to
late stationary phase (17-58 days). The amount of domoic acid (DA) present in the
growth media and in the homogenized cells has been determined by HPLC. Defined
samples of media, homogenized cells, whole cells, and whole cells in media have
been laser excited at 251 nm for the purpose of selectively exciting intense UV
resonance Raman spectra from DA in the samples. Neither media nor cell component
spectra from algae seriously interfere with DA spectra. The spectral cross
sections for the dominant 1652-cm-1 mode of DA have been determined for 242-, 251
, and 257-nm excitation. Maximum sensitivities are achieved with 251-nm
excitation because cross sections for DA are a maximum, and interference from
other algal components becomes very small. DA concentrations that have been
determined with 251-nm excitation by resonance Raman methods correlate closely
with values determined independently with HPLC, especially at higher DA
concentrations. The UV resonance Raman analysis of DA in phytoplankton algae is
shown to be very sensitive and quantitative as well as rapid and nonintrusive.
PMID- 10763268
TI - A field-portable plasma source monitor for real-time air particulate monitoring
AB - In this research, a novel portable instrument for on-site, real-time air
particulate monitoring was developed. It is highly desirable to use microwave
plasmas for on-site, real-time environmental and occupational hazard monitoring
because they can be sustained with various gases at relatively low power and
possess excellent detection capabilities for both metal and nonmetal air
pollutants. In the new instrument design, a microwave plasma was selected as an
excitation source and was used in conjunction with atomic emission spectrometry.
A small, integrated spectrometer with a charge-coupled detector (CCD) was used
for optical signal detection. An efficient, in situ air-sampling system was
developed for direct sampling of air particles into the plasma. Characterization
and calibration of the new instrument were achieved with an in-house-fabricated
high-efficiency nebulization-desolvation system. Tolerance of the microwave argon
plasma source to air introduction was tested, and the operational parameters were
optimized. Analytical performance and the feasibility of the newly developed
portable instrument for aerosol particle analysis were evaluated. Some advantages
and possible applications of the new instrument are discussed. The instrument
provides an innovative tool for rapid environmental and occupational hazard
monitoring.
PMID- 10763269
TI - Artificial neural networks for the automated detection of trichloroethylene by
passive Fourier transform infrared spectrometry
AB - Artificial neural networks are applied to the automated classification of
trichloroethylene (TCE) signatures from passive Fourier transform infrared remote
sensing interferogram data. Through the use of three data collection methods, a
combination of laboratory and field data is acquired that allows the methodology
to be evaluated under a variety of infrared background conditions and in the
presence of potentially interfering compounds such as sulfur hexafluoride, methyl
ethyl ketone, acetone, carbon tetrachloride, and ammonia. To maximize the
computational efficiency of the network optimization, experimental design
techniques are employed to develop a training protocol for the network that takes
into account the relationships among five variables that are related either to
the network architecture or to the training process. This protocol is implemented
for the case of a back-propagation neural network (BNN) and is used to develop an
optimized network for the detection of TCE. The classification performance of the
network is assessed by comparing both TCE detection capabilities and false
detection rates to similar classification results obtained with the technique of
piecewise linear discriminant analysis (PLDA). When applied to prediction data
withheld from the optimization of both the BNN and PLDA algorithms, the BNN
method is observed to outperform PLDA overall, with TCE detection rates in excess
of 99% and false detection rates less than 0.5%.
PMID- 10763270
TI - Calibration transfer algorithm for automated qualitative analysis by passive
Fourier transform infrared spectrometry
AB - The automated qualitative analysis of passive Fourier transform infrared (FT-IR)
remote sensing data is made difficult by the presence in the data of background
and instrument-specific variation. For data collected with a single instrument,
variation in the data arises from changes in the infrared background radiance,
changes in the atmospheric composition within the field-of-view of the
spectrometer, and changes in the instrument response function arising from
temperature variation in the spectrometer. When more than one spectrometer is
used, the variation in detector responses and phase signatures between
instruments serves to complicate further the task of implementing an automated
processing algorithm for detecting the signature of a target compound. In this
work, a combination of signal processing and pattern recognition methodology is
applied directly to the interferogram data collected by the FT-IR spectrometer to
implement an automated compound detection procedure that is independent of
background and instrument-specific variation. The key to this algorithm is the
use of highly attenuating digital filters to isolate in the interferogram the
frequencies associated with an analyte absorption or emission band while
suppressing information at other frequencies. For the test compounds, acetone and
sulfur hexafluoride, it is demonstrated that when this digital filtering
procedure is coupled with either piecewise linear discriminant analysis or a back
propagation neural network, an automated detection algorithm can be developed
with data from a primary instrument and then subsequently used to predict the
presence of analyte signatures in data collected with a secondary spectrometer.
Correct classification rates in excess of 92% are obtained for both compounds
when the algorithm is applied to data collected with the secondary instrument.
PMID- 10763271
TI - Trace analysis of phosphorus in water by sorption preconcentration and luminol
chemiluminescence
AB - A new, highly sensitive chemiluminescence method for the determination of sub-ppb
quantities of phosphorus in water is described. The method is based on sorption
preconcentration of phosphorus as a yellow vanadomolybdophosphoric heteropoly
acid (HPA) in the presence or absence of a cationic surfactant on a paper filter,
followed by direct chemiluminescence detection of the phosphorus concentrate via
reaction with an alkaline luminol solution. The molar ratio of cationic
surfactant to HPA in the ion associate sorbed on the filter is 4:1. The detection
limits for phosphorus are 0.02 microgram of P L-1 in the presence of surfactant
and 0.1 microgram of P L-1 in the absence of surfactant for a sample volume of
150 mL. The calibration plot is linear from 0.06 to 1.7 micrograms of P L-1 in
the presence of a surfactant, and the time required for analysis is 25 min. In
the absence of surfactant, the selectivities against Si4+ and As5+ are 5 and 40
times greater than those for the standard colorimetric method based on the
formation of the blue molybdophosphoric HPA. Applications of the method to the
analyses of river water, seawater, and the turbine vapor condensate from a coal
fired power plant are described. It is demonstrated that the sensitivity
advantage of the chemiluminescence technique can be combined with the magnesium
induced coprecipitation (MAGIC) method for a more selective measurement of
soluble reactive phosphorus.
PMID- 10763272
TI - Effects of alkaline hydrolysis and dynamic coating on the electroosmotic flow in
polymeric microfabricated channels.
AB - Protocols are described for control of the electroosmotic flow in microfabricated
channels in Vivak copolyester. Alkaline hydrolysis of surface ionizable groups
alone or such hydrolysis in combination with dynamic coating with
cetyltrimethylammonium bromide (CTAB) is shown to provide reproducible
electroosmotic flows. Dynamic coating with CTAB can be used to eliminate
electroosmosis or to reverse its direction, depending on the concentration
employed.
PMID- 10763273
TI - A MALDI sample preparation method suitable for insoluble polymers
AB - Polyamides are insoluble or poorly soluble in common organic solvents, which
makes normal sample preparation for matrix-assisted laser desorption/ionization
(MALDI) mass spectrometry very difficult. An new analytical protocol for MALDI
analysis of polyamides or other insoluble samples is described. It consists of
pressing a pellet from a solid mixture of the polymer and a matrix, both in the
form of finely ground powder. This sample preparation is compared with the common
dried droplet sample preparation method and found to perform much better, both in
terms of robustness against variation of experimental parameters and high-mass
capability.
PMID- 10763274
TI - Integration of a microextraction system on a glass chip: ion-pair solvent
extraction of Fe(II) with 4,7-diphenyl-1,10-phenanthrolinedisulfonic acid and tri
n-octylmethylammonium chloride
AB - An ion-pair solvent extraction was performed in a microchannel fabricated in a
quartz glass chip. the aqueous solution of Fe-bathophenanthrolinedisulfonic acid
complex and the chloroform solution of tri-n-octylmethylammonium chloride were
introduced into the microchannel, and a parallel two-phase laminar flow was
formed. The ion-pair product extracted in chloroform was monitored by the thermal
lens microscope. The ion-pair product was gradually extracted from aqueous
solution into chloroform when the flow was very slow or stopped, while nothing
was extracted into chloroform when the flow was fast. The time for extraction in
the present 250 microns microchannel, 45 s, roughly coincided with the molecular
diffusion time, and the extraction time was at least 1 order shorter compared
with the ordinary extraction time using a separatory funnel and mechanical
shaking. The microspace in the microchannel was characterized by the large
specific interface area and short diffusion distance, and these characteristics
may contribute to highly efficient extraction without mechanical shaking. The
success of this molecular transport may lead to the integration of more
complicated separation and chemical operations on a microchip and more
applications.
PMID- 10763275
TI - Solvent extraction coupled on-line to a reversed micellar mediated
chemiluminescence detection system for trace-level determination of atropine.
AB - A fast and sensitive method for the determination of atropine, an alkaloid
closely related to cocaine, is proposed. The principles of on-line ion-pair
formation of alkaloid-metal complexes and liquid-liquid extraction are applied to
the chemiluminescence determination of atropine. On mixing with a reversed
micellar medium of cetyltrimethylammonium chloride in dichloromethane-cyclohexane
(1:1 v/v)-water (0.3 M Na2CO3) containing luminol, the ion-pair complex of
tetrachloroaurate(III) with atropinium produced an analytical chemiluminescence
signal when it entered the reversed micellar water pool. Using the reverse-flow
injection and chemical conditions optimized for atropine in aqueous samples, a
detection limit of 1 ng/mL was achieved and a linear calibration graph was
obtained with a wide dynamic range from 10 ng/mL to 100 micrograms/mL. The
proposed method is simple and provides a good precision with a relative standard
deviation (n = 6) of ca. 3% at the atropine concentration of 100 ng/mL. After a
preliminary study involving the potential interference from species of organic,
inorganic, and metallic nature, the method was applied to the determination of
atropine in artificial urine samples and of atropine and scopolamine in
pharmaceutical formulations.
PMID- 10763276
TI - Amperometric biosensor for glutamate using prussian blue-based "artificial
peroxidase" as a transducer for hydrogen peroxide.
AB - The specially deposited Prussian Blue denoted as "artificial peroxidase" was used
as a transducer for hydrogen peroxide. The electrocatalyst was stable, highly
active, and selective to hydrogen peroxide reduction in the presence of oxygen,
which allowed sensing of H2O2 around 0.0 V (Ag/AgCl). Glutamate oxidase was
immobilized on the surface of the Prussian Blue-modified electrode in a Nafion
layer using a nonaqueous enzymology approach. The calibration range for glutamate
in flow injection system was 1 x 10(-7)-1 x 10(-4) M. The lowest concentration of
glutamate detected (1 x 10(-7) M) and the highest sensitivity in the linear range
of 0.21 A M-1 cm-2 were achieved. The influence of reductants was practically
avoided using the low potential of an indicator electrode (0.0 V Ag/AgCl). The
attractive performance characteristics of the glutamate biosensor illustrate the
advantages of Prussian Blue-based "artificial peroxidase" as transducer for
hydrogen peroxide detection.
PMID- 10763277
TI - Selective voltammetric and amperometric detection of uric acid with oxidized
diamond film electrodes.
AB - Electrochemically anodized diamond film electrodes were used for selective
detection of uric acid (UA) in the presence of high concentrations of ascorbic
acid (AA) by differential pulse voltammetry and chronoamperometry. Because the
oxidation peak potential for AA is approximately 450 mV more positive than that
for UA at anodized diamond electrodes, UA can be determined with very good
selectivity. By use of chronoamperometry, linear calibration curves were obtained
for UA over the concentration range up to 1 x 10(-6) M in 0.1 M HClO4 solution,
with the lowest experimental value measured being 5 x 10(-8) M. This is
consistent with the fact that a statistical analysis of the calibration curve
yielded a detection limit of 1.5 x 10(-8) M (S/N = 3). AA in less than 20-fold
excess does not interfere. The practical analytical utility of the method is
demonstrated by the measurement of UA in human urine and serum without any
preliminary treatment.
PMID- 10763279
TI - An ethnographic study of factors influencing cancer pain management in South
Africa.
AB - Although the knowledge exists to relieve cancer pain, inadequate pain relief
persists as an international health problem. The World Health Organization has
recommended a threefold strategy to improve cancer pain management: health
policy, drug availability, and education. Yet major barriers to effective cancer
pain management exist in every country of the world. Effective strategies to
improve pain management must be based on an understanding of the issues in
individual countries. This report evaluates cultural and other factors
influencing cancer pain management in the Republic of South Africa. This
ethnographic field study included multiple methods of data collection: analysis
of documents, participant observation, focused interviews, and in-depth
interviews of informants (n = 33) who represented multiple stakeholders in a
variety of settings. Cultural beliefs and practices form the context for
understanding cancer pain and how it is managed. Cultural variability exists
regarding cancer as a disease, pain expectations, pain tolerance, pain
expression, and health care practices. Key factors that influence how pain is
managed included standards, knowledge, resources, communication and the patient
provider relationship, and teamwork and professional relationships. The existence
of these factors promotes effective pain management, whereas their absence
creates a barrier to achieving this aim.
PMID- 10763278
TI - Measuring symptom distress in patients with lung cancer. A pilot study of
experienced intensity and importance of symptoms.
AB - Patients with cancer experience high levels of symptom distress. Current measures
of symptoms generally weight the importance of each symptom equally, and do not
generally address the relative importance of different symptoms to patients. The
purpose of this pilot study was to explore whether the assumption of equal
weighting is warranted in measurements of symptom distress. Consecutive patients
presenting with primary lung cancer at the Lung Medicine Unit of one Swedish
hospital completed the Symptom Distress Scale and a Thurstone scale eliciting
patients' weightings of the symptoms' relative importance three times: after
first contact with the unit, then 1 and 2 months later. The results show that
subjects weighted some symptoms as significantly more important than others, and
the ordering of symptoms was found to differ by intensity and perceived
importance in this group. Outlook was the symptom rated most important at T1.
Fatigue received the highest intensity score, but ranked second lowest in
importance. Kendall's coefficient showed minimal agreement among these patients
as to the specific order for the weighting of the importance of symptoms. In
addition to theoretical relevance, this issue is clinically relevant in selecting
symptoms that should be the focus of intervention and in determining how the
success of interventions should be judged.
PMID- 10763280
TI - Metastatic bone pain. Meanings associated with self-report and self-management
decision making.
AB - Patients with cancer and bone metastases are vulnerable to severe pain,
especially when changing their body position, and many such persons die with
unrelieved pain. One step in obtaining acceptable pain control is communicating
one's pain to health care providers. This descriptive study aimed to depict
possible gender differences in the meaning of pain in the context of pain self
report and self-management decision making for 10 men and 10 women with cancer
and bone metastasis. No clear gender differences were found in the narrative data
obtained during semistructured interviews. Both men and women equated pain with
cancer recurrence. Pain interfered with work, social activities, and
relationships. Most participants preferred not to tell others, even health care
providers, about their pain. More than one half of the 20 participants did not
take pain medications on schedules recommended by physicians. The study findings
provide oncology nurses with direction for education related to pain management
for persons with metastatic bone pain and their family members. Further research
with a larger sample is needed to clarify how to overcome barriers to better pain
management in this population.
PMID- 10763281
TI - Colon cancer screening among older women caregivers.
AB - Colorectal cancers are common causes of morbidity and mortality among women in
the United States. Many of these deaths are unnecessary because of the
availability of effective early detection methods. The demands of caregiving may
limit older women's participation in screening. The purposes of this exploratory
study were to describe the participation in colorectal cancer screening of older
women (n = 52; mean age 65 years) who were the primary caregivers for an ill
spouse or parent, and to investigate the relationship of the caregiving burden
and perceptions of health to participation in recommended colorectal cancer
screening tests. RESULTS: Only 36% of the older women (n = 16) had been screened
with both fecal occult blood testing (FOBT) and sigmoidoscopy. A number of women
had never participated in colorectal cancer screening: 10 (21%) had never
undergone FOBT and 22 (47%) had never undergone sigmoidoscopy. Only 20% (n = 9)
had received all of the recommended cancer screening tests: mammogram,
Papanicalaou smear, FOBT, and sigmoidoscopy. Those who did not participate in
cancer screening with sigmoidoscopy had significantly worse health perceptions
than those who did participate. Caregiver burden was not significantly associated
with differences in cancer screening participation. Only 14 of these older women
felt that they would have a good chance of survival if they received a diagnosis
of colon cancer. Further research is needed to investigate strategies to increase
participation of older women in colon cancer screening.
PMID- 10763283
TI - The emerging role of the breast care nurse in Australia.
AB - It is well documented that educated breast care nurses can provide essential
support and information to empower a woman with breast cancer to participate in
treatment decisions and take more control over her health and life. An evaluation
of Breast Cancer Support Services, a dynamic unit within the Anti-Cancer Council
of Victoria, Australia, conducted in 1994, recommended that breast cancer support
service nurses should increase their knowledge of breast cancer treatment and
management throughout the whole continuum from diagnosis to death. Greater
knowledge would enhance the nurse's role as a vital member of a multidisciplinary
team and a resource to women experiencing breast cancer at any stage in their
journey. Acting on these recommendations, the Anti-Cancer Council of Victoria, in
conjunction with La Trobe University, designed and developed the first national,
tertiary-level training program for breast care nurses. The Breast Cancer
Distance Education program, which has graduates from all states in Australia, has
been accredited by the Royal College of Nursing and positively evaluated by the
Centre for Behavioural Research in Cancer. The evaluation found that students
rated the course highly, and many planned to change their nursing practice as a
result of taking the course. Accredited breast care nurses are taught to use
accurate and up-to-date information in combination with advanced communication
skills. They do not hesitate to confer with other members of the
multidisciplinary team to ensure that women with breast cancer receive the
individualized support and continuity of care they deserve.
PMID- 10763282
TI - Barriers to prostate cancer screening.
AB - The revised prostate cancer screening guidelines of the American Cancer Society
recommend that men be informed of the risks associated with prostate cancer
screening. However, there are no published studies on men's fear of impotence and
its impact on prostate cancer screening. In addition, little is known about
barriers to prostate cancer screening when the two main barriers of cost and lack
of knowledge are eliminated. This study reports the association between barriers
and free prostate cancer screening after a prostate cancer education program. All
men were called 1 month after a prostate cancer education program and asked:
"What would (or did) make it hard for you to get your prostate checkup done?" A
total postbarrier score was created to measure how many barriers each man
indicated. The following barriers were significant in predicting participation in
prostate cancer screening: "put it off," "doctor hours not convenient," "didn't
know kind of doctor," "didn't know where to go," and "refuse to go." Fear of
impotence was not a significant barrier. Suggestions for reducing barriers to
prostate cancer screening are given.
PMID- 10763284
TI - Management of patients with malignant obstructive jaundice. Nursing perspective
from the interventional radiology room.
AB - Most patients with obstructive jaundice caused by primary pancreaticobiliary
malignancies and metastatic disease cannot be cured by surgical resection when
diagnosed. Biliary drainage in the management of obstructive jaundice therefore
represents one of the most important issues in the palliative treatment of these
patients. For more than 20 years, percutaneous transhepatic biliary drainage
procedures have allowed a nonsurgical approach to the management of malignant
biliary obstruction. Improvements in radiologic access systems have extended the
use of the percutaneous biliary approach, especially since the advent of metallic
stents. Nursing care of these patients before, during, and after the percutaneous
biliary intervention is challenging. Patient and family need to be educated about
the aim and consequences of the procedure as well as its complications. To care
for these patients, the nurse must understand the techniques of percutaneous
transhepatic biliary drainage. The purpose of this article is briefly to review
the etiology of biliary obstruction, the current treatments to relieve
obstructive jaundice, and the basic steps of biliary intervention techniques. The
nursing management throughout the procedure, the patient preparation before the
procedure, and most importantly, the postprocedural nursing care are discussed.
PMID- 10763285
TI - Oncology nurses' experience of dimethyl sulfoxide odor.
AB - This article presents findings of an exploratory descriptive study on the effects
of dimethyl sulfoxide (DMSO) odor in an oncology unit. The nursing staff, who had
reported their concerns about the unpleasant odor emitted from patients
undergoing peripheral stem cell transplantation, initiated the study. A
literature review revealed some evidence of the possible ill effects on staff
caring for patients having DMSO treatment, but many questions remain unanswered
such as what staff experience in dealing with DMSO odor and whether nursing care
is affected in any way? Data were collected through interviews with 22 oncology
nurses who all had experienced direct and indirect exposure to DMSO odor. Of the
22 nurses interviewed, 20 reported that they found DMSO odor unpleasant and
reported experiencing physical symptoms such as headaches and gastrointestinal
reactions. The study also revealed a situation in which nurses described odor
avoidance and distancing strategies that potentially compromised the nurse
patient relationship.
PMID- 10763286
TI - Facilitating day-to-day decision making in palliative care.
AB - As part of a larger grounded theory study investigating the process by which
palliative care patients make everyday choices, a secondary analysis of data was
conducted to investigate the ways nurses support or restrict patients'
participation in their care. Constant comparative methods were used to generate a
detailed, contextually grounded description of nurses' strategies that influenced
patients' participation in making everyday choices about their personal and
nursing care. Data consisted of field notes derived from observations of patients
and their caregivers in two hospital-based palliative care units and from 23
transcripts of interviews with participating nurses and patients. Nurses' efforts
to support patients' participation in decision making were described as a four
phase process: getting to know the patient, enhancing opportunities for choice,
being open to patient choice, and respecting choice. Factors influencing nurses'
use of supportive behaviors and behaviors that restricted patients' participation
in everyday choices were identified. Given the importance patients attributed to
making choices, these findings provide a foundation for the design of nursing
interventions that hold great potential for directly influencing quality of life.
PMID- 10763287
TI - Being a close relative of a dying person. Development of the concepts
"involvement in the light and in the dark".
AB - The current study is based on an earlier article in which relatives' involvement
in care was described as "involvement in the light" or "involvement in the dark."
Involvement in the light was characterized as the relative being well informed
and experiencing a meaningful involvement. The relatives involved in the dark
felt uninformed, that they were "grouping around in the dark" when they tried to
support the patient. The present study analyzed further the meaning of
"involvement in the light" and "involvement in the dark," and investigated
whether two different care cultures, the relationship with the staff, and a rapid
course of illness influence the involvement of relatives. Relatives of 52
patients who died, 30 at a surgical department and 22 in a hospice ward, were
interviewed after the patients' deaths. All the relatives of the patients in the
hospice ward and 13 of those in the surgical department were judged to be
involved in the light. Of the relatives judged to be involved in the dark, 12
either had a sick relative with a rapid course of illness or felt that the sick
relative had died unexpectedly. A pattern was clearly observed: The relatives
involved in the light described being met with respect, openness, sincerity,
confirmation, and connection, whereas the opposite was experienced by those
involved in the dark.
PMID- 10763288
TI - A simulation of the SA node by a phase response curve-based model of a two
dimensional pacemaker cells array.
AB - This paper presents a simulation of the sino-atrial (SA) node by a two
dimensional pacemaker cells array model, based on phase response curve (PRC)
interaction. This simple model of the cardiac pacemaker cells, involves only the
most basic functional properties, which play a direct role in the determination
of the SA node rhythm. The two most relevant functional properties of the
pacemaker cells are: The intrinsic cycle length, an "internal" feature of each
pacemaker cell, and the PRC, an "overall collective" function. The PRC contains
the "information" about the type of interactions of each pacemaker cell with the
outside world (i.e., interaction with neighboring cells, external stimulus,
etc.), and "strength" of the interaction (strong, weak, etc.). We studied the
spatial interaction among a large number of pacemaker cells (15 x 15), as a
function of the regional variation of cells properties, the "electrical" coupling
between cells (the PRC), and the appearance of regions with abnormal cycle
lengths. We investigated the influence of those parameters on the mutual
interaction between the pacemaker cells, on the activation pattern and conduction
time of the array, and on a pseudo-electrocardioigram (ECG) signal. This study
demonstrates that by representing the pacemaker cells in the SA node by only two
fundamental features, and by applying a simple physical-mathematical model, we
can create a global picture of the SA node system. This enables us to explore
physiological phenomena related to the genesis and maintenance of the SA node
activity, and to gain insight into the conditions which predispose the SA node
instability, and conduction disturbances.
PMID- 10763289
TI - Perturbations in hyperthermia temperature distributions associated with counter
current flow: numerical simulations and empirical verification.
AB - Two numerical techniques are used to calculate the effect of large vessel counter
current flow on hyperthermic temperature distributions. One is based on the
Navier-Stokes equation for steady-state flow, and the second employs a convective
type boundary condition at the interface of the vessel walls. Steady-state
temperature fields were calculated for two energy absorption rate distributions
(ARD) in a cylindrical tissue model having two pairs of counter-current vessels
(one pair with equal diameter vessels and another pair with unequal diameters).
The first assumed a uniform ARD throughout cylinder; the second ARD was
calculated for a tissue cylinder inside an existing four antenna Radiofrequency
(RF) array. A tissue equivalent phantom was constructed to verify the numerical
calculations. Temperatures induced with the RF array were measured using a
noninvasive magnetic resonance imaging technique based on the chemical shift of
water. Temperatures calculated using the two numerical techniques are in good
agreement with the measured data. The results show: 1) the convective-type
boundary condition technique reduces computation time by a factor of ten when
compared to the fully conjugated method with little quantitative difference
(approximately 0.3 degree C) in the numerical accuracy and 2) the use of
noninvasive magnetic resonance imaging (thermal imaging) to quantitatively access
the temperature perturbations near large vessels is feasible using the chemical
shift technique.
PMID- 10763290
TI - Parametric studies of human thermal mechanisms and measurements.
AB - A systematic methodology is proposed for mathematically quantifying the effects
of measurement inaccuracies due to instrument uncertainty in a human calorimetry
project. Human thermal mechanisms are poorly understood at the systems level and
this study investigates the importance of these mechanisms quantitatively. The
proposed methodology uses sensitivity derivatives combined with sensor accuracies
to quantify the effect of each heat transfer mechanism contributing to the errors
in the system equations. The method is applicable to any differentiable model to
be validated by experimentation. To illustrate the methodology, two example
cases, a reclining nude resting subject and a reclining clothed working subject,
are analyzed. The calculated expected errors clearly suggest specific
modifications.
PMID- 10763291
TI - Fusion of body surface potential and body surface Laplacian signals for
electrocardiographic imaging.
AB - Various approaches to the solution to the inverse problem of electrocardiography
have been proposed over the years. Recently, the use of inverse algorithms using
measured body surface Laplacians has been proposed, and in various studies this
technique has been shown to outperform the traditional use of body surface
potentials in certain model problems. In this paper, we compare the use of body
surface potentials and body surface Laplacians on two model problems with
different assumed cardiac sources. For the spherical cap model problems with an
anterior source, the epicardial estimates using body surface potentials had
smaller average relative errors than when body surface Laplacians were used. For
the spherical cap model problems with a posterior source, the epicardial
estimates using body surface potential or body surface Laplacian sensors
generally produced similar relative errors. For the radial dipole model, the
epicardial estimates using body surface Laplacians had smaller errors than when
body surface potentials were used. We introduce a fusion algorithm that combines
the different types of signals and generally produces a good estimate for both
model problems.
PMID- 10763292
TI - Prediction of neural excitation during magnetic stimulation using passive cable
models.
AB - A method for predicting neural excitation during magnetic stimulation using
passive cable models has been developed. This method uses the information of the
threshold capacitor voltage for magnetic stimulation coils to determine the
equivalent excitation thresholds for the passive transient (PT) and passive
steady-state (PSS) cable models as well as for the activating function. The
threshold values for the PT, PSS models, and the activating function vary only
with the pulsewidth of the stimulus for a variety of coils at different locations
and orientations. Furthermore, the excitation threshold for the PSS model is also
independent of axon diameter and best fitted to a simple mathematical function.
By comparing the transmembrane potential of the PSS model with the corresponding
threshold, the prediction of excitation during magnetic stimulation can be made.
Similarly, it is also possible to predict excitation using the PT model and the
activating function with the corresponding thresholds provided. By taking
advantage of the weighted pulsewidth, this method can even predict the excitation
for stimuli with various waveforms, greatly simplifying the determination of
neural excitation for magnetic stimulation.
PMID- 10763293
TI - Nonlinear system identification and overparameterization effects in multisensory
evoked potential studies.
AB - Traditional signal processing techniques have not been suitable in establishing
contributions from different sensory paths in multisensory evoked potentials. In
this paper, a nonlinear modeling technique is proposed to demonstrate the
possible mechanisms of interaction between sensory paths. The nonlinear
autoregressive with exogenous inputs (NARX) model is explored to establish a
relationship between electrical activities of the brain obtained by unimodal and
by bimodal stimulation. The intersensory phenomenon concept is extended using
nonlinear system theory and applied to show the possible interactions between the
visual and auditory sensory paths. In addition, the paper addresses the
compensation phenomenon caused by overparameterization in the NARX algorithm when
it is applied to event-related potentials. It is hoped that the nonlinear
modeling approach will generate hypotheses about the intersensory interaction
phenomenon, improving and advancing its theoretical formulation.
PMID- 10763294
TI - Development of speechreading supplements based on automatic speech recognition.
AB - In manual-cued speech (MCS) a speaker produces hand gestures to resolve
ambiguities among speech elements that are often confused by speechreaders. The
shape of the hand distinguishes among consonants; the position of the hand
relative to the face distinguishes among vowels. Experienced receivers of MCS
achieve nearly perfect reception of everyday connected speech. MCS has been
taught to very young deaf children and greatly facilitates language learning,
communication, and general education. This manuscript describes a system that can
produce a form of cued speech automatically in real time and reports on its
evaluation by trained receivers of MCS. Cues are derived by a hidden markov
models (HMM)-based speaker-dependent phonetic speech recognizer that uses context
dependent phone models and are presented visually by superimposing animated
handshapes on the face of the talker. The benefit provided by these cues strongly
depends on articulation of hand movements and on precise synchronization of the
actions of the hands and the face. Using the system reported here, experienced
cue receivers can recognize roughly two-thirds of the keywords in cued low
context sentences correctly, compared to roughly one-third by speechreading alone
(SA). The practical significance of these improvements is to support fairly
normal rates of reception of conversational speech, a task that is often
difficult via SA.
PMID- 10763295
TI - Vectorcardiographic loop alignment and the measurement of morphologic beat-to
beat variability in noisy signals.
AB - The measurement of subtle morphologic beat-to-beat variability in the
electrocardiogram (ECG)/vectorcardiogram (VCG) is complicated by the presence of
noise which is caused by, e.g., respiration and muscular activity. A method was
recently presented which reduces the influence of such noise by performing
spatial and temporal alignment of VCG loops. The alignment is performed in terms
of scaling, rotation and time synchronization of the loops. Using an ECG
simulation model based on propagation of action potentials in cardiac tissue, the
ability of the method to separate morphologic variability of physiological origin
from respiratory activity was studied. Morphologic variability was created by
introducing a random variation in action potential propagation between different
compartments. The results indicate that the separation of these two activities
can be done accurately at low to moderate noise levels (less than 10 microV). At
high noise levels, the estimation of the rotation angles was found to break down
in an abrupt manner. It was also shown that the breakdown noise level is strongly
dependent on loop morphology; a planar loop corresponds to a lower breakdown
noise level than does a nonplanar loop.
PMID- 10763296
TI - A new method for the extraction of fetal ECG from the composite abdominal signal.
AB - We developed a wavelet transform-based method to extract the fetal
electrocardiogram (ECG) from the composite abdominal signal. This is based on the
detection of the singularities obtained from the composite abdominal signal,
using the modulus maxima in the wavelet domain. Modulus maxima locations of the
abdominal signal are used to discriminate between maternal and fetal ECG signals.
Two different approaches have been considered. In the first approach, at least
one thoracic signal is used as the a prior to perform the classification whereas
in the second approach no thoracic signal is needed. A reconstruction method is
utilized to obtain the fetal ECG signal from the detected fetal modulus maxima.
The proposed technique is different from the classical time-domain methods, in
that we exploit the most distinct features of the signal, leading to more
robustness with respect to signal perturbations. Results of experiments with both
synthetic and real ECG data have been presented to demonstrate the efficacy of
the proposed method.
PMID- 10763297
TI - An ultrasonic method for noninvasive estimation of vascular impedance to an
absolute level: in vitro validation of the relationship between impedance and
phase velocity.
AB - Vascular impedance is a quantity that characterizes the properties of the
vascular bed. Assuming Newtonian fluid, laminar flow and linear system, impedance
is related to phase velocity. The agreement between theoretical relationship and
measured data is evaluated in an in vitro study. The setup consist of a computer
controlled flow generator, a variable fluid impedance and a measuring section.
Phase velocity is calculated from multiple recorded vessel pulsations detected by
ultrasonic pulse-echo technique. The reference impedance is calculated from
simultaneously measured high-fidelity pressure and flow data. The impedance is
analyzed in the range of 1-40 Hz with 1-Hz resolution. The evaluation of the
noninvasive ultrasonic technique is focused on the resonance frequencies and the
characteristic impedance. No significant difference (p > 0.05) is found in the
resonance frequencies nor in the characteristic impedance. However, the impedance
below 5 Hz is underestimated and the extension of the measuring section causes
spatial averaging effects with reduced frequency resolution.
PMID- 10763298
TI - Radiowave propagation from a tissue-implanted source at 418 MHz and 916.5 MHz.
AB - Tissue-implanted ultra-high frequency (UHF) radio devices are being employed in
both humans and animals for telemetry and telecommand applications. This paper
describes the experimental measurement and electromagnetic modeling of
propagation from 418-MHz and 916.5-MHz sources placed in the human vagina. Whole
body homogeneous and semi-segmented software models were constructed using data
from the Visible Human Project. Bodyworn radiation efficiencies for a vaginally
placed 418-MHz source were calculated using finite-difference time-domain and
ranged between 1.6% and 3.4% (corresponding to net body losses of between 14.7
and 18.0 dB). Greater losses were encountered at 916.5 MHz, with efficiencies
between 0.36% and 0.46% (net body loss ranging between 23.4 and 24.4 dB).
Practical measurements were in good agreement with simulations, to within 2 dB at
418 MHz and 3 dB at 916.5 MHz. The degree of tissue-segmentation for whole-body
models was found to have a minimal effect on calculated azimuthal radiation
patterns and bodyworn radiation efficiency, provided the region surrounding the
implanted source was sufficiently detailed.
PMID- 10763299
TI - Theoretical model for an MRI radio frequency resonator.
AB - A theoretical model is described for a magnetic resonance imaging (MRI) radio
frequency resonator (an MRI "coil") that is useful at ultrahigh frequencies. The
device is a "TEM resonator," which is based on a concept originally proposed by
Roschmann (1988). The coil comprises a circular cavity-like structure containing
several coaxial transmission lines operating in a transverse electromagnetic
(TEM) mode. The model developed herein treats the empty coil and is based on
multiconductor transmission line theory. This work generalizes and extends
similar analyses of the device by Roschmann (1995) and Chingas and Zhang (1996).
The model employs explicit calculation of per-unit-length parameters for TEM
lines having arbitrary geometries. Calculations of the resonator's frequency
response are found to compare well with measurements. Fields produced by linear
(single-point) and quadrature drive are also computed and compared to images of
low-permittivity phantoms.
PMID- 10763300
TI - A method for the reconstruction of ground reaction force-time characteristics
during gait from force platform recordings of simultaneous foot falls.
AB - This paper proposes a method for the reconstruction of foot-ground reaction
forces from force platform recordings of two consecutive footfalls. The
reconstruction algorithm uses zero-derivative criterion (inflection point) to
detect contralateral foot contacts and subtracts contralateral forces from the
combined force-time curve in order to reconstruct force-time data. Experimental
results suggest that the method can be applied to separate accurately foot
specific gait forces from corrupted force-time data as a result of incorrect
stepping on a force platform.
PMID- 10763301
TI - Compensation of the differential floating capacitance between dual
microelectrodes.
AB - A circuit for compensating the floating differential capacitance appearing
between two recording microelectrodes is presented. It is shown how this floating
capacitance can be neutralized so that current in any microelectrode can be
injected without any significant crosstalk picked up by the other.
PMID- 10763302
TI - Compensating for window effects in the calculation of spectrographic
instantaneous bandwidth.
AB - Exact results derived by Cohen and Lee are used to study the distortion induced
by the window in the computation of instantaneous bandwidth via the spectrogram.
These concepts have been recently used in an interesting study regarding lesion
induced blood flow disturbances, where an approximation was made to compensate
for the window effects. We show that this compensation is accurate for stationary
signals, but becomes increasingly poorer as the signal becomes less stationary
(e.g., large frequency modulations). We propose an alternative technique to
reduce the window distortions, and point out the use of other time-frequency
distributions that do not suffer such distortions.
PMID- 10763304
TI - Unity may preserve osteopathic ideals.
PMID- 10763303
TI - Correlation of esophageal conductance measurements with aortic and left
ventricular diameters and stroke volume.
AB - Esophageal conductance measurements were correlated with hemodynamic events in 9
dogs chronically instrumented for measurement of left ventricular (LV) and aortic
pressures, LV short axis and descending aortic diameters, and aortic blood flow.
A four-electrode conductance catheter was positioned in the esophagus. Both an
internal and an internal/external configuration were examined during anesthesia
with hemodilution, pulmonary lavage and dobutamine infusion. LV stroke volume was
altered by caval occlusion at each intervention. Stroke conductance was highly
correlated to aortic or LV diameters and stroke volume over a range of diameters
depending on the electrode configuration. Esophageal conductance measurements are
directly influenced by local hemodynamic events adjacent to the site of
measurement.
PMID- 10763305
TI - Multiple sclerosis article ignores conventional and osteopathic treatment
options.
PMID- 10763306
TI - AOA's voice supporting fair treatment of physicians in quality review process.
PMID- 10763307
TI - Physician awareness of domestic violence: does continuing medical education have
an impact?
AB - One hundred currently practicing physicians were surveyed regarding screening and
management of domestic violence to determine whether mandatory continuing medical
education (CME) is likely to increase awareness of and response to domestic
violence. The authors surveyed 25 family physicians and 25
obstetrician/gynecologists in each of two states, Florida and New Jersey. In
addition, they polled 26 family practice residents in the University of Medicine
and Dentistry of New Jersey-School of Osteopathic Medicine program. Practices
with a female physician were four times more likely to screen for domestic
violence than practices with all male physicians. No difference existed in
screening between family physicians and obstetrician/gynecologists; physicians in
Florida and those in New Jersey; or attending physicians and family practice
residents. Findings indicate that Florida's mandatory CME law does not appear to
have made an impact on the management of domestic violence. Practices with a
female physician were more likely to screen for domestic violence.
PMID- 10763308
TI - Refractory torticollis after a fall.
AB - Though multiple medical and psychiatric causes of torticollis have been
described, cervical dystonias resulting from distant somatic dysfunctions have
not. This article describes the treatment of a 62-year-old woman in whom
refractory retrotorticollis of surmised pelvic etiology developed after a fall.
Structurally, cervical dystonias have been addressed as problems that originate
in the head and neck, but this limited view of the musculoskeletal component of
torticollis may prevent physicians from directing osteopathic manipulative
treatment to the underlying problem.
PMID- 10763309
TI - Relationship of preadmission variables and first- and second-year course
performance to performance on the National Board of Osteopathic Medical
Examiners' COMLEX-USA Level 1 examination.
AB - The purpose of this study was to examine the relationship of performance on the
Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) Level 1
licensing examination to (1) academic performance during the first 2 years of the
curriculum, and (2) preadmission grade point averages (GPAs) and Medical College
Admission Test (MCAT) scores for one osteopathic medical school with the unique
mission of providing osteopathic family physicians for West Virginia and rural
Appalachia. Simple correlations were calculated for the 63 students at West
Virginia School of Osteopathic Medicine who completed all requirements of the
first 2 years of the curriculum in May 1998 and were first eligible for board
exams in June 1998. These included 26 (41.3%) female students and 5 (7.9%)
minority students. Students who had failed a year and/or a course but
subsequently successfully completed the first 2 years of the curriculum in May
1998 were included in this study. Every student who qualified to take the June
1998 administration of COMLEX-USA Level 1 did so at that time. For the 55
academic or preadmissions variables of interest, correlation coefficients with
COMLEX-USA Level 1 scores and significance levels were calculated using SPSS Base
9.0. The correlation of COMLEX-USA Level 1 performance with GPA for Phase I was
0.64; with GPA for Phase II, 0.67; and total GPA for the first 2 years, 0.70.
Grades in most individual courses also correlated significantly with COMLEX-USA
Level 1 performance. Given the special focus of this curriculum on the needs of
the Appalachian region and use of clinical performance measures or participation
measures in calculating academic GPAs, these correlations show a remarkable
degree of agreement between these two sets of performance measures. Further
research is needed to see if similar relationships exist for osteopathic medical
schools with other missions and with other curriculum structures. Preadmissions
GPAs and MCATs did not significantly relate to performance on COMLEX-USA Level 1.
PMID- 10763310
TI - Office evaluation of the patient with an overactive urinary bladder.
AB - Urinary incontinence affects between 13 and 17 million men and women in the
United States, with an annual cost exceeding $26 billion. Overactive urinary
bladder can be both neurologic (hyperreflexia) and nonneurologic (detrusor
instability). The spontaneous involuntary detrusor contractions that occur with
the overactive bladder often lead to urinary incontinence. Symptoms vary from
patient to patient, with urgency, increased frequency, and urinary urge
incontinence being the most bothersome complaints. Multiple components and
interactions of the nervous system are required for appropriate storage and
evacuation function of the bladder to occur normally. Thorough history taking and
physical examination along with appropriate urodynamic testing are necessary for
obtaining an accurate diagnosis and treatment planning. The quality of life for
many patients with overactive bladder and the resulting incontinence can be
dismal. Fortunately, most of these patients can be treated successfully.
PMID- 10763311
TI - Surgical and medical treatment options for urge incontinence.
AB - As the population ages, urinary incontinence is becoming an important health
issue. In the United States, urinary incontinence had an estimated annual cost of
$26 billion in 1995. The author presents a literature review to inform primary
care physicians about the most current medical and surgical treatment of urge
incontinence. Developments in medical research have produced oral medications
that are increasingly effective in controlling the symptoms of urge incontinence.
This advance has resulted in a decreasing need for surgical intervention.
Although surgical therapy has not been proven to be as effective as oral
medications in the treatment of urge incontinence, it is still considered to be a
viable therapy in select patient populations.
PMID- 10763312
TI - The overactive bladder in multiple sclerosis.
AB - Multiple sclerosis is a common neurologic disorder that often affects the
genitourinary system. One of the most common symptoms of multiple sclerosis is
the hyperactive bladder. These patients will have symptoms that may affect their
lifestyle, such as urinary incontinence, urgency, and frequency. They may also
suffer from debilitating urinary tract symptoms, such as frequent or recurrent
urinary tract infections and also on occasion, damage to the upper urinary tract.
Fortunately, the neurogenic bladder dysfunction associated with multiple
sclerosis can be treated with a reasonable chance of success. With proper
treatment, related symptoms may be brought under control, allowing the physician
to concentrate on the more debilitating aspects of this disease.
PMID- 10763313
TI - Interstitial cystitis: a retrospective analysis of treatment with pentosan
polysulfate and follow-up patient survey.
AB - To evaluate the efficacy and safety of pentosan polysulfate sodium (PPS) in
relieving symptoms of interstitial cystitis, the authors retrospectively reviewed
charts of 260 patients in whom interstitial cystitis had been diagnosed.
Subsequently, they conducted a follow-up phone interview or mail survey of those
patients who were treated with PPS to investigate changes in the patients'
symptoms, adverse effects, and change in quality of life. The control group
consisted of patients whose interstitial cystitis had been diagnosed at
cystoscopy and had a duration of at least 1 year and who had taken at least one
or more oral medications for their symptoms. The average length of treatment was
9.3 months among the 27 subjects on PPS therapy. The mean length of time that
they had diagnosed interstitial cystitis was 35.63 months and 48.78 months for
the PPS-treated and control groups, respectively, with no statistically
significant difference. Changes in frequency, urgency, and pain were greater in
the treatment group and statistically significant (P = .11, P = .49, and P =
.004, respectively). No change occurred in the rate of nocturia in the PPS
treated group compared with that in the control group. Symptoms of both groups
improved over time, but improvement was statistically significantly greater in
the treatment group (P = .001) over the treatment interval. The most common side
effect attributable to PPS was diarrhea in 15% of subjects. Pentosan proved to be
an efficacious option for reducing the debilitating symptoms of interstitial
cystitis.
PMID- 10763314
TI - Implantation of the totally implantable electronic hearing system TICA for the
treatment of sensorineural hearing loss.
PMID- 10763315
TI - [The results of treatment of hypopharyngeal carcinoma: some prognostic factors].
AB - Eighty nine patients with hypopharynx carcinoma treated from 1970 to 1997 at the
ENT Clinic of Pomeranian Medical Academy were studied retrospectively. There were
only IV stage patients. The treatment consisted of surgery alone (n = 21),
radiotherapy and post-radiotherapy surgery (n = 7), a planned combination of
surgery and post-operative radiotherapy (n = 61). The 3-year survival was 34.88%,
whereas the 5-year disease-free survival was 25.04%. The 5-year survival was
related to the preoperative nodal staging (N0--52.8%; N1--17.8%; N2--28.3% and N3
-0%), the number of lymph nodes metastases (no metastases 45.1%, 1--28.2%, 2-4-
23.9%, > 4--0%), and the size of nodes (0 cm--31.6%, 1-3 cm--21.9%, > 3 cm-
30.7%). Radiotherapy applied to operative treatment failed to exert any
meaningful positive influence on the overall percentage of survivals. 17 patients
had local recurrences and 6 node recurrences. Mainly following factors exerted
the influence on appearance of nodal recurrence: component N and the number of
metastatic nodes. It was pointed out that the result of treatment of hypopharynx
carcinoma are still poor and unchanged despite of developing our skills and using
new technology of treatment.
PMID- 10763316
TI - [Malignant ameloblastoma of the maxilla as an interdisciplinary problem].
AB - The clinico-pathological assessment of three cases of rare dentogenic tumours of
the maxilla was made (including one case described earlier). In two patients
primary malignant ameloblastoma was diagnosed. In one patient benign
ameloblastoma was treated few times; in this case we have observed the
transformation of benign disease to malignant because the occurring lymph node
metastases. The authors discussed clinical and morphological characteristics of
these tumours, which are under interest of many specialists.
PMID- 10763317
TI - [Clinical applications of photodynamic therapy in the treatment of laryngeal
lesions].
AB - Photodynamic therapy (PDT) has been used in the treatment of laryngeal lesions.
The disorders comprised primary dysplasia and leukoplakia of the vocal cords. The
patients after diagnosis were subjected to the therapy. Six hours prior to the
light irradiation the patients received 4% solution of delta-aminolevulinic acid
(ALA) during 30 minutes inhalation. After 6 hours all the changes were irradiated
using 400 nm wavelength light from 300 W halogen lamp (range: 380-420 nm) in
order to visualize them. Next, the wavelength was tuned to 650 nm (range 620-680
nm) and the total dose 120 J/cm2 for all cases. Control examinations in patients
revealed complete response of the lesions within 2-3 months after PDT.
PMID- 10763318
TI - [Pediatric neoplasms: laryngological manifestations].
AB - Ten children with neoplasms of the head and neck were treated in the Clinic of
Otolaryngology of Medical University in Wroclaw. In 4 children non-Hodgkin
lymphoma-type B (NHL-B) primarily situated in tonsils or adenoids were diagnosed,
3 patients suffered from embryonal rhabdomyosarcoma (RMS)--2 in the nasal cavity
and the paranasal sinuses and 1 in the middle ear. One boy presented
histiocytosis (LCH) in the orbit. In 1 case Hodgkin disease (HD) in the
preauricular lympho nodes was found and in 1 child neuroblastoma of
retromandibular region was detected. Our analysis revealed unsufficient
oncological awareness of the physician who had examined the children as the first
one. The neoplasms were detected in advanced stage. The onset of the treatment
was additionally delayed because of the long period of expecting for the
histological diagnosis.
PMID- 10763319
TI - [Cranial osteomas of atypical localization].
AB - Osteomas have a very characteristic localisation and frequency of occurrence.
Based on a representative materials the authors present literature review in
which the sequence of occurrence of osteomas in paranasal sinuses is described. A
very rare occurrence of osteomas out of the paranasal sinuses is stressed and the
hypothesis of development of osteomas in the sinuses and latter migration of
osteomas from sinuses to nasal cavities or orbit is mentioned. Three cases of
untypical size and localization of osteomas are presented, in two cases the
tumors have develop primary outside the paranasal sinuses and in one case the
osteoma was present in both frontal sinuses and in the ethmoid labyrinth.
PMID- 10763320
TI - [Frey syndrome: diagnosis and treatment].
AB - Observed lately increased of the Lucie Frey's syndrom occurance is related to
advanced frequency of the parotid gland surgery, especially because of neoplasmic
lesions of the gland. Symptoms which follow partial or total parotidectomy are
very bothersome for patients and unfortunately they strengthening with a lapse of
a time. For applied pharmacotherapy outcomes are in fact dubious. In this light
the recently applicated clostridium botulinum toxin of type A deserves of special
attention as patient therapeutic agent for Frey's syndrome because of very
promising results which can last for several months and even years. At first
discussing the anatomopatholophysiology as well as diagnostic tests. The authors
present their own experience as well as results obtained in application of the
botulin toxin for therapy of the Lucie Frey syndrome.
PMID- 10763321
TI - [Distortion product otoacoustic emissions in sensorineural hearing loss].
AB - The measurement of distortion product otoacoustic emissions (DPOE), one of the
types of otoacoustic emissions (OES) gives the possibility of frequency-
specific, objective assessment of cochlear function. Data were collected from 67
ears with sensorineural hearing loss and 30 normally hearing ears as a control
group. Percentage of DPOE response detected above the noise floor level was
evaluated in relation to the pure-tone audiometric thresholds. Analysis of
correlation coefficient between amplitude of DPOE and degree of hearing loss for
respective frequencies was performed. DPOE were detected in significantly lower
percentage in the group of ears with sensorineural hearing loss exceeding 60 dB
HL. The amplitude of DPOE decreased with the degree of hearing loss detected in
pure-tone audiometry. There was statistically significant correlation (r -0.65(-)
0.85) in all examined frequencies between DPOE and hearing loss (1-6 kHz).
PMID- 10763322
TI - [The application of aerodynamic method for the evaluation of the efficiency of
the vocal, articulation and respiratory organs during singing and playing wind
instruments].
AB - This paper discusses the application of the aerodynamic method for the estimation
of the efficiency of the vocal articulation and respiratory organ during singing
and playing wind instruments. An evaluation of the vocal and respiratory organ
was carried out on the basis of an analysis and correlation between the following
parameters: PV--phonation volume, MPT--maximum phonation/playing time, SP-
subglottal/blowing pressure, MFR--mean flow rate, GR--glottal resistance, EP-
expiratory power, W--work. Volume and airflow was measured by a pneumotachometr
with an electronic spirometer. The application of a plethysmographic booth made
it possible to carry out non-invasive, indirect measurements of the subglottal
and blowing pressure. Changes of pressure during singing and playing were
recorded in the form of an aerodynamogram curve. This curve was used to determine
the maximum duration of sound. Other quantities were derived from a mathematical
analysis.
PMID- 10763323
TI - [Endolaryngeal lipoaugmentation of the vocal cords].
AB - Unilateral vocal cord paralysis or the loss of vocal cord tissue results in
incomplete glottic closure (internal-paresis) with a consequent hoarseness and
poor voice quality. Improving glottic incompetence, instead of the previously
used paraffin, teflon is a widely accepted and most commonly used substance at
present for vocal cord medialization. Using intracordal teflon injection of for
decades had proven that it has limitations and potential complications to the
human body. Beside the well-known external "phono-surgical" methods, a wide
interest has been shown in endolaryngeal phono-surgery and in finding the ideal
and most available biocompatible substances for the procedure. Papers have been
issued about the promising results of autologus fat injection for medialization
of the paralyzed vocal fold in the early '90s. In this paper the authors report
on their slightly modified endolaryngeal intracordal autologus fat injection
procedure, and its promising results. The first three patients (a left side
glottic paralysis, a bilateral internal paresis and a left side internal paresis)
experienced an improvement in their voice right after the medialization
procedure, what remained the same during the 11 months follow-up period. Using
supraglottic jet ventilation during general anaesthesia provides very good access
to the operating field. Monitoring of neuro-muscular block makes possible an
intraoperative examination of glottic closure by the protective reflex of the
larynx. Incouraged by this initial results the authors suggest the autologus fat
as an easy available, ideal substance for increasing (augmenting) the loss of
vocal cord tissue.
PMID- 10763324
TI - [Videolaryngoscopic evaluation of the larynx and acoustic voice analysis of
children with laryngeal injuries after prolonged intubation].
AB - We present videolaryngoscopic findings of larynx of children with the injury
after prolonged intubation. We pay attention on the mechanisms of the injury,
risk factors and consequences. In our opinion videolaryngoscopy is a very
valuable method of child larynx examination. We use computed acoustic analysis of
voice to estimate results of phoniatric rehabilitation.
PMID- 10763325
TI - [A case of cylindroma of the parapharyngeal space].
AB - The authors show a case of parapharyngeal space cylindroma paying attention to
large diagnostic difficulties. This tumor has been characterized by a slow local
growth but after five years disease involved many organs with metastases.
PMID- 10763326
TI - [A case of laryngeal neurofibroma].
AB - A rare case of laryngeal neurofibroma is presented. An enlarged chordectomy via
laryngofissure was performed. The patient has survived 5 years with no symptoms
of recurrence.
PMID- 10763327
TI - [Is nasal cavity melanoma radioresistant? A case of long term control of neck
nodal metastasis by radiotherapy].
AB - Nasal cavity melanoma is a rare neoplasm bearing grave prognosis because of rapid
development of local failure and/or distant metastases, which are usually fatal.
A case of 56 year old woman, who was referred to Maria Sklodowska Memorial Cancer
Institute in Gliwice, Poland, for observation after radical maxillectomy because
of nasal cavity melanoma is described. After six months of follow-up she
developed large isolated lymphatic metastasis in heterolateral subdigastric node.
As a result of administering a course of radical radiotherapy (59 Gy in 24
fractions/30 days) complete remission of this lesion was attained. During next 11
years of follow-up neither locoregional recurrence nor distant metastases were
observed. The article describes current suggestions, based on Medline literature
search, regarding treatment of isolated nodal melanoma recurrence, with
particular emphasis on the possible role of radiotherapy in this clinical
setting.
PMID- 10763328
TI - [Approach to acute non-inflammatory increase in the circumference of the neck].
AB - We describe a case of spontaneous rupture of a left common carotid artery
aneurysm during coughing which had lead to the demise of the patient despite a
surgical intervention. This case is correlated with three cases of cervical
haematomas which also presented with an acute increase in the neck circumference.
Based on the literature and our own experience, we discuss the diagnostic and
surgical approach to patients suspected of having aneurysms of the great vessels
of the neck.
PMID- 10763329
TI - [Prosthesis to reconstruction of transmissive system in the middle ear].
AB - Authors have described prothesis to reconstruction of transmissive system in
middle ear, which has received using patent no PL 54142 Y1.
PMID- 10763330
TI - [Samuel Rosen (1897-1981): the originator of stapes mobilization].
AB - Samuel Rosen originator of the surgical procedure so called mobilization, was
second only to Juliusz Lempert as one of the great modern discoverers of new
surgical techniques in the treatment of otosclerosis. This was the result of a
chance discovery during routine stapes mobility test of the ossiculat chain
before fenestration. Rosen having had excellent scientific training and knowledge
was well prepared to interpret accidental stapes mobility and so design a new
surgical technique. This operation enabled thousands of patients with
otosclerosis to regain their hearing. However, he did not receive widespread
acclaim in his own country. He received many invitations from abroad, travelled
to several countries around the world where he taught stapes mobility testing and
demonstrated his surgical procedure. In 1957 he also visited Poland, where he was
born. He did not however limit himself to microsurgery of the ear. He created a
group of international scientists who on the basis of investigations carried out
by some of them, in the quiet noiseless African bush demonstrated that not only
hearing is protected and the ageing process of this sensory organ delayed but
also the development of arteriosclerosis is slowed down that which is the root
cause of more and more cases of heart disease which among other factors can be
attributed to the noisy stress ridden world we live in. After much success and
fame which he achieved throughout the world, the American Medical Association
awarded Sam Rosen a gold medal in 1967. But this too was not widely accepted by
all his colleagues in his own country. He died in 1981 in China.
PMID- 10763331
TI - [Concentrations of selected acute phase proteins and immunity immunoglobulins in
the treatment of head and neck carcinomas].
AB - Despite the constant development of diagnostic and therapeutic methods, there is
no specific test for patients with head and neck carcinoma, which can help in the
early diagnosis, monitoring of the follow ups. The thesis of that paper were
accompanied with remark that in many cases there is a level of change of some
acute phase protein and immunity immunoglobulins. The research group consisted of
146 men and 15 women, together 161 patients with head and neck carcinoma. 114
patients with larynx carcinoma, 32 with oral carcinoma, 7 with carcinoma of
ethomaxillary area, 6 with parotid gland carcinoma and 2 with ear carcinoma.
Patients were divided into 5 groups. The first group (52 patients) with diagnosed
carcinoma before treatment, second group (33 patients) with confirmed
recidivation after treatment, third group (20 patients) after radiotherapy with
no recidivation, fourth group (31 patients) after surgery treatment with no
recidivation, fifth group (25 patients) after combined treatment with no
recidivation. Sixth group (30 patients) was a control group. Particular acute
phase proteins serum level were measured; C-reactive protein (CRP), haptoglobin
(HPT), transferrin (TRF), protein C3 complement, immunity albumin's IgA, IgG,
IgM. The results of five groups were compared with results of control groups. One
of the ground of the statistically analyzed results were possible to draw such
conclusions: 1. C-reactive protein, haptoglobin, transferrin serum levels have a
significant correlation to carcinoma process. 2. Manifestation of carcinoma
recidivans after treatment causes statistically significant change of C-reactive
protein and haptoglobin concentration. 3. After radical antineoplasmatic
treatment there is a return of C-reactive protein and haptoglobin concentration
to normal level. 4. Protein C3 complement and immunity immunoglobulins medium
serum levels were normal and there were no differences compare to control group.
PMID- 10763332
TI - [Investigations of surgical possibilities of hearing improvement in children with
congenital ear malformations].
PMID- 10763333
TI - [Botanical alpine excursion around Zermatt].
PMID- 10763334
TI - [Phytoestrogens: potential agents for prevention and treatment of breast cancer.
2. Estrogenic and antiestrogenic plant substances].
PMID- 10763335
TI - [COX-2 inhibitors: current status and outlook].
PMID- 10763336
TI - [Plant protection: yesterday, today--tomorrow?].
PMID- 10763337
TI - [Magnets instead of radioisotope: pills in the gastrointestinal tract].
PMID- 10763338
TI - [The elderly and disease].
PMID- 10763339
TI - [Peptide antibiotics].
PMID- 10763340
TI - [Isolated systolic hypertension in the aged].
AB - The prevalence of isolated systolic hypertension (ISH) is age-related. Its
connection with the demographic shift experienced during the last century,
results in an outstanding role, mainly as risk factor for most disabling diseases
such as stroke. Epidemiological research suggests a high prevalence of the
disease and--since the cut-off for hypertension has been lowered by the Joint
National Committee--figures of the problem are, at the moment, probably
underestimated. Several studies provided reliable data about the role of ISH as
risk factor for mortality, and cardiovascular and cerebrovascular events. Large
clinical trials show that drug therapy has proved effective in lowering blood
pressure and in preventing fatal and non fatal related events.
PMID- 10763341
TI - [Alcohol-related liver diseases in the aged].
AB - In these last years the authors have devoted themselves to chronic alcoholism
rehabilitation. They have studied 99 over 65 years old subjects. In these
subjects gastrointestinal pathology alcohol correlated incidence has been
studied. An abdominal echography and an esophagogastroduodenoscopy have been
performed in all these subjects. In some subjects, on the guide line of these
tests, the authors have put through more tests: hepatosplenic scintigraphy,
hepatic biopsy, laparoscopy, colonoscopy. Statistic elaboration was performed by
chi-square test. The conclusions of this study are: 1) the diagnostic importance
of association between echography and scintigraphy; 2) the low prevalence of
severe hepatic alcohol related lesions in the elderly; 3) the importance of
alcohol in hepatocarcinoma etiopathogenesis; 4) the incidence and the importance
of phlogistic and ulcerous gastroduodenal lesions in elderly alcoholics.
PMID- 10763342
TI - [Adrenal adenoma and myelolipoma in an elderly patient with Conn's syndrome].
AB - Adrenal myelolipoma is an uncommon benign tumor usually discovered by chance in
patients with hypertension, obesity, atherosclerosis, cancer or endocrine
disorders. The association with adrenal endocrine dysfunctions appears to be the
most frequent. Myelolipoma has been found in patients affected by Cushing's
syndrome, hyperaldosteronism, Addison's disease, virilization. We report herein a
case of association, based on clinical and radiological signs, between
myelolipoma and adrenal adenoma in a patient with Conn's disease. The myelolipoma
was localized in the opposite adrenal gland to that of adenoma, at difference
with the other cases described.
PMID- 10763343
TI - [Functional dyspepsia in the aged].
AB - Functional dyspepsia (FD) is a very common syndrome in general population which
does not spare the elderly. To define the pathophysiology of FD (GI secretion and
motility, visceral sensitivity, psyche) in the elderly proves to be a difficult
task, because it is hard enough in itself to discriminate between troubles due to
"normal" ageing and manifestations of diseases to which the elderly are
particularly susceptible. At any event, unlike in non-elderly dyspeptics, in
elderly patients thorough GI investigations are always absolutely mandatory.
Dietary recommendations should be simple and reasonable. Drug therapy by
antisecretory and prokinetic agents should not be too strong, because the elderly
are particularly sensitive to drugs, and are often taking other drugs for extra
intestinal pathology.
PMID- 10763344
TI - [Age-related cognitive decline: evaluation and prevention strategy].
AB - The age-related decline of cognitive functions generally refers to a mild
deterioration in memory performance, executive functions, and speed of cognitive
processing. The terms "age-related cognitive decline" (ARCD) and "aging
associated cognitive decline" have been proposed recently to indicate an
objective decline in cognitive functioning associated to the ageing process but
within normal limits given the person's age. Whether ARCD is expression of a
normal ageing process or represents a distinct clinical entity or, eventually, is
a continuum with dementia is, at present, difficult to establish. The causes of
ARCD are unknown, but some studies have suggested that it may be prevented.
Avoidance of cardiovascular and other chronic diseases, high educational level,
and maintenance of vision and hearing have been identified as protective factors
from ARCD. On the contrary, hypertension, effects of altered metabolism of
steroid hormones, smoking, low-complexity occupation, higher density of
persons/bedroom in home, and low level of physical activity have been identified
as risk factors for ARCD. Recent findings suggest a possible role of diet in the
ARCD. In fact, in an elderly population of Southern Italy with a typical
Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be
associated with a high protection against cognitive decline. Dietary
antioxidants, specific macronutrients, estrogens, and anti-inflammatory drugs,
may act synergistically with other protective factors, opening new therapeutic
interventions for cognitive decline.
PMID- 10763345
TI - [Nutritional deficiency and Alzheimer's disease: how to identify and prevent].
AB - Weight loss is a very common problem for patients with Alzheimer's Disease (AD),
whether they live at home or in long-term care facilities. At any rate it depends
on an imbalance between energy expenditure and intake. Though in the initial
phases of the illness, the weight loss might be caused by socio-environmental and
psychological factors and reduced autonomy, in the following stages it depends on
Adversive Feeding Behaviours (AFBs). The AFBs invariably lead to protein, fat and
sugar deficits as well as a vitamin deficit which presents a positive correlation
with the cognitive performance level and negatively affects the course of the
disease. Thus it is important to identify AFBs (Blandford Scale) as soon as
possible, especially when they can be treated. Furthermore it is very important
to recognise weight loss immediately and identify a possible malnutrition state,
using investigative methods which allow for follow-up monitoring (Mini
Nutritional Assessment). Pharmacological therapy of cognitive deficit and AFBs
together with possible contemporary conditions (depression) and intervention on
the nutrition, will be useful to avoid a deficiency state and the consequent
negative repercussion on the disease.
PMID- 10763346
TI - [Congestive heart failure in the elderly: specific aspects].
AB - Heart failure is becoming the most prevalent cardiovascular disorder in the older
population, in part as a consequence of the declining fatality rate of
hypertension, myocardial infarction and ictus, resulting in progressive increment
of older subjects at increased risk of developing heart failure. In this review
the principal aspects of congestive heart failure in the elderly are described,
underlining the necessity of distinguish the "normal" ageing process from the
many noxae that cause this disease. Moreover a discussion is given about the
peculiarity of the physiopathology and symptomatology of heart failure in the
aged patients, with particular emphasis to the diastolic ventricular dysfunction
that is very frequent in these patients, posing complex problems of diagnosis and
therapy.
PMID- 10763347
TI - Cardiovascular regulation by the autonomic nervous system: a paradigm of self
organization, complexity and chaos.
AB - The understanding that there is an uninterrupted interaction of the brain with
the heart and blood vessels by means of the autonomic nervous system was only
possible due to recent electrophysiologic, biophysical and molecular advances in
the assessment of the autonomic nervous system and the cardiovascular system.
This article concerns this relationship, which is not noise, but music with a
superb orchestration, and its occasional poor tuning.
PMID- 10763348
TI - Idiopathic dilated cardiomyopathy in children: clinical profile and prognostic
determinants.
AB - Idiopathic dilated cardiomyopathy is a severe disease with a high mortality rate
in childhood. Its clinical evolution and prognosis are important for the
selection of cardiac transplantation candidates. In order to characterize its
evolution and identify prognostic factors, the clinical records of 41 children
with the diagnosis of idiopathic dilated cardiomyopathy, admitted from January
1985 to December 1997, were reviewed. Survivors (Group I) and deceased (Group II)
were separately analyzed, according to the following parameters: age, sex, race,
clinical severity, electrocardiographic, echocardiographic and haemodynamic
findings. Seven children were excluded from the study: six of them were lost to
follow-up and one died from a surgical complication. Of the remaining 34
children, 20 were male (M) and 14 were female (F) (M/F: 1.4). Age range at
diagnosis was 7 days to 14 years (median: 1.5 years), and follow-up time was from
18 days to 10.5 years (median: 2.5 years). Eleven (32.3%) children fully
recovered, 13 (38.2%) survived with left ventricular dysfunction, and ten (29.4%)
died, half of them within the first three months of follow-up. Mortality was
23.5% (8 out of 34 children) during the first year of follow-up and 29.4% (ten
out of 34 children) at five years. Unfavorable prognosis was more frequently
associated to: 1) clinical severity at the time of presentation; 2) lower mean
left ventricular shortening fraction (10 +/- 7% in group II and 13 +/- 5% in
group I); 3) occurrence of severe arrhythmia (40% in group II and 3.5% in group
I). In this series a group of higher mortality risk was identified, based on some
of the analyzed parameters, which should be considered as selection criteria for
early heart transplantation.
PMID- 10763349
TI - Prenatal diagnosis of congenital heart disease. Critical evaluation of a twelve
month experience.
AB - INTRODUCTION: A retrospective study of fetal echocardiographies performed in the
Ultrasound Unit of the Department of Obstetrics and Gynecology between January
and December 1998 was carried out. MATERIAL AND METHODS: We performed 271 fetal
echocardiographies (236 fetuses; 230 pregnant women). A triplex ultrasound
machine was used with a 5 or 3.5 MHz transabdominal probe. RESULTS: The median
maternal age was 31 years (17-44) and the median gestational age at the time of
the first examination was 27 weeks (15-38). A hundred and thirty-two pregnant
women (57.4%) were internal referrals and (98) 42.6% were referred by other
hospitals. The most common indications for referral were maternal age > or = 35
years old (n = 48), gestational diabetes (n = 38), family history of congenital
heart disease (n = 24) and insulin-dependent diabetes (n = 23). Accuracy of 32
echocardiographies was limited by technical difficulties. Out of 236 fetuses, 205
(86.9%) presented a normal scan, whereas 31 (13.1%) showed some abnormality: 22
structural cardiac defects; 5 rhythm anomalies and one with a mixed abnormality.
In three cases a pericardial effusion was detected in the absence of any
structural or rhythm anomaly and regressed spontaneously after birth. Three
fetuses were referred prenatally for treatment to another center. Eight out of
fifteen patients followed in the Pediatric Cardiology outpatient clinic were
submitted to surgical treatment. In four cases the parents opted for termination
of pregnancy and two neonatal deaths occurred. Four patients were lost for follow
up. DISCUSSION: Our study suggests that strict criteria for a referral of
pregnant women to specialized fetal echocardiography are still missing. The
median gestational age of 27 weeks at the time of the first examination was
clearly out of the generally accepted recommended period (18-24 weeks). It is
time to improve the collaboration between the different health professionals
involved in the care of pregnant women in order to increase the sensitivity of
screening for congenital heart disease.
PMID- 10763350
TI - Prenatal diagnosis of heart disease.
PMID- 10763351
TI - Myocardial architecture, texture and left ventricular heterogeneity in the pulsed
Doppler tissue imaging pattern.
AB - The regional contribution for the global ventricular functional performance is
complex and heterogeneous, the myocardial texture could reflect this particular
aspect, during the phases of myocardial contraction and relaxation. The objective
of our clinical study was to evaluate the relationship between the segmental
myocardial velocity pattern by Doppler tissue imaging and the ultrasound
characteristics of the left ventricular myocardium analysed by computerized
ultrasound densitometry with the calculation of its intensity (dB), in a
population of 22 subjects without clinical history of cardiovascular pathology,
50% female gender, mean age 43 +/- 11 years (19-66 years). In the methodology of
study, the left ventricular myocardium was divided in 16 segments, according with
the transthoracic echocardiographic recommendations of the American Society of
Echocardiography (A.S.E.). During one cardiac cycle interval, the ultrasound
characteristics of the left ventricular myocardium were evaluated continuously
and in a quantitative manner, applying the computerized ultrasound densitometry
method on the gray scale images of the ventricular myocardium, with the sample
size identical to the myocardial wall thickness. The peak (Vmax-cm/sec) and mean
(Vm-cm/sec) pulsed Doppler tissue imaging velocities, individuals, segmental and
a total velocities, contraction and relaxation velocities of the left ventricular
myocardium were obtained immediately after the computerized ultrasound
densitometry analysis. Ultrasound densitometry and Doppler tissue imaging data
were obtained in a total number of 352 left ventricular myocardial segments.
Using the multiple linear correlation matrix analysis, the ultrasound intensity
registered inverse significant correlation's with the Doppler tissue imaging Vmax
and Vm for the systolic "s" wave in the total segments and each one of them (r =
0.66; p = 0.001; interval 2-18 cm/sec; r = -0.52 to -0.70) and with the early
diastolic "e" wave (r = -0.42; p = 0.01; interval 2-19 cm/sec; r = -0.35 to
0.55). Direct correlation's were obtained for the computerized ultrasound
densitometry intensity and Doppler tissue imaging Vmax and Vm of the late
diastolic "a" wave in the total number of the left ventricular myocardial wall
segments and in each one of them (r = 0.51; p = 0.01; interval 1-17 cm/sec; r =
0.42 a 0.66). We conclude that in our study and under physiological conditions of
myocardial performance, a direct correlation was obtained between the ultrasound
characteristics of the ventricular myocardial imaging and its velocities of
contraction and relaxation. These facts reflect the close relationship between
left ventricular myocardial structure and function, analyzed by the new
ultrasound Doppler technologies.
PMID- 10763352
TI - [Clinical correlation of angiographic restenosis, isolated or associated with
stress test variables, with a population that had stent implantation].
AB - OBJECTIVE: We analyse the value of the clinical data, isolated or associated with
the stress EKG (SEKG) variables, in the detection of angiographic restenosis (AR:
lesion > 50%), in a group of patients (pts) submitted to coronary angioplasty
(PTCA) with stenting. POPULATION AND METHODS: 105 patients were followed
prospectively (male: 87%; age: 56 +/- 10); clinical evaluation was performed in
the 1st, 3rd and 6th month, SEKG in the 4th month and recatheterization for
angiographic control in the 6th month. The vascular risk factors, cause of
admission, medication at discharge, angiographic and procedure characteristics
were analysed. RESULTS: The most frequent vascular risk factors were hypertension
(42%), smoking (64%), and dyslipidemia (52%); 30% had previous ischemic heart
disease. The indication for PTCA was myocardial infarction (direct PTCA or
residual ischemia) in 42% and angina in 59%. All patients were discharged with
AAS and ticlopidine, 38% with beta-blockers, 59% with calcium channel blockers
and 92% with nitrates. Thirty-eight percent had multivessel disease. They were
submitted to dilatation with the implantation of 128 stents in 199 vessels. An
intraaortic balloon pump was used in 13% and Abciximab in 47% of the procedures.
In the recatheterization for angiographic control in the sixth month, 30 patients
had angiographic restenosis (AR rate = 25.2%). In the clinical evaluation, 22
patients (20.9%) had angina, and 14 of them had angiographic restenosis (clinical
restenosis rate = 13.3%). In the 16 asymptomatic patients with AR, 5 had positive
SEKG. CONCLUSION: The presence of angina in a group of patients submitted to
coronary angioplasty with stenting has a low sensitivity (54%), a good
specificity (88%), a positive predictive value of 64% and negative of 83% in the
detection of angiographic restenosis. The association with clinical data improves
sensitivity (83%), with a decrease in specificity (61%).
PMID- 10763353
TI - [The patient at risk of sudden death:value of drug therapy].
AB - The evaluation of antiarrhythmic therapy should be based on its effects on total
mortality assessed by controlled trials. The author reviews the large trials on
antiarrhythmic drugs, during the past ten years, and concludes with the current
importance of such therapy. Trials have been conducted in three kinds of high
risk populations: patients with malignant ventricular arrhythmias, survivors of
myocardial infarction and patients with congestive heart failure. The results
have been disappointing, showing either an increase in mortality with
antiarrhythmic drugs (class I, d-sotalol) or a neutral effect (amiodarone).
Trials conducted in patients with malignant arrhythmias have shown that the
implantable cardioverter-defibrillator was superior to the best available
antiarrhythmic therapy. In other high-risk populations, the only drugs that
consistently reduced mortality were betablockers, which might have other
mechanisms of action besides the antiarrhythmic effect. Amiodarone, the most
potent suppressor of ventricular arrhythmias, is indicated in highly symptomatic
patients; dl-sotalol is a good alternative to amiodarone. We may conclude from
these large trials that study endpoints must be correctly chosen in order to
assess the real value of an antiarrhythmic drug. The study population must have a
high risk of sudden death and be within an appropriate time window of maximal
risk. Antiarrhythmic trials must proceed, learning the lessons from the old
studies, trying to test new drugs or new therapeutic strategies, better selecting
study populations and new risk markers superior to those currently available.
PMID- 10763354
TI - [Diagnosis of a cardiac mass--a case report].
AB - The authors describe a case of a recidivant pericardial effusion associated to a
mass with an unusual, filamentous aspect that involved the upper part of right
atrium and surrounded the upper vena cava. Despite the diagnostic techniques
employed--transesophageal echocardiography and magnetic resonance imaging, the
etiologic diagnosis could not be done, so a biopsy of the mass was made by
percutaneous approach using transesophageal echocardiography to control the
procedure. The histopathological result was an angiosarcoma of the right atrium.
The authors make a brief review of the literature about this rare condition.
PMID- 10763355
TI - [Pulmonary thromboembolism: a typical case and its management].
AB - Pulmonary embolism (PE) has recently had important developments in its approach.
The authors present a case report of a 76 year-old woman with a massive PE after
orthopaedic surgery. The approach of this case raises some of the new issues
concerning the disease, which are reviewed in the discussion.
PMID- 10763356
TI - Left atrial calcified myxoma.
PMID- 10763357
TI - Aortic valve endocarditis with valve perforation visualized by echocardiography.
PMID- 10763358
TI - [A randomized study of the prevention of sudden death in patients with coronary
heart disease].
PMID- 10763359
TI - [Molecular diagnosis of the inherited long-QT syndrome in a woman who died after
near-drowning].
PMID- 10763360
TI - [Wound healing disorders in trauma surgery].
PMID- 10763361
TI - [Treatment strategies in wound healing disorders].
AB - Wound healing problems are caused by traumatic influence, due to iatrogenic
effects as well as special circumstances of the patient and a combination of all
these. The special difficulties of disturbed wound healing in trauma surgery are
the possible involvement of the fractured bone and the danger of osteitis. Acute
wound healing problems like infected hematoma, necrosis of the wound margins or
dehiscense require early or emergency revision surgery with debridement and
necrectomy. The sanitation of soft tissue problems encloses secondary sutures,
meshgraft as well as local or free flaps. The goal of treatment in wound healing
problems must be the avoidance of acute or chronic osteitis.
PMID- 10763362
TI - [Plate and screw osteosynthesis in femoral shaft fractures. Retrospective study
of 500 femur shaft fractures].
AB - The authors collected 500 cases of breaks of the thighbone shaft which were
treated using osteosynthesis with screws, between 1st January 1992 and 31st of
December 1996 at the Department for Traumatology of the University Medical Center
in Ljubljana. Most patients were male (70.6%), the average age was 36.6 years,
and the majority of patients had been injured in traffic accidents. In 50% of
cases, only the thighbone was broken, the rest had suffered multiple injuries, or
were polytraumatised. Their stay in hospital averaged 17 days, while the average
time to union was 21 weeks. In most cases (85%), treatment proceeded with no
complications. Chronical post-traumatic osteitis occurred in 9 of the patients
with open breaks (1.8%), and only in 2 patients (0.4%) with closed breaks, which
is within the limits of tolerance. With respect to our experience and results
with osteosynthesis with plates and screws in the thighbone shaft, we believe
that the mentioned method is good and gives results which are comparable to those
achieved using other methods.
PMID- 10763363
TI - [Therapy of aneurysmal bone cyst].
AB - The aneurysmal bone cyst represents a tumor-like lesion, which does not occur
frequently. Every site of the skeleton may be involved. Although it can be
observed at any age, it distinctly predominates from 10 to 20 years of age.
Distinction of aneurysmatic bone cysts from certain benign or malignant bone
tumours requires subtle imaging techniques and an experienced bone tumour
pathologist. Since the lesion shows a heterogeneous biological behaviour and
typically occurs in the growing skeleton, a wide range of surgical procedures
must be provided concerning tumour resection and defect reconstruction. In the
current retrospective study results of 41 surgically treated aneurysmal bone
cysts, thereof 5 latent, 31 active, and 5 aggressive lesions, were investigated.
While morbidity due to the therapeutic measures was comparatively low even in
extended lesions and demanding reconstructions, a recurrence rate of 19.5% had to
be observed in our series. Taking into consideration the biological activity of
the lesion, analysis of the recurrences revealed inappropriate surgical margins
had been chosen at the primary operation in all of these patients. Since the risk
of a local relapse is linked both to aggressiveness of the primary lesion and to
surgical radicality, therapy of aneurysmal bone cyst requires preoperative
staging and stage-dependent surgical procedures.
PMID- 10763364
TI - [Severe craniocerebral trauma in multiple trauma. An assessment of the
interaction of local and systemic mediator responses].
AB - Isolated severe head trauma (SHT) or SHT in combination with multiple injuries
are important factors for the prognosis of morbidity and mortality in patients
suffering from the consequences of accidents. The prognosis mainly depends on the
presence of primary mechanic brain injury and the development of secondary brain
damage. Causes for the development of secondary brain damage are the intracranial
space demand after traumatic injury and edema formation which may result in
iscemia, as well as inflammatory processes. Both isolated SHT and polytrauma with
or without brain damage may result in a systemic inflammatory response syndrome
(SIRS) due to the synthesis of cytokines and other inflammatory mediators which
may cause a single or multiple organ failure (MOF). Often the organism is able to
survive isolated traumatic injuries and functional disturbances, but in
combination or cumulation they may be lethal. The hypermetabolism after SHT is
often regarded as an interaction between the central nervous system and the whole
organism by the activation of the neuroendocrine axis. In contrast to the
consequences of SHT for the whole organism, multiple injuries after polytrauma
may affect brain functions, such as the shock dependent disturbance of the brain
perfusion accompanied by brain hypoxia which may lead to an aggravated prognosis.
Moreover, coagulation, metabolism and fracture healing are influenced by the
onset of SIRS as well. Our knowledge about the bidirectional inflammatory
interaction between brain and whole organism is still limited. In this context,
the effects of secondary surgical interventions which may additionally, stress a
traumatized body have to be considered and are the subject for actual clinical
discussions and experimental studies. This article tries to summarize some
important aspects on this topic.
PMID- 10763365
TI - [Carbon frames. Positioning and reduction aids in tibial intramedullary nailing
with unreamed technique].
AB - Intramedullary stabilisation of long bones is an established treatment option
since Kuntscher. Especially for tibial nailing different methods were proposed in
the past, were as the use of a fracture table was more or less the standard
procedure. Since 4 years now we are nailing tibial fractures without fracture
table. We are now using more and more a simple carbon fibre-frame, easily
assembled by parts of the AO external fixator. So we can minimize the additional
iatrogenic soft tissue damage during surgery and the logistic preoperative set-up
in the operation theatre is shorter.
PMID- 10763366
TI - [Effect of logistic and medical emergency resources on fatal outcome of severe
trauma].
AB - 122 cases of patients who died in sequel of an accident (recruitment period
1993/94, mean ISS 40 +/- 19) in reach of air rescue base Dresden, Germany, were
examined. Data were assessed from autopsy protocol and the protocol of the
physician who treated on scene. We analyzed the time course of the emergency, the
scheduled emergency medical service and the quality of prehospital diagnosis and
therapy by the emergency team. The mean response time was 8.1 +/- 5.9 min, the
mean distance between EMS bases und incident location 5.9 +/- 5.7 km. In 94.4% of
all cases a mobile intensive care unit--with an emergency physician as crew
member--was on scene, in 5.6% a paramedic car. Air rescue by helicopter,
including an emergency physician, was performed only in 8.7% of all cases
although a helicopter was available in 54% of all accidents. Mechanisms of injury
were traffic accident (71.4%), fall (14.3), 5.9% accident on building site, shot
and stab injuries (5.9%) and burns (1.7%). 82 patients reached the emergency room
alive (67.2% mean ISS 37 +/- 18). Only 26% of all patients were transported
directly to a level I trauma center. Mean survival time of all 122 patients was
146 +/- 30.4 h. Severe head injury described by autopsy protocol was diagnosed on
scene in 82%. Preclinical treatment was:intubation and ventilation (63%), O2
insufflation (17.4%), no specific treatment (19.6%). Severe thoracic trauma was
diagnosed in 54%. Preclinical treatment was:intubation and ventilation (64.8%),
O2 application (18.8%), no specific treatment (16.2%). Severe thoracic trauma
with hemato-pneumothorax (n = 26) was recognized by the emergency physician in
65.6%, specific therapy (application of chest drain) was performed in 7.1%.
Preclinical diagnosis rates concerning abdominal trauma were 29% and 27.8% in
case of unstable pelvis fracture. Hemorrhagic shock related to these injuries was
found in 44.2%, mean resuscitation volume applicated in these cases was 960 +/-
610 ml. Typical faults in diagnosis and treatment were underestimating of severe
trunk trauma and non-consistent use of invasive treatment procedures. Primary
transport of the severely injured patient to a level I trauma center by
helicopter was performed only rarely.
PMID- 10763367
TI - [Fractures of the diaphysis in childhood. II: Upper extremity].
PMID- 10763368
TI - [Fatal aorto-esophageal fistula as a late complication of traumatic aortic
rupture].
AB - We report on a case of a 23 years old man who was polytraumatized in a car
accident. He survived with excellent clinical outcome, but 113 days after the
accident he collapsed, massive bleeding out of the mouth started and the patient
died within a few minutes. A gastric ulcer bleeding was assumed, but autopsy
showed the break-in of a posttraumatic aortic aneurysm into the esophagus. The
difficulties of in time diagnosis of thoracic aorta lesions are discussed.
PMID- 10763369
TI - [Fatal streptococcal infection after tibial intramedullary nailing. Case report].
AB - A 29 years old patient with an unsuspicious medical history is reported, two
developed a toxic shock syndrome after intramedullary nailing for a closed tibia
fracture. The patient died within 24 hours. The infection was caused by
Streptococcus Group A. The diagnosis of the toxic shock syndrome was not without
difficulties and was delayed. Post mortem examination revealed an unknown acute
leukemia of the myeloic type.
PMID- 10763370
TI - [Bilateral rupture of the patellar ligament in diabetes mellitus].
AB - Bilateral ruptures of patellar tendon are a rare event and occur mainly in older
patients suffering from systemic diseases like lupus erythematosus, chronic renal
failure, rheumatoid arthritis or are taking longterm corticosteroids. Only few
cases of spontaneous bilateral rupture of patellar tendon without underlying
systemic disease are described in literature up to now. This report provides a
patient with bilateral patellar tendon rupture, where in further check up and
follow up only a mild diabetes mellitus treated by diet could be detected as
systemic disease. In current opinion diabetes mellitus does not belong to the
"typical" underlying systemic diseases for tendon ruptures. In literature
research diabetes mellitus was only mentioned once together with a bilateral
patellar tendon rupture.
PMID- 10763371
TI - [Limited surgical indications for elderly and multi-morbid patients].
PMID- 10763372
TI - [Management of periprosthetic femoral fractures in implanted knee joint
prosthesis with the LIS system].
PMID- 10763373
TI - [Covered aortic rupture in blunt thoracic trauma. Early or delayed surgical
management?].
PMID- 10763374
TI - Progress towards poliomyelitis eradication. Democratic Republic of the Congo,
1999.
PMID- 10763375
TI - Buruli ulcer.
PMID- 10763376
TI - A sequential study of experimental infection of pigs with porcine circovirus and
porcine parvovirus: immunostaining of cryostat sections and virus isolation.
AB - The sequential tissue distribution of virus was investigated using virus
isolation and immunofluorescence tests in 1-day-old piglets inoculated with
porcine circovirus 2 (PCV2) and/or porcine parvovirus (PPV). Enlarged mesenteric
lymph nodes were seen in the pig inoculated with PCV2 alone and killed at 26 days
post-inoculation (PI). One of the pigs inoculated with PCV2 and PPV and killed at
21 days PI had an enlarged liver. The pig killed at 26 days PI in this group had
enlarged liver, kidneys and heart. Histopathological changes were seen in
lymphoid tissues of the pigs inoculated with PCV2 alone and killed at 14 and 26
days PI. Similar, but more severe, lesions were observed in the pigs infected
with PCV2 and PPV and killed from 10 days PI onwards. Histological lesions of
nephritis, pneumonia and hepatitis were also apparent in these animals. Mild
nephritis was also seen in the pigs infected with PPV alone and killed at 14 and
26 days PI. Moderate amounts of PPV antigen were detected in tissues from the
pigs inoculated with PPV alone and killed at 14 days PI. Low levels of PCV
antigen were detected, mainly in lymphoid tissues, in the pigs inoculated with
PCV alone and killed at 14 days PI. Low to moderate amounts of PCV antigen were
detected in a wider range of tissues in the pig in this group killed at 26 days
PI. In the pigs inoculated with both viruses, PPV antigen was detected in tissues
of pigs killed from 3 to 26 days PI with maximal amounts detected between 6 and
14 days PI. PCV2 antigen was detected in low to moderate amounts in the tissues
of pigs killed at 14 days PI. Large amounts of PCV2 antigen were detected in most
of the tissues from pigs in this group killed between 17 and 26 days PI. Virus
isolation results for PCV2 generally correlated well with the results for
immunofluorescent staining. PPV was isolated from almost all tissues from pigs
inoculated with PCV2 and PPV, a much higher incidence of positive tissues than
observed for immunofluorescent staining.
PMID- 10763377
TI - Adaptation of reptilian paramyxovirus to mammalian cells (Vero cells).
AB - The reptilian paramyxovirus GOV was successfully adapted to Vero cells in 80
passages at 30 degrees C. The virus replicated with HA titres of 1:64 and 10(7.5)
TCID50/ml in the heterologous host cells forming syncytia, giant cells and
cytoplasmic inclusion bodies. After 80 passages GOV was identified by
immunofluorescence, by immune electron microscopy and by PCR. Sequencing of RT
PCR products of GOV after 80 passages did not reveal changes in the nucleotide
sequence of the partial L-gene of GOV.
PMID- 10763378
TI - Antimicrobial susceptibility of Staphylococcus spp. isolated from mammary
parenchymas of slaughtered dairy cows.
AB - The high prevalence of the great resistance to antimicrobials shown by the
aetiological agents of infectious bovine mastitis, often leads to chronic
recurrent mastitis, one of the main causes of early culling of dairy cows. The
purpose of this study was to determine the in vitro susceptibility pattern of
Staphylococcus spp. isolated from mammary parenchymas of slaughtered dairy cows,
to different anti-microbials. A total of 45 Staphylococcus spp. strains [33
coagulase-negative Staphylococcus (CNS) and 12 Staphylococcus aureus (SA)] were
used. These strains were tested with 12 different antimicrobials by the Kirby and
Bauer standardized disc diffusion method; 84.44% and 86.66% of the 45 strains
were resistant to ampicillin and penicillin, respectively. The highest
sensitivity was to cephalothin (84.44%), gentamicin (80%) and to sulphazotrin
(77.77%). CNS showed higher resistance (P < 0.05) than SA. The in vitro
susceptibility pattern of Staphylococcus spp. strains isolated from mammary
parenchymas studied in the present investigation was similar to that observed in
recent studies of in vitro and in vivo susceptibility patterns of Staphylococcus
spp. isolated from cases of bovine mastitis.
PMID- 10763379
TI - Excretion of Eimeria alabamensis oocysts in grazing calves and young stock.
AB - The aims of the present study were to investigate the excretion of Eimeria
alabamensis oocysts by young cattle during their first grazing season and during
the first 16 days of their second grazing period. In trial 1, nine first-season
grazing heifers were studied and found to have become infected with E.
alabamensis shortly after turnout. The next grazing period they were turned out
on to a permanent pasture together with two first-season grazing calves. Faecal
samples were collected before turnout and then daily from day 3 to day 16. The
second-season grazing heifers excreted insignificant numbers of E. alabamensis
oocysts, whereas one of the two first-season grazing calves excreted up to
703,000 oocysts/g of faeces (OPG), indicating that the pasture was contaminated.
In trial 2, faecal samples were collected from 12 calves before their first
turnout in May, daily from day 2 to day 20 after turnout and then once a week
until the end of September. The calves grazed pastures used in previous years by
first-season grazing calves. Nine of the calves developed clinical E. alabamensis
coccidiosis 4-7 days after turnout and excreted more than 950,000 OPG on days 9
10. By day 17 the oocyst excretion had decreased below 900 OPG and remained low
throughout the rest of the grazing season. The results of the two studies
indicate that reinfections with E. alabamensis are of little clinical importance
in calves grazing contaminated pastures, and that young stock infected with E.
alabamensis during their first grazing season may be used to cleanse contaminated
pastures without risk of developing clinical coccidiosis.
PMID- 10763380
TI - Carcass quality in certified organic production compared with conventional
livestock production.
AB - By studying carcass quality, expressed as affection, pathological findings,
slaughter-weight and evaluation, a picture of an animal's health and potential as
high quality food is achieved. This study compares the carcass quality in Swedish
certified organic meat production with that of conventional meat production
slaughtered during 1997. The study involves 3.9 million pigs, about 570,000
cattle and 190,000 sheep, all reared conventionally and 3483 pigs 4949 cattle and
4997 sheep reared according to organic standards. Pathological and additional
findings are registered by meat inspectors from the Swedish National Food
Administration at the post-mortem inspection. There was a significant difference
at the post-mortem inspection of growing-fattening pigs; 28% of conventionally
and 17% of the organically reared pigs had one or more registered lesion. The
carcass evaluation of swine shows a higher meat percentage in conventional swine
production. The total rate of registered abnormalities in cattle was systems
around 28% from organic and 27% from conventionally reared herds. Carcass
evaluation of cattle from organic herds gave higher classification in the EUROP
system, whereas the fat content was lower than that of conventionally reared
cattle. Sheep, reared both organically and conventionally, showed a lower rate of
registered abnormalities than swine and cattle.
PMID- 10763381
TI - Production and characterization of a panel of monoclonal antibodies for the
identification of antigens of Babesia bovis.
AB - A panel of monoclonal antibodies was produced and characterized by an indirect
fluorescent antibody test (IFAT), an enzyme-linked immunosorbent assay (ELISA)
and Western blotting with the aim of identifying antigens of Babesia bovis. After
fusion, the resultant hybrids were selected by the IFAT, cloned, maintained in
culture in vitro, and cryopreserved in liquid nitrogen. Ten clones producing
monoclonal antibodies were found to react against the entire merozoites, three
reacted on the surface of the merozoites, and one clone reacted against the polar
region of the merozoites. All monoclonal antibodies reacted in ELISA, with the
optical density varying from 0.368 to 0.502 (cut off = 0.022). The bands
recognized by the monoclonal antibodies in Western blotting had molecular weights
ranging from 162 to 19 kDa. Four clones recognized a single band of 73 kDa, and
another four did not react in Western blotting.
PMID- 10763382
TI - Decreased expression of L-selectin (CD62L) on lymphocytes in enzootic bovine
leukaemia.
AB - Expression of L-selectin was determined by single- and two-colour
immunofluorescence on granulocytes, peripheral blood mononuclear cells (PBMC) and
blasts of bovine origin by means of a monoclonal antibody IVA94 which recognizes
bovine L-selectin (CD62L). Cells were separated from peripheral blood of healthy
cattle and colleagues infected with bovine leukaemia virus (BLV). BLV-infected
animals comprised lymphocytotic and non-lymphocytotic cows. L-selectin was
expressed on 90-98% of granulocytes in all tested animals. The percentage of PBMC
expressing L-selectin was lower in cattle with persistent lymphocytosis than in
non-lymphocytotic or BLV-free cattle, and inversely correlated with lymphocyte
counts. The ratio of B lymphocytes stained for L-selectin was significantly
decreased from 60.2 +/- 1.9% in BLV-free cattle to 43.8 +/- 3.6 and 22.5 +/- 5.7%
in non-lymphocytotic and lymphocytotic cattle, respectively. B-lymphocytes
stained for L-selectin exhibited about 50% reduction in L-selectin expression in
BLV-infected cattle compared with BLV-free cattle, as judged by the mean
fluorescence intensity (MFI). The percentage of L-selectin-positive PBMC not
bearing surface immunoglobulin M (predominantly T lymphocytes) was comparable in
BLV-free and BLV-infected cattle. However, L-selectin expression on T lymphocytes
was reduced (about 50%) in BLV-infected cattle, as judged by the MFI. We suppose
that BLV infection results in a decreased L-selectin expression on lymphocytes,
and accordingly, it may contribute to deregulation of the host immune system.
PMID- 10763383
TI - Milk leucocyte populations in heifers free of udder infection.
AB - Improvement of udder health through a process of genetic selection is related to
heritability and the role of the specific trait in the probability of an
individual cow developing an infection. It was suggested that different patterns
of leucocyte population of the healthy gland are a significant factor in
mastitis. Thus, in order to analyse the heritability of a trait and its
correlation with udder health, the present study examined the leucocyte
populations of uninfected mammary glands, their variability among quarters in a
particular cow, and the changes that occur during lactation. Each one of the 20
cows examined was tested on average 3.06 times during lactation. The somatic cell
count (SCC)/ml ranged from 12,000 to 151,000, the coefficients of determination
(R2) were higher than 0.5 for SCC. No significant differences were found in the
dependent variables between the sampled times (test) nor any interaction between
the slopes calculated for the cows over time. No significant differences were
found among quarters within a cow for any of the dependent variables including
SCC. The effect of the cow trait was found to be significant for
polymorphonuclear (PMN), macrophage (MO), and T-lymphocyte-bearing CD4+. The
number of lymphocytes labelled with the anti-B monoclonal antibodies was
negligible. In conclusion the patterns of leucocyte populations in milk together
with the variance among cows should enable an analysis of the heritability of
this trait and its correlation with udder health in a future study.
PMID- 10763384
TI - Antimicrobial susceptibility of Arcanobacterium pyogenes isolated from cattle and
pigs.
AB - The minimum inhibitory concentrations (MICs) of 18 antimicrobial agents were
determined for 49 Arcanobacterium pyogenes isolates (42 bovine isolates and 7
porcine isolates). Benzylpenicillin and ampicillin were the most active
antibiotics, with MIC ranges of < or = 0.0125-0.05 microgram/ml for both bovine
and porcine isolates. All isolates were susceptible to penicillins and cephems.
MICs for 90% of the isolates of dihydrostreptomycin, gentamicin and
oxytetracycline for bovine isolates were > 100 micrograms/ml, 1.56 micrograms/ml
and 25 micrograms/ml, respectively. More resistance to dihydrostreptomycin
appeared among porcine isolates (85.7%) than among bovine isolates (52.4%).
Resistance to gentamicin occurred in only 3 (7.1%) of the bovine isolates.
Resistance to oxytetracycline also appeared more frequent among porcine isolates
(85.7%) than among bovine isolates (57.1%). All bovine isolates were susceptible
to erythromycin, tilmocosin and lincomycin, but two porcine isolates (28.6%) were
simultaneously resistant to these antibiotics. Tiamulin was as active as
tilmicosin, with an MIC for 50% of the isolates (MIC50) of 0.05 microgram/ml for
both bovine and porcine isolates. The MIC50s of chloramphenicol and its
derivatives florfenicol and thiamphenicol were all 1.56 micrograms/ml. The
fluoroquinolones enrofloxacin and ofloxacin were not so active as penicillins and
macrolides, with MIC50s of 0.78 microgram/ml and 1.56 micrograms/ml,
respectively, for both bovine and porcine isolates.
PMID- 10763385
TI - A comparative study of a new rapid and one-step test for the detection of
parvovirus in faeces from dogs, cats and mink.
AB - A one-step immunochromatographic test, based on the use of monoclonal antibodies,
was developed for the detection of canine parvovirus (CPV) in dog faeces. In
addition to canine parvovirus the test can also be used for the diagnosis of
infections with viruses causing parvovirus enteritis in cats (feline
panleukopenia virus) and mink (mink enteritis virus). Four hundred and forty
three faecal samples were evaluated by comparative testing between this one-step
test and three different enzyme-linked immunosorbent assays (ELISA) in Sweden,
Denmark and The Netherlands. The result of the evaluation showed an overall
relative sensitivity and specificity of 95.8 and 99.7%, respectively.
Furthermore, the comparative testing of 83 dog samples in Germany between the one
step test and an immune electron microscopy (IEM) agreed to 85.5%. The
sensitivity and specificity were 83.9 and 88.9%, respectively. These results show
that the one-step test is a rapid, simple, reproducible and sensitive diagnostic
test for the detection of parvovirus in faecal samples of dogs, cats and mink.
PMID- 10763386
TI - Isolation of Dermatophilus congolensis from a cat.
AB - Dermatophilus congolensis was isolated from a cat with dermatitis. The isolate
was sensitive to oxytetracyclin, streptomycin and penicillin but resistant to
ampicillin, amoxicillin, gentamycin and cefoperazone.
PMID- 10763387
TI - Public health, public persuasion.
PMID- 10763388
TI - Diabetes in aboriginal populations.
PMID- 10763389
TI - Technology list found wanting.
PMID- 10763390
TI - A new register for clinical trial information.
PMID- 10763391
TI - Migrants from China.
PMID- 10763392
TI - Red tape is strangling foreign-trained physicians.
PMID- 10763393
TI - What exactly were you highlighting?
PMID- 10763394
TI - It's uncanny.
PMID- 10763395
TI - The clinical burden of prostate cancer in Canada: forecasts from the Montreal
Prostate Cancer Model.
AB - OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of
diagnostic and therapeutic interventions to manage this disease. We developed a
Markov state-transition model--the Montreal Prostate Cancer Model--for improved
forecasting of the health care requirements and outcomes associated with prostate
cancer. We then validated the model by comparing its forecasted outcomes with
published observations for various cohorts of men. METHODS: We combined aggregate
data on the age-specific incidence of prostate cancer, the distribution of
diagnosed tumours according to patient age, clinical stage and tumour grade,
initial treatment, treatment complications, and progression rates to metastatic
disease and death. Five treatments were considered: prostatectomy, radiation
therapy, hormonal therapies, combination therapies and watchful waiting. The
resulting model was used to calculate age-, stage-, grade- and treatment-specific
clinical outcomes such as expected age at prostate cancer diagnosis and death,
and metastasis-free, disease-specific and overall survival. RESULTS: We compared
the model's forecasts with available cohort data from the Surveillance,
Epidemiology and End Results (SEER) Program, based on over 59,000 cases of
localized prostate cancer. Among the SEER cases, the 10-year disease-specific
survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91%
and 76% respectively, as compared with the model's estimates of 96%, 92% and 84%.
We also compared the model's forecasts with the grade-specific survival among
patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific
survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as
compared with the model's estimates of 91%, 73% and 37%. INTERPRETATION: The
Montreal Prostate Cancer Model can be used to support health policy decision
making for the management of prostate cancer. The model can also be used to
forecast clinical outcomes for individual men who have prostate cancer or are at
risk of the disease.
PMID- 10763396
TI - The economic burden of prostate cancer in Canada: forecasts from the Montreal
Prostate Cancer Model.
AB - BACKGROUND: We developed an economic model of prostate cancer management from
diagnosis until death. We have used the Montreal Prostate Cancer Model to
estimate the total economic burden of the disease in a cohort of Canadian men.
METHODS: Using this Markov state-transition simulation model, we estimated the
probability of prostate cancer, annual prostate cancer progression rates and
associated direct medical costs according to patient age, tumour stage and grade,
and treatment modalities in a 1997 cohort of Canadian men. The estimated lifetime
costs of prostate cancer included the costs of clinical staging, initial
treatments and complications, follow-up cancer therapies, routine outpatient
care, and palliative care following metastatic disease. RESULTS: The clinical
burden of prostate cancer forecasted using the model was similar to the
projections of the National Cancer Institute. In the 1997 cohort of 5.8 million
Canadian men between 40 and 80 years old, prostate cancer would be diagnosed in
an estimated 701,491 men (12.1%) over their lifetime. Direct medical costs would
total $9.76 billion, or $3.89 billion when discounted 5% annually.
INTERPRETATION: The Montreal Prostate Cancer Model indicates that the economic
burden of prostate cancer to Canada's health care system will be substantial.
Further analyses are needed to identify the most efficient means of treating this
disease.
PMID- 10763397
TI - Dilution of the 75-g oral glucose tolerance test increases postprandial glycemia:
implications for diagnostic criteria.
AB - BACKGROUND: Dilution has been noticed to increase the glycemic response to
various sugars, including glucose. This effect may contribute to the poor
reproducibility of the oral glucose tolerance test (OGTT). To test this
hypothesis we assessed the effect of diluting a 75-g OGTT on 2-hour postprandial
blood glucose based diagnostic outcomes, incremental glycemia and area under the
glucose curve. METHODS: On 3 different occasions, 10 subjects (mean age 40 [and
standard error of the mean (SEM) 3.2] years; mean body mass index 27.2 [and SEM
1.2] kg/m2) without previously diagnosed dysglycemia were given a 300-mL, 600-mL
or 900-mL 75-g OGTT in random order. The protocol followed the American Diabetes
Association's guidelines. Finger-prick capillary blood samples were obtained at
fasting and then 15, 30, 45, 60, 90 and 120 minutes after the start of the test.
RESULTS: At 30, 45 and 60 minutes, incremental glycemic concentrations were
significantly higher with the 900-mL meal (means [and SEMs]: 4.9 [0.4] mmol/L,
5.1 [0.6] mmol/L and 4.6 [0.8] mmol/L, respectively) than with the 600-mL (means
[and SEMs]: 4.0 [0.3] mmol/L, 4.2 [0.6] mmol/L and 3.6 [0.7] mmol/L,
respectively) and the 300-mL meals (means and [SEMs]: 3.8 [0.5] mmol/L, 4.0 [0.5]
mmol/L and 3.2 [0.6] mmol/L, respectively) (p < 0.05). The same was true for peak
incremental blood glucose, regardless of time (p < 0.05). The area under the
curve for the 900-mL meal (mean [and SEM] 404 [57] min.mmol/L) was significantly
higher than for the 600-mL (mean [and SEM] 331 [51] min.mmol/L) and 300-mL meals
(mean [and SEM] 280 [48] min.mmol/L) (p < 0.05). No other significant differences
were observed. INTERPRETATION: Dilution of the 75-g OGTT will likely not affect
current screening practices that use 2-h postprandial glucose levels as the basis
for diagnosis. It may, however, bias the interpretation of older criteria that
rely on intermediate time points because these midpoints appear to be sensitive
to alterations in the total volume of the meal ingested.
PMID- 10763398
TI - Disease-simulation models and health care decisions.
PMID- 10763399
TI - Direct and indirect randomized trials of screening: the A's and D's of evidence
based clinical practice guidelines.
PMID- 10763400
TI - Coronary artery bypass surgery for elderly patients: is our practice based on
evidence or faith?
PMID- 10763401
TI - Rheumatology: 1. Is it arthritis?
PMID- 10763402
TI - Frequent users of the emergency department: a program to improve care and reduce
visits.
AB - The authors describe a case-management program for frequent users of the
emergency department. The study had a single-subject design, with evaluation for
each patient of the number of visits to the emergency department for a 12-month
period before referral to the program and a similar period after implementation
of an individualized care plan. Referrals were made on the basis of 2 or more of
the following criteria: chronic medical condition, complex medical condition,
drug-seeking behaviour, violent behaviour and abusive behaviour. A
multidisciplinary team developed the individualized care plans. Twenty-four
patients agreed to participate. For the 12-month period before their referral,
these patients accounted for a total of 616 (median 26.5) visits to the emergency
department; for a similar period after implementation of the care plans, they
accounted for 175 (median 6.5) visits. The difficult-case management program
appeared to be effective in reducing the total number of visits to the emergency
department during the study period and in improving the care for these patients.
PMID- 10763403
TI - MRC changes its name, doubles its budget.
PMID- 10763404
TI - Canada among leaders in OECD health results.
PMID- 10763405
TI - West Nile fever in New York City.
PMID- 10763406
TI - The ER alternative: urgent care clinics coming of age.
PMID- 10763407
TI - Civilian facilities now provide care for Edmonton's 7000 soldiers, train military
MDs.
PMID- 10763408
TI - Adverse drug reaction reporting--1999.
PMID- 10763409
TI - Celecoxib (Celebrex): 1 year later.
PMID- 10763410
TI - Mapping and characterization of the eukaryotic early pregnancy factor/chaperonin
10 gene family.
AB - Early pregnancy factor and mitochondrial chaperonin 10 have very different
functions within mammals but the mature peptides have identical amino acid
sequences. In order to understand the mechanisms by which identical proteins can
have different functions and sites of activity, we have examined genomic DNA
which could encode the protein. In most species studied, there is a large gene
family of at least ten members with homology to the DNA sequence for this
protein. Using a monochromosomal somatic cell hybrid panel, we have mapped the
gene for human chaperonin 10 to chromosome 2. Other members of the human gene
family map to several chromosomes. Chromosomes 1, 2 and 9 contain pseudogenes
with Alu insertions while chromosome 16 has a pseudogene containing a short
direct repeat flanking an insert. Chromosomes 1 and 16 may also carry a
functional intronless copy of the EPF/Cpn10 sequence.
PMID- 10763411
TI - Analysis of mechanisms and frequency of CDKN2A/B gene loss during progression of
RAS-transformed rat embryo fibroblast clones.
AB - Rat embryo fibroblasts (REFs) are inefficiently transformed by RAS-oncogenes.
Induction of p16INK4A expression by RAS has been suggested to contribute to this
resistance. Glucocorticoid hormones, (DEX), enhance REF transformation by RAS and
facilitates the isolation of transformed and immortal cell lines. We show that
DEX induced cell proliferation is paralleled by a decrease in Cdkn2a gene
transcripts, suggesting a mechanism for hormone promotion. The mechanisms of
progression into hormone independent cell lines were examined. Twenty-two of 30
clones which reached a population size of approximately 10(6) cells could be
established as cell lines. All lines studied showed homozygous deletions of the
Cdkn2 loci (Cdkn2a and Cdkn2b) on RNO5. LOH was found for all RNO5 genetic
markers examined in 7 of 19 cell lines, suggesting non-disjunction events. In the
remaining 12 cell lines, both copies of Cdkn2 appeared to be lost by
deletions/rearrangements, some of which could by demonstrated by karyotype
analysis. We conclude that (i) clonal expansion of RAS-transfected REF by DEX is
paralleled by down-regulation of Cdkn2a expression; (ii) homozygous deletion of
Cdkn2 were estimated to occur at a frequency of 2 x 10(-8)/cell/generation or
higher, and (iii) deletion/rearrangements and nondisjunction appear to be the
main mechanisms leading to deletion of Cdkn2.
PMID- 10763412
TI - The Na+-dependent glutamate and aspartate transporter supports glutathione
maintenance and survival of CHO-K1 cells.
AB - Glutathione synthesis, a vital cellular process, depends on L-cystine uptake by
the amino acid transporter, System x-C. Here we show that a second transporter,
System X-AG, is required for normal System x-C activity and glutathione
maintenance by employing somatic cell mutants of CHO-K1. Uptake by System x-C in
two X-AG-null mutants is significantly lower than that of CHO-K1, either under
control conditions or after prolonged treatment with an electrophile. In
addition, levels of glutathione in control and treated mutant cells are less than
half those of wild-type CHO-K1 or of a pseudorevertant. The significance of this
reduction was tested by chemical challenge: mutants are twofold more sensitive
than wild type to reactive oxygen species generated by phenylbenzoquinone and to
damage produced by the anticancer drug, cisplatin. These results suggest that
System X-AG provides a significant portion of the glutamate used to energize the
uptake of cystine required for the synthesis of glutathione.
PMID- 10763413
TI - A human HP1 pseudogene maps to chromosome 11p14.
AB - The chromo multigene superfamily encodes numerous proteins involved in chromatin
structure or organization. The prototypical member of this superfamily is HP1 of
Drosophila melanogaster. We now present the sequence of a human HP1Hs gamma
pseudogene and assign it to chromosome 11p14 by radiation hybrid mapping. The
coding regions of at least three other human genes for HP1 orthologues and
another pseudogene are very similar in sequence. These results demonstrate that
HP1-type sequences have been duplicated multiple times in the mammalian genome.
PMID- 10763414
TI - Chromosomal localization of two human genes involved in phosphate homeostasis:
the type IIb sodium-phosphate cotransporter and stanniocalcin-2.
AB - Extracellular phosphate concentrations are maintained by coordinated regulation
of specific homeostatic mechanisms. A novel gene, the type IIb sodium-phosphate
cotransporter (Npt2b), was recently cloned and is expressed within intestinal
tissues, indicating that the transporter may be an important regulator of
phosphate reabsorption. Another gene, human stanniocalcin-2 (STC2), was
previously shown to decrease phosphate uptake into kidney cells in vitro. Because
of the important role that STC2 may play in phosphate homeostasis, we considered
the peptide hormone a candidate for the phosphate wasting disease autosomal
dominant hypophosphatemic rickets (ADHR), previously localized to chromosome
12p13. The purpose of our study was to determine the chromosomal localization of
human NPT2b and STC2. In the present work, NPT2b was localized to human
chromosome 4p15-p16, and STC2 to 5q33-tel. Because STC2 did not map to 12p13, the
hormone was excluded as the ADHR gene, however it should be considered a
candidate for other diseases involving phosphate homeostasis.
PMID- 10763415
TI - Inversion and transposition of Tc1 transposon of C. elegans in mammalian cells.
AB - Tc1/mariner transposons are widespread in the eukaryotes. In vitro transposition
test indicated that the transposase is the only protein that is needed in
transpositions. It was shown later that the reconstructed Tc1-like transposon,
"sleeping beauty" in fish, and the Tc1 transposon in C. elegans jumps in human
cells. This discovery indicates that the Tc1/mariner transposon may be engineered
as a somatic gene therapy vector if coupled with an efficient gene delivery
system. We introduced the Tc1 transposon from C. elegans into different mammalian
cell lines and detected the transposition events, indicating that Tc1 transposon
functions in different mammalian cells. Interestingly, a high inversion frequency
of the transposon was also detected, suggesting that this type of transposon may
add variations to host genome when it is horizontally transferred into a new
species.
PMID- 10763416
TI - Sequence analysis of the 5'-flanking region of the gene encoding human HOXA-7.
AB - We have isolated and characterized the immediate 5'-flanking region (886 bp) of
the gene encoding human HOXA-7. When the total sequence was compared with those
of mice, 93% of the 3' 518 bp (nt 370-886) sequences were identical, in which the
245 bases just preceding the AUG initiator codon (nt 614) was as highly conserved
as in the coding region (nt 614-886). Sequences further upstream (nt 1-370) by
comparison were highly diverged. In the 245 bp region, 8 stop and 3 initiation
(including the initiator) codons were located, and a 50-aa long presumptive
polypeptide was encoded. Nucleotide sequence analysis revealed three Sp1 and one
AP2 binding sites, as well as one CAAT box. However, there was no consensus
sequence for a TATA box in the 5' flanking region. One RARE repeat, one krox20
and three Hox-PBC binding sites were detected. Since many of the factor
recognition sites were located in the immediate 5' flanking sequences of a highly
conserved region, it might be speculated that a regulatory mechanism for Hox gene
expression is conserved throughout the evolution and one possible mechanism could
be at the post-translational level.
PMID- 10763417
TI - [Current chemotherapy of locally advanced or metastatic bladder tumors].
AB - Standard chemotherapy of transitional cell carcinoma of the bladder is actually
the combination of cisplatine, methothrexate, vinblastine and doxorubicine
(MVAC). Although a high response rate, long term survival are rarely observed.
More effective agents without toxicity are necessary. Several agents have
demonstrated activity alone or in combinations. Combinations regimens use,
paclitaxel, gemcitabine and Gallium nitrate, who prove activity alone or in
combination with cisplatine or carboplatine, with a response rate of 40 to 70% in
patient with visceral localisations. The optimal regimen is not yet determined.
PMID- 10763418
TI - [Unusual variety of bladder urothelial carcinoma: "nest type" microlobular
carcinoma: report of an anatomoclinical case and review of the literature].
AB - We report a case of nested cell carcinoma, an uncommon transitional tumor. These
tumors are composed of regular cuboidal transitional cells forming small nests
with minimal cytologic atypia. Despite the benign course, this tumor resembling
proliferation of Brunn's nests or inverted papilloma, must be considered as an
aggressive transitional tumor. Thus, morphologic criteria are needed to make the
diagnosis. Because of its aggressive behaviour, the surgical therapy depends on
the tumor's infiltration.
PMID- 10763419
TI - Pheochromocytoma of the urinary bladder: update on new diagnostic modalities plus
case report.
AB - Extra-adrenal pheochromocytoma (PCC) is a rare entity. Its occurrence in the
urinary bladder has only been reported less than 200 times. Here we present two
case reports of a bladder PCC with an update on the diagnostic techniques,
treatment modalities and follow-up of patients with this disease.
PMID- 10763420
TI - [Primary adenocarcinoma of the bladder: report of a case].
AB - The authors a case of primary adenocarcinoma of the bladder and studied the
clinical, histological, therapeutical and evolutive aspects of this unusual
tumor. It is a rare neoplasm that occurs for less than 2% of all bladder tumors
and it is more prevalent in males between 50 and 60 years. The symptoms, exepting
mucusuria, are non-specific, and hematuria is by far the most frequent presenting
symptom. Different etiologies have been theorized, but this tumor is generally
thought to arise through transitional epithelial metaplasia. The diagnosis is
based on the pathologic anatomy examination. The treatment still not codified,
but all of the authors advocate early aggressive surgery. The prognosis is poor.
PMID- 10763421
TI - [Carcinosarcoma of the bladder: a case report].
AB - Carcinosarcoma of the urinary bladder is a uncommon tumor with characteristic
histopathologic and immunohistochemical findings; his histogenesis have still not
been clear; the prognosis seems to be improved by radical cystectomy and
adjuvants therapies. We report a case of 47 years old women suffering from
suprapubic pains, dysuria and hematuria of five months duration and had a 10 cm
suprapubic mass that was found on physical examination. Radiographically, the
tumor invaded the dome of the urinary bladder and causes bilateral
hydronephrosis. Microscopically it was an urinary bladder carcinosarcoma. Our
objective is to discuss the histogenesis, the anatomoclinical and prognosis of
these rare tumors.
PMID- 10763422
TI - [Radiotherapy of localized prostatic cancer: follow-up of 48 patients. G.C.C.P.
(Cooperative Group for the Study of Prostatic Cancer)].
AB - OBJECTIVE: To evaluate the safety and long-term efficacy of curative-intent
radiation therapy in patients with apparently localized prostate cancer. METHOD:
48 patients with T < 3 M0 prostate cancer recruited between 1981 and 1985
received regular clinical follow-up for at least ten years or until their death.
Radiation therapy was given according to the protocols established by Ray and
Bagshaw. RESULTS: Radiation therapy was safe and effective in most patients. The
rate of escape phenomenon was less than 10% after two years. Tumor control rates
were greater than 80% after five years and 50% after ten years. Unfortunately,
local remission, even when prolonged, did not necessarily indicate a complete
cure: 20% of local recurrences developed five to 11 years after radiation
therapy. CONCLUSION: Radiation therapy may be the best first-line treatment in
men older than 75 years of age and in those whose life expectancy seems shorter
than ten years, but should probably not be considered curative.
PMID- 10763423
TI - [General treatment of metastatic prostatic cancer].
AB - Most of advanced prostatic carcinoma are hormono-sensitive. The use of combined
androgen blockade (CAB) appears to improve survival and quality of life but only
with the use of chemical castration by LH-RH analogue and non steroidal
antiandrogen. After CAB, further hormonal maneuvers remain efficacious as in a
first time antiandrogen withdrawal before estrogens, aromatase inhibitors and
after hormone resistance, chemotherapy. In bone lesions, bisphosphonates and
strontium 89 produce pain relief. The use of new methods for evaluation for
response and quality of life will allow the rapid identification of effective
treatments and powered phase III trials.
PMID- 10763424
TI - [Undifferentiated sarcoma of the prostate: report of a case].
AB - The authors report one case of indifferentiated sarcoma of the prostate revealed
by phlebitis of the right inferior limb and lung's metastases in a man 41 years
old. The tumor progress rapidly and infiltrate the bladder and the posterior
urethra. The patient died five months later. They review the literature and study
the clinical histological, therapeutic and evolutive aspects of this unusual
tumor.
PMID- 10763425
TI - [Local recurrence after radical prostatectomy for prostatic cancer].
AB - The local recurrence rate after radical prostatectomy for prostate cancer has
varied across studies but seems sufficiently high (20 to 40%) to warrant a
reappraisal of the oncological usefulness of this procedure performed in
isolation using current techniques. Local recurrence can be either biological or
clinical. In biological recurrences, the only abnormality is recurrent PSA
elevation. It has been suggested that this event, even in the absence of
ultrasound changes or histological documentation, should lead to additional
therapy, usually in the form of local radiation therapy, and that the efficacy
criterion for this treatment should be a fall in PSA to undetectable levels.
However, differences in the "ultrasensitive" assays used to detect PSA pose a
serious obstacle to comparisons of published studies. Furthermore, in most
publications, the pathological stage is more severe than the clinical stage, and
this clinical underestimation of disease severity complicates the evaluation of
recurrence rates. In clinical recurrences, rectal digital examination or
endorectal ultrasonography show abnormalities and, more importantly, examination
of a biopsy specimen establishes that these abnormalities are due to malignant
disease. Symptoms may or may not be present. Many authors, particularly in
Europe, feel that only clinical recurrences warrant additional treatment, usually
in the form of radiation therapy. However, as a preliminary, all available
imaging techniques should be used to confirm that the absence of metastases. A
valuable tool in this situation is the study of PSA kinetics (elevation rate or
postoperative doubling time). If the recurrence seems local, radiation therapy
alone is the best initial option, since concomitant hormone therapy leads to a
decrease in PSA levels even in the presence of metastatic disease, thus depriving
the patient and physician of a valuable therapeutic test. Success rates after
radiation therapy for recurrences have varied widely across studies. Some authors
consider that this treatment approach is ineffective or provides only transient
benefits. Follow-ups were often short, particularly given the considerable
variability of the natural history of prostate cancer. The enthusiasm initially
generated by radical prostatectomy should be tempered, at least regarding the
possibility of a complete cure.
PMID- 10763426
TI - [Schwannoma of the obturator nerve with urologic manifestations: report of a
case].
AB - Peripheral nerve tumors, which are called schwannomas because they arise from
nerve sheath Schwann cells, are rare tumors than can develop at any site in the
body but involve the limbs in over 50% of cases. Only 13% of schwannomas arise in
the trunk; about 3% of schwannomas are retroperitoneal, and about 4% of
retroperitoneal tumors are schwannomas. Pelvic schwannomas are equally uncommon
and can develop in a broad range of structures. The most common presenting
manifestation is a very large space-occupying lesion responsible for compression
of neighboring organs. Excision of the tumor is often extremely difficult or
impossible. Although obturator nerve schwannomas are exceedingly rare, their
paravesical location is suggestive of he diagnosis. Computed tomography and
magnetic resonance imaging are the most useful investigations, although they
cannot determine the exact nature of the tumor. During surgery, every effort
should be made to preserve the integrity of the nerve, although this is not
always possible; obturator nerve injury does not seem associated with severe
impairments.
PMID- 10763427
TI - Homosexuality, birth order, and evolution: toward an equilibrium reproductive
economics of homosexuality.
AB - The survival of a human predisposition for homosexuality can be explained by
sexual orientation being a polygenetic trait that is influenced by a number of
genes. During development these shift male brain development in the female
direction. Inheritance of several such alleles produces homosexuality. Single
alleles make for greater sensitivity, empathy, tendermindedness, and kindness.
These traits make heterosexual carriers of the genes better fathers and more
attractive mates. There is a balanced polymorphism in which the feminizing effect
of these alleles in heterosexuals offsets the adverse effects (on reproductive
success) of these alleles' contribution to homosexuality. A similar effect
probably occurs for genes that can produce lesbianism in females. The whole
system survives because it serves to provide a high degree of variability among
the personalities of offspring, providing the genotype with diversification and
reducing competition among offspring for the same niches. An allele with a large
effect can survive in these circumstances in males, but it is less likely to
survive in females. The birth order effect on homosexuality is probably a by
product of a biological mechanism that shifts personalities more in the feminine
direction in the later born sons, reducing the probability of these sons engaging
in unproductive competition with each other.
PMID- 10763428
TI - The evolution of sex differences in language, sexuality, and visual-spatial
skills.
AB - The evolutionary neurological and physical foundations for human sex differences
in language, sexuality, and visual spatial skills are detailed and primate and
human studies are reviewed. Trends in the division of labor were established
early in evolution and became amplified with the emergence of the "big brained"
Homo erectus. A bigger brain necessitated a size increase in the birth canal and
female pelvis. These and other physical changes, e.g., the swelling of the
breasts and buttocks, may have paralleled the evolution of full-time sexual
receptivity, the establishment of the home base, and exaggerated sex differences
in the division of labor (hunting vs. gathering), which in turn promoted innate
sex differences in visual spatial vs. language skills. For example, female
primates produce more social and emotional vocalizations and engage in more tool
use and gathering activities, whereas males tend to hunt and kill. Similar labor
divisions are evident over the course of human evolution. "Woman's work" such as
child rearing, gathering, and domestic tool construction and manipulation
contributed to the functional evolution of Broca's speech area and the angular
gyrus--which injects temporal sequences and complex concepts into the stream of
language and thought. These activities gave rise, therefore, to a female
superiority in grammatical (temporal sequential) vocabulary-rich language.
Hunting as a way of life does not require speech but requires excellent visual
spatial skills and, thus, contributed to a male visual-spatial superiority and
sex difference in the brain. Over the course of evolution males acquired modern
human speech through genetic inheritance and because they had mothers who taught
them language.
PMID- 10763429
TI - Sexual partner age preferences of homosexual and heterosexual men and women.
AB - The sexual age preferences of 192 adults (equal groups of heterosexual men,
heterosexual women, homosexual men, and homosexual women) were examined.
Participants rated the sexual attractiveness of pictures of 15 male and 15 female
faces arranged into five apparent average age categories ranging from 18 to 60
years. It was predicted that homosexual and heterosexual men would prefer younger
partners of their preferred sex than would homosexual and heterosexual women and
that age preference would not vary with participant age. Both predictions were
supported, although homosexual women preferred older partners than expected.
Results suggest that age and sex preferences develop independently.
PMID- 10763430
TI - Can self-reported drug use data be used to assess sex risk behavior in
adolescents?
AB - To better understand and control the spread of sexually transmitted diseases
among high-risk youth, we must first acquire reliable reports of sexual risk
behavior. This study evaluates one potential method for validating such reports.
We examined the association between marijuana and cocaine use reporting patterns
and the number of reported recent sexual partners in a sample of juvenile
arrestees/detainees. Using urinalysis to validate self-reported drug use, we
categorized drug use reporting patterns into four groups: overreporters,
underreporters, honest users, and honest nonusers. Analyses showed, in general,
that overreporters reported more sexual partners than either underreporters or
accurate reporters, suggesting that overreporters of drug use may also exaggerate
sex partner reports. Findings suggest a new method for validating self-reported
sexual behavior and provide a challenge to theories of juvenile delinquency.
PMID- 10763431
TI - Correlates of heterosexual behavior among 23-87 year olds in Denmark and Sweden,
1992-1998.
AB - Correlates of heterosexual behavior, with a particular focus on early and high
sexual activity, anal intercourse, prostitute visits, and HIV test activity, were
studied. Telephone interviews were conducted with 852 randomly chosen persons who
participated as controls in nationwide case-control studies of anogenital cancers
in Denmark and Sweden, 1992-1998. While partner numbers and the practice of anal
intercourse increased, age at sexual debut declined by 4-5 years (p < 0.001) and
the maturation interval between menarche and first coitus halved (from 7 to 3
years, p < 0.001) between persons born in or before 1920 and those born in or
after 1960. Women having high sexual activity were more often tested for HIV than
less sexually active women, but men visiting prostitutes and those with prior
STDs were not HIV tested more than other men. The increasing practice of anal
intercourse, particularly among women with many partners, deserves attention,
since this practice may erroneously be considered a safe sexual activity. Along
with their partners, men with a history of STDs and those visiting prostitutes
should be targeted in future safe sex campaigns, since these men appear to be
inadequately HIV tested.
PMID- 10763432
TI - Response to Milton Diamond and Cheryl Chase.
PMID- 10763433
TI - [The discovery of hybridization].
PMID- 10763434
TI - [Species: author definitions].
AB - For a long time the definitions of species have been mainly restricted to
logicians and philosophers; with the contribution of biologists, the number of
concepts increased dramatically. The concepts elaborated by authors of the
evolutionary synthesis seemed decisive for a time but the number of definitions
proposed was never as high as in the last half century. In the present review, a
list of classical or less well-known definitions are proposed with some
commentaries.
PMID- 10763435
TI - Inverse complementary homologues of short cysteine signatures.
AB - Inversions of short genomic sequences may play a central role in the generation
of protein complexity. We report here the existence of an heterogeneous group of
proteins (the trefoil precursors MUC-1 and MUA-1, six preproendothelins, and five
classes of zinc finger knot proteins) having both cysteine signatures (Cs) and
their inverse complementary sequences (Cs) in the same polypeptide chain. We have
also found cases in which the (Cs) of a given signature is not present in the
same protein, but elsewhere. TGEKPYK, a cysteine-free motif of the human
transcription factor, Krab, coexists with its inverse complementary sequence in
31 proteins; the inverse complementary alone is present in a great number of
proteins. Our findings suggest that short DNA inversions are a widespread feature
of the genome.
PMID- 10763436
TI - Multiple origins for Mediterranean olive (Olea europaea L. ssp. europaea) based
upon mitochondrial DNA polymorphisms.
AB - A study of nuclear and cytoplasmic genetic diversity of cultivated olive,
oleaster and other taxa belonging to the complex O. europaea was performed.
Nuclear DNA polymorphism (RAPDs) in oleaster displays a gradient between the east
and west of the Mediterranean Basin. In cultivars, the gradient is less visible
owing to their diffusion and selection. Furthermore, three mitotypes (ME1, MOM
and MCK) were detected in both cultivated olive and oleaster. A fourth mitotype,
ME2, was unique to some cultivars. The preponderant mitotype, ME1, marks the Near
Eastern origin of olive in oleaster. In the west of the Mediterranean, another
mitotype, MOM, was found in most oleaster. and a few cultivars. The third, MCK,
was found in a few oleaster from the west and in cultivars originating in Kabylie
and Languedoc. We argue that MCK marks an ancestral Mediterranean population. The
mitotypes mark independent cultivated olive origins which were not detected with
DNA nuclear diversity.
PMID- 10763437
TI - Determining body fuels of wintering mallards.
AB - Measuring body lipids and proteins of wild animals such as mallards is essential
to determine the impact of the environment on their body condition. A major
difficulty, however, is that biochemical analysis of carcass is tedious and
therefore cannot be applied at a large scale. The main objective of this study
was therefore to find out if simple measurements can be used as indices of total
body lipids and proteins. Four classes of lipid and protein indices, derived on a
'source' group, were defined according to their complexity and condition of
application (field or laboratory). Accuracy of the indices was evaluated on an
independent group, of which the body composition calculated from indices was
compared to carcass analysis. In live birds, body mass was an accurate and
convenient predictor for both lipid and protein masses. If carcasses are
available, extensive analysis provides a higher accuracy for body lipids only.
This can be simply obtained through multiple regressions using abdominal fat mass
and/or dry body mass.
PMID- 10763438
TI - Molecular phylogeography of western Mediterranean dusky grouper Epinephelus
marginatus.
AB - Intraspecific sequence variation in a portion of the gene coding for cytochrome b
in the dusky grouper (Epinephelus marginatus Lowe 1834), an endangered fish
species in various regions of the Mediterranean sea, was examined in 29
individuals from the western Mediterranean sea. Sixty-four phylogenetically
informative nucleotide positions were present in a 353-base pair cytochrome b
sequence, amplified using the polymerase chain reaction. Statistical analysis of
the sequence data using a variety of tree-building algorithms separated the taxa
into one group of dusky groupers corresponding to some of the Algerian
individuals and another regrouped set of fishes originating in France, Tunisia
and the remaining Algerian specimens. Although, on the basis of their morphology,
E. marginatus are now considered as a single species, our results suggest that a
subgroup of the Algerian dusky grouper constitutes a cryptic (undescribed)
species. These results suggest that morphological and genetic evolution may be
uncoupled in dusky grouper, resulting in morphological similarity between species
despite extensive genetic divergence. In addition, we cannot rule out the
possibility of gene introgression with other species of grouper. A more in depth
phylogenetic analysis (i.e. between and within the different Epinephelus species)
would likely affect many conservation management decisions about this assemblage
of groupers.
PMID- 10763439
TI - [The supra-occipital bone in cetaceans and burrowing rodents. morphological
convergence induced by the post-cephalic pole?].
AB - A comparative study of the cranial morphologies of cetaceans and of rodents that
use their incisors for burrowing brings out morphological convergences concerning
the supra-occipital bone. These phyletically very remote groups are both subject
to the same mechanical constraint, viz. the need for the spinal column to be
aligned with the anteroposterior axis of the skull. This constraint, which is
related to swimming in cetaceans and burrowing in rodents, entails three major
points of convergence: 1) a clearly backward facing foramen magnum; 2) a
shortened or even greatly shortened neck, sometimes with cervical vertebrae fused
together; and 3) an uprighted or even forward tilted supra-occipital bone.
PMID- 10763440
TI - [Effect of the moon on the nocturnal postnuptial migration of the skylark Alauda
arvensis L. in France].
AB - Night-migrating skylarks (Alauda arvensis) were captured during four successive
autumns in France. The study aimed at detecting a possible influence of the lunar
cycle on the nocturnal migration of this species. Though nocturnal postnuptial
migration of the skylarks can occur during every phase of the moon, main
nocturnal movements occurred when the moon was in its waxing gibbous phase. This
phase gives the best conditions for migration because from the very beginning of
night, it provides the necessary horizon for individuals to navigate and its
light allows the use of topographic cues. In addition it allows the species to
benefit from optimal conditions of illumination for almost a week.
PMID- 10763441
TI - [Seasonal evolution of the biogeochemical cycle in the southwest lagoon of New
Caledonia. Application of a compartmental model].
AB - A biogeochemical box model describing the south-west lagoon of New-Caledonia was
developed in order to simulate the seasonal cycle of carbon and nitrogen. We used
fluxes generated by a 3D hydrodynamic model to simulate horizontal exchanges
between boxes and added freshwater influxes as nitrogen sources from the land.
Average residence time proved to be less than 11 days for the lagoon as a whole.
Standard simulations showed baseline values of chlorophyll a between 0.2 and 0.4
microgram.L-1. Influences of freshwater influxes proved to be significant
(increases up to 1 microgram.L-1) only in shallow areas protected from wind
exposure and during short periods of heavy rainfall (tropical depressions).
Tropical climatic events have reduced impact in space and time and long-term
simulations over decades with increased nutrient inputs did not show any
significant process of eutrophication. Hydrodynamics seemed to be one of the
major control factors with respect to organic matter cycling in the lagoon.
PMID- 10763442
TI - A new lower jaw of Siamopithecus eocaenus from the Late Eocene of Thailand.
AB - We describe here a nearly complete lower jaw of Siamopithecus eocaenus from the
Late Eocene of Peninsular Thailand. It displays several new characters, such as
the symphysis, the horizontal branch, part of the vertical branch and most of its
anterior dentition. The symphysis is nearly vertical and bears most
characteristics of that of derived anthropoids but is unfused. Incisors were not
preserved. A large canine, P/2 alveolus and P/3-M/3 were preserved. P/2 is rooted
and reduced. The morphology of P/3 and P/4 is characteristic of that of
anthropoids, with an oblique position in the tooth row, a labially displaced
anterior root of P/3 and P/4 and the presence of a lingually developed metaconid
on P/4. The premolars display a primitive stage of anthropoid evolution. This
discovery confirms the anthropoid status of Siamopithecus, its attribution to the
family Amphipithecidae and demonstrates the importance of Asia in the evolution
of anthropoid primates.
PMID- 10763443
TI - Advances in the pharmacotherapy of migraine. How knowledge of pathophysiology is
guiding drug development.
AB - The pharmacotherapy of migraine has advanced in parallel with our understanding
of the pathophysiology of the disease. It is likely that it is the gap in our
knowledge of the pathogenesis as opposed to the pathophysiology of migraine which
hinders development of preventative agents. This century has seen the shift from
the vascular theory of migraine pathophysiology (i.e. that cranial vessels were
the prime movers in the disorder and thus vasoconstriction would be the prime
treatment) to a more integrated neurovascular theory. The neurovascular theory
takes the view that vascular change is secondary to neural activation, so changes
such as release of trigeminal neuropeptides is predicted, has been demonstrated
and suggests a possible new treatment. Similarly, it may be possible to block
trigeminal nociceptive transmission in the trigeminal nucleus which might avoid
the vascular adverse effects that, while small, plague current treatments. The
future for migraine and cluster headache, the neurovascular headaches, is bright
as we unravel their biology and this leads to further therapeutic advances.
PMID- 10763444
TI - Drugs in development for migraine. Summary and table.
PMID- 10763445
TI - Botulinum toxin A (Allergan). AGN 191622, Botox.
PMID- 10763446
TI - Dapitant. RPR 100893.
PMID- 10763447
TI - Gabapentin. CI 945, GOE 3450, Neurontin.
PMID- 10763448
TI - IS 159.
PMID- 10763449
TI - S-fluoxetine.
PMID- 10763450
TI - Vigabatrin. GVG, MDL 71754, RMI 71754, Sabril, Sabrilex, gamma-vinyl-GABA.
PMID- 10763451
TI - Zatosetron. (LY 191617, LY 277359).
PMID- 10763452
TI - Men's health. Summary and table.
PMID- 10763453
TI - Alprostadil (NexMed). Alprox-TD, Befar, Femprox, prostaglandin E1 (NexMed).
PMID- 10763454
TI - Apomorphine (TAP holdings). 6a beta-aporphine-10,11-diol hydrochloride
hemihydrate, apomorphine hydrochloride, spontane, Uprima.
PMID- 10763456
TI - Deslorelin. D-Trp-LHRH-PEA, LHRH agonist analogue, Somagard.
PMID- 10763455
TI - Bunazosin. Andante, Detantol, E 1015, E 643, EA 0643.
PMID- 10763457
TI - Follitropin-alpha. Follitropin-alpha, Gonal-F, recombinant human follicle
stimulating hormone (Ares-Serono), SJ 0021, rh-FSH, rhFSH (Ares-Serono).
PMID- 10763458
TI - Leuprorelin implant (ALZA). DUROS, leuprolide acetate implant, leuprolide
implant, Viadur.
PMID- 10763459
TI - Liarozole. Liarozole fumarate, Liazal, R 75251, R 85246.
PMID- 10763460
TI - Suramin sodium. CI 1003, Metaret, suramin, suramin hexasodium.
PMID- 10763461
TI - Vasoactive intestinal peptide/phentolamine. Invicorp, vasopotin.
PMID- 10763462
TI - Misreading of bioethics, root and branch.
PMID- 10763463
TI - Dying of ignorance.
PMID- 10763464
TI - A gene therapy death.
PMID- 10763465
TI - Pursued by happiness and beaten senseless. Prozac and the American dream.
PMID- 10763466
TI - The valorization of sadness. Alienation and the melancholic temperament.
PMID- 10763467
TI - Good science or good business?
PMID- 10763468
TI - A request for ICSI.
PMID- 10763469
TI - The Supreme Court, health policy, and new federalism.
PMID- 10763470
TI - Spiritual issues at the end of life: a call for discussion.
PMID- 10763471
TI - Passion, activity, and "the care of the self".
PMID- 10763473
TI - Alchemy revived.
PMID- 10763472
TI - Prozac, enhancement, and self-creation.
PMID- 10763474
TI - A community pediatric prevention partnership: linking schools, providers, and
tertiary care services.
AB - Integrated school health services traditionally have been provided through the
local board of education or health department. However, increased competitiveness
in the health care arena has challenged providers to find innovative models to
deliver health services to school-aged children. This article describes a
partnership among a hospital, a university, private providers, and a local school
system and health department to provide school health services. Noteworthy
aspects of the project include the organizational structure and funding of the
program, implementation of a case management model, and a focus on documenting
outcomes. This program has been successful in building local alliances to provide
health care services to school children. Implications for other school systems
struggling to fund health services for school-aged children are discussed.
PMID- 10763475
TI - The Minnesota DARE PLUS Project: creating community partnerships to prevent drug
use and violence.
AB - The research community has criticized Drug Abuse Resistance Education (D.A.R.E.)
because the extant literature indicates a lack of evidence that the elementary
school program prevents drug use. Yet D.A.R.E. continues to be the most widely
implemented drug use prevention program in the United States and has considerable
community support. To date, the junior high D.A.R.E. program has not been
evaluated. The Minnesota DARE PLUS Project is a randomized trial of 24 schools
and communities. During 1999-2001, students in eight schools will receive the
junior high D.A.R.E. curriculum in 7th grade; eight schools also will receive the
curriculum as well as additional parent involvement, peer leadership, and
community components in the 7th and 8th grades; and eight schools will serve as
controls. This article describes the background and conceptualization, the
curriculum and additional intervention components, and the evaluation methods of
the DARE PLUS Project.
PMID- 10763476
TI - Coaches' attitudes toward smokeless tobacco and intentions to intervene with
athletes.
AB - Smokeless tobacco use among athletes is alarming. Most of these athletes report
beginning smokeless tobacco use in middle or high school. West Virginia has
significantly higher rates of smokeless tobacco use among adolescent and adult
males than the general population. Since West Virginia athletes may be
particularly vulnerable to smokeless tobacco use, West Virginia coaches can be
critical agents in smokeless tobacco prevention and intervention. This study
surveyed West Virginia middle and high school coaches' 1) attitudes toward
smokeless tobacco, 2) actions toward athletes who use smokeless tobacco, 3)
intentions to provide intervention for users, and 4) tobacco use history. Results
indicated coaches had unfavorable attitudes toward smokeless tobacco, perceived
it as a problem, and were willing to help athletes quit. These findings provide
support for development of training programs for middle and high school coaches
to act as smokeless tobacco intervention agents.
PMID- 10763477
TI - Formative evaluation results from the Mariner Project: a coordinated school
health pilot program.
AB - This study determined the extent to which a coordinated school health program
(CSHP) infrastructure was in place and functioning adequately within a two- to
three-year developmental period in South Carolina. The Mariner Project's eight
component model was implemented in three middle schools and their four feeder
elementary schools in three communities. Evaluation criteria for the Mariner
Project reflect rigorous, minimum adequacy performance standards, and were based
on national standards for school health practice and research and objective
judgments of project performance. Eleven critical performance elements were
developed, and a modified indexing procedure was utilized for project evaluation
efforts. Results suggest that a combination of four critical performance
elements, 1) Administrative Support/Buy-In, 2)Coordination of the Eight-Component
Personnel School-Based Health Promotion Team, 3) Program
Champion/Liaison/Facilitator, and 4) Staff Wellness Coordinator, served as the
foundation for adequate or less-than-adequate performance for each school among
the remaining critical elements, and subsequently for the overall Mariner
Project.
PMID- 10763478
TI - Assessment of health knowledge after "a healthy adventure".
AB - This study evaluated the general health education program for third graders at
Hult Health Education Center (Hult HEC). A quasi-experimental, nonequivalent
pretest-posttest control group design with four groups was employed to collect
pretest and posttest data from 168 third graders. The four groups included a
control group, a traditional classroom health education group, a group that
visited Hult HEC, and a group that visited Hult HEC and incorporated center
curricular materials in the classroom. Analysis of covariance (ANCOVA) was
calculated to test for posttest differences among the four groups, while reducing
the effects of initial group pretest score differences. A statistically
significant difference occurred in posttest scores among the four groups (F =
120.62, df = 4, 163, p = .0001). Post hoc testing revealed the best results were
obtained when combining curricular materials with a visit to the Hult HEC.
PMID- 10763479
TI - Longitudinal tracking and retention in a school-based study on adolescent
smoking: costs, variables, and smoking status.
AB - Methods used to track a cohort of Grade 6 students through Grades 8 and 11, and
costs involved for survey completion in school and by mail for ever and never
smokers from the original group are detailed. At baseline, 1,598 students in
Scarborough, Canada, completed a questionnaire on smoking, drinking, and health,
and again in Grade 8 (N = 1,543/1,598) and Grade 11 (N = 1,454/1,598). In Grades
8 and 11, tracking and administering the questionnaire was more costly per
participant when the survey was administered by mail than in school. Average
completion costs were highest for Grade 11 students who used tobacco at baseline
($52.44). Students categorized as ever smokers in Grade 6 were harder to locate
at each phase of testing, which suggests that this group should be identified at
baseline so that closer tracking procedures may be employed between data
collection points.
PMID- 10763480
TI - [Environmental factors and human reproductive system].
AB - Problems concerning regularities and mechanisms of the environmental factor
influence on human reproductive system are discussed. It is indicated that the
response of reproductive system to external challenges is based on the
evolutionary formed links between the structures responsible for reproductive
organ function (epiphysis, hypothalamus, pituitary), the nature of environmental
factors and the regularities of their changes depending on the season and
geographical location. Damaging external challenges caused by biosphere pollution
by waste products of human economic activity and extreme ecological conditions
are realized both by direct influence on target tissues (ionizing radiation) and
indirectly through neuroendocrine mechanisms regulating reproductive organs
function. Factors and regularities of the development of diseases and
pathological conditions of human reproductive system, caused by external
challenge including the injurious industrial factor influence were analyzed.
PMID- 10763481
TI - [Participation of intracerebral monoamines in intracellular processes in the
neocortex neurons].
AB - Using complex of modern methods including histochemical and immunocystochemical
ones, the reactions of monoaminergic pyramidal neurons to the injury of afferent
inputs were for the first time established to be differently directed including
dysadaptive reorganizations, death of part of the pyramidal neurons of layers II
III and adaptive reactions of cells of the same type of layers V-VI. Neuron death
was different from apoptosis and from well known "dark" type of degeneration
which suggests a special mechanism of monoamine induced death of neurons.
Previously undescribed intranuclear inclusions in the form of vacuoles, vesicles,
myelin-like and fibrillar bodies and filament bundles were detected in pyramidal
neurons that react to the injury of monoaminergic systems. Nuclear, nucleolar and
cytoplasmic reorganizations that are also present are indicative of the
participation of monoamines in regulation of such intracellular processes as
nucleolar activity, intensity of transcription and processing as well as of
nucleo-cytoplasmic transport. These mechanisms mediate regulatory influences of
monoaminergic systems on functional activity of main efferent neocortical neurons
that participate in regulation of many CNS functions. The experimental phenomenon
of selective sensitivity and death of the part of pyramidal neurons obtained for
the first time is considered as a model for studying the pathogenesis of certain
psychoneurological diseases, caused by monoamine deficiency.
PMID- 10763482
TI - [Structural basis for the regulation of the neuronal sensitivity].
AB - Using light and electron microscopy structural bases for intracellular,
extracellular and integrative regulation of synaptic efficiency and neuron
sensitivity were established in rat sensomotor cortex. Intracellular regulation
is realized basically through modulation of postsynaptic components of the
synapse, while extracellular one is provided by synaptic endings of "recurrent"
axons on GABA-ergic relay and interneurons. Integrative regulation is realized by
means of concentration of similar axonal terminals in restricted cortical area
and arrangement of "neuromediatory" pool.
PMID- 10763483
TI - [Changes in the cholecystokinin-synthetizing hypothalamic system during
experimental diabetes mellitus in rats].
AB - The investigation was performed in 96 Wistar rats. Diabetes mellitus was induced
by single injection of 50 mg/kg of streptozotocin. Cholecystokinin (CCK)
synthesizing neurons were identified in hypothalamic structures using indirect
immunofluorescence. In latent period of diabetes (2 wks) number of CCK-
immunopositive neurons increases, especially in paraventricular and
suprachiasmatic nuclei, while in ventrolateral subnucleus of arcuate nucleus and
parvicellular subnucleus of paraventricular nucleus areas occupied by
immunoreactive material in neurons and their CCK content are reduced. By the end
of wk 5 of the disease increase in number of CCK immunopositive neurons was
registered only in medial parvicellular subnucleus of paraventricular nucleus
whereas in other structures their number was reduced. The administration of CCK
to intact animals causes increase of insulin content in endocrinocytes of
pancreatic islets, but does not affect the level of hypoglycemia. The
administration of the peptide to animals with diabetes leads to destruction of
pancreatic islets, decline in endocrinocyte number and insulin content and marked
hypoglycemia. Thus, the data obtained indicate the significant role of
hypothalamic peptidergic system and CCK in regulation of beta-endocrinocyte
function.
PMID- 10763484
TI - [Morphofunctional mechanisms of responses of sympathetic ganglia to the high
external temperature and pyrogen exposure].
AB - Reactive changes of structural and functional organization of pre- and
paravertebral sympathetic ganglia were studied in experimental fever and under
the effect of high temperatures using electron microscopy and histochemical
methods. Changes in histochemical and ultramicroscopic characteristics of
neuroglial complex, synaptic apparatus and of histohematic barrier were
demonstrated. Correlation between those changes and the dose and duration of the
challenge was established.
PMID- 10763485
TI - [Changes in the cerebral microcirculatory bed under molybdenum exposure].
AB - Histochemical study of brain hemisphere hemo-microcirculatory bed in rats treated
with large doses of molybdenum demonstrated significant 30-55% narrowing of
capillary diameter as compared to that in normal animals. This constriction is
likely to cause capillary trophic insufficiency syndrome that is important in
pathogenetic mechanisms of molybdenum-induced toxicosis.
PMID- 10763486
TI - [Response of the granulation tissue to acetylcholine and noradrenaline during
denervation].
AB - Granulation tissue from the wounds of back of both paws was studied in rats on
7th day of healing following crushing of right sciatic nerve and after repeated
applications of 0.2 g/l of acetylcholine (Ach) and noradrenaline (NA). In control
group (rats with intact nerves) applications of Ach intensified inflammatory
reaction and negatively affected the state of regenerating skin tissues: the
effect of NA consists in promoting fibroblastic and leukocytic reactions.
Simultaneous crushing of right sciatic nerve and infliction of the wound
amplified the pathologic reaction in the wounds of denervated rats as compared to
that in animals who did not undergo denervation, leading to rapid ulceration. NA
administration caused negative consequences in wounds both in right and left
sides. Crushing of the nerve was performed 7 days prior to wound infliction and
on day 7 of the study of neurodystrophic processes has shown that Ach influence
on denervated and non denervated wounds was positive, while NA influence was
negative. After reinnervation adreno- and cholinoreactivity of granulation tissue
was partially normalized both on the right and left sides.
PMID- 10763487
TI - [Morphofunctional changes in the rat spleen after capsaicin blockade of
peripheral afferent neurons].
AB - Certain parameters of spleen morphological state 2 wks following the
administration of neurotoxic (150 and 200 mg/kg) doses of capsaicine were studied
in male Wistar rats. Widening of veins, rise of splenorenal index, increase in
neutrophilic granulocyte number in red pulp, appearance of pyroninophilic
elements in it, intensification of plasmocytic reaction in germinal centres and
phagocytic siderophages activity, growth of number of megakaryocytes and
megakaryoblasts and formation of colonies of these cells were noted. Comparison
of the results obtained with the effects of surgical spleen deafferentation
suggest that sensory neuropeptide mediated neurons, possess bilateral connections
with central nervous system and may provide its control over peripheral
homeostatic functions.
PMID- 10763488
TI - [Comparative characteristics of immunoglobulin-synthesizing cell and
immunoregulatory T-lymphocyte subpopulation contents in human lymphatic nodes and
the spleen].
AB - The content of lymphocytes producing different classes of immunoglobulins (IgA,
IgM and IgG) and immunoregulatory T cell subpopulations (CD3, CD4, CD8) was
assessed in structural components of T- and B- zones of lymph nodes of visceral
and somatic groups and spleen in man. Forensic autopsy material obtained from 48
men of 2 age groups: 31-60 and 61-75 years was studied. The absence of direct
correlation between the quantity of plasma cells in B-zone of peripheral lymphoid
organs and their functional activity was shown. The results obtained may serve as
an initial point in studying immunomorphological reorganizations of human
peripheral lymphoid organs in development of immunopathological processes.
PMID- 10763489
TI - [Morphologic changes in popliteal lymph nodes subjected local irradiation with
low energy red laser].
AB - Changes of morphological parameters of relative area of structural components on
histological section, submicroscopic peculiarities of cells from regional and
contralateral popliteal lymph nodes (LN) of albino rats were found to correlate
with the dose of irradiation of low power laser (LPL) (3-30.0 J/cm2). It was
proven that 3.0 J/cm2 irradiation stimulates LN. It is essential that local
action of LPL causes similar reaction in the contralateral right popliteal LN,
which indicates systemic reaction of the immune system to this physical factor.
PMID- 10763490
TI - [Heterogeneity of the thymus epitheliocytes and their ultrastructure in newborn
rats with disturbed balance of glucocorticoids]].
AB - Four types of epitheliocytes were identified in thymus of intact newborn rats by
ultrastructural features and using the data from the literature. In progeny of
female rats receiving injections of hydrocortisone acetate, dark cells (type IV)
were prevalent. Signs of epitheliocyte hypertrophy and intensification of
intracellular differentiation were noted: thickening of tonfilaments bundles and
enlargement of vacuoles with electron dense amorphous contents, in type I
epitheliocytes, increase of number and size of cluster vacuoles in type II
epitheliocytes, signs of epitheliocyte destruction along with their hypertrophy
were detected in the thymus type I epitheliocytes of the progeny following
adrenalectomy of prynant females. The changes demonstrated are thought to be due
to increase of corticosteroid content in the developing organism.
PMID- 10763491
TI - [Nitric oxide-positive structures in the human lung].
AB - Localization and activity of NADPH-diaphorase was studied in lungs from foetuses
in the first and the second halves of intrauterine development and from people
aged 40-50 years. Bronchial epithelium, vascular endothelium and small
peribronchial nerves showed positive enzyme reaction. The highest NADPH
diaphorase activity was demonstrated in bronchial epithelium of foetuses at 35
37th weeks. In mature human subjects bronchi of the same diameter display
different enzymatic activity.
PMID- 10763492
TI - [Long-term changes in the rat gastric mucosa after truncal vagotomy and
pyloroplasty].
AB - In 40 male mature albino Wistar rats histological changes of gastric mucosa were
analyzed, parietal and chief cells were counted and gastric juice pH was
determined 120, 240 and 365 days after truncal vagotomy and pyloroplasty. In all
the groups gastric mucosa was attenuated and morphological signs of preatrophic
gastritis (decline in parietal cells number, a certain mucoidization of fundal
glands without changes in surface epithelium, alteration of mucosal lamina
propria) were present. On the background of atrophic changes compensatory and
adaptive processes (increase of mitotic activity of epitheliocytes--precursors of
differentiating cells, normalization of parietal cells differentiation along the
stem line, i.e. of ratio of differentiating, mature functioning and degenerating
cell forms) were noted, that lead to repair of histo-structure and function on
the whole, although at a lower level. Following long-term intervals after
vagotomy glandular gastric epithelium acquires its histo-typical form with
parietal secretory activity decreased to some extent.
PMID- 10763493
TI - [Morphologic characteristics of the endometrium in women with endometriosis].
AB - It was established that in accordance with certain phases of sexual cycle
(menstrual cycle in women and estral cycle in rats) on the background of hormone
action at follicular and luteal phase the surface of epitheliocytes acquires
specific relief (formation and degradation of microvilli appropriately in first
and second halves of the cycle, accordingly). Disturbance of cyclic change of the
relief of apical surface of epitheliocytes of the endometrium, persistence of
high binding activity of the cationic dye and formation of intercellular clefts
were demonstrated in developing endometriosis, which significantly interferes
with the reproductive function. This was suggested to be an unfavourable result
of cytotoxic effect of autoimmune processes that develop due to implantation of
cells of endometrium in abdominal cavity and initiation of cooperative cellular
response, which seems to be morphologically demonstrated by significant increase
in number of macrophages in tissues of the uterus and in menstrual discharge.
PMID- 10763494
TI - [The use of electromagnetic field in preparing hematoxylin].
PMID- 10763495
TI - [Morphogenesis of glands localized in walls of visceral organs].
PMID- 10763496
TI - [Methodological aspects of the development and use of teaching materials based on
the multimedia technology].
PMID- 10763498
TI - [In Process Citation]
PMID- 10763497
TI - [The 100th anniversary of the Department of Histology, Cytology, and Embryology
of the academician I. P. Pavlov St. Petersburg State Medical University].
PMID- 10763499
TI - Expression of the immediate early genes c-Fos and c-Jun after head injury in man.
AB - Immediate early genes (IEC) are expressed in a variety of experimental paradigms
including cerebral ischemia and trauma. There is a paucity of information on
whether the results of laboratory experiments can be extrapolated from animals
into man. To examine this further we hypothesized that expression of c-Fos and c
Jun occurs after contusional head injury in man. We also sought to identify
whether there was an association between the level of immediate early gene
expression and 1. the outcome one year after head injury, 2. the timing of
surgery after head injury. IEG expression was examined using in situ
hybridization and immunocytochemistry in brain tissue therapeutically removed in
14 patients with head injury 6 h to 6 days after contusional injury. IEG
expression was also examined in tissue removed during elective non-traumatic
neurosurgery for comparative purposes. Expression of c-fos and c-jun mRNA was
observed in 50% and 64% of head-injured patients respectively. Protein
immunoreactivity for these IEGs was evident in 67% of head injured patients. The
expression of c-Fos and c-Jun was associated with final outcome. Patients with
poorer outcomes had higher levels of gene expression (p = 0.08 for c-Fos and p =
0.006 for c-Jun). No correlation between the timing of surgery and the intensity
of gene expression was evident in the trauma patients (r2 = 0.09 and 0.10 for c
Fos and c-Jun respectively). In the non-trauma patients 36% expressed c-fos and
73% expressed c-jun mRNA, with all patients studied expressing c-Fos and c-Jun
proteins. We conclude that differential expression of c-Fos and c-Jun occurs in
the patients with cerebral contusions. The difference in expression rates between
mRNA and protein emphasises the need for analysis of gene products when
investigating gene expression. These results support the hypothesis that IEGs may
be involved in the pathogenetic mechanisms of contusional head injury.
Observations of IEG expression in human brain injury are important in steering
animal experimental programmes towards studies that may yield information
directly applicable to human brain injury.
PMID- 10763500
TI - Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P
magnetic resonance spectroscopy study.
AB - The decrease in intracellular creatine concentration in Duchenne muscular
dystrophy may contribute to the deterioration of intracellular energy homeostasis
and may thus be one of the factors aggravating muscle weakness and degeneration.
Oral creatine supplementation should have potential in alleviating the clinical
symptoms. To test this hypothesis, creatine was orally administered over a period
of 155 days to a 9-year-old patient with Duchenne muscular dystrophy. In
accordance with previous investigations on normal subjects and trained athletes,
the patient experienced improved muscle performance during creatine
supplementation. Further evidence supporting this hypothesis derived from plasma
creatine kinase and lactate dehydrogenase activities and repeated 31P magnetic
resonance spectroscopy of the gastrocnemius muscle. These preliminary
observations indicate a potential role for creatine supplementation in the
symptomatic therapy of patients with muscle disease.
PMID- 10763501
TI - High incidence of hyponatremia in patients with ruptured anterior communicating
artery aneurysms.
AB - We studied the incidence and timing of hyponatremia (Na < 135 mEq l-1) after
subarachnoid hemorrhage (SAH) with special reference to ruptured anterior
communicating artery (A-com) aneurysms. Hunt and Kosnik (HK) grading, symptomatic
vasospasm in A-com aneurysm, and hydrocephalus were analyzed for connections to
hyponatremia in 55 patients with ruptured A-com aneurysms, 65 with ruptured
internal cerebral artery (ICA) aneurysms, and 49 with ruptured middle cerebral
artery (MCA) aneurysms. Hyponatremia occurred in 28 (51%) of 55 patients with A
com aneurysms and in nine (18%) of 49 patients with MCA aneurysms. Severe
hyponatremia (Na < 130 mEq l-1) occurred in 16 patients (29%) in the A-com group,
four patients (6%) in the ICA group, and three patients (6%) in the MCA group.
The A-com aneurysm group had a significantly higher incidence of mild
hyponatremia (p < 0.01) and severe hyponatremia (p < 0.001) than other groups.
Among A-com cases, hyponatremia occurred significantly more often in HK grade III
and IV cases (p < 0.05), in cases with vasospasm (p < 0.001), and in cases with
hydrocephalus (p < 0.01). Respective days of onset for symptomatic vasospasm and
for hyponatremia were day 7.6 +/- 4.4 and day 10.6 +/- 5.8 following SAH,
representing a 3-day delay for hyponatremia (p < 0.05). In most patients
hyponatremia resolved within 28 days following SAH. Hyponatremia occurred more
often with A-com aneurysms, possibly because of vasospasm around the A-com or
hydrocephalus causing hypothalamic dysfunction. Since hypervolemic therapy can
cause hyponatremia, particularly careful observation is required during such
therapy in patients with A-com aneurysm.
PMID- 10763502
TI - Incidence of multiple sclerosis in Dijon, France: a population-based
ascertainment.
AB - Incidence of multiple sclerosis (MS) was prospectively determined within the
population of the city of Dijon (94,000 inhabitants under 60 years old) at 47
degrees northern latitude, in Burgundy, France. All the incident cases were
diagnosed according to the criteria of Poser, associated to the study of
cerebrospinal fluid, evoked potentials and cerebral magnetic resonance imaging.
Diagnosis was assessed in all the cases by a neurologist working either in the
University Hospital (four neurologists) or in private offices (seven
neurologists). The ascertainment was performed on a full 5-year period, from 1993
to 1997. Twenty-one cases were diagnosed in the population of 94,000 inhabitants,
with an incidence of 6.1/100,000/year in women, 3.3/100,000/year in men and
4.3/100,000/year in both sexes. The sex-ratio female/male was 2.5. Our data are
similar to those of the literature, in particular in countries around the
Burgundy area. Our data allow evaluation of the burden of MS in our area and
allow evaluation of the changes of incidence in the future.
PMID- 10763503
TI - Long-term intrathecal administration of glycine prevents mechanical hyperalgesia
in a rat model of neuropathic pain.
AB - Neuropathic pain has been postulated to be mediated, in part, by amino acid
neurotransmitters including glycine. The current study examined the effects of
continuous intrathecal glycine administration (0.1 mumol 0.5 microliter-1 h-1) on
the development of mechanical hyperalgesia and other features of neuropathic pain
evoked by unilateral loose ligation of the sciatic nerve in the rat. Each hind
paw was tested for withdrawal threshold to mechanical stimuli prior to, and after
ligation at intervals of 3, 6, 9, 12 and 16 days. Pain behavior (posture and
gait) and hind paw dystrophic features (redness and swelling) were also examined.
Glycine increased the normal mechano-nociceptive responses and prevented the
development of mechano-nociceptive hyperalgesia. Spontaneous nociceptive behavior
and hind paw dystrophic features, seen in the saline treated rats, were
significantly diminished. Our results suggest that spinal cord inhibitory
glycinergic activity is important for normal mechano-receptive responsitivity and
development of mechano-nociceptive hyperalgesia in this model.
PMID- 10763504
TI - The relationship of blunt head trauma, subarachnoid hemorrhage, and rupture of
pre-existing intracranial saccular aneurysms.
AB - Patients with a history of closed head trauma and subarachnoid hemorrhage are
uncommonly diagnosed with an intracranial saccular aneurysm. This study presents
a group of patients in whom a pre-existing aneurysm was discovered during work-up
for traumatic subarachnoid hemorrhage. Without an accurate pre-trauma clinical
history, it is difficult to define the relationship between trauma and the
rupture of a pre-existing intracranial saccular aneurysm. We retrospectively
reviewed 130 patients who presented to Detroit Receiving Hospital between 1993
and 1997 with a diagnosis of subarachnoid hemorrhage (SAH). Of these 130
patients, 70 were spontaneous, and 60 had a history of trauma. Mechanisms of
trauma include motor vehicle accident, assault, or fall from a height. Of the 60
patients with subarachnoid hemorrhage and a history of trauma, 51 (86%) did not
undergo conventional four-vessel angiography, and had no further neurological
sequelae. Nine patients (14%) had a suspicious quantity of blood within the basal
cisterns or Sylvian fissure and had a four-vessel angiogram. Five patients (8%)
were diagnosed with a saccular intracranial aneurysm, and all underwent surgical
clipping of the aneurysm. We conclude that the majority of patients (92%), with
post-traumatic SAH do not harbor intracranial aneurysms. However, during initial
evaluation, a high level of suspicion must be entertained when post-traumatic
subarachnoid hemorrhage is encountered in the basal cisterns or Sylvian fissure,
as 8% of our population were diagnosed with aneurysms.
PMID- 10763506
TI - Effectiveness of spray application of ACNU in the local control of malignant
gliomas: report of two cases.
AB - Malignant gliomas encompassing the eloquent areas cannot be removed totally and
their surgical extirpation is followed by adjuvant therapy for the residual
tumor. Recently, we have employed fibrin glue as a vehicle for the sustained
release of ACNU (nimustine hydrochloride) by spray application following subtotal
tumor removal in two patients with recurrent malignant gliomas. Follow-up MRI at
six months demonstrated no neuroradiological evidence of tumor recurrence in the
site of operation. We conclude, this novel mode of intra-operative local
chemotherapy by spray application of fibrin glue containing antineoplastic agent
is effective in the control of residual tumor progression and may also prevent
local recurrence and hence suggests its possible role as an adjuvant therapy in
the management of malignant gliomas.
PMID- 10763505
TI - Action of locally administered NMDA and AMPA/kainate receptor antagonists in
spinal cord injury.
AB - NMDA or AMPA/kainate receptor antagonists have been shown to provide
neuroprotection following in vitro spinal cord injury, but the mechanisms by
which these agents improve behavioral recovery and protect axonal function
remains unclear. We hypothesized that treatment of spinal cord injury with these
drugs would attenuate glutamate excitatory transmission by blocking the effects
of glutamate receptors at the injury site or would improve spinal cord blood
flow. To test these hypotheses, we observed the effects of locally administered
MK-801 (30 nmol) or NBQX (5 or 15 nmol) into the injured spinal cord on axonal
conduction and post-traumatic ischemia of the cord. The outcome measures were
multimodality evoked potentials and blood flow in an acute compression injury
model in rats. We found that locally administered MK-801 or NBQX 15 min after
spinal cord injury attenuated the amplitude, delayed the latency of sensory
evoked potentials and increased the sensory conduction time across the injury
site, but did not improve blood flow during the 4-h period of observation. These
results demonstrate that the NMDA and non-NMDA receptor antagonists produced a
blockade of glutamate excitatory transmission in the afferent pathways at the
injury site. It is suggested that the neuroprotection provided by these agents
following spinal cord injury is mediated through blockade of glutamate ionotropic
receptors in the injured spinal cord, but is not related to improvement of SCBF.
PMID- 10763507
TI - Fibroblast growth factor-1 inhibits medial smooth muscle cells apoptosis after
balloon injury.
AB - We performed balloon injury in the rat common carotid artery and identified
apoptosis of vascular smooth muscle cells (VSMCs) by in situ terminal
deoxynucleotidyl transferase-mediated dUTP nick end-labeling, 2 h after injury.
Balloon injury induces apoptosis and loss of bcl-X protein in the innermost
layers of the media of the common carotid artery. Treatment with acidic
fibroblast growth factor (aFGF, FGF-1) attenuated by 56% the balloon angioplasty
induced apoptosis. In addition, FGF-1 treatment also induces expression of the
bcl-X anti-apoptotic protein in the same site of the media showing VSMC
apoptosis. These data suggest that the anti-apoptotic effect of FGF in injured
vascular wall was mediated by a bcl-X pathway and identified FGF as an important
factor in vascular remodeling.
PMID- 10763508
TI - Vascular endothelial growth factor and malignant transformation of a meningioma:
case report.
AB - Although meningiomas are common benign intracranial tumors which grow slowly, we
occasionally encountered aggressive or malignant ones. One of these cases showed
an interesting relationship to vascular endothelial growth factor (VEGF). A 39
year-old woman underwent resection of a sphenoid ridge meningioma; the residual
tumor showed evidence of malignant transformation 14 years later. We
immunohistochemically examined six successive surgical specimens plus the autopsy
specimen of this patient's tumor for proliferative potential, vascularity, and
expression of various growth factors. In the latter stage of clinical courses,
proliferative potential and vascularity was seen to increase year by year.
Expression of VEGF was upregulated and correlated with vascularity. On the other
hand, basic fibroblast growth factor (bFGF), platelet-derived growth factor
(PDGF), and epidermal growth factor (EGF) were not overexpressed in this tumor.
This case suggests that overexpression of VEGF and increased angiogenic potential
might be involved in malignant transformation of meningiomas.
PMID- 10763509
TI - Intra-operative measurement of cortical arterial flow volumes in posterior
circulation using Doppler sonography.
AB - Little has been reported on the flow volume of cortical arteries in the posterior
circulation. During craniotomy in 28 patients, we measured the flow velocity of
the arteries using microvascular Doppler sonography and recorded their arterial
radii and the insonation angle. The flow velocities and radii were 25.7 cm sec-1
and 0.11 cm for the posterior cerebral artery (PCA), 19.5 cm sec-1 and 0.07 cm
for the superior cerebellar artery (SCA), 19.6 cm sec-1 and 0.04 cm for the
anterior inferior cerebellar artery (AICA), 14.9 cm sec-1 and 0.05 cm for the
posterior inferior cerebellar artery (PICA), 28.3 cm sec-1 and 0.18 cm for the
basilar artery, and 18.5 cm sec-1 and 0.16 cm for the vertebral artery,
respectively. Since the flow velocities of these arteries were confined in a
narrow range compared to the cross-sectional areas, the latter was considered to
be the primary determinant for flow volume in these arteries. Based on certain
assumptions, we estimated the flow volume of the PCA, SCA, AICA and ICA to be 60,
20, 10 and 10 ml min-1, respectively, which could be regarded as the current
reference values for the arterial flow volumes.
PMID- 10763510
TI - Effects of cerebrovascular autoregulation and CO2 reactivity in experimental
localized brainstem infarction.
AB - Using the previously reported method of experimental localized brainstem infarct
in dogs, we designed this study to elucidate sequential changes of regional
cerebral blood flow (rCBF) in three separate regions of the central nervous
system: the cerebral cortex, thalamus, and midbrain. The data obtained were
referred to in subsequent investigations of cerebrovascular autoregulation and
vasomotor reactivity to CO2. Localized brainstem infarct was produced by
permanently occluding the perforators of the posterior cerebral arteries between
the bilateral origins of the posterior communicating arteries. The hydrogen
clearance method was applied to measure rCBF. Cerebrovascular autoregulation and
CO2 reactivity were assessed in three regions 1, 3, and 5 h after vascular
occlusion, respectively. Vascular occlusion resulted in a decrease of rCBF that
was 65% in the midbrain and close to 30%-40% in the thalamus. However, no
significant change was seen in the cerebral cortex even 5 h after vascular
occlusion. Induced hypertension impaired autoregulation in the thalamus, while it
was preserved in the cerebral cortex. Induced hypotension did not alter
autoregulation in any of the three regions. A marked loss of CO2 reactivity was
observed in the ischemic brainstem, although it was well preserved in the
cerebral cortex. The results suggest that noradrenergic fibers originating from
the cervical sympathetic ganglia play a main role in the cerebrovascular
autoregulation in the cerebral cortex, while noradrenergic fibers possibly
originating from the autonomic centers in the brainstem are responsible in the
thalamus; that the noradrenergic neuron probably is not involved in the
maintenance of cerebral blood flow during hypotension; and that the effect of CO2
is mediated by its direct effect on the arteriolar wall in the central nervous
system.
PMID- 10763511
TI - Role of NO in endothelium-dependent relaxation of rabbit basilar artery in situ.
AB - The purpose of this study was to investigate the possible involvement of
endothelium-derived hyperpolarizing factor in endothelium-dependent relaxation of
the cerebral vasculature by testing the effectiveness of NO synthase inhibitors
at inhibiting endothelium-dependent relaxation in the rabbit basilar artery.
Acetylcholine (1.0 microM) and 0.1/0.2 microM sarafotoxin S6c, an endothelinB
receptor agonist, relaxed serotonin constricted basilar artery in situ by 100%
and 70%, respectively. NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) and 0.3 mM NG
nitro-L-arginine (L-NNA), NO synthase inhibitors, decreased the 1.0 microM
acetylcholine- and 0.1/0.2 microM sarafotoxin S6c-induced relaxations by 75% and
45%, respectively. Unexpectedly, the relaxations were abolished by the
combination of L-NMMA plus L-NNA. Furthermore, L-arginine (1.0 mM), but not D
arginine, restored the relaxations. Sodium nitroprusside-induced relaxation was
also inhibited by L-NMMA plus L-NNA, and the inhibition was reversed by L
arginine. KCl constricted vessels only minimally relaxed in response to sodium
nitroprusside, acetylcholine, and sarafotoxin S6c. These results demonstrate that
combined NO synthase inhibitors more effectively inhibit endothelium-dependent
relaxation than a single inhibitor. The mechanism underlying the greater
inhibition due to the combined NO synthase inhibitors may result from both
decreased NO release and secondary effects caused by decreased NO release, such
as membrane depolarization. The results further suggest that caution should be
used with respect to suggestions of the involvement of endothelium-derived
hyperpolarizing factor in endothelium-dependent relaxation based upon the partial
inhibitory effects of NO synthase inhibitors.
PMID- 10763512
TI - Effect of endothelin receptor antagonists on non-muscle matrix compaction in a
cell culture vasospasm model.
AB - Endothelin-1 (ET-1), a potent vascular smooth muscle constrictor, is one of the
possible spasmogens in cerebral vasospasm. However, the role of ET-1 in non
muscle compaction (another aspect of the pathogenesis of cerebral vasospasm) has
not been reported. This study was undertaken to demonstrate the effect of ET-1,
as well as erythrocyte lysate and bloody cerebrospinal fluid (CSF), on fibroblast
populated collagen lattice (FPCL) compaction. Human dermal fibroblasts were used
to form FPCL. The concentration-dependent effect of ET-1 was examined in the
absence and presence of an ETA receptor antagonist (BQ-485), or an ETB receptor
antagonist (BQ-788), or both. FPCL compaction was determined by measuring
reduction of areas over five days following treatment. To compare the effect of
ET-1 on lattice compaction, erythrocyte lysate and bloody CSF obtained from a
cerebral vasospasm patient were also tested. We found that ET-1 increased FPCL
compaction in a concentration-dependent (but not time-dependent) manner.
Erythrocyte lysate produced the strongest compaction, however, without time
dependence. Bloody CSF promoted FPCL compaction in a time-dependent fashion.
Compaction induced by ET-1 was inhibited by BQ-485 but not by BQ-788. We
concluded that ET-1 promotes FPCL compaction by activation of ETA receptors.
Other components in bloody CSF or erythrocytes may also contribute to FPCL
compaction.
PMID- 10763513
TI - Study of cerebrospinal fluid flow dynamics in TGF-beta 1 induced chronic
hydrocephalic mice.
AB - In a previous study, we found that the CSF level of transforming growth factor
beta 1 (TGF-beta 1) is elevated following subarachnoid hemorrhage (SAH) in
patients who later develop communicating hydrocephalus, while in mice, an
intrathecal injection of TGF-beta 1 can induce communicating hydrocephalus.
Recently, histopathological changes in the leptomeninges were studied using the
above TGF-beta 1 induced mice model of hydrocephalus. In the present study, in
order to further clarify the ventricular dilatation mechanism, we examined
cerebrospinal fluid (CSF) flow dynamics in TGF-beta 1 induced hydrocephalic mice.
To assess CSF flow, Indian ink was injected into the passage pathway and the time
taken for the ink to pass from the parietal intrameningeal CSF space to cervical
lymph nodes was determined. The ink study revealed a significant lengthening of
the ink passage time due to altered CSF flow dynamics, while a histological
examination showed ink stasis in the altered leptomeningeal CSF space compared to
PBS injected control mice. TGF-beta 1 induced increased cellularity in the
leptomeninx and fibrosis, and a subsequent narrowing of the intrameningeal CSF
space. This narrowing causes a disturbance in CSF flow, thus generating a mild
pressure gradient, which ultimately leads to the development of slowly
progressive ventricular dilatation. After SAH, elevated TGF-beta 1 in the CSF may
play a similar role, in concert with other factors, in the development of
communicating hydrocephalus in human.
PMID- 10763514
TI - Temporal profile of cytochrome c and caspase-3 immunoreactivities and TUNEL
staining after permanent middle cerebral artery occlusion in rats.
AB - Although apoptotic pathways play important roles in ischemic neuronal injury,
exact mechanism of apoptotic enzyme cascade has not been fully studied.
Immunohistochemical stainings for cytochrome c and caspase-3, and histochemical
staining for a terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP-biotin
nick end-labeling method (TUNEL) were examined in a rat model of permanent middle
cerebral artery (MCA) occlusion. Cytochrome c was strongly induced in neurons of
the ischemic penumbra from 3 h after MCA occlusion, and caspase-3 began to be
induced in the same area from 3 h with a peak at 8 h. Neuronal cells in MCA area
became TUNEL positive at delayed time, reaching a peak at 24 h. Thus, the peak of
induction of cytochrome c preceded that of caspase-3, and these two peaks were
also precedence of the peak of DNA-fragmentation. Western blot analysis showed
cytosolic expression of cytochrome c from mitochondria. This study demonstrated
1. Rapid release of cytochrome c from mitochondria to the cytosol, mainly in
neurons of the cortex at 3 h after ischemia. 2. Subsequent peaks of caspase-3 and
TUNEL in this order. These temporal profiles suggest a serial cascadic activation
of apoptotic pathways in neuronal death after permanent MCA occlusion of rats.
PMID- 10763515
TI - Vasostabilizing effect of Dotarizine (Ca(2+)-channel blocker) on cerebrovascular
reactivity in rabbits.
AB - Disturbances of the cerebrovascular reactivity in cases of migraine with aura are
well-known. It has been suggested that the vasostabilizing effects of novel
prophylactic pharmaceuticals are determined by their antiserotoninergic and/or
nitric oxide releasing properties. Dotarizine, a representative of Ca2+ channel
blockers from diphenilbutilpiperazines group also reveals antiserotoninergic 5
HT2A and 5-HT2C receptor-specific properties. The vasodilatatory and
antivasoconstrictive properties of this compound were reported previously. In
this study the efficacy of Dotarizine chronic oral administration on
cerebrovascular reactivity during hyperventilation was examined with respect to
its duration of action. Experiments were carried out on 13 rabbits. There was an
interval of two days between a five days compound administration and performed
hyperventilation. Blood flow velocities (BFV) in the middle cerebral artery (MCA)
and basilar artery (BA) were measured in control conditions, after 10 min
hyperventilation and in the tenth minute of recovery of normoventilation. Our
data reveal a decrease of antivasoconstrictive properties of Dotarizine between
its administration and vasoconstrictive test. Subsequent normoventilation showed
a distinct vasostabilising effect of this compound with evident regional
differences in its influence on cerebral vessels. Thus Dotarizine might be useful
as prophylactic medication in migraine therapy, due to its Ca2+ channel blocking
and antiserotoninergic properties, but the time-frame of its efficacy has to be
defined.
PMID- 10763516
TI - 1999 C. H. McCloy Research Lecture: children's control, learning, and performance
of motor skills.
PMID- 10763517
TI - Optimizing generalized motor program and parameter learning.
AB - Two experiments examined generalized motor program (GMP) and parameter learning.
Experiment 1 examined the effects of bandwidth knowledge of results (KR) about
relative timing in constant and variable practice. The purpose was to determine
if movement stability created by the bandwidth manipulation is associated with
increased GMP learning and if bandwidth KR interacts with constant and variable
practice. Participants were asked to depress four keys sequentially, using the
same relative timing structure. Constant practice had one absolute timing
requirement, whereas variable practice had three different absolute timing
requirements. The results indicated that GMP learning was enhanced by constant
practice (independent of the bandwidth KR condition) and by bandwidth KR, when
variable practice was used. The findings suggest practice conditions (bandwidth
KR, constant practice) that increase movement stability during practice enhance
GMP learning. Parameter learning (during transfer), however, was enhanced by
variable practice. Experiment 2 attempted to determine how constant and variable
practice conditions could be combined to enhance both GMP and parameter learning.
The results indicated that developing a stable GMP early in practice--by
providing learners with constant practice early in practice--and refining
parameter learning later in practice--by providing them with variable practice
late in practice--were effective for both GMP and parameter learning. This
suggests a hierarchy in the development of programmed actions with a stable GMP
being a requisite for developing an effective and stable parameter rule.
PMID- 10763518
TI - Teaching responsibility through sport education: prospects of a coalition.
AB - The purpose of this study was to provide a database analysis of a combined sport
model and from this to develop a theory from practice. In particular, the
original concern was to examine the extent to which the teaching of personal and
social responsibility (TPSR) could form a coalition with the Sport Education
model. Forty-five 6th-grade boys, who had a previous history of struggling with
the fair play requirements of Sport Education, participated in a 26-lesson season
of Xball, an invasion game designed by those students. As a general summary, it
was found that some of the features of TPSR strengthened the foundation of Sport
Education, but due to the need to introduce new tasks and problems for students,
a hybrid model (Empowering Sport) was developed. This hybrid, with a
predominately ecological integration perspective, presents a curriculum model
that allows for achievement within a powerful triangle of goals--sport skill
competence, social responsibility, and personal empowerment.
PMID- 10763519
TI - Assessment of physical activity with the Computer Science and Applications, Inc.,
accelerometer: laboratory versus field validation.
AB - Our purpose was to compare the validity of the Computer Science and Applications,
(CSA) Inc., accelerometer in laboratory and field settings and establish CSA
count ranges for light, moderate, and vigorous physical activity. Validity was
determined in 60 adults during treadmill exercise, using oxygen consumption (VO2)
as the criterion measure, while 30 adults walked and jogged outdoors on a 400-m
track. The relationship between CSA counts and VO2 was linear (R2 = .89 SEE =
3.72 ml.kg-1.min-1), as was the relationship between velocity and counts in the
field (R2 = .89, SEE = 0.89 mi.hr-1). However, significant differences were found
(p < .05) between laboratory and field measures of CSA counts for light and
vigorous intensity. We conclude that the CSA can be used to quantify walking and
jogging outdoors on level ground; however, laboratory equations may not be
appropriate for use in field settings, particularly for light and vigorous
activity.
PMID- 10763520
TI - Effects of uncontrollability and failure on the development of learned
helplessness in perceptual-motor tasks.
AB - The aim of this study was to distinguish between the roles of uncontrollability
and failure on learned helplessness in a perceptual-motor task. Forty-eight
junior high school students were randomly assigned in a 2 x 2 (Controllability:
Contingent vs. Yoked Noncontingent Feedback x Type of Outcome: Success vs.
Failure) factorial design to complete a gun-shooting task on a moving target
using a computer screen. Twelve other participants (control group) simply read a
passage. After filling out causal attribution and self-efficacy expectations
questionnaires, all participants carried out another gun-shooting task (test
task). Results showed that contingency led to higher performances than
noncontingency. Success conditions elicited higher self-efficacy expectations
than failure conditions. Failure entailed less persistence than success did for
participants who had been assigned to the contingency condition. Internalization
of failure was negatively correlated with persistence. Comparisons with the
control group showed that expectations and performance deficits of learned
helplessness were provoked by failure in noncontingent situations; persistence
deficits were due to failure in contingent situations. These results reveal that
both uncontrollability and failure can be responsible for different forms of
learned helplessness.
PMID- 10763521
TI - Differences in self-reported rationale for perceived increases in physical
activity by ethnicity and gender.
PMID- 10763522
TI - Physical activity participation of high school graduates following exposure to
conceptual or traditional physical education.
PMID- 10763523
TI - Effects of postural constraints on children's catching behavior.
PMID- 10763524
TI - Resting frontal asymmetry predicts self-selected walking speed but not affective
responses to a short walk.
PMID- 10763525
TI - Teachers' attitudes toward teaching physical activity and fitness.
PMID- 10763526
TI - Students' precision and interobserver reliability of performance assessment in
team sports.
PMID- 10763527
TI - Developmental kinematics of young girls' overarm throwing.
PMID- 10763528
TI - [Secure Sleep--SIDS prevention campaign by children's hospitals of Vienna].
PMID- 10763529
TI - [4th Austrian SIDS Consensus-Consultation and the Viennese SIDS prevention
campaign "Secure Sleep"].
AB - Despite numerous investigations the pathophysiologic mechanisms of SIDS have not
been fully elucidated. In large epidemiologic studies highly variable SIDS
mortality rates were noted between different countries and cultures. This
presumably is due not only to differences in diagnostics and classification of
SIDS but also in lifestyle and newborn care. The common denominator is the
identification and prevention of the main risk factors: smoking, sleeping in the
prone position, over-heating, wrong "bedding". SIDS prevention campaigns that
have focussed upon these risk factors have led to a dramatic reduction in the
incidence of SIDS. In preparation for the SIDS prevention campaign of Vienna
("Safe Sleep") the content, strategy and procedure of the Austrian prevention
campaigns were analysed. The current focus is to convey a clear and uniform
message in personal conversations before and after birth of the child. These
conversations with parents are the most important tool to detect SIDS related
anxiety and a possibly increased risk of SIDS. In the last 30 years various
polysomnographic parameters were published that were associated with an increased
risk of SIDS. Today there is international consent that polysomnography is not an
efficient screening method to demonstrate increased risk of SIDS. Therefore the
use of polysomnography, besides research purposes, has been limited to
investigating clinical symptoms of infants and children. Concerning monitoring it
is important to note that--in contrast to the undisputed importance of monitoring
breathing disorders--the effectiveness in SIDS prevention is unproven. State of
the art are instruments that monitor heart and breathing rate and have adequate
storage functions. The duration of monitoring should encompass the symptomatic
period as well as a safety period of three months. The monitor should not be
routinely prescribed for a year. The guiding principle is "As short as possible
with stringent indication". Prerequisite for the monitoring is good instruction
of the parents and a continuous consultation by competent outpatient clinics.
PMID- 10763530
TI - [Child's sudden death in 20th century--hypothesis, dogmas, dead wood].
AB - With the decline of the former main causes of death in early childhood-
infections and starvation--sudden infant death syndrome (SIDS) has emerged as the
most important single cause of postneonatal infant mortality. It has adopted the
role of a major indicator for the standard of public health care. Despite
extensive input into research, its pathophysiology has remained rather obscure.
The resulting helplessness of scientists and health care professionals have lead
to adherence to unconfirmed pathophysiological hypotheses and to pursuit of
preventive strategies of doubtful efficacy. In this overview, the medical and
technical background of five major hypotheses is being presented. A lot can be
learnt from the history of their development, efforts to refute them, and the
reasons for unreflected adherence to them. (1) Due to its illustrative nature,
the so-called 'status thymico-lymphaticus', the theory of asphixation by an
enlarged thymus, could not be eradicated although well-reknowned physicians-
including the Austrian pathologist Paltauf--have repeatedly attempted to do so.
(2) Assumed familiarity, an aspect which attracted the attention of pediatricians
to SIDS initially has been excluded, but an increased risk of SIDS for the
siblings of affected babies is still common belief. (3) The sleep-apnea
hypothesis has turned out a complete error with serious consequences, but home
apnea monitors are still being widely recommended. (4) The rise of SIDS in the
80ies and its subsequent decline in the 90ies has been interpreted as the advent
and successful control of an epidemic although significant numbers of cot death
have been reported long before the turn of the century, and the apparent increase
which paralleled the introduction of the 9th edition of the ICD code is most
likely due to improved registration. (5) Finally, SIDS is still being considered
a random event--ignoring all evidence of an obvious role of socioeconomical
factors.
PMID- 10763531
TI - [Home monitoring of infants at risk of sudden infant death: suggestions for
reconsideration of current practice].
AB - Considering the decreasing incidence of sudden infant death syndrome (SIDS) and
the yet unproven efficacy of home monitoring, current indications for home
monitoring should be reconsidered. Documented monitoring still appears to be
necessary in infants with apparent life-threatening events (ALTE) and in siblings
of two or more SIDS victims. Home monitoring is also indicated in infants on home
oxygen/ventilation or with specific respiratory control disorders, but is usually
not indicated in asymptomatic preterm infants or in those with a single SIDS
sibling, a mother indulging in drug abuse, or increased parental anxiety. The
risk of SIDS in these groups is lower than that in infants of mothers who are
heavy smokers, who are nowhere regarded as candidates for home monitoring. If
monitoring is considered necessary, new generation pulse oximeters with low false
alarm rates are probably the safest technical option because they sound the alarm
comparatively early, yet do not give too many false alarms. Home monitor
recommendations should be revisited, taking the above issues into account.
PMID- 10763532
TI - [SIDS and polygraphy].
AB - The description of an association between central apneas and the sudden infant
death syndrome (SIDS) by Steinschneider et al. in 1972 was followed by a sharp
rise of polygraphic studies. The hope to use these as a screening method for an
increased risk of SIDS could subsequently not be confirmed by prospective
studies. Pathological alterations, such as obstructive apneas and hypoxemias,
however, seem to have prognostical relevance. They thus represent a focus of
current research even though being unable as well to reliably predict a
predisposition to SIDS for an individual subject. Instead of being used as a
diagnostic tool for SIDS, polygraphic studies have nowadays acquired an accepted
role in the investigation of certain physical symptoms and signs such as
unexplained 'apparent life threatening events' (ALTE) or cyanotic attacks. Basic
technical requirements for a polygraphic laboratory include facilities to record
thoracic/abdominal respiration, nasal air flow, ECG/heart rate, oxygen
saturation, and to classify different stages of sleep. Registration of additional
parameters (EEG, breath sounds, video etc.) is optional, but may prove helpful to
arrive at an appropriate diagnosis. Recently, Austrian and German centres have
been trying in cooperation to standardize performance conditions and evaluation
criteria for polygraphic measurements in pediatric patients under the guidance of
the German Association for Sleep Medicine, Pediatric Workgroup. Their aim is to
establish common guidelines for the diagnosis and treatment of sleep and arousal
disorders in infancy and childhood.
PMID- 10763533
TI - [SIDS prevention program in Tyrol].
AB - In April 1994, an intervention campaign to reduce the incidence of sudden infant
death syndrome (SIDS) was established in the Tyrol. The campaign was intended to
increase knowledge concerning risk factors for SIDS in the general community and
to improve individual care for infants at risk. In contrast to interventional
programmes in other federal states of Austria (i.e. Vorarlberg, Styria), this
programme did not utilise polysomnography for identifying infants at risk. A part
of the intervention programme was the "Styrian risk questionnaire", a
standardised questionnaire concerning risk factors for SIDS. Individual
instructions for health care of children at risk (risk score > or = 7) were
provided and, if necessary, subscription of home monitoring was performed at the
out-patient department (SIDS out-patient service) of the Department of
Paediatrics in Innsbruck and other paediatric departments throughout the Tyrol.
The educational programme also included information concerning basic life
support. Psychological support was offered to parents of SIDS infants. Risk
factors for SIDS in the Tyrol before the campaign were assessed in a
retrospective case-control study (time period 1984-1994; 99 SIDS infants, 136
controls). The risk of SIDS was markedly reduced when parents had detailed
knowledge of the risk factors of SIDS (odds ratio (OR) 0.03; p < 0.001), which
emphasises the importance of information and educational programmes. The
incidence of SIDS declined after the beginning of the intervention campaign from
1.83/1000 live births (average incidence from 1984-1994) to 0.4/1000 live births
and remained at this level thereafter. Post-neonatal mortality also declined from
3.9 to 1.3/1000 live births. The prevalence of the prone sleeping position
declined immediately after the campaign (53.7% vs. 5.4%, p < 0.001), as did the
frequency of maternal smoking during pregnancy (22.9% vs. 14.5%, p < 0.01).
Breast feeding became more popular. In all, the low-cost intervention programme
in the Tyrol proved to be highly efficient in reducing the risk of SIDS and in
maintaining this effect for several years.
PMID- 10763534
TI - SIDS related anxiety--a risk factor analysis.
AB - BACKGROUND: The growing public interest in the Sudden Infant Death Syndrome
(SIDS) has led to a new psychological problem--SIDS related anxiety (SRA).
General public awareness, unfavourable experience in the past, present problems
with the infant or insufficient support from the family may lead or contribute to
SRA. OBJECTIVE: The study was conducted to explore which of these factors
contribute most to the development of SRA. PATIENTS AND METHODS: Families
visiting our outpatient clinic during 18 months were interviewed by means of a
structured questionnaire. We assessed demographic data, obstetric history,
experience of child loss, pregnancy and delivery complications, infant morbidity,
family-child interaction, family support and the relation of each of these single
factors to SRA. RESULTS: Of 169 families, 58% (98/169) admitted to suffer from
SRA and 21% (32/156) from severe SRA. We found a strong and significant
relationship between previous experience of child loss and SRA (OR: 2.95, 95% CI:
1.43-6.09, P < 0.005) and between pregnancy complications and SRA (OR: 2.19, 95%
CI: 1.18-4.08, P < 0.05). There were no significant relationships between SRA and
either delivery complications, child morbidity, impaired family-child interaction
or insufficient support from the family. CONCLUSIONS: SRA occurs in an
unexpectedly large proportion of families visiting a SIDS counseling clinic. SRA
must be taken seriously, and psychological or psychotherapeutic help should be
offered. Prevention of SRA should include psychological care for families who
experience loss of children or high-risk pregnancies.
PMID- 10763535
TI - [Viennese SIDS prevention campaign-- a quality management project].
AB - At the 4th Austrian SIDS Consensus Meeting (1998), consultation was the focus of
attention. Secure sleep, the Vienna SIDS prevention campaign, is an information
campaign in cooperation with the children's hospitals of Vienna with the aim of
reducing the incidence of SIDS in and around Vienna. The campaign was intended to
spread awareness concerning care measures to reduce SIDS as well as to reduce
SIDS related anxiety (SRA) among anxious parents. The Vienna SIDS prevention
campaign is a quality management project, the core of which is consultation.
Demands upon the structural quality of a SIDS consultation office include the
expertise, communication skills and psychological competence of the consulting
team. This can be achieved through interdisciplinary continuing education,
international networking and training in communication skills. Priority is given
to supporting care for the client by an interdisciplinary team headed by a case
manager with the required communication skills. The qualitative outcome is
defined by a primary objective medical goal (reduction of SIDS mortality) and a
secondary subjective psychological goal (reduction of SRA). It also includes
raising effectiveness and efficiency through optimal consultation and, finally,
reducing costs by saving expenditure for monitors. The quality of SIDS
consultation can be measured by evaluating satisfaction in patients as well as
among co-workers.
PMID- 10763536
TI - [Evaluation of the cardiorespiratory monitor SpiroGuard C for infants. Improved
registration of respiratory events by new sensors and intelligent alarm
management system].
AB - OBJECTIVES: The SpiroGuard C is a commercially available cardiorespiratory
monitor working with field plethysmography, wireless signal transmission and a
novel alarm management system. In order to determine the recognition rates for
central, mixed and obstructive apneas, a prospective clinical trial was performed
comparing frequency and kind of signals from the monitor with those
simultaneously registered by polysomnographic studies. DESIGN: Normal respiratory
and alarm signals of the monitor under investigation were integrated into a
polysomnographic setting. All central, mixed and obstructive apneas lasting more
than 10 seconds as well as all alarms obtained from the monitor were evaluated.
RESULTS: 47 series of monitor recordings could be evaluated in parallel to
polysomnographic studies: the detection rate for central apneas was 298/328
(90.85%), for mixed apneas 9/41 (21.95%) and for obstructive apneas 0/36 (0%).
Out of the total of 708 registered alarms 359 (50.71%) were false alarms, 307
(43.36%) were apnea-related and 42/708 (5.93%) were alarms due to technical
problems. 177 of the 359 false alarms (49.30%) occurred during apneas that were
shorter than 10 seconds, 119 (33.15%) were related to bad signal quality, and 55
(15.32%) were caused by movement artifacts. CONCLUSION: The recognition rate for
central apneas was high (> 90%), while sensitivity for mixed and obstructive
apneas was not satisfactory. Approximately half of the alarms were false alarms.
These could be reduced by setting the apnea detection time to > 15 seconds, by
tighter fastening of the respiration belt (improving the signal transmission),
and by turning off the instrument when the child is awake and physically active.
The wireless system renders the SpiroGuard C an attractive alternative for home
monitoring.
PMID- 10763537
TI - [Heart rate variability--physiology, methods of registration and application in
pediatric sleep laboratory].
AB - Heart rate variability (HRV) has become the focus of interest of a multitude of
investigations being a parameter that can easily be recorded. Accepted clinical
indications in adults include evaluation of diabetic neuropathy and prediction of
prognosis after myocardial infarction in adults. In children, HRV is regularly
being registered in the pediatric sleep laboratory in sleep related breathing
disorders, after apparent life threatening events, or in infants with assumed
increased risk for sudden infant death syndrome. However, uniform interpretation
criteria have not been established in these situations, at least partially due to
insufficient understanding of physiology and pathophysiology of HRV in this age
group. In this overview, current knowledge on HRV in infants and children is
summarized and its clinical relevance discussed. In addition, technical
requirements and methods of analysis which have a major impact on calculated
parameters are being presented.
PMID- 10763538
TI - HIV in prison; HIV and killer T cells.
PMID- 10763539
TI - HIV in China: an opportunity to halt an emerging epidemic.
PMID- 10763540
TI - HIV risk and healthcare attitudes among detained adolescents in rural Alabama.
AB - This qualitative study explored the dynamics of adolescent HIV risk through focus
group interviews of male and female adolescents at an Alabama juvenile detention
facility, key informant interviews, and through interviews of HIV-positive and
negative adults in institutional settings and public health clinics in Alabama.
The interviews revealed that commodified or unprotected sex with multiple
partners was a common risk activity for male and female adolescents, with a
related high risk of sexually transmitted disease. The adolescents were aversive
to condom use and lacked knowledge of the dynamics of HIV transmission.
Bisexually behaving males who engaged in same-sex prostitution for money or drugs
viewed female partners as the source of HIV infection. Illicit drug activity and
risky sexual behavior were highly related to economic and status anxiety.
Experiences of healthcare were often coercive or were undermined by negative
perceptions of health professionals. These negative perceptions and avoidance or
lack of access to healthcare compounded the already high risk of sexually
transmitted disease for this group of adolescents.
PMID- 10763541
TI - Antenatal screening for HIV infection.
PMID- 10763542
TI - Impact of antivirals and emergence of drug resistance: HSV-2 epidemic control.
AB - Genital herpes, caused by herpes simplex virus type-2 (HSV-2), affects more
people world-wide than any other sexually transmitted disease (STD). Antivirals
are effective in decreasing the duration of symptoms and in reducing viral
shedding; however, currently antiviral usage is extremely low. Increased usage of
antivirals would have a beneficial epidemic-level effect (due to the decreased
transmission of drug-sensitive strains) as well as potentially a detrimental
epidemic-level effect (if drug-resistant strains emerge and are transmitted).
Previously, we have developed a mathematical model that we have used to predict
(with a degree of uncertainty) the beneficial and the potential detrimental
epidemic-level effects of increased antiviral usage. Here, we use our model to
make further predictions about the impact of increasing antiviral usage. We
calculate the effect, on individual patients, of antiviral usage in terms of: (1)
the decrease in the average number of infectious days per year and (2) an
individual's lifetime probability of acquiring permanent drug resistance. We also
use our model: (1) to determine the probability of eliminating herpes by
antivirals and (2) to quantify the effect of increasing antiviral usage on
decreasing HSV-2 prevalence. Our results show that theoretically it would be
possible to eliminate herpes epidemics by using a drug that does not cure.
PMID- 10763543
TI - Cystic lymphoepithelial lesions of the parotid gland in HIV-1 infection.
AB - The benign cystic lymphoepithelial lesion (BLL) of the parotid gland is a rare
disorder affecting HIV-1-infected patients. Here we describe the clinical and
histopathological features of 10 cases of BLL, who presented to our observation
between November 1992 and December 1996, before the combination antiretroviral
therapy was introduced.
PMID- 10763544
TI - Disseminated histoplasmosis and AIDS: clinical aspects and diagnostic methods for
early detection.
AB - Disseminated histoplasmosis in AIDS patients is the focus of this paper.
Cutaneous lesions are reported as a frequent clinical sign. Bone marrow
aspiration and biopsy, blood cultures (lysis-centrifugation technique),
bronchoalveolar lavage, and skin lesion scrapings are the most effective
diagnostic methods. The identification of a specific antigen in blood and urine
may be a rapid means of evaluation and follow-up of patients with this disease.
PMID- 10763545
TI - Barriers to and facilitators of HIV-positive patients' adherence to
antiretroviral treatment regimens.
AB - HIV-positive patients must strictly adhere to antiretroviral regimens for the
medications to work properly. Little, however, is known about the obstacles that
patients face in adhering to the regimens or what, if anything, helps patients to
adhere. The goals of the project were to describe, from HIV-positive patients'
own perspectives, the barriers they face in adhering to antiretroviral regimens
and the strategies they use to maximize their adherence. Five main barriers
(forgetfulness, social/physical environment, complexity of the regimens,
medication side effects, and inadequate patient knowledge) to adherence and six
main facilitators (mechanical devices, "making a commitment," "routinizing,"
health beliefs, social support, and professional support) emerged from the data.
Patients may overcome some of these barriers by receiving better health education
about the need for adherence, professional and lay support for their efforts, and
mechanical devices such as alarm clocks and medi-sets. Other barriers, however,
such as the complexity of the medications, highlight the need for simplified
antiretroviral regimens.
PMID- 10763546
TI - New combination studied.
PMID- 10763547
TI - OIs despite HAART.
PMID- 10763548
TI - AMA advocates condoms.
PMID- 10763549
TI - [Ultrasonographic measurement of the sole horn thickness in bovine claw].
AB - Ultrasonographic thickness measurement and imaging of sole horn and the
encapsulated soft tissue layers was evaluated in 100 bovine claw specimens. The
claws were trimmed and examined in longitudinal planes using a 7.5 MHz linear
transducer. In each claw, ultrasonographic measurements of horn thickness of sole
and distance from outer claw surface to distal phalanx surface were made at three
marked points on the weightbearing surface. All claws were then frozen,
transected and anatomical reference measurements were made after thawing. The
sole horn, corium, subcutis and distal surface of the distal phalanx of all claws
were clearly visualized. The sole horn had a heterogeneous hypoechoic appearance,
the underlying soft tissue layer was predominantly anechoic. Corium and subcutis
could be differentiated. Best imaging of these structures was achieved in claws
with less than 10 mm sole horn thickness and soft sole horn. Statistical
correlation coefficients of 0.88 to 0.91 were found for ultrasonographic and
anatomical measurements of sole horn thickness. Therefore, B-mode ultrasonography
proved to be an accurate, non-invasive technique for measurement of the sole horn
thickness in bovine claws.
PMID- 10763550
TI - [Investigations of the effect of artificial and natural light on the development
of sex organs and fertility of female rabbits].
AB - 234 female fattening rabbits with slaughtering on day 84 of age (6 rounds) and 62
does (11 rounds) kept under three light regimes: a) natural light (NL) with an
intensity of 27 Lux on average, b) artificial light (AL 8) with 8 hours light a
day and c) artificial light (AL 16) with 16 hours light a day (both AL with a
mean light intensity of 60 Lux) were included in investigations. Weight of
ovaries and uteri was measured and percentage of females with follicular
development (follicles with diameter of > 1 mm, Corpora lutea, Corpora
hemorrhagica) was verified after slaughter in fattening rabbits. Data of
fertility (rate of conception, litter size and litter weight at birth and at
weaning) were recorded in does to calculate on this basis pup index. Weight of
ovaries was not influenced by light regime. Female rabbits kept under AL 8 had
significantly lowest mean weight of uterus and lowest percentage of animals with
follicular development (39.7% compared with 53.1% in AL 16 and 56.3% in NL).
Against this, highest rate of conception (69.3%) and highest pup index alive born
and weaned pups (593, 547 pups per 100 inseminated does resp.) were found in does
kept under AL 8. Corresponding values were 65.9% rate of conception, 565 alive
born and 539 weaned pups/100 does in AL 16 and 65.7%, 524, 505 pups resp. in NL.
PMID- 10763551
TI - The lack of binding ability of staphylococcal protein A and streptococcal protein
G to egg yolk immunoglobulins of different fowl species (short communication).
AB - The binding ability of staphylococcal protein A (SpA) and streptococcal protein G
(SpG) to egg yolk antibodies of four fowl species (turkey, duck, moskovy duck and
goose) was studied and compared with the binding ability to three serum
antibodies from chicken, horse and cattle. SpA and SpG were not able to bind to
any of the avian immunoglobulins.
PMID- 10763552
TI - [Electrophysiologic changes in rumen epithelium in their effect on magnesium
transport--a review].
AB - The forestomach is the main site of Mg2+ absorption in the gastrointestinal tract
of ruminants and maintains Mg2+ homeostasis. It has long been known that an
increase in K+ intake and, consequently, in ruminal K+ concentration ([K+])
decreases the apparent digestibility of Mg2+, which increases the risk of
hypomagnesemia and tetany. The present review summarizes new findings on the
mechanisms of Mg2+ absorption across the rumen epithelium. It has been shown that
transcellular and active Mg2+ transport is the predominant pathway for Mg2+
transport from lumen to blood. It is well established that the apical uptake of
Mg2+ is mediated by a PD-independent of K(+)-insensitive and by a parallel
working PD-dependent, K+ sensitive mechanisms. The predominant driving force for
the electro-diffusive Mg2+ uptake is PDa, the potential difference across the
apical membrane of the rumen epithelium, that amounts to -50 mV under
physiological conditions, permitting an effective Mg2+ absorption even at very
low luminal Mg2+ concentrations. The antagonism between K+ and Mg2+ absorption
can be explained by K+ dependent electrophysiological changes of the rumen
epithelium. An elevation of the ruminal [K+] has two different effects that are
responsible for the observed reduction of net Mg2+ absorption; (1) It depolarizes
PDa and thereby reduces the driving force for the electro-diffusive Mg2+ uptake
into the ruminal epithelial cells, hence decreases the cytosolic [Mg2+] and the
transcellular component of Mg2+ absorption; (2) It increases the transepithelial
potential difference (PDt; blood-side positive) and, hence causes a small,
passive backflow of Mg2+ via the paracellular route from the blood side into the
lumen. The second, PD-independent uptake mechanism is primarily working at high
ruminal [Mg2+]. Therefore the negative effect of K+ can be compensated by this K+
insensitive Mg2+ absorption, if high [Mg2+] are present in the ruminal fluid.
PMID- 10763553
TI - [Phamacokinetics of low-molecular-weight heparins Fragmin D in dogs].
AB - The pharmacokinetics of a low molecular weight heparin (LMWH; Fragmin D) was
studied in dogs after intravenous and subcutaneous administration, based on
antifactor Xa- (anti-fXa-) activity. Each dosage was examined in 5 adult Beagles.
After intravenous application of 25, 50 and 100 anti-fXaU./kg body weight (BW)
the mean peak plasma heparin activity of 0.52 +/- 0.12 (x +/- s), 1.08 +/- 0.23
and 1.86 +/- 0.17 anti-fXaU./ml, respectively, was measured. After subcutaneous
application of 50, 100 and 200 anti-fXaU./kg BW maximum heparin activity in the
plasma was determined after 144-216 minutes (mean values) of 0.28 +/- 0.01, 0.52
+/- 0.06 or 1.09 +/- 0.20 anti-fXaU./ml. Intravenous application of LMWH has a
short plasma terminal half-life (t50) between 49 and 76 minutes which depended on
the dosage. After administration of 50 anti-fXaU./kg BW (74 minutes) and 100 anti
fXaU./kg BW (76 minutes) no essential difference was shown. A distinctly longer
t50 was found after subcutaneous injection. After injection of 50, 100 and 200
anti-fXaU./kg BW t50 values of 81, 123 and 182 minutes were calculated. According
to this, with increasing dosage a decrease of the total clearance was found for
both application routes. The apparent volume of distribution after intravenously
applicated LMWH ranged between 50 and 70 ml/kg BW. The absolute bioavailability
calculated for the subcutaneous NMH-injection of 50 and 100 anti-fXaU./kg BW was
107% and 104%, respectively.
PMID- 10763554
TI - [Pyrogallol concentrations in rumen content, liver and kidney of cows at
pasture].
AB - Pyrogallol (1, 2, 3-trihydroxybenzene), the decomposition product of hydrolysable
tannins in oak bark, leaves and acorns, is suspected to be poisonous to animals.
The aim of our investigations was to correlate clinical signs and pathological
findings with pyrogallol concentrations in organs of poisoned and healthy
animals. In a field study, pyrogallol concentrations were determined in liver,
kidney, and rumen from seven cattle. In a herd of twelve cows, five animals
suffered from hemorrhagic diarrhea, anorexia, weakness, rumen stasis, dyspnoea,
and colic symptoms. Death was observed in five cows within five weeks after
repeated intake of green acorns and oak leaves. Toxicological analyses of rumen
content, liver, and kidney specimens of one cattle confirmed the suspicion of
pyrogallol contamination. In this animal, values ranged from 6 to 13 ng
pyrogallol per gram specimen. In control cattle, concentrations were clearly
lower than in perished cattle. Under antioxidative work-up conditions, detection
limit was 0.6 ng/g in rumen content and 1.0 ng/g in liver and kidney,
respectively.
PMID- 10763555
TI - Human health risk from exposure to natural dog treats.
PMID- 10763556
TI - First isolation of Lyme disease spirochete, Borrelia burgdorferi from blacklegged
tick, Ixodes scapularis, collected at Rondeau Provincial Park, Ontario.
PMID- 10763557
TI - Respiratory virus surveillance FluWatch Project.
PMID- 10763558
TI - Confidence bands for comparison of transition probabilities in a Markov chain
model.
AB - We consider graphs, confidence procedures and tests that can be used to compare
transition probabilities in a Markov chain model with intensities specified by a
Cox proportional hazard model. Under assumptions of this model, the regression
coefficients provide information about the relative risks of covariates in one
step transitions, however, they cannot in general be used to to assess whether or
not the covariates have a beneficial or detrimental effect on the endpoint
events. To alleviate this problem, we consider graphical tests based on
confidence procedures for a generalized Q-Q plot and for the difference between
transition probabilities. The procedures are illustrated using data of the
International Bone Marrow Transplant Registry.
PMID- 10763559
TI - Properties of added variable plots in Cox's regression model.
AB - The added variable plot is useful for examining the effect of a covariate in
regression models. The plot provides information regarding the inclusion of a
covariate, and is useful in identifying influential observations on the parameter
estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards
model derived by regarding the Cox model as a generalized linear model. This
paper proves and discusses properties of this plot. These properties make the
plot a valuable tool in model evaluation. Quantities considered include parameter
estimates, residuals, leverage, case influence measures and correspondence to
previously proposed residuals and diagnostics.
PMID- 10763560
TI - Exposure stratified case-cohort designs.
AB - A variant of the case-cohort design is proposed for the situation in which a
correlate of the exposure (or prognostic factor) of interest is available for all
cohort members, and exposure information is to be collected for a case-cohort
sample. The cohort is stratified according to the correlate, and the subcohort is
selected by stratified random sampling. A number of possible methods for the
analysis of such exposure stratified case-cohort samples are presented, some of
their statistical properties developed, and approximate relative efficiency and
optimal allocation to the strata discussed. The methods are compared to each
other, and to randomly sampled case-cohort studies, in a limited computer
simulation study. We found that all of the proposed analysis methods performed
well and were more efficient than a randomly sampled case-cohort study.
PMID- 10763561
TI - Fisher information for two gamma frailty bivariate Weibull models.
AB - The asymptotic properties of frailty models for multivariate survival data are
not well understood. To study this aspect, the Fisher information is derived in
the standard bivariate gamma frailty model, where the survival distribution is of
Weibull form conditional on the frailty. For comparison, the Fisher information
is also derived in the bivariate gamma frailty model, where the marginal
distribution is of Weibull form.
PMID- 10763562
TI - Estimation of the average survival function using a censored data regression
model.
AB - In the presence of covariates information, assuming the linear relationship
between a transformation of survival time and covariates, we propose a new
estimator of survival function and show its consistency. In addition, a
comparison of the proposed estimator with the product-limit estimator introduced
by Kaplan and Meier (1958) is performed through Monte Carlo simulation studies.
We illustrate the proposed estimator with the updated Stanford heart transplant
data.
PMID- 10763563
TI - Comparing sub-survival functions in a competing risks model.
AB - In the competing risks literature, one usually compares whether two risks are
equal or whether one is "more serious." In this paper, we propose tests for the
equality of two competing risks against an ordered alternative specified by their
sub-survival functions. These tests are naturally developed as extensions of
those based on hazard rates and cumulative incidence functions. We note that the
interpretation of the new test results is more direct compared to the situation
when the hypotheses are framed in terms of their cumulative incidence functions.
The proposed tests are of the Kolmogrov-Smirnov type, based on maximum
differences between sub-survival functions. Our simulation studies indicate that
they are excellent competitors of the existing tests, that are based mainly on
differences between cumulative incidence functions. A numerical example will
demonstrate the advantages of the proposed tests.
PMID- 10763564
TI - Independence and interdependence in diverse cultural contexts.
PMID- 10763565
TI - Individualism and the "western mind" reconsidered: American and Dutch parents'
ethnotheories of the child.
PMID- 10763566
TI - Homogeneity and heterogeneity in cultural belief systems.
PMID- 10763567
TI - Conceptualizing interpersonal relationships in the cultural contexts of
individualism and collectivism.
PMID- 10763568
TI - Uniformity and diversity in everyday views of the child.
PMID- 10763569
TI - Cross-cultural conflict and harmony in the social construction of the child.
PMID- 10763570
TI - National Public Health Week.
PMID- 10763571
TI - Medicare works.
PMID- 10763572
TI - Bruce C. Vladeck, PhD. Interview by Leah Z. Ziskin and Paul J. Hirsch.
PMID- 10763573
TI - Managing pain: a doctor-patient challenge.
PMID- 10763574
TI - Physicians speak out on Physicians Conference 2000
PMID- 10763575
TI - Collaboration efforts among physicians and office staff: a Physicians Conference
2000 goal
PMID- 10763576
TI - New Jersey State Board of Medical Examiners Conference on Physician Education.
PMID- 10763577
TI - HIV disease surveillance: medicine and public health working together.
AB - Public health surveillance is critical to the management of the HIV epidemic.
Surveillance helps to define changing trends, formulate and strategically
implement preventive initiatives, and evaluate the effectiveness of
interventions. Collaboration between clinical medicine and public health is
essential to reliable surveillance.
PMID- 10763578
TI - Treatment of chronic pain syndrome.
AB - We address the psychological and pharmacological treatment of chronic pain
syndrome. The commonly used pain management protocols in each area are described.
Psychological management procedures that are covered include relaxation methods,
patient education, cognitive therapy techniques, and patient compliance
enhancement. Concerning pharmacological management, the World Health Organization
ladder analgesic guidelines are described, as well as adjunct medications, such
as antidepressants, anxiolytics, and hypnotics.
PMID- 10763579
TI - In vitro screening of plant extracts and phytopharmaceuticals: novel approaches
for the elucidation of active compounds and their mechanisms.
AB - The advantages of cell culture systems for the screening of active compounds of
plant extracts and phytopharmaceuticals are discussed and exemplified for
hepatocytes and nerve cells. Recent developments and new experimental techniques
allow easy access even to complex specific functions of these cells and render it
possible to draw conclusions about molecular mechanisms. These in vitro
approaches, therefore, may contribute essentially to the reduction of animal use
in such studies. Furthermore, they may give full insight into not only the
therapeutic potential but also the possible dangers of phytopharmaceuticals and
may eventually lead to hints on new therapeutic fields that can be further
explored.
PMID- 10763580
TI - Glutathione adducts of helenalin and 11 alpha,13-dihydrohelenalin acetate inhibit
glutathione S-transferase from horse liver.
AB - The 2-mono- and 2,13-bis-glutathionyl adducts of helenalin and the 2
monoglutathionyl adduct of 11 alpha,13-dihydrohelenalin acetate were previously
shown to be formed by spontaneous Michael addition at physiological pH. In living
cells, glutathione (GSH) conjugation of many types of electrophilic agents is
catalysed by a family of GSH S-transferase enzymes (GST). The capability of a
glutathione S-transferase from horse liver to catalyze the reaction of helenalin
and other helenanolides with GSH was investigated. The enzyme did not accelerate
GSH conjugation of helenalin, 11 alpha,13-dihydrohelenalin, or 2-deacetyl-6
deoxychamissonolide. The GSH-adducts, formed by spontaneous reaction, were found
to be inhibitors of this enzyme. Free helenalin, a potent inhibitor of many
enzymes containing free sulfhydryl groups, did not show any inhibitory activity
on GST. It was thus demonstrated that GSH-adducts of sesquiterpene lactones
possess their own specific biological activity. Two further enzymes using GSH as
substrate, glutathione reductase and glyoxalase I, were not influenced by free
helenalin or its GSH-adducts.
PMID- 10763581
TI - Concentration-dependent potentiating and inhibitory effects of Boswellia extracts
on 5-lipoxygenase product formation in stimulated PMNL.
AB - Preparations from the gum of Boswellia spec. have been used in the traditional
medicine for the treatment of inflammatory diseases. Extracts from B. serrata gum
were shown to inhibit leukotriene biosynthesis by impairing the 5-lipoxygenase (5
LO) activity. In order to identify the minimal effective concentrations of
extracts in vitro we studied the effects of ethanolic extracts from commercially
available resins from two regions (B. serrata gum from India and Olibanum in
granis from Arabia) on the 5-LO product formation from endogenous substrate in
calcium and ionophore stimulated neutrophils in a defined concentration range.
Both extracts inhibited 5-LO product formation in vitro in concentrations greater
than 10 to 15 micrograms/ml as reported previously for an ethanolic B. serrata
extract. In contrast, lower concentrations of extracts (1 to 10 micrograms/ml)
even potentiated 5-LO product formation, especially the biosynthesis of 5(S)
HETE. The in vitro data underline the major importance of drug standardization
when Boswellia resin containing preparations are used for the treatment of
diseases.
PMID- 10763582
TI - Screening of anti-hypoxia/reoxygenation agents by an in vitro model. Part 1:
Natural inhibitors for protein tyrosine kinase activated by hypoxia/reoxygenation
in cultured human umbilical vein endothelial cells.
AB - Protein tyrosine kinase (PTK) signaling pathways play important roles in
ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injuries. Inhibition of
PTK activation can protect against I/R- or H/R-induced damages. As one part of
our work for seeking bioactive compounds from natural sources against I/R or H/R,
in the present study we examined the effects of 54 compounds purified from
various traditional Chinese herbs on H/R-induced PTK activation by means of an in
vitro H/R model in cultured human umbilical vein endothelial cells (HUVEC). The
results demonstrated that an increase in PTK activation was induced after 2 h of
reoxygenation. Compounds 2 (macrostemososide A), 3 (laxogenin-3-O-beta-D
xylopyranosyl-(1-->4)-alpha-L-arabinopyra nosyl- (1-->6)-beta-D-glucopyranoside),
4 (chinenoside II), 7 (ginsenoside-Rd), 52 (icariin), 53 (icariside), and 54
(icaritin) showed relatively obvious inhibition on this H/R-induced PTK
activation. Compounds 5 (beta-sitosterol) and 6 (daucosterine), especially 5,
completely blocked such an increased activation of PTK induced by H/R. On the
contrary, compound 29 (isocumarine) significantly promoted PTK activation
further. Moreover, the effects of these compounds on PTK activation were dose
dependent.
PMID- 10763583
TI - Screening of anti-hypoxia/reoxygenation agents by an in vitro method. Part 2:
Inhibition of tyrosine kinase activation prevented hypoxia/reoxygenation-induced
injury in endothelial gap junctional intercellular communication.
AB - In this study, we demonstrated that hypoxia/reoxygenation (H/R) induced an injury
in gap junctional intercellular communication (GJIC) after 2 h of reoxygenation
in cultured HUVEC. Free radical scavenger (DMSO) and antioxidant (SOD) did not
prevent this GJIC injury at all. Protein kinase C inhibitor (calphostin C) partly
blocked this injury. However, the protein tyrosine kinase (PTK) inhibitor
genistein completely inhibited this GJIC injury. Compounds 1 [laxogenin-3-O-alpha
L-arabinosyl-(1-->6)- beta-D-glucopyranoside], 2 (macrostemososide A), 3
[laxogenin-3-O-beta-D-xylopyranosyl-(1-->4)-alpha- L-arabinopyranosyl-(1-->6)
beta-D-glucopyranoside], 4 (chinenoside II), 5 (beta-sitosterol), 6
(daucosterine), 7 (ginsenoside-Rd), 29 (isocumarine), 52 (icariin), 53
(icariside), and 54 (icaritin), which showed obvious influence on H/R-induced PTK
activation as stated in Part 1 (except 1), were explored for their effects on
GJIC. The results showed that compounds 2-7 and 52-57 partly protected H/R
induced GJIC injury. Compounds 5 and 6 (especially 5), which showed the strongest
inhibitory effects on PTK activation, completely blocked H/R-provoked GJIC
injury. Compound 1, which did not influence PTK activation, failed to prevent
this GJIC injury. In contrast, compound 29, which significantly promoted PTK
activation, enhanced this H/R-induced GJIC injury further. Western blotting of
connexin 43, an important gap junctional protein for modulating GJIC in HUVEC,
revealed that interference with the gap junctional protein might be the most
direct mechanism for compounds 2, 5, 29, and 53 to affect H/R-injured GJIC.
PMID- 10763584
TI - Apoptosis-inducing activity of galloyl monosaccharides in human histiocytic
lymphoma U937 cells.
AB - Three galloyl monosaccharides contained in medicinal plants were examined for
apoptosis-inducing activity in human histiocytic lymphoma U937 cells.
Tetragalloyl glucose (TgG) induced apoptosis as found by chromatin condensation,
DNA ladder formation, and inhibition by a caspase inhibitor. Digalloyl hamamelose
had moderate activity, while monogalloyl glucose was only marginally active.
These findings suggest that the number and disposition of their phenolic groups
are important for apoptosis induction. TgG induced apoptosis in human colon and
stomach cancer cell lines as well, indicating it is potentially useful as an anti
cancer agent.
PMID- 10763585
TI - Hepatoprotective effect of Apocynum venetum and its active constituents.
AB - The leaves of Apocynum venetum L. are used as a tea material in north China and
Japan. A water extract (500 mg/kg/day, one week administration) of the leaves of
A. venetum showed protective effects against carbon tetrachloride (CCl4, 30
microliters/mouse) or D-galactosamine (D-GalN, 700 mg/kg)/lipopolysaccharide
(LPS, 20 micrograms/kg)-induced liver injury in mice. Tumor necrosis factor-alpha
(TNF-alpha) secreted from LPS-stimulated macrophages is the most crucial mediator
in the D-GalN/LPS-induced liver injury model. The extract had no significant
inhibition on the increase of serum TNF-alpha (1169 +/- 132 pg/ml vs. 1595 +/-
314 pg/ml of control), but exhibited a complete inhibition at the concentration
of 100 micrograms/ml on TNF-alpha (100 ng/ml)-induced cell death in D-GalN (0.5
mM)-sensitized mouse hepatocytes. Further activity-guided fractionation resulted
in the isolation of fifteen flavonoids viz. (-)-epicatechin (1), (-)
epigallocatechin (2), isoquercetin (3), hyperin (4), (+)-catechin (5), (+)
gallocatechin (6), kaempferol-6'-O-acetate (7), isoquercetin-6'-O-acetate (8),
catechin-[8,7-e]-4 alpha-(3,4-dihydroxpyhenyl)-dihydro-2(3H)-pyranone (9),
apocynin B (10), apocynin A (11), cinchonain Ia (12), apocynin C (13), apocynin D
(14) and quercetin (15). All the compounds showed inhibitory effects on TNF-alpha
induced cell death with different intensities. The flavonol glycosides 3, 4, 7
and 8 and the phenylpropanoid-substituted flavan-3-ols 11 and 12 showed potent
inhibitory effects on TNF-alpha-induced cell death with IC50 values of 37.5,
14.5, 31.2, 55.1, 71.9 and 41.2 microM, respectively. In contrast, the clinically
used 5 and its analogues 1, 2 and 6 showed apparent activity only at 80 microM.
These flavonoids appeared to be the hepatoprotective principles of the leaves of
A. venetum. The hepatoprotective effects exhibited by the extract and its
constituents suggest a validation of the leaves as a tea material.
PMID- 10763586
TI - Isolation and chemical analysis of a fatty acid fraction of Kalanchoe pinnata
with a potent lymphocyte suppressive activity.
AB - Previously we demonstrated that Kalanchoe pinnata (KP) leaf extracts inhibited in
vitro lymphocyte proliferation and showed in vivo immunosuppressive activity.
Here we attempt to identify the immunosuppressive substances present in KP guided
by the lymphoproliferative assays. From the ethanolic extract was purified a
fraction (KP12SA) twenty-fold more potent to block murine lymphocyte
proliferation than the crude extract. Chemical analysis by 1H- and 13C-NMR, IR
and GC-MS of KP12SA (methylated sample) showed 89.3% of palmitic acid (C16),
10.7% of stearic acid (C18) and traces of arachidic (C20) and behenic acids
(C22). This study provides evidence that fatty acids present in Kalanchoe pinnata
may be responsible, at least in part, for its immunosuppressive effect in vivo.
PMID- 10763587
TI - Essential oil of Croton nepetaefolius decreases blood pressure through an action
upon vascular smooth muscle: studies in DOCA-salt hypertensive rats.
AB - Experiments tested the hypothesis that hypotensive effects of intravenous (i.v.)
treatment with the essential oil of Croton nepetaefolius (EOCN) result from its
vasodilatory effects directly upon vascular smooth muscle. In both
deoxycorticosterone-acetate (DOCA)-salt hypertensive and uninephrectomised
control, conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) decreased
mean aortic pressure (MAP) and heart rate (HR) in a dose-related manner.
Treatment with DOCA-salt significantly enhanced EOCN-induced decreases in MAP
without affecting bradycardia. Likewise, both maximal percent and absolute
decreases in MAP elicited by i.v. hexamethonium (30 mg/kg), a ganglion blocker,
were significantly greater in DOCA-salt hypertensive than in control rats. In
DOCA-salt hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg)
reduced the bradycardia elicited by EOCN (50 mg/kg) without affecting the
enhancement of EOCN-induced hypotension. In isolated thoracic aorta preparations
from DOCA-salt hypertensive rats, EOCN (1-300 micrograms/ml) induced a
concentration-dependent reduction of phenylephrine-induced contraction. Arteries
from DOCA rats showed increased sensitivity to EOCN, as evidenced by the
significant decrease in the IC50 for EOCN-induced reduction of phenylephrine
induced contraction (16.4 +/- 3.6 vs. 112.9 +/- 23.4 micrograms/ml in
uninephrectomized controls). These results show that i.v. treatment with EOCN
dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive
rats, and this action is enhanced when compared with uninephrectomized controls.
This enhancement appears to be related mainly to an increase in EOCN-induced
vascular smooth muscle relaxation rather than to enhanced sympathetic nervous
system activity in this hypertensive model. Thus, the hypothesis that EOCN may be
a direct vasorelaxant agent is supported by the results of the present study.
PMID- 10763588
TI - Effect of ginseng saponins on cold tolerance in young and elderly rats.
AB - Acute systemic injection of ginseng saponin (GS) significantly elevated both the
total and maximum heat production in young rats (3-6 months) and improved their
cold tolerance under severe cold (-10 degrees C under helium-oxygen). However,
pretreating the animal with the optimal dose (10 mg/kg) of GS devoid of Rg1 and
Rb1 failed to elicit any beneficial effect in improving the cold tolerance.
Pretreating the animal with Rb1, but not Rg1, increased thermogenesis as well as
cold tolerance in young rats. A similar beneficial effect in improving cold
tolerance was also observed when old rats (26-28 months) were pretreated with the
same doses of Rb1 (2.5 and 5.0 mg/kg). Our results indicate that Rb1 is the key
ingredient in GS-mediated enhancement in thermogenic capacity and that both young
and old rats can benefit from this treatment for enhanced cold tolerance.
PMID- 10763589
TI - S-allylcysteine ameliorates doxorubicin toxicity in the heart and liver in mice.
AB - Doxorubicin, a potent anticancer drug, is effective against a wide range of human
neoplasms. However, the clinical uses of doxorubicin have been limited due to its
serious cardiotoxic effects, which are likely the result of generation of free
radicals and lipid peroxidation. S-Allylcysteine (SAC), an organosulfur compound
purified from garlic, has been reported to have antioxidant and radical
scavenging effects. Thus, we examined the effect of SAC on doxorubicin toxicity
in mice. Severe doxorubicin toxicity was induced in mice by a single
intraperitoneal injection (15 mg/kg body weight). SAC (30 mg/kg) was injected
intraperitoneally daily for 5 days, starting two days prior to the administration
of doxorubicin. Body weight was measured every alternate day. A measurement of
serum creatine phosphokinase (CPK) and a histopathological analysis of the heart
and liver was performed 6 days after the administration of doxorubicin. Death of
any of the animals was recorded during the observation period. Doxorubicin
injection induced a mortality rate of 58%, with SAC treatment reducing the
doxorubicin-induced mortality rate to 30%. The severe body weight loss caused by
doxorubicin (13%) was also significantly attenuated by SAC treatment (9%).
Although an elevation of the level of serum CPK was observed following
doxorubicin injection (5472 +/- 570 i.u./L), treatment with SAC significantly
reduced the level of CPK (1923 +/- 635 i.u./L). Histological analysis
demonstrated that heart and liver damage was significantly less severe in SAC
treated mice than in mice receiving only doxorubicin. These results suggest that
SAC research may ultimately lead to a resolution of the adverse effects of
doxorubicin treatment in cancer chemotherapy.
PMID- 10763590
TI - Modified Aloe barbadensis polysaccharide with immunoregulatory activity.
AB - Aloe barbadensis polysaccharide was partially digested with cellulase and further
purified by dialysis, stepwise ethanol precipitation, and size exclusion
chromatography. Crude modified Aloe polysaccharide (MAP) activated macrophage
cells and stimulated fibroblast growth. Under the same conditions, native Aloe
barbadensis gel had no effect on macrophage activation. MAP prevented ultraviolet
B (UVB) irradiation-induced immune suppression as determined by contact
hypersensitivity (CHS) response in C3H/HeN mice. This in vivo activity was
correlated with the activity of MAP to inhibit UVB irradiation-induced tumor
necrosis factor alpha (TNF-alpha) release from human epidermoid carcinoma cells
(KB cells). MAP with an average molecular weight of 80,000 Dalton (Da) contained
mannose, galactose, and glucose in a ratio of 40:1.4:1.0. MAP was likely a
linear, highly acetylated molecule.
PMID- 10763591
TI - The cytolytic effect of a glycoconjugate extracted from corms of saffron plant
(Crocus sativus) on human cell lines in culture.
AB - Corms of Crocus sativus L. (Iridaceae) contain a glycoconjugate that shows
cytotoxic activity on tumoral cells in culture. Studies of intracellular calcium
fluctuations, and release of lactate dehydrogenase in human cervical epitheloid
carcinoma cells, showed that this compound caused plasma membrane damage,
allowing movements of both calcium and macromolecules, and leading to cell lysis.
Analysis of DNA fragmentation showed that cell death was not mediated by
apoptosis. This molecule is active against human tumoral cells derived from
fibrosarcoma, cervical epithelioid carcinoma and breast carcinoma, with IC50
values of 7, 9 and 22 micrograms/ml, respectively. The proteoglycan is about 8
times more cytotoxic for malignant cells than for their normal counterparts. In
addition, 100 micrograms/ml of proteoglycan produced 50% in vitro lysis of normal
human erythrocytes, whereas 320 micrograms/ml induced about 60% cell death on
cultured human hair follicles. Altogether, these results suggests a distinctive
cytotoxic activity of this molecule on different human cell types.
PMID- 10763592
TI - Three new lanostane-type triterpene lactones from the stem bark of Abies
mariesii.
AB - Three new delta 8-lanostane-type triterpene lactones (1), (2) and (3) were
isolated from the stem bark of Abies mariesii M. and unambiguously characterized
on the basis of spectroscopic and chemical evidence. Chemical modification of
compound 1 showed potent inhibitory effects on Epstein-Barr virus early antigen
(EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol 13
acetate (TPA).
PMID- 10763593
TI - Isolation of 10-hydroxycoronaridine from Tabernaemontana penduliflora and its
estrogen-like activity.
AB - The methanol extract of Tabernaemontana penduliflora was found to appreciably
inhibit [3H]-estradiol binding to estrogen receptors. Activity-guided
fractionation led to the isolation of two known alkaloids, 10-hydroxycoronaridine
(1) and its 10-O-methyl ether, voacangine (2). These alkaloids together with
other related alkaloids were tested for their estrogenic activities. Among these
molecules, 1 was found to be the most potent estrogen agonist and is distinctly
more active than genistein.
PMID- 10763594
TI - Yomogin inhibits the degranulation of mast cells and the production of the nitric
oxide in activated RAW 264.7 cells.
AB - Yomogin (1), an eudesmane sesquiterpene isolated from Artemisia princeps, was
tested for the effects on the degranulation process of cultured mast cells and on
the nitric oxide production in LPS-activated murine macrophages. It demonstrated
a significant inhibition on the release of beta-hexosaminidase from the cultured
RBL-2H3 cells in a dose-dependent manner (IC50 value, 50 microM) and also
exhibited a potent inhibition on the nitric oxide production from the activated
RAW264.7 cells (IC50 value, 3 microM).
PMID- 10763595
TI - Squamocin and benzyl benzoate, acaricidal components of Uvaria pauci-ovulata bark
extracts.
AB - Annonaceae have been commonly described in traditional medicine as remedies
against head lice and for their insecticidal properties. Acaricidal effects of
Uvaria pauci-ovulata bark extracts were investigated on Dermatophagoides
pteronyssinus, the European house dust mite, and compared with those of benzyl
benzoate used as standard acaricidal compound. A dichloromethane extract was the
most effective with an EC50 = 0.028 g/m2 after a 24 h period as compared with
benzyl benzoate (EC50 = 0.06 g/m2). Bioassay-guided fractionation of this extract
led to the isolation of benzyl benzoate and squamocin; this latter compound also
had acaricidal properties (EC50 = 0.6 g/m2). Moreover, squamocin was shown to
potentiate the activity of benzyl benzoate using the fractional effective
concentration (FEC) method.
PMID- 10763596
TI - Biologically active triterpenoids of Syncarpia glomulifera bark extract from
Paluma, north Queensland, Australia.
AB - The crude chloroform bark extract of Syncarpia glomulifera (Myrtaceae) shows
antibacterial and cytotoxic activity. Bioactivity-directed separation led to the
isolation of oleanolic acid-3-acetate, ursolic acid-3-acetate and betulinic acid.
The relatively large abundance (10% of the crude extract) and high degree of
activity of betulinic acid are responsible for the bioactivity of the crude bark
extract.
PMID- 10763597
TI - Chemical composition and seasonal variations in the amount of secondary compounds
in Gentiana lutea leaves and flowers.
AB - The chemical investigation of MeOH extracts of Gentiana lutea leaves and flowers
showed that xanthones were one of the dominant class of compounds. Secoiridoids
and flavonoids were also recorded. The amount of secondary metabolites varied
depending on development stage. In the phase of flowering, leaves are rich with
compounds possessing C-glycoside structures while O-glycoside structures
accumulate mainly before flowering.
PMID- 10763598
TI - Distribution of verectin in Aloe vera leaves and verectin contents in clonally
regenerated plants and the commercial gel powders by immunochemical screening.
AB - Verectin antiserum raised in white rabbits was immunochemically applied to
examine verectin distribution in Aloe vera leaves during growth and flowering
seasons, and to quantify verectin in clonally regenerated plants and commercial
A. vera gel products.
PMID- 10763599
TI - 5-(4-Hydroxyphenethenyl)-4,7-dimethoxycoumarin, a new constituent of Monotes
engleri.
AB - A new coumarin, 5-(4-hydroxyphenethenyl)-4,7-dimethoxycoumarin (1) was isolated
from the combined ethyl acetate extracts of the root bark, root wood and stem
bark of Monotes engleri, and found to be cytotoxic against two cell lines in a
human tumor panel. Its structure was determined on the basis of spectroscopic
methods.
PMID- 10763600
TI - New naphthalenyl glycosides from the roots of Juglans mandshurica.
AB - Three new glycosides, 1,4,8-trihydroxynaphthalene-1-O-D-glucopyranosyl-(1-->6)
beta-D- xylopyranoside (1), 1,4,8-trihydroxynaphthalene-1-O-beta-D-glucopyranosyl
(1-->6)-alph a-L- arabinopyranoside (2), 1-hydroxy-4-methoxynaphthalene-1-O-beta
D-glucopyranosyl-(1-->6)- alpha-L-rhamnopyranoside (3), were isolated from the
roots of Juglans mandshurica and their structures were elucidated on the basis of
spectroscopic studies.
PMID- 10763601
TI - Two new quinones from Spallerocarpus gracillis.
AB - Further phytochemical investigation of the aerial parts of Sphallerocarpus
gracillis afforded two new quinones, named gracillisquinones A and B. Their
structures were elucidated on the basis of spectral evidence including 2D NMR and
X-ray techniques.
PMID- 10763602
TI - Eremophilenolides from Ligularia fischeri.
AB - The chemical investigation of Ligularia fischeri afforded three new
eremophilenolides which were identified as 6 beta-methoxy-8 beta-hydroxy
eremophil-7(11)-en-12,8 alpha-olide, ligufischerin, and 6-oxo-8 beta-hydroxy
eremophil-7(11)-en-12,8 alpha-olide by 1D- and 2D-NMR spectra. In addition, six
known eremophilenolides were also obtained.
PMID- 10763603
TI - A new trinortriterpenoid from Cleome chrysantha.
AB - A new trinortriterpenoid, 1-epibrachyacarpone, was isolated from aerial parts of
Cleome chrysantha. Its structure was elucidated as 1 by NMR investigations and X
ray crystallographic studies.
PMID- 10763604
TI - Solid phase microextraction of volatile constituents from individual fresh
Eucalyptus leaves of three species.
AB - Methyl polysiloxane solid-phase microextraction fibres were used for ten minutes
to adsorb volatile constituents from headspace above all or part of a single cut
up fresh eucalyptus leaf kept warm at 37 degrees C. The fibres were desorbed at
200 degrees C for programmed gas chromatography (40-187 degrees C) on a methyl
polysiloxane capillary. Substances were identified by mass spectra and/or
authentic sample retention. Results do not correspond to published values for
steam distilled oils, being richer in sesquiterpenes, of which three are common
to three different species; and also in esters in two species. Five Eucalyptus
citriodora leaves from the same tree over different months gave very similar
analyses to a fibre in 10 min of 72.9-80.5% citronellal, 3.5-5.4% citronellol,
1.0-3.8% citronellyl acetate, 9.2-11.8% caryophyllene and 1.4-1.7%
bicyclogermacrene. Six E. nicholii leaves yielded 67.2-73.7% cineole and 4.6-9.7%
limonene along with 10.5-16.5% sesquiterpenes, mostly hydrocarbons, particularly
bicyclogermacrene. E. globulus leaves gave only 54.0-61.3% cineole, with 19.5
24.3% alpha-pinene, 6.7-9.1% limonene and 2.1-5.4% alpha-terpinyl acetate; along
with 3.6-7.7% sesquiterpenes, particularly aromadendrene, but no
bicyclogermacrene.
PMID- 10763605
TI - In vitro propagation of Senna alata.
PMID- 10763606
TI - Xanthorrhizol: a potential antibacterial agent from Curcuma xanthorrhiza against
Streptococcus mutans.
PMID- 10763607
TI - Volatile constituents of three Thymus species grown wild in Iran.
PMID- 10763608
TI - Get your message to the media.
PMID- 10763609
TI - When a parent disagrees.
PMID- 10763610
TI - Next NP mission: Medicaid.
PMID- 10763611
TI - Rhinitis in autumn. An action plan.
PMID- 10763612
TI - Thyroid disease in the elderly.
PMID- 10763613
TI - After the cure. Long-term effects of childhood cancer.
PMID- 10763614
TI - Patient information. Treating and removing head lice.
PMID- 10763615
TI - Cytologic concerns in adolescents. Entering the transformation zone.
PMID- 10763616
TI - Adolescent risks, adult consequences.
PMID- 10763617
TI - Asthma and upper respiratory infection.
PMID- 10763618
TI - Degrees of success. Federal master's requirement speeds graduate movement.
PMID- 10763619
TI - Direct-to-consumer drug advertising.
PMID- 10763620
TI - Flexibility--an NP survival trait.
PMID- 10763621
TI - Peer review: mark of a profession or "who's in and who's out?".
PMID- 10763622
TI - Defying gravity and fear: the prevention of falls in community-dwelling older
adults.
AB - In older adults, falls represent a very common and dangerous problem. Older
adults lack the normal overlap or redundancy of cognitive, sensory, and
musculoskeletal mechanisms that help younger people avoid falling while remaining
active. Many of the risk factors for falls in older adults are modifiable and
deserve aggressive attention. Successful prevention of falls, fall-related
injuries, and fear of falling is complicated by the multifactorial nature of the
problem. Advanced practice nurses' comprehensive health assessment skills,
holistic orientation, and willingness to collaborate with healthcare providers
from a range of disciplines are helpful in dealing with the complexity of balance
problems and falls. Nurse practitioners can be effective case managers for older
adults at risk for falling. Older adults need accurate information, and sometimes
counseling, to realize that falls, fall-related injuries, and fear of falls are
warning signs that can provide direction and motivation for change and
prevention.
PMID- 10763623
TI - Shaken baby syndrome: identification, intervention, and prevention.
AB - More than 1 million children are severely abused annually. Shaken baby syndrome
(SBS), one example of physical abuse, is a leading cause of morbidity and
mortality in infants. There is a national annual incidence in the United States
of 750 to 3,750 cases of SBS. Shaken baby syndrome is defined as vigorous manual
shaking of an infant who is being held by the extremities or shoulders, leading
to whiplash-induced intracranial and intraocular bleeding with no external signs
of head trauma. Shaken baby syndrome should be suspected in infants with a wide
spectrum of clinical signs and symptoms. The classic findings of SBS are retinal
hemorrhages, usually bilateral, and intracranial injury. One third of the victims
of SBS survive with few or no sequelae, one third suffer permanent injury, and
one third die. Parental behaviors, environmental factors, and child
characteristics all may contribute to a shaking event. The nurse practitioner, in
a wide variety of clinical settings, is in a strategic position for the early
identification and intervention for families at risk for SBS. Prevention through
parent, caregiver, and community-wide education programs is the only option for
infants who are at risk for SBS.
PMID- 10763624
TI - Nurse practitioners in the county correctional facility setting: unique
challenges and suggestions for effective health promotion.
AB - The correctional facility practice setting is among the newer practice
specialties emerging for nurse practitioners (NPs). As with any new setting, a
variety of unique challenges continues to emerge. Because there is a relative
paucity of literature regarding NP practice in this particular specialty, those
practicing now do not have adequate resources to assist in the development of
their practice. This article discusses some of the challenges unique to this area
of practice and offers suggestions for incorporating theory-based health
promotion interventions. This article is also an effort to begin development of a
body of knowledge for NPs providing primary, secondary, and tertiary care to the
inmate population of jails and prisons. Hopefully, nurse practitioners in this
unique setting will be encouraged to share their own anecdotal and research-based
suggestions for improving correctional facility practice.
PMID- 10763625
TI - Nurse practitioner interventions for domestic violence.
AB - The purposes of this study were to (1) identify interventions used by a sample of
adult and family nurse practitioners (NPs) with suspected cases of domestic
violence and (2) determine if the interventions used had theoretical and
empirical support. Sixty vignette responses from 20 NPs were analyzed using
content analysis and compared with the literature. The NPs in this sample
diagnosed domestic violence in only 60% of the cases. A total of 12 intervention
categories (e.g., screening, physical examination, medical treatment, or
counseling) were developed. Twelve categories were theoretically supported, and
one category had empirical support. These findings support the need for
heightened awareness of domestic violence for proper diagnosis and for use of
theoretically and empirically supported interventions.
PMID- 10763626
TI - Performance evaluation and patient outcomes monitored by nurse practitioners and
certified nurse-midwives in Florida.
AB - In this descriptive survey study, four elements of performance evaluation of
advanced practice nurses (APNs) currently in clinical practice were examined:
evaluation frequency, evaluation responsibility, evaluation parameters, and
monitored patient outcomes. Questionnaires were mailed to 2,093 APNs living in
Florida and licensed by the Florida State Board of Nursing. Eight hundred twenty
two usable surveys were returned, for a 39% response rate. Of these respondents,
654 were in clinical practice as APNs, and comprised the final sample. The
majority (56.9%) received formal annual evaluations, and most (75.9%) were
evaluated primarily by physicians; only 17.5% reported peer evaluation. The most
frequent evaluation parameters were appropriateness of care, patient
satisfaction, patient outcomes, and patient volume. Patient outcomes fell into
four categories: clinical endpoints, complications, compliance, and functional
status. A need to increase the regularity, formality, and peer review elements of
APN performance evaluation was concluded.
PMID- 10763627
TI - Identifying barriers to the administration of HIV medications to county
correctional facility inmates.
AB - The purpose of this study was to investigate the process of HIV medication
administration at a county correctional facility. Anecdotal data suggested
serious barriers to the process. Professional and licensed practical nursing
staff practicing at a New Jersey county correctional facility participated in
focus group interviews designed to discuss the process of medication
administration and potential barriers to that process. Analysis of data revealed
five contextual themes: uniqueness of the county correctional facility setting,
barriers perceived by nursing staff, inmates' perceptions of HIV infection,
internal systems' barriers, and the role of systems external to the correctional
facility.
PMID- 10763628
TI - Evidence-based practice for nurse practitioners with clinical pathways.
AB - Evidence-based practice is essential for clinical excellence for nurse
practitioners (NPs). Client outcomes must be measured and clearly linked to
measurable nursing interventions. To ensure evidence-based practice, clinical
pathways can be used as a vehicle to implement care. Clinical pathways track
outcomes and interventions, and provide a means for accurate documentation. This
article discusses evidence-based practice and the use of clinical pathways by
psychiatric NPs in two settings: home care and an outpatient psychiatric clinic.
PMID- 10763629
TI - Appendectomy in pregnancy and postpartum: analysis of data from a large private
hospital.
AB - Little research is found in the nursing literature regarding appendicitis in the
pregnant patient. Appendicitis in pregnancy is associated with: perforation of
the appendix, peritonitis, and increased fetal and maternal mortality and
morbidity. Preterm labor and early delivery may further complicate the pregnancy.
Advanced practice nurses may encounter pregnant women with abdominal pain who
present in the primary care setting as well as in an obstetric office. Knowledge
of signs and symptoms of appendicitis in pregnancy, potential complications, and
outcomes is essential to nursing. Early recognition may decrease complications
and improve outcomes. A 10-year chart review was performed at a large urban
Midwestern hospital with a large obstetric department. Deliveries numbered more
than 66,000 during the 10 years. A total of 42 cases of appendicitis during
pregnancy and the 2 weeks following delivery was identified. The characteristics
of the population as well as considerations for practice are discussed.
PMID- 10763630
TI - Attaining role confirmation in nurse practitioner practice.
AB - Although nurse practitioners (NPs) as a collective group have reached the stage
of role confirmation, in new settings they must transition through several phases
of role development. The role confirmation issues for a team of NPs who were
hired to work in a large academic teaching hospital in the Southeastern part of
the United States are explored over a 3-year period. Characteristics of the
organization and strategies that the NPs implemented over time impacted favorably
on the evolution of the NP role in that setting. The NPs gained prescriptive
privileges, independent practice, and market-place salaries. Effective
negotiation and marketing strategies enhanced both personal and professional
development.
PMID- 10763631
TI - Pediatric resources on the Internet.
PMID- 10763632
TI - Profiles of the editorial board: from Australia to the Americas.
PMID- 10763633
TI - [Study of patients admitted to a telemetry unit].
AB - The current situation of the telemetry unit of Vigil de Quinones Hospital was
studied. Telemetry indications, results, and problems observed since the unit was
inaugurated were studied to determine the usefulness of telemetric heart rate
monitoring and centralized surveillance in an intensive care unit (ICU) in
detecting severe arrhythmias, controlling antiarrhythmic treatment, and
evaluating why and to what extent telemetry is clinically useful. In our center,
telemetry is used to monitor patients with well-established needs. In most cases,
arrhythmias are monitored, most frequently premature ventricular complexes, sinus
bradycardia and supraventricular tachycardia. Telemetry was useful in arrhythmia
treatment and the follow-up of patients with temporary or permanent pacemakers.
In a significant percentage of patients (8.62%), telemetry was the key to their
ICU admission and, possibly, their survival. There were generally few problems
with signal transmission.
PMID- 10763634
TI - [Evolution in the postoperative intensive care of patients with liver
transplantation].
AB - As liver transplantation has evolved (receptor selection, surgical technique,
immunosuppressant treatment, etc.), experience has increased and nursing care has
evolved. The admission of a patient to the ICU after liver transplantation no
longer requires changes in nursing schedules to ensure proper patient care. This
study was undertaken to evaluate differences in the evolution of nursing care in
two consecutive groups of patients. A retrospective study was made of all nursing
and medical records for two patient groups: patients who underwent
transplantation in 1994-95 (G-I) and patients who underwent transplantation in
1996-98 (G-II). Medical history, surgical incidents and postoperative evolution
(care treatment and complications) were evaluated for every patient. Mean age was
similar for both groups, 57.7 years. The patients in the 1996-98 group had a
shorter ICU stay, 3.5 days vs. 4.4 days for the 1994-95 group (p < 0.05). Oral
feeding was tolerated soon in all patients, but somewhat earlier for the patients
in the 1996-98 group. The infection rate (respiratory, urinary, vascular
catheter) was low; there were no surgical wound infections. The average number of
bacteriological controls was lower in the 1996-98 group, 5 vs. 19 for the 1994-95
group (p < 0.05). Other parameters were similar in both groups. In conclusion,
the shorter ICU stay and elimination of routine analyses over the years benefited
patients, reduced costs, and increased the availability of ICU beds. This was
achieved without any reduction in the quality of care or results obtained.
PMID- 10763635
TI - [Nursing care for patients with toxic epidermal necrolysis].
AB - Toxic Epidermal Necrolysis (TEN) is a severe skin disorder characterised by
separation of the dermal-epidermal junction, as it is observed in second degree
superficial burns, and it may also involve any mucosal surface area (otic,
buccal, conjunctival, respiratory, genital). This condition is generally induced
by the ingestion of drugs, particularly certain antibiotics, nonsteroidal
antiinflammatory drugs, and antiepileptic drugs. Mortality has decreased over the
last decades, from 80% to about 25% in recent series. This improvement in
survival rate has been related to early diagnosis, management in specialized burn
units, proper immunosuppressive treatment and intensive specialised nursing care.
The main nursing diagnosis include abnormalities in the skin and mucose membranes
integrity, risk of infection, loss of blood volume, risk of hypothermia, acute
pain, upper airway insufficiency and anxiety. We here review the nursing care of
patients with TEN. We emphasize the daily skin and mucose membranes care, and the
prevention of conjunctival sinequiae, including daily conjunctival cleaning and
debridement of necrotic tissue and fibrin debris using a handle needle.
PMID- 10763636
TI - [Continuing education and self evaluation. Review of knowledge on the respiratory
system and the gastrointestinal system].
PMID- 10763637
TI - [The professional profile of nurses in special units].
AB - A study was made of the professional profile of nurses working in the intensive
care or coronary units of the hospitals of the Community of Castilla-La Mancha,
Spain. The study was based on a questionnaire completed by a significant sample
of nurses working in these units. It synthesizes the most relevant concerns,
expectations, and opinions of these nursing professionals on the basis of the
results of the authors' analysis. Although most of the nursing professionals were
satisfied with the care that they provide, there is demand for further training
of nurses working in intensive care and coronary units. Ideas and questions about
the future of nursing professionals in special intensive care and emergency units
are discussed. The development of professional certification for special care is
considered, which undoubtedly would contribute to meeting the demands of these
professionals.
PMID- 10763638
TI - [Research in the 21st century: Euroconference].
AB - The INVESTEN group of the "Instituto de Salud Carlos III", INVESTEN-ISCIII,
organized the first Euro-conference related with Nursing Research, "Building a
European Nursing Research Strategy", which was held in Salamanca from 13-17 March
1999. The aim of the Euro-conference was to establish the priorities and
recommendations for Nursing Research needed to potentiate Nursing Research in
Europe at the Beginning of the next millennium. Fourty countries participated in
the Euro-conference, which was partially financed by the European Union. Based on
the Strasburg Recommendations, the Euro-conference included five main topics in
Nursing Research: structure and organization, integrating nursing research into
practice, training, financing and priorities. Topics were studied and discussed
in working groups of 15-20 participants. Each group was coordinated by different
members of the INVESTEN-ISCIII group, with experts on each subject and nurses
working in teaching, investigation and clinical practice. The objective was to
create a report reflecting the present state of Nursing Research.
PMID- 10763639
TI - [Continuous monitoring of oxygen saturation in the jugular vein bulb in severe
head injuries. Management and case reviews].
AB - Since october 1996, the Intensive Care Unit of the Hospital of Navarra has
carried out continuous monitoring of oxygen saturation in the bulb of the
internal jugular vein (SjO2). This technique, used in patients with severe
cranioencephalic trauma (SCET), is designed to facilitate care an ensure the use
of adequate therapeutic measures in such patients. The present study has two
parts: In the first part, SjO2 monitoring is defined and catheter insertion
techniques, technical problems, and nursing care are described. In the second
part, a retrospective review is made of patients admitted to the unit from
october 1996 to october 1997 who underwent SjO2 monitoring. A total of 11 cases
are included, the common features of which were: SCET, intracranial pressure over
20 mmHg, Glasgow score of 8 or less, and abnormal CAT study. This study provides
a basis for developing a nursing protocol because familiarity with the technique
allows problems to be prevented and/or resolved.
PMID- 10763640
TI - [Multiple organ dysfunction syndrome].
AB - Multiple organ dysfunction syndrome (MODS) is a clinical situation that has been
described as a result of the rapid progress and advances that have been made in
recent decades in the physiology, diagnosis, and therapeutic support of
critically ill patients. In 1991, in view of the confusing terminology used to
characterize processes coursing with systemic inflammatory response syndrome
(SIRS), a consensus conference was held. A series of basic definitions were
established and the term "multiple organ failure" was replace by MODS. In
response to outside aggression, the organism tries to defend itself with two
mechanisms: a non-specific humoral and cellular response called inflammation, and
a specific antigenic response that modifies the genetic codes of cells of the
defense system and constitutes an immunological response. At present it is
thought that the inflammatory response is activated (SIRS) in response to an
uncontrolled aggression, but an antiinflammatory response syndrome (ARS) exists
as well. An exaggerated SIRS can lead to MODS. MODS usually debuts with pulmonary
dysfunction. If the aggression persists, cardiovascular, renal, hepatic,
coagulation, central nervous system, gastrointestinal metabolism, neuroendocrine
and musculoskeletal failure follow. A series of causes often trigger this
syndrome and certain factors favor it. Prevention of these causes and factors in
fundamental for controlling the occurrence of MODS. At present, there is no clear
treatment for MODS, although numerous studies designed to block the release of
certain proinflammatory mediators or to neutralize antiinflammatory responses are
being carried out.
PMID- 10763642
TI - There is a growing interest in cancer patient narratives.
PMID- 10763641
TI - [Continuing education and self evaluation. Review of knowledge of multiple organ
dysfunction and initial care of patients with severe injuries].
PMID- 10763643
TI - Incidence of weight loss in head and neck cancer patients on commencing
radiotherapy treatment at a regional oncology centre.
AB - The aim of this prospective study was to investigate the incidence of weight loss
in head and neck cancer patients on commencing radiotherapy treatment at a
regional oncology centre. Of the 100 patients included in the study, 33%
presented with carcinoma of the larynx. Fifty-seven per cent of patients had lost
weight on commencing treatment. A mean weight loss of 6.5 kg, equating to
approximately 10% of body weight, was reported. A significant number of patients
experienced a dry and/or sore mouth, had difficulty masticating and swallowing
food, had altered taste perception, were missing meals or had symptoms of
uncontrollable nausea and constipation. Since radiotherapy treatment may further
limit oral intake, it is essential that dietetic intervention is addressed for
all head and neck cancer patients and incorporated into the treatment plan on
diagnosis before definitive management commences.
PMID- 10763644
TI - Young men's knowledge of testicular cancer and testicular self-examination: a
lost opportunity?
AB - Testicular cancer remains the most commonly occurring cancer in young men (aged
20-45 years) and recent trends suggest an increase throughout the western world.
Whilst testicular cancer is highly treatable late diagnosis resulting in poorer
treatment outcomes remains a problem. Testicular self-examination (TSE) a
procedure whereby young men can routinely systematically examine their testicles
has been advocated as a particularly effective health education intervention.
This study aimed to establish the knowledge of testicular cancer and prevalence
of TSE practice amongst young men. A descriptive survey approach using a 16-item
self-report questionnaire was administered to a convenience sample of 203 male
undergraduate and postgraduate students at the University of Huddersfield.
Results indicated that the majority of the respondents were either uninformed or
misinformed about the risks and symptoms of testicular cancer although 78%
indicated an interest in accessing information. Only 32% had prior knowledge of
TSE, 22% practiced TSE, and worryingly only a single respondent was able to
recognize the correct procedure and indicated he regularly practiced TSE. Sixty
eight per cent indicated that TSE should be a part of general health assessments
for men. Although some critics of TSE argue the cost of teaching TSE outweighs
the benefits in terms of early diagnosis this study suggests that young men may
be willing to participate in an aspect of personal health surveillance. If this
is the case then low cost strategies to increase impact on the target audience
should be considered.
PMID- 10763645
TI - Skin reactions during radiotherapy for breast cancer: the use and impact of
topical agents and dressings.
AB - Radiation skin reactions occur in the majority of cases of patients undergoing
radiotherapy for breast cancer with varying degrees of severity. Guidelines for
skin care and for the use of topical agents and dressings have developed over the
years of practice but there is little empirical evidence on which to base a
decision for best practice. This paper describes the incidence of radiation skin
reactions in a sample of 126 women treated for breast cancer post-lumpectomy. The
results show that by the end of whole breast irradiation between 4-8% of patients
will have no reaction and less than 10% will have moist desquamation as measured
by the RTOG acute scoring system. The majority of patients did not require
application of a topical agent during the treatment period. Statistical analysis
of relationships between the severity of radiation skin reaction and the use of
topical agents found no support for additional healing or preventative benefit.
However, these topical agents were found to promote comfort. The use of Fixomull
as a protector and potential preventive measure for moist desquamation is
described.
PMID- 10763646
TI - A patient preference study comparing raltitrexed ('Tomudex') and bolus or
infusional 5-fluorouracil regimens in advanced colorectal cancer: influence of
side-effects and administration attributes.
AB - Current chemotherapy regimens used in advanced colorectal cancer (ACRC) are
similar in terms of efficacy, but differ importantly in terms of side-effects and
administration profiles. These differences may impact significantly on patients'
lives. We have evaluated patient preferences between raltitrexed ('Tomudex') and
5-fluorouracil-based chemotherapy regimens, with regard to side-effect attributes
(raltitrexed and Mayo regimens) and administration attributes (raltitrexed, Mayo,
De Gramont and Lokich regimens) in a study based on 82 patients with ACRC.
Patients completed a series of rating tasks on how 'upsetting' these attributes
were to them using a visual analogue scale (VAS) in a structured interview
conducted by a research nurse. Mucositis and asthenia were the most and least
upsetting side-effects, respectively. The side-effect profile of raltitrexed was
clearly preferred by 78% of patients versus 14% for Mayo (P < 0.001). When side
effects and administration attributes were combined into an overall profile, 91%
of patients selected raltitrexed as their clearly preferred regimen, versus 6%
for Mayo (P < 0.001). The administration regimen of raltitrexed was ranked most
acceptable (mean rank score 1.5 compared with Mayo 2.6, De Gramont 2.7, and
Lokich 3.3). Given similar palliative effects, patients with ACRC exhibit
preferences for raltitrexed over other regimens, based on administration and/or
side-effect attributes. Such preferences should constitute an important part of
decisions relating to the choice of chemotherapy regimen in ACRC.
PMID- 10763647
TI - Women's breast cancer and epidemiology: Scotland and Iceland, contrasts and
comparisons.
AB - Epidemiology is a scientific discipline concerned with the distribution and
determinants of health and diseases, morbidity, injuries, disability and
mortality in populations. This article reviews the literature on women's breast
cancer from an epidemiological point of view. Special attention is given to
epidemiology and cancer in terms of sources of information, geographical
variations, incidence and mortality, risk factors and prevention. Iceland and
Scotland were chosen to compare and contrast the epidemiology of breast cancer.
These countries were chosen because of the author's general knowledge and
acquaintance with both countries and because of her experience in working with
breast cancer patients.
PMID- 10763648
TI - Learning to live with cancer: the UK experience of a European patient education
and support programme.
AB - 'Learning to Live with Cancer' is a structured education and support programme
for people with cancer and their families. The UK programme, now in its third
year, is based on the original American 'I Can Cope' educational package
pioneered by Dr Judi Johnson. The Learning to Live with Cancer programme was
developed collaboratively between Judi Johnson and Dr Gertrud Grahn, Sweden.
Based on sound educational principles, it has been promoted by the European
Oncology Nursing Society (EONS). The complexities of an individual's response to
the diagnosis of cancer is well documented. Needs for information and support
will change throughout the cancer experience. The Learning to Live with Cancer
programme aims to educate patients and families in order that people gain a
greater understanding and can explore ways of managing illness better. An 8-week
course of 2 h each week provides opportunities for learning, sharing experiences
and mutual support in meeting others undergoing a similar experience. Ongoing
work, now in progress, aims to develop further Learning to Live with Cancer
courses for professionals to facilitate in cancer centres throughout the UK.
PMID- 10763649
TI - What to do about fraud and abuse.
PMID- 10763650
TI - New leadership standard: sentinel event management.
PMID- 10763651
TI - 10 things to do when the surveyor picks you!
PMID- 10763652
TI - Wait a minute!
PMID- 10763653
TI - How OASIS data quality affects you!
AB - In general, each of these methods require time and energy from staff members and
therefore affect both clinicians and the home health agency. Because the assessor
is usually a field nurse or therapist, field staff are very vulnerable to a top
down audit approach unless staff are included in the development cycle to achieve
a non-threatening quality improvement process. Furthermore, an understanding of
the research concepts provides agencies with a creative opportunity to develop
their own audit processes. In addition, these concepts offer an awareness as to
why HCFA may have chosen the specific areas and methods they have recommended to
use when identifying errors. HCFA encourages agencies to consider different
methodologies and approaches and to use what works best in order to ensure data
accuracy. This is one of the first times in which HCFA has given so much latitude
to agencies and their staff. It is hoped that this article fosters interest and
insight as to why field staff should actively become involved in audit processes
that check their skills and accuracy, which directly correlates to such a huge
impact on all involved. In order to improve reliability, an agency should try to
minimize external sources of variation and standardize the conditions under which
measurement occurs. Initial and ongoing training sessions for staff on each of
the OASIS data elements can establish higher reliability and can be streamlined
and targeted on areas that staff have the most questions and areas that audits
indicate high error rates with data inaccuracies. It is important to remember
that each OASIS question has been proven to be valid and reliable; therefore, the
only variable left is the source, i.e., those who use the instrument to determine
where data inaccuracies could be generated (the field assessor, data entry staff,
vendor transmitters, etc.). Agencies should develop the audit functions that will
best meet their needs, and minimize the workload for all involved in finding
these data inaccuracies.
PMID- 10763654
TI - What home healthcare nurses should know about fraud and abuse.
AB - Home care nurses provide a critical linh in all services provided by a home
health agency. This article outlines basic information nurses can use to
understand fraud and abuse regulations, see the importance of corporate
compliance programs, and recognize the potential impact a focus on fraud and
abuse has on their practice.
PMID- 10763655
TI - The therapist's role in comprehensive assessment and OASIS.
AB - Looking for guidelines for using therapists to collect comprehensive assessment
data & OASIS? This article presents issues related to the involvement and
restrictions of physical therapists, speech-language pathologists, and
occupational therapists in comprehensive assessment functions. The scope of
practice and roles therapists can assume is outlined and provides references you
can use to develop your own policies.
PMID- 10763656
TI - Searching the Web.
AB - The Web is an extraordinarily dynamic medium that is growing in size and
complexity at a furious pace. Web pages already number in the billions and
roughly double each year. The contents of the Web are largely unstructured, which
may make finding specific information a considerable challenge. However, once you
develop some skill at navigating this realm, you'll reap considerable rewards.
Surfing the Net can become habit forming, and as your proficiency increases, the
challenge may well be knowing when to stop.
PMID- 10763657
TI - Research-based practice implications for patients with diabetes. Part II:
Diabetes self-efficacy.
AB - Part I of this two-part research article that describes diabetes knowledge pre-
and post-home care instruction was reported in last month's issue of Home
Healthcare Nurse. As indicated, foundational knowledge is a necessary
prerequisite to effective diabetes management. This article reports on patients'
self-efficacy for diabetes management before and after home care and demonstrates
that boosting a person's judgment of his or her ability to perform specific
diabetes activities is an important next step toward improving self-care.
PMID- 10763658
TI - Relief for home care? Could it be?
PMID- 10763659
TI - A gift from James.
PMID- 10763660
TI - Caring for the nation's first hand transplant patient.
PMID- 10763661
TI - Indignation.
PMID- 10763662
TI - Annie Altschul's legacy to 20th century British mental health nursing.
AB - Being knowledgeable about, learning from and building upon one's history is the
hallmark of an enlightened and progressive profession. This includes an
appreciation of the work of those who contributed to moulding the profession into
what it currently is. Mental health nursing has not distinguished itself by
respect for its former leaders. In this paper, the life and times of one of the
most outstanding mental health nurses of the century, Professor Annie Altschul,
are recalled and examined. She sought constantly to establish what should be the
essence of mental health nursing and what its role should be in the alleviation
of human suffering. As an outsider herself, she identified strongly with those
marginalized by society. Always a spokesperson for the centrality of nursing in
patient care, she saw nurses as those best placed to provide holistic care to
patients whilst other professionals specialized in their biomedical, social and
financial needs. Long after her retirement, Altschul remains active in
supervising and examining postgraduate nursing students. She is still a voice in
the mental health debate, someone whose opinions are sought and valued.
PMID- 10763663
TI - What are psychiatric nurses needed for? Developing a theory of essential nursing
practice.
AB - Contemporary developments in health care have encouraged a review of the
professional status of psychiatric nursing. However, little study has been made,
to date, of the discrete 'need' for psychiatric nursing within a
multidisciplinary service. Employing an adapted grounded theory methodology,
substantive theory was developed concerning the expressed need for psychiatric
nursing, by patients, their carers and mental health professionals, based on six
sites from England, Eire and Northern Ireland. The study found some consensus
across both recipients and providers of mental health care, that the essential
feature of nursing (the core category) involved a complex of relationships:
'knowing you--knowing me'. Within that complex, nurses either elected, or were
required, to move--or 'toggle'--between three discrete domains of relating: the
Ordinary Me (OM); the Pseudo-ordinary or Engineered Me (POEM); and the
Professional Me (PM). Four internal dimensions involving the nurses' depth of
knowing, power, use of time and use of translation, distinguished these domains.
The emergent theory is discussed within the context of the emergent growth in
user (consumer) influence and health care technology.
PMID- 10763664
TI - Altschul's legacy in mediating British and American psychiatric nursing
discourses: common sense and the 'absence' of the accountable practitioner.
AB - This paper contributes to an archaeology of knowledge in the field of psychiatric
and mental health nursing. It focuses on a principal concern of contributors to
literature on British psychiatric nursing: the problem of defining psychiatric
nursing. Early British writers describing psychiatric nursing accomplished the
'presence' of psychiatric nursing as a discursive object, by discursively
constructing the 'absence' of the psychiatric nurse doing, and being accountable
for, 'appropriate' work. Altschul's (1972) Patient-nurse Interaction was the key
text in this tradition, mediating British and American discourses, setting the
methodological and substantive agenda for an important body of subsequent British
psychiatric nursing research. The paper examines a number of topics in the
American and British discourses mediated by Altschul: the privileging of nurses'
presence and language in communication with patients; lay versus professional
knowledge, and interaction as gossip; 'common sense' as a topic; common sense as
different from 'identifiable perspective'; the problem of accountability and the
hierarchy of credibility; accountability, the 'absent' nurse, and issues of
method. Altschul's later work keeps in tension two potentially conflicting claims
-on the one hand, that the practice of psychiatric nursing depends on the 'kind
of person' the nurse is, and on the other, that specialist discourses have
priority in determining the basis for practice. Altschul played a crucial role in
establishing the role of research in British psychiatric nursing discipline:
locating the accountable individual practitioner, and devising remedies for
'absence'. In doing so, she anticipated current discourses on nurses'
accountability, particularly their inability to demonstrate 'evidence' of their
'effectiveness'.
PMID- 10763665
TI - An ethnographic study of psychiatric nursing.
AB - There is a well documented continuing anomaly between what is expected of a
psychiatric nurse and observations of practice. This paper presents an
ethnographic study carried out in three acute psychiatric in-patient units over
one year. Methods used were participant observation and semistructured interviews
of 15 trained nurses. Three themes were isolated during and following data
analysis: the difficulty of working closely with mentally disturbed individuals;
maintaining distance and congruent care. There was a notable dichotomy, that of
wanting to work with the patients but constantly feeling that what they
intuitively wanted to do was not right.
PMID- 10763666
TI - Disentangling dynamics: group sensitivity and supervision.
AB - In order to contextualize Altschul's interest in group dynamics we present a
brief history of staff group work approaches in the UK and USA. Using case
examples, the work of staff group sensitivity and group supervision is described.
The difficulties of working in staff groups are highlighted and the antipathy
towards group practice is discussed. It is argued that learning about conflict
resolution in staff groups prepares nurses for dealing with conflicts in clinical
practice. The case for re-invigorating interest in group theory and practice is
presented. In presenting our reflections on staff group work, we hope not only to
re-kindle the type of interest in groups that inspired Altschul but also to
represent the case that it is ill conceived to attempt the work of mental health
nursing without recourse to the supervisory resources of group theory, practice
and support. It is through group feedback that mental health nurses and other
health professionals can extend their learning about interpersonal relations,
achieve quality standardization through peer feedback and reflect on practice in
truly collaborative ways (Schon 1983).
PMID- 10763667
TI - Ten years on: the abiding presence of R.D. Laing.
AB - The life and work of Ronald David Laing forms the basis for a review of anti
psychiatry from the late 1960s until about the mid 1970s. That the period
concerned was not the jamboree of sex, drugs and anarchy by which it is normally
portrayed is evidenced by Laing's ambivalence towards anti-psychiatry as well as
his yearning for academic and medical respectability. Recent biographies of Laing
as well as interviews given shortly before his death were scanned in preparation
for this paper. However, some new perspectives are supplied. For example, the
curious neglect (by scholars) of the conservative psychiatric forces which
paralleled the Laingian critique is briefly examined and especially the attitudes
of such forces towards Laingian psychiatry. In addition, some connections are
made between Laing's upbringing and his work. Such speculations, always risky,
seem valid albeit Laing would probably smile. Lastly, whilst a comparable history
of seditious thought in nursing remains unwritten, because hidden, such a history
will ultimately depend on psychiatric nursing and especially the career of Annie
Altschul who, even earlier than Laing, had sought to define psychiatric care as
an interactive and humanizing event.
PMID- 10763668
TI - Melting straitjackets.
AB - A description of the author's psychiatric breakdown is offered, and a discussion
of how such wounded experiences can help in mental health work. Wounded healers
are currently under attack in the National Health Service in the UK, following
the Allitt affair. The author offers strong warnings against all forms of
desiccated and detached professionalism in both nursing and social work. Material
on Zen training, and how that relates to Shamanism, is discussed and Podvoll's
Buddhist principles of 'basic attendance' are outlined.
PMID- 10763669
TI - Enforced medication--a personal perspective.
PMID- 10763671
TI - An encounter with the work of Annie Altschul: reflections from down under.
PMID- 10763670
TI - Enforced medication and virtue-ethics.
PMID- 10763672
TI - Rubella among Hispanic adults--Kansas, 1998, and Nebraska, 1999.
AB - Since 1994, the incidence of rubella has been low; most reported rubella cases
have been associated with outbreaks (1,2). Recent outbreaks have occurred
primarily among adult Hispanics, many of whom are natives of countries where
rubella vaccination is not routine or has been implemented recently (1). This
report describes two workplace-associated outbreaks of rubella and summarizes the
characteristics of the recent outbreaks in the United States.
PMID- 10763674
TI - Behavioural neuroscience and child psychopathology: insights from model systems.
AB - We have just emerged from "the Decade of the Brain", yet in so many ways it was
the "Decade of the Genome". What relevance does the remarkable advance in
knowledge in genetics and neuroscience over that period have to our understanding
of child psychopathology? When the complexity of the genetic systems involved in
behavioural regulation of relatively simple organisms such as the nematode worm
Caenorhabditis elegans or the fruitfly Drosophila melanogaster is considered, the
possibility of comprehending the links from genes to behaviour in the developing
child seems remote. Yet, the principles of investigation in model systems are not
so different to those that should apply in humans. This review draws out the
parallels, and introduces recent findings from behavioural studies of C. elegans,
D. melanogaster, and the laboratory mouse, as well as humans, to illustrate the
point.
PMID- 10763673
TI - Adoption of perinatal group B streptococcal disease prevention recommendations by
prenatal-care providers--Connecticut and Minnesota, 1998.
AB - Group B streptococcal (GBS) infections are the leading bacterial cause of serious
neonatal disease in the United States (1). In 1996, in collaboration with the
American Academy of Pediatrics and the American College of Obstetricians and
Gynecologists, CDC issued consensus guidelines for preventing perinatal GBS
disease (2-4). These guidelines recommend using either a screening-based or a
risk-based strategy to identify women who should receive intrapartum
antimicrobial prophylaxis. To assess adoption of the GBS disease prevention
guidelines, the Connecticut and Minnesota state health departments surveyed
prenatal-care providers during January-April 1998. This report presents the
survey findings, which indicate that most prenatal-care providers in Connecticut
and Minnesota have adopted perinatal GBS disease prevention policies and that
strategy choice may vary by state and provider type.
PMID- 10763675
TI - Children's language learning: an interactionist perspective.
AB - This review of children's language learning considers historical accounts of
acquisition and individual variation, recent advances in methods for studying
language learning, research on genetic and environmental input that have
contributed to the interactionist perspective, and the relevance of cross
disciplinary work on language disorders and the biology of learning to future
theories. It concludes that the study of children's language development is
converging on an interactionist perspective of how children learn to talk,
incorporating the contributions of both nature and nurture to emergent,
functional language systems. Language learning is viewed as an integration of
learning in multiple domains.
PMID- 10763676
TI - Substance abuse in young people.
AB - Adolescent substance abuse, with its heterogeneity, its complexity and its
association with behavioural, physical and mental health problems is of
increasing interest to many; the politician, the economist, clinicians and
researchers, families and young people themselves. Data concerning the prevalence
and trends in use of a range of substances in different countries, cultures and
different groups are reviewed. The influence of associated mental and physical
health problems, the multiple definitions applied to use and abuse and the
confounding effect of different ideologies and cultural differences are
considered. There is now much interest in the understanding of risk and
protective influences, including multi focused prevention programmes among
vulnerable young people. Some positive effects of universal prevention programmes
are reported, although too often they lack thoroughness in programme
implementation, data collection and follow up. Indeed compared to the adult
addiction literature there is a death of research on adolescent treatment
outcomes. Research needs to address treatment and cost effectiveness in different
settings with different groups. The evidence tends to support multi faceted
interventions for high risk youths. However, the use of evidence based programmes
with a scientific basis should be supported and implemented.
PMID- 10763677
TI - Children and adolescents living with HIV and AIDS: a review.
AB - Worldwide, more than one million children are infected with human
immunodeficiency virus (HIV) and in the United States it has become the sixth
leading cause of death among 15-24-year-olds. Despite the trend of increasing
rates of infection, advances in therapies have led to survival past 5 years of
age for more than 65% of infected children. This global health threat will
therefore continue to have a significant impact on child and adolescent
psychiatry and psychology. This paper reviews current studies and reports on the
consequences of the acquired immunodeficiency syndrome (AIDS) epidemic in the
psychiatric care and development of children and adolescents infected by HIV.
From a search of all the English-language-based literature on pediatric AIDS, 140
studies are reviewed which address HIV infection and its psychological and social
implications. Several topics of mental health significance are examined: (1) the
epidemiology of HIV, (2) neurocognitive development among those infected, (3)
psychological impact of infection, and (4) the family and social context of HIV.
The transition of HIV from an acute, lethal disease to a subacute, chronic
disease has enormous implications for the neurocognitive and psychosocial
development of children and families. As children and adolescents infected with
HIV continue to live longer, normal developmental milestones and educational
needs will take on new significance. Many children will continue to be adversely
impacted by non-HIV factors such as poverty, inadequate medical services, and a
lack of social support. This review outlines recent developments that hold
promise to effectively reduce the treatment burden on the infected, their
families, and health care providers and to decrease the incidence of transmission
to the uninfected.
PMID- 10763678
TI - Child abuse and neglect and the brain--a review.
AB - Developmental psychology and the study of behaviour and emotion have tended to be
considered in parallel to the study of neurobiological processes. This review
explores the effects of child abuse and neglect on the brain, excluding
nonaccidental injury that causes gross physical trauma to the brain. It commences
with a background summary of the nature, context, and some deleterious effects of
omission and commission within child maltreatment. There is no post-maltreatment
syndrome, outcomes varying with many factors including nature, duration, and
interpersonal context of the maltreatment as well as the nature of later
intervention. There then follows a section on environmental influences on brain
development, demonstrating the dependence of the orderly process of
neurodevelopment on the child's environment. Ontogenesis, or the development of
the self through self-determination, proceeds in the context of the nature
nurture interaction. As a prelude to reviewing the neurobiology of child abuse
and neglect, the next section is concerned with bridging the mind and the brain.
Here, neurobiological processes, including cellular, biochemical, and
neurophysiological processes, are examined alongside their behavioural,
cognitive, and emotional equivalents and vice versa. Child maltreatment is a
potent source of stress and the stress response is therefore discussed in some
detail. Evidence is outlined for the buffering effects of a secure attachment on
the stress response. The section dealing with actual effects on the brain of
child abuse and neglect discusses manifestations of the stress response including
dysregulation of the hypothalamic-pituitary-adrenal axis, and parasympathetic and
catecholamine responses. Recent evidence about reduction in brain volume
following child abuse and neglect is also outlined. Some biochemical, functional,
and structural changes in the brain that are not reflections of the stress
response are observed following child maltreatment. The mechanisms bringing about
these changes are less clearly understood and may well be related to early and
more chronic abuse and neglect affecting the process of brain development. The
behavioural and emotional concomitants of their neurobiological manifestations
are discussed. The importance of early intervention and attention to the
chronicity of environmental adversity may indicate the need for permanent
alternative caregivers, in order to preserve the development of the most
vulnerable children.
PMID- 10763679
TI - Recent advances in the assessment of intelligence and cognition.
AB - In this paper, we review current issues in cognitive assessment. After addressing
important definitional and theoretical issues, we discuss some recently developed
cognitive assessment instruments as well as some recently revised instruments.
Tests that are scheduled for revision will also be mentioned. As most readers are
generally familiar with the widely used and nationally standardized IQ tests, we
will summarize these tests according to their general usage. The testing of
intelligence has been a major focus and contribution since the early days of
Psychology, when the birthplace of the intelligence testing movement began in
France with the work of Alfred Binet toward the end of the 19th century. Many of
the most widely known and used IQ tests have been developed in the U.S.A. and are
used internationally. In addition, other IQ tests have been developed in many
other countries outside the U.S.A. The use of IQ tests and selected assessment
considerations will be reviewed. Finally, we make some predictions about the
future role of cognitive assessment in the coming century.
PMID- 10763680
TI - Punctate midline myelotomy for the relief of visceral cancer pain.
AB - OBJECT: This study offers clinical support for the concept that neurosurgical
interruption of a midline posterior column pathway by performing a punctate
midline myelotomy (PMM) provides significant pain relief without causing adverse
neurological sequelae in cancer patients with visceral pain refractory to other
therapies. METHODS: A PMM of the posterior columns was performed in six cancer
patients in whom visceral pain had been refractory to other therapies. The cause
of the visceral pain was related to residual, progressive, or recurrent local
cancer or postirradiation effects. Clinical efficacy of the procedure was
examined by comparing patient pain ratings and narcotic usage pre- and post-PMM.
Follow-up periods ranged from 3 to 31 months. Examination of the results
indicates a significant reduction in pain ratings as well as a significant
reduction in daily narcotic use. No adverse neurological effects were observed.
One spinal cord has been recovered for postmortem examination. CONCLUSIONS: These
findings provide corroborating clinical evidence for the existence of a newly
recognized midline posterior column pathway that mediates the perception of
visceral pelvic and abdominal pain. Preliminary data indicate that significant
pain relief can be obtained following PMM with minimal neurological morbidity and
suggest that the procedure may provide an alternative treatment modality for
cancer-related pain in patients in whom adequate pain control with narcotics
cannot be achieved or narcotic side effects cannot be tolerated.
PMID- 10763681
TI - Duration of leg pain as a predictor of outcome after surgery for lumbar disc
herniation: a prospective cohort study with 1-year follow up.
AB - OBJECT: The aim of this study was to investigate different variables in the
duration of symptoms that can be used to predict outcome after lumbar
microdiscectomy. METHODS: In a prospective study of 132 consecutive patients who
underwent surgery for lumbar disc herniation, the authors evaluated the
prognostic value of different variables in the duration of symptoms for the 1
year period after surgery. The 1-year follow-up investigation was conducted by an
independent observer. Assessment of outcome was performed using a clinical
overall score (COS), which was recently assessed for its reliability and
validity. As for factors predictive of outcome, only duration of leg pain and
sick leave reached statistical significance in the multivariate analysis. Results
of the univariate analysis demonstrated that in patients experiencing
preoperative leg pain fewer than 4 months and between 4 and 8 months, a
significantly lower COS at the 1-year follow up was demonstrated compared with
those in whom the duration of leg pain was longer (> 8 months). One hundred eight
patients returned to work within the 1st year after surgery. Patients who took a
sick leave of more than 28 weeks before the operation were at higher risk of not
returning to work. CONCLUSIONS: Analysis of these results indicates that leg pain
lasting more than 8 months correlates with an unfavorable postoperative outcome
in patients with lumbar disc herniation, as well as a high risk of not returning
to work.
PMID- 10763683
TI - Management of low lumbar fractures by dorsal decompression, fusion, and
lumbosacral laminar distraction fixation.
AB - OBJECT: The authors conducted a study to assess the anatomical appropriateness of
using the S-2 dorsal neuroforamina as a hook fixation point, and they present the
results of their clinical experience of using a nonscrew alternative for the
surgical management of low lumbar (L-4 or L-5) burst fractures. METHODS: The
technique used involves lumbar laminar fixation, rod contouring (to preserve
lordosis), S- sublaminar wire fixation, S-2 dorsal neuroforaminal hook fixation,
cross-fixation, and distraction. Because the S-2 dorsal neuroforamina was used as
a unique fixation point, anatomical data obtained in 10 cadavers supporting the
technique's utility are provided. Surgery was performed in six patients by using
this technique, and solid fusion was achieved in all. CONCLUSIONS: The
reestablished lordotic posture was preserved in all but one patient. From an
anatomical perspective, the findings corroborate the use of the S-2 dorsal
foramina as a hook fixation point. This technique provides a viable adjunct or
alternative to sacral screw and ilial fixation techniques.
PMID- 10763682
TI - Pathoanatomy of clinical findings in patients with sciatica: a magnetic resonance
imaging study.
AB - OBJECT: Anatomical details of nerve root compression may explain the production
of the signs and symptoms of sciatica. The authors of anatomical studies have
offered many theories without clearly demonstrating the clinical relevance of the
observations. Clinicoanatomical series are scarce and are affected to a great
extent by selection bias. METHODS: The authors created a schematic drawing of the
lumbar anatomy based on both the literature and in vitro anatomical observations.
A diagnosis was then made with the aid of detailed and standardized clinical and
magnetic resonance (MR) imaging studies in primary-care patients who presented
with pain that radiated into the leg. Clinical and MR imaging findings were
correlated. Finally, the anatomical drawing was compared with the clinical data.
The higher the vertebral level of symptomatic disc herniations, the more likely
the compression will be more laterally situated. Classic symptoms of sciatica
(typically, dermatomal pain; increase in pain when coughing, sneezing, or
straining; and testing positive for pain during straight leg raising) were most
likely to occur with compression of the nerve root in the axilla and with
mediolateral disc herniations. CONCLUSIONS: The L-3, L-4, L-5, and S-1 nerve
roots each tend to be compressed at different sites along the rostrocaudal course
of the nerve root. Disc herniations become symptomatic at different sites for
each disc level. The schematic drawing produced a priori could well be used to
explain these findings. Expectations of particular clinical findings can be
predicted by specific pathoanatomical findings.
PMID- 10763684
TI - Outcome after surgical treatment of progressive posttraumatic cystic myelopathy.
AB - OBJECT: Progressive posttraumatic cystic myelopathy (PPCM) can occur after an
injury to the spinal cord. Traditional treatment of PPCM consists of inserting a
shunt into the cyst. However, some authors have advocated a more
pathophysiological approach to this problem. The authors of the present study
describe their surgical treatment protocol and outcome in a series of patients
with syringomyelia. METHODS: Medical records of 34 patients undergoing surgical
treatment for PPCM were reviewed. Laminectomies and intraoperative
ultrasonography were performed. In patients without focal tethering of the spinal
cord and in whom only a confluent cyst had been revealed on ultrasonography, a
syringosubarachnoid shunt was inserted; in those with both tethering and a
confluent cord cyst, an untethering procedure was performed first. When a
significant reduction (>50%) in the size of the cyst was shown after the
untethering procedure, no shunt was inserted. When no changes in cyst size were
demonstrated on ultrasonography, a short syringosubarachnoid shunt was used. The
mean follow-up period was 28.7 months (range 12-102 months). The interval between
the mechanism of injury and the operation ranged from 5 months to 37 years (mean
11 years). Pain was the most frequent symptom, which was followed by motor
deterioration and spasticity. Postoperative improvement was noted in 55% of
patients who experienced motor function deterioration and in 53% of those who
demonstrated worsening spasticity. In 14 of 18 patients with an associated
tethered spinal cord, tethering alone caused significant collapse of the cyst.
Postoperative magnetic resonance imaging demonstrated cyst collapse in 92% of
patients who had undergone untethering alone and in 93% of those who underwent
syringosubarachnoid shunt placement. Treatment failure was observed in 7% of the
former group and in 13% of the latter. CONCLUSIONS: Posttraumatic cystic
myelopathy can occur with or without the presence of tethered cord syndrome.
Intraoperative ultrasonography can readily demonstrate this distinction to aid in
surgical decision making. Untethering alone in patients with tethered cord
syndrome and cyst formation can reduce the cyst size and alleviate symptoms and
signs of posttraumatic cystic myelopathy in the majority of these cases.
Untethering procedures in which duraplasty is performed to expand the
subarachnoid space may be a more physiologically effective way of treating
tethered cord with associated syringomyelia.
PMID- 10763685
TI - Somatosensory evoked potential monitoring in anterior thoracic vertebrectomy.
AB - OBJECT: Spine surgeons have used intraoperative cortical and subcortical
somatosensory evoked potential (SSEP) monitoring to detect changes in spinal cord
function when intraoperative procedures can be performed to prevent neurological
deterioration. However, the reliability of SSEP monitoring as applied to anterior
thoracic vertebral body resections has not been rigorously assessed. METHODS: The
authors retrospectively reviewed hospital charts and operating room records
obtained between August 1993 and December 1998 and found that SSEP monitoring was
used in 44 surgical procedures involving an anterior approach for thoracic
vertebral body resections. There were no patients in whom SSEP changes did not
return to baseline during the surgical procedure. Patients in four cases, despite
their stable SSEP recordings throughout the procedure, were noted immediately
postoperatively to have experienced significant neurological deterioration. The
false-negative rate in SSEP monitoring was 9%. Sensitivity was determined to be
0%. CONCLUSIONS: It is important to recognize high false-negative rates and low
sensitivity of SSEP monitoring when it is used to record spinal cord function
during anterior approaches for thoracic vertebrectomies. The insensitivity of
SSEPs for motor deterioration during anterior thoracic vertebrectomies is likely
due to the limitation of SSEPs, which monitor only posterior column function
whereas motor paths are conveyed in the anterior and anterolateral spinal cord.
The authors believe that SSEPs can not be relied on to detect reversible spinal
damage during anterior thoracic vertebrectomies.
PMID- 10763686
TI - Treatment of severe retromastoid pain secondary to C1-2 arthrosis by using
cervical fusion.
AB - OBJECT: In this report the authors review their 5-year experience in the
diagnosis and management of nine patients with severe retromastoid pain secondary
to C 1-2 arthrosis. Patients with symptomatic joints unresponsive to nonoperative
therapy underwent cervical fusion procedures. METHODS: The mean age of the
patients was 71 years, and the onset of prior symptoms ranged from 6 months to 18
years. All patients suffered similar discrete nonneuropathic pain without
radicular symptoms ipsilateral to the diseased facet joint. Four patients
experienced relief from pain with the use of nonoperative therapy. Five patients
continued to experience intractable pain and underwent C1-2 fusion. The follow-up
period ranged from 6 to 26 months. The cervical fusion procedure was successful
in treating the retromastoid pain in all patients. In patients who underwent
surgery, complete relief of pain was demonstrated in four and significantly
reduced in the fifth. CONCLUSIONS: The authors have drawn several conclusions.
First, C1-2 arthrosis has a rather unique presentation and is a potential cause
of upper posterior neck and head pain predominantly in elderly patients. Second,
nonoperative management significantly improved the pain in nearly half of their
patients and should be the first line of treatment. Last, C1-2 fusion was
successful in treating the pain in patients in whom nonoperative management had
failed to resolve symptoms.
PMID- 10763687
TI - Monitoring of blood parameters following anterior cervical fusion.
AB - OBJECT: Both C-reactive protein (CRP) level and erythrocyte sedimentation rate
(ESR) were measured prospectively in 51 cases in which uncomplicated cervical
anterior fusion was performed. The object of the authors was to quantify the
differences in the responses of these parameters recorded in the immediate
postoperative period and to determine factors influencing their course. METHODS:
Nineteen one-level, 23 two-level, and nine three-level procedures for disc
herniation and degenerative disease of the cervical spine were performed in 22
female and 29 male patients (mean age 49.2 years). Blood samples were obtained 1
day before as well as on 10 consecutive days and 3 months following anterior
cervical fusion. Serum CRP level was measured using a fluorescence polarization
immunoassay and ESR was determined from the same samples. Operative time, the
number of blood transfusions, and drugs administered in the postoperative period
were recorded. In addition, hemoglobin, hematocrit, red blood cell count,
platelet count, white cell count, and axillary body temperature were checked
daily. CONCLUSIONS: Monitoring of CRP level is superior to that of ESR for early
detection of infections after cervical spine surgery. Although CRP was not
related to any of the factors that have been proposed to explain its peak value
variance in previous studies, individual acute-phase protein metabolism response
to tissue affection appears to be a more decisive element in this respect.
PMID- 10763688
TI - Image-guided surgery: applications to the cervical and thoracic spine and a
review of the first 120 procedures.
AB - OBJECT: The authors undertook a study to demonstrate that frameless stereotaxy
can be applied safely to the cervical and thoracic spine to minimize
complications and associated morbidity. METHODS: A retrospective review of cases
was conducted involving the use of an image-guidance system for the accurate
placement of surgical implants or for resection of lesions within the cervical
and thoracic spine. The outcome measures considered were neural injury, vascular
injury, wound infection, surgical revision, and death. CONCLUSIONS: Image
guidance systems are useful intraoperative tools that can be applied accurately
to spinal surgery. In addition, such systems can be of great use in the
preoperative planning of complex spinal surgery.
PMID- 10763689
TI - Coaxial double-lumen methylmethacrylate reconstruction in the anterior cervical
and upper thoracic spine after tumor resection.
AB - OBJECT: A unique method of anterior spinal reconstruction after decompressive
surgery was used to prevent methylmethacrylate-dural contact in cancer patients
who underwent corpectomy. The purpose of this study was to assess the efficacy
and stability of polymethylmethacrylate (PMMA) anterior surgical constructs in
conjunction with anterior cervical plate stabilization (ACPS) in these patients.
METHODS: Approximately 700 patients underwent spinal surgery at The University of
Texas M. D. Anderson Cancer Center over a 4-year period. The authors conducted a
retrospective outcome study for 29 of these patients who underwent anterior
cervical or upper thoracic tumor resections while in the supine position. These
patients were all treated using the coaxial, double-lumen, PMMA technique for
anterior spinal reconstruction with subsequent ACPS. No postoperative external
orthoses were used. Twenty-seven patients (93%) harbored metastatic spinal
lesions and two (7%) harbored primary tumors. At 1 month postsurgery, significant
improvement was seen in spinal axial pain (p<0.001), radiculopathy (p<0.001),
gait (p = 0.008), and Frankel grade (p = 0.002). A total of nine patients (31%)
underwent combined anterior-posterior 360 degrees stabilization. Twenty-one
patients (72%) experienced no complications. Complications related to
instrumentation failure occurred in only two patients (7%). There were no cases
in which the patients' status worsened, and there were no neurological
complications or infections. The median Kaplan-Meier survival estimate for
patients with spinal metastases was 9.5 months. At the end of the study, 13
patients (45%) had died and 16 (55%) were alive. Postoperative magnetic resonance
images consistently demonstrated that the dura and PMMA in all patients remained
separated. CONCLUSIONS: The anterior, coaxial, double-lumen, PMMA reconstruction
technique provides a simple means of spinal cord protection in patients in the
supine position while undergoing surgery and offers excellent results in cancer
patients who have undergone cervical vertebrectomy.
PMID- 10763690
TI - Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in
the rodent.
AB - OBJECT: Bone morphogenetic proteins (BMPs) have been shown to have significant
osteoinductive activity in numerous in vitro and in vivo assay systems, and BMP-2
and BMP-7 are currently being evaluated in human clinical studies. In the spinal
region, BMPs have been shown to promote spinal arthrodesis at a higher rate than
autologous bone alone. The delivery of BMPs via direct or ex vivo gene therapy
techniques is also currently being evaluated and has shown promise in several
mammalian models. The present study was designed to evaluate the efficacy of the
use of direct, percutaneous BMP-9 adenoviral gene therapy to promote spinal
fusion in the rodent. METHODS: Each animal was injected with 7.5x10(8) pfu of a
BMP-9 adenoviral vector in the lumbar paraspinal musculature and allowed to
survive 16 weeks. Computerized tomography studies and histological analysis
demonstrated massive bone induction at the injection sites, clearly leading to
solid spinal arthrodesis, without evidence of pseudarthroses, nerve root
compression, or systemic side effects. CONCLUSIONS: The results of this study
strongly support the advancement of BMP gene therapy techniques toward clinical
use.
PMID- 10763691
TI - The apical ligament: anatomy and functional significance.
AB - OBJECT: The authors conducted a study to describe the detailed anatomy of the
apical ligament and to acknowledge or refute its historical description as a
functionally significant contributor to craniocervical stability. METHODS: In 20
adult human cadavers measurements of the apical ligament were obtained, and its
detailed anatomy was observed. Ranges of motion were also assessed to discern the
function of the apical ligament. CONCLUSIONS: Results of the study support the
concept that the apical ligament is best described as a vestigial structure that
offers no significant added stability to the craniocervical junction. In fact,
this ligament was absent in 20% of the specimens examined. These data will aid
physicians who frequently view images or manage clinical problems of the
craniocervical junction because they may focus on other ligaments of this area
and not the apical ligament.
PMID- 10763693
TI - Spontaneous resolution and recurrence of a Chiari I malformation and associated
syringomyelia. Case report.
AB - The spontaneous resolution of syringomyelia has been reported infrequently. In
patients with Chiari I malformations, resolution of the syringomyelia has
sometimes been associated with improvement of their malformation. The authors
present a case of spontaneous resolution followed by recurrence of syringomyelia
and a corresponding change in the Chiari malformation. This case is of interest
in light of the theories postulated to explain spontaneous resolution of
syringomyelia.
PMID- 10763692
TI - Segmental cervical spine motion during orotracheal intubation of the intact and
injured spine with and without external stabilization.
AB - OBJECT: The purpose of this study was to establish a cadaveric model for
evaluating cervical spine motion in both the intact and injured states and to
examine the efficacy of commonly used stabilization techniques in limiting that
motion. METHODS: Intubation was performed in fresh human cadavers with intact
cervical spines, following the creation of a C4-5 posterior ligamentous injury.
Movement of the cervical spine during direct laryngoscopy and intubation was
recorded using video fluoroscopy and examined under the following conditions: 1)
without external stabilization; 2) with manual in-line cervical immobilization;
and 3) with Gardner-Wells traction. Subsequently, segmental motion of the occiput
through C-5 (Oc-C5) was measured from digitized frames of the recorded video
fluoroscopy. The predominant motion, at all levels measured in the intact spine,
was extension. The greatest degree of motion occurred at the atlantooccipital (Oc
C1) junction, followed by the C1-2 junction, with progressively less motion at
each more caudal level. After posterior destabilization was induced, the
predominant direction of motion at C4-5 changed from extension to flexion, but
the degree of motion remained among the least of all levels measured. Traction
limited but did not prevent motion at the Oc-C1 junction, but neither traction
nor immobilization limited motion at the destabilized C4-5 level. CONCLUSIONS:
Cadaveric cervical spine motion accurately reflected previously reported motion
in living, anesthetized patients. Traction was the most effective method of
reducing motion at the occipitocervical junction, but none of the interventions
significantly reduced movement at the subaxial site of injury. These findings
should be considered when treating injured patients requiring orotracheal
intubation.
PMID- 10763694
TI - Atlantal stenosis: a rare cause of quadriparesis in a child. Case report.
AB - The authors report the case of a 3-year-old boy who suffered from quadriparesis
and respiratory distress after failing to execute a somersault properly.
Neuroimaging revealed spinal cord contusion with marked spinal canal stenosis at
the level of the atlas. No subtle instability, occult fracture, or other
congenital abnormalities were confirmed. Spinal cord contusion with marked canal
stenosis is rare, and only several adult cases have been reported. Severe
stenosis at the level of the atlas may predispose individuals to severe spinal
cord contusion, as occurred in our patient after sustaining trivial trauma.
PMID- 10763695
TI - Myolipoma in a tethered cord. Case report and review of the literature.
AB - The intradural myolipoma is a very rare tumor, consisting of fully differentiated
striated muscle fibers mingled with fat. Only four previous cases have been
identified. The authors present a case in which this tumor was associated with a
symptomatic tethered spinal cord in an 18-year-old man.
PMID- 10763696
TI - Solitary fibrous tumor of the thoracic spine. Case report and review of the
literature.
AB - Solitary fibrous tumor (SFT) is a neoplasm first described as a tumor of
mesenchymal origin involving soft tissues. The authors provide a review of the
literature with detailed pathological analysis and radiological description of
SFTs involving the central nervous system. The authors report a rare case of a
SFT of the thoracic spine in an adult man presenting with myelopathy. Magnetic
resonance imaging revealed a well-circumscribed, intradural, extramedullary mass
at the T2-3 level. Histological examination demonstrated a proliferation of
predominantly spindle-shaped cells with a collagen-matrix background.
Immunohistochemical staining was positive for vimentin and CD34 and negative for
S-100 and epithelial membrane antigen with an MIB-1 labeling index of 2.6%.
Review of the literature revealed 10 cases in which this tumor, frequently found
in the pleura, was involved in the central nervous system. Although rare and
their clinical significance as yet unknown, SFTs may be considered in the
differential diagnosis of intradural spinal cord lesions. The natural history is
also unknown, but these tumors appear to be biologically benign.
PMID- 10763697
TI - Intradural cervical disc herniation. Case report and review of the literature.
AB - The authors describe a rare case of an intradural cervical disc herniation in a
40-year-old man presenting with Brown-Sequard's syndrome. Magnetic resonance
imaging revealed the pathological entity at the C5-6 disc space, which showed
suspicious signs of intradural extension of the disc herniation. After the
patient underwent microsurgical removal of the herniated disc via an anterior
approach, he experienced a complete remission of symptoms. The existing pertinent
literature is reviewed, and diagnostic and therapeutic implications are
discussed.
PMID- 10763698
TI - Trichinoechinococcosis T-5. Case report.
AB - Echinococcosis affecting the spine is rare. The authors present the case of a 23
year-old man in whom features of thoracic spinal cord compression were
demonstrated. Magnetic resonance imaging of the thoracic spine revealed an
extradural cystic lesion involving the spine and paraspinal musculature. At
surgery echinococcosis was confirmed, and subsequent histopathological
examination also revealed Trichinella infestation of the paraspinal musculature.
After undergoing decompressive surgery and albendazole therapy, the patient made
a remarkable improvement. Although primary echinococcosis can affect the spine,
concomitant infestation with Trichinella has not been reported. Surgery has to be
followed by albendazole therapy.
PMID- 10763699
TI - Multiple hemangiomas (hemangiomatosis) of the cauda equina and spinal cord. Case
report.
AB - A case of multiple hemangiomas of the cauda equina nerve roots, conus medullaris,
and lower spinal cord is described. The 74-year-old male patient presented with a
9-month history of progressive bilateral leg weakness. He had a history of
lymphoma at the age of 39 years and renal cell carcinoma in his early 40s.
Neither disease was evident at the time of this presentation. A magnetic
resonance image revealed multiple enhancing nodules in the cauda equina region as
well as on the pial surface of the lower thoracic spinal cord and conus
medullaris. The patient underwent an L2-3 laminectomy. Cauda equina nerve roots
were found to be studded with numerous purple nodules, the largest measuring 6 to
8 mm. The nodules were adherent to nerve roots from which they could not be
resected. Two lesions were histologically examined and found to be capillary
hemangiomas. Twelve months into an uneventful postoperative course, the patient
is neurologically unchanged. This unique case might represent a distinct form of
hemangiomatosis confined to the cauda equina nerve roots and spinal cord.
PMID- 10763700
TI - Delayed onset of generalized tonic-clonic seizures as a complication of halo
orthosis. Case report.
AB - The authors report on the case of a 29-year-old man who presented with new-onset,
generalized tonic-clonic seizures 11 years after being treated with a halo
orthosis for a neurologically intact C-7 fracture. Neuroimaging and surgical
findings indicated that the epileptic focus was scar tissue, which developed
secondary to halo pin penetration of the skull. This complication of halo
orthosis has not yet been reported in the literature.
PMID- 10763701
TI - Intradural cervical disc herniation and Brown-Sequard's syndrome. Report of three
cases and review of the literature.
AB - Although cervical disc herniation commonly requires surgical intervention, the
intradural sequestration of a herniated cervical disc fragment is rare. In
searching the world literature on this topic, the authors found six case reports.
They report three new cases of intradural cervical disc herniation in which the
patients presented with Brown-Sequard's syndrome and they review the literature.
Although Brown-Sequard's syndrome is a rare clinical finding in extradural disc
herniation, six of the nine patients with intradural cervical disc herniation
(our cases and those from the literature) presented with symptoms of this
syndrome. The remaining patients presented with para- or quadriparesis. This
suggests that intradural disc herniation should be considered preoperatively in
patients in whom there is magnetic resonance imaging or myelographic evidence of
cervical disc herniation and Brown-Sequard's syndrome. In patients who underwent
anterior cervical discectomy for the treatment of intradural cervical disc
herniations, better outcomes were demonstrated than in those in whom posterior
procedures were performed.
PMID- 10763702
TI - Removal of a lumbar melanotic schwannoma via the far-lateral approach in a
patient with Carney complex. Case report.
AB - The authors describe a patient with Carney's complex who presented with sciatica
due to a lumbar nerve root sheath tumor. A far-lateral approach was used to
resect a nonpsammomatous melanotic schwannoma. Neurosurgeons surgically treating
peripheral nerve sheath tumors should be aware of the features of Carney complex
because the extent of the preoperative evaluation and postoperative management of
an otherwise routine surgical condition can be significantly affected.
PMID- 10763703
TI - Laparoscopic treatment of an anterior sacral meningocele. Case illustration.
PMID- 10763704
TI - Metastatic spinal ependymoma presenting as a vestibular schwannoma. Case
illustration.
PMID- 10763705
TI - Iatrogenic quadriplegia and bone wax. Case illustration.
PMID- 10763706
TI - A role for MHC class II antigen processing in B cell development.
AB - For mature B cells, the encounter with foreign antigen results in the selective
expansion of the cells and their differentiation into antibody secreting cells or
memory B cells. The response of mature B cells to antigen requires not only
antigen binding to and signaling through the B cell antigen receptor (BCR) but
also the processing and presentation of the BCR bound antigen to helper T cells.
Thus, in mature B cells, the ability to process and present antigen to helper T
cells plays a critical role in determining the outcome of antigen encounter. In
immature B cells, the binding of antigen results in negative selection of the B
cell, inducing apoptosis, anergy or receptor editing. Negative selection of
immature B cells requires antigen induced signaling through the BCR, analogous to
the signaling function of the BCR in mature B cells. However, the role of class
II antigen processing and presentation in immature B cells is less well
understood. Current evidence indicates that the ability to process and present
antigen bound to the BCR is a late acquisition of developing B cells, suggesting
that during negative selection B cells may not present BCR bound antigen and
interact with helper T cells. However, the expression of class II molecules is an
early acquisition of B cells and recent evidence indicates that the expression of
class II molecules early in development is required for the generation of long
lived mature B cells. Here we review our current understanding of the processing
and presentation of antigen by mature B cells and the role for antigen processing
and class II expression during B cell development.
PMID- 10763707
TI - Development of neonatal Th1/Th2 function.
AB - Newborn animals generally mount poor T cell-mediated immune responses in vivo. As
a result, neonates fall prey to infectious agents and diseases which have little
impact on immunocompetent adult animals. For some time, it was believed that this
phenomenon was due to an intrinsic inability of newborns to mount developmentally
mature Th1 responses. Recent studies in mice have challenged that view; under
certain conditions, adult-level Th1 function has been achieved in newborns. More
often, however, neonates develop Th2-dominant responses. A major challenge in the
field of developmental immunology is to understand why the 'default' response for
neonates is Th2 function. Cell intrinsic as well as environmental influences may
contribute to Th2 skewing in neonates.
PMID- 10763708
TI - Cellular immune responses in neonates.
AB - Reduced numbers of lymphocytes and antigen presenting cells have been described
as some of the main factors responsible for antigenic tolerance or low
responsiveness in neonates. However, by changing the parameters of immunization,
such as dose of antigen and frequency of antigen presenting cells we and others
have shown that neonates have the option of developing the same variety of immune
responses seen in adults. Several aspects of the development of cellular immunity
in human and murine neonates are reviewed in this article, with a special focus
on the development of T cell mediated responses, from ontogeny to effector
function.
PMID- 10763709
TI - Vaccination in the neonatal period and early infancy.
AB - Immune maturation is responsible for a progressive increase in antibody responses
that can be elicited during the first year of life, such that neonatal
immunization may currently not be expected to induce strong antibody responses.
In contrast, B and T cell priming can be induced very early in life, without
interference of maternal immunity. Strong IL-5 and IL-13 responses in young mice,
and limited IL-12 and IFN-gamma release capacity by early life APC and T cells
both in young mice and infants, could contribute to the severity of infections
with intracellular pathogens in early life. It calls for evaluation of novel
delivery systems, adjuvants and/or prime-boost immunization strategies capable to
meet the challenge of both strong neonatal immunogenicity and acceptable
reactogenicity. The extent to which early life murine immunization models may be
useful for preclinical evaluation of infant responses is outlined in this review.
PMID- 10763710
TI - DNA vaccination and the immune responsiveness of neonates.
AB - Neonates often respond poorly to conventional vaccines or microbial infections.
Immaturity of the immune system has been considered to play a role in this
regard. However, accumulating evidence shows that in certain conditions, neonatal
inoculation of antigens leads to protective immunity. In the particular case of
DNA vaccines administered to neonates, the rule is immunity rather than
tolerance. Exceptions to the rule give opportunities to further understand the
neonatal responsiveness and the mechanism of DNA vaccination. Due to the very
nature of the vaccine vector, inhibition of neonatal DNA vaccination by maternal
antibodies may be limited to the humoral immunity.
PMID- 10763711
TI - Neonatal tolerant immunity for vaccination against autoimmunity.
AB - Autoimmunity arises when the immune system no longer tolerates self and
precipitates lymphocyte reactivity against our own antigens. Although the
developing T cell repertoire is constantly purging, self-recognition events do
exist when such tight control is evaded and autoreactive lymphocytes escape the
thymus (the sites of T cell development) and migrate to the periphery. Upon
activation these autoreactive cells may exert aggressive behavior toward one's
own tissues and organs leading to autoimmune disease. Multiple sclerosis,
Rheumatoid arthritis, and type I diabetes are autoimmune diseases mediated by
autoreactive T cells. A logical approach to prevent such autoimmunity would be to
reprogram those lymphocytes to tolerate the self antigen. Injection of antigen at
the neonatal stage promotes a state of tolerance such that successive encounter
with antigen does not precipitate aggressive reactions. The mechanism underlying
neonatal tolerance involves priming of T cells whose effector functions do not
cause inflammatory reactions upon recognition of antigen but rather induce
protective immunity. This form of tolerant immunity provides an attractive
strategy for vaccination against autoimmunity. Herein, it is shown that neonatal
exposure to a self-peptide-immunoglobulin chimera drives a tolerant immunity
toward the self-peptide and protects against the autoimmune disease, experimental
allergic encephalomyelitis.
PMID- 10763712
TI - Neonatal immunity and somatic mutation.
AB - Neonatal animals are able to mount an effective immune response, both humoral and
cellular, when immunized using conditions that maximize stimulation of antigen
presenting cells, T cells, and B cells. In adults, somatic mutation is a key
feature of the humoral immune response because it contributes to the generation
of high affinity memory B cells. Recent evidence that B cells in neonatal mice
and human infants can somatically mutate their immunoglobulin heavy chains
suggests that neonates can utilize somatic mutation not only to diversify their
restricted germline antibody repertoire, but also to improve upon this repertoire
by the generation of B cells which can produce higher affinity antibodies. By
extrapolation, if vaccination of children early in life resulted in somatic
mutation and affinity maturation, this could provide a more protective antibody
response to childhood diseases.
PMID- 10763713
TI - Classification of congenital anomalies of the upper limb.
AB - Six hundred and ninety-four patients with 993 anomalies of the upper limbs were
classified according to the classification of Swanson et al. (1983). The data
from these patients were compared with previous studies, and similar
discrepancies were found. One explanation for these discrepancies is a lack of
uniformity in the classification of Swanson et al., which may be caused by out
dated knowledge of the pathogenesis of congenital limb anomalies. Therefore, it
seems necessary to describe the anomalies instead of the diagnoses. A descriptive
method is being validated in our outpatient department that records all anomalies
of the upper limb.
PMID- 10763714
TI - Similarities between a conjoined nail and the palmar nail syndrome.
AB - The congenital palmar nail syndrome consists of a triad of palmar nail, absent
finger flexion and abnormalities of the distal phalanx. There are two main
theories about the pathogenesis of this syndrome: the ancestral reversion theory
and the duplication theory. In this paper, similarities between a conjoined nail
in conjoined twins and the palmar nail syndrome are described to support the
duplication theory.
PMID- 10763715
TI - Nail fold creation in complete syndactyly using Buck-Gramcko pulp flaps.
AB - We have used the double pulp flap technique described by Buck-Gramcko for nail
fold creation in 75 fingertips after separation of 38 complete syndactyly webs in
27 patients. The operative technique is described and the results are discussed.
Nail patterns in these complex syndactyly webs are analysed and a classification
is proposed.
PMID- 10763716
TI - Distraction lengthening of the forearm for congenital and developmental problems.
AB - Thirty-five callus distractions of the forearm were carried out in 23 patients,
who were divided into two groups according to the cause of the shortening. Eleven
cases in group A had congenital dysplasia, and the 12 cases in group B had growth
disturbances from tumours or infection. The mean amount of lengthening was 27 mm
in group A and 25 mm in group B. The mean percentage increase in length was 35%
and 17%, respectively. The mean duration of fixation was 159 days and 127 days,
respectively. The Healing Index had a positive correlation with the age at
surgery in group A, but not in group B. The main complication was callus
deformity after the removal of a fixator, which was especially frequent in group
A. To avoid complications, the aetiology of shortening and the age of the patient
should be considered when deciding the surgical protocol.
PMID- 10763717
TI - Long-term follow-up of surgical correction of Madelung's deformity with
conservation of the distal radioulnar joint in teenagers.
AB - Eleven wrists with painful Madelung deformity in seven patients were corrected
during adolescence by a closing wedge osteotomy of the radius and a shortening
osteotomy of the ulna, with conservation of the distal radioulnar joint. At late
follow-up (9.7 years) function was considerably improved. When the ulnar head was
correctly relocated during operation, a new distal radioulnar space developed.
Shortening of the ulna must be generous and combined with slight flexion at the
osteotomy.
PMID- 10763718
TI - Injuries to the hand from dog bites.
AB - A review of dog bite injuries referred to one surgeon over a 12 month period
demonstrated a significant association between a delay in referral and a
prolonged period of subsequent in-patient treatment. Two patients sustained
injuries when delivering material through a letter-box.
PMID- 10763719
TI - The use of ultrasound in the diagnosis of injuries of the ulnar collateral
ligament of the thumb.
AB - We describe the use of a specialist referral clinic and ultrasound assessment for
all injuries to the ulnar collateral ligament of the metacarpophalangeal joint of
the thumb presenting to an Accident and Emergency (A&E) department. Senior House
Officers in the A&E department were able to correctly diagnose only 45% of the
ruptures of the ulnar collateral ligament. The overall agreement between
specialist clinic examination and ultrasound for injury to the ulnar collateral
ligament was 85% (kappa 0.647). When compared with the operative finding
ultrasound had a positive predictive value for rupture of 94%. An algorithm is
presented for the assessment of injuries to the ulnar collateral ligament in A&E
departments.
PMID- 10763720
TI - Dynamic radial translation instability of the carpus.
AB - We report a case of a dynamic radial translation instability of the carpus,
secondary to avulsion of the ulnocarpal ligaments and attenuation of the short
radiolunate ligament. In addition, there was a peripheral detachment of the
distal radioulnar ligaments causing distal radioulnar instability. Reattachment
of the avulsed ligaments combined with a Sauve-Kapandji procedure resulted in an
excellent function, which was maintained 10 years after surgery.
PMID- 10763721
TI - Arthroscopic resection of dorsal wrist ganglia and treatment of recurrences.
AB - From 1995 to 1998, 30 patients with dorsal wrist ganglia and four with recurrent
dorsal ganglia underwent arthroscopic resection. At a mean follow-up of 16
months, no complications were seen, but minimal pain persisted in three patients.
Two recurrences were seen after arthroscopic resection of primary ganglia.
PMID- 10763722
TI - Functional scoring system for obstetric brachial plexus palsy.
AB - We suggest a new scoring system that measures the upper limb function both as a
unit and in separate parts. Our system was designed to study the recovery in
patients with obstetric brachial plexus palsy (OBPP). It measures active limb
movements and compares them with the normal side to obtain a ratio, which is then
converted to a score. Fifty-two patients with OBPP were studied with a follow-up
of 2 years. The progress of the patients was monitored using the system. Thirty
seven patients (71%) achieved very good recovery, eight patients (15%) achieved a
good score, and five patients (10%) achieved a poor score. Most of the recovery
occurred before the age of 6 months.
PMID- 10763723
TI - Classification of impairment of shoulder abduction in obstetric brachial plexus
palsy and its clinical significance.
AB - Shoulder abduction was studied in 25 cases of obstetric brachial plexus palsy
(OBPP). According to muscle function, electromyographic features and X-ray
examination, impairment of shoulder abduction could be classified into dynamic,
resistant or combined types. Five cases were the dynamic type, which was
characterized by paralysis of the shoulder abductors. Fifteen cases were
categorized as the resistant type, with contracture of the subscapularis muscle,
co-contraction of latissimus dorsi and teres major muscles and secondary
disorders of the shoulder joint. Five cases were classified as the combined type
in which there were both dynamic and resistant factors. Appropriate management
and surgical procedures in the shoulder affected by OBPP depend on the
pathological classification.
PMID- 10763724
TI - Developmental and behavioural outcome in obstetric brachial plexus palsy.
AB - Forty-four children with obstetric brachial plexus palsy were assessed for both
developmental attainment and behavioural problems. Analysis of the resulting data
revealed developmental and behavioural problems previously not identified,
particularly in those with more severe injuries. These effects were independent
of the general condition of the child at birth, as indicated by their Apgar
scores. Further studies are required to provide clarification of these children's
difficulties, the mechanisms by which they occur and effective strategies to
address them.
PMID- 10763725
TI - Obstetric brachial plexus palsy: a large animal model for traction injury and its
repair. Part 1: age of the recipient.
AB - A Sunderland type IV traction injury to the C6 root of the sheep or lamb brachial
plexus was used as a model for obstetric traction injury to the C5 root in
humans. The injury was created and immediately repaired using interfascicular
nerve autografts in a group of adult sheep and a group of newborn lambs. The
animals were examined using electrophysiological and morphometric techniques 1
year after operation. It was found that the recovery of neuromuscular function
was superior in the lambs. The implication is that nerves in newborn animals have
a better potential for regeneration than that seen in older individuals. This is
discussed with reference to the management of obstetric brachial plexus palsy.
PMID- 10763726
TI - A new classification for fingertip injuries.
AB - A new classification of fingertip injuries is presented. The PNB classification
separates the injury into its effect on the three components of the fingertip:
pulp, nail and bone. This provides a three digit number that accurately describes
the injury. This new classification can be used to record and document injuries,
without having to resort to lengthy description. It could also be used to provide
detailed instructions for treatment and indications for referral. Examples of the
application of the classification are given.
PMID- 10763727
TI - Immediate de-syndactylization of the reverse radial forearm flap.
AB - The reverse radial forearm flap was used to cover soft tissue defects on the
dorsal aspect of the hand and fingers with immediate de-syndactylization of the
distal part of the flap in four cases. A total of 14 fingers were covered with de
syndactylized segments and these were divided into two groups. In group A (nine
fingers) the defect extended to or just distal to the proximal interphalangeal
(PIP) joint. The defect in group B (five fingers) was proximal to the PIP joint.
Primary wound healing was observed in the proximal and lateral edges of the flap
in all cases. However, delayed wound healing was observed in the distal edge of
five of the 14 segments. All five segments that suffered from edge necrosis were
from group A, indicating that longer segments are more likely to develop distal
edge ischaemia. The fact that there was no major skin loss in any of the patients
despite immediate de-syndactylization indicates that the reverse radial forearm
flap has a reliable blood supply and can support a portion with a random blood
supply without significant necrosis.
PMID- 10763728
TI - De Quervain's disease. Changing pathology or changing perception?
AB - The basic anatomy of the first extensor compartment is presented with a review of
the pathology of de Quervain's stenosing tenovaginitis. The results in 100
medicolegal cases of de Quervain's disease are analysed and reasons are sought
for the poor results. A review of the known factors associated with the causation
of de Quervain's disease is presented with recommendations about the management
of this condition.
PMID- 10763729
TI - Histological appearances in post-partum de Quervain's disease.
AB - Six patients who developed de Quervain's disease during pregnancy or within 12
months of childbirth were treated surgically. Histopathological examination of
the tendon sheaths using alcian blue stain showed that myxoid degeneration was
responsible for the thickening observed in the sheath. Characteristic intramural
deposits of mucopolysaccharides were present, predominantly in the subsynovial
region. Acute or chronic inflammatory changes were not seen. These findings were
the same as those described in patients with de Quervain's disease unrelated to
pregnancy or childbirth.
PMID- 10763730
TI - Median nerve latency measurement agreement between portable and conventional
methods.
AB - A portable nerve conduction testing device was compared with a conventional
method of measuring median nerve distal latencies. In a population-based study, a
health questionnaire was mailed to a random sample of 3000 participants (aged 25
to 74 years). Two hundred and sixty-two responders with numbness and/or tingling
in the median nerve distribution, and 125 asymptomatic responders underwent
clinical examination as well as portable and conventional median nerve distal
latency measurements. Motor latency measured with the portable device was on
average 0.1 millisecond (ms) lower than motor latency measured with the
conventional method (95% limits of agreement, -0.8-0.5 ms). Sensory latency
(wrist-to-index finger) measured with the portable device was on average 0.3 ms
lower than sensory latency (long finger-to-wrist) measured with the conventional
method (95% limits of agreement, -0.7-0.1 ms). Strong correlations were found
between the latencies measured by the portable and conventional methods (Pearson
correlation coefficient, 0.90-0.93). The agreement between the portable and
conventional methods in measuring median nerve distal latencies appears to be
acceptable. The cut-off value for abnormal sensory latency needs to be lower for
the portable than the conventional method if the present measurement techniques
are used.
PMID- 10763731
TI - Primary flexor tendon repair in zone 1.
AB - This paper presents an analysis of the results of repair of 102 complete flexor
tendon disruptions in zone 1 which were rehabilitated by an early active
mobilization technique during a 7 year period from 1992 to 1998. These injuries
were subdivided into: distal tendon divisions requiring reinsertion; more
proximal tendon divisions but still distal to the A4 pulley; tendon divisions
under or just proximal to the A4 pulley; and closed avulsions of the flexor
digitorum profundus tendon from the distal phalanx. Assessment by Strickland's
original criteria showed good and excellent results of 64%, 60%, 55% and 67%
respectively in the four groups. However, examination of the results measuring
the range of movement of the distal interphalangeal (DIP) joint alone provided a
more realistic assessment of the affect of this injury on DIP joint function,
with good and excellent results of only 50%, 46%, 50% and 22% respectively in the
four groups.
PMID- 10763732
TI - Morphology and dynamics of the ulnar nerve in the cubital tunnel. Observation by
ultrasonography.
AB - We examined 200 normal elbows to assess the usefulness of ultrasonography in
examining the ulnar nerve in the cubital tunnel. On longitudinal images in elbow
extension, the nerve changed its course at the fibrous band region 11.5 (SD 2.8)
mm distal to the medial epicondyle. On axial images, the diameter of the major
axis of the nerve was 3.1 (0.5) mm and that of the minor axis was 1.9 (0.4) mm in
men. The respective values were 2.7 (0.4) mm and 1.8 (0.4) mm in women. Dynamic
studies showed that in 53 elbows (27%), the nerve moved on to the tip of the
epicondyle with the elbow flexed and in 39 elbows (20%), the nerve dislocated
anteriorly. The diameters of the hypermobile nerves were significantly larger
than nerves that did not displace.
PMID- 10763733
TI - Feasibility of partial A2 and A4 pulley excision: residual pulley strength.
AB - We investigated residual digital flexor pulley strengths after 75% excision of
the A2 and A4 pulleys. For direct pull-off tests, A2 and A4 pulleys from
cadaveric fingers were tested by pulling on a loop of flexor digitorum profundus
tendon through the pulley. For functional loading tests, fingers were positioned
with the metacarpophalangeal joint flexed to 90 degrees for A2 testing, and with
the proximal interphalangeal joint in 90 degrees flexion for A4 testing (with all
other joints in full extension). Excision of 75% of A2 and A4 pulleys reduced
pulley strengths determined by both testing methods. For the functional loading
tests, which are more clinically relevant, mean tendon forces at failure after
partial excision of A2 and A4 pulleys were 224 and 131 N respectively, which is
sufficient to withstand flexor tendon forces expected during activities of daily
living.
PMID- 10763734
TI - The role of magnetic resonance imaging in late presentation of isolated injuries
of the flexor digitorum profundus tendon in the finger.
AB - Four patients had magnetic resonance imaging (MRI) after a clinical diagnosis of
a flexor digitorum profundus tendon rupture of the hand. The delay before
presentation ranged from 1 to 5 weeks. Three patients had closed ruptures and one
had a minor laceration which had healed. MRI showed proximal retraction of the
profundus tendon to the palm in two patients and limited retraction in the other
two. MRI provides important preoperative information for surgical decision-making
and planning in patients who present late with closed flexor tendon injuries of
the hand.
PMID- 10763736
TI - Biomechanical effectiveness of taping the A2 pulley in rock climbers.
AB - Circular taping around the proximal phalanx is frequently used by rock climbers
to treat tenosynovitis and to prevent injuries to the A2 pulley. The aim of this
study was to determine the biomechanical effectiveness of such taping. Devices
were built to measure physiological bowstringing in vivo, and to determine the
force of bowstringing as well as the force applied to the pulley tape. Two kinds
of taping on 16 fingers were measured during the typical crimp grip position.
Taping over the A2 pulley decreased bowstringing by 2.8% and absorbed 11% of the
force of bowstringing. Taping over the distal end of the proximal phalanx
decreased bowstringing by 22% and absorbed 12% of the total force. Circular
taping is minimally effective in relieving force on the A2 pulley. It is probably
ineffective in preventing pulley ruptures.
PMID- 10763735
TI - The use of a graft from the second extensor compartment to reconstruct the A2
flexor pulley in the long finger.
AB - A 10 mm wide ring graft from the second extensor compartment with periosteum from
the floor of the sheath was used to correct bowstringing in six patients who
sustained an isolated rupture of the A2 pulley. It was attached to the lateral
rims of the sheath. Periosteum was used for additional graft fixation.
Bowstringing was assessed by magnetic resonance imaging and ultrasound
preoperatively and 19.5 months after surgery. It was corrected in five patients
and improved in one. Pain was reduced from 35 to 7 points on a visual analogue
scale. Digital circumference decreased from 76 to 71 mm. Flexion at the PIP joint
increased from 88 degrees to 116 degrees. Pinch grip improved from 28 to 56 N.
PMID- 10763737
TI - Rupture of the ulnar collateral ligament of the metacarpophalangeal joint of the
index finger.
AB - We report a case of chronic instability due to rupture of the ulnar collateral
ligament of the metacarpophalangeal joint of the index finger of the left hand.
Because of persistent instability after the initial conservative treatment,
surgical treatment was required.
PMID- 10763738
TI - An accessory extensor tendon of the thumb as a cause of dorsal wrist pain.
AB - An accessory extensor pollicis longus muscle within the third extensor
compartment resulted in dorsal wrist pain that resolved following excision of the
accessory muscle.
PMID- 10763739
TI - Bipartite scaphoid with proximal pole osteonecrosis in a patient with Holt-Oram
syndrome.
AB - The Holt-Oram syndrome features a spectrum of upper limb abnormalities, including
an abnormal shape of the scaphoid. Our report concerns a 19-year-old man with
Holt-Oram syndrome and flattening and sclerosis of the proximal pole of a
bipartite scaphoid. The initial ossification centre in the scaphoid was located
distally at 8 years of age. By age 13, a pair of ossific centres were present.
After an automobile accident at age 18, the proximal pole became sclerotic and
then began to fragment over a 22-month period. Computed tomography confirmed the
presence of two poles of the scaphoid and sclerosis and fragmentation of the
proximal pole.
PMID- 10763740
TI - New 434 MHz interstitial hyperthermia system monitored by microwave radiometry:
theoretical and experimental results.
AB - A new complete microwave interstitial hyperthermia system monitored automatically
by microwave radiometry and working at 434 MHz is described in this paper. This
system, which includes a new radiometer with two internal temperature references,
is detailed. All its characteristics for microwave heating and radiometry are
presented. The new possibilities are shown through numerous experiments on
acrylamide phantom and excised tissues, which have been carried out for different
antennae implantation corresponding to the clinical situation. The clinic
protocol, associate to the brachytherapy, imposes the use of semi-loop catheters.
Coaxial antennae, inserted in these catheters, are not, therefore, positioned in
a rectilinear manner but undergo a curve. So, models based on the FDTD formalism
are developed to determine the theoretical power deposition. Owing to these
models, the effects of this physical motive on radiation diagrams can be taken
into account. The results of the power deposition are presented for two antennae.
Thermal patterns can then be determined by the solution of the bioheat-transfer
equation in the steady state. Also, the comparison of the results given by the
new interstitial hyperthermia system with those obtained with the previous 915
MHz one shows an improvement of the thermal performances.
PMID- 10763741
TI - Resonance effects in applicator water boluses and their influence on SAR
distribution patterns.
AB - Spurious electromagnetic oscillations in the water layer of applicator water
boluses are investigated. Two oscillation types--volume oscillations (VO) and
surface standing wave oscillations (SWO)--are considered. Conditions leading to
their excitation in water boluses, commonly used in clinical practice for local
hyperthermia, are examined. It was found that the thickness d of the water layer
is the main critical parameter which determines the possibility of spurious
oscillation modes excitation. Analytical equations are derived, allowing
calculations of critical d(c) and resonance d(r) values for a given water bolus,
and determine the approximate structure of electrical field strength distribution
at its radiating plane, taking account of spurious oscillations. Calculated d(c)
and d(r) values are in satisfactory quantitative agreement with experimental
data, whereas experimentally observed complicated SAR distribution perturbations
correlate qualitatively with the calculations in terms of volume and/or surface
standing wave oscillations excited within the water bolus.
PMID- 10763742
TI - Directional power deposition from direct-coupled and catheter-cooled interstitial
ultrasound applicators.
AB - This research represents an experimental investigation of the directional power
deposition capabilities of interstitial ultrasound applicators intended for
applications in hyperthermia and thermal surgery for cancerous or benign disease.
Direct-coupled and catheter-cooled ultrasound applicators were fabricated using
cylindrical piezoceramic transducers sectored to produce 90 degrees, 180 degrees
or 270 degrees active acoustic zones. The applicators were characterized through
measurements of acoustic power output and intensity beam distributions in
degassed water, in vitro temperature measurements in a perfused kidney model, and
in vivo temperature distributions in pig thigh muscle. The angular power
deposition patterns obtained in water were closely correlated to the resultant
temperature distributions measured in the perfused kidney and in vivo pig thigh
muscle. These sectored catheter-cooled and direct-coupled devices both
demonstrated the ability to generate high temperatures (>50 degrees C) at
sustained high power output levels (6-12 W) without degradation of the ultrasound
transducers. Directional control of the energy deposition from the sectored
ultrasound applicators was verified with corresponding temperature profiles in
both the in vitro and in vivo experiments, as well as with angularly shaped
thermal lesions. This is significant in that it demonstrates that heating in the
angular expanse can be controlled with interstitial ultrasound applicators, thus
providing more conformal thermal therapy by directing the thermal energy in the
targeted tissue while protecting non-targeted tissue from thermal damage.
PMID- 10763743
TI - An accurate, convective energy equation based automated meshing technique for
analysis of blood vessels and tissues.
AB - An automated three-element meshing method for generating finite element based
models for the accurate thermal analysis of blood vessels imbedded in tissue has
been developed and evaluated. The meshing method places eight noded hexahedral
elements inside the vessels where advective flows exist, and four noded
tetrahedral elements in the surrounding tissue. The higher order hexahedrals are
used where advective flow fields occur, since high accuracy is required and
effective upwinding algorithms exist. Tetrahedral elements are placed in the
remaining tissue region, since they are computationally more efficient and
existing automatic tetrahedral mesh generators can be used. Five noded pyramid
elements connect the hexahedrals and tetrahedrals. A convective energy equation
(CEE) based finite element algorithm solves for the temperature distributions in
the flowing blood, while a finite element formulation of a generalized conduction
equation is used in the surrounding tissue. Use of the CEE allows accurate
solutions to be obtained without the necessity of assuming ad hoc values for heat
transfer coefficients. Comparisons of the predictions of the three-element model
to analytical solutions show that the three-element model accurately simulates
temperature fields. Energy balance checks show that the three-element model has
small, acceptable errors. In summary, this method provides an accurate, automatic
finite element gridding procedure for thermal analysis of irregularly shaped
tissue regions that contain important blood vessels. At present, the models so
generated are relatively large (in order to obtain accurate results) and are,
thus, best used for providing accurate reference values for checking other
approximate formulations to complicated, conjugated blood heat transfer problems.
PMID- 10763744
TI - Changes in blood flow in locally heated intestine of rats.
AB - Male Fischer rats were surgically castrated through a lower midline incision and
a 5-8 cm long segment of small intestine was fixed to the interior of the right
scrotum. Two weeks after the surgery, the herniated intestine was heated by
immersing the scrotum into a water bath at different temperatures and the blood
flow in the intestine was measured with the radioactive microsphere method. The
blood flow in the herniated intestine increased 1.5-2.0 times when the scrotum
was heated with 42.5 and 43.5 degrees C water baths for 60-90 min, but began to
decrease when heated longer, although the blood flow after heating for 120 min at
these temperatures was still slightly larger than the blood flow before heating.
Upon heating the scrotum with 44.5 degrees C water bath, the blood flow in the
herniated intestine increased to 3-fold of control by 90 min and then rapidly
recessed. Massive histological damage was observed 24 h after heating with 44.5
degrees C water bath for 60 min. The blood flow in the intestine measured 1 day
after 60 min heating with 43.5 degrees C and 44.5 degrees C water bath was found
to be only slightly decreased. Given the relatively small decrease in blood flow,
the severe damage in the intestine 24 h after heating may be attributed to direct
damage to parenchymal cells.
PMID- 10763745
TI - Heat-inducible vectors for use in gene therapy.
AB - The objectives of this study were to quantity and compare the activities of a
minimal heat shock (HS) promoter and other promoters used in gene therapy
applications, and to identify strategies to amplify the heat inducibility of
therapeutic genes. Human tumour cells were transiently or stably transfected with
the HS promoter driving expression of reporter genes. HS promoter activity was
induced transiently, with maximum activity 16-24 h after HS, and was dependent on
temperature. The activity of the minimal HS promoter was similar, after 42
degrees C HS for 1 h, to that of the cytomegalovirus (CMV) promoter. To determine
if the HS promoter could be used to activate a second conditional promoter, cells
were transiently transfected with vectors containing both the HS and human
immunodeficiency virus type 1 (HIV1) promoters. When the IL-2 gene was placed
downstream of the HIV1 promoter. IL-2 production was temperature-independent. The
addition of the HIV tat gene downstream of the HS promoter caused IL-2 to be
induced more than 3 fold after a single 42 degrees C HS. These data indicate that
the minimal HS promoter, following activation by clinically attainable
temperatures (< or = 42 degrees C), can drive expression of therapeutic genes at
levels comparable to the CMV promoter and be used in conjunction with a second
conditional promoter to drive temperature-dependent, gene expression.
PMID- 10763746
TI - Pre-treatment with mild whole-body heating prevents gastric ulcer induced by
restraint and water-immersion stress in rats.
AB - The purpose of this study was to assess the preventive effect of pre-mild whole
body heating (WBH) on gastric ulcer induced by restraint and water-immersion
stress. The ulcer index and ulcer area ratio in rats exposed to restraint and
water-immersion stress were significantly decreased (p < 0.05 for both) after pre
treatment with mild WBH, compared with non-pre-treated rats. Mortality of rats
among the pre-treated with mild WBH (0%) was lower than in the control group
(33%). The concentration of HSP 70f in the stomach (both fundic and pyloric
mucosal areas) of rats pre-treated with mild WBH was significantly higher than in
animals exposed to restraint and water-immersion stress alone (p < 0.05) before
exposed to stress, but was not significantly higher immediately after stress or 1
or 3 days later. The HSP 70f content of peripheral lymphocytes was increased by
the pre-treatment with mild WBH. These results suggest that HSP 70f induced by
pre-treatment with mild hyperthermia protects against more severe stress due to
restraint and water-immersion, thereby preventing gastric ulcer formation. Pre
treatment with mild WBH is the safest cytoprotective method through the
accumulation of HSP 70f. The concentration of HSP 70f in peripheral lymphocytes
may be a useful clinical laboratory indicator for assessing the level of HSP 70f
as having cytoprotective activity.
PMID- 10763747
TI - Structure and functional relationships of archaeal and eukaryal histones and
nucleosomes.
AB - A decade after the discovery of histones in Archaea, there is now also a
biochemical description of the archaeal nucleosome. A tetrameric core of archaeal
histones is encircled by approximately 80 bp of DNA, and nuclease digestions
indicate that adjacent archaeal nucleosomes exist in vivo compacting archaeal
genomic DNA. Most Eukarya employ a similar structure to organize their
chromosomal DNA, the eukaryal nucleosome, with a histone octamer and 146 bp of
DNA. Here we compare the properties of both nucleosomes in terms of DNA packaging
and the accessibility of the packaged DNA for transcription.
PMID- 10763748
TI - Mechanism, regulation, and ecological role of bacterial cyanide biosynthesis.
AB - A few bacterial species are known to produce and excrete hydrogen cyanide (HCN),
a potent inhibitor of cytochrome c oxidase and several other metalloenzymes. In
the producer strains, HCN does not appear to have a role in primary metabolism
and is generally considered a secondary metabolite. HCN synthase of
proteobacteria (especially fluorescent pseudomonads) is a membrane-bound
flavoenzyme that oxidizes glycine, producing HCN and CO2. The hcnABC structural
genes of Pseudomonas fluorescens and P. aeruginosa have sequence similarities
with genes encoding various amino acid dehydrogenases/oxidases, in particular
with nopaline oxidase of Agrobacterium tumefaciens. Induction of the hcn genes of
P. fluorescens by oxygen limitation requires the FNR-like transcriptional
regulator ANR, an ANR recognition sequence in the -40 region of the hcn promoter,
and nonlimiting amounts of iron. In addition, expression of the hcn genes depends
on a regulatory cascade initiated by the GacS/GacA (global control) two-component
system. This regulation, which is typical of secondary metabolism, manifests
itself during the transition from exponential to stationary growth phase. Cyanide
produced by P. fluorescens strain CHA0 has an ecological role in that this
metabolite accounts for part of the biocontrol capacity of strain CHA0, which
suppresses fungal diseases on plant roots. Cyanide can also be a ligand of
hydrogenases in some anaerobic bacteria that have not been described as
cyanogenic. However, in this case, as well as in other situations, the
physiological function of cyanide is unknown.
PMID- 10763749
TI - Involvement of the respiratory chain of gram-negative bacteria in the reduction
of tellurite.
AB - The terminal oxidases of the respiratory chain of seven strains of gram-negative
bacteria were shown to be involved in the reduction of tellurite. The rate of
tellurite reduction correlated with the intensity of respiration. The inhibitors
of terminal oxidases, carbon monoxide and cyanide, inhibited the reduction of
tellurite. In Pseudomonas aeruginosa PAO ML4262 and P. aeruginosa PAO ML4262 (pBS
10), the respiratory chain was found to contain three types of cytochrome c, one
of which (the carbon monoxide-binding cytochrome c) was involved in the reduction
of tellurite. Agrobacterium tumefaciens VKM B-1219, P. aeruginosa IBPM B-13, and
Escherichia coli G0-102bd++ cells contained oxidases aa3, bb3, and bd,
respectively. The respiratory chain of other strains contained two oxidases: E.
coli DH5alpha of bb3- and bd-type, and Erwinia carotovora VKM B-567 of bo3- and
bd-type. All the strains under study reduced tellurite with the formation of
tellurium crystallites. Depending on the position of the active center of
terminal oxidases in the plasma membrane, the crystallites appeared either in the
periplasmic space [P. aeruginosa PAO ML4262 and P. aeruginosa PAO ML4262
(pBS10)], or on the outer surface of the membrane (A. tumefaciens VKM B-1219 and
P. aeruginosa IBPM B-13), its inner surface (E. coli G0-102bd++), or on both
surfaces (E. coli DHaalpha and E. carotovora VKM B-567).
PMID- 10763750
TI - A mutated hygromycin resistance gene is functional in the n-alkane-assimilating
yeast Candida tropicalis.
AB - Development of a transformation system in the n-alkane-assimilating diploid yeast
Candida tropicalis requires an antibiotic resistance gene in order to establish a
selectable marker. The resistance gene for hygromycin B has often been used as a
selectable marker in yeast transformation. However, C. tropicalis harboring the
hygromycin resistance gene (HYG) was as sensitive to hygromycin B as the wild
type strain. Nine CTG codons were found in the ORF of the HYG gene. This codon
has been reported to be translated as serine rather than leucine in Candida
species. Analysis of the tRNA gene in C. tropicalis with the anticodon CAG
[tRNA(CAG) gene], which is complementary to the codon CTG, showed that the
sequence was highly similar to that of the C. maltosa tRNA(CAG) gene. In C.
maltosa, the codon CTG is read as serine and not leucine. These results suggested
that the HYG gene was not functional due to the nonuniversal usage of the CTG
codon. Each of the nine CTG codons in the ORF of the HYG gene was changed to a
CTC codon, which is read as leucine, by site-directed mutagenesis. When a plasmid
containing the mutated HYG gene (HYG#) was constructed and introduced into C.
tropicalis, hygromycin-resistant transformants were successfully obtained. This
mutated hygromycin resistance gene may be useful for direct selection of C.
tropicalis transformants.
PMID- 10763751
TI - Induction of carbon monoxide dehydrogenase to facilitate redox balancing in a
ribulose bisphosphate carboxylase/oxygenase-deficient mutant strain of
Rhodospirillum rubrum.
AB - A ribulose-1,5-bisphosphate carboxylase/oxygenase-deficient mutant strain (strain
I-19) of Rhodospirillum rubrum was capable of growth under photoheterotrophic
conditions in the absence of exogenous electron acceptors. These results
suggested that alternative means of removing reducing equivalents have been
acquired that allow this strain to remove reducing equivalents in the absence of
a functional Calvin-Benson-Bassham reductive pentose phosphate pathway.
Previously, the proton-reducing activity of the dinitrogenase complex was
implicated in helping to maintain redox balance. However, since considerable
amounts of CO2 were still fixed in this strain, the complete profile of enzymes
involved in alternative CO2 fixation schemes was assessed. A specific and
substantial induction of carbon monoxide dehydrogenase (CO dehydrogenase)
synthesis was found in the mutant strain; although none of the other CO2 fixation
pathways or enzyme activities were altered. These results suggested that CO
dehydrogenase contributes to the photoheterotrophic success of strain I-19.
Furthermore, the data implicate interacting and complex regulatory processes
required to maintain the proper redox balance of this organism and other
nonsulfur purple bacteria.
PMID- 10763752
TI - Purification and properties of a novel azide-sensitive ATPase of Exiguobacterium
aurantiacum.
AB - Exiguobacterium aurantiacum BL77/1 possesses at least two distinct membrane-bound
ATPases. One of them was solubilized with decanoyl N-methylglucamide, a non-ionic
detergent, and purified by successive chromatography on DEAE-Sepharose and
hydroxyapatite. The purified ATPase appears to consist of a single polypeptide
component with an apparent molecular mass of 54 kDa. Among the triphosphates of
various nucleosides tested, ATP was the best substrate. The enzyme exhibited a Km
of 0.5 mM for ATP and a Vmax of 109 micromol ATP (mg protein)(-1) min(-1); the
optimum pH for activity was near 6.5. The enzyme was sensitive to azide and
inactivated by N,N'-dicyclohexylcarbodiimide. Analysis of the inhibition kinetics
by N,N'-dicyclohexylcarbodiimide suggested that binding of the drug to a single
carboxyl group per ATPase molecule is sufficient for inactivation.
PMID- 10763753
TI - Hydroxyhydroquinone reductase, the initial enzyme involved in the degradation of
hydroxyhydroquinone (1,2,4-trihydroxybenzene) by Desulfovibrio inopinatus.
AB - The recently isolated sulfate reducer Desulfovibrio inopinatus oxidizes
hydroxyhydroquinone (1,2,4trihydroxybenzene; HHQ) to 2 mol acetate and 2 mol CO2
(mol substrate)-1, with stoichiometric reduction of sulfate to sulfide. None of
the key enzymes of fermentative HHQ degradation, i.e. HHQ-1,2,3,5
tetrahydroxybenzene transhydroxylase or phloroglucinol reductase, were detected
in cell-free extracts of D. inopinatus, indicating that this bacterium uses a
different pathway for anaerobic HHQ degradation. HHQ was reduced with NADH in
cell-free extracts to a nonaromatic compound, which was identified as
dihydrohydroxyhydroquinone by its retention time in HPLC separation and by HPLC
mass spectrometry. The compound was identical with the product of chemical
reduction of HHQ with sodium borohydride. Dihydrohydroxyhydroquinone was
converted stoichiometrically to acetate and to an unknown coproduct. HHQ
reduction was an enzymatic activity which was present in the cell-free extract at
0.25-0.30 U (mg protein)-1, with a pH optimum at 7.5. The enzyme was sensitive to
sodium chloride, potassium chloride, EDTA, and o-phenanthroline, and exhibited
little sensitivity towards sulfhydryl group reagents, such as copper chloride or
p-chloromercuribenzoate.
PMID- 10763754
TI - Paradoxical effect of inserting, in Enterococcus faecalis penicillin-binding
protein 5, an amino acid box responsible for low affinity for penicillin in
Enterococcus faecium.
AB - Penicillin-binding proteins 5 (PBP5s) of enterococci are structurally and
immunologically related proteins that are characterized by their low affinity for
penicillin. For this reason, they are mainly involved in penicillin resistance,
due essentially to their ability to take over the function of all other PBPs
already bound and inhibited by the beta-lactam. It has been demonstrated that
penicillin resistance in enterococci is acquired either by overproduction of PBP5
or by the presence of specific amino acid sequences in the protein that further
decrease the affinity for penicillin. In particular, a specific amino acid box
(ANNGA) previously identified in Enterococcus faecium is responsible for the high
penicillin resistance displayed by this species. Here, we describe the insertion
of the PBP5 amino acid box ANNGA in Enterococcus faecalis, an enterococcal
species usually more sensitive to penicillin, by site-directed mutagenesis.
Mutagenized PBP5 was re-introduced into a pbp5 mutant of E. faecalis obtained by
insertion of transposon Tn916. Data indicate that this amino acid box brings
about no reduction in penicillin sensitivity in the recipient E. faecalis strain,
but, paradoxically, dramatically lowers the penicillin minimal inhibitory
concentration caused by the native PBP5. We deduce that, although enterococcal
PBP5s are a family of closely related proteins as far as biological function is
concerned, differences exist in their three-dimensional structure that affect
penicillin affinity.
PMID- 10763755
TI - comB, a novel competence gene required for natural transformation of
Acinetobacter sp. BD413: identification, characterization, and analysis of growth
phase-dependent regulation.
AB - Here we describe five tandemly arranged and converging ORFs in Acinetobacter sp.
BD413, namely lytB, orfY, orfX, comB, and orfZ, located upstream of the
previously identified competence gene comC. The N-termini of the deduced proteins
OrfY and ComB exhibit the conserved endopeptidase cleavage motifs of prepilin
proteins; the deduced protein ComB is similar to type IV pilins. LytB is similar
to the Escherichia coli LytB, which has been implicated in the stringent
response. No homologues of OrfX, OrfY and OrfZ could be identified. A mutation in
orfY or orfZ led to 100-fold reduced transformation frequencies and a mutation in
comB resulted in a non-competent phenotype. Disruption of lytB did not affect the
natural transformation phenotype. Complementation studies clearly demonstrated
that comB is involved in natural transformation, whereas the transformation
deficient phenotypes of orfY and orfZ mutants were due to polar effects on comB
and comC, respectively. Analyses of the twitching motility phenotype and of the
ultrastructure of the noncompetent comB mutant suggested that the competence gene
comB is not essential for the biogenesis of type IV pili and expression of the
type IV pili-associated property of twitching motility. Transcriptional fusions
between comB and a promoter-free lacZ gene were constructed, and analysis of
growth-phase-dependent transcription revealed increased expression of comB during
prolonged exponential and stationary phases.
PMID- 10763756
TI - Construction and screening of Mycobacterium paratuberculosis insertional mutant
libraries.
AB - Mycobacterium paratuberculosis causes Johne's disease, a common wasting disease
in ruminants. As a first step in studying virulence mechanisms, libraries of
random mutants were produced in two M. paratuberculosis strains by using the
conditionally replicating shuttle phasmid phAE94 which contains the transposon
Tn5367. Two thousand mutants were screened for auxotrophy, carbon source
preference, and altered cell wall. Genes interrupted by insertion were identified
for seven mutants isolated from the screening process. Two mutants had insertions
in putative genes involved in synthesis of the cell wall.
PMID- 10763757
TI - Role of the fetus in perinatal infection and neonatal brain damage.
AB - Increasing evidence supports the view that infants exposed to perinatal infection
are at increased risk for brain injury. We suggest that elevated cytokines in the
amniotic fluid or in the fetal circulation be viewed as a humoral expression and
that inflammatory cells in chorionic plate or umbilical cord blood vessel walls
be viewed as a morphologic expression of the fetal inflammatory response. We
discuss the evidence supporting the hypothesis that the fetal inflammatory
response contributes to neonatal brain injury and later developmental disability.
Little support has been found for a maternal contribution. Intervention should be
designed with the fetus in mind.
PMID- 10763758
TI - Chemoprophylaxis of early-onset group B streptococcal disease in 1999.
AB - The evolution of the guidelines for selective intrapartum chemoprophylaxis (SIC)
of group B streptococcal early-onset disease is reviewed here. To assess the
benefits of the risk-based and culture-based strategies for prevention,
observational studies since 1996 are summarized. The effect of chorioamnionitis
on group B streptococcal early-onset disease, despite SIC, is emphasized. Optimal
management remains controversial, and alternative strategies for the selection of
women for chemoprophylaxis and for the management of infants are discussed.
PMID- 10763759
TI - Cerebral hypothermia for prevention of brain injury following perinatal asphyxia.
AB - The possibility that hypothermia has a therapeutic role during or after
resuscitation from severe perinatal asphyxia has been a longstanding focus of
research. Early studies using short periods of cooling had limited and
contradictory results. We now know that resuscitation can be followed by a
"latent" phase, characterized by transient recovery of cerebral energy
metabolism, before secondary deterioration occurs with seizures, cytotoxic edema,
and cerebral energy failure 6 to 15 hours after birth. Recent experimental
studies have shown that moderate cerebral hypothermia initiated as soon as
possible in the latent phase, before the onset of secondary injury, and continued
for 48 hours or more is associated with potent, long-lasting neuroprotection.
These encouraging results must be balanced against the well-known adverse
systemic effects of hypothermia. Randomized clinical trials are in progress to
test the safety and efficacy of cerebral hypothermia.
PMID- 10763760
TI - Developmental outcome of neonatal intensive care: what questions are we asking?
AB - Recent neonatal intensive care outcome studies are asking more focused research
questions and incorporating, at least implicitly, pathogenetic models. A few have
grappled with the complex issues of health-related quality of life and functional
outcomes and the many factors that affect these outcomes. The need to evaluate
high-risk obstetrics is increasingly recognized. Studies of risk factors for
neurodevelopmental outcomes provide valuable insights into mechanisms of and
recovery from central nervous system injury. Ongoing study of the efficacy and
effectiveness of interventions must continue amid concern about availability of
family and developmental support for increasing numbers of survivors of high-risk
obstetric and neonatal intensive care.
PMID- 10763761
TI - Long-term consequences of urinary tract infections.
AB - The past several years have brought marked changes in our understanding of the
consequences of urinary tract infections (UTIs). Studies of infants with
intrauterine dilatation of the urinary tract show that many children previously
thought to have incurred kidney damage after an infection actually have
congenital renal damage. The importance of vesicoureteric reflux (VUR) in the
pathogenesis of acute pyelonephritis has been downgraded with the recognition of
the frequency with which kidney infection occurs in the absence of VUR. Some
infants with intrauterine VUR and no history of UTI have impaired kidney function
or hypertension secondary to renal hypoplasia or dysplasia.
PMID- 10763762
TI - Genetics of the nephrotic syndrome.
AB - There are a large number of glomerular diseases that may be responsible for a
nephrotic syndrome, the most frequent in childhood being minimal change disease.
In the past few years, the molecular genetic basis of several conditions that may
cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier
syndrome are related diseases caused by mutations in the WT1 gene. Familial forms
of idiopathic nephrotic syndrome with focal and segmental glomerular
sclerosis/hyalinosis have been identified with an autosomal dominant or recessive
mode of inheritance and linkage analysis have allowed to localize several genes
on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital
nephrotic syndrome has been identified. This gene, named NPHS1, codes for
nephrin, which is located at the slit diaphragm of the glomerular podocytes and
is thought to play an essential role in the normal glomerular filtration barrier.
PMID- 10763763
TI - New developments in calcium and vitamin D metabolism.
AB - During the past review year, researchers have discovered the molecular
pathogeneses of disorders of calcium, vitamin D and bone. This review discusses
the roles of the extracellular calcium sensor, the renal 25-hydroxyvitamin D-1
alpha-hydroxylase, the vitamin D receptor, and new factors for bone cell
embryogenesis and function as a way of introduction to this exciting area of
medicine.
PMID- 10763764
TI - Dialysis for end-stage renal disease.
AB - Peritoneal dialysis is the major renal replacement therapy for children with end
stage renal disease, with hemodialysis used for a substantial number of pediatric
patients. Reduction of morbidity and mortality is a major goal with the use of
these modalities. Adequacy of dialysis and maintenance of peritoneal membrane
function are important considerations for children on long term dialysis. Both
adequacy and function are important to ensure optimal growth and nutrition and
improve morbidity in this population. Use of supplemental gastrostomy tube feeds
has improved calorie-protein malnutrition. Therapy advancements, such as growth
hormone and erythropoietin, have improved the quality of life for dialysis
patients. As the survival of the pediatric patient with end-stage renal disease
improves, issues regarding cardiovascular disease and other factors that increase
mortality in the adult population will need to be addressed.
PMID- 10763765
TI - Overview of new immunosuppressive therapies.
AB - This review covers the new immunosuppressive drugs that have appeared in the past
5 years. It begins with the newest formulation (Neoral, Sandoz Pharmaceuticals,
East Hanover, NJ, USA) of the clinically "mature" drug cyclosporin A and then
reviews the literature on tacrolimus, sirolimus, and mycophenolate mofetil. In
each case, the emphasis is on the evolution of experience with the drug and on
the questions that the drug poses for pediatricians considering the risk-benefit
ratio of the drug in children.
PMID- 10763766
TI - Past, present, and future role of ipecac syrup.
AB - Historically, ipecac syrup has played a principal role in the management of acute
poisonings and overdoses. Presently, its role largely has been relegated to
prompt decontamination of acute childhood poisonings for which emesis is not
contraindicated. However, even this specific and limited role has undergone
rigorous re-evaluation, and many toxicologists have discouraged against its use
in any circumstance. This article reviews the history, scientific literature, and
public health implications of ipecac syrup that support its present clinical
application.
PMID- 10763767
TI - Indications for, techniques of, complications of, and efficacy of gastric lavage
in the treatment of the poisoned child.
AB - Gastrointestinal decontamination is central to the care of poisoned patients, and
gastric lavage is one common method for gastrointestinal decontamination. Gastric
lavage in pediatric patients should be limited to children who present shortly
after a potentially life-threatening ingestion. The routine use of gastric lavage
has recently been questioned because of limited outcome data and increased
morbidity. If gastric lavage is deemed necessary, proper positioning of the
patient and strict attention to appropriate technique are essential to avert
complications.
PMID- 10763768
TI - Activated charcoal as the sole intervention for treatment after childhood
poisoning.
AB - Childhood poisonings account for approximately two thirds of all human toxic
exposures reported annually to the American Association of Poison Control
Centers. Activated charcoal (AC) is the mainstay of decontamination in the
emergency department setting. This review focuses on six concepts: 1) description
of AC and its method of action, 2) evolution of AC in the gastrointestinal
decontamination process, 3) prehospital use of AC, 4) superactivated charcoal, 5)
multiple-dose AC, and 6) complications of AC administration. The most recent
evolving trends in decontamination of the pediatric patient include trends toward
earlier decontamination, either in the home or by paramedics in the field. The
newer, "super" activated charcoals, with their greater surface area, may improve
compliance of oral administration of AC. Finally, guidelines have been set to
limit use of multiple-dose activated charcoal regimens to certain pharmaceuticals
only, as well as discouraging cathartic use with charcoal dosing.
PMID- 10763769
TI - When you hear hoof beats...do not forget the zebras.
PMID- 10763771
TI - Bibliography. Current world literature. Neonatology and perinatology.
PMID- 10763770
TI - Sudden infant death syndrome and secretin treatment for autism.
AB - The Back to Sleep Campaigns remain the greatest influence on the reduction of
sudden infant death syndrome. Blatt and Meguid review updates on the
effectiveness of these campaigns in reducing sudden infant death syndrome. They
also review studies on why parents do not follow this proven advice. The
contribution of the risks of other environmental factors are also reviewed. Also
discussed are commentaries from a study reviewed last on the link between a
prolonged QT electrocardiogram interval and sudden infant death syndrome. Church
provides a cogent and timely review of the reported effectiveness of hormone
secretin effectiveness in treating children with autism. This newly proposed
treatment has been in the spotlight of the lay public, the popular media, and the
scientific community. In short order, secretin as a treatment for autism has
moved from a chance observation to the subject of a double-blind, placebo
controlled study.
PMID- 10763772
TI - Bibliography. Current world literature. Nephrology.
PMID- 10763773
TI - Bibliography. Current world literature. Therapeutics and toxicology.
PMID- 10763774
TI - Pediatric nuclear medicine, Part I: Developmental cues.
AB - OBJECTIVE: Children provide a continuous challenge for the nuclear medicine
technologist. The task of successfully completing a nuclear medicine procedure
varies little among a 20-y-old, a 40-y-old and a 60-y-old patient. Successful
completion of a procedure varies much more among a 2-y-old, a 4-y-old and a 6-y
old. Successfully completing a pediatric nuclear medicine procedure includes
quick acquisitions, technically acceptable images or calculations, and satisfied
patients and parents. Understanding your patient is crucial, and it provides the
parents with a greater sense of comfort and confidence about the nuclear medicine
technologist and the procedure. After reading this article the nuclear medicine
technologist should be able to: (a) discuss the developmental stages of children
according to several major theories; (b) identify the physical and mental
expectations for each age group; (c) explain applications for incorporating this
information into common pediatric nuclear medicine practice; and (d) discuss the
common realities surrounding the behavior of children and their parents. A second
article will feature tips, indications and populations for common pediatric
procedures.
PMID- 10763775
TI - Nuclear pharmacy, Part I: Emergence of the specialty of nuclear pharmacy.
AB - OBJECTIVE: Nuclear pharmacy was the first formally recognized area in pharmacy
designated as a specialty practice. The events leading to nuclear pharmacy
specialty recognition are described in this article. After reading this article
the nuclear medicine technologist or nuclear pharmacist should be able to: (a)
describe the status of nuclear pharmacy before recognition as a specialty
practice; (b) describe the events that stimulated pharmacists to organize a
professional unit to meet the needs of nuclear pharmacists; and (c) identify the
steps by which nuclear pharmacists become board certified in nuclear pharmacy.
PMID- 10763776
TI - Clinical and technical considerations for imaging colorectal cancers with
technetium-99m-labeled antiCEA Fab' fragment.
AB - OBJECTIVE: Colorectal cancer is the third most common cancer, after lung and
breast cancers. Approximately 133,500 Americans develop colorectal cancer
annually and approximately 54,900 die of the disease. As many as 600,000
individuals in the US are under care after surgery for colorectal cancer. After
reading this article, the nuclear medicine technologist will be able to: (a)
describe the role of Arcitumomab in evaluating and managing patients with
recurrent colorectal carcinoma metastasizing to the liver; (b) discuss the
clinical use of CEA-Scan (Immunomedics, Inc., Morris Plains, NJ) and its overall
imaging performance characteristics and sensitivity related to specific
anatomical sites compared to conventional diagnostic modalities; (c) describe
radiopharmaceutical preparation and quality control; (d) identify the pertinent
patient history before starting the test; and (e) explain the imaging procedure,
processing and display of data to optimize study interpretation.
PMID- 10763777
TI - Clinical PET imaging with the C-PET camera.
AB - OBJECTIVE: Clinical PET studies require a high-performance and user-friendly PET
camera. The C-PET camera uses a simple design and a large field of view for these
purposes. METHODS: We describe the camera features, daily quality control, and
routine clinical study preparation, performance, processing and presentation from
the technologist's perspective. RESULTS: The C-PET camera is used for whole-body
cancer, cardiac and brain imaging. It operates clinically near its peak
performance. The 25.6-cm axial field of view (FOV), lack of interplane septa and
singles transmission capability allow 70 cm of the body to be surveyed in less
than 1 h with good image quality. Quality control procedures take 30 min per day.
Clinical scans and image processing are menu driven, allowing the technologist to
perform several tasks simultaneously. Fully corrected images typically are
available for physician review within 1 h of acquisition. The current procedures
are outlined. CONCLUSION: The C-PET camera uses a clinically oriented design for
rapid acquisition and presentation of high-quality PET images. Operation is
straightforward and user-friendly.
PMID- 10763778
TI - New functional polar maps for estimating regional cardiac function using ECG
gated technetium-99m-tetrofosmin SPECT.
AB - OBJECTIVE: The purpose of this work was to develop functional parameters to
analyze regional cardiac function using ECG-gated 99mTc-tetrofosmin SPECT. Our
goal was to develop a methodology that used slice thickness correction, the
generation of a time-activity curve and a polar map. METHODS: Fourteen normal
patients without evidence of coronary artery disease were studied. One hour after
intravenous injection of 740-1110 MBq (20-30 mCi) 99mTc-tetrofosmin, ECG-gated
SPECT data were acquired by dividing a cardiac cycle into 12 frames. The SPECT
data were reconstructed from 11 of 12 frames into 3 views. The reconstruction of
these images was repeated after performing slice thickness correction. Excluding
the effect of different apex-to-base lengths at any frame during a cardiac cycle,
10 short-axis images with the same slice thickness were obtained. Each short-axis
image was divided by 40 radii into 40 segments. The time-activity curve was
generated from the total counts included in each segment plus both neighboring
segments. Subsequently the curve fitting was performed using the second Fourier
function. RESULTS: From fitted curves and their differentials, we calculated end
systolic count, end-diastolic count, percent count increase, uptake, peak
contraction rate, peak distention rate and contraction time. CONCLUSION: The
functional polar maps visually demonstrated regional myocardial function. This
method is expected to be helpful for assessing regional cardiac function using
99mTc-tetrofosmin.
PMID- 10763779
TI - Quantitative gated myocardial SPECT: effect of collimation on left-ventricular
ejection fraction.
AB - OBJECTIVE: Left-ventricular ejection fraction (LVEF) can be computed from gated
myocardial perfusion SPECT studies using quantitative algorithms. The purpose of
this study was to compare the LVEF obtained using the conventional high
resolution parallel-hole collimator (HRC) to the Cardiofocal collimator (CFC)
(Siemens Medical Systems, Hoffman Estates, IL) using a quantitative LVEF program.
METHODS: Thirty-four patients (15 men, 19 women; mean age = 62 y) had either
treadmill or pharmacological stress testing with 25-30 mCi 99mTc sestamibi
injected at peak stress. Conventional gated SPECT imaging was performed
approximately 30 min poststress, first with the HRC collimator, then with the
CFC, using the same acquisition parameters on a single-head gamma camera.
Traditional (TRAD) determination of LVEF using planar gated blood pool and/or
cardiac catherization also was obtained for each patient. RESULTS: The
correlation in LVEF between the CFC and HRC acquisitions was excellent, r = 0.99.
The correlation between CFC and TRAD LVEF was good, r = 0.95, as was the HRC and
TRAD correlation, r = 0.97. The mean LVEF value for HRC was slightly less than
TRAD (54% vs. 55.4%), while the CFC mean LVEF was higher (62% vs. 55.4%).
Although CFC LVEF correlated well with HRC, mean LVEF value using CFC was higher
than HRC. CONCLUSION: The choice of collimator may alter the LVEF obtained from
gated SPECT perfusion studies.
PMID- 10763780
TI - The effect of gadolinium contrast media on radioiodine uptake by the thyroid
gland.
AB - OBJECTIVE: Patients with thyroid cancer may require detailed anatomic imaging
before 131I therapy. Imaging by contrast-enhanced CT is contraindicated because
it may result in saturation of tissues with iodine, decreasing the avidity of
thyroid or thyroid cancer cells to subsequent radioiodine for extended intervals.
Gadolinium-enhanced MRI offers an alternative to CT for detailed anatomic
imaging. However, it is not known whether gadolinium contrast affects uptake of
iodine by the thyroid gland since lanthanides affect ion transport in a variety
of ways. The objective of this project was to determine whether the gadolinium
MRI contrast injection alters thyroid uptake of radioiodine. METHODS: Radioiodine
uptake by the thyroid gland was measured at 6 h and 24 h after the oral
administration of 100 microCi 123I-Na-I. Three to seven days later, a standard
dose (20 mL) of Magnevist (gadolinium DTPA) was administered intravenously.
Another capsule of 100 microCi 123I Na-I immediately was given orally, and 6-h
and 24-h radioiodine uptake by the thyroid gland was again measured and compared
to baseline values. RESULTS: There was no statistically significant difference in
uptake of radioiodine uptake by the thyroid gland between baseline values and
those acquired immediately after the administration of Magnevist. CONCLUSION:
Contrast-enhanced MRI may be safely performed before contemplated determinations
of thyroid uptake of radioiodine, 131I therapy for hyperthyroidism, and
postsurgical 131I imaging and therapy for well-differentiated thyroid cancer.
PMID- 10763781
TI - A simple solution to prevent the loss of radioactive spot markers.
AB - OBJECTIVE: Most nuclear medicine technologists have experienced the misplacing
and/or the loss of a radioactive spot marker. We report on a simple solution to
prevent or at least minimize the loss of radioactive spot markers. METHODS: One
end of a metallic beaded chain was attached to the side of 57Co spot marker using
repair putty. The other end of the beaded chain was attached to a lead shield
that housed the radioactive source when not in use. RESULTS: This design has
allowed easy, unobstructed use of the 57Co spot marker for marking the right or
left side and anatomical position during imaging while preventing its loss.
CONCLUSION: A radioactive spot marker that is attached to a lead shield by a
beaded chain is a simple way to prevent its loss while allowing it to be used
easily during imaging.
PMID- 10763782
TI - Accessory spleens in the thoracic and abdominal cavities after a relapse of
idiopathic thrombocytopenic purpura: a case report.
AB - This case report presents a highly unusual finding of ectopic splenic tissue in
both the thoracic and abdominal cavities in a patient with recurrent idiopathic
thrombocytopenic purpura (ITP).
PMID- 10763783
TI - Volatility of radiopharmacy-prepared sodium iodide-131 capsules.
AB - OBJECTIVE: The aims of this study were to quantify the extent of volatilization
from 131I-NaI therapeutic capsules prepared in a centralized radiopharmacy and to
quantify the amount of volatile 131I released from a dispensing vial containing a
compounded 131I-NaI therapy capsule. METHODS: Therapy capsules were prepared by
injecting 131I oral solution into capsules containing anhydrous dibasic sodium
phosphate. Volatilized activity was obtained by filtering air drawn across
samples that were placed open on the bottom of a sample holder cup. Volatile 131I
was captured by filtering it through 3 triethylenediamine-impregnated carbon
cartridge filters, arranged in series. To quantify the amount of volatile 131I
released from a dispensing vial during a simulated patient administration, a vial
containing a compounded 131I therapy capsule was opened inside a collapsible
plastic bag and all the air was drawn across TEDA-impregnated carbon cartridge
filters. RESULTS: The 370-MBq (10-mCi) 131I capsules from the first part of the
experiment released an average of 0.035% (SD 0.031%) of the capsule activity on
the first day, 0.012% (SD 0.002%) on the second day, and 0.012% (SD < 0.001%) for
days 3 through 5. The 37-MBq (1-mCi) 131I capsules released an average of 0.058%
(SD 0.025%) on the first day, 0.029% (SD 0.009%) on the second day, and 0.020%
(SD 0.004%) on the third day. The activity released from the vial during a
simulated patient administration was 0.00093% of the 131I capsule activity.
CONCLUSION: The amount of 131I, which volatilized daily from the exposed therapy
capsules, was a small percentage of the capsule activity. The volatile 131I that
would be released during a patient administration was much less than the activity
that volatilized from the exposed therapy capsules.
PMID- 10763784
TI - Radioactive contamination of packing materials from a xenon-133 shipment.
AB - OBJECTIVE: We report on radioactive contamination of packing materials from a
133Xe shipment. METHODS: A 2-vial 133Xe shipment was monitored using a survey
meter before opening. Both vials were immediately assayed in a dose calibrator.
The packing materials were monitored and contamination was detected. RESULTS: The
maximum surface reading of the shipment was 7.0 microSv/h. This was higher than
previous shipments (1.1 +/- 0.3 microSv/h). One vial was 544 MBq while the other
vial was only 474 MBq. Previous shipments were 565 +/- 13 MBq/vial. Monitoring
and imaging revealed 133Xe contamination within the packing materials. Xenon-133
escaped from the packing materials over time. The lower activity vial continued
to leak 133Xe over time. CONCLUSION: Careful monitoring of 133Xe shipments before
and after opening along with assaying vials on receipt can indicate vial leakage
and radioactive contamination so steps can be taken to minimize radiation
exposure to the staff.
PMID- 10763785
TI - Needle capping blocks for nuclear medicine and nuclear pharmacy procedures.
PMID- 10763786
TI - Personal context as a focus for rehabilitation.
PMID- 10763787
TI - Evaluation of the benefits of monitoring fluid thickness in the dietary
management of dysphagic stroke patients.
AB - OBJECTIVE: Safe swallowing may be achieved in most patients with neurogenic
dysphagia by manipulating the viscosity of ingested fluids. However, in clinical
practice fluids are thickened using subjective judgement. This may lead to errors
in the preparation of drinks to the prescribed viscosity. The aim of the present
study is to examine whether the use of a viscometer improves the dietary
management of dysphagic stroke patients. STUDY DESIGN: A randomized controlled
study design was used. The speech and language therapist determined the optimal
fluid thickness for each patient. The prescribed fluid viscosity for the study
group was obtained using a viscometer. Patients in the control group received
fluids prepared according to current practice, i.e. the amount of thickener
required to produce the prescribed viscosity was judged subjectively by the
nursing staff. The two methods of fluid thickening were used for seven
consecutive days. Assessment was made blind to randomization. MAIN OUTCOME
MEASURE: Pulmonary aspiration, assessed clinically and with pulse oximetry. If
the patient did not drink all the fluid that was offered the residue was
measured. RESULTS: Ten patients in the study group (n = 23) and nine in the
control group (n = 23) aspirated. The mean viscosity of fluids offered to
patients in the control group was significantly higher than that of the study
patients. There was a statistically significant correlation between the viscosity
and the residual volume of fluid (Pearson's test: r = 0.7, p <0.02). The findings
of the study suggest that fluids prepared by subjectively assessing the amount of
thickener required to produce a given consistency tend to have a higher viscosity
than those prepared using the viscometer. However, the higher viscosity does not
appear to protect against pulmonary aspiration and may lead to a reduced fluid
intake. CONCLUSION: Manipulation of fluid thickness using objective measurements
with a viscometer may improve the dietary management of dysphagic stroke
patients.
PMID- 10763788
TI - Weight-bearing shifts of hemiparetic and healthy adults upon stepping on stairs
of various heights.
AB - OBJECTIVE: To examine and compare the effect of stepping on stairs of various
heights on lower extremity weight bearing in hemiparetic patients. SETTING:
Flieman Geriatric Rehabilitation Hospital, Haifa, Israel. SUBJECTS: Fifteen
ambulatory hemiparetic patients following an acute cerebrovascular accident, and
16 age-matched healthy controls. INTERVENTIONS: Each subject was tested twice on
two consecutive days in five weight-bearing positions which included level stance
and stepping with either leg on 10-cm- and 17-cm-high steps. Data concerning
weight distribution on the lower extremities were collected by two computerized
forceplates. MAIN OUTCOME MEASURE: Weight borne by each foot expressed as
percentage of overall body weight. RESULTS: In the attempted symmetrical level
stance, the percentage of body weight borne by the paretic limb of the stroke
patients was significantly lower than that of the nonparetic limb. Placing one
foot on a step induced a weight shift to the foot placed on the floor regardless
of step height. Weight shifting to the paretic limb was, however, significantly
lower than to the nonparetic limb. Weight shifting to the nonparetic limb was
significantly lower than to the corresponding limb of healthy individuals. Step
height had no significant effect on weight distributions on the feet.
CONCLUSIONS: Raising a foot on a step appears to be an appropriate strategy for
weight shift training of stroke patients. Since weight shifting to both the
paretic and nonparetic limb of stroke patients is impaired, treatment strategies
should include training in weight shifting to both lower extremities.
PMID- 10763789
TI - Prevalence of apraxia among patients with a first left hemisphere stroke in
rehabilitation centres and nursing homes.
AB - OBJECTIVE: To investigate the prevalence of apraxia in patients with a first left
hemisphere stroke. SUBJECTS: Left hemisphere stroke patients staying at an
inpatient care unit of a rehabilitation centre or nursing home and receiving
occupational therapy (n = 600). MEASURES: A short questionnaire on general
patient characteristics and stroke-related aspects was completed by occupational
therapists for every left hemisphere stroke patient they treated. A diagnosis of
apraxia or nonapraxia was made in every patient, on the basis of a set of
clinical criteria. RESULTS: The prevalence of apraxia among 492 first left
hemisphere stroke patients in rehabilitation centres was 28% (96/338) and in
nursing homes 37% (57/154). No relationship was found between the prevalence of
apraxia and age, gender or type of stroke (haemorrhage or infarct). CONCLUSIONS:
This study shows that approximately one-third of left hemisphere stroke patients
has apraxia.
PMID- 10763790
TI - Stress and coping in spouses of persons with spinal cord injuries.
AB - OBJECTIVE: To examine the sources of stress and the patterns of coping of spouses
of persons with spinal cord injuries (SCI) among Hong Kong Chinese. DESIGN: A
cross-sectional correlation design. A set of structured questionnaires and semi
structured interviews were administered. SUBJECTS: Forty spouses of persons with
SCI were recruited and interviewed. OUTCOME MEASURES: These included coping
strategies, depression, care-giving burden, life satisfaction and marital
adjustment. RESULTS: The most stressful situations reported by the participants
concerned health issues of their injured partners, the family and marital
interactions, and the care-giving burden imposed on them. Cluster analysis
indicated a potential at-risk group, characterized by high scores in external
locus of control, inadequate coping modes and limited social support. They were
noted to manifest high levels of depression, care-giving burden, low levels of
life satisfaction and marital adjustment. CONCLUSION: The identification of the
potential at-risk group indicates that spouses of persons with SCI suffer levels
of stress comparable to those of their injured partners. Rehabilitation plans
should include this potential at-risk group to help them release the stress and
to prevent them from developing clinically significant mental disorders.
PMID- 10763791
TI - Longitudinal changes in bone in men with spinal cord injury.
AB - INTRODUCTION: Quantitative bone assessment today is primarily based on the
analysis of bone mineral density (BMD). The geometric and structural properties
of bone, which are important parameters for skeletal strength, are generally not
considered in the routine clinical assessment of spinal cord injury-related
osteopenia. OBJECTIVE: To study changes in structural and geometric properties of
tibia bone longitudinally by means of peripheral quantitative computerized
tomography and a biomechanical test method (bone stiffness measurement device
Swing) in 12 subjects with spinal cord injury. DESIGN: Measurements were
conducted in the 5th week and around the 104th week after the spinal cord injury
in a university hospital. RESULTS: Paired Student's t-tests showed a significant
decrease in trabecular (p < 0.05) and cortical bone (p < 0.05), as well as a
significant decrease in geometric properties of tibia bone (p < 0.05) within two
years after the spinal cord injury. Phase velocity propagation changed in three
subjects within two years following the spinal cord injury. CONCLUSIONS: This
study indicates that beside changes in tissue composition, changes in bone
geometric indices and in structural properties occur in the lower extremity after
a spinal cord injury. In the tibia, consideration of geometric and biomechanical
parameters of bone combined with bone mineral density measurements could result
in an improved screening for spinal cord injury-related osteopenia and the
prediction of fracture risk in spinal cord injury.
PMID- 10763792
TI - Inter-rater reliability of the Nottingham method of stereognosis assessment.
AB - OBJECTIVE: To investigate the inter-rater reliability of stereognosis assessment
in stroke patients, as measured by the Nottingham Sensory Assessment (NSA).
SUBJECTS: Twenty stroke patients consented to participate in the study. The
subjects were aged between 40 and 93 years, and were no more than three months
post stroke. DESIGN: The stereognostic ability of the subjects was assessed by
two of three examiners within a 24-hour period. The method laid out by the NSA
was followed throughout the study. ANALYSIS: Point to point agreement of scores
and therefore reliability levels were assessed between examiners using the kappa
coefficient of agreement. RESULTS: The majority of subjects (n = 13) were found
to have impaired stereognosis on their affected side. A good level of reliability
was found for the majority of items (n = 32), with kappa values being rated as
substantial or higher for most of the objects tested. In eight cases the
reliability was fair or moderate. These cases included the glass, biro and 10p
coin when the affected side was assessed by examiners 1 and 2, and the pencil
when the same side was assessed by examiners 1 and 3. These levels of reliability
were acceptable, but were not as high as the researchers had hoped. CONCLUSION:
It is concluded that the Nottingham method of stereognosis assessment is a
reliable assessment tool between raters.
PMID- 10763793
TI - Unpacking the 'black box' of a nurse-led stroke support service.
AB - OBJECTIVES: To describe in detail the nature of the specialist nurse
interventions; to increase understanding of the principal problems facing stroke
patients and their care-givers in the first year following stroke and to
demonstrate how these problems may change over time; and to investigate the value
of qualitative research methodologies within the context of a randomized trial.
METHODS: Specialist nurses providing support in the year following stroke were
asked to maintain comprehensive written records of their involvement with all
patients and care-givers participating in a randomized controlled trial.
Qualitative methods were used to examine the problems faced by stroke patients
and their care-givers, and the actions taken by nurses in response. RESULTS:
Specialist nurses commenced 120 records. As 19 patients died or left the area
during the year-long interventions, we obtained 101 complete records. The
problems encountered by stroke patients and their care-givers were numerous,
diverse, complex and changed over time. Initially, practical difficulties were
noted; over time, these were accompanied by growing numbers of psychological
needs. The nurses responded by providing information, advice, support and
monitoring using a flexible, individualized approach. The nurses also
collaborated or liaised with 17 other professional groups and provided direct
support to care-givers. CONCLUSION: The need for many stroke patients and their
care-givers to be professionally supported during the stages of stroke
adjustment, for at least the first year and probably beyond, was emphasized by
this study.
PMID- 10763794
TI - An evaluation of neurobehavioural problems as perceived by family members and
levels of family stress 1-3 years following traumatic brain injury in Japan.
AB - OBJECTIVE: To ascertain the proportion of patients with traumatic brain injury
(TBI) admitted to a Japanese district hospital and to evaluate the levels of
stress and anxiety in fami ies living with those TBI patients. DESIGN: A
retrospective study of patients admitted to hospital from April 1995 to March
1997 and a questionnaire study of family members of survivors. SETTING AND
SUBJECTS: All patients referred or transferred to the Emergency Department at the
Saga Medical School Hospital, Japan with a primary diagnosis of TBI were studied.
Family members living with TBI patients were sent questionnaires. MAIN OUTCOME
MEASURES: The Barthel Index, the Patient Competency Rating Scale, the modified
Caregiver Strain Index and the Hospital Anxiety and Depression Scale. RESULTS:
There were 34 patients who required hospitalization for care relating to TBI. Of
these, nine family members took part in the questionnaire study. Three carers
reported fairly high levels of stress and another three carers were considered to
be at risk of anxiety and depression. There was a tendency for family members who
reported that patients had difficulties in performing behavioural tasks to have
higher levels of stress themselves. CONCLUSION: These preliminary results showed
that family members experienced certain levels of stress and were also at risk of
anxiety and depression. The impact of TBI on families as well as patients should
receive more attention.
PMID- 10763796
TI - A randomized controlled trial of the Geriatric Depression Scale in an inpatient
ward for older adults.
AB - OBJECTIVES: To measure the prevalence of high scores on the Geriatric Depression
Scale in an inpatient unit for older people and assess whether administration of
this instrument increased the use of antidepressant medication. DESIGN:
Randomized controlled trial. SETTING: Inpatient unit for assessment, treatment
and rehabilitation of older adults in a district hospital. SUBJECTS: Consecutive
admissions to the inpatient unit were approached. Of 198 people, 100 gave consent
and were randomized to receive the intervention. INTERVENTIONS: The Geriatric
Depression Scale and the Folstein Mini-mental State Examination were administered
to the intervention group. The Nottingham Instrumental Activities of Daily Living
questionnaire and the Folstein Mini-mental State Examination were administered to
the placebo group. The scores of these instruments and a copy of the completed
instrument were placed in the subject's case notes. For those subjects randomized
to receive the Geriatric Depression Scale an interpretation of the score was
written in the case notes. MAIN OUTCOME MEASURES: The primary outcome measure was
whether antidepressant medication was listed on the discharge summary for the
admission. Other outcome measures were death, readmission and use of
antidepressant medication three months after administration of the instruments.
RESULTS: There was a prevalence of Geriatric Depression Scale scores greater than
10 of 52% in the 50 people administered this instrument. Six out of 46 people
administered the Geriatric Depression Scale, who were discharged in the study
period, were on antidepressant medication at discharge. Three out of 47 people
administered the placebo instrument were on antidepressant medication at
discharge. The absolute difference in proportions was 6.7%, 95% confidence
interval 19 to -5.3%. CONCLUSIONS: A high proportion of patients admitted to an
inpatient unit for assessment, treatment and rehabilitation scored in the
depressed range on the Geriatric Depression Scale; however, use of the Geriatric
Depression Scale in this clinical setting did not increase the use of
antidepressant medication. This may be because the instrument is too nonspecific.
PMID- 10763795
TI - Preventing falls on an elderly care rehabilitation ward.
AB - OBJECTIVE: Comparison of two flooring types--carpet and vinyl--in the bed areas,
and two modes of physiotherapy--conventional therapy and additional leg
strengthening exercises--in avoiding falls. DESIGN: Randomized 2 x 2 controlled
trial. SETTING: Elderly care rehabilitation ward in a community hospital.
SUBJECTS: Fifty-four consecutive patients referred for rehabilitation. OUTCOME
MEASURES: The incidence of falls, and the change in strength. RESULTS: There were
10 falls on carpet, and only a single fall on vinyl floor covering (relative risk
8.3, 95% confidence interval 0.95-73, p = 0.05). There were four falls in those
receiving additional exercise, and seven falls in those receiving only
conventional physiotherapy (relative risk 0.21, 95% confidence interval 0.04-1.2,
p = 0.12). Fifty-nine per cent of patients were able to complete strength
measurements on admission and discharge. In these, handgrip strength improved
more in those given additional exercise than conventional physiotherapy (2.1 kg
versus -0.3 kg, p < 0.05). CONCLUSION: There is no evidence to support either
intervention in preventing falls on a rehabilitation ward, but within this low
powered study, there was a strong trend towards vinyl being superior.
PMID- 10763797
TI - An experimental controlled study on postural sway and therapeutic exercise in
subjects with low back pain.
AB - OBJECTIVES: To describe postural sway and its associations to background factors,
low back pain and functional capacity. To evaluate the changes in postural sway
after three months of therapeutic exercise in the gym or at home. DESIGN: A one
year randomized experimental trial evaluated postural sway in three study groups:
intensive training, home exercise and control group. SETTING: Subjects were
recruited from seven local occupational health care centres in Central Finland
and were examined at Central Finland Hospital by medical doctors. Measurements
and therapeutic exercise programmes were carried out in the Research Laboratory
of Sport and Health Sciences at Jyvaskyla University. SUBJECTS: Initially, 49
male and 41 female subjects (aged 20-55 years) with nonspecific and subacute low
back pain were examined. MAIN OUTCOME MEASURES: Postural sway using a force
platform, the Oswestry Index, as well as a measure of low back pain intensity
were measured at the initial stage of the study, directly after interventions, as
well as at three and nine months after the interventions. RESULTS: The background
variables were not strongly correlated with postural sway. No changes occurred in
the amplitude of sway during the study, but the sway velocity of the home
exercise group increased. CONCLUSIONS: Postural sway measurements with a force
platform may be suitable for detecting impairments of balance performance among
subjects with pronounced functional or activity limitations and severe low back
pain problems. In order to enhance balance performance, specific and customized
exercise programmes are required.
PMID- 10763798
TI - Discharge delays in a British NHS rehabilitation unit.
PMID- 10763799
TI - Clinical assessment of rehabilitation potential of the older patient: a pilot
study.
AB - Clinical assessment of 'rehabilitation potential' is an everyday occurrence in
hospitals, where scarcity of dedicated rehabilitation facilities require
clinicians to decide who is most likely to benefit from extended rehabilitation.
We examined the reliability of this judgement by different interdisciplinary team
members in 27 consecutive admissions to a geriatric rehabilitation ward. The
reliability of a clinical judgement was in general quite poor (kappa = 0.21). A
more reliable means of determining patient 'rehabilitation potential' is needed.
PMID- 10763800
TI - Criterion validity of lower extremity Motricity Index scores.
AB - OBJECTIVE: To examine the criterion validity of lower extremity Motricity Index
scores. DESIGN: Retrospective cross-sectional comparison of lower extremity
Motricity Index scores and hand-held dynamometer measurements obtained from 15
patients with stroke. RESULTS: For individual actions (ankle dorsiflexion, knee
extension and hip flexion) and all actions combined, Pearson correlations were
good to excellent (r= 0.78-0.91), significant (p < 0.001), and of high power (>
or =99%). CONCLUSIONS: The findings of this study support the criterion validity
of the lower extremity Motricity Index.
PMID- 10763801
TI - Fluorescence studies of the nicotinic acetylcholine receptor in its membrane
environment.
AB - Since the discovery of the fraction of immobilized lipid in contact with the
nicotinic acetylcholine receptor (AChR), the lipid-belt region around this
protein has become the focus of a variety of biophysical studies aimed at
defining its properties. Here we summarize recent spectroscopic studies from our
laboratory using Laurdan fluorescence to characterize distinct sites for lipids
and to describe their effect on the AChR microenvironment.
PMID- 10763802
TI - Verotoxin/globotriaosyl ceramide recognition: angiopathy, angiogenesis and
antineoplasia.
AB - Verotoxin (VT) is involved in the etiology of both hemorrhagic colitis and the
hemolytic uremic syndrome which are microvasculopathies of the colon and
pediatric renal glomerulus respectively. Thus, VT can be considered a vasotoxin.
Cell sensitivity in vitro varies according to the receptor glycolipid
(globotriaosyl ceramide-Gb3) expression and also to intracellular trafficking of
the receptor/toxin complex, such that in highly sensitive cells, the toxin is
targeted to the endoplasmic reticulum and nuclear envelope. Such cells include
tumor cells which have become drug resistant. Thus Gb3 is upregulated in certain
tumors and when such tumor cells become drug resistant, their sensitivity to
verotoxin increases. This may be due to a direct role of the MDRI drug efflux
pump in glycolipid biosynthesis. In addition to the tumor tissue, the toxin
receptor may also be expressed in the tumor neovasculature suggesting that
activated endothelial cells may be verotoxin sensitive. Thus VT may have both a
direct and indirect antineoplastic potential. VT has proved highly effective in a
xenograft cancer model and the possible therapeutic use of VT is discussed.
PMID- 10763803
TI - Biogenesis and evolution of photosynthetic (thylakoid) membranes.
AB - Work in molecular phylogeny during the past few years has documented that the
biogenesis, maintenance, adaptation, and controlled resorption of thylakoid
(photosynthetic) membranes are by far more complex than the requirements for
maintaining their function, especially in plants (eukaryotic photoautotrophs).
Plants, due to their genome compartmentation that originated in a cohabitation of
cells (endosymbiotic events), have evolved an exquisite set of regulatory
mechanisms for their energy-transducing organelles. These operate in concert with
basically ancient regulatory circuits originating in the organelle ancestors. It
appears that the biogenesis of thylakoid membranes, as that of chloroplasts in
general, cannot be understood without knowledge of the history of the cells.
PMID- 10763804
TI - Adherence of pathogenic mycoplasmas to host cells.
AB - The significant genome compaction in mycoplasmas was made possible by adoption of
a parasitic lifestyle. During their evolution and adaptation to a parasitic mode
of life the mycoplasmas have developed various genetic systems enabling their
attachment to host tissues as well as a highly plastic set of variable surface
proteins. The generation of a versatile surface coat through high-frequency phase
and size variation provides the organism with a useful tool for immune system
avoidance, allowing the mycoplasmas to escape antibody attack, explaining why
these minute organisms are such successful parasites.
PMID- 10763805
TI - The terminal enzymes of sialic acid metabolism: acylneuraminate pyruvate-lyases.
AB - The acylneuraminate pyruvate-lyase gene from Clostridium perfringens was
sequenced and found to be most similar to the lyase gene from Haemophilus
influenzae. Both the recombinant clostridial enzyme and the native enzyme from
pig kidney were purified in larger amounts and characterized. The properties of
the porcine lyase are similar to the microbial ones. However, the much higher
degree of similarity in comparison to the microbial enzymes that was found
between porcine lyase peptides and two putative mammalian lyase sequences show
that the latter form an own group apart from the microbial lyases. Actual models
of the acylneuraminate pyruvate-lyase reaction are discussed.
PMID- 10763806
TI - Involvement of glycolipid-enriched domains in the transduction mechanism of
neurotrophins in cultured neurons.
AB - Specialized domains, displaying a peculiar lipid and protein composition, are
present within the plasma membrane of mammalian cells and play a pivotal role in
fundamental membrane-associated events. Among lipids, sphingolipids (in
particular glycolipids and sphingomyelin) are characteristically enriched within
such domains. Moreover, a series of functionally related proteins is present,
suggesting the involvement of these membrane structures in the mechanism of
signal transduction and lipid/protein sorting. An increasing body of evidence
suggests that domains are dynamic structures, and that their dynamic fluctuations
can modulate the activity of domain-associated proteins through changes of
glycolipid protein interaction. Even if a large body of experimental
investigation has been carried out on eukaryotic cells, only little attention has
been paid to the neuron. The purpose of the present review is to summarize the
observations implying a functional role of glycolipid-enriched domains in
cultured rat cerebellar granule cells.
PMID- 10763807
TI - Conformational analysis of the phosphorylated epidermal growth factor receptor.
AB - Phosphorylation-induced conformational changes have been well documented with
different receptor tyrosine kinases. However. the susceptible epitopes and the
tyrosine residue(s) involved in particular structural alteration mostly remain to
be determined. Using a conformation-specific anti-peptide antibody, we have not
only identified one such domain in the C-terminal tail of the EGF receptor but
also identified the phosphate acceptor sites that are involved in the
conformational change.
PMID- 10763808
TI - Identification of the putative mannose 6-phosphate receptor protein (MPR 300) in
the invertebrate unio.
AB - In mammals, Mannose 6-phosphate receptor proteins (MPR 300 and MPR46) mediate
transport of lysosomal enzymes to lysosomes. Both receptors have been found in
non-mammalian vertebrates including fish. To investigate the presence of MPRs in
invertebrates, MPR 300 protein was isolated from the mollusc unio by affinity
chromatography. It was shown to exhibit biochemical and immunological properties
similar to mammalian MPR 300.
PMID- 10763809
TI - Thermodynamic analysis of chitooligosaccharide binding to Urtica dioica
agglutinin by isothermal titration calorimetry.
AB - UDA (Urtica dioica agglutinin) contains two hevein like domains with two non
identical interacting sites and is specific for chitooligosaccharides. The
binding of chitooligosaccharides to UDA was studied by Isothermal Titration
Calorimetry. Each site is composed of three subsites, each binding to a sugar
residue. Thermodynamic parameters obtained show that while chitobiose has two
independent non-interacting sites, chitotriose, chitotetrose and chitopentose
have two interacting sites on each monomer of UDA. Values of binding enthalpy
(deltaH) increase almost by a factor of 7 in going from chitobiose to chitotriose
indicating the existence of three subsites in the combining site of UDA. The
binding constant for chitotetrose and chitopentose increase without any further
enhancement in the values of deltaH indicating that for oligomers larger than
chitotriose interaction is favoured entropically.
PMID- 10763810
TI - Bacteria-host cell interaction mediated by cellular cholesterol/glycolipid
enriched microdomains.
AB - Gram negative bacterial infection is a leading cause of fatality and is
attributed, at least in part, to the bacteria's capacity to persist in the host
in spite of appropriate antibiotic therapy. It has been suggested that bacteria
evade antibiotics by hiding within host cells. We sought to investigate this
important aspect of infections in mast cells, which are inflammatory cells found
in close proximity to the host-environment interface and which have recently been
reported to play a crucial role in the early innate immune response to bacteria.
We examined mast cell interactions with FimH-expressing E. coli, one of the major
opportunistic pathogens of humans. We determined that in serum free conditions,
these bacteria were able to trigger mast cell uptake without loss of bacterial
viability. CD48, a mannose containing GPI (glycosylphosphatidylinositol)-linked
molecule was found to be the receptor of FimH-expressing E. coli in mouse mast
cells. We found that the internalization via CD48 was blocked by filipin, a
cholesterol binding drug known to disrupt cholesterol/glycolipid-enriched
microdomains and the bacteria-encasing vacuoles were rich in cholesterol inside
cells. Interestingly, we found that mast cells subsequently expelled majority of
the intracellular bacteria in 24 hours. This expulsion process was blocked by
lovastatin/cyclodextrin treatment, which is known to inhibit cellular trafficking
of cholesterol/glycolipid-enriched microdomains. Thus, the bacterial entry into
and expulsion from mast cells were critically dependent on cholesterol/glycolipid
enriched microdomains, which represents a novel mode of tussle between the
pathogen and the mast cell occurring in opsonin deficient sites in the body or
even at other sites in naive or immunocompromised hosts which have low systemic
levels of E. coli specific antibody.
PMID- 10763811
TI - DNA polymerase-associated lectin (DPAL) and its binding to the galactose
containing glycoconjugate of the replication complex.
AB - The highly purified DNA Pol-alpha from rat prostate tumor (PA-3) and human
neuroblastoma (IMR-32) cells appeared to be inhibited by Ricin (RCA-II), and Con
A. Loss of activity (40 to 60%) of a specific form of DNA polymerase from IMR-32
was observed when the cells were treated with tunicamycin [Bhattacharya, P. and
Basu, S. (1982) Proc. Natl. Acad. Sci., USA 79:1488-1492]. Binding of ConA and
RCA to human recombinant DNA polymerase-alpha showed a specific labile site in
the N-terminus [Hsi et al.. (1990) Nucleic Acid Res. 18:6231-6237]. The catalytic
polypeptide, DNA polymerase-alpha of eukaryotic origin, was isolated from
developing tissues or cultured cells as a family of 180 to 120 kDa polypeptides,
perhaps derived from a single primary structure. Immunoblot analysis with a
monoclonal antibody (SJK-237-71) indicated that the lower molecular weight
polypeptides resulted from either proteolytic cleavage of post-translational
modification after specific cleavages. Present results suggest DNA polymerase
alpha from embryonic chicken brain (ECB) contains an alpha-galactose-binding
subunit which may be involved in developmental regulation of the enzyme. It was
shown before that the catalytic subunit of DNA polymerase-alpha reduces from 186
kDa in 11-day-old ECB to 120 kDa in 19-day-old ECB [Ray, S. et al. Cell Growth
and Differentiation 2:567-573] by the treatment with methyl-alpha-galactose. The
low molecular weight DNA polymerase activity (120 kDa) can be reconstituted to
high molecular weight (Mr = 186 kDa) with an alpha-galactose binding, 56kDa
lectin-like protein. Polyclonal antibodies raised against the purified lectin
were able to precipitate DNA. Pol-alpha as determined by immunostaining with the
polymerase-alpha-specific monoclonal antibody SJK 132-20, suggesting this is a
DNA polymerase associated-lectin (DPAL). RCA-II and GS-I-Sepharose 4B
chromatographies resulted in significant purification of DNA-alpha and a complete
separation of polymerase complex and primase.
PMID- 10763812
TI - Ceramide glycanase activities in human cancer cells.
AB - Ceramide glycanase (CGase) activities have been detected in different human tumor
cells (colon, carcinoma Colo-205; neuroblastoma, IMR-32; breast cancer lines,
SKBr3 and MCF7). However, the level of enzymatic activity is lower in these cells
compared to that present in other mammalian tissues reported before (Basu, M.,
Kelly, P., Girzadas, M. A., Li, Z., and Basu, S. Methods Enzymol. (in press)).
The majority of CGase activity was found in the 100,000 g soluble supernatant
fraction isolated from all these cell lines and tissues. Using the soluble
enzyme, the requirement for optimum CGase activity was found to be consistent
with previous observations found for rat and rabbit tissues (Basu, M., Dastgheib,
S., Girzadas, M. A., O'Donnell, P. H., Westervelt, C. W., Li, Z., Inokuchi, J.
I., and Basu, S. (1998) Acta Pol. Biochim. 42:327). The CGase activities from
both Colo-205 and IMR-32 cells are optimum at a protein to detergent ratio of
one. All the mammalian CGases, including human cancer cells, show an optimum pH
between 5.5 and 5.8 in sodium acetate buffer. The CGase activities from cancer
cells are found to be cation-independent; however, mercury, zinc, and copper ions
seem to inhibit the enzyme activity substantially in both tumor cells lines. The
mercury ion inhibition of CGase activities from all different sources indicates a
possible structural homology in the CGase proteins. Radiolabeled substrates,
labeled at the sphingosine double bond or at the 3-position of sphingosine
without modifying double bond of sphingosine were used in this investigation.
Both were active substrates with all enzyme preparations isolated from different
cancer cells (apparent Km, 500 microM for nLcOse5[3H-DT]Cer and 350 microM for
GgOse4[sph-3-3H]Cer with Colo-205 enzyme). Structural analogues of ceramide and
sphingosine (L-PPMP. L-PDMP, alkylamines, and Tamoxifen) inhibited cancer cell
CGase activities in vitro.
PMID- 10763813
TI - Role of peripheral benzodiazepine receptors on secretion of surfactant in guinea
pig alveolar type II cells.
AB - Granular type II cells located in the alveolar epithelium synthesize and secrete
pulmonary surfactant and have specialized ion transport system. Alveolar type II
cells are stimulated to secrete pulmonary surfactant by a variety of agonists.
One mechanism by which extracellular signals are perceived by cells is the
mobilization of intracellular Ca2+. Peripheral benzodiazepine receptors (PBRs)
are present in both peripheral tissues and central nervous system. We have
previously reported the presence of high density PBRs in lung and alveolar type
II cells. It is known that both PBRs and beta-adrenergic receptors (beta-ARs)
play an important role in cellular Ca2+ transport. Furthermore, we have suggested
earlier that PBRs are someway functionally associated with the beta-ARs. The
objective of the present study was to determine whether PBRs play any role in the
secretion of surfactant by alveolar type II cells. Alveolar type II cells were
isolated from normal weanling guinea pigs by panning method and incubated with 3H
palmitic acid in minimum essential medium to synthesize labelled dipalmitoyl
phosphatidylcholine (DPPC). After washing, the cells were treated at 37 degrees C
for one hour with 10 microM isoproterenol (IP) in the presence and absence of 10
microM Ro 5-4864, an agonist for PBRs. After one hour, the release of labelled
DPPC in the medium was analyzed. The control cells released DPPC without any
addition of a ligand. However, the treatment of cells with IP, Ro 5-4864 and IP +
Ro 5-4864 caused 24, 52 and 17]% increase in the secretion of DPPC, respectively.
In another experiment, type II cells were loaded with Fura-2 dye and treated with
either IP or epineprine or Ro 5-4864. Both isoproterenol and epinephrine caused a
significant increase in the level of cytosolic free Ca2+. However, Ro 5-4864
caused not only a decrease in the level of cytosolic free Ca2+ but also
counteracted the stimulatory effect of IP. This may suggest that while ligands
for ARs stimulate Ca2+ release into cytosol, the ligand for PBRs stimulates
efflux of Ca2+ in alveolar type cells. Thus, the increased secretion of
surfactant by the ligand of PBRs in alveolar type II cells may be mediated
through its effects on increased Ca2+ efflux.
PMID- 10763814
TI - Evidence of mucin secretion in human lung adenocarcinoma cell lines NCIH650 and
NCIH2077 and effect of select secretagogues on mucin secretion.
AB - Mucins comprise an important class of tumor-associated antigens. The objectives
of the present study were (a) to establish an in vitro model system using human
non-small cell lung adenocarcinoma cell lines NCIH650 and NCIH2077 (b) provide
evidence that these cell lines secrete mucin in culture conditions and (c)
investigate the effects of select secretagogues on mucin secretion. The cell
lines were established in ACL-4 medium containing several growth factors and
retinoic acid and 5% fetal calf serum. The high molecular weight glycoconjugates
secreted in the culture medium were purified by ammonium sulfate precipitation
and Superose 6 and Superose 12 FPLC chromatography. The purified high molecular
weight glycoconjugate fraction and the carcinoma cells were shown to have mucin
by dot blot, Western blot and immunohistochemical analysis, respectively, using
specific antibodies to purified major mucin, HTM-1. Also, incorporation
experiments with mucin precursor 3H-glucosamine demonstrated that the cells
indeed synthesize high molecular weight mucins. The effects of secretagogues such
as, 8-bromocyclic AMP, ionomycin, phorbol-12-myristate-13-acetate and neutrophil
elastase on mucin secretion were also investigated. Only 8-bromocyclic AMP and
neutrophil elastase influenced mucin secretion. These studies provided strong
evidence that the lung adenocarcinoma cell lines secrete high molecular weight
mucins in culture conditions and only two of the four tested secretagogues
significantly increased mucin secretion. Thus, this in vitro model system may be
useful in determining alterations in mucin structure, if any, in lung
adenocarcinomas as well as in studying the regulation of mucin gene expression.
PMID- 10763815
TI - Matrix metalloproteinase in mammary gland remodeling-modulation by
glycosaminoglycans.
AB - Mammary gland which undergoes proliferation, differentiation and involution in
adult life is a useful model system to study the role of extracellular matrix
(ECM) in regulating tissue specific functions. The involution that follows
weaning results in the suppression of casein gene expression, collapse of
alveolar structures and degradation of basement membrane as evidenced by
biochemical analysis of matrix components like proteoglycans and collagen.
Differential expression of three different MMPs viz. 130 K, 68 K and 60 K with
varying specificity to Col IV of basement membrane and Col I of stroma, their
selective inhibition by TIMP and proteoglycans and modulation by estrogen
highlight the importance of these in the remodeling of the ECM in the mammary
gland. The inhibition of these MMPs by glycosaminoglycans, particularly CS and
change in the concentration of CS at different stages of mammary gland
development suggests the existence of a novel mechanism for the regulation of the
activity of MMPs at extracellular sites.
PMID- 10763816
TI - Retention and degradation of N-glycoproteins in the rough endoplasmic reticulum.
AB - Recent studies have shown that newly synthesized proteins and glycoproteins are
submitted to a quality control mechanism in the rough endoplasmic reticulum (ER).
In this report we present two models: One model will illustrate a transient
retention in rough ER leading to a further degradation of glycoproteins in the
cytosol, (soluble alkaline phosphatase expressed in Man-P-Dol deficient CHO cells
lines). The second model will illustrate a strict retention of glycoproteins in
rough ER without degradation nor recycling through the Golgi (E1, E2
glycoproteins of Hepatitis C virus in stably transfected UHCV-11.4 cells and in
infected Hep G2 cells). In both cases, oligomannoside structures are markers of
these phenomena, either as free soluble released oligomannosides in the case of
degradation, or as N-linked oligomannosides for strict retention in rough ER.
PMID- 10763817
TI - Auxiliary photosynthetic functions of Arabidopsis thaliana--studies in vitro and
in vivo.
AB - An improved cultivation system for Arabidopsis thaliana was developed, allowing
advanced biochemical studies in vitro and in vivo of this important model plant.
Highly functional Arabidopsis thylakoids were isolated and used to study both
basic and regulatory photosynthetic functions with the aim to create a platform
for the characterization of mutants deficient in auxiliary proteins. Light
induced proteolytic degradation of the D1 protein could be followed and shown to
be a subsequent event to photoinactivation of electron transport. The
phosphorylation and dephosphorylation of thylakoid proteins resembled that seen
in spinach leaves although phospho-CP43 revealed an unusual regulatory behavior.
PMID- 10763818
TI - p16 INK4a can initiate an autonomous senescence program.
AB - The tumor suppressor p16INK4a is a potent mediator of cell cycle arrest in
transient expression studies, is induced in senescing cells, and can impose
morphological features of senescence. Nonetheless, it is unclear whether p16INK4a
can block cell proliferation irreversibly. We explored this issue using
osteogenic sarcoma cell clones with inducible p16INK4a expression. Induction of
p16INK4a for 1 day arrested most cells in G1 phase. If the induction was then
interrupted, p16INK4a levels returned to baseline and robust growth resumed
within 3-5 days. When p16INK4a was induced for 6 days DNA synthesis remained
strongly inhibited and the cells acquired morphological features of senescence.
Moreover, if p16INK4a induction was interrupted at this point and the cells were
followed for 12 more days, most cells retained these morphologic features and
either failed to divide or died. This occurred despite the prompt return of
p16INK4a expression and retinoblastoma protein phosphorylation toward baseline
levels. In fact, some senescing cells appeared to enter S phase. These results
demonstrate that a sustained period of p16INK4a expression is sufficient in this
setting to impose a durable block to cell proliferation and that this state
becomes independent of p16INK4a expression, hypophosphorylation of pRB, or a
strict G1 arrest.
PMID- 10763819
TI - The promyelocytic leukemia (PML) protein suppresses cyclin D1 protein production
by altering the nuclear cytoplasmic distribution of cyclin D1 mRNA.
AB - The majority of the promyelocytic leukemia (PML) protein is present in nuclear
bodies which are altered in several pathogenic conditions including acute
promyelocytic leukemia. PML nuclear bodies are found in nearly all cells yet
their function remains unknown. Here, we demonstrate that PML and the eukaryotic
initiation factor 4E (elF-4E) co-localize and co-immunopurify. eIF-4E is involved
in nucleocytoplasmic transport of specific mRNAs including cyclin D1. eIF-4E
overexpression leads to increased cyclin D1 protein levels; whereas,
overexpression of PML leads to decreased cyclin D1 levels. Neither PML nor eIF-4E
cause significant changes in cyclin D1 mRNA levels. The association with eIF-4E
led us to investigate if PML could alter mRNA distribution as a possible post
transcriptional mechanism for suppressing cyclin D1 production. We show that
overexpression of PML results in nuclear retention of cyclin D1 mRNA and that
intact PML nuclear bodies are required. Addition of eIF-4E overcomes PML induced
retention and alters the morphology of PML bodies suggesting a mechanism by which
eIF-4E can modulate PML function. These results raise the possibility that PML
nuclear bodies may participate in the regulation of nucleocytoplasmic transport
of specific mRNAs.
PMID- 10763820
TI - Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin
E overexpression.
AB - Centrosome hyperamplification and the consequential mitotic defects contribute to
chromosome instability in cancers. Loss or mutational inactivation of p53 has
been shown to induce chromosome instability through centrosome
hyperamplification. It has recently been found that Cdk2-cyclin E is involved in
the initiation of centrosome duplication, and that constitutive activation of
Cdk2-cyclin E results in the uncoupling of the centrosome duplication cycle and
the DNA replication cycle. Cyclin E overexpression and p53 mutations occur
frequently in tumors. Here, we show that cyclin E overexpression and loss of p53
synergistically increase the frequency of centrosome hyperamplification in
cultured cells as well as in tumors developed in p53-null, heterozygous, and
wildtype mice. Through examination of cells derived from Waf1-null mice, we
further found that Waf1, a potent inhibitor of Cdk2-cyclin E and a major target
of p53's transactivation function, is involved in coordinating the initiation of
centrosome duplication and DNA replication, suggesting that Waf1 may act as a
molecular link between p53 and Cdk2-cyclin E in the control of the centrosome
duplication cycle.
PMID- 10763821
TI - Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells.
AB - The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human
tumours. In order to understand the mechanism by which ErbB2 mediates tumour
proliferation we have functionally inactivated the receptor using an
intracellularly expressed, ER-targeted single-chain antibody (scFV-5R). Inducible
expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line
leads to loss of plasma membrane localized ErbB2. Simultaneously, the activity of
ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active
ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of
functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of
the cell cycle. This was a result of reduction in CDK2 activity, which was
mediated by a re-distribution of p27Kip1 from sequestering complexes to cyclin
E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27KiP1
sequestration, decreased in the absence of functional ErbB2. Ectopic expression
of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a
partial G1 rescue. We propose that c-Myc is a primary effector of ErbB2-mediated
oncogenicity and functions to prevent normal p27Kip1 control of cyclinE/CDK2.
PMID- 10763822
TI - Similar but distinct effects of the tristetraprolin/TIS11 immediate-early
proteins on cell survival.
AB - The immediate early protein tristetraprolin (TTP) is required to prevent
inappropriate production of the cytokine TNF-alpha, and is a member of a zinc
finger protein family that is associated with RNA binding. TTP expression is
induced by TNF-alpha, and evidence indicates that TTP can bind and destabilize
the TNF-alpha mRNA. TTP and the closely related TIS11b and TIS11d proteins are
evolutionarily conserved, however, and induced transiently in various cell types
by numerous diverse stimuli, suggesting that they have additional functions.
Supporting this idea, continuous expression of each TTP/TIS11 protein at
physiological levels causes apoptotic cell death. By various criteria, this cell
death appears analogous to apoptosis induced by certain oncoproteins. It is also
dependent upon the zinc fingers, suggesting that it involves action on
appropriate cellular targets. TTP but not TIS11b or TIS11d also sensitizes cells
to induction of apoptosis by TNF-alpha. The data suggest that the TTP and TIS11
immediate early proteins have similar but distinct effects on growth or survival
pathways, and that TTP might influence TNF-alpha regulation at multiple levels.
PMID- 10763824
TI - A new predictive factor for hepatocellular carcinoma based on two-dimensional
electrophoresis of genomic DNA.
AB - Molecular genetic analyses have clarified that accumulation of genomic changes
provides important steps in carcinogenesis and have identified a number of
valuable genetic markers for certain cancers. To date, however, no prognostic
markers have been identified for hepatocellular carcinoma (HCC). In this study,
we used restriction landmark genomic scanning (RLGS), a new high-speed screening
method for multiple genomic changes, to detect unknown genetic alterations in
HCC. Thirty-one HCC samples and their normal counterparts were examined by RLGS.
Eight spot changes were common in several cases, and all were seen only on the
HCC profile. Five of these spots were detected in more than 12 of 31 cases
(38.7%). Viral infection had no influence on changes in the RLGS spots. The
disease-free survival rate for patients with > or =16 changed RLGS spots was
significantly lower than that for patients with fewer changed RLGS spots (< or
=15 spots) (P<0.001). In multivariate analysis, the number of changed spots was
proven to retain an independent prognostic value (relative risk 1.095: P =
0.0031). These results suggest that the number of changed RLGS spots may be a
useful biological marker for recurrence of HCC.
PMID- 10763823
TI - Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by
inducing mcl-1 via the mitogen-activated protein kinase pathway.
AB - Overexpression of epidermal growth factor receptor (EGFR) and establishment of
transforming growth factor alpha (TGF alpha)/EGF autocrine system are frequently
detected in tumor cells. In addition to mitogenic ability, we demonstrate in this
report that EGF protects a human esophageal carcinoma (CE) cell line, CE81T/VGH,
from staurosporine-induced apoptosis. The anti-apoptotic signal of EGF is
alleviated by a MEK inhibitor PD98059 or an ERK2 dominant negative mutant but not
by a phosphatidylinositol-3'-kinase (PI-3K) inhibitor wortmannin. Furthermore, v
raf blocks apoptosis induced by staurosporine. This evidence implies that the
survival signal of EGF is mediated via the Raf-MEK-ERK pathway but not the PI3-K
pathway. The survival effect of EGF is coincident with the induction of mcl-1, an
antiapoptotic gene in the bcl-2 family. PD98059 also suppresses the induction of
Mcl-1 by EGF, implying that EGF may up-regulate Mcl-1 via the MAP kinase pathway.
Overexpression of mcl-1 is sufficient to protect against apoptosis, while
transfection of a mcl-1 antisense plasmid causes cell death. The expression of
mcl-1 antisense plasmid also suppresses the anti-apoptotic effect of EGF. Taken
together, these results indicate that EGF may up-regulate Mcl-1 through the MAP
kinase pathway to suppress apoptosis.
PMID- 10763825
TI - The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate
preferences and activate similar intracellular signalling pathways.
AB - Inappropriate activation of Abl family kinases plays a crucial role in different
human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and
p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different
chromosomal translocation, has recently been described. In this study, the kinase
specificities of the Bcr-Abl and Tel-Abl proteins were compared to the
physiological Abl family kinases c-Abl and Arg (abl related gene). Using short
peptides which correspond to the target epitopes in known substrate proteins of
Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel
Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein
CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed
with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3
cells. GTPase analysis with a Ras-GTP-specific precipitation assay showed
constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl
proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated
to negatively regulate apoptosis, were also constitutively activated by both Bcr
Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have
catalytic specificities different from the normal kinases c-Abl and Arg and that
Tel-Abl is capable to activate at least some pathways which are also upregulated
by Bcr-Abl.
PMID- 10763826
TI - The loss of mdm2 induces p53-mediated apoptosis.
AB - The p53 tumor suppressor gene product is negatively regulated by the product of
its downstream target, mdm2. The deletion of mdm2 in the mouse results in
embryonic lethality at 5.5 days post coitum (d.p.c.) which can be overcome by
simultaneous loss of the p53 tumor suppressor, substantiating the importance of
the negative regulatory function of MDM2 on p53 function in vivo. Hence, the loss
of MDM2 allowed the unregulated p53 protein to continuously exert its growth
suppressing activity, which either led to a complete G1 arrest or induced the p53
dependent apoptotic pathway, resulting in the death of the mdm2-/- embryos. To
determine which of these possibilities is occurring, mouse embryo fibroblasts
(MEFs) from p53 null and p53/mdm2 double null embryos were transfected with a
retroviral vector carrying a temperature-sensitive p53 (tsp53) cDNA. Shifting of
single-cell clonal populations to the permissive temperature caused the p53-/
mdm2-/- fibroblasts expressing tsp53 to undergo apoptosis in a dose-dependent
manner. This phenotype was not observed in the tsp53 expressing p53-/- clones nor
the parental cell lines. Thus, our data indicate that the simple loss of mdm2 can
induce the p53-dependent apoptotic pathway in vivo.
PMID- 10763827
TI - Defects in TGF-beta signaling overcome senescence of mouse keratinocytes
expressing v-Ha-ras.
AB - Previous studies have shown that TGFbeta1 expression is upregulated in mouse
keratinocytes infected with a v-rasHa retrovirus, although the functional
significance of this has not been clear. Here we show that v-rasHa retrovirus
transduced primary mouse keratinocytes undergo hyperproliferation followed by a
TGFbeta1 dependent G1 growth arrest and senescence. The growth arrest is
accompanied by a 15-fold increase in total TGFbeta1 secreted and a fourfold
increase in secreted active TGFbeta1. When cultured in the presence of a
neutralizing antibody to TGFbeta1, the senescence response is suppressed. Levels
of the TGFbeta1 target p15ink4b increase during senescence as does association of
this kinase inhibitor with cyclinD/cdk4 complexes. However, p16ink4a, p53 and
p19ARF expression also increase during senescence. Genetic analysis shows that
TGFbeta1 null and dominant negative TbetaBRII expressing v-rasHa keratinocytes
resist the G1 growth arrest and do not senescence. This resistance is associated
with low expression of p15ink4b and p16ink4a, constitutive Rb phosphorylation and
high levels of cdk4 and cdk2 kinase activity. In contrast, inactivation of
TGFbetabeta1 secretion or response does not block the induction of p53 and
p19ARF, but the level of p21waf1, a p53 target gene, is reduced in cyclin D/cdk4
and cyclin E/cdk2 complexes. Thus, although multiple senescence pathways are
activated in response to a ras oncogene, inactivation of TGFbeta1 secretion or
response is sufficient to block the senescence program. Since v-rasHa transduced
TGFbeta1-/- keratinocytes form squamous cell carcinomas following skin grafting,
these results suggest that in mouse keratinocytes, defects in TGFbeta1 signaling
accelerate malignant progression by overcoming oncogene induced replicative
senescence.
PMID- 10763828
TI - v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the
oncogenic growth of cells.
AB - We investigated the effect of cell transformation by v-src on the expression and
tyrosine phosphorylation of SHPS-1, a putative docking protein for SHP-1 and SHP
2. We found that transformation by v-src virtually inhibited the SHPS-1
expression at mRNA level. While nontransforming Src kinases including c-Src,
nonmyristoylated forms of v-Src had no inhibitory effect on SHPS-1 expression,
transforming Src kinases including wild-type v-Src and chimeric mutant of c-Src
bearing v-Src SH3 substantially suppressed the SHPS-1 expression. In cells
expressing temperature sensitive mutant of v-Src, suppression of the SHPS-1
expression was temperature-dependent. In contrast, tyrosine phosphorylation of
SHPS-1 was rather activated in cells expressing c-Src or nonmyristoylated forms
of v-Src. SHPS-1 expression in SR3Y1 was restored by treatment with herbimycin A,
a potent inhibitor of tyrosine kinase, or by the expression of dominant negative
form of Ras. Contrary, active form of Mekl markedly suppressed SHPS-1 expression.
Finally, overexpression of SHPS-1 in SR3Y1 led to the drastic reduction of
anchorage independent growth of the cells. Taken together, our results suggest
that the suppression of SHPS-1 expression is a pivotal event for cell
transformation by v-src, and the Ras-MAP kinase cascade plays a critical role in
the suppression.
PMID- 10763829
TI - Evidence for a recessive inheritance of Turcot's syndrome caused by compound
heterozygous mutations within the PMS2 gene.
AB - Turcot's syndrome is a genetic disease characterized by the concurrence of
primary brain tumors and colon cancers and/or multiple colorectal adenomas. We
report a Turcot family with no parental consanguinity, in which two affected
sisters, with no history of tumors in their parents, died of a brain tumor and of
a colorectal tumor, respectively, at a very early age. The proband had a severe
microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa,
and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We
identified two germline mutations within the PMS2 gene: a G deletion (1221delG)
in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which
were inherited from the patient's unaffected parents. These results represent the
first evidence that two germline frameshift mutations in PMS2, an MMR gene which
is only rarely involved in HNPCC, are not pathogenic per se, but become so when
occurring together in a compound heterozygote. The compound heterozygosity for
two mutations in the PMS2 gene has implications for the role of protein PMS2 in
the mismatch repair mechanism, as well as for the presymptomatic molecular
diagnosis of at-risk family members. Furthermore, our data support and enlarge
the notion that high DNA instability in normal tissues might trigger the
development of cancer in this syndrome.
PMID- 10763830
TI - Translation of p15.5INK4B, an N-terminally extended and fully active form of
p15INK4B, is initiated from an upstream GUG codon.
AB - The expression of the cyclin-dependent kinase inhibitor p15INK4B in normal cells
after induction with TGF-beta1, or following overexpression from an adenovirus
encoded cDNA, appears on an SDS-polyacrylamide gel as a doublet. Here, the
underlying mechanism behind the synthesis of the two species has been studied. By
expressing cDNAs truncated at their 5' end, we found that the synthesis of the
more slowly migrating form, called p15.5INK4B, is dependent on a sequence
upstream of the first AUG codon thought to initiate translation of p15INK4B. Two
potential, in frame, alternative upstream initiation codons, ACG and GUG, were
individually changed to GCA encoding alanine. Analysis by in vitro translation,
or immunoblotting of lysates from transfected 293 cells, showed that translation
of p15.5INK4B is initiated at the GUG located 13 codons upstream of the first
AUG. When this AUG was mutated, p15INK4B was no longer made. Instead, a shorter
form, initiated at an in frame AUG located seven codons downstream, was
synthesized. Finally, when both these AUGs were mutated, only p15.5INK4B was
generated. Both p15INK4B and p15.5INK4B bound to CDK4 and CDK6, inhibited DNA
synthesis, and caused replicative senescence of a human glioma cell line. We thus
conclude that p15INK4B and p15.5INK4B, encoded by the CDKN2B gene, are
functionally indistinguishable as based on these assays.
PMID- 10763831
TI - Definitive functional evidence for a tumor suppressor gene on human chromosome
7q31.1 neighboring the Fra7G site.
AB - We have previously shown that loss of heterozygosity (LOH) on human chromosome
(hchr) 7 at q31.1 is common in a variety of tumors of epithelial origin. Frequent
LOH of a specific chromosomal marker is indicative of a closely linked tumor
suppressor gene (TSG). However, recent reports have also indicated that such a
high frequency of LOH could be due to the presence in this region of the second
most common aphidicolin-inducible fragile site in the human genome (Fra7G). To
address this controversy, we introduced single copies of hchr7 or hchr12 into a
highly aggressive human prostate carcinoma cell line (PC3) by microcell-mediated
transfer. The tumorigenicity of six clones of PC3/hchr7 hybrids and three clones
of PCRhchr12 hybrids, obtained in four separate fusion experiments, were studied
in BALB/c nude mice. All but one of the PC3/hchr7 hybrids increased tumor latency
by at least twofold, whereas none of the PC3/hchr12 hybrids delayed tumor onset.
No differences in the in vitro growth rate were observed among any of the cell
lines assayed (parental and hybrids) suggesting that the observed tumor
suppression was due to factors other than cell cycle regulation. Deletion mapping
of the PC3/hchr7 tumors obtained after reversion to the malignant phenotype
revealed a common region of loss centred around 7q31.1, supporting the TSG
hypothesis. The smallest commonly deleted region was approximately 1.5 Mb in size
and flanked by the markers D7S486 and D7S655.
PMID- 10763832
TI - Ectopic pregnancy.
AB - Ectopic pregnancy is a implantation occurring elsewhere than in the cavity of the
uterus, whereas ninety-nine percent of extrauterine pregnancies occur in the
fallopian tube. The incidence of extrauterine pregnancy has increased from 0.5%
thirty years ago, to a present day 1-2%. The most frequent cause of tubal
pregnancy is previous salpingitis. Mortality rates for tubal pregnancies used to
be approximately 1.7% in the 1970s but dropped to 0.3% in 1980s. DIAGNOSIS: Using
transvaginal ultrasound it is possible to obtain positive evidence of an ectopic
pregnancy at a very early stage. In cases of hCG titers>2,000 IU/l, intrauterine
pregnancy can be diagnosed with certainty. The most important differential
diagnosis of ectopic pregnancy is early intrauterine pregnancy. CLINICAL
MANAGEMENT AND THERAPY: Regardless of the therapeutic strategy selected by the
physician, informing the patient is a major aspect of the management of ectopic
pregnancy. If surgery is considered appropriate, the patient must be informed
about the nature, side effects and complications of the procedure. However, it
should be remembered that in some cases, the actual chances of cure first become
apparent at surgery. In asymptomatic patients with a serum hCG titer <1,000 IU/l
that is falling, it is appropriate to wait and watch. In clinically stable
patients with an unruptured tubal pregnancy and steady hCG levels, systemic
treatment with methotrexate might also be considered. In unruptured tubal
pregnancy with a hCG titer between 1,000 and 2,500, a further therapeutic
alternative is intratubal injection of prostaglandins, hyperosmolar glucose of
NaCl. Generally speaking, the currently widespread laparoscopic surgical
treatment of the fallopian tube hardly influences the risk of recurrence. If the
gestational mass is larger, the serum hCG titer higher than the approximate limit
of 2,500 mU/ml and/or the tube already ruptured, surgery is usually required.
PREVENTION: The most effective prevention is to avoid tubal inflammation or, in
cases of preexisting inflammation, to administer effective therapy.
PMID- 10763833
TI - Assisted internal autorotation with vacuum extractor. Description of an original
maneuver.
AB - The traditional treatment of arrest of internal rotation of fetal head is
forceps. We describe a maneuver for assisted internal autorotation of fetal head
with vacuum extractor. We have used this approach in 30 parturients. No neonatal
or maternal complications were noted.
PMID- 10763834
TI - A comparison between the effectiveness of epidural analgesia and parenteral
pethidine during labor.
AB - The study was aimed to define parturients' opinion on either epidural analgesia
or intravenous pethidine, and to determine the effect of both analgesics after
delivery. We interviewed and examined 401 consecutive parturients who requested
analgesia during the beginning of their active stage of labor. Of those, 131
women requested and underwent epidural analgesia, and 270 received parenteral
pethidine. The pain experienced before admission of any analgesia, was
significantly higher in the epidural group than in the parental group (mean
visual analog scale (VAS) score 8.9 and 8.4, respectively; P=0.004). However,
after analgesics, women from the epidural analgesia experienced significantly
less pain during labor as compared to those receiving pethidine (mean VAS scores
5.05 vs. 9.14, respectively; p<0.001). The pain scores 24 h after labor were
significantly lower in patients who underwent epidural analgesia (1.69 vs. 2.13,
respectively; p<0.001). We conclude that epidural analgesia is more effective
than parenteral analgesia in pain and discomfort relief. This method is helpful
also the day after delivery. Thus, epidural analgesia should be strongly
recommended to all patients who do not have any medical contraindications to this
method of treatment.
PMID- 10763835
TI - Serum leptin concentrations throughout the menstrual cycle.
AB - Leptin is a cytokine involved in the regulation of food intake and fertility in
rodents and in humans. No data exist about serum leptin serum levels during the
spontaneous menstrual cycle. In this study 16 ovulatory cycles of
endocrinologically normal volunteers were analyzed. Blood samples were taken on
alternate days throughout the menstrual cycle for measurement of serum estradiol,
progesterone, LH, FSH and leptin serum levels. No correlation of leptin values
with estradiol values (r = 0.07) or progesterone values (r = 0.14) were seen.
Mean leptin values during the luteal phase were significantly higher (16.67 +/-
9.45 ng/mL) compared to the follicular phase (13.50 +/- 8.75 ng/mL) (P < 0.02). A
strongly positive correlation with the progression of the menstrual cycle could
be seen (r = 0.91). The physiological significance of higher luteal phase leptin
levels is unknown.
PMID- 10763836
TI - Dynamic aspects of endometriosis in a mouse model through analysis of
implantation and progression.
AB - The aim of this study was to use normal immunocompetent mice to set up a model
for endometriosis which allowed to study the dynamic aspects involved in
initiation and progression of the disease. Thirty mice were surgically
transplanted with autologous endometrium and at 3 weeks showed evidence of
endometriosis. Diagnosis of endometriotic lesions was histologically confirmed.
Visual inspection using a caliper revealed that, after an initial decrease in
size (from 33.44+/-2.33 mm2 to 24.24+/-2.37 mm2 (p<0.01)) detected at 3 weeks
after transplantation, there was a significant increase of lesion area from
21.30+/-3.15 mm2 to 43.93+/-6.29 mm2 (p<0.05) in the following 4 weeks. When we
compared these results to those obtained in mice which underwent bilateral
annessiectomy, we observed that, when bilateral annessiectomy was performed
simultaneously to endometrial transplantation, lesion surfaces were similar
between mice which were or were not subjected to bilateral ovariectomy. On the
other hand, when bilateral annessiectomy was performed at second laparotomy and
then evaluated after 4 weeks, differently from what observed in control mice,
surface values decreased from 21.24+/-2.29 mm2 to 10.58+/-3.40 mm2 (p<0.01).
Finally, progression of lesions in estrogen supplemented mice seems less evident
than in control mice since only a slight but not significant increase in size
(from 21.32+/-3.32 mm2 to 26.18+/-6.98 mm2, p=0.32) was detected. The results
presented herein demonstrate that surgically induced endometrial implants in mice
are dynamic lesions and that implantation and progression of endometriosis
represent different stages in the ethiopathogenesis of the disease. Moreover, we
showed that progression, but not implantation, of ectopic endometrium is
dependent upon the functionally and structurally integrity of the ovaries. This
is a model of endometriosis established in normal immunocompetent mice, and,
consequently, may represent a reliable tool for testing new immunological
therapeutical approaches and studying the role of different genes using
transgenic mice.
PMID- 10763837
TI - Serum concentrations of soluble Fas antigen and soluble Fas ligand in mother and
newborn.
AB - We measured soluble Fas antigen and soluble Fas ligand, which are considered to
be an apoptotic substance, in maternal serum, umbilical cord serum and amniotic
fluid during cesarean section at full term pregnancy. Seventeen healthy
parturients with no fetal distress were studied. Soluble Fas antigen showed no
different levels between these measurement sites. Soluble Fas ligand showed a
difference, in which umbilical serum level was significantly higher than maternal
serum and amniotic fluid levels. The present results suggest high serum levels of
soluble Fas ligand in newborn. However, the reason for this evidence is entirely
unknown.
PMID- 10763838
TI - Anticardiolipin antibodies levels in healthy pregnant and non-pregnant woman.
AB - To determine the prevalence of anticardiolipin antibodies in healthy non pregnant
women and during normal pregnancy, 110 healthy women of mean age 25 years old and
53 healthy pregnant females of mean age 24.5 years old, who no one suffered from
any autoimmune disease, were studied. In all women the anticardiolipin antibodies
were measured in duplicate by the Enzyme Linked Immunosorbent Assay (ELISA).
There was no difference in the percentage of the positive anticardiolipin
antibodies between non pregnant and pregnant healthy women (9.1% and 5.6%
respectively). Also, there was no difference in the antibodies levels during
normal pregnancy, as well as, during an equal time of observation in non pregnant
women. The positive anticardiolipin antibodies levels were low.
PMID- 10763839
TI - Melatonin in postmenopausal females.
AB - There is little information about the interaction between melatonin, sexual
steroids and neuroendocrine system in postmenopausal females, even if former
research showed that melatonin is clearly involved in human physiology and
pathophysiology. We evaluated the overnight urinary excretion of 6
sulfatoxymelatonin (6-SMT) using a radioimmunoassay in 60 postmenopausal women.
The group has been divided into patients with insomnia (10), hyperprolactinemia
(7), depression (9), obesity (7) and controls (27). Compared to controls 6-SMT
values were significantly higher in depressive females. Patients with
hyperprolactinemia showed a trend toward a significantly elevated average
nocturnal melatonin concentration. Melatonin levels were significantly lower in
patients with insomnia and obese postmenopausal females than in controls. Since
previous studies described lower melatonin levels in postmenopausal than in
premenopausal women, the indication of melatonin therapy, especially for sleep
disorders in this collective, can be handled more generously. Melatonin should be
prescribed restrictively in patients with depression and in those with
hyperprolactinemia. The role of melatonin in obese females remains unclear.
PMID- 10763840
TI - Detection of tumor cells in leukapheresis products from patients with breast
cancer using immunocytochemical staining method.
AB - We used a combination of 4 monoclonal antibodies (BM7, BM8 against MUC1, 5D3
against CK8,18,19 and HEA125 against human epithelial antigen) and a sensitive
immunocytochemical staining using cytospin preparation to identify breast tumor
cells in leukapheresis products (LP). This assay allowed detection of one tumor
cell in 1x10(6) mononuclear cells (MC). In clinical specimens, tumor cells were
detected in LP from 6 of 42 (14.3%) patients in the adjuvant treatment group,
from 2 of 11 (18.2%) patients in the neoadjuvant treatment group and from 9 of 43
(20.1%) in the group of patients with metastatic disease. Tumor cell counts
ranged from 0.25-5 cells in 1x10(6) normal cells per LP. The median tumor cell
concentration was higher in specimens from patients with metastatic disease
(median=0.96) than in specimens from patients in the adjuvant and neoadjuvant
treatment groups (median=0.5 and 0.75). No significant differences between the
epithelial cell positive group and the epithelial cell negative group with
respect to tumor size, lymph nodes involvement, tumor grade, histological type
and receptor were found. We conclude that immunocytochemical staining of cytospin
preparation is a sensitive and simple method to detect and quantitate breast
cancer cells in LP.
PMID- 10763841
TI - Disseminated intravascular coagulopathy in pregnancy: thorough comprehension of
etiology and management reduces obstetricians' stress.
AB - In pregnancy and puerperium disseminated intravascular coagulopathy may accompany
abruptio placenta, intrauterine fetal demise with retained dead fetus, amniotic
fluid embolism, endotoxin sepsis, preecalampsia with HELLP and massive
transfusion. Clinical signs and symptoms of DIC can include oozing from
venipuncture sites and/or mucous membranes, red cell lysis from activation of the
complement system, hemorrhage from coagulopathy and possible uterine atony,
hypotension from hemorrhage and/or bradykinin release, and oliguria from end
organ insult and hypovolemia/hypotension. Treatment of DIC consists of
replacement of volume, blood products, and coagulation components and
cardiovascular and respiratory support with elimination of underlying triggering
mechanism.
PMID- 10763842
TI - Crohn's disease mimicking as bowel endometriosis. Are the symptoms reduced by
nafarelin acetate?
AB - We report a 27-year-old female with Crohn's disease clinically misdiagnosed with
intestinal endometriosis. Her complaints were abdominal pain and fullness, which
occurred monthly during her menstrual period. Although we had no
histopathological evidence, we diagnosed her as bowel endometriosis on the basis
of her clinical course. Since nafarelin acetate therapy started, the symptoms due
to mechanical subileus have improved. The transverse colon, a 70 cm segment of
the ileum, including the terminal ileum, were resected because of repeated
symptoms of bowel obstruction despite prolonged nafarelin therapy.
Histopathological findings of the resected specimen revealed Crohn's disease
without endometrial tissue. In our patient, an increased cortisol and ACTH
secretion, a side effect of nafarelin, was noted during the therapy. This case
showed that nafarelin therapy could increase serum concentration of ACTH and
cortisol, which was considered to suppress the pathology of Crohn's disease by
its anti-inflammatory action. We emphasize that intestinal examination must be
performed with Crohn's disease in mind, even if nafarelin acetate is effective.
PMID- 10763843
TI - Virilizing adrenal adenoma and primary amenorrhea in a girl with adrenal
hyperplasia.
AB - We report a 14-year-old girl with primary amenorrhea and virilization. The
chromosomal analysis showed a normal 46,XX female karyotype and the hormonal
assays disclosed high serum levels of testosterone (T): 450 ng/dL (normal 5-90),
dehidroepiandrosterone-sulfate (DHEA-S): 690 microg/dL (normal 30-450) and 17
hydroxiprogesterone (17-OHP) >20 ng/mL (normal <2). A pelvic ultrasound disclosed
a small uterus and bilateral enlargement of the ovaries, a computed axial
tomographic scan of the abdomen identified a large right mass in the adrenal
gland and a norcholesterol-I 131 adrenal gammagraphy revealed a functional
adrenal tumor. The histological analysis of the surgical removed tumor revealed
and adrenal adenoma. After surgery, a steep decline to normal serum levels of T
and DHEA-S was observed, remaining an elevated level of 17-OHP: 5.4 ng/mL. During
the first three months of follow up, the hirsutism declined sharply and
spontaneous mammary development occurred, remaining elevated the 17-OHP serum
level: 4.8 ng/mL. Prednisone 5 mg/day, was initiated decreasing the 17-OHP to
normal level: 1.4 ng/mL, appearing the menarche followed by cyclical menses. One
year after surgery, prednisone was withdrawn during one week, and an ACTH test
and HLA typing were done, disclosing a 17-OHP response of an heterozygote for
adrenal hyperplasia, and identifying B65 a subtype of B14, and DR1, that are
frequently associated to adrenal hyperplasia. Previous reports have informed
silent adrenal tumors associated to adrenal hyperplasia, but this is the first
report of a functional adrenal tumor associated to adrenal hyperplasia.
PMID- 10763844
TI - Prenatal diagnosis of succenturiate lobe by ultrasonography and color Doppler
imaging.
AB - At 16 weeks' gestation, ultrasonography demonstrated a band-like structure in the
amniotic cavity of a 27-year-old woman. Color Doppler imaging revealed blood flow
in this band-like structure and a diagnosis of a placenta with succenturiate lobe
rather than an amniotic band was made.
PMID- 10763845
TI - Deep vein thrombosis during administration of HMG for ovarian stimulation.
AB - We report a case of activated protein C (APC) resistance and deep calf vein
thrombosis under controlled ovarian stimulation for in vitro fertilization. The
thrombosis occurred before administration of human chorionic gonadotrophin for
ovulation induction on the 8th day of hMG (human menopausal gonadotrophin). The
patient was stimulated according to the long luteal protocol. Cases of arterial
and venous thrombosis as a result of ovarian stimulations are reviewed.
PMID- 10763846
TI - Prenatal diagnosis of cloacal exstrophy before rupture of the cloacal membrane.
AB - We describe a case of cloacal exstrophy what was diagnosed prenatally by
ultrasound and confirmed at birth. We also review the literature on 15 previous
prenatally diagnosed cloacal extrophy cases.
PMID- 10763847
TI - Pregnancy and delivery in young woman affected by isthmic coarctation of the
aorta.
AB - Coarctation of aorta is a rare cause of hypertension in pregnancy and the case
material reported in literature is limited without a univocal line of clinical
conduct. A case association between isthmic coarctation of the aorta and
pregnancy in a 17 year-old primigravida woman is described.
PMID- 10763848
TI - Uterine adenocarcinoma after GnRH agonist treatment.
AB - We report endometrial adenocarcinoma in two patients shortly after suspending
GnRH-agonist treatment for menometrorrhagia and uterine fibromata.
PMID- 10763849
TI - Contribution of receptor/G protein signaling to cell growth and transformation.
AB - While the effects of receptor/G protein systems on intermediary metabolism have
been intensively studied, it has only recently been appreciated that G protein
coupled receptors and G proteins (heterotrimeric GTP-binding proteins) play
important roles in the regulation of cell growth, differentiation and even
transformation. Naturally occurring mutations both in G protein-coupled receptors
and in G protein alpha-subunits lead to autonomous cell growth resulting in human
disease. One mechanism to transduce mitogenic signals from the cell membrane to
the nucleus is the engagement of the extracellular signal-regulated kinase
(ERK)mitogen-activated protein kinase (MAPK) cascade. Multiple distinct signal
transduction pathways have been characterized which link G proteins with the ERK
cascade. Receptor and non-receptor tyrosine kinases play central roles in these
pathways. Mitogenic signaling by receptor/G protein systems is realized as a
complex interplay between signals emanating from different classes of cell
surface receptors. The characterization of receptor-, G protein- and tyrosine
kinase-specific contributions to mitogenic signaling in a particular cell may
ultimately allow for the rational design and application of pharmaceuticals to
treat diseases involving uncontrolled cell proliferation.
PMID- 10763850
TI - Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel
compound exhibiting a marked preference for the human enzyme in intact cells.
AB - HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesu lfonamide),
a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel
series of COX inhibitors comprising bicyclic arylethersulfonamides; of this
series HN-56249 is the most potent and selective human COX-2 inhibitor. HN-56249
inhibited platelet aggregation as a measure of COX-1 activity only moderately
(IC50 26.5+/-1.7 microM). In LPS-stimulated monocytic cells the release of
prostaglandin (PG) F1alpha as a measure of COX-2 was markedly inhibited (IC50
0.027+/-0.001 microM). Thus, HN-56249 showed an approximately 1000-fold
selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a
potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 microM) only. COX-1 was
only weakly inhibited (IC50 867+/-181 microM). Hence, HN-56249 exhibited a
greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the
COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4
methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methyl
sulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and
threefold, respectively, and in the whole blood assays by approximately 40-fold.
Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw
oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximately
tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SEM). After
oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan
induced rat paw oedema test, however, some 30-fold less potently than diclofenac.
Comparing the inhibitory potency of HN-56249 against human COX-2 with that
against murine COX-2 in intact cells revealed a 300-fold selectivity for the
human enzyme. Similar effects were observed with other COX-2-selective
arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides,
including a highly selective COX-1 inhibitor, inhibited human and murine COX-2
approximately equipotently. In conclusion, HN-56249 is a novel potent and highly
selective COX-2 inhibitor with a marked preference for the human COX-2 enzyme in
vitro. Despite excellent bioavailability and the long plasma half-life of HN
56249, anti-inflammatory effects in rodents were only moderate. We suggest these
differing in vitro-in vivo effects observed could be due to significant
inflammatory prostaglandin synthesis by COX-1, or to the genetic differences
between human and rodent COX-2, or to both.
PMID- 10763851
TI - Interaction of a series of draflazine analogues with equilibrative nucleoside
transporters: species differences and transporter subtype selectivity.
AB - The equilibrative nucleoside transporters of mammalian cells play an important
role in the regulation of extracellular adenosine concentrations, and inhibition
of these transporters potentiates the biological effects of adenosine. Two
subtypes of equilibrative transporters have been defined by their differential
sensitivities to inhibition by nitrobenzylthioinosine (NBMPR; es/ENT1, sensitive;
ei/ENT2, insensitive). In addition, significant species differences have been
noted in es/ENT1 transporter affinity for a subset of inhibitors including
draflazine and dipyridamole. Draflazine and a series of 15 chemically related
compounds were compared for their abilities to: (a) inhibit the binding of
[3H]NBMPR to the es/ENT1 transporter in mouse Ehrlich cell and human erythrocyte
membranes, and (b) inhibit the es/ENT1 and ei/ENT2 transporter-mediated uptake of
[3H]uridine in Ehrlich cells. Compounds within this series represented over a
1000-fold range of affinities for the es/ENT1 and ei/ENT2 transporters with
subtype selectivities (ENT1/ENT2) ranging from 370 for R70527 to 0.17 for
soluflazine. Five other analogues were identified, in addition to soluflazine,
that had significantly higher affinity for the ei/ENT2 transporter compared with
es/ENT1. Structure activity analyses of these data identified the requirement of
a hydrophobic group connected to a 2-aminocarbonyl piperazine by a 5-carbon chain
for high-affinity interactions with es/ENT1. This hydrophobic moiety was not as
important for ei/ENT2 affinity and, in contrast to es/ENT1, a shorter alkyl chain
enhanced binding to ei/ENT2. These draflazine analogues also varied in their
differential affinities for mouse vs. human es/ENT1 transporters, and the degree
of species discrimination was strongly dependent on the position of the
aminocarbonyl group on the piperazine ring. This information, combined with
structural data derived from molecular studies with ENT1 and ENT2 recombinant
proteins, should guide further development of subtype-selective inhibitors of the
equilibrative nucleoside transporters.
PMID- 10763852
TI - Contribution of nitric oxide, prostanoids and Ca(2+)-activated K+ channels to the
relaxant response of bradykinin in the guinea pig bronchus in vitro.
AB - In the guinea pig bronchus with epithelium, pre-contracted with histamine,
bradykinin (BK), lysyl-BK, prostaglandin E2 (PGE2), cromakalim and S-nitroso-N
acetylpenicillamine each caused graded relaxation with mean EC50s of 34 nM, 11
nM, 0.1 nM, 0.3 microM and 3.4 microM, respectively. The addition of NO synthase
inhibitors N(W)-nitro-L-arginine (L-NOARG), N(G)-monomethyl-L-arginine or 7
nitroindazole reduced BK-induced relaxation by 41+/-6%, 59+/-4% and 51+/-2%,
respectively. The inhibition of BK response caused by L-NOARG was completely
reversed by L-, but not by D-arginine. Methylene blue and 6-(phenylamino)-5,8
quinolinedione (LY 83583) inhibited the BK response by 88+/-5% and 64+/-4%, while
1H-[1,2,4]oxadiazolo[4,3-a]quinolaxin- -one (ODQ) had no effect. However, ODQ
almost abolished SNAP-induced relaxation. Indomethacin and the cyclo-oxygenase 2
(COX-2) inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl
2(5H)-furanon e (DFU) caused graded inhibtion of BK responses with mean IC50s of
60 nM and 0.6 nM, respectively. Addition of tetraethylammonium (TEA),
charybdotoxin (ChTx), or iberotoxin (IbTx) inhibited BK-induced relaxation by
76+/-4%, 30+/-4% and 99+/-1%, respectively, but the relaxations of PGE2 and
cromakalim were unaffected. In contrast, 4-aminopyridine, apamin or glibenclamide
did not affect BK-induced relaxation. These results indicate that BK-induced
epithelium-dependent relaxation in the guinea pig bronchus is partially mediated
by release of NO or by NO-related substances, involving an activation of both
cyclo-oxygenase 1 (COX-1) and COX-2 enzymes, through a cyclic guanosine
monophosphate (cGMP)-independent mechanism. Furthermore, BK-induced relaxation
involves an activation of high-conductance Ca(2+)-activated K+ channels highly
sensitive to IbTx, and to a lesser extent to ChTx and TEA.
PMID- 10763853
TI - Ageing and epithelial integrity as modulators of airway smooth muscle
responsiveness to endothelin-1.
AB - This study has examined the effects of animal age on the contractile
responsiveness and inositol phosphate-generating capacities of guinea-pig (0-104
weeks) and rat (4-104 weeks) isolated tracheal smooth muscle in response to
endothelin-1 (ET-1). The influence of animal age on the specific binding of
[125I]ET-1 to guinea-pig and rat isolated tracheal tissue was also examined. The
potency (pD2) of ET-1 was three to four times greater in tracheal tissue taken
from 4-week-old rats than in similar tissue from 12- to 32-week-old animals,
although maximum response (Emax) was not significantly altered. Neither pD2 nor
Emax were influenced by ageing in epithelium-intact guinea-pig tracheal
preparations. In contrast, removal of the airway epithelium significantly
increased the contractile potency of ET-1 by two- to three-fold in tissue from
animals of 6-20 weeks of age, but not in tissue from newborn animals. Significant
falls in specific [125I]ET-1 grain density with ageing were demonstrated during
the maturation phase in both species. In the rat, the decrease between 4 and 12
weeks was reflected in the fall in ET-1 potency at 12 weeks. However, the age
associated reduction in airway smooth muscle ET receptor number in the guinea-pig
was not mirrored by significant changes in sensitivity to ET-1, suggesting the
presence of a functional receptor reserve. ET-1 (1 nM) caused significant
increases in intracellular inositol phosphates, with levels generally higher in
rat than in guinea-pig trachea. ET-1-induced inositol phosphate accumulation
decreased significantly with respect to animal age in both guinea-pig and rat
isolated tracheal tissue. However, this was not correlated with changes in
contractile pD2 or Emax. For example, in both rat and guinea-pig, the smallest ET
1-induced increases in intracellular inositol phosphates were measured in airway
smooth muscle from the oldest animals tested, although tissue sensitivity to ET-1
was stable in both species after 12 weeks of age. These data suggest that
relatively low levels of inositol phosphates were required to elicit Emax,
consistent with the presence of more than one signal transduction process.
PMID- 10763854
TI - Pharmacologic actions of the second generation leukotriene B4 receptor antagonist
LY29311: in vivo pulmonary studies.
AB - We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4
(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt).
Guinea pigs were used to evaluate the effect of this agent on (1) acute airway
obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte
infiltration and delayed onset airway obstruction resulting from a 4-h
leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with
the divalent cationic ionophore A23187 (6S
[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8
[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4
benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary
gas trapping measurements and lung inflammation was evaluated by bronchoalveolar
lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of
acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14
microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit
the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or
the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E
dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced
bronchoalveolar lavage granulocyte infiltration and delayed onset airway
obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary
inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We
conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist
with potent pulmonary anti-inflammatory activity.
PMID- 10763855
TI - The effect of the enantiomers of formoterol on inherent and induced tone in
guinea-pig trachea and human bronchus.
AB - The long-acting beta2-adrenoceptor agonist formoterol is, like all other members
of this class of drugs, used as a racemate in the clinic. While the effects of
the individual enantiomers have been studied on airway smooth muscle from guinea
pig, comparable data on human bronchial smooth muscle are scanty or absent.
Therefore, we compared the effects of the enantiomers of formoterol on inherent
and induced tone in isolated human bronchi with that on guinea-pig trachea in
vitro. The human bronchi either were studied under resting tension conditions or
were precontracted with 10 microM carbachol or 0.1 mM histamine. The guinea-pig
trachea was precontracted with 0.01, 0.1 or 1 microM carbachol. The racemate and
(R,R)-formoterol caused a concentration-dependent relaxation of all preparations
with an EC50 of about 1 nM. In the guinea-pig trachea, the concentration-effect
curve for formoterol was moved to the right in response to an increased
concentration of carbachol. In both human bronchus and guinea-pig trachea, (S,S)
formoterol was more than 1,000 times less potent than (R,R)-formoterol. Thus the
relaxing effect of formoterol in human airways as well as in guinea-pig trachea
was shown to lie with the (R,R)-enantiomer. Notably, (S,S)-formoterol did not
exert any contractile effects within the tested concentration range in either
airway preparation. Therefore, we conclude that with regard to relaxant effects
the pure (R,R)-enantiomer of formoterol does not offer a benefit over the
racemate.
PMID- 10763856
TI - beta-Adrenoceptor stimulation up-regulates phosphodiesterase 4 activity and
reduces prostaglandin E2-inhibitory effects in human neutrophils.
AB - Human neutrophils were treated for 4 h with a combination of salbutamol (1
microM), a beta2-adrenoceptor agonist, and rolipram (30 microM), a selective
phosphodiesterase 4 inhibitor, to investigate whether this treatment produces up
regulation of phosphodiesterase activity with functional consequences. Anion
exchange chromatography coupled with the use of selective activators and
inhibitors demonstrated that a phosphodiesterase activity with characteristics of
the isoenzyme type 4 was increased in drug-treated cells. Kinetic analysis showed
a approximately 1.5-fold increase in Vmax without alteration of Km values. The
augmented phosphodiesterase activity in drug-treated cells was abolished by
actinomycin D. Cyclic AMP content in drug-treated cells was higher than resting
values (27.28+/-2.79 pmol/10(6) cells vs. 0.34+/-0.03 pmol/10(6) cells). Reverse
transcriptase-polymerase chain reaction showed increased expression of mRNA
transcripts for PDE4B and PDE4A in drug-treated cells. Functionally, up
regulation of phosphodiesterase 4 reduced the inhibition by prostaglandin E2 of
zymosan-induced superoxide generation.
PMID- 10763857
TI - Atypical effect of minoxidil sulphate on guinea pig airways.
AB - The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and
bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig
airways in vitro and in vivo and on isolated portal veins from rats and guinea
pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of
isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/
0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim
caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04,
respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the
spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of
3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent
(pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline).
The airway relaxant effect of bimakalim, but not minoxidil sulphate, was
antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM.
Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive
guinea pigs (measured as increase in total lung resistance) was dose-dependently
reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg;
Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at
doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of
higher doses, both minoxidil sulphate and bimakalim reduced blood pressure.
Airways hyperreactivity to histamine induced by acute treatment of guinea pigs
with immune complex was dose-dependently reversed by bimakalim (ED50=0.5
microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30
mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity:
at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses
above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of
the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg
i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in
guinea pig airways is completely different from that of classical K(ATP) channel
openers such as bimakalim. Minoxidil sulphate is either only weakly active or
even inactive at K(ATP) channels in guinea pig airways or interacts with these
channels in a different manner. The current results are consistent with there
being differences between the K(ATP) channels in airways and blood vessels.
PMID- 10763858
TI - Clinically available NMDA receptor antagonists memantine and dextromethorphan
reverse existing tolerance to the antinociceptive effects of morphine in mice.
AB - The tail-flick test was used to investigate the effects of chronic administration
of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan,
memantine and MRZ 2/579, on the development and reversal of morphine tolerance in
mice in three separate experiments. Experiment 1 investigated the effects of NMDA
receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6
days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose
response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579
between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of
morphine tolerance. In experiment 2, in which the effects on the reversal were
investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days
(between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle,
vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice
treated with vehicle+vehicle remained morphine tolerant, whereas this residual
morphine tolerance was inhibited by administration of all three NMDA antagonists
(each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections
demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the
co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted
in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579
(10 mg/kg) inhibited the acute antinociceptive effect of morphine, but
dextromethorphan did not. These data indicate that low-affinity, clinically
available and/or therapeutically promising NMDA receptor antagonists may be used
to inhibit ongoing morphine tolerance.
PMID- 10763859
TI - Release of catecholamines in the locus coeruleus of freely moving and
anaesthetized normotensive and spontaneously hypertensive rats: effects of
cardiovascular changes and tail pinch.
AB - Noradrenaline turnover has been found to be increased in the locus coeruleus of
young spontaneously hypertensive rats (SHR). There is also evidence that the
noradrenergic projection from the locus coeruleus to the posterior hypothalamus
contributes to the development of genetic hypertension. To investigate whether
the release of noradrenaline and dopamine in the locus coeruleus is modified in
genetic hypertension, this brain region of adult SHR and normotensive Wistar
Kyoto (WKY) rats was superfused with artificial cerebrospinal fluid through a
push-pull cannula. Dopamine and noradrenaline released in the superfusate were
determined radioenzymatically. There was no difference in the basal release of
noradrenaline and dopamine in the locus coeruleus of conscious, anaesthetized or
diazepam-treated adult WKY rats and SHR. In conscious animals, a rise in blood
pressure elicited by intravenous infusion of phenylephrine enhanced the release
of noradrenaline and dopamine in both strains to the same extent. Intravenous
infusion of sodium nitroprusside elicited a fall in blood pressure and also
increased to the same degree the release of noradrenaline and dopamine in the
locus coeruleus of normotensive and hypertensive conscious rats. In anaesthetized
rats, baroreceptor activation by phenylephrine decreased the release of
noradrenaline and dopamine, while sodium nitroprusside lowered blood pressure and
enhanced the release rates of the two catecholamines. Treatment of conscious rats
with diazepam (10 mg/kg, i.p., 120 min prior to starting collection of the
superfusate) abolished the phenylephrine-evoked release of catecholamines
observed in conscious animals. The sensory stimulus tail pinch led to a slight
increase in blood pressure. In conscious animals, this aversive stimulus led to
enhanced release of noradrenaline and dopamine that lasted longer in SHR than in
WKY rats. The release of catecholamines evoked by tail pinch was abolished in
rats treated with diazepam, as well as in anaesthetized animals. Our findings
show that in adult rats, genetic hypertension does not modify the release of
noradrenaline and dopamine in the locus coeruleus. Since in anaesthetized rats
increases in blood pressure diminish, while decreases in blood pressure enhance,
the release of noradrenaline and dopamine, it seems that both amines possess a
counteracting, hypertensive function in the rat locus coeruleus. When
baroreceptor activation by phenylephrine is carried out on conscious animals,
stress predominates and the release of catecholamines is enhanced. This study
demonstrates the importance of the noradrenergic system of the locus coeruleus in
central cardiovascular control and in emotional, stress and pain-regulating
processes.
PMID- 10763860
TI - Modulation of cross-bridge interaction by 2,3-butanedione monoxime in human
ventricular myocardium.
AB - OBJECTIVES: 2,3-butanedione monoxime (BDM) has been suggested as an additive to
cardioplegic solutions, because it may reduce the energy cost associated with
force production in heart muscle. METHODS: The present study investigated the
effect of BDM (10 mM) on developed tension (DT), Ca(2+)-dependent myosin ATPase
activity (MYO) and tension cost (myosin ATPase activity/ tension ratio),
characterizing the cross-bridge detachment rate, of skinned fiber preparations
(1% Triton X, 20 h, 4 degrees C) of human left ventricular failing myocardium
(dilative cardiomyopathy, heart transplants, n=6) at increasing concentrations of
Ca2+ (0.01-32 microM). RESULTS: BDM decreased Ca2+ sensitivity of DT [EC50 Ca2+,
control: 1.3+/-0.2 microM, + BDM (10 mM): 4.5+/-0.3 microM] and MYO [EC50 Ca2+,
control: 0.9+/-0.2 microM, + BDM (10 mM): 3.1+/-0.3 mM]. In addition, BDM reduced
maximal DT [control: 26.0+/-1.9 mN/mm2, + BDM (10 mM): 8.1+/-1.1 mN/mm2] and MYO
[control: 124+/-21 RM ADP/s, + BDM (10 mM): 62 9 microM ADP/s]. However, the
influence of BDM on maximal DT (-69%) was more pronounced than on maximal MYO (
50%). The myosin ATPase activity/tension relation was significantly higher in the
presence of BDM. CONCLUSIONS: BDM exerts negative inotropic activity by reducing
the number of force-generating cross-bridges, possibly by increasing the cross
bridge detachment rate as well as by reducing force generation per cross-bridge
in human myocardium. As BDM reduces force generation more than ATPase activity,
BDM may not necessarily reduce energy demand in human myocardium.
PMID- 10763861
TI - The K(ATP) channel blocker HMR 1883 does not abolish the benefit of ischemic
preconditioning on myocardial infarct mass in anesthetized rabbits.
AB - Previous experimental studies showed that the benefit of ischemic preconditioning
(IPC) is abolished by K(ATP) channel blockade with glibenclamide. However, the
newly discovered K(ATP) channel blocker HMR 1883 (1-[[5-[2-(5-chloro-o
anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) shows marked
antifibrillatory activity in the dose range of 3 mg/kg to 10 mg/kg i.v. in
various experimental models without affecting blood glucose levels. In order to
investigate in a head to head comparison glibenclamide and HMR 1883 with respect
to their influence on IPC, experiments were performed in rabbits with ischemia
reperfusion using myocardial infarct mass as final read out. Male New Zealand
White rabbits (2.6-3.0 kg) were subjected to 30-min occlusion of a branch of the
left descending coronary artery (LAD) followed by 2-h reperfusion. For IPC
experiments the LAD was additionally occluded for two periods of 5 min, each
followed by 10-min reperfusion, before the long-term ischemia. Infarct mass was
evaluated by TTC staining and expressed as a percentage of area at risk. Rabbits
(n=7/group) were randomly selected to receive (i.v.) saline vehicle 5 min prior
to the 30-min occlusion period in infarct studies without IPC or to receive
glibenclamide (0.3 mg/kg) or HMR 1883 (3 mg/kg) in IPC experiments, these
substances being given 5 min prior to the first preconditioning or 5 min prior to
the long-term ischemia of 30 min. Myocardial risk mass as a percentage of left
ventricular mass did not differ between groups. The same was true for the ratio
of left ventricular mass to 100 g body weight. Myocardial infarct mass as a
percentage of the area at risk in the saline vehicle group without IPC was 41+/
3%. Whereas glibenclamide significantly increased infarct mass (from 41+/-3% to
55+/-4%), HMR 1883 did not affect it. IPC reduced infarct mass from 41+/-3% to
21+/-4% (P<0.05 vs. control without IPC). Glibenclamide given prior to IPC or
prior to the long-term ischemia totally abolished the IPC effect (42+/-2% and
55+/-4%, respectively; P<0.05 vs. control). In contrast, HMR 1883 under the same
conditions did not affect infarct size when given prior to IPC or prior to the
long-term ischemia (21+/-3% and 26+/-2%, respectively). The monophasic action
potential duration (MAP50) was reduced from 103+/-3 ms under normoxic conditions
to 82+/-2 ms, 5 min after ischemia in the absence of drugs. This ischemia-induced
shortening of the MAP was prevented by both HMR 1883 (MAP50 103+/-3 ms) and
glibenclamide (MAP50 106+/-3 ms). In conclusion, although both K(ATP) channel
blockers prevented ischemia-induced shortening of MAP, HMR 1883 did not abolish
the beneficial effects of IPC on myocardial infarct mass in rabbits, whereas
glibenclamide totally reversed this cardioprotective effect of IPC. This suggests
that the sarcolemmal ATP-sensitive potassium channels are not involved in the
mechanism of IPC.
PMID- 10763862
TI - Role of prostanoids in the contraction induced by a tachykinin NK2 receptor
agonist in the hamster urinary bladder.
AB - In isolated strips of the hamster urinary bladder the selective tachykinin NK2
receptor agonist [betaAla8]NKA(4-10) induced a concentration-dependent (1 nM-10
microM) contraction (EC50 104 nM) associated with significant release of
prostaglandin E2 (PGE2, 50+/-17 pg/mg tissue). In mucosa-free bladder strips
[betaAla8]NKA(4-10) was as potent as in the presence of mucosa (EC50 46 nM),
although the evoked PGE2 release was significantly less than in controls (6+/-1.7
pg/mg tissue). Dexketoprofen (10 microM) produced a significant but limited
rightward shift of the concentration/response curve to [betaAla8]NKA(4-10) both
in the presence and absence of the mucosal layer: the EC50 for [betaAla8]NKA(4
10) was increased five- and threefold, respectively. The evoked PGE2 release was
abolished in both cases. The selective tachykinin NK2 receptor antagonist,
nepadutant (10 nM-1 microM) produced a concentration-dependent and even
inhibition of both contraction and PGE2 release induced by [betaAla8]NKA(4-10).
The L-type calcium channel blocker, nifedipine (1 microM) and the non-selective
cationic channel blocker SKF 96365 (30 microM) both inhibited the contractile
response to [betaAla8]NKA(4-10) (89+/-2 and 83+/-2% inhibition, respectively).
The evoked PGE2 release was not affected by nifedipine but was almost abolished
by SKF 96365. Arachidonic acid (100 microM) induced a contractile response (5.9+/
0.7 mN) associated with a large production of PGE2 (383+/-78 pg/mg tissue). The
contractile response to arachidonic acid was inhibited by both nifedipine (1
microM) and SKF 96365 (30 microM) (83+/-5 and 79+/-3% inhibition, respectively).
The PGE2 production induced by arachidonic acid was markedly inhibited by SKF
96365 only (about 94% inhibition). Exogenous PGE2 contracted hamster bladder
strips in the presence of dexketoprofen (EC50 1 microM) and strongly potentiated
the contractile response to a submaximal concentration of [betaAla8]NKA(4-10). In
anaesthetized hamsters the administration of [betaAla8]NKA(4-10) (10 nmol/kg,
i.v.) produced a contractile response of the urinary bladder (13+/-0.4 mmHg) that
was inhibited partly by dexketoprofen (25+/-3 and 35+/-4% inhibition for 0.2 and
2 mg/kg, i.v. dexketoprofen, respectively). We conclude that activation of
tachykinin NK2 receptors determines prostanoid synthesis/release in the hamster
urinary bladder and that this effect is largely ascribable to structures present
in the bladder mucosa. Prostanoids generated following NK2 receptor activation
amplify the direct contractile effect of NK2 receptor agonists. This latter
response is largely due to activation of L-type calcium channels (nifedipine
sensitive) although this source of calcium apparently is not essential for
activation of prostanoid synthesis.
PMID- 10763863
TI - Inhibition of croton oil-induced oedema in mice ear skin by capsular
polysaccharides from cyanobacteria.
AB - The anti-inflammatory properties of hydrophilic extracts of the capsular polymers
of twelve cyanobacterial strains belonging to the genera Phormidium and Nostoc
from marine and terrestrial habitats were tested topically on croton oil-induced
oedema in mice ear skin. The screening program identified several strains as
producers of anti-inflammatory products (up to 56% inhibition of the oedema). The
inhibition response was dose-dependent. The application of trichloroacetic acid
treated extracts reduced the oedema by about 60%. On the other hand, one of the
strains enhanced the inflammatory response. Analysis of five of the extracts
showed the presence of neutral sugars (from 34.3% to 47.1%, w/w), uronic acids
(from 7.1% to 26.7%, w/w) and proteins (from 30.1% to 57.0%, w/w) in the crude
polymer. Rhamnose, fucose, arabinose, xylose, mannose, glucose, galactose,
galacturonic acid and glucuronic acid were detected as well as sulphate groups
(from 9.6% to 21.5%, w/w of sugars). The main components found were glucose and
mannose.
PMID- 10763864
TI - Chiral separation by capillary electrochromatography.
AB - The state of art in chiral capillary electrochromatography is reviewed. Chiral
separations by capillary electrochromatography were carried out using capillaries
packed with chiral stationary phases or achiral stationary phases in combination
with a chiral selector added to the mobile phase. Furthermore, the use of open
tubular capillaries containing the chiral selector coated to the capillary wall
was also reported. Among other separation principles moleculary imprinted
polymers represent a challenging approach for chiral capillary
electrochromatography. A recent trend is the use of polymeric continuous beds
with a chiral selector incorporated.
PMID- 10763865
TI - Lanthanide complexes as smart CD probes for chirality sensing of biological
substrates.
AB - Lanthanide tris(beta-diketonates) and porphyrinates acted as effective circular
dichroism (CD) probes for chirality sensing of neutral and zwitterionic guests.
They were electrically neutralized but formed highly coordinated 1:1 complexes
with various guests. When a chiral, non-chromophoric guest was combined with a
chromophoric lanthanide probe, the resulting highly coordinated complex exhibited
characteristic CD signal, the sign of which was dependent on the absolute
configuration of the bound guest. Since there are wide variations of coordinating
ligands and lanthanide centers, lanthanide coordination chemistry offers great
possibilities for the design of new CD chirality sensory systems especially for
biologically important guests.
PMID- 10763866
TI - Effective resolution of chiral 1,1':5',1"-ternaphthalene-2,2',6',2"-tetrol
through camphorsulfonylation, recrystallization and reductive desulfonylation
AB - Optical resolution of the title compound, TERNOL (1), having bis-bidentate sites
of axial chiralities was succesful. A racemic mixture of 1 was converted to the
tetracamphorsulfonate 2 in high yield, and a single recrystallization of 2 under
kinetic conditions effectively separated the diastereomers. The crystal part
obtained in 44% yield consisted of (S,S)-2 of 96% diastereomer excess (de), and
the solution part (50% yield) contained (R,R)-2 of 96% de. An additional
recrystallization of the each part resulted in diastereomerically pure 2 in high
yield. Hydride reduction of the ketones in the camphorsulfonyl groups of 2 caused
smooth intramolecular transesterification, and enantiomerically pure (R,R)-1 and
(S,S)-1 were obtained in good yields.
PMID- 10763867
TI - Stereospecific polymerization of alpha-(menthoxymethyl)acrylate
AB - Novel alpha-(alkoxymethyl)acrylates bearing a chiral substituent, racemic and
optically active benzyl alpha-(menthoxymethyl)acrylates ((+)- and (-)-BMnMA),
were synthesized and polymerized by radical and anionic methods. The effects of
the chiral substituent on the stereoregularity and chiroptical property of the
obtained polymers were investigated. 13CNMR spectra of the polymers obtained by
anionic polymerization of the racemic monomer showed sharper peaks than that of
the radically obtained polymers, indicating that the former polymers possessed
higher stereoregularity than the radically obtained polymers. The polymers
prepared from optically pure (-)-monomer with anionic initiators had low
solubility in common organic solvents. However, the THF-soluble parts were highly
isotactic, and exhibited lower specific rotation ([alpha]25(365) = -92 degrees)
than those of the monomer ([alpha]25(365) = -226 degrees) and the radically
obtained polymer ([alpha]25(365) = -201 degrees). The circular dichroism (CD)
spectra of the copolymers prepared from a (+)- and (-)-monomer mixture with
various optical purity suggested that the highly isotactic (-)-polymer may
possess a chiral helical conformation.
PMID- 10763869
TI - Catalytic asymmetrization of racemic dicyclopentadiene derivatives by using
chiral copper(II) catalyst
AB - Treatment of racemic dicyclopentadiene derivatives with tert-butyl peroxybenzoate
in the presence of a catalytic amount of Cu(II)-tris- or bis-(oxazoline) complex
directly gave optically active benzoyloxylated dicyclopentadiene derivatives,
useful building blocks bearing multiple asymmetric centers, in a highly
enantioselective manner (up to 87% ee).
PMID- 10763868
TI - Separation of enantiomers on HPLC chiral stationary phases based on human plasma
alpha1-acid glycoprotein: effect of sugar moiety on chiral recognition ability.
AB - HPLC chiral stationary phases based on human plasma alpha1-acid glycoprotein
(AGP) and partially deglycosylated AGP (pd-AGP) were prepared to investigate the
effects of sugar moiety of AGP on chiral discrimination of various solutes.
Removal of a sugar moiety of AGP by treatment with N-glycosidase was confirmed by
high-performance capillary electrophoresis, reversed-phase HPLC and matrix
assisted laser desorption-time of flight (MALDI-TOF) mass spectrometry. The
average molecular weights of AGP and pd-AGP were estimated to be ca. 33,000 and
30,600, respectively, by MALDI-TOF mass spectrometry. Next, AGP and pd-AGP were
bound to aminopropyl-silica gels activated with N,N '-disuccinimidylcarbonate.
The retentivity+ and enantioselectivity of the neutral, acidic and basic solutes
tested on the pd-AGP column were significantly or not significantly larger in
most solutes than those on the AGP column. This is ascribable to that by cleavage
of a sugar chain(s) by N-glycosidase, pd-AGP could become more hydrophobic than
AGP, and/ or that a solute could be easily accessible to the specific and/or non
specific binding sites of pd-AGP. It is interesting that warfarin enantiomers are
not resolved on the pd-AGP column, but resolved on the AGP column. A sugar
chain(s) of AGP cleaved by N-glycosidase might be involved in the
enantioselective binding of warfarin enantiomers.
PMID- 10763870
TI - Optical resolution of (+/-)-1-aryl-1-alkanols using enantioselective
transesterification by lipases.
AB - Enantioselective transesterification of 1-phenyl-1-alkanols (PhCH(OH)(CH2)n-2CH3;
n = 2, 3, 4, 5, 6, 9, 12, 18) with vinyl acetate catalyzed by lipases in benzene
has been studied to find the catalyst which is generally used for preparing
optically active 1-phenyl-1-alkanols having various alkyl chains. Amongst lipases
examined (lipases LIP, PS, AK, CAL and RML), the lipase from Pseudomonas
aeruginosa (LIP) is the best catalyst which shows high reactivity and
enantioselectivity and low substrate specificity. The rate of the LIP-catalyzed
transesterification decreases with increasing the alkylchain length till n = 4.
The catalysis of LIP recovers again toward the alkanols with n = 5-18. Other
lipases do not exhibit such an effect of alkyl-chain length and show very poor or
no catalysis for the alkanols with n > or = 4. LIP is also the best catalyst for
the enantioselective transesterification of 1-(1-naphthyl)-, 1-(2-naphthyl)- and
1-(1-pyrenyl)-1-propanols. Each optically pure 1-aryl-1-alkanol was isolated by
the present method.
PMID- 10763871
TI - Silver(I)-catalyzed asymmetric Mukaiyama aldol reaction
AB - Cationic Ag(I)-BINAP complex has been shown to be an effective catalyst for
Mukaiyama aldol reaction between aldehyde and silyl enol ether derivatives. AgPF6
BINAP is very active in this reaction and can achieve high enantiomeric excess
under mild conditions. Addition of a small amount of water enhanced the
reactivity to suggest the contribution of enolate anion intermediate. AgOAc
BINAP, which in noncationic species, showed an extraordinary high activity
although %ee was low.
PMID- 10763872
TI - Syntheses of chirally modified thiacalix
AB - New chirally modified p-tert-butylthiacalix[4]arenes were synthesized via
conformation- and/or regioselective etherification with ethyl bromoacetate
followed by hydrolysis of the ester moiety and then subsequent amidation with (S)
1-phenyl-ethylamine or (S)-1-(1-naphthyl)ethylamine. These chiral selectors were
coated with OV-17 on capillary columns to examine their ability as chiral
stationary phases (CSPs) for discrimination of enantiomeric amino acid, amine and
alcohol derivatives. It was found that CSP-(S)-4 prepared from cone-shaped tetra
(S)-1-phenylethylamide (S)-4 showed good to fair separations for all the samples
examined. On the contrary, the corresponding CSP-(S)-14 prepared from the cone
shaped tetraamide (S)-14 of the parent p-tert-butylcalix[4]arene did not indicate
any enantioseparation at all for the same samples, showing that the bridging
group of the calix[4]arene ring is critical for the advent of enantioselectivity.
The effect of the types and the numbers of the chiral amide groups in the chiral
selectors on enantioselectivity was also discussed.
PMID- 10763874
TI - Application of cis-2-amino-3,3-dimethyl-1-indanol as an efficient chiral
auxiliary to the asymmetric Ireland-Claisen rearrangement. Improvement of the
diastereoselectivity by combinational use of chlorodimethylsilane as a silylating
agent
AB - The asymmetric Ireland-Claisen rearrangement of allyl carboxylates having a
chiral substituent at the alpha-position of the carboxylate part gave the desired
products with excellent diastereoselectivity, when an oxazolidinone, which was
prepared from a non-natural chiral auxiliary, (1R,2S)-cis-2-amino-3,3-dimethyl-l
indanol, was used as the chiral substituent. Furthermore, the
diastereoselectivity was improved by using chlorodimethylsilane as a silylating
agent of the intermediary enolates.
PMID- 10763873
TI - Enantioresolution of aliphatic alcohols by lithocholamide.
AB - Lithocholamide (LCAM) forms inclusion compounds with aliphatic alcohols involving
over five carbon atoms. Enantioresolution of the racemic alcohols was studied in
channels of the inclusion compounds. X-ray crystallographic study clarified that
host assemblies exhibit guest-dependent polymorphism. In each polymorphic
crystal, the more longer or bulkier groups the alcohols have, the effective the
resolutions become. The inclusion spaces were analyzed by a computed tomographic
method, explaining the chiral recognition mechanism from a stereochemical
viewpoint.
PMID- 10763875
TI - Enantioresolution and absolute stereochemistry of omicron-substituted
diphenylmethanols
AB - omicron-Substituted diphenylmethanols were enantioresolved by the method of
chiral dichlorophthalic acid amide, yielding enantiopure alcohols. Their absolute
configurations were unambiguously determined by X-ray crystallography of chiral
dichlorophthalate esters.
PMID- 10763876
TI - Axial chirality of ortho-substituted N,N-diacylanilines: electronic effects of
acyl groups on racemization
AB - Studies on the racemization of optically active ortho-tert-butyl-N,N
diacylanilines 1c-e including the electronic effects of their acyl groups are
described. The racemization of 1c bearing a 4-methoxyphenyl substituent occurred
faster while that of le bearing a 4-trifluoromethylphenyl substituent was slower,
compared with that of 1d bearing a phenyl group. Thus, the rate of racemization
depends on the electronic effects of the acyl groups in addition to steric
effects of the acyl groups in la, b as reported previously (K. Kondo, H. Fujita,
T. Suzuki and Y. Murakami, Tetrahedron Lett. 1999, 40, 5577-5580).
PMID- 10763877
TI - Highly efficient kinetic resolution of beta-halohydrins catalyzed by a chiral 1,2
diamine.
AB - Kinetic resolution of racemic beta-halohydrins has been achieved by reaction with
benzoyl chloride in the presence of a catalytic amount (0.3 mol%) of a chiral
diamine combined with diisopropylethylamine to afford the corresponding benzoates
and unreacted beta-halohydrins in good to excellent enantioselectivities. The
benzoate can be converted to the corresponding allylic benzoate without loss of
optical purity by treatment with (1,5-diazabicyclo[4.3.0]non-5-ene).
PMID- 10763878
TI - Enantiomorphous control in chiral crystallization of achiral molecules by pseudo
seeding
AB - Several helical-type co-crystals of tryptamine and achiral carboxylic acids
having similar crystal structures were found to play the role of pseudo-seed
crystals in chiral crystallizations from solutions of tryptamine and different
carboxylic acids.
PMID- 10763879
TI - Synthesis, circular dichroism and absolute stereochemistry of
1,1',2,2',3,3',4,4',-octahydro-3,3'-dimethyl-4,4'-biphenanthryl
AB - In the course of synthetic studies of chiral olefins, (3R,3'R)-(P,P)-(E)-(-)
1,1',2,2',3,3',4,4'-octahydro3,3'-dimethyl-4,4'-biphenanthrylidene (1) and its
(3R, 3'R)-(P,P)-(Z)-(+)-isomer (2), chiral (3R,3'R,4R,4'R)-(-)
1,1',2,2',3,3',4,4'-octahydro-3,3'-dimethyl-4,4'-biphenanthryl (3) was obtained
as a by-product in the McMurry reaction of (3R)-(-)-2,3-dihydro-3-methyl-4(1H)
phenanthrenone (4). The relative and absolute stereostructures of (-)-3 were
fully determined by NMR, X-ray crystallographic, and CD spectral analyses.
PMID- 10763880
TI - Synthesis of enantiomerically pure C2-symmetric 4-pyrrolidinopyridine derivative
as a chiral acyl transfer catalyst for the kinetic resolution of secondary
alcohols
AB - The first chiral C2-symmetric 4-pyrrolidinopyridine (PPY) derivative was
synthesized in an enantiomerically pure form and successfully utilized as a
chiral nucleophilic catalyst for the kinetic resolution of secondary alcohols
leaving one enantiomer with high selectivity factors (up to s = 13.5).
PMID- 10763881
TI - Circular dichroism and absolute stereochemistry of
AB - Enantiopure [8]paracyclophane-10-carbonitrile (1) and related compounds were
prepared. The absolute stereochemistry of [CD(+)242.0]-1 was determined to be R
by theoretical calculation of its CD spectrum using the pi-electron SCF-CI-DV MO
method. The theoretical determination came to the same conclusion as the X-ray
crystallographic method had previously given. Other related compounds show
similar CD spectra leading to the R absolute stereochemistry.
PMID- 10763882
TI - Significant reduction in HIV-1 plasma viral load but not in proviral infected
cells during sub-optimal antiretroviral therapy.
AB - Attempts to eradicate HIV infection through highly active antiretroviral therapy
(HAART) in the very early stages of the infection have failed due to the
resumption of viral replication from unknown reservoirs. It has been postulated
that antiretroviral therapy capable of suppressing viral replication, as shown by
reduction of HIV-RNA copies in plasma and lymph nodes, should have less effect on
the number of HIV-DNA carrying cells in the same districts. To test this
hypothesis, plasma viremia and the proportion of provirally infected cells in
peripheral blood and in lymph nodes were measured in patients at 3 and 6 months
of treatment with zidovudine plus lamivudine. All patients showed a significant
decrease in plasma viremia at 3 months that was maintained at 6 months (mean
values of 1.6 +/- 0.6 log10 from baseline). Conversely the proportion of HIV-DNA
carrying cells slightly declined at 3 months but remained substantially stable
thereafter both in peripheral blood and in lymph nodes. Taken together these data
suggest that this therapeutic regimen, although sub-optimal, is effective in
significantly reducing the virus production by productively infected cells but
does not seem to substantially affect the load of provirally infected cells.
PMID- 10763883
TI - Complexity and dynamics of HIV-1 quasispecies.
AB - The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins mediate
virus entry into target cells by binding receptors of the cell membrane and
fusing viral and cellular structures. In particular, recent crystallographic
studies have clarified the complex role of the glycoprotein gp120 in the early
phase of the infection. In this context the inter- and intra-host variability of
the HIV-1 gp120 poses a major problem for the development of effective methods of
immunization against this virus. In the present report, the relevant aspects
emerging from the study of HIV-1 variability are addressed and several
methodological approaches to evaluate HIV-1 diversity discussed.
PMID- 10763884
TI - Viral dynamics and mutations in the pol gene during primary HIV-1 infection.
AB - The understanding of viral dynamics and appearance of mutations during primary
infection could be useful for the design of an efficient therapy. For this reason
a cohort of samples from naive primary patients was examined. The results pointed
out that only a few secondary mutations in protease gene (having no effect on
resistance) were found, while a single mutation conferring resistance to non
nucleosides inhibitors of reverse transcriptase was found both in plasma and
cerebrospinal fluid of a patient. As both the protease secondary mutations and
the single non nucleoside reverse transcriptase mutation map far from the
catalytical sites of the enzymes, neither one is able to impair viral fitness.
Overall data suggest that treated donors carrying resistant strains may be in
part unable to transfer them to the recipient, and/or virus in the recipient
tends to revert to wild type. These results should be taken into account in the
planning of early HAART treatment of HIV infection.
PMID- 10763885
TI - Genotype and phenotype resistance: an overview.
AB - Drug resistance is a major factor contributing to the failure of antiretroviral
therapy. The rapid turnover of the human immunodeficiency virus type 1 (HIV-1)
and the error-prone reverse transcriptase both contribute to the extensive
emergence of resistant variants. The understanding of resistance and cross
resistance patterns is essential for the appropriate selection of treatment
regimens for HIV-infected individuals. Although genotypic and phenotypic assays
of drug resistance are not currently recommended for routine use, preliminary
data has emphasized the role of resistance testing in guiding the choice of
initial antiretroviral therapy, in explaining reasons for failure, and in
selecting subsequent therapy for patients failing their current regimen. This
article reviews the advantages and disadvantages of currently available
resistance assays, as well as mechanisms and patterns of resistance and cross
resistance.
PMID- 10763886
TI - HIV neutralizing IgA in exposed seronegative subjects recognise an epitope within
the gp41 coiled-coil pocket.
AB - Human immunodeficiency virus (HIV)-specific IgA can be detected in cervical
secretions, saliva, and sera of HIV-infected and HIV-uninfected individuals with
a known exposure to the virus. IgA from HIV-uninfected exposed seronegative
individuals (ESN) neutralize in vitro primary strains of HIV-1. We analyzed the
epitopes of HIV recognized by serum HIV-specific IgA of ESN individuals to
identify the antigenic correlates of HIV neutralization in exposed-uninfected
subjects, and to verify whether different epitopes would be recognized by HIV
specific IgA of ESN and of HIV-infected patients. Results confirmed that HIV
neutralizing IgA are detected in sera of ESN and showed that neutralization of
primary HIV strains is mediated by the recognition of different epitopes in HIV
infected patients and ESN. Thus, whereas IgA of HIV+ individuals recognize
epitopes expressed both within gp120 and gp41, IgA of ESN exclusively bind to
gp41-expressed epitopes. Epitope mapping revealed that the epitope recognized by
serum IgA of ESN on gp41 is restricted to aa 581-584 (LQAR) and corresponds to
coiled coil pocket in the alpha helic region. In contrast, the epitope seen by
IgA of HIV-infected patients on gp41 is identified by two regions; the first is
contained within the cystein loop (aa 589-618), the second correspond to C
terminal region in the extra membrane region of gp 41 (aa 642-673). Thus, we have
identified and characterized the epitopes that mediate neutralization of HIV in
individuals in whom infection does not occur despite multiple exposures to the
virus. These results have important implications for the development of a new
therapy against HIV infection.
PMID- 10763887
TI - Control of viral replication and disease onset in cynomolgus monkeys by HIV-1 TAT
vaccine.
AB - The Tat protein of HIV is produced early after infection and it is essential for
viral replication and transmission. Tat is released by infected lymphocytes and
is detected in the serum of HIV-infected patients. Extracellular Tat enters
cells, where promotes HIV replication. Several studies suggest that humoral and
cellular anti-Tat immunity have a protective role and may control disease
progression. Of importance, Tat is conserved in its immunogenic regions among all
viral subtypes except O subtype. Thus, the immunization with Tat cannot block
virus entry but might block HIV replication and progression to disease. To test
this hypothesis, monkeys (Macaca fascicularis) were immunized with a biologically
active Tat protein. Tat was non toxic and induced specific humoral and cellular
immune responses. High titers of anti-Tat antibodies capable of neutralizing Tat
activity and the in vitro infection with the SHIV89.6P, Tat-specific
proliferation, CTLs, TNFalpha production and skin tests were detected in the
vaccinated monkeys. Most importantly, upon challenge with the highly pathogenic
SHIV89.6P (10 MID50, i.v.), 5/7 of the vaccinated monkeys showed no signs of
infection nor CD4+-T cell decline over a 19 months of follow-up, whereas 3/3
controls were highly infected. Thus, a Tat-vaccine is capable of controlling the
acute phase of infection in nonhuman primates. These data open new avenues for
the development of an AIDS vaccine.
PMID- 10763888
TI - Ex-vivo purging of circulating monocytes results in immunovirologic improvement
in partially HAART responder HIV-infected patients.
AB - AIDS pathogenesis results from a complex array of immune alterations which
include, among others, changes in the pattern of cytokine production. Some
monocyte-derived cytokines, like TNFalpha play a major role in HIV pathogenesis.
TNFalpha transactivates HIV NF-kB thereby inducing viral replication, potentiates
HIV replication in lymphomonocytes TNFalpha is one of the main factors of HIV
induced cachexia and might be involved in HAART-associated lipodystrophy. In
addition, monocytes are infectable by HIV in vitro and infected monocytes can be
recovered from the blood of HIV infected patients. For these reasons, we tested
whether renewal of the pool of circulating monocytes by selective monocyte
apheresis may improve the immune reconstitution which follows treatment with
highly active anti-retrovirals (HAART). HIV-infected HAART receiving (> 1 year)
patients who were either virologically non-responders (HIV-1 RNA >50,000
copies/ml) or immunologically non-responders (CD4 counts < 200) were treated with
a novel monocyte apheresis device (G-1 Adacolumn). Plasma HIV viral load,
proviral DNA and phenotypic and functional immunological analyses were performed.
G-1 apheresis was well tolerated, not accompanied by adverse responses, and
followed by clinical improvement. TNFalpha production was suppressed and CD4 T
cell counts increased. In one G-1 patient with elevated HIV-1 proviral DNA a
significant reduction (from 1,500 to 40 copies/10(5) cells) was observed. Neither
immunologic nor virologic parameters were modified in the control patients who
received HAART alone. Thus, purging of circulating monocytes by G-1 apheresis has
a dramatic suppressive effect on TNFalpha production and is followed by both
clinical and immunovirological improvement. G-1 apheresis should be considered in
patients in whom HAART is only partially effective.
PMID- 10763889
TI - HIV treatment: an overview.
PMID- 10763890
TI - HIV therapy in the post-eradication era.
AB - Over the past three years, most efforts of virologists and immunologists involved
in the field of Human Immunodeficiency Virus (HIV) have been focussed on
strategies aimed at eradicating the infection. So far, however, all the
approaches have been unsuccessful. Indeed, even if the currently available potent
antiretroviral regimens are able to induce a profound and durable suppression of
viral replication, they have poor effect on a viral reservoir of latently
infected CD4+ T lymphocytes that rapidly reactivate after treatment
discontinuation. Different approaches, including combined (immune based and
antiretroviral) therapies, are therefore under investigation. The goal is to
achieve an equilibrium where virus-induced immune dysfunction is prevented by an
effective anti HIV immune response.
PMID- 10763891
TI - Evaluation of T-cell response to CD3 plus CD28 monoclonal antibodies in HIV-1
infected subjects treated with highly active antiretroviral therapy.
AB - To investigate whether highly active antiretroviral therapy (HAART) could improve
CD28 molecule expression and CD28-costimulation pathway function we tested the
effect of CD28-costimulation on T cell receptor/CD3 induced proliferative
responses in a group of HIV-1-infected subjects with CD4+ cells>200/mmc before
and after HAART. CD3-mediated responses are recovered or improved after HAART.
However the ability of potentiating the responses through CD28-costimulation
seemed conserved before therapy and decreased in parallel with increase of
response to CD3 alone. These results confirm the integrity of CD28-pathway of
costimulation in patients with CD4+ cells>200/mmc and suggest an inverse
correlation between magnitude of response to CD3 alone and increase of CD3
response due to anti-CD28 addition.
PMID- 10763892
TI - Immunologic reconstitution by interleukin-2: facts and open questions.
AB - Interleukin-2 (IL-2), one of the most potent immunoregulatory and inflammatory
cytokines, is being tested in phase III clinical trials in order to demonstrate
its efficacy in combination with current antiviral agents in preventing the
occurrence of opportunistic infections and death in individuals infected by the
human immunodeficiency virus (HIV). In the meantime, its capacity to boost the
number of CD4+ T cells in peripheral blood has been confirmed by a number of
individual phase I/II trials conducted in different countries by independent
investigators. In the face of this remarkable result, little is known of the
effects exerted by this cytokine once administered to infected individuals in
terms of its impact on different immunologic functions. The recent acquisitions
on the important role played by latently infected cells in in vivo infection in
reinitiating HIV replication and cytopathicity once antiviral therapy is
suspended or becomes suboptimal, has shed new light on the possibility of
utilizing immunologic strategies, including IL-2, for eradicating the virus from
latent reservoirs. Results from a clinical trial conducted at our Institute
indicate a decrease in lymphocyte-associated HIV DNA after IL-2 administration,
supporting this hypothesis.
PMID- 10763894
TI - Proposal for a national PHI register (NPHIR)
PMID- 10763893
TI - Role of immune modulation in primary HIV infection.
AB - Hydroxyurea inhibits HIV without attacking the virus directly. By inhibiting a
cellular enzyme (ribonucleotide reductase) the drug decreases the intracellular
concentration of deoxynucleotide triphosphates, thus favoring the incorporation
of other drugs, such as the reverse transcriptase inhibitors, into the nascent
viral DNA. A large body of data has shown that hydroxyurea can be successfully
used during chronic infection. In this manuscript we review the use of
hydroxyurea during primary HIV infection. In several independent studies
hydroxyurea has been shown to: 1) inhibit HIV in combination with a reverse
transcriptase inhibitor and a protease inhibitor as efficiently as with standard
highly active antiretroviral therapies; 2) stimulate the immune system by
increasing the percentage of naive cells and the percentage of cells capable of
responding to antigens; 3) "cool down" the immune system hyper-activation. The
role of hydroxyurea in inducing control of HIV during structured treatment
interruptions remains to be clarified.
PMID- 10763895
TI - Prevalence of HIV-1 resistant strains in recent seroconverters.
AB - Twenty-nine HIV-1 recently infected subjects were retrospectively studied to
investigate both the prevalence of nucleoside reverse transcriptase inhibitors
(NRTI)-related mutations at primary infection and the proportion of naturally
occurring mutations in protease inhibitor (PI)-naive patients. Neither HIV-1
plasma viremia nor CD4 absolute count at baseline could distinguish patients with
NRTI pre-existing mutations from those with wild-type virus. An increasing
proportion of ZDV-related mutations was observed over time with an overall
frequency of 20.7% in the study period. Only 1 out of 6 patients (16.7%) with ZDV
related mutations showed a phenotypically ZDV resistant isolate. A striking
proportion of polymorphic changes was present in the protease region of pol gene
in newly infected individuals. As many as 80% of seroconverters presented at
least one naturally occurring substitution. Some PI-associated substitutions,
thought to be compensatory in protease enzymatic function, could confer
intermediate to high PI-resistance. Their role following PI administration
remains to be elucidated. Our data suggest that the choice of drugs should be
oriented by both genotypic and phenotypic evaluations to tailor individual
regimens in seroconverters.
PMID- 10763897
TI - Primary HIV infection: molecular approaches in diagnosis and monitoring.
AB - OBJECTIVE: The aim of this study was to evaluate, in patients with primary HIV
infection (PHI), the modification of HIV molecular parameters (HIV, RNA, and DNA)
induced by highly active antiretroviral therapy (HAART) in peripheral blood
mononuclear cells (PBMC) and in lymphoid tissue (LNMC). METHODS: Nineteen
patients with primary HIV infection, 4 women and 15 men with an average age of 35
years (range 27-62), were included in this study. Ten patients received 4 drugs:
zidovudine plus lamivudine plus saquinavir plus ritonavir, 7 patients received 3
drugs: zidovudine plus lamivudine plus saquinavir and 2 patients received a
different combination of 3 drugs: zidovudine plus lamivudine plus indinavir. As
control group we included 8 patients who had been enrolled in a placebo
controlled trial of zidovudine between 1991 and 1995: four received placebo and 4
were treated with zidovudine alone. Peripheral blood samples and lymphoid tissue
obtained by echo-driven fine needle biopsies were drawn to monitor molecular HIV
parameters. A quantitative in house PCR method in the HIV gag region was used to
monitor viral DNA burden and the NASBA system for viremia. RESULTS: A certain
heterogeneity in the baseline values of HIV, DNA, and RNA was observed. Early
HAART determined a rapid recovery of the CD4 cell number with normalisation of
the CD4/CD8 ratio in most patients. HIV-RNA levels dropped to undetectable levels
after a few months of therapy and HIV-DNA was consistently reduced although it
never reached undetectable levels. Lymph-node biopsies were well tolerated due to
the non-invasive sampling, however an optimisation of the method is needed to
improve cell recovery. In the valuable samples the amount of HIV DNA recovered is
comparable to that from peripheral blood samples, both at baseline and at follow
up.
PMID- 10763896
TI - Four drug-HAART in primary HIV-1 infection: clinical benefits and virologic
parameters.
AB - BACKGROUND: From a theoretical standpoint, primary HIV infection (PHI) represents
a great chance to modify the natural history of the disease. In this study we
purposed a four drugs regimen with zidovudine, lamivudine, ritonavir and
saquinavir to treat aggressively the infection and achieve a complete immune
reconstitution. METHODS: This is an Italian multicentric open label study. Adult
patients with PHI were eligible for the study if they met at least one clinical
criterion and one laboratory criterion of the following. Clinical criteria: Signs
and symptoms of acute retroviral syndrome within the past 70 days, exposure to
HIV-1 within the last 3 months, a preceding negative antibody test within the
past 6 months. Laboratory criteria: Detectable p24 antigen with neutralization in
serum; detectable HIV-RNA in plasma; indeterminate Western blot test with
negative or low positive value HIV antibody in ELISA test. RESULTS: Since April
1997 to April 1999 40 patients with PHI have been enrolled; 80% of this cohort
referred symptoms related to acute antiretroviral syndrome. Treatment has been
withdrawn in 17 patients (12 for intolerance, 3 for toxicity and 2 for failure).
At baseline the mean CD4+ T cells count and CD4/CD8 ratio were 537 (range 55
1287) and 0.58 (range 0.1-1.03) and the mean plasma HIV-RNA level was 5.9 log
copies/ml (range 3-7.15). Plasmatic HIV-1 RNA levels of all patients dropped
below 200 copies/ml in 68% of patients at week 12, 81% at week 24, 93% after 12
months and 100% after 18 months. Immunological parameters have been improved and
have achieved normal range since 6th month. CONCLUSIONS: A rapid virologic
suppression and immunological reconstitution are associated with PHI therapy.
However early treatment should be weighted against the potential disadvantages
such as immediate adverse events (intolerance and drug toxicity) and long term
manifestation (metabolic disorders).
PMID- 10763898
TI - Early production of HIV-1 neutralising antibodies in patients following highly
active antiretroviral treatment (HAART) during primary HIV infection.
AB - We investigate the effects of highly active antiretroviral therapy (HAART) on
humoral immune responses during a 24-month follow up of 15 HIV patients with
acute primary HIV infection. The patients were divided into three groups on the
basis of the therapeutic protocol they were following at the time of entry: a)
five naive patients (untreated or treated with only ZDV or AZT); b) five patients
following a triple combination of ZDV+ lamivudine (3TC)+ saquinovir (SQV); and c)
five patients on a four-drug combination of ZDV+3TC+SQV+ ritonavir (RTV). The
results show that the early introduction of HAART greatly reduces plasma viremia
levels and restores the number of CD4 cells. A significant correlation was found
between anti HIV neutralising activity and the four-drug, but not the three-drug
combination. The reduction in infectivity was directed against viruses of
different clades and associated with immunoglobulin fractions. Moreover, the
neutralising antibodies in the HAART-treated patients appeared after two weeks of
treatment and remained stable throughout the 24 months of follow up. The early
appearance of neutralising antibodies represent an important component of immune
responses during primary HIV infection, may contribute towards immune
reconstitution in patients on HAART, and give further information that may be
useful in developing new strategies designed to eradicate the disease.
PMID- 10763899
TI - Analysis of serum and plasma beta chemokines in primary HIV infection (PHI).
AB - The levels of certain beta-chemokines in biological fluids do not necessarily
reflect their circulating concentrations as they may be dramatically influenced
by ex vivo release during sample manipulation. In the present study beta
chemochine levels were evaluated in sequential paired plasma and serum samples
collected from a cohort of 18 patients with primary HIV infection (PHI), as well
as from 17 HIV-seronegative individuals. In plasma of PHI patients, a significant
increase of RANTES (mean 119.1 vs 15.85 ng/ml; p=0.0001) and MIP-1beta (mean 53.4
pg/ml vs 33.6 pg/ml; p=0.0001) was documented. Intra-patient covariance analysis
demonstrated no significant association between the variations of RANTES in
plasma and serum or between RANTES levels and platelet counts. Reproducibility
tests of RANTES measurements in plasma from PHI patients showed a mean
coefficient of variation of 1.8%. These data demonstrate that the plasma levels
of RANTES and, to a lesser extent, MIP-1beta are persistently perturbed during
the early phase of HIV infection. Furthermore they indicate that plasma and serum
levels are not directly correlated, being influenced by different physiological
phenomena that occur during the ex vivo preparation procedures of the two
biological fluids.
PMID- 10763901
TI - Tofu and cognitive function: food for thought.
PMID- 10763900
TI - Cyclosporin A in combination with HAART in primary HIV-1 infection.
AB - HAART is the cornerstone of HIV therapy, and has significantly reduced morbidity
and mortality associated with HIV disease. The institution of HAART during the
primary HIV-1 infection has a more profound influence on the ultimate pattern and
rate of disease progression than therapy commenced later on. However, it also
well demonstrated that HAART alone is not able to eradicate the virus, unless
over a life-long period of time. There is therefore the need to develop
alternative strategies aimed at modulating the immune responses in order to
achieve the long-term control of HIV even once HAART is discontinued. Among
immunomodulant agents, cyclosporin A in combination with HAART might play a role
in the treatment of people with primary HIV-1 infection.
PMID- 10763902
TI - Magnesium in human milk.
AB - Reported concentrations for magnesium in breast milk vary over a wide range (15
to 64 mg/L) with a median value of 31 mg/L and 75% of reported mean
concentrations below 35 mg/L. Constitutional variables such as adolescent
motherhood, gestation length, maternal undernutrition, metabolic disorders
(diabetes, galactosemia), race, stage of lactation, sampling techniques (foremilk
and hindmilk), as well as environmental variables such as socio-cultural
diversity, smoking habits, dietary calcium and magnesium (including
supplementation), vegetarianism, calciotropic agents (immunoreactive calcitonin,
vitamin D), medication (hormonal contraceptives, magnesium sulfate) are
critically reviewed in relation to changes in milk magnesium concentrations.
Magnesium secretion into breast milk does not seem to be affected by the studied
variables.
PMID- 10763903
TI - Micronutrients and the premenstrual syndrome: the case for calcium.
AB - Premenstrual syndrome afflicts millions of premenopausal women and has been
described as one of the most common disorders in women. Research over the past
few years suggests that a variety of nutrients may have an important role in the
phase related mood and behavioral disturbances of the premenstrual syndrome.
There is scientific evidence, at least for a few of these micronutrients,
specifically calcium and vitamin D, supporting cyclic fluctuations during the
menstrual cycle that may help explain some features of PMS. Ovarian hormones
influence calcium, magnesium and vitamin D metabolism. Estrogen regulates calcium
metabolism, intestinal calcium absorption and parathyroid gene expression and
secretion, triggering fluctuations across the menstrual cycle. Alterations in
calcium homeostasis (hypocalcemia and hypercalcemia) have long been associated
with many affective disturbances. PMS shares many features of depression, anxiety
and the dysphoric states. The similarity between the symptoms of PMS and
hypocalcemia is remarkable. Clinical trials in women with PMS have found that
calcium supplementation effectively alleviates the majority of mood and somatic
symptoms. Evidence to date indicates that women with luteal phase symptomatology
have an underlying calcium dysregulation with a secondary hyperparathyroidism and
vitamin D deficiency. This strongly suggests that PMS represents the clinical
manifestation of a calcium deficiency state that is unmasked following the rise
of ovarian steroid hormone concentrations during the menstrual cycle.
PMID- 10763904
TI - Plasma leptin association with body composition and energy expenditure in sickle
cell disease.
AB - OBJECTIVE: To examine the association between fasting plasma leptin
concentrations and the hypercatabolic state observed in sickle cell disease
(SCD). METHODS: Plasma leptin concentration and resting energy expenditure (REE)
were measured in 37 SCD patients (10 men, 12 boys 14 to 18 years-old, seven
women, and eight girls 14 to 18 year-old) and in 37 age, gender and fat mass (FM)
matched controls. Body composition was measured hydrostatically, REE by whole
room-indirect calorimeter, and plasma leptin using an RIA kit. RESULTS: Plasma
leptin concentration and leptin normalized for body fat (ng/dL*kg FM(-1)) were
significantly lower in SCD patients than in non-SCD controls (4.00+/-3.23 vs.
9.94+/-14.69, p=0.021 and 0.406+/-0.260 vs. 0.643+/-0.561, p=0.024,
respectively). A positive linear association between log plasma leptin and FM was
observed in both males and females, adjusting for age and SCD status. The
strength of this association was greater in females compared with males
(slope=0.699 and 0.382 log ng/mL per 10 kg FM, respectively; p=0.013). SCD
patients on average demonstrated a higher REE, adjusting for FFM (p<0.0001). Log
plasma leptin and FM were not statistically significant predictors of REE after
adjustment for FFM and SCD. CONCLUSIONS: Once corrected for body composition,
mean plasma leptin concentration was significantly lower among female SCD
patients than among non-SCD matched controls. Although REE was higher in SCD
patients, there is no simple association between leptin and REE in SCD.
PMID- 10763905
TI - Effects of early nutrition on free radical formation in VLBW infants with
respiratory distress.
AB - OBJECTIVE: We studied the development of essential fatty acid deficiency (EFAD)
and its effects together with those of vitamin E deficiency on the free radical
formation of very low birth weight (VLBW) infants with respiratory distress.
METHODS: Infants were divided into three groups based on the way each was
supplied with daily total energy intake: (1) by fat free parenteral nutrition
only or by nutrition composed of (2) less than or (3) higher than 25% of total
daily energy intake given in oral feeding. We measured plasma lipid parameters
and autoxidative susceptibility (AOS) of red blood cells (RBCs). RESULTS: Plasma
concentrations of linoleic acid were low in all the groups. After at least 14
days of feeding, eicosatrienoic acid (EA) was not detected. One week after the
introduction of oral feeding, the abnormal triene/tetraene ratio of the groups
had decreased, but was not normalized. Vitamin E deficiency was associated with
significantly increased AOS, but EFAD was not. The two factors together caused an
increase of AOS, that was additive. CONCLUSIONS: Our data confirm that EFAD
increases AOS of RBCs in VLBW infants. We assume that prevention of EFAD in VLBW
infants could decrease the prevalence of complications associated with free
radical formation.
PMID- 10763906
TI - Brain aging and midlife tofu consumption.
AB - OBJECTIVE: To examine associations of midlife tofu consumption with brain
function and structural changes in late life. METHODS: The design utilized
surviving participants of a longitudinal study established in 1965 for research
on heart disease, stroke, and cancer. Information on consumption of selected
foods was available from standardized interviews conducted 1965-1967 and 1971
1974. A 4-level composite intake index defined "low-low" consumption as fewer
than two servings of tofu per week in 1965 and no tofu in the prior week in 1971.
Men who reported two or more servings per week at both interviews were defined as
"high-high" consumers. Intermediate or less consistent "low" and "high"
consumption levels were also defined. Cognitive functioning was tested at the
1991-1993 examination, when participants were aged 71 to 93 years (n = 3734).
Brain atrophy was assessed using neuroimage (n = 574) and autopsy (n = 290)
information. Cognitive function data were also analyzed for wives of a sample of
study participants (n = 502) who had been living with the participants at the
time of their dietary interviews. RESULTS: Poor cognitive test performance,
enlargement of ventricles and low brain weight were each significantly and
independently associated with higher midlife tofu consumption. A similar
association of midlife tofu intake with poor late life cognitive test scores was
also observed among wives of cohort members, using the husband's answers to food
frequency questions as proxy for the wife's consumption. Statistically
significant associations were consistently demonstrated in linear and logistic
multivariate regression models. Odds ratios comparing endpoints among "high-high"
with "low-low" consumers were mostly in the range of 1.6 to 2.0. CONCLUSIONS: In
this population, higher midlife tofu consumption was independently associated
with indicators of cognitive impairment and brain atrophy in late life.
PMID- 10763907
TI - Bone status among postmenopausal women with different habitual caffeine intakes:
a longitudinal investigation.
AB - OBJECTIVE: Caffeine consumption has been proposed as a risk factor for bone loss
in postmenopausal women. Past epidemiologic studies on caffeine and bone have
been confounded by covariates including cigarette and alcohol use, differing
levels of physical activity and hormone replacement therapy. The purpose of the
study was to use a longitudinal design to determine the relationship between
habitual dietary caffeine intake and postmenopausal bone status. METHODS: Data
were collected at two time points separated by two years; 138 women with little
or no exposure to tobacco or to drugs known to affect bone status were seen at
Visit 1, and 112 returned for Visit 2. Ninety-two of these subjects had received
no drugs known to affect bone status over the two-year interval and were kept in
the sample. Nutrient and caffeine intake were assessed from three-day diet
records. Bone measurements were made by dual energy x-ray absorptiometry (DXA).
RESULTS: Correlation analyses indicated no association between dietary caffeine
intake and total body or femoral neck bone density or bone mass. Similarly, no
associations were found between caffeine consumption and longitudinal changes in
total body or femoral neck bone measurements. These results held true both with
and without statistical adjustment for calcium intake. CONCLUSIONS: This study
does not support the idea that caffeine is a risk factor for bone loss in healthy
postmenopausal women.
PMID- 10763908
TI - Effects of iron intake on iron stores in elderly men and women: longitudinal and
cross-sectional results.
AB - OBJECTIVE: For middle aged and elderly subjects there is a concern that increased
iron intake, especially heme iron associated with consumption of red meat, leads
to increased iron stores resulting in disturbed glucose homeostasis and risk for
cardiovascular disease and certain types of cancer. The aim of this study was to
investigate the influence of heme, non-heme and iron supplementation on iron
stores in healthy elderly men and women. METHOD: We conducted a 10 year
longitudinal study (48 men and 77 women) and a one year cross-sectional study
(165 men and 226 women) in healthy elderly men and women enrolled in the New
Mexico Aging Process Study. Iron stores were estimated by serum ferritin
concentrations and iron intake was determined by three-day food records in the
longitudinal study and by a food frequency questionnaire in the cross-sectional
study. RESULTS: We found no association between heme iron intake and iron stores
in either the longitudinal or cross sectional study. In the cross-sectional study
we found in women, but not in men, that age and supplemental iron intake were
significantly and positively associated with increased iron stores. CONCLUSION:
Iron stores in elderly men are thought to reach steady state levels where iron
absorption is adjusted to a level just sufficient to cover basal iron losses. In
elderly women, we speculate that not enough time has elapsed for postmenopausal
women to reach steady state levels of iron stores resulting in increases in iron
absorption with age. Another factor is that use of hormone replacement therapy
could further delay some women in reaching steady state iron levels due to
continued menstrual blood losses.
PMID- 10763909
TI - Body composition and energy expenditure after weight loss following bariatric
surgery.
AB - OBJECTIVES: To assess the effectiveness of biliopancreatic diversion (BPD) in the
treatment of morbid obesity and to evaluate how the procedure affects body
weight. SUBJECTS: Fourteen morbidly obese subjects studied before and 30 months
after BPD and fifteen healthy volunteers matched for age, sex and height
(controls). METHODS: Comparison of the following parameters were made in the
study groups before surgery and 30 months after BPD and with those of the
controls group: fat mass, fat-free mass, non-protein substrate oxidation, basal
metabolic rate, plasma glucose, insulin and free fatty acid concentrations.
RESULTS: Obese subjects lost 60.38+/-10.71 kg of weight during 18 months
following surgery and then remained stable for another 12 months, when this study
was performed. Weight loss was substantially due to a loss of fat mass (FM:
60.13+/-13.01 kg before and 19.02+/-8.61 kg after BPD; p<0.001). FM were not
statistically different between post-obese subjects and controls; however, post
obese patients retained significantly more fat free mass (FFM) than controls.
Subsequently, basal metabolic rates of post-obese subjects were higher than those
of the control group (p<0.05). Fasting non-protein respiratory quotient (npRQ)
was significantly lower before BPD than 30 months after the surgery (0.798+/-0.04
vs. 0.90+/-0.048, p<0.001), suggesting that, while obese, patients oxidized more
lipids than carbohydrates. Moreover, fasting and two-hour plasma glucose and
insulin concentrations decreased significantly after BPD to values comparable to
those of the control group. CONCLUSION: Weight loss in obese patients after BPD
is mainly due to lipid malabsorption, but increased energy expenditure associated
with retaining a high FFM in physically active post-obese subjects may also play
a role, enabling them to maintain long-term reduced body weights.
PMID- 10763910
TI - Weight loss is correlated with an improved lipoprotein profile in obese
postmenopausal women.
AB - BACKGROUND: Changes in plasma lipid and lipoprotein distributions that occur
after menopause increase the risk of cardiovascular disease in women, especially
in those who are overweight. OBJECTIVE: The purpose of this study was to evaluate
the impact of a nine-month weight reduction program on plasma lipids, dietary
intake and abdominal fat obesity. DESIGN: A partial crossover design was used to
study a weight loss treatment consisting of Phentermine hydrochloride (Fastin,
SmithKline Beecham Pharmaceuticals, Philadelphia, PA) therapy plus a low energy
diet (5040 kJ/d). Forty-seven obese, postmenopausal Caucasian women (BMI of 30-38
kg/m2) were randomized into two groups, both of which received drug and diet
treatment over six months. However, Group I started the intervention program
three months later than Group II. Plasma total, HDL and LDL cholesterol and
triacylglycerol were measured, body composition was assessed by anthropometry and
dual energy x-ray absorptiometry, and food frequency records were collected at
four timepoints. RESULTS: Over nine months, women in Group II reduced body weight
(14.4%), lowered plasma concentrations of LDL cholesterol (14% to 26%) and
triacylglycerol (15%) and raised plasma HDL cholesterol concentration (15%).
These plasma lipid changes decreased the total cholesterol/HDL cholesterol ratio
from 4.3 to 3.2. All subjects decreased abdominal fat measurements and energy and
cholesterol intakes, as well as percentage of energy derived from total and
saturated fat during the study. Most subjects also increased dietary fiber
consumption. CONCLUSION: Both weight loss and diet modifications are associated
with an improved plasma lipid profile in obese postmenopausal women.
PMID- 10763911
TI - Expression and activation of pro-gelatinase A by human melanoma cell lines with
different tumorigenic potential.
AB - The production of various proteolytic enzymes by tumor cells facilitate the
invasion of solid tumors into surrounding tissues. We examined three cell lines
(M1Dor, M4Be and M3Da) derived from malignant melanoma which exhibited different
abilities to grow in nude mice following subcutaneous grafting. By in vitro
invasion assay using Boyden-chambers technique, we found that none of those cell
lines were able to invade the Matrigel. Several studies have substantiated the
role of matrix metalloproteinases (MMP), mainly gelatinases MMP-9 and MMP-2, in
melanoma cell invasion. Each cell line constitutively produced MMP-2 (but not MMP
9) in its latent form only, with stronger production for the most tumorigenic
cell line in vivo (M3Da). Integrity of the MMP-2 activation process was studied
since MMP-2 was also recovered as zymogen at the cell plasma membrane. All cell
lines secreted TIMP-1 and TIMP-2 in a constitutive manner and again, but TIMP-2
production as well as MT1-MMP expression were found inversely related to their
tumorigenic potential. Plating cells onto type I or type IV collagen did not
trigger pro-MMP-2 activation; on the contrary, conversion of pro-MMP-2 to its
active form could be evidenced when melanoma cell lines were seeded in a three
dimensional type I collagen lattice.
PMID- 10763912
TI - Cytogenetic analyses of secondary liver tumors reveal significant differences in
genomic imbalances between primary and metastatic colon carcinomas.
AB - To investigate if karyotypic features of secondary liver tumors may provide
diagnostic information and if the cytogenetic patterns of primary and metastatic
colorectal carcinomas (CRC) are different, 33 liver metastases were analyzed: 25
CRC, 4 small intestine carcinoids, 1 ovarian carcinoid, 1 lobular breast cancer,
1 head-and-neck squamous cell carcinoma, and 1 uveal malignant melanoma.
Chromosomal aberrations were detected in 24 cases, whereas 5 had normal
karyotypes and 4 were uninformative due to lack of mitoses. Trisomy 12 was
detected in 2 small intestine carcinoids, suggesting that +12 may be of
pathogenetic importance in this tumor type. The breast and head-and-neck
carcinomas and the uveal melanoma displayed aberrations previously reported as
characteristic in primary tumors, e.g., der(1;16) and deletion of 3p in the
breast cancer, losses of 3p and 8p and partial gain of 8q in the head-and-neck
carcinoma, and monosomy 3 and i(8)(q10) in the uveal melanoma, indicating that
cytogenetic investigations provide important diagnostic information in secondary
liver tumors. In the 18 CRC metastases with chromosomal abnormalities, the
cytogenetic findings agreed well with previously reported primary CRC. Common
numerical abnormalities included gains of chromosomes 7, 11, 13, and 20, and
losses of Y, 4, 18, 21, and 22. Structural rearrangements most often affected
chromosome bands 1p13, 1q10, 3p21, 5q10, 5q11, 7q10, 8q10, 8q11, 12q13, 16p13,
17p11, 20p13, 20p11, and 20q10, and frequently resulted in losses of 1p, 8p, and
17p, and gains of 5p, 6p, 7p, 8q, and 20q. Comparing the present cases with
primary CRC previously analyzed in our department revealed that additional gains
of 6p, 6q, 7p, and 20q, and losses of 1p, 4p, 4q, 8p, 18p, 18q, and 22 were more
common (P < 0.05) in the metastases, suggesting that these genomic sites harbor
genes of importance in the metastatic process of CRC.
PMID- 10763913
TI - Carcinoembryonic antigen facilitates experimental metastasis through a mechanism
that does not involve adhesion to liver cells.
AB - Carcinoembryonic antigen (CEA) injected intravenously into athymic nude mice
increases the ability of weakly metastatic human colorectal carcinoma (CRC) cells
to colonize liver in an experimental metastasis assay. Since CEA acts as an
intercellular adhesion molecule in vitro, several investigators have postulated
that this facilitation of experimental metastasis may be mediated through
adhesion between CEA on CRC and CEA-binding proteins on Kupffer or other cells
lining the hepatic sinusoid. The present work tested this postulate both by
intravital fluorescence videomicroscopy in vivo and in adhesion assays in vitro
to enriched populations of Kupffer cells and hepatic sinusoidal endothelial cells
(SEC). The data indicate that CEA expression does not effect adhesion to enriched
Kupffer cells or SEC in vitro. These data suggest that CEA enhances liver
colonization through another mechanism, possibly one that involves modulation of
the hepatic response to tumor cell implantation.
PMID- 10763914
TI - Co-inoculation of human and murine carcinoma cells induces reciprocal suppression
of metastasis by both cell lines.
AB - The interactions of two cell lines having different metastatic properties, and
the subsequent effects on dissemination were investigated using the chicken
embryo metastasis assay. The highly aggressive human epidermoid cell line HEp-3
was tested alone or mixed with the mouse colon carcinoma cell line CL26 in this
assay. When inoculated individually, each cell line forms experimental metastases
in the chicken embryo, but only the HEp-3 cells give rise to spontaneous
metastases. In embryos co-inoculated with both cell lines there was an overall
reduction in metastatic burden in both the spontaneous and experimental
metastasis assays. Furthers studies revealed that CL26 cells, when co-inoculated
with HEp-3 cells did not acquire the ability to spontaneously metastasize.
However, in the presence of CL26 cells, spontaneous HEp-3 metastasis was reduced.
Intravenous co-inoculation of HEp-3 and CL26 cells also resulted in a reciprocal
suppression of experimental metastasis by both cell lines. These studies
demonstrate that the interactions of adjacent, phenotypically different tumor
cells can have a suppressive effect on dissemination of one or both cell types.
PMID- 10763915
TI - Minimal liver resection strongly stimulates the growth of human colon cancer in
the liver of nude mice.
AB - Partial hepatectomy has been widely employed in clinical practice as the therapy
of choice for primary and metastatic liver tumors. However, the recurrence rate
after the treatment remains high, which is most likely due to the growth of
residual microscopic lesions. Previous studies in murine models demonstrated that
a 70% hepatectomy significantly accelerated the growth of ectopically implanted
tumors. In this study, we reported the effect of partial hepatectomy on the
growth of two human colon cancers (Co-3 and AC3603) implanted in the liver of
nude mice using the technique of surgical implantation of histologically intact
tumor tissue. Our results showed a dramatic acceleration of tumor growth
following 30% partial hepatectomy, which resembles clinical procedures. Tumor
volumes were assessed with calipers on day-15 by abdominal palpation and on day
30 at autopsy by direct measurement. For both Co-3 and AC3603, tumor volumes in
the hepatectomized animals were significantly larger than the control at the
above two time points (P < 0.001). The results demonstrate the stimulating effect
of partial hepatectomy directly on the tumor growth in the liver, in contrast to
previous studies on ectopic tumors. Furthermore, since conservative partial
hepatectomy (30%) is normally used in clinical practice for surgical treatment of
liver metastasis, the animal models presented here should be useful for the
clinical investigation of the high recurrence rate of liver metastasis following
partial hepatectomy.
PMID- 10763916
TI - A nude mouse model of human osteosarcoma lung metastases for evaluating new
therapeutic strategies.
AB - The purpose of these studies was to develop a metastatic osteosarcoma nude mouse
model to evaluate the in vivo efficacy of new therapeutic compounds. Human SAOS-2
osteosarcoma cells (10(6) cells) were injected i.v. into nude mice. Cells
isolated from a rare pulmonary metastases 6 months later were established (SAOS
LM1) in culture and re-injected. This procedure was repeated 5 additional times
to produce the SAOS-LM6 cell line. Visible pulmonary nodules were present 8 weeks
following i.v. injection of 10(6) SAOS-LM6 cells as compared to 17 weeks using
SAOS-LM2 cells. Microscopic SAOS-LM6 pulmonary metastases were demonstrated at 6
weeks. Administration of adriamycin on week 9 resulted in regression of
macroscopic SAOS-LM6 lung tumors. The ability of the model to be used to evaluate
the effectiveness of a biologic agent against microscopic disease was also
verified. It was concluded that this model can assess therapeutic efficacy and
therefore, may have a role in investigating the potential of novel approaches
aimed at eliminating pulmonary metastatic osteosarcoma.
PMID- 10763917
TI - Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via
phosphatidylinositol 3-kinase.
AB - Hepatocyte growth factor (HGF) is known to be a potent mitogen and motogen for
epithelial cells. Hepatocellular carcinoma (HCC) often metastasizes, and the c
Met/HGF receptor is highly expressed by HCC cells. The aim of this study was to
investigate the signaling pathways associated with the motogenic effect of HGF on
HCC cells via c-Met. HCC cell lines (Hep3B, HepG2, PLC, and Huh-7) and HCC cells
harvested from patients were used for the Boyden chamber assay of chemotactic
activity as well as for immunoprecipitation and immunoblotting studies. HGF
stimulated the motility of Hep3B, HepG2, and Huh-7 cells in a dose-dependent
manner in association with tyrosine phosphorylation of c-Met and activation of
phosphatidylinositol 3-kinase (PI3-K). A tyrosine kinase inhibitor (genistein)
and a PI3-K inhibitor (wortmannin) prevented the migration of HCC cells. However,
migration was not prevented by calphostin C, an inhibitor of protein kinase C
(PKC), which is a downstream target of phospholipase Cgamma (PLCgamma). HGF also
stimulated the migration of HCC cells obtained from three patients, while
wortmannin prevented the migration of these cells. These results indicate that
HGF stimulates the migration of HCC cells through the tyrosine phosphorylation of
c-Met via activation of PI3-K.
PMID- 10763918
TI - A three-dimensional in-vitro model for the study of peritoneal tumour metastasis.
AB - Peritoneal metastasis is a frequent complication of gastrointestinal malignancy.
We have developed a three-dimensional model of the human peritoneum that
simulates the metastatic process in vitro. Peritoneal fibroblasts were
incorporated into collagen lattices, allowed to contract, then overlaid with
mesothelial cells. Scanning and transmission electron microscopy showed the model
to have similar physical properties to human peritoneum. Mesothelial expression
of the beta1 integrin family, the basement membrane proteins fibronectin,
laminin, collagen types III and IV, and the cell adhesion molecules ICAM-1, VCAM
1 and PECAM were assessed and showed similar results to in vivo tissue.
Gastrointestinal tumour cells seeded onto the model exhibited mesothelial
adhesion, cell spreading and vesicle formation, and invasion of the mesothelial
monolayer on scanning electron microscopy. Two distinct patterns of tumour cell
growth were observed using light microscopy: a superficial spreading layer, and
discrete invasive deposits. Invasion was accompanied by disruption of the
mesothelial monolayer, degradation and re-orientation of the matrix, and
rudimentary tumour cell differentiation. We believe the use of this in vitro
peritoneal model will facilitate the study of the molecular mechanisms involved
in the metastatic process.
PMID- 10763919
TI - Phosphodiesterase type III inhibitor, cilostazol, inhibits colon cancer cell
motility.
AB - Metastasis of cancer cells is initiated by the cellular migration into
extracellular matrix and surrounding vessels. We previously showed that elevation
of cAMP levels in cancer cells suppressed trans-cellular migration in vitro.
Drugs that can elevate cAMP levels in cancer cells effectively may be applied to
prevent metastasis in cancer patients. Cilostazol, an oral anti-platelet drug, is
a specific cAMP phosphodiesterase type III inhibitor and has been clinically used
to treat thrombosis patients. In chemotaxis assay, cellular migration of human
colon cancer cells, DLD- 1, was induced by 10 microg/ml of soluble fibronectin or
10% of fetal bovine serum (FBS). Treatment with cilostazol (50 microM) suppressed
92.3% or 84.6% of the migration in control cells, respectively. When DLD-1 cells
were stimulated by soluble fibronectin in phagokinetic assay, migration assessed
by the area of gold particle phagocytosis track was induced and cilostazol also
decreased 67.3% of the cellular migration in control cells. Furthermore, in the
trans-cellular migration assay, cilostazol suppressed cancer cell invasion
induced by FBS. Thus, cilostazol can suppress colon cancer cell motility and
might be effective as an anti-metastasis drug for cancer patients.
PMID- 10763920
TI - Oral administration of muscle derived small molecules inhibits tumor spread while
promoting normal cell growth in mice.
AB - Tumor metastases are extremely rare in striated muscles. This is surprising given
the fact that this tissue constitutes 60% of body weight. The present study
focuses on small molecules produced and secreted by muscle cells which possess
anti-cancer activity in vivo. Recently we have shown that a low molecular weight
fraction (< 1000 Dalton) of skeletal muscle cell conditioned medium (muscle
factor-MF), markedly inhibits the proliferation of carcinoma, sarcoma or melanoma
cell lines in vitro. The MF exerts a cytostatic effect on tumor cell growth and
arrests the cells in the G0/G1 of the cell cycle. However, normal cell
proliferation, such as bone marrow and fibroblasts, was stimulated following
incubation with MF. In this study, the effect of orally administered MF on
melanoma and sarcoma growth was examined in mice. The administration of MF to
mice inoculated intravenously with melanoma (B16-F10) or sarcoma (MCA-105) cells,
resulted in a statistically significant inhibition of metastatic lung foci. In a
different model, melanoma was induced in the foot pad and after development of a
local lesion, the leg was amputated. A prolonged survival time was observed in
the MF treated groups. Since the MF stimulated bone marrow cell proliferation in
vitro, we decided to test its efficacy as an inhibitor of the myelotoxic effect
exerted by chemotherapy, in vivo. MF, administered after chemotherapy, restored
the number of white blood cells and yielded an increased percentage of
neutrophils compared with the decline in these parameters after administration of
chemotherapy alone. Thus, it is indicated that MF exerted a systemic anti tumor
and chemoprotective effect when given orally. It can be concluded that it is
bioavailable and is not biodegradable in the digestive system. MF may be
considered as a potential therapy for the prevention of tumor spread.
PMID- 10763921
TI - Characterization of spontaneous metastasis in an aggressive breast carcinoma
model using flow cytometry.
AB - Studies of metastasis can be accelerated and provide more mechanistic information
using cell lines which reproducibly and aggressively metastasize, and which are
accurately and easily detected in tissues at all stages of the metastatic
process. Although reporter proteins such as green fluorescent protein (GFP) and
beta-galactosidase have improved the tracking of tumor cells in vivo, their
measurement has often been limited to visual observation and manual counting. In
this study, we exploited the highly sensitive and objective quantitation provided
by flow cytometry to characterize, in detail, the sequence of events associated
with orthotopic metastasis in a highly aggressive mouse model. Following stable
transfection of the MDA-MB-435 breast carcinoma cell line with GFP, we utilized
an in vivo selection process to isolate a variant exhibiting increased primary
tumor growth and metastasis. As few as one fluorescent tumor cell per 200,000
host cells could be accurately detected in dissociated tissues by flow cytometry,
allowing us to demonstrate that metastatic cells migrate to the lungs of SCID
mice very early after orthotopic implantation. Tumor burden in lungs increased in
a smooth continuous manner, until death approximately eight weeks later. Levels
of circulating tumor cells in blood were also detectable at an early timepoint,
but remained relatively low throughout the course of secondary tumor development
in the lungs. Surgical removal of the primary tumor at various times after
inoculation significantly affected lung tumor burden, supporting the concept that
circulating tumor cells in blood inefficiently initiate distal metastases.
Furthermore, the continuing contribution to metastasis by the primary tumor was
independent of tumor mass. The combined characteristics of enhanced orthotopic
metastasis and quantitative detection in blood and tissues will make this a
useful new model for the characterization of the multi-stage progression of
cancer, and the preclinical evaluation of anti-neoplastic therapies.
PMID- 10763922
TI - Continuing low colon cancer incidence in African populations.
PMID- 10763923
TI - Oral tolerance therapy in an experimental model of colitis.
PMID- 10763924
TI - Symptom expression in pain-predominant functional bowel syndrome: is visceral
hyperalgesia the whole truth?
PMID- 10763925
TI - Treatment of irritable bowel syndrome: new modalities for a new millennium.
PMID- 10763926
TI - A teardrop may not be resectable
PMID- 10763927
TI - Small matters
PMID- 10763928
TI - Tacrolimus for Crohn's fistulae
PMID- 10763929
TI - Do bacteria play a role in the pathogenesis of IBD?
PMID- 10763930
TI - Accelerated liver fibrosis: two risk groups
PMID- 10763931
TI - Colorectal cancer prevention 2000: screening recommendations of the American
College of Gastroenterology. American College of Gastroenterology.
PMID- 10763932
TI - The importance of clinicopathological correlation in the diagnosis of
inflammatory conditions of the colon: histological patterns with clinical
implications.
AB - Histological reaction patterns within the colon are not disease-specific but
reflect mechanisms of injury and duration of disease. By correlating these
patterns with known causes of colonic inflammation, we provide guidelines to
enhance the diagnostic value of colonoscopic samples. Normal histological
features are reviewed, and the sequence of inflammation and repair is used as the
basis for appreciating pathological deviations. The common histological patterns
of acute colitis with and without features of pseudomembranous or ischemic
colitis and the morphological features of chronic colitis with and without crypt
destruction are collated with clinical and endoscopic features to emphasize the
importance of dialogue between the pathologist and gastroenterologist. Less
common patterns, including eosinophilic colitis, graft-versus-host disease,
chronic mucosal prolapse, portal hypertensive colopathy, and nonspecific or
idiopathic ulcer, illustrate variations in the basic reaction patterns.
Difficulties in differential diagnosis are underscored, and biopsy strategies are
suggested.
PMID- 10763933
TI - What is the upper limit of normal for the common bile duct on ultrasound: how
much do you want it to be?
AB - Conventionally, the upper limit of normal for the common bile duct as measured by
ultrasound is considered to be 6 mm. This review is a somewhat personalized
account of how that number became the convention and cautions the reader to avoid
being slavish in the use of this number. Two specific cautions are not to apply
this limit to older patients and to consider where in the common bile duct the
measurement was taken, as measurements taken closer to the pancreas may be larger
than ones closer to the liver.
PMID- 10763934
TI - Functional bowel disorders in the geriatric patient: constipation, fecal
impaction, and fecal incontinence.
AB - Functional bowel disorders, including constipation, fecal impaction, and fecal
incontinence, are common gastrointestinal diseases in the elderly and a major
source of morbidity. Often the etiology is multifactorial. Evaluation should
investigate presenting symptoms and important historical clues. An appropriate
workup, including radiological studies, endoscopy, and physiological testing
should be individualized. Therapy should be directed against relieving the major
complaint and treating the underlying pathophysiological mechanism.
PMID- 10763935
TI - Accurate placement of the esophageal pH electrode for 24-hour pH monitoring using
a combined pH/manometry probe.
AB - OBJECTIVE: Accurate placement of a pH electrode requires manometric localization
of the lower esophageal sphincter (LES). Combined manometry/pH devices using
water-perfused tubes attached to pH catheters and the use of an electronic "LES
locator" have been reported. We investigated whether accurate placement of pH
probes can be achieved using such a probe, and whether this may reduce the need
for the performance of the usual stepwise pull-back manometry. METHODS: Thirty
consecutive patients (15 men, 15 women; median age, 56 yr; interquartile range,
42-68 yr) referred for manometry and pH testing were included in the study. The
localization of the LES was determined with standard esophageal manometry. After
that, a second 3-mm pH electrode with an internal perfusion port was passed into
the stomach. Using this catheter, a single stepwise pull-through manometry was
performed and the LES position was noted. LES location, mean pressure, and length
obtained with standard manometry were compared to data from the combined
pH/manometry catheter. Additionally the time necessary to perform each of the
procedures was noted and the patient's discomfort caused by the catheter was
evaluated using a standardized questionnaire. RESULTS: The LES location with the
pH/manometry probe was proximal to that with standard manometry in 19 patients
(63%), the same in nine patients (30%), and distal in two patients (7%). The
differences were <2 cm in 29 of 30 (97%) patients. The LES location with the
pH/manometry probe required a median of 6.5 min (interquartile range: 3.5-8.5
min) versus a median of 21.5 min (interquartile range: 14.5-26.5 min) for
standard manometry (p < 0.0001). In addition, LES evaluation using the combined
pH/manometry probe provided accurate data on the resting pressure, as well as
overall and intraabdominal length of the LES. All patients tolerated the
combination probe better than the standard manometry probe (p < 0.001).
CONCLUSIONS: Placement of the esophageal electrode for 24-h esophageal pH
monitoring using a combined pH/manometry probe is accurate. The technique is
simple, time-saving, and convenient for the patients. Because it is possible to
accurately evaluate the LES using this technique, it may even replace
conventional manometry before pH probe placement.
PMID- 10763936
TI - The short- and long-term efficacy of empirical esophageal dilation in patients
with nonobstructive dysphagia: a prospective, randomized study.
AB - OBJECTIVE: The efficacy of empirical esophageal dilation for nonobstructive
dysphagia (NOD) is unknown. Our aim was to assess the efficacy and safety of
empirical dilation with a large bougie in patients with NOD. METHODS: Patients
with NOD (normal barium swallow, free passage of a 13-mm barium pill, and normal
esophagogastroduodenoscopy) were randomized to dilation with either a 50-Fr
(Group A) or 26-Fr (Group B) Maloney dilator. Before dilation, the dysphagia
(DyspSC) and diet (DietSc) scores were recorded and an esophageal manometry
performed. Both scores were reassessed at 1, 3, 7, and 14 days after dilation.
Success was defined at day 14 as an improvement in the DietSc of at least 25%
from baseline, or a DyspSc of < or =3. Nonresponders were crossed-over to the
alternate dilator and restudied. RESULTS: Twenty-three patients (58.7+/-1.9 yr)
were enrolled: 13 in Group A and 10 in Group B. Both groups were matched for age,
baseline DyspSc (4.2+/-0.6 vs 3.8+/-0.5), baseline DietSc (13.3+/-1.7 vs 12.0+/
1.9), and manometric findings. A nonspecific motility disorder was seen in 43.4%
patients. Group A had an initial response rate significantly greater (84.6%) than
Group B (40%) (p = 0.03; odds ratio [OR] = 8.25). The DyspSc and DietSc were
better than baseline with both dilators, but only the DietSc improved
significantly in patients dilated with the 50-Fr dilator (5.3+/-1.9 vs 12.3+/
1.4; p = 0.004). At 2 yr, 80% of the patients responding to the 50-Fr Maloney had
a sustained response. CONCLUSION: Empirical dilation with a large (50-Fr) bougie
is safe, effective, and long-lasting in improving nonobstructive dysphagia.
PMID- 10763937
TI - Is Helicobacter pylori eradication associated with gastroesophageal reflux
disease?
AB - OBJECTIVES: A recent report has suggested an association between Helicobacter
pylori eradication and the development of gastroesophageal reflux disease (GERD).
We therefore assessed the incidence of GERD among comparable patients having
undergone successful versus failed H. pylori eradication in a controlled trial.
We also compared the H. pylori strains in the subjects that developed GERD to
those that did not. METHODS: Patients with a history of proven duodenal ulcer and
H. pylori infection were randomised into a H. pylori eradication study. Patients
subsequently underwent gastroscopy with gastric biopsies every 3 months for 1 yr.
At each visit, the presence of GERD symptoms and endoscopic esophagitis were
noted, and the incidence of these variables among patients in whom H. pylori
eradication was successful was compared to those in whom it was not. In a
subgroup, the presence of the cagA, cagE, and vacA genotypes and of cagA
antibodies were determined. RESULTS: Of 98 patients randomized into this study,
11 dropped out before determination of H. pylori eradication, leaving 87 patients
with analyzable results. H. pylori eradication was successful in 63 (72%). By the
end of the follow-up period, patients with GERD symptoms or endoscopic
esophagitis were more prevalent in the successful than in the failed eradication
group (37% [95% CI: 25-50%] vs 13% [95% CI: 3-32%], p = 0.04, 95% CI for the
difference: 6-42%), as were patients with GERD symptoms alone (29% [95% CI: 18
41%] vs 8% [95% CI: 1-27%], p = 0.04, 95% CI for the difference: 4-36%) or
esophagitis alone (21% [95% CI: 12-33%] vs 4% [95% CI: 0-21%], p = 0.10, 95% CI
for the difference: 4-29%, respectively). Multivariate analysis revealed no
significant association between the incidence of symptoms or esophagitis and age,
gender, Quetelet index, caffeine or alcohol intake, smoking, weight change, or
the presence of a hiatus hernia. There were also no differences in the prevalence
of H. pylori genotypes from patients who developed GERD as compared to those who
did not. CONCLUSIONS: In this patient population, the incidence of new GERD-type
symptoms or endoscopic esophagitis was greater in patients in whom successful
eradication was achieved. This difference does not appear to be attributable to
weight gain, habits, or specific H. pylori strains.
PMID- 10763938
TI - The gastric cardia: fact or fiction?
AB - OBJECTIVE: It is unclear whether the gastric cardia is present from birth or is
metaplastic and develops as a result of gastroesophageal reflux disease. To this
end, we evaluated the histology of the entire esophagogastric junction in
consecutive pediatric autopsies to determine the presence and extent of cardiac
mucosa. METHODS: The entire esophagogastric junction of 33 consecutive pediatric
(< or =18 yr) autopsies was examined. The precise location of the squamocolumnar
junction and its relationship to the esophagogastric junction was noted in all
cases. Slides were evaluated by two pathologists in a blinded fashion to look for
cardiac mucosa, characterized by unequivocal periodic acid-Schiff (PAS)-positive
mucous glands in a lobular configuration. Sections from the antrum and
esophagogastric junction were examined for the presence of Helicobacter pylori.
RESULTS: Three cases were excluded due to autolysis. The mean age of the 30
remaining patients was 6.3 yr (range: 16 days-18 yr). A regular-appearing
squamocolumnar junction was identified at the esophagogastric junction in all 30
cases. Cardiac mucosa was present in all specimens (mean length: 1.8 mm; range:
1.0-4.0 mm), always on the gastric side of the esophagogastric junction. There
was no significant association between patient age or gender and length of
cardiac mucosa. None of the patients had a known history of gastroesophageal
reflux disease or Barrett's esophagus, and none were taking acid-suppressing
medications before death. All were negative for Helicobacter pylori by Giemsa
stain. CONCLUSIONS: In an unselected pediatric patient population with little or
no propensity for gastroesophageal reflux disease, a short segment of cardiac
mucosa was consistently present on the gastric side of the esophagogastric
junction, independent of gender or age. These results support the concept that
the gastric cardia is present from birth as a normal structure.
PMID- 10763939
TI - Noninvasive antigen-based assay for assessing Helicobacter pylori eradication: a
European multicenter study. The European Helicobacter pylori HpSA Study Group.
AB - OBJECTIVE: In a recently published multicenter study involving 501 patients
undergoing esophagogastroduodenoscopy (EGD) throughout Europe, we showed the high
accuracy of a recently developed simple test (HpSA) to detect Helicobacter pylori
(H. pylori) antigens in stools of untreated patients. The aim of this study was
to assess the diagnostic usefulness of HpSA compared with 13C UBT shortly after
H. pylori eradication treatment. METHODS: Of the 501 patients enrolled in the
validation study, 279 were found to be H. pylori-positive. These patients were
given H. pylori eradicating regimen and asked to return for follow-up EGD with
biopsies, 13C UBT and HpSA testing 4 wk after therapy. Follow-up results were
available for 235 patients. Of these, 162 consented to all testing and 73
consented only to 13C UBT and HpSA testing. We assessed sensitivity and
specificity of both HpSA and 13C UBT compared with biopsy-based methods in the
162 patients, who accepted follow-up EGD. We also assessed sensitivity and
specificity of HpSA compared with 13C UBT, arbitrarily chosen as the gold
standard, in the whole population of 235 patients. RESULTS: Sensitivity and
specificity in 162 patients who consented to a second EGD were 93.8% (CI: 85.4
100%) and 96.9% (CI: 93.9-99.9%) for HpSA, and 90.6% (CI: 80.5-100%) and 99.2%
(CI: 97.7-100%) for UBT. Using EGD-based methods as the gold standard, 130 of the
162 treated patients' H. pylori infection were eradicated (125 HpSA-negative, one
borderline, and four false-positive; 129 13C UBT-negative, one false-positive),
and 32 remained H. pylori-infected (30 HpSA-positive, two false-negative, 29 13C
UBT-positive, three false negative). The overall eradication rate was 80.2%. The
sensitivity and specificity of HpSA relative to UBT as the gold standard in the
overall population (n = 235) were 95.6% (CI: 89.6-100%) and 94.7% (CI: 91.5
97.9%), respectively. CONCLUSIONS: HpSA has proven to be a useful method in
posttreatment eradication testing for H. pylori. Its ease of use, speed, and
noninvasive nature make HpSA testing an ideal method for post-treatment
monitoring where a second EGD may not be justified.
PMID- 10763940
TI - Sustained increase in gastric antral epithelial cell proliferation despite cure
of Helicobacter pylori infection.
AB - OBJECTIVE: Studies of the effect of Helicobacter pylori treatment on gastric
mucosa proliferation have yielded inconsistent results. We compared gastric
mucosa cell proliferation posttherapy and in uninfected controls. METHODS:
Biopsies were obtained from patients with H. pylori infection before treatment
and at intervals for up to 33 months. Epithelial cell proliferation was
determined using Ki-67 immunostaining. The labeling index (LI) is the proportion
of positively labeled cells with respect to the total number of cells. The
proliferative index was calculated by multiplying the labeling index (LI) and the
proliferation zone PZ (PZ = length of the area between the uppermost and lowest
labeled cells). RESULTS: The study included 27 patients with H. pylori gastritis
and 35 controls. Epithelial cell proliferation (LI) was greater with H. pylori
infection than without in both the antrum and corpus (65+/-5 vs 91+/-8 in the
antrum and 44+/-4 vs 72+/-8 in the corpus, for uninfected controls vs H. pylori
gastritis, respectively) (p = 0.0001). In the antrum there was no significant
decrease in epithelial cell proliferation after cure of the H. pylori infection
despite follow-up for >2 yr (labeling index = 83+/-10). In contrast, epithelial
cell proliferation decreased in the corpus and became similar to that in controls
after 7-13 months. CONCLUSIONS: Patients with H. pylori infection have sustained
high epithelial cell proliferation in the antrum compared to that in uninfected
subjects. A continued increase in proliferation in the antrum after cure of H.
pylori infection suggests continuing damage.
PMID- 10763941
TI - Rabeprazole is superior to ranitidine in the management of active duodenal ulcer
disease: results of a double-blind, randomized North American study.
AB - OBJECTIVE: The primary purpose of this study was to compare the efficacy and
tolerability of rabeprazole versus ranitidine in the treatment of patients with
active duodenal ulcer disease. METHODS: This multicenter, double-blind,
randomized, parallel-group study enrolled 376 patients. Patients were randomly
assigned to receive rabeprazole 20 mg administered once daily in the morning
(q.a.m.) with matching ranitidine placebo twice daily (b.i.d.) (n = 188), or
ranitidine 150 mg b.i.d. with matching rabeprazole placebo q.a.m. (n = 188).
Three visits were scheduled: wk 0 (baseline; days -3 to -1), wk 2 (day 15+/-3
days), and wk 4 (day 29+/-3 days). The primary efficacy response variable was
defined as complete regeneration of the mucosa at the site of all ulcers
identified during the study. Secondary efficacy variables included patients'
ratings of frequency and severity of ulcer pain, frequency of antacid use, and
improvement of overall physical well-being. Tolerability was evaluated with
analyses of adverse events, laboratory evaluations, fasting serum gastrin levels,
vital signs, body weight, and electrocardiograms. RESULTS: Up to 4 wk of
treatment with rabeprazole 20 mg q.a.m. produced significantly greater healing
rates, compared to treatment with ranitidine 150 mg b.i.d. (83% vs 73%; p =
0.017). Significant differences between treatment groups were also observed for
secondary efficacy indices. At wk 2, rabeprazole was more likely than ranitidine
to produce complete resolution of duodenal ulcer pain (39% vs 25%; p = 0.006),
improvement in duodenal ulcer nighttime pain severity (76% vs 65%; p = 0.044),
and improvement in overall well-being (55% vs 41%; p = 0.009). At wk 4, the
proportion of patients with normalization of overall well-being was significantly
higher in the rabeprazole group than in the ranitidine group (45% vs 29%; p =
0.003). Rabeprazole was safe and well tolerated in this study. CONCLUSIONS: In
patients with active duodenal ulcer disease, rabeprazole 20 mg q.a.m. is superior
to ranitidine 150 mg b.i.d. in healing, resolving ulcer pain frequency, improving
nighttime pain severity, and improving overall well-being. Rabeprazole is an
effective and well-tolerated alternative treatment for patients with active
duodenal ulcer disease.
PMID- 10763942
TI - "Familial hyperpepsinogenemia" and Helicobacter pylori infection.
AB - OBJECTIVE: Pepsinogen 1 (PG1) is a proenzyme precursor to pepsin, a protease
secreted by the gastric chief cell. PG1 levels correlate with maximal gastric
acid output. In 1979, Rotter et al. reported two pedigrees in which elevated PG1
levels and duodenal ulcers were prevalent. They proposed autosomal dominant
inheritance of elevated PG1 and suggested that it was a risk factor for duodenal
ulcer disease. In 1982, Helicobacter pylori (Hp) was discovered and was shown to
be an important factor in peptic ulcer disease. Hp infection is also associated
with increased PGI levels. We tested serum from one of the original pedigrees for
Hp antibodies to determine whether Hp infection could explain the ulcers and
elevated PG1 levels. METHODS: ELISA tests were performed using the urease
fraction of a crushed Hp extract. Banked serum from one of the original families
was thawed and tested. RESULTS: Of the subjects, 90% (nine of 10) with elevated
PG1 were seropositive for Hp, compared to only 31% (17 of 55) of those with
normal PG1 levels (p < 0.001). The mean PG1 level was higher in the seropositive
(94.1+/-13.3 ng/ml) than the seronegative subjects (54.8+/-3.6, p < 0.05). Three
of the four subjects with ulcers were Hp-seropositive. The prevalence of Hp
seropositivity and elevated PG1 declined in parallel in each successive
generation. When neither parent was seropositive, children were seronegative.
CONCLUSIONS: The etiology of elevated PG1 levels in this pedigree is more likely
due to Helicobacter pylori infection than to a genetic predisposition.
PMID- 10763943
TI - The effect of ammonia on omeprazole-induced reduction of gastric acidity in
subjects with Helicobacter pylori infection.
AB - OBJECTIVE: Omeprazole produces a higher intragastric pH during Helicobacter
pylori (H. pylori) infection than after cure. We tested the hypothesis that this
difference is due to the production of ammonia by H. pylori. METHODS: Gastric
acidity and acid output (AO) were measured overnight in 12 subjects, with and
without omeprazole, before and 1 and 6 months after cure of H. pylori infection.
Gastric ammonia ([NH3]), total bile acid ([TBA]) and protein concentrations and
plasma omeprazole levels were measured. RESULTS: During omeprazole, median AO
were 0.0 mmol/h before, 0.86 mmol/h (p = 0.003 vs before cure) at 1 month, and
0.34 mmol/h (p = 0.02) at 6 months after cure; median NH3 output was 0.17 mmol/h
before, 0.03 mmol/h (p = 0.002) at 1 month, and 0.02 mmol/h (p = 0.005) at 6
months after cure. AO and NH3 output were similar 1 and 6 months after cure. When
corrected for [NH3], AO and gastric pH curves were similar before and after cure.
Omeprazole plasma levels increased after cure and gastric [TBA] were unchanged.
CONCLUSIONS: The higher pH observed before cure of H. pylori during omeprazole
administration is attributable, in large part, to ammonia production. Other acid
neutralizing substances and changes in acid secretion may also be important, but
duodenogastric reflux and omeprazole pharmacokinetics are not involved.
PMID- 10763944
TI - Pancreatic duct stents for "obstructive type" pain in pancreatic malignancy.
AB - OBJECTIVE: Obstruction of the main pancreatic duct from malignancy with secondary
ductal hypertension may be an important contributor to pain. The aim of our study
was to determine the efficacy and safety of pancreatic stent placement for
patients with "obstructive" pain due to pancreatic malignancy. METHODS:
Pancreatic duct stents were placed in 10 consecutive patients with malignant
pancreatic duct obstruction and abdominal pain. Seven patients had "obstructive"
type pain and three had chronic unremitting pain. Nine had primary pancreatic
ductal adenocarcinoma and one had metastatic melanoma. There were eight women and
two men. Mean age was 61 yr (range, 47-80 yr). All patients had dominant main
pancreatic duct strictures with proximal dilation. Tumors were unresectable. All
patients took potent analgesics before endoscopic stent therapy. Polyethylene
pancreatic stents, 5- and 7-French, were successfully placed in seven patients,
and self-expanding metallic stents were successfully placed in three patients.
RESULTS: There were no procedure-related complications. One patient required a
single repeat examination to replace a migrated stent. Seven patients (75%)
experienced a reduction in pain. Analgesia was no longer required in five (50%).
Three patients who did not improve had chronic pain rather than "obstructive"
pain. CONCLUSIONS: Pancreatic stent placement for patients with "obstructive"
pain secondary to a malignant pancreatic duct stricture appears to be safe and
effective. It should be considered as a therapeutic option in these patients. It
does not seem to be effective for chronic unremitting pain.
PMID- 10763945
TI - Endoscopic ultrasound characteristics of mucinous cystic neoplasms of the
pancreas.
AB - OBJECTIVE: Mucinous cystic neoplasms of the pancreas have a more favorable
prognosis than ductal adenocarcinoma. Management of a subgroup, intraductal
papillary-mucinous neoplasms, is controversial. Endoscopic ultrasound (EUS) with
fine-needle aspiration biopsy may emerge as the imaging modality of choice. There
are few studies describing the EUS features of these tumors. METHODS: A total of
35 consecutive cases of cystic tumors of the pancreas with an established
pathological diagnosis were analyzed for characteristic EUS features. RESULTS:
Mucinous cystadenocarcinomas (n = 14) were more likely to be characterized by
hypoechoic cystic/solid mass or complex cyst and were frequently associated with
a dilated main pancreatic duct. Benign mucinous duct ectasia (n = 6) were
characterized by a dilated main pancreatic duct in conjunction with hyperechoic
thickening of the duct wall. The two cases of intraductal mucinous hyperplasia
additionally showed a hypoechoic mass. Intraductal papillary carcinoma (n = 11)
had features in common with mucinous cystadenocarcinoma but also had echogenic
foci in the mass and intraductal hyperechoic lesions. The two cases of
microcystic cystadenoma showed either a mixed hypoechoic solid/cystic mass or a
complex cyst without the additional features seen in mucinous cystadenocarcinoma.
CONCLUSIONS: EUS features seem to exist that may help to differentiate cystic
neoplasms from adenocarcinoma of the pancreas and, thus, to establish the
preoperative diagnosis of cystic tumors of the pancreas.
PMID- 10763946
TI - Treatment of experimental colitis by oral tolerance induction: a central role for
suppressor lymphocytes.
AB - OBJECTIVE: Inflammatory bowel diseases (IBD) are immune-mediated disorders
wherein an imbalance between proinflammatory (Th1) and antiinflammatory (Th2)
cytokines is thought to play a role in the pathogenesis. The aim of this study
was to test whether induction of oral tolerance to proteins extracted from
inflammatory colon alleviates experimental colitis, and whether oral tolerization
mediated by suppressor cells can induce immune tolerance. METHODS: Colitis was
induced in rats by intracolonic instillation of trinitrobenzenesulfonic acid
(TNBS). Rats received five oral doses of colonic proteins extracted from TNBS
colitis colonic wall. Splenocytes harvested from tolerized and control rats were
transplanted into irradiated naive rats. RESULTS: Feeding of colitis-extracted
proteins ameliorated colonic inflammation, as shown by reduction of colonic
ulcerations, as well as decreased diarrhea, intestine and peritoneal adhesions,
wall thickness, and edema. A marked reduction of the fraction of injured colonic
area and colon weight, and decrease in colon weight, were observed in tolerized
rats versus controls. Histological parameters for colitis were markedly improved
in tolerized animals that showed significant reduction in inflammatory response
and mucosal ulcerations. Tolerized rats developed an increase in TGFbeta1 and a
decrease in IFNgamma serum levels. TNBS-induced colitis was significantly
attenuated in naive recipients of splenocytes from tolerized rats, compared with
rats that received splenocytes from control donors. CONCLUSIONS: Induction of
oral tolerance to colitis-extracted proteins downregulates the anticolon immune
response, thereby ameliorating experimental colitis. Suppressor lymphocytes
mediate the tolerance by induction of a shift from a proinflammatory to an
antiinflammatory immune response.
PMID- 10763947
TI - What determines severity among patients with painful functional bowel disorders?
AB - OBJECTIVE: For patients with painful functional bowel disorders (FBD), physicians
frequently make diagnostic and treatment decisions based on the severity of the
pain reported; patients with severe painful complaints may receive extensive
diagnostic tests and treatments. Therefore, it would be important to determine
what clinical factors contribute to the judgment of severity among patients with
FBD. The aim of this study was to identify the psychosocial, behavioral, and
physiological (visceral sensitivity) factors that predicted severity in patients
with moderate to severe FBD. METHODS: Two hundred eleven female patients with
moderate or severe FBD, as determined by the Functional Bowel Disorder Severity
Index, entered a multicenter treatment trial at the University of North Carolina
and the University of Toronto. Patients filled out diary cards and were given
questionnaires and physiological testing (rectal sensitivity using barostat).
Analysis of covariance and logistic regression adjusting for demographic factors
were performed to determine which factors distinguished patients at study entry
with moderate from those with severe FBD. RESULTS: Patients with severe FBD were
characterized by greater depression and psychological distress, poorer physical
functioning and health-related quality of life, more maladaptive coping
strategies, and greater health care utilization. There was a trend for patients
with severe FBD to have lower rectal sensation thresholds. Regression analysis
indicated that severity was best predicted by behavioral features: poorer daily
physical function, difficulties related to eating, more phone calls to the
physician, and more days in bed for GI symptoms. CONCLUSIONS: We conclude that
patient illness behaviors are best correlated with severity in FBD. The use of
psychopharmacological agents (e.g., antidepressants) and psychological treatments
to treat psychiatric comorbidity and to improve behavioral coping styles is
recommended. Training to help medical physicians identify and respond to
psychosocial and behavioral features of these conditions is likely to improve
patient satisfaction with their care and the clinical outcome.
PMID- 10763948
TI - The combination of medical treatment plus multicomponent behavioral therapy is
superior to medical treatment alone in the therapy of irritable bowel syndrome.
AB - OBJECTIVE: Although the standard treatments for the irritable bowel syndrome
(IBS) are medical, growing evidence indicates the substantial therapeutic value
of psychological therapy. However, it has not been investigated whether the
combination of multicomponent behavioral therapy plus medical treatment is more
effective than medical treatment alone. The aim of this study was to investigate
this question in patients consulting a tertiary gastrointestinal (GI) referral
center. METHODS: Twenty-four IBS outpatients were randomly assigned to the
combination of standardized multicomponent behavioral therapy plus standard
medical treatment (SMBT) or standard medical treatment alone (SMT). SMBT included
IBS information and education, progressive muscle relaxation, training in illness
related cognitive coping strategies, problem-solving, and assertiveness training
in 10 sessions over 10 wk. SMT included standardized symptom-oriented medical
treatment and regular visits to a gastroenterologist every second week.
Posttreatment outcome measures consisted of quantification of GI, vegetative, and
psychological symptoms by means of daily symptom diaries and the assessment of
changes in rectovisceral perception thresholds, as well as of questionnaire
measures on psychological distress, overall well-being, illness-related coping
abilities, and quality of life. Follow-ups were conducted at 3- and 6-month
intervals. RESULTS: Pre- and posttreatment evaluations showed significantly (p <
0.01) greater IBS symptom reduction as measured by daily symptom diaries for the
SMBT group than for the SMT group. Rectovisceral perception remained unchanged by
either treatment. Overall well-being significantly improved in the SMBT group but
remained unchanged in the SMT group. Subjects in the SMBT group, unlike those in
the SMT group, felt significantly more in control of their health, and quality of
life was significantly improved in the SMBT group but remained unchanged in the
SMT group. CONCLUSIONS: The data provide evidence that the combination of medical
treatment plus multicomponent behavioral treatment is superior to medical
treatment alone in the therapy of IBS.
PMID- 10763949
TI - Use of the Functional Bowel Disorder Severity Index (FBDSI) in a study of
patients with the irritable bowel syndrome and fibromyalgia.
AB - OBJECTIVE: The purpose of this study was to evaluate the utility of the
Functional Bowel Disorder Severity Index (FBDSI) as a measure of severity of
disease among patients with the irritable bowel syndrome (IBS) and matched
controls. METHODS: A total of 75 IBS patients and 69 matched controls completed
questionnaires on bowel symptoms, health status, quality of life, psychological
distress, concerns, anxiety, and sense of coherence. All participants also were
tested for fibromyalgia (FS), a functional disorder of the musculoskeletal
system. All participants were administered a questionnaire that included the
FBDSI. On the basis of their responses to the questionnaire, the controls were
subdivided as healthy controls (n = 48) or IBS nonpatients (n = 21). On the basis
of the FS classification, 75 IBS patients were subdivided as IBS only (n = 50) or
IBS and FS combined (n = 25). RESULTS: The mean FBDSI score was higher for the
IBS patients than the controls (100.5+/-12.7 and 23.5+/-3.9, respectively; p <
0.001). IBS nonpatients had an intermediate score of 42.3+/-18.0. Patients with
both IBS and fibromyalgia had the highest mean FBDSI score: 138.8+/-31.5. There
was no association between FBDSI and age or gender, but FBDSI was significantly
associated with other measures of health status. CONCLUSIONS: An association was
found between the FBDSI and IBS patient status: IBS nonpatients, patients with
IBS only, and patients with both IBS and fibromyalgia had increasingly severe
scores. The results provide support for the validity of FBDSI as a measure of
illness severity in functional gastrointestinal disorders.
PMID- 10763950
TI - Further validation of the IBS-QOL: a disease-specific quality-of-life
questionnaire.
AB - OBJECTIVE: There has been growing interest in the investigation of health-related
quality of life (HRQOL) among patients with gastrointestinal (GI) disorders. We
recently reported on the development and preliminary validation of the IBS-QOL, a
specific quality-of-life measure for irritable bowel syndrome (IBS). The aim of
this study was to determine the longitudinal construct validity (responsiveness)
of the IBS-QOL. METHODS: Female patients enrolled in a multicenter treatment
trial for functional bowel disorders were studied pre- and posttreatment with the
IBS-QOL and other health status measures. Based on the response to treatment for
several variables (pain/14-day score, daily function, and days in bed/3 months),
patients were stratified into Responders, Partial Responders, and Nonresponders.
Change scores in the IBS-QOL were then statistically compared with changes in the
other variables to determine their correlation and whether Responders were
significantly different from non- and Partial Responders on the IBS-QOL. RESULTS:
There was a significant correlation between change scores on the IBS-QOL and the
other measures of treatment effect (Pain/14 days, r = 0.25, p < 0.002; Sickness
Impact Profile [SIP] Total Score, r = 0.28, p < 0.0004). In addition, the IBS-QOL
scores significantly differentiated Responders from Nonresponders for most of the
variables tested (regression trend test for Pain/14 days, p < 0.04; SIP Total, p
< 0.0001; SIP Physical, p < 0.0001; SIP Psychosocial, p < 0.002, and SIP Eating,
p < 0.04). CONCLUSION: The IBS-QOL is responsive to treatment in a referral-based
clinical population of patients with functional bowel disorders.
PMID- 10763951
TI - Diet as a risk factor for the development of ulcerative colitis.
AB - OBJECTIVE: Dietary factors have been considered as a possible risk factor for
ulcerative colitis (UC). However, available data are inconsistent. The aim of the
present study was to evaluate the etiological role of dietary factors in the
development of UC. METHODS: Recently diagnosed (<6 Months) UC patients (n = 43)
and age- and gender-matched population controls (n = 43) were studied in a case
control design. The crosscheck dietary history method was used to assess dietary
intake of 5 yr before the study. Adipose tissue fatty acid composition was used
as a biomarker of long-term fat intake. Conditional logistic regression-derived
odds ratios (OR), and 95% confidence intervals (CI) were used for statistical
analysis. Dietary intake ORs were adjusted for energy intake. RESULTS: High
intakes of monounsaturated fat (OR: 33.9 [95% CI 2.6-443.1]), polyunsaturated fat
(OR: 5.1 [95% CI 1.0-26.7]), and vitamin B6 (OR: 6.9 [95% CI 1.6-30.7]) were
associated with an increased risk to develop UC. No other significant
associations were found with UC risk. CONCLUSIONS: High intakes of mono- and
polyunsaturated fat and vitamin B6 may enhance the risk of developing UC. Whether
this observation is a true risk factor in the development of UC or rather a
reflection of a certain dietary lifestyle needs to be investigated.
PMID- 10763952
TI - Segmental colitis associated with diverticula: a prospective study. Gruppo di
Studio per le Malattie Infiammatorie Intestinali (GSMII).
AB - OBJECTIVE: Little is known about the clinical features and natural history of
segmental colitis associated with diverticula. Our aim was to evaluate the
incidence of segmental colitis associated with diverticula in patients undergoing
colonoscopy, its clinical picture, and its outcome. METHODS: This was a
multicenter, prospective study. Patients with inflammatory bowel disease (IBD)
like lesions limited to colonic segments with diverticula were enrolled. Patients
were treated with oral and topical 5-aminosalicylic (5-ASA) until remission was
achieved; clinical and endoscopic follow-up was planned at 6 wk and 12 months.
RESULTS: A total of 5457 consecutive colonoscopies were recorded at five
participating institutions; 20 patients (0.36%) met the endoscopic criteria for
segmental colitis associated with diverticula. All had lesions in the left colon,
and one also had lesions in the right colon. In six cases, a specific diagnosis
was made thereafter. The remaining 14 patients (0.25% of colonoscopies; eight
men; age range, 49-80 yr) were in clinical and endoscopic remission at the first
follow-up visit. At onset, 13/14 had hematochezia, seven had diarrhea, and five
had abdominal pain; only one had weight loss. No subject had fever. In all but
one case, blood chemistries were normal. Five patients had had similar symptoms
previously. Thirteen of 14 patients were in clinical and endoscopic remission at
12 months. CONCLUSIONS: This endoscopic picture is not an exceptional finding.
Hematochezia was the main clinical feature, and no relation with gender, age, or
smoking habit was found. Blood chemistries were generally normal and the rectum
was spared. The histological features were not diagnostic and most patients did
not complain of any abdominal symptoms 12 months after enrollment.
PMID- 10763953
TI - Fermentation of dietary starch in humans.
AB - OBJECTIVE: Dietary starch that escapes digestion in the small intestine may be
quantitatively more important than dietary fiber as a substrate for fermentation.
The products of fermentation have important implications in the pathogenesis of
colorectal cancer and other diseases of the large bowel, which are uncommon in
Africans but have a high prevalence in Western populations. METHODS: Maize
porridge is a staple of most blacks in South Africa. Stale maize porridge (high
resistant starch [HRS]) seems to induce greater fermentation in the large bowel
than fresh maize porridge (low-resistant starch [LRS]). RESULTS: In the present
study, healthy colostomy subjects fed stale maize porridge had significantly more
production of short-chain fatty acids (SCFA) (mean SCFA, HRS = 182.6; mean SCFA,
LRS = 116.1; p < 0.05) in their colostomy effluent together with a significant
drop in stool pH (mean pH, HRS = 5.91; mean pH, LRS = 6.70; p < 0.001). The SCFA
butyrate (mean, HRS = 35.1; mean, LRS = 17.6; p < 0.05) and acetate (mean, HRS =
93.9; mean, LRS = 65.8; p < 0.05) were significantly elevated on the stale maize
porridge diet when compared with consumption of fresh maize porridge. SCFA
propionate (mean, HRS = 43.1; mean, LRS = 24.8; p = 0.05), also increased with
stale maize porridge, but was not statistically significant. CONCLUSION: A high
resistant starch diet and its resultant increase in fermentation products may be
partly responsible for protecting the black population against colorectal cancers
and other large bowel diseases.
PMID- 10763954
TI - Crohn's disease, pregnancy, and birth weight.
AB - OBJECTIVE: Although there is general agreement that conception should be avoided
when Crohn's disease is active, many questions remain unanswered for the woman
with Crohn's disease in remission who becomes pregnant. METHODS: Sixty-five
charts of women with Crohn's disease quiescent at the start of pregnancy were
identified between January 1993 and December 1997. Each pregnancy was matched to
a healthy control pregnancy by date, age, parity, smoking status, and gestational
age +/- 1 wk, and comparisons were carried out using matched analyses. RESULTS:
The two groups were similar in terms of maternal height, weight, and body mass
index (BMI), in addition to the matched variables. The incidence of pregnancy
complications was similar for most of the complications examined, whereas the
incidence of poor maternal weight gain differed significantly between the groups
(17/65 vs 2/65, p < 0.001). Flare-up of the Crohn's disease was seen in 13/65
(20%) of pregnancies. The greatest differences in neonatal outcomes were in terms
of birth weight (3150+/-80 g vs 3500+/-60 g) and birth weight percentile (36.7%+/
.6% vs 57.5%+/-3.4%). Overall, there were 16 (24.6%) small for gestational age
(SGA) births in the Crohn's group, compared with only one (1.5%) in the control
group (p = 0.0007). Multivariate analysis was performed to identify factors
predictive of SGA births in the Crohn's group. Ileal Crohn's disease was a
statistically significant predictor (p = 0.035), whereas previous bowel resection
trended toward statistical significance (p = 0.065). CONCLUSIONS: In view of the
risk of low birth weight, all women with Crohn's disease who become pregnant
should be followed carefully during the pregnancy, particularly those who have
ileal disease or who have previously undergone bowel resection. Furthermore,
smoking cessation needs to be aggressively pursued in these patients.
PMID- 10763955
TI - Spatial and temporal organization of pressure patterns throughout the unprepared
colon during spontaneous defecation.
AB - OBJECTIVE: The aim of this study was to examine colonic motor events associated
with spontaneous defecation in the entire unprepared human colon under
physiological conditions. METHODS: In 13 healthy volunteers a perfused, balloon
tipped, 17-lumen catheter (outer diameter, 3.5 mm; intersidehole spacing, 7.5 cm)
was passed pernasally and positioned in the distal unprepared colon. RESULTS: In
the hour before spontaneous defecation, there was an increase in propagating
sequence frequency (p = 0.04) and nonpropagating activity when compared to basal
conditions (p < 0.0001). During this hour the spatial and temporal relationships
among propagating sequences demonstrated a biphasic pattern. Both the early
(proximal) and late (distal) colonic phases involved the whole colon and were
characterized by respective antegrade and retrograde migration of site-of-origin
of arrays of propagating sequences. There was a negative correlation between
propagating sequence amplitude and the time interval from propagating sequence to
stool expulsion (p = 0.008). CONCLUSIONS: The colonic motor correlate of
defecation is the colonic propagating sequence, the frequency and amplitude of
which begin to increase as early as 1 h before stool expulsion. During the
preexpulsive phase, the spatial and temporal relationship among the sites of
origin of individual propagating sequences demonstrate a stereotypic anal
followed by orad migration, which raises the possibility of control by long
colocolonic pathways.
PMID- 10763956
TI - Simultaneous measurements of serum alpha-fetoprotein and protein induced by
vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District
Study Group.
AB - OBJECTIVE: We evaluated the measurements of serum alpha-fetoprotein (AFP) and the
protein induced by vitamin K absence (PIVKA-II) in 734 patients with chronic
hepatitis (CH) and liver cirrhosis (LC) who had been followed-up for the
development of hepatocellular carcinoma (HCC). METHODS: Serum AFP and PIVKA-II
were measured every month and abdominal ultrasonography was performed every 3
months. Youden's index (sensitivity + specificity -1) was calculated. RESULTS: On
an average follow-up period of 374.5 days, HCC was detected in three HBsAg
positive LC patients (10.0%/yr), four anti-HCV-positive CH patients (1.35%/yr),
21 anti-HCV-positive LC patients (7.8%/yr), and one patient with both HBsAg- and
anti-HCV-positive LC (22.7%/yr). At the time of HCC detection, the size of HCC
was 4.7+/-0.6 (mean +/- SD) cm in HBsAg-positive patients and 2.4+/-1.3 cm in
anti-HCV-positive patents. Cut-off values of 20 ng/ml for AFP (Youden's index =
0.422) and 60 mAU/ml for PIVKA-II (Youden's index = 0.316) gave the highest index
for each marker. When these two markers were combined, cut-off values of 40 ng/ml
for AFP and 80 mAU/ml for PIVKA-II gave the highest index (Youden's index =
0.500, sensitivity = 65.5%, specificity = 85.5%, positive predictable value =
14.8%, negative predictable value = 98.3%). The levels of AFP or PIVKA-II
increased within three months before the detection of HCC. CONCLUSIONS:
Simultaneous measurements of serum AFP and PIVKA-II levels that are performed
every 3 months are useful for detecting a developing HCC. The optimal cut-off
values for AFP and PIVKA-II may be 40 ng/ml and 80 mAU/ml, respectively.
PMID- 10763957
TI - Successful interferon therapy reverses enhanced hepatic iron accumulation and
lipid peroxidation in chronic hepatitis C.
AB - OBJECTIVES: Hepatic iron deposition has been reported in chronic hepatitis C (CH
C), and iron-induced lipid peroxidation may be involved in the pathogenesis of CH
C. The aims of the present study were: 1) to determine whether patients with CH-C
have evidence of enhanced hepatic lipid peroxidation and to evaluate its relation
to iron status, compared with that in patients with chronic hepatitis B (CH-B);
and 2) to assess the effect of interferon (IFN) therapy on hepatic iron and lipid
peroxidation. METHODS: In the liver biopsies of 40 patients with CH-C and 26
patients with CH-B, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE)
protein adducts for evaluation of lipid peroxidation was performed, and hepatic
iron status was biochemically and histologically assessed. In 16 CH-C patients
with normal serum transaminases and undetectable serum HCV-RNA >6 months after
the end of IFN treatment (responders) and in 11 nonresponders, hepatic HNE
protein adducts and siderosis were evaluated in pre- and posttreatment liver
biopsies. RESULTS: Hepatocytic HNE-protein adducts and iron deposits were more
abundant in the patients with CH-C than in those with CH-B. No correlation was
found between the levels of hepatocytic HNE-protein adducts and hepatic iron
status in either of the two groups. In the responders to IFN treatment for CH-C,
hepatocytic HNE-protein adducts disappeared or attenuated with improvement of
hepatic siderosis after the treatment, whereas IFN treatment did not improve
hepatocytic expression of HNE-protein adducts and hepatic siderosis in the
nonresponders. CONCLUSIONS: Patients with CH-C have evidence of enhanced hepatic
iron accumulation and lipid peroxidation compared to those with CH-B. In CH-C,
hepatic siderosis and lipid peroxidation are improved with successful IFN
treatment. These results suggest that hepatic lipid peroxidation and iron may
potentially play contributory roles in the pathogenesis of CH-C.
PMID- 10763958
TI - Treatment of mastalgia with tamoxifen in male patients with liver cirrhosis: a
randomized crossover study.
AB - OBJECTIVE: Mastalgia is occasionally found in patients with liver cirrhosis,
especially in those receiving spironolactone for treatment of ascites. The
pathogenesis is still unclear. Estrogen excess in cirrhotic patients and
estrogenic effects of the spironolactone are possible leading causes. Treatment
directed against the preponderance of estrogenic stimulation in these patients
has never been investigated. This study was designed to investigate the efficacy
and safety of tamoxifen, an estrogen antagonist, on mastalgia in patients with
liver cirrhosis. METHODS: A total of 16 male cirrhotic patients with mastalgia
were randomly assigned to two groups. One group was treated with tamoxifen (20 mg
p.o., b.i.d.) for 1 month, followed by placebo for the next month. The other
group was treated in the reverse order. All patients received spironolactone for
ascites and/or peripheral edema, and the drug was continued during the study
period. The size of the breasts and the degree of breast pain and tenderness were
recorded in all subjects before and after the treatment periods. Serum levels of
estradiol and testosterone were measured using the radioimmunoassay method.
RESULTS: Of the 16 patients, 14 experienced a decrease or disappearance of the
breast pain and/or tenderness during the tamoxifen treatment period, whereas only
two of the 16 patients felt an improvement during the placebo period (p < 0.05).
There were significant improvements in the breast pain and tenderness scores and
decreases in the breast sizes during the tamoxifen treatment period (before vs
after: 1.4+/-0.3 vs 0.4+/-0.2, p = 0.002; 1.9+/-0.2 vs 0.5+/-0.2, p < 0.001; and
6.8+/-0.6 vs 5.5+/-0.6 cm, p = 0.02, respectively), whereas no obvious change was
seen during the placebo period. Serum levels of estradiol and testosterone did
not change significantly after the tamoxifen or placebo treatments (p > 0.05). No
major side effects were noted during the therapeutic periods. CONCLUSIONS:
Tamoxifen is effective and safe in the management of mastalgia in male cirrhotic
patients taking spironolactone.
PMID- 10763959
TI - Prognostic significance of circulating antibodies against carcinoembryonic
antigen (anti-CEA) in patients with colon cancer.
AB - OBJECTIVE: The discovery of antibodies against carcinoembryonic antigen (CEA) in
patients with digestive cancers, in the late 1970s, initiated a number of studies
on the role of these antibodies in patients with cancers of the GI tract. Our aim
was to determine the prevalence and prognostic significance of the IgG and IgM
anti-CEA antibodies in the serum of patients with colon cancer. METHODS: Using an
enzyme-linked immunoassay, the sera of 58 colon cancer patients were examined for
the presence of carcinoembryonic antigen (CEA) and for circulating antibodies
against the CEA (anti-CEA). An inhibition assay was carried out for the
determination of the specificity of the IgG and IgM anti-CEA antibodies. RESULTS:
The CEA was elevated (> or =10 ng/ml) in only 12 patients (20.6%). Anti-CEA IgM
and/or IgG antibodies were detected in 46 patients with colon cancer (79.1%). In
the control group (n = 28), 10% of the individuals had detectable amounts of IgG
and/or IgM anti-CEA antibodies. Patients with detectable amounts of circulating
IgM anti-CEA antibodies (n = 14, 30.5%) had a statistically significantly better
2-yr survival compared to the rest of the patients (p = 0.017). The IgM anti-CEA
antibodies can also be used as an independent prognostic factor in these patients
(p = 0.0323). CONCLUSIONS: In this study, a high number of colon cancer patients
have circulating anti-CEA antibodies in their sera. These may be used as
diagnostic markers and as independent prognostic factors. In addition, the
presence of these antibodies in the patients studied is associated with better
prognosis and significantly increased 2-yr survival. It was also found that the
anti-CEA antibodies (IgG and IgM) are more sensitive markers than CEA. These
findings underline the biological importance of the anti-CEA antibodies and
provide additional information on their potential use as markers of the immune
status in patients with colon cancer.
PMID- 10763960
TI - Factors influencing tissue concentration of vascular endothelial growth factor in
colorectal carcinoma.
AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) promotes proliferation of
various tumor cells by stimulating angiogenesis. Experimentally, hypoxia and
energy depletion are known to induce angiogenesis by increasing VEGF expression.
We investigated whether factors reflecting the general condition of the patients
influence the tissue concentration of VEGF in colorectal carcinoma. METHODS:
Tissue concentrations of VEGF in 81 colorectal carcinomas, 81 normal mucosas, and
30 colonic adenomas were determined. The expressions of VEGF and its receptor in
cancer tissue were evaluated immunohistochemically. For the assessment of the
general preoperative condition of the patients, the nutritional status was
evaluated and arterial blood gas was analyzed. RESULTS: The mean concentration of
VEGF in the cancer tissue was significantly higher than that in the normal
colonic mucosa and colonic adenoma. Tumor size, histological grade, serum
cholinesterase, and arterial level of PO2 were the independent factors that
influenced the tissue concentration of VEGF in colorectal cancer.
Immunohistochemically, the VEGF-positive cancer tended to have an increased
expression of VEGF receptor, kinase insert domain-containing receptor (KDR). In
patients with positive KDR in the tumor, the arterial levels of PO2 and O2
saturation were significantly lower than those in patients without its
expression. CONCLUSION: Tissue content of VEGF or expression of KDR in colorectal
carcinoma may be associated with disease status, including nutritional status,
systemic oxygenation, and tumor progression. The systemic-local regulating
mechanism of VEGF or KDR may play an important role in the constant growth of
tumor cells, especially in wasted colorectal cancer patients.
PMID- 10763961
TI - The bedpan.
PMID- 10763962
TI - Biliary tuberculosis mimicking cholangiocarcinoma: treatment with metallic
biliary endoprothesis.
AB - A 58-yr-old patient who presented with obstructive jaundice was evaluated with
ultrasonography (US), computed tomography (CT), and percutaneous transhepatic
cholangiography (PTC). Diffuse irregular stenosis of the extrahepatic bile ducts
and periductal ill-defined soft tissue density along the hepatoduodenal ligament
was determined. The patient was originally misdiagnosed with cholangiocarcinoma
and, because the extent of disease process made surgical bypass impossible, was
treated with a percutaneously inserted metallic stent. Histopathological
examination of the endoluminal biopsy revealed ductal tuberculosis (TB). Most of
the previous reports in the literature indicated that biliary obstruction was due
to enlarged tuberculous lymph nodes compressing the bile duct. To our knowledge,
only three cases of biliary stricture due to tuberculous involvement of the bile
ducts were reported previously. This case illustrates the importance of tissue
diagnosis in all cases of obstructive jaundice to avoid missing rare but curable
diseases.
PMID- 10763963
TI - Spontaneous candida mediastinitis diagnosed by endoscopic ultrasound-guided, fine
needle aspiration.
AB - Candida mediastinitis is a rare clinical entity associated with high mortality
and morbidity. It is emerging as an important clinical entity, probably due to
increased recognition of candida as a significant pathogen in mediastinitis.
Candida mediastinitis is usually associated with cardiothoracic surgery,
esophageal perforation, and head and neck infections. Optimal therapy for candida
mediastinitis remains undefined. Aggressive, combined surgical debridement and
antifungal therapy appears to be the most effective of available therapies. We
report a case of spontaneous candida mediastinitis diagnosed by endoscopic
ultrasound-guided, fine-needle aspiration and successfully treated with oral
antifungal therapy alone.
PMID- 10763964
TI - Verrucous carcinoma of the esophagus completely resected by endoscopy.
AB - Verrucous carcinoma of the esophagus is a very rare esophageal cancer. We present
a case of verrucous carcinoma of the esophagus, the 14th such case reported. In
contrast to the previous cases, our patient had no symptoms and did not have a
history of severe or repeated injury of the esophagus. The patient was completely
resected by endoscopy and was well after 3 yr of follow-up, without recurrence of
the disease.
PMID- 10763965
TI - Focal nodular hyperplasia contiguous with an echinococcal cyst.
AB - We report the first case of an Echinococcal cyst and focal nodular hyperplasia,
two usually isolated hepatic lesions, in direct contiguity. The patient presented
with right upper quadrant pain and subsequent imaging studies found a cystic and
solid lesion. These studies suggested that this lesion was an hepatic adenoma,
which had bled forming a hematoma. Pathological examination of the surgical
resection showed Echinococcus multilocularis with contiguous focal nodular
hyperplasia. Because focal nodular hyperplasia is a benign hepatic lesion the
etiology of which is thought to be abnormal arterial blood flow, we postulate
that the parasitic hepatic infection by E. multilocularis may have incited the
formation of this contiguous hepatic lesion.
PMID- 10763966
TI - Choledochocele imaged with magnetic resonance cholangiography.
AB - Choledochal cysts are rare developmental malformations of the biliary tree.
Percutaneous and endoscopic ultrasound, as well as endoscopic retrograde
cholangiopancreatography, are recommended diagnostic tools. Magnetic resonance
cholangiography may also contribute to the workup and treatment plan of patients
with choledochal cysts. We report a 25-yr-old white woman with episodic nausea
and moderate epigastric discomfort. Magnetic resonance cholangiography showed a
rather spherical, cyst-like, fluid-filled structure in continuity with the
prepapillary segment of the common bile duct, thus making a choledochocele (type
III choledochal cyst) likely. The patient was treated by endoscopic
sphincterotomy and, after a 6-month follow-up, is without complaints.
PMID- 10763967
TI - Virtual gastroscopy: a new look at the stomach.
PMID- 10763968
TI - Achalasia: from bad to worse?
PMID- 10763969
TI - Surgical treatment of achalasia: thoracoscopic or laparoscopic?
PMID- 10763970
TI - Celiac disease among patients referred for routine upper gastrointestinal
endoscopy: prevalence and diagnostic accuracy of duodenal endoscopic markers.
PMID- 10763971
TI - Re: Transient marked decrease in serum transaminases in chronic hepatitis C after
surgery.
PMID- 10763972
TI - Reversible protein-losing hypertrophic gastropathy: causal relationship with
Helicobacter pylori infection, or simple coincidence?
PMID- 10763973
TI - Clinical management of hepatic abscesses in HIV patients.
PMID- 10763974
TI - A patient with a prolonged prothrombin time due to an adverse interaction between
5-fluorouracil and warfarin.
PMID- 10763975
TI - Isolation of Mycobacterium avium subsp paratuberculosis from breast milk of
Crohn's disease patients.
PMID- 10763976
TI - Antineutrophil cytoplasmic antibodies in Turkish children with inflammatory bowel
disease.
PMID- 10763977
TI - E. coli O157:H7--another waterborne outbreak!
PMID- 10763978
TI - Hypocalcemia <7.5 mg/dl: early predictive marker for multisystem organ failure in
severe acute necrotizing pancreatitis, proposed by the study analyzing post-ERCP
pancreatitis.
PMID- 10763979
TI - Altered antigenicities of hepatitis B virus surface antigen carrying mutations
outside the common "a" determinant.
PMID- 10763980
TI - Obesity: a cause of steatohepatitis in children.
PMID- 10763981
TI - Leucopenia is a side effect of combination therapy for hepatitis C infection.
PMID- 10763982
TI - Re: Drug-resistant falciparum malaria with bowel symptoms.
PMID- 10763983
TI - The use of thumbtacks in massive presacral bleeding.
PMID- 10763984
TI - Temporary neurological improvement in a patient with acute or chronic liver
failure treated with a bioartificial liver device.
PMID- 10763985
TI - Endoscopic microwave coagulation therapy for bile duct cancer with intraductal
ultrasonographic monitoring: brief case report.
PMID- 10763986
TI - Hematological monitoring in patients receiving aminosalicylates.
PMID- 10763987
TI - Torulopsis glabrata esophagitis.
PMID- 10763988
TI - Re: Kreiss et al.: Pneumatosis intestinalis complicating C. difficile
pseudomembranous colitis.
PMID- 10763989
TI - Modified sclerotherapy needle is reliable during sphincterotomy bleed: it works
when you need it.
PMID- 10763990
TI - Enlargement or false enlargement of the liver? The trick of intraperitoneal
adhesions disclosed by laparoscopy in patients with the liver palpated at a
physical examination.
PMID- 10763991
TI - Hepatocellular carcinoma in the elderly: result of surgical management.
PMID- 10763992
TI - Spontaneous bacterial peritonitis caused by Streptococcus bovis.
PMID- 10763994
TI - Natural history of acoustic neuromas.
AB - OBJECTIVES/HYPOTHESIS: 1) Develop a computerized technique to accurately compare
acoustic neuroma size on routine computed tomography and magnetic resonance
imaging (MRI) scans; 2) use this technique to determine the growth pattern in a
large series of patients with acoustic neuroma who were conservatively managed;
3) describe the natural history of patients with acoustic neuromas who did not
receive surgical intervention and those who underwent subtotal resection; 4)
correlate the size and growth rate of acoustic neuromas to clinical presentation
and auditory and vestibular testing; and 5) recommend guidelines for the
management of patients with acoustic neuromas. STUDY DESIGN: A retrospective
study from 1974 to 1999 of patients with unilateral acoustic neuromas who had
conservative treatment by serial imaging studies (80 patients) or subtotal
resection (49 patients). METHODS: All patient charts were evaluated for
presenting symptoms, reasons for the type of management given, and clinical
outcome. Charts were also reviewed with respect to serial audiological
assessment, electronystagmography, and brainstem auditory evoked response.
Imaging studies were analyzed using a computer technique so that serial studies
could be compared to determine growth rates. RESULTS: Rigorous computer analysis
of tumor size and growth rate was statistically the same as the radiologist's
description of the tumor size and growth rate. Of 70 patients who were older than
65 years of age old at the time their tumor was discovered, 4 (5.7%) required
intervention and 18 (26%) were dead of unrelated causes. These patients had a
mean follow-up of 4.8 years (range, 0.01-17.2 y). Overall, growth rate for
nonsurgical patients was 0.91 mm per year. Nonsurgical tumors did not grow or
regressed in 42%. Overall postoperative growth rate for surgical subtotal
resection patients was 0.35 mm per year. Surgical tumors did not grow or
regressed after subtotal resection of acoustic neuroma in 68.5% of patients.
Three patients (6.1%) required revision surgery because of tumor growth or the
development of symptoms. Neither auditory nor vestibular testing was a reliable
measure for determining tumor growth. CONCLUSION: Measurement of the maximal
tumor diameter on MRI scans is a reliable method for following acoustic neuroma
growth. There is no need to perform a rigorous analysis of tumor size to
determine whether the tumor is growing significantly. The vast majority of
patients older than 65 years with acoustic neuromas do not require intervention.
The indications for intervention should be based on a combination of rapid tumor
growth with the development of symptoms.
PMID- 10763993
TI - A transgenic insertional inner ear mutation on mouse chromosome 1.
AB - OBJECTIVES/HYPOTHESIS: To clone and characterize the integration site of an
insertional inner ear mutation, produced in one of fourteen transgenic mouse
lines. The insertion of the transgene led to a mutation in a gene(s) necessary
for normal development of the vestibular labyrinth. STUDY DESIGN: Molecular
genetic analysis of a transgene integration site. METHODS: Molecular cloning,
Southern and northern blotting, DNA sequencing and genetic database searching
were the methods employed. RESULTS: The integration of the transgene resulted in
a dominantly inherited waltzing phenotype and in degeneration of the pars
superior. During development, inner ear fluid homeostasis was disrupted. The
integration consisted of the insertion of a single copy of the transgene.
Flanking DNA was cloned, and mapping indicated that the genomic DNA on either
side of the transgene was not contiguous in the wild-type mouse. Localization of
unique markers from the two flanks indicated that both were in the proximal
region of mouse chromosome 1. However, in the wild-type mouse the markers were
separated by 6.3 cM, indicating a sizable rearrangement. Analysis of the mutant
DNA indicated that the entire region between the markers was neither deleted nor
simply inverted. CONCLUSIONS: These results are consistent with a complex
rearrangement, including at least four breakpoints and spanning at least 6.3 cM,
resulting from the integration of the transgene. This genomic rearrangement
disrupted the function of one or more genes critical to the maintenance of fluid
homeostasis during development and the normal morphogenesis of the pars superior.
PMID- 10763995
TI - Ototoxicity of common topical antimycotic preparations.
AB - OBJECTIVE: To determine the ototoxic effects of five commonly used topical
antimycotic agents-clotrimazole, miconazole, nystatin, tolnaftate, and gentian
violet-in the guinea pig. DESIGN: A controlled animal study in which the
ototoxicity of commonly used topical antifungal agents was investigated by
measurement of hair cell loss. METHODS: Several readily available topical
antimycotic preparations were instilled into the middle ears of female Hartley
guinea pigs over a 1-week period. Two weeks after the last instillation, the
animals were euthanized. An active control group was treated with neomycin to
confirm the adequacy of the treatment in delivering a known ototoxin; an
untreated control group defined the normal distribution of hair cells. The
temporal bones were removed, and the cochleas were fixed and dissected. The
basilar membranes were examined under the scanning electron microscope. A map of
hair cell survival was made for each row in segments of each turn. RESULTS: The
untreated control animals had no discernible hair cell loss in the two lower
turns. In the apical turn and sometimes the third turn, loss of hair cells was a
common finding, this is a known effect of aging in this species. The animals
treated with neomycin had damage consistently in the basal turn, sometimes
extending into the second turn, as well as the expected hair cell loss in the
apical turn. Clotrimazole, miconazole, or tolnaftate did not cause any hair cell
loss in the first two turns. Hair cell loss in the third and fourth turns was
similar to that of the untreated control group. Likewise, nystatin exhibited no
evidence of ototoxicity. Of note, however, the preparation used in this study
left a persistent residue in the round window niche. Of the first four animals
treated with gentian violet, three developed pronounced behavioral signs of
vestibular damage, and three demonstrated extensive middle ear inflammation and
extensive new bone growth. Hair cell counts were not attempted because the
extreme bone growth interfered with successful perfusion and dissection.
CONCLUSIONS: Extrapolating from guinea pigs to humans requires caution. However,
it is likely that guinea pigs are, if anything, more susceptible to topical
ototoxins than are humans. The specific antimycotics clotrimazole, miconazole,
and tolnaftate appear to be safe. Gentian violet has the potential for severe
damage. The persistent residue left by the nystatin preparation is cause for
concern and is a reminder that both the active ingredient and vehicle must be
considered in evaluation of safety.
PMID- 10763996
TI - Manual rotational testing of the vestibulo-ocular reflex.
AB - OBJECTIVES/HYPOTHESIS: Manual whole-body and head-on-body rotational testing of
the vestibuloocular reflex (VOR) is comparable to conventional rotary chair
methods with and without visual fixation from 0.025 to 1 Hz. STUDY DESIGN:
Summary of four previously published trials from our laboratory and a fifth
prospective blinded study comparing whole-body and head-on-body rotation with
rotational chair results from 0.025 to 1 Hz in 10 patients with bilateral
vestibular dysfunction. METHODS: Subjects were fitted with standard electro
oculogram (EOG) electrodes and placed in the rotary chair for testing at 0.025,
0.05, 0.1, 0.25, 0.5, and 1 Hz in the dark (VOR) and in the light with a
stationary target (VVOR). They were then placed in an otolaryngology examination,
chair where an adjustable headband containing the velocity sensor and an opaque
visor were placed on the forehead. Whole-body rotational trials from 0.025 to 1
Hz and both passive and active head-on-body trials from 0.25 to 1 Hz were
performed with and without visual fixation. Data from each frequency were
analyzed cycle-by-cycle and averaged for gain, phase, and asymmetry. These values
were then compared to the results obtained during rotational chair testing.
RESULTS: Throughout the five studies, no systematic differences were noted
between the manual rotational methods and the rotary chair results. Specifically,
no consistent effect of volition or cervico-ocular reflex (COR) enhancement was
demonstrated. CONCLUSIONS: Manual rotational testing is a reliable technique for
measuring the VOR up to 1 Hz as compared with standard rotary chair methods.
Advantages to this technique include portability, lower equipment costs, and
potential application up to 6 Hz using head-on-body rotation.
PMID- 10763997
TI - Hearing results in pediatric patients with chronic otitis media after ossicular
reconstruction with partial ossicular replacement prostheses and total ossicular
replacement prostheses.
AB - OBJECTIVE: To examine hearing results in pediatric patients after ossicular
reconstruction with partial ossicular replacement prostheses (PORPs) and total
ossicular replacement prostheses (TORPs) in children with chronic otitis media.
METHODS: A retrospective chart review was performed on 55 pediatric patients with
chronic otitis media who underwent ossicular reconstruction from 1991 to 1998.
Patients' audiograms were evaluated preoperatively and postoperatively for pure
tone average (PTA), air-bone gap (ABG), speech reception threshold (SRT), method
of ossicular reconstruction, and management of the mastoid. RESULTS: Twenty-seven
patients underwent ossicular reconstruction with TORPs. The average preoperative
ABG was 40.1 dB, and the average postoperative ABG was 31.6 dB. Forty-one percent
of the children improved their PTA greater than 10 dB postoperatively, and 52% of
children did not change their ABG by more than 10 dB postoperatively. Nineteen
percent of children with TORPs had a postoperative ABG less than 20 dB, and 44%
of children with TORPs had a postoperative ABG less than 30 dB. Twenty-eight
patients underwent ossicular reconstruction with PORPs. The average preoperative
ABG was 29.7 dB, and the average postoperative ABG was 22.5 dB. Thirty-two
percent of patients improved their PTA by greater than 10 dB, while 57% of
children with PORPs did not change their ABG by more than 10 dB postoperatively.
Forty-three percent of children with PORPs had an ABG of less than 20 dB
postoperatively, and 71% of children with PORPs had a postoperative ABG less than
or equal to 30 dB. CONCLUSIONS: Children who underwent ossicular reconstruction
with PORPs had slightly better postoperative hearing than did children with
TORPs. Postoperative hearing was essentially unchanged in approximately 55% of
both groups. Preoperative hearing levels may be the most important factor
determining postoperative hearing in nonstaged surgery for children with chronic
otitis media Long-term hearing results in children with single-stage surgery were
not as good as those reported in the literature for staged surgery. Severe
mucosal disease and eustachian tube dysfunction may contribute to poorer hearing
results in children.
PMID- 10763998
TI - Transferrin microheterogeneity in human perilymph.
AB - OBJECTIVES/HYPOTHESIS: Assay for beta2-(asialo-) transferrin has been advocated
for use in diagnosis of cerebrospinal fluid (CSF) leak or perilymphatic fistula
based on the fact that it is present in these fluids but not in serum.
Quantitation of the sensitivity of transferrin assays has not been reported
previously. The present study was undertaken to quantify the sensitivity of a
microelectrophoretic assay of beta2-transferrin and assess its potential
applicability to clinical diagnosis of perilymphatic fistula. STUDY DESIGN: The
initial part of the study was a prospective bench biochemistry assessment of
assay sensitivity and reliability. Subsequent application of the assay was a
blinded prospective clinical trial. METHODS: Transferrin is a ubiquitous
monomeric glycoprotein consisting of 679 amino acids, two iron-binding sites, and
two N-linked complex glycan chains. The N-glycan chains branch in variable
degree, carrying from zero to eight sialic acid residues. This variation in
sialylation has been termed "microheterogeneity." When both iron-binding sites
are saturated, the microheterogeneity of sialic acid content results in
isoelectric points ranging from pH 5 to pH 6. Thus these nine transferrin
variants can be distinguished by isoelectric focusing. Samples of transferrin
solution or body fluids (serum, CSF, and perilymph) were incubated in iron
loading buffer to saturate both iron-binding sites and then subjected to
isoelectric focusing (IEF). The separated proteins were immunoprecipitated in the
IEF gel and silver stained for visualization. Serial dilutions of pure
transferrin solution were used to determine assay sensitivity. Neuraminidase was
used to digest sialic acid side chains from pure transferrin in solution, and the
reaction product was used as a reference standard for comparison to assay of
unknown fluids. Patient inner ear fluid samples obtained during stapedectomy or
cochlear implantation were used to assess clinical applicability of the assay.
RESULTS: This microelectrophoretic technique, using only 0.3 microL of iron
loaded sample, was able to consistently detect less than 250 pg of transferrin in
solution and separate the different sialylation variants based on their
isoelectric points. Assay of patient serum samples clearly demonstrated
transferrin microheterogeneity. Assay of CSF consistently showed the predicted
beta2-(asialo-) transferrin band. Assay of inner ear fluid samples also
demonstrated transferrin microheterogeneity. However, no inner ear fluid samples
had detectable levels of beta2-transferrin. Presumably, perilymph sample dilution
during iron loading and by admixture with serum, local anesthetic, or middle ear
secretions lowered the beta2-transferrin concentration below the detection limen
of the assay. CONCLUSIONS: Microelectrophoretic assay of iron-loaded transferrin
can detect as little as 250 pg of protein and can identify microheterogeneity in
serum, CSF, and perilymph. However, dilutional effects of sample handling and
preparation can lower the beta2-transferrin concentration of inner ear fluid
samples below the detection limen of the assay. Thus, depending on the relative
amounts of serum and perilymph (or CSF) in a mixed sample, electrophoretic
separation of transferrin variants may not be diagnostic.
PMID- 10763999
TI - An objective method of analyzing cochlear versus noncochlear patterns of
distortion-product otoacoustic emissions in patients with acoustic neuromas.
AB - OBJECTIVES: To objectify the effects of retrocochlear disease on distortion
product otoacoustic emissions (DPOAEs) by developing a computer-based software
strategy for classifying DPOAE patterns as cochlear or noncochlear and to
evaluate the sensitivities of these techniques in a large series of patients with
unilateral acoustic neuromas. STUDY DESIGN: Development of a novel, software
based method of DPOAE analysis, which was evaluated with data obtained from a
retrospective review of the results from audiometric tests performed in a series
of patients. METHODS: A computer-based software strategy was developed, using
frequency-specific data from normal-hearing adults, for the purpose of
distinguishing cochlear from noncochlear patterns of hearing loss, by determining
the discrepancies between DPOAEs and behavioral audiometry. Preoperative pure
tone thresholds and DPOAEs from 97 patients with surgically confirmed acoustic
neuroma were compared using an objective method and a standard, subjective
technique that was considered to be the gold standard. The effects of bilateral
hearing losses, such as noise-induced hearing loss and presbycusis, were
accounted for during the analysis to isolate the effects of the tumors on hearing
thresholds and DPOAEs. RESULTS: Overall, 55 (57%) of the tumor ears were assigned
to the cochlear group (i.e., DPOAEs consistent with hearing thresholds), 40 (41%)
to the noncochlear group (i.e., DPOAEs inconsistent with hearing thresholds), and
2 (2%) to an indeterminate group, using the subjective technique for classifying
DPOAEs. There was no significant difference in the categorization of the patients
with acoustic neuroma when employing the objective strategy. The objective
algorithm, when modified to maximize the number of noncochlear identifications,
led to assignments of 36 (37%) to the cochlear, 57 (59%) to the noncochlear, and
4 (4%) to the indeterminate categories. CONCLUSIONS: Subjective analysis of a
large series patients with acoustic neuromas showed that the majority of ears
with tumors demonstrated cochlear (57%), rather than non-cochlear (41%), patterns
of DPOAEs. The computerized, software-based algorithm developed for
differentiating cochlear from noncochlear patterns of DPOAEs in patients with
retrocochlear disease had a maximum sensitivity of 59%. This value was
significantly higher than that reported in previous studies.
PMID- 10764000
TI - Prospective, randomized outcome study of endoscopy versus modified barium swallow
in patients with dysphagia.
AB - OBJECTIVE: Aspiration pneumonia is a significant cause of morbidity and mortality
in both acute and long-term care settings While there are many reasons for
patients to develop aspiration pneumonia, there exists a strong association
between difficulty swallowing, or dysphagia, and the development of aspiration
pneumonia The modified barium swallow test (MBS) and endoscopic evaluations of
swallowing are considered to be the most comprehensive tests used to evaluate and
manage patients with dysphagia in an effort to reduce the incidence of pneumonia.
The purpose of this study was to provide an initial investigation of whether
flexible endoscopic evaluation of swallowing with sensory testing (FEESST) or MBS
is superior as the diagnostic test for evaluating and guiding the behavioral and
dietary management of outpatients with dysphagia. FEESST combines the standard
endoscopic evaluation of swallowing with a technique that determines
laryngopharyngeal sensory discrimination thresholds by endoscopically delivering
air pulse stimuli to the mucosa innervated by the superior laryngeal nerve. STUDY
DESIGN: Randomized, prospective cohort outcome study in a hospital-based
outpatient setting. METHODS: One hundred twenty-six outpatients with dysphagia
were randomly assigned to either FEESST or MBS as the diagnostic test used to
guide dietary and behavioral management (postural changes, small bites and sips,
throat clearing). The outcome variables were pneumonia incidence and pneumonia
free interval. The patients were enrolled for 1 year and followed for 1 year.
RESULTS: Seventy-eight MBS examinations were performed in 76 patients with 14
patients (18.41%) developing pneumonia; 61 FEESST examinations were performed in
50 patients with 6 patients (12.0%) developing pneumonia These differences were
not statistically significant (chi2 = 0.93, P = .33). In the MBS group the median
pneumonia-free interval was 47 days; in the FEESST group the median pneumonia
free interval was 39 days Based on Wilcoxon's signed-rank test, this difference
was not statistically significant (z = 0.04, P = .96). CONCLUSION: Whether
dysphagic outpatients have their dietary and behavioral management guided by the
results of MBS or of FEESST, their outcomes with respect to pneumonia incidence
and pneumonia-free interval are essentially the same.
PMID- 10764001
TI - Effects of thermal conducting media on the skin surface during laser irradiation.
AB - OBJECTIVES: To investigate the effects of thermally conductive, optically
transparent media placed on skin during treatment with the flashlamp excited dye
laser (FEDL). The use of higher energy densities to treat persistent cutaneous
vascular lesions may result in a decrease in the number of treatment sessions.
However, increased fluences can cause complications of scarring,
hyperpigmentation, infection, skin texture changes, or hypopigmentation. The
thermally conductive media should assist in dissipating surface thermal energy
and thereby protect the skin from the complications. STUDY DESIGN: This was a
prospective laboratory study using an animal model. The results were verified in
a prospective, pilot, human-use trial. METHODS: The threshold for acute skin
damage and measurements of the thermal transients were made using a rabbit model.
The threshold for purpura was noted with and without the use of a sapphire as a
thermal conductor. The thermal transients were measured with small thermocouples
placed subcutaneously. On a human subject, purpura intensities were photographed
and measured using computer morphometrics after treatment with the FEDL and skin
surface protection with air, glass, sapphire, and diamond as conductive media.
RESULTS: With the interposition of the sapphire thermal conductor during the FEDL
treatment, excessive temperature increases of the epidermis were prevented during
the laser pulse compared with glass and controls. Both sapphire and diamond
resulted in decreased purpuric intensities with the applications of equivalent
fluences. Wound recovery time for the purpura was decreased by approximately half
a day when any of the surface conductors were used. CONCLUSIONS: The decreased
transient temperature and decrease in purpura seen with the use of sapphire and
diamond protecting the epidermis during treatment with the FEDL should result in
fewer untoward effects during treatment of vascular lesions and facilitate their
management.
PMID- 10764002
TI - Down syndrome: analysis of airway size and a guide for appropriate intubation.
AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to prospectively evaluate the
airway size of children with Down syndrome (DS). Previous studies have observed
an increase in postintubation stridor in children with DS. Anesthetic literature
suggests using a smaller endotracheal tube in children with DS, but more specific
recommendations are not offered. With this study, recommendations are presented
for the appropriate endotracheal tube size to use in children with DS undergoing
intubation. STUDY DESIGN: A prospective, nonrandomized study was performed on a
cohort of 42 children with DS and 32 control subjects. Sizing of the airway was
assessed through measurement of an air leak around the endotracheal tube at
intubation. The size of the airway was also evaluated through measurements of the
tracheal diameter at the "tracheotomy point" on magnetic resonance imagine (MRI)
studies of the head and neck which were performed on a group of children with DS.
These were compared with normative values of the tracheal diameter in children.
METHODS: The proper size of endotracheal tube in a population of children with DS
and in a group of normal controls was determined. The "proper size" of an
endotracheal tube was defined as that size of tube which allowed an audible air
leak around the tube between 10 and 30 cm of H2O pressure. Anesthetic technique
was controlled and identical for all study subjects. Participants had no previous
history of airway compromise, stridor, or previous intubation. Weight and age
were recorded and evaluated for their influence on the results. A retrospective
evaluation was made of MRI studies of the neck that were performed on children
with DS. Using measurement techniques described by Reed et al., the tracheal
diameters at the "tracheostomy point" were compared with normative values for
children. Measurements were both obtained by the author and confirmed by a
pediatric radiologist. RESULTS: Using this prescribed method to determine the
proper size of endotracheal tube, the control group used endotracheal tubes that
were predicted from established anesthesia charts and formulas. However, children
with DS required endotracheal tubes at least two sizes smaller. Age was found to
be a more reliable factor in predicting the endotracheal tube size. A table of
endotracheal tube sizes for intubation in children with DS is presented.
Evaluation of the tracheal diameter at the tracheotomy point revealed that
children with DS have a smaller trachea when compared with control children. It
is not only the subglottis that is smaller; the tracheal diameter as well must be
assumed to be of a smaller diameter in children with DS. CONCLUSIONS: Children
with DS have smaller airways than other children. This is because of an overall
decrease in the diameter of the tracheal lumens. Initial intubation of a child
with DS should be performed with an endotracheal tube at least two sizes smaller
than would be used in a child of the same age without DS, to avert potential
trauma to the airway.
PMID- 10764003
TI - Importance of comorbidity in head and neck cancer.
AB - OBJECTIVES/HYPOTHESIS: Patients with head and neck cancer are staged according to
the morphology of the tumor with little or no attention given to the importance
of the other diseases, illnesses, or conditions. These other conditions are
generally referred to as comorbidities. Although not a feature of the cancer
itself, comorbidity is an important attribute of the patient with cancer.
Comorbidity has direct impact on the care of patients, selection of initial
treatment, and evaluation of treatment effectiveness. The objective of this
thesis is to demonstrate the importance of comorbidity in head and neck cancer.
Specifically, the aims are 1) to demonstrate the burden of comorbidity among head
and neck cancer patients by comparing the incidence of none, mild, moderate, and
severe comorbidity among patients with head and neck cancer to patients with
cancers of the colorectum, lung, breast, gynecological sites, or prostate, 2) to
demonstrate the independent impact of comorbidity on overall survival, and 3) to
demonstrate the importance of comorbidity in the assessment of initial treatment
effectiveness. STUDY DESIGN: This was a prospective cohort study of the impact of
comorbidity on head and neck cancer patients presenting for treatment between
January 1995 and December 1996. METHODS: In 1994, the author trained cancer
registrars at an academic teaching hospital to code comorbidity from the medical
record of new patients using a standard comorbidity index. Standard statistical
techniques, including multivariable analysis, were used to compare and contrast
the burden of comorbidity for patients with different cancers. Life survival
techniques and multivariable logistic regression analysis were used to assess the
independent prognostic impact of comorbidity. Further, the technique of
conjunctive consolidation was used to augment the TNM system with comorbidity
information, to more completely assess the impact of different initial treatments
for patients with head and neck cancers. RESULTS: The cohort consisted of 3,378
patients with cancers of the head and neck (341), colorectum (307), lung (655),
breast (483), gynecological sites (482), and prostate (1,110). The percentage of
head and neck cancer patients with moderate to severe comorbidity was 21%; this
degree of comorbidity burden was second only to patients with lung (40%) and
colorectal (25%) cancer. There was a significant relationship between severity of
comorbidity and overall survival (log-rank test, chi2 = 15.75; P < .0013). For
cancers of the head and neck, lung, breast, and prostate the prognostic
significance of comorbidity remained even after controlling for other factors,
such as age and TNM stage. CONCLUSIONS: The results of this study show that
comorbidity is an important feature of patients with head and neck cancer. Valid
instruments exist to measure and classify the overall severity of comorbidity.
The scientific evaluation of treatment and the care of patients are impeded by a
rigid adherence to a staging system based solely on morphological descriptions of
the cancer while ignoring suitable descriptions of the patient. The author
believes that the addition of comorbidity information will improve the value of
cancer statistics and the care of cancer patients.
PMID- 10764004
TI - Calciphylaxis: is there a role for parathyroidectomy?
AB - OBJECTIVE: Calciphylaxis, a rare disorder typically affecting renal failure
patients, results in vascular calcification with subsequent skin necrosis,
gangrene, and often death from sepsis. Parathyroid hormone is thought to act as a
tissue sensitizer leading to these soft tissue changes. As such,
parathyroidectomy is often advocated to control this complicated condition. A
discussion of calciphylaxis does not exist in the otolaryngology literature, and
head and neck surgeons performing parathyroidectomy should be aware of this
phenomenon. This study evaluates the success of parathyroidectomy in reversing
the ill effects of calciphylaxis in both our patient population and the
literature. STUDY DESIGN: Retrospective study and review of the literature.
METHODS: Five patients with calciphylaxis treated at our institution were
evaluated for mortality, surgical and perioperative complications, wound healing,
and predictors of patient outcomes. RESULTS: Two patients died from sepsis and
infectious complications of their calciphylaxis shortly after surgery. Of the
three survivors, two later died (15 and 18 mo after surgery) from causes not
directly related to calciphylaxis. The other long-term survivor required partial
amputation of a leg for osteomyelitis. There was one operative complication--
wound infection requiring antibiotic therapy, drainage, and packing.
Postoperative hypocalcemia required treatment in two patients. Immediate
perioperative survival was more likely in patients with leukocyte counts less
than 20,000 cells/mL. CONCLUSIONS: Calciphylaxis is a serious disease and
patients often succumb to sepsis and infectious complications. Patients with
extremely high leukocyte counts from coexistent infections may have a worse
prognosis. Although a conclusive effective therapy does not exist,
parathyroidectomy can be safely performed and may benefit some patients with what
is often an otherwise fatal disease. The literature to date generally confirms
our findings. Key Words: Calciphylaxis, parathyroid hormone, parathyroidectomy,
skin necrosis, chronic renal failure.
PMID- 10764005
TI - Patterns of maxillofacial injuries as a function of automobile restraint use.
AB - OBJECTIVE: To determine the pattern and severity of maxillofacial injuries
sustained in a motor vehicle accident (MVA) resulting from automobile restraint
use. DESIGN: Retrospective database review of patients injured in a MVA who were
admitted to the level I trauma center at the University of Louisville Hospital in
Louisville, Kentucky. METHODS: Demographic data, drug and alcohol impairment
screening, and comorbidity data were obtained from database searches of trauma
records. Forty-four patients had an airbag deployed, 34 patients wore seat belts,
and 94 patients were unrestrained. All maxillofacial Abbreviated Injury Scale
(AIS) ratings were compared among the three groups. RESULTS: Twenty-two of the 44
patients (50%) in the airbag group sustained only facial injuries. Fifteen of
them had lacerations; four others had only facial abrasions. Three of the airbag
patients had moderate facial injuries (AIS = 2); none required operative
management. The airbag group had a mean AIS rating of 1.13, the seat belt group a
mean AIS of 1.29, and the unrestrained group a mean AIS of 1.46. Patients using
either seat belts (mean age, 40.5 y) or airbags (mean age, 44.9 y) were older
than the unrestrained group (mean age, 39.6 y). Drug and/or alcohol impairment
was significantly greater in the unrestrained group (mean, 38%) compared with the
seat belt group (mean, 26%) and the airbag group (mean 11%.). CONCLUSIONS: Use of
airbags is associated with less severe maxillofacial injuries compared with
either a seat belt alone or no restraint. There is an inherent risk of minor
maxillofacial injuries with airbag usage, but the severity of injury is
distinctly reduced.
PMID- 10764006
TI - The uvulopalatal flap for reconstruction of the soft palate.
AB - OBJECTIVE: To determine the indications, complications, and outcomes of the
uvulopalatal flap in the reconstruction of defects of the soft palate. STUDY
DESIGN: Retrospective review. METHODS: Patient data were obtained from the
hospital records of 18 patients who had soft palate defects reconstructed with
the uvulopalatal flap over a 5-year period at a tertiary academic medical center.
RESULTS: Eleven patients had the uvulopalatal flap as the sole method of
reconstruction, whereas this flap was used in combination with a radial forearm
free flap, pectoralis flap, and skin graft in 4, 2, and 1 patients, respectively.
All flaps were successful in soft palate reconstruction. One flap was
successfully revised after additional tumor resection. A partial flap dehiscence
occurred in one patient and healed uneventfully. Speech and swallowing function
was dependent on initial tumor stage and the scope of tumor resection.
CONCLUSIONS: The uvulopalatal flap is a simple and effective method of soft
palate reconstruction either alone or in combination with other methods of
reconstruction for selected oropharyngeal defects.
PMID- 10764007
TI - Increased expression of transforming growth factor-beta1, acidic fibroblast
growth factor, and basic fibroblast growth factor in fetal versus adult
fibroblast cell lines.
AB - OBJECTIVES: Fetal wound healing occurs without scar tissue formation. Differences
in growth factor expression between fetal and adult fibroblasts have been
explored. Recently we used RNA expression studies to demonstrate that
transforming growth factor (TGF)-beta1, acidic fibroblast growth factor (alpha
FGF), and basic fibroblast growth factor (beta-FGF) could be detected in both
fetal and adult fibroblast cell lines. In addition, adult fibroblasts showed
greater relative expression of these growth factors than fetal fibroblasts. The
aim of this study was to identify the level of protein expression in fetal and
adult fibroblasts. STUDY DESIGN/METHODS: Fetal and adult fibroblasts were grown
in culture using standard and serum-free media. After protein extraction, Western
blot studies were performed to detect the presence and amount of TGFbeta-1, alpha
FGF, and beta-FGF growth factor proteins. beta-Tubulin was used as a control.
RESULTS: TGFbeta-1, alpha-FGF, and beta-FGF proteins were detected in fetal and
adult fibroblasts grown in standard and serum-free media. The fetal fibroblasts
showed higher levels of all three growth factor proteins compared with the adult
fibroblasts. CONCLUSIONS: Western blot studies suggest higher levels of TGFbeta
1, alpha-FGF, and beta-FGF expression in fetal fibroblasts. It is clear that
significant differences exist in the expression/production of these growth
factors and it seems likely that further study of these differences will help
elucidate the unique healing capabilities of fetal fibroblasts.
PMID- 10764008
TI - Pain, quality of life, and spinal accessory nerve status after neck dissection.
AB - OBJECTIVE: To assess quality of life (QOL) in patients with head and neck cancer
who underwent neck dissection and to compare QOL scores for patients in whom the
spinal accessory nerve (CN XI) was resected or preserved. SETTING AND DESIGN AND
OUTCOMES MEASURES: Three hundred ninety-seven patients who had undergone
treatment for head and neck cancer completed the University of Michigan Head and
Neck Quality of Life (HNQOL) instrument, the Medical Outcomes Study SF-12 General
Health Survey, and questions on "pain despite pain medications" and headaches.
RESULTS: Of the 397 patients, 222 had no neck dissection, 46 had neck dissections
resecting CN XI, and 129 had dissection sparing CN XI. Of the latter group, 68
patients had dissections sparing level V and 61 dissections included level V.
Age, sex, primary site distribution, and T stage were not different between the
groups. Patients who had neck dissections sparing CN XI had better scores on the
HNQOL pain domain (P = .002), had less shoulder or neck pain (P = .003), and took
pain medications less frequently (P = .0004) compared with patients who had neck
dissections sacrificing CN XI. When CN XI was preserved, patients who had no
level V dissection had better pain domain scores (P = .03) and eating domain
scores (P = .007) on the HNQOL, had less shoulder or neck pain (P = .006), and
had less physical problems (P = .03) than patients who had level V dissected. On
multivariate analysis, pain-related QOL scores after neck dissection were
significantly better (P < .01) if patients had dissections with preservation of
CN XI and if level V was not dissected. CONCLUSION: Neck dissections sparing CN
XI are associated with better pain scores on the HNQOL, less shoulder and neck
pain, and less need for medications. When CN XI is spared, not dissecting level V
of the neck is associated with better HNQOL pain scores, less shoulder or neck
pain, and fewer physical problems.
PMID- 10764009
TI - Supracricoid partial laryngectomy with cricohyoidoepiglottopexy and
cricohyoidopexy for glottic and supraglottic carcinomas.
AB - OBJECTIVES: To review the patients operated in our department with supracricoid
partial laryngectomy with either cricohyoidoepiglottopexy (CHEP) (59 cases) or
cricohyoidopexy (CHP) (10 cases) technique, for primary or recurrent
glottosupraglottic squamous cell carcinoma and compare the technique with other
surgical or conservative approaches for treatment of laryngeal carcinoma.
METHODS: From hospital charts, we retrospectively reviewed 69 patients who had
undergone supracricoid partial laryngectomy with the CHEP or CHP technique
between 1983 and 1996 for primary or recurrent glottosupraglottic squamous cell
carcinoma in our department. Statistical evaluation of oncological and functional
results were conducted. Results were compared with other surgical and
conservative treatment for glottosupraglottic carcinoma of the larynx that were
published previously in the literature. RESULTS: Sixty-nine patients had CHEP or
CHP for glottosupraglottic carcinoma of the larynx. Thirteen percent of the
patients received adjuvant radiotherapy. Minimum follow-up was 2 years or until
death. Five-year actuarial survival (Kaplan-Meier method) was 68%. Global local
control was achieved in 84% of cases. Among previously untreated patients (n =
54), local control rate was 94.5%. After 1 year, 92.7% of patients achieved
normal swallowing and respiration. Salvage total laryngectomy had to be performed
in four patients (5.7%) for persistent aspiration and in five patients (7.2%),
who were previously treated with radiotherapy, for local recurrence. No permanent
tracheostomy or gastrostomy was required. CONCLUSIONS: Our experience with
supracricoid partial laryngectomy with either CHP or CHEP suggests that this
technique is a valuable alternative to radiotherapy for T2-T4 glottosupraglottic
carcinomas, particularly those with extension and invasion of the anterior
commissure. It allows for preservation of a good laryngeal function without
altering the long-term survival, keeping total laryngectomy as a salvage
procedure.
PMID- 10764010
TI - The minimally invasive approach to olfactory neuroblastoma: combined endoscopic
and stereotactic treatment.
AB - OBJECTIVES: To describe a new treatment modality of olfactory neuroblastoma
consisting of endoscopic nasal and paranasal sinus surgery and stereotactic
radiosurgery. STUDY DESIGN: Retrospective review of three patients suffering from
olfactory neuroblastoma. METHODS: Review of the charts, the computed tomography,
and magnetic resonance imaging scans, the operation reports, radiosurgical data,
and follow-up. RESULTS: All three patients remained free of disease with
excellent quality of life in respective follow-up periods of 71, 50, and 39
months. CONCLUSION: The combination of two minimally invasive therapies,
endoscopic sinus surgery and stereotactic radiosurgery, provide a reliable new
approach to the treatment of a series of olfactory neuroblastomas that offers
excellent quality of life, less injury to the patient, fewer side-effects, and
fewer long-term effects than other treatment strategies.
PMID- 10764011
TI - Investigation of the causal relationship between tracheotomy and aspiration in
the acute care setting.
AB - OBJECTIVE: To investigate the causal relationship, if any, between tracheotomy
and incidence of aspiration in the acute care setting. STUDY DESIGN: Prospective,
consecutive. PATIENTS AND METHODS: Twenty adult patients evaluated between
February 1997 and October 1999 participated. Criteria for inclusion were a
dysphagia evaluation before tracheotomy, subsequent tracheotomy and placement of
a tracheotomy tube, and then a repeat dysphagia evaluation after tracheotomy
prior to decannulation. This permitted the causal relationship between
tracheotomy and incidence of aspiration to be investigated. Differences between
duration of tracheotomy placement and age were analyzed with the Student t test
and for non-parametric nominal data the chi2 test was applied. RESULTS: No causal
relationship between tracheotomy and aspiration was exhibited, as 19 of 20 (95%)
subjects exhibited the same aspiration status before and after tracheotomy. All
12 (100%) subjects who aspirated before tracheotomy also aspirated after
tracheotomy and 7 of 8 (88%) subjects who did not aspirate before tracheotomy
also did not aspirate after tracheotomy (P > .05). In addition, no significant
differences were observed between aspiration status and days since tracheotomy or
age (P > .05). CONCLUSION: In the acute care setting, no causal relationship
between tracheotomy and aspiration status was exhibited.
PMID- 10764012
TI - Effect of high laryngeal mask airway intracuff pressure on the laryngopharyngeal
mucosa of dogs.
AB - OBJECTIVES: To evaluate the effect of increased of laryngeal mask airway (LMA)
intracuff pressures on the laryngopharyngeal mucosa. STUDY DESIGN: Animal model.
METHODS: Sixteen mixed-breed dogs were randomly allocated to two groups, G1
(intracuff volume, 30 mL; n = 8) and G2 (intracuff volume, 54 mL; n = 8), to
produce, respectively, high or very high intracuff pressures. Anesthesia was
induced and maintained with pentobarbital. Intracuff pressures were measured
immediately after insertion and inflation of a No. 4 laryngeal mask airway (LMA)
and 30, 60, 90, and 120 minutes thereafter. The dogs were euthanized, and biopsy
specimens from eight predetermined areas of the laryngopharynx in contact with
LMA cuff were collected for light microscopic (LM) and scanning electron
microscopic (SEM) examination. RESULTS: Initial LMA cuff inflation in G1 and G2
resulted in intracuff pressures of 119 mm Hg +/- 4 mm Hg and 235 mm Hg +/- 13 mm
Hg, respectively. Over a 2-hour period, the intracuff pressure decreased
significantly in G1 (P < .001) and G2 (P < .01), and there was a significant
difference between the groups over time (P < .001). The LM study of
laryngopharyngeal mucosa in both groups showed mild congestion in the
subepithelial layer. There were no differences between the groups (P > .10) or
among the areas sampled (P > .10). In some areas of G2, the SEM study showed
epithelial desquamation that was more intense than that in G1. CONCLUSIONS: The
increase in LMA intracuff pressure caused only mild alterations in the
laryngopharyngeal mucosa of the dog.
PMID- 10764013
TI - Temperature profile in the nasal cavity.
AB - OBJECTIVES/HYPOTHESIS: Inspired air is heated and moistened as it passes the
nasal cavity. The temperature increase should be similar to a heated tube model,
depending on the airflow. STUDY DESIGN: Intranasal temperature values of 50
volunteers were measured after inspiration at different locations: nasal
vestibule, nasal valve area, anterior to the head of the middle turbinate, and
the nasopharynx. Temperature values were related to nasal airway resistance data.
METHODS: Intranasal temperature measurements were made with a miniaturized
thermocouple. Nasal airway resistance was detected by active anterior
rhinomanometry. RESULTS: A logarithmic increase of air temperature from the
anterior segment of the nose to the posterior part was noted. In the nasopharynx
temperature was approximately 34 degrees C. The highest increase in temperature
was observed in the nasal valve area. CONCLUSIONS: The temperature increase of
ambient air in the nasal airways can be compared with a logarithmic curve of the
heating of air passing a heated tube. As the heating of air is important for
water transport, the space between the nasal valve and the middle turbinate is of
special functional importance. No correlation to the results of rhinomanometry
was found.
PMID- 10764014
TI - Intractable benign paroxysmal positional vertigo in patients with Meniere's
disease.
AB - OBJECTIVE: To provide a detailed description of the coexistence of benign
paroxysmal positional vertigo (BPPV) and Meniere's disease in individuals and to
offer a possible mechanism that explains the findings in these patients. STUDY
DESIGN: Retrospective. METHODS: Chart review. RESULTS: Of 162 patients diagnosed
with Meniere's disease between January 1998 and January 1999, 9 were found to
have both "definite" Meniere's disease and "certain" BPPV. Meniere's symptoms
preceded the onset of BPPV in all of our patients. Seven of the 9 patients were
female. Except for one patient who experienced BPPV bilaterally, BPPV was limited
to the same ear as the Meniere's disease. All patients presented with intractable
BPPV that did not respond completely to otolith repositioning procedures. A
detailed description of five patients is presented. CONCLUSION: Our data, in
conjunction with that of others, suggest that Meniere's disease may predispose
patients to intractable BPPV. Hydropically induced damage to the maculae of the
utricle and saccule or partial obstruction of the membranous labyrinth may be
possible mechanisms that explain the coexistence of Meniere's disease and BPPV.
PMID- 10764015
TI - Rabbit facial nerve regeneration in autologous nerve grafts after antecedent
injury.
AB - OBJECTIVE: The effect of incomplete antecedent injuries on subsequent facial
nerve regeneration within cable graft repairs is not known. The purpose of this
study is to compare facial nerve regeneration after an immediate and delayed
neural cable graft repair. METHOD: Rabbit facial nerve regeneration after
complete transectional injuries of the buccal division was compared in two
experimental models. In one, a 10-mm segment of the nerve was transected, rotated
180 degrees, and immediately repaired as a cable graft (N=8). In the second, a
preliminary nerve crush was allowed to recover over a 4-week period and a 10-mm
segment of nerve centered on the crush site was then transected, rotated 180
degrees, and delay repaired as a cable graft (N = 7). Data are presented as total
numbers of regenerating myelinated axons that traverse the surgical repair to
innervate the cable graft and distal nerve stumps, as well as the percentage of
regenerating neurites compared with preoperative pooled and individual controls.
Subpopulations of regenerating neurons are delineated to quantify the pattern of
neural innervation. RESULTS: Five weeks after cable graft repair both groups had
similar myelinated outgrowth from the proximal nerve stump across the proximal
anastomosis to innervate the cable graft (3995 +/- 1209 vs. 3284 +/- 651; P =
.89). However, the delayed repair group had more intrafascicular regeneration
within cable grafts (2261 +/- 931 vs. 1660 +/- 1169; P = .02) and distal nerve
stump (1532 +/- 281 vs. 445 +/- 120; P = .004) than the immediate repair group.
The immediate repair group had greater extrafascicular nerve regeneration in the
cable graft (2335 +/- 1954 vs. 437 +/- 236; P = .001) and more myelin and axonal
debris in pre-existing neural fascicles of the cable graft (P = .02) and distal
nerve stump (463 +/- 187 vs. 103 +/- 87; P = .02). CONCLUSIONS: Antecedent
priming lesions do not enhance axonal survival as determined by regenerating
myelinated axonal counts. However, antecedent injuries enhance the efficiency of
neural innervation of the affected mimetic musculature by increasing the number
of myelinated intrafascicular neural regenerants in the cable graft and distal
nerve stump. This is accomplished by two factors: increased perineural fibrosis
and decreased intrafascicular myelin and axonal debris.
PMID- 10764016
TI - Identification of MUC5B mucin gene in human middle ear with chronic otitis media.
AB - OBJECTIVES: To identify the mucin gene and its expressing cells in the middle ear
mucosa with chronic otitis media (COM), and to study the correlation between
infiltration of inflammatory cells in the submucosa and expression of the mucin
gene in the mucosal epithelium with COM. STUDY DESIGN: Middle ear mucosal
specimens removed from the inferior promontory area of 19 patients undergoing
middle ear surgery for COM were studied. METHODS: Sections were stained with H&E,
Alcian blue-periodic acid Schiff (AB-PAS), polyclonal MUC5B antibody, and
specific MUC5B riboprobe for histological, histochemical, immunohistochemical,
and mucin mRNA analyses. RESULTS: H&E staining revealed pseudostratified
epithelia in 18 of the middle ear specimens with COM and cuboidal secretory
epithelia in one. AB-PAS staining of epithelia revealed abundant secretory cells
and their products (glycoconjugates). In situ hybridization and
immunohistochemistry studies demonstrated that the secretory cells of the middle
ear mucosa with COM expressed MUC5B mucin mRNA and its product MUC5B mucin.
CONCLUSIONS: The MUC5B mucin gene and its product were identified in the middle
ear secretory cells of patients with COM. Its expression was extensive in
pseudostratified mucosal epithelia and related to infiltration of inflammatory
cells in the submucosa of the middle ear cleft with COM, suggestive that
inflammatory cell products are involved in the production of MUC5B.
PMID- 10764017
TI - Anchored myringoplasty for total perforation with malleus adhesion to the
promontory.
PMID- 10764018
TI - Autologous transplantation of fascia into the vocal fold.
PMID- 10764019
TI - Intraoperative and postoperative assessment of frontal sinus patency by
transillumination.
PMID- 10764020
TI - Current limitations to nucleoside analogue therapy for chronic hepatitis B virus
infection in the liver transplant and non-transplant settings.
PMID- 10764021
TI - Gastro-oesophageal reflux disease in Asia.
AB - Gastro-oesophageal reflux disease (GORD) occurs more frequently in Europe and
North America than in Asia but its prevalence is now increasing in many Asian
countries. Many reasons have been given for the lower prevalence of GORD in Asia.
Low dietary fat and genetically determined factors, such as body mass index and
maximal acid output, may be important. Other dietary factors appear to be less
relevant. Increased intake of carbonated drinks or aggravating medicines may
influence the increasing rates of GORD in some Asian countries but no strong
evidence links other factors, such as the age of the population, smoking or
alcohol consumption, to GORD. The management of GORD in Asia is similar to that
in Europe and North America but the lower incidence of severe oesophagitis in
Asia may alter the approach slightly. Also, because Asians tend to develop
stomach cancer at an earlier age, endoscopy is used routinely at an earlier stage
of investigation. Gastro-oesophageal reflux disease is essentially a motility
disorder, so short-term management of the disease can usually be achieved using
prokinetic agents (or histamine (H2)-receptor antagonists). More severe and
recurrent GORD may require proton pump inhibitors (PPI) or a combination of
prokinetic agents and PPI. The choice of long-term treatment may be influenced by
the relative costs of prokinetic agents and PPI.
PMID- 10764022
TI - Extracorporeal shock wave lithotripsy of gallstones revisited: current status and
future promises.
AB - The improvement and refinement of extracorporeal shock wave lithotripsy (ESWL)
has made this non-invasive treatment modality not only more effective, but also
applicable to a larger population of gallstone patients. It can be performed
safely on an outpatient basis. Advances in lithotripsy technology have made it
possible to fragment stones into very small, sand-like particles (pulverization),
which clear the gall-bladder faster than large fragments. Recent studies provide
evidence that adjuvant bile acids may not be necessary in most cases in which
pulverization is achieved. Good gall-bladder emptying appears both to promote the
clearance of gallstones after ESWL and to decrease their recurrence. Although
generally found to be more expensive than surgery if bile acids are used, ESWL
should be cost-effective, as bile acids may not be necessary in all patients.
Elderly patients with radiolucent, solitary and less than 30 mm gallstones can
particularly benefit from lithotripsy.
PMID- 10764023
TI - Pathophysiology of the intrahepatic biliary epithelium.
AB - The intrahepatic bile duct epithelium modulates the fluidity and alkalinity of
the primary hepatocellular bile from which it reabsorbs fluids, amino acids,
glucose and bile acids, while secreting water, electrolytes and immunoglobulin A.
The transport function of the intrahepatic biliary epithelium is finely regulated
by a number of gastrointestinal hormones, neuropeptides and neurotransmitters
that promote either secretion or absorption. The intrahepatic biliary epithelium
appears to be a primary target in a broad group of chronic cholestatic disorders
that represent an important cause of morbidity and mortality. The spectrum of
cholangiopathies ranges from conditions in which a normal epithelium is damaged
by disordered autoimmunity, infectious agents, toxic compounds or ischaemia, to
genetically determined disorders arising from an abnormal bile duct biology, such
as cystic fibrosis or biliary atresia. Probably as a result of the known
heterogeneity in cholangiocyte function, different portions of the biliary tree
appear to be preferentially affected in specific cholangiopathies. From a
pathophysiological point of view, cholangiopathies are characterized by the
coexistence of cholangiocyte loss (by apoptotic or lytic cell death) with
cholangiocyte proliferation and various degrees of portal inflammation, fibrosis
and cholestasis. These basic disease mechanisms are discussed in detail. Better
understanding of cholangiocyte pathophysiology, in particular the immune
regulation of cholangiocyte function, will help in designing newer genetic or
pharmacological approaches to treat cholangiopathies.
PMID- 10764024
TI - Use of a dry latex agglutination test to measure eradication of Helicobacter
pylori infection.
AB - BACKGROUND AND METHODS: A total antibody latex serology test was compared with
enzyme immunoassay serology after treatment for Helicobacter pylori infection in
22 patients. RESULTS: Nineteen patients were cured of infection, but only nine
(47%) were negative by the latex test after 6 months. However a significant
decline in immunoglobulin (Ig)G was seen in 90% of the cured patients.
CONCLUSIONS: Although the latex test is suitable for initial diagnosis of H.
pylori infection, it is not suitable for monitoring treatment success. A decline
in IgG of more than 40% correlates well with successful eradication of H. pylori.
PMID- 10764025
TI - Helicobacter pylori infection occurs via close contact with infected individuals
in early childhood.
AB - BACKGROUND: The manner in which Helicobacter pylori is transmitted is of
fundamental importance when considering strategies for its control, yet, to date,
the exact mode of transmission remains uncertain. METHODS: The seroprevalence of
H. pylori in a relatively isolated rural town in Japan (A-town) was examined to
analyse the H. pylori infection route. The immunoglobulin G antibodies against H.
pylori in 1684 subjects who had received public health examinations in A-town
were determined with an enzyme-linked immunosorbent assay. The seroprevalence was
compared in five areas according to the water source. The possibility and
frequency of intrafamilial infection was analysed by comparing the seroprevalence
among family members residing in the same home. RESULTS: The seroprevalence of H.
pylori did not differ significantly between the five areas examined.
Seropositivity was significantly more common in the children whose mothers were
seropositive (45.0%, 27/60) than in the children whose mothers were seronegative
(10.0%, 2/20; odds ratio (OR) = 7.36, P = 0.0036, 95% confidence interval (CI) =
1.57-34.59). Seropositivity was significantly more common in the children whose
older siblings were seropositive (55.0%, 22/40) than in the children whose older
siblings were seronegative (23.5%, 20/85; OR = 3.97, P = 0.00051, 95% CI = 1.79
8.84). There was no significant relationship in seroprevalence between children
and fathers, grandchildren and grandfathers, grandchildren and grandmothers, or
within couples. Seropositivity was significantly more common in the adolescents
who had attended a nursery school (44.4%, 20/45) than in the adolescents who had
not attended a nursery school (25.6%, 109/426) (OR = 2.33, P = 0.0070, 95% CI =
1.24-4.36). CONCLUSIONS: The acquisition of H. pylori infection occurs by close
contact with infected individuals in early childhood, especially via contact with
infected mothers and other infected children.
PMID- 10764026
TI - Water extract of Helicobacter pylori stimulates interleukin-8 secretion by a
human gastric epithelial cell line (JR-St) through protein tyrosine
phosphorylation.
AB - BACKGROUND: Infection by Helicobacter pylori induces cytokine production in
gastric mucosal cells. Production of interleukin-8 (IL-8) is known to be markedly
increased and is believed to play an important role in gastric mucosal
inflammation. The aim of this study was to elucidate the effects of soluble
factors of H. pylori on IL-8 production in a gastric epithelial cell line, JR-St.
METHODS: JR-St cells were cocultured with a H. pylori water extract, live H.
pylori or culture medium supernatant for 24 h, then the IL-8 secreted into the
culture medium was assayed. The effects of three different inhibitors; (i) an
inhibitor of protein kinase C (PKC); (ii) an inhibitor of PKC and protein kinase
A (PKA); and (iii) an inhibitor of protein tyrosine kinase (PTK) were also
compared. Specific induction of IL-8 mRNA was also examined. RESULTS: Water
extract of H. pylori increased IL-8 secretion 7.72-fold, more than the control.
The increase was concentration dependent. Live bacteria, supernatant and water
extract significantly stimulated IL-8 secretion. Addition of live bacteria
increased IL-8 secretion most strongly, while the effect of water extract was
small (22% that of live bacteria). Secretion was not inhibited by the PKC
inhibitor staurosporine or the inhibitors of PKA and PKC H7. However, secretion
was significantly reduced by the PTK inhibitor herbimycin in a dose-dependent
manner. Furthermore, 24 h exposure to water extract increased IL-8 mRNA
expression, suggesting water extract increased production of IL-8. CONCLUSIONS:
Some soluble factors of H. pylori can stimulate IL-8 production by JR-St cells.
Stimulation was not dependent on PKA or PKC but was, at least partially,
dependent on protein tyrosine phosphorylation. This suggests that soluble factors
of H. pylori can play an important role in mediating the inflammatory response of
H. pylori gastritis.
PMID- 10764027
TI - Relationship between Helicobacter pylori infection and smoking and drinking
habits.
AB - BACKGROUND: Helicobacter pylori is a major cause of various gastroduodenal
diseases. Some risk factors related to H. pylori infection have been reported;
however, studies on the relationship between H. pylori infection and smoking or
drinking habits have given conflicting results. In the present study, these
relationships were investigated by collecting sera and information from 8837
subjects. METHODS: Serum H. pylori immunoglobulin G antibody was measured by an
enzyme-linked immunoassay. In addition to sex and age, information on smoking and
drinking habits was collected by questionnaire. Age- and sex-adjusted odds ratios
(95% confidence interval) of smoking and alcohol consumption were calculated for
H. pylori seropositivity using logistic regression models. RESULTS: Current
smokers had a 0.82 (0.74-0.91)-fold greater risk of H. pylori seropositivity than
those who had never smoked. Current cigarette consumption showed a dose
dependently negative association with H. pylori seropositivity, and the
association between smoking and H. pylori infection was strong in younger
subjects. Current drinkers had a 0.88 (0.79-0.98)-fold greater risk of H. pylori
seropositivity than those who had never drunk alcohol. The volume of alcohol
consumed showed a negative association with H. pylori seropositivity.
CONCLUSIONS: In the current study, smoking was negatively associated with H.
pylori infection. The risk of H. pylori seropositivity decreased linearly with
cigarette consumption per day. Increased gastric acidity in the stomach through
smoking may be a cause of the dose-dependently negative association between H.
pylori and smoking. Drinking was negatively and dose-dependently associated with
H. pylori positivity, although the effect of drinking was weaker than that of
smoking.
PMID- 10764028
TI - Effect of age and Helicobacter pylori infection on gastric acid secretion.
AB - BACKGROUND: Whether gastric acid secretion decreases with age is still
controversial. With the discovery of Helicobacter pylori, the association of this
bacterium with gastric acid secretion has also been discussed. The aim of this
study was to investigate the relationship between gastric acid secretion, age and
H. pylori infection. METHODS: The presence of H. pylori infection, the grade of
fundic atrophic gastritis (FAG), and gastric acid secretion were investigated in
280 subjects without localized lesions in the upper gastrointestinal tract.
Helicobacter pylori infection was confirmed by Giemsa and immunohistochemical
staining, and FAG of biopsy specimens was graded on a scale of 0-4. RESULTS: Both
basal and maximal acid output decreased with age in H. pylori-positive subjects,
while they did not change with age in H. pylori-negative subjects. Gastric acid
secretion decreased with the progression of FAG. An age-correlated decrease in
gastric acid secretion in H. pylori-positive subjects depended on an increasing
prevalence of FAG with age. CONCLUSIONS: In the population studied, advancing age
had no influence on gastric acid secretion in H. pylori-negative subjects.
Gastric acid secretion decreases with age in H. pylori-positive subjects because
of the increasing prevalence of FAG with age.
PMID- 10764029
TI - A 15-minute [13C]-urea breath test for the diagnosis of Helicobacter pylori
infection in patients with non-ulcer dyspepsia.
AB - BACKGROUND: Non-ulcer dyspepsia (NUD) accounts for the majority of dyspeptic
patients and studies on the epidemiology of Helicobacter pylori infection in NUD
depend on a non-invasive and rapid diagnostic test. This study was performed to
determine the sensitivity and specificity of a 15-min simplified protocol of the
[13C]-urea breath test ([13C]-UBT) for the diagnosis of H. pylori infection in
patients with NUD. METHODS: One hundred and thirty-six patients with a clinical
and endoscopic diagnosis of NUD were included. The [13C]-UBT was modified from
the European standard protocol. The baseline breath sample was collected 5 min
after the patient took a test meal and the 13CO2 was collected 15 min after the
patient drank 100 mg [13C]-urea. The gold standard used for comparison was either
a positive culture or positive histology + positive rapid urease test sampled on
upper gastrointestinal endoscopy. RESULTS: The prevalence of H. pylori infection
in NUD by the gold standard was 59.6%, whereas that calculated by the [13C]-UBT
was 60.3%. The sensitivity and specificity of [13C]-UBT was 93.8 and 89.1%
compared with the gold standard. The shortened collection time and simplification
of the procedure may have led to a decline in specificity. CONCLUSION: The 15-min
[13C]-UBT is a rapid but less specific protocol for detecting the presence of H.
pylori infection in patients with NUD.
PMID- 10764030
TI - Prevalence of enteric pathogens among community based asymptomatic individuals.
AB - BACKGROUND AND AIMS: The objective of this study was to describe the prevalence
of pathogenic microorganisms in asymptomatic individuals in a community study in
Melbourne, Australia. METHODS: The study population was a subset of 2803
individuals participating in the Water Quality Study; a community based
randomized trial. Faecal specimens (1091) were collected over a 3-month period
from asymptomatic individuals. Specimens were tested for a range of bacteria
including Salmonella, Shigella and Campylobacter species. Rotavirus and
adenovirus were detected using a Rota-Adeno latex kit, and protozoa were detected
using a permanent stain (modified iron-haemotoxylin). RESULTS: Twenty-eight known
pathogens were identified from the 1091 faecal specimens, a total carriage rate
of 2.6%. Giardia species were present in 18 specimens (1.6%), Salmonella in four
(0.4%), Campylobacter in one (0.1%), Cryptosporidium in four (0.4%) and
adenovirus in one (0.1%). Blastocystis hominis was found in 65 specimens. The
median age of those without a pathogen was 12.5 years compared with 6.6 years for
those with a pathogen (P=0.02). CONCLUSIONS: Except for Giardia, pathogens were
rarely found in asymptomatic individuals in the community. The prevalence of
pathogens was higher in children than adults.
PMID- 10764031
TI - Serum total bile acid level as a sensitive indicator of hepatic histological
improvement in chronic hepatitis C patients responding to interferon treatment.
AB - BACKGROUND AND METHODS: Serum total bile acid (TBA) levels are used clinically as
a sensitive and reliable index of hepatobiliary diseases. In the present study,
to assess the clinical usefulness of determining TBA in interferon (IFN)-treated
patients, changes in liver function test values, including TBA and liver
histology, were examined in 36 chronic hepatitis C patients for 3 years after a
sustained response to IFN treatment. RESULTS: Alanine aminotransferase and gamma
glutamyl transpeptidase values significantly decreased during the period of IFN
treatment compared to the same measures before IFN treatment. Albumin,
cholinesterase, total cholesterol and platelet count values temporarily decreased
during IFN treatment, then increased significantly and reached a plateau 6-12
months after the end of IFN treatment. The zinc sulphate turbidity test and TBA
values began to decrease during IFN treatment and continued to decrease during
the 3-year follow-up period. The histological activity index of the liver
(Knodell's score) significantly decreased, whereas the staging score was
unchanged 1 year after the end of IFN treatment. In patients who had a TBA value
> 10 micromol/L before IFN treatment, a significant correlation was observed
between the decrease of TBA and liver histology grading score. CONCLUSIONS: A
decrease in serum TBA level reflected histological improvement in the liver more
precisely than did changes in the other liver function test values following IFN
therapy.
PMID- 10764032
TI - Interferon treatment is not associated with a worsening of psychiatric symptoms
in patients with hepatitis C.
AB - AIM: To study prospectively the psychiatric side effects of interferon-alpha in
patients with hepatitis C. METHODS: Sixty-three consecutive patients at a
hepatitis clinic were recruited. All were assessed using a psychiatric interview
(SCID) and monitored using a self-reporting psychiatric symptom questionnaire
(SCL-90). RESULTS: Patients on interferon did not suffer a drop in mood or an
increase in anxiety or irritability. The subgroup with past depression also did
not suffer an increase in depressive symptoms. No patients attempted suicide.
CONCLUSIONS: The risk of serious psychiatric symptoms when being treated with
interferon-alpha may not be high. Psychiatric illness or the possibility of
psychiatric complications should not be used as a reason to refuse this treatment
to patients with hepatitis C.
PMID- 10764033
TI - Effect of nucleoside analogue therapy on duck hepatitis B viral replication in
hepatocytes and bile duct epithelial cells in vivo.
AB - BACKGROUND: Recent studies have implicated bile duct epithelial cells (BDEC) as a
reservoir of hepatitis B virus (HBV) infection that may be particularly important
in the development of post-liver transplant recurrence of hepatitis B. The aim of
this study was to compare the effects of antiviral therapy on duck HBV (DHBV)
expression in hepatocytes and BDEC and to determine if this was affected by
biliary hyperplasia. METHODS: Ducklings congenitally infected with DHBV received
penciclovir (10 mg/kg per day) treatment from 9 days of age. In order to mimic
the biliary hyperplasia that often accompanies severe post-liver transplant HBV
recurrence, half the animals underwent bile duct ligation. Duck HBV-DNA in serum
was measured at day 1, and serum and liver DHBV-DNA were determined when the
animals were killed on day 17. Intrahepatic expression of viral preS1 antigen and
DHBV-DNA was measured by immunohistochemistry and in situ hybridization,
respectively. RESULTS: Viraemia became undetectable in the penciclovir-treated
animals at day 17, following 8 days of therapy. Examination of liver tissue
revealed that all hepatocytes and the majority of BDEC contained DHBV preS1
antigen and DHBV-DNA. Penciclovir greatly reduced the intrahepatic viral burden,
but there was no antiviral effect on viral markers within BDEC. Despite the
increased number of BDEC after bile duct ligation, the same proportion of BDEC
was seen to be infected, and this was unaffected by antiviral therapy.
CONCLUSIONS: In the duck model with and without biliary hyperplasia, penciclovir
controls DHBV replication and reduces viral burden in hepatocytes, but not in
BDEC. The BDEC appear to be an important reservoir of virus that is relatively
unaffected by antiviral treatment, and may play an important role in disease
persistence and relapse following cessation of therapy.
PMID- 10764034
TI - Relationship between histological prognosis of chronic hepatitis C and amount of
hepatitis C virus core protein in serum.
AB - BACKGROUND: Hepatitis C virus (HCV) viraemia is one of the factors for
histological prognosis of chronic hepatitis C. METHODS: One hundred and thirty
five patients who received hepatic biopsies twice at intervals of 5 years or
longer were followed up for a mean of 9.7 +/- 4.0 years were studied
retrospectively. The amount of HCV viraemia present was measured as the
concentration of HCV core protein by using the fluorescence enzyme immunoassay
method. RESULTS: Multiple-regression analysis, using deterioration of the
histological stage as a dependent variable, showed that greater age (P = 0.041),
higher stage of hepatic histology at the start of follow up (P = 0.029), and
higher serum concentration of core protein (P < 0.001) were independent factors
affecting the deterioration of the liver's histological stage. At follow up, no
significant difference in histological stage was seen between patients with serum
HCV core protein > or = 100 pg/mL (n = 60) and those with serum core protein <
100 pg/mL (n = 75). The histological grade in patients with high serum core
protein levels tended to be significantly worse and the deterioration rate of the
histological stage was significantly higher than in those with low HCV core
protein levels (68 vs 35%, P < 0.001). The mutation rate of the HCV envelope
2/non-structural 1 (E2/NS1) nucleotide region was compared in two patients who
had high serum concentrations of HCV core protein and whose histological stage
had deteriorated with two patients who had low serum concentrations of the core
protein and whose histological stages remained unchanged. No significant
difference in E2/NS1 mutation was found. CONCLUSIONS: The amount of HCV viraemia
was suggested to be a significant factor for determining histological outcome in
patients with chronic hepatitis C. The mutation rate in the E2/NS1 region did not
seem to be associated with the prognosis of chronic hepatitis C.
PMID- 10764035
TI - Dysphagia after prophylactic endoscopic injection sclerotherapy for oesophageal
varices: not fatal but a distressing complication.
AB - BACKGROUND: Although dysphagia resulting from oesophageal strictures induced by
endoscopic injection sclerotherapy (EIS) is not a fatal complication, it is often
quite distressing for the patients. The aim of the current study was to clarify
the relationship between dysphagia resulting from oesophageal stricture following
prophylactic EIS and the volume of sclerosant consumed in the EIS series.
METHODS: Fifty-two patients with oesophageal varices, who had been treated by
prophylactic EIS, were selected as the subjects. RESULTS: Seventeen (32.7%)
patients developed dysphagia following prophylactic EIS, and five patients with a
severe stricture required bougie dilatation to take meals. The volume of
sclerosant used in the initial session of EIS for patients with subsequent
dysphagia (24.9 +/- 4.0 mL) was significantly larger than that for patients
without dysphagia (18.4 +/- 5.1 mL; P < 0.001). The mean volume of sclerosant
consumed per session during the EIS series for patients with dysphagia (16.5 +/-
3.0 mL) was also significantly larger than that for patients without dysphagia
(13.1 +/- 3.8 mL; P < 0.01). CONCLUSIONS: The injection of a superfluous amount
of sclerosant in prophylactic EIS brings about distressing dysphagia with
oesophageal stricture in the patients with oesophageal varices who had no such
complaint or symptoms before the therapy.
PMID- 10764036
TI - Images of interest. Gastrointestinal: oesophageal intramural
pseudodiverticulosis.
PMID- 10764037
TI - Images of interest. Hepatobiliary and pancreatic: a woman who underwent
cholecystectomy.
PMID- 10764038
TI - Complete disappearance of recurrent hepatocellular carcinoma with peritoneal
dissemination and splenic metastasis: a unique clinical course after surgery.
AB - Spontaneous regression of hepatocellular carcinoma (HCC) is a rare phenomenon. We
report a case of complete disappearance of intrahepatic, peritoneal and splenic
metastases in HCC after hepatectomy using treatment with tegafur and uracil
(UFT). The effect of UFT alone was not likely to have caused the disappearance of
this tumour because HCC recurrence advance markedly within 5 months of surgery
despite oral administration of UFT. This case demonstrates a unique postoperative
clinical course that suggests spontaneous regression of HCC. This is the first
case of complete disappearance of unresectable HCC with peritoneal seeding and
splenic metastasis.
PMID- 10764039
TI - Mucosa-associated lymphoid tissue lymphoma of the rectum that regressed
spontaneously.
AB - We report a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the
rectum that regressed spontaneously. A 76-year-old man visited our hospital
because of positive faecal occult blood testing. Colonoscopic examination
revealed a slightly yellowish protruded lesion with a grooved depression in the
lower rectum and two flat elevations in the upper rectum. Microscopic and
immunohistological studies led to a diagnosis of MALT lymphoma. As the patient
exhibited severe renal dysfunction and angina pectoris, the lesions were left
untreated. Three months later, the protruded lesion became flat and the other
lesions became unclear. He was followed up closely with endoscopy, but no relapse
of these lesions was detected 19 months after the diagnosis.
PMID- 10764040
TI - Diagnostic protein expression in human muscle biopsies.
AB - Using immunohistochemistry in diagnosing neuromuscular diseases is meant to
enhance the diagnostic yield in two ways. The first application aims at
visualizing molecules which are developmentally, neurally, and/or immunologically
regulated and not expressed by normal muscle. They are upregulated in
pathological conditions and may help assign a given muscular biopsy to one of the
main diagnostic entities (muscular dystrophies, inflammatory myopathy, neurogenic
atrophy). In the past, muscle-specific molecules with a defined expression
pattern during fetal myogenesis served as antigens, with the rationale that the
developmental program was switched on in new fibers. Recently, myofibers in
diseased muscle are thought of as targets of stimuli which are released by
macrophages in muscular dystrophy, by lymphocytes in inflammatory myopathies, or
by a lesioned peripheral nerve in neurogenic atrophies. This has somewhat blurred
the borders between the diagnostic groups, for certain molecules, e.g. cytokines,
may be upregulated after experimental necrotization, denervation, and also in
inflammatory myopathies. In the second part of this review we summarise the
experiences of a Centre in the North of England that specialises in the diagnosis
and clinical support of patients with muscular dystrophy. Emphasis is placed on
the use of protein expression to guide mutation analysis, particularly in the
limb-girdle muscular dystrophies (a group of diseases that are very difficult to
differentiate on clinical grounds alone). We confirm that genetic analysis is
essential to corroborate the results of protein analysis in certain conditions
(particularly in calpainopathy). However, we conclude that analysing biopsies for
abnormal protein expression is very useful in aiding the decision between
alternative diagnoses.
PMID- 10764041
TI - Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis.
AB - Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome,
clinically characterized by generalized tonic-clonic seizures with onset at 5 to
10 years of age and subsequent slowly progressive mental deterioration. The
patients may reach 50 or 60 years of age. A mutation responsible for the disease
has recently been identified in a novel gene on chromosome 8p23, encoding a
putative membrane protein with an unknown function. The present study, based on
three autopsied patients, is the first neuropathological analysis of the disease,
and showed intraneuronal accumulation of cytoplasmic autofluorescent granules.
The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff,
and Sudan black B methods in paraffin sections, and were immunoreactive for
subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A
and D. The intraneuronal storage was highly selective: the third layer of the
isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected,
while other layers of the isocortex, the CA1 sector, and the cerebellar cortex
were only minimally involved. The membrane-bound storage cytosomes showed a
curvilinear ultrastructure with admixture of some granular components. Western
blotting and N-terminal sequence analysis of purified storage material identified
subunit c as the major component. These findings establish Northern epilepsy as a
new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted
course.
PMID- 10764042
TI - Bag-1 and Bcl-2 gene transfer in malignant glioma: modulation of cell cycle
regulation and apoptosis.
AB - Bag-1 is a heat shock 70 kDa (Hsp70)-binding protein that can collaborate with
Bcl-2 in suppressing apoptosis under some conditions. Here, we report that 11 of
12 human glioma cell lines express Bag-1 protein in vitro. Moreover, 15 of 19
human glioblastomas expressed Bag-1 as assessed by immunohistochemistry in
primary tumor specimens. To examine the biological effects of Bag-1 in glioma
cells, we expressed Bag-1 or Bcl-2 transgenes in 2 human malignant glioma cell
lines, LN-18 and LN-229. Bag-1 significantly slowed glioma cell growth and
reduced clonogenicity of both cell lines in vitro. Coexpressed Bcl-2 abrogated
these effects of Bag-1. Intracranial LN-229 glioma xenografts implanted into nude
mice revealed a substantial growth advantage afforded by Bcl-2. Bag-1 had no such
effect, either in the absence or presence of Bcl-2. Upon serum starvation in
vitro, Bcl-2 prevented cell death whereas Bag-1 did not. Both Bcl-2 and Bag-1
slowed proliferation of serum-starved cells when expressed alone. Importantly,
coexpression of Bcl-2 and Bag-1 provided a distinct growth advantage under
conditions of serum starvation that is probably the result of (i) the death
preventing activity of Bcl-2 and (ii) the property of Bag-1 to overcome a Bcl-2
mediated enhancement of exit from the cell cycle. In contrast to these Bcl-2/Bag
1 interactions observed under serum starvation conditions, Bag-1 did not further
enhance the strong protection from staurosporine-, CD95 (Fas/Apo1) ligand-, Apo2
ligand (TRAIL)- or chemotherapeutic drug-induced apoptosis afforded by Bcl-2.
Taken together, these results indicate a role for Bag-1/Bcl-2 interactions in
providing a survival advantage to cancer cells in a deprived microenvironment
that may be characteristic of ischemic/hypoxic tumors such as human glioblastoma
multiforme, and suggest that Bcl-2/Bag-1 interactions also modulate cell
proliferation.
PMID- 10764043
TI - Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino
acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met.
AB - Mutations in the gene for the major protein component of peripheral nerve myelin,
myelin protein zero (MPZ, P0), cause hereditary disorders of Schwann cell myelin
such as Charcot-Marie-Tooth neuropathy type 1B (CMT1B), Dejerine-Sottas syndrome
(DSS), and congenital hypomyelinating neuropathy (CHN). More recently, P0
mutations were identified in the axonal type of CMT neuropathy, CMT2, which is
different from the demyelinating variants with respect to electroneurography and
nerve pathology. We screened 49 patients with a clinical and histopathological
diagnosis of CMT2 for mutations in the P0 gene. Three heterozygous single
nucleotide changes were detected: two novel missense mutations, Asp61Gly and
Tyr119Cys, and the known Thr124Met substitution, that has already been reported
in several CMT patients from different European countries. Haplotype analysis for
the P0 locus proved that our patients with the 124Met allele were not related to
a cohort of patients with the same mutation, all of Belgian descent and all found
to share a common ancestor. Our data suggest that P0 mutations account for a
detectable proportion of CMT2 cases with virtually every patient harbouring a
different mutation but recurrence of the Thr124Met amino acid substitution. The
high frequency of this peculiar genotype in the European CMT population is
presumably not only due to a founder effect but Thr124Met might constitute a
mutation hotspot in the P0 gene as well.
PMID- 10764044
TI - Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR
amplification distinguish de novo high grade pediatric astrocytomas from de novo
adult astrocytomas.
AB - Classification of high grade astrocytomas of children into genetic subtypes
similar to the adult remains to be defined. Here we report an extensive
characterization of 29 high grade pediatric astrocytomas, 7 WHO grade III and 22
WHO grade IV, for genetic alterations frequently observed in high grade adult
astrocytomas occurring in either the p53/MDM2/p14ARF or Rb/CDK4/p16INK4a tumor
suppressor pathways. In addition, we have assessed the contribution of EGFR
overexpression and amplification and LOH for chromosome 10, two genetic
alterations commonly associated with the development of de novo adult
glioblastoma for their roles in the development of de novo astrocytomas of
childhood. Our results suggest two major differences in the genetic pathway(s)
leading to the formation of de novo high grade astrocytomas in children compared
with those of the adult. Our findings show preferential inactivation of the p53
tumor suppressor pathway in >95% of pediatric astrocytomas versus inactivation of
the Rb tumor suppressor pathway in <25% of the same tumors. In addition, de novo
high grade pediatric astrocytomas lack amplification of the EGFR gene compared
with EGFR amplification in one-third of adult glioblastomas. Since drug
treatments and gene therapy strategies exploit specific genetic alterations in
tumor cells, our findings have important implications for the future development
of treatments for high grade pediatric astrocytomas.
PMID- 10764045
TI - Microglial activation and neuronal apoptosis in Bornavirus infected neonatal
Lewis rats.
AB - Lewis rats neonatally infected with Borna disease virus have a behavioral
syndrome characterized by hyperactivity, movement disorders, and abnormal social
interactions. Virus is widely distributed in brain; however, neuropathology is
focused in dentate gyrus, cerebellum, and neocortex where granule cells, Purkinje
cells and pyramidal cells are lost through apoptosis. Although a transient immune
response is present, its distribution does not correlate with sites of damage.
Neuropathology is instead colocalized with microglial proliferation and
expression of MHC class I and class II, ICAM, CD4 and CD8 molecules. Targeted
pathogenesis in this system appears to be linked to microglial activation and
susceptibility of specific neuronal populations to apoptosis rather than viral
tropism or virus-specific immune responses.
PMID- 10764046
TI - Introduction: Targeted modulation of neuronal apoptosis: a double-edged sword?
PMID- 10764047
TI - Energy requirement for caspase activation and neuronal cell death.
AB - Recent work has shown that execution of the apoptotic program involves a
relatively limited number of pathways. According to a general view, these would
converge to activate the caspase family of proteases. However, there is
increasing evidence that apoptotic-like features can be found also when cells are
treated with inhibitors of caspases as the cell permeable tripeptide, Z-Val-Ala
Asp-fluoro-methyl-ketone (Z-VAD-fmk), or analogous compounds. This has posed the
question as to whether apoptosis may occur in a caspase independent way, and
whether caspase inhibitors may then be used to treat diseases characterised by an
excess apoptosis. It is also becoming clear, that ATP depletion during the early
phases of apoptosis can preclude caspase activation, and consequently switch
execution of cell death towards necrosis. In vivo, a block or partial inhibition
of the typical apoptotic demise may have profound implications, as persistence of
damaged but "undead" cells within the nervous system, followed by delayed lysis
may favour neuroinflammatory reactions. In this review, we discuss some recent
findings, which suggest that cells may use diverging execution pathways, with
different implications in neuropathology and therapy.
PMID- 10764048
TI - Neuroprotection by the inhibition of apoptosis.
AB - Accumulating evidence strongly suggests that apoptosis contributes to neuronal
cell death in a variety of neurodegenerative contexts. Activation of the cysteine
protease caspase-3 appears to be a key event in the execution of apoptosis in the
central nervous system (CNS). As a result, mice null for caspase-3 display
considerable neuronal expansion usually resulting in death by the second week of
life. At present, 14 caspase family members have been identified and subdivided
into three subgroups on the basis of preference for specific tetrapeptide motifs
using a positional scanning combinatorial substrate library. Caspase-3 is a group
II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic
acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD)
for group II caspases is found in many structural, metabolic and repair proteins
essential for cellular homeostasis. Consistent with the proposal that apoptosis
plays a central in role human neurodegenerative disease, caspase-3 activation has
recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's
disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal
models of head injury and stroke suggesting that these compounds may be the
forerunners of non-peptide small molecules that halt apoptosis processes
implicated in these neurodegenerative disorders. A clear link between an
hereditary neurodegenerative disorder and failed caspase inhibition has recently
been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal
specific inhibitor of apoptosis (IAP) family member known as NAIP is often
dysfunctional due to missense and truncation mutations. IAPs such as NAIP
potently block the enzymatic activity of group II caspases (3 and 7) suggesting
that NAIP mutations may permit unopposed developmental apoptosis to occur in
sensory and motor systems resulting in lethal muscular atrophy. Conversely,
adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP
reduces the loss of CA1 hippocampal neurons following transient forebrain
ischemia. Taken together, these findings suggest that anti-apoptotic strategies
may some day have utility in the treatment of neurodegenerative disease. The
present review will summarize some of the recent evidence suggesting that
apoptosis inhibitors may become a practical therapeutic approach for both acute
and chronic neurodegenerative conditions.
PMID- 10764049
TI - Toward an understanding of polyglutamine neurodegeneration.
AB - Polyglutamine expansion is now recognized to be a major cause of inherited human
neurodegenerative disease. The polyglutamine expansion diseases identified so far
are slowly progressive disorders in which distinct yet overlapping brain regions
are selectively vulnerable to degeneration. Despite their clinical differences
these diseases likely share a common pathogenic mechanism, occurring at the
protein level and centered on an abnormal conformation of expanded polyglutamine
in the respective disease proteins. Recently there has been remarkable progress
in our understanding of polyglutamine disease, but still there are many
unanswered questions. In this review, I first outline some of the shared features
of polyglutamine diseases and then discuss several issues relevant to an
understanding of pathogenesis, paying particular attention to possible mechanisms
of neurotoxicity.
PMID- 10764050
TI - Apoptotic and anti-apoptotic synaptic signaling mechanisms.
AB - Although several prominent morphological features of apoptosis are evident in the
cell body (e.g., cell shrinkage, membrane blebbing, and nuclear DNA condensation
and fragmentation) the biochemical and molecular cascades that constitute the
cell death machinery can be engaged in synaptic terminals and neurites.
Initiating events such as oxyradical production and calcium influx, and effector
processes such as Par-4 production, mitochondrial alterations and caspase
activation, can be induced in synapses and neurites. Several prominent signal
transduction pathways in synaptic terminals play important roles in either
promoting or preventing neuronal death in physiological and pathological
conditions. For example, activation of glutamate receptors in postsynaptic spines
can induce neuronal apoptosis, whereas local activation of neurotrophic factor
receptors in presynaptic terminals can prevent neuronal death. Factors capable of
inducing nuclear chromatin condensation and fragmentation can be produced locally
in synaptic terminals and neurites, and may propogate to the cell body. Recent
findings suggest that, beyond their roles in inducing or preventing cell death,
apoptotic and anti-apoptotic cascades play roles in synaptic plasticity
(structural remodelling and long-term functional changes). For example, caspase
activation results in proteolysis of glutamate receptor (AMPA) subunits, which
results in altered neuronal responsivity to glutamate. Activation of neurotrophic
factor receptors in synaptic terminals can result in local changes in energy
metabolism and calcium homeostasis, and can induce long-term changes in synaptic
transmission. The emerging data therefore suggest that synapses can be considered
as autonomous compartments in which both pro- and anti-apoptotic signaling
pathways are activated resulting in structural and functional changes in neuronal
circuits. A better understanding of such synaptic signaling mechanisms may reveal
novel approaches for preventing and treating an array of neurodegenerative
conditions that are initiated by perturbed synaptic homeostasis.
PMID- 10764051
TI - January 2000: 12 year old boy with recent onset seizures.
AB - A 12-year old boy presented with new onset of seizures and a CT scan showed a
left frontal lobe tumor which was removed completely. Neuropathological
examination showed a pleomorphic ganglion cell tumor with necrosi, and
endothelial proliferation. The diagnosis was extraventricular atypical neurocytic
neoplasm ("cystic ganglioneurocytoma").
PMID- 10764052
TI - February 2000: Dementia with motor dysfunction in a patient with liver disease.
AB - Acquired (non-Wilsonian) hepatocerebral degeneration (AHCD) is an irreversible
neurological condition characterized by dementia, dysarthria, and motor
disturbances. It has been described in patients with severe liver disease of many
causes, and notably in patients with surgically or spontaneously created porto
systemic shunts. We report a case of AHCD in a patient with end-stage liver
disease due to alcohol abuse and hepatitis C. In addition, this patient showed
pathologic evidence of the less commonly reported "shunt myelopathy" in the
absence of a surgically created porto-systemic shunt. The myelopathy was
associated with a dramatic vacuolation involving especially the deep motor
cortex. Electron microscopy suggested that the vacuolation was due mainly to
disruption of abnormal astrocytes.
PMID- 10764053
TI - March 2000: 5 month old boy with occipital bone mass.
AB - A 5 month old boy was found by his mother to have a bony mass behind the left ear
which extended intracranially on MRI scan. At surgery it was entirely extradural
in location. Microscopically, a biphasic appearance consisting of large pigmented
cells arranged into tubules and small nonpigmented basophilic cells arranged into
nests gave rise to a diagnosis of melanotic neuroectodermal tumour of infancy
[MNETI]. One year after a wide local excision the patient is tumor-free and
developing normally. The prognosis for MNETI in general is excellent with no
requirement for additional radiotherapy or chemotherapy.
PMID- 10764054
TI - Health and environmental implications of using composted household and yard waste
bedding in a cattle feedlot.
AB - A study was conducted to determine the safety and feasibility of using municipal
solid waste compost (MSWC) as a bedding material for cattle feedlots. Two pens in
an open-front pole barn were bedded with either corn stalks or MSWC in each of
two feeding periods (blocks) with two pens (23 x 34 m) per block. Block 1 used
336 heifers (initial BW, 398 kg) during a 104-d period (summer), and Block 2 used
276 steers (initial BW, 412 kg) during a 92-d period (winter). Blood
concentrations of regulated elements (Cd, Cu, Mo, Pb, Ni, and Zn), electrolytes,
glucose, or liver and kidney enzymes were unaffected (P > .05) by use of either
bedding material. Polychlorinated biphenyls in perirenal fat were not detectable
(< .5 ppm) in cattle bedded with either material. At slaughter, kidney Cu and
kidney and liver Pb concentrations were greater (P < .05) for cattle bedded with
MSWC. Despite this, tissue concentrations of these elements were well within
those considered normal for healthy cattle. Regulated element concentrations of
feed did not differ (P > .05) between diets within period, and neither did DMI or
DM digestibility; therefore, cattle bedded with MSWC were likely inhaling
additional amounts of these elements and excreting them through feces. More MSWC
than corn stalks was required to supply a dry bed per animal daily (P < .05).
Soiled bedding (manure as-is) output was similar (P > .05) for both bedding
materials. On a DM basis, more manure (P < .05) was removed from the pen bedded
with MSWC in Block 2. Total manure N and P removed was similar for both bedding
materials. Nitrogen and P concentrations in manure were lower (P < .05) during
Block 2, but total manure N removed was greater (P < .05) during Block 2. Total
manure P removed from the pens was not affected by season. Under the conditions
of this study, MSWC seemed to be a safe and effective bedding material for cattle
feedlots.
PMID- 10764055
TI - Effects of supplemental soybean oil level on in vitro digestion and performance
of prepubertal beef heifers.
AB - In vitro digestion and growth studies were conducted to evaluate the effects of
level of soybean oil inclusion in forage-based diets. In Exp. 1, diets were
bromegrass hay (H), bromegrass hay and corn-soybean meal supplement (C), C with
3% added soybean oil (O3), and C with 6% added soybean (O6). Diets containing
supplements were formulated to be isonitrogenous and isocaloric. Treatment means
were compared using a single-degree-of-freedom contrast (H vs C, O3, and O6) and
orthogonal polynomial contrasts within diets C, O3, and O6. Diet H had the lowest
(P = .0003) IVDMD and a linear decline (P = .0001) in IVDMD was observed from C
to O6, but 24-h IVDMD disappearance was greatest (P = .001; quadratic) for O3.
Total VFA increased from C to O3 and then decreased from O3 to O6 (quadratic; P =
.001), and acetate:propionate ratio decreased linearly (P = .0001) from C to O6.
Changes in long-chain fatty acids reflected biohydrogenation by ruminal microbes;
however, only 18:3 was hydrogenated to the same extent across all diets. In Exp.
2, 36 Angus x Gelbvieh heifers (260.0 +/- 6.0 kg initial BW) were individually
fed C, O3, or O6 as mixed rations for 104 d. Diets were formulated to be
isonitrogenous and provide ADG of .91 kg. Feed efficiency and ADG was greatest (P
< .02; quadratic) for O3 heifers. Serum NEFA increased linearly (P = .02) and
serum glucose (P = .02), cholesterol (P = .002), and GH (P = .04) showed a
quadratic response to level of dietary soybean oil. Plasma proportions of 16:0,
16:1, 18:0, and 18:1 increased quadratically (P < .03), and 18:2 increased
linearly (P < .001) from C to O6. In Exp. 3, 42 Angus x Gelbvieh heifers (288.7
+/- 6.6 kg initial BW) were divided into six pens (two pens/treatment) in a
randomized complete block designed experiment. Rations were delivered as hay plus
a top-dressed supplement (C, O3, or O6). Heifers fed O3 conceived 10 d earlier
(quadratic; P = .06) than heifers fed C and O6. Other production estimates did
not differ (P > or = .10) among dietary treatments. Inclusion of soybean oil at
3% of a forage-based diet increased total VFA, many blood metabolites, ADG, and
feed efficiency, and it decreased time to conception. Adding soybean oil as 3% of
a forage-based diet is an acceptable feeding strategy for developing beef
heifers.
PMID- 10764056
TI - Near infrared spectroscopy for biomonitoring: cow milk composition measurement in
a spectral region from 1,100 to 2,400 nanometers.
AB - The potential of near infrared spectroscopy (NIRS; 1,100 to 2,400 nm) to measure
fat, total protein, and lactose content of nonhomogenized milk during milking and
the influence of individual characteristics of each cow's milk on the accuracy of
determination were studied. Milk fractions were taken during milking, twice per
month, for 6 mo. Samples were taken every 2nd and 4th wk at the morning and the
evening milkings. Teatcups were removed at each 3 L of milk yield as determined
with a fractional sampling milk meter. A total of 260 milk samples were collected
and analyzed with an NIRSystem 6500 spectrophotometer with 1-mm sample thickness.
Partial least squares (PLS) regression was used to develop calibration models for
the examined milk components. The comparison with the reference method was based
on standard error of cross validation (SECV). The obtained SECV varied from .107
to .138% for fat content, from .092 to .125% for total protein, and from .066 to
.096% for lactose content, and the accuracy of the reference method (AOAC, 1990,
method No 972.16) was .05% for all measured milk components. The obtained models
had lower SECV when an individual cow's spectral data were used for calibration.
The reduction of SECV for each cow's individual calibration, when compared with
SECV for the set of all samples, differed with the different constituents. For
fat content determination, the reduction reached 22.46%, for protein 26.40%, and
for lactose 31.25%. This phenomena was investigated and explained by principle
component analysis (PCA) and by comparing loading of PLS factors that account for
the most spectral variations for each cow and the measured milk components,
respectively. The results of this study indicated that NIRS (1,100 to 2,500 nm, 1
mm sample thickness) was satisfactory for nonhomogenized milk compositional
analysis of milk fractions taken in the process of milking.
PMID- 10764057
TI - The strategic use of estradiol to enhance fertility and submission rates of
progestin-based estrus synchronization programs in dairy herds.
AB - Two experiments were performed to evaluate the efficacy of a progestin-based
estrus synchronization program that incorporated the use of estradiol at the
initiation of progestin treatment and at 48 h after progestin withdrawal (Exp.
2). In Exp. 1, cyclic, lactating dairy cows (n = 112) were assigned to receive
either 1 (1mg) or 2 (2mg) mg of estradiol benzoate via an i.m. injection on d -9
(d 0 = initiation of the breeding season). All cows received an intravaginal
progesterone-releasing insert (IPI; CIDR-B) on d -9. On d -2, the IPI was
withdrawn and all cows were administered 500 microg of cloprostenol sodium.
Beginning on d 0, cows were bred by AI upon detection of estrus. Estrus was
observed in similar proportions of cows in each treatment during the first 6 d of
AI (90% across treatments), but the interval to estrus was shorter (P < .05) in
1mg (1.26 +/- .18 d) than in 2mg (1.77 +/- .18 d). Conception and pregnancy rates
did not vary among treatments; however, cows in estrus on d 0 tended to be less
fertile (P = .11) than those in estrus on d 1. In Exp. 2, 408 cyclic cows from
three herds were assigned to receive either no synchrony treatment (Control, n =
214) or the treatments described in Exp. 1 (1mg, n = 100; 2mg, n = 94). Anestrous
cows from all herds received an IPI from d -9 to -2 (n = 143; Anestrus). All cows
in the 1mg, 2mg, and Anestrus groups, with the exception of those detected in
estrus between d -1 and 0, also received 1 mg of estradiol benzoate on d 0.
Greater than 90% of cows that received an IPI were in estrus between d -1 and 3,
and 92.1% of cows in the Control group were in estrus by d 21. Conception rate to
first service in 2mg (61.7%) was similar to Control (57.0%), tended to be higher
(P = .06) than 1mg (49.0%), and was greater (P < .05) than Anestrus (39.9%). The
mean day of conception was earlier (P < .05) in the 2mg (d 13.1 +/- 2.0) than the
Control (d 23.2 +/- 1.6) and Anestrus (d 22.4 +/- 1.9) groups. Conception
occurred earlier in 1mg (d 17.4 +/- 2.1) than in Control. The proportion of cows
that were pregnant at the end of the breeding season tended (P = .09) to be
greater in the 2mg and Anestrus groups. This regimen of estrus synchronization
improved reproductive competence in cyclic cows and resulted in similar
reproductive performance in anestrous cows and untreated cyclic cows inseminated
at a spontaneous estrus.
PMID- 10764058
TI - Effect of dietary energy on milk production and metabolic hormones in thin,
primiparous beef heifers.
AB - Thirty-six primiparous heifers were used to determine the effect of dietary
energy on postpartum interval, milk production, serum concentrations of insulin,
insulin-like growth factor I (IGF-I), growth hormone, and cerebrospinal fluid
(CSF) concentrations of neuropeptide-Y (NPY). Low-quality hay was fed during the
last trimester of pregnancy to achieve suboptimal calving weight (370 +/- 5 kg)
and condition score (4.0 +/- .1). After calving, cows were allotted to one of
four dietary treatments that differed in metabolizable energy. Experimental diets
were fed at 2.5% of shrunk body weight and formulated to provide 1.8 (low), 2.1
(maintenance), 2.4 (maintenance high), or 2.7 (high) Mcal of ME/kg DM. Daily milk
production was estimated at approximately 30, 60, and 90 d postpartum. Condition
score change and weight change were defined as change from calving to d 90
postpartum. As energy intake increased, condition score change (P < .001), IGF-I
(P < .001) and insulin (P < .01) increased and postpartum interval decreased (P =
.04). No relationship existed between postpartum interval and CSF concentration
of NPY (P > .1). Condition score change was positively associated with IGF-I and
insulin (r = .71, P < .001; r = .38, P = .02, respectively) and negatively
associated with GH (r = -.67, P < .001). Weight change and serum concentrations
of GH did not differ (P > .10) among treatments. Increasing dietary energy intake
was associated with a curvilinear increase in milk yield (P = .04) and percentage
milk fat (P = .03) and a linear increase (P = .04) in energy available for milk
production. Greater milk yield at d 30 was associated with a longer postpartum
interval (r = .34, P < .05). In conclusion, a greater proportion of net energy is
partitioned to maternal tissue realimentation when cows receive high compared to
low-, maintenance-, or moderate-energy diets.
PMID- 10764059
TI - Use of trainer animals to improve performance and health of newly arrived feedlot
calves.
AB - Four trials were conducted to determine the efficacy of using trainer animals to
improve the health and performance of newly arrived feedlot calves. For all
trials, trainer animals were given 3 wk to adapt to the feedlot before arrival of
the feeder calves and initiation of the trials. Trainer animals were present with
newly received feedlot calves for 14 d after arrival and then were removed from
the pens for the remaining 14 d of the experiments. In Trial 1, trainer animals
were six crossbred beef steers and six mature cull beef cows. Newly received
calves were allotted to 18 pens with 10 calves/pen. Six pens contained a trainer
steer and six pens contained a trainer cow. Similar procedures were used for the
subsequent three trials, except 12 trainer cows and 24 pens were used, and in
Trial 4 half of the calves were allotted to pasture paddocks for 14 d before
placement in their feedlot pens. During wk 1 of Trial 1, calves with trainer cows
and steers gained weight more rapidly (P < .10) than those without a trainer
animal (1.12 vs .67 kg/d, respectively). During wk 2, this trend was reversed and
overall gains did not differ (P > .20) among treatment groups. Morbidity was 16.7
for control calves, 28.3% for calves with trainer steers, and 8.3% for calves
with trainer cows. Four of six trainer steers required antibiotic treatment for
respiratory disease. On d 1, a greater (P < .05) percentage of calves in the
trainer cow group (81.7%) were observed eating during the first 30 min after
feeding compared with either the steer trainer group (60%) or the control group
containing no trainer animal (48.3%). This trend continued on d 2 but was not
evident on d 3 or 7. In Trial 2, overall gains were 10% greater (P < .06) and
final BW was higher (P < .01) for calves with trainer cows than for those without
trainers. Trainer cows resulted in a substantial reduction (P < .01) in calf
morbidity compared with calves housed alone. In Trial 3, trainer cows did not
improve performance or health of newly received calves. More (P < .07) calves
with trainers than without were eating 5 min after feeding on d 1, 2, 4, and 8.
In Trial 4, the presence of trainer cows the first 2 wk did not affect (P > .27)
gains. However, calves placed on pasture after arrival had lower (P < .03) gains
during wk 1 than those housed in the feedlot. Calves placed in pasture paddocks
upon arrival had more than twice (P < .01) the incidence of morbidity of those
placed directly in the feedlot. In these trials, trainer cows had a significant
effect on eating behavior of newly received calves, but health and performance
benefits were variable.
PMID- 10764060
TI - Genotype x environment interactions in Angus, Brahman, and reciprocal-cross cows
and their calves grazing common bermudagrass, endophyte-infected tall fescue
pastures, or both forages.
AB - Reproductive and preweaning data on 190 Angus (A x A), Brahman (B x B), and
reciprocal-cross cows (A x B and B x A) and 434 two- and three-breed-cross calves
managed on common bermudagrass (BG), endophyte-infected tall fescue (E+), or a
combination of both forages (ROT) were used to evaluate the interaction of forage
type with individual and maternal heterosis and maternal and grandmaternal breed
effects. Cows were born from 1988 to 1991, and calves sired by 13 Polled Hereford
bulls were born from 1995 to 1997. Heterosis for calving rate was larger on E+
than on BG or ROT (P < .05), whereas maternal effects were larger on BG than on
ROT (P < .10). Maternal heterosis for birth weight was negative on BG (P < .11)
but positive on E+ and ROT (P < .10). Grandmaternal effects were evident on BG (P
< .10) and E+ (P < .01) but not on ROT. Forage effects were generally substantial
for 205-d weight, calf weaning hip height, and calf weaning weight:height ratio;
BG was highest, ROT was intermediate, and E+ was lowest. Maternal heterosis for
these traits was generally greater on E+ than on BG (P < .10). Grandmaternal
effects for 205-d weight, hip height, and weight:height ratio were not important
on any forage. Heterosis for weaning weight per cow exposed was substantial on
all forages (P < .01) and was significantly greater on E+ (P < .01) than on BG or
ROT, but maternal effects were not significant. Thus, we observed more advantage
to Brahman-cross cows over purebreds on E+ than on BG. We also observed that
moving cows and calves from E+ to BG in the summer will alleviate some, but not
all, of the deleterious effects of E+ on calf growth, although it may be more
beneficial for reproductive traits in purebred cows.
PMID- 10764061
TI - The effect of adipocyte and heart fatty acid-binding protein genes on
intramuscular fat and backfat content in Meishan crossbred pigs.
AB - Effects of genetic variation in porcine adipocyte and heart fatty acid-binding
protein genes, A-FABP and H-FABP, respectively, on intramuscular fat (IMF)
content and backfat thickness (BFT) were examined in F2 crossbreds of Meishan and
Western pigs. The involvement of each FABP gene in IMF accretion was studied to
confirm previous results for Duroc pigs. The F2 crossbred pigs were genotyped for
various markers including microsatellite sequences situated within both FABP
genes. Linkage analysis assigned the A-FABP and H-FABP genes to marker intervals
S0001-S0217 (20 cM) on SSC4 and Sw316-S0003 (16.6 cM) on SSC6, respectively,
refining previous chromosomal assignments. Next, the role of both chromosome
regions/genes on genetic variation in IMF content and BFT was studied by 1)
screening SSC4 and SSC6 for QTL affecting both traits by performing a line-cross
analysis and 2) estimation of the effect of individual A-FABP and H-FABP alleles
on both traits. In the first analysis, suggestive and chromosome-wise significant
evidence for a QTL affecting IMF was detected on SSC6. The H-FABP gene is a
candidate gene for this effect because it resides within the large region
containing this putative QTL. The second analysis showed a considerable but
nonsignificant effect of H-FABP microsatellite alleles on IMF content. Suggestive
evidence for a QTL affecting BFT was found on SSC6, but H-FABP was excluded as a
candidate gene. In conclusion, present and previous results support involvement
of H-FABP gene polymorphisms in IMF accretion independently from BFT in pigs.
Therefore, implementation of these polymorphisms in marker-assisted selection to
control IMF content independently from BFT may be considered. In contrast to
previous findings for Duroc pigs, no evidence was found for an effect of the A
FABP gene on IMF or BFT in this population.
PMID- 10764062
TI - Quantitative trait loci affecting growth and carcass composition of cattle
segregating alternate forms of myostatin.
AB - The effects of the bovine myostatin gene on chromosome 2 on birth and carcass
traits have been previously assessed. The objective of this study was to identify
additional quantitative trait loci (QTL) for economically important traits in two
families segregating an inactive copy of myostatin. Two half-sib families were
developed from Belgian Blue x MARC III (n = 246) and Piedmontese x Angus (n =
209) sires. Traits analyzed were birth (kg) and yearling weight (kg); hot carcass
weight (kg); fat depth (cm); marbling score; longissimus muscle area (cm2);
estimated kidney, pelvic, and heart fat (%); USDA yield grade; retail product
yield (%); fat yield (%); and wholesale rib-fat yield (%). Meat tenderness was
measured as Warner-Bratzler shear force at 3 and 14 d postmortem. The effect of
myostatin on these traits was removed by using phase information obtained from
the previous study with six microsatellite markers flanking the locus. Selective
genotyping was done on 92 animals from both families to identify genomic regions
potentially associated with retail product yield and fat depth, using a total of
150 informative markers in each family. Regions in which selective genotyping
indicated the presence of QTL were evaluated further by genotyping the entire
population and additional markers. For the family with Belgian Blue inheritance
(n = 246), a significant QTL for birth and yearling weight was identified on
chromosome 6. Suggestive QTL were identified for longissimus muscle area and hot
carcass weight on chromosome 6 and for marbling on chromosomes 17 and 27. For the
family with Piedmontese inheritance (n = 209), suggestive QTL on chromosome 5
were identified for fat depth, retail product yield, and USDA yield grade and on
chromosome 29 for Warner-Bratzler shear force at 3 and 14 d postmortem.
Interactions suggesting the presence of QTL were observed between myostatin and
chromosome 5 for Warner-Bratzler shear force at 14 d postmortem and between
myostatin and chromosome 14 for fat depth. Thus, in families segregating an
inactive copy of myostatin in cattle, other loci influencing quantitative traits
can be detected. These results are the initial effort to identify and
characterize QTL affecting carcass and growth traits in families segregating
myostatin.
PMID- 10764063
TI - Definition of animal breeding goals for sustainable production systems.
AB - What we do is determined by the way we "view" a complex issue and what sample of
issues or events we choose to deal with. In this paper, a model based on a
communal, cultural, or people-centered worldview, informed by a subjective
epistemology and a holistic ontology, is considered. Definitions and
interpretations of sustainable agriculture are reviewed. Common elements in
published definitions of sustainable agriculture and animal production among
those who seek long-term and equitable solutions for food production are resource
efficiency, profitability, productivity, environmental soundness, biodiversity,
social viability, and ethical aspects. Possible characteristics of future
sustainable production systems and further development are presented. The impact
of these characteristics on animal breeding goals is reviewed. The need for long
term biologically, ecologically, and sociologically sound breeding goals is
emphasized, because animal breeding determined only by short-term market forces
leads to unwanted side effects. Hence, a procedure for defining animal breeding
goals with ethical priorities and weighing of market and non-market values is
suggested. Implementation of non-market as well as market economic trait values
in the aggregate genotype, as suggested, may allow for breeding programs that
contribute to sustainable production systems. Examples of breeding goals in
salmon, cattle, and pigs are given, and the resulting genetic responses are
evaluated with respect to economic profit (or costs) and other criteria of
sustainability. Important prerequisites for breeding programs for sustainable
production are appropriate governmental policies, awareness of our way of
thinking, and a more communal worldview informed by a subjective epistemology and
a holistic ontology.
PMID- 10764064
TI - The effect of thermal environment and age on neonatal pig behavior.
AB - Three experiments were conducted to evaluate the ability of a radiant environment
and the presence of a littermate to attract pigs during the first 3 d of age. The
effect of stimuli on pig movement was studied in an enclosed rectangular aluminum
test chamber containing four similar sections that were heated independently. In
Exp. 1, all sections were at 34.8 degrees C to evaluate the chamber for biases of
where pigs located themselves at 1 (n = 24) and 2 d (n = 26) of age. More (P <
.025) pigs settled (e.g., no movement for 7 min) in end sections than in middle
sections. Age did not affect time to settle or settling location. The effect on
pig location of heating one chamber end section to either 23, 40, 48, 56, or 64
degrees C and leaving the remaining sections unheated (24 degrees C) was
determined in Exp. 2. Settling of pigs at 1 (n = 50) and 2 d (n = 50) of age was
affected by temperature (P < .001) but not by age. The minimum distance between
average pig location and the heated section occurred at 48 degrees C. Experiment
3 involved 15 pigs each at 1 and 3 d during a 1-h trial to compare the relative
pig attraction to 1) a heated chamber end section at 44.4 degrees C when
remaining sections were at 23.5 degrees C, 2) an anesthetized littermate in an
end section when all sections were at 24.1 degrees C, or 3) a choice test
involving a 45.5 degrees C end section and an anesthetized littermate in the
opposite end section with three unheated sections at 23.7 degrees C. Average
distance between the test animal and the heated section was greater (P < .01)
than that between the test animal and an anesthetized pig. Pigs that were allowed
a choice preferred to lie near an anesthetized littermate in a cold section
rather than alone in a 45 degrees C section (P < .01), and they were less (P <
.005) active when an anesthetized littermate was present in the chamber. Although
radiant heat effectively attracted pigs, heat was less attractive than an
anesthetized littermate. The greater attraction of pigs to a littermate than to
radiant heat may explain why pigs remain near the sow and littermates during d 1
and 2 after birth.
PMID- 10764065
TI - Effect of sensory stimuli on huddling behavior of pigs.
AB - Two experiments involving pigs at 1, 3, and 8 d of age were conducted to 1)
compare huddling between littermates and nonlittermates, 2) study the ability of
pigs to distinguish an anesthetized piglet from a piglet-shaped object, and 3)
explore the importance of physical contact between pigs on huddling behavior.
Experiments were conducted in an enclosed rectangular aluminum test chamber
having pressure sensors beneath floor panels to detect test pig location. Test
objects were placed on a platform at one end of the chamber and test pig location
was monitored during a 45 min trial. Experiment 1 involved a total of 45 pigs (5
pigs/treatment on d 1, 2, and 3). The results indicate that, regardless of age (P
> .05), when either a littermate or a nonlittermate occupied the platform,
average location of test pigs that "settled" (ceasing to move for 7 min or more)
was closer to the platform (P < .01), time spent near the platform was greater (P
< .01), and movement about the chamber was less (P < .01) than when the platform
was empty. No differences (P > .05) were observed between littermate and
nonlittermate stimuli for these variables. During Exp. 2, the platform was
covered with wire mesh. A total of 98 pigs were used in the study. Treatments
were a cage containing 1) no object (n = 24), 2) a wooden block (n = 25), 3) a
pig-shaped latex casting (n = 24), or 4) an anesthetized 8- to 10-d-old pig (n =
25). Pig age and treatment did not affect the percentage of time in each trial
that pigs spent within 23.5 cm of the cage or the percentage of pigs settling
within 23.5 cm of the cage. These studies show that pigs huddle similarly with
littermates and nonlittermates and that physical contact with another piglet but
not visual recognition of another piglet affects piglet huddling.
PMID- 10764066
TI - Growth performance and digestive and metabolic responses of gilts penned
individually or in groups of four.
AB - Two experiments were conducted to identify factors involved in the growth
retardation of pigs housed in groups. In each experiment, 60 gilts were allotted
to two treatments in a randomized complete block design. Twelve gilts were penned
individually with one feeder, one waterer, and a space allowance of 1.5 m2 per
pen. Forty-eight gilts were allocated to 12 groups of four and penned together
with four feeders, four waterers, and a space allowance of 6 m2 per pen. In Exp.
1 there were 60 growing gilts (initial and final BW of 17.9 and 50.8 kg,
respectively), and in Exp. 2 there were 60 finishing gilts (initial and final BW
of 46.0 and 118.3 kg, respectively). In Exp. 1 there was a trend (P < .10) toward
greater final BW, ADG, and average backfat thickness of gilts penned
individually. Apparent digestibilities of DM, CP, and energy tended (P < .10) to
be greater and plasma NEFA concentrations were lower (P < .05) for gilts penned
individually. Plasma concentrations of urea and glucose were similar between
treatments. In Exp. 2, ADG was greater (P < .05) and there was a trend (P < .10)
for greater final weight, ADFI, loin weight, and primal cut weight of gilts
penned individually. Apparent digestibilities of DM, CP, and energy and the
plasma concentrations of urea, glucose, and NEFA were similar in both treatments.
In summary, growing gilts penned four per group had reductions in daily gain,
backfat thickness, and apparent digestibilities of DM, CP, and energy and
increases in plasma NEFA concentrations. Finishing gilts penned four per group
had reductions in daily gain and feed intake with no changes in apparent nutrient
digestibilities or plasma metabolite concentrations compared to individually
penned gilts.
PMID- 10764067
TI - Differential effects of dexamethasone and clenbuterol on rat growth and on beta2
adrenoceptors in lung and skeletal muscle.
AB - Beta-adrenergic agonists increase growth rate, but their efficacy is reduced over
time as the number of beta2-adrenoceptors in muscle decreases. Dexamethasone
increases beta2-adrenoceptor density in many tissues, but this effect has not
been reported in skeletal muscle. In this study, male rats were treated daily for
10 d with either clenbuterol (4 mg/kg of feed), dexamethasone (.2 mg/kg BW,
s.c.), or clenbuterol plus dexamethasone. Untreated rats served as controls.
Dexamethasone caused a marked suppression of growth rate, which resulted in
decreased (P < .001) body weight (-29%), carcass weight (-30%), hind-limb muscles
(-22%), omental fat (-22%), and heart weight (-10%). Feed intake was reduced (
26%), but feed conversion efficiency was also impaired (P < .001). Clenbuterol
caused a small increase in growth rate (+6%; P < .05), with an increase in leg
muscle (+7%; P < .01) and heart mass (+8%; P < .05). Feed efficiency was improved
(P < .001) by clenbuterol. Rats given the combined treatment still showed a
reduction in growth rate (-81%). Clenbuterol caused only a mild attenuation of
the effects of dexamethasone on feed intake, BW, and carcass weight, but reduced
the catabolic effect of dexamethasone on hind-limb muscle to only -8%.
Clenbuterol caused a slight increase in the affinity beta2-adrenoceptors in lung
for binding to the radioligand (-)[125I]iodocyanopindolol. Relative to control
values, the density of beta2-adrenoceptors in lung was +31% with dexamethasone
treatment, -45% with clenbuterol, and -23% with the combined treatment.
Clenbuterol also decreased beta2-adrenoceptors in skeletal muscle (-35%), but so
did dexamethasone (-13%), so the effects of the beta-adrenergic agonist were not
attenuated through use of the combined treatment (-40%). The results show that
the inductive effect of glucocorticoids on beta2-adrenoceptors is tissue-specific
and that glucocorticoid treatment is not a useful adjunct to beta-adrenergic
agonist treatment in animal production.
PMID- 10764068
TI - Growth performance, metabolic and endocrine traits, and absorptive capacity in
neonatal calves fed either colostrum or milk replacer at two levels.
AB - Colostrum (CO) contains high amounts, whereas whole milk and milk replacer (MR)
contain small amounts, of bioactive and growth-promoting substances, such as IGF
I. An experiment was designed to study the effects of feeding CO or MR on the
first 3 d to neonatal calves, followed by whole milk up to d 7, at low and high
density. Intestinal absorptive capacity, plasma metabolite and hormone
concentrations, and growth performance were measured during the 1st wk of life.
Body weight increased (P < .05) similarly in calves fed low or high amounts of CO
but did not rise in MR-fed calves. Loose feces were more frequent (P < .05) and
absorption of xylose on d 5 was lower (P < .01) in MR- than in CO-fed calves, but
there were no effects of feeding density within CO-fed or within MR-fed groups.
However, high feeding density within CO-fed groups enhanced (P < .05) total
protein, globulin, triglyceride, cholesterol, and insulin concentrations, whereas
in the initially high and low MR-fed groups only plasma glucose and insulin after
the first meal and plasma NEFA on d 2 were modified (P < .05) by different
feeding density. Thus, feeding different amounts of CO partly influenced protein
and fat metabolism in calves during the 1st wk of life, but it did not measurably
affect intestinal function. However, feeding different amounts of MR, in the
absence of CO, barely affected metabolic and endocrine traits and absorptive
capacity. Thus, high density CO feeding, and therefore a high supply of
nutrients, together with greater amounts of bioactive and growth-promoting
substances influenced neonatal metabolism and growth more than a high density of
MR feeding containing only small amounts of bioactive and growth-promoting
substances. Factors in addition to nutrient density seem to be important for the
development of neonatal calves.
PMID- 10764069
TI - The influence of recombinant bovine somatotropin on dietary energy level-related
growth of Holstein-Friesian bull calves.
AB - Our objective for this study was to assess the effect of recombinant bovine
somatotropin (rbST) in overcoming the biological effects attributed to live
weight increase and age on growth and fat deposition in male cattle. Holstein
Friesian bull calves (n = 56; 182.2 +/- 14.7 d old) were allotted to four
subtreatments in a randomized complete block with a factorial arrangement of two
levels of rbST: 0 and 500 mg of Posilac, every 2 wk, and two dietary
metabolizable energy (ME) concentrations: low metabolizable energy (LME) and high
metabolizable energy (HME); 10 vs 11.3 MJ/kg DM, respectively. The effect of rbST
treatment on daily gain was expressed mostly on the HME diets. The rbST treatment
had no effect on the animals fed the LME diets before the age of 240 d was
reached. Dry matter intake and the effect of rbST treatment on DM intake were
inversely related to the energy concentration of the diet. The degree of fatness
of the animals was significantly reduced by rbST treatment and significantly
increased by energy concentration of the diet. The major effect of rbST, under
the experimental conditions, in regards to adipose tissue deposition, was on the
fat depots and not on the intramuscular fat. The concentration of bST, IGF-I, and
insulin in the plasma was increased (P < .001) owing to rbST treatment. Lower
metabolizable energy supply led to a higher (P < .001) plasma bST concentration,
nonsignificantly lower plasma IGF-I and thyroid hormone concentrations, and lower
(P < .001) plasma insulin concentration. A trend (P = .065) toward an increase in
PUFA was found in the muscle of the rbST-treated and the HME diet animals. At a
young age, when the natural growth potential is high, rbST treatment will be
efficient only when a diet allowing a high digestible energy intake is provided.
PMID- 10764070
TI - Effects of muscle type, castration, age, and compensatory growth rate on androgen
receptor mRNA expression in bovine skeletal muscle.
AB - The effect of testosterone on sexual dimorphism is evident by differential growth
of forelimb and neck muscles in bulls and steers. Divergent hormone sensitivites
may account for the differential growth rates of individual muscles. Therefore,
the objective of this study was to compare androgen receptor (AR) expression in
three different muscles of bulls and steers at various ages and growth rates.
Thirty Montbeliard bulls and 30 steers were assigned to four slaughter age
groups. Four or five animals of each sex were slaughtered at 4 and 8 mo of age.
Animals in the remaining two slaughter groups (12 and 16 mo) were divided into
groups of either restricted (R) or ad libitum (AL) access to feed. Five animals
of each sex and diet were slaughtered at the end of the restricted intake period
at 12 mo of age. To simulate compensatory growth, the remaining animals (R and
AL) were allowed ad libitum access to feed until slaughter at 16 mo of age. Total
RNA was extracted from samples of semitendinosus (ST), triceps brachii (TB), and
splenius (SP) muscles. Androgen receptor mRNA was quantified in 200-ng total RNA
preparations using an internally standardized reverse transcription (RT) PCR
assay. Data were analyzed using 18S ribosomal RNA concentrations as a covariable.
Steers had higher AR mRNA levels per RNA unit than bulls (P < .01). Androgen
receptor mRNA levels differed between muscles (P < .05), with lowest expression
in the SP. The pattern of AR expression differed (P < .05) for each muscle with
increasing age. Between 4 and 12 mo of age, AR mRNA levels increased (P < .05) in
SP but remained unchanged in the ST and TB. Feeding regimen had no effect on
muscle AR expression, but steers exhibiting compensatory growth had higher AR
mRNA levels than AL steers (P < .01) or bulls (P < .01). Our results show that AR
expression is muscle-specific and may be modulated by circulating testicular
hormones. These data suggest that the regulation of AR expression may be linked
to allometric muscle growth patterns in cattle and compensatory gain in steers.
PMID- 10764071
TI - Effect of fiber source on cecal fermentation and nitrogen recycled through
cecotrophy in rabbits.
AB - The influence of fiber source on fiber digestion in rabbits was investigated. Six
fibrous feedstuffs with wide differences in chemical composition and particle
size were selected: paprika meal, olive leaves, alfalfa hay, soybean hulls,
sodium hydroxide-treated barley straw, and sunflower hulls. Six diets were
formulated to contain one of these ingredients as the sole source of fiber. To
avoid nutrient imbalances, fiber sources were supplemented with different
proportions of a fiber-free concentrate, based on soy protein isolate, wheat
flour, lard, and a vitamin and mineral mix, to obtain diets containing at least
3% nitrogen and 5% starch. Daily soft feces excretion, and its NDF, and total and
microbial nitrogen content were determined in 60 fattening rabbits (10 per diet).
Seven days after the last cecotrophy control, the same animals were used to
determine weight of stomach, cecum and their contents, and cecal fermentation
traits (pH, VFA and ammonia concentrations, and buffer properties of cecal
contents). Stepwise regression analysis showed a positive effect (P < .001) on
soft feces excretion, total and microbial nitrogen concentrations in soft feces,
cecal acidity, and total VFA in the cecum of dietary pectic constituents (2.9,
3.5, 2.5, .9, and 6.6%) and proportion of fine particles (< .315 mm) (1.8, .9,
1.3, .15, and .9%) per each increment of one percentage unit of the independent
variables. Proportion of fine particles also increased weight of cecal contents
(P < .001). Soft feces excretion and weight of stomach and of its contents
increased (P < .001) by 5.2, 2.8, and 10.2% per each percentage unit increment of
proportion of large particles (> 1.25 mm). Degree of lignification of NDF
decreased total nitrogen concentration in soft feces and cecal VFA concentration
(P < .001). Source of fiber affected cecal pH not only by its influence on the
cecal concentrations of the final products of fermentation, but also through its
effect on the pH of dry cecal contents (P < .001). The latter was negatively
correlated with dietary proportion of fine particles, degree of lignification of
NDF, and base-buffering capacity of dry cecal contents (r = -.52, -.37, and -.49,
respectively). From these results, we conclude that pectic constituent
concentration, degree of lignification of NDF, and particle size are the
variables that best characterize the influence of the source of fiber on soft
feces excretion and cecal fermentation traits in rabbits.
PMID- 10764072
TI - Effects of a whey protein product and spray-dried animal plasma on growth
performance of weanling pigs.
AB - Five experiments were conducted to evaluate the effects of a high-protein, whey
protein product (WPP; 73% CP, 6.8% lysine, 12.8% fat, and 5% lactose) and spray
dried animal plasma (SDAP) on growth performance of weanling pigs. In all
experiments, pigs were fed experimental diets from d 0 to 14 after weaning in a
pelleted form and then a common diet in meal form for the remainder of the
experiment. Dietary treatments were established by substituting WPP or SDAP for
dried skim milk (Exp. 1) or soybean meal (Exp. 2, 3, 4, and 5) in the control
diet. In Exp. 1, we maintained a constant level of lactose in all diets by
adjusting the amount of added crystalline lactose. The amount of lactose in diets
used in Exp. 2 through 5 varied slightly by the addition of WPP. In Exp. 1 and 2,
180 weanling pigs (initially 5.8 kg and 19 +/- 1 d of age or 5.5 kg and 17 +/- 1
d of age, respectively) were used. Treatment diets contained SDAP (2.5 and 5%) or
WPP (2.7 and 5.4% in Exp.1, and 2.5 or 5.0% in Exp. 2). In Exp. 1, from d 0 to 7
after weaning, ADG and ADFI increased with increasing SDAP (linear, P < .01). No
other treatment effects were observed during the d 0 to 14 period. In Exp. 2,
from d 0 to 14 after weaning, ADG and G:F increased (linear, P < .04) with
increasing SDAP or WWP. In Exp. 3, 305 weanling pigs (initially 4.1 kg and 12 +/-
1 d of age) were used. The control diet contained 2.5% SDAP. The experimental
diets were similar to the control diet but contained an additional 2.5 or 5.0%
SDAP or 2.5 or 5.0% WPP. From d 0 to 14 after weaning, ADG, ADFI, and G:F
increased (quadratic, P < .05) with increasing SDAP up to 5.0%. Increasing WPP
increased ADG (quadratic, P < .07) and ADFI (linear, P < .09). In Exp. 4 and 5,
329 and 756 weanling pigs (initially 4.1 kg and 12 +/- 1 d of age and 5.2 kg and
18 +/- 1 d of age, respectively) were fed diets in which WPP was substituted for
0, 25, 50, 75, and 100% (Exp. 4) or 0, 50, and 100% (Exp. 5) of the SDAP in the
control diet. In Exp. 4 and 5, from d 0 to 14 after weaning, pigs fed a 1:1 blend
of each protein source had better ADG (quadratic, P < .04) than those only fed
SDAP. In conclusion, WPP can be used in combination with or as a total
replacement for SDAP in diets for weanling pigs without reducing performance.
PMID- 10764073
TI - The effects of branched-chain amino acids on sow and litter performance.
AB - Sows (n = 306; PIC, Line C-19; average parity 2.1) were used to evaluate the
interrelationship between valine, isoleucine, and leucine on sow and litter
performance. Our objective was to determine whether the increase in litter
weaning weight associated with added dietary valine is specific for valine or a
result of the total branched-chain amino acid (i.e., isoleucine and[or] leucine)
concentration of the diet. Eight dietary treatments (36 to 41 sows/treatment)
were arranged as a 2 x 2 x 2 factorial with two levels of valine (.80 and 1.20%),
isoleucine (.68 and 1.08%), and leucine (1.57 and 1.97%). This provided total
branched-chain amino acid levels of 3.05, 3.45, 3.85, and 4.25%. The lowest level
of each branched-chain amino acid was similar to that in a .90% lysine corn
soybean meal diet containing .15% L-lysine HCl. Amino acids other than valine,
isoleucine, and leucine met or exceeded their suggested estimates relative to
lysine using ratios derived from the National and Agricultural Research Councils.
Average number of pigs on d 2 of lactation was 11.2, and average lactation length
was 20.9 d. Number of pigs weaned (x = 10.6), sow ADFI (x = 5.85 kg), and sow
weight loss (x = 4.25 kg) were not affected by dietary treatment (P > .10). Sow
backfat loss (P < .02), litter weaning weight (P < .04), and litter weight gain
from d 2 to weaning (P > .05) increased as dietary valine increased. Litter
weight at weaning and litter weight gain were not affected by dietary isoleucine
(P > .80) or leucine (P > .60). Sixteen or 17 sows per treatment (129 total) were
milked manually on d 14 to 16 of lactation. Increasing dietary valine tended to
increase milk urea N (P < .07) but did not affect milk DM, CP, fat, lactose, or
ash. Increasing dietary isoleucine or leucine had no effects on milk composition.
These results confirm the importance of dietary valine for increased litter
weaning weight, independent of either additional dietary leucine or isoleucine.
PMID- 10764074
TI - A new phytase expressed in yeast effectively improves the bioavailability of
phytate phosphorus to weanling pigs.
AB - We have recently expressed a new phytase enzyme in a yeast system. Three
experiments with a total of 140 weanling crossbred pigs were conducted to examine
the efficacy of this enzyme in improving the bioavailability of phytate-P in corn
soybean meal diets to young pigs. Experiment 1 compared the efficacy of this new
phytase with a commercially available phytase (Natuphos, BASF) for 4 wk at an
inclusion level of 1,200 U/kg of diet. Experiment 2 compared the responses of
pigs to four doses of the new phytase supplementation (300, 600, 900, and 1,200
U/kg of diet) for 4 wk. Experiment 3 compared the efficacy of this new phytase
and Natuphos at a marginally optimal dose (700 U/kg of diet) for 5 wk. A group of
pigs were fed the P-deficient basal diet as a negative control in Exp. 1, and a
group of pigs were fed the basal diet plus .17 or .22% inorganic P as a positive
control in all experiments. In Exp. 1, pigs fed the two sources of phytase had
similar ADG (564 vs 567 g), gain/feed (.597 vs .589), plasma inorganic P
concentrations (8.9 vs 8.4 mg/dL), and mobility scores (4.25 vs 4.46) that were
higher (P < .05) than those of the negative control. In Exp. 2, plasma inorganic
P concentration was a fairly linear response to the phytase dose (r > .83) at wk
1 and 2. Overall ADG of pigs also tended to increase with the phytase dose (P =
.15). In Exp. 3, pigs fed the two sources of phytase had ADG (483 vs 506 g)
similar to that of the positive control (508 g). These two groups also had
similar plasma inorganic P concentrations (7.7 vs 7.4 mg/dL) that were lower (P <
.05) than those of the positive control group (9.7 mg/dL). There was no
significant effect of dietary treatments on ADFI in all three experiments. In
conclusion, our new phytase was as effective as Natuphos, at the inclusion level
of 700 or 1,200 U/kg of a P-deficient, corn-soybean meal diet, in improving
phytate-P utilization by young pigs.
PMID- 10764075
TI - Phosphorus bioavailability and digestibility of normal and genetically modified
low-phytate corn for pigs.
AB - We conducted two studies to determine the bioavailability and apparent
digestibility of P in a low-phytate corn hybrid (.28% total P, .10% phytate P)
genetically modified to be homozygous for the 1pa1-1 allele and a nearly isogenic
corn hybrid (normal) (.25% total P, .20% phytate P). Additionally, we conducted
an in vitro assay involving a peptic and pancreatin digestion to estimate P
availability. The first study used 50 individually penned pigs (initial body
weight 9 kg) and 10 treatments in a randomized complete block design. A
cornstarch-soybean meal basal diet (.6% Ca, .2% P) was used. Treatments consisted
of the basal diet and the basal diet plus .05, .10, or .15% P from monosodium
phosphate (MSP), low-phytate corn, or normal corn. After a 35-d feeding period,
pigs were killed to collect the fourth metacarpal for measurements of ash and
breaking load. Breaking load was regressed on added P intake, and the
bioavailability of P was determined by the slope ratio method. The
bioavailabilities of P (relative to MSP) for low-phytate and normal corn were 62
and 9%, respectively. These were similar to the determined in vitro values of 57
and 11% for low-phytate and normal corn, respectively. In the second study, 20
pigs (initial BW 20 kg) were used in a randomized complete block design with a 2
x 2 factorial arrangement of treatments. Two corn lines (low-phytate and normal)
and two levels of supplemental P (0 and .2%) from dicalcium phosphate were used.
Diets with no added P were formulated to contain .9% lysine, .6% Ca, and .34% P.
Apparent nutrient digestibilities were calculated from total collection of urine
and feces for 5 d. There were no differences among treatments for energy and
nitrogen digestibility. Pigs fed low-phytate corn with no added P had increased
digestibility and retention of P and reduced total P excretion (P < .05). We
conclude that low-phytate corn contains at least five times as much available P
as normal corn. The use oflow-phytate corn greatly reduced the amount of P
excreted by the pig and increased the N:P ratio in the manure.
PMID- 10764076
TI - The effects of citric acid on phytate-phosphorus utilization in young chicks and
pigs.
AB - Several bioassays were conducted with young chicks and pigs fed phosphorus (P)
deficient corn-soybean meal diets. With diets for chicks containing .62% Ca and
.42% P (.10% available P), graded doses of a citric acid + sodium citrate (1:1,
wt:wt) mixture (0, 1, 2, 4, or 6% of diet) resulted in linear (P < .01) increases
in both weight gain and tibia ash. Relative to chicks fed no citric acid, tibia
ash (%) and weight gain (g/d) were increased by 43 and 22%, respectively, in
chicks fed 6% citric acid. Additional chick trials showed that 6% citric acid
alone or sodium citrate alone was as efficacious as the citric acid + sodium
citrate mixture and that 1,450 U/kg of phytase produced a positive response in
bone ash and weight gain in chicks fed a diet containing 6% citrate. Varying the
Ca:available P ratio with and without citrate supplementation indicated that
citric acid primarily affected phytate-P utilization, not Ca, in chicks.
Moreover, chicks did not respond to citrate supplementation when fed a P
deficient (.13% available P), phytate-free casein-dextrose diet. Young pigs
averaging 10 to 11 kg also were used to evaluate citric acid efficacy in two
experiments. A P-deficient corn-soybean meal basal diet was used to construct
five treatment diets that contained 1) no additive, 2) 3% citric acid, 3) 6%
citric acid, 4) 1,450 U/kg phytase, and 5) 6% citric acid + 1,450 U/kg phytase.
Phytase supplementation increased (P < .01) weight gain, gain:feed, and
metatarsal ash, whereas citric acid addition increased only gain:feed (P < .05)
and metatarsal ash (P < .08). A subsequent 22-d pig experiment was conducted to
evaluate the effect of lower levels of citric acid (0, 1, 2, or 3%) or 1,450 U/kg
phytase addition to a P-deficient corn-soybean meal diet. Phytase supplementation
improved (P < .01) all criteria measured. Weight gain and gain:feed data
suggested a response to citric acid addition, but this was not supported by
fibula ash results (P > .10). The positive responses to phytase were much greater
than those to citric acid in both pig experiments. Thus, dietary citric acid
effectively improved phytate P utilization in chicks but had a much smaller
effect in pigs.
PMID- 10764077
TI - Ergotamine alters plasma concentrations of glucagon, insulin, cortisol, and
triiodothyronine in cows.
AB - Bovine plasma was assayed to determine whether ergotamine, an ergopeptide
isolated from endophytic tall fescue, affected cortisol, triiodothyronine,
insulin, and glucagon concentrations. In Exp. 1, four heifers received an i.v.
bolus injection of ergotamine tartrate (19 microg/kg BW) or saline vehicle in a
simple crossover design 2 d after induced luteolysis. Oxytocin (100 USP units)
was i.v. administered 4 h after ergotamine or saline. Treatment x time affected
(P < .01) respiration rates and plasma concentrations of cortisol,
triiodothyronine, insulin, and glucagon. Respiration rates were elevated (P <
.01) 2 to 7 h after ergotamine, but they were unchanged after saline. Plasma
cortisol concentrations were increased (P < .01) 1 to 3 h after ergotamine but
not after saline. Plasma triiodothyronine was elevated 2 h after ergotamine, but
it was unchanged in response to saline. Insulin decreased (P < .01) and glucagon
increased (P < .01) during the 1st h after ergotamine, but not in response to
saline. A second increase (P < .01) of glucagon was observed 3 h after
ergotamine. In Exp. 2, six cows were treated with an i.v. bolus injection of
ergotamine (20 microg/kg BW) or saline in a simple crossover design 10 d after
receiving a s.c. ear implant containing norgestomet. Oxytocin (100 USP units) was
i.v. administered 4 h after ergotamine or saline. Treatment x time affected (P <
.001) respiration rates, cortisol, insulin, and glucagon and tended to influence
(P = .12) triiodothyronine concentrations. Respiration rates were elevated (P <
.01) 1 to 7 h after ergotamine but were unaltered by saline. Plasma cortisol was
elevated (P < .01) 1 to 5 h after ergotamine, but not in response to saline.
Plasma triiodothyronine was elevated (P < .01) 1 to 2 h after ergotamine, but not
after saline. Insulin was decreased (P < .01) and glucagon increased (P < .01)
within 1 h after ergotamine treatment, but they were not altered by saline. A
second increase (P < .01) of glucagon occurred by 4 h after ergotamine. In Exp. 1
and 2, glucagon increased (P < .01) 1 h after oxytocin in saline and ergotamine
cows. Results indicate that ergotamine can alter plasma concentrations of
hormones that mediate nutrient metabolism and thermoregulation in cattle.
PMID- 10764078
TI - Response of C2C12 mouse and turkey skeletal muscle cells to the beta-adrenergic
agonist ractopamine.
AB - The effects of ractopamine (RAC) and ractopamine stereoisomers (RR, RS, SR, and
SS) on cyclic AMP (cAMP) production, total protein, and DNA concentrations in
mouse skeletal muscle cells (C2C12) were evaluated. The RAC (10 microM) caused an
approximately 30% increase in cell number, protein, and DNA concentrations in
myoblasts after 48 h; no differences were found in myotubes. The RAC-stimulated
increase of these variables in myoblasts was blocked by the presence of equimolar
concentrations of propranolol. At a later passage, myoblasts failed to exhibit an
increase in cell number, protein, or DNA upon exposure to RAC. Both myoblasts and
myotubes increased cAMP production in response to 10 microM RAC. The RAC isomers
ranked RR >> SR > RS approximately SS in ability to stimulate cAMP production,
with essentially no response to SS. The SR produced about 50% of the RR response.
Coincubation of propranolol (10 microM) and RAC (10 microM) prevented RAC
stimulated cAMP production in myotubes but not in myoblasts (approximately 35% of
cAMP produced by RAC alone). Turkey satellite cells (derived from biceps femoris
of 12-wk-old toms) produced essentially no increased cAMP when exposed to 10
microM RAC stereoisomers. Stability of RAC was evaluated under laboratory storage
and culture conditions. The RAC was stable for more than 4 mo when stored in
deuterated DMSO (>98% purity) at room temperature or in aqueous solutions at -80
degrees C, as determined from sequential nuclear magnetic resonance studies.
Radiolabeled RAC was incubated for 72 h in the presence of serum-containing
medium, with or without C2C12 cells. Ninety-eight percent of the parent compound
found in the medium at time zero was present in the medium as parent at the end
of 72 h. The cellular cAMP response to RAC through beta-adrenergic receptors
seems to be stereospecific. If the state of myoblasts and myotubes in vitro
reflects the in vivo state, then the ractopamine effect in vivo on cellular
processes (including cell division and protein and DNA accumulation) may be
independent of beta-adrenergic receptors in muscle.
PMID- 10764079
TI - Suppressor activity of bone marrow cells and localization of fluorescent-labeled
bone marrow cells within ovine endometrial tissue.
AB - Numbers of fluorescein isothiocyanate (FITC)-labeled bone marrow (BM) cells of
donor lambs were quantified within endometrial cell suspensions following their
administration to ovariectomized (OVX; control-and estradiol-17beta-treated) and
intact (estrus, d-14 cyclic and pregnant) ewes. The numbers of fluorescent BM
cells were greater (P < .05) for the estrous and d-14 cyclic ewes than for both
groups of OVX ewes. Fractionation of the endometrial cells with Percoll revealed
that the majority of fluorescent cells were low-density (1.002 to 1.056 g/mL)
cells. In coculture experiments, low-density cells from lamb BM not only
suppressed the incorporation of thymidine into phytohemagglutinin-treated
peripheral blood lymphocytes, but the cells also released suppressor factor into
the culture medium. Suppressor activity tended to be reversed (P < .1) by a pan
specific neutralization antibody to transforming growth factor-beta (TGF-beta);
however, the activity was unaffected by a neutralization antibody to TGF-beta2.
These findings suggest that ovine endometrial suppressor cells may represent a
population of low-density BM-derived natural suppressor cells, and their
trafficking and localization patterns may depend on an ovarian factor(s).
Further, suppressor activity does not seem to be mediated by TGF-beta2.
PMID- 10764080
TI - Digestibility of prairie hay diets supplemented with different levels of
magnesium-mica by beef heifers.
AB - Four ruminally fistulated, nonpregnant, nonlactating heifers (515 +/- 7.9 kg)
were offered chopped (10-cm screen size) prairie hay for ad libitum consumption
with 1.8 kg/d of supplements to provide 0, 45, 113, or 181 g/d of magnesium-mica
(MM) in a 4 x 4 Latin square design experiment. Heifers were adapted to diets for
7 d in drylot followed by a 19-d confinement period in individual stalls within a
metabolism facility. Total feces and urine were collected for 5 d, daily intake
and water consumption were monitored for 16 d, and in situ disappearance of fiber
(prairie hay) and CP (soybean meal) were determined during the confinement
period. Ruminal samples for fermentation product analyses were collected at
feeding and every 2 h thereafter for 12 h on d 18, and rumens were evacuated at
1100 on d 19 to determine rumen fill. Cubic responses (P < .05) to MM level were
observed for DM, OM, NDF, and ADF digestion and were characterized by a tendency
for improved digestion with 45 g/d compared with the control diet, followed by a
suppressive effect on digestion with 113 g/d, then little effect with 181 g/d MM.
In situ NDF disappearance at 72 and 96 h tended (P < . 10) to be influenced
quadratically by level of MM, but MM level had no apparent effect on ruminal fill
and passage rate, ciliated protozoa counts, in situ rate of disappearance of
fiber or CP, or nitrogen balance. Therefore, feeding MM at low levels to heifers
consuming a prairie hay diet with a 20% CP supplement seemed to be beneficial for
feed digestion with no measurable negative impact on intake or ruminal protein or
fiber digestion.
PMID- 10764081
TI - Pretanned leather shavings in a supplement mixture for steers: I. In situ and in
vitro disappearance, ruminal fermentation, and organic matter, nitrogen, and
fiber digestion.
AB - Two digestion studies were conducted to evaluate the use of pretanned leather
shavings as a component of a protein supplement. In Exp. 1, the in situ and in
vitro disappearance of pretanned leather shavings and soybean meal was evaluated.
Results revealed that less than 18.4% of the pretanned leather shavings was
solubilized and disappeared when exposed to McDougall's buffer for 48 h, but
there was 90.0% disappearance with 48-h exposure to a .1 N HCl/pepsin treatment
and 97.0% disappearance with exposure to a two-stage digestion. In situ
disappearance following 72 h in the rumen allowed 6.8% disappearance. Thus,
leather shavings seem to be relatively indigestible in the rumen, but postruminal
digestion may be possible. In Exp. 2, six Angus x Holstein steers, fitted with
ruminal and duodenal cannulas, were used in a replicated 3 x 3 Latin square to
evaluate ruminal and digestion effects of the following supplements combined with
fescue hay at 1.7% of BW (DM basis): no supplementation (control);
supplementation intraruminally with soybean meal at .07% of BW (as-fed basis);
and supplementation intraruminally with a combination of soybean meal and
pretanned leather shavings (17:8 ratio) at .05% of BW (isonitrogenous to soybean
meal; as-fed basis). Ruminal fluid passage rate was greater and fluid turnover
time was shorter in steers fed leather shavings than in those fed soybean meal (P
= .10). Ruminal pH was lower (P = .04) for supplemented steers than for control
steers and ruminal NH3 N concentration was greater (P = .01) in steers fed
soybean meal than in those fed leather shavings. Total VFA concentration was
increased (P = .02) by supplementation. Supplementation with soybean meal
increased (P < .05) ruminal molar proportions of butyrate, valerate, and
isovalerate compared with leather shavings. Duodenal OM flow and OM disappearing
in the intestines were increased by supplementation (P < .10), but not by the
type of supplement fed (P > .10). Ruminal digestion of OM and total tract OM
digestion were unaffected (P > .10) by supplementation and the type of supplement
fed. Flow and digestion of NDF were unaffected (P > .10) by the treatments. Flow
of N and the quantity of N disappearing in the intestines were increased (P <
.05) by supplementation but did not differ (P > .10) between supplementation
groups. Microbial N flow, N utilization for net microbial protein synthesis, and
ruminal N disappearance were unaffected (P > .10) by supplementation and the type
of supplement provided. Combining pretanned leather shavings with soybean meal
seemed to have no deleterious effects on digestion or fermentation and to allow
for escape of some N to the lower tract.
PMID- 10764082
TI - Pretanned leather shavings in a supplement mixture for steers: II. Digesta
kinetics, ruminal fermentation, and grazing behavior in steers grazing dormant
wheatgrass pasture.
AB - Twelve ruminally cannulated steers (Angus x Holstein; average initial BW = 533 +/
3.28 kg) were randomly allotted to one of three treatments (four
steers/treatment) to evaluate the use of pretanned leather shavings as a
component of a protein supplement for steers grazing dormant intermediate
wheatgrass (Thinopyrum intermedium Host). Steers were allotted to one of three
treatments: 1) no supplement (control); 2) supplementation intraruminally at 0700
with soybean meal at .2% of BW (as-fed basis); 3) supplementation intraruminally
with soybean meal and pretanned leather shavings (17:8 ratio, respectively) at
.16% of BW (as-fed basis). Supplements were formulated so that intakes were
isonitrogenous and were placed intraruminally once daily (0700). Sampling periods
were conducted February 3 to 16 and February 17 to March 5, 1995. In situ organic
matter disappearance of the soybean meal supplement was greater (P > .05) than
that of the leather shavings supplement at all incubation times (1, 3, 6, 9, 12,
24, and 48 h). Data suggested that pretanned leather shavings within the leather
shavings supplement were only 25% degradable within the rumen. Forage OM intake
(control = 12.7, soybean meal = 12.7, and leather shavings = 13.4 g/kg of BW),
grazing time, and grazing efficiency were not altered (P > .10) by
supplementation or type of supplement provided but did increase between the
February and March samplings. Total intake was increased (P = .09) with
supplementation and reflected the addition of the protein supplements.
Particulate and fluid passage estimates were unaffected (P > .10) by the
supplements; however, gastrointestinal fill increased (P = .01) between the
February and March samplings. Ruminal pH was lower (P = .04) and ruminal NH3 N
concentration was greater (P = .02) for supplemented steers than for control
steers, and supplementation treatments did not differ (P > .10). Total VFA
concentrations were increased (P = .01) by supplementation but were not affected
by type of supplement provided (P > .10). Ruminal molar proportions of acetate
and propionate and the ratio of these two VFA did not differ (P > .10) between
supplementation types. Nonetheless, supplementation increased molar proportions
of butyrate (P = .04), valerate (P = .02), and isovalerate (P = .05), and leather
shavings supplementation increased (P = .10) isobutyrate proportions over those
in steers supplemented with soybean meal. Combining pretanned leather shavings
with soybean meal seemed to have no deleterious effects on forage intake, digesta
passage, grazing behavior, or ruminal fermentation and seemed to provide effects
similar to those of soybean meal alone.
PMID- 10764083
TI - Response of nitrogen metabolism in preparturient dairy cows to methionine
supplementation.
AB - Three multiparous Holstein cows (607 kg of BW) were surgically prepared with an
elevated carotid artery and indwelling catheters in the hepatic, portal, and two
mesenteric veins to study the effects of methionine supplementation on amino acid
metabolism during the last 2 wk of pregnancy. The study began 15 d before the
expected calving date. Dietary treatments were Control (1.53 Mcal NE(l)/kg, 15.6%
CP, and 40% ruminally undegradable protein) and Control supplemented with 60 g/d
of ruminally protected methionine (MET, supplying 39 g/d of DL-methionine and
approximately 18 g/d of methionine available for intestinal absorption). Each cow
received both dietary treatments in a crossover design. Cows were fed once daily.
After 5 d on treatment, a blood flow marker (para-aminohippurate) was infused
into a mesenteric vein, and arterial, portal, and hepatic blood samples were
obtained at 0, 2, 6, 12, and 18 h after feeding. Net flux of methionine was
calculated as the plasma arteriovenous difference multiplied by plasma flow. Dry
matter intake (10.8 kg/d) and portal (824 L/h) and hepatic (995 L/h) plasma flows
were not affected (P > .10) by treatment. Arterial plasma concentration of
methionine was greater (P = .10) with MET (27.67 microM) than with Control (16.42
microM). Net portal absorption of methionine increased (P = .10) with MET (26.2
g/d) compared with Control (9.5 g/d). The net portal methionine flux was
negatively correlated (r = -.59; P < .001) with arterial urea concentrations. Net
flux of methionine across splanchnic tissues shifted (P = .06) from a net uptake
with Control (4 g/d) to a net output with MET (11 g/d). Therefore, MET increased
by 15 g/d the methionine supply to the rest of the body. The net uptake of
methionine by splanchnic tissues observed with Control indicated a net
mobilization of methionine by peripheral tissues. Results indicate that
methionine was the limiting amino acid with Control and that MET was beneficial
because it increased methionine supply to peripheral tissues and reduced arterial
urea concentrations.
PMID- 10764084
TI - Ruminal fermentation and duodenal flow following progressive inoculations of
fauna-free wethers with major individual species of ciliate protozoa or total
fauna.
AB - Naturally fauna-free (FF) wethers, equipped with ruminal and duodenal cannulas,
were used in two groups of eight (Group A) and seven (Group B) animals in six
consecutive experimental periods, each lasting for 28 d. The objective was to
measure ruminal fermentation traits, and flows of nonammonia nitrogen (NAN),
total amino acid (TAA), and bacterial nitrogen (BN) from the stomach after
inoculation with individual ciliate protozoa species in each period. The wethers
in both groups were fed a diet based on corn silage, haylage, and soybean meal,
and they remained FF during the first period. At the beginning of each other
period, the wethers were progressively inoculated intraruminally with one
individual major species of ruminal ciliate protozoa or total fauna (TF). Thus,
Group A was progressively inoculated (+) with Dasytricha ruminantium (DS),
Polyplastron multivesiculatum (PP), Isotricha intestinalis (IS), Entodinium
caudatum (EN) and TF-type A. Also, Group B was progressively inoculated (+) with
IS, DS, Epidinium ecaudatum (EP), Eudiplodinium maggi (EU), and EN. Duodenal
digesta and ruminal fluid were collected and sampled in each period on d 26 and
28, respectively, and subjected to chemical analyses. A significantly higher (P <
.05) pH (6.4) in ruminal fluid of the Group A wethers was obtained when each DS,
DS+PP, DS-PP-IS+EN, and TF population was present in the rumen than when the
wethers were FF (6.2). In the Group B wethers, pH (6.1) was lower (P < .05) for
the population of IS-DS-EP+EU than for other populations (6.2 to 6.3). The
concentration of total VFA in ruminal fluid was higher (P < .05) in the Group B
wethers when IS, IS+DS, or IS-DS+EP populations were present in the rumen than
when the wethers were FF. The flow of NAN, TAA, and BN from the stomach to the
intestinal tract was generally lower for different protozoa populations than for
the FF period. Largest decreases (P < .05) in the flow of NAN, TAA, and BN
occurred when EN was added into the rumen of wethers in the A and B groups, which
already contained populations of DS-PP+IS and IS-DS-EP+EU, respectively.
Holotrich protozoa had very little effect on the protein metabolism in the rumen,
but cellulolytic protozoa (PP, EP, and EU) and EN decreased the efficiency of
protein utilization by the ruminant host.
PMID- 10764085
TI - Effects of diet forage:concentrate ratio and metabolizable energy intake on
visceral organ growth and in vitro oxidative capacity of gut tissues in sheep.
AB - We used 28 crossbred wether lambs to determine the effects of dietary
forage:concentrate ratio and metabolizable energy intake on visceral organ growth
and oxidative capacity of gut tissues in lambs. Lambs were assigned randomly to a
factorial arrangement of dietary treatments consisting of pelleted diets
containing either 75% orchardgrass or 75% concentrate fed once daily at either
.099 or .181 Mcal ME x (kg BW(.75))(-1) x d(-1). After a 52-d feeding period,
lambs were slaughtered to obtain measurements of visceral organ mass and
composition and oxidative capacity of isolated epithelial cells. Lamb
performance, as measured by DMI, ADG, and efficiency of gain, was greater (P =
.0001) for both diets at high ME intake. Likewise, lambs fed 75% concentrate
gained faster and more (P < or = .01) efficiently than lambs fed 75% forage.
Total digestive tract (TDT; includes rumen, reticulum, omasum, abomasum, and
intestines) weight increased (P = .0001) with ME intake and was greater (P = .03)
in lambs fed 75% forage than in those fed 75% concentrate. As a percentage of
empty body weight (EBW), TDT weight increased with ME intake in lambs fed 75%
forage, but it was unaffected by ME intake in lambs fed 75% concentrate (diet x
intake, P = .03). Liver weight increased (P = .0001) with ME intake and was
greater (P = .005) in lambs fed 75% concentrate vs 75% forage; however, liver
weight as a percentage of EBW was increased (P = .0002) with ME intake but was
unaffected by diet. Greater ME intake increased (P < or = .02) small intestinal
(SI) epithelial and muscle mass of 15-cm sections, whereas jejunal epithelial
mass was greater (P = .01) for lambs fed 75% forage vs 75% concentrate. Rumen
epithelial concentrations of DNA and RNA increased (P < or = .02) with greater ME
intake, whereas SI concentrations of DNA and RNA were largely unaffected by diet
or ME intake. The activity of Na(+)-K(+)-ATPase increased in ileal epithelium (P
< or = .02) with ME intake and concentrate in the diet, but activity in ruminal
epithelium increased (P = .05) with concentrate. Total oxygen consumption by
isolated ruminal and intestinal epithelial cells was unaffected by treatment.
These data suggest that ME intake and level of dietary forage affect ruminal and
intestinal growth via changes in cellular hyperplasia. Additionally, this study
supports the concept that ME intake and diet composition alter gut energy
expenditure, at least in part, through changes in mass rather than mass specific
metabolism.
PMID- 10764086
TI - Effects of diet forage:concentrate ratio and metabolizable energy intake on
isolated rumen epithelial cell metabolism in vitro.
AB - Crossbred wether lambs were used to assess the effect of altered
forage:concentrate ratio and metabolizable energy intake on metabolism of
substrates by ruminal epithelium using an isolated cell system. Lambs (n = 28;
20.1 +/- 3 kg BW) were assigned randomly to a factorial arrangement of dietary
treatments consisting of either 75% forage or 75% concentrate fed once daily at
either .099 or .181 Mcal ME x(kg BW(.75))(-1) x d(-1) for 52 d. After a 52-d
feeding period, isolated rumen epithelial cells (IREC) were incubated in the
presence of an oxidizable substrate with a single 14C label (acetate, propionate,
butyrate, glucose, glutamate, and glutamine) at concentrations ranging from .1 to
50 mM, and substrate oxidation to 14CO2 or metabolism to beta-hydroxybutyrate
(beta-HBA), acetoacetate, pyruvate, and lactate was determined. For all
substrates, oxidation to CO2 was concentration-dependent and saturable within the
physiological range. Differences in substrate oxidation to CO2 by IREC at
specific substrate concentrations did not affect Vmax (maximal rate of substrate
oxidation, nmol oxidized to CO2 x 1 x 10(6) cells(-1) x 90 min(-1)) and K(ox)
(concentration of substrate at which half Vmax oxidation rate is achieved,
mmoles/L) estimates for the dietary treatments. Production of beta-HBA from
butyrate by IREC from the lambs fed 75% forage was not affected by ME intake;
however, production was elevated by high ME intake of the 75% concentrate diet
(diet x intake interaction; P < .02). Acetoacetate production from butyrate by
IREC from lambs fed at high ME intake was greater (P = .001) than from those fed
at low ME intake. Lactate and pyruvate production from glucose, glutamate, and
propionate were generally unaffected by dietary treatment; however, rate of
glutamine metabolism to lactate and pyruvate by IREC was increased with increased
ME intake. The observed changes in metabolite production rates across groups did
not affect the predicted Vmax and K(ox) parameter estimates. The estimated K(ox)
values corroborate that VFA are the primary oxidizable fuels used by ruminal
epithelial cells while illustrating that other substrates such as glucose,
glutamate, and glutamine would not be expected to be oxidized extensively in vivo
due to the high K(ox) relative to substrate concentrations in vivo. In
conclusion, the capacity of isolated ruminal epithelial cells to oxidize
substrates was largely unaffected by ME intake or dietary forage:concentrate
ratio of the diet.
PMID- 10764087
TI - Performance and meat quality of beef steers fed corn-based or bread by-product
based diets.
AB - A feeding trial was conducted with beef breed steers (120) to determine the
effects of substituting bread by-product (BBy) for whole shelled corn on
performance and meat quality. Chemical analysis of each diet ingredient and in
vitro rates of digestion from gas production of BBy and corn were determined to
provide accurate information for diet evaluations using the 1996 Beef NRC Model
Level 2. Bread by-product contained 16% CP (75.6% degradable) and 75.1% non
structural carbohydrates (70% as starch, which had a digestion rate of 16%/h).
The steers were given one estrogenic implant (Synovex-S) and started on the
experiment at 15 mo of age and an average weight of 364 kg. The cattle were
commercially slaughtered in three groups (40 steers at 101, 60 steers at 126, and
20 steers at 160 d on feed) weighing an average of 553 kg when they reached a
small degree of marbling. Carcasses were electrically stimulated to prevent cold
shortening of muscles. Warner-Bratzler shear force values were measured in rib
steaks at 5, 14, and 21 d after slaughter (n = 76). Rib steaks from 30 steers per
treatment were evaluated for palatability traits. Use of BBy at 55% of the diet
(substituted for 75% of the corn) significantly improved feed efficiency by 8.1%.
There were no statistically significant differences between the two diets for
effects on ADG, carcass characteristics, shear force values, or sensory panel
ratings of tenderness, juiciness, flavor, or overall acceptability. After
adjusting intestinal starch digestibility in Level 2 to 63% for the whole corn
and 90% for the BBy, predicted ADG matched that observed. Apparent NE(g) values
for BBy and corn were 1.57 and 1.41 Mcal/kg, respectively.
PMID- 10764088
TI - Rapid communication: linkage and physical mapping of the porcine melanocortin-4
receptor (MC4R) gene.
PMID- 10764089
TI - Pharmacokinetics of three gadolinium chelates with different molecular sizes
shortly after intravenous injection in rabbits: relevance to MR angiography.
AB - RATIONALE AND OBJECTIVES: To mimic an MR angiographic protocol, an experimental
model was developed in rabbits to determine gadolinium concentrations in blood
early after injection. Contrast agents with different molecular sizes were
compared. METHODS: The influence of injection parameters (injection rate,
duration of injection, volume of injection, dose) was assessed, and two blood
pool agents (P760, P717) were compared with the low-molecular-weight Gd-DOTA
under similar conditions. RESULTS: Two main phases were identified: bolus and
post-bolus. Injection parameters strongly influenced the pattern of the bolus
phase, but the postbolus phase was sensitive only to the injected dose. The blood
pool agents presented a bolus phase profile similar to that of Gd-DOTA, but 45
seconds after injection, 84% of P717 molecules were still present in the blood
compartment, compared with 65% of P760 molecules and only 51% of Gd-DOTA
molecules. CONCLUSIONS: Blood pool agents are useful for MR angiographic
protocols involving the postbolus phase. In protocols in which only the bolus
phase is imaged, blood pool agents provide similar data to Gd-DOTA, provided that
the injection rate, iso-T1 efficiency dose, and volume are similar.
PMID- 10764090
TI - Automated calibration in vascular X-ray images using the accurate localization of
catheter marker bands.
AB - RATIONALE AND OBJECTIVES: To develop a new automated calibration method for
vessel measurements in vascular x-ray images. METHODS: Radiopaque marker bands
mounted equidistantly on a small catheter were acquired in vitro at five image
intensifier (II) sizes in x-ray projection images. The positions of the marker
centers were detected by using a Hough transform and were computed at subpixel
precision by using either a novel, iterative center-of-gravity approach (CGA) or
a symmetry filter. Curve-fitting procedures were used to reject false-positive
marker detections and to calculate intermarker distances. The calibration factor
was calculated from the true marker distance and the average of the measured
distances in pixels. Results were compared statistically with a grid calibration
method, which was taken as the gold standard. A simulation study was performed to
assess the influence of image noise on the CGA method. RESULTS: The iterative CGA
method was convergent and faster than the symmetry-based technique. For four II
sizes (17, 20, 25, and 31 cm), the results from the CGA method were not
significantly different from the results obtained with grid calibration. For the
II size of 38 cm, a significant difference (0.3% of the grid calibration factor)
was found; however, this was caused by the quantification error in the image data
and was not clinically relevant. In general, the performance of the CGA method
improved with increasing signal-to-noise ratio. CONCLUSIONS: A practical new
calibration method for small catheter sizes was developed and validated for
quantitative vascular arteriography.
PMID- 10764091
TI - Molecular imaging of stretch-induced tissue factor expression in carotid arteries
with intravascular ultrasound.
AB - RATIONALE AND OBJECTIVES: Molecular imaging with targeted contrast agents enables
tissues to be distinguished by detecting specific cell-surface receptors. In the
present study, a ligand-targeted acoustic nanoparticle system is used to identify
angioplasty-induced expression of tissue factor by smooth muscle cells within
carotid arteries. METHODS: Pig carotid arteries were overstretched with balloon
catheters, treated with tissue factor-targeted or a control nanoparticle system,
and imaged with intravascular ultrasound before and after treatment. RESULTS:
Tissue factor-targeted emulsions bound and increased the echogenicity and gray
scale levels of overstretched smooth muscle cells within the tunica media, versus
no change in contralateral control arteries. Expression of stretch-induced tissue
factor in carotid artery media was confirmed by immunohistochemistry.
CONCLUSIONS: The potential for abnormal thrombogenicity of balloon-injured
arteries, as reflected by smooth muscle expression of tissue factor, was imaged
using a novel, targeted, nanoparticulate ultrasonic contrast agent.
PMID- 10764092
TI - Lobar distribution of emphysema in computed tomographic densitometric analysis.
AB - RATIONALE AND OBJECTIVES: The aims of this study were to determine the extent of
emphysema in individual lobes and to investigate whether the lobar distribution
of emphysema influences pulmonary function. METHODS: Helical CT and pulmonary
function tests were performed in 50 emphysema patients. Percentages of low
attenuation volume (extent of emphysema) were calculated for each lobe by using
CT densitometric analysis. RESULTS: The extent of emphysema of the whole lung in
these patients was 44%. Airflow limitation (r = -0.82, P<0.0001) and residual
volume (r = -0.52, P<0.01) were closely correlated with the extent of emphysema
in both lower lobes. Diffusing capacity (r = -0.61, P<0.0001) was closely
correlated with the extent of emphysema in both upper lobes. On the basis of the
lobar distribution of emphysema as determined by CT densitometry, we divided
these emphysema patients into predominantly upper-lobe disease and predominantly
lower-lobe disease groups. The predominantly lower-lobe disease group had
significantly greater severe airflow limitation (P<0.0001), greater residual
volume (P<0.01), and greater total lung capacity (P<0.05) than did the
predominantly upper-lobe disease group. CONCLUSIONS: CT densitometry showed a
distinct lobar distribution of emphysema. Pulmonary function is significantly
different between predominantly upper- and lower-lobe emphysema groups.
PMID- 10764093
TI - Head and neck lesions: determination of an optimal MT technique for prediction of
malignancies.
AB - RATIONALE AND OBJECTIVES: To determine an optimal magnetization transfer (MT)
technique for diagnosis of malignancies in the head and neck. METHODS: Lesion
magnetization transfer ratios (MTRs) and lesion-to-muscle MTRs were prospectively
measured in 52 head and neck lesions of 52 patients at frequency offsets of 0.3,
0.5, and 1 kHz from water resonance. The diagnostic capability for each MT pulse
was calculated by using receiver operating characteristic (ROC) curves, and an
optimal MT technique was determined for diagnosis of malignancies. RESULTS: The
lesion MTRs and the lesion-to-muscle MTRs in malignant tumors were statistically
significantly greater than those in benign lesions at both 0.5- and 1-kHz MT
pulses, but no significant differences were noted between them at the 0.3-kHz MT
pulse. Diagnosis with the lesion-to-muscle MTRs was better than that with the
lesion MTRs at each MT pulse. Among all MTRs, lesion-to-muscle MTRs at the 1-kHz
MT pulse showed the highest diagnostic capability for malignancies (area under
the ROC curve = 0.82+/-0.06). With a lesion-to-muscle MTR at a 1-kHz MT pulse of
0.61 or greater, the highest accuracy of 85% was attained with 90% sensitivity
and 77% specificity. CONCLUSIONS: Lesion-to-muscle MTRs at a 1-kHz MT pulse were
optimal for diagnosis of malignancies in the head and neck.
PMID- 10764094
TI - Assessment of the vascularization of neuroendocrine tumors by stimulated acoustic
emission of SH U 508A ultrasound contrast agent and color or power Doppler
sonography.
AB - RATIONALE AND OBJECTIVES: To assess the vascularization of neuroendocrine tumors
by stimulated acoustic emission (SAE) of SH U 508A during the blood pool phase in
comparison with contrast-enhanced Doppler sonography. METHODS: Thirty-six
patients with neuroendocrine tumors received contrast-enhanced Doppler sonography
and 21, an additional SAE. To classify tumor perfusion on Doppler sonography, a 4
step rating score was introduced: (1) no vessels (hypoperfusion); (2) one feeding
or central vessel (hypoperfusion); (3) some vessels (hyperperfusion); and (4)
disseminated vessels (hyperperfusion). In 36 patients, 1 pancreatic primary
tumor, 33 liver metastases, 1 splenic metastasis, and 1 lymph node metastasis
were examined. Results were correlated with biphasic spiral CT (n = 35) and
angiography (n = 2). RESULTS: Arterial-phase CT and digital subtraction
angiography revealed 18 hyper- and 18 hypoperfused lesions. Contrast-enhanced
Doppler correctly classified 15 of 18 patients (83%) with hyperperfused lesions
as well as 16 of 18 (89%) hypoperfused tumors by applying the rating score. SAE
correctly identified 4 of 9 hyperperfused lesions (44%), 2 were isoperfused
compared with normal liver tissue (22%), and 3 were hypoperfused (33%). Of 12
hypoperfused lesions, 11 were classified correctly (92%), and 1 showed
isoperfusion. Hence, the positive and negative predictive values for SAE were 80%
and 69%, respectively. For contrast-enhanced Doppler sonography, positive and
negative predictive values were 88% and 84%, respectively. CONCLUSIONS: Blood
pool SAE failed to determine subtle tumor perfusion correctly. The rating score
for contrast-enhanced Doppler sonography characterized tumor perfusion with high
accuracy. The use of a contrast agent significantly improved perfusion
characterization.
PMID- 10764095
TI - Digital radiography with a large-area, amorphous-silicon, flat-panel X-ray
detector system.
AB - RATIONALE AND OBJECTIVES: To investigate the image quality of a digital
radiography system with an amorphous-silicon, large-area, digital flat-panel
detector. METHODS: A flat-panel detector based on a matrix of amorphous silicon
was integrated into a projection radiography system. The scintillator consisted
of a layer of structured cesium iodide. The active matrix size of 30002 pixels
together with a pixel size of 143 microm provided a large image area of 43 x 43
cm2. Basic image quality parameters such as detective quantum efficiency (DQE)
and modulation transfer function (MTF) were measured and compared with those
obtained with conventional systems. RESULTS: The measurement of DQE yielded a
high value of 70% at zero spatial frequency. At a system dose equivalent to 400
speed, the DQE of the digital system was a factor of two larger than the DQE of a
storage phosphor or screen-film system within the entire spatial frequency range
between zero and the Nyquist limit of 3.5 line pairs per millimeter. The flat
panel detector furthermore has an MTF that is superior to that in regular screen
film systems and also provides a substantially larger dynamic range. CONCLUSIONS:
This new technology demonstrates its potential to provide equal or superior image
quality to conventional screen-film systems and to reduce patient exposure to
radiation dose. The advantages of digital radiography systems, based on a flat
panel detector as an instant image display, facilitation of work flow in the
radiology department, and digital networking and archiving, are well in sight.
PMID- 10764096
TI - Combined assessment of obstructive sleep apnea syndrome with dynamic MRI and
parallel EEG registration: initial results.
AB - RATIONALE AND OBJECTIVES: To detect obstructive pharyngeal changes in sleeping
patients with obstructive sleep apnea syndrome by dynamic MRI and concurrent EEG
monitoring during true apneic episodes. METHODS: Five volunteers and eight
patients with clinically diagnosed obstructive sleep apnea were
polysomnographically monitored inside the scanner before, during, and after sleep
discontinuation. After sleep interruption, the Mueller maneuver was performed to
compare induced pharyngeal collapse with real collapse during sleep. RESULTS: In
all patients, on-line EEG registration was achieved in the static magnetic field.
Sleep was proved in four of the eight patients who showed typical EEG findings. A
complete pharyngeal collapse was shown in two of the four sleeping patients. The
other patients predominately showed local epi- and oropharyngeal obstructions in
the apneic state. Compared with the apneic episodes, the Mueller maneuver did not
reveal the same extent of pharyngeal narrowing, nor a complete collapse.
CONCLUSIONS: Polysomnographically monitored MRI can directly assess findings
induced by the pathophysiology of sleep apnea and shows promise for use in sleep
investigation and therapy planning and monitoring.
PMID- 10764097
TI - Evidence for a generate-recognize model of episodic influences on word-stem
completion.
AB - Application of the process-dissociation procedure has shown that conceptual
encoding episodes do not lead to automatic influences of memory on purportedly
data-driven indirect tests of memory. Using 2 variants of the process
dissociation procedure with the word-stem completion task, the procedure is shown
to underestimate automatic influences of memory when prior encoding includes a
conceptual component. The underestimation is attributed to an awareness of past
occurrence that is particularly likely with conceptually encoded items. This
effect occurs even in the absence of the signature of a generate-recognize
strategy and suggests that prior conceptual encoding may contribute to automatic
influences of memory in stem completion. A multinomial generate-recognize model
is presented that fits these results and previous results typically taken as
support for the assumption that controlled and automatic influences of memory are
independent.
PMID- 10764098
TI - A mechanistic account of the mirror effect for word frequency: a computational
model of remember-know judgments in a continuous recognition paradigm.
AB - A theoretical account of the mirror effect for word frequency and of
dissociations in the pattern of responding Remember vs. Know (R vs. K) for low-
and high-frequency words was tested both empirically and computationally by
comparing predicted with observed data theory in 3 experiments. The SAC (Source
of Activation Confusion) theory of memory makes the novel prediction of more K
responses for high- than for low-frequency words, for both old and new items. Two
experiments used a continuous presentation and judgment paradigm that presented
words up to 10 times. The computer simulation closely modeled the pattern of
results, fitting new Know and Remember patterns of responding at each level of
experimental presentation and for both levels of word frequency for each
participant. Experiment 3 required list discrimination after each R response
(Group 1) or after an R or K response (Group 2). List accuracy was better
following R responses. All experiments were modeled using the same parameter
values.
PMID- 10764099
TI - Cross-modal source monitoring confusions between perceived and imagined events.
AB - Two experiments tested the prediction based on the source monitoring framework
that imagination is most likely to lead to false memories when related perceived
events have occurred. Consistent with this, people were more likely to falsely
remember seeing events when the events had been both imagined as seen and
actually heard than when they were just heard, just visually imagined, or
imagined both visually and auditorily. Furthermore, when people considered
potential sources for memories or more carefully evaluated features of remembered
events, source errors were reduced. On average, misattributed ("false") memories
differed in phenomenal qualities from true memories. Taken together, these
findings show that as different qualities of mental experience flexibly enter
into source attributions, qualities derived from related perceptual events are
particularly likely to lead to false claims that imagined events were seen, even
when the event involves a primary modality (auditory) different from the target
event (visual).
PMID- 10764100
TI - Working-memory capacity, proactive interference, and divided attention: limits on
long-term memory retrieval.
AB - Two experiments examined how individual differences in working-memory capacity
(WM) relate to proactive interference (PI) susceptibility. We tested high and low
WM-span participants in a PI-buildup task under single-task or dual-task ("load")
conditions. In Experiment 1, a finger-tapping task was imposed during encoding
and retrieval of each list; in Experiment 2, tapping was required during encoding
or retrieval. In both experiments, low spans showed greater PI than did high
spans under no load, but groups showed equivalent PI under divided attention.
Load increased PI only for high spans, suggesting they use attention at encoding
and retrieval to combat PI. In Experiment 2, only low spans showed a dual-task
cost on List 1 memory, before PI built up. Results indicate a role for
attentional processing, perhaps inhibitory in nature, at encoding and retrieval,
and are discussed with respect to theories of WM and prefrontal cortex function.
PMID- 10764101
TI - An individual differences analysis of ability and strategy influences: age
related differences in associative learning.
AB - The relationships among abilities, strategies, and performance on an associative
learning task were investigated for young (aged 17 to 34) and older adults (aged
60 to 82). Participants received extensive practice on a noun-pair task in which
they could use a visual-scanning strategy or a memory-retrieval strategy. Older
adults were more likely to use the scanning strategy. Age differences were
reduced when comparisons were made only for participants using a retrieval
strategy. Associative memory was predictive of learning on the task, and semantic
memory access speed was predictive of practiced performance. Practiced
performance on a memory-search task that also required associative learning was
predictive of practiced noun-pair performance. Models of ability-performance
relationships for skill acquisition are discussed.
PMID- 10764102
TI - A connectionist model of complacency and adaptive recovery under automation.
AB - Automation is intended to reduce the demands on operators in complex
environments, thereby enhancing overall system performance. Although automation
usually reduces workload, it is often accompanied by a decline in monitoring
performance, an effect known as complacency. The circumstances under which
complacency occurs and how it can be prevented, for example by intermittently
returning control to the operator, are empirically well understood. To date, that
empirical knowledge has not been accompanied by strong psychological theory. This
article presents a computational model of human performance under automation
based on connectionist principles. The model is shown to explain several
benchmark findings, among them the basic complacency effect; the effect of the
variability of automation reliability on complacency; the effect of task
complexity; and the effect of intermittently returning control to the operator.
PMID- 10764103
TI - Serial position effects in recognition memory for odors.
AB - Five experiments examined recognition memory for sequentially presented odors.
Participants were presented with a sequence of odors and then had to identify an
odor from the list in a test probe containing 2 odors. All experiments
demonstrated enhanced recognition of odors presented at the start and end of a
series, compared with those presented in the middle of the series when a 3-s
retention interval between list termination and test was used. In Experiments 2
and 3, when a 30-s or 60-s retention interval was used, participants performed at
slightly lower levels, although the serial position function was similar to that
obtained with the 3-s retention interval. These results were noted with a 5-item
(Experiments 1 and 4), 7-item (Experiment 2), 6-item (Experiment 3), and 4-item
(Experiment 5) list of odors. As the number of test trials increased, recognition
performance decreased, indicating a strong role for olfactory fatigue or
interference in these procedures. A verbal suppression task, used in Experiments
4 and 5, had little influence on serial-position-based performance.
PMID- 10764104
TI - Resistance to extinction of conditioned odor perceptions: evaluative conditioning
is not unique.
AB - A tasteless odor will smell sweeter after being sampled by mouth with sucrose and
will smell sourer after being sampled with citric acid. This tasty-smell effect
was found in experiments that compared odor-taste and color-taste pairings. Using
odors and colors with minimal taste (Experiment 1), the authors found that
repeated experience of odor-taste mixtures produced conditioned changes in odor
qualities that were unaffected by intermixed color-taste trials (Experiment 2).
An extinction procedure, consisting of postconditioning presentations of the odor
in water, had no detectable effect on the changed perception of an odor
(Experiments 3 and 4). In contrast, this procedure altered judgments about the
expected taste of colored solutions. Evaluative conditioning (conditioned changes
in liking) is claimed to be resistant to extinction. However, these results
suggest that resistance to extinction in odors is related to the way they are
encoded rather than to their hedonic properties.
PMID- 10764105
TI - Mechanisms of unconscious priming: I. Response competition, not spreading
activation.
AB - Four experiments were conducted to replicate and expand upon A. G. Greenwald, S.
C. Draine, and R. L. Abrams's (1996) demonstration that unconsciously perceived
priming words can influence judgments of other words. The present experiments
manipulated 2 types of relationships between priming and target stimuli: (a)
whether priming and target stimuli possess a preexisting semantic relationship
(an affective relationship in Experiments 1, 2, and 4; an associative
relationship in Experiment 3; and an animacy relationship in Experiment 4) and
(b) whether the primes and targets produce the same response. Large priming
effects were found only when the primes and targets possessed response
compatibility. No residual effects for affective, animacy, or semantic
relatedness were observed. Although these results strongly support the conclusion
that word meaning can be unconsciously activated, they do not support the claim
that the unconscious perception effects obtained in Greenwald et al.'s (1996)
paradigm are caused by automatic spreading activation of word meaning. Instead,
the results reported here are consistent with a claim that unconsciously
perceived words automatically trigger response tendencies that facilitate or
interfere with target responding.
PMID- 10764106
TI - Dissociative affective and associative priming effects in the lexical decision
task: yes versus no responses to word targets reveal evaluative judgment
tendencies.
AB - The affective priming effect (AP; i.e., shorter evaluative or lexical decision
latencies for affectively congruent prime-target pairs) has often been
interpreted as evidence for spreading activation from the prime to affectively
congruent targets. The present study emphasizes the view that in the lexical
decision task, the prime-target configuration is implicitly evaluated as a
question of the form "Is (prime) (target)?" (e.g., "Is death wise?") so that
there is a tendency to affirm in cases of congruency and to negate in cases of
incongruency. Therefore, after establishing the AP with the lexical decision task
in Experiment 1, in Experiment 2 the assignment of yes responses to words and
nonwords was varied. For the word = yes condition, the AP emerged, whereas the
data pattern was reversed for the word = no condition. In Experiment 3, a
comparable pattern of results was not found for symmetrical or backward
associatively related prime-target pairs.
PMID- 10764107
TI - Differences in the coding of spatial relations in face identification and basic
level object recognition.
AB - The purpose of this investigation was to determine if the relations among the
primitives used in face identification and in basic-level object recognition are
represented using coordinate or categorical relations. In 2 experiments the
authors used photographs of famous people's faces as stimuli in which each face
had been altered to have either 1 of its eyes moved up from its normal position
or both of its eyes moved up. Participants performed either a face identification
task or a basic-level object recognition task with these stimuli. In the face
identification task, 1-eye-moved faces were easier to recognize than 2-eyes-moved
faces, whereas the basic-level object recognition task showed the opposite
pattern of results. Results suggest that face identification involves a
coordinate shape representation in which the precise locations of visual
primitives are specified, whereas basic-level object recognition uses
categorically coded relations.
PMID- 10764108
TI - The balance of storage and computation in morphological processing: the role of
word formation type, affixal homonymy, and productivity.
AB - This article is concerned with the way in which the balance of storage-storing
and processing words through full-form representations-and computation-storing
and processing words through morpheme-based representations-in lexical processing
in the visual modality is affected by the following 3 factors: word formation
type (roughly, inflection vs. derivation), productivity, and affixal homonymy.
Experimental results for 5 different Dutch suffixes, combined with previous
results obtained for 4 comparable Finnish suffixes (R. Bertram, M. Laine, & K.
Karvinen, 1999) and 2 Dutch suffixes (R. H. Baayen, T. Dijkstra, & R. Schreuder,
1997), show that none of these factors in isolation is a reliable cross
linguistic predictor of the balance of storage and computation. The authors offer
a general framework that outlines how morphological processing is influenced by
the interaction of word formation type, productivity, and affixal homonymy.
PMID- 10764109
TI - Single word production in english: the role of subsyllabic units during
phonological encoding.
AB - Five experiments investigated the role of sublexical units in English single word
production. L. Ferrand, J. Segui, and G. W. Humphreys (1997) reported a priming
effect that was most effective when primes and targets shared the first syllable.
Experiments 1A and 1B failed to replicate this effect but Experiment 1B showed
that subsyllabic units play a role in speech production. This role was further
explored using a picture naming task in Experiment 2. Naming latencies were
shortest when the segmental overlap between prime and target (the picture name)
was largest, regardless of the syllable structure of the target. Experiments 3
and 4 replicated this segmental overlap effect with different sets of words as
targets. Experiment 5 showed that the magnitude of the overlap effect increased
with longer prime exposure duration. The implications of these results for
theories of phonological encoding in speech production are discussed.
PMID- 10764110
TI - Evidence for role-neutral initial processing of metaphors.
AB - Two models of metaphor processing are contrasted. The structure-mapping model
postulates an initially role-neutral alignment process, followed by directional
projection of inferences. The attributive categorization model postulates role
specific processing throughout comprehension. To test between these models, the
early stages of metaphor comprehension were probed using a technique based on S.
Glucksberg, P. Gildea, and H. Bookin's (1982) finding that metaphorical meaning
interferes with literal truthfulness judgments. In Experiment 1, interference
effects did not differ between normal metaphors and metaphors with reversed
terms, suggesting that initial processing is role-neutral. In Experiment 2, we
again found no role dependence in interference effects, even for highly
conventional metaphors. In Experiment 3, it was verified that (a) full
comprehension is role-sensitive and (b) full comprehension reaction times (RTs)
are far longer than interference RTs, buttressing the claim that interference is
an early-stage effect. Overall, the results support the structure-mapping model
of metaphor processing.
PMID- 10764111
TI - Laryngeal closure pressure during phonation in humans.
AB - We investigated the laryngeal closure pressure during sustained phonation in five
healthy adult men with no pathological lesions in the glottis using a round
pressure transducer with a diameter of 10 mm and a thickness of 1 mm. The
transducer was placed between the vocal processes through the mouth. Subjects
were asked to utter a sustained phonation of the vowel sound /eh/ at varying
pitch and intensity in modal register. The laryngeal closure pressure ranged from
0 to 200 cmH2O. At a comfortable pitch and intensity, the pressure was below 50
cmH2O. The pressure was correlated with pitch, but not with intensity.
PMID- 10764113
TI - Harmonics-to-noise ratios in normally speaking prepubescent girls and boys.
AB - This study examined harmonics-to-noise ratios (HNR) in 4 groups of normally
speaking children. HNRs were calculated for the vowels /ai/ and /inverted v/,
selected from conversational speech samples of 80 children aged 4, 6, 8, and 10
years (10 boys and 10 girls at each age level). HNR values for /inverted v/ were
significantly higher than those for /ai/. Significant age differences emerged for
/ai/ between ages 4 and 8, and ages 8 and 10. Girls obtained significantly higher
HNRs than boys for the /ai/ vowel. Overall, the HNR values for these normally
speaking children were lower than those reported for normally speaking adults.
These findings suggest that acoustic values for children cannot be validly
compared to those for adults, and that the child's gender and age should be taken
into account when applying spectral analyses to research and/or clinical
situations.
PMID- 10764112
TI - Effects of head extension and tongue protrusion on voice perturbation measures.
AB - Head extension with protruded tongue is the position for videolaryngoscopy and
simultaneous glottographic recordings including photoglottographic signals. This
study investigated the effect of head extension and tongue protrusion on the
measures of fundamental frequency, frequency perturbation (jitter), and amplitude
perturbation (shimmer). Acoustic signals recorded during sustained vowels were
obtained from 49 women and 66 men with no speech or voice disorders in different
head-tongue positions. Head extension was associated with increased fundamental
frequency and decreased shimmer. In men, head extension did not appear to affect
jitter. When the tongue was protruded, head extension tended to lower jitter. For
both genders, tongue protrusion was associated with decreased fundamental
frequency with head extension. In the men, tongue protrusion tended to increase
shimmer when the head was in the neutral position. In the women, tongue
protrusion was associated with increased jitter and increased shimmer and was
most evident in the head-neutral position. These findings supported a physical
linkage hypothesis of the relationship between vocal tract configuration and
vocal fold vibration, suggesting that head-tongue position must be taken into
account when comparing voice measures.
PMID- 10764114
TI - Comparison of acoustic and perceptual measures of voice in male-to-female
transsexuals perceived as female versus those perceived as male.
AB - The present study explored significant differences between male-to-female
transgendered speakers perceived as male and those perceived as female in terms
of speaking fundamental frequency (SFF) and its variability, vowel formants for
/a/ and /i/, and intonation measures. Fifteen individuals who identified
themselves as male-to-female transsexuals served as speaker subjects, in addition
to 6 biological female control subjects and 3 biological male control subjects.
Each subject was recorded reading the Rainbow Passage and producing the isolated
vowels /a/ and /i/. Twenty undergraduate psychology students served as listeners.
Results indicated that subjects perceived as female had a higher mean SFF and
higher upper limit of SFF than subjects perceived as male. A significant
correlation between upper limit of SFF and ratings of femininity was achieved.
PMID- 10764115
TI - Periodic variation in inspiratory volume characterizes speech as well as quiet
breathing.
AB - Variability in inspired lung volume prior to speech is only partially accounted
for by speech-related concerns such as the length and loudness of the planned
utterance. Control mechanisms known to influence volume variability in non-speech
breathing could potentially account for some of this variability, but only if
they operate during speech as well. This investigation was designed to test for
the presence of several such mechanisms during reading aloud. Lung volumes were
recorded from 5 normal females as they read silently, then aloud. Inspired
volumes were correlated with the volumes of the previous and following
expirations and with inspiratory duration. Coefficients of variation were
calculated for inspiratory volume, duration, and mean flow. Time-series analyses
were used to compare periodicity in inspired volume for quiet and speech
breathing. Control mechanisms operating during both quiet breathing and reading
aloud included slow oscillations in inspired volume and minimized variability in
mean flow. Inspired volume prior to speech was weakly but significantly
correlated with preceding and following expired volume. It is concluded that some
control strategies typical of quiet breathing contribute to volume variability in
speech breathing.
PMID- 10764116
TI - Effects of simulated source of tremor on acoustic and airflow voice measures.
AB - To test the effects of different sources of tremor on the voice, tremor was
simulated by external rhythmic perturbation of structures at the subglottal,
glottal, and supraglottal levels in 10 healthy subjects. The acoustic and airflow
signals simultaneously recorded during sustained phonation in the normal and the
3 simulated tremor conditions were analyzed and compared. Voice measures
included: fundamental frequency, 2 short-term perturbation measures (jitter and
shimmer), and 3 long-term tremor measures (prominence ratios of the spectral
peaks of the acoustic frequency contour, acoustic amplitude contour, and airflow
contour). Measures of fundamental frequency and percent shimmer were not
significantly affected by the simulated tremors. Measures of percent jitter and
the amplitudes of the long-term frequency and amplitude modulations were most
prominently increased when respiratory drive was perturbed by simulated tremor.
Spectral analysis of the acoustic amplitude contour was most useful in
distinguishing the 3 sites of simulated tremor.
PMID- 10764117
TI - The effects of preventive vocal hygiene education on the vocal hygiene habits and
perceptual vocal characteristics of training singers.
AB - The purpose of the present study was to determine the effects of vocal hygiene
education on the vocal hygiene behaviors and perceptual vocal characteristics of
untrained singers. Eleven adult untrained singers served as subjects. They
attended four 1-hour class sessions on vocal hygiene, including anatomy and
physiology of the phonatory mechanism, vocally abusive behaviors, voice disorders
commonly seen in singers, and measures to prevent voice disorders. Pre- and
postinstruction surveys were used to record subjects' vocal abuses and their
perceptions of their speaking and singing voice. They also rated their perceived
value of vocal hygiene education. Results revealed minimal changes in vocal
hygiene behaviors and perceptual voice characteristics. The subjects did report a
high degree of benefit and learning, however.
PMID- 10764118
TI - Preliminary report on hormone receptors in the human vocal fold.
AB - There has been an ongoing effort to describe the physiologic factors associated
with perceived and/or measured human voice changes that occur with age. In our
study we focused on possible endocrine involvement on voice by using
immunohistochemical staining to observe hormone receptor presence in vocal folds
from 42 deceased subjects (fresh cadavers), male and female, ranging in age from
2 months to 82 years (average 37.7 years). On statistical analysis, age and
gender were found to be associated with progesterone receptor staining of the
glandular nuclei (young>old P = 0.013; male>female, P = 0.060). Gender was
associated with androgen receptor staining in glandular cytoplasm (male>female, P
= 0.014) and progesterone receptor staining in the epithelial cytoplasm
(male>female, P = 0.039). No statistical significance was noted in other
categories. CONCLUSION: Hormone receptors are found in the nucleus and cytoplasm
of cells in the vocal fold with statistically significant differences in age and
gender distribution.
PMID- 10764119
TI - Maxillary dental arch form related to voice classification: a pilot study.
AB - This pilot study evaluated maxillary dental arch form dimensions and volume to
determine if these parameters could be predictors for or related to voice
classification. Nine white female professional singers ranging in age from 26
years to 53 years were studied. A maxillary dental impression and stone dental
casts were made using standard dental procedures. Measurements were made from 10
points on each cast to determine the depth of the palate measured from first
molar (depth A) and from first bicuspid (depth B), the width measured from cuspid
to-cuspid (width A) and from second molar to second molar (width B), and the
length of the palate. An impression of the palatal arch of each cast was made to
determine the volume of the palate using fluid displacement methods. Audio
recordings were made for each subject, and based on speaking fundamental
frequency, spectral analysis, voice profile, and tessitura confirmation, the
actual voice classification of each subject in soprano, mezzo, and alto was
achieved. Correlation and discriminant analysis tests were performed on the data.
The discriminant analysis revealed that no single measurement is a predictor for
voice classification. However, the discriminant analysis applied to the
predictors depth A, depth B, and volume gives optimal results, ie, each subject
was classified in her true group.
PMID- 10764120
TI - 24 hours prior to curtain.
AB - A retrospective review was conducted of 40 singers presenting with acute voice
problems prior to performance. The purpose of this study was to determine the
reasons for seeking emergent voice treatment, the types of acute voice disorders,
and the performance outcome. The patients were assessed by age, singing style,
years of experience, chief complaint, laryngovideostroboscopic findings, and
treatment regimens. The outcomes were classified as full, restricted, or no
performance. The majority of patients were classical singers.
Laryngovideostroboscopy frequently revealed a pattern of early glottic contact at
the mid-portion of the membranous vocal fold in patients with acute laryngitis.
Experienced singers uniformly sought treatment many days before their performance
compared with inexperienced singers who presented closer in time to performance.
Six patients initially withheld information, which had a bearing on their acute
management. The results of this study suggest that there is a need to accurately
diagnose and treat the singer's emergent problem and educate singers regarding
early evaluation of medical problems. With modern evaluation techniques and multi
modality treatment, 85% of the singers proceeded to full performance without
negative sequelae.
PMID- 10764121
TI - Paradoxical vocal fold motion: presentation and treatment options.
AB - Paradoxical vocal fold motion is a rare disorder in which adduction of the folds
occurs on inspiration. The disorder presents with signs of airway obstruction and
often airway distress, so proper diagnosis by the otorhinolaryngologist is
critical to subsequent management. We present a retrospective review of 10
patients with the diagnosis of paradoxical vocal fold motion seen over a 6-year
period. Eight patients were females, and 6 required an acute airway intervention
at presentation; 3 patients eventually underwent tracheotomy for respiratory
decompensation. Six patients had a prior diagnosis of asthma, and this was
determined to contribute to their respiratory status. Five patients were treated
with botulinum toxin and 2 with flexible nasolaryngoscopic biofeedback, which
improved the outcome. A review of the literature confirms a female predominance
of patients presenting with paradoxical adduction and airway distress, often with
a history of asthma and psychopathology. Our experience with botulinum toxin and
biofeedback suggests that these procedures are viable treatment options in the
management of patients with this disorder.
PMID- 10764122
TI - Combination thyroplasty and the "twisted larynx:" combined type IV and type I
thyroplasty for superior laryngeal nerve weakness.
AB - Vocal cord medialization through Isshiki type I thyroplasty is part of the
standard approach for patients with unilateral vocal cord immobility secondary to
recurrent laryngeal nerve paralysis. However, several other modalities have been
used to treat the symptomatic "twisted" larynx caused by unilateral superior
laryngeal nerve weakness. The Isshiki type IV thyroplasty (cricothyroid
approximation) specifically addresses cricothyroid muscle weakness, but, canine
studies at the Mayo Clinic demonstrated a trend toward decreased acoustic power
and sound intensity with simulated cricothyroid activity. Thus it is reasoned
that addition of an ipsilateral type I thyroplasty should help compensate for
this power loss. Using videostroboscopic and acoustic analysis, 9 patients with
unilateral superor laryngeal nerve weakness were treated with combination type IV
and type I thyroplasty. Subjective dysphonia and objective visual and acoustic
measurements revealed postoperative improvement in most patients. The combination
type IV and type I thyroplasty is recommended for surgical treatment of patients
with superior laryngeal nerve weakness, because it addresses cricothyroid muscle
weakness without compromising vocal power.
PMID- 10764123
TI - Phonomicrosurgical management of vocal fold polyps: the subepithelial microflap
resection technique.
AB - Vocal fold polyps are typically caused by acute and chronic trauma to the
microvasculature of the superficial lamina propria (SLP). Shearing stresses that
are induced by hyperfunctional glottal sound production lead to bleeding into the
SLP and malformed neo-vascularized masses. Because the primary process does not
involve the epithelium, the authors designed a technique to resect hemorrhagic
polyps by epithelial cordotomy with partial or complete preservation of the vocal
fold epithelium. This approach is different from the traditional microsurgical
resection of hemorrhagic polyps by amputation with or without the carbon dioxide
laser. Forty patients who underwent microlaryngoscopic resection of hemorrhagic
polyps from 1996 through 1998 were reviewed retrospectively. Thirty-six of the 40
procedures were by epithelial cordotomy and subepithelial removal of the polyp
contents. Sixteen of 36 were assisted by a subepithelial infusion of saline and
epinephrine, and all were 3 mm to 6 mm. Four of 40 polyps were amputated; all of
these were less than 3 mm and were pedicled on a narrow base. Cold instruments
were used exclusively in all 40 patients. Postoperative laryngeal stroboscopy
within 2 weeks revealed improved mucosal wave propagation and improved glottal
closure in all 33 patients in whom postoperative strobovideolaryngoscopy was
available. The epithelial cordotomy technique was introduced to minimize
disturbance of normal SLP and epithelium. Despite the hemorrhagic nature of these
lesions, cold instruments could be used exclusively with facility due to careful
microdissection between the polyp and the residual normal SLP and the enhanced
hemostasis provided by the subepithelial infusion of saline and epinephrine. The
rapid return to improved glottal function is the result of this ultra tissue
sparing technique.
PMID- 10764124
TI - Granular cell tumors of the larynx.
AB - Granular cell tumor is a rare neoplasm that may involve the larynx. It is almost
always benign. Laryngologists should be familiar with this unusual tumor, its
implications and appropriate treatment.
PMID- 10764125
TI - Ethnicity and socioeconomic status: impact on cardiovascular activity at rest and
during stress in youth with a family history of hypertension.
AB - OBJECTIVE: The purpose of the present study was to examine the potential
interaction of ethnicity and SES on hemodynamic functioning at rest and during
acute stress in normotensive adolescents with a family history of essential
hypertension (EH). DESIGN: The influences of ethnicity and socioeconomic status
(SES) on cardiovascular function were evaluated at rest and in response to five
different laboratory stressors. METHODS: 110 (50 female) Caucasian and 162 (85
female) African-American normotensive youth (initial age 11.2+/-2.4 years) with a
family history of essential hypertension (EH) were tested on two occasions, an
average of 2.5 years apart. Based on previous findings, it was predicted that
African Americans, particularly those of low SES, would exhibit higher resting
blood pressure (BP) and greater cardiovascular reactivity to acute laboratory
stressors than would Caucasians. RESULTS: As predicted, African-American youth
exhibited higher resting diastolic blood pressure (DBP) and total peripheral
resistance (TPR) than Caucasians on both visits (both Ps<.04). African Americans
exhibited greater systolic blood pressure (SBP) reactivity than did Caucasians to
the video game stressor during both lab visits (both Ps<.02) and greater heart
rate reactivity during the first lab visit (P<.01). African Americans exhibited
greater SBP and/or DBP, and TPR reactivity to the cold pressor during the first
lab visit and the parent-child discussion during the second visit (all Ps<.03).
CONCLUSION: As predicted, African Americans exhibited higher resting BP and TPR,
and greater cardiovascular reactivity than Caucasians. Although not in the
predicted direction, a pattern of interactions began to emerge on the second
evaluation. For example, upper SES youth exhibited greater heart rate reactivity
compared to all other groups on the social competence interview and parent-child
discussion stressors. Further study is needed to clarify the role cardiovascular
reactivity may play in the link between ethnicity, SES, and cardiovascular
disease risk.
PMID- 10764126
TI - Short-term impact of a church-based approach to lifestyle change on
cardiovascular risk in African Americans.
AB - While lifestyle modification decreases cardiovascular risk, there are barriers to
lifestyle education in usual clinical practice, especially among the medically
underserved. To address this gap, "Lighten Up," a church-based lifestyle program
was developed in collaboration with the local African-American Christian
community. Lighten Up includes a baseline health assessment (week 1), eight
educational sessions (weeks 2-9) combining study of scripture and a health
message, a short-term health check (week 10) and a long-term health check (week
52). Baseline and 10 week risk factor data have been obtained in 133 African
Americans from eight sites (83% women) and form the basis of this report. At
baseline, 76% of participants had two or more modifiable risk factors
(overweight, hypertension, borderline high cholesterol, or diabetes). The entire
group had significant short-term reductions in weight (-2.3 pounds, P<.01), mean
blood pressure (BP, -2.1 mm Hg, P<.05), and triglycerides (-11 mg/dl, P<.05).
Risk factor improvement was greater among the 60 subjects who attended 75% or
more of the educational sessions. In this group, weight fell 2.9+/-0.6 pounds
(mean +/- SEM; P<.01), mean BP declined 3.8+/-1.2 mm Hg (P<.01), total
cholesterol was lowered 6+/-4 mg/ dl (P = .12), and triglycerides were reduced
17+/-9 mg/dl (P = .05). Lighten Up is reaching a group with multiple
cardiovascular risk factors that is not optimally managed by existing healthcare
resources. Of the 133 participants, 70% attended half or more of the sessions,
and several components of the risk factor cluster were favorably affected.
PMID- 10764127
TI - Reduced mortality associated with body mass index (BMI) in African Americans
relative to Caucasians.
AB - Although obesity is especially common in African-American women, the relationship
between body mass index (BMI, kg/m2) and mortality primarily has been studied in
Caucasians, and almost exclusively in average weight populations. In order to
examine the relationship between race and mortality in a predominately overweight
population, we assessed mortality in 6,602 parents of obese African-American and
Caucasian subjects. Most parents of both races were overweight or obese: 87.8% of
African-American mothers (mean BMI = 37.7) and 78.6% of Caucasian mothers (mean
BMI = 34.9) had a BMI > or =27.3; 61.9% of African-American fathers (mean BMI =
31.5) and 63.6% of Caucasian fathers (mean BMI = 31.8) had a BMI > or =27.8. Even
though African Americans had equivalent (fathers) or higher (mothers) average BMI
and percentage overweight or obesity than Caucasians, unadjusted mortality rates
were consistently lower in African Americans than in Caucasians. In a combined
sample, income, age (linear, quadratic and cubic effects), gender, BMI (linear
and quadratic), and race were significant predictors of mortality. Linear and
quadratic effects of BMI were significant within race and in the combined sample,
after controlling for the effects of all other predictor variables. Therefore,
the mortality differences cannot be due to differences in age, income, BMI, or
gender distributions. In addition, there was significant heterogeneity between
races for all models examined, suggesting interactions between race and all other
predictor variables. Moreover, there was a strong residual effect for race after
accounting for the other variables. The highly selective and cross-sectional
nature of this sample limits our ability to make specific BMI-associated risk
estimates. However, the consistent differences between comparably ascertained
racial groups sampled from the upper extreme of the BMI distribution provide
support for a lower BMI-associated mortality rate in African Americans relative
to Caucasians.
PMID- 10764128
TI - Obesity and health conditions in elderly Mexican Americans: the Hispanic EPESE.
Established Population for Epidemiologic Studies of the Elderly.
AB - The objective of this analysis was to determine the prevalence of obesity and its
association with selected medical conditions in a non-institutionalized elderly
Mexican-American population. Data employed are from a representative sample of
3050 elderly Mexican Americans from the five Southwestern states: Texas,
California, Colorado, New Mexico, and Arizona. Complete Body Mass Index (BMI)
data were available for 2769 individuals. The in-home survey obtained socio
demographic data, anthropometric measurements, including height and weight, blood
pressure readings, self-reported health conditions and depressive symptomatology.
It was found that 23% of men and 35% of women were obese (BMI > or =30 kg/m2).
Using a weighted logistic regression model, a BMI of > or =26 kg/m2 was
associated with a significantly higher risk of diabetes; a BMI of > or =30 kg/m2
was significantly associated with arthritis and measured hypertension and a
BMI<22 kg/m2 was associated with a higher likelihood of self-reported cancer. In
addition, the prevalence of obesity was found to be much higher in this elderly
Mexican-American population than in the general population.
PMID- 10764129
TI - Educational level and risk for alcohol abuse and dependence: differences by race
ethnicity.
AB - OBJECTIVE: Using prospective data, we extend and strengthen prior evidence on the
relationship of educational level and the risk of alcohol abuse and dependence
among adults. Hypothesizing that risk of alcohol disorders would be greater among
individuals who dropped out of high school without getting a diploma, and among
those who entered college but then failed to get a degree, relative to those with
a college or higher degree, we examined these relationships by race-ethnicity.
METHODS: Data are from the total of 18,571 adult participants selected for the
Epidemiologic Catchment Area (ECA) program by probability sampling of households
and census tracts between 1980 and 1984. To assess occurrence of psychiatric
conditions over time, staff administered the Diagnostic Interview Schedule soon
after sampling and again at followup approximately one year later. The final
sample for this report was stratified: African Americans (N = 2856) and whites (N
= 7889). RESULTS: In multiple logistic regression analyses, we found that
dropping out of high school was associated with elevated risk for alcohol
disorders, relative to those with an Associate of Arts degree or higher, among
both African Americans (estimated relative risk [RR] = 4.0, 95% confidence
interval [CI], 1.1-14.3, P = .03), and whites (RR = 4.7, 95% CI, 2.2-10.0, P =
.0001). In contrast, entering college but failing to get a degree was associated
with a significantly increased risk only for whites; however, African Americans
were less numerous in the sample, causing attenuation of power. In order to
assess whether this relationship was confounded by macrosocial factors of the
neighborhood environment, cases were matched to non-cases by age and census
tract, and initial conditional logistic regression analyses also were completed.
CONCLUSIONS: If confirmed in other investigations, these findings may help to
identify groups that are at higher risk for developing alcohol abuse and alcohol
dependence in adulthood, and may aid in the development of prevention or early
intervention programs.
PMID- 10764130
TI - Taste sensitivity to sodium chloride and sucrose in a group of adolescent
children in Northern Nigeria.
AB - In a sub-population of Nigerian children in the southern rain forest of Edo
State, we recently observed widespread relative insensitivity to the taste of
sodium chloride (NaCl-salt). This prompted the present study, in which we
measured taste recognition threshold to NaCl (30, 60, 120, 180 mM) and sucrose
(15, 50, 100, 150 mM) in a group of fifth-and sixth-grade pupils in the
northeastern semi-Sahel part of Nigeria, in order to observe the extent to which
the findings cited above would apply to similar groups of Nigerians with
different ethnic backgrounds in other parts of the country. Three hundred twenty
eight pupils (149 boys, 179 girls) from 9 to 18 years of age were involved. Five
subjects were taste-blind to the highest concentration (180 mM) of NaCl. In
addition, 44.5% of the study population did not taste NaCl until a concentration
of 60 mm or higher was used. This distribution was influenced neither by gender
(x2 = 2.75, df = 3, P = .43) nor age (r = .029, P = .60). In addition, only 33%
of the population recognized sucrose sweetness at a sucrose concentration of 15
mm or lower. The remaining two-thirds of the population had sucrose threshold
values of 50 mm or higher and neither gender (x2 = 3.09, df = 3, P = .379) nor
age (r = .046, P = .41) influenced these findings. These results substantiate our
earlier observations that relative taste insensitivity to salt (NaCl) may be
common in Nigerian children. When compared to our earlier data, these results
indicate that taste insensitivity to NaCl and sucrose may be more common in
children in the northern parts of the country, thus suggesting that geographic
location and ethnicity may be important variables in taste perception of NaCl and
sucrose in adolescent Nigerians.
PMID- 10764131
TI - Trends in late-stage breast, cervical and colorectal cancers in blacks and
whites.
AB - OBJECTIVE: This study examined the black-white disparities in diagnosis of late
stage breast, cervical, and colorectal cancers, which could change over time,
especially in view of changes in the health-care system. METHODS: Recent trends
(1988-95) in stage distribution were examined by age group (<65 and 65+ years)
for the geographic areas covered by the National Cancer Institute's Surveillance,
Epidemiology and End Results (SEER) Program. RESULTS: Proportions of breast and
cervical (but not colorectal) cancers that were late-stage declined in both races
and black-white disparities had narrowed by 1995, especially for patients
diagnosed at age 65 years or older. The proportion of breast and cervical cancers
that were late stage declined for blacks in counties with a black poverty rate of
20% or higher. CONCLUSIONS: Some progress toward black-white equity in stage at
diagnosis was evident, consistent with reported trends in use of screening tests,
but further surveillance and research are needed.
PMID- 10764132
TI - Ethnic and racial differences in prostate cancer incidence and mortality.
AB - Prostate cancer (CaP) incidence and mortality vary strikingly among ethnic,
racial, and national groups. There is evidence that genetic, environmental, and
social factors jointly-and often in combination-contribute to the observed
differences in various populations. Noteworthy is the high rate of both CaP
incidence and mortality among African Americans. Changes in the epidemiology of
CaP since the advent of prostate specific antigen testing suggest that improved
access to screening and treatment may serve to reduce somewhat the differences
between the white and African-American populations. However, because the causes
of these differences are likely to be multifactorial, a variety of strategies
addressing the range of causes will be necessary to reduce the excess African
American mortality from this disease.
PMID- 10764133
TI - African-American attitudes regarding cancer clinical trials and research studies:
results from focus group methodology.
AB - Despite federal recommendations highlighting the need to include special
population groups (mainly minorities and women) in clinical research, recruitment
and retention of these groups present a great challenge to researchers. This
paper describes a focus group study that was conducted to examine factors related
to minority participation and retention in cancer clinical research studies. In
1996, the National Cancer Institute submitted a request for applicants to receive
support for regional conferences. The purpose of the proposed conferences was to
share current information and strategies to aid cancer clinical investigators in
recruiting and retaining minority participants in clinical cancer research and to
stimulate local/regional adaptations of these strategies. The University of
Alabama at Birmingham (UAB), The University of Alabama, and Tuskegee University
collaborated to respond to the request. Funding was granted by NCI for the
regional conference in Alabama. The conference was held in Tuskegee, Alabama, the
site of the infamous US Public Health Syphilis Study at Tuskegee. In planning for
the conference, focus group sessions were conducted with African-American men and
women who represented all regions of Alabama. The focus group information was
used to identify important issues to be addressed at the conference.
PMID- 10764134
TI - Community health survey in an urban African-American neighborhood: distribution
and correlates of elevated blood pressure.
AB - While considerable improvements have been made over the last 30 years in
hypertension (HTN) awareness, treatment, and control, a recent reversal of these
trends has been documented with African-American adults, particularly among those
continuing to suffer from uncontrolled hypertension and its adverse consequences.
This paper presents data from a cross-sectional representative survey of the
health status of an urban African-American community. The study was designed in
partnership with community leadership to improve HTN care and control. The
baseline survey was a face-to-face interview (including blood pressure [BP]
measurements) of 2,196 adults residing in randomly selected blocks in the
Sandtown-Winchester neighborhood in Baltimore City. These sample data were
compared with national data from the NHANES III survey, and demonstrated similar
awareness of hypertension. However, hypertension control rates among treated
hypertensives were significantly lower in the study community (28%) than in the
national survey (44%). Compared with normotensive individuals, those with HTN
were significantly older, had less education, were less likely to be employed,
and had lower annual incomes. Individuals with HTN were also significantly more
likely to rate their health as poor/fair, to report a history of heart disease,
stroke, diabetes, kidney disease, obesity, high cholesterol, and lack of
exercise, as well as to be at greater risk of alcoholism or alcohol problems.
Hypertensive individuals (88% with reported prior history, 12% newly detected)
were significantly more likely to have a usual source of care, have seen a health
professional in the last 12 months, and to be extremely satisfied with the
provider; however, 20% of individuals with hypertension reported no health
insurance. These data indicate the need for focused interventions to enhance
hypertension maintenance of care and adherence to treatment.
PMID- 10764135
TI - Country of birth and prevalence of gallbladder disease in Mexican Americans.
AB - OBJECTIVES: This research sought to describe the association between country of
birth and gallbladder disease (GBD) in Mexican Americans, identify subgroups at
especially high risk, and identify risk factors that may mediate a birthplace-GBD
association. DESIGN: Cross-sectional. METHODS: Our study population included 4157
Mexican Americans aged 20-74 who participated in the 1988-94 third National
Health and Nutrition Examination Survey. GBD was diagnosed by ultrasound.
Information on country of birth, education, income, and selected GBD risk factors
was obtained from interviews. Prevalence odds ratios (POR) for GBD in Mexico- vs.
US-born Mexican Americans were estimated by unconditional logistic regression,
along with 95% confidence intervals (CI). To evaluate the extent to which GBD
risk factors mediated the birthplace-GBD association, PORs for country of birth
were compared in models with and without additional covariates. RESULTS: Age
adjusted GBD prevalence was lower in Mexico- than in US-born Mexican-American
women (POR = 0.70, 95% CI 0.50, 0.98) and men (POR = 0.63, 95% CI 0.40, 0.97).
The difference was especially pronounced among subjects of lower socioeconomic
status. Despite substantial differences in GBD risk factor distributions by
birthplace, none could completely explain the prevalence difference. CONCLUSIONS:
The observation that GBD prevalence is higher among US-born Mexican Americans is
consistent with research showing poorer health in this group. Further research is
needed to identify strategies for reducing morbidity from GBD in Mexican
Americans.
PMID- 10764136
TI - Are interpregnancy intervals between consecutive live births among black women
associated with infant birth weight?
AB - OBJECTIVES: The purpose of this study was to determine whether the length of
interpregnancy intervals between consecutive live births among Black women had
any significant effect on mean birth weight as had previously been reported in
another study. DESIGN: We examined a sample (1,048 women, 66% of study
participants) from a study of non-Hispanic Black women whose infants were born at
a large, inner-city, public hospital in Georgia from October 1988 through August
1990. Data were evaluated for the 494 women whose current and immediately
previous pregnancies ended in the birth of a live infant weighing 500 grams or
more. METHODS: Linear regression and analysis of covariance models were
developed. RESULTS: The median interpregnancy interval was 15 months (range 1 to
207 months), with 19 (4%) of the women having intervals of less than 3 months.
After adjustment for parity, gestational age (in weeks), and smoking status, the
mean birth weight associated with an interpregnancy interval of three or more
months was 3,106 grams, 215 grams greater than that for an interval of less than
three months (P = .06). CONCLUSIONS: Although longer birth spacing has been
associated with certain positive social and health effects, the population
attributable effect on infant birth weight may not be very significant.
PMID- 10764137
TI - Knowledge and attitudes toward condom use--do they predict behavior among
Filipino Americans?
AB - Face-to-face interviews were conducted with 211 Filipino-American adolescents and
young adults residing in Los Angeles County to assess AIDS related knowledge,
attitudes and behaviors. Among both sexually active and never sexually active
respondents, HIV knowledge and self-efficacy with respect to condom use were
generally high, and the majority held peer norms that were supportive of condom
use. More than half of sexually active respondents reported condom use at last
intercourse. Knowledge of HIV transmission, demographic variables, barriers to
condom use, peer norms, and being comfortable asking a steady partner to
routinely use condoms were not related to condom use at last intercourse. Higher
self-efficacy (odds ratio 2.4, P<.06) and carrying condoms (odds ratio 1.9,
P<.08) were the only two variables that approached statistical significance in
their relationship to condom use at last intercourse. Findings suggest that
variables that are related to AIDS risk behavior among non-Asian populations may
not explain condom use among Filipinos. Therefore, future studies should identify
determinants of AIDS risk behavior among Filipinos and other Asian American
populations as a first step towards developing culturally relevant AIDS
prevention programs for these groups.
PMID- 10764138
TI - Factors that appear as obstacles to the control of high blood pressure.
AB - Blood pressure control at the population level is not what it should be, given
the results of therapeutic trials and the current knowledge on risk factors for
hypertension. Awareness and treatment of hypertension, as well as blood pressure
control under treatment, are low, whether looking at results in the general
population or in groups of people with little education, lower socioeconomic
status or of ethnic origin. Financial and cultural obstacles have been described
in the literature in relation to patient characteristics. Considering the poor
blood pressure control achieved among treated hypertensive subjects, the
interaction between health professionals and patients also needs to be better
understood. From a primary prevention perspective, a non-drug approach seems
moderately successful, particularly among lower socioeconomic groups and ethnic
minorities. However, a contradiction between individual counseling and societal
economic values placed on food seems to create an obstacle to this approach. To
achieve good blood pressure control in the entire population and particularly
underprivileged groups, policies on public health approaches (including
nutrition) to combat risk factors for hypertension are necessary.
PMID- 10764139
TI - MUM1: a step ahead toward the understanding of lymphoma histogenesis.
AB - In recent times, the field of B cell lymphoma histogenesis has progressed rapidly
due to the increasing availability of histogenetic markers. Genotypic markers of
B cell histogenesis are represented by mutations of IgV and BCL-6 genes, which
are somatically acquired at the time of B cell transit through the germinal
center (GC). Phenotypic markers are represented by BCL-6 and CD138/syndecan-1
protein expression and allow the distinction between GC and post-GC B cells. On
this basis, lymphomas may be histogenetically distinguished into: (1) lymphomas
devoid of somatic IgV and BCL-6 hypermutation, which derive from pre-germinal
center B cells; (2) lymphomas associated with somatic IgV and/or BCL-6
hypermutation and BCL-6 expression, which closely reflect germinal center B
cells; and (3) lymphomas associated with somatic IgV and/or BCL-6 hypermutation,
as well as CD138/syndecan-1 positivity, representing lymphomas of post-germinal
center B cells. In the March issue of Leukemia, Tsuboi et al report on the
expression pattern of MUM1 in normal lymphoid tissues and in lymphoma. Because
expression of MUM1 protein appears to be strictly regulated during lymphoid
differentiation, and because expression of the molecule is retained upon
neoplastic transformation, MUM1 may be added to the panel of phenotypic markers
of B cell lymphoma histogenesis. In particular, MUM1 may provide a marker for the
identification of transition from BCL-6 positivity (GC B cells) to CD138
expression (immunoblasts and plasma cells). These studies are of potential
clinical value, since in some B cell malignancies, histogenesis may influence
prognosis.
PMID- 10764140
TI - Genetic polymorphism of thiopurine methyltransferase and its clinical relevance
for childhood acute lymphoblastic leukemia.
AB - Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines,
including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic
polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal
recessive trait. If treated with standard doses of thiopurines, TPMTdeficient
patients accumulate excessive thioguanine nucleotides in hematopoietic tissues,
leading to severe hematological toxicity that can be fatal. However, TPMT
deficient patients can be successfully treated with a 10- to 15-fold lower dosage
of these medications. The molecular basis for altered TPMT activity has been
defined, with rapid and inexpensive assays available for the three signature
mutations which account for the majority of mutant alleles. TPMT genotype
correlates well with in vivo enzyme activity within erythrocytes and leukemic
blast cells and is clearly associated with risk of toxicity. The impact of 6
mercaptopurine dose intensity is also being clarified as an important determinate
of event-free survival in childhood leukemia. In addition, there are emerging
data that TPMT genotype may influence the risk of secondary malignancies,
including brain tumors and acute myelogenous leukemia. Ongoing studies aim to
clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk
for delayed toxicity. Together, these advances hold the promise of improving the
safety and efficacy of thiopurine therapy.
PMID- 10764141
TI - Fludarabine: an effective treatment in patients with splenic lymphoma with
villous lymphocytes.
AB - Splenic lymphoma with villous lymphocytes (SLVL) is a B cell chronic
lymphoproliferative disorder. Splenectomy and/or chlorambucil are usually
regarded as the most effective treatment in SLVL patients. However, a few
patients relapse and the second-line treatment remains questionable. In a
retrospective study, we evaluated the efficacy and toxicity of fludarabine (FDR)
in 10 SLVL patients. The median duration between diagnosis and treatment was 17
months (range, 1-30). Two patients were previously untreated. The patients
received FDR 25 mg/m2/day by venous infusion for 5 days with a median of four
cycles of chemotherapy (range, 2-6). All patients were assessable: five patients
achieved a good and persistent response after a median follow-up of 14 months (5
31), two achieved a good response but relapsed after a follow-up of 15 and 36
months. One out of the three partial responders have a persistent response. The
treatment was well tolerated. FDR appears to be an efficient therapy with a
favorable toxicity profile for patients in relapse after splenectomy or resistant
to CLB. Furthermore it could constitute an alternative to splenectomy in older
patients. A longer follow-up and the study of a larger group of patients are
warranted to confirm our findings.
PMID- 10764142
TI - Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients
with myeloid leukemias.
AB - Leukemic blasts from patients with acute phase chronic myeloid leukemic and
refractory acute myeloid leukemia are highly resistant to a number of cytotoxic
drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion
protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria
toxin (DT) with a (G4S)2 linker (L), expressed and purified the recombinant
protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias
and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3
receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative
cell lines based on assays of cytotoxicity using thymidine incorporation, growth
in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to
680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming
colonies in semi-solid medium (colony-forming units leukemia) > or =10-fold in
4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and
3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors
(colony-forming unit granulocyte-macrophage) from five different donors treated
and assayed under identical conditions showed intermediate sensitivity with three
to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic
progenitors from a number of acute phase CML patients suggests that this agent
could have therapeutic potential for some patients with this disease.
PMID- 10764143
TI - Methylation status of the p15INK4B gene in hematopoietic progenitors and
peripheral blood cells in myelodysplastic syndromes.
AB - We previously reported that the hypermethylation of the p15INK4B gene promoter
was frequently observed in myelodysplastic syndromes (MDS), and that it may be
associated with disease progression. An unanswered question is whether p15INK4B
gene methylation is restricted to undifferentiated blastic cells, or whether
differentiated cells such as granulocytes or erythrocytes of MDS origin also
harbor this epigenetic alteration. In this study, we analyzed the methylation
status of the p15INK4B gene in MDS by the methylation-specific PCR (MSP) method,
which is more sensitive than Southern blotting. The bone marrow mononuclear cells
(BM-MNCs) of 23 MDS patients were analyzed, and six of them showed p15INK4B
methylation. Progenitor assay with methylcellulose medium was also performed in
all patients. In two of the six patients with p15INK4B-methylated BM-MNCs,
erythroid and/or non-erythroid colonies formed were subjected to molecular
analysis. Colonies with and without p15INK4B methylation were detected in both
patients. Furthermore, X-chromosome inactivation (XCI) pattern of each colony was
simultaneously determined by MSP-based human androgen receptor gene analysis
(HUMARA-MSP), and all p15INK4B-methylated colonies showed the same XCI pattern,
which was dominant among the colonies, while p15INK4B-unmethylated colonies
showed both patterns of XCI, in each of the two patients. We then examined the
methylation status of the p15INK4B gene of granulocyte (PB-PMN) fractions from 10
patients with available peripheral blood cells. In all four patients with
p15INK4B-methylated BM-MNCs, their PB-PMNs showed p15INK4B methylation. These
results suggest that p15INK4B methylation in hematopoietic cells in MDS patients
is restricted to the MDS clone but not necessarily to blast cells.
PMID- 10764144
TI - The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin
and dynamin: implications for leukaemogenesis.
AB - The mixed lineage leukaemia gene, MLL (also called HRX, ALL-1) in acute leukaemia
is fused to at least 16 identified partner genes that display diverse structural
and biochemical properties. Using GST pull down and the yeast two hybrid system,
we show that two different MLL fusion partners with SH3 domains, EEN and Abi-1,
interact with dynamin and synaptojanin, both of which are involved in
endocytosis. Synaptojanin, a member of the inositol phosphatase family that has
recently been shown to regulate cell proliferation and survival, is also known to
bind to Eps15, the mouse homologue of AF1p, another fusion partner of MLL.
Expression studies show that synaptojanin is strongly expressed in bone marrow
and immature leukaemic cell lines, very weakly in peripheral blood leukocytes and
absent in Raji, a mature B cell line. We found that the SH3 domains of EEN and
Abi-1 interact with different proline-rich domains of synaptojanin while the EH
domains of Eps15 interact with the NPF motifs of synaptojanin. In vitro
competitive binding assays demonstrate that EEN displays stronger binding
affinity than Abi-1 and may compete with it for synaptojanin. These findings
suggest a potential link between MLL fusion-mediated leukaemogenesis and the
inositol-signalling pathway.
PMID- 10764146
TI - Induction of apoptosis in human hematopoietic U937 cells by granulocyte
macrophage colony-stimulating factor: possible existence of caspase 3-like
pathway.
AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced apoptosis in
human hematopoietic U937 cells by itself and in a synergistic manner with tumor
necrosis factor (TNF). GM-CSF-induced apoptosis was not inhibited by caspase
inhibitors YVAD-CMK, DEVD-CHO and z-VAD-FMK, under the condition that these
inhibitors potently suppressed TNF-induced apoptosis. Both GM-CSF and TNF induced
caspase 3-like activity in this cell line though the time course was distinct
between two cytokines, and combined stimulation of cells with GM-CSF plus TNF
induced additive or synergistic activation of caspase 3-like activity. Amount of
immunoreactive cleaved forms of caspase 3 recognized by specific antibody was
completely dissociated with its enzymatic activity when the cells were stimulated
with GM-CSF, but not with TNF. These results indicate that GM-CSF induces
apoptosis of U937 cells via unknown pathway, which seems to be mediated by
caspase 3-like activity, yet not caspase 3 itself, resistant to the caspase
inhibitors, and synergistically interacts with conventional caspase 3 pathway of
TNF. Possible involvement of caspases 1 and 8 (-like activity) but not caspase 7
in this pathway was also suggested.
PMID- 10764145
TI - Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis
by inhibition of PI3-kinase survival signals.
AB - Drug resistance remains a serious limiting factor in the treatment of acute
myeloid leukaemia (AML) either at initial presentation or following primary or
subsequent relapses. Using specific kinase inhibitors, this study has
investigated the contribution of the Ras/PI3-kinase regulated survival pathways
to drug resistance and suppression of apoptosis in a cell line derived from AML
(HL60). Inhibition of the Raf/MAP-kinase (ERK) pathway with a specific MAP-kinase
inhibitor, apigenin did not sensitise HL60 cells to drug-induced apoptosis,
indicating a lack of involvement in chemoresistance. In contrast, the PI3-kinase
inhibitors, LY294002 and wortmannin, did induce a significant increase in
apoptosis in combination with cytotoxic drugs. The contribution of downstream
mediators of PI3-kinase, p70S6-kinase and PKB/Akt were then investigated. While
inhibition of p70S6-kinase with rapamycin did not increase drug-induced
apoptosis, PI3-kinase inhibition resulted in notable dephosphorylation of PKB,
suggesting that the PI3-kinase/PKB survival pathway may play a major role in
chemoresistance in AML. This pathway has been reported to mediate heterodimer
interactions with the proapoptotic regulator, Bad. In contrast to previous
studies, we found no evidence of Bad binding to anti-apoptotic Bcl-2, Bcl-XL or
McI-1, or of alterations in Bax heterodimers. This suggests that alternative
targets of PI3-kinase/PKB, distinct from the Bcl-2 family may be responsible for
contributing to survival factor-mediated drug resistance in AML.
PMID- 10764147
TI - Mechanisms of resistance to apoptosis in human AML blasts: the role of
differentiation-induced perturbations of cell-cycle checkpoints.
AB - Alterations in the response of leukaemic cells to apoptosis-inducing stimuli may
account for resistance to chemotherapy and treatment failure, either by
disruption of the apoptotic pathway itself or by altered DNA repair; quiescent
cells and those with disrupted cell-cycle checkpoints may also display decreased
apoptosis. Quiescence can be induced by the differentiation of myeloid cells, and
this led us to investigate whether the modulation of drug-induced apoptosis
associated with differentiation might be a model for quiescence-associated
resistance generally. We have demonstrated that resistance to idarubicin-induced
apoptosis increased with greater duration of incubation of HL60 and U937 cells
with ATRA and 1,25(OH)2 D3 and that this protective effect correlated with the
degree of G0/G1 accumulation. In addition, the cytoprotective effects held for
other classes of cytotoxic drugs with different mechanisms of action to
idarubicin. Prolonged exposure to idarubicin or vinblastine was associated with
diminution of the protective effect and re-entry of cells into cycle. The full
cytoprotective effect was restored by resupplementation with ATRA or 1,25(OH)2 D3
during exposure to idarubicin, with concomitant persistence of G0/G1
accumulation. Differentiating agents prevented the accumulation of leukaemic
cells at the G2/M checkpoint in response to low concentrations of idarubicin.
Understanding how differentiating agents modulate these cell-cycle checkpoints,
and how quiescent cells evade apoptosis, may allow the development of therapeutic
strategies to limit such apoptosis-inhibiting effects and maximise cell kill from
chemotherapy.
PMID- 10764148
TI - Characterization of a novel negative regulatory element in the human interleukin
4 promoter.
AB - Interleukin 4 (IL-4) is a multifunctional cytokine that plays an important role
in hematopoiesis, tumor cell growth, and cellular immune responses. Expression of
the IL-4 gene is tightly controlled at the level of gene transcription, and many
positive regulatory cis-elements have been identified in the proximal IL-4
promoter region. Relatively little is known about factors that downregulate IL-4
transcription. We performed a detailed deletional analysis of the proximal human
IL-4 promoter and studied reporter gene activity in transiently transfected
Jurkat T lymphoblasts. In this report, we characterize a novel negative
regulatory element (termed P2 NRE) that is adjacent to a binding site for nuclear
factor of activated T cells. Mutation of P2 NRE significantly enhanced the
activity of a 175 base pair IL-4 promoter construct in transiently transfected
Jurkat T lymphoblasts. Using nuclear extracts from Jurkat cells, we identify a
candidate factor (termed Rep-1) that binds uniquely to the P2 NRE in DNA-binding
assays. Rep-1 is not related to other factors previously shown to interact with
the IL-4 promoter, and by UV cross-linking and SDS-PAGE analysis, we found that
it migrates with a molecular mass of approximately 150 kDa. Characterizing the
molecular mechanisms responsible for downregulating the IL-4 promoter should
enhance our understanding of IL-4-gene dysregulation in disease states.
PMID- 10764149
TI - Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia
of elderly patients.
AB - The biological and clinical importance of cytogenetic analysis in myelodysplastic
syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly
recognized. Recently, cytogenetic similarities were noted between elderly de novo
AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the
present study we analyzed the cytogenetic similarities between patients with AML
of different age and patients with MDS consecutively diagnosed during a 5-year
period at a single, primary referral, hematologic center. Of 246 patients aged
<86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases
were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML.
Patients were classified according to FAB criteria and were subdivided into four
groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than
refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB
T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients
with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65
years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic
similarities both in the frequency of normal karyotypes (31% and 27%), single
abnormalities (14% and 13%), double abnormalities (17% and 14%), complex
karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as
in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7
(27% and 27%). The only difference between the two groups was found in the median
number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early
MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic
features resembled otherwise those of 'late MDS' and 'old AML', and any
significant difference disappeared when patients with chronic myelomonocytic
leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in
the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML
and AML with trilineage dysplasia shared the same cytogenetic features of 'late
MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups,
particularly in the higher frequency of balanced translocations (29%; P<0.001)
and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of
complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%;
P<0.01) involvement. We conclude that in a population-based series of patients,
the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical
to that of elderly patients with AML both in the frequency and in the type of
chromosomal abnormalities. These results support the possibility that MDS and AML
of elderly patients may represent the same disease seen at different stages of
evolution.
PMID- 10764150
TI - Differential abilities of the Raf family of protein kinases to abrogate cytokine
dependency and prevent apoptosis in murine hematopoietic cells by a MEK1
dependent mechanism.
AB - In this study, the abilities of constitutive and conditional forms of the three
Raf kinases to abrogate the cytokine dependency of FDC-P1 cells were examined.
The constitutively active forms (delta) of all three Raf kinases were fused to
the hormone-binding domain of the estrogen receptor (ER), rendering their
activities conditionally dependent upon exogenous beta-estradiol. The vast
majority of deltaRaf:ER-infected FDC-P1 cells remained cytokine-dependent;
however, cells were obtained at low frequency in which expression of deltaRaf:ER
abrogated cytokine dependency. Isoform specific differences between the Raf
kinases were observed as cytokine-independent cells were obtained more frequently
from deltaA-Raf:ER than either deltaRaf-1:ER or deltaB-Raf:ER infected cells. To
determine whether the regulatory phosphorylation sites in the Raf proteins were
necessary for abrogation of cytokine dependency, they were changed by site
directed mutagenesis. Substitution with phenylalanine eliminated the transforming
ability of the deltaB-Raf:ER and deltaRaf-1:ER kinases. However, a similar
substitution in A-Raf did not extinguish its transforming activity. The activated
Raf proteins induced essential downstream MEK1 activity as treatment with the
MEK1 inhibitor, PD98059, suppressed Raf-mediated growth. Activated MAP kinases
(ERK1 and ERK2) were detected in deltaRaf:ER-transformed cells, and their
presence was dependent upon a functional MEK1 protein. The cytokine-independent
phenotype required the continued activity of the deltaRaf:ER proteins as removal
of beta-estradiol caused the cells to stop growing and undergo apoptosis. The Raf
responsive cells were found to express autocrine growth factors, which promoted
their growth. Constitutive activation of the Raf-1 oncogene resulted in malignant
transformation as cytokine-independent FDC-P1 cells infected with a retrovirus
encoding an activated Raf-1 protein formed tumors upon injection of
immunocompromised mice. In summary, Raf kinases can abrogate cytokine dependency,
prevent apoptosis and induce the tumorigenicity of a certain subpopulation of FDC
P1 cells by a MEK1-dependent mechanism.
PMID- 10764151
TI - Identification of a genetic locus modulating splenomegaly induced by granulocyte
colony-stimulating factor in mice.
AB - Clinically detectable splenomegaly and splenic rupture are uncommon but
potentially life-threatening consequences of G-CSF administration. Increased
spleen size in mice injected with G-CSF is a complex genetic trait amenable to
investigation in experimental inter-strain crosses by quantitative trait
analysis. A quantitative trait locus (QTL) with highly significant linkage (LOD
7.9) for splenomegaly was identified within a 22 centimorgan (cM) region on
chromosome 1. Inheritance of a C57BL/6 haplotype in this region was associated
with a greater spleen weight. The relevance of this locus was confirmed by
analysing the responses of mice congenic for the distal 12 cM of this region
(C57BL/6 and C57BL/6.SJL-Ptprc(a) Pep3(b)). Consistent with the QTL effect, mice
lacking C57BL/6 alleles in this region had reduced splenomegaly induced by G-CSF.
Intriguingly, peripheral blood neutrophilia and progenitor cell mobilisation
responses to G-CSF were also significantly influenced.
PMID- 10764152
TI - Biological effects induced by variable levels of BCR-ABL protein in the
pluripotent hematopoietic cell line UT-7.
AB - There is currently no satisfactory model allowing analysis of dose-effect
relationships of BCR-ABL proteins in human hematopoietic cells. To study
comparatively the proliferative, differentiative and anti-apoptotic actions of
different levels of BCR-ABL proteins in the context of the same cellular
background, we have introduced the BCR-ABL gene into the GM-CSF-dependent
pluripotent human cell line UT-7. Individual clones expressing BCR-ABL were
analyzed by Western blots. After normalization to equivalent levels of endogenous
ABL protein, 14 clones always grown in GM-CSF were found to express low but
variable levels of BCR-ABL whereas two clones selected in the absence of GM-CSF
expressed very high levels of BCR-ABL. All low-level BCR-ABL expressing clones
exhibited a behavior similar to that of the GM-CSF-dependent parental cells as
they ceased to proliferate upon growth factor deprivation and showed a strong
proliferative response upon GM-CSF addition. One out of 14 clones showed
progressive GM-CSF independence during culture over several weeks and was found
to have a significant increase of BCR-ABL expression at that time. The resistance
of this clone (E8-2) to different apoptotic stimuli was found to be increased as
compared to its low BCR-ABL-expressing counterpart (E8-1) and similar to that
observed in clones with very high levels of BCR-ABL (UT-7/9 and UT-7/11) which
were totally resistant to apoptotic stimuli. When injected into nude mice,
parental UT-7 cells and clones with low-level of BCR-ABL were not tumorigenic
over 10 weeks of observation whereas UT-7 clones with high levels of BCR-ABL (UT
7/9, UT-7/11 and UT-7/E8-2) induced aggressive tumors in 2-4 weeks with a
significant correlation between the amount of BCR-ABL protein and the rate of
tumor growth. In conclusion, the establishment of an in vitro and in vivo CML
model using UT-7 cells suggests for the first time in human cells, that the fully
transformed phenotype induced by BCR-ABL requires high levels of BCR-ABL
expression. These findings suggest that variable levels of BCR-ABL in primary
patient cells could also be responsible for the different phenotypic features
seen in chronic and acute phases of CML, such as the differentiation ability
induced by growth factors.
PMID- 10764153
TI - Immunoglobulin kappa gene rearrangements between the kappa deleting element and
Jkappa recombination signal sequences in acute lymphoblastic leukemia and normal
hematopoiesis.
AB - The kappa deleting element (kappaDE) located 24 kb downstream of the Ckappa gene
segment mediates the deletion of Ckappa and the Jkappa-Ckappa Intron enhancer,
which results in allelic exclusion of the immunoglobulin kappa light chain locus.
We here report that the kappaDE can recombine to each recombination signal
sequence (RSS) flankappaing Jkappa1 to Jkappa5 in normal hematopoiesis. Moreover,
usage of the JkappaRSS-kappaDE junctional sequence allows the detection of
minimal residual disease in acute lymphoblastic leukemia.
PMID- 10764154
TI - Biological characteristics and prognosis of adult acute myeloid leukemia with
internal tandem duplications in the Flt3 gene.
AB - Internal tandem duplications of the FIt3 gene (FIt3/ITDs) are present in about
18% of all AML cases and are therefore one of the most frequent somatic gene
mutations in AML. Little is known about the role of FIt3/ITDs in leukemogenesis
or their clinical relevance. In this study we compared 18 samples with FIt3/ITDs
and 63 AML samples without these mutations with respect to clinical prognosis,
cytokine responsiveness, progenitor cell content and repopulation in the NOD/SCID
mouse. We found that in patients with a mutation CR rates are reduced (P=0.03)
and relapse rates are increased (P=0.01), indicating the prognostic importance of
FIt3/ITDs. This is also emphasized by the finding that in patients under the age
of 60 years, as well as in older patients the event-free survival was more
unfavorable for the mutant patients (P=0.003 and P=0.03, respectively). At
diagnosis FIt3/ITD and non-mutant AML bone marrow samples did not differ in their
progenitor/stem cell frequencies. Cobblestone area forming cell (CAFC) subsets
showed a similar frequency distribution in mutant and non-mutant samples. In 7
day liquid cultures, FIt3/ITD samples showed a reduced growth in response to a
variety of myeloid growth factors. In contrast, FIt3/ITD samples displayed a
higher ability to engraft the NOD/SCID bone marrow with leukemic cells. Together
these data show that the FIt3/ITD represents an important diagnostic marker for
patient prognosis, and that the presence of these mutations is associated with
altered proliferative ability of progenitors in vivo and in vitro.
PMID- 10764155
TI - Prognostic factors in infants with acute myeloid leukemia.
AB - Little is known about the factors that affect treatment outcome in very young
children with acute myeloid leukemia (AML). We therefore analyzed the prognostic
impact of various presenting clinical and laboratory features by discrete age
group in 299 children with AML treated in four consecutive clinical trials
between 1980 and 1997. Differences in presenting features, as well as treatment
outcome, were compared between children aged 12 months or less (n = 28) or 13 to
24 months (n = 28) and those more than 24 months of age (n = 243). Children in
the two youngest groups (24 months of age or less) had similar presenting
features and treatment outcome. Collectively, these 56 children were
significantly more likely than the 243 older patients to have M4 or M5 leukemia
(70% vs 30%), CNS leukemia (33% vs 22%), the t(9;11) (p22;q23) (18% vs 6%) or
other 11q23 translocations (23% vs 3%), and less likely to have Auer rods (2% vs
54%) or the t(8;21) (q22;q22) (0% vs 17%). Among patients aged 24 months or less,
two factors independently predicted a favorable prognosis: FAB M4 or M5 leukemia
(relative risk of relapse, 0.4; 95% confidence interval, 0.2-0.9) and the t(9;11)
(relative risk, 0.3; 95% confidence interval, 0.1-1.0). Leukocyte count and 11q23
translocations other than the t(9;11) lacked prognostic significance. Among older
patients, a leukocyte count <50 x 10(9)/l and the presence of the t(9;11)
conferred a favorable prognosis.
PMID- 10764156
TI - Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic
leukemia patients depends on the type of preceding chemotherapy.
AB - Immunofluorescence stainings for the CD10 antigen and terminal deoxynucleotidyl
transferase (TdT) can be used for the detection of leukemic blasts in CD10+
precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) patients, but can also
provide insight into the regeneration of normal precursor-B-cells in bone marrow
(BM). Over a period of 15 years, we studied the regeneration of CD10+, TdT+, and
CD10+/TdT+ cells in BM of children with (CD10+) precursor-B-ALL during and after
treatment according to three different treatment protocols of the Dutch Childhood
Leukemia Study Group (DCLSG) which differed both in medication and time schedule.
This study included a total of 634 BM samples from 46 patients who remained in
continuous complete remission (CCR) after treatment according to DCLSG protocols
VI (1984-1988; n = 8), VII (1988-1991; n = 10) and VIII (1991-1997; n = 28).
After the cytomorphologically defined state of complete remission with CD10+ and
CD10+/TdT+ frequencies generally below 1% of total BM cells, a 10-fold increase
in precursor-B-cells was observed in protocol VII and protocol VIII, but not in
protocol VI. At first sight this precursor-B-cell regeneration during treatment
resembled the massive regeneration of the precursor-B-cell compartment after
maintenance treatment, and appeared to be related to the post-induction or post
central nervous system (CNS) therapy stops in protocols VII and VIII. However,
careful evaluation of the distribution between the 'more mature' (CD10+/TdT-) and
the 'immature' (CD10+/TdT+) precursor-B-cells revealed major differences between
the post-induction/post-re-induction precursor-B-cell regeneration (low
'mature/immature' ratio: generally <1.0), the post-CNS treatment regeneration
(moderate 'mature/immature' ratio: 1.2-2.8), and the post-maintenance
regeneration (high 'mature/ immature' ratio: 5.7-7.6). We conclude that a therapy
stop of approximately 2 weeks is already sufficient to induce significant
precursor-B-cell regeneration even from aplastic BM after induction treatment.
Moreover, differences in precursor-B-cell regeneration patterns are related to
the intensity of the preceding treatment block, with lower 'mature/immature'
ratios after the highly intensive treatment blocks. This information is essential
for a correct interpretation of flow cytometric immunophenotyping results of BM
samples during follow-up of leukemia patients. Particularly in precursor-B-ALL
patients, regeneration of normal precursor-B-cells should not be mistaken for a
relapse.
PMID- 10764157
TI - Expression of a functional inducible nitric oxide synthase in hairy cell
leukaemia and ESKOL cell line.
AB - The expression of nitric oxide synthase (NOS) isoforms was investigated in the
established ESKOL hairy cell line and in leukemic cells of patients with hairy
cell leukemia (HCL). By reverse transcription-polymerase chain reaction (RT-PCR),
these cells were found to spontaneously express inducible NOS (iNOS)-specific
mRNA, but not endothelial constitutive NOS (ecNOS) mRNA. The iNOS protein was
detected by immunofluorescence in the cytoplasm of permeabilized leukemic cells
and ESKOL cells, using different anti-iNOS monoclonal antibodies. A protein of
135 kDa was identified by Western blotting in ESKOL and HCL lysates, confirming
the presence of an iNOS in these cells. Cytosolic homogenates displayed NOS
catalytic activity, as measured by the conversion of 14C-labelled L-arginine into
14C L-citrulline and by detection in situ using the DAF-2DA (diaminofluorescein
diacetate) NO-sensitive fluorescent probe. Ligation of CD23 (low affinity IgE
receptor) was found to increase iNOS expression in ESKOL and conversely to
decrease the percentage of cells undergoing apoptosis, as measured by the
percentage of cells expressing annexin V. These results indicate that, as in
chronic B cell lymphocytic leukemia cells (B-CLL) a functional iNOS is expressed
constitutively in hairy cells that contributes to protecting these tumoral cells
from apoptosis.
PMID- 10764158
TI - p53 mutations in hairy cell leukemia.
AB - We have studied the frequency of p53 mutations in genomic DNA extracted from
peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR
SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17
cases, corresponding to a frequency of 28%. In four cases, mutations were
localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at
the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to
be mutated in seven cases. The mutations found could be divided into three major
categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations.
None of the three transitions found occurred at CpG dinucleotides. The rate of
p53 mutations found in this large cohort of HCL patients is unexpectedly high as
in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome.
The character of the mutations we have found is entirely different from that
described in other hematologic malignancies.
PMID- 10764159
TI - Ex vivo assessment of drug response by differential staining cytotoxicity (DiSC)
assay suggests a biological basis for equality of chemotherapy irrespective of
age for patients with chronic lymphocytic leukaemia.
AB - With a mean age at diagnosis for chronic lymphocytic leukaemia (CLL) of 65 years,
development of optimal therapeutic regimens has been hampered by the advanced age
of patients. In general, because of comorbidity older patients are not treated
with the intent of achieving a complete response and so do not attain the quality
of response of younger patients and do not survive as long. We have investigated
whether or not ex vivo cellular sensitivity to cytotoxic drugs could be an
underlying biological basis for this age differential in response and survival by
comparing ex vivo drug response with age in untreated CLL patients. Cells from
365 untreated CLL patients aged 31.1-87.1 years (average 65.3 years) were tested
for drug response by differential staining cytotoxicity (DiSC) assay with a panel
of 10 drugs. An average of 280 results (range 196-361) obtained for each drug was
compared with patient age. For chlorambucil, cyclophosphamide, prednisolone,
vincristine, doxorubicin, epirubicin, fludarabine, cladribine and
methylprednisolone, no relationship was found between ex vivo drug response and
age (r<0.12). For pentostatin, a possible but very weak relationship (r = 0.18; n
= 210; P = 0.06) was found. We conclude that cellular sensitivity to cytotoxic
drugs does not support the differential treatment of older and younger CLL
patients.
PMID- 10764160
TI - Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in
HTLV-I associated adult T cell leukemia/lymphoma.
AB - The combination of the anti-viral agents, zidovudine (AZT) and interferon-alpha
(IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma
(ATL). In this study we investigate the possible mechanism of action of this
combination by examining several cellular parameters including cell
proliferation, cell cycle distribution and apoptosis. The ATL-derived T cell
lines HuT-102 and MT-2 served as models. HTLV-I negative T cell lines (CEM and
Jurkat) were used as controls. No significant modification of cell growth was
observed except at suprapharmacological doses of AZT and IFN. Moreover, these
effects were less pronounced in HTLV-I-infected cell lines compared to control
cell lines. AZT and IFN treatment did not induce any significant modification of
the expression of bcl-2 and p53. Interestingly no in vitro cytotoxic effect of
AZT/IFN combination was observed on fresh leukemic cells derived from an acute
ATL patient at diagnosis despite achievement of in vivo complete remission using
the same therapy. These results suggest that the therapeutic effect of AZT and
IFN is not through a direct cytotoxic effect of these drugs on the leukemic
cells.
PMID- 10764161
TI - The incidence of acute promyelocytic leukemia appears constant over most of a
human lifespan, implying only one rate limiting mutation.
AB - It is believed that most malignancies become more common with increasing age due
to the requirement for several mutations to accumulate and subsequently interact.
The age specific incidence of acute promyelocytic leukemia (APL) was investigated
using population-based data from 77 million subject years of observation,
yielding 149 consecutive cases. The incidence appears approximately constant with
respect to age, an observation not previously reported with any other malignancy.
These findings are most easily explained by there being only one rate limiting
genetic event required to initiate the disease, although other, non-rate limiting
mutations may also be necessary for disease development. It is also argued that
this mutation is probably restricted to cells committed to differentiation, which
may explain why APL is curable by chemotherapy.
PMID- 10764163
TI - The expansion of murine bone marrow cells preincubated in hypoxia as an in vitro
indicator of their marrow-repopulating ability.
AB - In liquid cultures of murine bone marrow cells stimulated with interleukin-3 and
granulocyte/macrophage colony-stimulating factor, hypoxia (1% oxygen) induced a
reversible block of hematopoiesis, maintaining the progenitors' expansion
potential unreduced. Progenitors repopulating day-14 hypoxic cultures with cells
or granulocyte/macrophage colony-forming units (CFU-GM) were found, on the basis
of their maintenance in hypoxia (12% and 76%, respectively), to belong to
different subsets, the latter being much more efficiently maintained. The
maintenance in hypoxic cultures of progenitors detectable by marrow-repopulating
ability (MRA) assay was 18% for MRAcell progenitors and 69% for MRACFU
progenitors. Thus, the repopulation of hypoxic cultures with cells or CFU-GM
closely reflected the presence of progenitors capable of repopulating, with cells
or CFU-GM, the bone marrow of lethally irradiated syngeneic animals. Progenitors
repopulating hypoxic cultures were, like MRA progenitors, significantly resistant
to 5-fluorouracil, progenitors repopulating cultures with CFU-GM being two-fold
more resistant than those repopulating cultures with cells. We concluded that the
repopulation of day-14 hypoxic cultures occurring after their transfer to air is
to be considered an indicator of the maintenance of MRA progenitors in hypoxia.
The relevance of these results to stem cell biology and their potential practical
applications are discussed.
PMID- 10764162
TI - Stromal cell-independent differentiation of human cord blood CD34+CD38-
lymphohematopoietic progenitors toward B cell lineage.
AB - To study the cytokine regulation of early stages of human B-lymphopoiesis, we
developed a stroma-free two-step culture system. Single human cord blood
CD34+CD38- cells were individually cultured by micromanipulation with interleukin
(IL)-3, stem cell factor (SCF), fIt3 ligand (FL), IL-6 and granulocyte colony
stimulating factor (G-CSF). About 10% of the cells formed primary colonies, which
were individually tested for myeloid and B-lymphoid potentials by reculturing
aliquots of the primary colony cells into secondary myeloid and B-lymphoid
cultures. One third of the primary colonies proved capable of differentiation
into CD19+IgM+ cells, as well as into myeloid lineage cells. RT-PCR analyses
revealed that some cells in the primary culture had already matured to express B
cell-specific transcripts. Thus, the combination of IL-3, SCF, FL, IL-6 and G-CSF
supported the differentiation of CD34+CD38- lymphohematopoietic progenitors
toward B cell lineage in addition to myeloid lineages. Screening of cytokines to
identify the minimum requirement of cytokines in the primary culture revealed
that IL-3 and SCF were essential and that the addition of FL, and to a lesser
extent IL-6 or G-CSF, to the combination of IL3 and SCF remarkably enhanced the
primary colony formation and the generation of CD19+ cells in the secondary B
lymphoid culture.
PMID- 10764164
TI - Long-term follow-up of advanced-stage low-grade lymphoma patients treated upfront
with high-dose sequential chemotherapy and autograft.
AB - Long-term outcome, after first line intensified high-dose sequential (i-HDS)
chemotherapy, was evaluated in 46 patients, aged < or =65 years, with advanced
low-grade lymphoma. Seventeen patients had small lymphocytic lymphoma (SLL), 29
had follicular lymphoma (FL), 10 of them with histologic transformation. I-HDS
included: (1) tumor debulking, by 2 APO+2 DHAP courses; (2) sequential
administration of high-dose (hd) etoposide, methotrexate, and cyclophosphamide,
followed by peripheral blood progenitor cell (PBPC) harvest; (3) hd-mitoxantrone
+ melphalan with PBPC autograft. Ten FL patients had their PBPC immunologically
purged ex vivo. There were two treatment-related deaths; five FL patients had
short-lasting response followed by disease progression, five SLL reached a stable
PR; overall, 34 patients (74%) reached CR. At a median follow-up of 4.3 years,
the estimated 9-year OS and EFS were 84% and 45%, respectively. No significant
differences were observed in the OS among patients at low, intermediate or high
IPI score, with an estimated OS projection of 95%, 78%, and 75%, respectively. FL
had longer survival without evidence of residual disease (9-year EFS: 59%) as
compared to SLL patients (8.8-year EFS: 17%); however, both groups had prolonged
survival and no need of salvage treatment, as shown by the time to disease
progression curve, projected to 66% and 62% for SLL and FL, respectively. The
results indicate that hd-approach in low-grade lymphoma: (1) is associated with
longer progression-free survival as compared to conventional therapies; (2) may
imply higher tumor mass reduction in FL as compared to SLL patients; (3) offers
long life expectancy, with potential survival benefits at least for patients at
intermediate/high IPI score.
PMID- 10764165
TI - Variation in the frequency of Epstein-Barr virus-associated Hodgkin's disease
with age.
AB - A number of studies in developed countries have reported variation in the
frequency of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) with age.
A 'three disease' model for HD that incorporates the EBV association,
histological subtype of HD and age has recently been proposed. In this model,
Hodgkin's disease of childhood and older adults is commonly EBV-associated and of
mixed cellularity type, whereas young adult HD is generally not EBV-associated
and is usually characterised by nodular sclerosis disease. A case series of HD
diagnosed in the West Midlands between 1981 and 1997, inclusive, was used to
investigate the applicability of the 'three disease' model. In situ hybridisation
for the EBV early RNAs (EBERs) was used to determine the presence of EBV in the
malignant Hodgkin/Reed-Sternberg cells. In contrast to the 'three disease' model,
nodular sclerosis was the predominant subtype in each of the age groups within
the case series. In addition, overall there was little variation in EBV-positive
rates across the age ranges examined. However, when females were analysed
separately, older women (45+ years) were significantly more likely to have EBV
positive disease than their younger counterparts (<45 years). In summary our
results do not generally support the 'three disease' model.
PMID- 10764167
TI - Digoxigenin-end labeled oligonucleotides facilitate the detection of minimal
residual disease in acute lymphoblastic leukemia.
PMID- 10764166
TI - A real-time PCR assay for the quantification of residual malignant cells in B
cell chronic lymphatic leukemia.
AB - Several new therapeutic approaches for the treatment of monoclonal B cell
lymphomas are currently being investigated. In parallel with new therapeutic
modalities, more sensitive diagnostic methods are needed. These methods should be
highly sensitive in detecting very low amounts of malignant cells and should be
specific for the malignant clone. In addition, these methods should allow the
quantification of residual tumor cells. In this study a new real-time polymerase
chain reaction (LightCycler) was evaluated to quantify residual tumor cells in
monoclonal B cell malignancies. This technology combines the advantages of rapid
cycling PCR with the online detection of PCR products using fluorescent dyes. Our
assay is based on immunoglobulin heavy chain (IgVH)-specific PCR with allele
specific primers complementary to hypervariable CDRII and CDRIII regions. A set
of framework region III (FRIII)-specific hybridization probes was used for
detection of the specific amplification product, and IgVH copy number was
quantified with the cloned IgVH sequence as an external standard. The approach
was evaluated with the Hodgkin lymphoma cell line L428 in order to quantify L428
dilutions. L428 cells mixed with peripheral blood mononuclear cells (PBMNCs) were
detected and quantified with a sensitivity of one cell within 1 x 10(5) PBMNCs.
Sample DNA from the peripheral blood and from the bone marrow of two patients
with B-CLL was analyzed in the new set up at different time points before and
after therapy. Statistically significant changes in IgVH copy numbers were
documented in both patients. We conclude that this technology offers an
additional opportunity to detect and quantify residual tumor cells in B-CLL over
several log steps with a high sensitivity. The kinetics of residual tumor cell
counts in B-CLL can be analyzed by this method.
PMID- 10764168
TI - Leukaemic expression of anaplastic large cell lymphoma with
46,XX,ins(2;5)(p23;q15q35) in a child with dihydropyrimidine dehydrogenase
deficiency.
PMID- 10764169
TI - Discordant expression of AC133 and AC141 in patients with myelodysplastic
syndrome (MDS) and acute myelogeneous leukemia (AML)
PMID- 10764170
TI - Dynamic anatomy of upper airway: an essential paradigm.
PMID- 10764171
TI - Patient-controlled intranasal analgesia: effective alternative to intravenous PCA
for postoperative pain relief.
AB - PURPOSE: To investigate whether the nasal route for fentanyl administration in
patient-controlled analgesia (PCA) provides as effective postoperative analgesia
as intravenous PCA. METHODS: Patient-controlled intranasal or intravenous
analgesia with fentanyl was investigated in 48 patients (ASA I-III) on the day of
surgery (orthopedic, abdominal or thyroid) in a prospective, randomized, double
blind, double-dummy study. Fentanyl was given in a bolus of 25 microg for
intranasal and 17.5 microg for i.v. PCA, lockout interval six minutes. The first
requested dose was doubled in both groups. Pain intensity (101-point numerical
rating scale) and vital parameters were observed at 11 measurement points during
the 240 min study. Patients were asked for side effects at every measurement
point and for their satisfaction at the end of the study by the same investigator
(J.M.). RESULTS: Onset of analgesia, the first reduction in pain intensity on the
numerical rating scale, was 21 +/- 11 min (range 15-45 min) in intranasal and 22
+/- 16 min (range 15-90 min) in i.v. PCA. Pain intensity was reduced from 55 +/-
11 to 11 +/- 10 in the intranasal group and from 53 +/- 8 to 11 +/- 6 in the i.v.
PCA group. Vital parameters remained stable and side effects were comparable in
both groups. The judgement "excellent" or "good" was given by 21 of 23 patients
treated intranasally and 24 of 25 patients treated intravenously. CONCLUSION:
Intranasal PCA with fentanyl was an effective alternative to i.v. PCA in
postoperative patients.
PMID- 10764172
TI - Intrathecal morphine suppresses NK cell activity following abdominal surgery.
AB - PURPOSE: The effects of morphine on natural killer (NK) cell activity were
investigated in patients who underwent hysterectomy. METHODS: Forty patients were
divided into four groups of ten. The groups received intrathecal 0.5 mg morphine
(Group IT0.5), intrathecal 0.1 mg morphine (Group IT0.1) or 10 mg morphine i.v.
(Group IV). The remaining ten patients served as controls and received inhalation
anesthesia alone (Group C). Blood samples were withdrawn before and two hours
after surgery and on postoperative days one and two to determine the blood NK
cell activity using a chromium release assay with K562 cells as targets, plasma
catecholamines and cortisol levels. The postoperative pain score and side effects
were studied in the four groups. RESULTS: In Group IT0.5, the NK cell activity
was lower on postoperative day 1 (23.9 +/- 8.4%) than the baseline level (45.7 +/
13%) before surgery, and recovered on postoperative day 2. In Groups IT0.1, C
and IV, the NK cell activities showed no significant changes. In all four groups,
neither plasma adrenaline nor noradrenaline concentrations changed. In all four
groups, the plasma cortisol levels increased after surgery, on postoperative days
1 and 2. The pain score was lower two hours after surgery and on postoperative
day 1 in Group IT0.5 than in the other groups. CONCLUSION: These results suggest
that long-lasting analgesic effects of intrathecal 0.5 mg morphine suppress the
immune response following abdominal surgery.
PMID- 10764173
TI - Peroperative titration of morphine improves immediate postoperative analgesia
after total hip arthroplasty.
AB - PURPOSE: To determine the Influence of peroperative titrated morphine on
postoperative pain control. METHODS: Forty patients received general anesthesia
for total hip arthroplasty (THA) and were divided into two groups of 20. In the
Peroperative group (Perop group;) morphine was titrated at the end of surgery (3
mg i.v. every 5 or 10 min) in spontaneously breathing intubated patients, until
the respiratory rate (RR) decreased. No morphine was administered to Postop
group. In the Post Anesthesia Care Unit (PACU) patients in Perop and Postop
groups received morphine until adequate pain relief VAS < or = 30 mm. Patients
used patient-controlled analgesia (PCA) for the next 24 hr. In the PACU, the
delay for analgesia, doses of morphine used and incidence of side effects were
recorded. RESULTS: In the Perop group, patients received 10.3 +/- 1.3 mg (2-20
mg) as peroperative titration and had achieved adequate analgesia more rapidly
than in the Postop group (42 +/- 7 min vs 76 +/- 7 min); P = 0.0026). Analgesia
in the PACU in the Postop group required larger doses of morphine (15.4 +/- 1.5
mg;) than in the Perop group (7.3 +/- 1.3 mg; P = 0.0004). The respiratory rate
decrease during peroperative morphine titration was correlated to the morphine
dose needed in the PACU (P = 0.035). Respiratory depression in the PACU was more
common in the Postop group than in the Perop group (five patients vs no patient P
= 0.017). CONCLUSION: This study demonstrated that the peroperative
administration of morphine can facilitate immediate postoperative pain
management.
PMID- 10764174
TI - Airway complications in infants: comparison of laryngeal mask airway and the
facemask-oral airway.
AB - PURPOSE: To compare the incidence of airway complications in children less than
one year of age whose airways were maintained during anesthesia with either a
laryngeal mask airway (LMA) or a facemask and oral airway (FM-OA). METHODS: We
randomized 49 - ASA class 1&2 - infants to an LMA or FM-OA group. All infants
were undergoing minor general, urological or orthopedic procedures. Anesthesia
was induced and maintained with halothane in nitrous oxide 50% and oxygen. The
airway was removed in both groups when the infant was awake. The occurrence of
airway complications (breath-holding, coughing, laryngospasm, secretions,
obstruction and oxygen saturation < 95%) at induction of anesthesia,
intraoperatively and during emergence from anesthesia was recorded. RESULTS:
Airway complications occurred perioperaively in 15 of 27 infants in the LMA group
and in 5 of 22 infants in the FM-OA group (P: 0.02). CONCLUSION: In infants, the
use of the LMA is associated with an increased incidence of airway complications
compared with the use of the FM-OA.
PMID- 10764175
TI - Acupressure wristbands do not prevent postoperative nausea and vomiting after
urological endoscopic surgery.
AB - PURPOSE: To evaluate the efficacy of acupressure wristbands in the prevention of
postoperative nausea and vomiting (PONV). METHODS: Two hundred ASA I-II patients
undergoing elective endoscopic urological procedures were included in a
randomized, prospective, double blind, placebo-controlled study. Spherical beads
of acupressure wristbands were placed at the P6 points in the anterior surface of
both forearms in Group I patients (acupressure group, n = 100) whereas, in Group
2 (control group, n = 100) they were placed inappropriately on the posterior
surface. The acupressure wristbands were applied 30 min before induction of
anesthesia and were removed six hours postoperatively. Anesthesia was induced
with thiopental and maintained with nitrous oxide and oxygen, fentanyl,
isoflurane and vecuronium. The tracheas were extubated on the operation table
after patients received neostigmine and atropine. Post operative nausea and
vomiting were evaluated separately as none, mild, moderate or severe at the time
of patient's arrival in PACU, then at six hours and twenty-four hours after
surgery by a blinded observer. RESULTS: In the acupressure group, 25 patients had
PONV compared with 29 patients in the control group (P = NS). CONCLUSION:
Application of acupressure wristbands at the P6 of both forearms 30 min before
induction of anesthesia did not decrease the incidence of PONV in patients
undergoing endoscopic urological procedures.
PMID- 10764176
TI - Failed tracheal intubation using a laryngoscope and intubating laryngeal mask.
AB - PURPOSE: To report unexpected failed tracheal intubation using a laryngoscope and
an intubating laryngeal mask, and difficult ventilation via a facemask, laryngeal
mask and intubating laryngeal mask, in a patient with an unrecognized lingual
tonsillar hypertrophy. CLINICAL FEATURES: A 63-yr-old woman, who had undergone
clipping of an aneurysm seven weeks previously, was scheduled for ventriculo
peritoneal shunt. At the previous surgery, there had been no difficulty in
ventilation or in tracheal intubation. Her trachea remained intubated nasally for
11 days after surgery. Preoperatively, her consciousness was impaired. There were
no restrictions in head and neck movements or mouth opening. The thyromental
distance was 7 cm. After induction of anesthesia, manual ventilation via a
facemask with a Guedel airway was suboptimal and the chest expanded
insufficiently. At laryngoscopy using a Macintosh or McCoy device, only the tip
of the epiglottis, but not the glottis, could be seen, and tracheal intubation
failed. There was a partial obstruction during manual ventilation through either
the intubating laryngeal mask or conventional laryngeal mask; intubation through
each device failed. Digital examination of the pharynx, after removal of the
laryngeal mask, indicated a mass occupying the vallecula. Lingual tonsillar
hypertrophy (1 x 1 x 2 cm) was found to be the cause of the failure. Awake
fibrescope-aided tracheal intubation was accomplished. CONCLUSIONS: Unexpected
lingual tonsillar hypertrophy can cause both ventilation and tracheal intubation
difficult, and neither the laryngeal mask nor intubating laryngeal mask may be
helpful in the circumstances.
PMID- 10764177
TI - Visualization of a looped and knotted epidural catheter with a guidewire.
AB - PURPOSE: To describe the management of a looped and knotted epidural catheter
after analgesia for labour and delivery. CLINICAL FEATURES: Obstetrical epidural
pain relief was provided for a 37-yr old woman in early labour. A 20-gauge Portex
catheter was inserted at the L2-L3 interspace. Six centimetres of catheter was
left in the epidural space. After vaginal delivery the catheter could not be
removed. The catheter was left in situ for 24 hr. Repeated attempts at removal
were again unsuccessful. The epidural catheter was not visible with fluoroscopy
and it was impossible to inject radiopaque dye into the catheter. However, we
successfully advanced a 0.016 inch guidewire through the epidural catheter and
radiologically demonstrated a knot and part of a loop. The catheter was removed
by an orthopedic surgeon using blunt dissection under local anesthetic from the
soft tissue just lateral to the interspinous ligament. CONCLUSIONS: A knot can be
a rare cause of a trapped epidural catheter. A suggested approach to the trapped
lumbar epidural catheter: 1) Gentle traction on the catheter with the patient in
various positions and in various degrees of lumbar flexion. 2) Test for catheter
patency by injecting sterile, preservative-free, normal saline through the
catheter. 3) Radiological imaging to determine if a knot is present and to
determine its location, using radiopaque contrast for patent catheters or a
guidewire for occluded catheters. 4) The approach to definitive management is
based on the position of the knot. This can range from excision under local
anesthetic to consultation with a surgical specialty for more invasive retrieval.
PMID- 10764178
TI - Orthotopic liver transplantation for carcinoid tumour metastatic to the liver:
anesthetic management.
AB - PURPOSE: To report the anesthetic management of a patient with carcinoid tumour
metastatic to the liver who presented for orthotopic liver transplantation.
Anesthetic implications of metastatic carcinoid tumour on liver transplantation
and the use of octreotide are discussed. CLINICAL FEATURES: A 51-yr-old woman
with intestinal carcinoid tumour metastatic to the liver presented for orthotopic
liver transplantation, a recent treatment option for patients with extensive
hepatic carcinoid metastases and disabling symptoms unresponsive to conventional
therapy. Despite continuous administration of the somatostatin analogue
octreotide via a hepatic artery infusate pump, the patient suffered from daily
break through symptoms, which included flushing, palpitations, paroxysmal
hypertension, and dyspnea. The patient presented to the operating room with sinus
tachycardia and severe arterial hypertension. Octreotide and phentolamine were
used to prevent further mediator release and to control the paroxysmal
hypertension. Midazolam, fentanyl, thiopental, succinylcholine, vecuronium, and
isoflurane were used to induce and maintain anesthesia safely. An intravenous
octreotide infusion was initiated after induction and continued throughout the
case. Infrequent and non-threatening peaks in arterial blood pressure were
readily treated with small intravenous doses of vasoactive drugs and octreotide.
No other manifestations of the carcinoid syndrome occurred. The patient had an
uneventful recovery and was discharged on postoperative day #6. CONCLUSION: The
patient safely underwent orthotopic liver transplantation for treatment of
symptomatic carcinoid tumour metastatic to the liver. The anesthetic management
followed recent recommendations favouring the use of octreotide to prevent
patients from becoming symptomatic. Outlined dosing regimen for octreotide
provided satisfactory hemodynamic stability.
PMID- 10764179
TI - Airway changes during Cesarean hysterectomy.
AB - PURPOSE: To document whether hemorrhage and fluid administration during
peripartum hysterectomy results in changes in the airway that may predispose to
subsequent difficult intubation, in the event that intraoperative general
anesthesia is required during regional anesthesia. CLINICAL FEATURES: A 32-yr-old
underwent peripartum hysterectomy for placenta accreta. Blood loss of 5.5 L
occurred during surgery requiring 6 L crystalloid, 1 L hetastarch, five units
packed RBCs and two units fresh frozen plasma. Airway changes were followed using
Samsoon's modification of Mallampati airway classification. In addition, airway
photographs were obtained using a Polaroid camera. The airway of the patient
changed from class 2 preoperatively to class 4 in the immediate postoperative
period. The airway gradually returned to normal over the ensuing 48 hr, during
which a negative fluid balance of 4 L occurred due to substantial postoperative
diuresis. CONCLUSION: Peripartum airway changes were detected during Cesarean
hysterectomy and fluid resuscitation that gradually returned to normal within 48
hr after surgery.
PMID- 10764180
TI - Acute myopathy of intensive care in a child after heart transplantation.
AB - PURPOSE: Acute myopathy of intensive care has been described infrequently in
children and never after organ transplantation. We report a case of acute
myopathy of intensive care in a child after heart transplantation. CLINICAL
FEATURES: An 11-yr-old girl, with no previous medical history, developed acute
cardiomyopathy leading to cardiac shock. Family history revealed four cases of
unidentified myopathy and/or cardiomyopathy. Preoperatively, while muscle biopsy
was near normal, myocardial biopsy revealed non specific mitochondrial disorders.
A few days after heart transplantation, she developed acute hypotonia and flaccid
quadriplegia, consistent with the diagnosis of acute myopathy of intensive care.
Nerve conduction studies were normal, electromyography showed myopathic changes
and a new muscle biopsy from quadriceps femoris showed severe loss of myosin
filaments and ATPase activity in type 2 fibres. A large laboratory screening
failed to demonstrate a metabolic disease or a known myopathy. Muscle strength
recovered progressively in three weeks allowing home discharge. A few months
later, she was free of symptoms and muscle biopsy showed full histopathological
recovery. CONCLUSION: Acute myopathy of intensive care can occur in children
after heart transplantation. It should be suspected in the presence of muscle
weakness and difficulty in weaning from ventilatory support. Electromyography
confirmed a myogenic process and muscle biopsy allowed diagnosis. Full clinical
and histopathological recovery usually occur within three weeks.
PMID- 10764181
TI - Smoking does not alter the dose-requirements and the pharmacodynamics of
rocuronium.
AB - PURPOSE: Controversial data about the effect of smoking on the dose-requirements
and the pharamcodynamics of rocuronium have been reported recently. This study
was conducted to evaluate the dose-requirements and the pharmacodynamics of
rocuronium in smokers using target controlled infusion. METHODS: The dose
requirements of rocuronium for 60 min relaxation, using target controlled
infusion, given under intravenous anaesthesia with propofol, fentanyl and nitrous
oxide was studied in 37 smokers and 37 non-smokers. Initially 450 microg x kg(-1)
rocuronium were administered, neuromuscular effects were quantified by recording
the single twitch response of the adductor pollicis muscle after ulnar nerve
stimulation using a force transducer, and the neuromuscular block was kept at 80%
by target controlled infusion throughout the procedure. RESULTS: The dose
requirements for one hour relaxation were 867 +/- 116 microg x kg(-1) x hr(-1)
for smokers (S) and 839 +/- 149 microg x kg(-1) x hr(-1) for non-smokers (NS).
The duration to 10% and the spontaneous recovery from 25% to 75% of the control
twitch response also showed no differences between S (17.2 +/- 3.4 min, 10.6 +/-
0.9 min) and NS (18.9 +/- 4.3 min, 10.9 +/- 3.2 min), as well as maximum block,
onset time and infusion rate. CONCLUSION: Smoking does not alter the dose
requirements for rocuronium and no effects on the onset time, degree of block,
time to maximum block, duration 10% and spontaneous recovery index were observed.
PMID- 10764182
TI - Does chronic occupational exposure to volatile anesthetic agents influence the
rate of neutrophil apoptosis?
AB - PURPOSE: The purpose of this preliminary investigation was to determine whether
the rate of neutrophil apoptosis in health care workers is influenced by exposure
to volatile anesthetic agents. METHODS: Percentage neutrophil apoptosis (Annexin
V FITC assay) was measured in health care workers (n = 20) and unexposed
volunteers (n = 10). For the health care workers, time weighted personal exposure
monitoring to N2O, sevoflurane and isoflurane was carried out. RESULTS: The
sevoflurane and isoflurane concentrations to which health care workers were
exposed were less than recommended levels in all 20 cases. Percent apoptosis was
less at 24 (but not at one and 12) hr culture in health care workers [50.5
(9.7)%; P = 0.008] than in unexposed volunteers [57.3 (5.1)%]. CONCLUSION:
Inhibition of neutrophil apoptosis at 24 hr culture was demonstrated in health
care workers chronically exposed to volatile anesthetic agents. Exposure was well
below recommended levels in the both scavenged and unscavenged work areas in
which the study was carried out. Further study is required to assess the effect
of greater degrees of chronic exposure to volatile anesthetic agents on
neutrophil apoptosis.
PMID- 10764183
TI - Anti-allodynic effects of oral COX-2 selective inhibitor on postoperative pain in
the rat.
AB - PURPOSE: To examine the effect of a cyclooxygenase (COX)-2 inhibitor on the
maintenance of mechanical allodynia induced by skin incision (an animal model of
postoperative incident pain) in the rat. Also, to compare the effect of a COX-2
inhibitor with that of a nonselective COX-1 and COX-2 inhibitor and B2 receptor
antagonist. METHODS: A 1 cm longitudinal skin incision was made in the plantar
aspect of the foot. JTE522 (1-100 mg x kg(-1)), a COX-2 inhibitor, indomethacin
(1-30 mg x kg(-1)), a nonselective COX-1 and COX-2 inhibitor, or FR173657 (10 and
100 mg x kg(-1)), a bradykinin B2 receptor antagonist, was administered orally
five minutes after the end of the surgery. The level of mechanical allodynia was
assessed by measuring the frequency of foot withdrawal in response to the
application of a 12.5 g on Frey filament at 2, 4, 6, 8 and 24 hr after the drug
administration. RESULTS: Oral administration of JTE522 or indomethacin attenuated
the maximum response frequency in a dose-dependent manner at a dose between 1 and
30 mg x kg(-1) (P < 0.05). Oral FR 173657, (100 mg x kg(-1)), had no effect on
the maximum response frequency. CONCLUSION: These data indicated that a COX-2
inhibitor attenuated the level of mechanical allodynia in the rat model of
postoperative pain.
PMID- 10764184
TI - Suppressive effects of remifentanil on hemodynamics in baro-denervated rabbits.
AB - PURPOSE: To elucidate mechanisms by which remifentanil, an ultra-short-acting mu
opioid receptor agonist, causes hypotension and bradycardia. METHODS: Mean
arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity
(RSNA) were measured and recorded after bolus injections of 1, 2 or 5 microg x
kg(-1) of remifentanil in neuraxis intact (n=6 for each dose) and baro-denervated
rabbits (n=6 for each dose). Arterial baroreflex sensitivity was assessed by
depressor tests. An additional six baro-denervated animals received remifentanil,
5 microg x kg(-1) after pretreatment with naloxone, 40 microg x kg(-1). RESULTS:
All values were expressed in % change from baseline. In the neuraxis intact
animals, MAP and HR were decreased briefly immediately after remifentanil
injection. RSNA was increased dose-dependently: 137 +/- 8% (mean +/- SE), 170 +/-
14% (P < 0.05) and 225 +/- 29% (P < 0.05) after 1, 2 and 5 microg x kg(-1)
remifentanil, respectively. RSNA was increased even after MAP and HR had returned
to baseline values. The depressor tests revealed that remifentanil did not
attenuate arterial baroreflex sensitivity. In the baro-denervated animals, MAP
and HR decreased gradually to 77 +/- 3% (P < 0.05) and 94 +/- 1% (P < 0.05),
respectively 300 sec after 5 microg x kg(-1) remifentanil. At that time,
increased RSNA (159 +/- 9%, P < 0.05) had returned to baseline. Pretreatment with
naloxone in the baro-denervated animals abolished these changes. CONCLUSION:
Remifentanil decreases HR and MAP by its central vagotonic effect and by
stimulating peripheral mu-opioid receptors. These effects appear to be
counteracted and masked by its central sympathotonic effect and by maintaining
arterial baroreflex integrity.
PMID- 10764185
TI - In the arms of Morpheus the development of morphine for postoperative pain
relief.
AB - PURPOSE: To analyse the historical development of morphine for postoperative
analgesia and how this development was shaped by the evolution of anesthetic
techniques. METHODS: After a systematic review of the literature, information was
gathered from primary sources. PRINCIPAL FINDINGS: In ancient medicine, some
plant derivatives were used to alleviate pain including: alcohol, cannabis,
mandrake, and opium. Over the past two centuries, opium and its derivatives have
become the most widely used analgesics for severe pain. Before the development of
general anesthesia, surgery was only performed out of extreme necessity. It is
probable that an analgesic such as opium would have been given following surgery
although its use may not have been recorded. The first description of
postoperative opium was by James Moore in 1784. Morphine was isolated from opium
by Friedrich Serturner in 1805. However, it was not until the development of the
hypodermic needle and syringe nearly 50 yr later that the use of morphine became
widespread. Over the last century, various delivery systems for morphine have
been developed including subarachanoid and epidural injection, and more recently
patient-controlled intravenous, epidural and intranasal analgesia. In addition,
many new opioids have been synthesized. CONCLUSION: Since its isolation from
opium almost 200 yr ago, morphine remains the most widely used analgesic and the
standard against which all new opioids for postoperative pain relief are
compared.
PMID- 10764186
TI - Apnea after spinal anesthesia.
PMID- 10764187
TI - Amniotic fluid embolism.
PMID- 10764188
TI - Perioperative core temperature.
PMID- 10764189
TI - Factors associated with adequacy of diagnostic workup after abnormal breast
cancer screening results.
AB - BACKGROUND: Women with certain characteristics, such as those residing in rural
areas, are less likely screened for breast cancer. To enhance detection of early
breast cancer, it is imperative that all women who have abnormal screening
results receive appropriate diagnostic procedures. This study reports differences
in receipt of diagnostic services following abnormal screening results. METHODS:
Screening and diagnostic data were collected as part of a breast and cervical
cancer early detection program aimed at reaching women of lower socioeconomic
status. Women with completed diagnostic information after having abnormal
screening results were included. We based adequacy of diagnostic services on
guidelines from the Society for Surgical Oncology, The Commission on Cancer of
the American College of Surgeons, and the Centers for Disease Control and
Prevention. Several factors were assessed for their association with adequacy of
diagnostic follow-up: income, age, race, education, health insurance status,
rural-urban residence, reported breast lump, family history of breast cancer, and
clinical beast examination or mammogram results. RESULTS: Overall, 14.1% of the
351 abnormal findings were considered inadequately followed up based on the
algorithm used. Eighty percent involved an abnormal finding on a clinical breast
examination regardless of the mammogram results. Rural women, those with abnormal
clinical breast examination findings but normal or equivocal findings on
mammograms, and those who self-discovered a mass were less likely to receive
adequate follow-up than were their counterparts in multivariate analysis. Rural
women were less likely to receive a biopsy or fine-needle aspiration, although it
was indicated. One facility accounted for most of the inadequate follow-up
screenings among urban women. CONCLUSIONS: Women who have specific demographic
and clinical characteristics were less likely to have received adequate
diagnostic services. Breast cancers could have been missed initially as a result
of inappropriate follow-up. Further investigation of the clinical scenarios using
chart reviews is warranted.
PMID- 10764190
TI - How family physicians distinguish acute sinusitis from upper respiratory tract
infections: a retrospective analysis.
AB - BACKGROUND: The purpose of our study was to examine how physicians diagnose
sinusitis in practice. We addressed three specific questions: (1) what clinical
factors do physicians look for in evaluating and caring for patients with
suspected sinusitis, (2) to what extent do physicians use transillumination and
radiograph evaluations in diagnosing sinusitis, and (3) how does the diagnosis of
sinusitis influence the decision to prescribe antibiotic therapy? METHODS: We
conducted a retrospective review using charts from 25 local family physicians who
volunteered to participate in the study. After selecting a random sample of
charts of adult patients treated for sinusitis and for upper respiratory tract
infection (URI) by each physician, we reviewed the charts to determine the nature
of the information collected to differentiate between sinusitis and URI. RESULTS:
Rhinorrhea, sinus tenderness, visualization of purulent secretions, and a history
of sinusitis were significant predictors of the diagnosis of sinusitis.
Antibiotics were prescribed for 98.4% of patients with sinusitis and 13.1% of
patients with URI. CONCLUSIONS: This sample of physicians based the diagnosis of
sinusitis on three prominent clinical findings, which were also significant
factors in diagnosing sinusitis in previous studies. The history of sinusitis
might influence patient and physician expectations for the diagnosis.
PMID- 10764191
TI - Self-collection of antepartum anogenital group B streptococcus cultures.
AB - BACKGROUND: Group B streptococcus (GBS) from the maternal perineum is a leading
cause of serious neonatal infection. Recommendations by the Centers for Disease
Control and Prevention include cultures from anogenital swabs on all pregnant
women between 35 and 37 weeks' gestation. This study examines whether a
significant difference in test results exists between GBS cultures from swabs
done by physicians and those done by patients, and whether patients prefer to
perform the swab themselves, with the potential of enhancing patient satisfaction
and decreasing utilization of health care resources. METHODS: Study design was a
comparison of 250 obstetrics patients attending a military community hospital
family medicine clinic. Patients were assigned on an alternating basis to perform
an anogenital culture swab before or after the physician performed a swab.
Patients were designated to complete a preference survey before or after the
swabs were performed. Descriptive statistics, chi square, and McNemar's test
corrected for multiple comparisons, and the Kruskal-Wallis test on effect of
order on test outcome were used to analyze the data. RESULTS: Forty-two of 250
patients had positive cultures. There was no statistically significant difference
between swab results done by patients and those done by physicians. There was no
significant difference between results of first swabs and results of second
swabs. Of the 250 patients 145 preferred self-collection. There was no
statistically significant relation between preference and order of completion of
the questionnaire. CONCLUSIONS: Patient-collection technique is as accurate as
physician collection. A majority of patients in this study population preferred
self-collection of GBS swabs.
PMID- 10764192
TI - Activated protein C resistance: the most common risk factor for venous
thromboembolism.
AB - BACKGROUND: Venous thromboembolism is a major cause of morbidity and mortality.
Although activated protein C resistance (APC-R) is the most commonly recognized
inherited risk factor for venous thromboembolism, little is known about its long
term implications on health. METHODS: MEDLINE was searched from January 1989
through August 1999 using the key words "thromboembolism," "thrombosis,"
"activated protein C resistance," and "factor V Leiden." RESULTS: One in 1000
people in the United States is affected by venous thromboembolism annually. APC-R
is now understood to be responsible for up to 64% of these cases. APC-R, which
occurs widely in some ethnic groups and is nearly absent in others, is due to a
single point mutation in the gene for clotting factor V. As a result,
inactivation of factor V by activated protein C is impaired, leading to a
hypercoagulable state. This condition creates a lifelong increased risk of
thrombosis and, possibly, anticoagulant therapy.. CONCLUSION: Family physicians
have a new tool for assessing risks for venous thromboembolism. Recognizing that
up to 64% of patients with venous thromboembolism can have APC-R and treating
this disorder with prophylactic and therapeutic anticoagulation might reduce
patient morbidity and mortality from venous thromboembolism. Screening high-risk
patients might now be indicated.
PMID- 10764193
TI - Managing the nondeflating urethral catheter.
AB - BACKGROUND: Urethral catheterization is a routinely performed procedure in
hospitalized patients. Numerous complications have been reported secondary to
urethral catheter placement. METHODS: The medical literature was searched using
the following key words: "urethral catheter," "complications," and "management."
A case report is described and a review of the literature is provided to assist
in managing the nondeflating urethral catheter balloon. RESULTS AND CONCLUSIONS:
All physicians who order urethral catheters must be aware of the possibility of a
nondeflating catheter balloon and be comfortable with its initial management. The
literature has an abundance of techniques for managing the nondeflating urethral
catheter balloon. The approach and algorithm provided serve as a guide for the
management of this complication by the family physician.
PMID- 10764194
TI - Uterine inversion: a life-threatening obstetric emergency.
AB - BACKGROUND: Acute puerperal uterine inversion is a rare but potentially life
threatening complication in which the uterine fundus collapses within the
endometrial cavity. Although the cause of uterine inversion is unclear, several
predisposing factors have been described. Maternal mortality is extremely high
unless the condition is recognized and corrected. METHODS: MEDLINE was searched
from 1966 to the present using the key phrase "uterine inversion." Nonpuerperal
uterine inversion case reports were excluded from review except when providing
information on classification and diagnostic techniques. A summarized case
involving uterine inversion and a review of the classification, etiology,
diagnosis, and management are reported. RESULTS AND CONCLUSIONS: Although
uncommon, if left unrecognized, uterine inversion will result in severe
hemorrhage and shock, leading to maternal death. Manual manipulation should be
attempted immediately to reverse the inversion. Tocolytics, such as magnesium
sulfate and terbutaline, or halogenated anesthetics may be administered to relax
the uterus to aid in reversal. Intravenous nitroglycerin provides an alternative
to the tocolytics and offers several pharmacodynamic advantages. Treatment with
hydrostatic pressure may be attempted while waiting for medications to be
administered or for general anesthesia to be induced. In the most resistant of
inversions, surgical correction might be required.
PMID- 10764195
TI - Understanding the choices that patients make.
PMID- 10764196
TI - Acute quadriceps compartment syndrome and rhabdomyolysis in a weight lifter using
high-dose creatine supplementation.
PMID- 10764197
TI - Recurrent Clostridium difficile-associated diarrhea and colitis treated with
Saccharomyces cerevisiae (Baker's yeast) in combination with antibiotic therapy:
a case report.
PMID- 10764198
TI - Paraesophageal hernia and intrathoracic diverticulitis.
PMID- 10764199
TI - Current procedural terminology coding: do the experts agree?
PMID- 10764200
TI - Medical professionalism: can it, should it survive?
PMID- 10764202
TI - Following up abnormal breast cancer screening results: lessons for primary care
clinicians.
PMID- 10764201
TI - Does creatine supplementation increase the risk of rhabdomyolysis?
PMID- 10764203
TI - Preparing for the certification and recertification examination.
PMID- 10764204
TI - Severity-based classification of mood and anxiety symptoms.
PMID- 10764205
TI - Screening and counseling for Down syndrome.
PMID- 10764206
TI - Family physicians and firearm safety counseling.
PMID- 10764207
TI - Effects of extracellular Mg2+ on transepithelial capacitance and Na+ transport in
A6 cells under different osmotic conditions.
AB - The electrophysiological characteristics of monolayers of cultured renal
epithelial A6 cells were studied under short-circuit conditions. Replacing
basolateral isosmotic (260 mOsm/kg H2O) media by hyposmotic (140 mOsm/kg H2O)
solutions transiently increased the transepithelial capacitance (C(T)) by 57.3+/
2.3% after 16 min. The transepithelial Na+ current (I(Na)) increased
concomitantly from 4.2+/-0.7 to 26.1+/-2.6 microA/cm2 with a time course that was
noticeably slower, reaching its maximum after 60 min of hypotonicity. The
transepithelial conductance (G(T)) increased synchronously with I(Na). Analysis
of blocker-induced noise in I(Na), using the amiloride analogue 6-chloro-3,5
diaminopyrazine-2-carboxamide (CDPC), showed that the hypotonic shock increased
Na+ channel density (N(T)) at the apical border. The presence of 10 mM Mg2+ on
both sides of the epithelium suppressed the hypotonicity-induced C(T) increase to
14.3+/-0.5%, whereas the I(Na) increase was even larger than without Mg2+. Both
effects of Mg2+ were located at an extracellular, basolateral site, because
apical administration was without effect, whereas the acute basolateral addition
of Mg2+ at the moment of the hypotonic shock was sufficient. Interaction between
Mg2+ and Ca2+ influenced the behaviour of C(T). At constant osmolality (200
mOsm/kg H2O) 10 mM Mg2+ increased I(Na), leaving C(T) unaffected, whereas 10 mM
Ca2+ stimulated both I(Na) and CT. In the presence of 1 mM Mg2+, however, the
Ca(2+)-induced CT increase was abolished. The failure of CT to increase during
stimulation of I(Na) by Mg2+ suggests that the divalent cation activates pre
existing channels in the apical membrane. Noise analysis showed that the
natriferic effects of Mg2+ were also mediated by an increase in NT. The moderate
initial increase in CT in the presence of Mg2+ under hypotonic conditions,
occurring in parallel with increases in GT and I(Na), reflects most likely Na+
channel insertion induced by the hypotonic treatment. However, the large,
transient, Mg(2+)-sensitive increase in CT, not correlated with increases in GT
and I(Na), seems to be unrelated to Na+ channel recruitment.
PMID- 10764208
TI - Cationic amino acid transport through system y+L in erythrocytes of patients with
lysinuric protein intolerance.
AB - We test the hypothesis that lysinuric protein intolerance (LPI), a rare autosomal
recessive defect of cationic amino acid transport, results from the absence of
the recently described y+L amino acid transporter. We compare fluxes of lysine (1
microM) into erythrocytes of normal subjects with those of patients homozygous
for the LPI mutation. No significant differences in fluxes through system y+L in
normal or LPI cells were found, excluding the possibility that system y+L cannot
be expressed in patients with LPI. Reasons for supposing that there may be tissue
specific processing of two recently described genes encoding the y+L transporter
are discussed. Polymerase chain reaction measurement of expression of these two
genes in an erythroleukemic cell line suggests that alternatively there may be an
as-yet-unidentified additional member of this gene family.
PMID- 10764209
TI - Cycloleucine fluxes during rat vasa recta and loop microinfusions in vivo and
loop microperfusions in vitro.
AB - Amino acids are apparently recycled between loops of Henle and vasa recta in rat
papilla in vivo. To examine this process in the absence of metabolism, we
performed continuous microinfusions of rat renal papillary ascending thin limbs
(ATLs) and vasa recta in vivo, and microperflusions of isolated rat renal
papillary descending thin limbs (DTLs) and ATLs in vitro using the
nonmetabolizable, synthetic, neutral amino acid cycloleucine. Like naturally
occurring amino acids, approximately = 25% of radiolabeled cycloleucine
microinfused into ATLs in vivo was reabsorbed by a process that was not saturable
or inhibitable. Also, like naturally occurring amino acids, approximately = 47%
(relative to inulin) of radiolabeled cycloleucine microinfused into ascending
vasa recta in vivo was transferred directly into ipsilateral tubular structures
(probably DTLs) by a saturable and inhibitable process. In DTLs perfused in
vitro, unidirectional bath-to-lumen fluxes (Jbl) tended to exceed unidirectional
lumen-to-bath fluxes (Jlb), whereas in ATLs perfused in vitro Jlb tended to
exceed Jbl, but the differences were not statistically significant. Moreover,
none of the unidirectional fluxes was saturable or inhibitable, an observation
compatible with apparent reabsorption from ATLs in vivo but incompatible with
apparent movement from vasa recta to DTLs in vivo. These in vitro observations
are like those made previously for the naturally occurring neutral amino acid L
alanine. The lack of saturation and inhibition, like the previous data on L
alanine, suggest that transepithelial movement of amino acids in thin limbs of
Henle's loop may occur via a paracellular route and that regulation of amino acid
movement in vivo may involve vasa recta, not DTLs. They also suggest that
cycloleucine is a good nonmetabolizable surrogate for the study of neutral amino
acid transport in the kidney.
PMID- 10764210
TI - NG, NG-dimethylarginine and NG, NG-dimethylarginine in renal insufficiency.
AB - Asymmetric NG,NG-dimethylarginine (ADMA) and symmetric NG,NG-dimethylarginine
(SDMA) are basic endogenous amino acids with a guanidino group. Our renal
distribution study of dimethylarginines clearly indicates that, in mouse and rat,
ADMA and SDMA levels are most abundant as protein-incorporated compounds (95%).
ADMA represents almost 90% of this protein-incorporated dimethylarginine amount.
The four zones studied (cortex, outer and inner stripe of outer medulla, inner
medulla) contain more or less the same amount of protein-incorporated
dimethylarginine; the concentrations of both free dimethylarginines vary more in
the different zones. Plasma and urinary excretion levels in Man, rat and mouse
were determined, their changes in renal insufficiency were examined and compared
between species. Highly significant negative correlations between both plasma
dimethylarginine levels and creatinine clearances were found in Man and rat. The
correlation between urinary ADMA excretion levels and creatinine clearances was
highly significant and positive in Man and mouse; however, in rat the correlation
was negative. In patients with severe renal insufficiency, ADMA clearance was
only 9.5% of controls, and that of SDMA only 7.8%. Clearance of ADMA and SDMA in
nephrectomized mice was 60.5% and 53.8% of controls, respectively, whereas in
nephrectomized rat, ADMA clearance actually increased 5.4 times and that of SDMA
did not change significantly. Man, rat and mouse show similarities as well as
differences in metabolism.
PMID- 10764211
TI - Deoxycholic acid (DOC) affects the transport properties of distal colon.
AB - Secondary bile acids can induce diarrhea. In the present study we examined the
effects of deoxycholic acid (DOC) on equivalent short-circuit current (Isc) in
rabbit colon and the cellular mechanisms involved in DOC action (rabbit and rat).
Luminal DOC inhibited amiloride-sensitive Na+ absorption. In the presence of
amiloride luminal DOC had a concentration dependent effect on Isc. Low
concentrations (1-10 micromol/l) induced a lumen-positive current (51+/-3
microA/cm2, 10 micromol/l, n=7) which was inhibited by luminal Ba2+ suggesting
the activation of a luminal K+ conductance. Higher luminal concentrations induced
a lumen-negative current (-76+/-9 microA/cm2, 100 micromol/l, n=11). Basolateral
application of DOC, also in the presence of amiloride, only induced lumen
negative Isc, (-58+/-10 microA/cm2, 100 micromol/l, n=6, EC50= 3 micromol/l).
This current could be abolished completely by the K+ channel blocker 293B, a
selective inhibitor of cAMP-dependent Cl- secretion. This action of DOC on Isc
was additive to the effect of carbachol (CCH) but not additive to that of cAMP.
In intact rat colon mucosa pre-treated with DOC a significant increase in cAMP
production was observed. Fura-2 measurements of cytosolic Ca2+ activity ([Ca2+]i)
in isolated colonic crypts (rabbit and rat) showed that 100 micromol/l DOC
induced a weak [Ca2+]i increase. Whole-cell measurements of membrane voltage in
isolated rat colonic crypts revealed a hyperpolarization by DOC (4.9+/-0.8 mV,
100 micromol/l, n=8) but a depolarization by prostaglandin E2 (PGE2, via cAMP)
(24+/-7 mV, n=8). The present data show that DOC acts at more than one target in
the colon: in the intact mucosa it activates luminal K+ channels and Cl-
secretion and this is paralleled by an increase in cAMP production. In isolated
crypts DOC probably activates a Ca(2+)-regulated K+ conductance but has no effect
on cAMP. Hence DOC probably activates ion channels or channel-regulating factors
in colonocytes and acts on non-epithelial cells to activate Cl- secretion
indirectly.
PMID- 10764212
TI - Protein kinase-dependent phosphorylation and cannabinoid receptor modulation of
potassium A current (IA) in cultured rat hippocampal neurons.
AB - The potent cannabinoid receptor agonist WIN 55,212-2 produces positive shifts in
steady-state inactivation of the potassium A current (IA) in rat hippocampal
neurons via an adenosine 3',5'-cyclic monophosphate (cAMP)-, protein kinase A
(PKA)-dependent process. This effect is probably mediated by phosphorylation or
dephosphorylation of the IA channel protein. The role of protein phosphorylation
in this cascade was tested by testing cannabinoid actions in cultured hippocampal
neurons (pyramidal cells) that were exposed also to either the catalytic subunit
of PKA (PKAc), a PKA-specific phosphorylation inhibitor (IP-20, Walsh peptide),
or a potent protein phosphatase inhibitor (okadaic acid). Cannabinoids such as
WIN 55,212-2 produce a positive (rightwards) shift in the steady-state
inactivation of IA, thus providing increased current at a given membrane voltage.
Cells dialyzed with PKAc showed a negative shift in IA inactivation, opposite to
that produced by cannabinoids, and similar to that produced by increased levels
of cAMP. In addition, PKAc completely blocked the positive shift produced by WIN
55,212-2. In contrast, dialysis of cells with IP-20 produced a positive shift in
steady state inactivation of IA, similar to that produced by WIN, but the effects
were not additive with cannabinoid receptor activation. The phosphatase
inhibitor, okadaic acid produced a small negative shift in IA steady-state
inactivation when administered alone, and blocked the positive shift produced by
WIN 55,212-2. Okadaic acid also enhanced the negative shift in IA inactivation
when co-administered with forskolin. The effects of okadaic acid and WIN 55,212-2
were not additive, suggesting a common pathway. These results demonstrate that IA
is altered by direct manipulations of the phosphorylation status of the channel
protein, and that cannabinoid effects on IA are probably mediated by
dephosphorylation of the IA channel.
PMID- 10764213
TI - Characterization of delta-opioid receptors and effect of enkephalins on IRD 98
rat epithelial intestinal cell line.
AB - Using 3H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (3H-DADLE) as a radioligand, delta-opioid
binding sites on the IRD 98 rat epithelial cell line were identified. These sites
were found to be reversible, saturable, specific and displayed high affinity for
DADLE. Scatchard analysis revealed a dissociation constant (Kd) of 4.9+/-0.5
nmol/l, a maximum binding capacity (Bmax) of 1.7 pmol/mg protein, and 5x10(5)
binding sites per cell. The presence of opioid receptors suggests the possibility
that enkephalins directly control ion transport in enterocytes. In order to
verify this hypothesis, investigations were designed to determine whether these
receptors are functional and whether enkephalins can inhibit the stimulation of
adenosine 3',5' cyclic monophosphate (cAMP) synthesis induced by cholera toxin.
The increase in cAMP synthesis induced by cholera toxin was inhibited in a dose
dependent manner by H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH (DSLET), a delta-agonist. The
enkephalinase inhibitor thiorphan potentiated this effect on IRD 98 cells, which
contain enkephalinase. The action of DSLET was increased by 40% in the presence
of this inhibitor. This effect was reversed by naltrindole, a potent delta
antagonist. Enkephalins can regulate intestinal secretion by acting directly on
enterocytes: they thus have an antidiarrheal role, especially in the presence of
an enkephalinase inhibitor.
PMID- 10764214
TI - Low serum promotes maturation of excitation-contraction coupling in myotubes.
AB - Patch-clamping and the simultaneous fluorescence measurement of cytoplasmic Ca2+
([Ca2+]i) were used to analyze the effect of serum on the functional features of
excitation-contraction (E-C) coupling in mouse skeletal myotubes. In high-serum
treated (10%) myotubes, depolarization elicited Ca2+ release which continued for
tens of milliseconds following the end of the pulse, after which [Ca2+]i decayed
slowly. In low-serum-treated (0.5%) myotubes, the Ca2+ transient caused by
depolarization had an increased rate of rise and peak amplitude, and [Ca2+]i
began to decay rapidly upon repolarization. When a depolarizing pulse (0.5-1.0 s)
was applied to low-serum-treated myotubes during a Ca2+ transient induced by 5-10
mM caffeine, repolarization usually caused the caffeine transient to terminate
rapidly (RISC; repolarization-induced stop of caffeine-induced Ca2+ release). The
RISC was less prominent in high-serum-treated myotubes. These results suggest
that low serum promotes the maturation of myotubes so that Ca(2+)-release and
Ca(2+)-removal activities are accelerated. Additionally, the essential features
of the communication between the voltage sensor and the Ca(2+)-release channel
are shared by myotubes and adult muscle fibers.
PMID- 10764215
TI - Micromolar concentrations of steroids and of aldosterone antagonists inhibit the
outwardly rectifying chloride channel with different kinetics.
AB - We used the patch-clamp technique to analyse the open/close kinetics of single,
outwardly rectifying, intermediate-conductance (ORIC) Cl- channels from cultured
epithelial cells under control conditions and in presence of different
inhibitors. As observed previously in excised inside/out patches under control
conditions, the switching kinetics were characterized by one open-state time
constant (tau0 is approximately 30 ms) and three closed-state time constants
(tau(cl)is approximately = to 0.2 ms, tau(c2) is approximately = 2 ms and tau(c3)
is approximately = 60 ms). Aldosterone, six further steroids and two aldosterone
antagonists inhibited channel open probability (NPo) concentration dependently
with the potency at 10 micromol/l increasing in the sequence: hydrocortisone,
corticosterone, P-oestradiol, cortisone, aldosterone, testosterone, progesterone,
canrenone, spironolactone. Although all substances decreased tau(o), neither the
steroids nor the aldosterone antagonists affected tau(cl), tau(c2) or tau(c3) or
induced additional transitions with additional time constants. Instead, the
steroids increased the prevalence of tau(c2) in the dwell-time histograms and the
aldosterone antagonists increased the prevalence of tau(c3), both in a
concentration-dependent manner. These observations may be explained by a model in
which one open state leads to one of three closed states with rate constants
alpha, beta and gamma, and in which beta or gamma increase under the influence of
steroids or aldosterone antagonists, respectively. Cytosol, which contains a Cl-
channel inhibitor of unknown molecular structure, (Krick et al., Pflugers Arch
418:491, 1991) was also tested, but the results did not conform to the blocker
mechanisms described above. This shows that there are even further modes of
channel inhibition and argues against the cytosolic Cl- channel inhibitor being a
steroid.
PMID- 10764217
TI - Are there systemic changes in the arterial biomechanics of intracranial aneurysm
patients?
AB - Current theories on the development of intracranial aneurysm suggest that there
is a general weakness of vascular connective tissue. Potential systemic
alterations in arterial wall biomechanics were tested in the present study. A
three-dimensional in vitro stress-strain analysis was made in the 0-200-0 mmHg
pressure range on cylindrical segments excised from the anterior cerebral artery,
the radial artery and from the arteria dorsalis pedis of aneurysm patients and of
control cadavers. In the anterior cerebral artery from aneurysm patients
(intracranial artery segments directly not affected by the aneurysm or by the
subarachnoid bleeding), we found the wall thickness to be larger (0.1480+/-.019
versus 0.091+/-0.004 mm), the radius/wall thickness ratio smaller (9.7+/-1.4
versus 14.1+/-1.2), and the tangential wall stress lower [(0.122+/-0.019)x10(6)
versus (0.181+/-0.016)x10(6) N/m2 at 100 mmHg] than in control subjects. Reduced
radius was found in the extremity arteries studied. Elastic parameters, as
incremental distensibility and elastic modulus, were remarkable similar. Our
study demonstrates changes in the geometry of walls of arteries not directly
affected by aneurysm formation, and it thus confirms systemic vascular pathology
in this disease. At the same time, these data show that the molecular and
morphological defects of arterial connective tissue formation generally thought
to induce intracranial aneurysms will probably not affect the components
responsible for the passive elastic properties of the vascular wall.
PMID- 10764216
TI - Regulation of renin gene expression in kidneys of eNOS- and nNOS-deficient mice.
AB - Our study aimed to assess the roles of nitric oxide derived from endothelium NO
synthase (eNOS) and macula densa neuronal NO-synthase (nNOS) in the regulation of
renal renin expression. For this purpose renin mRNA levels and renin content were
determined in kidneys of wild-type (wt), nNOS-deficient (nNOS-/-), and eNOS
deficient (eNOS-/-) mice, in which the renin system was suppressed by feeding a
high-salt diet (NaCl 4%), or was stimulated by feeding a low-salt (NaCl 0.02%)
diet together with the converting-enzyme inhibitor ramipril (10 mg kg(-1) day(
1)). In all mouse strains, renin mRNA levels were inversely related to the rate
of sodium intake. In eNOS-/- mice renin mRNA levels and renal renin content were
50% lower than in wt mice at each level of salt intake, whilst in nNOS-/- mice
renin expression was not different from wt controls. Administration of the
general NO-synthase inhibitor nitro-L-arginine methyl ester (L-NAME, 50 mg kg(-1)
day(-1)) to mice kept on the low-salt/ramipril regimen caused a decrease of renal
renin mRNA levels in wt and nNOS-/- mice, but not in eNOS-/- mice. These
observations suggest that neither eNOS nor nNOS is essential for up- or
downregulation of renin expression. eNOS-derived NO appears to enhance renin
expression, whereas nNOS-derived NO does not.
PMID- 10764218
TI - cAMP sensitivity conferred to the epithelial Na+ channel by alpha-subunit cloned
from guinea-pig colon.
AB - The rate of Na+ (re)absorption across tight epithelia such as in distal kidney
nephron and colon is to a large extent controlled at the level of the epithelial
Na+ channel (ENaC). In kidney, antidiuretic hormone (ADH, vasopressin) stimulates
the expression/activity of this channel by a cAMP/protein-kinase-A- (PKA-)
mediated pathway. However, a clear upregulation of ENaC function by cAMP could
not be reproduced with cloned channel subunits in the Xenopus oocyte expression
system, suggesting the hypothesis that an additional factor is missing. In
contrast, we show here that membrane-permeant cAMP can activate ENaC expressed in
Xenopus oocytes (3.8-fold) upon replacement of the rat alpha-subunit by a new
alpha-subunit cloned from guinea-pig colon (gpalpha). This alpha-subunit is 76%
identical with its rat orthologue originating from ADH-insensitive rat colon. The
biophysical fingerprints of the hybrid ENaC formed by this guinea-pig alpha
subunit together with rat beta- and gamma-subunits are indistinguishable from
those of rat ENaC (rENaC). Injection of the PKA inhibitor PKI-(6-22)-amide into
the oocyte had no effect on the basal activity of rat ENaC but inhibited the
activity of gpalpha-containing hybrid ENaC and greatly decreased its stimulation
by cAMP. This suggests that, unlike for rat ENaC, tonic PKA activity is required
for basal function of gpalpha-containing ENaC and that PKA mediates its cAMP
induced activation. This regulatory behaviour is not common to all ENaCs
containing an alpha-subunit cloned from an ADH-responsive tissue since xENaC,
which was cloned from the ADH-sensitive Xenopus laevis A6 epithelia, is, when
expressed in oocytes, resistant to cAMP, similar to rat ENaC. This study
demonstrates that the PKA sensitivity of ENaC can depend on the nature of the
ENaC alpha-subunit and raises the possibility that cAMP can stimulate ENaCs by
different mechanisms.
PMID- 10764219
TI - Profile and kinetics of L-type calcium current during the cardiac ventricular
action potential compared in guinea-pigs, rats and rabbits.
AB - The substantial interspecies differences in mammalian cardiac action potentials
(APs) are attributed primarily to variations in K+ currents. In a comparative
study on isolated ventricular myocytes from guinea-pigs, rabbits and rats, we
investigated the influence of the species-based AP differences on the time course
of the L-type Ca2+ current (ICa,L). In addition, we tested whether also species
dependent properties of the ICa,L contribute to its time course during the AP. In
patch-clamp measurements, ICa,L was characterised using conventional square
pulses and digitised APs as command voltages. Special interest was directed to
the analysis of the actual time courses of ICa,L, and L-type channel activation
and inactivation during APs. Although species-specific differences in AP shape
strongly influence the amplitude and the time course of ICa,L, divergence in L
type channel inactivation was found as well. In each species ICa,L inactivation
was related to Ca2+ influx via L-type channels. However, while L-type channels
showed similar Ca2+ dependency in the rabbit and the rat, a 2-times higher Ca2+
influx was necessary to achieve a given degree of inactivation in the guinea-pig.
Thus, inactivation of ICa,L is delayed in the guinea-pig, thereby contributing to
the prolonged AP plateau in this species. Comparing the actual time course of
ICa,L, and L-type channel activation and inactivation revealed that, in each
species, fading of ICa,L during final repolarisation was caused by deactivation
(i.e. closure of the channel's d-gate) rather than inactivation.
PMID- 10764220
TI - Investigating the role of Ca2+-binding site IV in barnacle troponin C.
AB - Two genetically engineered, recombinant versions of native barnacle troponin C
(TnC) (BTnC,) were created from the bacterially expressed, recombinant, wild-type
BTnC (BTnCWT) to investigate the role of the Ca(2+)-specific sites in force
regulation. The mutant BTnC4- contains a single amino acid mutation in site IV
which results in the inactivation of site IV Ca2+ binding; the mutant BTnCTrunc
lacks the last II amino acids of the C-terminal, and hence most of site IV. Both
mutant proteins, which retain an active site II, bind to native TnC-depleted
myofibrillar bundles and restore approximately 40% of the tension-generating
capacity, about half that seen with purified native BTnC1 or BTnC2. This
observation implies that the Mg(2+)-dependent interaction with troponin I (TnI)
is at a location on TnC other than the C-terminal Ca(2+)-binding sites of BTnC2.
Replacement with BTnCTrunc increases the sensitivity of the myofibrillar bundle
to changes in ionic strength. Decreasing the ionic strength from 0.15 to 0.075 M
increased force by 34%, a value much greater that the 8% increase seen in control
bundles or bundles substituted with BTnC4-. These findings implicate TnC in
determining this fibre characteristic, although this cannot be simply due to the
alteration in the numbers of Ca2+ ions bound by the troponin complex since both
BTnC4- and BTnCTrunc bind only 1 mol Ca2+/mol protein.
PMID- 10764221
TI - Characterization of the ion transport responses to ADH in the MDCK-C7 cell line.
AB - The Madin-Darby canine kidney (MDCK) cell line expresses many characteristics of
the renal collecting duct. The MDCK-C7 subclone forms a high-resistance, hormone
responsive model of the principal cells, which are found in distal sections of
the renal tubule. The electrophysiological technique of short-circuit current
measurement was used to examine the response to antidiuretic hormone (ADH) in the
MDCK-C7 clone. Three discrete electrogenic ion transport phenomena can be
distinguished temporally and by the use of inhibitors and effectors. Initially
the cells exhibit anion secretion through the cystic fibrosis transmembrane
conductance regulator (CFTR). The presence of CFTR was confirmed by
immunoprecipitation followed by Western blotting. The CFTR-mediated anion
secretion is transient and is followed, in time, by a verapamil- and Ba(+)
sensitive anion secretion or cation absorption and, finally, by Na+ reabsorption
via epithelial Na+ channels (ENaC). In contrast to other studies of MDCK cells,
we see no indication that the presence of CFTR functionally inhibits ENaC. The
characterization of the various ion transport phenomena substantiates this cell
line as a model renal epithelium that can be used to study the hormonal and
metabolic regulation of ion transport.
PMID- 10764222
TI - Kinetic and ionic properties of the human HCN2 pacemaker channel.
AB - Human cDNA coding for the hyperpolarization-activated "pacemaker" channel HCN2
was expressed in Phoenix cells and yielded an inward current (IhHCN2) activated
on hyperpolarization. The average IhHCN2 was half-activated at -83.1 mV and its
kinetics could be described by second-order Hodgkin-Huxley gating. The time
constant curve was bell-shaped and peaked at -82.2 mV. With 115 mM external Na+
and 30 mM external K+, IhHCN2 reversed at -17.1 mV, and had a mean conductance of
5.6 nS. Reducing the external K+ or Na+ concentration led to a concentration
dependent reduction of the IhHCN2 conductance and to a hyperpolarizing shift of
reversal potential. External Cs+ ions (5 mM) blocked IhHCN2 in a voltage
dependent way according to a Woodhull-type block model, at an electrical distance
of 0.66 from the external membrane surface, and with a dissociation constant of
15 mM at 0 mV. Increasing cytoplasmic cAMP using forskolin increased IhHCN2 by
shifting the current activation curve to more positive voltages (11.7 mV).
Exposure of the intracellular side of inside-out macro-patches to cAMP led to a
depolarizing shift of the channel open probability curve (15.2 mV with 10 microM
cAMP). These results indicate that although hHCN2 channels share several
properties with native cardiac f-channels, differences also exist in permeability
and block properties, suggesting that native channels may not be composed simply
of homomeric constructs.
PMID- 10764224
TI - Compound exocytosis in voltage-clamped mouse pancreatic beta-cells revealed by
carbon fibre amperometry.
AB - Capacitance measurements of exocytosis were combined with carbon fibre
amperometry for time-resolved measurements of the properties of secretion in
single, insulin-secreting, mouse pancreatic beta-cells pre-loaded with the amine
serotonin (5-HT). Glucose-induced electrical activity was associated with the
appearance of brief and transient amperometric currents reflecting the serotonin
co-released with insulin. The integrated amperometric responses resulting from
voltage-clamp depolarisations were proportional to the corresponding increase in
cell capacitance. Both parameters exhibited U-shaped relationships to the
membrane potential with maximums around 0 mV. There was a variable latency (40
730 ms, average 230 ms) between the onset of the depolarisation and the
amperometric current. During high-frequency repetitive stimulation, a progressive
decrease in the exocytotic capacity ("depression") was observed. This was
paralleled by a corresponding reduction of the amperometric responses. Using the
carbon fibre to map the beta-cell for release sites indicated that exocytosis was
confined to the part of the cell containing the highest density of secretory
granules. Two types of amperometric responses were observed. In about 50% of the
cells, a smooth increase was observed with no discernible discrete events. In the
remaining cells, the amperometric records contained large spikes. These were ten
or more times larger than that expected for the fusion of individual secretory
granules. We propose that these large spikes reflect the exocytosis of
multigranular complexes formed inside the beta-cell prior to exocytosis.
PMID- 10764223
TI - Cyclosporin-A-induced effects on the free Ca2+ concentration in LLC-PK1-cells and
their mechanisms.
AB - Here we have examined the effects of Cyclosporin A (CyA) on the free
intracellular Ca2+ concentration ([Ca2+]i) of LLC-PK1/PKE20 cells to evaluate
mechanisms of CyA nephrotoxicity using Fura-2 microspectrofluorometry or digital
fluorescence video imaging. The CyA-associated changes were compared to the
effects of tacrolimus (Tac), a structurally unrelated immunosuppressant with
similar cellular pathways which also causes nephrotoxicity. CyA (EC50(: 1 nmol/l,
n=16) and Tac (EC50: 1 nmol/l, n=5) caused a concentration-dependent increase of
[Ca2+]i which was substantially attenuated by reducing the external Ca2+
concentration (10(-6) mol/l). Similarly Cyclosporin H, a non-immunosuppressive
analogue of CyA, stimulated a Ca2+ influx. Nicardipine (10(-6) mol/l) reduced the
CyA- and the Tac-induced Ca2+ influx to 52+/-16% (n=10) and 13+/-10% (n=13) of
control respectively. Diltiazem and verapamil (10(-6) mol/l) were also effective,
but flufenamate (10(-4) mol/l), Gd3+ (10(-5) mol/l) and La3+ (10(-5) mol/l) were
not. In the absence of extracellular Ca2+ CyA led to a small but significant
[Ca2+]i increase, indicating additional release from internal stores. Depletion
of inositol-1,4,5-trisphosphate-(InsP3-) sensitive Ca2+ stores by extracellular
ATP (10(4) mol/l) in low-Ca2+ solution completely suppressed the CyA-induced
[Ca2+]i rise. CyA had no effect on the cellular InsP3 concentration. Furthermore,
inhibition of phospholipase-Cbeta (PLCbeta) by U73122 (2x10(-5) mol/l) did not
alter the CyA-stimulated [Ca2+]i rise. A direct effect of CyA on InsP3-sensitive
Ca2+ stores, the InsP3 receptor, the Ca2+ content of the stores or involvement of
additional stores is assumed. Incubation with CyA for 1, 12 and 24 h enhanced the
rise in [Ca2+]i peak induced by ATP, arginine vasopressin (AVP) and angiotensin
II. In summary, CyA stimulated a [Ca2+]i increase in LLC-PK1 cells through Ca2+
release from InsP3-sensitive stores and Ca2+ influx via a nicardipine-sensitive
pathway. The CyA-mediated [Ca2+]i increase is independent of PLCbeta activity and
InsP3 metabolism. CyA caused long-term enhancement of the agonist-induced rise in
[Ca2+]i. The effects of CyA on Ca2+ signaling appear to be independent of its
immunosuppressive action.
PMID- 10764225
TI - Time-resolved two-dimensional X-ray diffraction study of the effect of shortening
on activation of contracting skeletal muscle.
AB - In twitch contractions of frog skeletal muscle, the isometric tension peaks when
intracellular calcium has fallen to near-resting levels. To understand the
mechanism of this delayed tension maintenance in the context of calcium
regulation, the time course of the tropomyosin movement on actin was monitored by
recording the intensity of the 2nd actin layer lines in a time-resolved two
dimensional X-ray diffraction study. The intensity rose ahead of tension,
reflecting the tropomyosin movement from its "off" to "on" positions, but it fell
with a time course similar to that of tension. Muscle shortening applied at the
tension peak was followed by a poor recovery of tension, and accelerated the fall
of the reflection intensity. The results suggest that the force-generating myosin
heads retain the tropomyosin in its "on" position after the fall of intracellular
calcium, and their shortening-induced detachment makes the tropomyosin return to
its "off" position, thereby preventing myosin reattachment to actin.
PMID- 10764226
TI - Isosmotic media prevent edema in amphibian larvae without cardiac function.
AB - The absence of cardiac and circulatory function causes severe edema in amphibian
embryos. Analyzing the roles of embryonic and larval circulation in respiration
may thus be confounded by the increased diffusion distance and decreased surface
area/volume ratio caused by edema. Similarly, detailed morphological analyses of
embryos/larvae with defective circulatory or renal function is difficult or
impossible due to the gross morphological anomalies engendered by edematous
swelling. To circumvent these problems, two media have been developed which are
isosmotic with the plasma of a common experimental amphibian species (Ambystoma
mexicanun). These media are remarkably effective in preventing fluid accumulation
in embryos and larvae lacking heart function and, when used in slightly lower
concentrations, cause no apparent harm to embryos and larvae with normal
circulation for periods up to 3 weeks. These media should prove useful for a
variety of studies on the developmental physiology of the circulatory system and
possibly also when examining the development of renal function and
ionoregulation.
PMID- 10764227
TI - Admittance-based measurement of membrane capacitance using the EPC-9 patch-clamp
amplifier.
AB - A software lock-in amplifier (SLIA) was developed to allow high-time-resolution
measurement of membrane capacitance as a single-cell assay of exocytosis. The
unique feature of this "virtual instrument" is that it is thoroughly integrated
with a computer-controlled patch-clamp amplifier (EPC-9) to allow estimation of
equivalent circuit parameters based upon calibrated admittance measurements
rather than just relative changes. Since the same software package ("PULSE")
controls both the EPC-9 and the SLIA, instrument settings which affect admittance
calculations (gain, filtering, etc.) are always "known" by the SLIA. Attenuation
and phase shifts introduced within the EPC-9 by low-pass filters and other
circuitry are modelled and automatically corrected by the software. In addition,
changes in the measured signal introduced by whole-cell capacitance and series
resistance compensation are accounted for. The noise of capacitance measurements
is nearly optimal and resistive parameters can vary over a large range without
inducing artifactual changes in capacitance estimates.
PMID- 10764228
TI - Accurate assessment of in situ isometric contractile properties of hindlimb
plantar and dorsal flexor muscle complex of intact mice.
AB - An isometric torque sensor for measuring in situ contractions of plantar or
dorsal flexors of intact mouse hindlimb has been developed and evaluated. With
this device, muscle torque can be accurately measured within the range of -14
mN.m to +14 mN.m. Special attention was paid to fixation of the mouse hindlimb to
the measurement device. Halothane-anaesthetized Swiss wild-type mice were
positioned on the thermostatic measurement platform, and fixated with a hip and
foot fixation system. The novel fixation unit was evaluated by measuring knee and
ankle displacements during a contraction. A mathematical muscle model was used to
quantify the effects of these displacements on the contractile parameters.
Measured ankle and knee displacement, due to non-absolute fixation. resulted in a
calculated muscle fibre shortening of 2.5%. Simulations of a contraction with
this degree of fibre shortening, using the mathematical muscle model, showed only
minor effects on maximal torque generation and the temporal parameters (half
relaxation time and 10-50% rise time). Furthermore, we showed that muscle torque
in our set-up is hardly affected by eccentricity between ankle and measurement
axis. Measured tetanic muscle torques of intact dorsal and plantar flexors were
3.2+/-0.4 mN.m and 11.8+/-1.6 mN.m, respectively. The half-relaxation time of
plantar flexors was significantly higher than that of dorsal flexors (12.9+/-2.7
ms versus 8.8+/-1.2 ms), whereas the 10-50% rise time was longer in plantar
(14.9+/-0.6 ms) than in dorsal (11.8+/-2.0 ms) flexors.
PMID- 10764229
TI - Structured education and the changes in ENT training: background to recent
changes in training.
PMID- 10764230
TI - The influence of middle ear disorders on otoacoustic emissions.
PMID- 10764231
TI - Markers in cancer of the larynx and pharynx.
PMID- 10764232
TI - The prevalence of nasal polyps in adults with cystic fibrosis.
AB - The endoscopic intranasal appearance of 211 adult patients with cystic fibrosis
was studied. The prevalence of nasal polyps in this study was 37%. The commonest
nasal symptoms were discharge, headache and obstruction. Intranasal endoscopy
usually demonstrated mucosal oedema and thin, clear discharge. The prevalence of
allergy, as diagnosed by skin prick testing, was almost twice that of the general
population. Tympanometry showed that middle ear effusion was uncommon in these
patients.
PMID- 10764233
TI - Expression of cyclin-dependent kinase inhibitor p21(WAF1) and p53 tumour
suppressor gene in laryngeal cancer.
AB - The prognostic value of the expression of the cyclin-dependent kinase inhibitor
p21 and the p53 tumour suppressor gene was examined using immunohistochemistry in
60 patients with laryngeal cancer. Multivariate analysis using Cox's proportional
hazard method, showed that p21 expression (P = 0.02) and advanced T stage (P =
0.003) significantly predicted survival. It was concluded that p21 expression may
be a useful prognostic indicator in laryngeal cancer.
PMID- 10764234
TI - The role of conservative management of vestibular schwannomas.
AB - Although microsurgery is generally regarded as the conventional treatment of
choice for most vestibular schwannomas, there remains a group of patients in whom
a conservative management approach may be a desirable alternative. The aim of
this study was to determine the natural history and outcome following the
conservative management of 72 patients with unilateral vestibular schwannomas.
The reasons for conservative management included poor general health, age,
patient preference, small tumour size, minimal or no symptoms, and tumour in the
only/better hearing ear. The mean duration of follow-up was 39.8 months (range 12
194 months). All patients underwent serial magnetic resonance imaging (MRI) for
assessment of tumour growth. Patients were deemed to have failed conservative
management if there was evidence of continuous or rapid radiological tumour
growth and/or increasing symptoms or signs. The mean tumour growth rate,
according to the 1995 guidelines of the American Academy of Otolaryngology/Head
and Neck Surgery, was 1.16 mm/year (range: 0.75 9.65 mm/year). Approximately 83%
of tumours grew at < 2 mm/year. Significant tumour growth was seen in 36.4%, no
or insignificant growth in 50%, and negative growth in 13.6% of tumours. The
growth rate of CPA tumours (1.4 mm/year) was significantly greater than that of
IAC tumours (0.2 mm/year) (P = 0.001). Failure of conservative management, in
which active treatment was required, occurred in 15.3%. The outcome of these
patients appeared to be as favourable to a comparable group who underwent primary
treatment, without a period of conservative management. The mean growth rate of
tumours in patients who failed conservative management (4.2 mm/year) was
significantly greater than that in patients who did not fail (0.5 mm/year) (P <
0.01). No factors predictive of tumour growth or failure of conservative
management were identified. Deterioration of mean pure tone average (0.5, 1, 2, 3
kHz) and speech discrimination scores occurred regardless of whether radiological
tumour growth was demonstrated or not. This study suggests that in a select
number of cases of vestibular schwannoma, a conservative management approach may
be appropriate. Regular follow-up with serial MRI is mandatory. Deterioration of
auditory function occurs even in the absence of tumour growth.
PMID- 10764235
TI - The accuracy of citation and quotation in otolaryngology/head and neck surgery
journals.
AB - A high rate of errors of citation and quotation has been reported in the
publications of many medical specialties. The aim of this study was to determine
the prevalence of citation and quotation errors in otolaryngology/head and neck
surgery journals. A retrospective analysis was performed based on the first issue
for 1997 of each of four journals: Laryngoscope; Annals of Otology, Rhinology and
Laryngology; Clinical Otolaryngyology; and Journal of Laryngology and Otology. A
sample of 50 references from each journal was randomly selected and each was
checked for accuracy against the original referenced paper. Citation errors were
categorized as major, intermediate or minor and quotation errors as major or
minor. Citation errors occurred in 37.5% of the references, 11.9% of which were
considered major errors. Quotation errors occurred in 17%, with 11.1% major
errors. This prevalence is similar to the established error rate in medical
literature.
PMID- 10764236
TI - Non-syndromic autosomal dominant progressive non-specific mid-frequency
sensorineural hearing impairment with childhood to late adolescence onset
(DFNA21).
AB - An autosomal dominant trait of progressive, non-syndromic, non-specific mid
frequency sensorineural hearing impairment was identified in a Dutch family. Many
affected family members (n = 21) were identified, among whom seven out of nine
relatives aged < 30 years do not show pure mid-frequency hearing impairment,
which suggests variable expression. Regression analysis was used to evaluate the
age-related hearing threshold data in a cross-sectional analysis in 24 affected
patients and in a longitudinal analysis in five of these. At all frequencies,
progression in hearing impairment (i.e. the regression coefficient) was
significant and fairly similar: the pooled value was about 1.0 dB/y. There was no
significant (i.e. not =0 dB) offset threshold (i.e. Y intercept at age 0) found
at any frequency. The regression lines could be pooled for the low frequencies
(0.25-0.5 kHz) and the mid/high frequencies (1-8 kHz) and this produced apparent
onset ages of about 3 and 4 years and annual threshold increases of 0.75 and 1.1
dB/y, respectively. In most patients there is a relatively late onset age
(maximum in the range of at least 25-45 years). However, based on the
longitudinal analysis of a patient from the age of 4 years onwards in some
patients sensorineural hearing impairment might be congenital/prelingual. Oculo
vestibular function was found to be normal. Results from linkage studies
tentatively position the underlying gene defect telomeric to the repositioned
DFNA13 locus at chromosome 6p21-22.
PMID- 10764237
TI - A retrospective analysis of high resolution computed tomography in the assessment
of cochlear implant patients.
AB - High resolution computed tomography (HRCT) of the temporal bone is performed
routinely in the preoperative evaluation for cochlear implantation. The largest
multicentre retrospective analysis of data was undertaken to compare the findings
on HRCT with the surgical findings in an attempt to determine the accuracy of
HRCT. Of the 1009 patients referred, 525 were scanned of whom 335 were implanted.
As part of this study we were also able to identify both radiological and non
radiological reasons for rejection of patients for cochlear implantation. the
commonest cause being adequate residual hearing. The accuracy of HRCT in
predicting cochlear ossification was 94.6%, with a 100% specificity and a 71%,
sensitivity. Meningitis was the leading cause of cochlear ossification (44%). We
conclude from this extensive multicentre study of both adult and paediatric
patients that HRCT is accurate in predicting cochlear abnormality. In post
meningitic patients magnetic resonance imaging (MRI) may be a useful additional
investigation.
PMID- 10764238
TI - Impairments, disabilities, and handicaps after acoustic neuroma surgery.
AB - The measurement of a patient's health-related quality of life following acoustic
neuroma surgery is important because the surgery itself can impose significant
symptoms postoperatively. This study describes the most common problems
experienced by the patients, using an open-ended questionnaire mailed to a series
of 70 patients who had undergone acoustic neuroma surgery. Patient responses were
classified by impairment, disability and handicap, according to the World Health
Organization (WHO) classification. Results showed that this group of patients had
a wide variety of symptoms and concerns, and particularly highlighted the
relative importance of visual (49% of the patients) and psychosocial problems
(34% of the patients) associated with surgery in contrast to tinnitus that seemed
to be of minor importance. Open-ended questionnaires are useful in assessing
outcomes from a quality of life perspective.
PMID- 10764239
TI - Neonatal hearing screening using the auditory brainstem response.
AB - A targeted screen of babies at risk of having a sensorineural hearing loss (SNHL)
using the auditory brainstem response has been in place since 1987 in Bradford
and Airedale. The aims of this paper were to ascertain what proportion of a 4
year cohort of children with SNHL should have been identified by the programme;
was identified by the programme; and the reasons for failing when children were
missed. The cohort of 49 children had moderate to profound SNHL (> 50 dB) and
were born between 1 April 1991 and 31 March 1995. Although 92% had at risk
factors (higher than in other series), 80% was the maximum that could have been
prospectively detected by the programme and only 37% were actually diagnosed as a
result of the screening programme. Apart from a generalised under-recruitment,
children with risk factors arising because of in utero, perinatal and postnatal
events (as opposed to family history, craniofacial abnormalities and syndromes)
tended to be missed (P < 0.01). The overall yield of the screening programme was
0.5/1000/year. While the yield of a universal neonatal screening programme based
on otoacoustic emissions should be double this, a targeted infant distraction
test later in infancy will be an essential backup. Improved liaison with
paediatricians in particular as well as simplification of the referral criteria
should improve targeting children at risk.
PMID- 10764240
TI - A critical review of the epidemiologic literature on health effects of
occupational exposure to vinyl chloride.
AB - We have attempted to critically review and summarise the collective epidemiologic
evidence concerning the association of occupational vinyl-chloride exposure with
human health outcomes, including cancer, liver cirrhosis, cardiovascular disease,
nonmalignant respiratory disease and acroosteolysis. Based on data from
individual reports, qualitative and, where possible, quantitative summaries are
presented. With respect to cancer, which has been extensively studied,
angiosarcoma of the liver is the only malignancy causally related to vinyl
chloride exposure. Hypothesised associations between vinyl chloride and cancers
of other sites, namely lung, brain and lymphohaematopoietic system, are not
consistently supported by the available data. Similarly, the epidemiologic data
relating vinyl chloride to nonmalignant disease, while quantitatively limited and
qualitatively suboptimal, do not support a causal association for any of the
studied disorders. In summary, a comprehensive review of the relevant
epidemiologic literature revealed that occupational vinyl-chloride exposure has
not been conclusively or causally linked to any adverse health outcome, with the
exception of angiosarcoma of the liver.
PMID- 10764241
TI - BSE in Portugal: anticipating the decline of an epidemic.
AB - BACKGROUND: Attention throughout Europe continues to focus on bovine spongiform
encephalopathy (BSE), with increasing evidence linking it to the new variant of
Creutzfeldt-Jakob disease in humans. In particular, recent attention has been
directed at Portugal, where the incidence of confirmed BSE cases continues to
rise. METHODS: We modelled the age-specific incidence of BSE in Portuguese-born
cattle by birth cohort as a function of: the survival distribution; the cohort
specific incidence of BSE infection; the age-specific probability, conditional on
survival, that an infected animal will experience clinical onset; and the under
reporting rate of BSE cases prior to 1998. RESULTS: We obtained good fits to the
age-specific incidence of BSE by birth cohort in Portugal. Under a range of
assumptions, the estimated incidence of BSE infection was relatively low
initially, except possibly in the 1989 cohort, and then rose gradually between
the 1992 and 1994 cohorts. The estimated decrease in infection incidence between
the 1994 and 1995 cohorts probably reflects the effectiveness of the ban on the
use of mammalian meat and bone-meal introduced in Portugal in mid-1994. Assuming
no infections in animals born after June 1995, the models predict that the
incidence of BSE cases in Portugal will peak in 1999 with BSE case-incidence
declining thereafter. DISCUSSION: Our results illustrate the power of
epidemiological analysis to detect decreasing trends in infection incidence prior
to the resulting decrease in case incidence. The findings should inform the
deliberations of the European Commission, which recently reported concerns about
the sharp increase in case incidence from 1997 to 1998.
PMID- 10764243
TI - A cohort study of cigarette smoking and risk of fibroadenoma.
AB - BACKGROUND: This cohort study examines the association between cigarette smoking
and risk of fibroadenoma. METHODS: The study was conducted among the 56,537 women
in the Canadian National Breast Screening Study (NBSS) who completed self
administered lifestyle and dietary questionnaires. (The NBSS is a randomised,
controlled trial of screening for breast cancer in women aged 40-59 at
recruitment.) Cases were the 222 women who were diagnosed with biopsy-confirmed
incident fibroadenoma. For comparative purposes, a subcohort, consisting of a
random sample of 5,681 women was selected from the full dietary cohort. After
exclusions for various reasons, the analyses were based on 222 cases and 5,488
non-cases. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were
estimated using Poisson regression. RESULTS: Cigarette smoking was associated
with reduced risk of fibroadenoma, the IRR (95% CI) for more than 550 cigarette
years of exposure being 0.66 (0.40-1.10). Although the reduction in risk was
evident for all smokers combined (ex-smokers and current smokers), it was
indicative largely of an inverse association in current smokers, in whom the IRR
(95% CI) for > 300 cigarette-years of exposure was 0.49 (0.24-0.98). The results
were mostly the same when examined in strata defined by method of detection of
fibroadenoma, menopausal status and history of previous breast disease. There was
no evidence for a reduction in risk with time since last use of cigarettes.
CONCLUSIONS: The results of this study suggest that cigarette smoking is
associated with reduced risk of fibroadenoma, especially in current smokers.
PMID- 10764242
TI - Self-reported smoking, cigarette yields and inhalation biochemistry related to
the incidence of coronary heart disease: results from the Scottish Heart Health
Study.
AB - BACKGROUND: Smoking is a well-known risk factor for coronary heart disease (CHD).
The components of tobacco that cause CHD have not yet been established; nor have
the relative dangers of cigarettes of different strengths. METHODS: This is a
cohort study of 2,849 men and 2,900 women with no symptoms of CHD at baseline in
the Scottish Heart Health Study. RESULTS: In a 7.7 year follow-up, to 1993, there
were 123 male and 49 female CHD events. After adjusting for age, cholesterol and
blood pressure, men who smoke > or = 20 cigarettes per day have a relative hazard
[95% confidence interval (CI)] of 1.93 (1.15-3.24) compared with non-smokers; for
women the corresponding relative hazard is 3.81 (2.00-7.27). Biochemical measures
(cotinine, thiocyanate and expired-air CO) are closely correlated with self
reported smoking (0.67 < or = r < or = 0.72), and have similar relationships with
CHD. Amongst cigarette smokers, relative hazards (third to first tertile), for
tar yield are 1.05 (0.54-2.07) for men and 4.00 (1.13-14.18) for women. Nicotine
and CO yields give similar results. Hazard ratios associated with heavy smoking
and strong cigarettes are thus much higher for women. CONCLUSION: Although
smoking was found to have a detrimental effect, this study was unable to suggest
a single major cause of CHD. The excess effects found in women compared with men
could be due to differences in former smoking habits. Furthermore, risk
differences for smoking are slightly greater for men, explained by the relatively
low incidence of CHD amongst women.
PMID- 10764244
TI - Kidney cancer mortality in The Netherlands, 1950-94: prediction of a decreasing
trend.
AB - BACKGROUND: Incidence and mortality rates of kidney cancer are known to be
increasing world-wide. The reasons for these increases are not clear, but despite
this it may still be possible to predict changes in the trend of occurrence.
METHODS: Male and female kidney (plus ureter and urethra) cancer mortality per
10(5) person-years, from 1950 to 94, were calculated using national demographic
and mortality data. Changes in the age structure of the Dutch population were
adjusted using direct standardisation to the European standard population. The
effects of age, calendar period and birth cohort on the temporal trend in
mortality were evaluated using log-linear modelling. RESULTS: Male mortality from
kidney cancer increased from three per 10(5) person-years in the 1950s to eight
per 10(5) in the mid 1980s and remained relatively stable thereafter. Female
mortality rates showed a comparable trend, from two per 10(5) in the 1950s to
four per 10(5) in the 1980s. In addition to the effects of age, the temporal
trend in males can be sufficiently explained as a birth cohort effect. Successive
birth cohorts appear to have higher risks of dying from kidney cancer until the
1930 cohort. The younger birth cohorts appear to have lower risks. The trend in
women is comparable to that in men but is less pronounced and shows only after
excluding women under the age of 45. CONCLUSION: The decreasing risk for
generations born after 1930 will probably result in a decreasing trend in kidney
cancer mortality in the near future. It is suggested that at least part of this
changing trend in men (but not in women) is caused by the changing smoking
behaviour of the Dutch population.
PMID- 10764245
TI - Family history and stroke: a community case-control study in Asturias, Spain.
AB - BACKGROUND: Family history of stroke has been considered as a risk factor for
stroke, but this relationship is controversial. Some, but not all, studies have
found an independent association between family history of stroke and stroke.
This study examines the relationship between family history of stroke and all
stroke types combined, cerebral infarction and intraparenchymatous haemorrhage.
METHODS: This is an incidence type, population-based case-control study. Cases
were defined following WHO criteria and controls were randomly selected from the
study-base population. Family history of stroke was obtained by medical
interview. A total of 470 cases and 477 controls, aged 40-85 years, form the
subjects of the study. RESULTS: Family history of stroke in a first-degree
relative is an independent risk factor for all stroke types combined,
multivariate adjusted odds ratio (OR) 1.74, 95% confidence interval (CI) 1.24
2.44, for cerebral infarction, OR = 1.79 (95% CI 1.25-2.56), but not for
intraparenchymatous haemorrhage, OR = 1.71 (95% CI 0.91-3.17). Risk of all stroke
types combined was independently associated with a positive history of father
with stroke OR = 1.93 (1.19-3.54) with a positive history of sibling with stroke,
OR = 1.67 (95% CI 1.03-2.71) and a borderline significant association with a
positive history of mother with stroke OR = 1.45 (95% CI 0.92-2.29). Cerebral
infarction was independently associated with a positive history of father with
stroke OR = 2.05 (95% CI 1.17-3.59), a positive history of sibling, OR = 1.69
(95% CI 1.01-2.84) and a borderline significant association with a positive
history of mother with stroke OR = 1.58 (95% CI 0.97-2.56). Intracerebral
haemorrhage was not significantly associated with a positive history of father
with stroke OR = 1.39 (0.55-3.58) with a positive history of sibling, OR = 1.83
(95% CI 0.77-4.40), or with a positive history of mother with stroke OR = 1.36
(95% CI 0.59-3.09). CONCLUSIONS: Family history of stroke is found in this study
to be an independent risk factor for all stroke types combined and for cerebral
infarction. Genetic factors may be involved, but it cannot be ruled out that the
observed relationship is confounded by other risk factors, especially family
aggregation of life-styles.
PMID- 10764246
TI - Effect of dichotomising a continuous variable on the assessment of familial
aggregation: an empirical study using body mass index data from the Busselton
Health Study.
AB - BACKGROUND: Continuous measures are often dichotomised according to some
meaningful threshold. When measures of association are the study focus, such as
in familial aggregation studies, we may use an odds-ratio (OR), instead of a
Pearson correlation coefficient, to measure correlation between outcomes. In this
paper, we examine the effect of using different threshold values on the resulting
OR estimates and their statistical efficiency. METHODS: We use an example based
on obesity data, in the form of BMI measurements on family members, to guide a
study of the OR based on four-fold probabilities which result when a pair of
normally distributed outcomes is dichotomised at a certain value. This leads to a
study of outcomes from simulated nuclear family data. As a possible alternative,
we also assess the performance use of a simple tetrachoric correlation
coefficient, the dichotomous analogue of Pearson's correlation coefficient.
RESULTS: The studies indicate that dichotomisation at values close to the mean
leads to results more comparable to the continuous equivalent. The results show
that, in our setting, there is a positive relationship between threshold value
and resulting OR, and between threshold value and resulting standard errors. The
value of the tetrachoric correlation coefficient decreases, relative to Pearson's
correlation coefficient, as threshold values deviate from the mean. DISCUSSION:
Familial OR that result from dichotomisation are influenced by the choice of
threshold value. We discuss implications of this and related issues on the
interpretation of results.
PMID- 10764247
TI - Estimating sensitivity and specificity when repeated tests are performed on the
same subject.
AB - BACKGROUND: When diagnostic tests are repeated on the same subject, a correlation
between test results is expected. This must be taken into account when computing
interval estimates. METHODS: The application of regression techniques for
correlated data to a logistic model is proposed in order to obtain correct point
and interval estimates. RESULTS: The use of different study designs and models of
analysis (marginal and 'random effects') is discussed. The advantages of studies
using multiple tests, possible sources of bias (including those specific to
multiple testing) and methods of correction are also discussed. An example
considering Doppler flow velocimetry in pregnancy is presented.
PMID- 10764248
TI - Markov chain models and estimation of absolute progression rates: application to
cataract progression in diabetic adults.
AB - BACKGROUND: We present a case study in the use of Markov chain models of disease
progression, with exponential regression to model the effects of covariates.
METHODS: An exponential regression model was developed for a three-state Markov
chain to model progression of cataracts in diabetic patients, with a view to
estimation of absolute progression rates. Two methods of estimation were applied,
a non-linear least squares approximation, and Markov Chain Monte Carlo (MCMC).
RESULTS: Both methods gave estimated transition rates which can readily be
transformed to absolute progression probabilities. Agreement was reasonable for
most but not all of the parameters. CONCLUSIONS: The MCMC estimates had more
conservative variance estimates.
PMID- 10764249
TI - Spinal surgery: the past century and the next.
PMID- 10764250
TI - Glioma immunology and immunotherapy.
AB - OBJECTIVE: Despite advances in conventional therapy, the prognosis for most
glioma patients remains dismal. This has prompted an intensive search for
effective treatment alternatives. Immunotherapy, one such alternative, has long
been recognized as a potentially potent cancer treatment but has been limited by
an inadequate understanding of the immune system. Now, increased insight into
immunology is suggesting more rational approaches to immunotherapy. In this
article, we explore key aspects of modern immunology and discuss their
implications for glioma therapy. METHODS: A thorough literature review of glioma
immunology and immunotherapy was undertaken to inquire into the basic immunology,
central nervous system immunology, glioma immunobiology, standard glioma
immunotherapy, and recent immunotherapeutic advances in glioma treatment.
RESULTS: Although gliomas express tumor-associated antigens and appear
potentially sensitive to immune responses, many factors work together to inhibit
antiglioma immunity. Not surprisingly, most clinical attempts at glioma
immunotherapy have met with little success to date. However, novel
immunostimulatory strategies, such as immunogene therapy, directed cytokine
delivery, and dendritic cell manipulation, have recently yielded dramatic
preclinical results in glioma models. This suggests that glioma-derived
immunosuppression can be overcome. CONCLUSION: Modern molecular biology and
immunology techniques have yielded a wealth of new data about glioma
immunobiology. Armed with this information, many investigators have proposed
novel means to stimulate antiglioma immune responses. Although definitive
clinical results remain to be seen, the current renaissance in glioma immunology
and immunotherapy shows great promise for the future.
PMID- 10764251
TI - Cerebral arteriovenous malformations and associated aneurysms: analysis of 305
cases from a series of 662 patients.
AB - OBJECTIVE: Spontaneous intracranial hemorrhage is the primary danger for patients
with cerebral arteriovenous malformations (AVMs). Associated aneurysms are
considered weak points that increase the risk of intracranial hemorrhage.
Aneurysms are classified as proximal aneurysms (PROXs) or intranidal aneurysms
(INs). METHODS: The present study was based on a series of 662 patients who
presented with AVMs between 1985 and 1995. Its purpose was to evaluate prestated
hypotheses using prospectively collected data. In 305 of these 662 patients, 372
INs and 313 PROXs were observed and analyzed with respect to their shapes,
locations, and sizes. Partial targeted endovascular treatment with n
butylcyanoacrylate was performed for 450 of the 662 patients (68%) in this
series, using a standard protocol. Of 450 treated patients, 181 (40%) had at
least one IN and 138 (30.7%) had at least one PROX. Analysis of changes in the
sizes of PROXs was based on the follow-up data for 83 treated patients, with a
total of 149 PROXs. Changes in the sizes of PROXs in treated patients were
analyzed with respect to PROX shapes, PROX locations, and treated AVM occlusion
rates. Univariate and multivariate event data analyses were used to study factors
influencing aneurysm shrinkage. False aneurysms were excluded from the series.
RESULTS: Presentation with intracranial hemorrhage was not correlated with any
type of aneurysm. However, INs demonstrated a higher rebleeding rate (P < 0.002)
before treatment. Among 181 patients, 92.2% of INs were occluded, together with
the related portions of the AVM nidi. In cases of PROXs, embolization of the
cerebral AVM compartment fed by the artery with the aneurysm was a priority.
During follow-up monitoring of 83 treated patients with 149 PROXs, 100% shrinkage
was observed for 12 PROXs and more than 50% shrinkage was observed for 33 PROXs.
The median time required for more than 50% shrinkage was 3.5 years. The shrinkage
of PROXs was influenced by the degree of AVM occlusion (P = 0.027) and occurred
faster for PROXs on midline structures, such as the anterior cerebral artery and
the circle of Willis, compared with arteries distal to the circle of Willis (P =
0.004). No rupture of untreated PROXs was observed after partial targeted
treatment of AVMs. CONCLUSION: PROXs are not primary treatment targets, compared
with AVMs themselves. INs should be primary targets of endovascular therapy,
because of their increased risk of rebleeding.
PMID- 10764252
TI - Angiographic long-term follow-up data for arteriovenous malformations previously
proven to be obliterated after gamma knife radiosurgery.
AB - OBJECTIVE: To investigate whether angiograms obtained 2 years after radiosurgery,
proving total arteriovenous malformation (AVM) occlusion, represent the final
state of treated AVMs and adjacent normal vessels. METHODS: Angiograms were
obtained for 48 patients 5 to 24 years after gamma knife radiosurgery and 4 to 17
years after the AVMs had been proven to be totally occluded after the treatment;
changes in normal vessels and signs of recanalization were recorded. Ten of the
patients developed clinical symptoms attributable to the AVMs or the treatment
after having been declared cured, whereas the other patients did not exhibit
symptoms. RESULTS: There was evidence of AVM nidi at the sites of previously
occluded AVMs for two patients and of nidi adjacent to those sites for another
two patients. Three of the four recurrent AVMs were associated with hemorrhaging.
All patients who experienced hemorrhaging from previously occluded AVMs were < or
= 14 years of age at the time of gamma knife radiosurgery. There were signs of
segmental narrowing in normal vessels that had been irradiated with high doses
(nine patients) or a low dose (one patient). The segmental narrowing decreased
with time for four of these patients, was unchanged for four, and increased for
two. These vascular changes did not produce clinical symptoms in any of the
patients. CONCLUSION: There is a small possibility that AVMs may reappear after
having been totally occluded after radiosurgery, especially in pediatric
patients. Segmental narrowing in normal arteries after radiosurgery is a benign
condition that rarely progresses and does not produce clinical symptoms.
PMID- 10764253
TI - Micro-arteriovenous malformations: significant hemorrhage from small
arteriovenous shunts.
AB - OBJECTIVE: Micro-arteriovenous malformations (AVMs) represent approximately 8 to
10% of surgically treated brain AVMs. We examined the clinical presentations,
radiological features, principles of surgical resection, and factors affecting
outcomes for micro-AVM lesions. METHODS: Twelve patients with micro-AVMs that had
been treated by surgical resection were retrospectively analyzed. The mean follow
up monitoring period was 35 months (range, 2-76 mo). Outcomes, as assessed in
follow-up visits and telephone interviews (using a questionnaire), were
classified according to the Glasgow Outcome Scale. RESULTS: All 12 patients
presented with intracranial hemorrhage, which was intraparenchymal and
superficially situated in 10 patients (83%) and intraventricular in 2 patients
(17%). Hemorrhages were large (mean volume, 23 ml3; range, 1-58 ml3) and were
associated with neurological deficits for 10 of 12 patients (83%). The
identification of an arterialized draining vein during surgery and stereotactic
angiography greatly facilitated surgical localization of the lesions. One patient
(8%) developed a mild permanent deficit as a result of surgery. Although Glasgow
Outcome Scale scores were excellent for all except one patient, nine patients
(75%) experienced long-term neurological problems. CONCLUSION: Micro-AVMs
typically present with large hemorrhages and are associated with significant
neurological deficits. If a superficial clot is present, surgical resection of
the lesion is strongly advocated. The ultimate clinical outcomes are determined
primarily by deficits present after the initial hemorrhaging episodes.
PMID- 10764254
TI - Orbital drainage from cerebral arteriovenous malformations.
AB - OBJECTIVE: To describe the neuro-ophthalmic findings in patients with orbital
drainage from cerebral arteriovenous malformations (AVMs). METHODS: We reviewed
the records of 100 consecutive adult patients with cerebral AVMs who presented to
our institution during a 4-year period. All patients with orbital drainage were
identified, and their neuro-ophthalmic evaluations were reviewed. RESULTS: Three
patients (3%) were identified with orbital drainage from a cerebral AVM. The
first patient presented with typical chiasmal syndrome (reduced visual acuity,
bitemporal hemianopia, and optic atrophy). Magnetic resonance imaging
demonstrated a large left temporal and parietal lobe AVM with compression of the
chiasm between a large pituitary gland and a markedly enlarged carotid artery.
The second patient presented with headaches and postural monocular transient
visual obscurations. Examination revealed normal visual function with minimal
orbital congestion and asymmetrical disc edema, which was worse in the left eye.
Magnetic resonance imaging revealed a large right parietal and occipital lobe AVM
without mass effect or hemorrhage and an enlarged left superior ophthalmic vein.
The third patient had no visual symptoms and a normal neuro-ophthalmic
examination; a right parietal lobe AVM was discovered during an examination for
the cause of headaches. CONCLUSION: Orbital drainage from cerebral AVMs is rare.
Manifestations may include anterior visual pathway compression, dilated
conjunctival veins, orbital congestion, and asymmetrical disc swelling.
PMID- 10764255
TI - False localization of rupture site in patients with multiple cerebral aneurysms
and subarachnoid hemorrhage.
AB - OBJECTIVE: Patients with subarachnoid hemorrhage and multiple intracranial
aneurysms present a unique challenge to the neurosurgeon. Unless all aneurysms
can be clipped through a single craniotomy, the surgeon must accurately determine
which aneurysm has ruptured. Misjudgment may result in disastrous postoperative
rebleeding from the untreated but true ruptured lesion. We assessed the risk of
false localization of the rupture site and subsequent rebleeding and documented
the problems in predicting the true rupture site when patients have multiple
intracranial aneurysms. METHOD: We reviewed the records of a consecutive series
of 93 patients treated over a period of 12 years who presented with their first
subarachnoid hemorrhage and who had multiple intracranial aneurysms. The rupture
site was determined on the basis of computed tomographic and angiographic
findings, and the supposed ruptured aneurysm was clipped within 2 days of
hemorrhage in each patient. Additional aneurysms that could not be accessed in
the same surgical session were operated on at a later stage. All patients'
records were reviewed, and all computed tomographic scans and angiograms,
including repeat studies performed in some patients, were retrospectively
reevaluated by the authors, who had no knowledge of the patients' clinical
information. RESULTS: The location of the aneurysm that ruptured was verified at
the time of surgery or during the autopsy in 76 patients (82%). The aneurysm that
ruptured was the one predicted as ruptured by the surgeon before surgery in 69
patients (91%) and in retrospect in 72 patients (95%). Five of the 6 patients in
whom the ruptured aneurysm was not correctly identified were thought to have only
a single aneurysm. Four patients rebled after surgery, and 2 patients died as a
result of the rebleeding. CONCLUSION: In the reported series, the most common
cause of rebleeding soon after aneurysm surgery was failure to obliterate the
ruptured aneurysm, usually because it was missed on the initial angiogram. The
results support not only meticulous radiological investigation of all
intracranial arteries before surgery but also thorough surgical inspection of the
target aneurysm in all cases of subarachnoid hemorrhage even after one candidate
lesion has been discovered.
PMID- 10764256
TI - Differing perspectives on outcome after subarachnoid hemorrhage: the patient, the
relative, the neurosurgeon.
AB - OBJECTIVE: To better understand patients' and relatives' views of outcome after
surgery for subarachnoid hemorrhage (SAH), we evaluated neurobehavioral changes,
psychological distress, and family burden of patients who had been considered by
their neurosurgeon as having a "good recovery" or a "moderate disability," as
rated on the Glasgow Outcome Scale. METHODS: A heterogeneous sample of 28
patients treated surgically for SAH from an aneurysm or an arteriovenous
malformation and their relatives separately underwent a semistructured interview.
They also completed a revised version of the Adjective Checklist to assess their
perceptions of the patient's neurobehavioral changes and the Brief Symptom
Inventory as a measure of their own psychological distress. Levels of family
burden on the relatives were evaluated with a Likert strain scale and the Zarit
Burden Interview. RESULTS: Approximately 19 months after surgery for SAH, the
majority of the patients reported significant negative neurobehavioral changes
and negative changes in employment, energy levels, tolerance to mild stressors,
leisure activities, and social and sexual relationships. Patients and relatives
both reported elevated levels of psychological distress, and the relatives
reported elevated levels of family burden. Patients' and relatives' perceptions
differed, with the relatives reporting more problems; both viewed the patient's
outcome more negatively than did the operating neurosurgeon. CONCLUSION: Despite
the neurosurgeon's classification of patients as having a "good recovery" or
"moderate disability," the majority of patients surgically treated for SAH
reported psychosocial and neurobehavioral changes that were disabling for them
and burdensome to their family. Patients and relatives who are interviewed
separately by an experienced clinician may provide differing perspectives on SAH
outcome that are not necessarily good.
PMID- 10764257
TI - Neurosurgical and neuroendovascular management of Takayasu's arteritis.
AB - OBJECTIVE: The roles of surgical and endovascular treatments for patients with
Takayasu's arteritis are not clear. We report our experience in the neurosurgical
and/or neuroendovascular treatment of patients with Takayasu's arteritis who
exhibited ischemic neurological symptoms. METHODS: Between 1994 and 1998, seven
patients with Takayasu's arteritis and neurological symptoms were treated at the
Stanford University Medical Center. All patients were angiographically evaluated
and received maximal medical therapy. Cerebral blood flow studies were performed
for six patients. Three patients underwent surgical revascularization procedures
alone, two underwent combinations of surgical and endovascular procedures, and
two underwent endovascular treatment alone. RESULTS: The most common neurological
symptoms were dysequilibrium, syncope, and visual disturbances. The
characteristic angiographic features of Takayasu's arteritis were identified for
all patients. The subclavian arteries and proximal carotid and vertebral arteries
were involved in all patients. Two patients exhibited improvement of their
symptoms after endovascular treatment alone. There were two deaths after surgery,
involving patients with severe global cerebral hypoperfusion. All other
surgically treated patients exhibited improvement of their symptoms, with patent
grafts, up to 4 years after surgery. Cerebral blood flow improved after
treatment. CONCLUSION: Improvement of symptoms can be achieved with surgical
revascularization and/or endovascular treatment. Staged revascularization might
be better than one-stage bilateral high-flow grafting for patients with severe
global hypoperfusion.
PMID- 10764258
TI - Intravenous low-dose native tissue plasminogen activator for distal embolism in
the middle cerebral artery divisions or branches: a pilot study.
AB - OBJECTIVE: We prospectively evaluated the safety and efficacy of an intravenous
infusion of low-dose native tissue plasminogen activator for distal embolisms in
the middle cerebral artery divisions or branches. METHODS: Twenty patients were
selected according to the following computed tomographic and angiographic
criteria and treated with intravenous infusion of 7.2 mg of tisokinase: 1) no
early ischemic changes on the initial computed tomographic scan, and 2) embolic
occlusion of the middle cerebral artery divisions or branches without the
involvement of the lenticulostriate arteries. For comparison, the records of 12
patients from previous years who met the above inclusion criteria but underwent
no thrombolytic therapy were reviewed retrospectively. The degree of neurological
recovery was assessed using the National Institutes of Health Stroke Scale at 24
hours after admission. Major neurological improvement was defined as a decrease
in the stroke score by 4 points or more. RESULTS: There was no significant
difference in stroke scores at the time of admission between the treatment group
(mean +/- standard deviation, 12.8 +/- 2.8) and the untreated group (14.0 +/-
2.4). In the treatment group, major neurological improvement was seen in 17 (85%)
of 20 patients, whereas in the untreated group only 5 (41.7%) of 12 patients
showed major neurological improvement (P < 0.05). The mean score at 24 hours in
the treatment group (3.6 +/- 3.5) was significantly lower than that in the
untreated group (9.4 +/- 7.3) (P < 0.05). There was no hemorrhagic complication
with neurological exacerbation in the treatment group. CONCLUSION: Even with
delayed initiation (>3 h after symptom onset), intravenous infusion of low-dose
tisokinase may be safe and effective for small distal emboli in the middle
cerebral artery divisions or branches, when early ischemic changes on computed
tomographic scans and involvement of the lenticulostriate arteries are absent.
PMID- 10764259
TI - Radiosurgical salvage therapy for patients presenting with recurrence of
metastatic disease to the brain.
AB - OBJECTIVE: Radiosurgery has emerged as an important modality in the management of
metastatic disease to the brain. A number of groups have published results
suggesting that high local control rates can be achieved, with improvements in
overall survival that rival the results of open surgical treatment. Typically,
however, whole-brain radiotherapy has been used in the salvage therapy of
patients who have undergone previous craniotomy or radiosurgery. We describe our
experience with radiosurgical salvage in this group of patients. METHODS: From
August 1994 to February 1999, 190 patients with brain metastasis were treated
with gamma unit radiosurgery at our institution. A subset of 45 patients, who
underwent radiosurgical salvage for new tumors in a region remote from an
initially treated tumor, form the population base for this study. The usual
criteria for repeat treatment were recurrence with five or fewer discrete lesions
outside of the previously treated radiosurgical volume and Karnofsky Performance
Scale score of at least 70. Survival and freedom from progression were measured
from the time of radiosurgical treatment and were computed by the Kaplan-Meier
product-limit method. Two or more curves were compared using the log-rank method.
RESULTS: In this subgroup of patients, a total of 176 tumors were treated. The
median time from first radiosurgical procedure to first salvage was 17.4 weeks.
Median survival from the second radiosurgical intervention was 28 weeks. Of the
45 study patients, 34 patients underwent a single salvage procedure, 10 patients
underwent two salvage procedures, and 1 patient had three salvage procedures. The
actuarial freedom from progression for treated tumors at 52 weeks was 92.4%.
Patients undergoing upfront whole-brain irradiation were less likely to require
salvage therapy (P = 0.008). There were 33 deaths after salvage radiosurgery
during the reporting period. Central nervous system causes accounted for 13
deaths, whereas 19 deaths resulted from systemic disease. The cause of death in
one patient could not be determined. No statistically significant advantage in
overall survival could be demonstrated in patients treated with whole-brain
irradiation. CONCLUSION: Radiosurgical salvage represents a valuable means of
treatment for central nervous system recurrence for patients who have undergone
previous treatment for metastatic disease to the brain. Whole-brain irradiation
may reduce the need for salvage therapy, but no advantage in overall survival
could be demonstrated in this subgroup.
PMID- 10764260
TI - Brain oxygen tension in severe head injury.
AB - OBJECTIVE: Ensuring adequate cerebral oxygenation and perfusion is of fundamental
importance in the treatment of patients with acute cerebral disorders. Online
continuous monitoring of brain oxygenation is possible with a parenchymal
microelectrode that measures local brain oxygen tension. The ultimate question is
whether therapeutic approaches can be targeted on the basis of such monitoring.
Before this question can be addressed, the technique requires validation in the
clinical setting. The frequency of occurrence of low values and its relation to
outcome need to be established. METHODS: One hundred one comatose head-injured
patients (Glasgow Coma Scale score < or = 8) were studied. Local brain oxygen
tension probes were inserted in an undamaged part of the frontal region. Patients
were treated in conformance with the European Brain Injury Consortium guidelines.
Outcome at 6 months was determined by Glasgow Outcome Scale score. RESULTS: Early
brain tissue hypoxia was frequently observed, despite aggressive treatment for
intracranial pressure and cerebral perfusion pressure. Values lower than 15 mm
Hg, for a duration longer than 30 minutes, were observed in 57 patients. Values
lower than 10 mm Hg in 42 patients, and lower than 5 mm Hg in 22 patients, were
observed during the first 24 hours. Depth and duration of tissue hypoxia were
related to outcome and proved to be an independent predictor of unfavorable
outcome and death. CONCLUSION: Monitoring the partial oxygen pressure of local
brain tissue is a safe and reliable method for regulating cerebral oxygenation.
Because brain tissue hypoxia occurs frequently and is significantly related to
poor outcome, future efforts should be aimed at the treatment of brain tissue
hypoxia. The effects of such brain hypoxia-targeted treatment need to be
established in a multicenter study.
PMID- 10764261
TI - Transcallosal interforniceal-transforaminal approach for removing lesions
occupying the third ventricular space: clinical and neuropsychological results.
AB - OBJECTIVE: The present study was undertaken to describe the clinical and
prospective neuropsychological results for our group of 30 patients who were
treated using a transcallosal interforniceal-transforaminal microsurgical
approach. METHODS: The transcallosal interforniceal and transcallosal
transforaminal approaches were used to treat 30 patients with space-occupying
lesions located in the anterior part of the third ventricle. We used a modified
anterior transcallosal microsurgical approach, as described recently. The
patients underwent extensive, pre- and postoperative, prospective
neuropsychological testing, using a specially designed test battery. RESULTS:
Twenty-three of 30 patients (77%) experienced excellent clinical outcomes
(Glasgow Outcome Scale Grade V). The surgical procedures described in this report
did not themselves impair attentional function. In both the early and late
postoperative neuropsychological testing sessions, deficits in verbal memory were
only rarely observed and were not noted to be correlated with the surgical
procedures. The most relevant neuropsychological results for individual patients
are reported in detail. CONCLUSION: The approach described here can be
successfully used for the resection of various space-occupying lesions in the
anterior part of the third ventricle. The anatomic landmarks we recently defined
and described (for example, the midline vessel on the trunk of the corpus
callosum, to direct the callosotomy) guide the surgical path. Furthermore, we
recommend the use of neuropsychological test batteries for both scientific and
rehabilitative purposes.
PMID- 10764262
TI - The pretemporal transcavernous approach to the interpeduncular and prepontine
cisterns: microsurgical anatomy and technique application.
AB - OBJECTIVE: To illustrate in a stepwise fashion the microsurgical anatomy of the
transcavernous approach to the interpeduncular and prepontine cisterns and to
discuss our initial results with 15 basilar tip aneurysms managed through that
approach. METHODS: Using 10 embalmed cadaveric heads perfused with colored
silicon, we performed bilateral stepwise dissections of the transcavernous
approach via an orbitozygomatic pretemporal craniotomy. Measurements of the
exposure of the basilar artery obtained along the dorsum sellae and upper clivus
were taken. Our clinical data were derived from a series of 15 patients with
large basilar tip aneurysms treated surgically via the transcavernous approach
between 1997 and 1999. Indications for surgery were based on the size of the
aneurysm (all were large) and its position in relation to the dorsum sellae
(eight were more than 5 mm below the level of the dorsum sellae). RESULTS: Good
exposure of the neurovascular structures of the interpeduncular and prepontine
cisterns (namely, the basilar artery) was obtained in all cases as compared with
other well-established approaches to the area. All patients in our surgical
series did well except that all incurred an expected third nerve palsy, caused by
surgical manipulation, which resolved over the course of 2 weeks to 3 months.
CONCLUSION: Although technically difficult, the transcavernous approach provides
better exposure of the interpeduncular and prepontine cisterns relative to that
afforded by other, more conventional approaches. The satisfactory results
obtained in our preliminary series of patients greatly support the use of this
approach for complex basilar tip aneurysms.
PMID- 10764263
TI - Brain tumor surgery with the Toronto open magnetic resonance imaging system:
preliminary results for 36 patients and analysis of advantages, disadvantages,
and future prospects.
AB - OBJECTIVE: Frameless navigation systems represent a huge step forward in the
surgical treatment of intracranial pathological conditions but lack the ability
to provide real-time imaging feedback for assessment of postoperative results,
such as catheter positions and the extent of tumor resections. An open magnetic
resonance imaging system for intracranial surgery was developed in Toronto, by a
multidisciplinary team, to provide real-time intraoperative imaging. METHODS: The
preliminary experience with a 0.2-T, vertical-gap, magnetic resonance imaging
system for intraoperative imaging, which was developed at the University of
Toronto for the surgical treatment of patients with intracranial lesions, is
described. The system is known as the image-guided minimally invasive therapy
unit. RESULTS: Between February 1998 and March 1999, 36 procedures were
performed, including 21 tumor resections, 12 biopsies, 1 transsphenoidal
endoscopic resection, and 2 catheter placements for Ommaya reservoirs. Three
complications were observed. All biopsies were successful, and the surgical goals
were achieved for all resections. Problems included restricted access resulting
from the confines of the magnet and the imaging coil design, difficulties in
working in an operating room that is less spacious and familiar, inconsistent
image quality, and a lack of nonmagnetic tools that are as effective as standard
neurosurgical tools. Advantages included real-time imaging to facilitate surgical
planning, to confirm entry into lesions, and to assess the extent of resection
and intraoperative and immediate postoperative imaging to confirm the extent of
resections, catheter placement, and the absence of postoperative complications.
CONCLUSION: Intraoperative magnetic resonance imaging has great potential as an
aid for intracranial surgery, but a number of logistic problems require
resolution.
PMID- 10764264
TI - Prevention of complications resulting from endovascular carotid sacrifice: a
retrospective assessment.
AB - OBJECTIVE: To determine the protective effects of various periprocedural
interventions in the prevention of cerebral ischemia as a complication of
endovascular carotid sacrifice (ECS). METHODS: Thirty-two cases of ECS performed
at our institution, between October 1987 and July 1998, were reviewed. Fifteen
patients underwent superficial temporal artery-to-middle cerebral artery bypass
surgery. In 21 patients, the carotid artery was occluded proximal to the target
lesion; and in 11 patients, a lesion trapping procedure was performed. Six
patients were prophylactically anticoagulated, 14 received antiplatelet agents
prophylactically, and 12 received no pharmacoprophylaxis. RESULTS: Among the six
patients who were anticoagulated, there were no embolic events. Embolic events
affected 4 of 14 patients receiving prophylactic antiplatelet agents, 2 of 12
patients receiving no pharmacoprophylaxis, 1 of 11 patients who underwent a
trapping procedure, and 5 of 21 patients whose carotid artery was occluded
proximal to the target lesion. Postocclusion cerebral ischemia developed in 7 of
15 patients who underwent bypass surgery, and in 1 of the remaining 17.
CONCLUSION: Superficial temporal artery-to-middle cerebral artery bypass did not
protect against postocclusion cerebral ischemia after ECS in this series (P =
0.01). Although the small number of patients studied precludes statistical
validity (P = 0.29), the trends suggest that antiplatelet agents provide no
protection against postocclusion cerebral emboli after ECS. Prophylactic
anticoagulation (P = 0.32) and lesion trapping (P = 0.12) may reduce the
frequency of postocclusion embolic events after ECS; however, because of the
small number of patients, statistical significance could not be demonstrated.
PMID- 10764265
TI - Balloon-protected carotid angioplasty.
AB - OBJECTIVE: We describe a method of protecting the distal cerebral circulation
during carotid angioplasty and report results using the technique in 17
procedures. METHODS: Eleven men and five women with carotid stenoses ranging in
severity from 70 to 95% underwent the procedure. The technique was used
bilaterally in one patient. A compliant silicone balloon was used to occlude the
distal internal carotid artery during the angioplasty phase, when the largest
number of emboli are generated. After angioplasty, debris was then flushed into
the external circulation while the occlusion balloon remained inflated. The
subsequent passage of an exchange guidewire through the angioplasty catheter,
with the occlusion balloon deflated, allowed continuous guidewire access across
the area of stenosis and facilitated the subsequent placement of a stent.
RESULTS: The technique was successful in 16 (94%) of 17 procedures. In the one
patient in whom the occlusion balloon could not be advanced across the stenosis,
the patient experienced a transient ischemic attack after subsequent angioplasty
that was performed without protection. Otherwise, no complications occurred among
the 15 patients undergoing successful, balloon-protected angioplasty. Inflation
times for the occlusion balloon did not exceed 5 minutes in any patient.
CONCLUSION: This method of cerebral protection prevents the intracranial
embolization of thrombus and atherosclerotic debris, while allowing continuous
guidewire access across the site of stenosis. The success of this technique and a
similar method used by Theron et al. supports the use of balloon protection as a
means of reducing the risk of stroke associated with carotid angioplasty.
PMID- 10764266
TI - Uniportal endoscopic superior thoracic sympathectomy.
AB - OBJECTIVE: A retrospective study presenting our experience with upper thoracic
endoscopic sympathectomy in patients with primary palmar hyperhidrosis. METHODS:
One hundred patients (46 women and 54 men) underwent bilateral uniportal
endoscopic thoracic sympathectomy since January 1, 1995. Age distribution ranged
from 12 to 54 years (mean, 23.4 yr). RESULTS: Sympathectomy on both sides was
accomplished within 30 minutes in a single stage. Ninety-six patients (96%) had
an uneventful postoperative course and were discharged the following day. Four
patients with residual hemothorax required intercostal drainage and were
discharged on the third postoperative day. Ninety-six patients were completely
satisfied with immediate and permanent relief of palmar perspiration.
Compensatory hyperhidrosis was the major complication, which was usually mild and
tolerable after reassurance. In only eight patients (8%) was the compensatory
hyperhidrosis considered bothersome, requiring treatment with aluminum chloride
in ethanol solution at 25%. There was no mortality. Recurrence of palmar
hyperhidrosis has been noticed in five patients (5%) during the follow-up period
(range, 2-56 mo; mean, 12 mo). At the time of reoperation, a remaining branch of
the sympathetic chain could be observed and coagulated. CONCLUSION: We consider
thoracoscopic sympathectomy to be a simple, safe, and effective method for
treating palmar hyperhidrosis. It is an effective method for treating patients
with palmar hyperhidrosis, with a shorter operation time, fewer hospital days,
and a better cosmetic result, as compared with the open approaches.
PMID- 10764267
TI - Pump-regulated lumbar subarachnoid drainage.
AB - OBJECTIVE: The diversion of cerebrospinal fluid (CSF) has been widely used in the
prevention and treatment of CSF fistulae. A common method is the use of a lumbar
drainage system. Although it is effective, several serious complications can
develop, which can be avoided by regulating the flow of CSF with a standard
intravenous infusion pump. TECHNIQUE: We present a simple, inexpensive, and
accurate method of flow-controlled lumbar subarachnoid drainage that minimizes
patient discomfort and the unpredictability of a gravity-dependent system. This
system uses a standard lumbar drain connected to an intravenous infusion pump to
provide drainage of CSF in a constant and predictable manner. RESULTS: A total of
42 patients from two institutions were treated with this method. CSF fistulae
occurred secondary to trauma in 9 patients, after spinal surgery in 11 patients,
after transsphenoidal surgery in 10 patients, and after cranial base surgery in
12 patients. Resolution of the fistula was attained in 36 of 42 patients. There
were no deaths, no cases of deep venous thrombosis, and no incidence of
meningitis. One patient developed tension pneumocephalus, and two patients
developed headache with nausea and vomiting. All patients were ambulatory, and
only three patients required narcotic analgesia for headaches. CONCLUSION: Pump
regulated lumbar subarachnoid drainage is safe and effective in the treatment of
CSF fistulae, as reported elsewhere in the literature. The advantage of this
method is that the drainage of CSF can be carefully controlled and titrated in a
predictable fashion. Because the system is independent of gravity to produce
drainage of CSF, patients are not confined to bed and serious complications of
overdrainage can be avoided.
PMID- 10764268
TI - Web-based surgical simulation for ventricular catheterization.
AB - We have used new developments in computer technology and the Internet to create a
small program that simulates catheterization of the lateral ventricle. The
program can run on most personal computers connected to the Internet. The program
allows trainee surgeons to practice the technique with varying degrees of visual
feedback--and no risk to the patient. It allows them to learn both the technique
and the associated anatomy. The trainees can be assessed while performing the
procedure. This is a small, early-stage application of virtual reality in
surgical education. There is a demand for surgical training techniques that
expose the patient to no risk; the use of computers is appropriate to meet this
demand. The technique presented here requires further development; in particular,
it needs a standardized assessment element that will allow it to be tested by
established surgeons and trainees. The real test of a good training technique is
how well it discriminates between trainee and trainer.
PMID- 10764269
TI - Vascular endothelial growth factor, hepatocyte growth factor/scatter factor,
basic fibroblast growth factor, and placenta growth factor in human meningiomas
and their relation to angiogenesis and malignancy.
AB - OBJECTIVE: Angiogenesis is mediated by a number of different growth factors and
appears vital for tumor growth. The understanding of angiogenic mechanisms could
offer new therapeutic perspectives; in this context, the role of four potentially
angiogenic growth factors was analyzed in a large series of meningiomas of
different grades. METHODS: Vascular endothelial growth factor (VEGF), placenta
growth factor, hepatocyte growth factor/scatter factor, and basic fibroblast
growth factor were quantified in 69 tumors by enzyme-linked immunosorbent assay.
Microvessel density and proliferative activity were determined on paraffin
sections, and clinical tumor invasiveness was rated. Induction of endothelial
chemotaxis and capillary-like tube formation were studied in vitro using modified
Boyden chamber assays and three-dimensional collagen gel assays, respectively.
RESULTS: Tumors included 40 benign (World Health Organization [WHO] Grade I), 21
atypical (WHO Grade II), and 8 anaplastic/malignant (WHO Grade III) meningiomas.
We found a correlation between meningioma grade and VEGF content (r = 0.37, P =
0.002), which was 2-fold higher in atypical than in benign meningiomas (P =
0.022) and 10-fold higher in malignant than in benign meningiomas (P = 0.025).
Among different subtypes of Grade I meningiomas, VEGF levels were 10-fold higher
in meningothelial than in fibrous meningiomas (P = 0.015). None of the other
three factors investigated showed any association with tumor grade, microvessel
density, or invasiveness, and VEGF also did not correlate with vascularity or
invasiveness. Moreover, vascularity did not increase with malignancy grade.
Endothelial chemotaxis and capillary-like tube formation in vitro were induced by
meningioma extracts and were most effectively blocked by co-addition of
antibodies against basic fibroblast growth factor, followed by anti-VEGF, whereas
anti-hepatocyte growth factor/scatter factor was not effective. The chemotactic
activity of meningioma extracts on endothelial cells correlated with their VEGF
content (r = 0.6, P = 0.003). CONCLUSION: Meningiomas do not show an angiogenic
switch involving VEGF and/or hepatocyte growth factor/scatter factor, as has
previously been found in gliomas. Nevertheless, the biological activity of VEGF
and basic fibroblast growth factor in meningiomas suggests that both are
potential targets for antiangiogenic therapy in meningiomas of all WHO grades.
PMID- 10764271
TI - Flow cytometric characterization of tumor-associated macrophages in experimental
gliomas.
AB - OBJECTIVE: Although microglia have been suggested to be a component of the
inflammatory reaction to tumors of the central nervous system, their role in
glioma biology remains unknown. One obstacle to studying the function of
microglia is the inability to effectively separate them from macrophages. Because
flow cytometry can effectively discern immune cells with similar surface
antigens, we evaluated its role in characterizing the mononuclear cell
infiltration in experimental gliomas. METHODS: Freshly prepared rat C6, 9L, and
RG-2 tumor specimens were labeled ex vivo with monoclonal antibodies against
CD11b/c, CD45, and CD8a antigens and analyzed by flow cytometry. The extent of
microglia (CD11b/c(high), CD45(low)), macrophage (CD11b/c(high), CD45(high)), and
lymphocyte (CD11b/c(negative), CD45(high)) infiltration into tumors, tumor
periphery, and contralateral tumor-free hemispheres was measured for each glioma
type. RESULTS: Microglia, which accounted for 13 to 34% of viable cells, were
distributed throughout the central nervous system and were present in the tumors,
tumor periphery, and contralateral tumor-free hemispheres. In contrast,
macrophages were less prominent within the tumors and tumor periphery (4.2-12%)
and were scarce in the contralateral tumor-free hemispheres (0.9-1.1%). Among the
tumor types, RG-2 gliomas had the least microglia/macrophage infiltration. The
frequency and the distribution pattern of lymphocytes also varied among tumor
models. Whereas lymphocytes accounted for more than one-third of the cells in C6
and 9L tumors, they represented only 1% of cells in RG-2 gliomas. CONCLUSION:
More abundant than macrophages and scattered throughout the central nervous
system, microglia account for a significant component of the inflammatory
response to experimental gliomas. A better understanding of microglial function
in gliomas may be important in the development of immunotherapy strategies.
PMID- 10764270
TI - Apoptosis occurs after cerebral contusions in humans.
AB - OBJECTIVE: Animal model systems have shown that head trauma can induce cell death
in regions of the brain away from the site of the impact via a process of
apoptosis. We sought to determine whether there was evidence of cellular
apoptosis in clinically collected materials from human head trauma patients, as
well as to attempt to determine the pathway by which it may occur. METHODS:
Thirty-one sequential specimens of brain tissue excised during emergency
craniotomy for evacuation of cerebral contusions with mass effect were examined.
Non-necrotic pericontusional tissues were detected in 11 samples. These were
examined for the presence of apoptotic cells by the terminal deoxynucleotide
transferase-mediated nick end labeling method as well as by immunohistochemistry
to detect possible expression of the apoptosis-related genes p53, bcl-2, and bax.
RESULTS: Bax expression was detected in all patients, whereas bcl-2 expression
was noted in six patients. Terminal deoxynucleotide transferase-mediated nick end
labeling-positive cells were noted in eight patients. One instance of p53
positive immunostaining was observed. Patients with bcl-2 expression had a better
survival rate than patients in whom no bcl-2 expression was noted (P = 0.01).
CONCLUSION: Although necrosis seemed to be the main finding in cerebral
contusions, these results support the hypothesis that apoptosis does occur in
patients after traumatic brain injury, and this may contribute to the secondary
injury processes that are seen with head injury. Patients in whom anti-apoptotic
bcl-2 is induced seem to have a better prognosis. This may have important
clinical significance in the development of bcl-2 homologs or bax inhibitors to
prevent apoptosis.
PMID- 10764272
TI - Effect of external stenting and systemic hypertension on intimal hyperplasia in
rat vein grafts.
AB - OBJECTIVE: Overdistention of vein grafts in arterial circulation and systemic
hypertension are thought to be influential risk factors contributing to vein
graft failures. This study tested the effects of external stenting in preventing
systemic hypertension and overdistention of the rat vein graft in the long term.
METHODS: Jugular vein grafts were interposed into the carotid artery of
normotensive (n = 39) and two-kidney, one-clip hypertensive (n = 30) rats.
Jugular vein grafts wrapped with 1.5-mm-diameter polyester stents were used in
normotensive (n = 26) and hypertensive (n = 25) rats. The vein grafts were
harvested at 1, 2, 4, 8, 12, and 24 weeks after the grafting procedure. The
neointimal area and wall thickness were measured by computerized planimetry, and
Ki-67 immunohistochemistry was used to detect replicative smooth muscle cells in
the graft wall. RESULTS: In each group, intimal hyperplasia was apparent at 1
week and increased gradually to 24 weeks. The number of Ki-67-positive cells was
most increased at 2 weeks after the grafting procedure and gradually decreased
thereafter. The numbers of Ki-67-positive cells and the extent of intimal
hyperplasia were not significantly different between normotensive and
hypertensive rats. Both neointima formation and cell proliferation in the graft
wall were significantly reduced by external stenting as compared with the results
with unstented grafts. CONCLUSION: Systemic hypertension by itself is not a risk
factor for intimal hyperplasia and experimental vein graft failure in the long
term. External stenting is effective against intimal hyperplasia, and it is
possible to reduce the subsequent atherosclerotic change of the vein graft wall
and improve the long-term patency of the vein graft with external stenting.
PMID- 10764273
TI - Histological effects of trigeminal nerve radiosurgery in a primate model:
implications for trigeminal neuralgia radiosurgery.
AB - OBJECTIVE: Stereotactic radiosurgical treatment of the proximal trigeminal nerve
is used to relieve the pain of trigeminal neuralgia. The mechanism of the
radiosurgical effect is not understood. METHODS: Two adult baboons underwent
stereotactic magnetic resonance imaging-guided radiosurgery, using a gamma knife.
A single 4-mm isocenter was targeted to each proximal trigeminal nerve, just
anterior to the pons, to deliver a maximal dose of 80 or 100 Gy (total of four
nerves). A nonirradiated baboon brain and nerves served as control specimens. Six
months after treatment, magnetic resonance imaging was again performed and the
brains and nerves were studied using light and electron microscopy. RESULTS:
Magnetic resonance imaging indicated a 4-mm-diameter area of contrast enhancement
at the target site in each nerve. All irradiated nerves exhibited axonal
degeneration and mild edema at the target, with remnants of some myelinated
axons. Large and small myelinated and unmyelinated fibers were affected. No
inflammation was observed. Nerve necrosis was identified after 100-Gy treatment.
The trigeminal ganglion appeared normal. CONCLUSION: Radiosurgery at 80 Gy causes
focal axonal degeneration of the trigeminal nerve. At higher doses, partial nerve
necrosis is observed. We think that these effects influence the physiological
features of trigeminal neuralgia.
PMID- 10764274
TI - Neurosurgery at the Royal Melbourne Hospital.
AB - The Department of Neurosurgery of the Royal Melbourne Hospital (RMH) is a major
neurosurgery program and academic leader in Australasia. In 1998, the RMH marked
its 150th anniversary. The department of neurosurgery was established in 1945
under the direction of R.S. Hooper and has produced many distinguished
neurosurgeons since its founding. The department is currently directed by Andrew
Kaye, who is also the James Stewart Professor of Surgery at the University of
Melbourne. In 1997-1998, the neurosurgery department received 2930 admissions and
performed 2225 operations, with 11 neurosurgeons on staff and a strong focus on
subspecialization. The neurosurgeons have varying time commitments to the
hospital and to research, but many are on site full-time. The RMH is a university
teaching hospital as well as a public hospital; therefore, there is no financial
burden for any patient. The RMH is closely linked to the adjacent Melbourne
Private Hospital, where privately insured patients are treated. The department of
neurosurgery maintains close links with the departments of neurology,
ophthalmology, and neuropsychiatry, which together form the Melbourne
Neuroscience Centre. There is a strong emphasis on undergraduate and postgraduate
teaching, as well as clinical and laboratory research. Neurosurgery trainees are
encouraged to undertake laboratory research and pursue higher academic degrees.
Despite economic restraints, the department continues to grow in strength, and we
remain optimistic of exciting times ahead for neurosurgery at the RMH in the new
millennium.
PMID- 10764275
TI - Lumbar radiculopathy secondary to gouty tophi in the filum terminale in a patient
without systemic gout: case report.
AB - OBJECTIVE AND IMPORTANCE: Gouty arthritis and gouty tophi of the spine are very
rare. We present a patient with the clinical manifestations of an intradural
tumor and histologically proven gouty deposits in the filum terminale. CLINICAL
PRESENTATION: The patient presented with typical symptoms of lumbar radiculopathy
and neurogenic claudication. There was no evidence of peripheral gout.
INTERVENTION: Imaging studies, including computed tomography and magnetic
resonance imaging, demonstrated a 1-cm, round, intradural, calcified lesion at
the L3 vertebral level, causing moderate spinal stenosis. The patient underwent a
two-level laminectomy and removal of the mass. A pathological examination of the
specimen revealed gouty deposits in the region of the filum terminale.
CONCLUSION: Spinal involvement in gout is very rare, and intradural gouty
deposits have not been previously described. Intradural gout should be considered
in the differential diagnosis of intradural masses.
PMID- 10764276
TI - Multilevel thoracic pedicle aplasia causing congenital thoracic kyphosis: case
report.
AB - OBJECTIVE AND IMPORTANCE: Congenital thoracic kyphosis is a rare cause of
treatable myelopathy. Multilevel thoracic pedicle aplasia as a cause of this
deformity has not been previously reported in the literature. We report a case
and describe the surgical management and outcome. CLINICAL PRESENTATION: A 14
year-old boy presented to us with a 4-month history of back pain and slowly
progressive spastic paraparesis. Radiographic studies revealed thoracic kyphosis
and bilateral aplasia of the pedicles of T4-T8. INTERVENTION: The patient
underwent surgical treatment via a posterior approach for decompression of T4-T8,
followed by arthrodesis from T2 to T12, using a hook claw construct with multiple
points of fixation and autologous bone grafting. CONCLUSION: Congenital vertebral
anomalies may be clinically occult, and delayed presentation may occur in
adolescence or adulthood. Aplasia of multiple thoracic pedicles can produce
kyphotic deformities with neurological compromise. A posterior approach with
multiple points of segmental instrumentation can be effective in treating
kyphotic deformities that are flexible and of moderate severity (<75 degrees).
PMID- 10764277
TI - Pediatric atlas fracture: a case of fracture through a synchondrosis and review
of the literature.
AB - OBJECTIVE AND IMPORTANCE: Although uncommon, atlas fractures occur in the
pediatric population. We present an illustrative case of a patient with a
fracture through a synchondrosis of the atlas, and we review previous reports of
pediatric first cervical vertebral fractures. The clinical and radiographic
findings are described. In addition, we describe the use of magnetic resonance
imaging in characterizing a pediatric atlas fracture. CLINICAL PRESENTATION: A 6
year-old boy who fell from a tree onto his vertex presented with neck pain,
cervical muscle spasm, and head tilt. Computed tomographic and magnetic resonance
imaging studies demonstrated a fracture through a left anterior synchondrosis
with surrounding edema. In the literature, 10 cases of pediatric atlas fracture
have been reported. INTERVENTION: Treatment of pediatric atlas fractures consists
of rigid bracing such as a Minerva jacket. All of the cases of isolated C1
fracture in children, except the patient originally described by Sir Geoffrey
Jefferson, survived and recovered with full function. Surgery is rarely indicated
for isolated atlas fractures. CONCLUSION: The classic clinical presentation,
combined with an appropriate injury scenario, should alert the clinician to the
possibility of a pediatric atlas fracture and should prompt rapid evaluation with
imaging studies to establish a diagnosis. When the injury is appropriately
diagnosed and treated, an excellent outcome can be expected.
PMID- 10764278
TI - Xanthoma of the temporal bone: case report.
AB - OBJECTIVE AND IMPORTANCE: Xanthomas of the cranium that are not accompanied by
endocrine or metabolic abnormalities are extremely rare. It is very important to
understand the pathological features of this disease, for differential diagnosis
from other diseases. CLINICAL PRESENTATION: A 62-year-old woman presented to the
hospital with headaches. Cranial x-rays revealed bone destruction in the right
temporal bone, with osteosclerosis in the area surrounding the lesion. In
computed tomographic scans, the bone cortex was intact and the diploe was dilated
because of the large mass of the lesion. T1-weighted magnetic resonance imaging
findings were heterogeneous, with areas of hypo- and isointensity; T2-weighted
magnetic resonance imaging findings were also heterogeneous, with areas of hypo-
and hyperintensity. INTERVENTION: Total removal of the tumor was performed,
followed by cranioplasty using artificial bone. DIAGNOSIS: Histologically, lipid
containing foamy cells were dense and a cholesterin granuloma was observed. There
was no reason to infer other diseases, and a diagnosis of xanthoma of the
temporal bone was reached. CONCLUSION: Xanthomatous lesions are observed in
various pathological conditions, including malignant diseases. Xanthomas are
benign lesions and the prognoses for patients with these lesions are
satisfactory, even after partial excision. Therefore, it is quite important to
distinguish xanthomas from other diseases that produce xanthomatous lesions.
PMID- 10764279
TI - Cerebral infarction after neuroendoscopic third ventriculostomy: case report.
AB - OBJECTIVE AND IMPORTANCE: This case illustrates an unusual complication of
neuroendoscopic third ventriculostomy. CLINICAL PRESENTATION: A 30-year-old man
with established hydrocephalus was treated with neuroendoscopic third
ventriculostomy during which bleeding occurred from a vessel deep in the floor of
the third ventricle. He subsequently had a third nerve palsy and developed
frontal lobe infarction. INTERVENTION: The complication was treated
conservatively. The patient subsequently required shunting. CONCLUSION: The cause
of the infarction is discussed. The general issue of complications of this
procedure is explored with a call for more open reporting of such occurrences.
PMID- 10764280
TI - Spontaneous pneumocephalus in the posterior fossa in a patient with a
ventriculoperitoneal shunt: case report.
AB - OBJECTIVE AND IMPORTANCE: A unique case of spontaneous pneumocephalus is
described. It appeared a few years after the uneventful introduction of a
cerebrospinal fluid shunt and was probably attributable to a defect of the
posterior mastoid plate. CLINICAL PRESENTATION: A 65-year-old man presented with
a subacute onset of vertigo, vomiting, and atactic gait instability. The patient
had undergone a ventriculoperitoneal shunt implantation 2 years previously for
communicating hydrocephalus. A computed tomographic scan revealed a posterior
fossa pneumatocele without hydrocephalus. INTERVENTION: A simple mastoidectomy
was performed. Detection of the area of the bone defect was followed by mastoid
obliteration with abdominal fat. CONCLUSION: Clinicians should be aware that
pneumocephalus can occur spontaneously, with or without obvious shunt problems.
Treatment should be directed toward the area through which air penetrated the
posterior fossa.
PMID- 10764281
TI - Precise cannulation of the foramen ovale in trigeminal neuralgia complicating
osteogenesis imperfecta with basilar invagination: technical case report.
AB - OBJECTIVE AND IMPORTANCE: Trigeminal neuralgia is a rare feature of basilar
invagination, which is itself a complication of osteochondrodysplastic disorders.
Microvascular decompression is an unattractive option in medically refractory
cases. The conventional percutaneous approach to the trigeminal ganglion is
anatomically impossible because the foramen ovale points inferiorly and
posteromedially. We report a new technique for image-guided trigeminal injection
in a patient with basilar invagination complicating osteogenesis imperfecta.
CLINICAL PRESENTATION: A 26-year-old woman with osteogenesis imperfecta presented
with a 3-year history of typical left maxillary division trigeminal neuralgia,
which was poorly controlled by carbamazepine at the maximum tolerated dose. She
had obvious cranial deformities, left optic atrophy, delayed left eye closure,
tongue atrophy, but normal facial sensation and corneal reflexes. A computed
tomographic scan and magnetic resonance imaging confirmed severe basilar
invagination. TECHNIQUE: Frameless stereotactic glycerol injection of the left
trigeminal ganglion was performed under general anesthesia using the infrared
based EasyGuide Neuro system (Philips Medical Systems, Best, The Netherlands)
with magnetic resonance imaging and computed tomographic registration. The
displaced and distorted left foramen ovale was cannulated via a true frameless
stereotactic method with the trajectory determined by virtual pointer elongation.
The needle placement was confirmed with injection of contrast medium into the
trigeminal cistern. The path needed to enter the foramen traversed the right
cheek, soft palate, and left tonsil. The patient went home pain-free with a
preserved corneal reflex and no complications. CONCLUSION: Frameless stereotaxy
allows customization to individual patient anatomy and may be adapted to a
variety of percutaneous procedures used in areas where the anatomy is complex.
PMID- 10764282
TI - Brachial plexus catheter reservoir for the treatment of upper-extremity cancer
pain: technical case report.
AB - OBJECTIVE AND IMPORTANCE: Infiltration of the brachial plexus with anesthetics
can provide relief of upper-extremity pain from invasive cancer. Because the
analgesia is short-lived, however, repeated invasive treatments are necessary. We
describe the implantation of a catheter reservoir system, in which anesthetic
injections through a subcutaneous port resulted in anesthetic infiltration of the
brachial plexus. CLINICAL PRESENTATION: A 47-year-old Hispanic man with squamous
cell carcinoma of the larynx had undergone surgical resection, radiation
treatment, and chemotherapy. Two years later, he had locally recurrent disease
involving the brachial plexus, neck, and chest wall. The patient's pain was
minimally responsive to narcotics, which also caused severe nausea and anorexia.
TECHNIQUE: The brachial plexus was localized percutaneously with a needle
electrode stimulator. Contrast injection under fluoroscopy confirmed entry into
the plexus sheath. With use of the Seldinger technique, two Silastic catheters
were placed within the brachial plexus and attached with a "Y" connector to a
reservoir. The patient experienced complete relief of upper-extremity pain after
a test injection with xylocaine. Thereafter, serial injections of bupivacaine
with triamcinolone at 1-week intervals provided complete pain relief. After the
treatments were initiated, the patient reported improved sleep and an improvement
in his quality of life. CONCLUSION: A catheter reservoir system for brachial
plexus analgesia can provide safe and effective analgesia for upper-extremity
pain. This technique negates the need for repeated invasive procedures and avoids
the complications of neurolysis.
PMID- 10764283
TI - Parent vessel Guglielmi detachable coil herniation during wide-necked aneurysm
embolization: treatment with intracranial stent placement: two technical case
reports.
AB - OBJECTIVE AND IMPORTANCE: Despite recent advances in technology, parent vessel
coil herniation occasionally complicates successful Guglielmi detachable coil
embolization, particularly in wide-necked aneurysms. We report endovascular stent
deployment performed in two patients specifically to treat this complication.
CLINICAL PRESENTATION: Two patients underwent Guglielmi detachable coil
embolization of cavernous segment aneurysms. Both developed coil herniation into
the internal carotid artery. In one patient, the herniation occurred during the
initial procedure; in the other, it was discovered in a delayed fashion during a
follow-up examination for ocular symptoms. INTERVENTION: In both patients,
endovascular stent deployment was performed to isolate the herniated portion of
the coil from the internal carotid lumen. Follow-up angiography at 6 months
demonstrated no aneurysm recanalization and no stenosis of the parent internal
carotid artery in the stented region in either patient. CONCLUSION: The use of
intraluminal stents has been reported to be a helpful technical adjunct to the
conventional endovascular treatment of aneurysms and balloon angioplasty. One
additional indication for the use of this technology is sequestering herniated
coils from the lumen of the parent artery to reduce potential embolic or
occlusive sequelae.
PMID- 10764284
TI - Pre- versus post-anterior clinoidectomy measurements of the optic nerve, internal
carotid artery, and opticocarotid triangle: a cadaveric morphometric study.
AB - OBJECTIVE: Published morphometric data supporting the microsurgical advantages of
anterior clinoidectomy are scant. The goal of this study was to quantify, with
direct measurements, the improved exposure of the optic nerve, internal carotid
artery (ICA), and opticocarotid triangle (OCT) after extradural removal of the
anterior clinoid process. METHODS: Ten formalin-fixed adult cadaver heads were
dissected bilaterally, and measurements were made both before and after anterior
clinoidectomy. Twenty sets of pre- and post-anterior clinoidectomy measurements
were collected, consisting of: 1) optic nerve length from the optic chiasm to the
optic canal (pre) and to the anulus of Zinn (post); 2) ICA length from the ICA
bifurcation to the distal limit of the anterior clinoid process (pre) and to the
ICA distal dural ring (post); 3) OCT width, the widest in situ distance between
the optic nerve and the ICA (pre) and the analogous measurement with allowable
retraction on the mobilized ICA and optic nerve (post); and 4) OCT length from
the point where the A1 segment crosses the optic chiasm to the optic canal (pre)
and to the anulus of Zinn (post). RESULTS: The right and left combined mean
values +/- standard error of the mean before and after removal of the anterior
clinoid process, respectively, were: optic nerve length, 10.28 +/- 2.30 mm and
22.83 +/- 2.54 mm; ICA length, 10.48 +/- 2.39 mm and 14.78 +/- 3.02 mm; OCT
width, 3.93 +/- 1.16 mm and 12.95 +/- 2.61 mm; and OCT length, 10.38 +/- 2.84 mm
and 23.55 +/- 2.79 mm. CONCLUSION: Anterior clinoidectomy can provide a twofold
increase in exposure of the optic nerve length and the OCT length, as well as a
three- to fourfold increase in the maximum OCT width. This dramatically improves
surgical exposure in the suprasellar and periclinoid regions.
PMID- 10764285
TI - Simple risk predictions for arteriovenous malformation hemorrhage.
PMID- 10764286
TI - Contemporary management of spinal osteomyelitis.
PMID- 10764287
TI - Stereotactic radiosurgery for trigeminal schwannomas.
PMID- 10764288
TI - Stereotactic targeting of the globus pallidus internus in Parkinson's disease:
imaging versus electrophysiological mapping.
PMID- 10764289
TI - Serum S-100B protein in severe head injury.
PMID- 10764290
TI - Introducing the "Update in Nonpulmonary Critical Care" series.
PMID- 10764291
TI - The rapidly changing management of cardiac arrhythmias.
PMID- 10764292
TI - Surfactant deficiency in hyaline membrane disease: the story of discovery.
PMID- 10764293
TI - Predicting the outcome of therapy for pulmonary tuberculosis.
AB - Patients vary considerably in their response to treatment of pulmonary
tuberculosis. Although several studies have indicated that adverse outcomes are
more likely in those patients with delayed sputum sterilization, few tools are
available to identify those patients prospectively. In this study, multivariate
models were developed to predict the response to therapy in a prospectively
recruited cohort of 42 HIV-uninfected subjects with drug-sensitive tuberculosis.
The cohort included 2 subjects whose initial response was followed by drug
sensitive relapse. The total duration of culture positivity was best predicted by
a model that included sputum M. tuberculosis antigen 85 concentration on Day 14
of therapy, days-to-positive in BACTEC on Day 30, and the baseline radiographic
extent of disease (R = 0.63). A model in which quantitative AFB microscopy
replaced BACTEC also performed adequately (R = 0.58). Both models predicted
delayed clearance of bacilli in both relapses (> 85th percentile of all subjects)
using information collected during the first month of therapy. Stratification of
patients according to anticipated response to therapy may allow TB treatment to
be individualized, potentially offering superior outcomes and greater efficiency
in resource utilization, and aiding in the conduct of clinical trials.
PMID- 10764294
TI - A new preadmission staging system for predicting inpatient mortality from HIV
associated Pneumocystis carinii pneumonia in the early highly active
antiretroviral therapy (HAART) era.
AB - A common severe complication of human immunodeficiency virus (HIV) infection has
been Pneumocystis carinii pneumonia (PCP). Recently, with increasing use of PCP
prophylaxis and multidrug antiretroviral therapy, the clinical manifestations of
HIV infection have changed dramatically and the predictors of inpatient mortality
for PCP may have also changed. We developed a new staging system for predicting
inpatient mortality for patients with HIV-associated PCP admitted between 1995
and 1997. Trained abstractors performed chart reviews of 1,660 patients
hospitalized with HIV-associated PCP between 1995 and 1997 at 78 hospitals in
seven metropolitan areas in the United States. The overall inpatient mortality
rate was 11.3%. Hierarchically optimal classification tree analysis identified an
ordered five-category staging system based on three predictors: wasting, alveolar
arterial oxygen gradient (AaPO(2)), and serum albumin level. The mortality rate
increased with stage: 3.7% for Stage 1, 8.5% for Stage 2, 16.1% for Stage 3,
23.3% for Stage 4, and 49.1% for Stage 5. This new staging system may be useful
for severity of illness adjustment in the current era while exploring current
variation in HIV-associated PCP inpatient mortality rates among hospitals and
across cities.
PMID- 10764295
TI - Cardiac contractility is not depressed in early canine endotoxic shock.
AB - We investigated effects of acute endotoxemia (Escherichia coli endotoxin, 1
mg/kg, intravenously) on left ventricular (LV) function in the first 4 h after
induction of endotoxic shock in anesthetized canine preparations (n = 7 each,
endotoxin and control groups). LV pressure and conductance (volume) catheters
were used to construct pressure-volume loops. Transient inferior vena cava
occlusion was used to rapidly and reversibly alter LV end-diastolic volume. LV
contractility was assessed from the slope of the LV end-systolic pressure-volume
relationship (Ees) and from preload-recruitable stroke work (PRSW), and from
their change (DeltaEes and DeltaPRSW, respectively, measured at 2 and 4 h only),
in response to a dobutamine infusion (5 microg/kg/min). Diastolic function and
arterial tone were assessed as the maximal negative change in filling pressure
versus time (max -dP/dt), filling rate, and arterial elastance (Ea),
respectively. Ees, PRSW, Ea, diastolic function, and hemodynamics were measured
hourly. Endotoxemia induced an immediate hypotensive, hyperdynamic, tachycardic
state with progressive lactic acidosis. By 2.5 h after endotoxin infusion, heart
rate returned to preendotoxin and control levels, but the other changes remained.
However, no change occurred in LV Ees, DeltaEes, PRSW, DeltaPRSW, diastolic
function, or Ea during the 4-h measurement interval. The cardiovascular collapse
seen during the first 4 h of endotoxemia is therefore not due even partly to
alterations in LV contractility.
PMID- 10764296
TI - Quality control of spirometry in the elderly. The SA.R.A. study. SAlute
Respiration nell'Anziano = Respiratory Health in the Elderly.
AB - We evaluated the outcome of the spirometry quality control program of the SA.R.A.
multicenter project, the aim of which is the multidimensional assessment of
asthma and COPD in the elderly (>/= 65 yr). The factors determining this quality
were also evaluated. The program was based on standardized procedures (ATS
recommendations), performed by specifically trained and certified personnel; a
fully-computerized spirometer with customized software was used for spirometry. A
reference center made monthly controls. Overall, 638 cases and 984 controls were
examined. Spirometric measurements were obtained in 607 cases and 912 controls;
508 and 747 tests with at least three acceptable curves were obtained in cases
and in controls, respectively (NS). The percentage of reproducible tests ranged
between 95.8% for FEV(1) in controls and 87.6% for FVC in cases. The average
reproducibility for FEV(1) was 61.6 ml in cases and 58.3 ml in controls (NS).
Cognitive impairment, shorter 6-min walk distance, and lower educational level
were found to be independent risk factors for a poorer acceptability rate
(logistic regression analysis). Male sex and age were risk factors for a poorer
reproducibility of FEV(1). Reproducibility tended to improve with time (p <
0.001). Although spirometry becomes increasingly difficult in aging patients, a
rigorous quality control program can ensure that reliable data are obtained in
the majority of patients.
PMID- 10764297
TI - Ethnic differences in pulmonary function in healthy nonsmoking Asian-Americans
and European-Americans.
AB - We investigated ethnic differences in spirometry and gas transfer (DL(CO)) in a
young, healthy population of nonsmoking physicians and medical students aged 22
33 yr, of European or Asian descent. Each answered questions detailing ethnic
background, medical history, level of physical activity, and length of residence
in the United States. Spirometry and single-breath DL(CO) maneuvers were
performed in accordance with ATS standards. Venous blood was measured for
hemoglobin (Hb). The same equipment was used to test all subjects. Data were
analyzed by multiple linear regression. Eighty subjects were studied, with 20 in
each of the following groups: European male, European female, Asian male, and
Asian female. Asian values for forced vital capacity, forced expiratory volume in
1 s (FEV(1)), and alveolar volume (VA') were significantly lower than for
Europeans, but DL(CO), DL(CO)/VA', and DL(CO)/VA'/Hb did not differ
significantly. These differences could not be attributed to age, length of
residence in the United States, activity level, or variance in baseline
characteristics and anthropometric measurements, and therefore represent a true
physiologic difference. Ethnic differences between individuals of Asian and
European backgrounds should be considered when interpreting pulmonary function
tests, especially when predicted values are based on populations of European
descent.
PMID- 10764298
TI - Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD.
The Association of Non-University Affiliated Intensive Care Specialist Physicians
of France.
AB - Low molecular weight heparins are as effective as unfractionated heparin in deep
vein thrombosis (DVT) prophylaxis for major surgery. However, there is no
evidence nor consensus for prophylaxis in medical patients. We compared the
efficacy and safety of nadroparin calcium (nadroparin) with placebo in medical
patients at high risk of DVT. A total of 223 patients mechanically ventilated for
acute, decompensated chronic obstructive pulmonary disease, were randomized to
treatment with subcutaneous nadroparin adjusted for body weight (0.4 ml, i.e.,
3,800 AXa IU, or 0.6 ml, i.e., 5,700 AXa IU) or placebo. The average duration of
treatment was 11 d. The incidence of DVT in patients receiving nadroparin was
significantly lower than that in patients receiving placebo (15.5 versus 28.2%; p
= 0.045). Although the incidence of adverse events was high in both groups, there
were no significant differences between nadroparin and placebo for total adverse
events (46.3 versus 39.8%; p = 0.33), serious adverse events (25.0 versus 19.5%;
p = 0.32), or those resulting in early permanent discontinuation of treatment
(12.0 versus 8.8%; p = 0.44). The most common adverse event was hemorrhage. There
was the same number of deaths in both treatment groups. Subcutaneous nadroparin
resulted in 45% decrease in incidence of DVT compared with placebo.
PMID- 10764299
TI - Physiologic determinants of ventilator dependence in long-term mechanically
ventilated patients.
AB - To investigate the pathophysiologic mechanisms of ventilator dependence, we took
physiologic measurements in 28 patients with COPD and 11 postcardiac surgery
(PCS) patients receiving long-term mechanical ventilation during a spontaneous
breathing trial, and in 20 stable, spontaneously breathing patients matched for
age and disease. After 40 +/- 14 min of spontaneous breathing, 20 of 28 patients
with COPD and all 11 PCS patients were judged ventilator-dependent (VD). We found
that in the 31 VD patients tidal volume was low (VT: 0.36 +/- 0.12 and 0.31 +/-
0.08 L for COPD and PCS, respectively), neuromuscular drive was high (P(0.1): 5.6
+/- 1. 6 and 3.9 +/- 1.9 cm H(2)O), inspiratory muscle strength was reduced
(Pdi(max): 42 +/- 12 and 28 +/- 15 cm H(2)O), and lung mechanics were abnormal,
particularly PEEPi (5.9 +/- 3.0 cm H(2)O) and lung resistance (22.2 +/- 9.2 cm
H(2)O/L/s) in COPD. The load/capacity balance was altered (Pdi/Pdi(max) and
Ppl/Ppl(max) > 0.4) and the effective inspiratory impedance was high
(P(0.1)/VT/TI >/= 10 cm H(2)O/L/s). Failure to wean occurred in patients with
f/VT > 105 breaths/min/L and 56% of patients with COPD with f/VT < 80
breaths/min/L. Those who failed despite a low f/VT ( < 80 breaths/min/L) either
showed ineffective inspiratory efforts, which artificially lowered f/ VT (n = 8),
or did not increase breathing frequency (n = 5), but P(0.1) and P(0.1)/VT/TI were
as high as in other VD patients. In the 31 VD patients, Pa(CO(2)) increased
during the weaning trial (+12.3 +/- 8.0 mm Hg). We conclude that in the presence
of a high drive to breathe, the imbalance between increased work load and reduced
inspiratory muscle strength causes respiratory distress and CO(2) retention.
Noninvasive measurements (breathing pattern, P(0.1), P(0.1)/ VT/TI) may give
better insight into weaning failure useful in clinical decision-making,
particularly in patients with COPD not showing rapid shallow breathing (56% in
this study).
PMID- 10764300
TI - Sleep deprivation per se does not decrease the hypercapnic ventilatory response
in humans.
AB - Several studies have found that sleep deprivation reduces the hypercapnic
ventilatory response (HCVR). Such results may have been affected by uncontrolled
activities or environmental influences during the sleep deprivation period. The
current study determined the "pure" effect of sleep deprivation on respiratory
control under strictly controlled behavioral and environmental conditions. After
2 d of acclimation in the laboratory, 10 subjects maintained wakefulness
(confirmed by EEG), a constant semirecumbent posture, ate regular small meals,
had constant interaction with experimenters, and stayed in an environment with
constant low light (10 lux) and constant room temperature for 41 consecutive
hours. Measurements of HCVR, resting ventilation, V O(2) and V CO(2) were
performed every 2 h. Comparisons were made of six pairs of measurements, with
each pair separated by 24 h of sleep deprivation. None of the respiratory
variables changed significantly with 24 h of sleep deprivation. Mean HCVR
increased by 17% with sleep deprivation (3.12 versus 3.54 L x min(-1) x mm Hg(
1); not significant). These results show that sleep deprivation per se does not
reduce the sensitivity of central chemoreceptors nor change resting ventilation
or metabolism. The reduced HCVR after sleep loss found in previous studies may
have been affected by uncontrolled activities or environmental influences during
sleep deprivation periods.
PMID- 10764301
TI - Respiratory function in survivors of the United Kingdom Extracorporeal Membrane
Oxygenation Trial.
AB - Extracorporeal membrane oxygenation (ECMO) improves survival in mature neonates
with reversible lung disease. However, ECMO could result in survival of infants
with severe respiratory dysfunction who would otherwise have died. Alternatively,
infants receiving ECMO might be spared prolonged ventilation and consequent
barotrauma, resulting in improved respiratory function. Our aim was to compare
respiratory function at 1 yr of age in infants assigned to receive either ECMO or
conventional management (CM). Seventy-eight surviving infants of the United
Kingdom (UK) ECMO trial (51 in the ECMO group) were studied at 1 yr of age.
Questionnaires provided details of respiratory symptoms, and laboratory
measurements of respiratory function were made for respiratory rate, tidal
volume, lung volume, airway conductance, specific airway conductance, and maximal
expiratory flow at FRC (Vmax (FRC)). Data were exchanged on floppy disk for cross
analysis and to ensure that investigators were blinded to the status of the
infants. There was a wide spectrum of respiratory function, from normal to
markedly abnormal. There were few differences between the groups, but in the CM
group lung volume was increased (95% confidence intervals [CIs] of the difference
in ECMO versus CM subjects: -67; -4 ml), and inspiratory specific conductance was
lower (95% CI: 0.03; 0.98 s(-)(1). kPa(-)(1)). There was a trend toward a lower V
max(FRC) (95% CI: -2; 67 ml/s(-)(1) in the CM group. In addition to providing a
survival advantage, ECMO did not worsen lung function in infants assigned to
receive it. Indeed, their lung function appeared slightly better than that of
infants treated conventionally.
PMID- 10764302
TI - Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in
stable chronic obstructive pulmonary disease.
AB - Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic
bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A
multicenter, randomized, double-blind, parallel group, placebo-controlled study
was conducted to evaluate the dose-response characteristics of tiotropium
inhalation powder given once daily to stable patients with chronic obstructive
pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were
randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon
for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients
measured and recorded their peak expiratory flow rates (PEFRs) three times each
day. Significant dose-related improvement in FEV(1) and significant improvement
in FVC occurred within 1 h after the first dose of tiotropium as compared with
placebo. Over the 29 d of the study, all doses of tiotropium produced significant
increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h
after the previous dose and just before the next dose of tiotropium), peak, and 6
h postdose average FEV(1) and FVC, and in PEFR, without a significant difference
among the different doses investigated. PEFR gradually returned to pretreatment
baseline levels over a 3-wk evaluation period following the discontinuation of
tiotropium. The overall safety profile for the tiotropium doses was similar to
that for placebo. In summary, tiotropium was shown to be safe and effective in
doses ranging from 4.5 to 36 microg delivered once daily. The improvements in
spirometry with once-daily dosing confirm the long duration of action of
tiotropium reported in single-dose studies, and its sustained improvement of
spirometric measures over the 1 mo of testing in the study points to utility of
tiotropium as a maintenance bronchodilator for patients with COPD. On the basis
of the comparable bronchodilator response at doses from 9 to 36 microg, and
advantages suggested by the safety profile at doses below 36 microg in this
study, a dose of 18 microg once daily was selected for use in long-term studies
of the safety and efficacy of tiotropium.
PMID- 10764303
TI - Exogenous granulocyte-macrophage colony-stimulating factor administration for
pulmonary alveolar proteinosis.
AB - Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the
accumulation of lipoproteinaceous material within the alveoli. Recent data
suggest that granulocyte-macrophage colony- stimulating factor (GM-CSF) may be
involved in the pathogenesis of PAP. To extend this understanding and clarify
whether GM-CSF replacement confers benefit, we report the preliminary results for
the first four patients in an open-label study of GM-CSF treatment for moderate
exacerbation of PAP. All four patients had idiopathic PAP confirmed by open lung
biopsy. Subcutaneous GM-CSF was self-administered once daily for 12 wk (dose
escalation from 3 to 9 microg/kg/d). Response was assessed from symptom scores,
arterial blood gas measurements, pulmonary function testing, and chest
radiographs. Three of the four patients experienced symptomatic, physiologic, and
radiographic improvement with GM-CSF. Responders experienced sufficient
improvement in oxygenation as to eliminate the need for supplemental oxygen, and
one patient was removed from the waiting list for lung transplantation. Improved
oxygenation was not apparent until 8 to 12 wk after the start of therapy.
Notably, expected increases in the peripheral white blood cell count did not
occur, suggesting lack of a hematopoietic response to exogenous GM-CSF in PAP. We
conclude that GM-CSF appears to benefit a subset of patients with adult PAP, and
may represent an alternative to whole-lung lavage in treating the disease.
PMID- 10764304
TI - The treatment of acidosis in acute lung injury with tris-hydroxymethyl
aminomethane (THAM).
AB - Mechanical hyperventilation of acidemic patients with acute lung injury (ALI)
requires the use of high volumes and pressures that may worsen lung injury.
However, permissive hypercapnia in the presence of shock, metabolic acidosis, and
multi-organ system dysfunction may compromise normal cellular function. Tris
hydroxymethyl aminomethane (THAM) may be an effective method to control acidosis
in this circumstance. Protonated THAM is excreted by the kidneys, so that carbon
dioxide production is not raised. In an uncontrolled study, we administered THAM
to 10 patients with acidosis (mean pH = 7.14) and ALI (mean lung injury score =
3.28) in whom adequate control of arterial pH could not be maintained during
either eucapnic ventilation or permissive hypercapnia ventilation. THAM was given
at a mean dose of 0.55 mmol/kg/h. Administration of THAM was associated with
significant improvements in arterial pH and base deficit, and a decrease in
arterial carbon dioxide tension that could not be fully accounted for by
ventilation. Although further studies are needed to confirm these observations,
THAM appears to be an effective alternative to sodium bicarbonate for treating
acidosis during ALI.
PMID- 10764305
TI - DETANONOate, a nitric oxide donor, decreases amiloride-sensitive alveolar fluid
clearance in rabbits.
AB - Inhaled nitric oxide (NO) has been administered to animals to selectively reduce
pulmonary hypertension via NO donors such as the NONOates. However, vectorial
Na(+) transport across confluent monolayers of alveolar type II (ATII)
pneumocytes has been decreased by NO. We tested the hypothesis that
administration of the NO donor, DETANONOate, would decrease alveolar fluid
clearance (AFC) in the rabbit in vivo. We instilled a solution of 5% albumin in
0.9% NaCl with 3 mM DETANONOate into anesthetized rabbits. Two hours later,
similar AFC values were measured in the presence and absence of 3 mM DETANONOate
(38 +/- 12% versus 43 +/- 13%; mean +/- SD). However, animals coadministered 1 mM
amiloride with one of three doses of DETANONOate (100 microM, 300 microM, or 3
mM) had significantly (p < 0.05) greater AFC values (23 +/- 8, 20 +/- 14, 28 +/-
12%, respectively) than those administered amiloride alone (10 +/- 7%). When 5%
albumin in a Cl(-)-free solution was administered in the presence or absence of
100 microM DETANONOate, neither AFC values nor alveolar Cl(-) concentrations were
different. DETANONOate decreases the amiloride-sensitive fraction of AFC but does
not decrease total AFC. DETANONOate does not influence total AFC secondary to an
increase in the amiloride-insensitive fraction of AFC that is not associated with
a decrease in alveolar Cl(-) secretion.
PMID- 10764306
TI - Clinical evaluation of a computer-controlled pressure support mode.
AB - We have designed a computerized system providing closed-loop control of the level
of pressure support ventilation (PSV). The system sets itself at the lowest level
of PSV that maintains respiratory rate (RR), tidal volume (VT), and end-tidal
CO(2) pressure (PET(CO(2))) within predetermined ranges defining acceptable
ventilation (i.e., 12 < RR < 28 cycles/min, VT > 300 ml [> 250 if weight < 55
kg], and PET(CO(2)) < 55 mm Hg [< 65 mm Hg if chronic CO(2) retention]). Ten
patients received computer-controlled (automatic) PSV and physician-controlled
(standard) PSV, in random order, during 24 h for each mode. An estimation of
occlusion pressure (P(0.1)) was recorded continuously. The average time spent
with acceptable ventilation as previously defined was 66 +/- 24% of the total
ventilation time with standard PSV versus 93 +/- 8% with automatic PSV (p <
0.05), whereas the level of PSV was similar during the two periods (17 +/- 4 cm
H(2)O versus 19 +/- 6 cm H(2)O). The time spent with an estimated P(0.1) above 4
cm H(2)O was 34 +/- 35% of the standard PSV time versus only 11 +/- 17% of the
automatic PSV time (p < 0.01). Automatic PSV increased the time spent within
desired ventilation parameter ranges and apparently reduced periods of excessive
workload.
PMID- 10764307
TI - Comparison testing of current (PPD-S1) and proposed (PPD-S2) reference tuberculin
standards.
AB - Since 1951, the tuberculin PPD-S1 has been used to standardize commercial PPD
reagents and perform special tuberculin surveys. PPD-S1 is now in short supply
and a new standard (PPD-S2) has been manufactured. To determine if PPD-S2 is
equivalent and can replace PPD-S1, we conducted a double-blind clinical trial.
Between May 14 and October 28, 1997, 69 subjects with a history of culture-proven
tuberculosis (TB patients) and 1,189 subjects with a very low risk for TB
infection were enrolled, received four skin tests (with PPD-S1, PPD-S2, and one
each of the commercially available PPDs), and had reactions measured by two
trained observers. Among the TB patients, we found statistically
indistinguishable immunogenicity (mean reaction size +/- standard deviation):
15.6 +/- 6.6 mm for PPD-S1 and 14.8 +/- 5.6 mm for PPD-S2. Among low-risk
subjects, the tests had equally high specificities (PPD-S1, 98.7% and PPD-S2, 98.
5%), using a 10-mm cutoff. The number of discordant (negative versus positive)
interpretations for PPD-S2, assuming that low-risk subjects who had a >/= 10 mm
reaction to PPD-S1 were truly infected, was low (0.5%) and indistinguishable from
the rate of discordant interpretations of the same test when read by two
different observers (0.8%). The study results indicate that PPD-S2 is qualified
to be used as the new U.S. reference standard for PPD tuberculin.
PMID- 10764308
TI - Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no
therapy on survival.
AB - The clinical records of 487 patients seen at Mayo Clinic Rochester (MCR) during
1994 through 1996 who were diagnosed as having idiopathic pulmonary fibrosis of
the usual interstitial pneumonia type (IPF/UIP) were reviewed. Computed
tomography (CT) had been done in 94.7% of patients and surgical open lung biopsy
(OLB) in 20.3%. Median survival was 3.2 yr. We compared survival as a function of
treatment program, based on intent to treat at the time of the initial contact
within the study window. Treatment advised included colchicine alone in 167, no
therapy in 157, prednisone at maintenance dosages alone in 54, colchicine plus
prednisone in 71, and other programs in 38. Oxygen therapy was advised in 133
patients. By univariate analysis, worse survival was associated with prednisone
therapy compared with no therapy, and with oxygen therapy compared with no oxygen
therapy. However, on multivariate analysis, worse survival was associated with
older age, male gender, lower diffusing capacity for carbon monoxide (DL(CO)),
lower alveolar volume (VA), and a history of worsening pulmonary function. When
adjustment was made for these factors, there was no significant difference in
survival between those patients treated with colchicine or prednisone and those
on no therapy, and no difference between those on oxygen therapy and those
without oxygen.
PMID- 10764309
TI - The relationship between chronic hypoxemia and activation of the tumor necrosis
factor-alpha system in patients with chronic obstructive pulmonary disease.
AB - Although circulating tumor necrosis factor (TNF)-alpha levels have been found to
be increased in weight-losing patients with chronic obstructive pulmonary disease
(COPD), the main causes for this phenomenon remain to be elucidated. Since
hypoxia itself can enhance the production of the TNF-alpha in vitro, we studied
the relationship between hypoxemia and activities of the TNF-alpha system,
including circulating TNF-alpha and soluble TNF-receptors (sTNF-R; sTNF-R55 and
R75) levels, in 27 COPD patients and 15 age-matched healthy controls. The COPD
patients showed a significant weight loss (body mass index = 18.1 +/- 2.8 versus
22.8 +/- 2.2 [mean +/- SD] kg/m(2); p < 0.0001. % fat = 16.3 +/- 5.9 versus 24.3
+/- 4.9 %; p < 0.001), and hypoxemia (Pa(O2 )= 62.2 +/- 9.5 versus 88.6 +/- 5.9
mm Hg; p < 0.0001) as compared with the healthy controls. Serum TNF-alpha (6.15
+/- 1.08 versus 5.41 +/- 1.60 pg/ml; p < 0.05) and plasma sTNF-R55 (1.15 +/- 0.49
versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.54 +/- 1.16 versus 2.25
+/- 0.43; p < 0.0001) levels were significantly higher in the COPD patients than
in the healthy controls. There were inverse correlations between Pa(O(2)) and
circulating TNF-alpha and sTNF-R levels in patients with COPD (TNF-alpha; r =
0.426, p = 0.0297; sTNF-R55: r = -0.587, p = 0.0027; sTNF-R75: r = -0.573, p =
0.0035). In addition, we found inverse correlations between sTNF-R levels and %
fat in COPD patients (sTNF-R55: r = -0.442, p = 0.0272; sTNF-R75: r = -0. 484, p
= 0.0155). TNF-alpha levels correlated well with sTNF-R levels (sTNF-R55: r =
0.488, p = 0.0127; sTNF-R75: r = 0.609, p = 0. 0019). These relationships were
not observed in the healthy controls. These data suggest that systemic hypoxemia
noted in patients with COPD is associated with activation of the TNF-alpha system
in vivo, which may be a factor contributing to the weight loss in patients with
the disease.
PMID- 10764310
TI - Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe
asthma: Clinical and biologic significance.
AB - The inflammatory events in the airways at the time of acute respiratory failure
from acute severe asthma are poorly understood. To determine the patterns of
cellular inflammation in the airways in acute severe asthma, we analyzed tracheal
aspirates collected within 12 h of intubation from patients intubated emergently
for acute severe asthma (n = 10) and from patients intubated electively for
nonpulmonary surgery (n = 14). The number of neutrophils in tracheal aspirates
from asthma patients was 10 times higher than normal (4.2 [0.6 to 335.0] [median,
range] versus 0.4 [0.009 to 9.4] x 10(6)/ml, p = 0.001), and there was a strong
trend for a positive relationship between neutrophil number and duration of
intubation (r(s) = 0.64, p = 0.06). Although eosinophil numbers were also
significantly higher than normal (0.5 [0.0 to 23.3] versus 0.0 [0.0 to 0.1] x
10(6)/ml, p = 0.003), the numbers of eosinophils were 8-fold less than
neutrophils, and there was no significant correlation between eosinophil number
and duration of intubation (r(s) = 0.4, p = 0.26). Interleukin-8 (IL-8), a
chemoattraction for neutrophils, was 19 times higher than normal in tracheal
aspirates from asthmatic patients (75.0 [9.0 to 168.0] versus 4.0 [0.08 to 24.0]
ng/ml, p < 0. 05) and correlated significantly with the neutrophil number (r(s) =
0.77, p = 0.03). Furthermore, the IL-8 levels correlated positively with the
duration of mechanical ventilation (r(s) = 0.74, p = 0.03). Surprisingly, the
number of neutrophils increased significantly during the period of intubation in
the asthmatic subjects, possibly because of intravenous corticosteroid treatment.
We conclude that neutrophils are the dominant inflammatory leukocyte
characterizing airway inflammation in acute severe asthma that requires
mechanical ventilation, and that IL-8 is an important mediator of this
neutrophilia.
PMID- 10764311
TI - Noninvasive ventilation with helium-oxygen in acute exacerbations of chronic
obstructive pulmonary disease.
AB - The use of helium-oxygen (HeO(2)) was tested in combination with noninvasive
ventilation (NIV) in 10 patients with acute exacerbation of chronic obstructive
pulmonary disease (COPD). Effort to breathe as assessed by the respiratory muscle
pressure-time index (PTI), work of breathing (WOB), and gas exchange were the
main endpoints. Results of NIV-HeO(2) were compared with those obtained with
standard NIV (AirO(2)), at two levels of pressure-support ventilation (PSV), 9 +/
2 cm H(2)O and 18 +/- 3 cm H(2)O. Significant reductions in PTI were observed
between HeO(2) and AirO(2) at both the low PSV level (n = 9; 160 +/- 58 versus
198 +/- 78 cm H(2)O/s/ min; p < 0.05) and the high PSV level (n = 10; 100 +/- 45
versus 150 +/- 82 cm H(2)O/s/min; p < 0.01). WOB also differed significantly
between HeO(2) and AirO(2) (7.8 +/- 4.1 versus 10.9 +/- 6.1 J/min at the low PSV
level, p < 0.05; and 5.7 +/- 3.3 versus 9.2 +/- 5. J/min, p < 0.01 at the high
PSV level). HeO(2) reduced Pa(CO(2)) at both the low PSV level (61 +/- 13 versus
64 +/- 15 mm Hg; p < 0.05) and the high PSV level (56 +/- 13 versus 58 +/- 14 mm
Hg; p < 0.05), without significantly changing breathing pattern or oxygenation.
We conclude that use of HeO(2) during NIV markedly enhances the ability of NIV to
reduce patient effort and to improve gas exchange.
PMID- 10764312
TI - Relation of FEV(1) to clinical outcomes during exacerbations of chronic
obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study
Group.
AB - FEV(1) is an objective measure of airflow obstruction used in clinical practice
and in therapeutic trials. The precise relationship of FEV(1) to clinical
outcomes is generally uncertain. As part of a randomized trial to assess systemic
corticosteroid efficacy, we obtained serial FEV(1) measurements in patients
hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).
Over the first 14 Study Days at least one FEV(1) value was obtained in 261
subjects. Sixty-four of these subjects experienced treatment failure, defined as
death, intubation, readmission for COPD, or intensification of drug therapy, by
Study Day 30. After adjustment, both FEV(1) at entry into the study (odds ratio
[OR] for a 100-ml increase, 0.87; 95% confidence interval [CI], 0.79 to 0.96) and
change in FEV(1) over the first two Study Days (OR for a 100 ml increase, 0.80;
95% CI, 0.69 to 0.92) predicted treatment failure. We identified no baseline
characteristic that was significantly related to FEV(1) at entry into the study.
Assignment to the systemic corticosteroid treatment arm was associated with a
significantly larger FEV(1) at Study Day two (p = 0.01). We conclude that FEV(1)
measurements at admission and over the first several days of hospitalization are
highly predictive of clinical outcomes during exacerbations of COPD.
PMID- 10764313
TI - Multiple combination bactericidal antibiotic testing for patients with cystic
fibrosis infected with Burkholderia cepacia.
AB - Most Burkholderia cepacia strains are resistant to many, or all, of the
antibacterial agents commonly used in cystic fibrosis (CF), and selection of
appropriate antibiotics for treatment of pulmonary exacerbations is therefore
difficult. We developed a technique for rapid in vitro testing of multiple
antibiotic combinations for B. cepacia isolates. For each of 119 multi-drug
resistant isolates of B. cepacia, our multiple combination bactericidal test
(MCBT) studied the bactericidal activity of 10 to 15 antimicrobial agents using
225 +/- 97 single, double, and triple antibiotic combinations. Of the 119
isolates, 50% were resistant to all single antibiotics tested, 8% were resistant
to all two-drug antibiotic combinations, but all were inhibited by at least one
bactericidal triple-drug combination. When used alone, meropenem, ceftazidime and
high-dose tobramycin (200 microg/ml) were bactericidal against only 47, 15, and
14% of in vitro isolates, respectively. Using a double antibiotic combination
improved bactericidal activity; meropenem-minocycline, meropenem-amikacin, and
meropenem-ceftazidime combinations were bactericidal against 76, 73, and 73% of
isolates, respectively. However, 47% of isolates demonstrated antagonism (growth
of an organism when a second antibiotic was added to a bactericidal single
antibiotic). Triple antibiotic combinations that contained tobramycin, meropenem,
and an additional antibiotic were most effective, and were bactericidal against
81 to 93% of isolates. We conclude that triple-antibiotic combinations are more
likely than double and single antibiotic combinations to be bactericidal against
B. cepacia in vitro. MCBT testing is a useful technique to help clinicians decide
on appropriate nonantagonistic combination antibiotic therapy for patients with
CF infected with B. cepacia.
PMID- 10764314
TI - The human bone marrow response to acute air pollution caused by forest fires.
AB - Atmospheric pollution increases cardiopulmonary morbidity and mortality by
unexplained mechanisms. Phagocytosis of fine particles (PM(10)) by rabbit
alveolar macrophages elevates white blood cells (WBC) by releasing precursors
from the bone marrow and this could contribute to the pathogenesis of
cardiopulmonary disease. The present study examined the association between acute
air pollution caused by biomass burning and peripheral WBC counts in humans.
Serial measurements of the WBC count made during the 1997 Southeast Asian Smoke
haze (Sep 29, Oct 27) were compared with a period after the haze cleared (Nov 21,
Dec 5) using peripheral blood PMN band cells to monitor marrow release. The
results showed that indices of atmospheric pollution were significantly
associated with elevated band neutrophil counts expressed as a percentage of
total polymorphonuclear leukocytes (PMN), with maximal association on zero and 1
lag day for PM(10) and 3, and 4 lag days for SO(2) (p value < 0.000). We conclude
that atmospheric pollution caused by biomass burning is associated with elevated
circulating band cell counts in humans because of the increased release of PMN
precursors from the marrow. We speculate that this response contributes to the
pathogenesis of the cardiorespiratory morbidity associated with acute air
pollution.
PMID- 10764315
TI - Airway nitric oxide diffusion in asthma: Role in pulmonary function and bronchial
responsiveness.
AB - If the nitric oxide (NO) diffusing capacity of the airways (DNO) is the quantity
of NO diffusing per unit time into exhaled gas (q) divided by the difference
between the concentration of NO in the airway wall (Cw) and lumen, then DNO and
C(w) can be estimated from the relationship between exhaled NO concentration and
expiratory flow. In 10 normal subjects and 25 asthmatic patients before and after
treatment with inhaled beclomethasone, DNO averaged 6.8 +/- 1.2, 25.5 +/- 3.8,
and 22.3 +/- 2.7 nl/s/ppb x 10(-3), respectively; C(w) averaged 149 +/- 31.9,
255.3 +/- 46.4, and 108.3 +/- 14.3 ppb, respectively; and DNOC(w) (the maximal
from diffusion) averaged 1,020 +/- 157.5, 6,512 +/- 866, and 2,416 +/- 208.5 nl/s
x 10(-3), respectively. DNO and DNOC(w) in the asthmatic subjects before and
after steroids were greater than in normal subjects (p < 0.0001), but C(w) was
not different. Within asthmatic subjects, steroids caused C(w) and DNOC(w) to
fall (p < 0.0001), but DNO was unchanged. DNOC(w) after steroids, presumably
reflecting maximal diffusion of constitutive NO, was positively correlated with
methacholine PC(20) and FEV(1)/FVC before or after steroids. The increased DNO
measured in asthmatic patients may reflect upregulation of nonadrenergic,
noncholinergic, NO-producing nerves in airways in compensation for decreased
sensitivity of airway smooth muscle to the relaxant effects of endogenous NO.
PMID- 10764316
TI - Anti-inflammatory effects of zileuton in a subpopulation of allergic asthmatics.
AB - The objective of this study was to determine the effects of allergen exposure on
leukotriene generation and inflammation within the airways of allergic asthmatics
and evaluate the effects of the 5-lipoxygenase inhibitor zileuton on these
responses. We measured leukotriene-B(4) (LTB(4)) and LTC(4)/D(4)/E(4),
inflammatory cytokine mediators, and cellular responses in bronchoalveolar lavage
fluid (BALF) before and 24 h after segmental ragweed antigen challenge in 18
asthmatic subjects at baseline. Before initiating therapy with the 5-lipoxygenase
inhibitor or placebo, only nine of 18 asthmatic subjects had a significant
increase (234 +/- 102-fold, mean +/- SE) in BALF LTC(4)/D(4)/E(4) levels 24 h
after segmental antigen challenge, whereas leukotriene levels were essentially
unchanged (1.14 +/- 0.22-fold) in the other nine subjects. The high LT producers
also had higher postantigen BALF levels of LTB(4), total protein, IL-5, IL-6, TNF
alpha, and recovery of more eosinophils than the low LT producers. Treatment with
the 5-lipoxygenase inhibitor zileuton reduced postantigen BALF eosinophil count
by 68% in the high LT producers, but had no detectable effect on BALF composition
in the low LT producers. These data suggest that leukotriene inhibition may be
more effective in a subset of asthmatics in whom leukotrienes are a major
contributory factor in causing allergic inflammation.
PMID- 10764317
TI - Exhaled nitric oxide following repeated spirometry or repeated plethysmography in
healthy individuals.
AB - Subjects with asthma have higher concentrations of exhaled nitric oxide (NO) than
normal individuals. It has been demonstrated that in asthmatics, repeated FVC
maneuvers reduce NO. Although the cause of this phenomenon is not known, it has
been hypothesized that deep breaths associated with FVC maneuvers reduce exhaled
NO by affecting neural sources of NO, possibly via a mechanism related to the
pathobiology of asthma. To establish whether FVC maneuvers influence NO
concentrations in normal individuals, we measured exhaled NO at baseline values
and after FVC maneuvers performed every 15 min for 1 h in subjects without
asthma. To investigate the role of deep breaths in reducing exhaled NO, we
compared these results with concentrations of exhaled NO after plethysmography.
Repeated FVC maneuvers over 60 min produced a decrease in NO concentrations in
mixed expired gas (F(E)NO; 24.6 +/- 5.1% decrease for F(E)NO, p < 0. 01 versus
baseline). In contrast to the results after spirometry, repeated specific airway
conductance (sGaw) maneuvers do not have a significant effect on F(E)NO (p =
0.16). These results, which demonstrate that in nonasthmatic subjects FVC
maneuvers-but not panting maneuvers-produce a fall in NO, suggest that the
mechanism responsible for the reduction in exhaled NO after FVC maneuvers is
related to volume history of the lung rather than the pathobiology of asthma.
PMID- 10764318
TI - Relationships of active and passive smoking to total IgE in adults of the
Epidemiological Study of the Genetics and Environment of Asthma, Bronchial
Hyperresponsiveness, and Atopy (EGEA).
AB - The increase of total IgE in relation to active smoking has been shown in the
general population, but little is known about subjects with a personal or family
history of asthma. The objective of this report is to analyze the relationships
of active and passive smoking to total IgE in the Epidemiological Study of the
Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy
(EGEA). The sample studied includes 122 asthmatic probands, 430 first-degree
relatives, and 190 control subjects, age 25 to 54 yr. As expected, first-degree
relatives had total IgE intermediate between cases and control subjects and men
had higher values than women. Current smokers had significantly higher IgE than
never smokers. The relationship was statistically significant restricting the
analysis in asthmatic probands. In a model taking into account gender, personal
and familial history of asthma, socio- occupational class, and the
nonindependence of subjects from the same family, IgE were in current smokers, ex
smokers, and never smokers 128, 61, and 76 IU/ml and 77, 41, and 55 IU/ml in men
(p = 0.01) and women (p = 0. 05), respectively. The relation was independent of
skin test response. Some increase in IgE was observed in both men and women first
degree relatives in relation to passive smoking. That relation was statistically
significant in women only (adjusted for asthma values: 103 IU/ml versus 48 IU/
ml, p = 0.02). Results show that an increase in total IgE in relation to active
smoking may be evidenced even in asthmatics despite the healthy smoker effect.
Susceptible subjects, such as women who are first-degree relatives of asthmatics,
may increase total IgE in relation to passive smoking.
PMID- 10764319
TI - Exhaled ethane is elevated in cystic fibrosis and correlates with carbon monoxide
levels and airway obstruction.
AB - Ethane is produced from lipid peroxidation and can be measured in the exhaled
air. Cystic fibrosis (CF) is characterized by recurrent respiratory infections,
release of reactive oxygen species by inflammatory cells, and increased oxidative
stress. We measured exhaled ethane in 23 CF subjects (mean age +/- SEM, 21 +/- 4
yr; 10 male, FEV(1) 62 +/- 4%) and compared it with two other noninvasive markers
of oxidative stress and inflammation, carbon monoxide (CO) and nitric oxide (NO).
Exhaled ethane was collected during a flow and pressure-controlled exhalation
into a reservoir discarding dead space air contaminated with ambient air. A
sample (2 ml) of the expired air was analyzed by chromatography. Ethane levels
were elevated in patients not on steroids (n = 13, 1.99 +/- 0.20 ppb) compared
with steroid-treated patients (n = 10, 0.67 +/- 0.09 ppb, p < 0.01) and with 14
nonsmoking control (8 men, age 33 +/- 2.8 yr) subjects (0.82 +/- 0.40 ppb, p <
0.05). In patients not on steroid treatment ethane was correlated to airway
obstruction as assessed by the ratio of residual volume to total lung capacity
(RV/ TLC) (r = 0. 66, p < 0.05) and exhaled CO (r = 0.65, p < 0.05). CO
concentrations were also higher in patients not on steroid treatment (3.4 +/- 0.2
ppm) than in steroid-treated patients (2.6 +/- 0.1 ppm, p < 0.05), whereas NO
concentrations were not influenced by steroid treatment (3.0 +/- 0.4 ppm and 2.9
+/- 0.2 ppm, p > 0.05) and were lower than in a control group (7.0 +/- 0.4 ppb, p
< 0.05). Exhaled ethane is elevated in CF, reduced in steroid-treated patients
and correlates with CO and RV/TLC; therefore, it may be a useful noninvasive
marker of oxidative stress.
PMID- 10764320
TI - High incidence of posttransplant lymphoproliferative disease in pediatric
patients with cystic fibrosis.
AB - A major cause of morbidity and mortality following lung transplantation is
posttransplant lymphoproliferative disease (PTLD). In a retrospective cohort
analysis of pediatric patients, we evaluated the risk factors associated with
PTLD in 128 first-time lung transplant recipients from 1990 to 1997. The greatest
risk factor for PTLD was a diagnosis of cystic fibrosis (CF). Of the 16 patients
in our analysis who had PTLD, 13 had a diagnosis of CF (odds ratio [OR]: 5.8;
confidence interval 95% [CI]: 1.6 to 21.4). Because of the high frequency of PTLD
in patients with CF (13 of 61; 23%), we performed a retrospective cohort analysis
in which patients with CF and PTLD were designated as cases and patients with CF
and without PTLD served as controls. In patients with CF, the only risk factor
associated with PTLD was two or more episodes of acute rejection within 3 mo
after transplantation (OR: 11.0; 95% CI: 2.7 to 55.7). Age, recipient Epstein
Barr virus or cytomegalovirus status, induction with antilymphocyte globulin or
antithymocyte globulin (ATG), or use of ATG or OKT3 for acute rejection episodes
were not risk factors for PTLD. The high frequency of PTLD in the subgroup of
patients with two or more episodes of graft rejection within 2 mo after lung
transplantation was unexpected, and warrants further investigation in prospective
clinical studies and basic laboratories.
PMID- 10764321
TI - Airway narrowing in healthy humans inhaling methacholine without deep
inspirations demonstrated by HRCT.
AB - Normal subjects prevented from taking a deep breath show changes in airflow
similar to those of asthmatics when challenged with methacholine (MCh). To
confirm airway narrowing by MCh in this setting and to determine its location, we
concurrently measured changes in airway lumenal area using high resolution
computed tomography (HRCT) and airflow using partial spirometry in five normal
subjects challenged with increasing doses of MCh under prohibition of deep
breaths. In an attempt to improve imaging accuracy, we corrected for the changes
in lung volume during bronchoprovocation. At every step of the provocation,
scanning was performed at approximately the same lung volume. On the HRCT images,
airway area decreased in response to the increasing doses of MCh to 91 +/- 2%, 88
+/- 2%, and 80 +/- 2% of baseline at the doses of MCh 0.25, 0.75, and 2.5 mg/ml,
respectively (p < 0.001). Airway narrowing showed no predilection for particular
airway sizes and occurred in a heterogeneous pattern. The changes in the mean
airway lumenal area as measured by HRCT and the mean partial spirometric outcomes
were highly correlated: FEV(1)p (r(2) = 0.46, p = 0.001), FVCp (r(2) = 0.20, p =
0.05), FEV(1)/FVCp (r(2) = 0.55, p = 0.002), MMEFp (r(2) = 0.31, p = 0.01), and
taup (r(2) = 0.51, p = 0.0004). We conclude that in normal subjects who are
prevented from taking a deep breath, the spirometric changes occurring with
aerosol MCh challenge are associated with conducting airway narrowing.
PMID- 10764322
TI - Longitudinal follow-up study of smoking-induced lung density changes by high
resolution computed tomography.
AB - To evaluate the ability of high-resolution computed tomography (HRCT) to detect
longitudinal changes in structural abnormalities caused by smoking, HRCT and
pulmonary function tests were used to examine nonsmokers, current smokers, and
past smokers annually for 5 yr. Inspiratory HRCT was taken for the upper, middle,
and lower lung fields, while expiratory images were obtained for the upper and
lower lung fields only. We estimated the three quantitative CT parameters
including MLD (mean CT value), HIST (CT value with the most frequent appearance),
and %LAA (relative area of low attenuation with CT values less than -912 HU).
Most of the pulmonary function tests, excepting FEV(1), did not change annually,
whereas many of the inspiratory HRCT parameters did. In nonsmokers, only %LAA in
the middle or lower lung fields exhibited an annual increase. In current smokers,
%LAA in the upper lung field was augmented, while inspiratory MLD or HIST in the
middle or lower lung field became more positive. In past smokers, %LAA in any
lung field examined increased. The annual change in %LAA in the upper lung field
was larger for past smokers than nonsmokers, with little difference between past
and current smokers. Expiratory CT parameters showed few annual changes in all
groups. In conclusion, (1) aging increases airspace abnormalities, mainly in the
lower lung field; (2) although continuous smoking worsens airspace abnormalities
mainly in the upper portion of the lung, this trend does not seem to slow down
even after smoking cessation; and (3) inspiratory HRCT images are superior to
expiratory images for longitudinal estimation of structural abnormalities caused
by aging and smoking.
PMID- 10764323
TI - Expression of myosin heavy-chain isoforms in the respiratory muscles following
inspiratory resistive breathing.
AB - We investigated the effect of inspiratory resistive breathing (IRB) on the
expression of the genes encoding fast and slow isoforms of myosin heavy chain
(MyHC) in respiratory muscles. Eleven mongrel dogs were studied for baseline MyHC
messenger RNA (mRNA) expression, seven of which were also used to study the
effects of IRB. For this latter objective, awake and spontaneously breathing
animals were subjected to 2 h of IRB (80 cm H(2)O/L/s) per day for four
consecutive days. mRNA expression was assessed in the diaphragm, external
intercostal muscle, and a limb muscle, using both slot- blot and in situ
hybridizations with isoform-specific probes. A current semiquantitative scoring
method (from 0 to 4) was used to quantify the in situ mRNA expression levels, and
slot-blot data were analyzed with densitometry. Prior to IRB, slow- and fast-MyHC
mRNA expression was moderate, similar, and homogeneous throughout the different
regions of the diaphragm, with scores of 1.50 +/- 0.54 (mean +/- SD) for slow and
2.13 +/- 0.35 for fast mRNAs in the costal region of the diaphragm, and of 1.81
+/- 0.37 for slow and 2. 13 +/- 0.64 for fast mRNAs in the crural region of the
diaphragm. Although expression of fast-MyHC mRNA remained unchanged after IRB,
the relative expression of the mRNA for the slow isoform increased in costal
(+30%), crural (+12%), and external intercostal (+27%) muscles. MyHC mRNA
expression did not change in limb muscles. We conclude that breathing with a
moderate inspiratory resistance for a short period induces the expression of slow
MyHC in respiratory muscles.
PMID- 10764324
TI - Inhibitory effects of a lecithinized superoxide dismutase on bleomycin-induced
pulmonary fibrosis in mice.
AB - Oxidant/antioxidant imbalance is thought to be involved in the pathogenesis of
idiopathic pulmonary fibrosis (IPF). Therefore, antioxidants, such as superoxide
dismutase (SOD), are expected to have an inhibitory potential against IPF. To
elucidate whether a lecithinized SOD (phosphatidylcholine [PC]-SOD) has the
potential to be a new therapeutic agent for IPF, we investigated the inhibitory
effects of PC-SOD at doses of 1 mg/kg/d (low dose) and 10 mg/kg/d (high dose) and
of methylprednisolone (mPSL) on bleomycin (BLM)-induced pulmonary fibrosis in
mice. Histopathologic evaluation and lung hydroxyproline content revealed that
the severity of fibrosis was attenuated in mice treated with low-dose PC-SOD,
whereas no significant effect was observed in other mice. In bronchoalveolar
lavage fluid on Day 1 after treatment with BLM, BLM-induced increases in total
cell number, populations of lymphocytes and neutrophils, and expression of
messenger RNA for interleukin-1beta and platelet-derived growth factor (PDGF)-A
were significantly suppressed in PC-SOD-treated mice. The suppression of PDGF-A
expression was significantly greater in mice treated with low-dose PC-SOD than in
mice treated with high-dose PC-SOD or mPSL. In summary, this study demonstrated
the inhibitory effects of low-dose PC-SOD on the development of pulmonary
fibrosis, which indicates the potential usefulness of PC-SOD as a new treatment
agent for IPF or at least for BLM-induced pulmonary fibrosis in humans.
PMID- 10764325
TI - Resistance of very young mice to inhaled allergen sensitization is overcome by
coexposure to an air-pollutant aerosol.
AB - The role of air pollution in the initiation of asthma is controversial. We sought
to model the potential effects of air pollution on immune responses to inhaled
allergens in developing lungs by using very young mice. Neonatal mice were
repeatedly exposed to aerosolized ovalbumin (OVA; 3% in phosphate-buffered saline
for 10 min/d, from Days 5 to 15 of age). Some mice were also exposed to leachate
of residual oil fly ash (ROFA-s), a surrogate for ambient air particles, for 30
min, on Days 6, 8, and 10 of age). Repeated exposure of very young mice to
allergen alone (OVA) or pollutant alone (ROFA-s) had no effect on airway
hyperresponsiveness (AHR, measured as enhanced pause (Penh) with noninvasive
plethysmography at Day 16 of age), and did not cause inflammation or OVA-specific
antibody production. Similar exposures of adult mice to either OVA alone or to
OVA + ROFA-s did result in AHR, without evidence of enhancement by combined
exposure. In contrast, very young mice exposed to both OVA and ROFA-s showed
significantly increased AHR (e.g., Penh with 50 mg/ml methacholine for OVA + ROFA
s versus OVA alone = 2.6 +/- 0.4 [mean +/- SE], versus 1.2 +/- 0.1; p < 0.01, n
>/= 15), and produced OVA-specific IgE and IgG upon allergen challenge a week
later. Immunostaining of airways taken from mice at Day 11 showed a marked
increase in Ia(+) cells after OVA + ROFA-s exposure. We conclude that exposure to
pollutant aerosols can disrupt normal resistance to sensitization to inhaled
allergens, and can thereby promote development of airway hypersensitivity in this
neonatal/juvenile mouse model.
PMID- 10764326
TI - Detection of granulocyte-macrophage colony-stimulating factor in patients with
pulmonary alveolar proteinosis.
AB - Pulmonary alveolar proteinosis (PAP) is an idiopathic lung disease in which the
alveolar spaces are filled with surfactant. Recently, it has been proposed that
PAP is caused by deficiency of granulocyte-macrophage colony-stimulating factor
(GM-CSF) because GM-CSF-knockout mice develop the disease. To examine this
possibility, we tested the two hypotheses that lung GM-CSF levels are low and
that alveolar macrophages (AM) do not respond to GM-CSF in patients with PAP.
Data from 10 adult patients with PAP who underwent therapeutic whole-lung lavage
were compared with those of 10 healthy volunteers who underwent bronchoalveolar
lavage (BAL) by fiberoptic bronchoscopy. Bronchoalveolar lavage fluid (BALF) and
plasma were collected and analyzed for total protein and levels of GM-CSF,
interleukin-3, and tumor necrosis factor (TNF)-alpha. Isolated AM were cultured
with or without lipopolysaccharide (LPS) or GM-CSF, and production of GM-CSF and
TNF-alpha was measured after 24 h. GM-CSF in BALF and plasma was higher in PAP
than in control subjects (p 85%. In contrast, c-Jun NH(2)-terminal
protein kinase (JNK) activation was similar in AT1Rwt- and AT1R(Del221/222)
transfected cells. Activation of ERK1/ERK2 by AT1Rwt was independent of Ca(2+),
whereas the low level of ERK1/ERK2 activation by AT1R(Del221/222) was completely
Ca(2+) dependent. Activation of ERK1/ERK2 in AT1Rwt required Ras, whereas
AT1R(Del221/222) required Rap1. These results demonstrate the presence of 2
different pathways for ERK1/ERK2 activation by Ang II, which differ in their
requirements for Ca(2+) and small G proteins (Ras versus Rap1). Furthermore, Ang
II prevented serum deprivation-induced apoptosis in cells transfected with AT1Rwt
but not AT1R(Del221/222). AKT was only phosphorylated by Ang II in AT1Rwt
transfected cells. Overexpression of constitutively active AKT significantly
reduced serum deprivation-induced apoptosis in cells transfected with
AT1R(Del221/222). This study shows for the first time a direct link between
kinase activation and inhibition of apoptosis dependent on amino acids 221 and
222 in the third cytoplasmic loop of the AT(1).
PMID- 10764406
TI - Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model
of familial hypertrophic cardiomyopathy.
AB - Familial hypertrophic cardiomyopathy (FHC) is an inherited cardiac disease that
can result in sudden death in the absence of any overt symptoms. Many of the
cases documented to date have been linked with missense mutations in the beta
myosin heavy chain gene. Here we present data detailing the functional impact of
one of the most deadly mutations, R403Q, on myosin motor function. Experiments
were performed on whole cardiac myosin purified from a mouse model of FHC to
eliminate potential uncertainties associated with protein expression systems. The
R403Q mutant myosin demonstrated 2.3-fold higher actin-activated ATPase activity,
2.2-fold greater average force generation, and 1.6-fold faster actin filament
sliding in the motility assay. The force- and displacement-generating capacities
of both the normal and mutant myosin were also characterized at the single
molecule level in the laser trap assay. Both control and mutant generated similar
unitary forces ( approximately 1 pN) and displacements ( approximately 7 nm)
without any differences in event durations. On the basis of the distribution of
mean unitary displacements, this mutation may possibly perturb the mechanical
coordination between the 2 heads of cardiac myosin. Any of these observations
could, alone or possibly in combination, result in abnormal power output and
potentially a stimulus for the hypertrophic response.
PMID- 10764407
TI - Rapid displacement of vimentin intermediate filaments in living endothelial cells
exposed to flow.
AB - Hemodynamic shear stress at the endothelial cell surface induces acute and
chronic intracellular responses that regulate vessel wall biology. The
cytoskeleton is implicated by acting both as a direct connector to local surface
deformation and as a distribution network for mechanical forces throughout the
cell; however, direct observation and measurement of its position during flow
have only recently become possible. In this study, we directly demonstrate rapid
deformation of the intermediate filament (IF) network in living endothelial cells
subjected to changes in hemodynamic shear stress. Time-lapse optical sectioning
and deconvolution microscopy were performed within the first 3 minutes after the
introduction of flow (shear stress, 12 dyn/cm(2)). Spatial and temporal dynamics
of green fluorescent protein-vimentin IFs in confluent endothelial cells were
analyzed. The imposition of shear stress significantly increased the variability
of IF movement throughout the cell in the x-, y-, and z-directions compared with
the constitutive dynamics noted in the absence of flow. Acute polymerization and
depolymerization of the IF network were absent. The magnitude and direction of
flow-induced IF displacement were heterogeneous at the subcellular level. These
qualitative and quantitative data demonstrate that shear stress acting at the
luminal surface of the endothelium results in rapid deformation of a stable IF
network.
PMID- 10764408
TI - Transient induction of cytokine production in human myocardial fibroblasts by
coxsackievirus B3.
AB - Cytokine expression in enterovirus infections of the heart may trigger
inflammation and have detrimental effects on myocytes. However, the induction of
cytokines in human myocardial cells by cardiotropic enteroviruses, for example,
Coxsackievirus B3 (CVB3), was not yet demonstrated. Fibroblasts are the
predominant cell type of the myocardial interstitium before inflammatory
infiltration develops. Hence, we investigated, by enzyme immunoassays, reverse
transcription-quantitative polymerase chain reaction (RT-qPCR), and nucleic acid
sequence-based amplification (NASBA), whether CVB3 induces cytokine expression in
cultured human myocardial fibroblasts. As early as 3 hours after infection, RT
qPCR demonstrated a 2-fold increase of interleukin (IL)-6 and IL-8 mRNA compared
with basal transcription, resulting in a significant increase of IL-6 and IL-8 to
a median level of 1500 pg/mL (range, 1246 to 1858) and 529 pg/mL (range, 428 to
601) in culture supernatants, respectively. IL-6 and IL-8 expression returned to
basal levels within 3 and 5 days, respectively, despite a persistent (carrier
state) CVB3 infection. For comparison, IL-6 and IL-8 were induced in dermal
fibroblasts later than 3 days after CVB3 infection. Although the low-level IL
1alpha transcription of myocardial fibroblasts was not significantly increased,
IL-1alpha was released from cells to culture supernatants 5 days after infection.
Furthermore, a suppression of interferon-beta transcription was demonstrated up
to 24 hours after CVB3 infection of myocardial fibroblasts by highly sensitive
NASBA. In conclusion, our results demonstrate a heart-specific pattern of a rapid
and transient induction of proinflammatory cytokines after CVB3 infection,
whereas the expression of protective interferon-beta was suppressed by CVB3.
PMID- 10764409
TI - Coupling of Ca(2+) to CREB activation and gene expression in intact cerebral
arteries from mouse : roles of ryanodine receptors and voltage-dependent Ca(2+)
channels.
AB - Pathological changes of the vasculature are characterized by changes in Ca(2+)
handling and alterations in gene expression. In neurons and other cell types,
[Ca(2+)](i) often drives changes in gene expression. However, the relationship
between Ca(2+) signaling and gene expression in vascular smooth muscle is not
well understood. This study examines the ability of Ca(2+) influx through voltage
dependent, L-type Ca(2+) channels (VDCCs) and Ca(2+) release through ryanodine
receptors (RyRs) to activate the transcription factor, cAMP-responsive element
binding protein (CREB), and increase c-fos levels in intact cerebral arteries.
Membrane depolarization increased the fraction of nuclei staining for
phosphorylated CREB (P-CREB) and levels of c-fos mRNA in intact mouse cerebral
arteries. Ryanodine, which inhibits RyRs, increased P-CREB staining and c-fos
levels. Forskolin, an activator of adenylyl cyclase, and sodium nitroprusside, an
NO donor, increased P-CREB and c-fos levels. Nisoldipine, an inhibitor of VDCCs,
reversed the effects of depolarization and ryanodine on P-CREB and c-fos levels,
but not the effects of forskolin or sodium nitroprusside. Inhibition of
Ca(2+)/calmodulin-dependent protein kinase (CaM kinase) blocked increases in P
CREB and c-fos levels seen with membrane depolarization, suggesting that CaM
kinase has an important role in the pathway leading from Ca(2+) influx to CREB
mediated changes in c-fos levels. Our data suggest that membrane depolarization
increases [Ca(2+)](i) through activation of VDCCs, leading to increased P-CREB
and c-fos, and that RyRs have a profound effect on this pathway by indirectly
regulating Ca(2+) entry through VDCCs. These results provide the first evidence
of Ca(2+) regulation of CREB and c-fos in arterial smooth muscle.
PMID- 10764410
TI - Direct visualization of lipid deposition and reverse lipid transport in a
perfused artery : roles of VLDL and HDL.
AB - The major goal of this study was to determine the interactions of VLDL surface
and core lipids with the artery wall. We first demonstrated in vitro that surface
lipid in VLDL could be traced using the phospholipid-like fluorescent probe 1,1'
dioctadecyl-3,3, 3',3'-tetramethyl-indocarbocyanine (DiI). The core of VLDL
particles was traced by fluorescently labeling apolipoprotein B with TRITC. The
labeled VLDLs were perfused through rat carotid arteries, and accumulation of the
fluorescently labeled VLDL components in the arterial walls was determined by
quantitative fluorescence microscopy. Addition of lipoprotein lipase increased
the accumulation of both DiI and TRITC by >2.3-fold. Histological examination
showed that DiI and TRITC were primarily localized to the endothelial layer;
however, DiI also accumulated as small "lakes" deeper in the artery, in a
subendothelial position. Addition of HDL to the perfusion decreased the
accumulation of surface lipid and apolipoprotein B-containing particles and
eliminated the DiI lakes. Moreover, the increase in endothelial layer
permeability associated with lipolysis was attenuated 21% by HDL. If VLDL surface
lipid first was allowed to accumulate in the arterial wall, its subsequent rate
of loss was more than twice as fast if HDL was included in the perfusate. These
studies directly demonstrate atherogenic effects of VLDL lipolysis and their
inhibition by HDL.
PMID- 10764411
TI - Increased microvascular reactivity and improved mortality in septic mice lacking
inducible nitric oxide synthase.
AB - Persistent vasodilation characteristic of septic shock may result from
overproduction of nitric oxide and can lead to pressor-refractory hypotension and
death. To evaluate the significance of cytokine-inducible nitric oxide synthase
(iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model
of sepsis and compared mortality and microvascular reactivity in wild-type (WT)
mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice
were made septic by cecal ligation and puncture. Treated mice were given fluids
and antibiotics every 6 hours. Microvascular vasoconstriction in response to
topical norepinephrine was measured in cremasteric arterioles (15 to 30 microm)
by videomicroscopy. Mortality at 48 hours was significantly lower in treated
septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated
septic iNOS-deficient mice (87%), or untreated WT mice (100%) (P<0.01).
Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC(50)
200+/-56 nmol/L) compared with WT and iNOS-deficient shams (16+/-4 and 13+/-6
nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient
mice (35+/-13 nmol/L, P<0.01). Microvascular catecholamine responsiveness and
survival were improved in iNOS-deficient mice in a clinically relevant model of
sepsis, suggesting that iNOS plays an important, but not exclusive, role in
refractory vasodilation in patients with septic shock.
PMID- 10764412
TI - Effect of platelet-derived growth factor receptor-alpha and -beta blockade on
flow-induced neointimal formation in endothelialized baboon vascular grafts.
AB - The growth of neointima and neointimal smooth muscle cells in baboon
polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal
smooth muscle cells express both platelet-derived growth factor receptor-alpha
and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis
that inhibiting either PDGFR-alpha or PDGFR-beta with a specific mouse/human
chimeric antibody will modulate flow-induced neointimal formation. Bilateral
aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17
baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow
through the ipsilateral graft while maintaining high flow in the contralateral
graft. The experimental groups received a blocking antibody to PDGFR-alpha (Ab
PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR-beta; 10 mg/kg; n=6) by
pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and
22 days after ligation. Controls received carrier medium alone (n=8). Serum
antibody concentrations were followed. Grafts were harvested after 28 days and
analyzed by videomorphometry. Serum Ab-PDGFR-alpha concentrations fell rapidly
after day 7 to 0, whereas serum Ab-PDGFR-beta concentrations were maintained at
the target levels (>50 microg/mL). Compared with controls (3.7+/-0.3), the ratio
of the intimal areas (normalized flow/high flow) was significantly reduced in Ab
PDGFR-beta (1.2+/-0.2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR
alpha decreased significantly the overall smooth muscle cell nuclear density of
the neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated
groups. PDGFR-beta is necessary for flow-induced neointimal formation in
prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological
strategy for suppressing graft neointimal development.
PMID- 10764413
TI - Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite
fashions.
AB - Cardiogenesis is a multistep process regulated by a hierarchy of factors defining
each developmental stage of the heart. One of these factors, leukemia inhibitory
factor (LIF), a member of the interleukin-6 family of cytokines, is expressed in
embryonic and neonatal cardiomyocytes and induces cardiomyocyte hypertrophy. Many
aspects of embryogenesis are faithfully recapitulated during in vitro
differentiation of embryonic stem cells in embryoid bodies. We exploited this
model to study effects of growth factors on commitment and differentiation of
cardiomyocytes and on maintenance of their phenotype. We identified LIF as a
factor affecting commitment and differentiation of cardiomyocytes in an opposite
manner. Diffusible LIF inhibited mesoderm formation and hampered commitment of
cardiomyocytes. Lack of both the diffusible and matrix-bound isoforms of LIF in
lif-/- embryoid bodies did not interfere with commitment, but it severely
suppressed early differentiation of cardiomyocytes. Onset of differentiation was
rescued by very low concentrations of diffusible LIF; however, consecutive
differentiation was attenuated in a concentration-dependent manner by diffusible
LIF both in wild-type and lif-/- cardiomyocytes. Differentiation of
cardiomyocytes was severely hampered but not completely blocked in lifr-/-
embryoid bodies, suggesting additional, LIF-receptor ligand independent pathways
for commitment and differentiation of cardiomyocytes. At the fully differentiated
state, both paracrine and autocrine LIF promoted proliferation and increased
longevity of cardiomyocytes. These findings suggest that both paracrine and
autocrine and both diffusible and matrix-bound isoforms of LIF contribute to the
modulation of cardiogenesis in a subtle, opposite, and developmental stage
dependent manner and control proliferation and maintenance of the differentiated
state of cardiomyocytes.
PMID- 10764414
TI - Enhanced cardiac function in transgenic mice expressing a Ca(2+)-stimulated
adenylyl cyclase.
AB - The predominant functional adenylyl cyclases normally expressed in cardiac tissue
and coupled to beta-adrenergic receptors are inhibited by micromolar Ca(2+)
concentration. To modify the overall balance of activities, we have generated
transgenic mice expressing the Ca(2+)-stimulatable adenylyl cyclase type 8 (AC8)
specifically in the heart. AC activity is increased by at least 7-fold in heart
membranes from transgenic animals and is stimulated by Ca(2+) in the same range
of concentration that inhibits the endogenous activity. Moreover, the in vivo
basal protein kinase A activity was augmented 4-fold. Overexpression of AC8 in
the heart has no detrimental consequences on global cardiac function. Basal heart
rate and contractile function, measured by noninvasive echocardiography, were
unchanged. In contrast, on release of parasympathetic tone, the intrinsic
contractility is heightened and unresponsive to further beta-adrenergic receptor
stimulation. AC8 transgenic mice thus represent an original model to investigate
the relative influence of Ca(2+) and cAMP on cardiac function within a phenotype
of enhanced cardiac contractility and relaxation.
PMID- 10764415
TI - Determinants of the cardiomyopathic phenotype in chimeric mice overexpressing
cardiac Gsalpha.
AB - Mice with overexpressed cardiac Gsalpha develop cardiomyopathy, characterized by
myocyte hypertrophy and extensive myocardial fibrosis. The cardiomyopathy likely
involves chronically enhanced beta-adrenergic signaling, because it can be
blocked with long-term propranolol treatment. It remains unknown whether the
genotype of the myocyte is solely responsible for the progressive pathological
changes. A chimeric population in the heart should answer this question.
Accordingly, we developed a chimeric animal, which combined cells from a
transgenic overexpressed Gsalpha parent and a Rosa mouse containing the LacZ
reporter gene, facilitating identification of the non-Gsalpha cells, which
express a blue color with exposure to beta-galactosidase. We studied these
animals at 14 to 17 months of age (when cardiomyopathy should have been present),
with the proportion of Gsalpha cells in the myocardium ranging from 5% to 88%.
beta-Galactosidase staining of the hearts demonstrated Gsalpha and Rosa cells,
exhibiting a mosaic pattern. The fibrosis and hypertrophy, characteristic of the
cardiomyopathy, were not distributed randomly. There was a direct correlation
(r=0.85) between the extent of myocyte hypertrophy (determined by computer
imaging) and the quantity of Gsalpha cells. The fibrosis, determined by picric
acid Sirius red, was also more prominent in areas with the greatest Gsalpha cell
density, with a correlation of r=0.88. Thus, the overexpressed Gsalpha can exert
its action over the life of the animal, resulting in a local picture of
cardiomyopathic damage in discrete regions of the heart, where clusters of the
overexpressed Gsalpha cells reside, sparing the clusters of normal cells derived
from the normal Rosa parent.
PMID- 10764416
TI - beta-blockade prevents sustained metalloproteinase activation and diastolic
stiffening induced by angiotensin II combined with evolving cardiac dysfunction.
AB - Angiotensin II (Ang II)-mediated sympathostimulation may worsen the progression
of cardiac failure, although the nature and mechanisms of such interactions are
largely unknown. We previously demonstrated that Ang II combined with evolving
cardiodepression (48-hour tachycardia pacing, 48hP) induces marked chamber
stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis
that both abnormalities stem from sympathostimulatory effects of Ang II. Forty
eight dogs were instrumented to serially assess conscious ventricular mechanics,
MMP abundance and activity, and myocardial histopathology. 48hP combined with 5
days of Ang II (15+/-5 ng. kg(-1). min(-1) IV) more than doubled chamber
stiffness (end-diastolic pressure >25 mm Hg, P<0.001), whereas stiffness was
unchanged by Ang II or 48hP alone. In vitro and in situ zymography revealed
increased MMP abundance and activity (principally 92-kDa gelatinase) from Ang
II+48hP. Both stiffening and MMP changes were prevented by cotreatment with high
dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but
not partial beta-blockade. Myocellular damage with fibroblast/neutrophil
infiltration from Ang II+48hP was also inhibited by high- but not low-dose
atenolol, whereas collagen content was not elevated with either dose. These data
support a role of sympathostimulation by Ang II in modulating myocardial MMP
abundance and activity and diastolic stiffening in evolving heart failure and
suggest a novel mechanism by which beta-blockade may limit chamber remodeling and
diastolic dysfunction.
PMID- 10764417
TI - Nerve sprouting and sudden cardiac death.
AB - The factors that contribute to the occurrence of sudden cardiac death (SCD) in
patients with chronic myocardial infarction (MI) are not entirely clear. The
present study tests the hypothesis that augmented sympathetic nerve regeneration
(nerve sprouting) increases the probability of ventricular tachycardia (VT),
ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and
complete atrioventricular (AV) block, we induced cardiac sympathetic nerve
sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion
(experimental group, n=9). Another 6 dogs with MI and complete AV block but
without NGF infusion served as controls (n=6). Immunocytochemical staining
revealed a greater magnitude of sympathetic nerve sprouting in the experimental
group than in the control group. After MI, all dogs showed spontaneous VT that
persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0
days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher
in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d,
P<0.05). Four dogs in the experimental group but none in the control group died
suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve
sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and
AV block augments sympathetic nerve sprouting and creates a high-yield model of
spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be
an important determinant of SCD in chronic MI.
PMID- 10764418
TI - Reduced myocardial nerve growth factor expression in human and experimental heart
failure.
AB - Maintenance of cardiac performance is tightly controlled by the autonomic nervous
system. In congestive heart failure (CHF), although the adverse
pathophysiological effects of cardiac sympathetic overactivity are increasingly
recognized, the paradoxical finding of reduced sympathetic innervation density in
the failing heart remains unexplained. Given these observations, we tested the
hypothesis that a reduction in the myocardial production of nerve growth factor
(NGF), which is important for the maintenance of sympathetic neuronal survival,
could explain the conflicting neurochemical and neuroanatomical profile of CHF.
In healthy humans (n=11), there was a significantly greater transcardiac
venoarterial plasma NGF gradient than in CHF patients (n=11, P<0.05). In a rat
model of CHF, a 40% reduction (P<0.05) NGF mRNA expression was apparent in
association with a 24% reduction in tissue NGF content (P<0.05). In conjunction,
evidence of reduced sympathetic innervation in the failing heart was apparent, as
measured histologically by catecholamine fluorescence and by expression of the
neuronal NGF receptor trkA. Norepinephrine (10 micromol/L) exposure reduced both
NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that
myocardial NGF downregulation may represent an adaptive response to sympathetic
overactivity. These data indicate that NGF expression in the heart is dynamic and
may be altered in cardiovascular disease states. In CHF, reduced NGF expression
may account for alterations in sympathetic neuronal function and neuroanatomy.
The full text of this article is available at http://www.circresaha.org.
PMID- 10764419
TI - Granulocyte-macrophage colony-stimulating factor: another cytokine with adjuvant
therapeutic benefit in melanoma?
PMID- 10764420
TI - Concurrent chemotherapy and pelvic radiation therapy compared with pelvic
radiation therapy alone as adjuvant therapy after radical surgery in high-risk
early-stage cancer of the cervix.
AB - PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT)
to pelvic radiation therapy (RT) will improve the survival of early-stage, high
risk patients with cervical carcinoma. PATIENTS AND METHODS: Patients with
clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with
radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic
lymph nodes and/or positive margins and/or microscopic involvement of the
parametrium were eligible for this study. Patients were randomized to receive RT
or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a
standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a
96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles,
with the first and second cycles given concurrent to RT. RESULTS: Between 1991
and 1996, 268 patients were entered onto the study. Two hundred forty-three
patients were assessable (127 RT + CT patients and 116 RT patients). Progression
free and overall survival are significantly improved in the patients receiving
CT. The hazard ratios for progression-free survival and overall survival in the
RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007),
respectively. The projected progression-free survivals at 4 years is 63% with RT
and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with
RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity
were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent
cisplatin-based CT to RT significantly improves progression-free and overall
survival for high-risk, early-stage patients who undergo radical hysterectomy and
pelvic lymphadenectomy for carcinoma of the cervix.
PMID- 10764421
TI - Adjuvant therapy of stage III and IV malignant melanoma using granulocyte
macrophage colony-stimulating factor.
AB - PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as
surgical adjuvant therapy in patients with malignant melanoma who are at high
risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with
stage III or IV melanoma were treated in a phase II trial with long-term,
chronic, intermittent GM-CSF after surgical resection of disease. Patients with
stage III disease were required to have more than four positive nodes or a more
than 3-cm mass. All patients were rendered clinically disease-free by surgery
before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles,
such that a dose of 125 microg/m(2) was delivered daily for 14 days followed by
14 days of rest. Treatment cycles continued for 1 year or until disease
recurrence. Patients were evaluated for toxicity and disease-free and overall
survival. RESULTS: Overall and disease-free survival were significantly prolonged
in patients who received GM-CSF compared with matched historical controls. The
median survival duration was 37.5 months in the study patients versus 12.2 months
in the matched controls (P <.001). GM-CSF was well tolerated; only one subject
discontinued drug due to an adverse event (grade 2 injection site reaction).
CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and
disease-free survival in patients with stage III and IV melanoma who are
clinically disease-free. These results support institution of a prospective,
randomized clinical trial to definitively determine the value of surgical
adjuvant therapy with GM-CSF in such patients.
PMID- 10764422
TI - Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients
with hematologic malignancies.
AB - PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and
antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant
immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas
exotoxin. PATIENTS AND METHODS: Patients with CD25(+) hematologic malignancies
for whom standard and salvage therapies failed were treated with LMB-2 at dose
levels that ranged from 2 to 63 microg/kg administered intravenously over 30
minutes on alternate days for three doses (QOD x 3). RESULTS: LMB-2 was
administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at
the 63 microg/kg level was reversible and included transaminase elevations in one
patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in
nine patients at the maximum-tolerated dose (40 microg/kg QOD x 3); toxicity was
transient and most commonly included transaminase elevations (eight patients) and
fever (seven patients). Only six of 35 patients developed significant
neutralizing antibodies after the first cycle. The median half-life was 4 hours.
One hairy cell leukemia (HCL) patient achieved a complete remission, which is
ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell
lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one
patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one
patient). Responding patients had 2 to 5 log reductions of circulating malignant
cells, improvement in skin lesions, and regression of lymphomatous masses and
splenomegaly. All four patients with HCL responded to treatment. CONCLUSION: LMB
2 has clinical activity in CD25(+) hematologic malignancies and is relatively
nonimmunogenic. It is the first recombinant immunotoxin to induce major responses
in cancer. LMB-2 and similar agents that target other cancer antigens merit
further clinical development.
PMID- 10764423
TI - Influence of biologic factors and anatomic site in completely resected
liposarcoma.
AB - PURPOSE: Soft tissue sarcoma (STS) encompasses a group of neoplasms that are
anatomically and biologically diverse. Retroperitoneal/visceral (RP/V) tumors
have a poorer prognosis than extremity/trunk (E/T) lesions, and this has been
attributed to frequent presentation with tumors of large size and multiorgan
involvement that precludes complete resection. The worse prognosis that is
associated with RP/V tumors has also been thought to be histopathologically
dependent and not necessarily related to anatomic site. The aim of this study was
to determine the role of anatomic site and biologic features in prognosis and
outcome in patients after complete resection by examining a large cohort of STS
patients with a single histopathology, ie, liposarcoma. METHODS: All patients who
were treated for liposarcoma from July 1, 1982, through July 1, 1998, were
included. Univariate analyses were performed using log-rank test and Kaplan-Meier
estimates, and multivariate analyses were performed using Cox regression. The
three end points examined were local recurrence (LR), distant recurrence, and
disease-specific survival (DSS). RESULTS: Seven hundred twenty patients with
liposarcoma were evaluated, and of these, 460 had completely resected primary or
completely resected locally recurrent disease. Breakdown of anatomic site was 65%
E/T (n = 301) and 35% RP/V (n = 159). The median follow-up period for patients
who underwent complete resection was 42 months (range, 1 to 194 months). We found
that RP/V site is a poor prognosticator that is independent of patient sex and
age; tumor size, grade, and margin; and recurrent presentation. Sixty-nine
percent of patients with RP/V tumors who died had local disease only and no
distant metastasis at the time of death. CONCLUSION: In liposarcoma, tumor
location exerts as strong an influence on prognosis as biology. In contrast to
extremity liposarcoma, LR without distant metastasis often results in death for
patients with RP/V tumors. For these patients, local control accomplished by
complete surgical resection +/- adjuvant radiation therapy should impact strongly
on DSS.
PMID- 10764424
TI - Chromosome instability as an indicator of malignant progression in laryngeal
mucosa.
AB - PURPOSE: Routine histologic examination cannot predict whether premalignant
laryngeal lesions will progress toward invasive growth. The acquisition of
changes in chromosome constitution has been suggested to be essential for driving
tumor progression by enhancing mutagenic mechanisms. The aim of the present study
was to determine whether chromosomal changes occur in the subsequent stages of
early laryngeal carcinogenesis and, if so, whether these changes can be of
prognostic value. MATERIALS AND METHODS: Numerical aberrations for chromosomes 1
and 7 were detected in tissue sections from archival material using an improved
in situ hybridization protocol. In total, eight benign laryngeal lesions, 37
premalignant laryngeal lesions, and 16 specimens containing histologically normal
epithelia adjacent to laryngeal squamous cell carcinomas were studied. Both the
histologic and the cytogenetic classifications were correlated with progression
to laryngeal cancer. RESULTS: No evidence for chromosome alterations was obtained
in the control group, nor in histologically normal epithelia adjacent to
laryngeal squamous cell carcinomas, nor in all but one hyperplastic lesion (n =
11). In contrast, 14 of 15 dysplastic lesions and nine of 11 carcinomas-in-situ
contained numerical chromosomal aberrations. Tetrasomy was present in the
majority of the dysplastic lesions. An unstable chromosome content (indicated by
the presence of chromosome imbalances and/or polyploidization) in the
premalignant lesion strongly predicted its malignant progression. CONCLUSION: Our
results show that laryngeal tumor development involves chromosome
tetraploidization. The further change from a stable to an unstable chromosome
constitution is of importance for malignant progression.
PMID- 10764425
TI - Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head
and neck cancer.
AB - PURPOSE: To achieve locoregional control of head and neck cancer, survival, and
organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND
METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100
mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days,
hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily
at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of
treatment were followed by 9 days of rest, during which time patients received
granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were
administered over 10 weeks (total radiotherapy dose, locoregional). Surgery
after concomitant chemoradiotherapy is feasible. Compliance with adjuvant
chemoprevention is poor. Identification of less toxic regimens and improved
distant disease control emerge as important future research goals.
PMID- 10764426
TI - Phase II trial of up-front accelerated thoracic radiotherapy combined with
chemotherapy and optional up-front prophylactic cranial irradiation in limited
small-cell lung cancer. Groupe d'Oncologie Thoracique des Regions Alpines.
AB - PURPOSE: To investigate the feasibility and outcome of bifractionated, up-front
thoracic radiotherapy (TR) (45 Gy in 30 fractions of 1.5 Gy twice daily over 3
weeks) combined with chemotherapy (CT) (six cycles of cisplatin and etoposide)
and optional low-dose, up-front prophylactic cranial irradiation (18 Gy in 10
fractions of 1.8 Gy twice daily over 5 days) in limited small-cell lung cancer.
PATIENTS AND METHODS: CT (etoposide 100 mg/m(2) for 3 days and cisplatin 25
mg/m(2) for 3 days) was started on day 8 or 15 after the first TR treatment. In
the five subsequent cycles, cisplatin was given as a single 100-mg/m(2) dose on
day 1 every 4 weeks. A total of 52 patients were entered (41 men and 11 women);
the median age was 55 years (range, 33 to 67 years). World Health Organization
performance status was 0 in 34 patients, 1 in 16 patients, and 2 in two patients.
Thirty-six patients (69%) received the full planned six cycles of CT. RESULTS:
All treated patients were assessable for response. Thirty-one patients (60%)
achieved a complete response, and 16 (30%) had a partial response. One-, 3-, and
4-year survival rates were 74% (95% confidence interval [CI], 60% to 84%), 34%
(95% CI, 21% to 49%), and 32% (95 CI, 16% to 46%), respectively. The median
survival time was 18 months. Event-free survival at 1 year was 45% (95% CI, 32%
to 58%) and at 3 years, 30% (95% CI, 18% to 44%). The main radiation-related
acute toxicity was esophageal: 38% of the patients experienced grade 3 or 4 acute
toxicity. CT was well tolerated. Although grade 3/4 neutropenia was observed in
86% of the patients, only 4% presented with associated fever. Grade 3/4 nausea
and vomiting was seen in 35% of patients. CONCLUSION: This trial demonstrates
that up-front accelerated TR associated with CT is feasible, has acceptable
toxicity, and shows considerable long-term survival potential.
PMID- 10764427
TI - Outcome at 8 years after breast-conserving surgery and radiation therapy for
invasive breast cancer: influence of margin status and systemic therapy on local
recurrence.
AB - PURPOSE: To examine the relationship between pathologic margin status and outcome
at 8 years after breast-conserving surgery and radiation therapy. PATIENTS AND
METHODS: The study population comprised 533 patients with International Union
Against Cancer/American Joint Committee on Cancer clinical stage I or II breast
cancer who had assessable margins, who received at least 60 Gy to the primary
tumor bed, and who had more than 8 years of potential follow-up. Each margin was
scored (according to the presence of invasive or in situ disease that touched the
inked surgical margin) as one of the following: negative, close, focally
positive, or extensively positive. Outcome at 8 years was calculated using crude
rates of first site of failure. A polychotomous logistic regression analysis was
performed. Median follow-up time was 127 months. RESULTS: At 8 years, patients
with close margins and those with negative margins both had a rate of local
recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate
of 27%, whereas patients with focally positive margins had an intermediate rate
of LR of 14%. In the polychotomous logistic regression model, margin status and
the use of systemic therapy were the only two variables that had significant
effects on the risk ratio of LR to remaining alive and free of disease. Among the
45 patients with focally positive margins who received systemic therapy, the
crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%). CONCLUSION:
Pathologic margin status and the use of adjuvant systemic therapy are the most
important factors associated with LR among patients treated with breast
conserving surgery and radiation therapy.
PMID- 10764428
TI - Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the
pathologic response of breast cancer to primary chemotherapy.
AB - PURPOSE: To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG)
positron emission tomography (PET) can predict the pathologic response of primary
and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS: Thirty
patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers
received eight doses of primary chemotherapy. Dynamic PET imaging was performed
immediately before the first, second, and fifth doses and after the last dose of
treatment. Primary tumors and involved axillary lymph nodes were identified, and
the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose
uptake ratio [DUR] and influx constant [K]). Pathologic response was determined
after chemotherapy by evaluation of surgical resection specimens. RESULTS: Thirty
one primary breast lesions were identified. The mean pretreatment DUR values of
the eight lesions that achieved a complete microscopic pathologic response were
significantly (P =.037) higher than those from less responsive lesions. The mean
reduction in DUR after the first pulse of chemotherapy was significantly greater
in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or
complete microscopic (P =.001) pathologic response. PET after a single pulse of
chemotherapy was able to predict complete pathologic response with a sensitivity
of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph
node metastases. Mean pretreatment DUR values in the metastatic lesions that
responded did not differ significantly from those that failed to respond (P
=.076). However, mean pretreatment K values were significantly higher in
ultimately responsive cancers (P =.037). The mean change in DUR and K after the
first pulse of chemotherapy was significantly greater in responding lesions (DUR,
P =.038; K, P =.012). CONCLUSION: [(18)F]-FDG PET imaging of primary and
metastatic breast cancer after a single pulse of chemotherapy may be of value in
the prediction of pathologic treatment response.
PMID- 10764429
TI - Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring
primary chemotherapy in breast cancer.
AB - PURPOSE: To address the role of positron emission tomography (PET) using
[(18)F]fluorodeoxyglucose (FDG) to monitor primary (neoadjuvant) chemotherapy in
patients with locally advanced breast cancer. PATIENTS AND METHODS:
Quantification of regional FDG uptake of the breast acquired after the first and
second courses of chemotherapy was compared with the baseline scan in 22 patients
with a total of 24 breast carcinomas. To evaluate the predictive value of PET
imaging, histopathologic response after completion of chemotherapy classified as
gross residual disease (GRD) or minimal residual disease (MRD) served as the gold
standard. RESULTS: Significant differences in tracer uptake between nonresponding
tumors (GRD) and responding lesions (MRD) were observed (P <.05) as early as
after the first course of chemotherapy. Tracer uptake showed little change in
tumors with GRD found later in pathologic analysis but decreased sharply to the
background level in most tumors with MRD. After the first course, all responders
were correctly identified (sensitivity 100%, specificity 85%) by a standardized
uptake value decrease below 55% of the baseline scan. At this threshold,
histopathologic response could be predicted with an accuracy of 88% and 91% after
the first and second courses of therapy, respectively. CONCLUSION: This study
demonstrates that in patients with advanced breast cancer undergoing primary
chemotherapy, FDG-PET differentiates responders from nonresponders early in the
course of therapy. This may help improve patient management by avoiding
ineffective chemotherapy and supporting the decision to continue dose-intensive
preoperative chemotherapy in responding patients.
PMID- 10764430
TI - Role of isolated locoregional recurrence of breast cancer: results of four
prospective studies.
AB - PURPOSE: We evaluated the effect on future prognosis of an isolated locoregional
recurrence (ILRR) after the primary diagnosis of breast cancer. Using data from
four prospective studies of the German Breast Cancer Study Group, we investigated
factors influencing prognosis after ILRR and defined a simple classification of
patients into groups with different prognoses. PATIENTS AND METHODS: From 1983 to
1989, 2,746 patients were recruited into four studies comparing different
treatments in primary breast cancer. After a median follow-up time of 8 years,
337 patients developed an ILRR as the first event. The influence of ILRRs on
disease progression was examined. The effects of different prognostic factors on
progression-free survival (PFS) and overall survival after ILRR were analyzed
after a median follow-up time of 4.5 years. RESULTS: ILRRs increased the risk
with respect to distant recurrence and death. After ILRR, 185 events occurred
with respect to the PFS end point, and 171 patients died. Primary nodal status,
tumor grade, estrogen receptor status of the primary tumor, and length of the
disease-free interval (DFI) until the time of the ILRR had a significant
prognostic impact. CONCLUSION: Determinants of prognosis after the ILRR should be
taken into account for designing future risk-adapted clinical studies for these
patients. Risk strata can be defined by a simple classification scheme based on
primary nodal status and DFI.
PMID- 10764431
TI - What threshold for adjuvant therapy in older breast cancer patients?
AB - PURPOSE: To consider the question of when to prescribe adjuvant treatment for
elderly breast cancer patients, particularly when comorbidities are present.
Knowledge of the threshold relapse risks above which adjuvant treatment is worth
prescribing would enhance decision making. PATIENTS AND METHODS: A Markov
analysis of data from the medical literature was conducted. Patients aged 65 to
85 years were considered, along with three levels of comorbidity. The threshold
risk of relapse at 10 years (RR10), at which time treatment provides absolute
reduction or reduction of an absolute 1% in relapse or mortality, was evaluated.
RESULTS: The threshold RR10 for an absolute reduction in mortality risk by
adjuvant treatment was low through the age of 85 years. However, for an absolute
1% reduction, the effect of treatment on relapse and the effect of treatment on
mortality increasingly diverged. The threshold RR10 for an absolute 1% reduction
in relapse risk remained fairly low (5% to 6% for tamoxifen, 12% to 19% for
chemotherapy). The threshold RR10 for an absolute 1% reduction in mortality risk,
although starting close to the RR10 for an absolute 1% reduction in relapse risk,
rose sharply. For tamoxifen, the difference between the two was 4% for an average
65-year-old, 6% at the age of 75 years, and 15% at the age of 85 years. For
chemotherapy, the differences were 6%, 12%, and 30%, respectively. Similarly,
thresholds increased with increasing comorbidity. In older and sicker patients,
the maximum benefit was reached after 5 years rather than 10 years. CONCLUSION:
Older breast cancer patients can expect a reduction in relapse that is fairly
similar to that of younger patients. However, the effect on mortality diverges
markedly, and attention should be paid to this difference in clinical decision
making. Comorbidity should be considered in recommendations for adjuvant
treatment, including clinical practice guidelines.
PMID- 10764432
TI - Economic impact of harmonizing medical practices: compliance with clinical
practice guidelines in the follow-up of breast cancer in a French Comprehensive
Cancer Center.
AB - PURPOSE: The introduction of clinical practice guidelines (CPGs) and the
increasing desire to harmonize clinical practices draw attention to the economic
impact of these trends. In 1994, CPGs were introduced in a French Comprehensive
Cancer Center (Centre Regional Leon Berard, Lyon). We evaluated the application
of these CPGs in addition to the consequences of harmonizing clinical practices
with respect to the distribution of resources by specifically analyzing the
posttherapeutic follow-up of patients with localized breast cancer. METHODS: A
before-and-after analysis of the records of patients who received posttherapeutic
follow-up for localized breast cancer as of either 1993 or 1995 was performed.
Two hundred records were chosen at random, 100 from 1993 and 100 from 1995.
Follow-up was continued for as long as possible and CPG compliance was studied
for each year of the follow-up periods. RESULTS: Follow-up that was not CPG
compliant required a significantly greater amount of resources. This difference
was due to neither consultations nor mammographies, but was due to other
examinations that were systematically performed without any warning signs to
justify them. Depending on the follow-up year, noncompliant follow-up cost the
Social Security from 2.2 to 3.6 times more than compliant follow-up. A noticeable
change in medical practices was observed after the introduction of CPGs in 1994.
This was confirmed by a sharp decrease in mean Social Security expenditure per
patient of more than one third between 1993 and 1995, regardless of the follow-up
year considered. CONCLUSION: In the follow-up of patients with localized breast
cancer, a large decrease in costs has been observed along with the evolution of
medical practices toward CPG compliance. This finding is probably generalizable
to other settings, but there is nothing that proves that it is applicable to
other treatment strategies.
PMID- 10764433
TI - Cardiovascular morbidity in long-term survivors of metastatic testicular cancer.
AB - PURPOSE: To determine whether long-term survivors of metastatic testicular cancer
have an increased risk of cardiovascular morbidity more than 10 years after
chemotherapy. PATIENTS AND METHODS: Eighty-seven patients treated with cisplatin
containing chemotherapy before 1987 who were in remission for at least 10 years
and whose ages were /= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine
cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and
vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three
cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic
radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC
and R/T arms. Women with enlarged para-aortic lymph nodes on image study were
ineligible unless results of cytologic or histologic studies were negative.
RESULTS: Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm
could be evaluated. The median duration of follow-up was 39 months. Thirty-one
percent of patients in the NAC arm and 27% in the R/T arm had relapse or
persistent diseases after treatment, and 21% in each group died of disease.
Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84%
for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no
significant differences in disease-free survival and overall survival.
CONCLUSION: NAC followed by radical hysterectomy and primary R/T showed similar
efficacy for bulky stage IB or IIA cervical cancer. Further study to identify
patient subgroups better suited for either treatment modality and to evaluate the
concurrent use of cisplatin and radiation without routine hysterectomy is
necessary.
PMID- 10764436
TI - Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted
antifolate agent in patients with advanced solid tumors.
AB - PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like
gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and
gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic
synergy. PATIENTS AND METHODS: Thirty-five patients (group I) received 164
courses (median, four; range, one to 14 courses) of treatment of gemcitabine at
doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300,
400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses
were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or
omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated
on an alternate schedule, with MTA administered on day 8 rather than day 1. This
group received 85 treatment courses (median, four; range, one to 10 courses).
RESULTS: The most common and dose-limiting toxicity was neutropenia. Other
toxicities included nausea, fatigue, rash, and elevated hepatic transaminases.
The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and
1,250/500 mg/m(2) for group II. Thirteen objective responses were documented
(colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma,
n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and
adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the
disposition of MTA. CONCLUSION: The gemcitabine/MTA combination is broadly active
and warrants further evaluation. The sequence of gemcitabine administered on days
1 and 8 with MTA administered on day 8 is better tolerated and is recommended for
further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).
PMID- 10764437
TI - Allopurinol: intravenous use for prevention and treatment of hyperuricemia.
AB - PURPOSE: To tabulate data obtained over a 21-year period to determine the
efficacy and safety of an intravenous (IV) allopurinol preparation. PATIENTS AND
METHODS: IV allopurinol was provided on a compassionate plea basis to patients of
any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to
chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven
investigators at multiple hospitals in the United States treated 1,172 patients
with IV allopurinol. The vast majority of these patients had a malignancy and
were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric
acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable
to the time period of IV allopurinol administration were collected, collated, and
analyzed retrospectively. There was no randomization. RESULTS: In patients
initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or
improved in 87% of adult patients and normalized or improved in 95% of pediatric
patients. IV allopurinol, administered prophylactically to patients at high risk
of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93%
of adults and 92% of children. Toxicities caused by IV allopurinol were minimal
and consisted of 10 instances of mild to moderate skin or allergic reactions.
CONCLUSION: IV allopurinol is as efficacious and safe as oral allopurinol and
will be of significant benefit to patients at risk of TLS and AUAN and unable to
take oral medication.
PMID- 10764438
TI - Growth factor usage patterns and outcomes in the community setting: collection
through a practice-based computerized clinical information system.
AB - PURPOSE: Although use of colony-stimulating factor (CSF) is widespread and
guidelines for use have been disseminated, actual practice patterns of medical
oncologists are unknown. The purpose of this study was to collect these data
using an office-based computerized clinical information system. PATIENTS AND
METHODS: Data were collected on patients at 10 community-based oncology
practices. Information regarding CSF use was captured at the time of prescribing
through a computerized clinical support tool and stored in a data warehouse, and
an analysis was carried out retrospectively. RESULTS: A total of 6,813 cancer
regimens administered to 5,034 patients were evaluated for growth factor use.
Overall, CSFs were used in 14% of regimens, with breast, lymphoma, lung, and
ovarian being the most common cancers for which CSFs were used. In 49.4% of
regimens, CSF was initiated during cycle 1, with an average duration of 1 week,
and was used in two or three cycles per regimen. Afebrile neutropenia is rarely
followed by CSF initiation. Granulocyte colony-stimulating factor (G-CSF) is
associated with fewer dose adjustments, delays, and hospitalizations when
compared with granulocyte-macrophage colony stimulating factor (GM-CSF). There is
wide variation among oncologists in CSF use, and several substantial differences
were noted between the prescribing behavior of American Society of Clinical
Oncology (ASCO) survey-reported oncologists and actual clinical practice, as
captured by the computerized clinical information system. CONCLUSION:
Computerized clinical information systems can collect detailed information
regarding practice patterns of medical oncologists. ASCO physician practice
survey data do not accurately reflect actual practice patterns and must be
interpreted with caution. Substantial deviations from ASCO growth factor
guidelines remain, and oncologists' use of CSFs demonstrates wide variation.
There may be important clinical differences between G-CSF and GM-CSF, but
definitive phase III trials are needed for confirmation.
PMID- 10764439
TI - Pathology data in the central databases of multicenter randomized trials need to
be based on pathology reports and controlled by trained quality managers.
AB - PURPOSE: Randomized multicenter trials form the basis of health care development.
Regarding cancer research, pathology data are crucial. To maintain the quality of
these trials, the auditing of subsequent processes is necessary. The aim of the
present study was to examine the completeness and accuracy of data obtained from
a special-purpose standardized pathology form compared with the data available
through traditional hospital pathology reports. PATIENTS AND METHODS: A
retrospective comparison of pathology data case record forms with hospital
pathology reports was performed using the data from 300 patients with primary
rectal cancer. All of these patients had been included in a large multicenter
trial in the Netherlands. Three independent audits were carried out. Special
attention was given to the accuracy of parameters, which are important for
prognosis and treatment decisions. Furthermore, various factors that possibly
influence the occurrence of errors were investigated. RESULTS: Quality control of
the pathology data revealed a high accuracy of 86.5% of all data items. However,
only one third of the forms were complete and correct. Missing values were most
prominent in the number of lymph nodes examined, whereas most errors were made in
relation to the circumferential margin. Trained review pathologists made fewer
major errors. Discrepancies were detected in all control rounds. CONCLUSION:
Successive rounds of quality control are required for accuracy and completeness
of pathology data in multicenter trials. In addition to the special-purpose
pathology forms, original pathology reports have to be collected, and the data
should also be controlled by a trained pathology quality manager.
PMID- 10764440
TI - Drug interactions in palliative care.
AB - PURPOSE: This review of drug interactions in palliative care examines the
relevant literature in this area and summarizes the information on interactions
of drugs, nutrients, and natural products that are used in the palliative care
setting. Particular emphasis is placed on describing the newer information on the
cytochrome P450 (CYP) system and the interactions of opioids, antidepressants,
and the antitussive, dextromethorphan. METHODS: We performed a search of the
MEDLINE database of the time period from 1966 until April 1998, using medical
subject headings such as the names of selective serotonin reuptake inhibitors and
other relevant medications in palliative care. Literature reviewed included both
human and animal articles as well as non-English literature. Bibliographies of
these articles and the personal libraries of several palliative care specialists
were reviewed. Software developed by The Medical Letter-The Drug Interaction
Program was also used. RESULTS: Drug interactions can be categorized in several
ways. Drug-drug interactions are the most well known and can be kinetic, dynamic,
or pharmaceutical. Pharmacokinetic interactions can involve CYP 2D6, which acts
on drugs such as codeine and is responsible for its conversion to morphine. Poor
metabolizers, either genotypic or due to phenocopying, are at risk for
undertreatment if not recognized. Pharmacodynamic interactions with
dextromethorphan may produce serotonin syndrome. CONCLUSION: Drug interactions
are important in palliative care as in other aspects of medicine. These
interactions are similar to those seen in other areas of medical care but have
significant consequences in pain management. Failure to recognize these
interactions can lead to either overdosing or undertreatment.
PMID- 10764441
TI - Misconceptions with staging of soft tissue sarcoma.
PMID- 10764442
TI - Standards of reporting quality of life in clinical trials.
PMID- 10764443
TI - Quality of life in non-small-cell lung cancer.
PMID- 10764444
TI - Letrozole: which dose to be used?
PMID- 10764445
TI - Maintenance chemotherapy in advanced ovarian cancer.
PMID- 10764446
TI - Plasma MMPs as surrogates of BAY 12-9566.
PMID- 10764447
TI - Hepatic arterial chemotherapy: still on trial.
PMID- 10764449
TI - Horizon of hope
PMID- 10764448
TI - Is tamoxifen cost-effective for prevention of breast cancer?
PMID- 10764450
TI - Transactions of the Eighteenth Annual Meeting of the American Gynecological and
Obstetrical Society. AGOS@Y2K: Presidential address.
PMID- 10764451
TI - Maternal mortality: confidential enquiries into maternal deaths in the United
Kingdom.
PMID- 10764452
TI - Expression of dioxin-related transactivating factors and target genes in human
eutopic endometrial and endometriotic tissues.
AB - OBJECTIVE: Although an association between dioxin exposure and endometriosis has
been proposed, the effects of this environmental toxin on human endometriosis are
not known. To understand the potential underlying molecular mechanisms we studied
the expressions of cytochrome P-450 genes (CYP1A1, CYP1A2, and CYP1B1 ), which
are induced by dioxin, and the expressions of cytosolic receptor for dioxin, aryl
hydrocarbon receptor, and its nuclear translocator, aryl hydrocarbon receptor
nuclear translocator protein, in endometriotic and eutopic endometrial tissues.
STUDY DESIGN: Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon
receptor, and aryl hydrocarbon receptor nuclear translocator protein were
determined by a quantitative reverse transcriptase-polymerase chain reaction and
Southern blot assay in total ribonucleic acid samples from endometriotic and
eutopic endometrial tissues. Eutopic endometrial tissue samples (n = 33) and
endometriotic tissue samples (n = 10) were obtained at the time of uterine
curettage and laparoscopy from disease-free women and from patients with
endometriosis. Portions of these eutopic endometrial and endometriotic tissues
were obtained simultaneously from the same patients (n = 8 pairs of samples).
Levels of transcripts of CYP1A1, CYP1A2, CYP1B1, aryl hydrocarbon receptor, and
aryl hydrocarbon receptor nuclear translocator protein were determined in
endometrial and endometriotic tissues during follicular and luteal phases of the
cycle and in cultured endometriotic stromal cells treated with forskolin, phorbol
diacetate, medroxyprogesterone acetate,and serum. RESULTS: Transcripts of dioxin
receptor, its nuclear translocator, and two dioxin-induced target genes (CYP1A2
and CYP1B1) were demonstrated during follicular and luteal phases of the cycle in
both eutopic endometrial tissues and tissues affected by pelvic endometriosis,
with no readily detectable differences between these tissues. On the other hand,
levels of transcripts of another dioxin-induced gene, CYP1A1, were found to be
strikingly higher in endometriotic tissues than in the eutopic endometrium. Mean
levels in endometriotic tissues were 8.7 times those found in eutopic
endometrium. Various hormonal treatments of endometriotic stromal cells did not
significantly alter these levels. CONCLUSION: We demonstrated for the first time
the expression of dioxin-related transcription factors aryl hydrocarbon receptor
and aryl hydrocarbon receptor nuclear translocator protein and target genes
CYP1A1, CYP1A2, and CYP1B1 in endometriotic tissues and stromal cells. Strikingly
elevated CYP1A1 transcripts in endometriosis may give rise to significantly
increased P-4501A1 enzyme activity and thus promote the development and growth of
endometriosis by either activating procarcinogens or inducing the formation of
catechol estrogens or both. In fact, the proposed link between dioxin exposure
and endometriosis may be explained in part by the up-regulation of the CYP1A1
gene expression in endometriotic tissues.
PMID- 10764453
TI - Cerebrospinal fluid levels of corticotropin-releasing hormone in women with
functional hypothalamic amenorrhea.
AB - OBJECTIVE: Women with functional hypothalamic amenorrhea are anovulatory because
of reduced gonadotropin-releasing hormone drive. Several studies have documented
hypercortisolemia, which suggests that functional hypothalamic amenorrhea is
stress-induced. Further, with recovery (resumption of ovulation), cortisol
decreased and gonadotropin-releasing hormone drive increased. Corticotropin
releasing hormone can increase cortisol and decrease gonadotropin-releasing
hormone. To determine its role in functional hypothalamic amenorrhea, we measured
corticotropin-releasing hormone in cerebrospinal fluid along with arginine
vasopressin, another potent adrenocorticotropic hormone secretagog, and beta
endorphin, which is released by corticotropin-releasing hormone and can inhibit
gonadotropin-releasing hormone. STUDY DESIGN: Corticotropin-releasing hormone,
vasopressin, and beta-endorphin levels were measured in cerebrospinal fluid from
14 women with eumenorrhea and 15 women with functional hypothalamic amenorrhea.
RESULTS: Levels of corticotropin-releasing hormone in cerebrospinal fluid and of
vasopressin were comparable and beta-endorphin levels were lower in women with
functional hypothalamic amenorrhea. CONCLUSIONS: In women with established
functional hypothalamic amenorrhea, increased cortisol and reduced gonadotropin
releasing hormone are not sustained by elevated cerebrospinal-fluid corticotropin
releasing hormone, vasopressin, or beta-endorphin. These data do not exclude a
role for these factors in the initiation of functional hypothalamic amenorrhea.
PMID- 10764454
TI - Methylation-dependent melting polymorphisms in genomic fragments of
deoxyribonucleic acid.
AB - OBJECTIVES: Denaturing gradient gel electrophoresis can detect single base
sequence differences in deoxyribonucleic acid and methylation differences in
small cloned fragments of deoxyribonucleic acid. We previously detected cell type
specific melting differences by denaturing gradient gel electrophoresis in paired
leukocyte and sperm cell samples of deoxyribonucleic acid. We proposed that these
differences were caused by differential methylation and that blotting strategies
using denaturing gradient gel electrophoresis might be useful in detecting in
vivo variations in methylation patterns. STUDY DESIGN: Genomic deoxyribonucleic
acid from leukocytes and sperm cells of 35 male subjects was analyzed by
denaturing gradient gel electrophoresis after digestion by 4-bp site enzymes and
Msp I and its methylation-sensitive isoschizomer Hpa II. Some fragments were
amplified by polymerase chain reaction. RESULTS: Cell type-specific melting
polymorphisms were detected in all genes from all subjects. Analysis of Msp I/Hpa
II sites demonstrated that differences noted correlated with the methylation
state. Cell type-specific differences were absent in fragments amplified by
polymerase chain reaction. CONCLUSIONS: The denaturing gradient gel
electrophoresis blotting technique is a fast and comprehensive method for
comparing in vivo methylation differences.
PMID- 10764455
TI - The urethrodetrusor facilitative reflex in women: results of urethral perfusion
studies.
AB - OBJECTIVE: This study was undertaken to describe the effects of urethral
perfusion on bladder activity, urethral pressure, and sensation in patients with
either incontinence or prolapse or both of these. STUDY DESIGN: Among 76
consecutive patients who were seen for urodynamic evaluations, 63 had vesical,
abdominal, and urethral pressures measured while the urethra was perfused with
fluid. A perfusion study result was considered positive if the perfusion provoked
a detrusor contraction. RESULTS: Of the 63 women 9 (14%) had a positive urethral
perfusion study result, and all of them had detrusor instability independent of
perfusion. Among the women with detrusor instability 53% (n = 9/17) had positive
study results, versus none of the 46 women without detrusor instability (P =.
000001). Women with mixed incontinence were more likely to have a positive
perfusion test result (n = 4/7; 57%) than were those without mixed incontinence
(n = 5/56; 10%; P =.006), although urethral hypermobility was not significantly
associated with a positive test result. Among the subjects 60% experienced
urgency during perfusion, and in half of these urethral pressure was concurrently
increased. Among those who had no urgency 84% demonstrated decreased urethral
pressure (P =.01). CONCLUSIONS: Positive perfusion study results were more common
among women with detrusor instability but did not discriminate any patient with
detrusor instability whose condition was not diagnosed by standard urodynamic
studies. The association of positive perfusion study results with mixed
incontinence seems primarily related to poor central inhibition of detrusor
activity rather than to urethral stimulation.
PMID- 10764456
TI - Further evidence of a decorin-collagen interaction in the disruption of cervical
collagen fibers during rat gestation.
AB - OBJECTIVE: Our purpose was to determine the histologic distribution and
expression of decorin in rat cervix throughout the course of rat gestation and to
correlate the findings with the known progression of collagen fiber disruption
and cellular turnover in this tissue. STUDY DESIGN: Cervices from pregnant
animals at 5, 11, 18, and 21 days were studied. A proteoglycan of low molecular
weight, decorin, was detected by sensitive and specific immunohistochemical
analysis with a biotin-avidin horseradish peroxidase method. RESULTS: Decorin was
not detected on day 5. By day 11 moderate decorin staining was detected in the
subepithelial layer and in the deep stroma. Decorin staining progressed to a
strong expression in the subepithelial layer and to a moderate expression in the
deep stroma on day 18. On day 21 (term in rat) the staining was fairly
homogeneous throughout the connective tissue stroma. CONCLUSION: These findings
clearly demonstrate that decorin expression increased progressively throughout
pregnancy and are consistent with the hypothesis that an excess of decorin near
term is capable of initiating a decorin-collagen interaction that leads to
collagen fibril disruption and decreased cervical tensile strength.
PMID- 10764457
TI - The clinical significance of the irregular fetal heart rhythm.
AB - OBJECTIVE: Irregular fetal heart rhythms are common in clinical practice, but
there is little information available on their significance or appropriate
management. STUDY DESIGN: This was a retrospective review of fetuses seen during
10 years that either were referred for fetal echocardiography because of a fetal
arrhythmia or were found incidentally to have an arrhythmia during fetal
echocardiography for other indications. RESULTS: From 1988 through 1997 we
performed 5566 fetal echocardiograms on 4838 different fetuses. There were 614
fetuses with irregular fetal heart rhythms. Among 595 referred for arrhythmias,
extrasystoles were found in 255 (42.9%), normal rhythms were seen in 330 (55.4%),
and hemodynamically significant arrhythmias were seen in 10. There were 2 fetuses
with arrhythmias and structural heart disease. Nine of 10 fetuses with
hemodynamically significant arrhythmias survived. An additional five neonates
were found to have hemodynamically significant arrhythmias only postnatally. A
total of 15 fetuses (2. 4%) among those referred for irregular rhythms had
significant arrhythmias. CONCLUSIONS: Irregular fetal heart rhythms signify
hemodynamically significant arrhythmias in a small but important proportion of
fetuses. Those without persistent irregularities on evaluation can be followed up
with routine prenatal care.
PMID- 10764458
TI - A case-control study of anatomic changes resulting from sexual abuse.
AB - OBJECTIVE: Our goal was to identify vulvar and hymenal characteristics associated
with sexual abuse among female children between the ages of 3 and 8 years. STUDY
DESIGN: Using a case-control study design, we examined and photographed the
external genitalia of 192 prepubertal children with a history of penetration and
200 children who denied prior abuse. Bivariate analyses were conducted by chi(2),
the Fisher exact test, and the Student t test to assess differences in vulvar and
hymenal features between groups. RESULTS: Vaginal discharge was observed more
frequently in abused children (P =.01). No difference was noted in the percentage
of abused versus nonabused children with labial agglutination, increased
vascularity, linea vestibularis, friability, a perineal depression, or a hymenal
bump, tag, longitudinal intravaginal ridge, external ridge, band, or superficial
notch. Furthermore, the mean number of each of these features per child did not
differ between groups. A hymenal transection, perforation, or deep notch was
observed in 4 children, all of whom were abused. CONCLUSION: The genital
examination of the abused child rarely differs from that of the nonabused child.
Thus legal experts should focus on the child's history as the primary evidence of
abuse.
PMID- 10764459
TI - Changes in umbilical venous velocities with physiologic perturbations.
AB - OBJECTIVE: The purpose of this study was to determine the direction of
transmission of umbilical venous Doppler flow velocity changes in human fetuses.
STUDY DESIGN: Strip chart recordings of simultaneously measured umbilical
arterial and venous velocities were examined at two sites in the umbilical cord,
one near the fetus (proximal) and one near the placenta (distal). Fetuses with
venous pulsations or breathing episodes were included. At both locations time
from venous pulsation to arterial systole was measured in fetuses with venous
pulsations and duration of phase delay between arterial diastolic velocity
minimum and venous velocity minimum was measured in fetuses with breathing
episodes. RESULTS: In 21 fetuses with venous pulsations the pulsations occurred
earlier in the cardiac cycle at proximal sites (0.12 +/- 0.04 second before
systole) and later at distal sites (0.02 +/- 0.04 second before systole;P <.001).
Phase delays in venous velocities in the 5 fetuses with breathing episodes were
also longer at distal sites than at proximal sites (P <.011). CONCLUSION: Changes
in umbilical venous velocities occurred earlier at sites that were closer to the
fetus. These findings suggest that changes in umbilical venous velocities
originate in the fetal venous system and are transmitted to, rather than from,
the placenta.
PMID- 10764460
TI - Effects of progestins and relaxin on glycodelin gene expression in human
endometrial cells.
AB - OBJECTIVE: Glycodelin is an endometrial protein proposed to play an important
role in embryonic implantation. We examined the effects of progestins and relaxin
on glycodelin transcription, synthesis, and secretion. STUDY DESIGN: Northern
blotting, metabolic labeling, and fluorography were used to assess glycodelin
messenger ribonucleic acid and protein synthesis in endometrial tissue and cells.
Luciferase reporter constructs transfected into endometrial adenocarcinoma cells
(Ishikawa cells) were used to determine whether progestins or relaxin could
activate the glycodelin gene promoter. RESULTS: Progestins but not relaxin
stimulated glycodelin secretion in primary epithelial cell cultures. A 452-base
pair fragment of the glycodelin gene promoter was activated 4.3 +/- 0.7 times
normal by 10-nmol/L promegestone; however, addition of relaxin to the same
construct repressed progestin-stimulate promoter activation by >30%. CONCLUSION:
Glycodelin transcription, synthesis, and secretion by endometrial epithelial
cells were stimulated by progestins. However, relaxin failed to stimulate
production of this immunomodulatory protein and, in fact, repressed progestin
stimulated activation of the glycodelin gene promoter.
PMID- 10764461
TI - Functional oxytocin receptors in a human endometrial cell line.
AB - OBJECTIVE: Our goal was to demonstrate expression and functionality of oxytocin
receptors in a human endometrial cell line. This cell line could then be used for
further investigation of the role of oxytocin in reproductive function at the
cellular level. STUDY DESIGN: Oxytocin receptor messenger ribonucleic acid
expression was determined by reverse transcriptase-polymerase chain reaction
deoxyribonucleic acid amplification with ribonucleic acid from confluent Ishikawa
cells. Ligand binding to whole cells was evaluated by nonlinear regression
analysis with an iodinated oxytocin antagonist. The coupling of the oxytocin
receptor to signaling pathways was evaluated by measuring oxytocin-stimulated
increases in intracellular calcium concentration, phosphorylation of ERK2
(extracellular-regulated protein kinase 2) mitogen-activated protein kinase, and
prostaglandin E(2) release. RESULTS: Polyacrylamide gel electrophoresis of the
reverse transcriptase-polymerase chain reaction products demonstrated the
presence of oxytocin receptor messenger ribonucleic acid in Ishikawa cells.
Ligand-binding analysis of these cells demonstrated a single class of
noninteracting sites, with a B(max) (maximal number of binding sites) of 77.7
fmol/mg deoxyribonucleic acid and an apparent dissociation constant of 8.3 x 10(
11) mol/L. Stimulation with 100-nmol/L oxytocin caused a rapid transient increase
in intracellular free calcium concentration, which was blocked by 1-micromol/L
oxytocin antagonist. Treatment of cells with oxytocin for 10 minutes resulted in
a marked increase in the phosphorylation of ERK2, as determined by Western blot
analysis, and a 5-fold increase in prostaglandin E(2) release. CONCLUSION: This
study is the first to demonstrate functional oxytocin receptors in an established
human endometrial cell line. This cell line will be useful in elucidating the
mechanisms of action of oxytocin in the reproductive tract at the molecular
level.
PMID- 10764462
TI - Treatment of human immunodeficiency virus during pregnancy: the shift from an
exclusive focus on fetal protection to a more balanced approach.
AB - A review is presented of policy and treatment guidelines for human
immunodeficiency virus infection in pregnancy. Interventions that serve the best
interests of pregnant women and their fetuses are suggested. Reproductive studies
with animals should be done routinely, and more research with pregnant women
should be conducted. Women and their health care providers need to shift away
from the "therapeutic nihilism" paradigm. All clinical decisions must be made
cautiously and thoughtfully, with the understanding that the health needs of the
pregnant woman are usually whatever is in the best interest of the developing
fetus.
PMID- 10764463
TI - Testing for high-risk human papillomavirus types will become a standard of
clinical care.
AB - Testing for high-risk human papillomavirus types should become a standard of care
for women in the United States because cervical cancer is an infectious disease.
Current care is based on cytologic screening and a pathologic staging of cellular
tissue changes. Before these cellular modifications, there is a demonstrable
pattern of human papillomavirus infection. Human papillomavirus is the most
frequently acquired sexually transmitted disease in women and is usually
eliminated without treatment. Persistence of high-risk human papillomavirus types
can lead to abnormal cervical cellular changes. When these cervical cellular
changes occur, physician interventions hasten human papillomavirus elimination.
Currently, adding human papillomavirus screening to the Papanicolaou smear
identifies a population for closer follow-up studies. In the future a vaccine
should be introduced to prevent infections, and medical treatments to hasten the
elimination of high-risk human papillomavirus types should become part of
standard medical practice.
PMID- 10764464
TI - Needle excision of the transformation zone: A new method for treatment of
cervical intraepithelial neoplasia.
AB - OBJECTIVE: This study was undertaken to evaluate a new needle electrode for
conization of the cervix that was developed in my department. STUDY DESIGN: This
was a prospective study of 58 unselected women with histologically verified
cervical intraepithelial neoplasia who underwent conization with the diathermy
needle. The operations were performed with local anesthesia as outpatient
procedures. Follow-up time was 5 years. RESULTS: All cones were removed in one
piece and were of high histologic quality. Mean (+/-SD) operating time, including
anesthesia, was 7.9 +/- 2.7 minutes. Mean depth of thermal damage was 0.29 +/-
0.21 mm, and mean blood loss was 12.5 +/- 9.4 mL. No late complications have been
noted, and 94.8% of patients have required no further treatment. CONCLUSION:
Needle excision of the transformation zone is a simple and effective outpatient
procedure that yields a one-piece cone specimen of high quality and carries a
success rate of 94.8%.
PMID- 10764465
TI - Pathogenesis of abnormal vaginal bacterial flora.
AB - OBJECTIVE: This study was undertaken to determine the relationships between
microscopy findings on wet mounts, such as lactobacillary grade or vaginal
leukocytosis, and results of vaginal culture, lactate and succinate content of
the vagina, and levels of selected cytokines. STUDY DESIGN: In a population of
631 unselected women seeking treatment at an obstetrics and gynecology outpatient
clinic, vaginal fluid was obtained by wooden Ayre spatula for wet mounting and pH
measurement, by high vaginal swab for culture, and by standardized vaginal
rinsing with 2 mL 0.9% sodium chloride solution for measurements of lactate,
succinate, interleukin 1beta, interleukin 8, leukemia inhibitory factor, and
interleukin 1 receptor antagonist concentrations. Lactate and succinate levels
were measured by gas-liquid chromatography and the cytokine concentrations were
measured by specific immunoassays. Both univariate analysis (Student t test,
Welch test, chi(2) test, and Fisher exact test) and multivariate regression
analysis (Cox analysis) were used. RESULTS: Increasing disturbance of the
lactobacillary flora (lactobacillary grades I, IIa, IIb, and III) was highly
correlated with the presence of Gardnerella vaginalis, Trichomonas vaginalis,
enterococci, group B streptococci, and Escherichia coli. Vaginal pH and
interleukin 8 and interleukin 1beta concentrations increased linearly with
increasing lactobacillary grade, whereas lactate concentrations and the presence
of epithelial cell lysis decreased. A similar pattern of associations with
increasing leukocyte count was clear, but in addition there was an increase in
leukemia inhibitory factor concentration. Multivariate analysis of vaginal
leukocytosis, lactobacillary grades, and the presence of positive vaginal culture
results showed that interleukin 1beta concentration was most closely related to
the lactobacillary grade, leukemia inhibitory factor concentration was most
closely related to the lactobacillary grade and positive culture results,
interleukin 8 concentration was most closely related to positive culture results,
and interleukin 1 receptor antagonist concentration was most closely related to
vaginal leukocytosis and positive culture results. The concentration ratio of
interleukin 1beta to interleukin 1 receptor antagonist remained stable, except
when vaginal leukocytosis increased. In its most severe form, with >10 leukocytes
per epithelial cell present, a decompensation of the vaginal flora with a
collapse in interleukin 1beta and interleukin 1 receptor antagonist
concentrations was seen, but there was a concurrent sharp increase in leukemia
inhibitory factor concentration. This pattern was completely different from the
course of the cytokine concentrations associated with a lactobacillary grade
increase. CONCLUSION: Both disturbed lactobacillary grade and the presence of
increasing vaginal leukocytosis were correlated with lactobacillary substrate
(lactate) concentration, pH, and the concentrations of a variety of cytokines.
There was a remarkably linear increase in these cytokines as either leukocytosis
or lactobacillary grade became more severe. In circumstances in which
leukocytosis was extreme, however, interleukin 1beta was no longer produced but
leukemia inhibitory factor concentrations increased. We speculate that in extreme
inflammation the body tries to limit the damage that can be done by exaggerated
cytokine production.
PMID- 10764466
TI - Ultrastructure of detrusor and urethral smooth muscle in women with urinary
incontinence.
AB - OBJECTIVE: We performed a quantitative study to determine whether mixed urinary
incontinence was associated with any ultrastructural changes in detrusor and
urethral smooth muscle. STUDY DESIGN: Detrusor and urethral smooth muscle biopsy
specimens were obtained at the time of laparotomy from 5 women aged 35 to 65
years with mixed urinary incontinence and from a control group of 5 continent
women. Smooth muscle morphologic characteristics were assessed from a systematic
random sample of electron micrographs. A further 16 urethral biopsy specimens
were similarly analyzed to confirm the findings of the initial study. RESULTS:
The electron-dense portion of the sarcolemma was smaller in urethral biopsy
specimens taken from patients with intrinsic sphincter deficiency than in those
from control subjects (chi(2)((1)) = 4.9; P =.027). No other morphologic
characteristics were unique to patients with incontinence. CONCLUSIONS: Our study
suggests that focal adhesion architecture is decreased in urethral smooth muscle
of patients with intrinsic sphincter deficiency.
PMID- 10764467
TI - Clinical significance of the qualification of atypical squamous cells of
undetermined significance: An analysis on the basis of histologic diagnoses.
AB - OBJECTIVE: This study was undertaken to evaluate the significance of further
qualification of atypical squamous cells of undetermined significance in routine
Papanicolaou smears. STUDY DESIGN: A retrospective medical records review was
conducted on 316 women whose Papanicolaou smears yielded diagnoses of either
atypical squamous cells of undetermined significance suggestive of the presence
of an intraepithelial lesion or atypical squamous cells of undetermined
significance suggestive of a reactive process. RESULTS: The overall incidence of
a squamous intraepithelial lesion (cervical intraepithelial neoplasia grades I,
II, and III) was higher in the group with atypical squamous cells of undetermined
significance suggestive of the presence of an intraepithelial lesion than in the
group with results suggestive of a reactive process (41.1% vs 22.3%; P =.0344).
Women with atypical squamous cells of undetermined significance suggestive of the
presence of an intraepithelial lesion were 9.7 times more likely to have high
grade squamous intraepithelial lesion (cervical intraepithelial neoplasia III)
develop than were women with atypical squamous cells of undetermined significance
suggestive of a reactive process (95% confidence interval, 1.26-74.64). The
incidence of high-grade squamous intraepithelial lesion was higher among women
35 years old (17.8% vs 6.3%; P =.0378).
CONCLUSION: Women with a diagnosis of atypical squamous cells of undetermined
significance suggestive of the presence of an intraepithelial lesion are more
likely to have intraepithelial lesions develop than are those with atypical
squamous cells of undetermined significance suggestive of a reactive process.
Aggressive evaluation of cases of atypical squamous cells of undetermined
significance suggestive of the presence of an intraepithelial lesion with
colposcopy and cervical biopsies may be appropriate. Age should be considered as
an independent factor in the plan of management.
PMID- 10764468
TI - Hidden costs of infertility treatment in employee health benefits plans.
AB - OBJECTIVES: Many employers exclude infertility treatment from coverage under
their health benefits plans. However, infertility treatment is often provided
under other diagnoses or in association with therapy rendered for other disease
processes. This study attempted to estimate those hidden costs and to determine
what the impact would be of providing coverage for infertility treatment. STUDY
DESIGN: A 1-year retrospective analysis was carried out to isolate the hidden
costs of infertility treatment from specific medical claims data gathered from a
large representative employer with no infertility benefit provided. Data were
analyzed in the context of the claims experience of a health plan covering
approximately 28,000 employees. Infertility treatment was excluded under this
plan. Medical claims for specific procedures and diagnoses in 1996 were analyzed
by using Current Procedural Terminology codes in conjunction with International
Classification of Diseases, Ninth Revision codes to estimate the hidden costs of
infertility treatment. Forty-one Current Procedural Terminology codes and 68
International Classification of Diseases, Ninth Revision codes were used for the
analysis. Clinical practice experience was used to set boundaries (conservative
and moderate estimate) regarding the likelihood of a given treatment being
associated with infertility. This was compared with 100% covered charges to
generate claims per employee per month. Procedures covered operative, diagnostic,
and laboratory services. These figures were used to compute a range of cost for
infertility treatment per member per month. RESULTS: Forty-one Current Procedural
Terminology codes were identified that indicated possible infertility treatment.
These covered the areas of laparoscopic and hysteroscopic surgery, lysis of
adhesions, neosalpingostomy, cyst drainage, oocyte retrieval or embryo transfer,
echography, and various hormonal analyses. Sixty-eight International
Classification of Diseases, Ninth Revision codes indicated the possibility of
infertility treatment. These included endocrine disorders, various uterine
pathologic conditions, pelvic pain, endometriosis, pregnancy loss, irregular
menses, and various ovulatory dysfunctions. The retrospective analysis found that
35 Current Procedural Terminology codes were involved in claims highly indicative
of infertility services, such as 56353, hysteroscopic division of uterine septum,
and 58345, transcervical fallopian tube catheterization. According to the 35
Current Procedural Terminology codes, $603,807.95 would have been paid if 100% of
the charges had been covered; this would have resulted in a claim per employee
per month of $1.12 by conservative estimate to $0.60 by moderate estimate.
Computed cost figures per member per month showed the hidden costs of infertility
to range between $0.27 and $0.50. CONCLUSION: On the basis of various cost
studies, rate filings, and employee data, the cost of providing coverage for
infertility treatment has previously been shown to vary between $0.20 and $2.00
per member per month. Through appropriate cost sharing, managed care, and
algorithms, infertility coverage can be offered at a cost of $0.40 to $0.50 per
member per month. This analysis indicates that at least some employers already
pay this much even when infertility is specifically excluded under the plan.
PMID- 10764469
TI - Increased concentrations of plasma neuropeptide Y in patients with eclampsia and
preeclampsia.
AB - OBJECTIVE: Epinephrine and norepinephrine are associated with the
hyperstimulation of the sympathetic nervous system. Neuropeptide Y is a potent
vasoconstrictive substance that is released in response to sympathetic nerve
stimulation. STUDY DESIGN: The concentrations of plasma neuropeptide Y in
pregnant patients with eclampsia (n = 8), preeclampsia (n = 8), and normotension
(n = 8) were measured by radioimmunoassay on admission and 6 days after delivery.
Correlations between plasma concentration of neuropeptide Y and mean arterial
blood pressure were also evaluated in these patients on admission and 6 days
after delivery. RESULTS: The plasma level of neuropeptide Y in women with
eclampsia (P <.001) and preeclampsia (P <.003) was found to be significantly
elevated with respect to that in normotensive pregnant women. At 6 days after
delivery the concentration of plasma neuropeptide Y was significantly decreased
in women with eclampsia, women with preeclampsia, and women with normotensive
pregnancies compared with the value measured on admission (P <.0001, P <.0001,
and P <.002, respectively). At admission the plasma neuropeptide Y level was
positively correlated with mean arterial blood pressure in women with eclampsia
and preeclampsia. However, no significant correlations were observed between
plasma neuropeptide Y concentration and mean arterial blood pressure both at
admission and 6 days after delivery in normotensive pregnant women and 6 days
after delivery in women with eclampsia and preeclampsia. CONCLUSION: We have
concluded that the level of neuropeptide Y in plasma is increased in women with
eclampsia and preeclampsia. Elevated plasma neuropeptide Y levels may play a key
role in the development of eclampsia and preeclampsia.
PMID- 10764470
TI - Correlation between amniotic fluid glucose concentration and amniotic fluid
volume in pregnancy complicated by diabetes.
AB - OBJECTIVE: Pregnancies complicated by diabetes are frequently characterized by an
increased volume of amniotic fluid, and the pathophysiologic mechanism of this
increase is not known. Our goal was to evaluate the relationship between amniotic
fluid glucose concentration and the amniotic fluid index in pregnancies
complicated by insulin-treated diabetes and to compare it with that seen in
normal pregnancies. STUDY DESIGN: Amniotic fluid index and amniotic fluid glucose
levels were measured before elective repeated cesarean delivery in 41 women with
insulin-treated diabetes and in 35 women without diabetes. Only singleton
gestations without anomalous fetuses were included. Women with diabetes were
hospitalized for approximately 4 weeks before delivery, during which time
glycemic control was optimized. Amniotic fluid index and amniotic fluid glucose
concentration were correlated with each other and were compared between the
groups with and without diabetes. RESULTS: The mean amniotic fluid index was
significantly increased in the diabetes group (16.6 +/- 5.0 cm in the diabetes
group vs 13.4 +/- 3.5 cm in the control group; P =.002). The amniotic fluid
glucose concentration was also significantly greater in the diabetes group than
in the control group (39 +/- 17 mg/dL in the diabetes group vs 24 +/- 11 mg/dL in
the control group; P <.001). Among women with diabetes the amniotic fluid glucose
concentration was significantly correlated with the amniotic fluid index (r =
0.32; P =.04), a correlation not found among the control women. The mean fasting
blood glucose concentration among the women with diabetes for the week before
amniocentesis was 82 +/- 11 mg/dL. CONCLUSION: The amniotic fluid index parallels
the amniotic fluid glucose level among women with diabetes. This finding raises
the possibility that the hydramnios associated with diabetes is a result of
increased amniotic fluid glucose concentration.
PMID- 10764471
TI - The effects of pregnancy and smooth muscle contractility on cervical
distensibility in the rat.
AB - OBJECTIVE: We sought to compare distensibility of the isolated rat cervix from
nonpregnant rats (n = 6), rats at midgestation (n = 5), and rats at term
gestation (n = 4). STUDY DESIGN: The cervix was excised, and one cervical channel
was cannulated from both ends and positioned in the organ chamber for perfusion
superfusion by a peristaltic pump at an intraluminal pressure of 30 mm Hg for 30
minutes. After the equilibration period, perfusion was stopped, the outlet was
closed, and the cervix was inflated with a syringe pump. The volume was increased
at a rate of 3.33 microL/s until intraluminal pressure reached approximately 120
mm Hg. The outlet was then opened, and the cervix was perfused at 30 mm Hg of
intraluminal pressure for another 30 minutes. The volume-pressure relationships
were obtained 3 times without any agent present and in the presence of 60-mmol/L
potassium chloride or 10(-4)-mol/L 3-morpholinosydnonimine hydrochloride (also
known as SIN-1). RESULTS: The volume-pressure relationship was shifted to the
right during progression of pregnancy, demonstrating increased compliance of the
cervix. The nonspecific depolarizing agent potassium chloride or the nitric oxide
donor 3-morpholinosydnonimine did not affect volume-pressure relationships in
cervices from nonpregnant rats, rats at midgestation, or rats at term gestation.
CONCLUSION: The volume-pressure relationship in the isolated cannulated rat
cervix reflects the resistance of the organ to increased intraluminal pressure.
The compliance of the cervix is increased as pregnancy progresses, demonstrating
decreased resistance to stretch. Activation or inhibition of cervical smooth
muscle does not contribute to the physical properties of the cervix, which
controls compliance-resistance.
PMID- 10764472
TI - Pregnancy outcomes after antepartum diagnosis of oligohydramnios at or beyond 34
weeks' gestation.
AB - OBJECTIVE: Our purpose was to assess whether antepartum oligohydramnios is
associated with adverse perinatal outcomes. STUDY DESIGN: Women delivered between
July 1, 1991, and September 30, 1996, who underwent ultrasonography at >/=34
weeks' gestation were analyzed. Oligohydramnios was defined as an amniotic fluid
index 50 mm. RESULTS: In our
analysis of 6423 pregnancies, 147 (2.3%) were complicated by oligohydramnios.
This complication was associated with increased labor induction (42% vs 18%; P
<.001), stillbirth (1. 4% vs 0.3%; P <.03), nonreassuring fetal heart rate (48%
vs 39%; P <. 03), admission to the neonatal intensive care nursery (7% vs 2%; P
<. 001), meconium aspiration syndrome (1% vs 0.1%; P <.001), and neonatal death
(5% vs 0.3%; P <.001). CONCLUSION: Antepartum oligohydramnios is associated with
increased perinatal morbidity and mortality.
PMID- 10764473
TI - Role of nucleotide cyclases in the inhibition of pregnant rat uterine
contractions by the openers of potassium channels.
AB - OBJECTIVE: Our objective was to study the involvement of adenylate and guanylate
cylases in spontaneous uterine contractions and inhibition induced by the opening
of potassium channels. STUDY DESIGN: Uterine rings from rats at mid and term
gestation and from rats at term gestation in labor were suspended in organ
chambers for isometric tension recording. Concentration-response relationships to
an opener of adenosine triphosphate-dependent potassium channels, levcromakalim,
or to an opener of calcium-dependent potassium channels, NS 1619, were studied in
the absence and presence of inhibitors of adenylate cyclase (MDL 12330 A, 2 x 10(
5) mol/L; SQ 22536, 10(-4) mol/L) or guanylate cyclase (LY 83583,3 x 10(-6)
mol/L). RESULTS: MDL 12330 A and SQ 22536 accentuated contractions in rings from
rats at mid gestation but not at term gestation or at term gestation in labor. LY
83583 inhibited contractions in the rings from all 3 groups. Levcromakalim was
equally effective in inhibiting contractions of rings from all 3 groups. MDL
12330 A, but not SQ 22536, decreased sensitivity and maximal inhibition induced
by levcromakalim (term gestation greater than mid gestation greater than term
gestation in labor). LY 83583 decreased the sensitivity to and maximal inhibition
induced by levcromakalim in rings from pregnant rats at mid gestation. NS 1619
attenuated contraction of rings from rats at mid gestation and, to a lesser
extent, at term gestation but accentuated contractions in rings from animals at
term gestation in labor. MDL 12330 A, but not SQ 22536 or LY 83583, attenuated
the changes induced by NS 1619 in rings from all 3 groups. CONCLUSIONS: (1) The
influence of nucleotide cyclases on basal uterine contractility depends on
gestational age. (2) The inhibition of uterine contractions that results from the
opening of calcium-dependent potassium channels depends on adenylate cyclase,
whereas that of adenosine triphosphate-dependent potassium channels depends on
both adenylate and guanylate cyclases. 3. Activation of adenosine triphosphate
dependent potassium channels is more efficient than activation of calcium
dependent potassium channels. 4. The inhibition induced by calcium-dependent
potassium channel openers, but not adenosine triphosphate-dependent potassium
channel openers, decreases as pregnancy progresses, and at delivery the
activation of spontaneous contractile activity is evident.
PMID- 10764474
TI - Expression and regulation of the messenger ribonucleic acid encoding the
prostaglandin F(2alpha) receptor in the rat myometrium during pregnancy and
labor.
AB - OBJECTIVE: We examined expression of messenger ribonucleic acid encoding the
prostaglandin F(2alpha) receptor in the rat myometrium throughout late gestation
and its regulation by progesterone and mechanical stretch. STUDY DESIGN: Normal
pregnant rats were killed on gestational day 15, 22, or 23 (during labor) or 1
day post partum. The effects of progesterone on prostaglandin F(2alpha) receptor
messenger ribonucleic acid levels were investigated by daily injections of
progesterone (4 mg) from day 20 of normal gestation or from day 17 in rats
bilaterally ovariectomized on day 17. To investigate the effects of myometrial
stretch, unilaterally pregnant rats underwent either sham surgery or placement of
a polyvinyl tube 3 mm in diameter in the nongravid uterine horn on day 15 or 18
and were killed 5 days later. Prostaglandin F(2alpha) receptor messenger
ribonucleic acid levels in the myometrium were determined by a semiquantitative
reverse transcription-polymerase chain reaction method. RESULTS: Myometrial
prostaglandin F(2alpha) receptor messenger ribonucleic acid levels significantly
increased during both term and ovariectomy-induced preterm labor. This increase
was blocked by progesterone. In rats with unilateral pregnancies prostaglandin
F(2alpha) receptor messenger ribonucleic acid levels in the nongravid horns were
similar to those in the contralateral gravid horns on day 20 and during labor
regardless of whether they were stretched by a 3-mm tube. CONCLUSION: Increased
myometrial expression of prostaglandin F(2alpha) receptor messenger ribonucleic
acid during term and preterm labor is temporally associated with progesterone
withdrawal but is not dependent on mechanical stretch of the myometrium.
PMID- 10764475
TI - Presence and localization of connexins 43 and 26 in cell cultures derived from
myometrial tissues from nonpregnant and pregnant women and from leiomyomas.
AB - OBJECTIVE: Our objective was to study the appearance and distribution of
connexins 43 and 26 in various human myometrial cell cultures. STUDY DESIGN:
Scrape loading, Western blotting, and immunohistochemical techniques were applied
to cultured cells derived from myometrial tissues obtained from nonpregnant and
pregnant women (upper and lower uterine segments) and from leiomyomas (tumor and
analogous myometrial tissues). RESULTS: Scrape loading revealed the presence of
metabolic coupling in all tissues. Indirect immunohistochemical studies showed
membrane localization of connexin 43 in all myometrial cultures. Western blots
and indirect immunohistochemical studies showed the presence and localization of
the connexin 26 protein and associated gap junctions in tissues from myomas and
from nonpregnant and pregnant women except for those derived from the upper
segment of the pregnant uterus. CONCLUSION: These results show that human
myometrial cultures express various gap junction proteins and that there are
regional differences in expression of connexins in tissues from pregnant women.
PMID- 10764476
TI - Nausea and vomiting during pregnancy: A prospective study of its frequency,
intensity, and patterns of change.
AB - OBJECTIVE: Our purpose was to provide a detailed description of patterns of
nausea and vomiting of pregnancy. STUDY DESIGN: A prospective study was performed
with 160 women who provided daily recordings of frequency, duration, and severity
of nausea and vomiting. RESULTS: Seventy-four percent of women reported nausea
lasting a mean of 34.6 days. "Morning sickness" occurred in only 1.8% of women,
whereas 80% reported nausea lasting all day. Only 50% of women were relieved by
14 weeks' gestation; 90% had relief by week 22. Data based on the McGill Nausea
Questionnaire indicate that the nausea experienced by pregnant women is similar
in character and intensity to the nausea experienced by patients undergoing
cancer chemotherapy. CONCLUSIONS: Traditional teachings about nausea and vomiting
of pregnancy are contradicted by our findings. Standardized tools for measuring
the distribution, duration, and intensity of nausea are applicable to the study
of nausea and vomiting of pregnancy and could be used in clinical trials to
assess palliative measures.
PMID- 10764477
TI - Hypertensive disorders in twin versus singleton gestations. National Institute of
Child Health and Human Development Network of Maternal-Fetal Medicine Units.
AB - OBJECTIVE: This study was undertaken to compare rates and severity of gestational
hypertension and preeclampsia, as well as perinatal outcomes when these
complications develop, between women with twin gestations and those with
singleton gestations. STUDY DESIGN: This was a secondary analysis of prospective
data from women with twin (n = 684) and singleton (n = 2946) gestations enrolled
in two separate multicenter trials of low-dose aspirin for prevention of
preeclampsia. End points were rates of gestational hypertension, rates of
preeclampsia, and perinatal outcomes among women with hypertensive disorders.
RESULTS: Women with twin gestations had higher rates of gestational hypertension
(relative risk, 2.04; 95% confidence interval, 1.60-2.59) and preeclampsia
(relative risk, 2. 62; 95% confidence interval, 2.03-3.38). In addition, women
with gestational hypertension during twin gestations had higher rates of preterm
delivery at both <37 weeks' gestation (51.1% vs 5.9%; P <. 0001) and <35 weeks'
gestation (18.2% vs 1.6%; P <.0001) and also had higher rates of small-for
gestational-age infants (14.8% vs 7. 0%; P =.04). Moreover, when outcomes
associated with preeclampsia were compared, women with twin gestations had
significantly higher rates of preterm delivery at <37 weeks' gestation (66.7% vs
19.6%; P <.0001), preterm delivery at <35 weeks' gestation (34.5% vs 6.3%; P
<.0001), and abruptio placentae (4.7% vs 0.7%; P =.07). In contrast, among women
with twin pregnancies, those who remained normotensive had more adverse neonatal
outcomes than did those in whom hypertensive complications developed.
CONCLUSIONS: Rates for both gestational hypertension and preeclampsia are
significantly higher among women with twin gestations than among those with
singleton gestations. Moreover, women with twin pregnancies and hypertensive
complications have higher rates of adverse neonatal outcomes than do those with
singleton pregnancies.
PMID- 10764478
TI - The role of diacylglycerol as a modulator of oxytocin-stimulated phasic
contractions in myometrium from pregnant and nonpregnant rats.
AB - OBJECTIVE: The role of diacylglycerol in the phosphatidylinositol-signaling
pathway is to activate protein kinase C. In the myometrium, protein kinase C
activation leads to inhibition of phasic contractions. These studies are designed
to determine why stimulation of the phosphatidylinositol-signaling pathway caused
by oxytocin does not cause a paradoxical suppression of contractions through
diacylglycerol production and protein kinase C activation. Specifically, these
studies were performed to test the hypothesis that diacylglycerol catabolism is
significant in myometrial tissue, thereby precluding its availability for the
activation of protein kinase C. STUDY DESIGN: For these studies, uterine tissue
was obtained from Sprague-Dawley rats both nonpregnant and with timed gestations.
In vitro contraction studies were performed with cumulative additions of oxytocin
(8-64 nmol/L) with and without R59022 (a diacylglycerol kinase inhibitor) or
RHC80267 (a diacylglycerol lipase inhibitor). The contraction data were computer
digitalized, analyzed for total contractile activity, normalized for tissue cross
sectional area, and reported as the percentage of spontaneous activity. RESULTS:
In myometrium from nonpregnant animals, inhibition of diacylglycerol lipase with
RHC80267 had little effect on oxytocin-stimulated contractile activity, whereas
inhibition of diacylglycerol kinase with R59022, although producing an increase
in contractile frequency, markedly suppressed total oxytocin-stimulated
contractile activity. In contrast, in myometrium from near-term pregnant animals
both RHC80267 and R59022 produced marked suppression of oxytocin-stimulated
contractile activity. CONCLUSIONS: These studies have demonstrated that
prevention of diacylglycerol degradation, especially in response to inhibition of
myometrial diacylglycerol kinase, results in the paradoxic oxytocin-mediated
suppression of total myometrial contractile activity. These observations support
the hypothesis that, when its catabolism is prevented, diacylglycerol produced in
response to stimulation of the phosphatidylinositol-signaling pathway by oxytocin
becomes available for protein kinase C activation, resulting in inhibition of
myometrial contractile activity.
PMID- 10764479
TI - The amniotic fluid index in normal twin pregnancies.
AB - OBJECTIVE: We sought to investigate the amniotic fluid index for individual
gestational sacs of twin pregnancies. STUDY DESIGN: Four hundred eighty-eight
patients with normal diamniotic twins were examined between 14 and 40 weeks'
gestation. The dividing membrane between twin fetuses was identified. An amniotic
fluid index was then obtained for each gestational sac. RESULTS: The median
amniotic fluid index in individual twin gestational sacs rises slowly from 14 to
16 weeks' gestation to 23 to 28 weeks' gestation and then gradually declines. The
median amniotic fluid index values by gestational age for twin A and twin B are
not statistically different. Although twin pregnancies have a slightly lower
median amniotic fluid index value than singleton pregnancies, the difference is
also not statistically significant. CONCLUSION: Individual amniotic fluid indices
can be obtained in twin pregnancies, and the values are comparable with those of
singleton gestations.
PMID- 10764480
TI - Nitroglycerin application during cesarean delivery: plasma levels, fetal/maternal
ratio of nitroglycerin, and effects in newborns.
AB - OBJECTIVE: We sought to investigate maternal and fetal nitroglycerin
metabolization and to assess the clinical condition of neonates after intravenous
nitroglycerin application during cesarean delivery. STUDY DESIGN: At the time of
the uterine puncture incision, either 0. 25 mg or 0.5 mg nitroglycerin or a
physiologic sodium chloride solution was administered as an intravenous bolus.
Plasma concentrations of nitroglycerin and its metabolites were measured in
maternal venous blood and in umbilical blood samples taken immediately after cord
clamping. Arterial blood pressure, pulse rates, and Apgar scores were recorded
for the neonates 1, 5, and 10 minutes after birth. RESULTS: Sixty-two patients
were included in the pharmacokinetic study. Median maternal plasma levels 1 and 5
minutes after injection of 0.5 mg nitroglycerin were 80 and 3.2 ng/mL,
respectively; median maternal plasma levels 1 and 5 minutes after injection of
0.25 mg nitroglycerin were 38 and 1.2 ng/mL, respectively. In the umbilical vein
1 minute after application of 0. 5 mg or 0.25 mg nitroglycerin, the plasma levels
were 0.41 and 0.09 ng/mL, respectively, and in the umbilical artery they were
0.03 and 0.008 ng/mL, respectively. Circulatory parameters and Apgar scores in
the neonates did not differ significantly from those found in the placebo group.
CONCLUSION: The level of nitroglycerin in umbilical plasma was two to three
orders of magnitude lower than that found in maternal plasma and clearly in a
subtherapeutic range. There was no indication that prenatal application of
nitroglycerin to facilitate obstetric management is hazardous for neonates.
PMID- 10764481
TI - Amniocentesis after multifetal pregnancy reduction: is it safe?
AB - OBJECTIVE: This report reviews the obstetric outcomes of women with multifetal
pregnancy reductions who subsequently underwent elective amniocentesis. STUDY
DESIGN: Five hundred eight patients underwent multifetal pregnancy reduction at
our institution. Among these, 91 patients underwent subsequent elective
amniocentesis. The obstetric outcomes of all 508 patients were followed up. By
means of logistic regression we evaluated several variables to determine any
association with loss rate: (1) the finishing number of fetuses, (2) the number
of fetuses undergoing reduction (starting number of fetuses minus the finishing
number of fetuses), (3) the gestational age at reduction, (4) the maternal age at
reduction, and (5) the procedure protocol. We observed that the finishing number
of fetuses, the number of fetuses removed, and the procedure protocol were
significantly associated with pregnancy loss rate. Women who underwent subsequent
amniocentesis were compared with those who did not undergo amniocentesis. By
means of multivariate conditional likelihood analysis we stratified the two
groups according to the previously mentioned significant variables to compare the
pregnancy loss rates. RESULTS: Among patients who subsequently underwent elective
amniocentesis the total uncorrected pregnancy loss rate was 9.0% and the early
premature delivery rate was 4.5%. The number of fetuses removed, the finishing
number of fetuses, and the procedure protocol were statistically significantly
associated with the loss rate. The adjusted odds ratio relating amniocentesis to
the pregnancy loss rate was 0.7 (95% confidence interval, 0.31.5; P =.3.)
CONCLUSIONS: The uncorrected rates of pregnancy loss and of early premature
delivery among patients with multifetal pregnancy reduction who underwent
subsequent amniocentesis were comparable to those of patients with multifetal
pregnancy reduction who did not undergo amniocentesis.
PMID- 10764483
TI - Isolated fetal choroid plexus cysts: role of ultrasonography in establishment of
the risk of trisomy 18.
AB - OBJECTIVE: The significance of isolated choroid plexus cysts found by
ultrasonographic scan during the second trimester as a marker for trisomy 18 is
still debated. We analyzed our data and reviewed the series published in the
English-language literature to calculate the likelihood ratio of trisomy 18 in
the presence of isolated choroid plexus cysts; that is, the factor by which the
individual risk of trisomy 18 is increased in the presence of isolated choroid
plexus cysts. STUDY DESIGN: Likelihood ratios were calculated as ratio of the
sensitivity to the false-positive rate. Sensitivity was defined as the rate of
isolated choroid plexus cysts detected at midgestation among fetuses with trisomy
18. False-positive rate was defined as the rate of choroid plexus cysts detected
at midgestation in the population without trisomy 18. The sensitivities of all
published series reporting rates of choroid plexus cysts at the time of the first
ultrasonographic examination between 14 and 24 weeks' gestation in populations
with trisomy 18 and in low-risk populations were included in the analysis. To
these we added all cases of trisomy 18 diagnosed at our institution during the
period January 1, 1988, through June 30, 1998, in which prenatal ultrasonographic
examination was performed between 14 and 24 weeks' gestation. RESULTS: The
prevalence of second-trimester ultrasonographic detection of isolated choroid
plexus cysts among fetuses with trisomy 18 was 6.7% (13/194), whereas that in the
population without trisomy 18 was 0.9% (752/79,583). The likelihood ratio
associated with isolated choroid plexus cysts was therefore 7.09 (95% confidence
interval, 3.97-12.18). CONCLUSION: The presence of isolated second-trimester
choroid plexus cysts increases the base risk of trisomy 18 by a factor of 7.09.
This likelihood ratio can be multiplied by the risk calculated according to
maternal age to obtain the individual risk of trisomy 18 and thus permit more
accurate counseling of the patient.
PMID- 10764482
TI - Ex vivo delineation of placental angioarchitecture with the microbubble contrast
agent Levovist.
AB - OBJECTIVE: The aim of this study was to delineate placental vasculature with the
microbubble contrast agent Levovist (99.9% galactose and 0.1% palmitic acid;
Schering AG, Berlin, Germany), with the ultimate goal of delineating placental
vascular anatomy in utero. STUDY DESIGN: A placental lobule from each of 11 term
human placentas was perfused on the fetal side of the circulation under
physiologic conditions. Randomly assigned dose-concentration combinations of
Levovist were administered through a chorionic artery into the corresponding
placental lobule, and the resultant echoenhancement with power Doppler imaging
was recorded for digital analysis. Interplacental variability was corrected for
by averaging the results of three injections at each dose-concentration
combination. RESULTS: Echoenhancement was seen at all dose-concentration
combinations in the injected lobule but not in adjacent control lobules. The
three dose-concentration combinations that achieved optimal maximal integrated
intensity and duration of action for both chorionic vessel and villus enhancement
were 100 microL/kg of 400-mg/mL Levovist, 200 microL/kg of 400-mg/mL Levovist,
and 400 microL/kg of 200-mg/mL Levovist. CONCLUSION: Microbubble contrast
injection into the fetal vasculature enabled power Doppler imaging
echoenhancement both in chorionic vessels and within the villus tree. We
speculate that fetal injection of contrast agent may be applied to the
delineation of placental lesions or areas of interfetal transfusion, although its
applicability will be hindered by the need for fetal blood sampling.
PMID- 10764484
TI - Prognostic significance of the pouch sign in fetuses with prenatally diagnosed
esophageal atresia.
AB - OBJECTIVE: Esophageal atresia may be diagnosed prenatally by ultrasonographic
visualization of the blind-ending esophagus during fetal swallowing, which is
referred to as the pouch sign. Our purpose was to determine whether this sign can
be used to predict outcomes of affected fetuses. STUDY DESIGN: Four cases of
esophageal atresia diagnosed in our center during the past 2 years were analyzed,
in conjunction with 3 cases from published series. Ultrasonographic features of
the pouch sign were categorized according to localization. RESULTS: In the neck
pouch group (n = 3) 1 fetus died in utero and 1 died before a corrective
operation could be undertaken. In the only fetus of this group to survive a
staged repair was necessary because of a long atretic gap. Conversely, 3 of the 4
fetuses with a mediastinal pouch survived after a successful corrective
operation, and primary repair was possible in all cases. CONCLUSIONS: The base of
the proximal blind-ending esophagus can be clearly localized by means of
ultrasonography. Our data suggest that a neck pouch may be associated with an
adverse outcome. This information may be useful in counseling parents when
esophageal atresia is diagnosed prenatally.
PMID- 10764485
TI - Fetal heart rate monitoring: is it salvageable?
AB - Fetal heart rate monitoring was introduced in the 1960s. After a number of
randomized controlled trials in the mid 1980s, doubt arose regarding the efficacy
of fetal heart rate monitoring in improving fetal outcome. The potential reasons
why fetal heart rate monitoring has not been shown to be efficacious are (1) use
of an outcome measure that is not related to variant fetal heart rate monitoring
patterns, (2) lack of standardized interpretation of fetal heart rate patterns,
(3) disagreement regarding algorithms for intervention of specific fetal heart
rate patterns, and (4) the inability to demonstrate the reliability, validity,
and ability of fetal heart rate monitoring to allow timely intervention. A recent
National Institutes of Health committee proposed detailed, quantitative,
standardized definitions of fetal heart rate patterns, which can serve as a basis
for determining whether fetal heart rate monitoring is reliable and valid. In
this article we examine reasons why fetal heart rate monitoring did not live up
to its original expectations and why the randomized controlled trials did not
demonstrate efficacy, and we make suggestions for determining whether electronic
fetal heart rate monitoring should be abandoned.
PMID- 10764486
TI - Benefits of maternal corticosteroid therapy in infants weighing 80%). Peak radioactivity in urine was recovered within 5.5 h following
injection in all three species, while in the feces peak levels of radioactivity
were recovered within 26 h postinjection. In all three species, urinary
metabolites were primarily excreted as conjugates (61-87%), whereas the
percentage of conjugated metabolites in feces was 50% or less. The number and
relative abundance of urinary and fecal [3H]cortisol metabolites were determined
by reverse-phase high-performance liquid chromatography (HPLC) and
immunoreactivity of the radioactivity peaks was assessed by screening HPLC
fractions with established cortisol, corticosterone, and 11-oxoetiocholanolone
enzyme immunoassays (EIA), the latter being a group-specific assay for measuring
11,17-dioxoandrostanes. HPLC separation of urinary and fecal extracts revealed
multiple peaks of radioactivity, several of which were common to all three
species. The relative proportion of these peaks, however, differed considerably
among species and between urine and feces. HPLC indicated that native cortisol
was a major urinary excretory product in the marmoset, while comparatively small
amounts were present in the urine of the macaque and chimpanzee. In contrast, in
feces, cortisol was only detected in low amounts in the marmoset and was
virtually absent in the macaque and chimpanzee. In all three species, one of the
major radioactivity peaks showed a retention time comparable to 11
oxoetiocholanolone and high immunoreactivity in the 11-oxoetiocholanolone EIA.
The measurement of urinary- and/or fecal-immunoreactive 11,17-dioxoandrostanes is
therefore implicated for noninvasive assessment of adrenal function in Old World
monkeys, New World monkeys, and great apes.
PMID- 10764554
TI - Cloning and expression, pharmacological characterization, and internalization
kinetics of the pituitary GnRH receptor in a metatherian species of mammal.
AB - Gonadotropin-releasing hormone receptors (GnRH-Rs) expressed in the pituitary of
eutherian species of mammal are unique in lacking the cytoplasmic C-terminal tail
characteristic of GnRH-Rs of nonmammalian vertebrates and other G protein-coupled
receptors. To further investigate evolutionary relationships among vertebrate
GnRH-Rs, a full-coding region cDNA of the pituitary GnRH-R was cloned from a
metatherian marsupial mammal, the Australian brushtail possum (Trichosurus
vulpecula). We have determined the pharmacological characteristics and
internalization kinetics of this GnRH-R from an early evolved, metatherian
species of mammal and compared it with the corresponding receptors in eutherian
species of mammal and nonmammalian vertebrates. The predicted GnRH-R protein from
the possum pituitary has high homology with the other mammalian GnRH-Rs (80%
identity) and, in common with other mammals, lacks an intracellular C-terminal
tail. The ligand selectivity of the possum GnRH-R transfected into COS-1 cells,
assessed using inositol phosphate assays and radioreceptor binding assays, was
similar to that of the other mammalian GnRH-Rs, and distinct from those of the
nonmammalian GnRH-Rs. The pharmacological characteristics of the possum GnRH-R
were similar to those of other mammalian GnRH-Rs, for a selection of agonists
(including naturally occurring GnRH ligands and superagonists) and antagonists.
Receptor-mediated internalization of GnRH agonist by the possum GnRH-R was
slightly more rapid than that of the human GnRH-R, while the internalization
kinetics of the chicken GnRH-R, in which a cytoplasmic C-terminal tail is
present, was considerably more rapid. In terms of the evolution of the GnRH-R in
vertebrates, the possum (a metatherian mammal) GnRH-R has a striking resemblance,
in both structure and pharmacological characteristics, to GnRH-Rs in eutherian
mammals, which are quite distinct from the nonmammalian vertebrate GnRH-Rs, and
are unique among G protein-coupled receptors in lacking an intracellular C
terminal tail. The distinct structure of the pituitary GnRH-R in mammalian
vertebrates is likely to have important functional consequences in the
reproductive physiology of mammals.
PMID- 10764555
TI - Photoperiodic regulation of the reproductive axis in male zebra finches,
Taeniopygia guttata.
AB - In arid central Australia, breeding of zebra finches (Taeniopygia guttata) tends
to take place immediately after the aperiodic rainfall-this being irrespective of
the time of year. As a result, zebra finches have traditionally been considered
nonphotoperiodic. Despite this, there are some published reports of photoperiodic
effects on behavior in zebra finches. Therefore, we transferred singly housed
male zebra finches from a photoperiod of 14 h light and 10 h dark per day
(14L:10D) to either 20L:4D or 8L:16D. Control birds remained exposed to 14L:10D.
Plasma LH, testicular volume, and body mass were assessed at the start of the
experiment and at intervals for a period of 56 days. Testicular mass was measured
at the end of the 56-day period. Plasma LH increased significantly in the 20L:4D
group after 14 days, but decreased again by 56 days, presumably an effect of
increased gonadal steroid negative feedback. Plasma LH did not change
significantly in the other two groups. Testicular volume increased steadily in
the 20L:4D group during the treatment period and it was significantly higher than
that of the 8L:16D group at the end of the experiment. After 56 days of
treatment, combined testicular mass in the 20L:4D group was much greater than
that of the 8L:16D group, but not quite statistically different from the 14L:10D
group. There was no statistical difference in testicular mass between the 14L and
8L groups. Body mass did not differ between any of the groups at any time in the
experiment. Our results are consistent with zebra finches being photoperiodic to
some degree, despite their opportunistic breeding strategy. When considered in
conjunction with recent reports of photoperiodic responses in tropical avian
species, these data suggest that the ability to respond to changing photoperiod
is more common among avian species than previously hypothesized.
PMID- 10764556
TI - Gonadotropin-releasing hormone stimulates thyroid activity in a freshwater
murrel, Channa gachua (ham.), and Carps, Catla catla (ham.) and Cirrhinus mrigala
(ham.).
AB - Injections of mammalian GnRH (mGnRH), salmon GnRH (sGnRH), and a homologous
murrel, Channa punctatus, GnRH (cGnRH) to a murrel, Channa gachua, and a carp,
Catla catla, at a dose of 1 microg/250 g body wt significantly increased plasma
thyroxine (T4) levels above control. Piscine GnRHs (sGnRH and cGnRH) had
significantly greater stimulatory effects compared with mGnRH. To observe whether
this stimulatory effect by GnRHs is direct or indirect, thyroid follicles were
isolated from hypobranchial muscles of freshwater murrel, C. gachua and incubated
(1 x 10(6) follicles/well) in vitro at 30 degrees C for 2 h without hormone and
for 3 h with hormones. Addition of these three GnRHs separately at a
concentration of 1 microg/well stimulated T4 secretion; sGnRH and cGnRH caused
greater secretion of T4 into the medium compared with mGnRH. Specificity of GnRH
action in vitro was assessed by using anti-GnRH antibody which significantly (P <
0.01) inhibited GnRH-augmented T4 secretion. To gain further insight, 125I uptake
by thyroid follicles and formation of [125I]T4 from this radioiodine pool was
monitored in the presence or absence of sGnRH. sGnRH greatly augmented 1251
uptake by the follicles which resulted a fourfold increase in [125I]T4 formation
out of this pool of 125I compared with the control. The results indicate GnRH
stimulation of thyroid hormone formation and release in these teleosts suggesting
a possible different mode of regulation of thyroid hormone secretion in teleosts.
PMID- 10764557
TI - Plasma-sulfated C21-steroids increase during the periovulatory period in female
common wolffish and are influenced by temperature during vitellogenesis.
AB - Plasma concentrations of steroids during the periovulatory period were measured
in female common wolffish reared at three different temperatures. Steroids were
quantified by radioimmunoassay (RIA). Two "broad-spectrum specificity" RIAs-one
which detects C21-steroids with a 17,20beta-dihydroxyl configuration (17,20beta
steroids) and the other which detects C21-steroids with a 5beta-reduced, 3alpha
hydroxyl configuration (5beta,3alpha-steroids)-picked up very large amounts of
cross-reacting material (1.7 microg ml(-1) in one fish) in the sulfate fraction
of plasma from ovulating females. Reverse-phase high-performance liquid
chromatography and thin-layer chromatography revealed two major steroids: 5beta
pregnane-3alpha,17,20beta-triol (80%) and 5beta-pregnane-3beta,17,20beta-triol
(20%). The sulfated forms of these steroids were elevated 4 to 6 days before and
during ovulation, compared with those of females in vitellogenic and postspawning
condition, in which concentrations were below 2.0 ng ml(-1). In the three groups
of fish held at 4, 8, and 12 degrees C during vitellogenesis, but returned to 4
degrees C just prior to the spawning season, the mean concentrations of sulfated
17,20beta-steroids in ovulating females were 530, 635, and 325 ng ml(-1),
respectively. The corresponding concentrations of free 17,20beta-dihydroxy-4
pregnen-3-one (17,20beta-P; the maturation-inducing steroid in many teleosts)
were 0.88, 0.86, and 0.57 ng ml(-1), respectively. Only minute amounts of
17,20beta,21-P and its sulfated derivatives were detected. Significantly lower
steroid concentrations in the 12 degrees C group indicate that steroid synthesis
and/or metabolism during the periovulatory period are influenced by the
temperature experienced during vitellogenesis. In male fish, plasma
concentrations of both sulfated 17,20beta-steroids and free 17,20beta-P were low
(< 2.0 ng ml(-1)) at all times.
PMID- 10764570
TI - Divergence in macromolecular assembly: X-ray crystallographic structure analysis
of lumazine synthase from Brucella abortus.
AB - We have determined the three-dimensional structure of 6, 7-dimethyl-8
ribityllumazine synthase (lumazine synthase) from Brucella abortus, the
infectious organism of the disease brucellosis in animals. This enzyme catalyses
the formation of 6, 7-dimethyl-8-ribityllumazine, the penultimate product in the
synthesis of riboflavin. The three-dimensional X-ray crystal structure of the
enzyme from B. abortus has been solved and refined at 2.7 A resolution to a final
R-value of 0.18 (R(free)=0.23). The macromolecular assembly of the enzyme differs
from that of the enzyme from Bacillus subtilis, the only other lumazine synthase
structure known. While the protein from B. subtilis assembles into a 60 subunit
icosahedral capsid built from 12 pentameric units, the enzyme from B. abortus is
pentameric in its crystalline form. Nonetheless, the active sites of the two
enzymes are virtually identical indicating inhibitors to theses enzymes could be
effective pharmaceuticals across a broad species range. Furthermore, we compare
the structures of the enzyme from B. subtilis and B. abortus and describe the C
teminus structure which accounts for the differences in quaternary structure.
PMID- 10764571
TI - A thermodynamic coupling mechanism can explain the GroEL-mediated acceleration of
the folding of barstar.
AB - Despite extensive structural and kinetic studies, the mechanism by which the
Escherichia coli chaperonin GroEL assists protein folding has remained somewhat
elusive. It appears that GroEL might play an active role in facilitating folding,
in addition to its role in restricting protein aggregation by secluding folding
intermediates. We have investigated the kinetic mechanism of GroEL-mediated
refolding of the small protein barstar. GroEL accelerates the observed fast
(millisecond) refolding rate, but it does not affect the slow refolding kinetics.
A thermodynamic coupling mechanism, in which the concentration of exchange
competent states is increased by the law of mass action, can explain the
enhancement of the fast refolding rates. It is not necessary to invoke a
catalytic role for GroEL, whereby either the intrinsic refolding rate of a
productive folding transition or the unfolding rate of a kinetically trapped off
pathway intermediate is increased by the chaperonin.
PMID- 10764572
TI - Experimental and computational studies of the G[UUCG]C RNA tetraloop.
AB - In prokaryotic ribosomal RNAs, most UUCG tetraloops are closed by a C-G base
pair. However, this preference is greatly reduced in eukaryotic rRNA species
where many UUCG tetraloops are closed by G-C base-pairs. Here, biophysical
properties of the C[UUCG]G and G[UUCG]C tetraloops are compared, using
experimental and computational methods. Thermal denaturation experiments are used
to derive thermodynamic parameters for the wild-type G[UUCG]C tetraloop and
variants containing single deoxy substitutions in the loop. A comparison with
analogous experiments on the C[UUCG]G motif shows that the two RNA species
exhibit similar patterns in response to the substitutions, suggesting that their
loop structures are similar. This conclusion is supported by NMR data that
suggest that the essential UUCG loop structure is maintained in both tetraloops.
However, NMR results show that the G[UUCG]C loop structure is disrupted prior to
melting of the stem; this behavior is in contrast to the two-state behavior of
the C[UUCG]G molecule. Stochastic dynamics simulations using the GB/SA continuum
solvation model, run as a function of temperature, show rare conformational
transitions in several G[UUCG]C simulations. These results lead to the conclusion
that substitution of a G-C for a C-G closing base-pair increases the intrinsic
flexibility of the UUCG loop.
PMID- 10764573
TI - Endoribonuclease RegB from bacteriophage T4 is necessary for the degradation of
early but not middle or late mRNAs.
AB - The RegB endoribonuclease from bacteriophage T4 cleaves early mRNAs specifically
in the middle of the sequence GGAG. We show here that RegB is required for the
degradation of bulk T4 early mRNA. In the absence of RegB, the chemical half-life
of early transcripts is increased nearly fourfold, whereas their functional half
life is increased twofold. RegB also regulates the translation of several
prereplicative genes. The synthesis of several early proteins is down-regulated,
probably as a consequence of RegB cleavages in the Shine-Dalgarno sequence of
these genes. The synthesis of several other proteins is up-regulated, suggesting
that processing by RegB might improve translation by changing the conformation of
a transcript. In contrast, RegB does not affect the average half-life of middle
and late mRNA. An analysis of the susceptibility to RegB of many GGAG motifs
carried by these mRNA species showed that most middle and all late GGAG-carrying
mRNAs escape RegB processing in spite of the fact that the enzyme is acting at
least until ten minutes post-infection. The sensitivity or resistance to RegB
observed during phage infection could be reproduced in uninfected Escherichia
coli cells and in vitro. This shows that the GGAG-carrying RNAs that are uncut
during T4 infection are not substrates, whatever the period of the T4 cycle when
the transcripts are made.
PMID- 10764574
TI - Gene structure prediction by spliced alignment of genomic DNA with protein
sequences: increased accuracy by differential splice site scoring.
AB - Gene identification in genomic DNA from eukaryotes is complicated by the vast
combinatorial possibilities of potential exon assemblies. If the gene encodes a
protein that is closely related to known proteins, gene identification is aided
by matching similarity of potential translation products to those target
proteins. The genomic DNA and protein sequences can be aligned directly by
scoring the implied residues of in-frame nucleotide triplets against the protein
residues in conventional ways, while allowing for long gaps in the alignment
corresponding to introns in the genomic DNA. We describe a novel method for such
spliced alignment. The method derives an optimal alignment based on scoring for
both sequence similarity of the predicted gene product to the protein sequence
and intrinsic splice site strength of the predicted introns. Application of the
method to a representative set of 50 known genes from Arabidopsis thaliana showed
significant improvement in prediction accuracy compared to previous spliced
alignment methods. The method is also more accurate than ab initio gene
prediction methods, provided sufficiently close target proteins are available. In
view of the fast growth of public sequence repositories, we argue that close
targets will be available for the majority of novel genes, making spliced
alignment an excellent practical tool for high-throughput automated genome
annotation.
PMID- 10764575
TI - A new look at the microtubule binding patterns of dimeric kinesins.
AB - The interactions of monomeric and dimeric kinesin and ncd constructs with
microtubules have been investigated using cryo-electron microscopy (cryo-EM) and
several biochemical methods. There is a good consensus on the structure of
dimeric ncd when bound to a tubulin dimer showing one head attached directly to
tubulin, and the second head tethered to the first. However, the 3D maps of
dimeric kinesin motor domains are still quite controversial and leave room for
different interpretations. Here we reinvestigated the microtubule binding
patterns of dimeric kinesins by cryo-EM and digital 3D reconstruction under
different nucleotide conditions and different motor:tubulin ratios, and
determined the molecular mass of motor-tubulin complexes by STEM. Both methods
revealed complementary results. We found that the ratio of bound kinesin motor
heads to alphabeta-tubulin dimers was never reaching above 1.5 irrespective of
the initial mixing ratios. It appears that each kinesin dimer occupies two
microtubule-binding sites, provided that there is a free one nearby. Thus the
appearances of different image reconstructions can be explained by non-specific
excess binding of motor heads. Consequently, the use of different apparent
density distributions for docking the X-ray structures onto the microtubule
surface leads to different and mutually exclusive models. We propose that in
conditions of stoichiometric binding the two heads of a kinesin dimer separate
and bind to different tubulin subunits. This is in contrast to ncd where the two
heads remain tightly attached on the microtubule surface. Using dimeric kinesin
molecules crosslinked in their neck domain we also found that they stabilize
protofilaments axially, but not laterally, which is a strong indication that the
two heads of the dimers bind along one protofilament, rather than laterally
bridging two protofilaments. A molecular walking model based on these results
summarizes our conclusions and illustrates the implications of symmetry for such
models.
PMID- 10764576
TI - A novel type of receptor protein, based on the lipocalin scaffold, with
specificity for digoxigenin.
AB - We demonstrate that the bilin-binding protein, a member of the lipocalin family
of proteins, can be structurally reshaped in order to specifically complex
digoxigenin, a steroid ligand commonly used for the non-radioactive labelling of
biomolecules. 16 amino acid residues, distributed across the four loops which
form the binding site of the bilin-binding protein, were subjected to targeted
random mutagenesis. From the resulting library the variant DigA16 was obtained by
combined use of phage display and a filter-sandwich colony screening assay,
followed by in vitro affinity maturation. DigA16 possesses strong binding
activity and high specificity for the digoxigenin group, with a K(D) of 30.2(+/
3.6) nM. The derivative compound digitoxigenin is bound even more tightly, with a
K(D) of 2.0(+/-0.52) nM, whereas the steroid glycoside ouabain is not recognized
at all. Fusion proteins between DigA16 and alkaline phosphatase were constructed
and shown to retain both the digoxigenin-binding function and enzymatic activity,
irrespective of whether the enzyme was fused to the N or the C terminus of the
bilin-binding protein variant. Our findings suggest that the lipocalin scaffold
can be generally employed for the construction of specific receptor proteins, so
called "anticalins", which provide a promising alternative to recombinant
antibody fragments.
PMID- 10764577
TI - Structure of the CAD domain of caspase-activated DNase and interaction with the
CAD domain of its inhibitor.
AB - Caspase-activated DNase (CAD), which causes a genome fragmentation at the final
stage of apoptosis, is a protein of about 40 kDa and exists as a complex form
with the inhibitor ICAD in living cells. There is sequence homology of about 80
amino acid residues at the N termini of CAD and ICAD (called the CAD domain).
Here, we report the three-dimensional structure of the CAD domain of CAD
determined by multi-dimensional NMR spectroscopy and the property of CAD domains
investigated by a surface plasmon resonance experiment. The CAD domain of CAD is
an independently folded domain composed of one alpha-helix and five beta-strands
forming a single sheet. The overall structure is categorized in the ubiquitin
superfold. This domain can bind strongly to the isolated CAD domain of ICAD
(dissociation constant: 5.48(+/-0.003)x10(-8) M). It suggests the function of the
CAD domains in the CAD-ICAD system, that the protein-protein interaction through
the CAD domains plays an important role in the inhibition of CAD DNase activity
and in the correct folding of CAD. On the basis of structural comparison with
other protein complexes containing the ubiquitin superfold, the interaction mode
of the CAD domains is proposed.
PMID- 10764578
TI - The 23 S rRNA environment of ribosomal protein L9 in the 50 S ribosomal subunit.
AB - Ribosomal protein L9 consists of two globular alpha/beta domains separated by a
nine-turn alpha-helix. We examined the rRNA environment of L9 by chemical
footprinting and directed hydroxyl radical probing. We reconstituted L9, or
individual domains of L9, with L9-deficient 50 S subunits, or with deproteinized
23 S rRNA. A footprint was identified in domain V of 23 S rRNA that was mainly
attributable to N-domain binding. Fe(II) was tethered to L9 via cysteine residues
introduced at positions along the alpha-helix and in the C-domain, and
derivatized proteins were reconstituted with L9-deficient subunits. Directed
hydroxyl radical probing targeted regions of domains I, III, IV, and V of 23 S
rRNA, reinforcing the view that 50 S subunit architecture is typified by
interwoven rRNA domains. There was a striking correlation between the cleavage
patterns from the Fe(II) probes attached to the alpha-helix and their predicted
orientations, constraining both the position and orientation of L9, as well as
the arrangement of specific elements of 23 S rRNA, in the 50 S subunit.
PMID- 10764579
TI - Structure and thermodynamics of RNA-protein binding: using molecular dynamics and
free energy analyses to calculate the free energies of binding and conformational
change.
AB - An adaptive binding mechanism, requiring large conformational rearrangements,
occurs commonly with many RNA-protein associations. To explore this process of
reorganization, we have investigated the conformational change upon spliceosomal
U1A-RNA binding with molecular dynamics (MD) simulations and free energy
analyses. We computed the energetic cost of conformational change in U1A-hairpin
and U1A-internal loop binding using a hybrid of molecular mechanics and continuum
solvent methods. Encouragingly, in all four free energy comparisons (two slightly
different proteins, two different RNAs), the free macromolecule was more stable
than the bound form by the physically reasonable value of approximately 10
kcal/mol. We calculated the absolute binding free energies for both complexes to
be in the same range as that found experimentally.
PMID- 10764580
TI - The structure of Antirrhinum centroradialis protein (CEN) suggests a role as a
kinase regulator.
AB - Expression of the plant protein centroradialis (CEN) leads to a morphological
switch between shoot growth and the development of flower structures
(inflorescence). We have determined the crystal structure of Antirrhinum CEN to
1.9 A resolution. This structure confirms the CEN proteins as a subset of the
family of phosphatidylethanolamine-binding proteins (PEBP), as predicted from
sequence homology. Mammalian forms of PEBP have been found to act as inhibitors
of MAP kinase signalling, a central signalling cascade regulating cell
differentiation. CEN and PEBP proteins share a similar topology dominated by a
large central beta-sheet. The strong conservation of a binding pocket at one end
of this sheet which is capable of binding phosphoryl ligands, suggests the
biological effects of CEN, like PEBP, arise from the ability of this region to
form complexes with phosphorylated ligands, hence interfering with kinases and
their effectors.
PMID- 10764581
TI - Crystallographic analysis of the reaction pathway of Zoogloea ramigera
biosynthetic thiolase.
AB - Biosynthetic thiolases catalyze the biological Claisen condensation of two acetyl
CoA molecules to form acetoacetyl-CoA. This is one of the fundamental categories
of carbon skeletal assembly patterns in biological systems and is the first step
in many biosynthetic pathways including those which generate cholesterol, steroid
hormones and ketone body energy storage molecules. High resolution crystal
structures of the tetrameric biosynthetic thiolase from Zoogloea ramigera were
determined (i) in the absence of active site ligands, (ii) in the presence of
CoA, and (iii) from protein crystals which were flash frozen after a short soak
with acetyl-CoA, the enzyme's substrate in the biosynthetic reaction. In the
latter structure, a reaction intermediate was trapped: the enzyme was found to be
acetylated at Cys89 and a molecule of acetyl-CoA was bound in the active site
pocket. A comparison of the three new structures and the two previously published
thiolase structures reveals that small adjustments in the conformation of the
acetylated Cys89 side-chain allow CoA and acetyl-CoA to adopt identical modes of
binding. The proximity of the acetyl moiety of acetyl-CoA to the sulfur atom of
Cys378 supports the hypothesis that Cys378 is important for proton exchange in
both steps of the reaction. The thioester oxygen atom of the acetylated enzyme
points into an oxyanion hole formed by the nitrogen atoms of Cys89 and Gly380,
thus facilitating the condensation reaction. The interaction between the
thioester oxygen atom of acetyl-CoA and His348 assists the condensation step of
catalysis by stabilizing a negative charge on the thioester oxygen atom. Our
structure of acetyl-CoA bound to thiolase also highlights the importance in
catalysis of a hydrogen bonding network between Cys89 and Cys378, which includes
the thioester oxygen atom of acetyl-CoA, and extends from the catalytic site
through the enzyme to the opposite molecular surface. This hydrogen bonding
network is different in yeast degradative thiolase, indicating that the catalytic
properties of each enzyme may be modulated by differences in their hydrogen
bonding networks.
PMID- 10764582
TI - Structural basis of recognition of monopartite and bipartite nuclear localization
sequences by mammalian importin-alpha.
AB - Importin-alpha is the nuclear import receptor that recognizes cargo proteins
which contain classical monopartite and bipartite nuclear localization sequences
(NLSs), and facilitates their transport into the nucleus. To determine the
structural basis of the recognition of the two classes of NLSs by mammalian
importin-alpha, we co-crystallized an N-terminally truncated mouse receptor
protein with peptides corresponding to the monopartite NLS from the simian virus
40 (SV40) large T-antigen, and the bipartite NLS from nucleoplasmin. We show that
the monopartite SV40 large T-antigen NLS binds to two binding sites on the
receptor, similar to what was observed in yeast importin-alpha. The nucleoplasmin
NLS-importin-alpha complex shows, for the first time, the mode of binding of
bipartite NLSs to the receptor. The two basic clusters in the NLS occupy the two
binding sites used by the monopartite NLS, while the sequence linking the two
basic clusters is poorly ordered, consistent with its tolerance to mutations. The
structures explain the structural basis for binding of diverse NLSs to the sole
receptor protein.
PMID- 10764583
TI - Structure of the coat protein-binding domain of the scaffolding protein from a
double-stranded DNA virus.
AB - Scaffolding proteins are required for high fidelity assembly of most high T
number dsDNA viruses such as the large bacteriophages, and the herpesvirus
family. They function by transiently binding and positioning the coat protein
subunits during capsid assembly. In both bacteriophage P22 and the herpesviruses
the extreme scaffold C terminus is highly charged, is predicted to be an
amphipathic alpha-helix, and is sufficient to bind the coat protein, suggesting a
common mode of action. NMR studies show that the coat protein-binding domain of
P22 scaffolding protein exhibits a helix-loop-helix motif stabilized by a
hydrophobic core. One face of the motif is characterized by a high density of
positive charges that could interact with the coat protein through electrostatic
interactions. Results from previous studies with a truncation fragment and the
observed salt sensitivity of the assembly process are explained by the NMR
structure.
PMID- 10764584
TI - Chemical dissection and reassembly of amyloid fibrils formed by a peptide
fragment of transthyretin.
AB - We have examined the chemical dissection and subsequent reassembly of fibrils
formed by a ten-residue peptide to probe the forces that drive the formation of
amyloid. The peptide, TTR(10-19), encompasses the A strand of the inner beta
sheet structure that lines the thyroid hormone binding site of the human plasma
protein transthyretin. When dissolved in water under low pH conditions the
peptide readily forms amyloid fibrils. Electron microscopy of these fibrils
indicates the presence of long (>1000 nm) rigid structures of uniform diameter
(approximately 14 nm). Addition of urea (3 M) to preformed fibrils disrupts these
rigid structures. The partially disrupted fibrils form flexible ribbon-like
arrays, which are composed of a number of clearly visible protofilaments (3-4 nm
diameter). These protofilaments are highly stable, and resist denaturation in 6 M
urea at 75 degrees C over a period of hours. High concentrations (>50%, v/v) of
2,2,2-trifluoroethanol also dissociate TTR(10-19) fibrils to the constituent
protofilaments, but these slowly dissociate to monomeric, soluble peptides with
extensive alpha-helical structure. Dilution of the denaturant or co-solvent at
the stage when dissociation to protofilaments has occurred results in the
efficient reassembly of fibrils. These results indicate that assembly of fibrils
from protofilaments involves relatively weak and predominantly hydrophobic
interactions, whereas assembly of peptides into protofilaments involves both
electrostatic and hydrophobic forces, resulting in a highly stable and compact
structures.
PMID- 10764585
TI - Similarities between the spectrin SH3 domain denatured state and its folding
transition state.
AB - We have expanded our description of the energy landscape for folding of the SH3
domain of chicken alpha-spectrin by a detailed structural characterization of its
denatured state ensemble (DSE). This DSE is significantly populated under mildly
acidic conditions in equilibrium with the folded state. Evidence from
heteronuclear nuclear magnetic resonance (NMR) experiments on (2)H, (15)N-labeled
protein suggests the presence of conformers whose residual structure bears some
resemblence to the structure of the folding transition state of this protein. NMR
analysis in a mutant with an engineered, non-native alpha-helical tendency shows
a significant amount of local non-native structure in the mutant, while the
overall characteristics of the DSE are unchanged. Comparison with recent
theoretical predictions of SH3 domain folding reactions reveals an interesting
correlation with the predicted early events. Based on these results and recent
data from other systems, we propose that the DSE of a protein will resemble the
intermediate or transition state of its nearest rate-limiting step, as a
consequence of simple energetic and kinetic principles.
PMID- 10764586
TI - A new folding intermediate of apomyoglobin from Aplysia limacina: stepwise
formation of a molten globule.
AB - Apomyoglobin from Aplysia limacina (al-apoMb), despite having only 20 % sequence
identity with the more commonly studied mammalian globins (m-apoMbs), properties
which result in an increased number of hydrophobic contacts and a loss of most
internal salt bridges, shares a number of features of their folding profiles. We
show here that it contains an unusually stable core which resists unfolding even
at 70 degrees C. The equilibrium intermediate (I(T)) at this high temperature is
distinct from the acid unfolded state I(A) which has many properties in common
with the acid intermediate observed for the mammalian apoproteins (I(AGH)). It
contains a smaller amount of secondary structure (27 % alpha-helical instead of
35 %) and is more highly solvated as evidenced from its fluorescence spectrum
(lambda(max)=344 nm instead of 338 nm). Its stability is greatly increased
(DeltaDeltaG(w)=-6.75 kcal mol(-1)) in the presence of high salt (2 M KCl),
lending support to the view that hydrophobic interactions are responsible for its
stability. Kinetic data show classical two-state kinetics between I(A) and the
folded state both in the presence and absence of salt. Both I(A) and I(T) can be
populated within the dead time of the stopped-flow apparatus, since initiating
the refolding reaction from I(T) or I(A) rather than the completely unfolded
state does not affect the observed refolding time-course. Our conclusion is that
al-apoMb, as other "apo" proteins (including for example alpha-lactalbumin in the
absence of Ca(2+)), may be described as "uncoupled" with an unusually high and
exploitable tendency to populate partially folded states.
PMID- 10764587
TI - PKC-zeta-associated CK2 participates in the turnover of free IkappaBalpha.
AB - The atypical PKC isoenzymes, zeta and iota, activate NF-kappaB, a mechanism
thought to mediate the anti-apoptotic and proliferative features of these
kinases. PKC-zeta has been shown to be associated with an IkappaBalpha kinase in
resting cells. In this study, we have sought to identify the PKC-zeta associated
kinase and understand how PKC-zeta mediates basal IkappaBalpha turnover in vivo.
We demonstrate that the PKC-zeta-associated IkappaBalpha kinase is CK2. This
kinase, previously shown to phosphorylate the PEST domain of IkappaB molecules,
co-precipitates with PKC-zeta in resting cells. In vitro, PKC-zeta interacts with
CK2-beta. The in vivo PKC-zeta-associated CK2 preferentially phosphorylates S293
of IkappaBalpha as compared to non-associated CK2. The functional relevance of
this observation is supported by the fact that the turnover of free IkappaBalpha
in resting cells is S293-dependent. Moreover, overexpressing PKC-zeta results in
lower steady-state protein levels of free IkappaBalpha, which is dependent on
S293. Lastly, it is shown that PKC-zeta wt but not kinase dead leads to the in
vitro phosphorylation of both CK2-alpha and beta. These studies demonstrate that
the association between CK2 and PKC-zeta may play a major role in the control of
the basal turnover of free IkappaBalpha, in the absence of extracellular stimuli.
PMID- 10764588
TI - Energetic basis of structural stability in the molten globule state: alpha
lactalbumin.
AB - The denatured states of alpha-lactalbumin, which have features of a molten
globule state, have been studied to elucidate the energetics of the molten
globule state and its contribution to the stability of the native conformation.
Analysis of calorimetric and CD data shows that the heat capacity increment of
alpha-lactalbumin denaturation highly correlates with the degree of disorder of
the residual structure of the state. As a result, the denaturational transition
of alpha-lactalbumin from the native to a highly ordered compact denatured state,
and from the native to the disordered unfolded state are described by different
thermodynamic functions. The enthalpy and entropy of the denaturation of alpha
lactalbumin to compact denatured state are always greater than the enthalpy and
entropy of its unfolding. This difference represents the unfolding of the molten
globule state. Calorimetric measurements of the heat effect associated with the
unfolding of the molten globule state reveal that it is negative in sign over the
temperature range of molten globule stability. This observation demonstrates the
energetic specificity of the molten globule state, which, in contrast to a
protein with unique tertiary structure, is stabilized by the dominance of
negative entropy and enthalpy of hydration over the positive conformational
entropy and enthalpy of internal interactions. It is concluded that at
physiological temperatures the entropy of dehydration is the dominant factor
providing stability for the compact intermediate state on the folding pathway,
while for the stability of the native state, the conformational enthalpy is the
dominant factor.
PMID- 10764589
TI - Structure, stability and function of RNA pseudoknots involved in stimulating
ribosomal frameshifting.
AB - Programmed -1 ribosomal frameshifting has become the subject of increasing
interest over the last several years, due in part to the ubiquitous nature of
this translational recoding mechanism in pathogenic animal and plant viruses. All
cis-acting frameshift signals encoded in mRNAs are minimally composed of two
functional elements: a heptanucleotide "slippery sequence" conforming to the
general form X XXY YYZ, followed by an RNA structural element, usually an H-type
RNA pseudoknot, positioned an optimal number of nucleotides (5 to 9) downstream.
The slippery sequence itself promotes a low level ( approximately 1 %) of
frameshifting; however, downstream pseudoknots stimulate this process
significantly, in some cases up to 30 to 50 %. Although the precise molecular
mechanism of stimulation of frameshifting remains poorly understood, significant
advances have been made in our knowledge of the three-dimensional structures,
thermodynamics of folding, and functional determinants of stimulatory RNA
pseudoknots derived from the study of several well-characterized frameshift
signals. These studies are summarized here and provide new insights into the
structural requirements and mechanism of programmed -1 ribosomal frameshifting.
PMID- 10764590
TI - Ligand-induced stabilization of PPARgamma monitored by NMR spectroscopy:
implications for nuclear receptor activation.
AB - Nuclear receptors are ligand-dependent transcription factors that are mediators
of the action of lipophilic hormones and other endogenous ligands and are the
targets of drugs useful in a variety of therapeutic areas. Peroxisome
proliferator-activated receptor (PPAR)gamma is a nuclear receptor that, acting as
a heterodimer with RXR, mediates a variety of cellular effects including
adipocyte-differentiation. Due to its role in modulating insulin sensitivity, it
is the target of therapeutically active anti-diabetic agents such as
rosiglitazone. We have assigned the chemical shifts of the backbone atoms of the
32 kDa ligand-binding domain of PPARgamma in the presence of bound rosiglitazone.
Three-dimensional HNCO spectra of the apo ligand-binding domain (LBD) have less
than half the expected number of cross-peaks. The missing cross-peaks are
restored upon binding strong agonists such as rosiglitazone. The NMR results
indicate that the apo-LBD of PPARgamma is in a conformationally mobile state, and
that agonist binding is associated with a marked stabilization of the
conformation. Mapping the missing peaks to the 3D X-ray crystallographic
structure indicates the region of mobility is extensive and includes the ligand
binding region and the cofactor-binding site. This leads to the conclusion that
activation of this nuclear receptor is a result of a population shift of a
dynamic ensemble of conformations, rather than a two-state switch from an
inactive to an active conformation. Our results have important implications for
the mechanisms by which antagonists, partial agonists, and agonists of nuclear
receptor function operate.
PMID- 10764591
TI - Quadruplet codons: implications for code expansion and the specification of
translation step size.
AB - One of the requirements for engineering expansion of the genetic code is a unique
codon which is available for specifying the new amino acid. The potential of the
quadruplet UAGA in Escherichia coli to specify a single amino acid residue in the
presence of a mutant tRNA(Leu) molecule containing the extra nucleotide, U, at
position 33.5 of its anticodon loop has been examined. With this mRNA-tRNA
combination and at least partial inactivation of release factor 1, the UAGA
quadruplet specifies a leucine residue with an efficiency of 13 to 26 %. The
decoding properties of tRNA(Leu) with U at position 33.5 of its eight-membered
anticodon loop, and a counterpart with A at position 33.5, strongly suggest that
in both cases their anticodon loop bases stack in alternative conformations. The
identity of the codon immediately 5' of the UAGA quadruplet influences the
efficiency of quadruplet translation via the properties of its cognate tRNA. When
there is the potential for the anticodon of this tRNA to dissociate from pairing
with its codon and to re-pair to mRNA at a nearby 3' closely matched codon, the
efficiency of quadruplet translation at UAGA is reduced. Evidence is presented
which suggests that when there is a purine base at position 32 of this 5'
flanking tRNA, it influences decoding of the UAGA quadruplet.
PMID- 10764592
TI - Effects of core histone tail domains on the equilibrium constants for dynamic DNA
site accessibility in nucleosomes.
AB - The N and C-terminal tail domains of the core histones play important roles in
gene regulation, but the mechanisms through which they act are not known. These
tail domains are highly positively charged and are the sites of numerous post
translational modifications, including many sites for lysine acetylation.
Nucleosomes in which these tail domains have been removed by trypsin remain
otherwise intact, and are used by many laboratories as a model system for highly
acetylated nucleosomes. Here, we test the hypothesis that one role of the tail
domains is to directly regulate the accessibility of nucleosomal DNA to other DNA
binding proteins. Three assays are used: equilibrium binding by a site-specific,
DNA-binding protein, and dynamic accessibility to restriction enzymes or to a non
specific exonuclease. The effects of removal of the tail domains as monitored by
each of these assays can be understood within the framework of the site exposure
model for the dynamic equilibrium accessibility of target sites located within
the nucleosomal DNA. Removal of the tail domains leads to a 1.5 to 14-fold
increase in position-dependent equilibrium constants for site exposure. The
smallness of the effect weighs against models for gene activation in which
histone acetylation is a mandatory initial event, required to facilitate
subsequent access of regulatory proteins to nucleosomal DNA target sites.
Alternative roles for histone acetylation in gene regulation are discussed.
PMID- 10764593
TI - NAP-2: histone chaperone function and phosphorylation state through the cell
cycle.
AB - We have recently cloned the human nucleosome assembly protein 2 (NAP-2). Here, we
demonstrate that casein kinase 2 (CKII) from HeLa cell nuclear extracts interacts
with immobilized NAP-II, and phosphorylates both NAP-2 and nucleosome assembly
protein 1 (NAP-1) in vitro. Furthermore, NAP-1 and NAP-2 phosphorylation in crude
HeLa cell extracts is abolished by heparin, a specific inhibitor of CKII.
Addition of core histones can stimulate phosphorylation of NAP-1 and NAP-2 by
CKII. NAP-2 is also a phosphoprotein in vivo. The protein is phosphorylated at
the G0/G1 boundary but it is not phosphorylated in S-phase. Here, we show that
NAP-2 is a histone chaperone throughout the cell cycle and that its cell-cycle
distribution might be governed by its phosphorylation status. Phosphorylated NAP
2 remains in the cytoplasm in a complex with histones during the G0/G1
transition, whereas its dephosphorylation triggers its transport into the
nucleus, at the G1/S-boundary, with the histone cargo, suggesting that binding to
histones does not depend on phosphorylation status. Finally, indirect
immunofluorescence shows that NAP-2 is present during metaphase of HeLa and COS
cells, and its localization is distinct from metaphase chromosomes.
PMID- 10764594
TI - A new model for the surface arrangement of myosin molecules in tarantula thick
filaments.
AB - Three-dimensional reconstructions of the negatively stained thick filaments of
tarantula muscle with a resolution of 50 A have previously suggested that the
helical tracks of myosin heads are zigzagged, short diagonal ridges being
connected by nearly axial links. However, surface views of lower contour levels
reveal an additional J-shaped feature approximately the size and shape of a
myosin head. We have modelled the surface array of myosin heads on the filaments
using as a building block a model of a two-headed regulated myosin molecule in
which the regulatory light chains of the two heads together form a compact head
tail junction. Four parameters defining the radius, orientation and rotation of
each myosin molecule were varied. In addition, the heads were allowed
independently to bend in a plane perpendicular to the coiled-coil tail at three
sites, and to tilt with respect to the tail and to twist at one of these sites.
After low-pass filtering, models were aligned with the reconstruction, scored by
cross-correlation and refined by simulated annealing. Comparison of the geometry
of the reconstruction and the distance between domains in the myosin molecule
narrowed the choice of models to two main classes. A good match to the
reconstruction was obtained with a model in which each ridge is formed from the
motor domain of a head pointing to the bare zone together with the head-tail
junction of a neighbouring molecule. The heads pointing to the Z-disc
intermittently occupy the J-position. Each motor domain interacts with the
essential and regulatory light chains of the neighbouring heads. A near-radial
spoke in the reconstruction connecting the backbone to one end of the ridge can
be identified as the start of the coiled-coil tail.
PMID- 10764595
TI - Small heat-shock protein structures reveal a continuum from symmetric to variable
assemblies.
AB - The small heat-shock proteins (sHSPs) form a diverse family of proteins that are
produced in all organisms. They function as chaperone-like proteins in that they
bind unfolded polypeptides and prevent uncontrolled protein aggregation. Here, we
present parallel cryo-electron microscopy studies of five different sHSP
assemblies: Methanococcus jannaschii HSP16.5, human alphaB-crystallin, human
HSP27, bovine native alpha-crystallin, and the complex of alphaB-crystallin and
unfolded alpha-lactalbumin. Gel-filtration chromatography indicated that HSP16.5
is the most monodisperse, while HSP27 and the alpha-crystallin assemblies are
more polydisperse. Particle images revealed a similar trend showing mostly
regular and symmetric assemblies for HSP16.5 particles and the most irregular
assemblies with a wide range of diameters for HSP27. A symmetry test on the
particle images indicated stronger octahedral symmetry for HSP16.5 than for HSP27
or the alpha-crystallin assemblies. A single particle reconstruction of HSP16.5,
based on 5772 particle images with imposed octahedral symmetry, resulted in a
structure that closely matched the crystal structure. In addition, the cryo-EM
reconstruction revealed internal density presumably corresponding to the flexible
32 N-terminal residues that were not observed in the crystal structure. The N
termini were found to partially fill the central cavity making it unlikely that
HSP16.5 sequesters denatured proteins in the cavity. A reconstruction calculated
without imposed symmetry confirmed the presence of at least loose octahedral
symmetry for HSP16.5 in contrast to the other sHSPs examined, which displayed no
clear overall symmetry. Asymmetric reconstructions for the alpha-crystallin
assemblies, with an additional mass selection step during image processing,
resulted in lower resolution structures. We interpret the alpha-crystallin
reconstructions to be average representations of variable assemblies and suggest
that the resolutions achieved indicate the degree of variability. Quaternary
structural information derived from cryo-electron microscopy is related to recent
EPR studies of the alpha-crystallin domain fold and dimer interface of alphaA
crystallin.
PMID- 10764596
TI - High-resolution structure of the OmpA membrane domain.
AB - The membrane domain of OmpA consists of an eight-stranded all-next-neighbor
antiparallel beta-barrel with short turns at the periplasmic barrel end and long
flexible loops at the external end. The structure analysis has been extended from
medium resolution to 1. 65 A (1 A=0.1 nm), and the molecular model has been
refined anisotropically to show oriented mobilities of the structural elements.
The improved data allowed us to locate five further detergent molecules and 11
more water molecules. Moreover, the two large non-polar packing contacts have now
been defined in detail. The analysis indicates that the beta-barrel constitutes a
solid scaffold such that the long external loops need not contribute to
stability. These loops are highly mobile and thus cause a major problem during
the crystallization process. The beta-barrel was related to those of lipocalins.
Two further crystal forms with exceptionally dense packing arrangements were
established at medium resolution.
PMID- 10764597
TI - Mapping the transition state of the WW domain beta-sheet.
AB - The folding kinetics of a three-stranded antiparallel beta-sheet (WW domain) have
been measured by temperature jump relaxation. Folding and activation free
energies were determined as a function of temperature for both the wild-type and
the mutant domain, W39F, which modifies the beta(2)-beta(3) hydrophobic
interface. The folding rate decreases at higher temperatures as a result of the
increase in the activation free energy for folding. Phi-Values were obtained for
thermal perturbations allowing the primary features of the folding free energy
surface to be determined. The results of this analysis indicate a significant
shift from an "early" (Phi(T)=0. 4) to a "late" (Phi(T)=0.8) transition state
with increasing temperature. The temperature-dependent Phi-value analysis of the
wild-type WW domain and of its more stable W39F hydrophobic cluster mutant
reveals little participation of residue 39 in the transition state at lower
temperature. As the temperature is raised, hydrophobic interactions at the
beta(2)-beta(3) interface gain importance in the transition state and the barrier
height of the wild-type, which contains the larger tryptophan residue, increases
more slowly than the barrier height of the mutant.
PMID- 10764598
TI - The pressure-temperature free energy-landscape of staphylococcal nuclease
monitored by (1)H NMR.
AB - The thermodynamic stability of staphylococcal nuclease was studied against the
variation of both temperature and pressure by utilizing (1)H NMR spectroscopy at
750 MHz in 20 mM Mes buffer containing 99.9 % (2)H(2)O, pH 5.3. Equilibrium
fractions of folded and unfolded protein species were evaluated with the proton
signals of two histidine residues as monitor in the pressure range of 30-3300 bar
and in the temperature range of 1.5 degrees C-35 degrees C. From the multi
parameter fit of the experimental data to the Gibbs energy equation expressed as
a simultaneous function of pressure and temperature, we determined the
compressibility change (Deltabeta), the volume change at 1 bar (DeltaV degrees )
and the expansivity change (Deltaalpha) upon unfolding among other thermodynamic
parameters: Deltabeta=0.02(+/-0.003) ml mol(-1) bar(-1); Deltaalpha=1.33(+/-0.2)
ml mol(-1) K(-1); DeltaV degrees =-41.9(+/-6. 3) ml mol(-1) (at 24 degrees C);
DeltaG degrees =13.18(+/-2) kJ mol(-1) (at 24 degrees C); DeltaC(p)=13.12(+/-2)
kJ mol(-1) K(-1); DeltaS degrees =0.32(+/-0.05) kJ mol(-1) K(-1 )(at 24 degrees
C). The result yields a three-dimensional free energy surface, i.e. the free
energy-landscape of staphylococcal nuclease on the P-T plane. The significantly
positive Deltabeta and Deltaalpha values suggest that, in the pressure-denatured
state, staphylococcal nuclease forms a loosely packed and fluctuating structure.
The slight but statistically significant difference between the unfolding
transitions of the His8 and His124 environments is considered to reflect local
fluctuations in the native state, leading to pre-melting of the His124
environment prior to the cooperative unfolding of the major part of the protein.
PMID- 10764599
TI - Evolutionary conservation in protein folding kinetics.
AB - The sequence and structural conservation of folding transition states have been
predicted on theoretical grounds. Using homologous sequence alignments of
proteins previously characterized via coupled mutagenesis/kinetics studies, we
tested these predictions experimentally. Only one of the six appropriately
characterized proteins exhibits a statistically significant correlation between
residues' roles in transition state structure and their evolutionary
conservation. However, a significant correlation is observed between the
contributions of individual sequence positions to the transition state structure
across a set of homologous proteins. Thus the structure of the folding transition
state ensemble appears to be more highly conserved than the specific interactions
that stabilize it.
PMID- 10764600
TI - SH3-SPOT: an algorithm to predict preferred ligands to different members of the
SH3 gene family.
AB - We have developed a procedure to predict the peptide binding specificity of an
SH3 domain from its sequence. The procedure utilizes information extracted from
position-specific contacts derived from six SH3/peptide or SH3/protein complexes
of known structure. The framework of SH3/peptide contacts defined on the
structure of the complexes is used to build a residue-residue interaction
database derived from ligands obtained by panning peptide libraries displayed on
filamentous phage. The SH3-specific interaction database is a multidimensional
array containing frequencies of position-specific contacts. As input, SH3-SPOT
requires the sequence of an SH3 domain and of a query decapeptide ligand. The
array, that we call the SH3-specific matrix, is then used to evaluate the
probability that the peptide would bind the given SH3 domain. This procedure is
fast enough to be applied to the entire protein sequence database. Panning
experiments were performed to search putative specific ligands of different SH3
domains in a database of decapeptides, or in a database of protein sequences. The
procedure ranked some of the natural partners of interaction of a number of SH3
domains among the best ligands of the approximately 5. 6x10(9) different
decapeptides in the SWISSPROT database. We expect the predictive power of the
method to increase with the enrichment of the SH3-specific matrix by interaction
data derived from new complex structures or from the characterization of new
ligands. The procedure was developed using the SH3 domain family as test case but
its application can easily be extended to other families of protein domains (such
as, SH2, MHC, EH, PDZ, etc.).
PMID- 10764602
TI - Editorial
PMID- 10764601
TI - Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A
(PKA) regulatory subunits: PKA isoform specificity in AKAP binding.
AB - Compartmentalization of cAMP-dependent protein kinase (PKA) is in part mediated
by specialized protein motifs in the dimerization domain of the regulatory (R)
subunits of PKA that participate in protein-protein interactions with an
amphipathic helix region in A-kinase anchoring proteins (AKAPs). In order to
develop a molecular understanding of the subcellular distribution and specific
functions of PKA isozymes mediated by association with AKAPs, it is of importance
to determine the apparent binding constants of the R-subunit-AKAP interactions.
Here, we present a novel approach using surface plasmon resonance (SPR) to
examine directly the association and dissociation of AKAPs with all four R
subunit isoforms immobilized on a modified cAMP surface with a high level of
accuracy. We show that both AKAP79 and S-AKAP84/D-AKAP1 bind RIIalpha very well
(apparent K(D) values of 0.5 and 2 nM, respectively). Both proteins also bind
RIIbeta quite well, but with three- to fourfold lower affinities than those
observed versus RIIalpha. However, only S-AKAP84/D-AKAP1 interacts with RIalpha
at a nanomolar affinity (apparent K(D) of 185 nM). In comparison, AKAP95 binds
RIIalpha (apparent K(D) of 5.9 nM) with a tenfold higher affinity than RIIbeta
and has no detectable binding to RIalpha. Surface competition assays with
increasing concentrations of a competitor peptide covering amino acid residues
493 to 515 of the thyroid anchoring protein Ht31, demonstrated that Ht31, but not
a proline-substituted peptide, Ht31-P, competed binding of RIIalpha and RIIbeta
to all the AKAPs examined (EC(50)-values from 6 to 360 nM). Furthermore, RIalpha
interaction with S-AKAP84/D-AKAP1 was competed (EC(50) 355 nM) with the same
peptide. Here we report for the first time an approach to determine apparent rate
and equilibria binding constants for the interaction of all PKA isoforms with
any AKAP as well as a novel approach for characterizing peptide competitors that
disrupt PKA-AKAP anchoring.
PMID- 10764603
TI - Preparation and analysis of the common urinary forms of human chorionic
gonadotropin.
AB - Human chorionic gonadotropin (hCG) is the hormone of pregnancy and forms the
basis of all pregnancy tests as well as diagnostic assays for a variety of
pathological states including certain types of cancers and some diseases of
pregnancy and genetic abnormalities. In recent years, the discovery of the
diagnostic utility of measurement of the free subunits and fragments of the
hormone, especially in urine, has proven of special use for diagnosis of very
early pregnancy loss, an important phenomenon related to infertility, as well as
part of screening programs for Down Syndrome and gynecological cancers. This
article summarizes existing and new methods for the preparation of hCG, its
subunits, and the beta core fragment from urinary sources. The methods for proper
analyses of these materials are also described to enable investigators to prepare
and analyze these materials in various quantities in their own laboratories.
PMID- 10764604
TI - Carbohydrate analysis of glycoprotein hormones.
AB - Complete carbohydrate composition analysis of glycoprotein hormones, their
subunits, and oligosaccharides isolated from individual glycosylation sites can
be accomplished using high-pH anion-exchange chromatography combined with pulsed
amperometric detection. Neutral and amino sugars are analyzed from the same
hydrolyzate by isocratic chromatography on a Dionex CarboPAC PA1 column in 16 mM
NaOH. Sialic acid is quantified following mild hydrolysis conditions on the same
column in 150 mM sodium acetate in 150 mM NaOH. Ion chromatography on a Dionex
AS4A column in 1.8 mM Na(2)CO(3)/1.7 mM NaHCO(3); postcolumn, in-line anion
micromembrane suppression; and conductivity detection can be used to quantify
sulfate, a common component of pituitary glycoprotein hormone oligosaccharides.
Mass spectrometric analysis before and after elimination of oligosaccharides from
a single glycosylation site can provide an estimate of the average
oligosaccharide mass, which facilitates interpretation of oligosaccharide
composition data. Following release by peptide N-glycanase (PNGase) digestion and
purification by ultrafiltration, oligosaccharides can be characterized by a high
resolution oligosaccharide mapping technique using the same equipment employed
for composition analysis. Oligosaccharide mapping can be applied to the entire
hormone, individual subunits, or individual glycosylation sites by varying PNGase
digestion conditions or substrates. Oligosaccharide release by PNGase is readily
monitored by SDS-PAGE. Site-specific deglycosylation can be confirmed by amino
acid sequence analysis. For routine isolation of oligosaccharides, addition of 2
aminobenzamide at the reducing terminus facilitates detection; however, the
oligosaccharide retention times are altered. Composition analysis is also
affected as the 2-aminobenzamide-modified GlcNAc peak overlaps the fucose peak.
PMID- 10764605
TI - Antibodies and immunoassays.
AB - As a glycoprotein hormone, human chorionic gonadotropin (hCG) is not a single
molecular entity. This term comprises not only the bioactive heterodimer hCG but
also an array of molecular protein backbone and glycosylation variants, such as
its free beta (hCGbeta) and alpha (hCGalpha) subunits and clipped, cleaved,
terminally differently sialylated, and overglycosylated forms. This heterogeneity
places great demands on selective detection systems for hCG-derived molecules.
Measurement of hCG and/or its derivatives is highly dependent on the selection of
target molecules and the natural variability of hCG in the specimens analyzed.
Monoclonal antibody (mAb)-based immunoassays are still the state-of-the-art
technique for both clinical and research applications but a major problem is the
different extents of recognition of hCG variants by mAbs used in different
immunoassays. On the whole, construction of sandwich-type assays obviously must
take into consideration mAb characteristics, such as main and fine specificities,
cross-reactivities, epitope locations and compatibilities, overlap and overhang
in specificities (pairs of mAbs), and, finally, overspecificity. Consequences of
overhang and overlap in antigen recognition of coating and detection mAb
specificities are nondesirable assay cross-reactions and competitive interference
by antigenic variants. The general agreement on the most favorable assay design
is contrasted by the variety of isotopic and nonisotopic detection systems in
current use. The immunoenzymometric assay (IEMA) technique is hampered by a
relatively small measuring range and limited sensitivity. By measuring substrate
absorption values off the absorption maximum, the measuring range of any IEMA can
be extended significantly, as shown for 3,3',5, 5'-tetramethylbenzidine (TMB),
without jeopardizing assay characteristics. Sensitivity of the IEMA can be
enhanced by modifying the horseradish peroxidase (HRPO) labeling technique by
using highly purified mAb preparations and higher-input HRPO/mAb ratios. We have
also compared the assay characteristics of time-resolved fluoroimmunoassay
(IFMA), IEMA, immunoradiometric assay (IRMA), and competitive radioimmunoassay
(RIA) based on identical mAbs. Reasons for the observed superiority of the IFMA
lie in its concept of signal detection and the high specific labeling of the
detection mAb which on a molar basis can be up to 7-fold and 15-fold higher
compared with (125)I and HRPO, respectively.
PMID- 10764606
TI - Bioassays of gonadotropins.
AB - Bioassays constitute a unique approach to determine the functional aspects of
gonadotropins. Indeed, these highly complex glycoprotein hormones, including
pituitary lutropin (LH) and follitropin (FSH), are heterogeneous in terms of both
peptidic and carbohydrate moieties, and, as a consequence, the bioactivity of the
different molecular forms often does not match their immunoreactivity. In this
article, we review the different types of LH and FSH bioassays. Conventional
methods for measuring FSH bioactivity are first described and include the in vivo
Steelman and Pohley bioassay, the radioligand receptor assays (RRAs), the in
vitro Sertoli cell bioassay, the in vitro granulosa cell bioassay, and the
inhibin immunoassay. Recent methods based on cell lines transfected with cloned
receptors, particularly the human FSH receptor, are then described. Methods for
developing these assays are presented, and the advantages and disadvantages of
the different bioassays are discussed.
PMID- 10764607
TI - Genetic engineering of single-chain gonadotropins and hormone-receptor fusion
proteins.
AB - The gonadotropin hormone family is distinguished by its heterodimeric structure
in which the members share a common alpha subunit and a hormone-specific beta
subunit. Since assembly of the heterodimer is often the rate-limiting step in
production of functional hormone, single-chain hormones have been engineered by
genetically linking the two subunits. The single-chain hormone can in turn be
fused to its receptor to produce a functional single-chain hormone-receptor
complex. These fusion constructs offer a valuable new approach in structure
function studies and in the generation of hormone analogs. In this article we
describe the experimental design for the generation of single-chain human
chorionic gonadotropin and single-chain hormone-receptor fusion complex and
strategies for the expression of these fusion proteins.
PMID- 10764608
TI - Human thyroid-stimulating hormone: structure-function analysis.
AB - This article provides the reader with an overview of methodological strategies to
investigate structure-function relationships of human thyroid-stimulating hormone
(hTSH). Various aspects of hTSH production, purification, and characterization
described here in more detail are not only relevant to studies on other members
of the glycoprotein hormone family, but also applicable to studies of other
glycosylated proteins. Knowledge of structure-function relationships of specific
hTSH domains is important for a better understanding of the molecular mechanisms
of its action. New insights from such studies permit the design of glycoprotein
hormone analogs with specific pharmacological properties and potential clinical
applications.
PMID- 10764609
TI - Detection of mutations in glycoprotein hormone receptors.
AB - The luteinizing, follicle-stimulating, and thyroid-stimulating hormone receptors
belong to the huge family of G-protein-coupled receptors. Identification of
either activating or inactivating mutations of these receptors has led to a
fundamental improvement in our understanding of glycoprotein hormone/receptor
interaction. Furthermore, clinical phenotypes such as precocious puberty,
follicle-stimulating hormone (FSH) insensitivity syndrome, and congenital
hypthyroidism are now being explained by mutated glycoprotein hormone receptors.
Since there is an ongoing worldwide search for certain clinical phenotypes that
might be caused by mutations of these receptors, there is a demand for strategies
and techniques that can be used to screen patients in a effective and reliable
way. This article focuses, therefore, on patient selection and techniques for the
detection of mutations of glycoprotein hormone receptors, and compiles useful
laboratory protocols to conduct such studies.
PMID- 10764610
TI - A novel cysteine proteinase (CP65) of Trichomonas vaginalis involved in
cytotoxicity.
AB - The goal of this study was to demonstrate the participation in cellular damage of
a Trichomonas vaginalis proteinase with a molecular mass of 65 kDa (CP65). By two
dimensional gelatin-gel electrophoresis of trichomonad proteins we detected four
spots with proteolytic activity on the 65 kDa region, but only one, pI 7.2, binds
to the HeLa cell surface. By indirect immunofluorescence, rabbit antibodies
against this proteinase localized the CP65 on the plasma membrane and in the
cytoplasm of T. vaginalis. Pretreatment of parasites with the specific anti-CP65
antibody reduced trichomonal cytotoxicity to HeLa cell monolayers. The specific
cysteine proteinase inhibitor, L-3-carboxy-2, 3-trans-epoxypropionyl-leucylamido
(4-guanidino) butane (E64) abrogated the proteinase activity and reduced
cytotoxicity levels of T. vaginalis in cell culture monolayers, indicating that
the trichomonad CP65 is a cysteine proteinase. Activity of the CP65 proteinase
was optimal at pH 5.5 and 37 degrees C, conditions similar to those of patients
with trichomonosis. Also, this proteinase degraded some of the proteins found in
the vagina, i.e. collagen IV and fibronectin, but not laminin-1 or haemoglobin.
Finally, immunoprecipitation assays showed that sera and vaginal washes from
trichomonosis patient possess anti-CP65 antibodies. In conclusion, results
presented in this work demonstrate that the CP65 is a surface cysteine proteinase
involved in T. vaginalis cytotoxicity to HeLa cell monolayers, as a virulence
factor. It is immunogenic during human infection and degrades some extracellular
matrix proteins, i.e. collagen IV and fibronectin.
PMID- 10764611
TI - Attachment of Moraxella catarrhalis occurs to the positively charged domains of
pharyngeal epithelial cells.
AB - Attachment of bacteria to host cells is the initial step in the pathogenesis of
infection. Several factors, such as hydrophobicity, surface electric charge, and
van der Waals force, are considered to be responsible for the attachment step.
However, it is not clear why bacteria and epithelial cells, both of which possess
a negative surface charge, do not repel one another. In the present study, we
used Moraxella catarrhalis and pharyngeal epithelial cells to study the surface
charges of structures involved in the attachment. By atomic force microscopy
(AFM) equipped with surface potential spectroscopy, it was found that the cell
surface microplicae have a positive charge of 30.1+/-3.6 mV (mean+/-SE). The
depressions between the microplicae have a negative surface charge of 43.5+/-4.0
mV. Using cationic ferritin and electron microscopy (EM) we confirmed that the
depressions between the microplicae have a negative charge. By AFM and by using
cationic ferritin with EM, it was found that the net surface charge of the
bacterial cells is negative. By both AFM and EM, it was found that the bacterial
cells attach to the microplicae of the pharyngeal epithelial cell. Our work
confirmed the general belief that both kinds of cells do have a net negative
charge. We conclude that there are positively and negatively charged domains on
the surface of human pharyngeal epithelial cells. M. catarrhalis evidently
attaches to the positively charged domain (i.e. microplicae) of pharyngeal
epithelial cells.
PMID- 10764612
TI - Recognition of B cells epitopes of the Klebsiella pneumoniae GroEL-like protein
by HLA-B27 positive subjects.
AB - The presence of antibodies against antigens of K. pneumoniae in HLA-B27 positive
patients with ankylosing spondylitis (AS), has been well documented. We have
previously reported that sera from HLA-B27 positive subjects react with the K.
pneumoniae GroEL-like protein (HSP60Kp) and have higher titers than HLA-B27
negative individuals. We cloned the gene that codes for this protein, determined
hydrophilic regions by computer analysis of the predicted amino acid sequence and
found that residues 389-397, 360-368 and 282-290, were possible B cell epitopes.
To test this prediction, and to determine if the HLA-B27 positive and negative AS
patients recognize the same or different epitopes, we truncated the hsp60Kp gene,
from the 3; terminal nucleotide, to obtain fragments having or not the predicted
epitopes. Four polypeptides of 40, 37, 30 and 18 kDa were obtained and analysed,
by ELISA and inhibition of ELISA, for their reactivity with IgG antibodies from
three high responders HLA-B27 positive AS patients and three HLA-B27 negative
subjects who recognized the rHSP60Kp. Sera from both HLA-B27 positive and
negative subjects reacted equally well with rHSP60Kp or with the 40 and 37 kDa
peptides, which do not have residues 389-397 and 360-368, respectively, but
reactivity was lost with the 30 kDa peptide, which also lacks residues 282-290.
Contrary to what we expected, antibodies from HLA-B27 negative and positive
individuals recognized the same epitope of the HSP60Kp. Our results indicate that
the important epitope for B cells could be the 282-290 region and that the
contribution of the two other predicted regions is minimal. We also conclude that
the differences in response to the HSP60Kp in HLA-B27 positive AS patients and
HLA-B27 negative individuals is not qualitative, but only quantitative.
PMID- 10764613
TI - Inactivation of the cysteine protease SpeB affects hyaluronic acid capsule
expression in group A streptococci.
AB - The human pathogen Streptococcus pyogenes expresses several virulence factors
that are required for the pathogens survival within the host and the concomitant
development of disease. To examine the influence of one virulence factor, the
extracellular cysteine protease SpeB, on the expression of other virulence
factors, the speB structural gene of a serotype M3 and M49 strain was
inactivated. Morphologic examination, quantification of extracellular hyaluronic
acid capsule, and Northern blot analysis of the isogenic speB -mutants revealed a
strain-dependent decrease of hyaluronic acid capsule production and an increase
in superoxide dismutase transcription. The transcription of streptolysin O (slo),
di- and oligo-peptide permease (dpp, opp), hyaluronidase (hyl), streptokinase
(ska) and streptococcal pyrogenic exotoxin A (speA) was unaffected.
PMID- 10764614
TI - Cellular invasion of Orientia tsutsugamushi requires initial interaction with
cell surface heparan sulfate.
AB - Role of transmembrane heparan sulfate proteoglycans on invasion of Orientia
tsutsugamushi into host cells was investigated. Pretreatment with heparan sulfate
and heparin inhibited the infection of O. tsutsugamushi for L cell, mouse
fibroblast, whereas other glycosaminoglycans had little effect. These same
treatments were also shown to reduce the infection in a dose-dependent manner,
and enzymatic treatment of cells with heparitinase, but not chondroitinase ABC,
inhibited the infection. In addition, mutant cell lines of Chinese hamster
ovarian cell defective in heparan sulfate synthesis but not chondrotin sulfate
synthesis and defective in all glycosaminoglycan synthesis showed marked
reduction in susceptibility to infection by O. tsutsugamushi. Also mutant cell
lines, which express heparan sulfate proteoglycans at low level, showed
intermediate level of infectivity. Finally O. tsutsugamushi bind to(35)S-labelled
heparin. Collectively, these findings provide strong evidence that heparan
sulfate proteoglycans contribute to the attachment of O. tsutsugamushi to the
cells.
PMID- 10764615
TI - Pleiotropic pigmentation mutants of Porphyromonas gingivalis.
AB - Porphyromonas gingivalis is a Gram-negative, black pigmented oral anaerobe
associated with adult periodontitis. The adherence of the bacterium to junctional
epithelial cells is the first step in infection and colonization. The molecular
mechanisms and genetics of colonization are, as yet, not well understood,
although it has been demonstrated that P. gingivalis fimbriae are involved in
adhesion. In addition, cell surface cysteine proteinases may play a role either
directly as adhesins or indirectly through their involvement in the biogenesis of
fimbriae. A link has been established between cysteine proteinase
hemagglutinating activity and colongy pigmentation on blood agar. In this study a
P. gingivalis ATCC 33277 transposon library was screened for white mutants.
Pleiotropic mutants were identified with altered pigmentation, proteinase,
hemagglutinin and haemolytic activities. Although the mutants fell into two
classes based on the above phenotypes, by electron microscopy both classes showed
increased fimbriation and decreased vesicle formation. Sequencing of genomic DNA
flanking the transposon insertions revealed that one class of mutants carried
disruptions in the gene encoding Lys-gingipain (kgp) and the other in a gene
homologous to a glycosyl transferase. Potential roles for these genes in
pigmentation, fimbriation, vesicle formation and attachment to epithelial cells
are discussed.
PMID- 10764616
TI - Detection of Coxiella burnetii DNA in dental pulp during experimental bacteremia.
AB - Colonization of dental pulp by blood-borne bacteria in the absence of previous
inflammation has been hypothetized but has never been convincingly demonstrated.
In order to provide convincing support for this hypothesis we attempted to detect
Coxiella burnetii DNA in the dental pulp of bacteremic, intraperitoneally
inoculated guinea-pigs by PCR amplification and direct sequencing of two
molecular targets. Coxiella burnetii DNA was recovered from 20-50% of the animals
depending on the molecular target, from 15-20 days after experimental challenge.
These results demonstrated, for the first time, that dental pulp is contaminated
by blood-borne bacteria and can be detected by molecular tools.
PMID- 10764617
TI - Introduction
PMID- 10764618
TI - HLA class I recognition by killer cell Ig-like receptors.
PMID- 10764620
TI - A family of inhibitory and activating Ig-like receptors that modulate function of
lymphoid and myeloid cells.
PMID- 10764619
TI - NK cell recognition of non-classical HLA class I molecules.
AB - NK cells recognize several HLA class Ib molecules employing both immunoglobulin
like (Ig-like) and C-type lectin receptors. The CD94/NKG2 and NKG2D lectin-like
molecules, respectively, interact with HLA-E and MICA; CD94/NKG2A functions as an
inhibitory receptor, while CD94/NKG2C and NKG2D trigger NK cell activity. HLA-E
predominantly presents nonamers from the leader sequences of other class I
molecules; a peptide derived from HLA-G1 constitutes the highest affinity ligand
for both CD94/NKG2 receptors. Members of the Ig-like transcript (ILT) or
leucocyte Ig-like receptor (LIR) family (ILT2 or LIR-1 and ILT4 or LIR-2),
expressed by other leucocyte lineages, interact with a broad spectrum of HLA
class Ia molecules and HLA-G1. Among Ig-like KIRs, the KIR2DL4 (p49) receptor has
been shown to specifically recognize HLA-G1; this molecule displays an unusual
hybrid structure, sharing features with inhibitory and triggering KIRs.
PMID- 10764621
TI - Surface receptors delivering opposite signals regulate the function of human NK
cells.
AB - The effector function of NK cells is regulated by a number of positive and
negative signals. The receptors involved in the negative regulation of NK cells
are known since several years: they are represented by different families of MHC
specific receptors characterized by ITIM sequences in their cytoplasmic tail. In
contrast, the surface molecules responsible for NK cell activation in the process
of natural cytotoxicity and tumor cell lysis have remained elusive until
recently. Three distinct NK-specific molecules termed 'natural cytotoxicity
receptors' (NCR) have recently been identified and cloned. They play a
complementary role in mediating NK cell activation in the interaction and lysis
of most tumor cells. They are associated with different ITAM-containing adaptor
proteins mediating signal transduction. Molecular cloning revealed novel members
of the Ig superfamily displaying a limited homology with known human receptors.
PMID- 10764622
TI - Signaling pathways engaged by NK cell receptors: double concerto for activating
receptors, inhibitory receptors and NK cells.
AB - Despite the absence of antigen-specific receptors at their surface, NK cells can
selectively eliminate virus-infected cells, tumor cells and allogenic cells. A
dynamic and precisely coordinated balance between activating and inhibitory
receptors governs NK cell activation programs. Multiple activating and inhibitory
NK cell surface molecules have been described, a group of them acting as
receptors for MHC class I molecules. In spite of their heterogeneity, activating
NK cell receptors present remarkable structural and functional homologies with T
cell- and B cell-antigen receptors. Inhibitory NK cell receptors operate at early
stages of activating cascades by recruiting protein tyrosine phosphatases via
intra- cytoplasmic motifs (ITIM), a strategy which is widely conserved in
hematopoietic and non-hematopoietic cells.
PMID- 10764623
TI - The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand
pairs expressed by NK cells and other immune cells.
AB - The CD2-subset of the immunoglobulin superfamily of cell surface receptors is an
emerging family of proteins involved in cellular activation. Members of this
family are CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule
(SLAM), 2B4 and Ly-9. These proteins are expressed on different leukocyte
populations and the receptors of this family, specifically CD2, 2B4 and SLAM,
contribute to the activation of T cells and natural killer cells. 2B4 and SLAM
associate with a protein termed SLAM-associated protein that is the genetic
defect in the immunodeficiency X-linked lymphoproliferative syndrome. Impaired
signaling via these receptors may contribute to this often-fatal
immunodeficiency.
PMID- 10764624
TI - NMR spectroscopic analyses of liver phosphatidylcholine and
phosphatidylethanolamine biosynthesis in rats exposed to peroxisome proliferators
A class of nongenotoxic hepatocarcinogens.
AB - Peroxisome proliferators (PPs) are commercial/industrial chemicals that display
tumor promoter activity in rodents. The mechanism is not completely understood,
and our ability to predict tumorigenicity a priori is even less developed. Wy
14,643, perfluorooctanoic acid (PFOA), and di(2-ethylhexyl)phthalate (DEHP) are
strong, moderate, and weak tumor promoters, respectively, while perfluorodecanoic
acid (PFDA) lacks promoter activity. This investigation examined the effects of
these PPs on the biosyntheses of phosphatidylcholine (PtdC) and
phosphatidylethanolamine (PtdE) in rat liver. After exposure to PPs, rats were
administered [1-(13)C]choline + [2-(13)C]ethanolamine and liver extracts were
analyzed by (31)P and (13)C NMR. The ratio of choline-derived to ethanolamine
derived phospholipids, R(c/e), was significantly affected by all PPs (p < 0. 05).
R(c/e) values were in the order Wy-14,643 > PFOA > DEHP > control > PFDA. The
amounts of PtdC derived via the CDP-choline pathway versus PtdE-N
methyltransferase (PEMT) activity was 71 vs 29% in controls. This distribution
was significantly affected by treatments with Wy-14,643 (95 vs 5%), DEHP (87 vs
13%), and PFDA (39 vs 61%) (p < 0.02). Data suggest that Wy-14,643, PFOA, and
DEHP cause a preference for choline and the CDP-choline pathway for biosynthesis
of PtdC. Additionally, Wy-14,643 and DEHP inhibited the PEMT pathway. In
contrast, PFDA-treated rats showed a preference for ethanolamine, and PtdC was
predominately synthesized through the PEMT pathway. These data corroborate
studies by Vance and co-workers which suggest that the pathways for PtdC
biosynthesis are important for hepatocarcinogenesis. Further studies to evaluate
the potential of these measurements as a biomarker for PP-associated
tumorigenesis is warranted.
PMID- 10764625
TI - The change of beta-adrenergic system in lead-induced hypertension.
AB - Lead exposure is considered to be a risk factor of cardiovascular disease. To
investigate the relationship between lead and cardiovascular disease/hypertension
in lead exposure, beta-adrenergic system is explored in this study. We address
three topics in this study: (a) the relationship between beta-adrenergic receptor
and lead level in heart, aorta, and kidney of lead-exposed rats; (b) the
relationship between beta-adrenergic receptor in heart, aorta, kidney, and blood
pressure in lead-exposed rats; and (c) the change of cyclic AMP level in heart,
aorta, and kidney of rats with different lead levels. Wistar rats were
chronically fed with 2, 1, 0. 5, 0.1, 0.05, and 0.01% lead acetate and water for
2 months. Plasma catecholamine level was measured by high-performance liquid
chromatography. Radioligand binding assay was measured by a method that fulfilled
strict criteria of beta-adrenoceptor using the ligand [(125)I]iodocyanopindolol.
Cyclic AMP (cAMP) level was determined by radioimmunoassay. The levels of lead
were determined by electrothermal atomic absorption spectrometry. The results
showed that increased plasma norepinephrine level, decreased aorta beta
adrenergic receptor and cAMP, and increased kidney beta-adrenergic receptor and
cAMP contributed to the elevation of blood pressure in lead-induced hypertension.
The decrement of beta-adrenoceptor and cAMP in heart resulted in decreased
contractility in heart.
PMID- 10764626
TI - Low-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is
associated with increased LRP expression and altered subcellular drug
distribution.
AB - The P-glycoprotein (P-gp)-negative epidermoid pharyngeal carcinoma cells KB-3-1
were grown in 0.25 mM benzo[a]pyrene (BaP) for 3 months and increased resistance
to doxorubicin, but not to vinblastine, colchicine, or cisplatin, was found.
Doxorubicin resistance was not altered by cyclosporin, the P-gp inhibitor.
Intracellular accumulation of BaP or calcein, a substrate for P-gp and multidrug
resistance protein (MRP), was not altered by inhibitors of the P-gp and MRP. The
expression of cytochrome P450 (CYP) 1A1, lung-resistance-related protein (LRP), P
gp, and MRP was investigated. Overexpression of CYP1A and LRP, on the mRNA and
protein levels, was found. BaP-treated KB-3-1 cells remained P-gp negative while
the level of MRP was not altered. Subcellular accumulation of BaP was found to be
localized in the cytoplasm and minimal in the nuclei in BaP treated cells. In
contrast, even penetration of BaP to the nuclei and cytoplasm was found in
untreated cells. Subcellular distribution of doxorubicin was altered following
BaP treatment with localized accumulation of the cancer drug in cytoplasmic
organelles but not in the nuclei. Our data suggested that LRP might play a
protective role against toxic compounds. The correlation of increased expression
of LRP, but not P-gp nor MRP, with decreased doxorubicin accumulation in the
nuclear target suggests a pivotal role of this perinuclear transporter in the MDR
phenotype of P-gp-negative cancer cells. These results also propose an
alternative mechanism of cancer drug resistance emergence, namely, induction of
LRP activity following treatment with BaP, an environmental toxicant and a
carcinogen.
PMID- 10764627
TI - Effect of acetaminophen on Na(+), K(+) ATPase and alkaline phosphatase on plasma
membranes of renal proximal tubules.
AB - In previous work we reported that 1 h after acetaminophen (APAP) administration,
tubular function remained at control values, while 16 h later a significant
deterioration of tubular function was observed. The aim of the present work was
to study if APAP induces its renal toxic effects by altering the normal activity
of key tubular plasma membrane enzymes. We analyzed the effects of a nephrotoxic
dose of APAP (1000 mg/kg b.wt., i.p.) on the activities of the brush-border
membrane (BBM) enzyme, alkaline phosphatase, and the basolateral membrane (BLM)
enzyme Na(+), K(+) ATPase 1 h (APAP(1h)) and 16 h (APAP(16h)) after dosing.
Na(+), K(+) ATPase abundance in homogenates and each membrane domain were
analyzed by Western blot. Cortical adenosine 5' triphosphate (ATP) content was
also evaluated. At each time studied, APAP promoted a diminution of alkaline
phosphatase in BBM. Na(+), K(+) ATPase activity in BLM showed a biphasic response
to APAP. One hour after APAP administration it was significantly increased, but
it was decreased 16 h after dosing. Na(+), K(+) ATPase protein abundance was
elevated in homogenates, BLM, and BBM after 1 h of APAP dosing. After 16 h,
Na(+), K(+) ATPase abundance was increased in homogenates, while in BLM it was
decreased. No differences were observed in cortical ATP content in each time
studied. Our present results could contribute to the understanding of the
molecular basis of the previously reported time course alteration in the
fractional excretion of sodium promoted by a nephrotoxic dose of APAP.
PMID- 10764628
TI - Apoptosis induction by the satratoxins and other trichothecene mycotoxins:
relationship to ERK, p38 MAPK, and SAPK/JNK activation.
AB - The satratoxins are members of the trichothecene mycotoxin family that are
produced by the fungus Stachybotrys and that have been etiologically associated
with building-related health problems. The purpose of this study was to relate
cytotoxic and apoptotic capacities of satratoxins and other trichothecenes to the
activation of three groups of mitogen-activated protein kinases (MAPKs)
(extracellular signal-regulated protein kinase (ERK), p38 MAPK, and stress
activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)). Two myeloid models,
RAW 264.7 murine macrophage and U937 human leukemic cells were used. Upon
evaluating representative trichothecenes in the 3-(4,5-dimethylthiazol-2-yl) 2,5
diphenyl tetrazolium bromide (MTT) cleavage assay, cytotoxicity was evident
according to the following rank order: satratoxin G, roridin A, and verrucarin A
> T-2 toxin, satratoxin F, H > nivalenol, and vomitoxin. Comparable results were
found when measuring trichothecene-mediated apoptosis using DNA fragmentation and
fluorescence microscopy assays, thus suggesting that cytotoxicity was mediated
through an apoptotic process. Assessment of MAPK activation using Western blot
analysis revealed that trichothecenes activated not only SAPK/JNK and p38 MAPK
but also ERK. Activation of MAPKs by satratoxins and other trichothecenes
correlated with and preceded apoptosis. The concentration of satratoxin G
sufficient for protein synthesis inhibition correlated with that required for
apoptosis and activation of all three MAPKs. Cycloheximide had similar effects to
trichothecenes, suggesting that ribosome binding or protein synthesis inhibition
may play roles in MAPK activation and apoptosis induction. Apoptosis induction by
satratoxin G and vomitoxin was markedly enhanced when ERK activation was
selectively inhibited by ERK-specific inhibitor PD98059, thus indicating a
negative role for ERK. Inhibition of p38 MAPK activity with the p38-specific
inhibitor SB203580 had no effect on apoptosis induction by the highly toxic
satratoxin G. However, SB203580 moderately inhibited apoptosis induction by the
less toxic trichothecene vomitoxin, thus implying a partial role of p38 MAPK in
trichothecene-induced apoptosis. The results suggest that the satratoxins are
among the most potent trichothecenes and that MAPKs may play integral roles in
the diverse toxic manifestations of these mycotoxins.
PMID- 10764629
TI - Sodium arsenite-induced dysregulation of proteins involved in proliferative
signaling.
AB - It is well accepted that arsenic is a human carcinogen, yet its mechanism of
action is not defined. Arsenic cannot be classified as an initiating agent or as
a promoter, although altered proliferative responsiveness has been proposed as a
mechanism by which arsenic exerts its carcinogenic effects. Based on the
hypothesis that arsenic exposure results in modulation of both positive and
negative regulators of cell proliferation, this study examined physiological and
biochemical changes in the proliferative response of murine fibroblasts grown
long-term in the maximum tolerated concentration of sodium arsenite. In response
to EGF stimulation, DNA synthesis and the proportion of cells entering S phase of
the cell cycle both were increased in cells grown long-term in arsenic compared
to control cells. Analysis of positive proliferative regulators revealed an
increase in the expression of c-myc and E2F-1, thereby supporting the hypothesis
that arsenic increases activity of positive growth modulators. In contrast, the
activity and expression of ERK-2 were unchanged, as was the expression of EGF
receptor and mSOS. When negative regulators of proliferation were examined,
expression levels of MAP kinase phosphatase-1 and p27(Kip1) were found to be
lower in arsenic-treated cells compared to control cells; this result supports a
model in which arsenic disinhibits normal regulation of cell proliferation. Taken
together, these data indicate that long-term exposure to sodium arsenite creates
conditions within the cell consistent with sensitization to mitogenic
stimulation. It is further postulated that the observed changes in mitogenic
signaling proteins contribute to the carcinogenic property of arsenic.
PMID- 10764630
TI - Distribution, teratogenicity, and embryonic delivered dose of retinoid Ro 23
9223.
AB - Ro 23-9223 is a highly lipophilic aromatic retinoid with antiproliferative and
sebum supressive effects in preclinical disease models of acne. To investigate
the relation between Ro 23-9223 developmental toxicity, drug distribution, and
transplacental transfer, groups of pregnant hamsters were given oral doses of 50
500 mg/kg Ro 23-9223 on days 8 and 9 of gestation. The teratogenic phenotype
induced at doses greater than 125 mg/kg per day was similar to that found after
exposure to doses of 13-cis-retinoic acid (isotretinoin, Accutane) greater than
37.5 mg/kg per day. Oral bioavailability of Ro 23-9223 was very low compared to
13-cis-retinoic acid. The highest concentrations of Ro 23-9223 were found in
maternal liver, lung, adipose tissue, cardiac muscle, and placenta, whereas only
little of the compound crossed the blood-brain barrier. Based on embryo AUC, Ro
23-9223 had a 30- to 50-fold greater embryo:maternal concentration ratio than 13
cis-retinoic acid plus its bioactive metabolites following similar doses of the
two retinoids. In preclinical pharmacology studies, oral doses of Ro 23-9223 (5
mg/kg per day) and 13-cis-retinoic acid (10 mg/kg per day) produced comparable
gland size reductions in the hamster ear sebaceous gland reduction assay. Under
these conditions, Ro 23-9223 plasma AUC was 40 times smaller than that of 13-cis
retinoic acid plus its bioactive metabolites. Assuming that the near linear dose
exposure relationship of Ro 23-9223 extends beyond the dose range of this study,
embryo AUCs of Ro 23-9223 and 13-cis-retinoic acid (plus metabolites) would be
near identical following pharmacologically equivalent doses. A comparison of
embryo retinoid AUCs suggests a 4-fold lower teratogenic potency of Ro 23-9223
compared to with 13-cis-retinoic acid. Despite high embryo levels in hamsters,
the data suggest an improved therapeutic index for Ro 23-9223 compared with 13
cis-retinoic acid in a preclinical acne disease model.
PMID- 10764631
TI - Cellular mechanisms of acrolein-induced alteration in calcium signaling in airway
smooth muscle.
AB - Acrolein, an unsaturated aliphatic aldehyde, is a potent respiratory irritant. We
have previously observed that acrolein administered ex vivo to isolated airways
alters subsequent airway responsiveness to muscarinic agonists in terms of both
mechanical activity of rings and calcium signaling in isolated cells. In the
present study, we have examined the mechanisms by which acrolein alters Ca(2+)
signaling. In freshly isolated rat tracheal smooth muscle cells, preexposure to
acrolein increased the [Ca(2+)](i) oscillation frequency in response to
endothelin 1 (ET-1, 0.1 microM), a contractile agonist that acts via the
activation of a receptor different from the muscarinic cholinoceptor. We then
studied acrolein-induced alteration in cell signaling with special attention to
the steps downstream of membrane receptor activation i.e., the inositol 1,4,5
trisphosphate (InsP(3)) signaling pathway. Pretreatment of cells with LiCl (20
mM), a modulator of InsP(3) concentration, mimicked the effect of acrolein
exposure on agonist-induced [Ca(2+)](i) response, i.e., increased the amplitude
of the first Ca(2+) rise and the oscillation frequency in response to 0.1 and 10
microM acetylcholine (ACh), respectively. Moreover, in tracheal smooth muscle,
preexposure to acrolein significantly increased carbachol-induced [(3)H]inositol
phosphates accumulation, up to 34 +/- 11% above unexposed tissue values. Finally,
in beta-escin permeabilized cells, injection of InsP(3) (0.1-10 microM) induced a
concentration-dependent [Ca(2+)](i) rise followed, for high InsP(3)
concentration, by [Ca(2+)](i) oscillations, a calcium response whose pattern was
similar to that induced by ACh. Exposure to acrolein did not alter the InsP(3)
induced [Ca(2+)](i) response. These results indicate that the effect of acrolein
exposure on Ca(2+) responses in airway smooth muscle is not restricted to
activation of the muscarinic cholinoceptor and is due to an enhancement in
agonist-induced InsP(3) production. Since acrolein does not modify InsP(3)
receptor channel sensitivity, we conclude that acrolein-induced alteration in
calcium signaling can be ascribed to its sole effect on InsP(3) production.
PMID- 10764632
TI - Perturbation by the PCB mixture aroclor 1254 of GABA(A) receptor-mediated calcium
and chloride responses during maturation in vitro of rat neocortical cells.
AB - GABA(A) receptors are targets of highly chlorinated environmental chemicals and
have important roles in developing neurons. As such, we examined effects of
polychlorinated biphenyls (PCBs) on GABA(A) receptor responses in primary
cultures of rat neocortical cells using fluorescence imaging techniques. Between
days in vitro (DIV) 5 and 8, the effect of GABA(A) receptor stimulation switched
from excitatory (Ca(2+) entry following a Cl(-) efflux; DIV /=7). GABA(A)-receptor-stimulated
increases in [Ca(2+)](i) were diminished in a concentration-dependent (1-20
microM) manner following 1 h of exposure to the PCB mixture Aroclor 1254 (A1254),
with significant reductions at concentrations as low as 2 microM. A1254 (1-20
microM) also led to concentration-dependent increases in basal [Ca(2+)](i),
irrespective of DIV. A1254 (10 and 20 microM) significantly increased basal
Ca(2+)(i); the Ca(2+)(i) was elevated to 426 +/- 39 nM by 20 microM A1254 but
this concentration was not cytotoxic at 1 h. In addition, the mixture, A1254, as
well as ortho- and non-ortho-chlorinated PCB congeners (IUPAC Nos. 4, 15, 126,
and 138; 5-10 microM) individually decreased GABA(A)-stimulated Ca(2+)(i)
responses and this tended not to depend on increases in basal Ca(2+)(i). In
cultures DIV 7 and older, A1254 (20 microM) also impaired inhibitory GABA(A)
responses as evidenced by an approximately 50% reduction of GABA(A)-stimulated
Cl(-) influx (from approximately 6 to 8 mM net accumulation in controls). The
results demonstrate that: (1) GABA(A) receptor increases in Ca(2+)(i) and Cl(
)(i) are inhibited by 2-20 microM A1254, regardless of whether the responses are
at excitatory or inhibitory stages of development; (2) Ca(2+)(i) homeostasis in
cortical cells is disrupted by 10 microM A1254; yet (3) disruption of excitatory
GABA(A) responses by A1254 or PCB congeners does not necessarily depend on
impaired Ca(2+) homeostasis. These novel observations suggest that GABA(A)
receptor responses are a sensitive target for PCB effects in the rat developing
nervous system.
PMID- 10764633
TI - Cyanide-induced apoptosis involves oxidative-stress-activated NF-kappaB in
cortical neurons.
AB - The central nervous system is one of the main target organs in cyanide toxicity.
Primary cultured cortical neurons were used to study the cellular mechanisms
underlying cyanide-induced cytotoxicity. After exposure to KCN (100-300 microM)
for 24 h, cortical neurons underwent apoptosis as characterized by positive TUNEL
staining. Reactive oxygen species (ROS) play an important role in cyanide-induced
neuronal apoptosis; immediately after cyanide (100-300 microM) treatment, ROS
generation was observed and continued to be elevated for up to 3 h. NMDA receptor
activation and subsequent Ca(2+) influx contribute in part to cyanide-induced ROS
formation, since the selective NMDA receptor antagonist MK801 and intracellular
Ca(2+) chelator BAPTA blocked ROS generation. Interestingly, caspases, recently
reported to be involved in neuronal apoptosis, play a role in the late phase of
ROS production after cyanide stimulation. Z-VAD, a nonspecific caspase inhibitor,
blocked ROS generated 1 h after cyanide treatment, but it had no effect on ROS
generated immediately after cyanide treatment. Nuclear factor kappaB (NF-kappaB),
a redox-sensitive transcription factor, was activated dose dependently after
cyanide treatment. Blockade of ROS generation by MK801, Z-VAD, and various
antioxidants also blocked the activation of NF-kappaB. SN50, a synthetic peptide
which inhibits the nuclear translocation of NF-kappaB, blocked cyanide-induced
apoptotic cell death. These results indicate that NF-kappaB plays an important
role in cyanide-induced apoptosis in cortical neurons, and the caspases may
contribute in part to the activation of NF-kappaB after cyanide treatment by
inducing the late phase of ROS generation.
PMID- 10764634
TI - Pharmacokinetics of [(14)C]Genistein in the rat: gender-related differences,
potential mechanisms of biological action, and implications for human health.
AB - Mass balance, plasma pharmacokinetics, tissue distribution, and metabolism of
[(14)C]genistein were investigated in male and female rats (n = 5) following an
oral dose of [(14)C]genistein (4 mg kg(-1)) to determine potential sites and
mechanisms of biological action. Mean total excretion of radioactivity in urine
and feces for both sexes was 66 and 33% of the dose respectively at 166 h after
administration. Mean and maximal concentrations of radioactivity in plasma were
significantly (p < 0.02) higher in male than female rats, with half-lives of 12.4
and 8.5 h, respectively. The concentration of radioactivity was significantly (p
< 0.002) higher in liver from females than males and in reproductive (vagina,
uterus, ovary, and prostate) compared with other peripheral organs. Analysis of
plasma extracts by radio-HPLC-MS indicated that the predominant metabolites were
genistein glucuronides, 4-hydroxyphenyl-2-propionic acid, and trace amounts of
parent compound (<5%). Radioactive residues in uterus and prostate were
predominantly parent compound and 4-hydroxyphenyl-2-propionic acid, respectively.
Significantly (p < 0. 05) increased retention of [(14)C]genistein or metabolites
was associated with reproductive organs, such as vagina, uterus, ovary, and
prostate, likely to contain relatively high concentrations of estrogen receptors
or binding proteins compared with other peripheral tissues. Factors liable to
influence bioavailability of biologically active genistein or metabolites, such
as dietary intake, warrant further investigation to determine the risks or
benefits for different consumer groups of phytoestrogen-containing foods.
PMID- 10764635
TI - Decreased hepatic ALT synthesis is an outcome of subchronic microcystin-LR
toxicity.
AB - Alanine aminotransferase (ALT; EC 2.6.1.2) is important for the transamination of
amino acids and is also an important serum marker of hepatic damage. However, we
had previously shown that hepatic ALT activity decreases with subchronic exposure
to the hepatotoxin, microcystin-LR (MCLR), a potent inhibitor of serine/threonine
protein phosphatases types 1 and 2A. These previous findings suggest that one
outcome of subchronic MCLR toxicosis is decreased ALT synthesis by hepatocytes.
This could affect the diagnostic sensitivity of serum ALT activity and metabolic
processes within the cell. This study was done to investigate the mechanism by
which ALT activity decreases following prolonged MCLR exposure. Immunoblots were
first performed on liver tissue from 12 Harlan-Sprague-Dawley rats that had been
treated with 0, 16, 32, or 48 microg/kg of microcystin-LR per day by continuous
intraperitoneal infusion for 28 days. These revealed a dose-dependent decrease in
ALT protein concentrations that correlated directly with hepatic ALT activity (r
= 0.8132; P = 0.0013). Sixteen additional rats, treated with the same doses of
MCLR showed a dose-dependent decrease in hepatic ALT activity to approximately
19% of values in saline-treated controls. Northern blot analysis revealed a
decrease in hepatic ALT mRNA that correlated directly to hepatic ALT activity (r
= 0.7909; P = 0.0004). It was concluded that subchronic MCLR exposure causes
decreased hepatic ALT protein and mRNA concentrations. These findings suggest
that one sequela of MCLR toxicosis is decreased hepatic ALT synthesis.
PMID- 10764636
TI - Glucocorticoid receptor regulation in the rat embryo: a potential site for
developmental toxicity?
AB - Glucocorticoids play a key role in controlling numerous cellular processes during
embryogenesis and fetal development. Excess glucocorticoids during development
have been linked to dysmorphogenesis and/or intrauterine growth impairment in
rodents. The actions of glucocorticoids are mediated by interaction with their
receptors. Negative feedback regulation of glucocorticoid receptor (GR) is
important for limiting cellular sensitivity to the hormones. Hence, acute
exposure of the adult rat to the synthetic glucocorticoid dexamethasone (DEX)
reduced both GR mRNA and protein in a variety of tissues that include hippocampus
and liver, in a dose- and time-dependent fashion. Reduction in GR mRNA and
protein were observable when DEX was given repeatedly at doses as low as 0. 05
mg/kg. In the control whole rat embryo, GR mRNA was low but measurable at as
early as gestational day (GD) 10, but underwent rapid ontogenetic increase in the
ensuring days. In contrast to the adult, neither GR mRNA nor protein in the whole
rat embryo was affected by acute or repeated DEX administration to pregnant rats
on GD10-13, even at doses as high as 0.8 mg/kg. Similar results were obtained in
embryonic palate and liver, tissues known to be glucocorticoid targets. These
data suggest that GR autoregulation does not occur during organogenesis in the
rat. Accordingly, hormonal elevations from stress or chemical insults can be
transduced unrestrictedly, ultimately leading to aberrant cell function and
development. The unique mode of GR regulation seen in the embryonic cells may
provide a potential common mechanism for developmental perturbation and toxicity
for a variety of insults.
PMID- 10764637
TI - Experiments and simulations of ion-enhanced interfacial chemistry on aqueous NaCl
aerosols
AB - A combination of experimental, molecular dynamics, and kinetics modeling studies
is applied to a system of concentrated aqueous sodium chloride particles
suspended in air at room temperature with ozone, irradiated at 254 nanometers to
generate hydroxyl radicals. Measurements of the observed gaseous molecular
chlorine product are explainable only if reactions at the air-water interface are
dominant. Molecular dynamics simulations show the availability of substantial
amounts of chloride ions for reaction at the interface, and quantum chemical
calculations predict that in the gas phase chloride ions will strongly attract
hydroxl radicals. Model extrapolation to the marine boundary layer yields daytime
chlorine atom concentrations that are in good agreement with estimates based on
field measurements of the decay of selected organics over the Southern Ocean and
the North Atlantic. Thus, ion-enhanced interactions with gases at aqueous
interfaces may play a more generalized and important role in the chemistry of
concentrated inorganic salt solutions than was previously recognized.
PMID- 10764638
TI - Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
AB - The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary
sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be
activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether
this channel contributes to chemical or thermal sensitivity in vivo is not known.
Here, we demonstrate that sensory neurons from mice lacking VR1 are severely
deficient in their responses to each of these noxious stimuli. VR1-/- mice showed
normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked
pain behavior, were impaired in the detection of painful heat, and showed little
thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential
for selective modalities of pain sensation and for tissue injury-induced thermal
hyperalgesia.
PMID- 10764639
TI - Titanium carbide nanocrystals in circumstellar environments.
AB - Meteorites contain micrometer-sized graphite grains with embedded titanium
carbide grains. Although isotopic analysis identifies asymptotic giant branch
stars as the birth sites of these grains, there is no direct observational
identification of these grains in astronomical sources. We report that infrared
wavelength spectra of gas-phase titanium carbide nanocrystals derived in the
laboratory show a prominent feature at a wavelength of 20.1 micrometers, which
compares well to a similar feature in observed spectra of postasymptotic giant
branch stars. It is concluded that titanium carbide forms during a short
(approximately 100 years) phase of catastrophic mass loss (>0.001 solar masses
per year) in dying, low-mass stars.
PMID- 10764641
TI - Atomic layer deposition of oxide thin films with metal alkoxides as oxygen
sources
AB - A chemical approach to atomic layer deposition (ALD) of oxide thin films is
reported here. Instead of using water or other compounds for an oxygen source,
oxygen is obtained from a metal alkoxide, which serves as both an oxygen and a
metal source when it reacts with another metal compound such as a metal chloride
or a metal alkyl. These reactions generally enable deposition of oxides of many
metals. With this approach, an alumina film has been deposited on silicon without
creating an interfacial silicon oxide layer that otherwise forms easily. This
finding adds to the other benefits of the ALD method, especially the atomic-level
thickness control and excellent uniformity, and takes a major step toward the
scientifically challenging and technologically important task of replacing silica
as the gate dielectric in the future generations of metal oxide semiconductor
field effect transistors.
PMID- 10764640
TI - Translating biomolecular recognition into nanomechanics.
AB - We report the specific transduction, via surface stress changes, of DNA
hybridization and receptor-ligand binding into a direct nanomechanical response
of microfabricated cantilevers. Cantilevers in an array were functionalized with
a selection of biomolecules. The differential deflection of the cantilevers was
found to provide a true molecular recognition signal despite large nonspecific
responses of individual cantilevers. Hybridization of complementary
oligonucleotides shows that a single base mismatch between two 12-mer
oligonucleotides is clearly detectable. Similar experiments on protein A
immunoglobulin interactions demonstrate the wide-ranging applicability of
nanomechanical transduction to detect biomolecular recognition.
PMID- 10764642
TI - Nanometer-size alpha-PbO(2)-type TiO(2) in garnet: A thermobarometer for
ultrahigh-pressure metamorphism
AB - A high-pressure phase of titanium dioxide (TiO(2)) with an alpha-PbO(2)-type
structure has been identified in garnet of diamondiferous quartzofeldspathic
rocks from the Saxonian Erzgebirge, Germany. Analytical electron microscopy
indicates that this alpha-PbO(2)-type TiO(2) occurred as an epitaxial nanometer
thick slab between twinned rutile bicrystals. Given a V-shaped curve for the
equilibrium phase boundary of alpha-PbO(2)-type TiO(2) to rutile, the
stabilization pressure of alpha-PbO(2)-type TiO(2) should be 4 to 5 gigapascals
at 900 degrees to 1000 degrees C. This suggests a burial of continental crustal
rocks to depths of at least 130 kilometers. The alpha-PbO(2)-type TiO(2) may be a
useful pressure and temperature indicator in the diamond stability field.
PMID- 10764643
TI - The influence of canadian forest fires on pollutant concentrations in the united
states
AB - High carbon monoxide (CO) concentrations from uncertain origins occurred
episodically in the southeastern United States during the summer of 1995. We show
that these episodes were caused by large forest fires in Canada. Over a period of
2 weeks, these natural emissions increased CO concentrations in the southeastern
United States as well as along the eastern seaboard, a region with one of the
world's highest rates of anthropogenic emissions. Within the forest fire plumes,
there were also high concentrations of ozone, volatile organic compounds, and
aerosols. These results suggest that the impact of boreal forest fire emissions
on air quality in the mid-latitudes of the Northern Hemisphere, where
anthropogenic pollutant sources have been considered predominant, needs to be
reevaluated.
PMID- 10764644
TI - Nonrandom extinction and the loss of evolutionary history.
AB - The hierarchical nature of phylogenies means that random extinction of species
affects a smaller fraction of higher taxa, and so the total amount of
evolutionary history lost may be comparatively slight. However, current
extinction risk is not phylogenetically random. We show the potentially severe
implications of the clumped nature of threat for the loss of biodiversity. An
additional 120 avian and mammalian genera are at risk compared with the number
predicted under random extinction. We estimate that the prospective extra loss of
mammalian evolutionary history alone would be equivalent to losing a monotypic
phylum.
PMID- 10764645
TI - Chaperone selection during glycoprotein translocation into the endoplasmic
reticulum.
AB - A variety of molecular chaperones and folding enzymes assist the folding of newly
synthesized proteins in the endoplasmic reticulum. Here we investigated why some
glycoproteins interact with the molecular chaperone BiP, and others with the
calnexin/calreticulin pathway. The folding of Semliki forest virus glycoproteins
and influenza hemagglutinin was studied in living cells. The initial choice of
chaperone depended on the location of N-linked glycans in the growing nascent
chain. Direct interaction with calnexin and calreticulin without prior
interaction with BiP occurred if glycans were present within about 50 residues of
the protein's NH2-terminus.
PMID- 10764646
TI - Convergence of the secretory pathways for cholera toxin and the filamentous
phage, CTXphi.
AB - Virulence of Vibrio cholerae depends on secretion of cholera toxin (CT), which is
encoded within the genome of a filamentous phage, CTXphi. Release of CT is
mediated by the extracellular protein secretion (eps) type II secretion system.
Here, the outer membrane component of this system, EpsD, was shown to be required
for secretion of the phage as well. Thus, EpsD plays a role both in pathogenicity
and in horizontal transfer of a key virulence gene. Genomic analysis suggests
that additional filamentous phages also exploit chromosome-encoded outer membrane
channels.
PMID- 10764647
TI - Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.
AB - Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal
model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative
disorder. To test a new therapeutic strategy for ALS, we examined the effect of
caspase inhibition in transgenic mice expressing mutant human SOD1 with a
substitution of glycine to alanine in position 93 (mSOD1(G93A)).
Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor,
delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1
activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing
evidence for a non-cell-autonomous pathway regulating caspase expression.
Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A)
mice, which suggests that caspase inhibition may have a protective role in ALS.
PMID- 10764648
TI - The outcome of acute hepatitis C predicted by the evolution of the viral
quasispecies.
AB - The mechanisms by which hepatitis C virus (HCV) induces chronic infection in the
vast majority of infected individuals are unknown. Sequences within the HCV E1
and E2 envelope genes were analyzed during the acute phase of hepatitis C in 12
patients with different clinical outcomes. Acute resolving hepatitis was
associated with relative evolutionary stasis of the heterogeneous viral
population (quasispecies), whereas progressing hepatitis correlated with genetic
evolution of HCV. Consistent with the hypothesis of selective pressure by the
host immune system, the sequence changes occurred almost exclusively within the
hypervariable region 1 of the E2 gene and were temporally correlated with
antibody seroconversion. These data indicate that the evolutionary dynamics of
the HCV quasispecies during the acute phase of hepatitis C predict whether the
infection will resolve or become chronic.
PMID- 10764649
TI - Regulation of area identity in the mammalian neocortex by Emx2 and Pax6.
AB - The contribution of extrinsic and genetic mechanisms in determining areas of the
mammalian neocortex has been a contested issue. This study analyzes the roles of
the regulatory genes Emx2 and Pax6, which are expressed in opposing gradients in
the neocortical ventricular zone, in specifying areas. Changes in the patterning
of molecular markers and area-specific connections between the cortex and
thalamus suggest that arealization of the neocortex is disproportionately altered
in Emx2 and Pax6 mutant mice in opposing manners predicted from their
countergradients of expression: rostral areas expand and caudal areas contract in
Emx2 mutants, whereas the opposite effect is seen in Pax6 mutants. These findings
suggest that Emx2 and Pax6 cooperate to regulate arealization of the neocortex
and to confer area identity to cortical cells.
PMID- 10764650
TI - Language discrimination by human newborns and by cotton-top tamarin monkeys.
AB - Humans, but no other animal, make meaningful use of spoken language. What is
unclear, however, is whether this capacity depends on a unique constellation of
perceptual and neurobiological mechanisms or whether a subset of such mechanisms
is shared with other organisms. To explore this problem, parallel experiments
were conducted on human newborns and cotton-top tamarin monkeys to assess their
ability to discriminate unfamiliar languages. A habituation-dishabituation
procedure was used to show that human newborns and tamarins can discriminate
sentences from Dutch and Japanese but not if the sentences are played backward.
Moreover, the cues for discrimination are not present in backward speech. This
suggests that the human newborns' tuning to certain properties of speech relies
on general processes of the primate auditory system.
PMID- 10764651
TI - The role of inflammation in cardiovascular disease.
PMID- 10764652
TI - Genetic mechanisms of age regulation of blood coagulation: factor IX model.
AB - Blood coagulation capacity increases with age in healthy individuals, apparently
because of increases in the plasma concentration of most procoagulant factors.
This phenomenon may play an important role in the advancing age-associated
increase of cardiovascular diseases and thrombosis. Through longitudinal analyses
of transgenic mice, we recently identified 2 critical age-regulatory elements,
AE5' and AE3', which are together essential for age regulation of the normal
human factor IX (hFIX) gene. AE5', present in the long interspersed repetitive
element-derived sequence of the 5' upstream region, containing polyomavirus
enhancer activator-3 or a closely related element, is responsible for age-stable
expression of the gene and functions in a position-independent manner. AE3',
present in the middle of the 3' untranslated region, is responsible for age
associated elevation of hFIX mRNA levels in the liver. Presence of both AE5' and
AE3' is needed to recapitulate normal age regulation of the hFIX gene. Because
factor IX clearance from the circulation is not significantly affected by age,
age regulation of hFIX levels is achieved primarily by a combination of
stabilization of gene transcription and age-dependent increases in the mRNA
levels, which are presumably due to increasing mRNA stabilization. The stage is
now set for further systematic studies of the genetic and molecular mechanisms of
age regulation of other key coagulation and anticoagulation factors in hopes of
understanding the overall age regulation of blood coagulation.
PMID- 10764653
TI - Fibroblast growth factor plays a critical role in SM22alpha expression during
Xenopus embryogenesis.
AB - Although smooth muscle cells (SMCs) are critical components of the circulatory
system, the regulatory mechanisms of SMC differentiation remain largely unknown.
In the present study, we examined the mechanism of SMC differentiation by using
Xenopus laevis SM22alpha (XSM22alpha) as an SMC-specific marker. XSM22alpha cDNA
contained a 600-bp open reading frame, and the predicted amino acid sequences
were highly conserved in evolution. XSM22alpha transcripts were first detected in
heart anlage, head mesenchyme, and the dorsal side of the lateral plate mesoderm
at the tail-bud stage, possibly representing the precursors of muscle lineage. At
the tadpole stage, XSM22alpha transcripts were restricted to the vascular and
visceral SMCs. XSM22alpha was strongly induced by basic fibroblast growth factor
(FGF) in animal caps. Although expressions of Xenopus cardiac actin were not
affected by the expression of a dominant-negative FGF receptor, its injection
dramatically suppressed the XSM22alpha expression. These results suggest that
XSM22alpha is a useful molecular marker for the SMC lineage in Xenopus and that
FGF signaling plays an important role in the induction of XSM22alpha and in the
differentiation of SMCs.
PMID- 10764654
TI - Antisense oligodeoxynucleotide inhibition of vascular angiotensin-converting
enzyme expression attenuates neointimal formation: evidence for tissue
angiotensin-converting enzyme function.
AB - It has been proposed that vascular angiotensin-converting enzyme (ACE) plays an
important role in regulating vascular growth. Indeed, ACE inhibitors have been
reported to prevent neointimal formation after vascular injury in a rat carotid
artery model. However, classic pharmacological experiments cannot exclude the
potential contributions of hemodynamics and the circulating renin-angiotensin
system (RAS). In this study, we used antisense oligodeoxynucleotide (ODN) to
obtain local blockade of vascular ACE expression without effects on systemic
hemodynamics and circulating RAS. To increase the effectiveness of antisense
action, we modified the hemagglutinating virus of Japan-liposome ODN delivery
method by cotransfection with nuclear protein (high mobility group 1 [HMG-1]) and
RNase H. In vitro experiments showed the enhanced efficacy of antisense ODN by
cotransfection of HMG-1 and RNase H compared with ODN alone. In vivo transfection
of antisense ACE ODNs into intact uninjured rat carotid artery resulted in a
significant reduction of vascular ACE activity, and cotransfection of HMG-1 and
RNase H showed further reduction. We examined the effects of local blockade of
vascular ACE expression on neointimal formation after vascular injury.
Transfection of antisense ACE ODNs resulted in the attenuation of neointimal
formation, whereas sense and scrambled ODNs did not. Blood pressure, heart rate,
and serum ACE activity were not affected by antisense treatment. The magnitude of
vascular ACE inhibition correlated with the suppression of the neointimal size.
Overall, this study demonstrates that local antisense ODN inhibition of vascular
ACE expression attenuates neointimal formation independent of hemodynamics and
circulating RAS. The results support the existence of a functional tissue
angiotensin system in the rat vessel wall.
PMID- 10764655
TI - Increased flow and shear stress enhance in vivo transforming growth factor-beta1
after experimental arterial injury.
AB - We have previously demonstrated that high-flow (HF) conditions inhibit
experimental intimal hyperplasia. We hypothesized that such flow conditions may
alter transforming growth factor-beta1 (TGF-beta1) after mural injury. The right
common carotid artery (CCA) was balloon-injured in 54 New Zealand White male
rabbits. Flow was thereafter preserved (normal flow [NF]), reduced by partial
outflow occlusion (low flow [LF]), or increased by ligation of the left CCA (HF).
Four sham-operated animals served as uninjured controls. Mean blood flow and
pressure in the right CCA were measured before and after flow modulation and
before euthanasia (3, 7, and 14 days). TGF-beta1 mRNA and protein levels in the
right CCA were determined by Northern and ELISA analyses at each time point. At 7
and 14 days, intimal hyperplasia was quantified, and the transmural localization
of TGF-beta1 was determined by immunohistochemical analysis. Mean flow was
reduced from 22+/-1 to 10+/-3 mL/min in the LF group and increased to 34+/-2
mL/min in the HF group (P<0.001). Blood pressure was not different among the flow
groups for all time points. Wall shear stress was markedly decreased in the LF
group to 14+/-4 dyne/cm(2) and increased in the HF group to 63+/-6 dyne/cm(2) at
7 days compared with values in uninjured controls (39+/-2 dyne/cm(2), P<0.001)
and the NF group (44+/-7 dyne/cm(2), P<0.001). At 14 days, wall shear stress was
similar among the flow groups. The intima-to-media ratio was 5- and 2-fold
greater in the LF group than in the HF and NF groups at 14 days. mRNA levels for
TGF-beta1 and its active ligand were increased in the HF group by at least 2- and
3-fold, respectively, at 3 and 7 days compared with levels in uninjured controls
and the LF group (P<0.05) but were not different among the flow groups at 14
days. TGF-beta1 preferentially localized in the abluminal vascular smooth muscle
cells of the HF arterial segments. Flow- and shear-mediated release of TGF-beta1
may therefore play a role in abrogating the proliferative and migratory response
of vascular smooth muscle cells in the early stages after mural injury.
PMID- 10764656
TI - Upregulation and activation of Stat6 precede vascular smooth muscle cell
proliferation in carotid artery injury model.
AB - The role of signal transducers and activators of transcription (STAT) proteins in
modulating proliferation and differentiation of various cell types in the
hematopoietic system and the central nervous system has been well established. In
contrast, the pathophysiological role of these proteins in vascular proliferative
diseases has remained unproven, despite in vitro observations emphasizing the
involvement of the STAT system in mediating vascular smooth muscle cell (VSMC)
proliferation. On the basis of our previous observations demonstrating the
occurrence of a specific modulation of Stat6 protein during the proliferative,
migratory, and differentiation phases of the developing brain, we investigated
whether Stat6 protein is present and modulated in arterial tissue challenged by
perivascular injury. The time course of expression and localization of Stat6
after arterial injury was analyzed by immunohistochemistry, Western blot
analysis, and confocal microscopy. Six hours after injury, the expression of
Stat6 was markedly increased. This overexpression preceded the onset of VSMC
proliferation and was downregulated starting from 7 days after injury, coincident
with the decline of VSMC proliferation. Moreover, early after injury, Stat6 was
predominantly localized at the nuclear level, denoting its functional activation.
Conversely, Stat6 staining at later time points was largely cytosolic, suggesting
silencing effects of this signaling pathway. These data indicate that Stat6
signaling may contribute to the modifications of gene expression underlying VSMC
activation in the context of acute vascular proliferative diseases.
PMID- 10764657
TI - Differential activation of mitogen-activated protein kinases in smooth muscle
cells by angiotensin II: involvement of p22phox and reactive oxygen species.
AB - The atherogenic effect of the renin-angiotensin system can be explained, in part,
by the influence of its effector, angiotensin II (Ang II), on vascular smooth
muscle cell (VSMC) growth. There is evidence that reactive oxygen species (ROS)
play a role in the atherogenesis and activation of mitogen-activating protein
(MAP) kinases, which are involved in proliferation and differentiation. The study
was performed to further characterize the role of ROS in Ang II-mediated MAP
kinase activation and the regulation of the transcription factor activator
protein-1 (AP-1). Rat VSMCs were stimulated with Ang II. The activities of MAP
kinases were assessed by Western blot analysis or by immunocomplex kinase assay.
AP-1 binding was determined by using an electrophoretic mobility shift assay. Rat
VSMCs were treated with Ang II-activated MAP kinases, extracellular signal
regulated kinase (ERK), c-Jun amino terminal kinase (JNK), p38 MAP kinase (p38
MAPK), and their downstream effector, AP-1. Interestingly, only the activation of
ERK1/2, but not JNK or p38 MAPK, was tyrosine kinase, protein kinase C, and
MEK1/2 dependent. Ang II also induced the rapid formation of ROS, which could be
inhibited by a specific antibody as well as by antisense against the p22phox
subunit of the NAD(P)H oxidase. JNK and p38 MAPK, but not ERK, activation was
inhibited by an inhibitor of NAD(P)H oxidase. Antisense against p22phox also
solely inhibited p38 MAPK but did not affect ERK. The results indicate that in
VSMCs, Ang II activates MAP kinases and AP-1 through different pathways; the
results further suggest that ROS, generated by p22phox, mediate Ang II-induced
JNK and p38 MAPK activation, which may contribute to the pathogenesis of
atherosclerosis.
PMID- 10764658
TI - Blockade of angiotensin II type 1 receptor and not of endothelin receptor
prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats via
adrenocortical steroid-independent mechanisms.
AB - We investigated the role of angiotensin II (Ang II) and endothelin-1 (ET-1) in
transgenic (mREN2)27 rats, a model of the monogenic renin-dependent form of
severe hypertension and cardiovascular disease. Four-week-old heterozygous male
transgenic (mREN2)27 rats (n=24) were matched according to body weight (BW) and
blood pressure (BP) and randomly allocated to receive a placebo (group P), the
mixed endothelin type A and B receptor antagonist bosentan (100 mg/kg BW PO,
group B), the Ang II type 1-specific receptor antagonist irbesartan (50 mg/kg BW
PO, group I), or the endothelin type A-selective antagonist BMS-182874 (52 mg/kg
BW PO, group BMS). After 4 weeks of treatment, during which BW and BP were
measured weekly, animals were euthanized, and the heart, left ventricle, right
ventricle, adrenal gland, brain, and kidney were weighed. The plasma levels of
adrenocortical steroids were measured by high-performance liquid chromatography.
The tension responses of ET-free segments of the thoracic aorta to 5 x 10(-6)
mmol/L phenylephrine, 60 mmol/L KCl, and cumulative doses of ET-1 were assessed.
The density of ET-1 receptor subtypes in the aorta and vascular structural
changes in the mesenteric arterioles (100 to 200 microm ID) were also measured
with autoradiography and myography, respectively. Compared with all other groups,
group I rats showed significantly (P<0.001) lower systolic BP (group I, 161+/-8
mm Hg; group P, 269+/-23 mm Hg; group B, 275+/-17 mm Hg; and group BMS, 254+/-21
mm Hg), left ventricular weight (2.28+/-0.15 versus 3. 71+/-0.26, 3.38+/-0.27,
and 3.96+/-0.51 mg/g BW, respectively), tension responses to vasoconstrictors,
and normalized media thickness of the mesenteric arterioles (22.3+/-0.6 versus
25.3+/-0.5, 25.5+/-0.7, and 24.1+/-1.5 microm, respectively). Compared with
levels in group P (78+/-25 pmol/mL), plasma aldosterone levels were significantly
decreased in group B (51+/-11 pmol/mL) and group I (40+/-16 pmol/mL). Thus,
endogenous ET-1 and Ang II contribute to the regulation of aldosterone, but only
Ang II is crucial for the development of hypertension and related target organ
damage via the Ang II type 1 receptor. Endogenous Ang II does not appear to
enhance cardiovascular production of ET-1 in this model of hypertension within
the time span of our experiment.
PMID- 10764659
TI - Apoptosis and regulation of Bax and Bcl-X proteins during human neonatal vascular
remodeling.
AB - To verify that apoptosis is one of the possible mechanisms of neonatal vascular
remodeling during the transition from fetal to neonatal circulation, we assayed
for apoptosis and evaluated the expression of apoptosis-regulatory proteins in
umbilical vessel versus ascending aorta, ductus arteriosus (DA) versus adjacent
pulmonary artery and aorta, or aorta versus its branching arteries. Twenty-two
umbilical cords (UCs), 6 DAs with adjacent aortas and pulmonary arteries, and 4
aortic arches with their branching great arteries were obtained from neonates.
Smooth muscle cell (SMC) apoptosis in umbilical vessels was identified in all
UCs. The expressions of Bax and Bcl-X were stronger in umbilical artery than in
the neonatal aorta, but Bcl-2 was weak in both arteries in immunohistochemistry.
In the immunoblot analysis of UCs, the expression of the proapoptotic short
isoform of Bcl-X was stronger than in other tissue, and caspase-3 was selectively
activated, whereas it was not in the other components of the cardiovascular
system. In contrast, the expression patterns of the FasAg and Fas ligand were
similar in umbilical artery and aorta. Regulation of Bcl-2 family proteins was
also observed in other vascular sites at which SMCs undergo apoptosis on
hemodynamic changes during birth, such as the DA and the branching points of the
great arteries from the aortic arch. Apoptosis is involved in the regression of
human umbilical vessels and the DA and in the remodeling of the branching great
arteries during the neonatal period, when Bcl-2 family proteins are likely to
play a key role.
PMID- 10764660
TI - Clinically used estrogens differentially inhibit human aortic smooth muscle cell
growth and mitogen-activated protein kinase activity.
AB - Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology;
however, whether such effects are mediated in part by estrogen receptors is
unknown. The purpose of this study was to evaluate whether the actions of
clinically used estrogens on human aortic SMC biology are mediated by estrogen
receptors. We examined the effects of various clinically used estrogens in the
presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured
human aortic SMC DNA synthesis ([(3)H]thymidine incorporation), cellular
proliferation (cell counting), cell migration (modified Boyden chamber), collagen
synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase
activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis,
platelet-derived growth factor-induced SMC migration, and mitogen-activated
protein kinase activity were significantly inhibited by physiological (10(-9)
mol/L) concentrations of 17beta-estradiol and low concentrations (10(-8) to 10(
7) mol/L) of 17beta-estradiol, estradiol valerate, estradiol cypionate, and
estradiol benzoate but not by estrone, estriol, 17alpha-estradiol, or estrone
sulfate. The inhibitory effects of 17beta-estradiol and other inhibitory
estrogens were completely reversed by 100 micromol/L ICI 182,780, and the rank
order potency of various estrogens to inhibit SMC biology matched their rank
order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC
biology are in part receptor-mediated. Because the cardioprotective effects of
hormone replacement therapy are most likely mediated by modification of SMC
biology, whether hormone replacement therapy protects a given postmenopausal
woman against cardiovascular disease will depend partially on the affinity of the
estrogen for estrogen receptors in vascular SMCs.
PMID- 10764661
TI - p53, p21(WAF1/CIP1), and MDM2 involvement in the proliferation and apoptosis in
an in vitro model of conditionally immortalized human vascular smooth muscle
cells.
AB - Using an in vitro model of a conditionally immortalized cell line, we have
investigated how human vascular smooth muscle cells (VSMCs) are affected by the
expression of simian virus 40 (SV40) large T antigen (LT antigen), which binds to
cell cycle regulators such as the tumor suppressor protein p53. Cells were
obtained after infection of saphenous vein-derived VSMCs with a nonreplicative
retroviral vector containing a temperature-sensitive mutant of SV40 LT antigen
and were shown to have maintained some characteristics and responses of VSMCs.
Under permissive-temperature conditions (36 degrees C), the increased rate of
cell proliferation was shown to be associated with expression of LT antigen and
with LT antigen binding to and inactivation of p53. p53 inactivation failed to
block apoptosis induced by serum withdrawal or UV irradiation. Downregulation of
LT antigen expression at a nonpermissive temperature (39 degrees C) was shown to
be associated with growth arrest, increased expression of the cell cycle
inhibitor p21(WAF1/CIP1), increased murine double minute-2 promoter activity, and
differential expression of murine double minute-2 gene products, suggesting that
p53-induced transcription/transactivation may be involved in VSMC cycle control
but not necessarily in apoptosis. The established SMC line HVTs-SM1 may be a
useful model for study of the processes involved in myointimal hyperplasia and
cellular aging, as well as for the study of cell cycle control in general.
PMID- 10764662
TI - Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle
cells.
AB - Lysyl oxidase is an essential catalyst for the cross-linking of extracellular
collagen and elastin. Abnormalities in lysyl oxidase activity may contribute to
the pathogenesis of arterial diseases characterized by abnormal matrix
remodeling. This study tested the hypothesis that interferon (IFN)-gamma, a
proinflammatory cytokine present in aortic aneurysm and arteriosclerotic plaque
rupture, downregulates lysyl oxidase gene expression in rat aortic smooth muscle
cells. Steady-state lysyl oxidase mRNA levels decreased in a concentration- and
time-dependent manner to 30% of control levels after 24 hours of treatment with
IFN-gamma. Cell layer lysyl oxidase activity decreased in parallel with the
observed changes in steady-state mRNA. Nuclear runoff studies suggested that
transcriptional regulation was responsible for at least 40% of the observed
downregulation. mRNA decay studies suggested that IFN-gamma also decreased lysyl
oxidase mRNA half-life from 9 to 6 hours. Downregulation of lysyl oxidase by IFN
gamma did not appear to require new protein synthesis. This study documents that
IFN-gamma downregulates lysyl oxidase gene expression in rat aortic smooth muscle
cells by transcriptional and posttranscriptional mechanisms. If similar
regulation occurs in vivo, it is possible that IFN-gamma-mediated changes in
lysyl oxidase may contribute to arterial diseases characterized by abnormal
extracellular matrix.
PMID- 10764663
TI - Endothelin-1 inhibits apoptosis of vascular smooth muscle cells induced by nitric
oxide and serum deprivation via MAP kinase pathway.
AB - Endothelin (ET)-1, an endothelium-derived vasoconstrictor and mitogen, acts as an
antiapoptotic factor against serum deprivation-induced apoptosis of endothelial
cells and fibroblasts but enhances apoptosis of some cancer cells. In the present
study, we examined whether nitric oxide (NO) and ET-1 modulate apoptosis of rat
vascular smooth muscle cells (VSMCs) via the mitogen-activated protein (MAP)
kinase pathway. Both serum deprivation and NO donors (FK409 and SNAP) caused
apoptosis of VSMCs, as demonstrated by TdT-mediated dUTP-biotin nick end
labeling, appearance of fragmented DNA, and induction of caspase-3 activity. ET-1
dose-dependently antagonized apoptosis induced by serum deprivation and NO
donors. A selective ET(A) receptor antagonist (BQ123) and a nonselective ET(A/B)
receptor antagonist (TAK044), but not a selective ET(B) receptor antagonist
(BQ788), inhibited the antiapoptotic effect of ET-1, indicating that the
antiapoptotic effect of ET-1 is mediated via the ET(A) receptor. ET-1 activated
MAP kinase, whose effect was inhibited by FK409. Transfection with an
unphosphorylated wild-type MAP kinase kinase-1 (MAPKK-1) or its constitutively
activated mutant protected VSMCs against apoptosis induced by serum deprivation
and NO donors. Inhibition of MAP kinase activity with PD98059, a specific
inhibitor of MAPKK-1, or by transfection of a dominant-negative MAPKK-1 mutant
antagonized the antiapoptotic effect of ET-1, suggesting the involvement of MAP
kinase in the antiapoptotic effect. The potent inhibitory effect of ET-1 on
apoptosis of VSMCs induced by serum deprivation and NO suggests that the
counterbalance between the 2 endothelium-derived factors contributes to the
process of vascular remodeling by determining VSMC survival and death,
respectively, via a common MAP kinase pathway.
PMID- 10764664
TI - Matrix metalloproteinase and alphavbeta3 integrin-dependent vascular smooth
muscle cell invasion through a type I collagen lattice.
AB - Smooth muscle cell (SMC) migration from the tunica media to the intima is a key
event in the development of atherosclerotic lesions and in restenosis after
angioplasty. SMCs require not only migratory but also degradative abilities that
enable them to migrate through extracellular matrix proteins, which surround and
embed these cells. We used a collagen type I lattice as a coating on top of a
porous filter as a matrix barrier in a chamber to test the invasive behavior of
SMCs in response to a chemoattractant (invasion assay) and compared that behavior
with simple SMC migration through collagen type I-coated filters (migration
assay). Inhibitors of matrix metalloproteinase, KB-R8301, tissue inhibitor of
matrix metalloproteinase-1 (TIMP-1), TIMP-2, and peptide 74, attenuated platelet
derived growth factor-BB (PDGF-BB)-directed SMC invasion across the collagen
lattice, whereas no effect was seen with these inhibitors on simple SMC migration
through collagen-coated filters. RGD peptide inhibited SMC invasion but did not
affect SMC migration. Anti-alphavbeta3 integrin antibody attenuated PDGF-BB
directed SMC invasion, whereas other antibodies against RGD-recognizing
integrins, namely alphavbeta5 and alpha5, had no effect. None of these antibodies
had any effect on simple SMC migration. RGD peptide and anti-alphavbeta3 antibody
inhibited the attachment and spreading of SMCs on denatured collagen but not on
native collagen. These findings indicate that there is a difference in the
mechanisms between simple SMC migration across a collagen-coated filter and SMC
invasion through a fibrillar collagen barrier. A proteolytic process is required
for SMC invasion, and the degradation of matrix proteins alters the relationship
between matrix protein molecules and SMC surface integrins.
PMID- 10764665
TI - Lysophosphatidylcholine inhibits endothelial cell migration and proliferation via
inhibition of the extracellular signal-regulated kinase pathway.
AB - Lysophosphatidylcholine (lysoPC), a major lipid component of oxidized low density
lipoprotein, inhibits endothelial cell (EC) migration and proliferation, which
are critical processes during angiogenesis and the repair of injured vessels.
However, the mechanism(s) of lysoPC-induced inhibition of EC migration and
proliferation has not been clarified. In this report, we demonstrate the critical
role of extracellular signal-regulated kinase (ERK) in growth factor-stimulated
EC migration and proliferation as well as their inhibition by lysoPC. EC
migration and proliferation stimulated by basic fibroblast growth factor (FGF-2)
were blocked by inhibition of ERK activity by both the specific mitogen-activated
protein kinase kinase (MEK) 1 inhibitor PD98059 and the overexpression of a
dominant-negative mutant of MEK1. Conversely, overexpression of a constitutively
active mutant of MEK1 increased EC migration and proliferation, which were
comparable to those of ECs stimulated with FGF-2. LysoPC inhibited FGF-2-induced
ERK activation via prevention of Ras activation without inhibiting tyrosine
phosphorylation of phospholipase C-gamma. Taken together, our data demonstrate
that ERK activity is required for FGF-2-induced EC migration and proliferation
and suggest that inhibition of the Ras/ERK pathway by lysoPC contributes to the
reduced EC migration and proliferation.
PMID- 10764666
TI - Sphingosine-1-phosphate and lysophosphatidic acid stimulate endothelial cell
migration.
AB - Endothelial cell migration is necessary for the formation of new blood vessels.
We investigated the effects of 2 lysophospholipid mediators, sphingosine-1
phosphate (S1P) and lysophosphatidic acid (LPA), on endothelial cell migration.
S1P and LPA stimulated migration of fetal bovine heart endothelial cells (FBHEs)
in a 3D-modified Boyden chamber assay with concentrations as low as 15 nmol/L
stimulating a 2-fold change and concentrations in the 1- to 2-micromol/L range
stimulating 14- to 20-fold changes. S1P specifically stimulated the migration of
several endothelial cell strains but did not stimulate the migration of tumor
cells or smooth muscle cells. LPA stimulated some endothelial and nonendothelial
cell types to migrate. For FBHEs, S1P and LPA were mostly chemokinetic in
checkerboard assays. S1P and LPA stimulated extracellular signal-regulated kinase
1/2 phosphorylation and enhanced paxillin localization to focal contacts, with no
discernible change in the actin cytoskeleton in FBHEs. To characterize
responsible receptor-dependent signaling pathways, we investigated the
involvement of G(i), Rho, and phosphoinositide 3-OH kinase in S1P- and LPA
stimulated migration. Although perturbation of all 3 signaling molecules resulted
in decreased migration, the mechanisms underlying the decreased migration were
different. Pertussis toxin treatment, to target G(i), caused endothelial cells to
develop dense bundles of F-actin and distribute paxillin staining to the cell
periphery in response to S1P or LPA. Modification of Rho with C3 toxin disrupted
the actin cytoskeleton. Inhibition of phosphoinositide 3-OH kinase decreased S1P-
or LPA-induced endothelial cell migration with only minor disruption of the actin
cytoskeleton. Inhibition of extracellular signal-regulated kinase kinase with
PD98059 caused a loss of phosphorylation of extracellular signal-regulated kinase
1/2, similar to pertussis toxin, but only a minimal decrease in migration. These
results indicate that S1P and, for some cells, LPA stimulate migration of
endothelial cells through a mechanism that likely requires a balance between G(i)
and Rho signaling to achieve the cytoskeletal remodeling necessary for cell
migration.
PMID- 10764667
TI - Apolipoprotein E inhibition of vascular smooth muscle cell proliferation but not
the inhibition of migration is mediated through activation of inducible nitric
oxide synthase.
AB - Initial experiments revealed that low concentrations of apolipoprotein (apo) E
(0.1 to 5 microg/mL) were effective in inhibiting platelet-derived growth factor
(PDGF)-directed smooth muscle cell (SMC) migration by 60% to 80%. In contrast,
higher concentrations of apoE, at 25 and 50 microg/mL, were necessary to achieve
similar inhibition of PDGF-induced SMC proliferation. The potential role of
nitric oxide (NO) in mediating the inhibitory effects of apoE was explored.
Results showed that, although 0.1 to 5 microg/mL of apoE had no effect on NO
production by SMCs, physiological concentrations of apoE (25 to 50 microg/mL)
enhanced NO synthesis by 2-fold in a dose-dependent manner (P<0.001). Reverse
transcription-polymerase chain reaction amplification of RNA obtained from
control and apoE-treated SMCs demonstrated a direct role of apoE in activating
inducible nitric oxide synthase (iNOS) gene expression. The apoE-induced nitric
oxide production was significantly reduced by coincubation of the cells with
aminoguanidine or N(G)-monomethyl-L-arginine (P<0.05) or with antisense iNOS
oligodeoxynucleotides (P<0.01). Moreover, the inhibition of iNOS was shown to
overcome apoE suppression of PDGF-induced vascular SMC proliferation. However,
apoE suppression of PDGF-directed SMC migration was not affected by these
treatments. Taken together, these results document that apoE exerts its
inhibitory effects on cell proliferation via activation of iNOS. However, apoE
inhibition of cell migration is mediated by a mechanism independent of iNOS
activation.
PMID- 10764668
TI - Expression of macrophage (Mphi) scavenger receptor, CD36, in cultured human
aortic smooth muscle cells in association with expression of peroxisome
proliferator activated receptor-gamma, which regulates gain of Mphi-like
phenotype in vitro, and its implication in atherogenesis.
AB - CD36 is one of the major receptors for oxidized low density lipoproteins
belonging to macrophage (Mphi) scavenger receptor (SR) class B and is thought to
play an important role in the foam cell formation from monocyte-Mphi in the
atherosclerotic lesions. Although it has been hypothesized that smooth muscle
cells (SMCs) may be the other origin of foam cells in vivo, supporting data are
still very limited. In the present study, we have tested the expression of a
variety of SRs, including CD36, in 8 lots of primary human aortic SMCs (HASMCs)
explanted from 8 different donors. Functional CD36 was expressed in cultured
HASMCs, and the levels of expression were widely ranged between the lots. SR
class A (SR-A) was expressed abundantly in CD36-negative lots. Other Mphi
markers, such as CD32 and CD68, were expressed in all lots tested. These data
suggest that the cultured HASMCs gained an Mphi-like phenotype. To determine the
mechanism for the above-described phenotypic change, we have tested the
expression of a nuclear receptor, peroxisome proliferator activated receptor
gamma, in those cells. This nuclear receptor was abundantly expressed in CD36
positive lots, whereas c-fms was expressed abundantly in CD36-negative/SR-A
positive lots. The synthetic ligand of peroxisome proliferator activated receptor
gamma, troglitazone, upregulated the expression of CD36 only in CD36-positive
lots. These observations demonstrate that cultured HASMCs can gain an Mphi-like
phenotype, possibly classified by the expression of CD36 or SR-A. The present
study may support the possibilities of transformation of HASMCs into foam cells
in vivo.
PMID- 10764669
TI - Rapid restoration of normal endothelial functions in genetically hyperlipidemic
mice by a synthetic mediator of reverse lipid transport.
AB - Endothelial dysfunction is a major pathophysiological consequence of
hypercholesterolemia and other conditions. We examined whether a synthetic
mediator of lipid transport from peripheral tissues to the liver (ie, the
"reverse" pathway) could restore normal endothelial function in vivo. Using
assays of macrovascular and microvascular function, we found that genetically
hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial
impairments. Treatment of the mice for 1 week with daily intravenous bolus
injections of large "empty" phospholipid vesicles, which accelerate the reverse
pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence,
and endothelial expression of vascular cell adhesion molecule-1 to normal or
nearly normal levels. These changes occurred despite the long-standing
hyperlipidemia of the animals and the persistence of high serum concentrations of
cholesterol-rich atherogenic lipoproteins during the treatment. Our results
indicate that dysfunctional macrovascular and microvascular endothelium in
apolipoprotein E knockout mice can recover relatively quickly in vivo and that
accelerated reverse lipid transport may be a useful therapy.
PMID- 10764670
TI - Asymmetric dimethylarginine increases mononuclear cell adhesiveness in
hypercholesterolemic humans.
AB - Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide
synthase, is elevated in hypercholesterolemia. This study was designed to
determine the role of ADMA in the increased mononuclear cell adhesiveness
observed in human hypercholesterolemia. In patient studies, plasma ADMA levels
were determined by high-performance liquid chromatography. Functional mononuclear
leukocyte adhesion assays were performed in parallel, and flow cytometry was used
to characterize bound monocytes and T lymphocytes. Hypercholesterolemic patients
were then placed on an oral L-arginine regimen of 14 or 21 g/d and studied over
12 weeks. In cell culture studies, bovine aortic endothelial cells were incubated
with varied concentrations of ADMA. Monocytoid cells were cocultured with these
bovine aortic endothelial cells, and their adhesiveness was assessed by use of a
binding assay. Flow cytometry was used to quantify adhesion molecule expression.
Plasma ADMA levels and adhesiveness of mononuclear cells (specifically, monocytes
and T lymphocytes) were elevated in hypercholesterolemic patients. Adhesiveness
was inversely correlated with the plasma L-arginine/ADMA ratio. Oral
administration of L-arginine normalized plasma L-arginine/ADMA ratios and
attenuated monocyte and T-lymphocyte adhesiveness. ADMA had no direct effect on
the adhesiveness of mononuclear cells. However, monocytes became hyperadhesive
when cocultured with ADMA-exposed endothelial cells. In human
hypercholesterolemia, the plasma L-arginine/ADMA ratio is inversely correlated
with mononuclear cell adhesiveness. Restoration of the L-arginine/ADMA ratio to
control levels normalizes mononuclear cell adhesiveness. Our studies suggest that
the elaboration of endothelium-derived nitric oxide affects the behavior of
circulating T lymphocytes and monocytes.
PMID- 10764671
TI - C-reactive protein is a strong but nonspecific risk factor of fatal stroke in
elderly persons.
AB - An elevated level of C-reactive protein is a strong predictor of cardiovascular
events in elderly persons. Whether C-reactive protein has direct adverse vascular
effects or is a marker of aspecific systemic inflammation remains to be
determined. The aim of this study was to investigate the relation between C
reactive protein and the occurrence of fatal strokes in elderly persons. In the
Leiden 85-Plus Study, a population-based prospective follow-up study, we studied
the levels of C-reactive protein in 80 participants who died from stroke within
the first 5 years of follow-up. Levels of C-reactive protein were determined in
serum samples at baseline. Levels of C-reactive protein were also determined in
82 control subjects who survived for the first 5 years of follow-up and in 83
participants who died from noncardiovascular causes. Mortality risks were
estimated with logistic regression and adjusted for differences in age, sex,
smoking, medication, total cholesterol, history of diabetes or hypertension, and
previous cardiovascular events. Levels of C-reactive protein at baseline were 2
fold higher in subjects who died from stroke than in control subjects (median 5.7
versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died
from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9
mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular
causes increased linearly up to 10-fold in subjects with the highest levels of C
reactive protein at baseline (P<0.001). The levels of C-reactive protein were
lower when more time had elapsed between blood sampling and time of death during
follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of
fatal stroke in old persons. The data do not support the idea that C-reactive
protein has direct vascular effects that underlie fatal cerebrovascular disease.
PMID- 10764672
TI - Serum C-reactive protein and self-reported stroke: findings from the Third
National Health and Nutrition Examination Survey.
AB - C-reactive protein may predict the risk of coronary heart disease, but its
association with stroke has not been well studied. We used data from the Third
National Health and Nutrition Examination Survey, conducted from 1988 to 1994, to
examine the association between serum C-reactive protein concentrations and self
reported past history of stroke among 8850 US men and women aged >/=40 years. The
unadjusted geometric mean of C-reactive protein concentration was higher among
participants with stroke than those without stroke (0. 45+/-0.02 versus 0.32+/
0.01, P<0.001). After adjusting for age, sex, race or ethnicity, education,
smoking status, systolic blood pressure, serum cholesterol, high density
lipoprotein cholesterol, history of diabetes mellitus, body mass index, and
physical activity, the odds ratio for stroke among participants with C-reactive
protein concentrations >/=0.55 mg/dL compared with participants with
concentrations 40 years. Large-scale epidemiological studies on this important issue,
however, are still sparse, and those available have yielded contradictory
results. The Bruneck Study involved a large random sample of men and women aged
40 to 79 years that were enrolled in 1990 and reevaluated 5 years later. Baseline
DHEA sulfate (DHEAS) levels were measured in 867 subjects after an overnight
fast. Development and progression of carotid atherosclerosis was monitored by
high-resolution duplex ultrasound. DHEAS levels declined with advancing age (29%
and 44% per decade in men and women) and showed a complex sex-specific
association with various vascular risk attributes and factors conferring
protection against atherosclerosis. Age- and sex-adjusted DHEAS baseline levels
did not differ between subjects with or without incident/progressive
atherosclerosis (geometric mean 1161 versus 1253 microg/L). After adjustment for
vascular risk factors and potential confounders, the odds ratio of
incident/progressive atherosclerosis comparing a 50% increase in DHEAS levels was
0.99 (95% CI 0.89 to 1.11). Lack of an association between DHEAS and
atherogenesis was confirmed in sex-specific and a variety of supplementary
analyses. Statistical power would be high enough to detect differences in DHEAS
between outcome categories as low as 15% (alpha=0.05). This prospective community
based study does not support a role for endogenous DHEA(S) in the development of
human atherosclerosis.
PMID- 10764680
TI - Mechanisms regulating LDL metabolism in subjects on peroral and transdermal
estrogen replacement therapy.
AB - To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by
peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized
postmenopausal women aged 48 to 62 years were randomized in a double-blind double
dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal
estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4.
19+/-0.83 (mean+/-SD) to 3.39+/-0.78 mmol/L (P<0.001) in the peroral group and
from 4.11+/-0.86 to 3.72+/-0.78 mmol/L (P<0.001) in the transdermal estrogen
group. Peroral estrogen did, but transdermal treatment did not, enhance the
fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB).
However, the decrease of LDL cholesterol was related to an increase in FCR for
LDL apoB on both peroral and transdermal ERT (r=-0.645, P<0.001 and r=-0.627,
P<0.001, respectively). These changes were associated with changes in the serum
estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to
10% (P<0.05). The effects of estrogen were not modified by the polymorphisms of
apoE and apoB or cholesterol 7alpha-hydroxylase. In conclusion, the ERT-induced
LDL cholesterol-lowering effect is related to changes in estrogen level, which
presumably enhance LDL receptor activity, which is manifested as an increase in
FCR for LDL apoB. The small decrease in the absorption efficiency of dietary
cholesterol does not seem to contribute largely to the cholesterol lowering on
either transdermal or peroral ERT.
PMID- 10764681
TI - Increased expression of lectin-like oxidized low density lipoprotein receptor-1
in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits.
AB - A novel lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) was
recently identified in bovine aortic endothelial cells. It is strongly suggested
to have a potential role in the initiation and development of atherosclerosis. In
this study, we have isolated cDNA clones encoding the rabbit homologue of LOX-1
by screening a rabbit placenta cDNA library. In amino acid sequence and domain
structure organization, the rabbit LOX-1 is highly conserved with the human
counterpart. Transfection of rabbit LOX-1 cDNA to HEK-293 cells confers on them
the activity to bind and internalize oxidized low density lipoprotein. Rabbit LOX
1 was identified as a 45-kDa protein by Western blot analysis with a specific
monoclonal antibody. Notably, analyses by reverse transcription-polymerase chain
reaction and Western blot revealed that LOX-1 was accumulated in 8-week-old
Watanabe heritable hyperlipidemic rabbit aortas compared with normal rabbit
aortas. Immunostaining confirmed that the augmented expression of LOX-1 was
primarily localized within the intima at the earliest stages of atherogenesis.
The most prominent staining was in the endothelial cells of lesions. Furthermore,
the distinctive staining of LOX-1 was identified in the endothelium of non-lesion
areas of Watanabe heritable hyperlipidemic rabbit aortas. Taken together, these
findings support the possibility that LOX-1 might be involved in the initiation
of atherosclerosis.
PMID- 10764682
TI - Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and
implications in apoptosis of human coronary artery endothelial cells: evidence
from use of antisense LOX-1 mRNA and chemical inhibitors.
AB - A specific lectin-like endothelial receptor for oxidized low density lipoprotein
(LOX-1), distinct from the scavenger receptor in monocytes/macrophages, has been
identified and cloned. In this study, we examined the regulation of LOX-1 by
oxidized low density lipoprotein (ox-LDL) and determined the role of LOX-1 in ox
LDL-induced apoptosis of cultured human coronary artery endothelial cells
(HCAECs). Incubation of HCAECs with ox-LDL (40 microg/mL), but not native LDL,
for 24 hours markedly increased LOX-1 expression (mRNA and protein). After 48
hours of preincubation of HCAECs with a specific antisense to LOX-1 mRNA
(antisense LOX-1), ox-LDL-mediated upregulation of LOX-1 was suppressed (P<0.01).
In contrast, treatment of HCAECs with sense LOX-1 had no effect. Ox-LDL also
induced apoptosis (determined by terminal deoxynucleotidyl transferase-mediated
dUTP nick end-labeling and DNA laddering) of HCAECs in a concentration- and time
dependent fashion. LOX-1 played an important role in ox-LDL-mediated apoptosis of
HCAECs because antisense LOX-1 inhibited this effect of ox-LDL. Polyinosinic acid
and carrageenan, 2 different chemical inhibitors of LOX-1, also decreased ox-LDL
mediated apoptosis of HCAECs. Nuclear factor (NF)-kappaB was markedly activated
in ox-LDL-treated HCAECs. The critical role of NF-kappaB activation became
evident in experiments with antisense LOX-1, which abolished ox-LDL-mediated NF
kappaB activation. In this process, an NF-kappaB inhibitor, caffeic acid
phenethyl ester, also inhibited ox-LDL-mediated apoptosis of HCAECs. These
findings indicate that ox-LDL upregulates its own endothelial receptor. Ox-LDL
induced apoptosis is mediated by the action of LOX-1. In this process, NF-kappaB
activation may play an important role as a signal transduction mechanism.
PMID- 10764683
TI - Aging influences development and progression of early aortic atherosclerotic
lesions in cholesterol-fed rabbits.
AB - The arterial wall in aged animals shows an increased susceptibility to develop
atherosclerotic lesions, although the mechanisms by which aging acts are still
unclear. We investigated early aortic lesions in aged rabbits (5 to 6 years old,
AH group) and young rabbits (2 months old, YH group) after 2 months of 0.2%
cholesterol feeding. Fatty streaks or spots mainly in the proximal segments
occupied a relative surface area that was greater in AH than in YH rabbits,
although plasma cholesterol and lipoprotein levels did not differ. YH lesions
showed an irregular endothelial profile mainly from accumulations of large,
rounded, RAM 11-positive macrophagic foam cells. There was a higher percentage of
myocytic, CD-5-positive, proliferating, and terminal deoxynucleotidyl transferase
mediated dUTP nick end-labeling (TUNEL)-positive cells and larger accumulation of
glycosaminoglycans in AH fatty streaks than in YH lesions. Ligation-mediated
polymerase chain reaction confirmed differences in apoptosis. Early fibromuscular
coats and subendothelial plasma-like insudate were also observed in AH lesions.
Aged-matched normocholesterolemic rabbits showed a diffuse aortic intimal
thickening composed of myocytic cells with a synthetic phenotype and
extracellular matrix rich in glycosaminoglycans. In addition, in aged rabbits, we
observed a spontaneous increase of monocytes adhering to the endothelial surface
and a reduced expression of endothelial nitric oxide synthase in areas distant
from the branches. These plasma cholesterol-independent spontaneous changes in
the aortic wall of aged rabbits seem to act as a multiple atherogenic risk
factor. Moreover, age-related differences in the distribution, composition, and
proliferative and apoptotic rates represent crucial events during the progression
of early fatty streaks to advanced plaques.
PMID- 10764684
TI - Major reduction in plasma Lp(a) levels during sepsis and burns.
AB - Plasma levels of lipoprotein(a) [Lp(a)], an atherogenic particle, vary widely
between individuals and are highly genetically determined. Whether Lp(a) is a
positive acute-phase reactant is debated. The present study was designed to
evaluate the impact of major inflammatory responses on plasma Lp(a) levels.
Plasma levels of C-reactive protein (CRP), low density lipoprotein cholesterol,
Lp(a), and apolipoprotein(a) [apo(a)] fragments, as well as urinary apo(a), were
measured serially in 9 patients admitted to the intensive care unit for sepsis
and 4 patients with extensive burns. Sepsis and burns elicited a major increase
in plasma CRP levels. In both conditions, plasma concentrations of Lp(a) declined
abruptly and transiently in parallel with plasma low density lipoprotein
cholesterol levels and closely mirrored plasma CRP levels. In 5 survivors, the
nadir of plasma Lp(a) levels was 5- to 15-fold lower than levels 16 to 18 months
after the study period. No change in plasma levels of apo(a) fragments or urinary
apo(a) was noticed during the study period. Turnover studies in mice indicated
that clearance of Lp(a) was retarded in lipopolysaccharide-treated animals. Taken
together, these data demonstrate that Lp(a) behaves as a negative acute-phase
reactant during major inflammatory response. Nongenetic factors have a major,
acute, and unexpected impact on Lp(a) metabolism in burns and sepsis.
Identification of these factors may provide new tools to lower elevated plasma
Lp(a) levels.
PMID- 10764685
TI - Colocalization of thrombin, PAI-1, and vitronectin in the atherosclerotic vessel
wall: A potential regulatory mechanism of thrombin activity by PAI-1/vitronectin
complexes.
AB - The serine protease thrombin is a mitogen for vascular smooth muscle cells. To
that end, thrombin cleaves the surface-exposed, protease-activated receptor type
1 (PAR-1), resulting in signal transduction and ultimately, proliferation of
these cells. Regulation of thrombin activity in the human atherosclerotic vessel
wall has not been studied in great detail, conceivably because the traditional
plasma thrombin inhibitor, anti-thrombin III, is not encountered at this
location. By using immunofluorescence confocal microscopy, we demonstrate that
the antigens of thrombin, plasminogen activator inhibitor 1 (PAI-1), and
vitronectin (Vn) colocalize in human neointimal atherosclerotic arterial tissue.
Furthermore, it is shown by in situ reverse zymography that these specimens
harbor the active form of PAI-1, which is the only configuration of PAI-1 capable
of complexing with Vn and inhibiting serine proteases, eg, thrombin. Two
different criteria were used to establish that neointimal atherosclerotic
material contains active alpha-thrombin, namely, its ability to bind to the
thrombin inhibitor hirudin and to convert the thrombin-specific chromogenic
substrate S2238. The latter activity could be fully prevented by preincubation
with the thrombin-specific inhibitor, phenyl-prolyl-arginyl-chloromethyl ketone.
The thrombin concentration measured by conversion of the chromogenic substrate
was 7 to 12 nmol/L in the vascular specimens studied. This concentration range
suffices to activate the PAR-1 receptor on vascular smooth muscle cells and to
cause neointimal proliferation. It is concluded that the human atherosclerotic
arterial vessel wall provides conditions that favor a regulatory mechanism of
thrombin activity by PAI-1/Vn complexes.
PMID- 10764686
TI - Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine
model of diet-induced obesity.
AB - An increased plasma plasminogen activator inhibitor-1 (PAI-1) level is a risk
factor for myocardial infarction, particularly when associated with visceral
obesity. Although the link between PAI-1 and obesity is well documented, little
is known about the physiological relevance of PAI-1 production by adipose tissue.
Therefore, we have compared adipose tissue development and insulin resistance
plasma parameters in PAI-1-deficient mice (PAI-1(-/-)) and wild-type littermates
(PAI-1(+/+)) in a model of nutritionally induced obesity. After 17 weeks of
consuming a high-fat diet (HFD), PAI-1(+/+) mice showed marked obesity, with a
52% increase in body weight compared with mice that were kept on a standard fat
diet (P<0.0001). This weight gain was accompanied by adipocyte hypertrophy and an
increase in the number of stroma cells in the gonadal fat pad, expressed as
stroma cells/adipocytes (0.67+/-0.05 versus 0.43+/-0. 02; P<0.001). In plasma,
the HFD induced a marked increase in PAI-1 antigen (5.1+/-0.56 versus 2+/-0.22
ng/mL; P<0.001), fasting insulinemia (1.1+/-0.21 versus 0.21+/-0.04 ng/mL;
P<0.001), and glycemia (7.4+/-0.5 versus 5+/-0.3 mmol/L; P<0.001), whereas plasma
triglyceride levels were not affected. When we compared PAI-1(-/-) and PAI-1(+/+)
mice on the HFD, PAI-1(-/-) mice gained weight faster than did PAI-1(+/+) mice,
with a significant difference in body weight between 3 and 8 weeks of the diet
(32+/-1.7 versus 26+/-1.6 g at 6 weeks; P<0.05). After 17 weeks of the HFD, its
effect on weight gain and the number and size of adipocytes was similar in PAI
1(+/+) and PAI-1(-/-) mice. By contrast, the increase in the number of stroma
cells presented by PAI-1(+/+) mice was not observed in PAI-1(-/-) mice. In obese
PAI-1(-/-) mice, tissue-type PA activity and antigen levels in the gonadal fat
pad were significantly higher than in obese PAI-1(+/+) mice (230+/-50 versus 47+/
20 arbitrary units/g, P<0.01; 40+/-13 versus 17+/-13 ng/g, P<0.05, respectively),
whereas urokinase-type PA activity and antigen levels were similar in both
groups. In plasma, nonobese PAI-1(-/-) mice displayed 62% higher insulin levels
(P<0.05) than did PAI-1(+/+) mice. Obese PAI-1(-/-) mice displayed 68% higher
triglyceride levels (P<0.01) and 21% lower glucose levels (P<0.05) than did PAI
1(+/+) mice. These data support an effect of PAI-1 on weight gain and adipose
tissue cellularity in the induction of obesity in mice. Moreover, PAI-1
influences glucidolipidic metabolism. The elevated expression of PAI-1 observed
in human obesity could be involved in mechanisms that control adipose tissue
development.
PMID- 10764687
TI - Hypoxia induces transcription of the plasminogen activator inhibitor-1 gene
through genistein-sensitive tyrosine kinase pathways in vascular endothelial
cells.
AB - A decline in oxygen concentration perturbs endothelial function, which promotes
local thrombosis. In this study, we determined whether hypoxia in the range of
that observed in pathophysiological hypoxic states stimulates plasminogen
activator inhibitor-1 (PAI-1) production in bovine aortic endothelial cells. PAI
1 production, measured by ELISA, was increased by 4.7-fold (P<0.05 versus
normoxic control, n=4) at 12 hours after hypoxic stimulation. Northern blot
analysis showed the progressive time-dependent increase in the steady-state level
of PAI-1 mRNA expression by hypoxia, which reached a 7.5-fold increase (P<0.05
versus control, n=4) at 12 hours. Deferoxamine, which has been known to bind heme
protein and to reproduce the hypoxic response, induced PAI-1 production at both
the mRNA and protein levels. The half-life of PAI-1 mRNA, as determined by a
standard decay assay, was not affected by hypoxia, suggesting that induction of
PAI-1 mRNA was regulated mainly at the transcriptional level. Transient
transfection assays of the human PAI-1 promoter-luciferase construct indicates
that a hypoxia-responsive region lies between -414 and -107 relative to the
transcription start site, where no putative hypoxia response element is found.
The hypoxia-mediated increase in PAI-1 mRNA levels was attenuated by the tyrosine
kinase inhibitors genistein (50 micromol/L) and herbimycin A (1 micromol/L),
whereas PD98059 (50 micromol/L, MEK1 inhibitor), SB203580 (10 micromol/L, p38
mitogen-activated protein kinase inhibitor), and calphostin C (1 micromol/L,
protein kinase C inhibitor) had no effect on the induction of PAI-1 expression by
hypoxia and deferoxamine. Genistein but not daidzein blocked the production of
hypoxia- and deferoxamine-induced PAI-1 protein. Thus, we conclude that hypoxia
stimulates PAI-1 gene transcription and protein production through a signaling
pathway involving genistein-sensitive tyrosine kinases in vascular endothelial
cells.
PMID- 10764688
TI - Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa
antagonists on platelet-mediated clot strength induced by tissue factor with use
of thromboelastography: differentiation among glycoprotein IIb/IIIa antagonists.
AB - In the present study, the in vitro efficacy of different platelet glycoprotein
IIb/IIIa (GPIIb/IIIa) antagonists on platelet-fibrin-mediated clot strength under
shear was compared with the antiaggregatory efficacy by using tissue factor (TF)
thromboelastography (TEG). The ability of platelets to augment the elastic
properties of blood clots under shear conditions was measured by computerized TEG
under conditions of maximal platelet activation accelerated by recombinant TF.
Under these conditions, platelets significantly enhance clot strength 8-fold
(relative to platelet-free fibrin clots). This effect was inhibited to a
different extent by various platelet GPIIb/IIIa receptor antagonists; this
inhibition appears to be dependent on the transmission of platelet contractile
force to fibrin via the GPIIb/IIIa receptors. The GPIIb/IIIa antagonists with
high binding affinity for resting and activated platelets and slow platelet
dissociation rates (class I) but not those with fast platelet dissociation rates
(class II) demonstrated potent and comparable inhibition of platelet aggregation
and TF-TEG clot strength. Platelet GPIIb/IIIa antagonists of class I, such as
XV459 (free-acid form of roxifiban), DMP802, XV454, and c7E3, demonstrated
comparable inhibitory dose responses of TF-TEG clot strength and platelet
aggregation, with an IC(50) of 50 to 70 nmol/L. In contrast, platelet GPIIb/IIIa
antagonists from class II, with comparable antiaggregatory efficacy, such as
DMP728, YZ202 (free-acid form of orbofiban), YZ211 (free-acid form of
sibrafiban), YZ751, and other antagonists, have a much lower efficacy in altering
the strength of TF-mediated clot formation (IC(50) >1.0 micromol/L). These data
suggest differential efficacy among different GPIIb/IIIa antagonists in
inhibiting platelet-fibrin clot retraction despite of equivalent antiaggregatory
potency.
PMID- 10764689
TI - Reduced thrombus formation by hyaluronic acid coating of endovascular devices.
AB - Biocompatible stent coatings may alleviate problems of increased (sub)acute
thrombosis after stent implantation. Hyaluronic acid (HA), a ubiquitous,
nonsulfated glycosaminoglycan, inhibits platelet adhesion and aggregation and
prolongs bleeding when administered systemically. However, the effects of
immobilized HA for reducing stent platelet deposition in vivo are unknown. We
therefore quantified the antithrombotic effects of coating stainless steel stents
and tubes with HA using an established baboon thrombosis model under
physiologically relevant blood flow conditions. HA-coated and uncoated (control)
stents (3.5 mm in diameter, n=32) and stainless steel tubes (4.0 mm in diameter,
n=18) were deployed into exteriorized arteriovenous shunts of conscious,
nonanticoagulated baboons. Accumulation of (111)In-radiolabeled platelets was
quantified by continuous gamma-camera imaging during a 2-hour blood exposure
period. HA coating resulted in a significant reduction in platelet deposition in
long (4 cm) tubes (0.24+/-0.15 x 10(9) versus 6.12+/-0.49 x 10(9) platelets;
P<0.03), short (2 cm) stainless steel tubes (0.18+/-0.06 x 10(9) versus 3.03+/
0.56 x 10(9) platelets; P<0.008), and stents (0.82+/-0.20 x 10(9) versus 1.83+/
0. 23 x 10(9) platelets; P<0.02) compared with uncoated control devices. Thus, HA
coating reduces platelet thrombus formation on stainless steel stents and tubes
in primate thrombosis models. These results indicate that immobilized HA may
represent an attractive strategy for improving the thromboresistance of
endovascular devices.
PMID- 10764691
TI - Insulin-like growth factor-binding protein-3 is associated with the presence and
extent of coronary arteriosclerosis
AB - Aging is associated with the progression of arteriosclerosis and the decline of
several endocrine functions. We therefore investigated the association of
coronary arteriosclerosis with hormones, the serum concentrations of which change
during aging. Coronary angiograms of 189 men <70 years old were evaluated by 3
semiquantitative score systems to estimate the extent of focal and diffuse vessel
wall alterations. Fasting sera were analyzed for levels of glucose, lipids,
thyroid-stimulating hormone, insulin, insulin-like growth factor I (IGF-I), IGF
binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEAS),
testosterone, and sex hormone-binding globulin (SHBG). After adjustment for age,
body mass index, and waist-to-hip ratio, 92 patients with >/=1 stenoses >70%
differed from 97 patients without such focal lesions by higher serum levels of
glucose, total and LDL cholesterol, and apolipoprotein (apo) B, as well as by
lower serum levels of IGFBP-3. Multivariate analyses revealed significant and
independent correlations of all 3 coronary scores with LDL cholesterol (or apoB)
and IGFBP-3; of 2 coronary scores with age, glucose, and insulin; and of 1 score
with IGF-I. No significant correlations existed for waist-to-hip ratio (or body
mass index) and DHEAS (or testosterone or SHBG). IGFBP-3 explained 9% to 14% and
3.5% to 10% of the variances of focal and diffuse lesions, respectively. In
conclusion, IGFBP-3 and, with much less strength and consistency, insulin and IGF
I, but not markers of hypothyroidism, adrenopause, and andropause, have
statistically significant and independent associations with coronary
arteriosclerosis in men.
PMID- 10764690
TI - Deposition of modified or native C-reactive protein in atherosclerotic arteries?
PMID- 10764692
TI - Insulin-like growth factor-binding protein-3 is associated with the presence and
extent of coronary arteriosclerosis
AB - Aging is associated with the progression of arteriosclerosis and the decline of
several endocrine functions. We therefore investigated the association of
coronary arteriosclerosis with hormones, the serum concentrations of which change
during aging. Coronary angiograms of 189 men <70 years old were evaluated by 3
semiquantitative score systems to estimate the extent of focal and diffuse vessel
wall alterations. Fasting sera were analyzed for levels of glucose, lipids,
thyroid-stimulating hormone, insulin, insulin-like growth factor I (IGF-I), IGF
binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEAS),
testosterone, and sex hormone-binding globulin (SHBG). After adjustment for age,
body mass index, and waist-to-hip ratio, 92 patients with >/=1 stenoses >70%
differed from 97 patients without such focal lesions by higher serum levels of
glucose, total and LDL cholesterol, and apolipoprotein (apo) B, as well as by
lower serum levels of IGFBP-3. Multivariate analyses revealed significant and
independent correlations of all 3 coronary scores with LDL cholesterol (or apoB)
and IGFBP-3; of 2 coronary scores with age, glucose, and insulin; and of 1 score
with IGF-I. No significant correlations existed for waist-to-hip ratio (or body
mass index) and DHEAS (or testosterone or SHBG). IGFBP-3 explained 9% to 14% and
3.5% to 10% of the variances of focal and diffuse lesions, respectively. In
conclusion, IGFBP-3 and, with much less strength and consistency, insulin and IGF
I, but not markers of hypothyroidism, adrenopause, and andropause, have
statistically significant and independent associations with coronary
arteriosclerosis in men.
PMID- 10764693
TI - Fibronectin in an extracellular matrix of cultured endothelial cells supports
platelet adhesion via its ninth type III repeat : A comparison with platelet
adhesion to isolated fibronectin
AB - We investigated the involvement of different domains of fibronectin in mediating
platelet adhesion to fibronectin in the extracellular matrix (ECM) of cultured
endothelial cells under flow conditions. Polyclonal anti-fibronectin antibodies
were absorbed with Sepharose to which no protein, intact fibronectin, or
different fibronectin fragments had been coupled to obtain supernatants (Sups)
(Sup(0), Sup(FN), and Sup(name of the fragment), respectively) from which a
specific part of the antibodies had been removed. Treatment of the ECM before
perfusion with Sup(0) resulted in a 36% decrease in platelet coverage, whereas
treatment with Sup(FN) resulted in maximal adhesion. Treatment of the ECM with
supernatants from which antibodies directed against the gelatin- or heparin
binding domain had been removed showed the same inhibition as treatment with
Sup(0). Removal of antibodies directed to the 120-kDa cell-binding domain
resulted in a level of adhesion equal to the level found when the ECM was treated
with Sup(FN). Further analysis of this central region showed that only treatment
with supernatants from which antibodies directed to the ninth type III repeat
(III-9) of fibronectin had been removed resulted in a significantly higher
adhesion than treatment with Sup(0). Studies of adhesion to the fragments
themselves showed that only fragments containing III-10 were able to support
adhesion. Mutation of the Arg-Gly-Asp (RGD) sequence into Arg-Gly-Glu (RGE) in
one of those fragments resulted in a complete loss of adhesive capacity. These
data suggest that platelet adhesion to fibronectin in the ECM depends on III-9,
whereas III-10 does not seem to be required. For platelet adhesion to isolated
fibronectin, an intact RGD sequence seems to be crucial.
PMID- 10764694
TI - The molecular and genetic base of congenital transport defects.
PMID- 10764695
TI - Is there still a need for albumin infusions to treat patients with liver disease?
PMID- 10764696
TI - GLP-1 and the gut.
PMID- 10764697
TI - Why treat chronic hepatitis B in childhood with interferon alpha?
PMID- 10764698
TI - Hepatic regeneration and TGF-beta: growing to a prosperous perfection.
PMID- 10764699
TI - Psychological stress and colitis.
PMID- 10764700
TI - A multicentre randomised study of intrasphincteric botulinum toxin in patients
with oesophageal achalasia. GISMAD Achalasia Study Group.
AB - BACKGROUND: Intrasphincteric injection of botulinum toxin (Botx) has been
proposed as treatment for oesophageal achalasia. However, the predictors of
response and optimal dose remain unclear. AIMS: To compare the effect of
different doses of Botx and to identify predictors of response. PATIENTS/METHODS:
A total of 118 achalasic patients were randomised to receive one of three doses
of Botx in a single injection: 50 U (n=40), 100 U (n=38), and 200 U (n=40). Of
those who received 100 U, responsive patients were reinjected with an identical
dose after 30 days. Clinical and manometric assessments were performed at
baseline, 30 days after the initial injection of botulinum toxin, and at the end
of follow up (mean 12 months; range 7-24 months). RESULTS: Thirty days after the
initial injection, 82% of patients were considered responders without a clear
dose related effect. At the end of follow up however, relapse of symptoms was
evident in 19% of patients who received two injections of 100 U compared with 47%
and 43% in the 50 U and 200 U groups, respectively. Using Kaplan-Meier analysis,
patients in the 100x2 U group were more likely to remain in remission at any time
(p<0.04), with 68% (95% CI 59-83) still in remission at 24 months. In a multiple
adjusted model, response to Botx was independently predicted by the occurrence of
vigorous achalasia (odds ratio 3.3) and the 100x2 U regimen (odds ratio 3.2).
CONCLUSIONS: Two injections of 100 U of Botx 30 days apart appeared to be the
most effective therapeutic schedule. The presence of vigorous achalasia was the
principal determinant of the response to Botx.
PMID- 10764701
TI - H pylori colocalises with MUC5AC in the human stomach.
AB - BACKGROUND: The bacterium Helicobacter pylori is able to adhere to and to
colonise the human gastric epithelium, yet the primary gene product responsible
as a receptor for its adherence has not been identified. AIMS: To investigate the
expression of the gastric mucins MUC5AC and MUC6 in the gastric epithelium in
relation to H pylori colonisation in order to examine their possible roles in the
binding of H pylori. PATIENTS: Seventy two consecutive patients suspected of
having H pylori infection. METHODS: MUC5AC, MUC6, and H pylori were detected in
single sections of antral biopsy specimens using immunohistochemical triple
staining. RESULTS: MUC5AC was expressed in the superficial epithelium and the
upper part of the gastric pits. MUC6 expression was detected in the lower part of
the gastric pits. The expression of both mucins in the epithelium was
complementary. In each patient, there was a sharply delineated transition between
MUC5AC and MUC6 producing cell populations. In all H pylori positive patients
there was a striking colocalization of H pylori and MUC5AC; more than 99% of the
bacteria were associated with either extracellular MUC5AC or the apical domain of
MUC5AC producing cells. CONCLUSIONS: H pylori is very closely associated with
extracellular MUC5AC and epithelial cells that produce MUC5AC. This indicates
that MUC5AC, but not MUC6, plays a role in the adhesion of H pylori to the
gastric mucosa.
PMID- 10764702
TI - Rapid and specific detection of Helicobacter pylori macrolide resistance in
gastric tissue by fluorescent in situ hybridisation.
AB - BACKGROUND: The development of macrolide resistance in Helicobacter pylori is
considered an essential reason for failure of antibiotic eradication therapies.
The predominant mechanism of resistance to macrolides, particularly
clarithromycin, is based on three defined mutations within 23S rRNA, resulting in
decreased binding of the antibiotic to the bacterial ribosome. AIM: To develop an
rRNA based whole cell hybridisation method to detect Helicobacter species in situ
within gastric tissue, simultaneously with its clarithromycin resistance
genotype. METHODS: A set of fluorescent labelled oligonucleotide probes was
developed, binding either to H pylori 16S rRNA or 23S rRNA sequences containing
specific point mutations responsible for clarithromycin resistance. After
hybridisation and stringent washing procedures, labelling of intact single
bacteria was monitored by fluorescence microscopy. The new approach was compared
with PCR based assays, histology, and microbiological culture. RESULTS: In
comparison with the phenotypic resistance measurement by E test, the genotypic
clarithromycin resistance correlated perfectly (100%) for 35 H pylori isolates
analysed. In a set of gastric biopsy specimens (27) H pylori infection was
confirmed by histology (17/27) and correctly detected by whole cell
hybridisation. Five clarithromycin resistant strains were identified in gastric
tissue specimens directly. Furthermore, non-cultivable coccoid forms of H pylori
were easily detectable by whole cell hybridisation. CONCLUSIONS: Whole cell
hybridisation of rRNA holds great promise for cultivation independent, reliable,
and rapid (three hours) genotypic determination of clarithromycin resistance in H
pylori. Compared with PCR techniques it is independent of nucleic acid
preparations, not prone to inhibition, and allows semiquantitative visualisation
of the bacteria within intact tissue samples.
PMID- 10764703
TI - Effect of Helicobacter pylori eradication on chronic gastritis during omeprazole
therapy.
AB - BACKGROUND: We have previously observed that profound acid suppressive therapy in
Helicobacter pylori positive patients with gastro-oesophageal reflux disease is
associated with increased corpus inflammation and accelerated development of
atrophic gastritis. AIM: To investigate if H pylori eradication at the start of
acid suppressive therapy prevents the development of these histological changes.
PATIENTS/METHODS: In a prospective randomised case control study, patients with
reflux oesophagitis were treated with omeprazole 40 mg once daily for 12 months.
H pylori positive patients were randomised to additional double blind treatment
with omeprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg twice daily
or placebo for one week. Biopsy sampling for histology, scored according to the
updated Sydney classification, and culture were performed at baseline, and at
three and 12 months. RESULTS: In the persistently H pylori positive group (n=24),
active inflammation increased in the corpus and decreased in the antrum during
therapy (p=0.032 and p=0.002, respectively). In contrast, in the H pylori
positive group that became H pylori negative as a result of treatment (n=33),
active and chronic inflammation in both the corpus and antrum decreased (p50 u/l). Transferrin
saturation and serum ferritin concentrations were measured in these patient
samples, and in 56 transferrin saturation was >60%. Further blood samples were
requested from these patients for genetic testing: 33 samples were obtained.
There were nine patients homozygous for the C282Y mutation of the HFE gene and
three compound heterozygotes (heterozygous for both C282Y and H63D mutations).
CONCLUSIONS: The association of raised ALT activity and transferrin saturation of
>60% could provide a simple, cost effective method for detecting individuals with
clinical haemochromatosis. Although many patients with GH may have been missed,
this study suggests that the clinical penetrance of the disorder may be much
lower than is generally supposed and that genetic screening will identify many
people who may never develop clinical haemochromatosis.
PMID- 10764717
TI - Liver iron excess in patients with hepatocellular carcinoma developed on viral C
cirrhosis.
AB - BACKGROUND: Liver iron deposits are frequent in viral C cirrhotic patients but
their role is not well defined. AIMS: To investigate the effect of liver iron
excess on the prevalence of hepatocellular carcinoma (HCC) in patients with viral
C cirrhosis. METHODS: Hepatic iron was evaluated retrospectively using a
semiquantitative method in liver biopsies of 104 viral C cirrhotic patients, 48
with HCC and 56 controls (HCC free). Corrected total iron score (0-60) was
defined by the sum of three scores: hepatocytic iron score (0-36), sinusoidal
iron score (0-12), and portal iron score (0-12), multiplied by 3/3, 2/3, or 1/3
according to the heterogeneous iron localisation in the nodules. RESULTS: After
adjustment for known risk factors for HCC, regression analysis showed that iron
deposits (corrected total iron score >0) were more frequent in HCC patients than
in controls (odds ratio 4.94; 95% confidence interval 1.59-15. 32; p=0.0056). The
median of corrected total iron score was significantly higher in HCC patients
than in controls (odds ratio 1. 092; 95% confidence interval 1.01-1.13; p=0.021).
This liver iron overload was sinusoidal (odds ratio 5.2; 95% confidence interval
1. 82-15.11; p=0.0022). CONCLUSIONS: Liver iron deposition was more frequent and
more important in viral C cirrhotic patients with HCC than in HCC free controls.
Liver iron overload seems to contribute to the development of HCC in patients
with viral C cirrhosis.
PMID- 10764718
TI - Long term effect of alpha interferon in children with chronic hepatitis B.
AB - BACKGROUND/AIMS: The purpose of this study was to better define the long term
prognosis of infection and disease in children with chronic hepatitis B treated
with interferon (IFN) alpha. PATIENTS: A total of 107 children with chronic
hepatitis B who received IFN alpha for three or six months in two clinical trials
were followed for a mean period of 69 (17) months. Response to treatment was
defined as loss of hepatitis B e antigen (HBeAg) within 12 months after stopping
treatment. A control group of 59 patients was also followed for a shorter mean
time (46 (19) months). RESULTS: Sixteen (15%) treated children responded during
therapy and 18 (17%) during post-treatment follow up; 31 (29%) non-responders
lost HBeAg during subsequent years. High pretreatment levels of transaminases and
a greater histological activity index were predictors of response. Kaplan-Meier
estimates of cumulative HBeAg clearance rates at five years were similar between
treated patients (60%) and controls (65%). After HBeAg clearance, all cases lost
hepatitis B virus DNA and 94% had normal transaminase levels. Loss of hepatitis B
surface antigen (HBsAg) occurred in four (25%) patients who responded during
treatment but in none of the other treated or untreated patients. CONCLUSIONS:
After five years' observation, the proportion of treated children with sustained
HBeAg clearance comprised an equal number of responders and non-responders and
did not differ from that observed in untreated controls, suggesting that IFN
simply accelerated a spontaneous event. However, IFN significantly improved the
rate of HBsAg loss in cases with more prominent disease activity who were early
responders, and may be particularly useful in this type of patient.
PMID- 10764719
TI - Modulation of transforming growth factor beta function in hepatocytes and hepatic
stellate cells in rat liver injury.
AB - BACKGROUND: Transforming growth factor beta (TGF-beta) regulates hepatocyte
proliferation and biosynthesis of the extracellular matrix. AIMS: This study
investigated alternations in sensitivity to TGF-beta1 and binding properties for
ligand in hepatocytes and hepatic stellate cells (HSC) after CCl(4)
administration. METHODS: Plasma TGF-beta1 levels in rats after CCl(4)
administration were determined using ELISA. Effects of TGF-beta1 were examined by
DNA synthesis in hepatocytes and by measurement of fibronectin production in HSC
after CCl(4) administration. Binding of (125)I TGF-beta1 was tested in these
cells. RESULTS: Plasma TGF-beta1 levels were increased as early as 24 hours and
were maximal by 48 hours. The antiproliferative response to TGF-beta1 decreased
in hepatocytes at 48 hours and normalised at 72 hours. Fibronectin production of
both normal and injured HSC was affected by TGF-beta1 treatment. Cross linked
ligand/receptor complexes were detected in normal hepatocytes and HSC. However,
these levels decreased specifically in hepatocytes at 48 hours and normalised by
72 hours. CONCLUSIONS: Downregulation of TGF-beta receptor occurred in
hepatocytes after chemical insult and TGF-beta1 could not transduce its
antiproliferative signal. Recovery of TGF-beta receptor expression causes the
signal to transduce to the nucleus at 72 hours. In HSC, whenever TGF-beta1 is
increased, TGF-beta1 can transduce its signal for fibronectin production via its
receptor because signalling receptors are expressed constantly.
PMID- 10764720
TI - Endotoxin, cytokines, and endotoxin binding proteins in obstructive jaundice and
after preoperative biliary drainage.
AB - BACKGROUND: Obstructive jaundice is associated with postoperative complications
related to increased endotoxaemia and the inflammatory response. In animals
obstructive jaundice is associated with endotoxaemia and cytokine induction,
which are reversed by internal biliary drainage. AIMS: To study endotoxaemia and
the subsequent inflammatory response in obstructive jaundiced patients and after
endoscopic biliary drainage. METHODS: In 15 patients with malignant distal
obstructive jaundice, inflammatory and bacteriological parameters were assessed
before endoscopic stent placement and after three weeks endoscopic drainage.
RESULTS: Drainage reduced bilirubin from 252.5 to 45.1 micromol/l. At baseline
low level endotoxaemia was detected (4.3 pg/ml) which was not affected after
drainage (4.5 pg/ml). Serum interleukin 8 (IL-8) and endotoxin binding proteins
were increased in jaundice and reduced after drainage (IL-8 113.6 to 20.7 pg/ml;
lipopolysaccharide binding protein 24.2 to 16.5 microg/ml; sCD14 17.4 to 7.6
microg/ml; bactericidal/permeability increasing protein 2.9 to 1.8 ng/ml). Levels
of other cytokines, augmented in animals, were only slightly increased and not
changed after drainage (tumour necrosis factor (TNF): 21.7 and 18.4 pg/ml; sTNFr
p55/75: 2.9/7.0 and 2.7/5.6 ng/ml; IL-6: 4.2 and 6.1 pg/ml; IL-10: 4.5 and 2.7
pg/ml). Elastase and lactoferrin tended towards reduction after drainage. All
bile cultures were positive after stenting. CONCLUSIONS: The effects of
obstructive jaundice in humans on endotoxin and cytokines are different from
those in animal models. Obstructive jaundice causes alterations in circulating
endotoxin binding proteins and IL-8. Concentrations of other mediators (TNF,
previously suggested as being responsible for systemic endotoxaemia effects) are
low and not affected by drainage.
PMID- 10764721
TI - Sporadic acute hepatitis E in the united kingdom: an underdiagnosed phenomenon?
AB - BACKGROUND: Hepatitis E (HEV) is the primary cause of enterically transmitted non
A non-B hepatitis worldwide. Case reports of HEV in individuals in the United
Kingdom relate to travel to endemic areas or contact with individuals who have
visited these areas. CASE REPORTS: Four individuals presented with acute
hepatitis to a hepatology clinic in a teaching hospital. Serology confirmed acute
hepatitis E in all four. Investigation by the Communicable Disease Control
Department established no links between the cases, no travel to an endemic area,
and no contacts. CONCLUSION: Contrary to current belief, community acquired
hepatitis E virus infection occurs sporadically in the United Kingdom and should
be considered as a cause of seronegative hepatitis.
PMID- 10764722
TI - Coeliac disease: it takes three to tango!
PMID- 10764726
TI - pH dependence of the inwardly rectifying potassium channel, Kir5.1, and
localization in renal tubular epithelia.
AB - The physiological role of the inwardly rectifying potassium channel, Kir5.1, is
poorly understood, as is the molecular identity of many renal potassium channels.
In this study we have used Kir5.1-specific antibodies to reveal abundant
expression of Kir5.1 in renal tubular epithelial cells, where Kir4.1 is also
expressed. Moreover, we also show that Kir5.1/Kir4.1 heteromeric channel activity
is extremely sensitive to inhibition by intracellular acidification and that this
novel property is conferred predominantly by the Kir5.1 subunit. These findings
suggest that Kir5.1/Kir4.1 heteromeric channels are likely to exist in vivo and
implicate an important and novel functional role for the Kir5.1 subunit.
PMID- 10764727
TI - NADE, a p75NTR-associated cell death executor, is involved in signal transduction
mediated by the common neurotrophin receptor p75NTR.
AB - The low affinity neurotrophin receptor p75NTR can mediate cell survival as well
as cell death of neural cells by NGF and other neurotrophins. To elucidate p75NTR
mediated signal transduction, we screened p75NTR-associated proteins by a yeast
two-hybrid system. We identified one positive clone and named NADE (p75NTR
associated cell death executor). Mouse NADE has marked homology to the human
HGR74 protein. NADE specifically binds to the cell-death domain of p75NTR. Co
expression of NADE and p75NTR induced caspase-2 and caspase-3 activities and the
fragmentation of nuclear DNA in 293T cells. However, in the absence of p75NTR,
NADE failed to induce apoptosis, suggesting that NADE expression is necessary but
insufficient for p75NTR-mediated apoptosis. Furthermore, p75NTR/NADE-induced cell
death was dependent on NGF but not BDNF, NT-3, or NT-4/5, and the recruitment of
NADE to p75NTR (intracellular domain) was dose-dependent. We obtained similar
results from PC12 cells, nnr5 cells, and oligodendrocytes. Taken together, NADE
is the first signaling adaptor molecule identified in the involvement of p75NTR
mediated apoptosis induced by NGF, and it may play an important role in the
pathogenesis of neurogenetic diseases.
PMID- 10764728
TI - The Caenorhabditis elegans sex determination protein FEM-1 is a CED-3 substrate
that associates with CED-4 and mediates apoptosis in mammalian cells.
AB - Sex-specific elimination of cells by apoptosis plays a role in sex determination
in Caenorhabditis elegans. Recently, a mammalian pro-apoptotic protein named
F1Aalpha has been identified. F1Aalpha shares extensive homology throughout the
entire protein with the C. elegans protein, FEM-1, which is essential for
achieving all aspects of the male phenotype in the nematode. In this report, the
role of FEM-1 in apoptosis was investigated. Overexpression of FEM-1 induces
caspase-dependent apoptosis in mammalian cells. FEM-1 is cleaved in vitro by the
C. elegans caspase, CED-3, generating an N-terminal cleavage product that
corresponds to the minimal effector domain for apoptosis. Furthermore, CED-4
associates with FEM-1 in vitro and in vivo in mammalian cells and potentiates FEM
1-mediated apoptosis. Similarly, Apaf-1, the mammalian homologue of CED-4 was
found to associate with F1Aalpha. These data suggest that FEM-1 and F1Aalpha may
mediate apoptosis by communicating directly with the core machinery of apoptosis.
PMID- 10764729
TI - Identification and characterization of beta V spectrin, a mammalian ortholog of
Drosophila beta H spectrin.
AB - Four mammalian beta-spectrin genes are currently recognized, all encode proteins
of approximately 240-280,000 M(r) and display 17 triple helical homologous
approximately 106-residue repeat units. In Drosophila and Caenorhabditis elegans,
a variant beta spectrin with unusual properties has been recognized. Termed beta
heavy (beta(H)), this spectrin contains 30 spectrin repeats, has a molecular
weight in excess of 400,000, and associates with the apical domain of polarized
epithelia. We have cloned and characterized from a human retina cDNA library a
mammalian ortholog of Drosophila beta(H) spectrin, and in accord with standard
spectrin naming conventions we term this new mammalian spectrin beta 5 (betaV).
The gene for human betaV spectrin (HUBSPECV) is on chromosome 15q21. The 11, 722
nucleotide cDNA of betaV spectrin is generated from 68 exons and is predicted to
encode a protein with a molecular weight of 416,960. Like its fly counterpart,
the derived amino acid sequence of this unusual mammalian spectrin displays 30
spectrin repeats, a modestly conserved actin-binding domain, a conserved membrane
association domain 1, a conserved self-association domain, and a pleckstrin
homology domain near its COOH terminus. Its putative ankyrin-binding domain is
poorly conserved and may be inactive. These structural features suggest that
betaV spectrin is likely to form heterodimers and oligomers with alpha spectrin
and to interact directly with cellular membranes. Unlike its Drosophila ortholog,
betaV spectrin does not contain an SH3 domain but displays in repeat 5 a 45
residue insertion that displays 42% identity to amino acids 85-115 of the E4
protein of type 75 human papilloma virus. Human betaV spectrin is expressed at
low levels in many tissues. By indirect immunofluorescence, it is detected
prominently in the outer segments of photoreceptor rods and cones and in the
basolateral membrane and cytosol of gastric epithelial cells. Unlike its
Drosophila ortholog, a distinct apical distribution of betaV spectrin is
inapparent in the epithelial cell populations examined, although it is confined
to the outer segments of photoreceptor cells. The complete cDNA sequence of human
betaV spectrin is available from GenBank(TM) as accession number.
PMID- 10764730
TI - A common interface on histidine-containing phosphocarrier protein for interaction
with its partner proteins.
AB - The bacterial phosphoenolpyruvate:sugar phosphotransferase system accomplishes
both the transport and phosphorylation of sugars as well as the regulation of
some cellular processes. An important component of this system is the histidine
containing phosphocarrier protein, HPr, which accepts a phosphoryl group from
enzyme I, transfers a phosphoryl group to IIA proteins, and is an allosteric
regulator of glycogen phosphorylase. Because the nature of the surface on HPr
that interacts with this multiplicity of proteins from Escherichia coli was
previously undefined, we investigated these interactions by nuclear magnetic
resonance spectroscopy. The chemical shift changes of the backbone and side-chain
amide (1)H and (15)N nuclei of uniformly (15)N-labeled HPr in the absence and
presence of natural abundance glycogen phosphorylase, glucose-specific enzyme
IIA, or the N-terminal domain of enzyme I have been determined. Mapping these
chemical shift perturbations onto the three-dimensional structure of HPr
permitted us to identify the binding surface(s) of HPr for interaction with these
proteins. Here we show that the mapped interfaces on HPr are remarkably similar,
indicating that HPr employs a similar surface in binding to its partners.
PMID- 10764731
TI - Energetics of copper trafficking between the Atx1 metallochaperone and the
intracellular copper transporter, Ccc2.
AB - The Atx1 metallochaperone protein is a cytoplasmic Cu(I) receptor that functions
in intracellular copper trafficking pathways in plants, microbes, and humans. A
key physiological partner of the Saccharomyces cerevisiae Atx1 is Ccc2, a cation
transporting P-type ATPase located in secretory vesicles. Here, we show that Atx1
donates its metal ion cargo to the first N-terminal Atx1-like domain of Ccc2 in a
direct and reversible manner. The thermodynamic gradient for metal transfer is
shallow (K(exchange) = 1.4 +/- 0.2), establishing that vectorial delivery of
copper by Atx1 is not based on a higher copper affinity of the target domain.
Instead, Atx1 allows rapid metal transfer to its partner. This equilibrium is
unaffected by a 50-fold excess of the Cu(I) competitor, glutathione, indicating
that Atx1 also protects Cu(I) from nonspecific reactions. Mechanistically, we
propose that a low activation barrier for transfer between partners results from
complementary electrostatic forces that ultimately orient the metal-binding loops
of Atx1 and Ccc2 for formation of copper-bridged intermediates. These
thermodynamic and kinetic considerations suggest that copper trafficking proteins
overcome the extraordinary copper chelation capacity of the eukaryotic cytoplasm
by catalyzing the rate of copper transfer between physiological partners. In this
sense, metallochaperones work like enzymes, carefully tailoring energetic
barriers along specific reaction pathways but not others.
PMID- 10764732
TI - Sphingolipids signal heat stress-induced ubiquitin-dependent proteolysis.
AB - Sphingolipids are essential eukaryotic membrane lipids that are structurally and
metabolically conserved through evolution. Sphingolipids have also been proposed
to regulate eukaryotic stress responses as novel second messengers. Here we show
that, in Saccharomyces cerevisiae, phytosphingosine, a putative sphingolipid
second messenger, mediates heat stress signaling and activates ubiquitin
dependent proteolysis via the endocytosis vacuolar degradation and 26 S
proteasome pathways. Inactivation of serine palmitoyltransferase, a key enzyme in
generating endogenous phytosphingosine, prevents proteolysis during heat stress.
Addition of phytosphingosine bypasses the requirement for serine
palmitoyltransferase and restores proteolysis. Phytosphingosine-induced
proteolysis requires multiubiquitin chain formation through the stress-responsive
lysine 63 residue of ubiquitin. We propose that heat stress increases
phytosphingosine and activates ubiquitin-dependent proteolysis.
PMID- 10764733
TI - Epidermal growth factor treatment enhances the kinase activity of kinase
suppressor of Ras.
AB - In Drosophila melanogaster and Caenorhabditis elegans, kinase suppressor of Ras
(KSR) functions as a positive modulator of Ras-dependent signaling either
upstream of or parallel to Raf. Attempts to characterize the biochemical and
biological properties of mammalian KSR, however, have had limited success.
Although some studies demonstrated a requirement of KSR kinase activity for its
action, others indicated the kinase function of KSR is dispensable and suggested
that KSR acts primarily as a scaffold protein. Interpretations of KSR function
are further hampered by the lack of a standardized assay for its kinase activity
in vitro. To address this issue, we established a two-stage in vitro kinase assay
in which KSR never comes in contact with any recombinant kinases other than c-Raf
1. Using this assay, we show that KSR immunoprecipitated from quiescent COS-7
cells overexpressing Flag-tagged KSR was inactive, but its activity was rapidly
and markedly induced upon epidermal growth factor treatment. Moreover, KSR
reconstituted mitogen-activated protein kinase activation was detected in KSR
immunoprecipitates depleted of all contaminating kinases (c-Raf-1, MEK1, ERK2) by
multiple high salt washes. Only full-length kinase-active KSR was capable of
signaling c-Raf-1-dependent activity as kinase inactive and C- and N-terminal
deletion mutants were without effect. Furthermore, endogenous KSR isolated from
A431 cells, which contain high levels of activated EGF receptor, displays
constitutively enhanced kinase activity. Hence, KSR kinase activity is not an
artifact of overexpression but a property intrinsic to this protein. The
recognition of EGF as a potent activator of KSR kinase activity and the
availability of a well defined in vitro kinase assay should facilitate the
definition of the function of KSR as a Ras-effector molecule.
PMID- 10764734
TI - Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness
due to preferential loss of EGF receptors.
AB - Wound healing is compromised in aging adults in part due to decreased
responsiveness of fibroblasts to extracellular signals. However, the cellular
mechanisms underlying this phenomenon are not known. Aged dermal fibroblasts with
reduced remaining replicative capacities demonstrated decreased epidermal growth
factor (EGF)-induced cell migrative and cell proliferative capacities, as
reported previously. Thus, as cells approach senescence, programmed in vivo or in
vitro, EGF responsiveness is preferentially lost. To define the rate-limiting
signaling event, we found that the activity of two different EGF receptor (EGFR)
signaling pathways to cell migration (phospholipase-C gamma) and/or mitogenesis
(extracellular signal/regulated-mitogen-activated kinases) were decreased in near
senescent cells despite unchanged levels of effector molecules. Aged cells
presented decreased levels of EGFR, although insulin receptor and transferrin
receptor levels were relatively unchanged. EGFR mRNA levels and production of new
transcripts decreased during aging, suggesting that this preferential loss of
EGFR was due to diminished production, which more than counteracts the reduced
ligand-induced receptor loss. Since these data suggested that the decrement in
EGF was rate-limiting, higher levels of EGFR were established in near senescent
cells by electroporation of EGFR cDNA. These cells presented higher levels of
EGFR and recovered their EGF-induced migration and proliferation responsiveness.
Thus, the defect in EGF responsiveness of aged dermal fibroblasts is secondary to
reduced EGFR message transcription. Our experimental model suggests that EGFR
gene delivery might be an effective future therapy for compromised wound healing.
PMID- 10764735
TI - Mechanisms for high affinity mannose 6-phosphate ligand binding to the insulin
like growth factor II/mannose 6-phosphate receptor.
AB - The two mannose 6-phosphate (Man-6-P) binding domains of the insulin-like growth
factor II/mannose 6-phosphate receptor (Man-6-P/IGF2R), located in
extracytoplasmic repeats 1-3 and 7-9, are capable of binding Man-6-P with low
affinity and glycoproteins that contain more than one Man-6-P residue with high
affinity. High affinity multivalent ligand binding sites could be formed through
two possible mechanisms: the interaction of two Man-6-P binding domains within
one Man-6-P/IGF2R molecule or by receptor oligomerization. To discriminate
between these mechanisms, truncated FLAG epitope-tagged Man-6-P/IGF2R constructs,
containing one or both of the Man-6-P binding domains, were expressed in 293T
cells, and characterized for binding of pentamannose phosphate-bovine serum
albumin (PMP-BSA), a pseudoglycoprotein bearing multiple Man-6-P residues. A
construct containing all 15 repeats of the Man-6-P/IGF2R extracytoplasmic domain
bound PMP-BSA with the same affinity as the full-length receptor (K(d) = 0.54 nm)
with a curvilinear Scatchard plot. The presence of excess unlabeled PMP-BSA
increased the dissociation rate of pre-formed (125)I-PMP-BSA/receptor complexes,
suggesting negative cooperativity in multivalent ligand binding and affirming the
role of multiple Man-6-P/IGF2R binding domains in forming high affinity binding
sites. Truncated receptors containing only one Man-6-P binding domain and mutant
receptor constructs, containing an Arg(1325) --> Ala mutation that eliminates
binding to the repeats 7-9 binding domain, formed high affinity PMP-BSA binding,
but with reduced stoichiometries. Collectively, these observations suggest that
alignment of Man-6-P binding domains of separate Man-6-P/IGF2R molecules is
responsible for the formation of high affinity Man-6-P binding sites and provide
functional evidence for Man-6-P/IGF2R oligomerization.
PMID- 10764736
TI - The small G-protein Rac mediates depolarization-induced superoxide formation in
human endothelial cells.
AB - Superoxide anions impair nitric oxide-mediated responses and are involved in the
development of hypertensive vascular hypertrophy. The regulation of their
production in the vascular system is, however, poorly understood. We investigated
whether changes in membrane potential that occur in hypertensive vessels modulate
endothelial superoxide production. In cultured human umbilical vein endothelial
cells, changes in membrane potential were induced by high potassium buffer, the
non-selective potassium channel blocker tetrabutylammonium chloride (1 mm), and
the non-selective cation ionophore gramicidin (1 micrometer). Superoxide
formation was significantly elevated to a similar degree by all three treatments
(by approximately 60%, n = 23, p < 0.01), whereas hyperpolarization by the K(ATP)
channel activator Hoe234 (1 micrometer) significantly decreased superoxide
formation. Depolarization also induced an increased tyrosine phosphorylation of
several not yet identified proteins (90-110 kDa) and resulted in a significant
increase in membrane association of the small G-protein Rac. Accordingly, the Rac
inhibitor Clostridium difficile toxin B blocked the effects of depolarization on
superoxide formation. The tyrosine kinase inhibitor genistein (30 micrometer, n =
15) abolished depolarization-induced superoxide formation and also prevented
depolarization-induced Rac translocation associated with it. It is concluded that
depolarization is an important stimulus of endothelial superoxide production,
which involves a tyrosine phosphorylation-dependent translocation of the small G
protein Rac.
PMID- 10764737
TI - Presenilin-1 mutations increase levels of ryanodine receptors and calcium release
in PC12 cells and cortical neurons.
AB - Many cases of early-onset inherited Alzheimer's disease (AD) are caused by
mutations in the presenilin-1 (PS1) gene. PS1 mutations may perturb cellular
Ca(2+) homeostasis and thereby render neurons vulnerable to excitotoxicity and
apoptosis. We now report that PC12 cells expressing PS1 mutations and primary
hippocampal neurons from PS1 mutant knockin mice exhibit greatly increased levels
of ryanodine receptors (RyR) and enhanced Ca(2+) release following stimulation
with caffeine. Double-labeling immunostaining and co-immunoprecipitation analyses
indicate that PS1 and RyR are colocalized and interact physically. Caffeine
treatment sensitizes neurons expressing mutant PS1 to apoptosis induced by
amyloid beta-peptide, a neurotic peptide linked to the pathogenesis of AD. When
taken together with recent evidence for alterations in RyR in brains of AD
patients, our data suggest that PS1 mutations may promote neuronal degeneration
in AD by increasing transcription and translation of RyR and altering functional
properties of ryanodine-sensitive Ca(2+) pools.
PMID- 10764738
TI - Microtubule-associated protein 1B is a component of cortical Lewy bodies and
binds alpha-synuclein filaments.
AB - Lewy bodies, neuropathological hallmarks of Parkinson's disease and dementia with
Lewy bodies, comprise alpha-synuclein filaments and other less defined proteins.
Characterization of Lewy body proteins that interact with alpha-synuclein may
provide insight into the mechanism of Lewy body formation. Double
immunofluorescence labeling and confocal microscopy revealed approximately 80% of
cortical Lewy bodies contained microtubule-associated protein 1B (MAP-1B) that
overlapped with alpha-synuclein. Lewy bodies were isolated using an
immunomagnetic technique from brain tissue of patients dying with dementia with
Lewy bodies. Lewy body proteins were resolved by polyacrylamide gel
electrophoresis. Immunoblotting confirmed the presence of MAP-1B and alpha
synuclein in purified Lewy bodies. Direct binding studies revealed a high
affinity interaction (IC(50) approximately 20 nm) between MAP-1B and alpha
synuclein. The MAP-1B-binding sites were mapped to the last 45 amino acids of the
alpha-synuclein C terminus. MAP-1B also bound in vitro assembled alpha-synuclein
fibrils. Thus, MAP-1B may be involved in the pathogenesis of Lewy bodies via its
interaction with monomeric and fibrillar alpha-synuclein.
PMID- 10764739
TI - Ligand binding and structural properties of segments of GABAA receptor alpha 1
subunit overexpressed in Escherichia coli.
AB - The gamma-aminobutyric acid, type A (GABA(A)), receptor is the target for
numerous therapeutic compounds. In the present study, the Gln(28)-Leu(296),
Gln(28)-Arg(276), Gln(28)-Arg(248), and Gln(28)-Glu(165) (numbering of bovine
precursor protein) segments of its alpha(1) subunit were overexpressed in
Escherichia coli, along with Cys(166)-Leu(296) produced previously, for
structural analysis by circular dichroism and ligand binding studies by
fluorescence spectroscopy. Results showed that the protein segments were rich in
beta-sheet structures. Binding of the fluorescent benzodiazepine Bodipy-FL Ro
1986 was evident from fluorescence resonance energy transfer and fluorescence
anisotropy measurements. The binding affinity was in the micromolar range. The
binding was attributable more to Cys(166)-Leu(296) than to Gln(28)-Glu(165) and
was inhibited by known central benzodiazepine site ligands. Three point
mutations, Y187A, T234A, and Y237A, were found to perturb protein secondary
structures. Studies with the single Trp mutants W198Y and W273Y indicated that
Trp(273) was closer to the binding site than Trp(198).
PMID- 10764740
TI - Two different signal transduction pathways are implicated in the regulation of
initiation factor 2B activity in insulin-like growth factor-1-stimulated neuronal
cells.
AB - Eukaryotic initiation factor eIF-2B plays an important role in translation
regulation and has been suggested to be implicated in the increased protein
synthesis promoted in response to growth factors. We have used primary cultured
neurons to delineate the signaling pathways by which insulin-like growth factor-1
(IGF-1), which plays a critical role in the survival of neuronal cells, promotes
eIF-2B and protein synthesis activation. Treatment of cortical neurons with IGF-1
(100 ng/ml) for 30 min stimulates [(3)H]methionine incorporation, and a parallel
increase in eIF-2B activity was observed. Wortmannin and LY294002 reversed both
effects, indicating that phosphatidylinositol 3-kinase mediates IGF-1-induced
protein synthesis and eIF-2B activation. IGF-1 induced glycogen synthase kinase-3
(GSK-3) inactivation in a phosphatidylinositol 3-kinase-dependent fashion because
it is inhibited by wortmannin and LY294002. By using GSK-3 immunoprecipitated
from untreated and IGF-1-treated cells, we demonstrate the phosphorylation of eIF
2B coincident with its inactivation. The treatment of cortical neurons with IGF-1
also promoted the activation of mitogen-activated protein kinase (MAPK). The MAPK
activating kinase (MEK) inhibitor PD98059 inhibited MAPK activation and reversed
IGF-1-induced protein synthesis and eIF-2B activation. These findings suggest
that IGF-1-induced eIF-2B activation on neurons is promoted through
phosphatidylinositol 3-kinase and GSK-3 kinase, and we report an IGF-1-induced
MEK/MAPK activation pathway implicated in eIF-2B activation.
PMID- 10764741
TI - Deterin, a new inhibitor of apoptosis from Drosophila melanogaster.
AB - Deterin, a new apoptosis inhibitor from Drosophila melanogaster, possesses an
unusual structure of only a single baculovirus inhibitor of apoptosis (IAP)-type
repeat and no RING finger motif. The biochemical actions of deterin are
demonstrated in SF9 and S2 cell transfection assays, in which the expressed
protein acts in the cytoplasm to inhibit or deter cells from apoptosis otherwise
induced by the caspase-dependent apoptosis activator reaper or by cytotoxicants.
A loss of function phenotype for deterin of cell death was indicated by
transfections with either a dominant negative deterin mutant or with inhibitory
RNA (RNAi) for deterin. The dominant negative C-terminal fragment that
antagonized antiapoptotic activity of deterin did not affect antiapoptotic
activity of DIAP1 or p35. Both the baculovirus IAP-type repeat (BIR) domain and
the alpha-helical C-terminal domain are necessary in both SF9 and S2 cells for
deterin to manifest its activity to prevent cell death. The approximately 650
base deterin transcript is present in embryos, third instar larvae, and late
stage nurse cells of adult females. The deterin transcript is distributed
throughout early stage embryos, whereas in later stage embryos it becomes
progressively restricted to the central nervous system and gonads. Whereas the
nematode survivin-type IAP has thus far been implicated only as a mitotic
regulator, Drosophila deterin constitutes the first invertebrate member of the
survivin-type IAP group to exhibit apoptosis-inhibitory activity.
PMID- 10764742
TI - A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required
for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase
2 by PDK1.
AB - Members of the AGC subfamily of protein kinases including protein kinase B, p70
S6 kinase, and protein kinase C (PKC) isoforms are activated and/or stabilized by
phosphorylation of two residues, one that resides in the T-loop of the kinase
domain and the other that is located C-terminal to the kinase domain in a region
known as the hydrophobic motif. Atypical PKC isoforms, such as PKCzeta, and the
PKC-related kinases, like PRK2, are also activated by phosphorylation of their T
loop site but, instead of possessing a phosphorylatable Ser/Thr in their
hydrophobic motif, contain an acidic residue. The 3-phosphoinositide-dependent
protein kinase (PDK1) activates many members of the AGC subfamily of kinases in
vitro, including PKCzeta and PRK2 by phosphorylating the T-loop residue. In the
present study we demonstrate that the hydrophobic motifs of PKCzeta and PKCiota,
as well as PRK1 and PRK2, interact with the kinase domain of PDK1. Mutation of
the conserved residues of the hydrophobic motif of full-length PKCzeta, full
length PRK2, or PRK2 lacking its N-terminal regulatory domain abolishes or
significantly reduces the ability of these kinases to interact with PDK1 and to
become phosphorylated at their T-loop sites in vivo. Furthermore, overexpression
of the hydrophobic motif of PRK2 in cells prevents the T-loop phosphorylation and
thus inhibits the activation of PRK2 and PKCzeta. These findings indicate that
the hydrophobic motif of PRK2 and PKCzeta acts as a "docking site" enabling the
recruitment of PDK1 to these substrates. This is essential for their
phosphorylation by PDK1 in cells.
PMID- 10764743
TI - Stepwise assembly of a glucocorticoid receptor.hsp90 heterocomplex resolves two
sequential ATP-dependent events involving first hsp70 and then hsp90 in opening
of the steroid binding pocket.
AB - A system of five purified proteins that assembles stable glucocorticoid receptor
(GR)-hsp90 heterocomplexes has been reconstituted from reticulocyte lysate. Two
proteins, hsp90 and hsp70, are required for the activation of steroid binding
activity that occurs with heterocomplex assembly, and three proteins, Hop, hsp40,
p23, act as co-chaperones that enhance activation and assembly (Morishima, Y.,
Kanelakis, K. C., Silverstein, A.M., Dittmar, K. D., Estrada, L., and Pratt, W.
B. (2000) J. Biol. Chem. 275, 6894-6900). Here we demonstrate that the first step
in assembly is the ATP-dependent and hsp40 (YDJ-1)-dependent binding of hsp70 to
the GR. After elimination of free hsp70, these preformed GR.hsp70 complexes can
be activated to the steroid binding state by the hsp70 free assembly system in a
second ATP-dependent step. hsp90 is required for opening of the steroid binding
pocket and is converted to its ATP-dependent conformation during this second
step. We predict that hsp70 in its ATP-dependent conformation binds initially to
the folded receptor and is then converted to the ADP-dependent form with high
affinity for hydrophobic substrate. This conversion initiates the opening of the
hydrophobic steroid binding pocket such that it can now accept the hydrophobic
binding form of hsp90, which in turn must be converted to its ATP-dependent
conformation for the pocket to be accessible by steroid.
PMID- 10764744
TI - Overexpression of catalase in the mitochondrial or cytosolic compartment
increases sensitivity of HepG2 cells to tumor necrosis factor-alpha-induced
apoptosis.
AB - The sensitivity of HepG2 cells overexpressing catalase in either the cytosolic or
mitochondrial compartment to tumor necrosis factor-alpha (TNF-alpha) and
cycloheximide was studied. Cells overexpressing catalase in the cytosol (C33
cells) and especially in mitochondria (mC5 cells) were more sensitive to TNF
alpha-induced apoptosis than were control cells (Hp cells). The activities of
caspase-3 and -8 were increased by TNF-alpha, with the highest activities found
in mC5 cells. Sodium azide, an inhibitor of catalase, reduced the increased
sensitivity of mC5 and C33 cells to TNF-alpha to the level of toxicity found with
control Hp cells. Azide also decreased the elevated caspase-3 activity of mC5
cells. A pan-caspase inhibitor prevented the TNF-alpha-induced apoptosis and
toxicity produced by catalase overexpression. Addition of H(2)O(2) prevented TNF
alpha-induced apoptosis and caspase activation, an effect prevented by
simultaneous addition of catalase. TNF-alpha plus cycloheximide increased ATP
levels, with higher levels in C33 and mC5 cells compared with Hp cells. TNF-alpha
did not produce apoptosis in mC5 cells maintained in a low energy state. TNF
alpha signaling was not altered by the overexpression of catalase, as activation
of nuclear factor kappaB and AP-1 by TNF-alpha was similar in the three cell
lines. These results suggest that catalase, overexpressed in the cytosolic or
especially the mitochondrial compartment, potentiates TNF-alpha-induced apoptosis
and activation of caspases by removal of H(2)O(2).
PMID- 10764745
TI - Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by
mitotic phosphorylation.
AB - RalBP1 and POB1, the downstream molecules of small GTP-binding protein Ral, are
involved in receptor-mediated endocytosis together with Epsin and Eps15. The
regulation of assembly of the complex of these proteins was examined. RalBP1,
POB1, Epsin, and Eps15 formed a complex with alpha-adaptin of AP-2 in Chinese
hamster ovary cells, but the formation was reduced in mitotic phase. RalBP1,
POB1, Epsin, and Eps15 were all phosphorylated in mitotic phase. The
phosphorylated forms of POB1 and Epsin were recognized by the antibody MPM2,
which is known to detect mitotic phosphoproteins. POB1 and Epsin were
phosphorylated by p34(cdc2) kinase in vitro. Their phosphorylation sites
(Ser(411) of POB1 and Ser(357) of Epsin) were determined. Phosphorylated Epsin
and Epsin(S357D) formed a complex with alpha-adaptin less efficiently than wild
type Epsin. Although the EH domain of POB1 bound directly to Epsin,
phosphorylation of Epsin inhibited the binding. Furthermore, Epsin(S357D) but not
Epsin(S357A) lost the effect of Epsin on the insulin-dependent endocytosis. These
results suggest that phosphorylation of Epsin in mitotic phase inhibits receptor
mediated endocytosis by disassembly of its complex with POB1 and alpha-adaptin.
PMID- 10764746
TI - TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF)
receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits
nuclear factor-kappa B activation.
AB - CD40 belongs to the tumor necrosis factor (TNF) receptor family. CD40 signaling
involves the recruitment of TNF receptor-associated factors (TRAFs) to its
cytoplasmic domain. We have identified a novel intracellular CD40-binding protein
termed TRAF and TNF receptor-associated protein (TTRAP) that also interacts with
TNF-R75 and CD30. The region of the CD40 cytoplasmic domain that is required for
TTRAP association overlaps with the TRAF6 recognition motif. Association of TTRAP
with CD40 increases profoundly in response to treatment of cells with CD40L.
Interestingly, TTRAP also associates with TRAFs, with the highest affinity for
TRAF6. In transfected cells, TTRAP inhibits in a dose-dependent manner the
transcriptional activation of a nuclear factor-kappaB (NF-kappaB)-dependent
reporter mediated by CD40, TNF-R75 or Phorbol 12-myristate 13-acetate (PMA) and
to a lesser extent by TRAF2, TRAF6, TNF-alpha, or interleukin-1beta (IL-1beta).
TTRAP does not affect stimulation of NF-kappaB induced by overexpression of the
NF-kappaB-inducing kinase (NIK), the IkappaB kinase alpha (IKKalpha), or the NF
kappaB subunit P65/RelA, suggesting it acts upstream of the latter proteins. Our
results indicate that we have isolated a novel regulatory factor that is involved
in signal transduction by distinct members of the TNF receptor family.
PMID- 10764747
TI - Molecular basis of ligand recognition by integrin alpha5beta 1. II. Specificity
of arg-gly-Asp binding is determined by Trp157 OF THE alpha subunit.
AB - Different beta(1) integrins bind Arg-Gly-Asp (RGD) peptides with differing
specificities, suggesting a role for residues in the alpha subunit in determining
ligand specificity. Integrin alpha(5)beta(1) has been shown to bind with high
affinity to peptides containing an Arg-Gly-Asp-Gly-Trp (RGDGW) sequence but with
relatively low affinity to other RGD peptides. The residues within the ligand
binding pocket that determine this specificity are currently unknown. A cyclic
peptide containing the RGDGW sequence was found to strongly perturb the binding
of the anti-alpha(5) monoclonal antibody (mAb) 16 to alpha(5)beta(1). In
contrast, RGD peptides lacking the tryptophan residue acted as weak inhibitors of
mAb 16 binding. The epitope of mAb 16 has previously been localized to a region
of the alpha(5) subunit that contains Ser(156)-Trp(157). Mutation of Trp(157)
(but not of Ser(156) or surrounding residues) to alanine blocked recognition of
mAb 16 and perturbed the high affinity binding of RGDGW-containing peptides to
alpha(5)beta(1). The same mutation also abrogated recognition of the
alpha(5)beta(1)-specific ligand peptide Arg-Arg-Glu-Thr-Ala-Trp-Ala (RRETAWA).
Based on these findings, we propose that Trp(157) of alpha(5) participates in a
hydrophobic interaction with the tryptophan residue in RGDGW, and that this
interaction determines the specificity of alpha(5)beta(1) for RGDGW-containing
peptides. Since the RGD sequence is recognized predominantly by amino acid
residues on the beta(1) subunit, our results suggest that Trp(157) of alpha(5)
must lie very close to these residues. Our findings therefore provide new
insights into the structure of the ligand-binding pocket of alpha(5)beta(1).
PMID- 10764748
TI - Molecular basis of ligand recognition by integrin alpha 5beta 1. I. Specificity
of ligand binding is determined by amino acid sequences in the second and third
NH2-terminal repeats of the alpha subunit.
AB - The NH(2)-terminal portion (putative ligand-binding domain) of alpha subunits
contains 7 homologous repeats, the last 3 or 4 of which possess divalent cation
binding sequences. These repeats are predicted to form a seven-bladed beta
propeller structure. To map ligand recognition sites on the alpha(5) subunit we
have taken the approach of constructing and expressing alpha(V)/alpha(5)
chimeras. Although the NH(2)-terminal repeats of alpha(5) and alpha(V) are >50%
identical at the amino acid level, alpha(5)beta(1) and alpha(V)beta(1) show
marked differences in their ligand binding specificities. Thus: (i) although both
integrins recognize the Arg-Gly-Asp (RGD) sequence in fibronectin, the
interaction of alpha(5)beta(1) but not of alpha(V)beta(1) with fibronectin is
strongly dependent on the "synergy" sequence Pro-His-Ser-Arg-Asn; (ii)
alpha(5)beta(1) binds preferentially to RGD peptides in which RGD is followed by
Gly-Trp (GW) whereas alpha(V)beta(1) has a broader specificity; (iii) only
alpha(5)beta(1) recognizes peptides containing the sequence Arg-Arg-Glu-Thr-Ala
Trp-Ala (RRETAWA). Therefore, amino acid residues involved in ligand recognition
by alpha(5)beta(1) can potentially be identified in gain-of-function experiments
by their ability to switch the ligand binding properties of alpha(V)beta(1) to
those of alpha(5)beta(1). By introducing appropriate restriction enzyme sites, or
using site-directed mutagenesis, parts of the NH(2)-terminal repeats of alpha(V)
were replaced with the corresponding regions of the alpha(5) subunit. Chimeric
subunits were expressed on the surface of Chinese hamster ovary-B2 cells (which
lack endogenous alpha(5)) as heterodimers with hamster beta(1). Stable cell lines
were generated and tested for their ability to attach to alpha(5)beta(1)
selective ligands. Our results demonstrate that: (a) the first three NH(2)
terminal repeats contain the amino acid sequences that determine ligand binding
specificity and the same repeats include the epitopes of function blocking anti
alpha subunit mAbs; (b) the divalent cation-binding sites (in repeats 4-7) do not
confer alpha(5)beta(1)- or alpha(V)beta(1)-specific ligand recognition; (c) amino
acid residues Ala(107)-Tyr(226) of alpha(5) (corresponding approximately to
repeats 2 and 3) are sufficient to change all the ligand binding properties of
alpha(V)beta(1) to those of alpha(5)beta(1); (d) swapping a small part of a
predicted loop region of alpha(V) with the corresponding region of alpha(5)
(Asp(154)-Ala(159)) is sufficient to confer selectivity for RGDGW and the ability
to recognize RRETAWA.
PMID- 10764749
TI - RGS4 binds to membranes through an amphipathic alpha -helix.
AB - RGS4, a mammalian GTPase-activating protein for G protein alpha subunits,
requires its N-terminal 33 amino acids for plasma membrane localization and
biological activity (Srinivasa, S. P., Bernstein, L. S., Blumer, K. J., and
Linder, M. E. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 5584-5589). In this
study, we tested the hypothesis that the N-terminal domain mediates membrane
binding by forming an amphipathic alpha-helix. RGS4 bound to liposomes containing
anionic phospholipids in a manner dependent on the first 33 amino acids. Circular
dichroism spectroscopy of a peptide corresponding to amino acids 1-31 of RGS4
revealed that the peptide adopted an alpha-helical conformation in the presence
of anionic phospholipids. Point mutations that either neutralized positive
charges on the hydrophilic face or substituted polar residues on the hydrophobic
face of the model helix disrupted plasma membrane targeting and biological
activity of RGS4 expressed in yeast. Recombinant mutant proteins were active as
GTPase-activating proteins in solution but exhibited diminished binding to
anionic liposomes. Peptides corresponding to mutants with the most pronounced
phenotypes were also defective in forming an alpha-helix as measured by circular
dichroism spectroscopy. These results support a model for direct interaction of
RGS4 with membranes through hydrophobic and electrostatic interactions of an N
terminal alpha-helix.
PMID- 10764750
TI - Site-directed chemical labeling of extracellular loops in a membrane protein. The
topology of the Na,K-ATPase alpha-subunit.
AB - We have mapped the membrane topology of the renal Na,K-ATPase alpha-subunit by
using a combination of introduced cysteine mutants and surface labeling with a
membrane impermeable Cys-directed reagent, N-biotinylaminoethyl
methanethiosulfonate. To begin our investigation, two cysteine residues (Cys(911)
and Cys(964)) in the wild-type alpha-subunit were substituted to create a
background mutant devoid of exposed cysteines (Lutsenko, S., Daoud, S., and
Kaplan, J. H. (1997) J. Biol. Chem. 272, 5249-5255). Into this background
construct were then introduced single cysteines in each of the five putative
extracellular loops (P118C, T309C, L793C, L876C, and M973C) and the resulting
alpha-subunit mutants were co-expressed with the beta-subunit in baculovirus
infected insect cells. All of our expressed Na,K-ATPase mutants were functionally
active. Their ATPase, phosphorylation, and ouabain binding activities were
measured, and the turnover of the phosphoenzyme intermediate was close to the
wild-type enzyme, suggesting that they are folded properly in the infected cells.
Incubation of the insect cells with the cysteine-selective reagent revealed
essentially no labeling of the alpha-subunit of the background construct and
labeling of all five mutants with single cysteine residues in putative
extracellular loops. Two additional mutants, V969C and L976C, were created to
further define the M9M10 loop. The lack of labeling for these two mutants showed
that although Met(973) is apparently exposed, Val(969) and Leu(976) are not,
demonstrating that this method may also be utilized to define membrane aqueous
boundaries of membrane proteins. Our labeling studies are consistent with a
specific 10-transmembrane segment model of the Na,K-ATPase alpha-subunit. This
strategy utilized only functional Na,K-ATPase mutants to establish the membrane
topology of the entire alpha-subunit, in contrast to most previously applied
methods.
PMID- 10764751
TI - Monomeric gamma -tubulin nucleates microtubules.
AB - gamma-Tubulin is required for nucleation and polarized organization of
microtubules in vivo. The mechanism of microtubule nucleation by gamma-tubulin
and the role of associated proteins is not understood. Here we show that in vitro
translated monomeric gamma-tubulin nucleates microtubules by lowering the size of
the nucleus from seven to three tubulin subunits. In capping the minus end with
high affinity (10(10) m(-1)) and a binding stoichiometry of one molecule of gamma
tubulin/microtubule, gamma-tubulin establishes the critical concentration of the
plus end in the medium and prevents minus end growth. gamma-Tubulin interacts
strongly with beta-tubulin. A structural model accounts for these results.
PMID- 10764752
TI - ATP crossing the cell plasma membrane generates an ionic current in xenopus
oocytes.
AB - The presence of ATP within cells is well established. However, ATP also operates
as an intercellular signal via specific purinoceptors. Furthermore, nonsecretory
cells can release ATP under certain experimental conditions. To measure ATP
release and membrane currents from a single cell simultaneously, we used Xenopus
oocytes. We simultaneously recorded membrane currents and luminescence. Here, we
show that ATP release can be triggered in Xenopus oocytes by hyperpolarizing
pulses. ATP release (3.2 +/- 0.3 pmol/oocyte) generated a slow inward current
(2.3 +/- 0.1 microA). During hyperpolarizing pulses, the permeability for ATP(4-)
was more than 4000 times higher than that for Cl(-). The sensitivity to GdCl(3)
(0. 2 mm) of hyperpolarization-induced ionic current, ATP release and E-ATPase
activity suggests their dependence on stretch-activated ion channels. The
pharmacological profile of the current inhibition coincides with the inhibition
of ecto-ATPase activity. This enzyme is highly conserved among species, and in
humans, it has been cloned and characterized as CD39. The translation, in Xenopus
oocytes, of human CD39 mRNA encoding enhances the ATP-supported current,
indicating that CD39 is directly or indirectly responsible for the
electrodiffusion of ATP.
PMID- 10764754
TI - Functional mapping of the GAGA factor assigns its transcriptional activity to the
C-terminal glutamine-rich domain.
AB - GAGA is a nuclear protein encoded by the Trithorax-like gene in Drosophila that
is expressed in at least two isoforms generated by alternative splicing. By means
of its specific interaction with DNA, GAGA has been involved in several nuclear
transactions including regulation of gene expression. Here we have studied the
GAGA(519) isoform as a transcription factor. In vitro, the transactivation domain
has been assigned to the 93 C-terminal residues that correspond to a glutamine
rich domain (Q-domain). It presents an internal modular structure and acts
independently of the rest of the protein. In vivo, in Drosophila SL2 cells, Q
domain can transactivate reporter genes either in the form of GAGA or Gal4BD-Q
fusions, whereas a GAGA mutant deleted of the Q-domain cannot. Our results give
support to the notion that GAGA can function as a transcription activating
factor.
PMID- 10764753
TI - Glc7p protein phosphatase inhibits expression of glutamine-fructose-6-phosphate
transaminase from GFA1.
AB - Inhibitor-1 (I-1) is a specific inhibitor of protein phosphatase-1 (PP1). We
assayed the ability of I-1 to inhibit Saccharomyces cerevisiae PP1, Glc7p, in
vivo. Glc7p like other PP1 catalytic subunits associates with a variety of
noncatalytic subunits, and Glc7p holoenzymes perform distinct physiological
roles. Our results show that I-1 inhibits Glc7p holoenzymes that regulate
transcription and mitosis, but holoenzymes responsible for meiosis and glycogen
metabolism were unaffected. Additionally, we exploited a genetic screen for
mutants that were dependent on I-1 to grow. This scheme can identify processes
that are negatively regulated by Glc7p-catalyzed dephosphorylation. In this paper
I-1-dependent gfa1 mutations were analyzed in detail. GFA1 encodes glutamine
fructose-6-phosphate transaminase. One or more phosphorylated proteins activate
GFA1 transcription because the pheromone response and Pkc1p/mitogen-activated
protein kinase pathways positively regulate GFA1 transcription. Our findings show
that an I-1-sensitive Glc7p holoenzyme reduces GFA1 transcription. Therefore,
GFA1 is a member of a growing list of genes that are negatively regulated by
Glc7p dephosphorylation.
PMID- 10764755
TI - A dynamic model for bilirubin binding to human serum albumin.
AB - Site-directed mutagenesis of human serum albumin was used to study the role of
various amino acid residues in bilirubin binding. A comparison of thermodynamic,
proteolytic, and x-ray crystallographic data from previous studies allowed a
small number of amino acid residues in subdomain 2A to be selected as targets for
substitution. The following recombinant human serum albumin species were
synthesized in the yeast species Pichia pastoris: K195M, K199M, F211V, W214L,
R218M, R222M, H242V, R257M, and wild type human serum albumin. The affinity of
bilirubin was measured by two independent methods and found to be similar for all
human serum albumin species. Examination of the absorption and circular dichroism
spectra of bilirubin bound to its high affinity site revealed dramatic
differences between the conformations of bilirubin bound to the above human serum
albumin species. The absorption and circular dichroism spectra of bilirubin bound
to the above human serum albumin species in aqueous solutions saturated with
chloroform were also examined. The effect of certain amino acid substitutions on
the conformation of bound bilirubin was altered by the addition of chloroform. In
total, the present study suggests a dynamic, unusually flexible high affinity
binding site for bilirubin on human serum albumin.
PMID- 10764756
TI - The additional 165 amino acids in the B protein of Escherichia coli DNA gyrase
have an important role in DNA binding.
AB - DNA gyrase is the only enzyme known to negatively supercoil DNA. The enzyme is a
heterotetramer of A(2)B(2) subunit composition. Alignment of the primary sequence
of gyrase B (GyrB) from various species shows that they can be grouped into two
classes. The GyrB of Gram-negative eubacteria has a stretch of about 165 amino
acids in the C-terminal half, which is lacking in other GyrB subunits and type II
topoisomerases. In Escherichia coli, no function has so far been attributed to
this stretch. In this study, we have tried to assess the function of this region
both in vivo and in vitro. A deletant (GyrBDelta160) lacking this region is non
functional in vivo. The holoenzyme reconstituted from gyrase A (GyrA) and
GyrBDelta160 shows reduced but detectable supercoiling and quinolone-induced
cleavage activity in vitro. GyrBDelta160 retains its ability to bind to GyrA and
novobiocin. However, when reconstituted with GyrA, the deletant shows greatly
impaired DNA binding. The intrinsic ATPase activity of the GyrBDelta160 is
comparable to that of wild type GyrB, but this activity is not stimulated by DNA.
These studies indicate that the additional stretch present in GyrB is essential
for the DNA binding ability of E. coli gyrase.
PMID- 10764757
TI - Mass spectrometry unravels disulfide bond formation as the mechanism that
activates a molecular chaperone.
AB - The heat shock protein Hsp33 is a very potent molecular chaperone with a
distinctive mode of functional regulation; its activity is redox-regulated. In
its reduced form all six cysteinyl residues of Hsp33 are present as thiols, and
Hsp33 displays no folding helper activity. Exposure of Hsp33 to oxidizing
conditions like H(2)O(2), however, rapidly converts Hsp33 into an efficient
molecular chaperone. Activated Hsp33 binds tightly to refolding intermediates of
chemically denatured luciferase and suppresses efficiently their aggregation in
vitro. Matrix-assisted laser desorption/ionization-mass spectrometry peptide
mapping in combination with in vitro and on target protein chemical modification
showed that this activation process of Hsp33 is accompanied by the formation of
two intramolecular disulfide bonds within Hsp33: Cys(232)-S-S-Cys(234) and
Cys(265)-S-S-Cys(268). Cys(141), although not involved in disulfide bond
formation, was found highly reactive toward chemical modifications. In contrast,
Cys(239) is readily accessible under reducing conditions but becomes poorly
accessible though still reduced when Hsp33 is in its active state. This indicates
a significant conformational change during the activation process of Hsp33. Mass
spectrometry, thus, unraveled a novel molecular mechanism by which alteration of
the disulfide bond structure, as a result of changes in the cellular redox
potential, results in the activation of a molecular chaperone.
PMID- 10764758
TI - Enzymatic activity of the Src homology 2 domain-containing inositol phosphatase
is regulated by a plasma membrane location.
AB - The negative regulatory role of the Src homology 2 domain-containing inositol 5
phosphatase (SHIP) has been invoked in a variety of receptor-mediated signaling
pathways. In B lymphocytes, co-clustering of antigen receptor surface
immunoglobulin with FcgammaRIIb promotes the negative effects of SHIP, but how
SHIP activity is regulated is unknown. To explore this issue, we investigated the
effect of SHIP phosphorylation, receptor tyrosine engagement by its Src homology
2 domain, and membrane recruitment of SHIP on its enzymatic activity. We examined
two SHIP phosphorylation kinase candidates, Lyn and Syk, and observed that the
Src protein-tyrosine kinase, Lyn is far superior to Syk in its ability to
phosphorylate SHIP both in vitro and in vivo. However, we found a minimal effect
of phosphorylation or receptor tyrosine engagement of SHIP on its enzymatic
activity, whereas membrane localization of SHIP significantly reduced cellular
phosphatidylinositol 3,4, 5-triphosphate levels. Based on our results, we propose
that a membrane localization of SHIP is the crucial event in the induction of its
phosphatase effects.
PMID- 10764759
TI - Transcriptional regulation of the Drosophila raf proto-oncogene by Drosophila
STAT during development and in immune response.
AB - The Drosophila raf (D-raf) gene promoter contains a recognition consensus
sequence for Drosophila STAT (D-STAT). By band mobility shift assay, we detected
a factor binding to the D-STAT-recognition sequence in extracts of cultured
Drosophila cells treated with vanadate peroxide. UV-cross-linking analyses
suggested the size of the binding factor to be almost same as that of D-STAT.
Furthermore, the binding activity was increased in cells cotransfected with HOP
and D-STAT expression plasmids. These results strongly suggest that D-STAT binds
to the D-STAT recognition sequence in the D-raf gene promoter. Transient
luciferase expression assay using Schneider 2 cells indicated that the D-raf gene
promoter is activated by D-STAT through the D-STAT-binding site. Furthermore,
analyses with transgenic flies carrying Draf-lacZ fusion genes with and without
mutations in the D-STAT-binding site pointed to an important role in D-raf gene
promoter activity throughout development. We also found that the D-STAT-binding
site is required for injury-induced activation of the D-raf gene promoter. Here
we propose that D-STAT can participate in regulation of the mitogen-activated
protein kinase cascade through D-raf gene activation.
PMID- 10764760
TI - Transactivation of naturally occurring HIV-1 long terminal repeats by the JNK
signaling pathway. The most frequent naturally occurring length polymorphism
sequence introduces a novel binding site for AP-1 factors.
AB - To study the role of MAPK cascades in the regulation of naturally occurring human
immunodeficiency virus type 1 long terminal repeats (HIV-1 LTRs), we analyzed
several HIV-1 LTRs from patients at different stages of disease progression. One
of these naturally occurring HIV-1 LTRs contains an insertion termed the most
frequent naturally occurring length polymorphism (MFNLP) and exhibited high
inducibility upon T cell activation. We found that the protein kinase mixed
lineage kinase 3/src-homology 3 domain-containing proline-rich kinase, a specific
activator of the stress-activated protein kinase (SAPK)/JNK signaling pathway in
T lymphocytes, induces high transcriptional activation of this promoter. Promoter
inducibility is inhibited by the SAPK/JNK inhibitor, the JNK binding domain of
the JNK interacting protein 1, and Tam-67 (N-terminal deletion mutant of c-Jun).
In electrophoretic mobility shift assay, several protein complexes were found to
bind to the MFNLP sequence in T cells. We identified AP-1 factors c-Fos and JunB
as MFNLP-binding proteins, whose binding is abolished by introducing point
mutations in the 3'-half of the MFNLP sequence. Introduction of these point
mutations into the MFNLP containing HIV-1 LTR reduced src-homology 3 domain
containing proline-rich kinase -mediated transactivation. These data indicate
that the AP-1-like binding site in the MFNLP sequence gives rise to a higher
inducibility of natural HIV-LTRs by the SAPK/JNK signaling pathway.
PMID- 10764761
TI - Dimerization of the insulin-like growth factor II/mannose 6-phosphate receptor.
AB - The insulin-like growth factor II/mannose 6-phosphate receptor (IGF2R) interacts
with lysosomal enzymes through two binding domains in its extracytoplasmic
domain. We report in the accompanying article (Byrd, J. C., and MacDonald, R. G.
(2000) J. Biol. Chem. 275, 18638-18646) that only one of the two extracytoplasmic
mannose 6-phosphate (Man-6-P) binding domains is necessary for high affinity Man
6-P ligand binding, suggesting that, like the cation-dependent Man-6-P receptor,
oligomerization of the IGF2R contributes to high affinity interaction with
lysosomal enzymes. In the present study, we have directly characterized both
naturally occurring and engineered forms of the IGF2R for their ability to form
oligomeric structures. Whereas gel filtration chromatography suggested that
purified bovine IGF2R species exist in a monomeric form, native gel
electrophoresis allowed for the separation of dimeric and monomeric forms of the
receptors with distinct phosphomannosyl ligand binding characteristics. The
ability of the IGF2R to form oligomeric complexes was confirmed and localized to
the extracytoplasmic domain through the use of epitope-tagged soluble IGF2R
constructs bearing deletions of the transmembrane and cytoplasmic domains.
Finally, chimeric receptors were engineered containing the extracytoplasmic and
transmembrane domains of the IGF2R fused to the cytoplasmic domain of the
epidermal growth factor receptor with which dimerization of the chimeras could be
monitored by measuring autophosphorylation. Collectively, these results show that
the IGF2R is capable of forming oligomeric complexes, most likely dimers, in the
absence of Man-6-P ligands.
PMID- 10764762
TI - Identification and characterization of leukocyte-associated Ig-like receptor-1 as
a major anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells.
AB - SHP-1, an SH2 domain-containing tyrosine phosphatase, has a crucial role in
hematopoiesis. Here we report that SHP-1 is associated with two major tyrosine
phosphorylated proteins in hematopoietic cells treated with the tyrosine
phosphatase inhibitor, pervanadate. One of the proteins corresponds to leukocyte
associated Ig-like receptor-1 (LAIR-1), a recently cloned transmembrane protein.
Molecular cloning revealed four isoforms of the protein. LAIR-1 is hyper
phosphorylated on tyrosyl residues in cells overexpressing a catalytically
inactive mutant form of SHP-1 as well as in pervanadate-treated cells. An
antibody against the extracellular domain of the protein also induced its
tyrosine phosphorylation. Tyrosine-phosphorylated LAIR-1 specifically interacts
with SHP-1 but not with SHP-2, a structurally related tyrosine phosphatase. Using
site-specific mutagenesis, we demonstrated that Tyr(233) and Tyr(263), each
embedded in an immunoreceptor tyrosine-based inhibitory motif, are responsible
for tyrosine phosphorylation of LAIR-1 and recruitment of SHP-1. Both tyrosyl
residues are required for SHP-1 binding. Protein kinases responsible for tyrosine
phosphorylation of LAIR-1 may belong to the Src family since PP1, a Src family
kinase inhibitor, significantly inhibited its phosphorylation. As a major binding
protein of SHP-1 on the plasma membrane, LAIR-1 may play an important role in
hematopoietic cell signaling.
PMID- 10764763
TI - Role of arginine 129 in heparin binding and activation of antithrombin.
AB - The contribution of Arg(129) of the serpin, antithrombin, to the mechanism of
allosteric activation of the protein by heparin was determined from the effect of
mutating this residue to either His or Gln. R129H and R129Q antithrombins bound
pentasaccharide and full-length heparins containing the antithrombin recognition
sequence with similar large reductions in affinity ranging from 400- to 2500-fold
relative to the control serpin, corresponding to a loss of 28-35% of the binding
free energy. The salt dependence of pentasaccharide binding showed that the
binding defect of the mutant serpin resulted from the loss of approximately 2
ionic interactions, suggesting that Arg(129) binds the pentasaccharide
cooperatively with other residues. Rapid kinetic studies showed that the mutation
minimally affected the initial low affinity binding of heparin to antithrombin,
but greatly affected the subsequent conformational activation of the serpin
leading to high affinity heparin binding, although not enough to disfavor
activation. Consistent with these findings, the mutant antithrombin was normally
activated by heparin for accelerated inhibition of factor Xa and thrombin. These
results support an important role for Arg(129) in an induced-fit mechanism of
heparin activation of antithrombin wherein conformational activation of the
serpin positions Arg(129) and other residues for cooperative interactions with
the heparin pentasaccharide so as to lock the serpin in the activated state.
PMID- 10764764
TI - NF-Y and Sp1 cooperate for the transcriptional activation and cAMP response of
human tissue inhibitor of metalloproteinases-2.
AB - The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of
MMPs (TIMPs) is a key determinant in the homeostasis of the extracellular matrix.
We have identified two cis-acting elements involved in the transcriptional
regulation of TIMP-2. The first is an inverted CCAAT box located at position -73
to -69 in the TIMP-2 promoter that binds the transcription factor NF-Y. The
second is a GAGGAGGGGG motif located at position -107 to -98, that binds the
transcription factors Sp1 and Sp3. NF-Y and Sp1 cooperate for the basal
transcription activity of the promoter. We then determined that TIMP-2 is
transcriptionally up-regulated by cAMP analogs. Up-regulation of TIMP-2 by
dibutyryl cAMP is a delayed response that requires de novo protein synthesis and
does not affect RNA stability. The NF-Y and the Sp1 binding site are both
involved in cAMP-dependent up-regulation of TIMP-2. Whereas NF-Y is essential for
cAMP mediated regulation, Sp1 alone is not sufficient but enhances the activity
of NF-Y. Dibutyryl cAMP has no effect on the expression of MMP-2 and MMP-9 and
switches the MMP-TIMP balance in favor of the inhibitor.
PMID- 10764766
TI - Stomachs of mice lacking the gastric H,K-ATPase alpha -subunit have achlorhydria,
abnormal parietal cells, and ciliated metaplasia.
AB - The H,K-ATPase of the gastric parietal cell is the most critical component of the
ion transport system mediating acid secretion in the stomach. To study the
requirement of this enzyme in the development, maintenance, and function of the
gastric mucosa, we used gene targeting to prepare mice lacking the alpha-subunit.
Homozygous mutant (Atp4a(-/-)) mice appeared healthy and exhibited normal
systemic electrolyte and acid-base status but were achlorhydric and
hypergastrinemic. Immunocytochemical, histological, and ultrastructural analyses
of Atp4a(-/-) stomachs revealed the presence of chief cells, demonstrating that
the lack of acid secretion does not interfere with their differentiation.
Parietal cells were also present in normal numbers, and despite the absence of
alpha-subunit mRNA and protein, the beta-subunit was expressed. However, Atp4a(-/
) parietal cells had dilated canaliculi and lacked typical canalicular microvilli
and tubulovesicles, and subsets of these cells contained abnormal mitochondria
and/or massive glycogen stores. Stomachs of adult Atp4a(-/-) mice exhibited
metaplasia, which included the presence of ciliated cells. We conclude that
ablation of the H,K-ATPase alpha-subunit causes achlorhydria and
hypergastrinemia, severe perturbations in the secretory membranes of the parietal
cell, and metaplasia of the gastric mucosa; however, the absence of the pump
appears not to perturb parietal cell viability or chief cell differentiation.
PMID- 10764765
TI - Mechanism and regulation of calcium/calmodulin-dependent protein kinase II
targeting to the NR2B subunit of the N-methyl-D-aspartate receptor.
AB - Calcium influx through the N-methyl-d-aspartate (NMDA)-type glutamate receptor
and activation of calcium/calmodulin-dependent kinase II (CaMKII) are critical
events in certain forms of synaptic plasticity. We have previously shown that
autophosphorylation of CaMKII induces high-affinity binding to the NR2B subunit
of the NMDA receptor (Strack, S., and Colbran, R. J. (1998) J. Biol. Chem. 273,
20689-20692). Here, we show that residues 1290-1309 in the cytosolic tail of NR2B
are critical for CaMKII binding and identify by site-directed mutagenesis several
key residues (Lys(1292), Leu(1298), Arg(1299), Arg(1300), Gln(1301), and
Ser(1303)). Phosphorylation of NR2B at Ser(1303) by CaMKII inhibits binding and
promotes slow dissociation of preformed CaMKII.NR2B complexes. Peptide
competition studies imply a role for the CaMKII catalytic domain, but not the
substrate-binding pocket, in the association with NR2B. However, analysis of
monomeric CaMKII mutants indicates that the holoenzyme structure may also be
important for stable association with NR2B. Residues 1260-1316 of NR2B are
sufficient to direct the subcellular localization of CaMKII in intact cells and
to confer dynamic regulation by calcium influx. Furthermore, mutation of residues
in the CaMKII-binding domain in full-length NR2B bidirectionally modulates
colocalization with CaMKII after NMDA receptor activation, suggesting a dynamic
model for the translocation of CaMKII to postsynaptic targets.
PMID- 10764767
TI - Functional interaction of STAT3 transcription factor with the cell cycle
inhibitor p21WAF1/CIP1/SDI1.
AB - Signal transducers and activators of transcription (STAT) factors are cytoplasmic
proteins that induce gene activation in response to cytokine receptor
stimulation. Following tyrosine phosphorylation, STAT proteins dimerize,
translocate into the nucleus, and activate specific target genes. Activation is
transient, and down-regulation of STAT signaling occurs within a few hours. In
the present study, we show that the cyclin-dependent kinase inhibitor
p21(WAF1/CIP1/SDI1) inhibits STAT3 transcriptional activation. Following leukemia
inhibitory factor stimulation, p21(WAF1/CIP1/SDI1) was found to associate with
STAT3 proteins in coimmunoprecipitation and pull down assays. In vivo,
overexpression of p21(WAF1/CIP1/SDI1) reduced transcriptional activation by STAT3
proteins but did not modify DNA binding activity. Interestingly, pull down
experiments showed that p21(WAF1/CIP1/SDI1) could interact with the CREB-binding
coactivator protein, and inhibition of STAT3 activity by p21(WAF1/CIP1/SDI1) did
not occur when CREB-binding protein was overexpressed. These results suggest a
model by which p21(WAF1/CIP1/SDI1) functions as an inhibitor of STAT3 signaling
and highlight a new activity for this cyclin-dependent kinase inhibitor.
PMID- 10764768
TI - Clarifying the catalytic roles of conserved residues in the amidase signature
family.
AB - Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme
responsible for the hydrolysis of a number of neuromodulatory fatty acid amides,
including the endogenous cannabinoid anandamide and the sleep-inducing lipid
oleamide. FAAH belongs to a large class of hydrolytic enzymes termed the "amidase
signature family," whose members are defined by a conserved stretch of
approximately 130 amino acids termed the "amidase signature sequence." Recently,
site-directed mutagenesis studies of FAAH have targeted a limited number of
conserved residues in the amidase signature sequence of the enzyme, identifying
Ser-241 as the catalytic nucleophile and Lys-142 as an acid/base catalyst. The
roles of several other conserved residues with potentially important and/or
overlapping catalytic functions have not yet been examined. In this study, we
have mutated all potentially catalytic residues in FAAH that are conserved among
members of the amidase signature family, and have assessed their individual roles
in catalysis through chemical labeling and kinetic methods. Several of these
residues appear to serve primarily structural roles, as their mutation produced
FAAH variants with considerable catalytic activity but reduced expression in
prokaryotic and/or eukaryotic systems. In contrast, five mutations, K142A, S217A,
S218A, S241A, and R243A, decreased the amidase activity of FAAH greater than 100
fold without detectably impacting the structural integrity of the enzyme. The pH
rate profiles, amide/ester selectivities, and fluorophosphonate reactivities of
these mutants revealed distinct catalytic roles for each residue. Of particular
interest, one mutant, R243A, displayed uncompromised esterase activity but
severely reduced amidase activity, indicating that the amidase and esterase
efficiencies of FAAH can be functionally uncoupled. Collectively, these studies
provide evidence that amidase signature enzymes represent a large class of serine
lysine catalytic dyad hydrolases whose evolutionary distribution rivals that of
the catalytic triad superfamily.
PMID- 10764769
TI - Species-specific alternative splice mimicry at the growth hormone receptor locus
revealed by the lineage of retroelements during primate evolution.
AB - In humans, growth hormone receptor (GHR) transcripts exist in two isoforms
differing by the retention (GHRfl) or exclusion (GHRd3) of exon 3, whereas in
mice GHRfl is solely expressed. This species-specific expression pattern is
believed to result from an alternative splice event that, on the basis of
conflicting data obtained in humans, has been considered to be tissue-,
developmentally, and/or individual-specific. To decipher the molecular basis of
this unusual trait, we isolated a 6.8-kilobase fragment spanning exon 3 from
individuals expressing GHRfl. Sequence analysis revealed the existence of two 99%
identical retroelements flanking this exon. Unexpectedly, individuals expressing
GHRd3 displayed a 2.7-kilobase deletion involving exon 3, which most likely
results from an ancestral homologous recombination between the two retroelements.
The lineage of these retroelements during primate evolution revealed the species
specificity of the GHRd3 allele. These findings led us to propose a model
underlying the existence of the sole GHRfl allele in most species. Such a
retrovirus-mediated alternative splice mimicry, which clears up several as yet
unexplained phenomena (i.e. the above-mentioned expression data, the Mendelian
inheritance of GHR expression patterns, and the deletion of nonconsecutive exons
in growth hormone resistant patients), represents a novel physiological mechanism
accounting for protein diversity between and within species.
PMID- 10764770
TI - Integrin dependence of brain natriuretic peptide gene promoter activation by
mechanical strain.
AB - Expression of the brain natriuretic peptide (BNP) gene in cultured neonatal rat
ventricular myocytes is activated by mechanical strain in vitro. We explored the
role of cell-matrix contacts in initiating the strain-dependent increment in
human BNP (hBNP) promoter activity. Coating the culture surface with fibronectin
effected a dose-dependent increase in basal hBNP luciferase activity and
amplification of the response to strain. Preincubation of myocytes with an RGD
peptide (GRGDSP) or with soluble fibronectin, each of which would be predicted to
compete for cell-matrix interactions, resulted in a dose-dependent reduction in
strain-dependent hBNP promoter activity. A functionally inert RGE peptide
(GRGESP) was without effect. Using fluorescence-activated cell sorting, we
demonstrated the presence of beta(1), beta(3), and alpha(v)beta(5) integrins in
myocytes as well as non-myocytes and alpha1 only in non-myocytes in our cultures.
Inclusion of antibodies directed against beta(1), beta(3), or alpha(v)beta(5),
but not alpha(1), alpha(2), or cadherin, was effective in blocking the BNP
promoter response to mechanical strain. These same antibodies (anti-beta(3),
beta(1), and -alpha(v)beta(5)) had a similar inhibitory effect on strain
stimulated ERK, p38 MAPK, and, to a lesser extent, JNK activities in these cells.
Cotransfection with chimeric integrin receptors capable of acting as dominant
negative inhibitors of integrin function demonstrated suppression of strain
dependent BNP promoter activity when vectors encoding beta(1) or beta(3), but not
beta(5), alpha(5), or a carboxyl-terminal deletion mutant of beta(3) (beta(3)B),
were employed. These studies underscore the importance of cell-matrix
interactions in controlling cardiac gene expression and suggest a potentially
important role for these interactions in signaling responses to mechanical
stimuli within the myocardium.
PMID- 10764771
TI - Inhibition of phospholipase D by amphiphysins.
AB - Two distinct proteins inhibiting phospholipase D (PLD) activity in rat brain
cytosol were previously purified and identified as synaptojanin and AP180, which
are specific to nerve terminals and associate with the clathrin coat. Two
additional PLD-inhibitory proteins have now been purified and identified as the
amphiphysins I and II, which forms a heterodimer that also associates with the
clathrin coat. Bacterially expressed recombinant amphiphysins inhibited both PLD1
and PLD2 isozymes in vitro with a potency similar to that of brain amphiphysin
(median inhibitory concentration of approximately 15 nm). Expressions of either
amphiphysin in COS-7 cells reduced activity of endogenous PLD as well as
exogenously expressed PLD1 and PLD2. Coprecipitation experiments suggested that
the inhibitory effect of amphiphysins results from their direct interaction with
PLDs. The NH(2) terminus of amphiphysin I was critical for both inhibition of and
binding to PLD. Phosphatidic acid formed by signal-induced PLD is thought to be
required for the assembly of clathrin-coated vesicles during endocytosis. Thus,
the inhibition of PLD by amphiphysins, synaptojanin, and AP180 might play an
important role in synaptic vesicle trafficking.
PMID- 10764772
TI - cDNA cloning, expression, and functional characterization of PI31, a proline-rich
inhibitor of the proteasome.
AB - The primary structure of PI31, a protein inhibitor of the 20 S proteasome, was
deduced by cDNA cloning and sequencing. The human protein has a calculated
molecular weight of 29,792, a value in excellent accord with 31,000, as estimated
by SDS-polyacrylamide gel electrophoresis for purified bovine PI31, and is not
similar to any other protein in current data bases. PI31 is a proline-rich
protein, particularly within its carboxyl-terminal half where 26% of the amino
acids are proline. Wild-type PI31 and various truncation mutants were expressed
in Escherichia coli and purified to homogeneity. Recombinant wild-type PI31
displayed structural and functional properties similar to those of PI31 purified
from bovine red blood cells and inhibited the hydrolysis of protein and peptide
substrates by the 20 S proteasome. Analysis of truncation mutants demonstrated
that proteasome inhibition was conferred by the carboxyl-terminal proline-rich
domain of PI31, which appears to have an extended secondary structure. Inhibition
of the 20 S proteasome by PI31 involved formation a proteasome-PI31 complex. In
addition to its direct inhibition of the 20 S proteasome, PI31 inhibited the
activation of the proteasome by each of two proteasome regulatory proteins, PA700
and PA28. These results suggest that PI31 plays an important role in control of
proteasome function, including that in ubiquitin-dependent pathways of protein
degradation.
PMID- 10764773
TI - Characterization and functional significance of calcium transients in the 2-cell
mouse embryo induced by an autocrine growth factor.
AB - Growth of preimplantation embryos is influenced by autocrine trophic factors that
need to act by the 2-cell stage, but their mode of action is not yet described.
This report shows that late zygote and 2-cell stage mouse embryos responded to
embryo-derived platelet-activating factor (PAF) with transient increases in
intracellular calcium concentration ([Ca(2+)](i)). [Ca(2+)](i) transients were
single global events and were specifically induced by embryo-derived PAF. They
were blocked by inhibition of phospholipase C (U 73122) and an inositol
trisphosphate (IP(3)) receptor antagonist (xestospongin C), indicating the
release of calcium from IP(3)-sensitive intracellular stores. Transients were
also inhibited by the absence of calcium from extracellular medium and partially
inhibited by treatment with dihydropyridine (nifedipine, 10 micrometer), but not
pimozide (an inhibitor of an embryonic T-type calcium channel). (+/-)BAY K8644
(an L-type channel agonist) induced [Ca(2+)](i) transients, yet these were
completely inhibited by nifedipine (10 micrometer). The complete inhibition of
BAY K8644, but only partial inhibition of PAF by nifedipine shows that L-type
channels were only partly responsible for the calcium influx. Depolarization of 2
cell embryos by 50 mm K(+) did not inhibit PAF-induced calcium transients,
showing that the influx channels were not voltage-dependent. Depletion of
intracellular calcium stores by thapsigargin revealed the presence of store
operated channels. The interdependent requirement for IP(3)-sensitive internal
calcium stores and extracellular calcium in the generation of PAF-induced
transients may be explained by a requirement for capacitative calcium entry via
store-operated channels. A functionally important role for the PAF-induced
transients is supported by the observation that inhibition of [Ca(2+)](i)
transients by a PAF-antagonist (WEB 2086) or an intracellular calcium chelator
(1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis-acetoxymethyl
ester; BAPTA-AM) caused marked inhibition of early embryo development. Growth
inhibition by BAPTA-AM was relieved by addition of exogenous PAF.
PMID- 10764774
TI - Functional properties of recombinant type I and type III inositol 1, 4,5
trisphosphate receptor isoforms expressed in COS-7 cells.
AB - Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are ubiquitous intracellular
Ca(2+) release channels whose functional characterization by transfection has
proved difficult due to the background contribution of endogenous channels. In
order to develop a functional assay to measure recombinant channels, we
transiently transfected the rat type I IP(3)R into COS-7 cells. Saponin
permeabilized COS cells transfected with type I IP(3)R showed a 50% increase in
inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release at saturating
[IP(3)] (10 micrometer) but no enhancement at subsaturating [IP(3)] (300 nm).
However, cotransfection of the IP(3)R and human sarco/endoplasmic reticulum
ATPase (SERCA)-2b ATPase cDNA resulted in 60 and 110% increases in Ca(2+) release
at subsaturating and saturating doses of IP(3), respectively. IP(3) or
adenophostin A failed to release (45)Ca(2+) from microsomal vesicles prepared
from cells expressing either type I IP(3)R or SERCA cDNAs alone. However,
microsomal vesicles prepared from cells doubly transfected with IP(3)R and SERCA
cDNAs released 33.0 +/- 0.04% of the A23187-sensitive pool within 30 s of 1
micrometer adenophostin A addition. Similarly, the initial rate of (45)Ca(2+)
influx into oxalate-loaded microsomal vesicles was inhibited by IP(3) only when
the microsomes were prepared from COS cells doubly transfected with SERCA-2b and
IP(3)R DNA. The absence of a functional contribution from endogenous IP(3)Rs has
enabled the use of this assay to measure the Ca(2+) sensitivities of IP(3)
mediated (45)Ca(2+) fluxes through recombinant neuronal type I (SII(+)),
peripheral type I (SII(-)), and type III IP(3)Rs. All three channels displayed a
biphasic dependence upon [Ca(2+)](cyt). Introduction of mutations D2550A and
D2550N in the putative pore-forming region of the type I IP(3)R inhibited IP(3)
mediated (45)Ca(2+) fluxes, whereas the conservative substitution D2550E was
without effect. This assay therefore provides a useful tool for studying the
regulatory properties of individual IP(3)R isoforms as well as for screening pore
mutations prior to more detailed electrophysiological analyses.
PMID- 10764775
TI - A conserved transcription motif suggesting functional parallels between
Caenorhabditis elegans SKN-1 and Cap'n'Collar-related basic leucine zipper
proteins.
AB - In Caenorhabditis elegans, the predicted transcription factor SKN-1 is required
for embryonic endodermal and mesodermal specification and for maintaining
differentiated intestinal cells post-embryonically. The SKN-1 DNA-binding region
is related to the Cap'n'Collar (CNC) family of basic leucine zipper proteins, but
uniquely, SKN-1 binds DNA as a monomer. CNC proteins are absent in C. elegans,
however; and their involvement in the endoderm and mesoderm suggests some
functional parallels to SKN-1. Using a cell culture assay, we show that SKN-1
induces transcription and contains three potent activation domains. The
functional core of one domain is a short motif, the DIDLID element, which is
highly conserved in a subgroup of vertebrate CNC proteins. The DIDLID element is
important for SKN-1-driven transcription, suggesting a likely significance in
other CNC proteins. SKN-1 binds to and activates transcription through the
p300/cAMP-responsive element-binding protein-binding protein (CBP) coactivator,
supporting the genetic prediction that SKN-1 recruits the C. elegans p300/CBP
ortholog, CBP-1. The DIDLID element appears to act independently of p300/CBP,
however, suggesting a distinct conserved target. The evolutionarily preservation
of the DIDLID transcriptional element supports the model that SKN-1 and some CNC
proteins interact with analogous cofactors and may have preserved some similar
functions despite having divergent DNA-binding domains.
PMID- 10764776
TI - Structure-function analysis of the dolichyl phosphate-mannose: protein O
mannosyltransferase ScPmt1p.
AB - Protein O-mannosylation is an essential protein modification. It is initiated at
the endoplasmic reticulum by a family of dolichyl phosphate-mannose:protein O
mannosyltransferases (Pmts), which is evolutionarily conserved from yeast to
humans. Saccharomyces cerevisiae Pmt1p is an integral membrane protein of the
endoplasmic reticulum. ScPmt1p forms a complex with ScPmt2p that is required for
maximum transferase activity. Recently, we proposed a seven-transmembrane
structural model for ScPmt1p. A large, hydrophilic, endoplasmic reticulum
oriented segment is flanked by five amino-terminal and two carboxyl-terminal
membrane-spanning domains. Based on this model, a structure-function analysis of
ScPmt1p was performed. Deletion mutagenesis identified the N-terminal third of
the transferase as being essential for the formation of a functional ScPmt1p
ScPmt2p complex. Deletion of the central hydrophilic loop eliminates
mannosyltransferase activity, but not ScPmt1p-ScPmt2p interactions. Alignment of
all fully characterized PMT family members revealed that this central loop region
contains three highly conserved peptide motifs, which can be considered as
signatures of the PMT family. In addition, a number of invariant amino acid
residues were identified throughout the entire protein sequence. In order to
evaluate the functional significance of these conserved residues site-directed
mutagenesis was performed. We show that several amino acid substitutions in the
conserved motifs significantly reduce ScPmt1p activity. Further, the invariant
residues Arg-64, Glu-78, Arg-138, and Leu-408 are essential for ScPmt1p function.
In particular, Arg-138 is crucial for ScPmt1p-ScPmt2p complex formation.
PMID- 10764777
TI - Tetramerization of glycosylphosphatidylinositol-specific phospholipase C from
Trypanosoma brucei.
AB - Glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC) is an integral
membrane protein in the protozoan parasite Trypanosoma brucei. Enzyme activity
appears to be suppressed in T. brucei, although the polypeptide is readily
detectable. The basis for the apparent quiescence of GPI-PLC is not known.
Protein oligomerization was investigated as a possible mechanism for post
translational regulation of GPI-PLC activity. An equilibrium between monomers,
dimers, and tetramers of purified GPI-PLC was detected by molecular sieving and
shown to be perturbed with specific detergents. Homotetramers dominated in
Nonidet P-40, and dimers and monomers of GPI-PLC were the major species in 3-[(3
cholamidopropyl)dimethylammonio]-1-propanesulfonate. The detergents were
exploited as tools to study the effect of oligomerization on enzyme activity.
Tetrameric GPI-PLC was 3. 6-20-fold more active than the monomeric enzyme.
Tetramer existence was confirmed by chemical cross-linking. In vivo cross-linking
revealed the oligomeric state of GPI-PLC during latency and after enzyme
activation. During quiescence, monomers were the predominant species in T.
brucei. Assembly of tetrameric GPI-PLC occurred when parasites were subjected to
conditions known to activate the enzyme. In Leishmania where heterologous
expression of GPI-PLC causes a GPI deficiency, the enzyme existed as a tetramer.
Hence, oligomerization of GPI-PLC is associated with high enzyme activity both in
vivo and in vitro.
PMID- 10764778
TI - Adenovirus E1A down-regulates LMP2 transcription by interfering with the binding
of stat1 to IRF1.
AB - The LMP2 gene, which encodes a protein required for efficient presentation of
viral antigens, requires both unphosphorylated Stat1 and IRF1 for basal
expression. LMP2 expression is down-regulated by the adenovirus protein E1A,
which binds to Stat1 and CBP/p300, and by the mutant E1A protein RG2, which binds
to Stat1 but not to CBP/p300, but not by the mutant protein Delta2-36, which does
not bind to either Stat1 or CBP/p300. Stat1 and IRF1 associate in untreated cells
and bind as a complex to the overlapping ICS-2/GAS element of the LMP2 promoter.
E1A interferes with the formation of this complex by occupying domains of Stat1
that bind to IRF1. These results reveal how adenovirus infection attenuates LMP2
expression, thereby interfering with the presentation of viral antigens.
PMID- 10764779
TI - The cytochrome bc1 and cytochrome c oxidase complexes associate to form a single
supracomplex in yeast mitochondria.
AB - The mitochondrial electron transport chain complexes are large multisubunit
complexes embedded in the inner membrane. We report here that in the yeast
Saccharomyces cerevisiae, the cytochrome bc(1) and cytochrome c oxidase complexes
co-exist as a larger complex of approximately 1000 kDa in the mitochondrial
membrane. Following solubilization with a mild detergent, the cytochrome bc(1)
cytochrome c oxidase complex remains stable. It was analyzed using the techniques
of gel filtration and blue native-polyacrylamide gel electrophoresis. Direct
physical association of subunits of the cytochrome bc(1) complex with those of
the cytochrome c oxidase complex was verified by co-immunoprecipitation analysis.
Our data indicate that the cytochrome bc(1) complex is exclusively in association
with the cytochrome c oxidase complex in yeast mitochondria. We term this complex
the cytochrome bc(1)-cytochrome c oxidase supracomplex.
PMID- 10764780
TI - A novel 68-kDa adipocyte protein phosphorylated on tyrosine in response to
insulin and osmotic shock.
AB - Osmotic shock can cause insulin resistance in 3T3-L1 adipocytes by inhibiting
insulin activation of glucose transport, p70S6 kinase, glycogen synthesis, and
lipogenesis. By further investigating the relationship between insulin and
hypertonic stress, we have discovered that osmotic shock enhanced by 10-fold the
insulin-stimulated tyrosine phosphorylation of a 68-kDa protein. Phosphorylation
by insulin was maximal after 1 min and was saturated with 50-100 nm insulin. The
effect of sorbitol was completely reversible by 2.5 min. pp68 was a peripheral
protein that was localized to the detergent insoluble fraction of the low density
microsomes but was not associated with the cytoskeleton. Stimulation of the
p42/44 and the p38 MAP kinase pathways by osmotic shock had no effect on pp68
phosphorylation. Treatment of adipocytes with the phosphotyrosine phosphatase
inhibitor phenylarsine oxide also enhanced insulin-activated tyrosine
phosphorylation of pp68 suggesting that osmotic shock may increase pp68
phosphorylation by inhibiting a phosphotyrosine phosphatase. Dissociation of pp68
from the low density microsomes with RNase A indicated that pp68 binds to RNA.
Failure to immunoprecipitate pp68 using antibodies directed against known 60-70
kDa tyrosine-phosphorylated proteins suggest that pp68 may be a novel cellular
target that lies downstream of the insulin receptor.
PMID- 10764781
TI - Transgenic overexpression of hexokinase II in skeletal muscle does not increase
glucose disposal in wild-type or Glut1-overexpressing mice.
AB - Glut1 transgenic mice were bred with transgenic mice that overexpress hexokinase
II in skeletal muscle in order to determine whether whole-body glucose disposal
could be further augmented in mice overexpressing glucose transporters.
Overexpression of hexokinase alone in skeletal muscle had no effect on glucose
transport or metabolism in isolated muscles, nor did it alter blood glucose
levels or the rate of whole-body glucose disposal. Expression of the hexokinase
transgene in the context of the Glut1 transgenic background did not alter glucose
transport in isolated muscles but did cause additional increases in steady-state
glucose 6-phosphate (3.2-fold) and glycogen (7.5-fold) levels compared with
muscles that overexpress the Glut1 transporter alone. Surprisingly, however,
these increases were not accompanied by a change in basal or insulin-stimulated
whole-body glucose disposal in the doubly transgenic mice compared with Glut1
transgenic mice, probably due to an inhibition of de novo glycogen synthesis as a
result of the high levels of steady-state glycogen in the muscles of doubly
transgenic mice (430 micromol/g versus 10 micromol/g in wild-type mice). We
conclude that the hexokinase gene may not be a good target for therapies designed
to counteract insulin resistance or hyperglycemia.
PMID- 10764782
TI - Identification of the functional domain in the transcription factor RTEF-1 that
mediates alpha 1-adrenergic signaling in hypertrophied cardiac myocytes.
AB - Cardiac myocytes respond to alpha(1)-adrenergic receptor stimulation by a
progressive hypertrophy accompanied by the activation of many fetal genes,
including skeletal muscle alpha-actin. The skeletal muscle alpha-actin gene is
activated by signaling through an MCAT element, the binding site of the
transcription enhancer factor-1 (TEF-1) family of transcription factors.
Previously, we showed that overexpression of the TEF-1-related factor (RTEF-1)
increased the alpha(1)-adrenergic response of the skeletal muscle alpha-actin
promoter, whereas TEF-1 overexpression did not. Here, we identified the
functional domains and specific sequences in RTEF-1 that mediate the alpha(1)
adrenergic response. Chimeric TEF-1 and RTEF-1 expression constructs localized
the region responsible for the alpha(1)-adrenergic response to the carboxyl
terminal domain of RTEF-1. Site-directed mutagenesis was used to inactivate eight
serine residues of RTEF-1, not present in TEF-1, that are putative targets of
alpha(1)-adrenergic-dependent kinases. Mutation of a single serine residue, Ser
322, reduced the alpha(1)-adrenergic activation of RTEF-1 by 70% without
affecting protein stability, suggesting that phosphorylation at this serine
residue accounts for most of the alpha(1)-adrenergic response. Thus, these
results demonstrate that RTEF-1 is a direct target of alpha(1)-adrenergic
signaling in hypertrophied cardiac myocytes.
PMID- 10764783
TI - Molecular cloning, expression, and functional analysis of a cis-prenyltransferase
from Arabidopsis thaliana. Implications in rubber biosynthesis.
AB - cis-Prenyltransferase catalyzes the sequential condensation of isopentenyl
diphosphate with allylic diphosphate to synthesize polyprenyl diphosphates that
play vital roles in cellular activity. Despite potential significance of cis
prenyltransferase in plant growth and development, no gene of the enzyme has been
cloned from higher plants. Using sequence information of the conserved region of
cis-prenyltransferase cloned recently from Escherichia coli, Micrococcus luteus,
and yeast, we have isolated and characterized the first plant cis
prenyltransferase from Arabidopsis thaliana. Sequence analysis revealed that the
protein is highly homologous in several conserved regions to cis
prenyltransferases from M. luteus, E. coli, and yeast. In vitro analyses using
the recombinant protein overexpressed in E. coli revealed that the enzyme
catalyzed the formation of polyprenyl diphosphates ranging in carbon number from
100 to 130 with a predominance of C(120). The enzyme exhibited a higher affinity
for farnesyl diphosphate than for geranylgeranyl diphosphate, with the K(m)
values being 0.13 and 3.62 micrometer, respectively, but a lower affinity for
isopentenyl diphosphate, with a K(m) value of 23 micrometer. In vitro rubber
biosynthesis analysis indicated that the Arabidopsis cis-prenyltransferase itself
could not catalyze the formation of higher molecular weight polyprenyl
diphosphates similar to natural rubber. A reverse transcriptase-polymerase chain
reaction analysis showed that the gene was expressed at low levels in Arabidopsis
plant, in which expression of the cis-prenyltransferase in leaf and root was
higher than that in stem, flower, and silique. These results indicate the tissue
specific expression of cis-prenyltransferase and suggest a potential role and
significance of the enzyme in the polyisoprenoid biosynthesis in plants.
PMID- 10764784
TI - Interactions of GroEL/GroES with a heterodimeric intermediate during alpha 2beta
2 assembly of mitochondrial branched-chain alpha-ketoacid dehydrogenase. cis
capping of the native-like 86-kDa intermediate by GroES.
AB - We showed previously that the interaction of an alphabeta heterodimeric
intermediate with GroEL/GroES is essential for efficient alpha(2)beta(2) assembly
of human mitochondrial branched-chain alpha-ketoacid dehydrogenase. In the
present study, we further characterized the mode of interaction between the
chaperonins and the native-like alphabeta heterodimer. The alphabeta heterodimer,
as an intact entity, was found to bind to GroEL at a 1:1 stoichiometry with a
K(D) of 1.1 x 10(-)(7) m. The 1:1 molar ratio of the GroEL-alphabeta complex was
confirmed by the ability of the complex to bind a stoichiometric amount of
denatured lysozyme in the trans cavity. Surprisingly, in the presence of Mg-ADP,
GroES was able to cap the GroEL-alphabeta complex in cis, despite the size of 86
kDa of the heterodimer (with a His(6) tag and a linker). Incubation of the GroEL
alphabeta complex with Mg-ATP, but not AMP-PNP, resulted in the release of alpha
monomers. In the presence of Mg-ATP, the beta subunit was also released but was
unable to assemble with the alpha subunit, and rebound to GroEL. The apparent
differential subunit release from GroEL is explained, in part, by the
significantly higher binding affinity of the beta subunit (K(D) < 4.15 x 10(-9)m)
than the alpha (K(D) = 1.6 x 10(-8)m) for GroEL. Incubation of the GroEL
alphabeta complex with Mg-ATP and GroES resulted in dissociation and discharge of
both the alpha and beta subunits from GroEL. The beta subunit upon binding to
GroEL underwent further folding in the cis cavity sequestered by GroES. This step
rendered the beta subunit competent for reassociation with the soluble alpha
subunit to produce a new heterodimer. We propose that this mechanism is
responsible for the iterative annealing of the kinetically trapped heterodimeric
intermediate, leading to an efficient alpha(2)beta(2) assembly of human branched
chain alpha-ketoacid dehydrogenase.
PMID- 10764785
TI - Mutational analysis of beta '260-309, a sigma 70 binding site located on
Escherichia coli core RNA polymerase.
AB - In eubacteria, the final sigma subunit binds to the core RNA polymerase and
directs transcription initiation from any of its cognate set of promoters.
Previously, our laboratory defined a region of the beta' subunit that interacts
with final sigma(70) in vitro. This region of beta' contained heptad repeat
motifs indicative of coiled coils. In this work, we used 10 single point
mutations of the predicted coiled coils, located within residues 260-309 of
beta', to look at disruption of the final sigma(70)-core interaction. Several of
the mutants were defective for binding final sigma(70) in vitro. Of these
mutants, three (R275Q, E295K, and A302D) caused cells to be inviable in an in
vivo assay in which the mutant beta' is the sole source of beta' subunit for the
cell. All of the mutants were able to assemble into the core enzyme; however,
R275Q, E295K, A302D were defective for Efinal sigma(70) holoenzyme formation.
Several of the mutants were also defective for holoenzyme assembly with various
minor final sigma factors. In the recently published crystal structure of Thermus
aquaticus core RNA polymerase (Zhang, G., Campbell, E. A., Minakhin, L., Richter,
C., Severinov, K. , and Darst, S. A. (1999) Cell 98, 811-824), the region
homologous to beta'(260-309) of Escherichia coli forms a coiled coil. Modeling of
our mutations onto that coiled coil places the most defective mutations on one
face of the coiled coil.
PMID- 10764786
TI - The p53 tumor suppressor stimulates the catalytic activity of human topoisomerase
IIalpha by enhancing the rate of ATP hydrolysis.
AB - DNA topoisomerase II is an essential nuclear enzyme for proliferation of
eukaryotic cells and plays important roles in many aspects of DNA processes. In
this report, we have demonstrated that the catalytic activity of topoisomerase
IIalpha, as measured by decatenation of kinetoplast DNA and by relaxation of
negatively supercoiled DNA, was stimulated approximately 2-3-fold by the tumor
suppressor p53 protein. In order to determine the mechanism by which p53
activates the enzyme, the effects of p53 on the topoisomerase IIalpha-mediated
DNA cleavage/religation equilibrium were assessed using the prototypical
topoisomerase II poison, etoposide. p53 had no effect on the ability of the
enzyme to make double-stranded DNA break and religate linear DNA, indicating that
the stimulation of the enzyme catalytic activity by p53 was not due to alteration
in the formation of covalent cleavable complexes formed between topoisomerase
IIalpha and DNA. The effects of p53 on the catalytic inhibition of topoisomerase
IIalpha were examined using a specific catalytic inhibitor, ICRF-193, which
blocks the ATP hydrolysis step of the enzyme catalytic cycle. Clearly manifested
in decatenation and relaxation assays, p53 reduced the catalytic inhibition of
topoisomerase IIalpha by ICRF-193. ATP hydrolysis assays revealed that the ATPase
activity of topoisomerase IIalpha was specifically enhanced by p53.
Immunoprecipitation experiments revealed that p53 physically interacts with
topoisomerase IIalpha to form molecular complexes without a double-stranded DNA
intermediary in vitro. To investigate whether p53 stimulates the catalytic
activity of topoisomerase II in vivo, we expressed wild-type and mutant p53 in
Saos-2 osteosarcoma cells lacking functional p53. Wild-type, but not mutant, p53
stimulated topoisomerase II activity in nuclear extract from these transfected
cells. Our data propose a new role for p53 to modulate the catalytic activity of
topoisomerase IIalpha. Taken together, we suggest that the p53-mediated response
of the cell cycle to DNA damage may involve activation of topoisomerase IIalpha.
PMID- 10764787
TI - Molecular cloning of allene oxide cyclase. The enzyme establishing the
stereochemistry of octadecanoids and jasmonates.
AB - Allene oxide cyclase (EC ) catalyzes the stereospecific cyclization of an
unstable allene oxide to (9S,13S)-12-oxo-(10,15Z)-phytodienoic acid, the ultimate
precursor of jasmonic acid. This dimeric enzyme has previously been purified, and
two almost identical N-terminal peptides were found, suggesting allene oxide
cyclase to be a homodimeric protein. Furthermore, the native protein was N
terminally processed. Using degenerate primers, a polymerase chain reaction
fragment could be generated from tomato, which was further used to isolate a full
length cDNA clone of 1 kilobase pair coding for a protein of 245 amino acids with
a molecular mass of 26 kDa. Whereas expression of the whole coding region failed
to detect allene oxide cyclase activity, a 5'-truncated protein showed high
activity, suggesting that additional amino acids impair the enzymatic function.
Steric analysis of the 12-oxophytodienoic acid formed by the recombinant enzyme
revealed exclusive (>99%) formation of the 9S,13S enantiomer. Exclusive formation
of this enantiomer was also found in wounded tomato leaves. Southern analysis and
genetic mapping revealed the existence of a single gene for allene oxide cyclase
located on chromosome 2 of tomato. Inspection of the N terminus revealed the
presence of a chloroplastic transit peptide, and the location of allene oxide
cyclase protein in that compartment could be shown by immunohistochemical
methods. Concomitant with the jasmonate levels, the accumulation of allene oxide
cyclase mRNA was transiently induced after wounding of tomato leaves.
PMID- 10764788
TI - Cystic fibrosis mutations lead to carboxyl-terminal fragments that highlight an
early biogenesis step of the cystic fibrosis transmembrane conductance regulator.
AB - Inefficient delivery of the cystic fibrosis transmembrane conductance regulator
(CFTR) to the surface of cells contributes to disease in the majority of cystic
fibrosis patients. Analysis of cystic fibrosis-associated missense mutations in
the first nucleotide binding domain (NBD1), including A455E, S549R, Y563N, and
P574H, revealed reduced levels of mature CFTR with elevated levels of carboxyl
terminal polypeptide fragments of 105 and 90 kDa. These fragments appear early in
biogenesis and degrade rapidly in four distinct cell types tested including the
bronchial epithelial IB3-1 cell line. They were detected at highest levels with
CFTRA455E where the 105-kDa fragment accounted for 40% of newly synthesized
polypeptide but for only 20 and 7% of nascent wild type and mutant DeltaF508
proteins, respectively. The bands represent core- and unglycosylated forms of the
same CFTR fragment supporting that precursor forms are correctly inserted into
the membrane of the endoplasmic reticulum. Proteolytic cleavage would be
predicted to occur on the cytosolic face of the endoplasmic reticulum within the
NBD1-R domain segment, but pharmacological testing did not support involvement of
the 26 S proteasome. The examined missense mutations in NBD1 manifest differently
than the major mutant, DeltaF508, and highlight a critical conformational aspect
of biogenesis of CFTR.
PMID- 10764789
TI - Development of a functional backbone cyclic mimetic of the HIV-1 Tat arginine
rich motif.
AB - We have used the backbone cyclic proteinomimetics approach to develop peptides
that functionally mimic the arginine-rich motif (ARM) of the HIV-1 Tat protein.
This consensus sequence serves both as a nuclear localization signal (NLS) and as
an RNA binding domain. Based on the NMR structure of Tat, we have designed and
synthesized a backbone cyclic ARM mimetic peptide library. The peptides were
screened for their ability to mediate nuclear import of the corresponding BSA
conjugates in permeabilized cells. One peptide, designated "Tat11," displayed
active NLS properties. Nuclear import of Tat11-BSA was found to proceed by the
same distinct pathway used by the Tat-NLS and not by the common importin alpha
pathway, which is used by the SV40-NLS. Most of the Tat-derived backbone cyclic
peptides display selective inhibitory activity as demonstrated by the inhibition
of the nuclear import mediated by the Tat-NLS and not by the SV40-NLS. The Tat
ARM-derived peptides, including Tat-11, also inhibited binding of the HIV-1 Rev
ARM to its corresponding RNA element (Rev response element) with inhibition
constants of 5 nm. Here we have shown for the first time (a) a functional mimetic
of a protein sequence, which activates a nuclear import receptor and (b) a
mimetic of a protein sequence with a dual functionality. Tat11 is a lead compound
which can potentially inhibit the HIV-1 life cycle by a dual mechanism:
inhibition of nuclear import and of RNA binding.
PMID- 10764790
TI - Proteolytic cleavage and activation of protein kinase C [micro] by caspase-3 in
the apoptotic response of cells to 1-beta -D-arabinofuranosylcytosine and other
genotoxic agents.
AB - Protein kinase C (PKC) mu is a novel member of the PKC family that differs from
the other isozymes in structural and biochemical properties. The precise function
of PKCmu is not known. The present studies demonstrate that PKCmu is cleaved
during apoptosis induced by 1-beta-d-arabinofuranosylcytosine (ara-C) and other
genotoxic agents. PKCmu cleavage is blocked in cells that overexpress the anti
apoptotic Bcl-x(L) protein or the baculovirus p35 protein. Our results
demonstrate that PKCmu is cleaved by caspase-3 at the CQND(378)S site. Cleavage
of PKCmu is associated with release of the catalytic domain and activation of its
kinase function. We also show that, unlike the cleaved fragments of PKCdelta and
theta, overexpression of the PKCmu catalytic domain is not lethal. Cells stably
expressing the catalytic fragment of PKCmu, however, are more sensitive to
apoptosis induced by genotoxic stress. In addition, expression of the caspase
resistant PKCmu mutant partially inhibits DNA damage-induced apoptosis. These
findings demonstrate that PKCmu is cleaved by caspase-3 and that expression of
the catalytic domain sensitizes cells to the cytotoxic effects of ara-C and other
anticancer agents.
PMID- 10764791
TI - Mapping the glycoprotein Ib-binding site in the von willebrand factor A1 domain.
AB - The von Willebrand factor (vWF) mediates platelet adhesion to exposed
subendothelium at sites of vascular injury. It does this by forming a bridge
between subendothelial collagen and the platelet glycoprotein Ib-IX-V complex
(GPIb). The GPIb-binding site within vWF has been localized to the vWF-A1 domain.
Based on the crystal structure of the vWF-A1 domain (Emsley, J., Cruz, M.,
Handin, R., and Liddington, R. (1998) J. Biol. Chem. 273, 10396-10401), we
introduced point mutations into 16 candidate residues that might form all or part
of the GPIb interaction site. We also introduced two mutations previously
reported to impair vWF function yielding a total of 18 mutations. The recombinant
vWF-A1 mutant proteins were then expressed in Escherichia coli, and the activity
of the purified proteins was assessed by their ability to support flow-dependent
platelet adhesion and their ability to inhibit ristocetin-induced platelet
agglutination. Six mutations located on the front and upper anterior face of the
folded vWF-A1 domain, R524S, G561S, H563T, T594S/E596A, Q604R, and S607R, showed
reduced activity in all the assays, and we suggest that these residues form part
of the GPIb interaction site. One mutation, G561S, with impaired activity occurs
in the naturally occurring variant form of von Willebrand's disease-type 2M
underscoring the physiologic relevance of the mutations described here.
PMID- 10764792
TI - Sperm motility is dependent on a unique isoform of the Na,K-ATPase.
AB - The Na,K-ATPase, a member of the P-type ATPases, is composed of two subunits,
alpha and beta, and is responsible for translocating Na(+) out of the cell and
K(+) into the cell using the energy of hydrolysis of one molecule of ATP. The
electrochemical gradient it generates is necessary for many cellular functions,
including establishment of the plasma membrane potential and transport of sugars
and ions in and out of the cell. Families of isoforms for both the alpha and beta
subunits have been identified, and specific functional roles for individual
isoforms are just beginning to emerge. The alpha4 isoform is the most recently
identified Na, K-ATPase alpha isoform, and its expression has been found only in
testis. Here we show that expression of the alpha4 isoform in testis is localized
to spermatozoa and that inhibition of this isoform alone eliminates sperm
motility. These data describe for the first time a biological function for the
alpha4 isoform of the Na,K-ATPase, revealing a critical role for this isoform in
sperm motility.
PMID- 10764793
TI - One or more labile proteins regulate the stability of chimeric mRNAs containing
the 3'-untranslated region of cholesterol-7alpha -hydroxylase mRNA.
AB - Multiple AUUUA elements similar to those that regulate the degradation of several
different mRNAs are conserved in the 3'-untranslated region (3'-UTR) of
cholesterol-7alpha-hydroxylase (CYP7A1) mRNAs from several species. We examined
if stabilization of mRNA decay could account for the >20-fold increase in the
expression of CYP7A1 mRNA without a detectable change in transcription following
dexamethasone treatment of rat hepatoma cells (L35 cells). Following RNA
polymerase II-dependent transcription block or protein synthesis block, the decay
of CYP7A1 mRNA displayed a short half-life ( approximately 30 min). Control
experiments showed that in cells pre-treated with a RNA polymerase II inhibitor,
dexamethasone had no detectable effect on CYP7A1 mRNA decay. Stable expression of
luciferase reporter mRNAs in L35 cells showed that the CYP7A1 3'-UTR was required
to observe a dexamethasone induction. To examine the hypothesis that a labile
protein is required for dexamethasone-induced mRNA stabilization, cells were
stably transfected with a tetracycline-repressible promoter that drives the
expression of a green fluorescent protein analogue (ECFP) with or without the 3'
UTR of CYP7A1. Cells expressing ECFP with the 3'-UTR of CYP7A1 displayed a 3-fold
dexamethasone induction of ECFP mRNA, whereas cells expressing ECFP without the
3'-UTR did not. Moreover, specific block of the transcription of ECFP containing
the 3'-UTR by adding the tetracycline analogue doxycycline clearly displayed
dexamethasone-induced stabilization of mRNA decay. These data provide compelling
evidence that a putative labile protein and the 3'-UTR of CYP7A1 act together to
decrease the rate of CYP7A1 mRNA degradation.
PMID- 10764794
TI - The Saccharomyces cerevisiae RNA-binding protein Rbp29 functions in cytoplasmic
mRNA metabolism.
AB - Here we report that the Saccharomyces cerevisiae RBP29 (SGN1, YIR001C) gene
encodes a 29-kDa cytoplasmic protein that binds to mRNA in vivo. Rbp29p can be co
immunoprecipitated with the poly(A) tail-binding protein Pab1p from crude yeast
extracts in a dosage- and RNA-dependent manner. In addition, recombinant Rbp29p
binds preferentially to poly(A) with nanomolar binding affinity in vitro.
Although RBP29 is not essential for cell viability, its deletion exacerbates the
slow growth phenotype of yeast strains harboring mutations in the eIF4G genes
TIF4631 and TIF4632. Furthermore, overexpression of RBP29 suppresses the
temperature-sensitive growth phenotype of specific tif4631, tif4632, and pab1
alleles. These data suggest that Rbp29p is an mRNA-binding protein that plays a
role in modulating the expression of cytoplasmic mRNA.
PMID- 10764795
TI - Mechanism of catalysis of the cofactor-independent phosphoglycerate mutase from
Bacillus stearothermophilus. Crystal structure of the complex with 2
phosphoglycerate.
AB - The structure of the complex between the 2, 3-diphosphoglycerate-independent
phosphoglycerate mutase (iPGM) from Bacillus stearothermophilus and its 3
phosphoglycerate substrate has recently been solved, and analysis of this
structure allowed formulation of a mechanism for iPGM catalysis. In order to
obtain further evidence for this mechanism, we have solved the structure of this
iPGM complexed with 2-phosphoglycerate and two Mn(2+) ions at 1. 7-A resolution.
The structure consists of two different domains connected by two loops and
interacting through a network of hydrogen bonds. This structure is consistent
with the proposed mechanism for iPGM catalysis, with the two main steps in
catalysis being a phosphatase reaction removing the phosphate from 2- or 3
phosphoglycerate, generating an enzyme-bound phosphoserine intermediate, followed
by a phosphotransferase reaction as the phosphate is transferred from the enzyme
back to the glycerate moiety. The structure also allowed the assignment of the
function of the two domains of the enzyme, one of which participates in the
phosphatase reaction and formation of the phosphoserine enzyme intermediate, with
the other involved in the phosphotransferase reaction regenerating
phosphoglycerate. Significant structural similarity has also been found between
the active site of the iPGM domain catalyzing the phosphatase reaction and
Escherichia coli alkaline phosphatase.
PMID- 10764796
TI - TROY, a newly identified member of the tumor necrosis factor receptor
superfamily, exhibits a homology with Edar and is expressed in embryonic skin and
hair follicles.
AB - In a signal sequence trap screening of the murine brain, we identified a new
member of the tumor necrosis factor receptor superfamily designated TROY. TROY is
a type I membrane protein of 416 amino acids with characteristic cysteine-rich
motifs in the extracellular domain and a tumor necrosis factor receptor
associated factor (TRAF) 2 binding sequence in the cytoplasmic domain of 223
amino acids. In fact, activation of nuclear factor kappaB was induced by the
overexpression of TROY and inhibited by dominant negative forms of TRAF2, TRAF5,
and TRAF6, indicating that TRAFs and nuclear factor kappaB are involved in the
signal transduction of TROY. We also cloned a cDNA for a human counterpart, which
showed a 75% homology with mouse TROY at the amino acid level. The extracellular
domain of TROY exhibits an extensive homology with that of Edar, a receptor that
specifies hair follicle fate. TROY mRNA is strongly expressed in brain and embryo
and moderately expressed in the heart, lung, and liver but not the spleen. In the
embryo, the expression level is particularly strong in the skin. Interestingly,
in situ hybridization analysis of the embryo showed that TROY mRNA was
exclusively expressed in the epithelium of many tissues. On the other hand, in
neonatal mice, TROY is expressed in hair follicles like Edar as well as in the
cerebrum, suggesting pleiotropic functions of TROY in development as well as in
the adult mice. The Troy gene is located near the waved coat (Wc) locus, a mutant
related to abnormalities in skin and hair.
PMID- 10764797
TI - Cyclic nucleotide-gated channels mediate membrane depolarization following
activation of store-operated calcium entry in endothelial cells.
AB - Calcium agonists induce membrane depolarization in endothelial cells through an
unknown mechanism. Present studies tested the hypothesis that pulmonary artery
endothelial cells express a cyclic nucleotide-gated (CNG) cation channel
activated by store-operated calcium entry to produce membrane depolarization. In
the whole-cell configuration, voltage-clamped cells revealed a large non
inactivating, outwardly rectifying cationic current in the absence of extra- or
intracellular Ca(2+) that was reduced upon replenishment of Ca(2+). The inward
current was non-selective for K(+), Na(+), Cs(+), and Rb(+) and was not inhibited
by high tetraethylammonium concentrations. cAMP and cGMP stimulated the current
and changed the cation permeability to favor Na(+). Moreover, 8-bromo-cAMP
stimulated the current in voltage-clamped cells in the perforated patch mode. The
cationic current was inhibited by the CNG channel blocker LY83,583, and reverse
transcriptase-polymerase chain reaction cloning identified expression of a CNG
channel resembling that seen in olfactory neurons. Activation of store-operated
calcium entry using thapsigargin increased a current through the CNG channel.
Stimulation of the current paralleled pulmonary artery endothelial cell membrane
depolarization, and both the current and membrane depolarization were abolished
using LY83,583. Taken together, these data demonstrate activation of store
operated calcium entry stimulates a CNG channel producing membrane
depolarization. Such membrane depolarization may contribute to slow feedback
inhibition of store-operated calcium entry.
PMID- 10764798
TI - The inhibition of interleukin-6-dependent STAT activation by mitogen-activated
protein kinases depends on tyrosine 759 in the cytoplasmic tail of glycoprotein
130.
AB - Mitogen-activated protein (MAP) kinases stimulated by phorbol 13-myristate 12
acetate (PMA) have been shown to inhibit interleukin-6-induced activation of
STAT3 (Sengupta, T. K., Talbot, E. S., Scherle, P. A., and Ivashkiv, L. B. (1998)
Proc. Natl. Acad. Sci. U. S. A. 95, 11107-11112). In the present study we
demonstrate that in addition to STAT3, also tyrosine phosphorylation of STAT1,
signal transducer gp130, and phosphotyrosine-phosphatase SHP2 underlies negative
regulation by MAP kinases. Stimulation of Erks by basic fibroblast growth factor
or a constitutively active mutant of Raf also led to down-regulation of STAT
activity. Using chimeric receptor mutants we show that tyrosine 759 of
glycoprotein 130 is crucial for the inhibitory effect of MAP kinases. Inhibition
is also dependent on gene transcription and translation indicating that newly
synthesized proteins are involved. Both PMA and basic fibroblast growth factor
rapidly stimulate mRNA expression of the suppressor of cytokine signaling-3 (SOCS
3) and this induction is strongly reduced by an inhibitor of MAP kinase
activation. Together with recent results demonstrating that SOCS-3 can bind in
vitro to a phosphorylated tyrosine 759 peptide of glycoprotein 130 these data
suggest SOCS-3 to be instrumental in the inhibition of the Janus kinase/STAT
pathway by MAP kinases.
PMID- 10764799
TI - Selective attenuation of metabolic branch of insulin receptor down-signaling by
high glucose in a hepatoma cell line, HepG2 cells.
AB - The effects of a high concentration of glucose on the insulin receptor-down
signaling were investigated in human hepatoma (HepG2) cells in vitro to delineate
the molecular mechanism of insulin resistance under glucose toxicity. Treatment
of the cells with high concentrations of glucose (15-33 mm) caused
phosphorylation of serine residues of the insulin receptor substrate 1 (IRS-1),
leading to reduced electrophoretic mobility of it. The phosphorylation of IRS-1
with high glucose treatment was blocked only by protein kinase C (PKC)
inhibitors. The high glucose treatment attenuated insulin-induced association of
IRS-1 and phosphatidylinositol 3-kinase and insulin-stimulated phosphorylation of
Akt. A metabolic effect of insulin, stimulation of glycogen synthesis, was also
inhibited by the treatment. In contrast, insulin-induced association of Shc and
Grb2 was not inhibited. Treatment of the cells with high glucose promoted the
translocation of PKCepsilon and PKCdelta from the cytosol to the plasma membrane
but not that of other PKC isoforms. Finally, PKCepsilon and PKCdelta directly
phosphorylated IRS-1 under cell-free conditions. We conclude that a high
concentration of glucose causes phosphorylation of IRS-1, leading to selective
attenuation of metabolic signaling of insulin. PKCepsilon and PKCdelta are
involved in the down-regulation of insulin signaling, and they may lie in a
pathway regulating the phosphorylation of IRS-1.
PMID- 10764800
TI - Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid
beta peptide and inhibit abeta -induced toxicity.
AB - Inositol has 8 stereoisomers, four of which are physiologically active. myo
Inositol is the most abundant isomer in the brain and more recently shown that
epi- and scyllo-inositol are also present. myo-Inositol complexes with Abeta42 in
vitro to form a small stable micelle. The ability of inositol stereoisomers to
interact with and stabilize small Abeta complexes was addressed. Circular
dichroism spectroscopy demonstrated that epi- and scyllo- but not chiro-inositol
were able to induce a structural transition from random to beta-structure in
Abeta42. Alternatively, none of the stereoisomers were able to induce a
structural transition in Abeta40. Electron microscopy demonstrated that inositol
stabilizes small aggregates of Abeta42. We demonstrate that inositol-Abeta
interactions result in a complex that is non-toxic to nerve growth factor
differentiated PC-12 cells and primary human neuronal cultures. The attenuation
of toxicity is the result of Abeta-inositol interaction, as inositol uptake
inhibitors had no effect on neuronal survival. The use of inositol stereoisomers
allowed us to elucidate an important structure-activity relationship between
Abeta and inositol. Inositol stereoisomers are naturally occurring molecules that
readily cross the blood-brain barrier and may represent a viable treatment for AD
through the complexation of Abeta and attenuation of Abeta neurotoxic effects.
PMID- 10764801
TI - The amino-terminal region of the fusion peptide of influenza virus hemagglutinin
HA2 inserts into sodium dodecyl sulfate micelle with residues 16-18 at the
aqueous boundary at acidic pH. Oligomerization and the conformational
flexibility.
AB - The conformation and interactions with membrane mimics of the NH(2)-terminal
fragment 1-25 of HA2, HA2-(1-25), of influenza virus were studied by
spectroscopic methods. Secondary structure analysis of circular dichroism data
revealed 45% helix for the peptide at pH 5.0. Tryptophan fluorescence quenching
by acrylamide and NMR experiments established that the Trp(14) is inside the
vesicular interior and residues 16-18 are at the micellar aqueous boundary. NBD
fluorescence enhancement of the NH(2)-terminal labeled fluorophore on the vesicle
bound peptide indicated that the NH(2) terminus of the fusion peptide was located
in the hydrophobic region of the lipid bilayer. No significant change in
insertion depth was observed between pH 5.0 and 7.4. Collectively, these
spectroscopic measurements pointed to an equilibrium between helix and non-helix
conformations, with helix being the dominant form, for the segment in the
micellar interior. The conformational transition may be facilitated by the high
content of glycine, a conformationally flexible amino acid, within the fusion
peptide sequence. Self-association of the 25-mer peptide was observed in the N-[2
hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine SDS-gel electrophoresis experiments.
Incorporating the NMR signal attenuation, fluorescence, and gel electrophoresis
data, a working model for the organization of the fusion peptide in membrane
bilayers was proposed.
PMID- 10764803
TI - Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin.
AB - Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue
type plasminogen activator (t-PA), circulates as a complex with the abundant
plasma glycoprotein, vitronectin. This interaction stabilizes the inhibitor in
its active conformation In this report, the effects of vitronectin on the
interactions of PAI-1 with fibrin clots were studied. Confocal microscopic
imaging of platelet-poor plasma clots reveals that essentially all fibrin
associated PAI-1 colocalizes with fibrin-bound vitronectin. Moreover, formation
of platelet-poor plasma clots in the presence of polyclonal antibodies specific
for vitronectin attenuated the inhibitory effects of PAI-1 on t-PA-mediated
fibrinolysis. Addition of vitronectin during clot formation markedly potentiates
PAI-1-mediated inhibition of lysis of (125)I-labeled fibrin clots by t-PA. This
effect is dependent on direct binding interactions of vitronectin with fibrin.
There is no significant effect of fibrin-associated vitronectin on fibrinolysis
in the absence of PAI-1. The binding of PAI-1 to fibrin clots formed in the
absence of vitronectin was characterized by a low affinity (K(d) approximately
3.5 micrometer) and rapid loss of PAI-1 inhibitory activity over time. In
contrast, a high affinity and stabilization of PAI-1 activity characterized the
cooperative binding of PAI-1 to fibrin formed in the presence of vitronectin.
These findings indicate that plasma PAI-1.vitronectin complexes can be localized
to the surface of fibrin clots; by this localization, they may modulate
fibrinolysis and clot reorganization.
PMID- 10764802
TI - Stabilization of MyoD by direct binding to p57(Kip2).
AB - Recent data have demonstrated the role of Cdk1- and Cdk2-dependent
phosphorylation of MyoD(Ser200) in the regulation of MyoD activity and protein
turnover. In the present study, we show that in presence of p57(Kip2),
MyoD(Ala200), a MyoD mutant that cannot be phosphorylated by cyclin-Cdk
complexes, displayed activity 2-5-fold higher than of MyoD(Ala200) alone in
transactivation of muscle-specific genes myosin heavy chain, creatine kinase, and
myosin light chain 1. Furthermore, p57(Kip2) increases the levels of MyoD(Ala200)
in cotransfected cells. This result implies that p57(Kip2) may regulate MyoD
through a process distinct from its function as a cyclin-dependent kinase
inhibitors. We report that overexpression of p57(Kip2) increased the half-life of
MyoD(Ala200). This increased half-life of MyoD involves a physical interaction
between MyoD and p57(Kip2) but not with p16(Ink4a), as shown by cross
immunoprecipitation not only on overexpressed proteins from transfected cells,
but also on endogenous MyoD and p57(Kip2) from C2C12 myogenic cells. Mutational
and functional analyses of the two proteins show that the NH(2) domain of
p57(Kip2) associates with basic region in the basic helix-loop-helix domain of
MyoD. Competition/association assays and site-directed mutagenesis of the NH(2)
terminus of p57(Kip2) identified the intermediate alpha-helix domain, located
between the Cdk and the cyclin binding sites, as essential for MyoD interaction.
These data show that the alpha-helix domain of p57(Kip2), which is conserved in
the Cip/Kip proteins, is implicated in protein-protein interaction and confers a
specific regulatory mechanism, outside of their Cdk-inhibitory activity, by which
the p57(Kip2) family members positively act on myogenic differentiation.
PMID- 10764804
TI - Cellular release of [18F]2-fluoro-2-deoxyglucose as a function of the glucose-6
phosphatase enzyme system.
AB - [(18)F]-2-Fluoro-2-deoxyglucose (FDG) is a glucose analog currently utilized for
positron emission tomography imaging studies in humans. FDG taken up by the liver
is rapidly released. This property is attributed to elevated glucose-6
phosphatase (Glc-6-Pase) activity. To characterize this issue we studied the
relationship between Glc-6-Pase activity and FDG release kinetics in a cell
culture system. We overexpressed the Glc-6-Pase catalytic unit in a Glc-6-Pase
deficient mouse hepatocyte (Ho-15) and in A431 tumor cell lines. Glc-6-Pase
enzyme activity and FDG release rates were determined in cells transfected with
the Glc-6-Pase gene (Ho-15-D3 and A431-AC3), in mock-transfected cells of both
cell lines, and in wild-type mouse hepatocytes (WT10) as control. Although the
highest level of Glc-6-Pase activity was measured in A431-AC3, Ho-15-D3 cells
showed much faster FDG release rates. The faster FDG release correlated with the
level of glucose 6-phosphate transporter (Glc-6-PT) mRNA, which was found to be
expressed at higher levels in Ho-15 compared with A431 cells. Overexpression of
Glc-6-PT in A431-AC3 produced a dramatic increase in FDG release compared with
control cells. This study gives the first direct evidence that activity of the
Glc-6-Pase complex can be quantified in vivo by measuring FDG release. Adequate
levels of Glc-6-Pase catalytic unit and Glc-6-PT are required for this function.
FDG-positron emission tomography may be utilized to evaluate functional status of
the Glc-6-Pase complex.
PMID- 10764805
TI - Depletion of intracellular Ca2+ by caffeine and ryanodine induces apoptosis of
chinese hamster ovary cells transfected with ryanodine receptor.
AB - Recent studies have suggested a central role for Ca(2+) in the signaling pathway
of apoptosis and certain anti-apoptotic effects of Bcl-2 family of proteins have
been attributed to changes in intracellular Ca(2+) homeostasis. Here we report
that depletion of Ca(2+) from endoplasmic reticulum (ER) leads to apoptosis in
Chinese hamster ovary cells. Stable expression of ryanodine receptor (RyR) in
these cells enables rapid and reversible changes of both cytosolic Ca(2+) and ER
Ca(2+) content via activation of the RyR/Ca(2+) release channel by caffeine and
ryanodine. Sustained depletion of the ER Ca(2+) store leads to apoptosis in
Chinese hamster ovary cells, whereas co-expression of Bcl-xL and RyR in these
cells prevents apoptotic cell death but not necrotic cell death. The anti
apoptotic effect of Bcl-xL does not correlate with changes in either the Ca(2+)
release process from the ER or the capacitative Ca(2+) entry through the plasma
membrane. The data suggest that Bcl-xL likely prevents apoptosis of cells at a
stage downstream of ER Ca(2+) release and capacitative Ca(2+) entry.
PMID- 10764806
TI - Three-amino acid extension loop homeodomain proteins Meis2 and TGIF
differentially regulate transcription.
AB - Three-amino acid extension loop (TALE) homeobox proteins are highly conserved
transcription regulators. We report that two members of this family, Meis2 and
TGIF, which frequently have overlapping consensus binding sites on complementary
DNA strands in opposite orientations, can function competitively. For example, in
the D(1A) gene, which encodes the predominant dopamine receptor in the striatum,
Meis2 and TGIF bind to the activator sequence ACT (-1174 to -1154) and regulate
transcription differentially in a cell type-specific manner. Among the five
cloned splice variants of Meis2, isoforms Meis2a-d activate the D(1A) promoter in
most cell types tested, whereas TGIF competes with Meis2 binding to DNA and
represses Meis2-induced transcription activation. Consequently, Meis2 cannot
activate the D(1A) promoter in a cell that has abundant TGIF expression. The
Meis2 message is highly co-localized with the D(1A) message in adult striatal
neurons, whereas TGIF is barely detectable in the adult brain. Our observations
provide in vitro and in vivo evidence that Meis2 and TGIF differentially regulate
their target genes. Thus, the delicate ratio between Meis2 and TGIF expression in
a given cell type determines the cell-specific expression of the D(1A) gene. We
also found that splice variant Meis2e, which has a truncated homeodomain, cannot
bind to the D(1A) ACT sequence or activate transcription. However, Meis2e is an
effective dominant negative regulator by blocking Meis2d-induced transcription
activation. Thus, truncated homeoproteins with no DNA binding domains can have
important regulatory functions.
PMID- 10764807
TI - Characterization and tRNA recognition of mammalian mitochondrial seryl-tRNA
synthetase.
AB - Animal mitochondrial protein synthesis systems contain two serine tRNAs
(tRNAs(Ser)) corresponding to the codons AGY and UCN, each possessing an unusual
secondary structure; the former lacks the entire D arm, and the latter has a
slightly different cloverleaf structure. To elucidate whether these two
tRNAs(Ser) can be recognized by the single animal mitochondrial seryl-tRNA
synthetase (mt SerRS), we purified mt SerRS from bovine liver 2400-fold and
showed that it can aminoacylate both of them. Specific interaction between mt
SerRS and either of the tRNAs(Ser) was also observed in a gel retardation assay.
cDNA cloning of bovine mt SerRS revealed that the deduced amino acid sequence of
the enzyme contains 518 amino acid residues. The cDNAs of human and mouse mt
SerRS were obtained by reverse transcription-polymerase chain reaction and
expressed sequence tag data base searches. Elaborate inspection of primary
sequences of mammalian mt SerRSs revealed diversity in the N-terminal domain
responsible for tRNA recognition, indicating that the recognition mechanism of
mammalian mt SerRS differs considerably from that of its prokaryotic counterpart.
In addition, the human mt SerRS gene was found to be located on chromosome
19q13.1, to which the autosomal deafness locus DFNA4 is mapped.
PMID- 10764808
TI - Folding and function of I domain-deleted Mac-1 and lymphocyte function-associated
antigen-1.
AB - In those integrins that contain it, the I domain is a major ligand recognition
site. The I domain is inserted between beta-sheets 2 and 3 of the predicted beta
propeller domain of the integrin alpha subunit. We deleted the I domain from the
integrin alpha(M) and alpha(L) subunits to give I-less Mac-1 and lymphocyte
function-associated antigen-1 (LFA-1), respectively. The I-less alpha(M) and
alpha(L) subunits were expressed in association with the wild-type beta(2)
subunit on the surface of transfected cells and bound to all the monoclonal
antibodies mapped to the putative beta-propeller and C-terminal regions of the
alpha(M) and alpha(L) subunits, suggesting that the folding of these domains is
independent of the I domain. I-less Mac-1 bound to the ligands iC3b and factor X,
but this binding was reduced compared with wild-type Mac-1. In contrast, I-less
Mac-1 did not bind to fibrinogen or denatured bovine serum albumin. Binding to
iC3b and factor X by I-less Mac-1 was inhibited by the function-blocking antibody
CBRM1/32, which binds to the beta-propeller domain of the alpha(M) subunit. I
less LFA-1 did not bind its ligands intercellular adhesion molecule-1 and -3.
Thus, the I domain is not essential for the folding, heterodimer formation, and
surface expression of Mac-1 and LFA-1 and is required for binding to some
ligands, but not others.
PMID- 10764809
TI - Studies on the subsite specificity of rat nardilysin (N-arginine dibasic
convertase).
AB - The subsite specificity of rat nardilysin was investigated using fluorogenic
substrates of the type 2-aminobenzoyl-GGX(1)X(2)RKX(3)GQ-ethylenediamine-2,4-
dinitrophenyl, where P(2), P(2)', and P(3) residues were varied. (The
nomenclature of Schechter and Berger (Schechter, I., and Berger, A. (1967)
Biochem. Biophys. Res. Commun. 27, 157-162) is used where cleavage of a peptide
occurs between the P(1) and P(1)' residues, and adjacent residues are designated
P(2), P(3), P(2)', P(3)', etc.) There was little effect on K(m) among different
residues at any of these positions. In contrast, residues at each position
affected k(cat), with P(2) residues having the greatest effect. The S(3), S(2),
and S(2)' subsites differed in their amino acid preference. Tryptophan and
serine, which produced poor substrates at the P(2) position, were among the best
P(2)' residues. The specificity at P(3) was generally opposite that of P(2).
Residues at P(2), and to a lesser extent at P(3), influenced the cleavage site.
At the P(2) position, His, Phe, Tyr, Asn, or Trp produced cleavage at the amino
side of the first basic residue. In contrast, a P(2) Ile or Val produced cleavage
between the dibasic pair. Other residues produced intermediate effects. The pH
dependence for substrate binding showed that the enzyme prefers to bind a
protonated histidine. A comparison of the effect of arginine or lysine at the
P(1)' or P(1) position showed that there is a tendency to cleave on the amino
side of arginine and that this cleavage produces the highest k(cat) values.
PMID- 10764810
TI - Kinetic and structural characterization of the glutathione-binding site of aldose
reductase.
AB - Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been
implicated in the etiology of secondary diabetic complications. However, the
physiological functions of AR under euglycemic conditions remain unclear. We have
recently demonstrated that, in intact heart, AR catalyzes the reduction of the
glutathione conjugate of the lipid peroxidation product 4-hydroxy-trans-2-nonenal
(Srivastava, S., Chandra, A., Wang, L., Seifert, W. E., Jr., DaGue, B. B.,
Ansari, N. H., Srivastava, S. K., and Bhatnagar, A. (1998) J. Biol. Chem. 273,
10893-10900), consistent with a possible role of AR in the metabolism of
glutathione conjugates of aldehydes. Herein, we present several lines of evidence
suggesting that the active site of AR forms a specific glutathione-binding
domain. The catalytic efficiency of AR in the reduction of the glutathione
conjugates of acrolein, trans-2-hexenal, trans-2-nonenal, and trans,trans-2,4
decadienal was 4-1000-fold higher than for the corresponding free alkanal.
Alterations in the structure of glutathione diminished the catalytic efficiency
in the reduction of the acrolein adduct, consistent with the presence of specific
interactions between the amino acid residues of glutathione and the AR active
site. In addition, non-aldehydic conjugates of glutathione or glutathione analogs
displayed active-site inhibition. Molecular dynamics calculations suggest that
the conjugate adopts a specific low energy configuration at the active site,
indicating selective binding. These observations support an important role of AR
in the metabolism of glutathione conjugates of endogenous and xenobiotic
aldehydes and demonstrate, for the first time, efficient binding of glutathione
conjugates to an aldo-keto reductase.
PMID- 10764811
TI - Nuclear localization and cell cycle-specific expression of CtIP, a protein that
associates with the BRCA1 tumor suppressor.
AB - The BRCA1 tumor suppressor has been implicated in a diverse spectrum of cellular
processes, including transcriptional regulation, DNA repair, and cell cycle
checkpoint control. CtIP was recently identified as a protein that associates
with BRCA1 and two other nuclear factors, CtBP1 and Rb1. To understand the
functions of CtIP, we have evaluated its biological properties with respect to
those of BRCA1. Our results show that CtIP, like its associated factors, is
predominantly a nuclear protein. A subset of the endogenous pool of CtIP
polypeptides exists in a protein complex that includes both BRCA1 and the BRCA1
associated RING domain protein (BARD1). At the protein level, CtIP expression
varies with cell cycle progression in a pattern identical to that of BRCA1. Thus,
the steady-state levels of CtIP polypeptides, which remain low in resting cells
and G(1) cycling cells, increase dramatically as dividing cells traverse the
G(1)/S boundary. In contrast to BRCA1, however, the G(1)/S induction of CtIP
expression is mediated primarily by post-transcriptional mechanisms. Finally, the
interaction between CtIP and BRCA1 is shown to be stable in the face of genotoxic
stress elicited by treatment with UV light, adriamycin, or hydrogen peroxide.
Together, these results indicate that CtIP can potentially modulate the functions
ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle
checkpoint control.
PMID- 10764812
TI - Amino acids in the second and third intracellular loops of the parathyroid Ca2+
sensing receptor mediate efficient coupling to phospholipase C.
AB - To determine the role of amino acids in the second and third intracellular (IC)
loops of the Ca(2+)-sensing receptor (CaR) in phospholipase C (PLC) activation,
we mutated residues in these loops either singly or in tandem to Ala and assessed
PLC activity by measuring high extracellular [Ca(2+)] ([Ca(2+)](o))-induced
inositol phosphate accumulation and protein expression by immunoblotting and
immunocytochemistry in human embryonic kidney 293 cells. Two CaR constructs in
the second IC loop, F707A CaR and to a lesser extent L704A CaR, demonstrated
reduced activation of PLC, despite levels of protein expression comparable with
the wild-type (wt) CaR. Substitution of Tyr or His for Phe-707, but not Leu, Val,
Glu, or Trp, partially restored the ability of high [Ca(2+)](o) to activate PLC.
Eight residues in the third IC loop were involved in PLC signaling. The responses
to high [Ca(2+)](o) in cells expressing CaRs with Ala substitutions at these
sites were <35% of the wt CaR. The L798A, F802A, and E804A CaRs were dramatically
impaired in their responses to [Ca(2+)](o) even up to 30 mm. Substitutions of Leu
798 with other hydrophobic residues (Ile, Val, or Phe), but not with acidic,
basic, or polar residues, produced reduced responses compared with wt. Phe-802
could be replaced with either Tyr or Trp with partial retention of the ability to
activate PLC. Glu-804 could only be substituted with Asp or Gln and maintain its
signaling capacity. Cell surface expression of the CaRs mutated at Leu-798 and
Phe-802 appeared normal compared with wt CaR. Cell surface CaR expression was,
however, reduced substantially in cells expressing several mutants at position
Glu-804 by confocal microscopy. These studies strongly implicate specific
hydrophobic and acidic residues in the second and third IC loops of the
parathyroid CaR (and potentially larger stretches of the third loop) in mediating
efficient high [Ca(2+)](o)-induced PLC activation and or CaR expression.
PMID- 10764813
TI - Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release
of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta
cells.
AB - The signaling pathway by which insulin stimulates insulin secretion and increases
in intracellular free Ca(2+) concentration ([Ca(2+)](i)) in isolated mouse
pancreatic beta-cells and clonal beta-cells was investigated. Application of
insulin to single beta-cells resulted in increases in [Ca(2+)](i) that were of
lower magnitude, slower onset, and longer lifetime than that observed with
stimulation with tolbutamide. Furthermore, the increases in [Ca(2+)](i)
originated from interior regions of the cell rather than from the plasma membrane
as with depolarizing stimuli. The insulin-induced [Ca(2+)](i) changes and insulin
secretion at single beta-cells were abolished by treatment with 100 nm wortmannin
or 1 micrometer thapsigargin; however, they were unaffected by 10 micrometer
U73122, 20 micrometer nifedipine, or removal of Ca(2+) from the medium. Insulin
stimulated insulin secretion was also abolished by treatment with 2 micrometer
bisindolylmaleimide I, but [Ca(2+)](i) changes were unaffected. In an insulin
receptor substrate-1 gene disrupted beta-cell tumor line, insulin did not evoke
either [Ca(2+)](i) changes or insulin secretion. The data suggest that autocrine
activated increases in [Ca(2+)](i) are due to release of intracellular Ca(2+)
stores, especially the endoplasmic reticulum, mediated by insulin receptor
substrate-1 and phosphatidylinositol 3-kinase. Autocrine activation of insulin
secretion is mediated by the increase in [Ca(2+)](i) and activation of protein
kinase C.
PMID- 10764814
TI - Tumor necrosis factor alpha inhibits insulin-induced mitogenic signaling in
vascular smooth muscle cells.
AB - Tumor necrosis factor alpha (TNFalpha) interferes with insulin signaling in
adipose tissue and may promote insulin resistance. Insulin binding to the insulin
receptor (IR) triggers its autophosphorylation, resulting in phosphorylation of
Shc and the downstream activation of p42/p44 extracellular signal-regulated
kinase 1/2 mitogen-activated protein kinase (ERK1/2), which mediates insulin
induced proliferation in vascular smooth muscle cells (VSMC). Since insulin
resistance is a risk factor for vascular disease, we examined the effects of
TNFalpha on mitogenic signaling by insulin. In rat aortic VSMC, insulin induced
rapid phosphorylation of the IR and Shc and caused a 5.3-fold increase in
activated, phosphorylated ERK1/2 at 10 min. Insulin induced a biphasic ERK1/2
activation with a transient peak at 10 min and a sustained late phase after 2 h.
Preincubation (30-120 min) with TNFalpha had no effect on insulin-induced IR
phosphorylation. In contrast, TNFalpha transiently suppressed insulin-induced
ERK1/2 activation. Insulin-induced phosphorylation of Shc was inhibited by
TNFalpha in a similar pattern. Since mitogenic signaling by insulin in VSMC
requires ERK1/2 activation, we examined the effect of TNFalpha on insulin-induced
proliferation. Insulin alone induced a 3.4-fold increase in DNA synthesis, which
TNFalpha inhibited by 48%. TNFalpha alone was not mitogenic. Inhibition of ERK1/2
activation with PD98059 also inhibited insulin-stimulated DNA synthesis by 57%.
TNFalpha did not inhibit platelet-derived growth factor-induced ERK1/2 activation
or DNA synthesis in VSMC. Thus, TNFalpha selectively interferes with insulin
induced mitogenic signaling by inhibiting the phosphorylation of Shc and the
downstream activation of ERK1/2.
PMID- 10764815
TI - Characterization of the tyrosine kinases RAFTK/Pyk2 and FAK in nerve growth
factor-induced neuronal differentiation.
AB - The related adhesion focal tyrosine kinase (RAFTK), a member of the focal
adhesion kinase (FAK) family and highly expressed in brain, is a key mediator of
various extracellular signals that elevate intracellular Ca(2+) concentration. We
investigated RAFTK and FAK signaling upon nerve growth factor (NGF) stimulation
of PC12 cells. NGF induced the tyrosine phosphorylation of RAFTK in a time- and
dose-dependent manner, whereas no change in the tyrosine phosphorylation of FAK
was observed. Chemical inhibition showed that RAFTK phosphorylation was inhibited
by blocking phospholipase Cgamma activity or intracellular Ca(2+). Blocking of
extracellular Ca(2+) or phosphatidylinositol 3-kinase activity partially reduced
the phosphorylation of RAFTK. In addition, disruption of actin polymerization
abolished RAFTK phosphorylation, indicating that an intact actin-based
cytoskeletal organization is required for RAFTK phosphorylation. The focal
adhesion molecule paxillin was co-immunoprecipitated with RAFTK, and its tyrosine
phosphorylation was increased in a Ca(2+)-dependent manner upon NGF stimulation.
Confocal microscopic analysis demonstrated that RAFTK translocated from the
cytoplasm to potential neurite initiation sites at the cell periphery, where
RAFTK co-localized with paxillin and bundled actin in the early phase (within 5
min) of NGF stimulation, whereas FAK co-localized with paxillin at "point
contacts," which are the primary cell adhesion sites in neuronal cells.
Significant distribution of RAFTK was observed in the neurites and growth cones
of differentiated PC12 cells. Furthermore, potassium depolarization induced the
tyrosine phosphorylation of both RAFTK and paxillin in an intracellular Ca(2+)
dependent manner in the differentiated PC12 cells. Taken together, these results
demonstrate that RAFTK is involved in NGF-induced cytoskeletal organization and
may play a role in neurite and growth cone function(s).
PMID- 10764816
TI - Regulation of SOCS-1 expression by translational repression.
AB - Accumulating evidence demonstrates that cytokine receptor signaling is negatively
regulated by a family of Src homology 2 domain-containing adaptor molecules
termed SOCS (suppressor of cytokine signaling). Previous studies have indicated
that the expression of SOCS-related molecules is tightly controlled at the level
of transcription. Furthermore, it has been reported that SOCS polypeptides are
relatively unstable in cells, unless they are associated with elongins B and C.
Herein, we document the existence of a third mechanism of regulation of SOCS
function. Our data showed that expression of SOCS-1, a member of the SOCS family,
is strongly repressed at the level of translation initiation. Structure-function
analyses indicated that this effect is mediated by the 5' untranslated region of
socs-1 and that it relates to the presence of two upstream AUGs in this region.
Further studies revealed that socs-1 translation is cap-dependent and that it is
modulated by eIF4E-binding proteins. In combination, these results uncover a
novel level of regulation of SOCS-related molecules. Moreover, coupled with
previous findings, they suggest that SOCS expression is tightly regulated through
multiple mechanisms, in order to avoid inappropriate interference with cytokine
mediated effects.
PMID- 10764817
TI - A conserved membrane-spanning amino acid motif drives homomeric and supports
heteromeric assembly of presynaptic SNARE proteins.
AB - Assembly of the SNARE proteins synaptobrevin/VAMP, syntaxin, and SNAP-25 to
binary and ternary complexes is important for docking and/or fusion of
presynaptic vesicles to the neuronal plasma membrane prior to regulated
neurotransmitter release. Despite the well characterized structure of their
cytoplasmic assembly domains, little is known about the role of the transmembrane
segments in SNARE protein assembly and function. Here, we identified conserved
amino acid motifs within the transmembrane segments that are required for
homodimerization of synaptobrevin II and syntaxin 1A. Minimal motifs of 6-8
residues grafted onto an otherwise monomeric oligoalanine host sequence were
sufficient for self-interaction of both transmembrane segments in detergent
solution or membranes. These motifs constitute contiguous areas of interfacial
residues assuming alpha-helical secondary structures. Since the motifs are
conserved, they also contributed to heterodimerization of synaptobrevin II and
syntaxin 1A and therefore appear to constitute interaction domains independent of
the cytoplasmic coiled coil regions. Interactions between the transmembrane
segments may stabilize the SNARE complex, cause its multimerization to previously
observed multimeric superstructures, and/or be required for the fusogenic
activity of SNARE proteins.
PMID- 10764818
TI - The isolation and characterization of a cDNA encoding phospholipid-specific
inositol polyphosphate 5-phosphatase.
AB - We report the cDNA cloning and characterization of a novel human inositol
polyphosphate 5-phosphatase (5-phosphatase) that has substrate specificity unlike
previously described members of this large gene family. All previously described
members hydrolyze water soluble inositol phosphates. This enzyme hydrolyzes only
lipid substrates, phosphatidylinositol 3,4,5-trisphosphate and
phosphatidylinositol 4,5-bisphosphate. The cDNA isolated comprises 3110 base
pairs and predicts a protein product of 644 amino acids and M(r) = 70,023. We
designate this 5-phosphatase as type IV. It is a highly basic protein (pI = 8.8)
and has the greatest affinity toward phosphatidylinositol 3,4,5-trisphosphate of
known 5-phosphatases. The K(m) is 0.65 micrometer, 1/10 that of SHIP (5.95
micrometer), another 5-phosphatase that hydrolyzes phosphatidylinositol 3,4,5
trisphosphate. The activity of 5-phosphatase type IV is sensitive to the presence
of detergents in the in vitro assay. Thus the enzyme hydrolyzes lipid substrates
in the absence of detergents or in the presence of n-octyl beta-glucopyranoside
or Triton X-100, but not in the presence of cetyltriethylammonium bromide, the
detergent that has been used in other studies of the hydrolysis of
phosphatidylinositol 4,5-bisphosphate. Remarkably SHIP, a 5-phosphatase
previously characterized as hydrolyzing only substrates with d-3 phosphates, also
readily hydrolyzed phosphatidylinositol 4,5-bisphosphate in the presence of n
octyl beta-glucopyranoside but not cetyltriethylammonium bromide. We used
antibodies prepared against a peptide predicted by the cDNA to identify the 5
phosphatase type IV enzyme in human tissues and find that it is highly expressed
in the brain as determined by Western blotting. We also performed Western
blotting of mouse tissues and found high levels of expression in the brain,
testes, and heart with lower levels of expression in other tissues. mRNA was
detected in many tissues and cell lines as determined by Northern blotting.
PMID- 10764819
TI - Mildly oxidized low density lipoprotein rapidly stimulates via activation of the
lysophosphatidic acid receptor Src family and Syk tyrosine kinases and Ca2+
influx in human platelets.
AB - In contrast to native low density lipoprotein (LDL), mildly oxidized LDL (mox
LDL) induced platelet shape change and stimulated during shape change the
tyrosine phosphorylation of specific proteins including Syk; the translocation of
Src, Fyn, and Syk to the cytoskeleton; and the increase of cytosolic Ca(2+) due
to mainly Ca(2+) entry. The stimulation of these early signal pathways by mox-LDL
was inhibited by desensitization of the lysophosphatidic acid (LPA) receptor and
specific LPA receptor antagonists, was independent of the alpha(IIb)beta(3)
integrin, and was mimicked by LPA. Stimulation of tyrosine phosphorylation and
Syk activation were independent of the increase of cytosolic Ca(2+) and were
suppressed by genistein and two specific inhibitors of the Src family tyrosine
kinases, PP1 and PD173956. In contrast to PP1 and PD 173956, genistein prevented
shape change by mox-LDL. The results indicate that mox-LDL, through activation of
the LPA receptor, stimulates two separate early signal pathways, (a) Src family
and Syk tyrosine kinases, and (b) Ca(2+) entry. The activation of these early
signaling pathways by mox-LDL probably plays a role in platelet responses
subsequent to shape change. The inhibition of mox-LDL-induced platelet activation
by LPA receptor antagonists or dietary isoflavonoids such as genistein could have
implications in the prevention and therapy of cardiovascular diseases.
PMID- 10764820
TI - Tumor necrosis factor-alpha production is differently regulated in gamma delta
and alpha beta human T lymphocytes.
AB - Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early defense
against pathogens. This cytokine is produced by several cell types including T
lymphocytes expressing the alphabeta as well as the gammadelta T cell receptor
(TcR). In human, the circulating gammadelta T cells, which mostly express
Vgamma9Vdelta2 TcR, have been strongly suggested to play an important protective
role against infectious agents. These activated cells early produce high amounts
of TNF-alpha, which induce a determinant beneficial effect against development of
intracellular pathogens; however, sustained production of this cytokine can
result in immunopathological diseases. The signals that regulate TNF-alpha
production in Vgamma9Vdelta2 T cells are totally unknown. In primary alphabeta T
cells, TNF-alpha production was shown to necessitate engagement of the TcR and
CD28, and to be independent of the p38 mitogen activated protein kinase pathway.
We demonstrate herein that, in contrast to alphabeta T cells, TNF-alpha
production in Vgamma9Vdelta2 T lymphocytes is independent of CD28 costimulation
and highly dependent on TcR-induced p38 kinase and extracellular signal-regulated
kinase 2 pathway activation for optimal cytokine release. Moreover, we bring
elements supporting the idea that the "activation threshold" of gammadelta T
cells leading to cytokine production is lower than that of alphabeta T cells.
PMID- 10764821
TI - The influence of glucan polymer structure and solution conformation on binding to
(1-->3)-beta-D-glucan receptors in a human monocyte-like cell line.
AB - Glucans are (1-3)-beta-D-linked polymers of glucose that are produced as fungal
cell wall constituents and are also released into the extracellular milieu.
Glucans modulate immune function via macrophage participation. The first step in
macrophage activation by (1-3)-beta-D-glucans is thought to be the binding of the
polymer to specific macrophage receptors. We examined the binding/uptake of a
variety of water soluble (1-3)-beta-D-glucans and control polymers with different
physicochemical properties to investigate the relationship between polymer
structure and receptor binding in the CR3- human promonocytic cell line, U937. We
observed that the U937 receptors were specific for (1-->3)-beta-D-glucan binding,
since mannan, dextran, or barley glucan did not bind. Scleroglucan exhibited the
highest binding affinity with an IC(50)of 23 nM, three orders of magnitude
greater than the other (1-->3)-beta-D-glucan polymers examined. The rank order
competitive binding affinities for the glucan polymers were
scleroglucan>>>schizophyllan > laminarin > glucan phosphate > glucan sulfate.
Scleroglucan also exhibited a triple helical solution structure (nu = 1.82, beta
= 0.8). There were two different binding/uptake sites on U937 cells. Glucan
phosphate and schizophyllan interacted nonselectively with the two sites.
Scleroglucan and glucan sulfate interacted preferentially with one site, while
laminarin interacted preferentially with the other site. These data indicate that
U937 cells have at least two non-CR3 receptor(s) which specifically interact with
(1-->3)-beta-D-glucans and that the triple helical solution conformation,
molecular weight and charge of the glucan polymer may be important determinants
in receptor ligand interaction.
PMID- 10764822
TI - N-Glycan processing by a lepidopteran insect alpha1,2-mannosidase.
AB - Protein glycosylation pathways are relatively poorly characterized in insect
cells. As part of an overall effort to address this problem, we previously
isolated a cDNA from Sf9 cells that encodes an insect alpha1,2-mannosidase
(SfManI) which requires calcium and is inhibited by 1-deoxymannojirimycin. In the
present study, we have characterized the substrate specificity of SfManI. A
recombinant baculovirus was used to express a GST-tagged secreted form of SfManI
which was purified from the medium using an immobilized glutathione column. The
purified SfManI was then incubated with oligosaccharide substrates and the
resulting products were analyzed by HPLC. These analyses showed that SfManI
rapidly converts Man(9)GlcNAc(2)to Man(6)Glc-NAc(2)isomer C, then more slowly
converts Man(6)GlcNAc(2)isomer C to Man(5)GlcNAc(2). The slow step in the
processing of Man(9)GlcNAc(2)to Man(5)GlcNAc(2)by SfManI is removal of the
alpha1,2-linked mannose on the middle arm of Man(9)GlcNAc(2). In this respect,
SfManI is similar to mammalian alpha1,2-mannosidases IA and IB. However,
additional HPLC and(1)H-NMR analyses demonstrated that SfManI converts
Man(9)GlcNAc(2)to Man(5)GlcNAc(2)primarily through Man(7)GlcNAc(2)isomer C, the
archetypal Man(9)GlcNAc(2)missing the lower arm alpha1,2-linked mannose residues.
In this respect, SfManI differs from mammalian alpha1,2-mannosidases IA and IB,
and is the first alpha1,2-mannosidase directly shown to produce
Man(7)GlcNAc(2)isomer C as a major processing intermediate.
PMID- 10764823
TI - Photoaffinity glycoprobes-a new tool for the identification of lectins.
AB - One of the proposed functions for the carbohydrate structures on glycoconjugates
is the transfer of information through interaction with specific lectin
receptors. However, the number of elucidated functional lectin-carbohydrate
interactions is still relatively small, largely due to the lack of adequate
methods to identify lectin activity in complex biological samples. Aiming to
solve this problem, we have developed a method based on the novel group of
compounds we named glycoprobes. The glycoprobe consists of three vital parts: (1)
glycan, (2) digoxin tag, and (3) photoreactive crosslinker. When incubated in
dark, oligosaccharide part of the glycoprobe forms a complex with lectin. After
illumination, covalent link between the probe and the lectin is formed resulting
in a digoxin-tagged lectin. Using antibodies against digoxin, this complex can
easily be identified immuno/cytochemically, or by Western blots. To demonstrate
the applicability of glycoprobes we have used Man(9)-glycoprobe (containing
Man(9)oligosaccharide) and YEE(ahGalNAc)(3)-glycoprobe (containing a synthetic
neoglycopeptide with three terminal N-acetyl-galactosamine residues; Lee and Lee,
Glycoconjugate J., 1987,4, 317) to identify lectins in bovine serum and rat liver
membranes. The simplicity of the method enables its application in routine
monitoring of changes in lectin activity during various developmental or
pathological processes. An example of GalNAc-binding analysis in human serum is
shown.
PMID- 10764824
TI - Molecular identification, tissue distribution and subcellular localization of
mST3GalV/GM3 synthase.
AB - A molecular screen for a mouse homologue of a Drosophila carbohydrate binding
protein, called Gliolectin, yielded a cDNA encoding mST3GalV/GM3 synthase (CMP
NeuAc: lactosylceramide alpha2, 3-sialyltransferase). By in situ hybridization
and immunohistochemistry, mST3GalV exhibits differential expression in neural and
non-neural tissues. Although expressed by all neurons in the central nervous
system, neuronal populations that contribute their axons to myelinated efferent
projections, such as cerebellar Purkinje cells and spinal motorneurons,
demonstrate the highest ST3GalV expression. When stained with anti-mST3GalV
antiserum (designated CS2), subpopulations of neurons display an elaborate Golgi
apparatus, frequently extending into one or more dendritic processes. The
extended spatial distribution of the neuronal Golgi apparatus, particularly in
spinal motorneurons, allowed the confocal immunohistochemical colocalization of
mST3GalV with markers for medial/trans-Golgi but not the cis-Golgi or trans-Golgi
network, consistent with previous observations suggesting that ganglioside
glycosyltransferases are enriched in late Golgi compartments. Among non-neural
tissues, liver and testes demonstrate cell-type specific CS2 staining. In liver,
endothelial cells lining a ring of sinusoids, concentric with the central vein,
express mST3GalV. Kupffer cells are also stained with CS2 antiserum but
hepatocyte expression is undetectable. In the seminiferous tubules of the testes,
ST3GalV is found in somatic (Leydig, Sertoli) and early germline cells
(spermatogonia and primary spermatocytes); the epididymal epithelium exhibits
intense ST3GalV expression. Since GM3 is a precursor for the synthesis of a- and
b-series gangliosides, the range of mST3GalV/GM3 synthase expression among
various cell populations indicates that certain cell types possess greater
reliance on ganglioside function than others.
PMID- 10764825
TI - alpha1,2Fucosyltransferase increases resistance to apoptosis of rat colon
carcinoma cells.
AB - Accumulation of histo-blood group antigens such as Lewis b, Lewis Y and H in
colon cancer is indicative of poor prognosis. It is accompanied by increase in
alpha1,2fucosyl-transferase activity, a key enzyme for synthesis of these
antigens. Using a model of colon carcinoma, we previously showed that
alpha1,2fucosylation increases tumorigenicity. We now show that tumorigenicity
inversely correlates with the cells' sensitivity to apoptosis. In addition,
poorly tumorigenic REG cells independently transfected with three different
alpha1,2fucosyltransferase cDNAs, the human FUT1, the rat FTA and FTB were more
resistant than control cells to apoptosis induced in vitro by serum deprivation.
Inversely, PRO cells, spontaneously tumorigenic in immunocompetent syngeneic
animals and able to synthesize alpha1,2fucosylated glycans, became more sensitive
to apoptosis after transfection with a fragment of the FTA cDNA in the antisense
orientation. Expression of alpha1,2fucosyl-transferase in poorly tumorigenic REG
cells dramatically enhanced their tumorigenicity in syngeneic rats. However, in
immunodeficient animals, both control and alpha1,2fuco-syltransferase transfected
REG cells were fully tumorigenic and metastatic, indicating that the presence of
alpha1,2fucosylated antigens allowed REG tumor cells to escape immune control.
Taken together, the results show that increased tumorigenicity mediated by
alpha1,2fucosyl-ation is associated to increased resistance to apoptosis and to
escape from immune control.
PMID- 10764826
TI - Glycopeptide export from mammalian microsomes is independent of calcium and is
distinct from oligosaccharide export.
AB - Glycopeptides are exported from the endoplasmic reticulum to the cytosol of
eukaryotic membranes in an ATP- and cytosol-requiring process (Romisch and Ali,
1997, Proc. Natl. Acad. Sci. USA,94, 6730-6734). Oligosaccharides of the
polymannose-type are also exported from the endoplasmic reticulum of mammalian
cells to the cytosol in an ATP-dependent fashion. These findings raise the strong
possibility that the two substrate classes are transported by the same mechanism
but the precise identity of the trans-location machinery for each substrate class
has not been fully defined. Here we have investigated the mechanism by which a
glycopeptide is exported from rat liver microsomes, and compare this to the
export of free polymannose oligosaccharides. Using EGTA and the endoplasmic
reticulum calcium mobilizing agents thapsigargicin and calcium ionophores A23187
and ionomycin, we show that glycopeptides, in contrast to oligosaccharides, are
exported by a calcium-independent mechanism. On the other hand, Mg(2+)is required
in the assay for the transport of glycopeptide from mammalian microsomes which is
in common with oligosaccharide export. Deoxynojirimycin and castanospermine,
inhibitors of ER glucosidases, when added to rat liver microsomes prior to
loading with peptide that bears an N -glycosylation sequon, had no effect on the
release of glucosylated glycopeptides from membranes, indicating that removal of
the alpha-glucose units from the oligomannose glycan structure of the
glycopeptide is not required for export. In contrast to oligosaccharides, where
transport is efficiently inhibited, mannosides were without effect or only weak
inhibitors of glycopeptide export. Taken together, these data suggest that
glycopeptides are exported by a distinct mechanism from oligosaccharides of the
polymannose-type and that the peptide moiety is an important structural
determinant for glycopeptide export and capable of directing translocation of
substrates to a specific transport pathway.
PMID- 10764827
TI - A fingerprinting method for chondroitin/dermatan sulfate and hyaluronan
oligosaccharides.
AB - A previously published method for the analysis of glycosaminoglycan disaccharides
by high pH anion exchange chromatography (Midura,R.J., Salustri,A., Calabro,A.,
Yanagishita,M. and Hascall,V.C. (1994), Glycobiology,4, 333-342) has been
modified and calibrated for chondroitin and dermatan sulfate oligosaccharides up
to hexasaccharide in size and hyaluronan oligosaccharides up to
hexadecasaccharide. For hyaluronan oligosaccharides chain length controls elution
position; however, for chondroitin and dermatan sulfate oligosaccharides elution
times primarily depend upon the level of sulfation, although chain length and
hence charge density plays a role. The sulfation position of GalNAc residues
within an oligosaccharide is also important in determining its elution position.
Compared to 4-sulfation a reducing terminal 6-sulfate retards elution; however,
when present on an internal GalNAc residue it is the 4-sulfate containing
oligosaccharide which elutes later. These effects allow discrimination between
oligosaccharides differing only in the position of GalNAc sulfation. Using this
simple methodology, a Dionex CarboPac PA-1 column with NaOH/NaCl eluents and
detection by absorbance at 232 nm, a quantitative analytical fingerprint of a
chondroitin/dermatan sulfate chain may be obtained, allowing a determination of
the abundance of chondroitin sulfate, dermatan sulfate, and hyaluronan along with
an analysis of structural features with a linear response to approximately 0.1
nmol. The method may readily be calibrated using either commercial disaccharides
or the di- and tetrasaccharide products of a limit digest of commercial
chondroitin sulfate by chondroitin ABC endolyase. Commercially available and
freshly prepared shark, whale, bovine, and human cartilage chondroitin sulfates
have been examined by this methodology and we have confirmed that freshly
isolated shark cartilage CS contains significant amounts of the biologically
important GlcA2Sbeta(1-3)GalNAc6S structure.
PMID- 10764828
TI - Cloning and characterization of mammalian UDP-glucose glycoprotein:
glucosyltransferase and the development of a specific substrate for this enzyme.
AB - The endoplasmic reticulum enzyme UDP-glucose glycoprotein:glucosyltransferase
(UGGT) has the unique property of recognizing incompletely folded glycoproteins
and, if they carry an N -linked Man(9)GlcNAc(2)oligosaccharide, of catalyzing the
addition of a glucose residue from UDP-glucose. Using peptide sequence
information, we have isolated the complete cDNA of rat liver UGGT and expressed
it in insect cells. The cDNA specifies an open reading frame which codes for a
protein of 1527 residues including an 18 amino acid signal peptide. The protein
has a C-terminal tetrapeptide (HEEL) characteristic of endoplasmic reticulum
luminal proteins. The purified recombinant enzyme shows the same preference for
unfolded polypeptides with N -linked Man(9)GlcNAc(2)glycans as the enzyme
purified from rat liver. A genetically engineered Saccharomyces cerevisiae strain
capable of producing glyco-proteins with Man(9)GlcNAc(2)core oligosaccharides was
constructed and secreted acid phosphatase (G0-AcP) was purified. G0-AcP was used
as an acceptor glycoprotein for UGGT and found to be a better substrate than the
previously used soybean agglutinin and thyroglobulin. Recombinant rat UGGT has a
K (m) of 44 microM for UDP-glucose. A proteolytic fragment of UGGT was found to
retain enzymatic activity thus localizing the catalytic site of the enzyme to the
C-terminal 37 kDa of the protein. Using site-directed mutagenesis and
photoaffinity labeling, we have identified residues D1334, D1336, Q1429, and
N1433 to be necessary for the catalytic activity of the enzyme.
PMID- 10764829
TI - Regulation of CD45-induced signaling by galectin-1 in Burkitt lymphoma B cells.
AB - It has been well established that Galectin-1 (GAL1), a beta-galactoside-binding
protein, regulates the viability of lymphoid cells. However, the signaling
pathway governed by the binding of GAL1 to the cell membrane is not understood.
As a first step towards the elucidation of GAL1-initiated signaling events
leading to a reduced viability of Burkitt lymphoma B cells, we tried to
characterize the initial events induced by the binding of GAL1 to its receptor.
This characterization was performed in BL36 cells, a Burkitt lymphoma cell line
sensitive to GAL1. The results were as follows: (1) when solubilized cell
membrane lysates were affinity bound to immobilized GAL1 and eluted by
competition, the tyrosine phosphatase glyco-protein CD45 was found in the eluate,
highlighting the role of CD45 as a receptor of GAL1; (2) the phosphatase activity
of cell membranes diminished after incubation with GAL1; (3) immunoprecipitation
experiments demonstrated that the phosphotyrosine kinase Lyn was dysregulated in
cells that have been cultured in medium containing 700 nM GAL1, and (4) that the
ratio between two isoforms of Lyn was modified during the treatment with GAL1.
The regulation of Lyn therefore seems to be a key event in the action of GAL1.
PMID- 10764830
TI - Remodeling of sugar chain structures of human interferon-gamma.
AB - Natural human interferon (IFN)-gamma has mainly biantennary complex-type sugar
chains and scarcely has multiantennary structures. We attempted to remodel the
sugar chain structures using IFN-gamma as a model glycoprotein. To obtain the
branching glycoforms of IFN-gamma, we introduced the genes for GnT-IV (UDP-N
acetylglucosamine:alpha-1,3-D-mannoside beta-1, 4-N
acetylglucosaminyltransferase) and/or GnT-V (UDP-N-acetylglucosamine:alpha-1,6-D
mannoside beta-1, 6-N-acetylglucosaminyltransferase) into Chinese hamster ovary
(CHO) cells producing human IFN-gamma. The parental CHO cells produced IFN-gamma
with biantennary sugar chains mainly. When the GnT-IV activity was increased,
triantennary sugar chains with a branch produced by GnT-IV increased up to 66.9%
of the total sugar chains. When the GnT-V activity was increased, triantennary
sugar chains with a corresponding branch increased up to 55.7% of the total sugar
chains. When the GnT-IV and -V activities were increased at a time,
tetraantennary sugar chains increased up to 56.2% of the total sugar chains. The
proportion of these multiantennary sugar chains corresponded to the intracellular
activities of GnT-IV and -V. What is more, lectin blot and flow cytometric
analysis indicated that the multi-branch structure of the sugar chains was
increased not only on IFN-gamma, one of the secretory glycoproteins, but also on
almost CHO cellular proteins by introducing either or both of the GnT genes. The
results suggest that the branching structure of sugar chains of glycoproteins
could be controlled by cellular GnT-IV and GnT-V activities. This technology can
produce glycoforms out of natural occurrence, which should enlarge the potency of
glycoprotein therapeutics.
PMID- 10764832
TI - MUC1: the polymorphic appearance of a human mucin.
PMID- 10764831
TI - Siglec-7: a sialic acid-binding lectin of the immunoglobulin superfamily.
AB - The Siglecs are a recently discovered family of sialic acid-binding lectins of
the immunoglobulin (Ig) superfamily. We report a molecule showing homology to the
six first reported Siglecs, with the closest relationship to Siglec-3(CD33),
Siglec-5, and Siglec-6(OBBP-1). The extracellular portion has two Ig-like
domains, with the amino-terminal V-set Ig domain including amino acid residues
known to be involved in sialic acid recognition by other Siglecs. The cytoplasmic
domain has putative sites of tyrosine phosphorylation shared with some Siglecs,
including an Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM). Expression
of the full-length cDNA induces sialic acid-dependent binding to human
erythrocytes. A recombinant chimeric form containing the extracellular Ig domains
selectively recognizes the sequence Neu5Acalpha2-6Galbeta1-4Glc, and binding
requires the side chain of sialic acid. Mutation of an arginine residue predicted
to be critical for sialic acid binding abolishes both interactions. Taken
together, our findings justify designation of the molecule as Siglec-7. Analysis
of bacterial artificial chromosome (BAC) clones spanning the known human genomic
location of Siglec-3 indicates that the Siglec-7 gene is also located on
chromosome 19q13.3-13.4. Human tissues show strong expression of Siglec-7 mRNA in
spleen, peripheral blood leukocytes, and liver. The combination of an
extracellular sialic acid binding site and an intracellular ITIM motif suggests
that this molecule is involved in trans-membrane regulatory signaling reactions.
PMID- 10764833
TI - Structural characterization of a xylanase from psychrophilic yeast by mass
spectrometry.
AB - The complete structural characterization of the xylanase, a glycoprotein
constituted of 338 amino acids, from psychrophilic antarctic yeast Criptococcus
albidus TAE85 was achieved both at the protein and carbohydrate level by
exploiting mass spectrometric procedures. The verification of the primary
structure, the definition of the S-S pattern, the assignment of glycosylation
sites and the investigation of glycosylation pattern were performed. This
analysis revealed the occurrence of N-glycosylation only at Asn254, modified by
high-mannose structure; moreover the protein resulted to be O-glycosylated with
GalGalNAc structures. The data obtained on both the N- and O-linked glycans in
the cold xylanase constitute the first description of the glycosylation pattern
in psychrophylic microorganisms and suggest that the glycosylation system in cold
adapted organisms might have similarities as well as differences with respect to
mesophylic and thermophylic cells. The cysteine pairings were eventually
identified as Cys173-Cys205 and Cys272-Cys278, with Cys89 showing a free thiol
group. These data suggest that a common folding motif might occur within the
entire xylanase family in which the second Cys is linked to the third one with
the fourth and fifth joined together.
PMID- 10764834
TI - Isolation of the receptor for Amaranthus leucocarpus lectin from murine naive
thymocytes.
AB - From murine medullary thymocytes we purified the receptor for the Amaranthus
leucocarpus lectin (ALL) using a complex with the biotin-labeled lectin and
avidin-agarose as the affinity matrix. Most ALL(+)thymocytes (83%) are naive
cells with the CD4(+)CD8(-)CD45RB(+)phenotype. The receptor for this lectin is a
70 kDa glycoprotein that contains 20% of sugar by mass. It is constituted mainly
by aspartic and glutamic acids, serine, proline, and glycine; its glycosidic
portion contains mainly O-glycosidically linked glycans with Gal, GalNAc and
NeuAc residues as well as one N-glycosidically linked glycan per molecule. Ionic
strength chromatography revealed that the ALL-thymocyte receptor (ALLTr) is made
up by three isoforms, which possess similar amino acid composition but show
slight differences in their sugar composition. The N-terminal amino acid residues
are blocked both in the receptor and its purified isoforms. Analyses of the
receptor's peptides, obtained by trypsin digestion with MALDI-TOF (matrix
assisted laser desorption ionization-time of flight), were compared with the
relative values obtained from the NCBInr (Swiss-Prot 10/01/99) database. Our
results indicate that the peptides of ALLTr show low homology (<17%) with the
human KIIA protein, the Fas-associated death domain protein, and the transforming
growth factor-beta type II receptor. Our results suggest that the ALL thymocyte
receptor could be considered a novel phenotypic marker specific for naive T
cells.
PMID- 10764835
TI - Heparanase expression in invasive trophoblasts and acute vascular damage.
AB - Heparan sulfate proteoglycans play a pivotal role in tissue function,
development, inflammation, and immunity. We have identified a novel cDNA encoding
human heparanase, an enzyme thought to cleave heparan sulfate in physiology and
disease, and have located the HEP gene on human chromosome 4q21. Monoclonal
antibodies against human heparanase located the enzyme along invasive
extravillous trophoblasts of human placenta and along endothelial cells in organ
xenografts targeted by hyperacute rejection, both sites of heparan sulfate
digestion. Heparanase deposition was evident in arterial walls in normal tissues;
however, vascular heparan sulfate cleavage was coincident with heparanase enzyme
during inflammatory episodes. These findings suggest that heparanase elaboration
and control of catalytic activity may contribute to the development and
pathogenesis of vascular disease and suggest that heparanase intervention might
be a useful therapeutic target.
PMID- 10764836
TI - Species-specific variation in glycosylation of IgG: evidence for the species
specific sialylation and branch-specific galactosylation and importance for
engineering recombinant glycoprotein therapeutics.
AB - Immunoglobulins (IgG) are soluble serum glycoproteins in which the
oligosaccharides play significant roles in the bioactivity and pharmacokinetics.
Recombinant immuno-globulins (rIgG) produced in different host cells by
recombinant DNA technology are becoming major therapeutic agents to treat life
threatening diseases such as cancer. Since glycosylation is cell type specific,
rIgGs produced in different host cells contain different patterns of
oligosaccharides which could affect the biological functions. In order to
determine the extent of this variation N-linked oligosaccharide structures
present in the IgGs of different animal species were characterized. IgGs of
human, rhesus, dog, cow, guinea pig, sheep, goat, horse, rat, mouse, rabbit, cat,
and chicken were treated with peptide-N-glycosidase-F (PNGase F) and the
oligosaccharides analyzed by matrix-assisted laser desorption/ionization time-of
flight mass spectrometry (MALDI-TOF-MS) for neutral and acidic oligosaccharides,
in positive and negative ion modes, respectively. The data show that for neutral
oligosaccharides, the proportions of terminal Gal, core Fuc and/or bisecting
GlcNAc containing oligosaccharides vary from species to species; for sialylated
oligosaccharides in the negative mode MALDI-TOF-MS show that human and chicken
IgG contain oligosaccharides with N-acetylneuraminic acid (NANA), whereas rhesus,
cow, sheep, goat, horse, and mouse IgGs contain oligosaccharides with N
glycolylneuraminic acid (NGNA). In contrast, IgGs from dog, guinea pig, rat, and
rabbit contain both NANA and NGNA. Further, the PNGase F released
oligosaccharides were derivatized with 9-aminopyrene 1,4,6-trisulfonic acid
(APTS) and analyzed by capillary electrophoresis with laser induced fluorescence
detection (CE-LIF). The CE-LIF results indicate that the proportion of the two
isomers of monogalactosylated, biantennary, complex oligosaccharides vary
significantly, suggesting that the branch specificity of beta1, 4
galactosyltransferase might be different in different species. These results show
that the glycosylation of IgGs is species-specific, and reveal the necessity for
appropriate cell line selection to express rIgGs for human therapy. The results
of this study are useful for people working in the transgenic area.
PMID- 10764837
TI - Two distinct domains of the beta-subunit of glucosidase II interact with the
catalytic alpha-subunit.
AB - Recent purification and cDNA cloning of the endoplasmic reticulum processing
enzyme glucosidase II have revealed that it is composed of two soluble proteins:
a catalytic alpha-subunit and a beta-subunit of unknown function, both of which
are highly conserved in mammals. Since the beta-subunit, which contains a C
terminal His-Asp-Glu-Leu (HDEL) motif, may function to link the catalytic subunit
to the KDEL receptor as a retrieval mechanism, we sought to map the regions of
the mouse beta-subunit protein responsible for mediating the association with the
alpha-subunit. By screening a panel of recombinant beta-subunit glutathione S
transferase fusion proteins for the ability to precipitate glucosidase II
activity, we have identified two non-overlapping interaction domains (ID1 and
ID2) within the beta-subunit. ID1 encompasses 118 amino acids at the N-terminus
of the mature polypeptide, spanning the cysteine-rich element in this region.
ID2, located near the C-terminus, is contained within amino acids 273-400, a
region occupied in part by a stretch of acidic residues. Variable usage of 7
alternatively spliced amino acids within ID2 was found not to influence the
association of the two sub-units. We theorize that the catalytic subunit of
glucosidase II binds synergistically to ID1 and ID2, explaining the high
associative stability of the enzyme complex.
PMID- 10764838
TI - The alpha- and beta-subunits are required for expression of catalytic activity in
the hetero-dimeric glucosidase II complex from human liver.
AB - The alpha- and beta-subunits of the hetero-dimeric glucosidase II complex from
human liver were cloned and expressed in COS-1 cells. The 4106 bp full-length
cDNA for the alpha-subunit contained a 2835 bp ORF encoding a 107 kDa
polypeptide. The 2095 bp cDNA for the beta-subunit encodes a approximately 60 kDa
protein in a continuous 1605 bp ORF. The alpha- and beta-subunits each contain
two potential Asn-Xaa-Thr/Ser acceptor sites, with only one site in the alpha
subunit (Asn97) being glycosylated. Additional lambda-clones were isolated for
each subunit containing in-frame insertions/deletions within the coding region,
indicating alternative splicing. Analysis of different human tissues revealed
approximately 4.4 kb and approximately 2.4 kb transcripts for alpha- and beta
subunit, respectively, consistent with their full-length cDNA. Coexpression of
the alpha- and beta-subunits in COS-1 cells resulted in >4-fold increase of
glucosidase II activity. An inactive protein was obtained, however, after
transfection with the alpha-subunit alone, showing that both subunits are
essential for expression of active glucosidase II. The observation that the
enzyme, previously purified from pig liver and lacking the beta-subunit, was
catalytically active indicates that the beta-subunit is involved in alpha-subunit
maturation rather than being required for enzymatic activity once the alpha
subunit has acquired its mature form. The alpha-subunit is expressed in COS-1
cells as an ER-located protein, whether inactive or part of a catalytically
active complex. This suggests that ER-localization of the alpha-subunit, when
associated with the dimeric enzyme complex, is mediated by the C-terminal HDEL
signal in the beta-subunit, whereas the apparently incompletely folded form of
the inactive alpha-subunit could be retained in the ER by the putative
"glycoprotein-specific quality control machinery. "
PMID- 10764839
TI - A sequence motif involved in the donor substrate binding by alpha1,6
fucosyltransferase: the role of the conserved arginine residues.
AB - Alpha1,6-fucosyltransferase catalyzes the transfer of fucose to the innermost
GlcNAc residue of an N-linked oligosaccharide. In order to identify the amino
acid residue(s) which are associated with the enzyme activity and to investigate
their function, we prepared a series of mutant human alpha1,6-fucosyltransferases
in which the conserved residues in the region homologous to alpha1,2
fucosyltransferase had been replaced. These proteins were then characterized by
kinetic analyses. The wild-type and mutant alpha1,6-fucosyltransferases were
expressed using a baculovirus-insect cell system. The activity assay showed that
replacement of Arg-365 by Ala or Lys led to a complete loss of activity while
substitution of Ala or Lys for the neighboring Arg-366 decreased the activity to
about 3% that of the wild type. Kinetic analyses revealed that the replacements
of Arg-366 lead to an increase in the apparent K (m) value for both GDP-fucose
and the acceptor oligosaccharide but did not markedly affect the apparent V
(max). When these mutants were inhibited by GDP in a competitive manner with
respect to the donor substrate, the K (i) values were found to be 50-100 times
higher than the value in the wild type. On the other hand, in the inhibition by
GMP, the K (i) values for the mutants were very similar to that of the wild type.
These findings suggest that Arg-366 contributes to the binding of GDP-fucose via
an interaction with the beta-phosphoryl group of the GDP moiety of the donor, and
that Arg-365 may also play an essential role in substrate binding. The results
suggest that the motif common to alpha1,2- and alpha1,6-fucosyltransferases is
critical for binding of the donor substrate, GDP-fucose.
PMID- 10764840
TI - Unusual N-glycosylation of a recombinant human erythropoietin expressed in a
human lymphoblastoid cell line does not alter its biological properties.
AB - Erythropoietin (Epo) is a 166 amino acids protein containing three N
glycosylation sites (Asn-24, Asn-38, and Asn-83) and 1 O- glycosylation site (Ser
126) and involved in the regulation of the level of red blood cells. Today, only
one recombinant human Epo (rHuEpo), produced in CHO cell line, is extensively
used in therapy to cure severe anemia. The structure of the glycan chains of this
rHuEpo slightly differ of those of the urinary human Epo (uHuEpo), considered as
the natural Epo molecule. In an attempt to produce a rHuEpo as close as possible
to the uHuEpo, Epo gene was expressed in a human lymphoblastoid cell line, named
RPMI 1788. In order to fully characterize the Epo-RPMI, structural
characterizations of the protein skeleton as well as glycan chains were
undergone. As expected, the amino acid sequence of the Epo-RPMI conformed to that
of uHuEpo. Surprisingly, the structure of some N-glycan chains, as mainly
determined by ESI-MS, revealed some unusual characteristics. Thus, 80% of N
glycans possess a bisecting GlcNAc residue, 25% bear a second fucose residue
which is present, in a large part, in a sialyl Le(x)motif, and 13% contain more
than three LacNAc repeats (up to five per molecule). Despite these unusual
structural characteristics, the data concerning the in vitro and in vivo
biological activities were not impaired when compared to Epo-CHO and uHuEpo.
PMID- 10764841
TI - Use of recombinant endomannosidase for evaluation of the processing of N-linked
oligosaccharides of glycoproteins and their oligosaccharide-lipid precursors.
AB - Although glucose residues in a triglucosyl sequence are essential for the N
glycosylation of proteins and in their monoglucosyl form have been implicated in
lectin-like interactions with chaperones, their removal is required for the
formation of mature carbohydrate units and represents the initial steps in the
glycoprotein processing sequence. In order to provide a probe for the
glucosylation state of newly synthesized glycoproteins obtained from normal or
altered cells, we have evaluated the usefulness of recombinant endo-alpha
mannosidase employing sodium dodecyl sulfate polyacrylamide gel electrophoresis
(SDS-PAGE) to monitor the change in molecular mass brought about by the release
of glucosylated mannose (Glc(1-3)Man). With this approach the presence of two
triglucosylated-N-linked oligosaccharides in vesicular stomatis virus (VSV) G
protein formed by castanospermine-treated CHO cells or the glucosidase I
deficient Lec23 mutant could be clearly demonstrated and an even more pronounced
change in migration was observed upon endomannosidase treatment of their more
heavily N-glycosylated lysosomal membrane glycoproteins. Furthermore, the G
protein of the temperature sensitive VSV ts045 mutant was found to be sensitive
to endomannosidase, resulting in a change in electrophoretic mobility consistent
with the presence of mono-glucosylated-N-linked oligosaccharides. The finding
that endomannosidase also acts effectively on oligosaccharide lipids, as assessed
by SDS-PAGE or thin layer chromatography, indicated that it would be a valuable
tool in assessing the glucosylation state of these biosynthetic intermediates in
normal cells as well as in mutants or altered metabolic states, even if the
polymannose portion is truncated. Endomannosidase can also be used to determine
the glucosylation state of the polymannose oligosaccharides released during
glycoprotein quality control and when used together with endo-beta-N-
acetylglucosaminidase H can distinguish between those terminating in a single N
acetylglucosamine or in a di-N-acetylchitobiose sequence.
PMID- 10764842
TI - Minimal structural and glycosylation requirements for ST6Gal I activity and
trafficking.
AB - The influence of N-linked glycosylation on the activity and trafficking of
membrane associated and soluble forms of the STtyr isoform of the ST6Gal I has
been evaluated. We have demonstrated that the enzyme is glycosylated on Asn 146
and Asn 158 and that glycosylation is not required for the endoplasmic reticulum
to Golgi transport of the membrane-associated form of the STtyr isoform. In
addition, N-linked glycosylation may stabilize the protein but is not absolutely
required for catalytic activity in vivo. In contrast, soluble forms of the
protein consisting of amino acids 64-403, 89-403, and 97-403 are efficiently
secreted and active in their fully glycosylated forms, but retained in the
endoplasmic reticulum and inactive in their unglycosylated forms. These results
suggest that membrane associated and soluble forms of the STtyr protein have
different requirements for N-linked glycosylation. Elimination of the
oligosaccharide attached to Asn 158 in the full length STtyr single and double
glycosylation mutants generates proteins that are not cleaved and secreted but
stably localized in the Golgi, like the STcys isoform of the ST6Gal I. This
stable Golgi localization is correlated with the observation that these two
mutants are active in in vivo assays but inactive in in vitro assays of membrane
lysates. We predict that removal of N-linked oligosaccharides leads to an
increased ability of the STtyr protein to self-associate or oligomerize which
subsequently allows more stable retention in the Golgi and increased aggregation
and inactivity when membranes are lysed in the in vitro activity assays.
PMID- 10764844
TI - The importance of the beta-cell in the pathogenesis of type 2 diabetes mellitus.
AB - beta-cell dysfunction and insulin resistance are two central, interrelated
defects in the pathophysiology of type 2 diabetes. By the time a patient's
hyperglycemia is recognized, disruption of the normal relationship between beta
cell function and insulin sensitivity is already well established. The
pathophysiology and progression of defects in glucose metabolism from normal
glucose tolerance to impaired glucose tolerance to frank type 2 diabetes have
been studied extensively. Insulin sensitivity has wide intersubject variability,
and many individuals at risk for type 2 diabetes are insulin resistant. beta-cell
changes in patients with type 2 diabetes include defects in insulin secretion,
proinsulin conversion to insulin, and amyloid deposition in the islet. Studies in
several ethnic groups have established that the progression from normal glucose
tolerance to frank type 2 diabetes results from a gradual deterioration in beta
cell function in the presence of insulin resistance. Furthermore, the recently
completed landmark United Kingdom Prospective Diabetes Study demonstrated that
type 2 diabetes is a progressive disease and that this progression is due to
declining beta-cell function.
PMID- 10764845
TI - The importance of insulin resistance in the pathogenesis of type 2 diabetes
mellitus.
AB - Many patients with type 2 diabetes have hyperglycemia as a result of deficiencies
in both insulin secretion and insulin action, that is, beta-cell dysfunction and
insulin resistance. Insulin resistance is a state of reduced insulin sensitivity,
an inability of insulin to lower plasma glucose levels through suppression of
hepatic glucose production and stimulation of glucose utilization in skeletal
muscle and adipose tissue. Insulin resistance stems from genetic and
environmental causes, and its extent varies considerably among individuals.
Studies have shown that enhanced insulin secretion can compensate for insulin
resistance and that enhanced insulin sensitivity can mask defects in beta-cell
function. However, insulin resistance is essential to the development of the
majority of cases of type 2 diabetes. Numerous epidemiologic studies have
demonstrated an increase in the prevalence of insulin resistance and type 2
diabetes in various ethnic populations that have migrated from their native lands
to more urbanized and westernized regions of the world. Type 2 diabetes has
already reached epidemic proportions worldwide. By 2025, an estimated 300 million
people will have diabetes, most of whom will inhabit China, India, and the United
States. These studies have also demonstrated the complex interrelationship of
hyperinsulinemia, obesity (primarily visceral adiposity), and free fatty acids
with beta-cell dysfunction, insulin resistance, and the development of type 2
diabetes. Although little can be done to avert a genetic predisposition to type 2
diabetes, normoglycemia can be preserved in individuals who remain insulin
sensitive. Lifestyle changes can be implemented and medications can be
administered to improve insulin sensitivity, insulin secretion, and glucose
utilization and reduce the prevalence of type 2 diabetes.
PMID- 10764846
TI - Combining sulfonylureas and other oral agents.
AB - Type 2 diabetes mellitus is a progressive disorder, and although oral monotherapy
is often initially successful, it is associated with a high secondary failure
rate, which contributes to the development of long-term diabetes complications
resulting from persistent hyperglycemia. For patients not taking insulin,
accumulating evidence suggests that combination therapy using oral antidiabetic
agents with different mechanisms of action may be highly effective in achieving
and maintaining target blood glucose levels. Low-dose combination therapy may be
associated with fewer side effects than higher-dose monotherapy and may achieve
similar or better glycemic control. The best-studied combination is that of
sulfonylurea compounds plus metformin, a therapeutic approach that addresses both
underlying defects in the disorder: insulin deficiency and insulin resistance.
Other multidrug regimens under investigation are sulfonylurea compounds plus
either alpha-glucosidase inhibitors or thiazolidinediones, and combinations of
various insulin-sensitizing agents. For many patients, combination oral therapy
may be used appropriately as primary management early in the course of type 2
diabetes, along with diet modification and exercise. Later in the course of the
disease, the use of combinations of oral agents may delay the need for insulin
while maintaining glycemic control, thus making aggressive oral treatment more
acceptable for many patients.
PMID- 10764847
TI - Combining insulin and oral agents.
AB - Type 2 diabetes mellitus is a progressive disorder, and maintenance of near
normal glycemic control has been demonstrated to reduce the risk of its
associated long-term vascular complications. This treatment goal can be achieved
in most patients with use of single oral agents, combinations of oral agents, or
insulin. Secondary failure rates for intensive oral or injected therapy are high,
however, especially in patients with long-standing disease. A substantial body of
evidence indicates that combination therapy with insulin and oral antidiabetic
agents can safely establish excellent glycemic control in most patients, while it
reduces the required dosage of insulin and, in some combinations, mitigates the
weight gain associated with insulin therapy. The availability of more convenient
insulin-delivery systems may render the addition of insulin to oral drug therapy
more acceptable to patients and clinicians. The most-studied combination is that
of insulin and the sulfonylurea drugs. Randomized, prospective clinical trials
have documented the benefits of thiazolidinediones, metformin, and acarbose in
combination with insulin. To date, however, clinical trial data are insufficient
for use in determining the optimal combination of agents, insulin formulations,
and dosages among the many currently available possibilities.
PMID- 10764848
TI - Refractive Error Study in Children: sampling and measurement methods for a multi
country survey.
AB - PURPOSE: The Refractive Error Study in Children was designed to assess the
prevalence of refractive error and vision impairment in children of different
ethnic origins and cultural settings. METHODS: Population-based cross-sectional
samples of children 5 to 15 years of age were obtained through cluster sampling.
Presenting, uncorrected, and best-corrected visual acuity, along with refractive
error under cycloplegia, were the main outcome measures. Amblyopia and other
causes of uncorrectable vision impairment were determined. RESULTS: Study design
and sample size calculations, survey enumeration and ophthalmic examination
methods, quality assurance monitoring, and da ta analyses and statistical methods
are described. CONCLUSIONS: The study design, sample size, and measurement
methods ensure that the prevalence of age-specific and sex-specific refractive
error can be estimated with reasonable accuracy in the target populations. With
commonality of methods, a comparison of findings between studies in different
ethnic origins and cultural settings is possible.
PMID- 10764849
TI - Refractive Error Study in Children: results from Shunyi District, China.
AB - PURPOSE: To assess the prevalence of refractive errors and vision impairment in
school-age children in Shunyi District, northeast of Beijing, the Peoples
Republic of China. METHODS: Random selection of village-based clusters was used
to identify a sample of children 5 to 15 years of age. Resident registration
books were used to enumerate eligible children in the selected villages and
identify their current school. Ophthalmic examinations were conducted in 132
schools on children from 29 clusters during May 1988 to July 1998, including
visual acuity measurements, cycloplegic retinoscopy, cycloplegic autorefraction,
ocular motility evaluation, and examination of the external eye, anterior
segment, media, and fundus. Independent replicate measurements of all children
with reduced vision and a sample of those with normal vision were done for
quality assurance monitoring in three schools. RESULTS: A total of 6,134 children
from 4,338 households were enumerated, and 5,884 children (95.9%) were examined.
The prevalence of uncorrected, presenting, and best visual acuity 0.5 (20/40) or
worse in at least one eye was 12.8%, 10.9%, and 1.8%, respectively; 0.4% had best
visual acuity 0.5 or worse in both eyes. Refractive error was the cause in 89.5%
of the 1,236 eyes with reduced vision, amblyopia in 5%, other causes in 1.5%,
with unexplained causes in the remaining 4%. Myopia -0.5 diopter or less in
either eye was essentially absent in 5-year-old children, but increased to 36.7%
in males and 55.0% in females by age 15. Over this same age range, hyperopia 2
diopters or greater decreased from 8.8% in males and 19.6% in females to less
than 2% in both. Females had a significantly higher risk of both myopia and
hyperopia. CONCLUSIONS: Reduced vision because of myopia is an important public
health problem in school-age children in Shunyi District. More than 9% of
children could benefit from prescription glasses. Further studies are needed to
determine whether the upward trend in the prevalence of myopia continues far
beyond age 15 and whether the development of myopia is changing for more recent
birth cohorts.
PMID- 10764850
TI - Refractive Error Study in Children: results from Mechi Zone, Nepal.
AB - PURPOSE: To assess the prevalence of refractive error and vision impairment in
school age children in the terai area of the Mechi zone in Eastern Nepal.
METHODS: Random selection of village-based clusters was used to identify a sample
of children 5 to 15 years of age. Children in the 25 selected clusters were
enumerated through a door-to-door household survey and invited to village sites
for examination. Visual acuity measurements, cycloplegic retinoscopy, cycloplegic
autorefraction, ocular motility evaluation, and anterior segment, media, and
fundus examinations were done from May 1998 through July 1998. Independent
replicate examinations for quality assurance monitoring took place in all
children with reduced vision and in a sample of those with normal vision in seven
villages. RESULTS: A total of 5,526 children from 3,724 households were
enumerated, and 5,067 children (91.7%) were examined. The prevalence of
uncorrected, presenting, and best visual acuity 0.5 (20/40) or worse in at least
one eye was 2.9%, 2.8%, and 1.4%, respectively; 0.4% had best visual acuity 0.5
or worse in both eyes. Refractive error was the cause in 56% of the 200 eyes with
reduced uncorrected vision, amblyopia in 9%, other causes in 19%, with
unexplained causes in the remaining 16%. Myopia -0.5 diopter or less in either
eye or hyperopia 2 diopters or greater was observed in less than 3% of children.
Hyperopia risk was associated with female gender and myopia risk with older age.
CONCLUSIONS: The prevalence of reduced vision is very low in school-age children
in Nepal, most of it because of correctable refractive error. Further studies are
needed to determine whether the prevalence of myopia will be higher for more
recent birth cohorts.
PMID- 10764851
TI - Refractive Error Study in Children: results from La Florida, Chile.
AB - PURPOSE: To assess the prevalence of refractive errors and vision impairment in
school-age children in a suburban area (La Florida) of Santiago, Chile. METHODS:
Random selection of geographically defined clusters was used to identify a
representative sample of children 5 to 15 years of age. Children in the 26
selected clusters were enumerated through a door-to-door survey and invited to
report to a community health clinic for examination. Visual acuity measurements,
cycloplegic retinoscopy, cycloplegic autorefraction, ocular motility evaluation,
and examination of the external eye, anterior segment, media, and fundus were
done from April through August 1998. Independent replicate examinations of all
children with reduced vision and a sample of those with normal vision were done
for quality assurance monitoring in six clusters. RESULTS: A total of 6,998
children from 3,830 households were enumerated, and 5,303 children (75.8%) were
examined. The prevalence of uncorrected, presenting, and best visual acuity 0.50
(20/40) or worse in at least one eye was 15.8%, 14.7%, and 7.4%, respectively;
3.3% had best visual acuity 0.50 or worse in both eyes. Refractive error was the
cause in 56.3% of the 1,285 eyes with reduced vision, amblyopia in 6.5%, other
causes in 4.3%, with unexplained causes in the remaining 32.9%. Myopia -0.50
diopter or less in either eye was present in 3.4% of 5-year-old children,
increasing to 19.4% in males and 14.7% in females by age 15. Over this same age
range, hyperopia 2.00 diopters or greater decreased from 22.7% to 7.1% in males
and from 26.3% to 8.9% in females. Females had a significantly higher risk of
hyperopia than males. CONCLUSIONS: Refractive error, associated primarily with
myopia, is a major cause of reduced vision in school-age children in La Florida.
More than 7% of children could benefit from the provision of proper spectacles.
Efforts are needed to make existing programs that provide free spectacles for
school children more effective. Further studies are needed to determine whether
the upward trend in myopia continues far beyond 15 years of age.
PMID- 10764852
TI - Shunt revision versus additional tube shunt implantation after failed tube shunt
surgery in refractory glaucoma.
AB - PURPOSE: To compare tube shunt revision with additional tube shunt after failed
tube shunt surgery. METHODS: We identified 281 patients who underwent a primary
tube shunt procedure from 1985 to 1998 at Indiana University and reviewed 33 eyes
of 33 patients that had failed and required further surgery. Shunt revision was
performed in 12, whereas an additional shunt was placed in 21 eyes. Intraocular
pressure, antiglaucoma medications, visual acuity, and complications were noted.
Success was defined as at least a 25% reduction in intraocular pressure that was
deemed clinically adequate. Qualified success was defined as a 25% intraocular
pressure reduction but with additional medications or a significant reduction in
medications with stable intraocular pressure for preoperative intraocular
pressure less than 21 mm Hg. RESULTS: Preoperative intraocular pressures (mean +/
95% confidence interval) for the revision and additional tube groups were 28.8
+/- 5.8 mm Hg and 29.8 +/- 2.7 mm Hg (P =.73), with an average follow-up period
of 25.2 months (range, 3 to 108 months) and 34.8 months (range, 6 to 84 months),
respectively. Final mean intraocular pressure was 25.3 +/- 6.7 mm Hg for the
revision group and 17.7 +/- 3.4 mm Hg for the additional tube group (P =.037).
Forty-two percent in the revision group versus 62% in the additional tube group
achieved at least a qualified success (P =.30, Fisher exact test). Corneal edema
was a common complication, especially in the additional tube group. Limitations
of this study include the small sample sizes and the uneven distribution of
neovascular glaucoma between the two groups (six of 12 in the revision group vs
two of 21 in the additional tube group; P =.015, Fisher exact test). CONCLUSIONS:
Our series showed that after failed tube shunt surgery, an additional tube shunt
offers better intraocular pressure control than revision by excision of an
encapsulated bleb.
PMID- 10764853
TI - Scanning laser polarimetry measurements after laser-assisted in situ
keratomileusis.
AB - PURPOSE: To evaluate the effect of laser-assisted in situ keratomileusis on
retinal nerve fiber layer thickness measurements obtained with scanning laser
polarimetry. METHODS: Thirteen consecutive eyes (13 patients) undergoing laser
assisted in situ keratomileusis were enrolled in this prospective study. Scanning
laser polarimetry (NFA-GDx; Laser Diagnostic Technologies, Inc, San Diego,
California) examination was performed 1 week before and 1 to 8 weeks after laser
assisted in situ keratomileusis surgery. Intraocular pressure was normal at all
preoperative and postoperative examinations. Total mean, and superior, temporal,
inferior, and nasal mean retinal nerve fiber layer thickness values before and
after laser-assisted in situ keratomileusis were compared by Student paired t
test. RESULTS: Mean +/- SD patient age was 34.6 +/- 10.9 years (range, 20 to 56
years). Mean +/- SD preoperative spherical equivalent refractive error was -6.6
+/- 3.1 diopters (range, -3.25 to -13.25 diopters) and mean +/- SD spherical
equivalent refractive surgical correction was -6.2 +/- 3.0 diopters (range, -2.9
to -12.25 diopters). Total mean retinal nerve fiber layer and superior, inferior,
temporal, and nasal mean retinal nerve fiber layer thicknesses were thinner after
laser-assisted in situ keratomileusis (P =.01, for all comparisons, paired t
test). CONCLUSIONS: Measurements of the retinal nerve fiber layer with scanning
laser polarimetry depend on a corneal compensator inherent in the device.
Keratorefractive surgery may affect scanning laser polarimetry measurements.
PMID- 10764854
TI - Small, overlapping tectonic keratoplasty involving graft-host junction of
penetrating keratoplasty.
AB - PURPOSE: To report the indications for and postoperative course of small tectonic
keratoplasties overlapping (and involving) the graft-host junction of preexisting
penetrating keratoplasties. METHODS: A retrospective study of 15 consecutive eyes
(15 patients) with small tectonic keratoplasties overlapping the graft-host
junction of preexisting penetrating keratoplasties. RESULTS: After tectonic
keratoplasty, follow-up times ranged from 5 months to 20 years (mean, 69 months).
Clinical indications included sterile corneal ulceration (seven cases), bacterial
keratitis (six cases), and fungal keratitis (two cases). In the six cases with
bacterial keratitis, five were suture abscesses, with four resulting in wound
dehiscence. Ten tectonic grafts were lamellar keratoplasties, and five were
penetrating keratoplasties. Postoperative best-corrected visual acuities were
unchanged from preoperative levels in every patient. After tectonic grafting, the
mean +/- SD change in keratometric astigmatism in the parent penetrating
keratoplasty was 1.75 +/- 1.50 diopters. The astigmatism increased in 10 cases,
decreased in three, and remained unchanged in two. There was no case of recurrent
ulceration or wound dehiscence in or around the tectonic grafts. The surgery did
not result in new glaucoma or worsening of preexisting glaucoma. CONCLUSIONS: In
the treatment of infectious or ulcerative foci at or near the graft-host junction
of penetrating keratoplasties, a small extirpative, tectonic graft over the
diseased junction appears to be a safe and effective alternative to either
repeating the original penetrating keratoplasty or performing an oversize
transplant.
PMID- 10764855
TI - Effects of penetrating keratoplasty rejection on the endothelium of the donor
cornea and the recipient peripheral cornea.
AB - PURPOSE: To determine the effects of penetrating keratoplasty rejection on the
recipient endothelium. METHODS: Twenty transplanted corneas of 20 keratoconus
patients were enrolled in this study. Ten of the corneas had undergone allograft
rejection and the other 10 grafts had an uneventful postsurgical course. The
endothelium of the donor cornea and the endothelium of the recipient peripheral
cornea were evaluated by wide-field specular microscopy. RESULTS: The
transplanted corneas that underwent allograft rejection showed a marked decrease
in endothelial cell density not only in central donor cornea but also in the
recipient peripheral cornea compared with that in the uneventful transplanted
corneas. Additionally, the recipient endothelium had significant pleomorphism in
the rejection group. There were no morphologic differences in the peripheral
donor cornea between the control group and the rejection group. CONCLUSIONS: Our
findings indicate that the recipient peripheral endothelium is also affected by
allograft rejection, perhaps because of the contribution of recipient endothelium
to the wound healing process after allograft rejection.
PMID- 10764856
TI - Increased expression of the type 1 growth factor receptor family in the
conjunctival epithelium of patients with keratoconjunctivitis sicca.
AB - PURPOSE: To investigate the expression of type 1 growth factor receptors
(epidermal growth factor receptor, ErbB2, and ErbB3) in the conjunctival
epithelium of patients with keratoconjunctivitis sicca. METHODS:
Immunofluorescent staining and Western blotting were performed to grade the level
of expression of the epidermal growth factor receptor ErbB2, and ErbB3 in
conjunctival epithelial impression cytologies taken from both eyes of seven
normal subjects and 22 patients with keratoconjunctivitis sicca. RESULTS:
Epidermal growth factor receptor staining was observed in a greater percentage of
keratoconjunctivitis sicca than normal samples (P <.05). ErbB2 and ErB3 staining
in the apical conjunctival epithelium was observed in both groups, but stronger
ErbB2 and ErbB3 staining was noted in keratoconjunctivitis sicca conjunctival
samples (P <.05). The relative levels of expression of these receptor proteins on
immunoblots were consistent with immunofluorescent staining. On immunoblots,
epidermal growth factor receptor protein was detected in 50% of
keratoconjunctivitis sicca samples, but none of the normal samples (P <.025). The
expression of ErbB2 and ErbB3 on immunoblots was also greater in the
keratoconjunctivitis sicca samples (P <.05). Immunofluorescent staining scores
for these receptors were correlated with conjunctival lissamine green staining
scores (r =. 574, P <.01 for epidermal growth factor receptor; r =.620, P <.0025
for ErbB2; r =.502, P <.025 for ErbB3) and with corneal fluorescein staining (r
=.409, P <.05 for ErbB2; r =.588, P <.005 for ErbB3). CONCLUSION: The expression
of the type 1 growth factor receptors is significantly greater in the
conjunctival epithelium of eyes with keratoconjunctivitis sicca than normal eyes.
The increased expression of these receptors was positively correlated with ocular
surface dye staining. The increased expression of these receptors may contribute
to the abnormal growth and differentiation of the conjunctival epithelium that
occurs in keratoconjunctivitis sicca.
PMID- 10764857
TI - Effect of eyelid botulinum toxin injection on lacrimal drainage.
AB - PURPOSE: To determine the effect of eyelid botulinum toxin injection on the
lacrimal drainage and to assess the use of botulinum toxin in dry eye conditions.
METHODS: Prospectively, three test groups were examined and one lacrimal system
investigated in each person in each group. Botulinum toxin A (3.75 IU) was
injected into the medial part of 13 lower eyelids of 13 normal test subjects and
the medial part of nine lower eyelids in nine patients with dry eyes. A dose of
2.5 IU was injected into the medial part of 10 lower eyelids and the medial part
of 10 upper eyelids of 10 patients with dry eyes. The drop test was used to
determine the lacrimal drainage capacity and the blink output, before and after
the injection. The subjective effect of the botulinum toxin injection on eye
comfort was investigated. RESULTS: Three weeks after lower eyelid botulinum toxin
injection, the mean blink output was reduced to 64% (1.19 of 1.87; P <.001) and
70% (0.94 of 1.35; P <.001) of the baseline values in the groups of normal
subjects and patients, respectively. After injection in both the upper and lower
eyelid, the mean blink output was reduced to 38% (0.54 of 1.41; P <.001) of the
baseline value. The patients with dry eyes reported an improved eye comfort in
six of nine cases after injection in the lower eyelid and in seven of 10 cases
after injection in both the upper and lower eyelid. Adverse effects included one
case of increased discomfort for 3 weeks after injection. CONCLUSION: Injection
of botulinum toxin into the medial part of the eyelids decreased the lacrimal
drainage, suggesting a new way to treat dry eye conditions. Further studies are
required to assess the clinical value of this treatment.
PMID- 10764858
TI - Tomographic assessment of vitreous surgery for diabetic macular edema.
AB - PURPOSE: To evaluate the retinal structure before and after vitrectomy for
diabetic macular edema and to assess the correlation between thickness of
neurosensory retina and best-corrected visual acuity. METHODS: Tomographic
features of 13 eyes (nine patients) with diabetic macular edema were
prospectively evaluated with optical coherence tomography before and after
vitrectomy. The foveal thickness (the distance between the inner retinal surface
and the retinal pigment epithelium) and the retinal thickness (thickness of
neurosensory retina) were measured by optical coherence tomography preoperatively
and postoperatively. The correlation of the best-corrected visual acuity with
foveal and retinal thickness was determined. RESULTS: All 13 eyes had retinal
swelling with low intraretinal reflectivity. In addition to retinal swelling,
there were cystoid spaces in five (38%) of 13 eyes, a serous retinal detachment
in three (23%), and both cystoid spaces and serous detachment in three (23%). Six
months postoperatively, the mean foveal thickness significantly decreased from
630 +/- 170 to 350 +/- 120 microm (P <.01, paired t test) and the mean thickness
of neurosensory retina decreased from 540 +/- 160 to 320 +/- 140 microm (P <.01,
paired t test). A serous retinal detachment occurred transiently in 3 eyes.
Compared with the preoperative level, the postoperative best-corrected visual
acuity level improved by more than 2 lines in five of the 13 eyes (38%), remained
the same in seven eyes (54%), and decreased in one eye (8%). The postoperative
thickness of neurosensory retina at the fovea and best-corrected visual acuity
level at the sixth postoperative month had a strong negative correlation
(correlation coefficient, -0.76; P <.01, Spearmans rank test). CONCLUSIONS:
Vitrectomy was generally effective in treatment of diabetic macular edema.
Optical coherence tomography demonstrated the intraretinal changes of macular
edema and the process of edema absorption. During the process of macular edema
absorption, intraretinal fluid appeared to move into the subretinal space in some
cases. Best-corrected visual acuity improvement was greater in eyes with less
preoperative increase in thickness of neurosensory retina.
PMID- 10764859
TI - Comparison of fluorescein angiography and indocyanine green angiography for
imaging of choroidal neovascularization in hemorrhagic age-related macular
degeneration.
AB - PURPOSE: To compare fluorescein angiography and indocyanine green angiography for
imaging of choroidal neovascularization located under subretinal hemorrhage, in
age-related macular degeneration. METHODS: In a retrospective study, 30 eyes of
30 consecutive patients with hemorrhagic age-related macular degeneration were
evaluated with fluorescein angiography and indocyanine green angiography. In each
eye, areas of macular hemorrhage, choroidal neovascularization, and total lesion
(hemorrhage plus choroidal neovascularization) were measured, and the choroidal
neovascularization was categorized as classic, occult, or mixed on fluorescein
angiography, and as hot spot, plaque, or combined lesion on indocyanine green
angiography. Results of the two techniques were compared for the ability to
identify a laser-treatable lesion. RESULTS: Fluorescein angiography showed
fluorescence in most cases (28, 93.3%). In 23 cases (76.6%), the fluorescence
pattern was compatible with occult choroidal neovascularization. Indocyanine
green angiography revealed defined patterns of fluorescence in 27 cases (90%): 12
hot spots, seven plaques, and eight combined hot spots and plaques. Twenty
lesions (66.6%) detected by indocyanine green angiography were considered
eligible for laser therapy. Nine of them (45%) were extrafoveal. CONCLUSIONS:
Indocyanine green angiography is beneficial for imaging choroidal
neovascularization located under subretinal hemorrhage. Choroidal
neovascularization demonstrated on indocyanine green angiography may be
considered eligible for laser treatment. Therefore, indocyanine green angiography
should be considered in cases of hemorrhagic age-related macular degeneration.
PMID- 10764860
TI - Experimental studies of indocyanine green dye-enhanced photocoagulation of
choroidal neovascularization feeder vessels.
AB - PURPOSE: To report a model of choroidal neovascularization feeder vessels that
reconciles current histologic, angiographic, and clinical data, and to report
experimental studies that investigate the potential of indocyanine-green-dye
enhanced photocoagulation to improve feeder-vessel treatment. METHODS: A model of
choroidal neovascularization feeder vessels was conceived to account for current
histologic and angiographic data. Based on that model, experimental studies of
the efficacy of indocyanine green-dye-enhanced photocoagulation were performed,
using pigmented rabbit eyes as a model system. A Zeiss fundus camera was modified
to permit visualization of choroidal blood flow by high-speed indocyanine green
angiography and to permit simultaneous delivery of 810-nm-wavelength diode laser
photocoagulation pulses to specific choroidal vascular targets during indocyanine
green-dye bolus transit. RESULTS: Choroidal neovascularization feeder vessels
appear to originate in the Sattler layer (that is, that portion of the choroidal
vasculature consisting of medium-diameter vessels) and enter the choriocapillaris
in close proximity to the small capillary-like vessels that penetrate Bruch
membrane and communicate with the choroidal neovascularization. The rabbit eye
experiments demonstrated that the presence of high indocyanine green dye
concentration in circulating blood enhances uptake of near-infrared laser energy
(three eyes); injection of sequential indocyanine green dye boluses results in
gradually decreased efficiency of dye-enhanced photocoagulation (two eyes); and
by application of laser energy during the initial transit of small-volume, high
concentration indocyanine green dye boluses, dye-enhanced photocoagulation of
large diameter choroidal arteries can be accomplished with relatively little
concomitant retinal tissue damage (three eyes). CONCLUSIONS: Although future
trials will be necessary to substantiate these initial findings in the clinical
arena, it appears that the efficiency of choroidal neovascularization feeder
vessel photocoagulation may be enhanced, while minimizing concomitant damage to
overlying retinal tissue, by delivery of 810-nm wavelength laser energy
immediately upon arrival of a high-concentration indocyanine green dye bolus in a
targeted feeder vessel. However, molecules of dye adhering to vessel walls or
lying in tissue interstitial spaces appear to divert laser energy from the
photocoagulation process, so efficiency of indocyanine green dye-enhanced
photocoagulation gradually diminishes as the number of injected dye boluses
increases.
PMID- 10764861
TI - Choroidal folds associated with increased intracranial pressure.
AB - PURPOSE: To determine whether a relationship exists between increased
intracranial pressure and the presence of idiopathic choroidal folds. METHODS: A
prospective study in which 12 consecutive patients presenting with choroidal
folds were evaluated by imaging studies (ultrasonography, magnetic resonance
imaging, and/or computed tomography) to rule out known causes of choroidal folds,
such as orbital disease, choroidal tumor, posterior scleritis, hypotony, and
choroidal neovascular membrane. A lumbar puncture was performed on each of these
patients, and measurement of opening pressure of cerebrospinal fluid was
obtained. RESULTS: Twelve patients with choroidal folds included nine men and
three women. Six patients (50%) presented with papilledema in the eye with
choroidal folds. The other six patients (50%) presented with only choroidal
folds. In this study, 10 (83%) of 12 patients had an opening pressure greater
than 230 mm H(2)O. In patients presenting with only choroidal folds, five (83%)
of six patients had an opening pressure greater than 230 mm H(2)O, with an
average opening pressure of 290 mm H(2)O. CONCLUSION: Depending on the timing of
the evaluation, papilledema may or may not be present, and only choroidal folds
may be seen as a reflection of increased intracranial pressure. We believe that
increased intracranial pressure from any source (that is, pseudotumor cerebri,
sinus thrombosis, or intracranial mass) can present with only choroidal folds;
therefore, these patients should have an appropriate work-up that should probably
include a lumbar puncture before the title of "idiopathic" is given to their
finding.
PMID- 10764862
TI - Progressive optic nerve cupping and neural rim decrease in a patient with
bilateral autosomal dominant optic nerve colobomas.
AB - PURPOSE: To document progressive optic nerve cupping and neural rim decrease in a
patient with normal intraocular pressures and bilateral autosomal dominant optic
nerve colobomas. METHODS: The ophthalmology records, stereoscopic fundus
photographs, and visual fields of a 27-year-old woman with familial (autosomal
dominant) optic nerve colobomas were reviewed. The appearance of the optic nerves
was documented over a 13-year period (1985 to 1998). RESULTS: Despite repeatedly
normal intraocular pressures, the patient showed progressive optic nerve cupping
and neural rim decrease in both eyes. Visual field testing was available over a 5
year period (1993 to 1998) and was abnormal, but no progression was seen.
CONCLUSIONS: This case of progressive cupping and neural rim decrease in a
patient with autosomal dominant optic nerve coloboma in both eyes may provide
insight into the optic nerve cupping associated with normal tension glaucoma.
Careful follow-up of patients with optic disk colobomas or patients is indicated
to detect possible optic nerve changes or field loss.
PMID- 10764863
TI - Adjustment of sutures 8 hours vs 24 hours after strabismus surgery.
AB - PURPOSE: To compare the postoperative results of adjustable-suture strabismus
surgery when suture adjustment was performed 8 hours (group 1) and 24 hours
(group 2) after surgery. METHODS: A retrospective clinical study was conducted in
two hospitals. Strabismus surgery and muscle adjustment were performed in 90
patients. All patients had horizontal strabismus (40 patients had esotropia and
50 patients had exotropia), and they underwent either primary surgery or
reoperation. Mean age of the patients was 29.9 +/- 14.1 (range, 14 to 74) years.
The angle of deviation was measured in all patients before surgery, after surgery
both before and after adjustment, and at the final follow-up examination. The
follow-up period was 6 to 40 months (mean, 19.6 months). RESULTS: Preoperative
data were similar in the two groups. The mean angle of deviation immediately
after muscle adjustment was 0.6 +/- 6. 1 prism diopters in group 1 and 0.4 +/-
6.3 prism diopters in group 2. This similar deviation in the two groups (P =.9)
changed during the follow-up period, and at the final examination the measured
angles in groups 1 and 2 were -1.0 +/- 7.9 and -2.5 +/- 10.3 prism diopters,
respectively (P =.48). The most considerable outcome measure was the calculated
drift values. At the last follow-up these values were -1.6 +/- 5.8 for group 1
and -2.9 +/- 11 prism diopters for group 2 (P =.5). Subdividing the patients on
the basis of their deviation before surgery, a postoperative drift toward
exotropia was found in most patients of group 1. In group 2, however, a greater
tendency toward exotropia was shown only by those patients who had displayed
exotropia preoperatively, whereas patients with preoperative esotropia showed a
greater tendency toward esotropia after surgery. CONCLUSION: In patients
undergoing horizontal extraocular muscle surgery with adjustable sutures, suture
adjustment 8 hours or 24 hours after surgery did not produce significantly
different results.
PMID- 10764864
TI - Myopia and vision 2020.
PMID- 10764865
TI - Cutaneous capillary hemangiomas of the eyelid, scalp, and digits in premature
triplets.
AB - PURPOSE: To document the unique occurrence of multiple cutaneous capillary
hemangiomas in healthy triplets. METHODS: Case reports. RESULTS: Triplets born 6
weeks prematurely were noted at birth to have classic cutaneous capillary
hemangiomas that enlarged in the first few months of life. At 3 months of age,
triplet #1 manifested a small capillary hemangioma on the left index finger and a
large hemangioma that involved the entire left upper eyelid and completely
occluded the visual axis. Triplet #2 had a small hemangioma on the thumb and a
large hemangioma on the scalp of the forehead. Triplet #3 displayed only a minor
hemangioma of the right upper eyelid that did not threaten her vision. The
parents of the triplets admitted having a history of periocular capillary
hemangioma that spontaneously resolved. Triplet #1 was managed with oral
corticosteroids, with dramatic regression of the mass and exposure of the visual
axis. CONCLUSIONS: Cutaneous capillary hemangioma is usually a sporadic
condition. We found this tumor in premature triplets whose parents had a history
of a similar tumor. This suggests that hereditary and environmental factors may
play a role in the development of this tumor. We advise that medical and family
histories be obtained in all children with cutaneous capillary hemangioma.
PMID- 10764866
TI - Bilateral orbital hemorrhage in a newborn.
AB - PURPOSE: To report a case of severe bilateral proptosis resulting from orbital
hemorrhage in a newborn and to discuss the differential diagnoses and management.
METHOD: Case report of a 13-day-old male infant with bilateral proptosis since
birth. The proptosis was monitored with clinical examinations and computed
tomography as well as magnetic resonance imaging (MRI) scans, and it was managed
with antibiotic ointment and patching. The MRI scans demonstrated bilateral
subperiosteal orbital hemorrhage. RESULTS: Proptosis decreased, and there was
successful, complete recovery without untoward sequelae in 14 days; follow-up
indicated no late complications at age 1 year. CONCLUSION: Spontaneous orbital
hemorrhage, unilateral or bilateral, is uncommon in an otherwise healthy newborn
without apparent history of birth trauma. Magnetic resonance imaging scans are
helpful in making the diagnosis of subperiosteal hemorrhage, and conservative
management is advised.
PMID- 10764867
TI - Hyphema caused by a metallic intraocular foreign body during magnetic resonance
imaging.
AB - PURPOSE: To report a 63-year-old man with a retained intraocular foreign body who
developed a hyphema during magnetic resonance imaging (MRI) of the brain.
METHODS: Case report and review of the current literature on ocular injury caused
by intraocular foreign bodies when subjected to an electromagnetic field.
RESULTS: Our patient underwent a brain MRI, and the intraocular foreign body
caused a hyphema and increased intraocular pressure. The presence and location of
the intraocular foreign body were determined by computed tomography (CT).
CONCLUSION: Magnetic resonance imaging can cause serious ocular injury in
patients with ferromagnetic intraocular foreign bodies. This case demonstrates
the importance of obtaining an occupational history, and, when indicated, a skull
x-ray or CT to rule out intraocular foreign body before an MRI study.
PMID- 10764868
TI - Markedly increased unilateral intraocular pressure during hemodialysis in a
patient with ipsilateral exfoliative glaucoma.
AB - PURPOSE: To report a man with markedly increased intraocular pressure in a
unilateral exfoliated eye during hemodialysis. METHOD: Case report. RESULTS: A 75
year-old man with unilateral exfoliative glaucoma complained of blurred vision in
his right eye during hemodialysis. The blurred vision always occurred during
hemodialysis, and the intraocular pressure was increased during hemodialysis. The
average increase in intraocular pressure during hemodialysis in the right eye was
22.5 mm Hg, and the intraocular pressure in the left eye remained in the normal
range during hemodialysis. Argon laser trabeculoplasty was performed on the right
eye, and a decrease in intraocular pressure was attained. CONCLUSION: Physicians
must be alert to intraocular pressure increases in these eyes during
hemodialysis.
PMID- 10764869
TI - A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy
after liver transplantation.
AB - PURPOSE: To report a case of bilateral optic neuropathy in a patient receiving
tacrolimus (FK 506, Prograf; Fujisawa USA, Inc, Deerfield, Illinois) for
immunosuppression after orthotropic liver transplantation. METHOD: Case report.
In a 58-year-old man receiving tacrolimus after orthotropic liver
transplantation, serial neuro-ophthalmologic examinations and laboratory studies
were performed. RESULTS: The patient had episodic deterioration of vision in both
eyes, with clinical features resembling ischemic optic neuropathies.
Deterioration of vision occurred despite discontinuation of the tacrolimus.
CONCLUSION: Tacrolimus and other immunosuppressive agents may be associated with
optic nerve toxicity.
PMID- 10764870
TI - Acute transient myopia induced by indapamide.
AB - PURPOSE: To report on a case of acute transient myopia associated with
ciliochoroidal detachment induced by indapamide. METHOD: Case report. Clinical
examination, ultrasonography, and fluorescein angiography were performed during
the acute phase of disease and convalescence. RESULTS: After indapamide was
discontinued, acute bilateral myopia, which was associated with anterior chamber
shallowing and diffuse choroidal thickening, resolved spontaneously 8 days after
onset. The initial angiography showed scattered islands of delayed fluorescein
filling that disappeared without any permanent change by day 30. CONCLUSION:
Indapamide can induce spontaneously resolving transient myopia associated with
diffuse choroidal thickening.
PMID- 10764871
TI - Lens minibar to facilitate refraction.
AB - PURPOSE: To describe a lens minibar that facilitates refraction. METHODS: Ten
lenses of 1-diopter increment were glued to form a hyperopic minibar (range from
+1.00 to +5.00) and a myopic minibar (range from -1.00 to -5.00), the size of a
credit card. RESULTS: The lens minibar allowed expedited refraction in children
and in consultations that took place outside the clinic. CONCLUSION: The lens
minibar is an inexpensive, small, lightweight tool that facilitates quick
refraction.
PMID- 10764872
TI - Optical coherence tomography in the study of the Goldmann-Favre syndrome.
AB - PURPOSE: To report a case of Goldmann-Favre syndrome with special emphasis on the
optical coherence tomography findings. METHODS: In a 23-year-old white man with
an 8-year history of visual impairment in both eyes and night blindness, vertical
and horizontal optical coherence tomography images were obtained through the
macula and through the retinoschisis located at the temporal side of the macula.
RESULTS: Optical coherence tomography showed in the left eye a clear loss of the
inner retinal layer at the fovea and the formation of inner and outer retinal
layer holes in the temporally located retinoschisis. The outer retinal layer hole
had rolled edges. CONCLUSION: In Goldmann-Favre syndrome, optical coherence
tomography demonstrated confluent macular cystoid changes and retinoschisis in
both eyes. In the left eye, a lamellar macular hole and retinoschisis with inner
retinal layer and outer retinal layer holes were observed. The outer retinal
layer hole had rolled edges.
PMID- 10764873
TI - Idiopathic polypoidal choroidal vasculopathy and sickle cell retinopathy.
AB - PURPOSE: To report a patient who had concomitant idiopathic polypoidal choroidal
vasculopathy and sickle cell retinopathy. METHOD: Case report. A 46-year-old
black woman presented with sudden onset of "blurring" in the left eye. Her ocular
history was unremarkable, and her medical history was relevant for sickle cell
disease with yearly episodes of sickle cell crises. RESULTS: Both eyes had
evidence of idiopathic polypoidal choroidal vasculopathy and peripheral retinal
neovascularization secondary to sickle cell disease. The left eye had hemorrhagic
retinal pigment epithelial detachments secondary to idiopathic polypoidal
choroidal vasculopathy. CONCLUSION: We present this case as an example of
concomitant sickle cell retinopathy and idiopathic polypoidal choroidal
vasculopathy. We are unaware of previous reports with these findings.
PMID- 10764874
TI - Vitreous hemorrhage after intravitreal tissue plasminogen activator (t-PA) and
pneumatic displacement of submacular hemorrhage.
AB - PURPOSE: To report the immediate complication of dense vitreous hemorrhage after
intravitreal injection of tissue plasminogen activator and gas for treatment of
two cases of sudden submacular hemorrhage associated with retinal arterial
macroaneurysm. METHODS: Case reports. RESULTS: Two patients, a 67-year-old woman
and a 92-year-old man, presented with sudden vision loss related to submacular
hemorrhage from a retinal macroaneurysm. Tissue plasminogen activator at a dose
of 50 microg to 75 microg and a sulfur hexafluoride (SF(6)) gas bubble were
injected intravitreally under local anesthesia. Dense vitreous hemorrhage was
noted on the first postoperative day in both cases, which subsequently required
pars plana vitrectomy removal. CONCLUSION: Sudden severe vitreous hemorrhage may
be an immediate complication after intravitreal injection of tissue plasminogen
activator and gas for treatment of submacular hemorrhage associated with retinal
arterial macroaneurysm.
PMID- 10764875
TI - Improvement in macular function after retinal translocation surgery in a patient
with age-related macular degeneration.
AB - PURPOSE: To assess focal electroretinographic findings before and after retinal
translocation surgery in a patient with age-related macular degeneration. METHOD:
Case report. A 79-year-old man with a well-defined subfoveal choroidal
neovascular membrane from age-related macular degeneration underwent preoperative
and postoperative focal electroretinography. RESULTS: After retinal translocation
surgery, best-corrected Snellen visual acuity improved from 9/200 to 20/60. A
significant increase in mean foveal amplitude, from 0.08 microV to 0.16 microV (P
= 0.008) was recorded. CONCLUSION: Age-related macular degenerative changes in
visual acuity and foveal electroretinogram amplitude may be reversible after
retinal translocation surgery.
PMID- 10764876
TI - A combination light-pipe, soft-tipped suction, and infusion cannula instrument
for macular translocation.
AB - PURPOSE: To describe a combination light-pipe, soft-tipped suction needle, and
infusion cannula instrument for use in macular translocation surgery. METHODS:
Macular translocation surgery was performed in human cadaver and live rabbit eyes
with a combination light-pipe, soft-tipped suction needle, and infusion cannula
instrument. RESULTS: A combination light-pipe, soft-tipped suction needle, and
infusion cannula can be used for macular translocation. This instrument is useful
for relocating the retina after a 360 peripheral retinotomy is created. It can
also be used for macular translocation with the scleral imbrication technique
when superior movement of the fovea is required. When used in combination with
another soft-tipped suction needle instrument, this surgical instrument allows
precise bimanual placement of the retina with simultaneous infusion of liquid
perfluorocarbon for fixating the macula to its new location. CONCLUSION: A
combination light-pipe, soft-tipped suction needle, and infusion cannula
instrument may be a useful tool for macular translocation surgery.
PMID- 10764877
TI - Hold up of dye in the arm during fluorescein angiography: a quantitative
demonstration.
AB - PURPOSE: To demonstrate a hold-up of part of the fluorescein bolus in the arm as
a result of arm position. METHOD: Case report. We obtained a fluorescein
angiogram with a calibrated confocal scanning laser ophthalmoscope in a 20-year
old healthy subject. During and after injection, the upper arm was held in
approximately 60 degrees abduction, 65 degrees exorotation, and slight
anteflexion. In the late venous phase, the subject moved the upper arm on the
injected side to a more neutral, downward position. RESULTS: We measured a
distinct rise in fluorescence level about 10 seconds after movement of the arm.
The most likely explanation is relief of a partial obstruction of the venous
drainage, which had been caused by the position of the upper arm described above.
CONCLUSION: Impaired venous drainage of the injected arm caused by exorotation
and abduction of the upper arm is a potentially common cause of delayed dye
arrival or unexpectedly reduced contrast level during fluorescein angiography.
Therefore, arm position needs attention in fluorescein angiography.
PMID- 10764878
TI - Monofocal outer retinitis associated with hand, foot, and mouth disease caused by
coxsackievirus.
AB - PURPOSE: To report symptoms and signs from an otherwise healthy man with
photopsia and monofocal outer retinitis occurring 3 days after the onset of hand,
foot, and mouth disease. METHOD: Case report. RESULTS: Ophthalmic examination
revealed a single circumscribed area of pigment epithelial mottling in the left
eye and a corresponding nonarcuate absolute scotoma. Fluorescein angiography
demonstrated attenuation of the retinal pigment epithelium. Serologic tests at 1
month after the onset disclosed serum antibody to enterovirus. CONCLUSION: The
close association between the cutaneous eruption and the onset of visual symptoms
suggests that the retinal lesion was caused by coxsackievirus infection.
PMID- 10764879
TI - Oxacillin-resistant Staphylococcus aureus endophthalmitis after ganciclovir
intraocular implant.
AB - PURPOSE: To describe a patient who developed oxacillin-resistant Staphylococcus
aureus endophthalmitis after insertion of a ganciclovir intraocular implant.
METHOD: Case report. RESULTS: A 42-year-old man with acquired immunodeficiency
syndrome (AIDS) and a history of cytomegalovirus retinitis was admitted with
right-sided eye pain and decreased visual acuity 10 days after receiving a second
ganciclovir intraocular implant in the right eye. A therapeutic vitrectomy, right
eye, was performed on the day of admission. A vitreal tap produced frank pus and
white, fluffy debris. Cultures of the vitreal fluid grew oxacillin-resistant S
aureus, sensitive only to vancomycin, rifampin, and
trimethoprim/sulfamethoxazole. The patient was successfully treated with removal
of both ganciclovir implants in the right eye and a 4-week course of vancomycin
and rifampin. However, the infection left the patient blind in the infected eye.
CONCLUSION: Bacterial endophthalmitis is an infrequent but serious complication
of the ganciclovir intraocular implant.
PMID- 10764880
TI - Increased expression of adrenomedullin mRNA in the tissues of intraocular and
orbital tumors.
AB - PURPOSE: To explore the possible involvement of adrenomedullin in the
pathophysiology of intraocular and orbital tumors. METHODS: Competitive reverse
transcription-polymerase chain reaction was used to determine adrenomedullin mRNA
levels in the tissues from 40 consecutive patients (40 eyes) undergoing
vitrectomy, orbital tissue biopsy, or enucleation for various ocular diseases,
including intraocular (n = 4) and orbital (n = 3) tumors, proliferative
vitreoretinopathy (n = 8), proliferative diabetic retinopathy (n = 8), age
related macular degeneration (n = 4), preretinal macular fibrosis (n = 9), and
acute retinal necrosis (n = 4). RESULTS: Adrenomedullin mRNA levels in the
tissues obtained from patients with intraocular or orbital tumors were
significantly higher than those of patients with proliferative vitreoretinopathy
(P <.05), proliferative diabetic retinopathy (P <.05), preretinal macular
fibrosis (P <.005), and acute retinal necrosis (P <.01). CONCLUSION:
Adrenomedullin may play a role in the pathophysiology of intraocular and orbital
tumors.
PMID- 10764881
TI - Induction of cataracts of varying degrees of hardness in human eyes obtained
postmortem for cataract surgeon training.
AB - PURPOSE: To report a method of inducing nuclear cataracts of varying degree of
hardness using intralenticular injection of the Karnovsky solution. METHODS:
Twelve postmortem human eyes were prepared according to the Miyake-Apple
posterior video technique. After performing capsulorhexis and
hydrodissection/delineation, 0.2 ml of the Karnovsky solution was injected into
the lens nucleus of the eyes. Manual extracapular cataract extraction techniques
and various two-handed phacoemulsification maneuvers were then practiced at
various time intervals after the injection. RESULTS: Uniform nuclear cataracts
with varying degrees of hardness were successfully induced in all globes. The
optimum dose of the Karnovsky solution and time for induction of nuclear hardness
of grade 3 (ideal for practicing two-handed phacoemulsification maneuvers) were
0.2 ml and 15 minutes, respectively. CONCLUSION: The Karnovsky solution can be
successfully used for the induction of hard, uniform nuclear cataracts for
learning/practicing extracapular cataract extraction and phacoemulsification.
PMID- 10764882
TI - Effects of physical and biological disturbances on algal turfs in Kaneohe Bay,
Hawaii.
AB - Disturbance in coral reef environments commonly results in an algal community
dominated by highly productive, small filamentous forms and cyanobacteria,
collectively known as algal turf. Research on the types of disturbance
responsible for this community structure has concentrated mainly on biological
disturbance in the form of grazing, although physical and other forms of
biological disturbances may be important in many coral reef areas. On the reef
flat in Kaneohe Bay, Oahu, Hawaii, algal turfs grow primarily upon coral rubble
that tumbles with passing swells. We manipulated the frequency of rubble tumbling
in field experiments to mimic the effects of physical disturbance by abrasion and
light reduction on algal biomass, canopy height, and community structure.
Treatments approximated a gradient of disturbance intensities and durations that
occur on the reef flat. Although sea urchins and herbivorous fishes are not
widespread and abundant on the reef flat, biological disturbances to algal turf
communities in the form of herbivory by small crabs and abrasion by tough
macroalgae contributed significantly to the variation in algal turf biomass.
Within all experiments increasing disturbance significantly reduced algal biomass
and canopy heights and the community structure shifted to more disturbance
tolerant algal forms. This study shows that the chronic physical disturbances
from water motion and biological disturbances other than grazing from large
herbivores can control algal communities in coral reef environments.
PMID- 10764883
TI - Underground mating in the fiddler crab Uca tetragonon: the association between
female life history traits and male mating tactics.
AB - Brood size and other life-history traits of females affect male investment in
mating. Female Uca tetragonon, producing relatively small broods, were attracted
to the burrows of males for underground mating (UM) while carrying eggs. Most UM
females released larvae and ovulated new broods during the pairing, averaging 3.9
days. While a female was incubating one brood, another brood was developing
within the ovaries because the females were feeding adequately during incubation.
These findings suggest that in U. tetragonon, a small-brood species, females
increase the total number of broods produced by breeding continually. In
contrast, in large-brood species, feeding by ovigerous females is relatively
brief and not enough to prepare the next brood during incubation, inducing
temporal separation between incubation and brood production. Unlike females in
other ocypodids where females with large broods remain in the breeding burrows of
males, most female U. tetragonon left the male after UM. Wandering in female U.
tetragonon after the pairs separate may occur because their small broods are
adequately protected by an abdominal flap. Relative brood size probably
determines the vulnerability of the incubated broods to the females' surface
behavior. Hence, male reproductive success in large-brood species may decrease
greatly if males expel their mates after ovulation, although this is not
necessarily so in small-brood species. Whether the male drives away the female or
not may depend on which behavior within either small- or large-brood species
yields the greater male reproductive success. In U. tetragonon some females
extruded eggs in their own burrows after surface mating as well as in males'
burrows after UM. It was unclear whether females chose a male with a larger
burrow as an UM mate unlike several large-brood species. Burrows of both UM males
and ovigerous females in U. tetragonon were relatively smaller than those in some
large-brood species, indicating that incubation of small broods does not require
large burrows. Rather than benefits of UM by female choice, wandering resulting
from intersexual conflict, and sperm competition may explain why some females
mate in males' burrows in this small-brood species.
PMID- 10764884
TI - Lipid content and energy density of forage fishes from the northern Gulf of
Alaska.
AB - Piscivorous predators can experience multi-fold differences in energy intake
rates based solely on the types of fishes consumed. We estimated energy density
of 1151 fish from 39 species by proximate analysis of lipid, water, ash-free lean
dry matter, and ash contents and evaluated factors contributing to variation in
composition. Lipid content was the primary determinant of energy density, ranging
from 2 to 61% dry mass and resulting in a five-fold difference in energy density
of individuals (2.0-10.8 kJg(-1) wet mass). Energy density varied widely within
and between species. Schooling pelagic fishes had relatively high or low values,
whereas nearshore demersal fishes were intermediate. Pelagic species maturing at
a smaller size had higher and more variable energy density than pelagic or
nearshore species maturing larger. High-lipid fishes had less water and more
protein than low-lipid fishes. In some forage fishes, size, month, reproductive
status, or location contributed significantly to intraspecific variation in
energy density. Differences in quality are sufficient to potentially affect diet
selection of breeding seabirds, especially when transporting food for their young
to the nest site.
PMID- 10764885
TI - Drifting algal mats as an alternative habitat for benthic invertebrates: Species
specific responses to a transient resource.
AB - Patchy occurrences of benthic drift algae (i.e. loose lying macroalgal mats) may
increase habitat complexity on normally bare soft bottoms, but at the same time,
extensive amounts of drifting algal mats are known to stress the benthic fauna.
This paper presents results of the first detailed study of the fauna associated
with drift algal mats in the northern Baltic Sea. In order to assess the
importance of drifting algae as an alternative habitat for benthic fauna, benthic
drift algal mats were sampled on shallow (2-9 m) sandy soft bottoms in the outer
archipelago of the Aland Islands (Finland). Species composition, abundance and
biomass of the macrofauna associated with algal mats were recorded. The results
show that drifting algae at times can harbour very high abundances of
invertebrates (up to 1116 individuals/g algal dryweight), surpassing invertebrate
densities recorded in seagrass communities. The algal fauna varied between sites
and over time, and factors such as ambient benthic fauna, exposure to wind-wave
disturbance, depth, and algal coverage and condition influenced the invertebrate
community composition of the algal mats. Abundance increased while individual
biomass of the animals decreased over time (summer season; July-October). A
series of laboratory experiments were conducted in order to test the ability of a
few important benthic species to move up into, and survive in a drifting algal
mat. Macoma balthica, Hydrobia spp., Nereis diversicolor and Bathyporeia pilosa
were used in the experiments, and significant differences in their survival and
mobility within drifting algae were recorded. This study shows that benthic
species differ significantly in their ability to utilise the algal mats, with
mainly opportunistic and mobile taxa such as Hydrobia spp., Chironomidae and
Ostracoda benefiting from the algae, whereas infaunal species such as M. balthica
and B. pilosa are negatively affected. The occurrence of eutrophication induced
drifting macroalgal mats has increased significantly during the last decade in
the northern Baltic Sea. Hence, the importance of drifting algae as a stress
factor and as an alternative habitat for benthic fauna increases.
PMID- 10764886
TI - Serological estimation of prey-protein gut-residence time and quantification of
meal size for grass shrimp consuming meiofaunal copepods.
AB - A series of experiments using serological reagents was conducted to examine
predation, ingestion and digestion in a model predator-prey system. The
harpacticoid copepod Amphiascoides atopus, obtained from mass culture, was used
as prey and the grass shrimp, Palaemonetes pugio, as predator. Bulk-gut passage
time in P. pugio was measured by visualization of latex beads and ranged from 0.5
to 4 h in starved and continuously-fed grass shrimp. A polyclonal antibody was
prepared from crude extracts of A. atopus; cross reactions with P. pugio and
three other crustaceans were either negligible or not detected using slide agar
gel-double-immunodiffusion (AGID) and Western blot preparations. The presence of
A. atopus antigens was detected with great sensitivity (e.g., seven copepods, 35
ug dry weight, gave positive results) in grass shrimp gut contents even when
proteins of other crustacean prey were present. Prey-proteins could be detected
for as long as 4 h with AGID and 8 h with Western blot techniques. Individual
grass shrimp that were fed A. atopus and consumed from 0 to 98 copepods h(-1)
were subjected to Western-blot preparation with chemiluminescence detection and
densitometric evaluation. There was a significant curvilinear relationship
between protein content and the number of copepod prey ingested. Results suggest
that serological techniques can be modified to estimate the mass or abundance of
standard-sized prey ingested by field-collected predators.
PMID- 10764887
TI - Sublethal effects of Texas brown tide on Streblospio benedicti (Polychaeta)
larvae.
AB - The Texas brown tide bloom is noted for a concordant decline in benthic biomass
and species diversity. However, the link between harmful effects induced by Texas
brown tide and benthos has not been demonstrated. It has been proposed there may
be a larval bottleneck, where larvae, but not adults, suffer adverse effects.
This study was performed to test the effect of brown tide alga, Aureoumbra
lagunensis, on mortality, growth and behavior of Streblospio benedicti larvae.
Growth rates and swimming speeds, but not mortality rates, of polychaete larvae
were reduced in cultures with brown tide relative to Isochrysis galbana, which is
about the same size as brown tide. Results from this research indicate that brown
tide does have harmful sublethal effects for one dominant species of
meroplanktonic larvae, which could help explain reduced adult population size.
PMID- 10764888
TI - Conditioned changes in appetitive and consummatory responses to flavors paired
with oral or nutrient reinforcement among adult rats.
AB - Recent studies of the behavioral organization of conditioned flavor preferences
have suggested the involvement of at least two separate learning systems-an
appetitive response system sensitive to the oral hedonic properties of the
reinforcer, and a consummatory response system sensitive to its nutrient
properties. However, these prior studies were conducted with weanling rats, that
differ from adults in terms of their prior experience with food, their learning
competencies, and the peculiar ontogenetic constraints on their behavior. It is,
therefore, unknown whether flavor preference behaviors are similarly organized in
adult rats. In this experiment, adult rats were trained to associate a specific
CS flavor with either the sweet taste or the postingestive nutrient effects of
sucrose. Conditioned appetitive orienting and consummatory oral responding to the
CS flavors were then measured. Unlike weanling rats, adult rats exhibited both
conditioned appetitive behavior and conditioned consummatory behavior in response
a CS that was previously paired with either oral hedonic or nutrient
reinforcement. These results suggest a set of important developmental changes in
the neurobehavioral mechanisms of flavor preference learning in the postweaning
period.
PMID- 10764889
TI - Fertility ratio in male rats: effects after denervation of two pelvic floor
muscles.
AB - Fertility ratio is defined here as the proportion of females that a male can
impregnate after a constant period of in-polygyny living. This ratio was
investigated in male rats after denervation of two pelvic floor muscles, the
pubococcygeus and iliococcygeus. Denervation was carried out by transecting the
somatomotor branch of the pelvic nerve. The lesion did not modify the sexual
behavior of males or their overall fertility, but decreased the weight of the
ejaculated seminal plug. Consequently, the number of days living in cohabitation
to induce pregnancy was increased in lesioned males (approximately 13 days)
compared with intact and sham animals (approximately 5 days). These results
showed that the fertility ratio was optimal when intact/sham males cohabited with
females for two consecutive estrous cycles, but that lesioned males needed up to
four cycles to induce most pregnancies. Two hypotheses are raised by our results.
The first is that pelvic floor denervation decreases the forceful tension
required to expel the semen from the prostatic urethra to the vagina, then an
incomplete seminal plug is expelled. The second is that denervation cut afferent
fibers that reflexively promote the continence of the semen deposited in the
prostatic urethra during seminal emission, allowing some to leak out before
ejaculation. The latter hypothesis can also explain the recovery of the fertility
ratio in lesioned males. It could be a compensatory mechanism mediated by the
pudendal nerve supply to the coccygeus muscle, the other pelvic floor muscle.
PMID- 10764890
TI - Paradoxical effect of imipramine in hyperprolactinemic female rats exposed to the
forced swimming test.
AB - This study was designed to investigate the effect of hyperprolactinemia, with
high or low estrogen levels, on the response to imipramine in the forced swimming
test. Three groups of female rats were studied: (1) ovariectomized controls, with
low serum prolactin (PRL) and estrogen levels, (2) ovariectomized, estrogen
treated rats, with high PRL and high estrogen levels, and (3) pituitary-grafted
rats, with high PRL and low estrogen levels. The hyperprolactinemic groups did
not show significant behavioral changes in the forced swimming test preceded by
saline injection. Imipramine decreased the immobility time by 37.5% in
ovariectomized controls but not in the pituitary-grafted group, and there was an
increment of 48.4% in immobility time following imipramine administration in the
estrogen-treated group (p<0.05). This paradoxical response to imipramine was
significantly correlated with serum PRL (r = 0.59, p<0.01) but not with estradiol
levels. These findings suggest that, at least in female rats submitted to the
forced swimming model, PRL may induce reversed behavioral effects in response to
imipramine, independently of circulating estrogen levels.
PMID- 10764891
TI - Effects of social stress on behavior and corpus luteum in female golden hamsters
(Mesocricetus auratus).
AB - The consequences of group-keeping as a social stressor on the solitary-living
golden hamster were studied. Two females at the same stage of the estrous cycle
were kept together for 5 weeks. Behavioral observations showed that the dominance
structures within groups were unstable. Intensity of aggression was highest at
metestrous, whereas the greatest activity was observed during the estrous stage.
After 1 week, the body masses of singly kept and group-kept hamsters were
different. Five weeks after the onset of the experiment, the body mass of the
singly kept hamsters had increased by 3.6%, and that of the group-kept hamsters
by 25%. The plasma progesterone level of group-kept females was 60 to 70% higher
than that of singly kept females. The absolute masses of the adrenal glands and
the ovaries were higher in group-kept females. Nevertheless, the relative masses
did not differ. Whereas a significant positive correlation between the weights of
both organs and the body mass was observed in singly kept females, in group-kept
females such a correlation was only observed between body and ovary weight.
Number and size of corpora lutea were enlarged in group-kept individuals, and
this seems to be responsible for elevated plasma progesterone titres. These
results indicate social stress in group-kept female hamsters.
PMID- 10764892
TI - Menthol desensitization of capsaicin irritation. Evidence of a short-term anti
nociceptive effect.
AB - Evidence is presented of a short-term antinociceptive effect of menthol that was
discovered in the course of investigating menthol's potential to sensitize the
mouth to capsaicin. Previous research had shown that treating the tongue with
menthol 15 min before exposure to capsaicin could enhance the irritancy of
capsaicin, and we wished to learn if this effect would increase as the time
between exposure to menthol and capsaicin decreased. We found instead that when
capsaicin followed menthol by only 3.5 min, or when it was presented in mixture
with menthol for 2-3 min, sensory irritation was reduced rather than enhanced. We
examined the duration of this apparent crossdesensitization in a second
experiment by varying the delay between exposure to menthol and a block of three
consecutive capsaicin stimuli. Cross-desensitization tended to decline as the
interstimulus interval (ISI) increased to 5 min, and even when desensitization
was maximal, it was significant only for the first of the three capsaicin
stimuli. In the final experiment we investigated how menthol self- and cross
desensitization can influence the perception of menthol-capsaicin mixtures.
During a series of five, 90-s stimulations, self- and cross-desensitization
became evident at the beginning of the second exposure, but the effect on mixture
intensity again diminished rapidly as stimulation continued. We infer from these
results that method can transiently desensitize capsaicin-sensitive fibers, but
that exposure to capsaicin rapidly overrides the effect. The implications these
findings have for menthol's potential as a topical analgesic are discussed.
PMID- 10764893
TI - Presynaptic L-type Ca(2)+ channels on excessive dopamine release from rat caudate
putamen.
AB - We investigated by means of behavioral and neurochemical studies the role of the
nerve terminal L-type voltage sensitive Ca(2)+ channel on dopamine (DA) release.
Microinjection of Bay K 8644 (BAYK), an L-type Ca(2)+ channel stimulant, into the
rat caudate putamen increased locomotor activity and rearing behavior in a dose
dependent manner, whereas injections into the amygdala had no effect. DA receptor
antagonists significantly blocked BAYK-induced hyperactivity. Significant
increases of extracellular DA levels were detected by microdialysis 20 min after
BAYK administration into caudate putamen and then declined. This increase was
influenced by tetrodotoxin, an axonal Na(+) channel blocker. Pretreatment with
nimodipine and nicardipine, but not nifedipine, which are 1, 4-dihydropyridine L
type Ca(2)+ channel antagonists, administered into the caudate putamen
significantly blocked BAYK-induced hyperactivity and DA efflux. These results
indicate that the extraordinary DA release in the caudate putamen was mediated by
extreme stimulation of the nicardipine and nimodipine-sensitive L-type Ca(2)+
channel present in the nerve terminal of striatal DA neurons.
PMID- 10764894
TI - Food aversion learning induced by lithium chloride in the crayfish Procambarus
clarkii.
AB - The ability of the crayfish Procambarus clarkii to develop a food aversion
learning was examined. For this purpose, in crayfishes fed with trout, a novel
food (chicken) was associated in a single trial with a well-known toxic
substance, lithium chloride (LiCl), and food intake was recorded for 10 days
afterward using a two-choice protocol. All during the experimental period, a
significant effect of treatment was observed that accounted for the lower chicken
intake in the LiCl-treated group, compared with the control groups (NaCl-treated
group and puncture group). In contrast, LiCl-treated animals had an increased
trout intake during the entire period. In addition, it was observed that total
food intake was similar among the three groups. These results indicate that the
crayfish may develop a food aversion learning when illness is induced by LiCl
after the animal accepts and eats a novel food.
PMID- 10764895
TI - Food anticipatory activity and photic entrainment in food-restricted BALB/c mice.
AB - The BALB/c mouse was evaluated as a model for the study of entrainment of
circadian rhythms by feeding schedules. Mice were housed in a 12:12-h light-dark
(LD) environment with food available for 3-5 h/day (5 h before dark onset). Food
anticipatory activity (FAA) rhythms were evident in all mice, ranging from robust
in some to weak and variable in others. Advancing transients of the end of
nocturnal activity were evident in many cases, culminating in a significant
shortening of the main bout of nocturnal activity. Transients and contraction of
nocturnal activity were not dependent on the expression of FAA. Following
restricted feeding, nocturnal activity expanded by a series of delaying
transients. On the first day of constant dark (DD) with ad libitum food access
following restricted feeding in LD, the phase from which activity free-ran was
advanced by comparison with control tests. Transients, compressed nocturnal
activity, and advanced phase of free-run suggest that feeding schedules cause
phase advancement of light-entrained rhythms in BALB/c mice. When restricted
feeding was imposed in DD, several mice expressed robust FAA concurrent with a
free-running activity component. In some cases, free-running rhythms entrained to
feeding time, and in other cases, the period of the free run lengthened toward 24
h. These data show that restricted feeding in BALB/c mice can engage a circadian
mechanism driving FAA rhythms and can also modulate the phase of photic
entrainment, possibly by a direct entraining effect on the light-entrained
rhythm. The BALB/c mouse strain, in several respects, appears to be a useful
model for the study of scheduled feeding and circadian rhythms.
PMID- 10764896
TI - Growth hormone, insulin-like growth factor-1, and the insulin-like growth factor
binding proteins in rats maintaining reduced body protein following lesions of
the lateral hypothalamus.
AB - Rats with lesions of the lateral hypothalamus (LH) maintain a reduced body
protein mass that they effectively defend when challenged by under- or over
nutrition. The two studies reported here evaluate the potential contributions of
growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the insulin-like
growth factor-binding (IGFBP) to this persistent maintenance of a reduced body
protein mass by LH rats. At 18 weeks postlesion, it was found that the serum
levels of GH, IGF-1, total IGFBP, and IGFBP-3 of LH rats maintaining reduced body
protein were not different from those of age-matched controls. However, closer to
the time of surgery, at which time the lesion-induced body protein adjustments
are known to occur, altered hormone and binding protein levels were observed.
Specifically, at 3 weeks after lesioning, the IGF-binding proteins of LH rats
were significantly elevated, whereas their GH levels were lower than those of
controls. Because the GH, IGF-1, and IGF-binding proteins of LH rats were
comparable to those of controls at 18 weeks after lesioning, none apparently
underlie the chronically reduced body protein mass that LH rats display. Closer
to the time of lesioning, however, altered GH and IGF binding protein levels may
contribute to the postlesion adjustments by which the body protein mass of LH
rats is lowered to its reduced level.
PMID- 10764897
TI - Effects of age on the feeding response to moderately low dietary protein in rats.
AB - Moderately low levels of dietary protein are associated with increased food
intake and body fat. We propose that the generation of this feeding signal is
dependent on the level of dietary protein relative to the protein requirement of
the animal, that is, that protein-dependent feeding is maximized when the level
of dietary protein is around the animal's protein requirement. One of the factors
that affects an animal's protein requirement is age. We predict that young,
growing animals are more responsive to a moderately low level of dietary protein
than are mature animals. The feeding response to moderately low dietary protein
(10% casein) was determined in young ( approximately 190 g) and more mature (
approximately 340 g) Sprague-Dawley rats for 12 days. As an index of amino acid
deamination, serum urea nitrogen concentrations were determined, as was the in
vitro release of neuropeptide Y (NPY) from hypothalamic tissue containing the
paraventricular nucleus. Young rats were more responsive to the feeding effects
of moderately low dietary protein than mature animals. In young rats, cumulative
food intake was inversely correlated with serum urea nitrogen concentration. No
correlation was found in mature animals. Although the amount of NPY remaining in
hypothalamic tissue after incubation was significantly greater (p = 0.04) in
young rats fed 10% casein as compared with rats fed the standard 20% casein diet,
no dietary difference in K(+)-stimulated NPY release was observed. We hypothesize
that the signal for low-protein-induced hyperphagia is a reduction in a compound
whose production is coupled to the level of amino acid deamination in the brain.
PMID- 10764898
TI - Effect of dietary lipid content on circadian rhythm of feeding activity in
European sea bass.
AB - In fish, dietary digestible energy (DE) content is a major factor controlling
feed intake. It was therefore of interest to determine how circadian rhythm of
feeding activity is influenced by the dietary DE levels. To that end, groups of
European sea bass were fed on demand by means of self feeders, under light-dark
and constant light conditions, with a fixed or an unlimited amount of feed with
variable lipid contents. Daily total feed intake, but not the feeding rhythm, was
adjusted in relation to the DE content of the diet regardless of the lighting
conditions. We conclude that a satiation mechanism was likely responsible for the
regulation of feed intake in relation to the dietary fat content but was not
acting in itself on the mechanisms that drive the free-running rhythms of feeding
activity. These results are giving additional evidence that a true endogenous
clock is driving feeding activity rhythms in fish.
PMID- 10764899
TI - Young women's food preferences and taste responsiveness to 6-n-propylthiouracil
(PROP).
AB - This study examined links between taste responsiveness to 6-n-propylthiouracil
(PROP), a heritable trait, and sensory responses to six common foods. Sixty-three
young women subjects were divided into PROP tasters (n = 25) and nontasters (n =
25), based on their responses to PROP-impregnated filter paper and mean
bitterness intensity ratings for seven PROP solutions. Thirteen subjects were
excluded as unclassifiable. The 50 subjects sampled Brussels sprouts, broccoli,
spinach, black coffee, soy milk, and soybean tofu. Sensory ratings for bitter
intensity; pleasantness of taste, odor, and texture, and overall food
acceptability scores were obtained using nine-point category scales. All subjects
completed a food-preference checklist and a modified food-frequency
questionnaire. PROP tasters rated Brussels sprouts as more bitter than did
nontasters (p<0.05). Subjects who perceived the foods as more bitter also rated
them as less pleasant and less acceptable. Taste preferences and food preferences
were linked. Self-reported food preferences and self-reported frequencies of
consumption for the same foods were also linked. Taste factors and food
preferences may impact dietary choices and the frequency of food consumption.
PMID- 10764900
TI - Psychophysiological stress responses in amputees with and without phantom limb
pain.
AB - The present experiment tested the hypothesis that phantom limb pain amputees show
a different pattern of psychophysiological reactivity to stress compared with
painfree amputees. Six phantom limb pain (PLP) and five painfree upper-extremity
amputees were administered two groups of tasks: stressful and relaxing. The
measured dependent variables were skin temperature recorded at both stump and
intact site, heart rate, blood pressure, subjective pain and stress ratings.
Phantom limb pain patients were characterized by higher stump temperature
compared with phantom limb painfree patients. This effect was observed during the
whole recording. Consistently with the between-subjects effect, when PLP patients
exhibited higher skin temperature (during relaxation, compared with during
stressful tasks), they perceived more pain. The experiment showed higher
cardiovascular reactivity in PLP patients, specifically to the stressful free
speech task, which focused on recollection of the amputation event. As compared
with the painfree patients, during the personal stressor, PLP patients' heart
rate and systolic blood pressure increased, indicating a greater sympathetic
response. Results indicate that peripheral factors, such as stump temperature
reliably differentiate PLP from painfree patients. Moreover, the clear
cardiovascular hyperreactivity observed in PLP patients during their report of
amputation suggests that PLP is associated with a long-term emotional memory for
the painful experience of that event. These results are consistent with most
reports in the literature relating phantom pain development to the experience of
preamputation pain.
PMID- 10764901
TI - Suppression of copulatory behavior by intracerebroventricular infusion of
antisense oligodeoxynucleotide of granulin in neonatal male rats.
AB - Sexual dimorphism of the rodent brain is manifested by the epigenetic action of
gonadal steroids. Our previous research identified the granulin (grn) precursor
gene as a sex steroid-inducible gene, which was shown to be expressed more
abundantly in male than female neonates at the mediobasal hypothalamic area. Grn
is a 6-kDa polypeptide promoting or inhibiting the growth of epithelial cells and
hematocytes in vitro. In this study, effects on male sexual behavior of male were
pursued under conditions in which grn gene expression was suppressed during the
critical period. To this end, an antisense oligodeoxynucleotide (ODN) of the grn
precursor gene was designed, incorporated into inactivated Sendai virus (HVJ)
liposome complexes, and infused into the third ventricle of 2-day-old male rats.
Two different control treatments were used: the first consisted of a control
sequence ODN that had little homology to known mRNAs; the second of vehicle (HVJ
liposome) alone. After maturation, animals treated with antisense ODN of grn
displayed significantly lower scores than control males on various parameters
assessing sexual behavior; i.e., mount, intromission, and ejaculation. The
antisense ODN, however, did not affect body growth or serum concentrations of
testosterone and luteinizing hormone. Further, there was no significant
difference in the volume of the sexual dimorphic nucleus of the preoptic area
between antisense ODN-treated and control animals. It was shown that inadequate
expression of the grn gene in the brain of male neonatal rats during the critical
period suppressed the induction of some type of male sexual behavior, suggesting
the grn was involved in the process of masculinization of the rat brain.
PMID- 10764902
TI - Effect of a serotonin 1-A agonist on food intake of Osborne-Mendel and S5B/P1
rats.
AB - The effect on food intake of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT),
a serotonin 1-A agonist, has been evaluated in two strains of rats that differ in
their sensitivity to becoming obese while eating a high-fat diet. Male Osborne
Mendel (OM) and S5B/Pl rats were tested at 8 weeks and 16 weeks of age. Both
strains were adapted to choose between two diets-a 56% fat energy diet, and a 10%
fat energy diet-which were equicaloric for protein (24% energy). Daily food
intake was measured for 2 weeks before injection of 8-OH-DPAT. The younger OM
rats had no diet preference, while the older OM rats preferred the high-fat diet.
The younger S5B/P1 rats preferred the low-fat diet, while the older S5B/P1 rats
had no diet preference. Satiated rats were injected subcutaneously with 8-OH-DPAT
at doses of 0.3, 1.0, or 3.0 mg/kg or vehicle. During the light phase,
subcutaneous 8-OH-DPAT increased the intake of the high-fat diet in the 16-week
old OM rats but not the 8-week-old OM rats. 8-OH-DPAT had no effect on the low
fat diet intake in either age OM rat. The 8-week-old S5B/P1 rats showed a
significant decrease in intake of the high-fat diet in response to 8-OH-DPAT,
whereas an increase in the intake of the low-fat diet was observed in the older
S5B/P1 rats. These data are consistent with the hypothesis that increased fat
preference in Osborne-Mendel rats may result in part from altered serotonin
activity of 5-HT(1A) receptors.
PMID- 10764903
TI - Relating acoustic startle reactivity and plasticity to alcohol consumption in
male Wistar rats.
AB - The purpose of this study was to investigate the relationship between the startle
response and ethanol. Aspects of the startle response, including initial and
average startle, habituation, and prepulse inhibition (PPI) were studied. The
startle response was measured to detect potential predictors of voluntary ethanol
consumption and to observe whether ethanol ingestion would affect startle in
subsequent tests. Rats were tested three times in a standard startle chamber.
After the initial startle test, rats categorized as showing high or low PPI were
allocated in a balanced way to a free-choice ethanol-water regime or to the water
regime control group. At the end of the ethanol period (lasting for 16 days,
including access to ethanol for 10 days), the rats were tested again in the
startle chamber 24 h after ethanol removal. After 5 weeks of ethanol abstinence,
rats were exposed to a final startle test. The response to the first 120-dB
stimulus showed an inverted U-shaped, curvilinear relationship to later ethanol
consumption. Startle habituation appeared to have predictive value regarding
ethanol consumption, with rats showing the most efficient habituation drinking
most. Data showed no relationship between PPI and ethanol intake. Rats given
access to ethanol showed greater habituation in the post-ethanol test than did
the water controls. After 5 weeks of abstinence, low ethanol-consuming rats
showed lower startle responses to the first 120-dB stimulus than did high ethanol
consuming rats. The present data suggest a two-way relationship between startle
response characteristics and alcohol.
PMID- 10764904
TI - Central vasopressin administration failed to influence anxiety behavior after
pinealectomy in rats.
AB - Experiments were performed to measure the influence of centrally applied arginine
vasopressin (AVP) on anxiety-related behavior in pinealectomized (PE) rats and
sham-operated (SO) controls. In the PE animals, microdialysis application of 200
pg AVP into the mediolateral septum, as well as intracerebroventricular
administration of 10 ng AVP, failed to influence anxiety-related behavior
measured in the elevated plus-maze test. However, in SO animals, the percentage
of time spent on the open arms of the elevated plus-maze was found to be higher
in both experiments. Pinealectomy alone was without effect in this respect. The
results suggest that central AVP may be involved in the modulation of anxiety
related behavior in rats, even though this modulation is dependent on an intact
pineal function.
PMID- 10764905
TI - Habituation of event-related potentials in patients with Parkinson's disease.
AB - Auditory event-related potential (ERP) was studied in idiopathic Parkinson's
disease (PD) using our new procedures. We examined 12 non-demented patients with
PD, and 9 age-matched control subjects. Ninety responses induced by rare
stimulation were continuously recorded from Fz, Cz, Pz referred to linked earlobe
electrode (A1A2), and were divided into nine blocks (one block = 10 responses)
for statistical analysis. We assessed the habituation of auditory ERP to detect
delicate changes related to the information processing in PD. N100 and P300
latencies were significantly longer in PD than in control subjects (p<0.05). P300
latency gradually increased with progression of recording blocks in both PD and
control subjects, whereas N100 latency increased only in PD. Three way analysis
of variance for P300 amplitude revealed significant effects of subject group,
recording electrode site, and trial block. P300 amplitude was smaller in PD than
in control subjects. Significant negative correlation between P300 amplitudes and
block numbers were observed at Cz and Pz in PD, and at Fz in the control group.
Previous reports as well as present results suggest that prolongation of N100
latency might be related to frontal lobe dysfunction, and abnormality of P300 to
dysfunction in both the frontal lobe and hippocampus in PD.
PMID- 10764906
TI - NMDA receptor antagonists extend the sensitive period for imprinting.
AB - Filial imprinting in the domestic chick occurs during a sensitive period of
development. The exact timing of this period can vary according to the methods
used to measure imprinting. Using our imprinting paradigm, we have shown that
normal, dark-reared chicks lose the ability to imprint after the second day post
hatching. Further, we reported that chicks treated 10 h after hatching with a
mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and
the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint
on day 8 after hatching, whereas controls treated with saline did not imprint. We
now show that the effect of the ketamine-xylazine mixture can be mimicked by
treating chicks with ketamine alone or with another noncompetitive NMDA receptor
antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55
mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect
on the sensitive period. However, prolonging the action of ketamine by treating
chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow
imprinting on day 8. In contrast, prolonging the action of xylazine had no effect
on the sensitive period for imprinting. Chicks treated with MK-801 were also able
to imprint on day 8. Thus, we have evidence that the NMDA receptor system is
involved in the mechanisms that control the sensitive period for imprinting.
PMID- 10764907
TI - Different preferences for oils with similar fatty acid profiles.
AB - While preference for fat can be influenced by concentration and physical form,
the influence of fatty acid composition on relative preference for oils has not
been systematically investigated. Therefore, the purpose of the present
investigation was to assess the relative preference for oils rich in oleic (Extra
Light Olive Oil and Extra Virgin Olive Oil) and linoleic (Safflower Oil) acid.
Male Fischer rats (n = 10) were used to determine preference in a two-choice
testing procedure in which three pairs of oils were each tested twice. Preference
testing occurred at dark onset at which time the rodent diet and water were
removed and each rat was allowed 2-h access to his assigned pair of oils. There
was a main effect of oil type (p<0.01), but no significant effect of oil pairing
and no interaction between oil pairing and oil type. Rats preferred the Extra
Light Olive Oil to the Extra Virgin Olive Oil (p<0.05). This is the first report
of preference testing in which two oils with similar fatty acid profiles were
included. The present data indicate that the fats with similar fatty acid
profiles were not equally preferred, suggesting that a property other than the
fatty acid composition of the oils accounts for the demonstrated preference.
PMID- 10764908
TI - Behavioral effects of acute and chronic imipramine in the elevated T-maze model
of anxiety.
AB - The elevated T-maze is an animal model of anxiety, consisting of three elevated
arms: one enclosed and two open. Inhibitory avoidance of the open arms
representing learned fear-has been related to generalized anxiety and the
unconditioned escape from one of the open arms to panic. In the present study, we
investigated the effects of acute and chronic (21 days) administration of
imipramine (5, 10, and 15 mg/kg; IP) in male Wistar rats that have been
previously exposed for 30 min to one of the open arms of the T-maze, 24 h before
the test. The results show that this preexposure shortens the first escape
latency, without changing open-arm avoidance. Under these experimental
conditions, chronic imipramine exerted anxiolytic-like effects in the two
elevated T-maze tasks; impaired the acquisition of inhibitory avoidance and
prolonged escape latency from the open arms. Acute imipramine enhanced both
avoidance and escape latencies. Both acute and chronic imipramine decreased
locomotor activity measured in a square arena. The obtained results are
compatible with the view that inhibitory avoidance and one-way escape in the
elevated T-maze reflect different types of fear/anxiety, that may be related to
generalized anxiety and panic disorder, respectively.
PMID- 10764909
TI - Ricinine-elicited seizures. A novel chemical model of convulsive seizures.
AB - The present investigation introduces ricinine-elicited seizures as a novel
chemical model of convulsive seizure. Ricinine, a neutral alkaloid obtained from
the plant Ricinus communis, induces seizures when administered to mice at doses
higher than 20 mg/kg. Animals presenting seizures showed a marked preconvulsive
phase followed by short duration hind limb myoclonus, respiratory spasms, and
death. The lethal nature of ricinine seizures is also pointed out as a good model
to study the events causing death in clonic seizures, particularly those related
to respiratory spasms, which are also observed in some types of human epilepsy.
The behavioral signs of ricinine-elicited seizures are accompanied by
electrographic alterations more evident during the preconvulsive phase in the
cerebral cortex and more intense during the ictal phase both in the cortex and in
the hippocampus. The ricinine-elicited seizures may be inhibited by diazepam but
not by phenobarbital, phenytoin, or ethosuximide. Micromolar concentrations of
ricinine cause a small decrease in the binding of [3H]-flunitrazepam to cerebral
cortex membranes, but do not alter the binding of other radioligands to AMPA, 5
HT(1A), muscarinic, and alpha(1)-adrenergic receptors. Although ricinine presents
a cyanide radical, only higher doses of ricinine (4 mM) caused a small impairment
of mitochondrial respiration. These results suggest that the mechanism of action
of ricinine probably involves the benzodiazepine site in the GABA(A) receptor.
This may represent a new mechanism of drug-elicited seizures that may contribute
to a better understanding of epilepsy and to new therapeutic approaches to this
disease.
PMID- 10764910
TI - The effect of amphetamine on locomotion depends on the motor device utilized. The
open field vs. the running wheel.
AB - The effect of amphetamine on the level of locomotion exhibited on two different
motor devices was examined in the Golden hamster. Increasing concentrations of
the psychostimulant from 4 to 10 mg/kg significantly enhanced locomotor activity
in hamsters exposed to an open field. A further increase to 25 mg/kg inhibited
ambulatory activity to levels below the control baseline, while augmenting the
occurrence of stereotypic behaviors. The activating effect of amphetamine on
ambulatory activity was observed regardless of the time of testing (day or night)
or lighting condition, with no apparent modulation by the circadian system. On
the other hand, home-cage wheel-running activity was maximally inhibited by 10
mg/kg amphetamine, whereas a smaller dosage (1.5 mg/kg) had no effect over the
wheel-running activity baseline of saline controls. Although both the running
wheel and the open field quantify locomotion, the dissociation obtained shows
that they measure different components of it. The results are interpreted within
Lyon and Randrup's hypothesis on the actions of amphetamine (16).
PMID- 10764911
TI - Effect of subchronic antidepressant treatments on behavioral, neurochemical, and
endocrine changes in the forced-swim test.
AB - The purpose of the present study was to examine the effect of subchronic
treatment (24 days) with antidepressants displaying differential effects on
noradrenaline and serotonin reuptake, on behavior, neurochemistry, and
hypothalamic-pituitary-adrenal (HPA) axis activity following FST exposure in the
rat. Desipramine (7.5 mg/kg, IP) significantly decreased immobility in the FST,
whilst paroxetine (7.5 mg/kg IP) and venlafaxine (10 mg/kg, IP) were without
effect. Nonetheless, treatment with all three antidepressants significantly
attenuated stress-related increases in amygdaloid and cortical serotonin
turnover. Of the three antidepressants examined, only desipramine attenuated the
stress-associated elevation in serum corticosterone. In conclusion, although FST
induced increases in serotonin turnover in the frontal cortex and amygdala were
attenuated following treatment with all three antidepressants, FST-induced
behavioral changes and increased HPA axis activity were normalized only following
desipramine treatment. In addition, these results suggest that neurochemical
mechanisms independent of increased serotonergic activity subserve the
normalization of behavior and HPA axis responses in the FST. These data also add
to our understanding of the interactions between antidepressants and stress
induced behavioral, neurochemical, and endocrine alterations, and illustrates
important differences between classes of antidepressants.
PMID- 10764912
TI - Effect of tricyclic antidepressants on taste responses in humans and gerbils.
AB - One of the side effects of antidepressant pharmacotherapy reported clinically is
impairment of the sense of taste. In this study, the taste effects of four
tricyclic antidepressant compounds (clomipramine HCl, desipramine HCl, doxepin
HCl, and imipramine HCl) were evaluated experimentally by topical application of
the drugs to the tongue. Taste detection threshold concentrations for all four
medications ranged from 0.1 mM to 0.2 mM in young persons but were elevated by as
much as 7.71 times that in elderly individuals who were taking no concurrent
medications. Each compound had a predominantly bitter taste with other qualities
including metallic, sour, and sharp-pungent. In addition, each tricyclic
antidepressant at concentrations from 1 mM to 5 mM blocked responses to a wide
range of taste stimuli in both humans and gerbils. The differential suppression
of other tastes by tricyclic antidepressants at the level of the taste receptors
may contribute to the clinical reports of dysgeusia and hypogeusia.
PMID- 10764913
TI - Decrement in operant performance produced by NMDA receptor antagonists in the
rat: tolerance and cross-tolerance.
AB - Current perspectives on the clinical use of NMDA receptor antagonists infer
repeated administration schedules for the management of different pathological
states. The development of tolerance and cross-tolerance between different NMDA
receptor antagonists may be an important factor contributing to the clinical
efficacy of these drugs. The present study aimed to characterize the development
of tolerance and cross-tolerance to the ability of various site-selective NMDA
receptor antagonists to produce a decrement of operant responding (multiple
extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute
administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03
0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1
30 mg/kg) differentially affected operant responding. Both increases and
decreases in response rates and accuracy of responding were observed. Repeated
preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral
disruption produced by an acute challenge with D-CPPen or ACEA-1021, but
potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the
present results, one can suggest that the repeated administration of a
competitive NMDA receptor antagonist differentially affects the functional
activity of various sites on NMDA receptor complex.
PMID- 10764914
TI - Intrathecal N-methyl-D-aspartate (NMDA) induces paradoxical analgesia in the tail
flick test in rats.
AB - The intrathecal (IT) administration of NMDA in rodents has usually been reported
to produce hyperalgesic reactions, although some articles describe that spinal
NMDA can lead to analgesia. We show here that the nociceptive behavior (biting,
scratching, licking; BSL) observed after NMDA injection (1-8 microg/rat; IT) is
followed by a long period of increased tail-flick latencies, not longer detected
24 h after NMDA administration. The NMDA-receptor antagonist CPP (10-100 ng/rat;
IT) blocked the BSL behavior induced by NMDA. In the tail-flick test, this
antagonist induced analgesia by itself, and was able, at 30 ng/rat, to prevent
the NMDA-mediated analgesia. The implication of opiate mechanisms was discarded
since naloxone (3 and 10 mg/kg; IP) did not antagonize NMDA-induced analgesia.
Finally, the involvement of the intracellular calcium binding protein calmodulin
was assessed. The calmodulin inhibitor, calmidazolium (30-300 microg/rat; IT)
only blocked the excitatory effect (BSL) without modifying the tail-flick
analgesia produced by NMDA (4 microg). These results show that a single
intrathecal administration of NMDA sequentially induces both nociceptive and
antinociceptive, nonopiate responses in rats.
PMID- 10764915
TI - Evidence that total extract of Hypericum perforatum affects exploratory behavior
and exerts anxiolytic effects in rats.
AB - Clinical trials have extensively reported the ability of Hypericum perforatum
extracts to exert a significant antidepressant activity. Hypericin, the main
constituent of H. perforatum extract, is no more regarded as the active principle
of the antidepressant activity of the drug. Hence, the question of which
constituents are involved in the basic activity of the total extract, is still
waiting for an answer. In the present study we focused our attention on the
potential anxiolytic activity of H. perforatum total extract, and of some pure
components such as protohypericin and a fraction containing hypericin and
pseudohypericin. Herein we report that the total extract of H. perforatum
increases the locomotor activity in the open field and exerts anxiolytic activity
in the light-dark test, whereas the single components did not show any effect.
Interestingly, the anxiolytic activity of the total extract was blocked by
pretreatment of rats with the benzodiazepine antagonist Flumazenil, hence
suggesting an implication of benzodiazepine receptor activation in the anxiolytic
effect of H. perforatum extract. Electrophysiological studies, performed to gain
more information on the mechanism of action, showed that hypericin reduced the
GABA-activated chloride currents, while pseudohypericin did an opposite effect.
Furthermore, both hypericin and pseudohypericin inhibited the activation of NMDA
receptors.
PMID- 10764916
TI - Pharmacology of flavor preference conditioning in sham-feeding rats: effects of
dopamine receptor antagonists.
AB - Opioid and dopamine systems are both implicated in the response to sweet
solutions. Our laboratory previously reported that the opioid antagonist,
naltrexone, reduced the intake of sweet solutions, yet had little or no effect on
sucrose-conditioned flavor preferences in sham-feeding rats. The present study
examined the role of dopamine D(1) and D(2) receptors in the expression of flavor
preferences conditioned by the sweet taste of sucrose. All sessions were
conducted under sham-feeding conditions to minimize postingestive influences.
Training was accomplished by adding a novel flavor (CS+) to a 16% sucrose
solution, a different flavor (CS-) to a less-preferred 0.2% saccharin solution in
alternating, one-bottle sessions. Preferences were assessed in two-bottle tests
with the CS+ and CS- flavors presented in mixed sucrose (8%)-saccharin (0.1%)
solutions following systemic doses of 0, 50, 200, 400, or 800 nmol/kg of the D(2)
antagonist, raclopride (Experiment 1) or the D(1) antagonist, SCH23390
(Experiment 2) under either food-restricted or unrestricted conditions. Rats
significantly preferred the CS+ solutions in vehicle tests, and displayed
equipotent and dose-dependent reductions in total intake and CS+ preference
following either D(1) or D(2) receptor antagonism. Similar results were obtained
with SCH23390 and raclopride in Experiment 3 conducted with water-restricted
rats. These data indicate that dopaminergic D(1) and D(2) receptors play pivotal
and functionally equivalent roles in the expression of flavor preferences
conditioned by the sweet taste of sucrose.
PMID- 10764917
TI - The anxiolytic-like properties of two selective MAOIs, moclobemide and
selegiline, in a standard and an enhanced light/dark aversion test.
AB - The present study was designed to investigate the putative anxiolytic effects of
moclobemide (MOC), a reversible inhibitor of type A monoamine oxidase enzyme
(RIMA) antidepressant, in an experimental model of anxiety in mice. The test
selected was the light/dark aversion test. In the present investigation, an
anxiogenic-like behavior was induced by light, alone as the stimulus (standard
version of the test) or by pretreatment with a subconvulsant dose of
pentylenetetrazole (PTZ) (15 mg/kg IP) 45 min before testing ("enhanced" version
of the test). In mice, the effect of repeated administration for 2 weeks of MOC
(0.5, 1, and 5 mg/kg IP) was compared with those of selegiline (SEL) (5, 10, and
20 mg/kg IP), an irreversible and selective MAO-B inhibitor. For comparative
purpose, the chronic effect of an established reference anxiolytic, such as
lorazepam (LOR) (0.025, 0.05, and 0.10 mg/kg IP), was also evaluated. Results
demonstrated that PTZ-treated mice showed a decrease in the number of transitions
as well as in the time spent in the lit area, when compared with vehicle
controls, an effect characteristic of an anxiogenic response. This anxiogenic
like behavior was reduced by chronic administration of LOR as well as MOC,
suggesting an anxiolytic-like effect (as shown in the "standard" version of the
test). In addition, the increased aversion of mice for the light compartment of
the light/dark box was significantly reduced compared to PTZ-treated mice or
vehicle controls. SEL failed to significantly alter the anxiogenic-like behavior
induced by subconvulsant doses of PTZ. These data provide additional evidence for
the anxiolytic-like effects of MOC administered chronically in the mouse.
PMID- 10764918
TI - (+)Amphetamine-stimulus generalization to an herbal ephedrine product.
AB - We have previously demonstrated that a (+)amphetamine stimulus generalizes both
to (-)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal
(IP) administration of 1.0 mg/kg of (+)amphetamine (ED(50) = 0.4 mg/kg) from
saline vehicle in a standard two-lever drug discrimination procedure, the present
investigation shows that the (+)amphetamine stimulus generalizes to
(+)amphetamine (ED(50) = 1.0 mg/kg) when administered via the intragastric (IG)
route, and that (+)amphetamine appears about 2. 5-fold less potent when
administered via the IG route compared to the IP route. Likewise, (-)ephedrine
(ED(50) = 10.8 mg/kg) and caffeine (ED(50) = 32.9 mg/kg) are also 2.5-fold less
potent when administered via the IG route compared to their potency when
administered via the IP route. The (+)amphetamine stimulus also generalizes to an
IG-administered herbal preparation (i.e., Herbal XTC; the herbal preparation
possesses an approximate potency roughly comparable to what might have been
expected on the basis of its reported ephedrine and/or caffeine content. These
results demonstrate, for the first time, that an ephedrine-containing herbal
preparation can produce a (+)amphetamine-like effect in animals.
PMID- 10764919
TI - Decreased accumbens dopamine release after cocaine challenge in behaviorally
sensitized female rats.
AB - The effects of the competitive NMDA receptor antagonist CPP on the initiation of
behavioral sensitization to acute cocaine and basal and acute cocaine-induced
dopamine (DA) release in the nucleus accumbens (NAC) were assessed in female
Sprague-Dawley rats. Cocaine pretreated rats (30 mg/kg IP, once daily for 7 days)
challenged with cocaine (10 mg/kg) on day 8 displayed increased motor activity
relative to controls challenged with cocaine on day 8. This effect was blocked in
rats receiving CPP (2 mg/kg) 15 min prior to all cocaine pretreatments. Basal DA
levels in the NAC of both cocaine-pretreated and CPP plus cocaine-pretreated rats
were higher on day 8 compared to controls. Acute cocaine challenge on day 8
resulted in increased extracellular DA concentrations in the NAC in control rats,
no increase in rats pretreated with CPP plus cocaine, and a decrease in rats
pretreated with cocaine only. These data demonstrate that development of
behavioral sensitization to cocaine in female Sprague-Dawley rats can be
completely blocked by a peripherally administered competitive NMDA receptor
antagonist and that an increase in DA release in the NAC after a cocaine
challenge is not an absolute requirement for expression of motor sensitization to
cocaine in female rats.
PMID- 10764920
TI - Nicotine enhances stimulus detection performance of middle- and old-aged rats: a
longitudinal study.
AB - The effects of nicotine on sustained attention were tested in F344xBN male rats
when they were chronologically middle and old aged. The rats (n = 11) were
trained in a two-choice, stimulus detection task in which a press of one of two
levers was reinforced with food, with the correct lever indicated by the position
of a briefly illuminated light. They were tested when they were 24-25 and 34-35
months of age (i.e., at 60-68% and 85-95%, respectively of their expected median
life span) after saline or 0.1-0.5 mg/kg doses of nicotine (SC). A significant
dose-related improvement in percent correct choices and decrease in choice
response times was found at both ages, and there was no significant main effect
of age or an age by dose interaction. These results support the position that
nicotine can enhance attentional processes in rats throughout their life span.
Nicotine and other nicotinic agonists may have efficacy in the treatment of
disorders such as Alzheimer's disease.
PMID- 10764921
TI - Effects of SCH-23390 and raclopride on cocaine discrimination in male and female
Wistar rats.
AB - Male and female rats were trained to discriminate 10.0 mg/kg cocaine from saline
in a two-lever discrimination task. Injection-appropriate responding was
reinforced by food pellet presentation on a tandem random-interval 30-s fixed
ratio 10 schedule. Generalization testing was conducted in extinction 10 min
following an injection of saline, 1.0, 3.0, 5.6, or 10.0 mg/kg cocaine. No
differences in the generalization gradients and ED(50)s were observed between
male and female rats. Following the determination of the cocaine generalization
gradient, the dopamine D(1) antagonist SCH-23390 (0.01-0.10 mg/kg) and the
dopamine D(2) antagonist raclopride (0.1-1.6 mg/kg) were administered
(independently) prior to the injection of the training dose of cocaine (10.0
mg/kg). Cocaine-antagonism tests were conducted in extinction. It was found, for
each dopamine antagonist, that as the dose increased, the percentage of cocaine
appropriate responding decreased. No sex differences were observed between these
generalization gradients.
PMID- 10764922
TI - The role of serotonin(2) receptors in mediating cocaine-induced convulsions.
AB - Previous research in our laboratory suggests that serotonin (5-HT)
neurotransmission mediates the expression of cocaine-induced convulsions. The
role of 5-HT in mediating this toxic effect of cocaine appears to be due to
activation of 5-HT(2) receptors, because cocaine-induced convulsions are blocked
by the 5-HT(2) antagonists cinanserin, ketanserin, and pirenperone. The present
study utilized a number of compounds that display a high affinity for 5-HT(2)
receptors to further examine the role of these sites in mediating this toxic
effect of cocaine. Cocaine-induced convulsions were observed following
pretreatment with various doses of the following 5-HT(2) antagonists: mianserin,
metergoline, MDL 11939, and methiothepin. In addition, 1-(2-methoxyphenyl)-4-[4
(2-phthalimido)butyl]piperazine (NAN 190) was tested to examine the influence of
5-HT(1) sites and the agonist compound 1-(3-triflurormethylphenyl)piperazine
(TFMPP) was examined to further explore the role of 5-HT(1) and 5-HT(2) sites.
Each 5-HT(2) antagonist attenuated cocaine-induced convulsions. Conversely, NAN
190 did not alter this toxic effect of cocaine. In addition, TFMPP significantly
potentiated cocaine-induced convulsions. The results from this study support the
hypothesis that 5-HT neurotransmission, acting primarily at 5-HT(2) receptors,
plays an important role in mediating cocaine-induced convulsions.
PMID- 10764924
TI - Acoustic startle and fear-potentiated startle in alcohol-preferring (P) and
nonpreferring (NP) lines of rats.
AB - The objective of the present study was to determine whether alcohol-preferring P
and -nonpreferring NP rats differ in their acoustic startle response and in fear
potentiated startle. In Experiment 1, male P and NP rats were tested on the
startle response to acoustic stimuli ranging from 90-115 dB. Experiments 2 and 3
examined fear-potentiated startle and extinction of the response. In Experiment
2, rats received two light foot shock training sessions separated by 3-4 h.
Testing consisted of ten acoustic startle (115 dB) and fear-potentiated startle
(light preceding the acoustic startle) presentations administered every 24 h for
9 consecutive days. To test potentiated startle learning under reduced training
conditions, a single training session was administered in Experiment 3, and a
single within-session extinction test of 50 startle and 50 potentiated startle
trials occurred the following day. Results of Experiment 1 indicated that P and
NP rats did not differ in startle at any of the acoustic intensities tested.
Following fear-potentiated startle conditioning in Experiment 2, however, both
acoustic startle and potentiated startle responding were consistently greater in
P than NP rats over most of the first 6 test days with P rats having
approximately a 100% greater acoustic startle and 50-100% greater potentiated
startle response. Moreover, following a single training session in Experiment 3,
only P rats showed significant fear-conditioned startle. Additionally, P rats
exhibited a 50-100% elevated acoustic startle response over that observed in NP
rats. Taken together, the data indicate that, although experimentally naive male
P and NP rats show similar acoustic startle responses, P rats become more
responsive to both startle-alone and potentiated startle stimuli following fear
conditioning. The change in general startle reactivity of the P rat following
aversive conditioning, along with facilitated light foot shock learning, suggests
that stress exposure may be an important variable in examining associations
between anxiety and alcohol drinking behavior.
PMID- 10764923
TI - Effects of H1 antagonists on cholinomimetic-induced tremulous jaw movements:
studies of diphenhydramine, doxepin, and mepyramine.
AB - In several previous studies, tremulous jaw movements in rats have been used to
assess the effects of antiparkinsonian drugs and atypical antipsychotics. Because
antihistamines such as diphenhydramine are used as antiparkinsonian agents, and
atypical antipsychotic drugs such as clozapine and olanzapine have high affinity
for histamine H1 receptors, the present study investigated the effects of H1
antagonists on cholinomimetic-induced jaw movements. Diphenhydramine, doxepin,
and mepyramine (all injected IP 2.5-20.0 mg/kg) were assessed for their ability
to block the jaw movements induced by 5.0 mg/kg of the anticholinesterase
tacrine. Within this dose range, only diphenhydramine produced a robust and
significant reduction in jaw movement activity. Thus, diphenhydramine was
subjected to further testing, which employed procedures previously used to assess
the effects of other antitremorogenic drugs, such as clozapine. Diphenhydramine
did not induce jaw movement activity. In addition to suppressing jaw movement
activity after acute injections, diphenhydramine also suppressed tacrine-induced
jaw movements after repeated (14-day) administration. In summary, the present
results show that diphenhydramine suppresses cholinomimetic-induced jaw
movements, an effect that is similar to other antiparkinsonian or antitremor
drugs such as anticholinergics, L-DOPA, DA antagonists, and clozapine.
Nevertheless, doxepin produced only mild effects, and mepyramine, which has a
higher affinity and selectivity than diphenhydramine for H1 receptors, failed to
suppress cholinomimetic-induced jaw movements. These results suggest that
diphenhydramine suppresses tremulous movements through a mechanism that does not
depend upon antagonism of histamine H1 receptors.
PMID- 10764925
TI - Pharmacology of sucrose-reinforced place-preference conditioning: effects of
naltrexone.
AB - Two experiments investigated the role of the opioid system in sucrose-reinforced
conditioned place preferences (CPPs) in rats. Experiment 1 examined the effects
of a general opioid antagonist, naltrexone, on the expression of a CPP acquired
in the absence of the drug. Subjects were trained to associate one compartment of
a two-compartment chamber with sucrose and the other compartment with water. Rats
displayed a preference for the sucrose-associated compartment in a choice test
without sugar or water available following vehicle saline treatment. Naltrexone
doses of 2.5 and 5.0 mg/kg reduced this preference for the sucrose-associated
compartment. Experiment 2 examined the effects of naltrexone on the acquisition
as well as the expression of CPPS. Different groups of rats received daily
injections of either saline, 0.1, 1.0, or 5.0 mg/kg of naltrexone prior to each
training session, and then these groups were given a choice test for the CPP
after saline or naltrexone injections. Although naltrexone treatment attenuated
the expression of CPPs in each group relative to saline treatment, there were no
group differences during these tests in the magnitude of the preferences.
Moreover, all groups displayed equal acquisition of CPPs despite the fact that
naltrexone dose dependently decreased sucrose intake during the training phase.
Together, the results indicate that the opioid system modulates the expression
but not the acquisition of sucrose-reinforced CPPs.
PMID- 10764926
TI - The role of benzodiazepine receptors in the acquisition and expression of
behavioral sensitization to methamphetamine.
AB - The GABA-benzodiazepine neurotransmission has been reported to be implicated in
various forms of plasticity such as kindling and learning. In a previous study,
we have shown that clonazepam (CZP), a GABA-benzodiazepine agonist, prevents the
acquisition of behavioral sensitization to methamphetamine (MA). The present
study was conducted to extend this finding by examining the effect of flumazenil
(Flu), a GABA-benzodiazepine antagonist on the prevention by CZP. Rats (male
Wistar-King rats) treated with MA (1 mg/kg, SC) for 10 days showed significantly
enhanced motor activity compared to those treated with saline when tested with MA
(1 mg/kg) after a 7-8-day withdrawal, indicating the acquisition of behavioral
sensitization. Representing the previous finding, pretreatment with CZP (0.5
mg/kg) prior to MA administration prevented the acquisition of the phenomenon.
Pretreatment with Flu (10 mg/kg) prior to MA administration has no influence on
the acquisition of sensitization. However, pretreatment with Flu prior to CZP
administration reversed the inhibitory effect of CZP. CZP showed no effect on the
expression of sensitization in the sensitized rats when given prior to the MA
readministration. These results strengthen the suggestion that stimulation of
GABA-benzodiazepine receptors plays a role in the acquisition but not in the
expression of behavioral sensitization to MA.
PMID- 10764927
TI - Neonatal nicotine exposure alters hippocampal EEG and event-related potentials
(ERPs) in rats.
AB - A consensus is forming that nicotine can damage the developing rat central
nervous system. However, few studies have assessed the electrophysiological
effects of neonatal nicotine exposure in rodents in brain regions known to be
sensitive to the teratogenic properties of nicotine. In a previous study it was
reported that 1.0 and 4.0 mg/kg/day nicotine exposure from postnatal days 4-9, a
developmental period corresponding to human third-trimester exposure,
significantly altered hippocampal event-related potentials (ERPs) but did not
effect cortical ERPs, cortical EEG, or hippocampal EEG. Because alterations in
behavior and cortical/hippocampal neurochemistry and morphology have been
reported following nicotine exposure, the present study used a higher dose of
nicotine during the postnatal period (6.0 mg/kg/day) determine if functional
changes in the EEG of these regions might contribute to behavioral changes that
have been observed. Male Sprague-Dawley rats were exposed to 6. 0 mg/kg/day
nicotine via gastric infusion using an artificial rearing, "pup-in-the-cup,"
technique for 6 consecutive days (postnatal days 4-9). At adulthood, EEG and
auditory ERPs were recorded from the cortex and hippocampus. There were no
significant differences in EEG or ERPs recorded from the cortex between nicotine
treated and control subjects. Examination of the hippocampal EEG revealed
significantly decreased power in the 1-2-Hz frequency band of nicotine-treated
rats. In addition, there was a significantly attenuated P300 ERP response to a
noise tone in the nicotine-treated rats compared to controls. These data indicate
that neonatal nicotine exposure alters functional activity in the hippocampus of
adult rats. These effects are likely to be the result of synaptic disorganization
in the hippocampus, and indicate that neonatal nicotine exposure exerts
teratogenic effects on the developing central nervous system, particularly the
hippocampus, which persist into adulthood.
PMID- 10764928
TI - Effects of chronic celiprolol treatment on brown fat, feeding, and drinking in
fa/fa Zucker rats.
AB - Celiprolol is a novel beta-adrenoceptor blocking drug that displays clinically
favorable effects on glucose and lipid metabolism. Because some other atypical
beta-adrenoceptor blocking drugs have been described to act as agonists on
beta(3)-adrenoceptors, we aimed to investigate the effects of celiprolol on brown
fat and beta(3)-adrenoceptors. Chronic treatment of obese fa/fa Zucker rats with
celiprolol (50 mg/kg/day orally for 20 days) increased GDP binding to brown fat
mitochondria by 1.5-fold, whereas beta(3)-adrenoceptor agonist ZD7114 ((S)-4-[2
[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl )phenoxyacetamide, 3
mg/kg/day) increased the binding by 3.3-fold. Weight gain was reduced by 19% due
to decreased water and food intakes in celiprolol-treated rats. Celiprolol did
not activate lipolysis in rat adipocytes in vitro or stimulate human beta(3)
adrenoceptors expressed in Chinese hamster ovary cells as measured with
Cytosensor microphysiometer. Therefore, celiprolol does not seem to activate
brown fat via beta(3)-adrenoceptors.
PMID- 10764929
TI - The NMDA antagonist EAA 494 does not impair working memory in an operant DNMTP
task in rats.
AB - There is contrasting evidence for an impairment of spatial working memory in
operant delayed matching/or nonmatching to position (DMTP/DNMTP) tasks, as both
delay-dependent and -independent disruption of choice accuracy has been found
following N-methyl-D-aspartate (NMDA) receptor blockade. Using a within-subjects
experimental design, the effect of the competitive NMDA receptor antagonist, EAA
494 (D-CPP-ene) (1, 1.5, 2 mg/kg IP 30 min prior), on working memory was
investigated in male Lister Hooded rats pretrained to the DNMTP task (0-16-s
delay in intervals). Metal barriers were inserted between the food magazine and
levers to inhibit the use of mediating strategies, such as orientation towards
the correct lever during the delay interval, because this behavior may contribute
to the delay-dependent disruption noted in previous studies. It was found that
EAA 494 did not modify working memory either in the presence or absence of
barriers. However, a dose-dependent impairment of task performance was recorded,
notably in the presence of barriers. These results indicate that competitive
blockade of NMDA receptors with EAA 494 does not result in impaired working
memory in rats and parallel the lack of effect of the compound upon working
memory in humans. Activation of NMDA receptors does not appear to be essential
for the performance of spatial tasks requiring working memory.
PMID- 10764930
TI - Gonadectomy enhances shock-induced behavioral inhibition in adult male rats:
implications for impulsive behavior.
AB - The effects of gonadectomy on shock-induced behavioral inhibition in a modified
Vogel's drinking conflict model and on diazepam-induced disinhibition and
sedation were investigated in adult male rats. Gonadectomy enhanced shock-induced
behavioral inhibition when determined 9, 21, 45, and 65 days, but not 3 days,
after operation, without affecting shock sensitivity or drinking motivation.
Testosterone-substitution for 21 days following gonadectomy prevented this
enhanced inhibition without significantly affecting the behavior in sham-operated
rats. Diazepam produced behavioral disinhibition both in sham-operated and
gonadectomized rats. However, after the highest dose (16 mg/kg, IP) the
disinhibited behavior decreased only in sham-operated animals, most likely due to
sedation. Moreover, whereas there was no difference in basal rotarod-performance
between controls and gonadectomized rats, the latter animals were less sensitive
to diazepam-induced disruption of rotarod walking ability. Sham-operated or
gonadectomized animals did not differ with respect to serum diazepam levels at
the postinjection times used in the behavioral tests. Taken together,
gonadectomized rats were less sensitive towards diazepam-induced sedation,
possibly due to a subsensitivity at or beyond GABA(A)/benzodiazepine receptors.
Furthermore, the finding that lack of testosterone enhanced shock-induced
inhibition could be interpreted to reflect increased impulse control and may
involve an altered activation of GABA(A)/benzodiazepine receptors.
PMID- 10764931
TI - Differential effects of beta-carbolines and antidepressants on rat exploratory
activity in the elevated zero-maze.
AB - Present experiments were designed to compare the effects of antidepressants
desipramine (10 and 20 mg/kg IP) and fluoxetine (5 and 10 mg/kg IP) with
anxiogenic beta-carboline DMCM (0.5 and 1.0 mg/kg IP) in the elevated zero-maze
test in rats. The second aim of this study was to assess the effects of pinoline
(6-methoxy-1,2,3, 4-tetrahydro-beta-carboline) in the rat elevated zero-maze test
in comparison with structurally unrelated beta-carboline DMCM and
antidepressants. The time spent in the open part of the elevated zero-maze was
not significantly affected by antidepressants, but was decreased by beta
carbolines pinoline and DMCM. The number of line crossings in the open parts and
the number of head dips were also decreased more by beta-carbolines in comparison
with antidepressants. Latency to enter the open part was statistically
significantly increased only by DMCM. Measurement of locomotor activity in a
separate experiment indicated that activity of the rats' time moving, distance
traveled, and number of rearings were reduced by all four drugs studied. These
results demonstrate that the effects of antidepressants in the elevated zero-maze
test differ from the effects of the reference anxiogenic compound DMCM. The
effects of pinoline and DMCM in the zero-maze test were similar, which suggests
the involvement of mechanisms other than serotoninergic in the action of
pinoline.
PMID- 10764932
TI - Kindling induced by pentylenetetrazole in rats is not directly associated with
changes in the expression of NMDA or benzodiazepine receptors.
AB - Repeated injections of a subconvulsant dose of pentylenetetrazole (PTZ, 30 mg/kg
IP three times weekly for 13 injections) in Wistar and hooded Lister rats
resulted in kindled seizures, the extent of which varied between strains. Wistar
rats achieved stage 4 of clonic-tonic seizures, whereas hooded Lister rats only
reached stage 2 of convulsive waves axially through the body. Rats were killed 10
days after their final injection, and radioligand binding was used to measure the
expression of NMDA receptors in cortex and hippocampus using [3H]MK-801 and [3H]L
689,560, the latter binding specifically to the NR1 subunit. [3H]Ro 15-1788
measured expression of GABA(A)-benzodiazepine binding sites containing alpha1,
alpha2, alpha3, or alpha5 subunits. Specific analysis of GABA(A) receptors
containing the alpha5 subunit, which are preferentially localized in the
hippocampus, was assessed with [3H]L-655,708. In the cortex, there was no effect
of strain or treatment on the K(D) or B(max) of any of the ligands. Similarly,
there was no effect of strain or treatment on hippocampal [3H]L-689,560 or [3H]Ro
15-1788 binding. However, in the hippocampus there was a significant, albeit
modest, effect of treatment on the B(max) of [3H]MK-801 binding and the B(max)
and K(D) of [3H]L-655,708 binding, i.e., PTZ-treated rats had fewer [3H]MK-801
and [3H]L-655,708 binding sites (NMDA and alpha5-containing GABA(A) receptors,
respectively), but, these reductions were significant only in the relatively
seizure-insensitive hooded Lister strain. This suggests that the increased
susceptibility to kindling in Wistar rats is not directly related to alterations
in the expression of NMDA or GABA(A) receptors.
PMID- 10764933
TI - A digital image analysis and neural network based system for identification of
third-stage parasitic strongyle larvae from domestic animals.
AB - A competitive learning vector quantization artificial neural network (ANN) was
trained to identify third-stage parasitic strongyle larvae from domestic animals
on the basis of quantitative data obtained from processed digital images of
larvae. For this reason, various quantitative features obtained from processed
digital images of larvae were tested as to whether they are variant or invariant
to the shape taken by the motile larvae during image recording. A total of 255
images of 57 individual larvae in various shapes belonging to five genera were
recorded. Following image processing, 16 features were measured, of which seven
were selected as invariant to larva shape. By trial and error, two of those
features, 'area' and 'perimeter', along with the quantitative features used in
conventional identification, 'overall body length', 'width' and 'extension of
sheath' (tip of larva to tip of sheath), were used as an effective training data
set for the ANN. This ANN coupled with an image analysis facility and a knowledge
relational database became the basis for developing a computer-based larva
identification system whose overall identification performance was 91.9%. The
advantages of this system are its speed and objectivity. The objectivity of the
system is based on the fact that it is not subject to inter- and intra-observer
variability arising from the user's profile of competency in interpreting
subjective and non-quantifiable descriptions. The limitations of the system are
that it cannot handle raw images but only data extracted from images, its
performance depends on the reliability of the input vectors used as training data
for the ANN, and its use is restricted only to well-equipped laboratories due to
its requirement for expensive instrumentation.
PMID- 10764934
TI - Intraoperative kinematic protocol for knee joint evaluation.
AB - Although knee kinematics has been investigated widely, no standard, objective
evaluation of the kinematics behaviour of the joint is used at present during
surgical treatment. We propose a kinematic protocol for a manual intraoperative
evaluation of the knee behaviour, with which the range of motion, the 'screw
home' mechanism and knee instabilities could be quantified. The method does not
require anatomical landmarks, because it is computed from standard tests used in
clinical practice and gives a decomposition of the knee movement comparable to
the well known Grood and Suntay analysis [E.S. Grood, W.J. Suntay, A joint
coordinate system for the clinical description of three-dimensional motions:
application to the knee, J. Biomech. Eng. 105 (1983) 136-144]. We describe the
protocol, report the evaluation of its numerical features and provide a
comparison with Grood and Suntay method on ten porcine knees.
PMID- 10764935
TI - Wavelet analysis and time-frequency distributions of the body surface ECG before
and after angioplasty.
AB - In a pilot study, electrocardiographic (ECG) recordings of patients with left and
right coronary stenosis taken before and after angioplasty were analyzed using
the continuous wavelet transform. Time-frequency distributions were obtained for
different leads in order to examine the dynamics of the QRS-spectrum and
establish features specific of ischemia in the time-frequency domain. We found
relevant changes in the mid-frequency range, reflecting the ECG's response to
percutaneous transluminal coronary angioplasty (PTCA). The changes appeared in
ECG leads close to ischemic zones of the myocardium. Time-frequency distributions
of the ECG during the QRS may thus become another electrocardiographic indicator
of ischemia, alternative to ST-level in standard ECG or body surface mapping. The
paper demonstrates the ability of the continuous wavelet transform to detect
short lasting events of low amplitude superimposed on large signal deflections.
PMID- 10764936
TI - Objective auscultation for traditional chinese medical diagnosis using novel
acoustic parameters.
AB - The goal of this work is to propose novel acoustic parameters of voice for the
purpose of providing a quantitative analysis of auscultation in traditional
Chinese medical diagnosis. There is rare amount of available literature related
to this topic. Four novel acoustic parameters, the average number of zero
crossings, the variations in local peaks and valleys, the variations in first and
second formant frequencies, and the spectral energy ratio, are presented to
analyze and identify the characteristics among non-vacuity, qi-vacuity, and yin
vacuity subjects. Among these acoustic parameters, two temporal parameters, the
average number of zero-crossings and the variations in local peaks and valleys,
outperformed other parameters in classifying both non-vacuity and deficient
subjects. The spectral energy ratio was adequate for the classification between
qi-vacuity and yin-vacuity patients. This research is a first step in an ongoing
effort to modernize the auscultation in traditional Chinese medical diagnosis.
PMID- 10764937
TI - Supporting the classification of pathology reports: comparing two information
retrieval methods.
AB - In this contribution two methods from the domain of information retrieval are
compared. The goal of the retrieval is to select from a library of pathology
reports those ones that are most similar to a given report. The SNOMED codes that
accompany these reports are presented to the pathologist who has to code the
given report with the aim to improve the quality of coding. The reports were
represented either as a vector of words or as a vector of N-grams. Both 4-, 5-
and 6-grams were used. The similarity of the reports was determined by comparing
the SNOMED terms that were added to the reports. It could be concluded that the
word-based method was consistently better than the N-gram method.
PMID- 10764938
TI - Validation of automated spectrofluroimetry for measurement of regional organ
perfusion using fluorescent microspheres.
AB - The fluorescent microsphere (FM) method for determination of regional organ blood
flow is labor intensive, requiring processing of 100 s to 1000 s of samples per
organ. To save time and reduce handling errors, we developed an automated
fluorescence analysis system by interfacing a commercially available
spectrofluorimeter and sample delivery unit to a PC, operated by a Windows95(R)
based program, WINFAC. WINFAC allows versatile analysis setup and instrument
control for fluorescent intensity acquisition at fixed wavelengths or by
synchronous scanning. Data is presented on screen, in real-time, and stored in
text format. Reference analyses are performed at specified intervals and the
coefficient of variation is continuously updated to monitor instrument
performance. The automated system was validated against radioactive microspheres
(RM) for lung perfusion in a pig and sheep and evaluated for analysis
reproducibility. Fluorescent and radioactive microspheres were delivered by
simultaneous injection into a femoral vein. Lungs were excised, flushed, dried at
total lung capacity, and cubed into approximately 2cm(3) pieces (n=833 and 1560,
pig and sheep, respectively). Radioactive count rates were determined for each
lung piece (corrected for decay, background and spillover). Fluorescent dyes were
extracted in solvent and intensities were determined at fixed wavelengths, using
the automated spectrofluorimeter (corrected for background and spillover). Multi
color reference solutions were measured every 50 samples to monitor instrument
reproducibility. Blood flow estimates for each piece determined by RM and FM
methods were highly correlated: R(2)=0.98+/-0.017, Slopes=1.00+/-0.007 and
Intercepts=0.00+/-0.006 (mean+/-SD). The CV of repeat reference analyses was
0.71%+/-0.16, a 30% to 50% reduction relative to manual analysis. Automated
spectrofluorimetry reduces measurement errors and is a reliable and time saving
advancement. With this technology, use of FM to measure regional lung perfusion
approaches the ease and accuracy of the RM method.
PMID- 10764939
TI - DEMS - a second generation diabetes electronic management system.
AB - Diabetes electronic management system (DEMS) is a component-based client/server
application, written in Visual C++ and Visual Basic, with the database server
running Sybase System 11. DEMS is built entirely with a combination of dynamic
link libraries (DLLs) and ActiveX components - the only exception is the
DEMS.exe. DEMS is a chronic disease management system for patients with diabetes.
It is used at the point of care by all members of the diabetes team including
physicians, nurses, dieticians, clinical assistants and educators. The system is
designed for maximum clinical efficiency and facilitates appropriately supervised
delegation of care. Dispersed clinical sites may be supervised from a central
location. The system is designed for ease of navigation; immediate provision of
many types of automatically generated reports; quality audits; aids to compliance
with good care guidelines; and alerts, advisories, prompts, and warnings that
guide the care provider. The system now contains data on over 34000 patients and
is in daily use at multiple sites.
PMID- 10764940
TI - Microcomputer program for automated action potential waveform analysis.
AB - A program for action potential waveform analysis based on a PC compatible
computer is described. Single or averaged action potentials are analyzed by
obtaining its first derivative and using criteria which allow automatic
measurement of several action potential components, including: depolarization
rate, repolarization rate, amplitude, duration, resting membrane potential and
afterhyperpolarization amplitude and slope. Data can be imported from pClamp
(Axon Instruments) and exported to other software such as Excel, Sigmaplot and
MatLab for example.
PMID- 10764941
TI - Portable data acquisition system for EKG measurements in marine environments.
AB - In the present paper, an electronic prototype designed to acquire
electrocardiographic signals from marine mammals has been developed. The system
consists of a portable device that allows the on-line acquisition of EKG signals
through a parallel port interface that is connected to a laptop computer. The EKG
waveform, the voltage level, the bandwidth and the most relevant information from
this type of signals is stored and analysed under real-time conditions by means
of specifically implemented software. The whole system has been successfully
tested to obtain the EKG from captive dolphins. The characteristics of the
equipment presented here, with its low cost, size and energy requirements
accomplish a portable system suitable for the acquisition of this type of signals
in conductive media such as the seawater.
PMID- 10764942
TI - Synergistic role of cAMP and IP(3) in corticotropin-releasing hormone-induced
cell shape changes in invertebrate immunocytes.
AB - Immunocytes from the mollusc Mytilus galloprovincialis express corticotropin
releasing hormone (CRH) receptor subtype (CRH-R1 and CRH-R2)-like mRNAs. Using
computer-assisted microscopic image analysis, we have found that exogenous CRH
provokes changes in the cellular shape of immunocytes, and that this response is
extracellular Ca(2+)-dependent. The various inhibitors of transduction signaling
pathways, i.e. suramin sodium, 2', 5'-dideoxyadenosine, neomycin sulfate,
calphostin C, H-89, and wortmannin, completely or partially inhibit these
changes. The present findings demonstrate that PKA, PKC, and PKB/Akt are involved
in CRH-induced cell shape changes in immunocytes, and that the cellular effect of
CRH needs the synergistic action of the two second messengers, cAMP and IP(3).
PMID- 10764943
TI - Distribution of PACAP-like immunoreactivity in the nervous system of oligochaeta.
AB - The marked similarity between the primary structures of human, other vertebrate,
and the invertebrate tunicate PACAP suggests that PACAP is one of the most highly
conserved peptides during the phylogeny of the metazoans. We investigated the
distribution of PACAP-like immunoreactivity in the nervous system of three
oligochaete (Annelida) worms with immunocytochemistry. The distribution pattern
of immunoreactivity was similar in all three species (Lumbricus terrestris,
Eisenia fetida, and Lumbricus polyphemus). The cerebral ganglion contains
numerous immunoreactive cells and fibers. A few cells and fibers were found in
the medial and lateral parts of the subesophageal and ventral cord ganglia. In
the peripheral nervous system, immunoreactivity was found in the enteric nervous
system, in epidermal sensory cells, and in the clitellum.
PMID- 10764944
TI - Proctolin antagonists bind to [(3)H]proctolin binding sites in the locust
hindgut.
AB - Proctolin caused dose-dependent (1-200 nM) contraction of the isolated hindgut of
S. gregaria which was abolished by [alpha-methyl-L-tyrosine(2)]-proctolin (1
microM). In comparison, cycloproctolin (5 microM) reduced the proctolin maximum
response by 41%. Hindgut homogenates contained [(3)H]proctolin binding sites with
a K(d) value of 660 nM, a B(max) value of 23.8 pmol/mg protein and a Hill
coefficient of 0.934. Cycloproctolin (IC(50,) 220 nM; K(i), 204 nM), unlabeled
proctolin (IC(50) 680 nM) and [alpha-methyl-L-tryosine(2)]-proctolin (IC(50) 3.1
microM, K(i), 2.9 microM) but not SchistoFLRFamide (1 nM-10 microM) were capable
of displacing bound [(3)H]proctolin.
PMID- 10764945
TI - N-terminal modified analogs of HVFLRFamide with inhibitory activity on the locust
oviduct.
AB - New N-terminal analogs of the peptide HVFLRFamide, the minimum sequence of the
insect myosuppressins capable of inhibiting spontaneous and induced contractions
of the locust oviduct, were synthesized and tested for biologic activity on
locust oviduct. Most active, as judged by the ability to inhibit proctolin
induced contractions of locust oviduct, was (N(alpha)-acetyl)-HVFLRFamide. D-Pro
HVFLRFamide was also highly inhibitory. Interestingly, low doses of the
pentapeptide analog (N(alpha)-imidazoleacrylyl)-VFLRFamide inhibited oviduct
contractions. This is the first pentapeptide analog shown to inhibit contractions
of locust oviduct, and this result indicates that the alpha-amino group of His is
not absolutely required for inhibitory activity. In all cases when His was
replaced by a D-amino acid, the analogs were stimulatory, resulting in an
increase in basal tonus of the locust oviduct. The results provide further
insight into the structural features of the HVFLRFamide molecule that are
required for inhibitory activity on locust oviduct muscle.
PMID- 10764946
TI - The cardiovascular effects of PFRFamide and PFR(Tic)amide, a possible agonist and
antagonist of neuropeptide FF (NPFF).
AB - Neuropeptide FF (NPFF), an endogenous opioid-related neuromodulater, has been
reported to show significant effects on the cardiovascular system, namely
elevation of arterial blood pressure (BP) and heart rate (HR) in rats. In the
present study, we synthesized two novel NPFF analogs, PFRFamide (putative NPFF
agonist) and PFR(Tic)amide (putative NPFF antagonist), and examined their
cardiovascular effect on BP and HR in anesthetized rats. The arterial mean BP and
HR were measured by way of direct femoral artery catheterization. The data showed
that PFRFamide increased BP in a dose-dependent manner, while PFR(Tic)amide
decreased BP dose-dependently. These results revealed the possibility of
PFRFamide and PFR(Tic)amide to be NPFF agonist and antagonist (or inverse
agonist), respectively. These two NPFF analogs may possess potential in new drug
design, and the NPFF system could be very important in mammalian cardiovascular
function.
PMID- 10764947
TI - Proopiomelanocortin (POMC) products in the central regulation of sympathetic and
cardiovascular dynamics: studies on melanocortin and opioid interactions.
AB - The proopiomelanocortin (POMC)-derived peptides are important regulators in a
number of central nervous system pathways especially as they relate to food
intake as well as metabolic and autonomic responses. In this study, we
investigated the sympathetic nervous and cardiovascular responses to
intracerebroventricular (i.c.v.) administration of alpha melanocyte stimulating
hormone (alphaMSH), beta-endorphin (beta-END) and adrenal corticotrophic hormone
(ACTH) alone or in the presence of a melanocortin antagonist, or an opioid
antagonist, in normal animals. The i.c.v. administration of alphaMSH and ACTH
resulted in a significant increase in the lumbar sympathetic nerve activity
(LSNA) that was accompanied by an increase in mean arterial pressure (MAP). On
the other hand i.c.v. administration of beta-END decreased the LSNA and MAP. The
pretreatment of animals with the melanocortin-4 (MC-4) receptor antagonist,
agouti protein, significantly antagonized the response to alphaMSH and also,
paradoxically, not only antagonized the response to beta-END but converted its
inhibitory responses on both the LSNA and MAP to a sympathetic activated and
pressor response. Pretreatment with the opioid antagonist, naloxone,
significantly antagonized the sympathetic nervous and cardiovascular response to
beta-END. It partially but significantly antagonized the MAP response to
alphaMSH, but the sympathetic response was unaffected. Neither agouti protein nor
naloxone altered the sympathetic nervous and cardiovascular response to ACTH.
From these studies, we conclude that i.c.v. administration of alphaMSH and ACTH
increases the LSNA and cardiovascular dynamics, whereas beta-END decreases it.
And, the MC-4 receptor antagonist reverses the endorphin response and the opioid
antagonist attenuates the alphaMSH response suggesting possible receptor or
central neural pathway interactions between MC-4 and the opioid receptor mediated
effects.
PMID- 10764948
TI - Interaction of alpha-melanotropin (alpha-MSH) and noradrenaline in the median
eminence in the control of female sexual behavior.
AB - In the present study, we examined the effects of the injection of alpha
melanotropin (alpha-MSH), noradrenaline (NA), and dopamine in the median eminence
of ovariectomized-adrenalectomized rats on female sexual behavior. The animals
were primed with l0 microg of estradiol benzoate, and 52-54 h later they were
injected into the median eminence with either 1 microl of artificial
cerebrospinal fluid, 1 microg/rat alpha-MSH, 200 ng/rat NA, 200 ng or 2
microg/rat dopamine, in 1 microl of artificial cerebrospinal fluid. Both alpha
MSH and NA significantly stimulated sexual behavior. This effect was antagonized
by two beta-adrenergic antagonists: propranolol (500 ng/rat) and metoprolol (400
ng/rat) applied 15 min before the alpha-MSH or NA. The alpha-adrenergic
antagonist prazosine (500 ng/rat) was ineffective in reducing the effect of alpha
MSH. The vehicle and dopamine at both doses had no effect on sexual activity.
These results indicate that alpha-MSH and NA in the median eminence stimulate
female sexual behavior and that NA mediates the action of alpha-MSH via beta
receptors.
PMID- 10764949
TI - Preprotachykinin gene expression in goldfish brain: sexual, seasonal, and
postprandial variations.
AB - Recently, we described the complete nucleotide sequence of gamma-preprotachykinin
(gamma-PPT) mRNA and the deduced amino acid sequence of the precursor on the
basis of molecular cloning and sequence analysis of cDNA from goldfish brain. In
the present study, gamma-PPT gene expression in the brain of goldfish was
examined using quantitative Northern blot analysis. The results showed that the
gamma-PPT gene is highly but differentially expressed in the olfactory bulbs,
hypothalamus, and posterior brain regions. There are sexual dimorphism and
seasonal variations in gamma-PPT gene expression. In addition, the postprandial
changes in gamma-PPT gene expression in the olfactory bulbs and hypothalamus
suggest that tachykinin peptides are involved in regulation of feeding behavior
in goldfish.
PMID- 10764950
TI - Amylin receptors mediate the anorectic action of salmon calcitonin (sCT).
AB - The teleost salmon calcitonin (sCT), but not mammalian CT, shows similar biologic
actions in the skeletal muscle as amylin and calcitonin gene-related peptide
(CGRP). The peptides have also been shown to reduce food intake in rams. Because
sCT, but not amylin, binds irreversibly to amylin binding sites, the aim of the
present study was to compare the anorectic potency of both peptides. To determine
whether sCT reduces food intake through interaction with amylin binding sites, we
also tested whether appropriate antagonists (CORP 8-37, AC 187) attenuate the
anorectic effect of sCT. Finally, we wanted to know whether rat calcitonin (rCT)
and sCT reduce food intake to the same extent. Peptides were injected
intraperitoneally at dark onset in 24 h food-deprived rats. At doses of 5 or 0.5
microg/kg, the anorectic effect of sCT was more potent and lasted much longer
(e.g. 5 microg/kg: sCT > 10 h; amylin approx. 2 h) than that of amylin. Both CORP
8-37 and AC 187 (10 microg/kg) markedly reduced the anorectic action of sCT (0.5
microg/kg). In contrast to sCT, rCT (0.5 microg/kg) had no effect on food intake.
It is concluded that sCT s anorectic effect is partly mediated by amylin
receptors. Irreversible binding of sCT to amylin receptors may lead to a stronger
and prolonged effect in comparison to amylin due to a sustained activation of the
binding sites. Similar to other actions of CTs, the anorectic potency of sCT in
rats was higher than that of mammalian (rat) CT. This agrees with binding
profiles of amylin, sCT, and rCT at amylin binding sites as observed in in vitro
studies.
PMID- 10764951
TI - New highly specific agonistic peptides for human melanocortin MC(1) receptor.
AB - A peptide with very high specificity for the human melanocortin MC(1) receptor
identified by phage display was used as a lead for the design of new peptides.
Two new peptides, MS05 and MS09, were synthesized and found to bind with sub
nanomolar affinities to the MC(1) receptor. Both these peptides showed strong
agonistic activity at the MC(1) receptor. The MS05 was the most MC(1) receptor
selective as it showed virtually no binding affinity for the MC(4) and MC(5)
receptors and only micromolar affinity for the MC(3) receptor. The selectivity
and potency of the new peptides make them potent tools for studies of MC(1)
receptors, as well as novel potential candidate drugs for the treatment of
inflammatory conditions.
PMID- 10764952
TI - Binding sites for melanin-concentrating hormone in the human brain.
AB - Binding sites for melanin-concentrating hormone (MCH) in human brain were
investigated and characterized by radioligand binding. Specific binding sites for
MCH were present in every region of human brain (cerebral cortex, cerebellum,
thalamus, hypothalamus, pons, and medulla oblongata) obtained at autopsy. alpha
Melanocyte stimulating hormone or ACTH was a poor inhibitor of (125)I-MCH binding
(IC(50) 1 microM) compared with MCH (IC(50) = 0.3 +/- 0.07 nM, mean +/- SEM, n =
3). Scatchard plots of (125)I-MCH binding in human brain (thalamus) gave a
dissociation constant of 0.2 +/- 0.06 nM and maximal binding of 5.8 +/- 0.3
fmol/mg protein (n = 3). These findings suggest that specific MCH binding sites
that differ from the melanocortin receptors exist in human brain.
PMID- 10764953
TI - Production and secretion of two vasoactive peptides, adrenomedullin and
endothelin-1, by cultured human adrenocortical carcinoma cells.
AB - The production and secretion of peptides by adrenocortical tumors have not been
well studied. We therefore studied the production and secretion of two vasoactive
peptides, adrenomedullin and endothelin-1 in SW-13 human adrenocortical carcinoma
cells by radioimmunoassay and Northern blot analysis. Both immunoreactive
adrenomedullin and immunoreactive-endothelin were detected in the culture medium
of SW-13 cells (27.7 +/- 1.6 fmol/10 (5) cells/24 h and 11.0 +/- 0.8 fmol/10 (5)
cells/24 h, respectively, mean +/- SEM, n = 6). Northern blot analysis showed the
expression of adrenomedullin mRNA and endothelin-1 mRNA in SW-13 cells. On the
other hand, no significant amount of calcitonin gene-related peptide,
corticotropin-releasing hormone, neuropeptide Y, or urocortin was secreted by SW
13 cells. Treatment with ACTH (10(-9)-10(-7) mol/l), angiotensin II (10(-9)-10(
7) mol/l), or dexamethasone (10(-8)-10(-6) mol/l) for 24 h had no significant
effects on immunoreactive-adrenomedullin levels and immunoreactive-endothelin
levels in the culture medium of SW-13. Treatment with tumor necrosis factor (TNF)
alpha (20 ng/ml) increased significantly both immunoreactive-adrenomedullin
levels and immunoreactive-endothelin levels in the culture medium. Interferon
gamma (100 U/ml) increased the immunoreactive-endothelin levels, but not
immunoreactive-adrenomedullin levels, whereas interleukin-1 (IL-1)beta (10 ng/ml)
increased immunoreactive-adrenomedullin levels, but not immunoreactive-endothelin
levels. These findings indicate that SW-13 human adrenocortical carcinoma cells
produce and secrete two vasoactive peptides, adrenomedullin, and endothelin-1 and
that the secretion of these two peptides is modulated differently by cytokines.
PMID- 10764954
TI - Effects of adrenomedullin and PAMP on membrane potential and neurotransmission.
AB - The effects of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide
(PAMP) on membrane potential and sympathetic neurotransmission were studied in
rat mesenteric arteries by using microelectrodes. AM (10(-7) M) but not PAMP (10(
6) M) produced membrane hyperpolarization, which was abolished by high K solution
or by glibenclamide, an ATP-sensitive K(+) (KATP) channel blocker. Neither AM nor
PAMP affected excitatory junction potentials, a measure of sympathetic,
purinergic neurotransmission. These findings suggest that AM hyperpolarizes the
membrane via activation of KATP channels, which may contribute to the
vasodilatory action of AM, whereas the mechanisms of the vasodepressor action of
PAMP remain unclear.
PMID- 10764955
TI - Immunohistochemical localization and distribution of VIP/PACAP receptors in human
lung.
AB - VIP and PACAP are distributed in nerve fibers throughout the respiratory tract
acting as potent bronchodilators and secretory agents. By using RT-PCR and
immunoblotting techniques, we have previously shown the expression of common
VIP/PACAP (VPAC(1) and VPAC(2)) and specific PACAP (PAC(1)) receptors in human
lung. Here we extend our aims to investigate by immunohistochemistry their
localization and distribution at this level. A clear immunopositive reaction was
obtained in human lung sections by using either anti-VPAC(1) or -VPAC(2) receptor
antibodies but not with anti-PAC(1) receptor antibody. However, PAC(1) receptor
(and VPAC(1) and VPAC(2) receptors) could be identified in lung membranes by
immunoblotting which supports that the PAC(1) receptor is expressed at a low
density. Both VPAC(1) and VPAC(2) receptors showed similar immunohistochemical
patterns appearing in smooth muscle cells in the wall of blood vessels and in
white blood cells (mainly in areas with inflammatory responses). The results
agree with previous evidence on the importance of both peptides in the immune
system and support their anti-inflammatory and protective roles in lung.
PMID- 10764956
TI - Parallel increase in substance P and VIP in rat duodenum in response to
irradiation.
AB - Irradiation was administered to the upper abdomen of rats, whereupon the duodenum
was examined. Numerous vasoactive intestinal peptide (VIP)- and substance P (SP)
like immunoreactive nerve fibers were seen in the damaged mucosa, often in close
association to each other. The intensity of the SP- and VIP-like immunoreaction
was increased in several of the tissue compartments and, as measured with
radioimmunoassay, the contents of SP- and VIP-like materials were increased after
30 Gray. The results show that SP and VIP levels increase after irradiation and
suggest that SP and VIP are involved in interactive reactions in the
reorganization and inflammatory processes in the gut after abdominal irradiation.
PMID- 10764957
TI - Neural and muscular receptors for motilin in the rabbit colon.
AB - Motilin receptors were classically recognized in the gastroduodenal area, where
they help to regulate interdigestive motility. More recently, motilin receptors
were identified in the colon where their biologic significance remains unclear.
We aimed here to characterize the motilin receptors of the rabbit colon. Distal
colon and duodenum were obtained from sacrificed rabbits. Tissues homogenized by
Polytron were submitted to differential centrifugation to obtain neural
synaptosomes or smooth muscle plasma membranes enriched solutions. Motilin
binding to these membranes was determined by the displacement of (125)I MOT by
the native peptide MOT 1-22, or by peptide analogues MOT 1-12 [CH(2)NH](10-11) or
GM-109 and by erythromycin derivative GM-611. Motilin binding capacity was
maximum in colon nerves (49.5 +/- 6.5 fmol/mg protein vs. 19.9 +/- 2.5 in colon
muscles or 9.4 +/- 2.8 and 6.6 +/- 1.2 in duodenal muscles and antral nerves
respectively); all tissues expressed similar affinity for MOT 1-22, and the
motilin agonist GM-611 bound equally to neural or muscle tissues from the rabbit
colon; the synthetic antagonist MOT 1-12 [CH(2)NH](10-11) showed greater affinity
for colon nerves than for colon muscles (plC50: 7.23 +/- 0.07 vs. 6.75 +/- 0.03).
Similar results were obtained with the peptide antagonist GM-109; receptor
affinity toward MOT 1-12 [CH(2)NH(10-11)] was always five times superior in
neural tissues, whether they came from the colon or the antrum, than in muscle
tissues, whether they were obtained from colon or from duodenum. Motilin
receptors are found in very high concentration in nerves and in muscles from
rabbit colon; specific motilin receptor subtypes are identified in nerves (N) and
muscles (M) of the rabbit colon; N and M receptor subtypes seem independent of
the organ location.
PMID- 10764958
TI - Valaminols, probably the most simplified peptide-analogs acting as pepsin
inhibitors.
AB - Recently, we have introduced simplified analogs of pepstatin A, representing
'tripeptides' with two valine residues which are C-terminated by an amino alcohol
moiety. In the present study, we have deleted one valine unit, yielding simple
molecules-called 'valaminols'-which can be prepared in big scale under really low
costs. First investigations on structure-activity relationships revealed that the
most active compound is a valaminol bearing both natural substituents either at
the N-terminus or at the C-terminal side chain. Its inhibitory activity fully
corresponds to the activity of tripeptides, hitherto reported by us, although one
valine residue has been omitted.
PMID- 10764959
TI - Inhibitory effect of intracerebroventricularly-administered [D-Arg(2), beta
Ala(4)]-dermorphin (1-4) on gastrointestinal transit.
AB - The inhibitory effect of intracerebroventricularly-administered [D-Arg(2), beta
Ala(4)]-dermorphin (1-4) (TAPA), a highly selective mu(1)-opioid receptor
agonist, on mouse gastrointestinal transit was compared with that of morphine and
[D-Ala(2), N-methyl-Phe(4), Gly(5)-ol]-enkephalin (DAMGO). When administered
intracerebroventricularly 5 min before the oral injection of charcoal meal, TAPA
(10-100 pmol), morphine (0.25-4 nmol), and DAMGO (20-80 pmol) dose-dependently
inhibited gastrointestinal transit of charcoal. The inhibitory effect of each mu
opioid receptor agonist was completely antagonized by naloxone, a nonselective
opioid receptor antagonist. The inhibitory effects of morphine and DAMGO were
significantly antagonized by both beta-funaltrexamine, a selective mu-opioid
receptor antagonist, and naloxonazine, a selective mu(1)-opioid receptor
antagonist. In contrast, the inhibitory effect of TAPA was not affected at all by
beta-funaltrexamine, naloxonazine, nor-binaltorphimine (a selective kappa-opioid
receptor antagonist), or naltrindole (a selective delta-opioid receptor
antagonist). These results suggest that the inhibitory effect of TAPA on
gastrointestinal transit may be mediated through an opioid receptor mechanism
different from that of morphine and DAMGO.
PMID- 10764960
TI - L-prolyl-l-leucyl-glycinamide and its peptidomimetic analog 3(R)-[(2(S)
pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) attenuate
haloperidol-induced c-fos expression in the striatum.
AB - Acute treatment of rats with haloperidol results in a rapid and transient
increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of
immediate early genes by haloperidol may be involved in the development of
extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has
been observed to antagonize the development of haloperidol-induced D(2) receptor
supersensitivity in rats. We investigated the modulatory effects of PLG on
haloperidol-induced c-fos and Fos protein expression in the rat striatum. We
report that coadministration of either PLG or the potent analog of PLG, 3(R)
[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA),
attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2
mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%,
respectively. These responses were attenuated by 170% and 75%, respectively, when
coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).
PMID- 10764961
TI - Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and
related peptides in the regulation of the hypothalamus- pituitary-adrenal axis.
AB - Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone
(PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary
adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP
secretin-glucagon family), which also includes growth hormone-releasing hormone
and exendins. All the members of this peptide family possess a remarkable amino
acid sequence homology, and bind to G-protein-coupled receptors, whose signaling
mechanism primarily involves AC/protein kinase A and phospholipase C/protein
kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the
regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review
we survey findings that also other members of the VIP-secretin-glucagon family
may have the same function. Secretin and secretin receptors are expressed in the
hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic
hormone (ACTH) release. No evidence is available for the presence of secretin
receptors in adrenal glands, but secretin selectively depresses the
glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R)
cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus,
and all the components of the HPA axis are provided with glucagon and glucagons
like-1 receptors. These peptides exert a short-term inhibitory effect on stress
induced pituitary ACTH release and depress the ZF/R cell response to ACTH by
inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic
arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal
adrenals, and are particularly abundant in some types of adrenocortical adenomas
and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade,
evokes a sizeable glucocorticoid secretagogue effect, leading to the
identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related
protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH
related protein receptors in all the components of the HPA axis. Both peptides
enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone
and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells,
respectively. The involvement of growth hormone-releasing hormone and exendins in
the functional regulation of the HPA axis has not yet been extensively
investigated.
PMID- 10764962
TI - Comparison of the TOX A/B test to a cell culture cytotoxicity assay for the
detection of Clostridium difficile in stools.
AB - The TOX A/B Test (Techlab, Blacksburg, VA, USA) was compared to cell culture
cytotoxicity assay on 1109 consecutive diarrheal stool samples collected from
patients with the presumptive diagnosis of Clostridium difficile disease. The TOX
A/B Test is an enzyme immunoassay in a microtiter format that detects both toxins
A and B. The procedure used for this study takes approximately 1.5 h to perform.
Cell culture cytotoxicity was performed by using a fibroblast cell line in a
microtiter format read at 4 h, 24 h, and 48 h. One hundred ninety-four of the
1109 samples were positive by the "gold standard" cytotoxicity assay, whereas 189
were positive by EIA. There was a 98.5% agreement between the two assays. When
compared to the cytotoxicity assay, the EIA had an initial sensitivity of 94.3%
and a specificity of 99.3%. However, after resolution of six discrepants using
another ELISA for toxin A detection the sensitivity, specificity, positive and
negative predictive values for the TOX A/B test are as follows: 94.5%; 100%;
100%; 98.8%. The corresponding values for the cytotoxicity assay are: 97%; 100%;
100%; and 99.3%. This test seems to have excellent sensitivity and specificity as
compared to an in-house cell culture cytotoxicity assay. It is sensitive enough
to use as a stand-alone test for the detection of C. difficile toxin in
laboratories that do not have cell culture cytotoxicity testing capability.
PMID- 10764963
TI - A global evaluation of the susceptibility of Candida species to fluconazole by
disk diffusion. Global Antifungal Surveillance Group.
AB - An improved fluconazole 25-mg disk diffusion method was used to test the
susceptibility of 20,900 consecutively isolated clinical strains of Candida
species from 40 hospital laboratories in 26 countries. The procedure is similar
to the National Committee for Clinical Laboratory Standards (NCCLS) M2-A6 method
for testing bacteria, except Mueller-Hinton agar is supplemented with 2% glucose
and 0.5 mcg/mL methylene blue. Plates were incubated at 35 degrees C and read
after 18 to 24h. Tentative zone interpretive criteria were based on the
correlation by regression analysis with the NCCLS M27-A Reference Method for
Broth Dilution Antifungal Susceptibility Testing of Yeasts: > =19mm Susceptible,
< = 12mm Resistant, and 13-18 mm Susceptible-Dose Dependent. Of 14,368 isolates
of Candida albicans, 2,073 C. glabrata, 869 C. tropicalis, 752 C. parapsilosis,
and 351 C. krusei, 99%, 67%, 90%, 94%, and 26%, respectively, were susceptible in
vitro to fluconazole. All study sites used the BIOMIC System to electronically
read zones on plates, interpret, record test results and verify quality control
data. This is the largest study to date that evaluated a broad range of
sequentially collected yeasts from various infections and different types of
hospitals. The modified disk testing procedure is facile and economical to
perform and offers a reproducible and accurate means to assess the in vitro
susceptibility of Candida species to fluconazole.
PMID- 10764964
TI - Heteroduplex mobility assay for rapid, sensitive and specific detection of
mycobacteria.
AB - We report an improved method for the detection and identification of mycobacteria
using PCR and the heteroduplex mobility shift assay (HMA). The HMA for detection
of mycobacteria was based on the microheterogeneity within the DNA coding
sequences for 16S rRNA. A remarkable shift between single-stranded, heteroduplex
and homoduplex bands in PAGE was observed among the Mycobacterium spp. tested.
The Mycobacteria HMA (MHMA) of amplified PCR products from mycobacteria DNA
coding for 16S rDNA derived from culture showed a specific heteroduplexes formed
among different Mycobacterium species. Other bacterium species were distinguished
from Mycobaterium due to slow migrating heteroduplexes mobility bands observed
when M. bovis (BCG), M. avium, or M. fortuitum were used as a standard. The
specific heteroduplexes were detected when as little as 1 etag of DNA template
was used, although better results were obtained with 5 etag and when PCR products
of sample test and mycobacterium standard were mixed at a ratio of 1.8. To
correctly evaluate the feasibility of using MHMA to detect and identify
mycobacteria, 15 clinical sample patients were tested. All MTB-positive clinical
samples were identified by MHMA as well as the negative samples. In addition,
MHMA will, in principle, be applicable to the detection and classification of any
microorganism showing differences within the 16S rRNA as well as to the
identification of new and unrecognized bacterial species.
PMID- 10764965
TI - Prospective study of IgM to Toxoplasma gondii on Beckman Coulter's Access(TM)
immunoassay system and comparison with Zeus ELISA and gull IFA assays.
AB - We compared a new assay for Toxoplasma IgM on the Access analyzer (Beckman
Coulter, Inc., Chaska, MN, USA), a random access instrument based on the
principle of paramagnetic particle enzyme immunoassay with an enzyme-linked
immunosorbent assay (ELISA) (Zeus Scientific, Inc., Raritan, NJ, USA) and an
immunofluorescent assay (IFA) (Gull Laboratories, Inc., Salt Lake City, UT, USA).
Four hundred fresh, unfrozen clinical samples from pregnant women (n = 154), HIV
positive patients (n = 41), and patients in whom infection with Toxoplasma gondii
was suspected (n = 200) were collected and assayed over a three month period. The
specificity of the Access assay was compared to the consensus results. Results
that were discrepant between the ELISA and IFA were resolved using a third IFA
(Zeus). Once resolved, the specificity for the Access assay, the Zeus ELISA and
the Gull IFA were 99.22%, 97.91%, and 99.45%, respectively. We conclude that the
Access assay specificity is comparable to consensus results, minimizing false
positive results; and because it is a random access instrument, it may be
preferable over batch methods.
PMID- 10764966
TI - Postantibiotic effect of trovafloxacin against Streptococcus pneumoniae,
Haemophilus influenzae, and Neisseria meningitidis in cerebrospinal fluid and
broth culture media.
AB - Trovafloxacin displays exceptional antimicrobial potency against pathogens
associated with community-acquired meningitis. The postantibiotic effect (PAE) of
trovafloxacin was assessed against two clinical strains each of Streptococcus
pneumoniae, Haemophilus influenzae Type B, and Neisseria meningitidis Group B.
Testing was performed simultaneously in broth culture media (broth) and pooled
CSF at concentrations equivalent to 0.5X and 4X MIC. Mean PAEs in broth at 0.5X
and 4X MIC ranged between 0.07 to 1.10 and 0.57 to 5. 83 h and between 0.07 to
1.67 and 0.47 to 6.00 h in CSF for all organisms. Overall, the incorporation of
CSF did not augment or diminish the duration of the trovafloxacin-induced PAE.
These data, together with its pharmacokinetic profile in CSF and antimicrobial
potency against these isolates, make trovafloxacin an agent of interest for the
treatment of meningitis.
PMID- 10764967
TI - Antibiotic resistance among recent clinical isolates of Haemophilus influenzae in
Japanese children.
AB - From January 1997 to July 1999, a total of 867 isolates of Haemophilus influenzae
were recovered in the microbiology laboratory of Chiba Children's Hospital. The
overall prevalence of beta-lactamase production was 12.8%. Ampicillin-MICs for
all of the 111 beta-lactamase-producing isolates was > or =4 microg/ml. A total
of 26 beta-lactamase-negative isolates (3.4% of all beta-lactamase-negative
isolates and 3.0% of all isolates) were found to be resistant to ampicillin. The
prevalence of beta-lactamase negative ampicillin-resistant strains (BLNAR)
increased remarkably to 8.9% during the last 7-month period. It is noteworthy
that the MICs not only of penicillins but also of cephems for BLNAR were
significantly higher than those for ampicillin-susceptible isolates. Eight beta
lactamase-producing isolates of H. influenzae (7.2% of all beta-lactamase
producing isolates) were resistant to amoxicillin-clavulanate (AMPC/CVA).
Consequently, the overall resistance to ampicillin was 15.8%, and that to
AMPC/CVA was 3.0%. The results of this study corroborate the findings of previous
investigators in the US (Doern et al., 1997) regarding the emergence of BLNAR and
beta-lactamase-producing AMPC/CVA-resistant strains (BLPACR) of H. influenzae.
Continued monitoring of susceptibility trends will be required to guide
appropriate chemotherapy.
PMID- 10764968
TI - Fluoroquinolone-resistant Haemophilus influenzae: frequency of occurrence and
analysis of confirmed strains in the SENTRY antimicrobial surveillance program
(North and Latin America).
AB - The incidence of fluoroquinolone-resistant (FQR) Haemophilus influenzae and
Moraxella catarrhalis isolated from clinical specimens remains very rare, and the
identification of such strains has been previously limited to case reports from
diverse geographic locations. During the 1997 through 1998 SENTRY Antimicrobial
Surveillance Program, four FQR-H. influenzae (0.13% of all strains) and one FQR
M. catarrhalis strains were identified and confirmed as having elevated MICs to >
or =5 FQ class drugs. Among H. influenzae strains, MICs to marketed FQs were > or
=0.12 microg/ml with ciprofloxacin MIC results > or =8-fold higher than wild type
susceptible strains. The FQR-H. influenzae isolates were then compared with two
previously reported strains that were determined to be identical using ribotyping
and other molecular methods. In contrast, the SENTRY isolates were all
genetically distinct and had mutations in parC and/or gyrA. Isolates having the
lowest MIC elevations had a single mutation in gyrA, while isolates with higher
MICs had at least one mutation in both studied genes. In general, the single gyr
A mutations involved the same position but differed in the amino acid
substitution (Ser84Leu or Phe or Ala). The isolates reported outside the SENTRY
Program (controls) had an unusual mutation in par C (Gly82Asp) and two mutations
in gyr A; producing the highest recorded FQR MICs. The FQR-M. catarrhalis strain
was discovered in late 1997 and has been reported before. Although detection of
these FQR isolates remains at <1% of all contemporary H. influenzae and M.
catarrhalis isolates, surveillance programs will be an important detection method
to determine the extent of emerging novel resistance patterns among clinically
prevalent fastidious pathogens.
PMID- 10764969
TI - Bacteremia due to Staphylococcus aureus with reduced susceptibility to
vancomycin.
AB - Four cases of bacteremia caused by Staphylococcus aureus with heteroresistance to
vancomycin (hetero-VRSA) were described. In at least two of these four
mortalities, the cause of death was temporally related to the hetero-VRSA
bacteremia. The vancomycin and teicoplanin MICs of the resistant subpopulations
of these four hetero-VRSA were 8 and 24 microg/ml, respectively. All isolates
were producers of beta-lactamase, produced penicillin-binding protein PBP2a, and
possessed the mecA gene accounting for methicillin resistance. Thickening of the
peptidoglycan cell wall was observed by electron microscopy. When ampicillin was
combined with vancomycin, in vitro synergism was detected using the checkerboard
titration method (epsilonFIC = 0.13). The use of vancomycin plus ampicillin
sulbactam could be a viable option in treating severe hetero-VRSA infection in
view of the higher affinity of ampicillin toward PBP2a.
PMID- 10764970
TI - Serious streptococcal infections produced by isolates resistant to streptogramins
(quinupristin/dalfopristin): case reports from the SENTRY antimicrobial
surveillance program.
AB - The emergence and sustained prevalence of Gram-positive organisms resistant to
antimicrobials has been of interest for over a decade. Quinupristin/dalfopristin
(formerly RP 59500 or Synercid) is a new injectable streptogramin combination
that has been reported to have activity against Gram-positive organisms, even
those with documented MLS(B) resistance. However, the two case reports presented
here illustrate three well-documented Streptococcus spp. strains (S. mitis, S.
pneumoniae) to be resistant to quinupristin/dalfopristin (MICs at 3, 8, and 12
microg/ml) following referral as routine isolates in the SENTRY Antimicrobial
Surveillance Program. The S. pneumoniae pleural fluid isolate was cross-resistant
to erythromycin. Both bacteremic S. mitis strains were resistant to macrolides
(erythromycin, azithromycin, clarithromycin), lincosamides (clindamycin), and
fluoroquinolones. Patient histories indicated no prior use of MLS class
antimicrobials for the S. mitis case, but the patient having the S. pneumoniae
isolate did receive prior treatment of erythromycin and clindamycin. All isolates
had modestly increased penicillin MICs of 0.12 microg/ml. The mode of resistance
to quinupristin/dalfopristin was not evident (sat A-negative by PCR); and these
cases illustrate the existence of streptogramin-resistant isolates before the
introduction of this antimicrobial class into human clinical practice.
PMID- 10764971
TI - Evaluation of three commercially available kits for serological diagnosis of
dengue haemorrhagic fever.
AB - Seventy one acute phase serum samples collected during an epidemic of dengue
hemorrhagic fever were tested by immunoblot, a rapid immunochromatographic assay
and Dengue Duo ELISA for presence of anti dengue IgM and IgG antibodies. A
concordance of 81.7% and 76.1% was seen between the three tests for the detection
of anti-dengue IgM antibodies and IgG antibodies respectively. The rapid test
takes only five minutes, can be easily carried out in most laboratories and
compares well with the ELISA and the immunoblot.
PMID- 10764972
TI - PCR fingerprinting analysis for differentiation of Streptococcus pneumoniae
reinfection versus relapse.
AB - Polymerase chain reaction fingerprint profiles of isolates obtained during an
episode of pneumococcal pneumonia with bacteremia differed significantly from
profiles of isolates obtained from the same patient during a subsequent episode
of pneumococcal meningitis with bacteremia. Polymerase chain reaction
fingerprinting provides a means of differentiating new infection from relapse,
and may be a simple molecular tool for comparison of Streptococcus pneumoniae
isolates.
PMID- 10764973
TI - Feed restriction in young bulls alters the onset of puberty in relationship with
plasma insulin-like growth factor-I (IGF-I) and IGF-binding proteins.
AB - The objectives of this study were to evaluate the effect of feed restriction and
re-alimentation on the onset of puberty and IGF status in peripubertal male
calves and to compare the radioimmunoassay (RIA) and western ligand blotting
(WLB) methods for bovine IGFBP-2. Twelve prepubertal 290 d-old Belgian Blue bulls
(mean weight: +/- 290 kg) were randomly assigned in three groups: a control group
(NG; n = 4) receiving a classic fattening diet to induce "normal" growth (1.48
kg/d), a feed restricted group (RG; n = 4) to obtain reduced growth (0.50 kg/d)
and, a severely restricted group (SG; n = 4) to nearly stop growth (0.08 kg/d).
The feed restriction period was maintained over a period of 114 d. After the
period of differential feeding, all animals received the control feed regime over
a period of 100 d. Blood samples were collected at fortnightly intervals.
Circulating IGF-I was measured by RIA whereas plasma IGFBPs was evaluated by WLB;
IGFBP-2 was additionally quantified by RIA procedure. At the beginning of the
trial, IGF-I levels were low (<100 ng/ml) and similar in the three groups in
accordance with prepubertal status. In the NG group, a progressive rise in IGF-I
was observed from Day 42 to Day 142 whereas in the RG and SG groups, IGF-I levels
did not change until the experimental restriction period ended. The delay of the
rise in plasma IGF-I was longer for the SG group, IGF-I remained low until 2 wk
after the end of the period of restricted feeding. Surprisingly, although
differences were detected for IGF-I levels between the three groups, the IGFBP-2
and -3 data, evaluated by WLB could only discriminate between NG and SG group and
not between NG and RG. However, by using a RIA method, an IGFBP-2 decrease was
observed in the NG group coincident with increasing IGF-I levels. For both RG and
SG groups, IGFBP-2 levels remained high throughout the feed restriction period
whereas plasma IGFBP-2 levels declined upon feeding in both groups. During this
feed restriction period, IGFBP-2 was significantly lower in NG than in RG or SG
groups. Moreover, SG group animals had higher levels in plasma IGFBP-2 than RG
animals. In conclusion, puberty is characterized by developmental changes in
plasma IGF-I and IGFBPs that were altered by feed restriction. Moreover, RIA
evaluation of plasma IGFBP-2 is able to better reflect group differences than
WLB.
PMID- 10764974
TI - Effect of cerebroventricular infusion of insulin and (or) glucose on hypothalamic
expression of leptin receptor and pituitary secretion of LH in diet-restricted
ewes.
AB - The objective was to determine the effect of central infusion of insulin and (or)
glucose on hypothalamic expression of leptin receptor and pituitary secretion of
LH in the ewe. Twenty-two ovariectomized ewes (32 wk of age) were fitted with two
lateral cerebroventricular (LCV) cannulae and fed 33% of NRC requirements for 8
wk. Ewes (n> or =5/group) were then infused, via LCV cannulae, with artificial
cerebrospinal fluid (aCSF) or aCSF containing physiological concentrations of
insulin (INS), glucose (GLU), or INS + GLU; the mass of each increasing linearly
from Day 0 (mass = 0 units/h) to Day 8 (mass of INS = 80 mIU/hr and GLU = 10
mg/hr). Jugular serum was collected every 12 min for 4 hr on Days 0, 2, and 4.
Ewes treated with INS or INS + GLU had greater (P<0.06) mean concentrations of LH
than aCSF treated ewes on Day 2 (13.8+/-1.8 and 12.5+/-1.3 > 8.0+/-3.3 ng/ml).
Furthermore, on Day 4, concentrations of LH in INS treated ewes exceeded that
(P<0.07) of aCSF treated ewes (14.8+/-2.0 > 7.4+/-3.0 ng/ml). Expression of NPY
mRNA did not differ between treatments (P = 0.87). Leptin receptor mRNA
expression was dramatically reduced (P<0.0002) in INS+GLU versus aCSF treated
ewes. These data provide evidence to suggest that insulin may be an important
component of hypothalamic mechanisms regulating secretion of LH and expression of
leptin receptors in undernourished ruminants.
PMID- 10764975
TI - Alterations of growth hormone, cortisol, luteinizing hormone, and insulin
concentrations in early-postnatal calves affected with diarrhea.
AB - The aim of the study was to investigate the influence of diarrheic infections
during the early postnatal phase of calves on the concentrations of hormones
controlling reproduction and metabolism. Blood samples were collected from 20
male and female calves via jugular vein catheters every 15 min for 6 hr at Days
3, 9, and 21 of life. The animals were classified into three groups. Group 1
(controls): healthy calves (n = 9). Group 2: calves affected with diarrhea at Day
9 (n = 7). Group 3: calves with diarrhea at Days 3 and 9 (n = 4). Infections
occurred spontaneously and were mainly due to E. coli infections. All affected
calves had recovered at Day 21. Mean GH concentrations in the calves in Groups 2
and 3 compared to control calves had increased by Day 3 (P<0.01; P<0.001).
Cortisol levels of calves in all groups were highest at Day 3 and decreased
thereafter (P<0.001). Cortisol concentrations were lower at Day 3 in animals in
Groups 2 (P<0.001) and 3 (P<0.05) than in controls. Pulsatile LH release was
detectable at Days 9 and 21 only in healthy calves. Insulin increased at Day 9
during diarrhea. The results indicate that cortisol concentrations decreased
whereas GH concentrations were increased before diarrhea was observed. The onset
of pulsatile LH release was delayed in diarrheic calves. It is concluded that
diarrhea exerts effects upon the release of reproductive and metabolic hormones
in early postnatal calves.
PMID- 10764976
TI - Intracellular regulation of endometrial PGF(2a) and PGE(2) production in dairy
cows during early pregnancy and following treatment with recombinant interferon
tau.
AB - Objectives were to examine how the conceptus and recombinant bovine interferon
tau (rbIFN-tau) regulate intracellular components of the PGF(2a) synthetic
pathway and to determine if arachidonic acid (AA) is limiting in endometrial
tissue of pregnant cows. In Experiment 1, uteri were collected from either cyclic
or pregnant dairy cows on Day 17 post-estrus. Intercaruncular explants were
dissected and incubated for 60 min to quantify PGF(2a) production in response to
oxytocin (10(-6) M), A23187 (10(-5) M), melittin (10(-5) M), and phorbol 12, 13
dibutyrate (PDBu, 10(-6) M). Additional explants from the same cows were
incubated for 24 h with and without AA. Oxytocin and A23187 did not stimulate
PGF(2a) in explants from either cyclic or pregnant cows. Both PDBu, melittin, and
A23187 + melittin stimulated PGF(2a) production in explants of cyclic cows, but
not in explants of pregnant cows. The addition of AA to explant cultures for 24
hr did not increase PGF(2a) production during a subsequent 60-min incubation. In
Experiment 2, explants were collected from cows that received intrauterine
infusions of either BSA (1.9 mg/1.2 ml) or rbIFN-tau (0.2 mg rbIFN-tau + 1.7 mg
BSA/1.2 ml) twice a day from Days 14 to 17 of the estrous cycle. Treatments of
rbIFN-tau attenuated PGF(2a) secretion induced by in vitro PDBu and A23187
treatments. However, rbIFN-tau treatment in vivo had no effect on the in vitro
induction of PGF(2a) secretion by melittin. IFN-tau may regulate the PGF(2a)
synthetic pathway by reducing activity of PKC or PKC mediated events.
PMID- 10764977
TI - The effect of intake level on whole body kinetics and hepatic removal of
somatotropin in growing beef steers.
AB - The effect of level of intake of a high concentrate diet (0.6, 1.0 and 1.6 x
maintenance requirements, M) on whole body somatotropin (St) kinetics was
evaluated in six growing, multicatheterized beef steers (398+/-27 kg), using a
double 3x3 Latin Square design with 21 d-periods. Simultaneously to St kinetics,
net hepatic removal of St was measured in 4 of the 6 steers. On the last day of
each period, concentrations and net fluxes of St were determined, first in basal
conditions for 5 hr, and then, during a primed (0.5 mg of St) infusion of bovine
St (1.5 mg/hr) administered for 3 hr. The following results are LSM +/- SEM for
0.6, 1.0, and 1.6 x M, respectively. Increasing feed intake linearly decreased
(P<0.01) basal St concentrations (5.6, 4.6, 3.1+/-0.62 ng/ml), mainly through a
linear increment (P<0.01) in the metabolic clearance rate (32.7, 37.1, 43.4+/
2.60 l/hr), although secretion rate also tended to decrease (P = 0.09; 189, 185,
135+/-27.2 microg/hr). During the infusion period, net liver removal of
immunoreactive ST averaged 60% of the total inflow of St. This confirms the liver
is capable of removing large amounts of St, suggesting it has an important role
in metabolic clearance of the hormone. Net liver removal of St, however, was not
affected by intake. There was a strong correlation between the metabolic
clearance rate of St with either whole body protein synthesis (r = 0.75, P<0.01)
or protein retention (r = 0.68, P<0.01). Together these results indicate the
importance of postsecretory metabolism of St in determining both arterial plasma
concentrations of St and whole body protein anabolism.
PMID- 10764978
TI - Differences in pituitary cell number but not cell type between genetically lean
and fat Coopworth sheep.
AB - Coopworth sheep selected for low backfat (lean genotype) have been shown to have
heavier pituitary glands than those selected for high backfat (fat genotype).
This paper investigated whether this difference was due to an increase in
pituitary cell number or cell size and whether the relative proportions of
different pituitary cell types differed between the genotypes. In three separate
trials, ram lambs aged 6 to 8 months were slaughtered and the pituitary glands
were processed for stereological or immunocytochemical studies. The pituitary
glands of lean genotype sheep were between 30 and 60% heavier than those of the
fat sheep. Lean sheep had a significantly (P<0.05) larger cross-sectional area of
the pituitary fossa (96.6 vs. 81.7 mm(2)) than fat genotype sheep. The
pituitaries from lean sheep contained significantly more total cells than fat
sheep (Trial 1: 290 vs. 183 million cells, P<0.01; Trial 2: 353 vs. 239 million
cells, P <0.05). The volume of individual cells did not differ between the
genotypes. Trial 3 showed that there was no difference between lean and fat sheep
in the percentage of cells staining positive for the five pituitary hormones
studied. It is concluded that the larger pituitary glands of lean compared to fat
genotype sheep are a result of a nonspecific increase in the size of the whole
gland through increased cell numbers, with no change in cell size or the relative
proportion of different cell types.
PMID- 10764979
TI - Mammary gland development and hormone levels in pregnant Upton-Meishan and large
white gilts.
AB - Genetic differences between Upton-Meishan (UM, n = 13) and Large White (LW, n =
14) gilts were studied with regard to mammary gland development and
concentrations of hormones. Gilts were weighed and their backfat measured at
mating, and at d 70 and 109 of gestation. Jugular blood samples were also
collected at these times and assayed for prolactin, cortisol, IGF-I, insulin,
glucose, progesterone, and estradiol. Gilts were slaughtered on d 110 of
gestation. One row of mammary glands was used for dissection and biochemical
analyses. The other row was used for determination of prolactin receptor number
and affinity. UM gilts weighed less (P<0.05) and had more backfat (P<0.01) than
LW gilts at all times. Parenchymal tissue weight was less (P<0.05) in UM gilts.
Percent fat (P<0.001) and dry matter (P<0.001) in parenchymal tissue were greater
in UM gilts while that of protein (P<0.001) was lower. Total protein weight in
parenchyma was also lower in parenchyma was also lower in UM gilts (P = 0.01).
Both DNA (P<0.001) and RNA (P<0.001) contents were lower in UM gilts while
RNA/DNA remained similar (P>0.1). Number of prolactin receptors were lower (P =
0.06) and affinity greater (P<0.05) in UM gilts. Cortisol levels were greater
(P<0.01) in UM gilts while other hormones were not affected (P> 0.1). Results
clearly demonstrate genetic differences with regard to mammogenesis in gilts and
suggest that the less mammary gland development in Upton-Meishan compared with
Large White breed of gilts may be related to lower number of prolactin receptors.
PMID- 10764980
TI - Plasma insulin-like growth factor-I concentrations increase during the estrous
phase in goats.
AB - The objective of this study was to characterize plasma insulin-like growth factor
I (IGF-I) profiles during the estrous cycle in goats. Frequent blood samples were
drawn during the day of estrus and during the luteal phase on Day 10 after
estrus, and plasma growth hormone (GH) and IGF-I profiles were examined. Then,
daily blood samples were drawn throughout the estrous cycle or during induction
of estrus by prostaglandin F(2alpha) (PGF(2alpha)) to further clarify the IGF-I
profiles. GH was secreted in an episodic manner in the estrous and luteal phases
in goats. There were no significant differences in the mean concentrations, pulse
amplitude and pulse frequency of GH between the estrous and luteal phases. IGF-I
concentrations during estrous phase were higher than those in the luteal phase
(P<0.05). Plasma IGF-I increased approximately two days before behavioral estrus,
and the IGF-I peak was observed in accordance with the appearance of estrus. The
elevated IGF-I levels then declined to basal values 4 to 5 days after estrus.
When estrus was induced by PGF(2alpha), plasma IGF-I concentrations increased
after treatment, and the concentration 2 days after treatment (day of appearance
of behavioral estrus) was significantly higher than concentrations before
treatment (P<0.05). The elevated IGF-I levels then declined during the 3 days
after treatment. These results indicate that plasma IGF-I concentrations increase
during estrus in goats.
PMID- 10764981
TI - Effects of intraovarian infusion of insulin-like growth factor-I on ovarian
follicular function in cattle.
AB - The objective of this study was to determine if increased secretion of
intraovarian insulin-like growth factor-I (IGF-I), experimentally induced via
minipumps, affects follicular function in cattle. Fourteen cycling Holstein cows
were divided equally into two groups: Control, osmotic minipumps (containing
vehicle) surgically inserted into each ovary, or IGF-I treated, osmotic minipumps
as in Controls but pumping 2.0 microg of recombinant human IGF-I per hr for 7
days. All cows were synchronized with prostaglandin F(2alpha) 0.10) between
Control and IGF-I-treated cows during Days 2 to 6 of treatment. IGF-I treatment
increased (P<0.05) estradiol concentrations in follicular fluid of small
follicles, but had no effect (P<0.10) on estradiol concentrations in follicular
fluid of large follicles, or on progesterone, androstenedione, or IGF binding
protein concentrations in small or large follicles. We conclude that a 7-day
infusion of IGF-I directly into the stroma of the ovary altered follicular growth
and follicular fluid estradiol concentrations.
PMID- 10764982
TI - Mediators of inflammation involved in UVB erythema.
AB - In this review, we discuss the mediators and inflammatory cells involved in UVB
induced inflammatory changes phase by phase. We especially stress the importance
of IFNgamma secreted by activated CD4(+) T cells in the development of UVB
erythema. We also speculate on the mechanism underlying regression of UVB
erythema.
PMID- 10764983
TI - Immune responses to photohaptens: implications for the mechanisms of
photosensitivity to exogenous agents.
AB - A photohaptenic moiety is one of the salient properties of photoallergic
chemicals. Clinically, it is likely that photohaptens are the main causative
substances in photoallergic contact dermatitis and drug photoallergy.
Photohaptens bind covalently to protein under exposure to ultraviolet A light
(UVA). Because of this photocoupling ability, cells are easily photoderivatized
with a photohapten by UVA irradiation, becoming immunogenic photohapten-modified
cells. Langerhans cells photomodified with a photohapten can stimulate immune T
cells when photomodification is performed with a non-phototoxic dose of UVA.
PMID- 10764984
TI - The role of cytokines in UV-induced systemic immune suppression.
AB - Exposure to ultraviolet radiation induces skin cancer. In addition, UV exposure
suppresses the immune response. The mechanism by which skin exposure to UV
induces systemic immune suppression is not entirely clear, but a role for
cytokines secreted by irradiated epidermal cells has been described. Ultimately,
these immune regulatory cytokines affect antigen presenting cell function at
distant sites. We describe here preliminary findings suggesting that one
consequence of UV exposure is an alteration of IL-12 production by lymph node
dendritic cells that result in impaired immune function.
PMID- 10764985
TI - Genetic factors in immunosuppression: precise genetic evidence that polymorphism
of TNF-alpha dictates UVB-susceptibility in mice.
AB - Acute low-dose treatment of murine skin with ultraviolet B (UVB) light impairs
induction of contact hypersensitivity (CH) to dinitrofluorobenzene (DNFB) in
certain inbred strains of mice (termed UVB-susceptible), but not in others
(termed UVB-resistant). These deleterious effects of ultraviolet radiation (UVR)
are mediated in part by TNF-alpha, which is released from UVR-exposed epidermal
and dermal cells. To test the hypothesis that polymorphism of TNF-alpha governs
the phenotype of UVB-susceptibility in vivo, various strains of mice received UVB
radiation followed by hapten application to induce contact hypersensitivity.
Results suggest that the polymorphism at the Tnf-alpha locus dictates UVB
susceptibility in vivo.
PMID- 10764986
TI - Indications and action mechanisms of phototherapy.
AB - Recently phototherapy has become one of the most commonly used modalities for the
treatment of a variety of skin diseases, although the action mechanisms have not
been fully understood. The inhibitory effect of UVR on DNA synthesis may be one
of the actions for proliferating skin diseases. However, phototherapy is also
used for the treatment of allergic or autoimmune diseases. It has been confirmed
that the skin is an important immunologic organ whose constitutive cells are all
involved in immunologic reactions. We have investigated the effects of PUVA and
UVB radiation on the immunocompetent cells, including Langerhans cells, T
lymphocytes, mast cells, endothelial cells and natural killer cells. Exposure to
UVR inhibits contact sensitization to haptens applied not only to the irradiated
skin area but also to the non-irradiated distant skin when the exposure dose is
relatively high and/or the application skin area is large. In addition, hapten
specific tolerance develops by the generation of suppressor T cells. Phototherapy
is also useful for immediate type hypersensitivity such as urticaria. Action mode
in the case may be the inhibitory effects of UVR on histamine release from mast
cells. The results obtained from these experiments suggest that phototherapy
exerts its anti-allergic and anti-inflammatory effects through immunosuppression.
PMID- 10764987
TI - Ultraviolet A radiation-induced biological effects in human skin: relevance for
photoaging and photodermatosis.
AB - There is increasing evidence that longwave ultraviolet (UV) radiation (UVA; 320
400 nm) plays an important role in the pathogenesis of photodermatoses such as
polymorphous light eruption as well as photoaging. In order to fully understand
these detrimental effects it is critical to analyze the photobiological and
molecular mechanisms by which UVA radiation affects the function of human skin
cells. In this review, our current knowledge about the signal transduction
pathway involved in UVA radiation-induced expression of proinflammatory genes
relevant to the pathogenesis of polymorphous light eruption will be summarized.
In addition, recent studies on the role of mitochondrial DNA mutations in UVA
radiation-induced photoaging of human skin will be discussed. For both biological
endpoints the UVA radiation-induced generation of singlet oxygen within human
skin appears to be of critical importance. These studies are of enormous clinical
relevance because they indicate that prevention of the generation of singlet
oxygen or inhibition of singlet oxygen-induced signaling pathways may prove to be
critical for effective protection of human skin against UVA radiation-induced
damage.
PMID- 10764988
TI - Risk and preventive factors for skin phototype.
AB - Risk and preventive factors for skin phototype are discussed. Skin phototype was
firstly proposed by Fitzpatrick based on skin response of the Caucasian, whereas
the Japanese skin type was proposed for Japanese skin by Satoh and Kawada. Since
skin phototype is determined by a personal interview of sunburn and suntan
experience, it has a limitation in accuracy for personal interview and racial
difference. The skin phototype concept is practicable and useful for predicting
individual's sensitivity to UV, risk and preventive factors, and choosing
sunscreens even with the limitation.
PMID- 10764989
TI - The roles of cytokines in photoaging.
AB - Photoaging comprises characteristic changes in appearance and function of the
skin as a result of repeated sun exposure rather than to passage of time alone.
Clinically, wrinkles, laxity, coarseness, mottled pigmentation, lentigenes,
teleangiectasia and purpura characterize photoaging. Photoaging is also
characterized by atrophy, fibrotic depigmented areas termed pseudoscars, and
ultimately premalignant and malignant neoplasms on sun exposed areas. These
features are the result of ultraviolet radiation (UVR) in the sunlight. UVR
stimulates and activates various cells and tissues to produce and release
cytokines that may play a significant role in the process of photoaging. However,
cytokines are the major orchestrators of the host defense processes and are
involved in response to exogenous and endogenous insults, and repair and restore
homeostasis. Therefore, cytokines may be beneficial in the course of photoaging.
Considering the complex cytokine network in the skin, focus will be taken on
several subjects that have seen major changes during the last few years. I will
first outline our knowledge of cytokines in the skin together with their
functions, then review our knowledge of the involvement of cytokines in
photoaging, and finally summarize the defense system related to cytokines.
PMID- 10764990
TI - Telomerase in cutaneous carcinogenesis.
AB - Telomerase is a ribonucleoprotein enzyme that catalyses the addition of telomeric
repeats to telomeres. Since the shortening of telomeres is thought to act as a
mitotic clock, activation of telomerase is crucial for the continued growth of
cancer cells. Telomerase is frequently activated in premalignant and malignant
skin tumors and even in normal skin from sun-exposed sites. Normal epidermis
contains a subpopulation with telomerase activity, although those might not be
stem cells. Telomerase activity correlates closely with the expression of human
telomerase catalytic subunits. The effects of acute and chronic UV exposure on
telomerase activity and their mechanisms should be studied in relevance to UV
carcinogenesis and photoaging.
PMID- 10764991
TI - UV-induced DNA damage in carcinogenesis and its repair.
AB - The purpose of this study is to ask what kind of DNA damage is involved in UV
carcinogenesis. Firstly, ras gene alterations were analyzed in UV-induced mice
skin cancers. Five types of base changes resulting in activated ras were detected
in nine UV-induced skin cancers. Unexpectedly, transversions predominated,
whereas previous findings using shuttle vectors indicated that UVC predominantly
causes transition-type mutations, which implies the involvement of DNA damage
other than dimers in UV carcinogenesis in vivo, in the presence of endogenous
photosensitizers. Secondly, we detected mutations both in p53 and ras of skin
cancers from patients with xeroderma pigmentosum (XP). Fifty percent of non
melanoma-skin cancers (NMSCs) from XP patients had mutations in p53. The mutation
occurred preferentially at CC sites and transitions predominated for p53, whereas
ras mutations were far less frequent over the same samples, indicating that DNA
damage caused by sunlight rarely hits the crucial sites of ras. Lastly, p53
mutations on NMSCs were compared between sun-exposed area and non/less sun
exposed area. The frequency of p53 mutations between these two groups were almost
comparable. However, 67% had the transition at dipyrimidine sites in NMSCs from
sun-exposed area, whereas only 20% had the same type of mutations from non/less
exposed area (P<0.05).
PMID- 10764992
TI - Preventive effect of antioxidant on ultraviolet-induced skin cancer in mice.
AB - Reactive oxygen species (ROS) have been shown to be responsible for inducing DNA
damage after ultraviolet radiation (UV). Antioxidant, vitamin E and
epigallocatechin gallate extracted from green tea, applied topically to the skin,
delayed the onset of UV-induced skin cancer in mice. Since olive oil is reported
to have a potent antioxidative effect in in vitro system, we asked whether,
topical use of olive oil reduces the number and delays the onset of UV-induced
skin cancer in mice. We found that super virgin olive oil painted immediately
after UVB radiation significantly delayed the onset and reduced the number of
skin cancer, but pretreatment of super virgin olive oil and pre- and/or post
treatment by regular olive oil neither retarded nor reduced skin cancer formation
in UV-irradiated mice. Further, 8-hydroxy-deoxyguanosine (8-OHdG) formation in
mice epidermis was apparently reduced by super virgin olive oil painted
immediately after UV radiation, although cyclobutane pyrimidine dimers and (6-4)
photoproducts were not reduced by olive oil treatment. Our results suggest that
daily topical use of super virgin olive oil after sun bathing may delay and
reduce UV-induced skin cancer development in human skin, possibly by decreasing
ROS-induced 8-OHdG which is responsible for gene mutation.
PMID- 10764993
TI - Photoprotective role of metallothionein in UV-injury - metallothionein-null mouse
exhibits reduced tolerance against ultraviolet-B.
AB - We have shown previously that injection of cadmium chloride (Cd(2+)) depletes the
number of ultraviolet B (UVB)-induced sunburn cells (SBC) in the mouse skin in
vivo and that Cd(2+) treatment enhances UVB resistance in cultured keratinocytes
in vitro, indicating the photoprotective role of Cd(2+)-induced metallothioneins
(MTs) with antioxidant property against UVB injury. However, there has been no
direct evidence for the role of MTs in UV protection. To improve our
understanding of MTs in photoprotection, MT-null mouse deficient in MT-1 and MT-2
genes was studied. Skin explants were preliminarily exposed to medium alone,
Cd(2+) and Cd(2+) plus buthionine S, R-sulfoximine (BSO), an inhibitor of
glutathione synthesis. We then compared the number of UVB-induced SBC and
apoptotic cells (AC) in the epidermis of MT-null mice with that of control mice
using organ culture systems. The skin of MT-null mice developed a greater number
of SBC and AC than did that of normal mice in all experimental conditions. These
findings indicate that the skin of MT-null mouse is readily injured by UVB
irradiation. MT-null mouse provided direct evidence of the photoprotective effect
of cellular MTs in the skin.
PMID- 10764994
TI - Recent advances in sun protection.
PMID- 10764995
TI - State of the art sunscreens for prevention of photodermatoses.
PMID- 10764996
TI - Impaired arteriolar mechanotransduction in experimental diabetes mellitus.
AB - Decreased arteriolar distensibility in diabetes may impair signal transduction
mechanisms that are required for converting a pressure stimulus into smooth
muscle contraction. These studies aimed to determine if pressure-induced
increases in arteriolar intracellular Ca(2+) are altered in diabetes and whether
diabetes is associated with alterations in composition of the extracellular
matrix. Studies of mechanical properties used single, isolated, and cannulated
cremaster arterioles from streptozotocin (60 mg/kg) diabetic rats and age-matched
controls. To measure Ca(2+)(i), arterioles were loaded with Fura 2 (5 microM)
after which preparations were examined by fluorescence microscopy and image
analysis. Matrix protein (type IV collagen, laminin, fibronectin) deposition was
studied by immunohistochemistry. Over a range of 30-120 mm Hg control vessels
showed a linear relationship (r = 0.98, p < 0.01) between intraluminal pressure
and Ca(2+)(i). Vessels from diabetic animals also showed a linear relationship (r
= 0.99, p < 0.01), however, the mean slope was significantly (p < 0.02) less in
the diabetic (0.17 +/- 0.05, n = 5) compared to controls (0.51 +/- 0.09, n = 7).
Similarly, the slope of the wall tension-Ca(2+)(i) relationship was significantly
decreased in vessels from diabetic animals. These differences were ameliorated by
treatment of diabetic animals (n = 5) with aminoguanidine. Increased content of
type IV collagen, laminin and fibronectin in vessel media was evident after 2
weeks of diabetes and showed a further increase with duration of diabetes. The
data suggest that for a given increase in luminal pressure arterioles from
diabetic animals response with an attenuated rise in smooth muscle Ca(2+)(i).
This mechanotransduction defect may relate to alterations in the composition of
the extracellular matrix within the arteriolar wall.
PMID- 10764997
TI - Plasma membrane fluidity and polarity of polymorphonuclear leukocytes from
children with type I diabetes mellitus.
AB - Polymorphonuclear leukocytes (PMN) from diabetic subjects have been found to be
abnormal in various functional activities. These activities are mediated by the
plasma membrane. This study was designed to evaluate plasma membrane fluidity and
polarity in children with type I diabetes mellitus using fluorescence
spectroscopy. PMN membrane fluidity and polarity were assessed in a group of 32
diabetic children. Membrane fluidity was investigated by measuring steady-state
fluorescence anisotropy and fluorescence decay of 1-[4-trimethylammonium-phenyl]
6-phenyl- 1,3,5-hexatriene (TMA-DPH), whereas membrane polarity was studied by
measuring the steady-state fluorescence emission and excitation spectra of 2
dimethylamino[6-lauroyl]-naphthalene (Laurdan). TMA-DPH and Laurdan are known to
be incorporated at the hydrophobic-hydrophilic interface of the bilayer. Our data
show a significant increase in steady-state fluorescence anisotropy in diabetic
PMN that reflects a decrease in membrane fluidity, and a decrease in TMA-DPH
lifetime distribution indicating a decrease in membrane heterogeneity. Laurdan
shows a blue shift of the fluorescence emission and a red shift of the excitation
spectra in diabetic PMN with respect to the control group, indicating a decrease
in membrane polarity. The results demonstrate a decrease in the phospholipid
order at the membrane surface and a decrease in membrane polarity in diabetic
PMN. These alterations in the physico-chemical properties of the plasma membrane
could be the basis of the modifications in functional activities of PMN. The
changes in the plasma membrane of PMN could be the result of metabolic and
chemical modification associated with type I diabetes.
PMID- 10764998
TI - Carnitine deficiency in diabetes mellitus complications.
AB - In this study, the serum total, free and ester carnitine levels in 24 type II
diabetes mellitus (DM) patients with complications and 15 type II DM patients
with no complications were investigated. The patients were investigated in four
groups; the control group included the patients with no complications (group 1),
the groups including the patients with retinopathy (group 2), hyperlipidemia
(group 3), and neuropathy (group 4). In addition, patients were grouped into two.
The first group included 10 patients who took insulin by injection (group 5), and
the second group included 29 patients using antidiabetic drugs orally (OAD)
(group 6). Free and ester carnitine levels were determined by using Boehringer
Manheim UV-enzymatic L-carnitine kit. Statistical analysis results showed that
both the plasma total and free carnitine levels of groups 2, 3, and 4 were found
to be low when compared to the levels of group 1 (p < 0.05). It was observed that
the plasma total and free carnitine levels of group 5 were lower when compared to
group 6. No significant difference was observed between the plasma ester
carnitine levels of all the groups investigated. As a result of this study, it
has been thought that carnitine plays an important role in diabetes mellitus
complications.
PMID- 10764999
TI - Deep foot infections in patients with diabetes and foot ulcer: an entity with
different characteristics, treatments, and prognosis.
AB - We report findings in 223 consecutively included people with diabetes, foot ulcer
and a deep foot infection treated by a multidisciplinary diabetic foot care team
at the University Hospital in Lund, Sweden. The aim of the present study was to
evaluate type and characteristics of deep foot infections and their relation to
choice of treatment and outcome. Three different groups of deep foot infections
were identified; osteomyelitis only (n = 112), deep soft tissue infection only (n
= 46) and combined infections (osteomyelitis and deep soft tissue infection, n =
65). The various types of deep foot infections had different characteristics,
treatment and prognosis. Patients with a deep soft tissue infection only or a
combined infection had a significantly (p < 0.05) higher; (1) body temperature
(38.0 and 38.0 vs. 37.3 degrees C), (2) erythrocyte sedimentation rate (75 and 80
vs. 56 mm/h) and (3) white blood count (11.0 and 12.0 vs. 8 x 10(9)) at diagnosis
compared with those who had osteomyelitis only. Patients with a deep soft tissue
infection only or a combined infection also had a significantly (p < 0.05)
shorter time to surgery (2 and 4 vs. 10 days), higher mean number of surgical
procedures (1.9 and 2.1 vs. 1.4 procedures) and higher percentage of patients had
intravenous antibiotics (87 and 84 vs. 46%) compared with those who had
osteomyelitis only. Amputation before healing was more common in patients with a
combined infection (62%) compared with those who had osteomyelitis only (37%) or
a deep soft tissue infection only (30%). The findings in the present study
indicate that deep foot infections in patients with diabetes is a heterogeneous
entity, in which the type of deep foot infection is related to choice of
treatment strategy and to outcome. Therefore, these various types of infections
has to be considered in future studies of deep foot infections in people with
diabetes.
PMID- 10765000
TI - Changes in superoxide dismutase activities and concentrations and myeloperoxidase
activities in leukocytes from patients with diabetes mellitus.
AB - To investigate whether the two free-radical scavengers, Cu, Zn- and Mn-superoxide
dismutase (SOD), are changed in leukocytes of diabetic patients, and the
alteration of these enzymes correlates with the diabetic state, we measured the
activity and concentration of these enzymes in leukocytes from diabetic patients.
Both Cu, Zn-SOD and Mn-SOD activities in neutrophils and lymphocytes were
significantly lower in patients with non-insulin-dependent diabetes mellitus than
in healthy controls. The concentrations of these enzymes in leukocytes from
diabetic patients, however, did not differ from those in controls. Cu, Zn-SOD and
Mn-SOD activities in neutrophils inversely correlated with HbA(1c)
concentrations. Myeloperoxidase activity in leukocytes was significantly reduced
in NIDDM patients. These findings suggest that changes in these enzymes may
affect the susceptibility to infection and immunocompetence of patients with
diabetes.
PMID- 10765001
TI - Differential alterations of spontaneous and stimulated 45Ca(2+) uptake by
platelets from patients with type I and type II diabetes mellitus.
AB - Diabetes mellitus (DM) is associated with hyperaggregability of platelets.
Although the mechanisms underlying this abnormality remain unknown, Ca(2+)
imbalance has been implicated. Both activators (alpha-adrenoceptor agonists,
collagen, and ADP) and inhibitors (beta-adrenoceptor agonists, iloprost and
dibutyryl cAMP) of platelet function, respectively, elicit the uptake of
[45Ca(2+)] in human platelets. It was determined that the [45Ca(2+)] uptake
methods employed reflected signal transduction events at the plasma membrane
rather than absolute changes of Ca(2+) fluxes or levels of cytosolic Ca(2+). In
the present study, basal (unstimulated) [45Ca(2+)] uptake by platelets from both
type I and type II diabetic patients was significantly enhanced when compared to
age-matched controls. When basal values were subtracted from stimulated values,
there were highly significant decreases in [45Ca(2+)] uptake in platelets from
type I diabetic patients compared to controls when stimulated with adrenaline,
isoprenaline, noradrenaline, collagen, A23187, or iloprost. In contrast, when
basal values were subtracted from stimulated values there were significant
increases in [45Ca(2+)] uptake by platelets from type II diabetic patients when
stimulated with adrenaline, isoprenaline, noradrenaline, A23187, iloprost, and
collagen. It is concluded that in type I and type II DM there are differential
alterations in [45Ca(2+)] sequestration linked to inhibitors and stimulators of
platelet activation. These data indicate that the hyperaggregability of platelets
that is associated with both type I and type II DM may be due to an aetiology
other than Ca(2+) mobilization linked to signal transduction.
PMID- 10765002
TI - Mitochondrial DNA mutations are associated with both decreased insulin secretion
and advanced microvascular complications in Japanese diabetic subjects.
AB - To assess the roles of various mitochondrial (Mt) DNA mutations in diabetic and
nondiabetic subjects, we screened Mt DNAs at the 3243 base pair (bp) and its
adjacent portion in unrelated Japanese diabetic and nondiabetic subjects.
Furthermore, to clarify the clinical features of diabetic subjects harboring a Mt
DNA mutation, we evaluated the ability of insulin secretion and microvascular
complications in diabetic subjects. Five hundred thirty-seven diabetic patients
and 612 unrelated nondiabetic subjects were recruited into this study. In Mt DNA
analyses, Mt DNA was isolated from peripheral leukocytes of the subjects, and
then an Mt DNA fragment surrounding the tRNA(Leu(UUR)) site was amplified by the
polymerase chain reaction (PCR) using two sets of primers. These fragments were
further digested with three kinds of restriction endonucleases and were subjected
to agarose gel electrophoresis. When a mutation was present, Mt DNA fragments
were directly sequenced with an autosequencer. Baseline characteristics in all
subjects were examined, and microvascular complications and insulin secretory
capacity in diabetic subjects were newly evaluated. Eight kinds of Mt DNA
mutations, which were point mutations, were found in 74 subjects. Each affected
subject had only one mutation in the Mt DNA examined. Among them, the mutations
at np 3316, 3394, 3593, and 3391 were accompanied by amino acid replacement.
Thirty-eight diabetic patients were affected (7.1%), including two subjects with
a point mutation at np 3243, and 26 nondiabetic subjects were affected (4.2%).
Thus, there was a higher prevalence in diabetic subjects than in nondiabetic
subjects. There was no significant difference in the prevalence of maternally
inherited diabetes between these two groups. The mean level of urinary C-peptide
excretion was lower in diabetic subjects with an Mt DNA mutation (DM+) than in
those without it (DM-). Although the prevalence of hypertension in DM+ was higher
than that in DM-, diabetic retinopathy and nephropathy in DM+ were problematic,
in comparison with those in DM-, when statistical corrections were performed for
the effect of hypertension. Furthermore, a strategy based on logistic regression
analysis revealed that advanced retinopathy and decreased urinary C-peptide
excretion in all diabetic subjects studied were strongly related to the presence
of Mt DNA mutation. Our results suggest that Mt DNA mutations in Japanese
diabetic subjects are related to the development of diabetes, and also that these
mutations are associated with not only a decrease in insulin secretion but also
advanced diabetic microvascular complications.
PMID- 10765003
TI - No association between MTHFR gene polymorphism and diabetic nephropathy in
Japanese type II diabetic patients with proliferative diabetic retinopathy.
AB - The development of diabetic nephropathy shows marked variation among individuals.
Not only hyperglycemia, but also genetic factors may contribute to the
development of diabetic nephropathy. Methylenetetrahydrofolate reductase (MTHFR)
is involved in remethylation of homocysteine to methionine. Decreased activity of
MTHFR which can result in hyperhomocysteinemia may lead to cerebrovascular
disease and coronary artery disease. Recently, a common C to T mutation at
nucleotide position 677 of the MTHFR gene (MTHFR677CT) has been reported to be
correlated with hyperhomocysteinemia and the severity of coronary artery disease
as macroangiopathy. In the present study, we recruited 173 of Japanese type II
diabetic patients with proliferative diabetic retinopathy who would be exposed to
long-term hyperglycemia, and examined the contribution of the MTHFR gene
polymorphism to the development of diabetic nephropathy as microangiopathy. The
frequency of the mutated allele was 43.3% in patients with nephropathy (n = 105)
versus 41.9% in those without nephropathy (n = 68). The genotype frequencies were
+/+, 16.2%; +/-, 54.3%; -/-, 29.5% in patients with nephropathy versus +/+,
13.2%; +/-, 57.4%; -/-, 29.4% in those without nephropathy (+ indicates the
presence of the mutation). The MTHFR genotype and allele frequencies were not
significantly different between patients with and without nephropathy. Therefore,
we conclude that the MTHFR gene polymorphism is not associated with the
development of diabetic nephropathy in Japanese type II diabetic patients.
PMID- 10765004
TI - Effects of long-acting somatostatin analogue (Sandostatin) on manifest diabetic
ketoacidosis.
AB - Insulin deficiency and counterregulatory hormone excess are the basic process in
the development of diabetic ketoacidosis (DKA). Somatostatin, which suppresses
the secretion of glucagon and growth hormone, has been known to attenuate the
rate of gluconeogesis and ketogenesis in insulin-dependent diabetes mellitus
patients. However, the therapeutic efficacy of somatostatin has not been approved
to be practical in the treatment of manifest DKA. To examine the additive effect
of octreotide, the synthetic long-acting somatostatin analogue SMS 201-995, to
conventional treatment of manifest DKA, we compared the correction time of
acidosis, ketonuria, and hyperglycemia of patients treated with an intravenous
infusion of low-dose insulin (4 units per hour) plus subcutaneous injection of
octreotide (50 microg every 6 hours) by low-dose insulin alone. The correction
time for hyperglycemia and acidosis did not show any difference between groups (p
= 0.089, p = 0.82). However, the time for disappearance of ketonuria of the
octreotide-treated group (38.0 +/- 32.0 h) was reduced significantly compared to
other group (68.3 +/- 26.0 h) (p = 0.048). These results indicated that the
addition of octreotide to conventional treatment of DKA might improve the
correction of ketosis, but would not allow more rapid control of acidosis and
hyperglycemia in manifest DKA.
PMID- 10765005
TI - Epidural spinal cord electrical stimulation in diabetic critical lower limb
ischemia.
AB - Spinal cord stimulation (SCS) has been suggested to improve microcirculatory
blood flow to relieve ischemic pain and to reduce amputation rate in patients
with peripheral arterial occlusive disease (PAOD). The aim of this study was to
evaluate the specific prognostic parameters in the prediction of successful SCS,
in diabetic patients, performing a retrospective data analysis. To perform this
evaluation, 64 diabetic patients (39 men, 25 women; mean age, 69 years)
classified as Fontaine's stage III and IV, with PAOD, were treated with SCS for
rest pain and trophic lesions with dry gangrene, after failed conservative or
surgical treatment. In clinical controls, pedal transcutaneous oxygen tension
(TcPO(2)), ankle/brachial blood pressure index (ABI), and toe pressure Doppler
measurements were utilized to select and follow-up the patients. After 58 months
of follow-up (range, 20-128 months), pain relief greater than 75% and limb
salvage were achieved in 38 diabetic patients. A partial success was obtained in
nine patients with pain relief greater than 50% and limb salvage for at least 6
months. The method failed in 17 patients or the device was removed due to
technical problems, and the limb was amputated in these patients. TcPO(2) was
assessed on the dorsum of the foot. Clinical improvement and SCS success were
associated with increase of TcPO(2), before and after implantation. Limb salvage
was achieved in the patients who had significant TcPO(2) increase within the 2
weeks of the testing period, independently of the stage of the disease. A TcPO(2)
increase of more than 50% in the first 2 months after implantation was predictive
of success, and was related to the presence of adequate paresthesias in the
painful area during the trial period. TcPO(2) significantly increased after long
term follow-up in all patients with limb salvage (from 22.1 to 43.1 mm Hg in the
rest pain patients, from 15.8 to 36.4 mm Hg in those with trophic lesions of less
than 3 cm(2), and from 12.1 to 28.1 in those with trophic lesions of greater than
3 cm(2), (p < 0.01). ABI did not changed under stimulation. In diabetic patients
with PAOD, the SCS increases the skin blood flow, is associated with significant
pain relief, and could be proven an excellent alternative therapy, improving the
life quality. Significant TcPO(2) increase within the 2-week test period, is a
predictive index of therapy success and should be considered before the final
decision in terms of cost effectiveness, before the permanent implantation.
PMID- 10765006
TI - Diabetic microangiopathic complications in young Chinese diabetic patients: a
clinic-based cross-sectional study.
AB - Microangiopathic complications are major causes of morbidity and mortality in
diabetic patients. We studied 150 consecutive young Chinese diabetic subjects
attending the Prince of Wales Hospital Diabetes Center on their presence of
diabetic microangiopathic complications and the relationships with other risk
factors. All patients with aged younger than 40 years and had an age of onset of
disease at younger than 35 years. Their known duration of diabetes was 57.2 +/-
5.0 months. Of these 150 patients, 50 (33.3%) had microangiopathic complications,
34 (22.7%) had albuminuria, 11 (7. 3%) had peripheral neuropathy, and 21 (14%)
had retinopathy. Using multiple logistic regression analysis, albuminuria was
independently associated with body-mass index and systolic blood pressure,
peripheral neuropathy was associated with fasting plasma glucose and lower high
density lipoprotein cholesterol, and retinopathy was associated with duration of
disease and fasting plasma glucose. In conclusion, there were high percentages of
microangiopathic complications, particularly albuminuria, in our young Chinese
diabetic patients. Obesity, high blood pressure, and poor glycemic control are
important for these complications.
PMID- 10765007
TI - The effects of intensive glycemic control on neuropathy in the VA cooperative
study on type II diabetes mellitus (VA CSDM).
AB - To determine whether a difference in HbA(1c) could be safely sustained between a
standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining
HbA(1c) levels in both arms within a range acceptable in community practice. The
effects of intensive treatment on various parameters were studied in this
feasibility trial. We report here the results of 24 months of INT on peripheral
and autonomic neuropathy.A prospective trial was conducted in five medical
centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes
for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment
group (one morning injection per day) or to an intensive therapy group designed
to attain near-normal glycemia and a clinically significant separation of
glycohemoglobin from the standard arm. A four-step plan was used in the intensive
therapy group along with daily self-monitoring of glucose: (1) an evening insulin
injection, (2) the same injection adding daytime glipizide, (3) two injections of
insulin alone, and (4) multiple daily injections. Peripheral neuropathy was
diagnosed clinically by a history and physical examination, and by abnormal
autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An
average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or
below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy
was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in
STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline,
but no different than STD). Though INT did not reverse all elements of peripheral
neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053
versus STD) and more frequent preservation of touch sensation in the upper
extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio
and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD,
the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p =
0.012 versus baseline and no different from STD). The prevalence of erectile
dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD,
and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from
STD. There was no change in the frequency of abnormal gastrointestinal or
sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control
did not decrease overall prevalence of peripheral or autonomic neuropathy. In
fact, the prevalence rose equivalently and significantly in both treatment arms.
There was some benefit, however, in decreased frequency of cranial neuropathy and
better preservation of touch sensation in INT.
PMID- 10765008
TI - Should cisapride be avoided in patients with diabetic gastroparesis?
AB - The gastrointestinal motility stimulants, cisapride and erythromycin, have been
used in the management of diabetic gastroparesis. However, drug interactions may
result in prolongation of the electrocardiographic QT interval with the risk of
ventricular arrhythmias. These drugs should, therefore, not be used in
combination. We report two cases that illustrate inappropriate use of these
agents. Moreover, patients with recurrent severe hypoglycemia or renal impairment
may be at increased risk from cisapride-related cardiotoxicity. Thus, even as
monotherapy, cisapride may pose dangers for high-risk diabetic patients.
PMID- 10765009
TI - A diabetic patient with a black penile tip.
AB - This is a report of a patient with diabetes mellitus type II who presented with
the rare complication of penile gangrene. The gangrene was unilateral and was
associated with ipsilateral partial stenosis of the common iliac artery. An
angioplasty followed by insertion of a stent, rehydration, and improved diabetic
control did not improve the penile lesion, and penile amputation was carried out.
In the postoperative period, the patient developed a bilateral basal pneumonia
with a significant growth of saprophyte Mycobacterium gordonae from the bronchial
aspirate. This is the first reported case of unilateral penile gangrene and also
that of Mycobacterium gordonae infection in a patient with diabetes mellitus.
PMID- 10765010
TI - The prevalence of incipient tubular dysfunction, but not of glomerular
dysfunction, is increased in patients with diabetes onset in childhood.
AB - The study investigated the prevalence of incipient renal dysfunction in two
cohorts with identical duration of type I diabetes but with childhood or adult
onset of the disease. The pattern of glomerular (albumin, alb) and tubular
(alpha(1)-microglobulin, alpha(1)-m, and N-acetyl-beta-D-glucosaminidase, NAG)
urinary protein excretion was studied in 97 patients with diabetes onset before
the age of 16 years and in 53 patients with manifestation of the disease after
this age. Diabetes duration was comparable in both groups [9.0 years (1.5-40.0)
versus 9.0 (1.0-34.0), p 30 microg/g creatinine), patients with diabetes onset in
childhood showed significantly higher excretion of NAG compared to those with
diabetes onset after the age of 16. The excretion of both tubular markers
(alpha(1)-m and NAG) correlated significantly with HbA(1c)-values in both groups.
In multiple regression analysis, tubular proteinuria (alpha(1)-m) and diabetes
duration correlated significantly to microabuminuria (multiple R = 0.60, p <
0.001). These data suggest that there is no difference concerning the prevalence
of incipient diabetic glomerulopathy between patients with an early or a late
onset of diabetes. However, a more frequent impairment of tubular function was
found in young patients with diabetes onset in childhood, which might be due to a
non-optimal glycemic control in this population.
PMID- 10765012
TI - Overview of contents.
PMID- 10765013
TI - The use of molecular diagnostics in bladder cancer.
AB - Bladder cancer is a common disease that causes significant morbidity and
mortality in the United States. Early detection and routine surveillance are
recommended in the management of this chronic and recurrent disease. Cystoscopic
examination has been used for detection and follow-up; however, it is costly and
is associated with patient discomfort. With advances in molecular biology and
biochemistry, many diagnostic assays have been developed to supplement
cystoscopy. The mechanisms and variable results of these assays are described. In
addition, the economic and social implications of bladder cancer detection and
surveillance are discussed.
PMID- 10765014
TI - Chemotherapy for prostate cancer.
AB - The development of chemotherapy for prostate cancer has been limited by the
toxicity of treatment in an elderly population. The evaluation of newer agents in
the 1990's has allowed chemotherapy to be given which has fewer side effects, and
has improved life quality. The investigation of adjuvant treatment may be
warranted in an attempt to improve the outlook of this condition.
PMID- 10765011
TI - Decreased plasma endothelin-1 levels in asymptomatic type I diabetic patients
with regional cerebral hypoperfusion assessed by Spect.
AB - The prevalence of stroke is increased in diabetic patients. The vasoconstrictor
peptide endothelin-1 (ET-1) has been implicated in the development of cerebral
vasospasm after stroke but its role in the physiological regulation of cerebral
blood flow (CBF) is not well known. Our aim was to assess the relationship
between CBF and plasma ET-1 levels in type I diabetic patients. Regional CBF was
assessed semi-quantitatively by 99Tc(m)-hexamethylpropylene-amine-oxime (99Tc(m)
HMPAO) single photon emission computed tomography (SPECT) in 50 cerebral "regions
of interest" (ROIs) of 19 type I diabetic patients without clinical evidence of
cerebral disease, and 10 healthy control subjects. In both groups, plasma ET-1
levels were measured. Results showed that type I diabetic patients had
significantly more hypoperfusion ROIs than control subjects. While up to 68.4% of
the type I diabetic patients showed 3 or more hypoperfusion ROIs, only 10% of the
control subjects did. Plasma ET-1 levels were lower in the type I diabetes
subgroup with 3 or more hypoperfusion ROIs than in the type I diabetes subgroup
with less than 3 hypoperfusion ROIs and in the control group. Moreover, an
inverse correlation between the number of hypoperfusion ROIs and plasma ET-1
levels (r = 0.47, p = 0.04) was found in the type I diabetes group. It is
concluded that plasma ET-1 is decreased in type I diabetic patients with
subclinical abnormalities of regional CBF assessed by cerebral SPECT. This fact
may reflect a compensatory response to the reduction of the brain perfusion in
order to prevent ischemic events in these patients.
PMID- 10765015
TI - The pattern of serum markers in patients with androgen-independent adenocarcinoma
of the prostate.
AB - In this exploratory study, our objectives were to correlate the serum and bone
marrow concentrations of putative markers of prostate cancer progression in
patients with advanced androgen-independent prostate cancer (AIPC), to assess the
frequency and quantity of relative expression of these markers, and to correlate
the expression of the markers with extent of disease (EOD) and overall survival.
In a cohort of 50 patients with AIPC with bone metastases, we obtained serum and
bone marrow samples and measured prostate specific antigen (PSA), serum
interleukin-6 (sIL-6), bone marrow interleukin-6, serum chromogranin A (sCgA),
bone marrow chromogranin A, and prostate specific membrane antigen (PSMA) by
immunoassays. EOD was determined by quantifying identifiable bone lesions on
radionuclide bone scans. Each variable was categorized into two groups (low and
high) based on the median found in this cohort or on the cutoff based on normal
limits when available. Analyses were performed in two subsets of patients with
EOD either <20 or >/=20. Results showed that: (1) PSA is associated with EOD but
not with outcome; (2) sIL-6 and sCgA may be intermediate markers of early
progression in AIPC, because they are predictive of outcome only in patients with
EOD <20; (3) elevated PSMA is associated with elevated sIL-6 but not with PSA,
suggesting that PSMA may be a useful marker in AIPC; and (4) the ratio of PSA to
putative markers of progression may reflect the complex clonal progression of
prostate cancer. We conclude that patients with advanced AIPC exhibit one of two
patterns of serologic marker expression: in some patients the disease status is
reflected by PSA, and in others it is reflected by other markers. If these data
are prospectively confirmed, this would help group patients with advanced AIPC
into clinically relevant categories.
PMID- 10765016
TI - Endorectal coil magnetic resonance imaging and clinicopathologic findings in T1c
adenocarcinoma of the prostate.
AB - Stage T1c prostate cancer has become the most commonly diagnosed clinical stage
of localized prostate cancer. Endorectal coil magnetic resonance imaging (erMRI)
can be used in the staging of such patients. The purpose of this study was to
correlate the preoperative erMRI findings with the pathologic characteristics of
the surgical specimens. A database review of 355 radical prostatectomy specimens
revealed 130 patients with T1c disease. Of these patients, 124 were clinically
staged with erMRI. Standard sensitivity analysis and multivariable analysis was
then applied to determine the utility of erMRI in the staging of patients with
T1c prostate cancer. The mean prostate specific antigen (PSA) value was 8.3 (1.0
33.6). Most patients had Gleason score of 5 or 6 (51.6%) or 7 (33.1%), with fewer
patients having Gleason scores between 2 and 4 (7.2%) or 8 and 10 (8.1%). The
positive predictive value of erMRI for extracapsular disease was 38.7%, negative
predictive value was 75.3%, and accuracy was 79%. Multivariable regression
analysis demonstrated that erMRI and preoperative PSA were predictive for seminal
vesicle involvement. However, erMRI was not predictive in multivariable or
univariable analysis for extracapsular extension or margin positivity. Previous
investigators demonstrated the utility and independent significance of
preoperative erMRI for a select subset of patients. However, it is not a useful
staging modality for patients with T1c cancer as a whole. Further stratification
of the T1c patients would be necessary to identify patients within this group who
may benefit from staging with erMRI.
PMID- 10765017
TI - Carcinoid tumor of the kidney. The use of somatostatin receptor scintigraphy in
diagnosis and management.
AB - Three patients were diagnosed with carcinoid tumors of the kidney. The diagnosis
was rendered after biopsy with the assistance of immunohistochemical stains. In
all three patients, a pentetreotide scan was helpful in staging. Metastatic
disease that was not evident by computed tomography was found in one patient. All
three patients are alive with stable or slowly progressive disease at 33, 36, and
40 months. Carcinoid tumors arising from the kidney are rare but must be
considered in the differential diagnosis of a renal mass. Immunohistochemical
staining is important in the diagnosis of these tumors and the pentetreotide scan
contributes to accurate staging.
PMID- 10765018
TI - The role of external beam irradiation in patients undergoing prostate
brachytherapy.
AB - 6. From this cohort, a matched-pair analysis was performed to better assess the
role of EBT and TIPPB (n = 215). PSA relapse-free survival was based on the
American Society for Therapeutic Radiology and Oncology Consensus Panel
definition. Kaplan-Meier actuarial survival curves were compared to assess
various prognostic factors. The median follow-up for all 215 matched patients was
44 months (range, 24-81) with an actuarial PSA relapse-free survival (RFS) at 5
years of 81.1%. Patients treated with EBT and TIPPB had a 5-year PSA RFS of 83.5%
whereas patients treated with TIPPB only had a 5-year PSA RFS of 79.4% (p =
0.715)10 ng/ml. Risk group analysis combining PSA, Gleason score, and stage
failed to identify any risk group for which the addition of EBT was significant.
Analysis of postimplant dosimetry using the dose to 90% of the prostate volume
(D90) failed to distinguish any difference between groups. A significant
advantage for combining EBT and TIPPB could not be demonstrated in this
retrospective matched-pair analysis. These data indicate that the role and
rationale of combined treatment in prostate brachytherapy requires better
clarification, with a prospective randomized trial.
PMID- 10765019
TI - Expression of the multidrug resistance gene in human prostate cancer.
AB - Prostate cancer has become the most common cancer in males and the second most
common cause of male cancer death in England and Wales. Death rates have doubled
over the last 20 years. Prostate cancer is characterized by a high initial
response rate to hormonal therapy. Drug-resistance is a significant cause of
relapse in cancer. The multidrug resistance genes (MDR) encode resistance to a
diverse family of cytotoxic chemotherapy agents. There are four known MDR genes,
two of which are present in humans. MDR1 encodes for P-glycoprotein, a 170-kDa
transmembrane calcium-dependent efflux pump. We examined P-glycoprotein
expression by immunocytochemistry in 96 patients with prostate cancer and 20
patients with benign prostatic hypertrophy. A direct correlate was found between
tumor grade, stage, and prostate specific antigen levels, indicating the possible
significance of this protein in recurrent prostate cancer.
PMID- 10765020
TI - In vitro fusion of human inguinal hernia with associated epithelial
transformation.
AB - The processus vaginalis (PV) is a peritoneal diverticulum which forms to allow
descent of the fetal testis to the scrotum. During human development fusion and
obliteration of the PV often fails to occur with the result that inguinal hernias
are the most prevalent congenital abnormality requiring surgery in childhood.
Androgen is proposed to regulate testicular descent via the genitofemoral nerve
which releases the neuropeptide calcitonin gene-related peptide (CGRP). It is
possible that subsequent fusion of the PV and tissue remodelling following
descent is indirectly controlled by androgen via CGRP action. An organ culture
assay was developed to assess fusion of the PV taken from inguinal herniotomy in
infants. Fusion was induced in vitro by CGRP but not by CGRP 8-37, CGRP 27-37 or
dihydrotestosterone in equimolar concentrations. Fusion was accompanied by
transformation of the epithelium, as shown by staining of intermediate filament
proteins, cytokeratin and vimentin. Localization studies for CGRP receptors on 25
specimens indicated CGRP acts on mesenchymal fibroblasts but not directly on PV
epithelium suggesting an indirect pathway. Hepatocyte growth factor/scatter
factor was found to induce fusion of PV and may be involved as an intermediate
molecule in the fusion cascade. This study represents the first approach to
understanding the humoral control and underlying mechanism by which the PV fuses.
PMID- 10765021
TI - Changes in gastroduodenal 5-hydroxytryptamine-containing cells induced by
dehydroleucodine.
AB - In previous work, we demonstrated that dehydroleucodine (DhL), a lactone isolated
from Artemisia douglasiana Besser, prevents gastroduodenal damage induced by
absolute ethanol (EtOH). The present study examined the effects of DhL - applied
alone or before EtOH - on gastroduodenal cells containing 5-hydroxytryptamine (5
HT), to clarify the mechanism of action of the drug. Mice were divided into four
groups: (I) control; (II) DhL; (III) EtOH, and (IV) DhL + EtOH. Stomachs and
duodena were studied by immunohistochemistry and image analysis. EtOH decreased
the immunopositive cell number and the area occupied by these cells. This effect
was prevented by DhL. DhL alone did not affect the gastric immunopositive cell
number and area. Duodena treated only with DhL exhibited a reduction of
immunopositive cell number, but no change in area was observed. We propose that
the drug probably inhibits the release of the inflammatory mediator 5-HT from
endocrine cells, acting as a 'cell stabilizer' in response to injury.
PMID- 10765022
TI - Oophorectomy-induced osteopenia in rats in relation to age and time
postoophorectomy.
AB - Oophorectomized (OVX) rats served for many years as a popular model for
'postmenopausal' osteoporosis in spite of the fact that the rat continues to grow
during these experiments. We performed OVX in rats at 1, 3, 6 and 10 months of
age and compared the histomorphometric (bone size, bone trabecular and cartilage
volume in different areas) and chemical (ash, Ca, P and Mg content) parameters at
2, 6, 8 and 20 weeks post-OVX (2-20 weeks) to those of sham-operated rats.
Significant differences were observed only in the animals that were OVX at a
young or young-mature age, i.e. mainly at 1 and 3 months and some of the rats at
6 months of age. There were no changes in bone ash and mineral contents in the
OVX animals in comparison to sham-operated rats, except 2 weeks post-OVX in the 1
month-old rats where these variables were reduced. The most significant finding
was a reduction in the metaphyseal bone volume. This was observed in the rats OVX
at 1, 3 and 6 months of age, but not in those OVX at 10 months. In the young OVX
rats there was also an increase in epiphyseal cartilage volume. The epiphyseal
and diaphyseal bone volumes were not different between the groups at any time
postsurgery, explaining the lack of differences in bone ash and mineral contents.
There were no significant changes in the results of the histomorphometric studies
between OVX and sham-operated rats when surgery was performed at 10 months of
age. Since OVX exerts significant changes only in young rapidly growing rats,
this approach is an inappropriate model for postmenopausal osteoporosis, which
occurs long after bone growth has ended.
PMID- 10765023
TI - Distribution of primary afferent neurons innervating the porcine oviduct and
their immunohistochemical characterization.
AB - Previous studies have revealed that some nerve fibres supplying the porcine
oviduct may be of sensory origin. Therefore, the present study was aimed at
disclosing the distribution of porcine 'oviductal' primary afferent neurons and
the pattern(s) of putative coincidence of substance P (SP), calcitonin gene
related peptide (CGRP), vasoactive intestinal peptide (VIP) and nitric oxide
synthase (NOS) within these nerve cell bodies using combined retrograde tracing
and double-labelling immunohistochemistry. We also investigated the existence and
coexistence of immunoreactivities to tyrosine hydroxylase (TH) and dopamine beta
hydroxylase within the neurons because in some mammals, dorsal root ganglia (DRG)
were previously found to contain perikarya immunoreactive (IR) to TH. Retrograde
labelling revealed a population of large sensory neurons located in the Th(10)
L(3) DRG. There were no significant differences in the number or distribution
between the ampulla- and isthmus-projecting neurons. Double-labelling
immunoflourescence allowed several subpopulations of the studied perikarya to be
distinguished. The largest one consisted of SP/CGRP-IR nerve cells, while the
smallest subpopulation comprised NOS/VIP-IR neurons. Either SP/NOS, solely SP- or
solely NOS-IR neurons were also found. Because identically coded nerve fibres
have been observed within the wall of the porcine oviduct, based on their
association with particular organ structures, it can be assumed that SP/CGRP-,
SP/NOS- or solely NOS-IR neurons are involved in the antidromic relaxation of the
oviductal vessels, SP-, NOS- or SP/CGRP-IR nerve cells control the oviductal
tonus and that some neurons project beneath the epithelium and are involved in
the transmission of sensory modalities from the oviduct to the spinal cord.
PMID- 10765024
TI - Response of zygomaticomaxillary suture to experimental malocclusion in rats.
AB - The purpose of this study was to examine the response of the zygomaticomaxillary
suture (ZMS) to experimental malocclusion in rats. Thirty-two male Wistar rats
were divided into two groups. Malocclusion was produced in the experimental group
(n = 20) by gluing a wire, 1 mm in diameter, on the upper left first molar.
Duration of the procedure was 20 min. In the control group (n = 12), rats were
forced to open their mouths for the same time as in the experimental group.
Histomorphological changes of the ZMS were examined at intervals of 1, 2, 4 and 8
weeks. The specimens were stained with hematoxylin-eosin and Mallory's azan. The
suture in the control group showed a regular functional arrangement of component
fibers, and osteoblasts lined the periphery of new bone at the inner half of the
suture. On the untreated side in the experimental group, osteoclasts were most
abundant after 2 weeks. Histomorphometric quantification of the sutural width
revealed that, at the inner half of the suture, the width of the sutural space on
the treated side in the experimental group was greater than that in the control
group after 4 weeks (p < 0.05). The argyrophilic nucleolar organizer region
(AgNOR) technique was used to investigate the transcriptional activity of
fibroblasts in the suture. At the inner half of the suture, the number of AgNORs
on the untreated side in the experimental group was greater than that on the
treated side and that in the control group after 2 weeks (p < 0.05). Around the
tip of the suture and at the outer half of the suture, there was no appreciable
difference in the AgNOR number between the experimental and control groups. It
was concluded that unilateral changes in occlusion had different effects on the
treated and untreated sides of the ZMS. Moreover, the inner and outer halves of
the suture showed different histological changes in response to experimental
malocclusion.
PMID- 10765025
TI - Gross morphology and topography of the adult intestinal tract of the tilapian
fish, Oreochromis niloticus L.
AB - The intestinal tract of the Nile tilapia, Oreochromis niloticus L., follows a
complex course involving multiple loops and coils arranged in a previously
undescribed form. From cranial to caudal, five principal regions were identified
and designated as the hepatic loop (HL), proximal major coil (PMC), gastric loop
(GL), distal major coil (DMC), and terminal segment (TS). The first four of these
regions each possessed a reversal flexure and thus could be divided into proximal
and distal limbs. Only the terminal segment was straight and undivided. The PMC
and DMC were disposed in a spiral, cone-shaped mass (spiral intestine) - their
proximal and distal limbs are thus designated as centripetal and centrifugal
limbs. These spiral limbs were arranged with each successive limb nested internal
to the previous one. Beginning from the stomach, the complete course of the gut
including designations of the subdivisions of the major regions was as follows:
proximal limb of the HL, distal limb of the HL, centripetal limb of the PMC,
centrifugal limb of the PMC, proximal limb of the GL, distal limb of the GL,
centripetal limb of the DMC, centrifugal limb of the DMC, and the TS. Though the
topographical relations of the various gut loops permitted ready identification
of each, external surface features were so similar among the segments that
extirpated segments of gut could not be identified as to region of origin. The
nesting of successive intestinal loops of the spiral intestine in this fish is
novel among patterns previously described, and also among the more intricate of
those that have been described.
PMID- 10765026
TI - Shape, orientation and spacing of the primary epidermal laminae in the hooves of
neonatal and adult horses (Equus caballus).
AB - Circumferential and proximodistal variations in the morphology of the primary
epidermal laminae of six neonatal and five adult equine feet were documented.
Three parameters were quantified: interlaminar spacing, the orientation of the
laminae with respect to the overlying wall, and any angulation within the laminae
themselves ('internal angle'). In adult feet, the laminae were most closely
spaced at the dorsum, the spacing increasing gradually towards the heels. In
foals there was a non-significant trend for the dorsal laminae to be more widely
spaced than those in more caudal parts of the foot. In both age groups, the
dorsal laminae were almost straight (mean divergence from linearity at all sites
2 degrees ), and were oriented at approximately 90 degrees to the tangent to the
overlying wall (mean orientation for all sites 91 degrees ). At the quarters, the
laminae were in general oriented caudally relative to the tangential position
from their epidermal to their dermal ends (mean orientation of >90 degrees at 12
of 16 sampling sites, where an orientation of >90 degrees defines a 'caudally
directed' orientation) and, in general, had a bend within their length (mean
absolute value of internal angle for all sites 9 degrees ). At the heels there
was greater variability in the data for both laminar orientation and internal
angle. Overall, the foal feet showed greater mediolateral symmetry and less
proximodistal variation than did the adult feet. In both age groups, rapid
spatial changes in laminar morphology were closely associated with the position
of the margins of the third phalanx.
PMID- 10765027
TI - Caroticotympanic artery: anatomically a normal branch or a variation of the
internal carotid artery?
AB - Most investigators consider the caroticotympanic artery to be a normal branch of
the petrous portion of the internal carotid artery, although some authors
disagree. The present study was conducted on forty human temporal bones removed
from adult cadavers of both sexes. Twenty pieces were injected and dissected
under a surgical microscope, 10 pieces were injected and submitted to corrosion,
and 10 were injected and diaphanized in order to observe the frequency of the
caroticotympanic artery in the petrous portion of the internal carotid artery.
The caroticotympanic artery was not observed in any of the pieces submitted to
microdissection and was observed in only 1 of the pieces (10%) submitted to
corrosion and also in 1 of the diaphanized pieces (10%). In both cases, only one
artery was present. Based on the present results showing that the rate of
occurrence of the caroticotympanic artery was very low by the three techniques
utilized (microdissection 0%; corrosion 10%; diaphanization 10%), it is possible
to conclude that, anatomically, the artery should be considered as a variation
and not as a normal branch of the petrous portion of the internal carotid artery,
in agreement with most literature reports.
PMID- 10765028
TI - Pharmacokinetics of a new derivative of partricin A (SPA-S-753) in rodents.
AB - Pharmacokinetics of a new semisynthetic polyene antibiotic (N-dimethylaminoacetyl
partricin A 2-dimethylaminoethylamide) in the form of its diaspartate salt (code
SPA-S-753) was studied in rats and mice following intravenous injection and in
rats following oral administration at different dose levels. In rats the urinary
and biliary recovery after intravenous administration was also determined. Rats
and mice received a single intravenous injection of 1.25 and 2.5 mg/kg of SPA-S
753 (about 1-2 mg/kg of free base) or 1 mg/kg of amphotericin B as reference
drug. Blood samples were obtained at 5 min to 96 h after injection. The half
lives at the elimination phase in serum were 21.3, 26.5, 10.8 h in rats and 11.7,
13.7, 19.8 h in mice, respectively, for 1.25 and 2.5 mg/kg of SPA-S-753 and 1
mg/kg of amphotericin B. The values of AUC(0-infinity) for SPA-S-753 were about 5
times higher in rats and twice higher in mice than those for amphotericin B. Rats
received also a single oral dose of 200 or 500 mg/kg of SPA-S-753. Serum samples
were obtained at 0.5-96 h after dosing. The compound is poorly absorbed by the
oral route. The mean cumulative urinary recovery of SPA-S-753 at 48 h after
intravenous injection of 1.25 mg/kg in rats accounts only for 0.5% of the dose,
while the cumulative recovery from the bile at 10 h after 2.5 mg/kg i.v.
administration in rats accounts for 5.5% of the dose.
PMID- 10765029
TI - Lack of in vitro and in vivo selection of bacterial resistance by roxithromycin.
AB - The in vitro and in vivo selective pressure exerted by roxithromycin on
Lancefield group A beta-haemolytic streptococci (GABHS) was investigated. In
vitro antimicrobial activity on fifty GABHS strains was determined by the
microdilution method and by boundary concentration (BC) determination. Insorgence
of resistance was evaluated by redetermining MIC and BC after exposure to 16 x
MIC roxithromycin concentration. In vivo insorgence of resistance was evaluated
by MIC and BC determinations on the GABHS strain recovered from infected mice
peritoneum, after treatment with 20 mg/kg roxithromycin. The roxithromycin serum
kinetics was established in healthy and infected mice. Neither significant
changes in GABHS MIC or BC after in vitro or in vivo exposure to roxithromycin
nor a difference in roxithromycin serum levels between healthy and infected mice
were detected, suggesting that the roxithromycin selection of resistance in GABHS
is low.
PMID- 10765030
TI - Antimicrobial resistance patterns in respiratory pathogens isolated in an Italian
university hospital during a period of eight years: a statistical analysis.
AB - The antimicrobial resistance patterns of respiratory pathogens isolated during an
8-year period (1990-1997) in an Italian hospital from patients with
bronchopulmonary infections were investigated. A global variation in the
resistance of Staphylococcus aureus to all relevant antibiotics was observed
during the years 1990-1997. With the exception of penicillin and amoxicillin, to
which Staphylococci were always resistant, and vancomycin, to which they were
always susceptible, in the first period (1990-1992) the percentage of resistance
to beta-lactams, aminoglycosides, macrolides, fluoroquinolones and cotrimoxazole
was about 15%, while in the last period (1993-1997) it was about 35%. No global
variation in resistance to the antimicrobials examined during the study period
was observed for gram-negative bacteria. The percentages of resistance to the
more recent beta-lactams, aminoglycosides and fluoroquinolones were generally
less than 10% for the KES group, less than 20% for Pseudomonas aeruginosa, and
less than 30% for other Pseudomonas species. A high percentage of resistance was
observed for the KES group to amoxicillin + clavulanic acid (60%) and to
cefoxitin (48%).
PMID- 10765031
TI - Postantibiotic effect of a combination of antimicrobial agents on pseudomonas
aeruginosa.
AB - Treatment of severe Pseudomonas infections often calls for multidrug therapy.
Combinations of aminoglycosides, beta-lactams and/or quinolones are generally
administered, the effect of which may be additive, synergistic or indifferent.
The present in vitro study was designed to find out the exact outcome of the
postantibiotic effect (PAE). The minimal inhibitory concentrations and the PAE of
three antibiotics (amikacin, ceftazidime and ciprofloxacin) were determined both
singly and in combination. Ceftazidime alone exhibited a negative PAE but a
synergistic effect was observed for the combination of ceftazidime with amikacin.
The combination of ceftazidime with ciprofloxacin and ciprofloxacin with amikacin
however gave an indifferent PAE. This synergistic PAE of amikacin with
ceftazidime has a significant effect on designing optimal dosage regimens.
PMID- 10765032
TI - Interaction of cefotetan and the metallo-beta-lactamases produced in Aeromonas
spp. and in vitro activity.
AB - Aeromonas spp. are increasingly being recognized as human pathogens. The presence
of metallo-beta-lactamases in these organisms represents a potential problem in
antimicrobial therapy. Mechanism-based inactivators of beta-lactamases are used
to overcome the resistance of clinical pathogens to beta-lactam antibiotics, but
no clinical useful inhibitors of the metallo-beta-lactamases are presently known.
Studying the interaction between cefotetan and Aeromonas spp. producing metallo
beta-lactamase activity, we observed that cefotetan behaved as a transient
inactivator for both the crude extracts of Aeromonas strains and the purified
enzymes from Aeromonas hydrophila AE036 and Aeromonas schubertii MNSA20. The
direct hydrolysis of cefotetan showed that it was a poor substrate for both
purified enzymes. In view of the minimum inhibitory concentrations, cefotetan
shows to be a useful antimicrobial agent against Aeromonas spp.
PMID- 10765033
TI - Comparative in vitro activity of S-4661, a new parenteral carbapenem, and other
antimicrobial agents against respiratory pathogens.
AB - The activity of S-4661, a new parenteral carbapenem antibiotic, was evaluated
against 202 recent clinical isolates of respiratory pathogens. S-4661 was similar
to or 2 times more active than imipenem, meropenem, and biapenem, and 8-128 times
more active than ceftazidime against gram-positive bacteria. Against gram
negative bacteria, S-4661 was slightly less active than meropenem, but 2-8 times
more active than the other agents. In particular, against Pseudomonas aeruginosa
S-4661 showed the most potent activity. Thus it was found that S-4661 possesses a
potent and well-balanced activity against respiratory pathogens.
PMID- 10765034
TI - Effect of navelbine on inhibition of tumor growth, cellular differentiation and
estrogen receptor status on Lewis lung carcinoma.
AB - We studied the antitumor activity of Navelbine (NVB) together with its ability to
induce cellular differentiation and to influence estrogen receptor status of
Lewis lung carcinoma (LLC). A total of 32 C(57)B1 mice divided into 5 groups were
used for transplantation of LLC. Four groups of mice were treated with 5.0, 2.5
and 1.25 mg/kg/day from day 1 to 9 and 1.25 mg/kg on days 1, 7 and 13. Eight mice
were controls. The dose of 1.25 mg/kg/day was the most effective and produced
72.7% inhibition of tumor growth. Ultrastructurally, on day 1 the cells showed
poor differentiation. On day 14, in the case of 72.7% inhibition of tumor growth
the study revealed a significant restoration of the morphology of the cells.
Estrogen receptors gave a positive value in contrast to the initial measurement
which was negative. The present study demonstrated good antitumor activity of NVB
on LLC. NVB may also induce cellular differentiation and influence the estrogen
receptor status.
PMID- 10765035
TI - Susceptibility of clinical strains of herpes simplex virus to three nucleoside
analogues.
AB - The susceptibility of clinical isolates of herpes simplex virus 1 (HSV1) (58
strains) and 2 (HSV2) (17 strains) from the Centre Hospitalier et Universitaire
de Nancy to three nucleoside analogues was compared by the dye uptake method. As
expected, all strains of HSV2 were resistant to brovavir or sorivudine. Aciclovir
and penciclovir activities were comparable; 2 strains of HSV1 were resistant to
these two compounds. Four strains isolated from immunocompromised patients gave
different results with brovavir as compared to aciclovir; resistance to aciclovir
(1 strain of HSV1) did not correlate with resistance to brovavir (3 strains of
HSV1). Following up antiviral susceptibility is of interest for the detection of
resistant strains in immunocompromised patients receiving prophylactic aciclovir.
PMID- 10765036
TI - In vitro effects of clarithromycin on human polymorphonuclear leukocyte
functions.
AB - BACKGROUND: It has been shown that antibacterial agents affect polymorphonuclear
leukocytes (PMNs), which are active in the body's first line of defense, in
different ways. However, few studies have investigated the effects of tablet
dosage forms as opposed to pure powder forms. There is a need to demonstrate the
clinical relevance of previous results with commercially available products.
METHODS: We examined the effects of clarithromycin solutions, prepared separately
from either pure powder or commercially available tablets (250 mg), on human
PMNs. The in vitro effects of each solution, adjusted to therapeutic
concentration (1 mg/l), on PMN adherence, chemotaxis, phagocytosis, candidacidal
capacity and superoxide production were studied. RESULTS: Solutions prepared from
pure clarithromycin powder did not affect the adherence, phagocytosis or
superoxide production of PMNs, but did inhibit (p<0.05) chemotaxis and
candidacidal capacity. By contrast, a decrease (p<0.05) in all functions except
phagocytosis was observed with solutions prepared from the tablet dosage form of
clarithromycin. CONCLUSION: The results of this study suggest that the tablet
dosage form of clarithromycin may have a more pronounced inhibitory effect on
human PMN functions than solutions prepared from the pure powder form.
PMID- 10765037
TI - Changes in susceptibility of Pseudomonas aeruginosa to gatifloxacin and
carbapenem in an in vitro urinary bladder model.
AB - To study the changes of bacterial susceptibility during exposure to
antimicrobials, the respective minimal inhibitory concentrations (MICs) of 50
colonies from each of various bacterial test strains were determined in an
experimental system using an in vitro urinary bladder model. The MICs of
gatifloxacin and meropenem for Pseudomonas aeruginosa strains were not
homogeneous before exposure to the drugs. The MICs of the strains examined
reflected only that of their dominant population. When starting from 10(7)CFU/ml,
the bacterial count was determined serially during exposure to gatifloxacin or
meropenem in therapeutic urinary concentrations. The MIC of the less susceptible
population of each strain was changed serially to a higher one. The more
susceptible strains were eradicated before the change of the MIC. The bacteria
originally consisted of strains having heterogeneous susceptibility to drugs, in
which major strains had susceptibility expressed by the MIC and minor ones had a
higher or lower MIC. This heterogeneity may be responsible for the change of
susceptibility in strains after exposure to the drugs.
PMID- 10765038
TI - Current status and fluconazole treatment of pelvic fungal gynecological
infections.
AB - The incidence of opportunistic fungal infections has recently been increasing in
many clinical fields. Fluconazole is commonly used against systemic fungal
infections. The present study was undertaken to investigate the current status
and the efficacy of fluconazole in pelvic fungal gynecological infections. Thirty
eight patients aged 36-72 years old diagnosed with pelvic peritonitis with
positive fungal culture in pelvic ascites were enrolled in this study and given
fluconazole treatment. Forty-two pathogens were isolated from the 38 assessable
patients. The predominant pathogen was Candida albicans with an incidence of
61.9% (26/42). Others included non-albicans Candida species amounting to 38.1%
(16/42): 19.0% (8/42) Candida glabrata, 7.1% (3/42) Candida tropicalis, 7.1%
(3/42) Candida parapsilosis and 4.8% (2/42) Candida krusei. The clinical cure
rate at the end of fluconazole treatment was assessed as 30/38 (78.9%), and the
fungal eradication rate as 26/42 (61.9%). Each rate was 29/38 (76.3%) and 26/42
(61.9%), respectively, at 1 week after the treatment, while the eradication rate
of C. albicans and non-albicans species was 20/26 (76.9%) and 6/16 (37.5%),
respectively. There was no adverse effect except for slight elevations of GOT,
GPT and LDH observed in 1 patient (2.6%), which returned to normal after the
treatment. It seems there may be an increasing trend of non-albicans species in
pelvic fungal gynecological infection, against which fluconazole appears to be
rather effective.
PMID- 10765039
TI - Prospective randomized study of antibiotic prophylaxis for nonlaparotomy surgery
in benign conditions.
AB - BACKGROUND: Although postoperative infections continue to be a major problem in
gynecologic surgery, there is still no consensus on the efficacy of antibiotic
prophylaxis. METHODS: This prospective randomized trial was conducted to
investigate the prevention of major operating site infections after nonlaparotomy
surgery, with treatment regimens as follows: the first group of patients received
2 g of intravenous cefotiam dihydrochloride (CTM) on the induction of anesthesia,
while the second group received 100 mg of oral cefpodoxime proxetil (CPDX- PR)
twice daily, from day 0 to day 2. RESULTS: Nineteen of the 207 patients enrolled
developed postoperative infections diagnosed by our simple criteria for
postoperative infection. The frequency of febrile morbidity was not significantly
less in patients who received CTM (9 cases; 8.6%) as compared with those in the
CPDX-PR group (10 cases; 9.8%) (p = 0.56). CONCLUSION: The administration of oral
CPDX-PR (100 mg, twice daily, for 3 days) appears to be a safe, cost-saving,
convenient prophylaxis which reduces overall expense.
PMID- 10765040
TI - Systemic infections with Candida sp. and Aspergillus sp. in immunocompromised
patients with hematological malignancies: current serological and molecular
diagnostic methods.
AB - Within recent years, novel serological and molecular methods have been developed
to improve the early diagnosis of invasive fungal infections especially in
patients with malignant hematological diseases being at highest risk of
developing these life-threatening infections. Early diagnosis is essential for
adequate therapeutic management, which, however, often remains difficult since
the diagnostic tools clinically used either lack specificity or sensitivity, or
both at worst. The clinical value, the advantages and remaining problems of
recently developed, more sensitive and specific serological assays and molecular
methods are reviewed.
PMID- 10765041
TI - Estrogen receptor gene polymorphisms in patients with Alzheimer's disease,
vascular dementia and alcohol-associated dementia.
AB - The association between the estrogen receptor (ER-alpha) gene and dementia was
examined in 223 patients with Alzheimer's disease (AD), 66 with vascular dementia
(VD), 17 with alcohol-associated dementia (ALD) and 134 healthy elderly control
subjects. The PvuII and XbaI restriction fragment length polymorphisms of the ER
alpha gene were represented as Pp (PvuII) and Xx (XbaI), with capital letters
signifying the absence of restriction sites and small letters the presence of
restriction sites. We found that the frequency of the ER-alpha gene P allele and
X allele in the late-onset AD (LOAD) group (P allele was 0.51, X allele was 0.30)
was significantly higher than that in controls (P 0.38, p < 0.01; X 0.20, p <
0.01), and that the frequency of the ER-alpha gene P allele and PP genotype was
significantly different between apolipoprotein E epsilon4 carriers and
noncarriers in LOAD. These findings suggest that the genotype of the ER-alpha
gene may be specific in LOAD, and that the ER-alpha gene was an additional risk
for LOAD.
PMID- 10765042
TI - Magnetic resonance imaging and histopathology in dementia, clinically of
frontotemporal type.
AB - The magnetic resonance imaging (MRI) and computed tomography findings in 28
patients with the clinical diagnosis of frontotemporal dementia (FTD) were
compared with the findings in a control group of 76 individuals without dementia
or stroke. A pattern of frontal and temporal atrophy with predominantly frontal
white matter changes was found in the FTD patients, and this was significantly
different from the radiological findings in the control group. Six of the FTD
patients have undergone autopsy. Histopathological evaluation showed a primary
cortical degenerative disease (frontal lobe degeneration of non-Alzheimer type)
in 3 of them, and primary white matter disorder, mainly frontal, of basically
ischemic type (selective incomplete white matter infarction) in 3 of them. MRI
could be a helpful tool to support the clinical diagnosis FTD, especially in
young patients. MRI may also be helpful for the differentiation of a primary
neurodegenerative from a mainly ischemic-vascular type of dementia.
PMID- 10765043
TI - Lipoprotein(a) phenotypes in patients with vascular dementia.
AB - We tried to examine if there is a particular distribution pattern of
lipoprotein(a) [Lp(a)] phenotypes specific for patients with vascular dementia
(VD). Fourteen cases of VD (9 males and 5 females), 18 cases of dementia of the
Alzheimer type (DAT)(7 males and 11 females), 29 cases of cerebrovascular disease
(CVD) in the chronic phase (18 males and 11 females) and 47 healthy individuals
as controls (25 males and 22 females) were examined for serum Lp(a). Serum
concentrations and phenotypes of Lp(a) were assessed by ELISA and a test kit for
the Lp(a) phenotype, respectively. Serum concentrations of Lp(a) were
significantly higher in patients with VD (p < 0.05) as well as patients with CVD
(p < 0.01) compared with those in healthy individuals. Serum concentrations of
Lp(a) did not significantly differ between patients with DAT and healthy
individuals. The incidences of Lp(a) phenotypes containing relatively low
molecular-weight apolipoprotein(a) isoforms were significantly higher in patients
with CVD in the chronic phase (p < 0.05) or those with VD (p < 0.01) compared
with those in healthy individuals. Distribution patterns of Lp(a) phenotypes did
not differ between patients with DAT and healthy individuals. Thus, high serum
levels of Lp(a) could be considered a clinical hallmark to distinguish VD from
DAT. Abnormally high serum levels of Lp(a) in patients with CVD and VD seemed to
be due to specific increases in low-molecular-weight apolipoprotein(a) isoforms
in Lp(a).
PMID- 10765045
TI - A 2-year follow-up of behavioural and psychological symptoms in Alzheimer's
disease.
AB - BACKGROUND: The aim was to examine the longitudinal occurrence and persistence of
behavioural and psychological symptoms of dementia (BPSD) in Alzheimer's disease
(AD). METHODS: Following 60 patients with mild to severe AD over a period of 2
years with annual evaluations, the prospective occurrence and persistence of BPSD
in AD were determined by using the Behavioural Abnormalities in AD Rating scale
(BEHAVE-AD). Clinical and demographic features of the AD patients were analysed
for their association with course features of these symptoms. RESULTS: All of the
60 AD patients experienced BPSD at some point during the 2-year period,
particularly agitation was present in every patient within this period. 2-year
persistence of BPSD in AD was frequently observed in patients with agitation and
with depressiveness, with less frequency in patients with anxiety and
aggressiveness, but not in patients with delusions or hallucinations. 2-year
persistent aggressiveness was associated with older age and more functional
impairment. More functional impairment was also related to 2-year non-persistent
hallucinations. CONCLUSIONS: Counselling AD patients and their families and
tailoring therapeutic strategies should take into account the different modi of
BPSD in AD occurring and persisting longitudinally and interacting with
functional disturbances.
PMID- 10765044
TI - Features of regional cerebral glucose metabolism abnormality in corticobasal
degeneration.
AB - We studied regional cerebral glucose metabolism in 15 patients with a clinical
diagnosis of corticobasal degeneration (CBD), 15 patients with probable
Alzheimer's disease (AD), and 15 healthy controls for 19 brain regions. Asymmetry
in regional glucose metabolism was found in the central and frontal cortices in
patients with CBD as compared with either the normal controls or the patients
with AD. Regional glucose metabolism in CBD patients was significantly lower in
the paracentral and superior parietal areas and thalamus than in patients with
AD. Relative glucose metabolism in patients with CBD was significantly higher in
the posterior cingulate, medial temporal and basal frontal areas, and
significantly lower in the paracentral and superior parietal areas than in those
with AD. These features of regional glucose metabolic abnormality in CBD may
correspond to neurological and cognitive disturbances peculiar to CBD.
PMID- 10765046
TI - A single-photon emission computed tomography imaging study of driving impairment
in patients with Alzheimer's disease.
AB - Single-photon emission computed tomography (SPECT) was used in this study to
examine the neurophysiologic basis of driving impairment in 79 subjects with
dementia. Driving impairment, as measured by caregiver ratings, was significantly
related to regional reduction of right hemisphere cortical perfusion on SPECT,
particularly in the temporo-occipital area. With increased severity of driving
impairment, frontal cortical perfusion was also reduced. Clock drawing was more
significantly related to driving impairment than the Mini-Mental State
Examination (MMSE). Driving impairment in Alzheimer's disease is related to
changes in cortical function which vary according to the severity of the disease.
Cognitive tests of visuoperceptual and executive functions may be more useful
screening tools for identifying those at greatest risk for driving problems than
examinations like the MMSE that are weighted toward left-hemisphere-based verbal
tasks.
PMID- 10765047
TI - Comparison between multiple lacunar infarcted patients with and without dementia
in nursing homes in shimane prefecture, Japan.
AB - We evaluated the activity of daily living (ADL) scores, the frequency of
hypertension (HT) and diabetes mellitus (DM), and the frequency and distribution
of white matter lesions in a vascular dementia group with multiple lacunar
infarctions (VD group; 20 cases) and a nondemented group with multiple lacunar
infarctions (non-D group; 32 cases), relative to a normal control group (29
cases). There were no significant differences in HT and DM among the three
groups. ADL scores were significantly lower in the VD than in the non-D group,
each of which was lower than in the control group. Frequency of white matter
lesions (Binswanger's disease-like lesions in the frontal and parietal lobes) was
significantly higher in the VD than in the non-D group, which was higher than in
the control group. We believe that for dementia with multiple lacunar
infarctions, diffusely affected cerebrum including white matter lesions, which
results in low ADL scores for symptoms, may be a prerequisite.
PMID- 10765048
TI - A longitudinal population study of the mini-mental state examination in the very
old: relation to dementia and education.
AB - We examined the Mini-Mental State Examination (MMSE) in relation to the
prevalence and incidence of dementia in a representative population sample (n =
494), followed from age 85 to 88. The study included a neuropsychiatric
examination (including the MMSE) and a key informant interview conducted by a
psychiatrist. Dementia was defined according to the DSM-III-R. Among non-demented
85-year-olds, 75% of those who scored below the cut-off score of 23/24 and 37% of
those scoring 24-25 became demented during the follow-up. Non-demented 85-year
olds who did not develop dementia during the following 3 years had a mean decline
in MMSE score of 0.6 per year, while those who became demented decreased by 2.3
points per year. A decrease of 4 or more points during the 3 years had a
sensitivity of 83% and a specificity of 80% for a diagnosis of dementia. High and
low MMSE score at base-line was related to a smaller decrease in MMSE score
between age 85 and 88. Higher education was related to higher scores on MMSE at
age 85 and to a smaller decline in scores between age 85 and 88. Change in MMSE
score in non-demented individuals is small especially among individuals with high
education. Non-demented individuals scoring below 26 should receive close
attention, as a high proportion are at risk of developing dementia.
PMID- 10765049
TI - Alzheimer disease and vascular dementia: relationships with fasting glucose and
insulin levels.
AB - Cerebrovascular disease and Alzheimer disease are the leading causes of dementia
in elderly subjects. In spite of it, relatively little is known about the
pathogenesis and risk factors for dementia. We evaluated fasting plasma glucose
and insulin, albumin, lipids, Lp(a) and uric acid levels in nondiabetic patients
of both sexes affected by vascular dementia (VD) and senile dementia of the
Alzheimer type (SDAT) as well as in a control group of age-matched nondemented
subjects. Following a covariance analysis by gender, body mass index, albumin
levels and prevalence of arterial hypertension, total and LDL cholesterol as well
as HDL cholesterol levels were not significantly different among the three
groups. Fasting glucose (p < 0.001 and p < 0.005, respectively) and insulin
levels (p < 0.05 for both differences) were higher in patients with VD and SDAT
than in control subjects. Our data show that nondiabetic patients with VD or SDAT
have higher fasting glucose and insulin levels than healthy control subjects.
These metabolic characteristics were not influenced by differences in gender,
adiposity, nutritional status, lipids or presence of arterial hypertension.
PMID- 10765050
TI - Therapies in muscular dystrophy: current concepts and future prospects.
AB - In the fast moving field of muscular dystrophy, therapeutic matters are now high
on the agenda. Despite little progress made in the understanding of the exact
pathogenesis, hopes have been raised with the advent of molecular medicine
applied to such disorders. A constellation of techniques or therapeutic solutions
are now available, but very few have reached the clinical stage. Gene therapy,
cell therapy and pharmacological therapy look more promising, but their clinical
application may still take years. We review the various alternatives and suggest
that some of them might be used in combination.
PMID- 10765051
TI - Angiotensin-converting enzyme gene deletion polymorphism determines an increase
in frequency of migraine attacks in patients suffering from migraine without
aura.
AB - Many authors have reported an association between the angiotensin-converting
enzyme (ACE)-D allele and coronary heart disease and other cardiovascular
diseases. The mechanism underlying the positive associations between the ACE-D
alleles and diseases are not yet clear. Previous reports showed an association
between migraine without aura and ACE-D allele polymorphism. The study is aimed
to evaluate if the DD genotype could also be associated with the frequency and
duration of migraine without aura. In 302 patients suffering from migraine
without aura (at least for 1 year), with no history of cardiovascular diseases
and major risk factors for ischemic events, the genotypes of the ACE gene, plasma
ACE activity, and the frequency (weekly) and duration of migraine attacks were
evaluated. No drugs were given before (4 weeks) and during the study. The same
evaluations were performed in 201 subjects without migraine. The molecular
biologist and the physician evaluating the patient data were blinded to the
clinical history and ACE-DD gene determination. Genotypes were determined by
polymerase chain reaction amplification. Plasma ACE activity was performed by the
HPLC method. The groups were similar for sex, age and smoking habit (migraines:
302 patients (200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects
(127 F/74 M), mean age 37.5 +/- 9.3 years). Patients with migraine without aura
showed higher incidence of the ACE-DD gene (48.34%) than control subjects
(37.32%), p < 0.05. The frequency of migraine (average attacks per week) was
higher in patients with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1.
44), p < 0.05. No difference in duration of migraine attacks (hours per week) was
observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our
data suggest that ACE-DD gene polymorphism could have an important role in
determining migraine attacks and the frequency of these attacks. Further data are
needed through further studies, especially on the biomolecular level.
PMID- 10765052
TI - Continuous facial myokymia in multiple sclerosis: treatment with botulinum toxin.
AB - Continuous facial myokymia (CFM) is an involuntary undulating, vermicular
movement that spreads across facial muscles and is associated with a
characteristic electromyographic pattern. It is an infrequent clinical sign that
almost always occurs in intrinsic brainstem lesions, particularly in multiple
sclerosis (MS). It is usually present for only a few weeks, but it may persist
for long periods of time being very troublesome for patients. We report 2 cases
with MS and continuous hemifacial myokymia persisting for up to 1 month which
disappeared after injection of botulinum toxin. Botulinum toxin A (BTX-A) has
been used successfully to treat a variety of focal dystonias and occasionally in
orbicularis myokymia, but its use has not been reported in continuous hemifacial
myokymia. BTX-A appears to be effective and safe for treating persistent facial
myokymia in MS patients.
PMID- 10765053
TI - Blink reflexes and lateral spreading in patients with synkinesia after Bell's
palsy and in hemifacial spasm.
AB - We compared various electrodiagnostical tests in patients with hemifacial spasm
and in patients who developed synkinesia after Bell's palsy. We examined the
evoked blink reflexes in the orbicularis oculi (o. oculi) and orbicularis oris
(o. oris) muscles in 23 patients with hemifacial spasm (HFS), in 10 patients with
synkinesia after Bell's palsy (BPS) and in 22 control subjects. In the patient
groups, we recorded synkinesia, latency and amplitude of compound muscle action
potential (CMAP) in the mental muscle after stimulation of the facial nerve and
we examined electromyographic activity of the o. oculi and mental muscles
synchronously. Furthermore, we studied the phenomenon of lateral spreading, also
known as ephaptic transmission, between the different facial nerve branches.
Patients with BPS had a prolonged R1 latency on the affected side in o. oculi and
smaller mental CMAP amplitude as an indication of facial nerve damage and nerve
fiber loss. This was not found in patients with HFS, who showed an increased
amplitude of the R1 and R2 responses in o. oris. Patients with BPS showed only an
increased R1 amplitude in o. oris. All patients had signs of synkinesia. Lateral
spreading with different patterns was present in all patients with HFS and in
half of the patients with BPS. Latencies of early and late responses showed no
differences between HFS and BPS. In addition to alterations in facial nucleus
excitability in both conditions, ectopic re-excitation of facial nerve axons in
HFS may explain the differences in neurophysiological findings between HFS and
BPS patients. A loss of control following synaptic stripping may also be a
contributing factor.
PMID- 10765054
TI - The development of synkinesis after facial nerve paralysis.
AB - In this study, the development of clinical synkinesis after facial nerve
paralysis (FP) and its relationship to electrophysiological findings were
investigated. Thirty-four patients who were examined within the first 5 days
after onset of FP and who could also be followed up for at least 4 months were
included in the study. Electrophysiological investigations consisted of: (1)
recording of the direct responses by facial nerve stimulation at the stylomastoid
fossa; (2) recording of the 'synkinetic spread' of the supraorbital nerve reflex
to the lower facial muscles; (3) recording of the 'lateral spread responses' by
stimulating the mandible and zygomatic branches of the facial nerve. Clinical
synkinesis developed in 14 of 18 patients (78%) with a direct response ratio
(DRr) of less than 40%. Among the 16 patients with a DRr of 40% or more,
synkinesis was observed in 3 cases (18.7%) only. The DRr provided reliable
information concerning the development of synkinesis. Forty percent seemed to be
a reasonable limit to distinguish the high-risk group for the development of
clinical synkinesis.
PMID- 10765055
TI - Shoulder, elbow and wrist components of physiologic tremor amplitudeas measured
using a laser penlight.
AB - OBJECTIVE: To measure the amplitude of physiological tremor in normal subjects
using a novel method in an attempt to characterize some of the components of
physiological tremor. BACKGROUND: Current methods of measuring tremor are limited
in their capability of measuring the contributions of various limb segments to
physiologic tremor. DESIGN AND METHODS: Subjects were asked to hold a laser
penlight aimed at a target. Photographs with an exposure of 1 s were taken to
record the path of the light. The angle of deflection was calculated under
various conditions by averaging the results from four trials spaced at 15-second
intervals. RESULTS AND CONCLUSIONS: The maximum amplitude under all conditions
tested was less than 0.25 degrees. Contributions from the wrist and fingers were
significantly greater than contributions from the elbow or shoulder. Rotational
movements were significantly more prominent than movements in other planes at the
shoulder but not the elbow or wrist.
PMID- 10765056
TI - Age-dependent change in the levels of Abeta40 and Abeta42 in cerebrospinal fluid
from control subjects, and a decrease in the ratio of Abeta42 to Abeta40 level in
cerebrospinal fluid from Alzheimer's disease patients.
AB - In order to address an age-dependent alteration in the concentration of beta
amyloid polypeptides (Abetas) within the central nervous system and its probable
predisposition to amyloidgenesis in Alzheimer's disease (AD), we measured two
species of soluble Abetas, Abeta40 and Abeta42, in cerebrospinal fluids (CSF)
from randomly selected Japanese control subjects at various ages (n = 33) and
then compared these data with those of probable Japanese AD patients (n = 23).
CSF concentrations of Abeta40 and Abeta42 peptides were age-dependent (ANOVA,
Bonferroni's multiple comparison; p < 0.01 and p < 0.05, respectively) and were
lower in the infant than in adults. From mid-20, the Abeta40 concentrations were
decreasing while Abeta42 were rather stable. Abetas in CSF from AD patients (n =
23), whose epsilon4 allele frequency of the apolipoprotein E gene was higher than
in controls (n = 83, p < 0.03), were not statistically different from those of
age-matched controls (n = 13). A linear relationship was detected between the
Abeta40 concentration and the Mini-Mental State Examination score (p < 0.05). The
ratio of the Abeta42 to the Abeta40 level measured in the AD CSF samples was
approximately 38% decreased compared to age-matched controls (p < 0. 05). These
data suggest that the physiological metabolism of soluble Abetas in the brain is
regulated in an age-dependent manner, and that the ratio of Abeta42 to Abeta40
level in the CSF would be a useful marker for monitoring progression of AD.
PMID- 10765057
TI - Age-dependent decline in the apolipoprotein E level in cerebrospinal fluid from
control subjects and its increase in cerebrospinal fluid from patients with
Alzheimer's disease.
AB - In order to address the significance of apolipoprotein E (apoE) in the
pathogenesis as well as the clinical diagnosis of Alzheimer's disease (AD), we
measured its level in cerebrospinal fluid (CSF) from randomly selected Japanese
control subjects at various ages (n = 36), which included 14 age-matched
controls, and from AD patients including early-onset (n = 11, EOAD) and late
onset (n = 14, LOAD) cases. The CSF apoE level in controls linearly decreased
during aging to over 80 years (r(2) = 0.323, p < 0.0001). The CSF apoE level in
AD patients was 31.9% elevated compared to the age-matched controls (n = 14, p <
0.05) and linearly increased with a decrement of the patients' Mini Mental State
Examination scores. Moreover, the CSF apoE level of EOAD patients (n = 11) was
higher than that of LOAD patients (n = 14, p < 0.05), whose APOE epsilon4 allele
frequency was significantly higher than that of controls (chi(2) = 7. 16, p <
0.03). Two-dimensional gel electrophoretic analysis of the heparin-Mn(2+)
precipitable lipoprotein fraction in CSFs showed that the ratio between the level
of CSF apoA-I and that of CSF apoE of controls was significantly higher than
those of all AD and LOAD subjects (p < 0.01, p < 0.05), while the CSF apoA-I-to
apoE ratios of the two AD groups were not significantly different. These results
suggest that overproduction of apoE protein may be a consequence of astroglial
response to neurodegeneration in AD and that the determination of CSF
apoliprotein levels serves as a clinical marker for monitoring the progression of
AD.
PMID- 10765058
TI - Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells
from multiple sclerosis patients.
AB - Several authors report that human herpesvirus 6 (HHV-6) variants have different
epidemiologies, in vivo tropism and pathogenic potentials. However, it is not
well known what pathogenic roles its neurotropism might have in the variant type.
As some active plaques of multiple sclerosis (MS) brain tissue harbor HHV-6 DNA
divergent from the prototype virus, the possibility that the variant strain may
play a role in the pathogenesis of MS has been suggested. Therefore, we tried to
investigate the role of HHV-6 variants in the pathogenesis of MS. As HHV-6 is
predominantly a T-cell-tropic virus, we examined HHV-6 DNA sequences in
peripheral blood mononuclear cells (PBMC) from 34 MS patients, 6 with idiopathic
transverse myelitis, 2 with optic neuritis and 20 healthy controls. Nested
polymerase chain reaction was used to detect the HHV-6 genome. To discern HHV-6
variants A and B, amplification products were digested by restriction enzyme. We
found that 7 of 34 MS patients and 2 of 6 patients with idiopathic transverse
myelitis had the HHV-6 genome. On the contrary, there was no HHV-6 genome in the
control group. All genomic sequences were of HHV-6 variant A (HHV-6A). Our
results suggest that the detection of HHV-6A in the PBMC of patients with MS may
raise the possibility of a relationship between latent HHV-6A infection and the
pathogenesis of MS.
PMID- 10765059
TI - Characteristic expression of thrombomodulin in the muscle sarcoplasm in patients
with the acute phase of rhabdomyolysis.
AB - The expression of thrombomodulin and neural cell adhesion molecule (NCAM) was
studied immunocytochemically in biopsied muscle specimens from 10 patients with
rhabdomyolysis with different etiologic factors, including 5 with malignant
hyperthermia. We have already reported that thrombomodulin was expressed on
regenerating muscle cell membranes as well as on vessel walls in patients with
various neuromuscular diseases, including Duchenne muscular dystrophy, Becker
muscular dystrophy and inflammatory myopathy. We found increased expression of
thrombomodulin not only on the sarcolemma, but also in the sarcoplasm of a fair
number of muscle fibers in the acute phase of rhabdomyolysis. The granular
pattern of thrombomodulin expression in the sarcoplasm seems to be a
characteristic finding in the acute phase of rhabdomyolysis. Most muscle fibers
which expressed NCAM on the sarcolemma also expressed thrombomodulin. However,
the muscle fibers which expressed thrombomodulin in the sarcoplasm did not
express NCAM, and showed a degenerative appearance on electron microscopic
examination. These results suggest that thrombomodulin is expressed in the
sarcoplasm during the acute degeneration phase of rhabdomyolysis in addition to
the expression on the sarcolemma during the muscle fiber regeneration as shown in
our previous study, and the former process, which is characterized by the
granular expression of thrombomodulin in the sarcoplasm, may be a characteristic
finding in rhabdomyolysis.
PMID- 10765060
TI - Combined amphetamine and cocaine abuse caused mesencephalic ischemia in a 16-year
old boy - due to vasospasm?
PMID- 10765061
TI - Cervical myelopathy following lumbar herpes zoster.
PMID- 10765062
TI - Resolution of transient ischemic attacks and aortic arch thrombi on anticoagulant
therapy.
PMID- 10765063
TI - Escalating immunotherapy with mitoxantrone in patients with very active relapsing
remitting or progressive multiple sclerosis.
PMID- 10765064
TI - Diagnosis of Hallervorden-Spatz disease using MRI, (123)I-beta-CIT-SPECT and
(123)I-IBZM-SPECT.
PMID- 10765065
TI - Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human
benign prostatic hyperplasia.
AB - OBJECTIVE: The development of the human benign prostatic hyperplasia clearly
requires a combination of testicular androgens and aging. Although the role of
androgens as the causative factor for human benign prostatic hyperplasia is
debated, they undoubtedly have at least a permissive role. The principal
prostatic androgen is dihydrotestosterone (DHT). Although not elevated in human
benign prostatic hyperplasia, DHT levels in the prostate remain at a normal level
with aging, despite a decrease in the plasma testosterone. RESULTS: DHT is
generated by reduction of testosterone. Two isoenzymes of 5alpha-reductase have
been discovered. Type 1 is present in most tissues of the body where 5alpha
reductase is expressed and is the dominant form in sebaceous glands. Type2 5alpha
reductase is the dominant isoenzyme in genital tissues, including the prostate.
Finasteride is a 5alpha-reductase inhibitor that has been used for the treatment
of benign prostatic hyperplasia and male-pattern baldness. At doses used
clinically, its major effect is through suppression of type 2 5alpha-reductase,
because it has a much lower affinity for the type 1 isoenzyme. Finasteride
suppresses DHT by about 70% in serum and by as much as 85-90% in the prostate.
The remaining DHT in the prostate is likely to be the result of type 1 5alpha
reductase. Suppression of both 5alpha-reductase isoenzymes with GI198745 result
in greater and more consistent suppression of serum dihydrotestosterone than that
observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and
clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745,
with selective type 2, such as finasteride, will be needed to determine the
clinical relevance of type 1 5alpha-reductase within the prostate. Two large
international multicenter, phase III trials have been published documenting the
safety and efficacy of finasteride in the treatment of human benign prostatic
hyperplasia. Combining these two studies, randomized, controlled data are
available for 12 months. Noncontrolled extension of these data from a subset of
patients, who elected to continue drug treatment for 3, 4 or 5 years, are also
available. Long-term medical therapy with finasteride can reduce clinically
significant endpoints such as acute urinary retention or surgery. According to
the meta-analysis of six randomised clinical trial with finasteride, finasteride
is most effective in men with large prostates. A more effective dual inhibitor of
type 1 and 2 human 5alpha-reductase may lower circulating DHT to a greater extent
than finasteride and show advantages in the treatment of human benign prostatic
hyperplasia and other disease states that depend on DHT. CONCLUSION: Clinical
evaluation of potent dual 5alpha-reductase inhibitors may help define the
relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of
benign prostatic hyperplasia and other androgen-dependent diseases.
PMID- 10765066
TI - Large benign prostatic hyperplasia means impossible ureteroscopy: myth or
reality?
AB - OBJECTIVE: We intended to ascertain the true role played by large-size prostatic
glands with BPH in impeding ureteroscopy; since no such impediment was
experienced by the authors, we then listed the most frequent obstacles to
ureteroscopy, contrary to what is commonly reported in literature. MATERIALS AND
METHODS: Endourological reports on a series of 2,147 diagnostic or therapeutic
ureteroscopies were examined, together with the patients' clinical records. Male
patients accounted for 1,288 cases. In 45 cases, the operators found the prostate
so enlarged as to be worthy of note. In 9 of these cases, the procedure was
performed bilaterally; thus, a total of 54 ureteroscopies was undertaken in
patients with enlarged prostates or large median lobes. RESULTS: None of the
surgical reports indicated that the ureteroscopic procedure was hindered by an
enlarged prostate. On the other hand, the most frequent causes preventing
ureteroscopy are, for both male and female patients, some types of tumor:
uterine, ovarian, ureteral, bowel, bladder and prostate cancer, and inflammation.
CONCLUSIONS: Benign prostatic hypertrophy (BPH) is not of itself an impediment to
ureteroscopy when it is performed by an expert operator equipped with suitable
instruments. On the other hand, tumours of the female reproductive system, as
well as bladder and prostate tumours and serious inflammations and infections may
make the procedure impossible or cause serious problems during its performance,
at times requiring combined antegrade and retrograde maneuverings. At the root of
this obstacle lies neoplastic or inflammatory infiltration and stiffening which
attaches itself to the organs and hardens their connections. In the case of BPH,
we do not find infiltration, but only a dislocation, which can be compensated by
means of a few technical stratagems. Some interesting expedients in the
incannulation of difficult meatuses were already suggested in 1914 by Heitz-Boyer
and Marion.
PMID- 10765067
TI - Diagnosis and management of eosinophilic cystitis: a pooled analysis of 135
cases.
AB - OBJECTIVE: Eosinophilic cystitis is a rare disease. We reviewed the literature
for clinical presentation, diagnosis and therapeutic options to establish
recommendations for diagnostic and therapeutic management. METHODS: A pooled
analysis was performed of 135 patients with eosinophilic cystitis presented in
the literature. The evaluation included patient age, sex and race, presenting
symptoms, diagnostic examinations, treatment and results, and complications.
RESULTS: The mean age at diagnosis was 41.6 years (range 5 days to 87 years). An
equal distribution existed between males (44%) and females (35%), but in children
(21%) boys were more often affected (14%) than girls (7%). The most common
presenting symptoms were frequency (67%), dysuria (62%), gross/microscopic
hematuria (68%), suprapubic pain (49%) and urinary retention (10%). All patients
had a cystoscopy and biopsy; a biopsy is mandatory to establish the diagnosis.
Positive urine cultures were found in 26% of the patients. Periferal eosinophilia
was present in 43%. An intravenous urography was performed in 66%,
ultrasonography in 15%, cystography in 23% and a CT scan in 10%. The majority of
patients was treated with combinations of corticosteroids, antihistaminics and
antibiotics (45%), avoiding of the suspected antigen (17%), transurethral
resection of the lesions (9%), partial cystectomy (4%) or total cystectomy (4%).
The success rates for the different treatments were variable: transurethral
resection combined with corticosteroids, antihistaminics or antibiotics seemed
most successful, while total cystectomy is reserved for patients with
unresponsive disease and hematuria. The most common complications were dilation
of the upper urinary tract (27%) and eosinophilic gastroenteritis (4.5%); all
other complications occurred in less than 3% of the patients. CONCLUSION:
Eosinophilic cystitis is equally distributed among the sexes, but in children
boys are affected more often than girls. The presenting symptoms are frequency,
dysuria, hematuria, suprapubic pain and urinary retention. The treatment of
choice is (radical) transurethral resection of the lesions in the bladder and a
combination of corticosteroids and antihistaminics. Antibiotics are given when a
urinary tract infection is present, or when dilation of the upper urinary tract
exists. Most patients are cured but recurrence is a frequent finding.
PMID- 10765068
TI - The role of Borrelia burgdorferi in interstitial cystitis.
AB - BACKGROUND/AIMS: Borrelia burgdorferi spirochete has been found both in bladder
biopsies and the urine of patients with Lyme disease (LD) as well as in
experimental animals. The urological symptoms in borreliosis resemble those of
interstitial cystitis (IC): frequency, urgency and nocturia. The aim of this
studies is to find the role of B. burgdorferi in interstitial cystitis. METHODS:
We studied antibodies against B. burgdorferi from serum samples of 50 IC patients
with two separate EIA tests. Patients with positive serology in both tests
underwent cystoscopy and a bladder biopsy was taken. The presence of borrelia DNA
was studied with borrelia-specific polymerase chain reaction (PCR), and with
universal bacterial PCR. RESULTS: IgM class antibodies to B. burgdorferi were not
found, but IgG antibodies were found in four samples (8%). This was higher than
in the control material (2%). One patient's sample was strongly positive, whereas
three samples were weakly positive. Bladder biopsies taken from the 4 patients
were negative for borrelia DNA in both PCR tests. None of the seropositive
patients had any symptoms consistent with LD. CONCLUSION: These results indicate
that persistent infection of B. burgdorferi has no role in the etiology of IC. On
the other hand a connection with a past borrelia infection and IC is not
excluded.
PMID- 10765069
TI - Correlation between chronic prostatitis syndrome and pelvic venous disease: a
survey of 2,554 urologic outpatients.
AB - OBJECTIVES: In this study we evaluated the association between chronic
prostatitis syndrome (CPS), varicocele and hemorrhoids as manifestations of a
pelvic venous disease. METHODS: Our retrospective study was based upon 2,554
patients treated in two general urology clinics over the past 10 years. We have
assessed the incidence of CPS among urological patients. RESULTS: We found 483
patients with CPS, representing 18.9% of the total number of visits at the
outpatient clinic. In this group the percentage of varicocele and hemorrhoids was
14.69 and 8.48%, whereas in a control group these figures were 5.02 and 5.84%,
respectively (p<0.001 and 0.1054). Such a difference is statistically significant
and suggests a higher prevalence of varicocele in the CPS group, but this may be
due to a methodological error of the retrospective study. CONCLUSION: Only a
prospective study, which is of importance due to the frequency of the disease,
can give a precise answer to this question.
PMID- 10765070
TI - Inflammation in prostate biopsies of men without prostatic malignancy or clinical
prostatitis: correlation with total serum PSA and PSA density.
AB - OBJECTIVE: Inflammation is a frequent histological finding in prostate biopsies,
performed on men without prostatic malignancy or clinical prostatitis. We
investigated the relationship between morphological parameters of inflammation in
prostatic tissue and total serum prostate-specific antigen (PSA) and prostate
specific antigen density (PSAD) levels to determine if subclinical inflammation
can cause elevation of PSA and PSAD. METHODS: We reviewed 268 prostate biopsies,
performed on 238 men with elevated PSA and/or abnormal digital rectal examination
of the prostate. All premalignant and malignant biopsies and cases of clinical
prostatitis were excluded. The inflammation in the remaining 145 prostate
biopsies was scored for extent of inflammation and aggressiveness of
inflammation, using the four-point scale designed by Irani and co-workers. In
this prostatic inflammation scoring system, extent of inflammation is graded from
0 up to 3 according to the degree of invasion of inflammatory cells in prostatic
tissue. Aggressiveness of inflammation is graded from 0 up to 3 according to the
degree of contact or disruption of prostatic glandular epithelium by inflammatory
cells. RESULTS: Each of the studied biopsies showed inflammatory cells. Median
PSA levels in grades 1, 2 and 3 of extent of inflammation were, respectively,
5.7, 6.8 and 13. 0. Median PSAD levels in these groups were 0.13, 0.16 and 0.33.
There was no significant difference between these grades for PSA nor for PSAD.
Median PSA levels in grades 0, 1 and 2 of aggressiveness of inflammation were,
respectively, 3.9, 5.9 and 8.9. Median PSAD levels in these groups were 0.12,
0.18 and 0.17. For both parameters, there was a significant difference between
grades (respectively, p = 0.0028 and p = 0.0330). CONCLUSION: Inflammation of the
prostate is a histological finding in almost every set of prostate biopsies, even
when there are no signs of clinical prostatitis. This subclinical inflammation
can cause PSA elevation. Not the extent of inflammation is of importance, but the
disruption of epithelial integrity caused by the inflammatory infiltrate. When
confronted with a patient with an elevated PSA level whose prostate biopsies
reveal no malignancy but only inflammation, this concept can help in determining
the need for quick repeat biopsies.
PMID- 10765071
TI - Risk factors for lower urinary tract symptoms in elderly men. For the Prostate
Study Group of the Austrian Society of Urology.
AB - OBJECTIVE: The aim of this study was to confirm previous studies with respect to
risk factors for lower urinary tract symptoms (LUTS) as assessed by the
International Prostate Symptom Score (IPSS) as well as, for the first time,
specifically for storage and voiding symptoms in elderly men. MATERIAL AND
METHODS: During a health survey organised in the area of Vienna in 1996, the
following parameters were obtained: (1) IPSS including the quality of life
question; (2) a detailed medical history; (3) assessment of all concurrent
medical therapies; (4) physical examination with assessment of age, weight,
height, body mass index, heart rate and blood pressure; (5) sociodemographic
parameters, and (6) a blood laboratory study including kidney and liver function
tests, low- and high-density lipoproteins, cholesterol and glucose. Only men aged
40 years or older without previous surgery to the prostate and without concurrent
medication for LUTS were analysed. The IPSS, its irritative (storage symptoms)
and obstructive (voiding symptoms) components were correlated to these parameters
by partial correlation analysis which was controlled for age. RESULTS: The data
of 1,557 men (mean age: 51.3 years; range: 40-96 years) were analysed. The most
important risk factor for the development of LUTS was age, as the IPSS
(correlation coefficient r = 0.294), its obstructive (r = 0.248) and irritative
(r = 0.261) components all correlated significantly (p<0.0001) with patient age.
In all life decades there was no significant difference of the IPSS, its
obstructive and irritative components in current smokers and non-smokers. The
irritative score, however, correlated significantly (p = 0.001; r = 0.158) with
the number of cigarettes smoked per day. In men aged 40-49 years, regular alcohol
consumption resulted in a higher total IPSS (p = 0.01) and irritative (p = 0.002)
score. This difference was not demonstrable in older age groups. Patient weight
and body mass index did not correlate with the IPSS, yet there was a trend for a
higher IPSS in men with elevated blood pressure and larger waist size.
CONCLUSIONS: This large-scale cross-sectional study underlines the importance of
age for the development of LUTS. Few avoidable risk factors for the development
of LUTS have been identified, such as obesity, cigarette smoking, elevated blood
pressure and alcohol consumption. The subcategorization of LUTS into
irritative/obstructive symptoms might provide new insights into the assessment of
risk factors for LUTS.
PMID- 10765072
TI - Safety and efficacy of sustained-release alfuzosin on lower urinary tract
symptoms suggestive of benign prostatic hyperplasia in 3,095 Spanish patients
evaluated during general practice.
AB - OBJECTIVES: This general practitioner-run study assess the security as well as
the efficacy and impact on health-related quality of life of a sustained-release
(SR) form of alfuzosin in Spanish patients suffering from lower urinary tract
symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). MATERIAL AND
METHODS: 3,095 patients with symptomatic BPH were enrolled into a national,
multicentric, open, phase IV observational study. The period of active treatment
studied (5 mg, twice daily) was 60 days. Safety was assessed by monitoring blood
pressure and spontaneous adverse events. Symptoms were assessed using a validated
Spanish International Prostate Symptom Score (I-PSS). Impact of symptoms on
health-related quality of life was assessed using the quality of life index (L).
RESULTS: 101 adverse events were reported in 82 patients (2.6%). 28 adverse
events (2.6%) were classified as severe. 49 patients (1.6%) dropped out of the
study due to adverse events but only 17 of these patients (0.5%) showed adverse
events related to vasodilation. Incidence of postural events (vertigo, postural
hypotension/hypotension, headache and dizziness) was low (55 patients, 1.8%) and
effects on sexual function were found not significant: no retrograde ejaculation
was reported and only 1 patient (0.03%) showed impotence. Blood pressure or heart
rate showed no clinically significant changes. All the I-PSS scores decreased
significantly during the treatment with alfuzosin, improvement being excellent in
60% of the patients. Symptomatic improvement was associated with a significant
improvement in health-related quality of life. CONCLUSIONS: This large study
conducted during general practice on Spanish BPH patients confirms the efficacy
on LUTS and good safety profile of SR alfuzosin, especially its low incidence of
postural symptoms and no deleterious effect on sexual function.
PMID- 10765073
TI - Effects of mepartricin (S-160) on spontaneous canine benign prostatic
hyperplasia.
AB - OBJECTIVE: The effects of mepartricin (S-160) on spontaneous canine benign
prostatic hyperplasia (BPH) were investigated by histological, histochemical and
biochemical analysis. METHODS: Aged beagle dogs (5-9 years old) with
spontaneously developed BPH were treated orally with a placebo or S-160 (5, 10 or
20 mg/kg/day) for 8 weeks. The methodology included measurement of prostatic
volume by transrectal ultrasonography, qualitative evaluation of prostatic
morphology, determination of plasma and intraprostatic estradiol level by
radioimmunoassay and immunohistochemical detection of estrogen receptors and
androgen receptors in the prostate. RESULTS: S-160 significantly reduced the
prostatic volume and regressed histologically the hyperplastic grade of prostate,
and also fairly decreased the plasma and intraprostatic estradiol concentration
and the estrogen and androgen receptors in the prostate. CONCLUSIONS: These
results suggest that the reduction of estradiol and estrogen receptors in the
prostate may play a crucial role in the regression of BPH by S-160.
PMID- 10765074
TI - Doppler resistive index in benign prostatic hyperplasia: correlation with
ultrasonic appearance of the prostate and infravesical obstruction.
AB - OBJECTIVE: This study was designed to characterize the resistive index (RI) of
prostatic blood flows obtained by transrectal power Doppler sonography (TRPDS) in
benign prostatic hyperplasia (BPH). METHOD: In 140 patients with lower urinary
tract symptoms, the RI was measured using TRPDS and compared with age and
planimetric parameters of the prostate obtained by conventional transrectal
sonography. In addition, the RI was related with pressure flow studies. RESULTS:
The RI was significantly higher in patients with BPH (0.72+/-0.06, p<0.0001) than
those with a normal prostate (0. 64+/-0.04). Although the RI correlated
significantly with age and all prostatic planimetric parameters, multiple
regression analysis revealed that age and presumed circle area ratio were
independent predictors for RI. The RI was also higher in patients with
infravesical obstruction than those without (0.74+/-0.06 vs. 0. 70+/-0.05,
p<0.005). There was a significant correlation between RI and urodynamic
parameters obtained in pressure flow studies. Out of 33 patients with
obstruction, 28 (85%) had an RI of 0.7 or more, while 11 out of 24 patients (46%)
without obstruction had an RI less than 0.7. CONCLUSION: The RI is promising as a
new parameter to estimate the intraprostatic pressure to investigate BPH. Its
value to represent urodynamic information during voiding remains to be studied.
PMID- 10765075
TI - Peripheral hypoechoic lesions of the prostate: evaluation with color and power
Doppler ultrasound.
AB - OBJECTIVE: To assess the usefulness of color and power Doppler ultrasound in
predicting the benignity and malignancy of the peripheral hypoechoic lesion of
the prostate. METHODS: Thirty-nine patients who had peripheral hypoechoic lesions
on transrectal ultrasound were evaluated with color and power Doppler ultrasound
followed by lesion-specific transrectal ultrasound-guided biopsies. The
interpretation of color and power Doppler ultrasound was not performed separately
and flow signals were categorized using a combination of the two modalities. The
amount of flow signals within the lesion was evaluated and categorized into three
groups: increased/equal/decreased flow compared to surrounding normal tissue on
ultrasound. Doppler spectra could be obtained from the lesions in 23 patients.
The amount of flow signals and resistive indexes of the spectra of the lesions
were compared with those of surrounding normal tissue using the Mann-Whithney U
test. RESULTS: Transrectal ultrasound-guided biopsy of the hypoechoic lesions
revealed prostate cancer in 20 patients and benign prostatic diseases in 19. Flow
signals within the lesions were of increased/equal/decreased flow compared to
surrounding normal tissue in 16/2/2 in the prostate cancer group and 3/9/7 in the
benign disease group, respectively. The difference was statistically significant
(p = 0.0003). Resistive indexes of the lesion were 0.58-1.0 (mean 0.75) in the
prostate cancer group and 0.57-1.0 (mean 0.80) in the benign disease group, and
there was no significant difference between the two groups (p = 0.82). If we
consider an increased flow signal within a peripheral hypoechoic lesion as a sign
of prostate cancer, color power Doppler ultrasound has a sensitivity of 80%, a
specificity of 84%, and an accuracy of 82%. CONCLUSION: Evaluation of peripheral
hypoechoic lesions of the prostate with color and power Doppler may enhance the
diagnostic capability of transrectal ultrasound.
PMID- 10765076
TI - Percentage of cancer on biopsy cores accurately predicts extracapsular extension
and biochemical relapse after radical prostatectomy for T1-T2 prostate cancer.
AB - PURPOSE: To perform a multivariate analysis to investigate the usefulness of
eight preoperative variables as predictors of final pathological stage (pT),
positive surgical margins (PSM) and biological progression after radical
prostatectomy (RP). MATERIALS AND METHODS: In 143 patients undergoing RP for T1
T2 prostate cancer, the respective values of age, clinical stage, preoperative
prostate-specific antigen (PSA), prostate-specific antigen density (PSAD), number
of positive biopsies (NPB), Gleason score, length of tissue core invaded by
cancer (LTI) and topography (uni/bilaterality) of positive biopsies for
predicting extracapsular extension, PSM and biochemical failure (PSA> or =0.05
ng/ml) were evaluated retrospectively. Univariate and multivariate analyses were
applied to define the statistical significance of each variable. Actuarial
survival without biological progression was calculated using the Kaplan-Meier
method (log-rank test). RESULTS: In this series, 44.8% of patients had
extracapsular extension with 41.3% PSM. The mean PSA was 12.4 ng/ml. In
univariate analysis, LTI (p<0.0001), NPB (p = 0.0023), PSA (p = 0.0039) and
Gleason score (p = 0.0136) were the most powerful variables to predict pT stage;
however, in logistic regression analysis, LTI was the most predictive feature.
For prediction of PSM, some variables (LTI, NPB and PSA) were found to be of
statistical value in univariate analysis, and LTI in combination with NPB and PSA
in multivariate analysis. For biological progression, statistical analysis (log
rank test) showed PSAD and LTI to be significant predictors. CONCLUSION: The
pathological report regarding the biopsy contains crucial information influencing
the prediction of pT stage, PSM and biological progression after RP. LTI, NPB and
PSA are the most useful parameters for this purpose.
PMID- 10765077
TI - Effect of high-grade prostatic intraepithelial neoplasia on total and percent
free serum prostatic-specific antigen.
AB - OBJECTIVE: To analyze the influence of high-grade prostatic intraepithelial
neoplasia (HGPIN) on total serum prostatic-specific antigen (PSA) and percent
free PSA. METHODS: Total and free serum PSA were determined in 81 consecutive
patients with clinical T1c prostate cancer who underwent radical prostatectomy.
HGPIN was detected in 62 specimens (76.5%). RESULTS: Median total PSA was 9.2
ng/ml when there was not HGPIN and 8.1 ng/ml when it existed, p>0.05. Median
percent free PSA was 11.7 and 9.1%, respectively, p<0.03. However, a multiple
linear regression analysis demonstrated there was no effect of HGPIN on total PSA
nor on percent free PSA. Percent free serum PSA was significantly influenced by
total PSA and the pathological tumor stage. CONCLUSION: HGPIN does not seem to
contribute significantly on serum total PSA and percent free PSA.
PMID- 10765078
TI - Clinical evaluation of percent free prostate-specific antigen using the AxSYM
system in the best analytical scenario.
AB - OBJECTIVE: Percent free prostate-specific antigen (PSA) is a promising tool for
prostate cancer (CaP) diagnosis. However, its diagnostic performances have not
yet been established. The present study was carried out with the aim of
evaluating percent free PSA in the most favourable analytical conditions.
MATERIALS AND METHODS: Eighty-eight patients affected by newly diagnosed,
untreated, primary CaP, and 169 cases with biopsy-confirmed, untreated, benign
prostatic hypertrophy (BPH) were prospectively enrolled. Abbott AxSYM total and
free PSA were measured by the same technician using the same instrument and the
same reagent batch. RESULTS: Percent free PSA was more effective than total PSA
in differential diagnosis between CaP and BPH in every evaluated dose range of
total PSA. In cases with total PSA >4 microg/l, percent free PSA could have
reduced by about 50% the rate of unnecessary biopsies with a probably still
acceptable 93% cancer detection rate. The likelihood of CaP after the
determination of percent free PSA was in fact higher than 50% using cut-off
points which provide low sensitivity values (i.e. 58% in men aged 50-59 years).
CONCLUSIONS: Percent free PSA is superior to total PSA in distinguishing primary
CaP from BPH in patients with total PSA between 2 and 30 microg/l and in reducing
the rate of unnecessary biopsies in men with total PSA higher than 4 microg/l.
However, percent free PSA should be cautiously interpreted in decision making in
individual patients since post-test probability is relatively low in men aged 50
70 years.
PMID- 10765079
TI - What is the optimal regimen for BCG intravesical therapy? Are six weekly
instillations necessary?
AB - OBJECTIVE: For more than 20 years, BCG intravesical therapy schedule has included
6 weekly instillations. Very few studies have, however, analyzed the rationale of
this regimen. We previously demonstrated that intravesical BCG induced an
increased peripheral immune response against mycobacterial antigens as compared
to pretreatment values. In the present work, we have studied the weekly evolution
of this immune response induced by intravesical BCG instillations. MATERIALS AND
METHODS: The evolution of the lymphoproliferative response of peripheral blood
mononuclear cells against BCG culture filtrate (CF), tuberculin (PPD) and BCG
extract (EXT) was tested before, every week during the BCG instillations and at 3
and 6 months follow-up in 9 patients with superficial bladder cancer treated with
6 weekly BCG instillations. Lymphoproliferation was measured by means of a
tritiated thymidine incorporation test. RESULTS: A significant increase in the
lymphoproliferative response against PPD, CF and EXT was observed in 9, 8 and 7
of the 9 patients, respectively, as compared to pre-BCG values. The maximal
lymphoproliferation was achieved after 4 instillations in 4/5 patients initially
reactive against mycobacterial antigens whereas 2 of 4 initially nonreactive
patients required 6 instillations. At 6 months' follow-up, lymphoproliferation
against BCG and the other mycobacterial antigens returned to pre-BCG values in
all patients. In 3 patients who received additional instillations because of
tumor recurrence within 1 year of follow-up, the maximum immune response was
observed already after 2 instillations. CONCLUSION: In most patients, the maximal
peripheral immune response is already observed after 4 weekly instillations.
However, patients not previously immunized against mycobacterial antigens may
require 6 weekly instillations to achieve a maximum stimulation level. Our data
support the need to further evaluate the role of this status before starting BCG
instillations. It could be of interest to study whether 6 BCG instillations are
really necessary in patients previously immune against mycobacterial antigens.
PMID- 10765080
TI - Transurethral resection and sequential chemo-immunoprophylaxis in primary T1G3
bladder cancer.
AB - OBJECTIVES: T1G3 superficial bladder cancer is considered to be at high risk for
progression, and in some institutions early cystectomy is advocated. Other
authors and personal experience suggest that conservative treatment, such as
TURBT followed by intravesical prophylaxis, may be adequate in the majority of
cases. The purpose of the present phase II study was to assess the tolerability
and efficacy of sequential intravesical administration of a chemotherapeutic
agent, epirubicin, followed by BCG, after TURBT. MATERIALS AND METHODS: 81
patients with primary T1G3 superficial bladder cancer, without evidence of Tis or
upper tract tumor, underwent TURBT and intravesical prophylaxis with weekly
epirubicin 50 mg for 8 weeks followed by weekly BCG Connaught 120 mg for 6 weeks.
A control cystoscopy with bladder mapping and/or TUR of suspicious areas was
performed at 15-17 weeks. Then patients were followed-up with 3-month urinary
cytology and cystoscopy. RESULTS: The sequential chemo-immunoprophylaxis was
generally well tolerated. After a mean follow-up of 48 months recurrent tumors
were found in 19 patients (23.4%) and progressive disease in 6 cases (7.4%). Of 6
progressions, 4 patients died (5%) of the disease. CONCLUSION: Sequential chemo
immunoprophylaxis with epirubicin followed by BCG is well tolerated and seems to
be efficacious in primary T1G3 bladder cancer. The recurrence progression and
disease-specific mortality rates were acceptable so that this study seems to
confirm previous data which show that TURBT and intravesical prophylaxis are
appropriate treatment for the majority T1G3 tumors.
PMID- 10765081
TI - Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from
renal oncocytoma.
AB - OBJECTIVE: Chromophobe renal cell carcinoma is a relatively uncommon variant of
renal carcinoma described in 1985. The main differential diagnosis is renal
oncocytoma. Hale's colloidal iron staining is a powerful adjunct to morphological
interpretation but it is not specific and is sometimes difficult to interpret. We
studied the immunohistochemical expression of cytokeratin 7 to determine its
value in distinguishing chromophobe renal cell carcinoma from renal oncocytoma.
METHODS: Immunostaining was performed on paraffin-embedded tumor tissue of 6
chromophobe renal cell carcinomas and 11 oncocytomas with an antibody to
cytokeratin 7 (clone OV-TL 12/30, Dako, France) using a streptavidin-biotin
method. RESULTS: All chromophobe renal cell carcinomas showed strong cytoplasmic
staining with peripheral cell accentuation. In contrast, 8 of 11 oncocytomas were
entirely negative and 3 showed only weak and focal staining in less than 5% of
the tumor cells. CONCLUSION: Immunohistochemical staining for cytokeratin 7 may
be useful for the differential diagnosis of renal oncocytomas and chromophobe
renal cell carcinomas when Hale's colloidal iron staining is uncertain.
PMID- 10765082
TI - Polymerase chain reaction based method for the detection of BCG retention after
intravesical instillation in guinea pig bladders.
AB - OBJECTIVE: In intravesical Bacille bilie de Calmette-Guerin (BCG) immunotherapy
of superficial bladder cancer, a T cell mediated immunological reaction is
associated with the antitumor activity. To gain insight into the approximate
number of BCG bacteria retained in the normal, noninjured, urinary bladder after
intravesical application responsible for induction of the immune reaction, the
utility of a sensitive polymerase chain reaction (PCR) based assay was
investigated in a guinea pig model. METHODS: After one single or six subsequent
weekly instillations with 1x10(7) CFU of BCG, the bladders were resected and
processed for BCG determination with PCR. The bladders were resected 24 h after
instillation, aiming at (semi)quantifying the number of BCG organisms able to
resist the natural voiding washout of the bladder. The PCR was based on
amplification of a 249 base pair fragment of the insertion element IS6110 and is
specific for bacteria belonging to the Mycobacterium tuberculosis complex which
includes Mycobacterium bovis BCG. RESULTS: After one single instillation no
detectable BCG retention was found. However, after six weekly instillations, BCG
bacteria could be demonstrated in 2 out of 5 guinea pig bladders, indicating that
the number of adhering BCG organisms was around the detection limit of the assay
(600-1,000 BCG bacteria per bladder). CONCLUSIONS: The data suggest that after
six instillations, the retention of BCG in the guinea pig bladder is enhanced as
compared with one single instillation. This finding is suggestive of a role of
the inflammatory process that is, besides immune system mediated reactions,
associated with intravesical BCG instillations. The nature of the molecules
involved in enhanced BCG retention after repeated instillations remains to be
investigated.
PMID- 10765083
TI - Area density of smooth muscle cells and response to endothelin 1 in human
hyperplastic prostate.
AB - BACKGROUND: alpha-Agonists and endothelins (ETs) are the only agents that have
been proved to induce significant contraction of the prostate. Although the
response to phenylephrine (PE) is dependent on the quality of smooth muscle (SM)
within the prostate, it is not clear whether the response to ET-1 is also
influenced by SM density. We evaluate the relationship between contractile
responsiveness to ET-1 and the area density of SM of the human prostate.
MATERIALS AND METHODS: Specimens were obtained from 17 patients with prostatic
hyperplasia that underwent transurethral resection of the prostate. Specimens
were used for isometric tension study (PE, KCl and ET) and also for quantitative
morphometric analysis. RESULTS: PE and ET-1 induced dose-dependent contractile
responses. There were no significant differences in the average maximum response
(E(max)) to these two agents. E(max) to KCl and PE showed direct positive
correlations with the area density of SM. E(max) to ET-1 also showed a positive
correlation with the SM density, although this relationship was weaker than those
for the other two agents. Moreover, there was a strong positive relationship
between E(max) to PE, KCl and that to ET-1. CONCLUSIONS: The area density of SM
appeared to significantly influence the contractile response to ET-1 as well as
the response to PE and KCl.
PMID- 10765084
TI - Effect of heat exposure on viability and contractility of cultured prostatic
stromal cells.
AB - OBJECTIVES: Different thermotherapeutic modalities such as transurethral
microwave therapy or transurethral needle ablation have been developed to provide
effective alternatives to surgical management of benign prostate hyperplasia
(BPH). The mechanisms of thermotherapy, however, are not completely understood.
We developed a model to investigate the effects of heat application on stromal
cell viability and contractility. METHODS: Cells isolated from prostatectomy and
cystoprostatectomy specimens were cultured in a selective medium. Temperatures
ranging from 37 to 50 degrees C were applied for 1 h. Cell contraction was
visualized by means of a cell culture microscope equipped with a time-lapse video
system. For quantitative analysis, the percentage of contracting cells was
evaluated; 10 microM of phenylephrine were applied for adrenergic stimulation of
the cells. RESULTS: On immunohistochemistry and phase-contrast microscopy, these
cells were identified as prostatic myofibroblasts. Incubation at 50 degrees C for
1 h in vitro induced immediate death of all cells, whereas at 45 degrees C all
cells survived. At 37 degrees C 55% of the cells were seen to contract after
addition of phenylephrine. Immediately after incubation at 45 degrees C
contraction rate decreased to 29%, but returned to 46% 1 day later. CONCLUSIONS:
With this model, it is possible to study the mechanisms of thermotherapy in
vitro. The results suggest that the effects of thermotherapy are due to the
induction of cell death rather than to reduced stromal cell contractility.
Furthermore, the data show that treatment is probably only successful if
temperatures in excess of 50 degrees C are maintained.
PMID- 10765085
TI - Vaginal calculi in a young woman.
AB - A case of a large vaginal stone in a 26-year-old woman is presented. Vaginal
stones are relatively rare. Various causes can lead to vaginal stone formation.
In our case, the calculi was due to vaginal outlet obstruction in childhood. The
diagnosis is usually easy to be done. In our patient, X-ray films using frontal
and lateral views of the urinary system permitted to establish the right
diagnosis. Treatment can vary, depending on the cause of the stone formation and
the consistency of the calculi. In this case, the treatment was surgical with
simple evolution. It permitted a normal social and sexual life to this young
patient.
PMID- 10765086
TI - Aetiology, pathology and staging of testicular tumours
PMID- 10765087
TI - The value of urodynamics in laser prostatectomy.
AB - OBJECTIVE: To present the results of laser prostatectomy on urodynamic
parameters, and to address the role of pressure/flow studies as diagnostic tools
for optimal selection of candidates for this treatment modality. MATERIAL AND
METHODS: The world literature, available on Medline, presenting urodynamic
parameters in patients subjected to laser prostatectomy was studied. We compared
the data of different series, and when it was feasible from intrinsic features of
a particular study, urodynamic results were plotted on the ICS Provisional
Nomogram. RESULTS: A general shift to a less obstructive status has been
documented in all series, using different methods of data interpretation. No
clear differences, in terms of elimination of obstruction, could be detected
among different types of laser. Plotting the data on the ICS Provisional
Nomogram, most series slide from the obstructed to the unobstructed zone. The
observation that clearly obstructed groups accomplish the most impressive
results, further emphasizes the value of urodynamics in the initial evaluation of
benign prostatic hyperplasia patients by assisting in the appropriate choice of
the therapeutic modality. CONCLUSIONS: Using the objective parameters of
infravesical obstruction, laser prostatectomy has proved an effective treatment
of benign prostatic hyperplasia. The role of pressure/flow studies in patient
selection is justified, as this investigation permits identification of those
cases who are going to have a direct benefit from a desobstructive procedure.
PMID- 10765088
TI - Where are the limits of elective nephron- sparing surgery in renal cell
carcinoma?
AB - OBJECTIVES: The indication for elective nephron-sparing surgery (NSS) in renal
cell carcinoma (RCC) is still controversial. The presented study was performed to
determine limitations for NSS regarding to multifocality and to characterize the
biological importance of these small tumor lesions. METHODS: In 372 patients who
underwent radical nephrectomy for RCC consecutively, nephrectomy specimens were
investigated by using 3-mm parenchyma sections regarding to local tumor spread
and multifocality. To characterize multifocal tumors, we performed cytogenetic
and molecular genetic investigations. RESULTS: Serial sections of 372 nephrectomy
specimens revealed a total of 92 multifocal tumors in 61 specimens (16.4%). The
correlation between tumor size and multifocality is shown as follows: tumor
diameter 1-20 mm: 12.5%; 21-30 mm: 23.4%; 31-40 mm: 10.2%; >40 mm: 16.7%. The
mean diameter of the multifocal tumors was 8.8x9.1x6.1 mm and the mean distance
to the primary tumor was 26.4 mm (5-84 mm). Using cytogenetic and molecular
genetic analysis, in nearly one third of all cases a concordance of chromosomal
aberrations in primary and secondary tumors was found. CONCLUSIONS: Multifocality
of renal cell carcinoma occurs independently from primary tumor size. The
evidence of structural and/or numeric aberrations, found in additional tumor
foci, obviously is an argument for their malignant potential. This findings have
to be considered in preparation of nephron-sparing surgery for patients with
renal cell carcinoma.
PMID- 10765089
TI - Impact of noninvasive imaging on increased incidental detection of renal cell
carcinoma.
AB - OBJECTIVE: To determine the impact of non-invasive imaging, specifically
ultrasound imaging and computed tomography, on the incidental detection of renal
cell carcinoma during two consecutive time periods, one prior and one subsequent
to the acquisition of imaging equipment. METHODS: All located patient charts (83%
of 207) of renal cell carcinoma cases (n = 172) were reviewed, and categorized by
presentation method as 'incidental' or 'nonincidental' cases, based on defined
criteria. Clinical information was recorded, cases were staged, and survival
estimates were calculated. RESULTS: More than a third of the 172 cases were
categorized as incidentally detected, most of which (82.5%) were detected during
the latter time period. Either ultrasound or CT imaging was credited with
detecting over 80% of the incidentally detected tumors. CONCLUSION: Ultrasound
and CT imaging have contributed to the incidental detection of renal cell
carcinomas during the two time periods. Stage significantly predicted survival
(p<0.001) in a Cox proportional hazard model that also controlled for
presentation, sex, and age.
PMID- 10765090
TI - Urinary retention in patients with BPH treated with finasteride or placebo over 4
years. Characterization of patients and ultimate outcomes. The PLESS Study Group.
AB - OBJECTIVES: Knowledge regarding the incidence and prevalence of acute urinary
retention and the ultimate outcome is very limited. The purpose of the present
analysis was to document the natural history and outcomes of acute urinary
retention (AUR) further specified as being either precipitated or spontaneous,
and to evaluate the potential benefit of finasteride therapy. MATERIALS AND
METHODS: Three thousand and forty men with moderate to severe symptoms of BPH and
enlarged prostate glands by digital rectal examination were enrolled into the 4
year placebo-controlled PLESS trial and were evaluated for occurrences of AUR and
BPH-related surgery. Men in the study were seen every 4 months; discontinued
patients were followed up 6 months after discontinuation and again at the end of
the 4-year trial. Complete 4-year data on outcomes (occurrence of AUR or BPH
related surgery) was available for 92% of the enrolled subjects in each treatment
group. An endpoint committee, blinded to treatment group and center, reviewed and
categorized all study-related documentation relating to retention and surgery.
RESULTS: Over the 4-year period, 99 of 1,503 placebo-treated patients (6.6%)
experienced one or more episodes of AUR in comparison with 42 or 1,513
finasteride-treated patients (2.8%; p<0. 001). Approximately half of the episodes
of retention were spontaneous and clearly BPH-related, while the other episodes
were precipitated by another factor (PAUR). After spontaneous AUR, subsequent
surgery was performed in 39 of 52 (75%) placebo-treated patients versus 8 of 20
(40%) finasteride-treated patients (p = 0. 01). BPH-related surgery was less
common in men who had a prior episode of PAUR (26% in the placebo group and 14%
in the finasteride group). CONCLUSION: There is a continual risk of spontaneous
and precipitated acute urinary retention in men with moderate to severe lower
urinary tract symptoms and an enlarged prostate gland. Fewer patients who
developed precipitated AUR than spontaneous AUR go on to need subsequent BPH
related surgery. Significantly fewer finasteride-than placebo-treated patients
developed AUR, and among those men, fewer ultimately needed BPH-related surgery.
PMID- 10765091
TI - Effect of inflammation and benign prostatic enlargement on total and percent free
serum prostatic specific antigen.
AB - OBJECTIVE: To analyze the influence of inflammation and benign prostatic
enlargement on total and percent free serum prostatic specific antigen (PSA).
PATIENTS AND METHODS: Total and free PSA serum levels were determined in 284
patients with no evidence of cancer in the sextant ultrasound-guided biopsy.
Double antibody immunoradiometric assay Tandem and Tandem free PSA were used.
Benign tissue without inflammation was found in 23.2% of the patients (group 1),
while in 68.3%, it was associated with chronic prostatitis (group 2) and with
acute prostatitis in 8.4% (group 3). RESULTS: Median serum PSA was 7.8 ng/ml in
group 1, 6.7 ng/ml in group 2 and 6.4 ng/ml in group 3, p>0.05. Median percent
free PSA was 14.1, 15.6 and 16.4%, respectively, p>0.05. Multiple linear
regression analysis showed that prostatic size was the only significant
contributor to serum PSA concentration. Moreover, total PSA and prostatic size
contributed significantly to the percent free serum PSA. Inflammation had no
significant influence on total or percent free serum PSA. CONCLUSION:
Inflammation has an important prevalence in cancer-free prostatic biopsy
specimens. It seems to have no significant influence on total and percent free
serum PSA. However, prostatic size seems to be the major contributor.
PMID- 10765092
TI - Quality of life of patients with newly diagnosed poor prognosis M1 prostate
cancer undergoing orchiectomy without or with mitomycin C. Results from the EORTC
Phase-III trial 30893.
AB - OBJECTIVES: To compare the quality of life (QL) of patients with poor prognosis
M1 prostate cancer treated with orchiectomy alone (ORCH) or orchiectomy combined
with adjuvant mitomycin C (MMC; 15 mg/m(2) i.v. q 6 weeks: ORCH+MMC; EORTC trial
30893). METHODS: Patients with newly diagnosed M1 poor prognosis prostate cancer
completed a truncated version of the EORTC QLQ-C30 (V 1.0) at randomization
(baseline) and every 6-12 weeks thereafter until going off the protocol. Five ad
hoc questions assessing lower urinary tract symptoms were included in the QL
questionnaire. RESULTS: At least one QL form was completed by 177 of the 189
patients included in the trial, with baseline questionnaires available for 113
patients (ORCH n = 52; ORCH+MMC n = 61). In both arms, pain and urinary
dysfunction improved during treatment. Compared with patients from the ORCH arm,
the use of adjuvant MMC was associated with a significant reduction in global
health status/QL and with impairment in 7 of 11 QL dimensions covered by the
questionnaire. Some improvement in QL was observed after discontinuation of MMC.
A survival benefit was not observed in the ORCH+MMC arm. CONCLUSIONS: Intravenous
MMC (15 mg/m(2) q 6 weeks) cannot be recommended as adjuvant treatment in M1 poor
prognosis prostate cancer due to its negative impact on QL and lack of efficacy.
In general, QL assessments should be mandatory when adjuvant chemotherapy is
evaluated in patients with metastatic prostate cancer.
PMID- 10765093
TI - Clinical significance of nonpalpable prostate cancer with favorable biopsy
features in Japanese men.
AB - OBJECTIVE: To assess the clinical significance of nonpalpable localized prostate
cancers with relatively favorable six sextant biopsy features in Japanese men.
PATIENTS AND METHODS: 136 nonpalpable prostate cancers of which biopsy features
confined to (1) a Gleason score of 6 or less, (2) one or two positive cores per
six sextant cores, and (3) 50% or less involvement of any positive core were
collected. The Gleason score, tumor extension, and cancer volume were compared
with preoperative serum PSA and PSA density for the patients who underwent
radical prostatectomy. PSA doubling time was measured for the patients who were
treated expectantly. RESULTS: Treatments chosen for 136 patients with favorable
biopsy features were radical prostatectomy alone for 48 and with preoperative
androgen deprivation for 30, radiation to the prostate for 12, androgen
deprivation therapy for 21, and watchful waiting for 25. Of 48 patients who
underwent radical prostatectomy without androgen deprivation therapy, 25% had
nonorgan-confined cancers. Seven cancers (14.6%) were Gleason score of 7, but no
cancers were 8 or greater. Among 42 prostatectomy specimens for which cancer
volume was measured, 22 (52.4%) had cancer volume >0.5 cm(3). Pretreatment serum
PSA levels were correlated neither with the Gleason score, tumor extension nor
cancer volume. There was only one nonorgan-confined cancer in the 23 cancers for
which PSA density was <0.2 ng/ml/g. The ability of PSA density to predict cancer
volume <0. 5 cm(3) was 0.61 using a cut-off of 0.2 ng/ml/g. Of the 25 patients
treated expectantly, the PSA doubling time was less than 2 years for 3 patients,
while it was stable or fluctuated for 13. CONCLUSIONS: Tumor extension can be
predicted based on PSA density in nonpalpable prostate cancer with favorable
biopsy features, but predictability of cancer volume based on PSA or PSA density
is not satisfactorily high. New parameters or biomarkers that complement needle
biopsy findings are needed to predict clinical significance of T1c prostate
cancer with favorable biopsy features.
PMID- 10765094
TI - The application of three-dimensional contrast-enhanced ultrasound to measure
volume of affected tissue after HIFU treatment for localized prostate cancer.
AB - INTRODUCTION: Adequate monitoring of volume and location of affected tissue might
provide helpful information when performing localized ablative therapy for
prostate cancer. We hypothesize that the change in blood flow patterns after
therapy in comparison to the blood flow pattern prior to therapy can be used to
locate and quantify the amount of affected tissue due to the therapy. We describe
the use of three-dimensional contrast-enhanced power Doppler ultrasound (3D-CE
PDU) to determine its additive value to visualize the extent of tissue defects
created by high-intensity focused ultrasound (HIFU) in correlation with the
histopathology of the prostatectomy specimen. MATERIALS AND METHODS: Nine
patients with biopsy-proven localized prostate cancer, who gave informed consent,
were included in the protocol. HIFU treatment was performed 1 week in advance of
radical retropubic prostatectomy (RRP) as part of a protocol to study the value
of HIFU treatment as local ablative therapy for clinical T(1-2)N(0)M(0) prostate
carcinoma. 3D-CE-PDU was performed 1 day prior to unilateral HIFU treatment of
the affected lobe on biopsy indication and 1 day before RRP using 2.5 g
Levovist((R)) (Schering AG, Germany) microbubble ultrasound contrast agent and a
Kretz((R)) Voluson 530D ultrasound scanner (Kretztechnik AG, Austria). Ultrasound
data and pathology whole-mount sections were stored digitally to allow off-line
processing. Human interpretations of HIFU measurements in three-dimensional
ultrasound data were based on gray-scale information (local increase in gray
level) in combination with power Doppler mode (absence of blood flow).
Histopathological analysis of the whole-mount section revealed a broad band of
hemorrhagic necrosis in the HIFU-treated area. Using both the ultrasound data and
the pathology sections, the total volume of the prostate and of the HIFU-treated
area was measured, and relative volumes were obtained. RESULTS: Visual inspection
of the three-dimensional reconstruction of contrast-enhanced Doppler measurements
revealed the HIFU-affected prostate tissue by the absence of a blood flow
pattern. Paired t tests of the relative HIFU volume indicated that Doppler
results (mean 21.7%, SD +/-10.8%) differed from the pathology results (mean
32.6%, SD +/-16.0%), but a good correlation was found between the relative
pathology HIFU volume (Pearson correlation r = 0.94, p<0.0015) and mean 3D-CE-PDU
HIFU. Closer inspection of the pathology specimen revealed that the outer ring of
the macroscopic hemorrhagic necrosis overestimated the actually dead tissue. On
microscopy, the border of dead tissue appeared to be 1-2 mm inside the
macroscopically identified red hemorrhagic band. 3D-CE-PDU HIFU volumes indicated
by the single observers were not statistically different and correlated very well
(Pearson correlation r = 0.98, p<0.001). CONCLUSION: The results illustrate that
3D-CE-PDU is a promising method to determine the size of the defect of HIFU
ablative therapy for prostate carcinoma. The absence of blood flow indicated by
three-dimensional power Doppler ultrasound images reflects affected tissue after
HIFU treatment, and volume measurements of these areas can quantify the amount of
affected tissue.
PMID- 10765095
TI - Paradoxical stimulation of prolactin secretion by L-dopa in metastatic prostate
cancer and its possible role in prostate-cancer-related hyperprolactinemia.
AB - OBJECTIVE: In addition to sex steroids, prolactin (PRL) may also stimulate
prostate cancer growth. Abnormally high blood levels of PRL have been noted in
metastatic prostate cancer patients. However, most studies have been limited to
the evaluation of basal levels of PRL rather than to investigate its secretion in
response to classical endocrine dynamic tests. This study was carried out to
analyze PRL secretion in metastatic prostate cancer patients both at basal
conditions and in response to L-Dopa and metoclopramide, which represents the
most classical inhibitory and stimulatory tests for PRL secretion, respectively.
METHODS: The study included 12 patients with metastatic prostate cancer. On
separate occasions, PRL secretion was evaluated in response to L-Dopa (500 mg
orally) and to metoclopramide (10 mg i.v. as a bolus). Serum levels of PRL were
measured by RIA. RESULTS: Mean PRL concentrations significantly increased after
metoclopramide administration, even though no PRL response occurred in 6 of 12
patients. L-Dopa was unable to reduce PRL levels, which, in contrast,
paradoxically significantly increased in response to L-Dopa, with mean values
comparable to those achieved after metoclopramide injection. CONCLUSION: By
showing a paradoxical stimulatory effect of L-Dopa on PRL secretion and a lack of
response to metoclopramide in some patients, this study would suggest the
existence of evident alterations in the neuroendocrine regulation of PRL release
in advanced prostate cancer.
PMID- 10765096
TI - Expression of activator protein 2 in prostate cancer is related to tumor
differentiation and cell proliferation.
AB - OBJECTIVES: Activator protein 2 (AP-2) is a DNA-binding transcription factor that
can activate the expression of p21 (waf1/cip1), which in turn causes growth
arrest of cells through inhibition of cyclin-dependent kinases required in G1-S
progression. The aims of the present study were to analyze the expression of AP-2
in prostate cancer and to relate the results of AP-2 immunohistochemistry to
other known prognostic factors and patient survival. METHODS: AP-2alpha was
demonstrated by an immunohistochemical method in 215 prostate cancer cases, and
the results of immunohistochemistry were related to other known prognostic
factors and patient survival. RESULTS: The expression of AP-2alpha in carcinomas
was usually weak and cytoplasmic, similar to normal prostatic epithelium adjacent
to tumors. In 6% of the tumors, the expression was strong, and in 15% no staining
signal was detected. Nuclear expression was detected in 22% of cases. Low
fraction of AP-2-expressing cells was related to high mitotic index, Ki67
labeling and high expression of p21 (waf1/cip1). Nuclear expression of AP-2 was
related to high Gleason score, advanced T category, DNA aneuploidy and high S
phase fraction. Nuclear expression was an indicator of unfavorable disease
outcome, but in multivariate analysis, expression of AP-2 had no prognostic
value. CONCLUSIONS: Cytoplasmic expression of AP-2alpha is reduced in poorly
differentiated prostate carcinomas. The rare nuclear expression occurs in a small
proportion of tumors which are aneuploid, have a high T category and high Gleason
score. The expression of AP-2 seems to have no prognostic value in prostate
cancer.
PMID- 10765097
TI - Do renal failure and hemodialysis have any effect on the elimination of free and
total prostate-specific antigen?
AB - OBJECTIVES: The aim of this study was first to determine the serum levels of free
prostate-specific antigen (f-PSA), total prostate-specific antigen (t-PSA) and f
PSA/t-PSA ratios in patients with renal failure, and secondary, to investigate
whether a significant difference between serum f-PSA and t-PSA levels consists in
patients with end-stage renal disease before and after hemodialysis. METHODS:
Serum concentrations of f-PSA and t-PSA were measured in 36 men with end-stage
renal disease before and after hemodialysis and in 95 healthy controls. A
chemiluminescent enzyme assay was used to determine the levels of f-PSA and t
PSA. RESULTS: The mean concentrations of serum t-PSA were 1.36+/-0.43 ng/ml in
patients on hemodialysis and 1.08+/-0.60 ng/ml in controls. There was no
significant difference in f-PSA and t-PSA levels between patients with renal
failure and controls. F-PSA and t-PSA levels in patients with renal failure also
showed no statistical differences before and after hemodialysis. CONCLUSIONS: The
limited kidney reserve in patients with end-stage renal disease is sufficient to
maintain the levels of t-PSA and f-PSA within normal ranges and hemodialysis does
not alter the serum levels of different PSA forms.
PMID- 10765098
TI - RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell
tumors? Results of a prospective multicenter trial including quality of life
assessment.
AB - BACKGROUND: In order to reduce therapy-related morbidity in patients with
nonseminomatous testicular germ cell tumors in clinical stage IIA/B, we performed
a prospective multicenter trial comparing the standard retroperitoneal lymph node
dissection (RPLND) +2 cycles of chemotherapy (arm A) with 3-4 cycles of primary
chemotherapy (arm B). METHODS: From February 1991 to July 1995, 57 participating
centers from Germany and Austria recruited 187 evaluable patients. 109 received
primary RPLND and 78 primary chemotherapy. Two different chemotherapies were
applied (PEB and CEB as adjuvant or inductive treatment). The quality of life
(QoL), therapy-related morbidity, suspected predictive factors (histology and
size of metastases), and outcome were assessed. RESULTS: In arm A, 12% had
pathological stage (PS) I, 70% PS II A/B, and 18% PS II C/III. In arm B, 67%
achieved complete remission with chemotherapy alone, 33% required a secondary
RPLND. After a median follow-up of 36 months, 7% of the patients in arm A and 11%
in arm B had relapsed. Two patients died due to complications of chemotherapy.
Surgical complications amounted to 12% in arm A and 27% of 26 postchemotherapy
RPLNDs (9% in arm B). Loss of ejaculation occurred in 32% in arm A, and 16% in
arm B. Acute toxicity of chemotherapy was higher in the group receiving primary
chemotherapy. CONCLUSION: We recommend primary RPLND because adjuvant
chemotherapy can be spared in PS I, two cycles of chemotherapy are less toxic
than 3 or 4 cycles, the primary operation is associated with less complications
than that following chemotherapy and, with modern surgical procedures,
ejaculation can be preserved in most of the patients, provided that the operation
is carried out by an experienced surgeon. No statistically significant
differences in the QoL outcome occurred between the treatment groups, suggesting
that chemotherapy alone is not superior to primary or secondary RPLND in this
respect.
PMID- 10765099
TI - The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer. A
Southwest Oncology Group Study.
AB - OBJECTIVES: An intergroup study (SWOG 8795) comparing two forms of adjunctive
therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC),
furnished preregistration index tumors for 244 patients with superficial,
papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether
DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict
disease recurrence or progression. METHODS: Cell cycle analysis using
commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder
cancers. Tumor grade, available for 223 cases, was assigned by a single study
pathologist. The SWOG statistical office reviewed follow-up information and other
data and performed statistical analysis. RESULTS: Disease recurrence occurred in
half the cases studied. The most parsimonious model predictive of recurrence
included only treatment arm and tumor grade, with the MMC arm and tumor grade
greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF
predicted recurrence-free survival or contributed prognostic information that was
additive to tumor grade. Within 5 years of follow-up, disease progression or
death from bladder cancer occurred for 29/223 (13%) of patients. The most
parsimonious model for progression-free survival included only grade greater than
I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF,
1.9). CONCLUSIONS: Knowledge of tumor proliferation (low versus high SPF)
contributes prognostic information about tumor progression that is additive to
tumor grade.
PMID- 10765100
TI - Urinary cytokeratin 20 as a marker for transitional cell carcinoma.
AB - OBJECTIVES: To determine if detection of cytokeratin 20 (CK20) gene expression,
by reverse transcriptase-polymerase chain reaction (RT-PCR) in urine from
transitional cell carcinoma (TCC) patients, can provide a new noninvasive tool
for the follow-up of patients with urothelial carcinoma of the bladder. METHODS:
Urine was collected from 95 patients previously diagnosed as TCC during their
follow-up, and from 27 healthy volunteers. All patients had a transurethal
resection of tumor or biopsies obtained from 'suspicious' areas in the bladder.
RNA was extracted from cells collected from the urine and RT-PCR was performed
with specific primers for the amplification of cytokeratin 8, a general marker
for epithelial cells, and of CK 20, a marker for TCC urothelium. RESULTS: CK20
expression was detected in 86.7% of TCC patients, and only in 3.3% of healthy
volunteers (specificity 96.7%). Strong correlation was found between tumor grade
and expression of CK20 in urine. All grade III and IV tumors demonstrated
positive CK20 expression (100% sensitivity), whereas the sensitivity for lower
grades was between 71 and 80%. Among 11 patients with a previous biopsy-proven
diagnosis of TCC and a current negative biopsy, in 9 patients CK20 expression was
detected. Further follow-up of these patients for a period of 6 months revealed
recurrence of TCC in 4 patients. CONCLUSION: CK20 detection in urine cells is a
simple, noninvasive method with a high potential to become the marker of choice
for monitoring and follow-up of TCC patients. More information is needed
regarding CK20 expression in nonmalignant urological disease, to evaluate its use
for routine screening purposes.
PMID- 10765101
TI - Brachytherapy with iridium-192 for bladder cancer.
AB - OBJECTIVE: Patients with invasive bladder cancer often need radical cystectomy
with its implications on quality of life. Bladder preservation combining surgery
and radiotherapy could maintain quality of life without compromising tumor
control. STUDY DESIGN: Twenty-eight selected patients with different stages of
invasive bladder cancer were treated with preoperative external beam radiotherapy
in a dosage depending on the tumor stage. Subsequently they underwent surgical
exploration with or without partial cystectomy and insertion of source carrier
tubes for afterloading with iridium-192. A close follow-up consisted of 3-monthly
urine cytology, cystoscopy and yearly CT scan. RESULTS: Sixteen patients (57%)
are alive with no evidence of disease. Five patients (18%) have died of non
cancer-related causes without evidence of recurrent tumor. Tumor progression was
seen in 7 patients (25%). CONCLUSIONS: Interstitial radiation can result in long
term complete remission in patients with small solitary invasive bladder tumors.
The afterloading technique is safe and effective. The selection of patients is
the most relevant key to success.
PMID- 10765102
TI - Microsurgical vasovasostomy versus microsurgical epididymal sperm
aspiration/testicular extraction of sperm combined with intracytoplasmic sperm
injection. A cost-benefit analysis.
AB - PURPOSE: Vasovasostomy (VVS) represents the standard therapy of choice for the
treatment of obstructive azoospermia following vasectomy. However, recently,
intracytoplasmic sperm injection (ICSI) has been suggested by some to represent
the solution for all cases of malefactor infertility regardless of its etiology
based on its success rates. Therefore, we compared VVS to microsurgical
epididymal sperm aspiration (MESA)/testicular extraction of sperm (TESE) and ICSI
in terms of pregnancy, complications, and costs. PATIENTS AND METHODS: Between
1/93 and 6/98, 157 VVS were performed microsurgically using the double-layer
technique. Between 9/94 and 9/97, 69 and 42 couples underwent MESA/ICSI and
TESE/ICSI, respectively, for epididymal obstruction and azoospermia of testicular
origin. RESULTS: The mean interval of vasal obstruction was 7.6 (0.5-18) years;
patency after VVS was 77%, pregnancy rate was 52%. Local complication rate was
4.7%, no major complications were observed. Costs per life birth after VVS were
5,447 DM or 2,793 Euro. Pregnancy rates after MESA/TESE and ICSI were 22.5 and
19.5%, respectively, with 16 singletons, 3 twins and 3 abortions; local
complications occurred in 3.9% of the men. Multiple births were noticed in 15.8%
following ICSI, but in only 0.7% following VVS. 5.7 and 1.4% of the female
partners experienced serious complications (mild or severe ovarian
hyperstimulation syndrome, respectively). Costs per life birth after a MESA/TESE
cycle amounted to 28,804 DM or 14,547 Euro. CONCLUSIONS: Even in the era of ICSI,
microsurgical VVS represents the standard approach for obstructive azoospermia
following vasectomy. Based on a cost-benefit analysis, VVS is more successful in
terms of pregnancy rates (52 vs. 22.5%). VVS does not expose the female partners
to complications following treatment of male infertility. In contrast to ICSI,
multiple birth rates do not increase after VVS. We conclude that MESA/ICSI should
be reversed for patients who are not amenable for microsurgical reconstruction.
PMID- 10765103
TI - Laparoscopic radical prostatectomy: preliminary results.
AB - BACKGROUND: Retropubic and perineal radical prostatectomy are used for curative
treatment of localized prostate cancer. More complex urological procedures are
now being done with laparoscopy. We present our initial results of
transperitoneal laparoscopic radical prostatectomy. MATERIALS AND METHODS: Twenty
laparoscopic radical prostatectomies were performed between May 1998 and May
1999. The mean age at the time of surgery was 64.2 years. There were 14 stage
T1c, 5 stage T2a and 1 stage T2b tumors. The preoperative PSA was 9. 3 ng/ml
(normal <4 ng/ml). The Gleason score for positive specimens in 6 random echo
guided endorectal biopsies was 5.7. Four trocars were used. Insufflation pressure
was 15 mmHg. The seminal vesicles were first dissected. The prostate was
dissected free from the anterior face of the rectum to the prostate apex. Then
the peritoneum was incised to find the apex of the prostate. The puboprostatic
ligaments were isolated and cut, and the dorsal vein complex was ligated and cut
to expose the urethra. The bladder neck was opened and dissected free from the
prostate. The lateral pedicles were coagulated before sectioning the urethra. The
radical prostatectomy specimen was left along the sigmoid colon, the bladder neck
was reconstructed, and a urethrovesical anastomosis was performed with 6
interrupted sutures. The prostatectomy specimen was removed intact in a sack by
enlarging the umbilical trocar port. All the prostatectomy specimens were
processed according to the Standford protocol. Prostate weight, tumor weight, the
Gleason score, and the tumor status of the capsule, seminal vesicles, lymph nodes
and surgical margins were studied. RESULTS: The operating time was 385 min. Two
patients were transfused. The mean hospital stay was 7. 8 days. The Foley
catheter was removed 10.7 days after the operation. Specimen weight was 61 (28
126) g, the Gleason score was 5.9, and tumor volume was 1.4 ml. There were 18
stage pT2, 1 stage pTa (capsular effraction) and 1 stage pT3b (seminal vesicle
invasion) tumors. There were four positive surgical margins (2 at the apex and 2
at the bladder neck). All the patients had a postoperative PSA level <0.1 ng/ml
at 1 month. The first patient had urethrovesical anastomotic leakage, and
required Foley catheterization for 21 days. There was 1 colostomy for rectal
injury and 1 urinoma because of urethrovesical anastomotic leakage that required
an open surgical procedure. One month after surgery, 15 (75%) patients were fully
continent. Six patients had erections, and 5 stated having sexual intercourse.
CONCLUSION: These preliminary results show that radical prostatectomy can be
performed laparoscopically. Laparoscopy offered excellent vision of all the
anatomical structures of the pelvis, permitting precise dissection. Long-term
follow-up and further studies are required to confirm and improve these results.
PMID- 10765104
TI - Initial experience of an objective structured clinical examination in evaluating
urology residents.
AB - OBJECTIVES: Objective Structured Clinical Examination (OSCE) is now generally
considered as the new gold standard for evaluating clinical competence. The
objective of this study was to assess the feasibility of OSCE in evaluating
urology residents. MATERIAL AND METHODS: 20 urology residents rotated through a
circuit of five standardized patient-based OSCE stations of 10 min duration. The
selection of problems was based on educational objectives of urology residency
programs. Written questionnaires based on Likert-type scales were used to measure
OSCE feasibility. The mean score was arbitrarily used as a passing score. Student
t test was only used to compare the performance between junior and senior
residents. RESULTS: Senior residents performed globally better, but without
significant differences (51.3+/-7.8 vs. 45.03+/-5.1, p>0.05). Senior resident
scores regarding outpatient problems were significantly higher (p = 0.04), more
senior residents reached the passing score (75 vs. 16% junior residents). All the
participants agreed that the clinical situations were realistic and that the
simulated patients were believable. Most participants agreed that the sampling of
cases were representative of urology practice. CONCLUSIONS: This is the first
reported OSCE applied to urology residency. The results of this pilot study
support the feasibility of an OSCE in assessing the performance of urology
residents. Our data raises questions regarding the training of outpatient
consultation skills to residents. This experiment warrants further series to
explore the study's psychometrics features.
PMID- 10765106
TI - Indinavir calculi: diagnosis with magnetic resonance urography.
PMID- 10765105
TI - Influence of linomide on local tumor growth and metastasis of the human hormone
resistant prostate cancer cell line PC3 in an orthotopic model.
AB - OBJECTIVE: It has been demonstrated that quinoline-3-carboxamide, linomide,
inhibited angiogenesis and reduced the volume of tumors grown from human hormone
resistant prostate cancer cell lines after subcutaneous implantation in mice.
However, subcutaneous xenograft models may not mimic human conditions due to the
absence of prostatic stromal cells at the ectopic site. Therefore, we
investigated the influence of linomide on local tumor growth and metastasis of
the human hormone-resistant prostate cancer cell line PC-3 in an orthotopic
model. METHODS: In 30 athymic nude mice, 5x10(5) PC-3 cells were injected into
the dorsal prostate after surgical exposure. After 7 days, group 1 (n = 15 mice)
received linomide 100 mg/kg/day in the drinking water (per os). The other 15 mice
(group 2) served as controls. All mice were sacrificed after 38 days followed by
macroscopical and histological evaluation of local tumor growth and metastasis.
Microvessel density was determined by immunohistochemical staining for von
Willebrand factor as well as silver staining followed by morphometric analysis in
an area of highest vessel density. RESULTS: In the control group, local
tumorigenicity and locoregional lymph node metastasis was 100%. The mean weight
of the local tumor was 894 mg (395- 1,261 mg). The mean transversal diameter of
the lymph node metastases was 4.0 mm (1.5-5. 4 mm). In the treatment group, local
tumor growth and lymph node metastasis was 100% with a mean local tumor weight of
869 mg (232-1, 131 mg) and a mean lymph node metastasis diameter of 4.6 mm (1.3
5.9 mm). Microvessel density of the local tumor in the control and treatment
group did not differ significantly. CONCLUSION: Contrary to the results reported
in subcutaneous animal models, linomide per os has no effect on net tumor growth
and metastasis after orthotopic implantation of the human hormone-resistant
prostate cancer cell line PC-3 in nude mice.
PMID- 10765107
TI - Imaging in childhood
PMID- 10765108
TI - Two types of K(+) channels are present in the apical membrane of the thick
ascending limb of the mouse kidney.
AB - We used the patch-clamp technique to study apical K(+) channels in the split
opened thick ascending limb (TAL) of mouse kidneys. We observed a low-conductance
K(+) channel in 8 patches and an intermediate-conductance K(+) channel in 11
patches from a total of 135 cell-attached patches with GOmega seals in the apical
membrane of the mouse TAL. Open probability (P(o)) of the low-conductance K(+)
channel was 0.85 and was not voltage-dependent between -60 mV and 0 mV. P(o) of
the intermediate-conductance was 0.6 at a spontaneous cell membrane potential and
decreased to 0.4 by 40 mV hyperpolarization. Both the low-conductance and
intermediate-conductance K(+) channels were an inwardly rectifying K(+) channel
with inward slope conductances of 26 pS and 74 pS between -20 and 20 mV,
respectively. The 74-pS K(+) channel was inhibited by 1 mM Ba(2+) and 10 mM
tetraethylammonium when they were applied to the bath facing the cytosolic
surface of inside-out patches. Furthermore, addition of 1 mM Mg-ATP reversibly
reduced the activity of the 74-pS K(+) channel by 90% within 1 min in inside-out
patches. A decrease in bath pH from 7.4 to 6.5 completely blocked the 74-pS K(+)
channel in inside-out patches. We conclude that two types of K+ channels are
present in the apical membrane of the mouse TAL and that the biophysical
properties of the apical 74-pS K(+) channel are identical to those in the rat
TAL.
PMID- 10765109
TI - Mechanisms of distal-nephron Li(+) reabsorption during dietary K(+) restriction
in rats.
AB - The mechanism by which dietary K(+) restriction induces distal-nephron Li(+)
reabsorption was investigated by administration of bendroflumethiazide (BFTZ) or
vehicle in conscious Wistar rats. Changes in fractional excretion of Li(+)
following administration of amiloride (DeltaFE(Li)) were used as an index of
distal tubular Li(+) reabsorption. The results revealed an absence of distal
tubular Li(+) reabsorption in K(+)-replete rats (DeltaFE(Li) = 3. 6+/-2.4%), in
contrast to K(+) restriction in which DeltaFE(Li) was 24.0+/-2.7%. The distal
tubular Li(+) reabsorption in K(+)-depleted rats was significantly reduced by
preadministration of BFTZ (DeltaFE(Li) = 9.2+/-0.9%). The fractions of Li(+) and
Na(+) reabsorbed in the amiloride-sensitive segment were different in K(+)
replete rats (9+/-6 vs. 60+/-6%), but similar in K(+)-depleted rats (61+/-5 vs.
73+/-4%). BFTZ administration to K(+)-depleted rats resulted in a proportional
decrease in these fractions, suggesting competition between Na(+) and Li(+) for
reabsorption in the distal-nephron segment during K(+) depletion. These results
are compatible with the hypothesis that during K(+) depletion the reabsorption of
Li(+ )in the distal-nephron segment is competitively inhibited by Na(+).
PMID- 10765110
TI - Effect of intrarenal infusion of angiotensin-(1-7) in the dog.
AB - Angiotensin-(1-7), (Ang-(1-7)), a metabolite of Ang II and /or Ang I, was infused
into the renal artery (i.r.a) of anesthetized dogs in order to demonstrate its
possible direct renal action. The dose administered, 15 Ig/kg BW/min in isotonic
saline (0.072 ml/kg BW/min) throughout the experiment, did not influence the
systemic arterial pressure and water and sodium excretion from the contralateral
noninfused kidney. Renal blood flow (RBF) was measured by an electromagnetic
flowmeter, glomerular filtration rate (GFR) by (exogenous) creatinine clearance.
In other groups of animals, either EXP 3174, an AT-1 receptor antagonist alone
(30 Ig/kg BW/ min) or together with Ang-(1-7) (15 Ig/kg BW/min), were infused. In
the last group, the AT-2 receptor antagonist PD 123319, 10 Ig/kg BW/min, was
added to the infusion of Ang-(1-7). A small but significant decrease of RBF from
4.51+/-0.32 to 3.8+/-0.29 ml/g BW/min occurred after Ang-(1-7); this decrease was
very similar when PD 123319 was added. However, an increase to 4.98+/-0.34 ml/g
BW/min was seen after the addition of EXP 3174 to the i.r.a. infusion of Ang-(1
7); this increase was similar to the increase observed after EXP 3174 alone
(5.21+/-0.33; p<0.02 in both cases). A very small but significant increase in GFR
was seen after Ang-(1-7) + EXP 3174 or after the AT-1 blocker alone (0.64+/-0.049
and 0.62+/-0.05 vs. 0.6+/-0.05 ml/g BW/min in the Time Control Group, p<0.01 and
0.05, respectively). Water, sodium and urea excretion rates were increased in all
groups infused with Ang-(1-7); after the combination of Ang-(1-7) + EXP 3174, all
increases were higher than after every substance alone; however, statistical
significance (p<0.05) was reached in sodium excretion values only. Potassium
excretion rates were increased just in those groups in which EXP 3174 was present
in the infusion fluid. In summary, Ang-(1-7) i.r.a. infusion in the dog is
followed by increases in water, sodium and urea (but not potassium) excretion
rates, highly probably of tubular origin. This effect is not completely blocked
by the AT-1 - and not at all by the AT-2 receptor antagonist - thus indirectly
suggesting another receptor could play a role. A small decrease in RBF disappears
after EXP 3174, thus indicating an AT-1 receptor action.
PMID- 10765111
TI - Pressor and renal effects of intracerebroventricularly administered angiotensins
II and III in rats.
AB - AIMS: Experiments were performed to assess the effects of intracerebroventricular
(ICV) angiotensin (ANG) III on blood pressure and renal function in rats with
normal and high sodium intake and to compare these effects with those produced by
ICV ANG II. METHODS: Male Sprague-Dawley rats on a normal sodium (0.3%) diet and
a normal sodium diet plus 1% NaCl as drinking water were administered ANG II and
ANG III ICV through a chronically implanted cannula. Blood pressure and renal
clearance function responses were measured before and during peptide
administrations. The effect of ICV ANG III on the renal efferent nerve activity
was also evaluated. RESULTS: ICV injections of ANG II and ANG III at 5 pmol in
rats on a normal sodium diet did not significantly alter the blood pressure, but
significantly increased renal plasma flow, glomerular filtration rate, urine
flow, and absolute and fractional excretions of sodium and potassium. Increased
doses of ANG II and III (10, 50 and 100 pmol) significantly increased blood
pressure and further enhanced these renal functional indices. Central ANG-III
induced increases in blood pressure and renal functional indices were not
significantly different from those produced by ANG II at each corresponding dose.
The pressor and renal effects of ANG III were blunted by a specific antagonist,
Ile(7)-ANG III. ICV administration of ANG III decreased the renal efferent nerve
activity. In rats with dietary NaCl loading, ICV injections of ANG II and III
also significantly enhanced renal function. CONCLUSIONS: Centrally administered
ANG III is as potent as ANG II in causing pressor and renal effects in rats on
normal and high sodium intake. As ANG II, brain ANG III reduced renal efferent
nerve activity which may be partly accounted for the augmented renal function.
PMID- 10765112
TI - Enalapril inhibits growth and proliferation of various tissues in rat
normotensive four-sixths kidney ablation nephropathy.
AB - Most experimental studies on kidney proliferation and its attenuation by
angiotensin-converting enzyme inhibitors were performed in the rat hypertensive
remnant-kidney model with a five-sixths kidney ablation. The developing
hypertension rose the objections on the hypertension and its treatment in control
rats. A normotensive four-sixths remnant-kidney model (Nx) was elaborated,
compared with sham-operated (S) animals, and a subantihypertensive dosage of
enalapril (E) was administered for 4 weeks of intensive kidney tissue
proliferation (NxE). The pair-fed groups increased their body weight and blood
pressure comparably. Moderately increased plasma creatinine and urea
concentrations were found in the Nx group; markedly increased levels in the NxE
group. Nx increased proteinuria, and E attenuated its increase. The remnant
kidney weight (Nx 912+/-31 vs. S 1,111+/-36 mg, p<0.001) was still lower, but
collagen (Col; Nx 164+/-2 vs. S 148+/-5 mg/100 g, p<0.05) and tubular protein/DNA
ratio (Nx 26.2+/-10.8 vs. S 9.8+/-1. 0, p<0.05) increased markedly in the Nx
group; E attenuated the kidney growth (NxE 719+/-31 vs. Nx 912+/-31 mg, p<0.01)
and decreased the tubular protein/DNA ratio remarkably (NxE 15.3+/-10.5 vs. Nx
26.2 +/-10.8), but E did not inhibit the Col accumulation. Nx decreased the heart
(Nx 1,002+/-28 vs. S 1,130+/-41 mg, p<0.05), but not liver weights and did not
influence Col concentrations or protein/DNA ratios either in heart or liver. E
potentiated the weight decrease of heart (NxE 862+/-20 vs. Nx 1,002+/-28 mg,
p<0.01) and liver (NxE 8.3+/-0.44 vs. Nx 10.3+/-0.51 g, p<0.001) and Col
accumulation (heart: NxE 113+/-6 vs. Nx 92+/-5 mg/100 g, p<0.01; liver: NxE 134+/
8 vs. Nx 101+/-9 mg/100 g, p<0.01). Nx did not influence either the soleus muscle
weight or its Col accumulation, but it increased its protein/DNA ratio (Nx 66.3+/
4.7 vs. S 35.5+/-2. 8 mg/100 g, p<0.01). E increased the Col concentration in
muscle (NxE 141+/-3 vs. Nx 110+/-5 mg/100 g, p<0.01), while it attenuated the
increase in protein/DNA ratio (NxE 36.6+/-2.1 vs. Nx 66.3+/-4.7, p<0.01). In
conclusion, kidney ablation nephropathy stimulating kidney proliferation evokes
only minor changes in heart, liver and striated muscle. E inhibits markedly the
kidney proliferation and functional recovery, but does not prevent the Col
accumulation. E evokes antiproliferative changes also in the heart and
surprisingly even in the liver. Alterations in soleus muscle are only borderline.
PMID- 10765113
TI - Grass carp (Ctenopharyngodon idellus) bile may inhibit the release of renal
dipeptidase from the proximal tubules by nitric oxide generation.
AB - There are many reports on acute renal failure (ARF) after ingestion of grass carp
bile (CB; Ctenopharyngodon idellus). Renal dipeptidase (RDPase; EC 3.4.13.19) is
a glycosylphosphatidylinositol-anchored ectoenzyme within the renal proximal
tubules (PTs) and is proposed as a diagnostic enzyme of renal disease. We
examined the release of RDPase following treatment with CB and various nitric
oxide (NO) related compounds in porcine PTs. The RDPase release from PTs was
inhibited by CB in a concentration-dependent manner and was also inhibited by
sodium nitroprusside (direct NO donor) and L-arginine (NO synthase substrate) in
the tested range (0-12 mM). CB-treated (0. 1 mg/ml) PTs showed a decreased RDPase
activity in comparison with the control group. This inhibition was blocked by 2
mM L-NAME (NO synthase inhibitor) and U73122 (inhibitor of phosphatidylinositol
specific phospholipase C) in a concentration-dependent manner. Eel bile (0-0.1
mg/ml), used as the control, did not significantly affect the RDPase release from
PTs. The NO concentration was observed as nitrite, the degradation product of the
NO metabolism, increased in proportion to CB and L-arginine. The increase of
nitrite to 151.5% by CB treatment (0.1 mg/ml) was blocked by 2 mM L-NAME (95.5%).
When the phospholipase C pathway was blocked by 10 and 20 microM U73122, the
nitrite generation decreased to 122.7 and 89.4%, respectively. These results
strongly suggest that NO generation and the phospholipase C pathway affect the
RDPase release from the PTs and that they may be involved in the development of
ARF in vivo following CB ingestion. The release of RDPase from PTs could be a
useful tool not only for this CB-caused ARF, but also for the elucidation of
other biochemical mechanisms.
PMID- 10765114
TI - Influence of mycophenolic acid and FK-506 on human platelet activation in vitro.
AB - BACKGROUND/AIM: FK-506 (FK) and mycophenolic acid (MPA) are immunosuppressive
agents used in kidney transplant recipients. Their effect on posttransplant
thromboembolic complications is either controversial (FK) or has not been
described (MPA). Thromboembolic events are among the consequences of platelet
hyperaggregability which can be identified by measuring platelet aggregation. The
aim of this study was to evaluate the in vitro effects of MPA and FK upon
platelet activation in healthy subjects. METHODS: Platelet-rich plasma from
healthy volunteers (n = 18) was incubated with FK (70 ng/ml), FK vehicle, and MPA
(30 microg/ml) before platelet aggregation was induced by the platelet agonists
adenosine diphosphate (2 and 5 microM) and collagen 0.5 and 1.0 microg/ml).
Aggregation was measured by recording the optical density. RESULTS: MPA resulted
in a significant decrease in the platelet response to collagen (1.0 microg/ml) in
platelet-rich plasma, whereas FK significantly increased platelet aggregation in
response to collagen (0.5 microg/ml). The vehicle of FK had no influence on
platelet aggregation with either agonist. CONCLUSIONS: The decreased platelet
activating response following preincubation with MPA may favor its use in kidney
transplant recipients to reduce thromboembolic events. The FK-induced enhancement
of platelet aggregation shown in vitro may lead to thromboembolic complications
in transplant recipients.
PMID- 10765115
TI - Effect of calcium channel blockers, nifedipine and benidipine, on death of
cultured mouse mesangi al cells.
AB - We examined the effects of the short-acting calcium channel blocker (CCB)
nifedipine and the long-acting CCB benidipine on the death of mouse cultured
mesangial cells induced by tumor necrosis factor alpha (TNF-alpha) and/or
cycloheximide (CHX). Cell death was evaluated by a morphological study using
semithin sections. The dead cells were divided into three types, i.e., apoptotic
cells (type 1), necrotic cells (type 3) and other types of dead cells, the so
called 'secondary necrotic cells' or 'postapoptotic necrotic cells' (type 2). In
the morphological study with semithin sections, cells in the presence of TNF
alpha or CHX and nifedipine or benidipine showed low percentages of all dead cell
types with 24 h incubation. Both nifedipine and benidipine have protective
effects against TNF-alpha or CHX. It is postulated that CCB might inhibit the
apoptotic or necrotic processes by TNF-alpha or CHX with 24 h incubation. With 36
h incubation, CCB increased the percentages of all types of dead cells except for
treatment with 1x10(-5) M benidipine and CHX. It appears that these cell
protective effects might be decreased after treatment with TNF-alpha or CHX and
CCB for 36 h. In conclusion, the short-acting CCB nifedipine and the long-acting
CCB benidipine have protective effects on mouse cultured mesangial cells against
TNF-alpha or CHX. However, nifedipine and benidipine did not inhibit specific
types of cell death using semithin sections in this study.
PMID- 10765116
TI - Native and oxidized low-density lipoproteins enhance superoxide production from
diabetic rat glomeruli.
AB - Oxygen free radicals have been implicated in mediating diabetic complications,
and patients with diabetic nephropathy frequently show increased levels of
circulating and oxidized low-density lipoproteins (LDL). In the present study, we
measured the superoxide production of glomeruli isolated from poorly controlled
diabetic (streptozotocin) rats sacrificed 1 week and 1, and 3 months after the
induction of diabetes. The animals were stimulated with native and oxidized LDL
isolated from normal humans with normolipidemia. The superoxide ion was measured
by using a spectrophotometer. The results demonstrated that the poorly controlled
diabetic rat glomeruli showed a significantly higher production of superoxide
than normal glomeruli under basal conditions, and this production increased
further with the progression of diabetes. Stimulation with either LDL or oxidized
LDL enhanced superoxide production by diabetic glomeruli, with oxidized LDL being
more potent than LDL. Our results suggest that oxidized LDL may play important
roles in the pathogenesis of diabetic nephropathy through enhanced generation of
oxygen free radicals.
PMID- 10765117
TI - FcgammaRIIa polymorphism in systemic lupus erythematosus.
AB - FcgammaRIIs are the most widely distributed of the Fcgamma receptor family and
play an important role in the clearance of immune complexes. Evidence that the
FcgammaRIIa-R131 allotype is less able to process and clear immune complexes
effectively suggests that this may be a disease susceptibility factor for
systemic lupus erythematosus (SLE). Data from studies published thus far do not
agree on the potential role of FcgammaRIIa polymorphism in the genetics of SLE.
Most studies in fact show no evidence for any correlation between polymorphism of
FcgammaRIIa and risk for SLE. However, it remains to be determined whether
FcgammaRIIa polymorphism may play a critical role in certain groups of patients,
especially in those of differing ethnic background. Polymorphism of FcgammaRIIa
may also be important in determining disease phenotype, and identification of
this influence may have important implications in patient care and in identifying
patients for more aggressive therapy.
PMID- 10765118
TI - A retrospective study of first indicators of breast cancer recurrence.
AB - This study was performed to evaluate the first indicators of breast cancer
recurrence in 1,145 patients treated at the University of Texas MD Anderson
Cancer Center, between July 1973 and December 1980. Twenty patients were excluded
due to incomplete data, resulting in a total number of 1,125 evaluable patients.
Data collection included the first metastatic site and its means of detection
(symptoms, self-examination, physical examination performed by a physician, and
the results of blood and radiological tests). Whether recurrence was found at the
scheduled follow-up visits or between the scheduled visits was also analyzed.
Symptoms were the primary indicator of relapse for 648 cases (57.6% of the study
population). An additional 361 cases (32.1% of the total group) were detected by
self-examination or by physician-performed physical examination. Other
investigations, e.g. bone scans, liver scans, chest X-rays, and blood tests,
revealed recurrent disease in only 116 patients (10. 3% of the population). Among
the 1,125 patients, 254 recurrences (22. 6% of the study population) were
detected at the scheduled follow-up surveillance and, among these, 64.6% were
found by history or physical examination. The distribution of metastatic sites
and first indicators of metastases remained constant over time. The scheduled
follow-up visits detected a mean of 25.9% of relapses during the first 36 months,
while after 36 months only 16.3% of relapses were detected by systematic
monitoring. There were no statistically significant differences in disease-free
overall survival rates between symptomatic and asymptomatic patients at the time
the first recurrence was detected. Moreover, the disease-free and overall
survival rates appeared to be the same in symptomatic and asymptomatic patients,
whether or not the recurrence was detected by a scheduled follow-up examination.
Two conclusions emerged from the present study. Extensive, routine laboratory
investigations are not justifiable following curative treatment of primary breast
cancer, and it seems reasonable and cost-effective to reduce follow-up
surveillance to careful history and physical examination only. The actual method
of surveillance does not significantly affect the time interval to metastasis
detection and seems inefficient. Clearly, more sensitive methods are needed for
earlier detection of recurrent metastatic breast cancer. In addition, early
detection of metastases would be even more valuable if more effective treatment
modalities of recurrent or metastatic breast cancer were available.
PMID- 10765119
TI - Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced
gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group.
AB - PURPOSE: To assess the efficacy and safety of S-1, a novel oral fluoropyrimidine
derivative, we conducted a multicenter late phase II study in patients with
advanced gastric cancer. PATIENTS AND METHODS: Fifty-one patients who had
received no previous chemotherapy were enrolled. Fifty patients were eligible for
efficacy and safety analyses. The overall response was evaluated for the 43
patients who had metastatic lesions. S-1 was administered orally after breakfast
and dinner for 28 days, followed by a 14-day break. The dosages were assigned
according to the patients' body surface area (BSA): BSA <1.25 m(2), 40 mg; 1.25
1.5 m(2), 50 mg, and BSA > or =1.5 m(2), 60 mg, twice daily. RESULTS: The overall
response to treatment was evaluated as partial response in 19 of the 43 patients
(44%; 95% confidence interval 30-59%). The median survival time in all patients
was 207 days with 1- and 2-year survival rates of 36.0 and 14.0%, respectively.
Grade 3 adverse reactions included decreased hemoglobin values in 2 patients,
leukopenia, neutropenia and diarrhea in 1 patient each. No other grade 4 or
unexpected adverse reactions were seen. CONCLUSIONS: S-1 is effective against
advanced gastric cancer. This oral treatment is suitable for outpatients because
of its mild toxicity. Further therapeutic benefits are likely to be obtained by
combining S-1 with other chemotherapeutic agents.
PMID- 10765120
TI - High-dose chemotherapy and autologous hematopoietic stem cell transplantation:
the lymphoma experience and its potential relevance to solid tumors.
AB - Lymphomas, which are frequently subdivided into Hodgkin's disease and non
Hodgkin's lymphoma, represent one of the more curable cancers that present as a
solid tumor. Unfortunately, most patients cannot be cured with conventional
chemotherapy, therefore new techniques have been developed including high-dose
chemotherapy and autotransplantation. Non-Hodgkin's lymphoma was one of the first
illnesses to be tested using the new methods and initial encouraging results in
relapsed lymphoma led to the testing of high-dose chemotherapy with
autotransplantation as a primary therapy for patients with lymphomas. Encouraging
results have been obtained in several randomized trials. Studies of the treatment
of lymphoma have identified several principles related to the application of
autotransplantation, which may be relevant to other solid tumors.
Autotransplantation is likely to be of benefit only when using active
chemotherapeutic agents that can be escalated in dose and when myelosuppression
is the dose-limiting toxicity. Chemotherapy-responsive tumors are obvious targets
for autotransplantation, whereas chemotherapy-resistant tumors are unlikely to
benefit. Other factors that should be taken into account when selecting patients
for high-dose chemotherapy regimens include the extent of disease, preceding
therapy and the performance status of the patient.
PMID- 10765121
TI - Low-grade fibromyxoid sarcoma.
AB - Described is a low-grade fibromyxoid sarcoma (LGFMS) of the abdominal wall
muscles in a 38-year-old black woman. There was no evidence of metastatic
disease. A 5.2-kg LGFMS - the largest case ever reported - was resected. One year
after surgery, the patient is alive without any sign of local recurrence or
distant metastasis. Follow-up comprises abdominal and thoracic CT scans at 6
month intervals.
PMID- 10765122
TI - Primary sarcomas of the central nervous system.
AB - The medical files of 14 patients with primary brain and spine sarcomas were
retrospectively reviewed. Ten patients had primary brain sarcomas and 4 primary
spinal sarcomas. The tumors probably originated in the brain substance or blood
vessels, in the meninges or in the inner aspect of the skull. The spinal tumors
originated in the nerve roots of the cauda equina and in the spinal substance or
blood vessels. The most common type was angiosarcoma. Removal of the brain tumors
was performed in 95% of the patients. Radiotherapy was delivered to 6 patients
with brain sarcomas and to all patients with primary spinal sarcomas. Metastatic
disease to the lung or pleural effusion was evident in 2 patients who underwent
total removal of their tumors followed by radiation therapy.
PMID- 10765123
TI - A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic
cancer: an Eastern Cooperative Oncology Group Study (E3296).
AB - Gemcitabine has recently been compared favorably to 5-fluorouracil (5-FU) as the
standard chemotherapy for advanced pancreas cancer. Based on phase I data that
combining gemcitabine with 5-FU is safe and has evidence for clinical activity, a
phase II trial was conducted by the Eastern Cooperative Oncology Group (ECOG).
Patients with metastatic disease, good performance status and organ function were
eligible and enrolled after providing informed consent. Patients were given
gemcitabine (1,000 mg/m(2)) followed by 5-FU (600 mg/m(2)) weekly for 3 weeks of
every 4. Of 37 patients enrolled over a 3-month period, 36 were eligible. Partial
responses were seen in 5 patients (14%). Median survival was 4.4 months with a 1
year survival rate of 8.6%. A randomized trial of the combination of 5-FU and
gemcitabine versus gemcitabine alone is currently accruing patients in ECOG.
PMID- 10765124
TI - Consolidation radiotherapy to bulky or semibulky lesions in the management of
stage III-IV diffuse large B cell lymphomas.
AB - BACKGROUND: To assess the impact on survival of consolidation radiotherapy to
bulky or semibulky lesions in patients with advanced diffuse large B cell
lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND
METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or
semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were
reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or
semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty
eight patients were irradiated to the involved field and 12 to the extended field
with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation
radiotherapy prevented relapses involving exclusively the bulky area, prolonged
time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year
overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced
relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p =
0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with
semibulky lesions. Multivariate analyses confirmed the independent association
between consolidation radiotherapy and survival, and showed that a dose > or =36
Gy was related to a longer OS, while the extension of the radiotherapy field did
not modify outcome. No treatment-related deaths were observed. Four patients
developed a second malignancy, none of whom had undergone consolidation
radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky
lesions significantly improved the outcome in patients with advanced DLCL in
complete remission after primary chemotherapy. Involved-field irradiation with 36
45 Gy made a prolonged disease control possible without either lethal toxicity or
a higher incidence of second malignancies.
PMID- 10765125
TI - Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant
treatment, in patients with high-risk colon cancer: a randomized phase III study
conducted by the Hellenic Cooperative Oncology Group.
AB - BACKGROUND: It has been shown in randomized studies that adjuvant treatment with
the combination of fluorouracil (FU) and levamisole reduced the risk of
recurrence and deaths of patients with stage III colon cancer. Pharmacological
studies of FU led to its use in combination with a number of modulating agents
including interferon-alpha and leucovorin (LV) that appear to enhance its
activity in vitro. Furthermore, a meta-analysis suggested that the combination of
FU with LV increased the response rate as compared to FU monotherapy in patients
with advanced colorectal cancer. PURPOSE: To evaluate the impact of adjuvant
treatment with the combination of FU and LV with or without interferon alfa-2a
(IFN) on disease-free survival (DFS) and overall survival (OS) for patients with
stage II or III colon cancer. PATIENTS AND METHODS: From August 1989 to July
1997, 280 patients with stage II and III colon cancer entered the study and were
randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6,
followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion,
followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same
chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year
(group B, 141 patients). RESULTS: A total of 109 patients (78.9%) of group A and
119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of
patients of group A and 53.9% of group B received > or =80% of the planned dose
of FU. One patient (group A) was found to be ineligible and was not included in
the analysis. The median relative dose intensity of FU in the two groups was 0.90
and 0.85, respectively. As of August 1998, after a median follow up of 4 years,
there was no significant difference in either 3-year DFS (group A, 83.1%; group
B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox
model, stage of disease, number of infiltrated nodes, tumor grade and presence of
regional implants were identified as significant prognostic factors for OS. Grade
3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A
and in 24.8% of group B. There were no treatment-related deaths. CONCLUSIONS: The
addition of IFN to the combination of FU with LV postoperatively does not improve
DFS and OS of patients with stage II or III colon cancer.
PMID- 10765126
TI - Alteration of a p53 gene status affects outcome of patients with recurrent
ovarian cancer.
AB - The aim of this longitudinal study was to examine whether and how the p53 gene is
altered in patients with recurrent ovarian cancer and to determine the
significance of p53 mutation in recurrent tumors. The primary and recurrent
tumors were examined in 15 patients who had recurrent epithelial ovarian cancer,
and whose primary tumor contained a wild-type p53 gene. The interval between
cytoreductive surgery and the appearance of recurrence ranged from 5. 2 to 63.6
months (mean 23.4 months). Mutations in the p53 gene were screened by polymerase
chain reaction single strand conformation polymorphism analysis and determined by
cycle sequencing. Mutation of the p53 gene in the recurrent tumor was found in 7
of the 15 patients (46.7%). Estimated 3- and 5-year survival rates were 57.1 and
0%, respectively, for patients with p53 gene mutation detected in the recurrence
tumor, and 75.0% and 37.5% for patients without the mutation (p = 0.0155). The
interval between cytoreductive surgery and the appearance of recurrence did not
differ between those groups (549.7 +/- 102.2 vs. 832.9 +/- 283.8 days). Mean
survival time after recurrence was significantly better in the patients without
mutation (438.6 +/- 56.4 vs. 873.0 +/- 157.5 days, p = 0.0125). The present study
suggests that p53 gene mutation frequently occurs in recurrent ovarian cancer and
that alteration of p53 gene status affects salvage chemotherapy. This phenomenon
affects the prognosis of recurrent disease and may predict outcome.
PMID- 10765127
TI - Vitamin D receptor gene BsmI polymorphism correlates with erbB-2/HER-2 expression
in human rectal cancer.
AB - Apart from the regulation of calcium metabolism, 1, 25-dihydroxyvitamin D(3)
plays an essential role in cell proliferation and differentiation in several
tissues. The vitamin D receptor (VDR) gene shows polymorphisms in humans that
appear to be clinically significant in some pathological conditions. In the
present study, the BsmI polymorphism of the VDR gene was studied in 59 Caucasian
patients with rectal cancer (mean follow-up: 48 months). The relationship between
VDR genotypes and the expression of oncogenes as well as their influence on
survival were also investigated. VDR polymorphism was examined in tumor and
normal mucosa cells by PCR technique. The expression of erbB-2/HER-2, p53, ras
and epidermal growth factor receptor (EGFR) was also detected by
immunohistochemistry and protein blotting. The presence of the VDR B allele
significantly correlated with the overexpression of the erbB-2 oncogene. There
was no difference in the VDR genotype between cancer and normal mucosal cells.
Coexpression of erbB-2, pan-ras, p53 and EGFR internal and external domains was
significantly higher in cancer cells than in normal mucosa. There was no
significant correlation between VDR genotypes and age, gender, tumor infiltration
depth, number and site of lymph node metastases and lymphatic or blood vessel
infiltration. The VDR genotype alone did not influence survival. Overexpression
of erbB-2 and EGFR was associated with a poor prognosis. In patients expressing
only one oncogene in cancer cells, the presence of the VDR B allele showed a
tendency to a poor prognosis. In conclusion, VDR gene BsmI polymorphism might
affect the development and prognosis of rectal cancer by influencing erbB-2
oncogene expression.
PMID- 10765128
TI - ets-1 expression in extrahepatic bile duct carcinoma and cholangiocellular
carcinoma.
AB - ets-1 is a transcription factor known to induce the expression of various genes
important for carcinoma progression. However, its clinical significance does not
seem to be uniform for all carcinomas. In this study, we investigated the ets-1
expression in 41 extrahepatic bile duct carcinomas (BDC) and 19 cholangiocellular
carcinomas (CCC). Epithelial cells of normal ducts only occasionally expressed
ets-1, whereas cells of reactive ducts and dysplastic ducts were often positive
for this protein. On the other hand, 61.0% of BDC and 21.6% of CCC were
classified as ets-1-positive, because more than 5% of the carcinoma cells
expressed ets-1. The expression of ets-1 showed inverse relationships with the Ki
67-labeling index and vascular and perineural invasion of BDC, whereas no such
relationships could be established in CCC. Furthermore, the well-differentiated
BCD more frequently expressed ets-1. These results suggest that ets-1 works as a
transcription factor in malignant transformation and progression in early phases
of BDC.
PMID- 10765129
TI - Prognostic significance of nuclear accumulation of c-myc and mdm2 proteins in
synovial sarcoma of the extremities.
AB - We retrospectively analysed a group of primary tumours from 32 patients with
synovial sarcomas of the extremities by using immunohistochemistry on paraffin
embedded tissue samples in order to investigate the prognostic significance of
the nuclear accumulation of c-myc and mdm2 proteins. Nuclear positive
immunostaining for c-myc or mdm2 proteins were revealed in 9/32 cases (28%) and
in 6/30 cases (20%), respectively. Since c-myc protein appears to be a key factor
for keeping cells in an active proliferative stage, we also analysed the growth
compartment of each tumour by using the MIB1 monoclonal antibody, specific for Ki
67 antigen. A high MIB1 index was found in 8/31 cases (26%) but was not
associated either with c-myc or mdm2 nuclear positivity. Analysis of clinical
outcome was performed in a subgroup of 27 patients with a minimum follow-up of 24
months. Among the clinicopathologic parameters and the biological markers, only
the nuclear accumulation of c-myc was significantly associated with a higher
relapse rate (p = 0.03). Accordingly, survival analysis confirmed a trend toward
a poor event-free survival rate and a worse outcome in c-myc-positive cases (p =
0.12). These data demonstrate that assessment of c-myc nuclear accumulation can
be useful to identify high-risk subsets of patients with synovial sarcoma of the
extremities.
PMID- 10765130
TI - Secretion of extracellular matrix (fibronectin), growth factor (transforming
growth factor beta) and protease (cathepsin D) by hepatoma cells.
AB - We investigated facilitation of invasion by growth factors and chemotactic
factors in tumor cell lines, particularly hepatocellular carcinoma. Hepatoma
cells (PLC/PRF/5 and Hep G2) showed strong chemotaxis toward their respective
conditioned media while metastatic pancreatic cancer cells (SU.86.86) and colon
cancer cells (LS 174T) did not migrate toward their respective conditioned media.
Based on immunoblotting, PLC/PRF/5 cells secrete fibronectin (an extracellular
matrix constituent), transforming growth factor-beta (TGFbeta; a growth factor),
and cathepsin D (a protease). Fibronectin induced a migratory response in
PLC/PRF/5 cells, and anti-fibronectin antibody abolished the migratory response
of these cells to their conditioned medium. Anti-integrin-beta(1) antibody also
impeded migration of these cells toward conditioned medium. Polyclonal anti
TGFbeta antibody and protease inhibitors (alpha(2)-macroglobulin and leupeptin)
added to culture media-modulated secretion of fibronectin by PLC/PRF/5 cells.
Although exogenous TGFbeta suppressed SU.86.86 cells, it enhanced PLC/PRF/5 cell
adhesion to substrate, increasing viable cell numbers. These actions indicate
that hepatocellular carcinoma may possess a forceful autocrine mechanism enabling
cells to survive and proliferate under cirrhotic conditions.
PMID- 10765131
TI - Genetic studies in neural tube defects. NTD Collaborative Group.
AB - Neural tube defects (NTD) are one of the most common birth defects and are caused
by both environmental and genetic factors. The approach to identifying the genes
predisposing to NTD, through linkage analysis and candidate gene analysis, is
reviewed along with characteristics of a large, nationally ascertained cohort of
families. Results from specific assessments of p53, PAX3 and MTHFR failed to
suggest that these genes play a major role in NTD development in these families.
Advances in genetic laboratory and statistical techniques have made this a prime
opportunity for investigation into the causes of complex disorders, such as NTD.
However, traditional approaches may prove to be challenging due to the difficulty
of ascertaining samplable multiplex families.
PMID- 10765132
TI - Spina bifida in Saudi Arabia: is consanguinity among the parents a risk factor?
AB - INTRODUCTION: Spina bifida is an important birth defect. Its incidence differs
from one country to another due to different factors. The aims of this study
were: (1) to estimate the incidence of spina bifida in Al-Madinah Al-Munawarah
and compare it with the Eastern part of the Kingdom, and (2) to find out if
consanguinity is a risk factor. METHODOLOGY: A prospective study was conducted
over the period from April 1996 to March 1997 in the city of Al-Madinah Al
Munawarah, Western Province, Saudi Arabia. New cases of spina bifida were studied
and compared to a control group of 72 cases. RESULTS: During the study period, 18
cases of spina bifida were detected. The incidence was 1.09 per 1,000 live
births. The male to female ratio was 2:1; however, this was not statistically
significant. Consanguinity of the parents was found in 89% of the spina bifida
parents and only 67% of the controls (p < 0.0005). CONCLUSION: (1) The incidence
of spina bifida in the city of Al-Madinah Al-Munawarah was similar to that
reported from the Eastern Province of Saudi Arabia. (2) The consanguinity of the
parents was a significant risk factor.
PMID- 10765133
TI - The effect of surgery for split spinal cord malformation on neurologic and
urologic function.
AB - The split spinal cord malformation (SSCM) is an occult spinal dysraphism which
causes tethering of the spinal cord. We performed a retrospective analysis of 15
patients who had split cord malformations (without associated open neural tube
defect) who underwent both pre- and postoperative urodynamic studies (UDS) in
order to determine if a significant percentage of these patients, even in the
absence of overt urologic symptoms, had evidence of urologic dysfunction. Eleven
patients presenting in early childhood and 4 patients presenting later in life
are reviewed. Despite the lack of preoperative urologic symptoms in almost all
patients, 73% of patients had voiding abnormalities on formal testing. UDS on
these patients before and after surgery was a useful adjunct to perioperative
management and decision making, helped define the success of surgery, and gave
objective information for cases in which retethering was suspected.
PMID- 10765134
TI - Aerobic and anaerobic microbiology of wound infection following spinal fusion in
children.
AB - OBJECTIVE: To study the aerobic and anaerobic microbiology of wound infections
following spinal fusion in children. METHODS: Retrospective review of clinical
and microbiological records. RESULTS: Aspirates of pus from 18 infection sites
showed bacterial growth. Anaerobic bacteria only were recovered in 3 (17%)
specimens, aerobic bacteria only in 3 (17%) and mixed aerobic and anaerobic
bacteria in 12 (67%). Forty-two isolates were recovered: 18 anaerobes (1.0
isolates per specimen) and 24 aerobes (1.3 per specimen). The predominant
anaerobes were Bacteroides sp. (9 isolates, including 8 Bacteroides fragilis
group) and 5 Peptostreptococcus sp. The predominant aerobes were Escherichia coli
(6) and Proteus sp. (5). An increase in recovery of E. coli and B. fragilis was
noted in children with bowel or bladder incontinence. CONCLUSIONS: This study
highlights the polymicrobial nature and predominance of anaerobic bacteria in
wound infections following spinal fusion in children.
PMID- 10765135
TI - Tectal gliomas: natural history of an indolent lesion in pediatric patients.
AB - The mesencephalic tectal glioma is a distinctive form of brain stem glioma with
an unusually benign clinical course. Periaqueductal location, lack of contrast
enhancement, and long periods of stability are classic features. The clinical
management of these lesions, especially at the time of radiographic enlargement
varies widely in the published literature. It is unclear whether these
progressive lesions need to be treated. Accordingly, clinical and radiologic
features of 7 patients were reviewed, with attention to the clinical course of
the disease after radiologic enlargement. The age at diagnosis ranged from 3.3 to
16.6 years. Six of 7 had MRI tumor enlargement beginning 0.3-5.7 years after
initial diagnosis. One of these 6 patients had radiographic progression coupled
with a new clinical symptom which was treated with stereotactic radiation
therapy. The remaining 5 patients with MRI progression and normal neurological
exams were not treated and remain free of new neurologic deficits 1.8-6.9 years
after the first radiographic tumor enlargement. The results suggest that
pediatric tectal gliomas are a very low-grade lesion. Conservative management in
the absence of new clinical symptoms could be argued, reserving radiotherapy or
chemotherapy for clinical progression.
PMID- 10765136
TI - Pediatric low-grade and ependymal spinal cord tumors.
AB - Our institutional experience with pediatric spinal cord tumors includes 25
patients with the diagnosis of ependymoma (EP; n = 4), myxopapillary ependymoma
(MPEP; n = 4), juvenile pilocytic astrocytoma (JPA; n = 5), nonpilocytic
astrocytoma (WHO grade I or II, n = 6), and other nonastrocytic spinal cord
tumors (n = 6) treated during the period 1974-1999. Nineteen patients required
radiation therapy (RT). The median progression-free survival following RT was 65
months (range 1-206 months). Seven patients recurred at an average of 22 months.
The EP patients recurred at an average of 8.5 months, while the patients with low
grade astrocytoma recurred at an average of 42 months. Including the 6
nonsurviving patients, the median overall survival was 96 months. Two EP patients
died with a progression-free survival of 9 months. One patient with MPEP died of
other causes at 7 months. The treatment of pediatric spinal cord tumors should be
individualized based on the histologic type. Radical surgery is indicated for
nonmyxopapillary EP and low-grade astrocytic tumors. The need for adjuvant
therapy most often depends on the extent of resection as well as the tumor type.
Patients with disseminated EP, MPEP, JPA and nonpilocytic astrocytoma may achieve
long-term progression-free survival with craniospinal irradiation.
PMID- 10765137
TI - Use of a portable CT scanner during resection of subcortical supratentorial
astrocytomas of childhood.
AB - The development of intraoperative imaging has made it possible to visualize
shifting brain structures during surgery, and may allow greater intraoperative
discrimination of normal and abnormal tissue. This may provide greater confidence
to the neurosurgeon to proceed with a more extensive resection while decreasing
postoperative morbidity. We investigated the intraoperative use of a portable CT
scanner in the resection of 4 cases of supratentorial, subcortical astrocytomas
of childhood to assess its usefulness in determining the endpoint of the
dissection. We operated on 4 patients, ages 3-17, with astrocytomas. Three were
thalamic, and 1 was based primarily in the caudate nucleus. The approach to the
basal ganglia was transcallosal in 3 and transtemporal in 1. Specific
observations on the intraoperative use of the portable CT scanner included its
overall facility, any additional operative time required, the overall quality of
the images, intraoperative decisions made based on the images and problems
associated with its use. These observations are presented with a review of
intraoperative imaging as it pertains to deep pediatric brain tumors. The CT
scanner was helpful in limiting the dissection of the hypothalamic and midbrain
regions and in localizing remaining abnormal tissue. The scans allowed informed
decisions about leaving margins of the tumor which were adjacent to vital
structures, but dit not prove to be a decisive factor in providing a complete
resection. The following observations are worth noting: (1) average imaging time
was 20 min per scan; (2) the extent and location of residual enhancing tumor was
easily identified despite other materials in the surgical bed; (3) air/tissue
interfaces limit resolution; (4) tumors retain contrast long enough to obtain
multiple scans without additional dye, and (5) the cost profile of a mobile CT
scanner is superior to that of a fixed intraoperative CT scanner.
PMID- 10765138
TI - Pediatric peri-insular hemispherotomy.
AB - A number of surgical procedures are available for patients with epilepsy
associated with diffuse hemispheric disorders. In this report, 16 pediatric
patients had hemispherectomy: 5 underwent hemidecortication and 11 had peri
insular hemispherotomy. The clinical records were retrospectively reviewed, and
the results and complications of the procedures were documented. The procedure
was feasible in very young children and in the absence of ventriculomegaly.
PMID- 10765139
TI - Fronto-orbitonasal intradiploic meningioma in a child.
AB - Intradiploic meningioma, which may be classified as a subgroup of intraosseous
meningioma, is a rarely encountered disorder. To date, less than 10 cases have
been reported. Here, we report a case of fronto-orbitonasal intradiploic
meningioma. A 12-year-old female with exophthalmos and diplopia was operated on
for a cranial intradiploic mass lesion. Histopathological evaluation of the
specimen confirmed the diagnosis of intradiploic psammomatous meningioma. Her
exophthalmos did not change, but the diplopia disappeared. This case is unique in
that it is an extensive case of intradiploic meningioma of the orbital roof and
frontal base in a child. Intradiploic meningiomas generally are of psammomatous
type. Especially tumors adjacent to the orbita cause exophthalmos; cases located
on the other side of the calvarium may not cause any symptom or sign other than
headache or sometimes a mass on the scalp. Treatment, as with meningiomas located
in the intracranial cavity, is total resection of the lesion.
PMID- 10765140
TI - Use of bipedicular advancement flaps for intrauterine closure of myeloschisis.
AB - Several groups have begun to explore the feasibility and utility of intrauterine
closure of myelomeningocele. A subset of these fetuses have defects which fall
into the category of myeloschisis, and therefore have inadequate skin to enable
primary closure. After considerable discussion, it was decided to utilize
bipedicular flaps to close these lesions. The procedure is described, and
representative examples are shown. To date, 13 of 56 fetuses have required this
approach for closure in utero. While this technique generally provides adequate
coverage of the dural sac, the cosmetic results have been less than optimal.
PMID- 10765141
TI - Introduction to antibody engineering and phage display.
AB - The vertebrate immune system, capable of rapidly producing highly specific
antibodies upon immunisation, has been used to produce murine monoclonal
antibodies (mAbs) via immortalisation and isolation of antibody-secreting cells.
These mAbs have had a profound impact in the fields of diagnostics and
therapeutics. However, the therapeutic use of murine mAbs is complicated by their
immunogenicity. To circumvent this immunogenicity, antibody engineering
techniques which render murine mAbs more compatible with the human immune system
have been devised. Over the last decade, the technique of antibody phage display,
which facilitates the production of human mAbs, has been developed. This review
serves as an introduction to antibody engineering, phage display and the
development of antibody fragments into viable diagnostic and therapeutic
reagents.
PMID- 10765142
TI - Detection of hepatitis C core antigen in the antibody negative 'window' phase of
hepatitis C infection.
AB - BACKGROUND AND OBJECTIVES: Despite improvements in assays for anti-HCV, there
remains a significant delay before the appearance of antibodies following
infection, during which, circulating viral RNA is present. We have evaluated a
prototype assay for the serological detection of hepatitis C virus (HCV) core
antigen with specimens derived from the early phase of HCV infection. MATERIALS
AND METHODS: Serial specimens from 24 individuals undergoing HCV seroconversion
were tested for the presence of anti-HCV, HCV RNA and HCV core antigen. RESULTS:
HCV antigen was detected at the same time as HCV RNA in 83% (20/24) cases. The
mean time to the first detection of HCV antigen was approximately 1 day later
than HCV RNA. Overall, 87% of HCV-RNA-positive specimens contained detectable HCV
core antigen. CONCLUSION: These results indicate that HCV core antigen can be
identified by routine serological ELISA in specimens from the early antibody
negative phase of HCV infection. A test for HCV core antigen may be a useful test
for identifying window phase blood donations from antibody negative donors
infected with HCV.
PMID- 10765143
TI - Studies on the removal of abnormal prion protein by processes used in the
manufacture of human plasma products.
AB - BACKGROUND AND OBJECTIVES: To identify if any process steps used in plasma
fractionation may have a capability of removing agents of human transmissible
spongiform encephalopathy (TSE). MATERIALS AND METHODS: Sixteen fractionation
steps were investigated separately by adding a preparation of hamster adapted
scrapie 263K to the starting material at each process step and determining the
distribution into resultant fractions of protease-K-resistant (abnormal) prion
protein by Western blot analysis. RESULTS: A number of process operations were
found to remove abnormal prion protein to the limit of detection of the assay.
These were cold ethanol precipitation of fraction IV (log reduction, LR, >/=3.0)
and a depth filtration (LR >/=4.9) in the albumin process; cold ethanol fraction
I+III precipitation (LR >/=3.7) and a depth filtration (LR >/=2.8) in the
immunoglobulin processes and adsorption with DEAE-Toyopearl 650M ion exchanger
(LR >/=3.5) in the fibrinogen process. In addition, a substantial degree of
removal of abnormal prion protein was observed across DEAE-Toyopearl 650M ion
exchange (LR = 3.1) used in the preparation of factor-VIII concentrate; DEAE
cellulose ion exchange (LR = 3.0) and DEAE-sepharose ion exchange (LR = 3.0) used
in the preparation of factor-IX concentrates and S-sepharose ion exchange (LR =
2.9) used in the preparation of thrombin. CONCLUSIONS: Plasma fractionation
processes used in the manufacture of albumin, immunoglobulins, factor-VIII
concentrate, factor-IX concentrates, fibrinogen and thrombin all contain steps
which may be capable of removing causative agents of human TSEs.
PMID- 10765144
TI - Transfusion thresholds in common elective surgical procedures in Finland.
AB - BACKGROUND AND OBJECTIVES: Transfusion practices and thresholds in common
elective surgical procedures were investigated in a nationwide multicenter survey
in Finland. MATERIALS AND METHODS: The records of 764 total hip replacement
(THR), 397 total knee replacement (TKR) and 343 transurethral resection of the
prostate (TURP) patients were reviewed by four anesthesiologists. RESULTS: The
allogeneic red cell (RBC) transfusion rates in THR, TKR and TURP operations were
92, 84 and 18%, respectively. In THR and TKR, 74% of patients who lost 20% or
less of their blood volume during hospitalization were transfused with RBCs.
Postoperatively, the median pretransfusion hemoglobin values were 9.6 g/dl in
orthopedic operations and 10.7 g/dl in TURP. In some hospitals, the median
transfusion threshold in TURP patients was as high as 11.2 g/dl. CONCLUSION: The
transfusion thresholds in all operations were liberal compared to recent
international recommendations. Inappropriate thresholds were reflected in the
high transfusion rates. This study accentuates the need for continuous discussion
and educational measures to find optimal indications for transfusion in surgery,
and to rationalize the transfusion policy in Finland.
PMID- 10765145
TI - Extracorporeal plateletpheresis induces the interaction of activated platelets
with white blood cells.
AB - BACKGROUND AND OBJECTIVES: In this study we investigated whether platelet
activation during apheresis results in the binding of platelets to white blood
cells. MATERIAL AND METHODS: Analysis of platelet-leukocyte interaction was
performed using multiparameter, three-color flow cytometry. RESULTS: Over the
duration of the procedure, there was an increase in the surface expression of
CD62p (P-selectin) and CD63 (p<0.05), and also in the binding of platelets to
monocytes (p<0.05), neutrophilic granulocytes (p<0.05) and to CD3+ cells
(initially to a low degree; p<0.05). Platelet binding to CD19+ cells did not
change significantly. CONCLUSION: This study demonstrates that platelets become
activated during apheresis and that following this process, interaction with
monocytes and neutrophilic granulocytes occurs.
PMID- 10765146
TI - Thrombopoietin levels in patients undergoing autologous peripheral blood stem
cell transplantation.
AB - BACKGROUND AND OBJECTIVES: High-dose chemotherapy with peripheral blood stem cell
transplantation (PBSCT) has become an important treatment for hematological and
solid tumors. Several reports on endogeneous production of thrombopoietin (TPO)
in patients undergoing intensive chemotherapy have been published. We measured
TPO levels in patients undergoing autologous PBSCT in order to elucidate the role
of TPO in megakaryopoiesis and platelet recovery following stem cell
transplantation. We also examined whether PBSC from different patient groups
(patients with lung cancer and malignant lymphoma) had different effects on TPO
levels. MATERIALS AND METHODS: Serum levels of TPO and other cytokines were
determined by ELISA before and after PBSCT in 10 patients with lung cancer and 18
patients with malignant lymphoma. RESULTS: Compared to platelet counts at 1 week
after transplantation, those at 3 weeks were significantly increased (p<0.001).
In contrast, serum TPO levels were significantly decreased 3 weeks after PBSCT
(p<0.01). There were no significant differences in levels of other cytokines
between 1 and 3 weeks after transplantation. A strong correlation was found
between serum TPO levels and circulating platelet counts (r = -0. 675; p<0.0001).
Platelet counts exhibited a significant recovery and TPO levels also decreased
significantly in malignant lymphoma patients after transplantation. There were no
significant differences in TPO levels in lung cancer patients, although the same
tendencies as for malignant lymphoma patients were observed for both platelet
count and TPO level. On analysis of transfused PBSC, we found that the numbers of
CFU-GM were similar in lung cancer and malignant lymphoma patients. However, the
numbers of CD34+ cells were significantly higher in lung cancer patients than in
malignant lymphoma patients. CONCLUSION: Our findings suggest that TPO plays a
critical role in the reconstitution of megakaryopoiesis and platelet production
following PBSCT, and that the type of stem cell, tumor, and preceding
chemotherapy affect serum TPO levels after transplantation.
PMID- 10765147
TI - Pretransfusion testing without serologic crossmatch: approaches to ensure patient
safety.
AB - BACKGROUND AND OBJECTIVES: A crossmatch is usual in pretransfusion testing, but
we eliminated it at our tertiary care university hospital. In place of the
crossmatch, we have introduced a system where, if an antibody screen is negative,
two technologists confirm the ABO of the same patient sample, and we release
blood of the patient's type without a serologic or electronic crossmatch.
MATERIALS AND METHODS: In 65,628 samples received for pretransfusion testing, we
studied the effect of common errors that occur from the time of receipt of a
sample until release of the blood unit, in order to decide if elimination of the
serologic crossmatch would affect patient safety. All sample labels were
inspected for acceptability. RESULTS: A total of 1,082 (1.64%) samples were
rejected for mislabeling. Discordance in patient ABO typing results between two
technologists was 0.43%. Such discrepancies were resolved before the release of
blood units. No donor unit mislabeling or unit release errors were detected.
CONCLUSION: Elimination of the crossmatch for red cell antibody-negative patients
is safe provided a system of error detection is used. This enhances patient care
through the quicker release of blood, increased laboratory efficiency and
decreased costs.
PMID- 10765148
TI - Therapeutic immunoadsorption increases the level of circulating soluble HLA
molecules.
AB - BACKGROUND AND OBJECTIVES: Immunoadsorption (IA) is an established procedure to
remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind
to human leucocyte antigen (HLA) molecules, we were interested to know whether
removal of Ig will also influence the plasma concentration of soluble HLA (sHLA).
PATIENTS AND METHODS: Nine patients suffering from severe autoimmune disease and
undergoing 17 single courses of IA treatment were monitored for their sHLA class
I (sHLA-I) and sHLA-DR plasma levels. Plasma was separated by a hollow-fiber-type
separator. Plasma samples were taken before therapy, after 15 min of
recirculation (without operating the adsorber), after 1 and 2 liters of plasma
adsorption, and 24 and 48 h after the end of IA. RESULTS: Before treatment the
mean levels of sHLA-I and sHLA-DR were 0.37 (+/-0.06 SEM) and 0. 32+/-0.05
microg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA
DR (0.80+/-0.10 microg/ml) was observed (p<0.001), whereas sHLA-I was only
slightly affected (mean: 0.45+/-0.06 microg/ml). sHLA concentrations returned to
initial levels after 24 h. CONCLUSION: The significant increase in sHLA-DR may
contribute to the immunomodulatory effect of IA.
PMID- 10765149
TI - Polymorphisms of RhD(Va) and a new RhD(Va)-like variant found in Japanese
individuals.
AB - BACKGROUND AND OBJECTIVES: Red cell type RhD(Va) lacks epD1 and 5 and is encoded
by hybrid RHD-CE(5)-D alleles. We analyzed RhD(Va) and RhD(Va)-like samples in
Japanese blood donors. MATERIALS AND METHODS: Ten RhD(Va) samples lacked epD1 and
5 and 3 RhD(Va)-like variants also lacked, epD2 and a part of 6/7. We identified
the full-length nucleotide sequences of the complementary DNA (cDNA) synthesized
from 4 samples: 3 of type D(Va) and the 4th a D(Va)-like variant. RESULTS:
Although their sequences differed from each other, all the substitutions were
exclusively in exon 5. Three D(Va) samples had hybrid RHD-CE(5)-D alleles, but
the D(Va)-like variant had a unique nucleotide substitution with a single amino
acid change, E233K. Exon 5 of the genomic DNA from all 13 samples was analyzed by
sequencing. No other sequences were identified. CONCLUSION: All RhD(Va) and
RhD(Va)-like variants had the substitution for E233. E233 seems to be a
determinant of epD1 and 5. A new category of RhD variant, DYO, was identified.
PMID- 10765150
TI - Splenic lymphoma presenting as warm autoimmune hemolytic anemia associated with
pure red cell aplasia.
AB - BACKGROUND AND OBJECTIVE: Warm autoimmune hemolytic anemia (AIHA) is a condition
in which peripheral red blood cell (RBC) destruction is induced by the presence
of an autoantibody. Pure red cell aplasia (PRCA) represents an isolated process
of decreased erythropoiesis. The combination of both is quite rare, with a very
poor prognosis. We describe a patient with isolated splenic lymphoma whose
presentation was a combination of AIHA and PRCA. The patient was resistant to all
treatment. MATERIALS AND METHODS: Erythroid colony assays were performed, in
order to compare the effect of the patient's serum on colonies with that of a
normal control. RESULTS: The patient's serum significantly suppressed normal
erythroid colony growth. A red cell eluate revealed the presence of a warm
autoantibody. CONCLUSIONS: The patient's serum contained warm autoantibody
responsible for peripheral RBC destruction and a humoral factor, perhaps the warm
autoantibody, which suppressed bone marrow erythropoiesis. Establishing an early
diagnosis, and treatment of the underlying disease might result in a better
prognosis.
PMID- 10765151
TI - A retrospective study of viral status of human plasma for practical classes.
PMID- 10765152
TI - Utility of prospective study of donors deferred as HTLV indeterminate.
PMID- 10765153
TI - Safety of multiple-unit transfusions.
PMID- 10765154
TI - Monocyte adhesion to platelet concentrate storage bags and cytokine production.
PMID- 10765156
TI - A Rose is a Rose is a Rose.
PMID- 10765155
TI - Monocyte activation in platelet concentrates.
PMID- 10765157
TI - Does Calcium Supplementation Reduce the Risk of Urinary Oxalate Calculi after
Jejunoileal Bypass for Morbid Obesity?
AB - Twelve patients having received an end-to-side jejunoileal bypass operation for
morbid obesity 6-10 years previously were studied over three periods of 2 weeks
each. The first period was used for baseline observations without any treatment.
For the second period patients were randomly assigned to equimolar (75 mmol/day)
oral calcium supplements administered either as a slow release or as a bolus
calcium preparation. During the third period these treatments were crossed over.
The calcium preparations used caused equal reductions in frequency of bowel
movements. Both preparations increased serum calcium and serum phosphate, but
significance (p < 0.05) was reached only during supplementation with the slow
release preparation. Despite the Intended raising of serum calcium levels, none
of the preparations influenced the 24-hour urine oxalate to creatinine ratio or
the urine stone index. There are several other reasons for supplying extra
calcium after intestinal bypass procedures, but our data do not support the
concept of preventing renal stone formation by means of calcium supplementation.
PMID- 10765158
TI - Myocardial Mass in Morbidly Obese Patients and Changes with Weight Reduction.
AB - Cardiac weight was determined at autopsy in 27 morbidly obese, but otherwise
healthy men (mean weight 168 kg) and women (mean weight 138 kg) who died
suddenly, prior to, or shortly after gastric restriction operations for relief of
obesity. They had lost no weight. Post-mortem examination revealed no cardiac or
other pathology explaining the cause of death. Cardiac weight was also measured
in 25 men and women of equivalent baseline weight and body mass index who, after
operation, subsisted on a hypocaloric diet for 3-4 months after operation, but
then died suddenly. Mean weight losses of this latter group were 45.8 kg in men
and 32.9 kg in women. No cardiac abnormalities and no organic causes of death
were found at autopsy. Decreases in heart weight were calculated. The baseline
measurements demonstrated that cardiac weight in the healthy obese rose with
increasingly severe obesity in both sexes, but the increase tended to lessen with
more extreme obesity. The generally quoted figures of cardiac weight as a
fraction of body weight are 0.043 and 0.040% for men and women, respectively. In
the group of morbidly obese men, cardiac weight was 0.035% of body weight or 16%
lower than predicted. In morbidly obese women, cardiac weight was 0.030% of body
weight or 25% lower than predicted. In men, a 28% body weight reduction due to
dietary restriction resulted In a proportionately similar 20% decrease in cardiac
weight. In contrast, in women after a 27% loss of body weight, cardiac weight
decreased only 5%. Severe dietary restriction with a drastic body weight loss did
not result in a disproportionate decrease of cardiac weight in either sex, when
final body weight had remained above or in the normal range.
PMID- 10765159
TI - Obesity: an indication rather than contraindication to laparoscopic
cholecystectomy.
AB - Obesity was originally designated as a contraindication to laparoscopic
cholecystectomy; however, as experience in the procedure develops, it is evolving
into an indication. Out of the first 325 consecutive patients undergoing
laparoscopic cholecystectomy, 91 were determined to be either obese or morbidly
obese. Group I (normal body habitus), consisted of 228 patients, group II (obese)
67 patients, and group III (morbidly obese) 24 patients. Six patients were
excluded because of inadequate follow-up data. The groups were fairly well
matched for age and seemed to differ only in height and weight. Operative time
was similar in groups I and II, while it was approximately 23% longer for group
III. The outcome of surgery was compared with respect to conversion to open
cholecystectomy, postoperative complications, mortality, length of postoperative
stay, and return to normal activity. None of the differences were statistically
significant with the exception of the slightly longer length of time for
laparoscopic cholecystectomy in the morbidly obese. Laparoscopic cholecystectomy
is a safe and effective treatment for obese patients and even for morbidly obese
patients, and should be the procedure of choice for these patients, avoiding
complications of prolonged bedrest and wound complications, so common in these
patients.
PMID- 10765160
TI - A Clinical Study of Protein Sparing Modified Fast (PSMF) Administered
Preoperatively to Morbidly Obese Patients: comparison of PSMF with natural food
products to originally prepared PSMF.
AB - Morbidly obese patients are generally in a malnutritional state with an extremely
high operative risk. In order to reduce the operative risk, surgeons should make
every effort before the operation. A protein sparing modified fast (PSMF) may
exhibit its high effectiveness when taken at least for 2 weeks preoperatively. In
this study, PSMF prescribed with natural food products was compared with prepared
PSMF having an ideal composition from the clinical standpoint. Though it is
natural for patients to favor the former, the latter proved to have a superior
effect in clinical practice. By performing a PSMF for 2 weeks preoperatively,
however, even the PSMF with natural food products seemed to fulfill its purpose
sufficiently.
PMID- 10765161
TI - PSMF in Preoperative Treatment of Gastric Restrictive Surgery: foods for special
dietary and medial purpose.
PMID- 10765162
TI - Hepatic Abnormalities in Obesity: comparison between mildly obese cases and
morbidly obese cases.
AB - Hepatic morphology and clinical course of mildly obese subjects with abnormal
liver tests were determined in comparison with those of surgically treated
morbidly obese cases. Twenty mildly obese subjects (mean body mass index, 27.9)
with elevated serum transaminase levels were followed up on a low-calorie diet.
Nineteen morbidly obese patients (mean body mass index, 39.2) had a surgical
biopsy at gastric restrictive surgery. In these two groups, the frequency and the
severity of hepatic steatosis and fibrosis were comparable, whereas intralobular
cell infiltration was somewhat greater in the mildly obese group. Follow-up
studies of the two groups showed remarkable improvement of serum transaminase
levels, the extent of which was greater in surgically treated cases. Thus, in
mildly obese subjects with abnormal liver tests, (1) hepatic histological
abnormalities are not milder than those in morbidly obese cases, and (2)
Improvement of serum transaminase levels upon diet therapy is less satisfactory
than that in morbidly obese cases treated surgically. It is suggested these two
groups may not be in the same spectrum of obesity-related hepatic disorders.
PMID- 10765163
TI - Weight Loss Comparison of Gastric Bypass and Silastictrade mark Ring Vertical
Gastroplasty.
AB - Thirty-five patients who had undergone primary bariatric surgery between 14
January 1988 and 16 September 1990 were selected for retrospective analysis based
on the availability of 3-month and 1-year (+/- 3 months) follow-up visit records.
Fourteen patients had undergone a Roux-en-Y gastric bypass (RGB), and 21 patients
had undergone a Silastictrade mark ring vertical gastroplasty (SRVG). Weight
loss, pre- and postoperative body mass index (BMI), and the postoperative
incidence of dumping syndrome, anemia, and food intolerance were compared. At 1
year (+/- 3 months), the average weight loss was 40 kg for the entire group. The
RGB patients lost an average of 41.7 kg, while the SRVG patients lost an average
of 39.4 kg (not significant). The average preoperative BMI was 46.4 kg/m(2) for
both the RGB and SRVG patients. The 1-year postoperative BMI was 30.6 kg/m(2) for
the RGB patients and 32.4 kg/m(2) for the SRVG patients (not significant). One
RGB patient developed a dumping syndrome, and one RGB patient showed evidence of
a nutritional anemia. Neither complication was incapacitating. The SRVG patients
had far more difficulty in advancing the consistency and variety of their diet in
the early postoperative period, with only 62% (13/21) of the SRVG patients
demonstrating an ability to tolerate a regular consistency diet at the end of 1
year. Seventy-six percent (16/21) of the SRVG patients reported occasional
vomiting at 1 year, compared to only 7% (1/14) of the RGB patients. This
retrospective analysis documented comparable weight loss for the RGB and SRVG
operations. A greater incidence of eating problems up to 1 year postoperatively
was observed in patients following SRVG in comparison to RGB.
PMID- 10765164
TI - Horizontal and Vertical Gastroplasties: extended follow-up and late results.
AB - In the late 1970s and early 1980s five individual series of gastroplasties were
performed with sequentially smaller pouch and stoma sizes. Three of the series
were horizontal gastroplasties and two were vertical gastroplasties. Stomas in
all but the last series were banded with multiple strands of nylon and in the
final series with a Teflon strip. Early and late weight loss results are
presented. Mean follow-up for all groups ranged from 5.4 to 6.5 years, some
patients being followed as long as 11.2 years. Weight loss results showed that
mean greatest percentage excess weight loss for the groups was 60-70%, with
losses ranging from unacceptable to ideal in all groups. Mean final percentage
excess weight losses were below the level of success in all but the Teflon-banded
vertical gastroplasties. The range of final data showed that percentage losses
ranged from negative (greater than pre-operative weight) to near ideal across the
groups. A small but significant number of patients in each group were considered
early failures, never having achieved a weight loss level meeting the criterion
of success. Maintained successful weight loss varied between the gastroplasty
groups from 11 to 27%. This was after a mean follow-up of from 7.3 to 9.4 years.
Stoma data showed a general trend to diminution in size as success increased;
however, range data showed great variability in stoma size associated with
success. Further analysis of stomas indicated that there was no absolute
correlation between weight loss and stoma size. Many of the gastroplasty failures
in all groups were converted to other types of procedures, the incidence varying
from 27 to 46.5% between groups. It is concluded that while weight loss after 2
years of follow-up was successful in the majority of instances and with all types
of gastroplasty, late follow-up indicated an ever-increasing failure rate that
varied between the series from 73 to 89%. It is therefore recommended that
authors reporting gastroplasty results take into account the foregoing facts and
clearly define length of follow-up and, where possible, present late, complete
follow-up data.
PMID- 10765165
TI - The Rationale and Results of Gastroplasty/Distal Gastric Bypass.
AB - A recent review of the results of gastroplasties done at the University of
Alberta Hospital showed that there was a high incidence of late weight loss
failure. Therefore a new operation, gastroplasty/distal gastric bypass, has been
performed on 263 patients. This operation results In a profound (mean greatest
percentage excess weight loss of 87% at approximately 2 years) and lasting weight
loss (mean final percentage excess weight loss of 78%) at 4 years, range 2-7.5
years post-operatively. Only 0.9 % of patients failed to maintain at least a 40%
excess weight loss. The operation achieves its effect through a moderate
restriction that permits patients to eat normal table food from the time of
discharge and with a mild metabsorption that is not ordinarily associated with
diarrhea or notable deficiencies. Certain patients required debanding of the
stoma and others developed staple-line eventration. Neither of these events after
long-term follow-up resulted in weight loss failure nor in other serious side
effects. It Is concluded that moderate failure of the gastroplasty stoma and
staple line does not necessarily result in weight loss failure, because the
malabsorptive portion of the operation remains intact. Low hemoglobin occurred in
16% of cases and deficiency of serum iron In 34%; a much smaller number of
patients had chronic or Intermittent deficiencies of these entities. Correction
was easily achieved with oral replacement. Deficiencies in albumin, calcium,
phosphorus and folate were rarely seen and minimal elevation of serum AST values
occurred In just over 1% of patients. Chronic deficiencies or elevations were not
seen in these patients. Stomal ulcer occurred in 6% of patients and bleeding
associated with stomal ulcer in 1%. Half the patients with ulcer were managed
with H&inf2; blockers, the other half with vagotomy. Both forms of treatment when
individualized effectively prevent re-ulceration.
PMID- 10765166
TI - Weight Loss and Complications After Vertical Banded Gastroplasty.
AB - We have performed 124 vertical banded gastroplasties (VBG) according to Mason,
except that we used a collar 5.5 cm in circumference. We carried out a midline
incision In 68 cases and a left subcostal incision in 56, with double application
of a 2-row stapler with reinforcement In the first 69 cases and a single
application of a 4-row stapler in 55 (15 with reinforcement, 40 without). We have
followed 107 (86.2%) patients for a mean of 30 months (range 3-84). The mortality
rate was nil. The intraoperative complications were three spleen lacerations
(splenectomy), and the early complications were two gastric leaks (re
intervention) and one gastric bleeding. The late complications were one gastric
perforation (re-intervention), four outlet stenoses (one re-intervention), one
bleeding by collar erosion and nine ventral hernias (occurring only with the
midline incision). The percentage excess weight loss was 46.3 +/- 16.4 at 6
months, 53.4 +/- 17.9 at 1 year, 47.8 +/- 19.6 at 3 years, and 45 +/- 23.3 at 5
years. In 12 cases the weight loss was unsatisfactory (less than 30% of the
initial excess weight). Often such failures were due to staple-line disruption.
We have had no staple-line disruptions since we stopped performing the
reinforcement. VBG has a low incidence of complications, but sometimes these may
be serious. In our opinion, the technical procedures which offer a stronger
vertical partition give better results for weight loss.
PMID- 10765167
TI - Observations on Nine Personal Cases Where Esophagitis Has Appeared as a
Complication of a Functioning Vertical Gastroplasty.
AB - This paper is based on observations on a personal series of patients who
presented with severe ulcerating esophagitis, unresponsive to medical treatment
following a vertical stapled gastroplasty. With one exception this was a late
complication in an effective weight loss procedure. The therapeutic modalities
chosen to treat this problem depended on patient choice, as well as personal
experience with treating earlier cases. Unfortunately, I could find little
guidance in the literature or from my colleagues on how to treat this problem.
Conversion to a Roux-Y gastric bypass seemed the most satisfactory solution to
the problem, relieving the symptoms and maintaining the weight loss.
PMID- 10765168
TI - Medical and Lay Information about Obesity Surgery.
AB - Reluctance or open opposition to new surgical techniques or surgical approaches
are common both with medical and non-medical groups, and they are mainly due to
lack of proper knowledge of the possibilities and limitations of these
procedures. In Mexico, there is a lag between medical and surgical progress and
the medical and lay information about them. The purpose of this study was to
assess the magnitude of this situation. The 238 physicians interviewed comprised
137 internists and 101 surgeons. 787 patients were also interviewed; all of them
were asked about obesity surgery, information on medical and non-medical
publications, advice about obesity surgery In a special case or patient, and type
of surgery performed. Among the physicians, none of the internists would advise
obesity surgery to any patient, and most of them only recall intestinal bypass as
the current procedure for obesity; only 3% had read about obesity surgery.
Surgeons, on the contrary, had more precise information about surgery, 25% had
read about techniques and results, and 20% would advise surgery for their
patients. The general population had a very vague idea of obesity surgery, with
confusion between liposuction and intestinal surgery; most of the individuals
interviewed had magic or miraculous conceptions about surgeons and their powers'
to eliminate fat. It is concluded that medical and non-medical groups lack the
adequate knowledge and comprehension of obesity surgical procedures, and this is
one of the problems obesity surgeons face in everyday practice.
PMID- 10765169
TI - The Effect of Gastric Bypass on Cholesterol, HDL, and the Risk of Coronary Heart
Disease.
AB - A review of 150 charts revealed that 36 patients had pro-operative serum
cholesterol greater than 200 mg% prior to Roux-Y gastric bypass. The average pre
operative weight was 266 lb (121 kg) and at 1 year postoperative 166 lb. (75 kg),
or 100 lb. (45 kg) lost (77% excess weight loss). We compared the following pre-
and postoperative data and found that: (1) cholesterol was decreased by 24% and
triglycerides decreased by 40%; (2) postoperative cholesterol/HDL-C ratio of 3.31
put our patients in the half of average risk category for a clinical pathological
coronary event according to the SmithKline Beecham Laboratories risk ratio chart.
We conclude that Roux-Y gastric bypass and its ability to produce a significant
weight loss and markedly affect cholesterol and triglyceride metabolism will also
reduce a patient's risk of myocardial infarction.
PMID- 10765170
TI - Post-operative Complications in a Series of Gastric Bypass Patients.
AB - In order to evaluate the short- and long-term complications of obesity surgery, a
review was done on 452 cases of morbidly obese patients who met the basic
guidelines for obesity surgery and were operated upon; gastric bypass was
performed in all of them. There were seven major complications: one myocardial
infarction, two pulmonary embolisms, two gastric fistulas, one sepals from bowel
infection and one acute thrombocytopenia purpura. Five of the patients died. It
is important to note, in those patients with abdominal complications, the absence
of classical signs and symptoms of peritonitis, and the need to act immediately
in order to solve the postoperative problem. As in other series, minor
complications were also present: subcutaneous infection in 18 cases, hernia in
four, peptic syndrome in three, mild anemia in 28 and hypovitaminosis A and B in
58; all received medical treatment without problem. It is concluded that obesity
surgery, like all major surgery in high-risk patients, may have complications,
and therefore It is necessary to recognize them in order to prevent them, and if
they emerge, diagnose and treat properly.
PMID- 10765171
TI - The Post-anaesthetic Recovery in Obesity Surgery: comparison between two
anaesthetic techniques.
AB - Forty morbidly obese patients, scheduled for restrictive gastric surgery, were
anaesthetized with two different techniques. In group A (20 patients) anesthesia
was induced and maintained with Propofol (total intravenous anesthesia, TIVA); in
group B (20 patients) anesthesia was induced with Thiopental and maintained with
Isoflurane (balanced anesthesia). At the end of surgery, recovery time (RT) and
recovery score (RS) were assessed according to a modified Aldrete score. There
was no difference of RS between group A and group B. RT was shorter (though not
statistically significant) in group A than in group B. Our experience suggests
that both techniques can be safely used in these patients, but with TIVA,
patients appeared more awake and cooperative earlier. Such an advantage may be
useful to prevent serious complications (thromboembolism and pulmonary failure)
in the postoperative period.
PMID- 10765172
TI - Scan of Hypothalamic Satiety Centers in the Control of Obesity: a preliminary
report.
AB - Using thioglucose labeled with goid-1 98 (Au-1 98) at doses of 2OuCi per patient,
we took specific scans of the hypothalamic satiety centers in 50 normal
volunteers and in 50 obesity patients, due to the ability of the hypothalamic
satiety centers to take up thioglucose in their glucostat receptors. From the 50
obesity patients, two were classified as having hypothalamic obesity. The rest
were controlled with serial scans in combination with nutritional, surgery and
clinical control of obesity, with satisfactory results for the 'obesity team'.
PMID- 10765173
TI - Changes in Sexual Patterns Following Vertical Banded Gastroplasty and Weight
Loss.
AB - Weight loss following vertical banded gastroplasty (VBG) is well established.
Herein the effect of weight loss on sexuality was examined. Twenty-seven females
and seven males (mean age 39 years) underwent VBG and returned completed
questionnaires regarding preoperative and postoperative sexuality. There was a
mean interval follow-up of 33 months, with a mean weight loss of 48.6 kg. In
general, there was an overall increase in frequency, quality, and enjoyment of
sex. Similarly, an improvement in body image, an increase in initiating sexual
intercourse, and an increase in the number of sexual partners was found. A small
number of patients developed psychosocial problems that limited sexual enjoyment.
In conclusion, weight loss after VBG improves sexual life, though not uniformly,
as new sexual problems can occur. Decreased sexual inhibition, increased sexual
enjoyment and frequency, and increased frequency of orgasm characterizes many of
the changes occurring after VBG with resultant weight loss. To help provide a
holistic approach to the care of morbidly obese patients after VBG, the potential
alterations in their sexual lives should be considered.
PMID- 10765174
TI - Technical Points in Vertical Gastroplasty for Morbid Obesity.
AB - The success of vertical gastroplasty may be jeopardized by gastric leakage or
ulceration due to failure of the technique. Reports of band erosion and staple
line leakage have led us to seek technical improvements to reduce technical
failures. We describe a modification to the technique of band placement and a
manoeuvre to aid the placement of staples when the TA90B staple gun is used.
PMID- 10765175
TI - The Non-surgical Treatment of Serious Obesity.
PMID- 10765176
TI - A Medieval Medical View on Obesity.
AB - Medieval medical views on obesity are presented from Avicenna's Canon of
Medicine. Health risks associated with obesity were appreciated, including
respiratory and cardiovascular problems, infertility and even sudden death.
PMID- 10765177
TI - Late Calcium Metabolic Consequences of Jejuno-ileal Bypass.
AB - Seventeen patients with previous jejuno-ileal bypass operation (JIB) for obesity
were included in a follow-up study 11 to 19 years after JIB. Evaluation of
calcium-parathyroid hormone axis was performed by a highly sensitive two-site
IRMA assay for serum intact parathyroid hormone and serum ionized calcium.
Evidence of a varying degree of secondary hyperparathyroidism was found. The
observed hyperparathyroidism was of clinical significance in a subpopulation
characterized by increased bone turnover and reduced bone mineral content. As a
consequence, the calcium metabolism with special attention to the parathyroid
function must be carefully monitored in JIB patients. Serum ionized calcium alone
and vitamin D metabolites do not identify patients at risk of bone loss.
PMID- 10765178
TI - Enforced Intermaxillary Fixation (IMF) as a Treatment of Obesity.
AB - Intermaxillary fixation (IMF) using metal cap splints and various linkages was
tried in a group of 11 patients who had requested restriction of solid diet as a
treatment for their obesity (Quetelet's index > 25-35). Compliance with treatment
protocols was successfully addressed by means of support from physicians,
dietitians, clinical psychologists and by peer groups. Non-compliance was defined
and agreed. The full cap splints for each dental arch, linked and enforced by
special rigid locking devices, proved to be a reliable technique of IMF for
periods of up to 3 months. Thereafter, the majority of the patients attempted
interference with the IMF linkage or detached the splints. Eight patients gained
weight after removal of the IMF. Two patients were successful in weight
stabilization after 2-14 kg weight loss during IMF. It is probable that
psychological and personal factors contributed to their success. It was concluded
that by Itself, rigidly enforced IMF for 3 months or longer was an unsuitable
treatment mode for the majority of obese patients but could be used as a
preparation for other forms of bariatric surgery.
PMID- 10765179
TI - Predictors of Two Obesity Complications: diabetes and hypertension.
AB - Gender, age, waist-hip ratio (WHR) and body mass index (BMI) have been reported
to herald two complications of obesity: diabetes or hypertension. Most literature
is based on patient populations with mean BMIs ranging from 22 to 35 kg/m(2).
This study population of severely obese patients selected for surgical treatment
of obesity had a mean age of 37 +/- 9.4 years, median WHR of 0.9 (0.4-2.1) and
median BMI of 44.0 (29-89) kg/m(2). It was found that age, WHR and BMI were
significant predictors for diabetes or hypertension. Gender was not found to be a
significant predictor for either diabetes or hypertension. A mathematical model
was used to calculate the predictive probability of developing diabetes or
hypertension using age, BMI and WHR.
PMID- 10765180
TI - Psychological Effects of Vertical Banded Gastroplasty on Pathologically Obese
Patients.
AB - For a period of 2 years the authors have examined on 16 pathologically obese
patients the psychological effects of the weight loss resulting from vertical
banded gastroplasty. At the time of surgery the patients' average age was 41
years. The patients' average weight of 125.9 kg (range 110-150 kg) decreased
after surgery to 89 kg, showing a decrease of 36.9 kg (range 20-69 kg). The
postoperative compliance has been good despite the fact that the remaining
gastric capacity allows for the ingestion of only 50-70 ml of food. Psychological
results, obtained through consultations, semi-structured interviews and a series
of tests, brought to light remarkable changes directly proportional to the weight
loss achieved. Psychic well-being, self-esteem, and improvements in the
interpersonal relations within the family and work environments represent in
summary the positive results of the weight loss achieved by patients with no
other possibility (voluntary) to keep their food intake under control (which we
termed 'food addiction'). The patients abandon their depressive traits and
achieve a degree of confidence that preserves them from stress and anxiety.
Patients improve their social mobility, and for many the sexual relations with
the partner become more frequent and intense. The weight loss plays an
indispensable role within itself but additionally is associated with a general
normalization of all physical parameters. Also, it starts an avalanche of
positive events which break the vicious cycle: aesthetic inadequacy
anxiety/depression-food-excess weight.
PMID- 10765181
TI - Revisional Surgery for Failed Gastric Restrictive Procedures for Morbid Obesity.
AB - As part of the Adelaide Obesity Surgery Study, we have reviewed all patients who
have undergone revisional surgery. Of the 31 0 trial patients, 63 (20%) had
revisions 1-69 (median 32) months following their original surgery-30% of all 105
gastrogastrostomy (GG) operations, 22% of 106 gastroplasty (GP) procedures, and
9% of 99 gastric bypasses (GB). Failure was due to stomal dilatation, 11% of all
trial patients (71% of GG revisions), stomal stenosis, 6% (52% of GP revisions)
and staple dehiscence, 4%. There was no mortality and a low hospital morbidity.
Long-term success was only 23% (follow-up at least 3 years) and was achieved at
considerable expense (3 reversals, 10 further revisions, 44 endoscopic
procedures). Revisional surgery was successful in 45% of patients with stomal
dilatation or dehiscence but in only 17% with stenosis. Overall, the most
successful operation was revision of, or conversion to, gastric bypass (58%
success rate), compared with gastroplasty (24%) and gastrogastrostomy (25%). Our
long-term results following revisional surgery were disappointing, particularly
for stenosis, and most failures followed revision to GG or GP. Roux-en-Y gastric
bypass is the procedure of choice when considering revision.
PMID- 10765182
TI - Gastric Bypass in Patients Weighing More Than 500 lb: technical innovations for
the 'ultraobese'
AB - The Roux-en-Y gastric bypass (RYGB) is a demanding operation. It is more
difficult to perform than most vertical pouch gastroplasties and is associated
with a greater number of life-threatening complications. This study addresses the
technical problems facing the bariatric surgeon when the RYGB is performed on
patients weighing more than 500 lb. It represents an 8-year operative experience
with 2050 morbidly obese patients, 23 (1.1%) of whom were classified as
'ultraobese'. Specific steps of the RYGB have been analyzed and refined. Using
the technical innovations described, the bariatric surgeon can perform the RYGB
in the ultraobese patient with a reasonable degree of morbidity and mortality.
Without the potential for safe surgical intervention, the prognosis for this
group of patients is grim at best.
PMID- 10765183
TI - Eutrophication: spontaneous progressive dermatoliponecrosis. A Fatal Complication
of Gross Morbid Obesity.
AB - Spontaneous and progressive dermatoliponecrosis and panniculitis is an unusual
complication of morbid obesity. A fatal case is reported, and the term
eutrophication is suggested as an appropriately descriptive name for this
intractable condition. A 45-year-old grossly morbidly obese female (weighing
286.4 kg) presented with spontaneous necrosis of skin and fat-folds of the
abdomen, trunk, and thighs. She also had congestive cardiac failure, respiratory
insufficiency and anemia. Congestive cardiac failure and anemia were treated
aggressively. However, all attempts at control of the superficial tissue necrosis
and the supervening infection failed. Superficial gangrene and putrefaction of
the fat-folds progressed relentlessly, and death finally ensued due to sepsis and
multiple system failure. The early signs of panniculitis, especially of grossly
dependent fat and skin-folds in the morbidly obese must be recognized early and
treated with aggressive weight loss, if this potentially fatal complication of
morbid obesity is to be avoided.
PMID- 10765184
TI - A Jejuno-ileal Bypass Patient Presenting with Recurrent Renal Stones due to
Primary Hyperparathyroidism.
AB - In the past, jejuno-ileal (JI) bypass operations were performed for the treatment
of massive intractable obesity. This procedure is known to be complicated by
numerous malabsorptive syndromes, occasionally resulting in electrolyte
abnormalities and oxalate renal calculi. Recurring renal stones and oxalate
nephropathy are cause to reverse the JI bypass. However, investigation of
recurring renal stones should be done to exclude causes that are not secondary to
the bypass procedure itself. We present a patient 13 years post JI bypass with
recurring renal calculi due to primary hyperparathyroidism.
PMID- 10765185
TI - Late Perforation of the Distal Roux-en-Y Anastomosis in a Patient with
Biliopancreatic Diversion.
AB - A 38-year old female with a history of biliopancreatic diversion for morbid
obesity developed a perforation at the distal Roux-en-Y anastomosis 13 months
after the original surgery. The etiology of this complication was not determined.
Perforation of a Roux-en-Y anastomosis occurring this late in the postoperative
period has not been described previously.
PMID- 10765186
TI - Vertical Banded Gastroplasty for Sleep Apnea Syndrome Associated with Morbid
Obesity.
AB - We report a case of morbid obesity accompanied by obstructive sleep apnea
syndrome (SAS) and obesity hypoventilation syndrome (OHS). Satisfactory weight
control was obtained without significant surgical complications after vertical
banded gastroplasty. With the reduction in weight, the symptoms of SAS and OHS,
as well as several other complications caused by the severe obesity, disappeared.
Quality of life also improved remarkably, as exhibited by improved activity
performance and disappearance of irritability at waking. Thus, it appears that
vertical banded gastroplasty is efficacious in the treatment of morbid obesity
with sleep apnea and hypoventilation.
PMID- 10765187
TI - Methods for Voluntary Weight Loss and Control.
PMID- 10765189
TI - Bariatric Surgery: is it legitimate- or what?
PMID- 10765188
TI - Diet Coke or Not?
AB - Many obese patients are attempting to diet. Furthermore, many gastric restrictive
procedures permit the ready flow of liquids, and the individual may want to be
assured that the liquid is in the "non-calorie" form. Many obese patients have
diabetes, and an incorrect or misrepresented beverage can result in elevated
plasma glucose with a disruption in glycemic control. The studies below have been
extended for orange-flavored carbonated beverages (Orange Crush, Fanta Orange,
etc.) with the same findings-no color change with the diet drink and immediate
brown color change with the regular drink on the Diastix.
PMID- 10765190
TI - Why Does the Gastric Bypass Control Type 2 Diabetes Mellitus?
AB - The remarkable control of diabetes by the gastric bypass remains to be explained.
Although it may be totally due to the weight loss Induced by the operation, it is
likely that the detour of the hormonally active foregut plays a role as well.
This keynote address explores the pathophysiology of non-insulin-dependent
diabetes mellitus and reviews the data which support the thesis that the gastric
antrum, duodenum, and proximal jejunum modulate glucose metabolism and insulin
action.
PMID- 10765191
TI - Psychiatric Issues in Bariatric Surgery.
AB - In this study, 100 patients were evaluated prior to surgery to assess psychiatric
status. The demographic anthropometric and psychological characteristics are
described. Seventeen patients developed severe psychiatric complications and
required hospitalization; the diagnoses which precipitated hospital admission
were most commonly affective disorders (especially major depression with suicidal
ideation). The only deaths in the sample of 100 occurred among the patients who
required post-surgical psychiatric hospitalization. The hospitalized group was
compared to a matched group drawn from the original 100 patients. Factors
associated with post-surgical psychiatric hospitalization were: presurgical
psychiatric hospitalization, presence of multiple pre-surgical Axis I psychiatric
diagnoses, and untreated Axis I diagnosis at the time of pre-surgical assessment.
Psychiatric screening criteria were revised and 31 subsequent patients were
evaluated; less than half of this group were found suitable for surgery at the
time of preliminary assessment.
PMID- 10765192
TI - Pulmonary Complications in Obesity Surgery.
AB - Massively obese patients undergoing abdominal surgery frequently develop
pulmonary complications. The basis of this predilection, syndromes and
suggestions to reduce risk are discussed.
PMID- 10765193
TI - Small Bowel Obstruction Following Gastric Bypass.
AB - Intestinal obstruction is no more frequent after gastric bypass than after any
other similar gastric surgical procedure. However, occurrence of any complication
requiring revisional surgery in these hugely obese patients may have serious
implications. Bariatric surgeons and physicians who take part in the care of such
patients must be aware of the different clinical pictures which accompany the
varying levels of obstruction following gastric bypass surgery. Particularly
critical is an understanding of closed loop gastroduodenal obstruction, a
potentially lethal complication, which can cause rapidly occurring hypovolemic
shock and death within a few hours of onset.
PMID- 10765194
TI - Biochemical Evidence of Metabolic Bone Disease in Women Following Roux-Y Gastric
Bypass for Morbid Obesity.
AB - Twenty-six female patients were recalled for examination 10 years after a Roux-Y
gastric bypass (RGB) procedure for morbid obesity, to determine whether there was
biochemical and/or bone densitometry evidence of metabolic bone disease. These
patients were compared with seven control patients who had achieved weight loss
by dietary restriction. The serum calcium (4.3 +/- 0.03 vs 4.6 +/- 0.06 mEq/l; p
= 0.002) was decreased in the RGB group. Both the serum alkaline phosphatase
level (121.0 +/- 7.6 vs 87.3 +/- 8.3 U/I; p = 0.018) and the serum osteocalcin
(12.6 +/- 1.2 vs 9.5 +/- 1.9 ug/ml; p = 0.078) level increased in the RGB group.
The 1,25(OH) vitamin D level (50.5 +/- 2.5 vs 40.5 +/- 4.9 pg/ml; p = 0.152) was
similar for both groups; the 25(OH) vitamin D level (24.3 +/- 1.6 vs 35.9 +/- 3.4
ng/ml; p = 0.008) was decreased in the RGB group as compared with the control
group. Bone mineral density was elevated in three of the lumbar measurement
sites, and marginally decreased (0.90 +/- 0.02 g/cm(2) vs 1.03 +/- 0.06 g/cm(2);
p = 0.067) in the femoral neck of the RGB group compared with the controls. This
biochemical pattern suggests the development of metabolic bone disease following
the RGB.
PMID- 10765195
TI - Revisional Surgery for Severe Obesity with Fascia Banded Stoma Roux-en-Y Gastric
Bypass.
AB - The fascia banded stoma Roux-en-Y gastric bypass (RYGBP) has been effective both
as a primary and revision operation for severe obesity or failure of another
operation. Since May 1984, 361 primary and 100 revisional fascia banded RYGBP
operations have been reported. Weight loss achieved a mean body mass index of 30
for primary and 31 for revision patients at most recent follow-up of 3-6 years
(mean 4.3 years) postoperatively. Mean overweight was 28% for primary, and 34%
for revision patients. Eighty percent of primary and 79% of revision patients
were within 50% of ideal weight. Revision rates for these patients were 0 for
primary and 1% for revision patients. Operative mortality was 0 for primary and
1% for revision patients. Since morbidity and mortality, although low, are higher
for revision than primary surgery, it is important to use an effective primary
operation.
PMID- 10765196
TI - Eating Behavior, Physical Symptoms and Psychological Factors Associated with
Weight Reduction Following the Scopinaro Operation as Modified by Gazet.
AB - Sixteen morbidly obese patients (12 females, four males) underwent the Scopinaro
operation according to Gazet. Profound weight loss occurred, along with marked
improvements in eating patterns, mood and psychosocial functioning which were
reported retrospectively 1 year and repeated 2 years after surgery. Continued
binge eating, comfort eating and 'eating sensibly/making up in private' were
associated with reduced weight loss, suggesting that a therapeutic cognitive
behavioral program to correct eating problems in association with the Scopinaro
operation may increase weight loss. Some physical symptoms were related to
increased (burping) or decreased (hunger, thirst) intake of food, but the
patterns of preoperative symptoms did not predict postoperative physical symptoms
or weight loss. Subjects were divided into two subgroups with (n = 8) or without
(n = 8) a history of self-damaging and addictive behaviors. The aberrant behavior
subgroup had more disturbed eating patterns preoperatively (higher BITE severity
scores) but similar BITE scores postoperatively. Mean BMIs were similar before
and after surgery. This suggested that patients with these aberrant behaviors
should not be denied surgery. Half of the female patients reported early sexual
abuse, and were lighter than the non-abused group. This merits further
investigation.
PMID- 10765197
TI - Calculating Follow-up Rates.
AB - Follow-up rates are presented as a percentage but the method of calculation is
seldom discussed. Determining a follow-up rate begins with identifying the
numerator and denominator used in the calculation. Four methods of calculating
follow-up rate after surgical treatment for weight reduction were studied. Method
1 follow-up rate, 91.2%, was calculated using patients with at least one follow
up contact as the numerator (6169) and the number of primary operations performed
as the denominator (6764). Method 2 calculated patient contact on or beyond a
specific time point: 65.9% for >/= 6 months (4232/6424), >/= 1 year (y) = 52.1%
(3111/5977), >/= 2 y = 29.8% (1455/ 4890), >/=3y=18.8% (710/3784), >/=4y=12.5%
(331/ 2643). Follow-up calculated using method 3 determined patient contact
within specific time points: 0-1 y = 89.7% (6064/6764), 1-2 y = 45.8%
(2739/5977), 2-3 y = 23.0% (1124/4890), 3-4 y=13.9% (526/3784), 4-5y=11.3%
(298/2643). Method 4 studied patient contact within time points according to ASBS
guidelines. Rates for method 4 were: 0-6 months = 58.8% (11,938/20,292), 6-12
months = 36.7% (4717/12,848), 1-2 y = 45.8% (2739/5977), 2-3 y = 23.0%
(1124/4890), 3-4 y = 13.9% (52613784). Results using these four methods of
calculation emphasize the need to standardize follow-up rate before operative
comparisons can be made.
PMID- 10765198
TI - Routine Gallbladder Ultrasonography Before Gastric Restrictive Bariatric Surgery:
is it worthwhile?
AB - Gallbladder ultrasonography is frequently included In the pre-operative
evaluation of bariatric surgical patients. A study was conducted to evaluate the
cost-benefit relationship of these studies. Sonographies were performed in 101
patients before their stapling procedure. The results were not made known to the
surgeon until after he had decided on the basis of findings at surgery whether to
remove or leave the gallbladder. In 92 of the 101 patients the radiologist was
willing to read the study as normal or abnormal; in nine patients the study was
felt to be indeterminate. There was one false positive sonogram, and one picked
up a lesion missed clinically. In one case stones were palpable at surgery but
missed by sonogram. Forty-three patients had no stones by either criterion but
had visible cholesterolosis, etc., and their gallbladders were removed. The
results suggest that in this group of patients the expense of routine
preoperative sonography may not be justified.
PMID- 10765199
TI - Helicobacter pylori Before and After Gastric Reduction for Morbid Obesity.
AB - Nine patients with morbid obesity were evaluated for the presence of Helicobacter
pylon (Hp) before gastric reduction, and all were negative. Fifteen patients,
Including those nine, were evaluated for the presence of Hp in antral and
'channel' region biopsies by culture and urease test after gastric reduction. Hp
negative patients totaled 73.3% by both tests, although chronic superficial
gastritis type 'B' was found In eight out of 13 (61.5%), and six out of seven
(85.7%) gastritis patients were positive for Holicobacter-like organisms in the
hematoxylin- and eosin-stained biopsies. Our data suggest that in stomachs of
morbid obesity patients before as well as after gastric reduction procedures, the
incidence of Hp is very low, and the reasons for this observation are yet
unknown.
PMID- 10765200
TI - Maximum Nutrition, Minimum Calories.
AB - There is more to losing weight, maintaining weight and choosing a healthy diet
after gastric bypass than simply limiting food intake and avoiding sugars.
Patients must learn to make food selections that have a high nutrient:energy
ratio. Considerable research indicates that the dietary fat level, independent of
total caloric intake, is a predictor of fat storage. A contributing factor is the
difference in metabolic efficiency of converting dietary fats to body fat
compared to the relative inefficiency of converting carbohydrates to body fat.
The recommendation that no more than 25% of daily caloric intake come from fat is
in keeping with good nutritional practices and may also lower the risk of heart
disease and cancer. Patients should have nutrition counseling supplemented with
written materials on label reading and recognizing high fat foods, types of fat
and cholesterol, serving sizes, meal planning, low fat cooking and dining out.
Choosing foods with a high nutrient:energy ratio allows the patient to eat an
increased volume and thus a wider variety of foods to meet their nutrient and
energy requirements.
PMID- 10765201
TI - Bariatric Surgery Preoperative Assessment and Teaching.
PMID- 10765202
TI - Waiting for Weight Loss.
PMID- 10765203
TI - Sleep-related Disorders in the Obese.
AB - Obesity is a well-known cause of upper airway narrowing, respiratory failure and
resulting hypoxemia and hypercapnia, and cardiac arrhythmias during sleep. Obese
patients are prone to snore loudly and to develop obstructive sleep apnea
syndrome and also obesity-hypoventilation syndrome. Repeated nocturnal upper
airway obstruction may cause respiratory failure and cor pulmonale and frequent
awakenings, and result in nocturnal choking, with daytime drowsiness, somnolence
and irritability. The purpose of this article is to review the evidence for these
accepted facts and to consider a variety of new information that relates to the
pathogenesis, symptomatology and treatment of sleep disorders caused by obesity.
PMID- 10765204
TI - The Future of Bariatric Surgery.
AB - Scientific evidence is pointing more and more strongly to the fact that serious,
or morbid, obesity is not a moral issue. Serious obesity is a consequence of a
genetically related, powerful biophysiological drive to consume more calories
than are burned. This concept must eventually become incorporated into lay and
medical paradigms of obesity. It will result in an increased understanding and
sympathy for the suffering of the seriously obese and, as a consequence, stronger
support for definitive treatment of serious obesity such as bariatric surgery.
Reoperative bariatric surgery principles, currently limited by individual
exposure and experience, will develop and evolve. Laparoscopic bariatric surgery
may, in time, be developed and prove itself to be of value. Bariatric surgeons
should also find it useful to enhance their teams' skills for nutritional,
behavioral and psychological management, as well as broaden their operative base
into other, related surgical areas such as partial ileal bypass procedures for
hyperlipidemia management. As fields mature, organizational maturation is a
natural and necessary accompaniment. An International Federation for Bariatric
Surgery, or similar entity, will be founded to constructively unite national
bariatric surgery and related organizations together. The international bariatric
surgery journal, Obesity Surgery, will become more and more accepted as the truly
professional and essential vehicle of communication concerning bariatric surgery
that it has been since its first issue. Medical management simulating the effects
of surgery will be employed successfully; it may arise out of the current genetic
work. It may ultimately, in the next 25 years or so, replace the surgical
treatment of serious obesity.
PMID- 10765205
TI - Biliopancreatic Diversion: early complications.
AB - The experience and early complications in 66 morbidly obese patients who
underwent biliopancreatic diversion are presented. There was one death, due to a
pulmonary embolus (PE) at home on the 15th postoperative day. Postoperative
complications occurred in nine patients, consisting of gastric hemorrhage (2),
gastric outlet obstruction (2), non-lethal PE (1), deep vein thrombosis (1),
wound dehiscence (1), and asymptomatic gastric leak (1). In addition, there were
12 superficial wound infections. Four patients required urgent reoperation for
gastric hemorrhage (2), gastric outlet obstruction (1), and wound dehiscence (1).
The high complication rate is believed to represent the early part of the
learning curve. Some reports of the early complications following other bariatric
operations are discussed.
PMID- 10765206
TI - Results of Vertical Banded Gastroplasty for Treatment of Morbid Obesity.
AB - The results of vertical banded gastroplasty were studied in 40 morbidly obese
patients from 1 to 6 years after operation. The mean weight loss in this period
varied from 37 to 45 kg and the Quetelet index from 28 to 32 kg/(2). In 30% of
the patients the individual weight loss is less than 25%. However, about 90% of
the patients expressed satisfaction with the operation result. The early and late
mortality was zero. The most common complications were wound infections and
incisions[ hernias. Vertical banded gastroplasty is a safe operation, which gave
a good or satisfactory result in 70% of the patients.
PMID- 10765207
TI - Use of the Round Ligament as a Natural Living Gastric Band for Weight Loss
Surgery: a preliminary report.
AB - With non-operative methods of treatment being notoriously refractory and prone to
failure, gastric partitioning and banding surgery has become a more acceptable
method of treating morbid obesity. The present method of simple gastric banding
has developed with modifications over several years, with the present fashionable
procedure creating an upper gastric pouch of about 50 ml by applying a
restrictive band of a suitable material just below the fundus of the stomach.
This article describes the development of this band which previously used
synthetic material, by using a live natural material, ligamentum fares (round
ligament), and thus finding a solution to the theoretical and actual problems of
infection and erosion from such synthetics.
PMID- 10765208
TI - Long-term Follow-up of Gastroplasty in a Patient with Prader-Willi Syndrome.
AB - To prevent the development of metabolic disturbances caused by overeating, we
performed vertical banded gastroplasty in an adult woman with Prader-Willi
syndrome. Her fasting blood sugar (FBS) and urinary sugar excretion (US)
decreased during 6 months after the surgery under strict dietary control in the
hospital. The insulin response to oral glucose at 6 months after surgery was as
good as in the normal controls. A barium meal study in the 11th postoperative
month revealed that the staple line was partially ruptured. After this, FBS and
US increased, and the glucose tolerance and insulin response worsened. At 24
months, US was still less than preoperative US, and the oral glucose tolerance
test showed a better result than before operation. At 29 months, her condition
was brought under control with use of Glibenclamide. At 60 months, her FBS and US
were at the same level as before operation. She was doing a part-time job. In
conclusion, the effect of gastroplasty in preventing worsening of glucose
metabolism in a case of Prader-Willi syndrome lasted satisfactorily for 24 months
in spite of the partial breakdown of the staple line.
PMID- 10765209
TI - Palliative Care in Oncology: Past, Present, and Future.
PMID- 10765210
TI - Overview of Hospice and Palliative Care in Oncology.
AB - BACKGROUND: The concept of palliative care in oncology has not yet reached the
forefront of American medicine, and hospice care may be underused. METHODS: Data
on increasing needs for palliative care and the development of the hospice
movement are compared with practice behavior patterns of physicians in regard to
palliative care. RESULTS: Hospice/palliative care has grown from an alternative
health care movement to an accepted part of the American health field.
Limitations of hospice/palliative care include health professionals' discomfort
with care of the terminally ill as well as difficulties in predicting limited
prognoses that may hinder access to such care. CONCLUSIONS: Hospice/palliative
care principles should be integrated into other elements of cancer control to
ensure comprehensive care for all cancer patients.
PMID- 10765211
TI - Pain and Symptom Management in Palliative Care.
AB - BACKGROUND: Pain, dyspnea, and anorexia are common symptoms experienced by
patients with cancer and often are poorly managed. METHODS: The incidence and
causes of these symptoms are described, as well as factors that exacerbate or
ameliorate their impact. RESULTS: Pharmacologic management of cancer pain is
based on the use of a sequential "ladder" that incorporates nonopioid, opioid,
and adjuvant drugs, depending on the severity of the pain. This approach usually
is effective. Other symptoms of advanced disease may be more difficult to
control. CONCLUSIONS: Adherence to an adequate pain-control strategy will
significantly enhance palliation of pain in patients with cancer.
PMID- 10765212
TI - Psychosocial Aspects of Palliative Care.
AB - BACKGROUND: Relief of suffering is a central goal for palliative care.
Achievement of this goal can be difficult, however, due to the complex nature of
suffering. METHODS: A psychosocial perspective is used to understand suffering
and to identify interventions to relieve suffering in patients with advanced
disease. RESULTS: Clinical experience and research suggest that attending to the
psychosocial aspects as well as the medical aspects of palliative care has the
potential of further reducing the suffering experienced by patients with advanced
disease. CONCLUSIONS: Suffering is best viewed as a subjective phenomenon t hat
can be influenced by biological, psychological and social processes.
Interventions in each of these areas can help to relieve patient suffering.
PMID- 10765213
TI - Quality-of-Life Assessment in Palliative Care.
AB - BACKGROUND: Understanding the effects of cancer on the quality of life of
affected patients is critical to clinical research as well as to optimal
management and care. METHODS: Nine instruments for assessing quality of life in
patients with cancer are identified, and their effectiveness during palliative
care is analyzed. RESULTS: Most of the instruments included physical, functional,
and symptom control, as well as psychologic and social aspects. Financial and
spiritual aspects were included less often. While all but two of the instruments
had adequate validity and reliability data published, only two - the Spitzer
Quality-of-Life Index and the Hospice Quality-of-Life Index - were designed and
validated for palliative care populations. CONCLUSIONS: Although a variety of
instruments is currently available, none is ideal for all palliative care
settings. Further development and refinement of instruments are needed.
PMID- 10765214
TI - Barriers to Palliative Care.
AB - BACKGROUND: Palliative care is received by a small number of patients with
terminal illness, most of them with cancer. METHODS: Data are reviewed and
evaluated that relate to the barriers and problems that limit access of patients
to appropriate palliative and/or hospice care. RESULTS: Palliative care generally
is not well integrated into the health care system. Access is limited, and many
health care professionals and laypeople are unaware of its possible benefits.
Cultural and religious barriers often apply, and problems exist in obtaining
narcotics. Palliative care for patients other than those with cancer may be
especially difficult to achieve. CONCLUSIONS: Recognizing and overcoming the
barriers to the provision of palliative care can bring about changes in
education, health care practices, and administration to achieve the desired
goals.
PMID- 10765215
TI - Hippocrates Meets Wall Street.
PMID- 10765216
TI - Right Vocal Cord Paralysis/Buckling With Medial Deviation of the Right
Aryepiglottic Fold.
PMID- 10765217
TI - Chemotherapy-Induced Nausea and Vomiting: Rationale for Cost-Effective
Management.
PMID- 10765218
TI - Bilateral and Multifocal Breast Cancer.
PMID- 10765219
TI - Physician-Assisted Suicide and the Right to Care.
PMID- 10765220
TI - Combinations of Radiotherapy and Chemotherapy: Strange Bedfellows or a Marriage
Made in Heaven?
PMID- 10765221
TI - Programmed Cell Death (Apoptosis) and Cancer Chemotherapy.
AB - BACKGROUND: Programmed cell death involves a genetic reprogramming of the cell to
promote an energy-dependent cascade of biochemical and morphological changes
within the cell that result in its death and elimination. METHODS: The
regulations and mechanisms of programmed cell death are reviewed with an emphasis
on how derangement of this mechanism may be involved in modulating responsiveness
to chemotherapy. RESULTS: Activation of this programmed death process is
controlled by a series of endogenous cell-type-specific signals. In addition, a
variety of exogenous cell-damaging treatments (eg, radiation, chemicals, and
viruses) and most chemotherapeutic drugs can activate this pathway if sufficient
injury to the cell occurs. Resistance to chemotherapy can involve alterations in
the ability of a malignant cell to activate the programmed cell death (apoptotic)
pathway when damaged by these exogenous agents. CONCLUSIONS: The most important
determinant of tumor resistance may be a generalized resistance to induction of
programmed cell death rather than resistance based on specific alteration in
drug/target interactions.
PMID- 10765222
TI - Concurrent Paclitaxel and Radiation Therapy for Solid Tumors.
AB - BACKGROUND: Combination radiation and chemotherapy has an intuitive appeal for
improving cancer treatment. Experimental results suggest that paclitaxel plus
radiation might produce additive or synergistic effects. METHODS: A series of
phase I and II trials to test tolerance and begin to evaluate effectiveness were
performed on patients with non-small cell lung cancer, high-grade astrocytic
brain tumors, and pancreatic and gastric cancers. RESULTS: Tolerance of the
combined drug and radiation programs was generally good. Esophagitis was dose
limiting for the intrathoracic tumors. Hematologic toxicity was mild, but
peripheral neuritis and cutaneous reactions were common. CONCLUSIONS: These
trials show that paclitaxel plus concurrent radiation is feasible at the dose
levels and schedules tested. Antitumor responses have been observed.
PMID- 10765223
TI - Role of Radiation Therapy and Fluoropyrimidines in the Treatment of
Gastrointestinal Malignancies.
AB - BACKGROUND: The use of combined chemotherapy and radiation for gastrointestinal
malignancies has several theoretical advantages, and clinical trials to determine
the type and extent of clinical benefits have been performed. METHODS: The basic
science and clinical trial data evaluating such combinations are reviewed, with
an emphasis on the interactions between fluoropyrimidines and radiation. RESULTS:
Improved outcomes from chemoradiotherapy have been demonstrated in patients with
selected stages of anal, esophageal, rectal, and pancreatic cancer. CONCLUSIONS:
Despite these positive results, further work is needed to demonstrate even more
effective and less toxic treatment regimens.
PMID- 10765224
TI - Management of Toxicities of Combined Modality Therapy for Intrathoracic
Malignancies.
AB - BACKGROUND: Combined radiation and chemotherapy for intrathoracic tumors can
produce appreciable morbidity. Apprehension about the severity of these
toxicities may inhibit optimal patient care. METHODS: The literature on
recognition, diagnosis, prophylaxis, and management of these toxicities is
reviewed and combined with the experiences of the authors to produce management
recommendations. RESULTS: Toxicities include acute and chronic esophagitis, early
and late pneumonitis with fibrosis, myelosuppression, and neurologic deficits.
Measures are available to minimize their severity and to reduce their impact on
the patient. CONCLUSIONS: The morbidity of combined radiation and chemotherapy
patients with intrathoracic tumors can be minimized by recognizing potential
toxicities and by applying appropriate prophylactic and management measures.
PMID- 10765225
TI - Metastatic Adenoid Cystic Carcinoma of Salivary Glands: Case Reports and Review
of the Literature.
AB - BACKGROUND: Adenoid cystic carcinoma is an uncommon tumor of the salivary gland.
Little has been published on the chemotherapy of this neoplasm. METHODS: The
literature on this disease is reviewed, and data from seven unpublished cases are
presented. RESULTS: Four patients received cyclophosphamide. One responded, and
another had pain relief. The literature review did not identify any single drug
or combination that might be regarded as the treatment of choice. CONCLUSIONS:
Systematic, multi-institutional studies are required to determine appropriate
systemic treatment for metastatic adenoid cystic carcinoma of salivary gland
origin.
PMID- 10765226
TI - Clinical Practice Guidelines: Tools for Raising Quality of Care and Reducing
Costs.
PMID- 10765227
TI - Clinical Practice Guidelines for Gynecologic Cancers.
PMID- 10765228
TI - Imaging in Oncology.
PMID- 10765229
TI - Early Empiric Antibiotic Therapy for Febrile Neutropenia Patients at Low Risk.
PMID- 10765230
TI - Non-Hodgkin's Lymphoma in the Elderly.
AB - BACKGROUND: The incidence of non-Hodgkin's lymphoma in the elderly continues to
increase. There has been a tendency among some treating physicians to minimize
appropriate workup and treatment, which may product a negative effect on
outcomes. METHODS: Several characteristics of non-Hodgkin's lymphoma in the
elderly are reviewed, including classification and staging, pathophysiology,
clinical presentation, and treatment strategies. RESULTS: The Working Formulation
remains the principal classification used. In order and younger individuals, the
prevalence of histologic subtypes and the stage at presentation are similar.
Regardless of the regimen chosen, doxorubicin or mitoxantrone should be included
if optimal responses are to be obtained. New purine analogs extend the
therapeutic armamentarium. CONCLUSIONS: Advanced age and comorbidities can impair
the capability for treatments to control non-Hodgkin's lymphoma. To enhance
results, more studies that focus on the elderly are needed on drug combinations
and the new purine analogs.
PMID- 10765231
TI - Can your patients afford a transplant?
PMID- 10765232
TI - Transplant medication resources available after Medicare.
PMID- 10765233
TI - Until we get lifetime coverage for immunosuppressive medications, the underground
will thrive.
PMID- 10765234
TI - A balanced scorecard approach to quality improvement in a renal transplant
program.
PMID- 10765235
TI - Networks to give "local" review of first-year renal transplant outcomes.
PMID- 10765236
TI - The workings of the transplant waiting list.
PMID- 10765237
TI - Defining the cost savings of a kidney transplant.
PMID- 10765238
TI - Chronic rejection cited as major issue.
PMID- 10765239
TI - Will chronic rejection impact the future of transplantation?
PMID- 10765240
TI - Dialysis units impacted by new "safe needle" policies.
PMID- 10765241
TI - Obesity: a serious risk factor in transplantation.
PMID- 10765242
TI - How does management affect clinical outcomes of care?
PMID- 10765244
TI - Outcomes measurement requires nursing to shift to outcome-based practice.
AB - The measurement of outcomes to demonstrate the effectiveness of nursing care
delivered is essential. This article will outline the history of outcomes
measurement in nursing, the definition and levels of outcomes, the
differentiation between process interventions and outcome statements, and the
monitoring of outcomes at the staff nurse and case manager levels. Care
management methodologies to assist in outcome management will be discussed. In
the end, the development of nursing knowledge and innovation in care strategies
and advanced clinical decision making is dependent on the measurement of
intermediate and end result outcomes.
PMID- 10765243
TI - Nurses always have measured outcomes.
PMID- 10765245
TI - A provocative look at performance measurement.
AB - A fascinating web of issues can be spun from the notion of performance
measurement. After a brief discussion about the background of performance
measurement, this article puts performance measurement into a fresh light by
examining three major issues: the concept of quality and its application to
performance measurement, the power of the patient and the transition of focus to
customers within health care organizations, and deliberations about data and
concomitant implications for information systems of the future.
PMID- 10765246
TI - University of Iowa Hospital and Clinics: outcomes management.
AB - Delivery of quality patient care and management of patient outcomes is critical
to the success of academic medical centers in the ever-changing health care
market. The University of Iowa Hospitals and Clinics (UIHC) promotes quality care
through the provision of organizational structures and processes that are
described in this article. In addition, quality of care and outcomes management
are described by members in various roles within the UIHC health care system. It
is the authors' belief that understanding quality from these various perspectives
helps UIHC work across departments to achieve excellence in patient care.
PMID- 10765247
TI - Blending case management and quality outcomes management into the family nurse
practitioner role.
AB - As health care reform moves into a new millennium, the importance of
comprehensive case management and quality outcomes management still has not
brought about the cost-effective quality of care that was hoped. The purpose of
this article is to explore further the potential impact that the family nurse
practitioner as a primary care provider might have on case management and the
management of quality outcomes of care.
PMID- 10765248
TI - The process of outcomes management in an acute care facility.
AB - Outcomes reports evaluate the care given to a patient population. The
establishment of a system to collect, analyze, and report outcomes is essential
because regulatory agencies require that comparisons of outcomes be made
externally. The outcomes manager at Mission Hospital Regional Medical Center
facilitated a team to evaluate the patient in active labor. The focus was to
establish a process of care that would maintain quality of care and decrease the
cesarean section rate. Cesarean section rate went from 22 percent to 16 percent.
Customer satisfaction scores were elevated and financial outcomes or cost savings
were $631,000 in 1998.
PMID- 10765249
TI - Toward a new millennium: outlook and obligations for 21st century health care
technology.
AB - This article will discuss key trends--from globalization to the culture of change
and the rise of the information age--fueling development and deployment of 21st
century IT. It will describe some of the new technologies, their applications,
and implications for nursing.
PMID- 10765250
TI - Nursing's visions for the 21st century in health care.
PMID- 10765251
TI - A theorist envisions the future and speaks to nursing administrators.
AB - Planning for a preferred future for nursing is based on a vision of the world of
the 21st century. A theorist shares her vision that stems from themes of
scientific changes in cosmology and quantum theory, as well as her thoughtful
reconsideration of the assumptions of her work for the future. These insights
provide principles for planning that the nursing administrator can use for change
at individual, institutional, and societal levels.
PMID- 10765252
TI - Nightingale II: nursing leaders re-membering community.
AB - As the health care field moves into the 21st century, the discipline is moving
into new forms of service and leadership. This article presents a view of nursing
leadership from the vantage point of community. Values, beliefs, and the changing
roles of nursing leadership in creation of new order are examined along with
skills and capacities necessary to accomplish the task at hand.
PMID- 10765253
TI - Retooling the nurse executive for 21st century practice: decision support
systems.
AB - Health care financing and care delivery systems are changing at almost warp
speed. This requires new responses and new capabilities from contemporary nurse
executives and calls for new approaches to the preparation of the next generation
of nursing leaders. The premise of this article is that, in these highly unstable
environments, the nurse executive faces the need to make high-impact decisions in
relatively short time frames. A standardized process for objective decision
making becomes essential. This article describes that process.
PMID- 10765254
TI - Zen leadership: balancing energy for mind, body, and spirit harmony.
AB - This article explores leadership characteristics and practices that assist us
both professionally and personally to be authentic and integrated in mind, body,
and spirit for harmony. The transformational leadership characteristics--courage;
belief in people; value driven; a life-long learner and teacher; a complexity,
ambiguity, and uncertainty expert; and a visionary leader--all deal with the
leader's ability to develop relationships through teamwork, collaboration,
networking, mentoring, and establishing boundaries. The author realized the
importance of reflection to maintaining a healthy relationship not only with
others but also with self.
PMID- 10765255
TI - Partnership 2000: a journey to the 21st century.
AB - Building partnerships is a valuable strategy for achieving success in forming a
strong foundation for nursing in the 21st century. The demands of the changing
health care environment require that managers and staff change the context in
which patient care delivery is accomplished. Managers must be willing to unleash
the power of the human capital of staff nurses. Staff nurses must be willing to
take a seat at the table and share the leadership role with their manager. Both
must engage in building an environment that facilitates continued learning,
establishes effective relationships with other health care team members and
patients, creates an environment that attracts and retains professional nursing
staff, expects professional development from one another, and realizes that
collective accountability can be achieved through sharing the leadership.
PMID- 10765257
TI - Nursing organizations face the future: will they thrive?
AB - As nursing organizations look forward to the new century, it's important that
they ensure their survival in the future by determining which actions they must
take in the present to maintain their relevance in a rapidly changing world. This
article describes today's nursing organization, contemplates the nursing
organization of the future, and discusses the importance of nursing associations
in organizational planning and community activism.
PMID- 10765256
TI - Vision 2000: the transformation of professional practice.
AB - This century has seen miraculous advances in health care. Despite all our
progress, however, there are some serious flaws in today's health care systems
that demand our attention. This article describes the approach our integrated
delivery system has taken to meet this challenge through implementation of the
Transformational Model for Professional Practice, and the outcomes we have
achieved.
PMID- 10765258
TI - Leadership: the key to quality outcomes.
AB - Nurse executives are charged with creating a workforce that provides quality care
in a creative and cost-effective manner. Style of leadership determines how nurse
executives relate to their professional nurses and ultimately how successful
their health care institutions will be. The practice-based theory of nursing
leadership called the Integrated Leadership Practice Model can be practiced by
nurse executives to promote employee satisfaction, assure that quality care is
provided based on standards and competencies, and promote an organizational
culture committed to quality. This article proposes the application of integrated
leadership to the practice of nurse executives and demonstrates how they can
foster and support this model for nursing leadership within their nurse managers.
PMID- 10765259
TI - The role of governance in improving clinical outcomes: opportunities for nurses.
AB - In this article, the authors explore how the role of governance has changed in
response to the field of performance measurement and the wide variety of
governance trends and share their views and experiences as nurses who have had
the opportunity to serve in governance roles. Recommendations are provided for
nurse executives interacting with the governance structures of their
organizations. Finally, strategies are shared for nurses interested in pursuing
governance opportunities in their local communities.
PMID- 10765260
TI - Using an interview guide to identify effective nurse managers: phase II,
outcomes.
AB - The investigators report validation of a survey tool called the Interview Guide
to assist in the selection of nurses who will be effective as managers. Nurse
administrators rated nurse managers at six months and two years after hire. The
Interview Guide rated the management qualities "seeing the big picture" and
potential for "rehire" as the best predictors of managerial success. After two
years, a good "self-concept" or a "flexible attitude" was the best predictor. The
ability to manage conflict was the most significant competency for predicting
rehire at both six months and two years.
PMID- 10765261
TI - Minding the store: how IT impacts outcomes measurement.
AB - Today, the question is not whether organizations should measure outcomes, but
how. Right now, there are several initiatives, but no single, collaborative
effort to tie them all together. This article will discuss the rise and early
history of outcomes assessment in health care and highlight some key current
initiatives (for example, OASIS [home health], QISMC [managed care
organizations], HCQIP [inpatient care], ACQIP [ambulatory care], Joint
Commission's ORYX accreditation initiative [hospitals, long-term care, home care,
behavioral health care, and networks]). It will also delineate some of the
problems with measuring outcomes and discuss where more work is needed. It will
go on to discuss the role of IT in outcomes measurement, including its
contributions, goals, effects, categories of IT support, infrastructure
solutions, and analysis.
PMID- 10765262
TI - Step-by-step guide to selecting mobile wireless devices.
AB - Make sense out of choosing portable radio frequency devices with these easy-to
follow steps for clinicians, information systems computing staff, and
administrators.
PMID- 10765263
TI - Advocate for your patients--and your nurses.
PMID- 10765264
TI - New managed-care glossary.
AB - EverCare, cherry picking, premium support, S/HMO--get the explanations behind the
fast-changing terminology of managed care in this third annual update.
PMID- 10765265
TI - What principles guide research with human participants?
AB - Before undertaking research that involves human subjects, read about the
pertaining laws and guidelines and core underlying principles of respect for the
person, beneficence, and justice.
PMID- 10765266
TI - Greater need for background checks.
AB - The push is on for a more uniform system of background checks for health care
employees. Studies and crimes against patients have prompted regulation by the
Health Care Financing Administration (HCFA), state governments, hospitals, and
Congress.
PMID- 10765267
TI - Navigating specialty certification.
PMID- 10765268
TI - Case managers drive care integration.
AB - Nurse leaders at an urban Level 1 trauma facility integrate patient-care
departments for a case-management system that works.
PMID- 10765269
TI - What to look for in an infusion pump.
PMID- 10765270
TI - Staying power.
PMID- 10765271
TI - Retain staff nurses with room to grow.
PMID- 10765272
TI - Lead the way, Leader.
AB - Effective leaders show objectivity, creativity, and knowledge. They develop
personal leadership styles from existing models and use their strength to
motivate staff, accomplish organizational goals, and develop future leaders.
PMID- 10765273
TI - New ways to evaluate chemotherapy competencies.
AB - At a large teaching hospital with seven oncology units, nurse-educators implement
a competency program to ensure that nurses with different backgrounds and patient
populations master a unified set of skills and knowledge.
PMID- 10765274
TI - Anatomy of a code. How do you feel at the start of a code blue?
AB - Prepare for a code by recognizing breathing and circulation signs before trouble
occurs. Know when to call a code, and how to move past your adrenaline rush to
act effectively.
PMID- 10765275
TI - Choosing a clinical information system.
AB - To best represent nurses' interest in selecting a new clinical information
system, nurse leaders can target problem areas, consider nursing's future needs,
and pinpoint areas to streamline.
PMID- 10765276
TI - Add genetics to your knowledge base.
AB - Genetics information will change how we think about our health, lead our lives,
and treat many illnesses. For clinicians to initiate new treatments, we must have
a clear, unified understanding of genetics and the ability to educate our
patients.
PMID- 10765277
TI - Cross-training in 3-D.
AB - With 3 hospitals and 10 perinatal nursing units, nurse leaders developed a cross
training program to unify staff for maximum flexibility, greater job
satisfaction, and savings.
PMID- 10765278
TI - Breathing life into customer satisfaction.
AB - The CPR model focuses on using the values of competence, pride, and respect to
raise customer satisfaction.
PMID- 10765279
TI - Four habits of highly successful change-skilled people.
PMID- 10765280
TI - Keep your eye on health care trends.
PMID- 10765281
TI - Transfers reach nurses and their patients.
AB - Understand how technology transfer works, how it applies to health care, and how
you can get the most out of the transfer process.
PMID- 10765282
TI - Sports metaphors. What game does your team play?
PMID- 10765284
TI - The appointment of a new Chief Nurse for England.
PMID- 10765283
TI - Ask AONE's experts ... about starting a program to reduce medication errors.
AB - Learn two strategies for reducing medication errors by working collaboratively-
and getting back to basics.
PMID- 10765285
TI - Setting safe staffing levels.
PMID- 10765286
TI - Why support a failing system?
PMID- 10765287
TI - Intuitive solutions.
PMID- 10765288
TI - Pooling talents.
PMID- 10765289
TI - Shared governance.
PMID- 10765290
TI - Career nurse or nursing as a career?
PMID- 10765291
TI - Nurse leadership in Scotland. Interview by Tom Keighley.
PMID- 10765292
TI - Raising standards in continuing care.
PMID- 10765293
TI - Joined up in Wales.
PMID- 10765294
TI - Delivering a promise: one woman's story of partnership and hope.
PMID- 10765295
TI - WIN against breast cancer programs.
PMID- 10765296
TI - The voice of cancer.
AB - Helping patients "find their voices" may also be referred to as advocacy or
empowerment. While the word itself has become overused, the concept of
empowerment is central to social work practice and is poignantly relevant to
oncology work. In serving people with cancer in ways that best respect their
unique voices, this author notes that social workers and nurses can work together
for the greater good.
PMID- 10765297
TI - Head and neck cancer and reconstruction revisited.
AB - People are known by their faces and voices. Wide resection of intraoral tumors
leaves faces that are unrecognizable and socially unacceptable, speech that may
be unintelligible, dietary needs not met in any restaurant, and isolation from a
society that puts a priority on smiles and meaningful communication.
PMID- 10765298
TI - Diagnosis and treatment of breast cancer.
AB - This article presents a thorough review of the diagnosis and treatment of breast
cancer, the most common type of cancer found among American women. Topics covered
in this article include risk factors, screening, types of breast cancer,
diagnostic procedures, surgical and nonsurgical treatments, staging, genetic
testing, and nutrition and complementary therapies.
PMID- 10765299
TI - Malignant melanoma: an update on treatments.
AB - Melanoma is the malignant tumor deriving from melanocytes through malignant
transformation. Melanocytes originate at the neuro-ectodermal crest (the tissue
matrix for the brain and medullary spine). These cells migrate during the early
fetal period into the skin and settle within the epidermis, becoming part of the
skin structure. Melanocytes differ from the other skin cells however; they have a
neuro-ectodermal origin, the potential of migrating, and the functional capacity
of nerve cell units.
PMID- 10765300
TI - Sunscreen use: an overview.
AB - Even to well-educated health care providers, sunscreen information continues to
be confusing in regard to adequate level of sun protection factor (SPF),
appropriate age of users, and whether sunscreen agents truly do prevent skin
cancers. The intent of this article is to present some of the current information
and controversies related to sunscreen use. It is strongly recommended that
nurses teach sunscreen use and sun avoidance strategies at every health care
opportunity. The message must be delivered that there is no such thing as a
"healthy tan."
PMID- 10765301
TI - Why you should know about melanoma. American Cancer Society.
PMID- 10765302
TI - Resource guide to professional cancer organizations, programs, and foundations.
PMID- 10765303
TI - Specimen handling: the nurse's responsibility.
PMID- 10765304
TI - Hints for taking multiple choice examinations.
PMID- 10765306
TI - Treatment of procedural pain.
PMID- 10765305
TI - Mandatory screening for physicians performing seriously invasive procedures: an
ethical analysis.
PMID- 10765307
TI - Switching to CFC-free inhalers.
PMID- 10765308
TI - Clinical governance and nursing.
PMID- 10765309
TI - A measurable framework for improving quality.
AB - Staff must believe in and value any quality programme being implemented. Quality
strategies should be based on the key principles that underline patient care.
Quality benefits the patient, staff and the organisation.
PMID- 10765310
TI - Home care for stem cell transplantation patients.
AB - Following high-dose chemotherapy patients need to undergo bone marrow rescue
through stem cell transplantation. Patients who received stem cell
transplantation at home expressed satisfaction with this form of therapy.
Performing stem cell transplantation in the home can reduce both costs and the
risk of infection.
PMID- 10765311
TI - Combining nursing roles in dermatology.
AB - There is an increasing demand for dermatology expertise among patients and
community nurses. Combining the role of dermatology nurse practitioner with that
of community dermatology liaison nurse allowed dermatology expertise to be
provided in both hospital and the community. The aim was to reduce waiting times,
provide a nursing alternative to dermatologists and open access for community
nurses to specialist expertise.
PMID- 10765312
TI - Achieving compliance in asthma management.
AB - Up to three million asthma patients take their medication using a metered dose
inhaler. The drive to reduce the world-wide use of chlorofluorocarbons (CFCs) has
resulted in the development of CFC-free metered dose inhalers. Nurses have an
important part to play in managing the transition to CFC-free inhaler devices.
This will provide an opportunity to improve levels of compliance with treatment
and reduce asthma-induced morbidity and mortality
PMID- 10765313
TI - Implementing evidence-based practice.
AB - Traditional methods of disseminating research findings through publication has
had only a limited impact on clinical practice. Issues of time and professional
territorialism may be barriers to change. More active interventions are needed to
ensure that findings are implemented.
PMID- 10765314
TI - The role of exercise in successful ageing.
AB - Older people are often expected to accept a passive role in society. Many
physical activities have been shown to benefit the mental and physical health of
older people. Nurses can help maintain older people's exercise levels by
incorporating programmes into nursing care.
PMID- 10765315
TI - Surgical treatment for morbid obesity.
AB - Many people find it difficult to lose weight. Surgery is often considered a last
resort for morbidly obese people after more traditional methods of weight control
have failed. Patients require expert nursing care peri-operatively.
PMID- 10765316
TI - Colorectal cancer. Part 3: Patient care.
AB - Treatment for colorectal cancer will almost inevitably result in toxicity. Roy's
model is ideal to enable nurses to monitor patients' physical and psychological
condition. Patients need information about toxicity so that they report it
promptly.
PMID- 10765317
TI - The management of procedural pain.
AB - The principles of acute pain management can be applied to the control of
procedural pain. The nurse should act as the patient's advocate to prevent undue
anxiety and suffering. Analgesia should be given before any potentially painful
procedure. Non-pharmacological pain management measures should be used alongside,
not instead of, analgesia.
PMID- 10765318
TI - Controlling the pain of venous leg ulceration.
AB - Compression therapy can often exacerbate the pain of venous leg ulceration. A
pain management programme using a team approach to care can promote compliance
with compression therapy. Nurses need to be sensitive and responsive to an
individual's pain.
PMID- 10765319
TI - Acute pain algorithm.
PMID- 10765320
TI - Preparing to make a difference.
PMID- 10765321
TI - Breast screening in older women.
PMID- 10765322
TI - Prostrate awareness among men.
PMID- 10765323
TI - The frequency of breast screening in older women.
AB - Increasing age is the main risk of breast cancer in women. Screening mammograms
are effective in women aged over 65 years for the early detection of breast
cancer. Older women's health beliefs affect their use of mammogram screening and
they tend not to take advantage of screening opportunities. Nurses must discuss
the benefits of screening mammograms with their older clients.
PMID- 10765324
TI - A review of senior nurses' roles in an acute trust.
AB - The relationship between the managerial and clinical roles of senior nurses
should be given more attention. Senior nurses believe some colleagues do not
understand their role and feel they need more support.
PMID- 10765325
TI - Protection for nurses during radiotherapy.
AB - Sealed sources of radiation usually take the form of a metal wire implanted
locally. These are removed intact and result in little or no residual
radioactivity in the patient. An unsealed source of radiation is distributed
around the patient's body and radiation will be excreted in the urine, saliva and
sweat. Nurses must follow local guidelines to protect themselves from radiation.
PMID- 10765327
TI - A mental health service after major trauma.
AB - Although 75-80% of people involved in a major trauma do not have any long-term
psychological problems, many will experience significant psychological distress
during the first four weeks. Most individuals will make a full recovery if
provided with local, immediate and appropriate support. People who have
experienced a major trauma should have access to support as soon as possible
after the event until symptoms are resolved.
PMID- 10765326
TI - Audit of pressure area care and documentation.
AB - Intensive care patients are at particular risk of pressure damage. Documentation
does not always fully reflect practice. Pressure sore identification remains a
subjective issue. Nurses do not always complete patient documentation.
PMID- 10765328
TI - Managing acutely disturbed behaviour.
AB - Managing acutely disturbed behaviour is difficult, particularly in environments
which are not designed for dealing with such conduct. An understanding of factors
which can lead to this behaviour and clear management policies and procedures are
needed.
PMID- 10765329
TI - Inhaler devices for use in asthma care.
AB - A patient's ability to use an asthma inhaler correctly will depend on his or her
age and manual dexterity. An up-to-date knowledge of the range of inhalers
available on the market, and their advantages and disadvantages, will aid
selection. Patients should be involved in the selection process as this will
encourage compliance.
PMID- 10765330
TI - Colorectal cancer. Part 4: Specialist nurse roles.
AB - The key nurse specialists involved in the management of colorectal cancer include
the colorectal nurse specialist, the stoma therapist and the chemotherapy nurse
specialist. The specialist nurse must integrate management, consultation,
research and education functions alongside the clinical role. The specialist
nurse provides expert advice and information and support and helps the person to
live with their diagnosis of cancer.
PMID- 10765331
TI - Planning a prostate awareness week.
AB - There are low consultation rates among men with prostate disease. Prostate
disease can affect the quality of life of both patients and their families.
Health promotional activities, such as a prostate awareness week, can empower men
to seek professional advice and treatment.
PMID- 10765332
TI - Electrical stimulation of the overactive bladder.
AB - Bladder overactivity is a significant health-care problem. Electrical stimulation
has been shown to be a safe and effective treatment option. Careful patient
selection may improve results obtained with this technique. Further studies are
required to determine optimal treatment parameters.
PMID- 10765333
TI - [Education and health regarding citizenship: a nurses' group practice].
AB - This study was run in a community committee of Nossa Senhora da Aparecida, a
surrounding city of Joao Pessoa, Paraiba. It aimed at characterizing nursing
practice there and discussing its occurrence. The analysis was run based on eight
inhabitants and four nurses speeches through semistructured interviews whose data
were collected qualitatively. It focused on the discussion which evolved from
questions regarding to education and health from the perspective of exercising
citizenship. In the participants of the study representations, education seemed
dynamic and implied awareness ... a question of life. Health is comprehended
under 3 points of view: the one of welfare, the one of suffering and the one of
biological balance. The perspective of citizenship exercise reveals itself
sometimes as conformism, through silence or resignation and sometimes as
resistance, through the ideal manifestation and courage for fighting for better
life condition.
PMID- 10765334
TI - [Nobody wants to lose a child--nurses' observations of family reactions].
AB - The presence of veterinary products in the houses without any minimum security
procedures has led to a poisoning case for a one-year old child who developed a
serious systemic reaction. This child was interned at a Pediatric Intensive Care
Unit at a public hospital in Fortaleza, Ceara. This study aims at identifying the
family reaction facing a poisoning of a child and analyzing these reactions,
interpreting its social cultural context. It has been developed as an
ethnographic study case, consisting of the exploration, decision and discovery
phases. It has been observed through the results that the family recognizes the
existence of risk factors in home environment but does not adopt any coherent
preventive methods with this experience. We do believe that these occurrences
reduction demand transforming educative actions which may lead the family to be
conscious towards the problematic that concerns poisoning for children, occurred
under their responsibility.
PMID- 10765335
TI - [Social profile of the black population in Brazil: implications for the nursing
profession].
AB - The discussion about the inequality conditions in which black population lives in
Brazil, has been disguised by today's economical conjuncture which apparently
sets with no restrictions the white, black and mestizos in absolute destitution
conditions. Considered unracist, entitled by 'Folha de Sao Paulo/Datafolha' as
Kind Racist, Brazil has being instituting way of living among races whose
discrimination is expressed by the lack of opportunity and access to consumption
services. This way, the insertion of the black in Brazilian society after slavery
abolition is our study object. This bibliographical discusses social indicators
aiming at describing this population strategies in conquering a social space.
This study shows up the difficulties faced by this populational group regarding
to its insertions to the work market as determinant factor to its social rising.
We have included black male and female as citizens which compose the labor force
in Nursing.
PMID- 10765336
TI - [Patient satisfaction: refinement of the instrument for health services
evaluation].
AB - This study reviewed the literature on Patient's Satisfaction in published
articles in national and international bulletins. The concepts and dimensions of
satisfaction have been identified since it is important to measure patient's
opinions on satisfaction, which we consider prominent points. Once we have
accomplished the analysis of several studies in this context, to serve as a basis
for future research geared at measuring patient's satisfaction, comparative
analysis of correlated subjects has been done, when several questionnaires on
Services Evaluation and Patient's Self-Evaluation on Satisfaction were studied
getting to a consensus that they could serve as subsidy for the orientation and
development in this kind of research with little adaptation and improvement.
PMID- 10765337
TI - [Experience of women in labor. Nurses' observations].
AB - This study emerged from my own experience in Obstetric Nursing and my living in
Obstetrics. I searched for comprehending the real meaning of delivery labor
experiences as a situated phenomenon. It is a qualitative research with
phenomenological approach. The lying-in women were the witnesses through the
question: 'What was your daily experience in the pre-delivery room like?' Through
analysis and hermeneutics of speeches, I have used the knowledge of Matin
Heidegger's philosophical-theoretical referential. Thus, I managed to clarify
that the parturient is fearful when left by herself in her experience, showing
surprise for the labor of delivery is singular, noting down the pain as a
possibility of the existential limit, being open to help and noticing the
impersonality of care provided. With this watchful sense, I approached the
comprehension of a lying-in woman as a being-in-a-world-with-health
professionals. This discovery indicated the possibility of new ways of caring in
Obstetrics.
PMID- 10765338
TI - [Feminist theory: the challenge of turning into a paradigm].
AB - From crisis of traditional paradigm and having feminist criticism as an
epicentre, this work attempts to present the challenge feminist theory faces for
becoming a new paradigm and for that, a bibliographical research is accomplished,
sustained by literature regarding to this theme. It is evidentiated that the
challenge of being a paradigm in ascension makes this theory to face theoretical,
conceptual and methodological problems which need a joined effort to be deepened
and solved. However, this theory development depend not only on the academic
world but is also linked to changes in social structure for it will more easily
emerge, from a more equalitary society, knowledge with no domination of gender.
PMID- 10765340
TI - [Nursing care at the Jardim Lidia mental health day hospital].
AB - The author describes her experience in this no insane asylum characteristics
institution. She points the possibility of intensive treatment for patients who
can stay home part-time. She elaborates individual activities and group therapy
in order to reinstate this patient to the society providing them a better life
quality.
PMID- 10765339
TI - [Performance of nursing students in the intramuscular administration of drugs].
AB - The goal of the present study was to compare the performance of two groups of
nursing undergraduate students, submitted to two different teaching methods, in
their ability to perform the intramuscular injection on clients needing the
procedure. Both, control (CG) and experimental group (EG) (n = 35 each) were
submitted to traditional method and instructional method respectively, according
to the methodological procedure described by Nogueira (1995). The performance of
the students was evaluated by a nurse who had no knowledge of the group each
student belong. The nurse used the "check-list" in order to evaluate the
performance of student. The results indicate that the time spent by the students
of each group was approximately the same i.e. 9.4 min for CG and 9.3 for EG. The
students of the control group showed ordinary performance (42.9%), good
performance (48.9%) and very good performance (8.5%) whereas those of the EG
showed ordinary performance (5.7%), good performance (60%) and very good
performance (34.3%). The present results shows that the students are responsible
by their own learning, motivating us to use new teaching methods on nursing
undergraduate course.
PMID- 10765341
TI - [Nursing process and structure for cancer patients].
AB - This study aimed at evaluating the structure for cancer patient assistance and
antineoplasic chemotherapy assistance process. It has been performed at six
internation units and one out-patient unit at a university hospital. Systematized
observation and semistructured interview were used from January to June, 1996. It
was noticed the there were some deficiencies in the physical area and
installations of the studied units. Generally, nursing team had no formal
training in Oncology, except for Chemotherapy Sector. The absence of a
systematized nursing assistance and differences among the studied units as for
technical organizational aspects for antineoplasic administration as well as
patients and staff interaction has been observed. Inadequations observed could be
minimized with such a politics which would be able to increase public sector
financing, planting of systematized care and inclusion of Oncology in the
permanent nursing team education.
PMID- 10765342
TI - [Art workshop: therapeutic activities of psychiatric nurses].
AB - This study is about experience of taking care, in the art workshop. With
objective to evidence new possibility of psychiatric nursing, the activity have
been develop if psychotic, usually the Services Mental Health. We concluded that
utilisation artistic resources of care, collaborate relationships and social
rehabilitation.
PMID- 10765343
TI - [Styles of conflict management among nurses. Instrument validation].
AB - The present study has as an object the modalities of conflict administration
adopted by nurses in professional praxis. Considering the Management Grid Theory
(BLAKE & MOUNTON, 1978), the conflict can be solved in different levels of
quality or even, not solved, influenced by the manager behavior model. It is
intended to identify nurses managing styles in conflict administration, analyzing
their interactions. A questionnaire composed with 25 items, in its majority of
popular adagios which express the five basic models of the Management Grid, has
been tested. The research was run at the Rio de Janeiro State University Pedro
Ernesto University Hospital from June, 1996 to August, 1997, and descriptive
method and check-list schedule type functional analysis technique have been used.
The factorial analysis of items has showed an occurrence of eight interdependent
factors which designing the following styles that have been adopted by nurses:
confrontation, negotiation, facing, conciliation, manipulation, acceptance,
submission and withdrawing. The authors recommend data collect instrument
revalidation.
PMID- 10765344
TI - [Perception of health professionals of the risk of chemical exposure].
AB - A great variety of substances are exposed to health workers every single day.
Such substances have noxious actions on biological organs generating pictures of
poisoning. Facing such a problem, this study aimed at identifying the Material
Center workers perceptions at a general hospital in Ribeirao Preto, Sao Paulo
having 12 nursing professionals/occupational, both sexes, aging between 23 to 55
years-old, as a sample. The used method was interviews through questionnaires.
The data have showed that the workers have no knowledge regarding to the relation
between exposure to chemical agents and its consequent health damage. According
to these data it has been concluded that: (1) professionals adopt security
behavior inadequately; (2) they find themselves demotivated; (3) there is lack of
interaction and authority for preventive control measures fiscalization; (4)
there are some failures in continued education process. Therefore, its the
nurse's major responsibility as for scientific development, so that it can avoid
evasive processes that generate profession no survival.
PMID- 10765345
TI - [Brazilian Nursing Association: 70 years of struggle for life].
AB - This work is about the Brazilian Nursing Association (ABEn), its origin, its
expansion and projection based on its philosophy and highlighting its
achievements from its origin in 1926 until today when its 70th anniversary is
being celebrated. This work aims at reporting this institution history and
narrating the support provided so that nursing may contribute decisively to the
construction of a body of profession knowledge itself, the legal definition of
professional practice, teaching regulamentation through its commissions.
Methodology has been composed of bibliographic research and interviews with
active professionals. It has been concluded that ABEn is stronger and stronger
and aware of the way on how to achieve many other goals which will bear great
conquests which will contribute for granting nursing power and space as a
profession set to the human, therefore, to a better life, with more love, peace
and social justice.
PMID- 10765346
TI - [Teaching nursing: 20 years at the university].
AB - During the twenty years in which nursing has been taught as a university subject
field, its teaching methods have undergone two stages: a first one about ten
years long in which the change produced in the orientation toward nursing care
originated a conceptual and methodological whirlwind advancing the profession in
a way which had never before occurred; and a second stage in which the conceptual
waters tend to subdue and the first doubts begin to appear about whether or not
the profession is walking down the right path. This article proposes to serve as
a reflection on the twenty year history of Nursing as a university subject field
as well as to reflect on how we can construct the future on this base, not only
in nursing studies themselves and the manner of teaching these studies, but in
the profession as a whole. The author presented this as a conference at the
Spanish Association of Nursing Teachers' XVIII "Working Days" Conference.
PMID- 10765347
TI - [Nursing publications. International scientific production. Current status].
PMID- 10765349
TI - [Sensory areas of the head].
PMID- 10765348
TI - [India, a nursing vision].
PMID- 10765350
TI - [Drugs in cardiopulmonary resuscitation. (I) Administration].
AB - After their classification and limitation based on their therapeutic measures to
their most scientifically contrasted efficiency measures, this article reviews
what is written for each pharmaceutical in the recommendations bearing more
weight in our field, those of the American Heart Association and those of the
European Resuscitation Council. A study is made of the various techniques which
can be used in administering these drugs as well as their utility and suitability
in the field of resuscitation.
PMID- 10765352
TI - [Portable peristaltic perfusion pumps].
AB - Portable peristaltic perfusion pumps allow one to administer pharmaceuticals in
hospitals as well as in primary health care centers and furthermore these pumps
present multiple advantages for patients and their families since they make it
possible to carry out treatment in a patient's home while at the same time
lowering the costs involved. The authors analyze the most out standing aspects of
portable peristaltic perfusion pumps along with their characteristics,
installation, programming, and how to turn them on; in addition, the authors list
the maintenance care which these pumps require.
PMID- 10765351
TI - [Sex education. An experience in elementary and middle schools].
AB - Two nurses at a Primary Health Care Center started up a "Sexual Education
Project" in schools in an urban Basic Health Zone. Over the course of the five
years this project has been in operation, classes in Sexual Education have been
taught in two Middle Schools and six Elementary Schools. During this time, some
4500 questions and doubts have been received and processed. The teaching staffs
have shown tremendous interest in this project; furthermore, no school placed any
impediments for the development of this program. The types of questions asked did
not vary substantially according to the different ages of students taught. The
program instructors became aware of the need to provide sexual education
information to adults beyond school age. The program directors discovered that it
was necessary to establish coordination among the schools and health centers as
well as to enlarge this kind of program to other areas of the general public.
This experience demonstrated that teaching activities employing nursing personnel
as educators in sexuality provides very satisfactory results.
PMID- 10765353
TI - [Respiratory allergy in children and passive smoking].
PMID- 10765354
TI - [Ostomies: what has to be understood].
PMID- 10765356
TI - [The relationship between nurse and patient].
PMID- 10765355
TI - [Collecting devices and skin protectors].
PMID- 10765357
TI - [The enterostoma therapists].
PMID- 10765358
TI - [The French Federation of Stoma Patients: a place of support and orientation for
patients with stomas].
PMID- 10765359
TI - [Day surgery: evidence of efficiency].
PMID- 10765360
TI - [Attempted suicide by adolescents: risking death in order to live].
PMID- 10765361
TI - [The nurse-anesthetists outgrow their definition].
PMID- 10765362
TI - [Congress of the French Society of Anesthetists at the opening. Interview by Eric
Charles].
PMID- 10765363
TI - [Practice of anesthesia: the big developments].
PMID- 10765364
TI - [Improving the caring relation].
PMID- 10765365
TI - [Listening to what the other has to say].
PMID- 10765366
TI - [Equipment: current integration].
PMID- 10765367
TI - [Nursing executives: they are real managers].
PMID- 10765368
TI - [Legal, penal and disciplinary responsibility].
PMID- 10765369
TI - [Responsible for the technical level: guarantors of the quality of care].
PMID- 10765370
TI - [Education of health care managers].
PMID- 10765371
TI - Guts.
PMID- 10765372
TI - Monitoring the latest in computer screens.
PMID- 10765373
TI - Ethics in action. A nursing colleague is secretly tube feeding a terminally ill
patient.
PMID- 10765374
TI - A portrait of postop a-fib.
PMID- 10765375
TI - Hospitalists. Good or bad news for nurses?
PMID- 10765376
TI - Tips for nurses who wash too much.
PMID- 10765377
TI - When the ache is not arthritis.
PMID- 10765378
TI - Easing the course of Guillain-Barre syndrome.
PMID- 10765379
TI - Colorectal cancer.
PMID- 10765380
TI - Support surfaces and specialty beds. Part 1: Prevention and early intervention.
PMID- 10765381
TI - Caring for the deaf. Do you do enough?
PMID- 10765382
TI - New quality standards for herbal products.
PMID- 10765383
TI - Alternative medicine.
PMID- 10765384
TI - Latex allergy and implications for urology nursing.
AB - Latex hypersensitivity is a major occupational health concern. Health care
workers as well as patients who are not yet diagnosed are the most at-risk
populations. Knowledge about everyday products that may increase one's exposure
to latex allergy is an important prevention strategy and will assist in
decreasing the overall incidence of latex allergy among patients and health care
workers.
PMID- 10765385
TI - The challenge of developing the nursing clinical practice guideline: neurogenic
bladder management.
AB - The development of the nursing clinical practice guideline was methodically
structured to create a research-based guideline to assist nurses in caring for
bladders of neurologically impaired individuals. The rigor with which it was
developed is reflected in the end product.
PMID- 10765386
TI - Homemade male incontinence pouch.
AB - It is estimated that more than 13 million Americans experience incontinence or
loss of bladder control. As a registered nurse specializing in urology, the
author created a male drip collector, made from a female sanitary napkin (ALWAYS
with Wings). This homemade male incontinence pouch is cost effective, comfortable
to use, easy to make, can absorb 20 cc to 70 cc of urine, and is available in any
store.
PMID- 10765387
TI - Unlocking the mystery of urodynamics.
AB - Urodynamic testing plays a key role in evaluating problems associated with the
urinary tract. Once the symptoms can be linked to an underlying cause through
urodynamics, the patient can be appropriately treated. Urodynamics must emphasize
patients' goals and desires, while recognizing their needs, fears, and concerns.
PMID- 10765388
TI - Transthoracic needle biopsy.
AB - Transthoracic needle biopsy (TNB) has emerged as the semi-invasive technique of
choice for the diagnosis of localized intrathoracic lesions. Using CT,
fluoroscopic, or sonographic guidance, TNB is highly accurate and safe when
combined with expert pathologic interpretation of the aspirated specimen. This
article details the preprocedural evaluation of the patient referred for TNB and
discusses the technical aspects of performing the biopsy and processing and
interpreting the material obtained. The reported results and complications of TNB
are reviewed and followed by a brief description of the cost effectiveness of the
technique and a comparison with alternative semi-invasive diagnostic techniques
including bronchoscopic and video-assisted thoracoscopic biopsy.
PMID- 10765389
TI - Special techniques in transthoracic needle biopsy of pulmonary nodules.
AB - We believe that each aspect of the performance of TNB needs to be considered
carefully. Meticulous attention to detail allows any nodule in the chest to
successfully undergo biopsy. There are techniques of needle tip repositioning
that can be quite helpful for obtaining diagnostic material from lung lesions,
particularly small nodules. A strong working relationship with pathologists
experienced in lung cytology is a vital element of any successful biopsy program.
Techniques available to the pathologist allow for quick and decisive
determination of the adequacy of the aspirated specimen and help guide the
radiologist performing the procedure. Newer cytopathologic techniques help the
pathologist make more complex diagnoses from the aspirated material. Finally,
techniques used to minimize complications should be considered by the operator
before the performance of the biopsy.
PMID- 10765390
TI - Transthoracic hilar and mediastinal biopsy.
AB - TNB of the mediastinum is an accurate, safe, and cost-effective diagnostic tool
for the evaluation of mediastinal masses and lymphadenopathy. The technique is
most useful in the staging of carcinoma, where it serves as a less expensive and
minimally invasive alternative to mediastinoscopy for establishing
unresectability. With recent advances in immunohistochemical and core biopsy
techniques, TNB has become more accurate for establishing the initial diagnosis
of lymphoma and for confirming recurrent disease. Core-needle biopsy has improved
the accuracy of TNB and is particularly useful when fine-needle aspiration fails
to yield a specific diagnosis, or when lymphoma or a noncarcinomatous lesion is
suspected.
PMID- 10765391
TI - Percutaneous needle biopsy of the pleura.
AB - Percutaneous needle biopsy of the pleura and thoracic wall is a relatively
simple, minimally invasive, and safe technique that may be performed in an
outpatient setting under local anesthesia. Image guidance, combined with the use
of core biopsy needles and immunohistochemical techniques, have lead to increased
diagnostic yield and overall accuracy. Open and thoracoscopic biopsies are
reserved for a minority of patients in whom pleural fluid cytology and
percutaneous needle biopsy are nondiagnostic.
PMID- 10765392
TI - CT fluoroscopy for thoracic interventional procedures.
AB - In the past several years, CT fluoroscopy has proved a valuable new technique in
guiding the performance of intrathoracic procedures. Several approaches to using
CT fluoroscopy are discussed. We have found an interrupted, real-time technique
optimal to facilitate biopsy of percutaneous lung nodules, particularly small
lesions. The technique is also valuable in assisting thoracic drainage
procedures. This article also discusses the use of CT fluoroscopy to guide
transbronchial needle aspiration, which is another potentially important
application.
PMID- 10765393
TI - Ultrasound-guided transthoracic biopsy of the chest.
AB - Recent studies have confirmed that US is a very useful diagnostic tool for
various diseases of the chest. The image information provided by US is helpful
for etiologic diagnosis and clinical management. US-guided needle biopsy provides
a precise and safe approach for transthoracic tissue sampling of lesions. The
diagnostic yield is high, and the procedure is relatively easy and very safe.
Color Doppler US and amplitude US angiography further extend the diagnostic
potential and safety of this invasive procedure. Vascular information can be
obtained and the needle shaft can be visualized clearly while conducting a
biopsy. US examination and US-guided needle aspiration biopsy have now become
indispensable diagnostic tools for various chest diseases.
PMID- 10765394
TI - Image-guided management of complicated pleural fluid collections.
AB - Percutaneous image-guided catheter drainage with adjunctive ICFT has become the
mainstay in the treatment of complicated pleural fluid collections. There are six
basic principles of image-guided drainage and ICFT that must be understood to
maximize the efficacy and safety of the procedure. 1. There must be a basic
understanding of why traditional nonguided thoracostomy drainage fails in a
significant percentage of patients. Tube malposition relative to fluid
loculations, fluid debris and viscosity, and the presence of a stage 3 pleural
peel are the primary reasons for failure. Image-guided placement of drains
addresses the issue of tube malposition and ICFT greatly facilitates drainage of
fibrinous fluid. 2. Proper use of cross-sectional imaging is one of the keys to
ultimate success. CT and ultrasound allow very accurate assessment of the
underlying pathologic process and are crucial in planning the drainage procedure,
guiding the actual placement of drains, and following the course and outcome of
treatment. The added costs of cross-sectional imaging are more than compensated
by the increase in success of the drainage procedure. 3. Aggressive catheter
management is the single most important factor in success. Multiple loculations
require multiple catheters for adequate drainage. Pleural adhesions may form
quickly as drainage progresses leading to the formation of undrained loculations.
Frequent cross-sectional imaging is needed to detect undrained loculations so
that additional drainage catheters may be placed if needed. It is crucial that
the drainage catheter always be properly positioned in relation to fluid
loculations. 4. Intracavitary fibrinolytic therapy is a very powerful adjunctive
therapy to aid in complete evacuation of fluid collections that contain fibrin
nets and debris. It can also partially debride the pleural surfaces of fibrinous
debris and facilitate complete re-expansion of the underlying lung. Intracavitary
fibrinolytic therapy should not be used in an attempt to salvage success by a
malpositioned chest tube. 5. The ultimate success of closed drainage for
complicated pleural fluid collections is closely related to the age of the
effusion at the time of drainage. A very high rate of clinical success may be
expected when these techniques are used in the treatment of stage 2
fibrinopurulent effusions. If drainage is delayed until the third stage (fibrous
pleural peel formation) then closed drainage likely will fail and a formal
thoracotomy and decortication will be necessary. Experience in the literature
suggests that effusions up to 4 to 6 weeks in duration may be drained
successfully but those older than 6 weeks likely will have an associated pleural
peel. Effective pleural drainage must be instituted early in the course of the
disease process. 6. There may be significant residual pleural and parenchymal
inflammatory changes after complete drainage of a stage 2 effusion. If the fluid
in the pleural space has been adequately drained and the visceral and parietal
pleural surfaces apposed, then the residual inflammatory pleural thickening and
associated lung consolidation resolve over 2 to 4 months and pulmonary function
returns to baseline. Imaging studies immediately after complete pleural drainage
are not normal. These residual abnormalities should not be interpreted as
evidence that open surgical drainage should have been performed. Effective closed
drainage carries lower morbidity, mortality, and cost than does open surgical
drainage. For radiologists and clinicians alike it does not suffice simply to
place one or more thoracostomy tubes, round daily, and hope that the occasional
use of fibrinolytic agents does the rest. Without a more aggressive approach to
catheter position and management the efficacy is no greater than that
historically seen with nonguided closed drainage and surgeons will continue to
plead for earlier effective open drainage.
PMID- 10765395
TI - Management of malignant pleural effusions and pneumothorax.
AB - Pneumothorax may occur spontaneously or result from underlying lung disease or as
a complication of interventional thoracic procedures. Percutaneous catheter
placement enables safe and effective drainage of pneumothoraces with rapid relief
of symptoms and restoration of vital capacity and oxygenation.
PMID- 10765396
TI - Percutaneous management of intrapulmonary air and fluid collections.
AB - The radiologist's role in the management of intrapulmonary air and fluid
collections is becoming more important. Improvements in percutaneous
interventional techniques now allow the radiologist to offer patients an
alternative treatment option with less morbidity and mortality than surgical
resection. The use of CT allows optimal catheter placement and enables safe and
effective percutaneous evacuation of intrapulmonary collections. In summary,
image-guided percutaneous catheter drainage should (1) be the initial procedure
performed to diagnose and treat lung abscesses not responding to conservative
therapy; and (2) because of its effectiveness and safety, be considered as a
treatment option in the management of symptomatic patients with intrapulmonary
mycetomas.
PMID- 10765397
TI - Stenting of the tracheobronchial tree.
AB - Endoscopic treatment of endobronchial obstructions is becoming increasingly
important. Tracheobronchial stents often are needed in the treatment of
obstructions from submucosal or extrabronchial lesions. Tube stents have been
available since the early 1960s but are underused because their insertion
requires the use of a rigid bronchoscope. With the recent development of metallic
stents, interventional radiologists increasingly are involved in the treatment of
tracheobronchial obstructions. Metallic stents, easily placed with flexible
bronchoscopy, are growing in popularity. All available tracheobronchial stents
have been shown in various clinical series to be able to achieve immediate
resolution of respiratory symptoms from various tracheobronchial obstructions. A
stent's performance, however, should not be based solely on short-term response.
Presently, there is no ideal stent because none is free of complications and none
are able to consistently maintain life-long patency. Gianturco stents are
associated with serious major complications (bronchial perforations and strut
fractures) and are no longer recommended for use in the tracheobronchial tree.
The Palmaz stent has also fallen into disfavor, because a strong external force,
such as a vigorous cough, can recompress it. The Strecker stent can only be used
in smaller airways, but may be useful in the accurate stenting of short segment
stenoses because it does not foreshorten on deployment. The Wallstent and
Ultraflex are our present metallic stents of choice. Both are easy to deploy,
available in covered forms, exert adequate radial force, remain relatively stable
in position, and have good longitudinal flexibility for use in tortuous airways.
Disadvantages include excessive granulation tissue formation and difficulty of
removal once the stent has been epithelialized. Metallic stents should be chosen
very carefully for use in benign lesions with ongoing active local inflammation
or when temporary stenting is needed. In the absence of an ideal stent,
technologic advancements will continue. Potential developments include removable
metallic stents, biodegradable stents, and chemically and radioactively coated
stents. Unquestionably, the expanding stent market will drive scientific research
toward the development of the ideal stent. Clearly, physicians need to be ready
to assess these technologic advancements.
PMID- 10765398
TI - Superior vena cava stenting.
AB - Treatment of SVC obstruction with metallic stents is a rewarding procedure. The
patients have symptoms that are severe and debilitating and cause significant
impairment of life-style. Stent placement rapidly alleviates the symptoms of SVC
syndrome and improves the patient's quality of life. The long-term patency rates
have not been established; however, in patients with SVC syndrome secondary to
malignant disease, stents usually remain patent for the lifetime of the patient.
Recurrences can be treated with further interventional radiographic techniques.
Currently, because the long-term patency rates of SVC stents are not known, most
interventional radiologists tend to treat SVC stenosis from benign causes with
balloon angioplasty before placing metallic stents.
PMID- 10765399
TI - Embolotherapy in the bronchial and pulmonary circulations.
AB - This two-part article first discusses the role of bronchial artery transcatheter
embolotherapy in the management of patients with hemoptysis. Following this
discussion, the authors review pulmonary arteriovenous malformations, their
embolization, follow-up protocols, and outcome criteria as currently practiced at
the authors' Vascular Malformation Center.
PMID- 10765400
TI - Geographical dimensions and correlates of trust.
AB - A sample of 323 residents of New Jersey stratified by neighborhood quality
(excellent, good, fair, poor) was gathered to determine if trust in science and
technology to protect public health and environment at the societal scale was
associated with trust of the local officials, such as the mayor, health officer,
developers, mass media, and legislators who are guardians of the local
environment. Societal (trust of science and technology) and neighborhood (mayor,
health officer) dimensions of trust were found. These societal and neighborhood
trust dimensions were weakly correlated. Respondents were divided into four trust
of-authority groups: high societal-high neighborhood, low societal-low
neighborhood, high societal-low neighborhood, and low societal-high neighborhood.
High societal-high neighborhood trust respondents were older, had lived in the
neighborhoods for many years, were not troubled much by neighborhood or societal
environmental threats, and had a strong sense of control over their environment.
In strong contrast, low societal-low neighborhood trust respondents were
relatively young, typically had lived in their present neighborhood for a short
time, were troubled by numerous neighborhood and societal environmental threats,
did not practice many personal public health practices, and felt little control
over their environment.
PMID- 10765401
TI - Fishing in urban New Jersey: ethnicity affects information sources, perception,
and compliance.
AB - Recreational and subsistence angling are important aspects of urban culture for
much of North America where people are concentrated near the coasts or major
rivers. Yet there are fish and shellfish advisories for many estuaries, rivers,
and lakes, and these are not always heeded. This paper examines fishing behavior,
sources of information, perceptions, and compliance with fishing advisories as a
function of ethnicity for people fishing in the Newark Bay Complex of the New
York-New Jersey Harbor. We test the null hypothesis that there were no ethnic
differences in sources of information, perceptions of the safety of fish
consumption, and compliance with advisories. There were ethnic differences in
consumption rates, sources of information about fishing, knowledge about the
safety of the fish, awareness of fishing advisories or of the correct advisories,
and knowledge about risks for increased cancer and to unborn and young children.
In general, the knowledge base was much lower for Hispanics, was intermediate for
blacks, and was greatest for whites. When presented with a statement about the
potential risks from eating fish, there were no differences in their willingness
to stop eating fish or to encourage pregnant women to stop. These results
indicate a willingness to comply with advisories regardless of ethnicity, but a
vast difference in the base knowledge necessary to make informed risk decisions
about the safety of fish and shellfish. Although the overall median income level
of the population was in the $25,000-34,999 income category, for Hispanics it was
on the border between $15,000-24,999 and $25,000-34,999.
PMID- 10765402
TI - Fundamentals of health risk assessment. Use, derivation, validity and limitations
of safety indices.
AB - We investigated the way results of human health risk assessments are used, and
the theory used to describe those methods, sometimes called the "NAS paradigm."
Contrary to a key tenet of that theory, current methods have strictly limited
utility. The characterizations now considered standard, Safety Indices such as
"Acceptable Daily Intake," "Reference Dose," and so on, usefully inform only
decisions that require a choice between two policy alternatives (e.g., approve a
food additive or not), decided solely on the basis of a finding of safety. Risk
is characterized as the quotient of one of these Safety Indices divided by an
estimate of exposure: a quotient greater than one implies that the situation may
be considered safe. Such decisions are very widespread, both in the U.S. federal
government and elsewhere. No current method is universal; different policies lead
to different practices, for example, in California's "Proposition 65," where
statutory provisions specify some practices. Further, an important kind of human
health risk assessment is not recognized by this theory: this kind characterizes
risk as likelihood of harm, given estimates of exposure consequent to various
decision choices. Likelihood estimates are necessary whenever decision makers
have many possible decision choices and must weigh more than two societal values,
such as in EPA's implementation of "conventional air pollutants." These estimates
can not be derived using current methods; different methods are needed. Our
analysis suggests changes needed in both the theory and practice of human health
risk assessment, and how what is done is depicted.
PMID- 10765403
TI - Reliability analysis for hazardous waste treatment processes.
AB - The reliability of a treatment process is addressed in terms of achieving a
regulatory effluent concentration standard and the design safety factors
associated with the treatment process. This methodology was then applied to two
aqueous hazardous waste treatment processes: packed tower aeration and activated
sludge (aerobic) biological treatment. The designs achieving 95 percent
reliability were compared with those designs based on conventional practice to
determine their patterns of conservatism. Scoping-level treatment costs were also
related to reliability levels for these treatment processes. The results indicate
that the reliability levels for the physical/chemical treatment process (packed
tower aeration) based on the deterministic safety factors range from 80 percent
to over 99 percent, whereas those for the biological treatment process range from
near 0 percent to over 99 percent, depending on the compound evaluated. Increases
in reliability per unit increase in treatment costs are most pronounced at lower
reliability levels (less than about 80 percent) than at the higher reliability
levels (greater than 90 percent, indicating a point of diminishing returns.
Additional research focused on process parameters that presently contain large
uncertainties may reduce those uncertainties, with attending increases in the
reliability levels of the treatment processes.
PMID- 10765404
TI - Hormesis: a highly generalizable and reproducible phenomenon with important
implications for risk assessment.
AB - From a comprehensive search of the literature, the hormesis phenomenon was found
to occur over a wide range of chemicals, taxonomic groups, and endpoints. By use
of computer searches and extensive cross-referencing, nearly 3000 potentially
relevant articles were identified. Evidence of chemical and radiation hormesis
was judged to have occurred in approximately 1000 of these by use of a priori
criteria. These criteria included study design features (e.g., number of doses,
dose range), dose-response relationship, statistical analysis, and
reproducibility of results. Numerous biological endpoints were assessed, with
growth responses the most prevalent, followed by metabolic effects, reproductive
responses, longevity, and cancer. Hormetic responses were generally observed to
be of limited magnitude with an average maximum stimulation of 30 to 60 percent
over that of the controls. This maximum usually occurred 4- to 5-fold below the
NOAEL for a particular endpoint. The present analysis suggests that hormesis is a
reproducible and generalizable biological phenomenon and is a fundamental
component of many, if not most, dose-response relationships. The relatively
infrequent observation of hormesis in the literature is believed to be due
primarily to experimental design considerations, especially with respect to the
number and range of doses and endpoint selection. Because of regulatory
considerations, most toxicologic studies have been carried out at high doses
above the low-dose region where the hormesis phenomenon occurs.
PMID- 10765405
TI - Adverse health experiences, environmental attitudes, and pesticide usage behavior
of farm operators.
AB - Water pollution from agricultural pesticides continues to be a public concern.
Given that the use of such pesticides on the farm is largely governed by
voluntary behavior, it is important to understand what drives farmer behavior.
Health belief models in public health and social psychology argue that persons
who have adverse health experiences are likely to undertake preventive behavior.
An analogous hypothesis set was tested here: farmers who believe they have had
adverse health experiences from pesticides are likely to have heightened concerns
about pesticides and are more likely to take greater precautions in dealing with
pesticides. This work is based on an original survey of a population of 2700 corn
and soybean growers in Maryland, New York, and Pennsylvania using the U.S.
Department of Agriculture data base. It was designed as a mail survey with
telephone follow-up, and resulted in a 60 percent response rate. Farm operators
report experiencing adverse health problems they believe are associated with
pesticides that is equivalent to an incidence rate that is higher than the
reported incidence of occupational pesticide poisonings, but similar to the
reported incidence of all pesticide poisonings. Farmers who report experiencing
such problems have more heightened concerns about water pollution from
fertilizers and pesticides, and illness and injury from mixing, loading, and
applying pesticides than farmers who have not experienced such problems. Farmers
who report experiencing such problems also are more likely to report using
alternative pest management practices than farmers who do not report having such
problems. This implies that farmers who have had such experiences do care about
the effects of application and do engage in alternative means of pest management,
which at least involve the reduction in pesticide use.
PMID- 10765406
TI - Estimating noncancer uncertainty factors: are ratios NOAELs informative?
AB - The prominent role of animal bioassay evidence in environmental regulatory
decisions compels a careful characterization of extrapolation uncertainties. In
noncancer risk assessment, uncertainty factors are incorporated to account for
each of several extrapolations required to convert a bioassay outcome into a
putative subthreshold dose for humans. Measures of relative toxicity taken
between different dosing regimens, different endpoints, or different species
serve as a reference for establishing the uncertainty factors. Ratios of no
observed adverse effect levels (NOAELs) have been used for this purpose;
statistical summaries of such ratios across sets of chemicals are widely used to
guide the setting of uncertainty factors. Given the poor statistical properties
of NOAELs, the informativeness of these summary statistics is open to question.
To evaluate this, we develop an approach to "calibrate" the ability of NOAEL
ratios to reveal true properties of a specified distribution for relative
toxicity. A priority of this analysis is to account for dependencies of NOAEL
ratios on experimental design and other exogenous factors. Our analysis of NOAEL
ratio summary statistics finds (1) that such dependencies are complex and produce
pronounced systematic errors and (2) that sampling error associated with typical
sample sizes (50 chemicals) is nonnegligible. These uncertainties strongly
suggest that NOAEL ratio summary statistics cannot be taken at face value;
conclusions based on such ratios reported in well over a dozen published papers
should be reconsidered.
PMID- 10765407
TI - Cancer risk estimation of genotoxic chemicals based on target dose and a
multiplicative model.
AB - A mechanistic model and associated procedures are proposed for cancer risk
assessment of genotoxic chemicals. As previously shown for ionizing radiation, a
linear multiplicative model was found to be compatible with published
experimental data for ethylene oxide, acrylamide, and butadiene. The validity of
this model was anticipated in view of the multiplicative interaction of mutation
with inherited and acquired growth-promoting conditions. Concurrent analysis led
to rejection of an additive model (i.e. the model commonly applied for cancer
risk assessment). A reanalysis of data for radiogenic cancer in mouse, dog and
man shows that the relative risk coefficient is approximately the same (0.4 to
0.5 percent per rad) for tumours induced in the three species. Doses in vivo,
defined as the time-integrated concentrations of ultimate mutagens, expressed in
millimol x kg-1 x h (mMh) are, like radiation doses given in Gy or rad,
proportional to frequencies of potentially mutagenic events. The radiation dose
equivalents of chemical doses are, calculated by multiplying chemical doses (in
mMh) with the relative genotoxic potencies (in rad x mMh-1) determined in vitro.
In this way the relative cancer incidence increments in rats and mice exposed to
ethylene oxide were shown to be about 0.4 percent per rad-equivalent, in
agreement with the data for radiogenic cancer. Our analyses suggest that values
of the relative risk coefficients for genotoxic chemicals are independent of
species and that relative cancer risks determined in animal tests apply also to
humans. If reliable animal test data are not available, cancer risks may be
estimated by the relative potency. In both cases exposure dose/target dose
relationships, the latter via macromolecule adducts, should be determined.
PMID- 10765408
TI - Ethical issues in risk communication: continuing the discussion.
AB - Proposed in this article is one possible framework for classifying multiple types
of ethical issues in risk communication research and practice to help continue a
discussion initiated in 1990 by Morgan and Lave. Some of the questions that each
stage of the process for planning risk communication strategies appears to pose
for ethics are discussed (e.g., selecting issues to be communicated, knowing the
issue, dealing with constraints). Also discussed briefly are some issues raised
by the possibility that risk communicators aspire to the status of a profession.
The purpose is to foster discussion rather than issue a conclusive statement on
the topic, because its very nature makes a definitive pronouncement indefensible.
PMID- 10765409
TI - Exposure to environmental tobacco smoke in the workplace and the impact of away
from-work exposure.
AB - Concentrating on exposure in workplaces where smoking occurs, we examined
environmental tobacco smoke (ETS)-related concentration data from the 16-City
Study. This study involved a large population of nonsmokers, used personal
monitors, and encompassed a wide selection of ETS-related constituents. This
first article in a series of three describes the 16-City Study, considers the
impact of demographic variables, and concludes that these variables did not
explain differences in exposure to ETS. We compared 16-City Study concentrations
obtained in the workplace to previously reported workplace concentrations and
determined that data from this study were representative of current ETS exposure
in nonmanufacturing workplaces where smoking occurs. Considering factors other
than demographic factors, we found that, not surprisingly, the number of
cigarettes observed in the workplace had an impact on exposure concentrations.
Finally, we compared people from homes where smoking occurs with people from
nonsmoking homes and found that people from smoking homes observed more smoking
in the workplace and experienced higher concentrations of ETS-related compounds
in the workplace, even when they observed the same number of cigarettes being
smoked in the workplace. In two subsequent articles in this series, we discuss
relationships between various ETS markers and provide estimates of distributions
of doses to nonsmoking workers employed in workplaces where smoking occurs.
PMID- 10765410
TI - Use of environmental tobacco smoke constituents as markers for exposure.
AB - The 16-City Study analyzed for gas-phase environmental tobacco smoke (ETS)
constituents (nicotine, 3-ethenyl pyridine [3-EP], and myosmine) and for
particulate-phase constituents (respirable particulate matter [RSP], ultraviolet
absorbing particulate matter [UVPM], fluorescing particulate matter [FPM],
scopoletin, and solanesol). In this second of three articles, we discuss the
merits of each constituent as a marker for ETS and report pair-wise comparisons
of the markers. Neither nicotine nor UVPM were good predictors for RSP. However,
nicotine and UVPM were good qualitative predictors of each other. Nicotine was
correlated with other gas-phase constituents. Comparisons between UVPM and other
particulate-phase constituents were performed. Its relation with FPM was
excellent, with UVPM approximately 1 1/2 times FPM. The correlation between UVPM
and solanesol was good, but the relationship between the two was not linear. The
relation between UVPM and scopoletin was not good, largely because of noise in
the scopoletin measures around its limit of detection. We considered the relation
between nicotine and saliva continine, a metabolite of nicotine. The two were
highly correlated on the group level. That is, for each cell (smoking home and
work, smoking home but nonsmoking work, and so forth), there was high correlation
between average continine and 24-hour time-weighted average (TWA) nicotine
concentrations. However, on the individual level, the correlations, although
significant, were not biologically meaningful. A consideration of cotinine and
nicotine or 3-EP on a subset of the study whose only exposure to ETS was
exclusively at work or exclusively at home showed that home exposure was a more
important source of ETS than work exposure.
PMID- 10765411
TI - Distribution of exposure concentrations and doses for constituents of
environmental tobacco smoke.
AB - The ultimate goal of the research reported in this series of three articles is to
derive distributions of doses of selected environmental tobacco smoke (ETS)
related chemicals for nonsmoking workers. This analysis uses data from the 16
City Study collected with personal monitors over the course of one workday in
workplaces where smoking occurred. In this article, we describe distributions of
ETS chemical concentrations and the characteristics of those distributions (e.g.,
whether the distribution was log normal for a given constituent) for the
workplace exposure. Next, we present population parameters relevant for
estimating dose distributions and the methods used for estimating those dose
distributions. Finally, we derive distributions of doses of selected ETS-related
constituents obtained in the workplace for people in smoking work environments.
Estimating dose distributions provided information beyond the usual point
estimate of dose and showed that the preponderance of individuals exposed to ETS
in the workplace were exposed at the low end of the dose distribution curve. The
results of this analysis include estimations of hourly maxima and time-weighted
average (TWA) doses of nicotine from workplace exposures to ETS (extrapolated
from 1 day to 1 week) and doses derived from modeled lung burdens of ultraviolet
absorbing particulate matter (UVPM) and solanesol resulting from workplace
exposures to ETS (extrapolated from 1 day to 1 year).
PMID- 10765412
TI - Heuristic-systematic information processing and risk judgment.
AB - The heuristic-systematic information processing model (HSM) holds that
individuals will use one or both of these modes of information processing when
attempting to evaluate information in order to arrive at a judgment. Systematic
processing is defined by effortful scrutiny and comparison of information,
whereas heuristic processing is defined by the use of cues to arrive more easily
at a judgment. Antecedents to the two processing modes include information
sufficiency, motivation, and self-efficacy. Structural equation modeling is used
to examine competing configuration of this model and to evaluate the model as
appropriate for predicting risk judgment. The model also is evaluated across
three groups that vary with respect to their level of concern. These analyses are
executed within a case study involving an epidemiological investigation of a
suspected cancer cluster. The analysis confirms the HSM's theoretically proposed
structure and shows it to be a useful vehicle for evaluating risk judgment. In
the overall analysis, antecedent variables generally function as specified by
theory. Systematic processing is predicted by greater motivation. Heuristic
processing is predicted by information sufficiency. Self-efficacy is a
significant predictor of both processing modes. And heuristic processing is shown
to be associated with judgment of less risk. However, when the analysis is
contrasted across three groups (those concerned about cancer, not concerned and
uncertain) it is shown that the model is significantly more robust for the
uncertain group. This finding may have implications for the use of the HSM in
risk research specifically, and in field research generally.
PMID- 10765413
TI - Task analysis for industrial work process from aspects of human reliability and
system safety.
AB - In the design, development, and manufacturing stage of industrial products,
engineers usually focus on the problems caused by hardware or software, but pay
less attention to problems caused by "human error," which may significantly
affect system reliability and safety. Although operating procedures are strictly
followed, human error still may occur occasionally. Among the influencing
factors, the inappropriate design of standard operation procedure (SOP) or
standard assembly procedure (SAP) is an important and latent reason for
unexpected results found during human operation. To reduce the error probability
and error effects of these unexpected behaviors in the industrial work process,
overall evaluation of SOP or SAP quality has become an essential task. The human
error criticality analysis (HECA) method was developed to identify the
potentially critical problems caused by human error in the human operation
system. This method performs task analysis on the basis of operation procedure.
For example, SOP, analyzes the human error probability (HEP) for each human
operation step, and assesses its error effects to the whole system. The results
of the analysis will show the interrelationship that exists between critical
human tasks, critical human error modes, and human reliability information of the
human operation system. To identify the robustness of the model, a case study of
initiator assembly tasks was conducted. Results show that the HECA method is
practicable in evaluating the operation procedure, and the information is
valuable in identifying the means to upgrade human reliability and system safety
for human tasks.
PMID- 10765414
TI - Critical radionuclide/critical pathway analysis for the U.S. Department of
Energy's Savannah River Site.
AB - Many different radionuclides have been released to the environment from the
Savannah River Site (SRS) during the facility's operational history. However, as
shown by this analysis, only a small number of the released radionuclides have
been significant contributors to potential doses and risks to off-site people.
This article documents the radiological critical contaminant/critical pathway
analysis performed for SRS. If site missions and operations remain constant over
the next 30 years, only tritium oxide releases are projected to exceed a
maximally exposed individual (MEI) risk of 1.0E-06 for either the airborne or
liquid pathways. The critical exposure pathways associated with site airborne
releases are inhalation and vegetation consumption, whereas the critical exposure
pathways associated with liquid releases are drinking water and fish consumption.
For the SRS-specific, nontypical exposure pathways (i.e., recreational fishing
and deer and hog hunting), cesium-137 is the critical radionuclide.
PMID- 10765415
TI - Factors in exposure assessment: ethnic and socioeconomic differences in fishing
and consumption of fish caught along the Savannah River.
AB - South Carolina has issued fish consumption advisories for the Savannah River
based on mercury and radionuclide levels. We examine differences in fishing rates
and fish consumption of 258 people interviewed while fishing along the Savannah
River, as a function of age, education, ethnicity, employment history, and
income, and test the assumption that the average consumption of fish is less than
the recreational value of 19 kg/year assumed by risk assessors. Ethnicity and
education contributed significantly to explaining variations in number of fish
meals per month, serving size, and total quantity of fish consumed per year.
Blacks fished more often, ate more fish meals of slightly larger serving sizes,
and consumed more fish per year than did Whites. Although education and income
were correlated, education contributed most significantly to behavior; people who
did not graduate from high school ate fish more often, ate more fish per year,
and ate more whole fish than people who graduated from high school. Computing
consumption of fish for each person individually indicates that (1) people who
eat fish more often also eat larger portions, (2) a substantial number of people
consume more than the amount of fish used to compute risk to recreational
fishermen, (3) some people consume more than the subsistence level default
assumption (50 kg/year) and (4) Blacks consume more fish per year than Whites,
putting them at greater risk from contaminants in fish. Overall, ethnicity, age,
and education contributed to variations in fishing behavior and consumption.
PMID- 10765416
TI - Chinese and Americans agree on what is fair, but disagree on what is best in
societal decisions affecting health and safety risks.
AB - Through surveys of students and junior professionals and interviews with business
and government executives, we studied Chinese choices and fairness perceptions in
risky health and safety decisions. The survey responses were compared with
American responses from an earlier study by Keller and Sarin. The survey results
show that the American and Chinese respondents had similar fairness perceptions,
but the Chinese did not make decisions that were consistent with their fairness
perceptions, whereas the Americans did. We found that the middle-age Chinese
professionals tended to make choices that were more different from the Americans
than were the choices of the young Chinese management students. It is likely that
these discrepancies were caused by cultural differences, with the younger Chinese
tending to face a stronger Western influence. The insights from the survey
results were enriched by interviews that revealed fairness perceptions of Chinese
business and government executives. A framework to interpret cultural influences
on decision making was also proposed.
PMID- 10765417
TI - A comparison of methods of benchmark-dose estimation for continuous response
data.
AB - Methods of quantitative risk assessment for toxic responses that are measured on
a continuous scale are not well established. Although risk-assessment procedures
that attempt to utilize the quantitative information in such data have been
proposed, there is no general agreement that these procedures are appreciably
more efficient than common quantal dose-response procedures that operate on
dichotomized continuous data. This paper points out an equivalence between the
dose-response models of the nonquantal approach of Kodell and West and a quantal
probit procedure, and provides results from a Monte Carlo simulation study to
compare coverage probabilities of statistical lower confidence limits on dose
corresponding to specified additional risk based on applying the two procedures
to continuous data from a dose-response experiment. The nonquantal approach is
shown to be superior, in terms of both statistical validity and statistical
efficiency.
PMID- 10765418
TI - Methods for detecting and estimating population threshold concentrations for air
pollution-related mortality with exposure measurement error.
AB - The association between daily fluctuations in ambient particulate matter and
daily variations in nonaccidental mortality have been extensively investigated.
Although it is now widely recognized that such an association exists, the form of
the concentration-response model is still in question. Linear, no threshold and
linear threshold models have been most commonly examined. In this paper we
considered methods to detect and estimate threshold concentrations using time
series data of daily mortality rates and air pollution concentrations. Because
exposure is measured with error, we also considered the influence of measurement
error in distinguishing between these two completing model specifications. The
methods were illustrated on a 15-year daily time series of nonaccidental
mortality and particulate air pollution data in Toronto, Canada. Nonparametric
smoothed representations of the association between mortality and air pollution
were adequate to graphically distinguish between these two forms. Weighted
nonlinear regression methods for relative risk models were adequate to give
nearly unbiased estimates of threshold concentrations even under conditions of
extreme exposure measurement error. The uncertainty in the threshold estimates
increased with the degree of exposure error. Regression models incorporating
threshold concentrations could be clearly distinguished from linear relative risk
models in the presence of exposure measurement error. The assumption of a linear
model given that a threshold model was the correct form usually resulted in
overestimates in the number of averted premature deaths, except for low threshold
concentrations and large measurement error.
PMID- 10765419
TI - Sensitivity of concentration and risk predictions in the PRESTO and MMSOILS
multimedia models: regression technique assessment.
AB - This paper describes the application of two multimedia models, PRESTO and
MMSOILS, to predict contaminant migration from a landfill that contains an
organic chemical (methylene chloride) and a radionuclide (uranium-238). Exposure
point concentrations and human health risks are predicted, and distributions of
those predictions are generated using Monte Carlo techniques. Analysis of
exposure point concentrations shows that predictions of uranium-238 in
groundwater differ by more than one order of magnitude between models. These
differences occur mainly because PRESTO simulates uranium-238 transport through
the groundwater using a one-dimensional algorithm and vertically mixes the plume
over an effective mixing depth, whereas MMSOILS uses a three-dimensional
algorithm and simulates a plume that resides near the surface of the aquifer. A
sensitivity analysis, using stepwise multiple linear regression, is performed to
evaluate which of the random variables are most important in producing the
predicted distributions of exposure point concentrations and health risks. The
sensitivity analysis shows that the predicted distributions can be accurately
reproduced using a small subset of the random variables. Simple regression
techniques are applied, for comparison, to the same scenarios, and results are
similar. The practical implication of this analysis is the ability to distinguish
between important versus unimportant random variables in terms of their
sensitivity to selected endpoints.
PMID- 10765420
TI - Exposure to persistent organochlorines in Canadian breast milk: a probabilistic
assessment.
AB - Exposure to persistent organochlorines in breast milk was estimated
probabilistically for Canadian infants. Noncancer health effects were evaluated
by comparing the predicted exposure distributions to published guidance values.
For chemicals identified as potential human carcinogens, cancer risks were
evaluated using standard methodology typically applied in Canada, as well as an
alternative method developed under the Canadian Environmental Protection Act.
Potential health risks associated with exposure to persistent organochlorines
were quantitatively and qualitatively weighed against the benefits of breast
feeding. Current levels of the majority of contaminants identified in Canadian
breast milk do not pose unacceptable risks to infants. Benefits of breast-feeding
are well documented and qualitatively appear to outweigh potential health
concerns associated with organochlorine exposure. Furthermore, the risks of
mortality from not breast-feeding estimated by Rogan and colleagues exceed the
theoretical cancer risks estimated for infant exposure to potential carcinogens
in Canadian breast milk. Although levels of persistent compounds have been
declining in Canadian breast milk, potentially significant risks were estimated
for exposure to polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans.
Follow-up work is suggested that would involve the use of a physiologically based
toxicokinetic model with probabilistic inputs to predict dioxin exposure to the
infant. A more detailed risk analysis could be carried out by coupling the
exposure estimates with a dose-response analysis that accounts for uncertainty.
PMID- 10765421
TI - Evaluation of the uncertainty in an oral reference dose for methylmercury due to
interindividual variability in pharmacokinetics.
AB - An analysis of the uncertainty in guidelines for the ingestion of methylmercury
(MeHg) due to human pharmacokinetic variability was conducted using a
physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics
in the pregnant human and fetus. Two alternative derivations of an ingestion
guideline for MeHg were considered: the U.S. Environmental Protection Agency
reference dose (RfD) of 0.1 microgram/kg/day derived from studies of an Iraqi
grain poisoning episode, and the Agency for Toxic Substances and Disease Registry
chronic oral minimal risk level (MRL) of 0.5 microgram/kg/day based on studies of
a fish-eating population in the Seychelles Islands. Calculation of an ingestion
guideline for MeHg from either of these epidemiological studies requires
calculation of a dose conversion factor (DCF) relating a hair mercury
concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in
this DCF across the population of U.S. women of child-bearing age, Monte Carlo
analyses were performed in which distributions for each of the parameters in the
PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the
resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median,
respectively. This estimate of variability is consistent with, but somewhat less
than, previous analyses performed with empirical, one-compartment pharmacokinetic
models. The use of a consistent factor in both guidelines of 1.5 for
pharmacokinetic variability in the DCF, and keeping all other aspects of the
derivations unchanged, would result in an RfD of 0.2 microgram/kg/day and an MRL
of 0.3 microgram/kg/day.
PMID- 10765422
TI - Evaluation of atmospheric transport models for use in phase II of the historical
public exposures studies at the Rocky Flats Plant.
AB - Five atmospheric transport models were evaluated for use in Phase II of the
Historical Public Exposures Studies at the Rocky Flats Plant. Models included a
simple straight-line Gaussian plume model (ISCST2), several integrated puff
models (RATCHET, TRIAD, and INPUFF2), and a complex terrain model (TRAC).
Evaluations were based on how well model predictions compared with sulfur
hexafluoride tracer measurements taken in the vicinity of Rocky Flats in February
1991. Twelve separate tracer experiments were conducted, each lasting 9 hr and
measured at 140 samplers in arcs 8 and 16 km from the release point at Rocky
Flats. Four modeling objectives were defined based on the endpoints of the
overall study: (1) the unpaired maximum hourly average concentration, (2) paired
time-averaged concentration, (3) unpaired time-averaged concentration, and (4)
arc-integrated concentration. Performance measures were used to evaluate models
and focused on the geometric mean and standard deviation of the predicted-to
observed ratio and the correlation coefficient between predicted and observed
concentrations. No one model consistently outperformed the others in all modeling
objectives and performance measures. About 75% of the maximum hourly
concentration predictions were within a factor of 5 of the observations. About
64% of the paired and 80% of the unpaired time-averaged model predictions were
within a factor of 5 of the observations. The overall performance of the RATCHET
model was somewhat better than the other models. All models appeared to
experience difficulty defining plume trajectories, which was attributed to the
influence of multilayered flow initiated by terrain complexities and the diurnal
flow patterns characteristic of the Colorado Front Range.
PMID- 10765423
TI - Estimating risk assessment exposure point concentrations when the data are not
normal or lognormal.
AB - The U.S. Environmental Protection Agency (EPA) recommends the use of the one
sided 95% upper confidence limit of the arithmetic mean based on either a normal
or lognormal distribution for the contaminant (or exposure point) concentration
term in the Superfund risk assessment process. When the data are not normal or
lognormal this recommended approach may overestimate the exposure point
concentration (EPC) and may lead to unecessary cleanup at a hazardous waste site.
The EPA concentration term only seems to perform like alternative EPC methods
when the data are well fit by a lognormal distribution. Several alternative
methods for calculating the EPC are investigated and compared using soil data
collected from three hazardous waste sites in Montana, Utah, and Colorado. For
data sets that are well fit by a lognormal distribution, values for the Chebychev
inequality or the EPA concentration term may be appropriate EPCs. For data sets
where the soil concentration data are well fit by gamma distributions, Wong's
method may be used for calculating EPCs. The studentized bootstrap-t and Hall's
bootstrap-t transformation are recommended for EPC calculation when all
distribution fits are poor. If a data set is well fit by a distribution,
parametric bootstrap may provide a suitable EPC.
PMID- 10765424
TI - Quantitative assessment of the risk of lung cancer associated with occupational
exposure to refractory ceramic fibers.
AB - We present the results of a quantitative assessment of the lung cancer risk
associated with occupational exposure to refractory ceramic fibers (RCF). The
primary sources of data for our risk assessment were two long-term oncogenicity
studies in male Fischer rats conducted to assess the potential pathogenic effects
associated with prolonged inhalation of RCF. An interesting feature of the data
was the availability of the temporal profile of fiber burden in the lungs of
experimental animals. Because of this information, we were able to conduct both
exposure-response and dose-response analyses. Our risk assessment was conducted
within the framework of a biologically based model for carcinogenesis, the two
stage clonal expansion model, which allows for the explicit incorporation of the
concepts of initiation and promotion in the analyses. We found that a model
positing that RCF was an initiator had the highest likelihood. We proposed an
approach based on biological considerations for the extrapolation of risk to
humans. This approach requires estimation of human lung burdens for specific
exposure scenarios, which we did by using an extension of a model due to Yu. Our
approach acknowledges that the risk associated with exposure to RCF depends on
exposure to other lung carcinogens. We present estimates of risk in two
populations: (1) a population of nonsmokers and (2) an occupational cohort of
steelworkers not exposed to coke oven emissions, a mixed population that includes
both smokers and nonsmokers.
PMID- 10765425
TI - Statistical evaluation of population data for calculation of radioactive material
transport accident risks.
AB - Calculation of accident dose-risk estimates with the RADTRAN code requires input
data describing the population likely to be affected by the plume of radioactive
material (RAM) released in a hypothetical transportation accident. In the
existing model, population densities within 1/2 mile (0.8 km) of the route
centerline are tabulated in three ranges (Rural, Suburban, and Urban). These
population densities may be of questionable validity since the plume in the
RADTRAN analysis is assumed to extend out to 120 km from the hypothetical
accident site. We present a GIS-based population model which accounts for the
actual distribution of population under a potential plume, and compare accident
risk estimates based on the resulting population densities with those based on
the existing model. Results for individual points along a route differ greatly,
but the cumulative accident risks for a sample route of a few hundred kilometers
are found to be comparable, if not identical. We conclude, therefore, that for
estimation of aggregate accident risks over typical routes of several hundred
kilometers, the existing, simpler RADTRAN model is sufficiently detailed and
accurate.
PMID- 10765426
TI - The power of perception: health risk attributed to air pollution in an urban
industrial neighbourhood.
AB - This paper describes a multi-stakeholder process designed to assess the potential
health risks associated with adverse air quality in an urban industrial
neighborhood. The paper briefly describes the quantitative health risk assessment
conducted by scientific experts, with input by a grassroots community group
concerned about the impacts of adverse air quality on their health and quality of
life. In this case, rather than accept the views of the scientific experts, the
community used their powers of perception to advantage by successfully advocating
for a professionally conducted community health survey. This survey was designed
to document, systematically and rigorously, the health risk perceptions community
members associated with exposure to adverse air quality in their neighborhood.
This paper describes the institutional and community contexts within which the
research is situated as well as the design, administration, analysis, and results
of the community health survey administered to 402 households living in an urban
industrial neighborhood in Hamilton, Ontario, Canada. These survey results served
to legitimate the community's concerns about air quality and to help broaden
operational definitions of 'health.' In addition, the results of both health risk
assessment exercises served to keep issues of air quality on the local political
agenda. Implications of these findings for our understanding of the environmental
justice process as well as the ability of communities to influence environmental
health policy are discussed.
PMID- 10765427
TI - Economic impact of accelerated cleanup on regions surrounding the U.S. DOE's
major nuclear weapons sites.
AB - The regional economic impacts of the U.S. Department of Energy's accelerated
environmental cleanup plan are estimated for the major nuclear weapons sites in
Colorado, Idaho, New Mexico, South Carolina, Tennessee, and Washington. The
analysis shows that the impact falls heavily on the three relatively rural
regions around the Savannah River (SC), Hanford (WA), and Idaho National
Engineering and Environmental Laboratory (ID) sites. A less aggressive phase-down
of environmental management funds and separate funds to invest in education and
infrastructure in the regions helps buffer the impacts on jobs, personal income,
and gross regional product. Policy options open to the federal and state and
local governments are discussed.
PMID- 10765428
TI - "How exposed is exposed enough?" Lay inferences about chemical exposure.
AB - The concept of exposure is central to chemical risk assessment and plays an
important role in communicating to the public about the potential health risks of
chemicals. Research on chemical risk perception has found some indication that
the model lay people use to judge chemical exposure differs from that of
toxicologists, thereby leading to different conclusions about chemical safety.
This paper presents the results of a series of studies directed toward developing
a model for understanding how lay people interpret the concept of chemical
exposure. The results indicate that people's beliefs about chemical exposure (and
its risks) are based on two broad categories of inferences. One category of
inferences relates to the nature in which contact with a chemical has taken
place, including the amount of a chemical involved and its potential health
consequences. A second category of inferences about chemical exposure relates to
the pragmatics of language interpretation, leading to beliefs about the motives
and purposes behind chemical risk communication. Risk communicators are
encouraged to consider how alternative models of exposure and language
interpretation can lead to conflicting conclusions on the part of the public
about chemical safety.
PMID- 10765429
TI - A model of consumers' risk perceptions toward recombinant bovine growth hormone
(rbGH): the impact of risk characteristics.
AB - This study estimates the effect risk characteristics, described as outrage
factors by Hadden, have on consumers' risk perceptions toward the food-related
biotechnology, recombinant bovine growth hormone (rbGH). The outrage factors
applicable to milk from rbGH treated herds are involuntary risk exposure,
unfamiliarity with the product's production process, unnatural product
characteristics, lack of trust in regulator's ability to protect consumers in the
marketplace, and consumers' inability to distinguish milk from rbGH treated herds
compared to milk from untreated herds. An empirical analysis of data from a
national survey of household food shoppers reveals that outrage factors mediate
risk perceptions. The results support the inclusion of outrage factors into the
risk perception model for the rbGH product, as they add significantly to the
explanatory power of the model and therefore reduce bias compared to a simpler
model of attitudinal and demographic factors. The study indicates that outrage
factors which have a significant impact on risk perceptions are the lack of trust
in the FDA as a food-related information source, and perceiving no consumer
benefits from farmers' use of rbGH. Communication strategies to reduce consumer
risk perceptions therefore could utilize agencies perceived as more trustworthy
and emphasize the benefits of rbGH use to consumers.
PMID- 10765430
TI - Simultaneous analysis of individual and aggregate responses in psychometric data
using multilevel modeling.
AB - Psychometric data on risk perceptions are often collected using the method
developed by Slovic, Fischhoff, and Lichtenstein, where an array of risk issues
are evaluated with respect to a number of risk characteristics, such as how
dreadful, catastrophic or involuntary exposure to each risk is. The analysis of
these data has often been carried out at an aggregate level, where mean scores
for all respondents are compared between risk issues. However, this approach may
conceal important variation between individuals, and individual analyses have
also been performed for single risk issues. This paper presents a new
methodological approach using a technique called multilevel modelling for
analysing individual and aggregated responses simultaneously, to produce
unconditional and unbiased results at both individual and aggregate levels of the
data. Two examples are given using previously published data sets on risk
perceptions collected by the authors, and results between the traditional and new
approaches compared. The discussion focuses on the implications of and
possibilities provided by the new methodology.
PMID- 10765431
TI - Trust, emotion, sex, politics, and science: surveying the risk-assessment
battlefield.
AB - Risk management has become increasingly politicized and contentious. Polarized
views, controversy, and conflict have become pervasive. Research has begun to
provide a new perspective on this problem by demonstrating the complexity of the
concept "risk" and the inadequacies of the traditional view of risk assessment as
a purely scientific enterprise. This paper argues that danger is real, but risk
is socially constructed. Risk assessment is inherently subjective and represents
a blending of science and judgment with important psychological, social,
cultural, and political factors. In addition, our social and democratic
institutions, remarkable as they are in many respects, breed distrust in the risk
arena. Whoever controls the definition of risk controls the rational solution to
the problem at hand. If risk is defined one way, then one option will rise to the
top as the most cost-effective or the safest or the best. If it is defined
another way, perhaps incorporating qualitative characteristics and other
contextual factors, one will likely get a different ordering of action solutions.
Defining risk is thus an exercise in power. Scientific literacy and public
education are important, but they are not central to risk controversies. The
public is not irrational. Their judgments about risk are influenced by emotion
and affect in a way that is both simple and sophisticated. The same holds true
for scientists. Public views are also influenced by worldviews, ideologies, and
values; so are scientists' views, particularly when they are working at the
limits of their expertise. The limitations of risk science, the importance and
difficulty of maintaining trust, and the complex, sociopolitical nature of risk
point to the need for a new approach--one that focuses upon introducing more
public participation into both risk assessment and risk decision making in order
to make the decision process more democratic, improve the relevance and quality
of technical analysis, and increase the legitimacy and public acceptance of the
resulting decisions.
PMID- 10765432
TI - Human interindividual variability in parameters related to health risks.
AB - This paper reviews existing data on the variability in parameters relevant for
health risk analyses. We cover both exposure-related parameters and parameters
related to individual susceptibility to toxicity. The toxicity/susceptibility
data base under construction is part of a longer term research effort to lay the
groundwork for quantitative distributional analyses of non-cancer toxic risks.
These data are broken down into a variety of parameter types that encompass
different portions of the pathway from external exposure to the production of
biological responses. The discrete steps in this pathway, as we now conceive
them, are: Contact Rate (Breathing rates per body weight; fish consumption per
body weight) Uptake or Absorption as a Fraction of Intake or Contact Rate General
Systemic Availability Net of First Pass Elimination and Dilution via Distribution
Volume (e.g., initial blood concentration per mg/kg of uptake) Systemic
Elimination (half life or clearance) Active Site Concentration per Systemic Blood
or Plasma Concentration Physiological Parameter Change per Active Site
Concentration (expressed as the dose required to make a given percentage change
in different people, or the dose required to achieve some proportion of an
individual's maximum response to the drug or toxicant) Functional Reserve
Capacity-Change in Baseline Physiological Parameter Needed to Produce a
Biological Response or Pass a Criterion of Abnormal Function Comparison of the
amounts of variability observed for the different parameter types suggests that
appreciable variability is associated with the final step in the process
differences among people in "functional reserve capacity." This has the
implication that relevant information for estimating effective toxic
susceptibility distributions may be gleaned by direct studies of the population
distributions of key physiological parameters in people that are not exposed to
the environmental and occupational toxicants that are thought to perturb those
parameters. This is illustrated with some recent observations of the population
distributions of Low Density Lipoprotein Cholesterol from the second and third
National Health and Nutrition Examination Surveys.
PMID- 10765433
TI - A perspective on nuclear waste.
AB - The management of spent nuclear fuel and high-level nuclear waste has the
deserved reputation as one of the most intractable policy issues facing the
United States and other nations using nuclear reactors for electric power
generation. This paper presents the author's perspective on this complex issue,
based on a decade of service with the Nuclear Waste Technical Review Board and
Board on Radioactive Waste Management of the National Research Council.
PMID- 10765434
TI - Historical relationship between performance assessment for radioactive waste
disposal and other types of risk assessment.
AB - This article describes the evolution of the process for assessing the hazards of
a geologic disposal system for radioactive waste and, similarly, nuclear power
reactors, and the relationship of this process with other assessments of risk,
particularly assessments of hazards from manufactured carcinogenic chemicals
during use and disposal. This perspective reviews the common history of
scientific concepts for risk assessment developed until the 1950s. Computational
tools and techniques developed in the late 1950s and early 1960s to analyze the
reliability of nuclear weapon delivery systems were adopted in the early 1970s
for probabilistic risk assessment of nuclear power reactors, a technology for
which behavior was unknown. In turn, these analyses became an important
foundation for performance assessment of nuclear waste disposal in the late
1970s. The evaluation of risk to human health and the environment from chemical
hazards is built on methods for assessing the dose response of radionuclides in
the 1950s. Despite a shared background, however, societal events, often in the
form of legislation, have affected the development path for risk assessment for
human health, producing dissimilarities between these risk assessments and those
for nuclear facilities. An important difference is the regulator's interest in
accounting for uncertainty.
PMID- 10765435
TI - The role of performance assessment in the regulation of underground disposal of
radioactive wastes: an international perspective.
AB - Much has been written about the development and application of quantitative
methods for estimating under uncertainty the long-term radiological performance
of underground disposal of radioactive wastes. Until recently, interest has been
focused almost entirely on the technical challenges regardless of the role of the
organization responsible for these analyses. Now the dialogue between regulators,
the repository developer or operator, and other interested parties in the
decision-making process receives increasing attention, especially in view of some
current difficulties in obtaining approvals to construct or operate deep
facilities for intermediate or high-level wastes. Consequently, it is timely to
consider the options for regulators' review and evaluation of safety submissions,
at the various stages in the site selection to repository closure process, and to
consider, especially, the role for performance assessment (PA) within the
programs of a regulator both before and after delivery of such a submission. The
origins and broad character of present regulations in the European Union (EU) and
in the OECD countries are outlined and some regulatory PA reviewed. The issues
raised are discussed, especially in regard to the interpretation of regulations,
the dangers from the desire for simplicity in argument, the use of regulatory PA
to review and challenge the PA in the safety case, and the effects of the
relationship between proponent and regulator. Finally, a very limited analysis of
the role of PA in public hearings is outlined and recommendations are made,
together with proposals for improving the mechanisms for international
collaboration on technical issues of regulatory concern.
PMID- 10765436
TI - Development of a performance assessment capability in the waste management
programs of the U.S. Nuclear Regulatory Commission.
AB - The U.S. Nuclear Regulatory Commission (NRC) staff has developed a performance
assessment capability to address three programmatic areas in nuclear waste
management: high-level waste, low-level waste, and decommissioning of licensed
facilities (license termination). The NRC capability consists of: (1)
methodologies for performance assessment; (2) models and computer codes for
estimating system performance; (3) regulatory guidance in various forms, such as
regulations, Branch Technical Positions, and Standard Review Plans; and (4) a
technical staff experienced in executing and evaluating performance assessments
for a variety of waste systems. Although the tools and techniques are refined for
each programmatic area, general approaches and similar issues are encountered in
all areas.
PMID- 10765437
TI - On intergenerational equity and its clash with intragenerational equity and on
the need for policies to guide the regulation of disposal of wastes and other
activities posing very long-term risks.
AB - This article begins with some history of the derivation of 40 CFR Part 191, the
U.S. Environmental Protection Agency (EPA) standard that governs the geologic
disposal of spent nuclear fuel and high-level and transuranic radioactive wastes.
This is followed by criticisms of the standard that were made by a Sub-Committee
of the EPA Science Advisory Board, by the staff of the U.S. Nuclear Regulatory
Commission, and by a panel of the National Academies of Science and Engineering.
The large disparity in the EPA approaches to regulation of disposal of
radioactive wastes and disposal of hazardous, long-lived, nonradioactive chemical
waste is illustrated. An examination of the intertwined matters of
intergenerational equity and the discounting of future health effects follows,
together with a discussion of the conflict between intergenerational equity and
intragenerational equity. Finally, issues related to assumptions in the
regulations concerning the future state of society and the biosphere are treated,
as is the absence of any national philosophy or guiding policy for how to deal
with societal activities that pose very long-term risks.
PMID- 10765438
TI - A decision theory perspective on the disposal of high-level radioactive waste.
AB - In this paper the problem of high-level nuclear waste disposal is viewed as a
five-stage, cascaded decision problem. The first four of these decisions having
essentially been made, the work of recent years has been focused on the fifth
stage, which concerns specifics of the repository design. The probabilistic
performance assessment (PPA) work is viewed as the outcome prediction for this
stage, and the site characterization work as the information gathering option.
This brief examination of the proposed Yucca Mountain repository through a
decision analysis framework resulted in three conclusions: (1) A decision theory
approach to the process of selecting and characterizing Yucca Mountain would
enhance public understanding of the issues and solutions to high-level waste
management; (2) engineered systems are an attractive alternative to offset
uncertainties in the containment capability of the natural setting and should
receive greater emphasis in the design of the repository; and (3) a strategy of
"waste management" should be adopted, as opposed to "waste disposal," as it
allows for incremental confirmation and confidence building of a permanent
solution to the high-level waste problem.
PMID- 10765439
TI - Total system performance assessment for waste disposal using a logic tree
approach.
AB - The Electric Power Research Institute (EPRI) has sponsored the development of a
model to assess the long-term, overall "performance" of the candidate spent fuel
and high-level radioactive waste (HLW) disposal facility at Yucca Mountain,
Nevada. The model simulates the processes that lead to HLW container corrosion,
HLW mobilization from the spent fuel, and transport by groundwater, and
contaminated groundwater usage by future hypothetical individuals leading to
radiation doses to those individuals. The model must incorporate a multitude of
complex, coupled processes across a variety of technical disciplines.
Furthermore, because of the very long time frames involved in the modeling effort
(>> 10(4) years), the relative lack of directly applicable data, and many
uncertainties and variabilities in those data, a probabilistic approach to model
development was necessary. The developers of the model chose a logic tree
approach to represent uncertainties in both conceptual models and model parameter
values. The developers felt the logic tree approach was the most appropriate.
This paper discusses the value and use of logic trees applied to assessing the
uncertainties in HLW disposal, the components of the model, and a few of the
results of that model. The paper concludes with a comparison of logic trees and
Monte Carlo approaches.
PMID- 10765440
TI - Performance assessments of nuclear waste repositories: a dialogue on their value
and limitations.
AB - Performance Assessment (PA) is the use of mathematical models to simulate the
long-term behavior of engineered and geologic barriers in a nuclear waste
repository; methods of uncertainty analysis are used to assess effects of
parametric and conceptual uncertainties associated with the model system upon the
uncertainty in outcomes of the simulation. PA is required by the U.S.
Environmental Protection Agency as part of its certification process for geologic
repositories for nuclear waste. This paper is a dialogue to explore the value and
limitations of PA. Two "skeptics" acknowledge the utility of PA in organizing the
scientific investigations that are necessary for confident siting and licensing
of a repository; however, they maintain that the PA process, at least as it is
currently implemented, is an essentially unscientific process with shortcomings
that may provide results of limited use in evaluating actual effects on public
health and safety. Conceptual uncertainties in a PA analysis can be so great that
results can be confidently applied only over short time ranges, the antithesis of
the purpose behind long-term, geologic disposal. Two "proponents" of PA agree
that performance assessment is unscientific, but only in the sense that PA is an
engineering analysis that uses existing scientific knowledge to support public
policy decisions, rather than an investigation intended to increase fundamental
knowledge of nature; PA has different goals and constraints than a typical
scientific study. The "proponents" describe an ideal, six-step process for
conducting generalized PA, here called probabilistic systems analysis (PSA); they
note that virtually all scientific content of a PA is introduced during the model
building steps of a PSA; they contend that a PA based on simple but
scientifically acceptable mathematical models can provide useful and objective
input to regulatory decision makers. The value of the results of any PA must lie
between these two views and will depend on the level of knowledge of the site,
the degree to which models capture actual physical and chemical processes, the
time over which extrapolations are made, and the proper evaluation of health
risks attending implementation of the repository. The challenge is in evaluating
whether the quality of the PA matches the needs of decision makers charged with
protecting the health and safety of the public.
PMID- 10765441
TI - Performance assessment in support of the 1996 compliance certification
application for the Waste Isolation Pilot Plant.
AB - The conceptual and computational structure of a performance assessment (PA) for
the Waste Isolation Pilot Plant (WIPP) is described. Important parts of this
structure are (1) maintenance of a separation between stochastic (i.e., aleatory)
and subjective (i.e., epistemic) uncertainty, with stochastic uncertainty arising
from the many possible disruptions that could occur over the 10,000-year
regulatory period that applies to the WIPP, and subjective uncertainty arising
from the imprecision with which many of the quantities required in the analysis
are known, (2) use of Latin hypercube sampling to incorporate the effects of
subjective uncertainty, (3) use of Monte Carlo (i.e., random) sampling to
incorporate the effects of stochastic uncertainty, and (4) efficient use of the
necessarily limited number of mechanistic calculations that can be performed to
support the analysis. The WIPP is under development by the U.S. Department of
Energy (DOE) for the geologic (i.e., deep underground) disposal of transuranic
(TRU) waste, with the indicated PA supporting a Compliance Certification
Application (CCA) by the DOE to the U.S. Environmental Protection Agency (EPA) in
October 1996 for the necessary certifications for the WIPP to begin operation.
The EPA certified the WIPP for the disposal of TRU waste in May 1998, with the
result that the WIPP will be the first operational facility in the United States
for the geologic disposal of radioactive waste.
PMID- 10765442
TI - Conditional uncertainty analysis and implications for decision making: the case
of WIPP.
AB - Uncertainty analyses and the reporting of their results can be misinterpreted
when these analyses are conditional on a set of assumptions generally intended to
bring some conservatism in the decisions. In this paper, two cases of conditional
uncertainty analysis are examined. The first case includes studies that result,
for instance, in a family of risk curves representing percentiles of the
probability distribution of the future frequency of exceeding specified
consequence levels conditional on a set of hypotheses. The second case involves
analyses that result in an interval of outcomes estimated on the basis of
conservative assumptions. Both types of results are difficult to use because they
are sometimes misinterpreted as if they represented the output of a full
uncertainty analysis. In the first case, the percentiles shown on each risk curve
may be taken at face value when in reality (in marginal terms) they are lower if
the chosen hypotheses are conservative. In the second case, the fact that some
segments of the resulting interval are highly unlikely--or that some more benign
segments outside the range of results are quite possible--does not appear. Also,
these results are difficult to compare to those of analyses of other risks,
possibly competing for the same risk management resources, and the decision
criteria have to be adapted to the conservatism of the hypotheses. In this paper,
the focus is on the first type (conditional risk curves) more than on the second
and the discussion is illustrated by the case of the performance assessment of
the Waste Isolation Pilot Plant in New Mexico. For policy-making purposes,
however, the problems of interpretation, comparison, and use of the results are
similar.
PMID- 10765443
TI - Resolution of the long-term performance issues at the Waste Isolation Pilot
Plant.
AB - The Waste Isolation Pilot Plant (WIPP) is a geological repository for disposal of
U.S. defense transuranic radioactive waste. Built and operated by the U.S.
Department of Energy (DOE), it is located in the Permian age salt beds in
southeastern New Mexico at a depth of 655 m. Performance assessment for the
repository's compliance with the 10,000-year containment standards was completed
in 1996 and the U.S. Environmental Protection Agency (EPA) certified in 1998 that
the repository meets compliance with the EPA standards 40 CFR 191 and 40 CFR 194.
The Environmental Evaluation Group (EEG) review of the DOE's application for
certification identified a number of issues. These related to the scenarios,
conceptual models, and values of the input parameters used in the calculations.
It is expected that these issues will be addressed and resolved during the first
5-year recertification process that began with the first receipt of waste at WIPP
on March 26, 1999, and scheduled to be completed in March 2004.
PMID- 10765444
TI - Risk perception in context: the Savannah River Site Stakeholder Study.
AB - Environmental managers are increasingly charged with involving the public in the
development and modification of policies regarding risks to human health and the
environment. Involving the public in environmental decision making first requires
a broad understanding of how and why the public perceives various risks. The
Savannah River Stakeholder Study was conducted with the purpose of investigating
individual, economic, and social characteristics of risk perceptions among those
living near the Savannah River Nuclear Weapons Site. A number of factors were
found to impact risk perceptions among those living near the site. One's
estimated proximity to the site and relative river location surfaced as strong
determinants of risk perceptions among SRS residents. Additionally, living in a
quality neighborhood and demonstrating a willingness to accept health risks for
economic gain strongly abated heightened risk perceptions.
PMID- 10765445
TI - Residential building codes, affordability, and health protection: a risk-tradeoff
approach.
AB - Residential building codes intended to promote health and safety may produce
unintended countervailing risks by adding to the cost of construction. Higher
construction costs increase the price of new homes and may increase health and
safety risks through "income" and "stock" effects. The income effect arises
because households that purchase a new home have less income remaining for
spending on other goods that contribute to health and safety. The stock effect
arises because suppression of new-home construction leads to slower replacement
of less safe housing units. These countervailing risks are not presently
considered in code debates. We demonstrate the feasibility of estimating the
approximate magnitude of countervailing risks by combining the income effect with
three relatively well understood and significant home-health risks. We estimate
that a code change that increases the nationwide cost of constructing and
maintaining homes by $150 (0.1% of the average cost to build a single-family
home) would induce offsetting risks yielding between 2 and 60 premature
fatalities or, including morbidity effects, between 20 and 800 lost quality
adjusted life years (both discounted at 3%) each year the code provision remains
in effect. To provide a net health benefit, the code change would need to reduce
risk by at least this amount. Future research should refine these estimates,
incorporate quantitative uncertainty analysis, and apply a full risk-tradeoff
approach to real-world case studies of proposed code changes.
PMID- 10765446
TI - Adaptive spatial sampling of contaminated soil.
AB - Suppose that a residential neighborhood may have been contaminated by a nearby
abandoned hazardous waste site. The suspected contamination consists of elevated
soil concentrations of chemicals that are also found in the absence of site
related contamination. How should a risk manager decide which residential
properties to sample and which ones to clean? This paper introduces an adaptive
spatial sampling approach which uses initial observations to guide subsequent
search. Unlike some recent model-based spatial data analysis methods, it does not
require any specific statistical model for the spatial distribution of hazards,
but instead constructs an increasingly accurate nonparametric approximation to it
as sampling proceeds. Possible cost-effective sampling and cleanup decision rules
are described by decision parameters such as the number of randomly selected
locations used to initialize the process, the number of highest-concentration
locations searched around, the number of samples taken at each location, a
stopping rule, and a remediation action threshold. These decision parameters are
optimized by simulating the performance of each decision rule. The simulation is
performed using the data collected so far to imput multiple probable values of
unknown soil concentration distributions during each simulation run. This
optimized adaptive spatial sampling technique has been applied to real data using
error probabilities for wrongly cleaning or wrongly failing to clean each
location (compared to the action that would be taken if perfect information were
available) as evaluation criteria. It provides a practical approach for
quantifying trade-offs between these different types of errors and expected cost.
It also identifies strategies that are undominated with respect to all of these
criteria.
PMID- 10765447
TI - An evaluation of risk estimation procedures for mixtures of carcinogens.
AB - The estimation of health risks from exposure to a mixture of chemical carcinogens
is generally based on the combination of information from several available
single compound studies. The current practice of directly summing the upper bound
risk estimates of individual carcinogenic components as an upper bound on the
total risk of a mixture is known to be generally too conservative. Gaylor and
Chen (1996, Risk Analysis) proposed a simple procedure to compute an upper bound
on the total risk using only the upper confidence limits and central risk
estimates of individual carcinogens. The Gaylor-Chen procedure was derived based
on an underlying assumption of the normality for the distributions of individual
risk estimates. In this paper we evaluated the Gaylor-Chen approach in terms of
the coverage probability. The performance of the Gaylor-Chen approach in terms
the coverages of the upper confidence limits on the true risks of individual
carcinogens. In general, if the coverage probabilities for the individual
carcinogens are all approximately equal to the nominal level, then the Gaylor
Chen approach should perform well. However, the Gaylor-Chen approach can be
conservative or anti-conservative if some or all individual upper confidence
limit estimates are conservative or anti-conservative.
PMID- 10765448
TI - Quantifying uncertainty in a risk assessment using human data.
AB - A call for risk assessment approaches that better characterize and quantify
uncertainty has been made by the scientific and regulatory community. This paper
responds to that call by demonstrating a distributional approach that draws upon
human data to derive potency estimates and to identify and quantify important
sources of uncertainty. The approach is rooted in the science of decision
analysis and employs an influence diagram, a decision tree, probabilistic
weights, and a distribution of point estimates of carcinogenic potency. Its
results estimate the likelihood of different carcinogenic risks (potencies) for a
chemical under a specific scenario. For this exercise, human data on formaldehyde
were employed to demonstrate the approach. Sensitivity analyses were performed to
determine the relative impact of specific levels and alternatives on the potency
distribution. The resulting potency estimates are compared with the results of an
exercise using animal data on formaldehyde. The paper demonstrates that
distributional risk assessment is readily adapted to situations in which
epidemiologic data serve as the basis for potency estimates. Strengths and
weaknesses of the distributional approach are discussed. Areas for further
application and research are recommended.
PMID- 10765449
TI - Comparison of six dose-response models for use with food-borne pathogens.
AB - Food-related illness in the United States is estimated to affect over six million
people per year and cost the economy several billion dollars. These illnesses and
costs could be reduced if minimum infectious doses were established and used as
the basis of regulations and monitoring. However, standard methodologies for dose
response assessment are not yet formulated for microbial risk assessment. The
objective of this study was to compare dose-response models for food-borne
pathogens and determine which models were most appropriate for a range of
pathogens. The statistical models proposed in the literature and chosen for
comparison purposes were log-normal, long-logistic, exponential, beta-Poisson and
Weibull-Gamma. These were fit to four data sets also taken from published
literature, Shigella flexneri, Shigella dysenteriae, Campylobacter jejuni, and
Salmonella typhosa, using the method of maximum likelihood. The Weibull-gamma,
the only model with three parameters, was also the only model capable of fitting
all the data sets examined using the maximum likelihood estimation for
comparisons. Infectious doses were also calculated using each model. Within any
given data set, the infectious dose estimated to affect one percent of the
population ranged from one order of magnitude to as much as nine orders of
magnitude, illustrating the differences in extrapolation of the dose response
models. More data are needed to compare models and examine extrapolation from
high to low doses for food-borne pathogens.
PMID- 10765450
TI - Cancer dose-response modeling of epidemiological data on worker exposures to
aldrin and dieldrin.
AB - The paper applies classical statistical principles to yield new tools for risk
assessment and makes new use of epidemiological data for human risk assessment.
An extensive clinical and epidemiological study of workers engaged in the
manufacturing and formulation of aldrin and dieldrin provides occupational
hygiene and biological monitoring data on individual exposures over the years of
employment and provides unusually accurate measures of individual lifetime
average daily doses. In the cancer dose-response modeling, each worker is treated
as a separate experimental unit with his own unique dose. Maximum likelihood
estimates of added cancer risk are calculated for multistage, multistage-Weibull,
and proportional hazards models. Distributional characterizations of added cancer
risk are based on bootstrap and relative likelihood techniques. The cancer
mortality data on these male workers suggest that low-dose exposures to aldrin
and dieldrin do not significantly increase human cancer risk and may even
decrease the human hazard rate for all types of cancer combined at low doses
(e.g., 1 microgram/kg/day). The apparent hormetic effect in the best fitting dose
response models for this data set is statistically significant. The decrease in
cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S.
Environmental Protection Agency's upper bound on cancer potency based on mouse
liver tumors. The EPA's upper bound implies that lifetime average daily doses of
0.0000625 and 0.00625 microgram/kg body weight/day would correspond to increased
cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate
from the Pernis epidemiological data is that there is no increase in cancer risk
in these workers at these doses or even at doses as large as 2 micrograms/kg/day.
PMID- 10765451
TI - Stringency of workplace air contaminant exposure limits: a case study of OSHA
risk management.
AB - Political context may play a large role in influencing the efficiency of
environmental and health regulations. This case study uses data from a 1989
update of the Occupational Safety and Health Administration (OSHA) Permissible
Exposure Limits (PELs) program to determine the relative effects of legislative
mandates, costly acquisition of information by the agency, and pressure applied
by special interest groups upon exposure standards. The empirical analysis
suggests that federal agencies successfully thwart legislative attempts to limit
agency discretion, and that agencies exercise bounded rationality by placing
greater emphasis on more easily obtained information. The 1989 PELs were less
significantly related to more costly information, contained "safety factors" for
chemicals presenting relatively more ambiguous risks, and the proposed standard
stringencies showed evidence of being influenced by vying industry and labor
interests.
PMID- 10765452
TI - Individual prior information in a physiological model of 2H8-toluene kinetics: an
empirical Bayes estimation strategy.
AB - Physiologically-based toxicokinetic (PBTK) models are widely used to quantify
whole-body kinetics of various substances. However, since they attempt to
reproduce anatomical structures and physiological events, they have a high number
of parameters. Their identification from kinetic data alone is often impossible,
and other information about the parameters is needed to render the model
identifiable. The most commonly used approach consists of independently
measuring, or taking fom literature sources, some of the parameters, fixing them
in the kinetic model, and then performing model identification on a reduced
number of less certain parameters. This results in a substantial reduction of the
degrees of freedom of the model. In this study, we show that this method results
in final estimates of the free parameters whose precision is overestimated. We
then compared this approach with an empirical Bayes approach, which takes into
account not only the mean value, but also the error associated with the
independently determined parameters. Blood and breath 2H8-toluene washout curves,
obtained in 17 subjects, were analyzed with a previously presented PBTK model
suitable for person-specific dosimetry. Model parameters with the greatest effect
on predicted levels were alveolar ventilation rate QPC, fat tissue fraction VFC,
blood-air partition coefficient Kb, fraction of cardiac output to fat Qa/co and
rate of extrahepatic metabolism Vmax-p. Differences in the measured and Bayesian
fitted values of QPC, VFC and Kb were significant (p < 0.05), and the precision
of the fitted values Vmax-p and Qa/co went from 11 +/- 5% to 75 +/- 170% (NS) and
from 8 +/- 2% to 9 +/- 2% (p < 0.05) respectively. The empirical Bayes approach
did not result in less reliable parameter estimates: rather, it pointed out that
the precision of parameter estimates can be overly optimistic when other
parameters in the model, either directly measured or taken from literature
sources, are treated as known without error. In conclusion, an empirical Bayes
approach to parameter estimation resulted in a better model fit, different final
parameter estimates, and more realistic parameter precisions.
PMID- 10765453
TI - Ethylene oxide cancer risk assessment based on epidemiological data: application
of revised regulatory guidelines.
AB - Ethylene oxide (EO) research has significantly increased since the 1980s, when
regulatory risk assessments were last completed on the basis of the animal cancer
chronic bioassays. In tandem with the new scientific understanding, there have
been evolutionary changes in regulatory risk assessment guidelines, that
encourage flexibility and greater use of scientific information. The results of
an updated meta-analysis of the findings from 10 unique EO study cohorts from
five countries, including nearly 33,000 workers, and over 800 cancers are
presented, indicating that EO does not cause increased risk of cancers overall or
of brain, stomach or pancreatic cancers. The findings for leukemia and non
Hodgkin's lymphoma (NHL) are inconclusive. Two studies with the requisite
attributes of size, individual exposure estimates and follow up are the basis for
dose-response modeling and added lifetime risk predictions under environmental
and occupational exposure scenarios and a variety of plausible alternative
assumptions. A point of departure analysis, with various margins of exposure, is
also illustrated using human data. The two datasets produce remarkably similar
leukemia added risk predictions, orders of magnitude lower than prior animal
based predictions under conservative, default assumptions, with risks on the
order of 1 x 10(-6) or lower for exposures in the low ppb range. Inconsistent
results for "lymphoid" tumors, a non-standard grouping using histologic
information from death certificates, are discussed. This assessment demonstrates
the applicability of the current risk assessment paradigm to epidemiological
data.
PMID- 10765454
TI - Vehicle emission unit risk factors for transportation risk assessments.
AB - When the transportation risk posed by shipments of hazardous chemical and
radioactive materials is being assessed, it is necessary to evaluate the risks
associated with both vehicle emissions and cargo-related risks. Diesel exhaust
and fugitive dust emissions from vehicles transporting hazardous shipments lead
to increased air pollution, which increases the risk of latent fatalities in the
affected population along the transport route. The estimated risk from these
vehicle-related sources can often be as large or larger than the estimated risk
associated with the material being transported. In this paper, data from the U.S.
Environmental Protection Agency's Motor Vehicle-Related Air Toxics Study are
first used to develop latent cancer fatality estimates per kilometer of travel in
rural and urban areas for all diesel truck classes. These unit risk factors are
based on studies investigating the carcinogenic nature of diesel exhaust. With
the same methodology, the current per-kilometer latent fatality risk factor used
in transportation risk assessments for heavy diesel trucks in urban areas is
revised and the analysis expanded to provide risk factors for rural areas and all
diesel truck classes. These latter fatality estimates may include, but are not
limited to, cancer fatalities and are based primarily on the most recent
epidemiological data available on mortality rates associated with ambient air PM
10 concentrations.
PMID- 10765455
TI - Monte Carlo sensitivity analysis of unknown parameters in hazardous materials
transportation risk assessment.
AB - The US Department of Transportation was interested in the risks associated with
transporting Hydrazine in tanks with and without relief devices. Hydrazine is
both highly toxic and flammable, as well as corrosive. Consequently, there was a
conflict as to whether a relief device should be used or not. Data were not
available on the impact of relief devices on release probabilities or the impact
of Hydrazine on the likelihood of fires and explosions. In this paper, a Monte
Carlo sensitivity analysis of the unknown parameters was used to assess the risks
associated with highway transport of Hydrazine. To help determine whether or not
relief devices should be used, fault trees and event trees were used to model the
sequences of events that could lead to adverse consequences during transport of
Hydrazine. The event probabilities in the event trees were derived as functions
of the parameters whose effects were not known. The impacts of these parameters
on the risk of toxic exposures, fires, and explosions were analyzed through a
Monte Carlo sensitivity analysis and analyzed statistically through an analysis
of variance. The analysis allowed the determination of which of the unknown
parameters had a significant impact on the risks. It also provided the necessary
support to a critical transportation decision even though the values of several
key parameters were not known.
PMID- 10765456
TI - Parameter uncertainty and variability in evaluative fate and exposure models.
AB - The human toxicity potential, a weighting scheme used to evaluate toxic emissions
for life cycle assessment and toxics release inventories, is based on potential
dose calculations and toxicity factors. This paper evaluates the variance in
potential dose calculations that can be attributed to the uncertainty in chemical
specific input parameters as well as the variability in exposure factors and
landscape parameters. A knowledge of the uncertainty allows us to assess the
robustness of a decision based on the toxicity potential; a knowledge of the
sources of uncertainty allows us to focus our resources if we want to reduce the
uncertainty. The potential dose of 236 chemicals was assessed. The chemicals were
grouped by dominant exposure route, and a Monte Carlo analysis was conducted for
one representative chemical in each group. The variance is typically one to two
orders of magnitude. For comparison, the point estimates in potential dose for
236 chemicals span ten orders of magnitude. Most of the variance in the potential
dose is due to chemical-specific input parameters, especially half-lives,
although exposure factors such as fish intake and the source of drinking water
can be important for chemicals whose dominant exposure is through indirect
routes. Landscape characteristics are generally of minor importance.
PMID- 10765457
TI - On modeling correlated random variables in risk assessment.
AB - Monte Carlo methods in risk assessment are finding increasingly widespread
application. With the recognition that inputs may be correlated, the
incorporation of such correlations into the simulation has become important. Most
implementations rely upon the method of Iman and Conover for generating
correlated random variables. In this work, alternative methods using copulas are
presented for deriving correlated random variables. It is further shown that the
particular algorithm or assumption used may have a substantial effect on the
output results, due to differences in higher order bivariate moments.
PMID- 10765458
TI - Health risk assessment of a modern municipal waste incinerator.
AB - During the modernization of the municipal waste incinerator (MWI, maximum
capacity of 180,000 tons per year) of Metropolitan Grenoble (405,000
inhabitants), in France, a risk assessment was conducted, based on four tracer
pollutants: two volatile organic compounds (benzene and 1, 1, 1 trichloroethane)
and two heavy metals (nickel and cadmium, measured in particles). A Gaussian
plume dispersion model, applied to maximum emissions measured at the MWI stacks,
was used to estimate the distribution of these pollutants in the atmosphere
throughout the metropolitan area. A random sample telephone survey (570 subjects)
gathered data on time-activity patterns, according to demographic characteristics
of the population. Life-long exposure was assessed as a time-weighted average of
ambient air concentrations. Inhalation alone was considered because, in the
Grenoble urban setting, other routes of exposure are not likely. A Monte Carlo
simulation was used to describe probability distributions of exposures and risks.
The median of the life-long personal exposures distribution to MWI benzene was
3.2 x 10(-5) micrograms/m3 (20th and 80th percentiles = 1.5 x 10(-5) and 6.5 x
10(-5) micrograms/m3), yielding a 2.6 x 10(-10) carcinogenic risk (1.2 x 10(-10)
5.4 x 10(-10)). For nickel, the corresponding life-time exposure and cancer risk
were 1.8 x 10(-4) micrograms/m3 (0.9 x 10(-4)-3.6 x 10(-4) micrograms/m3) and 8.6
x 10(-8) (4.3 x 10(-8)-17.3 x 10(-8)); for cadmium they were respectively 8.3 x
10(-6) micrograms/m3 (4.0 x 10(-6)-17.6 x 10(-6)) and 1.5 x 10(-8) (7.2 x 10(-9)
3.1 x 10(-8)). Inhalation exposure to cadmium emitted by the MWI represented less
than 1% of the WHO Air Quality Guideline (5 ng/m3), while there was a margin of
exposure of more than 10(9) between the NOAEL (150 ppm) and exposure estimates to
trichloroethane. Neither dioxins nor mercury, a volatile metal, were measured.
This could lessen the attributable life-long risks estimated. The minute (VOCs
and cadmium) to moderate (nickel) exposure and risk estimates are in accord with
other studies on modern MWIs meeting recent emission regulations, however.
PMID- 10765459
TI - A quantitative analysis of factors affecting PELs and TLVs for carcinogens.
AB - For carcinogens, this paper provides a quantitative examination of the roles of
potency and weight-of-evidence (WOE) in setting permissible exposure limits
(PELs) at the U.S. Occupational Safety and Health Administration (OSHA) and
threshold limit values (TLVs) at the private American Conference of Governmental
Industrial Hygienists (ACGIH). On normative grounds, both of these factors should
influence choices about the acceptable level of exposures. Our major objective is
to examine whether and in what ways these factors have been considered by these
organizations. A lesser objective is to identify outliers, which might be
candidates for further regulatory scrutiny. Our sample (N = 48) includes
chemicals for which EPA has estimated a unit risk as a measure of carcinogenic
potency and for which OSHA or the ACGIH has a PEL or TLV. Different assessments
of the strength of the evidence of carcinogenicity were obtained from EPA, ACGIH,
and the International Agency for Research on Cancer. We found that potency alone
explains 49% of the variation in PELs and 62% of the variation in TLVs. For the
ACGIH, WOE plays a much smaller role than potency. TLVs set by the ACGIH since
1989 appear to be stricter than earlier TLVs. We suggest that this change
represents evidence that the ACGIH had responded to criticisms leveled at it in
the late 1980s for failing to adopt sufficiently protective standards. The models
developed here identify 2-nitropropane, ethylene dibromide, and chromium as
having OSHA PELs significantly higher than predicted on the basis of potency and
WOE.
PMID- 10765460
TI - Risk-based assessment of soil and groundwater quality in The Netherlands:
standards and remediation urgency.
AB - To assess soil and groundwater quality two generic (i.e. multifunctional) risk
based standards, Target and Intervention Value, have been developed, in the
framework of the Dutch Soil Protection Act. These standards allow soil and
groundwater to be classified as clean, slightly contaminated or seriously
contaminated. The Target Value is based on potential risks to ecosystems, while
the Intervention Value is based on potential risks to humans and ecosystems. In
the case of serious soil contamination the site has, in principle, to be
remediated, making it necessary to determine the remediation urgency on the basis
of actual (i.e. site-specific) risks to humans and ecosystems and, besides,
actual risks due to contaminant migration.
PMID- 10765461
TI - Dose response models for infectious gastroenteritis.
AB - When pathogenic microorganisms enter the human body via ingestion with food or
drinking water, they encounter a system of barriers mounted by the host. In order
to reach parts of the intestinal tract that are suitable for growth and
attachment, each of the barriers must be overcome successfully. The present view
on infection states that at least one of the ingested pathogens must survive to
start colonization. This is the basis for dose response models, used for
quantitative risk assessment. In this paper, the usefulness of the Beta Poisson
model for multiple barriers is corroborated. Infection is associated with the
presence of elevated numbers of reproducing pathogens in the intestinal tract.
This does not necessarily imply illness symptoms: when intestinal microorganisms
engage in damaging activities, this may lead to illness symptoms. At the same
time, these activities probably elicit defensive measures from the host,
promoting the removal of pathogens and terminating infection. The duration of the
period of colonization reflects the balance between the colonization potential of
pathogens and the strength of host defenses. Starting from the assumption that
during infection the host has a certain hazard of becoming ill, a simple dose
response relation for acute gastroenteritis is developed. With the use of
literature data from volunteer experiments, we show that examples can be found
for three possible alternatives: an increase in the probability of illness with
increasing dose, a decrease with higher doses, and a probability of illness
(given infection) independent of the ingested dose. These alternatives may
reflect different modes of interaction between pathogens and host.
PMID- 10765462
TI - [The occurrence, distribution and toxicity of cyanobacteria in the estuary of
Lagoa dos Patos, Rio Grande do Sul].
AB - Several blooms of Microcystis aeruginosa have been observed in the Patos Lagoon
estuary during the last fifteen years without a proper investigation of their
ecological importance or possible toxicity. The present study has identified and
quantified the presence of cyanobacteria in the Patos Lagoon estuary,
particularly of M. aeruginosa. During this survey, identification and
quantification of the main phytoplankton groups were done in relation to
geographical distribution in the estuary. The presence of M. aeruginosa colonies
in the estuarine region confirmed their superficial distribution throughout the
estuarine waters during twelve months with a maximum of 1, 3.10(6) cells. L-1 in
December, 1994 and a minimum of 1, 5.10(5) cells. L-1 in August, 1995 and also
confirmed that M. aeruginosa originated from waters in the north of the estuary.
The period of the highest cell and colonies densities was coincident with high
chlorophyll-a levels in surface waters. Toxicity of M. aeruginosa bloom material
was determined by bioassay and concentrations of hepatotoxins microcystins were
identified by HPLC-DAD. M. aeruginosa blooms were considered highly toxic,
presenting a 24 h-LD50 lower than 100 mg.Kg-1 b.w. and a toxin content higher
than 1 microgram.mg-1 d.w. Several microcystin variants were found in the
extracts with microcystin-LR predominating.
PMID- 10765463
TI - Mitogenic activity of fetal bovine serum, fish fry extract, insulin-like growth
factor-I, and fibroblast growth factor on brown bullhead catfish cells--BB line.
AB - Bioassays were performed to assess the effects of different levels of growth
medium supplementation with fetal bovine serum (FBS), fish fry extract (FE),
combinations of FBS and FE, and addition of insulin-like growth factor I (IGF-I)
and fibroblast growth factor (FGF) on the proliferation of brown bullhead catfish
cells (BB line). Treatments (n = 4) were: 2.5, 5, 10, and 15.0% FBS or FE and
5/2.5, 5/5, 10/2.5, and 10/5 of a FBS/FE combination as supplement to the growth
medium, or the addition of 0.1, 1, 2.5, 10, 25, and 75 ng/ml of either IGF-I or
FGF to the growth media. Initial cell density was 1.1 x 10(6) cells per well on
uncoated 24-well plates. Incubation temperature was 29.5 +/- 0.7 degrees C. Six
hours after plating, initial culture medium was removed, plates rinsed with
Dulbecco's phosphate buffered saline, treatment media added, and cells allowed to
proliferate for 24 hours. Another bioassay was performed with rat myoblast omega
cells (RMo) using the same levels of growth medium supplemented with FBS, FE and
FBS/FE. Base growth medium was Dulbecco's MEM. The initial cell density was 7.2 x
10(6) cells per well, and the bioassay was carried out at 36.0 +/- 0.5 degrees C,
on a 95% air, 5% CO2 incubator. Increasing levels of FBS had a positive effect (P
< 0.05) on the proliferation of both BB and RMo cells. Increasing levels of FE
had a negative effect (P < 0.05) on the proliferation of BB cells and totally
inhibited the proliferation of RMo cells at any level of supplementation. Higher
levels of FE on the FBS/FE combinations presented a negative effect on the
proliferation of both BB and RMo cells (P < 0.05). Insulin-like growth factor I
had a positive quadratic effect (P < 0.05) on the proliferation of BB cells.
Apparently, mammalian growth factors slightly stimulated mitogenic activity in
fish cells, while FE contained factors which inhibited the mitogenic activity of
RMo and BB cell lines.
PMID- 10765464
TI - Gill infection of Leporinus macrocephalus Garavello & Britski, 1988
(Osteichthyes: Anostomidae) by Henneguya leporinicola n. sp. (Myxozoa:
Myxobolidae). Description, histopathology and treatment.
AB - Piaucus (Leporinus macrocephalus), were raised in 300 m2 ponds (density of 10
fish/m2) presenting asphyxia signals and daily mortality of 27 fishes. Specimens
with 8-cm total body length, were collected for necropsy. Mucus of body surface
and pieces of organs were collected and examined microscopically, in wet mounts,
stained or in histological sections. The smears examination showed the presence
of several spores in the secondary lamellae of the gill filaments, identified as
Henneguya leporinicola n.sp (Myxozoa: Myxobolidae). Histopathological study
showed epithelial hyperplasia and fulfilling of the spaces between the secondary
lamellae, congestion and telangiectasia sinusoidal. It was also observed
hyperplasia of the goblet cells and several cysts of parasite with 70.3 microns
diameter. Such cysts were situated among the secondary lamellae, covered or not
by the hyperplasic epithelium. With this diagnostic, three applications of
formalin solution 10 ml/m3 were carried out. Fifteen days after that, fish were
examined again to ascertain whether the treatment was efficient on disease caused
by the protozoa. The tissue alterations present in the gills after the treatment
were just a moderate sinusoidal congestion and a slight epithelial hyperplasia on
the base of the secondary lamellae.
PMID- 10765465
TI - Drug impurities: problems and regulations.
AB - The matter of impurities is a frequently debated issue, mainly focused on the
validation of the analytical methods and on the toxicology of potential
impurities. In the first part of the review, the classification, the source and
the chemical aspects of impurities are briefly considered according to the
current international regulations. A special attention is given to the analytical
control, in both qualitative and quantitative terms, of unexpected impurities
arising from changes in the manufacturing process or by degradation. The
thresholds for identification and qualification of impurities in new drug
substances and in new drug products are examined together with the safety
studies, when required. Finally, the acceptance limits for four classes of
residual solvents are also reported.
PMID- 10765466
TI - Determination of phenytoin in human plasma by gas chromatography.
AB - A gas chromatographic method for the determination of phenytoin in plasma is
described. This assay allows the determination of phenytoin for therapeutic drug
monitoring with a minimum detectable limit of 200 ngmL-1 for 500 mL plasma.
Separation was performed on 2 m x 2 mm i.d. 1.5% OV17, 1.95 OV210 packed column
using a flame-ionization detector. Barbital and tetramethyl ammonium hydroxide
were used as internal standard and derivatizing agent, respectively. This method
is simple, rapid and suitable for routine analysis of phenytoin in plasma.
PMID- 10765467
TI - Synthesis and fungicidal activity of some 5-(2-aminoalkanoyl)-8-aryl-4(5H)-oxo
1,2,4-triazolo[4,3-b]-1,4,2, 6-dithiadiazine 6,6-dioxide derivatives.
AB - Title compounds (5) were conveniently prepared from 5-aryl-3-mercapto-1,2,4
triazoles (1) and chloro-sulphonyl isocyanate (CSI) to give 8-aryl-4-(5H)-oxo
1,2,4-triazolo-[4,3-b]-1,4,2,6-dithiadiazine -6,6-dioxide (2). The Compound (2)
and one suspension of 2-(benzyloxycarbonylamino) akanoic acid (3) in the presence
of BOP reagent afforded Z-derivatives 8-aryl-5-(2-benzyloxycarbamoyl)alkanoyl
4(5H)-oxo- 1,2,4-triazolo[4,3-b]-1,4,2,6-dithiadiazine 6,6-dioxide (4). The Z
derivatives (4) gave aspected product (5) when treated with Pd-c 5% and formic
acid in DMF. These compounds have been tested in vitro for their fungicidal
activity against Aspergillus niger, Fusarium oxisporum and Cephalosporium
saccharii and results were compared with their parent dithidiazines.
PMID- 10765468
TI - Synthesis and preliminary anticonvulsant activity evaluation of new 2-thioxo-4,5
imidazolidinedione derivatives.
AB - A series of 1-substituted benzylideneamino-2-thioxo-3-allyl-4,5
imidazolidinediones (2a-j) were synthesized by the cyclization of 1-substituted
benzylidene-4-allylthiosemicarbazides (1a-j) with oxalyl chloride in anhydrous
ethereal medium. The structures of 2a-j were confirmed by analytical and spectral
data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for
anticonvulsant activity against maximal electroshock (MES) and subcutaneous
pentylenetetrazole (ScMet) induced seizures. Among the compounds tested, 2b and
2h exhibited some activity in anticonvulsant identification (Phase I) trials in
mice.
PMID- 10765469
TI - Use of acryclic and metacrylic acid derivatives as sustained release matrices for
theophylline hydrate tablets.
AB - Carbopol 941, an acrylic acid polymer and "Eudragit L100-55, a metacylic acid
polymer, were compared as sustained release matrix devices for theophylline
hydrate tablets. The theophylline tablets containing 0 to 30% of either of the
polymer were prepared using the direct compression method. In vitro drug release
studies were carried out in 0.1 N HCl, simulated gastric fluid without pepsin
(SGF) and simulated intestinal fluid without pancreatin (SIF). A relatively
prolonged release of theophylline from the two polymer matrices for an 8 hr
release period was detected. At 20% w/w and in 0.1 N HCl there were no
significant drug releases from the two matrices within the first 2 hrs; after
this period, carbopol 941 exerted a more retardant effect on drug releases. At
30% w/w, release rate from Eudragit L100-55 was faster for a 6 hr period with a
steady state release maintained at 50% for 4 hrs. The rates of theophylline
release from the matrices depended on the pH of the dissolution media and on the
properties of the two matrices. While drug release from Carbopol 941 was faster
in acidic media, faster release occurred from Eudragit L100-55 in alkaline
medium. Drug release kinetics from the two matrices was of a general mixed order,
but the first order and the diffusion-controlled mechanism were occurring
simultaneously. We can conclude that carbopol 941 can be considered a better
sustained release matrix in directly compressed theophylline tablets comparing
with Eudragit L100-55.
PMID- 10765470
TI - Effect of binders on anti hypertensive drugs.
AB - Tablets of antihypertensive drugs, Indapamide, Methyldopa and Clonidine have been
prepared and their physico-chemical properties were determined. The effect of
various binders viz. starch, acacia, sodium carboxymethyl cellulose (sod. CMC),
gelatin and lactose on the properties of these tablets were studied. Formulations
of tablets of indapamide, methyldopa and clonidine prepared in combination with
acacia, lactose and sod. CMC, respectively result in the best flow properties,
minimum percentage fines, low angle of repose and compressibility. The tablets
prepared from these granules possess all quality features including a good
dissolution profile. Gelatin, sod. CMC and starch have less effective granule
formation leading to poor quality of tablets in case of Indapamide, Methyldopa
and Clonidine, respectively.
PMID- 10765471
TI - [Round table: pharmacologist and ethical committee: a new role after the
legislation of March 18, 1998].
PMID- 10765472
TI - [Round table: The Italian Pharmacology Society and the drug industry: new
processes in drug discovery and the contribution of universities].
PMID- 10765473
TI - [Antileukotriene drugs: a new treatment for asthma].
AB - Asthma incidence and prevalence have significantly increased during the last 25
years, making this pathology to be one of the most diffused in the industrialized
world. It affects 5% of the adult population and the 10-15% of the children. The
aethipathogenesis of asthma clearly involves a number of mediators, among which
leukotrienes play an important role inducing bronchoconstriction, oedema and
mucus hypersecretion. Thus, compounds inhibiting either the action or formation
of these mediators are potentially interesting as antiasthma drugs. Two
strategies for modulating the actions of the leukotrienes are currently
undergoing clinical evaluation: cysteinyl leukotriene receptor antagonism and 5
lipoxygenase (5-LO) inhibition. These two classes of agents are here reviewed and
their clinical utility as antiasthma drugs is evaluated.
PMID- 10765474
TI - [The evaluation of the use of Shafiroff and Palmer modification (arterial
reconstruction prior to bony stabilization) of thumb replantation].
AB - The B. B. Shafiroff and A. K. Palmer modification of thumb replantation procedure
proposed in 1982 was evaluated. The reconstruction or repair of the artery and
sometimes digital nerve repair on the ulnar side of the thumb prior to bony
fixation is the mainstay of the modification. It was used in 11 thumb
replantations done by the author since 1987. The access to arteries and nerves is
grossly improved and operating time shortened. Short description of 6 cases is
given. All the replanted thumbs survived.
PMID- 10765475
TI - [Rehabilitation after upper extremity replantation at the wrist level -- own
experience].
AB - An amputation at the wrist level (the level with the best prognosis) has been
characterized. Rehabilitation protocol after replantation at the wrist level
developed on the ground of 328 replantations done in the Center over 25 years has
been presented. Its essential quality is an early initiation of active movements
(second postoperative day) and resistive movements on 10-14 days after surgery.
The differences between currently used protocols have been emphasized. Excellent
and good results were achieved in 65% of cases according to Chen's criteria.
PMID- 10765476
TI - [Median nerve decompression in ischemic contracture of the forearm].
AB - Ischemic contracture of the forearm known as Volkmann contracture develops from
untreated (or treated to late) compartment syndrome within the forearm. Surgery
is needed if function of the extremity is to be restored after fully developed
Volkmann contracture. The uniform management is accepted in our Department since
1982. Multi-stage surgical treatment is indicated, the first stage consisting of
median nerve neurolysis and removal of necrotic tissues to restore physiological
excursion of the nerve. A series of 48 patients (16 females, 32 males aged 5-42
years) treated between 1982 and 1995 was included in the study. Complete
neurolysis of the median nerve (microsurgical within proximal 1/3 of the forearm)
was done in all patients. Long-term assessment of the median nerve function was
done at half year to 3 years follow-up. Symptoms of nerve entrapment indicated
reoperation. The study confirmed usefulness of an early median nerve
decompression for prevention of neurological complications and improvement of the
extremity function.
PMID- 10765477
TI - [Evaluation of morphologic changes of the rabbit supraspinal muscle].
AB - The aim of this study was to evaluate morphologic changes within rabbit
supraspinatus after detachment of its tendon from the greater tubercle along with
infraspinatus and subscapularis tenotomy. Stained with hematoxylin and eosin
muscle sample has been examined after 6 weeks (group A), 3 months (group B) and 6
months (group C). There were 10 rabbits in each group. The muscle atrophy was
accompanied by statistically significant increase of the interstitium volume in
group B (24.5%) and C (26.3%) as opposed to A (15.4%). Statistically significant
differences were also found in interstitium volume of tenotomized and
contralateral supraspinatus muscle.
PMID- 10765478
TI - [Anamnestic and anthropometric assessment of patients with herniated lumbar
intervertebral disc].
AB - The paper presents results of anamnestic and anthropometric assessment of
patients with herniated lumbar intervertebral disc operated in the Department in
the years 1978-1987 (983 patients) and in the decade 1988-1997 (1308 patients).
Recent decade brought 33.1% increase in disectomies. Typically, discopathy
patient is tall individual, with relatively high BMI and aged between 19 and 48
years. The number of female patients increased by 8.2% in recent decade and
traumatic origin of the disc herniation was noted in 8.8% more than previously.
Special attention should be paid to the twofold increase of female smokers among
patients operated due to discopathy.
PMID- 10765479
TI - [Some aspect of revisional hip arthroplasty on the basis of Register of removed
orthopedic implants. One year data].
AB - The selected epidemiological data concerning revisional hip arthroplasties
analysis is presented. The data were collected at 25 Polish orthopaedic centers
(some 27% of all centers performing primary THR) during the year 1998. Survival
time of the artificial joint (the time between primary and revisional hip
replacement) appears as the main criterion of THR result. Failed cemented THR
dominate over cementless ones. Septic complications constitute 4.55%
complications demanding revisional arthroplasty. Distinct increase in revisional
THR is found 7 years after primary operation. An average survival time for
arthroplasty was 10.3 years, a little longer for acetabular component.
PMID- 10765480
TI - [Assessment of femoral mechanical durability in the supratrochanteric line and
brought together with various methods depending on the bone mineral density].
AB - Femoral stiffness toward torsion and axial thrust of 21 femoral preparations
after variety of osteosynthesis for supratrochanteric osteotomy is presented. All
the femora were obtained at autopsy from patients 65 years old or older. Bone
mineral density was evaluated radiographically and by dual energy X-ray
absorptiometry. Osteotomy site was stabilized with screws, angular plates, Zespol
hip fixator and Ender nails. No correlation between stiffness toward torsion and
against axial load was found. The greatest torsional stiffness was found in non
osteoporotic preparations fixed with Ender nails, Zespol hip fixator and AO plate
with compression screw. The last fixation proved most resistant against axial
load.
PMID- 10765481
TI - [Dual energy X-ray absorptiometry in Ilizarov lower extremity lengthening:
preliminary study].
AB - Ilizarov method for lower extremity lengthening has been employed in 107
patients. Some 25% of numerous complications are bony union disturbances. Dual
energy X-ray absorptiometry (DEXA) for assessment of new bone formation was
introduced to reduce these problems. Detailed densitometry methodology developed
on the ground of 93 measurements in 11 patients is presented. Pre-operative
measurement was followed by subsequent evaluations done every 3 weeks after the
onset of distraction. DEXA was capable of showing the callus 3-4 weeks earlier
than conventional radiography. DEXA allows for adjusting the pace of lengthening
to the extent of new bone mineralization, evaluation of lengthening achieved,
determining the timing for safe removal of the apparatus. The need for temporary
rearranging of the apparatus and troublesome image analysis are among the
drawbacks of the method.
PMID- 10765482
TI - [New concepts of monitoring and assessment of bone union stiffness in fractures
treated by Dynastab DK external fixation].
AB - This paper focuses on heuristic techniques based on artificial intelligence
namely artificial non-linear and multilayer neurons employed for assessment of
bone union in fractures treated by Dynastab DK external fixation. The software
used allowed for prediction of bone union curve at the early stage of treatment.
The training of the neural net has been done on the ground of 56 cases of
Dynastab DK treated fractures. The net served for periodical assessment of bone
union and its further prediction in 17 long bone shaft fractures. Bone mechanical
properties at the fracture site showed non-linear changes in time. Specifically
great changes were noted 4 months postoperatively. Flexion at the fracture site
is critical. Neuron net proved to be useful in predicting bone union curve.
PMID- 10765483
TI - [Treatment of giant cell tumor of bone: surgery or radiotherapy?].
AB - The results of treatment for giant cell tumor of bone in 41 patients subdivided
into 4 groups have been assessed. In group treated with radical surgery
(amputations, extensive excision) 100% patients were cured. In group treated with
curettage alone success rate was 33.3% and in radiotherapy group--72.3%.
Curettage and radiotherapy combined rendered 95% success rate and this mode of
treatment should be recommended.
PMID- 10765484
TI - [Aneurysmal bone cyst and solitary cyst of bone].
AB - Results of treatment of 7 cases of aneurysmal bone cysts and 12 cases of solitary
bone cysts in 19 patients treated in our Department between 1991 and 1996 are
presented. Changes were found in the humerus, femur, tibia and fibula. Curettage
or excision was the mode of treatment. Recurrence of the condition has been noted
in 4 cases. Excision of the change and filling of the defect with autologous or
homologous bone graft is more efficient than curettage alone.
PMID- 10765485
TI - [Free and pedicled omental flaps. Harvesting and transplanting].
AB - The paper describes technique of harvesting and transplanting of great omentum.
The flap is a useful alternative to other flaps particularly in large tissue
defects within upper extremity. Depending on general patient's condition and
local vascular status at acceptor site the flap can be transplanted as a free or
pedicled one. In the latter case immobilization of the extremity is required for
two weeks until the pedicle can be divided. Plastic properties of the flap are
underlined; postoperative management is also presented.
PMID- 10765486
TI - [Ochronotic changes in alkaptonuria: a case report].
AB - Alkaptonuria is a rare metabolic condition caused by congenital homogentisate
oxidase deficiency of recessive autosomal inheritance. Homogentisate polymers are
accumulated and cause urine darkening (alcaptonuria), brown/black pigmentation of
connective tissue (ochronosis), articular cartilage pathology, osteoporosis and
patomorphologic changes in internal organs. A case of 61 female with ochronotic
polyarthropathy is presented. An early result of Weller THR is encouraging.
Pathogenesis, clinical picture, diagnostics and treatment of alkaptonuria is
presented on the ground of the literature.
PMID- 10765487
TI - Pyogenic vertebral osteomyelitis.
AB - Pyogenic vertebral osteomyelitis is defined as a primary infection in the osseous
elements of the spine by pyogenic organisms with secondary involvement of the
intervertebral disc and adjacent soft tissue or epidural space. Epidemiology and
pathogenesis, clinical presentation, diagnosis, treatment and prognosis are
briefly reviewed in this article.
PMID- 10765488
TI - Quantitative anatomy: power beyond the images. An emerging characteristic of PET
imaging.
AB - Positron emission tomography (PET) is a frontier medical technology that, in
contrast to the other computer-assisted technologies providing anatomical
pictures, produces functional images. I argue that PET also opens up an avenue
for shifting from images (as a tool for representation of biomedical data) back
to analysis of measurements (as a tool for quantification of physiology).
Admittedly, quantification of function requires structural constraints. I coined
the emerging interpretational framework quantitative anatomy in an attempt to
conceptualize the PET merger between measuring and imaging, the two competing
means medicine uses to examine the human body. Anatomy justifies interpretations
that fit the existing knowledge of a larger clinical audience, while statistical
data possess an unexplored potential to introduce mathematical rigor in the
evaluation of function, but are still a black box for the majority of clinicians.
This epistemological change is being carried out by PET users in action as well
as in discourse.
PMID- 10765489
TI - Clinical specificity and the non-generalities of science. On innovation
strategies for neurological physical therapy.
AB - How to improve clinical practice and, in particular, that of physical therapy?
Currently, several strategies are used which all fit the label 'scientification'.
These scientific strategies have to make physical therapy's clinical practice
more homogeneous. Sometimes this homogenization is thought to be necessary for
other strategies of innovation including effectiveness research. But it has also
been suggested that more homogeneity in the clinic is already itself an
improvement. In this article we comment on these strategies. More specifically,
we direct our attention at attempts in physical therapy to establish a uniform,
generally adopted scientific language. We argue that these attempts fail to
appreciate the specificity of therapeutic work. The effectiveness research that
follows is therefore liable to take irrelevant variables into account. We
illustrate this argument with examples taken from analyses of diverging therapies
for stroke patients.
PMID- 10765490
TI - The concept of abnormality in medical genetics.
AB - This paper explores usage of the concept of abnormality in medical genetics and
proposes directives for more careful usage of this concept. The conceptual
difficulties are first explored, then a model is developed to assess actual
usage, followed by analysis of a sample of genetic textbooks and genetics
literature. It appears that fact and valuation are often intermingled, that
reference standards used to define 'genetic abnormalities' are often not clear
and that the concept of abnormality is often used independent of the degree of
certainty with which the altered genetype develops into a (seriously) harmful
phenotype. On the basis of these findings it is argued that more restraint and
more careful use of the concept of genetic abnormality of medical genetics is
appropriate as well as more agreement on the use of reference standards.
PMID- 10765491
TI - They might as well be in Bolivia: race, ethnicity and the problem of solid organ
donation.
PMID- 10765492
TI - Nosology and causal necessity; the relation between defining a disease and
discovering its necessary cause.
AB - The problem of disease definition is related to the problem of proving that a
certain agent is the necessary cause of a certain disease. Natural kind terms
like 'rheumatoid arthritis' and 'AIDS' refer to essences which are discoverable
rather than predeterminate. No statement about such diseases is a priori
necessarily true. Because theories on necessary causes involve natural kind
semantics, Koch's postulates cannot be used to falsify or verify such theories.
Instead of proving that agent A is the necessary cause of disease D, we include A
in a theoretical definition of D, take this to represent the real meaning of 'D',
and discard the pretheoretical definition. This is illustrated by Koch's own
attempt to prove he had discovered the necessary cause of tuberculosis.
Methodological arguments about disease causation require a clear view of our use
of diagnostic terms. Medical lexicographers should do more to provide such a
view.
PMID- 10765493
TI - View and visions for nursing: health care leaders speak out.
PMID- 10765494
TI - Social violence: a case for classification as a sub-phenomenon of community in
the ICNP.
AB - The study is intended to illustrate that the nursing phenomenon, Violence, exists
as a phenomenon of the aggregate and should thus be classified, under the higher
level phenomenon, Community, in the International Classification for Nursing
Practice (ICNP), published by the International Council of Nurses. This
proposition was confirmed during a meeting of an international team of
psychiatric nurses to plan reality-based postgraduate modules for the nine
countries they represented. Substantiating data, based on the team's module,
Violence, clinical investigation and a review of the literature, evolved from a
classroom project in north-east Brazil. The Master's Degree nursing students
conducted observations and interviews based on identified factors of the
phenomenon on children in two municipal day-care centres in targeted
neighbourhoods in Joao Pessoa, Paraiba, Brazil. Data were gleaned from
observations and verbalizations regarding their individual drawings depicting
sadness and happiness, from school records and observations of these children by
their teachers. The data, evolving from the time-limited classroom project, are
too sparse to be considered valid, but pave the road for further studies.
Professional and lay-literature substantiates the occurrence of violence in the
Brazilian society.
PMID- 10765495
TI - Semantic equivalence of the Nursing Phenomena Classification of ICNP: Alpha
Version in Brazilian Portuguese.
AB - This study presents the results obtained in the first phase of research carried
out to adapt the Nursing Phenomena Classification of ICNP Alpha to the Brazilian
context. This phase intended to attain semantic equivalence of the terms of this
classification through the use of the back-translation technique, with some
modifications. From the results obtained, it may be stated that the semantic
adaptation of the classification attained a rate of agreement of 98% for the
titles and the definitions of nursing phenomena. The 2% of terms that did not
reach an acceptable rate of agreement are related to coping, in the following
phenomena: coping; defensive coping; coping: disabling; ineffective coping
specific: rapetrauma, death, divorce; compromised health coping; and inadequate
family coping. From this result, it may be concluded that the Nursing Phenomena
Classification was translated in a semantically correct form.
PMID- 10765496
TI - Reproductive cloning and human health: an ethical, international, and nursing
perspective.
AB - Human reproductive cloning came to the public's attention when Dolly, a sheep,
was cloned in Scotland in 1997. This news quickly spread around the world causing
both excitement at the possibilities that cloning techniques could offer, as well
as apprehension about the ethical, social and legal implications should human
reproductive cloning become possible. Many international organizations, such as
the World Health Organization, the International Council of Nurses, and
governments were concerned about the impact of human reproductive cloning on
human health, dignity and human rights. To this end, many institutions have
drafted resolutions, protocols and position statements outlining their concerns.
This paper will outline some of the major ethical issues surrounding human
reproductive cloning, the position of various international organizations and
governments, and specifically the position of the International Council of
Nurses.
PMID- 10765497
TI - Acculturation and breast self-examination among immigrant Latina women in the
USA.
AB - This article is an extension of previous work, which identified acculturation as
an important variable in predicting breast self-examination (BSE) in this sample
of women. Here, acculturation is further examined as an intervening factor in
predicting BSE. This paper presents the association between level of
acculturation to mainstream culture in the USA and the practice of BSE among a
population of low-income immigrant Mexican and Puerto Rican women (n = 111) in an
urban area of the Midwest in the USA. The majority of women (84.7%) scored a low
level of acculturation and 85% did not practice correct BSE. The crude odds ratio
indicated that Latina women having a high level of acculturation (15.3%) were
twice as likely to practice correct BSE than women with low acculturation. We
would suggest that a clearer understanding of the variables that define the
performance of BSE will assist in enabling nurses globally to incorporate
assessments in their practice that will lead to more successful interventions.
PMID- 10765498
TI - The staff's experience of the death of a child and of supporting the family.
AB - The purpose of the study was to describe how staff members experience the death
of a child and how they support the grieving family. The goal is to find means to
improve supporting activities in the university hospital. The data for this study
were collected with a questionnaire given to the staff who encounter the death of
a foetus or infant at their work (n = 102). The questionnaire contained both
structured and open-ended questions. Altogether, 69 members of the staff (68%)
answered the questionnaire. The open-ended questions were analysed using content
analysis. The staff experiences of a child's death manifested themselves in
grief, feelings of injustice, experiences of one's limited resources, and relief.
About half (51%) of the respondents estimated that they were able to support
families rather well. Education in supporting the grieving family increased the
ability to support families. Social support for families included emotional,
informational, and concrete support. The majority of the staff expected support
from colleagues after the death of a child. The study results show that the
hospital staff supports the grieving family, but also recognizes their inadequacy
as supporters. The staff also needs support in order to be able to support the
grieving family.
PMID- 10765499
TI - Caring as experienced by minority ethnic patients.
AB - International nursing literature associates 'nursing' as inextricably linked with
'caring'. However, as Leininger (1995) suggests, although caring is a universal
phenomenon, its manifestation is very much dependent on culture. For caring to be
effectively received, the conceptualization of caring at both individual and
community level needs to be realized in practice. This paper focuses on a
qualitative research study on a sample of 20 male and 18 female respondents from
Pakistani communities in Bradford, West Yorkshire. UK, using face-to-face in
depth semi-structured interviews. The significance of ethno-linguistics, or the
relationship between language and culture, has been addressed by a number of
anthropologists. People associate what is meaningful to them as defined by their
culture. By eliciting various linguistic terms used for 'care' terms and applied
to health and 'well-being', the cultural meanings within an 'emic' perspective,
as well as variability of the use of the care terms in different contexts, could
be discovered. Hence the first stage of this study focused on the respondents'
understanding and perceptions of caring. Care themes and patterns emerged to form
seven themes. The same sample was later facilitated in exploring their recent
experiences of 'care' as delivered by nurses in hospital. The findings suggest
that a lack of congruence between patients' expectations and experiences of
caring received from nurses did exist. The paper concludes by suggesting possible
strategies to address the identified deficits, for example a cultural knowledge
base and enhancing assessment skills in nurses.
PMID- 10765500
TI - Myocardial injury-induced fibroblast proliferation facilitates retroviral
mediated gene transfer to the rat heart in vivo.
AB - BACKGROUND: Efficient and stable transfer of therapeutic DNA into injured
myocardium would be an initial step towards a genetic treatment aimed at
myocardial repair after myocardial infarction. Proliferating cardiac fibroblasts
in the healing myocardium could be a compelling target for retroviral infection.
We evaluated the feasibility of direct in vivo gene transfer into injured
myocardium using a high-titer, stable retroviral vector. METHODS: Using the TE
FLY-A-based MFG retroviral vector harboring nlsLacZ reporter, the gene transfer
efficiency was assessed first in vitro in rat cardiac fibroblasts, followed by in
vivo evaluation in healing rat myocardium after local freeze-thaw injury. A total
of 2.5 x 10(7) infectious units of retrovirus were injected into the injured
region of a beating rat heart. The transduced cells were identified by X-gal
staining and immunohistochemistry. RESULTS: Highly efficient transduction of
cardiac fibroblasts was observed in vitro with 98% of the cells transduced with
single infection. The cell proliferation index in the cardiac granulation tissue
appeared maximal 3 days after cryoinjury. Retroviral injection into the injured
beating heart induced gene expression localized to the wound repair region. One
week after retrovirus injection, 14% of the cells in the reparative tissue were
beta-gal-positive, while 4% were beta-gal-positive after 4 weeks. The transduced
cells were mostly myofibroblasts. CONCLUSIONS: Local gene transfer to the healing
rat heart is feasible by retrovirus in vivo. This observation may serve as a
useful guide for the development of gene therapy aimed at myocardial repair after
myocardial infarction.
PMID- 10765501
TI - Exogenous wt-p53 protein is active in transformed cells but not in their non
transformed counterparts: implications for cancer gene therapy without tumor
targeting.
AB - BACKGROUND: Expression of exogenous wild-type p53 (wt-p53) protein in tumor cells
can suppress the transformed phenotype whereas it does not apparently induce
detrimental effects in non-transformed cells. This observation may provide a
molecular basis for p53-mediated gene therapy of p53-sensitive cancers without
the need for tumor targeting. METHODS: To understand the molecular mechanisms
responsible for this different behavior in tumor versus normal cells, biochemical
and functional analyses of exogenous wt-p53 protein were performed on non
transformed C2C12 myoblasts and their transformed counterparts, the C2-ras cells.
RESULTS: The exogenous wt-p53 protein, which induced persistent growth arrest
only in transformed C2-ras cells, was shown to be significantly more stable in
transformed than in non-transformed cells. This different stability was due to
different p53 proteolytic degradation. Moreover, constitutively, exogenous wt-p53
protein was found to be transcriptionally active only in C2-ras cells but it
could also be activated in C2C12 cells by genotoxic damage. CONCLUSIONS: Non
transformed C2C12 cells present regulatory system(s) which control the expression
and the activity of exogenously expressed wt-p53 protein probably through
degradation and maintenance in a latent form. This regulatory system is
lost/inactivated upon transformation.
PMID- 10765502
TI - Reconstitution of a metabolic pathway with triple-cistronic IRES-containing
retroviral vectors for correction of tetrahydrobiopterin deficiency.
AB - BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor for catecholamine
and serotonin neurotransmitter biosynthesis. BH4 biosynthesis is carried out in a
three-enzyme pathway involving GTP cyclohydrolase I (GTPCH), 6-pyruvoyl
tetrahydropterin synthase (PTPS) and sepiapterin reductase (SR). Treatment of
genetic defects leading to BH4 deficiency requires neurotransmitter replacement
since synthetic cofactor does not efficiently penetrate the blood-brain barrier.
Autologous fibroblasts transplanted into the brain as depository cells for drug
delivery might offer an alternative. However, normal fibroblasts do not express
GTPCH, and fibroblasts from PTPS patients lack two biosynthetic enzymes for BH4
production. METHODS: We engineered primary fibroblasts by the use of triple
cistronic, retroviral vectors for cofactor production. RESULTS: Constitutive SR
activity in these cells enabled BH4 biosynthesis by transducing GTPCH and PTPS
cDNAs together with a selective marker coupled in a single transcript with two
IRES-elements in tandem. Upon reaching a critical concentration (> 400 pmol/mg
protein) of intracellular BH4, the fibroblasts efficiently released cofactor even
under non-dividing conditions. CONCLUSION: The use of triple-cistronic vectors
for single transduction to reconstitute metabolic pathways or to treat multi
genetic diseases may be useful for engineering, for instance, depository cells
for various organs, including the nervous system.
PMID- 10765503
TI - Formulations which increase the size of lipoplexes prevent serum-associated
inhibition of transfection.
AB - BACKGROUND: Cationic lipids are the most widely used nonviral vectors for gene
delivery. Upon complexation to DNA, they offer a nonimmunogenic alternative to
viral gene transfer. Unfortunately, their in vivo application has been limited
due to a serum-associated inhibition of transfection. As a result, significant
research effort has focused on overcoming this deleterious effect of serum.
METHODS: To better understand this phenomenon, we investigated the influence of
lipoplex colloidal stability on gene transfection in the presence of serum. In
addition, conditions of the reaction medium were modulated and their effects on
collidal stability and subsequent in vitro transfection efficiency were studied.
RESULTS: The colloidal stability of the cationic lipid-DNA complexes, which
depended on the charge ratio, determined the efficiency of in vitro transfection
in the presence of serum. In particular, large-sized, colloidally unstable
complexes of over 700 nm mean diameter induced efficient transfection in the
presence or absence of serum. Conversely, colloidally stable complexes of less
than 250 nm in size resulted in efficient transfection only in the absence of
serum. Furthermore, for the same charge ratio, both colloidally stable and
unstable lipoplexes could be obtained depending on the degree to which various
solution parameters (NaCl concentration, cationic lipid acyl chain length, pH and
DNA concentration) were altered. In each case, only those complexes lacking
colloidal stability resulted in high levels of in vitro transfection in the
presence of serum. This phenomenon was shown to be independent of both the
percent DNA internalized and of the lamellar organization of the cationic
lipid/DNA lipoplexes. CONCLUSIONS: Through the modulation of various mixture
conditions, large-sized lipoplexes can be formed which are resistant to the
transfection-inhibiting effect of serum.
PMID- 10765504
TI - Long-term reversal of hypercholesterolemia in low density lipoprotein receptor
(LDLR)-deficient mice by adenovirus-mediated LDLR gene transfer combined with
CD154 blockade.
AB - BACKGROUND: Deficiency of the low density lipoprotein receptor (LDLR) results in
abnormal elevation of cholesterol within the intermediate and low density plasma
lipoproteins (IDL/LDL), and predisposes to early onset atherosclerosis.
Cholesterol reduction after adenovirus-mediated LDLR gene transfer to LDLR
deficient animals is transient, due to the elicitation of an immune response.
METHODS: The LDLR-deficient mouse was used as a model to investigate adenovirus
mediated LDLR gene transfer combined with short-term immunosuppression as a
cholesterol lowering therapy. Mice were infused with replication-deficient
recombinant adenovirus encoding LDLR under control of the cytomegalovirus
promoter/enhancer (AdLDLR), and injected with a blocking antibody directed
against CD154 (CD40 ligand) to suppress immune responses against the vector and
foreign transgene product. RESULTS: Mice given AdLDLR and treated with anti-CD154
expressed LDLR on hepatocytes and maintained cholesterol levels below or within
normal range for at least 92 days. In contrast, without adjunct immunosuppression
LDLR expression was transient, corresponding to temporary decline in cholesterol
levels. Analysis of cholesterol concentrations in fractionated plasma showed
remarkable reduction in all lipoprotein fractions at early time-points after gene
transfer. At later time-points, non-immunosuppressed control mice regained the
disease profile with elevated IDL/LDL cholesterol, while profiles of anti-CD154
treated mice were similar to normal. LDLR mRNA transcripts were present in livers
of the anti-CD154-treated mice but not controls, 93 days after AdLDLR injection.
However, vector DNA was detected in livers of both groups. These results suggest
that loss of LDLR expression in the non anti-CD154-treated mice was in part due
to immune-mediated promoter silencing, and that anti-CD154 prevented this effect.
CONCLUSION: Treatment with anti-CD154 antibody inhibits immune-mediated loss of
transgene expression, enabling long-term reduction in cholesterol levels after
AdLDLR gene transfer to LDLR-deficient mice.
PMID- 10765505
TI - Periadventitial lacZ gene transfer to pig carotid arteries using a biodegradable
collagen collar or a wrap of collagen sheet with adenoviruses and plasmid
liposome complexes.
AB - BACKGROUND: Periadventitial gene therapy is a promising alternative for the
treatment of stenosis, vessel wall thickening and other complications in vascular
surgery. METHODS: We compared lacZ gene transfer efficiency of DOTMA: DOPE (1:1
w/w) plasmid/liposome complexes and adenoviruses in pig carotid arteries using
perivascular delivery with either a collagen collar or a wrap of collagen sheet.
Safety of the gene transfer was studied by clinical chemistry, tissue pathology
and PCR analysis of lung, liver, kidney, spleen, skeletal muscle and gonads.
RESULTS: Gene transfer efficiency using the periadventitial collar was fourfold
higher than using the collagen wrap with adenovirus at 7 days (10.22 +/- 2.96 vs
2.78 +/- 1.28 positive cells/mm2; p = 0.18) and 4.3-fold at 14 days (13.46 +/-
3.49 vs 3.11 +/- 0.88 positive cells/mm2; p = 0.03). Gene transfer efficiency at
7 days with adenovirus was fivefold higher than with the plasmid/liposome
complexes both using the collar (10.22 +/- 2.96 vs 2.07 +/- 0.95 positive
cells/mm2; p = 0.01) and the collagen wrap (2.78 +/- 1.28 vs 0.45 +/- 0.35
positive cells/mm2; p = 0.03). No lacZ activity was detected in plasmid/liposome
transfected arteries at 14 days. In spite of the local gene delivery methods a
moderate systemic distribution of the transgene was detected in the major organs
by PCR analysis. CONCLUSIONS: This study shows that: (i) adenovirus delivered
with the periadventitial collar or the collagen wrap is well tolerated and may
become an efficient new tool in vascular gene therapy, and (ii) gene transfer
vector delivered in the periadventitial collar reaches the target tissue more
efficiently than the vector in the collagen wrap.
PMID- 10765506
TI - HIV-based vectors: getting the best out of the worst.
PMID- 10765507
TI - The 6 billionth birth--how it affects perinatal medicine.
PMID- 10765508
TI - Inhaled nitric oxide in premature infants--a meta-analysis.
AB - The role of inhaled nitric oxide (iNO) in the treatment of severe hypoxemic
respiratory failure of term neonates has been firmly established in several
randomized trials. In contrast, the use of iNO in premature newborns has remained
controversial. As of 1999, there are data of three randomized controlled trials
involving a total of 210 infants below 33 weeks of gestation. None of the trials
was able to demonstrate a benefit of iNO with respect to mortality or chronic
lung disease. We performed a meta-analysis of the three published trials. Of 111
infants receiving iNO, 44 deaths were observed, compared to 40 of 99 control
infants (p = 0.91). The odds ratio in favor of iNO was 0.97 (95% confidence
interval 0.54-1.75). There was also no significant difference for treatment
failure, defined as death or chronic lung disease (iNO: 32 of 111 infants versus
control: 34 of 99, p = 0.39, odds ratio 0.77, 95% confidence interval 0.41-1.45).
The rates of intracranial hemorrhage were similar in both groups (35 of 111
infants receiving iNO vs 25 of 99 controls, p = 0.33, odds ratio 1.37, 95%
confidence interval 0.69-2.74). We conclude that the use of inhaled nitric oxide
may improve oxygenation but not survival in preterm infants with severe hypoxemic
respiratory failure.
PMID- 10765509
TI - Fetal transverse cerebellar diameter in different ethnic groups.
AB - AIMS: Transverse cerebellar diameter has been described as a tool to check for
gestational age, but there are no available studies that attempt to determine
differences in transverse cerebellar diameter between groups of different ethnic
origin. The present study was undertaken to check for differences in ultrasound
measured transverse cerebellar diameter between pregnant women of autochthonous
Belgian origin and migrant women from Morocco and Turkey. METHODS: A prospective
cross-sectional study was performed. Patients were pregnant women presenting
between 17 and 40 weeks of gestational age. Only uncomplicated singleton
pregnancies with a known date of the last menstrual period confirmed by first
trimester ultrasound were included. The father of the child had to be of the same
ethnic origin as the mother. Polynomial regression was fitted for the three
different ethnic groups. RESULTS: The transverse cerebellar diameter was obtained
in 471 singleton fetuses, including 333 Belgian, 69 Moroccan and 69 Turkish. F
tests on the residual sums of squares of different fits demonstrated significant
effects of ethnicity on the regression of the measurement versus gestational age
(P < 0.00005). In a third order polynomial regression model the second order
coefficient was significantly higher and the third order coefficient was
significantly lower for the Moroccan group. CONCLUSION: The transverse cerebellar
diameter is not independent of the ethnic origin of the patient. When using the
transverse cerebellar diameter for the evaluation of fetal growth or for dating a
pregnancy, care should be taken to rely on charts appropriate for the ethnic
group, as demonstrated here for Moroccan fetuses.
PMID- 10765510
TI - Randomized trial of administration of prostaglandin E2 gel for induction of labor
in the morning or the evening.
AB - OBJECTIVE: To compare the outcome of induction of labor and patient's preferences
using a protocol with the first dose of prostaglandin E2 endocervical gel in the
evening versus a protocol with the first dose in the morning. DESIGN: We
performed a randomized trial comparing administration of prostaglandin E2
endocervical gel in the morning with administration of prostaglandin E2 gel in
the evening, followed if necessary by a second dose being given after six hours
if labor had not started or the cervix was still unripe. Formal induction of
labor by amniotomy and oxytocin infusion was performed the morning after the
initial prostaglandin E2 dose. Patients' preferences were assessed using a
questionnaire that was completed after delivery. SETTING: Tertiary care hospital
in the Netherlands with 1,600 deliveries per year. PARTICIPANTS: One-hundred and
twenty-six women with viable singleton pregnancies at term who had induction of
labor with prostaglandins. MAIN OUTCOME MEASURES: Time of delivery (daytime,
evening or night) and patient's satisfaction. RESULTS: Fifty-eight women were
allocated for administration of gel in the morning, whereas 68 had their gel in
the evening. Administration of gel in the evening did not significantly reduce
delivery between 23.00 hours and 08.00 hours, although there was a reduction in
delivery between 23.00 hours and 08.00 hours in nulliparae. None of the
multiparous women delivered between 18.00 hours and 23.00 hours after induction
of labor in the evening. The relative risk for delivery by vacuum or forceps was
increased after allocation of gel in the evening (4.2; 95% confidence limits 1.4
to 13). Patients' preferences favored administration of gel in the morning.
CONCLUSIONS: There was no benefit in starting induction of labor with
prostaglandin E2 in the evening, compared with starting in the morning.
PMID- 10765512
TI - Endoscopic examination of the fetus in early pregnancy.
AB - OBJECTIVE: To assess if fetal examination is feasible by endoscopy in the late
first-early second trimester. SETTING: Tertiary referral center for high risk
obstetrics and genetics. PATIENTS AND METHODS: Patients (total number 9)
submitted to pregnancy termination for social reason (7) or for chromosomal
abnormality (2) between 10 and 14 weeks of pregnancy. Visualisation of the foetus
by a transabdominally introduced endoscope (19 gauge) under local anaesthesia.
Step by step examination of the foetal contour and double check of the recordings
by a senior Pathologist. RESULTS: Patients complained no serious discomfort.
Visualisation was accomplished in all cases with ease and the images were judged
satisfactory by the Pathologist. Fetal examination was found easier at 10-12
weeks of gestation rather than at 13-14 weeks. DISCUSSION: Endoscopy is a simple
and well tolerated procedure, which enables precise visualization of external
fetal anatomy as early as the first trimester of gestation. Therefore it can be
proposed before surgical termination of pregnancy.
PMID- 10765511
TI - Fetal sciatic nerve growth is delayed following repeated maternal injections of
corticosteroid in sheep.
AB - AIMS: A single course of prenatal corticosteroid reduces the mortality and
morbidity of preterm birth. Repeated courses of prenatal corticosteroids are
widely prescribed despite a lack of safety data. Repeated corticosteroids delay
myelination in the ovine central nervous system at the time of preterm delivery
but with catch-up at term. We aimed to evaluate their effect in the peripheral
nervous system. METHODS: Thirty date-mated ewes were administered either saline,
a single injection of betamethasone, or four injections of betamethasone between
104 and 124 days' gestation, with delivery on day 125 or 145 (term = 150 days).
Sciatic nerves were dissected and fixed in modified Karnovsky's fixative and
prepared for light and electron microscopy to determine the proportion of
myelinated axons and mean axon diameter. RESULTS: Repeated, but not single,
corticosteroid administration resulted in significant decreases in the total
cross-sectional and fascicle-containing areas of the sciatic nerve, and in the
mean diameter of myelinated and unmyelinated axons. Deficits persisted at term.
The proportion of myelinated axons was unaffected. CONCLUSION: Repeated prenatal
corticosteroids have the capacity to affect the growth of peripheral nerve axons
in sheep. Documentation of their effects in human pregnancy await randomized
trials.
PMID- 10765514
TI - Perinatal factors and preterm delivery in an Irish obstetric population.
AB - The aim of this study was to ascertain the incidence of preterm delivery, the
associated etiological factors and consequent perinatal mortality in an Irish
obstetrical population. All deliveries between 24 + 0 and 36 + 6 weeks of
gestation that occurred during the five year period 1992-1996 were included in
the study. The overall group of preterm deliveries was also analyzed separately
as an early preterm group (24 + 0-31 + 6 weeks gestation) and a late preterm
group (32 + 0-36 + 6 weeks gestation). The overall incidence of preterm delivery
was 5.5% (n = 683) with 1% (n = 122) occurring in the early preterm group and
4.5% (n = 561) in the late preterm group. The etiological factors contributing to
preterm delivery in our population together with their frequency of occurrence in
both early and late preterm groups are outlined. Spontaneous unexplained preterm
delivery, multiple pregnancy, and hypertensive disorders of pregnancy were the
commonest etiological factors for preterm delivery. The perinatal mortality rate
(PMR) was 57 per 1000 (n = 39) in the preterm group overall with a 213/1000 PMR
in the early preterm group and a 23/1000 PMR in the late preterm group.
PMID- 10765513
TI - The analysis of the complement activation product SC5 b-9 is applicable in
neonates in spite of their profound C9 deficiency.
AB - Native complement factors and complement activation products were measured in
healthy neonates (n = 72) and in a group of infants with premature prolonged
rupture of the membranes (PPROM) without sepsis (n = 10). Vitronectin
concentration in normal cord blood was not correlated with gestational age, and
the median value was 86.0% of adult values. This was markedly higher than other
native complement factors studied (factor B: 35.9%, C4: 45.1%, C3: 56.2%). The
concentration of C9 showed a positive correlation with gestational age and was
very low, 10.8% of normal adult values in cord blood and 8.3% in the patients.
Fifteen percent of the neonates had C9 levels lower than 2% of adult values. The
complement activation products Bb and SC5 b-9 were significantly elevated in the
patients (159% and 130% of control values, respectively), indicating alternative
and terminal pathway activation. In contrast, C4 bc and C3 bc levels were not
increased. The maximum amount of SC5 b-9 which could be generated in the neonatal
sera by cobra venom factor was highly correlated with C9 concentration (rs =
0.86, p = 0.0001) The profound C9 deficiency found in neonates is correlated with
gestational age, limits the capacity to form bacteriolytic C5 b-9 (m) and may
predispose for severe invasive bacterial infection. The plasma level of SC5 b-9
under normal conditions was very low, only 0.3% (0.1%-3.0%) of the values
obtained after CVF activation of the same samples. Therefore, we suggest that the
analysis of SC5 b-9 is applicable also in neonates, in spite of their extremely
low C9 levels.
PMID- 10765515
TI - Relation between brain tissue pO2 and dopamine synthesis of basal ganglia--a
18FDOPA-PET study in newborn piglets.
AB - Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic
morbidity and mortality in the neonatal period and later in childhood. There is
evidence that the dopaminergic system is sensitive to oxygen deprivation.
However, the respective enzyme activities have yet not been measured in the
living neonatal brain. In this study, we have used 18F-labelled 6-fluoro-L-3,4
dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET)
to estimate the activity of the aromatic amino acid decarboxylase (AADC), the
ultimate enzyme in the synthesis of dopamine, in the brain of newborn piglets
under normoxic and moderate asphyxial conditions. The study was performed on 8
newborn piglets (2-5 days old). In each piglet PET studies were performed under
control conditions and during 2-hour asphyxia. Simultaneously, brain tissue pO2
was recorded, cerebral blood flow (CBF) was measured with colored microspheres
and cerebral metabolic rate of oxygen (CMRO2) was determined. Asphyxia was
induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding
about 6% CO2 to the inspired gas. Asphyxia elicited a more than 3-fold increase
of the CBF (p < 0.01) so that CMRO2 remained unchanged throughout the asphyxial
period. Despite this, brain tissue pO2 was reduced from 19 +/- 4 mm Hg to 6 +/- 3
mm Hg (p < 0.01). Blood-brain transfer of FDOPA as well as permeability-surface
area product (PS) from striatum were unchanged. Striatal synthesis rate of fluoro
dopamine from FDOPA (k3) was, however, significantly increased (p < 0.01). This
increase of the AADC activity is associated with reduced brain tissue pO2.
Asphyxia-induced CBF increase impedes an alteration of brain oxidative
metabolism.
PMID- 10765516
TI - Premature closure of foramen ovale and renal vein thrombosis in a stillborn twin
homozygous for methylene tetrahydrofolate reductase gene polymorphism: a
clinicopathologic case study.
AB - Premature closure of the foramen ovale, 4-chamber cardiac hypertrophy, and renal
vein/vena cava thrombosis were found at autopsy of a stillborn dizygotic twin at
36 weeks gestational age. Review of the original prenatal sonograms showed
features suggestive of early closure of the foramen ovale. Homozygosity for the
5, 10 methylene tetrahydrofolate reductase mutation was shown only in the
affected twin after the parents were found to be heterozygous for the mutation.
The difference in outcome of the twins following prenatal treatment with beta
mimetics and corticosteroids for preterm labor may be related to the added
susceptibility factor for thromboembolism associated with presumed
hyperhomocysteinemia in the proband which was not shared by the surviving healthy
twin. The role of premature closure of the foramen ovale and prenatal treatment
are discussed but remain uncertain.
PMID- 10765517
TI - Agenesis of the ductus venosus and its correlation to hydrops fetalis.
AB - Absence of the ductus venosus is a rare vascular anomaly. We report a late onset
of a hydrops fetalis seen in a fetus at 34 completed weeks of gestation. A
persistence of the cranial parts of the left and right umbilical veins and of the
paired cranial vitelline veins with an absent ductus venosus led to a bilateral
hydrothorax, ascites and skin-edema. Postnatally the hydrops resolved within 7
days most probably due to the change from the fetal to the adult circulation. The
abnormal venous system was confirmed by angiography. Agenesis of the ductus
venosus can manifest in two different morphologic patterns: The umbilical vein
drains exclusively into the left branch of the intrahepatic portal vein or the
umbilical vein drains into the inferior vena cava or directly into the right
atrium by-passing the liver completely. In both patterns, the preferential
direction of the flow towards the foramen ovale is not present. While the first
pattern leads to hyperperfusion of the liver parenchyma, the latter would result
in reduced perfusion and oxygenation. Our findings suggest that agenesis of
ductus venosus might induce hydrops fetalis. We conclude, that in every case of
hydrops fetalis the venous system should be evaluated by ultrasonography
prenatally and/or immediately postnatally.
PMID- 10765518
TI - World Health Organization (WHO) and the World Heart Federation (WHF)
Pathobiological Determinants of Atherosclerosis in Youth (PBDAY) Study.
Histomorphometric investigation of the aorta and coronary arteries in young
people from different geographical locations.
AB - BACKGROUND AND AIM: At the Morphometric Reference Center of the World Health
Organization (WHO) and the World Heart Federation (WHF) for the Pathobiological
Determinants of Atherosclerosis in Youth (PBDAY) Project, histomorphometric
studies were carried out on aortic and coronary artery walls of 590 people
ranging from 5 to 34 yr of age, who were of European, American, Asian and African
origin (6 countries) and died of trauma. The aim was to evaluate the mean intimal
and medial thickness of arterial tissues. METHODS AND RESULTS: Computerized
operator-assisted morphometry with a semiautomatic image analyzer was carried out
on 2,893 histological slides (prepared at the WHO Reference Center in Malmo,
Sweden). Our data show that age-dependent trends for prevalence of fatty streaks
and atherosclerotic plaques in arteries are different: prevalence of fatty
streaks increases until a plateau is reached, while exponential growth
characterizes atherosclerotic plaque prevalence. Age is statistically associated
with an increase in mean intimal and medial thickness in all specimens.
CONCLUSIONS: Mean intimal and medial thickness differs in arterial wall specimens
of individuals from various geographic locations: persons from countries with
high mortality rates from cardiovascular disease tend to have greater mean
intimal thickness in youth. Men with hypertension and those who smoke have
significantly greater combined means of intimal thickness than normotensives and
non-smokers respectively. The also have significantly greater combined means of
medial thickness than normotensive men. Histomorphometric data provide evidence
of the development of atherosclerotic lesions at an early age and relate their
progression to ethnic and lifestyle factors and to major coronary heart disease
risk factors.
PMID- 10765519
TI - World Health Organization (WHO) and the World Heart Federation (WHF)
Pathobiological Determinants of Atherosclerosis in Youth (PBDAY) Study. Lipid and
raised lesion distribution in the right coronary artery of young people.
AB - BACKGROUND AND AIM: As part of the WHO-WHF PBDAY Study, we examined the proximal
segment of the right coronary artery (RCA) (n = 469) of 5-34 yr-old otherwise
healthy trauma victims from 15 countries to establish the topographical relation
of atherosclerotic lesions to age, sex and geographical location. METHODS AND
RESULTS: Topography and extent of lesions were analyzed by image processing and
probability-of-occurrence maps of lipid lesions (mostly fatty streaks) and raised
lesions on the intimal surface of the RCA were produced. Extension of lesions
varied considerably between the groups and between individuals in the same group.
The prevalence of lipid lesions was 68% (319/469) compared with 100% in the
aorta. The prevalence of raised lesions was 22% (102/469) compared with 7% and
26% in the thoracic and abdominal aorta. Females had more lipid lesions, whereas
raised lesions prevailed in males. Lipid lesion extent increased with age in both
sexes. CONCLUSIONS: High probability-of-occurrence areas for lipid and raised
lesions prevailed in the proximal 5 cm of the intimal surface of the RCA
(myocardial side) and were greatly overlapping. Regression analysis between lipid
and raised lesion extent in the thoracic or abdominal aorta and the RCA showed no
correlations between the lipid lesion extent, whereas significant correlations
were found between the raised lesion extent in the RCA and the thoracic aorta
only, showing that the two types of lesion behave differently in different
anatomical locations.
PMID- 10765520
TI - Relative importance of the saponified and unsaponified fractions of dietary olive
oil on mitochondrial lipid peroxidation in rabbit heart.
AB - The effects of four edible oils on lipid peroxidation have been investigated in
rabbit heart mitochondrial membranes. The experimental oils (olive oil from the
variety "picual", washed olive oil from the variety "picual", olive oil from the
variety "arbequina" and high-oleic sunflower oil) had a similar fatty-acid
composition, but differed in their unsaponified fraction (polyphenols,
tocopherols, and others). The lowest hydroperoxide levels were found with picual
and washed picual. No differences in mitochondrial membrane thiobarbituric acid
reactive substance (TBARS), alpha-tocopherol concentrations and cytosolic
antioxidant enzymes (superoxide dismutase, glutathione peroxidase, glutathione
reductase and catalase) were found, whereas the CoQ10 content correlated
inversely with hydroperoxide levels in all groups. These results suggest that
mitochondrial membranes with high levels of monounsaturated fatty acids generate
low levels of lipid peroxidation. Moreover, the saponified fraction of the
experimental diets proved more important in preventing lipid peroxidation than
the unsaponified fraction. Lastly, coenzyme Q may help to prevent peroxidative
stress damage in rabbit heart mitochondria.
PMID- 10765521
TI - Study of fluidity of low density lipoproteins from liver cirrhotic patients.
AB - BACKGROUND AND AIM: Liver disease is accompanied by major quantitative and
qualitative modifications in plasma lipoprotein metabolism. Alterations in plasma
lipoprotein composition and a lower susceptibility to in vitro peroxidation of
low density lipoprotein (LDL) and erythrocyte membranes have been observed in
liver cirrhosis. The main objective of the present work was to investigate LDL
chemical composition and fluidity in liver cirrhosis using the fluorescence
polarization (Pf) of the 1,6-diphenyl-1,3,5-hexatriene (DPH) probe. METHODS AND
RESULTS: The chemical composition of LDL was studied in 12 cirrhotic patients and
22 controls by conventional methods and its fatty acid composition by gas
chromatography. LDL fluidity was determined by measuring the DPH Pf values. A
decrease in molecular order was demonstrated by the significant (p < 0.05)
decrease in Pf values in the cirrhotics. Modifications in LDL fluidity are
correlated with its composition. A significant increase in triglyceride content
(p < 0.05), and significant increases in triglyceride/protein and
triglyceride/phospholipid ratios were observed in the cirrhotics. CONCLUSIONS:
Our results demonstrate that the higher LDL fluidity of cirrhotic patients may be
due to an increased triglyceride content.
PMID- 10765522
TI - Iron status and the risk of coronary heart disease.
PMID- 10765523
TI - Familial combined hyperlipoproteinemia: experts panel position on diagnostic
criteria for clinical practice. Committee of experts of the Atherosclerosis and
Dysmetabolic Disorders Study Group.
AB - The Atherosclerosis and Dysmetabolic Disorders Study Group, headed by Prof.
Rodolfo Paoletti, decided in 1994 to compose a committee of experts to formulate
a clear description of familial combined hyperlipoproteinemia (FCH), a disorder
illustrated in the literature, but still unknown to most physicians in spite of
its severity and relative diffusion. The Committee consists of experts from the
Lipid Clinics of the Universities of Ancona, Bari, Bologna, Ferrara, Genoa,
Milan, Naples, Padua, Palermo, Perugia, Rome, Sassari, Turin, Verona and Venice.
It has held several meetings coordinated by the national secretary at the
"Giancarlo Descovich" Atherosclerosis Centre of the University of Bologna. This
paper summarizes its conclusions.
PMID- 10765524
TI - What stops effective clinical audit?
PMID- 10765525
TI - Motor neuron disease--a review.
AB - It is now clear that patients with MND are best managed using a multi
disciplinary approach conforming to evidence-based guidelines. Whilst scientific
advances into the aetiology of MND have been of great importance in both the
understanding of this and other neurodegenerative disease, they have only
recently led to therapy directed at disease progression. The management of
patients with MND remains largely supportive but it is hoped that the future may
hold better prospects for those with the disease.
PMID- 10765526
TI - Assessing smoking prevalence amongst school children in a health board region.
AB - The objective of the study was to provide baseline data for Tayside in 1995 on
the prevalence of smoking cigarettes in school children, aged 11 to 15 years. The
design was a cross-sectional survey of 4675 children, obtained using a random
cluster sample of 79 schools, stratified by school year and deprivation category.
The main outcomes measures using a structured questionnaire, were the prevalence
and level of smoking, by age and gender. The prevalence rate of regular smoking
was 9% (95% CI 8.2%-9.8%). The rate rises appreciably for boys between 13 and 14
years and for girls between 12 and 13 years. Source of cigarettes was also an
outcome measure, most cigarettes were obtained from small shops. Health Boards
require a standard method for collecting regional baseline data on the prevalence
of smoking among children both for evaluation of targeted health promotion
initiatives by age and gender and also for comparison of regional smoking
prevalence with national targets.
PMID- 10765527
TI - Bacterial contamination of children's toys used in a general practitioner's
surgery.
AB - General practitioners--and other healthcare professionals are encouraged to make
their premises child friendly. One way of doing this is to provide toys for
children to use. We looked at the appearance and bacterial colonisation of 50
toys after a busy morning surgery in an inner city general practice. The toys
appeared generally unclean and 10% were contaminated by potential pathogens.
Bacteria were cultured more frequently from soft toys than from hard toys (odds
ratio 8.14; 95% confidence range 0.74-107.49). Although toys may appear to be
physically dirty after use, the bacteria isolated from their surfaces are
generally non-pathogenic to children with normal immune function and probably no
worse than other objects in the environment. However, there does exist an
appreciable (1 in 10) risk of cross-infection with the use of toys in a clinic.
Toys with a hard surface are preferred as these are less likely to be
contaminated and are more easily disinfected.
PMID- 10765528
TI - Health advice and the traveller.
AB - We studied advice given by travel agents, the experiences of recent travellers,
and the hidden costs for travellers to Kenya. There was a wide range of advice
given by United Kingdom travel agents, much of it at variance with advice given
by other travel agents and much of it incorrect. Nevertheless travel agents have
a responsibility to give advice because they are often the only point of contact
for health advice.
PMID- 10765529
TI - A three year review of injuries to professional footballers (1995-98) and
comparison with previous observations (1990-93).
AB - A prospective study over a three year period (1995-8) of footballers' injuries in
first team players was undertaken in a similar fashion to a previous study (1990
3). During the present study the Club had a major cup success and appeared to
have a younger squad with less major injury and subsequent time out of action. As
a result of the earlier paper it would appear that some lessons and observations
may have been put into action and helped produce a more consistent standard for
the club. Increasing recognition of the need to reduce and monitor the levels and
types of injuries seems now to be established.
PMID- 10765530
TI - Successful treatment of Graves disease in pregnancy with Lugol's iodine.
AB - We report a case of Grave's disease in pregnancy complicated by intolerance of
standard antithyroid drug therapy. We describe the success of prolonged use of
organic iodine as a primary treatment prior to surgical intervention.
PMID- 10765531
TI - Simultaneous presentation of ectopic pregnancy and hyperthyroidism.
AB - Hyperthyroidism is known to occur uncommonly in pregnancy (about 0.5 per 1000).
The incidence of ectopic pregnancy is approximately 9.6 per 1000 pregnancies.
Both conditions, if unrecognised and untreated can have potentially fatal
consequences. We describe a case of hyperthyroidism and ectopic pregnancy
presenting concurrently, and highlight the difficulties encountered in diagnosis
when two clinical conditions present with indistinguishable clinical signs.
PMID- 10765532
TI - What stops effective clinical audit? Reports from the front line.
AB - Semi-structured interview were conducted with 145 clinicians from a variety of
clinical backgrounds in twelve Trusts across three Scottish health boards.
Questions examined barriers to the audit process and obstacles that impeded the
implementation of changes in response to the audit findings as well as the need
for resources to facilitate the audit activity. The most difficult part of the
audit process was reported as data collection (32%) but almost half of
respondents would have changed the way the audit was done with hindsight. The
biggest barrier to doing the audit was perceived as lack of time (33%).
Colleagues' attitudes posed the biggest obstacles to making changes as a result
of the audit (26%). Few perceived the need for more resources but preferred
focused and proactive support from managers and audit support staff. Trusts need
to work harder at creating cultures where clinical audit is supported and
actively encouraged.
PMID- 10765533
TI - Howison, the Cramond Murderer, and last person to be hanged and dissected.
AB - An articulated skeleton in Edinburgh University's Anatomy Museum of "Howison, The
Cramond Murderer", shares a show-case with the articulated skeleton of "William
Burke, The Murderer". While the murderous activities of William Burke are well
known, because of his association and activities with William Hare, and because
they sold the bodies of their victims to Dr Robert Knox, the anatomist, little
these days is recalled of Howison. He was executed for the murder of a woman in
Cramond in December 1831, and was hanged on 21st January 1832. The case is
important because he was the last individual executed before the implementation
of the Anatomy Act of 1832. Accordingly, under the conditions of the previous
Act, of 1752, entitled "An Act for better preventing the horrid Crime of Murder",
his body had to be handed across to the surgeons to be "dissected and
anatomized", before it could be buried.
PMID- 10765534
TI - Quality of care within the Indian family welfare programme: a review of recent
evidence.
AB - India's family planning program represents one of the earliest and most ambitious
efforts in a developing country to address the issue of high fertility. Despite
its more than four decades of existence, little is known concerning how the
program is implemented at the field level, especially in relation to the quality
of services provided. In this article, empirical evidence on the accessibility
and quality of services provided through the Indian family planning program is
reviewed and synthesized. The review highlights the serious and systemic
shortcomings in quality of care that characterize the Indian program in such
areas as restricted method choice, limited information provided to clients, poor
technical standards, and low levels of follow-up and continuity of care. The
factors constraining higher service quality are subsequently reviewed, and the
prospects for improving quality of care within the Indian program are assessed.
PMID- 10765535
TI - The politics of population policy in the Islamic Republic of Iran.
AB - The Islamic Republic of Iran arguably has one of the most successful family
planning programs in the developing world. This success is all the more
interesting for advocates of population programs because the political leaders of
the Islamic regime were once strongly opposed to family planning. Indeed, after
gaining power following the 1979 revolution, they were responsible for
dismantling Iran's relatively new family planning program and introducing
pronatalist policies. This article provides an account of the different phases of
the population policy in Iran and examines the diverse elements that led politico
religious leaders to revise their views about fertility control and to
participate in creating a workable family planning program. The complex formal
and informal strategies that the political experts, the media, the religious
authorities, and the government of the Islamic Republic adopted in order to
achieve this about-face are described. The analysis is based on data collected by
the first author during anthropological field research in 1993-96, by means of
informal interviews with officials, with medical personnel, with family planning
clients, and with religious leaders.
PMID- 10765536
TI - Perceptions of the risks of sexual activity and their consequences among Ugandan
adolescents.
AB - The principal aim of this study of adolescents in Mbale District, Uganda, is to
provide program-related information about their behavior, motivations, and
perceptions of risk with regard to pregnancy and HIV transmission. Twelve single
sex focus-group discussions were conducted, six with young people aged 17-18 who
were still attending school, and six with people of the same age who were not.
The most important findings to emerge are that knowledge of safe-sex behavior and
reported behavior have little in common and that the fundamental barriers to
behavioral change lie within the economic and sociocultural context that molds
the sexual politics of youth. Young males' lack of responsibility for the
outcomes of their behavior is identified as an important barrier to improved
sexual health. The imperative to explore ways by which young women might achieve
status and identity and acquire material resources by means not related to their
sexuality is highlighted.
PMID- 10765537
TI - Premarital fertility in rural South Africa: a challenge to existing population
policy.
AB - The age pattern of fertility in a rural area of South Africa under demographic
surveillance (Agincourt subdistrict) was investigated over the 1992-97 period.
The total fertility rate (TFR) averaged 3.3 births per woman of reproductive age
over the period, a major drop from earlier estimates in the same area (6.0 births
in 1970-74). Age-specific fertility rates showed an atypical bimodal pattern.
They were decomposed into two components of similar magnitude: premarital
fertility (among women aged 12-26) and marital fertility (among women aged 15
49). The decomposition revealed the two underlying modes: a mode of premarital
fertility (among women aged 18-20) and a mode of marital fertility (among women
aged 28-30). Premarital fertility accounted for 21 percent of all births and for
47 percent of births among women aged 12-26. This pattern of high premarital
fertility appears to reflect a low incidence of contraceptive use before the
first birth, especially among adolescents, a low prevalence of abortion, and a
high contraceptive prevalence thereafter. This finding calls for a reorientation
of the family planning policy, which until now has targeted married women and
women who have been pregnant once, but has failed to address the contraceptive
needs of young women before their first pregnancy, especially adolescents.
PMID- 10765538
TI - Screening and syndromic approaches to identify gonorrhea and chlamydial infection
among women.
AB - The standard diagnostic tools to identify sexually transmitted infections are
often expensive and have laboratory and infrastructure requirements that make
them unavailable to family planning and primary health-care clinics in developing
countries. Therefore, inexpensive, accessible tools that rely on symptoms, signs,
and/or risk factors have been developed to identify and treat reproductive tract
infections without the need for laboratory diagnostics. Studies were reviewed
that used standard diagnostic tests to identify gonorrhea and cervical chlamydial
infection among women and that provided adequate information about the usefulness
of the tools for screening. Aggregation of the studies' results suggest that risk
factors, algorithms, and risk scoring for syndromic management are poor
indicators of gonorrhea and chlamydial infection in samples of both low and high
prevalence and, consequently, are not effective mechanisms with which to identify
or manage these conditions. The development and evaluation of other approaches to
identify gonorrhea and chlamydial infections, including inexpensive and simple
laboratory screening tools, periodic universal treatment, and other alternatives
must be given priority.
PMID- 10765539
TI - Family planning and sexual behavior in the era of HIV/AIDS: the case of Nakuru
District, Kenya.
AB - Recently, the prevalence of contraceptive use has increased in Kenya. The twin
risks of unwanted pregnancy and HIV/AIDS infection remain central concerns of
reproductive health programs. However, we do not know how sexually active men and
women perceive these risks, nor the strategies they consider appropriate to cope
with these risks, nor the difficulties they face in trying to adopt appropriate
sexual behaviors to minimize them. This study seeks to provide insights into
perceptions, coping strategies, and constraints in the changing behavior of
sexually active people in Nakuru District, Kenya. Twelve focus-group discussions
were conducted, the results of which show that people in the study area consider
the two risks to be serious problems, but that they neither use condoms within
marriage nor refuse their partners sex even if they perceive a risk of acquiring
HIV. These findings call for serious efforts toward fostering behavioral change
in this area.
PMID- 10765540
TI - Jordan Republic 1997: results from the demographic and health survey.
PMID- 10765541
TI - Mozambique 1997: results from the demographic and health survey.
PMID- 10765542
TI - [West Nile fever].
AB - Reviews the data on the history, distribution, ecology, epidemiology, and
clinical picture of West Nile (WN) fever and the ecology of the virus
(Flaviviridae, Flavivirus, Japanese encephalitis complex). Analyzes the causes of
sudden epidemic outbreaks with high mortality in Rumania in 1996, in European
Southern Russia, and in New York and its environs in 1999. Offers recommendations
on decreasing the damage inflicted by new and emerging infections leading to
epidemic emergencies.
PMID- 10765543
TI - [Isolation and study of recombinant strains of Salmonella typhimurium SL 7207,
producing HBcAG and HBcAG-HBs].
AB - Recombinant strains producing hepatitis B virus (HBcAg) core protein and chimeric
core protein exposing on its surface the major immunogenic epitope of HBsAg
(HBcAg-HBs) were constructed on the base of attenuated S. typhimurium SL 7202
strain. The resultant Salmonella strains produced proteins which were capable of
self-assembly into virus-like particles and showed antigenic properties of both
core and surface hepatitis B proteins. A single rectal immunization with
recombinant S. typhimurium induced humoral and cellular immune response to HBcAg
and HBsAg. Specific anti-HBcAg were detected in animal sera and intestinal
tissues, which indicated the formation of specific mucosal immunity.
PMID- 10765545
TI - [Assay for level of Marburg virus in blood and isolates from experimentally
infected animals].
AB - Measurements of concentrations of Marburg virus in guinea pig saliva, urine, and
feces showed that as early as by the end of incubation period the virus
concentrations in the feces and saliva were 2.3-3.3 lg LD50. In the blood the
content of the virus was high and increased by the end of the disease, while the
concentrations in the urine, saliva, and feces were virtually the same throughout
the disease.
PMID- 10765544
TI - [Detection of hepatitis C markers--nucleocapsid protein, RNA and virus-specific
antibodies in blood donor plasma].
AB - Comparative study of hepatitis C virus (HCV) markers (core protein, RNA, and
virus-specific antibodies) was carried out in plasma samples from 80 donors. A
method based on sandwich ELISA with monoclonal antibodies to recombinant protein
was developed for measuring core protein. Nucleocapsid protein was detected after
various treatments of precipitates obtained after concentration of virus
containing material from plasma samples. These treatments allowed differentiation
of core protein in virions, free nucleocapsids, and immune complexes circulating
in peripheral blood. The minimal detectable concentration was 5 pg/ml, maximal
850 pg/ml. The detection of core protein virtually coincided with the detection
of HCV RNA: 94.4% RNA-positive samples contained the virus protein. Other
parameters (activities of antibodies to HCV in ELISA and level of SGPT) did not
allow differentiation of plasma samples by the presence of actively replicating
virus. Assay of nucleocapsid protein in the plasma of subjects infected with HCV
in various populations of virus particles is important from practical (for blood
service) and theoretical viewpoints (for studies of virus pathogenesis
mechanisms).
PMID- 10765546
TI - [Preparation of T-lymphoblastoid cell lines from patients with T-cell leukemia
and asymptomatic carriers of HTLV-I: analysis of the viral genome status].
AB - Three HTLV-I-infected partially interleukin-2-dependent lymphoid cell lines were
derived from a patient with T-cellular leukemia (ATL) from Georgia and a carrier
of HTLV-I from Sakhalin. The strains cultured in the presence of 3-5% interleukin
2 were designated as NBK-1, NBK-2, and YE-1, respectively. Immunoblotting
analysis showed typical HTLV-I proteins in them except NBK-2 which expressed
nontypical proteins p40K and p28-29K. Unexpectedly, leukemic cell fraction
ATL/NBK from a patient contained gag proteins p19 (CA), p24 (MA), Pr53, and
unidentified protein p29. Southern blot analysis of primary leukemic cells NBK
showed one full-length non-defective provirus with restriction sites Sacl in both
LTRs. Limited restriction map of the provirus virtually did not differ from
previously described HTLV-I prototypes. Although the mechanism of abnormal
protein expression remains to be determined, this event can be explained by
defective provirus formation in NBK-2 cell line during coculturing of leukemic
cells with human umbilical cord blood lymphocytes.
PMID- 10765547
TI - [Specific immune response to vaccination with an inactivated flue vaccine
depending on prevaccine status and age of the person vaccinated].
AB - Specific antibody immune response to vaccination with commercial inactivated
trivalent vaccine A(H1N1) + A(H3N2) + B (IgA, IgG, IgG, subclasses G1, G3, G4,
and accumulation of antiCD8) was studied in subjects aged 20-95 years. The
initial immune status before vaccination is significant for a positive immune
response to the vaccine. Subjects responding to immunization by an increment in
specific IgG had a much lower prevaccination level of these antibodies than
subjects without these Ig conversion. Antibody immune response to vaccination
depended on patient's age. All vaccinees aged 20-25 years developed an increment
in IgG to at least one of influenza antigens used. Specific postvaccinal immune
response to inactivated influenza vaccine included accumulation of G1, G3, and A
antibodies, but not G4 or E antibodies. This latter fact suggests the absence of
sensitizing effect of vaccination. In elderly subjects an increment in G1, G3,
and A antibodies may not involve an increase in the total level of IgG. In part
of elderly subjects secretion of specific antibodies was observed in the presence
of increased concentration of antilymphocytic antibodies (antiCD8), indicating a
possibility of autoimmune reactions in subjects of this age after injection of
inactivated influenza vaccine.
PMID- 10765548
TI - [Synthesis and immunochemical properties of the recombinant major surface
glycoprotein E2 of the classical swine fever virus].
AB - Recombinant E2 protein from vaccine strain of classical swine fever virus (CSFV)
and from SCFV virulent strain Shimen was synthesized in SF-21 and High-Five cell
culture with baculovirus as the expressing vector. For secretion, hydrophobic C
terminal transmembrane domain was removed and N-terminal signal polypeptide of 38
amino acids was added. Maximum accumulation of recombinant products in SF-21
cells was observed after 48 h and in medium 96 h after infection with recombinant
baculovirus. In High-Five cells and in culture medium the maximum accumulation of
E2 was observed after 96 h. The level of E2 expression is 5-10 micrograms/106
cells. The products of expression were purified by affinity chromatography and
their specificity confirmed in immunochemical tests with a series of reference
monoclonal antibodies. The product can be used for detecting antibodies to SCFV
by competitive enzyme immunoassay.
PMID- 10765549
TI - [Use of recombinant protein E2 of the classical swine fever virus for
immunization of animals].
AB - Recombinant major surface glycoprotein E2 from virulent Shimen strain of
classical swine fever virus (CSFV) has been tested for immunogenicity in animal
immunization experiments. Immunization of 3-month-old piglets with 200 micrograms
of recombinant protein protected the animals from lethal challenge with virulent
CSFV strain. CSFV-specific antibody detection test based on competitive ELISA has
been developed using the recombinant E2 protein. The test can evaluate specific
antibody levels after subunit vaccination with recombinant E2 after immunization
with live vaccine based on attenuated CSFV strain.
PMID- 10765550
TI - [In vitro proliferative activity of lymphocytes from elderly persons after
separate and combined immunization with live and inactivated flu vaccines].
AB - Cellular (lymphocyte proliferation activity--LPA), humoral (serum antibodies),
and secretory (IgA antibodies from the upper respiratory tract) immune responses
were compared in 45 subjects aged 66-95 years, vaccinated with two influenza
trivalent A(H1N1) + A(H3N2) + B vaccines: Russian live attenuated cold-adapted
reassortant (LIV) and USA inactivated split-virus (IIV) vaccines. None of
immunization protocols suppressed LPA after in vitro stimulation of cell culture
with homologous virus antigens and nonspecific polyclonal mitogen (PHA).
Simultaneous LIV + IIV vaccination was the most effective method of immunization,
inducing humoral, secretory, and cellular immunity. LIV more actively than IIV
stimulated the lymphoproliferative immune responses. Fluctuations in the mean
values of cellular, humoral, and secretory immunity were in good correlation over
the entire period of observation (19 weeks). Analysis of individual immune
responses showed that a significant increase in quantitative parameters of LPA
was observed only in 39-52% vaccinees.
PMID- 10765552
TI - [Bacteremia management in neutropenia: approaches for the new millennium].
PMID- 10765551
TI - [Isolation of a panel of HIV-positive serum by blocking them with various HIV
antigens].
AB - A new methodological approach to preparation of a panel of positive sera
containing antibodies to individual viral proteins has been developed. The method
consists in exhaustion of initial sera from HIV-infected patients with the known
titers of antibodies by HIV antigens differing by the spectrum of virus proteins.
Antigen preparations containing the least amounts of envelope proteins were
selected for exhaustion. A set of HIV-positive sera containing antibodies mainly
to envelope proteins and differing in ELISA was obtained.
PMID- 10765553
TI - [Treatment of antibiotic-resistant bacteria at the intensive care unit: a therapy
dilemma].
PMID- 10765554
TI - [Rational treatment of severe nosocomial pneumonia: our experience].
PMID- 10765555
TI - [Use of antibiotics in the treatment of community-acquired infections of the
lower respiratory tract in the elderly].
PMID- 10765556
TI - [How should we modify the use of antibiotics at hospitals?].
PMID- 10765557
TI - Phenotypic and genetic factors in motives for smoking.
AB - Underlying phenotypic and genetic factors involving motives for smoking were
assessed using data from 1756 twins, including 390 complete pairs. Respondents
were aged 50 or older and included both current and former smokers. The Motives
for Smoking Questionnaire (MSQ) hypothesizes eight correlated but distinct
motives for smoking, which correspond to pharmacological and nonpharmacological
second-order factors. This paper concentrates on the pharmacological motives.
Principal-factor analysis recovered five categories. Items constituting Sedative,
Stimulative, and Addictive reasons for smoking merged into one factor, whereas
Automatic smoking, also considered to have pharmacological origins, formed a
separate factor. Twin analysis was used to test for genetic effects and to
determine whether these factors, although combined phenotypically, were affected
by distinct genetic or environmental influences. Genetic effects accounted for a
significant amount of the variance in the four hypothesized pharmacological
motives for smoking, as did shared environment. The separate factor for Automatic
smoking in the phenotypic analysis was due to environmental effects, and shared
environment was a greater influence on Automatic smoking for women than men. One
common effect explained the genetic variance; no genetic influence uniquely
affected any specific motive. Therefore, individual differences in the
hypothesized pharmacological motives for smoking appear to originate from a
common genetic pathway.
PMID- 10765558
TI - Detection and mapping of quantitative trait loci for haloperidol-induced
catalepsy in a C57BL/6J x DBA/2J F2 intercross.
AB - A genomewide scan was conducted to detect quantitative trait loci (QTLs) for
haloperidol-induced catalepsy in a C57BL/6J (B6) x DBA/2J (D2) F2 intercross (N =
678). Significant QTLs (LOD, > 4.3) were detected on chromosomes 1 and 9. The
relative position of the QTL on chromosome 1 is similar to open-field activity
QTLs previously identified by Flint et al. (1995) and Gershenfeld et al. (1997).
Given the broad confidence intervals for these QTLs, such associations must be
viewed cautiously. However, these data are consistent with the report of Kline et
al. (1998), who found a significant genetic associations between catalepsy and
open-field activity. The QTL interval on chromosome 9 stretched from
approximately 25 to 55 cM; this region contains numerous candidate genes,
including Drd2, Ncam, Acat1, and Htr1b. The data also suggest the presence of a
second QTL on chromosome 9 (LOD, > 3.5) in the proximal region of the chromosome.
Potential candidate genes in this region include Penk2 and Gria4. Overall, these
data support our previous observation (Kanes et al., 1996) that for the B6 x D2
genotypes, one or more polymorphisms on chromosome 9 are associated with the
variance in haloperidol response.
PMID- 10765559
TI - Is mitochondrial DNA involved in mouse behavioral laterality?
AB - The genetic effect of mitochondrial DNA (mtDNA) on behavioral laterality was
investigated in a quartet of strains of laboratory mice congenic for mtDNA. The
pattern of restriction of mtDNA differed in NZB/BINJ and CBA/H mice. Their
respective congenics for mtDNA were developed until the 22nd generation. This
quartet was tested under three independent conditions involving fore- and hind
paw preference or performance (laterality tests) and body orientation. Evidence
for the implication of mtDNA was observed on direction of laterality in two test
conditions and on degree of laterality in the three test conditions.
PMID- 10765560
TI - A quantitative genetic analysis of locomotor activity in CXB recombinant inbred
mice.
AB - Recent studies have identified genes that influence the length of the circadian
period maintained by mice housed under constant lighting conditions. However, a
less studied circadian activity variable is the amplitude of daily oscillations
in locomotor activity. This parameter reflects spontaneous activity exhibited
under standard lighting and housing conditions and, therefore, differs
conceptually from assessments of exploratory or open-field activity, voluntary
wheel-running, or circadian period during exposure to constant light or constant
darkness conditions. We recently observed a greater daily amplitude of
oscillation in spontaneous locomotor activity in C57BL/6 mice compared to
BALB/cBy mice. To identify genetic loci with potential linkage to circadian
variation in the amount of locomotor activity, we measured the spontaneous
activity of 13 CXB recombinant inbred (RI) strains of mice. The probability
density distributions of locomotor activity phenotypes for the 13 CXB RI strains
were consistent with the presence of a low number of major quantitative trait
loci affecting this trait. Regions of chromosomes 3, 8, 12, 13, and 19 showed
provisional linkage to strain variation in locomotor activity. Probabilities of
linkage were not sufficient for declaration of an activity-related quantitative
trait locus but were sufficient to warrant further analysis either with
additional RI strains or with F2 panels.
PMID- 10765561
TI - A quantitative genetic analysis of slow-wave sleep and rapid-eye movement sleep
in CXB recombinant inbred mice.
AB - Various inbred strains of mice show different daily amounts of slow-wave sleep
(SWS) and rapid-eye movement sleep (REMS), suggesting the possibility of genetic
influences on sleep propensity. Previous work by others studying the spontaneous
sleep patterns of seven strains of CXB recombinant inbred (RI) mice suggested
several candidate quantitative trait loci (QTLs) associated with variation in
REMS. Extending this approach, we evaluated the sleep patterns of 13 CXB RI
strains and conducted linkage analyses based on 223 discrete informative loci.
The probability density distribution of light phase REMS for the CXB RI strains
showed deflections that correspond approximately to the parental phenotypes. This
type of pattern is consistent with the presence of a low number of major effect
quantitative trait loci. Regions of chromosomes 4, 16, and 17 showed provisional
linkage to strain variation in REMS. The distribution of loci further suggested
that dark phase and light phase REMS may be regulated by different genetic
factors. Probabilities of linkage were not sufficient for declaration of a
quantitative trait locus for REMS but were sufficient to warrant further analysis
either with additional RI strains or with F2 panels.
PMID- 10765563
TI - Metacognitive knowledge about problem-solving methods.
AB - BACKGROUND: The effective application of a problem-solving method requires the
knowledge of what task is relevant, what the abilities involved are and how much
effort is needed. However, as yet too little is known about these metacognitive
representations. AIM: This study was aimed at describing beliefs about problem
solving methods and at assessing whether they vary according to the kind of
method and of problem and are modified by psychological courses attended. SAMPLE:
Forty-six Italian undergraduates in psychology and 37 in non-psychological
disciplines. METHODS: Participants had to rate how frequently each of five
problem-solving methods (free production, analogy, step-by-step analysis,
visualisation and combining) is employed and how effective and easy each one is
to apply. Ratings were requested for interpersonal, practical and study problems.
Participants were also asked to identify which abilities they thought would be
involved in each method. RESULTS: According to students' ratings, the most
frequently used problem-solving method was analogy, which was also considered the
easiest method to apply, whereas step-by-step analysis and combining were
considered the most difficult. Problem-solving techniques were perceived as being
relevant above all for practical problems, whereas they were conceived as less
suitable for interpersonal problems. For study problems the most relevant
strategy was step-by-step analysis. Students were aware of the abilities relevant
to each problem-solving method. CONCLUSIONS: Undergraduates both in psychology
and non-psychological disciplines can identify some critical features in the
methods used to solve problems, even though some misconceptions emerged. Since
metacognition plays a causal role in problem-solving, trainers should take into
account trainees' folk representations of problem-solving strategies.
PMID- 10765562
TI - A quantitative genetic analysis of slow-wave sleep in influenza-infected CXB
recombinant inbred mice.
AB - Influenza-infected C57BL/6J mice spend increased amounts of time in slow-wave
sleep (SWS) during the dark phase of the circadian cycle compared to healthy
mice. In contrast, infected BALB/cByJ mice show a normal or reduced time in SWS,
particularly during the light phase. To identify genetic loci with linkage to
these traits, we measured sleep in 13 CXB recombinant inbred (RI) strains derived
from a cross between C57BL/6ByJ and BALB/cByJ mice. The probability density
distribution of sleep patterns of influenza-infected CXB RI mice showed modes
that correspond roughly with the parental modes during the dark phase of the
circadian cycle and are intermediate or C57BL/6-like during the light phase.
These patterns are consistent with the presence of a low number of major effect
quantitative trait loci (QTLs). Chromosomal regions with provisional association
to strain variation in influenza-induced SWS patterns were identified. In
particular, a 10- to 12-cM interval on Chr 6 between D6Mit74 and D6Mit188
contains a QTL (LRS = 16.6 at 1 cM proximal to D6Mit316; genomewide p < .05) that
influences the SWS response to influenza infection during the light phase. We
have provisionally named this QTL Srilp1 (sleep response to influenza, light
phase 1). Candidate genes for mediation of this phenotype include Ghrhr (growth
hormone releasing hormone receptor), Crhr2 (corticotropin releasing hormone
receptor 2), and Cd8a (an epitope on cytotoxic T lymphocytes). Several other
intervals achieved suggestive probability scores that are sufficient to warrant
further analysis either with additional RI strains or with F2 panels. The
analysis also suggests that dark phase and light phase responses are regulated by
different genetic factors.
PMID- 10765564
TI - An evaluation of the factor structure and predictive utility of a test anxiety
scale with reference to students' past performance and personality indices.
AB - BACKGROUND: Scales of test anxiety have developed in parallel with the evolution
of the test anxiety construct. A recently refined version of the Revised Test
Anxiety scale offers the prospect of independently assessing different test
anxiety factors. AIMS: The study aims to ascertain if the four-factor structure
of the RTA scale found in Egyptian and American samples can be replicated in an
Irish sample, and to examine the comparative predictive utility of cognitive and
emotionality factors in relation to examination performance. The study also
examines whether results support an Interference or Deficits Model of test
anxiety, and assesses the relationship of test anxiety to personality variables
believed to be relevant to academic performance. SAMPLE: The participants were
117 male and female psychology students from the University of Ulster. Their
average age was 23 years. METHOD: Data were analysed using correlation analysis,
multiple regression, factor analysis and ANOVA. Examination performance was the
criterion variable; predictor variables were the four factors of test anxiety,
three personality measures and previous examination performance. RESULTS: Four
factor test anxiety invariance across diverse population is supported by the
model in the analysis. Cognitive factors are significant negative predictors of
performance. The data do not support either an Interference or Deficits Model of
test anxiety, and personality factors, especially self-efficacy, were
significantly (negatively) related to test anxiety. CONCLUSIONS: The two
cognitive factors have emerged as the most substantial negative predictors of
examination performance. Attention to these factors and to relevant personality
indices are commended as a potentially fruitful strategy for remedial
intervention.
PMID- 10765565
TI - Effects of student teachers' coping behaviour.
AB - BACKGROUND: When teachers employ ineffective ways of coping with stressful
encounters with pupils, this may result in feelings of distress and diminished
learning opportunities for pupils. In the case of beginning teachers, in
particular, problematic classroom interactions cause feelings of distress and may
result in dysfunctional teaching. AIM: This study examined the functional
relationship between student teachers' coping behaviour and the immediate
outcomes resulting from stressful encounters in the classroom. SAMPLE: About 300
responses related to problematic events were studied in a sample of 27 student
teachers enrolled in a graduate teacher education programme. METHOD: We assessed
the daily difficulties which the participants experienced in the classroom, the
ways they coped with these events, and two immediate outcomes (the pupils' time
on-task and the student teachers' satisfaction with the outcome). RESULTS: In
situations where pupil misbehaviour had been appraised as problematic, student
teachers demonstrated effective coping behaviour when they consistently raised
tension in the interaction with their pupils, and varied the intensity of
activities. As expected, the relation between coping behaviour and pupils' time
on-task was less strong in other classroom events (e.g., instruction or classroom
organisation). CONCLUSIONS: Student teachers have to be intrusive in order to
change pupils' misbehaviour and get them working. Inactive behaviour on the part
of student teachers was found to be ineffective in changing pupil misbehaviour.
However, we cannot conclude that a particular coping behaviour employed by
student teachers is effective or dysfunctional in changing pupils' time-on-task
without examining long-term outcomes as well.
PMID- 10765566
TI - Implicit and explicit dialogue structuring in virtual learning groups.
AB - BACKGROUND: The promotion of virtual learning groups by instructional means is
gaining importance with the spread of telematic learning. In virtual learning
groups, students discuss certain learning materials or cooperate in problem
solving by means of computer-mediated communication. Due to the specific features
of electronic communication, supportive means appear to be necessary for such
learning situations. AIMS: The investigation focuses on testing two different
forms of dialogue structuring in virtual learning groups, in which students
discuss a given subject matter together and clarify problems in understanding by
means of synchronous computer-mediated communication. SAMPLE: Forty-five students
from various disciplines at the University of Tubingen, except students of
physics, participated in the investigation. METHOD: An experiment was conducted
involving three-person groups in a telematic setting with two different kinds of
dialogue structuring: implicit structuring induced group discussion on the
subject matter by working on key questions in a preceding learning phase, whilst
explicit structuring provided additional rules for discussion. These rules
prompted group members to argue and aimed at directing them to equal
participation. RESULTS: Compared to a control group, both implicit and explicit
structuring showed greater orientation on the subject matter and showed less off
task talk. Moreover, explicit structuring led to more coherence in subject matter
discussion with regard to the completion of topics. However, post-test
performance showed no significant difference in knowledge over that of the
control group. CONCLUSION: The results of the investigation show that dialogue
structuring can be an adequate pedagogical approach for virtual learning groups.
PMID- 10765567
TI - The role of repetition in the processes of memorising and understanding: a
comparison of the views of German and Chinese secondary school students in Hong
Kong.
AB - BACKGROUND: Previous research has found that students and teachers in countries
of the Far East often see memorization and understanding as working together to
produce higher quality outcomes. In contrast, in the West it is more common to
associate memorizing with 'surface' and understanding with 'deep' approaches to
learning. AIM: The main purpose of this study was to explore and describe the
experiences of the role of repetition in the processes of memorizing and
understanding among students with Western (German) and Asian (Chinese)
backgrounds. In particular, we were interested in finding indications of possible
cultural differences in the experiences of the two ethnic groups. SAMPLE: The
participants were 48 Chinese (HKC) and 18 German senior secondary school students
in Hong Kong. METHOD: The study used a qualitative research approach. Data were
gathered by semi-structured in-depth interviews. Interview transcripts were
analysed in order to uncover, categorize and describe the variation of
experiences and conceptions of the role of repetition. The two ethnic groups were
then compared as to how many interviews were found in each category. RESULTS: A
similar proportion of both groups remembered being encouraged to recite by their
parents, but the HKC students more often said they were made to recite by their
primary teachers. While the HKC students focused on the value of the content of
these early memories, the German students focused on the value of the activity
itself. Moreover, while the German students tended to downplay the role of
repetition in the process of understanding, the HKC students sometimes emphasized
repetition combined with 'attentive effort'. By such effort they tried to
discover new meanings in the materials studied, in order to deepen their
understanding. CONCLUSION: While the findings of this study cannot be considered
definitive, it is suggested that the emphasis on attentive effort among HKC
students is consistent with a traditional, Confucian perspective on learning. The
results also indicate that 'the intention to both memorize and understand', found
in previous investigations of the study approaches of HKC students, may arise out
of being simultaneously aware of two possibilities inherent in repetition:
creating a deep impression on the mind and discovering new meaning. Finally, it
is argued that the differences between the two ethnic groups are consistent with
earlier research findings that Chinese, unlike Western, students tend to consider
effort attributions more salient than ability attributions.
PMID- 10765568
TI - Pupils' causal attributions for difficult classroom behaviour.
AB - BACKGROUND: Studies of causal attributions within educational contexts have
tended to concentrate on academic performance. There have been a smaller number
of investigations of teachers' attributions for pupils' behaviour in school.
AIMS: The present study examines the causal attribution made by pupils for
difficult behaviour in classrooms. It reveals the structure of these attributions
and serves as a comparison with the teacher studies. SAMPLE: The participants
were 105 pupils (52 males and 53 females) in the first year of secondary
schooling, all drawn from the same inner city school. METHOD: Four initial small
group interviews were used to identify a wide range of factors that pupils viewed
as being causes of difficult classroom behaviour in the 18 primary schools they
had previously attended. A questionnaire was then constructed incorporating items
from these discussions and administered to the whole of the year group of pupils,
but omitting the participants in the initial group discussions. RESULTS: The
results of a factor analysis indicated that pupils' attributions for misbehaviour
at school were best represented by four factors: (1) 'fairness of teacher's
actions', (2) 'pupil vulnerability', (3) 'adverse family circumstances' and (4)
'strictness of classroom regime'. While there were no gender differences, pupils
saw the 'fairness of teacher's actions' and 'pupil vulnerability' as more
significant contributors to pupil misbehaviour than either 'adverse family
circumstances' or 'strictness of classroom regime'. CONCLUSION: The attributions
by pupils for difficult classroom behaviour differ markedly from those obtained
in studies of teachers. Policy and practice initiatives which do not attend to
conflicting attributional styles are unlikely to succeed in improving levels of
pupil behaviour in schools.
PMID- 10765569
TI - The maintenance of cooperative and helping behaviours in cooperative groups.
AB - BACKGROUND: This study was a full-year investigation of whether children, who had
previously been trained to cooperate and help each other, were able to use these
behaviours in reconstituted groups without additional training one year later.
AIMS: (i) To examine whether children who have previously been trained to
cooperate demonstrate more cooperative and helping behaviours in their groups
than children who had no been trained and (ii) to determine the effect of prior
training on children's learning. SAMPLE: The study involved 144 Grade 2 children
(mean age = 94.5 months; third year of schooling), from nine schools in a similar
socio-demographic area of Brisbane, Australia. Sixty-four children, who had been
trained in cooperative group behaviours in the previous year, were assigned to
the Trained groups and 80 children, who had not received any training, were
assigned to the Untrained groups. METHOD: The children worked in four-person,
mixed-ability (high-, medium-, and low-ability), gender-balanced groups (2 males,
2 females) for one six-week social studies unit of work each term for three
school terms. Videotaping occurred in the 5-6 week of each work unit. Videotapes
were coded for behaviour and verbal interactions. Learning outcomes data were
also collected. RESULTS: The children in the trained groups exhibited more
cooperative behaviour and they provided more explanations, both in response to
explicit and implicit requests for help across the three periods of time. The
children in the trained groups used higher level cognitive strategies such as
providing specific concrete facts and reasons in their interactions and they also
obtained higher scores on the learning outcomes questionnaire than their
untrained peers. CONCLUSION: Young children who have been trained to cooperate
and help each other are able to demonstrate these behaviours in reconstituted
groups without additional training a year later.
PMID- 10765570
TI - Non-formal learning and tacit knowledge in professional work.
AB - BACKGROUND: This paper explores the conceptual and methodological problems
arising from several empirical investigations of professional education and
learning in the workplace. AIMS: 1. To clarify the multiple meanings accorded to
terms such as 'non-formal learning', 'implicit learning' and 'tacit knowledge',
their theoretical assumptions and the range of phenomena to which they refer. 2.
To discuss their implications for professional practice. METHOD: A largely
theoretical analysis of issues and phenomena arising from empirical
investigations. ANALYSIS: The author's typology of non-formal learning
distinguishes between implicit learning, reactive on-the-spot learning and
deliberative learning. The significance of the last is commonly overemphasized.
The problematic nature of tacit knowledge is discussed with respect to both
detecting it and representing it. Three types of tacit knowledge are discussed:
tacit understanding of people and situations, routinized actions and the tacit
rules that underpin intuitive decision-making. They come together when
professional performance involves sequences of routinized action punctuated by
rapid intuitive decisions based on tacit understanding of the situation. Four
types of process are involved--reading the situation, making decisions, overt
activity and metacognition--and three modes of cognition--intuitive, analytic and
deliberative. The balance between these modes depends on time, experience and
complexity. Where rapid action dominates, periods of deliberation are needed to
maintain critical control. Finally the role of both formal and informal social
knowledge is discussed; and it is argued that situated learning often leads not
to local conformity but to greater individual variation as people's careers take
them through a series of different contexts. This abstract necessarily simplifies
a more complex analysis in the paper itself.
PMID- 10765571
TI - An Advisory Committee Statement (ACS). Committee to Advise on Tropical Medicine
and Travel (CATMAT). Statement on meningococcal vaccination for travellers.
AB - The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides Health
Canada with ongoing and timely medical, scientific, and public-health advice
relating to tropical infectious disease and health risks associated with
international travel. Health Canada acknowledges that the advice and
recommendations set out in this statement are based upon the best current
available scientific knowledge and medical practices, and is disseminating this
document for information purposes to both travellers and the medical community
caring for travellers. Persons administering or using drugs, vaccines, or other
products should also be aware of the contents of the product monograph(s) or
other similarly approved standards or instructions for use. Recommendations for
use and other information set out herein may differ from that set out in the
product monograph(s) or other similarly approved standards or instructions for
use by the licensed manufacturer(s). Manufacturers have sought approval and
provided evidence as to the safety and efficacy of their products only when used
in accordance with the product monographs or other similarly approved standards
or instructions for use.
PMID- 10765572
TI - The Quebec midwifery experiment: lessons for Canada.
PMID- 10765573
TI - Putting the population into population health.
PMID- 10765574
TI - Exposure of school employees to extremely low frequency magnetic fields.
AB - This study was initiated to determine and compare daily occupational exposure
(OE) and non-occupational exposure (NOE) of three employee groups of teachers,
maintenance workers and secretarial staff in a Canadian school district. The time
weighted average (TWA) individual OE for subjects ranged from 0.4-3.8 milligauss
(mG), and the TWA NOE ranged from 0.2-7.1 mG. TWA OE and NOE were 1.2 mG and 1.5
mG for teachers, 1.8 mG and 1.2 mG for maintenance workers, and 2.9 mG and 2.1 mG
for secretarial staff. The differences between TWA OE and NOE of each group and
also among the three groups were not statistically significant. OE and NOE of
secretarial staff exceeded 10 mG 9.0% and 6.4% of the time--significantly (p <
0.001) higher rates than those of OE and NOE of teachers (1.0% and 1.4%) and
maintenance workers (2.8% and 0.1%). Exposures were well below recommended
criteria.
PMID- 10765575
TI - Drug testing in Canadian jails: to what end?
AB - Since 1995, Corrections Services Canada (CSC) has conducted randomized urinalysis
screening of a minimum of 5% of the federal inmate population on a monthly basis.
Urine samples are screened for a broad range of psychoactive substances. The
stated purpose of such screening is to reduce substance use in federal jails.
Analysis of data provided by CSC for testing between 1994 and 1998 reveals small
but statistically significant increases in the percentage of all urine samples
that tested positive over that time. Analysis of the results of screening for
opiates, cocaine and THC from data provided by CSC for the same time period,
shows steady rates of opiate and cocaine detection at maximum and medium levels
of security, decreases in opiate and cocaine detection in minimum security, and
statistically significant increases in THC detection at all levels of security.
The implications of these findings are discussed.
PMID- 10765576
TI - Knowledge and use of emergency postcoital contraception by female students at a
high school in Nova Scotia.
AB - PURPOSE: This study was performed in the context of a sexual health promotion
project in a Nova Scotia community. Community members wanted information about
adolescent females' knowledge and use of emergency contraception (EC). The study
was done to meet this need. METHODS: Female high school students aged 14 to 19
were administered a self-completion survey asking about their knowledge of EC,
the time frame for its use, its effectiveness, their personal use of EC,
unsuccessful attempts to obtain EC, and sources of knowledge of EC. RESULTS:
Eighty-five percent of 411 female students participated. Eighty percent knew
about EC, though few (8%) knew the time frame for EC use. Most (42%) heard of EC
at school. Eighteen percent used no contraception at last intercourse. Only 2%
ever had used EC. CONCLUSIONS: Adolescent women know about EC but use it
infrequently, even though they frequently lack contraception. These findings
raise questions about alternative methods for providing EC to young women.
PMID- 10765577
TI - Do condoms in public schools affect the pregnancy rate?
PMID- 10765578
TI - Canadian National Survey on Sun Exposure & Protective Behaviours: outdoor
workers.
PMID- 10765579
TI - The history of injury and industrial disease rates in British Columbia from 1950
to 1996.
AB - The purpose of this investigation is to describe changes in industrial injury and
disease rates in British Columbia between 1950 and 1996. Data on injury and
disease rates were abstracted manually from WCB Annual Reports for the years 1950
through 1996. A number of interesting patterns emerge. Death report rates
declined by 79% during the study period. Injury report rates also declined,
although less dramatically, by 29%, over the 46-year study period with much of
the decrease occurring prior to 1970. Accepted claims for impact injuries
declined prior to the 1970s. At the same time claims for strain injuries began to
increase with the pace of increase accelerating after 1970. A similar pattern was
observed for industrial disease as the incidence of strain-based disease claims
also increased rapidly after 1970. This pronounced trend towards "strain-related"
injuries and disease creates new challenges for adjudication and prevention. The
identification of work organizational and job structural features which
contribute to strain injury and disease and the elucidation of the relationship
between these conditions and "physical" strain injuries should be a priority for
injury epidemiologists and WCB.
PMID- 10765580
TI - Evaluation of the midwifery pilot projects in Quebec: an overview. L'Equipe
d'Evaluation des Projets-Pilotes Sages-Femmes.
AB - In 1990, the province of Quebec adopted a law authorizing the evaluation of the
practice of midwifery through eight pilot projects. The projects, which took the
form of birth centres outside hospitals, started operating in 1994. The
objectives of the evaluation were 1) to compare midwives' services to current
physician services with regard to maternal and neonatal mortality and morbidity,
the use of obstetrical intervention, individualization and continuity of care as
perceived by clients, and cost; and 2) to identify the professional and
organizational factors associated with the integration of midwives into the
health care system. A mixed evaluative design was used: a multiple case study
with each pilot project representing a case and a cohort study where 1,000 women
followed by midwives in the birth centres were matched with 1,000 women followed
by physicians in the usual hospital-based services. Various quantitative and
qualitative data collection instruments were used. Overall, many results were
favourable to midwifery practice, while some were favourable to medical care.
Following the evaluation, the Government of Quebec decided to legalize the
practice of midwifery.
PMID- 10765581
TI - Comparison of midwifery care to medical care in hospitals in the Quebec pilot
projects study: clinical indicators. L'Equipe dEvaluation des Projets-Pilotes
Sages-Femmes.
AB - The purpose of this study was to compare indicators of process and outcome of
midwifery services provided in the Quebec pilot projects to those associated with
standard hospital-based medical services. Women receiving each type of care (961
per group) were matched on the basis of socio-demographic characteristics and
level of obstetrical risk. We found midwifery care to be associated with less
obstetrical intervention and a reduction in selected indicators of maternal
morbidity (caesarean section and severe perineal injury). For neonatal outcome
indicators, midwifery care was associated with a mixture of benefits and risks:
fewer babies with preterm birth and low birthweight, but a trend toward a higher
stillbirth ratio and more frequent requirement for neonatal resuscitation. The
study design does not permit to conclude that the associations were causal in
nature. However, the high stillbirth rate observed in the group of women who were
selected for midwife care raises concerns both regarding the appropriateness of
the screening procedures for admission to such care and regarding the quality of
care itself.
PMID- 10765582
TI - Cost-effectiveness of midwifery services vs. medical services in Quebec. LEquipe
dEvaluation des Projets-Pilotes Sages-Femmes.
AB - This study compared the cost-effectiveness of midwife services provided in birth
centres operating as pilot projects with current hospital-based medical services
in the province of Quebec. One thousand midwives' clients were matched with 1,000
physicians' clients on the basis of socio-demographic characteristics and
obstetrical risk. Direct costs for the prenatal, intrapartum and postpartum
periods were estimated. Effectiveness was assessed on the basis of three clinical
indicators and four indices related to the individualization of care as assessed
by women. Results show that the costs of midwife services were barely lower than
or equal to those of physician services, but cost-effectiveness ratios were to
the advantage of the midwife group, except for one clinical indicator (neonatal
ventilation). Overall, this study provides rational support for the process of
legalizing midwifery in the province.
PMID- 10765583
TI - Integration of midwives into the Quebec health care system. L'Equipe d'Evaluation
des Projets-Pilotes Sages-Femmes.
AB - This paper reports on one aspect of the evaluation of the midwifery pilot
projects in Quebec: the identification of the professional and organizational
factors, as well as the mode of integrating midwives into the maternity care
system, that would promote the best outcomes and the autonomy of midwives. The
research strategy involved a multiple-case study, in which each midwifery pilot
project represented a case. Based on a qualitative approach, the study employed
various sources of data: individual interviews and focus groups with key
informants, site observations and analyses of written documents. Results show
that midwives were poorly integrated into the health care system during the
evaluation. Four main reasons were identified: lack of knowledge about the
practice of midwifery on the part of other health care providers; deficiencies in
the legal and organizational structure of the pilot projects; competition over
professional territories; and gaps between the midwives' and other providers'
professional cultures. Recommendations are provided to facilitate the integration
of midwives into the health care system.
PMID- 10765584
TI - Tracking the use and impact of a community social report: where does the
information go?
AB - The purpose of this paper is to report on a study evaluating the extent to which
a social report (entitled "Hamilton-Wentworth Profile on Children and Youth") was
read and used by recipients. Subjects were divided into two groups: an Active
Group which had worked on producing the Profile and/or requested copies of it
once it had been released, and a Passive Group which had received copies of the
Profile through a general mailing list used for other research reports.
Approximately one year later, 90% of the Active Group recalled the Profile
compared to 21% of the Passive Group. Similarly, 83% of Active Group respondents
had read the Profile compared to 8% of Passive Group subjects. 80% of Active
Group respondents and 5% of Passive Group respondents used the Profile. The
results suggest that if social reports are read by local community agencies and
individuals, they will be used to help improve conditions for children and youth.
Social reports at the local level are more likely to be read if potential users
are engaged in the process of report production and if the reports are
disseminated to the appropriate target audience.
PMID- 10765585
TI - Increased neonatal readmission rate associated with decreased length of hospital
stay at birth in Canada.
AB - PURPOSE: To assess the potential impact of early post birth discharge in Canada.
METHODS: Neonatal readmission was examined, based on hospital discharge data from
the Canadian Institute for Health Information, with a total of 2,144,205 infants
from fiscal year 1989/90 to fiscal year 1996/97. RESULTS: Neonatal readmission
rates increased from 27.3 per 1,000 in 1989/90 to 38.0 per 1,000 in 1996/97,
while mean length of hospital stay at birth decreased from 4.2 days to 2.7 days
during the same period. The increase in readmission rate was more evident for
dehydration and jaundice. The provinces and territories with decreased length of
hospital stay at birth usually had increased neonatal readmission rate and
earlier age at readmission. Between 1994/95 and 1996/97, compared with
Newfoundland, the risks for neonatal readmission for dehydration were 5.7 and
5.5, and for jaundice were 4.5 and 2.7, respectively, for Alberta and Ontario.
CONCLUSION: Neonatal readmission rates for several conditions have increased
substantially, associated with early post birth discharge policies adopted in
Canada.
PMID- 10765586
TI - How Baby-Friendly are Manitoba hospitals? The Provincial Infant Feeding Study.
Breastfeeding Promotion Steering Committee of Manitoba.
AB - The Breastfeeding Promotion Steering Committee of Manitoba conducted the cross
sectional Provincial Infant Feeding Study in 1996 to examine: correlation between
breastfeeding policies and actual practices in Manitoba hospitals; compliance
with Baby-Friendly Hospital Initiative (BFHI) criteria; and associations between
hospital practices and two-week breastfeeding duration. Three separate surveys
obtained information from: administrators concerning hospital policy; nursing
staff concerning hospital practices; and all women giving birth in a five-week
period, concerning breastfeeding rates and maternal perceptions of hospital
practices. The results highlighted the need for policy and practice changes to
comply with BFHI criteria. 92% initiated breastfeeding, and 84% were
breastfeeding at two weeks postpartum. Independent predictors of weaning
included: in-hospital supplementation (adjusted RR = 2.1, 95% CI 1.02-4.36, p =
0.04); temporarily interrupting breastfeeding while in hospital (adjusted RR =
4.9, 95% CI 2.7-8.9, p = 0.0001); no previous breastfeeding experience (adjusted
RR = 2.5, 95% CI 1.4-4.4, p = 0.002); and Grade 12 or less maternal education.
PMID- 10765587
TI - Heart disease and stroke in Canadian women: policy development.
PMID- 10765588
TI - [Recruitment of Montreal women of very low socioeconomic status for a randomized
clinical study].
AB - Studies show that it is difficult to recruit women of low socioeconomic status as
clinical research participants. Such an objective was attained though as our
results demonstrate in an evaluative study of a program implemented to lower the
percentage of low birthweight in four CLSCs of the Island of Montreal between
1994 and 1996. The global recruitment strategy enabled us to reach 56.2% of our
goal in 1994 and 77.4% in 1996. Two conclusions can be drawn from this result:
the effectiveness of the three methods of recruitment varied according to each
participating CLSC, and the global strategy, combined with the mobilization of
community resources, was successful in enrolling women of low socioeconomic
status.
PMID- 10765589
TI - Prevalence of depression among the elderly Chinese in Canada.
PMID- 10765590
TI - Using the U.S. Behavior Risk Factor Surveillance System's health related quality
of life survey tool in a Canadian city.
AB - As responsibility for health funding shifts from central to local governments,
providers find themselves in decision-making roles or asked to give guidance in
allocation of resources. To develop a picture of a population's health, data are
needed about the effects that illness and disability have on a person's ability
to function and thus on quality of life. This study assessed the validity in a
Canadian city, of a Health-related Quality of Life (HRQoL) instrument developed
by the US Centers for Disease Control and used in the US Behavioral Risk Factor
Surveillance System. The HRQoL was administered to a random sample of 1,042
adults. The patterns of association among the HRQoL questions, and the direction
of the relationships among independent variables and HRQoL were consistent with
those hypothesized. The accumulating evidence for validity of the HRQoL support
its use in monitoring the performance of local health initiatives in Canada.
PMID- 10765591
TI - Pertussis in adolescents and adults.
PMID- 10765592
TI - [Clinical method of newborn's maturity evaluation according to R. Klimek's
index].
AB - The object of the study was to evaluate R. Klimek's new simple clinical method of
computing newborn's maturity index (K) without having to use the computer-aided
method or understand the basics of the quantum mechanics or theory of relativity,
which gave rise to the modern definition of maturity. The study was based on the
material of 1000 successive newborns delivered in the Clinic of Gynecology and
Obstetrics of the Jagiellonian University. Their maturity was determined
routinely in BK scale, and confirmed by means of computer-aided method of birth
term prognosis. Posture, angle of the elbow, pulling an elbow to the middle line
of the body, breast appearance, presence of lanugo and plantar creases were
evaluated by means of K index with points from 0 to 2. Newborns' maturity index K
was 9.2 +/- 1.9 points (range 2-12). 2.6% newborns were immature and one third of
them (0.8%) were born with the gestational age < 37 weeks, 28 of which (77%) had
correct K index > or = 6 points. There is a high, statistically significant
correlation between maturity assessed in Ballard-Klimek scale and K index (r =
0.61, t = 24.78).
PMID- 10765593
TI - [N-acetyl-beta-glucosaminidase (NAG) activity in parturients with placental
insufficiency in postmature pregnancy and with EPH-gestosis].
AB - NAG activity evaluation was carried out in parturients' blood and placental
homogenates in regular pregnancies (n = 46) and complicated with biological
postmaturity (n = 30) and EPH-gestosis (n = 24). It was revealed that in the
blood of parturients with pregnancy complicated with gestosis there was
considerable increase of NAG activity (2.43 +/- 1.02 microKat/kg). Lower activity
level was found in parturients with entopic pregnancy (1.93 +/- 0.87
microKat/kg), and the lowest in those with postmature pregnancy (1.78 +/- 0.56
microKat/kg). The placental homogenates presented statistically significant
differences--the highest in postmature pregnancy (6.37 +/- 2.01 mKat/kg), lower
in pregnancy complicated with gestosis (4.85 +/- 1.52 mKat/kg) and the lowest in
normal pregnancy (3.52 +/- 1.21 mKat/kg). The elevated activity in blood serum of
parturient with gestosis may indicate kidney damage in the course of disease.
High activity in homogenate may indicate the processes of placental degradation
in postmature pregnancy. There is no evidence of correlation between NAG activity
in blood and activity in placental tissue.
PMID- 10765594
TI - [Aminopeptidases activity in the amniotic fluid in women in labor with EPH
gestosis].
AB - The thesis of this work was to compare the aminopeptidases activity in the
amniotic fluid obtained during the physiological labor and during the labor of
pregnant with EPH-gestosis, in presence of the beta-naphtlamidic L-amino-acids
(alanine, leucine, phenylalanine, tyrosine, histidine, cysteine) chromogenic
substrates. It was assumed the 3-7 times increase in the aminopeptidases activity
counted to the proteins from the labored with EPH-gestosis comparing to the
labored in physiological labor. Among the used substrates the highest activity in
both groups of labored women was measured in presence of substrates with exact
amino-acids in this order: L-Ala > L-Leu > L-Phe > L-Tyr > L-His > L-Cys.
PMID- 10765595
TI - [Molecular analysis of protein 4.1 gene in teratozoospermic and azoospermic
patients].
AB - In normal sperm, the 135 kD isoform of protein 4.1 is replaced by the 80 kD
variant. Transcript for protein 4.1 loses the 'upstream' initiation codon by a
stage-dependent alternative splicing and in mature sperm only 'downstream'
initiation codon is active. A mutation in the 'downstream' initiation codon may
be a reason for sperm differentiation arrest (azoospermia) or can be associated
with the presence of amorphous spermatozoa in ejaculate (teratozoospermia). The
aim of the study was the molecular analysis of gene coding for the protein 4.1,
carrying a 'downstream' translation initiation codon. We have screened DNA
samples obtained from azoospermic (blood) and teratozoospermic (spermatozoa)
patients using PCR amplification of gene fragment, AUG containing exon with
subsequent digestion (NlaIII) of CATG sequence. The absence of a cleavage site
for this restriction enzyme would suggest the presence of mutation in the AUG
codon. Analysis of DNA samples obtained from both azoospermic and
teratozoospermic patients did not reveal any changes in the 'downstream'
translation initiation codon. We concluded therefore that observed by others a
defective expression of protein 4.1 in amorphous sperm cells is probably due to
the other factor(s) than mutation in the 'downstream' translation initiation
codon.
PMID- 10765596
TI - [The effectiveness of the pimafucin 100 mg pill for intravaginal treatment of
vaginal candidiasis].
AB - The aim of this multicentre prospective study was assessing the effectiveness of
intravaginal treatment of vaginal candidiasis with Pimafucin 100 mg ovule.
Success was obtained among 81% pregnant and 86% nonpregnant women. The negative
predictive factors were intensive patients complains: pruritus or soreness.
PMID- 10765597
TI - [Total or subtotal hysterectomy?].
AB - We compared the risk and benefits subtotal (supracervical) hysterectomy and total
hysterectomy in women with nonmalignant conditions (perioperative mortality,
intra- and postoperative complications, quality of life, long-term effects on
other diseases). The main disadvantage of subtotal hysterectomy over total one is
the fact, that in 1 per 1000 women develops carcinoma in cervical stump.
CONCLUSION: Total hysterectomy is recommended in benign conditions of the uterine
corpus.
PMID- 10765598
TI - [Evidence-based medicine and medical databases in obstetrics and gynecology].
AB - Evidence-based medicine is a new trend in both teaching medicine and supporting
the clinical decisive process, answering the clinical questions. The basis of the
evidence-based medicine comprises of analysing and interpreting current and
reliable medical publications concerning certain subject. The important
condition, which has to be fulfilled is a possibility of an easy access to
current medical information--via internet, medical publications' databases and
publications themselves. It is crucial to use the proper hardware system (local
net) and proper software system--tools for using evidence-based medicine.
Regarding the medical research, nowadays, database systems became unavoidable. By
using such a programs process of data collection, control and analysis became
both easier and more reliable thanks to eliminating many "human based" errors. In
following paper own experience in introducing evidence-based medicine and medical
databases in the field of obstetrics and gynaecology will be presented.
PMID- 10765599
TI - [Report from Ist international symposium for gynecologist "Child sexual abuse:
diagnosis and treatment"].
PMID- 10765600
TI - [Evaluation of the hormonal replace therapy (HRT) effect on generation of
reactive oxygen intermediates (ROI) by neutrophil in peripheral blood of
menopausal women].
AB - About 30% of women population in Poland is already in the perimenopausal age. HRT
(hormonal replacement therapy) is the best way of diminishing the unfavorable
symptoms of this state. AIM OF STUDY: The effect of HRT on ROI production by
neutrophils before and after HRT, to determinate it's antioxidative influence on
cells. MATERIAL: We have examined 40 women both from the Dept. of Menopausal
Disease in the Research Institute Polish Mother's Memorial Hospital (RIPMMH) and
Out Patient Menopausal Clinic of RIPMMH with average age of 49.8; between October
1997 and January 1998. METHODS: We determined ROI generation by luminol-enhanced
chemiluminescence, using standard stimuli like fLMP, PMA and OZ. We used
Luminometer 1251, manufactured by Pharmacia-LKB. For statistic evaluation Fisher
test, Kolmogorow-Smirnow test and T-student test were used. RESULTS: We found
that estrogen-progestagen therapy had a suppressive effect on generation of ROI
by neutrophils in vitro and in vivo after using receptor dependent and non
dependent stimuli. ROI generation by neutrophils of peripheral blood induced by
PMA, a receptor dependent stimuli, is diminished, both, after HRT or as an effect
of estrogen-progestagen action in vitro. The results suggest direct inhibition
effect on the neutrophil ability to ROI generation.
PMID- 10765601
TI - [Immunohistochemical examination oncogenic c-erb-b2, egf-r proteins and
antioncogenic p53 protein in vulvar cancers HPV-16 positive and negative].
AB - In vulvar cancers HPV 16 positive, HPV 16 negative, and vulvar and vaginal
precancerous status (VIN, VAIN) immunohistochemical technik onko- and
antioncogenic proteins were evaluated. The contrary correlation between HPV 16
presence and overexpression p53 were detected. It suggest the heterogenic
etiology of these cancers. There was payed attention to high activity of virus
replication and intensive virion production in VAIN. Nontreated vaginal lesion
may make difficult to obtain a positive cervical HPV infection treatment.
PMID- 10765602
TI - [Biomarkers in primary ovarian cancers and after chemotherapy].
AB - The authors analyzed the expression of oncogen and antioncogen proteins using
immunoperoxidase technique with monoclonal antibodies in 49 primary ovarian
carcinomas and 38 cancers after chemotherapy (second look) There was not found
independent prognostic marker. But some results suggest, that in the individual
cases estimate proliferative activity and overexpression P53 may give some
information about intensitivity and quality of chemotherapy.
PMID- 10765603
TI - [The phenotype characteristics of cord blood lymphocytes in premature neonates].
AB - It has been observed high risk of infections in neonates as a result from
lymphocytes immaturity. It is connected to phenotype differences of lymphocytes
between neonates and adults. This high susceptibility to infections is especially
high in premature neonates. With the use of flow cytometry we have evaluated the
phenotype of cord blood lymphocytes in premature neonates. In comparison to
results of healthy newborns we have observed significant decrease in CD7+, CD3+,
CD4+, CD25+, CD57+ lymphocytes an increase in total number of CD8+ cells as well
as alteration in CD4/CD8 ratio. Our results suggest deeply damage of cellular
immunity in preterm infants.
PMID- 10765605
TI - [Estrogen receptor: superfamily of thyroid hormone receptors].
AB - Estrogen signal transduction plays an important role in mammary tissue. The
principal mechanism by which the effects of estrogen are mediated by target
tissues is via an initial interaction with the estrogen receptor (ER), a member
of the steroid/thyroid/retinoid receptor gene superfamily. The ER can be isolated
from the cytosol of target cell extracts as a large nontransformed 7-8S
oligomeric complex, which contains hsp 90 and hsp 70. Like other steroid
receptors, ER has six regions, A-F. The DNA-binding (region c) and the ligand
binding (region) domains of ER alpha and beta show 96% and 55% amino acid
sequence homology, respectively. The other regions (the hypervariable A/b domain,
the hinge region D, and the C-terminal F-domain) are less conserved. The heat
shock proteins function help fold the ER protein properly and to protect the
hydrophobic hormone binding domain from inappropriate interactions. Recently, a
novel ER, referred to as ER-beta was cloned and characterized rat prostate.
PMID- 10765604
TI - [The influence of antenatal TRH and glucocorticoids therapy for survival rate of
extremely low birth infant].
AB - Respiratory distress syndrome (RDS) as a consequence of lung immaturity remains a
major cause of perinatal morbidity and mortality. TRH used with glucocorticoids
shows synergistic influence on surfactant synthesis and morphological lung
maturation in preterm born infants. The purpose of this study was to examine the
influence of antenatal TRH + glucocorticoids treatment on survival rate of
extremely low birth infants (less than 1000 g). We evaluated 94 premature
neonates born between 1993 and 1997 at the Department of Obstetrics and
Perinatology of University School of Medicine in Lublin. Better survival rate of
extremely low birth infants was observed in the TRH + steroids group then in only
steroids one. The ratio of RDS was similar in both groups. Further investigations
to determine the safety and efficacy of antenatal TRH therapy are needed.
PMID- 10765607
TI - Coitus, the proximate determinant of conception: inter-country variance in sub
Saharan Africa.
AB - There is a general consensus in the literature that fertility differences between
populations can be accounted for by differences in just four key proximate
determinants: nuptiality, the postpartum non-susceptible period, contraception
and abortion. Natural fecundibility is generally assumed to be constant between
populations. This paper puts the theoretical and empirical case for a re
evaluation of that assumption, drawing on the under-utilized data on sexual
activity collected in the Demographic Health Surveys (DHSs). Using data for
married women in nine African countries, the analysis finds substantial
population level differences in mean monthly coital frequency, which, if
accurate, suggest an important demographic effect. There is a clear regional
patterning to these differences, with levels of activity considerably lower among
women in the West African populations included in the study than those from East
and southern Africa. For West Africa in particular the data indicate the
normality of exceptionally long periods of very infrequent or no intercourse by
married women outside the period of postpartum abstinence. The findings challenge
prevailing presumptions concerning susceptibility to pregnancy in marriage on
which statistics for unmet need for family planning are derived. While doubts are
raised over the precision of the sexual activity data used, the paper argues for
the need for a greater effort to operationalize the 'proximate determinant of
conception', not only for more accurate fertility modelling, but also as a
planning tool for a more sensitive provision of family planning services in
Africa.
PMID- 10765606
TI - [Novel estrogen receptor: a chance for more specific and safe endocrinological
treatment?].
AB - In 1996 Kuiper et al. have cloned a novel member of the nuclear receptor
superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library.
The new receptor was highly homologus to the rat estrogen receptor protein,
particularly in the DNA-binding domain. New protein consists of 485 amino acid
residues and its molecular weight is 54.2 kDa. Like other steroid receptors, ER
beta has six regions, A-F. A novel receptor is expressed in the secretory
epithelial cells of the prostate and also in the granulosa cells of the ovary.
Differences in the ligand-binding properties and transactivation function on
target genes may exist. The tissue distribution and relative level of ER alpha
and beta expression seems to be quite different, i.e. moderate to high expression
in uterus, testis, pituitary, ovary, kidney, and adrenal for ER alpha and
prostate, ovary, lung, bladder, brain, uterus and testis for ER beta. The
differences between the receptors subtypes in relative ligand binding affinity
and tissue distribution could contribute to the selective action of ER aginists
and antagonists in different tissues. These new findings bring up many questions.
The most intriguing is how has this second ER eluded investigators for so many
years? Perhaps a limited number of estrogen target tissues were screened. The
biological significance of the existence of two different ERs is at this moment
unclear. Perhaps the existence of two ERs subtypes provides an explanation for
the selective actions of estrogens in different target tissues.
PMID- 10765608
TI - Is low income a constraint to contraceptive use among the Pakistani poor?
AB - This paper examines whether low income is a barrier to contraceptive use in
Pakistan, a country in which economic conditions are deteriorating at a time when
the private sector is becoming a more important supplier of contraception.
Multivariate regression analysis performed using the Pakistan Contraceptive
Demand Survey suggests that low income is a deterrent to modern contraceptive use
in Pakistan. This is particularly the case for contraceptive methods supplied
through the private sector. It is concluded that, if the aim of family planning
programmes is to reach low-income people, the prices of contraceptives supplied
through the private sector should be kept as low as possible.
PMID- 10765609
TI - Genetic and environmental influences on alcohol use: DF analysis of NLSY kinship
data.
AB - Research designs to study alcohol use and abuse have included twin, adoption and
family history/high risk studies. Results have consistently implied a genetic
factor in the aetiology of alcohol abuse. However, less research has been
conducted in search of environmental factors. This study uses kinship structure
in a large national dataset (the National Longitudinal Survey of Youth) to
estimate (using DeFries-Fulker analysis) the extent of the shared genetic, non
shared genetic, shared environmental and non-shared environmental influences on
alcohol use. The NLSY kinship sample contained 3890 pairs of cousins, half
siblings, full-siblings and twins between the ages of 14 and 21 in the initial
year of the survey (1979). Estimates of heritability (h2) and shared environment
(c2) were small to moderate for the entire dataset for both light drinking and
heavy drinking behaviour, with h2 estimates slightly higher in each case. Non
shared genetic measures of self-esteem and locus of control accounted for a
significant portion of the remaining variance in heavy drinking behaviour. Race
and gender patterns showed c2 and h2 estimates that were also small to moderate
for both light and heavy drinking behaviour. Significant non-shared effects were
found for the White group for heavy drinking behaviour, and for male pairs for
both heavy and light drinking behaviour. Additionally, implications and future
directions are discussed.
PMID- 10765610
TI - Demographic and health status risk factors in childbearing among Indian women.
Evidence from hospital data for the later stages of fertility decline.
AB - Indirect estimates of maternal mortality in India indicate that fertility decline
has reduced maternal deaths by reducing the frequency of pregnancy and
childbirth. The earlier stages of fertility decline are also likely to have
lowered maternal mortality by reducing the risk of pregnancy and childbirth as
the proportion of births among risky multiparous, older women declines. However,
further fertility decline may well be associated with some increase in risk. Risk
will also remain high if the health status of Indian girls and women remains
poor. This study uses a sample of maternal deaths and deliveries among patients
who survived which occurred in Civil Hospital, Ahmedabad, Gujarat during 1982
1993 to investigate these issues further. The women in the sample have relatively
low fertility and represent a fairly late stage of fertility decline. They also
have persistently poor health status. Logit regression analysis reveals that
although fertility decline is associated with some increase in risk, poor health
status is the more important maternal mortality risk factor. Without attention to
female health, even childbearing among expectant mothers with low fertility
continues to be hazardous.
PMID- 10765611
TI - The effects of water supply and sanitation on childhood mortality in urban
Eritrea.
AB - Child mortality differentials according to water supply and sanitation in many
urban areas of developing countries suggest that access to piped water and toilet
facilities can improve the survival chances of children. The central question in
this study is whether access to piped water and a flush toilet affects the
survival chance of children under five in urban areas of Eritrea. The study uses
data collected by the Demographic and Health Survey (DHS) project in Eritrea in
1995. The results show that while the unadjusted effect of household environment
(water supply and toilet facility) is large and statistically significant during
the post-neonatal and child periods, it is relatively small and statistically
insignificant during the neonatal period. The effect of household environment
remains substantial during the post-neonatal and child periods, even when other
socioeconomic variables are held constant. However, the household environment
effect totally disappears during the neonatal period when the socioeconomic
factors are controlled for.
PMID- 10765612
TI - Teenage motherhood and infant mortality in Bangladesh: maternal age-dependent
effect of parity one.
AB - Nuptiality norms in rural Bangladesh favour birth during the teenage years. An
appreciable proportion of teenage births are, in fact, second births. This study
examines the relationship between teenage fertility and high infant mortality. It
is hypothesized that if physiological immaturity is responsible, then the younger
the mother, the higher would be the mortality risk, and the effect of mother's
'teenage' on mortality in infancy, particularly in the neonatal period, would be
higher for the second than the first births. Vital events recorded by the
longitudinal demographic surveillance system in Matlab, Bangladesh, in 1990-92
were used. Logistic regression was used to estimate the effects on early and late
neonatal (0-3 days and 4-28 days respectively) and post-neonatal mortality of the
following variables: mother's age at birth, parity, education and religion, sex
of the child, household economic status and exposure to a health intervention
programme. The younger the mother, the higher were the odds of her child dying as
a neonate, and the odds were higher for second children than first children of
teenage mothers. First-born children were at higher odds of dying in infancy than
second births if mothers were in their twenties. Unfavourable mother's
socioeconomic conditions were weakly, but significantly, associated with higher
odds of dying during late neonatal and post-neonatal periods. The results suggest
that physical immaturity may be of major importance in determining the
relationship between teenage fertility and high neonatal mortality.
PMID- 10765613
TI - What husbands in northern India know about reproductive health: correlates of
knowledge about pregnancy and maternal and sexual health.
AB - Women in India suffer from a high incidence of reproductive disease, disability
and death. Very little work has been done on men, but a much higher incidence of
sexual experience outside marriage and sexually transmitted diseases (STDs) among
males than previously expected for this population is now being documented. In
north India, women are dependent on their husbands and other family members for
health-related decisions. Therefore, the behaviour, knowledge and attitudes of
men are integral to the reproductive health status of couples there. This study
explores knowledge about three distinct areas of reproductive health among 6549
married men in five districts of the northern state of Uttar Pradesh, India.
Factors contributing to men's knowledge in the areas of fertility, maternal
health and STDs were investigated. Results showed that very few men had basic
knowledge in any of these areas. The likelihood of reporting knowledge was
associated with a set of determinants that differed in their magnitude and effect
across the areas of reproductive health explored. In particular, men's belief
about the ability of an individual to prevent pregnancy demonstrated an
independent association with men's knowledge. After controlling for factors such
as age, parity and educational and economic status, men who believed it not
possible to prevent a pregnancy were less likely to know when during the
menstrual cycle women would become pregnant and certain facts about STDs, but
they were more likely to be able to name two or more symptoms of serious maternal
health conditions. Possible explanations for this trend are discussed.
PMID- 10765614
TI - Fertility and mortality differentials among selected tribal population groups of
north-western and eastern India.
AB - Selection potential based on differential fertility and mortality has been
computed for six tribal groups inhabiting different geo-climatic conditions,
namely: Sahariya, Mina and Bhil of the State of Rajasthan, north-western India,
and Munda, Santal and Lodha of the State of West Bengal, eastern India.
Irrespective of the methodology, the total index of selection was found to be
highest among Lodhas (0.668), followed by Sahariyas (0.524), Santals (0.462),
Bhils (0.386), Mundas (0.353) and Minas (0.334). Incidentally, Lodha and Sahariya
are two of the seventy-four notified primitive tribal groups of India, and these
two study populations show the highest index of total selection, mainly because
of a higher embryonic and postnatal mortality. The relative contribution of the
fertility component to the index of total selection is higher than the
corresponding mortality component in all tribal groups. The analysis of postnatal
mortality components indicates that childhood mortality constitutes the bulk of
postnatal mortality, suggesting that children under 5 years need better health
care in these tribal groups.
PMID- 10765615
TI - Sibling mortality correlation in Kenya.
AB - This paper examines whether infant and child mortality risks among successive
siblings are closely correlated, and if so, whether the survival status of the
preceding child is an important factor affecting infant and child mortality in
Kenya. The data were drawn from the 1988/89 Kenya Demographic and Health Survey.
Logistic regression was used as the major method of data analysis. The results
show that both infant and child mortality rates are significantly higher among
subsequent children whose preceding siblings had died in infancy than for those
whose preceding sibling had survived through infancy. The effect of the survival
status of the preceding child on infant mortality was statistically strong, even
after a large number of control variables were taken into account. However, its
effect on child mortality appears to be spurious since it was rendered
statistically insignificant when just a few control variables were introduced
into the analysis. The results provide empirical evidence that infant and child
mortality risks among successive siblings are closely correlated in Kenyan
families, and that the effect of the survival status of the preceding child is
important in determining infant mortality but not child mortality.
PMID- 10765616
TI - Is the natural twinning rate now stable?
PMID- 10765617
TI - [Make an independent assessment of mammographic screening!].
PMID- 10765618
TI - [Lipid-related prevention of coronary disease without reduction of LDL
cholesterol. Two new intervention studies show that the old truths must be
modified].
PMID- 10765619
TI - [Iatrogenic vascular injuries demand a lot from the surgeon. Better to prevent-
errors and lack of knowledge can have serious consequences for the patient].
AB - To investigate causes and consequences of iatrogenic vascular injuries requiring
surgical repair, we retrospectively reviewed 18 cases during a ten year period
between 1989 and 1999 at Karolinska sjukhuset. We hoped to identify specific
injury patterns in these cases, which were found in all operating specialties.
Inattention to vascular structures was the single most common cause of iatrogenic
vascular injury. The second most common context was radical operations of cancers
in which the tumor was adjacent to the vessel. A third cause was misunderstanding
of the specific anatomy of the area. This study demonstrates that serious
iatrogenic vascular injuries pose a great challenge for the surgeon. Representing
a significantly increased risk for the patient, these serious incidents should be
preventable through modifications in surgical technique.
PMID- 10765620
TI - [Will the revolutionary knowledge of apoptosis play an important role in
medicine?].
PMID- 10765621
TI - [Apoptosis required for maintenance of homeostasis: familial hemophagocytic
lymphohistiocytosis caused by too little cell death].
AB - Apoptosis or programmed cell death is essential for the maintenance of tissue
homeostasis. Recent studies have implicated the dysregulation of apoptosis in a
plethora of human diseases. Hence, perturbation of the death program intrinsic to
every cell may result in essentially too little or too much apoptosis, which may
in turn lead to proliferative or degenerative diseases respectively. In the
present review, we discuss our current molecular understanding of the apoptotic
process and its possible role in human disease, with particular emphasis on the
rare and invariably fatal disease of early childhood, termed familial
hemophagocytic lymphohistiocytosis, in which mutations in the perforin gene were
recently identified.
PMID- 10765622
TI - [Familial hemophagocytic lymphohistiocytosis: diagnosis, treatment and
pathophysiological mechanisms].
AB - Familial hemophagocytic lymphohistiocytosis (FHL) is an invariably fatal disease
typically seen in infancy and early childhood, with a median survival without
therapy of two months. It is characterized by prolonged fever,
hepatosplenomegaly, cytopenia, and deficient NK-cell activity and T-cell
cytotoxic capacity. Severe neurological symptoms as well as coagulation disorders
and abnormalities in liver function and lipid status may also develop. Since the
mid 1980's there has been a remarkable increase in our understanding of this
disease. In a large-scale international collaborative effort mediated through the
Histiocyte Society, diagnostic criteria and an international treatment protocol
(HLH-94) based on immunochemotherapy and BMT have been developed. A large
proportion of affected children can now be cured and, moreover, successful
chemotherapy in utero of FHL has been achieved. It has been shown that the
symptoms and signs are mediated through a pronounced hypercytokinemia. Previous
suggestions that FHL may be caused by a deficiency in apoptosis were recently
confirmed when perforin gene defects were described, which may well explain the
disastrous lymphohistiocytic accumulation and subsequent T-cell activation.
PMID- 10765623
TI - [Deep venous thrombosis--news on diagnostics and treatment].
PMID- 10765624
TI - [Urinary incontinence--sabotaging the quality of life].
PMID- 10765625
TI - [An ambulance helicopter in Jamtland. A survival necessity in a county of
tourism].
AB - The county of Jamtland is a sparsely populated area in which an ambulance
helicopter has been in use since the middle of the 1970's. A prospective study
was undertaken during a six month period with the aim of evaluating the benefits
of the helicopter as compared with the use of road-ambulance transport alone.
Total number of patients involved was n = 249. Both flight nurses and receiving
doctors found that in most cases, patients transported by helicopter manned with
a flight nurse were given higher quality care. A follow-up study by specialists
from the receiving departments confirmed that for 3% (n = 8), transport by
ambulance-helicopter resulted in "probably better prognosis", and that for 2% (n
= 6) the result was "lifesaving".
PMID- 10765626
TI - [Promising cooperation of emergency services].
PMID- 10765627
TI - [The men of the Andree expedition probably died of botulism. A new hypothesis
explains these mysterious deaths].
AB - The last camp of the three members of the 1897 Swedish Andree balloon expedition
to the North Pole was found in Svalbard in 1930. The human remains and the
paraphernalia of the expedition including diaries were brought to Sweden and are
presently housed in a museum. The cause of the deaths has never been determined,
but several hypotheses have been put forward over the years. Trichinosis, scurvy,
and poisoning by carbon-monoxide, vitamin-A or lead are some of them. In this
article it is argued that botulism is a plausible explanation which is in better
accord with known facts.
PMID- 10765628
TI - [Create an individual-based national registry of mammographic screening].
PMID- 10765629
TI - [Mammographic screening--a comment to the debate].
PMID- 10765630
TI - [Protect enthusiasm of the teachers in medical education!].
PMID- 10765631
TI - [Is it retirement time for the ASAT analyses?].
PMID- 10765632
TI - [Abolition of the method only after a careful investigation!].
PMID- 10765633
TI - [High requirements put on the leadership of central laboratories--and physicians
in primary health care].
PMID- 10765634
TI - [On MedAnalys and Frolunda Specialists' Hospital].
PMID- 10765635
TI - [Journalism on mammography one more time].
PMID- 10765636
TI - Of oxen, foxes, and chicken coops: comments on medical errors.
PMID- 10765637
TI - Drug/drug interactions selective serotonin reuptake inhibitors (SSRI).
PMID- 10765639
TI - Successful marketing begins with patient satisfaction.
PMID- 10765638
TI - Remind your patients to get breast cancer screenings.
PMID- 10765640
TI - Ten misconceptions physicians have about marketing.
PMID- 10765641
TI - DES: a continuing health concern.
PMID- 10765642
TI - [Comparison evaluation of cost-effectiveness in bronchial asthma patients].
AB - A choice of a proper drug and method for clinically successful therapy in
patients with bronchial asthma has to be based on results of experimental and
clinical studies and cost analysis. Some problems connected with cost
effectiveness analysis are presented in relation to glucocorticosteroids, agonist
of beta2-adrenoreceptors and allergen-specific immunotherapy.
PMID- 10765643
TI - [Comparison of cost-effectiveness and efficacy of selected inhaled steroids in
asthma treatment from budget perspective].
AB - Due to limited resources, when choosing among available treatment opportunities,
it is necessary to include results of pharmaco-economic assessments. The aim of
this study was to compare cost-effectiveness of Pulmicort Turbuhaler and
Flixotide Rotadisc in asthma treatment. Result of randomised clinical study
reported in Great Britain was used as a source of efficacy data. Costs of
compared treatment options were calculated using the difference between full
pharmacy price and patient's co-payment of consumed pharmaceuticals, as recorded
in Warsaw open pharmacy shop in May 1999. It has been shown, statistically
significant difference of cost-effectiveness in favour of Pulmicort Turbuhaler.
PMID- 10765644
TI - [Fibrinolytic system in bronchial asthma after prednisone treatment].
AB - Forty one patients with recently recognised bronchial asthma were studied.
Activity of plasminogen activator inhibitor (PAI-1), platelet adhesion and
aggregation, antigens of tissue and urokinase plasminogen activators
(respectively, t-PA Ag and u-PA Ag), euglobulin lysis time (ELT), complexes of
plasmin-antiplasmin (PAP) and fibrin degradation products (FDP) were tested
before and after fourteen days administration of 20-30 mg/d prednisone.
Statistical significant increase of PAI-1 activity, on the average about 75%, was
found (8.35 +/- 9.38 U/ml before, and 14.6 +/- 13.3 U/ml after treatment; p <
0.02). In 31 asthmatic patients (75.6%), after prednisone treatment, increased of
PAI-1 activity together with platelet adhesion and aggregation were observed.
Among other studied fibrinolysis factors no statistical significant differences
before and after treatment were found. These results suggest that in asthmatic
patients after prednisone treatment raises PAI-1 activity, probability because of
releasing of the increased amount of PAI-1 from activated platelet.
PMID- 10765645
TI - [Adhesion molecules LFA-1(CD-11a), Mac-1(CD-11b) of t-lymphocytes in
bronchoalveolar lavage fluid and blood in patients with chronic respiratory tract
disease].
AB - Adhesion molecules play an important role in inflammatory processes and influence
on recruitment of effector cells. The aim of our study was to assess the
percentage of T-lymphocytes expressing LFA-1, Mac-1 and ICAM-1 in bronchoalveolar
fluid (BALF) and blood of patients with sarcoidosis, atopic bronchial asthma and
chronic bronchitis. The reference group consisted of patients with haemoptysis or
suspected of having bronchial carcinoma. Expression of adhesion molecules was
revealed by /APAAP/ alkaline phosphatase anti alkaline phosphatase method. The
highest percentage of lymphocytes expressing all adhesions molecules in BALF and
blood was observed in patients with chronic bronchitis. Reductions of T-cells in
BALF of patients with bronchial asthma and sarcoidosis may reflect of their
direct binding in inflammatory sites. This studies confirm the involvement of
adhesion molecules in maintenance of chronic inflammatory processes in the
respiratory tract.
PMID- 10765646
TI - [Changes in lymphocyte subsets in bronchoalveolar lavage fluid in patients with
systemic sclerosis].
AB - The aim of this study was to estimate if alterations of lymphocyte subsets
obtained by broncholaveolar lavage (BAL) were related to clinical data observed
in nonsmoking patients with systemic sclerosis (SSc). Clinical examination
included chest X-rays, spirometry and arterial blood gasometry. Patients were
divided into group A (pulmonary changes present, n = 15) and B (without any
changes, n = 7). Healthy subjects constituted the control group (n = 10). BAL
lymphocytes were phenotyped using monoclonal antibodies coupling CD4, CD8 (both
in coexpression with CD25), CD19 and HLA-DR human antigens and flow cytometer
FACStar (Becton-Dickinson). Parallel staining was performed in peripheral blood.
BAL lymphocyte typing was completed by BAL routine cytology. In SSc patients we
found increased BAL total cell number, percentage of neutrophils, eosinophils and
macrophage giant cells, as well as high percent of CD25+ and HLA-DR+ lymphocytes.
In the group A neutrophilic alveolitis was observed in nearly half of cases:
total lymphocyte number (per 1 ml of BAL fluid) and significantly reduced CD4/CD8
ratio were found. In the group B, as compared with controls, we found
significantly elevated lymphocyte total cell number per 1 ml of BAL fluid
(including particular subsets: CD3+, CD4+, CD8+). Also significantly high CD4+25+
lymphocyte percent was observed. Summing up, cytological and/or immunological
alterations were observed in all examined SSc patients. The intensity of these
alterations seems to be related to the clinical data. A decreased value of
CD4/CD8 ratio may play a role in the local appearance of pulmonary changes in the
course of systemic sclerosis.
PMID- 10765647
TI - [Serological screening examinations of atypical pathogens (Mycoplasma pneumoniae,
Chlamydia pneumoniae) in respiratory tract infection].
AB - Lower respiratory tract infections are a heterogeneous group of disorders induced
by plenty of pathogens. Atypical bacteria play an important role in the
respiratory tract pathology. In our study 90 patients with acute infection of the
respiratory tract were examined in serological screening test for Mycoplasma
pneumonia and Chlamydia pneumoniae. It was confirmed that in 21 patients with
community acquired pneumonia Mycoplasma pneumonia antibodies were detected in 38%
and Chlamydia pneumoniae in 10%. In our opinion this screening serological tests
are useful for early diagnosis of atypical bacterial infections of the
respiratory tract.
PMID- 10765648
TI - [Influence of isoniazid on selected parameters of immunological response].
AB - Isoniazid (INH), antituberculous drug with immunomodulatory properties, have been
described as lupus-like syndrome inducer. The development of autoimmunological
phenomena results from immunoregulatory disturbances. The goal of this work was
to determine the influence of INH on selected parameters of the immune response
in vivo and in vitro. In vivo (in B6AF1 mice) the influence of long-term
treatment on primary humoral response and cellular response was evaluated. Drug
dose was 25 mg/kg. In vitro (using peripheral blood of volunteers) the influence
of INH on mitogen induced proliferation, metabolic activity of granulocytes and
production of angiogenic cytokines by diverse subpopulation of mononuclear cells
was examined. The concentrations tested were 0.5 mg/ml, 5 mg/ml and 50 mg/ml. No
effect of INH could be demonstrated on the production anti-SRBC antibodies nor on
the cellular response in mice. In vitro INH added to the cell cultures increased
PHA and ConA stimulated proliferation. The chemiluminescence of human
granulocytes increased in the presence of INH. Drug enhanced production of
angiogenic cytokines by human lymphocytes CD4+ and suppressed angiogenic activity
of CD8+ cells. The results suggest that INH has strong immunomodulatory
properties which may explain its involvement in pathogenesis of lupus-like
disease.
PMID- 10765649
TI - [Measuring of the level of IGG antibodies against mycobacterial A60 antigen in
the differential diagnosis of lung tumors].
AB - In some cases it is difficult to define an etiology of lung tumour in the other
way than thoracotomy. In these diagnostic difficulties patients with tuberculous
tumour are also involved. The aim of the present study was to define if A60-ELISA
test, a new valuable tool in the diagnosis of tuberculosis, might be useful in
the differential diagnosing of lung tumours. The levels of IgG antibodies against
A60 antigen of mycobacteria was measured with the use of the ELISA test. 228
persons were enrolled into the study: 58 healthy controls (Group I), 26
nonmalignant and nontuberculous patients (Group II), 56 patients with the
diagnosis of pulmonary tuberculosis bacteriologically confirmed (Group III), 54
pulmonary tuberculosis patients culture negative (Group IV), 16 patients with
lung tumour, without histologic diagnosis before thoracotomy (Group V) and 18
patients with defined diagnosis of lung cancer (Group VI). By using 200 U/ml as a
cut-off point the test was positive in: 2/58 subjects from Group I, 2/26 from
Group II, 44/56 from Group III, 31/54 from Group IV, 3/16 from Group V and 0/18
from Group VI. In three patients from group V having positive result of A60-ELISA
test pulmonary tuberculosis was diagnosed when the thoracotomy was performed. We
conclude that the new, simple, noninvasive and inexpensive A60-ELISA test migt be
the useful tool in the differential diagnosing of lung tumours because of its
good sensitivity and specificity in pulmonary tuberculosis. We also consider that
in lung tumour patients with the positive result of this test the prophylactic
antituberculosis treatment have to be ordered before planned thoracotomy.
PMID- 10765650
TI - [Immunologic disorders in children with Lyme borreliosis].
AB - In this study we present evaluation of some immune parameters in children with
borreliosis. We examined subsets of blood lymphocyte (CD3, CD4, CD8, CD19, CD3
HLA DR) and NK cells using monoclonal antibodies and flow cytometry in 14
children age from 3 to 16 years. We observed an altered lymphocyte phenotypes and
NK cells in infected children compare to healthy control. We conclude that the
changes in host immune response may play an important role in the pathogenesis of
borreliosis and their monitoring may be helpful for the prognosis the course of
the disease.
PMID- 10765651
TI - [Efficacy of the FLUTTER VRP1 device for physiotherapy patients with chronic
pulmonary disease].
AB - Respiratory physiotherapy is essential to the treatment of all acute or chronic
respiratory disorders which expectoration difficulties are major problem. The
Flutter VRP1 is an easy to use physiotherapy device; combines safe endobronchial
positive expiratory pressure with vibratory effects. Flutter is a useful device
for sputum expectoration and markedly improvement of lung parameters.
PMID- 10765652
TI - [Wegener's granulomatosis].
AB - The authors present a case of Wegener's granulomatosis in a 22 year-old female
patient. They observed multi-organic changes concerning upper and lower
respiratory tracts, skin, oral cavity, joints, kidneys. The diagnosis was
confirmed in the Department for Infectious Diseases after two years of the
beginning of the disease. The diagnosis was based on a course of the disease,
histopathological changes of the skin, an increase of cANCA levels. CTX,
prednisolon, cyclosporin and immunoglobulins i.v. for 5 days were used in the
therapy. Apart from this symptomatic treatment was also introduced. The 14-month
remission of the disease was obtained.
PMID- 10765653
TI - [Difficulties in diagnosis of cystic fibrosis].
AB - In this study we have presented the diagnostic difficulties in a child with
cystic fibrosis recognised basing on the clinical picture of the disease,
together with two elevated values of sweat chloride tests. The diagnosis was
confirmed by an identification of delta F 508 mutation on both cystic fibrosis
chromosomes. Normal sweat test results in a first stage of diagnosis performed
twice in a newborn period were a factor which delated the diagnosis.
PMID- 10765654
TI - [Acrodermatitis enteropathica with mild course].
AB - Acrodermatitis enteropathica is a disorder due to zinc deficiency in a human
body. It is disease of autosomal recessive inheritance, that usually occurs in
infants, typically develops in early months of life. Classical findings include
acrodermatitis, diarrhea and alopecia. Natural course of disease is various from
observed ones in 70 tumoral cases to subclinical cases without severe diarrhoea
with improvement of post maturation period. We describe a 13-year-old girl with
acrodermatitis enteropathica diagnosed after nine years from first symptoms.
PMID- 10765655
TI - [The role of cytokines and reactive oxygen species in the pathogenesis of
sepsis].
AB - The role of cytokines and reactive oxygen species (ROS) in multiple and not fully
explained pathogenesis of sepsis was presented. Close attention was paid to the
contribution of inflammatory cytokines (TNF-alpha, IL-1, IL-6, IL-8) to the
enhanced phagocyte-derived oxidative metabolism and the activation of respiratory
burst. The pleiotropic interaction of these and the other cytokines creating so
called cytokine network was described, among other things in order to express the
phagocytic and endothelial receptors. The significant role of polymorphonuclear
leucocytes (PMNLs) and macrophages in the pathogenesis of sepsis was outlined,
presenting not only their bactericidal activity but immunoregulatory effect
connected with cytokine release as well. The significance of T cells cooperating
with PMNLs was presented as well. The participation of antiinflammatory cytokines
(IL-10, IL-13) and cytokine inhibitors e.g. soluble TNF receptor (sTNFR) and IL-1
receptor antagonist (IL-1 ra) was mentioned; all of them appear in septic
patients and are thought to be natural regulators of immunological response in
vivo. The key role of ROS generated by the activated phagocytes during sepsis has
been outlined; it is proposed that the hypermetabolic response to sepsis results
from enhanced ROS generation and so-called oxidant stress is a consequence of the
imbalance between their generation and detoxification. The consequences of the
action of oxygen free radicals resulting in lipid peroxidation followed by host
auto-injury were also described. At the end a possibility of immunotherapy of
sepsis connected with the application of pentoxifylline (PTXF) as TNF-alpha
inhibitor was recommended to take into consideration.
PMID- 10765656
TI - [The place of steroid treatment in nasal polyposis in light of last years
reports].
AB - On the basis of recent literature review the authors consider pharmacological
polypectomy, concentrating on the reasons for high efficacy of steroids. The
facts presented prove that in the case of nasal polyps steroids should be used
not only as a supplement of surgical procedures. Steroid-therapy a simple, not
invasive and effective management procedure should be used regularly reserving
surgical procedures for certain specific cases only.
PMID- 10765657
TI - [Pathogenesis of chronic urticaria].
AB - This article is a review of the role of mast cells and other inflammatory cells
in pathogenesis of chronic urticaria. The role of histamine in pathophysiology of
chronic urticaria has been established but interaction between IgE-bound mast
cells and allergen is unlikely to be the mechanism by which histamine release
occurs. The authors present some factors trigger mast cell degranulation and
mediator release as histamine releasing factor (HRF) generating by lymphocytes
and IgE autoantibodies against mast cell and basophil IgE receptors.
PMID- 10765658
TI - [Percutaneous absorption of heparin: a critical review of experimental results].
AB - Percutaneous penetration of heparin is limited by its large molecular weight,
negative charge and hydrophilicity. Although some authors did not find any
significant anticoagulant effect of transdermally delivered heparin but several
other papers indicate that heparin penetrates the skin barrier. The actual
article provides a critical review of the in vitro and in vivo studies on
percutaneous absorption of heparin and heparinoids. It is concluded that there is
no sufficient evidence that heparin is able to penetrate intact skin. However
under clinical conditions the integrity of the skin barrier may be changed what
results in promotion of heparin penetration and justifies usage of topical drug
formulations like ointments and gels.
PMID- 10765659
TI - [Epidemiology of nonspecific bronchial hyperreactivity].
AB - The aim of this paper is to characterize the prevalence of nonspecific bronchial
hyperresponsiveness and indicate the factors associated with the presence of this
disturbance in the general population, documented in the literature, published
after 1961. The nonspecific bronchial hyperresponsiveness is a main clinical
feature of bronchial asthma, but it also can occur in the course of other
diseases, respiratory and cardiovascular. It can also develop as a transient
disturbance in healthy subjects. Manifestation of symptoms of bronchial
hyperresponsiveness is associated with genetic predisposition and develops as the
consequence of exposure to environmental factors. Examination of nonspecific
bronchial hyperresponsiveness is used in the clinical diagnostic of bronchial
asthma and other respiratory diseases and in epidemiological studies concerning
the natural history of bronchial asthma in the population. Simple methods
assessing the bronchial hyperreactivity in the epidemiological studies are the
very valuable part of research protocol and should be used more widely than are
used now.
PMID- 10765660
TI - [Actual diagnostic possibilities of Lyme borreliosis].
AB - Recognising of Lyme disease is based on epidemiology investigation, clinical
manifestation of disease and results of diagnostic laboratory tests. Direct
methods as isolation and culturing of Borrelia burgdorferi are very difficult and
expensive. Depends on clinical stage PCR could be very useful but not often used.
The other methods are based on detection of specific antispirochaetal antibodies
produced in compartments or detection of antigens B. burgdorferi.
PMID- 10765661
TI - [Chromosomal cycle of sporozoa and the chromosome theory of heredity].
PMID- 10765662
TI - [The theory of evolution and studies on genetics].
PMID- 10765663
TI - [Heredity of actual and apparent values of somatic features].
PMID- 10765664
TI - [First results of combined implants of endocrine organs in anterior eye chamber
of guinea pigs].
PMID- 10765665
TI - [Environmental impact and hereditary manifestations in the animal world].
PMID- 10765666
TI - [Latent life].
PMID- 10765668
TI - [The relationships of interdependence among the diverse parts of the neuron].
PMID- 10765667
TI - [The problem of sleep].
PMID- 10765669
TI - [Statements of the concept of "biological point": origin of the cell].
PMID- 10765670
TI - [Transplantation of amphibian embryonic rudimentary limbs with special emphasis
on effects on central and peripheral nervous system].
PMID- 10765671
TI - [Homoplastic transplantation of ++cloacal elements in Anura amphibians (Bufo
bufo, Bufo viridis, Rana esculenta)].
PMID- 10765672
TI - [Vital cycle of neurons].
PMID- 10765673
TI - [Gynogenesis and polyploidy in the animal kingdom].
PMID- 10765674
TI - The discipline of biological science with special reference to the neurosciences.
PMID- 10765675
TI - Life as non-historical reality.
PMID- 10765677
TI - Gnosis and the genesis of the forms.
PMID- 10765676
TI - Rethinking the origin of species by natural selection.
PMID- 10765678
TI - On differentiation.
PMID- 10765679
TI - The four theories of evolution. Epilogue.
PMID- 10765680
TI - [Darwin, one hundred years later].
PMID- 10765681
TI - Where does biological form come from?
PMID- 10765682
TI - A structuralist approach to morphology.
PMID- 10765683
TI - On the classic case of natural selection.
PMID- 10765684
TI - Cognition without representations.
PMID- 10765685
TI - The chromosome field theory confirmed by DNA and hybridization.
PMID- 10765686
TI - Macroevolution and microevolution. Macromutations and micromutations.
PMID- 10765688
TI - Industrial melanism revisited.
PMID- 10765687
TI - Darwin & Co. on form and genes.
PMID- 10765689
TI - [Violence and women].
PMID- 10765690
TI - [Alcoholic ketoacidosis].
PMID- 10765691
TI - [What do we know about the extent of violence against women in Denmark?].
AB - At present, figures about the prevalence of violence against women in Denmark are
based upon regional studies from emergency departments and national surveys that
included a few questions about violence. In 1995/96, 0.2% of women aged 16-74
reported to have been exposed to domestic violence during the last 12 months, the
highest rate was among single mothers, 3.4%. In 1991, 3% of women above the age
of 15 reported to have ever been victims of rape, 7% among 15-24 year-olds. In
the period 1978-1994, between 1.4 and 4.5 permille of all emergency contacts were
female victims of violence. The incidence was 1.6-3.5 per 1000 women, highest in
the Copenhagen area and in the western part of Denmark. In other Nordic
countries, national surveys have focused upon gender-based violence, and report a
higher prevalence of violence than in the less focused Danish studies.
Furthermore, these studies contain information about the health sequels of
violence. There is an urgent need for similar data including risk factors of
violence in Denmark in order to prevent violence and the health consequences of
violence against women.
PMID- 10765692
TI - [Keratin diseases].
AB - The rapid development in human genome research has resulted in a tremendous
increase in our understanding of the molecular basis of many genetic skin
diseases. One outstanding example of this is diseases caused by mutations in
keratin genes, which comprise several disorders of the epidermis, as for example
the different types of epidermolysis bullosa simplex. In this respect, the most
important questions have been to 1. Define the molecular defect. 2. Unravel the
pathophysiological mechanisms that lead to the characteristic phenotype and 3.
Design of new therapeutic strategies. Molecular research has contributed
significantly to the first two issues whereas a therapeutic break-through has yet
to appear.
PMID- 10765693
TI - [Epidermolysis bullosa simplex: genotype-phenotype correlation in Danish
patients].
AB - Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inherited
skin disorders caused by mutations in the keratin genes K5 or K14. We examined
five Danish families with EBS-Weber-Cockayne (WC) or EBS-Koebner (K) and two
sporadic cases of EBS-Dowling-Meara (DM) in order to investigate the mutational
spectrum and evaluate the genotype-phenotype correlation in Danish patients.
Three new K14 mutations, one new and one previously described K5 mutation were
identified by DNA sequence analysis. The positions of the EBS-DM mutations were
consistent with previous studies, whereas the EBS-WC and EBS-K mutations were
found in regions of the keratin genes not typically associated with this type of
EBS mutations. In conclusion, we found a strict genotype-phenotype correlation.
Furthermore, we found that the position of the mutation in the keratin gene is
not the only determinant for severity of the disease; the nature of the amino
acid substitution should also be considered when predicting the severity of the
EBS disorder.
PMID- 10765694
TI - [Differences in definitions of irritable bowel syndrome].
AB - Irritable bowel syndrome is inconsistently defined. The resulting difference in
study populations may impede general application of results from one study to
another. The aim of this study was to evaluate the consistency of various
definitions. At a follow-up of a sex-and age-stratified randomly selected cohort,
participants filled in a questionnaire about abdominal symptoms. Questions
categorized the participants according to five different definitions of irritable
bowel syndrome:1) two Manning criteria,2) Rome criteria,3) consensus report by
Drossman,4) definition by Talley and 5) definition by Kay. The participation rate
was 64.4%. Manning and Rome criteria were consistent with a kappa value of 0.72.
Consistency was also present comparing definitions of Drossman. Tallay and Kay
(kappa values of 0.60-0.66) All other comparisons had kappa values below 0.42. It
is concluded that variations in study population selected by different
definitions of Irritable Bowel Syndrome are so large that they impede general
application of any results. There is a need for an international agreement on a
definition of irritable bowel syndrome.
PMID- 10765695
TI - [Shift work, social class and ischemic heart disease in middle-aged and elderly
men. A 22-year follow-up in the "Copenhagen Male Study"].
AB - Shift work has been reported as a risk factor for ischaemic heart disease. Most
studies have only partly controlled for social class differences, a recognized
risk factor for ischaemic heart disease (IHD), and the relative risk of 1.4 could
be a result of confounding. The Copenhagen Male Study was established in 1971 as
a prospective cohort study of 5,249 men, and included questions on working time,
social class and other potential confounders. The cohort was followed through
registers for 22 years. Risk of IHD and all cause mortality did not differ
between shift and day workers, the adjusted relative risk for IHD being 0.9 (0.7
1.1). Restriction to social class III led to lower risk estimates, with an
adjusted relative risk of 0.7 (0.5-1.0). The study gave no support to the
hypothesis that shift work is an independent risk factor for IHD. The role of
shift work as an independent risk factor for IHD is still controversial.
PMID- 10765696
TI - [Secondary anal sphincter repair following obstetric injury. Significance of age
for the functional result].
AB - Anal sphinctre repair for obstetric sphinctre lesion was performed on 24 patients
younger than 40 years and on 14 patients older than 40 years. Twenty patients
younger than 40 years (83%; 95% confidence interval: 63-95) became continent
compared to six (43%; 18-71) among women over the age of 40. Results of anorectal
physiological examination including pudendal nerve terminal motor latency had no
prognostic value. It is concluded that older females have a poorer outcome of
anal sphinctre repair for obstetric trauma compared with younger females.
PMID- 10765697
TI - [Bilateral shoulder fractures following generalized seizure].
AB - A 37 year-old man with bilateral shoulder fractures and posterior dislocation of
one shoulder following a tonic-clonic seizure is presented. The seizure was most
likely caused by alcohol withdrawal. The diagnosis was not suspected initially. X
ray and CT-scan led to the diagnosis. The relevant literature is reviewed with
special focus on causes, trauma mechanisms, symptoms and signs and the pitfalls
responsible for missing the diagnosis.
PMID- 10765698
TI - [Changes in medical education put new demands on library functions].
PMID- 10765699
TI - [Picture of the month. Cerebral MR imaging].
PMID- 10765700
TI - [Stenting in the treatment of renal artery stenosis?].
PMID- 10765701
TI - [Medical statistics and the new DRG system].
PMID- 10765702
TI - [Etiology--the science dealing with cause of disease].
PMID- 10765703
TI - [Treatment of uncomplicated urinary tract infections--in hospitals or general
practice?].
PMID- 10765704
TI - [Plasmodium Falciparum malaria].
PMID- 10765705
TI - [Transplantation status at the turn of the century].
PMID- 10765706
TI - [Cryptococcosis].
PMID- 10765707
TI - [Candida albicans vaginitis in pregnant women--what treatment is recommended?].
PMID- 10765708
TI - [Tympanometry].
AB - A flat tympanogram predicts a middle ear effusion in about 90% of cases. This
paper describes how to perform tympanometry, some common problems when doing it
and how to classify the curves in normal (type A), middle ear effusion (type B)
or negative pressure (type C). The theoretical background of impedance audiometry
is outlined. The stapedius reflex, pneumatic otoscopy, reflexometry and
otomicroscopy are described as supplements or alternatives in diagnosing fluid in
the middle ear. Tympanometry is recommended as a diagnostic modality for general
practitioners.
PMID- 10765709
TI - [Polyketides--status and perspective].
AB - The increased resistance among pathogenic bacteria is an important reason for
research into new drugs and into improved efficiency of the ones already
existing. A group of natural products, the polyketides, exhibits a range of
antibiotic and other important pharmacological activities. This group of natural
products has therefore attracted much attention from researchers world-wide. The
biosynthesis of polyketides occurs in a stepwise fashion on gigantic
multienzymes. Individual enzymatic entities within these multienzymes are
responsible for catalysis of each step in the biosynthetic pathway of the
polyketide chain. It has been demonstrated that there is a direct correlation
between the DNA-sequence encoding these enzymatic units and the order in which
the reactions are catalysed. Polyketide synthases may thus be considered a
molecular assembly line, and new polyketides can be designed by changing the
modules of the assembly line. An understanding of the rules governing the genetic
manipulation of the synthases is of course of the utmost importance for success.
The first major steps towards this goal have been taken with the results from a
number of new experiments.
PMID- 10765710
TI - [Malignant neuroleptic syndrome in treatment with the new, atypical antipsychotic
agents, risperidone and olanzapine].
PMID- 10765711
TI - [Acute inflammation of middle ear: etiology, pathogenesis and treatment].
AB - The paper presents the author's views on etiology, pathogenesis and treatment of
acute inflammation of the middle ear.
PMID- 10765712
TI - [Tympanoplasty: problems and realization].
AB - The authors describe how to provide safety and effectiveness of tympanoplasty,
the principle of standard preparation and performance of the operation. They
think it necessary to thoroughly assess stability of intralabyrinthine pressure
and retrochochlear functions, to normalize humoral immunity and rheological blood
properties, function of the acoustic tube, to choose optimal preserver and
technique of reconstruction, how to evaluate postoperative outcome. Adequate use
of the techniques widens the spectrum of reparative operations on the middle ear
applied in practice.
PMID- 10765713
TI - [Long-term results of closed sanatory operation in patients with chronic pyo
carious epimesotympanitis in preparation to hearing-improving surgery].
AB - Depending on the involvement of the middle ear cavities, 4 variants of sanitary
operations were performed in 219 patients with chronic pyo-carious
epimesotympanitis (CPCE). Morphological effect 6 months to 7 years after CPCE was
assessed by 6 objective parameters of healing of the operated ear. Functional
result was judged by tonal thresholds of the air-conducted sounds in combination
with bone-air interval before and after the operation. Cleaning of the purulent
focus was achieved in 83% of the patients. Plastic microsurgery as the second
surgical stage is justified only in 51% of the patients with epithelial variant
of tympanic healing. Surgical policy of the second stage is decided by
correlation of the "morphological" and "functional" efficiency of closed surgery.
PMID- 10765714
TI - [Treatment of chronic otitis media in continuous or recurrent purulent
discharge].
AB - It is proposed to treat otitis media purulenta chronica with combination of
antibacterial and, on demand, antifungal drugs. Pumping the drugs into the
airways of the middle ear produces better results than routine drops. If local or
general treatment is uneffective, it is recommended to conduct mastoidotomy
followed by mastoidoplasty. This allows to arrest persistent purulent discharge
and conversion of the purulent process into a dry one.
PMID- 10765715
TI - [Application of Nd-YAG laser in surgical treatment of otosclerosis patients].
AB - The review concerns application of impulse Nd-YAG laser (wave length 1.32 micron)
in stapedial operations. Laser beam provides more accurate and less traumatic
conduction of complex stages of stapedoplasty: dissection of the limbs of the
stapes with preservation of the stapedial muscle, arrest of bleeding from the
vestibule mucosal vessels, thinning of the base of the stapes. However,
perforation of the base of the stapes by impulse Nd-YAG laser is not safe because
of the treat of radiation and mechanical damage to essential structures of the
internal ear.
PMID- 10765716
TI - [Method of epiglottis reconstruction].
AB - A new technique of epiglottis reconstruction is proposed because of its loss at
laryngeal resection for tumor or severe laryngeal injury or scarring. New
epiglottis is created from a full-thickness graft taken from oral fundus in the
projection of the lower edge of the root of the tongue. Outline of the epiglottis
with the petal up is cut on the skin in this region (2.5 x 3.5 cm). The anterior
margin of the outline is round, the bottom is square. Hairy skin inside the
outline is removed. A cut is made throughout the layers of the oral cavity fundus
only in that part of the outline which belongs to the petal. Along the outline
only skin and subcutaneous fat are cut horizontally. The created petal is pushed
to the pharyngeal cavity. The hole in the oral bottom is closed with connection
of its upper edge with the lower one using two thick silk sutures through all
thickness of the wall. Illustrations are provided for reconstruction of the
epiglottis and lateral wall of the larynx removed during laryngeal resection for
tumor.
PMID- 10765718
TI - [Sarcoidosis of face and upper respiratory tracts].
AB - Data are available on 14 patients with sarcoidosis of the face and upper
respiratory tracts (11 females and 4 males, age from 29 to 71 years). 4 patients
had isolated ENT lesion. In 3 cases, sarcoidosis was found at histological
examination of the material removed in the course of surgery for chronic
tonsillitis, recurrent purulent cyst, pyopolypous maxilloethmoiditis. Pain at the
site of skin and mucosa affection was minor, ulceration was absent. Standard
treatment was effective. 12 patients were followed up for 3 to 15 years. Good
results were achieved in 2 patients, the rest were cured with a picture of
mucosal atrophy in the lesion zone.
PMID- 10765717
TI - [Reconstruction of paranasal sinus and orbit using polymeric and metalloceramic
materials in traumas].
AB - 43 patients with injury of the paranasal sinus walls and the orbit were treated
surgically: 23 osteoplastic operations on the walls of the orbit and maxillary
sinus and 20 operations of the walls of the frontal sinus. Complete recovery of
anatomofunctional and cosmetic structure was achieved in 36(83.7%) patients,
satisfactory results were observed in 7(16.3%) patients. Diagnosis and surgical
treatment are outlined of injuries of the facial skeleton with repair of frontal,
orbital and maxillary bone defects with plates made of superhighmolecular
polyethelene and network titanium covered with biosital. The result of the
operation depends on early and accurate diagnosis and treatment, valid choice of
surgical technique and aftercare.
PMID- 10765719
TI - [Leukocytic intoxication index in tonsillar diseases].
AB - Leukocytic intoxication index (LII) was calculated according to Ya. Ya. Kalf
Kalif formula in 184 patients with tonsillar affections. It grew from follicular
and lacunar angina to paratonsillitis and paratonsillar abscesses early in the
disease and fell on the treatment day 6. In chronic decompensated tonsillitis
before and after tonsillectomy LII was not informative. To predict outcomes in
anginas, paratonsillitis and paratonsillar abscesses, follow-up of LII is
recommended.
PMID- 10765720
TI - [Clinical features of tympanosclerosis].
AB - The analysis of 412 case histories of patients operated for chronic otitis media
was made. Tympanosclerosis (TS) was detected in 26(6.3%) patients. 19 patients
had bilateral TS, 7 patients--unilateral. TS exacerbations observed up to the age
of 13 frequently changed for long-term remission. All the patients had conductive
and mixed hypoacusis. A total of 36 standard hearing-improving operations were
made.
PMID- 10765721
TI - [Cases of profuse nasal bleeding which required ligation of external carotid
artery].
PMID- 10765722
TI - [Combined penetrating injury of left orbit, ethmoidal labyrinth and sphenoid
sinus].
PMID- 10765723
TI - [Complete destruction of temporal bone pyramid by cholesteatoma].
PMID- 10765724
TI - [Vestibuloocular reflex: functional value and mechanisms of development].
PMID- 10765726
TI - [Chronic purulent otitis media. Problem solving proposals by the members of
Moscow Otorhinolaryngology Society].
PMID- 10765725
TI - [Laryngeal papillomatosis: current knowledge of etiology, pathogenesis, clinical
presentation, diagnosis and treatment].
PMID- 10765727
TI - [Evolutionary relationship of Rickettsia and eukaryotic mitochondria].
AB - To clarify the evolutionary relationship of rickettsiae and mitochondria, the
conserved flat heat-shock protein Hsp60 was phylogenetically studied in detail by
using PHYLIP and PROTML packages. The ample data set (50 species) included as
many as possible representatives from the Rickettsiaceae family, mitochondrial
type homologs from Archezoa and mitochondrial homologs from Protozoa. Rickettsia
prowazekii (that is the genus Rickettsia) was shown to be the least diverging
member within Rickettsia--a sister group to the monophyletic clade of
mitochondria. These findings were also evidenced by the phylogenetic analysis of
16S rRNA. Rickettsia-like endosymbionts (the parasites Paramecium caudatum and
the etiological agent of hepatopancreatitis in shrimps) included within the order
Rickettsiales appear to have diverged prior to the Rickettsiaceae/mitochondria
cluster. Thus, the Rickettsiales does not seem to be a monophyletic group. An
idea concerning the nature of obligate intracellular parasitism of rickettsiae is
proposed in the paper from the suggested profound similarity of Rickettsiae genus
bacteria and mitochondria which could have a common evolutionary history.
PMID- 10765728
TI - [Determination of Ehrlichia genome size by pulse gel electrophoresis].
AB - Ehrlichia infections are more and more common in the USA and Europe. The genetics
and genome organization of Ehrlichia are little studied due to great difficulties
in cultivating these bacteria. Pulse gel electrophoresis was first used to
determine the sizes of a genome of 3 representatives of the genus Ehrlichia. The
sizes of a genome was established for E. sennetsu (881 kb), for E. risticii (867
kb), E. chaffeensis (1,236 kb).
PMID- 10765729
TI - [Suppression of graft versus host reaction by depositing a magnet-controlled
adriamycin dosage form in bone marrow allotransplantation in animal experiments].
AB - The main causes of failures during allogenous bone marrow transplantation is the
development of graft versus host reactions. The methods of its prevention and
treatment are the use of large doses of human toxic cytostatics and
immunosuppressants aimed against donor immunocompetent cells. A way of preventing
the adverse effects of cytostatics are targeted transport of long-acting
cytostatic dosage forms to an organ or target cell through carriers, such as
liposomes, microcapsules, microspheres and their conjugates with monoclonal
antibodies. For this purpose, the study used gelatin and gum arabic microspheres
containing the immunosuppressive cytostatic adriamycin. To enhance the efficiency
of cytostatic depositing at the site of transplantation, the procedure of
intraosseous transplantation of allogenous bone marrow transplantation with long
acting adriamycin depositing was developed. With this approach, the authors could
not only deposit the agent, but could substantially increase the proportion of
donor cells kept at the site of grafting as compared to the intravenous and
intraosseous infusion of donor cells. The main advantage of the new technique of
allogenous bone marrow transplantation in combination with a long-acting
cytostatic dosage form is that acute and chronic graft versus host reactions can
be inhibited long by using adriamycin in subtherapeutic dosages.
PMID- 10765730
TI - [Blood protein phenotypes and effectiveness of the treatment of patients with
pulmonary tuberculosis].
AB - Genetic polymorphism at 9 independent loci (HP, GC, TF, PI, PGM1, GLO1, C3, ACP1,
and ESD) was studied in two groups of patients with pulmonary tuberculosis and
healthy controls. The patients were subdivided into two subgroups depending on
their response to chemotherapy: 1) responsive and 2) unresponsive to adequate
chemotherapy. The control (Group 3) comprised 327-329 healthy persons; only 78 of
them were phenotyped for ESD-locus. A pairwise comparison of arcsinus-transformed
both phenotypic and allelic frequencies using t-test revealed significant
differences between Groups 1 and 3 in phenotypes--GC 1F-1S, (P = 3.73 x 10(-4),
C3 F-S (P = 4.10 x 10(-5), C3 S-S (P = 1.9 x 10(-6) and in alleles--C3*F (P = 4.2
x 10(-6), C3*S (P = 1.7 x 10(-6). These differences are reliable at the levels of
significance, Pc corrected by all numbers of times, k, of independent pairwise
comparisons (k = 126 for phenotypes, Pc = 0.00041; k = 60 for alleles, Pc =
0.000855). Differences between Groups 2 and 3 were significant as well: there
were 8 P values both for phenotypes and alleles, which rejected the null
hypothesis at 5% significance while the expected numbers of times, kch, to reject
the null-hypothesis by chance, were kch = 6.3 for phenotypes and kch = 3 for
alleles. Differences between the two subgroups of patients were found to be
insignificant because the P values were obtained, that rejected the null
hypothesis only 6 and 3 times for phenotypes and alleles, respectively. Principal
component analysis showed that the GLO1 locus was not informative for the
differences in the groups studied. The perspectives of further analysis of the
data presented using the remaining 8 loci are discussed.
PMID- 10765731
TI - [Effects of some growth factors and cytokines on ATP synthesis by plasma-membrane
enriched particles isolated from different human tumors].
AB - Plasma-membrane-enriched particles isolated from the tissues of malignant tumors
of different sites are shown to accumulate ATP under the influence of polypeptide
growth factors and cytokines whose receptors have a tyrosine kinase activity.
Polypeptide growth factors, such as EGF, FGF, NGF, TNF, insulin, and the cytokine
IL-2, were studied on the accumulation of adenosine-5'-triphosphate (ATP) by the
preparations of plasma-membrane-enriched particles isolated from the target
tissues of human malignant tumors. The tumor (transformed) cell plasma membranes
of the lung, bowel, stomach, pancreas, as well as the cells of neurinoma and a
retroperitoneal extra-organ malignant tumor (leiomyosarcoma) are demonstrated to
be able to synthesize ATP from inorganic phosphate and ADP under aerobic
conditions human with the participation of the cyanide-insensitive proton phoric
NADH-bound transversely oriented chain. Signal-stimulated accumulation of plasma
membranous ATP was found to increase in the tissues in malignant transformation
as compared to that in normal tissues. Experiments using selective inhibitors of
tyrosine kinases (tyrphostin-25, quercetin) indicated the involvement of plasma
membranous signal-transducing ATP in the activation of receptor tyrosine kinase
growth factors.
PMID- 10765733
TI - [Electrophysiological aspects of the indicators of hemispheric asymmetry during
reparative processes in the brain after unilateral lesions].
AB - The gears of the conjugate activity of hemispheres in the presence of damage in
one were studied before and after removal of a tumor by using an interhemispheric
asymmetry index. On left hemispheric exposure, the index decreased in the
anterior brain regions having mainly morphofunctional connections with the
activating structures of the stem. The posterior cortical regions changed the
index on exposures of the right hemisphere or synchronizing stem structures. In
an operated-on patients, the damaging action at any site reduced the index in the
anterior cortical regions. Interhemispheric asymmetry of the posterior regions
increased or unchanged with left hemispheric damage and decreased with right
hemispheric one. These changes are interpreted as a reflection of compensatory
rearrangements of interhemispheric interactions which are accomplished under the
influence of the activating and synchronizing systems of the brain stem.
PMID- 10765732
TI - [Molecular biological and clinical-morphological studies of gastric tumors
associated with Epstein-Barr virus].
AB - The paper presents the results of the studies of gastric cancer (GC) associated
with Epstein-Barr virus (EBV) among the patients residing in 4 geographical
regions. In situ hybridization (ISH) techniques revealed that 49(11.4%) of the
430 examinees were EBV positive (EBV+), the virus-specific marker mRNA-1 of EBV,
EBER-1) was found to be present in 80-100) of tumor cells. The proportion of
EBV(+)-associated GC cases in different geographic regions ranged from 7.3 to
15%. These tumors were predominant in males (15%) as opposite to females (5.5%).
Histological types most common among EBV+ tumors and their location in the
stomach are also described. Serological findings indicated that the increased
anti-EDV antibody response in 70% of GC cases coincided with the presence of the
viral genetic information detected by ISH. In contrast to a humoral response to
EBV, a humoral response to Helicobacter pylori was equal both in patients with
EBV(+)- and EBV(-)-associated gastric tumors. Further molecular biological
analysis of EBV isolates from virus positive and virus negative GC may answer the
question whether there are really the so-called tumor and non-tumor variants of
EBV.
PMID- 10765734
TI - [Duodenogastric reflux in humans].
AB - Human duodenogastric reflux (DGR) was comprehensively studied via measurement of
gastric juice bile acid levels, manometric, endoscopic and X-ray study in health
and benign gastrointestinal diseases and during exercise. DRG is shown to fall in
the physiological events that have a biologically determined circadian rhythm.
There was an association of DGR with gastric secretion. The "refluctant dilution
effect" was established which along with elimination provides a relative
constancy of the concentrations of bile ACIDS FROM 0.025 TO 0.422 NG/ML. DGR
regulation is effected by the coordinated motor and evacuatory performance of the
gastroduodenal junction and duodenum which is described as a lock two-way system.
It is concluded that DGR is involved in the formation of the internal gastric
environment and hence plays a role in gastric digestion. The findings may be used
in studies of the physiology of digestion and in clinical practice.
PMID- 10765735
TI - [Individual effects of physiotherapeutic procedures in the correction of sequelae
of psychoemotional stress in students].
PMID- 10765736
TI - [Principles of the autowave self-organization of biological fluids].
PMID- 10765737
TI - [Carbohydrate transport systems in Escherichia coli and regulation of
catabolism].
AB - The mechanism of carbohydrate uptake in E. coli with involvement of the
phosphoenol pyruvate-dependent phosphotransferase system (PTS) is dealt with. The
genetic structure of the glucose transport system and fructose operon is given in
detail. How the products of these systems can affect the total bacterial cellular
catabolism dependent of complex of cyclic 3'5'-monophosphate + protein regulator
of the above nucleotide is shown. Some section is devoted to the bacterial
transport of beta-glycosides with the participation of Po-independent terminator
and to the role of PTS as a highly sensitive sensory system associated with
carbohydrate catabolism.
PMID- 10765738
TI - Distraction osteogenesis and its use with dental implants.
PMID- 10765739
TI - Use of a porous-surfaced implant system.
PMID- 10765740
TI - The future role of growth factors in bone grafting.
PMID- 10765741
TI - The use of infection control for implant surgical procedures.
PMID- 10765742
TI - Performing ridge splitting to allow more bone for implant placement.
PMID- 10765743
TI - Implant system offers the advantage of shorter loading time.
PMID- 10765744
TI - The use of bioactive glass to enhance implant placement.
PMID- 10765745
TI - Current developments with growth factors and bone proteins.
PMID- 10765746
TI - Alveolar ridge augmentation with ramus buccal shelf autografts and impacted third
molar removal.
PMID- 10765747
TI - Oral health care in diabetes mellitus.
AB - Diabetes mellitus produces many complex changes in the lives of those affected.
Elevated blood glucose levels, which may occur in the absence of symptoms, lead
to late complications from tissue damage. There is an increased susceptibility to
infection, poor wound healing and periodontal disease. Furthermore, chronic oral
infection itself may contribute to raised blood glucose levels and hence to the
later complications of diabetes. Acute infection in the oral cavity needs
specific and aggressive management, just as in the acutely infected diabetic
foot. The dental team may not have made a significant contribution to the shared
management of the person with diabetes in the past; however, recent findings
suggests that the dental team may contribute greatly to the shared care of
diabetes with the diabetic team itself, and regular liaison is strongly
recommended.
PMID- 10765748
TI - The periodontal-endodontic interface.
AB - The periodontal tissues and the pulp-dentine complex form an intimate continuum
through which pathological changes of either one may lead to infection of the
other, and whose management can be fraught with diagnostic and therapeutic
difficulty. The purpose of this review paper is to explain the nature of that
relationship and to provide pointers which may assist in the diagnostic process
and thus enable appropriate management from the outset. Traditional
classifications of lesions affecting the periodontal-endodontic complex have
caused confusion by attempting to form diagnoses which indicate the putative
primary source of infection. We would suggest that the origin of the infection is
irrelevant to the management process, and that what is important is whether
either, or indeed both, of the tissues are viable or not. Successful therapy will
only result from the establishment of an accurate diagnosis, and forming such a
diagnosis requires a methodical multi-staged approach.
PMID- 10765749
TI - Neurological complications of local anaesthetics in dentistry.
AB - Neurological complications following the administration of a local anaesthetic
can be alarming. By reading reports of such incidents, dentists who find
themselves in similar situations will be able to reassure their patients and act
accordingly. The authors have reviewed the literature for those neurological
complications that have been reported and offer an explanation of their
aetiology. Examples of complications covered are facial nerve palsy, transient
amaurosis, post-injection paraesthesia, Horner's syndrome, transient paralysis of
combined cranial nerves III, IV and VI, sudden unilateral deafness and abducens
nerve palsy. A thorough knowledge of the relevant anatomy pertinent to the
various injections used in dental surgery is essential and is highlighted in the
text.
PMID- 10765750
TI - Management of the submerged deciduous tooth: 2. Treatment.
AB - The previous article in this series dealt with the aetiology, diagnosis and
potential consequences of submerging deciduous teeth. This paper will discuss the
appropriate treatment options. The management is highly dependent on whether the
permanent successor is present or absent. The degree of submergence and the age
of the patient are also important factors for consideration.
PMID- 10765751
TI - Orofacial disease: update for the dental clinical team: 8. Salivary complaints.
AB - Certain lesions exclusively or typically affect the salivary glands; these are
discussed in this article.
PMID- 10765752
TI - Drug abuse and dentistry.
AB - This paper describes the influence of the misuse of drugs on dental treatment and
the effects of drugs of abuse on the orodental structures.
PMID- 10765753
TI - The microbiology of periodontal disease.
AB - Periodontal disease result from mixed bacterial infections, in which both host
resistance barriers and bacterial interactions are important. Approximately ten
bacterial species are strongly implicated with various forms of periodontal
disease, although species that cannot yet be cultivated are likely also to be
relevant. New technologies have shown that pathogenic bacterial species are
present in defined complexes within subgingival plaque, thus identifying specific
targets for therapeutic intervention. In light of increasing antibiotic
resistance amongst oral bacteria, new strategies for control of periodontal
bacterial complexes must be developed that inhibit the bacterial factors
necessary for colonization and destruction of host tissues.
PMID- 10765754
TI - Improving aesthetics in patients with complete dentures.
AB - An increasing number of patients with complete dentures are requesting
improvements in the aesthetics of their dentures. This paper considers methods of
improving aesthetics, using the information available from the existing complete
dentures, pre-extraction records and resin stains.
PMID- 10765755
TI - Orthodontic auxiliaries: the way forward?
AB - Currently two-thirds of European countries employ orthodontic auxiliaries and the
UK is therefore unusual in not permitting their use. There is support from the
orthodontic specialty for the concept of delegating routine intra-oral tasks to
auxiliary personnel. The following describes a pilot project undertaken to
determine the possible training structure for orthodontic auxiliaries. The
modular course, which took place over a period of 4 weeks, is described and the
results and implications are discussed.
PMID- 10765756
TI - Root resorption of first permanent molar by a supernumerary premolar.
AB - A case is presented of root resorption of the lower right first permanent molar
caused by a supernumerary premolar tooth. The first permanent molar was
subsequently extracted.
PMID- 10765757
TI - Orofacial disease: update for the dental clinical team: 5. Lumps and swellings.
AB - This article discusses the more common conditions presenting with orofacial lumps
or swellings. The first article in this series presented several general
observations on diagnosis and treatment which should be borne in mind in relation
to this article.
PMID- 10765758
TI - What should we do about patients who smoke?
AB - The adverse consequences of smoking on both general and oral health are well
recognized. It is now accepted that brief advice from a healthcare professional
is an effective aid to stopping smoking and recently interest has focused on the
role of the dental team in this area. This paper provides an update on current
concepts of how smokers give up and makes practical suggestions as to how smoking
may be discussed in the dental clinic.
PMID- 10765759
TI - The long road to success.
AB - The conservation of teeth can involve the many facets of restorative dentistry in
an attempt to retain both functional and aesthetic demands. This case report
chronicles the management of a patient presenting with several traumatized teeth,
which progressed through orthograde endodontics, periodontal crown-lengthening
procedures, crown placement, surgical endodontics with attempted guided tissue
regeneration, to eventual tooth extraction and replacement with osseointegrated
implants.
PMID- 10765760
TI - The apically repositioned flap in tooth exposure.
AB - Methods of exposing impacted teeth in order to bring them into the line of the
arch include gingivectomy, the apically repositioned flap and closed eruption
techniques. These procedures aim to facilitate the eruption of the impacted tooth
with a minimum of disruption or damage to the tooth itself or adjacent
structures. The aim of this paper is to discuss the various surgical methods of
exposing impacted teeth and to help to identify where the use of the apically
repositioned flap is indicated. Clinical examples are presented and a surgical
method for carrying out this procedure recommended.
PMID- 10765761
TI - Functional appliances: mode of action and clinical use.
AB - Functional appliances are frequently used in the treatment of Class II division 1
malocclusions, either in isolation or, more commonly, before a course of fixed
appliance therapy. Extensive speculation and investigation into the precise mode
of action of these appliances has recently focused on their growth-restraining
effect on the maxilla, their growth-enhancing effect on the mandible and
dentoalveolar and soft tissue effects. The different types of functional
appliances are described in this article, with emphasis placed on practitioners
adopting a component approach to design. A checklist is provided to aid
identification of the more common problems occurring during treatment.
PMID- 10765762
TI - Communicating shades: a clinical and technical perspective.
AB - The creation of a natural-looking ceramic crown which blends harmoniously with
the surrounding dentition is not merely a matter of recording a shade. The
subtleties of colour, translucency, discrete staining, texture, lustre and shape
are all essential features. Accurate shade taking and correct tooth preparation
are all necessary elements but are of little value if the information cannot be
precisely communicated to the technician.
PMID- 10765764
TI - Diagnosis and management of trauma to primary dentition.
AB - This article seeks to aid the busy dentist by providing a basic guide to treating
fractured and traumatized primary teeth and soft tissues. Simple guidelines for a
step-by-step approach to the efficient care of traumatized primary teeth are
given.
PMID- 10765763
TI - Orofacial disease: update for the dental clinical team: 6. Complaints affecting
particularly the lips or tongue.
AB - Certain lesions are exclusively or typically found in specific sites; these are
discussed in this and the next two articles in this series.
PMID- 10765765
TI - Digital cameras and orthodontics: an overview.
AB - The need to record clinical images, for use in documenting treatments, patient
education, patient contracting, referral letters and sharing information with
colleagues, is increasing. This article reviews the advantages and disadvantages
of 35 mm and digital photography.
PMID- 10765766
TI - Predisposing and contributing factors for complete and incomplete tooth
fractures.
AB - The rehabilitation of fractured teeth may create problems for both patient and
clinician. This paper updates the reader on the many factors that have been
implicated in the aetiology of fractures, so highlighting a preventive rather
than curative perspective to clinical dentistry.
PMID- 10765767
TI - Minocycline-induced staining of the adult permanent dentition: a review of the
literature and report of a case.
AB - Tetracycline staining of teeth during tooth development is well documented. We
report here the rarer condition of tetracycline staining of adult teeth. This
occurrence appears to involve enamel surface demineralization/remineralization
and can produce staining clinically indistinguishable from that occurring during
tooth development.
PMID- 10765768
TI - Median mental sinus in twins.
AB - Sinus on the chin can be the result of a chronic apical abscess due to pulp
necrosis of a mandibular anterior tooth. The tooth is usually asymptomatic, and a
dental cause is therefore not apparent to the patient or the unsuspecting
clinician. Not infrequently, the patient may seek treatment from a dermatologist
or general surgeon instead of a dentist. Excision and repair of the fistula may
be carried out with subsequent breakdown because the dental pathology is not
removed. This paper reports the presence of median mental sinus of dental origin
in twins. One case healed following root canal therapy while the other required
both root canal therapy and surgery to eliminate the infection.
PMID- 10765769
TI - Rapid cystic involvement of a lower third molar.
AB - Cystic change can occur in association with partially and unerupted lower third
molars. This case report describes an inflammatory paradental cyst which
developed over a relatively short period of time and presented with acute
symptoms.
PMID- 10765770
TI - Orofacial disease: update for the dental clinical team: 4. Red, brown, black and
bluish lesions.
AB - This article discusses coloured lesions of the orofacial region.
PMID- 10765771
TI - Treatment of dental fears: pharmacology or psychology?
AB - Fear of dental treatment constitutes one of the major obstacles to receiving
dental treatment, in both the UK and the USA. Treatment for such fear can be
pharmacological or psychological, or a combination of both. In this article the
aetiology, diagnosis and treatment of dental fear will be described and the
treatment methods compared.
PMID- 10765772
TI - Adhesive solutions: report of a case using multiple adhesive techniques in the
management of enamel hypoplasia.
AB - Enamel hypoplasia is a common condition that may present a severe aesthetic
problem. Although the teeth affected may not be particularly susceptible to
caries, patients may request cosmetic improvement. Adhesive techniques may be
useful in such situations. This paper discusses the management of a patient with
enamel hypoplasia using a combination of adhesive systems including enamel- and
dentine-bonded veneers, dentine-bonded crowns, a cantilever resin-retained
bridge, bonded amalgam restorations and chairside tin plating. Where adhesion was
contraindicated, conventionally retained crowns were used.
PMID- 10765773
TI - Toothbrush handle adaptation using silicone impression putty.
AB - Some patients suffer from conditions that make holding toothbrushes difficult, if
not impossible. This article describes a quick, simple and flexible method of
adapting toothbrush handles to allow patients the best possible chance of
performing adequate oral care.
PMID- 10765774
TI - Management of the submerged deciduous tooth: I. Aetiology, diagnosis and
potential consequences.
AB - The management of submerged deciduous teeth can present a dilemma for general
practitioner and specialist alike. These teeth are often extracted to avoid
potential problems. The recent literature, mainly publications in specialist
journals of paediatric dentistry and orthodontics, suggests that a conservative
approach is often preferable, particularly when the permanent successor is
present. The purpose of this article is to review the aetiology, diagnosis and
potential consequences of submerging deciduous molars; a second paper will
discuss the treatment options available.
PMID- 10765775
TI - Familial cases of missing mandibular incisor: three case presentations.
AB - Hypodontia is the congenital absence of one or more teeth because of agenesis.
The most commonly missing teeth are the third molars, the maxillary lateral
incisors and the second premolars. Cases are presented of three patients with a
missing mandibular incisor.
PMID- 10765776
TI - Public knowledge of dental registration and management of common dental problems.
AB - The government has recently changed its policy on dental registration. There is
now a requirement to attend a dentist within 15 months of the previous
appointment or dental registration will lapse. The authors of this article
undertook a survey of the patients attending for dental treatment at the accident
and emergency department of their hospital to ascertain whether inappropriate
attendance was due to ignorance about general dental services. Of the 501
respondents 14% had not seen their general dental practitioner within the last 15
months and were therefore no longer registered--only 21% realized that they had
to keep regular appointments or dental registration would lapse. A proportion
(30%) had tried to contact the dentist outside normal working hours; 27% of these
were unhappy with the outcome. Telephone calls were unanswered in 38% of those
expressing dissatisfaction and 45% subsequently attended hospital for treatment.
PMID- 10765777
TI - Orofacial disease: update for the dental clinical team: 7. Complaints affecting
particularly the palate or gingivae.
AB - Certain lesions are exclusively or typically found in specific sites. This
article discusses in detail conditions that occur mostly on the palate or
gingivae.
PMID- 10765778
TI - The caries vaccine: a growing prospect.
AB - A vaccine against dental caries, for so long a subject of purely academic
research, is currently undergoing phase II clinical trials and could be available
commercially within 5 to 6 years. The approach, which is safe, effective, and
provides long-term protection for up to a year, is based on a topical application
and does not require any injections. The development of this vaccine has been
made possible by recent advances in molecular biology and genetic engineering.
Perhaps one of the most intriguing aspects has been the use of green plants to
produce the vaccine. This article describes a topical vaccine against
Streptococcus mutans, which is the main cause of dental caries.
PMID- 10765779
TI - Update on precancerous lesions.
AB - Oral cancer continues to be a serious problem in the UK and it is well known that
prevention and early recognition of potentially malignant lesions will provide
the best prognosis. This article discusses recent changes in the nomenclature of
lesions and current concepts in diagnosis and management.
PMID- 10765780
TI - Five-year follow-up of successful intentional replantation.
AB - Intentional replantation has been practised for many years as a treatment
modality for pulpless teeth. Although the success ratio for intentional
replantation is far below that for routine or surgical endodontics, one should
consider this procedure as an alternative to tooth extraction. Two cases of
mandibular second molars which were treated with intentional replantation and
retrograde fillings are reported in this article. At the 5-year recall visit, the
radiographs showed no evidence of pathological changes.
PMID- 10765781
TI - Provisional restoration of veneer preparations: a modified technique.
AB - It is sometimes necessary to construct temporary covers on labial veneer
preparations. A modification of an existing technique for making temporary
veneers is described that employs the advantages of transparent registration
material.
PMID- 10765782
TI - Domiciliary dental care.
AB - Domiciliary dental care is an important and growing area of treatment provision.
However, adequate training is required in order to develop the knowledge and
skills necessary to perform such care. This article draws attention to the likely
increase in demand for domiciliary dental care services and the reasons for it;
and highlights the issues and skills involved for dentists, hygienists and their
teams in providing domiciliary dental care in order to facilitate quality of care
and safe practice.
PMID- 10765783
TI - Does temporomandibular disorder pain dysfunction syndrome affect dietary intake?
AB - Temporomandibular disorder pain dysfunction syndrome (TDPDS) is the most common
cause of facial pain after toothache. The symptoms are varied but are likely to
affect the choice, intake and enjoyment of food. This has not been previously
investigated. In this paper a preliminary study of 35 patients attending a
department of oral and maxillofacial surgery at a general hospital is presented.
Thirty-one subjects reported that eating was a problem; 15 prepared food
differently and 24 considered that their choice of food was limited. Four of the
five foods most often reported to be difficult to eat are valuable in the diet:
meat (22), apples (20), bread (13), toast (7) and toffees (6). Twenty-three
subjects reported eating a softer diet. Most (25) reported pain when eating. Such
circumstances make it harder for TDPDS sufferers to meet current nutritional
guidelines, especially, perhaps, for some to achieve an adequate intake of iron.
PMID- 10765784
TI - Orofacial disease: update for the clinical team: 9. Orofacial pain.
AB - Orofacial pain, the main reason why many patients seek dental advice, usually has
a local cause--primarily the sequelae of dental caries--but a wide range of
diseases, particularly neurological, psychogenic and vascular disorders, can
cause orofacial pain. This article will discuss disorders that can present with
pain and the neurological, psychogenic and vascular causes of orofacial pain. The
first article in this series made several general observations on diagnosis and
treatment which should be borne in mind in relation to the material presented
here.
PMID- 10765785
TI - Moving towards a latex-free environment: advice from experiences in US dentistry.
AB - Most dental practitioners now routinely wear gloves while treating patients. The
most commonly used types of gloves contain latex. Latex is also present in other
personal protective equipment, such as masks, eyewear and clinic gowns. Increased
use of such items, unfortunately, has been linked to adverse skin and mucous
membrane reactions. Latex proteins and chemicals associated with the material's
production have been implicated. Exposure to such chemicals has also resulted in
allergic responses in dental patients. There is a strong movement in the USA to
limit exposure to latex in healthcare environments, including dentistry. The aim
of this article is to describe past, present and future efforts to create low
latex or latex-free environments.
PMID- 10765786
TI - The orthodontic implications of traumatized upper incisor teeth.
AB - With the demand for orthodontic treatment increasing, it is inevitable that the
practitioner will see a significant number of patients with previously
traumatized teeth who require orthodontic treatment. The possible risks and
guidelines for the management of these teeth during active tooth movements are
discussed. The use of orthodontic appliances in the management of incisors
traumatized during active orthodontic treatment is also discussed.
PMID- 10765787
TI - The psychology of facial appearance.
AB - Facial attractiveness is now recognized as being important in situations as
diverse as education, relationships and employment. An individual's facial
appearance is one of their most obvious characteristics and facial disfigurements
are judged to be among the least desirable 'handicaps'. A face which deviates
from the norm becomes a stigma. This paper looks at the complex area of facial
appearance and its importance in the field of dentistry. The relationship between
facial attractiveness and varying forms of dental and surgical intervention are
discussed, as well as some of the problems which may be encountered during
treatment.
PMID- 10765788
TI - A case report of pre-eruptive coronal resorption in a mandibular canine.
AB - A case of intracoronal resorption in a recently erupted mandibular canine in an
11-year-old girl is presented. Possible aetiology and approaches to treatment of
such lesions are discussed.
PMID- 10765789
TI - Reconstruction of a hemisectioned tooth with an adhesive ceramic restoration
using intraradicular retention.
AB - Hemisection may be a valuable form of treatment for molar teeth when one root is
considered unrestorable. However, following hemisection the clinician may
encounter difficulty in restoring the remaining tooth fragment, which may not
possess adequate bulk for the placement of a post. This case report describes an
adhesive technique in which a ceramic crown is bonded intraradicularly to the
hemisectioned root.
PMID- 10765790
TI - Patient motivation.
AB - This paper addresses the important issue of patient motivation. Research
indicates that non-compliance is a major problem for healthcare professionals,
with between a third and a half of all patients failing to comply with
recommended healthcare instructions. The paper outlines some of the
misconceptions associated with motivation and discusses six factors, together
with some brief additional factors, which it is hoped will contribute to a deeper
understanding of the subject and the improved dental health of patients.
PMID- 10765791
TI - Cleidocranial dysplasia: modern concepts of treatment and a report of an
orthodontic resistant case requiring a restorative solution.
AB - A case is presented of a young boy with cleidocranial dysplasia, whose multiple
supernumerary teeth prevented the eruption of most of his permanent teeth. His
maxillary incisor teeth failed to erupt following removal of anterior
supernumerary elements and orthodontic traction. Lack of abutment teeth and a
difficult maxillary base made prosthetic treatment almost impossible. A horseshoe
acrylic denture retained by milled crowns bonded to the deciduous canines and a
maxillary first molar proved a very successful restoration. The problems of
treating this group of patients are discussed.
PMID- 10765792
TI - Orofacial disease: update for the dental clinical team: 10. Halitosis and
disturbances of taste, orofacial movement or sensation.
AB - This article discusses halitosis, and disorders of taste, orofacial movement or
sensation.
PMID- 10765793
TI - Preparation and laboratory protocol for anterior perioprosthetic reconstruction.
PMID- 10765794
TI - Using indirect laminate veneers for restoring anterior teeth.
PMID- 10765795
TI - Using the double-cord packing technique of tissue retraction for making crown
impressions.
AB - The double-cord packing technique is effective and safe for impression taking as
long as the following steps are taken: Whenever possible, finish lines should be
placed supragingivally. The gingival tissues should always be in good periodontal
health. Two knitted cords of different sizes soaked in aluminum chloride solution
are used. The first cord should be left in place while making the impression.
Retraction cords should never be forced into the sulcus. Always remove both cords
before dismissing the patient.
PMID- 10765796
TI - Update on adhesive dentistry. Interview with Dr. David Hornbrook. Interview by
Phillip Bonner.
PMID- 10765797
TI - Mineral trioxide aggregate: a new material for the new millennium.
AB - A midroot strip perforation can be a difficult problem to treat. Surgical
treatment is arduous and has a poor prognosis. Variable success has been seen
with the classic repair materials for nonsurgical treatment. Mineral trioxide
aggregate seems to have incredible promise for sealing these defects with a good
long-term prognosis.
PMID- 10765798
TI - Occlusion and dental disease.
PMID- 10765800
TI - The PPSP procedure: the Pinero Precardiac Surgical Protocol.
PMID- 10765799
TI - The multiple cantilever system: a solution for a failed precision attachment
denture case.
AB - Multiple-cantilevered pontic bridges can be a great alternative to dental
implants and distal extension prostheses. Dental hygiene must be considered the
most important factor in preserving the status quo of the permanent restoration.
Traumatic occlusion, which can occur because of the widened periodontal space and
greater mobility of a multiple-cantilever bridge, is not automatically a sign of
failure. As long as the mobility of the fixed bridge does not increase and the
patient can function and feel comfortable with it, a successful therapy can be
concluded. If marginal periodontitis exists, destruction of the cervical
ligaments, bone resorption, and apical migration of the epithelium will occur.
Through loss of the supportive structures, hypermobility will increase. If the
destructive factors of marginal periodontitis are not eliminated, the
hypermobility can interfere with masticatory function. It is important that
patients be made aware of this possibility. Regular recalls in the beginning of
the maintenance program will emphasize the importance of the home-care system.
PMID- 10765801
TI - Nd:YAG laser-assisted gingivectomy, bleaching, and porcelain laminates, Part 2.
PMID- 10765802
TI - Nonorthodontic alignment: a multifaceted approach in the attainment of excellent
aesthetics.
PMID- 10765803
TI - Cutting time and expenses with the Cerec 2 CAD/CIM System.
PMID- 10765804
TI - Using pressed ceramic onlays to restore failed composites.
PMID- 10765805
TI - Iodoform gutta percha: MGP, a new endodontic paradigm.
PMID- 10765806
TI - Alveolar ridge aesthetics: extraction site bone grafting for the general dentist.
PMID- 10765807
TI - Implant options for restoring edentulous spaces.
PMID- 10765808
TI - The Andrews bar-and-sleeve-retained bridge: a clinical report.
PMID- 10765809
TI - The local delivery of chlorhexidine in a bioresorbable matrix.
AB - The use of local antimicrobial agents, such as the chlorhexidine chip, should be
used cautiously and not without thorough debridement or scaling and root planing
of the area in question. Because these chips are basically nonsurgical, patients
become enthusiastically excited and relieved to learn they don't need surgery.
But patients must be strongly advised that surgical intervention may be a next
step in the correction of the periodontal pocket if significant change is not
attained with local antimicrobials.
PMID- 10765810
TI - Dentistry at the turn of the century: an interview with Dr. Gordon Christensen.
Interview by Phillip Bonner.
PMID- 10765811
TI - Bases and liners: to use or not to use, a paradigm shift.
PMID- 10765812
TI - Laser-assisted cosmetic dentistry, Part 1.
PMID- 10765813
TI - Postorthodontic aesthetic improvements.
AB - Often, the aesthetic dentist will place veneers to nonorthodontically reposition
teeth. While this is a valid and beneficial treatment for many patients, the
outcome is still compromised by improper tooth alignment. It is a pleasure to
complete an interdisciplinary case where the tooth and arch alignment are ideally
positioned. Restorative dentists have the responsibility to let orthodontists
know what can and cannot be done restoratively.
PMID- 10765815
TI - The standardized-taper root canal preparation, Part 1: Concepts for variably
tapered shaping instruments.
PMID- 10765814
TI - A high-density posterior composite used for an amalgam replacement.
PMID- 10765816
TI - Breakthrough dental bridgework: the bio-logical dental bridge.
PMID- 10765817
TI - The intraoral camera: an indispensable diagnostic tool, Part 1.
PMID- 10765818
TI - A new saliva-based anticaries composition.
PMID- 10765819
TI - Do you feel protected?
PMID- 10765820
TI - Posterior composites experiencing growth trend. Interview by Phillip Bonner.
PMID- 10765821
TI - Dazzle camouflage.
PMID- 10765822
TI - Ten direct veneers.
PMID- 10765823
TI - Direct aesthetic bonding with a preformed facial matrix.
PMID- 10765824
TI - Case report of a ramus onlay graft followed by a dental implant restoration.
PMID- 10765825
TI - Er:YAG laser: a credible option for children.
PMID- 10765826
TI - The similarities between an acellular dermal allograft and a palatal graft for
tissue augmentation: a clinical case.
PMID- 10765827
TI - Transitional implants and modular prosthetic components, Part 1.
PMID- 10765828
TI - The clinical application of a new post.
PMID- 10765829
TI - Ethical dilemmas in dentistry. Interview by Alan J. Goldstein, DMD.
PMID- 10765830
TI - The aesthetic/restorative blueprint: don't start out without it!
PMID- 10765831
TI - The perfect gap: when are midline diastemas aesthetically acceptable?
AB - To close or not close a midline diastema is a very significant issue. Ultimately,
such decisions are subjective. The role of the dentist is to help patients
understand the various fundamental geometric laws of aesthetics. When the
relative balance and harmony of the distributed space are properly proportioned
and conform to the laws of nature, either scenario is acceptable. Simple
proportions using the Golden Rectangle can be used to help patients assess their
individual choice.
PMID- 10765832
TI - The art of the smile.
PMID- 10765833
TI - Orascopy: endodontics' vision for the new millennium.
PMID- 10765834
TI - Endodontics in the new millennium. Interview with Dr. Jack S. Roth. Interview by
Phillip Bonner.
PMID- 10765835
TI - Periodontal aesthetics to enhance a smile.
PMID- 10765836
TI - Improving the delivery of a fixed bridge.
AB - Force loading of dental prosthesis is generally a guessing game played by the
operator with the patient. Relying on a patient is comfort level to adjust
occlusion is now being replaced by sound force information provided by the T Scan
II. Proper use of the T Scan II when installing a segmental fixed prosthesis
gives a more precise, comprehensive occlusion. Porcelain surfaces, solder joints,
and the underlying abutment teeth can now be loaded with low-to-moderate forces
because the operator can fine-tune the occlusal forces precisely. With proper
force loading, greater material and prosthesis longevity is significantly
enhanced.
PMID- 10765837
TI - Contact air abrasion.
AB - The advantages of contact air abrasion techniques are readily apparent. The
first, of course, is the greatly increased ease of use. Working with contact also
tends to speed the learning curve by giving the process a more natural dental
feel. In addition, as one becomes familiar with working with a dust stream, the
potential for misdirecting the air flow is decreased. The future use of air
abrasion for deep decay removal will make this the treatment of choice for the
next millennium.
PMID- 10765838
TI - Correcting a single anterior tooth crossbite with a looped archwire.
PMID- 10765839
TI - Eating disorders. A multidisciplinary approach.
PMID- 10765840
TI - A perspective on dental beauty.
PMID- 10765841
TI - An eight-unit rehabilitation case using an all-ceramic restorative.
PMID- 10765842
TI - Building a better cosmetic practice.
PMID- 10765843
TI - A new paradigm for the construction and service of fixed prosthodontics.
AB - Some of the most disheartening things that can happen to restorative dentists is
to be faced with problems, complications, and failures in their own fixed
prosthodontics. A highly advantageous technique for removing existing
restorations and creating removable cement-retained fixed prosthodontics has been
described. In the history of crown and bridge prosthodontics, there has not been
a proven precision technique to remove these restorations, with the exception of
screw-retained implant prostheses, which exhibit many disadvantages. This new
paradigm provides a new dimension to the practice of dentistry and allows for the
repair, service, and maintenance of restorations in ways that have never been
done in the past. Removing crowns and fixed bridges can be learned like any other
dental skill, such as endodontics or taking accurate impressions. Skill and
confidence comes when the technique has been performed on a large variety of
cases. Being able to quickly and easily remove these restorations can certainly
be rewarding and reduce a lot of stress.
PMID- 10765844
TI - Using a fiber-reinforced ceromer for fixed restorations.
PMID- 10765845
TI - Trismus: what is it, what causes it, and how to treat it.
AB - Trismus is a common complication. In many ways, it is a pretty innocuous one, but
for the patient, it could give rise to many constraints, including social
injunctions that can cause anxiety and anger. In a few instances, there have been
instigation of lawsuits. Therefore, it is important for clinicians to be aware of
this significant condition, its primary causes, and its treatments.
PMID- 10765846
TI - Prosthetic considerations with periodontal root resective therapy, Part 1: Root
amputations.
AB - Root resective periodontal therapy is a procedure used to retain teeth needed for
restorative abutments or occlusal support. Contraindications of root resective
therapy include fused roots and inadequate bony support around remaining roots.
When these situations exist, extraction is necessary. But in the appropriate
cases, a patient with a periodontal condition resulting in alveolar bone loss in
the furcation region is amenable to treatment with a predictable result using a
combination of resective periodontal surgical therapy and subsequent timely
prosthetic rehabilitation.
PMID- 10765847
TI - The Arizona bridge: an alternate arrangement to the Maryland-style bridge.
AB - This case provided a significant difference in the patient's appearance and
eliminated pain and infection. It was also greatly satisfying because all the
treatment objectives were accomplished. Because of the restorations' design,
occlusal function on the veneers and pontics was kept to a minimum, except for
tooth No. 12 where there was significant tooth support for resistance and
retention. With proper daily hygiene and routine recare, this new style of bridge
using the latest adhesive techniques can be expected to last many years.
PMID- 10765848
TI - Using a chlorine dioxide antibacterial gel for soft tissue healing.
PMID- 10765849
TI - Oral surgery for the general practitioner: an update. Interview by Phillip
Bonner.
PMID- 10765850
TI - Design optimization and evolution of bonded ceramics for the anterior dentition:
a finite-element analysis.
AB - OBJECTIVE: Finite-element method was used to explore the stress distribution of
incisors restored with porcelain veneers. The design of the incisal palatal
finish line was analyzed as a function of incisal overlap and initial tooth
substance loss (coronal fractures). METHOD AND MATERIALS: The treatment of intact
and fractured incisors was investigated using 8 different designs of porcelain
veneer. The palatal finish line varied from butt margins to extended chamfers.
The stress distribution was assessed in a 2-dimensional finite-element model,
reproducing a buccolingual cross section of an incisor. A palatal 50-N horizontal
force was applied to the incisal edge to simulate an extreme functional load. The
palatal surface tangential stresses were calculated. RESULTS: Considerable
differences were detected in the stresses at the level of the incisal-palatal
restoration margin. The margins of restorations with limited incisal overlap
(butt margin or minichamfer) showed low tensile stresses or even compressive
stresses. Restorations with a long chamfer extending into the palatal concavity
were subjected to the highest tensile stresses. In the presence of moderate crown
fractures (incisal one third) or severe wear, butt margins limited the palatal
extension of ceramic, thus reducing the amount of stress at the restoration
interface. In the presence of severe crown fractures (incisal two thirds), the
margins (either butt or chamfered) were subjected to low tensile forces when
located in the smooth convex area of the cingulum. CONCLUSION: Because of the
geometry and natural elastic modulus of mineralized tooth structures, a
concentration of tensile stresses is formed at the palatal concavity of teeth
restored with porcelain veneers. Long chamfers extending into the palatal
concavity are unfavorable because thin extensions of ceramic are generated in an
area of maximum tensile stresses. Minichamfers or butt margins are generally
recommended, especially in the presence of moderate crown fractures or severe
wear.
PMID- 10765851
TI - Expansion of contaminated amalgams assessed by photoelastic resin.
AB - OBJECTIVE: Eight amalgam alloys, 6 high-copper and 2 low-copper, were assessed
for expansion via photoelastic resin. METHOD AND MATERIALS: The photoelastic
resin sheet was sectioned into 20 x 25-mm blocks, and two 4 x 8-mm holes were
drilled into the resin. The amalgam alloys were hand condensed into the prepared
holes. Test conditions for each alloy were (1) uncontaminated, (2) contaminated
with 5 microL of Ringer's solution, and (3) contaminated with 5 microL of cell
culture medium. RESULTS: Contaminated high-copper amalgam alloys may exhibit
expansion to varying degrees but do not show the classic delayed expansion. One
spherical, nonzinc high-copper alloy showed no expansion, whether it was
uncontaminated or contaminated, and 3 high-copper alloys with different amounts
of zinc (0% to 1%) showed slight expansion when contaminated. One low-copper
alloy displayed delayed expansion; within 17 days after initial expansion in the
photoelastic resin, it had exceeded the greatest stress observed in any
contaminated, high-copper zinc-containing alloy at 3 months. CONCLUSION:
Contamination of dental amalgam is to be avoided, but a zinc-containing high
copper amalgam will not exhibit classic delayed expansion even if contaminated.
PMID- 10765852
TI - Abrasion, erosion, and abfraction combined with linear enamel hypoplasia: a case
report.
AB - Linear enamel hypoplasia is a developmental disturbance of enamel resulting in
clinically visible horizontal defects in enamel that are present on eruption of
the tooth. Nondevelopmental lesions of the hard tissues of the tooth, including
carious, abrasion, erosion, attrition, and abfraction lesions, require varying
amounts of time after tooth eruption to develop. Because linear enamel hypoplasia
lesions are present on eruption and are exposed to the factors responsible for
abrasion, erosion, and abfraction, nondevelopmental lesions could occur within
them in any combination. This report describes a patient with multiple teeth with
linear enamel hypoplasia lesions containing nondevelopmental defects as well as
nondevelopmental defects that occurred separately. Severe pain and a unique
lesion morphology were associated with the linear enamel hypoplasia defects.
Affected teeth were extracted because of advanced periodontitis and were
sectioned to determine the nature of the enamel and dentin lesions.
PMID- 10765853
TI - Sjogren's syndrome.
AB - Sjogren's syndrome (SS) is a progressive autoimmune rheumatic disorder. Its
precise etiology is unknown, although several contributing factors have been
identified. One theory is that the condition results from complications related
to infection with the Epstein-Barr virus. Primary exposure to or reactivation of
Epstein-Barr virus elicits expression of the human leukocyte antigen complex.
This is recognized by T lymphocytes (CD 4+) resulting in the release of cytokines
(tumor necrosis factor, interleukin-2, interferon-gamma, and others). A genetic
marker specific for Sjogren's syndrome, HLA-DR4, has been identified. According
to the World Health Organization, the prevalence of Sjogren's syndrome is
unknown. A recent epidemiologic study in Sweden estimated the prevalence in the
adult population to be 2.7%. In the United States, 10 years ago, the number of
patients with Sjogren's syndrome was thought to be fewer than 100,000. This
number today is estimated to be more than 1 million. Sjogren's syndrome has been
reported in nearly every major country of the world, and the geographic
distribution of cases appears to be relatively uniform. Sjogren's syndrome
typically affects women (90%) during the fourth or fifth decade of life. Isolated
cases of Sjogren's syndrome in children have been reported.
PMID- 10765854
TI - The effect of parotid salivary flow rate on the levels of salivary antimicrobial
proteins in patients with Sjogren's syndrome.
AB - OBJECTIVE: The purpose of this study was to examine the effect of salivary flow
rate on the levels of antimicrobial salivary proteins in 24 patients with
Sjogren's syndrome and 22 age- and race-matched healthy control subjects. METHOD
AND MATERIALS: Parameters examined included stimulated salivary flow rate, total
salivary protein, lactoferrin, lysozyme, amylase, and secretory immunoglobulin A.
RESULTS: The mean total salivary protein and the mean salivary amylase were
significantly greater in patients than in controls. However, no significant
difference was observed in the mean stimulated salivary flow rates or the levels
of lactoferrin, lysozyme, or secretory immunoglobulin A of patients and controls.
To examine the effect of salivary flow rate on the levels of salivary
antimicrobial protein, the levels of these proteins in patients with salivary
flow rate of < or = 0.3 mL/min per gland were compared to those in healthy
controls with salivary flow rate > or = 0.4 mL/min per gland. Analyses showed the
levels of lactoferrin to be significantly higher among patients than among
controls. CONCLUSION: The levels of salivary amylase and lactoferrin may be
influenced by the levels of salivary output in patients with Sjogren's syndrome.
The relationship between salivary flow rate and the levels of amylase and
lactoferrin is not clear at the present time.
PMID- 10765855
TI - Root canal treatment of an invaginated maxillary lateral incisor with a C-shaped
canal.
AB - The endodontic treatment of an atypical maxillary lateral incisor that contained
a C-shaped root canal is described. The unusual anatomic configuration of this
particular tooth and the advantage of using image magnification to facilitate
endodontic treatment are discussed.
PMID- 10765857
TI - Interproximal integrity of posterior partial-coverage ceramic restorations:
sequence of delivery and finishing.
AB - The conservative, nonretentive cavity design of partial-coverage ceramic
restorations provides a number of distinct advantages over traditional cast-metal
options. However, unique challenges are associated with precise delivery of the
restoration and the cleanup of excess luting resin. Restorative success and long
term gingival health are dependent on interproximal integrity at the restoration
tooth interface. This article examines the variables that affect this integrity
and introduces a number of innovative techniques that assure meticulous delivery
of posterior partial-coverage ceramic restorations.
PMID- 10765856
TI - Enhanced retention of glass-ionomer sealant by enamel etching: a microleakage and
scanning electron microscopic study.
AB - OBJECTIVE: A microleakage study and a scanning electron microscopic investigation
were conducted to test whether etching of enamel would improve adhesion of glass
ionomer cement sealants to fissure enamel. METHOD AND MATERIALS: Forty-eight
extracted human molars and premolars were divided into 2 equal groups, and their
crowns were cleaned with pumice. In group 1 enamel was etched for 45 seconds with
37% phosphoric acid. In group 2, enamel was not etched. Glass-ionomer sealant was
applied to all 48 teeth. Twenty teeth from each group were thermocycled in water
(120 cycles between 0 degree C and 56 degrees C) and stained with 0.5% methylene
blue solution. The remaining 4 teeth from each group served as a control for the
scanning electron microscopic evaluation. Twelve teeth from each group were cut
into 5 sections, and 12 were cleaved into 3 sections in a buccolingual direction.
RESULTS: Statistically significant differences in amounts of microleakage were
found between group 1 and group 2. Minimal microleakage was detected in 90% of
the etched teeth, whereas extensive microleakage was observed in 85% of nonetched
teeth. The scanning electron microscopic evaluation correlated positively with
the microleakage observations. The etched teeth revealed a cohesive failure
within the sealant material, while the nonetched teeth demonstrated an adhesive
failure at the sealant-enamel interface. Observation of the nonthermocycled teeth
confirmed those findings. CONCLUSION: Results suggested that etching prior to
application enhances the bonding of glass-ionomer sealant to fissure enamel.
PMID- 10765858
TI - Effects of repeated use on bond strengths of one-bottle adhesives.
AB - OBJECTIVE: Most one-bottle adhesives contain organic solvents (acetone or
ethanol) that displace the water entrapped within the network of collagen fibers
in etched dentin. Acetone and ethanol are volatile substances that could easily
evaporate from bottles during use. The objective of this in vitro study was to
assess the effects of repeated opening of bottles on dentin shear bond strengths
of 4 adhesives. METHOD AND MATERIALS: Eighty freshly extracted bovine incisors
were mounted, polished to 600 grit, and randomly assigned to 8 groups (n = 10).
After the application of the materials to 40 specimens at baseline, adhesive use
was simulated by opening bottles for 1 minute, 2 times a day, for 3 weeks, except
during weekends, when the bottles were kept refrigerated. After 3 weeks of
simulated use, the same adhesives were applied to 40 additional specimens. Resin
composite was applied to dentin in a No. 5 gelatin capsule and was light-cured.
After 500 thermal cycles (5 degrees C to 55 degrees C), shear bond strength
testing was performed with a universal testing machine at 0.5 cm/min. RESULTS:
Adhesives containing ethanol or water had similar mean bond strengths at baseline
and at 3 weeks. The acetone-based material had a significantly lower mean bond
strength at 3 weeks than at baseline. CONCLUSION: Acetone-based adhesives may
have a shorter useful life than ethanol- and water-based adhesives.
PMID- 10765859
TI - Retention of a fluoride-containing sealant on primary and permanent teeth 3 years
after placement.
AB - OBJECTIVE: The aim of this study, conducted in 132 randomly selected children,
was to evaluate the retention of a fluoride-containing sealant on primary and
permanent teeth. METHOD AND MATERIALS: In autumn 1995, a total of 195 primary
molars in 36 children aged 4.5 years on average and 391 permanent premolars and
molars in 96 children aged 10.5 years on average were sealed with Helioseal-F.
The manufacturer's instructions were followed closely. The teeth were cleaned
with a slurry of pumice and a rotating brush, isolated with cotton rolls, dried
with air, etched for 60 seconds with an etching gel (37% phosphoric acid), rinsed
with an air-water combination spray, and dried. Sealant was applied with a
cannula and polymerized for 60 seconds. A saliva ejector was used throughout the
procedure. Sealant retention was checked 3 years after placement. RESULTS: In the
primary molars, full retention was found in 95.04%, partial retention in 3.12%,
and loss of the sealant in 1.84% of the treated teeth. In the permanent molars,
the corresponding rates were 95.81%, 2.83%, and 1.36%, respectively. CONCLUSION:
Very good sealant retention was found 3 years after placement. The observed
difference in retention between primary and permanent molars was not
statistically significant.
PMID- 10765860
TI - A 3-year study of inlays milled from machinable ceramic blocks representing 2
different inlay systems.
AB - OBJECTIVE: The aim of this study was to evaluate the clinical performance of
ceramic inlays made from machinable ceramic blocks. METHOD AND MATERIALS: The 2
inlay systems involved computer-aided design and computer-aided machining (Cerec
Cos 2.1) or copy-milling technique (Celay). The study comprised 15 Celay inlays
and 15 Cerec inlays placed in 17 patients. The inlays were evaluated clinically
at baseline (1 week) as well as 1 and 3 years later (modified California Dental
Association quality evaluation system). RESULTS: One Celay inlay fractured after
1 year of service, and 2 Cerec inlays were replaced, 1 after 6 months and 1 after
1 year, because of pulpal pain and persisting hypersensitivity. One Celay inlay
lost retention after 2 years. At the 3-year evaluation, chipping and hairline
cracks were seen in 2 Celay inlays. Progressive disintegration of the marginal
luting cement was seen for both Celay and Cerec inlays. The remaining 25 inlays
performed satisfactorily throughout the 3-year period. CONCLUSION: Because of
their relatively high failure rate, these inlays should be reserved for esthetic
indications.
PMID- 10765861
TI - Effects of Nd:YAG lasers on root canal walls: a light and scanning electron
microscopic study.
AB - OBJECTIVE: This study evaluated amounts of debris, smear layer, and
recrystallized dentin on root canal walls treated with an Nd:YAG laser. The
presence of carbonized material was also assessed. METHOD AND MATERIALS: The root
canals of 36 extracted incisors were prepared by stepdown and stepback techniques
and divided into 4 groups. One group was not treated further, while 3 others were
exposed to the laser beam at an energy density of 159, 239, or 318 J/cm2. The
roots were split longitudinally, photographed, and examined using a scanning
electron microscope. The amounts of debris, smear layer, and recrystallized
dentin were recorded from horizontal bands around the root, 2, 6, and 10 mm from
the apices. RESULTS: Mean smear layer scores were similar for all groups at the 3
levels examined, ranging from 2.157 to 2.851 on a scale of 0.0 to 3.0. Mean
debris scores were similar for all groups at the 3 levels examined, ranging from
0.774 to 1.408 on a scale of 0.0 to 3.0. Recrystallized dentin was recorded in
all 3 irradiated groups at the 2-mm level, but only in the group irradiated with
318 J/cm2 at the 6- and 10-mm levels. Severe carbonization was recorded at the 2
mm level. CONCLUSION: Use of the Nd:YAG laser did not reduce the mean amounts of
debris and smear layer compared to a nonirradiated group. Carbonization was
recorded in the apical part of the canal, but this is not obvious when only
scanning electron photomicrographs are examined.
PMID- 10765862
TI - The hopeless tooth: when is treatment futile?
AB - The decision to place a tooth in the hopeless category is by no means a simple
one. There is always the possibility of being wrong, the possibility that this
tooth may prove to be the exception and, against all odds, survive as a
functioning component of the masticatory apparatus. These are the decisions that
make us dentists rather than technicians.
PMID- 10765863
TI - Retain or extract: the decision process.
AB - It is difficult to give up attempts to save a tooth and decide to extract.
Sometimes the decision is easy because experience allows the dentist to evaluate
the patient and the situation and make an educated prognosis for the tooth. The
thought process is extremely involved and many variables must be taken into
consideration, some of which the dentist has very little control over. The
process was much less involved when there were fewer options available to the
patient and the dentist. Teeth in themselves are very rarely hopeless; it is the
desires of the patient, the expertise of the dentist, and the conditions of the
oral environment that lead to a hopeless prognosis. A tooth can be moved to
another place in the mouth or even into another patient's mouth, and the
treatment decision changes, making it not as hopeless. The wish of the patient is
usually the final, determining factor for how treatment is carried out. Patients
make the decision whether to spend their time and money to save the tooth with
extraordinary effort or whether to cut their losses and give up on the tooth.
PMID- 10765864
TI - A clinical, radiographic, and scanning electron microscopic evaluation of
adhesive restorations on carious dentin in primary teeth.
AB - OBJECTIVE: The purpose of this project was to evaluate the performance of a
dentin adhesive system on carious and noncarious primary dentin in vivo. METHOD
AND MATERIALS: Forty-eight primary molars with carious lesions were randomly
assigned to 2 different treatments: group 1 (control, n = 24)--All identifiable,
irreversibly infected dentin was removed prior to the application of the bonding
agent and restorative material; group 2 (experimental, n = 24)--Irreversibly
infected dentin was partially removed prior to the application of the bonding
agent and restorative material. The control and experimental teeth were
clinically monitored every 3 months and evaluated 12 months after restoration.
The teeth were extracted around the time of exfoliation and processed for
scanning electron microscopy. RESULTS: Retention rate, marginal integrity, and
pulpal symptoms were identical in both groups. Radiographically, the radiolucent
area associated with the experimental restorations did not increase with time in
75% of the cases. For the control group, the adhesive system formed a hybrid
layer. In the experimental group, there was morphologic evidence of the formation
of an acid-resistant "altered hybrid layer." An acid-resistant tissue, resulting
from the interdiffusion of adhesive resin within the area of carious dentin, was
observed adjacent to and under the altered hybrid layer. CONCLUSION: Application
of an adhesive restorative system to irreversibly infected dentin did not affect
the clinical performance of the restoration.
PMID- 10765865
TI - Enhanced post crown retention in resin composite-reinforced, compromised, root
filled teeth: a case report.
AB - The introduction of an intraradicular composite reinforcing technique, in
conjunction with the reestablishment of matching post canal spaces, has allowed
compromised, root-filled teeth to be restored with functional, esthetic post
crowns. This clinical case report suggests that reconstituted post canals, in
accurately adapting to passive, parallel-sided, matching, and well-fitting posts,
can enhance the retention of post crowns. Other factors of clinical importance
relating to the resin-reinforced technique are discussed, including fracture
resistance, depth of polymerization, dentin adhesion, polymerization shrinkage,
and coronal microleakage.
PMID- 10765866
TI - Evaluation of esthetic parameters of resin-modified glass-ionomer materials and a
polyacid-modified resin composite in Class V cervical lesions.
AB - OBJECTIVE: The purpose of this study was to compare the esthetics of 3 resin
modified glass-ionomer materials and 1 polyacid-modified resin composite to the
esthetics of a conventional glass-ionomer control material. METHOD AND MATERIALS:
One hundred eighty-seven Class V cervical restorations were observed clinically
over 18 months. The esthetic index system that was used evaluated color match,
translucency or opacity, and surface roughness. RESULTS: The tested materials
behaved very dissimilarly and inconsistently. In general, the esthetic results of
the resin-modified glass-ionomer materials and the polyacid-modified resin
composite were far from optimal. The esthetic appearance of restorations
seriously deteriorated during clinical service, mainly because of discoloration
of margins, changes in translucency and opacity, and rapidly appearing roughness
or dullness on the surface. Both the resin-modified glass-ionomer materials and
the polyacid-modified resin composite evaluated in this study performed better
esthetically than did the conventional glass-ionomer material. CONCLUSION:
Indications for these combination materials are limited to areas where esthetics
is not a primary concern but where their ease of application may guarantee a more
durable functional result.
PMID- 10765867
TI - Clinical application of a fiberscope for periodontal lesions: case reports.
AB - In dentistry, the endoscope has generally been used to visualize inaccessible
areas, e.g., inside root canals or coronal surfaces of teeth; however, it has not
been used in periodontally diseased lesions. In this study, a newly designed fine
fiberscope (0.8- to 1.0-mm outer diameter) with an irrigation system was used to
visualize root surfaces and periodontal tissues affected by periodontal disease.
The fiberscope was inserted through fistulas, periodontal pockets, or root
furcations in 5 patients to provide clear operational views without the
obstruction of blood or soft tissues. The irrigation system of the endoscope
effectively allowed differentiation of hard and soft tissues as well as
restorative materials. The fiberscope system developed in this study was
effective for diagnosis, for enhancing visualization for periodontal surgery, and
for treating lesions such as fistulous tracts or furcation lesions.
PMID- 10765868
TI - Aerosol reduction during air polishing.
AB - OBJECTIVES: Concern has been expressed about the obvious aerosol cloud that is
generated during air polishing of teeth. These concerns have included infection
control, potential systemic effects, and environmental surface contamination
associated with the particles of sodium bicarbonate powder, water, and patient
generated material. This in vitro study evaluated an aerosol reduction device
designed for use during air polishing. METHOD AND MATERIALS: Eight artificial
teeth on a Dentoform model were polished with and without the aerosol reduction
device. The polishing was performed within a plastic enclosure that had a grid on
the sides. The water supply for the air polisher contained a 1% fluorescein
solution. The aerosol contamination was determined by counting the number of
squares that showed fluorescent spots under an ultraviolet light. RESULTS: The
mean contamination without the aerosol reduction device was 175.59 cm2. The mean
contamination with the aerosol reduction device was 4.37 cm2, a greater than 97%
reduction in aerosol contamination. CONCLUSION: The aerosol reduction device
significantly decreased the contamination produced during air polishing.
PMID- 10765869
TI - Retrospective analysis of 15 cases of nasolabial cyst.
AB - The nasolabial cyst is classified as a nonodontogenic cyst and is the only
nonodontogenic cyst to occur in soft tissue. The aim of this retrospective
analysis was to gather demographic, clinical, radiographic, and histopathologic
data on the nasolabial cysts described in the files of the Oral Pathology
Laboratory of Minas Gerais University School of Dentistry. Fifteen cases were
included in the analysis. The mean age of the patients at the time of diagnosis
was 42 years, and there was a female predilection. All the cysts were
asymptomatic. Pseudostratified columnar (respiratory) epithelium, alone or in
combination with other types of epithelium, was present in all cysts. Recurrence
was not observed after surgical excision.
PMID- 10765870
TI - Use of gloves and prevalence of glove-related reactions in a sample of general
dental practitioners in Italy.
AB - OBJECTIVE: The purpose of this study was to evaluate the frequency of the use of
gloves and to assess the prevalence of glove-related symptoms in a sample of
Italian dentists with a high occupational exposure to latex gloves. METHOD AND
MATERIALS: A 31-question instrument was mailed to all dentists (n = 550)
practicing in the town of Bologna during 1994 to determine the type of procedures
for which gloves were worn by dentists and the prevalence of self-reported glove
related symptoms. RESULTS: Of the dentists who replied to the items (n = 160),
94% reported that they usually wear nonsterile latex examination gloves; and 46%
reported that they wear surgical gloves, even if not exclusively. About 98%
reported changing gloves after contact with each patient, and 14% reported using
disinfectants to treat examination gloves. Of the 106 respondents claiming to use
examination gloves for surgical activities, 79 (74%) reported wearing them for
extractions. Sterile surgical gloves were reported to be mostly worn for implant
placement (47%) and periodontal surgery (42%). There were 46 (29%) responses
indicating glove-related problems; of those subjects, 14 (30%) reported having
other allergies. CONCLUSION: The use of gloves is common in the sample of Italian
dentists, and the choice between nonsterile examination gloves and sterile
surgical gloves seems to be made appropriately.
PMID- 10765871
TI - Incisal edge reattachment: the effect of preparation utilization and design.
AB - OBJECTIVE: This study evaluated the effect of preparation utilization and design,
and addition of resin composite to the bonding interface, on the fracture
resistance of reattached incisal fragments. METHOD AND MATERIALS: Sixty bovine
incisors were distributed among 1 control group and 5 experimental groups.
Experimental specimens were sectioned 3.0 mm from the incisal edge with a 0.15-mm
wafering blade at a 25-degree inclination apically in a faciolingual direction.
Two groups received no further preparation. Specimens in the other 3 groups
received either external bevels, internal bevels, or combined external and
internal bevels. One preparationless group was reattached with dentin bonding
agent alone. All other fragments were reattached with a dentin bonding agent
resin composite interface. After thermocycling and 4 weeks of bond weathering,
specimens were sheared to failure in a universal testing machine. RESULTS: No
significant differences in fracture strength were observed among any of the
experimental groups, yet each displayed significantly less resistance to fracture
than the control group. Reattachment of fragments in all groups restored
approximately one half or one third the fracture strength of the control teeth
for crown or root fractures, respectively. CONCLUSION: Compared to the simple,
expedient regimen of using a dentin bonding agent alone, nonconservative tooth
modification and the addition of resin composite to the bonding interface did not
increase resistance to fracture and thus provided no retentive advantage.
PMID- 10765873
TI - Nightguard vital bleaching beneath existing porcelain veneers: a case report.
AB - Dentist-prescribed, at-home bleaching with 10% carbamide peroxide was used to
lighten the apparent color of teeth with preexisting porcelain veneers. Veneers
had been placed over unprepared, tetracycline-stained teeth; the translucency of
the veneers over the discolored teeth resulted in a graying of the veneers. A
custom-fitted tray with no reservoirs and no gingival scalloping was fabricated.
A 10% carbamide peroxide material was applied nightly for 9 months to achieve the
maximum change in the underlying tooth color. The patient was pleased with the
apparent color change. Tooth sensitivity during treatment was minimal (lasting 4
days total); the patient treated sensitivity by brushing with a potassium nitrate
containing toothpaste or applying fluoride in the tray.
PMID- 10765872
TI - A clinical study of the effect of pellicle on the degradation of 10% carbamide
peroxide within the first hour.
AB - OBJECTIVE: The purpose of this study was to determine the degradation of 10%
carbamide peroxide within the first hour of use and the effect of pellicle on the
degradation of carbamide peroxide in vivo. METHOD AND MATERIALS: Fifteen subjects
were assigned to wear nightguard trays filled with bleaching gel for 0.5, 2.5,
5.0, 10.0, 20.0, 40.0, and 60.0 minutes under 2 conditions: (1) subjects did not
receive a prophylaxis before each bleaching treatment (pellicle was assumed to be
present on the tooth surface); and (2) subjects received prophylaxis to remove
pellicle from the tooth surface. At each evaluation time, 3 types of sample were
collected: (1) a "grab sample," a sample of gel taken with a spatula from the
reservoir of the tray on the maxillary right central incisor; (2) the remaining
gel from the tray; and (3) the remaining gel scraped from the teeth. The
collected gel samples were analyzed for the amount of peroxide using the United
States Pharmacopeia-accepted method. Subjects were asked not to swallow the
saliva during treatment but to expectorate into a beaker. The collected saliva
was analyzed to determine the amount of peroxide. This sample represented the
approximate amount of peroxide that subject would ingest during treatment.
RESULTS: Pellicle did not affect the degradation of carbamide peroxide for the
teeth or grab samples. The degradation of carbamide peroxide was exponential,
except during the first 5 minutes, when the degradation rate was much higher. The
saliva collected from subjects during use of the bleaching tray revealed an
average of 2.1 mg of carbamide peroxide for 1 hour of bleaching treatment.
CONCLUSION: The degradation rate is not affected by the removal of the pellicle.
PMID- 10765874
TI - Nonvital tooth bleaching: a 2-year case report.
AB - A discolored, nonvital maxillary right central incisor was bleached with sodium
perborate and water, used as a "walking" bleach. An excellent result was
obtained, proving the efficiency of both the intracoronal bleaching technique and
the materials employed. A clinical evaluation performed 2 years later revealed
that the tooth was slightly stained but esthetically satisfactory.
PMID- 10765875
TI - Instructional characteristics of online continuing education courses.
AB - OBJECTIVE: The purpose of this study was to determine the instructional
characteristics of online continuing dental education courses on the World Wide
Web. METHOD AND MATERIALS: One hundred fifty-seven online courses offered by 32
providers were reviewed for 34 criteria. RESULTS: Courses of various types
spanned a variety of topics. Approximately half of all courses offered continuing
dental education credit. The relationship between credit hours and course length
was quite variable. Most courses consisted of text and images. Very few courses
used advanced media such as video clips. Measured against an index of
instructional quality developed for this study, the instructional quality of the
courses, in general, was poor. Most for-credit courses contained self-assessment
questions, but only 28% of courses scored the questions online. Basic information
that was missing on many courses included the authors' names (29%); the intended
audience (81%); goals and objectives (77%); and references (85%). In 47% of the
courses, there was no opportunity to provide feedback to either the author or the
provider. CONCLUSION: The theoretical advantages of Web-based continuing dental
education are numerous, but the currently available online resources are mostly
of unacceptable quality.
PMID- 10765876
TI - Development of standards for the design of educational software. Standards
Committee for Dental Informatics.
AB - The ready availability of computers, combined with the advent of sophisticated
software development tools, has resulted in a proliferation of dental
instructional software. The quality of these products varies widely. Working
Group 5 of the Standards Committee for Dental Informatics has published an
initial set of guidelines to help course designers develop high-quality
instructional materials. In the future, these guidelines will evolve into
standards. This article summarizes the guidelines and considers future actions
that may be taken once the standards are in place.
PMID- 10765877
TI - Postorthodontic stability of the new attachment achieved by guided tissue
regeneration following orthodontic movement: report of 2 cases.
AB - Orthodontic treatment was provided after guided tissue regeneration of intrabony
defects in 2 patients with periodontal disease. The new attachment obtained by
guided tissue regeneration remained stable when subjected to orthodontic forces.
PMID- 10765878
TI - Cyclosporine A-induced gingival overgrowth: a comprehensive review.
AB - Cyclosporine A, an extremely effective immunosuppressant, is also associated with
various untoward effects, including gingival overgrowth. Despite intense clinical
and laboratory investigation, the cellular-molecular mechanism through which
cyclosporine A simultaneously acts as a selective immunosuppressant while it
elicits a connective tissue reaction in the gingiva remains poorly understood. In
recent years, cellular and molecular biologic techniques have elucidated a
variety of growth factors that control connective tissue homeostasis. Two growth
factors known to be major elements in wound repair and connective tissue
homeostasis are platelet-derived growth factor and transforming growth factor
beta 1. Increased gingival levels of these factors may be responsible for
promoting fibroblastic proliferation and fibroblastic production of extracellular
matrix constituents in overgrown gingival tissues. Expression of these factors
has recently been shown to be upregulated in these tissues. The results of these
recent studies may provide a foundation for understanding the molecular mechanism
involved in the pathogenesis of cyclosporine A-induced gingival overgrowth.
PMID- 10765879
TI - Early-onset periodontitis in a patient with Ehlers-Danlos syndrome type III.
AB - This case history describes the course of disease in a 17-year-old boy with
Ehlers-Danlos syndrome type III and early-onset periodontitis. Flow cytometric
tests showed a reduced cell count in the specific immune system. Immunoglobulin
concentrations in saliva and serum were within normal limits. Infection with T
lymphotropic viruses was excluded. The phagocytic capacity of the peripheral
blood polymorphonuclear leukocytes was unimpaired. The anaerobic infection
present in the early-onset periodontitis was treated with systemic antibiotic
therapy and closed curettage. Following 14 days of this treatment, signs of acute
inflammation subsided, and 18 months after therapy ended, a slight gain in
clinical attachment was found, and bone growth was visible via radiology.
However, a continuing lack of adequate oral hygiene represents a risk to the
success of therapy in the long term.
PMID- 10765880
TI - Evaluation of a mucosal-plaque index (MPS) designed to assess oral care in groups
of elderly.
AB - An index, called the mucosal-plaque score (MPS), was tested for intra- and inter
examiner agreement at an institution for elderly individuals with mental
disabilities. This index was designed to evaluate oral health and oral hygiene in
groups of individuals, particularly in hospitals or at other institutions. MPS
consists of the sum of a four-point mucosal score (MS) and a four-point plaque
score (PS). Intra-examiner agreement was assessed for one dentist (BMH), who
examined 24 individuals twice with a one-week interval. Weighted kappa values
were 0.60 for MS, 0.62 for PS, and 0.62 for MPS. Inter-examiner agreement between
two dentists was conducted by duplicate examinations on 20 persons. Weighted
kappa values were 0.47 for MS, 0.71 for PS, and 0.70 for MPS. In a second
assessment of inter-examiner-agreement, eight individuals were each examined by a
dentist, two dental hygienists, and one medical nurse. Weighted kappa values were
0.79 for MS, 0.80 for PS, and 0.77 for MPS. These results support the conclusion
that the MPS can serve as a reliable measure for the assessment of oral health
care in groups of older individuals.
PMID- 10765881
TI - Functional status and untreated dental caries among nursing home residents aged
65 and over.
AB - This descriptive study examined the relationship between untreated dental caries
and functional status among 958 dentate nursing home residents aged 65 and over.
Functional status was measured by the Physical Self-Maintenance Scale (PSMS). The
PSMS assessment revealed that 32% of subjects were unable to perform all
activities, and only 10% could perform all activities. Overall, 59% of subjects
had untreated coronal decay and 46% had untreated root decay. In bivariate
analysis, untreated coronal and root caries experiences were significantly
associated with PSMS limitations, lack of dental care utilization, sex, and
number of remaining teeth. Stratified analysis suggested an interaction between
functional status and dental care utilization. Among subjects who had received
dental care in the preceding year, PSMS status was not significantly related to
untreated caries experience; but among subjects who had not received care, PSMS
status was significantly related to untreated caries experience. In logistic
regression analysis of untreated root decay, a significant interaction was found
between PSMS status and dental care utilization. However, in logistic regression
analysis of untreated coronal caries, no significant interaction was found;
significant independent effects were found for dental care utilization and number
of remaining teeth, but not for PSMS status.
PMID- 10765882
TI - Conflicting priorities: oral health in long-term care.
AB - Open-ended interviews were conducted with 109 individuals. These included:
administrators, staff, dental personnel, residents, and family members,
associated with 12 long-term-care (LTC) facilities to contrast different human
resource and organizational strategies for managing the delivery of oral health
care to the elderly residents. A multiple case-study analysis revealed that no
particular organizational strategy was ideal, although three important components
-oral hygiene, diagnostic assessments, and dental treatment--were common to all.
The dental personnel everywhere believed that oral health in the midst of other
conflicting priorities received inadequate attention, while the administrators
and staff acknowledged that they were weak at recognizing oral disorders and
assisting with oral hygiene. In all, the interviews offered a portrait of the
conflicting priorities associated with LTC, and they provide practical insights
to successful strategies of care in this population.
PMID- 10765883
TI - Preferences for an influences on oral health prevention: perceptions of directors
of nursing.
AB - Directors of Nursing (DONs) from 196 of 206 Nebraska long-term-care (LTC)
facilities were sent a pre-tested questionnaire. The aim was to assess available
on-site dental services, existing oral health education and prevention programs
as well as future needs/preferences, and the influence of 10 factors in assessing
and maintaining residents' oral health. Of the 196 DONs contacted, 126 (64%)
participated. Only 36% of DON responders reported having on-site dental services.
DONs indicated a preference for nursing staff (NS) oral health inservice training
over other educational and/or programmatic proposals. When asked to select the
five most influential factors in assessing and maintaining residents' oral health
in their respective facilities, DONs selected resident factors (mean, 2.8) more
often than NS factors (mean, 2.2). DONs most often identified residents' (R')
ability to perform oral hygiene (n = 99), R' cooperation with OH assistance (n =
98), R' interest in their oral health (n = 83), NS interest in R' dental health
(n = 70), and NS time constraints (n = 69).
PMID- 10765884
TI - The management of drooling problems in children with neurological dysfunction: a
review and case report.
AB - Drooling in children with neurological dysfunction indicates neurogenic failure
to coordinate the muscles of the tongue, soft palate, and face which act in the
first stage of swallowing. This causes excessive pooling of saliva in the
anterior part of the mouth and consequent overspill. Treatment for drooling
includes behavioral, pharmacological, and surgical modalities. Correcting a
malocclusion has also been reported to help eliminate drooling. This paper
describes the treatment of a child with neurofibromatosis, psychomotor,
developmental, and neurologic retardation, and difficulty with speech. The
patient was referred to our clinic to correct his drooling. Simple orthodontic
treatment succeeded in eliminating the drooling and improving his speech.
PMID- 10765885
TI - Oral health knowledge, practices, and status among outpatient veterans at the VA
Maryland Health Care System.
AB - Poor oral health can have a significant impact on overall health and quality of
life. Yet few studies have established the oral health needs of outpatient
veterans. The purpose of this study was to assess the oral health knowledge and
practices, the dental status, and the periodontal treatment needs of outpatient
veterans seeking primary care services at a statewide healthcare system. Veterans
were interviewed and received an oral examination by a trained examiner using
NIDCR criteria for dental caries detection and the Community Periodontal Index of
Treatment Needs (CPITN). The mean age of the study participants' (n = 135) was
57.7 (SD = 14.1) years. Ninety-five percent of the sample was male and 44%
African-American. Untreated coronal and root caries was present in 57% and 36% of
veterans, respectively. Sixty-nine participants received the periodontal
examination, with 29% of them in Category III. An interpretation of these
findings shows a high need for preventive and restorative oral health care among
outpatient veterans receiving primary services in an integrated and comprehensive
VA health care system.
PMID- 10765886
TI - Characteristics of patients with autistic disorder (AD) presenting for dental
treatment: a survey and chart review.
AB - A group of 43 patients with AD (mean age, 13.5; SD, 5.9 yrs) was identified from
the University Hospital School Pediatric Dentistry Clinic. We reviewed the
patients' charts to obtain demographic data, dental findings, and the management
techniques used for treatment. The patients were divided into groups according to
Frankl's categories of behavior, ranging from definitely negative to positive.
Descriptive data are provided for each group. Commonly used communications and
pharmacological management techniques, as well as physical restraints, enabled us
to treat all the patients in the traditional dental setting, when simple
procedures were planned. Treatment under general anesthesia in the operating room
was necessary in 37% of all patients when comprehensive care was required or
difficult procedures were carried out. A questionnaire was also sent out to the
caregivers to gather data on patients' nutrition and eating/chewing habits. In
the sample surveyed, two-thirds of the individuals reportedly exhibited a normal
eating pattern, while 14% pouched food. Soft, sweet, or sticky foods were
preferred by 41% of the patients.
PMID- 10765887
TI - An association between dentate status and hearing acuity.
AB - Hearing improvement following dental treatment has been reported in case studies,
yet few objective studies of this phenomenon have been conducted. To determine if
a relationship exists between dentate status and hearing acuity, we conducted a
retrospective study of elderly subjects enrolled in a health promotion clinical
trial. Air-conduction pure tone average thresholds (PTA) administered to left and
right ears at 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz, and 6000 Hz were used
to create six hearing outcome variables, and were compared between groups of
subjects who either had 25 or more teeth (n = 182) or were edentulous (n = 43).
Mean PTA thresholds were significantly greater (p < 0.05) in edentulous subjects
for each hearing outcome variable, and differences between unadjusted group means
ranged from 4.9 dB to 8.6 dB. Mean PTA thresholds adjusted for clinical factors
known to affect hearing also indicated worse hearing acuity in the edentulous
group. These pilot findings suggest an association between dentate status and
hearing acuity.
PMID- 10765889
TI - Dental care for children fed by tube: a critical review.
AB - No guidelines for the oral care of children fed by tube have been published. Poor
oral health (unrestored caries lesions, poor oral hygiene, dependence for oral
care) and tube-feeding are associated with the development of aspiration
pneumonia. Children fed by tube have abundant calculus, and low caries activity.
The potential for dental erosion related to gastro-esophageal reflux and oral
hypersensitivity is high. To optimize oral health and reduce the risk of
aspiration pneumonia, this population should receive dental care at more frequent
intervals than children fed orally. Modifications to dental procedures are
suggested to minimize the risks associated with dental treatment. Evidence-based
treatment guidelines are indicated to optimize dental care for children fed by
tube.
PMID- 10765888
TI - Using the GOHAI to assess oral health status of frail homebound elders:
reliability, sensitivity, and specificity.
AB - A pilot study assessed the clinically determined and self-reported oral health
status of 50 randomly selected homebound patients served by Boston's Home Medical
Service. The sample was largely female, low-income, and edentulous. The median
age of the patients was 81 years (range, 64-101). While 76% deemed themselves to
be in good to excellent oral health, 80% of the patients had not seen a dentist
within the last two years, and 80% were found to be in need of routine dental
care. To assess whether the Geriatric Oral Health Assessment Index (Atchison and
Dolan, 1990) could be used by non-dental health professionals to determine the
need for requesting dental consultation, the study physician repeated the
administration of the GOHAI for 23 of the 50 subjects within eight weeks of the
initial examination. For the 23 subjects having both dentist- and physician
administered GOHAI scores, the intraclass correlation coefficient was r = 0.61 (p
= 0.002), indicating good agreement between the dentist's and physician's
administrations of the GOHAI. However, given the high prevalence of need for
care, the GOHAI appears to be of less value than an examination for identifying
persons who need dental care in this population. Future research is needed to
examine the GOHAI's sensitivity and specificity in populations with low to
moderate prevalence of treatment need.
PMID- 10765890
TI - Opinions and feelings on eating with complete dentures: a qualitative inquiry.
AB - Our knowledge of variables affecting the coping strategies that lead to
acceptance of foods in populations wearing complete dentures is limited. Focus
groups were conducted with the specific aim of determining factors responsible
for successful adaptation to chewing with complete dentures. Each of the five
focus groups consisted of eight to 15 participants (mean = 11; mean age = 64
yrs), of mixed gender, with at least five years of denture-wearing experience
(mean = 7 years), and with groups varying in their socio-economic and ethnic
backgrounds. Participants' statements (n = 324) were sorted for their content, by
consensus between the two investigators, into 12 conceptually independent domains
(listed in decreasing order of frequency of mention): foods and food textures
causing difficulties when eating, foods being avoided, stability and retention of
dentures, social constraints, bolus size, general satisfaction with the current
dentures, general experience with dentures, sensation of temperature, experience
of pain during chewing, experiences with taste, experiences with rinsing the
dentures after eating, and time involved with chewing. In addition, further
analysis of statements showed that food texture was the most commonly mentioned
with foods that were either difficult to chew or avoided. These perceptions
significantly affected the choice of food. The results of this qualitative study
indicate that food texture is one of the major factors influencing the choice of
a coping strategy by denture wearers when trying to overcome difficulties in
chewing specific foods. As such, food texture may have a significant effect on
patients' success in the process of their functional adaptation.
PMID- 10765891
TI - Blood pressure measurement by community dentists.
AB - The benefit and implications of blood pressure (BP) measurement in dental
patients are a standard curricular component of most physical evaluation courses
in dental schools. However, previous research has indicated that preventive
procedures such as oral cancer examinations frequently are not completed or
documented. A survey of practicing dentists was conducted in a Midwest
metropolitan area to determine the frequency of BP measurement and conditions
under which this vital sign is likely to be measured. Two hundred four responses
were obtained from a telephone survey which included questions characterizing BP
measurement on the basis of patient age and medical diagnosis. The results of the
survey indicated that 57.4% of respondents do not check the BP of new patients
over the age of 65, while 74% do not check the BP of new patients under 30 years
of age. Fourteen percent admitted never measuring BP. The results varied by
graduation years and by dentist's completion of AEGD or GPR programs. The results
suggest great variation in the recording of BP and the criteria which are applied
to those decisions. Further study should investigate factors contributing to low
compliance with screening procedures such as the clinical measurement of BP and
other health-promotion measures.
PMID- 10765892
TI - Storm-related mortality--central Texas, October 17-31, 1998.
AB - On October 17, 1998, a series of storms moved across the central and south
regions of Texas, dropping up to 22 inches of rain in some areas and spawning
several tornados. Sixty Texas counties (24%) reported flooding during October 17
19. Thirty-six counties became eligible for federal and/or state assistance as a
result of damages suffered from this storm system during October 17-31. Estimated
flood damage was approximately $900 million, including damage to 12,000 homes,
700 businesses, and public property. This report summarizes findings of an
epidemiologic investigation of 31 deaths associated with the storm system.
PMID- 10765893
TI - Motor-vehicle occupant fatalities and restraint use among children aged 4-8 years
-United States, 1994-1998.
AB - In the United States, more children aged 4-8 years die as occupants in motor
vehicle-related crashes than from any other form of unintentional injury (1). To
reduce the number of deaths and injuries caused by motor-vehicle-related trauma,
child passengers in this age group should be restrained properly in a vehicle's
back seat (2). To characterize fatalities, restraint use, and seating position
among occupants aged 4-8 years involved in fatal crashes, CDC analyzed 1994-1998
data from the Fatality Analysis Reporting System (FARS), which is maintained by
the National Highway Traffic Safety Administration (NHTSA). This report
summarizes the results of that analysis, which indicate that during 1994-1998,
little change occurred in the death rate, restraint use, and seating position
among children aged 4-8 years killed in crashes.
PMID- 10765894
TI - Surgery and anaesthesia for amiodarone-associated thyrotoxicosis.
PMID- 10765895
TI - Schistosomiasis: clinical relevance to surgeons in Australasia and diagnostic
update.
AB - All surgeons working in Australasia should be prepared to encounter imported
cases of schistosomiasis. The disease should be considered when typical symptoms
are present, and there is evidence of skin exposure to fresh water in an endemic
area. Whether or not signs of urinary or intestinal tract schistosomiasis are
present, ectopic ova can involve and produce symptoms in almost any structure
including the liver, the lungs, the reproductive system and the central nervous
system, sometimes producing puzzling clinical abnormalities decades after primary
infection. Recovery of ova from urine, stool or their detection in a biopsy
confirms diagnosis but, when this is unsuccessful, immunological tests support
diagnosis. Imaging techniques (e.g. ultrasonography, standard radiology, computed
tomography or magnetic resonance imaging scans) may indicate and define
involvement of various organs and structures. The surgeon often has an important
role to play in the management of the protean complications of schistosomiasis.
PMID- 10765896
TI - Breast cancers invisible on mammography.
AB - BACKGROUND: A proportion of the cancers 'missed' at mammography are invisible
even with the benefit of hindsight. The aim of the present study was to identify
a group of women with proven breast cancer whose mammograms did not show a
suspicious lesion even in retrospect (i.e. the truly mammographically occult
cancers), and to compare them with mammogram-positive cancers. METHODS: A total
of 1757 breast cancers was diagnosed at the Wesley Breast Clinic's Screening or
Diagnostic Services between July 1987 and August 1997. One hundred and twenty
cases were identified where, after independent review by two of the authors, no
mammographic abnormality could be found in the region where the cancer was
subsequently found. These 120 cases were compared with 1548 cancers considered to
have a lesion visible on mammography, whether benign, indeterminate, suspicious
or malignant in appearance. RESULTS: In 90% of the mammogram-negative cancers, a
clinical abnormality led to further investigation, while the remainder were found
incidentally on ultrasound. There were a higher proportion of dense breasts, and
of women aged 40-49, in the mammogram-negative cancers than in the mammogram
positive cancers. The mammogram-negative cancers were of smaller size overall,
but three of them were surprisingly large (7-11 cm). In both the mammogram
positive and -negative cancers approximately 60% were ductal invasive cancers.
CONCLUSIONS: Where factors are present that make mammographically occult
malignancy more likely (e.g. age 40-49 and dense breasts), women may be targeted
for further investigation by other modalities. This is essential in the presence
of a clinical abnormality.
PMID- 10765897
TI - The operative management of screen-detected breast cancers.
AB - BACKGROUND: Mammographic screening for breast cancer not only reduces the overall
mortality from breast cancer but allows greater opportunities for breast
conserving operations. The predicted degree of breast conservation is not being
realized, but is increasing in centres that have published their results.
METHODS: The operative management of breast cancers diagnosed by BreastScreen
Central and Eastern Sydney Screening and Assessment Service were compared between
two time periods: January 1988-December 1992 (group 1) and January 1993-December
1995 (group 2). The rate of breast conservation, and other data were compared
between the two periods. An attempt was made with multivariate analysis to
identify some of the factors that made mastectomy rather than conservation more
likely. RESULTS: There were 723 cancers detected that were suitable for analysis
(group 1, n = 273; group 2, n = 450). In group 1 the breast conservation rate was
42.9%; this increased significantly to 60.4% in group 2 (P < 0.001). The data
were examined to determine if there was any other factor that had changed over
the time periods which might account for the increased rate of breast
conservation. The use of pre-operative diagnostic techniques such as fine needle
aspirate cytology and core biopsy increased significantly. Multivariate analysis
comparing the differences in patient age, diagnostic technique, tumour type,
grade, size, location and lymph node status, both independently and compositely
did not account for the increase in breast conservation in group 2. CONCLUSION:
The increase in breast conservation is due to other factors such as the surgeons'
approach and patient attitude. The use of pre-operative, minimally invasive
tissue sampling techniques is increasing.
PMID- 10765898
TI - Refractory amiodarone-associated thyrotoxicosis: an indication for thyroidectomy.
AB - BACKGROUND: Tasmania is an area of endemic iodine deficiency. Amiodarone is a
class III anti-arrhythmic drug that is widely used for the management of
ventricular and supraventricular tachydysrhythmias. Individuals from areas of
endemic iodine deficiency appear more likely to manifest hyperthyroidism
following amiodarone therapy, whereas hypothyroidism is a more frequent
complication in iodine-replete communities. METHODS: Cases series. The clinical
and biochemical response to medical and surgical management of five consecutive
Tasmanian patients presenting with severe type-II amiodarone-associated
thyrotoxicosis was reviewed. RESULTS: Five patients were identified. Combinations
of antithyroid therapy including propylthiouracil, lithium carbonate,
dexamethasone and cholestyramine were used. Thyroidectomy was required in two
cases (40%) due to severe unremitting thyrotoxicosis despite combined drug
regimens. Anaesthesia and total thyroidectomy were undertaken without
complication despite the presence of severe hyperthyroidism at the time of
surgery. In both cases thyroid histopathology demonstrated degenerative and
destructive follicular lesions with multinuclear cell infiltrate and focal
fibrosis. CONCLUSION: Amiodarone-associated thyrotoxicosis may be severe and
refractory to medical therapy. Despite the potential risks of anaesthesia
associated with uncontrolled thyrotoxicosis, thyroidectomy should be considered
in the setting of life-threatening thyrotoxicosis.
PMID- 10765900
TI - Laparoscopic anti-reflux surgery in New Zealand: a trend towards partial
fundoplication.
AB - BACKGROUND: The advent of laparoscopic anti-reflux surgery has generated
considerable debate regarding the best technique. The present study was
undertaken to determine the trends and current technique in laparoscopic anti
reflux surgery in New Zealand. METHODS: A confidential nationwide postal survey
was sent to all general surgeons in New Zealand; it was repeated after a month,
and followed up with a telephone prompt, if necessary. RESULTS: Of the 146
questionnaires sent out, 126 were returned (response rate: 86%), and 104 were
excluded (no anti-reflux surgery performed (n = 96); surgeon retired (n = 5);
paediatric surgeon (n = 3)). The number of operations performed by the 22 (16%)
adult general surgeons who had performed laparoscopic anti-reflux surgery
increased 4.6 times from 1991 to 1997 (474 open and 1218 laparoscopic
operations). The median number of cases per surgeon was 30 (range: 5-300). In
1997 there were 208 (60%) total fundoplications (TF) and 135 (40%) partial
fundoplications (PF) performed. Variations in the technique of TF included the
Nissen-DeMeester (10 surgeons), the Nissen-Rosetti (nine surgeons), division of
short gastric vessels (10 surgeons), and routine cruroplasty (14 surgeons). A PF
had never been performed by six surgeons, was preferred by six surgeons, and four
other surgeons were performing it more often. Variations in the technique of PF
included posterior (12 surgeons) and anterior (four surgeons) forms. CONCLUSION:
There is significant variation in the technique of laparoscopic anti-reflux
surgery in New Zealand. A TF is preferred by 16 surgeons, but there appears to be
a trend towards PF among the more experienced surgeons.
PMID- 10765899
TI - Thyroid surgery and voice-related outcomes.
AB - BACKGROUND: Vocal dysfunction in patients with thyroid pathology has been poorly
documented, and dysfunction after thyroid surgery is generally reported in terms
of recurrent laryngeal nerve or external laryngeal nerve palsy. But voice
dysfunction is more complex than simply nerve integrity. The present study
reports the incidence of dysphonia in patients presenting for thyroid surgery,
and relates postoperative changes in vocal function to recurrent and external
laryngeal nerve function, and the surgical handling of the strap muscles.
METHODS: Fifty patients were assessed by Visipitch before and after
thyroidectomy. Following surgery the patients filled out a questionnaire.
RESULTS: Overall 26 of 44 patients had no subjective postoperative voice change,
while 10 reported subjective deterioration and eight reported subjective
improvement in voicing. Postoperative objective assessment of these patients
found that 17 were the same, eight refused to come for testing because they felt
their voice had not changed, 13 were better and six were worse. Following surgery
two patients (4.5%) had temporary recurrent laryngeal nerve palsies (2.5% of
nerves at risk), and four patients (10%) suffered external laryngeal nerve
palsies. Division of strap muscles was not detrimental to voicing. Six patients
were lost to follow-up. Fifteen patients (34%) presented with vocal
abnormalities, six (40%) of whom improved postoperatively. CONCLUSIONS: Patients
may have voicing abnormalities before thyroid surgery is performed. Surgery may
improve or worsen the voice irrespective of the pre-operative voice status.
PMID- 10765901
TI - Gallstones and common bile duct calculi in infancy and childhood.
AB - BACKGROUND: Gallstones and common bile duct calculi have been increasingly
diagnosed in recent years in infants and children. The present study aims to
review the spectrum of this disorder in the last two decades. METHODS: During the
period 1979-96 a total of 102 consecutive infants and children were diagnosed in
Royal Alexandra Hospital for Children with gallstones or common bile duct
calculi. A detailed retrospective analysis and follow-up of these children form
the basis of the present report. RESULTS: The median age at presentation was 10
years. Recurrent right upper quadrant pain was the most common clinical
presentation. The male-to-female ratio was 3:2 and this male predominance was
noted in all the age groups. Aetiologically three identifiable groupings were
noted: idiopathic disease (n = 66), haematological diseases (n = 23) and specific
non-haematological disease (n = 13). The incidence of idiopathic and
haematological stones had increased two-fold in the second half of the study. The
majority of children (86%) underwent surgical correction. Choledocholithiasis
(CDL) was noted in 18 children (18%). Jaundice was commonly associated with
abdominal pain in this group. A higher incidence of common bile duct calculi was
noted in females and children less than 5 years of age (P < 0.01). Common bile
duct calculi were accurately diagnosed by pre-operative imaging in all 18
children. Surgical correction was required in all except two. CONCLUSIONS: The
present study suggests an increasing incidence of gallstones in children.
Cholelithiasis in children occurs commonly in boys, is idiopathic in aetiology
and presents with a vague right upper quadrant pain. Choledocholithiasis is not
uncommon in children, occurs more commonly in girls aged < 5 years and presents
with jaundice or abnormal liver function tests.
PMID- 10765902
TI - The use of laparoscopy in the management of adnexal pathologies in children.
AB - BACKGROUND: The authors' experience of using laparoscopy in the management of 23
girls (mean age: 8.9 years; range: 3 months-15 years) with various adnexal
pathologies over a 3-year period is reviewed. METHODS: Of the 23 patients, seven
were evaluated for congenital gonadal pathologies, 15 presented with abdominal
pain and one patient had an antenatally diagnosed adnexal mass. Detailed
laparoscopic examination of the pelvic cavity and laparoscopic gonadectomy were
successfully performed in all seven patients with congenital gonadal pathologies:
mosaic Turner's syndrome (n = 2), gonadal dysgenesis (n = 3) and testicular
feminization syndrome (n = 2). Of 15 patients presenting with abdominal pain, 11
had an adnexal mass, two had acute appendicitis and two had pelvic inflammatory
disease. RESULTS: Laparoscopic excision of the adnexal masses were successfully
performed in 10 of 11 patients. Conversion to open surgery was required in one
patient with a huge teratoma. Laparoscopic appendicectomy was successfully
performed in both patients with acute appendicitis while diagnostic laparoscopy
was the only procedure required in the two patients with pelvic inflammatory
disease. Laparoscopy in the infant with an antenatally diagnosed adnexal mass
confirmed this to be an omental cyst, which was successfully excised. All
patients recovered without complications and good cosmetic result was universally
achieved. CONCLUSION: Laparoscopy is safe and effective in both diagnosis and
treatment of adnexal pathologies in children.
PMID- 10765903
TI - Pilonidal disease in Singapore: clinical features and management.
AB - BACKGROUND: Pilonidal disease has not been well documented in Asian people. The
aims of the present study were to investigate any variations in the clinical
features and effectiveness of various surgical treatments in such a population.
METHODS: A prospectively collected computerized database of 61 consecutive
patients admitted to a specialist colorectal unit over a 9-year period was
studied. The five methods of surgical treatment used during this period (incision
and drainage; laying open; marsupialization; primary closure; and the flap
procedure) were compared. RESULTS: There were 38 men and 23 women with a mean age
of 27+/-1.02 years. Pilonidal disease was significantly more common among the
Indian people (52.5% of patients) than the other ethnic races in the Singaporean
community (P < 0.001). Chronic discharging sinuses were the most common
presentation (93.4%). There were no differences between the various surgical
techniques employed with regard to the time required for wound healing (mean:
48+/-21 days) and recurrence rates (4/61, 6.6%). Wound dehiscence after primary
wound closure (10%) and flap procedures (42%) meant that the overall healing rate
was not faster than when the wound was just laid open. Furthermore, flap
procedures required a longer hospitalization than other procedures (P = 0.005).
CONCLUSION: Pilonidal disease was more common among Indian people, the more
hirsute among the Singaporean population. Primary closure and flap procedure did
not improve overall wound healing because of dehiscence.
PMID- 10765904
TI - Pancreaticoduodenectomy with pancreaticogastrostomy: assessment of patients'
nutritional status, quality of life and pancreatic exocrine function.
AB - BACKGROUND: The changes in digestive function of patients with
pancreaticoduodenectomy (PD) and pancreaticogastrostomy reconstruction have not
been well-documented. The present study sought to assess the nutritional status,
quality of life and pancreatic exocrine function in this group of patients.
METHODS: The study group consisted of 11 PD with pancreaticogastrostomy patients.
The control group consisted of 11 consecutive patients who had subtotal
gastrectomy (SG) for distal stomach tumours. RESULTS: The median ages for the PD
and SG groups were 57 and 59 years, respectively. The median intervals between
surgery to assessment were 68 and 60 weeks, respectively. The PD group attained a
mean of 92.7% of their pre-surgery weight compared to 91.3% in the SG group. Both
groups had a comparable gastrointestinal quality of life index and Visick scale
scores. Exocrine insufficiency using the faecal chymotrypsin test was present in
36% of patients with PD. None of the patients in the SG group had exocrine
insufficiency. CONCLUSION: Pancreaticoduodenectomy patients had a significant
occurrence of pancreatic exocrine insufficiency compared to the SG group. But
patients with PD and pancreaticogastrostomy reconstruction maintained a
nutritional status and quality of life similar to those with curative SG for
stomach malignancy. Apart from exocrine insufficiency, the concomitant
gastrectomy in the PD group is an important factor responsible for their
inability to gain weight.
PMID- 10765905
TI - In-hospital mortality after transurethral resection of the prostate in Victorian
public hospitals.
AB - BACKGROUND: The purpose of the present paper was (i) to identify trends in in
hospital mortality after transurethral resection of the prostate (TURP) in
Victorian public hospitals; and (ii) to explore associations between in-hospital
mortality after TURP and age, adverse events, type of admission
(emergency/planned), location of the hospital (metropolitan/rural), teaching
status of the hospital and length of stay. METHODS: Trends in in-hospital
mortality after TURP and the associations between in-hospital mortality and the
aforementioned variables were studied using International Classification of
Diseases, 9th revision, Clinical Modification (ICD-9-CM) coded Victorian hospital
morbidity data from public hospitals between 1987-88 and 1994-95. Crude and
adjusted odds ratios (OR) and 95% confidence intervals (CI) were based on
univariate and multivariate logistic regression, respectively. RESULTS: After
adjustment for age, comorbidity, and other confounding variables, the trend in
mortality reduction over time was highly significant (P for trend < 0.0001, 95%
CI for trend: 0.84-0.95). Highly significant associations with mortality were
observed for emergency admissions (OR = 1.99, P < 0.0001), presence of adverse
events (OR = 2.69, P < 0.0001), length of hospital stay (P for trend < 0.0001,
95% for trend: 1.88-2.15) and age (P for trend < 0.0001; 95% CI for trend: 1.26
1.48). CONCLUSIONS: Routinely collected data from hospitals can provide tentative
evidence of improved effectiveness of a surgical treatment, provided analysis
takes careful account of potential sources of bias, especially those related to
possible changes in case selection over time. These kinds of data should
stimulate a joint effort between clinicians, quality assurance experts and
epidemiologists to confirm this attribution, and to locate the causative factors.
PMID- 10765906
TI - Management of gunshot wounds at a Sydney teaching hospital.
AB - BACKGROUND: Injuries caused by firearms account for only a small percentage of
trauma admissions and deaths in Australia but are frequently the subject of media
and public attention. The present study examines the epidemiology and management
of firearm injuries presenting to St Vincent's Hospital, which is located at the
edge of the central business district of Sydney. METHODS: The medical records of
all patients presenting to St Vincent's with a gunshot wound (GSW) from January
1988 to December 1998 were analysed. Additional details were acquired from New
South Wales State Coroner's Court reports and media archives, especially major
newspapers. RESULTS: Seventy-four patients presented to St Vincent's Hospital
with 103 GSW. The age (mean +/- SD) was 31+/-11 years. Sixty-seven patients (91%)
were male. Alcohol was identified as a factor in 24 cases (32%) while other drugs
were indicated in four cases (5%). Ten patients (14%) had intentionally self
inflicted wounds, seven (9%) had accidental wounds and 57 (77%) had wounds that
were caused by crime-related violence. Sixty patients (81%) underwent operation
for their injury. Thirty complications were seen in 18 patients (24%). Eleven
patients (15%) died. The length of hospital stay (mean +/- SEM) was 18+/-9 days.
CONCLUSIONS: The incidence of trauma due to firearms has not increased at St
Vincent's hospital in the period 1988-98. Most GSW were inflicted in the setting
of criminal violence, with a high proportion due to handguns. Patients were
mostly young men, and alcohol or other drugs were frequently involved. Outcomes
are comparable to other centres managing large volumes of penetrating trauma.
PMID- 10765907
TI - Unplanned admissions in day-case surgery as a clinical indicator for quality
assurance.
AB - BACKGROUND: Day surgery is a modern, effective and economical way to treat
patients while maintaining the same level of quality of patient care. Quality
improvement in day surgery units, however, continues to be an issue due to high
rates of unplanned admissions. The aim of the present retrospective study was to
investigate reasons for and methods of preventing unplanned postoperative
admissions in a day surgical unit over a 12-month period in respect to different
surgical specialties. METHODS: The study was based on an audit from the Endoscopy
and Day Surgery Unit (EDSU) at Launceston General Hospital, which provides health
care to a population of more than 120000. RESULTS: For the accounted period 920
outpatients had elective day surgical procedures. Overall the unplanned admission
rate was 4.7%, and surgical, anaesthetic and social reasons accounted for 58.2,
37.2 and 4.6% of the unplanned admissions, respectively. The highest rate of
unplanned admissions was for plastic and reconstructive surgery (12.8%) and
orthopaedic surgery (7.5%) despite the relatively small number of patients who
underwent such procedures in the day surgery unit. The results also showed a
correlation between age group, pre-operative medical status of the patients found
suitable for the day surgical procedure and unplanned admissions. CONCLUSIONS:
Strategies to reduce the unplanned admission rate which include patient selection
and pre-operative assessment, patient waiting time and education, pre-operative
anaesthesia, follow-up with nursing care and postoperative analgesia are
discussed.
PMID- 10765908
TI - Development of small diameter intramedullary nails made from ISO 5832-9 stainless
steel.
AB - BACKGROUND: In order to improve strength in small diameter intramedullary nails,
a system was designed in which the implants were manufactured from 30% coldworked
ISO 5832-9 stainless steel. METHODS: Nail diameters were 9 and 10 mm for the
femur, and 8 and 9 mm for the tibia. The nails were solid rods and the screws
were partially threaded. Pre-clinical bending yield tests established that the 8
, 9- and 10-mm diameter rods had strengths comparable, respectively, with 10-, 12
and 14-mm diameter Grosse-Kempf nails. Forty-eight femoral and 98 tibial shaft
acute fractures were treated with this system. Postoperatively, patients were
allowed to gently bear weight as tolerated. RESULTS: There was one broken nail,
occurring 10 months after femoral nailing. There were six broken screws,
occurring between 3 and 6 months postoperatively in two patients and after more
than 6 months in four patients. The broken screws had no adverse clinical effect.
Five patients required late bone grafting or exchange nailing, and 15 patients
required dynamization. CONCLUSION: This design of small diameter locked
intramedullary nails was strong enough to allow early weightbearing.
PMID- 10765909
TI - Teaching on the run: teaching skills for surgical trainees.
AB - BACKGROUND: Increasing recognition of the need for training in teaching skills
for clinical teachers has coincided with data that registrars and residents
conduct much 'on the job' teaching as part of their routine work. While attention
has been devoted to training consultants, support for the teaching role of the
junior staff has been relatively neglected. The aim of the present report is to
describe the teaching experiences of surgical registrars and the impact of a
registrar teaching workshop. METHOD: A half-day programme combining presentation
and discussion of surgical teaching with practical skills sessions was designed
for surgical registrars at Prince of Wales Hospital. The programme included
observation and feedback of brief teaching simulations at the bedside of
volunteer patients to newly commenced clinical students, and small group sessions
on clinic and operating theatre teaching. A pre-workshop questionnaire sought
information about the registrars' own teaching, and a survey 3 months after the
workshop determined if any changes to teaching practice had occurred. RESULTS:
The registrars were generally moderately to very confident with their teaching
ability but more than 75% felt that they were more confident after the workshop.
Only three of 39 registrars had received any instruction aimed at improving their
teaching skills, yet 34/39 had taught either on the ward, in the clinics or in
the operating room. Follow-up after 3 months revealed that most registrars were
enjoying their teaching tasks more, and half had increased their teaching since
the workshop and began discussing teaching with their surgical colleagues.
CONCLUSIONS: The present project demonstrates that relatively brief interventions
focused on skill development may enhance the confidence and enjoyment of junior
clinical teachers and increase the frequency of 'teaching on the run'.
PMID- 10765910
TI - Did Rembrandt's Bathsheba really have breast cancer?
AB - BACKGROUND: Rembrandt's Bathsheba (Louvre, Paris) reveals an abnormality of the
left breast and axilla. Previously breast cancer has been suggested as the
probable diagnosis. METHODS: The present paper reviews the clinical history as
well as the clinical findings. RESULTS: Inconsistencies, pitfalls in the
diagnosis and the consequences of the possibility of a different model for the
body of the figure are discussed. CONCLUSION: An alternative diagnosis of an
infective process such as tuberculous mastitis or, less likely, chronic
lactational breast abscess is suggested.
PMID- 10765912
TI - Endoscopic retrograde cholangiopancreatography-induced haemolytic uraemic
syndrome.
PMID- 10765911
TI - Symptomatic epidural lipomatosis following cyproterone acetate therapy.
PMID- 10765913
TI - Radionecrosis of internal carotid artery in nasopharyngeal carcinoma presenting
as epistaxis.
PMID- 10765914
TI - Blunt trauma to the appendix.
PMID- 10765915
TI - On the edge of the millennium: prospects and problems for our patients and us.
PMID- 10765916
TI - Report on the Fourth International Workshop on Reactive Arthritis.
AB - There are large differences in the antigenicity and biology of the ReA-associated
bacteria. For induction of arthritis, the relevance seems to be only that
antigenic material reaches the joint, alive or dead. If there is a common
antigen, it has to be a highly conserved one. Bacterial hsp60 seems to be an
immunodominant T cell antigen in ReA, but there must be other relevant antigens
shared by these different bacteria. An ineffective immune response (for example,
low production of TNFalpha) seems to contribute to the manifestations and course
of ReA. Although arthritis can also occur in its absence, HLA-B27 plays an
important role in the pathogenesis of ReA and the other SpA. Current data suggest
that B27 probably acts as an antigen-presenting molecule for a still-unknown
arthritogenic molecule. Comparison of ReA with IBD-associated arthritis suggests
that there might indeed be a common antigen shared by ReA-associated bacteria and
bacteria of the gut flora. CD8+ T cells seem to be important in ReA and other
SpA. In some parts of the world, such as in Mexico, ReA could be a major
predisposing cause of the development of AS. Antibiotic treatment is not
effective, probably because the triggering bacteria are already dead or in a
partly latent state at the time arthritis occurs. Based on this knowledge and on
new technologies, it should be possible in future years to derive answers to the
questions about ReA and the other SpA and, as a consequence, to find a cure.
PMID- 10765917
TI - Involvement of Fcgamma receptor IIIA genotypes in susceptibility to rheumatoid
arthritis.
AB - OBJECTIVE: To investigate a possible association of Fcgamma receptor IIIA
(FcgammaRIIIA) gene polymorphism at position 158 with susceptibility to, and the
outcome of, rheumatoid arthritis (RA). METHODS: One hundred seventeen RA patients
and 142 unrelated healthy control subjects from the same geographic area were
studied. Genotyping for FcgammaRIIIA-158V/F was performed by a method based on
polymerase chain reaction (PCR) and restriction fragment length polymorphism
analysis using amplification-created restriction sites. HLA-DRB1 typing by PCR
sequence-specific oligonucleotide hybridization (reverse hybridization) was also
performed. RESULTS: Allele and genotype distributions in healthy controls were
similar to those reported in other populations. The overall distribution of
genotypes in the patients was significantly different from that in the controls
(P = 0.023, by chi-square test from 3 x 2 contingency table). An
overrepresentation of the FcgammaRIIIA-158FF genotype in the patients was
observed (for 158FF versus non-158FF P = 0.01, odds ratio [OR] 1.98, 95%
confidence interval [95% CI] 1.16-3.4). However, the FcgammaRIIIA-158VF genotype
was increased in controls (for 158VF versus non-158VF P = 0.021, OR 0.54, 95% CI
0.32-0.92). No associations were found with any of a series of clinical
parameters. Analysis of FcgammaRIIIA-158FF along with shared epitope showed that
the presence of both factors increased the susceptibility to RA (P = 0.0009, OR
3.6, 95% CI 1.63-8.01); however, they probably do not interact to produce this
effect. CONCLUSION: These results indicate that the FcgammaRIIIA-158 genotypes
confer differential susceptibility to RA in our study population. Further studies
to elucidate the role of this polymorphism in the pathogenesis of RA and other
autoimmune diseases are warranted.
PMID- 10765918
TI - Role of Fc receptor gamma chain in inflammation and cartilage damage during
experimental antigen-induced arthritis.
AB - OBJECTIVE: To study the role of Fc receptor (FcR) gamma chain in inflammation and
cartilage destruction during antigen-induced arthritis (AIA). METHODS: FcR gamma
/- mice and controls were immunized with methylated bovine serum albumin (mBSA)
in Freund's complete adjuvant, followed by induction of arthritis by local
injection of mBSA into the right knee joint. Joint inflammation was studied by
99mTc uptake and by histology. Breakdown of proteoglycans from the cartilage
matrix was determined by loss of red staining in Safranin O-stained knee joint
sections, and matrix metalloproteinase (MMP)-mediated aggrecan degradation was
determined by immunolocalization using anti-VDIPEN antibodies. Chondrocyte death
was measured by determining empty lacunae in hematoxylin-stained sections and
with the TUNEL assay in cryostat sections. Erosion was detected as ruffling of
the cartilage surface. RESULTS: Joint swelling, as measured by 99mTc uptake on
days 1, 3, and 7, was significantly decreased in FcR gamma-/- mice compared with
controls. On day 7 after AIA induction, sustained joint inflammation, as seen
histologically, was not significantly lower in FcR gamma-/- deficient mice. In
various cartilage layers (femur, tibia, patella) of central arthritic knee
joints, marked depletion of proteoglycans (40-70%), chondrocyte death (25-50%),
and mild surface erosion were found. In FcR gamma-/- knee joints, depletion of
proteoglycans was comparable (40-70%). Strikingly, chondrocyte death and matrix
erosion were absent. Furthermore, MMP-induced aggrecan neoepitopes, which were
abundantly found in controls, were also absent in FcR gamma-/-. Nevertheless,
latent MMPs were present in the cartilage matrix as seen in APMA-activated
patellae. CONCLUSION: FcR gamma chain is involved in the severity of acute and
sustained inflammation and is a crucial factor in cartilage erosion during AIA,
probably by regulating activation of latent MMPs present in the cartilage matrix.
PMID- 10765919
TI - Tumor necrosis factor alpha 5'-flanking region, tumor necrosis factor receptor
II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis.
AB - OBJECTIVE: New polymorphisms affecting transcriptional activity were recently
reported within the 5'-flanking region of the tumor necrosis factor alpha gene
(TNFalpha). In addition, genome-wide linkage screening indicated 1p36 as one of
the candidate chromosomal regions where the TNF receptor II gene (TNFR2) is
located. In the present study, HLA-DRB1, TNFalpha promoter, and TNFR2 genotypes
were determined to examine whether these polymorphisms are associated with
rheumatoid arthritis (RA), either independently or in combination. METHODS:
Genotypes of HLA-DRB1, TNFalpha upstream promoter, and TNFR2 codon 196 were
determined in 545 Japanese patients with RA and 265 healthy controls. Association
of these genes with susceptibility to RA was analyzed both independently and
after stratification by one of the genotypes. RESULTS: As expected, the HLA-DRB1
shared epitope was strongly associated with RA. In addition, a significant
negative association of DRB1*1405 and 1302 was observed. Furthermore, DRB1*1405
was suggested to possess a protective role for the development of RA in DRB1*0405
positive individuals. A significant increase in TNFalpha-U02 in RA was detected,
which was not independent of DRB1*0405. A significant association was not
observed between TNFR2-196M/R polymorphism and RA. CONCLUSION: Among the 3 genes
examined in this study, HLA-DRB1 was considered to be most strongly associated
with RA.
PMID- 10765920
TI - Noninherited maternal antigens do not play a role in rheumatoid arthritis
susceptibility in Europe. European Consortium on Rheumatoid Arthritis Families.
AB - OBJECTIVE: It has been proposed that noninherited maternal antigens (NIMA) (HLA
DR antigens) might play a role in susceptibility to rheumatoid arthritis (RA),
especially in patients who are not genetically predisposed, such as those who are
HLA-DR4 and/or shared epitope (SE) negative. The present study was undertaken to
test the NIMA hypothesis in a large cohort of European RA patients assembled by
the European Consortium on RA Families (ECRAF). METHODS: HLA-DRB1 oligotyping was
performed in families of European RA patients for whom both parents were alive.
These families were consecutively recruited by the ECRAF between 1996 and 1998,
for association studies. The frequencies of HLA-DR NIMA were compared with those
of the noninherited paternal antigens (NIPA) after stratification for HLA-DR*04,
*0401 and/or *0404, and SE status. NIMA or NIPA that coincided with inherited HLA
DR antigens were considered redundant and excluded from analysis. Calculations
concerning the whole group and restricted to patients lacking parental RA were
performed. RESULTS: One hundred seventy families from France (n = 81), Belgium (n
= 23), Spain (n = 24), Italy (n = 19), Portugal (n = 14), and The Netherlands (n
= 9) were oligotyped. The group of probands was predominantly female (88%),
positive for rheumatoid factor, DR*04, and SE (71%, 58%, and 75%, respectively),
and had erosive disease (75%). Parental RA was reported in 21 families. Using the
NIPA as control, the frequency of HLA-DRB1*04, *0401 and/or *0404-, or SE
positive NIMA was not found to be increased in patients lacking these
susceptibility alleles. The same was true when the 21 probands with parental RA
were excluded from analysis. In DRB1*04-positive patients, we found no evidence
of a relevant effect of HLA-DR3 or DR6 in the NIMA. CONCLUSION: Our results do
not support the notion that noninherited maternal antigens have a role in
susceptibility to RA in the offspring.
PMID- 10765921
TI - Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the
inflamed joints of children with juvenile idiopathic arthritis.
AB - OBJECTIVE: To study the expression of chemokine receptors CCR5 and CXCR3 and the
Th1/Th2 cytokine balance in children with oligoarticular or polyarticular
juvenile idiopathic arthritis (JIA). METHODS: Using 3-color immunofluorescence,
we studied the expression of CCR5 and CXCR3 on, and T cell cytokine production
by, paired samples of synovial fluid (SF) and peripheral blood (PB) T cells from
20 patients with oligoarticular- or polyarticular-onset JIA. Chemokine and
cytokine phenotypes were also compared within the CD45RO+,CD3+ subsets. CCR5
genotypes were confirmed by polymerase chain reaction typing and sequencing.
RESULTS: In the majority of samples, the number of T cells that were CCR5+ and
CXCR3+ was higher in SF than in PB, and this difference was significant. One
child was homozygous for the null A32 CCR5 allele; 4 others had lower expression
of CXCR3 in SF than in blood. All samples showed strongly Th1-type cytokine
production by synovial T cells compared with that by PB T cells. Both features
were also markedly polarized within the synovial CD45RO+ subset compared with PB
CD45RO+ T cells. CONCLUSION: The high expression of CCR5 and CXCR3 and high
interferon-gamma:interleukin-4 ratios suggest a type 1 phenotype of SF T cells in
JIA. The difference between CD45RO+ T cells from SF and from PB suggests that
specific activation events have occurred in synovial T cells. We suggest that the
highly activated, Th1-type phenotype of T cells within the chronically inflamed
joints of children with JIA may reflect specific recruitment events that
contribute to the polarization of these cells.
PMID- 10765922
TI - Identification of known and novel genes in activated monocytes from patients with
rheumatoid arthritis.
AB - OBJECTIVE: To define gene activation patterns of monocytes (MO) in patients with
rheumatoid arthritis (RA). METHODS: A complementary DNA (cDNA) library was
constructed from first-leukapheresis MO obtained from an RA patient with active
disease; 32P-labeled cDNA from first-leukapheresis MO (activated pool) and third
leukapheresis MO (nonactivated pool) were used as probes for differential
hybridization. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used
to assess gene activation in MO from an additional 26 RA patients and 6 normal
controls. RESULTS: Subtraction of genes from first- and third-leukapheresis MO
resulted in 482 differentially expressed clones. In first-leukapheresis MO, these
clones included the following: 1) interleukin-1alpha (IL-1alpha), IL-1beta, IL-6,
tumor necrosis factor alpha, growth-related oncogene alpha (GROalpha)/melanoma
growth-stimulatory activity, macrophage inflammatory protein 2/GRObeta, ferritin,
alpha1-antitrypsin, lysozyme, transaldolase, Epstein-Barr virus-encoded RNA 1
(EBER-1)/EBER-2-associated-protein, thrombospondin 1, an angiotensin receptor II
(ATRII) C-terminal homolog, and RNA polymerase II elongation factor (elongin); 2)
two clones homologous to functionally undefined genes (BSK-67 and BSK-83); and 3)
three unknown cDNA sequences (BSK-66, 80, 89). In third-leukapheresis MO, the
clones included differentiation genes (HOX-B3, thymosin-beta4, PU.1,
glucocerebrosidase, MEL-18, and glucose-6-phosphate dehydrogenase) and 3
unknown/functionally undefined sequences. Differential expression of most genes
from the activated pool was confirmed in leukapheresis samples from 2 additional
RA patients. In MO from RA patients, not only were IL-1beta and the ATRII homolog
significantly overexpressed (maximum 36-fold), but also 4 of the
unknown/functionally undefined genes (maximum 102-fold). Notably, messenger RNA
levels of BSK-89 correlated positively with the erythrocyte sedimentation rate
(ESR), whereas those of BSK-83 correlated negatively with the ESR and C-reactive
protein level. CONCLUSION: The combined strategy of gene subtraction and
semiquantitative RT-PCR may allow the definition of MO activation patterns during
different disease phases (including therapy-induced remission) and the
identification of novel MO genes with pathogenetic relevance in RA.
PMID- 10765923
TI - Differentiated dendritic cells expressing nuclear RelB are predominantly located
in rheumatoid synovial tissue perivascular mononuclear cell aggregates.
AB - OBJECTIVE: Differentiated dendritic cells (DC) and other antigen-presenting cells
are characterized by the nuclear location of RelB, a member of the nuclear factor
kappaB/Rel family. To characterize and enumerate differentiated DC in rheumatoid
arthritis (RA) peripheral blood (PB), synovial fluid (SF), and synovial tissue
(ST), the expression and location of RelB were examined. METHODS: RelB protein
expression and cellular location were determined in RA PB, SF, and ST by flow
cytometry and immunohistochemical analysis of purified cells or formalin-fixed
tissue. DNA-binding activity of RelB was determined by electrophoretic mobility
shift-Western immunoblotting assays. RESULTS: Circulating RA PBDC resembled
normal immature PBDC in that they did not express intracellular RelB protein. In
RA ST serial sections, cells containing nuclear RelB (nRelB) were enriched in
perivascular regions. A mean +/- SD of 84 +/- 10% of these cells were DC. The
remaining nRelB+,HLA-DR+ cells comprised B cells and macrophages. Only 3% of
sorted SFDC contained nRelB. However, RelB present in the nucleus of these SFDC
was capable of binding DNA, and therefore capable of transcriptional activity.
CONCLUSION: Circulating DC precursors differentiate and express RelB after entry
into rheumatoid ST. Differentiated DC can thus be identified by
immunohistochemistry in formalin-fixed ST. Signals for DC maturation may differ
between RA ST and SF, resulting in nuclear location of RelB predominantly in ST.
This is likely to have functional consequences for the DC in these sites.
PMID- 10765924
TI - Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene
expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear
factor kappaB: differential regulation of collagenase 1 and collagenase 3.
AB - OBJECTIVE: To examine the mechanism of interleukin-1 (IL-1)-induced collagenase 3
(matrix metalloproteinase 13 [MMP-13]) gene expression in cultured chondrocytes
for the purpose of better understanding how the gene is induced in these cells,
and how it contributes to cartilage degradation in osteoarthritis. METHODS: The
transcriptional and posttranscriptional responses of the MMP-13 gene to IL-1 were
assessed first. Then, direct inhibitors of mitogen-activated protein kinase
(MAPK) signaling pathways and a constitutive repressor of nuclear factor kappaB
(NF-kappaB) were used to assess the role of each pathway in IL-1-mediated
induction of MMP-13. RESULTS: We found that IL-1 induction of MMP-13 requires p38
activity, c-Jun N-terminal kinase (JNK) activity and NF-kappaB translocation.
These results suggest that both NF-kappaB and activator protein 1 transcription
factors are necessary for IL-1 induction of MMP-13. We also compared the
signaling pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in
articular chondrocytes and chondrosarcoma cells and found that IL-1 induction of
MMP-1 requires different pathways from those required by MMP-13. In
chondrosarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of
the extracellular signal-regulated kinase pathway) and does not require JNK or NF
kappaB. In articular chondrocytes, inhibition of MEK had no effect, while
inhibition of p38 gave variable results. CONCLUSION: These studies demonstrate,
for the first time, that p38, JNK, and NF-kappaB are required for IL-1 induction
of MMP-13. The results also highlight the differential requirements for signaling
pathways in the induction of MMP-1 and MMP-13. Additionally, they demonstrate
that induction of MMP-1 by IL-1 in chondrocytic cells depends on unique
combinations of signaling pathways that are cell type-specific.
PMID- 10765925
TI - Production of tissue inhibitor of metalloproteinases 3 is selectively enhanced by
calcium pentosan polysulfate in human rheumatoid synovial fibroblasts.
AB - OBJECTIVE: To determine the effects of calcium pentosan polysulfate (CaPPS) on
the production of matrix metalloproteinases (MMPs) and their endogenous
inhibitors, tissue inhibitors of metalloproteinases (TIMP), in cultures of
rheumatoid synovial fibroblasts. METHODS: The production of MMP-1, -2, -3, -7,
8, -9, and -13 and of TIMP-1, -2, -3, and -4 in cultured rheumatoid synovial
fibroblasts treated with 0.1, 1, and 10 microg/ml CaPPS in the presence and
absence of 100 units/ml interleukin-1alpha (IL-1alpha) was examined by a sandwich
enzyme immunoassay system and/or immunoblotting. The messenger RNA (mRNA)
expression of TIMP-3 and membrane type 1 MMP was determined by Northern blotting,
and the cells expressing TIMP-3 gene in rheumatoid synovium were identified by in
situ hybridization. The synthesis and secretion of TIMP-3 protein were monitored
by pulse-chase experiments. TIMP-3 was immunolocalized in untreated or CaPPS
treated rheumatoid synovial fibroblasts and synovium using an avidin-biotin
peroxidase complex method. RESULTS: Treatment of cultured rheumatoid synovial
fibroblasts with CaPPS resulted in a dose-dependent increase in the production of
TIMP-3 in both cell lysates and media from the treated cells. However, CaPPS did
not affect the levels of the other MMPs or TIMPs examined. The production of TIMP
3 was further enhanced in the cells treated with both IL-1alpha and CaPPS.
Immunohistochemistry confirmed the enhanced production of TIMP-3 by cells exposed
to CaPPS. The mRNA level of TIMP-3 increased 3.4-fold by treating rheumatoid
synovial fibroblasts with IL-1alpha, but CaPPS itself did not alter the
expression levels in the IL-1alpha-treated or -untreated cells. Pulse-chase
studies demonstrated that translation for TIMP-3 protein was enhanced by CaPPS
treatment. In situ hybridization and immunohistochemistry indicated that TIMP-3
was expressed mainly in the hyperplastic lining cells of rheumatoid synovium, and
that the production of this protein by these immunoreactive lining cells was
significantly increased by treatment with CaPPS. CONCLUSION: The present study is
the first to demonstrate that the new antiarthritic drug, CaPPS, selectively
enhanced TIMP-3 production at the posttranscription level in cultured rheumatoid
synovial fibroblasts and in the lining cells of rheumatoid synovium. By this
mechanism, CaPPS may be able to modulate joint tissue destruction in rheumatoid
arthritis.
PMID- 10765926
TI - Expression of osteoclast differentiation factor at sites of bone erosion in
collagen-induced arthritis.
AB - OBJECTIVE: To investigate the cellular mechanism of bone destruction in collagen
induced arthritis (CIA). METHODS: After induction of CIA in DA rats, a histologic
study of the advanced arthritic lesion was carried out on whole, decalcified
joints from the hindpaws of affected animals. To conclusively identify
osteoclasts, joint tissue sections were stained for tartrate-resistant acid
phosphatase (TRAP) enzyme activity, and calcitonin receptors (CTR) were
identified using a specific rabbit polyclonal antibody. The expression of
messenger RNA (mRNA) for the osteoclast differentiation factor (also known as
receptor activator of nuclear factor kappaB ligand [RANKL]) was investigated
using in situ hybridization with a specific riboprobe. RESULTS: TRAP-positive and
CTR-positive multinucleated cells were invariably detected in arthritic lesions
that were characterized by bone destruction. Osteoclasts were identified at the
pannus-bone and pannus-subchondral bone junctions of arthritic joints, where they
formed erosive pits in the bone. TRAP-positive multinucleated cells were detected
within synovium and at the bone erosive front; however, CTR-positive
multinucleated cells were present only at sites adjacent to bone. RANKL mRNA was
highly expressed in the synovial cell infiltrate in arthritic joints, as well as
by osteoclasts at sites of bone erosion. CONCLUSION: Focal bone erosion in CIA is
attributed to cells expressing definitive features of osteoclasts, including CTR.
The expression of RANKL by cells within inflamed synovium suggests a mechanism
for osteoclast differentiation and activation at sites of bone erosion.
Inhibitors of RANKL may represent a novel approach to treatment of bone loss in
rheumatoid arthritis.
PMID- 10765927
TI - Regulation of macrophage migration inhibitory factor by endogenous
glucocorticoids in rat adjuvant-induced arthritis.
AB - OBJECTIVE: To explore the regulation of macrophage migration inhibitory factor
(MIF) by endogenous glucocorticoids in adjuvant-induced arthritis (AIA). METHODS:
Adrenalectomy or sham operation was performed 2 days prior to adjuvant arthritis
induction. Synovial explant supernatant levels of MIF and tumor necrosis factor
alpha (TNFalpha) were measured by enzyme-linked immunosorbent assay (ELISA).
Synovial MIF immunostaining was detected by 3-layer immunohistochemistry. Serum
MIF levels were measured by Western blotting. Pituitary MIF release was measured
by ELISA. Anti-MIF monoclonal antibody (mAb) or isotype-matched control antibody
was administered to adrenalectomized (ADX) animals throughout AIA development.
RESULTS: Compared with sham operation, adrenalectomy was associated with
significant exacerbation of clinical disease parameters (P < 0.05). Adrenalectomy
was associated with significantly reduced levels of synovial MIF, but not
TNFalpha. In contrast, adrenalectomy was associated with increased serum MIF
levels. Concomitant increased pituitary MIF levels were observed in ADX rats,
consistent with the pituitary being the principal source of this increase. The
administration of specific anti-MIF mAb conferred 100% protection from lethality
during arthritis development and decreased arthritis disease expression.
CONCLUSION: These findings provide the first in vivo confirmation of the
observation that endogenous glucocorticoids are involved in the regulation of MIF
in a site of inflammation, and that local and systemic MIF production are
differentially regulated in this setting. The reversal of disease in ADX rats by
anti-MIF mAb suggests that balance between glucocorticoids and MIF may influence
the expression of inflammatory disease.
PMID- 10765928
TI - CD8+, CD57+ T cells from healthy elderly subjects suppress neutrophil development
in vitro: implications for the neutropenia of Felty's and large granular
lymphocyte syndromes.
AB - OBJECTIVE: To investigate the ability of CD8+,CD57+ large granular lymphocytes
(LGL) from normal individuals and from Felty's syndrome (FS) or LGL syndrome
patients to suppress allogeneic neutrophil precursor development. METHODS: Six FS
patients, 5 LGL syndrome patients, and 13 elderly controls were studied.
CD8+,CD57+ T cells were cocultured with cord blood-derived stem cells, and
percentage inhibition was calculated. Recombinant chemokines and Fas-stimulating
molecules were used in separate cultures to address possible mechanisms of
suppression. Proliferation after stimulation with interleukin-2 (IL-2) and anti
CD3 was assessed. RESULTS: Significant (79%) suppression of colony-forming unit
granulocyte-macrophage (CFU-GM) by the CD8+,CD57+ subset was shown by 1 FS
patient. None of the CD8+,CD57+ cells from LGL syndrome patients had any effect.
Six of 13 controls studied showed >40% inhibition of CFU-GM, and all but 2 showed
at least some suppression. The suppressive effect was not mediated by Fas/Fas
ligand interactions or by the chemokines macrophage inhibitory protein 1alpha or
IL-8. LGL from both patients and controls were largely CD28- and had reduced
proliferative capacity. CONCLUSION: In a subset of FS patients, expansion of
CD8+,CD57+ T cells in the bone marrow may be responsible for neutropenia by
suppressing neutrophil precursors. This effect is also seen with normal LGL,
which are likely to have an important function in neutrophil homeostasis.
PMID- 10765929
TI - T lymphocytes are not required for the spontaneous development of entheseal
ossification leading to marginal ankylosis in the DBA/1 mouse.
AB - OBJECTIVE: Male mice of the DBA/1 inbred strain spontaneously develop
polyarthritis and toe stiffness when they are > or =4 months old. The arthritis
affects predominantly the proximal interphalangeal joints and the ankle of the
hind limbs. The current study was aimed at determining the importance of T
lymphocytes in this disease. METHODS: Histologic sections of hindpaws from
arthritic DBA/1 mice were examined. The role of T lymphocytes was studied by
using mice lacking either alpha/beta or gamma/delta T cells due to a deletion in
T cell receptor beta (TCRbeta) or TCRdelta genes. RESULTS: Arthritis was
associated with a massive proliferation of connective tissue (fibroblasts) in
synovium and adjacent tissues. Chondroid and bone tissue outgrowth at the
entheses generated periarticular osteophytes (enthesophytes) which were deposited
on the unchanged margins of the preexisting bone. In some cases, the
enthesophytes enlarged enough to bridge and fuse the bones by marginal ankylosis.
Articular cartilage was essentially unaffected. Abnormal chondroid tissue
formation was common in stiffened toes, suggesting that the same pathology may
underlie both joint stiffness and arthritis. Dividing chondrocytes were commonly
seen in tendons, but without correlation with arthritis or toe stiffness. Mice
lacking alpha/beta or gamma/delta T cells developed arthritis at the same
incidence as control littermates. CONCLUSION: The naturally occurring arthritis
in male DBA/1 mice is a T cell-independent enthesopathy characterized by
periarticular hyperostosis and marginal ankylosis. This suggests that the
ossification leading to peripheral ankylosis of the joints in human
enthesopathies, such as diffuse idiopathic skeletal hyperostosis and seronegative
spondylarthropathies, is a T cell-independent process.
PMID- 10765930
TI - Serum matrix metalloproteinase 3 as a predictor of the degree of joint
destruction during the six months after measurement, in patients with early
rheumatoid arthritis.
AB - OBJECTIVE: To evaluate whether matrix metalloproteinase 3 (MMP-3), a proteinase
that is expressed in rheumatoid synovial tissue and shows potent activity in
degrading the proteoglycan of cartilage, plays a pivotal role in the joint
destruction seen in early rheumatoid arthritis (RA). METHODS: In a prospective
study of patients with early RA, the relationship between the serum concentration
of MMP-3, as determined by a sandwich enzyme immunoassay system, and the
progression of joint destruction in patients with early RA, as measured by the
Larsen radiologic score, was investigated. RESULTS: Serum MMP-3 levels were
elevated in the RA patients compared with healthy controls, not only in the late
stage, but also in the early stage of the disease in patients whose duration of
RA was <4 months. The serum MMP-3 level at entry into the study had a strong
correlation with the Larsen score at 6 months and 12 months after entry (r = 0.58
and r = 0.49, respectively). Similarly, the serum MMP-3 level at 12 months and 24
months after entry showed a positive association with the Larsen score in the
subsequent 6-12 months. Suppression of the serum MMP-3 level in the first year
led to a decline in joint damage in the second year. CONCLUSION: The serum
concentration of MMP-3 is a useful marker for predicting bone damage in the early
stage of RA, and the suppression of MMP-3 production may be an effective
therapeutic approach for patients with early RA.
PMID- 10765931
TI - Influence of polymorphism in the manganese superoxide dismutase locus on disease
outcome in rheumatoid arthritis: evidence for interaction with glutathione S
transferase genes.
AB - OBJECTIVE: To determine whether polymorphism in the manganese superoxide
dismutase (MnSOD) gene is associated with susceptibility or disease outcome in
rheumatoid arthritis (RA). METHODS: We used a case-control approach with 153 RA
patients and 218 control subjects to examine for any associations between MnSOD
genotypes and susceptibility to RA. We also investigated the influence of
genotypes on radiologic outcome, as measured using the Larsen score for
radiographs of the hands and feet, and on functional outcome, as assessed by the
Health Assessment Questionnaire. MnSOD typing was carried out using polymerase
chain reaction-based methods. Results were analyzed using multiple regression
analysis, with adjustment for age, sex, and disease duration. In separate
analyses, we corrected for rheumatoid factor (RF) status and/or the presence of
the HLA-DRB1 "shared epitope" (SE). We also examined whether radiologic outcome
was influenced by interactions between MnSOD and glutathione S-transferase (GST)
genes. RESULTS: No association between MnSOD genotype and development of RA was
found. The MnSOD VV genotype was associated with a significantly higher (P =
0.04) Larsen score (104.4) than MnSOD AA (83.0), while MnSOD AV was associated
with an intermediate score (91.8). Correction for RF status had no significant
effect on the results of the analysis, but significance was lost (P = 0.09) after
correction for the presence of the SE. There was evidence of interaction between
the GSTT1 and MnSOD genotypes, with the MnSOD VV/GSTT1-null combination being
associated with the highest Larsen score (142.1; P = 0.007 after correction for
the SE). CONCLUSION: Polymorphism in the MnSOD gene is not associated with
susceptibility to RA. Our data suggest that MnSOD VV is associated with more
severe radiologic outcome, although this relationship may not be independent of
the effect of the SE. However, interaction between MnSOD and GST genes appears to
influence radiologic outcome independently of the SE.
PMID- 10765932
TI - Joint symmetry in early and late rheumatoid and psoriatic arthritis: comparison
with a mathematical model.
AB - OBJECTIVE: To establish a mathematical model to predict the probability of
symmetry of joint involvement as a function of the number of joints involved and
to compare expected with actual probabilities in psoriatic arthritis (PsA) and
rheumatoid arthritis (RA) and in early and late disease. METHODS: Random
involvement of joints was assumed, and the binomial theorem was used to give the
frequency distribution of involved joints as a function of each joint count. Ten
joint pairs were included: shoulder, elbow, wrist, metacarpophalangeal joints,
proximal interphalangeal (PIP) joints of the hands, hip, knee, ankle,
metatarsophalangeal joints, and PIP joints of the feet. Observed probabilities
were obtained from subjects with early (duration < or =12 months) and late PsA
and RA. RESULTS: The number of subjects in each of the disease subgroups was as
follows: early PsA n = 33, late PsA n = 77, early RA n = 61, late RA n = 93.
Observed probabilities of symmetry exceeded predicted probabilities for all
disease subgroups. The median number of involved joints in each group was as
follows: early PsA 4, late PsA 8, early RA 8, late RA 15 (chi2 = 95.3, 3 degrees
of freedom, P = 0.0001, by Kruskal-Wallis test). After correcting for the
discrepancy in the number of involved joints, no difference in joint symmetry was
found between the groups (chi2 = 1.77, P = 0.62 by Friedman two-way analysis of
variance). Similar results were obtained when individual hand and foot joints
were analyzed separately. CONCLUSION: The pattern of joint involvement is often
used to distinguish between rheumatoid and psoriatic arthritis. This study
confirms that symmetry is largely a function of the total number of joints
involved and that, in terms of joint pattern, differences between these disorders
are more quantitative than qualitative. Both disorders have high absolute values
of symmetry, particularly in the joints of the wrist and hand.
PMID- 10765933
TI - Responses of the sympathetic nervous system and the hypothalamic-pituitary
adrenal axis to interleukin-6: a pilot study in fibromyalgia.
AB - OBJECTIVE: To determine whether deficient activity of the hypothalamic
corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic
pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic
nervous system and inhibits ascending pain pathways, may be pathogenic in
patients with fibromyalgia (FM). METHODS: We administered interleukin-6 (IL-6; 3
microg/kg of body weight subcutaneously), a cytokine capable of stimulating
hypothalamic CRH release, and measured plasma levels of adrenocorticotropic
hormone (ACTH), cortisol, and catecholamines and their metabolites and
precursors. Thirteen female FM patients and 8 age- and body mass index-matched
female controls were studied. The diagnosis of FM was made according to American
College of Rheumatology criteria. Tender points were quantitated by pressure
algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls
also had catecholamine measurements. RESULTS: After IL-6 injection, delayed ACTH
release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes
(mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol
responses to IL-6 did not differ significantly between patients and controls.
Basal norepinephrine (NE) levels were higher in the FM patients than in the
controls. While a small, although not significant, rise in NE levels occurred
after IL-6 injection in the controls, NE levels dramatically increased over basal
levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both
peak NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P =
0.0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3)
versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM patients
than in controls. Heart rate was increased by IL-6 injection in FM patients and
controls, but rose to significantly higher levels in the FM patients from 30
minutes to 180 minutes after IL-6 injection (P < 0.03). CONCLUSION: Exaggerated
NE responses and heart rate increases, as well as delayed ACTH release, were
observed among female FM patients compared with age-matched female controls.
Delayed ACTH release after IL-6 administration in FM is consistent with a defect
in hypothalamic CRH neuronal function. Exaggerated NE release may reflect
abnormal regulation of the sympathetic nervous system, perhaps secondary to
chronically deficient hypothalamic CRH. The excessive heart rate response after
IL-6 injection in FM patients may be unrelated to the increase in NE, or it may
reflect an alteration in the sensitivity of cardiac beta-adrenoceptors to NE.
These responses to a physiologic stressor support the notion that FM may
represent a primary disorder of the stress system.
PMID- 10765934
TI - Autoantibody recognition of distinctly modified forms of the U1-70-kd antigen is
associated with different clinical disease manifestations.
AB - OBJECTIVE: To examine whether autoantibody recognition of modified forms of the
U1-70-kd RNP antigen correlates with manifestations of rheumatic disease.
METHODS: Blinded to clinical disease manifestations, sera from 27 rheumatic
disease patients with U1-70-kd antibodies were used to immunoblot control,
apoptotic, and oxidatively modified HeLa cell lysates. Using densitometry,
recognition of antigen fragments was quantitated. The presence or absence of 1)
lupus skin disease and 2) Raynaud's phenomenon (RP) was determined for each
patient by chart review. The ability of patient sera to recognize the different
fragments was compared for patients with and without skin disease and with and
without RP. RESULTS: Patients with lupus skin disease had higher recognition of
apoptotic U1-70 kd than did patients without skin disease (mean +/- SD fragment
recognition index [FRI] 1.35 +/- 0.57 versus 0.95 +/- 0.25; P < 0.024, by
Student's t-test). Patients with RP had higher recognition of oxidatively
modified U1-70 kd than did patients without RP (mean +/- SD FRI 0.95 +/- 0.80
versus 0.24 +/- 0.22; P < 0.048). CONCLUSION: Recognition of apoptotically and
oxidatively modified forms of the U1-70-kd autoantigen are associated with
distinct clinical rheumatic disease manifestations. This finding provides in vivo
evidence for the hypothesis that immune recognition of modified forms of self
antigens may be relevant to the pathogenesis of systemic rheumatic diseases.
Understanding the antigenic modifications to which patients react may help
predict the expression of rheumatic syndromes.
PMID- 10765935
TI - Increased concentrations of the circulating angiogenesis inhibitor endostatin in
patients with systemic sclerosis.
AB - OBJECTIVE: Endostatin is an angiogenesis inhibitor derived from type XVIII
collagen. The aim of this study was to determine the concentrations of
circulating endostatin in patients with systemic sclerosis (SSc), and to assess
the relationship between these concentrations, extension of tissular sclerosis,
and presence of cutaneous scars or ulcers. METHODS: The study involved 50
patients with SSc and 30 healthy subjects. Cutaneous extension of sclerosis was
graded according to Barnett's classification system: 33 patients had grade I SSc
and 17 patients had grades II or III SSc. The results of pulmonary function tests
were abnormal in 31 of 50 patients, 8 of whom also had abnormalities on chest
radiograms. Cutaneous scars or ulcers were found in 22 of 50 patients. Endostatin
concentrations were determined using a competitive enzyme immunoassay method.
RESULTS: The mean circulating endostatin concentration was significantly higher
in the SSc group than in the healthy subjects group (mean +/- SD 53.2 +/- 22.4
ng/ml versus 9.9 +/- 9.7 ng/ml; P < 10(-4)), in patients with grade II or grade
III SSc than in patients with grade I SSc (63.2 +/- 20.2 ng/ml versus 45.1 +/-
15.6 ng/ml; P < 10(-2)), in patients with abnormal findings on chest radiograms
than in patients with normal findings on chest radiograms (67.6 +/- 22.4 ng/ml
versus 50.4 +/- 21.6 ng/ml; P < 0.05), and in patients with cutaneous scars or
ulcers than in patients without these manifestations (60.9 +/- 25.9 ng/ml versus
47.2 +/- 13.3 ng/ml; P < 10(-2)). CONCLUSION: Circulating endostatin
concentrations are significantly increased in patients with SSc. Production of
endostatin may result from tissular sclerosis and could contribute to the
development of ischemic manifestations.
PMID- 10765936
TI - Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid
peroxidation in systemic sclerosis: evidence of free radical-mediated injury.
AB - OBJECTIVE: To elucidate whether oxidative injury occurs in systemic sclerosis
(SSc) and whether it affects the erythrocyte membrane (EM) properties. METHODS:
EM fluidity and lipid composition (cholesterol:phospholipid molar ratio [C:PL],
fatty acid composition) were studied in 52 patients with SSc and in 53 subjects
without SSc (32 with primary Raynaud's phenomenon [RP] and 21 healthy subjects
[controls]). Fluidity was measured as the fluorescence anisotropy of the
hydrophobic fluorescent probe DPH (1,6-diphenyl-1,3,5-hexatriene). Lipid
peroxidation products were determined as thiobarbituric acid-reactive substances
(TBARS). RESULTS: EM fluidity was significantly lower in SSc patients than in
primary RP patients and controls (P < 0.001). The EM C:PL molar ratio was
significantly higher in SSc patients than in primary RP patients and controls (P
< 0.05). Levels of EM polyunsaturated n6 fatty acids (PUFA n6) were significantly
lower in SSc patients than in primary RP patients and controls (P < 0.001). TBARS
were significantly increased in SSc patients compared with primary RP patients
and controls (P < 0.001). Multiple regression analyses indicated that the reduced
EM fluidity was partly due to its greater C:PL molar ratio, lower PUFA n6
content, and higher TBARS levels. EM fluidity was lower among patients with
nailfold capillary loss (P < 0.001) and digital ischemic ulcers (P < 0.05). EM
lipid peroxidation products were higher among patients with pulmonary involvement
(bibasal pulmonary fibrosis [P < 0.05] and reduced levels of diffusing capacity
for carbon monoxide [P < 0.001]) and among patients who were positive for anti
topoisomerase I antibodies (P < 0.05) or negative for anticentromere antibodies
(P < 0.001). CONCLUSION: Our findings support the idea that oxidative injury
occurs in SSc and that, through lipid peroxidation, it induces structural and
functional changes of the EM that may contribute to the development of the
microvascular abnormalities that are seen in the disease.
PMID- 10765937
TI - Study of 52 patients with idiopathic aortitis from a cohort of 1,204 surgical
cases.
AB - OBJECTIVE: To determine 1) the frequency of idiopathic aortitis in a large
surgical cohort, 2) how often aortitis was associated with a systemic disease,
and 3) whether the findings of aortitis in resected specimens predicted future
occurrences of clinically apparent vascular injury due to vasculitis. METHODS:
Retrospective chart and pathology review of 1,204 aortic surgical specimens that
were gathered over a period of 20 years at a tertiary care medical center. A
standardized database was used to compare features of aortitis patients with
those of controls in whom inflammation was not present. RESULTS: Among 1,204
aortic specimens, 52 (4.3%) were clinically and pathologically classified as
idiopathic aortitis. Sixty-seven percent of patients with idiopathic aortitis
were women. In 96% of idiopathic aortitis patients with aneurysm formation,
aortitis was present only in the thoracic aorta. Among 383 thoracic aortic
aneurysms, 12% had idiopathic inflammatory features. In 96% of patients with
idiopathic aortitis, symptoms of systemic illness had not been present at the
time of surgery. In 31%, aortitis was associated with a remote history of
vasculitis and a variety of other systemic disorders. During a mean followup
period of 41.2 months, new aneurysms were identified among 6 of 25 patients who
were not treated with glucocorticoids. None were identified among 11 patients who
were treated with glucocorticoids (mean followup 35.5 months). CONCLUSION: The
frequency of idiopathic aortitis in a large surgical cohort was found to be 4.3%.
Thoracic aorta aneurysm formation, in the absence of systemic illness, was the
most common manifestation. In the setting of a cardiovascular surgery practice,
aortitis may first become apparent only after pathologic evaluation of excised
specimens. The appropriate medical treatment for patients with incidentally
discovered aortitis is not known. Because 17% of our patients subsequently
developed new aneurysms, we suggest that it would be prudent for patients with
idiopathic aortitis identified at the time of surgery to be periodically
evaluated for recurrent or persistent disease.
PMID- 10765938
TI - Salivary gland lymphomas in patients with Sjogren's syndrome may frequently
develop from rheumatoid factor B cells.
AB - OBJECTIVE: Patients with Sjogren's syndrome (SS) have an increased risk of
developing monoclonal B cell non-Hodgkin's lymphomas (MNHL), which frequently
occur in the salivary glands (SG). The transition from the benign lymphocyte
infiltrate of the gland that characterizes SS to MNHL is not well understood.
Previous sequence analyses of the expressed variable (V) region genes have
supported the theory that the surface Ig (sIg) plays an important role in the
initial expansion of nonmalignant B cell clones and in lymphomagenesis. However,
the antigenic specificities of these B cells were unknown. We describe the
specificities of the Ig expressed by 2 cases of MNHL that developed in the SG of
2 patients with SS. METHODS: The expressed V genes were amplified by polymerase
chain reaction from biopsy specimens, sequenced, and subcloned into eukaryotic
expression vectors. The constructs were transfected into P3X63-Ag8.653 cells to
obtain 2 monoclonal cell lines, each secreting 1 of the sIg expressed by the
MNHL. These IgM were tested by enzyme-linked immunosorbent assay and
immunofluorescence against a panel of antigens potentially implicated in SS.
RESULTS: Our main finding was that the Ig products of the neoplastic B cells were
rheumatoid factors (RF). Contrary to expectations, they did not react with
nuclear or cytoplasmic antigens, double-stranded DNA, self antigens commonly
bound by natural autoantibodies, or SG tissue. CONCLUSION: Previous analyses of V
gene use have provided indirect evidence that SG MNHL may frequently express RF.
We demonstrate that this hypothesis is true in the 2 patients we studied. Large
scale studies will be needed to establish the exact frequency of RF specificity
among SS-associated MNHL.
PMID- 10765939
TI - Gastrointestinal health care resource use and costs associated with nonsteroidal
antiinflammatory drugs versus acetaminophen: retrospective cohort study of an
elderly population.
AB - OBJECTIVE: To estimate gastrointestinal (GI) health care resource use and direct
costs associated with prescription nonsteroidal antiinflammatory drugs (NSAIDs)
in an elderly population. METHODS: Using the Government of Quebec's health
insurance database, we obtained the medical, pharmaceutical, and demographic
records of 73,850 senior citizens who, between 1993 and 1997, had either an NSAID
or an acetaminophen prescription dispensed. The date of their first dispensed
prescription for an NSAID or acetaminophen was termed their index date. Patients
who were not taking oral corticosteroids or anticoagulants at their index date,
were not diagnosed with cancer at their index date, and were not hospitalized and
did not have any GI events during the year prior to their index date were
included in the study. Patients who had a dispensed NSAID prescription at their
index date formed the NSAID cohort; the others formed the acetaminophen cohort.
All patients were followed up for 2 years. The daily direct costs of GI events
incurred during NSAID therapy by the NSAID cohort were compared with those
incurred during a similar followup period by the acetaminophen cohort. The
difference in these average daily costs was attributed to NSAID use. RESULTS: The
NSAID cohort included 5,268 senior citizens and the acetaminophen cohort 2,245.
More GI adverse events were observed in the NSAID cohort (odds ratio 2.48, 95%
confidence interval 2.06, 3.00). The average daily direct cost of GI events for a
day of NSAID therapy attributed to the NSAIDs was $0.84 (Canadian). On average,
for each Canadian dollar spent on NSAIDs, an additional $0.66 was spent on their
side effects. CONCLUSION: Safer alternatives to NSAIDs would significantly reduce
medical care costs for patients in need of NSAID therapy.
PMID- 10765940
TI - Localization of a gene for familial juvenile hyperuricemic nephropathy causing
underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large
family.
AB - OBJECTIVE: Familial juvenile hyperuricemic nephropathy (FJHN, MIM 162000) is an
autosomal-dominant disease characterized by underexcretion-type hyperuricemia,
gout, and chronic renal failure. No loci responsible for this disease or any
underexcretion-type hyperuricemia/gout have ever been identified. The aim of the
study was to localize a gene responsible for FJHN by linkage analysis. METHODS: A
single large family with at least 20 affected members was analyzed. DNA was
obtained from 13 affected and 18 non-affected members after lymphoblastoid cell
lines were established. Initially, polymorphic data were obtained for 343
microsatellite loci covering all chromosomes except the X chromosome. Parametric
linkage analysis was performed using the obtained data with LINKAGE package
software. RESULTS: Following a genome-wide search using a set of highly
polymorphic microsatellite markers, initial evidence for linkage was obtained for
a marker on chromosome 16p. We subsequently genotyped the same subjects for 12
additional markers spanning approximately 30 cM on the short arm of chromosome
16. We obtained a maximum 2-point logarithm of odds (LOD) score of 6.04 at theta
= 0 with the marker D16S401; multipoint linkage analysis yielded a maximum LOD
score of 6.14 with markers D16S401 and D16S3113, and established a minimum
candidate interval of approximately 9 cM. CONCLUSION: A gene for FJHN was
localized to a candidate interval of approximately 9 cM at 16p12. These findings
will be useful for the presymptomatic diagnosis of FJHN in some families and for
testing genetic heterogeneity of FJHN in general.
PMID- 10765941
TI - Multicentric reticulohistiocytosis: case report with immunohistochemical analysis
and literature review.
AB - This report describes the case of a patient with multicentric
reticulohistiocytosis. Immunohistochemical analysis revealed prominent markers of
monocyte/macrophage origin, as well as the presence of tumor necrosis factor
alpha, interleukin-1beta (IL-1beta), and IL-12; the occurrence of the latter in
this disease has not previously been reported. Clinical, laboratory,
radiographic, and histologic findings in multicentric reticulohistiocytosis are
reviewed. In addition, all published cases of multicentric reticulohistiocytosis
which included reports of cytokine and immunohistochemical analysis are reviewed,
and evidence for a monocyte/macrophage origin and role in disease pathogenesis is
provided.
PMID- 10765943
TI - Clinical images: Diagnosis and treatment of retroperitoneal fibrosis (Ormond's
disease).
PMID- 10765942
TI - Autoreactivity against matrilin-1 in a patient with relapsing polychondritis.
AB - Relapsing polychondritis (RP) is a rare inflammatory disease of cartilage.
Chondritis of the auricular, nasal, and tracheal cartilages predominates in this
disease, suggesting a response to a tissue-specific antigen. One potential
antigen is matrilin-1, a cartilage matrix protein found uniquely in the tracheal,
auricular, and nasal cartilage of adults. We describe herein a patient with RP
who had both a humoral and a cellular immune response directed toward the
cartilage matrix protein matrilin-1.
PMID- 10765944
TI - Patients receiving etanercept may develop antibodies that interfere with
monoclonal antibody laboratory assays.
PMID- 10765945
TI - Possible correction of abnormal rheumatoid arthritis synovial cell function by
jun D transfection in vitro: comment on the article by Wakisaka et al.
PMID- 10765946
TI - Role of HLA-DQ in rheumatoid arthritis susceptibility: comment on the article by
de Vries et al.
PMID- 10765947
TI - MRI bone erosions and MRI bone lesions in early rheumatoid arthritis: comment on
the article by McGonagle et al.
PMID- 10765948
TI - Autoantibodies to human nuclear lamin B1 in systemic lupus erythematosus: comment
on the article by Senecal et al.
PMID- 10765949
TI - High frequency of t(14;18) translocation in Sjogren's syndrome: comment on the
article by Gellrich et al.
PMID- 10765950
TI - Are all clinical caries prevention studies biased?
PMID- 10765951
TI - Development and characterization of a tissue-engineered human oral mucosa
equivalent produced in a serum-free culture system.
AB - A problem maxillofacial surgeons face is a lack of sufficient autogenous oral
mucosa for reconstruction of the oral cavity. Split-thickness or oral mucosa
grafts require more than one surgical procedure and can result in donor site
morbidity. Skin has disadvantages of adnexal structures and a different
keratinization pattern than oral mucosa. In this study, we successfully
assembled, ex vivo, a human oral mucosa equivalent, consisting of epidermal and
dermal components, in a defined, essential-fatty-acid-deficient, serum-free
culture medium without a feeder layer, that could be used for intra-oral grafting
in humans. Autogenous oral keratinocytes were seeded onto a cadaveric dermis,
AlloDerm. The oral mucosa equivalent was cultured at an air-liquid interface for
2 wks. The resulting equivalent had a well-stratified parakeratinized epithelial
layer similar to native oral keratinized mucosa. Expression of differentiation
markers, filaggrin and cytokeratin 10/13, suggested a premature keratinized
state. The presence of proliferation markers, proliferating cell nuclear antigen
(PCNA) and Ki-67, suggested a state of hyperproliferation. Fatty acid composition
of the equivalent was similar to that of in vitro cultured oral keratinocytes but
differed from the that of in vivo native tissue, showing a lower content of 18:2
and 20:4, and a higher content of 16:1 and 18:1 fatty acids, respectively. The
keratinocytes of the equivalent appeared to be in a more active and proliferative
state than native keratinized mucosa. The dynamic nature of the cell population
on the oral mucosa equivalent may be beneficial for intra-oral grafting
procedures and for transfection of the keratinocytes.
PMID- 10765952
TI - Bond strength of resin to acid-etched dentin studied by 13C NMR: interaction
between N-methacryloyl-omega-amino acid primer and dentinal collagen.
AB - The application of the hydrophilic methacrylate primer to acid-etched dentin
increases the bond strength of the resin to the acid-etched dentin. However, the
mechanism for the bonding of the resin to dentinal collagen through the primer
remains to be determined. Before a more effective adhesive primer can be
developed, we must understand the adsorption behavior of the primer to the
dentinal collagen. The purpose of this study was to determine how 5 derivatives
of N-methacryloyl-omega-amino acid (NMomegaA) primers enhance the bonding of the
resin to acid-etched dentin. The interaction between the NMomegaA primers and
dentinal collagen was studied by the 13C NMR technique, including the observation
of spin-lattice relaxation times, T1. When the dentinal collagen was dispersed
into the NMomegaA solution, the T1 values of the two carbonyl carbons attributed
to the amide and the carboxylic acid in the NMomegaA molecule decreased
dramatically. This result was due to the interaction between the amide group and
the carboxylic acid group in the NMomegaA molecule and the dentinal collagen
molecule. The T1 values of these carbonyl carbons decreased when the number of
methylene groups in the NMomegaA molecule increased. The interaction became
stronger as the number of methylene groups in the NMomegaA molecule was
increased. Further, the bond strength of the resin to the acid-etched dentin
primed with NMomegaA increased with a decrease in the T1 value of the amide
carbonyl carbon. The strength of the interaction of the NMomegaA primer to the
dentinal collagen molecule, determined by the 13C NMR technique, showed a direct
correlation with the bond strength of the resin to acid-etched dentin that was
treated with the NMomegaA primer.
PMID- 10765953
TI - The effects of adhesive thickness on polymerization contraction stress of
composite.
AB - A layer of an unfilled adhesive resin placed between the tooth and composite
restoration has been shown to absorb some of the stress generated in the
composite during polymerization and to reduce interfacial leakage. The objectives
of this study were to measure the change in polymerization contraction stress of
bonded composite as the thickness of the resin adhesive was systematically
varied, and to correlate the effects of the adhesive thickness and reduced stress
on marginal leakage in class V cavities. The maximum contraction force of
composite (Herculite XRV) was measured in a tensilometer as the thickness of the
adhesive bonding agent (Scotchbond MP) was varied from 20 to 300 microm.
Composite was placed in Class V cavities prepared on the labial surfaces of
bovine teeth to which different thicknesses of adhesive had been applied by
layering, and a marginal leakage test was performed by means of staining with
silver nitrate. Contraction stress decreased significantly as the adhesive
thickness was increased. This result was supported by a theoretical examination
of the data. In class V cavities, additional adhesive layering in the marginal
area reduced the overall degree of microleakage. The contraction stress generated
during the placement of a composite restoration contributes significantly to
early marginal leakage, and this stress was significantly absorbed and relieved
by the application of an increasing thickness of low-stiffness adhesive.
PMID- 10765954
TI - Visco-elastic parameters of dental restorative materials during setting.
AB - Contraction stresses generated in restoratives during setting are among the major
problems in adhesive dentistry, since they often result in loss of adhesion from
the cavity walls or in post-operative pain. The rate of stress development and
the ultimate magnitude of the stress, which determine the seriousness of these
problems, depend on the relatively unknown visco-elastic behavior of the
restoratives during setting. The aim of this study was to determine the visco
elastic parameters during setting, to aid our understanding of the process of
contraction stress development. A dynamic mechanical method was used in which the
materials were subjected to periodic strain cycles in a universal testing machine
during the first 60 min of setting. The visco-elastic parameters (viscosity eta
and Young's modulus E) were calculated by analysis of the experimental stress
strain data with a simple mechanical model according to Maxwell. Two restorative
materials from different classes were investigated: a two-paste resin composite
and a conventional glass-ionomer cement. A comparison of the results showed
significant differences in the development of viscosity and stiffness in the
early stage of setting. The resultant relaxation time (eta/E) of the glass
ionomer remained at a low level during the first 15 min, whereas that of the
resin composite increased markedly. This is of clinical importance, since it
implies that, during the early setting stage, glass ionomers are better capable
of reducing the contraction stresses than resin composites, thus increasing the
likelihood that the bond with the cavity walls will form and survive during
setting.
PMID- 10765955
TI - Antibacterial activities and release kinetics of a newly developed recoverable
controlled agent-release system.
AB - We attempted to develop a resin with a recoverable antibacterial activity based
on the desorption/adsorption of a cationic bactericide by the ion-exchange
mechanism. The aims of this study were to investigate the release kinetics of the
agent and the antibacterial activity of this newly designed resin system. An
experimental resin was prepared by the addition of methacrylic acid as a cation
exchanger and a cationic antibacterial agent, cetylpyridinium chloride (CPC), to
triethyleneglycol dimethacrylate. The amount of CPC desorbed from the
experimental resin into buffer solutions at pH 4-8 was measured. The adsorption
of CPC to control resin and re-adsorption of CPC to the experimental resin, which
had once desorbed the agent, were also determined. The antibacterial activity of
experimental resin against Streptococcus mutans was evaluated, and the
relationship between bacterial acid production and antibacterial effect was
assessed. The experimental resin desorbed CPC at pH < or = 6, and the amount of
agent desorbed increased with increasing acidity. The control resin adsorbed CPC
when immersed in CPC aqueous solution at a rate determined by the concentration
of the agent and immersion time. The experimental resin, once desorbed CPC, could
re-adsorb the bactericide by being exposed to a solution of the agent. Less
plaque formed on the experimental resin, and the growth and survival of S. mutans
was inhibited in the condition in which acid was produced. These results
demonstrate that the resin system proposed was able to desorb and re-adsorb the
cationic bactericide by an ion-exchange mechanism and could show an inhibitory
effect on S. mutans growth and plaque formation.
PMID- 10765956
TI - Feasibility of computer-assisted recognition of different dental hard tissues.
AB - For pattern recognition, fuzzy set theory has been proven to be highly useful.
The aim of the present investigation was to combine the fuzzy set with an
ultrasonic scaler, to test its suitability for automatic detection of different
tooth substances. An experienced operator placed the tip of a piezoceramic
ultrasonic scaler on a tooth, thereby inducing oscillations in the contact area
around the ultrasonic tip. Each surface showed a characteristic oscillatory
behavior in the immediate vicinity of the tip. The oscillations were then re
transmitted to the scaler tip and recorded by the measurement of variations in
current and voltage. Because the ultrasonic scaler is driven by piezoceramics, it
can be used as both an oscillatory excitation and a sensor system. The data were
processed with Fast Fourier transformation and analyzed by means of a fuzzy
pattern recognition algorithm. Re-classification of the different measurements
was carried out by the experienced operator's assessment. With a combination of
six features (frequencies), re-classification was correct for 99% of all
surfaces. The diagnostic reliability of the system was tested by the assessment
of 50 teeth for which no learning data had previously been recorded. The unknown
samples were correctly classified to 100%. The excellent results of these
experiments suggest promising possibilities for the implementation of new
diagnostic and therapeutic instruments in periodontology practice.
PMID- 10765958
TI - Mass spectrometry of native rat amelogenins: primary transcripts, secretory
isoforms, and C-terminal degradation.
AB - Cloning technologies have established unambiguously that amelogenins always seem
larger in molecular weight (Mr) by gel electrophoresis (SDS-PAGE) than by mass
spectrometry (MS). This has caused many problems relating cloned versions of
amelogenin to proteins actually secreted by ameloblasts in vivo. In this study,
discrete protein fractions at 31-20 kDa (Mr(SDS)) were prepared from freeze-dried
rat incisor enamel by techniques optimized for preserving protein integrity. N
terminal sequence and amino acid compositional analyses indicated that the major
protein forming these fractions was amelogenin. As expected, the molecular
weights estimated by matrix-assisted laser desorption ionization (MALDI) and
electrospray ionization (ESI) MS were significantly less than their apparent
molecular weights estimated by SDS-PAGE. Plots of Mr(SDS) vs. Mr(MS) for all
fractions showed high linear correlation (r = 0.992). Analysis of MS data further
indicated that the major protein in the 27-kDa fraction corresponded to the R180
secretory isoform of rat amelogenin, whereas some minor proteins in the 23-kDa
fraction likely corresponded to a R156 secretory isoform. This was in contrast to
major proteins forming the 25-, 24-, and 23-kDa fractions (Mr(SDS)), which seemed
to represent proteolytic fragments of R180 progressively altered at the P169
A170, P164-L165, and F151-S152 C-terminal cleavage sites, respectively. Proteins
in the 20-kDa fraction (Mr(SDS)) most closely matched by ESI-MS fragments of the
R156 secretory isoform that were C-terminally-modified at the equivalent P164
L165 site.
PMID- 10765957
TI - The non-collagenous dentin matrix proteins are involved in dentinogenesis
imperfecta type II (DGI-II).
AB - Dentinogenesis Imperfecta type II (DGI-II) is a localized form of mesodermal
dysplasia of the dentin affecting both the primary and permanent dentitions. This
is an autosomal-dominant disease in which there is a disorder in dentin
mineralization. Several studies have localized DGI-II to human chromosome 4 in
the region 4q 12-21. Many ECM genes-such as OPN, DMP1, DMP2, DMP3 (DSPP), and BSP
have been mapped to the same locus. Biochemical studies indicated that dentin
phosphophoryn (DMP2) might be a candidate gene in DGI-II. In this study, we have
used histological and RFLP analyses of tissues from a DGI-II-affected patient, as
compared with two normal controls, to determine if DMP1, 2, or 3 was linked to
DGI-II. The histology of the affected tooth was very different in the DGI-II
patient as compared with the normals. In particular, the dentinal tubules in the
DGI-II patient were very irregular, which could be the result of perturbations in
the process of dentin formation. Patient and control DNA samples were digested
with EcoRI or PstI and Southern-hybridized with the DMP1, DMP2, and DMP3 cDNAs.
Few differences in the restriction pattern were observed between affected and
normal samples for DMP1 and DMP3-3' region (phosphophoryn-like sequences) probes.
On the other hand, DMP2 showed a dramatic shift in the restriction pattern in DGI
II. This study suggests that the different restriction enzyme digestion profiles
of the DNA from the DGI-II patient, as probed by DMP2, might be related to the
defective mineralization of dentin in DGI-II.
PMID- 10765959
TI - AgNOR are sensitive markers of radiation lesions in squamous epithelia.
AB - The possibility of detection of incipient cellular alterations is central to
early diagnosis and to clinician's capacity to discriminate between samples that
appear similar on routine preparations. We examined the value of silver-stained
nucleolar organizer regions (AgNOR) in detecting radio-induced alterations in a
model of squamous epithelium biologically similar to oral mucosa. Morphometry of
AgNOR has been proven to be of value in the detection of incipient cellular
alterations. This method allows for the quantitative evaluation of lesions
induced by high doses of radiation long before they become apparent in routine
preparations. We herein examine the capacity of AgNOR to reveal the response to
low doses of radiation, closer to the therapeutic or accidental dose to which the
epithelium of oral mucosa may be exposed.
PMID- 10765960
TI - Clinical and genetic analysis of a large North European Caucasian family affected
by early-onset periodontitis.
AB - Genetic studies of early-onset periodontitis (EOP) are hampered by several
factors. These include delayed onset of the trait, an upper age limit of
expression of the disease, and lack of phenotypic information for edentulous
family members. Segregation analyses of families with EOP support a major locus
hypothesis but fail to define clearly the criteria used for diagnosis of the
relatives. Confirmation of a proposed mode of inheritance and the identification
of risk genes is awaited by means of family linkage studies. It is suggested that
a system can be developed for the current and retrospective diagnosis of
relatives of EOP probands. In addition, it is hypothesized that the large family
presented here is suitable for a linkage study. Relatives of the proband who were
unavailable for a full periodontal examination, were edentulous, or were
deceased, were diagnosed by means of documented clinical evidence of periodontal
disease or from reported case histories. Segregation analysis was performed.
Analysis of the power of the pedigree to detect linkage was carried out by means
of the SIMLINK program. Three different categories were defined according to the
reliability of diagnosis of EOP. Segregation analysis indicated either autosomal
dominant or X-linked-dominant inheritance in this family. The simulations showed
lod scores above 3.0 for all locations of the disease gene, and for each category
of diagnosis. In conclusion, a method has been developed which can be used for
the diagnosis of relatives of EOP probands when ideal clinical data are
unavailable. The simulations suggest that this family is suitable for a genetic
linkage study with the aim of identifying the location of one or more
susceptibility genes.
PMID- 10765961
TI - Oral colonization with Actinomyces species in infants by two years of age.
AB - In early childhood, the human mouth is already colonized by actinomycetes. Due to
recent taxonomic changes within the genus Actinomyces, up-to-date data are
warranted on the time and succession of different Actinomyces species in the oral
cavity. By using a longitudinal study design and culture techniques, we examined
the age-related occurrence of Actinomyces species in saliva from 39 healthy
infants at 2, 6, 12, 18, and 24 months of age. Altogether 428 Actinomyces
isolates were available for this study. Identification was based on biochemical
tests and gas chromatographic demonstration of metabolic end-products, and when
needed, cellular fatty acid profiles were determined. The frequency of the total
actinomycetal flora increased from 31% to 97% within 2 years. A. odontolyticus
was the most prominent Actinomyces colonizer at all five sampling occasions. A.
naeslundii was the second most common Actinomyces sp. but was not detected before
the age of 1 year. As a novel observation, we found A. graevenitzii in the oral
cavity. The number of A. graevenitzii isolates indicates that this species is not
just occasionally present in infants' mouths. We also found A. viscosus, A.
gerencseriae, A. israelii, and A. georgiae. Based on the present results, we
suggest that A. odontolyticus is the main primary Actinomyces species on oral
mucosal surfaces in infants up to 2 years of age.
PMID- 10765962
TI - Diagnostic value of a chelating agent in patients with symptoms allegedly caused
by amalgam fillings.
AB - The chelating agent 2,3 dimercaptopropane-1-sulfonate (DMPS) has been used in a
mercury mobilization test for diagnoses in illnesses allegedly associated with
the presence of amalgam restorations. DMPS is an accepted antidote to heavy metal
poisoning. The aim of the present study was to evaluate the diagnostic value of
DMPS in patients with symptoms self-related to their amalgam fillings. The
subjects consisted of four groups: 19 healthy controls without amalgam
experience; 21 healthy controls with amalgam fillings; 20 patients who claimed
symptoms of "mercury poisoning" from dental amalgam; and 20 patients who had
amalgam fillings removed because of such symptoms. DMPS (2 mg/kg body weight) was
injected intravenously, and urine was collected prior to the injection, 30 and
120 min after the injection, and throughout the next 22 hrs. The samples were
analyzed for total mercury by cold vapor atomic absorption spectrophotometry. The
total median amounts of mercury excreted over 24 hrs for those with complaints
allegedly associated with amalgam and for the healthy controls with amalgam
fillings were similar. Persons with amalgam fillings excreted about three times
more mercury than those without. The controls, who had never had amalgam
fillings, and the subjects who had had their fillings removed excreted median
amounts of 8.5 microg and 7.2 microg mercury, respectively. The present DMPS
challenge test did not differentiate between patients with or those without
complaints self-related to their amalgam fillings but did confirm the higher
mercury values in patients with dental amalgam.
PMID- 10765963
TI - Caries in five-year-old children and associations with family-related factors.
AB - It is generally understood that the teeth of pre-school-aged children are
healthy, but the improvement in the dmft index has halted in the industrialized
countries. Those few children who have caries have more of it than before. Little
is known of the family-related factors which are associated with this
polarization of caries. A representative population-based sample consisted of
1443 mothers expecting their first child. The children were followed at well-baby
clinics and public dental health clinics for over five years. The objective was
to study the prevalence of dental caries and its predictors in five-year-old
children and to assess children's own dental health habits and the meaning of
family-related factors in dental health. The findings were based on questionnaire
data from parents and on clinical dental examinations of the five-year-old
children as completed by 101 public health dentists. In firstborn five-year-old
children, dental health was found to be good in 72%, fair in 20%, and poor in 8%
of the cases. The final multivariate analysis illustrated that the dmft index > 0
was independently associated with the mother's irregular toothbrushing (OR 2.2;
95% CI 1.4-3.5), annual occurrence of several carious teeth in the father (OR
2.6; 95% CI 1.9-3.6), daily sugar consumption at the age of 18 months (OR 2.4;
95% CI 1.4-4.1), occurrence of child's headaches (OR 3.7; 95% CI 1.5-8.8),
parents' cohabitation (OR 3.3; 95% CI 1.5-7.6), rural domicile (OR 2.4; 95% CI
1.2-4.5), and mother's young age (OR 5.0; 95% CI 1.3-19.8). The findings
indicated that attention should be paid not only to the child's dental health
care but also to that of the whole family. Parents should be supported in their
upbringing efforts and encouraged to improve their children's dental health
habits. In everyday life, parents function as role models for their children, and
therefore, parents' own dental hygiene habits are very meaningful.
PMID- 10765964
TI - Influence of maternal xylitol consumption on acquisition of mutans streptococci
by infants.
AB - Xylitol is effective as a non-cariogenic sugar substitute. Habitual xylitol
consumption appears to select for mutans streptococci (MS) with impaired adhesion
properties, i.e., they shed easily to saliva from plaque. One hundred sixty-nine
mother-child pairs participated in a two-year study exploring whether the
mothers' xylitol consumption could be used to prevent mother-child transmission
of mutans streptococci. All mothers showed high salivary levels of mutans
streptococci during pregnancy. The mothers in the xylitol group (n = 106) were
requested to chew xylitol-sweetened gum (65% w/w) at least 2 or 3 times a day,
starting three months after delivery. In the two control groups, the mothers
received either chlorhexidine (n = 30) or fluoride (n = 33) varnish treatments at
6, 12, and 18 months after delivery. The children did not chew gum or receive
varnish treatments. MS were assessed from the mothers' saliva at half-year
intervals and from the children's plaque at the one- and two-year examinations.
The MS were cultured on Mitis salivarius agars containing bacitracin. The
salivary MS levels of the mothers remained high and not significantly different
among the three study groups throughout the study. At two years of age, 9.7% of
the children in the xylitol, 28.6% in the chlorhexidine, and 48.5% in the
fluoride varnish group showed a detectable level of MS. In conclusion, therefore,
habitual xylitol consumption by mothers was associated with a statistically
significant reduction of the probability of mother-child transmission of MS
assessed at two years of age. The effect was superior to that obtained with
either chlorhexidine or fluoride varnish treatments performed as single
applications at six-month intervals.
PMID- 10765965
TI - Electrophysiology findings in a large family with central areolar choroidal
dystrophy.
AB - PURPOSE: To perform an electrophysiological study of central areolar choroidal
dystrophy (CACD) in the affected members of a four generation family. METHODS:
Eight affected family members from the last three generations of a family
affected by CACD were assessed by full-field electroretinograms (rod response,
maximal combined response, oscillatory potentials, single-flash cone response and
30 Hz flicker responses) and electro-oculograms. In addition three members of the
youngest generation, who were visually asymptomatic, had pattern visual evoked
potentials (PVEPs) and pattern electroretinograms (PERGs) performed. Affected
status had been determined previously by genetic analysis. RESULTS: Three
youngest generation family members, who were considered affected by genetic
haplotype analysis, had no visible optic nerve or retinal abnormalities. All of
these subjects had abnormal PVEPs and PERGs in both eyes. Abnormalities were also
detected in two of these subject's Rod ERGs, Cone ERGs and one of these subject's
Maximal ERGs and 30 Hz ERGs. Electrophysiological examination in the older
generations demonstrated a similar, more advanced, cone and rod dysfunction.
CONCLUSIONS: All affected, but clinically normal, youngest generation patients
had bilaterally abnormal PVEPs and PERGs. In CACD the PVEP and PERG proved to be
the most sensitive electrophysiological tests of preclincial macular dysfunction,
3/3 subjects abnormal. ERG recording to ISCEV guidelines were very useful in
these cases; 7/8 subjects abnormal. The EOG was less useful; 4/8 subjects
abnormal. CACD produces a widespread photoreceptor dysfunction in its later
stages.
PMID- 10765966
TI - Motion VEPs with simultaneous measurement of perceived velocity.
AB - The dependency of the N200 amplitude of the motion-onset VEP evoked by a
parafoveal grating of variable speed (0.25-13.5 deg/s, corresponding to 0.5-27
Hz) and constant contrast (4%) was studied. Additional measurements were made
with parafoveally presented gratings of constant speed (2 deg/s, corresponding to
4 Hz) and a variable contrast (0.5-64%) before and after adaptation to a
stationary or drifting grating. In this latter experiment, simultaneous
psychophysical measurements were made of the perceived speed. The amplitude of
the N200 wave increased with increasing stimulus speed within the slow speed
range up to 1.5 deg/s (corresponding to 3 Hz). Adaptation to a stationary grating
had no significant effect on the relationship between the N200 amplitude and
stimulus contrast. Contrary to this, adaptation to a slowly drifting grating (1
deg/s, corresponding to 2 Hz) or to a rapidly drifting grating (4 deg/s,
corresponding to 8 Hz) reduced the N200 amplitude significantly. Adaptation to a
stationary grating slightly reduced the perceived speed of subsequently viewed
gratings. Adaptation to a slowly drifting grating increased the perceived speed
of the subsequently viewed gratings, whereas adaptation to a rapidly drifting
grating decreased the perceived speed. The findings can be best explained by a
two-channel model of speed perception. While the motion VEP reflects the sum of
both channel activities, the psychophysical measures point to the antagonistic
encoding of low and high velocities.
PMID- 10765967
TI - A case report of frosted branch angiitis and its visual electrophysiology.
AB - We reported a 5-years old boy with frosted branch angiitis in both eyes. The
visual acuities of the two eyes were suddenly lost to 5/50. The fluorescein
angiography, electroretinograms (ERGs) and pattern evoked potentials (PVEPs) had
been tested at the acute and the recovery stage of the disease. At the onset of
the disease, fluorescein angiography showed obvious dye leakage from dilated
retinal veins. The PVEPs and whole field ERGs including rod, maximum, OPs and
cone responses were seriously decreased and prolonged, indicating that the visual
pathway's and retinal functions were greatly damaged. The patient had an
excellent response to systemic prednisone. One month after the treatment, the
visual acuities recovered to 60/50 in both eyes. The fluorescein angiography
showed that leakage from blood vessels was diminished, but the lesions at macula
and optic disc were persisted a longer time even to the end of treatment. Through
6 months medication, nearly all of the electrophysiological abnormalities had
been resolved.
PMID- 10765968
TI - Standard for clinical electroretinography (1999 update). International Society
for Clinical Electrophysiology of Vision.
PMID- 10765969
TI - A comparison of two multifocal ERG systems.
AB - The First Order Kernel responses (FOK) from a group of 15 normal subjects aged 21
36 yrs were recorded under clinical conditions with the multifocal ERG (MERG)
systems VERIS and RETIscan using system-specific software and hardware under
various parameter settings. First, the multifocal ERG's of normal subjects were
recorded with the standard-parameters of VERIS and RETIscan. Thereafter the VERIS
system parameters were set as close as possible to the RETIscan-setup, and the
recordings were repeated. The VERIS parameters changed were the luminance- and
contrast-settings of the stimulus-monitor and m-sequence-timing. In addition, the
effects of different sampling rates were also examined. The consequences of the
parameter changes were analyzed by displaying the peak times of the First-Order
Kernel (P1). The parameter-combinations used for recording lead to system
specific results. By varying the luminance/contrast settings and/or the m
sequence-timing the results can be changed. The amplitude of the recorded results
can be influenced by the luminance-settings of the stimulus-monitor, and the
topography of the P1 peak times is affected by the m-/f-frame-combination of the
recording stimulus. With their standard parameters, the two systems give
different measures of the P1 peak times. By adjusting the recording parameters,
these differences can be reduced significantly. The main parameter here is the m
sequence-timing, although the sampling rate must also be taken into account with
regard to the accuracy of the recording results.
PMID- 10765970
TI - Visual electrophysiological effect of a GABA transaminase blocker.
AB - Vigabatrin is an antiepileptic drug for the treatment of partial seizures. The
anticonvulsant effect is achieved by irreversible inhibition of the enzyme GABA
transaminase which catalyses the inactivation of GABA. Vigabatrin has been
associated with visual field loss and electrophysiological abnormalities. The
purpose of the study was to determine any alterations in normal volunteers of the
visual field and the visual electrophysiology resulting from a short exposure to
vigabatrin. A three-way, double-blind study of placebo, carbamazepine and
vigabatrin was undertaken at baseline and on days two, four and nine. Seven
subjects completed all three cycles and 14 subjects (six females and eight males;
mean age 27.3 years SD 6.7) completed at least one cycle. Static threshold
automated perimetry comprised Humphrey Visual Field Analyzer Programs 30-2 and
30/60-2. Electro-oculography and electroretinograms were performed with undilated
pupils using the Medelec Ganzfeld stimulator GS2000. The visual field was
unaffected by placebo, carbamazepine or vigabatrin. The group mean amplitudes and
latencies for the scotopic ERG, 30 Hz flicker ERG and the oscillatory potentials
remained unchanged for any cycle. The group mean photopic ERG b-wave latency
increased from baseline (p<0.05); no significant change occurred with
carbamazepine or placebo. The group mean Arden Index for vigabatrin decreased
from baseline to day 9 (p<0.01); no significant differences were present for
carbamazepine or placebo. Vigabatrin has a rapid effect on both the photopic ERG
and the EOG; however, the changes merely reflect alterations in retinal GABA
levels secondary to concomitant blocking of GABA transaminase by existing
vigabatrin therapy.
PMID- 10765971
TI - Lack of short-latency-potentials in the VEP reflects immature extra geniculate
visual function in delayed visual maturation (DVM).
AB - PURPOSE: To investigate children with delayed visual maturation (DVM) and
correlate the electrophysiological findings to visual development. METHODS: Three
children, one from each of the DVM-classification groups, were subjected to
routine ophthalmological examinations and electrophysiological examinations:
flash visual evoked potential (VEP) and skin electrode electroretinography (ERG).
RESULTS: All three children had normal ERGs but initially abnormal VEP-recordings
with marked delay of latency or grossly altered VEPs. When visual interest
developed with responsive smiling at 4, 4.5 and approximately 12 months of age, a
maturation in the VEPs also appeared, with development of a short-latency complex
(approximately 70 ms). In the normal neonatal development of the VEP, a
negativity at approximately 60-70 ms (N1) emerged at four to six weeks of
postnatal life when the child started responsive smiling and showing raised
visual interest. According to animal experimental research and human studies, the
development of the specific response (the short-latency complex) represents the
gradual onset of cortical activity mediated via the specific retino-geniculo
striatal pathway. Thus, when the short-latency complex of the VEP cannot be
identified, the visual function is mainly of subcortical origin. Since the VEP
developed in the same way in the children with DVM as in normal subjects, the
pathophysiological dysfunction and origins of DVM can partly be understood.
CONCLUSIONS: The results show that i) children with DVM has a period of visual
inattentiveness at a time when normal children show visual interest, ii) the VEP
is abnormal in children with DVM at the time of visual inattentiveness, iii) the
improvement of vision in DVM can be measured with VEP and iiii) the extra
geniculate system(s) provides for the visual function early neonatally in the
normal child and in a prolonged period in the DVM-child as long as the VEPs are
abnormal.
PMID- 10765972
TI - Cytokine-induced coordinate expression of enzymes of prostaglandin biosynthesis
and metabolism: 15-hydroxyprostaglandin dehydrogenase.
AB - The effects of pro-inflammatory cytokines on 15-hydroxyprostaglandin
dehydrogenase (PGDH) expression and prostaglandin (PG) metabolizing activity were
investigated in placental tissue. Treatment of trophoblast cells in primary
culture with interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF
alpha) resulted in decreased prostaglandin metabolizing activity. This was
assessed both by determining the ratio of production of prostaglandins to their
metabolites, and by Northern blot analysis of PGDH mRNA abundance. Dexamethasone
had similar inhibitory effect. We hypothesize that proinflammatory cytokines act
to enhance prostaglandin actions through coordinated effects on activities of
enzymes of both prostaglandin biosynthesis and metabolism, perhaps in concert
with effects on receptor function.
PMID- 10765973
TI - Subcellular localization of prostaglandin H synthase-2 in a human amnion cell
line: implications for nuclear localized prostaglandin signaling pathways.
AB - We have determined that prostaglandin H synthase-2 localises strongly to the
nuclear membrane as well as being found in the endoplasmic reticulum in human
amnion-derived WISH cells which have been stimulated with interleukin 1beta and
phorbol ester. This is consistent with findings in cells of non-reproductive
origin. There is strong evidence that prostaglandin J2 derivatives, which in
other tissues exhibit tumour suppressing, antiproliferative and/or
differentiation promoting activities, act through binding of intracellular
receptors which then enter the nucleus. In addition, some arachidonic acid
derivatives are clearly generated by enzymes at the nuclear envelope and localise
to sites in nuclei or bind sites in nuclei. The WISH cell line will make an
excellent system for studying these perinuclear intracellular prostanoid
signaling mechanisms.
PMID- 10765974
TI - Suppression of proto-oncogene (AP-1) in a model of skin epidermal
hyperproliferation is reversed by topical application of 13
hydroxyoctadecadienoic acid and 15-hydroxyeicosatrienoic acid.
AB - The present study was conducted to delineate whether a possible mechanism for 13
(S)-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatrienoic acid (15
HETrE) reversal of experimentally-induced skin hyperproliferation in guinea pig
is via the modulation of epidermal nuclear mitogen activator protein (AP-1), a
nuclear transcription factor associated with tissue turnover. The data revealed
that topical application of 13-HODE and/or 15-HETrE on the induced
hyperproliferative skin reversed the hyperproliferation and up-regulated the
suppressed AP-1 expression. A further analysis of the two major subunits of AP-1
(c-fos and c-jun) revealed a selective up-regulation of c-fos. These results
underscore the modulatory role of lipoxygenase-derived hydroxy fatty acids on
nuclear transcription factors and explains, at least in part, the
antiproliferative effects of 13-HODE and 15-HETrE.
PMID- 10765975
TI - Endogenous EP4 prostaglandin receptors coupled positively to adenylyl cyclase in
Chinese hamster ovary cells: pharmacological characterization.
AB - The purpose of these studies was to investigate the pharmacology of E-series and
selected prostaglandins of other classes on adenylyl cyclase activity in Chinese
hamster ovary (CHO) cells expressing an endogenous prostanoid receptor and to
compare these responses with those from immortalized human non-pigmented ciliary
epithelial (NPE) cells containing the EP2 receptor. 11-deoxy-PGE2 was the most
potent of the 16 prostanoid agonists tested for stimulating cAMP formation with a
potency (EC50) value of 26 +/- 6 nM in the CHO cells. The endogenous ligand,
PGE2, exhibited potencies of 40 +/- 7 nM (n = 24) in the CHO cells and 67 +/- 9
nM (n = 46) in the NPE cells. The EP2 receptor agonist, butaprost, produced an
EC50 value of 212 +/- 58 nM (n = 4) in the NPE cells while being inactive (EC50 >
10,000 nM, n = 6) in the CHO cells. The EP4 receptor selective antagonists,
AH22921 and AH23848B, at a concentration of 30 microM, caused a 2.2 +/- 0.5 (n =
4) and 8.2 +/- 2.7 (n = 4) fold rightward shift in the PGE2 concentration
response curves in the CHO cells, yielding apparent pKb values of 4.6 +/- 0.6 and
5.3 +/- 0.2 (n = 4), respectively. AH22921 and AH23848B were non-competitive
antagonists at the CHO cell EP4 receptor, but did not shift the PGE2
concentration-response curves in the NPE cells containing the EP2 receptor. These
studies have characterized the functional prostaglandin receptors in CHO cells
pharmacologically and shown them to be consistent with the EP4 subtype.
PMID- 10765976
TI - Analysis of the intestinal absorption of essential fatty acids in vivo in the
rat.
AB - The absorption and competition kinetics of the essential fatty acids (EFAs),
linoleic acid (LA), alpha-linolenic acid (alphaLnA) and arachidonic acid (AA) in
vivo were studied in the perfused rat jejunum. Uptake of each EFA on its own
followed saturable kinetics at low luminal concentrations, suggesting a
facilitative transport process, the affinity of which increased with chain length
and degree of unsaturation. Absorption of one EFA was enhanced by low, whilst
competitively inhibited by high, concentrations of a second EFA. Whereas LA and
alphaLnA each interfered with the absorption of one another, both had little
effect on AA. There was a strong inverse correlation between the relative
unsaturation of an EFA and the change in Km of its absorption observed upon
inhibition with another EFA. Overall, the results indicated a specific absorptive
mechanism, probably involving a transport protein, the affinity of which
increased with the degree of unsaturation of the EFA.
PMID- 10765977
TI - Effect of L-arginine-nitric oxide system on the metabolism of essential fatty
acids in chemical-induced diabetes mellitus.
AB - Several studies have shown that the activities of delta-6-desaturase and delta-5
desaturase are depressed in experimental diabetes and in humans with insulin- and
non-insulin-dependent diabetes mellitus (type I and type II diabetes mellitus
respectively). Furthermore, treatment with insulin is known to correct the
defects in desaturases in rats and humans with diabetes, especially in type I. In
a recent study, we demonstrated that L-arginine and nitric oxide can prevent
alloxan-induced beta cell damage, and the severity of diabetes, and restore the
antioxidant status to near normal levels. But, no information is available as to
the relationship between L-arginine-nitric oxide system and the metabolism of
essential fatty acids in diabetes mellitus. In the present study, it was noted
that the plasma levels of saturated fatty acids: stearic and palmitic were
increased where as unsaturated fatty acids such as oleic, linoleic, gamma
linolenic and eicosapentaenoic acids (OA, LA, GLA and EPA respectively) were
decreased in alloxan-induced diabetic rats. In the liver phospholipid (PL)
fraction, GLA, DGLA (dihomo-GLA) and alpha-linolenic acid (ALA) were decreased in
the alloxan-treated group; in the muscle PL fraction, LA, GLA and DGLA were low,
whereas an increase in the saturated fatty acid content was noted. L-arginine
(the precursor of nitric oxide) and sodium nitroprusside (a nitric oxide donor)
treatment of alloxan-induced diabetic rats enhanced the levels of LA, GLA and
DGLA. Further, nitric oxide synthase inhibitor, L-NMMA, prevented this beneficial
action of L-arginine-nitric oxide system on essential fatty acid metabolism. The
abnormalities in the essential fatty acid metabolism observed also reverted to
normalcy following control of diabetes with insulin. These results indicate that
nitric oxide can enhance the activities of delta-6- and delta-5 desaturases,
which are depressed in diabetes, and suggests that there is a close interaction
between L-arginine-nitric oxide system and the metabolism of essential fatty
acids.
PMID- 10765978
TI - Eicosanoid generation and responsiveness of human lymphatics in
hyperlipoproteinemia.
AB - In this work, the oxidation injury in hyperlipoproteinemia (HLP) was determined
by measuring the isoprostane 8-epi-prostaglandin (PG) F2alpha in human
lymphatics, lymph fluid, plasma, serum and urine. Lymphatics from 6 patients with
HLP generated less PGI2 and contained more 8-epi-PGF2alpha as compared to 6
normolipemics without risk factors. Likewise, plasma (29.3 vs 19.7 pg/ml), lymph
fluid (137.3 vs 65.3 pg/ml), serum (286.7 vs 204.1 pg/ml) and urinary (360.8 vs
241.0 pg/mg creatinine) values of 8-epi-PGF2alpha in HLP (as compared to
normolipemics) were significantly elevated. Lymphatics from HLP showed an
enhanced contractile response, less 14C-arachidonic acid conversion to PGI2 and
less PGI2-formation upon various stimuli compared to normolipemics of comparable
age. These findings indicate that HLP-induced oxidation injury, resulting in an
altered (iso-)eicosanoid production and function, may also significantly affect
(patho-) physiology of lymphathics.
PMID- 10765979
TI - Regulation of the G1 phase of the mammalian cell cycle.
AB - In any multi-cellular organism, the balance between cell division and cell death
maintains a constant cell number. Both cell division cycle and cell death are
highly regulated events. Whether the cell will proceed through the cycle or not,
depends upon whether the conditions required at the checkpoints during the cycle
are fulfilled. In higher eucaryotic cells, such as mammalian cells, signals that
arrest the cycle usually act at a G1 checkpoint. Cells that pass this restriction
point are committed to complete the cycle. Regulation of the G1 phase of the cell
cycle is extremely complex and involves many different families of proteins such
as retinoblastoma family, cyclin dependent kinases, cyclins, and cyclin kinase
inhibitors.
PMID- 10765980
TI - Embryonic and genetic manipulation in fish.
AB - Fishes, the biggest and most diverse community in vertebrates are good
experimental models for studies of cell and developmental biology by many
favorable characteristics. Nuclear transplantation in fish has been thoroughly
studied in China since 1960s. Fish nuclei of embryonic cells from different
genera were transplanted into enucleated eggs generating nucleo-cytoplasmic
hybrids of adults. Most importantly, nuclei of cultured goldfish kidney cells had
been reprogrammed in enucleated eggs to support embryogenesis and ontogenesis of
a fertile fish. This was the first case of cloned fish with somatic cells. Based
on the technique of microinjection, recombinant MThGH gene has been transferred
into fish eggs and the first batch of transgenic fish were produced in 1984. The
behavior of foreign gene was characterized and the onset of the foreign gene
replication occurred between the blastula to gastrula stages and random
integration mainly occurred at later stages of embryogenesis. This eventually led
to the transgenic mosaicism. The MThGH-transferred common carp enhanced growth
rate by 2-4 times in the founder juveniles and doubled the body weight in the
adults. The transgenic common carp were more efficient in utilizing dietary
protein than the controls. An "all-fish" gene construct CAgcGH has been made by
splicing the common carp beta-actin gene (CA) promoter onto the grass carp growth
hormone gene (gcGH) coding sequence. The CAgcGH-transferred Yellow River Carp
have also shown significantly fast-growth trait. Combination of techniques of
fish cell culture, gene transformation with cultured cells and nuclear
transplantation should be able to generate homogeneous strain of valuable
transgenic fish to fulfil human requirement in 21st century.
PMID- 10765981
TI - Molecular characters and morphological genetics of CAL gene in Chinese cabbage.
AB - BcpCAL, the homologous gene of CAL, was isolated from Chinese cabbage. Unlike
BobCAL of cauliflower, BcpCAL did not hold the terminating mutation in the fifth
exon. After crosses of cauliflower with Chinese cabbage, the resultant hybrids
failed to form curd, which implicates the genetic complement of BcpCAL to the
mutated BobCAL in the function of curd formation. One of CAL gene isolated from
the hybrid apparently comes from the female parent (Chinese cabbage) even though
there are a few of the bases substituted and deleted. The result offers the
molecular and genetic evidences for the study of biological function of CAL in
morphological genetics of curd.
PMID- 10765982
TI - Isolation and characteristics of autoreactive T cells specific to aggrecan G1
domain from rheumatoid arthritis patients.
AB - Our previous work showed that the cartilage proteoglycan aggrecan could induce an
erosive polyarthritis and spondylitis in BALB/c mice and the G1 globular domain
of the aggrecan (G1) contained the arthritogenic region. To elucidate whether
autoreactive T cells to G1 are expressed in rheumatoid arthritis patients, we
analyzed the frequency of human G1-specific T cells in the peripheral blood of
five rheumatoid arthritis patients and tried to establish G1-reactive T cell
lines from these rheumatoid arthritis patients. The results showed that the G1
specific T cells in PBL were detectable at the range of 4.97 +/- 0.5 x 10(-6) in
peripheral blood lymphocytes. We have also generated 15 G1-specific T lymphocyte
lines from these patients with a standard split-well method. All these cells
expressed fine specificity to human recombinant G1, but not to unrelated antigen.
All the 15 lines expressed a pan-T cell marker and 13 of them selectively used
the alphabeta T cell receptor. Two of them used gammadelta T cell receptor. The
13 of these T cell lines was CD4 positive. One line expressed CD8. One line
expressed both CD4 and CD8. Moreover, 14 out of 15 lines expressed the Th-1
cytokine profile, characterized by interferon-gamma positivity and IL-4
negativity. No Th-2 type cell line was generated. These data provide strong
evidence in favor of the presence of autoreactive T cells in the rheumatoid
arthritis patients. What is the mechanism(s) that these autoreactive T cells
attack self-target and whether these G1-specific, Th-1 type T cell lines can
induce arthritis in immune deficiency mice are currently under investigation.
PMID- 10765983
TI - Identification of gamma-aminobutyric acid transporter (GAT1) on the rat sperm.
AB - Some recent studies indicated that GABAergic system is involved in mammalian
sperm acrosome reaction (AR), but direct evidence pertaining to the expression of
gat1 in mammalian sperm is not yet demonstrated. In this study, we evaluated the
presence of 67kDa GAT1 protein and mRNA in rat testis by Western blotting and
reverse transcription-polymerase chain reaction. Meanwhile, immunohistochemical
and immunofluorescent analyses also identified GAT1 protein on the elongated
spermatid and sperm. These results indicated that rat testis is a novel site of
gat1 expression. Further studies should be taken to explore the role of GAT1
protein on sperm acrosome reaction.
PMID- 10765984
TI - Gamma-aminobutyric acid transporter (GAT1) overexpression in mouse affects the
testicular morphology.
AB - Gamma-aminobutyric acid and GABAergic receptors were previously reported to be
distributed in reproductive systems besides CNS and predicted to participate in
the modulation of testicular function. Gamma-aminobutyric acid transporter was
implicated to be involved in this process. However, the potential role of gamma
aminobutyric transporter in testis has not been explored. In this study, we
investigated the existence of mouse gamma-aminobutyric acid transporter subtype I
(mGAT1) in testis. Wild-type and transgenic mice, which overexpressing mGAT1 in a
variety of tissues, especially in testis, were primarily studied to approach the
profile of mGAT1 in testis. Mice with overexpressed mGAT1 develop normally but
with reduced mass and size of testis as compared with wild-type. Testicular
morphology of transgenic mice exhibited overt abnormalities including focal
damage of the spermatogenic epithelium accompanied by capillaries proliferation
and increased diameter of seminiferous tubules lumen. Reduced number of
spermatids was also found in some seminiferous tubules. Our results clearly
demonstrate the presence of GAT1 in mouse testis and imply that GAT1 is possibly
involved in testicular function.
PMID- 10765985
TI - Using a non-radioisotopic, quantitative TRAP-based method detecting telomerase
activities in human hepatoma cells.
AB - A non-radioisotopic, quantitative TRAP-based telomerase activity assay was
established mainly by using SYBR Green-I staining instead of radioisotope.
Comparing with conventional radioisotope based method, it was better in
reproducibility and accuracy. Using this method, we found telomerase activities
were absent in normal human liver cells, while detected in all of four human
hepatoma cell lines (BEL-7404, SMMC-7721, QGY-7903 and HCCM) without significant
differences.
PMID- 10765986
TI - Preliminary evidence for diurnal fluctuations in visual imagery.
AB - In a repeated measures design, the Vividness of Visual Imagery Questionnaire
(VVIQ; Marks, 1973) was administrated to 10 participants each half hour in a
single day between 8:00 and 20:00. The questionnaire was also administrated on
four consecutive days following the original administration at 8:00, 14:00 and
20:00. These results were then fitted to a model with the superposition of two
cosinusoidal functions. An analysis of the results suggested the coexistence of
ultradian and circadian cycles in the determination of the vividness of visual
imagery.
PMID- 10765987
TI - Physiological tremor: does handedness make a difference?
AB - The purpose of this study was to quantify with precision the characteristics of
normal physiological tremor in the dominant and nondominant hand of a group of
right-handed females. Twenty-two right-handed females (aged 20 to 40) gave
informed consent to participate. Manual dominance determined with a questionnaire
had to be equal to, or above 90%, for subjects to be accepted in the study. While
the subjects kept their eyes closed, tremor was recorded simultaneously in the
two extended index fingers during 40 s. Preceding the recording of postural
tremor there was a period during which the subjects were asked to relax (control
condition); to exert a pressure with the two index fingers on two strain gauges
(static condition); or to press on and off with both index fingers on two strain
gauges (dynamic condition). Each condition was recorded twice with two helium
neon velocity lasers. This procedure was repeated after permutation of the
lasers, thus a total of twelve sweeps of data were recorded. Seven parameters
were used to analyze the tremor signal including measures of harmonicity, median
frequency, proportional power in the 7-12 Hz range, amplitude, waveform
morphology, entropy, and nonlinearity. Significant differences between hands were
found in three parameters (median frequency, power in 7-12 Hz and entropy) but
not in tremor amplitude (RMS). In addition, significant differences were found in
five out of seven characteristics between conditions. These results suggest that
neuromotor activity preceding the recording of tremor has a significant influence
on tremor characteristics and that some of these characteristics are
significantly different between the right and left hand in right-handed females.
PMID- 10765988
TI - Ultradian sleep rhythms of lateral EEG, autonomic, and cardiovascular activity
are coupled in humans.
AB - This study compared the dynamics of multiple systems during sleep with earlier
results during waking rest. Three consecutive nights of data were collected from
three healthy adults for 10 variables: left and right central EEGs; the nasal
cycle (NC); beat-to-beat measures of CO, SV, HR, SBP, DBP, MAP, and hemoglobin
oxygen saturation. Time series analysis detected periods at 280-300, 215-275, 165
210, 145-160, 105-140, 70-100, and 40-65 min bins with the greatest spectral
power in longer periods. We found significance across subjects with all
parameters at 280-300, 105-140 (except left EEG power, left minus right EEG
power, and HR), 70-100, and 40-65 min. Significant periods were reported earlier
during waking for the NC, pituitary hormones, catecholamines, insulin, and
cardiovascular function in five bins at 220-340, 170-215, 115-145, 70-100, and 40
65 min, with 115-145, 70-100, and 40-65 min common across all variables. These
results suggest that lateral EEG power during sleep has a common pacemaker (the
hypothalamus), or a mutually entrained pacemaker, with the cardiovascular and
autonomic nervous systems (ANS), and that the waking ultradians of the
neuroendocrine and fuel regulatory hormones may also be coupled to lateral EEG
activity. Taken together these results present a new perspective for the Basic
Rest-Activity Cycle and the physiology of the ANS-central nervous system during
both waking and sleep.
PMID- 10765989
TI - The effect of pre and postnatal cadmium exposure on somatosensory evoked
potentials: relation to lipid peroxidation.
AB - Pregnant swiss albino rats were divided into three groups: control (C),
gestational exposure of cadmium (G-Cd) and gestational/postnatal exposure of
cadmium (GP-Cd) groups. Control animals received tap water and the rats of GP-Cd
group received Cd as CdCl2 in their drinking water during the experimental
period. G-Cd group was given Cd during pregnancy, but given tap water after
birth. Twenty-two days after birth, 15 rats (for each group) were taken from
their mothers and continued to be treated with Cd (GP-Cd group) or tap water (C
and G-Cd groups) for an additional 38 days. On postnatal day (PND) 60,
somatosensory evoked potentials (SEPS) of three groups were recorded following
left posterior tibial nerve (PTN) stimulation. The mean latencies of N1, P1, and
N2, components were significantly prolonged in both Cd groups compared with
control group. The mean latency of N1 in the GP-Cd group was longer than control
and the G-Cd groups. There was no significant amplitude differences among groups.
On the other hand, thiobarbituric acid reactive substances (TBARS), an indicator
of lipid peroxidation, were increased in the sciatic nerves of both groups
compared with control group. A significant increase in the TBARS level of the
brain was found only in GP-Cd group due to significant accumulation of Cd.
PMID- 10765990
TI - Serotonergic decompensation in the akinetic expression of Parkinson's disease.
AB - The current diagnostic and treatment paradigm for the akinetic form of
Parkinson's disease asserts that the majority of symptoms and treatment phenomena
arise from a dysfunctional dopaminergic system. Recent studies have attempted to
determine the roles of other biogenic amine neurotransmitters such as serotonin
and norepinephrine. Metabolic breakdown product studies of Parkinsonian and non
Parkinsonian cerebrospinal fluid (CSF) samples indicate significant differences
in the levels of serotonin and norepinephrine in addition to the levels of
dopamine. Such changes may suggest that current pharmacologic therapies that
attempt to restore only dopamine are inadequate, and require accompanying
therapies to elevate serotonin and norepinephrine levels.
PMID- 10765991
TI - Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic
lateral sclerosis.
AB - Abnormal glutamate metabolism is implied in the pathogenesis of Amyotrophic
Lateral Sclerosis (ALS) and cerebrospinal fluid (CSF) glutamate levels appear to
be elevated. Since nitric oxide (NO) inhibits glutamate transport, excessive
amounts of nitric oxide could underlie the glutamate induced neurotoxicity in
ALS. Stable metabolites of NO (NO2- + NO3-) levels were determined in serum and
CSF of sporadic ALS patients and control subjects. NO2- + NO3- levels were higher
in ALS, in males and in serum samples compared to controls, females and CSF,
respectively. Furthermore, while the difference between serum and CSF NO2- + NO3-
levels was significant in males (higher in serum) no such difference was observed
in females. Our results suggest that nitric oxide may be involved in the
pathogenesis of ALS directly or indirectly and in a sexually dimorphic manner.
PMID- 10765992
TI - Fatty acid mixture counters stress changes in cortisol, cholesterol, and impair
learning.
AB - A mixture of linoleic and alpha-linolenic acids (free non-esterified unsaturated
fatty acids) administered for 3 weeks prior to injection of cortisol (10 mg/kg),
or prior to immersion of rats in a 10 degree C saline bath, prevented elevation
of blood levels of cortisol and cholesterol and deficits in Morris water maze
spatial learning that usually accompany such stressful conditions. Differences
from controls on all behavioural and biochemical measures were statistically
significant (P < .05). It is proposed that induction of intense stress, and the
associated increase in cortisol, cholesterol and other corticosteroids may damage
hippocampal structures and help account for the cognitive decline witnessed in
Alzheimer's disease and other age-related conditions. The modulation of these
consequences by the fatty acid mixture may provide an alternative strategy for
the study of stress markers and for the development of other intervention options
in humans.
PMID- 10765993
TI - Intraventricular administration of substance p increases the dendritic
arborisation and the synaptic surfaces of Purkinje cells in rat's cerebellum.
AB - Substance P was infused in the lateral ventricles of twenty Lewis rats for twenty
days. On the twentieth day the animals were sacrificed and the cerebellar cortex
was processed for electron microscopy. The ultrastructural morphometric analysis
revealed that the Purkinje cell dendritic arborisation and the number of the
synapses between the parallel fibres and the Purkinje cell dendritic spines were
much higher than in control animals. Numerous unattached spines of the secondary
and tertiary dendritic branches of the Purkinje cells were also seen in the
molecular layer either free or surrounded by astrocytic sheath. The increased
number of synapses between the Purkinje cell dendrites and the parallel fibres in
the animals, which received substance P intraventricularly, in correlation to
control animals, supports a neurotrophine-like activity of the substance P in the
mammalian cerebellum, enforcing the pre-programmed capability of the Purkinje
cells to develop new synaptic surfaces.
PMID- 10765994
TI - The recognition potential and reversed letters.
AB - The effect of letter reversal on the detection of Gestalt patterns was
investigated by recording a short latency brain wave response known as the
recognition potential (RP). The native language of 12 subjects was English. It
was Chinese for 12 others. Three hypotheses were tested. (1) Strings of identical
characters displayed on a background of dissimilar characters will evoke the RP.
(2) RP latency will be less for normal letter targets than for reversed letter
targets. (3) The letter reversal effect will be greater for subjects having
longer experience with alphabetical characters. The hypotheses were confirmed.
Similar effects of letter reversal were also found for longer latency
electrophysiological responses and for behavioral reaction time (RT). The RP
latency difference equaled the RT difference. This suggested that letter specific
processes operated rapidly, not later, than the latency of the RP, and any
subsequent processing had no differential effect on RT.
PMID- 10765995
TI - Neurobehavioral characteristics of adolescents with behavioral dysregulation
disorder.
AB - BACKGROUND: There is growing recognition that violence and other forms of conduct
problems increase during adolescence. The exact relationship between biological,
psychological, and social variables has not been defined yet. OBJECTIVES: To
analyze whether Intelligence Quotients (IQS), neurological history, child
behavioral problems, executive functions, and soft neurological signs (SNS) can
differentiate between undisciplined and unreliable adolescents (Behavioral
Dysregulation Disorder subjects, BDD) and normal controls. METHOD: Twenty-five 13
to 16-year-olds, adolescents with BDD and 25 matched controls were used in this
study. WISC-R, executive function assessment, neurological history, child
behavioral problems, and SNS scores were analyzed using a Multivariate Analysis
of Variance (MANOVA). A Multiple Regression Stepwise with Criteria Probability of
F Analysis was used for predicting criteria variable variance. RESULTS: WISC-R
Verbal IQ (VIQ), Information, Similarities, and Vocabulary subtests presented
statistically significant differences between BDD and controls (p < .001). No
Performance IQ (PIQ) variables established significant differences between both
groups. Executive function scores did not detect significant differences between
groups either. Prenatal, neonatal, and neurological history scores were similar
between both groups. Two child behavioral problem variables were significantly
different, with higher scores in BDD group: use of weapons and drug-use (p <
.05). A Multiple Regression Stepwise (Criteria Probability of F < .05) model,
entering the predictive variables in each domain (intelligence, executive
function, neurological antecedents, child behavioral problems, and SNS), and
using the score on the criteria variable as dependent variable, found two
predictive models: (1) WISC-R Information (Ad-R-SQ = 0.172 F-Ch. = 11.176, p <
.01); and (2) WISC-R Information and drug-use (R-SQ: 0.26; F-Ch = 9.605 p <
.001). CONCLUSIONS: A verbal factor and drug-use predicted fairly 30% of the
variance of the criteria variable used for classifying adolescents with BDD.
These results would mean that a language underlying factor and an environmental
drug-use factor would be related to the BDD in adolescents.
PMID- 10765996
TI - Prediction of WAIS-R indices based on performance on the Luria Nebraska
Neuropsychological Battery-III.
AB - The purpose of this research was to examine the clinical utility of the Luria
Nebraska Neuropsychological Battery-Third Edition (LNNB-III) in estimating
intellectual functioning as measured by the WAIS-R. Ninety-one subjects were
administered the WAIS-R and the LNNB-III. Multiple regression were calculated to
examine the ability of the LNNB-III clinical scales to predict FSIQ, VIQ, and PIQ
indices. The LNNB-III General Intelligence Scale (GI) predicted FSIQ within 10
points 79% of the time, and within 15 points 97% of the time. Similarly, GI
predicted VIQ and PIQ indices with 67% accuracy within 10 points and with 91% and
87% accuracy, respectively, within 15 points. A combination of LNNB clinical
scales fared no better than GI alone when predicting the FSIQ index. However, a
combination of LNNB-III scales predicted VIQ with 80% accuracy within 10 points
and with 94% accuracy within 15 points. In contrast, a combination of LNNB-III
clinical scales predicted the PIQ index 76% of the time within 10 points and 90%
of the time within 15 points. GI appears to be a good alternative when an
estimate of intellectual functioning is desired given its less than 10 minute
administration time. When greater specificity regarding VIQ and PIQ estimates are
desired, a combination of specific LNNB-III scales appear preferable.
PMID- 10765997
TI - History of the National Kidney Foundation.
AB - Stimulated by a mother's desire to find a cure for her child's disease, the
National Kidney Foundation has grown from a small local group of interested lay
persons and medical professionals Into a major national organization with
affiliates around the country and national and International programming in renal
research funding, patient and family services, public and professional education,
and public policy advocacy.
PMID- 10765998
TI - History of the professional councils of the National Kidney Foundation.
AB - As the Councils move toward the new millennium, efforts to improve outcomes for
patients with renal disease will be at the forefront. Each council has
established a commitment to improving the quality of life for these individuals.
Toward this goal, the CNNT, the CRN, and the CNSW will each propose programs to
the NKF for improving the knowledge and skills of the professionals within these
councils, promoting research within the respective scope of these professions,
and working together to bring a better understanding of the issues confronted by
the patients and the professionals as well. As an example of the combined effort
of the Councils, the first joint project of the century will be to bring the
communications packages of each council under a common framework by joining the
newsletters of each council. It is an exciting time to be part of the NKF. As a
professional in the renal community, being a part of the CNNT, the CRN, or the
CNSW offers a professional enrichment and opportunities to participate in making
lives better for those with renal disease.
PMID- 10765999
TI - History of the National Kidney Foundation's research efforts.
AB - The research programs of the National Kidney Foundation (NKF) are designed to
foster research and training in renal disease by providing cutting edge,
excellent, state of the art training in basic science, clinical, and
translational research. Since the inception of the Fellowship training program in
1968, the beginning of the Young Investigator Grant program in 1987, and the
establishment of the Clinical Scientist Award in 1994, hundreds of nephrologists
and basic scientists have been supported by the NKF research programs. The annual
budget for the various research and training programs of the NKF has increased
from approximately $80,000 to more than $1,000,000 for the Fellowship training
program, from about $90,000 to more than $400,000 for the Young Investigator
Grant program, and from $50,000 to $500,000 annually for the Clinical Scientist
award for a total of more than $2,000,000 annually, while future plans are to
expand the research budget to almost $3,000,000 annually. In addition to these
programs to support outstanding research and training from the national office,
many Affiliate chapters of the NKF also support research and training as a
mission. It is the goal of the NKF that the research supported by the NKF will
ultimately be translated into improved quality of care for patients with kidney
disease. Because progress in many diseases is hampered by a lack of knowledge of
the underlying pathophysiology of the disease, improved understanding of the
mechanisms of renal disease will allow for the development of strategies to
prevent or limit renal disease. The NKF is committed to continuing its focus on
research and training as one of its major missions so that patients with kidney
disease can live better lives in the next millennium.
PMID- 10766000
TI - How end-stage renal disease (ESRD)-medicare developed.
AB - Uremia is a chemical, toxic, potentially fatal condition. In a variable pattern,
uremia ultimately kills almost every cell in the body. Uremia is produced by
hundreds of diseases, both kidney and systemic (e.g., diabetes). These kinds of
uremic conditions range from the acute and catastrophic to the slowly and
moderately progressive. Humans and medicine have struggled at least since
Hippocrates to understand, prevent and treat uremia and thereby prolong the
useful lives of the young and the aging. Accelerated by the spectacle of
premature uremic deaths from crush syndrome, shock, and forms of nephritis during
major wars and disasters, medicine fused clinical and basic science with
industrial technology and came up with two effective treatments. Dialysis in
several modes and kidney transplantation became feasible but proved complex and
expensive. How people, struggling to survive, were able to use a representative
form of government to treat all kidney patients, forms a human story: A "people"
story. Since it culminated within a single medical generation, it is possible to
tell the story as a participant and eye-witness. This is how the medical, social
and national organization of substitution therapy for uremia evolved. Since it is
legislatively called end-stage renal disease, we titled the entitlement, "How
ESRD-Medicare Developed."
PMID- 10766001
TI - 1971 Medicare amendment: reflections on the passage of the end-stage renal
disease Medicare program.
AB - In this article I reflect on events between 1968 and 1972 that influenced the
enactment of the End-Stage Renal Disease (ESRD) Amendment to Public Law 92-603.
PMID- 10766002
TI - The partnership with affiliates: our stories.
AB - The National Kidney Foundation (NKF) began as a grass roots federation of
affiliates. In the 1950s, there were five original affiliates: Illinois, Michigan
New York/New Jersey, Ohio, and Wisconsin. Twenty-two affiliates developed in the
1960s and 12 more in the 1970s; the 1980s and 1990s brought changing affiliate
configurations. After 50 years of progress, there are 52 affiliates in the NKF.
As the national organization has grown, evolved, and prospered, each affiliate
has also grown in unique and individual directions. Each affiliate has its own
important history; unfortunately, space limitations preclude recounting all of
them. Instead, we offer a limited collection of diverse anecdotes, stories, and
vignettes from our affiliates. We hope that these reflect the richness and
diversity of the ongoing histories of the affiliates of the NKF.
PMID- 10766003
TI - The dialysis outcomes quality initiative: history, impact, and prospects.
AB - Rigorously developed clinical practice guidelines have the potential to improve
patient outcomes. It is toward that end that the National Kidney Foundation (NKF)
launched in March 1995 the Dialysis Outcome Quality Initiative (DOQI), an
ambitious effort to develop evidence-based clinical practice guidelines for the
care of patients with end-stage renal disease (ESRD). Independent,
interdisciplinary work groups conducted a structured review of the content and
methodologic rigor of all the published literature pertinent to four selected
topics: hemodialysis adequacy, peritoneal dialysis adequacy, vascular access, and
anemia. Following expert, organizational, and public review, the guidelines were
issued in September and October 1997. An implementation plan that called for
widespread dissemination of the guidelines and facilitation of adoption of them
has resulted in their broad acceptance and Integration into quality improvement
efforts. Additional guidelines on nutrition have recently been completed, while
others on bone disease, hypertension, and hyperlipidemia are in various stages of
planning or development. A major determinant of poor outcome of maintenance
dialysis patients is the debilitated state of many individuals with ESRD at the
time that they commence dialysis therapy. The recognition of this problem has
stimulated an interest in extending the guidelines to management of patients with
less severe renal insufficiency, well before they need renal replacement therapy;
and to the early detection of renal insufficiency by a proteinuria and
albuminuria risk assessment, detection, and elimination (PARADE) program. What
started as an initiative to improve the quality of care of dialysis patients has
evolved into a considerably expanded effort to making lives better for all
individuals with any level of renal insufficiency.
PMID- 10766004
TI - The modern National Kidney Foundation: broad scope, clear vision, better lives.
AB - The mission of the National Kidney Foundation is very broad, going well beyond
what its name implies. The Foundation works for, cares about, and represents
millions of Americans, from the child who wets the bed to the diabetic with
hypertension to the grandfather on dialysis. It is dedicated to making lives
better through a variety of educational programs for patients and their families
as well as physicians, social workers, nurses, dietitians, technicians,
administrators, and clinical and transplant coordinators. It supports research,
promotes organ and tissue donation, provides direct services to patients, and
advocates for patients through public policy and legislative initiatives. Its
programs aid people at risk of kidney and urinary tract disease, individuals
affected by these diseases, living organ donors and families of donors, and
recipients of all types of lifesaving organ and tissue transplants.
PMID- 10766005
TI - Restructuring the National Kidney Foundation.
AB - The National Kidney Foundation reorganized its governance structure for the first
time in its 50-year history. Following a 2-year review, which involved all
constituents of the Foundation and took advantage of the advice of professional
consultants, the NKF delegated governance responsibilities to the Board of
Directors and created a General Assembly of affiliate leaders and professional
staff. NKF national and affiliate leaders agreed on this course of action so that
power would be more appropriately shared between the national organization and
the affiliates and the overall organization would be better positioned to succeed
in the NKF's first national fund raising campaign.
PMID- 10766006
TI - Nephrology in the 21st century: revolutionary changes.
AB - The new millennium will be characterized by revolutionary changes in medical
practice, including nephrology. These changes will occur as a result of the
translation of fundamental discoveries or developments in molecular genetics,
informatics, cyberbiology, and cyberpharmacology. The dialysis population may
shrink as a consequence of new and effective therapies or preventive strategies
in renal disease. The organization of medical practice will evolve into new,
integrated systems of care. The disparity between the "haves" and the "have-nots"
will widen. Profound challenges and opportunities await nephrology in the new
millennium.
PMID- 10766007
TI - The scientific and professional challenges for the National Kidney Foundation in
the 21st century.
AB - The coming century will witness many changes in the science and practice of
nephrology and in cultural attitudes and behavior that should have profound
effects on the National Kidney Foundation (NKF). There will be marked advances in
our understanding and treatment of kidney disease. Concomitantly, there should be
continued advances in the technology of communication and more widespread
utilization of this technology by the NKF. There should be substantial growth in
the numbers of individuals with end-stage renal disease and a growing recognition
of and respect for the psychosocial and material needs of these individuals.
Rising prosperity will lead to many improvements in the delivery of health care
to patients with renal disease and renal failure. It is anticipated that the
financial resources of the NKF will continue to increase and that this factor
will enhance the ability of the NKF to carry out its many programs. These changes
will present new opportunities and new challenges to the NKF. It is anticipated
that these changes will be manifest in at least the following five areas of NKF
activity: (1) There will be increased advocacy for funding for renal research
from federal agencies, especially from the National Institutes of Health; the NKF
research fellowship and grants program will also grow. (2) There will be a
continued NKF commitment to facilitate the translation of new scientific and
medical advances into routine health care delivered to the average renal patient.
(3) There will be improved techniques for professional education. (4) There will
be greater international cooperation among kidney-focused organizations,
particularly among different kidney foundations. (5) There will be an increase in
the scope of activities that promote patient empowerment and rehabilitation.
PMID- 10766008
TI - Proteinuria: its clinical importance and role in progressive renal disease.
AB - In patients with essential hypertension and in those with diabetes mellitus, the
presence of increased amounts of urinary protein or albumin has been shown to be
an important and independent risk for an increased incidence of cardiovascular
morbidity and mortality. A constellation of cardiovascular risk factors has been
described in these individuals, as well as evidence for diffuse endothelial cell
dysfunction, which suggests these individuals are particularly susceptible to the
development of extensive vascular disease. Recent studies have also suggested
that proteinuria is not only a marker for renal disease but it also predicts
those patients at greatest risk for the development of chronic and progressive
renal insufficiency. This effect of proteinuria was evident in patients in whom
urinary protein excretion rates exceeded 1 g/24 hours, but probably is true even
in patients with smaller amounts of proteinuria. This effect of proteinuria on
progression of renal disease is independent of other risk factors such as level
of renal function, blood pressure, and dyslipidemia. Recent clinical studies have
demonstrated that modification of proteinuria by the use of angiotensin
converting enzyme (ACE) inhibitors independent of reductions in systemic blood
pressure results in slowing of the rate of loss of renal function and even
stabilization of renal function over longer periods of treatment. In patients
with renal disease, the totality of evidence suggests that multiple
pharmacological and dietary modifications will be necessary to achieve the
optimal slowing of the progression of renal disease. In addition, strategies will
be required to reduce risks involved in the development of cardiovascular disease
to ensure optimal patient survival. The similarity of risk factors involved in
cardio-renal disease progression should allow us to achieve this goal with our
current therapeutic armamentarium.
PMID- 10766009
TI - Future developments in the treatment of end-stage renal disease: a North American
perspective.
AB - New technology for the treatment of end-stage renal disease will need to be
pharmacoeconomically persuasive in reducing the life-cost of treatment to obtain
entry into the market. Increased automation, with closed-loop sensing technology,
will occur in the near term. Clearance-based terminology for quantifying
performance of equipment will give way to direct quantification of toxin removal.
Experiments on the frequency and duration of treatment will redefine what is
considered to be adequate therapy in terms other than simple urea removal. Near
term changes in current vascular access technology will be driven by the current
cost of access failure. Automated peritoneal dialysis will displace continuous
ambulatory peritoneal dialysis, and online compounding of solution for use is
likely for both hemodialysis and peritoneal dialysis. In a longer time frame
these technologies will merge. Xenografting from the pig will be a reality, and
gene therapy of the mesothelium will provide a more user-friendly therapy for end
stage renal disease.
PMID- 10766010
TI - Cardiovascular disease and chronic renal disease: a new paradigm.
AB - Cardiovascular disease (CVD) is a major cause of morbidity and mortality among
patients with chronic renal disease (CRD). Despite Improvement in treatment for
CVD over the past 30 years, CVD mortality is approximately 15 times higher in
dialysis patients than in the general population. The high prevalence of CVD
among Incident dialysis patients suggests that CVD begins in earlier stages of
CRD, and that implementation of risk factor reduction strategies earlier in the
course of CRD may provide an opportunity to prevent CVD in CRD. Based on
parallels between CVD and renal disease progression, we have proposed a paradigm
that CVD and CRD are outcomes of the same underlying disorders. We propose that
risk factor reduction strategies used to prevent CVD in the general population
also be applied to patients with CRD, with the hope of preventing progression of
renal disease, as well as preventing CVD.
PMID- 10766011
TI - Psychosocial factors in adult end-stage renal disease patients treated with
hemodialysis: correlates and outcomes.
AB - The first three decades of the ESRD program were devoted to extending patient
survival. Few data have been generated regarding the factors associated with
successful patient adjustment. Depression and perception of the effects of
illness are important responses to the experience of ESRD and may be associated
with differential survival. Perception and extent of social support can moderate
these factors. The association of psychosocial factors and assessments of quality
of life are incompletely understood and are topics of research interest. The role
of variation in socioeconomic status in association with these factors has not
been extensively studied. The challenges for the next 30 years include
understanding the relationship of psychosocial factors to demographic and medical
factors in large ESRD patient populations and the refinement of associations
between psychosocial factors and patient outcomes, including adjustment,
compliance, morbidity, and mortality.
PMID- 10766012
TI - Renal rehabilitation: obstacles, progress, and prospects for the future.
AB - The definition of rehabilitation for end-stage renal disease (ESRD) patients has
changed significantly over the past 40 years. Initially, the concept focused on
return to employment. In the early days, most members of the small, select group
of patients chosen for dialysis met this criterion and were considered
successfully rehabilitated. However, this "success" could not be replicated in
the broader ESRD population when Medicare coverage was expanded to include older
and more debilitated patients. This raised serious questions about the
feasibility of renal rehabilitation efforts. Government policy makers and the
nephrology community responded by (1) gathering data to enable the measurement
and improvement of health-related quality of care, and (2) redefining
rehabilitation and its goals. Today, renal rehabilitation is defined broadly, in
terms of optimal functioning for individual patients and restoration to
productive activities-not simply employment. To foster renal rehabilitation and
guide program development, the Life Options Rehabilitation Advisory Council
(LORAC) identified five core principles, called the "5 E's"-Encouragement,
Education, Exercise, Employment, and Evaluation. Considerable progress has been
made in measuring outcomes of care and in establishing a connection between
rehabilitation interventions and improved outcomes. Increasingly, research is
focused on the relationship between patient self-reports and health status
outcomes. In the years ahead, clinicians and researchers will see growing
evidence of relationships between specific rehabilitation interventions, improved
outcomes (including health-related quality of life), and cost-effective delivery
of care.
PMID- 10766013
TI - Outcomes of renal replacement therapy among blacks and women.
AB - The outcomes of renal replacement therapy differ dramatically by race and gender.
Compared with white patients, black patients have poorer outcomes in five
clinical parameters (anemia, hypertension, vascular access, adequacy of dialysis,
compliance), employment, and access to transplantation. Compared with males,
females have poorer outcomes in hospitalization, three clinical parameters
(anemia, vascular access, nutrition), quality of life, and access to
transplantation. Despite several poorer intermediate outcomes, blacks and women
do better than whites and men in survival. Eliminating racial and gender
differences in outcomes of renal replacement therapy requires that we (1) become
aware of such differences, (2) determine barriers to optimal outcomes, and (3)
develop interventions to overcome these barriers. This approach can lead to
improved outcomes not just among blacks and women but among all renal patients.
Examining racial and gender differences can also lead to an increased
understanding of renal disease.
PMID- 10766014
TI - Transplantation.
AB - The history of solid organ transplantation is traced from its beginnings in the
19th century to the beginning of the 21st century. Surgical techniques, advances
in immunology, and a review of major immunosuppressive milestones are reviewed.
Over the last 50 years, transplantation has moved from experimental to accepted
clinical therapy. The technology of transplantation has been widely disseminated
throughout the United States. This paper reviews the major ethical and social
problems that still need to be addressed in regards to transplantation. These
include organ supply, organ distribution, access to care, funding, and
xenotransplantation.
PMID- 10766015
TI - Genetics of kidney disease.
AB - Perhaps nothing in the fields of medicine and nephrology is moving more rapidly
than genetics. From this movement are opportunities for discovery, new therapy,
and better counseling for patients. At a level of basic science, renal medicine
has been a consistent contributor to this emerging discipline, but our current
approach to training in the methods and uses of human genetics probably will not
keep up with the technology, nor the needs of the modern bedside practitioner.
The facile use of genetics in the next century will require the construction and
exploration of new disease models, rededication to human informatics, and
teaching the language of molecular and population genomics.
PMID- 10766016
TI - Regulation of eye formation by the Rx and pax6 homeobox genes.
AB - The Rx and pax6 homeobox genes are among the earliest genes expressed in the eye
primordia and play crucial roles in the specification of ocular fate. These genes
exhibit strong conservation of sequence and expression patterns among
vertebrates. As transcription factors, Rx and Pax6 exert their effects through
the activation and repression of downstream targets. Overexpression of each
protein induces ectopic retinal tissue formation, as well as induction of the
other. pax6 gene mutations have been correlated with an array of human diseases,
and a similar array of mutations potentially exists for the human Rx gene. Based
on functional studies, the vertebrate Rx and pax6 genes are likely to regulate
cell proliferation and are required for the initial commitment to retinal and
lens cell fate, respectively, while pax6 appears to play additional roles in the
formation of the retina and cornea.
PMID- 10766017
TI - Determination of Drosophila photoreceptors: timing is everything.
AB - This review covers recent findings concerning the specification of the
photoreceptor subtypes in the Drosophila eye. Particular attention is paid to
aspects of retinal patterning and differentiation where relative timing of events
seems to be tightly controlled and essential for proper assembly of the compound
eye. For example, specification of the founding photoreceptors of each cluster
requires sequential positive and negative signaling through the Notch pathway,
and reiterated signaling through the epidermal growth factor receptor leads to
the pairwise recruitment of the distinct types of photoreceptors in discrete
zones across the eye. Results suggest that different signaling environments for
these two receptors may exist across the disc, and that receiving cells may
constantly shift their predisposition to respond to such signals by adopting
given fates. In addition, considerable data exist that the rate of expansion of
retinal patterning across the disc is restricted to allow the orderly patterning
of retinal precursors, and that one mechanism for controlling this rate may be
the co-ordinated expression anterior to the furrow of factors which both inhibit
and promote the expansion of retinal patterning. Finally, this review considers
the possibility that the morphogenetic furrow serves as a moving source of
morphogens which supply spatial information to both anterior and posterior
tissue, providing temporal cues that regulate the many events involved in orderly
assembly of the precise array of retinal cell types in the compound eye.
PMID- 10766018
TI - Determination of vertebrate retinal progenitor cell fate by the Notch pathway and
basic helix-loop-helix transcription factors.
AB - The retina is an excellent system in which to study neural cell fate decision
mechanisms. It is an organized laminated structure with a limited array of cell
types. During the last 5 years, experiments that perturb normal gene expression
have highlighted some molecular mechanisms involved in cellular fate choice in
the retina. By controlling when a retinoblast is allowed to differentiate, Delta
Notch signaling plays a critical role in the generation of neuronal diversity in
the vertebrate retina. When cells are released from the inhibition mediated by
the Delta-Notch pathway, basic helix-loop-helix (bHLH) transcription factors act
as intrinsic factors that bias neuroblasts towards particular fates. In this
review, we present an overview of the data leading to these conclusions on the
role of the Delta-Notch pathway and the bHLH proteins on cell fate decisions
during vertebrate retinogenesis.
PMID- 10766019
TI - Soluble factors and the development of rod photoreceptors.
AB - Photoreceptors are the most abundant cell type in the vertebrate neural retina.
Like the other retinal neurons and the Muller glia, they arise from a population
of precursor cells that are multipotent and intrinsic to the retina.
Approximately 10 years ago, several studies demonstrated that retinal precursor
cells (RPCs) are competent to respond to environmental factors that promote cell
type determination and differentiation. Since those studies, significant effort
has been directed at identifying the molecular nature of these environmental
signals and understanding the precise mechanisms they employ to drive RPCs
towards the different retinal fates. In this review, we describe the recent
progress toward understanding how environmental factors influence the development
of vertebrate rod photoreceptors.
PMID- 10766020
TI - RNA processing and human disease.
AB - Gene expression involves multiple regulated steps leading from gene to active
protein. Many of these steps involve some aspect of RNA processing. Diseases
caused by mutations that directly affect RNA processing are relatively rare
compared with mutations that disrupt protein function. The vast majority of
diseases of RNA processing result from loss of function of a single gene due to
mutations in cis-acting elements required for pre-messenger RNA (mRNA) splicing.
However, a few diseases are caused by alterations in the trans-acting factors
required for RNA processing and in the vast majority of cases it is the pre-mRNA
splicing machinery that is affected. Clearly, alterations that disrupt splicing
of pre-mRNAs from large numbers of genes would be lethal at the cellular level. A
common theme among these diseases is that only subsets of genes are affected.
This is consistent with an emerging view that different subsets of exons require
different sets of cis-acting elements and trans-acting factors.
PMID- 10766021
TI - Biomolecular stability and life at high temperatures.
AB - It is not clear what the upper temperature limit for life is, or what specific
factors will set this limit, but it is generally assumed that the limit will be
dictated by molecular instability. In this review, we examine the thermal
stability of two key groups of biological molecules: the intracellular small
molecules/metabolites and the major classes of macromolecules. Certain small
molecules/metabolites are unstable in vitro at the growth temperatures of the
hyperthermophiles in which they are found. This instability appears to be dealt
with in vivo by a range of mechanisms including rapid turnover, metabolic
channelling and local stabilisation. Evidence to date suggests that proteins have
the potential to be stable at substantially higher temperatures than those known
to support life, but evidence concerning degradative reactions above 100 degrees
C is slight. DNA duplex stability is apparently achieved at high temperature by
elevated salt concentrations, polyamines, cationic proteins, and supercoiling
rather than manipulation of C-G ratios. RNA stability seems dependent upon
covalent modification, although secondary structure is probably also critical.
The diether-linked lipids, which make up the monolayer membrane of most organisms
growing above 85 degrees C are chemically very stable and seem potentially
capable of maintaining membrane integrity at much higher temperatures. However,
the in vivo implications of the in vitro instability of biomolecules are
difficult to assess, and in vivo data are rare.
PMID- 10766022
TI - Chemical properties of alcohols and their protein binding sites.
AB - Alcohols affect a wide array of biological processes including protein folding,
neurotransmission and immune responses. It is becoming clear that many of these
effects are mediated by direct binding to proteins such as neurotransmitter
receptors and signaling molecules. This review summarizes the unique chemical
properties of alcohols which contribute to their biological effects. It is
concluded that alcohols act mainly as hydrogen bond donors whose binding to the
polypeptide chain is stabilized by hydrophobic interactions. The
electronegativity of the O atom may also play a role in stabilizing contacts with
the protein. Properties of alcohol binding sites have been derived from X-ray
crystal structures of alcohol-protein complexes and from mutagenesis studies of
ion channels and enzymes that bind alcohols. Common amino acid sequences and
structural features are shared among the protein segments that are involved in
alcohol binding. The alcohol binding site is thought to consist of a hydrogen
bond acceptor in a turn or loop region that is often situated at the N-terminal
end of an alpha-helix. The methylene chain of the alcohol molecule appears to be
accommodated by a hydrophobic groove formed by two or more structural elements,
frequently a turn and an alpha-helix. Binding at these sites may alter the local
protein structure or displace bound solvent molecules and perturb the function of
key proteins.
PMID- 10766023
TI - Lecticans: organizers of the brain extracellular matrix.
AB - Lecticans are a family of chondroitin sulfate proteoglycans, encompassing
aggrecan, versican, neurocan and brevican. These proteoglycans are characterized
by the presence of a hyaluronan-binding domain and a C-type lectin domain in
their core proteins. Through these domains, lecticans interact with carbohydrate
and protein ligands in the extracellular matrix and act as linkers of these
extracellular matrix molecules. In adult brain, lecticans are thought to interact
with hyaluronan and tenascin-R to form a ternary complex. We propose that the
hyaluronan-lectican-tenascin-R complex constitutes the core assembly of the adult
brain extracellular matrix, which is found mainly in pericellular spaces of
neurons as 'perineuronal nets'.
PMID- 10766024
TI - Generation of cellular immune responses to antigenic tumor peptides.
AB - Tumor immunotherapy is currently receiving close scrutiny. However, with the
identification of tumor antigens and their production by recombinant means, the
use of cytokines and knowledge of major histocompatibility complex (MHC) class I
and class II presentation has provided ample reagents for use and clear
indications of how they should be used. At this time, much attention is focused
on using peptides to be presented by MHC class I molecules to both induce and be
targets for CD8+ cytolytic T cells. Many peptides generated endogenously or given
exogenously can enter the class I pathway, but a number of other methods of
entering this pathway are also known and are discussed in detail herein. While
the review concentrates on inducing cytotoxic T cells (CTLs), it is becoming
increasingly apparent that other modes of immunotherapy would be desirable, such
as class II presentation to induce increased helper activity (for CTL), but also
activating macrophages to be effective against tumor cells.
PMID- 10766026
TI - The role of M cells in mucosal immunity.
AB - Mucosa-associated lymphoid tissue in the respiratory and digestive tracts are
covered by a specialized epithelium, the follicle-associated epithelium, which
includes M cells, which are specialized for the uptake and transcytosis of
macromolecules and microorganisms. Following transcytosis, antigens are released
to cells of the immune system in lymphoid aggregates beneath the epithelium where
antigen processing and presentation and stimulation of specific B and T
lymphocytes are achieved. Circulation of the lymphoid cells enables their homing
to their original, and other, mucosal sites where they exert the effector
function. Such a response may be dominated by secretory immunoglobulin A release
and may include cytotoxic T lymphocyte action. Binding of particles to the apical
M cell membrane may be nonspecific or due to specific interaction between
molecules such as integrins and lectins. Exploiting the specific binding to M
cells is an aim for mucosal vaccination, for example to increase the efficiency
of uptake of an oral vaccine by its conjugation to an M-cell-specific molecule.
Alternatively, an M-cell-specific live vector, such as attenuated Salmonella
bacteria, may be used to deliver epitopes of other organisms. Mucosal vaccination
efficiency may also be enhanced by a temporary increase in the number of M cells.
Therefore, investigation of the properties and ontogeny of M cells must be
pursued to allow the development of better mucosal vaccines for the future.
PMID- 10766025
TI - P58IPK, a novel cochaperone containing tetratricopeptide repeats and a J-domain
with oncogenic potential.
AB - Tetratricopeptide repeats (TPRs) are loosely conserved 34-amino acid sequence
motifs that have been shown to function as scaffolding structures to mediate
protein-protein interactions. TPRs have been identified in a number of proteins
with diverse functions and cellular locations. Recent studies suggest that
individual TPR motifs can confer specificity in promoting homotypic and/or
heterotypic interactions, often in a mutually exclusive manner. These features
are best exemplified by the P58IPK protein, an influenza virus-activated cellular
inhibitor of the PKR protein kinase, whose different TPR motifs mediate
interactions with distinct proteins. P58IPK, which possesses cochaperone and
oncogenic properties, represents a unique class of TPR proteins containing a J
domain. Here we review recent progress on the structural and functional
characterization of P58IPK, and discuss the possible mechanisms by which P58IPK
modulates PKR and induces tumorigenesis in view of present knowledge of TPR
proteins and molecular chaperones.
PMID- 10766027
TI - Resveratrol-type oligostilbenes from Iris clarkei antagonize 20-hydroxyecdysone
action in the Drosophila melanogaster B(II) cell line.
AB - Bioassay-guided high-performance liquid chromatography analysis of a MeOH extract
of Iris clarkei seeds yielded the resveratrol-type oligomeric stilbenes,
ampelopsin B and alpha-viniferin, which antagonize the action of 20
hydroxyecdysone; with a 20-hydroxyecdysone concentration of 50 nM, the ED50
values were 33 microM and 10 microM, respectively. The structures of these
compounds were determined by spectroscopic analysis, notably ultraviolet, liquid
secondary ion mass spectrometry and modern one- and two-dimensional nuclear
magnetic resonance techniques.
PMID- 10766028
TI - Unordered structured of proinsulin C-peptide in aqueous solution and in the
presence of lipid vesicles.
AB - Proinsulin C-peptide ameliorates renal and autonomic nerve function and increases
skeletal muscle blood flow, oxygen uptake and glucose transport in patients with
insulin-dependent diabetes mellitus. These effects have in part been ascribed to
the stimulatory influence of C-peptide on Na+,K+-ATPase and endothelial nitric
oxide synthase. To evaluate the capacity of C-peptide to insert into lipid
bilayers and form ion channels, C-peptide secondary structure and membrane
interactions were studied with circular dichroism spectroscopy and size exclusion
chromatography. C-peptide is shown to lack a stable secondary structure, both
when part of proinsulin and when free in aqueous solution, although the N
terminal third of the peptide exhibits an alpha-helical conformation in
trifluoroethanol. Moreover, C-peptide remains disordered in the aqueous solvent
in the presence of lipid vesicles, regardless of vesicle composition. In
conclusion, C-peptide is unlikely to elicit physiological effects through stable
conformation-dependent interactions with lipid membranes.
PMID- 10766030
TI - Notes on the reform of scientific work assessment systems in post-communist
countries.
PMID- 10766029
TI - The amino acid sequence of the agglutinin isolated from the red marine alga
Bryothamnion triquetrum defines a novel lectin structure.
AB - The primary structure of a lectin isolated from the red alga Bryothamnion
triquetrum was established by combination of Edman degradation of sets of
overlapping peptides and mass spectrometry. It contains 91 amino acids and two
disulphide bonds. The primary structure of the B. triquetrum lectin does not show
amino acid sequence similarity with known plant and animal lectin structures.
Hence, this protein may be the paradigm of a novel lectin family.
PMID- 10766031
TI - Expression of cardiac renin and its modulation by stress in normotensive and
hypertensive rats.
AB - Renin is the rate-limiting step in angiotensin II production. Existence of the
cardiac renin is still ambiguous in healthy animals, although there is evidence
that under some pathological conditions the heart might express mRNA for renin.
Therefore, the aim of the present study was to (i) detect the renin gene
expression in the whole rat heart, ventricles, atria and in isolated and purified
myocytes, (ii) determine the effect of stress on renin mRNA and protein levels,
and (iii) compare the response of renin gene expression to stress in normotensive
and spontaneously hypertensive rats. Renin mRNA was determined by reverse
transcription and polymerase chain reaction and quantified relatively to beta
actin and glyceraldehyde-3-phosphate dehydrogenase. Protein message was detected
by monoclonal antibody against renin. Renin mRNA was found in all parts of the
heart and in myocytes. Renin protein was found in the heart ventricles and atria,
but not in cardiomyocytes. Immobilization stress affected renin on both, the mRNA
and the protein level. The effect of stress was observed in the hearts of
normotensive, but not in genetically hypertensive rats. Thus, renin might be
involved in the development of the pathophysiological state in rat heart.
PMID- 10766032
TI - Cholinesterases in dexrazoxane-treated daunorubicin cardiomyopathy in rabbits.
AB - Changes in cholinesterases activities in daunorubicin cardiomyopathy and in
dexrazoxane (DRZX)-treated daunorubicin cardiomyopathy were investigated in
rabbits. Acetyl- and butyrylcholinesterase (AChE and BuChE) were determined using
Ellman's method. In the serum, a significant decrease of BuChE was observed in
the daunorubicin group (9.05 at the beginning and 7.15 microcat/l at the end of
the experiment). After DRZX, no significant changes were found and a significant
increase in BuChE was observed in the control group (10.26-12.38 microcat/l).
AChE activity in the left and right cardiac ventricles was not significantly
different between the groups while in the septum there was a significantly lower
AChE activity found in the daunorubicin group only. BuChE activity was
significantly decreased in the left (15.64 ncat/g) and right (19.27 ncat/g) heart
ventricles, in the septum and in the liver in the daunorubicin group. A
significant decrease in serum total protein and albumin was demonstrated only in
the daunorubicin group. Our results support the hypothesis about the influence of
daunorubicin on protein (and enzyme) synthesis in the liver and heart. A
protective effect of DRZX on cholinesterases activity was observed. The changes
in cholinesterase activities may thus reflect their possible role in
cardiomyopathy.
PMID- 10766033
TI - Modulation of LH/hCG receptors and physical state of ovarian membranes in rat
pseudopregnancy.
AB - Previous investigations have demonstrated that increased ovarian function during
pseudopregnancy in the rat may be associated with alterations of the physical
state of membranes. Changes in rigidity of membrane lipids were observed during
the formation as well as regression of corpora lutea. The effects of
cyclooxygenase inhibitors (indomethacin and acetylsalicylic acid (ASA)) and of
selected steroids (estradiol, testosterone and dihydrotestosterone) on the
functional state of luteinized ovaries were studied. The compounds were
administered to the animals in silastic capsules on different days after hCG
injection. ASA and indomethacin administration on days 10 and 11 after hCG
injection resulted in an increase in the LH/hCG receptor binding activity and
rigidity of ovarian membrane lipids, as determined by fluorescence polarization
of 1,6-diphenyl-1,3,5 hexatriene (DPH) probe. This effect was apparent within 7
days after indomethacin and ASA treatment. Both estradiol and testosterone
significantly increased the ovarian LH/hCG binding activity, however estradiol
did not affect the membrane lipid rigidity. Unlike testosterone, the
administration of dihydrotestosterone induced a decrease in membrane lipid
rigidity and reduced the accessibility of the LH/hCG receptor. Inhibitors of
prostaglandin F2alpha (PGF2alpha) synthesis, as the endogenous mediator of
luteolysis, were shown to delay the regression of the corpora lutea and to
prolong the luteal activity in pseudopregnant rats.
PMID- 10766034
TI - An active-medium model of organic substance transformation in soil and its
dynamic properties.
AB - An analysis of the behaviour of the soil system considered as an active medium
with distributed energy sources was undertaken. This approach enabled the authors
to build a heuristic model of soil which accounts for processes of organic
substance production, migration and utilisation. The soil body is presented as a
spatially distributed trophic chain with non-linear interactions of adjacent
links. The level of this non-linearity appears to be the key parameter
determining the dynamic behaviour of the model system in one-, two- and three
dimensional cases. The conditions for the existence of pulse-generating and
autowave modes in this system were determined by computer simulations. Of
particular interest is the behaviour of damaged soil, especially its self
regeneration potential. Inoculation autowave was proven to restore the initial
state of the soil if two adjacent or separated trophic links fall out. Possible
ways of the further development of the proposed model are also discussed.
PMID- 10766035
TI - The effect of partial deglycosylation on the structure of alpha1-acid
glycoprotein.
AB - Changes in structure of alpha1-acid glycoprotein were followed after
deglycosylation with neuraminidase, peptide N-glycohydrolase F or with a mixture
of exoglycosidases. Partially deglycosylated preparations of alpha1-acid
glycoprotein free of sialic acids, one complete saccharide component, sialic
acids and one saccharide component and sialic acids and some of the external
saccharides were obtained. The effect of these changes in saccharide components
on the glycoprotein structure was studied by temperature perturbation difference
spectroscopy, fluorescence spectroscopy, fourth-derivative of absorption spectra
and spectra of CD. Partial deglycosylation resulted in transformation of the
molecule to a more compact state in which phenylalanyl residues were even more
buried, tyrosyl residues became more uniform and tryptophyl residues were less
exposed. The content of ordered secondary structures decreased. The thermal
stability of the molecule was not significantly affected. Removal of one of the
five saccharide components from the native molecule had apparently deeper effect
than total desialyzation of the glycoprotein.
PMID- 10766036
TI - Evidence of complex formation between alkaline phosphatase and a pro-apoptotic
hemoprotein cytochrome c.
AB - Two proteins, alkaline phosphatase (AP) and cytochrome c (cyt c) which seem to be
involved in the apoptotic cell death program were examined on their interaction.
Intestinal AP affects ferricytochrome c (cyt c(FeIII)) by changing its optical
properties, redox state and conformation. The effect proceeded over the course of
hours with a gradual decrease in free cyt c(FeIII) as the AP concentration
increased. A heme containing high molecular species was created in the first
stage of interaction of the proteins in neutral, acidic (pH 2.6), alkaline (pH
8.3), low ionic strength (10 mmol/l phosphate), and high ionic strength (0.5
mol/l NaCl) media. Further complexation was favored by higher pH values and
temperature. Differential scanning calorimetry revealed a decrease in enthalpy of
the thermodenaturation temperature (Tm) of cyt c at 84.5 degrees C due to the AP
addition. Increments of AP in the mixtures resulted in the appearance of Tm peaks
at 68 degrees C and 61 degrees C. Electrophoretic analysis of the commercial
samples of intestinal APs showed main fractions from 63.2 kDa to 72.9 kDa and
from 172.9 up to 179.0 kDa. Changes in positions and intensities of the bands
were detected upon longer incubation (24 h) with cyt c. The electrophoretic
pattern of the bacterial AP was homogeneous with one fraction of 43.7 kDa showing
no alteration due to the cyt c presence. Gel permeation chromatography of
incubated mixtures of intestinal APs and cyt c confirmed the creation of new heme
containing complexes.
PMID- 10766037
TI - Biomaterials for tissue engineering.
AB - Biomaterials play a critical role in the engineering of new functional
genitourinary tissues for the replacement of lost or malfunctioning tissues. They
provide a temporary scaffolding to guide new tissue growth and organization and
may provide bioactive signals (e.g., cell-adhesion peptides and growth factors)
required for the retention of tissue-specific gene expression. A variety of
biomaterials, which can be classified into three types--naturally derived
materials (e.g., collagen and alginate), acellular tissue matrices (e.g., bladder
submucosa and small-intestinal submucosa), and synthetic polymers [e.g.,
polyglycolic acid, polylactic acid, and poly(lactic-co-glycolic acid)]--have
proved to be useful in the reconstruction of a number of genitourinary tissues in
animal models. Some of these materials are currently being used clinically for
genitourinary applications. Ultimately, the development or selection of
appropriate biomaterials may allow the engineering of multiple types of
functional genitourinary tissues.
PMID- 10766038
TI - Systems for therapeutic angiogenesis in tissue engineering.
AB - The goals in tissue engineering include the replacement of damaged, injured, or
missing body tissues with biologically compatible substitutes. To overcome
initial tissue-mass loss, improved vascularization of the regenerated tissue is
essential. Two pathways of tissue neovascularization are known: vasculogenesis,
the in situ assembly of capillaries from undifferentiated endothelial cells (EC),
and angiogenesis, the sprouting of capillaries from preexisting blood vessels.
Recent advances in our understanding of the process of bloodvessel growth have
provided significant tools for the neovascularization of bioengineered tissues.
Several growth factors serve as stimuli for EC proliferation and migration as
well as the formation of new blood vessels. They convey their effects via
specific receptors expressed on the surface of EC. Vascular epithelial growth
factor (VEGF) is a major regulator of neovascularization. VEGF plays a major role
in the early development of blood-cell progenitors. Basic fibroblast growth
factor (bFGF) was identified as the first angiogenic factor. It is a potent
inducer of EC proliferation and blood-vessel growth in vitro and in vivo. VEGF
and bFGF have been injected into undervascularized ischemic tissues, resulting in
new blood-vessel formation and tissue perfusion. Gene-therapy approaches using
VEGF cDNA injection into ischemic tissues have augmented the formation of
collateral vessels. Angiogenic factors such as VEGF and bFGF have also been
incorporated into bioengineered tissues and have facilitated blood-vessel growth.
Other approaches such as prevascularization of the matrix prior to cell seeding
and incorporation of EC into the bioengineered tissues have produced encouraging
results. This article reviews the process of blood-vessel growth and tissue
vascularization, placing emphasis on strategies that can be employed for
efficient vascularization of engineered tissues in vitro and in vivo.
PMID- 10766039
TI - Organ-specific acellular matrix for reconstruction of the urinary tract.
AB - In urology, replacement of organs or organ segments has proved problematic.
Current techniques do not replicate complete organ function, and they cause well
known complications. With the acellular organ-specific matrix we have found a way
to regenerate tissue components seen in the normal lower urinary tract. The time
required for regeneration depends on the matrix size and function. The matrix is
covered by urothelium migrating from the host, after which neovascularization
occurs, followed by formation of smooth-muscle cells and nerves. In our studies,
normal muscle lining and nerves providing functional tissue were demonstrable and
no sign of antigenicity was evident, even after heterologous grafting. The
regenerated rat bladder was evaluated by organ bath as well as by in vivo
functional tests and demonstrated properties and functions similar to those of
host tissue. Besides our obtaining encouraging results in the rat bladder, we
also studied the organ-specific acellular matrix in other species (dog and
rabbit) and other organ segments (ureter and urethra).
PMID- 10766041
TI - Urothelium-lined enteric segments.
PMID- 10766040
TI - Urologic tissue engineering with small-intestinal submucosa: potential clinical
applications.
AB - Small-intestinal submucosa (SIS) is a unique biomaterial that has been shown to
induce tissue-specific regeneration in numerous organ systems. In the urinary
tract, animal studies have demonstrated that SIS promotes functional bladder
regeneration. Other preliminary studies have suggested that SIS may also be
extremely useful for several other types of urologic surgery application where
new tissue is needed or reinforcement of native structures is desired. This
article reviews past and current work with SIS in the urinary tract and focuses
on applications that will likely have future clinical utility.
PMID- 10766042
TI - Tissue engineering of the bladder.
AB - When gastrointestinal tissue is used for bladder augmentation or replacement,
multiple complications may ensue, such as infection, metabolic disturbances,
urolithiasis, perforation, increased mucous production, and malignancy.
Therefore, alternative methods are being sought for cystoplasty. There has been a
resurgence of interest in the use of acellular collagen-based matrices as
scaffolds for bladder regeneration. Experimental work involving several collagen
matrices, such as allogenic bladder and intestinal tissues, is currently being
conducted in several academic centers. Recently, functional bladder tissue has
been engineered using selective cell transplantation. The approach that has been
followed for bioengineering of bladder tissue involves the use of autologous
cells, thus avoiding rejection, whereby a biopsy of tissue is obtained from the
host, after which the cells are dissociated and expanded in vitro, reattached to
a matrix, and implanted into the same host.
PMID- 10766043
TI - Reconstruction of the lower urinary tract using autologous muscle transfer and
cell seeding: current status and future perspectives.
AB - Functioning free-muscle transfer has established itself for the treatment of
skeletal muscle deficiency over the last two decades. The capability of skeletal
muscle to empty a spherical reservoir has been shown to be lessened if the muscle
has contracted due to dissection. Currently there is no established curative
treatment for bladder acontractility. Experimental data and preliminary clinical
results have shown that innervated free latissimus dorsi muscle (LD) may serve as
a substitute for a dysfunctional detrusor. In a clinical protocol, latissimus
dorsi detrusor myoplasty (LDDM) was applied in 11 patients (age 9-68 years) with
bladder acontractility due to spinal cord injury (seven patients), congenital
malformations (two patients), detrusor myopathy (one patient), and idiopathic
causes (one patient) who had required catheterization for bladder emptying for a
minimum of 2 years. In all, 10 of 11 patients were capable of voiding
volitionally, with eight of them no longer requiring catheterization, throughout
the follow-up period of 12-46 months. Transplanted LD activity was confirmed by
ultrasonography and flow-mode computerized tomography. It can thus be concluded
that emptying of the bladder can be induced through the contractility of
reinnervated free LD that has been wrapped around the bladder. An innervated free
LD flap does not undergo the severe muscle fibrosis, contracture, and atrophy
that occur after transfer of completely or partially denervated pedicled muscle.
Apart from the restoration of deficient detrusor function, microneurovascular
transfer of a free-LD flap may be combined with tissue engineering to serve as a
basis for bladder augmentation and substitution.
PMID- 10766044
TI - Tissue-engineered therapies for the treatment of urinary incontinence and
vesicoureteral reflux.
PMID- 10766045
TI - Myoblast therapy for stress urinary incontinence and bladder dysfunction.
AB - The field of tissue engineering and gene therapy has an exciting and promising
future. During the past few years we have begun a comprehensive effort to
investigate the use of myoblasts to improve and expand the treatment of stress
urinary incontinence and bladder dysfunction. Moreover, we can expect the
application of myoblast-mediated ex vivo gene transfer in the field of urology.
In this paper we discuss the compositions of and methods involving the use of
myogenic or muscle-derived cells for tissue engineering and cell-mediated gene
therapy.
PMID- 10766046
TI - Tissue-engineering applications for phallic reconstruction.
AB - Pathologic penile conditions often require reconstructive surgery. Due to the
limited amount of autologous tissues available for reconstruction, other tissue
substitutes have been used. Phallic reconstruction using engineered autologous
genital tissue, i.e., tissue derived from the patient's own cells, may be
preferable. In this article we describe tissue-engineering approaches that may be
applicable to genital reconstruction.
PMID- 10766047
TI - Experimental and clinical experience using tissue regeneration for urethral
reconstruction.
AB - Various urethral conditions often require additional tissue for reconstruction.
Although several innovative tissues have been proposed for possible use as free
grafts for urethral repair, all have specific advantages and disadvantages. The
use of these tissues may be associated with additional procedures for graft
retrieval, prolonged hospitalization, and donor-site morbidity. For these
reasons, alternate materials have been sought for urethral repair. Our laboratory
has developed an acellular collagen matrix that has shown adequate urothelial
cell epithelialization and urethral-tissue regeneration both experimentally and
clinically. After a 3-year follow-up period, all patients who have had their
urethras reconstructed with the acellular matrix are doing well, showing no
clinical change from their immediate postoperative results. Other acellular
materials may soon be tried clinically. Long-term studies need to be conducted
before any of these materials can be accepted for routine use in urethral
reconstructive procedures.
PMID- 10766048
TI - Renal therapy using tissue-engineered constructs and gene delivery.
AB - Currently available renal replacement therapies are not optimal for most
patients. In addition to the inherent shortage of transplant organs, significant
complications are associated with renal transplantation and immunosuppressive
therapy. Dialysis neglects the resorptive, homeostatic, metabolic, and
endocrinologic functions of the kidney and only partially replaces its filtration
properties, resulting in morbidity and mortality. Application of tissue
engineering techniques may improve many aspects of renal function replacement.
Identification of the growth factors capable of directing tissue development and
of the technique to be used for their delivery would aid in the engineering of
human tissue. The combination of tissue-engineering strategies with gene therapy
might allow the transfection of diseased tissues with designated cDNA to
eliminate inherent or acquired defects. Devices that have been targeted at
replacing a single aspect of renal function, in addition to three-dimensional
renal units that are capable of excreting urine-like solutes, have been used
experimentally. Combination of these strategies may allow the formation of tissue
engineered kidneys in the future.
PMID- 10766049
TI - Controlled release of therapeutic agents: slow delivery and cell encapsulation.
AB - Some of the most promising systems for the controlled release of bioactive
agents, i.e., peptides or hormones, involve the encapsulation or entrapment of
hormones or peptides in biocompatible polymeric devices that enable their
continuous release over prolonged periods. In urology, two major pathologic
conditions, androgen deficiency and prostate cancer, currently benefit from
treatments based on controlled delivery. Leuprolide acetate depot (Lupron-depot)
was one of the first controlled-delivery systems used for the treatment of
prostate cancer. Clinical studies indicate that patients with prostate cancer who
undergo therapy with leuprolide acetate depot can benefit from this treatment.
Currently available androgen-replacement therapies include the oral
administration of testosterone tablets or capsules, depot injections, sublingual
treatment, and skin patches. However, side effects such as metabolic inactivation
of testosterone on oral administration; fluctuations in levels of the hormone;
and burning, rash, and skin necrosis during the use of skin patches may occur.
These side effects may be avoided through the application of encapsulated Leydig
cells, which produce testosterone. Studies in our laboratory have shown that
Leydig cells encapsulated in alginate/poly-L-lysine/alginate microspheres are
capable of secreting testosterone in culture and in vivo. Microencapsulated
Leydig cells delivered intraperitoneally into castrated rats maintained a
testosterone level of 0.51 ng/ml for more than 3 months without any human
chorionic gonadotropin stimulation. Similar studies are also being conducted in
our laboratory on encapsulation of ovarian cells for the secretion of
progesterone and estrogen in culture and in vivo using microencapsulation
techniques.
PMID- 10766050
TI - Tissue engineering from Adam to the zygote: historical reflections.
AB - Tissue engineering, long a matter of myth and dream throughout the history of
medicine, is now a practical reality. A wide spectrum of biological materials are
used in the field of urology to treat disease and to overcome human disabilities,
including tissue grafts and organ transplantation. Laboratory-engineered
bioproducts for the off-the-shelf replacement and reconstruction of tissue is now
almost at hand. This article presents a glimpse into the past by highlighting a
number of early pioneering works in the field of tissue transplantation and cell
culture technologies.
PMID- 10766051
TI - Laparoscopic lumbar spine surgery.
AB - The use of transperitoneal endoscopic approaches to the distal segments of the
lumbar spine has recently been described. This has been the catalyst for the
development of other minimally invasive anterior approaches to the spine. This
review looks at the published results so far, and highlights the principles,
techniques and complications. The limitations of laparoscopic approaches have
meant that surgeons are moving on to endoscopic extraperitoneal and mini-open
approaches, but important lessons have been learnt during this short rapid phase
of development. The efficacy and safety of minimal access techniques in the spine
have been established, and outcome standards set by which future techniques can
be judged. The importance of proper training is emphasised.
PMID- 10766052
TI - Endoscopic approaches to the thoracic spine.
AB - Endoscopic surgery of the thoracic spine has up to now been considered as an
experimental procedure. Reports published in recent years have shown that the
results achieved with this technique are as good as, or for some indications
superior to, those reported for classic open approaches. A review of the
indications, limitations, advantages and disadvantages is presented. Although
there is still resistance to acknowledging the effectiveness of this procedure,
experience has shown that the results are as good, complications are fewer and
postoperative recovery is improved, thus shortening the total hospitalization
time.
PMID- 10766053
TI - Anterior thoracoscopic spine release in deformity surgery: a meta-analysis and
review.
AB - Videoassisted thoracoscopic surgery (VATS) allows the surgeon to perform an
anterior thoracoscopic spine release for spinal deformities. It is an alternative
to open thoracotomy. Several years after its introduction the present author
gives an update on the indications, surgical techniques, results, and
complications of this new technology. A meta-analysis of previously published
papers is organized in tables in an attempt to answer all the questions and
controversies that this technique has aroused. A series of ten selected articles
were available for review, comprising a total of 151 procedures. No study had any
long-term follow-up. Most series were pediatric and involved a variety of
etiologies (mostly neuromuscular, adolescent idiopathic scoliosis, and
Scheuermann's kyphosis). The surgical technique was for most authors a convex
side approach in the lateral decubitus through four or more ports in the anterior
or midaxillary line. Single lung ventilation was used in most cases. Posterior
surgery was carried out the same day in most cases. The total number of discs
excised varied between 4 and 7, but the quality of disc excision was rarely
reported. Most authors carried out a spine fusion at the time of the disc
release. The total VATS procedure lasted between 2 h 30 min and 4 h, depending on
the series and the surgeon's previous experience. In most series curves were in
the range of 55 degrees-80 degrees, with an average of 65 . The percentage of
Cobb angle correction was 55%-63% after VATS and posterior spine fusion. For
kyphotic deformities only one series had significant numbers to allow conclusions
to be drawn. The mean preoperative Cobb angle was 78 degrees and postoperatively
the kyphosis was corrected to 44 degrees. Length of hospital stay was quite
similar in most series and was around 9 days. The cost of the VATS procedure was
studied in one series and was found to be 28% more expensive than thoracotomy.
The total complications reported were 18%; most were pulmonary complications with
prolonged ventilatory support in patients with neuromuscular pathologies. The
VATS procedure has been used with success in most series for pediatric curves
(average Cobb angle of 65 degrees or kyphosis of 75 degrees). No report of the
surgical outcome (balance, rate of fusion, rib hump correction, cosmetic
correction, pain, and patient satisfaction) was available for any series. Further
prospective study including these parameters will be required to determine the
real benefit of such procedures to the patient, bearing in mind that the
correction of spinal deformities is the result of the surgeon's experience,
skill, and the available technology.
PMID- 10766054
TI - Posterior endoscopic discectomy (and other procedures).
AB - Percutaneous approaches to lumbar discectomy were somewhat controversial, because
of their limited indications. They have not proven to be as effective as standard
open lumbar disc surgery, because of longer operating times and some technical
problems in addressing all the different aspects of lumbar disc herniations. New
percutaneous posterior procedures for lumbar disc disease have been described in
the last few years, but the MicroEndoscopic Discectomy (MED) introduced by Foley
and Smith in 1997 seems to be the most promising one. MED, and METR'x which
evolved from it,. allow the surgeon to address not only contained lumbar disc
herniations, but also free-fragment disc pathology and symptomatic lateral recess
stenosis secondary to bony hypertrophy. The surgical technique is summarized and
some preliminary clinical results of a prospective multicenter study with 13
months' mean follow-up are presented.
PMID- 10766055
TI - Five years' experience of the retroperitoneal lumbar and thoracolumbar surgery.
AB - Retroperitoneal videoscopic spine surgery has been developed in our department
since 1994. It has been used not only at the lumbar, but also at the
thoracolumbar and lumbosacral level. Thirty-eight patients have been operated on.
We have performed 12 thoracolumbar approaches, 23 lumbar approaches, and 3
retroperitoneal lumbosacral approaches. In every case, a video-assisted technique
has been employed. These techniques have been used for anterior grafting in 18
cases of fracture, for corporectomy and grafting with or without anterior
osteosynthesis in 6 cases of malunion, for cage implantation or isolated grafting
in 10 cases of degenerative disc disease, and for the treatment of 4 cases of
spondylodiscitis. Results were satisfactory for every type of pathology. The
complications related to the approach were the same as those seen with open
surgery; however, the videoscopic approach seems to us less invasive, with
cosmetic benefit, less blood loss, and more rapid recovery. A video-assisted
technique appears to be a good compromise between videoscopic technique and open
surgery. With the development of these techniques, few indications remain for
open anterior surgery on the lumbar spine in our opinion.
PMID- 10766056
TI - The ALIF concept.
AB - The terms 'minimally invasive' or 'less invasive surgery' have been used recently
to describe surgical approaches or operations that are performed with less trauma
to anatomical structures on the way to or surrounding the surgical 'target area'.
These types of surgical procedures are usually performed with the help of 'high
tech' instruments such as surgical endoscopes or surgical microscopes, modern
video techniques and automated instruments. Within the last 10 years, such
techniques have been developed in the field of spinal surgery. The application of
minimally or less invasive procedures has concentrated predominantly on anterior
approaches to the thoracic and lumbar spine. This article describes two anterior
approach techniques for performing anterior lumbar interbody fusion (ALIF)
through a minimally invasive retroperitoneal or transperitoneal approach. The
technical principles are microsurgical modifications of traditional anterior
approaches to the lumbar spine. Through small (4-cm) skin incisions, the target
area can be exposed. Preliminary results suggest decreased peri - and
postoperative morbidity, less blood loss, earlier rehabilitation and acceptable
complication rates. The technique is currently used by the author for all
patients requiring anterior lumbar interbody fusion.
PMID- 10766057
TI - Synframe: a preliminary report.
AB - Both endoscopic lumbar spinal surgery and the non-standardized and unstable
retractor systems for the lumbar spine presently on the market have disadvantages
and limitations in relation to the minimally invasive surgical concept, which
have been gradually recognized in the last few years. In an attempt to resolve
some of these issues, we have developed a highly versatile retractor system,
which allows access to and surgery at the lumbar, thoracic and even cervical
spine. This retractor system - Synframe - is based on a ring concept allowing 360
degrees access to a surgical opening in anterior as well as posterior surgery.
The ring is concentrically laid over the surgical opening for the approach and is
used as a carrier for retractor arms, which are instrumented with either
different sizes or types of blades and/or different sizes of Hohmann hooks. In
posterior surgery, nerve root retractors can also be installed. This ring also
functions as a carrier for fiberoptic illumination devices and different sizes of
endoscopes, used to transmit the surgical procedure out of the depth of the
surgical exposure for both teaching purposes and for the surgical team when it
has no longer direct visual access to the procedure. The ring is stable, being
fixed onto the operating table, allowing precise minimally open approaches and
surgical procedures under direct vision with optimal illumination. This ring
system also opens perspectives for an integrated minimally open surgical concept,
where the ring may be used as a reference platform in computer-navigated surgery.
PMID- 10766058
TI - Minimally invasive 360 degrees instrumented lumbar fusion.
AB - A retrospective preliminary study was undertaken of combined minimally invasive
instrumented lumbar fusion utilizing the BERG (balloon-assisted endoscopic
retroperitoneal gasless) approach anteriorly, and a posterior small-incision
approach with translaminar screw fixation and posterolateral fusion. The study
aimed to quantify the clinical and radiological results using this combined
technique. The traditional minimally invasive approach to the anterior lumbar
spine involves gas insufflation and provides reliable access only to L5-S1 and in
some cases L4-5. A gas-mediated approach yields many technical drawbacks to
performing spinal surgery. A minimally invasive posterior approach involving
suprafascial pedicle screw instrumentation has been developed, but without wide
spread use. Translaminar facet fixation may be a viable alternative to
transpedicular fixation in a 360 degrees instrumented fusion model. Past studies
have shown open 360 degrees instrumented lumbar fusion yields high arthrodesis
rates. The study examined the cases of 46 patients who underwent successful 360
degrees instrumented lumbar fusion using a combined minimally invasive approach.
Anterior lumbar interbody fusion (ALIF) at one or two levels was performed
through the BERG approach; a gasless retroperitoneal approach to the lumbar spine
allowing the use of standard anterior instrumentation. Posteriorly, all patients
underwent successful decompression, translaminar fixation, and posterolateral
fusion at one or two levels through one small (2.5-5.0 cm) incision. Results
showed mean hospital stay of 2.02 days; mean combined blood loss was 255 cc; and
mean pain relief was 56%, with 75.5% of patients reporting good, excellent, or
total pain relief. Forty-two of 46 patients (93.2%) achieved a solid fusion 24
months after surgery. A total of 47% of all patients working prior to surgery
returned to work following surgery. The study showed that minimally invasive 360
degrees instrumented lumbar fusion, when performed utilizing these approaches,
yields a high rate of solid arthrodesis (93.3%), good pain relief, short hospital
stays, low blood losses, accelerated rehabilitation, and a quick return to the
workforce. The BERG approach offers technical advantages over the traditional gas
mediated laparoscopic approach to the anterior lumbar spine.
PMID- 10766060
TI - Computer-assisted surgery in posterior instrumentation of the cervical spine: an
in-vitro feasibility study.
AB - Transarticular C1/2 screws are widely used in posterior cervical spine
instrumentation. The use of pedicle screws in the cervical spine remains
uncommon. Due to superior biomechanical stability compared to lateral mass
screws, pedicle screws can be used, especially for patients with poor bone
quality or defects in the anterior column. Nevertheless there are potential risks
of iatrogenic damage to the spinal cord, nerve roots or the vertebral artery
associated with both posterior cervical spine instrumentation techniques.
Therefore, the aim of this study was to evaluate whether C1/2 transarticular
screws as well as transpedicular screws in C3 and C4 can be applied safely and
with high accuracy using a computer-assisted surgery (CAS) system. We used 13
human cadaver C0-C5 spine segments. We installed 1.4-mm Kirschner wires
transarticular in C 1/2, using a specially designed guide, and drilled 2.5-mm
pedicle holes in C3 and C4 with the assistance of the CAS system. Hole positions
were evaluated by palpation, CT and dissection. Forty-eight (92%) of the 52
drilled pedicles were correctly positioned after palpation, imaging and
dissection. The vertebral artery was not injured in any specimen. All of the 26
C1/2 Kirschner wires were placed properly after imaging and dissection
evaluations. No injury to vascular or bony structures was observed. C /2
transarticular screws as well as transpedicular screws in the cervical spine can
be applied safely and with high accuracy using a CAS system in vitro. Therefore,
this technique may be used in a clinical setting, as it offers improved accuracy
and reduced radiation dose for the patient and the medical staff. Nevertheless,
users should take note of known sources of possible faults causing inaccuracies
in order to prevent iatrogenic damage. Small pedicles, with a diameter of less
than 4.0 mm, may not be suitable for pedicle screws.
PMID- 10766059
TI - Computer-assisted spine surgery.
AB - Computer assistance has been shown to improve significantly the accuracy and
safety of pedicle screw insertion under clinical conditions. The technique of
image-guided navigation is described in this article, based on the authors'
clinical experience of over 4 years. The value of navigation systems for
preoperative planning is discussed. Clinical results of the application of this
new method in the cervical, thoracic, and lumbosacral spine as well as the
iliosacral joints are presented by means of the authors' own studies and reports
from the literature. Pros and cons of computer guidance are discussed. The
authors predict computer navigation will be used in percutaneous and minimally
invasive procedures in the near future.
PMID- 10766061
TI - Hybrid computer-guided and minimally open surgery: anterior lumbar interbody
fusion and translaminar screw fixation.
AB - Less invasiveness is the way forward for spinal surgery. Minimal disruption of
tissue, preservation of muscle function, and restoration of normal spinal
alignment are still the goals of most surgical procedures. An anterior lumbar
fusion technique using a less invasive procedure with the addition of
translaminar screws is described. The autograft is harvested from the vertebral
body, thus avoiding the morbidity associated with an iliac crest bone graft. The
operative steps for the procedure are described.
PMID- 10766062
TI - A new approach to computer-aided spine surgery: fluoroscopy-based surgical
navigation.
AB - A new computer-based navigation system for spinal surgery has been designed. This
was achieved by combining intraoperative fluoroscopy-based imaging using
conventional C-arm technology with free-hand surgical navigation principles.
Modules were developed to automate digital X-ray image registration. This is in
contrast to existing computed tomography- (CT) based spinal navigation systems,
which require a vertebra-based registration procedure. Cross-referencing of the
image intensifier with the surgical object allows the real-time image-interactive
navigation of surgical tools based on one single registered X-ray image, with no
further image updates. Furthermore, the system allows the acquisition and real
time use of multiple registered images, which provides an advanced multi
directional control (pseudo 3D) during surgical action. Stereotactic instruments
and graphical user interfaces for image-interactive transpedicular screw
insertion have been developed. A detailed validation of the system was performed
in the laboratory setting and throughout an early clinical trial including eight
patients in two spine centers. Based on the resulting data, the new technique
promises improved accuracy and safety in open and percutaneous spinal surgery.
PMID- 10766063
TI - Cages: designs and concepts.
AB - Many new interbody fusion cages have been recently developed, but clinical
studies analyzing fusion outcome are still scarce. Radiological methods to assess
fusion are not standardized and are often unreliable. Cages have been stated to
provide good segmental distraction, provide axial load support and reduce
segmental mobility, but there have been reports of failed fusions because of
implant failure. This paper presents a critical opinion on current cage designs,
stressing their clinical and biomechanical implications. Threaded cage designs
compromise endplate integrity, and when placed in pairs have inherent limitations
for distraction. Non-threaded cage designs usually preserve endplate integrity,
but geometry may be inadequate to provide a good surface match to the endplate.
The concept of an open frame type cage is believed to have biological advantages,
because large graft volumes inside the cage can be in direct contact with host
bone. Cadaveric tests suggest that open frame constructs have compressive
strength similar to that of full surface contact cages. Restoration of segmental
height, sagittal balance and increased neuroforaminal clearance are all functions
of disc space distraction. The effect of cage instrumentation on axial load
distribution, however, is not well understood. Biomechanical experiments strongly
suggest supplementing cage instrumentation with posterior fixation, to achieve a
marked increase in initial segmental stability. In the absence of gross segmental
instability, micromotion at the host graft interface may still exist. As a
result, fusion will never occur, instead a pseudoarthrosis will develop. For
monitoring fusion, the use of non-metallic cages has distinct advantages, because
no metal artifacts will disturb radiological assessment.
PMID- 10766064
TI - Biomechanics of stand-alone cages and cages in combination with posterior
fixation: a literature review.
AB - Interbody cages in the lumbar spine have met with mixed success in clinical
studies. This has led many investigators to supplement cages with posterior
instrumentation. The objective of this literature review is to address the
mechanics of interbody cage fixation in the lumbar spine with respect to three
dimensional stabilization and the strength of the cage-vertebra interface. The
effect of supplementary posterior fixation is reviewed. Only three-dimensional
stabilization evaluations in human cadaveric models are included. These studies
involve the application of different loads to the spine and the measurement of
vertebral motion in flexion-extension, axial rotation, and lateral bending. There
are no published studies which detected any differences between different cage
designs. However, it does seem that cages inserted from an anterior direction
provide better stabilization to the spine than those inserted from a posterior
direction. In general, anterior cages stabilize better than posterior cages in
axial rotation and lateral bending. Cages from both directions stabilized well in
flexion, but not in extension. Supplementary posterior fixation with pedicle or
translaminar screws substantially improves the stabilization in all directions.
The strength of the cage-vertebra interface from studies using human cadaveric
specimens is also reviewed. The axial compressive strength of this interface is
highly dependent upon vertebral body bone density. Other factors such as
preservation of the subchondral bony end-plate and cage design are clearly less
important in the compressive strength. Supplementary posterior instrumentation
does not enhance substantially the interface strength in axial compression.
PMID- 10766065
TI - Biological cages.
AB - Restoring a stable anterior column is essential to achieve normal spinal
biomechanics. A variety of mechanical spacers have been developed and advocated
for both anterior and posterior approaches. The ability to radiographically
assess the "biology" of bone incorporation in these mechanical (metal) spacers is
an inherent limitation. The femoral ring allograft (FRA) and posterior lumbar
interbody fusion (PLIF) spacers have been developed as biological cages that
permit restoration of the anterior column with a machined allograft bone
(biological cage). Test results demonstrate that the FRA and PLIF Spacers have a
compressive strength over 25,000 N. The pyramid shaped teeth on the surfaces and
the geometry of the implant increase the resistance to expulsion at clinically
relevant loads (1053 and 1236 N). The technique of anterior column reconstruction
with both the FRA and the PLIF biological cages are discussed. Clinical
experience with the PLIF biological cage (10 patients) and the FRA biological
cage (90 patients) has not revealed any graft migration, infection, or
subsidence. Additional posterior instrumentation may increase the stability of
the motion segment, but the degree of stability necessary to achieve a biological
union remains unclear. The incorporation of these biological cages can be
monitored by conventional radiographic techniques. The method of insertion
preserves the vertebral end-plates and can be performed by a minimally invasive
or standard open procedure.
PMID- 10766066
TI - Cages: outcome and complications.
AB - The coincidental development of minimal intervention techniques for carrying out
anterior lumbar spinal fusion and the introduction of cages to provide mechanical
support of introduced bone graft led to the development of a type of cage
suitable for both minimal intervention use (laparoscopic) and for the standard
open procedure (the BAK cage). Reported results concentrated in the main on
feasibility, safety and fusion rate achieved, rather than clinical outcome.
Laparoscopic insertion at the lumbosacral level was as safe as if the procedure
was an open one, although there was a slighter higher incidence of retrograde
ejaculation. Immediate post-operative morbidity was less with the laparoscopic
procedure and discharge home and return to work was earlier. There was no long
term benefit from the laparoscopic procedure. Laparoscopic insertion at the L4/5
level was attended by a greater incidence of complications, and had a longer
learning curve.
PMID- 10766067
TI - Minimally invasive bone harvesting tools.
AB - The most readily available source for autologous bone graft used in spinal fusion
(the gold standard) is the iliac crest. However, the open surgical approach for
harvesting corticocancellous iliac bone is associated with a marked increase in
morbidity. This study suggests two alternatives to the traditional open
harvesting procedure. For anterior interbody fusion procedures using a cage, the
autologous bone is harvested regionally from a neighboring vertebral body.
Alternatively, using minimally invasive techniques, a custom bone graft harvester
with a flexible tube and cutting tip allows harvesting of autologous bone from a
single entry point at the iliac crest. The effect on the mechanical strength of a
lumbar vertebra of removing a cylindrical regional bone graft was studied in a
cadaveric model. The bone defect was filled using three different filler
materials: a porous tri-calcium phosphate plug, a porous tantalum plug, and a
self-setting calcium phosphate cement. After plug removal, the vertebral body's
strength in flexion/compression loading was reduced significantly, but could be
restored to at least intact values with any of the three filler materials. The
minimally invasive bone graft harvester was tested in three cadaveric pelves.
With the cutting tip being guided within the cortical boundaries of the pelvis,
cancellous bone volumes of 10-20 cc could be harvested from each iliac bone.
Regional bone graft harvest in anterior spine surgery is suggested to be
anatomically safe and biomechanically acceptable. Any of the three filler
materials can restore the vertebral body's mechanical strength, but the filler's
long-term resorption/remodeling or osteointegration behavior is unknown. The
minimally invasive bone graft harvester is a novel tool, which performed
satisfactorily under laboratory conditions, but clinical results are still
missing.
PMID- 10766069
TI - Posterior percutaneous spine instrumentation.
AB - Eighty consecutive cases of suprafascial pedicle screw stabilization were
reviewed. Intraoperative fluoroscopy aided the percutaneous screw placement after
structural anterior interbody graft(s) were placed. During routine outpatient
hardware removal, all intradiscal fusions were stressed via the Shanz screws
under fluoroscopy. Anterior reconstruction via a mini open approach coupled with
this minimally invasive posterior approach led to a 96% successful fusion rate.
PMID- 10766068
TI - Osteoinductive bone graft substitutes.
AB - This review will summarize the major efforts currently underway to develop
osteoinductive bone graft substitutes for minimally invasive spine fusions. The
primary categories of substitute include purified bone growth factors,
recombinant bone growth factors, and growth factors delivered by gene therapy
approaches. Clinical trials are underway for the purified and recombinant bone
growth factors and pre-clinical studies have yielded promising results for a
variety of gene therapy techniques for generating bone.
PMID- 10766070
TI - Cervical radiculopathy and myelopathy: when and what can surgery contribute to
treatment?
AB - Indications and timing of surgical treatment for cervical radiculopathy and
myelopathy, and the long-term results for the conditions, were reviewed. Advances
in spinal imaging and accumulation of clinical experience have provided some
clues as to indications and timing of surgery for cervical myelopathy. Duration
of myelopathy prior to surgery and the transverse area of the spinal cord at the
maximum compression level were the most significant prognostic parameters for
surgical outcome. Thus, when myelopathy is caused by etiological factors that are
either unchangeable by nature, such as developmental canal stenosis, or
progressive, such as ossification of the posterior longitudinal ligament,
surgical treatment should be considered. When an etiology of myelopathy is
remissible, such as soft disc herniation and listhesis, surgery may be reserved
until the effects of conservative treatment are confirmed. When surgery is
properly carried out, long-term surgical results are expected to be good and
stable, and the natural course of myelopathy secondary to cervical spondylosis
may be modified. However, little attention has been paid to the questions "When
and what can surgery contribute to treatment of cervical radiculopathy?". A well
controlled clinical study including natural history should be done to provide
some answers.
PMID- 10766071
TI - Nucleus pulposus inhibits the axonal outgrowth of cultured dorsal root ganglion
cells.
AB - Although it is well established that nucleus pulposus cells may induce structural
and functional changes in adjacent nerve roots when placed epidurally, it is not
known whether this is due to direct neurotoxic effects or whether the nerve roots
are affected indirectly by reduction of nutrition and inflammatory/immunologic
mechanisms. In the present study we assessed the effects of various tissues on
cultured dorsal root ganglions from newborn rats. Nucleus pulposus was found to
have a toxic effect on the axons by blocking axonal outgrowth, but no similar
effects on the nerve cell bodies (extra-ganglionic nerve cell density, nerve cell
arborisation) were found as compared to the series with only culture medium.
Sterile water for 1 or 24 h (positive controls) induced significant effects by
all four criteria, whereas medium without nerve growth factor, fat and frozen
nucleus pulposus had no statistically significant effects. The study thus showed
that there are direct axonotoxic effects induced by the nucleus pulposus, and
since frozen nucleus pulposus did not have any effects, it may be assumed that
the mechanisms are related to substances produced by the nucleus pulposus cells.
The presented model allows for future studies on the neurotoxic properties of
nucleus pulposus cell-derived candidate substances.
PMID- 10766072
TI - Biomechanical stability of five stand-alone anterior lumbar interbody fusion
constructs.
AB - Anterior lumbar interbody fusion (ALIF) cages are expected to reduce segmental
mobility. Current ALIF cages have different designs, suggesting differences in
initial stability. The objective of this study was to compare the effect of
different stand-alone ALIF cage constructs and cage-related features on initial
segmental stability. Human multisegmental specimens were tested intact and with
an instrumented L3/4 disc level. Five different ALIF cages (I/F, BAK, TIS,
SynCage, and ScrewCage) were tested non-destructively in axial rotation,
flexion/extension and lateral bending. A cage 'pull-out' concluded testing.
Changes in neutral zone (NZ) and range of motion (ROM) were analyzed. Cage
related measurements normalized to vertebral dimensions were used to predict NZ
and ROM. No cage construct managed to reduce NZ. The BAK and TIS cages had the
largest NZ increase in flexion/extension and lateral bending, respectively. Cages
did reduce ROM in all loading directions. The TIS cage was the least effective in
reducing the ROM in lateral bending. Cages with sharp teeth had higher 'pull-out'
forces. Antero-posterior and mediolateral cage dimensions, cage height and wedge
angle were found to influence initial stability. The performance of stand-alone
ALIF cage constructs generally increased the NZ in any loading direction,
suggesting potential directions of initial segmental instability that may lead to
permanent deformity. Differences between cages in flexion/extension and lateral
bending NZ are attributed to the severity of geometrical cage-endplate surface
mismatch. Stand-alone cage constructs reduced ROM effectively, but the residual
ROM present indicates the presence of micromotion at the cage-endplate interface.
PMID- 10766073
TI - Early histologic changes in lower lumbar discs and facet joints and their
correlation.
AB - Biomechanical and histologic studies have highlighted the close functional
relationship between lumbar discs and their associated facet joints, and it is
conceivable that their degenerative changes are interdependent. However,
separation of cause from effect remains controversial. Hitherto, no study in
humans has correlated the changes histologically. The present study assessed
histologic changes in lower lumbar discs and their associated facet joints in
patients under the age of 40 years using classification systems developed for
this investigation. A specific objective was to correlate changes in discs and
facet joints. Data from 15 lower lumbar spine specimens were obtained. Three
parasagittal sections per disc and one section per facet joint were graded
histologically. The results were correlated with age, within the functional
spinal unit (FSU), and with the adjacent level. Histologic changes were found in
discs and facet joints from all FSUs. There was no correlation between the age of
the subject and the degree of degeneration of the disc or facet joints at either
level. The extent of disc degeneration at L4/5 correlated significantly with
changes at L5/S1 (P < 0.01). There was no correlation between changes in discs
and the associated facet joints at either level. The results of the study showed
that microscopic changes are seen in the disc and facet joints from an early age
and can be quite marked in some individuals before the age of 40 years. A
correlation of degenerative changes within the FSU could not be established.
PMID- 10766074
TI - Tissue response to bioactive glass and autogenous bone in the rabbit spine.
AB - Bioactive glass S53P4 and autogenous bone were used as bone graft materials in an
experimental rabbit model for spinal fusion. The study focused on differences in
bone formation using bioactive glass and autogenous bone as bone graft materials.
Bioactive glass, a mixture of bioactive glass and autogenous bone or autogenous
bone was implanted for 4 and 12 weeks at the thoracolumbar level. Undecalcified
sections were prepared for histological and histomorphometric evaluation. New
bone formation was seen in all implanted areas, with the bone growing from the
surface of the vertebrae enclosing both glass and autogenous bone in the bone
fusion mass. During the observation period, the measured amount of bone remained
at the same level in the autograft group, while in the glass and the
glass/autograft bone groups it increased. By 12 weeks, no significant difference
in bone formation between the three groups was observable. The bone formation in
two selected standardized areas at 12 weeks was 21 and 24% in the glass group, 23
and 28% in the glass/autograft bone group and 27 and 26% in the autograft bone
group. We consider bioactive glass as a potential bone graft material in
experimental spinal fusion.
PMID- 10766075
TI - Lumbar disc high-intensity zone: the value and significance of provocative
discography in the determination of the discogenic pain source.
AB - Disagreement still exists in the literature as to the significance of the high
intensity zone (HIZ) demonstrated on magnetic resonance imaging (MRI) as a
potential pain indicator in patients with low back pain. A prospective blind
study was therefore conducted to evaluate the lumbar disc high-intensity zone
with the pain provocation response of lumbar discography. Consecutive patients
with low back pain unresponsive to conservative treatment and being considered
for spinal fusion were subjected to MRI followed by lumbar discography as a pre
operative assessment. The discographer was blinded to the results of the MRI
scans. We used the chi-squared test to analyse our results. Ninety-two HIZs were
identified in 73 patients, mainly occurring at L4/5 (48%) and L5/S1 (35%).
Significant correlation was found between abnormal disc morphology and the HIZ (P
< 0.001). In morphologically abnormal discs (grades 3, 4 and 5), there was a
significant correlation between the HIZ and exact or similar pain reproduction (P
< 0.001). The sensitivity, specificity and positive predictive value for pain
reproduction were high, at 81%, 79% and 87% respectively. The nature of the HIZ
remains unknown, but it may represent an area of secondary inflammation as a
result of an annular tear. We conclude from our study that the lumbar disc HIZ
observed on MRI in patients with low back pain is likely to represent painful
internal disc disruption.
PMID- 10766076
TI - Posterior lumbar interbody fusion combined with instrumented postero-lateral
fusion: 5-year results in 60 patients.
AB - The technique of posterior lumbar interbody fusion allows decompression of the
spinal canal and interbody fusion through one posterior incision. A number of
techniques exist to achieve additional posterior stability. The literature
reports wide variation in outcomes for these different techniques. We assessed
retrospectively the clinical and radiological outcome of posterior lumbar
interbody fusion (PLIF) supplemented with an instrumented postero-lateral fusion
(IPLF) using a pedicle screw system. Between July 1987 and April 1997, 60
patients underwent PLIF + IPLF. Clinical outcome was measured with physical
examination in the outpatient setting and a patient questionnaire (patient
satisfaction, analgesic use, return to work, Oswestry Disability Index).
Radiological outcome was assessed with serial radiographs. If doubt existed
regarding fixation, flexion/extension radiographs and plain tomograms were
performed. The mean age was 44 years (range 19-69 years). The average follow-up
was 5.3 years (range 1-10 years). Eighty percent of patients returned
sufficiently completed questionnaires; 83% of these patients rated their outcome
as good or excellent. Fifty percent of patients were able to return to full-time
employment. All patients showed radiographic evidence of stable fixation. Four
patients sustained a neurological complication, three of which resolved
completely. The combination of PLIF with IPLF demonstrates clinical success, a
stable circumferential fixation and a low complication rate.
PMID- 10766077
TI - Sagittal alignment in lumbosacral fusion: relations between radiological
parameters and pain.
AB - The objective of this study was to conduct a radiological analysis of posture
before and after lumbosacral fusion to evaluate the influence of spinal alignment
on the occurrence and pattern of post surgical pain. The study included 81
patients, of whom 51 had a history of previous low back surgery. We excluded
patients with suspected or confirmed nonunion. In the fusion group, the 27
patients who were pain free after the procedure were compared to the 54 patients
with residual pain. Thirty patients had pain only or primarily when they were
standing immobile, 18 when they were sitting immobile, and six in both positions.
Measurements were done on full-length lateral radiographs of the spine, with the
patient standing according to Duval Beaupere criteria. The subgroup with
postfusion pain was characterized at baseline by a more vertical sacrum with less
sacral tilt (ST) (P < 0.0062) and more pelvic tilt (PT) (P < 0.0160). PT at last
follow-up (PT fu) correlated with the presence of postfusion pain (NP: P =
0.0003). In the patients with postfusion pain, PT was almost twice the normal
value. ST at last follow-up (ST fu) in the standing position was also correlated
with the presence of postfusion pain (P < 0.0001) indicating that the sacrum
remained abnormally vertical in the subjects with postfusion pain. Using logistic
regression, the only prognostic factor for residual pain at last follow-up was ST
fu. Both at pre-operative evaluation and at last follow-up, patients with pain in
the standing position or in both the standing and sitting positions were
characterized at pre-operative status by a more vertical sacrum with less sacral
tilt. The results of this study indicate that, achieving a strong fusion should
not be the only goal. Appropriate position of the fused vertebrae is also of
paramount importance to minimize muscle work during posture maintenance. The main
risk is failing to correct or to causing excessive pelvic retroversion with a
vertical sacrum leading to a sagittal alignment that replicates the sitting
position. This situation is often accompanied by loss of lumbar lordosis and
adversely affects stiff or degenerative hips.
PMID- 10766078
TI - Odontoid fractures: high complication rate associated with anterior screw
fixation in the elderly.
AB - This study is a retrospective analysis of patients older than 65 years with
odontoid fractures. The series consisted of 29 consecutive patients with odontoid
fractures (18 women, mean age 78, range 66-99 years). Twenty-six patients were
neurologically intact, Frankel E, whereas three had neurological symptoms: two
Frankel D and one Frankel C. Eleven patients were treated with anterior screw
fixation according to Bohler, seven with a posterior C1-C2 fusion. Ten patients
with either minimally displaced fractures or with complicating medical conditions
were treated conservatively. At follow-up, 7/7 patients with posterior fusion had
healed without any problems, whereas 8/11 patients treated with anterior screw
fixation, and 7/10 conservatively treated patients were either failures or had
healed, but after a complicated course of events. We conclude that anterior screw
fixation according to Bohler is associated with an unacceptably high rate of
problems in the elderly. Probable causes may be osteoporosis with comminution at
the fracture site, or stiffness of the cervical spine preventing ideal
positioning of the screws. As non-operative treatment also often fails, the
method of choice seems to be posterior C1-C2 fusion.
PMID- 10766079
TI - The anatomic variability of human cervical pedicles: considerations for
transpedicular screw fixation in the middle and lower cervical spine.
AB - Transpedicular screw fixation has recently been shown to be successful in
stabilizing the middle and lower cervical spine. Controversy exists, however,
over its efficacy, due to the smaller size of cervical pedicles and the proximity
of significant neurovascular structures to both lateral and medial cortical
walls. To aid the spinal surgeon in the insertion of pedicle screws, a number of
studies have been performed to quantify the gross dimensions and angulations of
the cervical pedicle. Notwithstanding these quantitative studies, there has been
a conspicuous absence of research reporting the qualitative characteristics of
the cervical pedicle. The purpose of our study was to provide comparative
graphical data that would systematically document the anatomic variability in
cervical pedicle morphology. Such information should better elucidate the
complexity of the pedicle as a three-dimensional structure and provide the spinal
surgeon with a more complete understanding of cervical pedicle architecture.
Twenty-six human cervical vertebrae (C3-C7) from six fresh-frozen spines were
secured to a thin sectioning apparatus to produce three 0.7-mm-thick pedicle
slices along its axis. Radiographs taken of these pedicle slices were scanned,
digitized, and traced to facilitate visual comparison. The pedicle slices were
found to exhibit substantial variability in composition and shape, not only
between individual spines and vertebral levels, but also within the pedicle axis.
However, the lateral cortex was consistently found to be thinner than the medial
cortex in all samples. These physical findings must be noted by surgeons
attempting transpedicular screw fixation in the cervical spine.
PMID- 10766080
TI - A retrospective study of surgical and conservative treatment for spinal
extradural abscess.
AB - The management of spinal extradural abscess (SEA), particularly the choice
between surgical and conservative treatment, is controversial. We therefore
undertook a retrospective study of patients admitted with this diagnosis: Details
of presentation, treatment and outcome were obtained by review of inpatient notes
and radiology. Twenty-five individuals with SEA aged 10-79 years were admitted
between 1989 and 1995. Nine were treated non-operatively with antibiotics, of
which three also underwent diagnostic CT-guided biopsy, and 16 underwent surgical
drainage. There was no significant difference in the neurological features at
presentation between the two groups. Two patients (8%) died; 11 (44%) patients
remained the same and 12 (48%) improved following treatment. Four patients
treated conservatively (44%) and seven treated surgically (43%) were capable of
return to work or school, whilst a further seven patients (three treated
conservatively and four treated surgically) were able to lead independent lives.
No significant difference in outcome was demonstrated between patients treated
non-operatively and those treated surgically. We conclude that certain carefully
selected patients can be treated conservatively, but that surgery should remain
the mainstay of management.
PMID- 10766081
TI - Spondylodiscitis and epidural abscess due to Candida albicans.
AB - A 32-year-old woman, addicted to heroin, presented with a dorsal spondylodiscitis
due to Candida albicans associated with epidural abscess. Antimycotic treatment
was successful, and no neurosurgical decompression was necessary. To our
knowledge, this is the first case of documented epidural involvement in candidal
spondylodiscitis. The diagnosis of candidal spondylodiscitis should be considered
in cases of para- or tetraplegia occurring in intravenous drug abusers.
PMID- 10766082
TI - Surgical treatment of aspergillus spondylodiscitis.
AB - Four cases of aspergillus spondylodiscitis were treated with operative
debridement and fusion. In this rarely encountered mycotic infection of the spine
in immunocompromised patients rapid destruction of the intervertebral disc and
vertebral bodies can occur. In advanced cases antimycotic drug therapy is thought
to be ineffective and a forcing indication for surgery exists when the
destruction is progressive and spinal cord compression is imminent or manifest.
Spinal instrumentation can be of help in maintaining or restoring spinal
stability and maintaining spinal alignment. In our four patients the aspergillus
spondylodiscitis was successfully eradicated and fusion achieved. In two of three
patients with a neurologic deficit, this deficit disappeared. Two patients died
within 6 months after the operative treatment, due to complications related to
the underlying illness. One patient was left with a subtotal paraplegia.
PMID- 10766083
TI - Spinal epidural abscess following blunt pelvic trauma.
AB - A 17-year-old patient with pre-existing grade II spondylolisthesis of L5/S1
sustained a partial disruption of the left sacroiliac joint with haematoma of the
iliac muscle after a fall. The haematoma probably led to occlusion of the left
ureter, resulting in a urinary tract infection. After initial conservative
treatment the patient developed fever and radicular pain of the left leg.
Magnetic resonance imaging (MRI) revealed a left-sided epidural abscess at L5/S1,
which had probably spread from the infected iliac haematoma along the injured
sacroiliac joint. Prompt surgical drainage and antibiotic coverage with
cefuroxime and flucloxacillin led to rapid clinical improvement. Staphylococcus
aureus was identified as the pathogen. At follow-up 6 months postoperatively all
symptoms had resolved, while MRI still revealed residual osseous oedema of the
sacroiliac joint. The haematoma of the iliac muscle resolved without surgical
intervention.
PMID- 10766084
TI - Spontaneous remission of a solitary intraspinal synovial cyst of the lumbar
spine.
AB - We report on a 15-year-old boy in whom a spontaneous remission of a symptomatic
synovial cyst, possibly emanating from the L4-5 facet joint, was noted. The
medical history suggested that sport-related overactivity and/or minor trauma was
the underlying cause. Conservative treatment for several months may be one
treatment option if the cyst wall is not calcified and the symptoms and signs
related to radiculopathy show a gradual decrease.
PMID- 10766085
TI - Neoadjuvant and adjuvant radio- and radio-chemotherapy of rectal carcinomas.
AB - The objectives in treating rectal cancer are to achieve locoregional tumor
control and to prolong overall survival. With surgery alone the reported local
failure rates in recent decades have been unacceptably high, and this is
associated with substantial morbidity and mortality. Perioperative radiotherapy
with or without concomitant chemotherapy has been used extensively to reduce the
high frequency of local recurrence. Adjuvant radiotherapy reduces the local
recurrence rate dramatically if the dose is high enough and is administered
preoperatively. Although a higher dose has been used in most postoperative
radiotherapy trials, the reduction has not proven particularly pronounced. If the
reduction were as great as that with preoperative radiotherapy, it would also
have a positive effect on survival, which as yet has not been achieved with
postoperative radiotherapy. However, postoperative irradiation combined with
chemotherapy yields a survival benefit of the same magnitude as preoperative
irradiation. Modern radiation techniques allow preoperative radiotherapy to be
delivered without interfering substantially in the postoperative healing process;
it does not increase mortality or morbidity and entails a low rate of late
toxicity if the radiation technique is optimal. A major question today is whether
radiotherapy is necessary if surgery is optimal. Control trials report an average
local recurrence rate of 29% with standard surgery. With optimal surgery the
figure reported from institutional series is about 10%. Other questions to be
answered include whether to use superfractionation or standard fractionation in
radiotherapy, and how chemotherapy should be given, concomitantly to radiotherapy
or in the classical method of postoperative intravenous treatment.
PMID- 10766086
TI - Preoperative staging of rectal cancer.
AB - With the widespread introduction of preoperative radiotherapy for rectal cancer
and the development of transanal endoscopic microsurgery for selected early
lesions, preoperative radiological staging of these tumours has taken on
increasing importance. This study is a systematic review to evaluate computed
tomography (CT), endorectal sonography (ES) and magnetic resonance imaging (MRI)
as preoperative staging modalities in rectal cancer. A Medline-based search
identifying studies using CT, ES, or MRI in preoperative staging of rectal cancer
between 1980 and 1998 was undertaken. The list of papers was supplemented by
extensive cross-checking of citation lists. Studies were included if they met
predetermined criteria. Data from the accepted studies were entered into pooled
tables comparing radiological and pathological staging results for each modality
both in determining bowel wall penetration and involvement of lymph nodes.
Accuracy, sensitivity, specificity, positive predictive value, negative
predictive value, positive likelihood ratio and negative likelihood ratio were
determined for the pooled results. Eighty-three studies from 78 papers including
4,897 patients met the inclusion criteria. In determining the wall penetration of
the tumour the values for sensitivity for CT, ES, MRI and MRI with endorectal
coil were 78%, 93%, 86% and 89%; for specificity 63%, 78%, 77% and 79%; and for
accuracy 73%, 87%, 82% and 84%, respectively. In determining the nodal
involvement by tumour the sensitivity values for CT, ES, MRI and MRI with
endorectal coil 52%, 71%, 65% and 82%; for specificity 78%, 76%, 80% and 83%; and
for accuracy 66%, 74%, 74% and 82%, respectively. MRI with an endorectal coil is
the single investigation that most accurately predicts pathological stage in
rectal cancer.
PMID- 10766087
TI - Genetic testing and surgical decision making in hereditary colorectal cancer.
AB - Hereditary colorectal cancer results from specific genetic alterations. The
causative genes for familial adenomatous polyposis, juvenile polyposis, Peutz
Jeghers syndrome, and hereditary nonpolyposis colorectal cancer have been cloned
and characterized within the past decade. Genetic testing has therefore become
more widely used to confirm the clinical diagnosis of each of those syndromes, to
provide adequate surveillance, to allow screening of at-risk family members, and
to help the surgeon in surgical decision making. The aim of this review is to
analyze the importance of genetic testing in view of the clinical and surgical
management of those gene-carriers individuals, and to discuss how should the
surgeon integrate genetic testing in the evaluation of such patients.
PMID- 10766088
TI - Colorectal high-grade adenomas: incidence, localization and adenoma
adenocarcinoma ratio in a retrospective and comparative population-based study of
225 consecutive cases between 1988 and 1996.
AB - Colorectal high-grade adenomas can be regarded as precancerous lesions. This
study collected epidemiological data from a defined region (Luxembourg) that can
serve as reference data for designing a national screening program for early
colorectal cancer detection. Nine pathologists diagnosed and reviewed slides
retrospectively from 288 new colorectal and anal in situ carcinomas from the
period 1988-1996 (63 were excluded for various reasons). In all, 225 new
colorectal high-grade adenomas were considered. There were 129 men (57%) and 96
women (42%), and 78% of patients were aged over 60 years. Over this period we
found an increase in incidence of high-grade colorectal adenomas (11 cases in
1988, 40 cases in 1996) for both sexes. The overall incidence rate was 2.9 x
100,000 in 1988 and 9.6 x 100,000 in 1996. The average annual age-standardized
incidence rate for this period was 3.7+/-0.5 (95% confidence interval); the
cumulative rate (0-74 years) was 0.4%. Three-fourths of the adenomas were
situated in the rectum (n=78, 35%) or sigmoid colon (n=92, 41%). Histological
diagnosis was provided by 160 total polypectomy specimens (71%), 30 surgical
resections (13.3%), and 35 biopsy specimens (16%). Over the study period there
was an increased incidence of new colorectal adenocarcinomas. There were eight
times as many adenocarcinomas (n=1782) as adenomas (n=225); the distribution of
anatomical sites was comparable. These epidemiological data on 225 new colorectal
high-grade adenomas can be the basis for quality assurance in clinical and
histological diagnostic procedures, especially in regard to the 1:8 ratio between
high-grade adenomas and invasive adenocarcinomas and may provide additional data
for the design of a regional or national colorectal cancer screening program.
PMID- 10766089
TI - Clinical characteristics of Peutz-Jeghers syndrome in Korean polyposis patients.
AB - Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized
by hamartomatous polyps in the small bowel and mucocutaneous pigmentation.
Patients with Peutz-Jeghers syndrome often present as surgical emergencies with
complications of the polyps, such as intussusception, bowel obstruction, and
bleeding. Recently an increased risk of malignancies has also been reported. This
study was initiated to determine the clinical features of Peutz-Jeghers syndrome
in Korean patients, with special attention to the development of malignancies.
Thirty patients with Peutz-Jeghers syndrome were investigated; their median age
was 23.5 years, and symptoms appeared at a median age of 12.5 years. Family
history was positive in one-half of cases, and mucocutaneous pigmentation was
observed in almost all patients (93%). The jejunoileum was the most frequent site
of the polyps, and there were generally 10-100 polyps. Multiple laparotomies were
performed in a substantial portion of the patients, due mainly to polyp-induced
bowel obstruction, and the surgical interventions were begun at a relatively
young age (average 21.4 years). Four cases of small-bowel cancer and one case of
breast cancer were detected in probands, at a relatively young age (mean 36
years). Cancers of the small bowel, stomach, colon, breast and cervix were
diagnosed in the first relatives of the probands. Close follow-up from an early
age should thus be performed in patients with Peutz-Jeghers syndrome as they are
at high risk of surgical emergency and development of malignancy.
PMID- 10766090
TI - Deficiency of epithelial basement membrane laminin in ulcerative colitis affected
human colonic mucosa.
AB - Imbalances in epithelium-matrix interactions have been discussed as a
pathomechanism in ulcerative colitis, causing a colonic mucosal barrier
dysfunction. Laminin, the major noncollagenous component of the basement
membrane, plays a role in epithelial basal lamina formation and promotes
differentiation of human enterocytes. We therefore investigated the distribution
of laminin in ulcerative colitis affected colonic tissues. Tissue specimens from
both affected and nonaffected colonic regions were obtained from ten patients
with ulcerative colitis during colonoscopies or operations. Healthy tissue from
five patients with colorectal cancer was used as control. After histological
classification, the localization and distribution of the basement membrane
associated extracellular matrix proteins were determined by immunohistochemistry.
Paraffin-embedded sections were incubated with antibodies against laminin and
type IV and V collagen. No positive immunoreactivity against laminin was found in
most of the epithelial basement membranes surrounding the crypts in affected
colonic tissues, without involvement of the subendothelial structures. In
contrast, a type IV and V collagen accumulation occurred in all these tissue
samples. The lack of laminin in combination with an overexpression of type IV and
V collagen, as reported for the first time in this paper, leads to changes in
basement membrane structure. These findings indicate that the three-dimensional
network of the colonic epithelial basement membrane and its function are
seriously disturbed in exacerbating ulcerative colitis. This provides new
insights into the importance of cell-matrix interactions for physiological and
pathological mechanisms in the etiology of ulcerative colitis.
PMID- 10766091
TI - Outcome of ileal pouch after secondary diagnosis of Crohn's disease.
AB - Ileal-pouch anal anastomosis is sometimes performed inappropriately in Crohn's
disease patients. The aim of this study was to evaluate long-term results in this
subset. In 54 ileal-pouch anal anastomoses performed between 1985 and 1997 for
CUD the patient was eventually diagnosed as having Crohn's disease in seven
cases. A retrospective review was performed. Definitive diagnosis was established
on histopathology, endoscopy, and clinical presentation. The principal outcome
factors were pouch failure, reason for failure, and functional results in cases
of retained pouch. Patients ranked their quality of life between 1 and 10. We
found three failures due to pelvic abscess, anoperineal disease, and anovulvar
fistula. The pouch was excised in the latter patient; four patients retained
their pouch. Functional results were good in the four (7 year follow-up): 7.25
bowel movements per day, ability to discriminate flatus from feces in three,
soiling in one, urgency in one, perianal pad in one, ability to differ bowel
movement for 66 min, diet, and antidiarrheal medication all four, pouchitis in
one, sexual troubles in one woman, no urinary or obstetric trouble. Quality of
life was judged satisfactory by six of the seven patients. Our 13% rate of
inadvertent ileal-pouch anal anastomosis is higher than results usually reported.
This difference is explained by the diagnostic criteria, whose validity is
controversial. Three-stage surgery to decrease inadvertent restorative
coloproctectomy is worth considering. Even if results are good when the pouch is
functioning, Crohn's disease remains a contraindication to ileal-pouch anal
anastomosis because of its high rate of failure and excision.
PMID- 10766092
TI - Fecal continence after rectocele repair: a prospective study.
AB - Combined transvaginal/transanal rectocele repair was performed in series of 89
consecutive women (mean age 55, range 35-81 years) with obstructed defecation due
to a rectocele with a depth of more than 3 cm. The impact of this procedure on
anal sphincter pressure and continence status was evaluated prospectively.
Anorectal manometry was carried out before and after surgery (at 3, 6, 12, and 24
months). The following measurements were performed: maximal anal resting pressure
(MARP), maximal anal squeeze pressure (MASP), and rectal sensory perception
including first initial sensation, urge to defecate, and maximum tolerable
volumes (MTV). The outcome was successful in 71% of patients with respect to
symptoms such as the need for straining at defecation, manual assistance,
feelings of incomplete evacuation, sense of rectal fullness, constipation,
abdominal pain, and the use of laxatives. However, after rectocele repair seven
patients experienced deterioration in fecal continence, and dyspareunia developed
in 41% of the sexually active patients. Manometric studies revealed a significant
decline in mean of 18% of MARP and 16% of MASP. In contrast to MASP, MARP
gradually improved during the follow-up period. Distending volumes required for
initial sensation and urge to defecate did not change after the procedure. MTV
values were significantly lower 3 and 6 months after rectocele repair than those
before and 24 months after surgery. MARP and MASP values after surgery did not
differ between patients with impaired and those with normal continence. In
conclusion, transvaginal/transanal rectocele repair is beneficial for patients
with obstructed defecation; however, care should be taken in sexually active
patients, and patients at risk of developing fecal incontinence.
PMID- 10766093
TI - Stereotactic core biopsy: a return of the nattering nabobs of negativism.
PMID- 10766094
TI - Is the stat Gram stain helpful during percutaneous image-guided fluid drainage?
AB - RATIONALE AND OBJECTIVES: The purpose of this study was to use logistic
regression to analyze both Gram stain results and other clinical information to
create a decision rule capable of predicting which abdominal or pelvic fluid
collections would later prove to be infected and therefore require catheter
drainage. MATERIALS AND METHODS: The authors retrospectively collected Gram stain
results and clinical data (postoperative status and antibiotic use) regarding 124
abdominal or pelvic fluid drainage procedures performed between 1991 and 1996.
They then analyzed these data by using logistic regression to create an equation
that predicted the presence of fluid infection. Finally, they validated this
equation by applying it to 39 abdominal or pelvic fluid drainage procedures
performed in 1997. RESULTS: The resulting equation predicted that a fluid
collection was likely to be infected if any of the following were present: Gram
stain positive for bacteria, Gram stain showing moderate or many white blood
cells, and purulent fluid at visual inspection. For the initial data set, the
sensitivity of the decision rule was 91%, the specificity was 54%, and the
overall accuracy was 77%. For the 1997 data set, the sensitivity of the decision
rule was 88%, the specificity was 50%, and the accuracy was 77%. CONCLUSION: When
combined with clinical information, Gram stain results are sensitive but
nonspecific in the detection of abdominal or pelvic fluid infection. Use of the
decision rule could prevent unnecessary catheter placement in a minority of
patients with abdominal or pelvic fluid collections.
PMID- 10766095
TI - Comparison of woman-specific versus breast-specific data for reporting screening
mammography performance.
AB - RATIONALE AND OBJECTIVES: Screening mammography data can be reported on a breast
specific or woman-specific level, and much mammography data available for
research is woman-specific. The purpose of this study was to determine if woman
specific screening mammography data are sufficient for research and reporting by
measuring and comparing the accuracy of screening mammography on a breast
specific and on a woman-specific level. MATERIALS AND METHODS: Definitions for
true-positive and false-positive mammography results were developed to
distinguish between breast-specific and woman-specific calculations. The
sensitivity, specificity, and positive predictive values of screening mammography
were calculated on a breast-specific and on a woman-specific basis for the entire
population of the Carolina Mammography Registry and for a randomly selected
subset of the population. RESULTS: Only small differences were found in breast
specific versus woman-specific calculations of sensitivity, specificity, and
positive predictive values for both the entire population and the smaller subset
population. For both populations, woman-specific sensitivity and positive
predictive values were slightly higher than the same breast-specific values, and
woman-specific specificity was slightly lower. CONCLUSION: For research and
reporting, woman-specific data are sufficient.
PMID- 10766096
TI - Quantitation of T2 lesion load in patients with multiple sclerosis: a novel
semiautomated segmentation technique.
AB - RATIONALE AND OBJECTIVES: The authors designed a segmentation technique that
requires only minimal operator input at the initial and final supervision stages
of segmentation and has computer-driven segmentation as the primary determinant
of lesion boundaries. The technique was applied to compute total T2-hyperintense
lesion volumes in patients with multiple sclerosis (MS). A semi-automated
segmentation technique is presented and shown to have a test-retest reliability
of <5%. MATERIALS AND METHODS: The method used a single segmented section with MS
lesions. A probabilistic neural net performed segmentation into four tissue
classes after supervised training. This reference section was deconstructed into
the entire set of possible 4 x 4-pixel subregions, which was used to segment all
brain sections in steps of 4 x 4-pixel, adjacent image blocks. Intra- and
interimage variabilities were tested by using 3-mm-thick, T2-weighted, dual-echo,
spin-echo MR images from five patients, each of whom was imaged twice on the same
day. Five different reference sections and three temporally separated. training
sessions involving the same reference section were used to test the segmentation
technique. RESULTS: The coefficient of variation ranged from 0.013 to 0.068 (mean
+/- standard deviation, 0.037 +/- 0.039) for results from five different
reference sections for each brain and from 0.007 to 0.037 (mean, 0.027 +/- 0.021)
for brains segmented with the same reference section on three temporally
separated occasions. Test-retest (intra-imaging) reliability did not exceed 5%
(except for a small lesion load of 1 cm3 in one patient). Interimaging
differences were approximately 10%. CONCLUSION: The segmentation technique
yielded intra-imaging variabilities (2%-3%, except for very small MS lesion
loads) that compare favorably with previously published results. New
repositioning techniques that minimize imaging-repeat imaging variability could
make this approach attractive for resolving MS lesion detection problems.
PMID- 10766097
TI - Follow-up of benign results of stereotactic core breast biopsy.
AB - RATIONALE AND OBJECTIVES: The purpose of this study was to obtain long-term
follow-up data on women with benign histologic results of a breast stereotactic
core needle biopsy (CNB). MATERIALS AND METHODS: Mammography charts of 300
consecutive women who underwent prone stereotactic CNB with digital radiography
were reviewed. Women with frankly malignant or suspicious histologic findings (51
patients) or a technically unsuccessful stereotactic CNB (one patient) were
excluded. The remaining 248 benign core biopsies in 229 women were included in
the study. RESULTS: Follow-up mammograms were obtained for 152 lesions with
benign histologic results following stereotactic CNB. The mean length of follow
up after stereotactic CNB was 34.6 months. Cancer was diagnosed in six women who
underwent surgical biopsies 1/2 to 30 months after benign stereotactic CNB. An
initial chart review demonstrated that no follow-up data were available for 64
lesions, and information was missing for an additional seven. CONCLUSION: SCNB
remains a sampling procedure that can result in false-negative histologic
results. Intrinsic procedural issues were identified that could minimize the
potential for missing a malignancy. Goals for patient compliance with follow-up
recommendations fell short of expectations.
PMID- 10766098
TI - X-ray attenuation coefficients of high-atomic-number, hexanuclear transition
metal cluster compounds: a new paradigm for radiographic contrast agents.
AB - RATIONALE AND OBJECTIVES: The purpose of this study was to examine the radiologic
attenuation properties of the parent cluster compounds, particularly attenuation
as a function of discrete photon energy, before investigating ligand
substitutions, which are necessary to improve cluster biocompatibility and to
impart desirable physicochemical properties. MATERIALS AND METHODS: The linear
attenuation coefficients for solutions of the cluster compounds Ta6Br14,
K8Ta6O19, and (H3O)2W6Cl14 were determined at 60, 80, 103, 122, and 140 keV from
gamma-ray transmission measurements with americium-241, xenon-133, gadolinium
153, cobalt-57, and technetium-99m radioactive sources. Transmission measurements
were obtained for a fixed time interval that ensured a statistically accurate
count distribution exceeding 20,000 counts through the sample for each trial.
RESULTS: On a strictly mole per liter basis, a 0.075 mol/L aqueous solution of
K8Ta6O19 showed 1.08 times the attenuation of 0.063 mol/L aqueous iohexol at 60
keV and 3.30 times the attenuation at 80 keV. Similarly, a 0.05 mol/L methanolic
solution of (H3O)2W6Cl4 showed 0.96 times (96%) the attenuation of 0.063 mol/L
aqueous iohexol at 60 keV but 3.09 times the attenuation of the iohexol solution
at 80 keV. Attenuations of 0.063 mol/L aqueous iohexol and 0.0125 mol/L Ta6Br14
(ie, at approximately one-fifth the iohexol concentration) were comparable at
greater than 60 keV. CONCLUSION: These results confirm the theoretic potential
for use of early transition metal cluster compounds as radiographic contrast
agents. At higher x-ray energies, cluster compounds demonstrate multiplied x-ray
attenuation relative to iodinated contrast agents.
PMID- 10766099
TI - World Wide Web program for optimizing and assessing medical student performance
during the radiology clerkship.
AB - RATIONALE AND OBJECTIVES: The purpose of this study was to adapt the technology
of the World Wide Web to the teaching and evaluation of medical students
participating in the radiology clerkship at our institution. MATERIALS AND
METHODS: Teaching modules were placed on a local intranet site. One hundred two
student evaluations were conducted online as a standardized, written- and image
based test that was administered both before and after the clerkship. The
computer-delivered test consisted of 40 standardized questions that were sorted
by category (based on American College of Radiology code criteria) and randomly
administered from a pool of 200 potential questions. Scores from before and after
the clerkship were analyzed statistically to evaluate the effectiveness of the
educational program and the student performance. Student case presentation
scoring and clerkship administration tasks were also evaluated both before and
after implementation of the modules during the first 12 months of this project
(July 1997 to July 1998). RESULTS: A statistically significant (P < .001)
improvement in test performance was found in 102 consecutive students, and all
102 students (100%) preferred the digital-testing format. The amount of time
needed to tabulate the teacher evaluation, grade the test, and score the oral
presentations decreased substantially with the digital system. CONCLUSION: An
intranet-based method of evaluating students in an ongoing fashion allows for
additional growth in content and ease of use during the radiology clerkship.
PMID- 10766100
TI - Personal diary: starting out--thoughts of a 1st-year resident.
PMID- 10766101
TI - Current status of full-field digital mammography.
PMID- 10766102
TI - Report from the biomedical imaging program of the national cancer institute.
Status of funding programs.
PMID- 10766103
TI - Predictors of irrational thinking in regular slot machine gamblers.
AB - Previous research has suggested that irrational thinking may play a central role
in the maintenance of behavior in slot machine gambling (M. B. Walker, 1992b).
The present study is an evaluation of the validity and predictors of irrational
thinking in a sample of regular gamblers (N = 20) drawn from the general
community. The results were generally consistent with earlier findings; 75% of
gambling-related cognitions were found to be irrational. Irrationality was
unrelated to the amount of money lost or won during sessions but was positively
related to risk taking. The most common irrational cognitions included false
beliefs concerning the extent to which outcomes could be controlled or predicted
and the attribution of human qualities (personification) to gambling devices.
Gender comparisons showed that women were more likely than men to personify the
machines. The validity of the speaking-aloud approach and suggestions for future
research are discussed.
PMID- 10766104
TI - Some experimental influences of lawyers' complicated questions on eyewitness
confidence and accuracy.
AB - Eyewitness evidence and the confidence the eyewitness expresses in such evidence
are crucial in many criminal trials. The present study is an examination of the
influence of confusing questions often used by attorneys to examine witnesses in
court. Participants viewed a videotaped incident and were questioned about the
incident 1 week later. Half the participants were asked questions framed in a
confusing form; the remaining half were asked the same questions in
straightforward language. Confusing questions reduced the participant witnesses'
accuracy and suppressed the confidence-accuracy relationships compared with the
condition in which simple questions were asked. However, the number of absolutely
sure responses was the same in both conditions, although these responses were
almost always accurate in the simplified condition, whereas in the confusing
question condition, accuracy was comparatively poor. This experiment demonstrates
the importance of ensuring that lawyers ask witnesses simple, clear questions.
PMID- 10766105
TI - Examination for professional practice in psychology subtest scores of
professional and traditional clinical psychology program graduates.
AB - Professional school clinical psychology graduates not only exhibit inferior
performance on the research subtest of the Examination for Professional Practice
in Psychology (EPPP; D. I. Templer & M. E. Tomeo, 1998), but they also perform
less well on the four more professionally oriented subtests: diagnosis,
intervention, professional/ethical/legal issues, and application to social
systems. Graduates of free-standing professional schools exhibited performances
inferior to those of graduates of non-free-standing professional schools on the
diagnosis, intervention, and professional/ethical/legal subtests.
PMID- 10766106
TI - Searching for reliable relationships with statistics packages: an empirical
example of the potential problems.
AB - Many social scientists appear to possess an overconfidence in the reliability of
research results from a single, small-sample, inferential study. In this article,
the authors speculate that "user-friendly" statistics packages have the potential
to exacerbate statistical misinterpretation by providing researchers with a tool
to explore data easily and identify what is interpreted as "reliable"
relationships. This article contains an empirical demonstration of the potential
problems that arise when a large number of statistical tests are interpreted.
Results show that statistically significant results may be unreliable. Also, a
zero relationship can erroneously appear as a medium to large effect size
relationship when a small sample is used (e.g., n = 30). The authors suggest the
need for multiple replications as the criterion of a reliable finding.
PMID- 10766107
TI - The Mackworth Clock Test: a computerized version.
AB - The Mackworth Clock Test (MCT; N. H. Mackworth, 1948) was developed to evaluate
vigilance in British Air Force radar technicians during World War II. Homemade
versions of the MCT have since varied with respect to both the characteristics of
the device and the procedures of its administration. This article is a report on
a computerized version of the MCT developed by the authors to closely emulate
Mackworth's test. MCT data were collected from 25 undergraduate students; their
performance was found to be equivalent to Mackworth's participants' data. This is
the first MCT version that has been validated against the original.
PMID- 10766108
TI - Cardiac disorders and antidepressant medications.
AB - Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) have
been associated with an increase in cardiovascular disorders, especially in
depressed patients who have pre-existing cardiac disease. These disorders are
less likely to occur when a therapeutic dosage is administered. Injuries because
of falls are more likely in elderly depressed patients, and orthostatic
hypotension occurs with the use of TCAs. Selective serotonin reuptake inhibitor
(SSRI) antidepressants differ structurally and in side effects from TCAs and
MAOIs. They appear to be effective for treatment of depression, and their side
effect profiles appear safer than those of earlier approved antidepressants used
by depressed patients with cardiovascular disorders.
PMID- 10766109
TI - The role of job control as a moderator of emotional dissonance and emotional
intelligence-outcome relationships.
AB - Job control may be defined as the latitude to make decisions and the freedom to
select the most appropriate skills to complete the task. Emotional dissonance may
be defined as the conflict between expressed and experienced emotions. In this
study, job control and self-efficacy were theorized to jointly affect emotional
dissonance. Individuals with high self-efficacy were found to be more satisfied
under conditions of little job control, whereas those with low self-efficacy
favored high job control. The impact of job control on emotional intelligence was
also studied. Emotional intelligence may be defined as the set of skills that
contribute to accurate self-appraisal of emotion as well as the detection of
emotional cues in others and the use of feelings to motivate and achieve in one's
life. Emotional intelligence and job control explained significant amounts of the
variance in both job satisfaction and organizational commitment. Theoretical and
practical implications are discussed.
PMID- 10766110
TI - The affective dimension of response elicitation data: a projective measure.
AB - In this research, the Rorschach Affective Ratio, a measure for frequency of
response elicitation, was used to examine the affective dimension of response
elicitation data. The purpose of this study was to apply the Rorschach Affective
Ratio to an examination of the psychodynamic roots of political behavior. This
measure compares the number of responses to colored cards, considered as
emotional stimuli, with those revealed by the other (black and white) cards of
the test. Israeli undergraduates (N = 26) completed a questionnaire composed of
20 questions about peace. Participants who were more supportive of the peace
process in the Middle East were found to have a lower Affective Ratio than those
who were less supportive. This result suggests that measurable affective aspects
may be as important as cognitive aspects of response elicitation in understanding
an individual's political attitudes.
PMID- 10766111
TI - Novel methods for analyzing multifaceted personality scales: sense of coherence
and depression as an example.
AB - Multifaceted personality scales assess multiple related facets or dimensions and,
as such, they are typically made up of correlated subscales. In some cases, the
degree of correlation among subscales can be so high as to render the use of
standard procedures for evaluating a subscale's relative importance (e.g., beta
weights or bivariate correlations) dubious. In such cases of high predictor
multicollinearity, researchers are faced with few viable options and, in
response, many turn to multiple regression when examining predictor-criterion
associations (for example, interpreting semipartial correlations and incremental
variance estimates). In an effort to broaden researchers' options and thereby
allow for greater interpretive clarity, z tests for comparing dependent zero
order correlations and R. G. Malgady's (1987) methods for comparing two dependent
semipartial correlations and for comparing dependent semipartial and zero-order
correlations are proposed as additional techniques for analyzing predictor (or
subscale) criterion associations in the context of predictor collinearity. Worked
examples of both techniques are provided, using a dataset on sense of coherence
and depression. Finally, relevant computer programs for implementing the
aforementioned techniques are noted.
PMID- 10766112
TI - Psychological profile of pedophiles and child molesters.
AB - Pedophiles and child molesters share some characteristics. Most are male, and
they can be heterosexual, homosexual, or bisexual. Some prefer adult sex partners
but choose children because they are available and vulnerable. The sexual abuse
perpetrated may be a 1-time incident and may consist only of fondling.
Penetration is unlikely with young children. Perpetrators' ages range from teens
to midlife. Most victims are girls, and the perpetrator usually is a relative,
friend, or neighbor. The home of the victim is often the setting for the
incident. When boys are victims, sexual abuse may take place outside the home,
and perpetrators may be strangers. Perpetrators of sexual abuse of children often
claim that they themselves were victims of childhood sexual abuse. Psychological
profiles are helpful but are compromised partly because many perpetrators are
prisoners and control groups are lacking for this research.
PMID- 10766113
TI - Meat hygiene controls: new rules on enforcement.
PMID- 10766114
TI - Self-selection of the analgesic drug carprofen by lame broiler chickens.
AB - Lame and sound broilers, selected from commercial flocks, were trained to
discriminate between different coloured feeds, one of which contained carprofen.
The two feeds were then offered simultaneously and the birds were allowed to
select their own diet from the two feeds. In an initial study to assess the most
appropriate concentration of drug, the plasma concentrations of carprofen were
linearly related to the birds' dietary intake. The walking ability of lame birds
was also significantly improved in a dose-dependent manner and lame birds tended
to consume more analgesic than sound birds. In a second study, in which only one
concentration of analgesic was used, lame birds selected significantly more
drugged feed than sound birds, and that as the severity of the lameness
increased, lame birds consumed a significantly higher proportion of the drugged
feed.
PMID- 10766115
TI - Efficacy of two non-antibiotic therapies, oxytocin and topical liniment, against
bovine staphylococcal mastitis.
AB - Eight cows were challenged by a single quarter intramammary infusion of a
relatively low-virulence strain of Staphylococcus aureus on four occasions five
weeks apart and, after each challenge, each cow received one of four treatments,
according to a duplicated Latin-square design. The treatments were massage alone
(negative control), massage with a proprietary liniment, oxytocin, and a single
course of a proprietary intramammary antibiotic. The massage treatments were
applied at every milking for three weeks, oxytocin was given for one week, and
the antibiotic was given after three successive milkings. Milk samples were
collected immediately before and for three weeks after each challenge, and a
scoring system was used to quantify the presence of bacteria during the whole of
the period. None of the treatments completely eliminated bacteria from all the
cows. Relative to the negative control, the liniment had no significant effect,
but both oxytocin and the antibiotic reduced the numbers of bacteria
significantly and did not differ significantly in efficacy.
PMID- 10766116
TI - Prevalence and pathogenicity of retroviruses in wildcats in France.
AB - Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) are
frequently encountered in domestic cats (Felis catus) and in wild felids, but
only FeLV has been previously identified in wildcats (Fellis silvestris). Thirty
eight wildcats, either captured alive or found dead, were sampled in eastern and
central France. Nine of them (23.7 per cent) carried the FeLV p27 antigen, and
three (7.9 per cent) had antibodies to FIV. There was a significant relationship
between two measures of body condition and FeLV status; the FeLV-positive cats
being in poorer condition than the FeLV-negative cats. The results suggest that
FeLV is common in wildcats and may increase mortality in this species. The FIV
positive results constitute the first indication of a FIV-related virus in
wildcats.
PMID- 10766118
TI - Seasonal variation in the morphology of a bovine nasal granuloma.
PMID- 10766117
TI - Concurrent candidiasis, listeriosis and adenovirus infections in a raccoon
(Procyon lotor).
PMID- 10766119
TI - Tendering for LVI work.
PMID- 10766120
TI - Tendering for LVI work.
PMID- 10766121
TI - Tendering for LVI work.
PMID- 10766122
TI - Retired members of the RCVS.
PMID- 10766123
TI - Animal minds and animal welfare.
PMID- 10766124
TI - Students' animal welfare society.
PMID- 10766125
TI - Sarcocystis encephalomyelitis in cattle.
PMID- 10766126
TI - FLUTD study.
PMID- 10766127
TI - Costs of procedures.
PMID- 10766128
TI - Poly(ethylene glycol) (PEG)-mediated fusion between pure lipid bilayers: a
mechanism in common with viral fusion and secretory vesicle release?
AB - Membrane fusion is fundamental to the life of eukaryotic cells. Cellular
trafficking and compartmentalization, import of food stuffs and export of waste,
inter-cellular communication, sexual reproduction, and cell division are all
dependent on this basic process. Yet, little is known about the molecular
mechanism(s) by which fusion occurs. It is known that fusing membranes must
somehow be docked and brought into close contact. Specific proteins, many of
which have been identified within the past decade, accomplish this. An electrical
connection or 'fusion pore' is established between compartments surrounded by the
fusing membranes. Three primary views of the mechanism of pore formation during
secretory and viral fusion have been proposed within the past decade. In one
view, a protein ring forms an initial transient connection that expands slowly by
recruiting lipid so as to form a lipidic junction. In another view, the initial
fusion pore consists of a protein-lipid complex that transforms slowly until the
fusion proteins dissociate from the complex to form an irreversible lipidic pore.
In a third view, the initial pore is a transient lipid pore that fluctuates
between open and closed states before either expanding irreversibly or closing.
Recent work has helped define the mechanism by which poly(ethylene glycol) (PEG)
mediates fusion of highly curved model membranes composed only of synthetic
phospholipids. PEG is a highly hydrated polymer that can bring vesicle membranes
to near molecular contact by making water between them thermodynamically
unfavourable. Disrupted packing in the contacting monolayers of these vesicle
membranes is necessary to induce fusion. The time course and sequence of
molecular events of the ensuing fusion process have also been defined. This
sequence of events involves the formation of an initial, transient intermediate
in which outer leaflet lipids have mixed and small transient pores join fusing
compartments ('stalk'). The transient intermediate transforms in 1-3 min to a
fusion-committed, second intermediate ('septum') that then 'pops' to form the
fusion pore. Inner leaflet mixing, which is shown to be distinct from outer
leaflet mixing, accompanies contents mixing that marks formation of the fusion
pore. Both the sequence of events and the activation energies of these events
correspond well to those observed in viral membrane fusion and secretory granule
fusion. These results strongly support the contention that both viral and
secretory fusion events occur by lipid molecule rearrangements that can be
studied and defined through the use of PEG-mediated vesicle fusion as a model
system. A possible mechanism by which fusion proteins might mediate this lipidic
process is described.
PMID- 10766129
TI - Manipulation of activity and orientation of membrane-reconstituted di-tripeptide
transport protein DtpT of Lactococcus lactis.
AB - The di-tripeptide transport system (DtpT) of Lactococcus lactis was purified to
apparent homogeneity by pre-extraction of crude membrane vesicles with
octaethylene glycol monodecyl ether (C10E8), followed by solubilization with n
dodecyl-beta-D-maltoside (DDM) and chromatography on a Ni-NTA resin. The DtpT
protein was reconstituted into detergent-destabilized preformed liposomes
prepared from E. coli phospholipid/phosphatidylcholine. A variety of detergents
were tested for their ability to mediate the membrane reconstitution of DtpT and
their effectiveness to yield proteoliposomes with a high transport activity. The
highest activities were obtained with TX100, C12E8 and DM, whereas DDM yielded
relatively poor activities, in particular when this detergent was used at
concentrations beyond the onset of solubilization of the preformed liposomes.
Parallel with the low activity, significant losses of lipid were observed when
the reconstitution was performed at high DDM concentrations. This explained at
least part of the reduced transport activity as the DtpT protein was highly
dependent on the final lipid-to-protein ratios in the proteoliposomes. Consistent
with the difference in mechanism of DDM- and TX100-mediated membrane protein
reconstitution, the orientation of the DtpT protein in the membrane was random
with DDM and inside-in when TX100 was used. The methodology to determine the
orientation of membrane-reconstituted proteins from the accessibility of
cysteines for thiol-specific reagents is critically evaluated.
PMID- 10766130
TI - The red blood cell band 3 variant (band 3Biceetrel:R490C) associated with
dominant hereditary spherocytosis causes defective membrane targeting of the
molecule and a dominant negative effect.
AB - Hereditary spherocytosis (HS), a common human inherited haemolytic anaemia, is
associated with partial deficiency of different erythrocyte membrane proteins. In
a subset of dominant HS, a partial membrane expression deficiency of band 3, the
erythrocyte anion exchanger (AE1), have previously been characterized, and
several mutations in the band 3 gene have been found: amino acid substitutions at
conserved positions in the membrane domain, nonsense and frameshift mutations. In
HS patients bearing missense mutations, the mutated transcript was present,
whereas only the normal transcript was found in HS patients with frameshift
mutations. In the former group, the membrane expression deficiency of band 3 was
significantly more important than that observed in the latter group of HS
patients with frameshift mutations, suggesting that missense mutations may have a
dominant negative effect. In the present study, transient and stable
transfections of K562 and COS-7 cells were used to demonstrate, by immunoblots of
cell lysates and immunofluorescence studies, that the band 3 membrane domain
bearing the R490C mutation (band 3Bicetrel) is not targeted to the plasma
membrane and is retained in the endoplasmic reticulum. Transient cotransfections
of K562 cells with plasmid coding for the normal membrane domain of band 3,
together with increasing amounts of plasmid coding for the mutated R490C membrane
domain, demonstrated that the band 3 mutant polypeptide exerts a dominant
negative effect on the plasma membrane targeting of the normal band 3.
PMID- 10766131
TI - The endoplasmic reticulum: structure and function.
PMID- 10766132
TI - Fellow eye prognosis in patients with severe visual field loss in 1 eye from
chronic open-angle glaucoma.
AB - OBJECTIVES: To examine the prognosis for the fellow eye of patients with severe
visual field loss in 1 eye from chronic forms of open-angle glaucoma, and to
identify risk factors for visual field progression in such eyes. METHODS: Review
of 36 patients followed in an academic medical center with monocular severe
visual field loss (Advanced Glaucoma Intervention Study score > or =12) from open
angle glaucoma either at initial Humphrey visual field testing or during follow
up. Change in Advanced Glaucoma Intervention Study visual field score and
clinical evaluation were used to determine visual field progression. Kaplan-Meier
survival analysis and Cox proportional hazards survival regression were used to
estimate visual field progression in fellow eyes and assess possible risk
factors. RESULTS: During 67+/-32 months (mean +/- SD), 12 of 36 first-affected
eyes (33%) and 6 fellow eyes (17%) had significant visual field progression. The
Kaplan-Meier estimate of visual field progression in the fellow eye was 12.4% at
5 years after severe visual field loss in the first eye. Compared with stable
fellow eyes, fellow eyes with visual field progression had significantly larger
initial cupdisc ratio, smaller between-eyes difference in the initial Advanced
Glaucoma Intervention Study score, and lower calculated ocular perfusion
pressure. Ocular perfusion pressure was the only variable significantly
associated with visual field progression by Cox proportional hazards survival
regression (P = .019). During an average of 10.2 years of disease, 2 patients
(6%) became bilaterally blind from glaucoma. CONCLUSIONS: In this predominantly
white population, fellow eyes of patients with severe visual field loss in 1 eye
from open-angle glaucoma were not at particularly high risk for further visual
field progression, and few patients became bilaterally blind. Fellow eye visual
field progression was associated with lower calculated ocular perfusion pressure.
PMID- 10766133
TI - Rate of visual field loss in progressive glaucoma.
AB - OBJECTIVE: To investigate the rate of visual field (VF) loss in progressive
glaucoma. SETTING: Outpatient department, nonreferral base. METHODS: A cohort of
34 patients with normal-pressure glaucoma (NPG), 68 patients with primary open
angle glaucoma (POAG), and 125 patients with ocular hypertension (OHT) were
followed up for an average of 9 years. Visual fields were obtained annually with
automated perimetry. The rate of VF loss as a percentage per year was calculated.
RESULTS: Twenty-three eyes with NPG, 31 with POAG, and 10 with OHT showed
progression of VF loss. The mean (+/-SD) rates of VF deterioration were 3.7%+/
3.3% per year in NPG, 2.5%+/-1.8% in POAG, and 2.3%+/-1.3% in OHT converting to
POAG, and did not differ significantly. No difference in the rate of VF loss was
found between eyes with and without optic disc hemorrhages (2.7%+/-2.9% and
3.1%+/-2.1%, respectively). The rate of VF loss was not related to the initial VF
status. The rate of VF loss between the superior and inferior hemifields was
correlated in patients with NPG (r(s) = 0.67, P = .04). Comparison of visual
field loss with linear regression analysis showed significant slopes in only
37.5% of eyes with progression, which had a progression rate of 4.2%+/-3.0%.
CONCLUSIONS: The rate of VF loss did not differ between patients with NPG and
POAG. The rate of deterioration was related neither to initial VF status nor to
the presence of disc hemorrhages. Linear regression is applicable only in a
portion of the patients who have progression of VF loss.
PMID- 10766135
TI - Effect of perifoveal tissue dissection in the management of acute idiopathic full
thickness macular holes.
AB - OBJECTIVE: To evaluate the efficacy of perifoveal tissue dissection (PTD) on
patients undergoing pars plana vitrectomy for idiopathic macular holes of less
than 1-year's duration. METHODS: Pars plana core vitrectomy was performed on 107
eyes of 104 consecutive patients with acute idiopathic macular holes. One cohort
had routine PTD. In the other cohort, no attempt was made to strip preretinal
tissue. Follow-up was longer than 6 months (follow-up range, 6 to 36 months).
RESULTS: Overall, 95 (89%) of all macular holes were closed. Visual acuity
improved 2 lines or more of the Snellen letter chart in 91 eyes (85%). A
postoperative visual acuity of 20/50 or better was achieved in 79 eyes (74%). A
transient increase in intraocular pressure (230 mm Hg) developed in 25 eyes
(23.4%). In 6 eyes (5.6%) a retinal detachment developed. One eye had retinal
pigment epithelial changes and 1 patient reported peripheral field loss. No
statistically significant differences were noted between eyes having PTD and
those without PTD for any outcome measure. CONCLUSION: In this series, no
beneficial or adverse effect could be demonstrated by performing PTD in eyes
undergoing pars plana core vitrectomy for acute idiopathic macular holes.
PMID- 10766134
TI - Glaucoma follow-up when converting from long to short perimetric threshold tests.
AB - OBJECTIVES: To study the influence of test length in automated perimetry follow
up of glaucomatous eyes and, particularly, to determine if it is possible to
usefully interpret test results obtained using a testing algorithm shorter than
that used for baseline testing. METHODS: Automated perimetry findings were
retrospectively evaluated in 31 patients with glaucoma for whom multiple Humphrey
30-2 tests were available on the Full Threshold strategy and the SITA Standard
strategy. RESULTS: Variability around the mean deviation regression lines was
smaller with SITA than with the Full Threshold strategy. Mean deviation values
with SITA averaged about 1 dB less severe. Although localized scotomas measured
in decibels were deeper on the Full Threshold strategy, number of significantly
depressed points on total deviation and pattern deviation probability plot
analyses did not differ significantly between the 2 strategies. CONCLUSIONS: The
SITA strategy showed test-retest consistency that was at least as good as that of
the Full Threshold strategy. The 2 strategies produced similar results when
analyzed relative to their respective normal significance limits. Generally, it
is appropriate to establish a new baseline when converting from one perimetric
algorithm to another. When necessary, however, results may be usefully compared
if such comparisons are based on total and pattern deviation probability maps
rather than on decibel values.
PMID- 10766136
TI - Evaluation of efficacy and complications: primary pediatric orbital implants
after enucleation.
AB - BACKGROUND: Orbital implants are used routinely in pediatric patients at the time
of enucleation. Complications, such as exposure, ptosis, and infection, may occur
after implantation. Controversy continues regarding the rate of complications
with newer implants in the pediatric population. OBJECTIVE: To examine the
effects of orbital implants on children whose eyes have been enucleated. METHODS:
Records of orbital implantation after enucleation performed by 5 surgeons on 120
pediatric patients (123 eyes) over a 10.5-year period were reviewed
retrospectively. Demographic data, ocular diagnosis, prior ophthalmic surgery,
implant characteristics, and postoperative complications were described using a
standardized format for all patients, with a minimum of 6 months of follow-up
(mean, 3 years). RESULTS: Complications were observed in 7 eyes (5.7%). Implant
exposure (1 [0.8%]), implant extrusion (0 [0%), and implant migration (3 [2.4%)
were rare. One hundred eighteen eyes (96%) had good cosmesis and 120 (98%) had
good motility. CONCLUSIONS: Orbital implantation after enucleation is successful
in the pediatric population. Complications are minimal. Hydroxyapatite implants
were not associated with unacceptable complications in this pediatric population.
PMID- 10766137
TI - Immunostaining of heat shock proteins in the retina and optic nerve head of
normal and glaucomatous eyes.
AB - PURPOSE: To examine immunostaining of 60-kd and 27-kd heat shock proteins (HSP 60
and HSP 27), which are known to increase cell survival in response to stress, in
glaucomatous retina and optic nerve head. METHODS: Six postmortem eyes from
patients with primary open-angle glaucoma, 6 eyes from patients with normal
pressure glaucoma, and 6 eyes from age-matched normal subjects were studied by
immunohistochemistry. The sections of the retina and optic nerve head were
examined after immunostaining with antibodies to HSP 60 and HSP 27. RESULTS: The
intensity of the immunostaining and the number of labeled cells for heat shock
proteins (HSPs) were greater in retina sections from glaucomatous eyes than in
sections from normal eyes from age-matched donors. Retinal immunostaining of HSP
60 was prominent in the retinal ganglion cells and photoreceptors, whereas
immunostaining of HSP 27 was prominent in the nerve fiber layer and ganglion
cells as well as in the retinal vessels. In addition, retinal immunostaining of
these HSPs exhibited regional and cellular differences. Optic nerve heads of
glaucomatous eyes exhibited increased immunostaining of HSP 27, but not HSP 60,
which was mostly associated with astroglial cells in the lamina cribrosa.
CONCLUSION: The increased immunostaining of HSP 60 and HSP 27 in the glaucomatous
eyes may reflect a role of these proteins as a cellular defense mechanism in
response to stress or injury in glaucoma. CLINICAL RELEVANCE: These findings
suggest that immunoregulation is an important component of glaucomatous optic
neuropathy.
PMID- 10766138
TI - Biphasic ocular inflammatory response to endotoxin-induced uveitis in the mouse.
AB - OBJECTIVE: To examine the kinetics and mechanisms of endotoxin-induced uveitis in
the mouse. METHODS: C3H/HeN mice were injected subcutaneously with 0.3 mg of
Salmonella typhimurium lipopolysaccharide (LPS) in 0.1 mL of phosphate-buffered
saline solution or phosphate-buffered saline solution alone in 3 separate
experiments; mice were killed after 1, 3, 5, and 7 days. In 2 other separate
experiments, mice were killed 1, 3, 6, and 24 hours after LPS injection. All eyes
were collected for histological examination, immunohistochemical analyses,
aqueous protein level determination, and reverse transcriptase-polymerase chain
reaction for ocular interleukin (IL)1alpha, IL-6, tumor necrosis factor alpha,
and granulocyte-macrophage colony-stimulating factor messenger RNA (mRNA). Enzyme
linked immunosorbent assay was used to measure tumor necrosis factor alpha and IL
6 levels in aqueous and serum samples. RESULTS: Results were consistent for all
experiments. Numbers of ocular inflammatory cells and levels of aqueous protein
peaked 1 and 5 days after LPS injection. Control mice did not develop
inflammation. Serum and aqueous IL-6 and ocular IL-6 mRNA levels peaked at 1 day
and subsided at 3 days. However, ocular IL-1alpha, tumor necrosis factor alpha,
and granulocyte-macrophage colony-stimulating factor mRNA appeared, peaked, and
subsided at 3, 5, and 7 days, respectively. Predominant infiltrating cells were
neutrophils at 1 day and macrophages at 5 days. Although no ocular inflammatory
cells were detected before 24 hours after LPS injection, tumor necrosis factor
alpha mRNA was noticed at 1 hour, peaked at 3 hours, and disappeared at 6 hours
and granulocyte-macrophage colony-stimulating factor mRNA was spotted only at 3
hours after LPS injection. CONCLUSIONS: The ocular inflammatory response to C3H/
HeN mouse endotoxin-induced uveitis is biphasic for 7 days. The first wave
appears at day 1 and subsides by day 3. A second, higher peak appears at day 5.
The 2 inflammatory waves are related to the kinetics of the different cytokines
released in the eye. This is in contrast to the rat monophasic endotoxin-induced
uveitis model, which has only one peak of intense inflammation associated with
cytokine release. CLINICAL RELEVANCE: A biphasic inflammatory response associated
with cytokine release lasting several days is observed in C3H/HeN mice with
endotoxin-induced uveitis. Because human anterior uveitis has a tendency to be
recurrent in nature, this might be a better experimental model.
PMID- 10766139
TI - Elevated glutamate levels in the vitreous body of an in vivo model of optic nerve
ischemia.
AB - OBJECTIVE: To explore the possibility that an elevation of glutamate levels in
the vitreous might be associated with the microvascular compromise of the optic
nerve. MATERIALS AND METHODS: Endothelin-1, 0.1 microg/d (5 rabbits), or balanced
salt solution (4 rabbits) was delivered to the perineural region of the anterior
optic nerve by osmotically driven minipumps for 2 weeks. Vitreous specimens were
obtained, and their amino acid contents were determined by high-performance
liquid chromatography. RESULTS: There was a statistically significant elevation
in the mean +/- SEM vitreous concentrations of glutamate (264% +/-41%; P = .04),
aspartate (269% +/-31%; P = .04), and glycine (232% +/-26%; P = .04) in the eyes
subjected to endothelin-1 when compared with the fellow control eyes. CONCLUSION:
Administration of endothelin-1 to the microvasculature of the optic nerve leads
to elevation of glutamate, aspartate, and glycine concentrations in the vitreous.
CLINICAL RELEVANCE: The increase of excitatory amino acids in the vitreous might
be associated with various ischemic processes of the optic nerve, including
glaucomatous optic neuropathy, and may play a role in the neuronal damage that is
seen in these diseases.
PMID- 10766141
TI - Acquired nystagmus.
AB - Traditionally, acquired forms of nystagmus have been classified in descriptive
terms based on their clinical features and recorded waveforms. In the past 20
years, the mechanisms of several major forms of nystagmus have been elucidated;
animal and mathematical models for these ocular oscillations have been developed.
These advances, which owe much to modern anatomical, physiological, and
pharmacological techniques, have enhanced the diagnostic value of nystagmus and
provide the basis for developing rational therapy.
PMID- 10766142
TI - What can we expect in neuro-ophthalmology in the next century?
PMID- 10766140
TI - Mutation analysis of 3 genes in patients with Leber congenital amaurosis.
AB - OBJECTIVE: To assess the frequency of mutations in the CRX, GUCY2D, and RPE65
genes in patients with Leber congenital amaurosis (LCA). PATIENTS: One hundred
seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with
the largest subgroup being 39 probands from India. METHODS: Samples were screened
with single-strand conformation polymorphism analysis followed by DNA sequencing
of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. RESULTS: Of
the 176 probands, 28 (15.9%) harbored possible disease-causing mutations. The
relative contribution of each gene to the total number of mutations was as
follows: CRX, 2.8%; GUCY2D, 6.3%; and RPE65, 6.8%. No patients who harbored
mutations in these genes had associated systemic abnormalities. Molecular
diagnosis allowed definitive genetic counseling in a family affected with Best
disease and LCA. CONCLUSIONS: Molecular diagnosis may be of benefit to patients
affected with LCA. The relative paucity of mutations found in this study suggests
that more LCA-associated genes remain to be discovered. CLINICAL RELEVANCE:
Molecular diagnosis can confirm and clarify the diagnosis of LCA. As genotype
data accumulate, clinical phenotypes associated with specific mutations will be
established. This will facilitate the counseling of patients on their visual
prognosis and the likelihood of associated systemic anomalies.
PMID- 10766143
TI - What has the American Medical Association done for you lately?
PMID- 10766144
TI - Malignant melanoma of the conjunctiva with intraocular extension.
AB - Intraocular extension of a malignant melanoma of the conjunctiva is a rare
entity. A 75-year-old woman underwent repeated surgery after receiving the
diagnosis of a multilocular recurrent malignant melanoma arising from a primary
acquired melanosis. Treatment included 2 lamellar sclerokeratectomies and
percutaneous radiotherapy. Five years after initial surgery, intraocular
extension of the melanoma was observed, and enucleation was performed. Findings
from histopathological examination revealed a malignant melanoma occupying part
of the ciliary body, the trabecular meshwork, and the iris. Eyes with recurrent
malignant melanoma of the conjunctiva should be carefully monitored for
intraocular extension. Deep excision of conjunctival melanoma, including lamellar
sclerokeratectomy, may abolish the natural barrier against intraocular extension
of malignant melanomas of the conjunctiva.
PMID- 10766145
TI - Retinal vasoproliferative tumors: surgical management and histological findings.
AB - Vascular masses occurring in the peripheral retina have been described
extensively in the literature. Many terms, including "presumed acquired
hemangiomas," "hemangioma-like," "angiomatous masses," "angioma-like,"
"peripheral retinal telangiectasis," and "vasoproliferative tumors," have been
suggested that reflect the lack of the known histological features and the
potentially variable causes. We describe the histological features of 2 patients
who underwent transcleral local resection as management for suspected choroidal
melanoma. Pathological examination of these tumors reveals the constituents to be
primarily benign glial cell proliferation with secondary vasoproliferation. The
weight of the literature agrees with a reactionary process. We therefore suggest
the term "reactionary retinal glioangiosis." Transcleral resection has a place
where diagnosis is difficult. It prevents an unnecessary enucleation and allows
accurate tissue diagnosis.
PMID- 10766146
TI - Xanthomonas maltophilia endophthalmitis after cataract surgery.
PMID- 10766147
TI - Pseudodefects of the retinal nerve fiber layer examined using optical coherence
tomography.
PMID- 10766148
TI - Complications of systemic chemotherapy as treatment of retinoblastoma.
PMID- 10766149
TI - Persistent hyperplastic primary vitreous associated with septo-optic-pituitary
dysplasia and schizencephaly.
PMID- 10766151
TI - Tear of the retinal pigment epithelium and serous retinal detachment in a case of
IgA nephropathy after renal transplantation.
PMID- 10766150
TI - Combined choroidal and retinal ischemia during interferon therapy: indocyanine
green angiographic and microperimetric findings.
PMID- 10766152
TI - A single-suture technique for placement of the ganciclovir implant.
AB - The ganciclovir implant is a surgically implanted sustained-release drug delivery
system used for the treatment of cytomegalovirus retinitis. The device is
suspended in the vitreous cavity through a pars plana incision. Previous reports
of the surgical procedure have described securing the implant on 1 suture, tied
with an external knot. The ends of this suture were left long to avoid sharp ends
eroding through the conjunctiva. The wound was then closed with 1 or more
additional sutures, with the ends tied and cut short. We describe a technique
whereby the wound is closed and the implant secured with a single running suture.
The advantages of this technique include efficiency and elimination of exposed
knots. We have observed no complications attributable to this technique.
PMID- 10766153
TI - A lost contact lens and Actinomyces colonization in an asymptomatic patient.
PMID- 10766154
TI - Occlusive retinal vasculitis associated with systemic lupus erythematosus.
PMID- 10766155
TI - Intraorbital branch.
PMID- 10766156
TI - Primary orbital Ewing sarcoma in a middle-aged woman.
PMID- 10766157
TI - p53 Antibodies in the sera of patients with various types of cancer: a review.
AB - p53 antibodies (p53-Abs) were discovered 20 years ago during the course of tumor
associated antigens screening. The discovery of p53 mutation and accumulation of
p53 in human tumors shed new light on the p53 humoral response. In the present
review, we have compiled more than 130 papers published in this specific field
since 1992. We demonstrate that p53-Abs are found predominantly in human cancer
patients with a specificity of 96%. Such antibodies are predominantly associated
with p53 gene missense mutations and p53 accumulation in the tumor, but the
sensitivity of such detection is only 30%. It has been demonstrated that this
immune response is due to a self-immunization process linked to the strong
immunogenicity of the p53 protein. The clinical value of these antibodies remains
subject to debate, but consistent results have been observed in breast, colon,
oral, and gastric cancers, in which they have been associated with high-grade
tumors and poor survival. The finding of p53-Abs in the sera of individuals who
are at high risk of cancer, such as exposed workers or heavy smokers, indicates
that they have promising potential in the early detection of cancer.
PMID- 10766158
TI - Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis.
AB - Despite well-documented cardiotoxic effects, doxorubicin remains a major
anticancer agent. To study the role of myocardial apoptosis following doxorubicin
administration, male Wistar rats were exposed to 1.25, 2.5, and 5 mg/kg of i.p.
doxorubicin and terminated on days 1-7 in groups of five. Doxorubicin caused a
significant (P < 0.001) and dose-dependent induction of cardiomyocyte apoptosis
at 24-48 h after the injection. Repeated injections of 2.5 mg/kg given every
other day resulted in peaks of apoptosis at 24 h after each injection. However,
no additive effect of repeated dosing was noted. In histological samples,
alterations in the cytoskeletal apparatus with focal loss of contractile elements
were seen after a single injection. Myocyte necrosis was absent. Thus, acute
doxorubicin-induced cardiotoxicity involves cardiomyocyte apoptosis, a
potentially preventable form of myocardial tissue loss.
PMID- 10766159
TI - Antitumor activity of endostatin against carcinogen-induced rat primary mammary
tumors.
AB - Endostatin, a Mr 20,000 fragment of collagen XVIII, potently inhibits the growth
of experimental tumors implanted in mice. Here we report the cloning, expression,
and antitumor activity of the rat form of endostatin. When tested on breast
carcinomas arising in female virgin rats after intragastric administration of
9,10-dimethyl-1,2-benzanthracene (DMBA), endostatin induced significant
inhibition of mammary tumor growth in all of the treated rats during a 4-week
treatment period without signs of systemic toxicity. Interestingly, this arrest
of tumor growth persisted throughout a four-week off-therapy period. Moreover,
endostatin was effective in counteracting the development of multiple primary
tumors. These results confirm that rat endostatin is a potent anticancer agent in
a carcinogen-induced, spontaneously arising rat breast cancer model. It not only
stops the growth of existing tumors but also decreases the incidence of the
development of multiple neoplastic lesions.
PMID- 10766160
TI - Gene transfer into brain parenchyma elicits antitumor effects.
AB - Gene therapy strategies for cancer currently aim at targeting gene delivery to
the malignant cell. In a mouse model of intracerebral Lewis lung carcinoma (3LL),
adenoviral vectors transduce not only 3LL cells but also brain parenchymal cells
including endothelial cells, neurons, microglia, and astrocytes in vivo.
Furthermore, transgene expression persists longer in brain than in tumor.
Transfer of IFN-gamma into brain parenchymal cells rather than tumor is both
necessary and sufficient to generate antitumor therapeutic benefits. Therefore,
parenchymal cells represent an effective and necessary target for delivery of
genes that render the brain uninhabitable by the tumor.
PMID- 10766161
TI - Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma
cell lines.
AB - Both inactivation of the tumor suppressor gene, PTEN/MMAC1, and oncogenic
activation of RAS have been described in human cutaneous melanoma. In mice,
activation of a RAS-containing pathway is a necessary step in the pathogenesis of
murine melanomas. Because PTEN negatively regulates on the downstream effects of
phosphatidylinositol-3-kinase (PI3-K), we hypothesized that the loss of
PTEN/MMAC1 and the activation of RAS may be largely equivalent because RAS is a
known positive upstream regulator of PI3-K. We expanded our previous survey of
PTEN/MMAC1 mutations and analyzed the RAS status of 53 cutaneous melanoma cell
lines, 18 glioma cell lines, and 17 uncultured cutaneous melanoma metastasis.
Overall, 51% of the cell lines had alterations in either PTEN/MMAC1 or RAS. We
found 16 cell lines (30%) with alterations in PTEN/MMAC1 and 11 cell lines (21%)
with activating NRAS mutations; only 1 cell line had concurrent alterations in
both genes. Moreover, glioma cell lines with a high frequency of PTEN/MMAC1
inactivation had no identifiable RAS alterations. Ectopic expression of PTEN in
several cutaneous melanoma cell lines suppressed colony formation irrespective of
PTEN/MMAC1 status; furthermore, PTEN expression in cell lines carrying activated
RAS also suppressed colony formation. The relative reciprocity of PTEN/MMAC1
abrogation and NRAS activation suggests that the two genetic changes, in a subset
of cutaneous melanomas, are functionally overlapping.
PMID- 10766162
TI - Cyclooxygenase-2, a colorectal cancer nonsteroidal anti-inflammatory drug target,
is regulated by c-MYB.
AB - Cyclooxygenase-2 (COX-2) is an important pharmacological target with great
promise in the prevention and treatment of colorectal cancer (CRC). The mechanism
underlying COX-2 overexpression in CRC is unresolved. On the basis of the
coincident high levels of the transcription factor c-MYB and COX-2 in CRC, we
hypothesized that c-MYB is a candidate activator of COX-2 transcription. We
identified 13 c-Myb binding sites in the human COX-2 promoter. Eight of these
sites were moderate to high-affinity DNA binding targets. Promoter studies
indicated that c-Myb can activate COX-2 transcription, whereas dominant-negative
Myb mediated repression. These data provide the first rational basis for
overexpression of COX-2 in CRC and offer an additional potential target for
managing this disease.
PMID- 10766163
TI - Estrogen receptor protects p53 from deactivation by human double minute-2.
AB - We and others have demonstrated that estrogen receptor alpha (ERalpha) and p53,
two important regulatory proteins in breast cancer, bind to each other. In this
report, using the glutathione S-transferase pull-down methodology, we show the
ligand-independent interaction of ERalpha with the NH2-terminal region of p53, a
region known to bind the p300 and human double minute-2 (hdm2) regulatory
factors. Furthermore, we have demonstrated that ERalpha is capable of binding
hdm2 directly. The interaction of ERalpha and p53 does not interfere with the
binding between p53 and hdm2; rather, these proteins form a ternary complex. The
effect of ERalpha on the p53-hdm2 regulatory loop has been examined. Our results
indicate that ERalpha protects p53 from being deactivated by hdm2. It is evident
from these investigations that the ligand-independent protection of p53 by
ERalpha is a novel role for this protein in addition to its classic regulatory
function as a ligand-inducible transcription factor. This study also describes a
new mechanism of cellular regulation of p53 activity.
PMID- 10766164
TI - Antibody response to the tumor-associated inhibitor of apoptosis protein survivin
in cancer patients.
AB - Antibody reactivity against survivin, a recently identified tumor-associated
protein, was determined in sera from patients with lung (n = 51) or colorectal
cancer (n = 49). The same collection of sera was tested for the presence of
antibodies against p53. Eleven sera from lung cancer patients and four sera from
colorectal cancer patients reacted with purified recombinant survivin in an ELISA
(21.6% and 8.2%, respectively), whereas four sera from lung cancer patients and
nine sera from colorectal cancer patients contained anti-p53 antibodies (7.8% and
18.4%, respectively). The increase in prevalence when anti-survivin and anti-p53
antibodies were determined in parallel was statistically significant (29.4%
versus 7.8%, P = 0.005 in lung cancer population; 26.6% versus 8.2%, P = 0.015 in
colorectal cancer population). The high prevalence of anti-survivin antibodies
makes these antibodies an attractive novel marker for the diagnosis of lung and
colorectal cancer, particularly in patients lacking anti-p53 antibodies.
PMID- 10766165
TI - Inhibitor of apoptosis protein hILP undergoes caspase-mediated cleavage during T
lymphocyte apoptosis.
AB - Several endogenous or viral inhibitors of apoptosis, including Bcl-2, Bcl-xL,
FLIP, p35, and CrmA, have been shown to be cleaved by caspases during apoptosis.
In this study, we demonstrate that the endogenous inhibitor of apoptosis,
hILP/XIAP, is also cleaved in apoptotic T lymphocytes, generating at least one
prominent fragment of 29 kDa. This p29 cleaved fragment was detected in Jurkat
cells induced to apoptose by anti-Fas antibody, staurosporin, or VP-16. The
cleavage of hILP appears to be caspase mediated because the production of the p29
protein was inhibited by the pan-caspase peptide inhibitor, Z-VAD.FMK. In Jurkat
cells engineered to overexpress CrmA, cleavage of hILP in response to anti-Fas
antibody or staurosporin was inhibited, whereas overexpression of Bcl-2 abrogated
the cleavage in response to VP-16. Cleavage of hILP was also observed in cell
free reactions using in vitro translated hILP and recombinant caspase-3 or -7.
Moreover, we found that the p29 hILP fragment retained the ability to bind
caspase-3 and -7, as shown previously for full-length or BIR-2 hILP. The p29
cleavage product was also detected during T-cell receptor-mediated apoptosis in
peripheral blood lymphocytes from normal donors. Furthermore, tumor-associated T
lymphocytes purified from ascites of patients with ovarian cancer expressed
fragmented hILP, which was not detected in control T cells purified from
peripheral blood of normal donors. Our results suggest that the cleavage of hILP
represents an important event in apoptosis of T lymphocytes in both normal and
pathological in vivo settings.
PMID- 10766166
TI - Identification of B94 (TNFAIP2) as a potential retinoic acid target gene in acute
promyelocytic leukemia.
AB - Acute promyelocytic leukemia (APL) is characterized by a block to myeloid
differentiation caused by expression of the fusion oncoprotein promyelocytic
leukemia-retinoic acid receptor alpha (PML-RARalpha). The purpose of this study
was to identify genes that are regulated in a PML-RARalpha-dependent fashion by
retinoic acid (RA), because such genes may be integrally involved in APL
pathogenesis and/or myeloid differentiation. A cDNA microarray approach was used
to identify genes induced in response to RA in TF1 myeloid leukemia cells
expressing PML-RARalpha (TF1-PR cells). The B94 gene (TNFAIP2; Unigene
Hs.101382), originally identified as a tumor necrosis factor alpha-inducible gene
in endothelial cells, was one of several genes found to be induced by RA
specifically in TF1-PR cells, but not in TF1-neo (control) cells. The induction
of B94 was most pronounced in cells expressing the PML-RARalpha short isoform and
was negligible in cells that expressed a mutant PML-RARalpha protein containing a
deletion of the PML coiled-coil domain. B94 induction by RA occurred within 1 h,
did not require new protein synthesis, and was inhibited by actinomycin D,
suggesting rapid transcriptional activation. B94 was also induced by RA in NB4,
UF1, and HL-60 cells, but not in other hematopoietic cell lines tested,
suggesting that its up-regulation by RA may be specific to cells that express PML
RARalpha or are at the late myeloblast or promyelocyte stage of myeloid
development. A screen of bone marrow cells from normal donors or patients with
acute myelogenous leukemia showed that B94 was highly expressed in normal marrow
and in marrow from patients with acute myelogenous leukemia French-American
British subtypes M0-M2, but was repressed in marrow cells from APL patients.
Treatment of APL blasts in vitro with all-trans-RA resulted in up-regulation of
B94 mRNA. These results suggest that B94 plays a role in myeloid development and
support the hypothesis that B94 is a target gene of PML-RARalpha in APL.
PMID- 10766167
TI - Oncogenic base substitution mutations in circulating leukocytes of normal
individuals.
AB - The background frequency of mutations in human tissues is an important issue in
cancer susceptibility and genotoxic exposure determinations. Here we report the
detection of rare mutant leukocytes containing oncogenic base substitutions of
the Harvey-ras, N-ras, and p53 genes by the Needle-in-a-Haystack mutation assay
with a sensitivity of one cell in a million. Altogether, we detected and
identified 17 independent mutations of 66 separate base site analyses of
peripheral blood specimens obtained from 19 apparently normal individuals. Two
individuals harbored a substantially increased frequency of mutant cells,
representing 9 of the 17 independent mutations found. These results suggest that
up to 1 in 10 normal individuals may harbor a significant frequency of oncogenic
mutations in circulating leukocytes.
PMID- 10766168
TI - Hypermethylation of multiple genes in pancreatic adenocarcinoma.
AB - Hypermethylation of CpG islands is a common mechanism by which tumor suppressor
genes are inactivated. We studied 45 pancreatic carcinomas and 14 normal
pancreata for aberrant DNA methylation of CpG islands of multiple genes and
clones using methylation-specific PCR (MSP) and bisulfite-modified sequencing.
Using MSP, we detected aberrant methylation of at least one locus in 60% of
carcinomas. The genes analyzed included RARbeta (methylated in 20%), p16 (18%),
CACNA1G (16%), TIMP-3 (11%), E-cad (7%), THBS1 (7%), hMLH1 (4%), DAP kinase (2%),
and MGMT (0%). In addition, aberrant methylation was found in three CpG islands
(MINT31, -1, and -2) in 38, 38, and 14% of carcinomas, respectively.
Hypermethylation was largely confined to the carcinomas with only three loci (E
cad, DAP kinase, and MINT2) harboring methylation in some normal pancreata (36,
21, and 14%, respectively). Simultaneous methylation of at least four loci was
observed in 5 of 36 (14%) pancreatic adenocarcinomas. We defined this subgroup of
pancreatic adenocarcinomas as "CpG island-methylator-phenotype positive (CIMP+)."
Two of four carcinomas with microsatellite instability harbored promoter
hypermethylation of hMLH1, and both cases were CIMP+. Thus, we conclude that many
pancreatic carcinomas hypermethylate a small percentage of genes, whereas a
subset displays a CIMP+ phenotype.
PMID- 10766169
TI - A splice variant of the neuron-restrictive silencer factor repressor is expressed
in small cell lung cancer: a potential role in derepression of neuroendocrine
genes and a useful clinical marker.
AB - The neuron-restrictive silencer factor [NRSF (RE-1 silencing transcription
factor/X box repressor)] is a transcriptional silencer, which we have previously
implicated in deregulation of the vasopressin promoter in small cell lung cancer
(SCLC). Here we describe a novel splice variant of the NRSF transcript, which is
highly expressed in SCLCs. The variant was detected in both established cell
lines and primary SCLC cultures as well as in some primitive neuroectodermal
tumor biopsies. It was present at very low levels in human brain tissue, non-SCLC
tumors, and normal bronchial epithelium. This human splice variant, which is
massively overexpressed in SCLCs, incorporates a 50-bp insert between exons 5 and
6, introducing a stop codon and predicting translation of a truncated NRSF
isoform. We propose that the encoded isoform may antagonize repression of the
vasopressin promoter and other "neuronal" genes with neuron-restrictive silencer
elements in SCLCs. Thus, up-regulated expression of this NRSF isoform may be a
key early factor in defining the neuroendocrine phenotype of these tumors. The
NRSF splice variant represents a specific clinical marker that could prove useful
in detection of the majority of SCLCs.
PMID- 10766170
TI - Nuclear factor-kappaB activation is involved in LMP1-mediated transformation and
tumorigenesis of rat-1 fibroblasts.
AB - The mechanism of latent membrane protein LMP1 of EBV in inducing cell
transformation and tumorigenesis was investigated in Rat-1 fibroblasts. A plasmid
encoding a site-specific mutant of LMP1 defective in binding to tumor necrosis
factor receptor-associated death domain protein was constructed. This LMP1(TRADD)
gene is 75% defective in nuclear factor (NF)-kappaB activation and 100% defective
in activator protein-1 activation. When introduced into Rat-1 cells through
retrovirus, the Rat-1-LMP1(TRADD) cells showed a significant reduction of focus
formation and decreased tumor growth in nude mice as compared with Rat-1-LMP1
cells, suggesting that NF-kappaB or activator protein-1 activation may be
important for LMP1-induced cell transformation. To further delineate the
determinants of LMP1-mediated cellular transformation, a retrovirus with a
dominant-negative I kappaB alpha was introduced into the transformed Rat-1-LMP1
cells. The presence of I kappaB alpha significantly suppressed both focus
formation and tumorigenicity of Rat-1-LMP1 cells. Our results suggest that the
activation of NF-kappaB may play an important role in LMP1-mediated cell
transformation and tumorigenesis.
PMID- 10766171
TI - Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adducts in ras codon
61 mutational hot spots.
AB - The fjord region diol-epoxide metabolites of polycyclic aromatic hydrocarbons
display stronger tumorigenic activities in rodent studies than comparable bay
region diol-epoxides, but the molecular basis for this difference between fjord
and bay region derivatives is not understood. Here we tested whether the variable
effects of these genotoxic metabolites of polycyclic aromatic hydrocarbons may
result from different DNA repair reactions. In particular, we compared the
repairability of DNA adducts formed by bay region benzo[a]pyrene (B[a]P) diol
epoxides and the structurally similar but significantly more tumorigenic fjord
region diol-epoxide metabolites of benzo[c]phenanthrene (B[c]Ph). For that
purpose, we incorporated both types of polycyclic aromatic hydrocarbon adducts
into known hot spot sites for carcinogen-induced proto-oncogene activation.
Synthetic DNA substrates were assembled using a portion of human N-ras or H-ras
that includes codon 61, and stereospecific B[a]P or B[c]Ph adducts were
synthesized on adenine N6 at the second position of these two ras codon 61
sequences. DNA repair was determined by incubating the site-directed substrates
in human cell extracts, followed by electrophoretic visualization of radiolabeled
oligonucleotide excision products. These cell-free assays showed that all tested
bay region B[a]P-N6-dA adducts are removed by the human nucleotide excision
repair system, although excision efficiency varied with the particular
stereochemical configuration of each B[a]P residue. In contrast, all fjord region
B[c]Ph-N6-dA adducts located in the identical sequence context and with exactly
the same stereochemical properties as the corresponding B[a]P lesions were
refractory to the nucleotide excision repair process. These findings indicate
that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol
epoxides may be attributed, at least in part, to slow repair of the stable base
adducts deriving from the reaction of these compounds with DNA.
PMID- 10766172
TI - Spontaneous and nitrosourea-induced primary tumors of the central nervous system
in Fischer 344 rats exposed to frequency-modulated microwave fields.
AB - In a 2-year bioassay, we exposed Fischer 344 rats to a frequency-modulated (FM)
signal (836.55 MHz +/- 12.5 KHz deviation) simulating radiofrequency exposures in
the head of users of hand-held mobile phones. We tested for effects on
spontaneous tumorigenicity of central nervous system (CNS) tumors in the
offspring of pregnant rats and also for modified incidence of primary CNS tumors
in rats treated with a single dose of the neurocarcinogen ethylnitrosourea (ENU)
in utero. ENU dosage (4 mg/kg) was selected to give an expected brain tumor
incidence of 10-15% over the mean life span of 26 months. Pregnant dams (n = 102)
were randomly assigned to six groups. Their offspring were treated as cohorts in
each of the six groups (n = 90 per group; total, n = 540): Sham ENU/Sham Field,
Sham ENU/Field Exposed, ENU/Sham Field, ENU/Field Exposed, ENU/Cage Control, and
Sham ENU/Cage Control. Intermittent field exposures began on gestation day 19 and
continued until weaning at 21 days, resuming thereafter at 31 days and continuing
until experiment termination at 731-734 days. Energy absorption rates (SARs) in
the rats' brains were similar to localized peak brain exposures of a phone user
(female, 236 g, 1.0 W/kg; male, 450 g, 1.2 W/kg). Of the original 540 rats, 168
died before the termination of the experiment. In these rats, ENU significantly
reduced survival from a mean of 708 days in three groups without ENU treatment to
645 days in three groups treated with ENU (P < 0.0005). There were no effects on
survival attributable to FM field exposure in either ENU-treated or in sham
treated groups. Spontaneous CNS tumor incidence in control groups was 1.1-4.4%
but sharply higher in rats receiving ENU (14.4-22.2%; P < 0.0001). No FM field
mediated changes were observed in number, incidence, or histological type of
either spontaneous or ENU-induced brain tumors, nor were gender differences
detected in tumor numbers. These negative findings with FM fields contrast with
our study using standard digital phone fields pulsed on and off at 50/se, where a
trend was noted toward reduced incidence of both spontaneous and ENU-induced CNS
tumors (W. R. Adey et al., Radiat. Res., 152: 293-302, 1999). Although consistent
but not attaining significance in the experiment overall (spontaneous CNS tumors,
P < 0.08 one-tailed; P < 0.16 two-tailed; ENU-induced CNS tumors, P < 0.08 one
tailed, P < 0.16 two-tailed), the trend was significant (P < 0.015 one-tailed, P
< 0.03, two-tailed) in rats that received ENU and died prior to experiment
termination, with a primary brain tumor as the cause of death. We discuss
differences in the signaling structure of digital and FM fields. Certain
bioeffects induced by either amplitude-modulated or pulsed radiofrequency fields
at athermal levels have not been seen with fields of similar average power but
unvarying in intensity (continuous wave or frequency-modulated fields).
PMID- 10766173
TI - Chemopreventive efficacy of combined piroxicam and difluoromethylornithine
treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc
mutant embryos.
AB - Genetic knockout or pharmacological inhibition of cyclooxygenase-2 decreases the
number and size of adenomas in mouse models of familial adenomatous polyposis.
Epidemiological and clinical studies in humans indicate that the entire class of
nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit both COX-1 and COX-2
enzymes are promising colon cancer chemopreventive agents. We used the Apc mutant
Min mouse model to test combinations of agents that might maximize preventive
benefit with minimal toxicity because they act via different mechanisms. Min mice
(n = 144) were exposed to low doses of the nonselective COX inhibitor piroxicam
and the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO),
beginning at the time they were weaned and continuing throughout the duration of
the experiment. Piroxicam at 12, 25, and 50 ppm in the diet caused dose-dependent
decreases in the number of tumors in the middle and distal portions of the small
intestine. This decrease in tumor multiplicity was associated with a striking
decrease in the size of those tumors that did grow out. In contrast, none of the
doses of piroxicam alone decreased tumor multiplicity in the proximal portion of
the intestine (duodenum). Exposure to DFMO (0.5 or 1.0% in water) caused a dose
dependent decrease in tumor multiplicity in the middle and distal portions of the
small intestine. However, this decreased multiplicity was not associated with a
striking decrease in the size of the tumors. Combined treatment of mice with
piroxicam plus DFMO was much more effective than either agent alone and resulted
in a significant number of mice totally free of any intestinal adenomas (P <
0.001), in contrast to the 100% incidence and high multiplicity in control Min
mice. In addition to this profound effectiveness in reducing tumor number, the
few residual tumors in mice treated with the combined drugs were markedly smaller
in size than tumors that arose from control Min mice. These experiments suggest
that selective COX-2 inhibition combined with ODC inhibition is a very promising
approach for colon cancer prevention. These COX-2 and ODC inhibitor drugs were
not overtly toxic at the doses used when administered to mice after weaning.
However, when treatment was begun in utero, the Mendelian expected progeny ratio
of 1:1 that we routinely obtained in untreated control litters was no longer
observed. Apc(min)/+ progeny of pregnant dams treated with piroxicam and/or DFMO
were reduced in number and their ratio to Apc+/+ progeny was decreased to
approximately 0.28:1. Thus, these agents are effective against adenomas that have
homozygous mutation of the APC gene and also select against fetuses bearing a
heterozygous mutation in the APC gene.
PMID- 10766174
TI - A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for
biological and clinical activity.
AB - Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the
posttranslational modification of ras and a number of other polypeptides, has
emerged as an important target for the development of anticancer agents. SCH66336
is one of the first FT inhibitors to undergo clinical testing. We report a Phase
I trial to assess the maximum tolerated dose, toxicities, and biological
effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid
tumors received 92 courses of escalating SCH66336 doses given orally twice a day
(b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea,
vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336
b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from
gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation
in buccal mucosa cells of patients treated with SCH66336 was demonstrated,
confirming that SCH66336 inhibits protein farnesylation in vivo. One partial
response was observed in a patient with previously treated metastatic non-small
cell lung cancer, who remained on study for 14 months. This study not only
establishes the dose for future testing on this schedule (350 mg b.i.d.) but also
provides the first evidence of successful inhibition of FT in the clinical
setting and the first hint of clinical activity for this class of agents.
PMID- 10766176
TI - Adenosine-mediated killing of cultured epithelial cancer cells.
AB - Because micromolar concentrations of adenosine (Ado) have been documented
recently in the interstitial fluid of carcinomas growing in animals, we examined
the effects of low concentrations of Ado on the growth of cultured human
carcinoma cells. Ado alone had little effect upon cell growth. In the presence of
one of a number of Ado deaminase (ADA) inhibitors, Ado led to significant growth
inhibition of all cell lines tested. Similar effects were found when ATP, ADP, or
AMP was substituted for Ado. Surprisingly, the ADA inhibitor coformycin (CF) had
a much greater potentiating effect than did 2'-deoxycoformycin (DCF), although
DCF is a more potent ADA inhibitor. The growth inhibition of the Ado/CF
combination was not abrogated by pyrimidines or caffeine, a nonspecific Ado
receptor blocker. Toxicity was prevented by the addition of the Ado transport
inhibitor dipyridamole or the Ado kinase inhibitor 5'-amino 5'-deoxyadenosine. S
Adenosylhomocysteine hydrolase is not involved because neither homocysteine
thiolactone nor an S-adenosylhomocysteine hydrolase inhibitor (adenosine
dialdehyde) potentiated toxicity of the Ado/CF combination. Unexpectedly,
substitution of 2'-deoxyadenosine (the toxic moiety in congenital ADA deficiency)
for Ado, did not lead to equivalent toxicity. The Ado/CF combination inhibited
DNA synthesis and brought about morphological changes consistent with apoptosis.
Together, these findings indicate that the Ado-mediated killing proceeds via an
intracellular route that requires the action of Ado kinase. The enhanced cofactor
activity of CF may be attributable to its being a more potent inhibitor of AMP
deaminase than is DCF.
PMID- 10766175
TI - Antiangiogenic scheduling of chemotherapy improves efficacy against experimental
drug-resistant cancer.
AB - To reveal the antiangiogenic capability of cancer chemotherapy, we developed an
alternative antiangiogenic schedule for administration of cyclophosphamide. We
show here that this antiangiogenic schedule avoided drug resistance and
eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with
the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were
made drug resistant before therapy, the antiangiogenic schedule suppressed tumor
growth 3-fold more effectively than the conventional schedule. When another
angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of
cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose
of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of
endothelial cells within tumors, and endothelial cell apoptosis preceded the
apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more
pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells
induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising
4.5% of body weight were eradicated. Thus, by using a dosing schedule of
cyclophosphamide that provided more sustained apoptosis of endothelial cells
within the vascular bed of a tumor, we show that a chemotherapeutic agent can
more effectively control tumor growth in mice, regardless of whether the tumor
cells are drug resistant.
PMID- 10766177
TI - Antileukemic activity of Flt3 ligand in murine leukemia.
AB - Flt3-ligand (Flt3-L) is an early acting costimulatory cytokine that has been
shown to possess antitumor properties in murine solid tumor models. Flt3-L is a
trans-membrane protein (tm) but can be proteolytically cleaved to a soluble form,
which is also biologically active. In this study, the antitumor effect of both
soluble and tmFlt3-L was evaluated in a mouse leukemia model. To mimic the
multiorgan involvement characteristic of human leukemia, a factor-dependent cell
line FDC.P1 was made leukemogenic by transfection with the human BCR/ABL gene.
The resulting cell line, AW, expresses BCR/ABL RNA and protein. It maintains a
similar in vitro growth rate as the parent cell line, but unlike the parent cell
line, AW cells are factor independent and tumorigenic. Growth of FDC.P1 and AW
cells are unaffected by the addition of soluble human Flt3-L to the culture
medium. Also, AW growth is unaltered after transduction with a retroviral vector
expressing the tm isoform of human Flt3-L (AW/tmFlt3-L). When 10(5) AW cells were
i.v. injected into syngeneic DBA/2 mice, fatal leukemia developed in nine of nine
(100%) mice within 4-6 weeks with involvement of the blood, bone marrow, spleen,
and thymus. Systematic administration of soluble human Flt3-L (500 microg/kg/day)
for 10 days protected mice from leukemia, with 11 of 17 mice tumor free at week 8
(64.7%) The tm isoform of Flt3-L also was protective. When 10(4) AW/tmFlt3-L
cells were injected i.v. into mice, only 35.7% (5 of 14) developed leukemia
versus 100% in control groups. Adoptive transfer of immunity was also
demonstrated; T cells obtained from tumor-free animals conferred protection to
87% (seven of eight) naive mice challenged with AW cells. These results
demonstrate that both soluble and membrane-bound human Flt3-L has antitumor
activity in this leukemia model.
PMID- 10766178
TI - Anthracyclines trigger apoptosis of both G0-G1 and cycling peripheral blood
lymphocytes and induce massive deletion of mature T and B cells.
AB - The anthracyclines daunorubicin and doxorubicin were shown to induce apoptosis of
hematopoietic cell lines. Here we report that they induce apoptosis of both
nonactivated and phytohemagglutinin-activated human peripheral blood lymphocytes.
Apoptosis demonstrated by surface expression of phosphatidylserine and typical
nuclear alterations reached a maximum after 48 h of incubation with these agents.
In contrast to topoisomerase inhibitors (etoposide and camptothecin) and
antimetabolites (methotrexate and 5-fluorouracil) that induced apoptosis of
activated cells only, daunorubicin and doxorubicin triggered apoptosis of cells
in the G0-G1 phases of the cell cycle. In agreement with in vitro data, a single
i.p. injection of daunorubicin or doxorubicin in BALB/c mice induced T- and B
cell depletion in spleen, lymph nodes, and to a lesser extent in the thymus.
Soluble Fas-Fc, CD95 antagonistic antibodies, as well as the p55 tumor necrosis
factor receptor-immunoglobulin fusion protein, did not inhibit drug-induced
apoptosis. The level of reactive oxygen species was significantly increased in
the presence of daunorubicin or doxorubicin only in nonactivated lymphocytes.
However, antioxidants such as N-acetyl-L-cysteine or glutathione did not prevent
apoptosis. Activation of caspase-3 after daunorubicin or doxorubicin treatment of
either nonactivated or activated lymphocytes was demonstrated by the cleavage of
poly(ADP-ribose) polymerase, which was, as apoptosis, inhibited by the peptide
benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Finally, daunorubicin and
doxorubicin induced a rapid production of ceramides. These data indicate that
anthracyclines may induce major peripheral T-cell deletion, a property not shared
by many cytotoxic agents.
PMID- 10766179
TI - Lysis of MYCN-amplified neuroblastoma cells by MYCN peptide-specific cytotoxic T
lymphocytes.
AB - The effectiveness of cell-mediated immunotherapy for cancer can be limited by
loss-of-antigen mutations that occur during tumor growth. In neuroblastoma,
amplification of the MYCN oncogene correlates with rapid tumor progression and a
poor prognosis overall. We propose that the MYCN protein, the high-level
expression of which is required for maintenance of the malignant phenotype, would
be an ideal target for vaccine therapy. The MYCN-derived S9K peptide (amino acids
7-15; STMPGMICK), which contains an HLA-A1 binding motif, was used to generate
CTLs from the peripheral blood lymphocytes of an HLA-A1+ healthy donor and an HLA
A1+ patient with MYCN-amplified neuroblastoma These CTL lines specifically lysed
HLA-matched, MYCN-amplified neuroblastoma tumor cells. They did not lyse either
HLA-mismatched, MYCN-amplified, or matched/nonmatched, non-MYCN-amplified tumor
cells. The CTL activity was inhibited by a monoclonal antibody to a class I HLA
monomorphic determinant but not by one specific for HLA class II, consistent with
a class I-restricted mechanism of cytotoxicity. Antibodies to CD8, but not those
to CD4, also inhibited CTL activity, identifying CD8+ lymphocytes as the effector
cell population. These results show that MYCN-derived peptides can serve as tumor
specific antigens and suggest a rational approach to cell-mediated immunotherapy
for MYCN-amplified neuroblastoma.
PMID- 10766181
TI - The human antimouse immunoglobulin response and the anti-idiotypic network have
no influence on clinical outcome in patients with minimal residual colorectal
cancer treated with monoclonal antibody CO17-1A.
AB - Murine monoclonal antibodies (mAbs), when administered to patients, induce a
human antimouse immunoglobulin immune response, especially when multiple
infusions are required to obtain therapeutic efficacy. In a randomized Phase II
clinical study, 83 patients with colorectal carcinoma of stage Dukes C were
treated with the murine IgG2a mAb 17-1A (ab1) after curative surgery. The regimen
consisted of a single infusion of 500mg of 17-1A within 2 weeks after surgery,
followed by 100mg of mAbs four times every 4 weeks. Sera were taken every 2-3
weeks and screened for human antimouse antibodies (HAMA). HAMA were measured by a
capture ELISA and an indirect antihuman immunoglobulin ELISA for the analysis of
IgG and IgM isotypes. Anti-idiotypic antibodies (ab2) were detected by an
inhibition ELISA, and anti-anti-idiotypic antibodies (ab3), recognizing the
original antigen, were determined by flow cytometric analysis. About 20% of
patients failed to develop HAMA; in the other patients, antibody titers were
initially low after the first two infusions and reached their maximum only after
a fifth infusion at 18-20 weeks after surgery. An analysis that differentiated
between patients who developed recurrences and those who remained tumor-free did
not show any difference in antibody titers between the two groups, neither for
total HAMA nor for IgG, IgM, or ab2. The formation of ab3 was analyzed in eight
patients and proved to be negative in all of them. HAMA remained detectable up to
2 years after the last treatment. In patients who experienced adverse events
associated with therapy, HAMA titers tended to rise earlier; this difference,
however, was not statistically significant. Thus, neither a beneficial nor a
detrimental effect of HAMA formation could be determined for the clinical
response to antibody therapy.
PMID- 10766180
TI - Aberrant expression of photoreceptor-specific calcium-binding protein (recoverin)
in cancer cell lines.
AB - Cancer-associated retinopathy (CAR) is an ocular manifestation of a
paraneoplastic syndrome whereby immunological reactions to retinal antigens
aberrantly expressed in tumor cells lead to the degeneration of retinal
photoreceptor cells. In our previous study (H. Ohguro et al., Invest. Ophthalmol.
Vis. Sci., 40: 82-89, 1999), recoverin, a retina-specific calcium-binding
protein, and heat shock cognate protein 70 (hsc 70) were identified as
autoantigens recognized by sera from patients with CAR. Therefore, we suggested
that autoimmune reactions against both recoverin and hsc 70 might be involved in
the pathogenesis of CAR. To elucidate the initial step of the molecular pathology
of CAR, we examined the expression of recoverin and hsc 70 by reverse
transcription-PCR and Western blot using cell lines of several kinds of cancers,
including lung small cell carcinoma, lung adenocarcinoma, gastric cancer,
pancreatic cancer, breast cancer, uterine cervical cancer, endometrial cancer,
and leukemia. Recoverin was expressed in 21 of the 31 cancer cell lines. The
expression levels of hsc 70 were significantly higher in cancer cell lines than
in noncancerous cell lines. However, no difference in the expression levels of
hsc 70 was observed between recoverin-positive and -negative cell lines.
Immunofluorescence labeling by the affinity-purified recoverin antibody revealed
the immunoreactivity to recoverin as a granular pattern within the cancer cells.
Lung adenocarcinoma A549 cells, which did not express recoverin, exhibited a
significant reduction in cell proliferation upon transfection with human
recoverin cDNA. Taken together, our present data suggest that the retina-specific
calcium-binding protein recoverin is expressed in more than 50% of a variety of
cancer cells and may play a significant role in the cell proliferation of these
tumor cells.
PMID- 10766182
TI - Resistance to lysis by cytotoxic T cells: a dominant effect in metastatic mouse
prostate cancer cells.
AB - Better understanding of the immunology of prostate cancer is needed for the
development of new therapeutic approaches that can be used in conjunction with
current treatment methods. The present study was designed to compare the
immunological properties of a genetically matched pair of primary tumor- and
metastasis-derived prostate cancer cell lines generated from the mouse prostate
reconstitution (MPR) model. Only the primary prostate cancer cells were
immunogenic in that prior immunization with irradiated primary but not the
metastatic prostate cancer cells delayed the growth of subsequently injected live
cancer cells. The lack of immunogenicity of the metastatic cells was not
attributable to their inability to induce antitumor cytotoxic T cells. Both
primary and metastatic cells induced antitumor CTLs in syngeneic hosts, but
unlike the primary cells, the metastatic cells were resistant to CTL lysis.
Differential resistance to cytolysis in metastatic versus primary prostate cancer
cells was not attributable to the differential expression of molecules such as
transporter associated with antigen processing (TAP)-1, TAP-2, low molecular
weight protein of the proteasome complex (LMP)-2, and LMP-7 that contribute to
antigen presentation by class I MHC. IFN-gamma induced surface class I MHC
expression, as well as gene expression of TAP-1, TAP-2, LMP-2, and LMP-7 in the
metastatic cells, yet the cells remained resistant to cell lysis induced by CTLs.
Interestingly, although in comparison to the primary cells the metastatic cells
were resistant to cytolysis, both cell types were susceptible to DNA
fragmentation induced by CTLs. Cell fusion between primary and metastatic cancer
cells resulted in hybrids that also resisted the cytolytic activity of CTLs.
Therefore, there is a dominant factor(s) in the metastatic prostate cancer cells
that confers specific protection against CTL cytolysis in this model system.
PMID- 10766183
TI - Granulocyte macrophage colony-stimulating factor and interleukin 4 enhance the
number and antigen-presenting activity of circulating CD14+ and CD83+ cells in
cancer patients.
AB - Antigen-presenting cells (APCs) are essential for stimulating antigen-specific
immunity, including immunity against tumor cells. We hypothesized that systemic
administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and
interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells
in vitro, might enhance the number and antigen-presenting activity of CD14+ cells
in vivo. Patients with metastatic solid malignancies were treated with daily s.c.
injections of either GM-CSF alone (2.5 microg/kg/day) or GM-CSF in combination
with IL-4 (0.5-6.0 microg/kg/day) in a multicohort study. When given alone, GM
CSF increased the number of CD14+ cells but did not enhance the cells' expression
of APC markers or antigen-presenting activity. In contrast, combination therapy
with GM-CSF and IL-4 stimulated CD14+ cells to acquire several APC
characteristics including increased expression of HLA-DR and CD11c, decreased
CD14, increased endocytotic activity, and the ability to stimulate T cells in a
mixed leukocyte reaction. Combination therapy also induced a dose-dependent
increase in the number of CD14-/CD83+ cells with APC activity. Clinically
significant and sustained tumor regression was observed in one patient. Systemic
therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number
and function of APCs in patients with cancer.
PMID- 10766184
TI - VHL alterations in human clear cell renal cell carcinoma: association with
advanced tumor stage and a novel hot spot mutation.
AB - To elucidate the role of somatic alterations for renal cancer etiology and
prognosis, we analyzed 227 sporadic renal epithelial tumors for mutations and
hypermethylations in the von Hippel-Lindau tumor suppressor gene VHL. Tumors were
classified according to the recommendations of the Union Internationale Contre le
Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Somatic VHL
mutations were identified by PCR, single-strand conformation polymorphism
analysis, and sequencing, and hypermethylations were identified by restriction
enzyme digestion and Southern blotting. Frequencies of VHL alterations were
established, and an association with tumor type or tumor type and tumor stage was
evaluated. VHL mutations and hypermethylations were identified in 45% of clear
cell renal cell carcinomas (CCRCCs) and occasionally (3 of 28) in papillary
(chromophilic) renal cell carcinomas (RCCs). Lack of VHL mutations and
hypermethylations in chromophobe RCCs and oncocytomas was statistically
significant (P = 0.0001 and P = 0.0004, respectively). RCCs carrying VHL
alterations showed, in nine cases (12%), mutations at a hot spot involving a
thymine repeat (ATT.TTT) in exon 2. Tumor staging was critical to the VHL
mutation/hypermethylation detection rate in CCRCCs shown by separate evaluation
of patients from medical centers in Munich, Heidelberg, and Mainz. The spectrum
of pT1, pT2, and pT3 CCRCCs and the VHL mutation/hypermethylation detection rate
varied among these three groups. Altogether, VHL alterations were significantly
associated with pT3 CCRCCs (P = 0.009). This is the first evidence of frequent
somatic VHL mutations at a particular site within exon 2 and an association of
VHL mutations/hypermethylations with a standard prognostic factor.
PMID- 10766185
TI - High resolution chromosome 3p allelotyping of human lung cancer and
preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous
sites of 3p allele loss and three regions of frequent breakpoints.
AB - Allele loss involving chromosome arm 3p is one of the most frequent and earliest
known genetic events in lung cancer pathogenesis and may affect several potential
tumor suppressor gene regions. To further study the role of chromosome 3p allele
loss in the pathogenesis of lung cancer, we performed high resolution loss of
heterozygosity (LOH) studies on 97 lung cancer and 54 preneoplastic/preinvasive
microdissected respiratory epithelial samples using a panel of 28 3p markers.
Allelic losses of 3p were detected in 96% of the lung cancers and in 78% of the
preneoplastic/preinvasive lesions. The allele losses were often multiple and
discontinuous, with areas of LOH interspersed with areas of retention of
heterozygosity. Most small cell lung carcinomas (91%) and squamous cell
carcinomas (95%) demonstrated larger 3p segments of allele loss, whereas most
(71%) of the adenocarcinomas and preneoplastic/preinvasive lesions had smaller
chromosome areas of 3p allele loss. There was a progressive increase in the
frequency and size of 3p allele loss regions with increasing severity of
histopathological preneoplastic/preinvasive changes. In analyses of the specific
parental allele lost comparing 42 preneoplastic/preinvasive foci with those lost
in the lung cancer in the same patient (n = 10), the same parental allele was
lost in 88% of 244 comparisons for 28 3p markers (P = 1.2 x 10(-36) for this
occurring by chance). This indicates the occurrence of allele-specific loss in
these foci similar to that seen in the tumor by a currently unknown mechanism.
Analysis of all of the data indicated multiple regions of localized 3p allele
loss including telomere-D3S1597, D3S1111-D3S2432, D3S2432-D3S1537, D3S1537,
D3S1537-D3S1612, D3S4604/Luca19.1-D3S4622/Luca4.1, D3S4624/Luca2.1,
D3S4624/Luca2.1-D3S1582, D3S1766, D3S1234-D3S1300 (FHIT/FRA3B region centered on
D3S1300), D3S1284-D3S1577 (U2020/DUTT1 region centered on D3S1274), and D3S1511
centromere. A panel of six markers in the 600-kb 3p21.3 deletion region showed
loss in 77% of the lung cancers, 70% of normal or preneoplastic/preinvasive
lesions associated with lung cancer, and 49% of 47 normal, mildly abnormal, or
preneoplastic/preinvasive lesions found in smokers without lung cancer; however,
loss was seen in 0% of 18 epithelial samples from seven never smokers. The 600-kb
3p21.3 region and the 3p14.2 (FHIT/FRA3B) and 3p12 (U2020/DUTT1) regions were
common, independent sites of breakpoints (retention of heterozygosity by some
markers and LOH by other markers in the immediate region). We conclude that 3p
allele loss is nearly universal in lung cancer pathogenesis; involves multiple,
discrete, 3p LOH sites that often show a "discontinuous LOH" pattern in
individual tumors; occurs in preneoplastic/preinvasive lesions in smokers with
and without lung cancer (multiple lesions often lose the same parental allele);
frequently involves breakpoints in at least three very small defined genomic
regions; and appears to have allele loss and breakpoints first occurring in the
600-kb 3p21.3 region. These findings are consistent with previously reported LOH
studies in a variety of tumors showing allele loss occurring by mitotic
recombination and induced by oxidative damage.
PMID- 10766186
TI - LRP-DIT, a putative endocytic receptor gene, is frequently inactivated in non
small cell lung cancer cell lines.
AB - A variety of studies suggest that allelic losses at chromosome 2q are associated
with aggressive behavior of various forms of human neoplasia. Using a probe to
detect homozygous deletions on chromosome 2q21.2 in kidney and bladder cancer
cell lines, we identified a new candidate tumor suppressor gene, lipoprotein
receptor-related protein-deleted in tumors (LRP-DIT). The predicted LRP-DIT
product of 4599 amino acids has extensive homology to a gigantic receptor, LRP1,
which mediates endocytosis of multiple proteins from the cell surface. Homozygous
deletions in LRP-DIT were detected in 17% (4 of 23) of non-small cell lung cancer
(NSCLC) cell lines. The expression of only abnormal transcripts missing portions
of the LRP-DIT sequence was demonstrated in an additional 30% (11 of 36) of NSCLC
lines. Finally, a missense mutation at codon 3157 was detected in one of four
NSCLC lines tested for the large open reading frame. In contrast, no LRP-DIT
alterations were identified in a major fraction of SCLC cell lines, indicating
that this gene is preferentially inactivated in one histological type of lung
cancer. Our data suggest that inactivation of LRP-DIT occurs in at least 40% of
NSCLC lines and thus may play an important role in tumorigenesis of NSCLCs.
PMID- 10766187
TI - Gene amplifications characterize acral melanoma and permit the detection of
occult tumor cells in the surrounding skin.
AB - Acral melanoma (AM) is commonly distinguished from superficial spreading melanoma
(SSM), the most common type of melanoma, by its clinical presentation as well as
its ethnic distribution. However, justification for such a distinction is
controversial because of histological overlap and lack of prognostic
significance. We analyzed chromosomal aberrations of 15 AMs and 15 SSMs that were
comparable for tumor thickness and patient age, using comparative genomic
hybridization. All AMs had at least one (mean, 2.0) gene amplification,
significantly more than the SSMs, in which only 2 of 15 (13%) had one
amplification each (P < 0.0001). At least 15 different genomic regions were
amplified in AM. These involved small portions of chromosomal arms, sometimes
including known oncogenes implicated in melanoma. The most frequently amplified
regions in AMs occurred at 11q13 (47%), 22q11-13 (40%), and 5p15 (20%).
Comparison of the amplification levels of invasive and noninvasive portions of
the tumors using fluorescence in situ hybridization suggested that amplifications
occurred before the formation of the invasive portion. The finding of
amplifications of 11q13 in three of five additional cases of AM in situ further
supports the notion that amplifications arise early in the progression of AM.
Very significantly, we found isolated melanocytes with amplifications in the
epidermis up to 3 mm beyond the histologically recognizable extent of the
melanomas in 5 of 15 invasive AMs. In conclusion, our data show that AM is a
distinct type of melanoma characterized by focused gene amplifications occurring
early in tumorigenesis, and that malignant cells are present beyond the
histologically detectable boundary, thereby revealing one mechanism of local
recurrence.
PMID- 10766188
TI - Mutations in the XPC gene in families with xeroderma pigmentosum and consequences
at the cell, protein, and transcript levels.
AB - Xeroderma pigmentosum (XP)-C is one of the more common complementation groups of
XP, but causative mutations have thus far been reported for only six cases (S. G.
Khan et al., J. Investig. Dermatol., 115: 791-796, 1998; L. Li et al., Nat.
Genet., 5: 413-417, 1993). We have now extended this analysis by investigating
the genomic and coding sequence of the XPC gene, the level of expression of the
XPC transcript and the status of the XPC protein in 12 unrelated patients,
including all of the 8 Italian XP-C cases identified thus far and in 13 of their
parents. Eighteen mutations were detected in the open reading frame of the XPC
gene, 13 of which are relevant for the pathological phenotype. The mutations are
distributed across the gene, with no indication of any hotspots or founder
effects. Only 1 of the 13 relevant changes is a missense mutation, the remainder
causing protein truncations as a result of nonsense mutations (3), frameshifts
(6), deletion (1) or splicing abnormalities (2). These findings indicate that the
XPC gene is not essential for cell proliferation and viability and that mutations
causing minor structural alterations may not give an XP phenotype and may not,
therefore, be identified clinically. XP13PV was the only patient carrying a
missense mutation (Trp690Ser on the paternal allele). This was also the only
patient in which the XPC transcript was present at a normal level and the XPC
protein was detectable, although at a lower than normal level. No quantitative
alterations in the transcript or protein levels were detected in the XP-C
heterozygous parents. However, the expression of the normal allele predominated
in all of them, except the father of XP13PV, which suggests the existence of a
possible mechanism for monitoring the amount of the XPC protein.
PMID- 10766189
TI - Molecular determinants of apoptosis induced by the cytotoxic ribonuclease
onconase: evidence for cytotoxic mechanisms different from inhibition of protein
synthesis.
AB - Cytotoxic endoribonucleases (RNases) possess a potential for use in cancer
therapy. However, the molecular determinants of RNase-induced cell death are not
well understood. In this work, we identify such determinants of the cytotoxicity
induced by onconase, an amphibian cytotoxic RNase. Onconase displayed a
remarkable specificity for tRNA in vivo, leaving rRNA and mRNA apparently
undamaged. Onconase-treated cells displayed apoptosis-associated cell blebbing,
nuclear pyknosis and fragmentation (karyorrhexis), DNA fragmentation, and
activation of caspase-3-like activity. The cytotoxic action of onconase
correlated with inhibition of protein synthesis; however, we present evidence for
the existence of a mechanism of onconase-induced apoptosis that is independent of
inhibition of protein synthesis. The caspase inhibitor benzyloxycarbonyl-Val-Ala
Asp(OMe) fluoromethyl ketone (zVADfmk), at concentrations that completely prevent
apoptosis and caspase activation induced by ligation of the death receptor Fas,
had only a partial protective effect on onconase-induced cell death. The
proapoptotic activity of the p53 tumor suppressor protein and the Fas
ligand/Fas/Fas-associating protein with death domain (FADD)/caspase-8
proapoptotic cascade were not required for onconase-induced apoptosis.
Procaspases-9, -3, and -7 were processed in onconase-treated cells, suggesting
the involvement of the mitochondrial apoptotic machinery in onconase-induced
apoptosis. However, the onconase-induced activation of the caspase-9/caspase-3
cascade correlated with atypically little release of cytochrome c from
mitochondria. In turn, the low levels of cytochrome c released from mitochondria
correlated with a lack of detectable translocation of proapoptotic Bax from the
cytosol onto mitochondria in response to onconase. This suggests the possibility
of involvement of a different, potentially Bax- and cytochrome c-independent
mechanism of caspase-9 activation in onconase-treated cells. As one possible
mechanism, we demonstrate that procaspase-9 is released from mitochondria in
onconase-treated cells. A detailed understanding of the molecular determinants of
the cytotoxic action of onconase could provide means of positive or negative
therapeutic modulation of the activity of this potent anticancer agent.
PMID- 10766190
TI - Expression of metallothionein II in intestinal metaplasia, dysplasia, and gastric
cancer.
AB - Differential display is a valuable tool for the identification of differentially
expressed genes in human carcinogenesis and development. The search for
differentially expressed genes in gastric cancer and its premalignant lesions may
help to define molecular alterations in the gastric mucosa that may precede the
development of gastric cancer. Using the differential display technique, we
identified a cDNA fragment, encoding metallothionein (MT) IIa mRNA. We performed
immunohistochemical analysis using a monoclonal antibody directed against human
MT and tissues obtained from 34 patients with gastric cancer and 20 healthy
individuals to determine the expression and localization of MT in gastric cancer
and its associated premalignant lesions and to correlate our findings with
histomorphological features and Helicobacter pylori status. In addition, MT
expression was assessed in gastric tissues obtained from patients with gastric
cancer and first-degree relatives of patients with gastric cancers and healthy
individuals using reverse transcription-PCR analysis. Northern blot analysis
confirmed the overexpression of MT IIa in gastric cancer. In the normal gastric
tissues, no MT immunoreactivity was observed at the superficial gastric
epithelium toward the top of gastric glands. However, MT immunoreactivity was
detected at the foveolar neck of the gastric glands. Immunohistochemical analysis
revealed an intense MT immunoreactivity in gastric cancer cells, independent of
tumor stage, grade of differentiation, or tumor type. Furthermore, areas of
dysplasia and intestinal metaplasia also exhibited intense MT immunoreactivity.
Reverse transcription-PCR analysis of gastric biopsies obtained from first-degree
relatives of patients with gastric cancer revealed the frequent expression of MT
Ia in this high-risk group as compared with healthy subjects (P < 0.01). The
overexpression of MT in gastric cancer and the expression of MT in intestinal
metaplasia and dysplasia, as well as the expression of MT in the gastric mucosa
of first-degree relatives of patients with gastric cancer, point to a role for MT
in the early process of malignant transformation of the gastric mucosa.
PMID- 10766191
TI - Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that
DPC4 inactivation occurs late in neoplastic progression.
AB - Infiltrating adenocarcinomas of the pancreas are believed to arise from
histologically identifiable intraductal precursors [pancreatic intraepithelial
neoplasias (PanINs)] that undergo a series of architectural, cytological, and
genetic changes. The role of DPC4 tumor suppressor gene inactivation in this
progression has not been defined. Immunohistochemistry for the Dpc4 protein in
formalin-fixed, paraffin-embedded tissue is a sensitive and specific marker for
DPC4 gene status, providing a tool to examine DPC4 status in these putative
precursor lesions. A total of 188 PanINs were identified in 40 pancreata, 38
(95%) of which also contained an infiltrating adenocarcinoma. Sections containing
these 188 duct lesions were labeled with a monoclonal antibody to Dpc4. All 82
flat (PanIN-1A), all 54 papillary (PanIN-1B), and all 23 atypical papillary
(PanIN-2) intraductal lesions expressed Dpc4. In contrast, 9 of 29 (31%) severely
atypical lesions (PanIN-3 lesions, carcinomas in situ) did not. The difference in
Dpc4 expression between histologically low-grade (PanIN-1 and -2) and
histologically high-grade (PanIN-3) duct lesions was statistically significant (P
< 0.0001). In three cases, the pattern of Dpc4 expression in the PanIN-3 lesions
did not match the pattern of expression in the associated infiltrating
carcinomas, indicating that these high-grade lesions did not simply represent
infiltrating carcinoma growing along benign ducts. Loss of Dpc4 expression occurs
biologically late in the neoplastic progression that leads to the development of
infiltrating pancreatic cancer, at the stage of histologically recognizable
carcinoma.
PMID- 10766192
TI - Insulin-like growth factor-I protects colon cancer cells from death factor
induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen
activated protein kinase and nuclear factor kappaB signaling pathways.
AB - Resistance of cancer cells against apoptosis induced by death factors contributes
to the limited efficiency of immune- and drug-induced destruction of tumors. We
report here that insulin and insulin-like growth factor-I (IGF-I) fully protect
HT29-D4 colon carcinoma cells from IFN-gamma/tumor necrosis factor-alpha (TNF)
induced apoptosis. Survival signaling initiated by IGF-I was not dependent on the
canonical survival pathway involving phosphatidylinositol 3'-kinase. In addition,
neither pp70(S6K) nor protein kinase C conveyed IGF-I antiapoptotic function.
Inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal
regulated kinase (ERK) with the MAPK/ERK kinase inhibitor PD098059 and MAPK/p38
with the specific inhibitor SB203580 partially reversed, in a nonadditive manner,
the IGF-I survival effect. Inhibition of nuclear factor kappaB (NF-kappaB)
activity by preventing degradation of the inhibitor of NF-kappaB (IkappaB-alpha)
with BAY 11-7082 also blocked in part the IGF-I antiapoptotic effect. However,
the complete reversal of the IGF-I effect was obtained only when NF-kappaB and
either MAPK/ERK or MAPK/p38 were inhibited together. Because these pathways are
also those used by TNF to signal inflammation and survival, these data point to a
cross talk between IGF-I- and TNF-induced signaling. We further report that TNF
induced IL-8 production was indeed strongly enhanced upon IGF-I addition, and
this effect was totally abrogated by both MAPK and NF-kappaB inhibitors. The IGF
I antiapoptotic function was stimulus-dependent because Fas- and IFN/Fas-induced
apoptosis was not efficiently inhibited by IGF-I. This was correlated with the
weak ability of Fas ligation to enhance IL-8 production in the presence or
absence of IGF-I. These findings indicate that the antiapoptotic function of IGF
I in HT29-D4 cells is based on the enhancement of the survival pathways initiated
by TNF, but not Fas, and mediated by MAPK/p38, MAPK/ERK, and NF-kappaB, which act
in concert to suppress the proapoptotic signals. In agreement with this model, we
show that it was possible to render HT29-D4 cells resistant to Fas-induced
apoptosis provided that IGF-I and TNF receptors were activated simultaneously.
PMID- 10766193
TI - Detection of hypoxia in human squamous cell carcinoma by EF5 binding.
AB - Localization and quantitation of 2-nitroimidazole drug binding in low pO2 tumors
is a technique that can allow the assessment of hypoxia as a predictive assay.
EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] is
such a drug, and it has been shown to be predictive of radiation response in
rodent tumors. Using fluorescence immunohistochemical techniques, we provide data
on the presence, distribution, and levels of EF5 binding as a surrogate for
hypoxia in human head and neck and uterine cervix squamous cell cancers (SCCs).
Six patients with SCC were studied. Four patients had head and neck tumors, and
two had uterine cervix cancers. The incubation of fresh tissue cubes in EF3 under
hypoxic conditions ("reference binding") demonstrated that all tumors were
capable of binding drug, and that this binding varied by a factor of 2.9-fold
(174.5-516.1) on an absolute fluorescence scale. In the five patients treated at
the lowest drug doses (9 mg/kg), in situ binding was quantitatable. For all six
patients, the maximum rate of in situ binding varied by a factor of 6.7 between
the lowest and highest binding tumor (24.8-160.3) on an absolute fluorescence
scale. In tumors with high binding regions, intratumoral heterogeneity was large,
extending from minimal fluorescence (<1%) up to 88.6% of reference binding. In
tumors with minimal binding, there was little intratumoral heterogeneity. These
studies demonstrate substantial heterogeneity of in situ binding between and
within individual squamous cell tumors.
PMID- 10766194
TI - S-phase arrest and apoptosis induced in normal mammary epithelial cells by a
novel retinoid.
AB - The addition of all-trans-retinoic acid has been found to mediate a G1 cell cycle
phase arrest but not apoptosis in normal mammary epithelial cells. We have now
found that addition of the novel retinoid 6-[3-(1-adamantyl)]-4-hydroxyphenyl]-2
naphthalene carboxylic acid (CD437), which appears to function through a pathway
independent of retinoic acid nuclear receptors, results in an S-phase arrest that
is preceded by a 4-fold elevation in the levels of the cyclin-cyclin dependent
kinase (cdk) inhibitor p21WAF1/CIP1. Failure to inhibit E2F-1 activation of genes
through its phosphorylation by the cyclin cdk2 kinase has been shown to result in
S-phase arrest and apoptosis in a number of cell types. Although exposure of the
normal mammary cells to CD437 does not result in modulation of cyclin A or cdk2
levels, an increase in E2F-1 levels and a marked inhibition of cyclin A/cdk2
kinase activity are observed. Exposure to CD437 results in enhanced E2F-1 binding
to its DNA consensus sequences and transcriptional activity during S phase. We
hypothesize that this enhanced E2F-1 transcriptional activity results in S-phase
arrest and subsequent apoptosis that has been observed in other systems.
PMID- 10766195
TI - Fibrinogen assembly, secretion, and deposition into extracellular matrix by MCF-7
human breast carcinoma cells.
AB - A hallmark of breast carcinoma is the deposition of fibrinogen (FBG) without
subsequent conversion to fibrin in the tumor stroma. In this study, the ability
of the MCF-7 human breast cancer epithelial cell line to synthesize, secrete, and
deposit FBG into the extracellular matrix (ECM) was examined. Whereas MCF-7 cells
produced low levels of intact FBG, abundant levels of FBG intermediate complexes
or degraded Aalpha, Bbeta, and gamma chain polypeptides were observed. Most of
the Bbeta chain was degraded and missing an NH2-terminal peptide fragment.
Reverse transcription-PCR analysis indicated that only gamma chain mRNA was
present in detectable steady-state levels, although Southern hybridization
revealed that the FBG Aalpha, Bbeta, and gamma chain genes were intact in MCF-7
cells. Immunostaining showed that extracellular FBG was bound to the surface of
MCF-7 cells in a punctate pattern, reminiscent of receptor binding, rather than a
fibrillar pattern characteristic of mature ECM. A similar punctate pattern of
staining was observed when MCF-7 FBG was added to fibroblasts that normally
assemble exogenous FBG into an extensive, fibrillar ECM, suggesting that MCF-7
cells are defective in assembly of a fibrillar ECM. The loss of FBG Bbeta chain
NH2-terminal peptides may contribute to the lack of intact FBG assembly in MCF-7
cells, which may further affect its ability to assemble FBG into a fibrillar ECM.
Taken together, the data suggest that endogenous synthesis and secretion of FBG
is, at least in part, the source of FBG deposition in the ECM of breast cell
carcinomas.
PMID- 10766196
TI - 1,25-Dihydroxyvitamin D3 and all-trans-retinoic acid sensitize breast cancer
cells to chemotherapy-induced cell death.
AB - We investigated the capacity of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and all
trans-retinoic acid (ATRA) to sensitize three breast cancer cell lines to the
cell killing effects of paclitaxel (Taxol) and Adriamycin, two chemotherapeutic
agents commonly used in the treatment of breast cancer. In tissue culture colony
assays, 1,25(OH)2D3 and ATRA were synergistic in inhibiting the clonogenicity of
MCF-7 and T-47D cells that expressed estrogen receptor; vitamin D receptor;
retinoic acid receptors (RARs) alpha, beta, and gamma; and retinoid X receptors
alpha, beta, and gamma but were not additive in MDA-MB-231 cells that lacked
expression of estrogen receptor, RARalpha, and RARbeta. The hormones used
individually or in combination induced up to 40-50% cell death by a trypan blue
exclusion assay in a dose-dependent manner up to concentrations of 10(-7) M in
MCF-7 and T-47D cells, more modestly in MDA-MB-231 cells, and not at all in MCF
10 and MCF-12 nontransformed mammary epithelial cells. Pretreating the cancer
cell lines with 1,25(OH)2D3 and ATRA individually or in combination for 3 days
prior to a 1-h incubation with paclitaxel or Adriamycin decreased the ED50 for
inhibition of colony formation or for cell death by trypan blue by up to 2 logs
for paclitaxel and up to 1 log for Adriamycin in all three cell lines but had no
effect on chemotherapy-induced MCF-12 cell death. The effects of the hormones
were synergistic with those of the chemotherapy agents in all of the breast
cancer cell lines, generally at the higher concentrations. Cell death took place
by apoptosis. To determine one potential reason for the greater potentiation of
the effects of paclitaxel than those of Adriamycin, we determined the effects of
preincubation of MCF-7 cells on paclitaxel-induced phosphorylation of Bcl-2.
Pretreatment of MCF-7 cells with either 1,25(OH)2D3 or ATRA increased the
phosphorylation of Bcl-2 by variable concentrations of paclitaxel. These data
suggest that pretreatment of breast cancer with 1,25(OH)2D3 or ATRA lowers the
threshold for cell killing by chemotherapy agents and may provide a novel
treatment option for this disease.
PMID- 10766198
TI - Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in
vivo.
AB - Glucocorticoid resistance was investigated in human leukemic CCRF-CEM cells. A
mutation (L753F), which renders the human glucocorticoid receptor (hGR) gene
functionally hemizygous, was identified in all CEM-derived cell lines analyzed.
Allele-specific PCR identified the same mutation in lymph node biopsy material
from patient CEM cells. Given the correlation between hGR concentration and
glucocorticoid sensitivity, this suggests that loss of functional heterozygosity
may result in resistance to glucocorticoid-based chemotherapy. The L753F mutation
was probably not responsible for the ontogeny of the disease because it did not
appear to be present in all leukemic cells. Thus, it is unlikely that hGR
mutations would be detected in leukemic patients at presentation, but they may
occur, and be selected for, during treatment. Deletions and point mutations in
the hGR gene of cells selected for steroid resistance in vitro were investigated
by PCR-single strand conformation polymorphism analysis. Loss of hGR mRNA
expression resulted from 5'-deletion of the hGR gene and nonsense mutations in
exon 6. These results provide the first evidence for somatic mutation in the hGR
gene of a patient with acute lymphoblastic leukemia, offer a potential in vivo
mechanism for acquisition of steroid resistance in leukemia, and suggest that
screening for additional in vivo mutations will require analysis of genomic DNA.
PMID- 10766197
TI - BCR-ABL tyrosine kinase activity regulates the expression of multiple genes
implicated in the pathogenesis of chronic myeloid leukemia.
AB - The BCR-ABL chimeric protein is thought to play a central role in the
pathogenesis of Philadelphia (Ph) chromosome-positive leukemias, notably chronic
myeloid leukemia (CML). There is compelling evidence that malignant
transformation by BCR-ABL is critically dependent on its protein tyrosine kinase
(PTK) activity. As a result, multiple signaling pathways are activated in a
kinase-dependent manner, and thus the activation of such pathways may affect the
expression of genes that confer the malignant phenotype. In this study, we used
differential display to investigate the alterations of gene expression in BV173,
a CML cell line derived from lymphoid blast crisis, after exposure to ST1571,
which selectively inhibits ABL PTK activity. We show that the expression of a set
of 12 genes is correlated with the kinase activity and that the profile of these
genes reflects mechanisms implicated in the pathogenesis of CML. Several of the
genes show a consistent pattern of altered regulation in all Ph-positive lymphoid
cell lines, whereas others appear to be unique to BV173 cells. We conclude that
BCR-ABL PTK activity drives the expression of specific target genes that
contribute to the malignant transformation of Ph-positive cells. The
identification of downstream molecules with a consistent regulation pattern may
provide suitable targets for therapeutic intervention in the future.
PMID- 10766199
TI - Don't blame NASA alone for Mars mission failures
PMID- 10766200
TI - Complaints grow over delays in UK animal licence processing.
PMID- 10766201
TI - Global warming could be bad news for Arctic ozone layer
PMID- 10766202
TI - Japan squares up to conservationists over grey whale's status.
PMID- 10766203
TI - US court tests the breadth of patent protection on proteins.
PMID- 10766205
TI - Reshuffle lifts French synchrotron hopes
PMID- 10766204
TI - Baja peninsula claims five victims in tragic accident
PMID- 10766206
TI - Cereal gene bank accepts need for patents...
PMID- 10766207
TI - NASA pays the price of its dash for Mars
PMID- 10766208
TI - Royal society delays conference on origins of HIV.
PMID- 10766209
TI - South African government tight-lipped over AIDS.
PMID- 10766210
TI - Whatever happened to leptin?
PMID- 10766212
TI - Fooled, but not foolish.
PMID- 10766211
TI - Assessment mismatches must be sorted out: they leave species at risk.
PMID- 10766213
TI - How much use is the Human Genome Project?
PMID- 10766214
TI - Genes: we can't expect full understanding yet.
PMID- 10766216
TI - Learn lateral thinking first and specialize later
PMID- 10766215
TI - Garlic study vindicated by official investigation.
PMID- 10766217
TI - Religion has its place but don't pretend it's science.
PMID- 10766218
TI - Abstraction and idealism.
PMID- 10766219
TI - The new laureate speaks.
PMID- 10766220
TI - When Greenland ice melts
PMID- 10766221
TI - The good taste of genomics.
PMID- 10766223
TI - A new spin on magnets
PMID- 10766222
TI - Bacterial cheaters.
PMID- 10766224
TI - Dendrites go up, axons go down.
PMID- 10766225
TI - British birds by number.
PMID- 10766227
TI - George Ledyard Stebbins (1906-2000).
PMID- 10766226
TI - Cell cycle. A new check on issuing the licence.
PMID- 10766228
TI - Payment for labour in monkeys.
PMID- 10766229
TI - Sex and the single lichen.
PMID- 10766230
TI - Non-haemolytic beta-amino-acid oligomers.
PMID- 10766231
TI - Stomach rinsing in rays.
PMID- 10766232
TI - Semaphorin 3A is a chemoattractant for cortical apical dendrites.
AB - The apical dendrites of pyramidal neurons integrate inputs from various cortical
layers and are central to information processing. Here we show that the growth of
apical dendrites towards the pial surface is regulated by a diffusible
chemoattractant present at high levels near the marginal zone. A major component
of this signal is semaphorin 3A (Sema3A), which was previously characterized as a
chemorepellant for cortical axons. Soluble guanylate cyclase is asymmetrically
localized to the developing apical dendrite, and is required for the
chemoattractive effect of Sema3A. Thus the asymmetric localization of soluble
guanylate cyclase confers distinct Sema3A responses to axons and dendrites. These
observations reveal a mechanism by which a single chemotropic signal can pattern
both axons and dendrites during development.
PMID- 10766233
TI - Identification of comet Hyakutake's extremely long ion tail from magnetic field
signatures
AB - Observations of the varying orientations of comet tails led to the suggestion of
the existence of the solar wind--a continuous outflow of ionized material from
the Sun. It is now well established that gas from comets is ionized by several
processes and joins the solar wind, forming an ion (plasma) tail that points away
from the Sun. The plasma environments of three comets have been measured in situ,
but only in the upstream direction or less than 8,000 km downstream of the
nucleus. Here we report a fortuitous crossing by a spacecraft of the plasma tail
of comet Hyakutake (C/1996 B2), at a distance of more than 3.8 astronomical units
(550 million kilometres) from its nucleus. This surpasses the tail length of 2 AU
determined for the Great March Comet of 1843 (C/1843 D1). Our measurements reveal
that, at this distance, the tail of comet Hyakutake was a structured entity at
least 7 million kilometres in diameter.
PMID- 10766234
TI - Interception of comet Hyakutake's ion tail at a distance of 500 million
kilometres
AB - Remote sensing observations and the direct sampling of material from a few comets
have established the characteristic composition of cometary gas. This gas is
ionized by solar ultraviolet radiation and the solar wind to form 'pick-up' ions,
ions in a low ionization state that retain the same compositional signatures as
the original gas. The pick-up ions are carried outward by the solar wind, and
they could in principle be detected far from the coma (Sampling of pick-up ions
has also been used to study interplanetary dust, Venus' tail and the interstellar
medium.) Here we report the serendipitous detection of cometary pick-up ions,
most probably associated with the tail of comet Hyakutake, at a distance of 3.4
AU from the nucleus. Previous observations have provided a wealth of physical and
chemical information about a small sample of comets, but this detection suggests
that remote sampling of comet compositions, and the discovery of otherwise
invisible comets, may be possible.
PMID- 10766235
TI - A scalable quantum computer with ions in an array of microtraps
AB - Quantum computers require the storage of quantum information in a set of two
level systems (called qubits), the processing of this information using quantum
gates and a means of final readout. So far, only a few systems have been
identified as potentially viable quantum computer models--accurate quantum
control of the coherent evolution is required in order to realize gate
operations, while at the same time decoherence must be avoided. Examples include
quantum optical systems (such as those utilizing trapped ions or neutral atoms,
cavity quantum electrodynamics and nuclear magnetic resonance) and solid state
systems (using nuclear spins, quantum dots and Josephson junctions). The most
advanced candidates are the quantum optical and nuclear magnetic resonance
systems, and we expect that they will allow quantum computing with about ten
qubits within the next few years. This is still far from the numbers required for
useful applications: for example, the factorization of a 200-digit number
requires about 3,500 qubits, rising to 100,000 if error correction is
implemented. Scalability of proposed quantum computer architectures to many
qubits is thus of central importance. Here we propose a model for an ion trap
quantum computer that combines scalability (a feature usually associated with
solid state proposals) with the advantages of quantum optical systems (in
particular, quantum control and long decoherence times).
PMID- 10766236
TI - Magnetoresistance from quantum interference effects in ferromagnets
AB - The desire to maximize the sensitivity of read/write heads (and thus the
information density) of magnetic storage devices has stimulated interest in the
discovery and design of new magnetic materials exhibiting magnetoresistance.
Recent discoveries include the 'colossal' magnetoresistance in the manganites and
the enhanced magnetoresistance in low-carrier-density ferromagnets. An important
feature of these systems is that the electrons involved in electrical conduction
are different from those responsible for the magnetism. The latter are localized
and act as scattering sites for the mobile electrons, and it is the field tuning
of the scattering strength that ultimately gives rise to the observed
magnetoresistance. Here we argue that magnetoresistance can arise by a different
mechanism in certain ferromagnets--quantum interference effects rather than
simple scattering. The ferromagnets in question are disordered, low-carrier
density magnets where the same electrons are responsible for both the magnetic
properties and electrical conduction. The resulting magnetoresistance is positive
(that is, the resistance increases in response to an applied magnetic field) and
only weakly temperature-dependent below the Curie point.
PMID- 10766237
TI - Communication at millimetre-submillimetre wavelengths using a ceramic ribbon
AB - Following the discovery by Kao and Hockman that ultra-low-loss optical fibres
could be made from pure silica through the elimination of impurities, the ability
to guide signals effectively at optical wavelengths has been assured. But there
remains an important region of the spectrum--from 30 to 3,000 GHz (the millimetre
submillimetre band)--where low-loss waveguides are unknown. The main problem here
in finding low-loss solids is no longer one of eliminating impurities, but is due
to the presence of intrinsic vibration absorption bands. And the use of highly
conducting materials is also precluded owing to high skin-depth losses in this
part of the spectrum. Here we show that a combination of material and waveguide
geometry can circumvent these difficulties. We adopt a ribbon-like structure with
an aspect ratio of 10:1, fabricated from ceramic alumina (Coors' 998 Alumina),
and the resulting waveguide has an attenuation factor of less than 10 dB km(-1)
in the millimetre-submillimetre band. This attenuation is more than 100 times
smaller than that of a typical ceramic (or other dielectric) circular rod
waveguide and is sufficient for immediate application.
PMID- 10766238
TI - Functional hydrogel structures for autonomous flow control inside microfluidic
channels
AB - Hydrogels have been developed to respond to a wide variety of stimuli, but their
use in macroscopic systems has been hindered by slow response times (diffusion
being the rate-limiting factor governing the swelling process). However, there
are many natural examples of chemically driven actuation that rely on short
diffusion paths to produce a rapid response. It is therefore expected that
scaling down hydrogel objects to the micrometre scale should greatly improve
response times. At these scales, stimuli-responsive hydrogels could enhance the
capabilities of microfluidic systems by allowing self-regulated flow control.
Here we report the fabrication of active hydrogel components inside microchannels
via direct photopatterning of a liquid phase. Our approach greatly simplifies
system construction and assembly as the functional components are fabricated in
situ, and the stimuli-responsive hydrogel components perform both sensing and
actuation functions. We demonstrate significantly improved response times (less
than 10 seconds) in hydrogel valves capable of autonomous control of local flow.
PMID- 10766239
TI - Substantial contribution to sea-level rise during the last interglacial from the
Greenland ice sheet
AB - During the last interglacial period (the Eemian), global sea level was at least
three metres, and probably more than five metres, higher than at present.
Complete melting of either the West Antarctic ice sheet or the Greenland ice
sheet would today raise sea levels by 6-7 metres. But the high sea levels during
the last interglacial period have been proposed to result mainly from
disintegration of the West Antarctic ice sheet, with model studies attributing
only 1-2 m of sea-level rise to meltwater from Greenland. This result was
considered consistent with ice core evidence, although earlier work had suggested
a much reduced Greenland ice sheet during the last interglacial period. Here we
reconsider the Eemian evolution of the Greenland ice sheet by combining numerical
modelling with insights obtained from recent central Greenland ice-core analyses.
Our results suggest that the Greenland ice sheet was considerably smaller and
steeper during the Eemian, and plausibly contributed 4-5.5 m to the sea-level
highstand during that period. We conclude that the high sea level during the last
interglacial period most probably included a large contribution from Greenland
meltwater and therefore should not be interpreted as evidence for a significant
reduction of the West Antarctic ice sheet.
PMID- 10766240
TI - Rapid and early export of Phaeocystis antarctica blooms in the Ross Sea,
Antarctica.
AB - The Southern Ocean is very important for the potential sequestration of carbon
dioxide in the oceans and is expected to be vulnerable to changes in carbon
export forced by anthropogenic climate warming. Annual phytoplankton blooms in
seasonal ice zones are highly productive and are thought to contribute
significantly to pCO2 drawdown in the Southern Ocean. Diatoms are assumed to be
the most important phytoplankton class with respect to export production in the
Southern Ocean; however, the colonial prymnesiophyte Phaeocystis antarctica
regularly forms huge blooms in seasonal ice zones and coastal Antarctic waters.
There is little evidence regarding the fate of carbon produced by P. antarctica
in the Southern Ocean, although remineralization in the upper water column has
been proposed to be the main pathway in polar waters. Here we present evidence
for early and rapid carbon export from P. antarctica blooms to deep water and
sediments in the Ross Sea. Carbon sequestration from P. antarctica blooms may
influence the carbon cycle in the Southern Ocean, especially if projected
climatic changes lead to an alteration in the structure of the phytoplankton
community.
PMID- 10766241
TI - Developmental cheating in the social bacterium Myxococcus xanthus.
AB - Cheating is a potential problem in any social system that depends on cooperation
and in which actions that benefit a group are costly to individuals that perform
them. Genetic mutants that fail to perform a group-beneficial function but that
reap the benefits of belonging to the group should have a within-group selective
advantage, provided that the mutants are not too common. Here we show that social
cheating exists even among prokaryotes. The bacterium Myxococcus xanthus exhibits
several social behaviours, including aggregation of cells into spore-producing
fruiting bodies during starvation. We examined a number of M. xanthus genotypes
that were defective for fruiting-body development, including several lines that
evolved for 1,000 generations under asocial conditions and others carrying
defined mutations in developmental pathways, to determine whether they behaved as
cheaters when mixed with their developmentally proficient progenitor. Clones from
several evolved lines and two defined mutants exhibited cheating during
development, being overrepresented among resulting spores relative to their
initial frequency in the mixture. The ease of finding anti-social behaviours
suggests that cheaters may be common in natural populations of M. xanthus.
PMID- 10766242
TI - A family of candidate taste receptors in human and mouse.
AB - The gustatory system of mammals can sense four basic taste qualities, bitter,
sweet, salty and sour, as well as umami, the taste of glutamate. Previous studies
suggested that the detection of bitter and sweet tastants by taste receptor cells
in the mouth is likely to involve G-protein-coupled receptors. Although two
putative G-protein-coupled bitter/sweet taste receptors have been identified, the
chemical diversity of bitter and sweet compounds leads one to expect that there
is a larger number of different receptors. Here we report the identification of a
family of candidate taste receptors (the TRBs) that are members of the G-protein
coupled receptor superfamily and that are specifically expressed by taste
receptor cells. A cluster of genes encoding human TRBs is located adjacent to a
Prp gene locus, which in mouse is tightly linked to the SOA genetic locus that is
involved in detecting the bitter compound sucrose octaacetate. Another TRB gene
is found on a human contig assigned to chromosome 5p15, the location of a genetic
locus (PROP) that controls the detection of the bitter compound 6-n-propyl-2
thiouracil in humans.
PMID- 10766243
TI - High mobility of proteins in the mammalian cell nucleus.
AB - The mammalian cell nucleus contains numerous sub-compartments, which have been
implicated in essential processes such as transcription and splicing. The
mechanisms by which nuclear compartments are formed and maintained are unclear.
More fundamentally, it is not known how proteins move within the cell nucleus. We
have measured the kinetic properties of proteins in the nucleus of living cells
using photobleaching techniques. Here we show that proteins involved in diverse
nuclear processes move rapidly throughout the entire nucleus. Protein movement is
independent of energy, which indicates that proteins may use a passive mechanism
of movement. Proteins rapidly associate and dissociate with nuclear compartments.
Using kinetic modelling, we determined residence times and steady-state fluxes of
molecules in two main nuclear compartments. These data show that many nuclear
proteins roam the cell nucleus in vivo and that nuclear compartments are the
reflection of the steady-state association/dissociation of its 'residents' with
the nucleoplasmic space. Our observations have conceptual implications for
understanding nuclear architecture and how nuclear processes are organized in
vivo.
PMID- 10766244
TI - PAR3 is a cofactor for PAR4 activation by thrombin.
AB - Identification of the mechanisms by which the coagulation protease thrombin
activates platelets is critical for understanding haemostasis and thrombosis.
Thrombin activates cells at least in part by cleaving protease-activated G
protein-coupled receptors (PARs). PAR3 and PAR4 are thrombin receptors expressed
in mouse platelets. Inhibition of thrombin binding to mPAR3 (ref. 4) and knockout
of the mPAR3 gene inhibited mouse platelet activation at low but not high
concentrations of thrombin. Thus PAR3 is important for thrombin signalling in
mouse platelets. Expression of human PAR3 in heterologous expression systems
reliably resulted in responsiveness to thrombin. Curiously, despite its
importance for the activation of mouse platelets by thrombin, mouse PAR3 (mPAR3)
did not lead to thrombin signalling even when overexpressed. We now report that
mPAR3 and mPAR4 interact in a novel way: mPAR3 does not itself mediate
transmembrane signalling but instead functions as a cofactor for the cleavage and
activation of mPAR4 by thrombin. This establishes a paradigm for cofactor
assisted PAR activation and for a G-protein-coupled receptor's acting as an
accessory molecule to present ligand to another receptor.
PMID- 10766245
TI - ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.
AB - The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM
gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene,
share a variety of phenotypic abnormalities such as chromosomal instability,
radiation sensitivity and defects in cell-cycle checkpoints in response to
ionizing radiation. The ATM gene encodes a protein kinase that is activated by
ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein
complex that is involved in responses to DNA double-strand breaks. Here, because
of the similarities between AT and NBS, we evaluated the functional interactions
between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and
induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not
be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was
phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo
after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation
site abrogated an S-phase checkpoint induced by ionizing radiation in normal
cells and failed to compensate for this functional deficiency in NBS cells. These
observations link ATM and p95/nbs1 in a common signalling pathway and provide an
explanation for phenotypic similarities in these two diseases.
PMID- 10766246
TI - Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate
AP-1 activity.
AB - Integrin adhesion receptors transduce signals that control complex cell functions
which require the regulation of gene expression, such as proliferation,
differentiation and survival. Their intracellular domain has no catalytic
function, indicating that interaction with other transducing molecules is crucial
for integrin-mediated signalling. Here we have identified a protein that
interacts with the cytoplasmic domain of the beta2 subunit of the alphaL/beta2
integrin LFA-1. This protein is JAB1 (Jun activation domain-binding protein 1), a
coactivator of the c-Jun transcription factor. We found that JAB1 is present both
in the nucleus and in the cytoplasm of cells and that a fraction of JAB1
colocalizes with LFA-1 at the cell membrane. LFA-1 engagement is followed by an
increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun
containing AP-1 complexes to their DNA consensus site and increased
transactivation of an AP-1-dependent promoter. We suggest that signalling through
the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1
nuclear localization. This represents a new pathway for integrin-dependent
modulation of gene expression.
PMID- 10766247
TI - XCDT1 is required for the assembly of pre-replicative complexes in Xenopus
laevis.
AB - In eukaryotic cells, chromosomal DNA replication begins with the formation of pre
replication complexes at replication origins. Formation and maintenance of pre
replication complexes is dependent upon CDC6 (ref. 1), a protein which allows
assembly of MCM2-7 proteins, which are putative replicative helicases. The
functional assembly of MCM proteins into chromatin corresponds to replication
licensing. Removal of these proteins from chromatin in S phase is crucial in
origins firing regulation. We have identified a protein that is required for the
assembly of pre-replication complexes, in a screen for maternally expressed genes
in Xenopus. This factor (XCDT1) is a relative of fission yeast cdt1, a protein
proposed to function in DNA replication, and is the first to be identified in
vertebrates. Here we show, using Xenopus in vitro systems, that XCDT1 is required
for chromosomal DNA replication. XCDT1 associates with pre-replicative chromatin
in a manner dependent on ORC protein and is removed from chromatin at the time of
initiation of DNA synthesis. Immunodepletion and reconstitution experiments show
that XCDT1 is required to load MCM2-7 proteins onto pre-replicative chromatin.
These findings indicate that XCDT1 is an essential component of the system that
regulates origins firing during S phase.
PMID- 10766248
TI - The Cdt1 protein is required to license DNA for replication in fission yeast.
AB - To maintain genome stability in eukaryotic cells, DNA is licensed for replication
only after the cell has completed mitosis, ensuring that DNA synthesis (S phase)
occurs once every cell cycle. This licensing control is thought to require the
protein Cdc6 (Cdc18 in fission yeast) as a mediator for association of
minichromosome maintenance (MCM) proteins with chromatin. The control is
overridden in fission yeast by overexpressing Cdc18 (ref. 11) which leads to
continued DNA synthesis in the absence of mitosis. Other factors acting in this
control have been postulated and we have used a re-replication assay to identify
Cdt1 (ref. 14) as one such factor. Cdt1 cooperates with Cdc18 to promote DNA
replication, interacts with Cdc18, is located in the nucleus, and its
concentration peaks as cells finish mitosis and proceed to S phase. Both Cdc18
and Cdt1 are required to load the MCM protein Cdc21 onto chromatin at the end of
mitosis and this is necessary to initiate DNA replication. Genes related to Cdt1
have been found in Metazoa and plants (A. Whitaker, I. Roysman and T. Orr-Weaver,
personal communication), suggesting that the cooperation of Cdc6/Cdc18 with Cdt1
to load MCM proteins onto chromatin may be a generally conserved feature of DNA
licensing in eukaryotes.
PMID- 10766249
TI - Obesity in the new millennium.
AB - Obesity has increased at an alarming rate in recent years and is now a worldwide
public health problem. In addition to suffering poor health and an increased risk
of illnesses such as hypertension and heart disease, obese people are often
stigmatized socially. But major advances have now been made in identifying the
components of the homeostatic system that regulates body weight, including
several of the genes responsible for animal and human obesity. A key element of
the physiological system is the hormone leptin, which acts on nerve cells in the
brain (and elsewhere) to regulate food intake and body weight. The identification
of additional molecules that comprise this homeostatic system will provide
further insights into the molecular basis of obesity, and possibilities for new
treatments.
PMID- 10766250
TI - Obesity as a medical problem.
AB - Obesity is now so common within the world's population that it is beginning to
replace undernutrition and infectious diseases as the most significant
contributor to ill health. In particular, obesity is associated with diabetes
mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing
disorders. Obesity is defined by a body-mass index (weight divided by square of
the height) of 30 kg m(-2) or greater, but this does not take into account the
morbidity and mortality associated with more modest degrees of overweight, nor
the detrimental effect of intra-abdominal fat. The global epidemic of obesity
results from a combination of genetic susceptibility, increased availability of
high-energy foods and decreased requirement for physical activity in modern
society. Obesity should no longer be regarded simply as a cosmetic problem
affecting certain individuals, but an epidemic that threatens global well being.
PMID- 10766251
TI - Genetics of body-weight regulation.
AB - The role of genetics in obesity is twofold. Studying rare mutations in humans and
model organisms provides fundamental insight into a complex physiological
process, and complements population-based studies that seek to reveal primary
causes. Remarkable progress has been made on both fronts, and the pace of advance
is likely to accelerate as functional genomics and the human genome project
expand and mature. Approaches based on mendelian and quantitative genetics may
well converge, and lead ultimately to more rational and selective therapies.
PMID- 10766252
TI - Towards a molecular understanding of adaptive thermogenesis.
AB - Obesity results when energy intake exceeds energy expenditure. Naturally
occurring genetic mutations, as well as ablative lesions, have shown that the
brain regulates both aspects of energy balance and that abnormalities in energy
expenditure contribute to the development of obesity. Energy can be expended by
performing work or producing heat (thermogenesis). Adaptive thermogenesis, or the
regulated production of heat, is influenced by environmental temperature and
diet. Mitochondria, the organelles that convert food to carbon dioxide, water and
ATP, are fundamental in mediating effects on energy dissipation. Recently, there
have been significant advances in understanding the molecular regulation of
energy expenditure in mitochondria and the mechanisms of transcriptional control
of mitochondrial genes. Here we explore these developments in relation to
classical physiological views of adaptive thermogenesis.
PMID- 10766253
TI - Central nervous system control of food intake.
AB - New information regarding neuronal circuits that control food intake and their
hormonal regulation has extended our understanding of energy homeostasis, the
process whereby energy intake is matched to energy expenditure over time. The
profound obesity that results in rodents (and in the rare human case as well)
from mutation of key signalling molecules involved in this regulatory system
highlights its importance to human health. Although each new signalling pathway
discovered in the hypothalamus is a potential target for drug development in the
treatment of obesity, the growing number of such signalling molecules indicates
that food intake is controlled by a highly complex process. To better understand
how energy homeostasis can be achieved, we describe a model that delineates the
roles of individual hormonal and neuropeptide signalling pathways in the control
of food intake and the means by which obesity can arise from inherited or
acquired defects in their function.
PMID- 10766254
TI - Medicinal strategies in the treatment of obesity.
AB - When prevention fails, medicinal treatment of obesity may become a necessity. Any
strategic medicinal development must recognize that obesity is a chronic,
stigmatized and costly disease that is increasing in prevalence. Because obesity
can rarely be cured, treatment strategies are effective only as long as they are
used, and combined therapy may be more effective than monotherapy. For a drug to
have significant impact on body weight it must ultimately reduce energy intake,
increase energy expenditure, or both. Currently approved drugs for long-term
treatment of obesity include sibutramine, which inhibits food intake, and
orlistat, which blocks fat digestion.
PMID- 10766255
TI - Next-generation biologists must straddle computation and biology.
PMID- 10766256
TI - Companies of all sizes are prospecting for proteins.
PMID- 10766257
TI - United States gives priority to skills shortage.
PMID- 10766258
TI - Europe seeks solution to bioinformatics shortfall.
PMID- 10766259
TI - Resident macrophages activated by lipopolysaccharide suppress muscle tension and
initiate inflammatory response in the gastrointestinal muscle layer.
AB - A great number of macrophages is found to be evenly distributed in the muscle
layer of the gastrointestinal tract. We investigated their effects on smooth
muscle contraction and the initiation of immune reactions such as inflammatory
responses. Macrophages were demonstrated by the uptake of FITC-dextran and their
ultrastructural features were elucidated by electron microscopy. Muscle layers of
rats' ilea were incubated with lipopolysaccharide (LPS) for 4-8 h and the force
of smooth muscle contraction was measured. The induction effect of inducible
nitric oxide synthase (iNOS) on macrophages was then checked by
immunohistochemistry. The expression of major histocompatibility complex (MHC)
class II was also examined. Macrophages in the muscle layer were confirmed as
resident macrophages and were different from a population of dendritic cells.
After incubation with LPS, macrophages began to express iNOS and produced NO, and
it reduced smooth muscle contraction. iNOS-immunopositive cells increased in a
time-dependent manner. Macrophages also began to express MHC class II. The total
number of macrophages did not alter after incubation. Results indicate that
resident macrophages in the muscle layer induced iNOS as an inflammatory
reaction, affected smooth muscle contraction, and initiated immune response in
the smooth muscle layer of the gastrointestinal tract, when activated by LPS.
PMID- 10766260
TI - Adenylyl cyclase isoform expression in non-diabetic and diabetic Goto-Kakizaki
(GK) rat pancreas. Evidence for distinct overexpression of type-8 adenylyl
cyclase in diabetic GK rat islets.
AB - Glucose-induced insulin release is markedly decreased in the spontaneously
diabetic Goto-Kakizaki (GK) rat pancreas. This defect was recently shown to be
reversed by forskolin which markedly enhances cAMP generation in GK islets. These
effects of forskolin were associated with overexpression of type-3 adenylyl
cyclase (AC) mRNA due to the presence of two functional point mutations in the
promoter region of AC3 gene in GK rat. Nine AC isoforms have been described, but
their expression pattern in relation to the main pancreatic islet cell types, as
well as their involvement in the diabetic state, is still unknown. Using
antibodies raised against AC1-8, we have studied by double immunofluorescence the
localisation of these AC isoforms in different endocrine cell types in both
normal and diabetic GK rat pancreas. Our results demonstrated a clear
immunoreaction (IR) to AC1-4 and 6 in normal and GK islet beta-cells, while a
smaller number of ACs were expressed in alpha- and delta-cells. No AC-IR was
observed in pancreatic polypeptide cells. Moreover, we have found an increased IR
of the Ca2+-stimulated ACl, AC3 and AC8 in diabetic beta- and alpha-cells,
compared with the corresponding IR in control pancreas. Most noticeable was the
eliciting of a markedly enhanced AC8-IR in GK rat beta- and alpha-cells, in
contrast to a barely discernible AC8-IR in corresponding normal cells. In
conclusion, AC expression exhibits a complex pattern in the endocrine pancreas,
with specific differences between the normal and diabetic state.
PMID- 10766261
TI - Coexistence of gland mucous cell-type mucin and lysozyme in gastric gland mucous
cells.
AB - Class III mucin, identified by paradoxical concanavalin A staining, is confined
to gastric gland mucous cells and is an essential component of the gastric
surface mucous gel layer. The pretreatment required has hampered the application
of this method to electron microscopic studies. Antibody HIK1083 reacts
selectively with class III mucins. The present study was undertaken to explore,
electron microscopically, the immunoreactivity of the human stomach to HIK1083.
We examined normal mucosa from resected human stomachs (five cases; formalin
fixed, paraffin-embedded) and gastric biopsy specimens from patients with early
gastric cancer [nine cases; glutaraldehyde- and osmium-fixed, epoxy-embedded
(seven cases) and half-strength Karnovsky's solution-fixed, Lowicryl K4M-embedded
(two cases)]. Immunostaining with HIK1083 and anti-lysozyme antibody was examined
under light and electron microscopes. Gland mucous cells were labeled with
HIK1083, and lysozyme was detected in some gland mucous cells and surface mucous
cells. Electron microscopically, the secretory granules of gland mucous cells
contained a single electron-dense core. HIK1083-positive mucins and lysozyme
coexisted in the secretory granules of gastric gland mucous cells. HIK1083
reactive mucins and lysozyme were distributed in the matrix and in the dense core
of these secretory granules, respectively. HIK1083 can be used for electron
immunohistochemistry.
PMID- 10766262
TI - Concomitant increases in myonuclear and satellite cell content in female
trapezius muscle following strength training.
AB - A skeletal muscle fibre maintains its cytoplasmic volume by means of hundreds of
myonuclei distributed along its entire length. Therefore it is hypothesised that
changes in fibre size would involve modifications in myonuclear number. In this
study, we have examined whether 10 weeks of strength training can induce changes
in the number of myonuclei and satellite cells in female trapezius muscles.
Biopsies were taken pre- and posttraining from the upper part of the descending
trapezius muscle of nine subjects. Muscle samples were analysed for fibre area
and myonuclear and satellite cell number using immunohistochemistry. There was a
36% increase in the cross-sectional area of muscle fibres. The hypertrophy of
muscle fibres was accompanied by an approximately 70% increase in myonuclear
number and a 46% increase in the number of satellite cells. Myonuclei number was
positively correlated to satellite cell number indicating that a muscle with an
increased concentration of myonuclei will contain a correspondingly higher number
of satellite cells. The acquisition of additional myonuclei appears to be
required to support the enlargement of multinucleated muscle cells following 10
weeks of strength training. Increased satellite cell content suggests that
mitotic divisions of satellite cells produced daughter cells that became
satellite cells.
PMID- 10766263
TI - Induction of the blood-brain barrier marker neurothelin/HT7 in endothelial cells
by a variety of tumors in chick embryos.
AB - Neurothelin/HT7, a transmembrane glycoprotein of the immunoglobulin superfamily,
is a marker of blood-brain barrier (BBB)-forming endothelial cells. We have
studied the expression of neurothelin in tumors grown on the chorioallantoic
membrane (CAM) of chick embryos. We inoculated each 3-5 x 10(6) rat C6 glioma,
rat 10AS pancreatic carcinoma, human A375 melanoma, and human mammary duct
adenoma cells on the CAM of 10-day-old chick embryos. The tumors were harvested
on day 17. All four tumor cell lines formed solid tumors which were supplied by
vessels of CAM origin. Foci of bleeding were regularly observed within the
tumors. All four tumors induced the expression of neurothelin/HT7 (but not of
glucose transporter-1) in tumor endothelial cells, whereas expression in adjacent
endothelial cells of normal CAM did not occur. Confocal laser scanning microscopy
revealed that the pattern of neurothelin expression in tumor endothelial cells
was different from that in normal central nervous system (CNS) endothelium, but
the relative molecular weight of neurothelin, studied by western blot analysis,
was the same in brain and in tumors. It has been shown that, with increasing
malignancy, vessels of CNS tumors lose their morphological characteristics, and
BBB markers such as the glucose transporter-1 are downregulated. Our results show
that, in contrast, the BBB marker, neurothelin, is expressed de novo in tumor
endothelial cells. Potential common functions of neurothelin in endothelial cells
of the CNS and tumors are discussed.
PMID- 10766264
TI - Ultrastructural colocalization of nidogen-1 and nidogen-2 with laminin-1 in
murine kidney basement membranes.
AB - Nidogen-1, a key component of basement membranes, is considered to function as a
link between laminin and collagen type IV networks. Recently a new member of the
nidogen family, nidogen-2, has been characterized. Preliminary
immunohistochemical data indicated that nidogen-1 and nidogen-2 show a similar
tissue distribution at the light microscopic level. We have now localized nidogen
1 and nidogen-2, as well as their corresponding mRNAs, at the light and electron
microscopic levels in adult mouse kidney, by in situ hybridization and immunogold
histochemistry, as well as carrying out double labeling with laminin-1. Both
nidogen-1 and nidogen-2 mRNAs are found not only in mesenchymal cells of
embryonic tissues, but also in all epithelial and endothelial cells in adult
mouse kidney. Both nidogens are ubiquitous basement membrane components in the
mouse kidney, being found in glomerular, tubular, and capillary compartments and
Bowman's capsule. Furthermore, a substantial fraction of nidogen-1 and nidogen-2
colocalizes with laminin-1. The results indicate that nidogen-1 and nidogen-2
could well substitute for one another in some of their biological activities in
kidney, for example, stabilizing basement membrane networks in vivo.
PMID- 10766265
TI - Response of bronchiolar Clara cells induced by a domestic insecticide. Analysis
of CC10 kDa protein content.
AB - Clara cells are the most reactive to xenobiotics among the mammalian respiratory
tract cells. In this report, the response of Clara cells to acute or repetitive
exposure to a commercial insecticide was studied, correlating the changes in the
cell ultrastructure with the intracellular content of CC10 kDa protein as
quantified by immunocytochemical morphometry. After a single exposure to
insecticide, Clara cells reveal great expansion of their volume which is
accompanied by a remarkable proliferation of smooth endoplasmic reticulum,
swelling of the mitochondria, and changes in the nucleus. Morphometric analysis
of CC10 bronchiolar content showed significant increases in both the number of
Clara cells and the immunostained areas in individual cells. By western blot,
CC10 immunoreactive bands strongly increased in lungs after insecticide
treatment, but they were only slightly higher than the control when the vehicle
of the insecticide was tested. By repetitive exposure to the insecticide, the rat
bronchiolar epithelium undergoes extensive alterations, particularly on Clara
cells, the number of which is considerably reduced. The remaining Clara cells
shrink in size and the typical dome-like cytoplasm is lost. Secretory granule
release is no longer seen and the changes of their shape and secretory content
reflect a marked degradation and condensation process. Repetitive exposures to
the insecticide produced a severe blockage of the proteinopoietic activity,
particularly on the synthesis of CC10. Results reported here reveal that the
acute inhalation of a commercial insecticide produces hypertrophy of Clara cells,
a significant augmentation of CC10 synthesis, and probably differentiation de
novo of Clara cells, and morphological changes compatible with a detoxification
process. By contrast, exposure for 5 days provoked a general inhibitory effect on
Clara cell activity with the loss of cell capability to synthesize and secrete
CC10 kDa protein.
PMID- 10766266
TI - Lineage-related sensitivity to apoptosis in human tumor cells undergoing
hyperthermia.
AB - In this study the role of hyperthermia as an apoptotic trigger was analyzed in
four human tumor cell lines: HL60, U937, DOHH2, and K562. These cell lines were
chosen because of their well known and different expression of bcl-2 and bcr-abl
genes, the expression of which is known to be an antiapoptotic condition. HL60
and U937 cells were strongly susceptible to heat exposure, while DOHH2 cells were
weakly sensitive and K562 cells were resistant, thus suggesting a possible gene
involvement in this type of programmed cell death. The mechanisms underlying this
apoptosis were investigated by flow cytometry, agarose gel electrophoresis, and
light and electron microscopy. A subdiploid peak and DNA laddering, both of which
are parameters specifically correlated to programmed cell death, were present in
HL60 and U937 and, even if less evident, in DOHH2 cells undergoing hyperthermic
treatment, and were absent in K562 cells. In addition, DNA single-strand cleavage
was revealed by in situ nick translation, observed by confocal microscopy.
Morphological analysis confirmed these results and revealed the typical chromatin
changes, followed by the appearance of micronuclei and apoptotic bodies.
PMID- 10766267
TI - A versatile chondrogenic rat calvaria cell line R-tTA-24 that permits
tetracycline-regulated gene expression.
AB - The clonal rat calvaria cell line RCJ3.1C5.18 (RCJ) undergoes chondrogenic
differentiation after long-term culture post confluence. To allow flexible
genetic manipulation, a tetracycline-regulated gene expression system was
established in this cell line. Treatment with tetracycline in operational doses
does not affect the differentiation of RCJ cells with respect to the markers
tested. After stable transfection with pUHD15.1 containing the tetracycline
transactivator (tTA) in the presence of pTK-hyg for hygromycin selection, 28
clones were isolated and characterized for alcian blue staining of cartilage
specific proteoglycans and for collagen type II expression. Clone R-tTA-24 was
selected on the basis of phenotype and displayed tetracycline-dependent down
regulation of luciferase activity (tet-OFF system) by two orders of magnitude (57
149-fold) after stable transfection with the reporter gene pBI-EGFP/luc. The
novel, chondrogenic cell line R-tTA-24 may be stably transfected with various
genes of interest for tetracycline-regulated gene expression using neomycin
selection and may be a valuable tool to study the process of chondrogenic
differentiation in vitro.
PMID- 10766268
TI - Properties of saccade-related neurons in the cat superior colliculus: patterns of
movement fields and discharge timing.
AB - The discharge characteristics of saccade-related neurons in the superior
colliculi (SC) of trained cats were investigated in order to understand the
involvement of the SC in dynamic control of saccades. In particular, two aspects
of saccade-related collicular activity in relation to visually guided saccades
were quantitatively analyzed: the bounded pattern of amplitude tuning and the
timing of neural activity in relation to saccade offset. In order to determine
whether the amplitude tuning of SC cells is bounded or unbounded, we
characterized it with a quantitative index, the unbounded-field (UF) index.
Analysis of the characteristics of the distribution of this index, including the
absence of unbounded fields for cells within the central 10 degrees, suggested
that all cells form a single class and that apparent unbounded amplitude tuning
is an artifact occurring when the range of gaze shift is truncated by restraining
the head. This interpretation is supported by the results of a computer
simulation based on truncation of gaze-shift range that closely replicated the
experimental data. Analyses of relative location of peak motor activity in the
spatial and temporal dimensions revealed that the peak discharge was more closely
linked to the midpoint of the saccade than to the offset of saccade, regardless
of the pattern of amplitude tuning. These results do not support the proposal
advanced by the moving-hill hypothesis: the bounded pattern of amplitude tuning
is inconsistent with rostral migration of the activity locus during execution of
a saccade, and the relative location of the peak motor activity is inconsistent
with the idea that the SC activity encodes dynamic motor error (the difference
between desired and current gaze directions).
PMID- 10766269
TI - Human presupplementary motor area is active before voluntary movement: subdural
recording of Bereitschaftspotential from medial frontal cortex.
AB - Bereitschaftspotential (BP) was recorded directly from the right supplementary
motor area proper (SMA-proper) and its rostral part by chronically implanted
subdural electrodes in three patients with intractable focal motor seizure.
Cortical electrical stimulation of the SMA-proper revealed the somatotopy as
previously reported, and the supplementary negative motor area (SNMA) was
identified just anterior to the SMA-proper in two of three cases. In patient 1,
eight kinds of simple movements, i.e., left and right middle finger extension,
left arm abduction, left and right foot dorsiflexion, left knee extension, tongue
protrusion and saccadic eye movement, were studied to record BP. In patient 2,
three kinds of movements, i.e., left and right middle finger extension and left
foot dorsiflexion, were adopted as movement tasks. In patient 3, four kinds of
movements, i.e., left and right middle finger extension and left and right foot
dorsiflexion, were adopted. In the SMA-proper, somatotopically distributed BP
preceding movements were observed in all three patients. In the SNMA and its
rostrally adjacent areas, "SNMA-plus" BPs were generated invariably regardless of
the sites of movement. There was no significant difference in the onset time of
BPs between the SMA-proper and the SNMA-plus. The present findings suggest that
the SNMA-plus is more consistently involved in the preparation for various simple
movements than the SMA-proper. This functionally independent region (SNMA-plus)
just rostral to the SMA-proper most likely corresponds to a part of the
presupplementary motor area which was originally defined in nonhuman primates.
Since a part of this area elicited the inhibition of various movements by
cortical stimulation, and since it generated BPs regardless of the sites of
movement, it may play a higher role in the movement preparatory process than the
SMA-proper.
PMID- 10766270
TI - Kainate-induced neuronal injury leads to persistent phosphorylation of cAMP
response element-binding protein in glial and endothelial cells in the
hippocampus.
AB - Intracerebroventricular kainate treatment in rats induces neuronal cell death,
followed by proliferation and hypertrophy of glial cells in the lesioned area. To
further understand the activated signal transduction pathways and to get insights
into potential target gene activation, the present study aims to elucidate long
term effects on the phosphorylation state of cAMP response element-binding
protein (CREB) in the hippocampal formation. One to four weeks after kainate
injection, we found high levels of phosphorylated and hence activated CREB
(pCREB) in glial cells of the degenerating CA fields. As shown by electron
microscopy, pCREB immunoreactivity was present in reactive astrocytes,
oligodendrocyte precursor cells and endothelial cells of blood vessels. It is
postulated that pCREB could drive the expression of downstream genes in these
cells to promote cell proliferation and survival.
PMID- 10766271
TI - Enslaving effects in multi-finger force production.
AB - When a person produces isometric force with one, two, or three fingers, the other
fingers of the hand also produce a certain force. Enslaving is the involuntary
force production by fingers not explicitly involved in a force-production task.
This study explored the enslaving effects (EE) in multi-finger tasks in which the
contributions of the flexor digitorum profundus (FDP), flexor digitorum
superficialis (FDS), and intrinsic muscles (INT) were manipulated. A new
experimental technique was developed that allows the redistribution of the muscle
activity between the FDP, FDS, and INT muscles. In the experiment, ten subjects
were instructed to perform maximal voluntary contractions with all possible one-,
two-, three-, and four-finger combinations. The point of force application was
changed in parallel for the index, middle, ring, and little fingers from the
middle of the distal phalanx, to the distal interphalangeal joint, and then to
the proximal interphalangeal joint. It was found that: (1) the EE of similar
amplitude were present in various experimental conditions that involved different
muscle groups for force production; (2) the EE were large on average--the slave
fingers could produce forces reaching 67.5% of the maximal forces produced by
themselves in a single-finger task; (3) the EE were larger for neighboring
fingers; and (4) the EE were non-additive--in most cases, the EE from two or
three fingers were smaller than the EE from at least one finger. EE among
different muscles suggest a widespread neural interaction among the structures
controlling flexor muscles in the hand as the main mechanism of finger enslaving.
PMID- 10766272
TI - Neuromuscular-skeletal constraints upon the dynamics of unimanual and bimanual
coordination.
AB - In the first of three experiments, 11 participants generated pronation and
supination movements of the forearm. in time with an auditory metronome. The
metronome frequency was increased in eight steps (0.25 Hz) from a base frequency
of 1.75 Hz. On alternating trials, participants were required to coordinate
either maximum pronation or maximum supination with each beat of the metronome.
In each block of trials, the axis of rotation was either coincident with the long
axis of the forearm, above this axis, or below this axis. The stability of the
pronate-on-the-beat pattern, as indexed by the number of pattern changes, and the
time of onset of pattern change, was greatest when the axis of rotation of the
movement was below the long axis of the forearm. In contrast, the stability of
the supinate-on-the-beat pattern was greatest when the axis of rotation of the
movement was above the long axis of the forearm. In a second experiment, we
examined how changes in the position of the axis of rotation alter the activation
patterns of muscles that contribute to pronation and supination of the forearm.
Variations in the relative dominance of the pronation and supination phases of
the movement cycle across conditions were accounted for primarily by changes in
the activation profile of flexor carpi radialis (FCR) and extensor carpi radialis
longus (ECR). In the final experiment we examined how these constraints impact
upon the stability of bimanual coordination. Thirty-two participants were
assigned at random to one of four conditions, each of which combined an axis of
rotation configuration (bottom or top) for each limb. The participants generated
both inphase (both limbs pronating simultaneously, and supinating simultaneously)
and antiphase (left limb pronating and right limb supinating simultaneously, and
vice versa) patterns of coordination. When the position of the axis of rotation
was equivalent for the left and the right limb, transitions from antiphase to
inphase patterns of coordination were frequently observed. In marked contrast,
when the position of the axis of rotation for the left and right limb was
contradistinct, transitions from inphase to antiphase patterns of coordination
occurred. The results demonstrated that when movements are performed in an
appropriate mechanical context, inphase patterns of coordination are less stable
than antiphase patterns.
PMID- 10766273
TI - Effects of noxious skin heating on spontaneous cell activity in the magnocellular
red nucleus of the cat.
AB - Neurones were extracellularly recorded in the magnocellular red nucleus (RNm) of
decerebrated cats and identified by their monosynaptic responses to stimulation
of the contralateral brachium conjunctivum (BC), and by their antidromic
responses after stimulation of the rubrospinal tract in the cord. After each cell
was isolated, noxious stimulation was applied to the skin, by touch-free radiant
heat. The large majority of the cells (91.5%) responded to noxious stimulation of
the skin, even after the RNm was deprived of cerebellar input by sectioning the
contralateral BC. About half of this cell group was activated by noxious
stimulation and the other half was inhibited. To obtain responses in RNm cells,
the stimulus had to be above the thermal pain threshold, and the stimulation area
had to be inside the somatic receptive field of the cell for low-threshold
afferents. Thus, the receptive fields for nociceptive and low-threshold afferents
are similarly organized somatotopically. Noxious stimulation sometimes induced a
rhythmic pattern of spike bursts in RNm cells, which could be a reflection of the
locomotor-like activity generated in the spinal cord. The results indicate that
nociceptive information participates in sensorimotor control via the
spinorubrospinal loop, which may also transmit low-threshold cutaneous input and
corollary discharge of the activity in spinal motor centres to the RNm.
PMID- 10766274
TI - Compound grating discrimination in extrafoveal and amblyopic vision.
AB - Compound grating discrimination was measured in normal foveal and extrafoveal
vision as well as in central vision of amblyopic subjects. Two types of
discrimination were examined: 0 degrees versus 180 degrees and 90 degrees versus
270 degrees phase shift of the second harmonic relative to the fundamental. In
common with several previous studies, we found that both 0/180 and 90/270
discriminations are possible in extrafoveal vision. However, we show that
differences in foveal and extrafoveal sensitivity can be eliminated for both
types of discrimination by scaling the stimulus size appropriately. The extent of
spatial magnification necessary to equate foveal and extrafoveal performance
differed markedly, with 90/270 discriminations requiring much more magnification.
In the amblyopic subjects, the magnitude of the 90/270 deficit was greater than
the 0/180 deficit in all six amblyopes tested. In common with previous
investigations, we suggest that the visual system adopts a discrimination
strategy, based upon differences in local features, between the patterns to be
discriminated. One process registers positional relationships, while a second
process registers local contrast differences. In this context, the reduced
ability of the normal periphery and amblyopic fovea to perform mirror-symmetric
discriminations is explained in terms of losses in positional acuity.
PMID- 10766275
TI - Reaction time differences in spatially constrained bilateral and unilateral
movements.
AB - Previous investigations of bilateral-unilateral reaction time (RT) differences
have reported equivocal findings. Studies where bilateral RT has been found
longer than unilateral RT have often emphasized movement precision, while studies
reporting non-significant differences have placed little emphasis on precision.
To test the hypothesis that movement precision is an important factor in the
bilateral unilateral difference, we investigated the influence of changes in
spatial accuracy constraints on RT for unilateral and bilateral movements. Ten
self-declared right-handed subjects performed fast and accurate 45 degrees
unilateral and bilateral elbow flexion movements to small (1.5 degrees) and large
(12.0 degrees) targets. For bilateral movements, spatial accuracy was emphasized
for only one arm (the "aiming" arm), while the contralateral ("mirroring") arm
performed a simultaneous flexion movement with no emphasis on movement accuracy.
We found that while changes in target size had no significant effect on movement
latency, changing the hand (right vs left) for which accuracy was emphasized did.
When subjects performed right-arm aiming, bilateral movements, unilateral and
bilateral RT did not differ significantly. In contrast, when subjects performed
left-arm aiming, bilateral movements, RT was significantly longer than for
unilateral movements. We conclude that while spatial accuracy per se (i.e.,
target size) does not differentiate bilateral and unilateral movements, the role
of the left hand (i.e., aiming vs mirroring) does. Differences in the hemispheric
control of right- and left-hand aiming movements are discussed.
PMID- 10766276
TI - Influence of motion parallax in the control of spontaneous body sway.
AB - Visual control of postural sway during quiet standing was investigated in normal
subjects to see if motion parallax cues were able to improve postural stability.
In experiment 1, six normal subjects fixated a fluorescent foreground target,
either alone or in the presence of full room illumination. The results showed
that subjects reduced body sway when the background was visible. This effect,
however, could be mediated not only by parallax cues but also by an increase in
the total area of visual field involved. In experiment 2, other parameters such
as image angular size and target distance were controlled for. Twelve subjects
fixated a two light-emitting diode (LED) target placed at 45 cm from their eyes
in a dark room. A second similar two-LED target was placed either at 170 cm
(maximum parallax) or at 85 cm (medium parallax) from the fixated target, or in
the same plane of the fixated target (0 cm, no parallax). It was found that the
amplitude of sway was reduced significantly, by approximately 20%, when the two
targets were presented in depth (parallax present) as compared to when they were
in the same plane (no parallax). The effect was only present in the lateral
direction and for low frequency components of sway (up to 0.5 Hz). We confirmed
in experiment 3 on eight subjects with a design similar to that used in
experiment 2 that the effect of motion parallax on body sway was of monocular
origin since observed with monocular and binocular vision. Geometrical
considerations based on these results support the existence of two modes of
visual detection of body sway, afferent (retinal slippage) and efferent (extra
retinal or eye-movement based).
PMID- 10766277
TI - Detection of tenascin-C in surgically excised choroidal neovascular membranes.
AB - BACKGROUND: Increase of tenascin-C (TN-C) expression has been found in pathologic
tissues in which angiogenesis occurs. The aim of this study was to investigate TN
C expression in human choroidal neovascularization (CNV). METHODS: Ten choroidal
neovascular membranes were surgically removed from 10 patients with age-related
macular degeneration (n=6) and multifocal choroiditis (n=4). All membranes
underwent immunohistochemical evaluation using monoclonal antibodies against TN-C
and factor VIII. RESULTS: All membranes were positive for TN-C, which was
abundantly and diffusely expressed in the extracellular matrix. CONCLUSIONS: Our
results support the concept that TN-C has a role in cell proliferation and
neovascularization in humans. TN-C, as a marker of angiogenesis, may provide
novel rationales for the development of pharmacologic therapies for neovascular
disorders, particularly CNV.
PMID- 10766279
TI - Vertical and cyclotorsional deviations following peribulbar anesthesia.
AB - BACKGROUND: Motility disorders may occur consecutive to peribulbar anesthesia.
The underlying pathology is still debated. The aim of the study was to contribute
to the discussion by a meticulous orthoptic examination of a series of patients.
METHODS: In a series of 16 patients with diplopia after peribulbar anesthesia,
measurements of the angle of squint in the nine directions of gaze,
Bielschowsky's headtilt test and motility analysis were performed. The findings
were discussed with regard to the possible types of muscular lesions. RESULTS:
Hypotropia and deorsoadduction accompanied by relatively small cyclotropia were
found in all cases. Bielschowsky's head-tilt test mostly revealed neutral
findings. CONCLUSION: The findings were discussed under the hypothesis of a
fibrotic muscular change in the superior oblique and inferior rectus muscle. This
hypothesis turned out to be concordant with the orthoptic measurements, implying
that treatment of the disorder should consist in low-dosage recession of the
fibrotic muscles, which in our experience was rewarding.
PMID- 10766278
TI - Management and outcome of cataract surgery in ocular cicatricial pemphigoid.
AB - BACKGROUND: Patients with ocular cicatricial pemphigoid (OCP) lose vision due to
corneal disease or cataract, which may be senile, drug induced or complex. The
success of cataract surgery in these patients may be limited by an increased risk
of surgical complications due to difficult access and visualisation, exacerbation
of the cicatrising disease following surgery or later progression of the corneal
disease. We report our experience on cataract surgery in OCP. METHODS: Cataract
surgery was performed on 15 eyes of 13 patients. In the pre- and postoperative
examinations the stage of the condition (according Foster's classification), the
degree of conjunctival hyperaemia and the visual acuity (VA) were evaluated and
topical and systemic medication recorded. All procedures used a corneal incision.
The technique was intracapsular (ICCE) in 1, extracapsular (ECCE) in 4 and
phacoemulsification in 10 eyes. In 13 of 15 cases an intraocular lens was
implanted. The unoperated fellow eyes constituted a control group. Duration of
postoperative follow-up was 35.8+/-39.1 months. RESULTS: 10 of 15 eyes had stage
III disease or worse before surgery. Two eyes following ECCE showed early
postoperative progression of the disease. Postoperative visual acuity improved in
14 eyes by 2 or more lines. Preoperatively 5 eyes met the criteria for blind
registration, whereas postoperatively all eyes achieved a VA of at least 0.1. In
6 eyes the VA was sufficient to allow driving. However, by the 22nd postoperative
month progressive cicatricial and ocular surface disease resulted in a regression
of the achieved visual rehabilitation in 8 eyes. CONCLUSION: OCP does not prevent
successful cataract surgery if appropriate techniques are used and precautions
taken. Systemic perioperative immunosuppression is necessary in patients with
active conjunctival inflammation. The use of small clear corneal incision surgery
is recommended to reduce the risk of an acute exacerbation of conjunctival
inflammation. Although visual rehabilitation may be only temporary due to
progression of the conjunctival or corneal disease in OCP, cataract surgery can
provide some benefit, in severely disabled patients, without precipitating an
acute exacerbation of OCP.
PMID- 10766280
TI - Naso-temporal asymmetry and contraction anisocoria in the pupillomotor system.
AB - BACKGROUND: Differences between the pupillomotor sensitivity of nasal and
temporal retinal hemifields may contribute to the relative afferent pupillary
defect (RAPD) seen in optic tract or pretectal lesions. To understand the
architecture of the pupillary pathway, it is necessary to know the size and the
prevalence of such naso-temporal differences and also of contraction anisocoria
(unequal direct and consensual pupillary responses) in normal individuals. The
results of previous studies have been only partially consistent. METHODS: We
registered the direct and consensual pupillary light reactions in both central
retinal hemifields of 42 healthy subjects by means of IR video pupillography.
Stimuli were generated under mesopic conditions on a computer screen as half
circles with 4.6 cd/m2 and 10 deg radius. Stimulus duration was 200 ms with a
stimulation interval of 4 s. RESULTS: The nasal retina was significantly more
sensitive than the temporal retina, and the direct pupillary reactions were
significantly larger than the consensual reactions. For the nasal retina, direct
pupillary reactions exceeded the consensual reactions, whereas there was nearly
no difference between direct and consensual reactions for the temporal retina.
CONCLUSION: RAPD in optic tract damage or pretectal lesions cannot be explained
by the only slightly more sensitive nasal retina. Considerably more input would
be needed from the contralateral than from the ipsilateral retina into the optic
tract. The nearly equal direct and consensual pupil reactions when stimulating
the temporal retina suggest an input of temporal retina to both sides of the
pretectum. Such a crossing of temporal fibres may take place in the chiasm.
PMID- 10766281
TI - Long-term follow-up of Ru-106/Rh-106 brachytherapy for posterior uveal melanoma.
AB - BACKGROUND: Currently available information about survival, local tumor control
rates, secondary enucleation rates, and visual acuity following Ru-106/Rh-106
applicator therapy for choroidal and ciliochoroidal melanomas is limited in terms
of duration of follow-up among surviving patients. METHODS: The authors performed
a retrospective descriptive study of the rates of survival, local treatment
failure, secondary enucleation, and visual acuity decrease in 140 patients (141
eyes) with choroidal or ciliochoroidal melanoma treated by Ru-106/Rh-106
applicator radiotherapy between 1964 and 1976. Median follow-up duration among
surviving patients in this series was 17.3 years (mean 18.6 years). The Kaplan
Meier method was used to estimate cumulative survival rates and event rate
curves. Multivariate Cox proportional hazards modeling was used to identify
prognostic clinical variables associated with the various evaluated outcomes.
RESULTS: The 15-year survival rate based on all causes of death was 48.0%
(standard error=4.4%), and that based on confirmed and suspected metastatic uveal
melanoma was 66.7% (standard error=4.5%). The cumulative 15-year rates of local
treatment failure and secondary enucleation were 36.8% (standard error=4.4%) and
34.4% (standard error=4.5%) respectively. The cumulative 10-year rates of visual
acuity loss to less than 20/200 and no light perception were 62.8% (standard
error=4.4%) and 40.6% (standard error=5.2%) respectively. Prognostic factors
associated with death from confirmed and suspected metastatic melanoma were
greater tumor diameter and anterior tumor location. Greater tumor diameter was
associated with local treatment failure. Baseline visual acuity equal to or worse
than 20/200 was associated with profound visual acuity loss. CONCLUSIONS:
Although a high proportion of treated eyes eventually lost a great deal of
vision, and although many treated eyes ultimately underwent secondary
enucleation, a substantial number of patients treated by plaque radiotherapy in
this series survived for well over 10 years and retained the tumor-containing eye
with a visual decrease of varying severity.
PMID- 10766282
TI - Reliability of intraocular lens power calculation after cataract surgery in
patients with relative anterior microphthalmos.
AB - BACKGROUND: Patients with relative anterior microphthalmus (RAM) are
characterized by special anatomical features (corneal diameters <11 mm, anterior
chamber depth <2 mm and normal axial length) that sometimes make intraocular lens
(IOL) power calculation difficult. PATIENTS AND METHODS: Seventy-five patients
aged 75.6+/-10.3 years with RAM were evaluated for preoperative target refraction
and postoperative refraction after cataract surgery. We used biometric formulas
as modified by Haigis for IOL power calculation. RESULTS: The average IOL power
implanted was 25.2+/-2.8 dptr (one-piece all-PMMA IOL; range 19-31 dptr). The
preoperatively calculated target refraction was -0.71+/-1.43 dptr (range -4.3 to
+2.2 dptr). The average postoperative spherical equivalent was -0.41+/-1.50 dptr
(range -5.5 to +6.0 dptr). The mean difference between target and end refraction
was -0.30+/-1.54 dptr Fifty-seven percent of cases did not differ by more than 1
dptr from target refraction, 81.3% by not more than 2 dptr, and 94.7% by not more
than 3 dptr; only 5.3% of cases deviated by more than 3 dptr. There was no
correlation of the amount of deviation between target and postoperative
refraction with axial length, corneal diameter and anterior chamber depth. There
was, however, a significant correlation between target refraction and amount of
deviation of spherical equivalent. The largest differences were found with target
refractions greater than +2 dptr. CONCLUSIONS: In spite of the special anatomical
conditions in patients with RAM the biometric formulas as modified by Haigis
produced reliable IOL power calculations. The best accuracy was achieved when
aiming at a target refraction in the range of +/-2 dptr.
PMID- 10766283
TI - Transscleral suture fixation of posterior chamber intraocular lenses in children
under 3 years.
AB - BACKGROUND: Children who have undergone lentectomy for congenital or traumatic
cataract do not have adequate capsular support for secondary posterior chamber
intraocular lens (PC-IOL) implantation and thus will become severely amblyopic if
contact lens intolerance occurs. In order to prevent amblyopia we fixed PC-IOLs
by transscleral sutures in three children younger than 3 years. Clinical outcome,
visual acuity and course of refraction were studied. METHODS: Four eyes of three
children with contact lens intolerance were operated. Posterior chamber lenses
(PC-IOL) were sutured in the ciliary sulcus by transscleral sutures. Two children
had monocular traumatic cataract and one child underwent surgery on both eyes for
congenital cataract. To allow adjustment of refraction in situ without removing
the primarily implanted and transsclerally fixed PC-IOL we used the piggyback
intraocular lens system for implantation. RESULTS: Visual acuity improved in all
four eyes. The two children with traumatic cataract achieved visual acuity of 0.7
and 1.0, respectively, and stereopsis. No complications related to the technique
of transscleral suture fixation of the PC-IOL were observed. Postoperative
changes in refractive power were caused by a myopic shift between -1.0 D and -9.0
D. Follow-up was 25-70 months. CONCLUSION: Transscleral suture fixation of PC
IOLs did not cause specific complications during follow-up of up to 70 months.
This technique offers an important option for the correction of an aphakic
refractive error which cannot be corrected otherwise. In future the piggyback
intraocular lens system may help to rather atraumatically correct postoperative
changes in refractive power.
PMID- 10766284
TI - Clonidine provides an allergy-free alternative in glaucoma patients with proven
allergy to apraclonidine.
AB - PURPOSE: The aim of this study was to determine allergic responses to clonidine
hydrochloride 0.25% in glaucoma patients with proven allergic reaction to
apraclonidine 0.5%. METHODS: Fifteen consecutive glaucoma patients with allergic
reaction to apraclonidine were prospectively challenged with clonidine
hydrochloride 0.25% and evaluated for recurrence of allergic reactions and
efficacy of treatment. Intraocular pressure (IOP), conjunctival hyperemia, blood
pressure and resting pulse rate were determined at baseline and after 1, 3, 6 and
12 months. RESULTS: None of the patients developed ocular allergic reaction
during 12 months on clonidine therapy. Blood pressure and pulse rate did not
change significantly with clonidine treatment. Clonidine caused a significant
reduction of IOP from baseline. In one patient, topical clonidine caused fatigue,
dizziness and dry mouth. CONCLUSION: Clonidine did not cause allergic reaction in
patients with proven allergy to apraclonidine, indicating that there is no cross
reactivity with apraclonidine. Due to the small series, however, we cannot assume
that allergy will not occur with clonidine 0.25% given time and a larger number
of patients.
PMID- 10766285
TI - The epidemiology of serious eye injuries from the United States Eye Injury
Registry.
AB - BACKGROUND: Trauma remains a major problem throughout the world. The prognosis of
severe eye injuries is commonly bleak. This paper focuses on the epidemiology of
eye trauma, the role of ocular epidemiology, and identification and reduction of
risk factors. METHODS: An analysis of the first 8,952 patients reported with
severe eye injuries, defined as those eye injuries resulting in permanent and
significant (measurable and observable on routine eye examination) structural
and/or functional changes to the eye, from the United States Eye Injury Registry
as of 31 July 1998. RESULTS: The age of patients entered was from the 1st year of
life to 103 years. Fifty-eight percent of those injured were less than 30 years
of age. The male to female ratio was 4.6:1, reaching 7.4:1 in the fourth decade
of life. Almost half of the injuries involved the retina, and 77% of the injured
eyes required one or more surgical procedures, including a large proportion which
have undergone vitreoretinal surgical procedures. CONCLUSION: Injuries remain the
most serious public health problem facing developed nations. Yet, a persistent
inadequacy exists both in the standardized documentation of eye injuries and in
their treatment. With appropriate surgical and medical intervention, a majority
of the reported injured eyes recovered functional levels of visual acuity. It
appears that glasses, including prescription glasses and even non-prescription
sunglasses, can offer measurable protection which results in a lower incidence of
severe eye injuries to those wearing glasses.
PMID- 10766286
TI - Indocyanine green angiography in Sorsby's fundus dystrophy.
AB - PURPOSE: To report the indocyanine green angiographic findings in patients with a
fundus dystrophy characterized by subretinal deposits, macular atrophic or
neovascular degeneration and peripheral chorioretinal atrophy which is most
likely Sorsby's fundus dystrophy. METHODS: A series of 11 clinically affected
patients and 4 asymptomatic carriers, belonging to one autosomal dominant
pedigree were examined with stereoscopic funduscopy, fluorescein and indocyanine
green angiography. RESULTS: Subretinal deposits were found in 20 eyes of 10
patients. These deposits stained slightly on indocyanine green angiography,
causing a reticular pattern. Two eyes had a disciform lesion and 3 geographic
atrophy in the macula. A peripheral disciform lesion was found in 1 eye.
Indocyanine green angiography identified peripapillary choroidal
neovascularization in 2 eyes. Peripheral chorioretinal atrophy was found in 8
eyes of 4 patients, associated with peripheral plaques that could only be
identified by indocyanine green angiography in 6 eyes of 3 patients. CONCLUSION:
Indocyanine green angiography in Sorsby's fundus dystrophy may indicate the
presence of homogeneously staining, well-demarcated peripheral areas of
hyperfluorescence associated with chorioretinal atrophy. These plaques correspond
in our opinion to choroidal neovascularization which is otherwise unsuspected.
PMID- 10766287
TI - Continued progression of retinopathy despite spontaneous recovery to
normoglycemia in a long-term study of streptozotocin-induced diabetes in rats.
AB - BACKGROUND: This long-term (2.3 years) study determines the temporal relationship
between systemic glucose levels and the progression of diabetic retinopathy
during the natural course of streptozotocin-induced diabetes in rats. METHODS: Of
367 rats, 200 were randomly assigned into a group injected with streptozotocin
(50 mg.kg(-1)) and 167 into a control group. Subsets of the rats were killed at
6, 28, 40, 65, 90 and >100 weeks post induction to allow the severity of
retinopathy to be assessed quantitatively and qualitatively by trypsin digests of
the retinal vasculature. Concurrently blood glucose, body weight and death rate
were monitored. RESULTS: Three glycemic phases were observed in the
streptozotocin rats. In phase 1 (0 to 36-40 weeks) hyperglycemia was established
and maintained. In phase 2 (36-40 to 84-90 weeks) normoglycemia was restored, and
maintained during phase 3 (84-90 to 120 weeks). Control rats were normoglycemic
throughout. The retinal microangiopathy was marked at 28 weeks during phase 1,
developed more slowly in phase 2 and continued to worsen with loss of capillaries
in all retinas and saccular microaneurysms present in 50% of retinas in phase 3.
Cumulative death rate in streptozotocin rats also followed three phases, with
maximum vulnerability occurring between 28 and 40 weeks. Body weight was
significantly lower in streptozotocin rats throughout, increasing slowly in phase
1, then more rapidly during and after spontaneous glycemic recovery. CONCLUSION:
The worsening retinopathy, despite sustained recovery to normoglycemia, implies
that good glucose control alone does not stop the progression of the retinal
microangiopathy at this late stage.
PMID- 10766288
TI - Repopulation of denuded murine Descemet's membrane with life-extended murine
corneal endothelial cells as a model for corneal cell transplantation.
AB - BACKGROUND: Corneal endothelial cell transplantation has been an intriguing
concept as an alternative to full-thickness penetrating keratoplasty. Using a
murine corneal transplantation model, we sought to establish the optimal
conditions to repopulate, ex vivo, denuded murine Descemet's membrane with life
extended cell cultures of murine corneal endothelial cells. These ex vivo
repopulated corneas were used as donor corneas in a murine orthotopic corneal
transplantation model to assess, in vivo, the function of the transplanted, life
extended murine corneal endothelial cells (MCEC). METHODS: Mouse corneas were
surgically trephined and the native corneal endothelium was removed mechanically
using a sterile cotton swab. Cultured murine corneal endothelial cells (life
extended by expression of the SV40 large T antigen) were added onto the denuded
Descemet's membrane and allowed to attach in culture at 37 degree C. Evidence of
corneal cell attachment to Descemet's membrane was determined between 1 and 8 h
by scanning and transmission electron microscopy. Donor life-extended corneal
endothelial cells were labeled with a fluorescent dye to allow tracking of the
donor cells following seeding onto denuded Descemet's membrane. In four
independent experiments, the Descemet's repopulated corneas were placed into
syngeneic mice and evaluated for corneal clarity after 6 weeks. RESULTS: We could
detect attachment of the life-extended murine CEC by scanning and transmission
electron microscopy to denuded Descemet's membrane. The optimal time for
adherence was 2 h and these repopulated corneas were used as donors in a murine
model of penetrating keratoplasty. Of 20 mice evaluated after 6 weeks, 4
displayed corneal clarity, and fluorescent evaluation demonstrated that only the
donor corneal endothelial cells were present. CONCLUSIONS: This experimental
protocol establishes that "life-extended" MCEC can bind to Descemet's membrane ex
vivo and form a distinct monolayer. The repopulated Descemet's membrane allowed
us to directly test the hypothesis that cultured life-extended corneal
endothelial cells are functional when reintroduced into an in vivo milieu and
provides evidence that specific corneal endothelial cell transplantation may be a
viable alternative to pentrating keratoplasty.
PMID- 10766289
TI - Effect of perfluorodecalin on human retinal pigment epithelium and human corneal
endothelium in vitro.
AB - BACKGROUND: Perfluorocarbon liquids are useful intraoperative tools in
complicated vitreoretinal surgery. They are usually removed at the end of the
procedure, but small amounts may remain in the eye. Recently, contradictory
results have been reported on the damage in association with residual
perfluorocarbon liquids in the eye. This study examined the effects of
perfluorodecalin on human retinal pigment epithelium and corneal endothelium in
vitro. METHODS: Vitality and proliferative capacity of cell cultures were
measured after incubation with perfluorodecalin. Vitality of cell cultures were
measured using the Life-Dead assay. Cell proliferation was determined by
measuring incorporation of 5-bromo-2'-deoxyuridine into cellular DNA.
Furthermore, endothelium of organ-cultured human corneas was examined after
incubation with perfluorodecalin by photodocumentation. RESULTS: Both cell types
showed less extinctions in the Life-Dead assay after incubation with
perfluorodecalin. After removing perfluorodecalin from the cultures, cells showed
the same capacity of proliferation as the control cells. Compared to control
corneas, perfluorodecalin induced a decrease in endothelial cell density. In four
corneas, endothelial cell necrosis was observed. CONCLUSION: Decreasing
extinctions in the Life-Dead assay after incubation with perfluorodecalin can be
interpreted as showing a decreasing amount of vital cells. Because cell
proliferation showed no significant changes the results suggest that
perfluorodecalin may not be directly toxic to cells in vitro. It may exert an
indirect or mechanical effect on cell function by impeding the normal metabolic
exchange between endothelium and medium. Based on these results perfluorodecalin
should be completely removed after operation.
PMID- 10766290
TI - Biodegradable scleral implant for intravitreal controlled release of ganciclovir.
AB - BACKGROUND: The aims of this study were to develop biodegradable scleral implants
that could overcome previously reported disadvantages such as an adverse burst in
the late phase of release and to investigate the release profile of modified
scleral implants in vitro and in vivo. METHODS: The modified scleral implants
(weight 8.5 mg, length 5 mm) were made of mixtures of poly(DL-lactide) (PLA) with
different molecular weights and contained 25 weight % of ganciclovir (GCV). The
release of GCV was evaluated in vitro by spectrophotometry. Intravitreal GCV
concentrations in vivo were measured by high-performance liquid chromatography
following plug implantation in pigmented rabbits. The biocompatibility of the
device was determined by indirect ophthalmoscopy and light microscopy. RESULTS:
The in vitro release studies showed stable, long-term sustained and slow release.
The in vivo release studies showed that the implants had long-term release in the
diffusional phase of the triphasic release pattern and only a minor adverse burst
of GCV in the late phase. No significant retinal toxicity was observed by
histologic examination. CONCLUSION: Our findings showed that this newly modified
scleral implant may provide suitable intravitreal drug delivery for treatment of
cytomegalovirus retinitis.
PMID- 10766291
TI - In vivo gene transfer into choroidal neovascularization by the HVJ liposome
method.
AB - PURPOSE: To evaluate the efficacy of the HVJ liposome method for gene transfer in
rats with experimentally induced choroidal neovascularization. METHODS: Plasmid
DNA containing the LacZ reporter gene, or fluorescein isothiocyanate (FITC)
labeled double-stranded phosphorothioate oligodeoxynucleotides (S-ODNs), was
encapsulated in liposomes. The liposomes were coated with the envelope of
inactivated hemagglutinating virus of Japan (HVJ). Intense laser burns were
applied to the posterior pole of the retina of pigmented rats to induce choroidal
neovascularization. Following photocoagulation, HVJ liposome suspension was
injected into the vitreous. On days 3, 7, 14, and 28 after injection, the eyes
were removed and fixed. The eyes injected with LacZ gene were reacted with X-gal,
frozen, and cut into thin sections. The sections were examined for the expression
of the LacZ gene by light microscopy. The enucleated eyes injected with double
stranded S-ODNs were frozen, cut into thin sections, and examined a confocal
scanning laser microscope for FITC labeling. Eyes without injection of HVJ
liposomes served as controls. RESULTS: Expression of LacZ genes (beta
galactosidase activity), or localization of FITC labeling, was observed mainly in
the laser-induced choroidal neovascular tissue from 3 to 28 days after the
intravitreal injection of HVJ liposome. CONCLUSIONS: We conclude that the HVJ
liposome method achieved effective gene transfer into choroidal neovascular
tissue. Thus, this method can be used as a nonviral gene therapy system for the
treatment of choroidal neovascularization in vivo.
PMID- 10766292
TI - Report of a patient with aortic dissection evolving into binocular ischemic
retinopathy.
AB - BACKGROUND: Carotid artery disease is known to cause a variety of ischemic ocular
syndromes. We report a patient with an aortic dissection that evolved into
binocular ischemic retinopathy. METHODS: Case report. RESULTS: A 49-year-old male
patient presented with stomach pains and with no ophthalmologic symptoms. After
extensive examination, a diagnosis of aortic dissection was made to account for
the acute abdominal pain. Sixteen days later, he noted binocular photopsia and
ophthalmoscopy revealed ischemic retinopathy. Arterial stent implantation and
right coronary reconstitution surgery were performed. Subsequently, the ischemic
lesions in the retina disappeared and no abnormality was observed by retinal
angiography 1 year later. CONCLUSION: Binocular ischemic retinopathy can be a
sign of aortic or carotid dissection, and these observations suggest that aortic
dissection should be included in the differential diagnosis whenever ischemic
changes are detected in the retina.
PMID- 10766293
TI - The role of thymidine phosphorylase/PD-ECGF in cancer chemotherapy: a chemical
perspective.
AB - The angiogenic growth factor thymidine phosphorylase/PD-ECGF has been identified
as a potential target in the development of anti-cancer drugs. This review
firstly discusses the biological role of TP/PD-ECGF and its importance in the
activation of 5-fluorouracil and its prodrugs. The chemistry and chemotherapeutic
potential of TP/PD-ECGF inhibitors are also discussed.
PMID- 10766294
TI - A comparative cell-based high throughput screening strategy for the discovery of
selective tyrosine kinase inhibitors with anticancer activity.
AB - Growth factor receptor tyrosine kinases (RTK) have been implicated in tumor
growth, metastasis and angiogenesis, and are thus considered promising targets
for therapeutic intervention in malignant diseases. We present a novel drug
discovery strategy to find inhibitors of RTKs based on comparative screening of
compound libraries employing functional cellular assays. Cell lines stably
expressing HER2 and the receptors for hepatocyte growth factor (HGF), vascular
endothelial growth factor (VEGF), insulin-like growth factor-I (IGF-I) and
epidermal growth factor (EGF) have been established. All cell lines are based on
FDC-P1, a murine myeloid progenitor cell line which allows a direct comparison of
results obtained in primary screens. In addition, the same cell lines are
suitable for compound optimization and for animal studies. Using this strategy we
report the identification of promising lead candidates for further drug
development which are highly selective, non-cytotoxic and cell permeable with
potencies in the low micromolar range.
PMID- 10766295
TI - Structure-based design of potent inhibitors of EGF-receptor tyrosine kinase as
anti-cancer agents.
AB - In a systematic effort to design inhibitors of the epidermal growth factor
receptor (EGFR) family protein tyrosine kinases (PTK) as anti-cancer agents, we
have constructed a three-dimensional homology model of the EGFR kinase domain and
used molecular modeling methods for the structure-based design of analogs of the
active metabolite of leflunomide (LFM) with potent and specific inhibitory
activity against EGFR. These docking studies identified alpha-cyano-beta-hydroxy
beta-methyl-N-[4-(trifluoromethoxy)phenyl]-p ropenamide (LFM-A12) as our lead
compound, which was predicted to bind to the EGFR catalytic site in a planar
conformation. LFM-A12 inhibited the proliferation (IC50 = 26.3 microM) and in
vitro invasiveness (IC50 = 28.4 microM) of EGFR positive human breast cancer
cells in a concentration-dependent fashion. Similarly, the model of the EGFR
binding pocket was used in combination with docking procedures to predict the
favorable placement of chemical groups with defined sizes at multiple
modification sites on another class of EGFR inhibitors, the 4-anilinoquinazoline.
This approach has led to the successful design of a dibromo quinazoline
derivative, WHI-P97, which had an estimated Ki value of 0.09 microM from modeling
studies and a measured IC50 value of 2.5 microM in EGFR kinase inhibition assays.
WHI-P97 effectively inhibited the in vitro invasiveness of EGFR-positive human
cancer cells in a concentration-dependent manner. However, unlike LFM-A12, the
quinazoline compounds are not specific for EGFR.
PMID- 10766296
TI - A similarity model for the human angiogenic factor, thymidine
phosphorylase/platelet derived-endothelial cell growth factor.
AB - Thymidine phosphorylase (EC 2.4.2.4), identical to the angiogenic factor,
platelet-derived endothelial cell growth factor (PD-ECGF), is up-regulated in
several tumour types. A similarity model of human thymidine phosphorylase was
built, based on the crystal structure of the Escherichia coli enzyme. The high
residue conservation between the two enzyme sources (39% sequence identity and
53% sequence similarity) aided model building. The human model was very similar
to the E. coli enzyme's crystal structure, with the main tertiary structure
difference being the destruction of helix 15 in E. coli by the presence of a loop
in the human model. The model was used to rationalize the nature of the binding
of the substrates thymine and thymidine, and of known inhibitors using a
quantitative docking algorithm. Ab initio calculations on the nM inhibitor 5
chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride gave its
conformation and distribution of charge. Subsequent quantitative docking studies
have led to the suggestion, for the first time, that this inhibitor behaves as an
oxycarbenium ion transition-state analogue, explaining its strong reported
inhibition.
PMID- 10766297
TI - Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as
potential antitumor agents.
AB - We have reported previously that unsymmetrical disulfide inhibitors of the human
thioredoxin/thioredoxin reductase redox system (hTrx/TR) possess antitumor
activity. We have broadened the search for more potent inhibitors and evaluated a
large range of mono- and bis-disulfide compounds, prepared using parallel
syntheses. Reaction of isothioisourea-HCI salts (R') or bis-salts (R) with
aromatic or aryl thiols (R") in wells of 96-well plates produced >450 derivatives
with the structures R"SSR' and R"SSRSSR". The excellent yield and purity of the
disulfides provided sufficient material for evaluations of enzyme inhibition and
cytotoxicity. Selection criteria based on the IC50 values for hTrx/TR inhibition
and for cytotoxicities of the disulfides identified agents for subsequent scale
up syntheses and in vivo evaluations of antitumor activity. These scale-up
studies confirmed the original activities of agents synthesized in the plates and
validated the parallel synthetic approach. Structure-activity information derived
from the hTrx/TR IC50 data allow for a number of generalizations. The most potent
inhibitors of the Trx system contained two heteroatoms ortho to the disulfide
moiety in an aromatic functionality. The thioalkylating moieties had greatest
activity with one branch point alpha to the disulfide. In the absence of
branching, more potent inhibition was observed with the electron withdrawing
functionalities. Bis-disulfides showed patterns of activity which depended on
chain length, with optimum activity observed when the disulfide units were
separated by 3.9 A, a similar distance to that separating the thioredoxin active
site cysteine residues. From the agents selected for scale-up syntheses, three
disulfide compounds were studied for their antitumor activity in vivo against
human tumor xenografts in scid mice. One of the analogues discovered through the
combinatorial syntheses/screening for Trx inhibition, 1-phenylethyl 2-imidazolyl
disulfide, N1 (ProlX agent PX-C5), has demonstrated excellent in vivo activity
against the MCF-7 human breast cancer and the HL-60 human leukemia, thus
validating this approach for novel drug discovery.
PMID- 10766298
TI - A DNA binding indolocarbazole disaccharide derivative remains highly cytotoxic
without inhibiting topoisomerase I.
AB - NB-506 is a glucosylated indolocarbazole related to the antibiotic rebeccamycin
and is currently under clinical trials as an anticancer drug. This compound is a
DNA intercalating agent and a potent topoisomerase I poison. The glucose residue
attached to the planar indolocarbazole chromophore plays a significant role in
the interaction of the drug with nucleic acids and contributes positively to the
stabilization of topoisomerase I-DNA covalent complexes. To investigate further
the influence of the carbohydrate moiety, we studied the DNA binding and
topoisomerase I inhibition properties of an analogue of NB-506 bearing a
disaccharide side chain. Fluorescence and footprinting studies indicate that the
replacement of the glucose chain of NB-506 with a maltose residue does not hinder
the capacity of the drug to bind to DNA and to recognize GC-rich sequences. The
addition of the second sugar residue does not reinforce the interaction with DNA
but abolishes the capacity of the drug to inhibit topoisomerase I. Unexpectedly,
the disaccharide analogue of NB-506 has totally lost its capacity to stimulate
DNA cleavage by topoisomerase I. In addition, like NB-506, the new analogue is
not an inhibitor of topoisomerase II. However, despite the absence of
topoisomerase poisoning activity, the cytotoxic activity is fully maintained. The
maltosyl-indolocarbazole drug proved to be as potent as NB-506 at inhibiting the
growth of various human and murine tumour cell lines. The study raises the
question as to whether topoisomerase I poisoning is important for the antitumour
activity of rebeccamycin analogues.
PMID- 10766299
TI - The quinobenzoxazines: relationship between DNA binding and biological activity.
AB - The quinobenzoxazine compounds, derived from antibacterial quinolones, is active
in vitro and in vivo against murine and human tumors. In this contribution, we
show that the relative DNA binding affinity of the quinobenzoxazine compounds
correlates with their cytotoxicity, their ability to inhibit gyrase-DNA complex
formation, and the decatenation of kinetoplast DNA by human topoisomerase II. DNA
binding studies with the descarboxy-A-62176 analogue indicate that the beta-keto
acid moiety of the quinobenzoxazine compounds plays an important role in their
interaction with DNA.
PMID- 10766300
TI - Pyrimido[4,5,6-kl]acridines. Synthesis, in vitro cytotoxicity and structure
activity relationships.
AB - In a previous report we described the synthesis and biological properties of a
group of pyrimido[4,5,6-kl]acridines 2, related to the pyrazolo[4,5,6
kl]acridines 1, promising antitumor agents possessing a broad spectrum of
activity. Since the substitution of the pyrazole ring of the pyrazoloacridine
chromophore with a pyrimidinone leads to derivatives that retain in vitro
cytotoxic activity, we decided to further investigate the pyrimido[4,5 6
kl]acridines. Modifications at the ring system level, leading to chromophores
with different characteristics, changes of substituent groups in position 6,
simultaneous alteration of the chromophore and the introduction of a second
cationic side chain in position 1 afforded 29 new pyrimido[4,5,6-kl]acridines,
which were tested in vitro against the human colon adenocarcinoma HT29 cell line.
Interesting structure-activity relationships could be drawn. Some selected
derivatives were screened for their cytotoxic activity on the National Cancer
Institute cell panel (60 human tumor lines).
PMID- 10766301
TI - The exchange of cognate TATA boxes results in a corresponding change in the
strength of two HSV-1 early promoters.
AB - Previous analysis of two Herpes Simplex Virus Type-1 (HSV-1) promoters
controlling expression of mRNA encoding early genes (U(L)37 and U(L)50) showed
that the U(L)50 (dUTPase) promoter is at least 6-fold stronger both in its normal
genomic location and in the non-essential gC locus. In the present report we
demonstrate that the TATA element of either promoter is the major determinant of
promoter strength. When the U(L)37 TATA element (CGTATAAC) was mutated with two
base changes to the U(L)50 TATA sequence (CATAAAAC) in recombinant viruses, the
activity of the U(L)37 promoter was increased to that of the U(L)50 promoter.
Conversely, when the U(L)50 TATA element was changed to that of the U(L)37
promoter, U(L)50 promoter activity was reduced to the level of the U(L)37
promoter. In addition, we investigated the spacing of the TATA box with respect
to upstream promoter elements. We found that re-positioning the U(L)37 TATA box
to a location equivalent to that of the U(L)50 promoter relative to the
transcript start site; i.e. three bases upstream of its cognate location,
significantly diminished activity. Substitution of the U(L)50 TATA box at the new
position could only partially restore promoter activity. Thus, we also conclude
that the spacing of TATA elements vis-a-vis upstream promoter elements is also a
critical determinant of promoter strength.
PMID- 10766302
TI - Identification of a novel plant virus promoter using a potyvirus infectious
clone.
AB - A putative promoter from the strawberry vein banding caulimovirus (SVBV) genome
was identified by its ability to drive infection with full-length cDNA of the
zucchini yellow mosaic RNA potyvirus (ZYMV). A high rate of infection was
obtained with the cDNA under control of the SVBV promoter using particle
bombardment technology. The SVBV promoter shows 60% homology to the cauliflower
mosaic virus 35S promoter in the domain spanning the conserved motifs of CCACT
(at -83) and the TATA box (at -31), to the transcription start. The 3'-end one
third of the putative promoter (328 bp) was sufficient to invoke full infectivity
with the ZYMV clone, and drove transient reporter gene expression in Solanaceae
and Cucurbitaceae transformed with a binary plant transformation vector. Stable
expression of a reporter gene (GUS) under control of the truncated SVBV promoter
was shown in transformed tobacco shoots in roots, leaves and stems.
PMID- 10766303
TI - Clones of cotton leaf curl geminivirus induce symptoms atypical of cotton leaf
curl disease.
AB - The causative agent of cotton leaf curl disease has previously been shown to be
transmissible by the whitefly Bemisia tabaci (Gennadius) and a begomovirus
(Geminiviridae) was shown to be associated with the disease. This virus was
provisionally called cotton leaf curl virus (CLCuV) although no causal
relationship between virus and disease was shown. In the present study full
length clones of CLCuV, equivalent to the DNA A component of bipartite
begomoviruses, were obtained. The clones of CLCuV were systemically infectious to
both Nicotiana benthamiana and cotton. Infected plants did not exhibit symptoms
characteristic of cotton leaf curl disease, producing mild leaf curling,
yellowing and some stunting. Efforts to identify a second genomic component were
not successful. These findings suggest that the begomovirus, CLCuV, is not or not
the sole cause of cotton leaf curl disease. The transmission of cotton leaf curl
disease by B. tabaci, however, may indicate that the begomovirus plays a part in
the transmission of the disease. The implications of these findings are
discussed.
PMID- 10766304
TI - Herpes simplex virus 1 (HSV-1) strain HSZP glycoprotein B gene: comparison of
mutations among strains differing in virulence.
AB - The nonpathogenic HSZP strain of HSV-1 induces large polykaryocytes due to a syn3
mutation (His for Arg at residue 858) in the C-terminal endodomain of
glycoprotein B (gB) (40). We determined the nucleotide (nt) sequence of the UL27
gene specifying the gB polypeptide of HSZP (gBHSZP) and found 3 mutations in its
ectodomain at aminoacids (aa) 59, 79 and 108. The ANGpath virus, which also has a
syn3 mutation in the C-terminal endodomain of gB (Val for Ala at residue 855) is
pathogenic for adult mice (39), but can be made nonpathogenic by replacing the
gBANGpath gene by the corresponding gBKOS sequence (21). The gBANGpath had three
ectodomain mutations (at aa 62, 77 and 285), while gBKOS had at least four
ectomain mutations (aa 59, 79, 313, and 553). Two mutations (aa 59 and 79) in the
latter, located in the variable antigenic site IV/D1 were common for gBKOS and
gBHSZP. These together with the gBANGpath mutations at aa 62 and 77 create a
cluster of 4 mutations in diverse region of the N-terminal part of gB (between aa
59-79), in which the gBs of pathogenic ANGpath and 17 viruses differ from the gBs
of nonpathogenic HSZP and KOS viruses. The lower pathogenicity of KOS as related
to gBKOS, is furthermore associated with the change of Ser to Thr at aa 313
(locus III/D2). The possibility is discussed that mutations in both above
mentioned antigenic loci could result in higher immunogenicity of the
corresponding antigenic epitopes, which, in turn, would contribute to the
decreased virulence of HSZP and KOS viruses.
PMID- 10766306
TI - Common elements of spiroplasma plectroviruses revealed by nucleotide sequence of
SVTS2.
AB - DNA of SpV1-like spiroplasma plectroviruses (rods with single-stranded circular
DNA) is scattered in the genome of the phytopathogen Spiroplasma citri and has
significant consequences for evolution of the S. citri genome. We determined the
complete nucleotide sequence of SVTS2, a SpV1-like virus of S. melliferum, a
honeybee pathogen, to ascertain, by comparison with S. citri SpV1 viruses
(GenBank U28974 and X51344), the defining features of this important group. The
6,824 nt DNA contains nine ORFs homologous to ORFs of S. citri SpV1 viruses and
five ORFs unique to SVTS2. The predicted amino acid sequences of the homologous
ORFs were 17-38% identical to those of their S. citri counterparts. The SVTS2
predicted ORF 1 product (Mr 47,031) was considerably smaller than those of known
S. citri SpV1 viruses. Also, in contrast to those viruses, SVTS2 lacked an ORF
with recognizable similarity to a transposase. ORF 2 of all three viruses had a
homologue among the products of genes of MVL-1, a virus of Acholeplasma
laidlawii, another plectrovirus. The results suggest that, at most, only slightly
more than half of SpV1 genomes consists of genes shared by all spiroplasma
viruses of the group.
PMID- 10766305
TI - TT virus as a human pathogen: significance and problems.
AB - In 1997 TTV was detected using representational difference analysis (RDA) in
serum of a patient with posttransfusion hepatitis unrelated to known hepatitis
viruses. The genome of TTV is a circular single-stranded DNA molecule of 3852 nt
with negative polarity. TTV possibly can be grouped either into the existing
family Circoviridae or into a recently established virus family "Circinoviridae".
Analysis of the complete DNA nucleotide sequence of TTV identified three
partially overlapping open reading frames (ORFs). Neither DNA nucleotide nor
corresponding amino acid sequences of TTV do show significant homologies to known
sequences. TTV DNA nucleotide sequences amplified by PCR from sera of different
patients show considerable sequence variations. Although the natural route of
transmission of TTV is still unknown, there is clear evidence for a transmission
of TTV through blood and blood products. TTV DNA can be detected in the feces of
infected individuals suggesting that it may be possible to attract TTV infection
from environmental sources. Since the discovery of TTV, numerous studies have
investigated the prevalence of TTV infections in different human population
groups all over the world. All these studies are based on PCR detection systems,
but the technical aspects of the PCR systems vary significantly between the
different investigators. The results of the epidemiological studies do not show a
clear picture. The discovery of TTV as a viral agent and particularly the
identification of a high percentage of infected carriers in the healthy human
population raises the following questions: Firstly, what is the origin and
molecular relatedness of TT virus. Secondly, what is the significance of TTV as a
human pathogen. And thirdly, what are the exact molecular mechanisms of viral
replication. To answer these questions it will be necessary to determine the
primary structure and the coding capacity of several TTV patient isolates.
PMID- 10766307
TI - Construction of a full length infectious clone for dengue-1 virus Western
Pacific,74 strain.
AB - The flavivirus dengue 1 Western Pacific,74 (DEN1 WP) virus has a positive
stranded RNA genome of 10,735 nucleotides. DEN1 WP genomic RNA was amplified into
three overlapping fragments by RT-PCR. These fragments were assembled into a full
length cDNA clone in the yeast-E. coli shuttle vector pRS424, using homologous
recombination in yeast. RNA produced by in vitro transcription of this clone was
infectious upon electroporation into LLCMK2 cells, as shown by cytopathic effects
and detection of viral antigens by indirect immunofluorescence, and by
propagation of the virus released into the culture media. Biological properties
of the transcript-derived virus, such as the pattern of dengue-specific protein
synthesis and growth rate in LLCMK2 or C6/36 cells, resembled those of the parent
DEN1 WP virus.
PMID- 10766308
TI - The human papillomavirus type 16 E5 protein modulates ERK1/2 and p38 MAP kinase
activation by an EGFR-independent process in stressed human keratinocytes.
AB - The human papillomavirus type 16 E5 gene product has been shown to upregulate the
activation of MAP kinases ERK1/2 and cellular proliferation promoted by EGF in a
ligand-dependent process. We now report the growth factor-independent modulation
of MAP kinases by HPV 16 E5 in human keratinocytes. After treatment with 600 mM
sorbitol or low concentrations of anisomycin, E5-expressing cells upregulate the
activation of ERK1/2. In addition, E5 enhances p38 activation after anisomycin
but not after sorbitol treatment, but it has no effect on MAP kinases activation
after shocking the cells with 300 mM sodium chloride. The E5-mediated, sorbitol
dependent increase in ERK1/2 activation is EGF-independent and is only partially
inhibited by tyrphostin AG1478, which is known to inhibit specifically EGF
receptor activation.
PMID- 10766310
TI - Complete nucleotide sequence of the rice tungro spherical virus genome of the
highly virulent strain Vt6.
AB - The complete nucleotide sequence of rice tungro spherical virus (RTSV) strain
Vt6, originally from Mindanao, the Philippines, with higher virulence to
resistant rice cultivars, was determined and compared with the published sequence
for the Philippine-type strain A (RTSV-A-Shen). It was reported that RTSV-A was
not able to infect a rice resistant cultivar TKM 6 (10). RTSV-Vt6 and RTSV-A-Shen
share 90% and 95% homology at nucleotide and amino-acid levels, respectively. The
N-terminal leader sequence of RTSV-Vt6 contained a 39-amino acids-region
(positions 65 to 103) which was totally different from that of RTSV-A-Shen; the
difference resulted from frame shifting by nucleotide insertions and deletions.
To confirm the amino-acid sequence differences of the leader polypeptide, the
same region was cloned and sequenced using a newly obtained variant of RTSV-type
6, which had been collected in the field of IRRI, and seven field isolates from
Mindanao, the Philippines. Since all the sequences of the target region are
identical to that of the Vt6 leader polypeptide, the sequence difference in the
leader region seems not to correlate with the virulence of Vt6.
PMID- 10766309
TI - Phylogenetic analysis of two potyvirus pathogens of commercial cowpea lines:
implications for obtaining pathogen-derived resistance.
AB - As a prelude to developing engineered resistance to two important potyvirus
pathogens of cowpea, a phylogenetic analysis of strains of Cowpea aphid-borne
mosaic virus (CAbMV) and Bean common mosaic virus--blackeye cowpea strain (BCMV
B1C) was undertaken. Nucleotide sequences for the coat protein genes and 3'
untranslated regions of four CAbMV and one BCMV-B1C strains were determined and
included in an analysis with published sequences. While all the newly sequenced
viruses showed strong homology with the existing respective sequences in the
database, the CAbMV group showed a divergence into two subgroups. These groups
differed from each other by more than some CAbMV strains differed from the South
African Passiflora virus (CAbMV-SAP), which has distinct biological
characteristics. The implications of the sequence analyses are discussed with
respect to a strategy for the generation of engineered resistance to both groups
of viruses.
PMID- 10766312
TI - Colonoscopy without sedation.
PMID- 10766311
TI - Expression of four genes of bacteriophage MB78 from contiguous open reading
frames: the genomic organization as deduced by sequence analysis.
AB - Four proteins of bacteriophage MB78 having apparent molecular weights as 35, 14,
21 and 16 kDa are expressed from 3.9 kb SalI-HindIII fragment located almost in
the middle of the phage genome. Analysis of the sequence supported by some
experimental evidences suggest that these four proteins are expressed from
polycistronic message without any intercistronic gap. Stop and start codons of
consecutive ORFs overlap and rare initiation codons are used. Computer analysis
of the sequence suggests the presence of two more open reading frames within the
ORFs of 35 and 16 kDa proteins but in the opposite orientation, i.e. in the
complementary strand.
PMID- 10766313
TI - The impact of dyspepsia definition on prevalence estimates: considerations for
future researchers.
PMID- 10766314
TI - 24-H pharyngeal pH monitoring in healthy volunteers: a normative study.
AB - BACKGROUND: Gastropharyngeal reflux has been associated with disorders of the
upper and lower airways. It may be shown by pharyngeal pH-metry, but reports on
normality in healthy volunteers are scarce. No definite consensus has been
reached considering the upper limit of normality (ULN). The aim of the present
study was therefore to quantify the occurrence of pharyngeal acid exposure (pH <
4) in healthy volunteers and, further, to examine its relation to acid exposure
of the oesophagus and oesophageal motility and its occurrence in relation to age,
sex, and body position. METHODS: Forty healthy volunteers underwent ambulatory 24
h pH-metry, using antimony electrodes positioned 2 cm above the upper oesophageal
sphincter and 5 cm above the lower oesophageal sphincter on the basis of
manometry. Technical artefacts were excluded before calculation of all results.
RESULTS: Gastropharyngeal reflux occurred in most healthy volunteers without any
significant relation to age, sex, or body weight. Pharyngeal acid reflux occurred
mainly in the upright position. The ULN for pharyngeal acid exposure time was
assessed to 0.9% (0.2% after exclusion of mealtimes). The ULN for the number of
acid events in the pharynx was 18 (6.1). The corresponding ULNs for the
oesophagus were 7% and 84. CONCLUSION: Gastropharyngeal reflux may be effectively
monitored by ambulatory pH-metry. The present study provides reference limits, a
prerequisite for evaluating the pathophysiologic importance of the phenomenon.
PMID- 10766315
TI - Omeprazole does not interfere with the antiplatelet effect of low-dose aspirin in
man.
AB - BACKGROUND: Experimental studies have shown that omeprazole and other anti
inflammatory agents compromise the therapeutic activity of nonsteroidal anti
inflammatory drugs and aspirin in rats. It is not known whether this effect will
occur in humans. Our aim was to determine whether omeprazole affects the
antiplatelet effects of low-dose aspirin in humans. METHODS: Platelet
lumiaggregation, skin bleeding time, plasma levels of aspirin and salicylic acid,
and serum gastrin levels were determined in 14 healthy men before and after the
ingestion of 125 mg aspirin with or without previous treatment with 20 mg/day of
omeprazole for 4 days before testing. RESULTS: Omeprazole increased serum gastrin
levels from 64 (median; range, 52-91) pg/ml to 80.5 (median; range, 56-455) pg/ml
(P < 0.05) but did not significantly affect the plasma concentration of aspirin
or salicylic acid. Aspirin increased skin bleeding time in all subjects, and the
increase was similar with and without previous omeprazole treatment. Aspirin
inhibited platelet aggregation in response to both collagen and arachidonic acid
regardless of omeprazole treatment. CONCLUSION: A single dose of 20 mg omeprazole
daily does not interfere with the biologic activity of 125 mg aspirin on
platelets in humans.
PMID- 10766316
TI - Expression of nuclear factor-kappaB in Helicobacter pylori-infected gastric
mucosa detected with southwestern histochemistry.
AB - BACKGROUND: The transcription factor nuclear factor-kappaB (NF-kappaB) plays a
pivotal role in inflammatory responses by upregulating mRNA expression of, for
example, proinflammatory cytokines and chemokines. Although in vitro studies have
shown that Helicobacter pylori can induce NF-kappaB activation in gastric cancer
cell lines, there is little information on cellular localization of NF-kappaB in
H. pylori-infected gastric mucosa. METHODS: H. pylori-infected and -negative
patients with various endoscopic findings were examined. NF-kappaB expression was
studied by means of Southwestern histochemistry, a new method of localizing
transcription factors. Labeled double-stranded oligo-DNA with specific consensus
sequence for the NF-kappaB binding site was reacted with frozen sections from
gastric biopsy specimens. We compared mucosal interleukin-8 (IL-8) and IL-1beta
levels as measured with enzyme-linked immunosorbent assay with the degree of NF
kappaB expression. RESULTS: NF-kappaB expression was often evident in nuclei of
epithelial cells in H. pylori-infected gastric mucosa. The degree of NF-kappaB
expression on the epithelium was significantly more severe in H. pylori-infected
than in -negative mucosa. The degree of NF-kappaB expression also correlated with
mucosal IL-8 levels but not with IL-8. CONCLUSIONS: H. pylori infection increases
the expression of NF-kappaB in gastric mucosa, suggesting that NF-kappaB is
involved in inflammatory responses to H. pylori.
PMID- 10766317
TI - Helicobacter pylori infection is a major risk factor for gastric carcinoma in
young patients.
AB - BACKGROUND: Helicobacter pylori has been established as a risk factor for gastric
carcinoma (GCa). Since before the discovery of H. pylori, atrophic gastritis and
intestinal metaplasia have been linked to GCa, especially the intestinal-type
tumor. The prevalence of H. pylori infection and atrophic gastritis increase with
age. Thus, analysis of H. pylori infection in young patients with GCa could help
clarify the role of this bacterium in the development of GCa. Accordingly, we
investigated the relationship between H. pylori infection, GCa, and histologic
gastritis in patients less than 30 years old. METHODS: Fifty GCa patients less
than 30 years (mean, 26.4 years) and 100 sex- and age-matched controls (mean,
26.8 years) were examined for the presence of H. pylori infection and histologic
gastritis. RESULTS: The prevalence of H. pylori infection was significantly
higher in GCa patients than in controls (94% versus 40%, P < 0.01). Its
prevalence was not associated with tumor location, tumor stage, or histologic
type. Gastritis, atrophy, and intestinal metaplasia significantly increased the
risk of GCa. By means of multiple logistic regression analysis, the odds ratio
for the risk of GCa in H. pylori-positive subjects was found to be 23.5 (95%
confidence interval, 6.84-80.7). CONCLUSIONS: We confirmed a strong association
between H. pylori infection and GCa in young patients. Along with H. pylori
infection, histologic gastritis might play an important role in the pathogenesis
of GCa in these patients.
PMID- 10766318
TI - Efficacy of different Helicobacter pylori eradication regimens in patients
affected by insulin-dependent diabetes mellitus.
AB - BACKGROUND: Patients with insulin-dependent diabetes mellitus (IDDM) are often
affected by chronic infections; antibiotic absorption, however, may be influenced
by the disease. H. pylori eradication appears to be reduced in IDDM patients. The
aim of the study was to evaluate the efficacy of the most common H. pylori
eradication regimens in a population of IDDM-infected patients. METHODS: One
hundred and seventy-two IDDM patients were evaluated. H. pylori infection was
assessed through the 13C-urea breath test. Infected patients were randomly
assigned to three different standard 7-day eradication regimens: 1) amoxicillin,
clarithromycin, pantoprazole; 2) tinidazole, clarithromycin, ranitidine bismuth
citrate; or 3) tinidazole, clarithromycin, pantoprazole. Patients in whom
eradication was not successful in the first cycle were subsequently submitted to
a 7-day therapy with tinidazole, tetracycline, bismuth, and pantoprazole.
RESULTS: Thirty-seven per cent of IDDM patients were infected. None of the triple
therapies used provided an eradication higher than 62%. Conversely, the quadruple
regimen was successful in 88% of the patients. Ten per cent of the subjects
undergoing the triple therapies showed minor side effects, without significant
differences among groups, whereas side effects occurred in 25% of the patients
treated with the quadruple therapy (P < 0.05). CONCLUSIONS: IDDM patients show a
low H. pylori eradication rate with a standard triple therapy regardless of the
regimen utilized, the dosage and/or the duration of the therapy used appearing
not to be sufficient to eradicate the infection efficiently. The use of a
quadruple regimen leads to the cure of a large percentage of the infected
patients in whom the eradication was unsuccessful in the first therapy, although
it is accompanied by a greater incidence of minor side effects.
PMID- 10766319
TI - A population study on irritable bowel syndrome and mental health.
AB - BACKGROUND: Irritable bowel syndrome (IBS) is commonly thought to be associated
with psychologic distress. However, in some studies only persons who had sought
medical care for IBS (IBS patients) showed an increased frequency of psychiatric
symptoms, and nonpatients did not differ significantly from normal subjects. Our
aims were 1) to estimate the prevalence of IBS in the population aged 18-45
years, 2) to find the proportion seeking medical care for IBS, and 3) to compare
IBS subjects with normals, and IBS patients with IBS nonpatients with regard to
mental health. METHODS: Questionnaires on IBS symptoms and the General Health
Questionnaire (GHQ) were mailed to 5000 randomly sampled persons aged 18-45
years. The response rate was 58%. RESULTS: IBS was found in 7.4% of the men and
13.3% of the women. Those who had sought medical attention had more severe
symptoms. The Likert mean score on the GHQ was 4.7 (95% confidence interval, 4.4
5.0) points higher for the IBS group than for normals (P < 0.001). There was no
difference in GHQ scores between IBS patients and nonpatients. CONCLUSIONS: The
results indicate that IBS per se is associated with more psychiatric distress,
regardless of medical care-seeking. Seeking medical care is associated with more
severe IBS symptoms.
PMID- 10766320
TI - Gastric emptying and plasma neurotensin levels in untreated celiac patients.
AB - BACKGROUND: Upper gastrointestinal motor abnormalities could account for some of
the dyspeptic symptoms of celiac patients. However, the data on gastric emptying
time are conflicting, and the pathophysiology of motor disturbances is still
unclear. Neurotensin modulates upper gastrointestinal motor activity, and its
postprandial increase is a reliable index of nutrient delivery to the ileum. We
therefore assessed both plasma neurotensin levels and gastric emptying in
untreated celiacs. METHODS: The gastric antral area of nine untreated celiac
patients and nine controls was measured with ultrasound at base line and every 30
min after a fatty meal (227 kcal, 45% fat); the base-line and postprandial
neurotensin plasma levels were determined by means of radioimmunoassay. The data
are mean values +/- standard deviation and were analyzed by using non-parametric
tests. RESULTS: The overall and half gastric emptying time were significantly
longer in the patients (203+/-32 versus 133+/-15 min, P = 0.0117, and 137+/-32
versus 78+/-11 min, P = 0.0001). The pattern of the changes in antral area was
similar in both groups during the observation period as a whole but differed
significantly in the first 120 min (P = 0.0343). Base-line neurotensin levels
were significantly higher in the patients (41.6+/-23.9 versus 18.2+/-5.5 pg/ml, P
= 0.0214) and their net postprandial increase was lower than in controls (15.0+/
15.9 versus 29.8+/-13.0 pg/ml, P = 0.046). In both groups the base-line
neurotensin levels were related to the half gastric emptying time (P = 0.023).
CONCLUSIONS: In untreated celiac patients gastric emptying time is longer than in
controls and is concomitant with an increase in base-line plasma neurotensin
levels.
PMID- 10766321
TI - Three years' follow-up of bone density in adult coeliac disease: significance of
secondary hyperparathyroidism.
AB - BACKGROUND: The mechanisms of disturbances in bone mineral density (BMD) in
coeliac disease are not completely understood. The aim of this prospective study
was to investigate the possible significance of secondary hyperparathyroidism
(SHPT) with regard to BMD in patients with untreated coeliac disease. METHODS:
One hundred and five adult patients with untreated coeliac disease were examined
for BMD and serum parathyroid hormone (PTH) concentration. BMD in the hip, lumbar
spine, and forearm were examined up to 3 years after the introduction of a gluten
free diet. RESULTS: SHPT was found in 27% (28 of 105) of the patients. In
patients with SHPT serum levels of 25-hydroxy-vitamin D were lower and those of
alkaline phosphatase higher than in patients with normal PTH, but ionized serum
calcium did not differ between the two groups. BMD was more severely reduced in
patients with SHPT. Although the BMD increment was more rapid in patients with
than in those without SPTH, only in the latter group did mean BMD became normal
after 1-3 years on a gluten-free diet (GFD). After 3 years on a GFD more than
half of the patients with initial SHPT still had low BMD in both the hip and the
forearm. Furthermore, in patients with SHPT the intestinal mucosa more often
remained atrophic at the 1-year follow-up, despite good compliance with the diet.
CONCLUSIONS: Low BMD in patients with untreated coeliac disease is often
associated with SHPT. After 3 years on a GFD the BMD remains low only in patients
with initial SHPT. We therefore suggest that PTH should be measured when the
diagnosis of coeliac disease is made, as an indicator of more serious intestinal
disorder and complicating bone disease.
PMID- 10766322
TI - Simple mucosal biopsy criteria differentiating among Crohn disease, ulcerative
colitis, and other forms of colitis: measurement of validity.
AB - BACKGROUND: Recently established mucosal biopsy criteria reliably differentiate
idiopathic inflammatory bowel disease (IBD) from other forms of colitis (non
IBD), and Crohn disease involving the colon (CD) from ulcerative colitis (UC) but
were inconvenient in practical use because of the need for relatively complicated
calculations. Our objectives were to establish simple criteria in which
calculation could be done in the user's head and to measure their validity.
METHODS: On the basis of the above original criteria, we constructed two sets of
criteria in which coefficients and constants were simplified to integral numbers.
The first set of criteria consisted of the diagnostic categories 'definite IBD',
'probable IBD', 'unknown', 'probable non-IBD', and 'definite non-IBD'. Similarly,
the second set had five categories from 'definite CD' to 'definite UC'. The
validity of the criteria was evaluated in 117 patients with CD, 125 with UC, and
484 with non-IBD. RESULTS: In categories of probable IBD and probable non-IBD
both sensitivity and specificity exceeded 96.3%. Probable CD and probable UC
showed sensitivities of 95.7% and 92.0% and specificities of 93.6% and 98.3%.
CONCLUSIONS: Despite simplified coefficients and constants, the validity appeared
to be high enough to apply the present criteria to routine work.
PMID- 10766323
TI - Crohn disease arthropathy: antigens in synovial fluid share epitopes with strains
of two species of viridans streptococci.
AB - BACKGROUND: There is evidence to suggest that Crohn disease is caused by an
immunologic response to an unknown intestinal luminal antigen, probably of
bacterial origin. The reported demonstration of yersinia antigen in the synovial
fluid of patients with yersinosis therefore prompted a search for bacterial
antigens in the synovial fluid of patients with Crohn arthropathy. METHODS:
Antisera were raised in rabbits to synovial fluids obtained from seven patients
with Crohn arthropathy and from seven 'control' subjects with other forms of
arthropathy. These antisera were used to probe sonicates of the bacteria cultured
from the gastric juice of patients with gastric Crohn disease. RESULTS: The
antisera made from the Crohn synovial fluids, but none of those made from the
controls, reacted uniquely with antigens in sonicates of strains of two species
of viridans streptococci (Streptococcus parasanguis and an atypical S. oralis)
isolated from four of the five patients with gastric Crohn disease. CONCLUSIONS:
These findings suggest that the arthropathy of Crohn disease and, possibly, the
intestinal disease itself may involve an immunologically mediated inflammatory
response to these antigens.
PMID- 10766324
TI - Nipple valve anastomosis for preventing recurrence of Crohn disease in the
neoterminal ileum after ileocolic resection. A prospective pilot study.
AB - BACKGROUND: Crohn disease may recur within months in the neoterminal ileum after
ileocolic resection. Coloileal reflux may be a factor contributing to recurrence.
This study tests the effect of a nipple valve anastomosis in preventing
symptomatic and endoscopic neoileal recurrence. METHODS: Between January 1993 and
April 1997, 25 patients with Crohn disease were resected and anastomosed with an
ileocolic nipple valve. Postoperatively, the patients were given 5-aminosalicylic
acid, 0.75-3 g/daily. Regular follow-up included the Harvey-Bradshaw index,
ileocolonoscopy, and hydrocolonic sonography. RESULTS: After 1 year 2 of 25
patients (8%) had a symptomatic and 3 of 23 patients (13%) an endoscopic
recurrence. There was no symptomatic neoileal recurrence between 1 and 5 years.
After 3 years 6 of 13 patients (46%) had an endoscopic recurrence. After 5 years
4 of 11 patients (36%) had a symptomatic recurrence. CONCLUSIONS: These results
may suggest that a nipple valve anstomosis delays and perhaps prevents
symptomatic recurrence of Crohn disease in the neoterminal ileum.
PMID- 10766325
TI - Time-dependent changes in the luminal surface and mass of the rat colon during
prolonged systemic treatment with epidermal growth factor.
AB - BACKGROUND: Systemic treatment with epidermal growth factor (EGF) for 4 weeks
increases the colonic mucosal weight and surface area. The present study was
initiated to describe the time-dependent colonic changes during prolonged
treatment with EGF. METHODS: Forty-eight female Wistar rats were allocated into
five groups receiving subcutaneous EGF treatment (150 microg/kg/day) for 0
(controls), 1, 2, 3, or 4 weeks. EGF was administered in the weeks before they
were killed. By means of modern stereologic techniques (point counting and
vertical sections), the weights of the colonic wall layers and the luminal
surface area were measured on histologic sections. The colon was subdivided into
proximal and distal parts. RESULTS: The weight of the total colon increased
relatively more than the total body weight. After 1 week of treatment with EGF
the surface area and wet weight of the total colon increased by 47% and 10%, and
after 4 weeks by 62% and 37%, respectively. After 4 weeks the weight increase was
mainly due to increased mucosal weight (by 65%, P < 0.01) and less prominently
the submucosa (by 45%, P < 0.01) and the muscularis propria (by 32%, P < 0.01).
On the basis of the wet weight increase, the proximal colon was more responsive
to EGF treatment than the distal colon. CONCLUSIONS: Systemic treatment with EGF
for 1 week increased the luminal surface area relatively more than the mass of
the colon. Treatment with EGF for more than 1 week caused only a minor further
surface area increase, whereas the colonic mass continued to increase in a time
dependent manner.
PMID- 10766326
TI - Detection of colorectal tumor and inflammatory bowel disease during follow-up of
patients with initial diagnosis of irritable bowel syndrome.
AB - BACKGROUND: We wanted to estimate the incidence of irritable bowel syndrome (IBS)
and functional dyspepsia (FD) in the general population, and the detection of
colorectal tumor (CRT) and inflammatory bowel disease (IBD) after the diagnosis
of IBS and FD. METHODS: Patients aged 20-79 years newly diagnosed with IBS (N =
2956) or FD (N = 9900), together with a comparison cohort randomly sampled from
the general source population, were followed-up during a mean time of 3 years.
RESULTS: We found an overall incidence of 10.3 per 1000 person-years for FD and
2.6 per 1000 person-years for IBS. There was a greater prevalence of depression,
stress, fatigue, and pain disorders among IBS and FD patients than in the general
population. During the 1st year after a diagnosis of IBS the cumulative risk of
detecting CRT was close to 1% in IBS patients. After the 1st year the risk of CRT
in IBS patients was close to that in the general population. We found a
significantly increased risk of detecting IBD among patients initially diagnosed
as having IBS (relative risk (RR), 16.3; 95% confidence interval (CI), 6.6-40.7),
which was constant during all the follow-up period. No association was found
between dyspepsia and CRT, or IBD. CONCLUSION: IBS and FD shared some comorbidity
features, yet demographics and incidence rates were different. Unlike the
detection of colorectal tumor, the excess risk of IBD after an initial diagnosis
of IBS was cumulatively increased during all the follow-up period. The
continuously increased risk of IBD detection in IBS patients favors a true
association between IBS and IBD.
PMID- 10766327
TI - Survival and incidence of colorectal cancer in patients with ulcerative colitis
in Funen county diagnosed between 1973 and 1993.
AB - BACKGROUND: The aim of the study was to determine the death rate and the risk of
developing colorectal cancer in patients with ulcerative colitis in Funen County.
METHODS: The medical records of 801 patients with ulcerative colitis diagnosed in
1973-93 in Funen County were scrutinized with regard to colectomy, survival, and
colorectal cancer, and in 1998 a follow-up was carried out. RESULTS: The patients
were managed at nine different hospitals: one university hospital, one central
hospital, and seven smaller hospitals. The mean age at diagnosis was 41 years,
and the mean duration of disease was 10.11 years. Sixty-one per cent of the
patients were classified as having proctosigmoiditis, 21% as having left-sided
colitis, and 18% as having pancolitis. In 127 patients who underwent
proctocolectomy during the study period lethal complications occurred in 8 cases:
5 of 110 in Odense University hospital and 3 of 17 in the other hospitals. One
hundred and twenty patients in the cohort died during the period of observation,
nine of them of colitis-related causes. There was a slightly increased risk of
early death in the cohort after 15 years of disease. Six colorectal cancers were
found, whereas four were expected, giving a standard incidence ratio of 1.665.
The cumulative cancer risk after 20 years' disease duration was 5.3% in the
observed group, contrasting with an expected rate of 0.49%, and 10.1% after 25
years. CONCLUSION: In this cohort of ulcerative colitis patients the mortality
and the risk of developing colorectal cancer were slightly higher than expected
compared with the background population.
PMID- 10766328
TI - Gastric tonometry in assessing splanchnic tissue perfusion in acute pancreatitis.
AB - BACKGROUND: Hypovolemia is typical early in acute pancreatitis. Despite fluid
resuscitation splanchnic hypoperfusion may be present and may have a role in the
course of pancreatitis. To test this hypothesis, we assessed gastric mucosal pH
(pHi) and P(CO)2 during the first 48 h of hospitalization for acute pancreatitis.
METHODS: Thirty-three patients were studied. A gastric tonometer was inserted on
admission, and gastric mucosal pH and P(CO)2 were measured on admission and then
every 12 h during next 48 h. RESULTS: On the basis of the Atlanta classification
there were 22 cases of mild and 8 of severe pancreatitis. Three patients were
excluded because of consent withdrawal. The groups were similar with regard to
age, sex ratio, and etiology of pancreatitis. Independently of disease severity
the gastric pHi decreased, and the gastric mucosal-arterial P(CO)2 difference and
pH difference both increased over time as compared with base line. No difference
was seen in these values between mild and severe pancreatitis. CONCLUSIONS:
Moderate gastric mucosal hypoperfusion was found early in acute pancreatitis.
However, gastric pHi measurement with tonometry has no obvious value as a
screening tool to assess the severity of pancreatitis.
PMID- 10766329
TI - Local treatment of hepatic metastases with low-level direct electric current:
experimental results.
AB - BACKGROUND: Several authors have recently reported encouraging results from low
level direct current therapy in easily accessible malignant tumors. However,
antitumoral effects in colorectal metastases have not been investigated
experimentally. METHODS: Using an animal model with induced hepatic metastases,
we analyzed the effectiveness and the tumor growth dynamics after direct current
application. Three weeks after induction tumor volumes were estimated with
magnetic resonance imaging (MRI). Then direct current (80 C/cm3) was applied in
the treatment group by means of one anode in the tumor center and four cathodes
peripherally. In the control group electrodes were placed without applying
current. Tumor growth dynamics was analyzed with MRI after 3 and 5 weeks. After
this all animals were killed, and the livers histologically examined. RESULTS:
After 5 weeks MRI showed a 1.6-fold tumor enlargement in the treatment group
versus a 2.9-fold enlargement in the control group (Student t test, P=0.0051).
The histopathologic analysis of the treated livers yielded a 21% complete
response rate and a 78% partial response rate. No necroses were found in the
control group. CONCLUSIONS: These results confirm the effectiveness of low-level
direct current application as a potential modality for the treatment of hepatic
metastases.
PMID- 10766330
TI - The diagnostic value of electron microscopy in human immunodeficiency virus
positive patients with gastrointestinal disease.
AB - BACKGROUND: Our aim was to determine the diagnostic value of electron microscopy
in evaluating the etiology of gastrointestinal disease in patients infected with
the human immunodeficiency virus (HIV). METHODS: A retrospective review of
electron microscopic and light microscopic results of all HIV-positive patients
with gastrointestinal and liver diseases was made during a 3-year period from
June 1995 to June 1998. RESULTS: A total of 145 HIV-positive patients had their
electron microscopy specimens reviewed. Of these, 136 were investigated for
diarrhea, and the other 9 for increased liver enzymes. Twenty-seven of the 145
(18.6%) HIV-positive patients had a pathogen identified by electron microscopy,
compared with only 13 of 145 (9%) identified by light microscopy (P < 0.005). The
sensitivity of light microscopy for detecting opportunistic pathogens was 68%.
Twenty-one of the 27 (77.8%) patients diagnosed by electron microscopy had
microsporidiosis, and the most commonly diagnosed species was Enterocytozoon
bieneusi. Light microscopy failed to identify 12 cases of microsporidiosis and 2
cases of leishmaniasis. CONCLUSIONS: Electron microscopy contributes
substantially to the identification of pathogens in HIV-positive patients. Light
microscopy failed to identify one of every two pathogens diagnosed by electron
microscopy.
PMID- 10766331
TI - Rib metastasis revealing hepatocellular carcinoma.
AB - Bone metastasis infrequently appears as the first manifestation of hepatocellular
calcinoma (HCC), and in any case in most patients the primary tumour is detected
a few months after its development. We report the case of a patient with
alcoholic liver disease, increased levels of alpha-fetoprotein, and no evidence
of hepatic lesion in the different imaging modalities, in whom metastasis of HCC
was detected in the ribs, whereas the primary tumour was not diagnosed until 15
months later. We believe that all patients with increased levels of alpha
fetoprotein should be tested in an intensified search for HCC and possible
metastases, given that hepatic lesions may not be detected until many months
alter the diagnosis of metastatic disease.
PMID- 10766332
TI - Ternary complex formation between VO(IV)-picolinic acid or VO(IV)-6
methylpicolinic acid and small blood serum bioligands.
AB - In order to assess the role of the low molecular mass bioligands of blood serum
in vanadium binding, a study was made of the interactions of the complexes formed
in the VO(IV)-picolinic acid and VO(IV)-6-methylpicolinic acid systems with
various low molecular mass constituents of blood serum, such as oxalate, lactate,
citrate and phosphate. The speciation of VO(IV) in these ternary systems and also
in the binary VO(IV)-picolinic acid and VO(IV)-6-methylpicolinic acid systems was
studied by pH-potentiometry at 25 degrees C and at an ionic strength I = 0.2 M
(KCl). The binding modes of the complexes formed were determined by spectral
(electronic absorption and EPR) methods. Picolinic acid and 6-methylpicolinic
acid were found to form mono and bis complexes through the pyridine nitrogen and
carboxylate oxygen, but the presence of the methyl group in 6-methylpicolinic
acid surprisingly decreases the stability of its complexes significantly. The
results obtained on the ternary systems reveal that mixed ligand complex
formation is favoured in these systems, especially with citrate, and must
therefore be taken into account in the speciation description of VO(IV) in blood
serum.
PMID- 10766333
TI - Metalloporphyrins inhibit beta-hematin (hemozoin) formation.
AB - Metal-substituted protoporphyrin IXs (Cr(III)PPIX (1), Co(III)PPIX (2),
Mn(III)PPIX (3), Cu(II)PPIX (4), Mg(II)PPIX (5), Zn(II)PPIX (6), and Sn(IV)PPIX
(7)) act as inhibitors to beta-hematin (hemozoin) formation, a critical
detoxification biopolymer of malarial parasites. The central metal ion plays a
significant role in the efficacy of the metalloprotoporphyrins to inhibit beta
hematin formation. The efficacy of these compounds correlates well with the water
exchange rate for the octahedral aqua complexes of the porphyrin's central metal
ion. Under these in vitro reaction conditions, metalloporphyrins 5, 6 and 7 are
as much as six times more efficacious than the free ligand protoporphyrin IX in
preventing beta-hematin formation and four times as efficacious as chloroquine,
while metalloporphyrins 3 and 4 are three to four times more effective at
preventing beta-hematin formation than the free protoporphyrin IX base. In
contrast, the relatively exchange inert metalloporphyrins 1 and 2 are only as
efficacious as the free ligand and only two-thirds as effective as chloroquine.
Aggregation studies of the heme:MPPIX using UV-Vis and fluorescence
spectroscopies are indicative of the formation of pi-pi hetero-metalloporphyrin
assemblies. Thus, hemozoin inhibition is likely prevented by the formation of
heme:MPPIX complexes through pi-stacking interactions. The ramifications of such
hetero-metalloporphyrin assemblies, in the context of the emerging structural
picture of hemozoin, are discussed.
PMID- 10766335
TI - Metabolic fate of the insoluble copper/tetrathiomolybdate complex formed in the
liver of LEC rats with excess tetrathiomolybdate.
AB - Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of
Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of
Wilson disease, can be removed from the MT with tetrathiomolybdate (TTM).
However, the insoluble Cu/TTM complex formed with excess TTM is known to be
deposited in the liver. The metabolic fate of the insoluble Cu/TTM complex was
investigated in the present study. LEC rats were injected with TTM at the dose of
10 mg/kg body weight for 8 consecutive days and were fed with a standard or low
Cu diet for 14 days after the last injection. About 95% of the Cu in the liver
became insoluble together with Mo. The concentration of Cu in the liver
supernatants of rats fed with the standard diet increased significantly compared
with that in rats dissected 24 h after the last injection (control rats), while
the concentration in rats fed with the low Cu diet remained at a comparable level
to that in the controls. The rate of Cu accumulation in the livers of rats fed
with the standard diet did not differ before and after the treatment, suggesting
that there was no rebound effect by treatment with TTM. These results suggest
that the insoluble Cu/TTM complex is resolubilized in the liver, and that the
solubilized complex is excreted into the bile and blood, i.e., the insoluble
Cu/TTM complex is not the source of Cu re-accumulation in the form bound to MT in
the liver after TTM treatment. It was concluded that, once Cu is complexed with
TTM, the metal is excreted either immediately in the soluble form or slowly in
the insoluble form into the bile and blood.
PMID- 10766337
TI - Mixed-ligand complexes of copper(II) ions with AMP and CMP in the systems with
polyamines and non-covalent interaction between bioligands.
AB - The occurrence of non-covalent interactions and formation of molecular complexes
between adenosine 5'-monophosphate (AMP) or cytidine 5'-monophosphate (CMP) and
the polyamines, putrescine, 1,7-diamino-4-azaheptane (3,3-tri), spermidine and
1,11-diamino-4,8-diazaundecane (3,3,3-tet), were detected in metal-free systems.
The stoichiometric composition of the adducts and their stability constants were
determined on the basis of computer analysis of the titration data, taking into
account the fact that the acid-base properties of the system change as a result
of these interactions. Spectral analysis allowed an identification of the
interaction centers in the adducts as protonated amine groups of polyamines,
phosphate groups as well as nitrogen atoms of high electron density from
nucleotides. Unexpectedly, no participation of the phosphate group from AMP in
the formation of molecular complexes with tetramine-3,3,3-tet was detected. The
stoichiometric composition and stability constants of mixed-ligand complexes in
the systems of Cu(II) with AMP or CMP and polyamines were obtained. Analysis of
the results of equilibrium studies and 13C, 31PNMR, UV-Vis, IR and EPR data
permitted determination of the mode of coordination. In the systems with metal
ions, the formation of molecular complexes Cu(CMP)H4(3,3-tri) was found, apart
from heteroligand complexes of the MLL' and MLL'Hx type. In protonated complexes
the occurrence of non-covalent interactions leading to stabilization of the
coordination compounds was observed. The differences in the character of
coordination biogenic amines and their biologically inactive analogs were
identified.
PMID- 10766338
TI - Hydrogen abstraction from thiols by adenosyl radicals: chemical precedent for
thiyl radical formation, the first catalytic step in ribonucleoside triphosphate
reductase from Lactobacillus leichmannii.
AB - Aqueous solutions of adenosylcobalamin (AdoCbl) were thermolyzed with excess beta
mercaptoethanol under anaerobic conditions. The product studies reveal that
approximately 90% Co-C bond homolysis occurs, to yield Co(II)cobalamin, 5'
deoxyadenosine, and the disulfide product from the combination of two HOCH2CH2S*
radicals, 2,2'-dithiodiethanol; there is also approximately 10% Co-C bond
heterolysis, yielding Co(III)cobalamin, adenine, and 2,3-dihydroxy-4-pentenal.
The kinetic studies show there is a first-order dependence on AdoCbl and zero
order dependence on thiol under the higher [RSH] experimental conditions used,
consistent with the rate-determining step at high [RSH] being the generation of
Ado*. The kinetic results require that, in enzyme-free AdoCbl solution, adenosyl
radical (Ado*) is formed as a discrete intermediate which then abstracts H* from
the added thiol. The activation parameters for Co-C bond homolysis in the
presence of thiol trap are the same within experimental error as the activation
parameters for Co-C bond homolysis without trap, standard delta H(obs) = 29(2)
kcal mol(-1) and standard delta S(obs) = -1(5) e.u. The results, in comparison to
the rate of Co-C bond homolysis in ribonucleoside triphosphate reductase (RTPR),
reveal that RTPR accelerates Co-C bond cleavage in AdoCbl by approximately
10(10+/-1). The recent literature evidence bearing on the exact mechanism of RTPR
enzymic cleavage of the Co-C bond of AdoCbl is briefly discussed, notably the
fact that this mechanism is presently controversial, but does involve at least
coupled (and possibly concerted) Co-C cleavage, -S-H cleavage, and C-H (Ado-H)
formation steps.
PMID- 10766339
TI - Zinc causes a shift toward citrate at equilibrium of the m-aconitase reaction of
prostate mitochondria.
AB - Prostate secretory epithelial cells have the unique function and capability of
accumulating and secreting extraordinarily high levels of citrate. To achieve
this, these cells possess a uniquely limiting mitochondrial (m)-aconitase
activity that minimizes the oxidation of citrate via the Krebs cycle. The steady
state citrate/isocitrate ratio of mammalian tissues is generally maintained at
about 10-11/l, independent of the concentration of citrate, which is the result
of the chemical equilibrium reached in the presence of m-aconitase. In contrast,
the citrate/isocitrate ratio of prostate tissue is about 30-40/l. Zinc, which is
also accumulated in prostate cells at much higher levels than in other cells,
inhibits m-aconitase activity thereby minimizing citrate oxidation. This current
report is concerned with an effect of zinc on the equilibrium of the reaction
catalyzed by m-aconitase. Studies were conducted with mitochondrial extract
preparations from rat ventral prostate epithelial cells. With citrate as the
initial substrate, the addition of zinc (7-10 microM) to the prostate
mitochondrial preparation resulted in a change in the citrate/isocitrate ratio at
equilibrium from an average of 10.5/l to 13.5/l. In contrast, the identical
treatment of kidney mitochondrial preparations resulted in no zinc-induced change
in the citrate/isocitrate ratio. When either cis-aconitate or isocitrate was
employed as the initial substrate, the addition of zinc did not alter the
citrate/isocitrate ratio of prostate or kidney preparations. Partial purification
of the prostate preparation revealed that the prostate mitochondrial extract
contained a putative protein (which we have designated as 'citrate factor
protein') that is required for the zinc-induced increase in the
citrate/isocitrate ratio. This novel effect of zinc provides another mechanism by
which it is assured that the accumulation of citrate is maximized in citrate
producing prostate epithelial cells.
PMID- 10766340
TI - Synthesis, characterization, and antibacterial activity of novel Mn(II), Co(II),
Ni(II), Cu(II), and Zn(II) complexes with vitamin K3-thiosemicarbazone.
AB - Vitamin K3-thiosemicarbazone (C12H11N3NaO4S2 x 5H2O, abbreviated as VT), a new
Schiff base derivative, has been synthesized. Its crystal structure, determined
by X-ray diffraction, is triclinic, space group P1. We have also prepared five
novel complexes of VT with transition metals: [M(VT)(2)2H2O] x nH2O, (n = 1 and 2
for M = Cu(II) and Zn(II), respectively) and [M'(HVT)2Cl2] x mH2O, (m = 4, 5, and
7 for M' = Co(II), Mn(II), and Ni(II), respectively). These compounds were
characterized by IR and UV-Vis spectroscopy, molar conductivity, thermal
analyses, complexometric titration, and elemental analysis. In all the complexes,
the VT ligand coordinates through sulfur and oxygen atoms, and the geometry
around metal atom is best described as octahedral. In vitro tests of
antibacterial activity showed that VT and its complexes with Mn(II), Co(II),
Ni(II), Cu(II), and Zn(II) all had strong inhibitory actions against G(+)
Staphylococcus aureus, G(+) Hay bacillus, and G(-) Escherichia coli.
PMID- 10766341
TI - Activation of host antitumoral responses by cationic lipid/DNA complexes.
AB - A model of lipoplex-induced peritonitis was used to characterize the inflammatory
response to cationic lipid:DNA lipoplexes with respect to activation of host
antitumoral effector mechanisms. Three different cationic lipids were used in
these studies: N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N-(1-[2,3
dioleoyloxylpropyl)-N,N,N-trimethylammonium chloride (DOTAP), and N-(1-[2,3
dioleyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTMA). The DODAC and DOTMA
lipoplexes exhibited similar transfection properties in vitro, whereas the DOTAP
lipoplexes transfected quite poorly in all cell lines tested. Intraperitoneal
injection of cationic lipoplexes into immunocompetent mice resulted in a profound
infiltration of inflammatory cells, secretion of interferon-gamma, and increased
natural killer activity within the peritoneal cavity. Both DODAC and DOTMA
lipoplexes produced similar inflammatory responses, lasting at least 5 days. The
inflammation induced by DOTAP lipoplexes peaked by day 3 and resolved to near
control levels by day 5. These data indicate that although cationic lipid DNA
complexes may differ in their inflammatory properties, the natural killer
activation and interferon-gamma secretion that follow lipoplex administration
should provide a functional adjuvant for cancer gene therapies that benefit from
immunostimulation.
PMID- 10766342
TI - Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and
prolongs survival by inducing cell senescence.
AB - It is estimated that there will be >184,500 new cases of prostate cancer and
42,000 prostate cancer deaths in the United States this year. In the majority of
patients diagnosed with prostate cancer, the disease will be too advanced for
cure with standard medical treatment. New therapeutic strategies against advanced
prostate cancer are desperately needed. As alterations in tumor-suppressor gene
p16 are common in prostate cancer, one novel approach is gene therapy using a
replication-deficient, E1/E3-deleted adenovirus type 5 containing a p16 under the
control of a truncated Rous sarcoma virus promoter (AdRSVp16). In vitro, PC-3
cells that had been stably transfected with p16 expression vector under the
control of an inducible promoter had a 70% reduction in cell number compared with
the parental and control vector-transfected PC-3 cells. Similarly, AdRSVp16
significantly inhibited the growth of PPC-1 and PC-3 prostate cancer cells in
culture. Furthermore, PPC-1 tumors grown in nude mice treated by a single
injection of AdRSVp16 had a marked reduction in tumor size compared with
untreated control-treated or viral control-treated PPC-1 tumors. Animals bearing
tumors treated with AdRSVp16 also had longer survival. Adenovirally mediated
expression of transgene was detected in xenograft tumors for at least 2 weeks.
Taken together, these results suggest that AdRSVp16 should be considered for
prostate cancer gene therapy in human clinical trials.
PMID- 10766343
TI - Adenovirus-mediated anti-K-ras ribozyme induces apoptosis and growth suppression
of human pancreatic carcinoma.
AB - Human pancreatic cancer is a lethal malignancy, and the lesions show a very high
incidence of point mutations of the K-ras oncogene. These alterations can be used
as potential targets for specific ribozyme (Rz)-mediated growth suppression of
the cancer cells. We designed an anti-K-ras Rz against mutant K-ras gene
transcripts (codon 12, GGT to GTT) and generated a recombinant adenovirus (rAd)
to express the Rz (rAd/anti-K-ras Rz). More than 95% of Capan-1 human pancreatic
cells were infected with rAd/anti-K-ras Rz when treated with the virus at 200
plaque-forming units/cell. The virus, rAd/anti-K-ras Rz, significantly suppressed
mutant K-ras gene expression and inhibited the growth of Capan-1 cells. At 3 days
postinfection, we observed maximum growth suppression of the cells,
characteristic morphological changes of apoptosis such as nuclear condensation
and oligonucleosomal DNA fragmentation, and suppression of bcl-2 oncoprotein.
These changes were not found in control virus-infected cells. Our results
indicated that the virus rAd/anti-K-ras Rz specifically down-regulated the K
ras/bcl-2 pathway and induced apoptotic changes in Capan-1 pancreatic carcinoma
cells. High-efficiency adenovirus-mediated delivery of anti-K-ras Rz could become
a significant gene therapy strategy against human pancreatic cancer.
PMID- 10766344
TI - Treatment of human breast cancer cells with antisense RNA to the type I insulin
like growth factor receptor inhibits cell growth, suppresses tumorigenesis,
alters the metastatic potential, and prolongs survival in vivo.
AB - The type I insulin-like growth factor receptor (IGF-IR) plays an important role
in the growth and transformation of breast cancer cells. In this study, we
investigated the effects of treatment with an antisense IGF-IR construct on cells
from the highly metastatic estrogen receptor-negative human breast cancer cell
line MDA-MB-435s. The cells carrying the antisense IGF-IR had a markedly reduced
expression of IGF-IR, had a significant decrease in cell proliferation, and lost
the ability to form colonies in soft agar. There was a delay in tumor formation
and a dramatic reduction in tumor size when cells carrying the antisense IGF-IR
were injected into either nude or severe combined immunodeficient (scid) beige
mice. We have also provided data that show that the scid beige mouse is a more
suitable model for studying metastasis of the MDA-MB-435s cells. All of the scid
beige mice injected with cells carrying the control construct had metastasis to
the lungs, whereas lungs from the nude mice had no apparent metastatic sites
after 11 weeks. When cells carrying antisense IGF-IR were injected subcutaneously
in scid beige mice, the animals had a significant increase in survival compared
with mice injected with cells carrying the control construct. Taken together,
these results indicate that the IGF-IR can play a critical role in the
progression of breast cancer. Our studies provide a basis for the development of
future treatment strategies targeting the IGF-IR in metastatic breast cancer.
PMID- 10766345
TI - The cellular oncogene EWS/activating transcription factor 1 is unable to activate
adenovirus-borne promoters: implications for cytotoxic prodrug therapy of
malignant melanoma of soft parts.
AB - The cellular oncoprotein Ewing's sarcoma oncogene (EWS)/activating transcription
factor 1 (ATF1) is a highly specific marker for malignant melanoma of soft parts
(MMSP) and is a potent activator of several cAMP-inducible promoters, including
the somatostatin promoter. Here we explored the potential for using the
somatostatin promoter to direct toxic gene expression in MMSP cells. When
introduced into MMSP cells, a somatostatin-herpes simplex virus thymidine kinase
fusion gene confers strong and cell-specific sensitivity to the cytotoxic prodrug
ganciclovir. Ganciclovir sensitivity requires the ATF-binding site present in the
somatostatin promoter, indicating that toxic gene expression is caused by
EWS/ATF1. We also tested the efficacy of recombinant adenoviruses adenoviruses
for gene delivery and expression in two MMSP cell lines (DTC1 and Su-ccs-1).
Surprisingly, several promoters (including somatostatin) that are strongly
activated by EWS/ATF1 in transient assays are not activated in DTC1 and Su-ccs-1
cells when present in an adenovirus vector. In summary, our findings demonstrate
the potential for using the somatostatin promoter for cytotoxic prodrug therapy
for MMSP. However, first-generation adenovirus vectors cannot be used as promoter
delivery vehicles for toxic gene expression in MMSP cells.
PMID- 10766346
TI - Inhibition of cell proliferation in HCC-9204 hepatoma cells by a c-myc specific
ribozyme.
AB - A ribozyme (RZ) gene targeting c-myc mRNA was synthesized and cloned. Cleavage
reaction showed that cleavage of the RZ was efficient and specific. The RZ gene
containing retrovirus vector pDOR-RZ was transfected into HCC-9204 hepatoma
cells, which constitutively express high levels of c-myc using Lipofectamine.
Positively transfected cells were selected using G418. In situ hybridization
showed that both pDOR-RZ and pDOR vectors had been integrated into the chromosome
of HCC-9204 cells. Dot blot hybridization indicated that expression of the RZ was
only evident in pDOR-RZ-transfected HCC-9204 cells. Avidin-biotin complex enzyme
linked immunosorbent assay showed that c-myc expression was down-regulated.
Chromatin aggregation into compact masses, cytoplasmic vacuole degeneration, and
blurring of cytoplasm structure were observed by transmission electron microscopy
in HCC-9204-RZ cells. These results suggest that the use of a c-myc mRNA cleaving
enzyme could be most effective in tumor cells that are highly proliferative and
constitutively express high levels of c-myc.
PMID- 10766347
TI - Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C
glioma model: effect of the percentage of thymidine kinase-positive glioma cells
on treatment effect, survival time, and tissue reactions.
AB - Herpes simplex virus thymidine kinase (HSV-tk) gene transfer and ganciclovir
(GCV) administration have been suggested for the treatment of malignant gliomas.
To understand tissue responses and possible ways to improve the treatment effect,
we studied tumor growth, tissue reactions, and survival time after HSV-tk/GCV
treatment in a syngeneic BT4C rat glioma model by mixing various ratios of stably
transfected HSV-tk-expressing BT4C-tk glioma cells with wild-type BT4C glioma
cells (percentage of BT4C-tk cells: 0%, 1%, 10%, 30%, 50%, and 100%), followed by
injection into BDIX rat brains (n = 79). With the exception of some animals with
end-stage tumors, very little astroglia or microglia reactivity was detected in
the wild-type tumors as analyzed by immunocytochemistry using glial fibrillary
acid protein (GFAP)-, vimentin-, human histocompatibility leukocyte antigen-DR-,
OX-42-, and CD68-specific monoclonal antibodies. After 14 days of GCV treatment,
tumors induced with > or = 10% BT4C-tk cells showed a significant reduction in
tumor size (P < .05) and prolonged survival time (P < .01). Astrogliosis, as
indicated by a strong GFAP and vimentin immunoreactivity, was seen in the tumor
scar area. GFAP and vimentin reactivity was already present after the GCV
treatment in tumors induced with 1% BT4C-tk cells. Much less human
histocompatibility leukocyte antigen-DR-positive microglia was seen in the
treated animals, indicating low microglia reactivity and immunoactivation against
the tumor. However, GCV-treated tumors were positive for apoptosis, indicating
that apoptosis is an important mechanism for cell death in the BT4C-tk glioma
model. Our results suggest that > or = 10% transfection efficiency is required
for a successful reduction in BT4C glioma tumor size with HSV-tk/GCV treatment in
vivo. Tissue reactions after 14 days of GCV treatment are characterized by
astrogliosis and apoptosis, whereas microglia response and immunoactivation of
the brain cells appear to play a minor role. Stimulation of the microglia
response by gene transfer or other means might improve the efficacy of the HSV
tk/GCV treatment in vivo.
PMID- 10766348
TI - Adenovirus-mediated p53 gene therapy inhibits human sarcoma tumorigenicity.
AB - Mutations of the p53 tumor-suppressor gene are the most frequent genetic
abnormality in soft tissue sarcomas. Because these rare tumors also respond
poorly to standard chemotherapy and bear a 50% 5-year mortality rate, we
investigated the possible therapeutic benefits of p53 gene restoration in
sarcomas. We constructed Ad5p53, which is an E1A-deleted, replication-deficient
adenovirus expressing a cytomegalovirus promoter-driven wild-type p53 cDNA with a
Flag sequence tag. SKLMS-1 human leiomyosarcoma cells containing a mis-sense p53
point mutation were effectively transduced with Ad5p53. Increasing levels of Flag
p53 protein, as well as dose-dependent p21Cip1 induction, were observed through a
dose range of 10-500 plaque-forming units (PFU)/cell. In vitro administration of
Ad5p53 as a single 100 PFU/cell dose caused 40-60% growth inhibition of SKLMS-1
cells at posttreatment days 4, 6, and 8 compared with untreated or viral control
treated-cells (P < .05, Student's t test). Relative to these same controls, in
vivo treatment of SKLMS-1-bearing severe combined immunodeficient mice with 6 x
10(9) PFU of Ad5p53 by intratumoral injection resulted in a 35-day tumor growth
delay and complete tumor regression in 40% of mice (P < .05, Student's t test).
The expression of virally derived p53 mRNA in Ad5p53-treated tumor tissues was
detected in treated tumor specimens by reverse transcriptase polymerase chain
reaction. Reduced intratumoral cellularity and the presence of p53 staining in
adjacent normal tissue, consistent with delivery of exogenous p53 to the tumor
target, were evident only in Ad5p53-treated tumors after immunohistochemical
staining for p53. These results indicate that wild-type p53 gene restoration in
sarcomas retards tumor growth and may come to be usefully applied to the clinical
treatment of this disease as a single regimen or in combination with conventional
therapies.
PMID- 10766350
TI - Gene therapy of metastatic colon carcinoma: regression of multiple hepatic
metastases by adenoviral expression of bacterial cytosine deaminase.
AB - Colon carcinoma accounts for 20% of deaths due to malignancies in the Western
world. Once metastases occur, therapeutic options are limited, with an
approximate 5-year survival of only 5%. To investigate the potential of new gene
therapeutic approaches, a hepatic micrometastasis model of colon carcinoma in
BALB/c mice was established. Inoculation of syngeneic MCA26 colon carcinoma cells
into the spleens of 18- to 20-week-old mice resulted in the formation of multiple
hepatic metastases. Selective transduction of developing hepatic metastases was
demonstrated using a beta-galactosidase-expressing recombinant adenovirus.
Cytosine deaminase (CD) can metabolize 5-fluorocytosine into the chemotherapeutic
reagent 5-fluorouracil (5FU). The antitumoral potential of this suicide gene
therapy approach was explored by systemic application of a recombinant
replication-deficient adenovirus encoding for the bacterial CD gene under the
control of the cytomegalovirus promoter (Ad.CMV-CD). Injection into the tail vein
of tumor-bearing mice resulted in delayed tumor growth with significant reduction
in hepatic metastases. The potential of this experimental approach for possible
future clinical applications was evaluated by investigating adenoviral
transduction efficiency, 5FU sensitivity, and 5-fluorocytosine-dependent Ad.CMV
CD toxicity in a variety of human colon cancer cell lines. Although the murine
cell lines MCA26 and CC36 were highly sensitive to 5FU, the human colon cancer
cell lines showed a 1-100 times higher resistance to 5FU. Specific Ad.CMV-CD
toxicity correlates with 5FU toxicity. Transduction efficiency in human colon
carcinoma cell lines was shown to be 10-1700 times higher compared with murine
cell lines, thus compensating for 5FU resistance. In conclusion, suicide gene
therapy using CD may be promising as an adjuvant treatment regimen for hepatic
micrometastases of human colon carcinoma.
PMID- 10766349
TI - A prototype transduction tag system (delta LNGFR/NGF) for noninvasive clinical
gene therapy monitoring.
AB - The dramatic expansion of clinical gene therapy trials requires the development
of noninvasive clinical monitoring procedures, which provide information about
expression levels, expression kinetics, and spatial distribution of transduced
therapeutic genes. With the development of such procedures, invasive sampling of
tissue probes from patients potentially could be reduced significantly. In this
study, an experimental platform for the rational design and in vitro testing of
suitable receptor-ligand couples as components of future transduction tag systems
for noninvasive gene therapy monitoring applications was developed. Initially,
the feasibility of the delta LNGFR/nerve growth factor (NGF) transduction tag
system was investigated; this system employs a mutated version of the low
affinity nerve growth factor receptor (p75mut or delta LNGFR) lacking the entire
cytoplasmic domain. Specific binding of 125I-radiolabeled NGF was demonstrated
for two stable delta LNGFR-transduced cell lines, but not for delta LNGFR
negative parental control cell lines. An additional binding analysis performed in
a MicroImager directly confirmed binding of radiolabeled ligands (125I-NGF, 125I
anti-p75 monoclonal antibody) to the p75mut expressed on intact target cells, but
not on control cells. Subsequent binding studies employing NGF radiolabeled with
the positron-emitting isotope 124I demonstrated a specific binding for LNGFR+
PC12 cells. Consequently, the first in vitro proof of a transduction tag approach
based on the specificity of the 124I-NGF/LNGFR interaction was provided, which
opens up the possibility for future noninvasive positron emission tomography
monitoring in clinical gene therapy trials.
PMID- 10766351
TI - SEREX analysis for tumor antigen identification in a mouse model of
adenocarcinoma.
AB - Evaluation of immunotherapy strategies in mouse models of carcinoma is hampered
by the limited number of known murine tumor antigens (Ags). Although tumor Ags
can be identified based on cytotoxic T-cell activation, this approach is not
readily accomplished for many tumor types. We applied an alternative strategy
based on a humoral immune response, SEREX, to the identification of tumor Ags in
the murine colon adenocarcinoma cell line MC38. Immunization of syngeneic C57BL/6
mice with MC38 cells by three different methods induced a protective immune
response with concomitant production of anti-MC38 antibodies. Immunoscreening of
an MC38-derived expression library resulted in the identification of the
endogenous ecotropic leukemia virus envelope (env) protein and the murine ATRX
protein as candidate tumor Ags. Northern blot analysis demonstrated high levels
of expression of the env transcript in MC38 cells and in several other murine
tumor cell lines, whereas expression in normal colonic epithelium was absent.
ATRX was found to be variably expressed in tumor cell lines and in normal tissue.
Further analysis of the expressed env sequence indicated that it represents a
nonmutated tumor Ag. Polynucleotide immunization with DNA encoding the env
polypeptide resulted in strong and specific antibody responses to this self Ag in
all immunized mice. Thus, SEREX offers a rapid means of identifying tumor Ags in
murine cancer models.
PMID- 10766353
TI - A novel, long-circulating, and functional liposomal formulation of antisense
oligodeoxynucleotides targeted against MDR1.
AB - The goal of this study was to develop a small, stable liposomal carrier for
antisense oligodeoxynucleotides (asODN) that would have high trapping
efficiencies and long circulation times in vivo. Traditional cationic liposomes
aggregate to large complexes and, when injected intravenously, rapidly accumulate
in the liver and lung. We produced charge-neutralized liposome-asODN particles by
optimizing the charge interaction between a cationic lipid and negatively charged
asODN, followed by a procedure in which a layer of neutral lipids coated the
exterior of the cationic lipid-asODN particle. The coated cationic liposomes had
an average diameter of 188 nm and entrapped 85-95% of the asODN. The
biodistribution and pharmacokinetics of an 18-mer 125I-labeled phosphorothioate
ODN formulated by this method were determined after tail vein injection in mice.
The majority of the asODN was cleared from blood, with a half-life of >10 hours
compared with <1 hour for free asODN. When coupled with an anti-CD19 targeted
antibody, this formulation was also effective at delivering an MDR1 asODN to a
multidrug-resistant human B-lymphoma cell line in vitro, decreasing the activity
of P-glycoprotein. No inhibition was found for nontargeted formulations or for
free asODN. A number of therapeutic opportunities exist for the use of small,
stable, long-circulating, and targetable liposomal carriers such as this, with
high trapping efficiencies for asODN.
PMID- 10766352
TI - Enhancement of immunogenicity of tumor cells by cotransfection with genes
encoding antisense insulin-like growth factor-1 and B7.1 molecules.
AB - Insulin-like growth factor-1 (IGF-1) is expressed in many tumor cell lines and
has a role in both normal cell proliferation and in the growth of cancers. Tumor
cells transfected with a vector encoding an IGF-1 antisense cDNA transcriptional
cassette driven by the mouse metallothionein-1 promoter become immunogenic and
lose their tumorigenicity in syngeneic animals. The enhanced immunogenicity is
associated with an up-regulation in the expression of major histocompatibility
complex class I molecule on cell surfaces. Blockade of the expression of IGF-1 in
tumor cells by the IGF-1 antisense RNA approach is not uniformly effective in the
induction of antitumoral protective immunity in low and nonimmunogenic tumor
model systems. Here, we report that the immunogenicity of hepa 1-6 hepatoma and
SMCC-1 colon carcinoma cells, which are poorly immunogenic and unresponsive to
antisense IGF-1 gene transfer, can be induced by cotransfection with genes
encoding antisense IGF-1 and mouse B7.1 molecules. The tumor cells modified in
this manner become strongly immunogenic and can be used as a cellular vaccine to
induce a protective immune response in vivo. Immunization with the transfected
tumor cells also results in regression of the established hepa 1-6 hepatoma and
SMCC-1 colon cancer. The immunity is tumor-specific and is mediated by CD3+ CD8+
T cells. Cytotoxic T lymphocytes generated in vitro by priming naive spleen cells
and in vivo by immunizing mice with the double-transfected tumor cells
specifically lysed autologous tumors cells and were effective in adoptive
immunotherapy. The data suggest that modification of tumor cells in vitro by
cotransfection with genes encoding antisense IGF-1 and B7.1 molecules may open a
new avenue for cancer immunogene therapy.
PMID- 10766354
TI - Construction and function of a recombinant adenovirus encoding a human aquaporin
1-green fluorescent protein fusion product.
AB - Transfer of the human aquaporin 1 (hAQP1) gene provides a novel way to
potentially correct the severe salivary hypofunction associated with therapeutic
radiation for head and neck cancer. To facilitate the study of individual cells
transduced with this gene, we have designed a fusion product of the hAQP1 and
jellyfish green fluorescent protein (GFP) cDNAs. An expression plasmid,
pACCMVhAQP1GFP, and a recombinant adenovirus, AdhAQP1GFP, encoding this fusion
product were constructed. Both the recombinant plasmid and virus directed the
expression of the encoded, 55-kDa fusion protein (hAQP1GFP), which was detected
in the plasma membranes of several epithelial cell lines (293, SMIE, and A5).
hAQP1GFP was functionally active and facilitated fluid movement across a
polarized salivary epithelial cell monolayer (approximately 5-fold noninfected
controls) in response to an osmotic gradient. In response to a hypotonic
challenge, individual epithelial cells expressing the fusion protein exhibited
significantly more capacitance (used herein as an indicator of cell swelling)
than control cells. Conversely, in response to a hypertonic challenge, individual
infected cells shrunk more rapidly (approximately 2- to 3-fold) and to a greater
extent than control cells. We conclude that AdhAQP1GFP is a useful experimental
tool to identify and study individual cells expressing a water channel transgene.
PMID- 10766355
TI - Characterization and transduction of a retroviral vector encoding human
interleukin-4 and herpes simplex virus-thymidine kinase for glioma tumor vaccine
therapy.
AB - Vaccination with cytokine-transduced tumor cells represents a potentially
important approach to the treatment of central nervous system tumors. We have
recently demonstrated the therapeutic efficacy of tumor cell vaccines expressing
the murine interleukin 4 (IL-4) and the herpes simplex virus-thymidine kinase in
a rat brain tumor model in which nonirradiated vaccine cells can be eliminated by
the subsequent administration of ganciclovir. In this report, we demonstrate the
construction and characterization of a retroviral vector that encodes human IL-4,
neomycin phosphotransferase, and herpes simplex virus-thymidine kinase genes for
use in human clinical trials. An MFG-based retroviral vector was used to generate
the recombinant retrovirus, TFG-hIL4-Neo-Tk, in which a long terminal repeat
driven polycistronic transcript encodes three cDNAs that are linked and
coexpressed using two intervening internal ribosome entry site fragments from the
encephalomyocarditis virus. The amphotropic retroviral vector TFG-hIL4-Neo-Tk was
then used to infect human primary glioma cultures and skin-derived fibroblasts.
After infection and G418 selection, cells produced 89-131 ng/10(6) cells/48 hours
of human IL-4, which was determined to be biologically active. Transduced glioma
cells were highly sensitive to the cytotoxic effect of ganciclovir. These data
demonstrate the suitability of the TFG-hIL4-Neo-Tk vector for therapeutic studies
of cytokine-transduced autologous tumor vaccination in patients with malignant
gliomas.
PMID- 10766356
TI - Anti-K-ras ribozyme induces growth inhibition and increased chemosensitivity in
human colon cancer cells.
AB - Colon cancer is one of the carcinomas that is resistant to a variety of
therapies. To develop a new therapy by regulating the activated K-ras gene in
colon cancers, we prepared synthetic DNA encoding the ribozyme (catalytic RNA),
and inserted it into an expression vector (LNCX) originated from a retrovirus.
Transfection of the vector into SW620 human colon cancer cells brought about
significant suppression of K-ras mRNA synthesis and inhibition of the cell
growth. Studies in athymic mice, in which K-ras ribozyme-introduced SW620 cells
were transplanted, also revealed a marked reduction of tumor growth in vivo.
Furthermore, the ribozyme-introduced tumors became more sensitive to treatment
with anti-cancer drugs such as cisplatin, adriamycin, 5-fluorouracil,
vincristine, and etoposide. These data suggest that the possible efficacy of anti
K-ras ribozyme increases the chemosensitivity of human colon cancers as well as
the inhibitory effect on the growth of human colon cancers.
PMID- 10766357
TI - B-cell lymphoma idiotypes chimerized by gene targeting can induce tumor immunity.
AB - Immunization with modified immunoglobulin (Ig) idiotypes (Ids) of B-cell
lymphomas is an attractive approach of experimental tumor immunotherapy. We show
here that B-lymphoma cells can be gene-modified by homologous recombination at
the Ig heavy chain locus. Although it has been demonstrated previously that a
protein vaccine containing a mouse/human chimeric Ig had no immunostimulatory
effect, we show that a xenogeneic Fc segment attached to the Id by gene targeting
in autologous murine tumor cells can serve as an immunogenic carrier and is
capable of inducing tumor protection. A prerequisite for successful vaccination
is the delivery of tumor cells that have been engineered to express the Id in the
chimeric form rather than administration of the soluble chimeric protein. Also
DNA vaccination with plasmids encoding chimeric Ids was reported to induce an
anti-idiotypic response, suggesting that there might be related mechanisms such
as enhanced antigen presentation. Immunization with engineered lymphoma cells is
a very potent protocol: in the cell-based setting, minute levels of expression in
the gene-targeted cells are sufficient to confer tumor immunity. Because the
titers of anti-Id antibodies induced do not reflect the degree of tumor
protection, the immune mechanisms responsible for tumor rejection cannot be
ascribed exclusively to a humoral response.
PMID- 10766358
TI - Equipment for drug release testing of medicated chewing gums.
AB - An apparatus was specially designed and constructed for release testing of
medicated chewing gums. The adjustable instrumental settings such as temperature,
chewing frequency, chewing time, volume of test medium, distance between the jaws
and twisting angle increased the versatility of the apparatus. Selection of the
test medium was also an important parameter. Each sample was kneaded mechanically
in separate test chambers and the drug release was followed by sampling and HPLC
analysis. Different gum formulations were tested and the obtained results
demonstrated satisfactory release curves for a variety of formulations and active
ingredients. The tested gum formulations comprised nicotine, meclizine,
dimenhydrinate and xylitol. The apparatus proved to be suitable in product
control of commercial batches but also a useful tool in the research and
development of medicated gum formulations.
PMID- 10766359
TI - The analysis of basic and acidic compounds using non-aqueous CE and non-aqueous
CE-MS.
AB - It has been shown that non-aqueous capillary electrophoresis (NACE) can provide
improved separations in comparison to those obtained using conventional CE under
aqueous conditions (ACE). Previous work carried out in our laboratories involving
initial investigations into the technique have been reported. Based on the
findings of that work it was possible to separate a variety of basic
pharmaceuticals from selected impurities and to obtain the successful separation
of some hydrophobic sulphonic acids. The successful coupling of NACE to mass
spectrometry (NACE-MS) has also been demonstrated.
PMID- 10766360
TI - Analysis of ACE-inhibitors by CE using alkylsulfonic additives.
AB - Capillary electrophoresis (CE) was applied to the determination of angiotensin
converting enzyme (ACE) inhibitors in pharmaceuticals (tablets). Since a free
solution CE system failed to reach a complete separation of closely related
compounds (lisinopril, ramipril, benazepril, quinapril), alkylsulfonic additives
(sodium heptansulfonate and (+)-10-camphorsulphonic acid) were added to the
running buffer: improved separations were obtained suggesting a favourable effect
of ion-pairing interactions between analytes and additives. The separations were
carried out in acidic medium and a systematic investigation of electrophoretic
parameters was made to evaluate the performance of the selected additives. Under
the optimized conditions, ramipril and benazepril in their commercial dosage
forms were determined confirming the applicability of the developed CE approach
to the analysis of pharmaceutical samples; the results were also compared with
those obtained applying a previously described and validated HPLC method.
PMID- 10766361
TI - Quantitation and validation of cis-camphoric acid 3-methyl ester and cis
camphoric acid 1-methyl ester using CE.
AB - The 1- and 3-methyl esters of cis-camphoric acid, the active agents of a mild
laxative (Flubilar) have been simultaneously assayed using capillary
electrophoresis (CE). The compounds are completely separated using a sodium
acetate buffer pH 4.0, 40 mmol/l. In order to obtain reproducible results, [+]
naproxen has been used as internal standard (IS). Initially migration times
changed over 50% within a series of 20 runs. This problem has been overcome by
using an overnight capillary preconditioning (1 mol/l NaOH, 1.5 h) and subsequent
equilibrating (running buffer, 12 h). Thereby a precision corresponding to a CV
%, of about 1.17 and 1.42 for the cis-camphoric acid methyl esters has been
obtained (six series of n = 10 runs each). The method has been validated
regarding specificity, accuracy, precision, linearity and robustness. In order to
test robustness, all key parameters have been considered. The result of the
validation is given in nine tables. In the case under investigation, lamp age and
wavelength accuracy are the most critical parameters. Therefore, the lamp age
should be limited to about 1000 h. The wavelength accuracy can be indirectly
controlled using quality assurance samples. According to the fundamental
mechanisms in CE, changes in the voltage and in the temperature influence
migration times and peak areas. However, these effects are very well compensated
using an IS. Slight variations of the parameters buffer pH and molarity rinsing
times, storage conditions of buffers and samples as well as the capillary
material had little or no influence on the analytical results.
PMID- 10766362
TI - LC-MS-MS determination of exemestane in human plasma with heated nebulizer
interface following solid-phase extraction in the 96 well plate format.
AB - A sensitive, specific and rapid analytical method for the quantitation of
exemestane (EXE) in human plasma has been developed. EXE, 6-methylen-androsta-1,4
diene-3,17-dione, is an orally active irreversible steroidal aromatase inhibitor
used for the therapy of metastatic postmenopausal breast cancer, with estrogen
dependent pathological conditions. The method involves extraction of EXE from
human plasma by solid phase extraction using C2 endcapped sorbent in the 96 well
plate format (50 mg/2 ml). After conditioning of the sorbent with 1 ml of
acetonitrile (x2) the plates were rinsed with 1 ml of water (x2). The prepared
samples (0.5 ml plasma, spiked with [13C3] EXE as internal standard (IS) and
diluted with 0.5 ml water) were loaded and drawn through the plate with a minimum
of vacuum. The plates were then washed with 1 ml acetonitrile:water (10:90)
followed by a drying step for 30 min at full vacuum. Elution was by 0.15 ml of
0.1% trifluoracetic acid in acetonitrile (x2) under a minimum of vacuum. Aliquots
of 80 microl were finally injected into the LC-MS-MS system. A Zorbax SB C8
column (4.6 x 150 mm, 5 microm) was used to perform the chromatographic
separation; the mobile phase was 100% acetonitrile. MS detection used the heated
nebulizer interface, with multiple reaction monitoring (MRM) (297-->121 m/z for
EXE and 300-->123 m/z for IS) operated in positive ion mode. A weighed linear
regression analysis (weighing factor 1/x2) was used to calculate EXE
concentration in standard and unknown samples. The method was fully validated in
the concentration range 0.05-25 ng ml(-1).
PMID- 10766363
TI - Determination of linsidomine in human plasma by tandem LC-MS with ESI.
AB - A sensitive method for the determination of linsidomine in plasma was developed,
using high-performance liquid chromatographic (HPLC) separation with tandem mass
spectrometric detection. Linsidomine was derivatised with propyl chloroformate
and extracted with tert-butyl methyl ether/1,2-dichloroethane (55:45, v/v), back
extracted into HCl (0.01 M) followed by alkalinisation and back-extraction into
ether; the final ether extract evaporated, reconstituted in mobile phase and then
separated on a Phenomenex Luna C18 (2) 5 micron 2.1 x 150 mm column with a mobile
phase consisting of methanol water formic acid (98/100%) (400:600:0.05, v/v/v) at
a flow-rate of 0.4 ml min(-1). Detection was achieved by a Finnigan MAT mass
spectrometer (LCQ) at unit resolution in the selected reaction monitoring (SRM)
mode monitoring the transition of the protonated molecular ion m/z 257.0 to the
product ion m/z 86.0. The mean recovery for linsidomine was 51% with a lower
limit of quantification of 0.70 ng/ml using 1 ml plasma for extraction. This LC
MS/MS method for the determination of linsidomine in human plasma allows for
better specificity and a higher sample throughput than the traditional LC-UV
methods. It also demonstrates the profound effect that the composition of acidic
modifiers and matrix constituents can have on the electrospray ionisation (ESI)
of the analyte.
PMID- 10766364
TI - The determination of RWJ-38705 (tramadol N-oxide) and its metabolites in
preclinical pharmacokinetic studies using LC-MS/MS.
AB - A rapid and reliable analytical method is described for the simultaneous
determination of RWJ-38705 (tramadol N-oxide) and several of its major
metabolites in the plasma of Sprague-Dawley rats and Beagle dogs. Sample
preparation using solid phase extraction was followed by reversed phase liquid
chromatography (LC) coupled with tandem mass spectrometric (MS/MS) detection in
the positive ionization mode. The assay was linear for all analytes over
concentrations ranging from approximately 6 to 2000 ng/ml. The inter-assay
reproducibility was generally less than 15% while accuracy values were within 13%
of theoretical. The overall recovery of the analytes ranged from approximately 40
to 64% in rat plasma and 53-75% in dog plasma. This assay has proven to be
sensitive, specific and reproducible, and it has been readily implemented in
preclinical PK studies. Representative plasma concentration versus time profiles
resulting from administration of TNO to rats and dogs are presented in this
communication.
PMID- 10766365
TI - LC and LC-MS-MS analyses of undeclared codeine in antiasthmatic Chinese
proprietary medicine.
AB - This paper describes an accurate and sensitive reversed phase high-performance
liquid chromatographic (RP-HPLC) method for the detection and quantification of
undeclared codeine in a Chinese Proprietary Medicine (CPM) for asthma. A rapid
and specific liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS)
method was applied to confirm the presence of codeine by selected reaction
monitoring (SRM). Codeine was extracted from the capsules by dissolving in sodium
dihydrogen phosphate buffer (10 mM, pH = 2.2) and ethanol, then made alkaline (pH
= 9) and extracted using chloroform. The amount of codeine in AsthmaWan was found
to be 61.8 microg/capsule (R.S.D. = 7.9%, n = 9). Excellent resolution was
obtained despite the complexity of the product which claimed to contain at least
nine herbal ingredients, none of which will give rise to codeine. As a further
confirmation method, LC-MS-MS is accurate and specific. The LC method has been
validated for linearity, limit of detection, limit of quantification, accuracy
and specificity. Greater awareness of and control over undeclared drugs in
complementary medicine are necessary to ensure patients' safety.
PMID- 10766366
TI - The determination of oxalic acid, oxamic acid, and oxamide in a drug substance by
ion-exclusion chromatography.
AB - Oxalic acid, oxamic acid and oxamide are potential impurities in some active
pharmaceutical ingredients (API). The retention and separation of oxalic and
oxamic acids are particularly challenging using conventional reversed-phase HPLC
due to their high polarity. An ion-exclusion chromatography (IEC) method has been
shown to provide good separation and sensitivity for the three oxalate-related
impurities in a hydrophobic API matrix. The method uses a Dionex IonPac ICE-ASI
column with 95/5 (v/v) 0.1% sulfuric acid/acetonitrile as the mobile phase and UV
detection at 205 nm. Development and validation of this method are described.
PMID- 10766367
TI - Validation of a method for the determination of zolpidem in human plasma using LC
with fluorescence detection.
AB - A sensitive and selective high-performance liquid chromatography (HPLC) method
was developed for the determination of zolpidem in human plasma. Zolpidem and the
internal standard (trazodone) were extracted from human plasma that had been made
basic. The basic sample was loaded onto a conditioned Bond Elut C18 cartridge,
rinsed with water and eluted with methanol. Forty microliters were then injected
onto the LC system. Separation was achieved on a C18 column (150 x 4.6 mm, 5
microm) with a mobile phase composed of acetonitrile:50 mM potassium phosphate
monobasic at pH 6.0 (4:6, v/v). Detection was by fluorescence, with excitation at
254 nm and emission at 400 nm. The retention times of zolpidem and internal
standard were approximately 4.7 and 5.3 min, respectively. The LC run time was 8
min. The assay was linear in concentration range 1-400 ng/ml for zolpidem in
human plasma. The analysis of quality control samples for zolpidem (3, 30, and
300 ng/ml) demonstrated excellent precision with relative standard deviations
(RSD) of 3.7, 4.6, and 3.0%, respectively (n = 18). The method was accurate with
all intraday (n = 6) and overall (n = 18) mean concentrations within 5.8% from
nominal at all quality control sample concentrations. This method was also
performed using a Gilson Aspec XL automated sample processor and autoinjector.
The samples were manually fortified with internal standard and made basic. The
aspec then performed the solid phase extraction and made injections of the
samples onto the LC system. Using the automated procedure for analysis, quality
control samples for zolpidem (3, 30, and 300 ng/ml) demonstrated acceptable
precision with RSD values of 9.0, 4.9, and 5.1%, respectively (n = 12). The
method was accurate with all intracurve (n = 4) and overall (n = 12) mean values
being less than 10.8% from nominal at all quality control sample concentrations.
PMID- 10766368
TI - Determination of MAG-camptothecin, a new polymer-bound camptothecin derivative,
and free camptothecin in dog plasma by HPLC with fluorimetric detection.
AB - A high throughput. selective and sensitive high-performance liquid
chromatographic (HPLC) method for the determination of a water-soluble polymer
bound Camptothecin conjugate (MAG-CPT) and Camptothecin (CPT) in dog plasma has
been developed and validated. The method involved the analysis of free and total
CPT (free + polymer-bound). Free CPT (intact lactone plus carboxylate) was
extracted from acidified plasma using Oasis SPE material in 96-well plates. For
the assay of the total CPT, plasma proteins were first precipitated with methanol
in a 96-well plate containing a 10-microm melt blown polypropylene membrane. The
methanolic supernatant was separated and collected into a second 96-well plate by
simply applying vacuum to the plate. After hydrolysis at pH 9.8 for 18 h and re
acidification, samples were injected directly from the collection plate onto the
HPLC system. MAG-CPT concentration was then calculated by subtraction of free
from total CPT. The LLOQs of the method were 1.17 ng/ml for free CPT and 103.10
ng/ml (as CPT equivalent) for MAG-CPT using 0.1 and 0.05 ml of plasma,
respectively. Linearity, precision, accuracy and recovery of the method were
evaluated. The stability of MAG-CPT in plasma alone and after its stabilisation
was carefully evaluated. No interference from blank dog, mouse and human plasma
was observed. The suitability of the method for in vivo samples was assessed by
the analysis of samples obtained from dogs that had received a single and 5-day
repeated dose of MAG-CPT.
PMID- 10766369
TI - Evaluation of degradation of urinary catecholamines and metanephrines and
deconjugation of their sulfoconjugates using stability-indicating reversed-phase
ion-pair HPLC with electrochemical detection.
AB - The possibility of the deconjugation of urinary catecholamine sulfates (CA-S) and
metanephrine sulfates (MN-S) during storage was studied using a reversed-phase
ion-pair HPLC method with electrochemical detection. Stability profiles of
catecholamines (norepinephrine (NE), epinephrine (E) and dopamine (DA)) and
metanephrines (normetanephrine (NM) and metanephrine (MN)) in preserved and
unpreserved pooled urine and aqueous samples stored at 10 and 30 degrees C over 8
days were compared. Results showed that these compounds exhibited stable or
declining profiles in aqueous samples but fluctuating profiles in pooled urine
samples. It was concluded that deconjugation of CA-S and MN-S occurred in both
preserved and unpreserved urine samples. Therefore, at 10 and 30 degrees C,
levels of detected urinary catecholamines and metanephrines could be affected by
both the degradation of the free amines and deconjugation of the CA-S and MN-S.
Based on these findings, another batch of unpreserved urine and aqueous samples
were prepared and stored at -80 degrees C. Under this condition, all compounds
were found to be stable with less than 10% variations in both unpreserved urine
and aqueous samples for at least 22 days. These indicated that urine samples
could be stored unpreserved at -80 degrees C for at least 3 weeks without
significant degradation of the free amines or deconjugation of their
sulfoconjugates.
PMID- 10766370
TI - Determination of the kinetics of rat UDP-glucuronosyltransferases (UGTs) in liver
and intestine using HPLC.
AB - Uridinediphosphoglucuronosyl transferases (UGTs) are a group of membrane bound
proteins which catalyze the transfer of glucuronic acid from UDP-glucuronic acid
to a wide variety of xenobiotics and drug molecules enabling them to be
eliminated. The major UGT isoforms found in the rat are 1A1, 1A6, 2B1 and 2B12.
Conventional methods for the assay of glucuronides (GLs) include TLC, extraction
and colorimetry or quantification of the aglycone, liberated after hydrolyzing
the GL with beta-glucuronidase. However these techniques cannot distinguish
between isomeric GLs or GLs of multiple acceptor site substrates. Therefore the
purpose of this study was to develop simple and sensitive HPLC methods for the
direct and simultaneous analysis of the GL(s) and their aglycones without the
drawbacks of the conventional methods. The three classical substrates we chose
were 4-methylumbelliferone (4MU), testosterone (TES) and 8-hydroxyquinoline
(8HOQ) representing UGT isoforms 1A6, 2B1 and 2B12 of the rat family,
respectively. Here we report the validated HPLC conditions, for the detection and
separation of 4-methylumbelliferone glucuronide (4MUG), testosterone glucuronide
(TESG) and 8-hydroxyquinoline glucuronide (8HOQG) and their aglycones in
incubation media containing male Sprague-Dawley rat liver and intestinal
microsomal preparations. The separations were achieved on a Zorbax SB-CN column
(150 x 4.6 mm, 5 micron). The analysis time for the separation of TES, 8HOQ and
4MU and their glucuronides were 17, 12 and 30 min, respectively. The methods
showed excellent linearity (r2 > 0.99) over the concentration ranges tested (0.25
5.0 nmoles of TESG; 0.125-18.75 nmoles of 8HOQG and 0.125-12.5 nmoles of 4MUG),
good precision and accuracy (RSD<2.5%). Inter-day variability studies (n = 3)
showed no significant difference between the regression lines obtained on the
three days. Recoveries were good ( > 90%) at all three points (low, mid-point,
high) of the standard curve. The limits of detection were 0.125, 0.1 and 0.1
nmole for TESG, 8HOQG and 4MUG. respectively. The above methods were used to
estimate kinetic parameters such as Vmax and Km for the GLs of the three
substrates in both liver and intestinal tissue preparations and the values were
comparable with previously reported results. UGT2B1 was found primarily in the
liver while UGTs 1A6 and 2B12 were present in comparable amounts in both tissues.
PMID- 10766371
TI - Stability-indicating LC assay of and impurity identification in homoharringtonine
samples.
AB - Homoharringtonine (HHT) is a potent myelosuppressive agent and has antitumor
activity. Recent studies suggest that it inhibits tumor growth by inducing
apoptosis. HHT is an ester of the alkaloid cephalotaxine. It is isolated from
genus Cephalotaxus. At least ten HHT analogs have been identified from
cephalotaxus extracts. High performance liquid chromatography (HPLC) separations
of the cephalotaxine alkaloids in plant extracts have been reported, they have
not been validated as specific and stability-indicating for HHT. Due to the
complexity of the alkaloid extracts, it is conceivable that additional analogs
may still be unresolved from HHT. This paper presents an improved and validated
HPLC assay for HHT. The assay is stability-indicating, precise (R.S.D. < 1%),
linear (r2 = 0.9999), and accurate (error < 1%). The assay reveals three
congeners present as impurities in HHT samples. Two are new and have not been
previously reported. Identities of the impurities and forced decomposition
products, elucidated with their HPLC retention and spectral data, are also
presented.
PMID- 10766372
TI - Determination of loperamide in rat plasma and bovine serum albumin by LC.
AB - A rapid, isocratic liquid chromatographic (LC) method was developed for the
determination of loperamide (Lop) in solutions of bovine serum albumin (BSA) and
rat plasma. Prior to LC analysis, BSA solutions or rat plasma samples were
treated with metaphosphoric acid to precipitate protein. Supernatant was directly
injected onto a C18 reverse phase column and loperamide was monitored by a UV
detector set at 195 nm. The concentrations of Lop in both rat plasma and BSA
solution samples were determined by comparison with their calibration curves,
which were generated from the peak area ratio of Lop to internal standard,
clomipramine versus loperamide concentration. The calibration curves were linear
in the range 0-3.0 microg ml(-1) of Lop for the BSA solution sample and 0-1.0
microg ml(-1)for the rat plasma sample. Overall recoveries of loperamide added to
BSA and rat plasma samples were 101.4 and 95.5%, respectively. The method is
simple (no extraction), rapid (22 min separation time), sensitive (the detection
limit of loperamide is 50 ng ml(-1) for the BSA solution sample and 100 ng ml(-1)
for the rat plasma sample), reproducible (within-day R.S.D. of 2.59-7.11%, among
day R.S.D. of 1.25-5.97%), and suitable for routine analysis of loperamide in rat
plasma and BSA solution samples.
PMID- 10766373
TI - Bioanalysis of PUFA metabolism and lipid peroxidation in coronary
atherosclerosis.
AB - Twenty eight men (age 34-77 years) who underwent an elective coronary angiography
for coronary artery disease (CAD), were studied. They were divided into group A
(luminal narrowing < 50%; n = 11) and group B (luminal narrowing > 50%; n = 17).
Capillary gas chromatography was used for determination of fatty acids. Retinol
and alpha-tocopherol were analyzed by reversed-phase high-performance liquid
chromatography (HPLC), other parameters were determined spectrofluorometrically
and spectrophotometrically. Severe coronary atherosclerosis in group B was
associated with higher serum low density lipoprotein/high density lipoprotein
(LDL/HDL) cholesterol ratio, triacylglycerols, and phospholipids (P < 0.05).
Erythrocyte membrane fatty acids C14:0, C16:1 and C22:6n3 were significantly
higher in group B (P < 0.05). We found significantly higher plasma
polyunsaturated fatty acids (PUFA) C18:3n6 in group B, whereas plasma linoleic
acid was not changed significantly. There was a significant increase of IDL
C18:0, LDL-C14:0 and HDL-C22:6n3 PUFA in group B. We conclude that disturbances
in saturated fatty acids (SUFA) and PUFA metabolism are associated with coronary
atherogenesis. Such abnormalities may include enhanced extrahepatic transport of
C14:0 SUFA via LDL and its incorporation into cell membranes, and enhanced
clearance of anti atherosclerotic C22:6n3 PUFA via serum HDL.
PMID- 10766374
TI - Validation of a method for the determination of (R)-warfarin and (S)-warfarin in
human plasma using LC with UV detection.
AB - A sensitive and selective chiral high-performance liquid chromatography (HPLC)
method was developed for the determination of (R)-warfarin and (S)-warfarin in
human plasma. (R)- and (S)-warfarin and the internal standard (oxybenzone) were
extracted from human plasma that had been made acidic with 1 N sulfuric acid into
ethyl ether. The ethyl ether layer was removed and evaporated, and the residue
was reconstituted in 200 microl of acetonitrile. A 50-microl aliquot was injected
onto the HPLC system. Separation was achieved on a beta-cyclodextrin column (250
x 4.6 mm, 5 microm) with a mobile phase composed of acetonitrile:glacial acetic
acid:triethylamine (1000:3:2.5, v/v/v). Detection was by ultraviolet absorbance
at 320 nm. Late-eluting peaks were diverted from the analytical column by using a
beta-cyclodextrin precolumn (50 x 4.6 mm, 5 microm) and a column switching
device. The retention times of (R)- and (S)-warfarin and the internal standard
were approximately 7.7, 6.9 and 4.0 min, respectively. The run time was 15 min.
The assay was linear in concentration ranges of 12.5-2500 ng/ml for (R)- and (S)
warfarin in human plasma. The analysis of quality control samples for (R)- and
(S)-warfarin (25.0, 400 and 2000 ng/ml) demonstrated excellent precision with
relative standard deviations (R.S.D.) for (R)-warfarin of 10.9, 2.8, and 2.8%,
respectively (n = 18), and for (S)-warfarin of 7.0, 2.4 and 2.6%, respectively (n
= 18). The method was accurate with all overall (n = 18) mean concentrations
being less than 6.0% from nominal at all quality control sample concentrations.
PMID- 10766375
TI - Enantiomeric separation of an aryloxyphenoxypropanoic acid by CE and LC.
AB - A capillary electrophoresis (CE) and an high performance liquid chromatography
(HPLC) chiral separation have been developed for an aryloxyphenoxypropanoic acid,
2-[4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy]propanoic acid, a new antitumor agent.
The racemic mixture is analyzed, without derivatization, as the free acids. The
CE assay is based on inclusion complexation with hydroxypropyl-beta-cyclodextrin.
HPLC separation is achieved with a CSP column with the glycopeptide, teicoplanin,
as the chiral selector. Both methods give baseline resolution to the R-and S
isomers. The methods were validated for assay and for optical purity assessment
of the R-isomer. For assay, the HPLC method is precise (RSD < 0.6%), accurate
(error, 0.5%) and linear (r2 = 0.9998). It is able to precisely (RSD = 0.5%) and
accurately (error, 0.9%) detect 0.3-6.0% of one isomer (S) in the other (R). The
CE assay is much less precise and accurate than HPLC. It is a good alternative to
separate and detect the enantiomers, however.
PMID- 10766376
TI - The stability of intracellular zidovudine and its anabolites in extracts of
peripheral blood mononuclear cells (PBMCs).
PMID- 10766377
TI - Development of ion exchange chromatography methods for monoclonal antibodies.
PMID- 10766378
TI - Simultaneous determination of levodopa, carbidopa and their metabolites in human
plasma and urine samples using LC-EC.
AB - In this study levodopa (L-DOPA), carbidopa (C-DOPA) and their metabolites were
resolved from other endogenous components present in human plasma and urine and
determined quantitatively. The developed technique involved the use of a second
pump, a switching valve, and a pre-column in the LC system in order to perform on
line sample clean-up and enrichment. This procedure is dependent on an effective
removal of the many interfering matrix components that vitiate HPLC analysis.
Several unknown endogenous electroactive compounds, present in plasma, were
eliminated by the purification step, or suppressed by the pre-treatment or
detection conditions. The analyses were separated on an Octyl-bonded reversed
phase column followed by amperometric detection using a carbon fibre
microelectrode flow cell operated at +0.8 V versus silver/silver phosphate
reference electrode. The cell was compatible with the mobile and the stationary
phase used in the flow system without any complex surface reaction. The peak
currents obtained for the different analytes were directly proportional to the
analyse over the concentration range 0.02-4.0 microg ml(-1). Using this method,
the minimum detectable concentration was estimated to be 5 and 8 ng ml(-1) for L
DOPA and C-DOPA, respectively. Recovery studies performed on human plasma samples
ranged from 93.83 to 89.76%, with a relative standard deviation of < 6%. The
intra- and inter-assay coefficients of variation were < 7%. The accuracy of the
assay, which was defined as the percentage difference between the mean
concentration found and the theoretical (true) concentration, was 12% or better.
The electrochemical pre-treatment regime described in this work permitted a
longer application of the same microelectrode. The method showed a good agreement
with other available methods described in the introduction and offers the
advantages of being simple, less time and labour consuming, does not require
additional solvents for extraction, inexpensive and suitable for routine analysis
and kinetic purposes.
PMID- 10766379
TI - Wavefront-guided laser in situ keratomileusis: early results in three eyes.
AB - PURPOSE: Wavefront optical aberrations induced by refractive corneal surgery
correction of myopia are probably the reason for deterioration of visual
performance in some eyes after surgery. Customized photoablation of the cornea to
correct both the sphero-cylindrical refractive error as well as individual
optical aberrations may improve postoperative visual acuity and visual
performance. METHODS: In 3 eyes of 3 patients the wavefront deviations were
measured by means of an aberrometer of the Tscherning-type. Based on these
measurements an ablation pattern was determined and applied during a LASIK
procedure using a Wavelight Allegretto scanning spot excimer laser with a spot
size of 1 mm and a laser repetition rate of 200 Hz. The 3 eyes are part of a
prospective study on wavefront-guided LASIK started in July 1999. RESULTS: At 1
month after LASIK, all 3 eyes had gained up to 2 lines of best spectacle
corrected visual acuity. Best spectacle-corrected visual acuity improved to 20/10
in all 3 eyes, uncorrected visual acuity was 20/10 in two eyes, and 20/12.5 in 1
eye 1 month postoperatively. The wavefront deviations were reduced by 27% on
average. At 3 months, best spectacle-corrected visual acuity was 20/10 in 2 eyes
and 20/12.5 in 1 eye. CONCLUSION: Wavefront-guided LASIK is a feasible approach
in refractive corneal surgery. Optimized ablation patterns may further improve
the visual results.
PMID- 10766380
TI - Photoastigmatic refractive keratectomy in myopes. Nidek US Investigators Group.
AB - PURPOSE: Photoastigmatic refractive keratectomy (PARK) was studied in a multi
center clinical trial. The Nidek EC-5000 excimer laser was evaluated for its
effect on refraction, visual acuity, and safety measures as part of a U.S. Food
and Drug Administration (FDA) regulated study. METHODS: Eight U.S. centers
enrolled adults with eyes having refractive astigmatism up to 4.00 D and a myopic
spherical equivalent refraction up to -8.00 D. Results are reported for 749 eyes
of 486 patients with at least 6 months follow-up. The rectangular beam scanning
Nidek EC-5000 used a 5.5-mm-diameter treatment zone, a 7.0-mm-diameter peripheral
blend zone, and a 40 Hz pulse rate for surface treatment of myopic astigmatism.
Nomogram corrections to machine settings were required to achieve the desired
results. RESULTS: Preoperative average spherical equivalent refraction of -4.90+/
1.74 D was reduced to -0.02+/-0.79 D at 6 months. Refractive stability was
established at 3 months. Over 62% of eyes were within +/-0.50 D of desired
correction at 6 months, with over 86% within +/-1.00 D. Uncorrected visual acuity
improved by an average of 10 Snellen lines; over 64% of eyes saw 20/20 or better
uncorrected and over 93% saw 20/40 or better uncorrected at 6 and 12 months. PARK
treatment effectively reduced astigmatism with little average axis error or
magnitude error. Corneal haze and safety concerns were minimal. CONCLUSIONS:
Photoastigmatic refractive keratectomy using the Nidek EC-5000 excimer laser
provided significant reduction of myopia and astigmatism, with minimal
complications.
PMID- 10766381
TI - Role of the corneal epithelium in refractive changes following laser in situ
keratomileusis for high myopia.
AB - PURPOSE: Epithelial hyperplasia is one of the factors that plays a role in myopic
regression after photorefractive keratectomy (PRK). We evaluated the role of the
epithelium following excimer laser in situ keratomileusis (LASIK) performed on
highly myopic eyes. METHODS: Fifty eyes of 32 patients (18 females and 14 males;
mean age, 31.7+/-6.5 years) were treated with LASIK for myopia with an attempted
correction ranging between -8.50 and -12.25 D (mean, -10.48+/-1.43 D). No sutures
were placed. The thickness of the central epithelium was evaluated either with a
50-MHz ultrasonic pachymeter or an ultrasound biomicroscope. Postoperatively,
topical corticosteroid drops were administered for at least 1 month. RESULTS:
Follow-up was at least 12 months. Epithelium measurements were thicker compared
to preoperative measurements from the first week postoperatively (mean, +1.9
microm, +2.77%; P<.05). Epithelial thickness peaked at the third month after
LASIK (mean, +6.5 microm, +9.5%; P<.05) and remained stable through 12 months. A
negative correlation between epithelium thickness and manifest refraction from
the first month postoperatively to the end of follow-up was present. CONCLUSION:
The epithelium seemed to have a role in the regression of refractive effect after
LASIK to correct high myopia.
PMID- 10766383
TI - Feasibility of intraoperative corneal topography monitoring during
photorefractive keratectomy.
AB - PURPOSE: We propose a feasibility study of new corneal topography technology with
the aim of monitoring intraoperative corneal topography during excimer laser
photorefractive keratectomy. The PAR system measures corneal topography with
single grid projection and triangulation but requires fluorescent fluid to be
deposited on the corneal surface for shape extraction. We propose and demonstrate
a novel corneal topography system based on structured incoherent visible light
projection and triangulation that does not require addition of fluorescent fluid.
METHODS: We used a binary liquid crystal spatial light modulator to display
multiple fringe patterns onto the cornea. The depth accuracy of the corneal
topography system was measured using a white reflected test sphere mounted on a
micrometer translation stage. The performance of the corneal topography system
was tested on 5 de-epithelialized swine eyes in vitro ablated with a VISX excimer
laser. RESULTS: Depth accuracy on the test sphere was 0.5+/-0.75 microm over an
area of 17.6 mm2. On de-epithelialized swine corneas, ablation at the apex of the
cornea treated with an excimer laser was measured without addition of
fluorescein. CONCLUSIONS: This new corneal topography system achieved an adequate
level of accuracy on a test sphere.
PMID- 10766382
TI - Laser in situ keratomileusis for ametropia after penetrating keratoplasty.
AB - PURPOSE: To evaluate the efficacy of excimer laser in situ keratomileusis (LASIK)
in the treatment of refractive errors after penetrating keratoplasty. METHODS:
Eight eyes underwent LASIK after a mean 71 months (SD 60) following the initial
penetrating keratoplasty. A full ophthalmic assessment was performed before LASIK
and at 1 week, 1, 3, 6, and 12 months after surgery. Mean follow-up was 8.6
months (SD 3.2). RESULTS: No eyes lost any Snellen lines of best spectacle
corrected visual acuity at the latest follow-up. Mean reduction in spherical
equivalent refraction was 91% from -6.79 D (SD 4.17) to -0.64 D (SD 1.92) and
mean reduction of cylinder was 72% from -6.79 D (SD 3.28) to -1.93 D (SD 1.17) at
6 months. Mean surgically induced astigmatism was 5.50 D (SD 2.42) and the index
of surgically induced astigmatism divided by the initial cylinder expressed as a
percentage was 81%. Mean outcome indices were: correction index 0.87, index of
success 0.31, and angle of error 0.95 degrees. Three eyes (43%) achieved a
spherical equivalent refraction of +/-0.50 D and 4 eyes (57%) achieved a
spherical equivalent refraction of +/-1.00 D of emmetropia. CONCLUSIONS: The
efficacy of LASIK after penetrating keratoplasty was good compared to incisional
or surface based excimer laser methods and has the advantage of reducing the
myopic spherical equivalent refraction in addition to astigmatism, thus improving
the uncorrected visual acuities.
PMID- 10766384
TI - Mathematical models of picosecond laser keratomileusis for high myopia.
AB - PURPOSE: Picosecond laser keratomileusis (PLK) is a refractive surgical procedure
in which an intrastromal lenticle is created using the Nd:YLF picosecond laser
and removed by lifting the anterior flap in the cornea. The purpose of this study
was to assess the predictability of picosecond laser keratomileusis for high
myopia. METHODS: The results from a recent clinical series of non-sighted
patients who had undergone picosecond laser keratomileusis with the Nd:YLF
picosecond laser were retrospectively simulated with two mathematical models. In
one model, the change in corneal curvature resulting from the collapse of a
lenticular intrastromal cavity was predicted from a geometric analysis. A second
model was developed using the finite element method. The results of both
predictive models were compared to the clinical results at 1 and 6 months
following surgery. RESULTS: An average -13.30 D of flattening (range, -6.80 to
20.50 D) was measured at 6 months. The geometric model predicted an average
correction of -23.10 D (range, -18.00 to -34.00 D), whereas the finite element
model predicted an average curvature change of -17.40 D (range, -14.50 to -22.50
D). An average decrease in central pachymetry of 91 microm was measured at 6
months, as compared to a predicted decrease in thickness of 112 microm.
CONCLUSIONS: The outcome of picosecond laser keratomileusis for high myopia
predicted using a finite element based model shows greater change in the corneal
curvature and corneal thickness compared to clinical results. The relatively
thick lenticules that are removed for high myopia cause considerable
deformational changes in the cornea, which preclude the use of a purely
geometric/optical approach for predicting the resultant corneal curvature
changes.
PMID- 10766385
TI - Laser in situ keratomileusis for recurrent hyperopia following laser thermal
keratoplasty.
AB - PURPOSE: Laser thermal keratoplasty (LTK) has its main indication in the
correction of hyperopia. However, regression of refractive effect following LTK
is a limitation. Laser in situ keratomileusis (LASIK) may provide a good
alternative to correct residual refractive errors. METHODS: Fifty hyperopic eyes
with varying amounts of regression after LTK underwent LASIK. The Chiron
Automated Corneal Shaper microkeratome was used to make a flap of 160 microm and
laser ablation was performed with the Technolas 217 Planoscan excimer laser.
Postoperative follow-up was 6 months. RESULTS: Mean spherical equivalent
refraction improved from +2.92+/-1.60 D to +0.36+/-1.48 D. Mean best spectacle
corrected visual acuity changed from 0.78+/-0.14 before LASIK to 0.76+/-0.16 D 6
months after LASIK. Mean uncorrected visual acuity changed from 0.37+/-0.16 to
0.66+/-0.24. Forty-two percent (21 eyes) were within +/-0.50 D of intended
correction, 60% (30 eyes) were within +/-1.00 D, and 76% (38 eyes) were within +/
2.00 D. After LASIK, confluent haze between previous LTK spots was observed in
most eyes, as LASIK ablation took place at the sites of the LTK spots.
CONCLUSIONS: LASIK after LTK is a good alternative for hyperopic regression.
Predictability and efficacy are less than with primary LASIK for hyperopia, but
the procedure is equally safe.
PMID- 10766386
TI - Laser in situ keratomileusis retreatment for residual myopia and astigmatism.
AB - PURPOSE: To evaluate the visual and refractive results of laser in situ
keratomileusis (LASIK) retreatment on eyes with residual myopia with or without
astigmatism. METHODS: LASIK retreatment was performed on 35 eyes of 23 patients
for correction of residual myopia, with or without astigmatism, with a mean
manifest spherical equivalent refraction of -2.17+/-0.82 D (range, -1.00 to -3.87
D) and mean refractive astigmatism of -0.55+/-0.61 D (range, 0 to -1.75 D).
Retreatment was performed 3 to 18 months after primary LASIK (mean, 5.1+/-2.6
mo). The corneal flap of the previous LASIK was lifted and laser ablation was
performed using the Chiron-Technolas Keracor 116 excimer laser. Follow-up was 12
months for all eyes. RESULTS: At 1 year after retreatment, manifest spherical
equivalent refraction was reduced to a mean -0.23+/-0.28 D (range, 0 to -0.87 D),
and refractive astigmatism was reduced to a mean -0.16+/-0.25 D (range, 0 to
0.75 D). Thirty-two eyes (91.5%) had a manifest spherical equivalent refraction
within +/-0.50 D of emmetropia, and 33 eyes (94.3%) had 0 to 0.50 D of refractive
astigmatism. Uncorrected visual acuity was 20/20 or better in 11 eyes (31.4%).
Spectacle-corrected visual acuity was not reduced in any eye after retreatment.
There were no significant complications. CONCLUSION: LASIK retreatment was
effective for correction of residual myopia or astigmatism after primary LASIK.
Refractive results were predictable with good stability after 3 months. Lifting
the flap during LASIK retreatment was relatively easy to perform and did not
result in visual morbidity in eyes treated from 3 up to 18 months after primary
LASIK.
PMID- 10766387
TI - A mathematical model for laser in situ keratomileusis and photorefractive
keratectomy.
AB - PURPOSE: The purpose of ablation refractive surgery is to remove the refractive
error from the inherently asymmetric aspheric cornea. Although the technique is
gaining wide acceptance and popularity, some patients are left with irregular
corneas. Our objective was to develop a methodology to analyze corneal shape,
reduce the shape to arcs, modify the local arc value to the desired new arc
value, and render a new continuous Euclidean surface without discontinuity.
METHODS: The method to reconstruct the corneal surface consists of importing
scanner output elevation data points into a computer-aided design (CAD)
application to form the surface model. The corneal arc measurements are derived
at 5 degrees increments and centered about the Gauss point of symmetry. Each arc
is manipulated to adjust the corresponding arc on the proposed corneal surface to
reflect the new arc value, correcting for the refractive error. The method
determines the amount of corneal tilt and ablation depth at a given diameter
required for the refractive error with a smooth transition zone to the base
cornea. RESULTS: The case example is a patient who began with a spherical
refraction of -8.75 D and after LASIK was emmetropic, but had irregular
astigmatism and 20/30 best spectacle-corrected Snellen visual acuity. The
proposed mathematical model compares the achieved surface shape to the
mathematically planned surface contour. An enhancement procedure to remove the
LASIK-induced corneal irregularity was designed. CONCLUSION: A mathematical
technique to plan myopic ablative surgery to make the corneal surface regular and
symmetric is proposed.
PMID- 10766388
TI - Laser in situ keratomileusis enhancement after radial keratotomy.
AB - PURPOSE: To present results of laser in situ keratomileusis (LASIK) enhancement
after radial keratotomy (RK). METHODS: Sixteen eyes of 10 patients were treated
with LASIK for residual myopia and hyperopia after RK. Mean preoperative
spherical equivalent refraction was -3.14+/-3.04 D (range, -6.675 to +6.00 D).
Best spectacle-corrected visual acuity was 20/20 in 9 eyes, 20/25 in 6 eyes, and
20/30 in 1 eye. Uncorrected visual acuity was better than 20/40 in only 2 eyes.
Patients were followed at 1 day, 1 week, 1, 3, and 6 months, and 1 year. Mean
follow-up was 8.3 months (range, 1 to 17 mo). RESULTS: All eyes received one
LASIK enhancement. Mean final spherical equivalent refraction was +0.16+/-0.68 D
(range, -1.00 to +1.75 D). No eyes experienced any visual loss. Five eyes gained
1 line of best spectacle-corrected visual acuity. Uncorrected visual acuity was
20/20 in 9 eyes, 20/25 in 6 eyes, and 20/30 in 1 eye. Two eyes of one patient had
the previous RK incisions open. CONCLUSION: LASIK was an effective treatment for
correction of residual myopia and hyperopia after RK.
PMID- 10766389
TI - Mycobacterium keratitis after laser in situ keratomileusis.
AB - PURPOSE: The authors report two cases of Mycobacterium keratitis following LASIK.
METHODS: The case reports are based on a retrospective review of clinical history
and associated findings. RESULTS: Two patients developed infectious keratitis
after undergoing laser in situ keratomileusis (LASIK). In case #1, the infection
developed after manipulation of the lamellar flap to remove epithelium from the
stromal bed. In case #2, prior radial keratotomy may have been a contributing
factor to development of the infection. Corneal infiltrates appeared as focal,
white, stromal deposits. Cultures isolated Mycobacterium fortuitum from case #1
and Mycobacterium chelonae from case #2. Topical fortified amikacin,
clarithromycin, tobramycin, and ciprofloxacin eventually controlled the
infection. Topical prednisolone acetate and bandage contact lenses were necessary
to control inflammation and pain. Infiltrates were slow to resolve until focal
necrosis eroded through the flaps leading to rapid clearing of the infiltrates;
however, scarring of the cornea developed at the site of necrosis. Visual
recovery was good in the first case but limited in the second. CONCLUSIONS:
Mycobacterium keratitis complicating LASIK may be difficult to eradicate until
the sequestered stromal infiltrate drains. Rapid recognition of the causative
organism and aggressive medical and surgical management of the infection may
improve the outcome.
PMID- 10766390
TI - Measure central corneal thickness to avoid iatrogenic keratectasia.
PMID- 10766391
TI - Oral pemphigus: long term behaviour and clinical response to treatment with
deflazacort in sixteen cases.
AB - Systemic corticosteroids remain the mainstay of therapy for pemphigus. Their use
has transformed what was almost invariably a fatal illness into one whose
mortality is now below 10%. Unfortunately, the high doses and prolonged
administration of corticosteroids that are often needed to control the disease
result in numerous side effects, many of which are serious or even life
threatening. Sixteen patients affected by oral pemphigus vulgaris were
retrospectively examined to illustrate the natural course of the disease and to
describe the efficacy of the treatment we utilised. Deflazacort, used with
azathioprine, is the steroid of first choice in our therapeutic protocols, while
cyclophosphamide and methylprednisolone "pulse therapy" are reserved for cases
unresponsive to high doses of oral corticosteroids. In addition, the literature
on oral pemphigus vulgaris was reviewed with respect to clinical history, signs
and symptoms, management, and treatment outcome.
PMID- 10766392
TI - Oral findings in three different groups of immunocompromised patients.
AB - The objective of this study was to determine the frequency of oral, dental and
periodontal findings in three different groups of immunocompromised patients and
in a healthy control group, to evaluate whether there is a correlation between
manifestations of disease and immunologic parameters. The survey included 46
patients with a diagnosis of systemic lupus erythematosus, 48 heart transplant
recipients, and 53 adult patients suffering from acute leukemias. Fifty matched
healthy subjects were used as a control group. Each patient had to answer
questions on medical and dental health and underwent a thorough oral, dental and
serological investigation. Oral mucosal lesions were found in nearly half of all
immunocompromised patients (49.6%), but in only 26% of control patients. No
significant associations were found between different types of oral lesions and
the underlying cause of immunosuppression. Leukemia patients showed age-unrelated
higher scores in periodontal indices (P<0.05). Laboratory parameters failed to be
significant in the assessment of oral health.
PMID- 10766393
TI - Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese.
AB - To determine the alterations of the p16/MTS1 gene in oral squamous cell carcinoma
(OSCC), we examined in Taiwanese patients the mutation, deletion and methylation
of p16/MTS1 in primary OSCCs associated mostly with betel quid (BQ)/tobacco use.
Among 110 tumors undergoing mutational analyses, seven (6%) showed mutations in
exon 2 or the intron 1/exon 2 splice site. All but one mutation disrupted the
encoded proteins. Base transitions represented the vast majority (6/7) of the
mutations identified in BQ/tobacco consuming subjects. It was noted that 15/56
(27%) tumors examined by restriction fragment methylation analysis revealed a
significant level of methylation in different loci of exon 1 as compared with the
respective non-cancerous tissue. Mutation of p16/MTS1 was exclusively identified
in carcinomas of buccal mucosa, whereas methylation of the p16/MTS1 promoter
region occurred preferentially in carcinomas of the tongue (54%) rather than at
other sites (22%). Homozygous deletion was not found in 56 paired samples
examined, nor was hemizygous deletion indicated in 12 informative cases. The
results indicated aberrant methylation and mutation as the molecular abnormality
of p16/MTS1 in the OSCC from Taiwanese.
PMID- 10766394
TI - Cyclin D1 expression in oral squamous cell carcinomas: clinicopathological
relevance and correlation with p53 expression.
AB - The aim of the present study is to study the relationship between cyclin D1 and
the clinicopathological features of oral squamous cell carcinomas. The cyclin D1
and p53 expression in oral squamous cell carcinomas from 56 patients (45 men, 11
women) was studied by immunohistochemistry using monoclonal antibodies. The
correlation between cyclin D1 and the clinicopathological features of the oral
cancers was evaluated. Cyclin D1 expression was found in 63% of oral squamous
cell carcinomas; it was often weak but was more frequently positive in high-grade
lesions (P=0.019). The expression was positively correlated with p53 expression
(P= 0.06). Radiation therapy did not alter the expression of either cyclin D1 or
p53 proteins. Expression of these proteins was not related to the age, gender or
survival of the patients, or to stages of the tumors. The cyclin D1 expression
was more frequently seen in patients with squamous cell carcinomas of oropharynx,
palate, floor of mouth and gingiva. To conclude, cyclin D1 was frequently
expressed in oral squamous cell carcinomas. This expression was related to the
grade of the tumors and was not similar in various regions in the oral cavity,
which may indicate the different tumor biology of cancers from these regions.
PMID- 10766396
TI - p53, bcl-2 and bax abnormalities in non-Hodgkin's lymphomas of the head and neck.
AB - In the present study, mutations or protein expression of p53, bcl-2 and bax are
reported in 13 non-Hodgkin's B-cell lymphomas of the head and neck. Nine of 13
cases (69.2%) expressed p53 protein and 7 (53.8%) showed gene mutations. On
comparing the results of immunostaining and SSCP analysis, there were two cases
showing discrepancies between the p53 protein expression and gene mutations. Bcl
2 protein expression was observed in only two cases of follicular lymphoma. On
the other hand, bax protein was detected in all 13 cases. One case with mutated
bax gene showed a lower expression with a reduced frequency of bax-positive cells
than the other 12. These results suggest that inactivation of p53 may be closely
related to development and/or progression of these NHLs, and that bcl-2 and bax
protein may not have a role.
PMID- 10766395
TI - Overexpression of p53 and bcl-2 proteins and the presence of HPV infection are
independent events in head and neck cancer.
AB - The expression of p53 and bcl-2 proteins by immunohistochemistry and the
identification of human papillomavirus (HPV) infection by a non-isotopic
polymerase chain reaction (PCR)based method were investigated in 30 patients with
head and neck cancer. Ten cases were HPV-positive (33%), mostly as double or
multiple infections by high- or intermediate-risk types. Twenty-one patients were
p53-positive (70%), 9/10 with HPV-positive tumours and 12/20 with HPV-negative
tumours; this difference was not statistically significant. Only four cases were
bcl-2-positive, irrespective of the presence of either HPV or p53. No correlation
was found between these biological factors and tumour stage, differentiation
grade, and alcohol or tobacco use. Our findings indicate that p53 is involved in
the majority of cases, bcl-2 is rare, and high-risk HPV could play a key role,
especially in tumours of tongue and tonsil. In conclusion p53 and bcl-2 protein
expression and the presence of HPV infection are independent events in these
malignancies.
PMID- 10766398
TI - Health for all in the 21st century?
AB - Approximately two decades ago world health authorities met in Alma-Ata to discuss
the unequal distribution of health and other global questions. The meeting
produced a declaration that emphasized the role of primary care in the provision
of health services. Furthermore, adequate socioeconomic support, such as
availability of food security, clean water, appropriate housing, and education,
were all considered integral parts of health development. After the meeting, the
World Health Organization developed a programme called 'Health for All by 2000',
outlining strategies towards maximal health improvements all over the world.
Thereafter, individual countries have developed national modifications from this
agenda, and global development of health has on average been favourable. In the
economically least developed countries, however, progress has been significantly
slower than elsewhere. This editorial discusses the problem of inadequate
socioeconomic development and increasing global health disparity through an
example from Lungwena, a rural area in Sub-Saharan Africa. In the 21st century,
poverty reduction is the key strategy towards health improvement in the least
developed countries.
PMID- 10766397
TI - Solitary fibrous tumour of the oral cavity: clinicopathological and
immunohistochemical characterization of three cases.
AB - Solitary fibrous tumour (SFT) is an uncommon mesenchymal neoplasm rarely located
in the oral cavity. To characterize further oral SFT, we describe three new
cases. Each tumour originated in the buccal mucosa of a middle-aged/elderly
patient. Histological examination showed well-circumscribed tumours with densely
cellular areas alternating with hypocellular areas in a variedly collagenous,
vascular stroma. Mast cells were abundant. The spindle-shaped, neoplastic cells
immunostained strongly for CD34 antigen and vimentin and weakly for bcl-2, but
not for epithelial cell markers, alpha-smooth muscle actin, or neurofilament or S
100 proteins. Compatible with the virtual absence of mitoses and of marked
nuclear atypia, the overall frequency of proliferating cells expressing Ki-67 was
low. The expression of CD34 was useful in the differential diagnosis. The
consistent location in the cheek and expansion of one tumour after local trauma
does not preclude a traumatic element in the development of oral SFT.
PMID- 10766399
TI - Urinary excretion of aquaporin-2 in pathological states of water metabolism.
AB - Aquaporin-2 (AQP-2) is an arginine vasopressin (AVP)-regulated water channel in
renal collecting duct cells. Approximately 3 % of AQP-2 in collecting duct cells
is excreted into urine. Urinary excretion of AQP-2 varies widely in different
physiological conditions, and it has a positive correlation with plasma AVP
levels. Urinary excretion of AQP-2 was significantly increased by the single
injection of AVP in patients with central diabetes insipidus. The urinary
excretion of AQP-2 was one-eighth over in patients with central diabetes
insipidus and three times greater in patients with impaired water excretion than
that in normal subjects. In a hypertonic saline test, the urinary excretion of
AQP-2 promptly increased 6-12-fold in normal subjects, but remained low in
patients with central diabetes insipidus. In addition, exaggerated urinary
excretion of AQP-2 persisted after an acute water load in patients with impaired
water excretion. These results indicate that urinary excretion of AQP-2 is a
potent marker for the diagnosis of water metabolism disorders dependent on AVP.
PMID- 10766400
TI - Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy.
AB - The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) can be related to
abnormalities in the metabolism and disposition of sex hormones and/or bile
acids, determined by a genetic predisposition interacting with environmental
factors. The total amount of oestrogens and progesterone circulating in the blood
or excreted in the urine of ICP patients is similar to normal pregnancies. Thus,
the search for the cause has been focused on abnormal hormone metabolites. The
cholestatic potential of some D-ring oestrogen metabolites is supported by
experimental and clinical data. Similar observations with regard to bile acids
and progesterone metabolites are still scarce. This article reviews current
knowledge in this field, including our own data. Bile acid synthesis appears to
be reduced in patients with ICP, in whom primary conjugated bile acids are
retained in blood. The major bile acid in blood and urine of these patients is
cholic acid instead of chenodeoxycholic acid present in normal pregnancies.
Hydroxylation and sulfation of bile acids are enhanced, while glucuronidation
appears to be of lesser importance. The synthesis of progesterone appears
unimpaired, while the profiles of progesterone metabolites in plasma and urine
are different from normal pregnancies, with a larger proportion of mono- and
disulfated metabolites, mainly 3alpha,5alpha isomers. Glucuronidated metabolites,
however, are unchanged. With the administration of ursodeoxycholic acid (UDCA) to
patients with ICP, pruritus and serum liver values are improved, the
concentration of bile acids in blood is diminished and the proportion of their
conjugated metabolites returned to normal. Simultaneously, the concentration of
sulfated progesterone metabolites in blood and their urinary excretion are
reduced. The serum levels of bile acids and progesterone metabolites before UDCA
administration and their decrease during treatment do not correlate with each
other. We propose that patients with ICP have a selective defect in the secretion
of sulfated progesterone metabolites into bile and speculate that this may be
caused by genetic polymorphism of canalicular transporter(s) for steroid sulfates
or their regulation. Interaction with oestrogen metabolites and/or some exogenous
compounds may further enhance the process triggering ICP in genetically
predisposed individuals.
PMID- 10766401
TI - Development of oral bacterial flora in young children.
AB - The intimate relationship with bacteria is a fundamental factor in the health
status of an individual. After birth infants are exposed to continuous person-to
person and environmental contacts with microbes, and the development of the
indigenous microflora begins on the surfaces of the human body. In a developing
ecosystem microbial colonization may easily occur because of the still inadequate
host response. Adhesion is the initial event in the colonization of bacteria. In
the mouth, only mucosal surfaces are available during the first months of life.
After teeth emerge, the number of attachment sites and potential niches increases
significantly. Bacteria adhere not only to oral surfaces but also to each other,
forming multigeneric communities where specific partner relationships influence
their composition and stability. Viridans streptococci and a strictly anaerobic
species, Fusobacterium nucleatum, are of interest in this context. The oral
colonization pattern differs between individuals already in infancy; variable
bacterial load in saliva of attendants and other close contacts and the frequency
of this bacterial exposure may partly account for individual differences. In
addition, the exposure of an infant to antibiotics affects the quality of
colonizing bacteria. This article presents an overview of the age-related
acquisition of oral bacteria and the role of the indigenous oral microflora in
health and disease.
PMID- 10766402
TI - Lasers in the treatment of ischaemic heart disease.
AB - Mounting evidence showing that transmyocardial laser revascularization (TMR) is a
safe and effective treatment for angina pectoris arrives just as an increasing
number of patients who have undergone angioplasty and coronary artery bypass
grafting experience failure with time. TMR, nevertheless, remains controversial.
It appears to relieve the symptoms without treating the underlying
atherosclerotic disease, and its method of action is unproven. Like angioplasty
and coronary bypass, TMR in fact offers palliation rather than a cure for
atherosclerotic heart disease. The most sensible current formulations of the
therapeutic mechanism of TMR posit a reconfiguration of the microcirculation,
with blood shunted from epicardial to endocardial areas. These unresolved issues
notwithstanding, TMR benefits patients with end-stage coronary disease and
represents a pioneering effort to remodel the microcirculation of patients with
arteriosclerotic occlusive disease.
PMID- 10766403
TI - Apolipoprotein E4: an allele associated with many diseases.
AB - Apolipoprotein E (apoE) was discovered as a plasma protein involved in
lipoprotein metabolism. ApoE is synthesized by the liver and is also made locally
in the brain. There are three common variants of apoE, resulting from common
genetic variation, called E2, E3 and E4. The E3 allele is the most prevalent
form, and the proportion of the three alleles differs between populations.
Epidemiological studies have found that the E4 allele is associated with
decreased longevity, increased plasma cholesterol levels and increased prevalence
for cardiovascular disease and particularly for Alzheimer's disease. The apoE
polymorphism also affects response to head trauma, cognitive decline upon ageing
and several other disorders. Thus, common genetic variation in the apoE gene may
be associated with successful ageing.
PMID- 10766404
TI - Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets
psychiatric treatment.
AB - Pharmacogenetic research into neurotransmitter-related genes is helping to
unravel genetic factors that determine antipsychotic response. Several genetic
mutations in neurotransmitter receptors targeted by antipsychotic drugs have been
found to be related to clinical response. Modern molecular genetic techniques
will facilitate the identification of those mutations that determine treatment
response. Future psychiatric prescription will include the genetic
characterization of neurotransmitter receptors for the selection of the most
beneficial drug according to the individual's pharmacogenetic profile.
PMID- 10766405
TI - Relationship between fibrinolytic and metabolic variables: a study in patients
attending a lipid clinic.
AB - We investigated the relationship between plasma levels of metabolic and
fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these
patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia
(NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t
PA) activity, was impaired as a result of high plasminogen activator inhibitor
type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis
identified insulin and triglyceride levels as independent determinants of plasma
PAI-1 levels (R2 = 0.18; P = 0.0001). When the patients were stratified into
tertiles according to their levels of triglyceride and insulin, PAI-1 antigen
levels were found to increase with rising levels of triglyceride in each insulin
tertile. In contrast, the increase of PAI-1 with rising insulin levels was
evident in the highest triglyceride tertile. In addition, subjects in the lowest
tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and
subjects in the highest tertile of both triglyceride and insulin had the highest
levels of PAI-1. Both basal and stimulated levels of t-PA antigen were
significantly higher in HTG than in NTG. Multiple stepwise regression analysis
identified triglyceride level as the sole major determinant of t-PA antigen
levels (R2 = 0.13; P = 0.00003). The observation that both insulin and
triglycerides correlate with PAI-1, whereas triglycerides were involved only in
the increased secretion of t-PA, suggests that these two proteins are regulated
by different mechanisms.
PMID- 10766406
TI - Cardiovascular risk factors of young adults in relation to parental socioeconomic
status: the Cardiovascular Risk in Young Finns Study.
AB - The socioeconomic status (SES) of the family influences the cardiovascular risk
status of children and adolescents; however, it is not as well known whether
parental SES has any effect on the risk factor profile of young adults. The aim
of the present study was to investigate the relations of different aspects of
parental SES, namely occupation, education, income and living area, to the common
cardiovascular risk factors of their offspring (n = 919) aged 18, 21 and 24 years
as a part of the Cardiovascular Risk in Young Finns Study in 1986. Subjects from
farming families and rural areas had the highest serum total and low-density
lipoprotein cholesterol values, and the lowest diastolic blood pressure compared
with subjects from other occupational groups and subjects from urban regions. The
diet of young adults from farming families and from rural areas contained more
saturated fatty acids and less monounsaturated and polyunsaturated fatty acids.
In addition, the body mass index was lower in subjects from urban regions
compared with rural regions, and physical inactivity was less common in the urban
group. Subjects with the highest parental occupational status smoked less
compared with those with the lowest status. Parental education related inversely
to physical inactivity and directly to dietary polyunsaturated fatty acids. The
income level of the family associated positively with frequent inebriation by
alcoholic beverages and inversely with the percentage of dietary energy from fat.
In conclusion, there were modest inverse associations between different
indicators of the SES of parents and some of the traditional risk factors of
their offspring in young adulthood, which may contribute to the future risk of
cardiovascular diseases.
PMID- 10766407
TI - Urinary 8-oxo-2'-deoxyguanosine--source, significance and supplements.
AB - Oxidative damage to cellular biomolecules, in particular DNA, has been proposed
to play an important role in a number of pathological conditions, including
carcinogenesis. A much studied consequence of oxygen-centred radical damage to
DNA is 8-oxo-2'-deoxyguanosine (8-oxodG). Using numerous techniques, this lesion
has been quantified in various biological matrices, most notably DNA and urine.
Until recently, it was understood that urinary 8-oxodG derives solely from DNA
repair, although the processes which may yield the modified deoxynucleoside have
never been thoroughly discussed. This review suggests that nucleotide excision
repair and the action of a specific endonuclease may, in addition to the
nucleotide pool, contribute significantly to levels of 8-oxodG in the urine. On
this basis, urinary 8-oxodG represents an important biomarker of generalised,
cellular oxidative stress. Current data from antioxidant supplementation trials
are examined and the potential for such compounds to modulate DNA repair is
considered. It is stressed that further work is required to link DNA, serum and
urinary levels of 8-oxodG such that the kinetics of formation and clearance may
be elucidated, facilitating greater understanding of the role played by oxidative
stress in disease.
PMID- 10766408
TI - Electrochemical, UV--visible and EPR studies on nitrofurantoin: nitro radical
anion generation and its interaction with glutathione.
AB - This paper deals with the reactivity of the nitro radical anion electrochemically
generated from nitrofurantoin with glutathione. Cyclic voltammetry (CV) and
controlled potential electrolysis were used to generate the nitro radical anion
in situ and in bulk solution, respectively and cyclic voltammetry, UV--Visible
and EPR spectroscopy were used to characterize the electrochemically formed
radical and to study its interaction with GSH. By cyclic voltammetry on a hanging
mercury drop electrode, the formation of the nitro radical anion was possible in
mixed media (0.015M aqueous citrate/DMF, 40/60, pH 9) and in aprotic media. A
second order decay of the radicals was determined, with a k2 value of 201 and 111
M(-1) s(-1), respectively. Controlled potential electrolysis generated the
radical and its detection by cyclic voltammetry, UV--Visible and EPR spectroscopy
was possible. When glutathione (GSH) was added to the solution, an unambiguous
decay in the signals corresponding to a nitro radical anion were observed and
using a spin trapping technique, a thiyl radical was detected. Electrochemical
and spectroscopic data indicated that it is possible to generate the nitro
radical anion from nitrofurantoin in solution and that GSH scavenged this
reactive species, in contrast with other authors, which previously reported no
interaction between them.
PMID- 10766409
TI - Role of nitric oxide in the reperfusion induced injury in hyperthyroid rat
hearts.
AB - We recently reported that hyperthyroidism affects the heart response to
ischemia/reperfusion. A significant tachycardia during reperfusion was associated
with an increase in the oxidative stress of hearts from T3-treated animals. In
the present study we checked the possible role of nitric oxide (NO) in this major
stress induced by the hyperthyroid state. We compared the functional recovery
from ischemia/reperfusion of Langendorff preparations from euthyroid (E) and
hyperthyroid (H, ten daily intraperitoneal injections of T3, 10 microg/100 g body
weight) rats, in the presence and in the absence of 0.2 mM Nomega-nitro-L
arginine (L-NNA). At the end of the ischemia/reperfusion protocol (10 min
preischemic perfusion, 20 min global ischemia, 30 min reperfusion) lipid
peroxidation, antioxidant capacity (CA) and susceptibility to in vitro oxidative
stress were determined on heart homogenates. The main effect of hyperthyroidism
on the reperfusion functional response was confirmed to be a strong tachycardic
response (154% recovery at 25 min reperfusion) accompanied by a low recovery in
both left ventricular diastolic pressure (LVDP) and left ventricular dP/dtmax.
This functional response was associated with a reduction in CA and an increase in
both lipid peroxidation and susceptibility to oxidative stress. Perfusion of
hearts with L-NNA per se had small but significant negative chronotropic and
positive inotropic effects on preischemic performance of euthyroid rat hearts
only. More importantly, L-NNA perfusion completely blocked the reperfusion
tachycardic response in the hyperthyroid rats. Concomitantly, myocardium
oxidative state (lipid peroxidation, CA and in vitro susceptibility to oxidative
stress) of L-NNA perfused hearts was similar to that of E animals. These results
suggest that the higher reperfusion-induced injury occurring in hyperthyroid
animals is associated with overproduction of nitric oxide.
PMID- 10766410
TI - No significant paraquat-induced oxidative DNA damage in rats.
AB - The metabolism of paraquat generates oxygen radicals. Paraquat has thus been
suggested as a model compound to induce oxidative damage to DNA, lipids and
proteins in different cells and tissues, although experimental data are
inconsistent. In order to explore the possibilities for an animal model of
oxidative DNA damage in vivo, rats were treated with 20 mg/kg paraquat or vehicle
i.p. One and five days later we measured DNA oxidation in terms of 7-hydro-8-oxo
2'-deoxyguanosine (8-oxodG) in the liver and lung as well as the urinary
excretion of 8-oxodG. No significant effects on the level of 8-oxodG in the
liver, the lung or the urinary excretion, could be distinguished following
paraquat treatment. We found, however, a significant correlation (r = 0.69;
p<0.0002) between the 8-oxodG level in the lung and the urinary excretion, but no
significant correlation between the level in the liver and the urinary excretion
or between the levels in the liver and the lung. During the experiment the rats
were clearly affected by the paraquat as they were very lethargic compared to the
controls. Accordingly, even at toxic doses, paraquat did not cause detectable
oxidative damage to DNA. The data do not support the use of paraquat as a model
compound in experiments investigating effects or prevention of oxidative damage
to DNA.
PMID- 10766411
TI - The lactate-dependent enhancement of hydroxyl radical generation by the Fenton
reaction.
AB - The effect of lactic acid (lactate) on Fenton based hydroxyl radical (*OH)
production was studied by spin trapping, ESR, and fluorescence methods using DMPO
and coumarin-3-carboxylic acid (3-CCA) as the *OH traps respectively. The *OH
adduct formation was inhibited by lactate up to 0.4 mM (lactate/iron
stoichiometry = 2) in both experiments, but markedly enhanced with increasing
concentrations of lactate above this critical concentration. When the H2O2
dependence was examined, the DMPO-OH signal was increased linearly with H2O2
concentration up to 1 mM and then saturated in the absence of lactate. In the
presence of lactate, however, the DMPO-OH signal was increased further with
higher H2O2 concentration than 1 mM, and the saturation level was also increased
dependent on lactate concentration. Spectroscopic studies revealed that lactate
forms a stable colored complex with Fe3+ at lactate/Fe3+ stoichiometry of 2, and
the complex formation was strictly related to the DMPO-OH formation. The complex
formation did not promote the H2O2 mediated Fe3+ reduction. When the Fe3+
lactate (1:2) complex was reacted with H2O2, the initial rate of hydroxylated 3
CCA formation was linearly increased with H2O2 concentrations. All the data
obtained in the present experiments suggested that the Fe3+-lactate (1:2) complex
formed in the Fenton reaction system reacts directly with H2O2 to produce
additional *OH in the Fenton reaction by other mechanisms than lactate or
lactate/Fe3+ mediated promotion of Fe3+/Fe2+ redox cycling.
PMID- 10766412
TI - The role of antioxidants in the long-term glycation of low density lipoprotein
and its Cu2+-catalyzed oxidation.
AB - In the present study we investigated the influence of antioxidants such as EDTA,
alpha-tocopherol, troglitazone and acetylsalicylic acid on the long-term
glycation of LDL and its copper ion-catalyzed oxidation. We observed that (a) all
antioxidants inhibited AGE-formation, while Amadori product formation was only
diminished by extreme concentrations of acetylsalicylic acid, (b) glycated LDL
was more susceptible to copper-catalyzed oxidation than unglycated LDL, and (c)
the oxidation of native LDL was more dramatically inhibited by the antioxidants
than that of glycated LDL. The observed differences may be a consequence of the
significantly higher endogenous content in hydroperoxides of glycated LDL as
compared to native LDL. Therapeutic implications of these findings regarding
vitamin E, which is supposed to slow atherogenesis and the development of
microvascular complications in diabetes, are obvious: Vitamin E-monotherapy,
while blocking oxidative and AGE-modification of LDL, is unable to inhibit its AP
formation. As a consequence, tocopherol is susceptible to increased consumption
by AP-associated radical production in hyperglycemic patients, which could be
checked in part by the tocopherol-protecting agent troglitazone and/or by
acetylsalicylic acid.
PMID- 10766413
TI - Copper--ligand interactions and the physiological free radical processes. Part 3.
Influence of histidine, salicylic acid and anthranilic acid on copper-driven
Fenton chemistry in vitro.
AB - With a view to the possible use of copper(II)-*OH inactivating ligand (OIL)
complexes as regulators of inflammation, the reactivity of the copper(II)
ascorbate system with hydrogen peroxide has been investigated in the presence of
three key substances: histidine (the main copper(II) low molecular mass ligand in
extracellular fluid), salicylic acid (the well-known nonsteroidal
antiinflammatory drug, previously shown to be potentiated by copper(II) in animal
models of inflammation), and anthranilic acid (an inactive substance by itself,
known to be activated by copper(II) in the same models) at physiological pH (7.4)
and inflammatory pH (5.5). Such substances may affect the amount of TBARS
detected in solution following copper-mediated Fenton-like reactions through
three distinct mechanisms: (i) by decreasing the Cu(II)/Cu(I) redox potential,
i.e. at the expense of *OH radical production, (ii) by scavenging *OH radicals in
the body of the solution, and/or (iii) by acting as a true OIL, i.e. at the
expense of *OH detection. Redox potential measurements of initial solutions have
been performed in parallel to TBARS determinations to help discriminate between
different ligand influences. Computer-aided speciation has been used to
understand the role of copper(II) distribution on the ligand effects
characterised. Contrary to previous interpretations, histidine has been found to
mainly affect *OH production by lowering the redox potential of the Cu(II)/Cu(I)
couple. Salicylate, which has no effect on *OH production, has been confirmed to
mainly scavenge *OH radicals in the body of the solution. Anthranilate, which
both increases *OH production and decreases *OH detection, behaves as a potential
OIL. These results tend to confirm our previous hypothesis that copper
potentiation of antiinflammatory substances is indirect, i.e. independent of any
interaction between metal and drug, whereas copper activation of substances that
are inactive by themselves results from specific metal-substance interactions
taking place at inflammatory sites.
PMID- 10766414
TI - Coffee drinking increases levels of urinary hydrogen peroxide detected in healthy
human volunteers.
AB - Freshly-voided human urine contains significant concentrations of hydrogen
peroxide (H2O2). This H2O2 appears to arise in whole or in part by superoxide
dependent autoxidation of urinary biomolecules. Since instant coffee also
contains high levels of H2O2, we examined the effect of coffee drinking on
urinary levels of H2O2. Studies on healthy human volunteers showed that coffee
drinking is rapidly and reproducibly followed by increased levels of H2O2
detectable in the urine for up to 2 h after drinking the coffee. The levels of
H2O2 detected in urine suggest that exposure of human tissues to H2O2 may be
greater than is commonly supposed. It is possible that H2O2 in urine could act as
an antibacterial agent, and that H2O2 is involved in the regulation of glomerular
function.
PMID- 10766415
TI - Salubrious effect of vitamin C and vitamin E on tamoxifen-treated women in breast
cancer with reference to plasma lipid and lipoprotein levels.
AB - Tamoxifen, a non-steroidal antiestrogen, has been used in the hormonal treatment
for breast cancer. The hepatic estrogenic effect of tamoxifen causes severe
triglyceridemia. The combined effect of tamoxifen, vitamin C and vitamin E on
plasma lipid and lipoprotein is important, since, vitamin C and vitamin E
encumbered the lipid abnormalities instigated by tamoxifen. Therefore
supplementation of vitamin C (Celin 500 mg) and vitamin E (Evion 400 mg) for 90
days along with tamoxifen (10 mg twice a day) to postmenopausal breast cancer
patients was ventured. In tamoxifen-treated patients, total cholesterol (TC),
free cholesterol (FC), phospholipids (PL), free fatty acids (FFA), low density
lipoprotein cholesterol (LDL) levels were decreased and the triglycerides (TG),
ester cholesterol (EC), high density lipoprotein cholesterol (HDL) and very low
density lipoprotein cholesterol (VLDL) levels were increased. Combination therapy
reduce all the cholesterol level and VLDL, LDL. TG levels were significantly
decreased and HDL, EC levels were significantly increased. These results
suggested that tamoxifen treatment is the most effective during co-administration
of vitamin C and vitamin E in that they reduce the tamoxifen-induced
hypertriglyceridemia.
PMID- 10766416
TI - The effects of 1-nitropyrene, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and
7,12-dimethylbenz[a]anthracene on 8-hydroxy-2'-deoxyguanosine levels in the rat
mammary gland and modulation by dietary 1,4-phenylenebis(methylene)
selenocyanate.
AB - Humans are exposed to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and
1-nitropyrene (1-NP) via several environmental sources and both are known mammary
carcinogens in rodents, with the former being more potent (K. El-Bayoumy, Y.-H.
Chae, P. Upadhyaya, A. Rivenson, K. Kurtzke, B. Reddy, S.S. Hecht, Comparative
tumorigenicity of benzo[a]pyrene, 1-nitropyrene, and 2-amino-1-methyl-6
phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats,
Carcinogenesis 16 (1995) 431-434). Following their metabolic activation, both
carcinogens are known to bind covalently to DNA. However, it remains to be
determined whether these carcinogens can also induce DNA-base oxidation. Our goal
was to determine the effects of PhIP and 1-NP on the levels of 8-hydroxy-2'
deoxyguanosine (8-OHdG; a marker of oxidative DNA damage) in rat mammary glands
and to evaluate the effect of the chemopreventive agent 1,4-phenylenebis(
methylene)selenocyanate (p-XSC) as an inhibitor of such damage. As an established
potent mammary carcinogen, the synthetic 7,12-dimethylbenz[a]anthracene (DMBA)
was included in this study. Female CD rats were fed a high-fat AIN-76A diet
(23.5% corn oil) supplemented with p-XSC (10 ppm as selenium) or unsupplemented
control diet for 1 week. At 50 days of age, each rat (12 rats/group) was gavaged
with either PhIP (22 mg (100 micromol) per rat) or I-NP (20 mg (80 micromol) per
rat) in trioctanoin (0.5 ml), DMBA (5 mg (20 micromol) per rat] in olive oil (0.2
ml), or the corresponding vehicle. Rats were sacrificed 6 and 24 h after
carcinogen treatment (six rats per time point). Mammary fat pads were excised and
DNA was isolated and enzymatically hydrolyzed. The hydrolysates were analyzed for
8-OHdG using HPLC with EC detection. PhIP significantly increased the levels of 8
OHdG by 83% after 6 h (P < 0.05), but the increase (47%) at the 24 h point was
not significant. p-XSC alone had no effect on the levels of 8-OHdG. However, the
elevation of 8-OHdG caused by PhIP at 6 h was significantly inhibited by p-XSC to
levels similar to those measured in rats treated with the vehicle only (P <
0.05). p-XSC had no effect on PhIP-induced 8-OHdG at 24 h. I -NP had no effect on
the levels of 8-OHdG at either time point. Levels of 8-OHdG were increased by 22%
6 h after DMBA administration and, significantly, rose to 84% at 24 h (P < 0.01);
at either time point, this elevation was not inhibited by p-XSC. Although the
mechanisms remain to be determined, to our knowledge, this is the first report
demonstrating that PhIP and DMBA are capable of enhancing 8-OHdG levels in the
rat mammary tissue in vivo.
PMID- 10766417
TI - Vitamin E serum levels and gastric cancer: results from a cohort of patients in
Tuscany, Italy.
AB - Alpha-tocopherol has been reported to play an important role against oxidative
damage and in the inhibition of cell transforming and mutagenesis. We analysed
vitamin E serum levels in 51 cases of patients affected by gastric cancer at
different stages of the disease, and in 49 age-matched controls. All patients had
normal values of alpha-tocopherol. However, when patients have been grouped
according to histotype of gastric lesions, a significant vitamin E increase has
been found in diffuse gastric cancer histotype compared to the intestinal
histotype. Our results suggest that a correlation between vitamin E serum levels
and gastric cancer histotype should be considered.
PMID- 10766418
TI - Accumulation of diacylglycerol in the liver membrane of the Long-Evans Cinnamon
(LEC) rat with hepatitis: FT-IR spectroscopic and HPLC detection.
AB - Long-Evans Cinnamon (LEC) rats develop severe hepatitis and subsequent hepatoma
with excess accumulation of copper in the liver with increasing age. Lipids
extracted from the LEC rat liver membrane were studied using FT-IR spectroscopy
and an HPLC technique at the stages of pre-hepatitis and hepatitis, i.e. at 10
and 16 weeks of age, respectively. The 10-week-old rats exhibited an IR spectrum
characteristic of a phosphatidylcholine and phosphatidylethanolamine mixture with
a ratio of 2:1. The 16-week-old rats developed new absorption bands at 1161 and
1070 cm(-1), which were assigned to the spectra of triglyceride, neutral lipid,
and diacylglycerol, an endogenous activator of protein kinase C, respectively.
The diacylglycerol was estimated to amount to ca. 10% (w/w) of phospholipid
extract by comparing the spectrum with those of model compounds. This was
confirmed using an HPLC assay. Previously, we found that a serum response factor
is activated by copper in the LEC rat liver, and suggested that it must mediate
proto-oncogene c-fos induction. The results obtained here suggest that
accumulation of diacylglycerol plays an important role in development of hepatoma
in LEC rats by mediating proto-oncogene c-fos induction.
PMID- 10766419
TI - Cells in cryptophycin-induced cell-cycle arrest are susceptible to apoptosis.
AB - Exposure of murine leukemia L1210 cells to the antitumor antibiotic cryptophycin
52 (C52) led to cell-cycle arrest at the prometaphase/metaphase interface within
18 h, but apoptotic nuclei did not appear until 36 h later. To determine whether
accumulation of cells in early metaphase might have delayed the apoptotic
process, cells were treated with C52 for 18 h and a photodynamic process was used
to initiate the release of mitochondrial cytochrome c. Apoptosis was observed
within 60 min, indicating that the slow apoptotic response was not caused by an
impaired ability of genomic DNA to undergo endonucleosomal cleavage during cell
cycle arrest induced by cryptophycin 52.
PMID- 10766420
TI - Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon
carcinoma cells.
AB - Interleukin-6 (IL-6) is a pleiotropic cytokine which exerts biological activities
on various cell types including neoplastic cells. We have investigated the
biological effect of IL-6 and the expression of IL-6 receptors (IL-6R) on human
colorectal carcinoma cell lines. Isreco-1 was derived from the primary site of a
colon cancer while Isreco-2 and Isreco-3 were established from a liver and
peritoneal metastasis of the same patient. IL-6 stimulated colony formation in
methylcellulose of Isreco-1 cells to 150% (P < 0.05). The effect was even more
pronounced on the metastatic Isreco-2 line where colony numbers in the presence
of IL-6 were enhanced up to four-fold (P < 0.0001) in a dose-dependent fashion.
An anti-IL-6 antibody completely abolished this growth stimulatory effect of IL
6. RT-PCR analysis revealed transcripts for IL-6Ralpha and gp 130 in these cell
lines. Experiments with additional cell lines confirmed the general expression of
gp130 but showed limited expression of the IL-6Ralpha chain. Surprisingly, about
half of the cell lines tested expressed IL-6 mRNA at low levels which was not
translated into protein. Our results suggest that IL-6 can potently stimulate
anchorage-independent growth of some colorectal carcinoma cells. This stimulation
appears to occur through a paracrine mechanism.
PMID- 10766421
TI - Involvement of p27(kip1) in ceramide-mediated apoptosis in HL-60 cells.
AB - Ceramide acts as a mediator of apoptosis in various cell lines, but little is
known regarding the molecular mechanism linked to the cell cycle. In the present
study, we examined the expression of p27(kip1) and its relationship to apoptosis
induced by ceramide. We demonstrated that treatment of HL-60 cells with C6
ceramide resulted in G1 phase elevation followed by apoptotic cleavage associated
with increase in the level of cdk inhibitor p27(kip1). Ceramide inhibited the
kinase activities of cdk2 and cdk4 within 24 h of treatment. Ceramide-induced
inhibition of cdk2 and cdk4 kinase activities was accompanied by increase of
p27(kip1) in the cdks complexes. In addition, we have shown that both the cell
death and expression of p27(kip1) protein induced by ceramide were significantly
decreased in HL-60 cells overexpressing bcl-2. Furthermore, ceramide induced a
significant increase in Bax protein expression coincided with increase in
p27(kip1) protein level. These findings indicate that p27(kip1) may play
important roles in mediating ceramide-induced apoptosis and its expression can be
regulated by Bax and Bcl-2.
PMID- 10766422
TI - Differentiation status modulates transcription factor NF-kappaB activity in
unstimulated human hepatocellular carcinoma cell lines.
AB - We report herein a novel finding that under an unstimulated condition, a group of
four human hepatocellular carcinoma (HCC) cell lines with varying degrees of
differentiation, can spontaneously activate NF-KB. The propensity of activation
coincided inversely with the differentiation status, with order being SK-Hep-1 >
J5 > Hep3B > HepG2. Further studies indicate that this pattern of activation
correlates excellently with the descending order of intracellular GSH/GSSG ratios
as well as with the ascending order in the ability of these cells to generate
hydrogen peroxide. Taken together, our data suggest that differentiation status
may play a pivotal role in modulating intracellular thiol redox status and the
extent of catalase expression, which may be crucial in the control of NF-kappaB
activity in these HCC cells.
PMID- 10766423
TI - Effect of tumor-conditioned medium on intercellular communication and
proliferation of Balb/c 3T3 cells.
AB - The possible role of tumor cell-derived factors in the regulation of gap
junctional intercellular communication and proliferation of fibroblasts was
studied in a model system of Balb/c 3T3 cells growing in tumor conditioned medium
by Lucifer Yellow CH dye-transfer and BrdU incorporation assays. Six to 24 h
incubation of Balb/c 3T3 cells in a medium conditioned by WiDr adenocarcinoma
cells enhanced the gap junctional communication between the cells by 25-40% as
revealed by intercellular transfer of a fluorescent dye Lucifer Yellow CH.
Simultaneously the cell proliferation rates were examined and found to be reduced
by 23% at 24 h treatment. Since adenocarcinoma cells are known to secrete
different growth factor-like polypeptides into their conditioned medium, we
suppose that tumors that produce these molecules might alter their host
environment through the enhancement of cell-cell communication thereby
facilitating the exchange of modulatory factors.
PMID- 10766424
TI - Involvement of insulin-like growth factor binding protein-3 in the retinoic acid
receptor-alpha-mediated inhibition of hepatocellular carcinoma cell
proliferation.
AB - We examined the relationship between the expression of retinoic acid receptor
alpha (RAR-alpha) and upregulation of insulin-like growth factor binding protein
3 (IGFBP-3) in the retinoid-induced inhibition of hepatocellular carcinoma (HCC)
cell proliferation. HCC cell lines showed a marked expression of RAR-alpha,
whereas the expression levels of RAR-beta and RAR-gamma were relatively lower. An
RAR-alpha agonist significantly inhibited the HCC cell proliferation both in
vitro and in vivo. The RAR-alpha expression closely related to the upregulation
of IGFBP-3 as compared with RAR-beta or RAR-alpha expressions. RAR-alpha agonist
would be beneficial to inhibit the growth of HCC.
PMID- 10766425
TI - Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal
development.
AB - Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa
resulting in embryotoxicity and developmental defects in their offspring. This
study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa
following treatment with the antineoplastic drug, cisplatin. The formation of
spermatozoa cisplatin-DNA adducts showed dose and time-dependent increases both
in vitro, and in vivo up to 168 h (7 days) after dosing. Treatment of rats with
10 mg cisplatin/kg resulted in spermatozoa Pt-GG adduct levels of approximately
1.0 fmol/microg DNA. When cisplatin-treated male rats were bred to untreated
females 6-24 h after cisplatin administration, no adverse developmental effects
or decreases in body weight were seen in the offspring although there was a trend
towards increased early embryo mortality.
PMID- 10766426
TI - Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of
patients with gastric cancer.
AB - Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been
reported to be related to disease progression in patients with gastric cancer.
However, the prognostic significance of plasma TIMP-1 concentrations has not been
clarified. Concentrations of TIMP-1 protein were measured by enzyme-linked immuno
sorbent assay in plasma samples of 147 preoperative patients who subsequently
underwent gastric resection, and prognosis was compared. The cut-off value of
plasma TIMP-1 concentrations was defined as 112.5 ng/ml, referring to the TIMP-1
levels in patients with intramucosal gastric cancer. Twenty-nine out of 147
patients had higher plasma TIMP-1 levels than the cut off value. When the
patients were divided into those with elevated values and those with normal TIMP
1, such parameters as age, serosal invasion, metastases to lymph nodes,
peritoneum, and liver, lymphatic invasion, curability, and stage were
significantly different between the two. By univariate analysis of the factors
affecting survival, macroscopic type, histology, serosal invasion, metastasis to
lymph node, peritoneum, and liver, vessel invasions, curability, and plasma TIMP
1 were significant. However, multivariate analysis revealed that TIMP-1 was the
only significant factor. In patients with gastric cancer, plasma TIMP-1 seem to
be an independent and most powerful prognosticator for the survival.
PMID- 10766427
TI - Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in
human breast cancer tissue and its relationship to GSTP1 and COMT genotypes.
AB - Reactive oxygen species (ROS) induced damage to DNA plays a major role in
carcinogenesis. In order to estimate the level of oxidative damage and its role
in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA
isolated from human breast tissue. Furthermore, we investigated whether
polymorphisms in genes for enzymes involved in generation and elimination of ROS
had any association with the level of 8-OHdG in breast tissue. In this study, the
level of 8-OHdG in DNA was measured by the high performance liquid chromatography
electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450
(CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O
methyltransferase (COMT) were determined by PCR-based restriction fragment length
polymorphism analysis. A total of 61 Japanese patients were included in the
study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95
per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous
breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA
of breast cancer tissues were significantly higher than those of their
corresponding non-cancerous breast tissues (P < 0.0001). There was negative
correlation between the clinical stage and the mean level of 8-OHdG in DNA of
breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity
had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the
contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher
among patients with genotype of high COMT activity. Our findings support the
assumption that cancer cells are more exposed to oxidative stress than adjacent
non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism
may have a role in individual susceptibility to oxidant-related breast disease.
At the same time, reduction of oxidative stress is thought to be a very important
measure for primary prevention of breast cancer.
PMID- 10766428
TI - In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin
D3.
AB - Inhibitory effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the
proliferation of a variety of cancer cell lines have been extensively reported.
We have studied the effect of 1,25-(OH)2D3 (10(-11)-10(-6) M) on the
proliferation of a number of human and rat liver cancer cell lines. Additionally,
the effect of 1,25-(OH)2D3 (0.02-0.5 microg/kg per day) on the rate of growth of
liver cancer cell line xenografts in nude mice was also investigated. In vitro,
proliferation of Hep-3B, PLC/PRF/5, and SKHEP-1 cells was significantly inhibited
by 1,25-(OH)2D3, while HTC and Novikoff cells were more resistant to the
inhibitory effects of the drug. In vivo, treatment of SKHEP-1 tumor bearing nude
mice with different doses of 1,25-(OH)2D3 significantly retarded tumor growth
without the development of hypercalcemia.
PMID- 10766429
TI - Synergistic effects of thearubigin and genistein on human prostate tumor cell (PC
3) growth via cell cycle arrest.
AB - There is evidence that habitual consumption of green tea by Japanese men is
correlated with a reduction in cancers, including prostate; soybean isoflavones
are also associated with increased protection. The present study compared the
anti-proliferative effect of black tea (Camellia sinensis) polyphenol,
thearubigin (TR), alone or combined with the isoflavone genistein, on human
prostate (PC-3) carcinoma cells. TR administered alone did not result in any
alteration of cell growth. When combined with genistein, however, TR
significantly inhibited cell growth and induced a G2/M phase cell cycle arrest in
a dose dependent manner. These findings indicate the potential use of combined
phytochemicals to provide protection against prostate cancer.
PMID- 10766430
TI - Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells
in culture.
AB - The effects of carotenoids--alpha-carotene, beta-carotene, lycopene, beta
cryptoxanthin, zeaxanthin, lutein, canthaxanthin, astaxanthin--on the invasion of
rat ascites hepatoma AH109A cells were investigated by co-culturing the hepatoma
cells with rat mesentery-derived mesothelial cells (M-cells). All the carotenoids
examined inhibited AH109A invasion in a dose-dependent manner up to 5 microM.
Cancer cells previously cultured with hypoxanthine (HX) and xanthine oxidase (XO)
showed a highly invasive activity. Carotenoids, 5 microM of beta-carotene and
astaxanthin, suppressed this reactive oxygen species-potentiated invasive
capacity by simultaneously treating AH109A cells with the carotenoids, HX and XO.
These results suggest that the antioxidative property of these carotenoids may be
involved in their anti-invasive action.
PMID- 10766431
TI - Iron-sulfur proteins: ancient structures, still full of surprises.
AB - This article is a survey of the properties and functions of Fe-S proteins under
the following headings: sulfur and iron; iron-sulfur clusters; evolution of
cofactor use; early observations; complex and extended clusters; sulfur exchange
and core interconversions; synthesis and biosynthesis of Fe-S clusters; functions
of Fe-S clusters: electron transfer, electron delocalization, spin states and
magnetism, covalency of sulfur bonds; non-electron transfer functions of Fe-S
clusters: substrate binding and catalysis, regulatory and sensing functions.
PMID- 10766432
TI - Electronic structure contributions to electron transfer in blue Cu and Cu(A).
AB - The experimentally determined electronic structures of mononuclear blue Cu and
binuclear Cu(A) centers are summarized and their relation to intra- and inter
protein electron transfer (ET) kinetics are described. Specific contributions of
the electronic structures of these two broad classes of Cu ET proteins to H(AB),
lambda, and deltaE degrees are discussed. Also, the role of the protein structure
in determining key geometric features which define the electronic structures of
the metal sites in these proteins is considered.
PMID- 10766433
TI - Probing the electronic structure of transition metal ion centres in proteins by
coherent Raman-detected electron paramagnetic resonance spectroscopy.
AB - The simultaneous excitation of a paramagnetic sample with optical (laser) and
microwave radiation can cause an amplitude or phase modulation of the transmitted
light at the microwave frequency. The detection of this modulation indicates the
presence of coupled optical and electron paramagnetic resonance (EPR) transitions
in the sample. Here we report the first application of this technique to a
biomolecule: the blue copper centre of Pseudomonas aeruginosa azurin. Using
optical excitation at 686 nm, in the thiol to copper(II) charge transfer band, we
measure a coherent Raman-detected EPR spectrum of a frozen aqueous solution. Its
lineshape is characteristic of the magnetic circular dichroism along each
principal g-value axis. This information allows electronic and structural models
of transition metal ion centres in proteins to be tested.
PMID- 10766434
TI - Single crystal EPR studies of the oxidized active site of [NiFe] hydrogenase from
Desulfovibrio vulgaris Miyazaki F.
AB - The Ni-A and the Ni-B forms of the [NiFe] hydrogenase from Desulfovibrio vulgaris
Miyazaki F have been studied in single crystals by continuous wave and pulsed EPR
spectroscopy at different temperatures (280 K, 80 K, and 10 K). For the first
time, the orientation of the g-tensor axes with respect to the recently published
atomic structure of the active site at 1.8 A resolution was elucidated for Ni-A
and Ni-B. The determined g-tensors have a similar orientation. The configuration
of the electronic ground state is proposed to be Ni(III) 3d1/z 2 for Ni-A and Ni
B. The gz principal axis is close to the Ni-S(Cys549) direction; the gx and the
gy axes are approximately along the Ni-S(Cys546) and Ni-S(Cys81) bonds,
respectively. It is proposed that the difference between the Ni-A and Ni-B states
lies in a protonation of the bridging ligand between the Ni and the Fe.
PMID- 10766435
TI - Circular dichroism spectra of the individual rotamers of [Pt(N,N-dmen)(GpG)]+
(N,N-dmen=N,N-dimethylethylenediamine) indicate that the base-base oscillator
coupling is not the main source of ellipticity in cis-PtG2L2 head-to-head
complexes.
AB - The asymmetrical platinum complex [PtCl2(N,N-dmen)] (N,N-dmen = N,N
dimethylethylenediamine) reacts with the dinucleotide GpG to form two isomeric
chelates of the formula [Pt(N,N-dmen)(GpG)]+ [9]. One of the isomers forms two
stable rotamers separable by HPLC, whereas the other apparently prefers one
single rotameric form. The favored conformations of these three forms were
elucidated by means of molecular mechanics and dynamics techniques. In parallel,
we have prepared the adduct, isolated the three rotamers, and recorded their
solution circular dichroism (CD) spectra. For the first time we were thus able to
correlate the CD features of individual rotamers of a cis-Pt(GpG) chelate with
their structures. We show here that the two forms labeled in Inagaki's paper 1'e
and 2e have the same right-handed helicoidal arrangement of the guanine bases but
display different CD spectra in which the prominent bands have inverted signs.
Thus, base-base interactions cannot be the principal cause of the CD of these
compounds.
PMID- 10766436
TI - Dynamic relaxometry: application to iron uptake by ferritin.
AB - We introduce dynamic relaxometry as a novel technique for studying biochemical
reactions, such as those leading to mineral formation (biomineralization). This
technique was applied to follow the time course of iron oxidation and hydrolysis
by the protein ferritin. Horse spleen apoferritin was loaded with single
additions of 4, 10, 20, 40, and 100 ferrous ions per protein, and with multiple
additions of 4, 10, 20, and 100 ferrous ions. The NMR T2 relaxation time was then
measured sequentially and continuously for up to 24 h. At low loading factors of
4-10 Fe atoms/molecule, the iron is rapidly bound and oxidized by the protein on
a time scale of approximately 15 s to several minutes. At intermediate loading
factors (10-40), rapid initial oxidation was observed, followed by the formation
of antiferromagnetic clusters. This process occurred at a much slower rate and
continued for up to several hours, but was inhibited at lower pH values. At
higher loading factors (40-1000), iron oxidation may occur directly on the core,
and this process may continue for up to 24 h following the initial loading.
Dynamic relaxometry appears to be a potentially powerful technique that may well
have applications beyond the study of iron uptake by the ferritin protein.
PMID- 10766437
TI - Amonabactin-mediated iron acquisition from transferrin and lactoferrin by
Aeromonas hydrophila: direct measurement of individual microscopic rate
constants.
AB - The effectiveness and mechanism of iron acquisition from transferrin or
lactoferrin by Aeromonas hydrophila has been analyzed with regard to the
pathogenesis of this microbe. The ability of A. hydrophila's siderophore,
amonabactin, to remove iron from transferrin was evaluated with in vitro
competition experiments. The kinetics of iron removal from the three molecular
forms of ferric transferrin (diferric, N- and C-terminal monoferric) were
investigated by separating each form by urea gel electrophoresis. The first
direct determination of individual microscopic rates of iron removal from
diferric transferrin is a result. A. hydrophila 495A2 was cultured in an iron
starved defined medium and the growth monitored. Addition of transferrin or
lactoferrin promoted bacterial growth. Growth promotion was independent of the
level of transferrin or lactoferrin iron saturation (between 30 and 100%), even
when the protein was sequestered inside dialysis tubing. Siderophore production
was also increased when transferrin or lactoferrin was enclosed in a dialysis
tube. Cell yield and growth rate were identical in experiments where transferrin
was present inside or outside the dialysis tube, indicating that binding of
transferrin was not essential and that the siderophore plays a major role in iron
uptake from transferrin. The rate of iron removal from diferric transferrin shows
a hyperbolic dependence on amonabactin concentration. Surprisingly, amonabactin
cannot remove iron from the more weakly binding N-terminal site of monoferric
transferrin, while it is able to remove iron from the more strongly binding C
terminal site of monoferric transferrin. Iron from both sites is removed from
diferric transferrin and it is the N-terminal site (which does not release iron
in the monoferric protein) that releases iron more rapidly! It is apparent that
there is a significant interaction of the two lobes of the protein with regard to
the chelator access. Taken together, these results support an amonabactin
dependent mechanism for iron removal by A. hydrophila from transferrin and
lactoferrin. The implications of these findings for an amonabactin-dependent
mechanism for iron removal by A. hydrophila from transferrin and lactoferrin are
discussed.
PMID- 10766439
TI - Mutation of the surface valine residues 8 and 44 in the rubredoxin from
Clostridium pasteurianum: solvent access versus structural changes as
determinants of reversible potential.
AB - The Pr(i) sidechains of two adjacent valine residues, V8 and V44, define the
surface of the rubredoxin from Clostridium pasteurianum and control access to its
Fe(S-Cys)4 active site. To assess the effect of systematic change of the steric
bulk of the alkyl sidechains, eight single and three double mutant proteins have
been isolated which vary G (H), A (Me), V (Pr(i)), L (Bu(i)) and I (Bu(s)) at
those positions. X-ray crystal structures of the Fe(III) forms of the V44A and
V44I proteins are reported. Positive shifts in reversible potential of up to 116
mV are observed and attributed to increased polarity around the Fe(S-Cys)4 site
induced by (1) changes in protein backbone conformation driven by variation of
the steric demands of the sidechain substituents and (2) changes in solvent
access to the side-chains of ligands C9 and C42. Data for the V44A mutant show
that a minor change in the steric requirements of a surface residue can introduce
a NH...Sgamma hydrogen bond at the active site and lead to a shift in potential
of + 50 mV.
PMID- 10766438
TI - Metal-ion stoichiometry of the HIV-1 RT ribonuclease H domain: evidence for two
mutually exclusive sites leads to new mechanistic insights on metal-mediated
hydrolysis in nucleic acid biochemistry.
AB - Crystallographic studies of the Mn(2+)-doped RNase H domain of human
immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) have revealed two
bound Mn2+ separated by approximately 4A and surrounded by a cluster of four
conserved carboxylates. Escherichia coli RNase H is structurally similar to the
RNase H domain of HIV-1 RT, but requires one divalent metal cation for its
activity, implying either that the HIV-1 RT RNase H domain contrasts in its
ability to bind two divalent metal ions, or that the crystallographic data
reflect specific use of Mn2+ and/ or the doping technique employed. Metal binding
stoichiometry has been determined for Mn2+ and the biologically more relevant
Mg2+ cation by solution calorimetric studies of native and recombinant p66/p51
HIV-1 RT. Three Mn2+ ions bind to HIV-1 RT apo-enzyme: one at the DNA polymerase
and two at the RNase H catalytic center, the latter being consistent with
crystallographic results. However, only one Mg2+ ion is bound in the RNase H
catalytic center. Several mechanistic implications arise from these results,
including the possibility of mutually exclusive Mg2+ binding sites that might be
occupied according to the specific reaction being catalyzed by the
multifunctional RNase H domain. The occurrence of distinct binding
stoichiometries for Mg2+ and Mn2+ to multifunctional enzymes has previously been
reported.
PMID- 10766440
TI - Oligonucleotide conjugates of Eu(III) tetraazamacrocycles with pendent alcohol
and amide groups promote sequence-specific RNA cleavage.
AB - Eu(III) complexes of two neutral bifunctional tetraaaza macrocyclic ligands ?1-[1
carboxamido-3-(4-nitrophenyl)propyl]-4,7,10-tris(2-hydroxyethyl)-1 ,4,7,10
tetraazacyclododecane and 2-(4-nitrobenzyl)-1,4,7,10-tetrakis(2-hydroxyethyl)
1,4,7,10-tetraaza cyclododecane? are prepared. Eu(III) complexes of the
isothiocyanate derivatives of these macrocycles are treated with oligonucleotides
containing 2'-O-propyl-amine linkers to form conjugates. Hydrolytic cleavage of
an oligoribonucleotide is promoted by Eu(III) macrocyclic oligonucleotide
conjugates containing complementary (antisense) sequences. Cleavage is not
observed in the presence of Eu(III) conjugates containing scrambled sequences nor
by free complex. Despite the fact that one of the free macrocyclic complexes is
more reactive than the other, the extent of cleavage observed is similar for
conjugates containing either Eu(III) macrocyclic complex.
PMID- 10766441
TI - Spectroscopic characterization of Co(II)-, Ni(II)-, and Cd(II)-substituted wild
type and non-native retroviral-type zinc finger peptides.
AB - The nucleocapsid protein (NCP) from Mason-Pfizer monkey virus (MPMV) contains two
evolutionary invariant Cys-X2-Cys-X4-His-X4-Cys retroviral-type zinc finger
structures, where the Cys and His residues provide ligands to a tetrahedrally
coordinated Zn(II) ion. The N-terminal zinc finger (F1) of NCP from MPMV contains
an immediately contiguous Cys in the -1 position relative to the start of this
conserved motif: Cys-Cys-X2-Cys-X4-His-X4-Cys. Metal complexes of 18-amino acid
peptides which model the native zinc finger sequence, SER-Cys-X2-Cys-X4-His-X4
Cys (F1-SC), and non-native Cys-SER-X2-Cys-X4-His-X4-Cys (F1-CS) and SER-SER-X2
Cys-X4-His-X4-Cys (F1-SS) sequences have been spectroscopically characterized and
compared to the native two-zinc-finger protein fragment, MPMV NCP 21-80. All
Co(II)-substituted peptide complexes adopt tetrahedral ligand geometries and have
S- -->Co(II) ligand-to-metal charge-transfer (LMCT) transition intensities
consistent with three Co(II)-S bonds for F1-SC and F1-CS. The non-native F1-CS
peptide binds Co(II) with KCo= 1.5 x 10(6) M(-1), comparable to that of the
native complex, and approximately 100-fold tighter than F1-SS. Like the Co(II)
derivative, the absorption spectrum of Ni(II)-substituted NCP 21-80 is most
consistent with tetrahedral Ni(II) complexes with multiple thiolate donors. In
contrast, Ni(II) complexes of F1-SC and F1-CS exhibit a single absorption band in
the 400-550 nm region (epsilon approximately 200-300 M(-1) cm (-1), distinct in
the two complexes, assignable to a degenerate d-d transition envelope
characteristic of non-native square-planar coordination geometry, and an intense
LMCT transition in the UV (epsilon255 approximately 14,000 M(-1) cm(-1)). Cd(II)
complexes have intense absorption in the UV (lambda(max)=233nm), with absolute
intensities consistent with approximately 5000 M(-1) cm(-1) per Cd(II)-S bond.
113Cd NMR spectroscopy of 113Cd MPMV NCP gives delta=649 ppm, consistent with S3N
coordination. Co(II) and Cd(II) complexes of non-native F1-CS peptides are more
sensitive to oxidation by O2, relative to F1-SC, suggestive of a higher lability
in the non-native chelate. The implications of these findings for the
evolutionary conservation of this motif are discussed.
PMID- 10766442
TI - Bathocuproine-assisted reduction of copper(II) by human albumin.
AB - Human albumin (studied here as the recombinant protein rHA), a copper-binding
protein in blood plasma, is shown to reduce Cu(II) to Cu(I) in the presence of a
Cu(I) chelator, bathocuproinedisulfonate (BD). This reaction was accelerated at
low pH, when there was little binding of Cu(II) to rHA. The addition of a
competitive metal ion, Ni(II), or an increase in the concentration of BD,
enhanced the reduction of Cu(II) to Cu(I). It was concluded that the oxidant was
the Cu(II) complex of BD, which is likely to bind strongly to albumin. The free
thiol at Cys34 was ruled out as the sole reducing agent, since Cys34-blocked
albumin also gave rise to Cu(I) in the presence of BD. Reactions with amino acids
and peptides suggested that Tyr and possibly His side-chains are potential
reductants. BD and its homologues are frequently used as Cu(I)-specific chelators
in biological experiments, but the strong oxidant activity of [Cu(II)(BD)2]2- and
its ability to bind to biological macromolecules should not be overlooked, and
may artificially trigger/accelerate Cu(II) reduction.
PMID- 10766443
TI - The complex of Bacillus pasteurii urease with acetohydroxamate anion from X-ray
data at 1.55 A resolution.
AB - The structure of Bacillus pasteurii urease inhibited with acetohydroxamic acid
was solved and refined anisotropically using synchrotron X-ray cryogenic
diffraction data (1.55 A resolution, 99.5% completeness, data redundancy = 26, R
factor = 15.1%, PDB code 4UBP). The two Ni ions in the active site are separated
by a distance of 3.53 A. The structure clearly shows the binding mode of the
inhibitor anion, symmetrically bridging the two Ni ions in the active site
through the hydroxamate oxygen and chelating one Ni ion through the carbonyl
oxygen. The flexible flap flanking the active site cavity is in the open
conformation. The possible implications of the results on structure-based
molecular design of new urease inhibitors are discussed.
PMID- 10766444
TI - Enantiomeric ruthenium(II) complexes binding to DNA: binding modes and
enantioselectivity.
AB - A series of enantiomerically pure polypyridyl ruthenium(II) complexes, delta- and
lambda-[Ru(bpy)2 (HPIP)](PF6)2 (delta-1 and lambda-1; bpy=2,2'-bipyridine, HPIP =
2-(2-hydroxyphenyl)imidazo[4,5-f][1,10]phenanthroline), delta and lambda
[Ru(bpy)2(HNAIP)](PF6)2 (delta-2 and lambda-2; HNAIP = 2-(2-hydroxy-1
naphthyl)imidazo[4,5-f][1,10]phenanthroline), delta- and lambda-[Ru(bpy)2
(HNOIP)](PF6)2 (delta-3 and lambda-3; HNOIP = 2-(2-hydroxy-5
nitrophenyl)imidazo[4,5-f][1,10]phenanthroline), and delta- and lambda
[Ru(bpy)2(DPPZ)](PF6)2 (delta-4 and lambda-4; DPPZ= dipyridophenazine), have been
synthesized. Binding behavior of these chiral complexes to calf thymus DNA (CT
DNA) has been investigated by electronic absorption, steady-state emission, and
circular dichroism spectroscopies, as well as by viscosity measurements and
equilibrium dialysis binding studies. Several points came from the results. (1)
The DNA-binding properties were distinctly different for the [Ru(bpy)2L]2+
(L=HPIP, HNAIP, HNOIP) series of ruthenium(II) complexes, which indicates that
the photophysical behavior of the complexes on binding to DNA can be modulated
through ligand design. (2) Different binding rates of individual enantiomers of
complexes 1 and 4 to DNA were observed through dialysis experiments. The lambda
enantiomer bound more rapidly than the lambda enantiomer and their different
intercalative binding geometries were suggested to be responsible. (3) Both delta
2 and lambda-2 bound weakly to CT-DNA; delta-2 may bind through a partial
intercalation mode, whereas lambda-2 may bind in the DNA groove. (4) There was no
noticeable enantioselectivity for complexes 1, 3, and 4 on binding to CT-DNA.
Both of their enantiomers can intercalate into DNA base pairs. It is noted that
delta-3 and lambda-3 exhibited almost identical spectral changes on addition of
CT-DNA, and a similar binding manner of the isomers to the double helix was
proposed.
PMID- 10766445
TI - The binding of trivalent chromium to low-molecular-weight chromium-binding
substance (LMWCr) and the transfer of chromium from transferrin and chromium
picolinate to LMWCr.
AB - A recent model for the role of chromium in insulin signaling requires that the
oligopeptide low-molecular-weight chromium-binding substance (LMWCr) tightly bind
four chromic ions before the oligopeptide obtains a conformation required for
binding to the tyrosine kinase active site of the insulin receptor. To test this
model, the chromium-binding constant of LMWCr was determined, and the ability of
LMWCr to remove chromium from Cr2-transferrin and the nutritional supplement
chromium picolinate, Cr(pic)3, was examined. These results are consistent with
the model of the mode of action of LMWCr; a Hill study indicates the four chromic
ions bind to apoLMWCr in a highly cooperative fashion (n =3.47) with a binding
constant of 1.54x 10(21). Chromium is readily transferred from transferrin to
apoLMWCr at near neutral pH. The results also suggest that reduction of the
chromic center of Cr(pic)3 may be required for the supplement to release
chromium; thus, release of chromium is related to a mechanism by which Cr(pic)3
may generate hydroxyl radicals in cells.
PMID- 10766446
TI - A hypothesis: SNARE-ing the mechanisms of regulated exocytosis and pathologic
membrane fusions in the pancreatic acinar cell.
AB - The pancreatic acinar cell has been a classic model to study regulated exocytosis
occurring at the apical plasma membrane. The acinar cell is also an excellent
model with which to study pathologic membrane fusion events, including aberrant
zymogen granule fusion with the lysosome and basolateral exocytosis, which are
the earliest cellular events of acute pancreatitis. However, despite much effort,
little is known about the precise mechanisms that mediate these physiologic and
pathologic membrane fusion events until recently. Over the past 5 years, there
has been a major advance in the fundamental understanding of vesicle fusion based
on the SNARE hypothesis. A basic tenet of the SNARE hypothesis is that the
minimal machinery for membrane fusion is a cognate set of v- and t-SNAREs on
opposing membranes. A corollary to this hypothesis is that these SNARE proteins
are prevented from spontaneous assembly by clamping proteins. Here, the recent
developments in the identification of cognate v- and t-SNAREs and clamping
proteins are reviewed, which are strategically located to mediate these
physiologic exocytic and pathologic fusion events in the pancreatic acinar cell.
PMID- 10766447
TI - The antiangiogenesis effect of interleukin 12 during early growth of human
pancreatic cancer in SCID mice.
AB - Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor
effect through its pleiotropic actions. It was recently reported that IL-12 has
also a potent antiangiogenic effect through the induction of IFN-gamma, which
triggers the production of chemokines such as IP-10 that has been shown to have
antiangiogenesis properties. In this study we transfected the IL-12 gene into a
human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the
green fluorescence protein (gfp) gene were used as positive controls. The in
vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and
gfp/PK-1) were compared with those of parental cells. The SCID mice used in this
study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to
deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber
model, we observed and recorded tumor angiogenesis by intravital microscopy. In
vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild
type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop
into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo
GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in
mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to
gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in
the skinfold chamber model. These results indicate that the antiangiogenesis
effect of IL-12 alone, without immune system involvement, is sufficient to block
the growth of human pancreatic cancer.
PMID- 10766448
TI - Investigation of the interleukin 1 gene cluster and its association with acute
pancreatitis.
AB - The interleukin 1 (IL-1) gene cluster has been implicated in acute pancreatitis.
Penta-allelic and bi-allelic polymorphisms exist in the IL-1RN and IL-1B genes,
respectively. The aim of the study was to investigate these polymorphisms in
acute pancreatitis. Genotype and allele frequencies were determined in patients
(n = 116) and healthy controls (n = 170) using the polymerase chain reaction. PCR
products from the IL-1B study were further digested with Taq I restriction
endonuclease. Patients were categorised according to aetiology, severity, and
organ-failure scores. Allele 1 of the IL-1RN polymorphism was significantly
increased in patients compared with controls (72.0 vs. 63.0%; p = 0.029, Pc =
0.029), in severe cases compared with controls (81.9 vs. 63.0%; p = 0.002, Pc =
0.004), in idiopathics compared with controls (82.4 vs. 63.0%; p = 0.002, Pc =
0.006), and in severe cases compared with mild cases (81.9 vs. 67.5%; p = 0.023,
Pc = 0.046). Allele 2 was significantly decreased in severe cases compared with
controls (18.1 vs. 33.0%; p = 0.013, Pc = 0.026), in idiopathics compared with
controls (17.6 vs. 33%; p = 0.013, Pc = 0.039), and in severe cases compared with
mild cases (18.1 vs. 32.5%; p = 0.023, Pc = 0.046). No significant differences
were found for the Taq I allele or genotype frequencies between controls and
patients/subgroups of patients. IL-1RN appears to determine severity of acute
pancreatitis and susceptibility to idiopathic acute pancreatitis. No association
was found between IL-1B and the disease.
PMID- 10766449
TI - Tachykinins in the porcine pancreas: potent exocrine and endocrine effects via NK
1 receptors.
AB - The localization, release, and effects of substance P and neurokinin A were
studied in the porcine pancreas and the localization of substance P
immunoreactive nerve fibers was examined by immunohistochemistry. The effects of
electrical vagus stimulation and capsaicin infusion on tachykinin release and the
effects of substance P and neurokinin A infusion on insulin, glucagon,
somatostatin, and exocrine secretion were studied using the isolated perfused
porcine pancreas with intact vagal innervation. NK-1 and NK-2 receptor
antagonists were used to investigate receptor involvement. Substance P
immunoreactive nerve fibers were localized to islets of Langerhans, acini, ducts,
and blood vessels. Vagus stimulation had no effect on substance P and neurokinin
A release, whereas capsaicin infusion stimulated release of both. Substance P and
neurokinin A infusion increased release of insulin, glucagon, and exocrine
secretion, whereas somatostatin secretion was unaffected. The effect of substance
P on insulin, glucagon, and exocrine secretion was blocked by the NK-1 receptor
antagonist. The effect of electrical stimulation of vagus nerves on insulin and
exocrine secretion was not influenced by tachykinin receptor antagonists. We
conclude that tachykinins stimulate both endocrine and exocrine pancreatic
functions through NK-1 receptors. Tachykinins are not involved in vagal
regulation of pancreatic secretion in pigs but could constitute part of an
alternative stimulatory system.
PMID- 10766450
TI - Tumor angiogenesis in chronic pancreatitis and pancreatic adenocarcinoma: impact
of K-ras mutations.
AB - Chronic pancreatitis (CP) is one condition in which epidemiologic studies have
demonstrated a definite association with pancreatic adenocarcinoma (PAC). The
pathophysiologic and molecular events that either predispose to the development
of, or potentiate the growth of, PAC are unknown. Mutation of the codon 12 K-ras
gene is one genetic aberration commonly associated with development of PAC. Tumor
angiogenesis, or microvascular proliferation of new capillaries, is another
pathophysiologic alteration associated with PAC. Although activated ras oncogenes
modulate tumor angiogenesis/neovascularization in some tumors, the importance of
tumor angiogenesis and the role of K-ras mutation in regulating angiogenesis in
CP and PAC are unknown. The aim of this study was to elucidate the relationship
between angiogenesis and K-ras mutations in CP and PAC. Tumor angiogenesis and K
ras mutations were evaluated in resected specimens from 25 CP (23 CP plus two CP
with PAC) and 16 PAC patients. Tumor angiogenesis was determined using
immunohistochemistry of factor VIII-related antigen (FVIIIRAg) and ras mutations
were identified by enriched-nested polymerase chain reaction. The mean number of
FVIIIRAg-positive blood vessels was significantly (p < 0.005) higher in PAC (23.0
+/- 7.5), CP with a mutant K-ras genome (17.7 +/- 2.8) and CP with a normal K-ras
genome (6.5 +/- 3.8), compared to unaffected areas. Codon 12 K-ras mutations were
detected in three of 25 CP specimens (12%) and in 15 of 16 PAC specimens (94%).
In CP patients with mutant K-ras in their genome, microvessel density was
significantly (p < 0.01) elevated, compared to patients with a normal K-ras
genome. Statistical analyses (Spearman rank-difference correlation coefficient,
Student t test, and chi2 analysis) indicated a significant association between
codon 12 K-ras mutations and tumor angiogenesis in both CP and PAC. This study
demonstrates a significant association between angiogenesis and K-ras mutation in
both PAC and CP. At a minimum, K-ras mutation is associated with the events that
increase angiogenesis and it may potentiate or promote tumor angiogenesis.
PMID- 10766451
TI - Role of protein kinase C isoenzymes in fatty acid stimulation of insulin
secretion.
AB - Although hyperlipidemia is frequently associated with hyperinsulinemia. the
stimulation of insulin secretion by fatty acids in the in vitro studies has
remained a matter of constant debate, partly because of the uncertainty about a
clearly defined mechanism to explain such a direct effect. In this study, we used
a pharmacologic approach to test the hypothesis that protein kinase C (PKC)
signal-transduction pathway is involved in fatty acid-stimulated insulin
secretion. Isolated rat islets were perifused with either palmitate (C(16:0)) or
linoleate (C(18:2)) in the absence or presence of selective inhibitors of PKC
isoenzymes. Our results suggest a role for Ca2+-independent PKC isoenzymes in the
signal transduction of fatty acid-stimulated insulin secretion. The data imply
that either the nonconventional and/or atypical isoforms of PKC are involved in
the stimulation of insulin release induced by fatty acids.
PMID- 10766452
TI - Islet amyloid polypeptide regulates multiple steps in stimulus-secretion coupling
of beta cells in rat pancreatic islets.
AB - Islet amyloid polypeptide (IAPP) is produced in pancreatic beta cells. Intraislet
function of IAPP is still uncertain. In the present study, we investigated
effects of IAPP and somatostatin on stimulus-secretion coupling of beta cells in
isolated rat pancreatic islets. Insulin secretion induced by 22.2 mM glucose was
increased by an IAPP antiserum (0.1%) or an IAPP antagonist (IAPP8-37, 10
microM). Pretreatment of islets with pertussis toxin (PTX) abolished the
stimulating effect of IAPP8-37 on glucose-induced insulin secretion. In contrast,
IAPP antiserum and IAPP8-37 did not change insulin secretion induced by 30 mM
KCl. Somatostatin (1 nM) inhibited insulin secretion induced by 22.2 mM glucose,
10 mM L-arginine, 25 microM forskolin, and 200 microM carbachol. IAPP (10 microM)
enhanced the inhibitory effect of somatostatin on insulin secretion induced by L
arginine or forskolin. PTX pretreatment abolished the effects of somatostatin and
IAPP on arginine-induced insulin secretion. In conclusion, IAPP regulates
multiple steps in signal transductions of beta cells. The effects of IAPP on beta
cells are mediated by PTX-sensitive regulatory G proteins.
PMID- 10766453
TI - Cell loss in isolated human islets occurs by apoptosis.
AB - Purified islet allografts have largely failed to maintain long-term glucose
homeostasis in human recipients, and the reasons for this are unclear. It is
noteworthy, however, that islet isolation destroys or removes cellular and
noncellular elements of the pancreas that could play an important role in
supporting islet survival. The purpose of this study was to determine whether
human islet isolation leads to the induction of programmed cell death. Human
islets were enzymatically isolated from cadaveric donor pancreata using Liberase
or Collagenase P, purified over a discontinuous BSA gradient, then cultured in
RPMI 1640 at 37 degrees C in 5% CO2 for < or = 7 days. Islets were examined daily
by routine histology and immunocytochemistry for islet hormones, DNA
fragmentation [cell death; enzyme-linked immunosorbent assay (ELISA) and TUNEL
assay] and for transglutaminase (TG) activity, two indicators of apoptosis. TG
activity and DNA fragmentation increased by 1,000% and 1,890%, respectively (p <
0.05) This corresponded to the appearance of pyknotic nuclei on light microscopy,
the presence of apoptotic bodies on electron microscopy, and the demonstration of
TUNEL-positive cells. These were present primarily in a distribution that
corresponded to the insulin-immunoreactive cells. At 5 days, 31.4 +/- 2.2% of
islet cells were TUNEL positive. In summary, apoptosis of islet cells appears
soon after islet isolation, and involves primarily the beta cell. This is the
first report of apoptosis of islet cells after human islet isolation. The loss of
beta-cell mass could be implicated in the failure of islet transplantation and
merits further investigation.
PMID- 10766454
TI - Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate
secretion.
AB - Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic
bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To
determine whether this effect was due to systemic hyperinsulinemia or to reduced
endogenous insulin production, we examined the effect of hyperglycemia on
secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were
created in six dogs. After 30 minutes of equilibration, a computer-assisted
hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150
mg/dL above basal in clamp animals; control animals received volume- and rate
matched infusions of 0.9% saline. One hour after beginning the clamp period,
intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose
every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not
differ between groups. INS and GLU levels in clamp animals were significantly
elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods.
For the same periods, HCO3 secretion was not significantly changed despite
profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does
not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback
regulation on the pancreas, we propose that suppression of endogenous INS
secretion mediates the previously reported inhibitory response.
PMID- 10766455
TI - Peptidergic regulation of maturation of the stimulus-secretion coupling in fetal
islet beta cells.
AB - The stimulus-secretion coupling of the insulin-producing pancreatic islet beta
cell is subject to functional maturation during fetal life. We studied the
maturation of a glucose-responsive insulin release from fetal rat islets and
specifically investigated the impact of peptidergic regulation. To this end,
islets were isolated from 21-day-old fetal rats and maintained for 7 days in
tissue culture at 3.3 or 11.1 mM glucose and various supplements. In islets
cultured in low glucose, acutely raising the ambient glucose concentration to
16.7 mM evoked a modest stimulation of short-term insulin release that was more
pronounced in islets maintained in high glucose. Moreover, the insulin content
was much higher in islets cultured in high than in low glucose. Culture with
growth hormone (GH) markedly amplified both basal and stimulated short-term
insulin secretion from islets maintained in either low or high glucose.
Additionally, GH significantly elevated the insulin content in islets maintained
in low glucose. Transforming growth factor alpha (TGF-alpha) increased basal, but
not glucose-stimulated, insulin release and insulin content in islets cultured in
low glucose. Gastrin, expressed in islets during fetal life, did not affect basal
or glucose-stimulated insulin release, or insulin content, in islets maintained
in either low or high glucose. The addition of gastrin to TGF-alpha did not
affect the results obtained with the latter peptide. Gastrin-releasing peptide
failed to influence basal or glucose-responsive insulin secretory rates, and
insulin content, at either glucose concentration during culture. The somatostatin
analog Sandostatin (octreotide acetate) neither influenced basal nor stimulated
short-term insulin release at any glucose concentration present during culture,
whereas the hormone significantly decreased the insulin content of islets
cultured in high glucose. Pancreastatin, produced by porcine islet beta and delta
cells, failed to influence basal or glucose-responsive insulin secretory rates,
and islet insulin content, at either glucose concentration during culture.
Culture with gastric inhibitory peptide (GIP) or glucagon-like peptide I (GLP-1),
two proposed incretins, did not affect short-term insulin secretion in response
to 3.3 or 16.7 mM glucose irrespective of the ambient glucose concentration
during culture. To the contrary, GLP-1, but not GIP, increased the content of
insulin in islets cultured in low glucose. We conclude that islet beta-cell
differentiation and functional maturation of the stimulus-secretion coupling can
be modulated in vitro in fetal rat pancreatic tissue by peptidergic regulation
and glycemic stimulation. We suggest that GH and TGF-alpha stimulate, while
somatostatin, through paracrine interaction, may inhibit, these processes. These
effectors may be of regulatory significance in the in vivo development of glucose
sensitive beta cells, and defects in these mechanisms may result in glucose
intolerance in adult subjects.
PMID- 10766456
TI - In situ characterization of dendritic cells occurring in the islets of nonobese
diabetic mice during the development of insulitis.
AB - Type 1 diabetes mellitus in nonobese diabetic (NOD) mice, a well-known model of
human type 1 diabetes, has been considered to be caused by the destruction of
insulin-producing beta cells in the islets of the pancreas by self-reactive T
cells. Antigen-presenting cells like dendritic cells (DCs) and macrophages are
expected to be involved in the processes from their role in generating regulatory
or effector T cells. These immunohistochemical studies revealed that CD11c
positive DCs already appeared in the islets of NOD mice as early as 4 weeks old
when lymphocytes were not yet infiltrated in the islet, and thus insulitis was
not developed. DCs were first observed to locate around swollen parainsular
vessels. From age 7 weeks onward to age 13 weeks, more DCs were present in
parainsular areas where lymphocytes had also accumulated, and the number of DCs
in the islets as well as lymphocytes increased. However, at the end stage of
insulitis from age approximately 17 weeks onward, the number of DCs in the islets
decreased. In contrast, accumulation of DCs in the para- and periislets was not
observed in 7- and 17-week-old ICR female mice that do not develop type 1
diabetes. Double-staining studies using confocal laser scanning microscopy showed
that the CD11c-positive DCs coexpress both major histocompatibility (MHC) class
II and costimulatory molecules, CD80 and CD86. Electron-microscopy studies
further demonstrated that cell bodies and processes of the DCs make close contact
with lymphocytes. These results suggest that DCs infiltrated into the pancreatic
islets are capable of stimulating T cells by the MHC class II-antigenic peptide
complex, together with costimulatory molecules, which eventually lead to the beta
cell destruction in NOD mice.
PMID- 10766457
TI - Nitric oxide decreases endothelial activation by rat experimental severe
pancreatitis-associated ascitic fluids.
AB - To clarify the roles of nitric oxide (NO) in acute pancreatitis (AP), we examined
the effects of NO on the endothelial activation induced by ascitic fluids from
rats with experimental severe AP. Necrotizing hemorrhagic pancreatitis was
induced in male Wistar rats with sodium taurocholate. Six hours later, peritoneal
exudates were collected, centrifuged, and human umbilical vein endothelial cells
were treated with the supernatants. Then (a) the mRNA level of endothelial-type
NO synthase (ecNOS) was examined by reverse transcription-polymerase chain
reaction; (b) effects of an NO donor, sodium nitroprusside (SNP) and an inhibitor
of NOS, N(omega)-nitro-L-arginine (L-NNA) on the ascitic fluids-induced
expression of intercellular adhesion molecule-1, vascular cell adhesion molecule
1, and interleukin-8 were assessed by enzyme-linked immunoassay; (c) nuclear
translocation of nuclear factor-kappa B (NF-kappaB) was examined by
electrophoretic mobility shift assay; and (d) effects of SNP and L-NNA on the
adhesion of U937 cells to endothelial monolayer were assessed. The ecNOS mRNA
level was decreased by the ascitic fluids; ascitic fluids-induced expression of
adhesion molecules and interleukin-8 as well as the nuclear translocation of NF
kappaB were attenuated by SNP, whereas L-NNA augmented them; and the effects on
the endothelial activation were paralleled by the altered adhesion of U937 cells
to endothelium. The ability of NO to limit endothelial activation and inhibit
leukocyte adhesion might contribute to its antiinflammatory properties in AP.
PMID- 10766458
TI - Dietary soya beans and kidney beans stimulate secretion of cholecystokinin and
pancreatic digestive enzymes in 400-day-old Hooded-Lister rats but only soya
beans induce growth of the pancreas.
AB - The effects of age on cholecystokinin (CCK) release, pancreatic enzyme secretion,
and growth of the pancreas mediated by dietary kidney beans or soya beans were
evaluated in trials with 30-, 90-, 250-, and 400-day-old rats. Soya beans
increased blood CCK and caused hypersecretion of digestive enzymes and rapid
pancreatic growth in all rats. Kidney beans also elevated circulating CCK and
stimulated enzyme secretion. However, with 90-, 250-, and 400-day-old rats, the
secretory responses were attenuated. Furthermore, kidney beans did not induce
pancreatic growth in 250- and 400-day-old rats.
PMID- 10766459
TI - Magnetic resonance cholangiopancreatography in cystic lesions of the pancreas.
AB - There are few reports about magnetic resonance cholangiopancreatography (MRCP) in
cystic lesions of the pancreas (KLP). For this reason, we have undertaken a
prospective study evaluating the diagnostic efficiency of MRCP as compared with
ultrasonography. Twenty-four patients with KLP were examined with magnetic
resonance imaging (MRI), and standard and cholangiopancreatography. There were
seven cases of cysts associated with acute pancreatitis, 11 patients with KLP and
chronic calcifying pancreatitis, five cases of cystic neoplasms of the pancreas,
and one polycystic disease of the gland. All cases were first submitted to
ultrasonography, which failed to diagnose only a case of cyst associated with
chronic pancreatitis depicted by MRCP. We used a GE Signa Horizon 1.5-T system
(20 examinations) and a Siemens Magneton Plus 1.5-T machine (four examinations).
Eleven patients were operated on. In all cases, it was possible to identify the
cysts, the main pancreatic duct and the biliary tree, and verify the relationship
of the cyst with neighboring organs. Communication of the cyst with the main
pancreatic duct was described in five instances, but we cannot be sure that MRCP
would have depicted all cyst-duct communications. The MRI and MRCP images were
confirmed by surgery in the 11 operated-on cases. The diagnosis of duct
alterations and small pancreatic stones in initial cases of chronic calcifying
pancreatitis may be problematic. Clinical findings are very important data to be
considered in the differential diagnosis of KLP. Together with the clinical data,
MRCP is a very important technique in the diagnostic and therapeutic decision
making of KLP. Standard magnetic resonance is advisable as part of the
examination in all cases. MRCP is not invasive, is reliable if one knows its
limitations, and the patient can return at once to his activities. It allows the
analysis of many variables in one examination, contributing to better therapy.
PMID- 10766460
TI - No strict correlation between necrosis and organ failure in acute pancreatitis.
AB - The aim of this study was to determine the relationship between pancreatic
necrosis and organ failure in acute pancreatitis. Two hundred seventeen patients
with acute pancreatitis were prospectively included. All of them had been
examined by computed tomography (CT) within 72 hours of admission. Initial organ
failure was defined according to the Atlanta classification (arterial pO2 <60 mm
Hg, serum creatinine >2 mg/dL after rehydration). Organ failure during the total
hospital stay was defined as necessity for artificial ventilation and/or dialysis
treatment, independent of initial organ failure. One hundred seventy-five (81%)
patients had interstitial and 52 (19%) necrotizing pancreatitis. Forty-two (19%)
had initial organ failure and 54 (25%) organ failure during the total hospital
stay. There was a significant correlation between the incidence of initial
pancreatic necrosis and initial organ failure as well as initial pancreatic
necrosis and organ failure during hospital stay (p < 0.001). However, 24 (57%) of
the 42 patients with pancreatic necrosis had no initial organ failure, and 19
(45%) no organ failure during hospital stay, and vice versa, 24 (14%) patients
had initial and 31 (18%) organ failure during the total hospital stay in the
absence of pancreatic necrosis. Initial organ failure and organ failure during
the total hospital stay were independent of the extent of pancreatic necrosis.
The incidence of initial organ failure and organ failure during the total
hospital stay increased significantly with the CT score (p < 0.001). However, 24
(15%) and 31 (18%) of the patients with interstitial pancreatitis had initial
organ failure and organ failure during the total hospital stay, respectively.
Patients with pancreatic necrosis are not necessarily at risk of having initial
organ failure or organ failure during the total hospital stay and vice versa.
Thus, these groups should be considered separately in therapy studies.
PMID- 10766461
TI - Relationship of CogScreen-AE to flight simulator performance and pilot age.
AB - OBJECTIVES: We report on the relationship between CogScreen-Aeromedical Edition
(AE) factor scores and flight simulator performance in aircraft pilots aged 50
69. METHODS: Some 100 licensed, civilian aviators (average age 58+/-5.3 yr)
performed aviation tasks in a Frasca model 141 flight simulator and the CogScreen
AE battery. The aviation performance indices were: a) staying on course; b)
dialing in communication frequencies; c) avoiding conflicting traffic; d)
monitoring cockpit instruments; e) executing the approach; and f) a summary
score, which was the mean of these scores. The CogScreen predictors were based on
a factor structure reported by Kay (11), which comprised 28 CogScreen scores.
Through principal components analysis of Kay's nine factors, we reduced the
number of predictors to five composite CogScreen scores: Speed/Working Memory
(WM), Visual Associative Memory, Motor Coordination, Tracking, and Attribute
Identification. RESULTS: Speed/WM scores had the highest correlation with the
flight summary score, Spearman r(rho) = 0.57. A stepwise-forward multiple
regression analysis indicated that four CogScreen variables could explain 45% of
the variance in flight summary scores. Significant predictors, in order of entry,
were: Speed/WM, Visual Associative Memory, Motor Coordination, and Tracking
(p<0.05). Pilot age was found to significantly improve prediction beyond that
which could be predicted by the four cognitive variables. In addition, there was
some evidence for specific ability relationships between certain flight component
scores and CogScreen scores, such as approach performance and tracking errors.
CONCLUSIONS: These data support the validity of CogScreen-AE as a cognitive
battery that taps skills relevant to piloting.
PMID- 10766462
TI - Perception of surrounding space controls posture, gaze, and sensation during
Coriolis stimulation.
AB - BACKGROUND: Motion sickness evokes not only discomfort but also marked
equilibrium ataxia. However, its mechanism of ataxia remains unclear. HYPOTHESIS:
We supposed that stance, gaze, and sensation may be uniformly controlled by the
perception of the surrounding space. METHODS: Using Coriolis stimulation, we
examined eight normal subjects and two patients with bilateral labyrinthine loss.
They were asked to stand on a platform; then while being rotated clockwise 60
degrees x s(-1), they tilted their head 30 degrees. Displacement of the center of
pressure and ocular movements were recorded using a force platform set on the
device and an infrared CCD-video camera fixed to goggles, respectively. RESULTS:
In normal subjects with eyes covered, tilting of the head resulted in shifts of
the center of pressure and torsional or vertical nystagmus. When they could see
the surroundings, they showed stable posture and optokinetic nystagmus regardless
of head tilting status. In contrast, the two patients were not affected by head
tilting when their eyes were covered, although they showed remarkable body
swaying even while they were static. CONCLUSIONS: From the present study, it
seems probable that posture, gaze, and sensation are absolutely controlled by the
perception of surrounding space, which may be theoretically represented as a
vector in the head.
PMID- 10766463
TI - The incidence, nature, and severity of injuries in New Zealand civil aviation.
AB - BACKGROUND: Strategies to improve aviation safety can be directed at the pre
crash, in-crash, or post-crash phases of aircraft crashes. For resources to be
made available for in-crash interventions, and for these to be well designed, it
is necessary in the first instance to have a detailed understanding of the
injuries sustained in crashes. The purpose of this study was to describe the
incidence, nature, and severity of injuries sustained in aircraft crashes and
other related events in civil aviation in New Zealand. METHODS: National injury
databases were searched for fatalities and hospitalizations sustained in aircraft
crashes and related events, and cases were linked with Civil Aviation Authority
accident records to identify the aircraft involved. Rates were based on estimates
of total hours flown by active pilots. RESULTS: There were 104 fatalities
identified for the period 1988-1992, giving a rate of 2.57 per 100,000 flight
hours. There were 120 hospitalizations identified for the period 1988-1993,
giving a rate of 2.45 per 100,000 flight hours. Most fatalities involved injury
to multiple body regions, with at least one injury being sufficient in itself to
cause death in 48% of cases. For hospitalizations, the lower extremities (23%),
spine (20%), and head and face (18%) were the body regions most commonly injured,
with fractures being predominant. While the majority of fatalities and
hospitalizations occurred in fixed- and rotary-wing aircraft, the highest rates
were for microlight and home-built aircraft. CONCLUSIONS: Different patterns of
injury were evident for fixed- and rotary-wing aircraft. Reasons for these are
suggested. Future research will seek to determine the relative risk associated
with potentially modifiable risk factors.
PMID- 10766464
TI - Increased formaldehyde in jet engine exhaust with changes to JP-8, lower
temperature, and lower humidity irritates eyes and respiratory tract.
AB - BACKGROUND: Formaldehyde (FA) in exhaust from F-4 aircraft with low smoke
combustor(LSC) J79 engines has been reported to be of sufficient concentration to
cause irritation. It has also been noted that eye and respiratory irritation
became more frequent and severe after the fuel was changed from JP-4 to JP-8. The
present sturdy investigated the effect of jet fuel and power setting on
formaldehyde concentrations in the exhaust. We also investigated the exposure to
formaldehyde among pilots and flight line personnel. METHODS: The exhaust from
LSC J79 engines using different types of fuel (JP-8 and JP-4) was sampled 50 m
behind the engine at different power settings in July (summer season in Japan)
and February (winter season ). It was also sampled at 75% power settings using JP
8 in July. RESULTS: At an idle power setting, the FA concentration was higher in
the exhaust of engines using JP-8 (1.31 ppm in July and 2.78 ppm in February)
than in engines using JP-4 (0.95 ppm in July and 1.84 ppm in February). The FA
concentration increased as both ambient temperature and relative humility
decreased in the sampling atmosphere. The FA concentration of JP-8 fuel at an
idle power setting (65%) was higher than that at a 71.5% power setting (1.32 ppm
and 0.86 ppm, respectively). CONCLUSIONS: The FA concentrations in LSCJ79 engine
exhaust varies depending on the type of fuel, engine power settings, and ambient
air conditions. A high FA concentration at ground level due to a change in the
fuel type, low temperature, and humidity, causes frequent severe eye respiratory
irritation.
PMID- 10766465
TI - Effects of quick rotating shift schedules on the health and adjustment of air
traffic controllers.
AB - INTRODUCTION: Many Air Traffic Control Specialists (ATCSs) in the United States
work shift schedules that involve counterclockwise rapid rotations. Researchers
have reported negative health effects associated with shiftwork, suggesting that
workers on rotating shift schedules suffer the greatest consequences. The purpose
of this study was to assess the extent of health, sleep, and shiftwork adaptation
problems experienced by ATCSs. HYPOTHESIS: It was hypothesized that shiftwork
related problems would be identified. METHODS: A total of 210 ATCSs completed a
modified version of the National Institute for Occupational Safety and Health
(NIOSH) General Health and Adjustment Questionnaire (25). The questionnaire
included a broad range of health, sleep, job, and lifestyle questions. Health and
sleep pattern index scores were computed for this paper. Comparisons were
conducted based on the following shift characteristics: length of shift (8- vs. 9
h), number of early morning shifts, number of midnight shifts, and schedule
preference. RESULTS: Over half of the sample in this study reported periods of
severe fatigue or exhaustion and symptoms of gastrointestinal disturbance
typically found among shift workers. Better health and sleep pattern index scores
were reported by those who preferred rotating schedules and by those who did not
work night shifts. DISCUSSION: The ATCSs in this sample were relatively young and
are required to pass a yearly physical to maintain employment. Thus, this may
have resulted in low frequencies of reported medical problems. However, reports
of sleepiness, fatigue, and falling asleep seem to indicate that countermeasures
for sleepiness at work and on the drive home could benefit ATCSs.
PMID- 10766466
TI - Inflight cabin ozone aboard long duration C-5 airlift missions: a historical
issue revisited.
AB - BACKGROUND: Past research has shown that U.S. Air Force C-5 aircrews have been
occasionally exposed to ambient, stratospheric ozone concentrations in excess of
Federal Aviation Administration (FAA) ceiling and time-weighted average (TWA)
standards. Although strategies such as steering around meteorological areas of
high ozone concentrations or outfitting the C-5 with ventilation system
modifications were recommended by past investigators, review has shown that such
changes were not adopted. Informal interviews with current C-5 aircrews indicate
mucosal dryness and irritation are routinely encountered during long duration
flights. Such symptoms could be due to low humidity or perhaps, ozone-induced
irritation. With the advent of miniaturized, highly accurate, electronic air
quality monitoring equipment, a repeat study of cabin ozone was believed to be
warranted to better clarify exposure risk and to look for other possible
explanations for the encountered symptoms. METHODS: A portable, electronic air
quality monitor was used to monitor breathing zone cabin air during 47 h of
flight. Ozone, carbon dioxide, carbon monoxide, temperature, and relative
humidity were recorded for the duration. Ozone levels were corrected for altitude
using a calibration curve derived by earlier, unpublished hypobaric chamber work.
RESULTS: Ozone levels were not found to exceed the FAA ceiling limit. Two flights
had 3-h time-weighted average values that minimally exceeded FAA standards.
Carbon dioxide and carbon monoxide levels were well below health effect
threshold. Relative humidity reached a nadir of 3% and could well have explained
symptoms of mucosal irritation. CONCLUSIONS: Current evidence suggests that C-5
aircrews are exposed to relatively low concentrations of ozone. Review of the
literature regarding observed short-term and long-term toxicity to low dose ozone
exposure would indicate that no further operational or aircraft design action is
required.
PMID- 10766468
TI - Gastric myoelectric activity during low frequency oscillation.
AB - BACKGROUND: The normal 3 cycles per minute (3 c/m) resting activity of the
stomach has been reported to shift into the range of 4-9 c/m (tachyarrhythmia) in
subjects with symptoms of motion sickness. Previous studies have provoked motion
sickness with an optokinetic stimulus and have not normally reported changes
relative to a control condition. The present experiment investigated changes in
the electrogastrogram (EGG) during a control condition and during exposure to
0.125 Hz off-axis yaw oscillation of the body. METHODS: There were 16 male
subjects who participated in the two conditions 1 wk apart. The
electrogastrogram, respiration rate and subjective ratings of sickness were
monitored throughout both conditions. Spectral analysis of the EGG time histories
provided measures of 3 c/m power and tachyarrhythmia power, which were also
expressed as a percentages of EGG power over the total EGG frequency range (0.04
to 0.16 Hz.). The median frequency of the EGG over this bandwidth was also
calculated. RESULTS: During motion exposure, the median frequency of the EGG and
the percentage tachyarrhythmia power increased and the percentage 3 c/m power
decreased relative to a pre-exposure baseline period and relative to the static
control condition. CONCLUSIONS: Low frequency off-axis yaw oscillations disrupted
the normal resting gastric myoelectric activity relative to a control condition.
PMID- 10766467
TI - Reducing the dose of combined caffeine and ephedrine preserves the ergogenic
effect.
AB - BACKGROUND: Ingestion of a combination of 5 mg x kg(-1) caffeine (C), and 1 mg x
kg(-1) ephedrine (E) was reported to have an ergogenic effect on high intensity
aerobic exercise performance, but 25% of the subjects experienced vomiting and
nausea while engaging in hard exercise after the treatment. The present study was
undertaken to investigate whether reduced levels of C+E would alleviate the
problem and maintain the ergogenic effect. METHODS: Twelve healthy untrained male
subjects completed four randomized and double-blind, cycle ergometer trials to
exhaustion at a power output equivalent to approximately 85% Vo2peak 1.5-2 hours
after ingesting a placebo (P) or a mixture of C+E in the following doses: 5 mg x
kg(-1) of C plus 0.8 mg x kg(-1) of E (CLE); 4 mg x kg(-1) of C plus 1 mg x kg(
1) of E (LCE); or 4 mg x kg of C plus 0.8 mg x kg(-1) of E (LCLE). Trials were
separated by 1 wk. Venous blood samples were obtained and analyzed for caffeine
and ephedrine levels 1.5 h post-drug ingestion. Vo2, Vco2, VE, and RQ were
measured every minute throughout the exhaustion ride. Heart rate and perceived
exertion (RPE) were also recorded every 5 min and at the end of the exercise
session. RESULTS: Plasma levels of C and E immediately before the exhaustion ride
were (mean +/- SD): 38.7+/-5.2 micromol x L(-1) C, 1.285+/-0.275 micromol x L(-1)
E in the CLE trial; 33.2+/-5.8 micromol x L(-1) C, 1.462+/-0.283 micromol x L(-1)
E in the LCE trial; 33.0+/-2.9 micromol x L(-1) C, 1.229+/-0.202 micromol x L(-1)
E in the LCLE trial. The times to exhaustion for the treatment trials (CLE =
27.5+/-12.4 min, LCE = 27.6+/-10.9 min, LCLE = 28.2+/-9.3 min) were similar and
were significantly greater than placebo (p = 17.0+/-3.0 min). The drugs did not
affect Vo2, Vco2, or VE. Heart rates were significantly higher for the drug
trials while RPE was lower compared with P. No incidents of nausea or vomiting
occurred with the lowest dose of the C+E, LCLE. CONCLUSIONS: A lower dose of C+E
resulted in an ergogenic effect similar in magnitude to that reported previously
with a higher dose, and with a reduced incidence of negative side effects.
PMID- 10766469
TI - Comparison of sitting height measurement using three anthropometric measuring
techniques.
AB - Accurate, reproducible, anthropometric measurements are essential in the aviation
community. Three methodologies were evaluated to determine how they compared with
respect to variability and accuracy. One of the methods, an anthropometric chair,
is currently used to screen naval aviation candidates. Another method, employing
anthropometers (calipers), has been widely used for anthropometric surveys. A
third method, referred to as the digital anthropometric video imaging device
(DAVID), is a computer-based technique that digitizes a video image for the
purpose of determining anthropometric measurements. For this comparison study,
sitting height was measured by 15 subjects using the 3 cited methods. An
evaluation of sitting height was used because of its importance to aviation and
because it requires attention to both posture and measurement technique.
Statistical analysis showed no statistical difference between the three
methodologies.
PMID- 10766470
TI - Fear of flying treatment programs for passengers: an international review.
AB - BACKGROUND: There are facilities established around the world for treating
passenger flight anxiety, often as a joint activity of airlines and private
entrepreneurs or mental health professionals. In the scientific and professional
literature, there is little information about how these facilities operate and
what the components of their treatment programs are. This paper is the first
review to date to provide this information. METHOD: There were 212 airlines and
treatment facilities approached for information on treatment programs for flying
phobia, 43 of which were active in this field. Extensive information could be
obtained from 15, which were the best known and well-developed. Information was
collected both with a questionnaire and by meeting representatives from 15
international fear of flying treatment facilities that participated in the First
International Conference on Fear of Flying (Feb. 1996). RESULTS: Fear of flying
among passengers is a phenomenon with epidemic proportions, effecting roughly 10
40% of the adult population. All treatment programs share two basic elements, an
information component and a test flight. The programs vary considerably in terms
of treatment components. However, there is little available information on
efficacy. CONCLUSIONS: To date there is a wide variety between facilities for the
treatment for fear of flying in terms of methods and protocols used. Experts
agree on the clear-cut need for standardization of a "best" minimum protocol for
fear of flying treatment programs for which the main components where identified.
PMID- 10766471
TI - Fear of flying--no longer a symptom without a disease.
AB - This commentary accompanies the article "Fear of flying treatment programs for
passengers: an international review," by Van Gerwen and Diekstra, a report on the
international aviation community's approach to fearful air travelers. Most of the
aeromedical literature has dealt with fear of flying in aircrew; little has been
written about such fears among passengers. The aviation community has dealt with
fearful passengers through variations in cognitive-behavioral methods, but
without any underlying medical model. As a result, these programs go mainly
unsupervised and unregulated, and do not address such matters as differential
diagnosis, informed consent for treatment, clear therapeutic goals, organized
follow-up, or outcome criteria and statistics. Treating agencies also tend to
apply the same treatment methods to all applicants, in spite of emerging data
that show that, in fact, different causes call for different treatments. This
commentary reviews these findings in the larger context of the medical model and
calls for further research along the lines developed by Van Gerwen and Diekstra
(11).
PMID- 10766472
TI - The future of commercial aviation medicine.
PMID- 10766473
TI - Airlines emergency medical kits.
PMID- 10766474
TI - Aerospace medicine in Germany: from the very beginnings.
AB - The roots of German Aerospace Medicine are in Berlin. High altitude research was
performed by physiologists like Nathan Zuntz and the very first Army flight
surgeons, Koschel and Flemming. With the founding of the Scientific Society for
Aeronautics in 1912, a medical committee was established to determine guidelines
for the physical examination of flyers. In World War I aviation medicine became a
military science, which came to an end with the Treaty of Versailles. In 1927,
with the establishment of the first Aeromedical Institute in Hamburg, Ludolph
Brauer restarted the civilian academic aeromedical research effort, which,
thereafter, fell more and more under military influence. At the end of World War
II, German scientists were invited to work at the USAAF Aero Medical Center (AMC)
in Heidelberg (1945-47), to gather the results of German aeromedical research
performed before and during the war. Some of this group of German scientists were
invited to work in the USA. In Germany, on the other hand, the effect of this
"brain drain" was a period of stagnation. In the 1950's, a new civilian institute
of aviation medicine was established in Bonn. It grew to be the nucleus of the
DLR Institute of Aviation Medicine in Cologne. The German Air Force Institute of
Aviation Medicine was founded in Fuerstenfeldruck in 1959, and in the GDR the
Institute of Aviation Medicine was established in 1961: the first East German
cosmonaut S. Jaehn 1978 (Soyuz-31), was succeeded by the first West German
astronaut, U. Merbold in 1983 (Spacelab).
PMID- 10766475
TI - Antisocial personality: a case study.
PMID- 10766476
TI - Flightline birth.
PMID- 10766478
TI - Handbook of aviation human factors
PMID- 10766477
TI - Treatment of cutis marmorata (cutis)
PMID- 10766479
TI - Quantitative analysis of acetates in cigarette tobacco using solid-phase
microextraction and gas chromatography-mass spectrometry.
AB - A method incorporating solid-phase microextraction (SPME) and gas chromatography
mass spectrometry for the headspace analysis of selected volatile organic
compounds present in cigarette tobacco is developed and evaluated. Quantitative
information on methyl, ethyl, n-propyl, isopropyl, isopropenyl, vinyl, and butyl
acetates present in 29 different flavor variants (full, light, and ultra-light)
of the top ten selling brands in the United States is presented. The
concentrations of the various acetate analytes range from the low nanaogram to
microgram levels per cigarette. Clear differences are observed in the
concentrations of various acetates when comparing the levels in brands from
different manufacturers. The SPME technique provides a method that allows high
sample throughput, requires little sample preparation, and yields useful
analytical information. High precision is obtained on multiple measurements of
cigarettes from an individual pack, but lower precision levels are observed in
general when comparing results obtained on the analysis of cigarettes from
different packs of the same brand. The higher pack-to-pack variations may be due
in part to product aging with a proportionate amount of evaporative loss of the
relatively volatile acetates.
PMID- 10766480
TI - Separation and tentative identification of the main pigment fraction of raisins
by thin-layer chromatography-Fourier transform infrared and high-performance
liquid chromatography-ultraviolet detection.
AB - The soluble color pigments of raisin are separated by reversed-phase thin-layer
chromatography (TLC), and the capacity of TLC-Fourier transform infrared (FTIR)
with both on-line and off-line coupling is assessed for the identification of the
main fraction. TLC has also been used as a pilot technique for the development of
a gradient elution method for the separation of pigments by high-performance
liquid chromatography (HPLC). On-line TLC-FTIR cannot be used for identification
because of the strong adsorbance of the stationary phase. Off-line TLC-FTIR
combined with the retention behavior of the main pigment fraction indicates that
it is a polymer, caramel-like compound composed of erythrose and fructose
monomers. Baseline separation of pigments is achieved by HPLC using TLC as a
pilot method.
PMID- 10766481
TI - Liquid chromatographic method for the analysis of buspirone HCl and its potential
impurities.
AB - An accurate, reproducible, and sensitive method for the determination of
buspirone HCl and its potential impurities is developed and validated. The
validated liquid chromaography method is conducted to meet the Food and Drug
Administration/ International Conference on Harmonization requirements for the
analysis of buspirone HCI in the presence of its impurities. Five buspirone HCI
potential impurities, including 1-(2-pyrimidinyl)-piperazine (I), propargyl
chloride (II), 3,3'-tetramethylene glutarimide (III), propargyl glutarimide (IV),
and the Mannich base-condensate of I-IV fumarate (V), are separated using a
microBondapack C18 column by gradient elution with a flow rate 2.0 mL/min. The
initial mobile phase composition is 90:10 (v/v) 10mM KH2PO4 (pH 6.1)
acetonitrile. After a 1-min initial hold, a linear gradient is performed in 26
min to 35:65 (v/v) 10mM KH2PO4 (pH 6.1)-acetonitrile. The samples are detected at
210 and 240 nm using a photo-diode array detector. The linear range of detection
for buspirone HCI was between 1.25 ng/microL and 500 ng/microL, with a limit of
quantification of 1.25 ng/microL. The linearity, range, peak purity, selectivity,
system performance parameters, precision, accuracy, and robustness for all of the
impurities were also shown to have acceptable values.
PMID- 10766482
TI - Temperature effects on packed-capillary liquid chromatography of the X-ray
contrast agent iodixanol.
AB - The effect of varying the operating temperature from 6 to 90 degrees C on the
chromatographic performance of the exo-exo and exo-endo isomers of the X-ray
contrast agent lodixanol in packed-capillary reversed-phase liquid chromatography
shows increasing interconversion rates between the two isomeric conformers with
increasing temperature. At 90 degrees C, Iodixanol elutes as one sharp peak due
to an increased interconversion rate between the two isomeric conformers.
Consequently, increased sensitivity is achieved. Temperature programming from 6
to 40 degrees C is utilized to optimize the resolution and determination of the
exo-exo and exo-endo isomers. Temperature programming provides a significant
decrease in the retention times in comparison with the isothermal separations
while still preserving baseline separation of the isomers.
PMID- 10766483
TI - Simple in-line postcolumn oxidation and derivatization for the simultaneous
analysis of ascorbic and dehydroascorbic acids in foods.
AB - A new analytical procedure for the simultaneous determination of L-ascorbic acid
(AA), isoascorbic acid (IAA), L-dehydroascorbic acid (DHAA), and
isodehydroascorbic acid (IDHAA) in food by high-performance liquid chromatography
(HPLC) is developed. After separation on an HPLC column, an in-line oxidation of
AA and IAA to DHAA and IDHAA, respectively, is performed on a short column of
activated charcoal. The dehydroascorbic acids are derivatized with a 1,2
phenylenediamine solution in a heated capillary Tefzel reactor into fluorescent
quinoxaline compounds and monitored fluorometrically. The chromatographic method
provides good separation of LAA, LDHAA, and their diastereoisomers in a
relatively short time (-10 min). After optimization of postcolumn derivatization
conditions, calibration runs and recovery tests are performed. The fluorescent
response in terms of peak area is highly proportional to the concentration of all
derivatives examined over a range of 0.1 to 100 microg/mL solution for LAA,
LDHAA, IAA, and IDHAA. Recoveries were in the range of 97 to 103%. The detection
limit is 0.1 mg of each ascorbic acid derivative per 100 g food. A wide variety
of foods (fruits, fruit juices, vegetables, vegetable products, milk, liver, and
sausage) are analyzed by the developed procedure. The Vitamin C (LAA and LDHA)
contents determined according to the present analytical method are in the same
order of magnitude as the result of precolumn derivatization and the fluorometric
methods. The described method is a highly specific procedure for determining
Vitamin C in food. It is simple to handle, only slightly susceptible to
disturbance, perfectly suitable for serial determinations, and yields
reproducible results.
PMID- 10766484
TI - High-performance liquid chromatography-electrospray ionization-mass spectrometry
study of ginkgolic acid in the leaves and fruits of the ginkgo tree (Ginkgo
biloba).
AB - A method is developed for qualitative analysis of ginkgolic acids in the leaves
and fruits of Ginkgo biloba by high-performance liquid chromatography (HPLC)
electrospray ionization-mass spectrometry technique. Negative ionization mode is
successful in obtaining a very abundant deprotonated molecule [M - H]-. The mass
detection sensitivity is higher than ultraviolet detection but relies heavily on
the concentration of acetic acid in the HPLC eluent, which consists of
acetonitrile-water-acetic acid. The method is also very specific for the analysis
of ginkgolic acid with no interferences from the sample matrix.
PMID- 10766485
TI - Analysis and quantitation of rotenoids and flavonoids in Derris (Lonchocarpus
urucu) by high-temperature high-resolution gas chromatography.
AB - A glass capillary column coated with PS-086 (15% phenyl-80% methylpolysiloxane,
15 m x 0.30-mm i.d., 0.1-microm film thickness) is used to analyze extracts from
Lonchocarpus urucu (Derris urucu). Several secondary metabolites (8 flavonoids,
10 rotenoids) are characterized without derivatization, and the rotenoids are
quantitated by high-temperature high-resolution gas chromatography (HTHRGC) and
HTHRGC coupled with mass spectrometry (HTHRGC-MS). The limit of detection in
flame ionization detection of rotenone is approximately 0.5 microg/mL, and the
limit of quantitation was 2 microg/mL. Derris urucu bark is an excellent source
of rotenone isomers (80 mg/g), deguelin (30 mg/g), and rotenolone (26 mg/g).
Single solvent extractions (hexane, methylene dichloride, acetone, or methanol)
are not able to fully extract the flavonoids and rotenoids. Complete extraction
is achieved using a mixture of methanol-methylene dichloride (1:1), indicating a
complex association of these compounds with the plant tissue. HTHRGC and HTHRGC
MS are shown to be quick and informative tools for the rapid analysis of crude
extracts without the need for prior derivatization and fractionation.
PMID- 10766486
TI - Gas chromatography problem solving and troubleshooting
PMID- 10766487
TI - The effects of the participation of patients with cancer in teaching
communication skills to medical undergraduates: a randomised study with follow-up
after 2 years.
AB - The importance of good doctor-patient communication is widely recognised. The
aims of this study were to evaluate the immediate effects of the participation of
patients with cancer on the attitudes and skills of undergraduate medical
students receiving an interview skills training programme, and to assess the
effects of the participation of patients with cancer on the attitudes and
interview performance of students 2 years later. It was hypothesised that the
participation of cancer patients would have specific beneficial effects on
attitudes and interview performance. Before participating in a 6-session
interview methods course in third year, students were randomised to be taught
with patients who had cancer (experimental group) or with patients with other
diagnoses (control group). Before and after participating in the course, 233
students (94% response rate) completed an Attitudes Questionnaire. When they
reached their fifth year, 54 students again completed the Attitudes Questionnaire
and, in addition, made a video recording of an interview with a patient who had
gynaecological cancer. These recordings were rated independently by two
researchers using the Interview Rating Instrument. Immediately after the course,
a number of differences were found between the two groups. For example, students
in the experimental group were more likely to consider the ability to listen an
extremely important characteristic of hospital doctors and to consider more
strongly that trust is an essential part of the doctor-patient relationship. 2
years after the course, the ability of hospital doctors to communicate with
patients, and the need for clinical decisions to reflect patients' wishes, were
considered to be more important by students in the experimental group, although
even 96% of controls felt both these issues were very or extremely important. As
hypothesised, the experimental group had better ratings in terms of responding
empathically, showing regard and concern for the patient, and assessing the
impact of the symptoms on the patient's life. The participation of patients with
cancer has beneficial and enduring effects on the attitudes and interview
performance of medical undergraduates. Medical schools should consider how best
patients with cancer can make an important contribution to communication skills
training.
PMID- 10766488
TI - Diagnosis and management of gastrointestinal bleeding.
PMID- 10766490
TI - Professional parallels for older dentists.
PMID- 10766489
TI - DDU warning in members' interest. Dental Defence Union.
PMID- 10766491
TI - Proceedings of the Anaesthetic Research Society Meeting. University of Edinburgh,
November 11-12, 1999.
PMID- 10766492
TI - Selected papers from the 19th Annual Conference on Peritoneal Dialysis.
Charlotte, North Carolina, USA. February 1999.
PMID- 10766493
TI - Recombination, replication, repair: from complexity to harmony. Proceedings or
the third 3Rs meeting. Villejuif, France, June 1999.
PMID- 10766494
TI - Shortage of antimicrobials wider, more severe than thought.
PMID- 10766495
TI - Erythromycin remains gold standard for treatment of pertussis in infants.
PMID- 10766496
TI - Revised guidelines for latent TB infection to be released.
PMID- 10766497
TI - Photo quiz: high fever and chest pain. Diagnosis: needle prick-induced
sporotrichosis.
PMID- 10766498
TI - Photo Quiz. Diagnosis: needle prick-induced sporotrichosis.
PMID- 10766499
TI - Mixed Poisson regression models with covariate dependent rates.
AB - This paper studies a class of Poisson mixture models that includes covariates in
rates. This model contains Poisson regression and independent Poisson mixtures as
special cases. Estimation methods based on the EM and quasi-Newton algorithms,
properties of these estimates, a model selection procedure, residual analysis,
and goodness-of-fit test are discussed. A Monte Carlo study investigates
implementation and model choice issues. This methodology is used to analyze
seizure frequency and Ames salmonella assay data.
PMID- 10766500
TI - Linkage between quantitative trait loci and marker loci: resolution power of
three statistical approaches in single marker analysis.
AB - This paper presents a comparison of three methods of parameter estimation in
analysis of linkage between a quantitative trait locus (QTL) and a marker locus:
maximum likelihood, mean square for trait cumulative distribution function, and
method of moments, employing simulated backcross data. The sensitivity of
estimates to violation of assumptions of normality and equal variances were also
studied. Some measures of discrepancy between the trait distributions in the QTL
groups are considered to evaluate the potential dependence of the resolution
capacity of the QTL substitution effect with respect to trait mean value and
variance.
PMID- 10766501
TI - Simultaneous confidence intervals for pairwise multiple comparisons in a two-way
unbalanced design.
AB - Turkey's (1953, The Problem of Multiple Comparisons, unpublished report,
Princeton University) procedure is widely used for pairwise multiple comparisons
in one-way ANOVA. It provides exact simultaneous pairwise confidence intervals
(SPCI) for balanced designs and conservative SPCI for unbalanced designs. In this
paper, we will extend Turkey's procedure to two-way unbalanced designs. Both the
exact and the conservative methods will be introduced. The application of the new
procedure is illustrated with sample data from two experiments.
PMID- 10766502
TI - Efficiency of regression estimates for clustered data.
AB - Statistical methods for clustered data, such as generalized estimating equations
(GEE) and generalized least squares (GLS), require selecting a correlation or
convariance structure to specify the dependence between observations within a
cluster. Valid regression estimates can be obtained that do not depend on correct
specification of the true correlation, but inappropriate specifications can
result in a loss of efficiency. We derive general expressions for the asymptotic
relative efficiency of GEE and GLS estimators under nested correlation
structures. Efficiency is shown to depend on the covariate distribution, the
cluster sizes, the response variable correlation, and the regression parameters.
The results demonstrate that efficiency is quite sensitive to the between- and
within-cluster variation of the covariates, and provide useful characterizations
of models for which upper and lower efficiency bounds are attained. Efficiency
losses for simple working correlation matrices, such as independence, can be
large even for small to moderate correlations and cluster sizes.
PMID- 10766504
TI - Goodness-of-fit in generalized nonlinear mixed-effects models.
AB - In recent years, generalized linear and nonlinear mixed-effects models have
proved to be powerful tools for the analysis of unbalanced longitudinal data. To
date, much of the work has focused on various methods for estimating and
comparing the parameters of mixed-effects models. Very little work has been done
in the area of model selection and goodness-of-fit, particularly with respect to
the assumed variance-covariance structure. In this paper, we present a goodness
of-fit statistic which can be used in a manner similar to the R2 criterion in
linear regression for assessing the adequacy of an assumed mean and variance
covariance structure. In addition, we introduce an approximate pseudo-likelihood
ratio test for testing the adequacy of the hypothesized convariance structure.
These methods are illustrated and compared to the usual normal theory likelihood
methods (Akaike's information criterion and the likelihood ratio test) using
three examples. Simulation results indicate the pseudo-likelihood ratio test
compares favorably with the standard normal theory likelihood ratio test, but
both procedures are sensitive to departures from normality.
PMID- 10766505
TI - Measurement of interrater agreement with adjustment for covariates.
AB - The kappa coefficient measures chance-corrected agreement between two observers
in the dichotomous classification of subjects. The marginal probability of
classification by each rater may depend on one or more confounding variables,
however. Failure to account for these confounders may lead to inflated estimates
of agreement. A multinomial model is used that assumes both raters have the same
marginal probability of classification, but this probability may depend on one or
more covariates. The model may be fit using software for conditional logistic
regression. Additionally, likelihood-based confidence intervals for the parameter
representing agreement may be computed. A simple example is discussed to
illustrate model-fitting and application of the technique.
PMID- 10766506
TI - Kinetic and thermodynamic analysis of the cyclodextrin-allyl isothiocyanate
inclusion complex in an aqueous solution.
AB - The decomposition of allyl isothiocyanate (AITC) in an aqueous solution was
depressed in the presence of cyclodextrin (CD), it's suppression effect
increasing in the order of none < beta-CD < alpha-CD. The results of kinetic and
thermodynamic analysis of the CD-AITC inclusion complexes showed that the
inclusion process was mostly governed by an enthalpy change (delta H degree)
rather than by an entrophy change (delta S degree), and that Van der Waals forces
played a primary role int he inclusion. Steric factors were important for the
reaction activity of AITC inclusion into the CD cavity, especially significant
being the stereospecificity between the size of the CD cavity and the AITC
molecule which is the main factor concerning it's activity. Our results suggest
that the association stability and activity of the included AITC molecule are
important factors in the suppression mechanism for CDs. Therefore, both these
factors would make an alpha-CD-AITC system more advantageous than a beta-CD-AITC
system, and the marked suppression effect of alpha-CD on the decomposition of
AITC can be attributed to the formation of inclusion complexes in an aqueous
solution.
PMID- 10766507
TI - Asymmetric reduction of ethyl 2-methyl e-oxobutanoate by fungi.
AB - Seven fungi, which are found to reduce ethyl 3-oxobutanoate in high yields, were
tested for their reducing ability for ethyl 2-methyl 3-oxobutanoate. We obtained
some interesting findings. In particular, Penicillium purpurogenum reduced ethyl
2-methyl 3-oxobutanoate to the corresponding alcohols with the diastereomer
(anti/syn) ratio of 93/7 with the enantiomeric excess of anti-(2S,3S)- and syn
(2S,3R)- hydroxy esters of 90 and >99 ee%, respectively.
PMID- 10766508
TI - Ovomucoid rendered insoluble by heating with wheat gluten but not with milk
casein.
AB - The effect of wheat gluten, soybean protein and milk casein on the heat-induced
in solubilization of egg white ovomucoid was investigated by using ELISA
inhibition and immunoblotting analysis. Heat treatment at 180 degree C for 10 min
of egg white mixed with wheat gluten specifically accelerated the heat-induced
change in ovomucoid. Such an effect was weakly brought about by soybean protein,
but not by casein.
PMID- 10766509
TI - Effects of glutathione-related compounds on increased caspase-3 and caspase-6
like activities in ricin-treated U937 cells.
AB - Both caspase-3 and -6-like activities increased in the cytosolic extract from
ricin-treated U937 cells that were inhibited by glutathione disulfide (GSSG) in a
dose-dependent manner, but reduced glutathione (GSH) had no effect.
Interestingly, caspase-6 like activity was more sensitive to GSSG than caspase-3
like activity. The IC50 of GSSG against caspase-3 and caspase-6 like activities
were estimated to be 2.8 mM and 0.8 mM, respectively. Cystine but not cysteine
also showed similar inhibitory effect on caspase-3-like activity. The inhibitory
effect of GSSG on these caspase-like activities was prevented by the addition of
DTT to the assay mixture. These results suggest that an intact disulfide portion
of GSSG is required for the effective inhibition of caspase activity.
PMID- 10766510
TI - Efficiency of D-tryptophan as Niacin in rats.
AB - L-tryptophan is a very important precursor of niacin in mammals. Food preparation
in which proteins are exposed to an alkali and/or high temperature for a long
period generate appreciable amounts of D-amino acids from racemization. The
efficiency of D-tryptophan as niacin was thus investigated by using weanling
rats. The availability of D-tryptophan was almost the same as that in L
tryptophan as the precursor of niacin and was 1/6 as active as niacin.
PMID- 10766511
TI - Thymocyte apoptosis by T-2 toxin in vivo in mice is independent of Fas/Fas ligand
system.
AB - To find whether Fas/Fas ligand (FasL) pathway is involved in T-2 toxin (T-2)
mediated thymocyte apoptosis, we used lpr/lpr (lpr) and gld/gld (gld) mice, whose
Fas and FasL proteins, respectively, are functionally deficient. Based on the DNA
fragmentation profile in gel electrophoresis and measurement of apoptotic cell
percent by flow cytometry, the levels of thymocyte apoptosis in lpr and gld mice
that had received T-2 showed that both lpr and gld mice had undergone apoptosis
essentially to the same magnitude as those of corresponding wild type mice (+/+).
These results strongly suggest that T-2-induced thymocyte apoptosis in vivo in
mice is independent of the Fas/FasL pathway.
PMID- 10766512
TI - Optimal daily intakes of micronutrients.
PMID- 10766513
TI - Honour your oath.
PMID- 10766514
TI - 3rd International Symposium on PRRS and Aujeszky's Disease. Ploufragan, France,
June 21-24, 1999. Proceedings and abstracts.
PMID- 10766515
TI - Patenting genes: is it necessary and is it evil?
PMID- 10766516
TI - Folding and binding: problems with proteins.
PMID- 10766517
TI - Protein-nucleic acid interactions.
PMID- 10766518
TI - Good learning doesn't just happen...
PMID- 10766519
TI - The supply of health care for nomads.
PMID- 10766520
TI - Internet research in the new millennium: a powerful tool.
PMID- 10766521
TI - Ph-positive acute lymphocytic leukemia in a man with Klinefelter syndrome.
PMID- 10766522
TI - Nonclonal abnormalities in leukemia.
PMID- 10766523
TI - Lack of deletions of the PTEN/MMAC1 and MXI1 loci in renal cell carcinoma by
interphase cytogenetics.
PMID- 10766524
TI - Becoming proactive about birth defects. National Folic Acid Information Campaign
begins.
PMID- 10766525
TI - [Double approval in Bavaria--the conflict has ended!].
PMID- 10766526
TI - Renovascular hypertension: the diagnosis and management of renal ischaemia.
PMID- 10766527
TI - Serum insulin-like growth factor is not a useful marker of prostate cancer.
PMID- 10766528
TI - A century of prostatic surgery.
PMID- 10766529
TI - Religious circumcision: a Jewish view.
PMID- 10766530
TI - Retention of urine: an unusual complication of the Plastibell device.
PMID- 10766531
TI - Steinstrasse: a comparison of incidence with and without J stenting and the
effect of J stenting on subsequent management.
PMID- 10766532
TI - Flexible ureterorenoscopy for the treatment of refractory upper urinary tract
stones.
PMID- 10766533
TI - [Spontaneous fracture in chronic cholestasis. Hepatic osteopathy caused by
vitamin D deficiency].
PMID- 10766534
TI - [Maintaining independence despite osteoporosis. Challenges for the general
practice team].
PMID- 10766535
TI - [Informed consent in children: exemplified by vaccinations. When parents make
"irresponsible" decisions].
AB - Medical information for juveniles (less than 18 years of age) in Germany is a
special situation, e.g. because the parents must give their consent to medical
treatment instead of the child/adolescent. This is illustrated by the example of
vaccinations. Doctors are also given advice on ho how to react if recalcitrant
parents refuse their consent.
PMID- 10766536
TI - [Botulinum toxin A for treatment of localized hyperhidrosis].
PMID- 10766537
TI - [Only 80 cents for a blood test!].
PMID- 10766538
TI - [Glucocorticoids: ENT specialty provides broad indications spectrum for low-dose
therapy].
PMID- 10766539
TI - [Psychotropic drugs--pills without power?. Interview by Dr. Dagmar van Thiel].
PMID- 10766540
TI - [Surgical robot in endoprosthetics. How CASPAR assists on the hip] the hip].
PMID- 10766541
TI - [Revised thinking in benign prostatic hyperplasia syndrome].
PMID- 10766542
TI - [How dangerous is the pill really?].
PMID- 10766543
TI - [Drug guidelines. Put on hold for the next 4 years. Interview by Peter Jentsch].
PMID- 10766544
TI - [Whiplash trauma: pain can now be assessed?. Interview by Dr. Brigitte Moreano].
PMID- 10766545
TI - [Blood pressure control with effectiveness].
PMID- 10766546
TI - [First drug for prevention of breast cancer].
PMID- 10766547
TI - [Informing patients].
PMID- 10766548
TI - [Do pharmacists and the state increase drug costs?].
PMID- 10766549
TI - [Pharmaceutical organization recommends to budget-concerned physicians: simply do
without some prescriptions!].
PMID- 10766550
TI - [CRH antagonists against depression. Viagra for the mind?. Interview by Dr.
Stephanie Czajka].
PMID- 10766551
TI - [Will heart catheters besides hospitalization also become superfluous?. Interview
by Dr. med. Ulrike Wepner].
PMID- 10766552
TI - ["Doctor, I cannot go on anymore"].
PMID- 10766553
TI - Developments in adipose tissue biology. Satellite meeting of the 9th European
Congress of Obesity. Portonovo Ancona, Italy, June 6-9, 1999. Abstracts.
PMID- 10766554
TI - [Therapy recommendations for sarcoidosis].
PMID- 10766555
TI - Iron deficiency anemia in pregnant and lactating mothers in rural Ethiopia.
PMID- 10766556
TI - The somatoform conundrum: a question of nosological valves.
PMID- 10766557
TI - Manic episode in an ifosfamide-treated patient.
PMID- 10766558
TI - Mothers murdering their newborns in the hospital.
PMID- 10766559
TI - Structural biology and functional genomics. Proceedings of the NATO Advanced
Research Workshop. Trieste, Italy, 4-8 May 1998.
PMID- 10766560
TI - Peripheral arthropathies in inflammatory bowel disease.
PMID- 10766561
TI - HFE and alcoholic liver disease.
PMID- 10766562
TI - Ileal pouch-anal anastomosis for Crohn's disease.
PMID- 10766563
TI - Excess nitric oxide in ulcerative colitis may be generated by nitric oxide
synthase independent pathways.
PMID- 10766564
TI - [Evolution in programmed cell death].
PMID- 10766565
TI - Proceedings of the 10th hGH Symposium. Seville, April 23-24, 1999.
PMID- 10766566
TI - Back to the roots of a new exon--the molecular archaeology of a SP100 splice
variant.
AB - Retropseudogenes are intronless DNA sequences sharing a high degree of homology
with the cDNA of their corresponding active genes. They are thought to have
originated by reverse transcription of messenger RNA and reintegration of the
cDNA into the genome. Usually considered a type of evolutionary waste, they melt
into the background of their surrounding DNA by the loss of similarity to the
active gene or disappear from the genome by the accumulation of deletions. On the
other hand, in this paper we describe the evolutionary recycling of this genomic
waste. Recently, a splice variant of the gene encoding the nuclear protein SP100
was identified in which the 3' part of the cDNA is replaced by an alternative
exon apparently encoding an HMG1-DNA-binding domain. We were able to show that
this HMG box is contributed by a new exon arising from an HMG1 retropseudogene
that we have molecularly characterized in detail. In addition to being found in
human cells, corresponding fusion transcripts were shown in Pan troglodytes,
Gorilla gorilla, and Hylobates lar, but not in Macaca mulatta. Genomic DNA from
M. mulatta enabled us to amplify by PCR the 5' part but not the 3' part of the
HMG1 retropseudogene. From our data we thus can date the underlying
retrotransposition to more than 35 million years ago. Our findings offer a model
as to how new exons may evolve during evolution. To our knowledge this is the
first example of a retropseudogene becoming part of an active gene in which both
parental parts are well characterized and remain in-frame with their cDNA.
PMID- 10766567
TI - Homologous radioimmunoassay and radioreceptorassay of gonadotropic hormone for an
Indian carp Catla catla.
AB - A homologous radioimmunoassay (RIA) for Indian carp (C. catla) gonadotropin (GtH)
was developed by using purified Catla GtH and its specific antiserum. In
Ouchterlony agar diffusion, antisera raised against purified Catla GtH (cGtH),
showed clear crossreaction. Catla-anti GtH (anti-cGtH) did not cross-reacted with
Catla TSH enriched fraction. Immunocrossreaction was further confirmed with
competitive binding inhibition studies where displacement of radiolabelled cGtH
was precisely linear against increasing concentrations of cGtH, hence this was
later used as standard curve for RIA. Competitive binding inhibition was also
observed with purified murrel GtH, silver carp GtH and Cyprinus GtH, using varied
doses. Both murrel and silver carp GtH showed clear parallelism with cGtH, while
Cyprinus GtH inhibition slope was less steeper. Mammalian GtHs (hCG, oLH, oFSH),
bTSH and bPRL had no crossreaction with anti-cGtH. Radioreceptorassay (RRA) for
cGtH was developed by preparing plasma membranes from Catla oocytes. Binding of
125I-cGtH to oocyte plasma membranes showed saturability with high affinity (Ka =
0.11 X 10(13)M-1) and low capacity (17 fmol/mg protein). Displacement of 125I
cGtH in receptorassay by cold cGtH was linear and therefore served as standard
curve. The interassay and intrassay variability in RIA was 7.9% and 3% while that
of RRA was 5% and 3% respectively. Sensitivity of RIA was in the picogram level
whereas it was in nanogram level by RRA. Determination of carp pituitary and
serum GtH content by RIA and RRA showed the consistency, precision and validity
of these assays. Although RRA was comparatively less sensitive than RIA, it was
convenient, quick and less expensive.
PMID- 10766568
TI - Bioethics.
PMID- 10766569
TI - Unsubstantiated conclusions can impede progress in lung cancer.
PMID- 10766570
TI - Corrected abstracts: American Academy of Allergy, Asthma and Immunology 56th
annual meeting.
PMID- 10766571
TI - Commentary: The role of neuromuscular blockade in palliative medicine.
PMID- 10766572
TI - Ketamine for cancer pain.
PMID- 10766573
TI - Re: The use of phenobarbitone in the management of agitation and seizures at the
end of life.
PMID- 10766574
TI - Analgesic effects of auricular acupuncture for cancer pain.
PMID- 10766575
TI - [Substance abuse and "legitimate drugs"].
PMID- 10766576
TI - Influence of respiration and portal pressure on transabdominal duplex Doppler
ultrasound measurement of portal blood flow: a porcine model for experimental
studies.
AB - Transabdominal duplex Doppler ultrasonography (TDDU) is commonly used for
measuring hepatic blood flow (HBF) in clinical practice. Flow velocity and the
cross-sectional area (CSA) of vessels are obtained separately and used to compute
blood flow. Respiration and changes in portal pressure are known to cause
variations in the CSA of the portal vein, but the impact of these parameters on
TDDU measurement of portal blood flow is unclear. Eight Yorkshire pigs (20.7-25.1
kg) were used for the study. TDDU determination of portal blood flow was carried
out using CSA of the portal vein obtained at inspiration (maximal) and at
expiration (minimal) for computation, and the differences obtained were compared.
Determination of HBF was carried out simultaneously on the same animals using
diisopropyliminodiacetic acid (DISIDA) clearance. A physiological increase in
portal pressure was then created by 50% hepatectomy and TDDU measurement
similarly carried out on the second postoperative day. Computing portal blood
flow in the intact liver using maximal and minimal CSA gave rise to a mean
difference of 7.0 ml kg(-1) min(-1) (P < 0.001). A significant correlation was
obtained between HBF and portal flow computed from maximal CSA (Pearson's
correlation = 0.85, P < 0.033). The respiratory index of the portal vein (maximal
CSA/minimal CSA) decreased from 1.5 to 1.2 after hepatectomy, which also caused a
90% increase in portal pressure. Respiration and portal pressure thus
significantly impact on TDDU determination of HBF, and in this porcine model,
computation using maximal CS more accurately reflects HBF.
PMID- 10766577
TI - Venovenous modified ultrafiltration after cardiopulmonary bypass in children: a
prospective randomized study.
PMID- 10766578
TI - Searching for the closest living relative(s) of tetrapods through evolutionary
analyses of mitochondrial and nuclear data.
AB - The phylogenetic relationships of the African lungfish (Protopterus dolloi) and
the coelacanth (Latimeria chalumnae) with respect to tetrapods were analyzed
using complete mitochondrial genome DNA sequences. A lungfish + coelancanth clade
was favored by maximum parsimony (although this result is dependent on which
transition:transversion weights are applied), and a lungfish + tetrapod clade was
supported by neighbor-joining and maximum-likelihood analyses. These two
hypotheses received the strongest statistical and bootstrap support to the
exclusion of the third alternative, the coelacanth + tetrapod sister group
relationship. All mitochondrial protein coding genes combined favor a lungfish +
tetrapod grouping. We can confidently reject the hypothesis that the coelacanth
is the closest living relative of tetrapods. When the complete mitochondrial
sequence data were combined with nuclear 28S rRNA gene data, a lungfish +
coelacanth clade was supported by maximum parsimony and maximum likelihood, but a
lungfish + tetrapod clade was favored by neighbor-joining. The seeming
conflicting results based on different data sets and phylogenetic methods were
typically not statistically strongly supported based on Kishino-Hasegawa and
Templeton tests, although they were often supported by strong bootstrap values.
Differences in rate of evolution of the different mitochondrial genes (slowly
evolving genes such as the cytochrome oxidase and tRNA genes favored a lungfish +
coelacanth clade, whereas genes of relatively faster substitution rate, such as
several NADH dehydrogenase genes, supported a lungfish + tetrapod grouping), as
well as the rapid radiation of the lineages back in the Devonian, rather than
base compositional biases among taxa seem to be directly responsible for the
remaining uncertainty in accepting one of the two alternate hypotheses.
PMID- 10766579
TI - Multilocus phylogeny of cichlid fishes (Pisces: Perciformes): evolutionary
comparison of microsatellite and single-copy nuclear loci.
AB - Among vertebrates, cichlid fishes are the paradigmatic example of adaptive
radiation and ecological specialization. In turn, molecular genetic studies of
cichlids have focused primarily on more recently diverged groups. Here, we
present an evolutionary hypothesis of the major lineages of cichlid fishes based
on DNA sequence data from two nuclear loci. One marker, Tmo-4C4, is a single-copy
locus containing a region of amino acid similarity to the muscle protein TITIN.
Flanking sequence from a second, microsatellite, locus Tmo-M27, shows similarity
to mammalian RAS guanine nucleotide-releasing factor. We compare and combine data
from these loci to evaluate phylogenetic performance. In separate and combined
analyses, the sequence data support and clarify previous morphological hypotheses
of cichlid major-group relationships. Indian and Malagasy cichlids form a basal,
paraphyletic group. Neotropical cichlids are the sister clade to an African
assemblage composed of the paraphyletic west and Pan-African lineages and a group
of east African rift lake taxa. We use a consensus phylogeny of the Cichlidae to
trace evolutionary changes in the microsatellite repeat motif at Tmo-M27.
Analysis reveals that the repeat region was nearly lost in the ancestor to
cichlids and then amplified extensively in African taxa. Results demonstrate that
the two new DNA markers could be widely applied in perciform systematics.
Furthermore, the comparative approach can unveil mutational dynamics of simple
sequence repeat loci over long periods of fish evolution. Simple-sequence repeat
regions are increasingly being found in introns of important regulatory genes. We
address issues involving their function and suggest caution in making assumptions
of strict neutrality.
PMID- 10766580
TI - [Dihydropyrimidine dehydrogenase and thymidylate synthase activities in colonic
cancer tissue and sensitivity to 5-fluorouracil].
PMID- 10766581
TI - Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV
infected patients who have a response to antiretroviral therapy. Terry Beirn
Community Programs for Clinical Research on AIDS.
AB - BACKGROUND: Several agents are effective in preventing Mycobacterium avium
complex disease in patients with advanced human immunodeficiency virus (HIV)
infection. However, there is uncertainty about whether prophylaxis should be
continued in patients whose CD4+ cell counts have increased substantially with
antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized
trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in
HIV-infected patients whose CD4+ cell counts had increased from less than 50 to
more than 100 per cubic millimeter in response to antiretroviral therapy. The
primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A
total of 520 patients entered the study; the median CD4+ cell count at entry was
230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was
below the level of quantification. The median prior nadir CD4+ cell count was 23
per cubic millimeter, and 65 percent of the patients had had an acquired
immunodeficiency syndrome-defining illness. During follow-up over a median period
of 12 months, there were no episodes of confirmed M. avium complex disease in
either group (95 percent confidence interval for the rate of disease in each
group, 0 to 1.5 episodes per 100 person-years). Three patients in the
azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had
bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent
confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of
HIV disease nor the mortality rate differed significantly between the two groups.
Adverse effects led to discontinuation of the study drug in 19 patients assigned
to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1
percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can
safely be withheld in HIV-infected patients whose CD4+ cell counts have increased
to more than 100 cells per cubic millimeter in response to antiretroviral
therapy.
PMID- 10766582
TI - Neural-tube defects.
PMID- 10766583
TI - Neural-tube defects.
PMID- 10766584
TI - Neural-tube defects.
PMID- 10766585
TI - Alcohol consumption and the risk of stroke.
PMID- 10766586
TI - Alcohol consumption and the risk of stroke.
PMID- 10766588
TI - Insurance payments for bone marrow transplantation in metastatic breast cancer.
PMID- 10766587
TI - Predictors of success of methotrexate treatment in women with tubal ectopic
pregnancies.
PMID- 10766589
TI - Taenia saginata.
PMID- 10766590
TI - Taenia saginata.
PMID- 10766591
TI - The effect of managed care on medical education.
PMID- 10766592
TI - The effect of managed care on medical education.
PMID- 10766593
TI - The effect of managed care on medical education.
PMID- 10766594
TI - The effect of managed care on medical education.
PMID- 10766595
TI - The effect of managed care on medical education.
PMID- 10766596
TI - Reduction in blood cyclosporine concentrations by orlistat.
PMID- 10766597
TI - Uproar at Oxford as suspended professor returns to work.
PMID- 10766599
TI - Japan's cloning ban will allow stem cell experiments.
PMID- 10766598
TI - Protests force primate farm to close.
PMID- 10766600
TI - [Can a person with a pacemaker use and receive calls via a cellular telephone?].
PMID- 10766601
TI - Peripheral antinociceptive actions of desimipramine and fluoxetine in an
inflammatory and neuropathic pain test in the rat.
PMID- 10766602
TI - The self of philosophy and the self of immunology.
PMID- 10766603
TI - Is ozone therapy therapeutic?
PMID- 10766604
TI - Adaptive evolution of highly mutable loci in pathogenic bacteria.
PMID- 10766605
TI - Asilomar revisited: lessons for today?
PMID- 10766606
TI - Middle Miocene hominoid origins.
PMID- 10766607
TI - Middle Miocene hominoid origins.
PMID- 10766608
TI - Conservation. Conflict in Congo threatens bonobos and rare gorillas.
PMID- 10766609
TI - Genetics. Chipping away at the causes of aging.
PMID- 10766610
TI - Infectious disease. Drug-resistant TB on the rise.
PMID- 10766611
TI - Public health. Bat researchers dispute rabies policy.
PMID- 10766612
TI - In the crossfire: Collins on genomes, patents, and 'rivalry'. Interview by Eliot
Marshall, Elizabeth Pennisi, and Leslie Roberts.
PMID- 10766613
TI - Epidemiology. When an entire country is a cohort.
PMID- 10766614
TI - Intellectual property. Patent suit pits postdoc against former mentor.
PMID- 10766615
TI - Lunar and Planetary Science Conference. Oddities both lunar and Martian.
PMID- 10766616
TI - Asilomar revisited.
PMID- 10766617
TI - Respect for the opposition.
PMID- 10766618
TI - Respect for the opposition.
PMID- 10766619
TI - Close encounters: details veto depth from shadows.
PMID- 10766620
TI - Molecular biology. RNA interference.
PMID- 10766621
TI - Structural biology. Bit players in the trombone orchestra.
PMID- 10766622
TI - Molecular biology. Running the red light.
PMID- 10766623
TI - William Hamilton (1936-2000).
PMID- 10766625
TI - Study of HIV transmission sparks ethics debate.
PMID- 10766624
TI - Serotonin and the therapeutic effects of ritalin.
PMID- 10766626
TI - AIDS research head to retire from NIH.
PMID- 10766627
TI - Academic employment. Jury awards $545,000 in Stanford case.
PMID- 10766628
TI - Academic employment. UCSF researchers leave, charging bias.
PMID- 10766629
TI - Hazel trees offer new source of cancer drug.
PMID- 10766630
TI - Biochemistry. Chemical tags speed delivery into cells.
PMID- 10766631
TI - Genetics. Uphill battle to honor monk who demystified heredity.
PMID- 10766632
TI - Genetics. Was Lamarck just a little bit right?
PMID- 10766633
TI - Mental health. Global survey examines impact of depression.
PMID- 10766634
TI - HIV-1 nomenclature proposal.
PMID- 10766635
TI - Essays on science and society: Intimations of immortality.
PMID- 10766636
TI - Structural biology. Unraveling a membrane protein.
PMID- 10766637
TI - Neurobiology. Receptors as kissing cousins.
PMID- 10766638
TI - Nota bene. Awakening aurora.
PMID- 10766639
TI - On the move.
PMID- 10766640
TI - Biologists and engineers create a new generation of robots that imitate life.
PMID- 10766641
TI - In nature, animals that stop and start win the race.
PMID- 10766642
TI - Tracking the movements that shape an embryo.
PMID- 10766643
TI - BCG vaccination by multipuncture method.
PMID- 10766644
TI - Respiratory care units for non-invasive mechanical ventilation in motor neurone
disease.
PMID- 10766645
TI - Asthma deaths in Scotland and in Wales.
PMID- 10766646
TI - Nebulised fluticasone.
PMID- 10766647
TI - Pyoderma gangrenosum.
PMID- 10766648
TI - Therapeutic equivalence of inhaled salbutamol.
PMID- 10766650
TI - [The deaf can be hearing--cochlear implantation. The Danish Society of
Otolaryngology, Head and Neck Surgery].
PMID- 10766649
TI - Thrombophilic factors in patients with Syndrome X.
PMID- 10766651
TI - [Clinical microbiology 1999. The Danish Society of Clinical Microbiology].
PMID- 10766652
TI - [Hand transplantation and implantation of nerve chips. New developments within
hand surgery].
AB - Injuries and diseases of the hand naturally have an enormous impact on hand
function and on quality of life, both occupational and social. The majority of
hand-injury patients are under 30 years of age. Hand surgery, an established
specialty in Sweden since 1969, is of great importance in terms of clinical
developments, education and research. In the coming decade, scientific and
clinical advances are to be expected in several fields such as nerve injuries
including brachial plexus lesion, microsurgery, flexor tendon injuries and tendon
transfer. Bioimplant research and new advances at the biotechnological interface
will yield new options in nerve reconstruction, microchip implants in the nervous
system, and the restoration of muscle-tendon function following injury.
Artificial limbs with advanced motor and sensory functions will be important
future aids in the rehabilitation of amputees. Transplantation of human hands is
another promising reconstructive procedure which may open iup new perspectives in
the coming millennium.
PMID- 10766653
TI - [Follow-up after infraligamental PTA treatment].
AB - A total of 48 percutaneous transluminal angioplasties (PTAs) of the superficial
femoral and popliteal artery performed between 1993 and 1998 were evaluated with
ultrasound duplex scanning and ankle-arm pressure. Twenty-seven (60%) patients
presented with claudication and 18 (40%) had limb-threatening ischaemia. Three
patients had bilateral PTA. The PTAs were initially successful, corresponding to
an early patency rate of 87.5% within the first four weeks. The 12 month patency
rate, calculated by life table method, was 68% and 72%, respectively (non
significant). The mortality was 4% and 33% respectively during the first year (p
< 0.05). In spite of the size of the material, PTA of the femoropopliteal
arterial segment is considered as a valid alternative treatment to vascular
surgery in patients presenting with claudication and in patients presenting limb
threatening ischemia.
PMID- 10766654
TI - [Endoscopic decompression of the carpal tunnel].
AB - The aim of the study was to evaluate the efficiency and safety of endoscopic
carpal tunnel release using the Wolf one-portal system. The case records for all
decompressions performed between January 1995 and June 1998 were reviewed
retrospectively. Preoperative complaints, intraoperative findings and
postoperative results were recorded for a total of 168 procedures in 138
patients. The median follow-up period was 10.4 weeks (1.1-170.9). An improvement
in symptoms was noted after 82.9% of the procedures. The complication rate was
8.9% at the time of follow-up. Nine procedures were converted to open release. No
patients sustained nerve or vascular injury. The findings in this study indicate
that carpal tunnel release performed using the Wolf one-portal system provides a
safe and effective treatment for carpal tunnel syndrome. The technique is today
used as a routine in the department in uncomplicated cases of carpal tunnel
syndrome.
PMID- 10766655
TI - [Clinical, radiological, histopathological and genetic findings in a Danish
"CADASIL" family].
AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is a rare adult-onset inherited arterial disease
with a distinctive neuropathological phenotype. Owing to its recent
identification and variable mode of presentation, the disease is often
misdiagnosed. The CADASIL gene is Notch 3 and has been mapped on chromosome 19q12
in several unrelated families. Knowledge of the phenotypic range of CADASIL,
however, remains incomplete. Clinical, pathological radiological, and genetic
findings in the first known Danish CADASIL pedigree are presented. Genetic
testing confirmed a Notch 3 mutation. The mutation consisted of the substitution
of a nucleotide at position 475 leading to the replacement of amino acid arginine
for cysteine at position 133 in the third EGF motif.
PMID- 10766656
TI - [Reintroduction of medical abortion in Denmark].
AB - Medical termination of early pregnancy with mifepristone (RU 486) followed by a
prostaglandin analogue (Cervagem) is a fairly new abortion method in surgical and
gynaecological departments in Denmark. Sixty-two patients were evaluated during
the period December 1, 1997 to the June 10, 1998 at Kalundborg hospital. The
success rate was 97%. Side effects were rare. The study illustrates the need for
strong analgesics in half of the patients. In conclusion RU 486 followed by a
prostaglandin analogue provides an efficient and attractive alternative to
surgical abortion methods.
PMID- 10766657
TI - [Necrotizing fasciitis].
AB - Necrotizing fasciitis is a progressive destructive infection in the subcutaneous
tissue. It represents a serious problem in medicine both in making the correct
early diagnosis and in treatment. We describe the symptoms, the clinical and
paraclinical findings and the guidelines for treatment. Nine cases of necrotizing
fasciitis are reported schematically, three cases are presented in text. Only two
patients survived, one of these received intravenous immunoglobulin. Of the seven
dead, five received intravenous immunoglobulin.
PMID- 10766658
TI - [A rare cause of osteomyelitis. A case of Mycobacterium bovis in a wrist].
AB - A cases of longstanding infection with Mycobacterium bovis is described in 79
year-old retired butcher presenting with broad erosions of the right wristbones.
Further investigations revealed a chronic infection with Mycobacterium bovis
present for 58 years. The patient was treated with antibiotics. The importance of
having tuberculosis in mind when investigating lytic bone destruction is
discussed.
PMID- 10766659
TI - [Picture of the month. Systemic lupus erythematosus after light exposure].
PMID- 10766660
TI - [Ghrelin--a new hormone].
PMID- 10766661
TI - [Smoking-related diseases and prevention at department of internal medicine].
PMID- 10766662
TI - [Accreditation and clinical indicators: experiences from Australia].
PMID- 10766663
TI - [New treatment of chronic myeloid leukemia. A breakthrough in molecular
biology?].
PMID- 10766664
TI - [Alcohol and ischemic heart disease--"Number needed to drink"].
PMID- 10766665
TI - [Pelvic loosening].
PMID- 10766666
TI - [Hippocrates and scientific articles].
PMID- 10766667
TI - ["Insulin sensitizers" (glitazones), obesity, insulin resistance--is there a
connection?].
PMID- 10766668
TI - [The organization of and ways to improve surgical care in the Air Forces].
PMID- 10766669
TI - [The contribution of A. S. Georgievskii to the study of the history of the
Military Medical Academy].
PMID- 10766670
TI - [The 255th anniversary of Orenburg Military Hospital].
PMID- 10766671
TI - [Dissertations defended in 1999].
PMID- 10766672
TI - [On the centenary of the birth of Anton Vasil'evich Bondarchuk].
PMID- 10766673
TI - [Evgenii Ivanovich Babichenko (on the 75th anniversary of his birth)].
PMID- 10766674
TI - Proceedings of the 26th annual meeting of the International Society of Oxygen
Transport to Tissue. Budapest, Hungary, August 23-28, 1998.
PMID- 10766675
TI - Proceedings of the 2nd International Rushmore Conference on Mechanisms in the
Pathogenesis of Enteric Diseases. Rapid City, South Dakota, USA. September 30
October 3, 1998.
PMID- 10766676
TI - A rejoinder on "research".
PMID- 10766677
TI - Dedicated AIDS units vs. scattered-bed units.
PMID- 10766678
TI - Low cardiorespiratory fitness and physical inactivity as predictors of mortality
in men with type 2 diabetes.
AB - BACKGROUND: Although physical activity is recommended as a basic treatment for
patients with diabetes, its long-term association with mortality in these
patients is unknown. OBJECTIVE: To evaluate the association of low
cardiorespiratory fitness and physical inactivity with mortality in men with type
2 diabetes. DESIGN: Prospective cohort study. SETTING: Preventive medicine
clinic. PATIENTS: 1263 men (50+/-10 years of age) with type 2 diabetes who
received a thorough medical examination between 1970 and 1993 and were followed
for mortality up to 31 December 1994. MEASUREMENTS: Cardiorespiratory fitness
measured by a maximal exercise test, self-reported physical inactivity at
baseline, and subsequent death determined by using the National Death Index.
RESULTS: During an average follow-up of 12 years, 180 patients died. After
adjustment for age, baseline cardiovascular disease, fasting plasma glucose
level, high cholesterol level, overweight, current smoking, high blood pressure,
and parental history of cardiovascular disease, men in the low-fitness group had
an adjusted risk for all-cause mortality of 2.1 (95% CI, 1.5 to 2.9) compared
with fit men. Men who reported being physically inactive had an adjusted risk for
mortality that was 1.7-fold (CI, 1.2-fold to 2.3-fold) higher than that in men
who reported being physically active. CONCLUSIONS: Low cardiorespiratory fitness
and physical inactivity are independent predictors of all-cause mortality in men
with type 2 diabetes. Physicians should encourage patients with type 2 diabetes
to participate in regular physical activity and improve cardiorespiratory
fitness.
PMID- 10766679
TI - Effect of segment length on risk for neoplastic progression in patients with
Barrett esophagus.
AB - BACKGROUND: The increased risk for esophageal adenocarcinoma associated with long
segment (> or =3 cm) Barrett esophagus is well recognized. Recent studies suggest
that short-segment (<3 cm) Barrett esophagus is substantially more common;
however, the risk for neoplastic progression in patients with this disorder is
largely unknown. OBJECTIVE: To examine the relation between segment length and
risk for aneuploidy and esophageal adenocarcinoma in patients with Barrett
esophagus. DESIGN: Prospective cohort study. SETTING: University medical center
in Seattle, Washington. PATIENTS: 309 patients with Barrett esophagus.
MEASUREMENTS: Patients were monitored for progression to aneuploidy and
adenocarcinoma by repeated endoscopy with biopsy for an average of 3.8 years. Cox
proportional hazards analysis was used to calculate adjusted relative risks and
95% Cls. RESULTS: After adjustment for histologic diagnosis at study entry,
segment length was not related to risk for cancer in the full cohort (P > 0.2 for
trend). When patients with high-grade dysplasia at baseline were excluded,
however, a nonsignificant trend was observed; based on a linear model, a 5-cm
difference in segment length was associated with a 1.7-fold (95% CI, 0.8-fold to
3.8-fold) increase in cancer risk. Among all eligible patients, a 5-cm difference
in segment length was associated with a small increase in the risk for aneuploidy
(relative risk, 1.4 [CI, 1.0 to 2.1]; P = 0.06 for trend). A similar trend was
observed among patients without high-grade dysplasia at baseline. CONCLUSIONS:
The risk for esophageal adenocarcinoma in patients with short-segment Barrett
esophagus was not substantially lower than that in patients with longer segments.
Although our results suggest a small increase in risk for neoplastic progression
with increasing segment length, additional follow-up is needed to determine
whether the patterns of risk occurred by chance or represent true differences.
Until more data are available, the frequency of endoscopic surveillance should be
selected without regard to segment length.
PMID- 10766680
TI - Invasive and noninvasive strategies for management of suspected ventilator
associated pneumonia. A randomized trial.
AB - BACKGROUND: Optimal management of patients who are clinically suspected of having
ventilator-associated pneumonia remains open to debate. OBJECTIVE: To evaluate
the effect on clinical outcome and antibiotic use of two strategies to diagnose
ventilator-associated pneumonia and select initial treatment for this condition.
DESIGN: Multicenter, randomized, uncontrolled trial. SETTING: 31 intensive care
units in France. PATIENTS: 413 patients suspected of having ventilator-associated
pneumonia. INTERVENTION: The invasive management strategy was based on direct
examination of bronchoscopic protected specimen brush samples or bronchoalveolar
lavage samples and their quantitative cultures. The noninvasive ("clinical")
management strategy was based on clinical criteria, isolation of microorganisms
by nonquantitative analysis of endotracheal aspirates, and clinical practice
guidelines. MEASUREMENTS: Death from any cause, quantification of organ failure,
and antibiotic use at 14 and 28 days. RESULTS: Compared with patients who
received clinical management, patients who received invasive management had
reduced mortality at day 14 (16.2% and 25.8%; difference, -9.6 percentage points
[95% CI, -17.4 to -1.8 percentage points]; P = 0.022), decreased mean Sepsis
related Organ Failure Assessment scores at day 3 (6.1+/-4.0 and 7.0+/-4.3; P =
0.033) and day 7 (4.9+/-4.0 and 5.8+/-4.4; P = 0.043), and decreased antibiotic
use (mean number of antibiotic-free days, 5.0+/-5.1 and 2.2+/-3.5; P < 0.001). At
28 days, the invasive management group had significantly more antibiotic-free
days (11.5+/-9.0 compared with 7.5+/-7.6; P < 0.001), and only multivariate
analysis showed a significant difference in mortality (hazard ratio, 1.54 [CI,
1.10 to 2.16]; P = 0.01). CONCLUSIONS: Compared with a noninvasive management
strategy, an invasive management strategy was significantly associated with fewer
deaths at 14 days, earlier attenuation of organ dysfunction, and less antibiotic
use in patients suspected of having ventilator-associated pneumonia.
PMID- 10766681
TI - Potentiation of vitamin K antagonists by high-dose intravenous
methylprednisolone.
AB - BACKGROUND: Oral anticoagulants and pulse high-dose intravenous
methylprednisolone are often administered concomitantly, but no data on potential
interactions are available. OBJECTIVE: To assess possible potentiation of oral
anticoagulation by high-dose intravenous methylprednisolone. DESIGN: Prospective
cohort study. SETTING: University hospital in Paris, France. PATIENTS: 10
consecutive patients concomitantly receiving methylprednisolone and oral
anticoagulants (fluindione and acenocoumarol) and 5 consecutive controls
receiving methylprednisolone alone. MEASUREMENTS: Serial determinations of the
international normalized ratio (INR) and clotting factors during administration
of pulse methylprednisolone. The total plasma fluindione concentration was
determined in 3 patients. RESULTS: The mean INR was 2.75 (range, 2.02 to 3.81) at
baseline and increased to 8.04 (range, 5.32 to 20.0) after methylprednisolone
administration. Plasma fluindione concentrations and the INR increased after
methylprednisolone administration. Methylprednisolone alone did not increase
prothrombin time. CONCLUSIONS: The action of oral anticoagulants is potentiated
by intravenous high-dose methylprednisolone. The INR should be monitored daily
during concomitant administration of these medications.
PMID- 10766682
TI - The effect of coenzyme Q10 in patients with congestive heart failure.
AB - BACKGROUND: Coenzyme Q10 is commonly used to treat congestive heart failure on
the basis of data from several unblinded, subjective studies. Few randomized,
blinded, controlled studies have evaluated objective measures of cardiac
performance. OBJECTIVE: To determine the effect of coenzyme Q10 on peak oxygen
consumption, exercise duration, and ejection fraction. DESIGN: Randomized, double
blind, controlled trial. SETTING: University and Veterans Affairs hospitals.
PATIENTS: 55 patients who had congestive heart failure with New York Heart
Association class III and IV symptoms, ejection fraction less than 40%, and peak
oxygen consumption less than 17.0 mL/kg per minute (or <50% of predicted) during
standard therapy were randomly assigned. Forty-six patients completed the study.
INTERVENTION: Coenzyme Q10, 200 mg/d, or placebo. MEASUREMENTS: Left ventricular
ejection fraction (measured by radionuclide ventriculography) and peak oxygen
consumption and exercise duration (measured by a graded exercise evaluation using
the Naughton protocol) with continuous metabolic monitoring. RESULTS: Although
the mean (+/-SD) serum concentration of coenzyme Q10 increased from 0.95+/-0.62
microg/mL to 2.2+/-1.2 microg/mL in patients who received active treatment,
ejection fraction, peak oxygen consumption, and exercise duration remained
unchanged in both the coenzyme Q10 and placebo groups. CONCLUSION: Coenzyme Q10
does not affect ejection fraction, peak oxygen consumption, or exercise duration
in patients with congestive heart failure receiving standard medical therapy.
PMID- 10766683
TI - Education of physicians-in-training can decrease the risk for vascular catheter
infection.
AB - BACKGROUND: Procedure instruction for physicians-in-training is usually
nonstandardized. The authors observed that during insertion of central venous
catheters (CVCs), few physicians used full-size sterile drapes (an intervention
proven to reduce the risk for CVC-related infection). OBJECTIVE: To improve
standardization of infection control practices and techniques during invasive
procedures. DESIGN: Nonrandomized pre-post observational trial. SETTING: Six
intensive care units and one step-down unit at Wake Forest University Baptist
Medical Center, Winston-Salem, North Carolina. PARTICIPANTS: Third-year medical
students and physicians completing their first postgraduate year. INTERVENTION: A
1-day course on infection control practices and procedures given in June 1996 and
June 1997. MEASUREMENTS: Surveys assessing physician attitudes toward use of
sterile techniques during insertion of CVCs were administered during the baseline
year and just before, immediately after, and 6 months after the first course.
Preintervention and postintervention use of full-size sterile drapes was
measured, and surveillance for vascular catheter-related infection was performed.
RESULTS: The perceived need for full-size sterile drapes was 22% in the year
before the course and 73% 6 months after the course (P < 0.001). The perceived
need for small sterile towels at the insertion site decreased reciprocally (P <
0.001). Documented use of full-size sterile drapes increased from 44% to 65% (P <
0.001). The rate of catheter-related infection decreased from 4.51 infections per
1000 patient-days before the first course to 2.92 infections per 1000 patient
days 18 months after the first course (average decrease, 3.23 infections per 1000
patient-days; P < 0.01). The estimated cost savings of this 28% decrease was at
least $63000 and may have exceeded $800000. CONCLUSIONS: Standardization of
infection control practices through a course is a cost-effective way to decrease
related adverse outcomes. If these findings can be reproduced, this approach may
serve as a model for physicians-in-training.
PMID- 10766684
TI - Gene therapy for lung disease: hype or hope?
AB - Gene therapy, the treatment of any disorder or pathophysiologic state on the
basis of the transfer of genetic information, was a high-priority goal in the
1990s. The lung is a major target of gene therapy for genetic disorders, such as
cystic fibrosis and alpha1-antitrypsin deficiency, and for other diseases,
including lung cancer, malignant mesothelioma, pulmonary inflammation, surfactant
deficiency, and pulmonary hypertension. This paper examines general concepts in
gene therapy, summarizes the results of published clinical trials, and highlights
areas of research aimed at overcoming challenges in the field. Although progress
has been slower than anticipated, gene transfer has been safely achieved in
patients with lung diseases. Recent advancements in understanding of the
molecular basis of lung disease and the development of improved vector systems
make it likely that gene therapy will be an important tool for the 21st-century
clinician.
PMID- 10766685
TI - The Lyme disease vaccine: conception, development, and implementation.
AB - In the past 20 years, remarkable strides have been made toward understanding and
preventing Lyme disease in humans. In December 1998, the U.S. Food and Drug
Administration approved a recombinant outer surface protein A vaccine against
Lyme disease (LYMErix, SmithKline Beecham, Philadelphia, Pennsylvania). The
vaccine, which is derived from a lipidated outer surface protein of the causative
spirochete Borrelia burgdorferi, is important because it may decrease the
morbidity and financial costs associated with Lyme disease. Its mechanism is
unique because it works inside the tick vector itself, preventing the human from
becoming infected.
PMID- 10766686
TI - Combating sloth as well as gluttony: the role of physical fitness in mortality
among men with type 2 diabetes.
PMID- 10766687
TI - On being a doctor 2.
PMID- 10766688
TI - More on alternative medicine.
PMID- 10766689
TI - Doctor's daughter.
PMID- 10766690
TI - Homocyst(e)ine and cardiovascular disease.
PMID- 10766691
TI - Standardization of hemoglobin A1c values.
PMID- 10766692
TI - Hyperhomocysteinemia in hypothyroidism.
PMID- 10766693
TI - Rapid-onset subfulminant liver failure associated with troglitazone.
PMID- 10766694
TI - Factor VIII antibodies developing after a spider bite.
PMID- 10766695
TI - Cooling methods for heatstroke victims.
PMID- 10766696
TI - Abolished vagal tone associated with thyrotoxicosis triggers prinzmetal variant
angina and paroxysmal atrial fibrillation.
PMID- 10766697
TI - Cocaine washout syndrome.
PMID- 10766698
TI - Acute pancreatitis associated with celecoxib.
PMID- 10766699
TI - Use of bromelain for mild ulcerative colitis.
PMID- 10766700
TI - Apoptosis in cardiac myxoma.
PMID- 10766701
TI - Propanolol administration in a patient with thyroid storm.
PMID- 10766702
TI - Ischemic colitis associated with decongestant use.
PMID- 10766703
TI - Parvovirus B19 and glomerulonephritis in a healthy adult.
PMID- 10766704
TI - Conference roundup: HIV and AIDS.
PMID- 10766705
TI - The invisible hand of the government in medical education.
PMID- 10766706
TI - Children of the 90s.
PMID- 10766707
TI - Covert video surveillance.
PMID- 10766708
TI - Economic disadvantages of palivizumab.
PMID- 10766709
TI - Evidence in favour of NHS Direct.
PMID- 10766710
TI - Infanticide or SIDS, double jeopardy.
PMID- 10766711
TI - Parent initiated and conventional preschool health surveillance.
PMID- 10766712
TI - Prognosis for vesicoureteric reflux.
PMID- 10766713
TI - Recommendations for the management of galactosaemia.
PMID- 10766714
TI - Vagal nerve stimulation for epilepsy.
PMID- 10766715
TI - Vet's actions endorsed by court.
PMID- 10766716
TI - Effects of irradiance and spectral quality on leaf structure and function in
seedlings of two Southeast Asian Hopea (Dipterocarpaceae) species.
AB - We studied the development of leaf characters in two Southeast Asian dipterocarp
forest trees under different photosynthetic photon flux densities (PFD) and
spectral qualities (red to far-red, R:FR). The two species, Hopea helferi and H.
odorata, are taxonomically closely related but differ in their ecological
requirements; H. helferi is more drought tolerant and H. odorata more shade
tolerant. Seedlings were grown in replicated shadehouse treatments of differing
PFD and R:FR. We measured or calculated (1) leaf and tissue thicknesses; (2)
mesophyll parenchyma, air space, and lignified tissue volumes; (3) mesophyll air
volumes (V(mes)/A(surf)) and surfaces (A(mes)/A(surf)); (4) palisade cell length
and width; (5) chlorophyll/cm and a/b; (6) leaf absorption; and (7)
attenuance/absorbance at 652 and 550 nm. These characters varied in response to
light conditions in both taxa. Characters were predominantly affected by PFD, and
R:FR slightly influenced many characters. Leaf characters of H. odorata were more
plastic in response to treatment conditions. Characters were correlated with each
other in a complex fashion. Variation in leaf anatomy is most likely a
consequence of increasing leaf thickness in both taxa, which may increase
mechanical strength and defense against herbivory in more exposed environments.
Variation in leaf optical properties was most likely affected by pigment photo
bleaching in treatments of more intense PFD and was not correlated with A(max).
The greater plasticity of leaf responses in H. odorata helps explain the
acclimation over the range of light conditions encountered by this shade-tolerant
taxon. The dense layer of scales on the leaf undersurface and other anatomical
characters in H. helferi reduced gas exchange and growth in this drought-tolerant
tree.
PMID- 10766717
TI - The development of Archaeopteris: new evolutionary characters from the structural
analysis of an Early Famennian trunk from southeast Morocco.
AB - A 5 m long trunk of a young Archaeopteris/Callixylon erianum tree from the Late
Devonian of Morocco shows new branching patterns for early lignophytes. This
progymnosperm tree produces a helical pattern of traces that we infer belonged to
reduced, short-lived, primary (apical) branches (type A) as well as two types of
adventitious traces (types B and H). We infer that type-B traces supplied
branches that initiate close to the site of attachment on the trunk of some, but
not all type-A branches in an irregular but nonrandom pattern. Unlike ephemeral
type-A branches, those of type B persist and become long-lived, potentially
permanent units of the architecture of Archaeopteris trees. Type-H adventitious
traces are also short-lived and occur singly or in serial groups, but differ from
traces of either type A or B branches by lacking differentiation into a readily
identifiable organ category. We interpret type-H traces as supplying latent
primordia that could develop into either adventitious roots or shoots depending
on extrinsic factors. Our new data suggest that Archaeopteris had a wide range of
branch primordium amplitude. Type-B branches compare with axillary lateral branch
buds of some Early Carboniferous spermatophytes (Calamopitys) and are a major
developmental departure from the strictly apical, pseudomonopodial shoot
branching of older aneurophyte progymnosperms. Type-H traces suggest that
Archaeopteris trees had some potential for formation of adventitious roots or
shoots in response to environmental factors, such as partial burial by overbank
sedimentation. Collectively, these novel methods of tree branching may partly
explain the extraordinary success and worldwide dominance of Archaeopteris
forests on fluvially dominated, Late Devonian floodplains.
PMID- 10766718
TI - Wood biomechanics and anatomy of PACHYCEREUS PRINGLEI.
AB - We report the longitudinal, biomechanical, and anatomical trends observed for
tissue samples drawn from the parallel aligned, prismatic woody vascular bundles
running the length of a Pachycereus pringlei plant measuring 5.22 m in height.
The main vertical stem of this plant was cut into five segments (labeled A
through E in the acropetal direction) measuring ~1.02 m in length. Four of the 14
vascular bundles in each segment were surgically removed to obtain 20 vascular
bundle segments that were tested in bending to determine their stiffness measured
in the radial E(R) and tangential E(T) direction. We also determined the lignin
content of representative samples of wood.A nonlinear trend in stiffness was
observed: E(R) and E(T) were highest in segments B or C (1.67 GN/m and 1.09 GN/m,
respectively), lower in segment A (E(R) = 1.18 GN/m and E(T) = 0.35 GN/m), and
lowest in segment E (E(R) = 0.03 GN/m and E(T) = 0.20 GN/m). Similar longitudinal
trends were seen for axial tissue volume fraction and fiber wall thickness, which
achieved their highest values in segment B (69.8% and 6.59 MUm, respectively).
Wood stiffness also correlated significantly with cell wall lignin content: with
respect to segment B (which had the highest lignin content, and was thus used as
the standard reference for percent lignin content), lignin content, was 15, 60,
85, and 43% in segments E, D, C, and A, respectively. Fiber cell length, which
increased toward the base of the stem and toward the vascular cambium in the most
proximal vascular bundle segment, did not correlate with E(R) or E(T).Basic
engineering principles were used to calculate stem stresses resulting from self
loading and any wind-induced bending moment (produced by drag forces).
Calculations indicated that the less stiff wood produced in segment A eliminates
a rapid and potentially dangerous increase in stresses that would otherwise occur
in segments B or C. The less stiff wood in segment A also reduces the probability
of shear failure at the cellular interface between the wood and surrounding
tissues in this portion of the stem.We conclude that P. pringlei wood stiffness
is dependent on the volume fraction and lignification of axial tissues, less so
on fiber wall thickness, and that wood development in this species is adaptively
responsive to self-loading and differentially applied external mechanical forces.
PMID- 10766719
TI - Phylogeny of the Bangiophycidae (Rhodophyta) and the secondary endosymbiotic
origin of algal plastids.
AB - The Rhodophyta (red algae) are composed of the subclasses Bangiophycidae and
Florideophycidae. Two evolutionarily interesting features of the Bangiophycidae
are: (1) they are the ancestral pool from which the more morphologically complex
taxa in the Florideophycidae have arisen and (2) they are the sources of the
plastids, through secondary endosymbioses, for the Cryptophyta, Haptophyta, and
the Heterokonta. To understand Bangiophycidae phylogeny and to gain further
insights into red algal secondary endosymbioses, we sequenced the plastid-encoded
small subunit ribosomal DNA (rDNA) coding region from nine members of this
subclass and from two members of the Florideophycidae. These sequences were
included in phylogenetic analyses with all available red algal plus chlorophyll a
+ c algal plastid rDNA coding regions. Our results are consistent with a
monophyletic origin of the Florideophycidae with these taxa forming a sister
group of the Bangiales. The Bangiophycidae is of a paraphyletic origin with
orders such as the Porphyridiales polyphyletic and distributed over three
independent red algal lineages. The plastids of the heterokonts are most closely
related to members of the Cyanidium-Galdieria group of Porphyridiales and are not
directly related to cryptophyte and haptophyte plastids. The phylogenies provide
strong evidence for the independent origins of these "complex" algal plastids
from different members of the Bangiophycidae.
PMID- 10766720
TI - Patterns of fruit and seed set within inflorescences of Pancratium maritimum
(Amaryllidaceae): nonuniform pollination, resource limitation, or architectural
effects?
AB - We investigated patterns of fruit and seed production on inflorescences of a
population of Pancratium maritimum in northwest Spain over a 2-yr period. Initial
findings showed that the earliest opening flowers on an inflorescence are more
likely to set fruit and produce more seeds than later opening flowers and that
this pattern is maintained throughout the flowering season. Supplementary
pollination and flower-removal experiments were performed to investigate whether
the observed pattern is attributable (a) to variation in pollen receipt, (b) to
sequestration of resources by the earliest flowers on an inflorescence, and/or
(c) to "architectural" limitations on the fruit/seed production of later flowers.
Supplementary pollination did not improve fruit or seed production by late
flowers in either of the 2 yr of study. In flower-removal experiments, the
remaining flowers showed improved fruit set and mean number of seeds per flower,
by comparison with flowers in the same position on control inflorescences. When
all flowers except the latest third were removed, these showed fruit set and seed
production similar to those of early flowers on control inflorescences. These
results strongly suggest that the observed within-inflorescence patterns of fruit
and seed production in P. maritimum are mainly attributable to competition for
resources (i.e., explanation b), though other adaptive explanations cannot be
ruled out.
PMID- 10766721
TI - The effects of population size limitation on fecundity in mosaic populations of
the clonal macrophyte Scirpus maritimus (Cyperaceae).
AB - The clonal macrophyte Scirpus maritimus (Cyperaceae) propagates locally by
rhizomes and reproduces sexually by achenes. The purpose of this paper was to
examine whether in size-limited habitats in patchy and discrete marshes in two
Mediterranean wetlands in southern France natural populations may suffer from a
reduced maternal fecundity due to a deficit in outcross pollen. We first verified
that S. maritimus suffers from a reduced fecundity when self-pollinated. At a
site in the Camargue, mean fecundity (mean number of achenes per centimetre of
spikelet) measured in 1995 and 1996 in seven and nine populations, respectively
(surface area from 50 to 4500 m) increased significantly with population surface
area in 1995 but not in 1996. In the second wetland at Roquehaute, which is
composed of small ponds, fecundity was very low in all 12 local populations
studied in 1996 (1.1 achenes per spikelet, SD = 1.2) and was not correlated with
the population surface area (from 10 to 400 m). We performed a pollen
supplementation experiment in five local populations at Roquehaute to determine
whether this low fecundity may be due to a pollen limitation. A significant
increase in fecundity after among-pond pollinations compared to within-pond
pollinations indicated that local populations suffer from a deficit in outcross
pollen, since each pond appears to contain one or a few number of clones (or
incompatibility types). In S. maritimus, clonal spread may have a cost in terms
of reduced fecundity in small habitats because each habitat is colonized by very
few clones.
PMID- 10766722
TI - Gender specialization in heterodichogamous Grayia brandegei (Chenopodiaceae):
evidence for an alternative pathway to dioecy.
AB - We examined components of male and female reproductive success in protogynous and
protandrous sexual morphs of the heterodichogamous and largely monoecious
chenopod shrub Grayia brandegei. Percentage femaleness of flowering stalks ranged
from 0 to 37.6% female ( = 15.5%) for protandrous plants and from 14 to 100%
female ( = 55.8%) for protogynous plants. Functional gender estimates based on
ovule production at two locations ranged from 23.0 to 31.8% female for the
protandrous morph, and from 65.3 to 77.0% female for the protogynous morph.
Realized gender estimates based on total seed production ranged in value from 3.6
to 16.8% female for the protandrous morph and from 76.5 to 96.4% for the
protogynous morph, depending on location and year. Differences in reproductive
success of the two morphs were largely due to a reduction in the female function
of protandrous plants. Protogynous plants produced more female flowers per stalk
and had a higher percentage of seed-filled fruits than did protandrous plants.
Differences between sexual morphs were more pronounced in dry areas or years in
which overall seed production was minimal. Differential seed production between
morphs likely reflects temporal patchiness in environmental conditions,
particularly in water availability. The significance of these findings in support
of heterodichogamy as an evolutionary pathway to dioecy is discussed.
PMID- 10766723
TI - Sex expression, skewed sex ratios, and microhabitat distribution in the dioecious
desert moss Syntrichia caninervis (Pottiaceae).
AB - The moss Syntrichia caninervis is the dominant soil bryophyte in a blackbrush
(Coleogyne ramosissima) community in the southern Nevada Mojave Desert, with a
mean cover of 6.3%. A survey of the 10-ha study site revealed an expressed ramet
sex ratio of 14? : 1? (N = 890), with 85% of ramets not expressing sex over their
life span, and an expressed population sex ratio of 40? : 2? : 1?? (female : male
: mixed-sex, N = 89), with 52% of populations not expressing sex. A greater
incidence of sex expression was associated with shaded microsites, higher soil
moisture content, and taller ramets. Shaded microsites had higher surface soil
moisture levels than exposed microsites. In the exposed microhabitat, surface
soil moisture was positively correlated with ramet height but not with sex
expression. Male ramets and populations were restricted to shaded microhabitats,
whereas female ramets and populations were found in both shaded and exposed
microhabitats, suggesting gender specialization. The rarity of mature
sporophytes, found in 0% of the ramets sampled and in only 3% of the populations,
is probably due to the rarity of mixed-sex populations. We hypothesize that mixed
sex populations are rare because of factors relating to male rarity and that the
differential cost of sex expression reduces the clonal growth capacity of male
individuals.
PMID- 10766724
TI - Pollen competition in a natural population of Cucurbita foetidissima
(Cucurbitaceae).
AB - The pollen competition hypothesis predicts that when the number of pollen grains
deposited onto stigmas exceeds the number of ovules, selection can operate in the
time frame between deposition and fertilization. Moreover, because of the overlap
in gene expression between the two phases of the life cycle, selection on
microgametophytes may alter the resulting sporophytic generation. The extent to
which pollen competition occurs in nature has been unclear, because tests of the
predictions of the pollen competition hypothesis have used cultivars and/or
artificial growth conditions and hand-pollination techniques. In this study we
used a wild species, Cucurbita foetidissima, in its natural habitat (southern New
Mexico) to determine the amount and timing of the arrival of pollen onto stigmas,
the relationship between pollen deposition and seed number, and the effects of
the intensity of pollen competition on progeny vigor. We found that ~900 pollen
grains are necessary for full seed set and that a single visit by a pollinator
results in the deposition of 653.0 +/- 101.8 pollen grains. About 29% of the
flowers receiving a single pollinator visit had 900 or more pollen grains on its
stigma. Moreover, within 2 h of anthesis, >4000 pollen grains were deposited onto
a typical stigma, indicating that multiple pollinator visits must have occurred.
Fruits produced by multiple visits had greater seed numbers (206 vs. 147) than
fruits produced by a single visit. Finally, the progeny produced by multiple
pollinator visits were more vigorous than those produced by single visits with
respect to five measures of vegetative growth (MANCOVA, Wilks' lambda = 0.96,
F(6,370) = 2.54, P < 0.02. These data demonstrate that conditions for pollen
competition exist in nature and support the prediction that pollen competition
enhances offspring vigor.
PMID- 10766725
TI - Circumnutation behavior of an exotic honeysuckle vine and its native congener:
influence on clonal mobility.
AB - Virtually all plant parts rotate slightly about a central axis, a movement called
circumnutation, but vines show exaggerated circumnutation. This study contrasts
circumnutation in two congeneric twining vines, specifically focusing on
differences in erect and prostrate shoots, and examines the impact of
circumnutation on exploitation of available climbing supports and exploration for
more distant ones. Elongating shoots of Lonicera japonica and L. sempervirens
growing in a common garden were classed as (1) erect but not climbing, (2)
climbing on a trellis, or (3) prostrate, and their circumnutation quantified by
tracking the compass direction of shoot tips. To quantify the impact of different
circumnutation behaviors, the climbing success of erect shoots and the maximum
dispersion and rooting success of prostrate shoots were measured. Erect shoots of
both species circumnutated at similar rates (averaging 31 degrees /h), and did
not differ in their success rate of exploiting trellises (averaging 76.8%).
Prostrate shoots differed, with those produced by L. japonica having reduced
circumnutation. In contrast, prostrate shoots of L. sempervirens continued to
circumnutate as much as erect shoots. The specialized circumnutation behavior of
the prostrate shoots of L. japonica results in increased rooting success and
maximum dispersion compared to the unspecialized shoots of L. sempervirens.
PMID- 10766726
TI - Carbon and nitrogen allocation to male and female reproduction in Rocky Mountain
Douglas-fir (Pseudotsuga menziesii var. glauca, Pinaceae).
AB - We measured carbon (respiration, photosynthesis, and production) and nitrogen
allocation to male and female cones of Rocky Mountain Douglas-fir (Pseudotsuga
menziesii var. glauca) to quantify gender-specific: (1) resource allocation to
reproduction, and (2) contribution to carbon costs of reproduction via
photosynthesis. We also measured foliar photosynthesis and nitrogen concentration
([N]) near and far from female cones to examine the relationship between
reproduction and foliar physiology. Over one growing season, male cones required
only 8% of all carbon allocated to reproduction, with females consuming the
remaining 92%. Female cones, however, had maximum instantaneous refixation rates
of 54%, which, integrated over the season, offset 6% of their total carbon
requirements, while male cones were completely dependent on vegetative tissues
for carbon. Male cones received 22% of all nitrogen allocated to reproduction and
female cones received the remaining 78%. Foliage near female cones had elevated
photosynthesis during the early stages of cone development and consistently lower
[N] than foliage far from cones. Although female cones may photosynthesize, the
annual sum of carbon fixed by reproductive structures is minor in comparison to
the total carbon allocated to production and respiration.
PMID- 10766727
TI - Systematic affinities of Rhizophoraceae and Anisophylleaceae, and intergeneric
relationships within Rhizophoraceae, based on chloroplast DNA, nuclear ribosomal
DNA, and morphology.
AB - A cladistic analysis of sequences from the chloroplast gene rbcL was used to
determine the systematic affinities of Rhizophoraceae and Anisophylleaceae. This
analysis rejects close relationships of Rhizophoraceae with Celastraceae or
Elaeocarpaceae, suggested previously, and identifies Erythroxylaceae as sister
group within the Malpighiales, supported by several morphological and anatomical
characters. Our molecular results also indicate that Anisophylleaceae are nested
within Cucurbitales. Although this placement is novel, this affinity is also well
supported by shared morphological characters. Tribal and generic relationships
within Rhizophoraceae are evaluated with a combination of six molecular data sets
(rbcL, atpB-rbcL intergenic spacer, trnL-trnF intergenic spacer, ITS1, ITS2, and
5.8S) and a morphological data set. These relationships are compared with results
from previous morphological cladistic analyses. Against the background of the
molecular results, we briefly discuss the evolution of morphological characters
traditionally used for tribal subdivision as well as characters presumably
significant for adaptation to mangrove habitats, namely, aerial stilt roots and
vivipary.
PMID- 10766728
TI - Phylogenetic analysis of Silphium and subtribe Engelmanniinae (Asteraceae:
Heliantheae) based on ITS and ETS sequence data.
AB - The phylogenetic relationships of Silphium and subtribe Engelmanniinae were
examined using DNA sequence data. The internal transcribed spacer (ITS) region
and the external transcribed spacer (ETS) region were sequenced for 39 specimens
representing the six genera of subtribe Engelmanniinae (Berlandiera, Chrysogonum,
Dugesia, Engelmannia, Lindheimera, and Silphium), plus five additional genera
identified as closely related to the Engelmanniinae by chloroplast DNA
restriction site analysis, and three outgroups. Phylogenetic analysis supported
the monophyly of Silphium with Lindheimera as sister. Silphium can be divided
into two sections based upon two well-supported clades that correspond to root
type and growth form. These results also supported the expansion of subtribe
Engelmanniinae to include Balsamorhiza, Borrichia, Rojasianthe, Vigethia, and
Wyethia. We hypothesize that subtribe Engelmanniinae originated in Mesoamerica
and later radiated to the United States. We suggest that the cypsela complex,
which is present in Berlandiera, Chrysogonum, Engelmannia, and Lindheimera, arose
only once and was subsequently lost in Silphium.
PMID- 10766729
TI - Intra- and interspecific phylogeny of wild Fagopyrum (Polygonaceae) species based
on nucleotide sequences of noncoding regions in chloroplast DNA.
AB - The intra- and interspecific phylogeny of Fagopyrum (Polygonaceae) species was
studied using nucleotide sequence data from two noncoding regions in chloroplast
DNA, the trnK (UUU) intron and the trnC (GCA)-rpoB spacer. Thirty-seven
accessions of ten species and two unidentified samples in the urophyllum group of
Fagopyrum were analyzed. Both of the studied regions showed high variability,
including nucleotide substitutions, insertion/deletions, and inversions. Separate
parsimony analyses of the two regions generated phylogenies that were largely
consistent with each other. A single most parsimonious tree derived from the
combined data of the two regions suggested that (1) either F. statice or F.
leptopodum was derived from the ancestor more than once, (2) F. gracilipes, a
tetraploid species, has recently been derived from diploid ancestor and rapidly
spread out to its present distribution areas, and (3) F. pleioramosum, F.
macrocarpum, and F. callianthum, three newly discovered species endemic to the
upper Min River valley, differentiated from their common ancestral species in the
present distribution area.
PMID- 10766730
TI - Understanding population history for conservation purposes: population genetics
of Saxifraga aizoides (Saxifragaceae) in the lowlands and lower mountains north
of the Alps.
AB - Several alpine species have outlying populations in the lowlands and lower
mountains north of the Alps. These small, isolated populations are usually
described as either (1) glacial relics, (2) descendants from populations living
on forelands and moraines during the ice ages, or (3) populations founded by long
distance dispersal after glaciation. A floristic survey of the historic and
present distributions and an allozyme investigation were performed on one of
these relic species, Saxifraga aizoides. The species was historically more
abundant and had more stations in more regions of northeastern Switzerland. The
former population structures within regions, nowadays destroyed, were still
reflected in distinct and high regional genetic diversity and variation. There
was weak evidence of increased inbreeding in outlying populations, but
populations did not deviate from Hardy-Weinberg equilibrium. No geographic
pattern of genetic variation above the regional scale (>10 km) was found. Based
on the spatial and genetic structures found, it was not possible to discriminate
between the abovementioned hypotheses. Nevertheless, the study shows how a
thorough evaluation of distribution and abundance data aids the interpretation of
genetic data with respect to population history, biogeography, and conservation
biology.
PMID- 10766731
TI - RAPD marker diversity within and divergence among species of Dendroseris
(Asteraceae: Lactuceae).
AB - Random Amplified Polymorphic DNA (RAPD) markers were used to measure genetic
diversity within and divergence among species of Dendroseris (Asteraceae:
Lactuceae), a genus endemic to the Juan Fernandez Islands, Chile. Results were
compared to previous studies employing allozymes. For five of the species, RAPD
banding patterns distinguished all individuals examined, and different mutilocus
genotypes were found even in species exhibiting no allozyme diversity. RAPD band
diversities ranged from 0.003 to 0.022 within species; >90% of total diversity
was among species and <10% within them. Relative levels of allozyme and RAPD
diversity were similar for some species, particularly those with highest and
lowest diversities, but overall there was no significant correlation.
Relationships inferred from a neighbor-joining tree generated from RAPD bands
were similar to results obtained from morphology, chloroplast DNA (cpDNA)
restriction site mutations, and sequences from the internal transcribed spacer
regions of nuclear ribosomal DNA (ITS), but somewhat better resolution was
achieved. Relationships shown by allozymes differed from trees based on other
data; this ostensibly is a result of the sharing of ancestral alleles and the
absence of alleles generated subsequent to speciation. Dendroseris represents an
example where RAPD markers, because of their greater variability, provide a
useful alternative to allozymes for assessing diversity in rare species endemic
to oceanic islands and for resolving relationships among the species.
PMID- 10766732
TI - Zebrafish mutations and functional analysis of the vertebrate genome.
PMID- 10766733
TI - Conserved and divergent mechanisms in left-right axis formation.
PMID- 10766734
TI - Ro ribonucleoproteins contribute to the resistance of Deinococcus radiodurans to
ultraviolet irradiation.
AB - The genome of the radiation-resistant eubacterium Deinococcus radiodurans
contains an ortholog of an RNA-binding protein known as the Ro 60-kD autoantigen.
This protein, which was previously identified only in higher eukaryotes, is
normally bound to small RNAs known as Y RNAs. We show that the Ro protein
ortholog Rsr contributes to the resistance of D. radiodurans to UV irradiation.
Rsr binds several small RNAs, encoded upstream of rsr, that accumulate following
UV irradiation. One of these RNAs resembles a Y RNA. These results suggest that
Ro RNPs could similarly contribute to the recovery of higher cells following UV
irradiation.
PMID- 10766735
TI - Distinct protein interaction domains and protein spreading in a complex
centromere.
AB - Fission yeast (Schizosaccharomyces pombe) centromeres are composed of large (40
100 kb) inverted repeats that display heterochromatic features, thus providing a
good model for higher eukaryotic centromeres. The association of three proteins
that mediate region-specific silencing across centromere 1 has been mapped by
quantitative chromatin immunoprecipitation. Swi6 and Chp1 are confined to the
flanking outer repeats and Swi6 can spread across at least 3 kb of extraneous
chromatin in cen1. In contrast, Mis6 coats the inner repeats and central core.
tRNA genes demarcate this transition zone. These analyses clearly define two
distinct domains within this complex centromere which interact with different
proteins.
PMID- 10766736
TI - P-TEFb kinase recruitment and function at heat shock loci.
AB - P-TEFb, a heterodimer of the kinase Cdk9 and cyclin T, was isolated as a factor
that stimulates formation of productive transcription elongation complexes in
vitro. Here, we show that P-TEFb is located at >200 distinct sites on Drosophila
polytene chromosomes. Upon heat shock, P-TEFb, like the regulatory factor HSF, is
rapidly recruited to heat shock loci, and this recruitment is blocked in an HSF
mutant. Yet, HSF binding to DNA is not sufficient to recruit P-TEFb in vivo, and
HSF and P-TEFb immunostainings within a heat shock locus are not coincident.
Insight to the function of P-TEFb is offered by experiments showing that the
direct recruitment of a Gal4-binding domain P-TEFb hybrid to an hsp70 promoter in
Drosophila cells is sufficient to activate transcription in the absence of heat
shock. Analyses of point mutants show this P-TEFb stimulation is dependent on
Cdk9 kinase activity and on Cdk9's interaction with cyclin T. These results,
coupled with the frequent colocalization of P-TEFb and the hypophosphorylated
form of RNA polymerase II (Pol II) found at promoter-pause sites, support a model
in which P-TEFb acts to stimulate promoter-paused Pol II to enter into productive
elongation.
PMID- 10766737
TI - Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F
proteins mediate activation and repression.
AB - The E2F transcription factor plays a pivotal role in the timely activation of
gene expression during mammalian cell cycle progression, whereas pRB and related
proteins control cell growth in part through the ability to block the action of
E2F. To identify physiologically important E2F-responsive promoters and to study
their occupancy and histone acetylation state in vivo, we have taken advantage of
a cross-linking approach in synchronized, living cells. We find that the pattern
of E2F and pRB-related polypeptides recruited to these promoters changes in a
strikingly dynamic fashion as cells progress from quiescence into G(1) and S
phase: Repression of each promoter in quiescent cells is associated with
recruitment of E2F-4 and p130 and low levels of histone acetylation, but by late
G(1), these proteins are replaced largely by E2F-1 and E2F-3, in concert with
acetylation of histones H3 and H4 and gene activation. These findings suggest
that repression and activation of E2F-responsive genes may occur through distinct
E2F heterodimers that direct the sequential recruitment of enzymes able to
deacetylate and then acetylate core histones.
PMID- 10766738
TI - Ribosome shunting in the cauliflower mosaic virus 35S RNA leader is a special
case of reinitiation of translation functioning in plant and animal systems.
AB - The shunt model predicts that small ORFs (sORFs) within the cauliflower mosaic
virus (CaMV) 35S RNA leader and downstream ORF VII are translated by different
mechanisms, that is, scanning-reinitiation and shunting, respectively. Wheat germ
extract (WGE) and rabbit reticulocyte lysate (RRL) in vitro translation systems
were used to discriminate between these two processes and to study the mechanism
of ribosomal shunt. In both systems, expression downstream of the leader occurred
via ribosomal shunt under the control of a stable stem and a small ORF preceding
it. Shunting ribosomes were also able to initiate quite efficiently at non-AUG
start codons just downstream of the shunt landing site in WGE but not in RRL. The
short sORF MAGDIS from the mammalian AdoMetDC RNA, which conditionally suppresses
reinitiation at a downstream ORF, prevented shunting if placed at the position of
sORF A, the 5'-proximal ORF of the CaMV leader. We have demonstrated directly
that sORF A is translated and that proper termination of translation at the 5'
proximal ORF is absolutely required for both shunting and linear ribosome
migration. These findings strongly indicate that shunting is a special case of
reinitiation.
PMID- 10766739
TI - An aminoacylation-dependent nuclear tRNA export pathway in yeast.
AB - Yeast Los1p, the homolog of human exportin-t, mediates nuclear export of tRNA.
Using fluorescence in situ hybridization, we could show that the export of some
intronless tRNA species is not detectably affected by the disruption of LOS1. To
find other factors that facilitate tRNA export, we performed a suppressor screen
of a synthetically lethal los1 mutant and identified the essential translation
elongation factor eEF-1A. Mutations in eEF-1A impaired nuclear export of all
tRNAs tested, which included both spliced and intronless species. An even
stronger defect in nuclear exit of tRNA was observed under conditions that
inhibited tRNA aminoacylation. In all cases, inhibition of tRNA export led to
nucleolar accumulation of mature tRNAs. Our data show that tRNA aminoacylation
and eEF-1A are required for efficient nuclear tRNA export in yeast and suggest
coordination between the protein translation and the nuclear tRNA processing and
transport machineries.
PMID- 10766740
TI - The mouse homolog of Drosophila Vasa is required for the development of male germ
cells.
AB - Restricted expression of a mouse Vasa homolog gene (Mvh) expression is first
detected in primordial germ cells (PGCs) after colonization of the genital
ridges. Subsequently, Mvh is maintained until postmeiotic germ cells are formed.
Here, we demonstrate that male mice homozygous for a targeted mutation of Mvh
exhibit a reproductive deficiency. Male homozygotes produce no sperm in the
testes, where premeiotic germ cells cease differentiation by the zygotene stage
and undergo apoptotic death. In addition, the proliferation of PGCs that colonize
homozygous male gonads is significantly hampered, and OCT-3/4 expression appears
to be reduced. These results indicate that the loss of Mvh function causes a
deficiency in the proliferation and differentiation of mouse male germ cells.
PMID- 10766741
TI - Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma
deficient mice.
AB - Phosphorylation of IkappaB, an inhibitor of NF-kappaB, is an important step in
the activation of the transcription factor NF-kappaB. Phosphorylation is mediated
by the IkappaB kinase (IKK) complex, known to contain two catalytic subunits:
IKKalpha and IKKbeta. A novel, noncatalytic component of this kinase complex
called NEMO (NF-kappaB essential modulator)/IKKgamma was identified recently. We
have generated NEMO/IKKgamma-deficient mice by gene targeting. Mutant embryos die
at E12.5-E13.0 from severe liver damage due to apoptosis. NEMO/IKKgamma-deficient
primary murine embryonic fibroblasts (MEFs) lack detectable NF-kappaB DNA-binding
activity in response to TNFalpha, IL-1, LPS, and Poly(IC) and do not show
stimulus-dependent IkappaB kinase activity, which correlates with a lack of
phosphorylation and degradation of IkappaBalpha. Consistent with these data,
mutant MEFs show increased sensitivity to TNFalpha-induced apoptosis. Our data
provide in vivo evidence that NEMO/IKKgamma is the first essential, noncatalytic
component of the IKK complex.
PMID- 10766742
TI - The Drosophila HEM-2/NAP1 homolog KETTE controls axonal pathfinding and
cytoskeletal organization.
AB - In Drosophila, the correct formation of the segmental commissures depends on
neuron-glial interactions at the midline. The VUM midline neurons extend axons
along which glial cells migrate in between anterior and posterior commissures.
Here, we show that the gene kette is required for the normal projection of the
VUM axons and subsequently disrupts glial migration. Axonal projection defects
are also found for many other moto- and interneurons. In addition, kette affects
the cell morphology of mesodermal and epidermal derivatives, which show an
abnormal actin cytoskeleton. The KETTE protein is homologous to the transmembrane
protein HEM-2/NAP1 evolutionary conserved from worms to vertebrates. In vitro
analysis has shown a specific interaction of the vertebrate HEM-2/NAP1 with the
SH2-SH3 adapter protein NCK and the small GTPase RAC1, which both have been
implicated in regulating cytoskeleton organization and axonal growth. Hypomorphic
kette mutations lead to axonal defects similar to mutations in the Drosophila NCK
homolog dreadlocks. Furthermore, we show that kette and dock mutants genetically
interact. NCK is thought to interact with the small G proteins RAC1 and CDC42,
which play a role in axonal growth. In line with these observations, a kette
phenocopy can be obtained following directed expression of mutant DCDC42 or DRAC1
in the CNS midline. In addition, the kette mutant phenotype can be partially
rescued by expression of an activated DRAC1 transgene. Our data suggest an
important role of the HEM-2 protein in cytoskeletal organization during axonal
pathfinding.
PMID- 10766744
TI - Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3
and -5 markedly reduce IGF-I binding and alter their biologic actions.
AB - Insulin-like growth factor-binding protein-3 and -5 (IGFBP-3 and -5) have been
shown to bind insulin-like growth factor-I and -II (IGF-I and -II) with high
affinity. Previous studies have proposed that the N-terminal region of IGFBP-5
contains a hydrophobic patch between residues 49 and 74 that is required for high
affinity binding. These studies were undertaken to determine if mutagenesis of
several of these residues resulted in a reduction of the affinity of IGFBP-3 and
5 for IGF-I. Substitutions for residues 68, 69, 70, 73, and 74 in IGFBP-5
(changing one charged residue, Lys(68), to a neutral one and the four hydrophobic
residues to nonhydrophobic residues) resulted in an approximately 1000-fold
reduction in the affinity of IGFBP-5 for IGF-I. Substitutions for homologous
residues in IGFBP-3 also resulted in a >1000-fold reduction in affinity. The
physiologic consequence of this reduction was that IGFBP-3 and -5 became very
weak inhibitors of IGF-I-stimulated cell migration and DNA synthesis. Likewise,
the ability of IGFBP-5 to inhibit IGF-I-stimulated receptor phosphorylation was
attenuated. These changes did not appear to be because of alterations in protein
folding induced by mutagenesis, because the IGFBP-5 mutant was fully susceptible
to proteolytic cleavage by a specific IGFBP-5 protease. In summary, residues 68,
69, 70, 73, and 74 in IGFBP-5 appear to be critical for high affinity binding to
IGF-I. Homologous residues in IGFBP-3 are also required, suggesting that they
form a similar binding pocket and that for both proteins these residues form an
important component of the core binding site. The availability of these mutants
will make it possible to determine if there are direct, non-IGF-I-dependent
effects of IGFBP-3 and -5 on cellular physiologic processes in cell types that
secrete IGF-I.
PMID- 10766743
TI - The Caenorhabditis elegans APC-related gene apr-1 is required for epithelial cell
migration and Hox gene expression.
AB - Inactivation of the Caenorhabditis elegans APC-related gene (apr-1) has pointed
at two separate functions of apr-1. First, apr-1 is required for the migration of
epithelial cells during morphogenesis of the embryo. In this process, APR-1 may
act in a Cadherin/alpha-Catenin/beta-Catenin complex as a component of adherens
junctions. Second, apr-1 is required for Hox gene expression, most likely by
positively regulating the activity of the Wingless signaling pathway. During
embryogenesis, apr-1 is required for the expression of ceh-13 labial in anterior
seam and muscle cells and during larval development, apr-1 is necessary for the
expression of lin-39 deformed in the vulval precursor cells. Thus, APR-1 may
positively regulate the activity of the beta-Catenin/Armadillo-related proteins
HMP-2 in migrating epithelial cells and BAR-1 in the vulval precursor cells.
PMID- 10766745
TI - Ikaros interactions with CtBP reveal a repression mechanism that is independent
of histone deacetylase activity.
AB - We have previously shown that Ikaros can repress transcription through the
recruitment of histone deacetylase complexes. Here we provide evidence that
Ikaros can also repress transcription through its interactions with the co
repressor, C-terminal binding protein (CtBP). CtBP interacts with Ikaros isoforms
through a PEDLS motif present at the N terminus of these proteins but not with
homologues like Aiolos which lack this motif. Mutations in Ikaros that prevent
CtBP interactions reduce its ability to repress transcription. CtBP interacts
with Sin3A but not with the Mi-2 co-repressor and it represses transcription in a
manner that is independent of histone deacetylase activity. These data strongly
suggest that CtBP contributes to a histone deacetylase activity independent
mechanism of repression by Ikaros. Finally, we show that the viral oncoprotein
E1A, which binds to CtBP, also shows a strong association with Ikaros. This
Ikaros-E1A interaction may underlie Ikaros's decreased ability to repress
transcription in E1A transformed cells.
PMID- 10766746
TI - The AhpC and AhpD antioxidant defense system of Mycobacterium tuberculosis.
AB - The peroxiredoxin AhpC from Mycobacterium tuberculosis has been expressed,
purified, and characterized. It differs from other well characterized AhpC
proteins in that it has three rather than one or two cysteine residues.
Mutagenesis studies show that all three cysteine residues are important for
catalytic activity. Analysis of the M. tuberculosis genome identified a second
protein, AhpD, which has no sequence identity with AhpC but is under the control
of the same promoter. This protein has also been cloned, expressed, purified, and
characterized. AhpD, which has only been identified in the genomes of
mycobacteria and Streptomyces viridosporus, is shown here to also be an
alkylhydroperoxidase. The endogenous electron donor for catalytic turnover of the
two proteins is not known, but both can be turned over with AhpF from Salmonella
typhimurium or, particularly in the case of AhpC, with dithiothreitol. AhpC and
AhpD reduce alkylhydroperoxides more effectively than H(2)O(2) but do not appear
to interact with each other. These two proteins appear to be critical elements of
the antioxidant defense system of M. tuberculosis and may be suitable targets for
the development of novel anti-tuberculosis strategies.
PMID- 10766747
TI - The GAG-like protein of the yeast Ty1 retrotransposon contains a nucleic acid
chaperone domain analogous to retroviral nucleocapsid proteins.
AB - The reverse transcription process for retroviruses and retrotransposons takes
place in a nucleocore structure in the virus or virus-like particle. In
retroviruses the major protein of the nucleocore is the nucleocapsid protein (NC
protein), which derives from the C-terminal region of GAG. Retroviral NC proteins
are formed of either one or two CCHC zinc finger(s) flanked by basic residues and
have nucleic acid chaperone and match-maker properties essential for virus
replication. Interestingly, the GAG protein of a number of retroelements
including Spumaviruses does not possess the hallmarks of retroviral GAGs and in
particular lacks a canonical NC protein. In an attempt to search for a nucleic
acid chaperone activity in this class of retroelements we used the yeast Ty1
retrotransposon as a model system. Results shows that the C-terminal region of
Ty1 GAG contains a nucleic acid chaperone domain capable of promoting the
annealing of primer tRNA(i)(Met) to the multipartite primer binding site, Ty1 RNA
dimerization and initiation of reverse transcription. Moreover Ty1 RNA
dimerization, in a manner similar to Ty3 but unlike retroviral RNAs, appears to
be mediated by tRNA(i)(Met). These findings suggest that nucleic acid chaperone
proteins probably are general co-factors for reverse transcriptases.
PMID- 10766748
TI - X-ray scattering studies of Methylophilus methylotrophus (sp. W3A1) electron
transferring flavoprotein. Evidence for multiple conformational states and an
induced fit mechanism for assembly with trimethylamine dehydrogenase.
AB - Small angle x-ray solution scattering has been used to generate a low resolution,
model-independent molecular envelope structure for electron-transferring
flavoprotein (ETF) from Methylophilus methylotrophus (sp. W(3)A(1)). Analysis of
both the oxidized and 1-electron-reduced (anionic flavin semiquinone) forms of
the protein revealed that the solution structures of the protein are similar in
both oxidation states. Comparison of the molecular envelope of ETF from the x-ray
scattering data with previously determined structural models of the protein
suggests that ETF samples a range of conformations in solution. These
conformations correspond to a rotation of domain II with respect to domains I and
III about two flexible "hinge" sequences that are unique to M. methylotrophus
ETF. The x-ray scattering data are consistent with previous models concerning the
interaction of M. methylotrophus ETF with its physiological redox partner,
trimethylamine dehydrogenase. Our data reveal that an "induced fit" mechanism
accounts for the assembly of the trimethylamine dehydrogenase-ETF electron
transfer complex, consistent with spectroscopic and modeling studies of the
assembly process.
PMID- 10766749
TI - Mimosine is a cell-specific antagonist of folate metabolism.
AB - Iron deficiency and iron chelators are known to alter folate metabolism in
mammals, but the underlying biochemical mechanisms have not been established.
Although many studies have demonstrated that the iron chelators mimosine and
deferoxamine inhibit DNA replication in mammalian cells, their mechanism of
action remains controversial. The effects of mimosine on folate metabolism were
investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings
indicate that mimosine is a folate antagonist and that its effects are cell
specific. MCF-7 cells cultured in the presence of 350 microm mimosine were growth
arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine
altered the distribution of folate cofactor forms in MCF-7 cells, indicating that
mimosine targets folate metabolism. However, mimosine does not influence folate
metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism
is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT)
expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to
mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter
activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited
by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT
transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines
demonstrate that although the effect of mimosine on cell cycle is independent of
its effects on cSHMT expression, it inhibits both processes through a common
regulatory mechanism.
PMID- 10766750
TI - Nonaromatic products from anoxic conversion of benzoyl-CoA with benzoyl-CoA
reductase and cyclohexa-1,5-diene-1-carbonyl-CoA hydratase.
AB - The enzymes benzoyl-CoA reductase and cyclohex-1, 5-diene-1-carbonyl-CoA
hydratase catalyzing the first steps of benzoyl-CoA conversion under anoxic
conditions were purified from the denitrifying bacterium, Thauera aromatica.
Reaction products obtained with [ring-(13)C(6)]benzoyl-CoA and [ring
(14)C]benzoyl-CoA as substrates were analyzed by high pressure liquid
chromatography and by NMR spectroscopy. The main product obtained with
titanium(III) citrate or with reduced [8Fe-8S]-ferredoxin from T. aromatica as
electron donors was identified as cyclohexa-1, 5-diene-1-carbonyl-CoA. The cyclic
diene was converted into 6-hydroxycyclohex-1-ene-1-carbonyl-CoA by the hydratase.
Assay mixtures containing reductase, hydratase, and sodium dithionite or a
mixture of sulfite and titanium(III) citrate as reducing agent afforded cyclohex
2-ene-1-carbonyl-CoA and 6-hydroxycylohex-2-ene-1-carbonyl-CoA. The potential
required for the first electron transfer to the model compound S-ethyl
thiobenzoate yielding a radical anion was determined by cyclic voltammetry as
1.9 V versus a standard hydrogen electrode. The energetics of enzymatic ring
reduction of benzoyl-CoA are discussed.
PMID- 10766751
TI - Methylation-dependent silencing of the testis-specific Pdha-2 basal promoter
occurs through selective targeting of an activating transcription factor/cAMP
responsive element-binding site.
AB - In this study, we demonstrate that methylation-dependent repression of the Pdha-2
core promoter is mediated regionally through a consensus activating transcription
factor/cAMP-responsive element-binding site located between nucleotides -54 and
62 upstream of the major transcriptional start site. Targeting of the CpG
dinucleotide within this cis-element significantly disrupts the ability of this
basal promoter to activate gene expression in vitro and completely abolishes
promoter activity in vivo. DNase I footprinting experiments indicated that
availability of the nuclear factor(s) binding this element is limiting in
sexually immature mouse testis, and as such, these factors may play an important
role in the coordinate activation of early spermatogenic gene expression.
Interestingly, CpG dinucleotides associated with the hypersensitive region
flanking the activating transcription factor/cAMP-responsive element-binding site
appear to confer some conformational structure on the promoter since mutations at
these specific CpG dinucleotides result in elevated basal levels of
transcription. This raises the possibility of a potential bifunctional role for
CpG dinucleotides in either methylation-dependent or -independent processes. Our
data support the notion that hypomethylation and transcription factor recruitment
are necessary events that precede gene activation at the early stages of
spermatogenesis.
PMID- 10766752
TI - Distinct antitumor properties of a type IV collagen domain derived from basement
membrane.
AB - Vascular basement membrane is an important structural component of blood vessels.
During angiogenesis this membrane undergoes many alterations and these changes
are speculated to influence the formation of new capillaries. Type IV collagen is
a major component of vascular basement membrane, and recently we identified a
fragment of type IV collagen alpha2 chain with specific anti-angiogenic
properties (Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H.,
Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., and
Kalluri, R. (2000) J. Biol. Chem. 275, 1209-1215). In the present study we
characterize two different antitumor activities associated with the
noncollagenous 1 (NC1) domain of the alpha3 chain of type IV collagen. This
domain was previously discovered to possess a C-terminal peptide sequence (amino
acids 185-203) that inhibits melanoma cell proliferation (Han, J., Ohno, N.,
Pasco, S., Monboisse, J. C., Borel, J. P., and Kefalides, N. A. (1997) J. Biol.
Chem. 272, 20395-20401). In the present study, we identify the anti-angiogenic
capacity of this domain using several in vitro and in vivo assays. The
alpha3(IV)NC1 inhibited in vivo neovascularization in matrigel plug assays and
suppressed tumor growth of human renal cell carcinoma (786-O) and prostate
carcinoma (PC-3) in mouse xenograft models associated with in vivo endothelial
cell-specific apoptosis. The anti-angiogenic activity was localized to amino
acids 54-132 using deletion mutagenesis. This anti-angiogenic region is separate
from the 185-203 amino acid region responsible for the antitumor cell activity.
Additionally, our experiments indicate that the antitumor cell activity is not
realized until the peptide region is exposed by truncation of the alpha3(IV)NC1
domain, a requirement not essential for the anti-angiogenic activity of this
domain. Collectively, these results effectively highlight the distinct and unique
antitumor properties of the alpha3(IV)NC1 domain and the potential use of this
molecule for inhibition of tumor growth.
PMID- 10766753
TI - Butadiene-induced intrastrand DNA cross-links: a possible role in deletion
mutagenesis.
AB - To initiate studies designed to identify the mutagenic spectrum associated with
butadiene diepoxide-induced N(2)-N(2) guanine intrastrand cross-links, site
specifically adducted oligodeoxynucleotides were synthesized in which the
adducted bases were centrally located within the context of the human ras 12
codon. The two stereospecifically modified DNAs and the corresponding unmodified
DNA were ligated into a single-stranded M13mp7L2 vector and transfected into
Escherichia coli. Both stereoisomeric forms (R, R and S,S) of the DNA cross-links
resulted in very severely decreased plaque-forming ability, along with an
increased mutagenic frequency for both single base substitutions and deletions
compared with unadducted DNAs, with the S,S stereoisomer being the most
mutagenic. Consistent with decreased plaque formation, in vitro replication of
DNA templates containing the cross-links by the three major E. coli polymerases
revealed replication blockage by both stereoisomeric forms of the cross-links.
The same DNAs that were used for replication studies were also assembled into
duplex DNAs and tested as substrates for the initiation of nucleotide excision
repair by the E. coli UvrABC complex. UvrABC incised linear substrates containing
these intrastrand cross-links with low efficiency, suggesting that these lesions
may be inefficiently repaired by the nucleotide excision repair system.
PMID- 10766754
TI - Use of six chimeric proteins to investigate the role of intramolecular
interactions in determining the kinetics of carnitine palmitoyltransferase I
isoforms.
AB - The two isoforms of carnitine palmitoyltransferase I (CPT I; muscle (M)- and
liver (L)-type) of the mitochondrial outer membrane have distinct kinetic
characteristics with respect to their affinity for one of the substrates (l
carnitine) and the inhibitor malonyl-CoA. Moreover, they differ markedly in their
hysteretic behavior with respect to malonyl-CoA and in their response to changes
in the in vivo metabolic state. However, the two proteins are 62% identical and
have the same overall structure. Using liver mitochondria, we have previously
shown that the protein is polytopic within the outer membrane, comprising a 46
residue cytosolic N-terminal sequence, two transmembrane segments (TM1 and TM2)
separated by a 27-residue loop, and a large catalytic domain (also cytosolic)
(Fraser, F., Corstorphine, C. G., and Zammit, V. A. (1997) Biochem. J. 323, 711
718). We have now conducted a systematic study on six chimeric proteins
constructed from combinations of three linear segments of rat L- and M-CPT I and
on the two parental proteins to elucidate the effects of altered intramolecular
interactions on the kinetics of CPT activity. The three segments were (i) the
cytosolic N-terminal domain plus TM1, (ii) the loop plus TM2, and (iii) the
cytosolic catalytic C-terminal domain. The kinetic properties of the chimeric
proteins expressed in Pichia pastoris were studied. We found that alterations in
the combinations of the N-terminal plus TM1 and C-terminal domains as well as in
the N terminus plus TM1/TM2 pairings resulted in changes in the K(m) values for
carnitine and palmitoyl-CoA and the sensitivity to malonyl-CoA of the L-type
catalytic domain. The changes in affinity for malonyl-CoA and palmitoyl-CoA
occurred independently of changes in the affinity for carnitine. The kinetic
characteristics of the M-type catalytic domain and, in particular, its malonyl
CoA sensitivity were much less susceptible to influence by exchange of the other
two segments of the protein. The marked difference in the response of the two
catalytic domains to changes in the N-terminal domain and TM combinations
explains the previously observed differences in the response of L- and M-CPT I to
altered physiological state in intact mitochondria and to modulation of altered
lipid molecular order of the mitochondrial outer membrane in vivo and in vitro.
PMID- 10766755
TI - Structural requirements for N-trimethylation of lysine 115 of calmodulin.
AB - Calmodulin is trimethylated at lysine 115 by a highly specific methyltransferase
that utilizes S-adenosylmethionine as a co-substrate. Lysine 115 is found within
a highly conserved six-amino acid loop (LGEKLT) that forms a 90 degrees turn
between EF-hand III and EF-hand IV in the carboxyl-terminal lobe. In the present
work a mutagenesis approach was used to investigate the structural features of
the carboxyl-terminal lobe that lead to the specificity of calmodulin
methylation. Three structural regions within the carboxyl-terminal lobe appear to
be involved in methyltransferase recognition: the highly conserved six-amino acid
loop-turn region that contains lysine 115 as well as the adjacent alpha-helices
(helix 6 and helix 7) from EF-hands III and IV. Site-directed mutagenesis of
residues in the loop show that three residues, glycine 113, glutamate 114, and
leucine 116 are essential for methylation. In addition, subdomain (individual
helix or Ca(2+) binding loop) exchange mutants show that the substitutions of
either helix 6 (EF-hand III) with helix 2 (EF-hand I) or helix 7 (EF-hand IV)
with helix 3 (EF-hand II) compromises methylation. Charge-to-alanine mutations in
helix 7 show that substitution of conserved charged residues at positions 118,
120, 122, 126, and 127 reduced lysine 115 methylation rates, suggesting possible
electrostatic interactions between this helix and the methyltransferase. Single
substitutions in helix 6 did not affect calmodulin methylation, suggesting this
region may play a more indirect role in stabilizing the conformation of the
methyltransferase recognition sequence.
PMID- 10766756
TI - Phosphorylation of Bcl-2 protein by CDC2 kinase during G2/M phases and its role
in cell cycle regulation.
AB - Although it has been reported that Bcl-2 phosphorylation is associated with
certain types of apoptosis, there is much controversy over the functional
significance of and the kinases responsible for the phosphorylation. In this
study, we examined whether Bcl-2 is phosphorylated by CDC2 kinase, a master
regulator of G(2)/M transition in the eukaryotic cell cycle. When CDC2 was
activated by okadaic acid in HL-60 cells, Bcl-2 phosphorylation was readily
induced. The phosphorylation was correlated with the accumulation of cells in
G(2)/M phases, but was not proportional to the level of apoptosis. Furthermore,
we found that Bcl-2 was phosphorylated during G(2)/M phases of normal cell cycle.
The ability of CDC2 to phosphorylate Bcl-2 was confirmed by in vitro kinase assay
with a highly purified CDC2-cyclin B complex. Using synthetic peptides and mutant
cell lines, we identified threonine 56, one of two consensus sites for CDC2
within the Bcl-2 sequence, as a residue phosphorylated by CDC2. Mutation at
threonine 56 abrogated the cell cycle inhibitory effect of Bcl-2 without
affecting anti-apoptotic function. These results suggest that two distinct
functions of Bcl-2 (anti-apoptosis and cell cycle inhibition) are differentially
regulated by post-translational mechanisms such as phosphorylation. CDC2-mediated
phosphorylation of Bcl-2 may play some physiological roles in the negative
regulatory events during mitosis.
PMID- 10766757
TI - Tyrosine phosphorylation of HoxA10 decreases DNA binding and transcriptional
repression during interferon gamma -induced differentiation of myeloid leukemia
cell lines.
AB - The DNA binding affinity of HoxA10 is increased by partnering with Pbx proteins.
A consensus sequence for Pbx1-HoxA10 DNA binding has been derived, but genuine
target genes have not been identified. We noted that the derived Pbx-HoxA10 DNA
binding consensus is similar to a repressor element in the CYBB promoter. The
CYBB gene, which encodes the respiratory burst oxidase component gp91(phox), is
expressed only in myeloid cells that have differentiated beyond the promyelocyte
stage. In these studies, we demonstrate that interferon gamma (IFN-gamma)-induced
differentiation of myeloid cell lines abolishes in vitro Pbx-HoxA10 binding to
either the derived consensus or the similar CYBB sequence. We also demonstrate
that HoxA10, overexpressed in myeloid cell lines, represses reporter gene
expression from artificial promoter constructs with Pbx-HoxA10 binding sites. We
determine that HoxA10 has endogenous repression domains that are not functionally
altered by IFN-gamma treatment. However, IFN-gamma-induced differentiation of
myeloid cell lines leads to HoxA10 tyrosine phosphorylation, which decreases in
vitro DNA binding to Pbx-HoxA10 binding sites. Therefore, these investigations
identify the CYBB gene as a potential target for HoxA10 and define repression of
genes expressed in mature myeloid cells as a novel role for HoxA10 during myeloid
differentiation.
PMID- 10766758
TI - Molecular mechanism of calcium channel block by isradipine. Role of a drug
induced inactivated channel conformation.
AB - The role of the inactivated channel conformation in the molecular mechanism of
Ca(2+) channel block by the 1,4-dihydropyridine (DHP) (+)-isradipine was analyzed
in L-type channel constructs (alpha(1Lc); Berjukow, S., Gapp, F., Aczel, S.,
Sinnegger, M. J., Mitterdorfer, J., Glossmann, H., and Hering, S. (1999) J. Biol.
Chem. 274, 6154-6160) and a DHP-sensitive class A Ca(2+) channel mutant (alpha(1A
DHP); Sinnegger, M. J., Wang, Z., Grabner, M., Hering, S., Striessnig, J.,
Glossmann, H., and Mitterdorfer, J. (1997) J. Biol. Chem. 272, 27686-27693)
carrying the high affinity determinants of the DHP receptor site but inactivating
at different rates. Ca(2+) channel inactivation was modulated by coexpressing the
alpha(1A-DHP)- or alpha(1Lc)-subunits in Xenopus oocytes with either the beta(2a)
or the beta(1a)-subunit and amino acid substitutions in L-type segment IVS6
(I1497A, I1498A, and V1504A). Contrary to a modulated receptor mechanism assuming
high affinity DHP binding to the inactivated state we observed no clear
correlation between steady state inactivation and Ca(2+) channel block by (+)
isradipine: (i) a 3-fold larger fraction of alpha(1A-DHP)/beta(1a) channels in
steady state inactivation at -80 mV (compared with alpha(1A-DHP)/beta(2a)) did
not enhance the block by (+)-isradipine; (ii) different steady state inactivation
of alpha(1Lc) mutants at -30 mV did not correlate with voltage-dependent channel
block; and (iii) the midpoint-voltages of the inactivation curves of slowly
inactivating L-type constructs and more rapidly inactivating alpha(1Lc)/beta(1a)
channels were shifted to a comparable extent to more hyperpolarized voltages. A
kinetic analysis of (+)-isradipine interaction with different L-type channel
constructs revealed a drug-induced inactivated state. Entry and recovery from
drug-induced inactivation are modulated by intrinsic inactivation determinants,
suggesting a synergism between intrinsic inactivation and DHP block.
PMID- 10766759
TI - Phosphorylation of osteopontin is required for inhibition of vascular smooth
muscle cell calcification.
AB - Osteopontin (OPN) is a non-collagenous, glycosylated phosphoprotein associated
with biomineralization in osseous tissues, as well as ectopic calcification. We
previously reported that osteopontin was co-localized with calcified deposits in
atherosclerotic lesions, and that osteopontin potently inhibits calcium
deposition in a human smooth muscle cell (HSMC) culture model of vascular
calcification. In this report, the role of phosphorylation in osteopontin's
mineralization inhibitory function was examined. The ability of OPN to inhibit
calcification completely depended on post-translational modifications, since
bacteria-derived recombinant OPN did not inhibit HSMC mineralization. Following
casein kinase II treatment, phosphorylated OPN (P-OPN) dose-dependently inhibited
calcification of HSMC cultured in vitro about as effectively as native OPN. The
inhibitory effect of osteopontin depended on the extent of phosphorylation. To
determine the specific structural domains of OPN important for inhibition of
calcification, we compared OPN fragments (N-terminal, C-terminal, and full
length), and compared the inhibitory effect of both phosphorylated and non
phosphorylated fragments. While none of the non-phosphorylated OPN fragments
effected calcification, P-OPN caused dose dependent inhibition of HSMC
calcification. P-OPN was treated with alkaline phosphatase to create
dephosphorylated OPN. Dephosphorylated OPN did not have an inhibitory effect on
calcification. The expression of OPN mRNA and P-OPN secretion by HSMC were
decreased in a time-dependent manner during culture calcification. These results
indicate that phosphorylation is required for the inhibitory effect of OPN on
HSMC calcification, and that regulation of OPN phosphorylation represents one way
in which mineralization may be controlled by cells.
PMID- 10766760
TI - Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product
that promotes cell death.
AB - Mcl-1 is a member of the Bcl-2 family that is regulated transcriptionally and
post-transcriptionally, with expression of the full-length Mcl-1-encoded gene
product resulting in enhanced cell survival. As reported here, the human Mcl-1
gene can also undergo differential splicing, which yields an internally deleted,
death-inducing gene product, Mcl-1(s/Delta)(TM). Whereas full-length Mcl-1
derives from three coding exons (instead of the two present in Bcl-2 and other
anti-apoptotic members of this family), the Mcl-1(s/Delta)(TM) splice variant
results from the joining of the first and third exons with skipping of the
central exon. Because of the skipped exon and a shift in the reading frame
downstream, the Bcl-2 homology domain (BH3) remains intact, whereas the BH1-, BH2
, and transmembrane-encoding domains do not. Mcl-1(s/Delta)(TM) thus has features
similar to BH3 only, pro-apoptotic Bcl-2 family members and, accordingly, was
found to promote cell death. In addition to a variety of other types of
regulation, the Mcl-1 gene appears ideally designed for the generation of either
a Bcl-2-like viability promoting or, as reported here, a BH3 only death-inducing
gene product.
PMID- 10766761
TI - Functional characterization of the Candida albicans MNT1 mannosyltransferase
expressed heterologously in Pichia pastoris.
AB - The alpha1,2-mannosyltransferase gene MNT1 of the human fungal pathogen Candida
albicans has been shown to be important for its adherence to various human
surfaces and for virulence (Buurman, E. T. , Westwater, C., Hube, B., Brown, A.
P. J., Odds, F. C., and Gow, N. A. R. (1998) Proc. Natl. Acad. Sci. U. S. A. 95,
7670-7675). The CaMnt1p is a type II membrane protein, which is part of a family
of proteins that are important for both O- and N-linked mannosylation in fungi
and which represent a distinct subclass of glycosyltransferase enzymes. Here we
use heterologous expression of CaMNT1 in the methylotrophic yeast Pichia pastoris
to characterize the properties of the CaMnt1p enzyme as an example of this family
of enzymes and to identify key amino acid residues required for coordination of
the metal co-factor and for the retaining nucleophilic mechanism of the
transferase reaction. We show that the enzyme can use both Mn(2+) and Zn(2+) as
metal ion co-factors and that the reaction catalyzed is specific for alpha-methyl
mannoside and alpha1,2-mannobiose acceptors. The N-terminal cytoplasmic tail,
transmembrane domains, and stem regions were shown to be dispensable for
activity, whereas truncations to the C-terminal catalytic domain destroyed
activity without markedly affecting transcription of the truncated gene.
PMID- 10766762
TI - Characterization and expression of a novel alternatively spliced human
angiopoietin-2.
AB - Angiopoietin-2 (Ang2) is a naturally occurring antagonist of angiopoietin-1
(Ang1) that competes for binding to the Tie2 receptor and blocks Ang1-induced
Tie2 autophosphorylation during vasculogenesis. Using the polymerase chain
reaction, we isolated a cDNA encoding a novel shorter form of Ang2 from human
umbilical vein endothelial cell cDNA and have designated it angiopoietin-2(443)
(Ang2(443)), because it contains 443 amino acids. Part of the coiled-coil domain
(amino acids 96-148) is absent in Ang2(443) because of alternative splicing of
the gene. Like Ang2, recombinant Ang2(443) expressed in COS-7 cells is secreted
as a glycosylated homodimeric protein. Recombinant Ang2(443) binds to the Tie2
receptor but does not induce Tie2 phosphorylation. Pre-occupation of Ang2(443) on
Tie2 inhibits Ang1 or Ang2 binding and inhibits Ang1-induced phosphorylation.
Expression of Ang2(443) mRNA is detectable in primary endothelial cells, several
nonendothelial tumor cell lines, and primary tumor tissues. Interestingly, two
cervical carcinoma cell lines express relatively moderate levels of Ang2(443)
mRNA and protein. Macrophages express mainly Ang2 mRNA, but the expression of
Ang2(443) mRNA is temporarily up-regulated during macrophage differentiation.
These results suggest that Ang2(443) is a functional antagonist of Ang1 and could
be an important regulator of angiogenesis during some tumorigenic and
inflammatory processes.
PMID- 10766763
TI - Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping
through a nonevolutionary conserved intronic element.
AB - In monosymptomatic forms of cystic fibrosis such as congenital bilateral absence
of vas deferens, variations in the TG(m) and T(n) polymorphic repeats at the 3'
end of intron 8 of the cystic fibrosis transmembrane regulator (CFTR) gene are
associated with the alternative splicing of exon 9, which results in a
nonfunctional CFTR protein. Using a minigene model system, we have previously
shown a direct relationship between the TG(m)T(n) polymorphism and exon 9
splicing. We have now evaluated the role of splicing factors in the regulation of
the alternative splicing of this exon. Serine-arginine-rich proteins and the
heterogeneous nuclear ribonucleoprotein A1 induced exon skipping in the human
gene but not in its mouse counterpart. The effect of these proteins on exon 9
exclusion was strictly dependent on the composition of the TG(m) and T(n)
polymorphic repeats. The comparative and functional analysis of the human and
mouse CFTR genes showed that a region of about 150 nucleotides, present only in
the human intron 9, mediates the exon 9 splicing inhibition in association with
exonic regulatory elements. This region, defined as the CFTR exon 9 intronic
splicing silencer, is a target for serine-arginine-rich protein interactions.
Thus, the nonevolutionary conserved CFTR exon 9 alternative splicing is modulated
by the TG(m) and T(n) polymorphism at the 3' splice region, enhancer and silencer
exonic elements, and the intronic splicing silencer in the proximal 5' intronic
region. Tissue levels and individual variability of splicing factors would
determine the penetrance of the TG(m)T(n) locus in monosymptomatic forms of
cystic fibrosis.
PMID- 10766764
TI - Cloning and functional expression of two families of beta-subunits of the large
conductance calcium-activated K+ channel.
AB - We report here a characterization of two families of calcium-activated K(+)
channel beta-subunits, beta2 and beta3, which are encoded by distinct genes that
map to 3q26.2-27. A single beta2 family member and four alternatively spliced
variants of beta3 were investigated. These subunits have predicted molecular
masses of 27. 1-31.6 kDa, share approximately 30-44% amino acid identity with
beta1, and exhibit distinct but overlapping expression patterns. Coexpression of
the beta2 or beta3a-c subunits with a BK alpha-subunit altered the functional
properties of the current expressed by the alpha-subunit alone. The beta2 subunit
rapidly and completely inactivated the current and shifted the voltage dependence
for activation to more polarized membrane potentials. In contrast, coexpression
of the beta3a-c subunits resulted in only partial inactivation of the current,
and the beta3b subunit conferred an apparent inward rectification. Furthermore,
unlike the beta1 and beta2 subunits, none of the beta3 subunits increased channel
sensitivity to calcium or voltage. The tissue-specific expression of these beta
subunits may allow for the assembly of a large number of distinct BK channels in
vivo, contributing to the functional diversity of native BK currents.
PMID- 10766765
TI - Differential biosynthesis of polysialic acid on neural cell adhesion molecule
(NCAM) and oligosaccharide acceptors by three distinct alpha 2,8
sialyltransferases, ST8Sia IV (PST), ST8Sia II (STX), and ST8Sia III.
AB - Polysialylated neural cell adhesion molecule (NCAM) is thought to play a critical
role in neural development. Polysialylation of NCAM was shown to be achieved by
two alpha2,8-polysialyltransferases, ST8Sia IV (PST) and ST8Sia II (STX), which
are moderately related to another alpha2,8-sialyltransferase, ST8Sia III. Here we
describe that all three alpha2,8-sialyltransferases can utilize oligosaccharides
as acceptors but differ in the efficiency of adding polysialic acid on NCAM.
First, we found that ST8Sia III can form polysialic acid on the enzyme itself
(autopolysialylation) but not on NCAM. These discoveries prompted us to determine
if ST8Sia IV and ST8Sia II share the property of ST8Sia III in utilizing low
molecular weight oligosaccharides as acceptors. By using a newly established
method, we found that ST8Sia IV, ST8Sia II, and ST8Sia III all add oligosialic
and polysialic acid on various sialylated N-acetyllactosaminyl oligosaccharides,
including NCAM N-glycans, fetuin N-glycans, synthetic sialylated N
acetyllactosamines, and on alpha(2)-HS-glycoprotein. Our results also showed that
monosialyl and disialyl N-acetyllactosamines can serve equally as an acceptor,
suggesting that no initial addition of alpha2,8-sialic acid is necessary for the
action of polysialyltransferases. Polysialylation of NCAM by ST8Sia IV and ST8Sia
II is much more efficient than polysialylation of N-glycans isolated from NCAM.
Moreover, ST8Sia IV and ST8Sia II catalyze polysialylation of NCAM much more
efficiently than ST8Sia III. These results suggest that no specific acceptor
recognition is involved in polysialylation of low molecular weight sialylated
oligosaccharides, whereas the enzymes exhibit pronounced acceptor specificities
if glycoproteins are used as acceptors.
PMID- 10766767
TI - Yeast cystathionine beta-synthase is a pyridoxal phosphate enzyme but, unlike the
human enzyme, is not a heme protein.
AB - Our studies of cystathionine beta-synthase from Saccharomyces cerevisiae (yeast)
are aimed at clarifying the cofactor dependence and catalytic mechanism and
obtaining a system for future investigations of the effects of mutations that
cause human disease (homocystinuria or coronary heart disease). We report methods
that yielded high expression of the yeast gene in Escherichia coli and of
purified yeast cystathionine beta-synthase. The absorption and circular dichroism
spectra of the homogeneous enzyme were characteristic of a pyridoxal phosphate
enzyme and showed the absence of heme, which is found in human and rat
cystathionine beta-synthase. The absence of heme in the yeast enzyme facilitates
spectroscopic studies to probe the catalytic mechanism. The reaction of the
enzyme with L-serine in the absence of L-homocysteine produced the aldimine of
aminoacrylate, which absorbed at 460 nm and had a strong negative circular
dichroism band at 460 nm. The formation of this intermediate from the product, L
cystathionine, demonstrates the partial reversibility of the reaction. Our
results establish the overall catalytic mechanism of yeast cystathionine beta
synthase and provide a useful system for future studies of structure and
function. The absence of heme in the functional yeast enzyme suggests that heme
does not play an essential catalytic role in the rat and human enzymes. The
results are consistent with the absence of heme in the closely related enzymes O
acetylserine sulfhydrylase, threonine deaminase, and tryptophan synthase.
PMID- 10766768
TI - Roles of the histone H2A-H2B dimers and the (H3-H4)(2) tetramer in nucleosome
remodeling by the SWI-SNF complex.
AB - SWI-SNF is an ATP-dependent chromatin remodeling complex required for expression
of a number of yeast genes. Previous studies have suggested that SWI-SNF action
may remove or rearrange the histone H2A-H2B dimers or induce a novel alteration
in the histone octamer. Here, we have directly tested these and other models by
quantifying the remodeling activity of SWI-SNF on arrays of (H3-H4)(2) tetramers,
on nucleosomal arrays reconstituted with disulfide-linked histone H3, and on
arrays reconstituted with histone H3 derivatives site-specifically modified at
residue 110 with the fluorescent probe acetylethylenediamine-(1,5)-naphthol
sulfonate. We find that SWI-SNF can remodel (H3-H4)(2) tetramers, although
tetramers are poor substrates for SWI-SNF remodeling compared with nucleosomal
arrays. SWI-SNF can also remodel nucleosomal arrays that harbor disulfide-linked
(H3-H4)(2) tetramers, indicating that SWI-SNF action does not involve an
obligatory disruption of the tetramer. Finally, we find that although the
fluorescence emission intensity of acetylethylenediamine-(1,5)-naphthol sulfonate
modified histone H3 is sensitive to octamer structure, SWI-SNF action does not
alter fluorescence emission intensity. These data suggest that perturbation of
the histone octamer is not a requirement or a consequence of ATP-dependent
nucleosome remodeling by SWI-SNF.
PMID- 10766769
TI - E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent
of p53 and dependent on Bax and caspase 3.
AB - Although B-amyloid (AB) is suggested to play an important role in Alzheimer's
disease, the mechanisms that control AB-evoked toxicity are unclear. We
demonstrated previously that the cell cycle-related cyclin-dependent kinase
4/6/retinoblastoma protein pathway is required for AB-mediated death. However,
the downstream target(s) of this pathway are unknown. We show here that neurons
lacking E2F1, a transcription factor regulated by the retinoblastoma protein, are
significantly protected from death evoked by AB. Moreover, p53 deficiency does
not protect neurons from death, indicating that E2F1-mediated death occurs
independently of p53. Neurons protected by E2F1 deficiency have reduced Bax
dependent caspase 3-like activity. However, protection afforded by E2F1, Bax, or
caspase 3 deficiency is transient. In the case of E2F1, but not with Bax or
caspase 3 deficiency, delayed death is accompanied by DEVD-AFC cleavage activity.
Taken together, these results demonstrate the required role of E2F1, Bax, and
caspase 3 in AB evoked death, but also suggest the participation of elements
independent of these apoptosis regulators.
PMID- 10766770
TI - Nuclear export of the DEAD box An3 protein by CRM1 is coupled to An3 helicase
activity.
AB - We have recently identified the Xenopus laevis An3 protein as a bona fide
substrate for the nuclear export receptor CRM1 (Exportin 1). An3 binds directly
to CRM1 with high affinity via a leucine-rich nuclear export signal located in
the extreme N terminus. An3 is a member of the DEAD box family of RNA helicases,
which unwind RNA duplexes. RNA unwinding is coupled to hydrolysis of nucleoside
triphosphates by the helicase, and the ATPase activity of several helicases is
greatly stimulated by various polynucleotides. Here we report that dATP
hydrolysis by An3 is stimulated approximately 6-fold by total RNA from X. laevis
oocytes, whereas poly(U) RNA fails to enhance hydrolysis, suggesting the
existence of a specific RNA activator for An3. Kinetic analysis reveals that a
mutation within the conserved DEAD box motif reduces the rate of dATP hydrolysis
by approximately 6-fold. In accordance with this, the DEAD box mutant is unable
to unwind double-stranded RNA. Microinjection of the An3 DEAD box mutant into X.
laevis oocytes nuclei reveals a significantly lower export rate as compared with
wild-type An3 protein. This is not because the mutant has lower affinity toward
CRM1, nor is it due to altered RNA binding capacity. This suggests that nuclear
export of An3 protein by CRM1 is coupled to An3 helicase activity.
PMID- 10766771
TI - Kinetic cooperativity of human liver alcohol dehydrogenase gamma(2).
AB - Previous studies showed that natural human liver alcohol dehydrogenase gamma
exhibits negative cooperativity (substrate activation) with ethanol. Studies with
the recombinant gamma(2) isoenzyme now confirm that observation and show that the
saturation kinetics with other alcohols are also nonhyperbolic, whereas the
kinetics for reactions with NAD(+), NADH, and acetaldehyde are hyperbolic. The
substrate activation with ethanol and 1-butanol are explained by an ordered
mechanism with an abortive enzyme-NADH-alcohol complex that releases NADH more
rapidly than does the enzyme-NADH complex. In contrast, high concentrations of
cyclohexanol produce noncompetitive substrate inhibition against varied
concentrations of NAD(+) and decrease the maximum velocity to 25% of the value
that is observed at optimal concentrations of cyclohexanol. Transient kinetics
experiments show that cyclohexanol inhibition is due to a slower rate of
dissociation of NADH from the abortive enzyme-NADH-cyclohexanol complex than from
the enzyme-NADH complex. Fluorescence quenching experiments confirm that the
alcohols bind to the enzyme-NADH complex. The nonhyperbolic saturation kinetics
for oxidation of ethanol, cyclohexanol, and 1-butanol are quantitatively
explained with the abortive complex mechanism. Physiologically relevant
concentrations of ethanol would be oxidized predominantly by the abortive complex
pathway.
PMID- 10766772
TI - Sequence-specific interaction between the disintegrin domain of mouse ADAM 2
(fertilin beta) and murine eggs. Role of the alpha(6) integrin subunit.
AB - Little is yet known about the biological and biochemical properties of the
disintegrin-like domains of ADAM (a disintegrin and metalloprotease) proteins.
Mouse ADAM 2 (mADAM 2; fertilin beta) is a sperm surface protein involved in
murine fertilization. We produced recombinant proteins containing the disintegrin
like domain of mADAM 2 in both insect cells and in bacteria. The protein produced
in insect cells (baculo D+C) contained a signal sequence followed by the
disintegrin-like and cysteine-rich domains; it was purified from the medium of
recombinant baculovirus-infected cells. A bacterial construct containing the
disintegrin-like domain was produced in Escherichia coli as a glutathione S
transferase chimera. Baculo D+C, as well as the D domain of the bacterial
construct (released with thrombin), bound to the microvillar surface of murine
eggs. Using concentrations in the range of 1 to 5 microM, both recombinant
proteins strongly inhibited sperm-egg binding and fusion; the baculovirus
produced protein exhibited a somewhat greater extent of inhibition (approximately
75 versus approximately 55% maximal inhibition). Substitution of alanine for each
of the five charged residues within the disintegrin loop of mADAM 2 revealed a
critical importance for the aspartic acid at position nine. Binding of both
recombinant proteins to the egg was inhibited by the function blocking anti
alpha(6) monoclonal antibody, GoH3, but not by a nonfunction-blocking anti
alpha(6) monoclonal antibody. Binding was also inhibited by a peptide analogue
of, and with an antibody against, the disintegrin loop of mADAM 2.
PMID- 10766773
TI - Human lens beta-crystallin solubility.
AB - The human lens is composed primarily of water and proteins called crystallins.
Insolubility of these crystallins is correlated with aging and cataractogenesis.
The alpha-crystallins have chaperone-like activity in maintaining the solubility
of denatured beta- and gamma-crystallins. One established test of this chaperone
activity is the ability of alpha-crystallin to prevent thermal destabilization of
beta-crystallins. Several studies have addressed the effects of structural
modifications of alpha-crystallin on chaperone activity, but little is known
about the solubilities of the various beta-crystallins or the effects of post
translational modifications. Understanding the solubilities of different forms of
beta-crystallins is important to elucidating the mechanism of chaperone activity.
In this study, the solubilities of beta-crystallins were examined. The beta
crystallins included the gene products of betaB2, betaA1/A3, betaA4, and betaB1
as well as forms modified in vivo. Analysis of the beta-crystallins by high
performance liquid chromatography and mass spectrometry before and after heating
revealed large differences in the relative solubilities of the beta-crystallins.
These results demonstrate a decreased solubility of specific beta-crystallins and
post-translational modifications that may play a role in the crystallin
insolubility associated with aging and cataract.
PMID- 10766774
TI - The twin arginine consensus motif of Tat signal peptides is involved in Sec
independent protein targeting in Escherichia coli.
AB - In Escherichia coli a subset of periplasmic proteins is exported through the Tat
pathway to which substrates are directed by an NH(2)-terminal signal peptide
containing a consensus SRRXFLK "twin arginine" motif. The importance of the
individual amino acids of the consensus motif for in vivo Tat transport has been
assessed by site-directed mutagenesis of the signal peptide of the Tat substrate
pre-SufI. Although the invariant arginine residues are crucial for efficient
export, we find that slow transport of SufI is still possible if a single
arginine is conservatively substituted by a lysine residue. Thus, in at least one
signal peptide context there is no absolute dependence of Tat transport on the
arginine pair. The consensus phenylalanine residue was found to be a critical
determinant for efficient export but could be functionally substituted by
leucine, another amino acid with a highly hydrophobic side chain. Unexpectedly,
the consensus lysine residue was found to retard Tat transport. These
observations and others suggest that the sequence conservation of the Tat
consensus motif is a reflection of the functional importance of the consensus
residues. Tat signal peptides characteristically have positively charged carboxyl
terminal regions. However, changing the sign of this charge does not affect
export of SufI.
PMID- 10766775
TI - Surface expression of Kv1 channels is governed by a C-terminal motif.
AB - Voltage-gated K(+) channel subunits must reach the plasma membrane to repolarize
action potentials. Yet the efficiency of cell surface targeting varies among Kv
subunits with some requiring auxiliary subunits for optimal expression. Here we
identify a conserved motif located in the variable C-terminal region of Kv1
channels that controls the efficiency of functional channel expression.
Variations among wild type channels in the optimal sequence VXXSL produce
differences in distribution and the requirement for auxiliary subunits.
Furthermore, deletion of this motif decreases subunit glycosylation and surface
localization but does not prohibit subunit multimerization. Finally, the action
of the essential sequence is shown to be independent of the chaperone effect of
Kvbeta subunits. Thus, the newly identified C-terminal motif governs processing
and cell surface expression of Kv1 voltage-gated K(+) channels.
PMID- 10766776
TI - Exploration of the Drosophila acetylcholinesterase substrate activation site
using a reversible inhibitor (Triton X-100) and mutated enzymes.
AB - Cholinesterases are activated at low substrate concentration, and this is
followed by inhibition as the level of substrate increases. However, one of these
two components is sometimes lacking. In Drosophila acetylcholinesterase, the two
phases are present, allowing both phenomena to be studied. Several kinetic
schemes can explain this complex kinetic behavior. Among them, one model assumes
that activation results from the binding of a substrate molecule to a non
productive site affecting the entrance of a substrate molecule into the active
site. To test this hypothesis, we looked for an inhibitor competitive for
activation and we found Triton X-100. Using organophosphates or carbamates as
hemisubstrates, we showed that Triton X-100 inhibits or increases phosphorylation
or carbamoylation of the enzyme. In vitro mutagenesis of the residues lining the
active site gorge allowed us to locate the Triton X-100 binding site at the rim
of the gorge with glutamate 107 playing the major role. These results led to the
hypothesis that substrate binding at this site affects the entrance of another
substrate molecule into the active site cleft.
PMID- 10766777
TI - Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its
association with phospholipids.
AB - Dynamin I is phosphorylated in nerve terminals exclusively in the cytosolic
compartment and in vitro by protein kinase C (PKC). Dephosphorylation is required
for synaptic vesicle retrieval, suggesting that its phosphorylation affects its
subcellular localization. An in vitro phospholipid binding assay was established
that prevents lipid vesiculation and dynamin lipid insertion into the lipid.
Dynamin I bound the phospholipid in a concentration-dependent and saturable
manner, with an apparent affinity of 230 +/- 51 nM. Optimal binding occurred with
mixtures of phosphatidylserine and phosphatidylcholine of 1:3 with little binding
to phosphatidylcholine or phosphatidylserine alone. Phospholipid binding was
abolished after dynamin I phosphorylation by PKC and was restored after
dephosphorylation by calcineurin. Matrix-assisted laser desorption/ionization
time of flight mass spectrometry revealed the phosphorylation site in PKCalpha
phosphorylated dynamin I as a single site at Ser-795, located near a binding site
for the SH3 domain of p85, the regulatory subunit of phosphatidylinositol 3
kinase. However, phosphorylation had no effect on dynamin binding to a
bacterially expressed p85-SH3 domain. Thus, phosphorylation of dynamin I on Ser
795 prevents its association with phospholipid, providing a basis for the
cytosolic localization of the minor pool of phospho-dynamin I that mediates
synaptic vesicle retrieval in nerve terminals.
PMID- 10766778
TI - Postulated role of interdomain interaction within the ryanodine receptor in
Ca(2+) channel regulation.
AB - Localized distribution of malignant hyperthermia (MH) and central core disease
(CCD) mutations in N-terminal and central domains of the ryanodine receptor
suggests that the interaction between these domains may be involved in Ca(2+)
channel regulation. To test this hypothesis, we investigated the effects of a new
synthetic domain peptide DP4 corresponding to the Leu(2442)-Pro(2477) region of
the central domain. DP4 enhanced ryanodine binding and induced a rapid Ca(2+)
release. The concentration for half-maximal activation by agonists was
considerably reduced in the presence of DP4. These effects of DP4 are analogous
to the functional modifications of the ryanodine receptor caused by MH/CCD
mutations (viz. hyperactivation of the channel and hypersensitization of the
channel to agonists). Replacement of Arg of DP4 with Cys, mimicking the in vivo
Arg(2458)-to-Cys(2458) mutation, abolished the activating effects of DP4. An N
terminal domain peptide DP1 (El-Hayek, R., Saiki, Y., Yamamoto, T., and Ikemoto,
N. (1999) J. Biol. Chem. 274, 33341-33347) shows similar activation/sensitization
effects. The addition of both DP4 and DP1 produced mutual interference of their
activating functions. We tentatively propose that contact between the two (N
terminal and central) domains closes the channel, whereas removal of the contact
by these domain peptides or by MH/CCD mutations de-blocks the channel, resulting
in hyperactivation/hyper-sensitization effects.
PMID- 10766779
TI - D-tyrosyl-tRNA(Tyr) metabolism in Saccharomyces cerevisiae.
AB - The Saccharomyces cerevisiae YDL219w (DTD1) gene, which codes for an amino acid
sequence sharing 34% identity with the Escherichia coli D-Tyr-tRNA(Tyr)
deacylase, was cloned, and its product was functionally characterized.
Overexpression in the yeast of the DTD1 gene from a multicopy plasmid increased D
Tyr-tRNA(Tyr) deacylase activity in crude extracts by two orders of magnitude.
Upon disruption of the chromosomal gene, deacylase activity was decreased by more
than 90%, and the sensitivity to D-tyrosine of the growth of S. cerevisiae was
exacerbated. The toxicity of D-tyrosine was also enhanced under conditions of
nitrogen starvation, which stimulate the uptake of D-amino acids. In relation
with these behaviors, the capacity of purified S. cerevisiae tyrosyl-tRNA
synthetase to produce D-Tyr-tRNA(Tyr) could be shown. Finally, the phylogenetic
distribution of genes homologous to DTD1 was examined in connection with L
tyrosine prototrophy or auxotrophy. In the auxotrophs, DTD1-like genes are
systematically absent. In the prototrophs, the putative occurrence of a deacylase
is variable. It possibly depends on the L-tyrosine anabolic pathway adopted by
the cell.
PMID- 10766780
TI - A structural requirement for activation of skeletal ryanodine receptors by
peptides of the dihydropyridine receptor II-III loop.
AB - The solution structures of three related peptides (A1, A2, and A9) corresponding
to the Thr(671)-Leu(690) region of the skeletal muscle dihydropyridine receptor
II-III loop have been investigated using nuclear magnetic resonance spectroscopy.
Peptide A1, the native sequence, is less effective in activating ryanodine
receptor calcium release channels than A2 (Ser(687) to Ala substitution). Peptide
A9, Arg(681)-Ser(687), does not activate ryanodine receptors. A1 and A2 are
helical from their N terminus to Lys(685) but are generally unstructured from
Lys(685) to the C terminus. The basic residues Arg(681)-Lys(685), essential for
A1 activation of ryanodine receptors, are located at the C-terminal end of the
alpha-helix. Peptide A9 was found to be unstructured. Differences between A1 and
A2 were observed in the C-terminal end of the helix (residues 681-685), which was
less ordered in A1, and in the C-terminal region of the peptide, which exhibited
greater flexibility in A1. Predicted low energy models suggest that an
electrostatic interaction between the hydroxyl oxygen of Ser(687) and the
guanidino moiety of Arg(683) is lost with the Ser(687)Ala substitution. The
results show that the more structured peptides are more effective in activating
ryanodine receptors.
PMID- 10766781
TI - Nitrite as a substrate and inhibitor of myeloperoxidase. Implications for
nitration and hypochlorous acid production at sites of inflammation.
AB - Myeloperoxidase is a heme enzyme of neutrophils that uses hydrogen peroxide to
oxidize chloride to hypochlorous acid. Recently, it has been shown to catalyze
nitration of tyrosine. In this study we have investigated the mechanism by which
it oxidizes nitrite and promotes nitration of tyrosyl residues. Nitrite was found
to be a poor substrate for myeloperoxidase but an excellent inhibitor of its
chlorination activity. Nitrite slowed chlorination by univalently reducing the
enzyme to an inactive form and as a consequence was oxidized to nitrogen dioxide.
In the presence of physiological concentrations of nitrite and chloride,
myeloperoxidase catalyzed little nitration of tyrosyl residues in a heptapeptide.
However, the efficiency of nitration was enhanced at least 4-fold by free
tyrosine. Our data are consistent with a mechanism in which myeloperoxidase
oxidizes free tyrosine to tyrosyl radicals that exchange with tyrosyl residues in
peptides. These peptide radicals then couple with nitrogen dioxide to form 3
nitrotyrosyl residues. With neutrophils, myeloperoxidase-dependent nitration
required a high concentration of nitrite (1 mM), was doubled by tyrosine, and
increased 4-fold by superoxide dismutase. Superoxide is likely to inhibit
nitration by reacting with nitrogen dioxide and/or tyrosyl radicals. We propose
that at sites of inflammation myeloperoxidase will nitrate proteins, even though
nitrite is a poor substrate, because the co-substrate tyrosine will be available
to facilitate the reaction. Also, production of 3-nitrotyrosine will be most
favorable when the concentration of superoxide is low.
PMID- 10766782
TI - Yeast lacking Cu-Zn superoxide dismutase show altered iron homeostasis. Role of
oxidative stress in iron metabolism.
AB - Saccharomyces cerevisiae lacking copper-zinc superoxide dismutase (sod1) shows a
series of defects, including reduced rates of aerobic growth in synthetic glucose
medium and reduced ability to grow by respiration in glycerol-rich medium. In
this work, we observed that addition of iron improved the respiratory growth of
the sod1 mutant and in glucose medium total intracellular iron content was higher
in the sod1 mutant than in wild type cells. Transcription of the high affinity
iron transporter gene, FET3, was enhanced in the sod1 mutant, suggesting that
iron transport systems were up-regulated. An sod1/fet3 double mutant showed
increased sensitivity to oxygen and increased transcription of FET4, an
alternative, low affinity, iron transporter. We propose that this increased iron
demand in the sod1 mutant may be a reflection of the cells' efforts to
reconstitute iron-sulfur cluster-containing enzymes that are continuously
inactivated in conditions of excess superoxide.
PMID- 10766783
TI - Peroxidase and phosphatase activity of active-site mutants of vanadium
chloroperoxidase from the fungus Curvularia inaequalis. Implications for the
catalytic mechanisms.
AB - Mutation studies were performed on active-site residues of vanadium
chloroperoxidase from the fungus Curvularia inaequalis, an enzyme which exhibits
both haloperoxidase and phosphatase activity and is related to glucose-6
phosphatase. The effects of mutation to alanine on haloperoxidase activity were
studied for the proposed catalytic residue His-404 and for residue Asp-292, which
is located close to the vanadate cofactor. The mutants were strongly impaired in
their ability to oxidize chloride but still oxidized bromide, although they
inactivate during turnover. The effects on the optical absorption spectrum of
vanadium chloroperoxidase indicate that mutant H404A has a reduced affinity for
the cofactor, whereas this affinity is unchanged in mutant D292A. The effect on
the phosphatase activity of the apoenzyme was investigated for six mutants of
putative catalytic residues. Effects of mutation of His-496, Arg-490, Arg-360,
Lys-353, and His-404 to alanine are in line with their proposed roles in
nucleophilic attack, transition-state stabilization, and leaving-group
protonation. Asp-292 is excluded as the group that protonates the leaving group.
A model based on the mutagenesis studies is presented and may serve as a template
for glucose-6-phosphatase and other related phosphatases. Hydrolysis of a phospho
histidine intermediate is the rate-determining step in the phosphatase activity
of apochloroperoxidase, as shown by burst kinetics.
PMID- 10766784
TI - Sphingolipid-enriched membrane domains from rat cerebellar granule cells
differentiated in culture. A compositional study.
AB - Sphingolipid-enriched membrane domains, characterized by a particular protein and
lipid composition, have been detected in a variety of cells. However, limited
data are available concerning these domains in neuronal cells. We analyzed the
lipid and protein composition of a sphingolipid-enriched membrane fraction
prepared from primary rat cerebellar granule cells differentiated in culture.
Although the protein content of this fraction was only 1.4% of total cellular
protein, 60% of the gangliosides, 67% of the sphingomyelin, 50% of the ceramide,
and 40% of the cholesterol were located in this fraction. The protein pattern of
the sphingolipid-enriched domain fraction was dramatically different from that
associated with the cell homogenate. This fraction contained 25% of the tyrosine
phosphorylated proteins and was enriched in two proteins with apparent molecular
masses of 135 and 15 kDa. 12% of cellular glycerophospholipids were located in
the fraction, with phosphatidylcholine having the highest enrichment. The molar
ratio between proteins, glycerophospholipids, cholesterol, sphingomyelin,
ceramide and gangliosides in cerebellar granule cells was 1.6:41.6:6. 1:1.3:0.3:1
in the cell homogenate and 0.04:8.3:4.0:1.4:0.2:1 in the sphingolipid-enriched
membrane fraction. These data indicate that selected proteins segregate with
sphingolipids in specialized domains in the membrane of cultured neurons.
PMID- 10766785
TI - Distinct roles for recombinant cytosolic 5'-nucleotidase-I and -II in AMP and IMP
catabolism in COS-7 and H9c2 rat myoblast cell lines.
AB - Catabolism of AMP during ATP breakdown produces adenosine, which restores energy
balance. Catabolism of IMP may be a key step regulating purine nucleotide pools.
Two, cloned cytosolic 5'-nucleotidases (cN-I and cN-II) have been implicated in
AMP and IMP breakdown. To evaluate their roles directly, we expressed recombinant
pigeon cN-I or human cN-II at similar activities in COS-7 or H9c2 cells. During
rapid (more than 90% in 10 min) or slower (30-40% in 10 min) ATP catabolism, cN-I
transfected COS-7 and H9c2 cells produced significantly more adenosine than cN-II
transfected cells, which were similar to control-transfected cells. Inosine and
hypoxanthine concentrations increased only during slower ATP catabolism. In COS-7
cells, 5'-nucleotidase activity was not rate-limiting for inosine and
hypoxanthine production, which was therefore unaffected by cN-II- and actually
reduced by cN-I- overexpression. In H9c2 cells, in which 5'-nucleotidase activity
was rate-limiting, only cN-II overexpression accelerated inosine and hypoxanthine
formation. Guanosine formation from GMP was also increased by cN-II. Our results
imply distinct roles for cN-I and cN-II. Under the conditions tested in these
cells, only cN-I plays a significant role in AMP breakdown to adenosine, whereas
only cN-II breaks down IMP to inosine and GMP to guanosine.
PMID- 10766786
TI - A distinct seven-residue trigger sequence is indispensable for proper coiled-coil
formation of the human macrophage scavenger receptor oligomerization domain.
AB - We have recently identified a distinct 13-residue sequence pattern that occurs
with limited sequence variations in many two-stranded coiled coils but not in
trimers, tetramers, or pentamers. This coiled-coil trigger pattern was
demonstrated to be indispensable for the assembly of the oligomerization domain
of the actin-bundling protein cortexillin I from Dictyostelium discoideum and the
leucine zipper domain of the yeast transcriptional activator GCN4. With the aim
to extend our knowledge on trigger sequences we have investigated the human
macrophage scavenger receptor type A oligomerization domain as a representative
of three-stranded coiled coils. We prepared a variety of recombinant N- and C
terminal deletion mutants from the full-length oligomerization domain by
heterologous gene expression in Escherichia coli and assessed their ability to
form trimeric coiled-coil structures by circular dichroism spectroscopy and
analytical ultracentrifugation. Deletion mapping identified a distinct seven
residue sequence that was absolutely required for proper coiled-coil formation,
supporting our previous results that heptad repeats alone are not sufficient for
oligomerization. The finding that all fragments containing this particular
sequence exhibited similar thermal stabilities indicates primarily a stabilizing
function of the coiled-coil trigger. Based on sequence similarity, we suggest
that functionally related sites are present in other three-stranded coiled-coil
proteins.
PMID- 10766787
TI - Formation of the main UV-induced thymine dimeric lesions within isolated and
cellular DNA as measured by high performance liquid chromatography-tandem mass
spectrometry.
AB - UVB radiation-induced formation of dimeric photoproducts at bipyrimidine sites
within DNA has been unambiguously associated with the lethal and mutagenic
properties of sunlight. The main lesions include the cyclobutane pyrimidine
dimers and the pyrimidine (6-4) pyrimidone adducts. The latter compounds have
been shown in model systems to be converted into their Dewar valence isomers upon
exposure to UVB light. A new direct assay, based on the use of liquid
chromatography coupled to tandem mass spectrometry, is now available to
simultaneously detect each of the thymine photoproducts. It was applied to the
determination of the yields of formation of the thymine lesions within both
isolated and cellular DNA exposed to either UVC or UVB radiation. The cis-syn
cyclobutane thymine dimer was found to be the major photoproduct within cellular
DNA, whereas the related (6-4) adduct was produced in an approximately 8-fold
lower yield. Interestingly, the corresponding Dewar valence isomer could not be
detected upon exposure of human cells to biologically relevant doses of UVB
radiation.
PMID- 10766789
TI - Preferential activation of the 8-17 deoxyribozyme by Ca(2+) ions. Evidence for
the identity of 8-17 with the catalytic domain of the Mg5 deoxyribozyme.
AB - The 8-17 deoxyribozyme is a small RNA-cleaving DNA molecule of potential
therapeutic interest. Here, the cleavage rates of 16 variants of the 8-17
deoxyribozyme were measured in the presence of different divalent metal ions.
Despite the fact that 8-17 was originally selected in vitro for activity in the
presence of Mg(2+) (Santoro, S. W., and Joyce, G. F. (1997) Proc. Natl. Acad.
Sci. U. S. A. 94, 4262-4266) nearly all the 8-17 variants exhibited substantially
higher (up to 20-fold) reaction rates in Ca(2+) as compared with Mg(2+). This
preference for calcium ions critically depended on the nucleoside residues at two
specific positions of the deoxyribozyme core. The Ca(2+) specificity of 8-17 is
strongly reminiscent of the properties of Mg5, an RNA phosphodiester-cleaving
deoxyribozyme previously isolated by Faulhammer and Famulok (Faulhammer, D., and
Famulok, M. (1996) Angew. Chem. Int. Ed. Engl. 35, 2837-2841). Indeed, analysis
of the Mg5 sequence revealed the presence of a complete 8-17 motif, coincident
with the conserved region of Mg5. An 8-17 deoxyribozyme modeled after the Mg5
conserved region displayed catalytic features comparable with those reported for
the full-length Mg5 deoxyribozyme.
PMID- 10766788
TI - Identification of the proximal ligand His-20 in heme oxygenase (Hmu O) from
Corynebacterium diphtheriae. Oxidative cleavage of the heme macrocycle does not
require the proximal histidine.
AB - The coordination and spin-state of the Corynebacterium diphtheriae heme oxygenase
(Hmu O) and the proximal Hmu O H20A mutant have been characterized by UV-visible
and resonance Raman (RR) spectrophotometry. At neutral pH the ferric heme-Hmu O
complex is a mixture of six-coordinate high spin and six-coordinate low spin
species. Changes in the UV-visible and high frequency RR spectra are observed as
a function of pH and temperature, with the six-coordinate high spin species being
converted to six-coordinate low spin. The low frequency region of the ferrous RR
spectrum identified the proximal ligand to the heme as a neutral imidazole with a
Fe-His stretching mode at 222 cm(-1). The RR characterization of the heme-CO
complex in wt-Hmu O confirms that the proximal imidazole is neither ionized or
strongly hydrogen-bonded. Based on sequence identity with the mammalian enzymes
the proximal ligand in HO-1 (His-25) and HO-2 (His-45) is conserved (His-20) in
the bacterial enzyme. Site-specific mutagenesis identified His-20 as the proximal
mutant based on electronic and resonance Raman spectrophotometric analysis.
Titration of the heme-Hmu O complex with imidazole restored full catalytic
activity to the enzyme, and the coordination of imidazole to the heme was
confirmed by RR. However, in the absence of imidazole, the H20A Hmu O mutant was
found to catalyze the initial alpha-meso-hydroxylation of the heme. The product
of the aerobic reaction was determined to be ferrous verdoheme. Hydrolytic
conversion of the verdoheme product to biliverdin concluded that oxidative
cleavage of the porphyrin macrocycle was specific for the alpha-meso-carbon. The
present data show that, in marked contrast to the human HO-1, the proximal ligand
is not essential for the initial alpha-meso-hydroxylation of heme in the C.
diphtheriae heme oxygenase-catalyzed reaction.
PMID- 10766790
TI - Novel aromatic residues in transmembrane domains IV and V involved in agonist
binding at alpha(1a)-adrenergic receptors.
AB - We examined the role that aromatic residues located in the transmembrane helices
of the alpha(1a)-adrenergic receptor play in promoting antagonist binding. Since
alpha(1)-antagonists display low affinity binding at beta(2)-adrenergic
receptors, two phenylalanine residues, Phe-163 and Phe-187, of the alpha(1a)-AR
were mutated to the corresponding beta(2)-residue. Neither F163Q nor F187A
mutations of the alpha(1a) had any effect on the affinity of the alpha(1)
antagonists. However, the affinity of the endogenous agonist epinephrine was
reduced 12.5- and 8-fold by the F163Q and F187A mutations, respectively. An
additive loss in affinity (150-fold) for epinephrine was observed at an alpha(1a)
containing both mutations. The loss of agonist affinity scenario could be
reversed by a gain of affinity with mutation of the corresponding residues in the
beta(2) to the phenylalanine residues in the alpha(1a). We propose that both Phe
163 and Phe-187 are involved in independent aromatic interactions with the
catechol ring of agonists. The potency but not the efficacy of epinephrine in
stimulating phosphatidylinositol hydrolysis was reduced 35-fold at the
F163Q/F187A alpha(1a) relative to the wild type receptor. Therefore, Phe-163 and
Phe-187 represent novel binding contacts in the agonist binding pocket of the
alpha(1a)-AR, but are not involved directly in receptor activation.
PMID- 10766791
TI - Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by reactive
oxygen species.
AB - c-Jun NH(2)-terminal kinase (JNK) is activated by a number of cellular stimuli
such as inflammatory cytokines and environmental stresses. Reactive oxygen
species also cause activation of JNK; however, the signaling cascade that leads
to JNK activation remains to be elucidated. Because recent reports showed that
expression of Cas, a putative Src substrate, stimulates JNK activation, we
hypothesized that the Src kinase family and Cas would be involved in JNK
activation by reactive oxygen species. An essential role for both Src and Cas was
demonstrated. First, the specific Src family tyrosine kinase inhibitor, PP2,
inhibited JNK activation by H(2)O(2) in a concentration-dependent manner but had
no effect on extracellular signal-regulated kinases 1 and 2 and p38 activation.
Second, JNK activation in response to H(2)O(2) was completely inhibited in cells
derived from transgenic mice deficient in Src but not Fyn. Third, expression of a
dominant negative mutant of Cas prevented H(2)O(2)-mediated JNK activation but
had no effect on extracellular signal-regulated kinases 1 and 2 and p38
activation. Finally, the importance of Src was further supported by the
inhibition of both H(2)O(2)-mediated Cas tyrosine phosphorylation and Cas.Crk
complex formation in Src-/- but not Fyn-/- cells. These results demonstrate an
essential role for Src and Cas in H(2)O(2)-mediated activation of JNK and suggest
a new redox-sensitive pathway for JNK activation mediated by Src.
PMID- 10766792
TI - Glycosylation of macrolide antibiotics. Purification and kinetic studies of a
macrolide glycosyltransferase from Streptomyces antibioticus.
AB - The oleD gene has been identified in the oleandomycin producer Streptomyces
antibioticus and it codes a macrolide glycosyltransferase that is able to
transfer a glucose moiety from UDP-glucose (UDP-Glc) to many macrolides. The
glycosyltransferase coded by the oleD gene has been purified 371-fold from a
Streptomyces lividans clone expressing this protein. The reaction product was
isolated, and its structure determined by NMR spectroscopy. The kinetic mechanism
of the reaction was analyzed using the macrolide antibiotic lankamycin (LK) as
substrate. The reaction operates via a compulsory order mechanism. This has been
shown by steady-state kinetic studies and by isotopic exchange reactions at
equilibrium. LK binds first to the enzyme, followed by UDP-glucose. A ternary
complex is thus formed prior to transfer of glucose. UDP is then released,
followed by the glycosylated lankamycin (GS-LK). A pH study of the reaction was
performed to determine values for the molecular pK values, suggesting possible
amino acid residues involved in the catalytic process.
PMID- 10766793
TI - Examination of the function of RANTES, MIP-1alpha, and MIP-1beta following
interaction with heparin-like glycosaminoglycans.
AB - Chemokines are a group of small proteins that have a variety of functions,
including the activation and recruitment of immune cells during episodes of
inflammation. In common with many cytokines, it has been observed that chemokines
have the potential to bind heparin-like glycosaminoglycan molecules, which are
normally expressed on proteoglycan components of the cell surface and
extracellular matrix. The significance of this interaction for chemokine activity
remains a subject of debate. In this study, Chinese hamster ovary cells were
transfected separately with the human chemokine receptors CCR1 and CCR5, and
these receptors were shown to induce an intracytoplasmic Ca(2+) flux and cellular
chemotaxis following stimulation with the natural CC chemokine ligands (MIP
1alpha, RANTES (regulated on activation normal T cell expressed), and MIP-1beta).
In further experiments, mutant CHO cells, with a defect in normal
glycosaminoglycan (GAG) expression, were also transfected with, and shown to
express similar levels of, CCR1 and CCR5. Although these receptors were
functional, it was found that the mutant cells required exposure to higher
concentrations of ligands than the wild-type cells in order to produce the same
intracytoplasmic Ca(2+) flux. Radioligand binding experiments demonstrated that
specific chemokine receptors expressed by wild-type cells had a significantly
greater affinity for MIP-1alpha than similar receptors expressed by GAG-deficient
mutants. However, there was no significant difference between these cells in
their affinity for RANTES or MIP-1beta. In conclusion, it has been demonstrated
clearly that GAG expression is not necessary for the biological activity of the
chemokines MIP-1alpha, RANTES, or MIP-1beta. However, the presence of cell
surface GAGs does enhance the activity of low concentrations of these chemokines
by a mechanism that appears to involve sequestration onto the cell surface.
PMID- 10766794
TI - Synergism between the calmodulin-binding and autoinhibitory domains on
calcineurin is essential for the induction of their phosphatase activity.
AB - Elevation of the intracellular calcium concentration is necessary for cell growth
and the activation of several lymphokine genes. The immunosuppressive drugs
cyclosporin A and FK506 profoundly inhibit the calcium-dependent signaling
pathway in T lymphocytes by interfering with the activity of the
calcium/calmodulin (CaM)-dependent serine/threonine phosphatase, calcineurin
(CN). Little is known, however, about how activation of CN enzyme activity or
interaction with its substrate, nuclear factor of activated T cell (NF-AT), is
regulated. We show here that the binding of CaM to CN may affect the conformation
of CN at both the CaM-binding and the autoinhibitory (AI) domains and that this
is critical for activation of CN to dephosphorylate NF-AT. Dissociation of the AI
domain from the enzyme active site on CN leads to expose a binding site for NF-AT
at the N terminus of CN and allows the CN binding to NF-AT. Since the cytoplasmic
form of NF-AT can interact with CN mutants lacking enzyme activity, the
interaction of the two molecules is independent of CN enzyme activity and occurs
prior to the dephosphorylation of NF-AT. Dephosphorylation converts NF-AT from
the cytoplasmic to the nuclear form by exposing the DNA-binding domain on NF-AT,
and the nuclear form of NF-AT brings CN together into the nuclei. We therefore
propose that the activation of CN by the CaM binding independently regulates the
interaction with NF-AT and the dephosphorylation of NF-AT.
PMID- 10766795
TI - Cellular release of and response to ATP as key determinants of the set-point of
signal transduction pathways.
AB - The determinants of "basal" activity of signaling pathways regulating cellular
responses are poorly defined. One possibility is that cells release factors to
establish the set-point of such pathways. Here we show that treatment of Madin
Darby canine kidney cells with the nucleotidase apyrase decreases basal
arachidonic acid release and cAMP production 30-40% and that inhibitors of P2Y
receptor action also affect basal and forskolin-stimulated cAMP accumulation.
Changing medium prominently increases extracellular levels of ATP in Madin-Darby
canine kidney, COS-7, and HEK-293 cells. Mechanical stimulation of ATP release
likely occurs in virtually every experimental protocol with cultured cells,
implicating such release and P2Y receptor activation as critical in establishing
the set-point for signal transduction pathways.
PMID- 10766796
TI - Magnesium-induced linear self-association of the FtsZ bacterial cell division
protein monomer. The primary steps for FtsZ assembly.
AB - The bacterial cell division protein FtsZ from Escherichia coli has been purified
with a new calcium precipitation method. The protein contains one GDP and one
Mg(2+) bound, it shows GTPase activity, and requires GTP and Mg(2+) to polymerize
into long thin filaments at pH 6.5. FtsZ, with moderate ionic strength and low
Mg(2+) concentrations, at pH 7.5, is a compact and globular monomer. Mg(2+)
induces FtsZ self-association into oligomers, which has been studied by
sedimentation equilibrium over a wide range of Mg(2+) and FtsZ concentrations.
The oligomer formation mechanism is best described as an indefinite self
association, with binding of an additional Mg(2+) for each FtsZ monomer added to
the growing oligomer, and a slight gradual decrease of the affinity of addition
of a protomer with increasing oligomer size. The sedimentation velocity of FtsZ
oligomer populations is compatible with a linear single-stranded arrangement of
FtsZ monomers and a spacing of 4 nm. It is proposed that these FtsZ oligomers and
the polymers formed under assembly conditions share a similar axial interaction
between monomers (like in the case of tubulin, the eukaryotic homolog of FtsZ).
Similar mechanisms may apply to FtsZ assembly in vivo, but additional factors,
such as macromolecular crowding, nucleoid occlusion, or specific interactions
with other cellular components active in septation have to be invoked to explain
FtsZ assembly into a division ring.
PMID- 10766797
TI - Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the
3'-untranslated region.
AB - The cyclooxygenase (COX)-2 enzyme is responsible for increased prostaglandin
formation in inflammatory states and is the major target of nonsteroidal anti
inflammatory drugs. Normally COX-2 expression is tightly regulated, however,
constitutive overexpression plays a key role in colon carcinogenesis. To
understand the mechanisms controlling COX-2 expression, we examined the ability
of the 3'-untranslated region of the COX-2 mRNA to regulate post-transcriptional
events. When fused to a reporter gene, the 3'-untranslated region mediated rapid
mRNA decay (t(1/2) = 30 min), which was comparable to endogenous COX-2 mRNA
turnover in serum-induced fibroblasts treated with actinomycin D or
dexamethasone. Deletion analysis demonstrated that a conserved 116-nucleotide AU
rich sequence element (ARE) mediated mRNA degradation. In transiently transfected
cells, this region inhibited protein synthesis approximately 3-fold. However,
this inhibition did not occur through changes in mRNA stability since mRNA half
life and steady-state mRNA levels were unchanged. RNA mobility shift assays
demonstrated a complex of cytoplasmic proteins that bound specifically to the
ARE, and UV cross-linking studies identified proteins ranging from 90 to 35 kDa.
Fractionation of the cytosol showed differential association of ARE-binding
proteins to polysomes and S130 fractions. We propose that these factors influence
expression at a post-transcriptional step and, if dysregulated, may increase COX
2 protein as detected in colon cancer.
PMID- 10766798
TI - Identification of the pore-forming region of the outer chloroplast envelope
protein OEP16.
AB - The chloroplast outer envelope protein OEP16 forms a cation-selective high
conductance channel with permeability to amines and amino acids. The region of
OEP16 directly involved in channel formation has been identified by
electrophysiological analysis of a selection of reconstituted OEP16 mutants.
Because analysis of these mutants depended on the use of recombinant protein, we
evaluated the electrophysiological properties of OEP16 isolated directly from pea
chloroplasts and of the recombinant protein produced in Escherichia coli. The
results show that the basic properties like conductance, selectivity, and open
probability of the channel formed by native pea OEP16 are comparable with the
channel activity formed by the recombinant source of the protein. Following
electrophysiological analysis of OEP16 mutants we found that point mutations and
insertion of additional amino acid residues in the region of the putative helix 1
(Glu(73) to Val(91)) did not change the properties of the OEP16 channel. The only
exception was a Cys(71)-->Ser mutation, which led to a loss of the CuCl(2)
sensitivity of the channel. Analysis of N- and C-terminal deletion mutants of
OEP16 and mutants containing defined shuffled domains indicated that the minimal
continuous region of OEP16, which is able to form a channel in liposomes, lies in
the first half of the protein between amino acid residues 21 and 93.
PMID- 10766799
TI - Disulfide bond formation is not required for human chorionic gonadotropin subunit
association. Studies with dithiothreitol in JEG-3 cells.
AB - To study the influence of disulfide bridge formation on the assembly of the
subunits of human chorionic gonadotropin in JEG-3 choriocarcinoma cells,
dithiothreitol (DTT) was used to create a reducing milieu in the endoplasmic
reticulum (ER) in vivo. In the presence of 5 mM DTT during pulse-chase
experiments all of the beta-subunit precursors observed in unperturbed cells
(pbeta(0), pbeta(1), pbeta(2), and beta(*)) collapsed into the pbeta(0) form. The
reducing milieu of the ER was reoxidized in less than 5 min after removal of DTT
from the medium. DTT markedly increased the half-life of the pbeta(0) precursor
from 8.8 to 65.2 min. Under reoxidation conditions, the beta-subunit precursors
folded back from pbeta(0) in less than 5 min. In unperturbed JEG-3 cells, the
alpha-subunit was present in both fully glycosylated and monoglycosylated
precursor (pre-alpha) forms. The attachment of the second N-linked glycan residue
of the alpha-subunit was accelerated in the presence of DTT, and consequently pre
alpha-subunit was missing from the DTT-treated cultures. The formation of
alphabeta-dimers appeared to be at least partially independent of the oxidation
state in the ER. The alphabeta-dimer was present under conditions in which
disulfide bridge formation was prevented by exposure to 5 mM DTT before and
during the pulse period. This clearly suggests that the human chorionic
gonadotropin subunits may acquire association-competent conformations even when
no disulfide bridge formation has taken place.
PMID- 10766800
TI - Organization of diphtheria toxin in membranes. A hydrophobic photolabeling study.
AB - Diphtheria toxin (DT) is a disulfide linked AB-toxin consisting of a catalytic
domain (C), a membrane-inserting domain (T), and a receptor-binding domain (R).
It gains entry into cells by receptor-mediated endocytosis. The low pH (
approximately 5.5) inside the endosomes induces a conformational change in the
toxin leading to insertion of the toxin in the membrane and subsequent
translocation of the C domain into the cell, where it inactivates protein
synthesis ultimately leading to cell death. We have used a highly reactive
hydrophobic photoactivable reagent, DAF, to identify the segments of DT that
interact with the membrane at pH 5.2. This reagent readily partitions into
membranes and, on photolysis, indiscriminately inserts into lipids and membrane
inserted domains of proteins. Subsequent chemical and/or enzymatic fragmentation
followed by peptide sequencing allows for identification of the modified
residues. Using this approach it was observed that T domain helices, TH1, TH8,
and TH9 insert into the membrane. Furthermore, the disulfide link was found on
the trans side leaving part of the C domain on the trans side. This domain then
comes out to the cis side via a highly hydrophobic patch corresponding to
residues 134-141, originally corresponding to a beta-strand in the solution
structure of DT. It appears that the three helices of the T domain could
participate in the formation of a channel from a DT-oligomer, thus providing the
transport route to the C domain after the disulfide reductase separates the two
chains.
PMID- 10766801
TI - Mutation of divergent region 1 alters caffeine and Ca(2+) sensitivity of the
skeletal muscle Ca(2+) release channel (ryanodine receptor).
AB - Replacement of amino acids 4187-4628 in the skeletal muscle Ca(2+) release
channel (skeletal ryanodine receptor (RyR1)), including nearly all of divergent
region 1 (amino acids 4254-4631), with the corresponding cardiac ryanodine
receptor (RyR2) sequence leads to increased sensitivity of channel activation by
caffeine and Ca(2+) and to decreased sensitivity of channel inactivation by
elevated Ca(2+) (Du, G. G., and MacLennan, D. H. (1999) J. Biol. Chem. 274, 26120
26126). In further investigations, this region was subdivided by the construction
of new chimeras, and alterations in channel function were detected by measurement
of the caffeine dependence of in vivo Ca(2+) release and the Ca(2+) dependence of
[(3)H]ryanodine binding. Chimera RF10a (amino acids 4187-4381) had a lower EC(50)
value for activation by caffeine, and RF10c (4557-4628) had a higher EC(50)
value, whereas the EC(50) value for chimera RF10b (4382-4556) was unchanged.
Chimeras RF10b and RF10c were more sensitive to activation by Ca(2+), whereas
RF10a was less sensitive to inactivation by Ca(2+), implicating RF10b and RF10c
in Ca(2+) activation and RF10a in Ca(2+) inactivation. Deletion of much of
divergent region 1 sequence to create mutant Delta4274-4535 led to higher
caffeine and Ca(2+) sensitivity of channel activation and to lower Ca(2+)
sensitivity for inactivation. Thus, deletion results demonstrate that caffeine,
Ca(2+), and ryanodine binding sites are not located in amino acids 4274-4535.
Nevertheless, the properties of the deletion and chimeric mutants demonstrate
that amino acids 4274-4535 and three shorter sequences in this region (F10a,
amino acids 4187-4381; F10b, 4382-4556; and F10c, 4557-4628) in RyR1 modulate
Ca(2+) and caffeine sensitivity of the Ca(2+) release channel.
PMID- 10766802
TI - Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to
hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde.
AB - Cyclooxygenases catalyze the oxygenation of arachidonic acid to prostaglandin
endoperoxides. Cyclooxygenase-2- and the xenobiotic-metabolizing cytochrome P450s
1A and 3A are all aberrantly expressed during colorectal carcinogenesis. To probe
for a role of P450s in prostaglandin endoperoxide metabolism, we studied the 12
hydroxyheptadecatrienoate (HHT)/malondialdehyde (MDA) synthase activity of human
liver microsomes and purified P450s. We found that human liver microsomes have
HHT/MDA synthase activity that is concentration-dependent and inhibited by the
P450 inhibitors, ketoconazole and clotrimazole with IC(50) values of 1 and 0.4
microM, respectively. This activity does not require P450 reductase. HHT/MDA
synthase activity was present in purified P450s but not in heme alone or other
heme proteins. The catalytic activities of various purified P450s were determined
by measuring rates of MDA production from prostaglandin endoperoxide. At 50
microM substrate, the catalytic activities of purified human P450s varied from 10
+/- 1 to 0.62 +/- 0.02 min(-1), 3A4 >> 2E1 > 1A2. Oxabicycloheptane analogs of
prostaglandin endoperoxide, U-44069 and U-46619, induced spectral changes in
human P450 3A4 with K(s) values of 240 +/- 20 and 130 +/- 10 microM,
respectively. These results suggest that co-expression of cyclooxygenase-2 and
P450s in developing cancers may contribute to genomic instability due to
production of the endogenous mutagen, MDA.
PMID- 10766803
TI - Conformational changes of transcobalamin induced by aquocobalamin binding.
Mechanism of substitution of the cobalt-coordinated group in the bound ligand.
AB - Binding of aquo-, cyano-, or azidocobalamin (Cbl.OH(2), Cbl.CN, and Cbl.N(3),
respectively) to the recombinant human transcobalamin (TC) and haptocorrin from
human plasma was investigated via stopped-flow spectroscopy. Association of
cobalamins with haptocorrin always proceeded in one step. TC, however, displayed
a certain selectivity for the ligands: Cbl.CN or Cbl.N(3) bound in one step with
k(+1) = 1 x 10(8) M(-1) s(-1) (20 degrees C), whereas binding of Cbl.OH(2) under
the same conditions occurred in two steps with k(+1) = 3 x 10( 7) M(-1) s(-1)
(E(a) = 30 kJ/mol) and k(+2) = 0.02 s(-1) (E(a) = 120 kJ/mol). The second step of
Cbl.OH(2) binding was interpreted as a transformation of the initial "open"
intermediate TC.Cbl.OH(2) to the "closed" conformation TC(Cbl) with displaced
water. The backward transition from the closed to the open conformation was the
reason for the identical rate-limiting steps during substitution of H(2)O in
TC.Cbl.OH(2) for cyanide or azide according to the reaction TC(Cbl) -->
TC.Cbl.OH(2) + CN(-)/N(3)(-). The cyano and azido forms of holo-TC which were
produced behaved as the open proteins. Different conformations of holo-TC,
determined by the nature of the active group in the bound Cbl, may direct
transportation of cobalamins in the organism.
PMID- 10766804
TI - Transcriptional activation of the rice tungro bacilliform virus gene is
critically dependent on an activator element located immediately upstream of the
TATA box.
AB - To investigate the transcriptional mechanisms of rice tungro bacilliform virus,
we have systematically analyzed an activator element located immediately upstream
of the TATA box in the rice tungro bacilliform virus promoter and its cognate
trans-acting factors. Using electrophoretic mobility shift assays, we showed that
rice nuclear proteins bind to the activator element, forming multiple specific
DNA-protein complexes via protein-protein interactions. Copper-phenanthroline
footprinting and DNA methylation interference analysis indicated that multiple
DNA-protein complexes share a common binding site located between positions -60
to -39, and the proteins contact the activator element in the major groove. DNA
UV cross-linking assays further showed that two nuclear proteins (36 and 33 kDa),
found in rice cell suspension and shoot nuclear extracts, and one (27 kDa),
present in root nuclear extracts, bind to this activator element. In protoplasts
derived from a rice (Oryza sativa) suspension culture, the activator element is a
prerequisite for promoter activity and its function is critically dependent on
its position relative to the TATA box. Thus, transcriptional activation may
function via interactions with the basal transcriptional machinery, and we
propose that this activation is mediated by protein-protein interactions in a
position-dependent mechanism.
PMID- 10766805
TI - Single nucleotide patch base excision repair is the major pathway for removal of
thymine glycol from DNA in human cell extracts.
AB - The repair pathways involved in the removal of thymine glycol (TG) from DNA by
human cell extracts have been examined. Closed circular DNA constructs containing
a single TG at a defined site were used as substrates to determine the patch size
generated after in vitro repair by cell extracts. Restriction analysis of the
repair incorporation in the vicinity of the lesion indicated that the majority of
TG was repaired through the base excision repair (BER) pathways. Repair
incorporation 5' to the lesion, characteristic for the nucleotide excision repair
pathway, was not found. More than 80% of the TG repair was accomplished by the
single-nucleotide repair mechanism, and the remaining TGs were removed by the
long patch BER pathway. We also analyzed the role of the xeroderma pigmentosum,
complementation group G (XPG) protein in the excision step of BER. Cell extracts
deficient in XPG protein had an average 25% reduction in TG incision. These data
show that BER is the primary pathway for repair of TG in DNA and that XPG protein
may be involved in repair of TG as an accessory factor.
PMID- 10766806
TI - The mitochondrial permeability transition augments Fas-induced apoptosis in mouse
hepatocytes.
AB - Tumor necrosis factor-alpha receptor 1 and Fas recruit overlapping signaling
pathways. To clarify the differences between tumor necrosis factor alpha
(TNFalpha) and Fas pathways in hepatocyte apoptosis, primary mouse hepatocytes
were treated with TNFalpha or an agonist anti-Fas antibody after infection with
an adenovirus expressing an IkappaB superrepressor (Ad5IkappaB). Treatment with
TNFalpha induced apoptosis in Ad5IkappaB-infected mouse hepatocytes, as we
previously reported for rat hepatocytes. Ad5IkappaB plus anti-Fas antibody or
actinomycin D plus anti-Fas antibody rapidly induced apoptosis, whereas anti-Fas
antibody alone produced little cytotoxicity. The proteasome inhibitor (MG-132)
and a dominant-negative mutant of nuclear factor-kappaB-inducing kinase also
promoted TNFalpha- and Fas-mediated apoptosis. Expression of either crmA or a
dominant-negative mutant of the Fas-associated death domain protein prevented
TNFalpha- and Fas-mediated apoptosis. In addition, the caspase inhibitors, DEVD
cho and IETD-fmk, inhibited TNFalpha- and Fas-mediated apoptosis. In Ad5IkappaB
infected hepatocytes, caspases-3 and -8 were activated within 2 h after treatment
with anti-Fas antibody or within 6 h after TNFalpha treatment. Confocal
microscopy demonstrated onset of the mitochondrial permeability transition (MPT)
and mitochondrial depolarization by 2-3 h after anti-Fas antibody treatment and 8
10 h after TNFalpha treatment, followed by cytochrome c release. The combination
of the MPT inhibitors, cyclosporin A, and trifluoperazine, protected Ad5IkappaB
infected hepatocytes from TNFalpha-mediated apoptosis. After anti-Fas antibody,
cyclosporin A and trifluoperazine decreased cytochrome c release but did not
prevent caspase-3 activation and cell-death. In conclusion, nuclear factor-kappaB
activation protects mouse hepatocytes against both TNFalpha- and Fas-mediated
apoptosis. TNFalpha and Fas recruit similar but nonidentical, pathways signaling
apoptosis. The MPT is obligatory for TNFalpha-induced apoptosis. In Fas-mediated
apoptosis, the MPT accelerates the apoptogenic events but is not obligatory for
them.
PMID- 10766808
TI - Reconstitution of higher plant chloroplast chaperonin 60 tetradecamers active in
protein folding.
AB - Unlike the GroEL homologs of eubacteria and mitochondria, oligomer preparations
of the higher plant chloroplast chaperonin 60 (cpn60) consist of roughly equal
amounts of two divergent subunits, alpha and beta. The functional significance of
these isoforms, their structural organization into tetradecamers, and their
interactions with the unique binary chloroplast chaperonin 10 (cpn10) have not
been elucidated. Toward this goal, we have cloned the alpha and beta subunits of
the ch-cpn60 of pea (Pisum sativum), expressed them individually in Escherichia
coli, and subjected the purified monomers to in vitro reconstitution experiments.
In the absence of other factors, neither subunit (alone or in combination)
spontaneously assembles into a higher order structure. However, in the presence
of MgATP, the beta subunits form tetradecamers in a cooperative reaction that is
potentiated by cpn10. In contrast, alpha subunits only assemble in the presence
of beta subunits. Although beta and alpha/beta 14-mers are indistinguishable by
electron microscopy and can both assist protein folding, their specificities for
cpn10 are entirely different. Similar to the authentic chloroplast protein, the
reconstituted alpha/beta 14-mers are functionally compatible with bacterial,
mitochondrial, and chloroplast cpn10. In contrast, the folding reaction mediated
by the reconstituted beta 14-mers is only efficient with mitochondrial cpn10. The
ability to reconstitute two types of functional oligomer in vitro provides a
unique tool, which will allow us to investigate the mechanism of this unusual
chaperonin system.
PMID- 10766807
TI - Alternative excision repair pathway of UV-damaged DNA in Schizosaccharomyces
pombe operates both in nucleus and in mitochondria.
AB - The fission yeast, Schizosaccharomyces pombe, possesses a UV-damaged DNA
endonuclease-dependent excision repair (UVER) pathway in addition to nucleotide
excision repair pathway for UV-induced DNA damage. We examined cyclobutane
pyrimidine dimer removal from the myo2 locus on the nuclear genome and the coI
locus on the mitochondrial genome by the two repair pathways. While nucleotide
excision repair repairs damage only on the nuclear genome, UVER efficiently
removes cyclobutane pyrimidine dimers on both nuclear and mitochondrial genomes.
The ectopically expressed wild type UV-damaged DNA endonuclease was localized to
both nucleus and mitochondria, while modifications of N-terminal methionine
codons restricted its localization to either of two organelles, suggesting an
alternative usage of multiple translation initiation sites for targeting the
protein to different organelles. By introducing the same mutations into the
chromosomal copy of the uvde(+) gene, we selectively inactivated UVER in either
the nucleus or the mitochondria. The results of UV survival experiments indicate
that although UVER efficiently removes damage on the mitochondrial genome, UVER
in the mitochondria hardly contributes to UV resistance of S. pombe cells. We
suggest a possible UVER function in mitochondria as a backup system for other UV
damage tolerance mechanisms.
PMID- 10766809
TI - Medial Golgi but not late Golgi glycosyltransferases exist as high molecular
weight complexes. Role of luminal domain in complex formation and localization.
AB - To investigate the organization of Golgi glycosyltransferases and their mechanism
of localization, we have compared the properties of a number of medial and late
acting Golgi enzymes. The medial Golgi enzymes, N-acetylglucosaminyltransferase I
and II (GnTI and GnTII) required high salt for solubilization and migrated as
high molecular weight complexes on sucrose density gradients. In contrast, the
late acting Golgi enzymes, beta1,4-galactosyltransferase and alpha1, 2
fucosyltransferase, were readily solubilized in low salt and migrated as
monomers/dimers by sucrose density gradient centrifugation. Analysis of membrane
bound GnTI chimeras indicates that the formation of high molecular weight
complexes does not require the transmembrane domain and cytoplasmic tail
sequences of GnTI. Furthermore, a soluble form of GnTI, containing the stem
region and catalytic domain, accumulated in the Golgi prior to secretion, in
contrast to beta1,4-galactosyltransferase. Soluble GnTI, which also associated
with high molecular weight complexes, was comparable with membrane-bound GnTI in
its ability to glycosylate newly synthesized glycoproteins in vivo. Mutation of
charged residues within the stem region of GnTI, known to be important for "kin
recognition", had no effect on the efficiency of Golgi localization, the
inclusion into high molecular weight complexes, nor functional activity in vivo.
The differences in behavior between the medial and late acting Golgi enzymes may
contribute to their differential localization and their ability to glycosylate
efficiently in the correct Golgi subcompartment.
PMID- 10766810
TI - Alpha(1) adrenergic agonist induction of p21(waf1/cip1) mRNA stability in
transfected HepG2 cells correlates with the increased binding of an AU-rich
element binding factor.
AB - Stimulation of transfected HepG2 cells (TFG2) with the alpha(1)-adrenergic
agonist phenylephrine (PE) significantly activated p21(waf1/cip1) gene expression
without affecting p53 gene expression. Northern blotting and reporter assay
demonstrated that this induction was due to PE stimulation of p21(waf1/cip1) mRNA
stability. To further define the underlying mechanism, we prepared a
chloramphenicol acetyltransferase (CAT)-p21(waf1/cip1) 3'-untranslated region (3'
UTR) hybrid construct by inserting the 3'-UTR of p21(waf1/cip1) mRNA just
downstream from the CAT coding sequence and transfected it into TFG2 cells. PE
treatment enhanced the activity of this construct by 6-fold. Deletion analyses
indicated that an AU-rich element (AURE) located between 553 to 625 within the
p21(waf1/cip1) 3'-UTR was required for this induction. RNA gel shift assays
demonstrated that this AURE bound an RNA-binding protein. This protein has been
purified 5000-fold from PE-treated TFG2 cells by heparin-Sepharose and RNA
affinity chromatography. SDS-polyacrylamide gel electrophoresis, UV cross
linking, and Northwestern analyses indicated the molecular mass of this protein
as 24 and 52 kDa. Finally, PE treatment markedly enhanced this RNA-protein
binding by a p42/44 mitogen-activated protein kinase-dependent mechanism. These
data suggest that the AURE located between 553 and 625 within the p21(waf1/cip1)
mRNA 3'-UTR, which binds an RNA-binding protein, is responsible for PE-induced
p21(waf1/cip1) mRNA stability.
PMID- 10766811
TI - p300 and p300/cAMP-responsive element-binding protein associated factor interact
with human T-cell lymphotropic virus type-1 Tax in a multi-histone
acetyltransferase/activator-enhancer complex.
AB - The human T-cell lymphotropic virus, type (HTLV)-1 trans-activator, Tax,
coordinates with cAMP-responsive element-binding protein (CREB) and the
transcriptional co-activators p300/CBP on three 21-base pair repeat elements in
the proviral long terminal repeat (LTR) to promote viral mRNA transcription.
Recruitment of p300/CBP to the activator-enhancer complex, however, is
insufficient to support Tax-dependent LTR trans-activation. Here, we report that
the p300/CBP-associated factor (P/CAF) is a critical and integral component of
the functional HTLV-1 activator-enhancer complex. The HTLV-1 Tax protein directly
binds P/CAF in vitro and co-immunoprecipitates with this co-activator in vivo.
The Tax mutants (K88A and V89A) defective for p300/CBP-binding and LTR trans
activation, retained their abilities to interact with P/CAF. The M47 mutant
(L319R, L320S) protein, which has previously been shown to interact with
p300/CBP, by contrast, failed to form complexes with P/CAF and is impaired in LTR
trans-activation. Furthermore, LTR trans-activation by Tax is competitively
inhibited by the adenoviral E1A 12S gene product, which displaces P/CAF from
p300/CBP and inhibits the histone acetyltransferase activities of both P/CAF and
p300/CBP. This inhibition is partially reversed by exogenously added P/CAF. These
results imply that simultaneous recruitment of two distinct co-activators
(p300/CBP and P/CAF) by Tax is essential for the assembly of a trans-activation
competent, nucleoprotein complex.
PMID- 10766812
TI - Conditional expression of fibroblast growth factor-7 in the developing and mature
lung.
AB - Effects of fibroblast growth factor-7 (FGF-7) on lung morphogenesis, respiratory
epithelial cell differentiation, and proliferation were assessed in transgenic
mice in which the human FGF-7 cDNA was controlled by a conditional promoter under
the direction of regulatory elements from either the human surfactant protein-C
(SP-C) or rat Clara cell secretory protein (ccsp) genes. Expression of FGF-7 was
induced in respiratory epithelial cells of the fetal lung by administration of
doxycycline to the dam. Prenatally, doxycycline induced FGF-7 mRNA in respiratory
epithelial cells in both Sp-c and Ccsp transgenic lines, increasing lung size and
causing cystadenomatoid malformation. Postnatally, mice bearing both Ccsp-rtta
and (Teto)(7)-cmv-fgf-7 transgenes survived, and lung morphology was normal.
Induction of FGF-7 expression by doxycycline in the Ccsp-rtta x (Teto)(7)-cmv-fgf
7 mice caused marked epithelial cell proliferation, adenomatous hyperplasia, and
pulmonary infiltration with mononuclear cells. Epithelial cell hyperplasia caused
by FGF-7 was largely resolved after removal of doxycycline. Surfactant proteins,
TTF-1, and aquaporin 5 expression were conditionally induced by doxycycline. The
Sp-c-rtta and Ccsp-rtta activator mice provide models in which expression is
conditionally controlled in respiratory epithelial cells in the developing and
mature lung, altering lung morphogenesis, differentiation, and proliferation.
PMID- 10766814
TI - Observation of a partially opened triple-helix conformation in 1-->3-beta-glucan
by fluorescence resonance energy transfer spectroscopy.
AB - This study used fluorescence resonance energy transfer (FRET) spectroscopy as an
indirect method to investigate the effect of NaOH treatment on the conformation
of a triple-helix (1-->3)-beta-D-glucan and then evaluated the effect of
conformation on biological activity. Previous studies have suggested that
treatment of the triple-helix glucans with NaOH produces single-helix conformers.
FRET spectra of the triple-helix glucan, laminarin, doubly labeled with 1
aminopyrene as donor probe and fluorescein-5-isothiocyanate as acceptor probe
attached at the reducing end, showed that a partially opened triple-helix
conformer was formed on treatment with NaOH. Increasing degrees of strand opening
was associated with increasing concentrations of NaOH. Based on these
observations we propose that a partially opened triple-helix rather than a single
helix, is formed by treating the triple-helix glucans with NaOH. After
neutralizing the NaOH, changes in FRET indicated that the partially opened
conformer gradually reverts to the triple-helix over 8 days. Laminarian was
stabilized at different degrees of partial opening and its biological activity
examined using the Limulus amebocyte lysate assay and nitric oxide production by
alveolar macrophage. Both Limulus amebocyte lysate activity and nitric oxide
production were related to the degree of opening of the triple-helix. Partially
open conformers were more biologically active than the intact triple-helix.
PMID- 10766813
TI - Clustered DNA damage, influence on damage excision by XRS5 nuclear extracts and
Escherichia coli Nth and Fpg proteins.
AB - Ionizing radiation and radiomimetic anticancer agents induce clustered DNA
damage, which are thought to reflect the biological severity. Escherichia coli
Nth and Fpg and nuclear extracts from XRS5, a Chinese hamster ovary Ku-deficient
cell line, have been used to study the influence on their substrate recognition
by the presence of a neighboring damage or an abasic site on the opposite strand,
as models of clustered DNA damage. These proteins were tested for their
efficiency to induce a single-strand break on a (32)P-labeled oligonucleotide
containing either an abasic (AP) site, dihydrothymine (DHT), 7,8-dihydro-8-oxo
2'deoxyguanine, or 7, 8-dihydro-8-oxo-2'deoxyadenine at positions 1, 3, or 5 base
pairs 5' or 3' to either an AP site or DHT on the labeled strand. DHT excision is
much more affected than cleavage of an AP site by the presence of other damage.
The effect on DHT excision is greatest with a neighboring AP site, with the
effect being asymmetric with Nth and Fpg. Therefore, this large inhibition of the
excision of DHT by the presence of an opposite AP site may minimize the formation
of double-strand breaks in the processing of DNA clustered damages.
PMID- 10766815
TI - The mouse Na(+)-sulfate cotransporter gene Nas1. Cloning, tissue distribution,
gene structure, chromosomal assignment, and transcriptional regulation by vitamin
D.
AB - NaSi-1 is a Na(+)-sulfate cotransporter expressed on the apical membrane of the
renal proximal tubule and plays an important role in sulfate reabsorption. To
understand the molecular mechanisms that mediate the regulation of NaSi-1, we
have isolated and characterized the mouse NaSi-1 cDNA (mNaSi-1), gene (Nas1), and
promoter region and determined Nas1 chromosomal localization. The mNaSi-1 cDNA
encodes a protein of 594 amino acids with 13 putative transmembrane segments,
inducing high affinity Na(+)-dependent transport of sulfate in Xenopus oocytes.
Three different mNaSi-1 transcripts derived from alternative polyadenylation and
splicing were identified in kidney and intestine. The Nas1 gene is a single copy
gene comprising 15 exons spread over 75 kilobase pairs that maps to mouse
chromosome 6. Transcription initiation occurs from a single site, 29 base pairs
downstream to a TATA box-like sequence. The promoter is AT-rich (61%), contains a
number of well characterized cis-acting elements, and can drive basal
transcriptional activity in opossum kidney cells but not in COS-1 or NIH3T3
cells. We demonstrated that 1,25-dihydroxyvitamin D(3) stimulated the
transcriptional activity of the Nas1 promoter in transiently transfected opossum
kidney cells. This study represents the first characterization of the genomic
organization of a Na(+)-sulfate cotransporter gene. It also provides the basis
for a detailed analysis of Nas1 gene regulation and the tools required for
assessing Nas1 role in sulfate homeostasis using targeted gene manipulation in
mice.
PMID- 10766816
TI - Identification and characterization of KLK-L4, a new kallikrein-like gene that
appears to be down-regulated in breast cancer tissues.
AB - Kallikreins are a subgroup of serine proteases and these proteolytic enzymes have
diverse physiological functions in many tissues. Growing evidence suggests that
many kallikreins are implicated in carcinogenesis. In rodents, kallikreins
constitute a large multigene family, but in humans, only three genes were
identified. By using the positional candidate gene approach, we were able to
identify a new kallikrein-like gene, tentatively named KLK-L4 (for kallikrein
like gene 4). This new gene maps to chromosome 19q13. 3-q13.4, is formed of five
coding exons and four introns, and shows structural similarity to other
kallikreins and kallikrein-like genes. KLK-L4 is expressed in a variety of
tissues including prostate, salivary gland, breast, and testis. Our preliminary
results show that KLK-L4 is down-regulated, at the mRNA level, in breast cancer
tissues and breast cancer cell lines. Its expression is regulated by steroid
hormones in the breast cancer cell line BT-474. This gene may be involved in the
pathogenesis and/or progression of breast cancer and may find applicability as a
novel cancer biomarker.
PMID- 10766817
TI - An internal ribosome entry segment promotes translation of the simian
immunodeficiency virus genomic RNA.
AB - The retroviral genomic RNA is the messenger for the synthesis of the group
specific antigen (gag) and polymerase precursors of the major structural proteins
and enzymes of the virion. The 5'-untranslated leader of the simian
immunodeficiency virus (SIV) genomic RNA is formed of highly structured domains
involved in key steps of the viral life cycle. Thus, the presence of stable RNA
structures between the 5'-cap and the gag start codon are thought to strongly
inhibit scanning of a 43 S preinitiation ribosomal complex. This prompted us to
look for an alternative to the canonical ribosome scanning. By using a standard
bicistronic assay in the rabbit reticulocyte lysate, we show that the SIVmac 5'
leader contains an internal ribosome entry segment (IRES) and that gene
expression driven by this IRES is stimulated upon cleavage of eukaryotic
initiation factor 4G. Deletion analysis revealed that the sequence between the
major splice donor and the gag AUG codon is required for IRES activity. DNA
transfection and viral transduction experiments in both NIH-3T3 and COS-7 cells
confirmed that translation driven by the SIV leader is IRES-dependent and thus
insensitive to the immunosuppressant rapamycin. Identification of an IRES in SIV
is of particular interest for the understanding of lentivirus replication and
also for the design of novel lentiviral vectors suitable for gene transfer.
PMID- 10766818
TI - Constitutive activation of retinoic acid receptor beta2 promoter by orphan
nuclear receptor TR2.
AB - The orphan nuclear receptor TR2 functions as a constitutive activator for the
endogenous retinoic acid receptor beta2 (RAR(beta2)) gene expression in P19
embryonal carcinoma cells and for reporters driven by the RAR(beta2) promoter in
COS-1 cells. The activation of RAR(beta2) by TR2 is mediated by the direct repeat
5 (DR5) element located in the RAR(beta2) promoter. Furthermore, cAMP exerts an
enhancing effect on the activation of RAR(beta2) by TR2, which is mediated by the
cAMP response element located in the 5'-flanking region of the DR5. The
constitutive activation function-1 (AF-1) of TR2 is mapped to amino acid residues
10-30 in its N-terminal A segment. A direct molecular interaction occurs between
CREMtau and TR2, detected by co-immunoprecipitation, which is mediated by the N
terminal AB segment of TR2. In gel mobility shift assays, TR2 competes with P19
nuclear factor binding to the RAR(beta2) promoter, and TR2 and CREMtau bind
simultaneously to this DNA fragment. The role of TR2 in the early events of RA
signaling process is discussed.
PMID- 10766819
TI - Filling the gap in vitamin A research. Molecular identification of an enzyme
cleaving beta-carotene to retinal.
AB - Vitamin A and its derivatives (retinoids) are essential components in vision;
they contribute to pattern formation during development and exert multiple
effects on cell differentiation with important clinical implications. It has been
known for 50 years that the key step in the formation of vitamin A is the
oxidative cleavage of beta-carotene; however, this enzymatic step has resisted
molecular analysis. A novel approach enabled us to clone and identify a beta
carotene dioxygenase from Drosophila melanogaster, expressing it into the
background of a beta-carotene (provitamin A)-synthesizing and -accumulating
Escherichia coli strain. The carotene-cleaving enzyme, identified here for the
first time on the molecular level, is the basis of the numerous branches of
vitamin A action and links plant and animal carotene metabolism.
PMID- 10766820
TI - Protein kinase C-beta and oxygen deprivation. A novel Egr-1-dependent pathway for
fibrin deposition in hypoxemic vasculature.
AB - Fibrin deposition is a salient feature of hypoxemic vasculature and results from
induction of tissue factor. Such tissue factor expression in an oxygen deficient
environment is driven by the transcription factor Early Growth Response (Egr)-1.
Using homozygous null mice for the protein kinase C beta-isoform gene (PKCbeta
null), PKCbeta is shown to be upstream of Egr-1 in this oxygen deprivation
mediated pathway for triggering procoagulant events. Whereas wild-type mice
exposed to hypoxia (6%) displayed a robust increase in tissue factor transcripts
and antigen, and vascular fibrin deposition, PKCbeta null animals showed a
markedly blunted response. Consistent with a central role for Egr-1 in hypoxia
induced expression of tissue factor, PKCbeta null mice subjected to oxygen
deprivation displayed at most a minor elevation in Egr-1 transcripts, antigen,
and intensity of the gel shift band by electrophoretic mobility shift assay,
compared with normoxic animals. These data firmly establish PKCbeta as a trigger
for events leading to induction of Egr-1 and tissue factor under hypoxic
conditions, and provide insight into a biologic cascade whereby oxygen
deprivation recruits targets of PKCbeta and Egr-1, thereby amplifying the
cellular response.
PMID- 10766821
TI - Induction of endothelial nitric-oxide synthase in rat brain astrocytes by
systemic lipopolysaccharide treatment.
AB - In the brain, three isoforms of nitric oxide (NO) synthase (NOS), namely neuronal
NOS (nNOS, NOS1), inducible NOS (iNOS, NOS2), and endothelial NOS (eNOS, NOS3),
have been implicated in biological roles such as neurotransmission,
neurotoxicity, immune function, and blood vessel regulation, each isoform
exhibiting in part overlapping roles. Previous studies showed that iNOS is
induced in the brain by systemic treatment with lipopolysaccharide (LPS), a Gram
negative bacteria-derived stimulant of the innate immune system. Here we found
that eNOS mRNA is induced in the rat brain by intraperitoneal injection of LPS of
a smaller amount than that required for induction of iNOS mRNA. The induction of
eNOS mRNA was followed by an increase in eNOS protein. Immunohistochemical
analysis revealed that eNOS is located in astrocytes of both gray and white
matters as well as in blood vessels. Induction of eNOS in response to a low dose
of LPS, together with its localization in major components of the blood-brain
barrier, suggests that brain eNOS is involved in early pathophysiologic response
against systemic infection before iNOS is induced with progression of the
infection.
PMID- 10766822
TI - Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding
lipid raft domains.
AB - Trp1 has been proposed as a component of the store-operated Ca(2+) entry (SOC)
channel. However, neither the molecular mechanism of SOC nor the role of Trp in
this process is yet understood. We have examined possible molecular interactions
involved in the regulation of SOC and Trp1 and report here for the first time
that Trp1 is assembled in signaling complex associated with caveolin-scaffolding
lipid raft domains. Endogenous hTrp1 and caveolin-1 were present in low density
fractions of Triton X-100-extracted human submandibular gland cell membranes.
Depletion of plasma membrane cholesterol increased Triton X-100 solubility of
Trp1 and inhibited carbachol-stimulated Ca(2+) signaling. Importantly,
thapsigargin stimulated Ca(2+) influx, but not internal Ca(2+) release, and
inositol 1,4,5-triphosphate (IP(3))-stimulated I(soc) were also attenuated.
Furthermore, both anti-Trp1 and anti-caveolin-1 antibodies co-immunoprecipitated
hTrp1, caveolin-1, Galpha(q/11), and IP(3) receptor-type 3 (IP(3)R3). These
results demonstrate that caveolar microdomains provide a scaffold for (i)
assembly of key Ca(2+) signaling proteins into a complex and (ii) coordination of
the molecular interactions leading to the activation of SOC. Importantly, we have
shown that Trp1 is also localized in this microdomain where it interacts with one
or more components of this complex, including IP(3)R3. This finding is
potentially important in elucidating the physiological function of Trp.
PMID- 10766823
TI - The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans
Golgi network and present in clathrin-coated vesicles.
AB - In recent years, a large family of phosphoinositide 3-kinase (PI3K) isozymes has
been characterized and cloned. Several of these PI3K enzymes have overlapping
tissue distributions and it remains unclear if and how their 3-phosphoinositide
products elicit differential, intracellular effects. One possibility is that the
PI3K enzymes display a restricted distribution within the cell to produce their 3
phospholipid products in specific, subcellular compartments. In the present study
we characterize the subcellular distribution of the novel class II PI3K isozyme
PI3K-C2alpha in several mammalian cell types. Differential centrifugation of COS
1 and U937 cells together with Western blot analysis demonstrated that PI3K
C2alpha is constitutively associated with phospholipid membranes. Centrifugation
of rat brain homogenates and Western blotting revealed that in contrast to the
class IA PI3K enzymes, PI3K-C2alpha could be co-purified with a population of
clathrin-coated vesicles (CCVs). Furthermore, a PI3K activity refractory to
wortmannin treatment was detected in CCV preparations consistent with the
presence of the PI3K-C2alpha isozyme. These biochemical observations were
supported by immunofluorescence analysis that revealed PI3K-C2alpha to have a
punctate distribution and an enrichment of immunoreactivity within a perinuclear
site consistent with its presence in the endoplasmic reticulum or Golgi
apparatus. Dual label immunofluorescence demonstrated that in this region, the
distribution of PI3K-C2alpha closely paralleled that of gamma-adaptin, a
component of the AP-1 adaptor that is present in the trans-Golgi and the trans
Golgi network (TGN) resident protein TGN-46. Neither the phospholipid association
nor the subcellular localization of PI3K-C2alpha was dependent upon either its
COOH-terminal PX or C2 domains. Mutants lacking these domains demonstrated a
similar distribution to the wild type enzyme when expressed as recombinant
proteins. Treatment of cells with brefeldin A disrupted the perinuclear staining
pattern of both PI3K-C2alpha and the AP-1 complex demonstrating that the
localization of both molecules at the TGN is dependent upon ADP-ribosylation
factor GTPase activity.
PMID- 10766824
TI - Identification of the subunit of cAMP receptor protein (CRP) that functionally
interacts with CytR in CRP-CytR-mediated transcriptional repression.
AB - At promoters of the Escherichia coli CytR regulon, the cAMP receptor protein
(CRP) interacts with the repressor CytR to form transcriptionally inactive CRP
CytR-promoter or (CRP)(2)-CytR-promoter complexes. Here, using "oriented
heterodimer" analysis, we show that only one subunit of the CRP dimer, the
subunit proximal to CytR, functionally interacts with CytR in CRP-CytR-promoter
and (CRP)(2)-CytR-promoter complexes. Our results provide information about the
architecture of CRP-CytR-promoter and (CRP)(2)-CytR-promoter complexes and rule
out the proposal that masking of activating region 2 of CRP is responsible for
the transcriptional inactivity of the complexes.
PMID- 10766825
TI - Cloning of a second dendritic cell-associated C-type lectin (dectin-2) and its
alternatively spliced isoforms.
AB - Using a subtractive cDNA cloning strategy, we isolated previously five novel
genes that were expressed abundantly by the murine dendritic cell (DC) line XS52,
but not by the J774 macrophage line. One of these genes encoded a unique, DC
associated C-type lectin, termed "dectin-1." Here we report the characterization
of a second novel gene that was also expressed in a DC-specific manner. Clone
1B12 encoded a type II membrane-integrated polypeptide of 209 amino acids
containing a single carbohydrate recognition domain motif in the COOH terminus.
The expression pattern of this molecule, termed "dectin-2," was almost
indistinguishable from that for dectin-1; that is, both were expressed abundantly
at mRNA and protein levels by the XS52 DC line, but not by non-DC lines, and both
were detected in spleen and thymus, as well as in skin resident DC (i.e.
Langerhans cells). Interestingly, reverse transcriptase-polymerase chain reaction
and immunoblotting revealed multiple bands of dectin-2 transcripts and proteins
suggesting molecular heterogeneity. In fact, we isolated additional cDNA clones
encoding two distinct, truncated dectin-2 isoforms. Genomic analyses indicated
that a full-length dectin-2 (alpha isoform) is encoded by 6 exons, whereas
truncated isoforms (beta and gamma) are produced by alternative splicing. We
propose that dectin-2 and its isoforms, together with dectin-1, represent a
unique subfamily of DC-associated C-type lectins.
PMID- 10766826
TI - X-ray crystal structure and characterization of halide-binding sites of human
myeloperoxidase at 1.8 A resolution.
AB - The x-ray crystal structure of human myeloperoxidase has been extended to 1.8 A
resolution, using x-ray data recorded at -180 degrees C (r = 0.197, free r =
0.239). Results confirm that the heme is covalently attached to the protein via
two ester linkages between the carboxyl groups of Glu(242) and Asp(94) and
modified methyl groups on pyrrole rings A and C of the heme as well as a
sulfonium ion linkage between the sulfur atom of Met(243) and the beta-carbon of
the vinyl group on pyrrole ring A. In the native enzyme a bound chloride ion has
been identified at the amino terminus of the helix containing the proximal
His(336). Determination of the x-ray crystal structure of a myeloperoxidase
bromide complex (r = 0.243, free r = 0.296) has shown that this chloride ion can
be replaced by bromide. Bromide is also seen to bind, at partial occupancy, in
the distal heme cavity, in close proximity to the distal His(95), where it
replaces the water molecule hydrogen bonded to Gln(91). The bromide-binding site
in the distal cavity appears to be the halide-binding site responsible for shifts
in the Soret band of the absorption spectrum of myeloperoxidase. It is proposed
that halide binding to this site inhibits the enzyme by effectively competing
with H(2)O(2) for access to the distal histidine, whereas in compound I, the same
site may be the halide substrate-binding site.
PMID- 10766827
TI - Requirement of phosphatidylinositol 3-kinase activity for translocation of
exogenous aFGF to the cytosol and nucleus.
AB - Acidic fibroblast growth factor (aFGF) is a potent mitogen for many cells.
Exogenous aFGF is able to enter the cytosol and nucleus of sensitive cells. There
are indications that both activation of the receptor tyrosine kinase and
translocation of aFGF to the nucleus are of importance for mitogenesis. However,
the mechanism of transport of aFGF from the cell surface to the nucleus is poorly
understood. In this work we demonstrate that inhibition of phosphatidylinositol
(PI) 3-kinase by chemical inhibitors and by expression of a dominant negative
mutant of PI 3-kinase blocks translocation of aFGF to the cytosol and nucleus.
Translocation to the cytosol and nucleus was monitored by cell fractionation, by
farnesylation of aFGF modified to contain a farnesylation signal, and by
phosphorylation by protein kinase C of aFGF added externally to cells. If aFGF is
fused to diphtheria toxin A-fragment, it can be artificially translocated from
the cell surface to the cytoplasm by the diphtheria toxin pathway. Upon further
incubation, the fusion protein enters the nucleus due to a nuclear localization
sequence in aFGF. We demonstrate here that upon inhibition of PI 3-kinase the
fusion protein remains in the cytosol. We also provide evidence that the
phosphorylation status of the fusion protein does not regulate its
nucleocytoplasmic distribution.
PMID- 10766828
TI - Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by
phosphatidylinositol 3-kinase.
AB - Ischemia is reported to stimulate glucose uptake, but the signaling pathways
involved are poorly understood. Modulation of glucose transport could be
important for the cardioprotective effects of brief intermittent periods of
ischemia and reperfusion, termed ischemic preconditioning. Previous work
indicates that preconditioning reduces production of acid and lactate during
subsequent sustained ischemia, consistent with decreased glucose utilization.
However, there are also data that preconditioning enhances glucose uptake. The
present study examines whether preconditioning alters glucose transport and
whether this is mediated by either phosphatidylinositol 3-kinase (PI3K) or p38
MAP kinase. Langendorff-perfused rat hearts were preconditioned with 4 cycles of
5 min of ischemia and 5 min of reperfusion, with glucose as substrate. During the
last reflow, glucose was replaced with 5 mM acetate and 5 mM 2-deoxyglucose
(2DG), and hexose transport was measured from the rate of production of 2
deoxyglucose 6-phosphate (2DG6P), using (31)P nuclear magnetic resonance.
Preconditioning stimulated 2DG uptake; after 15 min of perfusion with 2DG, 2DG6P
levels were 165% of initial ATP in preconditioned hearts compared with 96% in
control hearts (p < 0.05). Wortmannin, an inhibitor of PI3K, did not block the
preconditioning induced stimulation of 2DG6P production, but perfusion with
SB202190, an inhibitor of p38 MAP kinase, did attenuate 2DG6P accumulation (111%
of initial ATP, p < 0. 05 compared with preconditioned hearts). SB202190 had no
effect on 2DG6P accumulation in nonpreconditioned hearts. Preconditioning
stimulation of translocation of GLUT4 to the plasma membrane was not inhibited by
wortmannin. The data demonstrate that ischemic preconditioning increases hexose
transport and that this is mediated by p38 MAP kinase and is PI3K-independent.
PMID- 10766829
TI - Essential role of neural Wiskott-Aldrich syndrome protein in neurite extension in
PC12 cells and rat hippocampal primary culture cells.
AB - Neural Wiskott-Aldrich syndrome protein (N-WASP) is an actin-regulating protein
that induces filopodium formation downstream of Cdc42. It has been shown that
filopodia actively extend from the growth cone, a guidance apparatus located at
the tip of neurites, suggesting their role in neurite extension. Here we examined
the possible involvement of N-WASP in the neurite extension process. Since
verprolin, cofilin homology and acidic region (VCA) of N-WASP is known to be
required for the activation of Arp2/3 complex that induces actin polymerization,
we prepared a mutant (Deltacof) lacking four amino acid residues in the cofilin
homology region. The corresponding residues in WASP had been reported to be
mutated in some Wiskott-Aldrich syndrome patients. Expression of Deltacof N-WASP
suppressed neurite extension of PC12 cells. In support of this, the VCA region of
Deltacof cannot activate Arp2/3 complex enough compared with wild-type VCA.
Furthermore, H208D mutant, which has been shown unable to bind to Cdc42, also
works as a dominant negative mutant in neurite extension assay. Interestingly,
the expression of H208D-Deltacof double mutant has no significant dominant
negative effect. Finally, the expression of the Deltacof mutant also severely
inhibited the neurite extension of primary neurons from rat hippocampus. Thus, N
WASP is thought to be a general regulator of the actin cytoskeleton indispensable
for neurite extension, which is probably caused through Cdc42 signaling and
Arp2/3 complex-induced actin polymerization.
PMID- 10766831
TI - Megalin acts in concert with cubilin to mediate endocytosis of high density
lipoproteins.
AB - Cubilin has recently been shown to function as an endocytic receptor for high
density lipoproteins (HDL). The lack of apparent transmembrane and cytoplasmic
domains in cubilin raises questions as to the means by which it can mediate
endocytosis. Since cubilin has been reported to bind the endocytic receptor
megalin, we explored the possibility that megalin acts in conjunction with
cubilin to mediate HDL endocytosis. While megalin did not bind to HDL,
delipidated HDL, or apoA-I, it was found to copurify with cubilin isolated by HDL
Sepharose affinity chromatography. Cubilin and megalin exhibited coincident
patterns of mRNA expression in mouse tissues including the kidney, ileum, thymus,
placenta, and yolk sac endoderm. The expression of both receptors in yolk sac
endoderm-like cells was inducible by retinoic acid treatment but not by
conditions of sterol depletion. Suppression of megalin activity or expression by
treatment with either megalin antibodies or megalin antisense
oligodeoxynucleotides resulted in inhibition of cubilin-mediated endocytosis of
HDL. Furthermore, megalin antisense oligodeoxynucleotide treatment resulted in
reduced cell surface expression of cubilin. These data demonstrate that megalin
acts together with cubilin to mediate HDL endocytosis and further suggest that
megalin may play a role in the intracellular trafficking of cubilin.
PMID- 10766830
TI - Rho-A is critical for osteoclast podosome organization, motility, and bone
resorption.
AB - Rho plays a regulatory role in the formation of actin stress fibers and focal
adhesions, and it is also involved in integrin-mediated signaling events. To
study the role of Rho in alpha(v)beta(3)/gelsolin-dependent signaling, the HIV
Tat peptide, hemagglutinin (HA)-tagged Rho(Val-14) (constitutively active) and
Rho(Asn-19) (dominant negative) were transduced into avian osteoclasts. Protein
transduction by HA-Tat was highly efficient, and 90-100% of the cells were
transduced with HA-tagged proteins. We demonstrate here that Rho(Val-14)
transduction (100 nM) stimulated gelsolin-associated phosphatidylinositol 3
kinase activity, podosome assembly, stress fiber formation, osteoclast motility,
and bone resorption, mimicking osteoclast stimulation by
osteopontin/alpha(v)beta(3.) The effects of Rho(Val-14) transduction stimulation
was time-dependent. C3 exoenzyme blocked the effects of Rho(Val-14) and induced
podosome disassembly, loss of motility, and inhibition of bone resorption.
Transduction of Rho(Asn-19) produced podosome disassembly, and blocked
osteopontin stimulation. These data demonstrate that integrin-dependent
activation of phosphoinositide synthesis, actin stress fiber formation, podosome
reorganization for osteoclast motility, and bone resorption require Rho
stimulation.
PMID- 10766832
TI - The yeast mitochondrial citrate transport protein. Probing the secondary
structure of transmembrane domain iv and identification of residues that likely
comprise a portion of the citrate translocation pathway.
AB - The mitochondrial citrate transport protein (CTP) has been investigated by
replacing 22 consecutive residues within transmembrane domain IV, one at a time,
with cysteine. A cysteine-less CTP retaining wild-type functional properties
served as the starting template. The single Cys CTP variants were overexpressed
in Escherichia coli, isolated, and functionally reconstituted in a liposomal
system. The accessibility of each single Cys mutant to three methanethiosulfonate
reagents was evaluated by determining the pseudo first order rate constants for
inhibition of CTP function. These rate constants varied by seven orders of
magnitude. With three independent data sets we observed peaks and troughs in the
rate constant data at identical amino acid positions and a periodicity of four
was observed from residues 177-193. Based on the pattern of accessibility we
conclude that residues 177-193 exist as an alpha-helix. Furthermore, a water
accessible face of the helix has been defined consisting of Pro-177, Val-178, Arg
181, Gln-182, Asn-185, Gln-186, Arg-189, Leu-190, and Tyr-193, and a water
inaccessible face has been delineated consisting of Ser-179, Met-180, Ala-183,
Ala-184, Ala-187, Val-188, Gly-191, and Ser-192. We infer that the water
accessible face comprises a portion of the substrate translocation pathway
through the CTP, whereas the water-inaccessible surface faces the lipid bilayer.
PMID- 10766833
TI - Formation and characterization of a single Trp-Trp cross-link in indolicidin that
confers protease stability without altering antimicrobial activity.
AB - Indolicidin is a 13-residue cationic, antimicrobial peptide-amide isolated from
the cytoplasmic granules of bovine neutrophils. The unique composition of
indolicidin distinguishes it from alpha-helical and beta-structured cationic
peptides, because five of indolicidin's 13 residues are tryptophans: H-Ile-Leu
Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH(2). Solid phase synthesis of
indolicidin gave rise to a minor byproduct that possessed unusual fluorescence
and UV absorbance properties compared with authentic indolicidin. The byproduct
was purified by combined ion exchange and reversed phase high pressure liquid
chromatography steps and was shown be identical to authentic indolicidin in its
microbicidal activity against Staphylococcus aureus, Escherichia coli, Candida
albicans, and Cryptococcus neoformans. Mass analysis of the byproduct revealed a
2-atomic mass unit reduction compared with indolicidin, suggesting the
deprotonation of two indole side chains to form an intrachain delta(1),delta(1)'
ditryptophan derivative. We confirmed the nature of the cross-linked byproduct,
termed X-indolicidin, by absorbance and fluorescence spectroscopy, peptide
mapping, and sequence analysis. Edman degradation revealed that Trp-6 and Trp-9
were covalently cross-linked. Compared with indolicidin, X-indolicidin was
partially resistant to digestion with trypsin and chymotrypsin, suggesting that
the ditryptophan stabilizes a subset of molecular conformations that are protease
resistant but that are absent in the native structure.
PMID- 10766834
TI - Inhibition of phosphatidic acid synthesis alters the structure of the Golgi
apparatus and inhibits secretion in endocrine cells.
AB - In mammalian cells, activation of a Golgi-associated phospholipase D by ADP
ribosylation factor results in the hydrolysis of phosphatidylcholine to form
phosphatidic acid (PA). This reaction stimulates the release of nascent secretory
vesicles from the trans-Golgi network of endocrine cells. To understand the role
of PA in mediating secretion, we have exploited the transphosphatidylation
activity of phospholipase D. Rat anterior pituitary GH3 cells, which secrete
growth hormone and prolactin, were treated with 1-butanol resulting in the
synthesis of phosphatidylbutanol rather than PA. Under these conditions transport
from the ER through the Golgi apparatus and secretion of polypeptide hormones
were inhibited quantitatively. Furthermore, the in vitro synthesis of
phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) by Golgi membranes was
inhibited quantitatively. Most significantly, in the presence of 1-butanol the
architecture of the Golgi apparatus was disrupted, resulting in its disassembly
and fragmentation. Removal of the alcohol resulted in the rapid restoration of
Golgi structure and secretion of growth hormone and prolactin. Our results
suggest that PA stimulation of PtdIns(4,5)P(2) synthesis is required for
maintaining the structural integrity and function of the Golgi apparatus.
PMID- 10766835
TI - Receptor-mediated endocytosis in the procyclic form of Trypanosoma brucei.
AB - In Trypanosomatids, endocytosis and exocytosis occur exclusively at the flagellar
pocket, a deep invagination of the plasma membrane where the flagellum extends
from the cell. Both bloodstream and procyclic trypanosomes are capable of
internalizing macromolecules. However, structures resembling coated vesicles were
only identified in bloodstream form and not in procyclic form trypanosomes. Due
to the apparent absence of coated vesicles in procyclics, the significance of
receptor-mediated endocytosis in procyclic trypanosomes has been considered of
minimal importance. We show that the flagellar pocket associated cysteine-rich
acidic transmembrane protein (CRAM) may function as an high density lipoprotein
receptor in the procyclic form trypanosome. Using anti-CRAM IgG we have
characterized the process of CRAM-mediated endocytosis in procyclic form
trypanosomes. The wild type procyclic trypanosome binds and internalizes anti
CRAM IgG but not the non-immune IgG in a saturable and time-dependent manner; the
binding and uptake of (125)I-labeled anti-CRAM IgG are inhibited by excess
unlabeled anti-CRAM IgG. Uptake and degradation of anti-CRAM IgG do not occur at
4 degrees C. At 28 degrees C, the internalized anti-CRAM IgG were efficiently
degraded through a process that is inhibited by incubation at 4 degrees C and
sensitive to the presence of chloroquine. The uptake and degradation of anti-CRAM
IgG does not occur in the CRAM null mutant cell line. These results suggested
that the uptake of anti-CRAM IgG in the wild type procyclics occurs via receptor
mediated endocytosis of the CRAM protein. Deletion of the cytoplasmic extension
of CRAM drastically reduced the degradation but not the binding of anti-CRAM IgG.
This result indicated that potential internalization signals may be present in
the cytoplasmic extension of CRAM. This is the first time that the importance of
receptor-mediated endocytosis in procyclic form trypanosomes has been
demonstrated.
PMID- 10766836
TI - Regulation of microfilament reorganization and invasiveness of breast cancer
cells by kinase dead p21-activated kinase-1.
AB - Stimulation of growth factor signaling has been implicated in the development of
invasive phenotype and p21-activated kinase (PAK1) activation in human breast
epithelial cancer cells. To further explore the roles of PAK1 in the invasive
behavior of breast cancer cells, in the present study we investigated the
influence of inhibition of PAK1 activity on the reorganization of cytoskeleton
components that control motility and invasiveness of cells, using a highly
invasive breast cancer MDA-MB435 as a model system. Our results demonstrate that
overexpression of a kinase dead K299R PAK1 mutant leads to suppression of motile
phenotypes as well as invasiveness of cells both in the absence or presence of
exogenous heregulin-beta1. In addition, these phenotypic changes were accompanied
by a blockade of disassembly of focal adhesion points, stabilization of stress
fibers, and enhanced cell spreading and were dependent on the presence of the
kinase dead domain but independent of the presence of the Rac/cdc42 intact
(Cdc42/Rac interactive binding) domain of PAK1. We also demonstrated that in
K299R PAK1-expressing cells, F-actin filaments were stabilized by persistent co
localization with the actin-binding proteins tropomyosin and caldesmon. Extension
of these studies to invasive breast cancer MDA-MB231 cells illustrated that
conditional expression of kinase-defective K299R PAK1 was also accompanied by
persistent cell spreading, multiple focal adhesion points, and reduced
invasiveness. Furthermore, inhibition of PAK1 activity in breast cancer cells was
associated with a reduction in c-Jun N-terminal kinase activity, inhibition of
DNA binding activity of transcription factor AP-1, and suppression of in vivo
transcription driven by AP-1 promoter (known to be involved in breast cancer
invasion). These findings suggest that PAK1 downstream pathways have a role in
the development and maintenance of invasive phenotypes in breast cancer cells.
PMID- 10766837
TI - Amastin mRNA abundance in Trypanosoma cruzi is controlled by a 3'-untranslated
region position-dependent cis-element and an untranslated region-binding protein.
AB - The genome of Trypanosoma cruzi contains tandem arrays of alternating genes
encoding amastin and tuzin. Amastin is a surface glycoprotein abundantly
expressed on the intracellular mammalian amastigote form of the protozoan
parasite, and tuzin is a G-like protein. We demonstrated previously that the
amastin-tuzin gene cluster is polycistronically transcribed to an equal extent in
all parasite life cycle stages. The steady state level of amastin mRNA, however,
is 68-fold more abundant in amastigotes than in epimastigotes. Here we show that
the half-life of amastin mRNA is 7 times longer in amastigotes than in
epimastigotes. Linker replacement experiments demonstrate that the middle one
third of the 630-nucleotide 3'-untranslated region (UTR) is responsible for the
amastin mRNA up-regulation. This positive effect is dependent on the distance of
the 3'-UTR segment from the stop codon and the polyadenylation site as well as on
its orientation. A protein or protein complex more abundant in amastigotes than
in epimastigotes binds to this minimally defined 3'-UTR segment and may be
involved in its regulatory function.
PMID- 10766838
TI - Human ribosomal protein L5 contains defined nuclear localization and export
signals.
AB - Ribosomal protein L5 is part of the 60 S ribosomal subunit and localizes in both
the cytoplasm and the nucleus of eukaryotic cells, accumulating particularly in
the nucleoli. L5 is known to bind specifically to 5 S rRNA and is involved in
nucleocytoplasmic transport of this rRNA. Here, we report a detailed analysis of
the domain organization of the human ribosomal protein L5. We show that a signal
that mediates nuclear import and nucleolar localization maps to amino acids 21-37
within the 297-amino acid L5 protein. Furthermore, carboxyl-terminal residues at
positions 255-297 serve as an additional nuclear/nucleolar targeting signal.
Domains involved in 5 S rRNA binding are located at both the amino terminus and
the carboxyl terminus of L5. Microinjection studies in somatic cells demonstrate
that a nuclear export signal (NES) that maps to amino acids 101-111 resides in
the central region of L5. This NES is characterized by a pronounced clustering of
critical leucine residues, which creates a peptide motif not previously observed
in other leucine-rich NESs. Finally, we present a refined model of the
multidomain structure of human ribosomal protein L5.
PMID- 10766839
TI - A novel role for phosphatidylinositol 3-kinase beta in signaling from G protein
coupled receptors to Akt.
AB - The protein kinase Akt plays a central role in a number of key biological
functions including protein synthesis, glucose homeostasis, and the regulation of
cell survival or death. The mechanism by which tyrosine kinase growth factor
receptors stimulate Akt has been recently defined. In contrast, the mechanism of
activation of Akt by other cell surface receptors is much less understood. For G
protein-coupled receptors (GPCRs), conflicting data suggest that these receptors
stimulate Akt in a cell type-specific manner by a yet to be fully elucidated
mechanism. Here, we took advantage of the availability of cells, where Akt
activity could not be enhanced by agonists acting on this large family of cell
surface receptors, such as NIH 3T3 cells, to investigate the pathway linking
GPCRs to Akt. We present evidence that expression of phosphatidylinositol 3
kinase (PI3K) beta is necessary and sufficient to transmit signals from G
proteins to Akt in these murine fibroblasts and that the activation of PI3Kbeta
may represent the most likely mechanism whereby GPCRs stimulate Akt, as the vast
majority of cells do not express PI3Kgamma, a known G protein-sensitive PI3K
isoform. Furthermore, available evidence indicates that GPCRs activate Akt by a
pathway distinct from that utilized by growth factor receptors, as it involves
the tyrosine phosphorylation-independent activation of PI3Kbeta by G protein
betagamma dimers.
PMID- 10766840
TI - Ubiquitination of free cyclin D1 is independent of phosphorylation on threonine
286.
AB - Cyclin D1 binds and regulates the activity of cyclin-dependent kinases (CDKs) 4
and 6. Phosphorylation of the retinoblastoma protein by cyclin D1.CDK4/6
complexes during the G(1) phase of the cell cycle promotes entry into S phase.
Cyclin D1 protein is ubiquitinated and degraded by the 26 S proteasome. Previous
studies have demonstrated that cyclin D1 ubiquitination is dependent on its
phosphorylation by glycogen synthase kinase 3beta (GSK-3beta) on threonine 286
and that this phosphorylation event is greatly enhanced by binding to CDK4
(Diehl, J. A., Cheng, M. G., Roussel, M. F., and Sherr, C. J. (1998) Genes Dev.
12, 3499-3511). We now report an additional pathway for the ubiquitination of
free cyclin D1 (unbound to CDKs). We show that, when unbound to CDK4, a cyclin D1
T286A mutant is ubiquitinated. Further, we show that a mutant of cyclin D1 that
cannot bind to CDK4 (cyclin D1-KE) is also ubiquitinated in vivo. Our results
demonstrate that free cyclin D1 is ubiquitinated independently of its
phosphorylation on threonine 286 by GSK-3beta, suggesting that, as has been shown
for cyclin E, distinct pathways of ubiquitination lead to the degradation of free
and CDK-bound cyclin D1. The pathway responsible for ubiquitination of free
cyclin D1 may be important in limiting the effects of cyclin D1 overexpression in
a variety of cancers.
PMID- 10766841
TI - Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to
tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and
pro-MMP-2 activation.
AB - Previous studies have shown that membrane type 1-matrix metalloproteinase (MT1
MMP) (MMP-14) initiates pro-MMP-2 activation in a process that is tightly
regulated by the level of tissue inhibitor of metalloproteinase (TIMP)-2.
However, given the difficulty in modulating TIMP-2 levels, the direct effect of
TIMP-2 on MT1-MMP processing and on pro-MMP-2 activation in a cellular system
could not be established. Here, recombinant vaccinia viruses encoding full-length
MT1-MMP or TIMP-2 were used to express MT1-MMP alone or in combination with
various levels of TIMP-2 in mammalian cells. We show that TIMP-2 regulates the
amount of active MT1-MMP (57 kDa) on the cell surface whereas in the absence of
TIMP-2 MT1-MMP undergoes autocatalysis to a 44-kDa form, which displays a N
terminus starting at Gly(285) and hence lacks the entire catalytic domain.
Neither pro-MT1-MMP (N terminus Ser(24)) nor the 44-kDa form bound TIMP-2. In
contrast, active MT1-MMP (N terminus Tyr(112)) formed a complex with TIMP-2
suggesting that regulation of MT1-MMP processing is mediated by a complex of TIMP
2 with the active enzyme. Consistently, TIMP-2 enhanced the activation of pro-MMP
2 by MT1-MMP. Thus, under controlled conditions, TIMP-2 may act as a positive
regulator of MT1-MMP activity by promoting the availability of active MT1-MMP on
the cell surface and consequently, may support pericellular proteolysis.
PMID- 10766842
TI - Functional analysis of the C-terminal region of recombinant human thrombopoietin.
C-terminal region of thrombopoietin is a "shuttle" peptide to help secretion.
AB - Thrombopoietin (TPO) is a cytokine that primarily stimulates megakaryocytopoiesis
and thrombopoiesis. TPO has a unique C-terminal tail peptide of about 160 amino
acids that consists mostly of hydrophilic residues and contains six N-linked
sugar chains. In order to investigate the biological function of the C-terminal
domain, two series of mutations were performed. One is systematic truncation from
the C terminus. Another is elimination of N-glycosylation sites in the C-terminal
domain by Asn to Gln mutations. After the mutant proteins were expressed by
mammalian cells, it was found that the elimination of the N-linked sugar sites
did not affect the biological activity, whereas truncation of the C-terminal
domain resulted in elevation of in vitro activity up to 4-fold. The C-terminal
peptide itself was found to inhibit the in vitro activity. Moreover, both the C
terminal truncation and the elimination of the N-glycosylation sites decreased
the secretion level progressively down to (1)/(10) that of wild type, and the
amount of the mutant left in the cell increased. The N-glycosylation in the C
terminal region was found to be important for secretion of TPO. Among six N
glycosylation sites in the C-terminal region, two locations, Asn-213 and Asn-234,
were found to be critical for secretion, and two other locations, Asn-319 and Asn
327, did not affect the secretion.
PMID- 10766843
TI - Cyclooxygenase-2 expression inhibits trophic withdrawal apoptosis in nerve growth
factor-differentiated PC12 cells.
AB - Cyclooxygenase-2 (Cox-2), an enzyme responsible for catalyzing the committed step
in prostanoid biosynthesis, is the product of an immediate early gene capable of
being up-regulated by diverse stimuli. Significantly Cox-2 mRNA is absent from
rat pheochromocytoma (PC12) cells, both basally and following stimulation with a
range of agonists. Using PC12 cells engineered to stably express isopropyl-1-thio
beta-D-galactopyranoside-inducible Cox-2 (PCXII-4), we have investigated the
putative effects of Cox-2 expression on differentiation, proliferation, and
trophic withdrawal apoptosis. Cox-2 bioactivity had no effect on nerve growth
factor-induced differentiation, epidermal growth factor-induced proliferation, or
aromatic L-amino acid decarboxylase expression. However, trophic withdrawal
apoptosis, induced by the removal of nerve growth factor following
differentiation, was markedly reduced in the PCXII-4 when compared with control
cells, as assessed by annexin V staining, DNA laddering, and Hoechst 33258
staining. The specificity of this effect was confirmed using two
pharmacologically distinct nonsteroidal anti-inflammatory drugs, indomethacin and
NS398. Investigations showed that the activity of the pro-apoptotic protease
caspase-3 was reduced in PCXII cells. This study demonstrates that Cox-2-derived
prostaglandins exert cytoprotective effects in trophic factor withdrawal
apoptosis and provides evidence that this is, at least in part, due to
suppression of caspase-3 activity.
PMID- 10766844
TI - The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1)
interacts with Pelle and regulates NFkappaB activity.
AB - A member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF)
family was identified in Drosophila. DTRAF1 contains 7 zinc finger domains
followed by a TRAF domain, similar to mammalian TRAFs and other members of the
family identified in data bases from Caenorhabditis elegans, Arabidopsis, and
Dictyostelium. Analysis of DTRAF1 binding to different members of the human TNF
receptor family showed that this protein can interact through its TRAF domain
with the p75 neurotrophin receptor and weakly with the lymphotoxin-beta receptor.
DTRAF1 can also self-associate and binds to human TRAF1, TRAF2, and TRAF4.
Interestingly, DTRAF1 interacts with human cIAP-1 and cIAP-2 but not with
Drosophila DIAP-1 and -2. By itself, DTRAF1 did not induce significant NFkappaB
activation when overexpressed in mammalian cells, although it specifically
increased NFkappaB induction by TRAF6. In contrast, TRAF2-mediated NFkappaB
induction was partially inhibited by DTRAF1. Mutants of DTRAF1 lacking the N
terminal region inhibited NFkappaB induction by either TRAF2 or TRAF6. DTRAF1
specifically associated with the regulatory N-terminal domain of Pelle, a
Drosophila homolog of the human kinase interleukin-1 receptor-associated kinase
(IRAK). Interestingly, though Pelle and DTRAF1 individually were unable to induce
NFkappaB in a human cell line, co-expression of Pelle and DTRAF1 resulted in
significant NFkappaB activity. Interactions of DTRAF1 with human TRAF-, TNF
receptor-, and IAP-family proteins imply strong evolutionary conservation of TRAF
protein structure and function throughout Metazoan evolution.
PMID- 10766845
TI - Differential role of hepatocyte nuclear factor-1 in the regulation of glucose-6
phosphatase catalytic subunit gene transcription by cAMP in liver- and kidney
derived cell lines.
AB - In liver and kidney, the terminal step in gluconeogenesis is catalyzed by glucose
6-phosphatase. To examine the effect of the cAMP signal transduction pathway on
transcription of the gene encoding the catalytic subunit of glucose-6-phosphatase
(G6Pase), G6Pase-chloramphenicol acetyltransferase (CAT) fusion genes were
transiently transfected into either the liver-derived HepG2 or kidney-derived LLC
PK cell line. Co-transfection of an expression vector encoding the catalytic
subunit of cAMP-dependent protein kinase (PKA) markedly stimulated G6Pase-CAT
fusion gene expression, and mutational analysis of the G6Pase promoter revealed
that multiple regions are required for this PKA response in both the HepG2 and
LLC-PK cell lines. A sequence in the G6Pase promoter that resembles a cAMP
response element is required for the full PKA response in both HepG2 and LLC-PK
cells. However, in LLC-PK cells, but not in HepG2 cells, a hepatocyte nuclear
factor-1 (HNF-1) binding site was critical for the full induction of G6Pase-CAT
expression by PKA. Changing this HNF-1 motif to that for the yeast transcription
factor GAL4 reduces the PKA response in LLC-PK cells to the same degree as
deleting the HNF-1 site. However, co-transfection of this mutated construct with
chimeric proteins comprising the GAL4-DNA binding domain ligated to the coding
sequence for HNF-1alpha, HNF-1beta, HNF-3, or HNF-4 completely restored the PKA
response. Thus, we hypothesize that, in LLC-PK cells, HNF-1 is acting as an
accessory factor to enhance PKA signaling through the cAMP response element by
altering G6Pase promoter conformation or accessibility rather than specifically
affecting some component of the PKA signal transduction pathway.
PMID- 10766846
TI - Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes.
AB - In rat embryos, fibroblast growth factor (FGF)-16 is predominantly expressed in
brown adipose tissue. To elucidate the role of FGF-16, we examined the expression
of FGF-16 mRNA in rat embryonic brown adipose tissue at different developmental
stages by Northern blotting analysis and in situ hybridization. FGF-16 mRNA was
expressed abundantly in brown adipose tissue during embryonic day 17. 5,
embryonic days 17.5-19.5, and thereafter at lower levels into the neonatal
period. The expression profile of FGF-16 mRNA well corresponds to the
proliferative profile of embryonic brown adipose tissue reported. We also
examined the mitogenic activity of recombinant rat FGF-16 for primary brown
adipocytes prepared from rat embryonic brown adipose tissue. FGF-16 showed
significant mitogenic activity for primary brown adipocytes. The mitogenic
activity was found to be exerted by binding and activating FGF receptor-4 in the
brown adipose tissue. As a great induction of proliferation of rat brown adipose
tissue during cold acclimation was reported, we also examined the expression of
FGF-16 mRNA in the brown adipose tissue during cold acclimation by Northern
blotting analysis. The expression of FGF-16 mRNA was not increased, but rather
decreased. The expression profile of FGF-16 mRNA and the mitogenic activity of
FGF-16 reported here indicate that FGF-16 is a unique growth factor involved in
proliferation of embryonic brown adipose tissue.
PMID- 10766847
TI - The downstream regulatory element of the proU operon of Salmonella typhimurium
inhibits open complex formation by RNA polymerase at a distance.
AB - The intracellular concentration of K(+)-glutamate, chromatin-associated proteins,
and a downstream regulatory element (DRE) overlapping with the coding sequence,
have been implicated in the regulation of the proU operon of Salmonella
typhimurium. The basal expression of the proU operon is low, but it is rapidly
induced when the bacteria are grown in media of high osmolarity (e.g. 0.3 M
NaCl). It has previously been suggested that increased intracellular
concentrations of K(+)-glutamate activate the proU promoter in response to
increased extracellular osmolarity. We show here that the activation of the proU
promoter by K(+)-glutamate in vitro is nonspecific, and the in vivo regulation
cannot simply be mimicked in vitro. In vivo specificity requires both the
chromatin-associated protein H-NS and the DRE; they are both needed to maintain
repression of proU expression at low osmolarity. How H-NS and the DRE repress the
proU promoter in vivo has so far been unclear. We show that, in vivo, the DRE
acts at a distance to inhibit open complex formation at the proU promoter.
PMID- 10766848
TI - Maximal inhibition of SERCA2 Ca(2+) affinity by phospholamban in transgenic
hearts overexpressing a non-phosphorylatable form of phospholamban.
AB - Phospholamban is a phosphoprotein in the cardiac sarcoplasmic reticulum (SR)
which regulates the apparent Ca(2+) affinity of the SR Ca(2+)-ATPase (SERCA2). To
determine the levels of phospholamban which are associated with maximal
inhibition of SERCA2, several lines of transgenic mice were generated which
expressed increasing levels of a non-phosphorylatable form of phospholamban
(S16A,T17A) specifically in the heart. This mutant form of phospholamban was
chosen to prevent phosphorylation as a compensatory mechanism in vivo.
Quantitative immunoblotting revealed increased phospholamban protein levels of
1.8-, 2.6-, 3.7-, and 4.7-fold in transgenic hearts compared with wild types.
There were no changes in the expression levels of SERCA2, calsequestrin,
calreticulin, and ryanodine receptor. Assessment of SR Ca(2+) uptake in hearts of
transgenic mice indicated increases in the inhibition of the affinity of SERCA2
for Ca(2+) with increased phospholamban expression. Maximal inhibition was
obtained at phospholamban expression levels of 2.6-fold or higher. Transgenic
hearts with functional saturation in phospholamban:SERCA2 (>/=2.6:1) exhibited
increases in beta-myosin heavy chain expression, associated with cardiac
hypertrophy. These findings demonstrate that overexpression of a non
phosphorylatable form of phospholamban in transgenic mouse hearts resulted in
saturation of the functional phospholamban:SERCA2 ratio at 2.6:1 and suggest that
approximately 40% of the SR Ca(2+) pumps are functionally regulated by
phospholamban in vivo.
PMID- 10766849
TI - The lipophilicity of phorbol esters as a critical factor in determining the
pattern of translocation of protein kinase C delta fused to green fluorescent
protein.
AB - Our previous study showed differential subcellular localization of protein kinase
C (PKC) delta by phorbol esters and related ligands, using a green fluorescent
protein-tagged construct in living cells. Here we compared the abilities of a
series of symmetrically substituted phorbol 12,13-diesters to translocate PKC
delta. In vitro, the derivatives bound to PKC with similar potencies but differed
in rate of equilibration. In vivo, the phorbol diesters with short, intermediate,
and long chain fatty acids induced distinct patterns of translocation. Phorbol
12,13-dioctanoate and phorbol 12,13-nonanoate, the intermediate derivatives and
most potent tumor promoters, showed patterns of translocation typical of phorbol
12-myristate 13-acetate, with plasma membrane and subsequent nuclear membrane
translocation. The more hydrophilic compounds (phorbol 12,13-dibutyrate and
phorbol 12,13-dihexanoate) induced a patchy distribution in the cytoplasm, more
prominent nuclear membrane translocation, and little plasma membrane localization
at all concentrations examined (100 nM to 10 microM). The highly lipophilic
derivatives, phorbol 12,13-didecanoate and phorbol 12, 13-diundecanoate, at 1
microM caused either plasma membrane translocation only or no translocation at
incubation times up to 60 min. Our results indicate that lipophilicity of phorbol
esters is a critical factor contributing to differential PKC delta localization
and thereby potentially to their different biological activities.
PMID- 10766850
TI - A role for the dynamic acylation of a cluster of cysteine residues in regulating
the activity of the glycosylphosphatidylinositol-specific phospholipase C of
Trypanosoma brucei.
AB - The glycosylphosphatidylinositol-specific phospholipase C or VSG lipase is the
enzyme responsible for the cleavage of the glycosylphosphatidylinositol anchor of
the variant surface glycoprotein (VSG) and concomitant release of the surface
coat in Trypanosoma brucei during osmotic shock or extracellular acidic stress.
In Xenopus laevis oocytes the VSG lipase was expressed as a nonacylated and a
thioacylated form. This thioacylation occurred within a cluster of three cysteine
residues but was not essential for catalytic activity per se. These two forms
were also detected in trypanosomes and appeared to be present at roughly
equivalent amounts. A reversible shift to the acylated form occurred when cells
were triggered to release the VSG by either nonlytic acid stress or osmotic
lysis. A wild type VSG lipase or a gene mutated in the three codons for the
acylated cysteines were reinserted in the genome of a trypanosome null mutant for
this gene. A comparative analysis of these revertant trypanosomes indicated that
thioacylation might be involved in regulating enzyme access to the VSG substrate.
PMID- 10766851
TI - Single repeat deletion in ApoA-I blocks cholesterol esterification and results in
rapid catabolism of delta6 and wild-type ApoA-I in transgenic mice.
AB - The deletion mutation Delta6 apolipoprotein A-I lacks residues 143-164 or repeat
6 in the mature apoA-I protein. In vitro studies show this mutation dramatically
reduces the rate of lecithin:cholesterol acyltransferase (LCAT) catalyzed
cholesterol esterification. The present study was initiated to investigate the
effect of this mutation on in vivo high density lipoprotein (HDL) cholesterol
esterification and metabolism. Transgenic mice expressing human Delta6 apoA-I
(TgDelta6 +/+) were created and then crossed with apoA-I knockout mice (-/-) to
generate mice expressing only human Delta6 apoA-I (TgDelta6 -/-). Human Delta6
apoA-I was associated with homogeneous sized alpha-HDL, when wild-type mouse apoA
I was present (in TgDelta6 +/+ and +/- mice). However, in the absence of
endogenous mouse apoA-I, Delta6 apoA-I was found exclusively in cholesterol ester
poor HDL, and lipid-free HDL fractions. This observation coincides with the 6
fold lower cholesterol ester mass in TgDelta6 -/- mouse plasma compared with
control. Structural studies show that despite the structural perturbation of a
domain extending from repeat 5 to repeat 8 (137-178), Delta6 apoA-I binds to
spherical unilamellar vesicles with only 2-fold less binding affinity. In
summary, these data show a domain corresponding to apoA-I repeat 6 is responsible
for providing an essential conformation for LCAT catalyzed generation of
cholesterol esters. Deletion of apoA-I repeat 6 not only blocks normal levels of
cholesterol esterification but also exerts a dominant inhibition on the ability
of wild-type apoA-I to activate LCAT in vivo.
PMID- 10766852
TI - Multiple O-glycoforms on the spore coat protein SP96 in Dictyostelium discoideum.
Fuc(alpha1-3)GlcNAc-alpha-1-P-Ser is the major modification.
AB - A decreased level of fucosylation on certain spore coat proteins of Dictyostelium
discoideum alters the permeability of the spore coat. Here the post-translational
modifications of a major spore coat protein, SP96, are studied in a wild type
strain (X22) and a fucosylation-defective mutant (HU2470). A novel phosphoglycan
structure on SP96 of the wild type strain, consisting of Fuc(alpha1-3)GlcNAc
alpha-1-P-Ser(,) was identified by electrospray ionization mass spectrometry and
NMR. It was shown using monosaccharide and gas chromatography mass spectrometry
analysis that SP96 in the mutant HU2470 contained approximately 20% of wild type
levels of fucose, as a result of a missing terminal fucose on the novel glycan
structure. The results support previous predictions, based on inhibition studies
on different fucose-deficient strains, about the nature of monoclonal antibody
epitopes identified by monoclonal antibodies MUD62 and MUD166, which are known to
identify O-linked glycans (Champion, A., Griffiths, K., Gooley, A. A., Gonzalez,
B. Y., Gritzali, M., West, C. M., and Williams, K. L. (1995) Microbiology 141,
785-797). Quantitative studies on wild type SP96 indicated that there were
approximately 60 sites with phosphodiester-linked N-acetylglucosamine-fucose
disaccharide units and a further approximately 20 sites with fucose directly
linked to the protein. Over 70% of the serine sites are modified, with less than
1% of these sites as phosphoserine. Threonine and tyrosine residues were not
found to be modified.
PMID- 10766853
TI - Lead and calcium produce rod photoreceptor cell apoptosis by opening the
mitochondrial permeability transition pore.
AB - Calcium overload is suggested to play a fundamental role in the process of rod
apoptosis in chemical-induced and inherited retinal degenerations. However, this
hypothesis has not been tested directly. We developed an in vitro model utilizing
isolated rat retinas to determine the mechanisms underlying Ca(2+)- and/or Pb(2+)
induced retinal degeneration. Confocal microscopy, histological, and biochemical
studies established that the elevated [Ca(2+)] and/or [Pb(2+)] were localized to
photoreceptors and produced rod-selective apoptosis. Ca(2+) and/or Pb(2+) induced
mitochondrial depolarization, swelling, and cytochrome c release. Subsequently
caspase-9 and caspase-3 were sequentially activated. Caspase-7 and caspase-8 were
not activated. The effects of Ca(2+) and Pb(2+) were additive and blocked
completely by the mitochondrial permeability transition pore (PTP) inhibitor
cyclosporin A, whereas the calcineurin inhibitor FK506 had no effect. The caspase
inhibitors carbobenzoxy-Leu-Glu-His-Asp-CH(2)F and carbobenzoxy-Asp-Glu-Val-Asp
CH(2)F, but not carbobenzoxy-Ile-Glu-Thr-Asp-CH(2)F, differentially blocked post
mitochondrial events. The levels of reduced and oxidized glutathione and pyridine
nucleotides in rods were unchanged. Our results demonstrate that rod mitochondria
are the target site for Ca(2+) and Pb(2+). Moreover, they suggest that Ca(2+) and
Pb(2+) bind to the internal metal (Me(2+)) binding site of the PTP and
subsequently open the PTP, which initiates the cytochrome c-caspase cascade of
apoptosis in rods.
PMID- 10766854
TI - mRNA and protein stability regulate the differential expression of pro- and anti
inflammatory genes in endotoxin-tolerant THP-1 cells.
AB - The products of proinflammatory genes such as interleukin-1beta (IL-1beta) and
cyclooxygenase-2 (COX-2) initiate many of the events associated with sepsis.
Transcription of these genes is subsequently down-regulated, whereas expression
of anti-inflammatory genes such as secretory interleukin-1 receptor antagonist
(sIL-1 RA) is maintained. Differential expression is associated with endotoxin
tolerance, a cellular phenomenon common to sepsis and characterized by reduced
proinflammatory gene expression after repeated exposure to lipopolysaccharide. As
a model for endotoxin tolerance, we examined the expression of COX-2 and sIL-1 RA
in a human promonocyte cell line, THP-1. We observed a 5-fold decrease in COX-2
protein in endotoxin-tolerant cells relative to control cells. In contrast, sIL-1
RA protein increased 5-fold in control and tolerant cells and remained elevated.
Decreased COX-2 production is due to repressed transcription and not enhanced
mRNA degradation. In addition, COX-2 protein is turned over rapidly.
Transcription of sIL-1 RA is also repressed during tolerance. However, sIL-1 RA
mRNA is degraded more slowly than COX-2 mRNA, allowing continued synthesis of sIL
1 RA protein that is very stable. These results indicate that differential
expression during endotoxin tolerance occurs by transcriptional repression of COX
2 and by protein and mRNA stabilization of sIL-1 RA.
PMID- 10766855
TI - Reversible phosphorylation of the signal transduction complex in Drosophila
photoreceptors.
AB - In the Drosophila visual cascade, the transient receptor potential (TRP) calcium
channel, phospholipase Cbeta (no-receptor-potential A), and an eye-specific
isoform of protein kinase C (eye-PKC) comprise a multimolecular signaling complex
via their interaction with the scaffold protein INAD. Previously, we showed that
the interaction between INAD and eye-PKC is a prerequisite for deactivation of a
light response, suggesting eye-PKC phosphorylates proteins in the complex. To
identify substrates of eye-PKC, we immunoprecipitated the complex from head
lysates using anti-INAD antibodies and performed in vitro kinase assays. Wild
type immunocomplexes incubated with [(32)P]ATP revealed phosphorylation of TRP
and INAD. In contrast, immunocomplexes from inaC mutants missing eye-PKC,
displayed no phosphorylation of TRP or INAD. We also investigated protein
phosphatases that may be involved in the dephosphorylation of proteins in the
complex. Dephosphorylation of TRP and INAD was partially suppressed by the
protein phosphatase inhibitors okadaic acid, microcystin, and protein phosphatase
inhibitor-2. These phosphatase activities were enriched in the cytosol of wild
type heads, but drastically reduced in extracts prepared from glass mutants,
which lack photoreceptors. Our findings indicate that INAD functions as RACK
(receptor for activated PKC), allowing eye-PKC to phosphorylate INAD and TRP.
Furthermore, dephosphorylation of INAD and TRP is catalyzed by PP1/PP2A-like
enzymes preferentially expressed in photoreceptor cells.
PMID- 10766856
TI - Persistent activation of ERK contributes to glutamate-induced oxidative toxicity
in a neuronal cell line and primary cortical neuron cultures.
AB - Oxidative stress can trigger neuronal cell death and has been implicated in
several chronic neurological diseases and in acute neurological injury. Oxidative
toxicity can be induced by glutamate treatment in cells that lack ionotrophic
glutamate receptors, such as the immortalized HT22 hippocampal cell line and
immature primary cortical neurons. Previously, we found that neuroprotective
effects of geldanamycin, a benzoquinone ansamycin, in HT22 cells were associated
with a down-regulation of c-Raf-1, an upstream activator of the extracellular
signal-regulated protein kinases (ERKs). ERK activation, although often
attributed strictly to neuronal cell survival and proliferation, can also be
associated with neuronal cell death that occurs in response to specific insults.
In this report we show that delayed and persistent activation of ERKs is
associated with glutamate-induced oxidative toxicity in HT22 cells and immature
primary cortical neuron cultures. Furthermore, we find that U0126, a specific
inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and
immature primary cortical neuron cultures from glutamate toxicity. Glutamate
induced ERK activation requires the production of specific arachidonic acid
metabolites and appears to be downstream of a burst of reactive oxygen species
(ROS) accumulation characteristic of oxidative stress in HT22 cells. However,
inhibition of ERK activation reduces glutamate-induced intracellular Ca(2+)
accumulation. We hypothesize that the precise kinetics and duration of ERK
activation may determine whether downstream targets are mobilized to enhance
neuronal cell survival or ensure cellular demise.
PMID- 10766857
TI - Cellular differentiation causes a selective down-regulation of interleukin (IL)
1beta-mediated NF-kappaB activation and IL-8 gene expression in intestinal
epithelial cells.
AB - Interleukin (IL)-1beta signals through various adapter proteins and kinases that
lead to activation of numerous downstream targets, including the transcription
factors including NF-kappaB. In this study, we analyzed and characterized the
effect of the differentiation of intestinal epithelial cells on IL-1beta-mediated
NF-kappaB activation and IL-8 gene expression. We report that IL-8 mRNA
accumulation and protein secretion were down-regulated in IL-1beta- and
lipopolysaccharide-stimulated differentiated HT-29 cells (HT-29/MTX, where MTX is
methotrexate) compared with undifferentiated cells (HT-29/p), whereas no
differential effects were found following tumor necrosis factor (TNF)-alpha or
phorbol myristate acetate stimulation. Cross-linking and affinity binding studies
reveal that IL-1beta exclusively binds the type I receptor (IL-1RI) and not IL
1RII in both HT-29/p and HT-29/MTX cells. IL-1beta-mediated IkappaB kinase and c
Jun N-terminal kinase (JNK) activity were both diminished in differentiated HT-29
cells. DNA binding activity in differentiated HT-29 cells relative to HT-29/p
cells was strongly reduced following IL-1beta exposure but not after TNF-alpha
stimulation. The proximal IL-1 signaling molecule IL-1 receptor-associated kinase
was not degraded in IL-1beta-stimulated HT-29 cells, in contrast to Caco-2 cells.
kappaB-luciferase reporter gene activity was 16-fold higher following TNF
receptor-associated factor-6 transfection after IL-1beta stimulation in HT-29/MTX
cells. We conclude that cellular differentiation of HT-29 cells selectively
impairs the IL-1beta signaling pathway inhibiting both NF-kappaB and JNK activity
in response to IL-1beta. This relative unresponsiveness to IL-1beta may represent
an important regulatory mechanism of differentiated intestinal epithelial cells.
PMID- 10766858
TI - Transcriptional regulation of the divergent paa catabolic operons for
phenylacetic acid degradation in Escherichia coli.
AB - The expression of the divergently transcribed paaZ and paaABCDEFGHIJK catabolic
operons, which are responsible for phenylacetic acid (PA) degradation in
Escherichia coli, is driven by the Pz and Pa promoters, respectively. To study
the transcriptional regulation of the inducible paa catabolic genes, genetic and
biochemical approaches were used. Gel retardation assays showing that the PaaX
regulator binds specifically to the Pa and Pz promoters were complemented with in
vivo experiments that indicated a PaaX-mediated repression effect on the
expression of Pa-lacZ and Pz-lacZ reporter fusions. The region within the Pa and
Pz promoters that is protected by the PaaX repressor in DNase I footprinting
assays contains a conserved 15-base pair imperfect palindromic sequence motif
that was shown, through mutational analysis, to be indispensable for PaaX binding
and repression. PA-coenzyme A (PA-CoA), but not PA, specifically inhibited
binding of PaaX to the target sequences, thus confirming the first intermediate
of the pathway as the true inducer and PaaX as the only bacterial regulatory
protein described so far that responds to an aryl-CoA compound. Superimposed in
the specific PaaX-mediated regulation is transcriptional activation by the cAMP
receptor protein and the integration host factor protein. These global regulators
may adjust the transcriptional output from Pa and Pz promoters to the overall
growth status of the cell.
PMID- 10766859
TI - Distinct effects of N-acetylcysteine and nitric oxide on angiotensin II-induced
epidermal growth factor receptor phosphorylation and intracellular Ca(2+) levels.
AB - These studies describe inhibitory effects of N-acetylcysteine on several
biochemical events associated with the activation of extracellular signal
regulated kinases (ERK) by angiotensin II in the cardiac fibroblast and compare
these effects with those of the nitric oxide donor, S-nitroso-N
acetylpenicillamine, an agent we showed previously to inhibit angiotensin II
induced ERK activation and the concomitant phosphorylation of proline-rich
tyrosine kinase 2 (Wang, D., Yu, X., and Brecher, P. (1999) J. Biol. Chem. 274,
24342-24348). The transactivation of the epidermal growth factor receptor by
angiotensin II, a process required for the activation of ERK, was inhibited by N
acetylcysteine but not by nitric oxide. The transactivation of the epidermal
growth factor receptor by angiotensin II was shown to be independent of
intracellular calcium increases. Nitric oxide, but not N-acetylcysteine,
inhibited the angiotensin II-induced increase in intracellular Ca(2+). Neither
nitric oxide nor N-acetylcysteine inhibited either phospholipase C activation or
inositol triphosphate generation in response to angiotensin II. N-Acetylcysteine
did inhibit the phosphorylation of the calcium sensitive tyrosine kinases PYK2
and Src, effects that also occurred using nitric oxide. These studies describe a
novel effect of N-acetylcysteine on cross-talk between a G protein-linked
receptor and a tyrosine kinase receptor and offer additional molecular insight to
explain how N-acetylcysteine and nitric oxide act at different sites and might
have an additive effect on specific hormonal responses.
PMID- 10766860
TI - The role of Sp1 in the differential expression of transforming growth factor-beta
receptor type II in human breast adenocarcinoma MCF-7 cells.
AB - Progression of MCF-7 cells from early passage (MCF-7E, <200 passage) to late
passage (MCF-7L, >500 passage) correlates with a loss of sensitivity to exogenous
TGFbeta1. We have previously shown that loss of TGFbeta sensitivity is due to
decreased expression of the transforming growth factor receptor type II
(TbetaRII) and is associated with increased tumorigenicity in nude mice. Reduced
TbetaRII expression in MCF-7L cells is caused by decreased TbetaRII promoter
activity in this cell line. Our previous studies using 5' deletion constructs of
this promoter revealed that MCF-7L cells were unable to support transcription of
the minimal promoter (-47 to +2) to the same levels as the MCF-7E cells. This
region of the promoter contains an Sp1 element at position -25 from the major
transcription start site. In this study, we investigated the role of Sp1 in
TbetaRII transcription. Mutation of the Sp1 site resulted in decreased
transcription of TbetaRII in MCF-7E and MCF-7L cells, indicating that this site
played a role in transcription of this promoter. Gel shift assays using the
proximal Sp1 site from the TbetaRII promoter showed enhanced DNA:protein complex
formation with nuclear proteins isolated from MCF-7E cells compared with MCF-7L
cells. Supershift analysis identified this binding activity as Sp1. Western blot
analysis of Sp1 levels demonstrated that MCF-7E cells contain increased Sp1
protein compared with MCF-7L cells, paralleling the increased binding activity.
Differential Sp1 activity was also demonstrated by higher levels of transcription
of an Sp1-dependent insulin-like growth factor II promoter construct in MCF-7E
cells compared with MCF-7L cells. Co-transfection of an Sp1 expression vector
with a TbetaRII promoter construct in MCF-7L cells induced the expression from
the promoter-CAT constructs and resulted in an increase of endogenous TbetaRII
protein levels. These results demonstrate that the transcriptional repression of
TbetaRII in MCF-7L cells is caused, in part, by lower Sp1 levels.
PMID- 10766861
TI - Functional properties of a new voltage-dependent calcium channel alpha(2)delta
auxiliary subunit gene (CACNA2D2).
AB - We have positionally cloned and characterized a new calcium channel auxiliary
subunit, alpha(2)delta-2 (CACNA2D2), which shares 56% amino acid identity with
the known alpha(2)delta-1 subunit. The gene maps to the critical human tumor
suppressor gene region in chromosome 3p21.3, showing very frequent allele loss
and occasional homozygous deletions in lung, breast, and other cancers. The
tissue distribution of alpha(2)delta-2 expression is different from alpha(2)delta
1, and alpha(2)delta-2 mRNA is most abundantly expressed in lung and testis and
well expressed in brain, heart, and pancreas. In contrast, alpha(2)delta-1 is
expressed predominantly in brain, heart, and skeletal muscle. When co-expressed
(via cRNA injections) with alpha(1B) and beta(3) subunits in Xenopus oocytes,
alpha(2)delta-2 increased peak size of the N-type Ca(2+) currents 9-fold, and
when co-expressed with alpha(1C) or alpha(1G) subunits in Xenopus oocytes
increased peak size of L-type channels 2-fold and T-type channels 1.8-fold,
respectively. Anti-peptide antibodies detect the expression of a 129-kDa
alpha(2)delta-2 polypeptide in some but not all lung tumor cells. We conclude
that the alpha(2)delta-2 gene encodes a functional auxiliary subunit of voltage
gated Ca(2+) channels. Because of its chromosomal location and expression
patterns, CACNA2D2 needs to be explored as a potential tumor suppressor gene
linking Ca(2+) signaling and lung, breast, and other cancer pathogenesis. The
homologous location on mouse chromosome 9 is also the site of the mouse
neurologic mutant ducky (du), and thus, CACNA2D2 is also a candidate gene for
this inherited idiopathic generalized epilepsy syndrome.
PMID- 10766862
TI - Evidence for the presence of peroxisome proliferator-activated receptor (PPAR)
alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation
modulates the effects of interleukin-1beta on rat chondrocytes.
AB - Peroxisome proliferator-activated receptor (PPAR) alpha, PPARgamma, and retinoid
acid receptor-related orphan receptor (ROR) alpha are members of the nuclear
receptor superfamily of ligand-activated transcription factors. Although they
play a key role in adipocyte differentiation, lipid metabolism, or glucose
homeostasis regulation, recent studies suggested that they might be involved in
the inflammation control and especially in the modulation of the cytokine
production. This strongly suggests that these transcriptional factors could
modulate the deleterious effects of interleukin-1 (IL-1) on cartilage. However,
to date, their presence in cartilage has never been investigated. By quantitative
reverse transcription-polymerase chain reaction, Western blot, and
immunocytochemistry analysis, we demonstrated, for the first time, the presence
of PPARalpha, PPARgamma, and RORalpha in rat cartilage, at both mRNA and protein
levels. Comparatively, the PPARalpha mRNA content in cartilage was much lower
than in the liver but not significantly different to that of the adipose tissue.
PPARgamma mRNA expression in cartilage was weak, when compared with adipose
tissue, but similar to that found in the liver. RORalpha mRNA levels were similar
in the three tissues. mRNA expression of the three nuclear receptors was very
differently modulated by IL-1 or mono-iodoacetate treatments. This indicates that
they should be unequally involved in the effects of IL-1 on chondrocyte, which is
in accordance with results obtained in other cell types. Indeed, we showed that
15d-PGJ2 mainly, but also the drug troglitazone, that are ligands of PPARgamma
could significantly counteract the decrease in proteoglycan synthesis and NO
production induced by IL-1. By contrast, PPARalpha ligands such as Wy-14,643 or
clofibrate had no effect on this process. Therefore, the presence of PPARgamma in
chondrocytes opens up new perspectives to modulate the effects of cytokines on
cartilage by the use of specific ligands. The function of the two other
transcription factors, PPARalpha and RORalpha identified in chondrocytes remains
to be explored.
PMID- 10766863
TI - Epidermal growth factor receptor tyrosine kinase mediates Ras activation by
gonadotropin-releasing hormone.
AB - Gonadotropin releasing hormone (GnRH) contributes to the maintenance of
gonadotrope function by increasing extracellular signal-regulated kinase (ERK)
activity subsequent to binding to its cognate G-protein-coupled receptor. As the
GnRH receptor exclusively interacts with G(q/11) proteins and as receptor
expression is regulated in a beta-arrestin-independent fashion, it represents a
good model to systematically dissect underlying signaling pathways. In alphaT3-1
gonadotropes endogenously expressing the GnRH receptor, GnRH challenge resulted
in a rapid increase in ERK activity which was attenuated by the epidermal growth
factor receptor (EGFR)-specific tyrosine kinase inhibitor AG1478. In COS-7 cells
transiently expressing the human GnRH receptor, agonist-induced ERK activation
was independent of free Gbetagamma subunits but could be mimicked by short-term
phorbol ester treatment. Most notably, G(q/11)-induced ERK activation was
sensitive to N17-Ras and to expression of the C-terminal Src kinase but also to
other dominant negative mutants of signaling components localized upstream of
Ras, like Shc and the EGFR. GnRH as well as phorbol esters led to Ras activation
in COS-7 and alphaT3-1 cells, which was dependent on Src and EGFR tyrosine
kinases, indicating that both tyrosine kinases act downstream of protein kinase C
(PKC) and upstream of Ras. However, Src did not contribute to Shc tyrosine
phosphorylation. GnRH or phorbol ester challenge resulted in PKC-dependent EGFR
autophosphorylation. Furthermore, a 5-min phorbol ester treatment was sufficient
to trigger tyrosine phosphorylation of the platelet-derived growth factor-beta
receptor in L cells. Thus, in several cell systems PKC is able to stimulate Ras
via activation of receptor tyrosine kinases.
PMID- 10766864
TI - Facilitated loading of RecA protein is essential to recombination by RecBCD
enzyme.
AB - Although the RecB(2109)CD enzyme retains most of the biochemical functions
associated with the wild-type RecBCD enzyme, it is completely defective for
genetic recombination. Here, we demonstrate that the mutant enzyme exhibits an
aberrant double-stranded DNA exonuclease activity, intrinsically producing a 3'
terminal single-stranded DNA overhang that is an ideal substrate for RecA protein
promoted strand invasion. Thus, the mutant enzyme constitutively processes double
stranded DNA in the same manner as the chi-modified wild-type RecBCD enzyme.
However, we further show that the RecB(2109)CD enzyme is unable to coordinate the
loading of RecA protein onto the single-stranded DNA produced, and we conclude
that this inability results in the recombination-defective phenotype of the
recB2109 allele. Our findings argue that the facilitated loading of RecA protein
by the chi-activated RecBCD enzyme is essential for RecBCD-mediated homologous
recombination in vivo.
PMID- 10766865
TI - Urokinase plasminogen activator/urokinase-specific surface receptor expression
and matrix invasion by breast cancer cells requires constitutive p38alpha mitogen
activated protein kinase activity.
AB - Overexpression of urokinase plasminogen activator (uPA) and its receptor (uPAR)
has been well documented in a wide variety of tumor cells. In breast cancer,
expression of uPA/uPAR is essential for tumor cell invasion and metastasis.
However, the mechanism responsible for uPA/uPAR expression in cancer cells
remains unclear. In the studies reported here, we show that endogenous p38 MAPK
activity correlates well with breast carcinoma cell invasiveness. Treatment of
highly invasive BT549 cells with a specific p38 MAPK inhibitor SB203580
diminished both uPA/uPAR mRNA and protein expression and abrogated the ability of
these cells to invade matrigel, suggesting that p38 MAPK signaling pathway is
involved in the regulation of uPA/uPAR expression and breast cancer cell
invasion. We also demonstrated that SB203580-induced reduction in uPA/uPAR mRNA
expression resulted from the de- stabilization of uPA and uPAR mRNA. Finally, by
selectively inhibiting p38alpha or p38beta MAPK isoforms, we demonstrate that
p38alpha, rather than p38beta, MAPK activity is essential for uPA/uPAR
expression. These studies suggest that p38alpha MAPK signaling pathway is
important for the maintenance of breast cancer invasive phenotype by promoting
the stabilities of uPA and uPAR mRNA.
PMID- 10766866
TI - Identification of CCAAT/enhancer-binding protein alpha as a transactivator of the
mouse amelogenin gene.
AB - Amelogenin expression is ameloblast-specific and developmentally regulated at the
temporal and spatial levels. In a previous transgenic mouse analysis, the
expression pattern of the endogenous amelogenin gene was recapitulated by a
reporter gene driven by a 2. 2-kilobase mouse amelogenin proximal promoter. To
understand the molecular mechanisms underlying the spatiotemporal expression of
the amelogenin gene during odontogenesis, the mouse amelogenin promoter was
systematically analyzed in mouse ameloblast-like LS8 cells. Deletion analysis
identified a minimal promoter (-70/+52) containing a CCAAT/enhancer-binding
protein (C/EBP)-binding site upstream of the TATA box. In transient transfection
assays, C/EBPalpha up-regulated the promoter activity in a dose-dependent manner.
The C/EBP-binding site was necessary for both C/EBPalpha-mediated transactivation
and basal promoter activity. Electrophoresis mobility shift assays demonstrated
that C/EBPalpha bound to its cognate site in the amelogenin promoter and that the
binding was specific. Endogenous C/EBPalpha was detected in LS8 cells, and
overexpression of exogenous C/EBPalpha in LS8 cells was able to increase the
expression level of the endogenous amelogenin protein. The activity of the
amelogenin promoter in rat parotid Pa-4 cells and Madin-Darby canine kidney cells
was minimal, ranging from 20 to 30% of the activity in ameloblast-like cells.
Transient transfection experiments showed that C/EBPalpha transactivated the
mouse amelogenin reporter gene in Pa-4 cells, but not in Madin-Darby canine
kidney cells. Taken together, these data indicate that C/EBPalpha is a bona fide
transcriptional activator of the mouse amelogenin gene in a cell type-specific
manner.
PMID- 10766867
TI - A common temperature-sensitive allelic form of human tyrosinase is retained in
the endoplasmic reticulum at the nonpermissive temperature.
AB - Oculocutaneous albinism type 1TS is caused by mutations that render the
melanocyte-specific enzyme tyrosinase temperature-sensitive (ts); the enzyme is
inactive in cells grown at 37 degrees C but displays full activity in cells grown
at 31 degrees C. To distinguish whether the ts phenotype of the common R402Q
variant of human tyrosinase is due to altered enzymatic activity or to misfolding
and a defect in intracellular trafficking, we analyzed its localization and
processing in transiently transfected HeLa cells. R402Q tyrosinase accumulates in
the endoplasmic reticulum (ER) at 37 degrees C but exits the ER and accumulates
in endosomal structures in cells grown at 31 degrees C. The inability of the
R402Q variant to exit the ER is confirmed by the failure to acquire
endoglycosidase H resistance at 37 degrees C and cannot be accounted for solely
by enhanced proteasome-mediated degradation. ER retention at 37 degrees C is
mediated by the lumenal domain of R402Q tyrosinase, is not dependent on tethering
to the membrane, and is irreversible. Finally, a wild-type allelic form of
tyrosinase is partially ts in transiently transfected HeLa cells. The data show
that human tyrosinase expressed in non-melanogenic cells folds and exits the ER
inefficiently and that R402Q tyrosinase exaggerates this defect, resulting in a
failure to exit the ER at physiologic temperatures.
PMID- 10766868
TI - Differences in DNA binding characteristics of the androgen and glucocorticoid
receptors can determine hormone-specific responses.
AB - The basis for specificity of gene regulation by steroid hormone receptors remains
an important problem in the study of steroid hormone action. One possible
mechanism for steroid specificity is the difference in DNA binding
characteristics of the receptors, although they share a high homology in their
DNA-binding domains. Indeed, the androgen-specific expression of, for example,
the probasin (PB) gene can be explained by the presence of an androgen response
element (ARE) in its promoter (PB-ARE-2), specifically recognized by the androgen
and not by the glucocorticoid receptor. Three residues in the DNA-binding domain
of the AR were identified as main determinants for its high affinity for the PB
ARE-2. In addition, the direct repeat nature of this ARE seems to prohibit high
affinity binding by the glucocorticoid receptor. This is confirmed by the fact
that several imperfect direct repeats of the 5'-TGTTCT-3' core recognition
sequence are recognized by the androgen receptor and not by the glucocorticoid
receptor. Up to now, only differences between the androgen and glucocorticoid
receptor in the transcription activation functions were invoked to explain the
specificity of their genomic actions. In the present study, we describe the
influence of the DNA-binding domain on the specificity of androgen action. The
novelty of our working hypothesis resides in the demonstration of the capacity of
the AR-DNA-binding domain to recognize elements with a direct repeat structure.
PMID- 10766869
TI - Change of specificity mutations in androgen-selective enhancers. Evidence for a
role of differential DNA binding by the androgen receptor.
AB - The androgen and glucocorticoid receptors recognize identical DNA motifs, leaving
unanswered the question of how steroid specificity of transcriptional regulation
is established in cells containing both receptors. Here, we provide evidence that
subtle differences in low affinity DNA recognition might be a crucial element in
the generation of steroid-specific responses. Here we identify simple hormone
response elements in the mouse sex-limited protein enhancer and the human
secretory component androgen response unit to be essential for the androgen
specificity of both enhancers. We describe specific in vitro binding to these
motifs by the DNA-binding domain of the androgen but not the glucocorticoid
receptor. Both elements can be considered partial direct repeats of the 5'-TGTTCT
3' core binding motif. In addition, we show that specific point mutations in
their left half-sites, essentially changing the nature of the repeats, strongly
enhance the glucocorticoid sensitivity of the respective enhancers, whereas they
have no effect on their androgen responsiveness. Accordingly, these mutations
allow specific binding of the glucocorticoid receptor DNA-binding domain to both
elements in vitro. With these experiments, we demonstrate that differential
recognition by the androgen receptor of nonconventional steroid response elements
is, at least in some cases, an important mechanism in androgen-specific
transcriptional regulation.
PMID- 10766870
TI - Dynamics of the HIV-1 reverse transcription complex during initiation of DNA
synthesis.
AB - Initiation of human immunodeficiency virus-1 (HIV-1) reverse transcription
requires formation of a complex containing the viral RNA (vRNA), tRNA(3)(Lys) and
reverse transcriptase (RT). The vRNA and the primer tRNA(3)(Lys) form several
intermolecular interactions in addition to annealing of the primer 3' end to the
primer binding site (PBS). These interactions are crucial for the efficiency and
the specificity of the initiation of reverse transcription. However, as they are
located upstream of the PBS, they must unwind as DNA synthesis proceeds. Here,
the dynamics of the complex during initiation of reverse transcription was
followed by enzymatic probing. Our data revealed reciprocal effects of the
tertiary structure of the vRNA.tRNA(3)(Lys) complex and reverse transcriptase
(RT) at a distance from the polymerization site. The structure of the initiation
complex allowed RT to interact with the template strand up to 20 nucleotides
upstream from the polymerization site. Conversely, nucleotide addition by RT
modified the tertiary structure of the complex at 10-14 nucleotides from the
catalytic site. The viral sequences became exposed at the surface of the complex
as they dissociated from the tRNA following primer extension. However, the
counterpart tRNA sequences became buried inside the complex. Surprisingly, they
became exposed when mutations prevented the intermolecular interactions in the
initial complex, indicating that the fate of the tRNA depended on the tertiary
structure of the initial complex.
PMID- 10766871
TI - Antagonism between members of the CNC-bZIP family and the immediate-early protein
IE2 of human cytomegalovirus.
AB - The HCMV IE2 protein negatively autoregulates its own expression as well as
represses the transactivation activity of p53. Using the repression domain of IE2
as bait in the yeast two-hybrid system, Nrf1 and Nrf2, members of the CNC-bZIP
family, were found to be IE2-interacting proteins. Residues 331-448 encompassing
the DNA-binding and the dimerization domains of Nrf1 are sufficient for the
interaction. The interaction was further confirmed in vitro by a glutathione S
transferase pull-down assay and in vivo by co-immunoprecipitation. In transient
transfection studies, transcription driven by six copies of an NF-E2 site or by
chimeric proteins between the DNA-binding domain of LexA and members of the CNC
bZIP family is repressed by IE2. Importantly, the DNA binding activity of the
Nrf1/MafK heterodimer is not impeded by IE2. In a parallel study, CNC-bZIP
factors attenuate the negative autoregulation of IE2. The attenuation could be
explained by the finding that Nrf1 functions alone and synergistically with its
heterodimerization partner, MafK, in inhibiting the DNA binding activity of IE2.
Taken together, these results demonstrate the existence of antagonism between
members of the CNC-bZIP family and IE2.
PMID- 10766872
TI - Electrophysiological study of a novel large pore formed by Bax and the voltage
dependent anion channel that is permeable to cytochrome c.
AB - The Bcl-2 family of proteins, consisting of anti-apoptotic and pro-apoptotic
members, regulates cell death by controlling mitochondrial membrane permeability
that is crucial for apoptotic signal transduction. We have recently shown that
some of these proteins, such as Bcl-x(L), Bax, and Bak, directly modulate the
mitochondrial voltage-dependent anion channel (VDAC) and thus regulate
apoptogenic cytochrome c release and potential loss. To elucidate the molecular
mechanisms of VDAC regulation by Bcl-2 family proteins, an electrophysiological
study was carried out. It was found that VDAC and pro-apoptotic Bax created a
large pore, with conductance levels 4- and 10-fold greater than those of the VDAC
and Bax channels, respectively. Although the VDAC and Bax channels both show ion
selectivity and voltage-dependent modulation of their activity, the VDAC-Bax
channel had neither of their properties. Anti-apoptotic Bcl-x(L) and its BH4
oligopeptide completely closed the VDAC, in contrast to the Bax. Cytochrome c
passed through a single VDAC-Bax channel but not through the VDAC or Bax channel
in a planar lipid bilayer. These data provide direct evidence that VDAC forms a
novel large pore together with Bax.
PMID- 10766873
TI - Accumulation of adenine DNA glycosylase-sensitive sites in human mitochondrial
DNA.
AB - The mitochondrial respiratory chain inevitably produces reactive oxygen species
as byproducts of aerobic ATP synthesis. Mitochondrial DNA (mtDNA), which is
located close to the respiratory chain, is reported to contain much more 8
oxoguanine (8-oxoG), an oxidatively modified guanine base, than nuclear DNA.
Despite such a high amount of 8-oxoG in mtDNA (1-2 8-oxoG/10(4) G), mtDNA is
barely cleaved by an 8-oxoG DNA glycosylase or MutM, which specifically excises 8
oxoG from a C:8-oxoG pair. We find here that about half of human mtDNA molecules
are cleaved by another 8-oxoG-recognizing enzyme, an adenine DNA glycosylase or
MutY, which excises adenine from an A:8-oxoG pair. The cleavage sites are mapped
to adenines. The calculated number of MutY-sensitive sites in mtDNA is
approximately 1.4/10(4) G. This value roughly corresponds with the
electrochemically measured amount of 8-oxoG in mtDNA (2.2/10(4) G), raising the
possibility that 8-oxoG mainly accumulates as an A:8-oxoG pair.
PMID- 10766874
TI - Functions of the N-terminal region of cyclic nucleotide phosphodiesterase 3 (PDE
3) isoforms.
AB - The N-terminal portion of phosphodiesterase (PDE) 3 was arbitrarily divided into
region 1 (amino acids 1-300), which contains a large hydrophobic domain with six
predicted transmembrane helices, and region 2 (amino acids 301-500), with a
smaller hydrophobic domain ( approximately 50 residues). To analyze these
regions, full-length human (H)PDE3A and mouse (M)PDE3B and a series of N-terminal
truncated mutants were synthesized in Sf9 cells. Activities of HPDE3A, H3A
Delta189, MPDE3B, and M3B-Delta196, which retained all or part of the hydrophobic
domain in region 1, were recovered almost entirely in particulate fractions. H3A
Delta321 and M3B-Delta302, containing region 2, were recovered essentially
equally in particulate and cytosolic fractions. H3A-Delta397 and H3A-Delta457,
lacking both hydrophobic domains, were predominantly cytosolic. H3A-Delta510 and
M3B-Delta604, lacking both regions 1 and 2, were virtually completely cytosolic.
M3B-Delta196 eluted as a large aggregated complex during gel filtration. With
removal of greater amounts of N-terminal sequence, aggregation of PDE3 decreased,
and H3A-Delta607, H3A-Delta721, and M3B-Delta604 eluted as dimers. Truncated
HPDE3A proteins were more sensitive than full-length HPDE3A to inhibition by
lixazinone. These results suggest that the hydrophobic domains in regions 1 and 2
contain structural determinants important for association of PDE3 with
intracellular membranes, as well for self-association or aggregation during gel
filtration and sensitivity to a specific inhibitor.
PMID- 10766875
TI - Mutations in calcium-binding epidermal growth factor modules render fibrillin-1
susceptible to proteolysis. A potential disease-causing mechanism in Marfan
syndrome.
AB - Most extracellular proteins consist of various modules with distinct functions.
Mutations in one common type, the calcium-binding epidermal growth factor-like
module (cbEGF), can lead to a variety of genetic disorders. Here, we describe as
a model system structural and functional consequences of two typical mutations in
cbEGF modules of fibrillin-1 (N548I, E1073K), resulting in the Marfan syndrome.
Large (80-120 kDa) wild-type and mutated polypeptides were recombinantly
expressed in mammalian cells. Both mutations did not alter synthesis and
secretion of the polypeptides into the culture medium. Electron microscopy after
rotary shadowing and comparison of circular dichroism spectra exhibited minor
structural differences between the wild-type and mutated forms. The mutated
polypeptides were significantly more susceptible to proteolytic degradation by a
variety of proteases as compared with their wild-type counterparts. Most of the
sensitive cleavage sites were mapped close to the mutations, indicating local
structural changes within the mutated cbEGF modules. Other cleavage sites,
however, were observed at distances beyond the domain containing the mutation,
suggesting longer range structural effects within tandemly repeated cbEGF
modules. We suggest that proteolytic degradation of mutated fibrillin-1 may play
an important role in the pathogenesis of Marfan syndrome and related disorders.
PMID- 10766876
TI - ch-TOGp is required for microtubule aster formation in a mammalian mitotic
extract.
AB - Microtubules induced to polymerize with taxol in a mammalian mitotic extract
organize into aster-like arrays in a centrosome-independent process that is
driven by microtubule motors and structural proteins. These microtubule asters
accurately reflect the noncentrosomal aspects of mitotic spindle pole formation.
We show here that colonic-hepatic tumor-overexpressed gene (ch-TOGp) is an
abundant component of these asters. We have prepared ch-TOGp-specific antibodies
and show by immunodepletion that ch-TOGp is required for microtubule aster
assembly. Microtubule polymerization is severely inhibited in the absence of ch
TOGp, and silver stain analysis of the ch-TOGp immunoprecipitate indicates that
it is not present in a preformed complex and is the only protein removed from the
extract during immunodepletion. Furthermore, the reduction in microtubule
polymerization efficiency in the absence of ch-TOGp is dependent on ATP. These
results demonstrate that ch-TOGp is a major constituent of microtubule asters
assembled in a mammalian mitotic extract and that it is required for robust
microtubule polymerization in an ATP-dependent manner in this system even though
taxol is present. These data, coupled with biochemical and genetic data derived
from analysis of ch-TOGp-related proteins in other organisms, indicate that ch
TOGp is a key factor regulating microtubule dynamics during mitosis.
PMID- 10766877
TI - Epidermal growth factor negatively regulates chondrogenesis of mesenchymal cells
by modulating the protein kinase C-alpha, Erk-1, and p38 MAPK signaling pathways.
AB - During limb development, epithelial cells in the apical ectodermal ridge keep the
underlying mesenchymal cells in a proliferative state preventing differentiation
by secreting signaling molecules such as epidermal growth factor (EGF). We
investigated the molecular mechanism of the EGF effect on the regulation of
micromass culture-induced chondrogenesis of chick limb bud mesenchymal cells as a
model system. We found that expression and tyrosine phosphorylation of the EGF
receptor was increased transiently during chondrogenesis. Exogenous EGF inhibited
chondrogenic differentiation of mesenchymal cells, and this effect was reversed
by the EGF receptor inhibitor AG1478. EGF treatment also inhibited the expression
and activation of protein kinase C-alpha, whereas it activated Erk-1 and
inhibited p38 mitogen-activated protein kinase, all of which appeared to be
involved in the EGF-induced inhibition of chondrogenesis. Stimulation of the EGF
receptor blocked precartilage condensation and altered the expression of cell
adhesion molecules such as N-cadherin and integrins alpha(5) and beta(1). All
these EGF effects were reversible by AG1478. The data indicate that EGF
negatively regulate chondrogenesis of chick limb bud mesenchymal cells by
inhibiting precartilage condensation and by modulating signaling pathways
including those of protein kinase C-alpha, Erk-1, and p38 mitogen-activated
protein kinase.
PMID- 10766878
TI - Osteoporosis in neurological disorders.
PMID- 10766879
TI - Clinical evaluation of patients with stroke is still worthwhile.
PMID- 10766880
TI - How effective is radiosurgery for arteriovenous malformations?
PMID- 10766881
TI - HTLV-1 and HIV infections of the central nervous system in tropical areas.
PMID- 10766882
TI - How well does the Oxfordshire community stroke project classification predict the
site and size of the infarct on brain imaging?
AB - OBJECTIVES: The Oxfordshire Community Stroke Project (OCSP) classification is a
simple clinical scheme for subdividing first ever acute stroke. Several small
studies have shown that when an infarct is visible on CT or MRI, the
classification predicts its site in about three quarters of patients. The aim was
to further investigate this relation in a much larger cohort of patients in
hospital with ischaemic stroke. METHODS: Between 1994 and 1997, inpatients and
outpatients with ischaemic stroke were assessed by one of several stroke
physicians who noted the OCSP classification. A neuroradiologist classified the
site and extent of recent infarction on CT or MRI. RESULTS: Of 1012 patients with
ischaemic stroke, 655 (65%) had recent visible infarcts. These radiological
lesions were appropriate to the clinical classification in 69/87 (79%) patients
with a total anterior circulation syndrome, 213/298 (71%) with a partial anterior
circulation syndrome, 105/144 (73%) with a lacunar syndrome, and 105/126 (83%)
with a posterior circulation syndrome. Overall, 75% of patients with visible
infarcts were correctly classified clinically. If patients without a visible
infarct did have an appropriate lesion in the brain (best case), the
classification would have correctly predicted its site and size in 849/1012 (84%)
patients, compared with only 492/1012 (49%) in the worst case scenario.
CONCLUSION: The OCSP classification predicted the site of infarct in three
quarters of patients. When an infarct is visible on brain imaging, the site of
the infarct should guide the use of further investigations, but if an infarct is
not seen, the OCSP classification could be used to predict its likely size and
site.
PMID- 10766884
TI - Wallenberg's syndrome.
PMID- 10766883
TI - Results of radiosurgery for brain stem arteriovenous malformations.
AB - OBJECTIVE: To assess the treatment results of radiosurgery for brain stem
arteriovenous malformations (AVMs) and to seek optimal dose and treatment volume
prescription for these lesions. METHODS: The clinical and radiological data of 30
consecutive patients with brain stem AVM treated with gamma knife radiosurgery
were retrospectively reviewed with a mean follow up period of 52.2 months. There
were 26 patients with previous haemorrhages and 21 with neurological deficit.
Seventeen AVMs were located in the midbrain, 11 in the pons, and two in the
medulla oblongata. All of the lesions were small with the intra-axial component
occupying less than one third of the area of brain stem parenchyma on axial
section of multiplanar MRI or CT. The mean diameter of the nidus was 1.26 cm, and
the nidus volume within the brain stem parenchyma ranged from 0.1 to 2.0 cm(3).
The mean radiation dose to the AVM margin was 18.4 Gy. RESULTS: The actuarial 3
year obliteration rate was 52.2%; 69.4% in cases treated with standard doses
(minimum target dose, 18-20Gy), and 14.3% in cases treated with low doses (<18
Gy) (p<0.05). Two patients sustained symptomatic radiation injury, but there was
no permanent neurological deficit caused by radiosurgery. Five patients had
haemorrhage from the AVM after irradiation, including four fatal cases, resulting
in a 4.0% annual rate of post-treatment bleeding. CONCLUSIONS: Radiosurgery is a
viable treatment modality for patients with small deep parenchymal brain stem
AVMs. A standard radiosurgical dose is safe and effective when directed to a
small treatment volume. However, latent interval haemorrhage remains a
significant problem until the nidus is obliterated completely.
PMID- 10766885
TI - Functional outcome and quality of life after angiography and operation for
unruptured intracranial aneurysms. On behalf of the MARS Study Group.
AB - OBJECTIVES: To assess outcome after elective treatment for unruptured
intracranial aneurysms. METHODS: Of 193 consecutive patients with subarachnoid
haemorrhage 626 first degree relatives (parents, siblings, children) were
screened with magnetic resonance angiography. Subsequently, 18 relatives
underwent elective angiography and operation. Outcome was assessed in terms of
impairments (neurological examination), disabilities (Barthel index), handicaps
(Rankin scale), and quality of life (sickness impact profile (SIP) and short form
36 (SF-36)) 3 months and 1 year after operation; it was compared with baseline
measurements. RESULTS: Before angiography all patients had a normal neurological
examination, optimal Barthel and Rankin scores, and a quality of life similar to
that in a reference population. Three months postoperatively five patients (28%;
95% confidence interval (95% CI) 10-54%) had neurological impairments (one after
angiography), two (11%; 95% CI 1-35%) had a decrease in Barthel index, and 15
(83%; 95% CI 59-96%) had suboptimal Rankin scores (none was dependent in daily
living). Quality of life (SIP and SF-36) was reduced for most domains. After 1
year, five patients still had neurological impairments, all had an optimal
Barthel index, and eight (47%; 95% CI 23-72%) had suboptimal Rankin scores.
Quality of life returned to baseline levels for all SIP and most SF-36 domains.
CONCLUSIONS: Treatment of unruptured aneurysms has a considerable short term
negative impact on functional health and quality of life in most patients,
despite the low rate of impairments. Outcome improves markedly but not completely
within 1 year after operation.
PMID- 10766886
TI - Risk analysis of treatment of unruptured aneurysms.
AB - OBJECTIVES: To calculate the expected number of life-years saved by surgical
treatment of unruptured intracranial aneurysms at ages over 20 years. METHODS: An
actuarial risk analysis of the treatment of unruptured intracranial aneurysms
based on data from the International Study of Unruptured Intracranial Aneurysms
(ISUIA). The benefits of operative treatment are calculated in terms of average
life-years saved. RESULTS: Results are presented as graphs of life-years saved or
lost against age at the time of operative treatment for three groups of
aneurysms: those under 10 mm in diameter with no history of subarachnoid
haemorrhage (SAH) from another aneurysm, those under 10 mm in diameter and a
history of previous SAH from a different aneurysm, and those over 10 mm in
diameter. Life-years are lost at all ages in the group under 10 mm with no
history of SAH. For the group under 10 mm with a history of SAH about 4 years are
saved at age 20 declining to 0 at around age 50. For aneurysms 10 mm or more in
diameter about 8 life-years are saved at age 20 declining to 0 at around 50.
CONCLUSIONS: Clipping of unruptured aneurysms under 10 mm in diameter with no
history of subarachnoid haemorrhage is not justified on actuarial grounds.
Intervention in other unruptured aneurysms produces benefits in life expectancy
up to the age of 50. There may be subgroups of aneurysms in which larger benefits
exist.
PMID- 10766887
TI - Monitoring of head injury by myotatic reflex evaluation.
AB - OBJECTIVES: (1) To establish the feasibility of myotatic reflex measurement in
patients with head injury. (2) To test the hypothesis that cerebral dysfunction
after head injury causes myotatic reflex abnormalities through disordered
descending control. These objectives arise from a proposal to use reflex
measurements in monitoring patients with head injury. METHODS: The phasic stretch
reflex of biceps brachii was elicited by a servo-positioned tendon hammer.
Antagonist inhibition was evoked by vibration to the triceps. Using surface EMG,
the amplitude of the unconditioned biceps reflex and percentage antagonist
inhibition were measured. After standardisation in 16 normal adult subjects, the
technique was applied to 36 patients with head injury across the range of
severity. Objective (1) was addressed by attempting a measurement on each patient
without therapeutic paralysis; three patients were also measured under partial
paralysis. Objective (2) was addressed by preceding each of the 36 unparalysed
measurements with an assessment of cerebral function using the Glasgow coma scale
(GCS); rank correlation was employed to test a null hypothesis that GCS and
reflex indices are unrelated. RESULTS: In normal subjects, unconditioned reflex
amplitude exhibited a positive skew requiring logarithmic transformation.
Antagonist inhibition had a prolonged time course suggesting presynaptic
mechanisms; subsequent measurements were standardised at 80 ms conditioning test
interval (index termed "TI(80)"). Measurements were obtained on all patients,
even under therapeutic paralysis (objective (1)). The unconditioned reflex was
absent in most patients with GCS less than 5; otherwise it varied little across
the patient group. TI(80) fell progressively with lower GCS, although patients'
individual GCS could not be inferred from single measurements. Both reflex
indices correlated with GCS (p<0.01), thereby dismissing the null hypothesis
(objective (2)). CONCLUSION: Cerebral dysfunction in head injury is reflected in
myotatic reflex abnormalities which can be measured at the bedside. With greater
reproducibility, reflex measurements may assist monitoring of patients with head
injury.
PMID- 10766888
TI - The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the
pharmacokinetic and clinical response to Sinemet CR in Parkinson's disease.
AB - OBJECTIVES: Entacapone is a specific, potent, peripherally acting catechol-O
methyltransferase (COMT) inhibitor. It has been shown to improve the
bioavailability of plasma levodopa and extend its clinical effect when used as an
adjunct to standard levodopa preparations, but there is little experience of the
effect of entacapone on controlled release levodopa preparations. METHODS: A
double blind, placebo controlled, single dose, randomised, cross over trial was
performed in 14 patients with Parkinson's disease with motor fluctuations to
investigate the clinical effect of a single dose of entacapone (200 mg) when
administered with either standard levodopa-carbidopa (Sinemet) or controlled
release levodopa-carbidopa preparations (Sinemet CR). RESULTS: When entacapone
was administered with standard Sinemet the duration of the clinical response to
standard Sinemet was longer in comparison with the response after placebo
(p=0.02). Moreover, in the same patients, entacapone significantly increased the
duration of the clinical response to Sinemet CR (p=0.05) without prolonging the
latency of response or enhancing dyskinesias. CONCLUSIONS: These data confirm the
clinical efficacy of entacapone-standard Sinemet combination. They also indicate
that adding entacapone to controlled release levodopa preparations might provide
a useful treatment option in patients with Parkinson's disease with motor
fluctuations. A double blind clinical trial with a chronically administered
entacapone-Sinemet CR combination is, however, required to verify this viewpoint.
PMID- 10766889
TI - Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral
subthalamic stimulation.
AB - OBJECTIVE: To assess the effects of high frequency stimulation of the subthalamic
nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's
disease (PD). METHODS: The efficacy of STN stimulation on total motor disability
score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated
in 10 patients with severe Parkinson's disease. The subscores were then studied
separately for limb akinesia, rigidity, and tremor, which are known to respond to
levodopa, and axial signs, including speech, neck rigidity, rising from a chair,
posture, gait, and postural stability, which are known to respond less well to
levodopa. Patients were clinically assessed in the "off" and "on" drug condition
during a levodopa challenge test performed before surgical implantation of
stimulation electrodes and repeated 6 months after surgery under continuous STN
stimulation. A complementary score for axial symptoms from the "activities of
daily living" (ADL)-that is, speech, swallowing, turning in bed, falling,
walking, and freezing-was obtained from each patient's questionnaire (UPDRS, part
II). RESULTS: Improvements in total motor disability score (62%), limb signs
(62%), and axial signs (72%) obtained with STN stimulation were statistically
comparable with those obtained with levodopa during the preoperative challenge
(68%, 69%, and 59%, respectively). When levodopa and STN stimulation were
combined there was a further improvement in total motor disability (80%) compared
with preoperative levodopa administration. This consisted largely of an
additional improvement in axial signs (84%) mainly for posture and postural
stability, no further improvement in levodopa responsive signs being found. Axial
symptoms from the ADL showed similar additional improvement when levodopa and STN
stimulation were combined. CONCLUSION: These findings suggest that bilateral STN
stimulation improves most axial features of Parkinson's disease and that a
synergistic effect can be obtained when stimulation is used in conjunction with
levodopa treatment.
PMID- 10766890
TI - Coughing and choking in motor neuron disease.
AB - OBJECTIVES: To assess the frequency and severity of coughing and choking
episodes, possible related factors, and their association with chest infections
in patients with motor neuron disease (MND). METHODS: Thirty seven patients with
MND and 23 healthy volunteers were studied. Cough was assessed using a
questionnaire and a 3 day diary, and volitional cough quantified by peak cough
flow and sound intensity. Other clinical symptoms, smoking habit, affective
state, oral secretions, bulbar signs, and quantitative assessments of swallowing
and respiratory function were documented. RESULTS: Patients with MND coughed and
choked significantly more often and to a greater degree than the healthy
volunteers (26 of 37 patients with MND and 2 of 23 volunteers, p<0.001). Female
sex, older age, abnormal speech, reduced swallowing capacity, and low forced
vital capacity (FVC)% predicted were each significantly associated with excessive
coughing and choking episodes in patients with MND. Smokers had significantly
more severe and prolonged episodes of coughing and choking than non-smokers
(p<0.05). Patients with upper motor neuron bulbar signs had a greater tendency to
severe and prolonged episodes of coughing and choking than those without (p<0.
05). Chest infections were reported only rarely among the patients who coughed
and choked. CONCLUSIONS: Coughing and choking episodes are common in patients
with MND but infrequently associated with overt chest infection. Upper motor
neuron bulbar signs may both promote factors (for instance, dysphagia) which
trigger cough and reduce volitional capacity to suppress it.
PMID- 10766891
TI - Accumulation of NACP/alpha-synuclein in lewy body disease and multiple system
atrophy.
AB - OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial
Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in
sporadic Parkinson's disease and other related disorders including diffuse Lewy
body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were
examined immunocytochemically using anti-NACP/alpha-synuclein antibodies.
METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's
disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with
Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and
dementia, one with Huntington's disease, two with progressive supranuclear palsy
(PSP), one with Pick's disease, one with myotonic dystrophy, and three with late
cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined.
RESULTS: In addition to immunoreactive Lewy bodies, widespread accumulation of
NACP/alpha-synuclein was found in neurons and astrocytes from the brainstem and
basal ganglia to the cerebral cortices in Parkinson's disease/DLBD. NACP/alpha
synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to
the cerebellar white matter, and inferior olivary neurons in MSA. These
widespread accumulations were not seen in other types of dementia or
spinocerebellar ataxia. CONCLUSION: Completely different types of NACP/alpha
synuclein accumulation in Parkinson's disease/DLBD and MSA suggest that
accumulation is a major step in the pathological cascade of both diseases and
provides novel strategies for the development of therapies.
PMID- 10766892
TI - A new family with paroxysmal exercise induced dystonia and migraine: a clinical
and genetic study.
AB - OBJECTIVE: To characterise the phenotype of a family with paroxysmal exercise
induced dystonia (PED) and migraine and establish whether it is linked to the
paroxysmal non-kinesigenic dyskinesia (PNKD) locus on chromosome 2q33-35, the
familial hemiplegic migraine (FHM) locus on chromosome 19p, or the familial
infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome) locus on
chromosome 16. METHODS: A family, comprising 30 members, was investigated.
Fourteen family members in two generations including three spouses were examined.
Haplotypes were reconstructed for all the available family members by typing
several microsatellite markers spanning the PNKD, FHM, and ICCA loci.
Additionally, the four exons containing the known FHM mutations were sequenced.
RESULTS: Of 14 members examined four were definitely affected and one member was
affected by history. The transmission pattern in this family was autosomal
dominant with reduced penetrance. Mean age of onset in affected members was 12
(range 9-15 years). Male to female ratio was 3:1. Attacks of PED in affected
members were predominantly dystonic and lasted between 15 and 30 minutes. They
were consistently precipitated by walking but could also occur after other
exercise. Generalisation did not occur. Three of the affected members in the
family also had migraine without aura. Linkage of the disease to the PNKD, FHM,
or ICCA loci was excluded as no common haplotype was shared by all the affected
members for each locus. In addition, direct DNA sequential analysis of the FHM
gene (CACNL1A4) ruled out all known FHM point mutations. CONCLUSIONS: This family
presented with the classic phenotype of PED and is not linked to the PNKD, FHM,
or ICCA loci. A new gene, possibly coding for an ion channel, is likely to be the
underlying cause of the disease.
PMID- 10766893
TI - Cognitive changes after cerebrospinal fluid shunting in young adults with spina
bifida and assumed arrested hydrocephalus.
AB - OBJECTIVES: To establish whether surgery can improve the neuropsychological
functioning of young adult patients with spina bifida and apparent clinically
arrested hydrocephalus showing abnormal intracranial pressure. METHODS: Twenty
three young adults with spina bifida and assumed arrested hydrocephalus
(diagnosed as active or compensated by continuous intracranial pressure
monitoring) underwent surgery. All patients received neuropsychological
examination before surgery and 6 months later. Neuropsychological assessment
included tests of verbal and visual memory, visuospatial functions, speed of
mental processing, and frontal lobe functions. RESULTS: Shunt placement in this
subgroup of patients improves neuropsychological functioning, especially in
verbal and visual memory and attention and cognitive flexibility. CONCLUSIONS:
Young adults with spina bifida and suspected non-functioning shunt or non-shunted
ventriculomegaly should be carefully monitored to identify those who could
benefit from shunting.
PMID- 10766894
TI - Smoking, drinking, and incident cognitive impairment: a cohort community based
study included in the Gospel Oak project.
AB - OBJECTIVES: Recent longitudinal studies have reported that smoking increases risk
for cognitive impairment and that moderate alcohol intake could be preventive.
The association between both cigarette smoking and alcohol drinking and incident
cognitive impairment was studied in a representative population. METHODS: This is
a 1 year prospective population based cohort study of all residents aged 65 or
over in the electoral ward of Gospel Oak in London, UK (n=889). Cognitive
impairment was assessed at baseline and 1 year later using the organic brain
syndrome (OBS) cognitive impairment scale from the short CARE structured
assessment. Subjects who were cognitively impaired at baseline were excluded from
this analysis. RESULTS: The prevalence of OBS cognitive impairment was 10.4% at
index assessment and the 1 year cumulative incidence of cognitive impairment was
5.7%. Cognitive impairment was not associated with use of alcohol, although there
was a non-significant association in the direction of a protective effect against
onset of cognitive impairment for moderate drinkers compared with non-drinkers
and heavy drinkers. Current smoking status predicted cognitive impairment (risk
ratio (RR) 3.7; (95% confidence interval (95% CI)=1.1-12.3) independently from
sex, age, alcohol, occupational class, education, handicap, depression, and
baseline cognitive function. CONCLUSIONS: Smoking seems to be a prospective risk
factor for incident cognitive impairment; thus encouragement of older people to
stop smoking could be considered as part of a strategy to reduce the incidence of
cognitive impairment.
PMID- 10766895
TI - Lesion heterogeneity in multiple sclerosis: a study of the relations between
appearances on T1 weighted images, T1 relaxation times, and metabolite
concentrations.
AB - OBJECTIVES: Multiple sclerosis lesions appear as areas of high signal on T2
weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI,
appear hypointense compared with surrounding white matter. These hypointense T1
lesions are thought to represent areas of greater tissue damage compared with the
more non-specific, total T2 lesion load. This study aimed to better characterise
the properties of high signal T2 lesions with differing appearances on T1
weighted MRI using quantitative MR techniques. METHODS: Eleven patients with
secondary progressive multiple sclerosis were studied. Two high signal T2 lesions
were selected from each patient-one of which appeared hypointense and one
isointense on a T1 weighted image. A voxel was positioned around each lesion and
for this volume of brain the metabolite concentrations were estimated using
proton MR spectroscopy ((1)H-MRS) and the T1 relaxation time within each voxel
calculated from a T1 map generated using a multislice technique. RESULTS:
Compared with isointense T1 lesions, hypointense T1 lesions exhibited a
significantly lower absolute concentration of N-acetyl derived metabolites (tNAA)
and a significantly higher absolute concentration of myo-inositol (Ins). T1
relaxation time correlated significantly with both tNAA (r=-0.8, p < 0.001) and
Ins (r=0.5, p=0. 012). There was no correlation between T1 relaxation times and
creatine/phosphocreatine or choline containing compounds. CONCLUSIONS: Prolonged
T1 relaxation times seem to reflect the severity of axonal damage or dysfunction
(inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in
chronic multiple sclerosis lesions.
PMID- 10766896
TI - Conduction deficits of callosal fibres in early multiple sclerosis.
AB - OBJECTIVE: To study the diagnostic usefulness of transcallosal inhibition (TI)
elicited by transcranial magnetic stimulation (TMS) in detecting central
conduction deficits in early multiple sclerosis. Corticospinally mediated
excitatory responses evoked by TMS are accepted as a sensitive diagnostic tool in
multiple sclerosis. Recently, TI evoked by TMS has been introduced as a new
paradigm to test the function of callosal fibres interconnecting both hand
associated motor cortices. METHODS: Focal TMS of the motor cortex was performed
in 50 patients with early relapsing-remitting multiple sclerosis. Corticospinally
mediated (central motor latencies, amplitudes) and transcallosally mediated
(onset latency and duration of TI) stimulation effects were investigated.
RESULTS: TMS disclosed abnormalities of corticospinally mediated responses in 62%
and of TI in 80% of the patients. CONCLUSION: The assessment of TI allows the
discovery of lesions within the periventricular white matter that were not
accessible by neurophysiological techniques before. This new paradigm increases
the sensitivity of TMS with which to detect central conduction deficits in early
multiple sclerosis.
PMID- 10766897
TI - Ocular microtremor (OMT): a new neurophysiological approach to multiple
sclerosis.
AB - Using a piezoelectric transducer, the frequency and pattern of ocular microtremor
(OMT) between 50 normal subjects and 50 patients with multiple sclerosis were
compared. Controls were age matched. All records were analysed blindly. The
frequency of OMT in the normal group was 86 (SD 6) Hz, which was significantly
different from that of the multiple sclerosis group (71 (SD) 10 Hz, p<0.001).
Those in the multiple sclerosis group with clinical evidence of brain stem or
cerebellar disease (n=36) had an average OMT frequency of 67 (SD 9) Hz (p<0.001)
compared with normal (n=86), whereas those with no evidence of brain stem or
cerebellar involvement (n=14) had a frequency of 81.2 (SD 6) Hz (p<0.05, n=64).
The differences between the two multiple sclerosis groups were also significant
(p<0. 001, n=50). At least one abnormality (frequency and pattern) of OMT
activity was seen in 78% of patients with multiple sclerosis. In the presence of
brain stem or cerebellar disease 89% had abnormal records whereas in the absence
of such disease 50% had abnormal records. This is the first report of the
application of this technique to patients with multiple sclerosis. The results
suggest that OMT activity may be of value in the assessment of multiple
sclerosis.
PMID- 10766898
TI - Detailed analysis of the oligodendrocyte myelin glycoprotein gene in four
patients with neurofibromatosis 1 and primary progressive multiple sclerosis.
AB - Neurofibromatosis 1 (NF1) is a common autosomal disorder with a wide range of
neurological manifestations. The case histories of five patients, including two
siblings, are reported who have both neurofibromatosis 1 and primary progressive
multiple sclerosis (PPMS). A further patient with both NF1 and PPMS has since
been identified. More recently, a systematic clinical review of 138 unselected
adult patients with NF1 identified one patient with a slowly progressive spastic
paraparesis and multiple high signal hyperintensities on T2 weighted MRI.
Molecular genetic studies suggest a mechanism by which the clinical association
of progressive white matter disease and NF1 might arise. The gene for NF1 is
located on chromosome 17q, spans 350 kb of genomic DNA, and contains 60 exons.
The gene for oligodendrocyte myelin glycoprotein (OMgp) is embedded within intron
27b of the NF1 gene. OMgp is a membrane glycoprotein that appears in the human
CNS at the time of myelination. It can be detected immunohistochemically on CNS
myelin and on the surface of cultured oligodendrocytes. Structurally, OMgp has
the potential to function as an adhesion molecule and could contribute to the
interactions between the plasma membranes of oligodendrocytes and axons required
for myelination and/or axon survival. This study considers the specific
hypothesis that PPMS in patients with NF1 results from concurrent mutation of the
OMgp gene. The OMgp genes of four unrelated patients with NF1 and PPMS were
examined using a combination of Southern blot, dosage polymerase chain reaction,
and chemical cleavage of mismatch. The entire OMgp coding sequence, all intronic
sequence, the intron-exon boundaries, and 1 kb of flanking sequence were
screened. The DNA from two patients was found to contain an alteration in the
OMgp gene resulting in an amino acid change of glycine to aspartic acid at codon
21. It is concluded that PPMS in patients with NF1 can occur without concurrent
mutation of the OMgp gene. The glycine to aspartic acid polymorphic alteration at
codon 21 is neither sufficient nor necessary for the development of PPMS.
PMID- 10766899
TI - Status-like recurrent pilomotor seizures: case report and review of the
literature.
AB - A diabetic 66 year old man who presented with pilomotor seizures in his right
hemibody is described. The seizures recurred with an increasing frequency,
leading to a status-like condition associated with Korsakoff's syndrome. An EEG
was performed and several electroclinical seizures were recorded. Brain MRI was
negative. The patient, who was treated with carbamazepine, became seizure free
after 1 week. Memory and behaviour gradually returned to normal within 3 weeks.
There was no further neurological episode during an 8 year follow up.
Hyperosmolar, non-ketotic hyperglycaemia was considered to be the cause of the
seizures. The pathophysiology of pilomotor seizures is discussed and the
literature on the subject reviewed.
PMID- 10766900
TI - Pathological switching between languages after frontal lesions in a bilingual
patient.
AB - Cerebral lesions may alter the capability of bilingual subjects to separate their
languages and use each language in appropriate contexts. Patients who show
pathological mixing intermingle different languages within a single utterance. By
contrast, patients affected by pathological switching alternate their languages
across different utterances (a self contained segment of speech that stands on
its own and conveys its own independent meaning). Cases of pathological mixing
have been reported after lesions to the left temporoparietal lobe. By contrast,
information on the neural loci involved in pathological switching is scarce. In
this paper a description is given for the first time of a patient with a lesion
to the left anterior cingulate and to the frontal lobe-also marginally involving
the right anterior cingulate area-who presented with pathological switching
between languages in the absence of any other linguistic impairment. Thus, unlike
pathological mixing that typically occurs in bilingual aphasia, pathological
switching may be independent of language mechanisms.
PMID- 10766901
TI - Cerebral white matter lesions are not associated with apoE genotype but with age
and female sex in Alzheimer's disease.
AB - Cerebral white matter lesions, such as leukoaraiosis, may be a result of damage
from cerebral ischaemia, and may also be associated with the degenerative process
in Alzheimer's disease. The apolipoprotein epsilon4 (apoepsilon4) genotype is a
genetic risk factor for both Alzheimer's disease and ischaemic brain damage
through acceleration of atherosclerosis. The aim was to determine whether
apoepsilon4 may be related to the formation of cerebral white matter lesions in
Alzheimer's disease. The association of apoE genotype, sex, age, and the presence
of several vascular risk factors, with the presence of white matter lesions in 55
patients clinically diagnosed with Alzheimer's disease was investigated. The
cerebral white matter lesions were identified by T2 weighted MRI and classified
on a 4 grade scale from no lesion to diffuse lesion. The odds ratio (OR) of the
factors mentioned above to the presence of white matter lesions was determined
and tested by Fisher's exact test. The association of the lesion grades with
these factors was analysed by non-parametric tests. The apoE 4 genotype was
strongly associated with Alzheimer's disease (p=0.0001), but not associated with
the presence or the degree of cerebral white matter lesions in Alzheimer's
disease (OR=1.09, p>0.99). Aging (>70 years old) was a significant risk factor
for white matter lesions (OR=7.2, p=0.0006) and age was significantly correlated
with the lesion (p=0.0075). The OR of female sex to the lesion grades was 2.89
(p=0.084) and the lesion grade of female sex was significantly higher than that
of the male sex (p=0.047). Other vascular risk factors were not significantly
associated with the presence of white matter lesions. These findings suggest that
there is a sex difference in white matter pathology in Alzheimer's disease.
PMID- 10766902
TI - Functional recovery despite prolonged bilateral loss of somatosensory evoked
potentials: report on two patients.
AB - A bilateral loss of short latency somatosensory evoked potentials (SSEPs) after
head trauma or non-traumatic brain damage is normally associated with a
deleterious neurological outcome. An adequate recovery in reported in two deeply
comatose patients with head trauma or severe hypertensive encephalopathy despite
prolonged bilateral loss of SSEPs over days, found in repeated recordings. Hence,
a bilateral loss of SSEPs should not be considered alone for prediction of
outcome in cerebral injury.
PMID- 10766903
TI - Frataxin point mutations in two patients with Friedreich's ataxia and unusual
clinical features.
AB - Two patients with a progressive ataxia are presented with clinical features
consistent with classic Friedreich's ataxia (FRDA), but also with features
unusual for FRDA. Analysis of DNA showed that each patient is heterozygous for
the expanded GAA repeat of FRDA, but carries a base change on his other frataxin
allele. For one patient a non-conservative arginine to cysteine amino acid change
is predicted at amino acid 165 whereas the other mutation is found at the
junction of exon one and intron one. Muscle biopsy showed an absence of frataxin
immunoreactivity in the patient harbouring the intronic mutation, confirming the
pathological nature of the base change. These mutations extend the range of point
mutations seen in FRDA, and agree with recent reports suggesting phenotypic
variation in patients with FRDA harbouring point mutations in conjunction with an
expanded GAA repeat.
PMID- 10766904
TI - Acute myelitis after asthma attacks with onset after puberty.
AB - A poliomyelitis-like illness after asthma attacks has been found and is called
asthmatic amyotrophy (Hopkins' syndrome). All of the previously reported cases
were under 13 years of age. Three patients are described who developed acute
myelitis after asthma attacks at 15, 22, and 73 years of age. All of them showed
acute flaccid monoparesis, and needle EMG disclosed denervation potentials in the
relevant muscles. In addition, in the two adult patients the sensory or pyramidal
tracts were involved, and evoked potential studies confirmed an involvement of
the pyramidal tracts in one of them. This 22 year old patient showed a second
episode of monoparesis in the other limb after another asthma attack. All three
patients had no significant changes in their antiviral antibody titres, whereas
every patient had hyperIgEaemia and allergen specific IgE. These findings suggest
that asthmatic amyotrophy can develop after puberty and that patients who develop
this disease in adulthood seem to show both a widespread involvement of the
spinal cord and a more varied course.
PMID- 10766905
TI - Reliability and responsiveness of a graduated tuning fork in immune mediated
polyneuropathies. The Inflammatory Neuropathy Cause and Treatment (INCAT) Group.
AB - The interobserver and intraobserver reliability of the Rydel-Seiffer (RS)
graduated tuning fork was evaluated in 113 patients with a clinically stable
immune mediated polyneuropathy (83 patients who had had Guillain-Barre syndrome
(GBS) in the past, 22 with a chronic inflammatory demyelinating polyneuropathy
(CIDP), and eight with a polyneuropathy associated with a gammopathy of
undetermined significance). Additionally, the responsiveness of this instrument
was serially investigated in 20 patients with recently diagnosed GBS or CIDP and
changing clinical conditions. The measures were done in triplicate at eight
different locations in the limbs and the values were compared with the recently
published vibration threshold reference values. Good interobserver and
intraobserver agreements (quadratic weighted kappa=0.67-0.98) and high
responsiveness values (standardised response mean scores>0.8) were demonstrated
for the RS tuning fork. These results provide, in addition to literature
findings, further evidence for incorporation of this easily applicable instrument
in routine neurological examination.
PMID- 10766906
TI - Absence of unidentified CAG repeat expansion in patients with Huntington's
disease-like phenotype.
AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder
caused by an expanded (CAG)n repeat on the huntingtin gene. It is characterised
by motor, psychiatric and cognitive disturbances. Diagnosis can be confirmed by
direct genetic testing, which is highly sensitive and specific and is now
considered definitive. This study focused on 21 patients presenting with a
clinical phenotype showing strong similarity to HD, but who do not have an
expanded CAG in the huntingtin gene. However, other possible diagnoses could be
evoked for most of them. Seven patients (3.5% of our cohort) could be considered
as phenocopies of HD with no alternative diagnosis. Samples were screened for
other triplet repeat diseases with similar presentation (DRPLA, SCA-1, SCA-2, SCA
3, SCA-6, and SCA-7) and were all negative. The repeat expansion detection
technique (RED) was used to detect uncloned CAG repeat expansions and samples
were also analysed by polymerase chain reaction for expansions of the polymorphic
CAG-ERDA-1 and CTG18.1 trinucleotide repeats. RED expansion (>40 repeats) was
detected in only one patient. The results suggest that unstable CAG/CTG repeat
expansions corresponding to known or unknown sequences are not involved in the
aetiology of HD-like disorders. It is hypothesised that some of these phenocopies
could correspond to mutations in other unidentified genes with other unstable
repeats (different from CAG) or in unknown genes with other mutations.
PMID- 10766907
TI - Cystic dysplasia of the corpus callosum in interhemispheric disconnection
syndrome.
PMID- 10766909
TI - Mild head injury. A guide to management
PMID- 10766908
TI - A giant carotid aneurysm preventing correct swallowing.
PMID- 10766910
TI - McAlpine's multiple sclerosis. Third edition
PMID- 10766911
TI - Advances and technical standards in neurosurgery. Vol 25
PMID- 10766912
TI - Steroidal influences on oxytocin neurones.
AB - Oxytocin is essential for successful lactation. Without it, a babe that sucks at
a nipple will go hungry, even if the breast at which it sucks is engorged with
milk. In lactating rats, oxytocin cells respond to suckling with brief,
explosive, synchronous bursts of electrical activity (Lincoln & Wakerley, 1974).
This behaviour is not observed in virgin rats even in response to stimuli that
strongly excite oxytocin cells, and is not even observed in lactating rats in
response to any stimulus other than suckling.
PMID- 10766913
TI - What determines the initiation of the heartbeat?
AB - The origin of the heartbeat in the sino-atrial (SA) node is usually thought to
arise from the sequential activation of a variety of ionic currents in pacemaker
cells (Irisawa et al. 1993). Recently, the possibility has been considered that
heart rate might be influenced by transient changes in cytosolic Ca2+. Rubenstein
& Lipsius (1989) demonstrated that in cat subsidiary pacemaker cells the late
phase of diastolic depolarization was slowed in the presence of ryanodine to
selectively inhibit Ca2+ release from the sarcoplasmic reticulum (SR). Primary
pacemaker cells also have a SR-dependence of cardiac pacemaking since the rate of
beating of guinea-pig SA node/atrial preparations was slowed in the presence of
either ryanodine or cyclopiazonic acid (an inhibitor of the SR Ca2+-ATPase). The
reduction in rate was associated with changes in action potential characteristics
recorded intracellularly (Rigg & Terrar, 1996). The role of Ca2+ release from the
SR in influencing pacemaker rate appears to be a common mechanism in many types
of pacemaking tissue since the rate reducing effects of ryanodine have been
observed in other mammalian cells (rabbit SA, e.g. Hata et al. 1996; and
atrioventricular node, Hancox et al. 1994) and in amphibian pacemaker cells (Ju &
Allen, 1998).
PMID- 10766914
TI - Two mechanisms of genistein inhibition of cystic fibrosis transmembrane
conductance regulator Cl- channels expressed in murine cell line.
AB - 1. The isoflavone genistein may either stimulate or inhibit cystic fibrosis
transmembrane conductance regulator (CFTR) Cl- channels. To investigate how
genistein inhibits CFTR, we studied CFTR Cl- channels in excised inside-out
membrane patches from cells expressing wild-type human CFTR. 2. Addition of
genistein (100 microM) to the intracellular solution caused a small decrease in
single-channel current amplitude (i), but a large reduction in open probability
(Po). 3. Single-channel analysis of channel block suggested that genistein (100
microM) may inhibit CFTR by two mechanisms: first, it may slow the rate of
channel opening and second, it may block open channels. 4. Acidification of the
intracellular solution relieved channel block, suggesting that the anionic form
of genistein may inhibit CFTR. 5. Genistein inhibition of CFTR Cl- currents was
weakly voltage dependent and unaffected by changes in the extracellular Cl-
concentration. 6. Channel block was relieved by pyrophosphate (5 mM) and ATP (5
mM), two agents that interact with the nucleotide-binding domains (NBDs) of CFTR
to greatly stimulate channel activity. 7. ATP (5 mM) prevented the genistein
induced decrease in Po, but was without effect on the genistein-induced decrease
in i. 8. The genistein-induced decrease in i was voltage dependent, whereas the
genistein-induced decrease in Po was voltage independent. 9. The data suggest
that genistein may inhibit CFTR by two mechanisms. First, it may interact with
NBD1 to potently inhibit channel opening. Second, it may bind within the CFTR
pore to weakly block Cl- permeation.
PMID- 10766915
TI - Small conductance Ca2+-activated K+ channels are regulated by Ca2+-calmodulin
dependent protein kinase II in murine colonic myocytes.
AB - 1. Ca2+ regulates the activity of small conductance Ca2+-activated K+ (SK)
channels via calmodulin-dependent binding. We investigated whether other forms of
Ca2+-dependent regulation might control the open probability of SK channels. 2.
Under whole-cell patch-clamp conditions, spontaneous openings of SK channels can
be resolved as charybdotoxin-insensitive spontaneous transient outward currents
(STOCs). The Ca2+-calmodulin-dependent (CaM) protein kinase II inhibitor KN-93
reduced the occurrence of charybdotoxin-insensitive STOCs. 3. The charybdotoxin
insensitive STOCs are related to spontaneous, local release of Ca2+. KN-93 did
not affect spontaneous Ca2+-release events. 4. KN-93 and W-7, a calmodulin
inhibitor, decreased the open probability of SK channels in on-cell patches but
not in excised patches. 5. Application of autothiophosphorlated CaM kinase II to
the cytoplasmic surface of excised patches increased the open probalibity of SK
channels. Boiled CaM kinase II had no effect. 6. We conclude that CaM kinase II
regulates SK channels in murine coloni myocytes. This mechanism provides a
secondary means of regulation, increasing the impact of a given Ca2+ transient on
SK channel open probability.
PMID- 10766916
TI - Pregnancy switches adrenergic signal transduction in rat and human uterine
myocytes as probed by BKCa channel activity.
AB - 1. We used large conductance Ca2+-activated K+ (BKCa) channel activity as a probe
to characterize the inhibitory/stimulatory G protein (Gi/Gs) signalling pathways
in intact cells from pregnant (PM) and non-pregnant (NPM) myometrium. 2.
Isoprenaline (10 microM) enhanced the outward current (Iout) in PM cells and
inhibited Iout in NPM cells. Additional application of the alpha2-adrenoceptor
(alpha2-AR) agonist clonidine (10 microM) further enhanced the isoprenaline
modulated Iout in PM cells but partially antagonized Iout in NPM cells. Clonidine
alone did not affect Iout. The specific cAMP kinase (PKA) inhibitor H-89 (1
microM) abolished the effects of isoprenaline and clonidine. The specific BKCa
channel blocker iberiotoxin (0.1 microM) inhibited Iout by approximately 80 %;
the residual current was insensitive to isoprenaline. 3. Inhibition of Gi
activity by either pertussis toxin or the GTPase activating protein RGS16
abolished inhibitory as well as stimulatory effects of clonidine on Iout. 4.
Transducin-alpha, a scavenger of Gi betagamma dimers, converted the stimulatory
action of clonidine on Iout into an inhibitory effect. Free transducin-betagamma
enhanced both the stimulatory and the inhibitory effects of isoprenaline on Iout.
5. The results demonstrate that BKCa channel activity is a sensitive probe to
follow adenylyl cyclase-cAMP-PKA signalling in myometrial smooth muscle cells.
Both Gialpha-mediated inhibition and Gibetagamma-mediated stimulation can occur
in the same cell, irrespective of pregnancy. It is speculated that the coupling
between alpha2-AR and Gi proteins is more efficient during pregnancy and that
Gibetagamma at high levels simply override the inhibitory action of Gi alpha.
PMID- 10766917
TI - Regulation of a hyperpolarization-activated chloride current in murine
respiratory ciliated cells.
AB - 1. The properties of a hyperpolarization-activated Cl- current (Ihyp-act) in
murine ciliated respiratory cells have been studied using whole cell patch
clamping. 2. The current-voltage relationship was inwardly rectifying which was
due to voltage-dependent gating of the channel. 3. Inward current was markedly
sensitive to the extracellular Cl- concentration, an effect that was not related
to changes in transmembrane Cl- gradient. Decreasing extracellular Cl-
concentration to 6 mM caused a 70 % reduction in inward current with the dose
response relationship exhibiting a Hill coefficient of approximately 2.0 and an
IC50 of 29 mM. 4. External anion replacement gave a selectivity sequence of Br-
>= I- > Cl- > gluconate = aspartate. The more permeant halides significantly
increased current density while the less permeant anions decreased current
density, indicating that an extracellular anion is important for channel
activity. 5. The conductance was unaffected by exposure to anisotonic pipette
solutions or to increases in intracellular cAMP; however, current density was
reduced dose dependently by increases in intracellular calcium concentration from
0.1 to 0.5 microM. These results indicate that Ihyp-act is unlikely to be
involved in either volume regulation or cAMP/Ca2+-stimulated fluid secretion. 6.
Decreasing extracellular pH to 5.0 irreversibly inhibited Ihyp-act. However, the
current was fully active over the pH range 5.4-9.0 making it unlikely that it is
modulated by extracellular pH under physiological conditions. 7. We speculate
that Ihyp-act may have a role in basal Cl- absorption, acting as a Cl- sensor to
maintain optimal volume and composition of airway surface liquid.
PMID- 10766918
TI - Enhancement of NMDA receptor-mediated currents by light in rat neurones in vitro.
AB - 1. N-Methyl-D-aspartate (NMDA) receptor function can be modified by the action of
several endogenous and exogenous modulatory processes. In the present study, we
report that brief pulses of light potentiate NMDA, but not non-NMDA glutamatergic
receptor-mediated whole-cell and single channel currents in rat cortical neurones
in vitro. In addition, light also potentiated NMDA receptor-mediated whole-cell
responses in isolated rat retinal neurones. 2. Potentiation of NMDA whole-cell
currents in cortical neurones was readily observed during and following a brief
(< 2 s) exposure of neurones to wavelengths of less than 324 nm of relatively
bright light (0.09 microW microm-2). In addition, prolonged exposures (> 30 s) to
visible wavelengths (> 380 nm) or to attenuated light (1-3 % transmittance of non
attenuated light) were also sufficient to enhance NMDA receptor-mediated
responses. 3. The light-induced potentiation of NMDA receptor-mediated currents
persisted for several minutes, slowly reversing to control levels with a time
constant of approximately 5 min. A subsequent exposure to light could potentiate
NMDA receptor-mediated currents for a second time. 4. Light did not alter the
apparent affinity of the NMDA receptor for the co-agonists NMDA and glycine.
Additionally, potentiation of the NMDA-induced currents was not mediated by a
change in the pH sensitivity of the receptor. In excised outside-out membrane
patches, the effects of light on NMDA-activated unitary currents were manifested
as a twofold increase in channel open frequency without alterations in single
channel amplitude or open time. 5. Our results suggest the presence of a light
sensitive moiety within the NMDA receptor, or in a closely associated structure,
which affects channel properties. This previously unrecognized form of NMDA
receptor modulation may provide a tool for understanding the conformational
changes associated with its gating. In addition, it is possible that light may
affect NMDA receptor-mediated function or dysfunction in the retina.
PMID- 10766919
TI - Action potential waveform voltage clamp shows significance of different Ca2+
channel types in developing ascidian muscle.
AB - 1. Early in development, ascidian muscle cells generate spontaneous, long
duration action potentials that are mediated by a high-threshold, inactivating
Ca2+ current. This spontaneous activity is required for appropriate physiological
development. 2. Mature muscle cells generate brief action potentials only in
response to motor neuron input. The mature action potential is mediated by a high
threshold sustained Ca2+ current. 3. Action potentials recorded from these two
stages were imposed as voltage-clamp commands on cells of the same and different
stages from which they were recorded. This strategy allowed us to study how
immature and mature Ca2+ currents are optimized to their particular functions. 4.
Total Ca2+ entry during an action potential did not change during development.
The developmental increase in Ca2+ current density exactly compensated for
decreased spike duration. This compensation was a function purely of Ca2+ current
density, not of the transition from immature to mature Ca2+ current types. 5. In
immature cells, Ca2+ entry was spread out over the entire waveform of spontaneous
activity, including the interspike voltage trajectory. This almost continuous
Ca2+ entry may be important in triggering Ca2+-dependent developmental
programmes, and is a function of the slightly more negative voltage dependence of
the immature Ca2+ current. 6. In contrast, Ca2+ entry in mature cells was
confined to the action potential itself, because of the slightly more positive
voltage dependence of the mature Ca2+ current. This may be important in
permitting rapid contraction-relaxation cycles during larval swimming. 7. The
inactivation of the immature Ca2+ current serves to limit the frequency and burst
duration of spontaneous activity. The sustained kinetics of the mature Ca2+
current permit high-frequency firing during larval swimming.
PMID- 10766920
TI - Corticosteroids decrease mRNA levels of SERCA pumps, whereas they increase
sarcolipin mRNA in the rat diaphragm.
AB - 1. In order to explore the potential role of the sarcoplasmic-endoplasmic
reticulum Ca2+-ATPase (SERCA)-type pumps and of their modulators phospholamban
(PLB) and sarcolipin (SLN) in the functional alterations of the diaphragm induced
by corticosteroid treatment, expression of SERCA, PLB and SLN was assessed by RT
PCR in the diaphragm of rats treated daily for 5 days either with triamcinolone
(80 mg kg-1, n = 8) or with saline (control; 0.6 ml, n = 8). 2. Triamcinolone
treatment reduced the normalised overall amount of all SERCA mRNA in diaphragm by
70 % compared to controls (P < 0.05). This reduction was accounted for by a
relatively larger decrease in the SERCA1 mRNA (-69 %, P < 0.05) whilst the
decrease in SERCA2 mRNA (-49 %, P = 0.09) did not reach statistical significance.
As a result the relative proportion of SERCA2 mRNA was increased from 43 +/- 7 %
in control diaphragm to 52 +/- 4 % after triamcinolone treatment (P < 0.05). 3.
Only the adult isoform of SERCA1 (i.e. SERCA1a) mRNA was found in the diaphragm
of the 15-week-old control rats. Furthermore, triamcinolone treatment resulted in
reduced levels of SERCA2a (-40 %, P < 0.05) and increased levels of SLN mRNA
(+100 %, P < 0.05), while the decrease in PLB mRNA (-31 %, P = 0.277) did not
reach statistical significance. SERCA1b, SERCA2b and SERCA3 mRNA levels fell
below the detection limit in the diaphragm of both control and triamcinolone
treated rats. 4. Compared to control diaphragm, control rat heart showed a
relatively high PLB/(SERCA1 + SERCA2) mRNA ratio of 7.88 while this ratio
amounted only to 0.16 in control extensor digitorum longus (EDL) muscle.
Remarkably, the SLN/(SERCA1 + SERCA2) mRNA ratio in normal cardiac muscle (0.96)
was nearly the same as in diaphragm, but in EDL it amounted to only 0.05 that in
diaphragm. This indicates the very low expression of SLN in rat EDL. 5. These
data reveal that considerable alterations in SERCA mRNA levels accompany the
functional changes seen in diaphragm after corticosteroid treatment. The
relatively larger decrease in SERCA1 mRNA is in agreement with the selective type
II fibre atrophy previously observed in the diaphragm of triamcinolone-treated
rats, but the magnitude of SERCA alterations is more pronounced than expected on
the basis of the structural changes in the diaphragm. The increase in SLN mRNA
levels may represent a compensatory mechanism.
PMID- 10766922
TI - Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker
cells.
AB - 1. The cellular mechanisms governing cardiac atrial pacemaker activity are not
clear. In the present study we used perforated patch voltage clamp and confocal
fluorescence microscopy to study the contribution of intracellular Ca2+ release
to automaticity of pacemaker cells isolated from cat right atrium. 2. In
spontaneously beating pacemaker cells, an increase in subsarcolemmal
intracellular Ca2+ concentration occurred concomitantly with the last third of
diastolic depolarization due to local release of Ca2+ from the sarcoplasmic
reticulum (SR), i.e. Ca2+ sparks. Nickel (Ni2+; 25-50 microM), a blocker of low
voltage-activated T-type Ca2+ current ((ICa,T), decreased diastolic
depolarization, prolonged pacemaker cycle length and suppressed diastolic Ca2+
release. 3. Voltage clamp analysis indicated that the diastolic Ca2+ release was
voltage dependent and triggered at about -60 mV. Ni2+ suppressed low voltage
activated Ca2+ release. Moreover, low voltage-activated Ca2+ release was
paralleled by a slow inward current presumably due to stimulation of Na+-Ca2+
exchange (INa-Ca). Low voltage-activated Ca2+ release was found in both sino
atrial node and latent atrial pacemaker cells but not in working atrial myocytes.
4. These findings suggest that low voltage-activated ICa,T triggers
subsarcolemmal Ca2+ sparks, which in turn stimulate INa-Ca to depolarize the
pacemaker potential to threshold. This novel mechanism indicates a pivotal role
for ICa,T and subsarcolemmal intracellular Ca2+ release in normal atrial
pacemaker activity and may contribute to the development of ectopic atrial
arrhythmias.
PMID- 10766921
TI - Modulation of focal and global Ca2+ release in calsequestrin-overexpressing mouse
cardiomyocytes.
AB - 1. Focal and global Ca2+ releases were monitored in voltage-clamped control and
hypertrophied calsequestrin (CSQ)-overexpressing mouse cardiomyocytes, dialysed
with fluo-3, using rapid (120-240 frames s-1) two-dimensional confocal imaging.
2. Spontaneous focal Ca2+ releases (Ca2+ sparks) were absent or significantly
reduced in frequency in hypertrophied myocytes of CSQ-overexpressing mice
compared to their age-matched controls. Sporadic Ca2+ sparks seen in CSQ
overexpressing myocytes had intensities and durations similar to those of
controls although quantitative analysis showed a trend towards more diffuse focal
releases. 3. Activation of Ca2+ current (ICa) failed to produce the typical
sarcomeric Ca2+ striping pattern consistently seen in control myocytes. Instead,
focal Ca2+ releases appeared as a disorganized patchwork of diffuse or 'woolly'
fluorescence signals, resulting in slowly developing and reduced global Ca2+
transients. 4. Although the density of ICa in CSQ-overexpressing myocytes was
only slightly smaller than that of controls, the inactivation kinetics of the
current were greatly reduced, consistent with the much smaller rate of rise of
cytosolic Ca2+. 5. Enhancement of ICa by elevation of [Ca2+]o from 2 to 10 mM or
addition of 3 microM isoproterenol (isoprenaline) failed to normalize the
frequency of spontaneous Ca2+ sparks at rest or the pattern and the magnitude of
ICa-gated Ca2+ transients. Isoproterenol was somewhat more effective than
elevation of [Ca2+]o. 6. In sharp contrast, low (0.5 mM) caffeine concentrations
that produced no measurable effects on ICa or Ca2+ transients in control
myocytes, re-established spontaneous focal Ca2+ releases in CSQ-overexpressing
cells, triggered large ICa-gated cellular Ca2+ transients, and strongly enhanced
the kinetics of inactivation of ICa. 7. Our data suggest that impaired Ca2+
signalling in CSQ-overexpressing myocytes results from reduced co-ordination and
decreased frequency of Ca2+ sparks. The impaired Ca2+ signalling could not be
restored by procedures that increased ICa, but was mostly restored in the
presence of caffeine, which may alter the Ca2+ sensitivity of the ryanodine
receptor.
PMID- 10766923
TI - Tonotopic variations of calcium signalling in turtle auditory hair cells.
AB - Turtle cochlear hair cells are electrically tuned by a voltage-dependent Ca2+
current and a Ca2+-dependent K+ current (IBK(Ca)). The effects of intracellular
calcium buffering on electrical tuning were studied in hair cells at apical and
basal cochlear locations tuned to 100 and 300 Hz, respectively. Increasing the
intracellular BAPTA concentration changed the hair cell's resonant frequency
little, but optimized tuning at more depolarized membrane potentials due to a
positive shift in the half-activation voltage (V ) of the IBK(Ca). The shift in V
depended similarly on BAPTA concentration in basal and apical hair cells despite
a 2. 4-fold difference in the size of the Ca2+ current at the two positions. The
Ca2+ current amplitude increased exponentially with distance along the cochlea.
Comparison of V values and tuning properties using different BAPTA concentrations
with values measured in perforated-patch recordings gave the endogenous calcium
buffer as equivalent to 0.21 mM BAPTA in low-frequency cells, and 0.46 mM BAPTA
in high-frequency cells. High conductance Ca2+-activated K+ (BKCa) channels
recorded in inside-out membrane patches were 2-fold less Ca2+ sensitive in high
frequency than in low-frequency cells. Confocal Ca2+ imaging using the
fluorescent indicator Calcium Green-1 revealed about twice as many hotspots of
Ca2+ entry during depolarization in high-frequency compared to low-frequency hair
cells. We suggest that each BKCa channel is gated by Ca2+ entry through a few
nearby Ca2+ channels, and that Ca2+ and BKCa channels occupy, at constant channel
density, a greater fraction of the membrane area in high-frequency cells than in
low-frequency cells.
PMID- 10766924
TI - A novel role for membrane potential in the modulation of intracellular Ca2+
oscillations in rat megakaryocytes.
AB - 1. The effect of membrane potential (Vm) on ADP-evoked [Ca2+]i oscillations was
investigated in rat megakaryocytes, a non-excitable cell type recently shown to
exhibit depolarisation-evoked Ca2+ release from intracellular stores during
metabotropic purinoceptor stimulation. 2. Hyperpolarising voltage steps caused a
transient fall in [Ca2+]i and either abolished Ca2+ oscillations or reduced the
oscillation amplitude. These effects were observed in both the presence and
absence of extracellular Ca2+ and also in Na+-free saline solutions, suggesting
that hyperpolarisation leads to a reduction in the level of ADP-dependent Ca2+
release without a requirement for altered transmembrane Ca2+ fluxes. 3. In the
presence of Ca2+ oscillations, depolarising voltage steps transiently enhanced
the amplitude of Ca2+ oscillations. Following run-down of Ca2+ oscillations,
depolarisation briefly restimulated oscillations. 4. Simultaneous [Ca2+]i and
current-clamp recordings showed that Ca2+ and Vm oscillate in synchrony, with an
average fluctuation of approximately 30-40 mV, due to activation and inactivation
of Ca2+-dependent K+ channels. Application of a physiological oscillating Vm
waveform to non-oscillating cells under voltage clamp stimulated [Ca2+]i
oscillations. 5. Analysis of the relationship between [Ca2+]i and Vm showed a
threshold for activation of hyperpolarisation at about 250-300 nM. The
implications of this threshold in the interaction between Vm and Ca2+ release
during oscillations are discussed. 6. We conclude that the ability of voltage to
control release of endosomal Ca2+ in ADP-stimulated megakaryocytes is bipolar in
nature. Our data suggest that Vm changes are active components of the
feedback/feedforward mechanisms contributing to the generation of Ca2+
oscillations.
PMID- 10766925
TI - Evidence of elevated intracellular calcium levels in weaver homozygote mice.
AB - 1. A mutation in the G-protein-linked, inwardly rectifying K+ channel GIRK2 leads
to the loss of cerebellar and dopaminergic mesencephalic neurons in weaver mice.
The steps leading to cell death are not well understood but may involve
constitutive influx of Na+ and Ca2+ into the neurons. 2. We found that resting
[Ca2+]i was dramatically higher in cerebellar neurons from weaver mice compared
to wild-type neurons. 3. High-K+ stimuli elicited much smaller changes in [Ca2+]i
in weaver cerebellar neurons compared to wild-type neurons. 4. weaver cerebellar
granule cells could be rescued from cell death by the GIRK2wv cationic channel
blocker, QX-314. 5. QX-314 lowered resting intracellular Ca2+ levels in weaver
cerebellar granule cells. 6. These results suggest that changes in resting
[Ca2+]i levels and alterations in K+ channel function are most likely to
contribute to the developmental abnormalities and increased cerebellar cell death
observed in weaver mice.
PMID- 10766926
TI - 17-Oestradiol modulates in vitro electrical properties and responses to kainate
of oxytocin neurones in lactating rats.
AB - 1. Intracellular current clamp recordings were performed from identified oxytocin
(OT) neurones in acute hypothalamic slices taken from lactating Wistar rats at
early (5th day: LD-5) and late (21st day: LD-21) lactation. 2. The basic
electrophysiological properties of LD-21 OT neurones differed from those of LD-5
OT neurones: their resting membrane potential was more depolarised (-51.5 versus
54.9 mV); their action potential duration was longer (1.6 versus 1.2 ms); their
hyperpolarising after-potential (HAP) following single spikes and after
hyperpolarisation (AHP) following a burst of action potentials had smaller
amplitudes (-46 and -67 %, respectively); and they lacked spike frequency
adaptation during a burst. 3. In LD-21 neurones bath application of 17beta
oestradiol (10-7 M, 6-14 min) reversibly restored all these properties to values
observed in LD-5 cells. This treatment had no effect on LD-5 neurones. 4. LD-21
neurones were less sensitive to kainate than LD-5 neurones. 17beta-Oestradiol
significantly potentiated the kainate-induced response in LD-21, but not in LD-5
neurones. 5. The effects of 17beta-oestradiol were presumably mediated through a
non-genomic mechanism since they occurred within a few minutes of administration,
and disappeared within 30-40 min of washout. They were not inhibited by
tamoxifen, an antagonist of the nuclear oestrogen receptor ER-alpha. Lastly,
cholesterol, a non-active lipophilic molecule, had no effect. 6. Our observations
demonstrate that, in the absence of 17beta-oestradiol, the basic electrical
properties and sensitivity to kainate of OT neurones become altered between early
and late lactation. However, the rise in circulating levels of oestrogens during
the late phase of lactation may contribute to maintain OT neurone reactivity as
long as suckling continues.
PMID- 10766927
TI - ATP facilitates spontaneous glycinergic IPSC frequency at dissociated rat dorsal
horn interneuron synapses.
AB - 1. The ATP action on spontaneous miniature glycinergic inhibitory postsynaptic
currents (mIPSCs) was investigated in rat substantia gelatinosa (SG) neurons
mechanically dissociated from the 2nd layer of the dorsal horn in which their
presynaptic glycinergic nerve terminals remained intact. 2. ATP reversibly
facilitated the frequency of the mIPSCs in a concentration-dependent manner
without affecting their amplitude distribution. The ATP agonist, 2-methylthioATP
(2MeSATP), mimicked the ATP action, while another ATP receptor agonist, alphabeta
methylene-ATP (alpha,beta-meATP), had no effect on mIPSCs. 3. The ATP receptor
antagonists, suramin (1 x 10-6 M) and pyridoxal-5-phosphate-6-azophenyl-2',4'
disulphonic acid (PPADS) (1 x 10-5 M), completely blocked the facilitatory effect
of ATP on glycine release (102.0 +/- 11.2 % and 99.3 +/- 16.2 %, n = 6,
respectively) without altering the current amplitude distributions. 4. N
Ethylmaleimide (NEM), a sulphydryl alkylating agent, suppressed the inhibitory
effect of adenosine on mIPSC frequency (111.2 +/- 13. 3 %, n = 4) without
altering the current amplitude distribution. However, ATP still facilitated the
mIPSC frequency (693.3 +/- 245.2 %, n = 4) even in the presence of NEM. 5. The
facilitatory effect of ATP (1 x 10-5 M) on mIPSC frequency was not affected by
adding 1 x 10-4 M Cd2+ to normal external solution but was eliminated in a Ca2+
free external solution. 6. These results suggest that ATP enhances glycine
release from nerve terminals, presumably resulting in the inhibition of SG
neurons which conduct nociceptive signals to the CNS. This presynaptic P2X-type
ATP receptor may function to prevent excess excitability in SG neurons, thus
preventing an excessive pain signal and/or SG cell death.
PMID- 10766928
TI - Contributions of intrinsic and synaptic activities to the generation of neuronal
discharges in in vitro hippocampus.
AB - 1. Extracellular and intracellular records were made from guinea-pig hippocampal
slices to examine the contributions of intrinsic cellular properties and synaptic
events to the generation of neuronal activity. Extracellular signals were
filtered to pass action potentials, which could be detected within a distance of
about 80 microm from a discharging cell. 2. Spontaneous action potentials were
invariably detected in records from the stratum pyramidale of CA3 region.
Blocking excitatory synaptic transmission with NBQX and APV reduced their
frequency by 23 +/- 35 %. Suppressing synaptic inhibition, while excitation was
already blocked, increased the rate of spike discharge to 177 +/- 71 % of its
control value. 3. Most action potentials recorded intracellularly from CA3
pyramidal cells were initiated in the absence of a detectable synaptic event. In
contrast, most action potentials generated by inhibitory cells located close to
stratum pyramidale were preceded by an EPSP. 4. In 31 simultaneous recordings,
intracellular pyramidal cell action potentials appeared consistently to initiate
extracellular spikes with a mean latency of 2.2 +/- 1.0 ms. Single inhibitory
cell action potentials could initiate a reduction in the frequency of
extracellular spikes of duration 10-30 ms. 5. Some identified extracellular
spikes (n = 9) consistently preceded intracellularly recorded IPSPs. IPSPs were
initiated monosynaptically with latencies of 0.9-1.5 ms. In reciprocal
interactions, single pyramidal cell action potentials could trigger the discharge
of an identified unit that in turn appeared to initiate an IPSP in the same
pyramidal cell. 6. These data suggest that intrinsic cellular mechanisms underly
much of the spontaneous activity of pyramidal cells of the CA3 region of the
hippocampus in vitro. Both synaptic inhibition and a strong excitation of
inhibitory cells by pyramidal cells act to reduce population activity.
PMID- 10766929
TI - Primary afferent synaptic responses recorded from trigeminal caudal neurons in a
mandibular nerve-brainstem preparation of neonatal rats.
AB - 1. Whole-cell patch-clamp recordings were made from the neurons in the
superficial trigeminal caudal nucleus (substantia gelatinosa) visually identified
in a parasagittal brainstem slice of neonatal rat with the mandibular nerve
attached. 2. Stimulation of the mandibular nerve at 0.03 Hz evoked compound
excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) in trigeminal
caudal neurons. When stimulated at higher frequency (> 0.5 Hz), compound synaptic
responses were largely attenuated and a small component remained. This component
had a monosynaptic nature, following high-frequency stimulation (33-50 Hz) with a
stable synaptic latency. 3. The N-methyl-D-aspartate (NMDA) receptor antagonist
D(-)-2-amino-5-phosphonopentanoic acid (D-AP5, 50 microM) largely attenuated the
slow polysynaptic EPSCs. The AMPA/kainate receptor antagonist 6-cyano-7
nitroquinoxaline-2,3-dione (CNQX, 10 microM) largely attenuated monosynaptic
EPSCs, but only weakly attenuated slow polysynaptic EPSCs. Simultaneous
application of CNQX and D-AP5 completely abolished EPSCs. The monosynaptic EPSCs
isolated by repetitive stimulation had both NMDA and non-NMDA components. 4.
Monosynaptic EPSCs having high threshold had a relatively long latency. During
repetitive stimulation (0.5-5.0 Hz), EPSCs having high threshold and long latency
underwent a stepwise potentiation in an activity-dependent manner. The conduction
velocity estimated for these EPSCs fell into the range of C-fibres. The activity
dependent potentiation was observed for both non-NMDA and NMDA EPSCs and was
accompanied by a significant decrease in the coefficient of variation of EPSC
amplitude. 5. We suggest that the activity-dependent potentiation of EPSCs is
induced presynaptically and that it may underlie the wind-up phenomenon, an
activity-dependent hyperexcitability of the primary afferent C-fibres.
PMID- 10766930
TI - Release probability modulates short-term plasticity at a rat giant terminal.
AB - 1. Modulation of release probability is a major factor underlying short-term
synaptic plasticity in the central nervous system. We have investigated the
relationship between release probability ((Pr) and paired-pulse modulation at a
large auditory calyceal synapse containing many transmitter release sites. Whole
cell patch electrode recordings were made of excitatory postsynaptic currents
(EPSCs), evoked by stimulation of auditory nerve fibres giving rise to the
endbulbs of Held. 2. Quantitative estimates of Pr and quantal amplitude were
obtained using the recently developed variance-mean analysis technique. Release
probability conditions were modulated by bath application of cadmium, elevated
calcium and protein kinase C activation by phorbol esters. 3. Our results show
that, under physiological conditions, most sites released neurotransmitter
following a single presynaptic nerve impulse, with a mean Pr of 0.6. The mean
quantal amplitude was 44 pA, which was consistent with the mean amplitude of
miniature EPSCs (47 pA). 4. Under high release probability conditions with
elevated calcium or phorbol esters, Pr at all sites approached 1.0. At these high
Pr values, variance-mean analysis indicated a significant postsynaptic
contribution to paired-pulse depression. The miniature EPSC amplitudes were
decreased following stimulation in elevated calcium, confirming a postsynaptic
component of paired-pulse depression at this glutamatergic connection. 5. A
notable feature was the large variability between neurons in the relationship
between paired-pulse ratio and Pr. Based on current models of vesicle release and
ultrastructural evidence, we suggest that this variability may be partly due to
morphological differences between endbulb specializations, particularly in the
ratio of fusion-ready to reserve populations of vesicles at endbulb release
sites.
PMID- 10766931
TI - Prenatal hypoxia impairs the postnatal development of neural and functional
chemoafferent pathway in rat.
AB - 1. To define the effects of prenatal hypoxia on the postnatal development of the
chemoafferent pathway, ventilation and metabolism, pregnant rats were exposed to
normobaric hypoxia (10 % oxygen) from embryonic day 5 to embryonic day 20.
Offspring were studied at 1, 3 and 9 weeks of age in three separate protocols. 2.
Prenatal hypoxia decreased the dopamine content in the carotid bodies at all
ages, and decreased the utilisation rate of noradrenaline in the caudal part of
the A2 (A2c), A1 and A5 noradrenergic brainstem cell groups at 3 weeks after
birth. At 9 weeks of age, the level of dopamine in the carotid bodies was still
reduced but the utilisation rate of noradrenaline was enhanced in A1. 3. Rats
from dams subjected to hypoxia during pregnancy hyperventilated until 3 weeks
after birth. In these rats, the biphasic hypoxic ventilatory response was absent
at 1 week and the increase in minute ventilation was amplified at 3 weeks. 4.
Prenatal hypoxia disturbed the metabolism of offspring until 3 weeks after birth.
A weak or absent hypometabolism in response to hypoxia was observed in these rats
in contrast to control animals. 5. Prenatal hypoxia impairs the postnatal
development of the chemoafferent pathway, as well as the ventilatory and
metabolic responses to hypoxia. These alterations were mostly evident until 3
weeks after birth.
PMID- 10766932
TI - The effects of PO2 upon transepithelial ion transport in fetal rat distal lung
epithelial cells.
AB - 1. Isolated rat fetal distal lung epithelial (FDLE) cells were cultured (for 48
h) at PO2 levels between 23 and 142 mmHg. Higher PO2 levels between 23 and 142
mmHg. Higher PO2 was associated with increased short circuit current (ISC) and
increased abundance of the Na+ channel protein alpha-ENaC. PO2 had no effect upon
ISC remaining after apical application of amiloride (10 microM). 2. Studies of
cells maintained (for 48 h) at PO2 levels of 23 mmHg or 100 mmHg, and
subsequently nystatin permeabilized (50 microM), showed that high PO2 increased
Na+ pump capacity. This response was apparent 24 h after PO2 was raised whilst it
took 48 h for the rise in ISC seen in intact cells to become fully established.
Both parameters were unaffected by raising PO2 for only 30 min. 3. Basolateral
application of isoprenaline (10 microM) did not affect ISC in cells maintained at
23 mmHg but evoked progressively larger responses at higher PO2. The response
seen at 142 mmHg was larger than at 100 mmHg, the normal physiological alveolar
PO2. 4. Isoprenaline had no effect on Na+ pump capacity at PO2 levels of 23 mmHg
or 100 mmHg, but stimulated Na+ extrusion at 142 mmHg. Increasing PO2 above
normal physiological levels thus allows the Na+ pump to be controlled by
isoprenaline. This may explain the enhanced sensitivity to isoprenaline seen
under these slightly hyperoxic conditions. 5. Changes in PO2 mimicking those
occurring at birth thus exert profound influence over Na+ transport in FDLE cells
and the Na+ pump could be an important locus at which this control is exercised.
PMID- 10766933
TI - Neuroeffector transmission to different layers of smooth muscle in the rat penile
bulb.
AB - 1. Using intracellular recording techniques, two distinct layers of smooth muscle
were identified in the rat penile bulb. The inner muscle layer (parenchyma)
exhibited spontaneous action potentials, while the outer sheet (sac) was
electrically quiescent. 2. In the parenchyma, transmural stimulation initiated
non-adrenergic, non-cholinergic (NANC) inhibitory junction potentials (IJPs)
which were abolished by Nomeganitro-L-arginine (LNA) or 1H-[1,2, 4]oxadiazolo[4,3
a]quinoxalin-1-one (ODQ). The amplitude of IJPs was reduced by ouabain,
dinitrophenol or decreasing the extracellular potassium concentration ([K+]o) but
not by several K+ channel blockers. 3. The parenchyma also received an excitatory
innervation mediated by alpha-adrenoceptors which caused a contraction that was
not associated with a membrane potential change. 4. In the sac, transmural
stimulation initiated two component excitatory junction potentials (EJPs)
mediated by alpha-adrenoceptors and associated action potentials. The initial
component was more dramatically suppressed than the secondary component by
caffeine, ryanodine or cyclopiazonic acid (CPA). Lowering of the extracellular
chloride concentration ([Cl-]o) selectively inhibited the rapid component of
EJPs, while niflumic acid was less potent. 5. These results suggest that IJPs in
the parenchyma result from the release of NO which stimulates sodium pump
activity following the activation of guanylate cyclase. In the sac, the
activation of alpha-adrenoceptors initiates EJPs by releasing Ca2+ from
intracellular stores which activates Ca2+-activated channels.
PMID- 10766934
TI - Mechanisms of excitatory neuromuscular transmission in the guinea-pig urinary
bladder.
AB - 1. In smooth muscle of the guinea-pig bladder, either membrane potential
recordings or [Ca2+]i measurements were made simultaneously with isometric
tension recordings. 2. Single transmural stimuli initiated excitatory junction
potentials (EJPs) which triggered action potentials, transient increases in
[Ca2+]i and associated contractions. These responses were abolished by alpha,
beta-methylene ATP, suggesting that they resulted from the activation of
purinoceptors by neurally released ATP. 3. Nifedipine abolished action potentials
leaving the underlying EJPs and reduced the amplitude of both nerve-evoked
increases in [Ca2+]i and associated contractions. The subsequent co-application
of caffeine and ryanodine inhibited the residual responses without inhibiting
EJPs. These results indicate that stimulation of purinoceptors activates both
Ca2+ influx through L-type Ca2+ channels and Ca2+ release from intracellular Ca2+
stores. 4. In the presence of alpha, beta-methylene ATP, trains of stimuli failed
to initiate EJPs but increased the frequency of action potentials. Trains of
stimuli also initiated oscillatory increases in [Ca2+]i and associated
contractions. These responses were abolished by hyoscine, indicating that they
resulted from the activation of muscarinic receptors by neurally released ACh. 5.
Oscillatory increases in [Ca2+]i and associated contractions were inhibited by
either nifedipine or caffeine, indicating that the stimulation of muscarinic
receptors activates both Ca2+ influx through L-type Ca2+ channels and Ca2+
release from intracellular Ca2+ stores.
PMID- 10766935
TI - In vivo characterization of renal iron transport in the anaesthetized rat.
AB - 1. In vivo microinjections of 55FeCl3 were made to assess renal iron (Fe2+/3+)
transport in the anaesthetized rat. 2. Following microinjection into proximal
convoluted tubules (PCTs), 18.5 +/- 2.9 % (mean +/- s.e.m., n = 11) of the 55Fe
was recovered in the urine. This recovery was not dependent on the injection site
indicating that iron is not reabsorbed across the surface convolutions of the
proximal tubule. 3. Following microinjection into distal convoluted tubules
(DCTs) 46.1 +/- 6.1 % (n = 8) of the injected 55Fe was recovered. Taken together
the recovery data from the PCT and DCT microinjection studies indicate that the
transport of iron occurs in the loop of Henle (LH) and collecting duct system. 4.
In vivo luminal microperfusion was used to examine iron transport by the LH in
more detail. In tubules perfused with 7 micromol l-1 55FeCl3, 52.7 +/- 8. 3 % (n
= 8) of the perfused 55Fe was recovered in the collected fluid, indicating
significant iron reabsorption in the LH. Addition of copper (Cu2+ as 7 micromol l
1 CuSO4), manganese (Mn2+ as 7 micromol l-1 MnSO4) or zinc (Zn2+ as 7 micromol l
1 ZnSO4) to the perfusate did not affect reabsorption of water, Na+ or K+, but
increased recovery of 55Fe to 83.5 +/- 6.8 % (n = 8, P < 0.04), 75.8 +/- 5.9 (n =
6, not significant, n.s.) and 67.9 +/- 3.8; (n = 9, n.s. ), respectively. 5.
Thus, iron transport in the LH can be reduced by the addition of copper or
manganese to the luminal perfusate suggesting that these ions may compete with
iron for a common transport pathway. However, this pathway may not be shared by
zinc.
PMID- 10766937
TI - Effects of changing stance conditions on anticipatory postural adjustment and
reaction time to voluntary arm movement in humans.
AB - 1. The effect on reaction time (RT) and anticipatory postural adjustment (APA) of
unexpectedly changing stance conditions was studied using a push or pull arm
movement task. The aim was to evaluate the modifiability of RT and APA by an
external perturbation associated with an automatic compensatory reaction. 2.
Subjects standing on a moveable platform were asked to push or pull a rigid
handle as quickly and as strongly as possible in response to the 'go-signal', a
visual signal from a green or red light-emitting diode. Forward and backward
translations of the platform were randomly induced at four time intervals after
the go-signal. In some experiments to detect unspecific arousal there were no
platform translations but an acoustic signal was given before the go-signal.
Surface electromyographic activity (EMG) of upper arm and lower leg muscles was
analysed. 3. During the push task both RT and the duration of APA (onset of APA
till the force signal indicating hand action) were shorter during backward than
during forward translation. During the pull task the effect of platform
translations was the reverse. The delay between go-signal and onset of APA
remained constant. Consequently, RT and APA became shorter when the platform was
translated in the same direction as that in which the upper body was displaced by
the push or pull movement, and longer when it was translated in the opposite
direction. The effects were maximal when translations were induced 250 ms after
the go-signal, but a difference was detected up to 375 ms. 4. Furthermore, with
forward and backward platform translations RT was shorter when the translations
were induced early rather than late after the go-signal. This was associated with
a shortening of the delay between the go-signal and onset of APA, while APA
duration remained constant. The shortened RT was in the range of that obtained
when an acoustic signal was given just before the go-signal. 5. It is concluded
that (i) both the RT and the duration of APA can be modified by a translation of
the support surface in a functionally appropriate way by updating the internal
representation of the actual stance condition within the central nervous system.
Both RT and APA are shortened when the body displacement induced by the push or
pull movement and platform translation have the same direction; conversely, an
inappropriate translation of the feet requires a greater APA and leads to a
longer RT; (ii) both APA and RT are modifiable by platform translation for more
than half the time between the go-signal and the focal push or pull movement;
(iii) an unspecific effect of platform translation on RT can be identified; it
may be mediated by a different neuronal substrate.
PMID- 10766936
TI - Heat production in human skeletal muscle at the onset of intense dynamic
exercise.
AB - 1. We hypothesised that heat production of human skeletal muscle at a given high
power output would gradually increase as heat liberation per mole of ATP produced
rises when energy is derived from oxidation compared to phosphocreatine (PCr)
breakdown and glycogenolysis. 2. Five young volunteers performed 180 s of intense
dynamic knee-extensor exercise ( approximately 80 W) while estimates of muscle
heat production, power output, oxygen uptake, lactate release, lactate
accumulation and ATP and PCr hydrolysis were made. Heat production was determined
continuously by (i) measuring heat storage in the contracting muscles, (ii)
measuring heat removal to the body core by the circulation, and (iii) estimating
heat transfer to the skin by convection and conductance as well as to the body
core by lymph drainage. 3. The rate of heat storage in knee-extensor muscles was
highest during the first 45 s of exercise (70-80 J s-1) and declined gradually to
14 +/- 10 J s-1 at 180 s. 4. The rate of heat removal by blood was negligible
during the first 10 s of exercise, rising gradually to 112 +/- 14 J s-1 at 180 s.
The estimated rate of heat release to skin and heat removal via lymph flow was <
2 J s-1 during the first 5 s and increased progressively to 24 +/- 1 J s-1 at 180
s. The rate of heat production increased significantly throughout exercise, being
107 % higher at 180 s compared to the initial 5 s, with half of the increase
occurring during the first 38 s, while power output remained essentially
constant. 5. The contribution of muscle oxygen uptake and net lactate release to
total energy turnover increased curvilinearly from 32 % and 2 %, respectively,
during the first 30 s to 86 % and 8 %, respectively, during the last 30 s of
exercise. The combined energy contribution from net ATP hydrolysis, net PCr
hydrolysis and muscle lactate accumulation is estimated to decline from 37 % to 3
% comparing the same time intervals. 6. The magnitude and rate of elevation in
heat production by human skeletal muscle during exercise in vivo could be the
result of the enhanced heat liberation during ATP production when aerobic
metabolism gradually becomes dominant after PCr and glycogenolysis have initially
provided most of the energy.
PMID- 10766938
TI - A view on the science: physical anthropology at the millenium.
PMID- 10766939
TI - Georgian and kurd mtDNA sequence analysis shows a lack of correlation between
languages and female genetic lineages.
AB - Mitochondrial DNA sequences from Georgians and Kurds were analyzed in order to
test the possible correlation between female lineages and languages in these two
neighboring West Eurasian groups. Mitochondrial sequence pools in both
populations are very similar despite their different linguistic and prehistoric
backgrounds. Both populations present mtDNA lineages that clearly belong to the
European gene pool, as shown by 1) similar nucleotide and sequence diversities;
2) a large number of sequences shared with the rest of European samples; 3)
nonsignificant genetic distances; and 4) classification of the present lineages
into the major European mtDNA haplogroups already described. The outlier position
of the populations from the Caucasus according to classical genetic markers is
not recognized in the present Georgian mtDNA sequence pool. This result suggests
that the differentiation of mtDNA sequences in West Eurasia and the outlier
features of Caucasian populations should be attributed to different processes.
Moreover, the putative linguistic relationship between Caucasian groups and the
Basques, another outlier population within Europe for classical genetic markers,
is not detected by the analysis of mtDNA sequences.
PMID- 10766940
TI - Comparison of narrow-band reflectance spectroscopy and tristimulus colorimetry
for measurements of skin and hair color in persons of different biological
ancestry.
AB - We have used two modern computerized handheld reflectometers, the Photovolt
ColorWalk colorimeter (a tristimulus colorimeter; Photovolt, UMM Electronics,
Indianapolis, IN) and the DermaSpectrometer (a specialized narrow-band
reflectometer; Cortex Technology, Hadsund, Denmark), to compare two methods for
the objective determination of skin and hair color. These instruments both
determine color by measuring the intensity of reflected light of particular
wavelengths. The Photovolt ColorWalk instrument does so by shining a white light
and sensing the intensity of the reflected light with a linear photodiode array.
The ColorWalk results can then be expressed in terms of several standard color
systems, most importantly, the Commission International d'Eclairage (CIE) Lab
system, in which any color can be described by three values: L*, the lightness;
a*, the amount of green or red; and b*, the amount of yellow or blue. Instead of
a white light and photodiodes, the DermaSpectrometer uses two light-emitting
diodes (LEDs), one green and one red, to illuminate a surface, and then it
records the intensity of the reflected light. The results of these readings are
expressed in terms of erythema (E) and melanin (M) indices. We measured the
unexposed skin of the inner upper arm, the exposed skin of the forehead, and the
hair, of 80 persons using these two instruments. Since it is important for the
application of these measures in anthropology that we understand their
relationship across a number of different pigmentation levels, we sampled persons
from several different groups, namely, European Americans (n = 55), African
Americans (n = 9), South Asians (n = 7), and East Asians (n = 9). In these
subjects, there is a very high correlation between L* and the M index for the
inner arm (R(2) = 0.928, P < 0.001), the forehead (R(2) = 0.822, P < 0.001), and
the hair (R(2) = 0.827, P < 0.001). The relationship between a* and the E index
is complex and dependent on the pigmentation level. We conclude that while both
types of instruments provide accurate estimates of pigment level in skin and
hair, measurements using narrow-band instruments may be less affected by the
greater redness of certain body sites due to increased vascularization.
PMID- 10766942
TI - Estimation of height from the length of long bones in a Portuguese adult
population.
AB - Research was undertaken on 200 individuals (100 males and 100 females) from the
northern districts of Portugal, all Caucasian, between the ages of 20 and 59.
Height and bones were measured directly. Estimation of stature is obtained by
applying a mathematical method based on a multivariable linear regression between
the height of the cadaver and the lengths of humerus and femur. Humerus is
measured on full length; femur is measured on both physiological and maximum
lengths. Regression formulae and tables for males and females are produced for
application in forensic anthropology when studying human skeletal remains.
Comparisons are made between these tables and those of earlier authors, allowing
us to verify important differences. One of the conclusions concerns the
application of regression formulae based on some segment measurements. Due to the
extremely high values of standard deviations, these may have no practical
application.
PMID- 10766941
TI - A study of contemporary levels and temporal trends in inbreeding in the Tangier
Island, Virginia, population using pedigree data and isonymy.
AB - In this study we describe inbreeding in a large pedigree from Tangier Island,
Virginia, in which we compare two commonly used methods to estimate inbreeding in
humans: pedigree and isonymy (identical surnames of spouses). Genealogical data
on 3,512 individuals dating back to 1722 were used. Using the pedigree method, we
determined an average inbreeding coefficient (F) of 0.00873 for the community as
a whole, and 0.018 for inbred individuals. Analysis of temporal trends showed
that inbreeding began around 1800 and peaked at 0.0109 in 1824-1849 and 1875
1899. Thereafter, inbreeding steadily declined to 0.00565 in 1975-1997. Analysis
of pedigree structure complexity over time showed that close consanguinity
contributes to inbreeding in the earlier cohorts, and remote consanguinity
accounts for much of the inbreeding in the later cohorts. The number of common
ancestors increases over time, as does the number of paths connecting inbred
individuals to these common ancestors. Inbreeding estimates based on the isonymy
approach yielded a 2.2-fold higher value of F (0.01945) compared to the pedigree
method. Total isonymy estimates over 25-year cohorts overestimated inbreeding
values from pedigree data between 1. 5-8-fold. We speculate that the
overestimation is probably due to the inability of our data to satisfy the
method's assumption of monophyletic origin of each surname. In conclusion,
inbreeding in the Tangier Island population is consistent with the isolated
nature of its population, and temporal trends reflect patterns in emigration and
a breakdown in isolation over time.
PMID- 10766943
TI - Auricular exostoses in the prehistoric population of Gran Canaria.
AB - Auditory exostoses are bone anomalies located in the external auditory canal. The
bulk of clinical observations and some experimental data support the idea that
their development depends on prolonged exposure to cold water. This study was
performed in order to analyze the prevalence of auditory exostoses among the
prehispanic population of Gran Canaria, comparing it between men and women and
between individuals buried in coastal regions and central highlands. We analyzed
323 crania, 41 of which showed auditory exostoses. Marked differences in
prevalence were observed between the individuals buried in the central highlands
(0.88%) and those buried in coastal regions (40.21%). Among the latter, the
prevalence was similar in men (41.67%) and in women (38.89%). These data support
the hypothesis that individuals buried in coastal regions performed economic
activities related to exploitation of marine resources, whereas those living in
the central highlands did not; however, diachronic variation cannot be excluded.
PMID- 10766944
TI - Growth of skeletal components in the young squirrel monkey (Saimiri sciureus
boliviensis): a longitudinal experiment.
AB - A functional skeletal criterion, as an extension of the van der Klaauw's cranial
theory, was adopted in the present study. The null hypothesis tested was: "The
major skeletal components of the platyrrhine body grow linearly, regardless of
their functional dependence to different demands." The acceptance of the
hypothesis will imply that all Saimiri skeletal growth may be satisfactorily
explained by independent variables in a single equation. The rejection will
suggest that such skeletal growth patterns have to be explained by variables in
several different equations, and perhaps these equations may vary with the effect
of sex and undernutrition. Control and undernourished squirrel monkeys were
radiographed monthly for 2 years; they were also measured; and their volumetric
and morphometric neurocranial, facial, and pelvic indices were calculated. The
curves that best described each of the 24-point sequences were obtained. Three
main growth patterns were observed: 1) Simple linear (femur length for all
groups, and pelvic index for control and undernourished females), for which the
simple regression equation explained more than 95% of the variation; 2) Complex
linear (pelvic index for control and undernourished males, and neurocranial and
facial indices for all of the groups), for which more than 95% of the variation
was explained by one of the four four-function type equations; and 3)
Noncorrelated with age (neurofacial index for undernourished males, and
pelviofemoral index for control females and undernourished males and females),
which showed nonsignificant correlations with respect to age. The food intake and
the oscillations of the environmental temperature might help to explain the
undulating growth trajectory observed in the complex linear components.
PMID- 10766945
TI - Dental eruption sequence among colobine primates.
AB - Dental development is one aspect of growth that is linked to diet and to life
history but has not been investigated among colobines since the work of Schultz
[1935]. This study establishes the dental eruption sequence for several colobine
species and compares it to that of other catarrhines. The mandibles and maxillae
of two hundred and four juvenile colobine specimens were scored for presence or
absence of permanent teeth and for stages of partial eruption. Eruption was
defined as ranging between tooth emergence (any part of a tooth crown above the
alveolar margin) and full occlusion, with three intermediate levels manifest
between these boundaries. In African colobines, represented by C. guereza, C.
angolensis and P. badius, M2 erupts before I2, and in C. angolensis it also
erupts before I1. The canine is delayed, erupting after the premolars in females
and after M3 in males. Asian colobines show greater diversity in eruption
sequences. Nasalis shows no early eruption of the molars and is very similar to
Macaca. In Trachypithecus and Pygathrix M(2) erupts before I(2). The canine in
Trachypithecus is delayed, erupting after the premolars and, in some males, after
M3. In Presbytis M2 erupts before both incisors; M3 erupts before C in both
sexes, and often before both premolars. Although the actual timing of eruption is
unknown, all colobine species examined except N. larvatus showed some degree of
relatively early eruption of M2 and M3. The lack of this tendency in Nasalis sets
this genus apart from all other colobines represented in this study. Dental
eruption sequence is thought to reflect life history patterns. Early molar
eruption in colobines was thought by Schultz (1935) to be a primitive character
reflecting shorter life history. Faster growth rates found in folivorous primates
have been interpreted as being related to an adaptation to folivory (Leigh 1994),
and early eruption of molars may be part of this dietary specialization. The
relationships between dental development and both diet and life history are
investigated.
PMID- 10766946
TI - Uniqueness of primate forelimb posture during quadrupedal locomotion.
AB - Among the characteristics that are thought to set primate quadrupedal locomotion
apart from that of nonprimate mammals are a more protracted limb posture and
larger limb angular excursion. However, kinematic aspects of primate or
nonprimate quadrupedal locomotion have been documented in only a handful of
species, and more widely for the hind than the forelimb. This study presents data
on arm (humerus) and forelimb posture during walking for 102 species of mammals,
including 53 nonhuman primates and 49 nonprimate mammals. The results demonstrate
that primates uniformly display a more protracted arm and forelimb at hand
touchdown of a step than nearly all other mammals. Although primates tend to end
a step with a less retracted humerus, their total humeral or forelimb angular
excursion exceeds that of other mammals. It is suggested that these features are
components of functional adaptations to locomotion in an arboreal habitat, using
clawless, grasping extremities.
PMID- 10766947
TI - Craniofacial variation in Homo habilis: an analysis of the evidence for multiple
species.
AB - The question of heterogeneity in the Homo habilis sample continues to be
controversial. Various lines of evidence have been used to reject the null
hypothesis of intraspecific variation. This evidence derives from analyses of
endocranial volume variation, probability estimates of sexual dimorphism, facial
variation, cranial angles, CV analysis of craniofacial variation, the
multivariate pattern of sexual dimorphism, the pattern of variability (CV)
profiles, distance data using exact randomization methods, and various kinds of
quantitative ordinations of fossils. Although consensus is lacking as to how the
H. habilis sample is to be split, there is a growing perception that the degree
of variation among the fossils is too great and the pattern of variation is too
different to be explained by intraspecific variation. This has resulted in the
recognition of new species such as "Homo rudolfensis." The present study
critically examines the evidence commonly cited as the basis for recognizing
multiple species in the extended H. habilis hypodigm. Reanalysis and
reinterpretation of these data indicates that: (1) the degree of variation in the
H. habilis sample is typical of modern hominoids, and (2) the pattern of
variation among specimens of the H. habilis sample is consistent with
intraspecific variation. Thus, at present, there is no sound basis to reject the
null hypothesis of intraspecific variation as an adequate explanation of the
morphological variation seen among specimens of the extended H. habilis sample.
If multiple species are indeed represented, then their presence has not yet been
satisfactorily demonstrated.
PMID- 10766948
TI - Multiregional, not multiple origins.
AB - Multiregional evolution is a model to account for the pattern of human evolution
in the Pleistocene. The underlying hypothesis is that a worldwide network of
genic exchanges, between evolving human populations that continually divide and
reticulate, provides a frame of population interconnections that allows both
species-wide evolutionary change and local distinctions and differentiation.
"Multiregional" does not mean independent multiple origins, ancient divergence of
modern populations, simultaneous appearance of adaptive characters in different
regions, or parallel evolution. A valid understanding of multiregional evolution
would go a long way toward reducing the modern human origins controversy.
PMID- 10766949
TI - Transmembrane domains of viral ion channel proteins: a molecular dynamics
simulation study.
AB - Nanosecond molecular dynamics simulations in a fully solvated phospholipid
bilayer have been performed on single transmembrane alpha-helices from three
putative ion channel proteins encoded by viruses: NB (from influenza B), CM2
(from influenza C), and Vpu (from HIV-1). alpha-Helix stability is maintained
within a core region of ca. 28 residues for each protein. Helix perturbations are
due either to unfavorable interactions of hydrophobic residues with the lipid
headgroups or to the need of the termini of short helices to extend into the
surrounding interfacial environment in order to form H-bonds. The requirement of
both ends of a helix to form favorable interactions with lipid headgroups and/or
water may also lead to tilting and/or kinking of a transmembrane alpha-helix.
Residues that are generally viewed as poor helix formers in aqueous solution
(e.g., Gly, Ile, Val) do not destabilize helices, if located within a helix that
spans a lipid bilayer. However, helix/bilayer mismatch such that a helix ends
abruptly within the bilayer core destabilizes the end of the helix, especially in
the presence of Gly and Ala residues. Hydrogen bonding of polar side-chains with
the peptide backbone and with one another occurs when such residues are present
within the bilayer core, thus minimizing the energetic cost of burying such side
chains.
PMID- 10766950
TI - S curve, a graphic representation of protein secondary structure sequence and its
applications.
AB - A secondary structure sequence is a symbolic string composed of three kinds of
letters, indicating the helix, strand, and coil (including turns), respectively.
A graphic representation for this abstract symbolic sequence is proposed here,
called the S curve. The S curve is the unique representation for a given
secondary structure sequence in the sense that the sequence and the S curve can
be uniquely determined from the other. Therefore, the S curve contains all the
information that the secondary structure sequence contains. Different geometrical
properties of the S curve are studied in details, which reflect the basic
characteristics of the secondary structure sequences. The S curves are used to
display, analyze, and compare the secondary structure sequences. Detailed
application examples are presented. One advantage of the S curve methodology is
that the main patterns of a given secondary structure sequence can be grasped
quickly in a perceivable form. This is particularly useful in the cases in which
longer sequences are involved and structures of proteins are unknown.
PMID- 10766951
TI - Synthesis and conformational analysis of apamin analogues with natural and non
natural cystine/selenocystine connectivities.
AB - By replacing two cysteine residues in apamin with selenocysteine, the three
possible isomers related to the side-chain connectivities of a bis-cystinyl
peptide were synthesized in regioselective manner exploiting the low redox
potential of the diselenide bond. Nuclear magnetic resonance conformational
analysis of monoselenocystine analogue apamin with the natural
diselenide/disulfide network confirmed the highly isomorphous character of the
sulfur replacement with selenium despite its slightly larger atomic radius and
increased bond lengths. The comparative conformational analysis of the apamin
analogues containing the non-natural side-chain links with wild type apamin
clearly revealed retention of the main structural fold and thus the high
propensity of these small molecules to adopt the secondary structure elements
present in natural apamin. These findings offered interesting hints for a better
understanding of the oxidative refolding pathway of the bis-cystinyl peptide that
leads exclusively to the correct natural isomer.
PMID- 10766952
TI - A three-dimensional model of the delta-opioid pharmacophore: comparative
molecular modeling of peptide and nonpeptide ligands.
AB - A comparative molecular modeling study of delta-opioid ligands was performed
under the assumption that potent peptide and nonpeptide agonists may have common
three-dimensional (3D) arrangement of pharmacophore groups upon binding to the
delta-receptor. Low-energy conformations of the agonists 7
spiroindanyloxymorphone (SIOM) and 2-methyl-4a-alpha-(3-hydroxyphenyl)
1,2,3,4,4a,5,12, 12a-alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and
a partial agonist oxomorphindole (OMI) were determined by high-temperature
molecular dynamics (MD). A good spatial overlap was found for the pharmacophore
groups of SIOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl,
and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model
for nonpeptide delta-opioid agonists with a distance of 7.0 +/- 1.3 A between the
two aromatic rings and of 8.2 +/- 1.0 A between the nitrogen and phenyl ring. The
potent and highly delta-opioid receptor selective agonist [(2S,3R)-TMT(1)]DPDPE,
which shares global backbone constraints of the 14-membered disulfide cycle and a
strong preference for the trans rotamer of the TMT(1) side chain, was chosen as a
peptide template of the delta-opioid pharmacophore. Extensive MD simulations at
300 K with the AMBER force field were performed for [(2S,3R)-TMT(1)]DPDPE and the
less potent [(2S, 3S)-TMT(1)]DPDPE analogue. Multiple MD trajectories were
collected for each peptide starting from the x-ray structures of DPDPE and [L
Ala(3)]DPDPE and from models proposed in the literature. Low-energy MD
conformations were filtered by the nonpeptide pharmacophore query and then
directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)
TMT(1)]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms
deviation 5varepsilon)-Gly(11),
designed to mimic the calcium coordination site I of Calmodulin, has been
synthesized and its conformation and calcium binding properties have been
investigated by means of CD and nmr spectroscopy. The nmr analysis of the free
peptide, carried out in DMSO and in TFE/H(2)O at different pH values, shows the
presence in solution of one stable conformer, exhibiting trans configuration
around both Proline residues. The nmr results in both solvents suggest for the
molecule a rectangular shape constituted by two antiparallel beta-strands
connected by two beta-turns. Interproton distances, evaluated by NOE contacts,
have been used to obtain feasible models by means of Restrained Molecular Dynamic
(RMD). The average models from RMD calculations, for both solvents, exhibit good
analogies with Calmodulin site I. The model system, when compared with the
reference system (Asp(20)-Glu(31) segment in CaM), shows similar dimensions and
an effective superimposition of the respective sequence segments Ala(1)-Glu(4)
and Thr(28)-Glu(31). The remaining segments of the model peptide exhibit a
bending that is intermediate between that of the free and Ca(2+)-coordinated site
I. CD spectra, recorded in TFE solutions, point to a 1:1 stoichiometry for the
Ca(2+)-peptide complex, with an association constant of at least 1 x 10(5) M(-1).
PMID- 10766955
TI - Special issue dedicated to the memory of therese M. cotton
PMID- 10766954
TI - One nanosecond molecular dynamics simulation of the N-terminal domain of the
lambda repressor protein.
AB - We have carried out molecular dynamics simulation of the N-terminal domain of the
lambda repressor protein in a surrounding environment including explicit waters
and ions. We observe two apparent dynamics substates in the nanosecond protein
simulation, the transition occurring around 500 ps. The existence of these two
apparent substates results from a high flexibility of the arm in each monomer, a
relative flexibility of both arms with respect to each other, and a relative
displacement of the recognition helices from 30 to 40 A of interhelical distance.
Many amino acid residues, including those involved in DNA recognition, undergo a
simultaneous transition in their side-chain conformations, consistent with the
relationship between side-chain conformation and secondary structural elements,
as observed in protein crystal structures. This result suggests plausible
conformational changes experienced by the protein upon DNA binding. On the whole,
the non-consensus monomer appears to be more flexible than its consensus
counterpart.
PMID- 10766956
TI - UV resonance Raman study of angiotensin II conformation in nonaqueous
environments: lipid micelles and acetonitrile.
AB - We used 206.5-nm excited resonance Raman measurements to examine the angiotensin
II (AII) secondary structure in H(2)O in the presence of dodecylphosphocholine
(DPC) micelles, sodium dodecylsulfate (SDS) monomers and micelles, and in a 70%
acetonitrile (ACN-d)-30% water solution. Our AII-SDS titration absorption studies
indicate the formation of a 1:2 AII:SDS complex in which two negatively charged
SDS molecules attach to the AII positively charged N terminus and to Arg(2). Our
206.5-nm excited Raman results indicate that the 1:2 AII:SDS complexation
increases the AII beta-turn composition. We also used 228.9-nm Raman excitation
to probe the local solvent accessibility of Tyr(4) (AII) in DPC and SDS micelles.
Our Tyr (AII) solvent accessibility studies suggest that the Tyr residue is more
exposed to the aqueous environment in SDS micelles than in DPC micelles.
PMID- 10766957
TI - Selective enhancement of resonance Raman spectra of separate bacteriopheophytins
in Rb. sphaeroides reaction centers.
AB - Tunable dye laser excitation of carefully prepared samples of Rb. sphaeroides
reaction centers provides richly detailed resonance Raman (RR) spectra of the
bacteriopheophytins, H, and the accessory bacteriochlorophylls, B. These spectra
demonstrate selective enhancement of the separate bacteriopheophytins on the
active (H(L)) and inactive (H(M)) sides of the reaction centers. The spectra are
assigned with the aid of normal coordinate analyses using force fields previously
developed for porphyrins and reduced porphyrins. Comparison of the H(L) and H(M)
vibrational mode frequencies reveals evidence for greater polarization of the
acetyl substituent in H(L) than H(M). This polarization is expected to make H(L)
easier to reduce, thereby contributing to the directionality of electron transfer
from the special pair, P. In addition, the acetyl polarization of H(L) is
increased at low temperature (100 K), helping to account for the increase in
electron transfer rate. The polarizing field is suggested to arise from the
Mg(2+) of the neighboring accessory bacteriochlorophyll, which is 4.9 A from the
acetyl O atom. The 100 K spectra show sharpening and intensification of a number
of RR bands, suggesting a narrowing of the conformational distribution of
chromophores, which is consistent with the reported narrowing of the distribution
in electron transfer rates. Excitation at 800 nm produces high-quality RR spectra
of the accessory bacteriochlorophylls, and the spectral pattern is unaltered on
tuning the excitation to 810 nm in resonance with the upper exciton transition of
P. Either the resonance enhancement of P is weak, or the bacteriochlorophyll RR
spectra are indistinguishable for P and B.
PMID- 10766958
TI - Circular dichroism and resonance raman comparative studies of wild type
cytochrome c and F82H mutant.
AB - The UV-visible, circular dichroism (CD), and resonance Raman (RR) spectra of the
wild type yeast iso-1-cytochrome c (WT) and its mutant F82H in which
phenylalanine-82 (Phe-82) is substituted with His are measured and compared for
oxidized and reduced forms. The CD spectra in the intrinsic and Soret spectral
region, as well as RR spectra in high, middle, and low frequency regions, are
discussed. From the analysis of the spectra, it is determined that in the
oxidized F82H the two axial ligands to the heme iron are His-18 and His-82
whereas in the reduced form the sixth ligand switches from His-82 to Met-80
providing the coordination geometry similar to that of WT. Based on the
spectroscopic data, the conclusion is that the porphyrin macrocycle is less
distorted in the oxidized F82H compared to the oxidized WT. Similar distortions
are present in the reduced form of the proteins. Frequency shifts of Raman bands,
as well as the decrease of the alpha-helix content in the CD spectra, indicate
more open conformation of the protein around the heme.
PMID- 10766959
TI - Detection and identification of labeled DNA by surface enhanced resonance Raman
scattering.
AB - The detection of specific sequences of DNA bases in a single strand can be
achieved by hybridization of a known sequence of synthetic DNA. Due to the low
concentrations usually used, a fluorescent label is required to detect the probe.
Surface enhanced resonance Raman scattering (SERRS) also has the required
sensitivity and provides a specific set of signals that are more applicable to
discrimination of a number of probes without separation. A reliable SERRS method
is reported here using two probes specifically designed for SERRS. It was
possible to detect a 2 x 10(-12)M solution of labeled DNA, which illustrated the
sensitive nature of SERRS for DNA analysis.
PMID- 10766960
TI - Surface-enhanced Raman spectroscopy of DOPA-containing peptides related to
adhesive protein of marine mussel, Mytilus edulis.
AB - The common blue marine mussel adheres to underwater surfaces using an adhesive
protein (Mefp-1) extruded from its foot. This highly hydroxylated protein
contains a number of unusual amino acids, including 3,4-dihydroxyphenylalanine
(DOPA), which is thought to contribute to the crosslinking of the extruded
threads and adhesion to the substratum. Mefp-1 adheres to a wide variety of
surfaces and is ultimately biodegradable. In this study we use surface-enhanced
Raman spectroscopy (SERS) to characterize the adsorption of DOPA-containing
peptides on colloidal gold. The peptides are simplified fragments of the Mefp-1
consensus decapeptide repeat, Ala-Lys-Pro-Ser-Tyr-DHP-Hyp-Thr-DOPA-Lys. Our
results show that the peptides TDeltaKA, PTDeltaKA, and PPTDeltaKA (where Delta
represents DOPA) coordinate to the gold surface through the catechol oxygens of
the DOPA residue and through primary amine groups. The diproline sequence
introduces conformational constraints that influence the conformations of the
adsorbed peptides. These findings lay the groundwork for developing synthetic
adhesives for underwater and medical applications.
PMID- 10766961
TI - Raman spectroscopy of model membrane monolayers of dipalmitoylphosphatidic acid
at the air-water interface using surface enhancement from buoyant thin silver
films.
AB - A novel method for the acquisition of surface enhanced Raman (SER) spectra of
model membranes of dipalmitoylphosphatidic acid (DPPA) in Langmuir layers at the
air-water interface is reported. The approach is based on the electrochemical
formation of a buoyant thin layer of coalesced silver colloids in the vicinity of
the phosphatidic acid head groups at the interface. This Ag layer is an excellent
platform for SER scattering, which shows the spectral features from all parts of
the molecule and water between the Ag surface and the DPPA layer. The observation
of the spectral response from the phosphatidic acid head groups is of particular
significance, allowing insight into their chemical state and orientation at the
air-water interface.
PMID- 10766962
TI - Assembly of long chain phosphatidylcholines at a liquid-liquid interface.
AB - The molecular-level organization of mixed and pure saturated symmetric chain 1,2
diacyl-sn-glycero-3-phosphocholines (PCs) adsorbed at a carbon tetrachloride
aqueous interface is explored by probing the hydrocarbon chain conformation
within the adsorbed layer. PCs of the chain lengths found most frequently in
biological systems, which in pure form are seen to form either very well-ordered
or disordered layers, are observed in these studies to assemble into interfacial
layers ranging from disordered to ordered states when mixed in various
proportions. Independently, while C(16) and shorter chain PCs tend to form
disordered layers, a strong increase in ordering is observed for C(18) and longer
chain PCs in which the hydrocarbon chains are found to be primarily in an all
trans conformation. Pure C(17)-PCs adsorbed at the interface produce layers with
an intermediate degree of chain ordering. The ability to tune interfacial layer
properties in mixed systems as a function of molecular composition, including PC
chain length as demonstrated here, is an important mechanism by which surface
characteristics of oil-water emulsion systems can be controlled both in vivo and
in numerous commercial applications.
PMID- 10766963
TI - In memorial: Clement L. Markert.
PMID- 10766964
TI - Respiratory gas transport, metabolic status, and locomotor capacity of the
Christmas Island red crab Gecarcoidea natalis assessed in the field with respect
to dichotomous seasonal activity levels.
AB - Red crabs, Gecarcoidea natalis, exhibit seasonal activity patterns: low activity
during the dry season when they shelter in burrows to avoid dehydration, and high
activity during the wet season. Red crabs were examined in situ in the rainforest
of Christmas Island to determine if there were underlying seasonal differences in
the capacity for exercise and associated metabolism. During both seasons, free
ranging (FR) crabs engaged in their normal activities and, together with crabs
induced to exercise for 5 min, were sampled for haemolymph and muscle tissue.
Respiratory gases in the haemolymph and key metabolites were measured to assess
differences in metabolic status of FR and exercised crabs. Actively foraging FR
crabs during the wet season exhibited a relative haemolymph hypoxia (2.9 kPa) and
accumulated an extra 3 mmol. litre(-1) of CO(2) compared to the relatively
inactive FR crabs during the dry season. Wet-season crabs appeared to be in a
state of relative respiratory acidosis compared to dry-season animals. This
hypercapnia may arise as a consequence of a relative hypoventilation in animals
with a relatively higher metabolic rate during the wet season. Oxygenation of
pulmonary and arterial haemolymph was similar and remained high after 5 min of
exercise, indicating that the gills and lungs functioned similarly in gas
exchange in both FR and exercised crabs. During exercise, venous O(2) reserves
decreased and red crabs experienced a mixed respiratory/metabolic acidosis.
Similar changes, after 5 min of enforced exercise, in metabolite concentrations,
pH and respiratory gas status in the haemolymph during both sampling seasons
suggest that the crabs maintain similar capacity to increase exercise during the
wet and the dry seasons, despite the differences in underlying physiological
status. This is important since after prolonged inactivity during the dry season,
with the arrival of moonsoonal rains, red crabs must engage in their annual
breeding migration.
PMID- 10766965
TI - Effects of prey type on motor pattern variance in tetraodontiform fishes.
AB - It is unclear whether the high variance of electromyographic parameters measured
in feeding teleost fishes reflects functionally significant motor variation that
is under control of the fish, or functionally insignificant variation
characteristic of EMG data. We addressed this issue by examining the effect of
three prey, differing in physical characteristics, on the feeding motor pattern
in three fishes of the Order Tetraodontiformes: the filefish, Monacanthus
hispidus; the triggerfish, Balistes capriscus; and the puffer, Sphoeroides
nephelus. EMG recordings were made from subdivisions of the mouth closing
adductor mandibulae muscle and the mouth opening levator operculi muscle in four
fish from each species feeding on live fiddler crabs, live shrimp, and pieces of
cut squid mantle. Analysis of variance was used to test for effects of prey type
on the standard deviation of muscle burst duration, burst onset time, and average
burst amplitude in the adductor muscles. The filefish exhibited a doubling of
standard deviation of burst duration in all muscles when feeding on fiddler
crabs; triggerfish showed increased standard deviations in onset times and
duration of two muscles when feeding on squid mantle; and the puffer showed no
effects of prey on motor variability. The observation that prey type can elicit
more than a doubling in the standard deviation of some EMG traits indicates that
a large portion of the within-prey type variance is under direct control of the
individual fish, suggesting an even greater level of fine motor control in
teleost feeding mechanisms than previously recognized.
PMID- 10766966
TI - Effects of dehydration on plasma osmolality, thirst-related behavior, and plasma
and brain angiotensin concentrations in Couch's spadefoot toad, Scaphiopus
couchii.
AB - Under dehydrating conditions, many terrestrial vertebrates species exhibit
increases in plasma osmolality and their drinking behavior. Under some
circumstances, this behavioral change is accompanied by changes in plasma and
central angiotensin concentrations, and it has been proposed that these changes
in angiotensin levels induce the thirst-related behaviors. In response to
dehydration, the spadefoot toad, Scaphiopus couchii, exhibits thirst-related
behavior in the form of cutaneous drinking. This behavior has been termed water
absorption response (WR) behavior. Spadefoot toads live in harsh desert
environments and are subject annually to dehydrating conditions that may induce
thirst-related behavior. We tested the hypothesis that an increase in WR behavior
is associated with both an increase in plasma osmolality and an increase in
plasma and brain angiotensin concentrations. First, we determined the degree of
dehydration that was necessary to initiate WR behavior. Animals dehydrated to 85%
of their standard bladder-empty weight via deprivation of water exhibited WR
behavior more frequently than control toads left in home containers with water
available. Next, using the same dehydration methods, we determined the plasma
osmolality and sodium concentrations of dehydrated toads. Toads dehydrated to 85%
standard weight also had a significant increase in plasma osmolality, but
exhibited no overall change in plasma sodium concentrations, indicating that
while an overall increase in plasma osmolality appears to be associated with WR
behavior in S. couchii, changes in sodium concentrations alone are not sufficient
to induce the behavior. Finally, plasma and brain angiotensin concentrations were
measured in control toads and toads dehydrated to 85% standard weight. Plasma and
brain angiotensin concentrations did not increase in dehydrated toads, indicating
that dehydration-induced WR behavior that is associated with changes in plasma
osmolality may not be induced by changes in endogenous angiotensin concentrations
in S. couchii.
PMID- 10766967
TI - Calculation of volumes and systolic indices of heart ventricle from Halobatrachus
didactylus: echocardiographic noninvasive method.
AB - The purpose of this work is to calculate end-systolic and end-diastolic volumes
of Halobatrachus didactylus ventricles, from two-dimensional (2D)
echocardiographic images, comparing four different linear methods, and to derive
systolic indices of ventricular function-fractional shortening, ejection
fraction, stroke volume, and cardiac output independent of the Fick principle.
Echocardiography provided high resolution images of cardiac structures and
allowed accurate linear measurements. The Simpson algorithm proved to be the best
method of calculating ventricle volumes. As a corollary, ventricular mass can be
derived from echocardiographic volume data. This noninvasive method promises wide
utilization in experimental comparative cardiovascular biology.
PMID- 10766968
TI - Serotonergic regulation of blood glucose levels in the crayfish, Procambarus
clarkii: site of action and receptor characterization.
AB - The present study investigated the site of action of 5-hydroxytryptamine (5-HT)
and pharmacologically characterized the receptors involved in regulating blood
glucose levels in the crayfish, Procambarus clarkii. Injection of 5-HT into
intact animals increased glucose levels in a dose-dependent manner. In contrast,
5-HT failed to elicit a hyperglycemic response in eyestalk-ablated animals.
Effects of several 5-HT receptor agonists and antagonists were examined. 5-CT,
oxymetazoline (both 5-HT(1) receptor agonists) and alpha-methyl-5-HT (a 5-HT(2)
receptor agonist), but not 1-phenylbiguanide, m-CPBG (both 5-HT(3) receptor
agonists), or RS 67333 (a 5-HT(4) receptor agonist), induced hyperglycemic
responses in a dose-dependent manner. In addition, 8-OH-DPAT (a 5-HT(1A) receptor
agonist), L-694,247 (a 5-HT(1B/1D) receptor agonist), and DOI (a 5-HT(2A)
receptor agonist) were effective in significantly increasing the glucose levels,
whereas both BW 723C86 (a 5-HT(2B) receptor agonist) and m-CPP (a 5-HT(2C)
receptor agonist) were ineffective. Finally, ketanserin (a 5-HT(2A) receptor
antagonist), but not p-MPPF (a 5-HT(1A) receptor antagonist), GR 55562 (a 5
HT(1B/1D) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or
tropisetron (a 5-HT(3) receptor antagonist), was able to block 5-HT-induced
hyperglycemia. The combined results support the hypothesis that 5-HT exerts its
hyperglycemic effect by enhancing the release of hyperglycemic factor(s) from the
eyestalks, and suggest that 5 HT-induced hyperglycemia is mediated by 5-HT(1)-
and 5-HT(2)-like receptors.
PMID- 10766969
TI - Spontaneous contractions in elasmobranch vessels in vitro.
AB - Isolated vessels from four elasmobranchs, yellow stingray (Urolophus
jamaicensis), clearnose skate (Raja eglanteria), ghost shark (Hydrolagus
novaezelandiae), and spiny dogfish (Squalus acanthias), were examined for the
presence of spontaneous contractions (SC). SC were observed in otherwise
unstimulated dorsal aortas (DA) from stingray and ghost shark, but not in skate
DA. Unstimulated ventral aortas (VA) did not exhibit SC. After treatment of VA
with a contractile agonist, SC appeared in stingray and skate but not ghost shark
or dogfish. SC in stingray VA were subsequently inhibited by either epinephrine
(10(-5) M) or indomethacin (10(-4) M). Agonist contraction also elicited strong
SC in ductus Cuvier from stingray, but not from ghost shark or dogfish. SC in
dogfish hepatic portal veins (HPV) produced a rhythmical oscillation in tension.
The frequency of HPV SC was highest (approximately 1 min(-1)) in intact veins and
lower (approximately 3 min(-1)) in vein segments, indicative of a dominant
pacemaker in the intact vessel. SC in HPV were depressed during the first 30 min
of hypoxia, but there was substantial recovery over an additional 30 min of
hypoxia and complete recovery upon return to normoxia. Addition of 80 mM KCl
completely inhibited HPV SC and lowered resting tone. These results show that SC
are a common feature of elasmobranch vessels and there appears to be a
correlation between swimming behavior and the propensity for SC. KCl inhibition
of SC and tonus in HPV is highly unusual for vascular smooth muscle.
PMID- 10766970
TI - Novel tissue culture method: skeletal muscle implantation under gizzard serous
membrane of a chick.
AB - A novel method for a long-term culture of skeletal muscle is described. Skeletal
muscle pieces from young chicks were implanted under the gizzard serous membrane
of the same chicks. Following muscle degeneration, new well-grouped muscle fibers
were formed by the fusion of myocytes that differentiated from surviving
satellite cells, and the regenerated muscle tissues were maintained in position
for longer than 60 days. The implants were in the vital circulatory system,
receiving trophic and oxygen supplies, and are completely free from motor nerve
innervation and cell contamination with exogenous muscle cells, not as in intra
muscular implantation. Therefore, this tissue culture method should be useful for
studying skeletal muscle regeneration and maturation over a long period.
Furthermore, osteogenesis and feather development were also found in the implants
of embryonic limbs by using the same method. These observations showed that not
only skeletal muscle tissues but also other tissues could be cultured under the
gizzard serous membrane.
PMID- 10766971
TI - Direct influence of melatonin on the thyroid and comparison with prolactin.
AB - Melatonin administered in vivo had previously been shown to inhibit thyroid cell
proliferation and subsequent in vitro thyroxine (T(4)) secretion in anuran
tadpoles. Melatonin in vitro also directly reduced the sensitivity of the thyroid
to thyrotropin (TSH). The present work sought to determine whether melatonin
directly affected baseline, unstimulated T(4) secretion, and to compare its
effect with that of prolactin (PRL). Thyroids from larval Rana catesbeiana or
adult Rana pipiens were incubated in control or melatonin (0.01 to 100 microg/ml)
media. Melatonin directly inhibited T(4) secretion by thyroids from both tadpoles
and frogs at all concentrations of melatonin used and at both prometamorphic and
climax tadpole stages. PRL, used in vitro at 10 microg/ml, did not influence the
response of the thyroid to TSH (0.2 microg/ml) in young tadpoles, or the baseline
secretion of T(4) by thyroids at any stage of larval life except climax, when
T(4) secretion was significantly decreased by the third day of culture. Thus
although both melatonin and PRL have been shown to antagonize the action of T(4)
in vitro, and to decrease metamorphic rate, melatonin is a much more effective
thyroid gland inhibitor than PRL.
PMID- 10766972
TI - ACTH(4-12) is the minimal message sequence required to induce the differentiation
of mouse epidermal melanocytes in serum-free primary culture.
AB - It is well known that alpha-melanocyte stimulating hormone (MSH) induces the
differentiation of mouse epidermal melanocytes in vivo and in vitro. Although
adrenocorticotropic hormone (ACTH) possesses the same amino acid sequence as MSH
does, it is not clear whether the peptide and its fragments induce the
differentiation of mouse epidermal melanocytes. In this study, the
differentiation-inducing potencies of human ACTH and its fragments were
investigated by adding them into a culture medium (0.001-1,000 nM) from the
initiation of primary culture of epidermal cell suspensions. Their potencies were
compared with the potency of alpha-MSH. After 2-4 days of primary cultures with
ACTH(1-13), ACTH(1-17), ACTH(1-24), ACTH(1-39), ACTH(4-12), ACTH(4-13), and alpha
MSH, pigment granules appeared in the cytoplasms and dendrites of melanoblasts
that were in contact with the adjacent keratinocyte colonies. By 14 days,
cultures contained mostly pigmented melanocytes. The order of potencies of ACTH
fragments and alpha-MSH shown by the ED(50) value was as follows: alpha-MSH =
ACTH(1-13) = ACTH(1-17) = ACTH(4-12) = ACTH(4-13) > ACTH(1-24) > ACTH(1-39). The
length of their peptide chains was inversely proportional to the potency. On the
contrary, ACTH(1-4), ACTH(11-24), and ACTH(18-39) failed to induce the
differentiation of melanocytes. In contrast, ACTH(1-10), ACTH(4-10), ACTH(4-11),
and ACTH(5-12) possessed a weak potency at high doses only (100 and 1,000 nM).
These results suggest that ACTH(4-12) is the minimal message sequence required to
induce the differentiation of mouse epidermal melanocytes in culture completely.
The amino acids of Met(4) and Pro(12) are suggested to be important for its
potency.
PMID- 10766974
TI - Branchial Na(+)K(+)ATPase activity in brook charr (Salvelinus fontinalis): effect
of gonadal development in hypo- and hyperosmotic environments.
AB - Changes in gill Na(+)K(+)ATPase activity were examined following the transfer of
brook charr (Salvelinus fontinalis) from fresh water (FW) to seawater (SW).
Gonadal development was altered at the hatching stage using three doses of
ionizing radiation (IR): 6.2, 7.8, and 11.4 Gray (Gy). A non-irradiated control
group was also included in the experimental set-up. Following 15 and 19 months of
growth in FW, assessment of gill activity in regard to gonadal status (sterile
vs. mature) and level of IR exposure was realized by conducting two estuarine
challenge tests. A first introduction was performed during June (period of
highest osmoregulatory capacities for this species) (summer experiment). A second
introduction was conducted during October (period of diminished osmoregulatory
capacities) (fall experiment). Gill Na(+)K(+)ATPase activity and water content
were measured at different times and two FW control samplings were added in
October and January. In the summer experiment (June-December), normal gonadal
development of female brook charr was related to reduced gill Na(+)K(+)ATPase
activity during the spawning period as compared to sterile fish (4.0+/-1.5 and
7.2+/-1.9 micromole Pi. mg protein(-1). hr(-1)) (P<0.0002). Similar results were
not observed in FW conditions, implying that a lack of gonadal growth does not
initiate a significant advantage when the osmoregulatory system including the
gills are not highly in demand, i.e. in a FW environment. Ionizing radiation
exposure of < or =11.4 Gy at the hatching stage had no significant negative or
positive effect on Na(+)K(+)ATPase activity either in FW or SW conditions.
PMID- 10766973
TI - Evaluation of somatic and reproductive immunotoxic effects of the porcine zona
pellucida vaccination.
AB - Immunological, immunocytochemical and fertility analyses were performed to
determine the potential toxic side effects of porcine zona pellucida (pZP)
vaccinations on target animals, including horses and dogs. The study was designed
to determine the effect of antibodies, raised against highly purified pZP, on
somatic tissues. Immunocytochemical studies performed with fixed tissues showed
that rabbit anti-pZP antiserum did not crossreact with brain, heart, lung,
kidney, liver, bladder, stomach, small intestine, large intestine, muscle, skin,
spleen, pancreas, or lymph node of either the dog or horse. To determine the
effect or oral intake on nontarget animals, female rabbits were fed a
contraceptive vaccine containing pZP glycoproteins and the synthetic trehalose
dicorynomycolate in drakeol (S-TDCM) adjuvant. Enzyme-linked immunoadsorbent
assay (LISA) analyses showed that rabbits fed with the adjuvanted pZP proteins
did not develop circulating anti-pZP IgG antibodies that crossreacted with pZP.
Furthermore, fertility studies performed on rabbits fed with adjuvanted pZP
revealed no significant differences in the number of embryos or stage of the
embryos produced between the treated and control animals. Results of these
studies suggest that the pZP vaccine delivered to dogs or horses in field studies
have no recognizable somatic tissue effects. Moreover, there were no side effects
on nontarget animals should they eat the vaccine. This substantiates field trials
results about the safety of the pZP immunocontraceptive vaccine.
PMID- 10766975
TI - cDNA cloning of rat prolyl oligopeptidase and its expression in the ovary during
the estrous cycle.
AB - A cDNA for rat prolyl oligopeptidase was cloned which contained an open reading
frame of 2,130 nucleotides encoding a protein of 710 amino acids. The deduced
amino acid sequence is around 95% homologous to other mammalian prolyl
oligopeptidases and about 40% to bacterial prolyl oligopeptidases. The
recombinant prolyl oligopeptidase generated in E. coli was purified and its
properties were examined. The substrate specificity and the susceptibility to
proteinase inhibitors were similar to those of the native enzyme. Northern blot
analysis showed wide expression of the prolyl oligopeptidase gene. Using ovaries
from hormone-treated rats, it was found that both the mRNA expression and enzyme
activity increased in the luteal phase. These findings suggest the involvement of
prolyl oligopeptidase in events associated with corpus luteum formation and/or
luteal regression.
PMID- 10766976
TI - Rapid morphological oscillation of mitochondrion-rich cell in estuarine
mudskipper following salinity changes.
AB - Morphological changes in the chloride cells or mitochondrion-rich (MR) cells in
the skin under the pectoral fin of the estuarine mudskipper (Periophthalmus
modestus) were examined in relation to intertidal salinity oscillation in river
mouth. MR cells were distinguished between those in contact with the water (cells
labeled with both mitochondrial probe DASPEI and Concanavalin-A, an apical
surface marker of MR cells) and those that are not (DASPEI-positive only). After
transfer of the fish from seawater to freshwater, no difference in the total MR
cell density was observed, but the subpopulation of MR cells that are
Concanavalin-A-positive decreased dramatically within 30 min. After 6 hr in
freshwater, the fish were returned to seawater; the number of Con-A-positive MR
cells increased to the initial levels rapidly. Thus, in seawater, mudskippers
seem to open the apical crypts of the MR cells to secrete salt; in freshwater,
they close the crypt of the MR cells tentatively, and tolerate hypotonicity until
the rising tide. This unique response of chloride cells may also be seen in gills
of other estuarine species.
PMID- 10766977
TI - Value of a clinical morphology examination in autism.
AB - In an effort to delineate more homogeneous autism subgroups for genetic study, we
evaluated 133 consecutive individuals referred to the University of Missouri
Autism Center. Each index case underwent a diagnostic evaluation, including a
clinical morphology examination, laboratory studies, brain MRI, EEG, and
collection of historical, medical, and family data. The 71% (94/133) who
fulfilled DSM-IV and CARS autism diagnostic criteria were included in this study.
Six of 94 were diagnosed with a known genetic disorder. Of the remaining 88 with
apparently "idiopathic autism," 58% (51/88) were phenotypically normal, 22%
(19/88) were clearly abnormal, and for 20% (18/88) the clinical morphology
examination was equivocal. The percentage of phenotypically abnormal individuals
is higher than generally thought and disagrees with the perception that children
with autism are usually normally formed. The phenotypically abnormal individuals
were 10 times more likely to be diagnosed with a known genetic syndrome (21% vs.
2%) and were more than twice as likely (29% vs. 14%) to have structurally
abnormal brain MRIs than the phenotypically normal propositi. Moreover, the male
to female ratio correlated with the presence of physical anomalies. The total
study group had a male to female ratio of 4.2:1; the morphologically normal
subgroup, defined on the basis of a normal physical examination, had a sex ratio
of 7.5:1 and the normal subgroup, defined on the basis of both a normal physical
examination and a structurally normal brain by MRI had a 23:1 sex ratio. For the
phenotypically abnormal subgroup, the sex ratio was 1.7:1. Since differences in
sex ratio are presumably a reflection of differences in genetic constitution, we
postulate that the phenotypically normal subgroup of individuals with "idiopathic
autism" is genetically different from the phenotypically abnormal individuals and
that differences in the sex ratio in different autism populations is one
indicator of a population's genetic heterogeneity.
PMID- 10766978
TI - Heterogeneity and minor anomalies.
PMID- 10766979
TI - Genetic effects on the liability of developing pre-eclampsia and gestational
hypertension.
AB - Genetic factors are known to be important in the etiology of pre-eclampsia and
possibly also gestational hypertension, but the degree of genetic influence has
not been quantified. To estimate the genetic and environmental effects on the
liability of developing pre-eclampsia and gestational hypertension, we cross
linked the population-based Swedish Twin Register and the Swedish Medical Birth
Register. We included female twin pairs with known zygosity, both of whom gave
birth in Sweden from 1973 through 1993; in all 917 monozygotic and 1,199
dizygotic twin pairs. For pre-eclampsia, the estimates of heritability and
nonshared environmental effect were 0. 54 (95% confidence interval 0-0.71) and
0.46 (0.29-0.67), respectively; corresponding estimates for gestational
hypertension were 0.24 (0-0.53) and 0.76 (0.47-1.00), respectively. When
considering both diseases as a single entity (pregnancy-induced hypertensive
diseases), the heritability estimate was 0.47 (0.13-0. 61). These results suggest
that genetic factors are important in the development of pre-eclampsia as well as
gestational hypertension. The heritability estimates can be of importance when
planning genetic linkage studies. In efforts to identify women with elevated risk
of developing pre-eclampsia during pregnancy, a question about family history of
pre-eclampsia should be included.
PMID- 10766980
TI - Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis.
AB - Encephalocraniocutaneous lipomatosis (ECCL) is a congenital neurocutaneous
syndrome that comprises unilateral porencephalic cysts with cortical atrophy;
ipsilateral hamartomas of scalp, eyelid, and outer part of the eye; lipomas of
the central nervous system (CNS); cranial asymmetry; and characteristic cutaneous
lesions. We report on the antenatal and postnatal sonographic and radiologic, and
on the postnatal pathologic findings of an infant diagnosed with ECCL at birth.
The antenatal sonogram at 28 weeks of gestation showed normal intracranial
structures; the sonogram at 38 weeks of gestation showed asymmetry of the
cerebral hemispheres and ventriculomegaly. Magnetic resonance imaging at age 6
weeks demonstrated a porencephalic cyst on the left, hemiatrophy of the left
cerebrum with cortical dystrophy, and a lipoma in the middle cranial fossa.
Histologic findings of the resected cutaneous lesion confirmed the presence of
fibrolipoma hamartoma. This case offers a unique insight into the antenatal and
postnatal development of the hamartoneoplastic lesions of ECCL, and it highlights
the difficulties inherent in the antenatal sonographic diagnosis of
hamartoneoplastic syndromes.
PMID- 10766981
TI - Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation:
analysis of the X-inactivation patterns.
AB - We report on a mother and daughter both with a 45,X/46,X,r(X)(p22. 3q28)
karyotype and mental retardation. Fluorescence in situ hybridization (FISH) and
microsatellite analyses for 14 loci/region at Xp22.3 and seven loci/region at
Xq28 indicated that the ring X chromosome was missing a roughly 12-Mb region from
Xp22.3 with the breakpoint between DXS85 and DXS9972, and another region of less
than 100 kb from Xq28 with the breakpoint distal to the region defined by the
FISH probe c8.2/1. X-inactivation analysis, using the methylation status of the
AR gene (exon 1) as an indicator, showed that the normal and ring X chromosomes
in the X,r(X)(p22.3q28) cell lineage were randomly inactivated. The Xp22.3
deleted region partially overlaps with the regional intervals of MRX19, MRX21,
MRX24, MRX37, MRX43, and MRX49 associated with heterozygote manifestation.
Therefore, it is likely that one or more of these MRX genes, subject to X
inactivation, are lost from the ring X chromosome, and that reduced expression of
the MRX gene(s) caused by random X-inactivation has resulted in mental
retardation in the mother and daughter.
PMID- 10766982
TI - Apparent Sotos syndrome (cerebral gigantism) in a child with trisomy 20p11.2
p12.1 mosaicism.
AB - We report on a child with apparent Sotos syndrome (cerebral gigantism) and
partial duplication of the short arm of chromosome 20 mosaicism. Trisomy 20p11.2
p12.1 was diagnosed using cytogenetic and FISH studies. The somatostatin receptor
4 (SSTR4) gene is included in the duplicated segment. This suggests that a dosage
effect of this gene might be related to some of the clinical findings observed in
our patient. The present observation emphasizes the importance of chromosome
analysis in patients with well-delineated but sporadic conditions.
PMID- 10766983
TI - CFTR mutations in three Latin American countries.
AB - We analyzed 192 cystic fibrosis (CF) alleles in three Latin American countries:
Mexico, Colombia, and Venezuela. Mutation screening was performed by polymerase
chain reaction (PCR) and a reverse dot blot detection kit that enables
determination of 16 of the most common CF mutations worldwide. Mutations were
detected in 47.9% of the screened CF alleles. The most prevalent CF allele was
DeltaF508 (39. 6%). The remaining 16 non-DeltaF508 detectable mutations
represented 8.3% of the CF alleles. Among them, the G542X, N1303K, and 3849+10kb
C>T were the most common. Although the frequency of DeltaF508 described here is
lower than that reported for Caucasian populations, including in Spain, it is
remarkable that mutation prevalences found in this study resemble those observed
in Spain. Two of these mutations, G542X and 3849+10kb C>T, that were relevant in
this analysis, have a particularly high incidence in Spanish communities. The low
frequency of DeltaF508 described here may be explained by the Amerindian,
Caucasian, and Black admixture that occurred in Latin America after the discovery
of the New World, and also by the probable occurrence of mutations contributed by
the original natives, which were undetectable in this analysis.
PMID- 10766984
TI - Two brothers with distal arthrogryposis, peculiar facial appearance, cleft
palate, short stature, hydronephrosis, retentio testis, and normal intelligence:
a new type of distal arthrogryposis?
AB - We report on two brothers, a 22-month-old boy and a 7-month-old boy, with
multiple distal arthrogryposis (DA), peculiar facial appearance, cleft palate,
short stature, hydronephrosis, retentio testis, and normal intelligence and
karyotypes. The parents were cousins once removed. The combination of the
clinical manifestations in the patients and the lack of involvement in their
parents are incompatible with any known types of DA, and suggest a new type of
DA. The parental consanguinity in the family suggests that the disorder is an
autosomal recessive condition, although X-linked inheritance is not ruled out.
PMID- 10766985
TI - Trisomy 7p resulting from 7p15;9p24 translocation: report of a new case and
review of associated medical complications.
AB - The authors report on a young girl with generalized developmental deficits
originally thought to be caused by an unusual reaction to DPT vaccination. At the
age of 4(1/2) years, chromosome analysis showed that the terminus of the short
arm of chromosome 9 had extra material believed to originate from 7p terminus,
thus she was considered to be trisomic for a segment of 7p and monosomic for a
small portion of 9p [46,XX,der (9), t(7;9)(p15;p24)]. Ten years later, molecular
cytogenetic testing using fluorescence in situ hybridization (FISH) confirmed
that the extra chromosomal material represented partial trisomy 7p. The proposita
had a high and large forehead, hypertelorism, and broad nasal bridge, findings
seen in most individuals with trisomy 7p. Long-term follow-up showed the presence
of hypothyroidism, obesity, and cerebral palsy. A review of all published cases
of trisomy 7p with focus on associated complications suggests a well-defined
pattern of abnormalities characterized by musculoskeletal, cardiovascular,
neurological, genital, and ocular abnormalities in decreasing frequency. At least
one-third of affected individuals died in infancy and close to half had severe
mental retardation. FISH was essential in the confirmation of the cytogenetic
abnormality and further delineation of the chromosomal disorder.
PMID- 10766986
TI - Mental and psychomotoric retardation in two brothers with pure partial trisomy
7q32-q34 due to a maternal insertion (14;7).
AB - We present two brothers with mental retardation, seizures disorder, generalized
muscular hypertonia, kyphoscoliosis, minor anomalies and a prominent midface. GTG
banded chromosome analysis showed a derivative chromosome 14 without clues toward
the origin of the rearrangement. Microdissection of the derivative chromosome 14
and subsequent reverse painting demonstrated partial trisomy 7q32-q34 as the
unbalanced product of a maternal insertion (14;7). Thus, we identified two cases
with pure trisomy 7q32-q34 that allowed further delineation of this aneusomy
syndrome.
PMID- 10766987
TI - Phenotypic heterogeneity of growth and psychometric intelligence in Prader-Willi
syndrome: variable expression of a contiguous gene syndrome or parent-child
resemblance?
AB - Phenotypic variability in children with Prader-Willi syndrome (PWS) was
investigated with respect to variable expression of the contiguous gene syndrome
and trait variance. In a prospective study, parent/child resemblance of
anthropometric and psychometric measures was analyzed in 22 children with PWS (11
females and 11 males; 18 deletions, 4 uniparental disomy (UPD)) and in a control
group (88 females and 88 males). The average child-midparent Z-score difference
for height in females was -1.9 and in males -0.9, head circumference -1.7 and
1.0, and body mass index (BMI) 2.3 and 2.7, respectively. Intellectual
performance of females and males was, on average, -2.7 and -2.6 below maternal
performance. Range and standard deviation were moderately increased for height
and head circumference, doubled for BMI, and unchanged for IQ. Parent/child
correlations for anthropometric and psychometric measurements in the study group
did not significantly differ from those of the control group. Exceptions were
higher correlations between mothers and daughters for height (P < 0.05) and BMI
(P < 0.01), and lower correlations for head circumference between midparent
values and daughters (P < 0.05) than in the control group. In conclusion, parent
child resemblance in growth and intellectual development among children with PWS
was found to be comparable to that noted in the normal population, indicating a
strong determination by trait variance. Children with PWS differed significantly
with respect to a lower trait level and-with the exception of IQ-a larger
variability. The latter may indicate a variable expression of the contiguous gene
syndrome.
PMID- 10766988
TI - Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with
inflammation.
AB - Mutations in dysferlin were recently described in patients with Miyoshi myopathy,
a disorder that preferentially affects the distal musculature, and in patients
with Limb-Girdle Muscular Dystrophy 2B, a disorder that affects the proximal
musculature. Despite the phenotypic differences, the types of mutations
associated with Miyoshi myopathy and Limb-Girdle Muscular Dystrophy 2B do not
differ significantly. Thus, the etiology of the phenotypic variability associated
with dysferlin mutations remains unknown. Using genetic linkage and mutation
analysis, we identified a large inbred pedigree of Yemenite Jewish descent with
limb-girdle muscular dystrophy. The phenotype in these patients included slowly
progressive, proximal, and distal muscular weakness in the lower limbs with
markedly elevated serum creatine kinase (CK) levels. These patients had normal
development and muscle strength and function in early life. Muscle biopsies from
4 affected patients showed a typical dystrophic pattern but interestingly, in 2,
an inflammatory process was seen. The inflammatory infiltrates included primarily
CD3 positive lymphocytes. Associated with this phenotype, we identified a
previously undescribed frameshift mutation at nucleotide 5711 of dysferlin. This
mutation produced an absence of normal dysferlin mRNA synthesis by affecting an
acceptor site and cryptic splicing. Thus, splice site mutations that disrupt
dysferlin may produce a phenotype associated with inflammation.
PMID- 10766989
TI - Dual-probe fluorescence in situ hybridization assay for detecting deletions
associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci.
AB - Over 90% of patients with DiGeorge syndrome (DGS) or velocardiofacial syndrome
(VCFS) have a microdeletion at 22q11.2. Given that these deletions are difficult
to visualize at the light microscopic level, fluorescence in situ hybridization
(FISH) has been instrumental in the diagnosis of this disorder. Deletions on the
short arm of chromosome 10 are also associated with a DGS-like phenotype. Since
deletions at 22q11.2 and at 10p13p14 result in similar findings, we have
developed a dual-probe FISH assay for screening samples referred for DGS or VCFS
in the clinical laboratory. This assay includes two test probes for the loci,
DGSI at 22q11.2 and DGSII at 10p13p14, and centromeric probes for chromosomes 10
and 22. Of 412 patients tested, 54 were found to be deleted for the DGSI locus on
chromosome 22 (13%), and a single patient was found deleted for the DGSII locus
on chromosome 10 (0. 24%). The patient with the 10p deletion had facial features
consistent with VCFS, plus sensorineural hearing loss, and renal anomalies.
Cytogenetic analysis showed a large deletion of 10p [46, XX,del(10)(p12.2p14)]
and FISH using a 10p telomere region-specific probe confirmed the interstitial
nature of the deletion. Analysis for the DGSI and the DGSII loci suggests that
the deletion of the DGSII locus on chromosome 10 may be 50 times less frequent
than the deletion of DGSI on chromosome 22. The incidence of deletions at 22q11.2
has been estimated to be 1 in 4000 newborns; therefore, the deletion at 10p13p14
may be estimated to occur in 1 in 200,000 live births.
PMID- 10766990
TI - Birth malformations in Babylon and Assyria.
AB - In this paper, we intend to study the oldest systematic descriptions of birth
malformations in the history of medicine, as they appear in cuneiform texts
written four millennia ago in the land between the two rivers, Mesopotamia, the
cradle of civilization, the land of Assyro-Babylonian culture. The core of our
work will be an omen text, which was published in 1970 and, since then, has
remained confined to the field of Assyriological studies; thus, the history of
medicine and disease have not taken advantage of its knowledge. This text is
known in Assyriology by its Akkadian name: "shumma izbu" (Izbu), "if an anomaly"
[Leichty, 1970: The Omen series shumma izbu, Texts from Cuneiform Sources IV].
PMID- 10766991
TI - Williams-Beuren syndrome 35 years after the diagnosis in one of the first Beuren
patients.
PMID- 10766992
TI - Situs inversus with hypertrophic cardiomyopathy in identical twins.
AB - We describe identical twin sisters born to nonconsanguineous, healthy parents.
Both twins had situs viscerum inversus and developed hypertrophic cardiomyopathy
in adulthood.
PMID- 10766993
TI - Fetal sonographic findings: analysis of the most frequent patterns and their
specificity of association.
AB - A major goal of obstetric sonography is the detection of patterns of anomalies in
order to make a diagnosis, or to determine which pregnant women should be offered
invasive testing. Previous studies have analyzed patterns from the perspective of
a specific anomaly and its associations, e.g., increased nuchal translucency
measurement and structural heart disease. In this study we applied the technique
of cluster analysis to a population data set that consisted of fetuses with at
least two sonographically detectable anomalies. The specificity of association of
the most frequent patterns found in our population was evaluated by means of the
ratio of the observed number of fetuses with the findings (O) over the expected
number of such fetuses (E). The observation that different patterns aggregate in
a relatively small number of clusters was then evaluated by means of cluster
analysis for binary data. Results show that several patterns can be considered in
nonrandom associations, based on the O/E ratio. Most of these patterns are well
known to clinicians but validate this new approach. As cluster analysis is
applied to antenatal sonographic data sets, new patterns of associations of
anomalies may be detected.
PMID- 10766994
TI - Spondylocarpotarsal synostosis syndrome and cervical instability.
AB - Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal
recessive condition comprising short stature with short trunk, failure of normal
spine segmentation resulting in block vertebrae and fusion of posterior elements,
carpal and/or tarsal coalition, scoliosis, lordosis, pes planus, dental enamel
hypoplasia, decreased range of motion or dislocation of the elbow, renal
anomalies, and hearing loss. The vertebral segmentation defects may involve
noncontiguous areas of the cervical, thoracic, and lumbar spine. Odontoid
hypoplasia was noted in two cases. We report on a sporadic case of
spondylocarpotarsal synostosis in a 5-year-old girl with hypoplasia of C1 and
odontoid and subluxation of C2 upon C3. This brings the number of well-documented
cases of spondylocar- potarsal synostosis to 19, and is the first documenting
cervical spine instability. Careful evaluation for this complication should be
considered in other cases.
PMID- 10766995
TI - Phenotypic manifestation in a child with 46,X,der(X)t(X;1)(q24;q31.1).
AB - We report on a 5-year-old girl with multiple congenital anomalies, developmental
delay, and a de novo unbalanced translocation between chromosomes X and
1[46,X,der(X)-t(X;1)(q24;q31.1)] resulting in partial trisomy 1q and partial
monosomy Xq. The karyotype shows inactivation of the abnormal X chromosome. The
translocated portion of 1q remains active in the tissues studied. This is the
third case report with partial trisomy 1q and partial monosomy Xq. However, it is
the first with specific breakpoints at 1q31.1 and Xq24.
PMID- 10766996
TI - Novel mutation (E113X) of antithrombin III gene (AT3) in a woman with gestational
recurrent thrombosis.
AB - A 35-year-old Japanese woman with a low level (42-54%) of blood antithrombin (AT)
III, experienced two induced abortions due to deep venous thrombosis at 8 weeks
of gestation (GW) and cerebral thrombosis at 10 GW. The present pregnancy was
successfully managed with intravenous administration of AT III (6,000-8,000
U/wk). Analysis of polymerase chain reaction (PCR)-single strand conformation
polymorphism (SSCP) for exons 3A and 4 of the AT III gene (AT3) using her DNA
revealed extra expansion bands with altered migration. The DNA sequencing
demonstrated novel mutations in exon 3A of AT3: a G to T substitution at
nucleotide position 5333 in codon GAG for Glu 113, causing a stop codon (E113X),
and an A to T substitution at position 5338 in codon AAA for Lys 114, forming Asn
(K114N). These novel mutations, especially E113X, in AT3 may be related to
recurrent thrombosis in the pregnancy.
PMID- 10766997
TI - Newborn infant with inherited ring and de novo interstitial deletion on
homologous chromosome 22s.
AB - A 2-day-old infant was evaluated and suspected of having 22q11.2 deletion based
on microcephaly, short and narrow palpebral fissures, a prominent nose with
hypoplastic alae nasi, thin fingers, and a right aortic arch. He also had an
imperforate anus, which is not in the del 22q11.2 syndrome. Karyotype analysis
identified a ring 22, while fluorescence in situ hybridization (FISH) for the
DiGeorge syndrome critical region identified a 22q deletion on the other
homologue. The karyotype designation was 46,XY,r(22)(p13q13.3).ish
del(22)(q11.2q11.2) (D22S75-). Both parents function in the mildly mentally
retarded range. The father's karyotype was normal whereas the mother had the ring
22 that was inherited by her son. This is the first case reported for
abnormalities on both 22 homologues.
PMID- 10766998
TI - No association between alpha-1-antichymotrypsin polymorphism and Alzheimer's
disease in Koreans.
AB - To examine the possible involvement of the alpha-1-antichymotrypsin gene (ACT)
polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed
genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients
with probable AD and 209 nondemented controls. No significant difference was
obtained in genotypic (chi(2)=1.98, df=2, P>0.1) and allelic frequencies
(chi(2)=1.61, df=1, P>0.1) of ACT between the AD and control groups. No
overexpression of the ACT A/A genotype and ACT A allele was found when we
analyzed the late-onset AD patients and the early-onset AD patients, separately.
Then we stratified the ACT genotypes based on the presence or absence of the APOE
epsilon4 allele to evaluate the possible interaction between them. In the APOE
epsilon4-negative subjects, although the ACT A allele tended to be overexpressed
in the AD group, the differences in the frequencies of the ACT A allele
(chi(2)=2.79, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.16, df=1, P>0.1) were
not statistically significant. No significant overrepresentations of the ACT A
allele (chi(2)=0.02, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.17, df=1, P>0.1)
were found in the APOE epsilon4-positive subjects, either. In addition, the
status of the ACT genotype did not influence the age-at-onset of AD (F=0.03,
df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the
development of AD independently or interactively with the APOE epsilon4 allele in
Koreans.
PMID- 10766999
TI - Fiscal impact of a potential legislative ban on second trimester elective
terminations for prenatally diagnosed abnormalities.
AB - This study was designed to determine the fiscal impact of a theoretical
legislative ban on elective terminations for prenatally diagnosed abnormalities
at Hutzel Hospital/Wayne State University. A fiscal comparison was completed for
patients who had second trimester elective terminations for prenatally diagnosed
abnormalities versus not allowing the procedure. An eight-year database of
genetics cases and hospital and physician cost estimates for performing elective
terminations for prenatally diagnosed abnormalities, and published reports of the
average lifetime costs per selected birth defects, were used to calculate the net
cost. The estimated lifetime cost for an average cohort year of a legislative ban
on elective terminations for prenatally diagnosed abnormalities was found to be
at least $8.5 million for patients treated at Hutzel Hospital. Extrapolated, a
similar ban on second trimester elective terminations would have a net cost of
$74 million in Michigan and $2 billion annually in the United States.
PMID- 10767000
TI - Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical,
biochemical, and molecular study of the family.
AB - A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in
four sibs at different ages. The first three, including a pair of twins, had
retarded psychomotor development, poor social contact, and seizures.
Biologically, hyperhomocysteinemia and hypomethioninemia were found associated
with low folate levels in serum and red cells, especially undetectable
methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was
not conclusive because of moderate decrease of enzymatic activity in chorionic
villi and trophoblast. The girl was also affected, as shown by
hyperhomocysteinemia and low folate levels found several days after birth. A 677C
->T (Ala-->Val) mutation was found in a homozygous state in the four children and
in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an
arginine to cysteine also was identified in all of the children, whereas the
distantly consanguineous parents were heterozygous. This amino acid substitution
affecting an arginine residue in a sequence located at the end of catalytic
domain seems critical for the function of the enzyme. The difficulty of prenatal
diagnosis is discussed given the variability found in enzymatic activity and in
the clinical phenotypes.
PMID- 10767001
TI - WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and
molecular studies.
AB - The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and
Myelokathexis. The latter refers to the retention of white cells in the marrow,
which becomes hypercellular. We have found approximately 20 examples of WHIM
syndrome in the literature under various designations; the first examples are
Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and
hypercellular bone marrow represent defective release of marrow cells into the
peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in
form. Condensed nuclei connected by long, stringy filaments and vacuolated
cytoplasm suggest apoptosis. Fever or other stress increases the release of
neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper
respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia).
Patients have numerous warts, some venereal, with resultant cervical and vulval
premalignant dysplasia. We report on a kindred of 6 affected individuals in 3
generations with autosomal dominant WHIM syndrome. The sex ratio among reported
patients and in our kindred is 17 female to 8 male. Because there had been no
male-to-male transmssion, search of the entire X-chromosome including the
pseudoautosomal area was carried out and no linkage was found. Recently, the
propositus has had an unaffected daughter, confirming our finding that the gene
is not X-linked. A genome-wide search is being carried out.
PMID- 10767002
TI - Identification of Y chromatin directly in gonadal tissue by fluorescence in situ
hybridization (FISH): significance for Ullrich-Turner syndrome screening in the
cytogenetics laboratory.
AB - The presence of Y chromatin in individuals with Ullrich-Turner syndrome (UTS)
confers a risk for gonadoblastoma. In mosaic cases, little is known about Y
chromatin distribution in gonads. Fluorescence in situ hybridization (FISH) is a
direct approach to assess the extent of Y chromatin mosaicism in gonads. Gonadal
tissue from four patients with mosaic karyotypes were analyzed by routine
cytogenetics and FISH with X and Y centromere probes. Y chromatin was present in
gonads in varying percentages in these patients. The distribution of Y chromatin
in gonads of UTS individuals did not completely correlate with that found in
blood lymphocytes. The finding of Y chromatin in the blood samples from these
patients prompted the development of a screening strategy in our cytogenetics
laboratory to detect low-level Y chromatin mosaicism in patients with UTS.
PMID- 10767003
TI - Supernumerary chromosome inherited from a maternal balanced translocation leading
to pure trisomy 9p.
AB - We describe a child with a supernumerary chromosome defined as der(9)t(9;22)
(q12;p11), resulting in trisomy 9p and trisomy 22p. The mother carried the
balanced translocation. In G- and C-banding the derivative chromosome 9 appeared
to be dicentric and to contain 22q material. Using in situ hybridization we
defined the exact breakpoints of the translocation and ruled out the possibility
of a centric fission in the mother's chromosomes.
PMID- 10767004
TI - Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with
branchio-oculo-facial syndrome.
AB - In addition to craniofacial, auricular, ophthalmologic, and oral anomalies, the
distinctive phenotype of the branchio-oculo-facial (BOF) syndrome (MIM 113620)
includes skin defects in the neck or infra/supra-auricular region. These unusual
areas of thin, erythematous wrinkled skin differ from the discrete cervical pits,
cysts, and fistulas of the branchio-oto-renal (BOR) syndrome (MIM 113650).
Although the BOF and BOR syndromes are sufficiently distinctive that they should
not be confused, both can be associated with nasolacrimal duct stenosis,
deafness, prehelical pits, malformed pinna, and renal anomalies. Furthermore, a
reported father and son [Legius et al., 1990, Clin Genet 37:347-500] had features
of both conditions. It was not clear whether they had an atypical presentation of
either BOR or BOF syndrome, or represented a private syndrome. In light of these
issues, we selected the BOR locus (EYA1) as a possible gene mutation for the BOF
syndrome. In five BOF patients, there were no mutations detected in the EYA1
gene, suggesting that it is not allelic to the BOR syndrome.
PMID- 10767005
TI - Oculo-ectodermal syndrome: report of two further cases.
AB - We describe the clinical findings in two previously unreported, unrelated cases
with aplasia cutis congenita and epibulbar dermoids, similar to the cases
reported by Toriello et al. [1993]. In addition, one patient had bladder
exstrophy with epispadias. These cases provide further evidence for the
identification of the oculo-ectodermal syndrome as a distinct entity.
PMID- 10767006
TI - Bone loading.
PMID- 10767009
TI - Glycopeptide and Oligosaccharide Libraries.
AB - Despite the burgeoning interest in the various biological functions and
consequent therapeutic potential of the vast number of oligosaccharides found in
nature on glycoproteins and cell surfaces, the development of combinatorial
carbohydrate chemistry has not progressed as rapidly as expected. The reason for
this imbalance is rooted in the difficulty of oligosaccharide assembly and
analysis that renders synthesis a rather cumbersome endeavor. Parallel approaches
that generate series of analogous compounds rather than real libraries have
therefore typically been used. Since generally low affinity is obtained for
interactions between carbohydrate receptors and modified oligosaccharides
designed as mimetics of natural carbohydrate ligands, glycopeptides have been
explored as alternative mimics. Glycopeptides have been proven in many cases to
be superior ligands with higher affinity for a receptor than the natural
carbohydrate ligand. High-affinity glycopeptide ligands have been found for
several types of receptors including the E-, P-, and L-selectins, toxins,
glycohydrolases, bacterial adhesins, and the mannose-6-phosphate receptor.
Furthermore, the assembly of glycopeptides is considerably more facile than that
of oligosaccharides and the process can be adapted to combinatorial synthesis
with either glycosylated amino acid building blocks or by direct glycosylation of
peptide templates. The application of the split and combine approach using ladder
synthesis has allowed the generation of very large numbers of compounds which
could be analyzed and screened for binding of receptors on solid phase. This
powerful technique can be used generally for the identification and analysis of
the complex interaction between the carbohydrates and their receptors.
PMID- 10767010
TI - Integration of Layered Redox Proteins and Conductive Supports for Bioelectronic
Applications.
AB - Integration of redox enzymes with an electrode support and formation of an
electrical contact between the biocatalysts and the electrode is the fundamental
subject of bioelectronics and optobioelectronics. This review addresses the
recent advances and the scientific progress in electrically contacted, layered
enzyme electrodes, and discusses the future applications of the systems in
various bioelectronic devices, for example, amperometric biosensors, sensoric
arrays, logic gates, and optical memories. This review presents the methods for
the immobilization of redox enzymes on electrodes and discusses the covalent
linkage of proteins, the use of supramolecular affinity complexes, and the
reconstitution of apo-redox enzymes for the nanoengineering of electrodes with
protein monolayers of electrodes with protein monolayers and multilayers.
Electrical contact in the layered enzyme electrode is achieved by the application
of diffusional electron mediators, such as ferrocene derivatives, ferricyanide,
quinones, and bipyridinium salts. Covalent tethering of electron relay units to
layered enzyme electrodes, the cross-linking of affinity complexes formed between
redox proteins and electrodes functionalized with relay-cofactor units, or
surface reconstitution of apo-enzymes on relay-cofactor-functionalized electrodes
yield bioelectrocatalytic electrodes. The application of the functionalized
electrodes as biosensor devices is addressed and further application of
electrically "wired" enzymes as catalytic interfaces in biofuel cells is
discussed. The organization of sensor arrays, self-calibrated biosensors, or
gated bioelectronic devices requires the microstructuring of biomaterials on
solid supports in the form of ordered micro-patterns. For example, light
sensitive layers composed of azides, benzophenone, or diazine derivatives
associated with solid supports can be irradiated through masks to enable the
patterned covalent linkage of biomaterials to surfaces. Alternatively, patterning
of biomaterials can be accomplished by noncovalent interactions (such as in
affinity complexes between avidin and a photolabeled biotin, or between an
antibody and a photoisomerizable antigen layer) to provide a means of organizing
protein microstructures on surfaces. The organization of patterned
hydrophilic/hydrophobic domains on surfaces, by using photolithography, stamping,
or micromachining methods, allows the selective patterning of surfaces by
hydrophobic, noncovalent interactions. Photoactivated layered enzyme electrodes
act as light-switchable optobioelectronic systems for the amperometric
transduction of recorded photonic information. These systems can act as optical
memories, biomolecular amplifiers, or logic gates. The photoswitchable enzyme
electrodes are generated by the tethering of photoisomerizable groups to the
protein, the reconstitution of apo-enzymes with semisynthetic photoisomerizable
cofactor units, or the coupling of photoisomerizable electron relay units.
PMID- 10767011
TI - Recent Trends in the Application of Evanescent Wave Biosensors.
PMID- 10767012
TI - Polysaccharide Sequencing.
PMID- 10767013
TI - Direct Detection of Hydrogen Bonds in Biopolymers by NMR Spectroscopy.
PMID- 10767014
TI - Electrochemically Directed Self-Assembly on Gold We gratefully acknowledge
partial funding from the Polymer Interfaces Center, an Industry/University
Cooperative Research Center at Lehigh University, sponsored by the National
Science Foundation and Lehigh University. We thank AT&T Bell Laboratories (now
Lucent, Inc.) for a gift of the triple-track testers. We also thank A. C. Miller
for assistance with the XPS measurements, L. Lowe-Krentz for allowing the use of
the fluorescence microscope and G. Freund for translating the manuscript into
German.
PMID- 10767016
TI - Ring-Closing Alkyne Metathesis: Application to the Stereoselective Total
Synthesis of Prostaglandin E(2)-1,15-Lactone This work was supported by the
Deutsche Forschungsgemeinschaft (Leibniz program) and the Fonds der Chemischen
Industrie. K.G. thanks the Alexander von Humboldt Foundation for a fellowship.
PMID- 10767015
TI - Building Supramolecular Nanostructures at Surfaces by Hydrogen Bonding Fruitful
discussions with A. de Vita, B. Muller, and H. Brune are acknowleged.
PMID- 10767017
TI - IR-Thermographic Screening of Thermoneutral or Endothermic Transformations: The
Ring-Closing Olefin Metathesis Reaction.
PMID- 10767018
TI - Host within a Host: Encapsulation of Alkali Ion - Crown Ether Complexes into a
PMID- 10767019
TI - Substituted Diazadibenzoperylenes: New Functional Building Blocks for
Supramolecular Chemistry This work was supported by the Ulmer
Universitatsgesellschaft, the Fonds der Chemischen Industrie (Liebig grant for F.
W.), and the Deutsche Forschungsgemeinschaft (Habilitandenstipendium for F. W.).
We are indebted to Dr. J. Schilling for the crystal structure determination and
to Dr. E. Mena-Osteritz for helpful discussions about fluorescence measurements.
We thank BASF AG and Degussa-Huls AG for the donation of chemicals and Prof. P.
Bauerle for his support.
PMID- 10767020
TI - A Unified Bonding Picture for the Metallic Triel Elements This work was supported
by the Swedish National Science Research Council (NFR) and the Goran Gustafsson
Foundation.
PMID- 10767021
TI - Olefinic Peptide Nucleic Acids (OPAs): New Aspects of the Molecular Recognition
of DNA by PNA The team at the University of Bern thanks the Swiss National
Science Foundation and Novartis Pharma AG, Basel, for generous financial support.
PMID- 10767022
TI - An Unexpected Coupling - Isomerization Sequence as an Entry to Novel Three
Component-Pyrazoline Syntheses This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie. We thank Prof. Dr.
H. Mayr for his generous support.
PMID- 10767024
TI - [Mo]
PMID- 10767023
TI - Novel Water-Soluble Calix
PMID- 10767025
TI - Synthesis of an Isolable Diphosphaisobenzene and a Stable Cyclic Allene with Six
Ring Atoms Phosphorus Compounds, Part 147. This work was supported by the Fonds
der Chemischen Industrie and the Deutsche Forschungsgemeinschaft (Graduate
College "Phosphorus chemistry as link between different chemical disciplines").
Part 146: C. Peters, F. Tabellion, A. Nachbauer, U. Fischbeck, F. Preuss, M.
Regitz, Organometallics 2000, in press.
PMID- 10767026
TI - Self-Assembled Hydrogen-Bonded Dimeric Capsules with High Kinetic Stability This
work was supported by the Deutsche Forschungsgemeinschaft (Bo523/14-1) and the
Fonds der Chemischen Industrie. We also thank Prof. J. Okuda, (Institut fur
Anorganische Chemie) for generous access to the NMR facilities.
PMID- 10767027
TI - A Supramolecular Enzyme Mimic That Catalyzes the 15,15' Double Bond Scission of
beta,beta-Carotene This research was supported by the Swiss National Science
Foundation, Novartis International AG, and F. Hoffmann-La Roche AG. We are
grateful to F. Hoffmann-La Roche AG for the generous gift of carotenoids, and we
also thank Prof. Dr. Jakob Wirz, Insitut fur Physikalische Chemie der Universitat
Basel, for the calculation of the binding constant K(a) of 1 to the receptor 3.
PMID- 10767028
TI - The Spatial Demand of Dendrimers: Deslipping of Rotaxanes We thank Dr. S. Hoger,
MPI fur Polymerforschung, Mainz, for discussions. This work was supported by the
Deutsche Forschungsgemeinschaft (Vo 145/47-1).
PMID- 10767030
TI - Trishomoaromatic Dianions of 1,3,5-Triboracyclohexanes This work was supported by
the Deutsche Forschungsgemeinschaft (Schwerpunkt Polyeder).
PMID- 10767029
TI - Bishomoaromatic 1,2,4-Triboracyclopentane Dianions: Strong Three-Center, Two
Electron Bonds between Three Boron Atoms This work was supported by the Deutsche
Forschungsgemeinschaft (Schwerpunktprogramm "Polyeder"), the Fonds der Chemischen
Industrie, and by the U.S. National Science Foundation.
PMID- 10767031
TI - A General Catalyst for the Asymmetric Strecker Reaction This work was supported
by the NIH (GM-43214). A postdoctoral fellowship to M.S.S. (NIH), and a
predoctoral fellowship to P.V. sponsored by Alfred Bader are gratefully
acknowledged.
PMID- 10767032
TI - Binding Cesium Ions with Nucleosides: Templated Self-Assembly of Isoguanosine
Pentamers This research was supported by the Separations and Analysis Program,
Division of Chemical Sciences, Office of Basic Energy Sciences, U.S. Department
of Energy. J.T.D. thanks the Dreyfus Foundation for a Teacher-Scholar Award. We
thank Drs. Bryan Eichhorn, Steve Rokita, and Lyle Isaacs for advice.
PMID- 10767034
TI - Crystal Engineering of Metalloporphyrin Zeolite Analogues This research was
supported in part by the Israel Science Foundation administered by the Israel
Academy of Sciences and Humanities.
PMID- 10767033
TI - The Localization of Guests in Water-Soluble Oligoethyleneoxy-Modified
Poly(propylene imine) Dendrimers This work was supported by the Netherlands
Foundation for Chemical Research (CW), with financial aid from the Netherlands
Organisation for Scientific Research (NWO). The authors thank Stefan Meskers,
Harry Dekkers, Marcel van Genderen, and Rint Sijbesma for stimulating
discussions. DSM Research is acknowleged for providing the poly(propyleneimine)
dendrimers. M.B. and R.K. acknowledge financial support under the TMR/LSF program
of the European Union (No. ERBFMGECT980134) to the EMBL Hamburg outstation.
PMID- 10767035
TI - Charge Separation in a Molecular Triad Consisting of an Iridium(III) - bis-terpy
Central Core and Porphyrins as Terminal Electron Donor and Acceptor Groups We
thank the French CNRS, the Italian CNR, and the European Commission COST
programme D11/0004/98 ("New Aspects of Supramolecular Photochemistry: From Light
Harvesting Arrays to Molecular Machines") for financial support, and the French
Ministry of Education, Research, and Technology for a fellowship to I.M.D. We are
also grateful to Johnson Matthey for a generous loan of IrCl(3).
PMID- 10767037
TI - Synthesis and Structure of the Dicationic Bisborate Adduct
PMID- 10767036
TI - A Hermaphrodite Molecule: Quantitative Copper(I)-Directed Formation of a Doubly
Threaded Assembly from a Ring Attached to a String We are grateful to Jean-Daniel
Sauer for high-field NMR experiments and to Raymond Hubert and Helene
Nierengarten for MS measurements. We also gratefully acknowledge the help of
Prof. Jean Fischer and Dr. Nathalie Kyritsakas (Laboratoire de Cristallochimie et
de Chimie Structurale, Universite Louis Pasteur). M.C.J. thanks the European
Commission for a Grant (TMR Contract No. ERBFMBICT972547).
PMID- 10767038
TI - A G-Quartet Formed in the Absence of a Templating Metal Cation: A New 8-(N,N
dimethylaniline)guanosine Derivative This work was supported by the Robert A.
Welch foundation. We thank Dr. Ben Shoulders and the staff at the NMR facility at
the University of Texas for their assistance.
PMID- 10767039
TI - Discovery of Carbohydrate Sulfotransferase Inhibitors from a Kinase-Directed
Library We thank Sharon Long and Dave Keating for providing both the NodH
sulfotransferase and APS Kinase during our preliminary experiments and Jack
Kirsch for numerous helpful conversations. J.I.A. and K.G.B were supported by NIH
Molecular Biophysics Training Grant (No. T32GM0895). This research was funded by
grants to C.R.B. from the Pew Scholars Program, the W. M. Keck Foundation and the
American Cancer Society (Grant No. RPG9700501BE).
PMID- 10767040
TI - Facile and Clean Oxidation of Alcohols in Water Using Hypervalent Iodine(III)
Reagents This research was supported in part by a Grant-in-Aid for Scientific
Research (B) (No. 10470469) from the Ministry of Education, Science, Sports, and
Culture, Japan and a Grant-in-Aid for Encouragement of Young Scientists (No.
11771382) from the Japan Society for the Promotion of Science.
PMID- 10767041
TI - Total Synthesis of (+)-Concanamycin F We thank the EPSRC (GR/K54052), Knoll
Pharmaceuticals (CASE Studentship to V.A.D.), the Cambridge Commonwealth Trust
(M.D.M.), and Merck for support, and Dr R. Norrie (Knoll Pharmaceuticals) for
helpful discussions. We also thank Prof. A. Zeeck (Gottingen) for kindly
providing copies of (1)H NMR spectra of concanamycin F (concanolide A).
PMID- 10767042
TI - Organo-Lewis Acid Cocatalysts in Single-Site Olefin Polymerization-A Highly
Acidic Perfluorodiboraanthracene This research was supported by DOE Grant 86 ER
13511. D.J.S. thanks the Dow Chemical Co. for a postdoctoral fellowship. The
authors thank Drs. Mark McAdon and Eugene Chen for helpful discussions.
PMID- 10767043
TI - Photocontrol of Triple-Helix Formation by Using Azobenzene-Bearing
Oligo(thymidine) This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, and Culture, Japan
(Molecular Synchronization for the Design of New Material Systems). The grant
from the "Research for the Future" program of the Japanese Society for the
Promotion of Science (JSPS-RFTF97I00301) is also acknowledged.
PMID- 10767044
TI - Synthesis of Dicationic Telluranes by Remote Oxidation through a pi-Conjugated
System This work was supported by the Ministry of Education, Science, Sports and
Culture, Japan (Grant-in-Aid for Scientific Research on Priority Areas: Grant No.
09239104, Grant-in Aid for Scientific Research (B): Grant No. 11440186, and Grant
in-Aid for Encouragement of Young Scientists: Grant No. 10740286), and the Fund
of Tsukuba Advanced Research Alliance (TARA) project (University of Tsukuba).
PMID- 10767045
TI - Pyrone-Like Structures as Novel Oxygen-Based Organic Superbases The authors thank
CSIC for computer time at the CESGA and the CIEMAT.
PMID- 10767046
TI - Enantioselective beta-Amino Acid Synthesis Based on Catalyzed Asymmetric Acyl
Halide - Aldehyde Cyclocondensation Reactions The National Science Foundation
(CHE-9875735) and the University of Pittsburgh are gratefully acknowledged for
support of this work. We thank Prof. Peter Wipf for helpful discussions during
the preparation of this manuscript.
PMID- 10767047
TI - Introduction to the third special issue: clinical applications of therapeutic
apheresis.
PMID- 10767048
TI - Evaluation of clinical studies of the efficacy of therapeutic apheresis.
PMID- 10767049
TI - Therapeutic apheresis in autoimmune and rheumatic diseases.
PMID- 10767050
TI - Therapeutic apheresis in hematological and oncological diseases.
PMID- 10767051
TI - Therapeutic apheresis in renal and metabolic diseases.
PMID- 10767052
TI - Therapeutic apheresis in neurological disorders.
PMID- 10767054
TI - Index of indication categories for therapeutic apheresis and page index
PMID- 10767053
TI - Therapeutic pediatric apheresis.
PMID- 10767055
TI - Chronic social stress reduces dendritic arbors in CA3 of hippocampus and
decreases binding to serotonin transporter sites.
AB - Male rats housed in mixed-sex groups in a visible burrow system (VBS) form a
dominance hierarchy in which subordinate animals show stress-related changes in
behavior, endocrine function and neurochemistry. Dominants also appear to be
moderately stressed compared to controls, although these animals do not develop
the more pronounced behavioral and physiological deficits seen in the
subordinates. In the present study, we examined the effects of chronic
psychosocial stress on the morphology of Golgi-impregnated CA3 pyramidal neurons.
In addition, since serotonin has been implicated in the mechanisms mediating the
dendritic remodeling seen with other chronic stress regimens, we used
quantitative autoradiography to measure binding to the serotonin transporter
(5HTT) in hippocampus and dorsal and median raphe. Chronic social stress led to a
decrease in the number of branch points and total dendritic length in the apical
dendritic trees of CA3 pyramidal neurons in dominant animals compared to
unstressed controls; subordinates also had a decreased number of dendritic branch
points. [(3)H]paroxetine binding to the 5HTT was decreased in Ammon's horn in
both dominants and subordinates compared to controls, while 5HTT binding remained
unchanged in dentate gyrus and raphe. The similarity of the changes in 5HTT
binding and dendritic arborization between both groups of VBS animals, despite
apparent differences in stressor severity, suggests that these changes may be
part of the normal adaptive response to chronic social stress. The mechanisms
underlying dendritic remodeling in CA3 pyramidal neurons are likely to involve
stress-induced changes in glucocorticoids and in 5HT and other transmitters.
PMID- 10767056
TI - Effects of NADH on dopamine release in rat striatum.
AB - Nicotinamide adenine dinucleotide (NADH) may be utilized for the synthesis and
regeneration of tetrahydrobiopterin (BH(4)), which in turn is an essential
cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of
dopamine (DA). NADH has been reported to relieve some of the symptoms of
Parkinson's disease, presumably by altering dopaminergic function. The present
study examines the efficacy of NADH in influencing DA activity in the rat
striatum. In striatal slices, NADH (350 microM) significantly increased basal DA
and DOPAC efflux and caused a 2-fold increase in the DA overflow evoked by high
KCl (25 mM). Tissue levels of BH(4), basal BH(4) efflux, and KCl-evoked BH(4)
overflow were unaffected by NADH, as was [(3)H]DA uptake into striatal
synaptosomes. In contrast to the effects of NADH on DA function in vitro, no
effects were observed when NADH was administered systemically. NADH (10 or 100
mg/kg, s.c.) did not influence the tissue content of DA, 5-HT, or their
metabolites in the midbrain or striatum, nor did it alter DA extracellular
concentrations. These results indicate that NADH can increase DA release from
striatal slices, although we are as yet unable to detect this effect in vivo.
PMID- 10767057
TI - Effects of phentermine and fenfluramine on extracellular dopamine and serotonin
in rat nucleus accumbens: therapeutic implications.
AB - Combined administration of the amphetamine analogs phentermine and fenfluramine
(PHEN/FEN) has been used in the treatment of obesity. While these medications are
thought to modulate monoamine transmission, the precise neurochemical effects of
the PHEN/FEN mixture have not been extensively studied. To assess the mechanism
of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus
accumbens of conscious freely moving rats. A series of amphetamine derivatives
including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio),
were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM)
or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for
dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with
electrochemical detection. When infused locally, phentermine preferentially
increased extracellular DA, whereas fenfluramine selectively increased
extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN
mixture caused parallel elevations of both transmitters. Analogous results were
obtained when the drugs were injected systemically. Phentermine stimulated robust
locomotor activity in mice, whereas chlorphentermine and fenfluramine did not.
PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect
at the highest dose. Accumulating evidence suggests that chronic drug and alcohol
abuse is associated with deficits in both DA and 5-HT neuronal function. Thus,
dual activation of DA and 5-HT neurotransmission with monoamine releasing agents
may be an effective treatment strategy for substance use disorders, as well as
for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.
PMID- 10767058
TI - Decrease in phorbol ester-induced potentiation of noradrenaline release in
synapsin I-deficient mice.
AB - Synapsin I is involved in regulating amino acid neurotransmitter release, but has
a less clear role in noradrenergic nerve terminals. To better understand the role
of synapsin I in the function of noradrenergic nerve terminals, we compared
noradrenaline release in wild-type and synapsin I-deficient mice. No difference
was found in the accumulation or in the Ca(2+)-independent release of
[(3)H]noradrenaline in cerebrocortical synaptosomes from wild-type and synapsin I
deficient mice. Synaptosomes lacking synapsin I also displayed no gross
alterations in either the time course or the Ca(2+)-dependency of
[(3)H]noradrenaline release when stimulated by depolarizing secretagogues or
ionophore treatment. In wild-type synaptosomes, activation of protein kinase C by
phorbol ester treatment resulted in a Ca(2+)-dependent increase in
[(3)H]noradrenaline release evoked by depolarizing secretagogues and ionophore
treatment. The phorbol ester-mediated enhancement of [(3)H]noradrenaline release
evoked by depolarizing secretagogues, but not by ionophore treatment, was greatly
reduced in synapsin I-deficient synaptosomes. These results indicate that
synapsin I plays a role in regulating noradrenaline release.
PMID- 10767059
TI - Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic
markers in the striatum of parkinsonian monkeys.
AB - GM1 ganglioside administration has previously been shown to increase striatal
dopamine levels and to enhance the density of tyrosine hydroxylase-positive
fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine (MPTP). The present study examined the extent to which GM1
administration promotes recovery of dopamine terminals and reverses lesion
induced changes in postsynaptic receptors in the striatum of MPTP-treated
monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated
monkeys exhibited significant functional recovery after 6 weeks of treatment,
whereas saline-treated controls remained parkinsonian over the same time period.
MPTP exposure resulted in profound decreases in [(3)H]-mazindol binding to
dopamine transporters in the caudate and putamen and increased D1 and D2 receptor
binding in several striatal regions. GM1 treatment resulted in significant
increases in striatal [(3)H]-mazindol binding and decreases in D1 binding
compared to control animals in many striatal regions. GM1 treatment did not
significantly affect D2 binding. These results show that GM1 treatment can
partially restore striatal dopaminergic terminals and partially reverse
postsynaptic changes in dopamine receptors in a nonhuman primate model of
parkinsonism.
PMID- 10767060
TI - Haloperidol reverses the changes in striatal glutamatergic immunolabeling
following a 6-OHDA lesion.
AB - We reported previously that 3 months following a unilateral lesion of the
nigrostriatal pathway with 6-hydroxydopamine (6-OHDA), there was a decrease in
the extracellular level of striatal glutamate as determined by in vivo
microdialysis. This resulted in an accumulation or increase in the density of
nerve terminal glutamate immunolabeling (Meshul et al., 1999). We also reported
on blockade of dopamine D-2 receptors with haloperidol resulting in
ultrastructural changes within the striatum consistent with increased functioning
of the glutamatergic corticostriatal pathway (Meshul and Tan 1994). We
hypothesized that administration of haloperidol to 6-OHDA-lesioned rats may be
capable of activating the corticostriatal pathway and thereby counteracting the
effects of the unilateral nigrostriatal lesion. Striatal glutamatergic function
was evaluated using electron microscopy and quantitative glutamate
immunocytochemistry. Starting 1 month after a unilateral lesion of the
nigrostriatal pathway with 6-OHDA, haloperidol (0.5 mg/kg/d) was administered for
the next 2 months. Within the dorsolateral caudate nucleus, the main area of
innervation from the motor cortex, haloperidol blocked the 6-OHDA-induced
increase in the density of nerve terminal glutamate immunolabeling. Within all
three experimental groups (6-OHDA, haloperidol, 6-OHDA/haloperidol) there was an
increase in the mean percentage of striatal asymmetrical synapses containing a
perforated postsynaptic density. In addition, haloperidol treatment resulted in a
reduction in the number of apomorphine-induced contralateral rotations in
unilaterally 6-OHDA lesioned rats. The data suggests that the decrease in
striatal glutamatergic function 3 months following a unilateral 6-OHDA lesion can
be reversed by daily haloperidol treatment. This finding is discussed in terms of
current therapy for Parkinson's disease. Synapse 36:129-142, 2000. Published 2000
Wiley-Liss, Inc.
PMID- 10767061
TI - Divergent effects of putative anxiolytics on stress-induced fos expression in the
mesoprefrontal system of the rat.
AB - Previously, we reported that R(+)HA-966, a weak partial agonist for the
glycine/NMDA receptor, and guanfacine, a noradrenergic alpha2 agonist, have
anxiolytic-like actions on the biochemical activation of the mesoprefrontal
dopamine neurons and fear-induced behaviors. Here, we examined these two putative
anxiolytic agents, both with primary actions independent of GABAergic systems,
for their ability to alter stress-induced Fos-like immunoreactivity in the
mesoprefrontal cortex and in tyrosine hydroxylase-stained, presumed dopaminergic,
neurons in the ventral tegmental area. The benzodiazepine agonist, lorazepam, and
partial agonist, bretazenil, were also tested in this footshock paradigm [10 x
0.5 sec, 0.8 mA paired with a 5-sec tone]. In saline-treated rats, footshock
resulted in an increase in Fos-li in the prelimbic and infralimbic cortices and
tyrosine hydroxylase-labeled cells in the ventral tegmental area. Treatment with
lorazepam or bretazenil prevented the stress-induced activation in Fos-li nuclei
in all regions of the medial prefrontal cortex and in dopaminergic neurons in the
ventral tegmental area. In contrast, the actions of the novel anxiolytic-like
agents on stress-induced Fos-li were different than those observed with
benzodiazepine agonists. Both putative anxiolytics, R(+)HA-966 and guanfacine,
did not reduce, but significantly enhanced the stress-induced Fos-li in the
prelimbic region of the medial prefrontal cortex. Additionally, treatment with
R(+)HA-966 completely blocked, while guanfacine attenuated, the stress-induced
increase in the number of Fos-li, TH-li cells in the ventral tegmental area.
These results indicate that the putative anxiolytics, R(+)HA-966 and guanfacine,
have actions on the stress-sensitive mesoprefrontal system which appear distinct
from those of traditional anxiolytics.
PMID- 10767062
TI - Turbo STIR magnetic resonance imaging as a whole-body screening tool for
metastases in patients with breast carcinoma: preliminary clinical experience.
AB - This study was undertaken to assess the utility of whole-body turbo short tau
inversion recovery (STIR) magnetic resonance imaging (MRI) to detect metastases
to liver, brain, and bone as a single examination in women with breast cancer.
Seventeen patients with biopsy-proven breast cancer and suspected metastatic
disease attending over a 12-month period referred for both conventional imaging
and whole-body MRI were included in the study. Three patients were found to be
free of metastases at both conventional and MR imaging. Appendicular or axial
skeletal metastases were identified in 11 of 17 patients, with correlation
between findings at whole-body MRI and scintigraphy in 15 of the 17 patients.
Five patients had evidence of hepatic metastases on whole-body MRI, of which
metastases were identified in only three patients at CT despite contrast
enhancement. Four patients had brain abnormalities (metastases in three patients,
meningioma in one patient) detected on both whole-body and dedicated brain MRI.
Preliminary clinical experience suggests that turbo STIR whole-body MRI may
represent a convenient and cost-effective method of total body screening for
metastases in patients with breast carcinoma.
PMID- 10767063
TI - Dynamic breast MRI with spiral trajectories: 3D versus 2D.
AB - A three-dimensional (3)D spiral sequence was developed for dynamic breast
magnetic resonance (MR) imaging with much improved image quality. Partial Z phase
encoding was applied to obtain thinner slices for a coverage of the whole breast.
Comparison between the 3D and a previously developed multi-slice 2D spiral
sequences was performed on ten healthy volunteers without contrast and five
breast patients with gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA).
The 3D spiral images had significantly less off-resonance blurring and spiral
artifacts. With a small compromise on temporal resolution (7.7 seconds in 2D and
10.6 seconds in 3D), we obtained 32 interpolated 3-5 mm slices (with 20 Z phase
encodes) for a full coverage of 10-16 cm breast with the same 1 x 1 mm2 in-plane
resolution as the 2D sequence, which had 12 8-13 mm slices. Contrast between
glandular and soft tissue in normal breasts was increased by about 25%. The
reduced repetition time in the 3D spiral acquisition led to an increased Gd
enhanced signal. The difference between the enhancement of malignant and benign
lesions increased by sevenfold. We expect that this new development could lead to
improved specificity in characterizing breast lesions using MR imaging.
PMID- 10767064
TI - A method for fast multislice T1 measurement: feasibility studies on phantoms,
young children, and children with Canavan's disease.
AB - We have developed a multislice protocol for quantitative T1 measurements in which
the processing time and the acquisition time are under 2 minutes each for a
complete brain study of 15 slices. An echoplanar, inversion-recovery image
sequence is designed to collect data suitable for analysis using a linear
regression algorithm. The precision is approximately twice the noise to signal
ratio of the images. The accuracy of the protocol is better than 1% for T1 in the
range 0-2 seconds and deviates slightly for longer T1 values. The protocol is
insensitive to B1 field values. If needed, the data can be postprocessed using a
slow, nonlinear algorithm to give an accuracy of less than 1% and a precision of
approximately the noise to signal ratio throughout a range of T1 values from 0 to
4 seconds.
PMID- 10767065
TI - Three-dimensional contrast-enhanced moving-bed infusion-tracking (MoBI-track)
peripheral MR angiography with flexible choice of imaging parameters for each
field of view.
AB - A technique to image peripheral arteries with flexible choice of scan parameters
for separate stations was developed based on moving-bed single-bolus three
dimensional gradient-recalled echo magnetic resonance angiography. A volunteer
study yielded higher signal- and contrast-to-noise ratios, less venous
enhancement, and better subjective interpretability compared with imaging with
fixed parameters for each station. Additionally, six patients were imaged to test
the feasibility of the new method in a clinical setting. Imaging peripheral
arteries with the new technique in volunteers yielded better image quality and is
feasible for patients.
PMID- 10767066
TI - Enhanced image detail using continuity in the MIP Z-buffer: applications to
magnetic resonance angiography.
AB - In this paper a new algorithm is presented for the segmentation and display of
blood vessels from images obtained with magnetic resonance angiography (MRA) and
other three-dimensional (3D) angiographic imaging techniques. The algorithm
developed is based on the observation that vessels are strongly evident in the
maximum intensity projection (MIP) Z-buffer as regions of high continuity and low
local roughness. Roughness is measured here by the minimum chi2 value of a low
order local least-squares fit in the principal directions through each point in
the MIP Z-buffer. Although some background pixels in the Z-buffer exhibit low
local roughness, the size of the connected region is nearly always much smaller
than even the very smallest vessels that appear in the MIP image. It is shown
that by applying connectivity to the regions of low roughness, there is nearly
complete separation between vascular detail and background. When connectivity is
further applied in the original 3D image, vascular bed segmentation becomes
nearly complete. The algorithm consists of three basic steps: a) determination of
the minimum local roughness at each point in the MIP Z-buffer; b) connection of
all neighboring points of low local roughness; and c) connection of all points in
the original 3D image matrix that are connected to the points determined in the
MIP Z-buffer and that are above an intensity threshold. The algorithm as
presented is not optimized but demonstrates a very strong potential for improved
portrayal of vascular detail.
PMID- 10767067
TI - Free-breathing 3D coronary MRA: the impact of "isotropic" image resolution.
AB - During conventional x-ray coronary angiography, multiple projections of the
coronary arteries are acquired to define coronary anatomy precisely. Due to time
constraints, coronary magnetic resonance angiography (MRA) usually provides only
one or two views of the major coronary vessels. A coronary MRA approach that
allowed for reconstruction of arbitrary isotropic orientations might therefore be
desirable. The purpose of the study was to develop a three-dimensional (3D)
coronary MRA technique with isotropic image resolution in a relatively short
scanning time that allows for reconstruction of arbitrary views of the coronary
arteries without constraints given by anisotropic voxel size. Eight healthy adult
subjects were examined using a real-time navigator-gated and corrected free
breathing interleaved echoplanar (TFE-EPI) 3D-MRA sequence. Two 3D datasets were
acquired for the left and right coronary systems in each subject, one with
anisotropic (1.0 x 1.5 x 3.0 mm, 10 slices) and one with "near" isotropic (1.0 x
1.5 x 1.0 mm, 30 slices) image resolution. All other imaging parameters were
maintained. In all cases, the entire left main (LM) and extensive portions of the
left anterior descending (LAD) and the right coronary artery (RCA) were
visualized. Objective assessment of coronary vessel sharpness was similar (41% +/
5% vs. 42% +/- 5%; P = NS) between in-plane and through-plane views with
"isotropic" voxel size but differed (32% +/- 7% vs. 23% +/- 4%; P < 0.001) with
nonisotropic voxel size. In reconstructed views oriented in the through-plane
direction, the vessel border was 86% more defined (P < 0.01) for isotropic
compared with anisotropic images. A smaller (30%; P < 0.001) improvement was seen
for in-plane reconstructions. Vessel diameter measurements were view independent
(2.81 +/- 0.45 mm vs. 2.66 +/- 0.52 mm; P = NS) for isotropic, but differed (2.71
+/- 0.51 mm vs. 3.30 +/- 0.38 mm; P < 0.001) between anisotropic views. Average
scanning time was 2:31 +/- 0:57 minutes for anisotropic and 7:11 +/- 3:02 minutes
for isotropic image resolution (P < 0.001). We present a new approach for "near"
isotropic 3D coronary artery imaging, which allows for reconstruction of
arbitrary views of the coronary arteries. The good delineation of the coronary
arteries in all views suggests that isotropic 3D coronary MRA might be a
preferred technique for the assessment of coronary disease, although at the
expense of prolonged scan times. Comparative studies with conventional x-ray
angiography are needed to investigate the clinical utility of the isotropic
strategy.
PMID- 10767068
TI - A comparison between segmented k-space FLASH and interleaved spiral MR coronary
angiography sequences.
AB - A direct comparison of segmented fast low-angle short (FLASH) imaging and
interleaved spiral magnetic resonance coronary angiography (MRCA) during free
respiration using navigator echo has been performed. MRCA images were acquired in
30 normal subjects and 15 patients with coronary artery disease (CAD). Images of
the right coronary artery were acquired during free respiration using navigator
echo gating for both a segmented k-space FLASH sequence (8 views/segment, segment
duration 105 msec) and an interleaved spiral sequence (20 interleaves, spiral
read-out period 19 msec). Image quality was scored by three independent blinded
observers, and coronary artery signal-to-noise ratio (SNR) and coronary
artery/epicardial fat contrast-to-noise ratio (CNR) were measured. There was a
significant improvement in image quality when coronary images were acquired with
the interleaved spiral sequence (spiral 2. 3 vs. FLASH 1.8; P = 0.002). This was
associated with an increase in the coronary artery SNR (16.6 +/- 6.9 vs. 11.8 +/-
5.0; P < 0.001), the coronary artery/epicardial fat CNR (12.5 +/- 6.1 vs. 7.4 +/-
4.0, P < 0.001), and the image resolution (256 x 256 vs. 256 x 128). However,
there was a 12% increase in acquisition time for the interleaved spiral sequence.
Image quality, SNR, CNR, and resolution can be improved using an interleaved
spiral sequence. These improvements are secondary to the intrinsic
characteristics of spiral imaging and the short acquisition period, which reduces
the effects of both cardiac and respiratory motion.
PMID- 10767069
TI - Contrast-enhanced MR angiography in patients with aortic occlusion (Leriche
syndrome).
AB - The diagnostic utility of contrast-enhanced three-dimensional magnetic resonance
angiography (3D MRA) was retrospectively evaluated in 24 patients with Leriche
syndrome. 3D MRA was performed either of the abdomen alone (n = 6), the abdomen
and chest (n = 2), the abdomen and lower extremities (n = 12), or of all stations
(n = 4). MRA image sets were evaluated regarding the location of the aortic
occlusion, the presence of concomitant occlusive disease affecting the renal and
visceral arteries, the type and extent of collateralization, and the level of the
most proximal graftable arterial segments. Intravenous digital subtraction
angiography was available for correlation in two patients, while surgical
correlation was possible in 14 patients. MRA permitted classification of the
level of aortic occlusion as juxtarenal (n = 8), infrarenal, and cranial to the
origin of the inferior mesenteric artery (IMA; n = 11), and infrarenal but caudad
to the IMA (n = 5). Extraanatomical grafts were displayed to similar advantage as
collateral parietal and visceral pathways. Contrast-enhanced 3D MRA thus appears
to be well suited for assessment of patients with suspected Leriche syndrome.
PMID- 10767070
TI - Left ventricular quantification in heart failure by cardiovascular MR using
prospective respiratory navigator gating: comparison with breath-hold
acquisition.
AB - Cardiovascular magnetic resonance (CMR) is the reference standard for the
assessment of cardiac function. Faster sequences, such as breath-hold (BH) fast
low-angle shot, have made CMR more clinically acceptable and cost effective. In a
significantly large patient group, however, holding their breath is difficult,
resulting in poor-quality images. We compared prospective navigator-echo
respiratory gating (NE), which allows image acquisition during free breathing,
and BH imaging in 14 patients with heart failure and 10 normal volunteers. There
was good agreement between both NE and BH volumes, mass, and ejection fraction.
The image quality of both NE basal and apical slices was significantly better
than the corresponding BH slices in both the heart failure (P < 0.01) and normal
groups (P < 0.05). The NE image acquisition was more time efficient than the BH
acquisition in the heart failure group (P < 0. 01), with no difference in the
normal group (P = 0.2). Thus, prospective navigator-echo gating, previously only
described in coronary artery imaging, can be used in the assessment of cardiac
function. It is particularly useful in patients who find it difficult to hold
their breath in whom NE provides good-quality, time-efficient images.
PMID- 10767071
TI - MR contrast agents in acute experimental cerebral ischemia: potential adverse
impacts on neurologic outcome and infarction size.
AB - The purpose of the study was to investigate the effects of magnetic resonance
(MR) contrast agents on neurologic outcome and infarction size in a rat stroke
model. Focal cerebral ischemia was induced in 80 rats using an endovascular
occlusion technique of the middle cerebral artery. Four hours after occlusion, 64
animals (4 groups of 16 each) received gadodiamide (Gd-DTPA-BMA) in a single (0.1
mmol/kg) or triple (0.3 mmol/kg) clinical dose or the ultrasmall
superparamagnetic iron oxide particles contrast agent NC 100150 in a single (0.03
mmol/kg, 1.5 mg Fe(2+)/kg) or double (0.06 mmol/kg, 3.0 mg Fe(2+)/kg) clinical
dose, respectively. Sixteen animals received equivolumetric saline (control
group). Neurologic score and body weight were recorded every 8 hours. Twenty-four
hours after vessel occlusion, infarction size was measured by 2,3, 5-triphenyl
tetrazolium-chloride (TTC) staining. Neither the normal nor the triple clinical
dose of gadodiamide or NC 100150 in the single or double dose had any
statistically significant effects on infarction volume, mortality, body weight,
or neurologic outcome (P > 0.05). Our results suggest that bolus injection of
gadodiamide and the ultrasmall superparamagnetic iron oxide particles NC 100150
in clinically relevant doses does not significantly affect infarction volume and
clinical outcome of acute cerebral ischemia.
PMID- 10767072
TI - Unsupervised segmentation of multiparameter MRI in experimental cerebral ischemia
with comparison to T2, diffusion, and ADC MRI parameters and histopathological
validation.
AB - This study presents histological validation of an objective (unsupervised)
computer segmentation algorithm, the iterative self-organizing data analysis
technique (ISODATA), for analysis of multiparameter magnetic resonance imaging
(MRI) data in experimental focal cerebral ischemia. T2-, T1-, and diffusion (DWI)
weighted coronal images were acquired from 4 to 168 hours after stroke on
separate groups of animals. Animals were killed immediately after MRI for
histological analysis. MR images were coregistered/warped to histology. MRI
lesion areas were defined using DWI, apparent diffusion coefficient (ADC) maps,
T2-weighted images, and ISODATA. The last techniques clearly discriminated
between ischemia-altered and morphologically intact tissue. ISODATA areas were
congruent and significantly correlated (r = 0.99, P < 0.05) with histologically
defined lesions. In contrast, DWI, ADC, and T2 lesion areas showed no significant
correlation with histologically evaluated lesions until subacute time points.
These data indicate that multiparameter ISODATA methodology can accurately detect
and identify ischemic cell damage early and late after ischemia, with ISODATA
outperforming ADC, DWI, and T2-weighted images in identification of ischemic
lesions from 4 to 168 hours after stroke.
PMID- 10767073
TI - Detection of a relation between respiration and CSF pulsation with an echoplanar
technique.
AB - The flow of cerebrospinal fluid (CSF) through the aqueduct was studied with an
echoplanar imaging technique. Images (1024) of a slice perpendicular to the
aqueduct were acquired with a repetition time of 107 msec and a flip angle of 90
degrees. This imaging technique is very sensitive for flow into the selected
slice, although a quantitative assessment of flow velocities is not possible.
Simultaneously with the image data acquisition, data from a pulse oximeter and a
respiration belt were recorded. For each data point, a delay time to the
preceding cardiac pulse was determined from the recorded pulse wave. The signal
intensities could then be assigned to the cardiac cycle. Each cardiac interval
was assigned to one of eight respiratory phases, and an average signal curve
during the cardiac interval was calculated for each respiration phase. The
evaluation showed to signal maxima within the cardiac interval, which could be
identified as a downward flow at 10% and an upward flow at 80% of the cardiac
pulse interval by measurements with additional saturation pulses. In examinations
of 22 healthy volunteers, an influence of respiration on the flow through the
aqueduct was found. In spite of interindividual variability, comparable effects
could be observed in all volunteers. In the late expiration phase the caudally
directed flow was at its maximum, whereas the cranially directed flow was maximal
in the post-inspiration phase.
PMID- 10767074
TI - Reduced power multislice MDEFT imaging.
AB - A novel method is presented for acquiring multislice T1-weighted images. The
method utilizes non-slice-selective inversion pulses followed by a series of
slice-selective excitations. k-space is divided into a number of segments equal
to the number of slices. Successive segments of k-space are assigned to
successive slice-selective pulses, and the order in which the slices are excited
is manipulated to ensure that images of each slice have identical contrast and
point spread function (PSF). This method is applied to the MDEFT experiment, a
particular version of the inversion recovery experiment. The implications of this
acquisition scheme on the PSF are examined, and it is shown that, provided the k
space modulation function does not change sign, a good PSF is achieved. For a
given maximum number of slices, the total experimental duration depends only on
TR and the number of phase-encoding steps. A method of accelerating the
experiment by multiply exciting each slice is described. An experimental
demonstration of the proposed sequences is given by imaging the human head at 3
T.
PMID- 10767075
TI - Magnetic resonance imaging of ultrasound fields: gradient characteristics.
AB - Phase-contrast magnetic resonance imaging (MRI) is used to image particle
displacements arising from a 0.515-MHZ focused ultrasound (US) field. The
technique used a phase-locked, self-resonant gradient matched to the US frequency
in conjunction with a spin-echo sequence to generate phase images of US-induced
displacement parallel to the US propagation direction. The gradient design was
numerically optimized to provide maximum linearity and magnitude while minimizing
gradient inductance. The windings were fabricated of Litz wire to minimize
resistive losses and mounted in an oil-cooled imaging chamber. When driven by a
resonance power supply, a peak magnetic field gradient of 0.40 T/m was attained
with a peak current of 20 amp in a volume of 53 cm(3), achieving stable
oscillation at the required US frequency. Clear detection of the nanometer scale
particle motions of the US field was achieved and allowed quantitative,
noninvasive visualization of the entire US field. While the required gradient
slew rate for US detection is beyond that recommended for in vivo application,
this imaging method opens new possibilities for in vitro or ex vivo research in
the study of the interaction of US with tissue.
PMID- 10767076
TI - A three-coil comparison for MR angiography.
AB - The purpose of this work was to compare intracranial magnetic resonance
angiography (MRA) image quality using three different radiofrequency coils. The
three coil types included a reduced volume quadrature birdcage coil with endcap,
a commercially available quadrature birdcage head coil, and a four-element phased
array coil. Signal-to-noise ratio (SNR) measurements were obtained from
comparison studies performed on a uniform cylindrical phantom. MRA comparisons
were performed using data acquired from 15 volunteers and applying a thick-slab
three-dimensional time-of-flight sequence. Analysis was performed using the
signal difference-to-noise ratio, a quantitative measure of the relative vascular
signal. The reduced-volume endcap and phased-array coils, which were designed
specifically for imaging the intracranial volume of the head, improved the image
SNR and vascular detail considerably over that obtained using the commercially
available head coil. The endcap coil configuration provided the best vascular
signal overall, while the phased-array coil provided the best results for
arteries close to the coil elements.
PMID- 10767077
TI - Effect of gradient and section orientation on quantitative analysis of knee joint
cartilage
PMID- 10767078
TI - Endoderm and heart development.
AB - Since the first half of the 20th century, experimental embryologists have noted a
relationship between endoderm cells and the development of cardiac tissue from
mesoderm. During the past decade, the accumulation of evidence for an obligatory
interaction between endoderm and mesoderm during the specification and terminal
differentiation of myocardial, and more recently endocardial, cells has markedly
accelerated. Moreover, the endoderm-derived molecules that may regulate these
processes are being identified. It now appears that endoderm-derived growth
factors regulate the formation of both myocardial and endocardial cells during
specification, terminal differentiation, and perhaps morphogenesis of cells in
the developing embryonic heart.
PMID- 10767079
TI - Transforming growth factor beta2, but not beta1 and beta3, is critical for early
rat lung branching.
AB - Mesenchymal-epithelial tissue interactions are critical for lung branching
morphogenesis, and polypeptide growth factors are likely involved in these tissue
interactions. Transforming growth factorbetas (TGFbetas) have been implicated in
lung development, but their involvement in early lung branching morphogenesis is
unclear. In the present study, we investigated the role of the three mammalian
TGFbeta subtypes (beta1, beta2, and beta3) and their receptors (type III (TbetaR
III), type II (TbetaR-II), and two types I (TbetaR-I), ALK-1 and ALK-5) in early
rat lung organogenesis by using an embryonic rat lung explant culture.
Transcripts and proteins for all three TGFbetas and their receptors were detected
during the embryonic period of fetal rat lung development. Inhibition of
TGFbeta2, but not beta1 and beta3, with antisense oligonucleotides and
neutralizing antibodies resulted in significant inhibition of early lung
branching in culture. Addition of minute amounts (60 minutes to
identify causes for delay. Feedback was directed to pharmacy, nursing, and
physician staff. Biannual reports were distributed throughout the hospital and
the emergency department. Nursing-specific feedback led to the development of
protocols for all aspects of the delivery of thrombolytic agents. The choice of
thrombolytic agent was not dictated by the protocol, but the physician staff was
continuously updated on the results of the latest clinical trials comparing one
thrombolytic agent with another. The mean age was 58 years for men and 67 years
for women in this cohort consisting of 78% men and 22% women. Thirty-seven
percent of the myocardial infarctions were in an anterior location and 56% were
in an inferior location. The median duration of chest pain before presentation to
the emergency department was 120 minutes. Hospital mortality was 3%. Median door
to-needle time fell from 46 (1989-1991) to 36 (1992-1994) minutes, P& < 0.01. The
percentage of patients with a door-to-needle time >60 minutes decreased from 35%
(1989-1991) to 16% (1992-1994) minutes, P < 0.0001. Corresponding with the ISIS-3
report, there was a significant increase in the proportion of patients receiving
streptokinase over the first 3 years of the study (P < 0.0001), which changed to
a trend toward increased utilization of tissue plasminogen activator with the
GUSTO report in the final 6 months of the study. In conclusion, a quality
assurance program led to a significant reduction in the door-to-needle time, and
recent megatrials were found to influence the choice of thrombolytic agent used.
PMID- 10767111
TI - Angiographic Morphology Following Heparin and Aspirin Therapy in Patients with
Acute Coronary Syndromes and Intracoronary Thrombus.
AB - This series included 26 patients with acute myocardial infarction (15 patients)
or unstable angina (11 patients), with thrombotic lesions identified by
angiography and treated with intravenous heparin (mean 8 +/- 3 days, aPTT 1.5-2.5
times baseline) and aspirin (250 mg/day). A quantitative angiographic analysis
was performed, and comparison of the lesion morphology before and after the
antithrombotic treatment was conducted, using a computer-based analysis of the
lesion contour. On average, minimal lumen diameter increased by 15.6% (1.15 +/-
0.5mm to 1.33 +/- 0.5mm, P = 0.02), percent diameter stenosis decreased by 10.7%
(60.0 +/- 18% to 53.6 +/- 19%, P = 0.009), percent area stenosis decreased by
6.5% (80.0 +/- 14% to 74.8 +/- 16%, P = 0.05), and TIMI flow increased by 8% (2.5
+/- 0.9 to 2.7 +/- 0.7, P = 0.02). A significant improvement in the lesion
morphology was more often observed in the right coronary artery (n = 9), than the
left coronary artery (n = 16). We conclude that heparin and aspirin therapy
improves the angiographic morphology and TIMI flow of thrombotic lesions in
patients sustaining the acute coronary syndrome. This improvement was primarily
found when the lesion was located in the right coronary artery.
PMID- 10767112
TI - Effect of a Change in the Sleep/Wake Cycle on the Diurnal Variation of
Fibrinolytic Parameters.
AB - The mechanism underlying the circadian rhythm of fibrinolysis is not well
understood. To evaluate the influences of wakefulness and of the intrinsic
circadian rhythm on fibrinolytic activity, we examined diurnal changes (8:00 am
vs. 8:00 pm) in plasminogen activator inhibitor-1 (PAI-1) activity, tissue
plasminogen activator (t-PA) antigen levels, and t-PA activity, as well as in
plasma serum cortisol levels, in 10 healthy males (21 +/- 2 years) for two
consecutive days. On the first day, subjects remained awake all day and night.
They slept during the daytime (8:30 am to 5:30 pm) on the following day. PAI-1
activity and cortisol levels were significantly decreased, and t-PA activity
tended to increase during the daytime on the first day. On the morning following
overnight wakefulness, PAI-1 activity and cortisol levels did not return to the
levels of the previous morning. On the second day, the afternoon decrease in PAI
1 activity, but not cortisol levels, was still observed, although its magnitude
was substantially attenuated. No significant diurnal changes were observed in the
levels of t-PA antigen throughout the study period. These findings suggest that
the diurnal variation of fibrinolytic activity may be governed by an intrinsic
circadian rhythm of PAI-1, which can be modified by a change in the time of
wakefulness.
PMID- 10767113
TI - Lack of Correlation Between Activation of Hemostatic Mechanism and Inflammation
in Unstable Angina Pectoris.
AB - In the acute phase of unstable angina, activation of the hemostatic mechanism is
demonstrated by an increase in the plasma levels of markers of thrombin
generation (prothrombin fragment 1+2) and thrombin activity (fibrinopeptide A).
Increased concentrations of plasma C-reactive protein, an acute-phase reactant,
have also been reported in patients with unstable angina. However, whether there
is a correlation between the activation of the hemostatic mechanism and the acute
phase reaction of inflammation remains unclear. We measured the plasma levels of
prothrombin fragment 1+2, fibrinopeptide A, and C-reactive protein in 91 patients
consecutively hospitalized with recent-onset rest angina (Class IIIB Braunwald's
classification), finding that they were above the normal limits in 48 (53%), 45
(49%), and 30 (33%) patients, respectively. There was no correlation between
prothrombin fragment 1+2 and fibrinopeptide A (P = 0.34), prothrombin fragment
1+2 and C-reactive protein (P = 0.10), or fibrinopeptide A and C-reactive protein
(P = 0.75). Plasma levels of prothrombin fragment 1+2 and fibrinopeptide A were
both above normal levels in 32% of patients; 19% had both prothrombin fragment
1+2 and C-reactive protein, and 18% both fibrinopeptide A and C-reactive protein
levels above the upper normal limits. All three markers were abnormally high in
11% of patients. According to the kappa cofficient test, the agreement between
the elevation of the plasma concentrations of the markers was "random." In
approximately half of the patients with acute unstable angina, there was an
increase in the markers of the activation of the hemostatic mechanism and, in a
smaller proportion, an increase in plasma C-reactive protein levels. The
activation of the coagulation cascade and the acute-phase reaction of
inflammation were infrequently associated in individual patients.
PMID- 10767114
TI - Routine Coronary Arteriography Following Thrombolytic Therapy for Acute
Myocardial Infarction: An Unsettled Controversy.
AB - Although coronary artery disease remains the leading cause of death in
industrialized countries, the management of patients recovering from acute
myocardial infarction varies significantly. The issue of routine arteriography
and revascularization following thrombolytic therapy remains controversial
despite substantial evidence associating infarct-related artery patency with
improved cardiac function and survival. Randomized trials of routine intervention
after myocardial infarction have generally failed to demonstrate advantages of
this invasive approach but methodological problems limit their application to
current practice. High-risk patients should be referred for arteriography. While
awaiting definitive trials addressing the influence of routine arteriography on
patient survival and its cost effectiveness, the management of other patient
groups must be individualized.
PMID- 10767115
TI - Drug-Induced Thrombocytopenia: Is it a Serious Concern for Glycoprotein IIb/IIIa
Receptor Inhibitors?
AB - Over the past decade, several glycoprotein IIb/IIIa receptor antagonists have
been developed and tested clinically as adjuncts to coronary intervention and/or
treatment of acute coronary syndromes. Thrombocytopenia associated with this
class of compounds has been described in most large studies to date and when it
occurs in combination with bleeding represents a major safety concern. Cases of
thrombocytopenia caused by GP IIb/IIIa antagonists vary in their clinical
presentation according to time of onset (following the first dose or delayed),
severity (profound, i.e., <20,000 cells/mm(3), or mild), and may or may not be
associated with clinically important bleeding. More than one etiology appears
responsible for thrombocytopenia associated with GP IIb/IIIa antagonists,
including acute, idiosyncratic, as well as delayed immune-mediated mechanisms.
Comparison of the incidence of thrombocytopenia across the different agents
currently being studied and the one agent commercially available is complicated
by varying definitions of thrombocytopenia used to date; different clinical
settings in which GP IIb/IIIa antagonists have been studied; use of concomitant
medications such as heparin, which itself may cause thrombocytopenia; relatively
infrequent occurrence of thrombocytopenia; and the limited number of patients
exposed to these agents. Review of the large studies presented and published to
date suggests that thrombocytopenia due specifically to GP IIb/IIIa receptor
antagonists occurs in less than 5% of treated patients and may vary depending on
the type of agent, concomitant therapy, and clinical scenario. Current standard
management includes immediate cessation of the GP IIb/IIIa antagonist and, in
severe cases, platelet transfusions. In cases with associated hemorrhage, other
anticoagulants and antiplatelet agents should be discontinued and possibly
reversed. There may be a role for IV IgG and steroids, especially for cases of
thrombocytopenia that are immune-mediated; however, further investigations are
necessary.
PMID- 10767116
TI - Thrombin Generation in Patients with Acute Myocardial Infarction Treated with
Front-Loaded rt-PA and Recombinant Hirudin (HBW 023).
AB - Thrombin contributes to the pathogenesis of acute myocardial infarction and
reocclusion after thrombolysis. Thrombolytic therapy is known to induce a
paradoxic increase in thrombin generation. Specific thrombin inhibition enhances
thrombolytic therapy in experimental models. The aim of this study was to
determine thrombin generation in patients with acute myocardial infarction
treated with rt-PA and conjunctive therapy with the specific thrombin inhibitor,
recombinant hirudin. Thrombin generation was determined in 17 patients with acute
myocardial infarction treated with front-loaded rt-PA (100 mg/90 min) and
conjunctive therapy with recombinant hirudin (HBW 023 bolus 0.4 mg/kg, infusion
of 0.15 mg/kg/h) over 48 hours. Mean free hirudin plasma levels of 1320-1545
ng/mL produced a stable anticoagulation with mean aPTT values between 63 and 81
seconds throughout the treatment period. Thrombin generation increased during
thrombolysis, indicated by a transient elevation of prothrombin fragment 1.2
levels, which were 3.0 nmol/L at baseline, 11.1 nmol/L after 30 minutes, 8.3
nmol/L after 60 minutes, 3.1 nmol/L after 12 hours, and 1.5 nmol/L after 24
hours, respectively. In contrast, thrombin-antithrombin III complex levels during
and after thrombolysis did not exceed the baseline level of 21.8 ug/L. Thrombin
hirudin complex levels increased constantly during the 48-hour treatment period
from 3.1 ug/L at baseline to 64.2 ug/L. All patients had an open infarct vessel
(TIMI 2/3 potency) after 36-48 hours. Thrombolysis with rt-PA is associated with
a significant increase in thrombin generation, which is not blocked by r-hirudin,
whereas circulating thrombin seems to be effectively inhibited by r-hirudin.
PMID- 10767117
TI - Where Are we with Vitamin E?
AB - Oxidative modification of low-density lipoproteins appears to significantly
enhance their role in atherogenesis. Inhibition of this process with naturally
occurring antioxidants has been proposed as a mechanism to retard the progression
of coronary artery disease. Vitamin E has been among those natural antioxidants
found to reduce atherosclerotic lesion formation in animal models. Further
supported by a substantial accumulation of observational epidemiologic data
demonstrating an association between antioxidant vitamin intake and reduced risk
of cardiovascular mortality, vitamin E has been examined in a number of case
control and prospective cohort studies as a potential agent in the primary and
secondary prevention of morbidity and mortality from coronary artery disease.
These efforts have generated a large body of evidence suggesting a protective
role, but conflict in the data remains. In addition, even with large, well
conducted prospective epidemiologic studies, the potential effects of residual
confounding may be on the same order of magnitude as the reported benefit. The
several small randomized interventional trials and two larger placebo-controlled
studies that have been completed to date leave some key questions unanswered.
Currently ongoing are several large randomized interventional trials that will
serve to further clarify the role of this promising agent in the primary and
secondary prevention of atherosclerotic coronary disease.
PMID- 10767118
TI - Thrombin: Structure, Biochemistry, Measurement, and Status in Clinical Medicine.
AB - Thrombin remains a molecule of great interest to scientists and clinicians alike
because of its important role in hemostasis, thrombosis, inflammation and
vascular remodeling. Yet one of the great challenges has been the inhibition of
thrombin generation to a degree that minimizes intravascular thrombosis while
preserving physiologic hemostasis. It has become increasingly clear that high
levels of anticoagulation with either direct or indirect thrombin antagonists are
not beneficial and, in fact, are quite detrimental. Despite the overwhelming
shift of interest toward the platelet in clinical trials of acute coronary
syndromes, much can be gained through further investigation of coagulation
processes responsible for thrombin generation and activity.
PMID- 10767119
TI - Effect of Shear Stress on Acute Platelet Thrombus Formation in Canine Stenosed
Carotid Arteries: An In Vivo Quantitative Study.
AB - We investigated the in vivo effect of percent stenosis, trans-stenotic pressure,
and shear stress (SS) on platelet accumulation (PA) in canine mechanically
injured and stenosed carotid arteries. In 10 dogs, intimal damage and controlled
variations in stenosis were produced on the carotid artery. Blood flow through
the stenosis, trans-stenotic pressure, and stenosis geometry were measured. A NaI
gamma detector was collimated and placed over the stenosis to detect gamma rays
emitted by autologous radiolabeled platelets as they accumulated inside the
stenosis. The SS was obtained from the finite difference solution of the Navier
Stokes equations. As the flow declined during thrombus formation, the radioactive
count accumulated in an inverse fashion. The rate of flow decline directly
correlated with the rate of PA during thrombus formation (r(2) > 0.9). Compared
with the undamaged and unstenosed artery, the PA increased by 52 +/- 34% due to
mild stenosis (40-60%). PA increased by 94 +/- 66% due to severe stenosis (60
70%) and by 145 +/- 56% due to critical stenosis (70-80%; P > 0.01). The platelet
accumulation produced totally occlusive thrombus formation at levels of stenosis
higher than 70 +/- 5% (diameter narrowing), and for trans-stenotic pressure
gradients higher than 50 +/- 5 mmHg producing SS greater than 100 +/- 10 Pa. The
PA was maximum at the stenotic portion of the vessel where the level of SS is the
highest (P < 0.001). In vivo platelet-mediated thrombosis increases with SS and
occurs at the stenotic portion of the stenosis where the SS is the highest.
Severe stenoses produce critical levels of SS that potentiate thrombosis and lead
to life-threatening arterial occlusion.
PMID- 10767120
TI - Effect of Poloxamer 188 on Collateral Blood Flow, Myocardial Infarct Size, and
Left Ventricular Function in a Canine Model of Prolonged (3-Hour) Coronary
Occlusion and Reperfusion.
AB - Poloxamer 188 is a surfactant with hemorheological, antithrombotic, and
neutrophil-inhibitory properties. This agent has been demonstrated to reduce
infarct size and to improve left ventricular function in animal models of
myocardial infarction and reperfusion, and recently in a randomized trial of
patients receiving thrombolytic therapy for acute myocardial infarction. In
addition to reducing reperfusion injury, poloxamer 188 might be beneficial by
increasing collateral blood flow. The purpose of this study was to determine the
effect of poloxamer 188 on collateral blood flow, myocardial infarct size, and
left ventricular function in a canine model of prolonged (3 hours) coronary
occlusion and reperfusion. Closed-chest dogs (n = 21) underwent a 3-hour coronary
occlusion and 3 hours of reperfusion. At 1 hour of occlusion, dogs received
poloxamer 188, 75 mg/kg IV bolus, followed by 150 mg/kg/h IV for the final 2
hours of coronary occlusion and throughout reperfusion, or a saline placebo.
Regional myocardial blood flow was measured using colored microspheres.
Myocardial infarct size and area at risk were determined by postmortem
histochemical staining. Compared with controls, poloxamer 188-treated dogs showed
no significant increase in collateral blood flow during the final 2 hours of a 3
hour coronary artery occlusion. In addition, poloxamer 188 treatment had no
beneficial effect on infarct size or left ventricular function in this model.
Increased collateral blood flow is unlikely to be a beneficial mechanism of
poloxamer 188 in myocardial infarction. These data also question the benefit of
this agent to reduce reperfusion injury in the setting of more prolonged (3-hour)
coronary occlusion.
PMID- 10767121
TI - Bleeding Complications and INR Control of Combined Warfarin and Low-Dose Aspirin
Therapy in Patients with Unstable Angina and Non-Q-Wave Myocardial Infarction.
AB - The purpose of this study was to compare bleeding complications in patients with
non-Q-wave myocardial infarction and unstable angina receiving combination
therapy with aspirin plus warfarin versus aspirin alone. A post-hoc analysis was
performed on patients enrolled in the Antithrombotic Therapy in Acute Coronary
Syndrome (ACTACS) study, which was a prospective, randomized, multicenter trial
of antithrombotic therapy in unstable angina or non-Q-wave myocardial infarction.
A total of 358 patients admitted within 48 hours of chest pain were randomized to
antithrombotic therapy with either (1) aspirin alone or (2) aspirin (162.5 mg)
plus heparin followed by aspirin plus warfarin, and were prospectively followed
up for 12 weeks. Major and minor bleeding episodes, hemoglobin levels, and
prothrombin times or INR levels were prospectively recorded. Major bleeding
episodes were subclassified as relating to CABG/PTCA or not. The rate of major
bleeding complications not associated with CABG or PTCA was 2.0%, and did not
differ between therapy assignments. Among 55 patients undergoing CABG, 29 (53%)
required transfusion of two or more units of blood. Minor bleeding was also
infrequent (2.8%). All patients with minor bleeding had a full clinical recovery,
and only one patient with a major bleed resulted in minor disability. Warfarin
was well managed, with 50% of INRs falling between 1.9 and 2.7. Combination
therapy with low-dose aspirin and warfarin (INR mean 2.5) produces an
insignificant rise in the incidence of major and minor bleeding. These events are
infrequent and do not usually result in major disability. The effect of longer
duration combination therapy remains to be determined.
PMID- 10767122
TI - Effects of Marine Fish Oils on the Anticoagulation Status of Patients Receiving
Chronic Warfarin Therapy.
AB - The purpose of this placebo-controlled, randomized, double-blinded, parallel
study was to determine the existence and magnitude of effect of various doses of
fish oil supplements on International Normalized Ratio (INR) determinations in
patients receiving chronic warfarin therapy. Patients from anticoagulation
clinics from both the Brady Green Community Health Center and Audie L. Murphy
Veterans Administration in San Antonio, Texas were enrolled in the study. The
enrolled subjects included 5 males and 11 females, all of whom were receiving
chronic warfarin therapy for indications requiring oral anticoagulation. All
enrolled patients underwent a 4-week placebo monitoring period in which INRs were
determined on a weekly basis. If the INRs were found to be stable, patients were
randomized to receive a 4-week treatment period of either placebo capsules (n =
6), 3 grams of fish oil daily (n = 5), or 6 grams of fish oil daily (n = 5).
Patients were followed on a twice-weekly basis for INR determinations and adverse
reactions. Five patients were discontinued from the study due to noncompliance
(2) and unstable INRs (3). There was no statistically significant difference in
INRs between the placebo lead-in and treatment period within each group (P =
0.82). There was also no difference in INRs found between groups (P= 0.41). One
bruising episode was reported, yet no major bleeding episodes were observed
during the study. Fish oil supplementation in doses of 3-6 grams per day does not
seem to create a statistically significant effect on the anticoagulation status
of patients receiving chronic warfarin therapy.
PMID- 10767123
TI - Angiotensin-Converting Enzyme Gene Polymorphism and Plasminogen Activator
Inhibitor 1 Levels in Subjects with Cerebral Infarction.
AB - It has been suggested that the insertion/deletion (I/D) polymorphism of the
angiotensin-converting enzyme (ACE) gene is an independent risk factor for
coronary artery disease, but its relation to cerebral infarction is still
controversial. Plasminogen activator inhibitor 1 (PAI-1) is also a predictor of
risk of atherothrombotic disease. In this study we investigated the association
of the ACE gene polymorphism and plasma PAI-1 levels in subjects with cerebral
infarction. We evaluated the genotype of the ACE gene in 26 subjects with and 28
subjects without a history of ischemic stroke. The ACE genotype was analyzed by
the polymerase chain reaction. Plasma PAI-1 antigen levels were measured by
ELISA. There were no differences in accepted risk factors between the groups with
or without cerebral infarction. However, the frequency of the D allele was
significantly higher in subjects with cerebral infarction (0.63) than in those
without infarction (0.39) (chi(2) = 6.306, P = 0.012). The frequency of the DD
genotype of the ACE gene was also significantly higher in subjects with than in
those without cerebral infarction (DD: 46.2%, ID: 34.6%, II: 19.2% vs. DD: 14.3%,
ID: 50.0%, II: 35.7%, chi(2) = 6.689, P = 0.035). Plasma PAI-1 levels were not
significantly different between groups with and without cerebral infarction.
There was no association between the ACE genotype and PAI-1 levels. The DD
genotype of the ACE gene is associated with cerebral infarction, which is
independent of plasma PAI-1 level.
PMID- 10767125
TI - Preface.
PMID- 10767124
TI - The Laboratory of Hypercoagulability: A Review of Present-Day Techniques.
PMID- 10767126
TI - Practices in the Prevention of Venous Thromboembolism.
AB - Objective: The objective of this study was to determine the proportion of
Massachusetts Medicare patients who received prophylaxis for venous
thromboembolism following colectomy, hysterectomy, or total hip arthroplasty.
Sample frame: All 90 Massachusetts acute care hospitals. Time frame: 1 April
through 30 September, 1994. Target population: Patients discharged with an
International Classification of Disease (ICD-9-CM) discharge diagnostic code
(recorded in the Massachusetts Medicare Claims Database) for colectomy,
hysterectomy, or total hip arthroplasty were used to identify the target patient
population. Sample population: 1,397 patients randomly selected from the target
population, including 467 total hip arthroplasties, 474 colectomies, and 456
hysterectomies. Data extraction: Medical records were reviewed by trained nurse
abstractors who collected information on the use of prophylaxis for venous
thromboembolism. Results: Prophylaxis for venous thromboembolism was employed by
surgeons practicing in Massachusetts hospitals in 93% of total hip arthroplasty
cases (regional variation 85-98%), 84% of colectomies (regional variation 57
93%), 66% of hysterectomies (regional variation 35-71%), and in 87% of the subset
of 111 hysterectomies with malignancy (regional variation 25-100%). Conclusions:
The results of this statewide study demonstrated significant regional and
hospital-to-hospital variation in the use of prophylaxis for venous
thromboembolism following major surgery. A lower rate of prophylaxis use was
observed in hospitals with fewer than 200 beds and in hospitals that did not have
teaching programs. Hospitals with below-average rates of prophylaxis were
targeted for intensive quality improvement interventions.
PMID- 10767128
TI - Optimal Frequency of Patient Monitoring and Intensity of Oral Anticoagulation
Therapy in Valvular Heart Disease.
AB - The antithrombotic effect of oral anticoagulation therapy and the incidence of
anticoagulant-related bleeding complications are both closely correlated with the
intensity of treatment. The optimal intensity of oral anticoagulation for an
individual patient is the target INR that results in the lowest incidence of
thromboembolic plus bleeding complications. For patients with native valve
lesions, one must consider the cardiac morphology and pathophysiology, for
example, the etiology of the disease, left atrial diameters, loss of active
atrial contraction (atrial fibrillation), left ventricular pump function, and
left ventricular diameters, to determine an optimal INR target. In patients with
prosthetic devices, the "thrombogenicity" of the heart valve prosthesis is an
additional risk factor for intracardiac thrombus formation and thromboembolic
episodes. This "thrombogenicity" may vary significantly from device to device.
INR self-testing improves the overall prognosis of patients on lifelong oral
anticoagulation therapy because patients remain more precisely within that target
therapeutic INR range. For most patients under phenprocoumon, one to two INR
measurements per week are a sufficient frequency to provide a stable intensity of
anticoagulation.
PMID- 10767127
TI - Anticoagulation Management as a Risk Factor for Adverse Events: Grounds for
Improvement.
AB - Oral anticoagulation therapy has a high risk/benefit profile because of its
narrow therapeutic index and the influence of concomitant patient
characteristics. The manner in which oral anticoagulation is managed is seldom
mentioned as a risk factor for adverse events, but recent studies identify it as
such. There are two general models of anticoagulation management, characterized
as routine medical care and coordinated care. The literature suggests a rate of
major hemorrhage of approximately 10% under the former model, compared with
approximately 3.5% under the latter model. Similar, if not greater, differences,
are seen for the rate of thrombotic events ( approximately 12% vs. 3.5%). Because
of fewer adverse events, coordinated care results in cost savings due to reduced
hospitalizations and emergency room visits. If the full benefit of
anticoagulation is to be gained, there is a strong rationale for the development
and promotion of anticoagulation management services.
PMID- 10767129
TI - Patient Self-Management of Oral Anticoagulant Therapy: An International Update.
AB - The clinical use of oral anticoagulant therapy has been complicated by the
necessity for frequent determinations of the prothrombin time (PT) to ensure
safety and therapeutic efficacy. This requirement has often imposed a significant
burden on both providers and patients. In 1985 a German patient, Heike Moller
Jung, initiated her own patient self-testing (PST) and patient self-management
(PSM). Today there are over 15,000 patients in Germany managing their oral
anticoagulant therapy with PSM options. Pilot PST and PSM programs are in place
in many other countries. In the United States, two devices have recently been
approved for PST. This method of monitoring has been shown to be as accurate as
that of traditional central laboratory PT determinations, to improve the amount
of time patients are within the therapeutic INR range, and to decrease the
incidence of adverse events associated with anticoagulant therapy.
PMID- 10767130
TI - Outpatient Therapy of Deep Vein Thrombosis.
AB - The initial treatment of acute venous thrombosis using low-molecular-weight
heparin (LMWH) in the outpatient setting has been shown to be feasible,
effective, and safe for selected patients when compared with in-hospital
treatment using continuous intravenous heparin. There will always be a
significant population of patients, however, who require in-hospital treatment
with either LMWH or unfractionated heparin. It is clear that substantial cost
savings can be achieved with the out-of-hospital treatment of venous thrombosis,
but several logistic problems require solutions before these savings can be
realized. Numerous strategies, including the development of anticoagulation
management clinics, are under review, especially for the management of arterial
or venous thrombosis with LMWH. It is likely that the outpatient management of
venous thrombosis will vary, depending on the referral base of the institution
involved.
PMID- 10767131
TI - Platelet Inhibition in Cardiovascular Disease Management: Aspirin and Beyond.
AB - Intracoronary thrombosis is the central event in the pathophysiology of the acute
coronary syndromes and of the complications of percutaneous coronary
intervention. Hemostasis and thrombosis involve a complex series of interactions
of both platelets and the coagulation system. Standard antithrombotic therapy for
cardiovascular disease typically combines use of antiplatelet therapy with
aspirin and antithrombin therapy with heparin. Ticlopidine appears to be a
reasonable alternative as an antiplatelet agent in the patient who is intolerant
of aspirin. The combination of ticlopidine and aspirin may be especially
effective in preventing coronary events in the post-coronary stenting patient.
Clopidogrel may offer incremental benefit beyond aspirin in a broad array of
vascular diseases, but the cost effectiveness of such a strategy remains to be
determined. Finally, potent antiplatelet therapy with platelet glycoprotein
IIb/IIIa receptor inhibition clearly improves angioplasty outcomes and may have a
role in the treatment of patients with acute coronary syndromes.
PMID- 10767132
TI - Antithrombotic Therapy in Stroke Prevention and Treatment: A Review.
AB - Current knowledge of antithrombotic therapy based on controlled clinical trials
has revolutionized the way clinicians approach stroke prevention and treatment.
This review article addresses the pathogenesis of stroke and summarizes
information from clinical trials regarding the use of antiplatelet agents,
heparin, warfarin (particularly in nonvalvular atrial fibrillation), and
thrombolytics in stroke prevention and treatment.
PMID- 10767133
TI - The View from the Inside: Personal Reflections.
PMID- 10767134
TI - Workshop: Credentialing of Anticoagulation Providers: A Proposed Model.
AB - The winter 1997 survey of Anticoagulation Forum members identified a strong
desire for an anticoagulation provider certification program. The Anticoagulation
Provider Certification Working Group (APCWG) is a multidisciplinary committee
formed (1) to develop the objectives and process required to achieve the
competencies for anticoagulation therapy providers, (2) to propose a framework
for a national certification process that validates achievement of
anticoagulation therapy provider competencies, and (3) to create a reproducible
educational framework for all clinicians involved with anticoagulation therapy.
The APCWG assessed the need for credentialing the levels of mastery expected of
anticoagulation providers, identified key elements of a certification program,
assessed published anticoagulation provider competencies, studied elements of a
successful regional credentialing program, proposed core anticoagulation domains
of knowledge and associated competencies, and solicited and incorporated broad
based multidisciplinary feedback on such domains and competencies. As a result,
the APCWG has developed a draft of five knowledge domains:
physiology/pathophysiology of thromboembolic disorders, patient assessment and
management, patient education, pharmacology of antithrombotic agents, and
operational processes surrounding the coordinated care of an anticoagulated
patient. These draft domains of knowledge and the accompanying list of detailed
competencies were distributed to all attendees of the May 1997 Anticoagulation
Forum Meeting for review and feedback. The plan is to incorporate comments and
revise the documents, develop and pilot a certification process, and present the
results of the pilot(s) to a national organization to serve as a foundation of a
valid and accepted national certification process.
PMID- 10767135
TI - Workshop: Patient Self-Management: Update of Ongoing Studies in Sweden.
AB - Anti-vitamin K (AVK) therapy (e.g., warfarin) requires regular blood tests for
adequate dosing of the drug. The therapeutic window for these drugs is narrow,
with a risk of bleeding if the dose is too high and of thrombotic complications
if the dose is too low. Moreover, the required dose to achieve an optimal level
of anticoagulation is individual and depends on such factors as the general
health of the patient, food intake, and concomitant medication. Although control
requires regular monitoring, most patients are reluctant to visit an
anticoagulation clinic (ACC) more than 6-12 times yearly because each visit costs
the patient both money and time. The development of prothrombin time (PT)
monitors that are simple to operate and highly portable has made self-management
possible for large groups of patients on long-term AVK therapy. Self-management
increases the safety of AVK therapy through frequent testing (3-4 times per
month) and timely dose adjustments when they are indicated. The concept of self
management of AVK therapy was introduced in Germany a decade ago with great
success. Swedish patient education in self-management was started in September
1996. As of May 1997, 38 patients have completed the training program, 37 of whom
have continued with self-management. Experience with the first seven groups of
patients has convinced us that self-management is possible and has great
potential. Randomized controlled studies are needed to determine the cost
effectiveness of self-management with regard to a reduction in bleeding and
thrombotic complications.
PMID- 10767136
TI - Workshop: Developing an Agenda for Anticoagulation Management Research.
PMID- 10767138
TI - Alexei Scheludko (1920-1995).
PMID- 10767139
TI - Structure and Rheology of Simulated Gels Formed from Aggregated Colloidal
Particles.
AB - Soft, elastic, solvent-rich materials made from networks of aggregated colloidal
particles are called particle gels. The networks may be regarded as being
permanent or transient depending on whether the short-range attractive forces
between the particles arise from strong irreversible bonding or weak reversible
interactions. Understanding the relationships between the interparticle forces
and the structure and rheology of particle gels is a challenging problem. This
article shows how useful insight is being provided by Brownian dynamics
simulations involving systems of spherical particles interacting with a
combination of bonded and nonbonded interparticle potentials. Copyright 2000
Academic Press.
PMID- 10767140
TI - Solubilization of Hydrophilic Compounds in Copolymer Aggregates.
AB - The solubilization of five hydrophilic water-soluble aroma compounds in self
aggregating triblock amphiphilic copolymers of poly(ethylene oxide)
poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), with similar
percentages of PEO and different molecular weights, was studied. The five
hydrophilic compounds (diacetyl, 2-methylpyrazine, pyrrole, furfural, guaiacol)
were carefully selected to represent hydrophilic molecules with a similar
molecular weight and molecular volume, but with different abilities to interact
with the micellar core of PPO moieties and with the PEO palisade side chains. It
was found that the solubilized solute mole fraction increased and the aggregate
water partition coefficients of the solutes decreased with increasing free solute
concentration in the aqueous phase. The partition coefficients were smaller than
those obtained for hydrophobic compounds and equilibrium was reached at lower
solubilization values. Guaiacol was the least hydrophilic molecule and had the
highest partition coefficient. Diacetyl was the most water-soluble compound and
exhibited the smallest partition coefficient. The data reveal that the higher
molecular weight polymers solubilized more solute than the low-molecular-weight
polymers. Moreover it is supposed that at low solute concentrations, guaiacol
(containing a hydroxyl electron acceptor group) penetrates the core of the
micelle and displaces water while at more elevated concentrations it seems to be
solubilized in the micelle corona. Diacetyl, the most hydrophilic solute
investigated (consisting of electron donor groups), prefers mainly the corona
since its affinity for the polymeric core is very weak. The solubilization occurs
in the palisade layer and the partition coefficient is independent of the free
solute concentration. Selective site (palisade vs core) solubilization of
hydrophilic compounds in polymeric micelles can be a powerful tool to protect
sensitive materials from reactants present in the continuous water phase and to
conduct surface-sensitive organic reactions. Furthermore, selective release
properties of reactants and products can be designed. Copyright 2000 Academic
Press.
PMID- 10767137
TI - Plasticity in adult cat visual cortex (area 17) following circumscribed monocular
lesions of all retinal layers.
AB - 1. In eight adult cats intense, sharply circumscribed, monocular laser lesions
were used to remove all cellular layers of the retina. The extents of the retinal
lesions were subsequently confirmed with counts of alpha-ganglion cells in
retinal whole mounts; in some cases these revealed radial segmental degeneration
of ganglion cells distal to the lesion. 2. Two to 24 weeks later, area 17
(striate cortex; V1) was studied electrophysiologically in a standard
anaesthetized, paralysed (artificially respired) preparation. Recording single-
or multineurone activity revealed extensive topographical reorganization within
the lesion projection zone (LPZ). 3. Thus, with stimulation of the lesioned eye,
about 75 % of single neurones in the LPZ had 'ectopic' visual discharge fields
which were displaced to normal retina in the immediate vicinity of the lesion. 4.
The sizes of the ectopic discharge fields were not significantly different from
the sizes of the normal discharge fields. Furthermore, binocular cells recorded
from the LPZ, when stimulated via their ectopic receptive fields, exhibited
orientation tuning and preferred stimulus velocities which were indistinguishable
from those found when the cells were stimulated via the normal eye. 5. However,
the responses to stimuli presented via ectopic discharge fields were generally
weaker (lower peak discharge rates) than those to presentations via normal
discharge fields, and were characterized by a lower-than-normal upper velocity
limit. 6. Overall, the properties of the ectopic receptive fields indicate that
cortical mechanisms rather than a retinal 'periphery' effect underlie the
topographic reorganization of area 17 following monocular retinal lesions.
PMID- 10767141
TI - Light Scattering Study of the Effect of n-Butanol on the Micellar Properties of
Undecylammonium Chloride in Aqueous Electrolyte Solutions.
AB - Light scattering measurements have been performed on aqueous solutions of
undecylammonium chloride in the presence of 0 to 0.2 mol dm(-3) NaCl and 0 to 0.5
mol dm(-3) n-butanol at 25 degrees C. The critical micelle concentration (CMC),
aggregation number, and degree of dissociation of the micelles have been
determined. The observed decrease of the CMC with the increase of the n-butanol
concentration was explained by the effect of the n-butanol on water structure and
by the selective solvation of the micelles with n-butanol, which counteract the
decrease of the polar character of the solvent caused by n-butanol addition. An
observed increase in the degree of dissociation of the micelles and a decrease in
the aggregation number following alcohol addition have been explained by
considering the effect of this additive on the electrostatic and other
interactions involved in free energy of micellization. Our results support the
concept of opposing effects between n-butanol and NaCl on the cooperativity in
the micellization process of this surfactant, with the n-butanol disfavoring
micellar growth. Copyright 2000 Academic Press.
PMID- 10767142
TI - Solubilization Site of Organic Perfume Molecules in Sodium Dodecyl Sulfate
Micelles: New Insights from Proton NMR Studies.
AB - The site of incorporation of solubilizates in sodium dodecyl sulfate (SDS)
micellar systems has been investigated by proton NMR spectroscopy. The
solubilizate molecules chosen for the present study are phenol, 4-methylphenol, 4
allyl-2-methoxyphenol, anisole, 4-methylanisole, 4-propenylanisole, 1,8-cineole,
and limonene. These molecules possess a wide variety of functional groups with
different degrees of hydrophilic/hydrophobic character and are thereby
solubilized at different micellar locations. Aromatic compounds, especially those
having a phenolic-OH group, showed a large upfield shift of SDS methylene protons
that are closely linked to the terminal sulfate groups. Additionally, in the case
of phenolic compounds, the unresolved signals of the nine straight-chain bulk
methylene protons of SDS are split into a broad doublet with uneven intensity.
This splitting of methylene protons was found to be dependent on the
concentration of the substrate. Based on these observations, probable
solubilization sites and orientation of the substrate molecule within the
micelles are discussed. Phenolic compounds, being the most hydrophilic among the
present set, reside at the hydrophilic/hydrophobic boundary of micelle-water
interface and thus influence the resonances of SDS protons the most. Aromatic
methoxy and aliphatic compounds, being relatively more hydrophobic in nature,
reside inside the micellar core and thereby result in smaller shifts. Copyright
2000 Academic Press.
PMID- 10767143
TI - Magnetic Hetero-flocculation of Paramagnetic Colloidal Particles.
AB - The feasibility of a high-gradient magnetic separation process, utilizing
magnetite as the energizable element in lieu of stainless steel wool, is
evaluated by means of an equilibrium, two-particle, magnetic hetero-flocculation
model. The model calculates the net force, defined as the sum of the magnetic,
electrostatic, and van der Waals forces, exerted on a paramagnetic nanoparticle
that is in the proximity of a fixed magnetite particle. Since the nanoparticle
magnetite system is assumed to be in direct contact with the moving fluid, the
influence of the hydrodynamic force on the magnetic attractive force between the
two particles is also explored. This model clearly reveals the ranges and
conditions over which each of these various forces contributes to the net force
relative to Brownian (thermal) motion. The model also reveals the feasibility of
using magnetite particles instead of stainless steel as the energizable element
for high-gradient magnetic separation. Important variables investigated include
the size and surface charge of the particles, the magnetic field, the flow
velocity, the electrolyte concentration, and the magnetic susceptibility of the
nanoparticle. Copyright 2000 Academic Press.
PMID- 10767144
TI - Study of Ligand Substitution Reactions at Pentacyanoferrates(II) in Aqueous Salt
and Micellar Solutions.
AB - The ligand substitution reactions Fe(CN)(5)(4-(t)bupy)(3-) + 4-CNpy and
Fe(CN)(5)(4-(t)bupy)(3-) + pzCO(2)(-) (4-(t)Bupy = 4-tert-butylpyridine; 4-CNpy =
4-cyanopyridine; pzCO(2)(-) = pyrazinecarboxylate) were studied in several
aqueous salt and micellar solutions. Kinetic data in aqueous solutions showed
that the two processes follow a dissociative mechanism, D, and the dependence of
the first-order rate constants on [salt] on electrolyte aqueous solutions allow
the estimation of the activation volumes corresponding to both reactions. Under
true first-order conditions no kinetic micellar effects were found in anionic
(SDS) and nonionic (Triton X-100) aqueous micellar solutions. In cationic
micellar solutions (CTAB, CTAC, and TTAB) small kinetic micellar effects were
found. These were related to the different ionic concentrations and the different
polarity and structure of the Stern layer surrounding the cationic micellar
aggregates, where the reactions take place, with respect to pure water. Copyright
2000 Academic Press.
PMID- 10767145
TI - An Aqueous Polymer Two-Phase System as Carrier in the Spray-Drying of Biological
Material.
AB - This investigation describes a novel concept in the formulation of carrier
systems for the spray-drying of biological materials. As carrier material a
system composed of poly(vinyl pyrrolidone) (PVP) and dextran was used. This
system yields an aqueous two-phase system in which each phase is enriched in one
of the polymers. By varying the composition of the system, the effective
structure of a "stirred" system can be varied, covering the entire range from
dextran continuous to PVP continuous. This facilitates encapsulation of either of
these polymers in a spray-drying operation. In an attempt to investigate the
spray-drying from such a system, the surface composition of the spray-dried
powder obtained from various compositions of the two-phase system was analyzed by
electron spectroscopy for chemical analysis (ESCA), providing information on the
distribution of the polymers in the powder and thus also in the spray droplets.
The two-phase system was applied for the spray-drying of live bacteria. The
survival rate of the bacteria depended on the composition of the two-phase
system. The storage stability of the bacteria in these formulations was
investigated after storage at room temperature under dry conditions for 4 weeks,
and it was found that the survival rate was 10-45%. The results therefore show
that this type of formulation holds promise for future applications for micro
organisms as well as other sensitive biological materials such as proteins.
Copyright 2000 Academic Press.
PMID- 10767146
TI - Spectral Response to Protonation of 4-(4-(4
(Didodecylamino)phenylazo)phenyl)butyric Acid in Its Langmuir-Blodgett Monolayer.
AB - 4-(4-(4-(Didodecylamino)phenylazo)phenyl)butyric acid is synthesized, and its
Langmuir-Blodgett (LB) monolayer is successfully fabricated. The drastic changes
in electronic spectra of this compound are found in acidic solution and in LB
monolayer upon exposure to HCl vapor (mainly the decrease in absorption at 416 nm
and great increase at 540 nm). The UV-visible and infrared spectra reveal a
mechanism of protonation to either azo group or amino group. This phenomenon has
been suggested to have its prospective application in fundamental interfacial
materials for pH sensors. Copyright 2000 Academic Press.
PMID- 10767147
TI - Interaction of Chlorpromazine and Trifluoperazine with Anionic Sodium Dodecyl
Sulfate (SDS) Micelles: Electronic Absorption and Fluorescence Studies.
AB - The characteristics of binding of two phenothiazine antipsychothic drugs,
chlorpromazine (CPZ) and trifluoperazine (TFP), to anionic sodium dodecyl sulfate
(SDS) monomers and/or micelles were investigated using electronic absorption and
fluorescence spectroscopies. Binding constants K(b) and pK(a) values for the
drugs in SDS micelles were estimated using the red shifts of the maximum
absorption and changes in absorption upon alkalization or in the presence of
surfactant. The pK(a) shift of CPZ due to its interaction with SDS micelles is
about 0.7 unit to higher values, as compared to the reported value of pK(a)
obtained in buffer around 9.3. For TFP the pK(a) shift is 0.4 unit to higher
values compared to that in buffer, reported as 4.0. The electronic absorption
spectroscopic data suggest a biphasic interaction as a function of detergent
concentration which is quite dependent of the protonation states of the drugs. In
the case of TFP a very strong binding takes place when the drug is fully
protonated (pH 2.0) and a distinct binding takes place at stoichiometric (low)
surfactant concentrations (interaction via surfactant monomers) and at higher
concentrations (in the presence of micelles). Static fluorescence probe analysis
using pyrene was used to study the nature of the phenothiazine-surfactant
premicellar and self-aggregates. The I(3)/I(1) and I(475)/I(1) ratios associated
to pyrene fluorescence vibronic bands and excimer intensities ratios,
respectively, were monitored for several ratios [SDS]/[drug] and significant
changes, dependent of the drug presence and its protonation state, have been
observed revealing a hydrophobic microenvironment provided by TFP-SDS aggregates
in comparison with CPZ both at pH 7.0 and 4.0. Static anisotropy was also used to
monitor the changes of the self-aggregates and micellar packing in the presence
of the phenothiazine drugs. In aqueous solutions the anisotropy of the
fluorescent probe dipyridamole (DIP) is quite low, being around 0.005 at pH 7.0
and 0.025 at pH 4.0, and the addition of detergent leads to an increase in the
values of anisotropy to 0.030 at pH 7.0 and 0.070 at pH 4.0. In the presence of
the phenothiazine drugs, and in the premicellar detergent concentration range,
the anisotropy of DIP increases to 0.134 and 0.111 (dependent on drug
concentration) for CPZ and TFP, respectively, at pH 4.0. These results suggest
that the presence of both phenotiazine drugs makes the premicellar aggregates
more rigid by decreasing the probe mobility, and are consistent with a more polar
localization of the CPZ in the micelles as compared with TFP. At pH 7.0 the
anisotropy changes are smaller, suggesting a slight decrease in CMC induced by
the phenothiazines. Copyright 2000 Academic Press.
PMID- 10767148
TI - Pulsed Electric Linear Dichroism of Triphenylmethane Dyes Adsorbed on
Montmorillonite K10 in Aqueous Media.
AB - Electric linear dichroism (ELD) spectra of two cationic triphenylmethane dyes,
crystal violet (CV) and malachite green (MG), bound to sodium montmorillonite K10
(MK-10) were studied at 20 degrees C in aqueous media at two mixing ratios, D/S,
of 0.10 and 0.24 in the 700- to 400-nm wavelength region and in the applied
electric field strength range between 0 and 3 kV/cm. The specific parallel and
perpendicular dichroism (Delta A( ||)/A and Delta A( perpendicular)/A) spectra of
dye-adsorbed MK-10 suspension were measured at a fixed field strength with an
apparatus equipped with a 512-channel photodiode array detector. By changing the
field strength over a wide range, a series of the reduced dichroism values of the
bound dyes were measured at a fixed wavelength. By fitting these dichroism values
to theoretical orientation functions, the intrinsic reduced dichroism (Delta
A/A)(int) spectra at the limiting high fields (ELD spectrum) were determined for
CV and MG bound to MK-10. No appreciable difference was observed at the two D/S
values. The ELD spectra of these bound dyes are undulatory but never constant,
throughout their absorption region; thus, the dye plane does not lie flatly
either on the surface or between layers of MK-10 particle. The isotropic
absorption spectra, A, of bound CV and MG were each deconvoluted to eight partial
absorption bands, which were grouped into three differently polarized
transitions, i.e., one out-of-plane and two mutually perpendicular in-plane. The
optical transition dipole moment direction of each group was found to make a
considerable angle with respect to the symmetry axis of the disklike MK-10
particle, whose plane (or surface) tends to orient toward the applied electric
field at the limiting high fields. By simulating the observed ELD spectra of
bound CV and MG with those deconvoluted bands, the roll, tilt, and inclination
angles of both dyes were evaluated quantitatively with a new analytical method.
The average angles (+/-θ(R), +/- θ(T), |θ(N)|) are -(34-47)
degrees, 34 degrees, and 51 degrees for bound CV and -44 degrees, 32 degrees, and
53 degrees for bound MG at two D/S values; thus, the triangular plane of each dye
is rolled as well as tilted with a large inclination angle. Copyright 2000
Academic Press.
PMID- 10767149
TI - Fluoride Adsorption on Goethite in Relation to Different Types of Surface Sites.
AB - Metal (hydr)oxides have different types of surface groups. Fluoride ions have
been used as a probe to assess the number of surface sites. We have studied the
F(-) adsorption on goethite by measuring the F(-) and H(+) interaction and F(-)
adsorption isotherms. Fluoride ions exchange against singly coordinated surface
hydroxyls at low F(-) concentrations. At higher concentrations also the doubly
coordinated OH groups are involved. The replacement of a surface OH(-) by F(-)
suggests that all F charge (-1) is located at the surface in contrast to
oxyanions which have a charge distribution in the interface due to the binding
structure in which the anion only partially coordinates with the surface.
Analysis of our F(-) data with the CD-MUSIC approach shows that the formation of
the fluoride surface complex is accompanied by a redistribution of charge. This
is supposed to be due to a net switch in the H bonding as a result of the change
of the type of surface complex from donating (FeOH, FeOH(2)) to proton accepting
(FeF). The modeled redistribution of charge is approximately equivalent with the
change of a donating H bond into an accepting H bond. At high F(-) concentrations
precipitation of F(-), as for instance FeF(3)(s), may occur. The rate of
formation is catalyzed by the presence of high electrolyte concentrations.
Copyright 2000 Academic Press.
PMID- 10767150
TI - High-Temperature Adsorption of n-Octane, Benzene, and Chloroform onto Silica Gel
Surface.
AB - The adsorption properties of silica gel surface for compounds differing in types
of intermolecular interactions were studied under conditions in which the same
silica was investigated by means of a "gas phase titration" method, i.e., at high
temperature and low surface coverage. Adsorption isotherms of n-octane, benzene,
and chloroform were determined at 373, 363, and 353 K. Based on these isotherms
the isosteric heat of adsorption was calculated. Moreover, the adsorption energy
distribution function and the derivative of film pressure with respect to the
adsorbed amount were computed from the isotherms determined at 373 K. The
obtained results were compared to those determined by gas phase titration. It was
stated that on the dependencies of film pressure derivative some linear sections
appeared that corresponded to the inflection points on gas phase titration
curves. The results are discussed in terms of both the type and the strength of
surface-molecule interactions. Copyright 2000 Academic Press.
PMID- 10767151
TI - Formation of Copper(II) Thiocyanato and Cadmium(II) Iodo Complexes in Micelles of
Nonionic Surfactants with Varying Poly(ethylene oxide) Chain Lengths.
AB - Formation of copper(II) thiocyanato and cadminum(II) iodo complexes in micelles
of poly(ethylene oxide) (PEO)-type nonionic surfactants with varying PEO chain
lengths of 9.5 (Triton X-100), 30 (Triton X-305), and 40 (Triton X-405) has been
studied by titration spectrophotometry and calorimetry at 298 K. In a given
surfactant solution, all data obtained were analyzed by assuming formation of
ternary complexes MX(n)Y(m)((2-n)+) (M = Cu(II),Cd(II); X = SCN(-), I(-); Y =
surfactant), and the complexes thus form in aqueous phase (m = 0) or in micelles
(m = 1). In the Cu(II)-SCN(-) system, spectrophotometric data obtained by varying
concentrations of the surfactant can be explained well in terms of formation of
Cu(NCS)(2)Y in micelles and Cu(NCS)(+) and Cu(NCS)(2) in an aqueous phase, and it
turned out that formation constant of Cu(NCS)(2)Y increases with increasing PEO
chain length. In the Cd(II)-I(-) system, the formation of CdI(3)Y(-) and
CdI(4)Y(2-) is concluded in micelles, and that of CdI(+), CdI(3)(-), and CdI(4)(2
) in an aqueous phase. Interestingly, formation enthalpies of CdI(3)Y(-) and
CdI(4)Y(2-) become significantly less negative with increasing PEO chain length.
This suggests that transfer of the complexes from aqueous solution to a
hydrophobic octylphenyl (OP) moiety in micelles is significantly more exothermic
than that to a hydrophilic PEO one. Thermodynamic parameters of transfer of
CdI(3)(-) and CdI(4)(2-) from aqueous solution to the OP and PEO moieties of
micelles have been evaluated. Copyright 2000 Academic Press.
PMID- 10767152
TI - Probing Ganglia Dissolution and Mobilization in a Water-Saturated Porous Medium
using MRI.
AB - Magnetic resonance imaging (MRI) is used to probe the evolution of geometric
characteristics such as the volume, shape, surface area, and cluster size of
octanol ganglia trapped in a model porous medium, in this case a packing of
spheres, as they dissolve into a mobile aqueous phase. The resulting pore-scale
information is used to assess various assumptions used in existing models of the
dissolution process. Dissolution of the ganglia was characterized by a reduction
in the overall number of ganglia with little effect on the shape and mean of the
volume distribution of the ganglia. This apparently anomalous result is explained
by dissolution of the ganglia until they reach a critical size, which is
dependent on the structure of the pore space, at which point they are mobilized
and subsequently removed from the porous medium. The shape of the entrapped
ganglia is characterized by a fractal dimension in the range 2.2-2.3, suggesting
that models which assume a Euclidean geometry for the entrapped ganglia are
appropriate. No significant change in the shape of entrapped ganglia is observed
during dissolution. In agreement with the results of earlier workers, most
hydrocarbon ganglia exist as singlets within the pore structure. Copyright 2000
Academic Press.
PMID- 10767153
TI - Different Interactions between Isomeric Tetrakis-(N-Hexadecylpyridiniumyl)
Porphyrins and CdS Nanoparticles.
AB - Using porphyrin amphiphiles TC(16)PyP(2), TC(16)PyP(3), and TC(16)PyP(4) as
photosensitizers, the interaction between amphiphilic porphyrins and colloidal
CdS nanoparticles was studied by observing their absorption spectra, fluorescence
spectra, and fluorescence lifetimes. The experimental results reveal that upon
addition of CdS nanoparticles to a TC(16)PyP(3) or TC(16)PyP(4) solution,
TC(16)PyP(3) or TC(16)PyP(4) is adsorbed onto the surface of the colloidal
nanoparticles due to electrostatic action. The absorption spectra display the
characteristic absorption of metalloporphyrin. Moreover, this adsorption also
leads to red-shifted fluorescence spectra and the quenching of fluorescence
emission. These changes are related to the formation of complexes. Nearly 90% of
the fluorescence emission of 5x10(-6) mol/L TC(16)PyP(4) can be quenched with
6.8x10(-4) mol/L CdS colloid nanoparticles. Only 60% of the fluorescence emission
of 5x10(-6) mol/L TC(16)PyP(3) can be quenched with 6.8x10(-4) mol/L CdS
nanoparticles. The fluorescence quenching is attributable mainly to static
quenching. According to the fluorescence quenching curves, the apparent
association constants of TC(16)PyP(4) and TC(16)PyP(3) with colloidal CdS
nanoparticles are 1.42x10(3) (mol/L)(-1) and 6.76x10(2) (mol/L)(-1),
respectively. However, TC(16)PyP(2) does not adsorb onto the surface of colloid
nanoparticles due to its larger steric hindrance; its absorption and fluorescence
spectra are unchanged. Copyright 2000 Academic Press.
PMID- 10767154
TI - Effect of Polydispersity and Charge Heterogeneity on the Depletion Interaction in
Colloidal Systems.
AB - The effect of polydispersity in the macromolecule size and surface potential on
the depletion attraction and structural repulsion between two charged spherical
particles in a solution of nonadsorbing charged spherical macromolecules was
investigated using a modified form of the force-balance model of J. Y. Walz and
A. Sharma [J. Colloid Interface Sci. 168, 495 (1994)]. The distribution of sizes
and potentials was described by a log-normal distribution with values of the
coefficient of variation (CV) as large as 60%. Comparisons with the case of
purely monodisperse macromolecules were made under the condition of either
constant macromolecule number density, rho(infinity), or constant volume
fraction, φ. For purely hard spheres, polydispersity increases the depletion
attraction at constant rho(infinity) but decreases the interaction at constant
φ. A simple scaling analysis is used to show that these trends are true for
any arbitrary distribution of macromolecule size. Surface charge is found to
amplify the effect of polydispersity at constant φ but actually negates the
effect at constant rho(infinity). The repulsive structural contribution, arising
from the interaction between the macromolecules themselves, is significantly
decreased by polydispersity except for the case of charged macromolecules at
constant rho(infinity), where the effect is relatively small. Finally,
polydispersity in the macromolecule surface potential (no polydispersity in size)
has only a minor effect on both the depletion attraction and structural
repulsion, even for CV values as large as 60%. Copyright 2000 Academic Press.
PMID- 10767155
TI - Wetting of Crystalline Solids by Associating Fluids.
AB - The wetting behavior of Lennard-Jones associating fluid on a crystalline surface
is studied using Monte Carlo simulation in the isobaric-isothermal ensemble. We
explore the structure of the adsorbed film, characterized by the distribution of
all particles and the distributions of centers of mass of dimers, as well as by
orientational distributions of the dimers. The simulations performed indicate the
existence of a prewetting-like behavior of the adsorption isotherm. The results
for a crystalline surface are compared with simular results obtained for a
structureless surface. Finally, we present some density functional theory
evaluations and compare them with the simulation results at a high temperature.
Copyright 2000 Academic Press.
PMID- 10767156
TI - Electrical Double-Layer Structure at the Rutile-Water Interface as Observed in
Situ with Small-Period X-Ray Standing Waves.
AB - X-Ray standing wave (XSW) measurements were made of Rb and Sr adsorbed from
aqueous solutions at the rutile (110)-water interface. These experiments were
performed to address the extent to which direct measurements of electrical double
layer structure are possible. The experimental results show that the Bragg XSW
technique, using small-period standing waves generated by Bragg diffraction from
the substrate, can precisely measure ion locations within the condensed layer and
the in situ partitioning of ions between the condensed and diffuse layers.
Differences in condensed layer ion positions were observed for Sr ions (measured
in situ) as compared with Rb ions (in situ) and also for Sr ions (ex situ). An
additional constraint on the ex situ Sr site geometry was provided by
polarization-dependent surface EXAFS measurements. Such measurements can provide
important constraints for the development and verification of electrical double
layer theory especially as applied to ion adsorption at the solid-water
interface. Copyright 2000 Academic Press.
PMID- 10767157
TI - Hydrodynamic and Colloidal Interactions in Concentrated Charge-Stabilized Polymer
Dispersions.
AB - Hydrodynamic and colloidal interactions are explored in concentrated, charge
stabilized colloidal dispersions by measuring the dependence of rheology (e.g.,
low and high-shear viscosity, high-frequency viscosity, and modulus) and self
diffusivity on salt content, particle size, and concentration. Model, sulfonated
polystyrene lactices of varying diameter are prepared and investigated by shear
rheology, high-frequency torsional resonance, electrophoresis, titration, and
dynamic light scattering. The high-frequency and high-shear viscosity both are
dominated by hydrodynamic interactions, but are shown not to be identical, due to
the microstructure distortion resulting from high shear rates. The short-time
self-diffusion is also shown to be insensitive to direct particle interactions,
but has a different concentration dependence than the high-frequency viscosity,
further illustrating a predicted violation of a generalized Stokes-Einstein
relationship for these properties. The apparent colloidal surface charge is
extracted from the high-frequency elastic modulus measurements on concentrated
dispersions. The surface charge is in good agreement with results from critical
coagulation concentration measurements and perturbation theories, but disagrees
with electrophoretic mobility experiments. This indicates that the effective
surface charge determined by torsional high-frequency measurements is a more
reliable predicter of the salt stability of charge-stabilized dispersions, in
comparison to zeta-potentials determined from electrophoretic mobilities.
Further, we demonstrate by direct comparison that measurements of the apparent
plateau modulus by rotational rheometry underestimate the true, high-frequency
modulus and provide unreliable estimates for the surface charge. Copyright 2000
Academic Press.
PMID- 10767158
TI - A Two-Level, Discrete-Particle Approach for Simulating Ordered Colloidal
Structures.
AB - We devise a new, two-level discrete-particle model to simulate ordered colloidal
structures with vastly different scales. We use the molecular dynamics paradigm
with a Lennard-Jones-type potential to define colloidal particle system and
dissipative particle dynamics (DPD) to model the solvent. The initially mixed,
disordered particle ensemble undergoes a phase transition. We observe the
spontaneous creation of spherical or rod-like micelles and their crystallization
in stable hexagonal or worm-like structures, respectively. The ordered arrays
obtained by using the particle model are similar to the two-dimensional colloidal
crystals observed in laboratory experiments. The micelle shape depends on the
ratio between the scaling factors of the colloid-colloid to colloid-solvent
particle interactions. The properties of the DPD solvent, such as the strongly
variable viscosity and partial pressure, determine the speed of crystallization.
The intriguing features of colloidal arrays and their exotic symmetries, which
persist also over two-dimensional domains, can be simulated numerically by using
the two-level discrete-particle approach and are illustrated here. Copyright 2000
Academic Press.
PMID- 10767159
TI - An Opportunity to Develop Software for Gas/Solid Adsorption Measurements.
AB - It is generally necessary to describe a measured gas/solid isotherm with an
equation including two or three parameters descriptive of the physical properties
of the adsorbent or adsorbate. For this reason it is very important to select the
appropriate isotherm equation. The fitting procedures alone are not sufficient
for this purpose. The function psi(p) is proposed for this aim. This function can
be calculated from the measured isotherms because, based on the implicit form,
psi (p) = (n(s)/p)(dp/dn(s)), a PC can be used to calculate an explicit result.
The explicit function psip) provides exact information on: (i) the
thermodynamically and mathematically appropriate isotherm equation; (ii) the mono
or multilayer domains of the measured isotherms; (iii) the change in free energy
of the surface; and (iv) the specific surface area of the adsorbent. These
calculations can be summarized in software, so it is proposed that this be
applied to adsorption experiments. Copyright 2000 Academic Press.
PMID- 10767160
TI - Water Adsorption on Thin Film Media.
AB - Disk drives experience a wide range of temperature and humidity during storage
and operation. Humidity influences media tribology through the effects of
adsorbed water on the interaction of Zdol lubricant hydroxyl end groups with the
carbon overcoat. We measured the effects of Zdol 4000 thickness and chemisorption
on the water adsorption isotherm and surface energy. The potential distortion
model of Adamson was employed to derive the film thickness at saturation from the
isotherms and contact angles. The isotherm was surprisingly independent of the
Zdol chemisorption and thickness up to 1.8 nm, because, in this range of Zdol
thickness, the adsorbed water resides in pores which exclude the larger Zdol end
groups. The water adsorption isotherm provides a sensitive probe of overcoat
structure due the ability of water to reach pores in the overcoat which are
inaccessible to Zdol. Above a Zdol thickness of 1.8 nm there is a jump in the
water adsorption as additional adsorption takes place on the "free" hydroxyl
groups. The mechanism for the previously observed decrease in Zdol lubricated
media durability at low humidity is derived from the effect of adsorbed water on
Zdol surface diffusion and chemisorption. Copyright 2000 Academic Press.
PMID- 10767161
TI - Diffuse Double-Layer Interaction between Two Identical Spherical Colloidal
Particles.
AB - A simple method is given for calculating the potential energy of the diffuse
double-layer interaction between two identical spherical colloidal particles in a
symmetrical electrolyte solution with the help of Derjaguin's approximation. This
method uses accurate analytic expressions for the corresponding interaction
energy between two parallel similar plates obtained previously (Colloids Surf. A
Physicochem. Eng. Asp. 146, 213 (1999); J. Colloid Interface Sci. 212, 130
(1999)). Agreement with numerical data provided by Honig and Mul (J. Colloid
Interface Sci. 36, 258 (1971)) is excellent particularly for small particle
separations. Copyright 2000 Academic Press.
PMID- 10767162
TI - The Effects of Radiofrequency Electromagnetic Radiation on the Adhesion Behavior
of Aqueous Suspensions.
AB - The effect of radiofrequency treatment on the adhesion behavior of amidine and
carboxylated polystyrene latexes was investigated. The isoelectric points pH(IEP)
of copper and zinc were initially measured as 9.4 and 9.5, respectively, using a
technique proposed by N. Kallay, Z. Torbic, M. Golic, and E. Matijevic [J. Phys.
Chem. 95, 7028 (1991)] based on the attachment of charged colloids to metallic
surfaces in an aqueous medium. Statistical analysis showed that the technique was
repeatable with a coefficient of variation less than 6% and an accuracy greater
than 95%. The effect of a radiofrequency signal (27 MHz) on adhesion behavior was
evaluated and it was found that there was reduced attachment at pH values when
the colloid and metallic surface were oppositely charged and enhanced attachment
between similarly charged particles. It is proposed that this is due to a
reduction in the surface potential of the charged particles due to thickening of
the adsorbed layer by hydrogen and hydroxyl ions. Copyright 2000 Academic Press.
PMID- 10767163
TI - Creaming Stability of Flocculated Monodisperse Oil-in-Water Emulsions.
AB - The influence of droplet flocculation on the creaming stability of monodisperse n
hexadecane oil-in-water emulsions was studied. The creaming velocity of emulsions
with different droplet radii (0.43 and 0.86 um), droplet concentrations (1-67
vol%), and sodium dodecyl sulfate (SDS) concentrations (7-80 mM) were measured.
Depletion flocculation was observed in the emulsions when the aqueous phase SDS
concentration exceeded a particular level ( approximately 40 mM for 0.43-um
droplets and approximately 15 mM for 0.86-um droplets). Creaming was monitored by
measuring the back-scattered light from an emulsion as a function of its height.
The creaming velocity increased with increasing flocculation and decreased with
increasing droplet concentration. These results have important implications for
the formulation of emulsion-based materials. Copyright 2000 Academic Press.
PMID- 10767164
TI - Thickness Measurements of Thin Perfluoropolyether Polymer Films on Silicon and
Amorphous-Hydrogenated Carbon with X-Ray Reflectivity, ESCA and Optical
Ellipsometry.
AB - Experimental techniques used to measure structural parameters of thin films such
as thickness, density, and coverage provide important insights into the physical
properties of these films. Structural parameters are also often used to predict
the eventual performance of thin films. In this study, we use three different
measurement techniques-X-ray reflectivity (XRR), electron spectroscopy for
chemical analysis (ESCA), and optical ellipsometry-to measure the thickness of
molecularly thin perfluoropolyether (PFPE) polymer films on silicon substrates
and carbon overcoats. PFPE films are commonly used to lubricate surfaces in
magnetic recording devices. Here, we use XRR to measure the absolute thickness of
the films, which, in turn, is used to test the validity of ESCA and ellipsometry
thickness measurements. Excellent agreement is found among the three methods,
provided that a 25-A electron mean-free path (MFP) is used for the PFPE film and
the substrate in ESCA (single MFP model), that the bulk PFPE refractive index is
used in ellipsometry, and that adventitiously adsorbed hydrocarbons are properly
taken into account. Copyright 2000 Academic Press.
PMID- 10767165
TI - Adsorption of Sodium Dodecyl Sulfate to Colloidal Titanium Dioxide: An
Electrophoretic Fingerprinting Investigation.
AB - The adsorption of sodium dodecyl sulfate to colloidal titanium dioxide was
investigated using the electrophoretic fingerprinting approach. An
electrophoretic fingerprint is a contour diagram of the observed electrophoretic
mobility as a function of the bulk solution pH and plambda, the log of the bulk
solution conductivity. Surfactant adsorption was observed to be strong under
acidic conditions, as illustrated in the dramatic changes in the electrophoretic
fingerprints. Electrokinetic data were compared with adsorption isotherm data
obtained by a depletion method and good qualitative agreement was found. The
observed pH changes associated with surfactant adsorption suggested ligand
exchange as a possible mechanism of adsorption. Electrophoretic fingerprinting
was shown to be a powerful means of examining surfactant adsorption to colloidal
particles. Copyright 2000 Academic Press.
PMID- 10767166
TI - Electrophoretic Mobility of Soft Particles in Concentrated Suspensions.
AB - A general theory is developed for the electrophoretic mobility of spherical soft
particles (i.e., spherical hard colloidal particles of radius a coated with a
layer of polyelectrolytes of thickness d) in concentrated suspensions in an
electrolyte solution as a function of the particle volume fraction φ on the
basis of Kuwabara's cell model. In the limit d-->0, the mobility expression
obtained tends to that for spherical hard particles in concentrated suspensions,
whereas in the limit a-->0, it becomes that for spherical polyelectrolytes
(charged porous spheres with no particle core). Simple approximate analytic
mobility expressions are derived for the case where relaxation effect is
negligible. It is found that in practical cases, the φ dependence of the
mobility is negligible for d<>a, the mobility strongly
decreases with increasing φ. Copyright 2000 Academic Press.
PMID- 10767167
TI - Investigation of Thin Aqueous Films on Silica Using a Modified Interferometric
Technique.
AB - The thinning behavior of liquid films between free bubbles and silica is
investigated using the interferometric technique. Stable films were obtained at
higher salt concentrations compared to previous studies because of the improved
cleaning procedure. In contrast to the captive bubble technique used in the past,
the free bubble method employed more closely approximates such processes as
flotation. The results obtained for aqueous films at low and high ionic strengths
are in better agreement with theoretical predictions than those in previous
studies. Copyright 2000 Academic Press.
PMID- 10767168
TI - Electroosmotic Flow through an Annulus.
AB - The electro-osmosis through an annulus is investigated. The electric potential
and flow velocity profile are obtained by solving the linearized Poisson
Boltzmann equation and the Stokes equation. Both the thin and thick double layer
limits are analyzed. Under the condition of thin double layer, the electro
osmotic mobility can be described by the Helmholtz-Smoluchowski equation with a
geometry-dependent correction factor. There exist net flows even for zero area
averaged surface charge density due to the curvature differences between the
inner and outer walls. The flow direction is determined by the sign of the charge
on the inner cylinder. We also found that under certain circumstances the flow
direction in an annulus is opposite to that in a capillary with the same sign of
the net charge. Copyright 2000 Academic Press.
PMID- 10767169
TI - Single-Microparticle Injection and Microabsorptiometry: Direct Analysis of
Sorption Processes.
AB - Sorption processes of methylene blue in a single silica gel microparticle in an
aqueous solution was kinetically analyzed by a new technique combined with the
microcapillary injection/manipulation and microabsorptiometry of the single
particle. The observed sorption rates were analyzed in terms of the solute
concentration in water and the particle size. The sorption processes were
governed by diffusion of the solute in the particle. Copyright 2000 Academic
Press.
PMID- 10767170
TI - Silver Nanowires as Templates for Preparation of Amorphous Carbon Nanotubes.
AB - In this report, we describe a novel method for preparing amorphous carbon
nanotubes (ACNT) from silver nanowires using a carbon replica technique. ACNT
size and shape are determined by the template silver nanowire. Interspaces
between carbon grains present in the ACNT wall cause the wall to act as a
permeable membrane through which reactants pass freely. Simple chemical
modifications can be used to modify the diameter of the silver filaments within.
We anticipate that this method will prove useful in preparing a wide variety of
nanometer-sized filaments, perhaps with the replica itself able to serve as a
template in casting nanomaterials of assorted shapes. Copyright 2000 Academic
Press.
PMID- 10767171
TI - Molecular basis of mendelian disorders among Jews.
PMID- 10767173
TI - A heteroallelic mutant mouse model: A new orthologue for human
hyperphenylalaninemia.
AB - Hyperphenylalaninemias (HPA) are Mendelian disorders resulting from deficiencies
in the conversion of phenylalanine to tyrosine. The vast majority are explained
by a primary deficiency of phenylalanine hydroxylase (PAH) activity. The majority
of untreated patients experience irreversible impairment of cognitive
development. Although it is one of the best known hereditary metabolic disorders,
mechanisms underlying the pathophysiology of the disease are still not fully
understood; to this end, the availability of an orthologous animal model is
relevant. Various mutant hyperphenylalaninemic mouse models with an HPA
phenotype, generated by N-ethyl-N'-nitrosourea (ENU) mutagenesis at the Pah
locus, have become available. Here we report a new hybrid strain, ENU1/2, with
primary enzyme deficiency, produced by cross breeding. The ENU1, ENU1/2, and ENU2
strains display mild, moderate, and severe phenotypes, respectively, relative to
the control strain (BTBR/Pas). The Pah enzyme activities of the various models
correlate inversely with the corresponding phenylalanine levels in plasma and
brain and the delay in plasma clearance response following a phenylalanine
challenge. The maternal HPA effect on the fetus correlates directly with the
degree of hyperphenylalaninemia, but only the ENU2 strain has impaired learning.
PMID- 10767172
TI - Structure and analysis of the human dimethylglycine dehydrogenase gene.
AB - Dimethylglycine dehydrogenase (DMGDH; E.C. 1.5.99.2) is an enzyme involved in the
catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine
(DMG) to form sarcosine. Subsequently, sarcosine dehydrogenase (SDH; E.C.
1.5.99.1) converts sarcosine to glycine via a similar reaction. Both enzymes are
found as monomers in the mitochondrial matrix, and both contain 1 mol of
covalently bound flavin adenine dinucleotide. DMGDH and SDH also utilize a
noncovalently bound folate coenzyme that receives the "1-carbon" groups that are
removed by DMGDH and SDH, forming "active formaldehyde." We have recently
described a new inborn error of metabolism of DMGDH characterized by an unusual
fish-like body odor. To augment our study of this new disorder, we have isolated
two human genomic clones that together contain 16 exons of coding sequence for
the hDMGDH gene. Fluorescent in situ hybridization analysis of the hDMGDH gene
indicates that it is found on chromosome 5q12.2-q12.3. In addition, several
polymorphisms have been identified in the hDMGDH cDNA sequence. Population
analysis of two Ser/Pro polymorphisms found 367 amino acids apart reveals a skew
of alleles, with the haplotypes Ser/Pro or Pro/Ser (79%) overrepresented compared
to the number of Ser/Ser or Pro/Pro alleles observed. Possible functional
consequences of these findings are discussed. Characterization of the gene
structure for hDMGDH will aid in the study of patients with inherited defects of
this enzyme.
PMID- 10767174
TI - The correlation of genotype and phenotype in Portuguese hyperphenylalaninemic
patients.
AB - To understand the basis for the clinical heterogeneity of phenylalanine
hydroxylase deficiency among Portuguese hyperphenylalaninemic patients, genotype
phenotype correlations were established. A group of 61 patients was completely
genotyped, leading to the identification of 20 different mutant alleles in 36
different genotypic combinations, including a mutant allele not reported
previously. The severity of those mutations found within this
hyperphenylalaninemic population, which have not been previously expressed in
vitro, were assessed. The results obtained by the present study exhibit a strong
correlation between the predicted residual enzyme activity, as deduced from the
genotype of the patients, and the biochemical phenotype represented by the
diagnostic parameters (phenylalanine levels before the beginning of treatment and
the dietary phenylalanine tolerance). It was observed that only a judicious
follow-up and compliance with the appropriate diet permits the correct assessment
of the clinical phenotype of the patients. Additionally, based upon the
correlation observed between genotypes and diagnostic parameters, it was possible
to predict the potential residual enzyme activity of those mutations (identified
in our patients) which have not yet been studied in vitro.
PMID- 10767175
TI - The V388M mutation results in a kinetic variant form of phenylalanine
hydroxylase.
AB - The molecular mechanism underlying the metabolic defect in phenylketonuria (PKU)
patients carrying the V388M missense mutation of the phenylalanine hydroxylase
(PAH) gene has been characterized. An in vitro prokaryotic expression system has
been used to produce both the wild-type and the mutant form of the human PAH
(hPAH) protein. The recombinant enzymes, obtained as fusion proteins, were
purified by immobilized metal affinity chromatography and recovered in high
yields. The wild-type hPAH possessed a high specific activity and its kinetic
properties were the same as those reported for the enzyme isolated from human
liver and other recombinant wild-type hPAH enzymes. The recombinant V388M mutant
form exhibited a reduced specific activity equivalent to 30% of the wild-type
hPAH enzyme when assayed using the synthetic cofactor (6-methyltetrahydropterin).
Lower values were obtained (23 and 19%) when the mutant enzyme was assayed with
the natural cofactor ((6R)-tetrahydrobiopterin) and different concentrations of l
phenylalanine. The enzyme kinetic studies of the V388M mutant protein revealed
that this enzyme was a kinetic variant form of hPAH with a reduced affinity for l
phenylalanine and for the natural cofactor ((6R)-tetrahydrobiopterin). The
residual activities determined for the V388M form of hPAH were compatible with
the phenotype presented by the PKU patients harboring the V388M mutation in the
PAH gene.
PMID- 10767176
TI - Carrier assessment in families with lowe oculocerebrorenal syndrome: novel
mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular
examination.
AB - Lowe oculocerebrorenal syndrome (OCRL) (MIM 309000) is a rare X-linked
multisystem disorder characterized by congenital cataracts, muscular hypotonia,
areflexia, mental retardation, maladaptive behavior, renal tubular dysfunction,
vitamin-D-resistant rickets, and scoliosis. The underlying gene OCRL1 is located
on chromosome Xq25-q26 and contains 24 exons. It encodes a 105-kDa
phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P(2)) 5-phosphatase that is
localized to the Golgi complex. To confirm the clinical diagnosis and to assess
the carrier state of female relatives for genetic counseling we examined 6
independent patients and their families (a total of 23 individuals) using an
improved mutation screening strategy for the OCRL1 gene by sequencing of large
PCR amplicons. Four novel and two known mutations were identified: three
premature terminations caused by either frameshift mutations (1899insT in exon 17
and 2104-2105delGT in exon 18) or a nonsense mutation (1399C > T in exon 12), two
missense mutations (1676G > A and 1754C > T in exon 15), and a 6-bp deletion
(1609-1614delAAGTAT in exon 14). An ophthalmological examination was performed in
all patients and 14 female relatives. All genotypically proven carrier females
showed characteristic lenticular opacities, while all proven noncarriers were
lacking this phenotypic finding. The results confirm that ophthalmological
evaluation is an apparently reliable first-line method to ascertain the carrier
state in Lowe oculocerebrorenal syndrome. The high expressivity of lenticular
symptoms in OCRL1 gene carriers is consistent with the hypothesis that
(PtdIns[4,5]P(2)) 5-phosphatase activity has low functional reserve capacity for
maintaining a balanced homeostasis of lenticular metabolism.
PMID- 10767177
TI - Screening human EST database for identification of candidate genes in respiratory
chain deficiency.
AB - Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are now recognized
as major causes of human metabolic diseases and several mutations of
mitochondrial and nuclear genes encoding respiratory chain components have been
reported. Interestingly, mutations of nuclear genes involved in mitochondrial
respiratory chain assembly, protein trafficking, and iron metabolism are also
known to alter oxidative phosphorylation. While several hundred of these genes
have been described in yeast, only a few nuclear genes have been hitherto
identified in humans. Yeast gene databases present therefore an invaluable tool
for identification of human homologues that should be regarded as candidate genes
in OXPHOS diseases. In an attempt to identify the human counterparts of yeast
genes, we developed a systematic comparison of yeast protein sequences to the
GenBank dbEST database. Starting from 340 yeast protein sequences as templates,
we searched the human dbEST counterparts using the BLAST similarity searching
program and identified 102 groups of human EST likely to represent orthologues of
yeast genes because of significant homology. This collection of human genes
possibly related to mitochondrial OXPHOS may help identify nuclear genes
responsible of mitochondrial disorders.
PMID- 10767178
TI - Development of the intestinal SGLT1 transporter in rats.
AB - Glucose absorption from the small intestine is largely mediated via the sodium
coupled glucose transporter (SGLT1). The goal of this study was to investigate
the ontogenesis of the SGLT1, using the rat as an animal model at three stages of
development: during lactation, at weaning, and at physiologic maturity. The
techniques involved upper small intestinal perfusions with solutions containing
200 mM glucose and 50 mM NaCl, with or without 1 mM phloridzin (Phl), as an
inhibitor of SGLT1. Molecular expression of the SGLT1 was also investigated via
Western blot analysis from intestinal specimens of the three growth periods.
Glucose absorption in weanling rats, in the absence of Phl, was several times
higher than in sucklings and approximately double that of mature animals, and the
effects of Phl were the greatest in weanlings. Furthermore, the physiologic data
correlate to the molecular analysis of the SGLT1 which showed an increase in
expression of the SGLT1 in both the weanlings and the adults compared to the
sucklings. At all three stages of development Phl abolished Na absorption, and in
sucklings there was a net outflow of Na. Due to the coupling between Na and water
transport, net water absorption and the influx/efflux ratio, a more sensitive
indicator of changes in unidirectional fluid movement, were similarly affected by
Phl at the three stages of development. Net water absorption was highest in
weanling animals. These findings are consistent with an early development of
SGLT1 in rat small intestine and an apparent burst of activity at weaning. Less
than complete maturity of other absorptive mechansims is occurring at this time.
PMID- 10767179
TI - Studies on human porin XXI: gadolinium opens Up cell membrane standing porin
channels making way for the osmolytes chloride or taurine-A putative approach to
activate the alternate chloride channel in cystic fibrosis.
AB - We recently proposed that cell-membrane-integrated vertebrate porin/voltage
dependent anion-selective channel (VDAC) forms part of the outwardly rectifying
chloride channel (ORCC) complex that may be involved in volume regulation. The
results we present here support this thesis. According to light scattering
measurements micromolar concentrations of Gd(3+) induce cell swelling of human
healthy and cystic fibrosis (CF) B-lymphocyte cell lines in isotonic Ringer
solution. In high-potassium Ringer solution additional swelling is observed.
Gd(3+) induces excessive cell swelling of cell lines in hypotonic Ringer
solutions, containing 70 mM NaCl or 135 mM taurine, respectively. The gadolinium
effect is lost when NaCl is replaced by Na-gluconate. Using video camera
monitoring we show that HeLa cells also swell in micromolar concentrations of
Gd(3+) in isotonic taurine Ringer solution. The dose-dependent effect of the
agonist was always blocked by extracellular application of anti-human type-1
porin antibodies. Together with data on a decreasing effect of micromolar amounts
of gadolinium on the voltage dependence of reconstituted human porin the results
prove the involvement of porin channels in the swelling behavior in different
cell lines. As a mechanism we propose that ionic gadolinium opens up plasmalemma
integrated porin channels, chloride or taurine then following their concentration
gradients into the cells. Furthermore, our data argue for a single pathway for
inorganic and organic osmolytes during regulatory volume decrease after cell
swelling. There is indirect evidence that porin forms part of the cystic fibrosis
relevant ORCC channel. Gadolinium thus may work to open the alternate chloride
channel in CF.
PMID- 10767180
TI - Molecular cloning of junctin from human and developing rabbit heart.
AB - Canine junctin is a 26-kDa transmembrane protein found in the sarcoplasmic
reticulum (SR) membrane in cardiac and skeletal muscle. Junctin has recently been
shown to bind directly to calsequestrin, the ryanodine receptor, and triadin.
Junctin is thought to play a role in facilitating (and perhaps regulating) Ca(2+)
release from the SR. Immature heart exhibits decreased utilization of SR Ca(2+)
stores for cell contraction. We have cloned human and rabbit cardiac junctin and
investigated the expression of junctin in developing rabbit heart. Human junctin
was cloned from an adult cardiac cDNA library. Rabbit junctin was cloned by RT
PCR. Northern blot analysis demonstrates a single primary mRNA transcript of
approximately 2.8 kb in hearts from both species. Sequence analysis demonstrates
greater than 97% homology between the predicted amino acid sequences of human,
rabbit, and canine junctin in the putative transmembrane domain and subsequent
initial 61 amino acid portion of the putative luminal domain. These domains also
exhibit sequence homology with triadin. The C-terminal region shows much lower
(72 to 75%) sequence homology among the three species. In addition, Northern blot
analysis demonstrates that the expression of junctin increases markedly in
postnatal rabbit myocardium. These findings suggest that the putative
transmembrane domain and subsequent initial portion of the putative luminal
domain of junctin play an important role in the binding of junctin to
calsequestrin, the ryanodine receptor, and triadin in the postnatal heart.
Furthermore, the previously described increase in SR Ca(2+) release with
development is associated with the increased expression of junctin.
PMID- 10767181
TI - Identification of a novel mutation in patients with medium-chain acyl-CoA
dehydrogenase deficiency.
AB - A novel mutation was identified in two unrelated patients with medium-chain acyl
CoA dehydrogenase deficiency. First, a 19-year-old Caucasian female presented
with a devastating illness, resulting in sudden death in adulthood which is
unusual. The second patient, now a 3.5-year-old male, presented at 17 months of
age with a hypoglycemic seizure and dehydration. Sequence analysis revealed a
novel mutation G617T in exon 8 resulting in an arginine to leucine substitution
at codon 206 (R206L). Both patients were compound heterozygous for this G617T and
the common mutation A985G.
PMID- 10767183
TI - The interstitial pneumonias: understanding the acronyms.
PMID- 10767182
TI - An unexpected affected female patient in a classical Lesch-Nyhan family.
AB - Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by
defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase
(HPRT), resulting from mutation in the corresponding gene on the long arm of the
X chromosome (Xq26). The classical phenotype, which includes spasticity,
involuntary movements, developmental disability, and self-injurious behavior,
occurs exclusively in males, while heterozygous, carrier females are clinically
normal. We analyzed an Argentine family in which there were male and female
siblings with clinically identical classic features of Lesch-Nyhan disease. The
mother and an older daughter were carriers and had normal phenotypes. We
identified the HPRT mutation in the family. It is a C --> T transition at
position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169)
to the TGA stop codon (R169X). The female patient was karyotypically normal and
heterozygous for the mutation. She inherited the HPRT mutation from her mother,
but she also had unexpected nonrandom inactivation of the paternal X chromosome
carrying the normal HPRT gene. This additional genetic alteration is the cause of
the clinical expression of disease in this female patient.
PMID- 10767184
TI - The use of ultrasound in the diagnosis of invasive lobular carcinoma of the
breast less than 10 mm in size.
AB - AIM: To assess the ability of ultrasound to detect small (<10 mm) invasive
lobular carcinoma (ILC) of the breast. Previous reporters have suggested very low
sensitivity rates for identifying these tumours on ultrasound. We reviewed our
own experience to see how our figures compared. MATERIALS AND METHODS: We
retrospectively analysed all cases of pure small ILC diagnosed at Breast Test
Wales over the first 9-year period of the National Health Breast Screening
Programme. All mammograms and ultrasound examinations were reviewed and findings
assessed. We also obtained similar information on small invasive ductal carcinoma
(IDC) for comparison. RESULTS: Sixteen cases of pure small ILC were diagnosed
during the study period. Fourteen of the 15 patients (93%) who underwent an
ultrasound examination had abnormal findings. A definitive pre-operative
diagnosis using ultrasound guided sampling was obtained in all 14 patients. A
larger number of small IDCs (152) were diagnosed during the same study period and
the sensitivity of ultrasound in this group was recorded as 80%. CONCLUSION: Our
findings suggest a much higher sensitivity for ultrasound in the detection of
small ILC than has been previously described. Its use should be encouraged
particularly as it facilitates biopsy and pre-operative diagnosis.
PMID- 10767185
TI - Gastroduodenal obstruction from ovarian cancer: imaging features and clinical
outcome.
AB - OBJECTIVE: The purpose of this study was to describe the imaging features and
clinical significance of gastroduodenal obstruction from ovarian cancer.
MATERIALS AND METHODS: Eleven women with symptomatic gastroduodenal obstruction
were identified over a 3-year period of prospective clinicoradiological review of
cases managed in a specialist gynaecological oncology unit, during which period
438 women with ovarian cancer were managed. Imaging features were verified by
surgery, intervention and clinicoradiological follow-up for a minimum of 12
months or until death. Management and outcome were independently reviewed by a
medical oncologist not involved in primary care. RESULTS: The frequency of
gastroduodenal obstruction was 2.5% (11 of 438 women). Disease stages of these
women at initial diagnosis were: stage II (four women), stage III (six), stage IV
(one). Histology was grade 3 in eight of the 11 women. Symptomatic gastroduodenal
relapse occurred at 9-103 months after initial diagnosis (median 20 months).
There were five cases of predominant involvement of the gastric body and six of
the gastric outlet and duodenum. In six cases, focal mass disease resulted in
obstruction, in two cases there was diffuse gastric invasion, and in three cases
encysted malignant ascites in the lesser sac caused gastric
compression/obstruction - the 'squashed stomach syndrome'. Diagnosis of
obstruction was with CT in 10 of 11 cases. Palliative interventional procedures
relieved symptoms in these three cases, surgery was performed in three cases and
the remainder were treated with chemotherapy and other palliative measures. Two
women are alive and well at 16 and 38 months who had loculated ascitic disease.
Otherwise median survival was 5 months after symptomatic gastroduodenal
involvement. CONCLUSIONS: Gastroduodenal obstruction is rare in women with
ovarian cancer. Identification and drainage of encysted lesser sac ascites as its
cause may be associated with long term survival, otherwise the prognosis is poor.
CT accurately demonstrates the level and cause of obstruction and gives
information about the wider extent of recurrent disease.
PMID- 10767186
TI - The magnetic resonance imaging appearances of the brain in acute carbon monoxide
poisoning.
AB - AIMS: To describe the magnetic resonance imaging (MRI) appearances of the brain
in acute carbon monoxide poisoning, the commonest cause of accidental poisoning
in Europe and the U.S.A. To attempt to correlate the imaging findings with
patient outcome as an aid to prognosis. MATERIALS AND METHODS: Brain MRI was
performed on 19 consecutive patients, who had sustained acute carbon monoxide
poisoning, as soon as possible after their referral to the regional Hyperbaric
Unit at the Royal Hospital, Haslar. All patients were unconscious on arrival, and
had received at least one treatment with hyperbaric oxygen by the time of first
MR. The imaging findings were analysed independently by two experienced MR
radiologists, with a third radiologist arbitrating on discrepant results.
RESULTS: Thirteen male and six female patients, age range 21-70 years (mean 38.7
years) underwent MR an average of 35.6 h (range 6-126 h) following presentation
at the referring centre. MR (at 0.5T) revealed abnormalities in the following
areas: globus pallidus (n = 12); other basal ganglia [ n = 5: entire lentiform
(globus pallidus and putamen), putamen alone, caudate nucleus, thalamus]; white
matter (n = 6: periventricular, subcortical, other); cerebral cortex (n = 5),
either localized or general; medial temporal lobe in the region of the
hippocampus (n = 4). The majority of the patients with hyperintensity in the
region of the hippocampus (n = 3) had no other area of cortical involvement. Two
patients showed abnormalities in the cerebellum. Normal appearances were seen on
the initial MR in seven patients. CONCLUSION: The appearances of the brain
following acute CO poisoning are varied, and have previously been the subject of
case reports or small studies, most of which have have addressed the delayed
sequelae of this condition. This study, the first large series undertaken in the
acute phase, confirms that, although the globus pallidus is the commonest site of
abnormality in the brain, the effects of CO poisoning are widespread. The extent
of damage correlates with clinical outcome, and therefore aids management and
prognosis.
PMID- 10767187
TI - CT-guided transthoracic needle biopsy of pulmonary nodules smaller than 20 mm:
results with an automated 20-gauge coaxial cutting needle.
AB - AIMS: To evaluate the efficacy and the complication rate of CT-guided
percutaneous lung biopsy of pulmonary nodules smaller than 20 mm in diameter
using a 20-gauge coaxial automated biopsy device. MATERIAL AND METHODS: A
prospective study was undertaken of 200 patients who underwent 202 consecutive
biopsies of pulmonary nodules, performed with a single type of automated biopsy
device. Sixty-seven biopsies of nodules smaller than 20 mm in diameter were
performed in 66 patients (group A). One hundred and thirty-five biopsies of
lesions of 20 mm or greater in size were performed in 134 patients (group B).
Patient characteristics, lesion and procedure variables, the accuracy and
complication rates were compared. RESULTS: In group A, the final diagnosis of the
nodules was malignant in 47 and benign in 19 cases (prevalence of malignancy 71.
2%). In group B, there were 111 malignant and 21 benign diagnoses (prevalence of
malignancy 82.2%). In group A, the sensitivity and specificity for a diagnosis of
malignancy were 89.5 and 100%, respectively (positive predictive value 100%,
negative predictive value 76%). A specific diagnosis of benignity was obtained in
nine out of 19 (47%) biopsies. The pneumothorax rate was 15% (10 patients) of
which two (3%) required drainage. CT signs thought to reflect alveolar
haemorrhage were noted in 28 (43%) and haemoptysis occurred in five patients
(5.9%). In group B, the sensitivity and specificity for a diagnosis of malignancy
were 95.5% and 100%, respectively (positive predictive value 100%, negative
predictive value 82.7%). A specific diagnosis of benignity was made in 14 cases
(58.3%). Complications included pneumothoraces in 22 cases (16.2%) requiring
drainage in one (0.7%). Presumed alveolar haemorrhage was recorded in 19 cases
(14.1%) and haemoptysis occurred in seven (5. 2%). There were no significant
differences between group A and group B, except for alveolar haemorrhage (P <
0.001). CONCLUSION: The accuracy and complication rate of percutaneous CT-guided
biopsy of nodules smaller than 20 mm, performed using an automated 20-gauge
coaxial biopsy device, are comparable to those for larger lesions.
PMID- 10767188
TI - A radiologico-anatomical comparative study of the cochlear aqueduct.
AB - AIM: A comparative radiologico-anatomical study of the cochlear aqueduct (CA) was
performed. MATERIALS AND METHODS: Eight cadavers and 23 dry temporal bones were
studied. High-resolution computed tomography (HRCT) was carried out on each
cadaver before microdissection. Microdissection was carried out in a plane
parallel to the HRCT sections. RESULTS: The CA was found to be located an average
of 7 mm inferior to the internal acoustic meatus and at the superior edge of the
jugular foramen. The external aperture of the CA was triangular in shape in 18
bones (78.3%). The petrosal fossa was located just inferior to the external
aperture and housed the glossopharyngeal nerve, which had an incomplete bony
canal in four bones (17.4%) and a complete bony canal in three bones (13%). It
was possible to demonstrate the petrosal portion of the CA on both coronal and
axial HRCT. The otic capsule segment of the CA was impossible to demonstrate on
coronal sections. CONCLUSION: The CA cannot be visualized in only one section of
the plane in HRCT. Both the otic capsule and petrosal segments can be
demonstrated on axial HRCT.
PMID- 10767189
TI - An assessment of the aggressive potential of radiolucencies related to the
mandibular molar teeth.
AB - AIM: The purpose of this study was to outline the radiographic appearance of
radiolucent lesions related to the molar teeth and to determine which features
indicate aggressive lesions. PATIENTS AND METHODS: Panoramic radiographs were
reviewed in 66 patients with radiolucencies related to the molar teeth. The
radiographic appearances of the lesions were assessed with regard to location and
size, and the relationship to the molar teeth. Radiographic evidence of
aggression was assessed and pathology reviewed. RESULTS: Nineteen patients had
aggressive and 47 had non-aggressive radiolucent lesions. The aggressive lesions
included keratocysts, unicystic ameloblastoma, adenoid cystic carcinoma, giant
cell granuloma, myxofibroma, chondroblastic osteosarcoma, mestastases and
squamous cell carcinoma of the tongue invading the mandible. CONCLUSION: The
differential diagnosis of radiolucent lesions in the mandible can be difficult
using panoramic radiographs alone. Helpful features in determining aggression
were older patients, larger lesions, Lodwick type IC tumour border, condition of
the mandibular cortex, movement of adjacent teeth and the relationship of the
inferior alveolar canal.
PMID- 10767190
TI - Bronchocentric granulomatosis: computed tomographic findings in five patients.
AB - AIM: The aim of this study was to assess the CT manifestations of bronchocentric
granulomatosis. SUBJECTS AND METHODS: The CT results of five patients with
bronchocentric granulomatosis were retrospectively analysed. The patients ranged
from 20 to 72 years of age and included three men and two women. The diagnosis of
bronchocentric granulomatosis was made at lobectomy (n = 2), open lung biopsy (n
= 2), and transbronchial biopsy (n = 1). Only one of the five patients had
asthma. RESULTS: The main findings consisted of a spiculated mass lesion (n = 3)
or lobar consolidation with associated mild volume loss (n = 2). One of the two
patients with consolidation had extensive mucoid impaction. The abnormalities
involved predominantly an upper lobe in four patients and a lower lobe in one
patient. In the four resected specimens, the macroscopic pathological appearance
was consolidation (n = 2) and mass lesion (n = 2). Microscopically, the typical
histology of airway-centred necrotizing granulomata was present in all cases.
Aspergillus hyphae were identified in two cases. Nocardia sp. was cultured from
the biopsy specimen in one case. CONCLUSION: The CT manifestations of
bronchocentric granulomatosis consist of a focal mass or lobar consolidation with
atelectasis. These reflect the presence of granuloma formation with or without
associated bronchial obstruction.
PMID- 10767191
TI - Relationship of MRI and clinical staging to outcome in invasive bladder cancer
treated by radiotherapy.
AB - AIM: To compare MRI and clinical staging of invasive bladder cancer prospectively
and identify additional prognostic features on MRI before radiotherapy. METHODS
AND MATERIALS: 143 patients with a pathological diagnosis of transitional cell
carcinoma underwent MRI (1.0 T) of the abdomen and pelvis before radical
radiotherapy. Tumour size, site, degree of infiltration, presence of adenopathy
and hydronephrosis were assessed and an appropriate radiological stage assigned.
Following radiotherapy all patients received regular cystoscopic follow-up. Date
of first relapse and date of death were recorded. RESULTS: The median follow-up
was 2.8 years for survivors. Those patients upstaged from T2a clinically to T3b
on MRI had a significantly worse outcome (P = 0.0078). In univariate analysis a
number of MRI features were significantly associated with adverse outcome: tumour
size, circumferential tumour extent, and presence of hydronephrosis (all P <
0.05). After adjustment for clinical T stage and histological grade, all these
MRI features and the MRI T stage were found to confer additional prognostic
information in predicting early disease relapse and death (P < 0.05). CONCLUSION:
This study demonstrates that MRI before radiotherapy provides valuable additional
prognostic information compared to clinical staging.
PMID- 10767192
TI - A prospective study of soft-tissue ultrasonography in sickle cell disease
patients with suspected osteomyelitis.
AB - AIM: A prospective study was done to assess the accuracy of soft tissue
ultrasonography in patients with sickle cell disease (SCD) presenting with
suspected osteomyelitis. MATERIALS AND METHODS: Thirty-one SCD patients had soft
tissue ultrasonography on 38 occasions (18 men, 13 women; mean age 8.2 years).
The initial ultrasonographic signs and diagnosis were compared with the final
clinical diagnosis, which was based on clinical progress and scintigraphy.
RESULT: The overall sensitivity of ultrasound in diagnosing osteomyelitis was 74%
with a specificity of 63%. The principal ultrasonographic finding of
subperiosteal fluid was present in 14 (74%) patients with osteomyelitis and seven
(37%) patients without infection. A finding of a subperiosteal fluid depth of 4
mm or more was significantly associated with osteomyelitis (P < 0.01).
CONCLUSION: Ultrasonography should be the initial investigation in SCD patients
if osteomyelitis is suspected clinically. In such a clinical setting, a finding
of 4 mm depth or more of subperiosteal fluid appears to be diagnostic. Previous
statements that the presence of any subperiosteal fluid indicates infection are
shown to be inaccurate. Patients with less than 4 mm of subperiosteal fluid
require further imaging or aspiration to establish the diagnosis of
osteomyelitis.
PMID- 10767193
TI - MR imaging of intramedullary spinal cysticercosis: A report of two cases.
PMID- 10767194
TI - Metastases to the liver from extraskeletal myxoid chondrosarcoma and successful
treatment with percutaneous ethanol injection.
PMID- 10767195
TI - Bronchial artery embolization: the importance of preliminary thoracic
aortography.
PMID- 10767196
TI - An internal iliac artery aneurysm masquerading as a rectal mass.
PMID- 10767197
TI - Isolated pneumoretroperitoneum secondary to acute bowel infarction.
PMID- 10767198
TI - MR findings of myocardial sarcoidosis.
PMID- 10767199
TI - With advances in medical imaging can the radiologist reliably diagnose Wilms'
tumours?
PMID- 10767201
TI - Reply to screaton
PMID- 10767200
TI - Does a joint ultrasound guided cytology clinic optimize the cytological
evaluation of head and neck masses?
PMID- 10767202
TI - Seminal vesicle fistula.
PMID- 10767216
TI - Publishing supplements.
PMID- 10767217
TI - Do you speak the language of dyspnea?
PMID- 10767218
TI - A Doubting Thomas dealing with pulmonary rehabilitation.
PMID- 10767219
TI - Diagnosis of sarcoidosis: when is a peek good enough?
PMID- 10767220
TI - Can we make sense out of cytokines?
PMID- 10767221
TI - Ethnic differences: word descriptors used by African-American and white asthma
patients during induced bronchoconstriction.
AB - STUDY OBJECTIVES: To determine if African-American and white patients with asthma
(1) differ in the words they use to describe their breathlessness, and (2) differ
in their perception of breathlessness. DESIGN: Descriptive cross-sectional
design. SETTING AND PARTICIPANTS: The study setting was located in Northern
California, an ethnically and economically diverse area. A total of 32 subjects,
16 per group, completed the study. MEASUREMENTS: All had a provocation
concentration of methacholine chloride causing a 30% fall in FEV(1) (PC(30)) of
/= 2 months during a
12-year period. RESULTS: These subjects accounted for 39 asthmatic episodes
lasting from 2 to 74 months (median, 7 months). The duration of the episodes
positively correlates with the severity of asthma (p = 0.02) at the initial part
of the episodes. All episodes demonstrated a similar pattern, with symptom
severity greatest at the onset and gradually diminishing until recovery. The
relatively symptom-free intervals between the episodes ranged from 1.5 to 63
months (median, 13 months). Fifty-six percent of the episodes (95% confidence
interval [CI], 40% to 72%) were associated with symptoms very suggestive or
suggestive of an infection of the upper respiratory tract at the onset of the
episodes; 33% of the episodes (95% CI, 19% to 50%) had possible symptoms
suggestive of an infection; whereas only 10% of the episodes (95% CI, 3% to 24%)
had questionable or no symptoms suggestive of an infection of the upper
respiratory tract. Thirty-four episodes had the onset between September and
March, whereas only 5 episodes occurred between April and August (p < 0. 001).
CONCLUSIONS: These observations indicate that prolonged episodes of unexplained,
persistent asthma lasting for months to years constitute a distinct clinical
pattern of asthma with characteristic clinical features.
PMID- 10767223
TI - Additive bronchoprotective and bronchodilator effects with single doses of
salmeterol and montelukast in asthmatic patients receiving inhaled
corticosteroids.
AB - OBJECTIVE: We wished to evaluate whether the combination of a leukotriene
receptor antagonist and long-acting beta(2)-agonist might confer additive
beneficial effects in terms of bronchoprotection and bronchodilatation, in mild
to moderate asthmatic patients who were suboptimally controlled on inhaled
corticosteroids alone. METHODS: Twelve asthmatic patients were enrolled into a
single-blind, placebo-controlled, crossover study, receiving additive therapy as
either of the following: (1) montelukast alone, 10 mg (ML(10)); (2) inhaled
salmeterol alone, 50 microg (SM(50)); (3) ML(10) and SM(50); (4) ML(10) and
inhaled salmeterol, 100 microg (SM(100)); or (5) placebo inhaler and tablet.
Trough measurements were made of adenosine monophosphate (AMP) bronchial
challenge (the provocative concentration of a drug [AMP] causing a fall of >/=
20% in FEV(1) [PC(20)]) as the primary end point, and spirometry, following
single doses of either placebo or active treatments (12 h after salmeterol, and
24 h after monteleukast, respectively). RESULTS: Compared to placebo, all active
treatments led to significant improvements (p < 0.05) in geometric mean AMP
PC(20): placebo, 42 mg/mL; ML(10), 106 mg/mL; SM(50), 115 mg/mL; ML(10) and
SM(50), 183 mg/mL; and ML(10) and SM(100), 247 mg/mL. The effects of montelukast
and salmeterol were numerically additive, with ML(10) and SM(100) being
significantly different (p < 0.05) from ML(10) alone. For mean FEV(1) and forced
expiratory flow rate between 25% and 75% of vital capacity, there were
significant differences (p < 0.05) between both combination therapies vs ML(10)
alone. CONCLUSIONS: Our results suggest additive benefits of a single dose of a
long-acting beta(2)-agonist and leukotriene antagonist, in terms of
bronchoprotection and bronchodilation. Further studies in more severe asthmatics
are required to evaluate long-term clinical effects.
PMID- 10767224
TI - Perception of respiratory sensation assessed by means of histamine challenge and
threshold loading tests.
AB - BACKGROUND: Some asthmatic patients perceive the severity of their disease rather
poorly. These patients may not receive optimal therapy because of
underpresentation of their respiratory symptoms. It is therefore important to
identify these patients. The present study evaluates a new threshold loading
device for measuring the perception of respiratory sensation. This method for
measuring the perception of respiratory sensation may be a viable alternative to
the bronchial provocation test. The aim of the present study was to investigate
whether the assessment of the perception of respiratory sensation based on a
threshold loading test (inspiratory and expiratory) identifies the same subjects
as poor perceivers as compared to assessment by histamine bronchial provocation
test. METHOD: In 36 subjects, the perception of respiratory sensation through a
threshold loading device was compared to the perception of respiratory sensation
during a histamine provocation test. Each test was performed with scoring of the
magnitude of the respiratory sensation on a visual analog scale (VAS). The
magnitude of the stimulus intensity was indicated by the percentage of decrease
in FEV(1) during the histamine challenge test and by the percentage of the
subject's maximum mouth pressure (percent maximal inspiratory pressure and
percent maximal expiratory pressure) during the threshold loading test. The
relationship between VAS values and the stimulus intensity was analyzed by
determining the linear regression coefficient between the two parameters.
RESULTS: No relationship was found between the perception of the sensation
induced by the histamine challenge and that during breathing through a threshold
loading device for both inspiration (Rs = 0.15; p = 0.40) and expiration (Rs =
0.13; p = 0.47). We did find a significant relation between the perception of
respiratory sensation during the inspiratory and expiratory threshold loading
test (Rs = 0.67; p = 0. 0001). Furthermore, we defined a subgroup of patients of
special interest: those with low symptoms of breathlessness and high bronchial
responsiveness. Compared to the inspiratory and expiratory threshold loading
test, the histamine challenge test identified more patients in the special
interest group as poorest perceivers. CONCLUSION: The measurement of perception
by means of a threshold loading device and a histamine provocation test did not
identify the same subjects as poor perceivers, probably because we did not
measure the patient's perceptiveness for exactly the same stimuli. In the
population with relatively more severe asthma and very low symptoms of
breathlessness, the histamine-induced bronchoconstriction test identified more
patients as poorest perceivers compared to the threshold loading test.
PMID- 10767225
TI - Hypoxic and hypercapnic breathlessness in patients with type I diabetes mellitus.
AB - STUDY OBJECTIVES: The putative role of the performance of inspiratory muscles and
breathing pattern in inducing dyspnea has been recently assessed during hypoxic
stimulation in patients with type I diabetes (IDDM). Compared to a hypoxic
stimulus, a hypercapnic stimulus, which may differently affect the pattern of
breathing, could therefore modulate the coupling between respiratory effort and
ventilatory output, which is involved in dyspnea sensation. SUBJECTS: Eight
stable patients aged 19 to 48 years old, with IDDM (duration of disease, 36 to
240 months) and no smoking history, cardiopulmonary involvement, or autonomic
neuropathy; and an age- and sex-matched control group. MEASUREMENTS: Pulmonary
volumes, diffusing capacity of the lung for carbon monoxide, time and volume
components (tidal volume [VT] and respiratory frequency), dynamic elastance
(Eldyn), and swings in pleural pressure (Pessw) were measured. Maximal
inspiratory pleural pressure (Pes) during a maximal sniff maneuver (Pessn),
respiratory muscle effort or output (Pessw%Pessn), tension time index (TTI) =
TI/total breathing cycle time x Pessw(%Pessn), and swing in Pes during VT as a
percentage of Pessn were also evaluated. Dyspnea sensation was assessed by a
modified Borg scale. Subjects were studied at baseline and during hypoxic and
hypercapnic rebreathing tests. RESULTS: Compared to control subjects, patients
exhibited normal routine spirometric function and Pessn, but a higher Eldyn,
indicating peripheral airway involvement. In patients, but not in control
subjects, Eldyn increased during both chemical stimuli and increased more during
hypoxia than during hypercapnia. Also, changes in both VT and Pessw(%Pessn) on
changes in PCO(2) were lower, while changes in Pessw(%Pessn)/VT, an index of
neuroventilatory dissociation (NVD) of the ventilatory pump, on changes in PCO(2)
were greater. Changes in VT and NVD for unit change in arterial oxygen saturation
were lower and higher, respectively. Changes in Borg scale per changes in NVD
were greater during both stimuli. Furthermore, compared to hypoxic conditions, a
greater VT for any level of both minute volume and Pessw(%Pessn), and lower
changes in Borg scale on changes in Pessw(%Pessn) and Pessw(%Pessn)/VT were found
in hypercapnia. Changes in NVD and Borg scale related to changes in Eldyn with
both chemical stimuli. CONCLUSIONS: In IDDM, the greater perception of dyspnea is
associated with changes in inspiratory effort being out of proportion to changes
in VT. The greater increase in Eldyn and the lower increase in VT may, in part,
account for the greater perception of breathlessness during hypoxia.
PMID- 10767226
TI - Relationship between impaired pulmonary diffusion and cardiopulmonary exercise
capacity after heart transplantation.
AB - STUDY OBJECTIVES: Diffusion impairment and reduced performance in cardiopulmonary
exercise testing (CPX) have been found in patients after heart transplantation.
The pathogenesis of these abnormalities is unclear. In particular, the
contribution of pulmonary interstitial changes has not yet been verified. DESIGN:
We analyzed pulmonary function tests, high-resolution CT (HRCT),
echocardiography, left heart catheterization, and CPX in transplanted patients.
PATIENTS: Forty long-term survivors were studied at a median of 47 months (range,
12 to 89 months) after heart transplantation. RESULTS: Diffusion was impaired in
40% (transfer factor for carbon monoxide) or 82.5% (carbon monoxide transfer
coefficient) of the patients. Diffusion impairment was caused by a decreased
diffusing capacity of the alveolar capillary membrane in 89% and/or by a
decreased blood volume of the alveolar capillaries in 46% of cases. In five
patients (12.5%), CT revealed interstitial lung changes. These patients did not
have different values of diffusion capacity. Maximal oxygen uptake and
ventilatory efficiency during exercise (minute ventilation/carbon dioxide output
slope) were impaired in 92% and 46% of the cases, respectively. CONCLUSIONS: Our
data show that the diffusion abnormalities are caused by an impaired diffusion
status of the alveolar capillary membrane. Interstitial changes detectable in
HRCT were found not to be involved in this process. The reduced performance in
CPX in our long-term survivors is caused by pulmonary perfusion abnormalities and
low tidal volume, which is due to the deconditioning of respiratory muscle,
rather than by interstitial changes or diffusion abnormalities.
PMID- 10767227
TI - Long-term effects of outpatient rehabilitation of COPD: A randomized trial.
AB - OBJECTIVE: To examine the short- and long-term effects of an outpatient pulmonary
rehabilitation program for COPD patients on dyspnea, exercise, health-related
quality of life, and hospitalization rate. SETTING: Secondary-care respiratory
clinic in Barcelona. METHODS: We conducted a randomized controlled trial with
blinding of outcome assessment and follow-up at 3, 6, 9, 12, 18, and 24 months.
Sixty patients with moderate to severe COPD (age 65 +/- 7 years; FEV(1) 35 +/-
14%) were recruited. Thirty patients randomized to rehabilitation received 3
months of outpatient breathing retraining and chest physiotherapy, 3 months of
daily supervised exercise, and 6 months of weekly supervised breathing exercises.
Thirty patients randomized to the control group received standard care. RESULTS:
We found significant differences between groups in perception of dyspnea (p <
0.0001), in 6-min walking test distance (p < 0.0001), and in day-to-day dyspnea,
fatigue, and emotional function measured by the Chronic Respiratory Questionnaire
(p < 0. 01). The improvements were evident at the third month and continued with
somewhat diminished magnitude in the second year of follow-up. The PR group
experienced a significant (p < 0.0001) reduction in exacerbations, but not the
number of hospitalizations. The number of patients needed to treat to achieve
significant benefit in health-related quality of life for a 2-year period was
approximately three. CONCLUSION: Outpatient rehabilitation programs can achieve
worthwhile benefits that persist for a period of 2 years.
PMID- 10767228
TI - Influence of lung parenchymal destruction on the different indexes of the
methacholine dose-response curve in COPD patients.
AB - STUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose
response curves in COPD is still a matter of debate. Bronchial
hyperresponsiveness (BHR) in patients with COPD could be influenced by the
destruction of the parenchyma and the augmented mechanical behavior of the lung.
Therefore, we studied the interrelationships between indexes of BHR, on the one
hand, and markers of lung parenchymal destruction, on the other. PATIENTS AND
METHODS: COPD patients were selected by clinical symptoms, evidence of chronic,
nonreversible airways obstruction, and BHR, which was defined as a provocative
dose of a substance (histamine) causing a 20% fall in FEV(1) (PC(20)) of 5 mg/L) in asthmatics undergoing
research bronchoscopy, and to determine whether subject or procedure
characteristics are associated with higher SLC. DESIGN: Prospective,
observational study. SETTING: Academic research center. PARTICIPANTS: Fifty-one
volunteers with mild to moderate asthma enrolled in three separate bronchoscopy
protocols to study airway inflammation in asthma. INTERVENTIONS: Lidocaine was
administered topically to the upper airway and tracheobronchial tree to achieve
local anesthesia for bronchoscopy. Venous blood was sampled during bronchoscopy,
30 min after upper airway anesthesia was completed (time 1), and 30 min after
bronchoscopy was completed (time 2). MEASUREMENTS AND RESULTS: The mean total
amount of lidocaine administered was 600 +/- 122 mg (8.2 +/- 2.0 mg/kg). No signs
or symptoms of lidocaine toxicity were observed in any of the subjects. SLC
ranged between 0.10 and 2.90 mg/L at time 1 and 0.50 and 3.20 mg/L at time 2. SLC
was significantly correlated with the total amount of lidocaine
(milligrams/kilogram) administered at both points (time 1, r = 0.33, p = 0.021;
time 2, r = 0.33, p = 0.023). No statistically significant relationship was
observed between SLC and subject age, sex, weight, baseline FEV(1), procedure
length, or study protocol. No statistically significant relationship was found
between subject FEV(1) and either total lidocaine dose or procedure length.
CONCLUSIONS: An average total dose of 600 mg (8.2 mg/kg) of lidocaine appears to
be safe in mild to moderate asthmatics undergoing research bronchoscopy.
PMID- 10767240
TI - Predicting effective continuous positive airway pressure.
AB - PURPOSE: The purpose of this study was to compare the pressure required to
abolish apneas as predicted from a previously derived algorithm (Ppred) with the
true effective pressure (Peff) determined during a continuous positive airway
pressure (CPAP) titration study. SETTING: Sleep clinic of a university hospital.
METHODS: We prospectively studied 329 patients with sleep apnea undergoing CPAP
titration. The following protocol was employed. Titration began at a pressure
(Ppred) calculated from a previously derived equation based on body mass index,
neck circumference, and apnea/hypopnea index (AHI). If AHI at Ppred was > 10, the
pressure was increased in steps of 1 cm H(2)O until AHI became < 10. If, on the
other hand, AHI at Ppred was < 10, the pressure was reduced in increments of 1 cm
H(2)O until AHI became > 10. The lowest pressure that abolishes sleep apnea is
defined as the Peff. Paired t tests, linear correlation, and distribution of
(Ppred - Peff) were used to compare Peff and Ppred. RESULTS: Successful titration
was accomplished in 276 patients (84%). Mean Ppred was similar to mean Peff (8.1
+/- 2.2 vs 8.1 +/- 2.6 cm H(2)O, respectively). There was a significant
correlation between these two pressures (r = 0.73; p = 0.0001). Examination of
the distribution of (Peff - Ppred) revealed that in 63% of patients, Ppred was
within +/- 1 cm H(2)O of Peff; in 83% of patients, the two measures were within
+/- 2 cm H(2)O; and in 95%, within +/- 3 cm H(2)O. CONCLUSION: We conclude that
pressure predicted from an algorithm based on simple anthropometric and sleep
variables constitutes a good starting point for CPAP titration, allowing the
optimum pressure to be achieved with only a few incremental changes.
PMID- 10767241
TI - Dose-dependent effects of mandibular advancement on pharyngeal mechanics and
nocturnal oxygenation in patients with sleep-disordered breathing.
AB - STUDY OBJECTIVES: To examine dose-dependent effects of mandibular advancement on
collapsibility of the passive pharynx and sleep-disordered breathing (SDB).
DESIGN: Prospective, randomized study. SETTING: University hospital. PATIENTS:
Thirty-seven adult patients with SDB. INTERVENTIONS: Oral appliances with 2-, 4-,
and 6-mm advancement of the mandible. MEASUREMENTS AND RESULTS: Overnight
oximetry was performed with and without oral appliances. Each 2-mm mandibular
advancement coincided with approximately 20% improvement in number and severity
of nocturnal desaturations. Percentages of patients producing a > 50% improvement
rate of the number of desaturations were 25%, 48%, and 65% with use of oral
appliances with 2-, 4-, and 6-mm mandibular advancement, respectively. Static
pharyngeal mechanics were evaluated in six completely paralyzed patients with SDB
under general anesthesia with and without the oral appliances. Advancement of
mandibular position was found to produce dose-dependent closing pressure
reduction of all pharyngeal segments. Normalization of nocturnal oxygenation was
associated with negative closing pressure, especially at the velopharynx.
CONCLUSIONS: We conclude that improvement of both nocturnal oxygenation and
pharyngeal collapsibility significantly depends on the mandibular position.
PMID- 10767242
TI - Detection of upper airway resistance syndrome using a nasal cannula/pressure
transducer.
AB - STUDY OBJECTIVES: To determine the diagnostic utility of a nasal cannula/pressure
transducer (NC), in comparison to thermistor (TH), during routine, clinical
nocturnal polysomnography (NPSG). DESIGN: We analyzed the respiratory arousal
index (RAI) using TH (RAI-TH) or NC (RAI-NC) in patients with suspected sleep
disordered breathing (SDB). SETTING: Sleep disorders center of a university
affiliated teaching hospital. PATIENTS: Fifty consecutive, nonselected patients
referred for evaluation of suspected SDB. MEASUREMENTS AND RESULTS: Twenty
patients were found to have obstructive sleep apnea/hypopnea syndrome (OSA), 25
had upper airway resistance syndrome (UARS), and 5 had primary snoring (PS). Mean
RAI-NC was greater than the mean RAI-TH by 25%, 302%, and 500% in OSA, UARS, and
PS, respectively. RAI-NC was >/= 14 (mean, 25.2) in UARS and < 14 (mean, 9) in
PS. Mean RAI-TH was 8.4 in UARS and 1.8 in PS, with significant overlap between
the two groups. CONCLUSIONS: NC is more sensitive than TH in detecting
respiratory events during NPSG and may represent a simple, objective means to
identify UARS among patients with a range of SDB.
PMID- 10767243
TI - Expiratory airflow patterns in children and adults with cystic fibrosis.
AB - STUDY OBJECTIVE: To determine whether tidal expiratory airflow patterns change
with increasing airways obstruction in patients with cystic fibrosis. DESIGN: An
observational study. SETTING: Lung function laboratory. PATIENTS: Sixty-four
children and young adults with cystic fibrosis. MEASUREMENTS: After measuring
FEV(1) and airways resistance using body plethysmography, each subject was seated
and asked to mouth breathe through a pneumotachograph for 2 min. The collected
data were analyzed, and three expiratory airflow pattern-sensitive indexes were
computed. The first index was derived from the ratio of the time to reach peak
expiratory flow to the total expiratory time (tPTEF/tE). The second index, Trs,
was an estimate of the time constant of the passive portion of expiration. The
third index, f1.gif" BORDER="0">, describes the slope of the whole post-peak
expiratory flow pattern after scaling. RESULTS: Compared with FEV(1), the index
tPTEF/tE was a poor indicator of airways obstruction (r(2) = 0.15, p = 0.002).
Trs showed a strong relationship with the severity of airways obstruction (r(2) =
0.46, p < 0.001). Using f1.gif" BORDER="0">, the postexpiratory profile could be
categorized into three shapes, and provided a good indicator of airways
obstruction when linear and concave-shaped profiles occurred (r(2) = 0.42, p <
0.001). Convex-shaped flow profiles had to be treated separately and were
indicative of normal lung function. CONCLUSIONS: In a cross-sectional study of
patients with cystic fibrosis, increase in airways resistance above normal is
reflected by quantifiable changes in the expiratory airflow pattern.
PMID- 10767245
TI - Oral absorption of clarithromycin in acute illness and during convalescence in
patients with community-acquired pneumonia.
AB - STUDY OBJECTIVE: To compare the extent of oral clarithromycin absorption in
patients during an illness and in health. DESIGN: Sequential two-phase
prospective study including an acutely ill pneumonia phase (PP) and a subsequent
convalescent phase (CP). STUDY POPULATION: Patients >/= 18 years old with
radiographically confirmed community-acquired pneumonia (CAP) who were admitted
to the hospital. METHODS: During both study phases, patients received one single
500-mg dose of oral clarithromycin. Serial blood samples were drawn over a 24-h
period in order to characterize the plasma concentration-time curves. Area under
the curve from zero to 24 h (AUC(0-24)), maximum plasma concentration (Cmax), and
time to maximum concentration (Tmax) were determined for both clarithromycin and
its metabolite, 14-hydroxyclarithromycin, and compared between the two phases.
RESULTS: Twelve patients completed both phases of the study. For clarithromycin,
there was a significant increase AUC(0-24) (47.37 +/- 8.51 microg/h/mL vs 36.22
+/- 6.09 microg/h/mL) in favor of the PP. There were no significant differences
detected with respect to Cmax (4.32 +/- 0.63 microg/mL vs 3.57 +/- 0.46
microg/mL), or Tmax (3.50 +/- 0.50 h vs 2.83 +/- 0.59 h) between PP and CP. For
14-hydroxyclarithromycin, the AUC(0-24) and Cmax were significantly higher (5.84
+/- 1.08 microg/h/mL vs 8.84 +/- 1.92 microg/h/mL; 0.42 +/- 0.08 microg/mL vs
0.76 +/- 0.23 microg/mL) in the CP as compared to the PP. Tmax remained
unchanged. CONCLUSION: The extent of absorption of oral clarithromycin was not
diminished during an acute illness with CAP.
PMID- 10767244
TI - Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis
and does not correlate with cystic fibrosis genotype.
AB - STUDY OBJECTIVES: Inducible nitric oxide synthase (iNOS) is upregulated in a
number of inflammatory lung conditions, and exhaled nitric oxide (NO)
concentration is increased. However, previous studies in children with cystic
fibrosis (CF) have shown that exhaled NO is reduced. The purpose of this
investigation was to study exhaled NO concentration in adults with CF, and to
investigate the effect of CF genotype and respiratory tract infection on this
measurement. DESIGN: Exhaled and nasal NO levels were measured in 54 adult CF
subjects and 37 healthy nonsmoking age-matched subjects using a chemiluminesence
analyzer. Spirometry (FEV(1) and FVC), CF genotype, and bacterial colonization
were also recorded. SETTING: This study was conducted at a national CF center.
RESULTS: The mean age of patients was 26.9 years, and the mean FEV(1) was 50.5%
predicted (range, 17 to 104%). Nasal NO in the CF patients (mean, 520 parts per
billion [ppb]; confidence interval [CI], 452 to 588) was significantly lower (p <
0.001) than in control subjects (987 ppb; CI, 959 to 1,015). Exhaled NO was
significantly lower (p < 0. 001) in CF patients (5.0 ppb; CI, 4.1 to 6.1) than in
control subjects (7.3 ppb; CI, 6.8 to 7.8). FEV(1) did not correlate with nasal
or exhaled NO. No association was observed between genotype and NO values or
colonization with Pseudomonas aeruginosa. CONCLUSIONS: Despite the airway
inflammation that is characteristic of CF, both nasal and exhaled NO were
reduced. There was no association with genotype or infection status. As NO has
bacteriostatic effects and may augment mucociliary clearance, this observation
may be of clinical importance.
PMID- 10767246
TI - Sex differences in left ventricular geometry in aortic stenosis: impact on
outcome.
AB - OBJECTIVE: This study of surgical aortic stenosis characterized sex differences
in left ventricular (LV) geometry and outcome. MATERIALS AND METHODS: We examined
92 women and 82 men who underwent echocardiography before valve replacement for
aortic stenosis. RESULTS: Women had a smaller cavity size (LV end-diastolic
diameter 48.2 +/- 7 mm in women vs 53.6 +/- 7.6 mm in men; p = 0.0001) and higher
ejection fraction (59% in women vs 54% in men; p = 0.02). LV mass was greater in
men than women (300.4 +/- 88 g in men vs 250.6 +/- 85.8 g in women; p = 0.0055)
but when corrected for body surface area, the difference was not significant. The
prevalence of LV hypertrophy was similar in both sexes (51% in women vs 49% in
men; p = 0.62). The 5-year survival was 82% in women and 79% in men (p = 0. 9).
CONCLUSION: Several descriptors of LV geometry differed between men and women.
These differences were largely eliminated after normalizing for body surface
area. No differences in surgical mortality or long-term outcome were noted.
PMID- 10767247
TI - Spinal muscular atrophy type 1: A noninvasive respiratory management approach.
AB - STUDY OBJECTIVE: To determine whether spinal muscular atrophy (SMA) type 1 can be
managed without tracheostomy and to compare extubation outcomes using a
respiratory muscle aid protocol vs conventional management. DESIGN: A
retrospective cohort study. METHODS: Eleven SMA type 1 children were studied
during episodes of respiratory failure. Nine children required multiple
intubations. Along with standard treatments, these children received manually and
mechanically assisted coughing to reverse airway mucus-associated decreases in
oxyhemoglobin saturation. Extubation was not attempted until, most importantly,
there was no oxygen requirement to maintain oxyhemoglobin saturation greater than
94%. After extubation, all patients received nasal ventilation with positive end
expiratory pressure. Successful extubation was defined by no need to reintubate
during the current hospitalization. RESULTS: Two children have survived for 37
and 66 months and have never been intubated despite requiring 24-h nasal
ventilation since 5 and 7 months of age, respectively. One other child underwent
tracheostomy for persistent left lung collapse and inadequate home care, another
for need for frequent readmission and intubation, and one child was lost to
follow-up 3 months after successful extubation. The other six children have been
managed at home for 15 to 59 (mean 30.4) months using nocturnal nasal ventilation
after an episode of respiratory failure. The nine children were successfully
extubated by our protocol 23 of 28 times. The same children managed
conventionally were successfully extubated 2 of 20 times when not using this
protocol (p < 0.001 by the two-tailed Fisher's Exact t Test). CONCLUSION:
Although intercurrent chest colds may necessitate periods of hospitalization and
intubation, tracheostomy can be avoided throughout early childhood for some
children with SMA type 1.
PMID- 10767249
TI - Effect of varying the case mix on the standardized mortality ratio and W
statistic: A simulation study.
AB - OBJECTIVE: To evaluate the validity of using the standardized mortality ratio
(SMR) and the W statistic as risk-adjusted measures of hospital mortality to
judge ICU performance. DESIGN: APACHE (acute physiology and chronic health
evaluation) II data were collected prospectively from the surgical ICU (SICU) at
a single institution using all adult admissions (n = 6806) over an 8-year period
(excluding cardiac surgical patients, burn patients, and patients under 16 years
of age). Using a computer simulation technique, virtual ICUs (VICUs) with
mortality rates between 5% and 16% were constructed. After first dividing the
original data set into deciles of risk, each VICU was constructed by randomly
resampling between 10 and 680 patients from each decile. The SMR, W statistic,
and Z statistic were calculated for 10,000 different case mixes. SETTING: The
SICU at a 450-bed teaching hospital. PATIENTS: A group of 6,806 adult patient
admissions, excluding cardiac surgical patients and burn patients. MEASUREMENTS
AND RESULTS: VICUs were created from a data set of actual patients treated at one
institution in order to test the hypothesis that the SMR and W statistic would
remain invariant when applied to subsets of patients from a single institution.
Instead, the SMR and W statistic were found to be very sensitive to changes in
case mix. The SMR and W statistic were linear functions of the simulated ICU
mortality rate. CONCLUSION: This simulation demonstrates that the SMR and the W
statistic based on APACHE II cannot be used to compare outcomes of ICUs. We have
proposed a revision of the SMR that eliminates the effect of case mix and allows
for more accurate comparisons of ICU performance.
PMID- 10767248
TI - Nasal continuous positive airway pressure: A method to avoid endotracheal
reintubation in postoperative high-risk patients with severe nonhypercapnic
oxygenation failure.
AB - OBJECTIVES: To study whether nasal continuous positive airway pressure (nCPAP)
improves pulmonary oxygen transfer and avoids reintubation in patients with
severe nonhypercapnic oxygenation failure after major cardiac, vascular, or
abdominal surgery. DESIGN: Prospective interventional study. SETTING: Surgical
ICU of a university hospital. PATIENTS: Twenty consecutive patients after
thoracic, abdominal, or combined thoracoabdominal operations, in whom pulmonary
oxygen transfer deteriorated continuously following elective extubation after
initial mechanical ventilation. Respiratory failure was due to atelectasis and/or
left heart failure, and all patients met predefined criteria for reintubation.
INTERVENTIONS: nCPAP therapy (8 to 10 cm H(2)O) was initiated if PaO(2) had
decreased to < 80 mm Hg despite application of 100% oxygen (flow, 25 L/min),
intermittent mask continuous positive airway pressure, and maximum conventional
therapy. MEASUREMENTS AND RESULTS: nCPAP treatment was started 24.1 +/- 3.4 h
after elective extubation. PaO(2) was < 80 mm Hg in all patients, in 13 patients
it was < 60 mm Hg, and in 3 patients it was < 50 mm Hg. Mean PaO(2)/fraction of
inspired oxygen (FIO(2)) ratio had decreased to 60 +/- 2.6, and increased within
the first hour of nCPAP to 136 +/- 12 (p < 0.001). The clinical condition in all
patients improved further, and after 35.2 +/- 6.3 h, all patients were well
oxygenated by face mask at ambient pressure (PaO(2)/FIO(2) ratio, 146 +/- 14).
Two patients were reintubated for reasons unrelated to oxygenation or ventilation
(data are presented as mean +/- SEM). CONCLUSIONS: nCPAP is safe, easy to apply,
and effective to improve arterial blood oxygenation in < 1 h in postoperative
patients with severe nonhypercapnic oxygenation failure. In these patients, who
otherwise would have been reintubated, nCPAP can avoid endotracheal reintubation
and mechanical ventilation.
PMID- 10767250
TI - Atrial function during cardiac arrest caused by ventricular fibrillation.
AB - OBJECTIVES: To report observations on preserved regular atrial electrical and
mechanical systole during ventricular fibrillation (VF) and to quantitate blood
flow generated by atrial contractions in this setting. METHODS: In 10 rats, right
atrial pressure pulses were continuously recorded before and for an interval of 8
min after inducing VF. In 3 isolated, perfused rat hearts, epicardial right
atrial electrograms were recorded after inducing VF. In 15 pigs, transesophageal
echo-Doppler measurements were obtained with pulsed and color-Doppler
visualization of flow across the mitral valve after onset of VF. RESULTS: In each
rat, regular right atrial pressure pulses were documented during VF. These
persisted over an average interval of 7.5 min. In isolated, perfused hearts,
right atrial contractions were accompanied by regular atrial depolarizations. In
pigs, regular atrial contractions generated atrial stroke volumes of
approximately 12 mL, or 25% of prearrest values during the first minute after
onset of VF, but those declined to approximately 6 mL after 10 min of untreated
cardiac arrest. Blood flow from the left atrium into the left ventricle failed to
advance significantly into the systemic circuit. During atrial diastole, we
observed reversal of flow into the left atrium. CONCLUSIONS: Atrial contractions
are preserved during the initial 8 min or more after cardiac arrest due to VF.
Substantial forward flow into the left ventricle failed to advance through the
outflow tract but regurgitated into the atrium during atrial diastole.
PMID- 10767251
TI - Prevention of air leakage by spraying vivostat fibrin sealant after lung
resection in pigs.
AB - STUDY OBJECTIVES: To evaluate Vivostat fibrin sealant in the prevention of air
leakage after experimental lung resection in pigs. DESIGN: Randomized study.
SETTING: University laboratory. METHODS: Six Landrace pigs were operated on in
both lungs through a median sternotomy. Five different resection sites were
created in each lung. INTERVENTION: Randomization was performed to either
application of Vivostat fibrin sealant (ConvaTec; Skillman NJ) or human albumin
20% (control) at the resection sites. The lung parenchyma was occluded with a
soft clamp for either 1, 2, 5, or 10 min in the treatment group and 10 min in the
control group. After removal of the clamp, the lung was ventilated with an
increasing intrabronchial pressure of 20, 30, and 45 cm H(2)O for 2 min at each
step. RESULTS: At inspiratory pressures of 20 and 30 cm H(2)O air leaks were
found in the control group but not in the Vivostat group (p < 0.001). At an
inspiratory pressure of 45 cm H(2)O, there were two small air leaks in the
Vivostat group at each clamping time (four at 5 min), compared with five small
and seven large leaks in the control group. Analysis of the data after 10 min of
clamping showed that the Vivostat group was superior to the human albumin group
(p = 0.002). CONCLUSIONS: This randomized study shows that Vivostat fibrin
sealant is effective in preventing air leakage after small lung resections in
pigs, even at high inspiratory pressures.
PMID- 10767252
TI - The epidemiologic, pathologic, and clinical features of AIDS-associated pulmonary
Kaposi's sarcoma.
AB - AIDS-related Kaposi's sarcoma (KS) occurs principally in homosexual or bisexual
men infected with the newly identified human herpes virus-8, also called KS
associated herpes virus. Unlike classical forms of the disease, AIDS-associated
KS is a multicentric entity that frequently involves lymph nodes and the GI
tract. KS may also occur in the lung, commonly in the setting of extensive
mucocutaneous disease and very rarely as an isolated event. The exact incidence
of intrathoracic KS in patients with AIDS is unknown. Before the advent of highly
active antiretroviral therapy (HAART), pulmonary KS had been reported in
approximately 10% of patients with AIDS, 25% of patients with cutaneous KS, and
in roughly 50% of postmortem examinations of patients with AIDS, KS, and
respiratory infections. In the HAART era, the incidence of KS has declined
precipitously in North America and Europe but not in third world countries where
HAART is largely unavailable. Pulmonary KS may cause radiographic infiltrates and
respiratory symptoms that mimic a variety of other infectious and neoplastic
processes. An aggressive diagnostic evaluation of patients who have this
condition is essential because chemotherapy and radiation therapy may provide
significant palliation, particularly if used in conjunction with HAART. This
review briefly explores the changing epidemiology of KS. The pathology and
pathogenesis of KS is also reviewed, along with the clinical and radiographic
presentation, diagnosis, and management of pulmonary KS.
PMID- 10767253
TI - Office spirometry for lung health assessment in adults: A consensus statement
from the National Lung Health Education Program.
AB - COPD is easily detected in its preclinical phase using spirometry, and successful
smoking cessation (a cost-effective intervention) prevents further disease
progression. This consensus statement recommends the widespread use of office
spirometry by primary-care providers for patients >/= 45 years old who smoke
cigarettes. Discussion of the spirometry results with current smokers should be
accompanied by strong advice to quit smoking and referral to local smoking
cessation resources. Spirometry also is recommended for patients with respiratory
symptoms such as chronic cough, episodic wheezing, and exertional dyspnea in
order to detect airways obstruction due to asthma or COPD. Although diagnostic
quality spirometry may be used to detect COPD, we recommend the development,
validation, and implementation of a new type of spirometry-office spirometry-for
this purpose in the primary-care setting. In order to encourage the widespread
use of office spirometers, their specifications differ somewhat from those for
diagnostic spirometers, allowing lower instrument cost, smaller size, less effort
to perform the test, improved ease of calibration checks, and an improved quality
assurance program.
PMID- 10767254
TI - Anti-inflammatory cytokines.
AB - The anti-inflammatory cytokines are a series of immunoregulatory molecules that
control the proinflammatory cytokine response. Cytokines act in concert with
specific cytokine inhibitors and soluble cytokine receptors to regulate the human
immune response. Their physiologic role in inflammation and pathologic role in
systemic inflammatory states are increasingly recognized. Major anti-inflammatory
cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL
11, and IL-13. Specific cytokine receptors for IL-1, tumor necrosis factor-alpha,
and IL-18 also function as proinflammatory cytokine inhibitors. The nature of
anti-inflammatory cytokines and soluble cytokine receptors is the focus of this
review. The current and future therapeutic uses of these anti-inflammatory
cytokines are also reviewed.
PMID- 10767255
TI - Chronic infiltrative lung diseases: value of gadolinium-enhanced MRI in the
evaluation of disease activity--early report.
AB - STUDY OBJECTIVE: To determine the value of gadolinium-enhanced MRI in the
assessment of disease activity in chronic infiltrative lung diseases (CILDs).
DESIGN: Retrospective study. SETTING: University hospital. MATERIALS AND METHODS:
Twenty-five consecutive patients with CILD were studied. The following diseases
were diagnosed: sarcoidosis (n = 10), bronchiolitis obliterans organizing
pneumonia (n = 3), usual interstitial pneumonia (n = 4), radiation pneumonia (n =
2), desquamative interstitial pneumonia (n = 1), rheumatoid lung (n = 1),
vasculitis (n = 1), alveolar proteinosis (n = 1), bronchioloalveolar carcinoma (n
= 1), and chronic eosinophilic pneumonia (n = 1). In each patient, the disease
activity was assessed by one or more of the following studies: BAL (n = 18),
gallium-radioisotope lung scanning (n = 6), serum angiotensin-converting enzyme
assay (n = 10), and open lung biopsy (n = 4). T1-weighted breath-hold MRI studies
were obtained before and after IV injection of gadolinium. The MRI examinations
were analyzed to assess the presence or absence of lesional enhancement. RESULTS:
The presence of enhanced pulmonary lesions was seen in 14 patients. All of these
patients had active disease. Of the 17 patients with active disease, 14 had
enhanced lesions, and 3 had unenhanced lesions. Pulmonary lesions were not
enhanced in any patients with inactive disease. The difference was statistically
significant (Fisher Exact Test, p < 0.05). CONCLUSION: Gadolinium-enhanced MRI
may prove to be a useful tool in assessing disease activity in CILDs.
PMID- 10767256
TI - Videothoracoscopic approach to primary mediastinal pathology.
AB - STUDY OBJECTIVES: Personal results and validity of videothoracoscopic (VTS)
approach to primary mediastinal diseases are analyzed. DESIGN: Retrospective
review of personal experience. SETTING: Department of Surgery, San Giuseppe
Hospital, University of Milano, Italy. PATIENTS: From September 1991 to January
1999, of a personal series of 1,653 VTS procedures, 118 regarded primary
mediastinal diseases. In 47 cases, diagnostic videothoracoscopy was performed to
obtain large biopsy specimens or to carry out accurate staging; in 71 cases, full
resection was anticipated. INTERVENTIONS: The patient, intubated with a double
lumen Carlen's tube and in the lateral decubitus position, underwent
videothoracoscopy. Two ports and a small anterior utility thoracotomy were
completed. Thorough exploration of the mediastinum and, if possible, complete
resection of the lesion were accomplished. MEASUREMENTS AND RESULTS:
Videothoracoscopy yielded adequate diagnosis or staging in all patients operated
on for diagnostic purposes. Of 71 patients operated on with resective intent, 66
had complete thoracoscopic resection (22 stage-I thymomas, 4 thymic cysts, 21
myasthenia gravis associated with thymic hyperplasia, 19 miscellaneous tumors).
Conversion was required in five cases, mostly for invasion of mediastinal
structures. Complications included the following: one patient developed
intraoperative bleeding controlled endoscopically, two patients experienced
postoperative bleeding requiring re-thoracoscopy, and one patient had
postoperative pneumonia requiring assisted ventilation. One recurrence of
malignant thymoma occurred 4 years postoperatively. CONCLUSIONS:
Videothoracoscopy can attain a leading role in obtaining large samples in
lymphatic mediastinal diseases. Dysembriomas, schwannomas, simple cysts, and
similar lesions can benefit from VTS removal. Total thymectomy for myasthenia
gravis associated with thymic hyperplasia can be performed thoracoscopically.
Further data and more extensive experience are needed.
PMID- 10767257
TI - Unexpected postoperative course after right pneumonectomy.
PMID- 10767258
TI - Utility of on-site cytopathology assessment for bronchoscopic evaluation of lung
masses and adenopathy.
AB - STUDY OBJECTIVES: To determine the extent to which on-site cytopathology
assessment improves diagnostic yield when sampling lung nodules or masses and/or
hilar or mediastinal lymphadenopathy by fiberoptic bronchoscopy (FOB). DESIGN:
Prospective cohort study. SETTING: Two teaching hospitals in Baltimore, MD.
PATIENTS: Consecutive adult patients (>/= 18 years) undergoing FOB for evaluation
of lung nodules or masses and/or hilar or mediastinal lymphadenopathy.
INTERVENTION: Prospective collection of data on patient factors and details of
the procedure on standardized report forms. MEASUREMENTS AND RESULTS: The primary
outcome measure was a new diagnosis obtained by FOB. On-site assessment was used
in 81 of 204 cases (40%), and overall diagnostic yield was 62%. Yield was greater
when on-site cytopathology assessment was used, in unadjusted analysis (81% vs
50%, p < 0.001) and in a multivariate model (odds ratio, 4.5; 95% confidence
interval, 2.1 to 10.0). Other significant predictors of a new diagnosis included
older patient age, higher dose of narcotic used during FOB, and shorter procedure
time. CONCLUSIONS: We conclude that diagnostic yield was greater when on-site
cytopathology was used to assist FOB evaluation of intrathoracic adenopathy
and/or lung nodules or masses. Increasing the use of on-site cytopathology
assessment may improve the quality of FOB services.
PMID- 10767259
TI - A 43-year-old man with a large recurrent right-sided pleural effusion. Diagnosis:
Constrictive pericarditis.
PMID- 10767260
TI - Hypercalcemia due to talc granulomatosis.
AB - Pulmonary disease due to talc, a group of hydrous magnesium silicates, is almost
exclusively encountered after occupational exposure. One form of this rare
disorder is talc granulomatosis. In varying degrees, hypercalcemia is typical of
granulomatous disease but has not yet been reported in talcosis. We report the
case of a former mold maker who presented with hypercalcemia. Laboratory findings
indicated extra-renal 1-alpha-hydroxylation of 25-hydroxyvitamin D. Pulmonary
infiltrates prompted a lung biopsy that disclosed talc granulomatosis. We suggest
that talc granulomatosis should be added to the list of granulomatous disorders
capable of causing hypercalcemia due to increased extra-renal 1-alpha
hydroxylation of 25-hydroxyvitamin D.
PMID- 10767261
TI - Bilateral diaphragm paralysis secondary to central von Recklinghausen's disease.
AB - Bilateral paralysis of the diaphragm is either idiopathic or associated with
several medical conditions, including trauma or thoracic surgery, viral
infections, and neurologic congenital or degenerative disorders. We describe the
case of a 36-year-old man with a history of neurofibromatosis who developed
severe bilateral diaphragmatic paralysis from involvement of the phrenic nerve
roots with neurofibromas. The patient manifested progressive exertional dyspnea
and debilitating orthopnea requiring the use of noninvasive mechanical
ventilation at night. A review of the literature reveals that neurofibromatosis
is an unrecognized cause of diaphragmatic paralysis.
PMID- 10767262
TI - Diaphragmatic rupture: A complication of violent cough.
AB - The cough is a complex physiologic response designed to protect airways from
unwanted secretions and foreign materials. Violent and paroxysmal coughs are
associated with many complications. In this article, we will discuss a patient
who sustained diaphragmatic rupture as a result of violent coughing. The possible
mechanisms of this rare complication are explained.
PMID- 10767263
TI - Infection of left atrial thrombus associated with mitral stenosis: A case report.
AB - We describe the first reported case of an infected left atrial thrombus. The case
of the 65-year-old male patient in this report was associated with mitral
stenosis and involved Escherichia coli, and was treated successfully with
surgical resection of the infected thrombus. This case suggests that such
infection should be considered as a possible complication of intracardiac
thrombus when bacteremia is present.
PMID- 10767264
TI - Echocardiographic follow-up of Chlamydia psittaci myocarditis.
AB - Chlamydia psittaci myocarditis has been infrequently reported. A case of
serologically confirmed C psittaci myocarditis with dilated left ventricle and
severely impaired left ventricular function is described. Serial echocardiograms
demonstrated complete recovery after therapy. An early diagnosis has important
prognostic implications.
PMID- 10767265
TI - Acute airway obstruction secondary to bilateral broncholithiasis.
AB - We report a case of acute airway obstruction secondary to bilateral broncholiths.
Successful management was achieved with rigid bronchoscopy.
PMID- 10767266
TI - Primary ciliary dyskinesia associated with a novel microtubule defect in a child
with Down's syndrome.
AB - We present a child with Down's syndrome, bilateral lower lobe bronchiectasis,
sinusitis, and severe ear disease who was found to have a novel ciliary defect,
with a frequent, partial absence of the walls of the A subunits of some
peripheral doublets. The defect caused the A subunits to be "U-shaped" rather
than "O-shaped." A nuclear nasal mucociliary transport study confirmed that this
defect was associated with abnormal mucociliary transport. The ciliary defect was
not observed in a biopsy performed in a second patient who had Down's syndrome.
PMID- 10767267
TI - Retrieval of an IV catheter fragment from the pulmonary artery 11 years after
embolization.
AB - The use of a peripherally inserted central catheter (PICC) is occasionally
complicated by intravascular fracture and central embolization of the catheter
fragment. We present a patient in whom a PICC fragment was retrieved from the
pulmonary artery 11 years after embolization following its incidental detection.
Despite a history of IV drug abuse and mitral regurgitation, this patient
remained asymptomatic and without complications. The catheter fragment was
retrieved since the patient was believed to be at risk for endocarditis. This may
be the longest duration reported of an embolized catheter fragment that was
successfully removed. As the natural history of asymptomatic-retained central
venous foreign bodies remains unclear, the decision to remove them should be
individualized. In selected cases, these foreign bodies may be retrieved without
complications even several years after embolization.
PMID- 10767268
TI - Heliox for acute severe asthma.
PMID- 10767269
TI - Heliox effect or rapid-onset acute severe asthma.
PMID- 10767270
TI - Inhaled indomethacin in bronchorrhea in bronchioloalveolar carcinoma: role of
cyclooxygenase.
PMID- 10767271
TI - A role for anaerobic bacteria in patients with ventilatory acquired pneumonia:
yes or no?
PMID- 10767272
TI - A possible pathologic link between chronic cough and sleep apnea syndrome through
gastroesophageal reflux disease in older people.
PMID- 10767273
TI - Infants exposed to maternal smoking and with a family history of asthma.
PMID- 10767274
TI - Tracheal colonization in pneumonia.
PMID- 10767275
TI - The "breathing-bag" sign in the diagnosis of tracheoesophageal fistula in
patients receiving mechanical ventilation.
PMID- 10767276
TI - Noninvasive ventilation and intubation.
PMID- 10767281
TI - Substrate specificity in glycoside hydrolase family 10. Tyrosine 87 and leucine
314 play a pivotal role in discriminating between glucose and xylose binding in
the proximal active site of Pseudomonas cellulosa xylanase 10A.
AB - The Pseudomonas family 10 xylanase, Xyl10A, hydrolyzes beta1, 4-linked xylans but
exhibits very low activity against aryl-beta-cellobiosides. The family 10 enzyme,
Cex, from Cellulomonas fimi, hydrolyzes aryl-beta-cellobiosides more efficiently
than does Xyl10A, and the movements of two residues in the -1 and -2 subsites are
implicated in this relaxed substrate specificity (Notenboom, V., Birsan, C.,
Warren, R. A. J., Withers, S. G., and Rose, D. R. (1998) Biochemistry 37, 4751
4758). The three-dimensional structure of Xyl10A suggests that Tyr-87 reduces the
affinity of the enzyme for glucose-derived substrates by steric hindrance with
the C6-OH in the -2 subsite of the enzyme. Furthermore, Leu-314 impedes the
movement of Trp-313 that is necessary to accommodate glucose-derived substrates
in the -1 subsite. We have evaluated the catalytic activities of the mutants
Y87A, Y87F, L314A, L314A/Y87F, and W313A of Xyl10A. Mutations to Tyr-87 increased
and decreased the catalytic efficiency against 4-nitrophenyl-beta-cellobioside
and 4-nitrophenyl-beta-xylobioside, respectively. The L314A mutation caused a 200
fold decrease in 4-nitrophenyl-beta-xylobioside activity but did not
significantly reduce 4-nitrophenyl-beta-cellobioside hydrolysis. The mutation
L314A/Y87A gave a 6500-fold improvement in the hydrolysis of glucose-derived
substrates compared with xylose-derived equivalents. These data show that
substantial improvements in the ability of Xyl10A to accommodate the C6-OH of
glucose-derived substrates are achieved when steric hindrance is removed.
PMID- 10767282
TI - Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector
pathway.
AB - Stimulation of beta-adrenergic receptor normally results in signaling by the
heterotrimeric G protein G(s), leading to the activation of adenylyl cyclase,
production of cAMP, and activation of cAMP-dependent protein kinase (PKA). Here
we report that cell death of thymocytes can be induced after stimulation of beta
adrenergic receptor, or by addition of exogenous cAMP. Apoptotic cell death in
both cases was observed with the appearance of terminal deoxynucleotidyl
transferase-mediated UTP end labeling reactivity and the activation of caspase-3
in S49 T cells. Using thymocytes deficient in either Galpha(s) or PKA, we find
that engagement of beta-adrenergic receptors initiated a Galpha(s)-dependent, PKA
independent pathway leading to apoptosis. This alternative pathway involves Src
family tyrosine kinase Lck. Furthermore, we show that Lck protein kinase activity
can be directly stimulated by purified Galpha(s). Our data reveal a new signaling
pathway for Galpha(s), distinct from the classical PKA pathway, that accounts for
the apoptotic action of beta-adrenergic receptors.
PMID- 10767284
TI - The effect of lipid environment and retinoids on the ATPase activity of ABCR, the
photoreceptor ABC transporter responsible for Stargardt macular dystrophy.
AB - ABCR is a photoreceptor-specific ATP-binding cassette transporter that has been
linked to various retinal diseases, including Stargardt macular dystrophy, and
implicated in retinal transport across rod outer segment (ROS) membranes. We have
examined the ATPase and GTPase activity of detergent-solubilized and
reconstituted ABCR. 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
solubilized ABCR had ATPase and GTPase activity (K(m) approximately 75 micrometer
V(max) approximately 200 nmol/min/mg) that was stimulated 1.5-2-fold by all-trans
retinal and dependent on phospholipid and dithiothreitol. The K(m) for ATP
decreased to approximately 25 micrometer after reconstitution, whereas the V(max)
was strongly dependent on the lipid used for reconstitution. ABCR reconstituted
in ROS phospholipid had a V(max) for basal and retinal activated ATPase activity
that was 4-6 times higher than for ABCR in soybean or brain phospholipid. This
enhanced activity was mainly due to the high phosphatidylethanolamine (PE)
content of ROS membranes. PE was also required for retinoid-stimulated ATPase
activity. ATPase activity of ABCR was stimulated by the addition of N
retinylidene-PE but not the reduced derivative, retinyl-PE. ABCR expressed in COS
1 cells also exhibited retinal-stimulated ATPase activity similar to that of the
native protein. These results support the view that ABCR is an active retinoid
transporter, the nucleotidase activity of which is strongly influenced by its
lipid environment.
PMID- 10767286
TI - The mammalian peroxin Pex5pL, the longer isoform of the mobile peroxisome
targeting signal (PTS) type 1 transporter, translocates the Pex7p.PTS2 protein
complex into peroxisomes via its initial docking site, Pex14p.
AB - In mammals, two isoforms of the peroxisome targeting signal (PTS) type 1 receptor
Pex5p, i.e. Pex5pS and Pex5pL with an internal 37-amino acid insertion, have
previously been identified. Expression of either type of Pex5p complements the
impaired PTS1 import in Chinese hamster ovary pex5 mutants, but only Pex5pL can
rescue the PTS2 import defect noted in a subgroup of pex5 mutants such as ZP105.
In this work, we found that Pex5pL directly interacts with the PTS2 receptor
Pex7p, carrying its cargo PTS2 protein in the cytosol. Pex5pL, but not Pex5pS,
mediated the binding of PTS2 protein to Pex14p by translocating Pex7p,
demonstrating that Pex5pL plays a pivotal role in peroxisomal PTS2 import. Pex5p
was localized mostly in the cytosol in wild-type CHO-K1 and Pex14p-deficient
mutant cells, whereas it accumulated in the peroxisomal remnants in cell mutants
defective in Pex13p or the RING family peroxins such as Pex2p and Pex12p.
Furthermore, overexpression of Pex14p, but not Pex10p, Pex12p, or Pex13p, caused
accumulation of Pex5p in peroxisomal membranes, with concomitant interference
with PTS1 and PTS2 import. Therefore, Pex5p carrying the cargoes most likely
docks with the initial site (Pex14p) in a putative import machinery, subsequently
translocating to other components such as Pex13p, Pex2p, Pex10p, and Pex12p.
PMID- 10767287
TI - Disruption of the interaction of the longer isoform of Pex5p, Pex5pL, with Pex7p
abolishes peroxisome targeting signal type 2 protein import in mammals. Study
with a novel Pex5-impaired Chinese hamster ovary cell mutant.
AB - We isolated peroxisome biogenesis-defective Chinese hamster ovary cell mutants
from TKaG2 cells, wild-type CHO-K1 cells transformed with two cDNAs encoding rat
Pex2p and peroxisome targeting signal (PTS) type 2-tagged green fluorescent
protein, by the 9-(1'-pyrene)nonanol/UV selection method. Ten mutant clones
showed cytosolic PTS2-green fluorescent protein, indicative of a defect in PTS2
import, and were classified in five complementation groups, i.e. pex1, pex2,
pex5, pex14, and group A. One PEX5-deficient mutant, ZPG231, showed a novel
phenotype: PTS2 proteins in the cytosol, but PTS1 proteins and catalase in
peroxisomes. In ZPG231, two isoforms of the PTS1 receptor Pex5p, a shorter Pex5pS
and a longer Pex5pL, were expressed as in wild-type cells, but possessed the
missense point mutation S214F in both Pex5p isoforms, termed Pex5pS-S214F and
Pex5pL-S214F, respectively. The S214F mutation was located only one amino acid
upstream of the Pex5pL-specific 37-amino acid insertion site. Pex5pS-S214F and
Pex5pL-S214F interacted with peroxisomal proteins, including PTS1 protein,
catalase, and Pex14p, as efficiently as normal Pex5p. In contrast, the S214F
mutation severely affected the binding of Pex5pL to the PTS2 receptor Pex7p.
Expression of Pex5pL-S214F in pex5 cell mutants defective in PTS1 and PTS2
transport restored peroxisomal import of PTS1, but not PTS2. Together, the
results indicate that ZPG231 is the first cell mutant providing evidence that
disruption of the Pex5pL-Pex7p interaction completely abolishes PTS2 import in
mammals.
PMID- 10767288
TI - Calcineurin controls the transcription of Na+/Ca2+ exchanger isoforms in
developing cerebellar neurons.
AB - The Na(+)/Ca(2+) exchanger (NCX) and the plasma membrane Ca(2+)-ATPase export
Ca(2+) from the cytosol to the extracellular space. Three NCX genes (NCX1, NCX2,
and NCX3), encoding proteins with very similar properties, are expressed at
different levels in tissues. Essentially, no information is available on the
mechanisms that regulate their expression. Specific antibodies have been prepared
and used to explore the expression of NCX1 and NCX2 in rat cerebellum. The
expression of NCX2 became strongly up-regulated during development, whereas
comparatively minor effects were seen for NCX1. This was also observed in
cultured granule cells induced to mature in physiological concentrations of
potassium. By contrast, higher K(+) concentrations, which induce partial
depolarization of the plasma membrane and promote the influx of Ca(2+), caused
the complete disappearance of NCX2. Reverse transcription-polymerase chain
reaction analysis showed that the process occurred at the transcriptional level
and depended on the activation of the Ca(2+) calmodulin-dependent protein
phosphatase, calcineurin. The NCX1 and NCX3 genes were also affected by the
depolarizing treatment: the transcription of the latter became up-regulated, and
the pattern of expression of the splice variants of the former changed. The
effects on the NCX1 and NCX3 genes were calcineurin-independent.
PMID- 10767290
TI - A kinesin mutation that uncouples motor domains and desensitizes the gamma
phosphate sensor.
AB - Conventional kinesin is a processive, microtubule-based motor protein that drives
movements of membranous organelles in neurons. Amino acid Thr(291) of Drosophila
kinesin heavy chain is identical in all superfamily members and is located in
alpha-helix 5 on the microtubule-binding surface of the catalytic motor domain.
Substitution of methionine at Thr(291) results in complete loss of function in
vivo. In vitro, the T291M mutation disrupts the ATPase cross-bridge cycle of a
kinesin motor/neck construct, K401-4 (Brendza, K. M., Rose, D. J., Gilbert, S.
P., and Saxton, W. M. (1999) J. Biol. Chem. 274, 31506-31514). The pre-steady
state kinetic analysis presented here shows that ATP binding is weakened
significantly, and the rate of ATP hydrolysis is increased. The mutant motor also
fails to distinguish ATP from ADP, suggesting that the contacts important for
sensing the gamma-phosphate have been altered. The results indicate that there is
a signaling defect between the motor domains of the T291M dimer. The ATPase
cycles of the two motor domains appear to become kinetically uncoupled, causing
them to work more independently rather than in the strict, coordinated fashion
that is typical of kinesin.
PMID- 10767293
TI - Distinctive cyclic AMP-dependent protein kinase subunit localization is
associated with cyst formation and loss of tubulogenic capacity in Madin-Darby
canine kidney cell clones.
AB - Polycystic kidney disease is characterized by abnormal morphological development.
Mechanisms that regulate cyst development may involve multiple signaling
pathways. Cyst formation by Madin-Darby canine kidney (MDCK) cells in three
dimensional culture is assumed to be cyclic AMP-dependent and due to cyclic AMP
dependent protein kinase (cAPK) activation based on pharmacological
responsiveness. To determine if different cyclic AMP (cAMP) pathways are
associated with morphological development, the role of cAMP in regulating
morphological change was examined in MDCK clones that form tumor-like or tubular
structures under basal conditions. Pharmacological cAMP pathway activators induce
cyst formation and diminish formation of other structures in three clones,
whereas one clone is unaffected. Tyrosine kinase-mediated morphogens have little
effect. Although all clones have intact cAMP signaling pathways, each has a
unique subcellular distribution of cAPK regulatory subunits. This may reflect
distinct mechanisms for cAPK anchoring, allowing cAPK subtype regulation of the
unique phenotypic character of each clone through preferential access to
substrates. These observations suggest a molecular basis for differential cAMP
responsiveness in cells that develop distinct morphological phenotypes. This
evidence establishes these MDCK clones as models for understanding the mechanism
and functional significance of cAPK subunit localization and may have broader
implications for cystogenesis in polycystic kidney disease.
PMID- 10767297
TI - Transcriptional activation by the Ewing's sarcoma (EWS) oncogene can be cis
repressed by the EWS RNA-binding domain.
AB - The Ewing's sarcoma (EWS) oncogene contains an N-terminal transcriptional
activation domain (EWS activation domain, EAD) and a C-terminal RNA-binding
domain (RBD). Although it has been established that the EAD is a potent trans
activation domain that is required for the oncogenic activity of several EWS
fusion proteins (EFPs), the precise function of the RBD and the normal role of
intact EWS are poorly characterized. Here we show that a cis-linked RBD can
strongly and specifically repress trans-activation by the EAD. Fusion proteins
containing the RBD are expressed at normal levels, are nuclear-localized, and can
bind to DNA both in vitro and in vivo, demonstrating that the RBD represses trans
activation directly at the promoter. The RNA recognition motif within the RBD is
not required for repression, whereas regions of the RBD containing multiple RGG
motifs play a critical role. The finding that the RBD can antagonize
transcriptional activation by EWS provides the first direct evidence of a role
for the RBD in transcription. Further studies of the repression phenomenon should
illuminate key molecular interactions that distinguish EWS from EFPs and provide
insights into the normal cellular function of EWS.
PMID- 10767298
TI - Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates
cell cycle progression.
AB - 14-3-3 sigma, implicated in cell cycle arrest by p53, was cloned by expression
cloning through cyclin-dependent kinase 2 (CDK2) association. 14-3-3 sigma shares
cyclin-CDK2 binding motifs with different cell cycle regulators, including p107,
p130, p21(CIP1), p27(KIP1), and p57(KIP2), and is associated with cyclin.CDK
complexes in vitro and in vivo. Overexpression of 14-3-3 sigma obstructs cell
cycle entry by inhibiting cyclin-CDK activity in many breast cancer cell lines.
Overexpression of 14-3-3 sigma can also inhibit cell proliferation and prevent
anchorage-independent growth of these cell lines. These findings define 14-3-3
sigma as a negative regulator of the cell cycle progression and suggest that it
has an important function in preventing breast tumor cell growth.
PMID- 10767308
TI - Autism: recent molecular genetic advances.
AB - Autism (MIM 209850) is a severe neuropsychiatric disorder of unknown aetiology
with profound consequences for patients and their families. Strong evidence from
twin and family studies indicates the importance of genetic factors in the
development of idiopathic autism, although it is clear that these influences are
complex. This review focuses on recent molecular investigations to identify
susceptibility loci implicated in autistic disorder.
PMID- 10767309
TI - A role for Caenorhabditis elegans in understanding the function and interactions
of human disease genes.
AB - A growing number of medical research teams have begun to explore the experimental
advantages of using a genetic animal model, the nematode worm Caenorhabditis
elegans, with a view to enhancing our understanding of genes underlying human
congenital disorders. In this study, we have compared sequences of positionally
cloned human disease genes with the C.elegans database of predicted genes.
Drawing on examples from spinal muscular atrophy, polycystic kidney disease,
muscular dystrophy and Alzheimer's disease, we illustrate how data from C.elegans
can yield new insights into the function and interactions of human disease genes.
PMID- 10767310
TI - Neural cell recognition molecule L1: relating biological complexity to human
disease mutations.
AB - Human single gene disorders that affect the nervous system provide a host of
natural mutations that can be deployed in the quest to understand its development
and function. A paradigm for this approach is the study of disorders caused by
mutations in the gene for the neural cell recognition molecule L1. L1 is the
founder member of a subfamily of cell adhesion molecules that are primarily
expressed in the nervous system, and to date it is the only one to be associated
with a hereditary disease. In this review we will summarize how the analysis of
pathological mutations in L1 is complementing the study of mouse models and in
vitro analysis of L1 function.
PMID- 10767311
TI - Recent advances in the molecular pathogenesis of Friedreich ataxia.
AB - Friedreich ataxia, the most frequent cause of recessive ataxia, is due in most
cases to a homozygous intronic expansion resulting in the loss of function of
frataxin. Frataxin is a mitochondrial protein conserved through evolution. Yeast
knock-out models and histological data from patient heart autopsies have shown
that frataxin defect causes mitochondrial iron accumulation. Biochemical data
from patient heart biopsies or autopsies have revealed a specific deficiency in
the activities of aconitases and of mitochondrial iron-sulfur proteins. These
results suggest that frataxin may play a role either in mitochondrial iron
transport or in iron-sulfur cluster assembly or transport. Iron abnormalities
suggest a pathogenic mechanism involving free radical production and oxidative
stress, a process that might be sensitive to antioxidant therapies.
PMID- 10767312
TI - Towards new models of disease and physiology in the neurosciences: the role of
induced and naturally occurring mutations.
AB - There is a dearth of good mouse models for central nervous system (CNS)
disorders. However, the development of gene-targeted technology and the
recognition of the importance of the mouse as a model organism have led to the
development of a range of behavioural tests for mice. Spontaneous mutations in
mice have already provided important information about the role of novel gene
products in disorders such as epilepsy and deafness. This has provided the
impetus to the establishment of large-scale mutagenesis programmes to generate
new mutations. Tests of sensory and motor function have previously been most
frequently used as these are simple to perform and the phenotypes are relatively
obvious. Subtle phenotypes, of relevance to pyschiatric disorders such as anxiety
and schizophrenia, can be detected using more complex tests. Screens such as
prepulse inhibition and startle have been adapted for mice and these can be run
with relatively high throughput using fully automated equipment. Other behaviours
such as sleep and circadian rhythms, learning and memory and nociception can also
be assessed. New technological advances in non-invasive imaging and neurochemical
analyses have meant that these techniques can be readily applied to mouse
phenotyping. The use of these screens together with mutagenesis is already
beginning to increase the numbers of mouse models of potential relevance to CNS
diseases.
PMID- 10767313
TI - Understanding the molecular basis of fragile X syndrome.
AB - Fragile X syndrome, a common form of inherited mental retardation, is mainly
caused by massive expansion of CGG triplet repeats located in the 5'-untranslated
region of the fragile X mental retardation-1 ( FMR1 ) gene. In patients with
fragile X syndrome, the expanded CGG triplet repeats are hypermethylated and the
expression of the FMR1 gene is repressed, which leads to the absence of FMR1
protein (FMRP) and subsequent mental retardation. FMRP is an RNA-binding protein
that shuttles between the nucleus and cytoplasm. This protein has been implicated
in protein translation as it is found associated with polyribosomes and the rough
endoplasmic reticulum. We discuss here the recent progress made towards
understanding the molecular mechanism of CGG repeat expansion and physiological
function(s) of FMRP. These studies will not only help to illuminate the molecular
basis of the general class of human diseases with trinucleotide repeat expansion
but also provide an avenue to understand aspects of human cognition and
intelligence.
PMID- 10767314
TI - Fourteen and counting: unraveling trinucleotide repeat diseases.
AB - The pathological expansion of unstable trinucleotide repeats currently is known
to cause 14 neurological diseases. Over the past several years, researchers have
concentrated on the challenging task of identifying the mechanism by which the
expanded trinucleotide repeat leads to abnormal cellular function. As a
consequence, the trinucleotide repeat field has grown dramatically since the
initial discovery of dynamic mutations less than a decade ago. Trinucleotide
repeat expansions may prove to cause pathology through a variety of mechanisms
including interference with DNA structure, transcription, RNA-protein interaction
and altered protein conformations/interactions. The goal of this review is to
provide a brief description of the genes harboring expanded repeats, coupled with
new insights into the molecular pathways most likely to be disrupted by these
expansions. Data from studies of patient material, cell culture and animal models
demonstrate the complexity of the pathogenic mechanisms in each of the diseases.
PMID- 10767315
TI - Vertebrate eye development as modeled in Drosophila.
AB - Pax6, a member of the paired-box family of transcription factors, is critical for
oculogenesis in both vertebrates and insects. Identification of potential
vertebrate Pax6 targets has been guided by studies in Drosophila, where the Pax6
homologs eyeless ( ey ) and twin of eyeless ( toy ) function within a network of
genes that synergistically pattern the developing fly eye. These targets, which
share homology with the fly genes sine oculis, eyes absent and dachshund, exist
in mice and humans as the Six, Eya and Dach gene families. Members of these gene
families are present in the developing vertebrate eye, and preliminary studies
suggest that they may function in a network analogous to that in the fly. Thus,
despite radically different architecture, a similar molecular scaffold underlies
both vertebrate and fly eye patterning, suggesting that the considerable power of
Drosophila genetics can be harnessed to study mammalian ocular development.
PMID- 10767316
TI - Recent progress in psychiatric genetics-some hope but no hype.
AB - The reputation of the field of psychiatric genetics has recently become tarnished
in the view of many human geneticists. Too many linked loci were claimed and
withdrawn, too many association studies published and not confirmed and, more
recently, too many new and different chromosomal regions have been implicated for
the same disorder. Here, we summarize recent trends, focusing on research that
moves away from traditional linkage studies. Some promising strategies include
psychopharmacogenetics, and consideration of endophenotypes such as
neurophysiological and behavioral markers in addition to the clinical diagnosis.
Utilization of rapid and automated methods for scoring genetic variants in large
scale association studies followed by multivariate analyses, which include
environmental as well as genetic data, will likely fare better than traditional
linkage analysis in disentangling the complex genetics of psychiatric disorders.
Some notable areas of recent progress include quantification of the genetic
complexity of autism, identification of genetic variants protecting individuals
from alcoholism, and the description of several polymorphisms likely to be
relevant to behavior and psychiatry. The most notable example may be a common
variant that affects the transcription rate in the promoter for the serotonin
transporter gene that may be relevant for individual differences in the response
to common anti-depressants.
PMID- 10767317
TI - Analysis of mammalian central nervous system gene expression and function using
bacterial artificial chromosome-mediated transgenesis.
AB - The anatomical complexity of the mammalian central nervous system (CNS) presents
special problems for the analysis of CNS gene expression and function. The most
difficult challenge is presented by the simple fact that there are hundreds of
functionally and morphologically defined cell types in the CNS. Given this
complexity, the interpretation of CNS phenotypes is often problematic. The
preparation of transgenic mice carrying marked bacterial artificial chromosomes
(BACs) provides an important avenue for improving our understanding of CNS
expressed genes and phenotypes. This approach can allow efficient analysis of
patterns of gene expression, subcellular localization of their encoded products
and neuronal projection patterns. BAC transgenic mice can also provide access to
information relevant to gene function based on phenotypes arising from increased
gene dosage or expression of activating and dominant-negative alleles. This
review will concentrate on these issues and their relevance to the analysis of
CNS-expressed genes.
PMID- 10767318
TI - Zebrafish developmental genetics and central nervous system development.
AB - The central nervous system (CNS) is the most complex tissue of vertebrates.
Recently, the zebrafish has emerged as a powerful genetic system for studying
early development, and large-scale mutagenic screens for embryonic patterning
defects have been accomplished. Mutants isolated in these screens are proving
helpful in unravelling the molecular hierarchies involved in the development of
the CNS. We review here recent studies in zebrafish which shed light on the
genetic pathways involved in induction and regionalization of the CNS.
PMID- 10767319
TI - Dissection of behavior and psychiatric disorders using the mouse as a model.
AB - Mouse genetic models have played an important role in the elucidation of
molecular pathways underlying human disease. This approach is becoming an
increasingly popular way to study the genetic underpinning of psychiatric
disorders. Genes within candidate regions for susceptibility to psychiatric
illness can be evaluated through the phenotypic assessment of mutants mapped to
the corresponding regions in the mouse genome. Alternatively, one can search for
mouse mutants displaying characteristics that might correspond to physiological
and behavioral markers of a psychiatric disorder, sometimes referred to as
endophenotypes. Mice with anomalies in these traits can be generated by targeted
mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can
be identified among progeny of mice in a random mutagenesis screen (phenotype
based mutagenesis or forward genetics). In this review, we discuss recently
generated behavioral mutants in the mouse. We also give an overview of several
robust and commonly used behavioral phenotypes, their relevance to human disease
and lessons learned from recent successes in mouse behavioral genetics.
PMID- 10767320
TI - Structural features of normal and mutant human lysosomal glycoside hydrolases
deduced from bioinformatics analysis.
AB - Lysosomal storage diseases are due to inherited deficiencies in various enzymes
involved in basic metabolic processes. As with other genetic diseases, accurate
structure data for these enzymatic proteins should help in better understanding
the molecular effects of mutations identified in patients with the corresponding
lysosomal diseases; however, no such three-dimensional (3D) structure data are
available for many lysosomal enzymes. Thus, we herein intend to illustrate for an
audience of molecular geneticists how structure information can nonetheless be
obtained via a bioinformatics approach in the case of five human lysosomal
glycoside hydrolases. Indeed, using the two-dimensional hydrophobic cluster
analysis method to decipher the sequence information available in data banks for
the large group of glycoside hydrolases (clan GH-A) to which these human
lysosomal enzymes belong, we could deduce structure predictions for their
catalytic domains and propose explanations for the molecular effects of mutations
described in patients. In addition, in the case of human beta-glucuronidase for
which experimental 3D data have been reported, we also show here that
bioinformatics methods relying on the available 3D structure information can be
used to obtain further insights into the effects of various mutations described
in patients with Sly disease. In a broader perspective, our work stresses that,
in the context of a rapid increase in protein sequence information through genome
sequencing, bioinformatics approaches might be highly useful for generating
structure-function predictions based on sequence-structure interrelationships.
PMID- 10767321
TI - Untangling tau-related dementia.
AB - Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated
protein tau are a characteristic pathological observation in several
neurodegenerative disorders such as Alzheimer's disease, Pick's disease,
frontotemporal dementia, cortico-basal degeneration and progressive supranuclear
palsy. The recent finding that mutations in the tau gene are responsible for
frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has
provided convincing evidence that tau protein plays a key role in
neurodegeneration. In the short period since the identification of pathogenic
mutations in tau, remarkable progress has been made in understanding some of the
mechanisms by which these mutations lead to neurodegeneration. Understanding the
disease processes will hopefully provide us with new leads in developing
effective therapies for dementia.
PMID- 10767322
TI - The proteolipid protein gene and myelin disorders in man and animal models.
AB - The two proteins, proteolipid protein and DM20, which are encoded by alternative
transcripts from the proteolipid protein ( PLP ) gene, are major components of
central nervous system myelin. In man, mutations of these proteins cause
Pelizaeus-Merzbacher disease (PMD), an X-linked dysmyelinating neuropathy. The
mutations found are very varied, ranging from deletions, loss-of-function and
missense mutations to additional copies of the gene. This same range of known
genetic defects has been observed in animal models with spontaneous and
engineered Plp gene mutations. The relationship between genotype and phenotype is
remarkably close in the animal models and the PMD cases, making them useful
models for studying the mechanisms of PLP gene-related disease. As a result, it
has become clear that the PLP gene plays a wider role in neural development in
addition to its function as a structural component of myelin. It has also emerged
that duplications of the PLP gene are the commonest mutation in PMD. Genetic
disorders arising from a dosage effect may be more common than previously
recognized. The study of the PLP gene in this rare disorder is, therefore,
contributing both to our understanding of neural development and maintenance and
to the mechanisms of human genetic disorders.
PMID- 10767323
TI - Mouse models for neural tube closure defects.
AB - Neural tube closure defects (NTDs), in particular anencephaly and spina bifida,
are common human birth defects (1 in 1000), their genetics is complex and their
risk is reduced by periconceptional maternal folic acid supplementation. There
are > 60 mouse mutants and strains with NTDs, many reported within the past 2
years. Not only are NTD mutations at loci widely heterogeneous in function, but
also most of the mutants demonstrate variable low penetrance and some show
complex inheritance patterns (e.g. SELH/Bc, Abl / Arg, Mena / Profilin1 ). In
most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly)
or spina bifida or both, reflecting failure of neural fold elevation in well
defined, mechanistically distinct elevation zones. NTD risk is reduced in various
models by different maternal nutrient supplements, including folic acid ( Pax3,
Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ). Lack of de novo
methylation in embryos ( Dnmt3b -null) leads to NTD risk, and we suggest a
potential link between methylation and the observed female excess among cranial
NTDs in several models. Some surprising NTD mutants ( Gadd45a, Terc, Trp53 )
suggest that genes with a basic mitotic function also have a function specific to
neural fold elevation. The genes mutated in several mouse NTD models involve
actin regulation ( Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl ), support the
postulated key role of actin in neural fold elevation, and may be a good
candidate pathway to search for human NTD genes.
PMID- 10767324
TI - Large and diverse numbers of human diseases with HIKE mutations.
AB - HIKE is a highly conserved sequence motif identified as a candidate pleckstrin
homology (PH) domain binding site in Gbeta proteins, protein kinases, ankyrin and
kinesin. HIKE motifs occur also in gelsolin, neurogranin, neuromodulin and in the
PH domain of Bruton tyrosin kinase (BTK). Phosphatidylinositol-binding sequences
more distantly related to HIKE are present in gelsolin, in the G protein-coupled
receptor kinase 4 and in Trop-2. HIKE regions have been demonstrated to bind both
proteins and lipids, and to regulate the interaction of Gbeta, neuromodulin and
the BTK PH domain with downstream effectors and the cell membrane. Remarkably,
mutations of the HIKE regions are common in diverse human genetic diseases.
Several HIKE mutations in protein kinases lead to constitutive activation and
cellular transformation, e.g. in MEN-2B, acute myeloid and mast cell leukemias,
hereditary papillary renal carcinomas and multiple myeloma. Kinase-inactivating
HIKE mutations cause Hirschsprung's disease, piebaldism, insulin resistance and
developmental dysplasias. HIKE mutations in the PH domain of BTK lead to X-linked
agammaglobulinemia, and different forms of amyloidosis are caused by mutations of
HIKE-bearing molecules, for example gelsolin, Ret and Trop-2. Thus, quite diverse
genetic diseases might share common molecular mechanisms. These include altered
interactions of the mutated molecules with downstream effectors or the cell
membrane, and defects in intracellular transport.
PMID- 10767325
TI - Single nucleotide polymorphism and linkage disequilibrium within the TCR
alpha/delta locus.
AB - Much attention is being given to the identification of common disease genes
through whole-genome linkage disequilibrium (LD) screens with single nucleotide
polymorphisms (SNPs). Simulation studies have suggested that useful LD is
unlikely to extend beyond 3 kb, and that > 500,000 SNPs may be needed for
comprehensive coverage of the genome. The TCR alpha/delta locus on chromosome 14q
contains many V, J and D segments that combine with constant domains to produce
either an alpha or a delta chain of the T cell receptor. Multiple SNPs have been
recognized within the V segments, and it has been suggested that variation within
the locus may modify the course of autoimmune and allergic diseases. We have
examined LD within an 850 kb section of the TCR alpha/delta locus on chromosome
14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and
fifty-nine nuclear and extended families were genotyped in order to derive
haplotypes, and the pair-wise LD between SNPs was investigated in 600 haplotypes
from unrelated individuals (the parents). The mean extent of useful LD was much
greater than suggested by simulations: significant LD was relatively common at
250 kb and was detectable beyond 500 kb. The mean extent of LD was twice as far
between alleles of low frequency than between common alleles. The distribution of
LD was highly irregular and concentrated in three distinct islands. The results
differ from those obtained by simulation, and if they are typical of other
genomic regions, suggest that the minimum number of markers necessary for
comprehensive LD mapping may be reduced by at least an order of magnitude.
PMID- 10767326
TI - Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in
aberrant ocular development.
AB - Anterior segment developmental disorders, including Axenfeld-Rieger anomaly
(ARA), variably associate with harmfully elevated intraocular pressure (IOP),
which causes glaucoma. Clinically observed dysgenesis does not correlate with
IOP, however, and the etiology of glaucoma development is not understood. The
forkhead transcription factor genes Foxc1 (formerly Mf1 ) and Foxc2 (formerly
Mfh1 ) are expressed in the mesenchyme from which the ocular drainage structures
derive. Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior
segment defects and glaucoma in various families. We show that Foxc1 (+/-)mice
have anterior segment abnormalities similar to those reported in human patients.
These abnormalities include small or absent Schlemm's canal, aberrantly developed
trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced
Schwalbe's line. The penetrance of clinically obvious abnormalities varies with
genetic background. In some affected eyes, collagen bundles were half normal
diameter, or collagen and elastic tissue were very sparse. Thus, abnormalities in
extracellular matrix synthesis or organization may contribute to development of
the ocular phenotypes. Despite the abnormalities in ocular drainage structures in
Foxc1 (+/-)mice, IOP was normal in almost all mice analyzed, on all genetic
backgrounds and at all ages. Similar abnormalities were found in Foxc2 (+/-)mice,
but no disease-associated mutations were identified in the human homolog FKHL14
in 32 ARA patients. Foxc1 (+/-)and Foxc2 (+/-)mice are useful models for studying
anterior segment development and its anomalies, and may allow identification of
genes that interact with Foxc1 and Foxc2 (or FKHL7 and FKHL14 ) to produce a
phenotype with elevated IOP and glaucoma.
PMID- 10767327
TI - Biochemical evidence for association of dystrobrevin with the sarcoglycan
sarcospan complex as a basis for understanding sarcoglycanopathy.
AB - The sarcoglycan complex is composed of four membrane-spanning dystrophin
associated proteins (DAPs) and is essential for skeletal muscle survival, since
the absence or markedly reduced expression of this complex due to mutation of any
one of the sarcoglycan genes causes a group of muscular dystrophies, collectively
termed sarcoglycanopathy. Although one of the putative functions of the
sarcoglycan complex is its participation in signaling processes, detailed studies
have been scarce. Very recently, it was shown that gene knockout mice for a DAP,
alpha-dystrobrevin, exhibit a dystrophic phenotype, possibly due to defects in
muscle cell signaling. To clarify the putative function of the sarcoglycan
complex, it is essential to determine whether or not there is a link between it
and the intracellular signaling molecules. To elucidate this, we developed new
methods for preparing various DAP complexes containing the sarcoglycan complex
from the purified dystrophin-DAP complex. It was suggested from one of the
complexes prepared that the sarco-glycan-sarcospan complex (the sarcoglycan
complex associated with sarcospan) is associated with syntrophin and/or
dystrobrevin. Further analysis of this complex revealed that the N-terminal half
of dystrobrevin participates in this association. It is thus considered that the
sarcoglycan-sarcospan complex is linked to the signaling protein neuronal nitric
oxide synthase via alpha-syntrophin associated with dystrobrevin.
PMID- 10767328
TI - Sequential deletion of C-terminal amino acids of the E(1)alpha component of the
pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of
functional E(1)alpha(2)beta(2) tetramers: implications for patients with PDH
deficiency.
AB - Human pyruvate dehydrogenase (PDH) complex deficiency is an extremely
heterogeneous disease in its presentation and clinical course. We have
characterized novel mutations that affect the C-terminal portion of the PDH
E(1)alpha-coding sequence. Although the molecular defects underlying these
mutations are different, both effectively produce a stop codon prematurely three
amino acids from the C-terminus. The clinical and biochemical consequences of
these mutations are unusual in that the affected individuals are very long-term
survivors with PDH complex deficiency despite having low (<20%) activity in skin
fibroblasts. These findings prompted us to investigate the C-terminus of
E(1)alpha in greater detail. We constructed and expressed a series of PDH
E(1)alpha deletion mutants in a cell line with zero PDH complex activity due to a
null E(1)alpha allele. Sequential deletion of the C-terminus by one, two, three
and four amino acids resulted in PDH complex activities of 100, 60, 36 and 14%,
respectively, compared with wild-type E(1)alpha expressed in PDH complex
deficient cells. The immunodetectable protein was decreased by the same amount as
the activity, suggesting that the stability and/or assembly of the
E(1)alpha(2)beta(2)heterotetramer might depend on the intactness of the PDH
E(1)alpha C-terminus. In addition, we compared the somatic and the testis
specific isoforms of E(1)alphaand concluded that they are biochemically
equivalent.
PMID- 10767329
TI - Genome-wide scan for schizophrenia in the Finnish population: evidence for a
locus on chromosome 7q22.
AB - We report the results of a four-stage genome-wide scan in a schizophrenia study
sample consisting of 134 affected sib-pairs collected in Finland. In stage I we
genotyped 370 markers from the Weber 6 screening set ( N = 52 affected sib
pairs); in stage II we followed up 40 markers by typing first-degree relatives of
the sib-pairs; in stage III we genotyped 15 markers in 134 families; and in stage
IV we genotyped a denser marker map in the two most promising regions, one on
chromosome 1 and another on chromosome 7, in all families. Diagnoses were based
on three nationwide health care registers and consensus diagnosis based on review
of all medical records. The most significant finding was a two-point lod score of
3.18 with marker D7S486 using a dominant model and treating all individuals with
either schizophrenia, schizoaffective disorder or other schizophrenia spectrum
disorder as affected. Multipoint analysis with MAPMAKER/SIBS resulted in a MLS of
3.53 between markers D7S501 and D7S523 using the broadest diagnostic model,
including major depressive disorder and bipolar type I as affecteds in addition
to the aforementioned phenotypes. These results were obtained by including in the
analyses only individuals from the late settlement region of Finland settled in
the 16th century. Additionally, some support was obtained for linkage to
chromosome 1, in a region previously identified in a genome-wide scan of a study
sample from a sub-isolate of Finland. Our data demonstrate the importance of
genealogical information for studies aiming at identification of predisposing
loci in complex diseases.
PMID- 10767330
TI - Genetic and cellular defects contributing to benign tumor formation in
neurofibromatosis type 1.
AB - Neurofibromatosis type 1 (NF1) is a common inherited cancer predisposition
syndrome. The NF1 gene product, neurofibromin, is hypothesized to function as a
tumor suppressor and nearly all NF1 patients develop benign peripheral nerve
tumors. These neurofibromas presumably arise from NF1 inactivation in
S100(+)Schwann cells, but there is no formal proof for this mechanism. We
demonstrate that fibro-blasts isolated from neurofibromas carried at least one
normal NF1 allele and expressed both NF1 mRNA and protein, whereas the
S100(+)cells typically lacked the NF1 transcript. Our findings further indicate
that additional molecular events aside from NF1 inactivation in Schwann cells
and/or other neural crest derivatives contribute to neurofibroma formation.
PMID- 10767331
TI - LMX1B transactivation and expression in nail-patella syndrome.
AB - Lmx1b, a member of the LIM homeodomain protein family, is essential for the
specification of dorsal limb fates at the zeugopodal and autopodal level in
vertebrates. We and others have shown that a skeletal dysplasia, nail-patella
syndrome (NPS), results from mutations in LMX1B. While it is a unique mesenchymal
determinant of dorsal limb patterning during vertebrate development, the
mechanism by which LMX1B mutations generate the NPS phenotype has not been
addressed at a transcriptional level or correlated with its spatial pattern of
gene expression. In this study, in situ hybridizations of Lmx1b on murine limb
sections reveal strong expression in dorsal mesenchymal tissues (precursors of
muscle, tendons, joints and patella) and, interestingly, also in anterior
structures of the limb, explaining the anterior to posterior gradient of joint
and nail dysplasia observed in NPS patients. Transfection studies showed that
both the LIM domain-interacting protein, LDB1, and the helix-loop-helix protein,
E47/shPan1, can regulate LMX1B action. While co--transfections of E47/shPan1 with
LMX1B result in a synergistic effect on reporter activity, LDB1 down-regulated
LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins
containing human mutations affecting each of the helices or the N-terminal arm of
the homeodomain abolished transactivation, while LIM B and truncation mutations
retained residual activity. These mutations fail to act in a dominant-negative
manner on wild-type LMX1B in mixing studies, thereby supporting
haploinsufficiency as the mechanism underlying NPS pathogenesis.
PMID- 10767332
TI - Characterization of the sialidase molecular defects in sialidosis patients
suggests the structural organization of the lysosomal multienzyme complex.
AB - Sialidosis is an autosomal recessive disease caused by the genetic deficiency of
lysosomal sialidase, which catalyzes the hydrolysis of sialoglycoconjugates. The
disease is associated with progressive impaired vision, macular cherry-red spots
and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like
phenotype, dysostosis multiplex, mental retardation and hepatosplenomegaly
(sialidosis type II). We have analyzed the genomic DNA from nine sialidosis
patients of multiple ethnic origin in order to find mutations responsible for the
enzyme deficiency. The activity of the identified variants was studied by
transgenic expression. One patient had a frameshift mutation (G623delG deletion),
which introduced a stop codon, truncating 113 amino acids. All others had
missense mutations: G679G-->A (Gly227Arg), C893C-->T (Ala298Val), G203G-->T
(Gly68Val), A544A-->G (Ser182Gly) C808C-->T (Leu270Phe) and G982G-->A
(Gly328Ser). We have modeled the three-dimensional structure of sialidase based
on the atomic coordinates of the homologous bacterial sialidases, located the
positions of mutations and estimated their potential effect. This analysis showed
that five mutations are clustered in one region on the surface of the sialidase
molecule. These mutations dramatically reduce the enzyme activity and cause a
rapid intralysosomal degradation of the expressed protein. We hypothesize that
this region may be involved in the interface of sialidase binding with lysosomal
cathepsin A and/or beta-galactosidase in their high-molecular-weight complex
required for the expression of sialidase activity in the lysosome.
PMID- 10767333
TI - Alleviation of neuronal ganglioside storage does not improve the clinical course
of the Niemann-Pick C disease mouse.
AB - Niemann-Pick disease Type C (NP-C) is a progressive neurodegenerative disorder
caused by mutations in the NPC1 gene and characterized by intracellular
accumulation of cholesterol and sphingo-lipids. The major neuronal storage
material in NP-C consists of gangliosides and other glycolipids, raising the
possibility that the accumulation of these lipids may participate in the
neurodegenerative process. To determine if ganglioside accumulation is a crucial
factor in neuropathogenesis, we bred NP-C model mice with mice carrying a
targeted mutation in GalNAcT, the gene encoding the beta-1-4GalNAc transferase
responsible for the synthesis of GM2 and complex gangliosides. Unlike the NP-C
model mice, these double mutant mice did not exhibit central nervous system (CNS)
accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histological
analysis revealed that the characteristic neuronal storage pathology of NP-C
disease was substantially reduced in the double mutant mice. By contrast,
visceral pathology was similar in the NP-C and double mutant mice. Most notably,
the clinical phenotype of the double mutant mice, in the absence of CNS
ganglioside accumulation and associated neuronal pathology, did not improve. The
results demonstrate that complex ganglioside storage, while responsible for much
of the neuronal pathology, does not significantly influence the clinical
phenotype of the NP-C model.
PMID- 10767334
TI - Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in
transcription regulation?
AB - Spinal muscular atrophy is an autosomal recessive neurodegenerative disease of
childhood, resulting from deletion or mutation of the survival motor neuron ( SMN
) gene on chromosome 5q13. SMN exists as part of a 300 kDa multi-protein complex,
incorporating several proteins critically required in pre-mRNA splicing. Although
SMN mutations render SMN defective in this role, the specific alpha-motor neuron
degenerative phenotype seen in the disease remains unexplained. Here we
demonstrate the isolation from mouse brain of the murine homologue of a recently
identified novel RNA helicase of the DEAD box family, DP103, and its direct and
specific binding of SMN. Previous work has shown that DP103 binds viral proteins
known to interact with a cellular transcription factor to modulate gene
expression. We suggest that the interaction between SMN and DP103 is further
evidence for a role for SMN in transcriptional regulation and that SMN may be
involved in the regulation of neuron-specific genes essential in neuronal
development.
PMID- 10767335
TI - Expression of arylamine N-acetyltransferases in pre-term placentas and in human
pre-implantation embryos.
AB - Arylamine N -acetyltransferases (NATs) catalyse the acetylation from acetyl-CoA
of arylamines and hydrazines. There are two human isoenzymes which show
polymorphism, and both enzymes are involved in the activation and detoxification
of environmental carcinogens and teratogens. The two human isoenzymes NAT1 and
NAT2 show different tissue distribution, with human NAT2 being found in liver and
intestine whilst human NAT1 is expressed in many tissues including erythrocytes,
bladder, lymphocytes and neural tissue, as well as liver and intestine. It has
been proposed that NAT1 has an endogenous role in the acetylation of the folate
catabolite p -aminobenzoyl-L-glutamate (pABGlu) to produce the major urinary
product, N -acetyl-pABGlu. The murine homologue of human NAT1 is known to be
concentrated in the neural tube during development. We show here that human NAT1
but not human NAT2 is expressed in pre-implantation embryos at the blastocyst
stage and show that NAT1 is also expressed in early human placenta at the
earliest available stage, 5.5 weeks. We demonstrate that there is inter
individual variation in NAT1 expression. In view of the role of folate in
protecting against neural tube defects, we propose that NAT1 is a candidate risk
factor for susceptibility to neural tube defects.
PMID- 10767336
TI - Genome-wide scan for adult onset primary open angle glaucoma.
AB - Adult onset primary open angle glaucoma is a leading cause of blindness
throughout the world. The disease results in an apoptotic death of retinal
ganglion cells that is usually associated with an elevation of intraocular
pressure. Familial aggregation of the disorder provides evidence for strong
genetic influences that are likely to be the result of multiple susceptibility
genes. A two-stage genome scan to identify the genomic locations of glaucoma
susceptibility genes was performed using an initial pedigree set of 113 affected
sibpairs and a second pedigree set of 69 affected sibpairs. Linkage analysis was
performed using both model-dependent (lod score) and model-independent affected
relative pair and sibpair methods. Twenty-five regions identified by the initial
scan were further investigated using the second pedigree set. In the combined
data analysis, regions located on chromosomes 2, 6, 9, 11, 14, 17 and 19
continued to produce model-dependent lod scores and/or an MLS >1.0, while five
regions (2, 14, 17p, 17q and 19) produced an MLS >2. 0. Multipoint analysis using
ASPEX also showed significant results on chromosomes 2, 14, 17p, 17q and 19.
These results are an important step towards the identification of genes
responsible for the genetic susceptibility to this blinding condition.
PMID- 10767337
TI - Long-read sequence analysis of the MECP2 gene in Rett syndrome patients:
correlation of disease severity with mutation type and location.
AB - Mutations in the methyl-CpG-binding protein gene MECP2 at Xq28 cause Rett
syndrome (RTT), an X-linked dominant neurodevelopmental disorder characterized by
a period of stagnation followed by regression in the development of young girls.
Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven
families with possible familial RTT and five sporadic females with features
suggestive, but not diagnostic of RTT. Long distance PCR coupled with long-read
direct sequencing was employed to sequence the entire MECP2 gene coding region in
all cases. Mutations were identified in 44/55 (80%) unrelated classical sporadic
and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but
non-diagnostic features of RTT. Twenty-one different mutations were identified
(12 missense, four nonsense and five frame-shift mutations); 14 of these were
novel. All missense mutations were located either in the methyl-CpG-binding
domain or in the transcription repression domain. Nine recurrent mutations were
characterized in a total of 33 unrelated cases (73% of all cases with MECP2
mutations). Significantly milder disease was noted in patients carrying missense
mutations as compared with those with truncating mutations ( P = 0. 0023), and
milder disease was associated with late as compared with early truncating
mutations ( P = 0.0190).
PMID- 10767338
TI - Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+)
pump.
AB - Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized
by suprabasal cell separation (acantholysis) of the epidermis. Previous genetic
linkage studies localized the gene to a 5 cM interval on human chromosome 3q21.
After reducing the disease critical region to <1 cM, we used a positional cloning
strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a
new class of P-type Ca(2+)-transport ATPase, which is the homologue for the rat
SPLA and the yeast PMR1 medial Golgi Ca(2+)pumps and is related to the
sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase
(PCMA) families of Ca(2+)pumps. The predicted protein has the same apparent
transmembrane organization and contains all of the conserved domains present in
other P-type ATPases. ATP2C1 produces two alternative splice variants of
approximately 4.5 kb encoding predicted proteins of 903 and 923 amino acids. We
identified 13 different mutations, including nonsense, frameshift insertion and
deletions, splice-site mutations, and non-conservative missense mutations. This
study demonstrates that defects in ATP2C1 cause HHD and together with the recent
identification of ATP2A2 as the defective gene in Darier's disease, provide
further evidence of the critical role of Ca(2+)signaling in maintaining epidermal
integrity.
PMID- 10767339
TI - (Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical
features.
AB - Fragile X syndrome is a common cause of mental retardation involving loss of
expression of the FMR1 gene. The role of FMR1 remains undetermined but the
protein appears to be involved in RNA metabolism. Fmr1 knockout mice exhibit a
phenotype with some similarities to humans, such as macroorchidism and behavioral
abnormalities. As a step toward understanding the function of FMR1 and the
determination of the potential for therapeutic approaches to fragile X syndrome,
yeast artificial chromosome (YAC) transgenic mice were generated in order to
determine whether the Fmr1 knockout mouse phenotype could be rescued. Several
transgenic lines were generated that carried the entire FMR1 locus with extensive
amounts of flanking sequence. We observed that the YAC transgene supported
production of the human protein (FMRP) which was present at levels 10 to 15 times
that of endogenous protein and was expressed in a cell- and tissue-specific
manner. Macro-orchidism was absent in knockout mice carrying the YAC transgene
indicating functional rescue by the human protein. Given the complex behavioral
phenotype in fragile X patients and the mild phenotype previously reported for
the Fmr1 knockout mouse, we performed a more thorough evaluation of the Fmr1
knockout phenotype using additional behavioral assays that had not previously
been reported for this animal model. The mouse displayed reduced anxiety-related
responses with increased exploratory behavior. FMR1 YAC transgenic mice
overexpressing the human protein did produce opposing behavioral responses and
additional abnormal behaviors were also observed. These findings have significant
implications for gene therapy for fragile X syndrome since overexpression of the
gene may harbor its own phenotype.
PMID- 10767340
TI - Deletion and expression analysis of AZFa genes on the human Y chromosome revealed
a major role for DBY in male infertility.
AB - Three distinct regions, designated AZFa, b and c from proximal to distal Yq, are
required for normal spermato-genesis in humans. Deletions involving AZFa
(deletion interval 5C/D) seem to occur less frequently in infertile men and to be
associated with a more severe testicular phenotype, with almost complete absence
of germ cells. AZFa contains three genes, named USP9Y, DBY and UTY, and presents
high homology with the mouse Delta Sxr (b) interval, deletion of which causes a
severe spermatogenic impairment. However, the specific role of these genes in
human spermatogenesis is still unknown and it is not clear which of them is
responsible for the AZFa phenotype. Here we describe a complete sequence map of
the AZFa region, the genomic structure of AZFa genes and their deletion analysis
in a large number of infertile men characterized by well-defined spermatogenic
alterations. Both USP9Y and DBY may cause severe testiculopathies, but DBY
appears to be the major AZFa candidate. DBY is frequently deleted in infertile
patients and its absence produces severe spermatogenic damage leading to a
significant reduction of germ cells or even to their complete absence. Expression
analysis of AZFa genes and their X-homologues revealed ubiquitous expression for
all of them except DBY; this gene produces a long transcript which is
ubiquitously expressed in addition to a shorter transcript which is only
expressed in the testis, suggesting a specific role for DBY in the spermatogenic
process. This hypothesis is further supported by the high similarity of DBY to
other DEAD box proteins belonging to the PL10 subclass.
PMID- 10767341
TI - Identical mutations in the CSB gene associated with either Cockayne syndrome or
the DeSanctis-cacchione variant of xeroderma pigmentosum.
AB - Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two hereditary
disorders in which photosensitivity is associated with distinct clinical and
cellular phenotypes and results from genetically different defects. We have
identified the primary molecular alteration in two patients in whom clinical
manifestations strongly reminiscent of a severe form of XP were unexpectedly
associated with the CS cellular phenotype and with a defect in the CSB gene.
Sequencing of the CSB -coding region in both cDNA and genomic DNA showed that
these patients had identical alterations to those in a patient with the clinical
features of the classical form of CS. These data, together with fluorescence in
situ hybridization analysis, demonstrated that the two siblings with XP as well
as the CS patient were homozygous for the same CSB mutated allele, containing a
silent C2830T change and a nonsense mutation C2282T converting Arg735 to a stop
codon. The finding that the same inactivating mutation underlies different
pathological phenotypes indicates that there is no simple correlation between the
molecular defect and the clinical features. Therefore, alterations in the CSB
gene give rise to the same repair defect at the cellular level but other genetic
and/or environmental factors determine the pathological phenotype.
PMID- 10767342
TI - Did nucleotides or amino acids drive evolutionary conservation of the WT1 +/-KTS
alternative splice?
AB - Evolutionary comparisons frequently pinpoint crucial parts of a protein but, even
within coding regions, nucleotides can do more than determine amino acid
sequence. One highly conserved feature of the Wilms' tumour suppressor gene, WT1,
is the potential, following alternative pre-mRNA splicing, to insert three amino
acids (KTS) between the third and fourth zinc fingers. The nucleotides at this
position simultaneously define amino acids and the alternative splice site. At
the protein level this insertion influences DNA binding affinity and specificity,
protein-protein interactions and subnuclear localization. Mutations within the +/
KTS splice junction lead to severe urogenital developmental abnormalities such as
Frasier syndrome, indicating that the isoform ratio is critical for wild-type
function. Using a series of site-directed mutations in both the genomic and cDNA
context, the nucleotide-amino acid relationship was investigated. Mutational
analysis within the cDNA suggests that the precise amino acids inserted may not
be critical, but rather the disruption of the zinc finger structure alone may be
sufficient to generate proteins with different in vitro properties. However,
analysis within the genomic context suggests that the precise structure of the
splice junction is crucial in retaining the balance between the isoforms, and
this may account for the high nucleo-tide conservation of this unusual gene
structure from fish to mammals.
PMID- 10767343
TI - Transgenic mice carrying large human genomic sequences with expanded CTG repeat
mimic closely the DM CTG repeat intergenerational and somatic instability.
AB - Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the
DM protein kinase (DMPK) gene. A very high level of instability is observed
through successive generations and the size of the repeat is generally correlated
with the severity of the disease and with age at onset. Furthermore, tissues from
DM patients exhibit somatic mosaicism that increases with age. We generated
transgenic mice carrying large human genomic sequences with 20, 55 or >300 CTG,
cloned from patients from the same affected DM family. Using large human flanking
sequences and a large amplification, we demonstrate that the intergenerational
CTG repeat instability is reproduced in mice, with a strong bias towards
expansions and with the same sex- and size-dependent characteristics as in
humans. Moreover, a high level of instability, increasing with age, can be
observed in tissues and in sperm. Although we did not observe dramatic expansions
(or 'big jumps' over several hundred CTG repeats) as in congenital forms of DM,
our model carrying >300 CTG is the first to show instability so close to the
human DM situation. Our three models carrying different sizes of CTG repeat
provide insight on the different factors modulating the CTG repeat instability.
PMID- 10767344
TI - Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the
molecular basis of Refsum's disease.
AB - Refsum's disease (RD) is an inherited neurological syndrome biochemically
characterized by the accumulation of phytanic acid in plasma and tissues.
Patients with RD are unable to degrade phytanic acid due to a deficient activity
of phytanoyl-CoA hydroxyl-ase (PhyH), a peroxisomal enzyme catalysing the first
step of phytanic acid alpha-oxidation. To enable mutation analysis of RD at the
genome level, we have elucidated the genomic organization of the PHYH gene. The
gene is approximately 21 kb and contains nine exons and eight introns. Mutation
analysis of PHYH cDNA from 22 patients with RD revealed 14 different missense
mutations, a 3 bp insertion, and a 1 bp deletion, which were all confirmed at the
genome level. A 111 bp deletion identified in the PHYH cDNA of several patients
with RD was due to either one of two different mutations in the same splice
acceptor site, which result in skipping of exon 3. Six mutations, including a
large in-frame deletion and five missense mutations, were expressed in the yeast
Saccharomyces cerevisiae to study their effect on PhyH activity. The results
showed that all these mutations lead to an enzymatically inactive PhyH protein.
PMID- 10767345
TI - Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen
syndrome: evidence for a common mechanism of chromosome breakage.
AB - Folate-sensitive fragile sites are associated with the expansion and
hypermethylation of CCG-repeats. The fragile site in 11q23.3, FRA11B, has been
shown to cause chromosome deletions in vivo, its expression being associated with
Jacobsen (11q-) syndrome. However, the majority of Jacobsen deletions are distal
to FRA11B and are not related to its expression. To test the hypothesis that
other unidentified fragile sites might be located in 11q23.3-24 and may cause
these deletions, we have identified and characterised CCG-trinucleotide repeats
within a 40 Mb YAC contig spanning distal chromosome 11q. Only eight CCG-repeats
were identified within the entire YAC contig (not including FRA11B ), six of
which map to the region of 11q23.3-24 that includes Jacobsen deletions. We have
previously collated the deletion mapping data of 24 Jacobsen patients with the
physical map of chromosome 11q, and accurately localised six breakpoints to short
intervals corresponding to individual YAC clones. We now show that in each of
these cases, YAC clones found to contain a deletion breakpoint also contain a CCG
repeat. The improved analysis of one of these deletions, together with those of
several new Jacobsen cases, further strengthens this association by localising
five breakpoints to individual PAC clones containing CCG-repeats. These data
provide strong evidence for the non-random clustering of chromosome deletion
breakpoints with CCG-repeats, and suggests that they may play an important role
in a common mechanism of chromosome breakage.
PMID- 10767346
TI - Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of
pregnancy: evidence for a defect in protein trafficking.
AB - Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with
serious consequences for the mother and fetus. Two pedigrees have been reported
with ICP in the mothers of children with a subtype of autosomal recessive
progressive familial intrahepatic cholestasis (PFIC) with raised serum gamma
glutamyl transpeptidase (gamma-GT). Affected children have homozygous mutations
in the MDR3 gene (also called ABCB4 ), and heterozygous mothers have ICP. More
frequently, however, ICP occurs in women with no known family history of PFIC and
the genetic basis of this disorder is unknown. We investigated eight women with
ICP and raised serum gamma-GT, but with no known family history of PFIC. DNA
sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3
in one patient, which results in the missense substitution of the wild-type
alanine with an aspartic acid. We performed functional studies of this mutation
introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated
cell sorting (FACS) and western analysis indicated that this missense mutation
causes disruption of protein trafficking with a subsequent lack of functional
protein at the cell surface. The demonstration of a heterozygous missense
mutation in the MDR3 gene in a patient with ICP with no known family history of
PFIC, analysed by functional studies, is a novel finding. This shows that MDR3
mutations are responsible for the additional phenotype of ICP in a subgroup of
women with raised gamma-GT.
PMID- 10767347
TI - Inactivation of the Friedreich ataxia mouse gene leads to early embryonic
lethality without iron accumulation.
AB - Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused
in almost all cases by homozygous intronic expansions resulting in the loss of
frataxin, a mitochondrial protein conserved through evolution, and involved in
mitochondrial iron homeostasis. Yeast knockout models, and histological and
biochemical data from patient heart biopsies or autopsies indicate that the
frataxin defect causes a specific iron-sulfur protein deficiency and
mitochondrial iron accumulation leading to the pathological changes. Affected
human tissues are rarely available to further examine this hypothesis. To study
the mechanism of the disease, we generated a mouse model by deletion of exon 4
leading to inactivation of the Frda gene product. We show that homozygous
deletions cause embryonic lethality a few days after implantation, demonstrating
an important role for frataxin during early development. These results suggest
that the milder phenotype in humans is due to residual frataxin expression
associated with the expansion mutations. Surprisingly, in the frataxin knockout
mouse, no iron accumulation was observed during embryonic resorption, suggesting
that cell death could be due to a mechanism independent of iron accumulation.
PMID- 10767348
TI - Analysis of ALK-1 and endoglin in newborns from families with hereditary
hemorrhagic telangiectasia type 2.
AB - ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming
growth factor (TGF)-beta superfamily, is the gene mutated in hereditary
hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using
a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human
umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose
affected members had normal endoglin levels. ALK-1 levels were specifically
reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two
newborns not carrying the missense mutations present in the clinically affected
relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP
binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function
of the mutant allele due to a reduction in either protein level or activity. We
also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and
E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-beta1
and -beta3 receptor complexes in association with endoglin and TbetaRII, but not
in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not
detectable in the TGF-beta1 or -beta3 receptor complexes. However, in the absence
of ligand, ALK-1 and endoglin interactions were observed by
immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2
patients. Our data suggest a transient association between these two proteins of
the TGF-beta superfamily, both required at a critical level to ensure vessel wall
integrity.
PMID- 10767349
TI - Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic
recombination.
AB - Segregation analysis of CEPH and other pedigrees yielded six paternal crossover
breakpoints in the approximately 85 kb interval between the minisatellite loci
D16S309 (MS205) and D16S83 (EKMDA2) in 16p13.3. Three crossovers were mapped to
within the same small (<3 kb) interval, which does not co-localize with any
tandem repeat array or expressed sequence. Haplotyping of loci harbouring single
nucleotide polymorphism (SNP) markers in this interval confirmed the exchange of
flanking markers in the three recombinant individuals. Sequence analysis revealed
the presence of recombination-associated motifs and binding sites for the protein
translin. Haplotyping of 108 individuals from three European populations at four
loci harbouring SNPs showed substantial linkage equilibrium across this interval.
Hence molecular and population genetic data are consistent with the presence of
an intense male-specific recombination hotspot at this locus.
PMID- 10767350
TI - A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes
cytochrome c oxidase deficiency.
AB - Cytochrome c oxidase (COX) defects are found in a clinically and genetically
heterogeneous group of mitochondrial disorders. To date, mutations in only two
nuclear genes causing COX deficiency have been described. We report here a
genetic linkage study of a consanguineous family with an isolated COX defect and
subsequent identification of a mutation in a third nuclear gene causing a
deficiency of the enzyme. A genome-wide search for homozygosity allowed us to map
the disease gene to chromosome 17p13.1-q11.1 (Z (max)= 2.46; theta = 0.00 at the
locus D17S799). This region encompasses two genes, SCO1 and COX10, encoding
proteins involved in COX assembly. Mutation analysis followed by a
complementation study in yeast permitted us to ascribe the COX deficiency to a
homozygous missense mutation in the COX10 gene. This gene encodes heme
A:farnesyltransferase, which catalyzes the first step in the conversion of
protoheme to the heme A prosthetic groups of the enzyme. All three nuclear genes
now linked to isolated COX deficiency are involved in the maturation and assembly
of COX, emphasizing the major role of such genes in COX pathology.
PMID- 10767351
TI - Identification of mutations in the MSX2 homeobox gene in families affected with
foramina parietalia permagna.
AB - Foramina parietalia permagna (FPP) is an autosomal dominant condition
characterized by cranial defects of the parietal bones. It can be present as an
isolated feature, but it is also one of the characteristics of a contiguous gene
syndrome associated with deletions on chromosome 11p11-p12. One of the proteins
known to be involved in skull development is the MSX2 homeobox protein.
Previously, MSX2 has been shown to be mutated in patients suffering from Boston
type craniosynostosis. We have now analyzed the MSX2 gene in five families
affected with FPP. An intragenic microsatellite marker did not reveal any
recombination and a cumulated LOD score of +3.2 at theta = 0 was obtained.
Sequence analysis further showed that in four out of five families an MSX2
mutation was responsible for the skull defect. Moreover, it appears that FPP is
caused by haplo-insufficiency of the MSX2 gene. This implies that Boston type
craniosynostosis and FPP are allelic variants of the same gene, with FPP caused
by loss of MSX2 function and craniosynostosis Boston type due to gain of MSX2
function.
PMID- 10767352
TI - Identification of activated tumor antigen-reactive CD8+ cells in healthy
individuals.
AB - We investigated the ability of HER-2 peptide E75, which maps an immunodominant
CTL epitope for ovarian and breast tumor-associated lymphocytes (TAL), to
activate effector functions in freshly isolated CD8+ cells from healthy
individuals. IFN-gamma was rapidly induced by E75 within 20-24 h, in five of six
healthy donors, in the presence of IL-12 and was detectable as early as 6 h. The
IFN-gamma levels were Ag-concentration dependent. Similar results were obtained
with peptides mapping CTL epitopes from two other tumor Ag: folate binding
protein (FBP) and amino-enhancer of split of Notch (AES). IFN-gamma was also
detected, from freshly isolated, unstimulated PBMC in response to HLA-A2 matched
tumors + IL-12 but not of IL-12 alone. The major source of IFN-gamma were CD45RO+
CD8+ cells. Induction of IFN-gamma and IL-2 from CD8+ cells and of IL-12 from
dendritic cells (DC) by CD8+ cells reactive with E75 mirrored their induction by
the influenza matrix peptide (M1: 58-66) in the same individual. Responses to M1
are used to define the presence of activated memory cells in healthy individuals.
Compared to M1 responses E75 recognition induced 2-4-fold lower levels of IL-12
from the same APC and IFN-gamma and IL-2 from the same CD8+ cells. At lower Ag
concentrations the endogenous IL-12 induced by E75-reactive CD8+ cells did not
reach the threshold required to co-stimulate for IFN-gamma. alphaB7.1 synergized
with E75 in increasing the overall levels of IL-2 induced within 24 h. The
presence of tumor Ag-reactive activated CD8+ cells in healthy individuals may
improve our understanding of the mechanisms of immunosurveillance and regulation
of immune responses by tumors.
PMID- 10767353
TI - Combined treatment with TNP-470 and 5-fluorouracil effectively inhibits growth of
murine colon cancer cells in vitro and liver metastasis in vivo.
AB - The combined effects of TNP-470 (TNP), a semisynthetic analogue of fumagillin,
and 5-fluorouracil (5FU), a representative chemotherapeutic agent for colorectal
cancer, were investigated using murine colon 26 adenocarcinoma (CT 26) cells. In
a cell-proliferation study in vitro, 50% inhibitory concentrations (IC50) were
determined to be 5.2 microg/ml and 240 ng/ml for TNP and 5FU, respectively. When
CT 26 cells were treated with TNP and 5FU in combination, a remarkable cytotoxic
effect was obtained. Isobologram analysis revealed synergism of these two agents
in inhibition of the cell growth. In vivo, using a dorsal air sac assay, we found
that TNP significantly inhibited the CT 26-induced angiogenesis. In addition, the
combination of TNP and 5FU exerted a synergistic anti-tumor effect in a model of
hepatic metastasis by portal injection of CT 26 cells. Since TNP is known to
exert inhibitory effects on tumor cell growth through suppression of cell cycle
progress from the G1 to S phases as well as neovascularization, it is speculated
that the treatment with TNP enhanced the anti-tumor effect of 5FU through
suppression of the cell cycle and tumor-derived angiogenesis. Taken together,
these results suggest that combined treatment with TNP and 5FU is potentially
useful for inhibition of tumor cell growth and liver metastasis of colorectal
cancer.
PMID- 10767354
TI - Cellular kinetics and expression of bcl-2 and p53 in ductal carcinoma of the
breast.
AB - In this study, the expression of p53 (wild-type and mutated form) and bcl-2 in
ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) of the
breast was evaluated by immunohistochemistry and PCR-SSCP and correlated with
cellular kinetic parameters, i.e., mitotic index (MI) and apoptotic index (AI).
The results showed a significant inverse correlation between p53 and bcl-2
expression in all cases of DCIS and IDC. In the DCIS group, two subgroups with
different kinetic characteristics were identified. The first group was
characterized by p53 positivity, bcl-2 negativity and high values of MI and AI;
the other group was characterized by p53 negativity, bcl-2 positivity and low
values of MI and AI. Conversely, in IDC some cases were p53 negative, bcl-2
positive and with high values of AI and MI, other cases were p53 positive, bcl-2
negative and with low AI and MI. Molecular biological analysis showed that p53
was wild-type in DCIS, while it was in the mutated form in IDC. These results
suggest that in IDC mutated p53 contributes to a change in cellular kinetics and
the selection of genetically aberrant cells, thereby favouring neoplastic
progression. The coexistence of bcl-2 positivity and high AI could be explained
by the presence of of apoptosis that work independently of bcl-2.
PMID- 10767355
TI - Conservation treatment intensified with an anti-estrogen agent and CAF
chemotherapy for stage I and II breast cancer.
AB - In order to improve both cosmetic results and survival rates, we performed breast
conservation treatment (BCT) intensified with tamoxifen and CAF chemotherapy to
218 out of 224 patients who visited our department with the desire of breast
conservation between August 1989 to December 1998. Of these patients, 68
presented with tumors of stage I, and another 122 stage II. All patients were
administered tamoxifen (for pre-menopausal women) or tremifene (for post
menopausal women) orally: tamoxifen and tremifene administration was started just
after confirmation of the breast cancer based on the findings of fine-needle
aspiration cytology. All patients underwent lumpectomy with or without axillary
dissection (level I and II). For patients with T2 tumors, the lumpectomy was
performed following two to four times of CAF chemotherapy. Following conservative
surgery, patients were treated with radiation therapy to the intact breast and
ipsilateral axilla to a total dose of 4400 cGy with a conedown to a total median
dose of 5300 cGy. At the end of March 1999, the mean follow-up time was 49.0
months. In spite of high-positivity (approximately 30%) of microscopically
surgical margin, local recurrence rate is considerably low, and only 2 patients
experienced local recurrence. Cause-specific survival rate for patients of stage
I is 100%, and that of stage II is 91.7% at 5 years. The cosmetic results of
therapy were also considered good.
PMID- 10767356
TI - A phase III randomized study comparing doxifluridine and 5-fluorouracil as
supportive chemotherapy in advanced and recurrent gastric cancer.
AB - We conducted a phase III randomized study to investigate effects of supportive
chemotherapy with oral doxifluridine (group A, 75 patients) or 5-fluorouracil
(group B, 75 patients) in advanced gastric cancer when intensive chemotherapy was
not an option. Although there were no significant differences between the groups
with regard to survival, hospital-free survival and time to progression, median
values of 3 endpoints were superior in group A. Secondary analysis showed that
group A patients with prior chemotherapy tended to have longer survival and
hospital-free survival and significantly longer time to progression.
PMID- 10767357
TI - Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate
with good responses to platinum-based chemotherapy in non-small cell lung cancer.
AB - In order to determine whether expression of the cyclin-dependent kinase inhibitor
p27 in non-small cell lung cancer (NSCLC) correlates with chemotherapeutic
response, resected tumors from 22 patients with recurrent lung cancer who had
undergone complete resection and received chemotherapy after the initial tumor
recurrence were subjected to p27 immunostaining. Histological examination of the
resected tumors revealed 14 adenocarcinomas, 7 squamous cell carcinomas and one
adenosquamous cell carcinoma. Fifty percent or less and over 50% of the cells in
the resected tumors of 11 patients each (groups 1 and 2, respectively) were p27
immunopositive. All but one patient received platinum-based chemotherapy after
recurrence. Only one in group 1 achieved a partial response (PR) in chemotherapy
whereas 2 and 4 in group 2 achieved complete and PRs, respectively. The
chemotherapy response rate of group 2 (54%) was significantly higher than that of
group 1 (9%, p=0.022). The times to recurrence after tumor resection of the 2
groups did not differ significantly (log-rank p=0.23, Wilcoxon p=0. 32), but
survival after chemotherapy of group 2 was significantly better than that of
group 1 (log-rank p=0.045, Wilcoxon p=0.028). It is suggested that high p27
expression levels in tumors may predict the good responses to platinum-based
chemotherapy for NSCLC.
PMID- 10767358
TI - Screening of human bladder carcinomas for the presence of Ha-ras codon 12
mutation.
AB - Contradictory results were obtained from previous studies aiming at defining the
frequency of Ha-ras codon 12 mutations in bladder tumors. Differences in the
sensitivities of the methods used could account for this discrepancy. In this
study, we reevaluated the frequency of Ha-ras codon 12 mutations in a series of
87 human bladder tumors using a combination of two different methods. The first
was derived from the protocol of Ooi et al and consisted in a one-step allele
specific polymerase chain reaction using mismatched primers in two separate PCR.
This method is very rapid and highly sensitive, detecting the presence of minor
populations (less than 10%) of mutant alleles. The second strategy consisted in
screening all tumors using natural restriction fragment length polymorphism
(RFLP) analysis. The two methods were in complete concordance and enabled us to
show that only one out of 87 primary bladder carcinomas (1%) exhibited the
mutation, in accordance with previous studies. These results strongly suggest
that, even if minor cell populations overexpress codon 12 Ha-ras mutation, the
analysis of this mutation cannot be used to screen potentially invasive
transitional cell tumors of the bladder.
PMID- 10767359
TI - Colitis-related rat colon carcinogenesis induced by 1-hydroxy-anthraquinone and
methylazoxymethanol acetate (Review).
AB - Patients with long-standing ulcerative colitis (UC) have an increased risk for
developing colorectal cancer (CRC) compared to the general population. For
investigation of the mechanisms and prevention of UC and UC-related CRC,
establishment of a promising animal model for such disease is important. 1
hydroxyanthraquinone (1-HAQ) present in certain medicinal plants such as Rubia
tinctorum L. is a genotoxic and rodent colon carcinogen. Long-term feeding of 1
HAQ induced hyper-cell proliferation in rat colonic crypts with ulcerative
changes, crypt abscess, severe inflammation and erosion before the occurrence of
tumors, which are similar to those found in human UC. In addition, 1-HAQ has a
synergistic effect with methylazoxymethaol (MAM) acetate on colon carcinogenesis.
The polymerase chain reaction-single strand conformation polymorphism analysis
revealed no mutations in Ki-ras and p53 in colonic neoplasms induced by MAM
acetate + 1-HAQ, MAM acetate alone or 1-HAQ alone. Also, no mutations of APC were
found in these tumors. These findings are similar to those found in human
ulcerative colitis-associated colon cancer in contrast with sporadic colon
cancers. A previous study revealed that induced colonic tumors had beta-catenin
mutation with high frequency, suggesting tumor development by activation of the
beta-catenin-Tcf signaling pathway. Increased expression in TNF-alpha and IL
1alpha was found in these induced colonic neoplasms, and the expression was more
remarkable in colonic mucosa of rats exposed to MAM acetate + 1-HAQ, MAM acetate
or 1-HAQ when compared with that in untreated rats. Thus, these cytokines may act
as growth factors in rat colon carcinogenesis by MAM acetate and 1-HAQ and the
synergistic effect of 1-HAQ with MAM acetate might be related to the biological
effects of the cytokines expressed in the inflammatory conditions induced by 1
HAQ.
PMID- 10767360
TI - An embryonal carcinoma multiple phenotype locus maps to the proximal position of
the mouse X chromosome.
AB - A mutant embryonal carcinoma cell line, NR1-6, was established subsequent to
retroviral insertion. The insertion was shown to be causative for a number of
aberrant properties associated with the mutant cells. Analysis of >17 kb of the
insertion site flanking region failed to reveal any homology between this locus
and any reported sequence with the exception of one EST of unknown function and a
few repetitive elements including B1 element and a CA dinucleotide repeat. CA
repeats occur commonly in the mouse genome and usually show size variation. In
this study, we mapped this multiphenotype locus using CA repeat polymorphism and
Jackson Laboratory's interspecific backcross panels. The locus maps to the
proximal end of the X chromosome between MGI offsets 1.5 and 4.5 and has been
designated DXUalb1. There are several interesting candidate genes within this
region. Analyses of their expression pattern may lead us to a better
understanding of the molecular regulation of the variant mutant phenotypes.
PMID- 10767361
TI - A multivariate analysis for predicting cisplatin-induced delayed emesis.
AB - The present study was designed to address the question of the early
identification of patients at risk of developing cisplatin (CP)-related delayed
emesis. This study included demographic, clinical, biological and pharmacological
data and was conducted on 110 consecutive patients treated by CP-based
chemotherapy. A previously validated single-point CP pharmacokinetic evaluation
was performed in all patients. A total of 110 cycles was analyzed. Delayed
vomiting (i.e., occurring between day 3 and day 7 following CP administration)
was observed in 36.4% of cycles. Among the tested variables, the occurrence of
delayed emesis was significantly related to elevated ultrafilterable (UF)
platinum concentration (measured 16 h after the end of CP administration) and to
low plasma magnesium concentration (measured 48 h before CP administration). Risk
thresholds for delayed emesis were established for UF platinum and magnesemia, at
60 ng/ml and 58 mmol/l, respectively. In the sub-group of patients with
magnesemia determination, this later parameter was the only significant predictor
of delayed emesis. Gender, cycle number, primary cancer location and age were not
associated with the risk of developing delayed emesis. The ability to select
patients at risk of delayed vomiting may offer a practical means of targeting
administration of specific treatments.
PMID- 10767362
TI - Histological and molecular mapping of adenocarcinoma of the oesophagus and
gastroesophageal junction: loss of heterozygosity occurs in histologically normal
epithelium in the oesophagus and stomach.
AB - Seventy malignant, premalignant and histologically normal biopsies from 7
oesophagogastrectomy specimens of adenocarcinomas of the lower oesophagus and
gastroesophageal junction were analysed for loss of heterozygosity (LOH) at 9
known or putative gene loci. LOH was detected in 20 of 27 (74%) malignant
biopsies, 4 of 7 (57%) biopsies of dysplasia, 2 of 12 (25%) biopsies of
histologically normal oesophagus adjacent to adenocarcinoma, and in 2 of 14 (14%)
biopsies of histologically normal stomach adjacent to adenocarcinoma. LOH at the
VHL, APC, CDKN2 and DCC tumour suppressor and MSH3 mismatch repair gene loci can
be detected in histologically normal tissue and in adjacent adenocarcinoma, and
are potential markers of early neoplastic progression.
PMID- 10767364
TI - Identification of occult micrometastases in patients with early gastric cancer
using anti-cytokeratin monoclonal antibodies.
AB - The presence of occult micrometastases was evaluated in 1488 lymph nodes removed
from 139 patients with node-negative early gastric cancer (EGC). Additional
multiple levels of the lymph nodes were examined with haematoxylin-eosin staining
and keratin immunostaining. Occult nodal micrometastases were detected in 24
patients (17%) in one or more lymph nodes dissected after a gastrectomy. The
cases investigated were a small group from a total of 412 EGC patients who
underwent surgical treatment in our hospital between 1976 and 1997; the mean
follow-up period was 9 years (range 1-22). We found no significant differences
between cytokeratin-negative and positive patients regarding the following
clinicopathological parameters: age, gender, tumour size and site, macroscopic
and microscopic type, depth of invasion and type of infiltration, according to
Kodama's classification. The survival rate at 5 years was 88% and 87% for
cytokeratin-negative and positive patients, respectively (log-rank = 0.6; ns).
Our data suggest that occult micrometastases do not add useful information and
immunohistochemical studies to detect them are probably unnecessary.
PMID- 10767363
TI - Identification of a 7-cM region of frequent allelic loss on chromosome band
16p13.3 that is specifically associated with anaplastic thyroid carcinoma.
AB - A total of 17 primary thyroid cancer specimens including seven anaplastic
cancers, two papillary cancers adjacent to the anaplastic cancers, and eight
papillary cancers were analyzed for loss of heterozygosity (LOH) on chromosome
arm 16p. All tumors of anaplastic cancer showed LOHs at one or more loci, and a 7
cM region of the smallest deleted region was found on 16p13.3 between D16S423 and
D16S406. This LOH was specifically found in the anaplastic cancer and not in the
papillary thyroid cancer. Our present results suggest localization of the
putative tumor suppressor gene on 16p13.3, which is likely to play an important
role in the anaplastic transformation of thyroid cancer.
PMID- 10767365
TI - Expression of variant CD44 containing variant exon v8-10 in gallbladder cancer.
AB - We studied the Cd44v8-10 expression in gallbladder cancer immunohistochemically.
Eighteen of 37 gallbladder cancer tissues expressed CD44v8-10. There were
significant correlations between CD44v8-10 immunoreactivity and perineural
invasion, venous invasion, and lymph node metastasis. Patients with CD44v8-10
positive tumors showed poor prognoses, whereas those with CD44v8-10-negative
tumors had favorable prognoses. A multivariate analysis using the Cox regression
model showed the immunoreactivity of CD44v8-10 to be an independent prognostic
indicator of gallbladder cancer. The results suggest that CD44v8-10 expression
may be a biologic marker of prognostic significance in gallbladder cancer.
PMID- 10767366
TI - Intermittent adjuvant chemo-immunotherapy after resection of non-small cell lung
cancer with multilevel mediastinal lymph node metastasis.
AB - The prognosis of patients with multilevel mediastinal lymph node metastasis
remains poor notwithstanding the progress in multimodal therapy in non-small cell
lung cancer. We conducted a feasible study of intermittent adjuvant chemo
immunotherapy after surgery for patients with multilevel mediastinal lymph node
metastasis of non-small cell lung cancer. Eleven patients with pathologically N2
or N3 lung cancer (10, adenocarcinomas; 1, squamous cell carcinoma) were
enrolled. Five completely resected cases received systemic chemo-immunotherapy
and six incompletely resected cases received local chemo-immunotherapy by an
indwelling catheter in the thoracic cavity. Cisplatin-based and dose-dependent
anti-cancer drugs were selected on the basis of sensitivity tests. Either
adoptive immunotherapy with interleukin-2 and lymphokine-activated killer cell or
combination of interferon gamma# and OK432 were administered after chemotherapy.
This adjuvant therapy was performed every 2-3 months after surgery for 2 years.
The 2-year survival rate for all cases were 72.7% and the 2-year disease-free
survival were 36.4%. The 2-year survival rate for five completely resected cases
and six incompletely resected cases was 80% and 66.7%, respectively. Combined
intermittent chemo-immunotherapy after surgical resection of tumors may be a
promising modality to improve the survival of patients with multilevel
mediastinal lymph node metastasis in non-small cell lung cancer.
PMID- 10767367
TI - Prospective analysis of DNA ploidy, proliferative index and epidermal growth
factor receptor as prognostic factors for pretreated uterine cancer.
AB - For the purpose of identifying prognostic factors for pretreated uterine cancer,
DNA ploidy, proliferative index (P.I.) and epidermal growth factor receptor
(EGFR) expression were analyzed in a large prospective series of 76 cervical
cancer and 64 endometrial cancer patients observed for 5 years or more (median 76
months). The frequency of aneuploid cells was 62.0% (44/71) in cervical cancer
and 16.7% (10/60) in endometrial cancer. There was no association between DNA
ploidy and the clinicopathological findings without clinical stage, in which
aneuploid cervical and endometrial cancers were significantly more common among
advanced tumors (cervical: p<0. 05, endometrial: p<0.01). The P.I. was
significantly higher in the patients with aneuploid tumors (cervical: p<0.05,
endometrial p<0. 01). EGFR expression was detected in 56.6% (30/53) in cervical
cancer and 59.6% (34/57) in endometrial cancer, and the mean EGFR level was
17.8+/-37.7 and 9.5+/-42.5 fmol/mg. protein, respectively. There was no
correlation between EGFR expression and DNA ploidy, P.I. and clinicopathological
findings analyzed. Five-year survival rate in patients with aneuploid tumors
tended to have a worse outcome in cervical cancer cases (p=0.1003, log-rank
test), and was significantly worse in endometrial cancer (p=0.0048, log-rank
test). No significant relationship was noted between P.I., EGFR expression and 5
year survival. Cox multivariate analysis showed that DNA ploidy, P.I., and EGFR
expression are not association with the risk of death. Our data showed neither
DNA ploidy, P.I. nor EGFR expression were independent prognostic factors for
pretreated uterine cancer.
PMID- 10767368
TI - Selection of mRNA markers for detection of lymph node micrometastases in breast
cancer patients.
AB - The aim of this study was to search for specific and sensitive mRNA markers or a
combination of markers for RT-PCR detection of micrometastases in axillary lymph
nodes (LNs) from patients with breast cancer. LNs (n=177) from 17 patients were
examined with Cytokeratin20 (CK20), melanoma-associated genes (MAGE1, MAGE3),
carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), mammaglobin
(MGB1) and mammaglobin B (MGB2) as molecular markers. CK20, MAGE1 and MAGE3 were
slightly positive in primary tumors and CEA, PSA, MGB1 and MGB2 were highly
positive. MGB1 and MGB2 were 100% positive in HE-positive LNs while CEA and PSA
were only 35.7% and 57.1% positive. MGB1 and MGB2 were also 30.1% and 17.8%
positive in HE-negative nodes. Thus, MGB1 and MGB2 are specific and a combination
of the two should be useful for detection of micrometastases in axillary LNs of
breast cancer patients.
PMID- 10767369
TI - Anticorresponding mutations of the KRAS and PTEN genes in human endometrial
cancer.
AB - PTEN is a newly isolated candidate tumor suppressor gene and its mutation is the
most frequently found in endometrial cancer (EC), a very common female pelvic
malignant disease. Mutations of the KRAS gene are also reported in this disease.
Recent analysis of the PTEN protein suggested the possibility that this protein
acts in the same pathway as does the RAS protein. To elucidate this possibility
further, we performed a mutation analysis of these two genes in 44 endometrial
cancer specimens (38 primary tumors and 6 cell lines). Altogether 23 (52%) of 44
tumors had mutations in either PTEN or KRAS, but none of them had mutations in
both of these genes. These results support the idea that the protein products of
these two genes act in the same growth regulatory pathway in the endometrium.
PMID- 10767370
TI - Treatment results of esophageal carcinoma of clinical T3, T4M0: historical
comparison between neoadjuvant chemoradiotherapy followed by surgery or
definitive radiotherapy and conventional surgery.
AB - We investigated results for thoracic T3-T4 esophageal squamous cell carcinoma in
two strategies. The protocol group (46 patients) consisted of neoadjuvant
chemoradiotherapy (44 Gy, CDDP, 5-FU), followed by either definitive radiotherapy
(total 70 Gy) for responders or surgery for non-responders. The surgery group (26
patients) underwent esophagectomy with regional lymph node dissection. Nineteen
of them received postoperative radiotherapy. Surgical candidates in both groups
received intraoperative radiotherapy for abdominal lymphatics since 1991. In the
protocol group, 23 patients underwent radical surgery after neoadjuvant
chemoradiotherapy and the remaining 23 underwent definitive radiotherapy. The
rates of recurrence were 64% in the protocol group, and 62% in the surgery group.
Overall 3- and 5-year survival rates were 48% and 31% in the protocol group
compared to those of 30% and 30% in the surgery group. The rate of the was 39% in the protocol group. There was no mortality in either
group. Our protocol had at least comparable prognostic values with historical
conventional surgery, and was excellent in having feasibility for organ
preservation.
PMID- 10767371
TI - Nuclear accumulation of p53 protein in gastric cancer strongly correlates with
enlargement of nuclear area of cancer cells.
AB - The nuclear area (NA) of cancer cells have been reported to be a useful
prognostic indicator in various tumors. However, this image analysis of cancer
nucleus has only rarely been applied to gastric adenocarcinoma. Moreover, it
remains to be shown what types of biological factors influence this nuclear
feature. In this study, we analyzed the area of cancer nuclei in tumors from 97
patients with advanced gastric cancer (t3, n0, stage II) by using hematoxylin and
eosin stained slides with a computer-assisted image-analysis system. The
morphometric data were compared with clinicopathological and biological status of
the tumors. The mean NA of 50 tumors with venous invasion (50 microm2) was
significantly larger than that of 47 tumors without venous invasion (38 microm2,
p<0.0001). There was a significant correlation between the NAs of cancer cells
and the p53 labeling indices of tumors (p=0.0012) and Ki-67 labeling indices of
tumors (p=0.0324). However, no significant correlation was detected between the
NAs of cancer cells and other factors, such as, tumor size, DNA ploidy pattern,
expression of vascular endothelial growth factor (VEGF), or microvessel density
of tumors. The five-year survival rate of 49 patients with large nuclear area (NA
> or =41 microm2, 63%) was significantly lower than that of 48 patients with
small nuclear area (NA <41 microm2, 78%, p=0.043). Data from computerized
morphometry are objective and can be obtained rapidly by conventional microscopic
analysis. The NA of cancer cells in advanced gastric cancer appears to predict
the ability to invade the microvessels in the gastric wall. This nuclear
morphological feature strongly correlated with p53 accumulation in the nuclei of
gastric adenocarcinoma.
PMID- 10767372
TI - Cell cycle status and apoptosis of hematopoietic progenitor cells released into
the peripheral blood after taxanes and granulocyte colony-stimulating factor in
breast cancer patients.
AB - Paclitaxel and its analogue docetaxel show a significant antitumor activity,
particularly evident in breast cancer. Paclitaxel has also been proved to be
effective as a peripheral blood progenitor cell (CPC) mobilizing agent. To
optimize the use of active, disease-specific drugs as CPC priming, we have
evaluated the effects of either paclitaxel or docetaxel both at standard dosages
and followed by granulocyte colony-stimulating factor (G-CSF), on circulating CPC
release and function in 18 patients with advanced breast cancer who had failed
previous anthracycline-based regimens. The reported differences in biological
behaviour between bone marrow and blood-derived hematopoietic progenitor cells
and the ability of both paclitaxel and docetaxel to induce apoptosis, prompted us
to simultaneously evaluate the cell cycle perturbations induced on CD34+ cells.
Median CD34+ peaks were 24 microl (range: 10-58) in the paclitaxel-treated
patients and 39 microl (range: 17-91), respectively, in the patients who received
docetaxel. After paclitaxel, the percentage of CD34+ cells in S-phase was low
(bromodeoxyuridine, BrdU, labelling index = 3.4+/-2%) with a concomitant presence
of early apoptotic cells (8.1+/-3%). On the contrary, after docetaxel, the
percentage of CD34+ cells in S-phase was higher (BrdU labelling index = 14.5+/
4%, p<0.05 vs. paclitaxel), while early apoptotic cells were detected at a
similar rate (8. 6+/-3%, p = n.s. vs. paclitaxel). In conclusion, when used at
standard dosages, with respect to paclitaxel + G-CSF, docetaxel + G-CSF is a more
satisfactory tool to mobilize CPC and to induce them into the cell cycle. These
data should be taken into account when combinations of docetaxel with other
agents are explored as CPC mobilizing regimens for autografting.
PMID- 10767373
TI - Polymorphic variation of the ARP gene on 3p21 in Japanese esophageal cancer
patients.
AB - Allelic loss of the short arm of chromosome 3 is common in esophageal squamous
cell carcinoma (ESC) and its premalignant lesions. The ARP gene (Arginine Rich
Protein) was mapped to 3p21, and frequent variations of the triplet, AGG, repeat
around codon 50 of the ARP gene were reported in a variety of human cancers. To
examine the involvement of the ARP gene in esophageal cancer, we screened
mutations around codon 50 in 35 ESC tumours and matched normal tissues. Sequence
variants were observed in four ESC tumours; two (AGG)2 insertions, one ATG50-to
AGG substitution and one AGG deletion. However, they were also found in its
corresponding normal tissues, suggesting that variation of the ARP gene found in
ESC is polymorphic. We next analyzed sequence changes in 48 unrelated Japanese
healthy individuals. They consist of 33 wild-type homozygotes, nine (AGG)2
insertion/wild-type heterozygotes, two (AGG)2 insertion homozygotes, one AGG
deletion/wild-type heterozygote and three ATG50-to-AGG substitution/wild-type
heterozygotes. Allele frequencies for wild-type, (AGG)2 insertion, ATG50-to-AGG
substitution and AGG deletion are 0.82, 0.14, 0.03 and 0.01, respectively.
Observed genotype frequencies fit well with the Hardy-Weinberg's law. Significant
difference was not observed between allele distributions in normal and cancer
patient populations.
PMID- 10767374
TI - Diagnostic accuracy of needle biopsy of uterine leiomyosarcoma.
AB - We previously reported on the efficacy of transcervical needle biopsy of a
uterine muscle tumor. In this study, to examine diagnostic accuracy of our needle
biopsy with small specimen size, previous slide preparations were used from 8
cases diagnosed with leiomyosarcoma and from 24 post-operative leiomyoma cases.
Each tissue specimen was examined through needle biopsy-sized slit that had been
randomly positioned over the slide. Three predictors: mitotic index, cytologic
atypism, and tumor cell necrosis were evaluated on a 3-point scale (0, 1, or 2
points). When the diagnostic cut-off value was set to two, the sensitivity was
92.5% and the specificity was 100%.
PMID- 10767375
TI - Effects of lentinan on colorectal carcinogenesis in mice with ulcerative colitis.
AB - Lentinan; i.e., polysaccharides extracted from a kind of black mushroom shiitake,
has been clinically applied as an antitumor and antimetastatic drug, and has been
reported to prevent both chemical and viral carcinogenesis. It is known that
lentinan affects the tumorous vascular system resulting in the induction of
hemorrhagic necrosis which is dependent on T-cells in the tumor. Repeated mucosal
necrosis-regeneration sequence in chronic ulcerative colitis induced with 3%
dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane
pretreated mice. In the present study, the additive treatment with lentinan in
the azoxymethane-dextran sulfate sodium treated mice enhanced the colorectal high
grade dysplasia, though not significantly, and the splenic weight. This may show
the proliferation of pathogenic splenic T cells resulting in a change for the
worse of ulcerative colitis, anemia induced with hemorrhage and colorectal
carcinogenesis; i.e., high-grade dysplasia of the mucosa and/or invasive
adenocarcinomas of the colorectum. The present results may recommend
chemoimmunotherapy while using lentinan, but not immunotherapy using lentinan
alone, is indicated for the management of cancer patients.
PMID- 10767376
TI - Epidermal growth factor receptor expression correlates with poor prognosis in non
small cell lung cancer patients with p53 overexpression.
AB - To determine whether cancer patients with tumor suppressor gene abnormality
survive for a shorter time when their growth was stimulated by growth factors, we
examined 290 non-small cell lung cancer (NSCLC) specimens for p53 and epidermal
growth factor receptor (EGFR) protein expressions using immunohistochemical
staining. The distribution of cases by pathological stage of tumor was 155 cases
of stage I, 30 cases of stage II, 96 cases of stage III and 9 cases of stage IV.
Pathological types were 142 adenocarcinomas, 127 squamous cell carcinomas, 17
large cell carcinomas and 4 other types of malignancy. Immunohistochemical
staining was performed on the formalin fixed, paraffin-embedded materials with
monoclonal antibodies DO-7 and clone EGFR.133. positive staining for EGFR was
seen in 124 (42.8%) cases. More EGFR positive cases were found in squamous cell
carcinomas than in non-squamous cell carcinomas (p=0.0121). Staining for p53
protein was observed in 147 (50.7%) specimens. Multivariate proportional hazard
model analyses revealed EGFR protein expression as a risk factor in the patients
with NSCLC (p=0.0240). Patients negative for both EGFR and p53 survived for a
longer period of time (p=0.0427).
PMID- 10767378
TI - Rate of progression to advanced stage in depressed-type colorectal adenoma.
AB - To better estimate the likelihood of depressed-type adenoma developing into more
advanced colorectal cancer, we assumed that a given colorectal cancer had a
depressed type origin when depressed non-polypoid-type cancerous glands remained
microscopically identifiable. Among 100 adenomas, depressed non-polypoid-type
glands were found in 15, and lesion size in tumor with depressed non-polypoid
type did not differ from that in others. Among 100 submucosally invasive cancers,
depressed non-polypoid-type glands were found in 14, and lesion size in tumor
with depressed non-polypoid-type did not differ from that in others. Among 100
cancers invading the muscularis propria, depressed non-polypoid-type glands were
found in 15; these were significantly smaller lesions than those without
depressed non-polypoid-type cancers (p<0.05). Among 100 more deeply invasive
cancers, depressed non-polypoid-type grands were found in 16, with no difference
in size from other similarly invasive lesions. We concluded that the rate of
depressed-type adenoma progression to invasive cancer was about 15% and that
depressed non-polypoid-type cancers are likely to invade the muscularis propria
even when smaller than cancers of other types.
PMID- 10767377
TI - Nuclear morphometry and glutathione S-transferase pi expression in breast cancer.
AB - Glutathione S-transferase pi (GST-pi) is a phase II detoxification enzyme whose
expression is increased in estrogen receptor (ER)-poor breast cancers and in
breast cancers resistant to certain chemotherapeutic agents. The aim of this
study was to investigate the immunohistochemical expression of GST-pi in invasive
breast carcinoma and to correlate the findings with those of nuclear morphometry.
Formalin-fixed paraffin-embedded tissue specimens obtained from 21 invasive
breast cancers and 16 adjacent (benign) tissues were immunohistochemically
stained using polyclonal anti-human GST-pi antibody. There was positive (defined
as >10% immunoreactive tumor cells) but variable expression of GST-pi in 10 (48%)
cases. Nuclear morphometry in these 10 tumors revealed immunoreactive malignant
cells to be larger (mean area 41.7+/-1.0 microm2) and more rounded in form when
compared with non-staining cancer cells (mean area 28.7+/-0.7 microm2). It was
also observed that GST-pi immunonegative tumor cells in GST-pi expressing tumors
had different morphologies from malignant cells in the remaining 11 (52%) cancers
that were regarded as GST-pi negative. Increased GST-pi expression determined by
the percentage of positively staining tumor cells, was found to be significantly
correlated with increased variability in nuclear area and perimeter (Spearman's
rho=0.821, p=0.044 for both) in the subset of node-positive tumors. Our findings
suggest that there exists two sub-populations of cancer cells with distinct
nuclear morphologies in GST-pi positive tumors; factors other than GST-pi
expression are likely to have a phenotypic effect on breast cancer cells; and
there may be a special significance of this enzyme in axillary node-positive
breast tumors.
PMID- 10767379
TI - Does macrophage-colony stimulating factor stimulate rat haematopoietic cells?
AB - It is known that colony stimulating factors (CSFs) stimulate the myeloid cells of
bone marrow and splenic cells in rodents. The effects of macrophage (M)-CSF on
the activities of thymidylate synthase and thymidine kinase, involved in de novo
and salvage pathways for pyrimidine nucleotide synthesis, respectively, in
haematopoietic cells of bone marrow and spleen were investigated in rats. A
single M-CSF injection did not elevate the mRNA expression levels of the enzymes
in bone marrow cells 6 h after treatment, but it enhanced the splenic thymidylate
synthase mRNA expression. M-CSF stimulated the splenic thymidylate synthase
activity without an increase of the peripheral granulocytes. The effect of M-CSF
on granulocytes is considered to be weak compared with that of granulocyte (G)
CSF, because of the indirect secretion of endogenous G-CSF from the cells with M
CSF receptors stimulated by exogenous M-CSF. Since M-CSF was able temporarily to
lead progenitor cells from long G1-phase into S-phase, M-CSF might accelerate the
anticancer effects when used together with anticancer agents.
PMID- 10767380
TI - An in vitro examination of a 5-fluorouracil regimen involving continuous venous
infusion using cultured cell lines derived from ovarian cancers.
AB - To examine the antitumor effectiveness of continuous venous infusion of 5
fluorouracil (5-FU), such a regimen was mimicked in vitro using cultured ovarian
cancer cell lines. Two ovarian carcinoma cell lines, HRA and KK with cell
doubling times (DT) of 16 h and 45 h, respectively, were grown under three
incubation conditions with respect to 5-FU exposure, and the extent of growth
inhibition was compared among the three conditions and between the two cell
lines. Protocol I: 6 h-intermittent exposure to 5-FU, protocol II: 24 h
intermittent exposure to 5-FU, protocol III: uninterrupted exposure to 5-FU. The
50% growth inhibitory concentrations (IC50) of 5-FU obtained for KK cells grown
under protocols I and II were both two times higher than that obtained under
protocol III. Regarding HRA cells, IC50 obtained under protocol I was two times
higher than that obtained under protocol III, while that obtained under protocol
II was 3.7 times higher than that obtained under protocol III. Results obtained
from the present in vitro examination suggested that the drug-free interval in
the intermittent infusion of 5-FU should be shorter than the DT of the targeted
tumor cells to obtain an efficacy corresponding to that obtained by uninterrupted
exposure to the drug. In establishing an effective intermittent continuous
infusion therapy with 5-FU with fewer side effects, the drug-free interval should
be shorter than the DT of tumor cells, but longer than the DT of proliferating
cells in normal tissues, including gastrointestinal mucosa cells assuming that
these normal cells possess shorter DT than tumor cells.
PMID- 10767381
TI - A conditioned medium from a human liposarcoma-derived cell line induces p53
dependent apoptosis in several tumor cell lines.
AB - A novel cell line, named LSA, has been obtained, stabilized, and characterized
from a human liposarcoma. These cells have morphological and biochemical features
strongly resembling the adipocytes and were able to grow in the Ham's F12 medium,
in presence or absence of FCS. A conditioned medium (LSA-CM) was obtained by
growing the LSA cells in the F12 medium in the absence of FCS. LSA-CM had
cytostatic and cytotoxic effects (apoptosis and necrosis) associated with down
regulation of c-myc and upregulation of p53 in several human cell lines (breast,
lung, glioblastoma, etc. ). The MCF-7 and glioblastoma cells were killed by LSA
CM in 5-6 days, whereas the same cells were killed by LSA-CM co-incubated with
low doses of cisplatin in 30 h. LSA-CM peri-tumoral injections for 15 days in
Balb-c-fc3H mice affected by mammary tumors, resulted in the rapid disruption of
tumors and absence of metastases. In contrast, in the untreated animals the tumor
masses were 4 times larger than initial lesions, and numerous metastases were
found in the lungs. The toxicity analysis of LSA-CM, performed on three different
animal species, showed that LSA-CM is absolutely free of acute, subacute, and
subchronic toxicity. The possible use of LSA-CM/cisplatin for cancer treatment is
discussed.
PMID- 10767382
TI - Significance of pretreatment serum hemoglobin and survival in epithelial ovarian
cancer.
AB - Tumor anemia is common in patients with malignant tumors and it was repeatedly
demonstrated to be associated with impaired prognosis in patients with malignant
tumors. We conducted a retrospective analysis based on 553 patients with
histologically proven epithelial ovarian cancer. Blood hemoglobin levels were
determined before surgery and patients with values <12 g/dl were considered
anemic. Data analysis included univariate and multiple Cox models. Tumor anemia
was present in 143 (25.9%) patients before surgery. Tumor anemia was present in
143 (25.9%) patients before surgery. In a multivariate Cox model, pretreatment
hemoglobin values proved to be an independent prognostic factor for patients with
stage I-II epithelial ovarian cancer (n=203), but failed to attain significance
in patients with stage III-IV disease (n=350). Tumor anemia defined as
pretreatment hemoglobin values <12 g/dl may indicate patients with stage I and II
epithelial ovarian cancer, who are at increased risk of relapse.
PMID- 10767384
TI - Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis.
AB - Twenty-five patients with ovarian clear cell carcinoma (CC-Ca) were enrolled in
this study, and tumor cell expression of vascular endothelial growth factor
(VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) was
investigated, and correlated with the microvessel count (MVC) and the impact of
complication endometriosis. Expression of VEGF was strongly positive in 16 cases,
weakly positive in 6 cases, and negative in 3 cases. Expression of PD-ECGF was
strongly positive in 11 cases, weakly positive in 6 cases, and negative in 8
cases. VEGF expression and the MVC were significantly correlated (p<0.01), and
there were no correlations among complication by endometriosis, expression of
VEGF, expression of PD-ECGF, and MVC.
PMID- 10767383
TI - Cloning, characterisation and bacterial expression of full length cDNA for the
mouse liver microsomal glutathione S-transferase.
AB - We have isolated a cDNA encoding full length microsomal glutathione S-transferase
(MGST) from mouse liver. The cDNA was isolated by RT-PCR using primers designed
from published cDNA sequence of rat MGST with the addition of 5' Nde-1 and 3'
HindIII sites, and cloned into bacterial expression vector pSP19T7LT. Deduced
amino acid sequence (155 amino acids, calculated mol.mass 17512 Dalton) confirmed
the identity of microsomal GST from mouse liver which has sequence homology with
that of rat and human liver MGST1. Recombinant GST cDNA (Genbank accession #
159050) was expressed in BL21(DE3) in the presence of 1 mM IPTG at 30 degrees C.
The expressed GST protein was found to be localised in the bacterial membrane as
determined by measuring catalytic activity using CDNB and cumene hydroperoxide
substrates, SDS-PAGE and Western blot analysis. We have demonstrated the cloning
and expression of full length cDNA for MGST from mouse liver and have
characterised the functionally active product as MGST protein. These results
should facilitate studies on the role of MGST in the regulation of chemical
carcinogenesis and in the prevention of oxidative stress caused by endogenous and
exogenous chemicals.
PMID- 10767385
TI - Clinical evaluation of mature teratomas containing malignant elements.
AB - We investigated the possibility of preoperative diagnosis and clinical features
of mature ovarian teratoma containing malignant elements (MOTME). Between 1982
and 1998 in our hospital, MOTME accounted for 2.0% (5 cases) of the total of 251
patients with mature ovarian teratoma (ages, 37-72; mean age, 60.6). Serum CA19
9, CA125, SCC and CEA levels were high. All cases were strongly suspected
malignancies, preoperatively diagnosed using serum tumor markers with diagnostic
imaging. Two cases of stage I squamous cell carcinoma and one case of borderline
malignancy survived, while the other two advanced cases died within 8 months.
PMID- 10767386
TI - Transdermal fentanyl during high-dose chemotherapy and autologous stem cell
support.
AB - We report on our experience in the use of transdermal fentanyl in management of
acute pain due to mucositis WHO-grade IV during high-dose chemotherapy (HDC) and
autologous stem cell support (APBSCT). Between 8/96 and 12/98 74 patients
received HDC and PBSCT for progressive disease or relapse of non-Hodgkin's
lymphoma (n=32), multiple myeloma (n=37), Hodgkin's lymphoma (n=5). All patients
suffered from mucositis WHO-grade IV with a need for continuous pain management.
Instead of pethidine i.v. fentanyl TTS was used. Sufficient analgesia was
achieved mostly with a dose of 50 microg/h. There was no need of supplementary
analgesia. Relevant fentanyl-associated side effects were not seen. Patient
compliance and acceptance were excellent. The results suggest that transdermal
fentanyl is reliable in pain management of chemotherapy-associated mucositis
grade IV.
PMID- 10767387
TI - The influence of the oncogene N-ras on cell cycle delay in a human melanoma cell
line with reduced radioresistance.
AB - In a previous study we found that transfection of a human melanoma cell line with
the oncogene N-ras led to increased radiosensitivity as measured by clonogenic
assays. Since a shift in radiosensitivity is often correlated with altered G2/M
delay, we investigated whether this was also the case in this oncogene containing
melanoma cell line (IGRras). A human melanoma cell line, stably transfected with
mutated N-ras, and its parental cell line transfected with the neomycin
phosphotransferase gene only (IGRneo), were irradiated with 5 Gy and cell cycle
distribution was measured at hourly time intervals by DNA staining with propidium
iodide. Next, the effect of ionising radiation on the duration of the S-phase was
determined by pulse labelling cells with BrdUrd before irradiation. Both cell
lines showed a radiation induced G2/M delay, which was most prolonged for the ras
transfected cell line. After 5 Gy, the S-phase duration was unaltered, although
the shape of the relative movement (RM) curves was slightly different. No G1
delay was observed in either cell line. Ras transfection in a melanoma cell line
leads to prolonged G2/M delay after radiotherapy. This prolongation is associated
with increased radiosensitivity and not with radioresistance. These data throw
doubt on the use of oncogene expression or G2/M delay as predictors of
radiosensitivity.
PMID- 10767388
TI - Serum anti-p53 antibodies in patients with lung cancer.
AB - Antibodies against the p53 protein are produced by some cancer patients. In some
tumour entities, the presence of p53 autoantibodies have been linked to poorer
survival. This study was designed to assess the prevalence and prognostic
implications of p53 autoantibodies in patients with lung cancer. Serum samples of
180 patients were tested for antibodies against p53 protein using an ELISA. We
studied 134 patients with primary lung cancer [histology: small cell lung
carcinoma (SCLC) n=35; non-small cell lung carcinoma (NSCLC) n=99]. The control
group consisted of 46 patients without lung cancer. In 17/134 (12.6%) of the
cancer patients, p53 autoantibodies were detected (4/35 SCLC, 13/99 NSCLC). Most
of the positive results were found in advanced stages of NSCLC (stage I-IIIA:
1/34; stage IIIB/IV: 12/65). One of the 46 control patients tested positive.
Statistical analysis of survival shows no correlation with p53 antibody status in
SCLC, but a significant correlation with shorter survival in NSCLC (p=0.01).
After correction for stage of disease this correlation remains significant (stage
IIIB/IV: p=0.02). In our series, the presence of anti-p53 autoantibodies is
almost exclusively linked to the presence of malignant disease. Prognosis for
patients with NSCLC, but not SCLC seems to be linked to the p53 autoantibody
status.
PMID- 10767389
TI - Prognostic value of simultaneous expression of p21 and mdm2 in breast carcinomas
treated by adjuvant chemotherapy with antracyclin.
AB - One hundred and sixty-two breast carcinomas treated by adjuvant chemotherapy were
investigated in immunohistochemistry for expression of p53 and two wild-type p53
regulated induced proteins, mdm2 and p21/waf1. p21 and mdm2 were expression
stongly correlated with Ki67 but not with survival. The p53+/p21+, p53+/p21- and
p53+/mdm2- phenotypes were associated with the worst prognosis. The p53+/p21+/
mdm2+ tumors were associated with a better outcome than the other phenotypes,
they may be tumors expressing wild-type p53 and p21, and a form of mdm2 that
might lead to the stabilization of p53. It is suggested that p21/mdm2 expression
should be investigated in all cases of p53 positive breast cancer.
PMID- 10767391
TI - Neutrophil intracellular pH and phagocytosis after thermal trauma.
AB - Severe burn trauma induces an acquired dysfunction of neutrophil granulocytes. As
neutrophil function is considerably influenced by intracellular pH (pH(i)), the
pH(i) of blood neutrophils was longitudinally determined in 19 patients with
major burns. pH(i) was measured by a flow cytometric method using the pH
sensitive fluoroprobe carboxy-semi-naphthorhodafluor-1; mechanisms influencing
the pH(i) were examined by addition of amiloride (inhibition of Na(+)/H(+)
countertransport), diphenylene iodonium (inhibition of NADPH oxidase) and N
formyl-methionyl-leucyl-phenylalanine (activation of H(+) extrusion). The
neutrophil phagocytic activity was measured in parallel. Patients showed distinct
alterations of neutrophil pH(i), depending on whether they developed sepsis in
the postburn period or not. In the sepsis patients pH(i) did not deviate from the
values found in healthy volunteers in the first days after injury, but rose
afterwards, with significant intracellular alkalinization in the second postburn
week (P<0.05). In contrast, patients without sepsis had increased pH(i) in the
first (P<0.01 at days 1-2), but not in the second week after burn trauma.
Inhibition studies showed that postburn intracellular alkalinization is not
solely caused by activation of Na(+)/H(+) countertransport. A clear relation
between pH(i) changes and phagocytosis could not be established.
PMID- 10767390
TI - Distribution of serum apolipoproteins A-I and B and lipoprotein(a) in European
elderly. The SENECA study.
AB - The purpose of this study is to describe sex and geographic differences in
apolipoproteins (apo) A-I and B and lipoprotein(a) [Lp(a)] concentrations in
elderly Europeans. Subjects were 2164 elderly participants of the SENECA study
from different regions of Europe. Sera for apo A-I, apo B, and Lp(a) measurement
were available for 1703 individuals. In men, mean values ranged from 1.38 to 1.79
g/l for apo A-I, 1.03-1.36 g/l for apo B, and 0.26-0.67 g/l for Lp(a). In women,
mean values ranged from 1.54 to 1.98, 1.20-1.51, and 0.26-0.68 g/l for apo A-I,
apo B, and Lp(a), respectively. A comparison of northern (Norway, Denmark,
Netherlands), middle (France, Switzerland), and southern (Portugal, Spain, Italy,
Greece) communities showed a less atherogenic profile in the south, including
lower LDL cholesterol, apo B, TC/HDL cholesterol ratio, and apoB/apo A-I ratio.
Men, but not women, also had significantly higher HDL cholesterol and apo A-I
concentrations in the South. Paradoxically, Lp(a) concentrations were generally
high among all elderly and were significantly higher in the southern communities.
These data show that the elderly in Europe are very heterogeneous with respect to
plasma lipoproteins, including apo A-I, apo B, and Lp(a).
PMID- 10767392
TI - Aberrant forms of alpha(2)-macroglobulin purified from patients with multiple
sclerosis.
AB - The biochemical properties of alpha(2)-macroglobulin were investigated in four
patients with multiple sclerosis and compared to alpha(2)-macroglobulin from
healthy controls. An impaired stability of alpha(2)-macroglobulin from the
multiple sclerosis patients was demonstrated as a spontaneous conversion to an
electrophoretic"fast" form of alpha(2)-macroglobulin upon purification and
storage, with a concomitant decrease in functional capacity to inhibit
proteinases. The ability to form complexes with proteinases was significantly
reduced in alpha(2)-macroglobulin purified from the multiple sclerosis patients.
The aberrant molecular arrangements of the protein were not due to proteinase
cleavages in the bait regions of alpha(2)-macroglobulin, as demonstrated by gel
electrophoresis and protein sequencing. The number of functional thiol esters,
however, was reduced in alpha(2)-macroglobulin purified from the multiple
sclerosis patients, an observation compatible with the impaired proteinase
binding property. Furthermore, differences in isoelectric points were observed
between alpha(2)-macroglobulin from the multiple sclerosis patients and alpha(2)
macroglobulin from healthy controls. The results suggest that aberrant forms of
alpha(2)-macroglobulin may be present in patients with multiple sclerosis.
PMID- 10767393
TI - Effect of epithelial debridement on glycosaminoglycan synthesis by human corneal
explants.
AB - The purpose of the present work was to investigate the effects of mechanical
epithelial debridement upon glycosaminoglycan synthesis by human corneal
explants. Corneal explants were maintained under tissue culture conditions for 2
72 days and the glycosaminoglycans synthesized in 24 h were metabolically labeled
by addition of 35S-sulfate to the culture medium. These compounds were isolated
from the tissue explants and analyzed by a combination of agarose gel
electrophoresis and enzymatic degradation with specific mucopolysaccharidases.
The glycosaminoglycans synthesized by isolated epithelial cells and by corneas
previously submitted to epithelial cell debridement were compared to controls.
Keratan sulfate (26 kDa) and dermatan sulfate (43 kDa) were the main corneal
glycosaminoglycans, each one corresponding to about 50% of the total.
Nevertheless, the main 35S-labeled glycosaminoglycan was 35S-dermatan sulfate
(73%), with smaller amounts of 35S-keratan sulfate (15%) and 35S-heparan sulfate
(12%), suggesting a lower synthesis rate for keratan sulfate. The main
glycosaminoglycan synthesized by isolated epithelial cells was heparan sulfate.
The removal of epithelial layer caused a decrease in heparan sulfate labeling and
induced the synthesis of dermatan sulfate by stromal cells. This increased
synthesis of dermatan sulfate suggests a relationship between epithelium and
stroma and could be related to the corneal opacity that may appear after
epithelial cell debridement.
PMID- 10767394
TI - Free and total magnesium in lymphocytes of migraine patients - effect of
magnesium-rich mineral water intake.
AB - Dietary surveys performed in Western countries show magnesium intakes lower than
the recommended dietary allowances, suggesting a large prevalence of magnesium
deficiency. Low brain magnesium as well as impaired magnesium metabolism have
also been reported in various diseases such as migraine. To detect these
deficiencies, a non-invasive and sensitive test assessing magnesium status is
needed. Because magnesium is an intracellular cation, either total or ionized
magnesium (Mg(2+)) of blood cells were suggested as the most adequate tests.
Total magnesium levels in plasma, erythrocytes and lymphocytes and Mg(2+) in
lymphocytes were analyzed in a group of 29 migraine patients and 18 control
subjects. Results show significantly lower concentrations of total magnesium in
erythrocytes (50.7+/-4.7 vs. 53.5+/-2.9 mg/l; P<0.01) and of Mg(2+) in
lymphocytes (12.0+/-3.5 vs. 14.2+/-3.8 mg/l; P<0.05) in migraine patients as
compared to controls. While a significant difference of mean values was noted
between migraine patients and controls, an overlap of individual values was
observed. These analyses were repeated on migraine patients before and after a 2
week intake of a mineral water containing 110 mg/l magnesium, and a significant
increase in all intracellular magnesium concentrations with no effect on plasma
magnesium was observed. These increased intracellular magnesium concentrations
demonstrate the bioavailability of magnesium from this mineral water. Among the
analyzed parameters, Mg(2+) in lymphocytes appears to be the most sensitive index
of magnesium deficiency with a 15% decrease in migraine patients when compared to
controls and a 16% increase after 2 weeks of a magnesium-rich mineral water
intake.
PMID- 10767395
TI - Identification of a dysfibrinogen, the substitution of gamma308Asn(AAT) to
Lys(AAG), using coagulation tests, immunoblot analysis, and allele-specific
polymerase chain reaction.
AB - During the past 3 years, we encountered 12 new cases suspected of being
dysfibrinogenemias, via plasma coagulation screening tests, which included
determination of fibrinogen concentration both by thrombin time and immunologic
methods. We performed sodium dodecyl sulfate-polyacrylamide gel electrophoresis
under reducing conditions and immunoblot analysis for these plasma fibrinogens.
We identified two cases that were characterized by two distinct gamma-chain
bands, similar to previous observations with Matsumoto-II (the substitution of
gamma308Asn to Lys). Therefore, in order to identify the gamma308Lys variant
easily and rapidly, we established an allele-specific polymerase chain reaction
(AS-PCR). AS-PCR results indicated that the two cases were indeed heterozygous
for the gamma308Lys variant; ten other cases were negative for this mutation. In
conclusion, the ratio of fibrinogen concentrations determined by functional and
antigenic methods in combination with the immunoblot analysis made these cases
attractive for identifying the gamma308Lys mutation. The AS-PCR method proved to
be a useful procedure to identify the gamma308K mutation.
PMID- 10767396
TI - Identification of undescribed medium-chain acylcarnitines present in urine of
patients with propionic and methylmalonic acidemias.
AB - In urine of patients with propionyl-CoA carboxylase deficiency or with
methylmalonic acidemia, carnitine esters of 2-methyl-branched fatty acids of all
chain lengths between 4 and 9 atoms of carbon were identified during the acute
phase of the diseases. The chemical structure of these compounds was obtained by
gas chromatography-mass spectrometry analysis of their fatty acid moieties in
their free and picolinyl ester forms. We suggest mechanisms for the biosynthesis
of these branched fatty acids, and their accumulation in urine during episodes of
caloric imbalance.
PMID- 10767397
TI - Reactions of direct LDL-cholesterol assays with pure LDL fraction and IDL:
comparison of three homogeneous methods.
AB - According to the definition of the Lipid Research Clinic's protocol, low-density
lipoprotein (LDL) refers to the lipoprotein of density (d)=1.006-1.063 g/ml which
contains another atherogenic lipoprotein, IDL (d=1.006-1.019 g/ml). Because
metabolic properties are largely different between LDL and IDL, LDL is now
defined as the lipoprotein of d=1.019-1.063 g/ml. Recently direct LDL-cholesterol
assay kits using novel surfactants (the homogeneous methods) have become
commercially available and widely used in Japan. The aim of this study is to
examine how three direct LDL-cholesterol assay kits, LDL-EX, Choletest-LDL and
Determinor-L LDL, react with pure LDL (d=1. 019-1.063 g/ml) and IDL (1.006-1.019
g/ml) fractions isolated by ultracentrifugation. Thirty-one healthy subjects and
one type III dysbetalipoproteinemic patient were enrolled in this study. All
homogeneous methods highly correlated with LDL-cholesterol (r=0.95-0. 98),
although the values for LDL-EX were closer to the values for ultracentrifugation
than were those of the other two methods (95 vs. 86-87%, P<0.0001). Cross
reactivity with IDL was 31, 47 and 64% for LDL-EX, Choletest-LDL, and Determinor
L LDL, respectively. Similar results were obtained in the IDL from a type III
dysbetalipoproteinemic patient. These results suggest that LDL-cholesterol
measured by LDL-EX better reflects pure LDL fraction with weaker cross-reaction
with IDL than other homogeneous methods.
PMID- 10767398
TI - Development of specific monoclonal antibodies and a sensitive discriminatory
immunoassay for the circulating tumor markers SCCA1 and SCCA2.
AB - The squamous cell carcinoma antigen (SCCA) serves as a serologic marker for
advanced squamous cell carcinomas (SCC) of the uterine cervix, lung, esophagus,
head and neck and vulva. Elevations in serum levels of SCCA following treatment
for SCC correlate with tumor relapse or metastasis. Recent molecular studies show
that SCCA is transcribed by two nearly identical genes (SCCA1 and SCCA2) that
encode for members of the high molecular weight serine proteinase inhibitor
(serpin) family. Despite a high degree of similarity in their amino acid
sequences, SCCA1 and SCCA2 have distinct biochemical properties: SCCA1 is an
inhibitor of papain like cysteine proteinases, such as cathepsins (cat) L, S and
K, whereas SCCA2 inhibits chymotrypsin-like serine proteinases, catG and mast
cell chymase. In this paper, we report the generation and characterization of
anti-SCCA1 and anti-SCCA2 specific monoclonal antibodies (MAbs). Using these
MAbs, we developed an enzyme-linked immunoassay (ELISA) that discriminated
between SCCA1 and SCCA2 without any cross-reaction. This assay measured both the
native and complexed forms of SCCA1 and SCCA2. The sensitivity of detection of
SCCA1 and SCCA2 assays were 0.17 ngml(-1) and 0.19 ngml(-1), respectively. Mean
inter- and intra-assay coefficients of variation were 12.1% and 9.9% for SCCA1
assay and 12% and 8.8% for SCCA2 assay, respectively. Recovery and parallellism
studies indicated that SCCA1 and SCCA2 were detected in the plasma and amniotic
fluids without any major interference by the biologic fluid components. This
assay provides a simple and accurate procedure for the quantitation of total
SCCA1 and SCCA2.
PMID- 10767399
TI - Effect of timosaponin E1 and E2 on superoxide generation induced by various
stimuli in human neutrophils and on platelet aggregation in human blood.
AB - We have reported that six steroidal saponins isolated from Anemarrhenae rhizoma
had various effects on stimulus-induced superoxide generation in human
neutrophils. In this paper, two novel steroidal saponins, timosaponins E1 and E2
were isolated from Anemarrhenae rhizoma, and the effects of these steroidal
saponins on superoxide generation in human neutrophils were investigated.
Timosaponins E1 and E2 significantly inhibited N-formyl-methionyl-leucyl
phenylalanine (fMLP)-induced superoxide generation in a concentration-dependent
manner, but not that induced by arachidonic acid (AA). On the other hand, both
compounds enhanced superoxide generation induced by phorbol 12-myristate 13
acetate (PMA) in a concentration-dependent manner. The superoxide generation
induced by PMA with timosaponins E1 and E2 was suppressed by staurosporine, an
inhibitor of protein kinase C, but was not suppressed by genistein, an inhibitor
of protein tyrosine kinase. Tyrosyl phosphorylation of a 58 kDa protein, which
was increased by fMLP, was inhibited by timosaponins E1 and E2. Timosaponins E1
and E2 also inhibited the generation of a 47 kDa protein and platelet aggregation
in human blood. The results suggest that protein tyrosine kinase participates in
fMLP-mediated superoxide generation by timosaponin E1- and E2-treated human
neutrophils.
PMID- 10767400
TI - Antioxidant ability of caffeine and its metabolites based on the study of oxygen
radical absorbing capacity and inhibition of LDL peroxidation.
AB - Although caffeine has been suggested as an antioxidant at millimolar
concentrations, little information is available about the antioxidant activity of
caffeine and its metabolites at physiological concentrations. Antioxidant
activity was measured by oxygen-radical absorbing capacity (ORAC) using 2, 2'
azobis(2-amidinopropane) dihydrochloride (AAPH) as a peroxyl radical generator.
The antioxidant ability was tested at 40 micromol/l by determining the level of
thiobarbituric acid reactive substances (TBARS) and conjugated dienes produced
from the oxidation of human low density lipoprotein (LDL) by 45 mmol/l AAPH.
There was neither antioxidant activity nor protective ability present with
caffeine, 1,7-dimethylxanthine, 3,7-dimethylxanthine, or 1, 3-dimethylxanthine at
this micromolar concentration. The antioxidant activity was however significant
with 1-methylxanthine (1-X) and 1-methyluric acid (1-U), the main metabolites of
caffeine in humans. The relative ORAC values of Trolox, ascorbic acid, uric acid,
1-X, and 1-U were 1:0.47:0.86:0.58:0.81, respectively, on a molar basis. These
compounds also significantly reduced the level of TBARS and conjugated dienes
produced from the LDL peroxidation. The antioxidant effect of 1-X is equivalent
to ascorbic acid and 1-U is to uric acid.
PMID- 10767401
TI - Analysis of 7-ketocholesterol in low density lipoprotein and fatty acid
composition in erythrocyte membranes of patients on maintenance hemodialysis and
healthy controls.
AB - We established a method to quantify 7-ketocholesterol (7-KC) in low density
lipoprotein by using the heparin-citrate method and gas chromatography-mass
spectrometry. We examined the concentration of 7-ketocholesterol in LDL using
this method to assess the pathological conditions in uremic patients with
hemodialysis and healthy controls. We also examined the fatty acid composition in
erythrocyte membranes to estimate the modification of biological membranes. We
showed that the concentrations of 7-KC/cholesterol in LDL were significantly
increased in hemodialysis patients compared to healthy controls (3.68+/-0.45 vs.
2.41+/-0.19, P<0.05) and the ratio of polyunsaturated fatty acids to saturated
fatty acids in erythrocyte membranes was significantly decreased in hemodialysis
patients compared to healthy controls (0.499+/-0.014 vs. 0.655+/-0. 017,
P<0.001). There was no significant difference in 7-KC concentration in LDL or
fatty acid composition in erythrocyte membranes between pre- and post
intervention of hemodialysis. We concluded that hemodialysis patients are under
oxidative stress, which modifies LDL and erythrocyte membranes and we speculated
these modifications may participate in the process of atherosclerosis. We believe
that the method to quantify 7-KC in this study is concise and reliable and may be
used to investigate various diseases.
PMID- 10767402
TI - Antioxidant defence in recurrent abortion.
AB - Increased free radical activity has been implicated in the pathogenesis of
recurrent abortion. This investigation was conducted to determine if changes in
some parameters of the antioxidant system contribute to this condition. Plasma
ascorbic acid, alpha-tocopherol, total thiols, ceruloplasmin, uric acid, albumin,
and erythrocyte glutathione (GSH) were assayed in 25 nonpregnant (NP) healthy
women, 25 normotensive pregnants (NTP), and 120 women with recurrent abortion.
Recurrent aborters were divided into four subgroups according to the etiology:
autoimmune (AUTO, n=25), luteal phase defect (LPD, n=25), anatomical defect (AD,
n=20) and unexplained (UNEx, n=50). Plasma levels of ascorbic acid, alpha
tocopherol, and erythrocyte GSH were significantly decreased in AUTO, UNEx and
LPD subgroups than those in two control groups and the AD group (ANOVA). Plasma
thiols of UNEx and AUTO aborters were diminished according to controls and other
abortion subgroups (ANOVA). Ceruloplasmin levels showed a decline in AUTO and
UNEx subgroups when compared to controls, AD and LPD aborters (ANOVA). When UNEx,
AUTO and LPD recurrent abortion subgroups were compared with each other
(Student's t-test) total thiols and erythrocyte GSH of UNEx and AUTO subgroups
were diminished in comparison with LPD. We suggest that decreased concentrations
of plasma ascorbic acid, alpha-tocopherol, total thiols and erythrocyte GSH in
UNEx, AUTO and LPD reflect the increased oxidative stress, expressing a progress
of the condition. Also, the imbalance between antioxidant defence and free
radical activity is more evident in the AUTO subgroup. As a conclusion, although
impaired antioxidant defence may be responsible for recurrent abortions, the
recurrent abortions may also result in oxidative stress and depletion and
weakness of antioxidant defence.
PMID- 10767403
TI - Detection of cocaine metabolite in serum and urine: frequency and correlation
with medical diagnosis.
AB - Review of toxicology screening results in our level 1 trauma center revealed that
approximately 15% of urine drug screens were positive for cocaine metabolite. Our
objective was to determine the prevalence of true acute cocaine intoxication and
if measurement of serum would improve upon the accuracy of toxicology screening
for identifying acute cases of cocaine poisoning. Cases were analyzed for cocaine
metabolite (benzoylecgonine, BE) in matched serum and urine specimens and for
acute cocaine intoxication by retrospective chart review. BE was identified in
3.8% of serum and 14.6% of urine specimens. For the identification of the acutely
poisoned patient, the predictive value of toxicology screening was 53.4% for
serum and 17.8% for urine. Of patients who screen positive for BE in serum, the
odds of intoxication are 44:1 (95% CI 4.85-396.7). We conclude that subjects who
test positive for BE in serum have a high probability of acute cocaine
intoxication and that analyzing serum improves the predictive value of testing by
3-fold.
PMID- 10767404
TI - Alternative method for diagnosis of two polymorphisms in the human transforming
growth factor-beta1 by PCR-mediated double site-directed mutagenesis.
AB - Cytokine transforming growth factor-beta1 plays an important role in
physiological processes during ontogenesis, cell differentiation, immune
responses, carcinogenesis, inflammation, wound healing, fibroproduction,
progression of renal insufficiency and arteriosclerotic lesion development. Its
biological function is influenced through the two signal peptide polymorphisms.
We describe a new, economical, easy and fast alternative method which allows
detection of both polymorphisms from one PCR product with subsequent restriction
analysis with two different restriction enzymes. This method could facilitate
further research on the role of this cytokine in human disease.
PMID- 10767405
TI - Rapid parathyroid hormone measurement during venous localization.
AB - The development of a rapid format for intact parathyroid hormone (PTH)
immunometric assays has facilitated the use of these assays intraoperatively as a
guide to parathyroid surgery. The near real-time characteristics of this rapid
PTH assay led us to evaluate its utility in the angiography suite in a patient
who underwent venous localization for persistent primary hyperparathyroidism. The
assay provided the angiographers with almost immediate feedback and thereby
facilitated accurate parathyroid adenoma localization. We conclude that the
performance characteristics of the rapid PTH assay extend its diagnostic utility
to near real-time analysis of plasma PTH levels in patients undergoing venous
catheterization for parathyroid localization.
PMID- 10767406
TI - The reduction potential of the beta-carotene.+ /beta-carotene couple in an
aqueous micro-heterogeneous environment.
AB - There is a resurgence of interest in the role of electron transfer reactions
involving beta-carotene in photosynthesis. There is also current debate on the
health benefits of dietary carotenoids and the possible deleterious effects on
certain sub-populations such as smokers. The impact of dietary carotenoids on
health may well be also related to radical reactions. A key parameter in
biological systems is therefore the one-electron reduction potential of the
carotenoid radical cation, now reported for the first time in a model biological
aqueous environment. The value obtained is 1.06+/-0. 01 V and is sufficiently
high to oxidise cell membrane proteins, but is low enough to repair P(680).+ in
the photosynthetic reaction centre.
PMID- 10767407
TI - Interaction of fMet-tRNA(fMet) with the C-terminal domain of translational
initiation factor IF2 from Bacillus stearothermophilus.
AB - Analytical ultracentrifugation studies indicated that the C-terminal domains of
IF2 comprising amino acid residues 520-741 (IF2 C) and 632-741 (IF2 C-2) bind
fMet-tRNA with similar affinities (K(d) at 25 degrees C equal to 0.27 and 0.23
microM, respectively). Complex formation between fMet-tRNA(fMet) and IF2 C or IF2
C-2 is accompanied by barely detectable spectral changes as demonstrated by a
comparison of the Raman spectra of the complexes with the calculated sum of the
spectra of the individual components. These results and the temperature
dependence of the K(d) of the protein-RNA complexes indicate that complex
formation is not accompanied by obvious conformational changes of the components,
and possibly depends on a rather small binding site comprising only a few
interacting residues of both components.
PMID- 10767408
TI - Characterisation of calmodulin binding to cyclic nucleotide-gated ion channels
from Arabidopsis thaliana.
AB - The recently identified cyclic nucleotide-gated ion channels (AtCNGCs) from
Arabidopsis thaliana have the ability to bind calmodulin. Using two different
methods, we mapped the binding site of AtCNGC1 to the last predicted alpha helix
of the cyclic nucleotide binding domain. This is in contrast to CNGCs from
animals, where the calmodulin binding site is located in the N-terminus, implying
that different mechanisms for CNGC modulation have evolved in animals and plants.
Furthermore, we demonstrate that AtCNGC1 and AtCNGC2 have different calmodulin
binding affinities and we provide evidence for target specificities among
calmodulin isoforms.
PMID- 10767409
TI - Cloning and expression of human TRAAK, a polyunsaturated fatty acids-activated
and mechano-sensitive K(+) channel.
AB - The two P domain hTRAAK K(+) channel has been cloned from human brain. hTRAAK
cDNA encodes a 393 amino acid polypeptide with 88% of homology with its mouse
counterpart. The hTRAAK gene has been mapped to chromosome 11q13 and the study of
its organization indicates that the hTRAAK open reading frame is contained in six
exons. hTRAAK is expressed abundantly in brain and placenta. In COS cells, hTRAAK
currents are K(+)-selective, instantaneous and non-inactivating. These currents
are insensitive to the classical K(+) channels blockers 4-aminopyridine,
tetraethylammonium, barium and quinidine, but are strongly stimulated by
application of arachidonic acid as well as other polyunsaturated fatty acids.
hTRAAK can also be activated by a stretch of the membrane.
PMID- 10767410
TI - FHA domain boundaries of the dun1p and rad53p cell cycle checkpoint kinases.
AB - Dun1p and Rad53p of the budding yeast Saccharomyces cerevisiae are members of a
conserved family of cell cycle checkpoint protein kinases that contain forkhead
associated (FHA) domains. Here, we demonstrate that these FHA domains contain 130
140 residues, and are thus considerably larger than previously predicted by
sequence comparisons (55-75 residues). In vivo, expression of the proteolytically
defined Dun1p FHA domain, but not a fragment containing only the predicted domain
boundaries, inhibited the transcriptional induction of repair genes following
replication blocks. This indicates that the non-catalytic FHA domain plays an
important role in the transcriptional function of the Dun1p protein kinase.
PMID- 10767411
TI - Site-specific recombination in mammalian cells catalyzed by gammadelta resolvase
mutants: implications for the topology of episomal DNA.
AB - We have transferred the prokaryotic gammadelta resolvase system to mammalian
cells and present a comparative analysis of recombination by wild-type and two
mutant resolvases (E124Q and E102Y/E124Q). Transient co-transfection assays using
beta-galactosidase as reporter for recombination reveal that episomal DNA does
not contain a significant level of unconstrained negative supercoiling, since
only mutant resolvases are recombination-proficient. We also show that the
efficiency of recombination by the resolvase double mutant is comparable to that
observed with Cre, which indicates that resolvase can be used as a new tool for
controlled manipulations of episomal DNAs.
PMID- 10767412
TI - GRP94 (endoplasmin) co-purifies with and is phosphorylated by Golgi apparatus
casein kinase.
AB - A phosphorylatable protein band of about 94 kDa (as judged by SDS-PAGE) which co
purifies and co-immunoprecipitates with Golgi apparatus casein kinase (G-CK) from
rat lactating mammary gland has been shown by mass spectrometric sequence
analysis to be identical or very similar to the glucose-regulated protein, GRP94.
GRP94 is also readily phosphorylated by G-CK (K(m)=0.2 microM) at seryl sites
which are different from the sites affected by casein kinase-2 (CK2) in the same
protein. A study with peptide substrates would indicate that the G-CK sites in
GRP94 conform to the motif S-R/K-E-X (X being different from D and E) which is
not recognized by CK2.
PMID- 10767413
TI - Mammalian calcitonin receptor-like receptor/receptor activity modifying protein
complexes define calcitonin gene-related peptide and adrenomedullin receptors in
Drosophila Schneider 2 cells.
AB - Differential glycosylation of human and rat (r) calcitonin (CT) receptor-like
receptors (CRLR) as a result of interactions with accessory receptor activity
modifying proteins (RAMP)1 or -2 was considered to define CT gene-related peptide
(CGRP) or adrenomedullin (ADM) receptors in mammalian cells. Here, Drosophila
Schneider (S2) cells stably co-expressed rCRLR and RAMP1 or -2 as functional CGRP
or ADM receptors. Different from mammalian cells, rCRLR expressed in S2 cells are
uniformly glycosylated proteins independent of RAMP1 or RAMP2.
Bis(sulfosuccinimidyl)suberate cross-linking revealed receptor components with
the size of rCRLR, increased by the molecular weights of the corresponding RAMPs
and [(125)I]CGRP or [(125)I]ADM. In conclusion, [(125)I]CGRP/rCRLR/RAMP1 and
[(125)I]ADM/rCRLR/RAMP2 complexes have been recognized in Drosophila S2 cells.
PMID- 10767414
TI - The distribution of T-DNA in the genomes of transgenic Arabidopsis and rice.
AB - Almost all the nuclear genes of four Gramineae (maize, wheat, barley, rice) and
pea are located in DNA fractions covering only a 1-2% GC range and representing
between 10 and 25% of the different genomes. These DNA fractions comprise large
gene-rich regions (collectively called the 'gene space') separated by vast gene
empty, repeated sequences. In contrast, in Arabidopsis thaliana, genes are
distributed in DNA fractions covering an 8% GC range and representing 85% of the
genome. Here, we investigated the integration of a transferred DNA (T-DNA) in the
genomes of Arabidopsis and rice and found different patterns of integration,
which are correlated with the different gene distributions. While T-DNA
integrates essentially everywhere in the Arabidopsis genome, integration was
detected only in the gene space, namely in the gene-rich, transcriptionally
active, regions of the rice genome. The implications of these results for the
integration of foreign DNA are discussed.
PMID- 10767415
TI - Scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom.
AB - A novel peptide, scorpine, was isolated from the venom of the scorpion Pandinus
imperator, with anti-bacterial activity and a potent inhibitory effect on the
ookinete (ED(50) 0.7 microM) and gamete (ED(50) 10 microM) stages of Plasmodium
berghei development. It has 75 amino acids, three disulfide bridges with a
molecular mass of 8350 Da. Scorpine has a unique amino acid sequence, similar
only to some cecropins in its N-terminal segment and to some defensins in its C
terminal region. Its gene was cloned from a cDNA library.
PMID- 10767416
TI - The plant ribosome inactivating proteins luffin and saporin are potent inhibitors
of HIV-1 integrase.
AB - The ribosome inactivating proteins (RIPs) are a group of proteins that are able
to inactivate eukaryotic protein synthesis by attacking the 28S ribosomal RNA.
Recent studies have shown that some RIPs possess strong anti-human
immunodeficiency virus (HIV) activity. In this study, several common plant RIPs
including agrostin, gelonin, luffin, alpha-momorcharin, beta-momorcharin, saporin
and trichosanthin were examined for the ability to interfere with HIV-1
replication in a variety of mechanistic assays in vitro. These assays included
the CD4/gp120 interaction assay, HIV-1 reverse transcriptase (RT) assay, HIV-1
protease assay and HIV-1 integrase assay. At the concentration of 100 nM, all
RIPs appeared to enhance the CD4/gp120 interaction by about 50%. These RIPs
exhibited a very weak suppressive effect on HIV-1 RT and on HIV-1 protease. In
contrast, with the exception of agrostin, all the RIPs tested could strongly
inhibit HIV-1 integrase, the extent of inhibition ranging from 26.1 to 96.3% in
an ELISA-based assay. Two RIPs, saporin and luffin, which licited over 90%
inhibition in the ELISA-based assay, were further characterized in a radiometric
assay. Both of these two RIPs evoked a strong dose-dependent inhibition in the 3'
end processing and strand-transfer activities of integrase. The results from this
study suggest that the anti-HIV property of RIPs may be due to inhibition of HIV
1 integrase.
PMID- 10767417
TI - Selective inhibition of DNA gyrase in vitro by a GC specific eight-ring hairpin
polyamide at nanomolar concentration.
AB - The influence of an eight-ring hairpin DNA minor groove binder on the gyrase
mediated DNA supercoiling and cleavage reaction step of the enzyme was
investigated. The results demonstrate that supercoiling is affected by the
hairpin polyamide in the millimolar concentration range while the enzyme
catalyzed cleavage of a 162 bp fragment of pBR322 containing a single strong
gyrase site is effectively inhibited at nanomolar concentration. As demonstrated
by footprint analysis the latter effect is caused by a specific binding of the
hairpin forming polyamide to the enzyme recognition site (GGCC), which indicates
that the gyrase activity to produce a double strand break is blocked at this
site. The pyrrole-imidazole hairpin polyamide is the most potent inhibitor of the
gyrase mediated cleavage reaction compared to other known anti-gyrase active DNA
binding agents.
PMID- 10767418
TI - Formation of native structure by intermolecular thiol-disulfide exchange
reactions without oxidants in the folding of bovine pancreatic ribonuclease A.
AB - It has been shown previously that the oxidative folding of bovine pancreatic
ribonuclease A proceeds through parallel pathways with two major native-like
three-disulfide (3S) intermediates. We show here that, under some conditions, the
native disulfide bonds can also be regenerated through disproportionation
reactions; in other words, the protein can serve as its own redox reagent. The
results also show that disulfide species of the unstructured 3S ensemble have a
strong propensity to participate in intermolecular interactions. These
interactions are favored at high protein concentration, temperature and pH, and
lead to formation of the native structure during disulfide reshuffling in the
rate-determining step.
PMID- 10767419
TI - Production of recombinant soluble human integrin alpha4beta1.
AB - Integrin alpha4beta1 is a major leukocyte adhesion receptor that is a key target
for the development of anti-inflammatory therapeutics. With the dual long-term
goals of developing a reagent for use in high-throughput inhibitor screening
assays and for crystallisation trials and subsequent structure determination, we
have generated a recombinant soluble alpha4beta1 receptor. Both subunits were
truncated prior to the transmembrane domains by site-directed mutagenesis and
expressed using baculovirus infection of insect cells. The molecular weights of
the recombinant subunits were as expected for post-translationally unmodified
protein. In addition, as observed for the native subunit, a proportion of the
alpha4 subunit was proteolytically processed into two fragments. ELISA and solid
phase ligand-binding assays were performed to investigate the folding and
functionality of the soluble integrin. The data suggest that the receptor was
correctly folded and that it bound recombinant ligands with similar kinetics to
the native molecule.
PMID- 10767420
TI - Induction of superoxide in glioma cell line U87 stimulated with
lipopolysaccharide and interferon-gamma: ESR using a new flow-type quartz cell.
AB - The production of superoxide and nitric oxide induced in U87 glioma treated with
lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was examined by
electron spin resonance (ESR) spectroscopy using a newly designed flow-type
quartz cuvette without detaching cells from the culture plate. ESR spectra of
2,2,6, 6-tetramethyl-4-hydroxy-1-piperidinyloxy (TEMPOL) with U87 cells on a
quartz culture plate were measured at 15 min intervals. The signal intensity of
TEMPOL decreased in the presence of U87 cells at the pseudo-first order rate. The
signal decay was accelerated in the U87 cells treated with LPS/IFN-gamma for 24
h, and was suppressed in the presence of superoxide dismutase and catalase. By
the spin-trapping method, nitric oxide from U87 cells pretreated with LPS/IFN
gamma for 24 h was measured by the ESR, but only a weak signal of nitric oxide
adducts was detected. Further, the nitrite and nitrate levels in the medium did
not increase for 24 h. By the ESR measurement of cells on culture plates without
detachment stress, it was found that the production of superoxide was induced by
LPS/IFN-gamma, but that of nitric oxide was not, in U87 glioma cells.
PMID- 10767421
TI - Identification and characterization of a eukaryotically encoded rubredoxin in a
cryptomonad alga.
AB - We have identified an open reading frame with homology to prokaryotic rubredoxins
(rds) on a nucleomorph chromosome of the cryptomonad alga Guillardia theta. cDNA
analysis let us propose that the rd preprotein has an NH(2)-terminal extension
that functions as a transit peptide for import into the plastid. Compared to rds
found in non-photosynthetic prokaryotes or found in bacteria that exhibit an
anoxigenic photosynthesis apparatus, nucleomorph rd has a COOH-terminal
extension, which shows high homology exclusively to the COOH-termini of
cyanobacterial rds as well as to a hypothetical rd in the Arabidopsis genome.
This extension can be divided into a putative membrane anchor and a stretch of
about 20 amino acids with unknown function linking the common rd fold to this
anchor. Overexpression of nucleomorph rd in Escherichia coli using a T7 RNA
polymerase/promotor system resulted in a mixture of iron-containing
holorubredoxin and zinc-substituted protein. Preliminary spectroscopic studies of
the iron form of nucleomorph rd suggest the existence of a native rd-type iron
site. One-dimensional nuclear magnetic resonance spectroscopy of recombinant Zn
rd suggests the presence of a stable tertiary fold similar to that of other rd
structures determined previously.
PMID- 10767422
TI - The sorcin-annexin VII calcium-dependent interaction requires the sorcin N
terminal domain.
AB - Surface plasmon resonance experiments show that at neutral pH the stability of
the complex between sorcin and annexin VII (synexin) increases dramatically
between 3 and 6 microM calcium; at the latter cation concentration the K(D) value
is 0.63 microM. In turn, the lack of complex formation between the sorcin Ca(2+)
binding domain (33-198) and synexin maps the annexin binding site to the N
terminal region of the sorcin polypeptide chain. Annexin VII likewise employs the
N-terminal domain, more specifically the first 31 amino acids, to interact with
sorcin [Brownawell, A.M. and Creutz, C.E. (1997) J. Biol. Chem. 272, 22182
22190]. The interaction may involve similar structural motifs in the two
proteins, namely GGYY and GYGG in sorcin and GYPP in synexin.
PMID- 10767423
TI - Transcript levels of the nuclear-encoded respiratory genes in rice decrease by
oxygen deprivation: evidence for involvement of calcium in expression of the
alternative oxidase 1a gene.
AB - We investigated the effect of oxygen on the expressions of respiratory genes
encoded in the nuclear and mitochondrial genomes of rice (Oryza sativa L.).
Hypoxic treatment decreased the transcript levels of nuclear-encoded, but not
mitochondrial-encoded respiratory genes. The effects of ruthenium red (an
inhibitor of Ca(2+) fluxes from organelles) and/or CaCl(2) on plants under
hypoxic conditions suggested that Ca(2+) is a physiological transducer of a low
oxygen signaling pathway for expression of the alternative oxidase 1a gene
(AOX1a), but not for expressions of genes involved in the cytochrome respiratory
pathway, in rice.
PMID- 10767425
TI - GroES co-chaperonin small-angle X-ray scattering study shows ring orifice
increase in solution.
AB - GroES consists of seven identical 10 kDa subunits and is involved in assisting
protein folding as the partner of another oligomeric protein, the GroEL
chaperonin. Here we studied the GroES structure in solution using small-angle X
ray scattering (SAXS). The SAXS pattern, calculated for the GroES crystal
structure, was found to be different from the experimental one measured in
solution. The synchronic shift in the radial direction and some turning of the
protein subunits eliminate the difference and result in the increase of the hole
diameter in the GroES ring-like structure from 8 A in the crystal to 21 A in
solution.
PMID- 10767424
TI - Molecular cloning, functional expression and chromosomal localization of an
amiloride-sensitive Na(+) channel from human small intestine.
AB - Amiloride-sensitive Na(+) channels belonging to the recently discovered NaC/DEG
family of genes have been found in several human tissues including epithelia and
central and peripheral neurons. We describe here the molecular cloning of a cDNA
encoding a novel human amiloride-sensitive Na(+) channel subunit that is
principally expressed in the small intestine and has been called hINaC (human
intestine Na(+) channel). This protein is similar to the recently identified
rodent channel BLINaC and is relatively close to the acid sensing ion channels
(ASICs) (79 and 29% amino acid identity, respectively). ASICs are activated by
extracellular protons and probably participate in sensory neurons to nociception
linked to tissue acidosis. hINaC is not activated by lowering the external pH but
gain-of-function mutations can be introduced and reveal when expressed in Xenopus
oocytes, an important Na(+) channel activity which is blocked by amiloride
(IC(50)=0.5 microM). These results suggest the existence of a still unknown
physiological activator for hINaC (e.g. an extracellular ligand). The presence of
this new amiloride-sensitive Na(+) channel in human small intestine probably has
interesting physiological as well as physiopathological implications that remain
to be clarified. The large activation of this channel by point mutations may be
associated with a degenerin-like behavior as previously observed for channels
expressed in nematode mechanosensitive neurons. The hINaC gene has been mapped on
the 4q31.3-q32 region of the human genome.
PMID- 10767426
TI - Targeting of the gene product encoded by ORF UL56 of human cytomegalovirus into
viral replication centers.
AB - The highly conserved DNA-binding protein pUL56 of human cytomegalovirus (HCMV)
was found to be predominantly localized throughout the nucleus as well as in
viral replication centers of infected cells. The latter localization was
abolished by phosphono acetic acid, an inhibitor of viral DNA replication.
Immunofluorescence revealed that pUL56 co-localized in replication centers
alongside pUL112-113 and pUL44 at late times of infection. By co
immunoprecipitations, a direct interaction with pUL44, a protein of the
replication fork, was detected. These results showed for the first time that HCMV
pUL56 is localized in viral replication centers, implicating that DNA replication
is coupled with packaging.
PMID- 10767427
TI - Amylosucrase from Neisseria polysaccharea: novel catalytic properties.
AB - Amylosucrase is a glucosyltransferase that synthesises an insoluble alpha-glucan
from sucrose. The catalytic properties of the highly purified amylosucrase from
Neisseria polysaccharea were characterised. Contrary to previously published
results, it was demonstrated that in the presence of sucrose alone, several
reactions are catalysed, in addition to polymer synthesis: sucrose hydrolysis,
maltose and maltotriose synthesis by successive transfers of the glucosyl moiety
of sucrose onto the released glucose, and finally turanose and trehalulose
synthesis - these two sucrose isomers being obtained by glucosyl transfer onto
fructose. The effect of initial sucrose concentration on initial activity
demonstrated a non-Michaelian profile never previously described.
PMID- 10767428
TI - Functional conservation between yeast and plant endosomal Na(+)/H(+) antiporters.
AB - Vacuolar compartmentation of Na(+) is an essential mechanism for salinity
tolerance since it lowers cytosolic Na(+) levels while contributing to osmotic
adjustment for cell turgor and expansion. The AtNHX1 protein of Arabidopsis
thaliana substituted functionally for ScNHX1, the endosomal Na(+)/H(+) antiporter
of yeast. Ion tolerance conferred by AtNHX1 and ScNHX1 correlated with ion uptake
into an intracellular pool that was energetically dependent on the vacuolar
(H(+))ATPase. AtNHX1 localized to vacuolar membrane fractions of yeast. Hence,
both transporters share an evolutionarily conserved function in Na(+)
compartmentation. AtNHX1 mRNA levels were upregulated by ABA and NaCl treatment
in leaf but not in root tissue.
PMID- 10767429
TI - Contribution of the different modules in the utrophin carboxy-terminal region to
the formation and regulation of the DAP complex.
AB - The carboxy-terminal region of utrophin, like the homologous proteins dystrophin,
Drp2 and dystrobrevins, contains structural domains frequently involved in
protein-protein interaction. These domains (WW, EF hands, ZZ and H1-H2) mediate
recognition and binding to a multicomponent complex of proteins, also known as
dystrophin-associated proteins (DAPs) for their association with dystrophin, the
product of the gene, mutated in Duchenne muscular dystrophy. We have exploited
phage display and in vitro binding assays to study the recognition specificity of
the different domains of the utrophin carboxy-terminus. We found that none of the
carboxy-terminal domains of utrophin, when isolated from its structural context,
selects specific ligand peptides from a phage-displayed peptide library. By
contrast, panning with an extended region containing the WW, EF hands, and ZZ
domain defines the consensus binding motif, PPxY which is also found in beta
dystroglycan, a component of the DAP complex that interacts with utrophin in
several tissues. WW-mediated binding to PPxY peptides and to beta-dystroglycan
requires the presence of the EF hands and ZZ domain. When the ZZ domain is either
deleted or engaged in binding to calmodulin, the utrophin beta-dystroglycan
complex cannot be formed. These findings suggest a potential regulatory mechanism
by means of which the attachment of utrophin to the DAP complex can be modulated
by the Ca(2+)-dependent binding of calmodulin. The remaining two motifs found in
the carboxy-terminus (H1-H2) mediate the formation of utrophin-dystrobrevin
hybrids but do not select ligands in a repertoire of random nonapeptides.
PMID- 10767430
TI - A cytochrome c-GFP fusion is not released from mitochondria into the cytoplasm
upon expression of Bax in yeast cells.
AB - To study Bax-induced release of cytochrome c in vivo, we have expressed a
cytochrome c-GFP (green fluorescent protein) fusion in Saccharomyces cerevisiae
cells null for the expression of the endogenous cytochrome. We show here that
cytochrome c-GFP is efficiently localised to mitochondria and able to function as
an electron carrier between complexes III and IV of the respiratory chain.
Strikingly, while natural cytochrome c is released into the cytoplasm upon
expression of Bax, the cytochrome c-GFP fusion is not. Nevertheless, cells co
expressing Bax and the cytochrome c-GFP fusion die, indicating that mitochondrial
release of cytochrome c is not essential for cell death to occur in yeast. The
failure to release cytochrome c-GFP is presumed to arise from increased bulk due
to the GFP moiety. We propose that in intact yeast cells, Bax-induced release of
cytochrome c into the cytoplasm occurs through a selective pore and not as a
consequence of the non-specific breakage of the mitochondrial outer membrane.
PMID- 10767431
TI - The dimer contact area of sorghum NADP-malate dehydrogenase: role of aspartate
101 in dimer stability and catalytic activity.
AB - During thioredoxin-mediated activation of chloroplastic NADP-malate
dehydrogenase, a homodimeric enzyme, the interaction between subunits is known to
be loosened but maintained. A modeling of the 3D structure of the protein
identified Asp-101 as being potentially involved in the association between
subunits through an electrostatic interaction. Indeed, upon site-directed
substitution of Asp-101 by an asparagine, the mutated enzyme behaved mainly as a
monomer. The mutation strongly affected the catalytical efficiency of the enzyme.
The now available 3D structure of the enzyme shows that Asp-101 is protruding at
the dimer interface, interacting with Arg-268 of the neighbouring subunit.
PMID- 10767432
TI - Diverse expression profiles of 21 rice peroxidase genes.
AB - Secretory class III plant peroxidases (POXs) catalyze the oxidation of various
reductants, and are encoded by a large multigene family. In rice, 42 independent
expressed sequence tags for POXs have been identified. By RNA gel blot analysis
using specific probes, we show here that 21 rice POX genes are unique in their
developmental, organ specific and external stimuli-responsive expression. This
would suggest that encoded POX isoenzymes are involved in a broad range of
physiological processes in rice plants, individually.
PMID- 10767434
TI - ATP-induced activation of expressed RyR3 at low free calcium.
AB - Ca(2+) channel properties of the mink ryanodine receptor type 3 (RyR3), expressed
in HEK293 cells, were studied in planar lipid bilayers to which RyR3 rich
membrane fragments had been fused. RyR3 channels were not active at resting
levels of Ca(2+)(free) but were gated by an additional 1 mM ATP, exhibiting long
open times. The second major finding was the absence of channel inactivation at
millimolar Ca(2+)(free). Insertion of a myc tag at the N-terminus of RyR3 did not
affect the channel properties. As to skeletal muscle, the observed type 3 channel
properties appear physiologically meaningful by assisting type 1 channels in
calcium release.
PMID- 10767435
TI - Corrigendum to: prediction of human cDNA from its homologous mouse full-length
cDNA and human shotgun database.
PMID- 10767433
TI - Evidence that the glucoamylases and alpha-amylase secreted by Aspergillus niger
are proteolytically processed products of a precursor enzyme.
AB - A 125-kDa starch hydrolysing enzyme of Aspergillus niger characterised by its
ability to dextrinise and saccharify starch [Suresh et al. (1999) Appl.
Microbiol. Biotechnol. 51, 673-675] was also found to possess activity towards
raw starch. Segregation of these activities in the 71-kDa glucoamylase and a 53
kDa alpha-amylase-like enzyme supported by antibody cross-reactivity studies and
the isolation of mutants based on assay screens for the secretion of particular
enzyme forms revealed the 125-kDa starch hydrolysing enzyme as their precursor. N
terminal sequence analysis further revealed that the 71-kDa glucoamylase was the
N-terminal product of the precursor enzyme. Immunological cross reactivity of the
53-kDa amylase with antibodies raised against the precursor enzyme but not with
the 71- and 61-kDa glucoamylase antibodies suggested that this enzyme activity is
represented by the C-terminal fragment of the precursor. The N-terminal sequence
of the 53-kDa protein showed similarity to the reported Taka amylase of
Aspergillus oryzae. Antibody cross-reactivity to a 10-kDa non-enzymic peptide and
a 61-kDa glucoamylase described these proteins as products of the 71-kDa
glucoamylase. Identification of only the precursor starch hydrolysing enzyme in
the protein extracts of fungal protoplasts suggested proteolytic processing in
the cellular periplasmic space as the cause for the secretion of multiple forms
of amylases by A. niger.
PMID- 10767436
TI - Chitinozoan zonation of the Late Ordovician and the Early Silurian of the island
of Anticosti, Quebec, Canada.
AB - A reappraisal of chitinozoan distribution across the Ordovician-Silurian boundary
on the Island of Anticosti has led to the recognition of a new zone, the
Ancyrochitina ellisbayensis biozone, in the uppermost part of the Ellis Bay
Formation. This biozone lies between the well defined Upper Ordovician
Spinachitina taugourdeaui biozone and the lowest Silurian (Rhuddanian)
Plectochitina nodifera biozone of the Becscie Formation. The occurrence of such
diagnostic species as P. nodifera, Belonechitina postrobusta, Conochitina electa
and Ancyrochitina ramosaspina in the Lower Silurian of Anticosti points to a
close similarity to faunas in Estonia and north Latvia and indicates an age
ranging from the Parakidograptus acuminatus to the Coronograptus cyphus in terms
of graptolite zones. The chitinozoan biozonation harmonizes with that based on
conodonts and, to a lesser extent, with the known graptolite faunal succession.
Five new species: Ancyrochitina ellisbayensis sp. nov., Clathrochitina
postconcinna sp. nov., Conochitina gunriveris sp. nov., Clathrochitina perexilis
sp. nov., Bursachitina basiconcava sp. nov. and three species in open
nomenclature are described.
PMID- 10767437
TI - Cervicornus wenshanensis, gen. et sp. nov, a Pragian (Early Devonian) plant with
forked leaves from Yunnan, China.
AB - Cervicornus wenshanensis gen. et sp. nov. is described from compressions of leaf
bearing, vegetative stems of Pragian age (Early Devonian). Stelar anatomy is not
preserved. The plant is described as herbaceous with leaves arranged in openly
spaced helices. The distal portion of each of the leaves is divided three times,
resulting in eight segments resembling the antler of a deer. The arrangement and
morphology of the leaves suggest a possible relationship with the lycopsid family
Protolepidodendraceae in which, among the genera, the leaves are helically
arranged and variously divided. Additionally, the members of the family are
united on the basis of stelar anatomy and the presence of sporangia. Neither of
the latter characteristics, which are essential to the unequivocal assignment to
the family, are preserved in Cervicornus. The genus is a noteworthy morphological
variant among Devonian plants, but the arrangement of the leaves and their
morphology cannot be used alone to infer an affinity with a taxon of higher rank.
As with many other fragmentary paleobotanical entities, lacking sufficient
definitive characteristics and awaiting discovery and description of additional
specimens, we have proposed a classification of this new genus and species as
incertae sedis.
PMID- 10767438
TI - Computer simulation of sphenopsid architecture. I. Principles and methodology.
AB - The modelling system AMAP 1 provides morphological models that reproduce the
series of shapes developed in a plant structure during its growth. It is
applicable to plants that have architectural features consistent with the
principles introduced by Halle et al. (Halle, F., Oldeman, R.A.A., Tomlinson,
P.B., 1978. Tropical Trees and Forest. Springer, Berlin, 441 pp.). We present the
main principles of the methodology including the use of an architectural template
and the statistical processing of the data collected on sample plants and a
description of its components and parameters. We use models of Equisetum
telmateia aerial shoots as examples of adaptations of this methodology to plants
represented by a limited number of specimens. The main features of this approach
that make it especially relevant for modelling incomplete and fragmented fossil
plants include the use of architectural templates constructed by adding discrete
morphological entities limited to a number of axial components as follows: as
many branch orders as are identified in the sample plants, a single extension
unit per branch order, and its internodes. This approach is viewed as a means to
provide visual representations of plants at different ontogenetical stages,
expressing our current knowledge of their growth and branching strategies, and of
the parameters that control their geometries.
PMID- 10767439
TI - Computer simulation of sphenopsid architecture. Part II. Calamites multiramis
Weiss, as an example of Late Paleozoic arborescent Sphenopsids.
AB - A late Carboniferous arborescent sphenopsid has been modelled for the first time
with the AMAP 1 system. The natural entity consisting of the three form species
'Calamites multiramis/Annularia stellata/Calamostachys tuberculata' (respectively
the trunk/branches and foliage/cones) representing the aerial part of this plant
is reconstructed and its architecture modelled. The different growth stages are
extrapolated, generating a dynamic view that did not exist until now. The model
is based on the hypothesis that the modelled part is not preformed but results
from the successive production and elongation of internodes. This growth led to
old ontogenetic stages of the plant in agreement with Remy and Remy's
reconstruction (Remy, W., Remy, R., 1977. Die Floren des Erdaltertums. Verlag
Gluckauf, Essen, 468 pp.). With its verticillate sterile organs and cone-shaped
fructifications similar to the extant herbaceous relative Equisetum, this
calamite is distinguished from the latter taxon by having possible 'throw-away'
phyllomorphic branches. We assumed the presence of a restricted zone of branches
located in the apical part of the trunk. Moreover, the production of reproductive
organs that succeeds the vegetative stage implies a major photosynthetic phase
associated with a monocarpical form of development of the fossil plant.
PMID- 10767440
TI - Zhutheca Liu, Li et Hilton gen. nov., the fertile pinnules of Fascipteris densata
Gu et Zhi and their significance in marattialean evolution.
AB - The morphology of the fertile pinnules of Fascipteris densata Gu et Zhi have been
subjected to a detailed morphological investigation based on recently collected
specimens from the Upper Permian of Yunnan Province, south China. These
investigations have revealed that this species possesses synangia of the
Asterotheca-type, situated in two or three rows either side of the midrib on a
Fascipteris-type pinnule. This arrangement of Asterotheca-type synangia is
extremely unusual considering that all other reports of this genus are with a
single row of synangia located on each side of the midrib of a pecopteroid-type
pinnule. As a consequence of this unique morphological arrangement, a new genus,
Zhutheca densata Liu, Li et Hilton gen. et comb. nov. has been created to
distinguish this material from other specimens of the Asterotheca and Fascipteris
types. The structure and arrangement of the fertile pinnule of Zhutheca are
compared with other Palaeozoic and Mesozoic marattialean taxa with which it
shares certain features of its morphology. In addition, the stratigraphic,
evolutionary and phylogenetic significance of Zhutheca are considered in detail.
PMID- 10767441
TI - Overactive Bladder and Its Treatments Consensus Conference. London, United
Kingdom, July 4, 1999.
PMID- 10767442
TI - Behavioral therapy for overactive bladder.
AB - What is behavioral therapy? On the one hand there is no consensus in the
literature as to the definition of the treatment or the optimal mode of delivery.
On the other hand, it is possibly the "best" single treatment for urinary
incontinence when viewed from a risk:benefit analysis. There is general agreement
that within this framework wide variations exist in intensity of treatment,
expertise required to deliver the treatment, and the subsequent cost of therapy.
A definition of behavioral therapy should include at least the following
techniques: first, education and explanation of normal lower urinary tract
function; second, micturition charts and diaries; and finally, timed
voiding/bladder training regimens. All of the behavioral methods are demonstrably
effective, with improvement rates in incontinence episodes uniformly in excess of
50%. Our challenge is to define the critical parts of behavioral therapy and
develop algorithms that can be delivered to the incontinent population in the
most cost-effective manner.
PMID- 10767443
TI - Nonpharmacologic treatments for overactive bladder-pelvic floor exercises.
AB - The theory behind the use of physical therapies (electrical stimulation or pelvic
floor muscle [PFM] training with or without biofeedback) for overactive bladder
is to (1) inhibit detrusor muscle contraction by voluntary contraction of the
PFMs at the same time as the urge to void; and (2) prevent sudden falls in
urethral pressure by a change in PFM morphology, position, and neuromuscular
function. Few trials have evaluated the effect of PFM training on symptoms of
overactive bladder. Most studies are flawed because they include several
diagnoses and treatment modalities in the same intervention. Because of the lack
of evidence, no firm conclusion can be drawn on the effect of PFM exercise on
overactive bladder. There are some initially promising results, but there is
still a need for high-quality, randomized controlled trials on the effect of PFM
training on the inhibition of detrusor contraction in human beings. The efficacy
of PFM training in combination with other treatments, such as pharmacotherapy,
also requires investigation.
PMID- 10767445
TI - Overactive bladder and its treatments- questions andanswers after christopher K.
Payne, K. B, and anders mattiasson
PMID- 10767444
TI - Discussion: bladder and pelvic floor muscle training for overactive bladder.
PMID- 10767446
TI - Electrical stimulation in overactive bladder.
AB - Electrical stimulation is an effective and well-tolerated treatment for
overactive bladder. Initial work in animals indicated the potential of this
treatment, and early clinical experience in Europe further supported its likely
efficacy. Although the mechanism of action of electrical stimulation remains
unproven in humans, it is believed to be a neuromodulating therapy which affects
the neural signaling that controls continence. There is also strong evidence that
electrical stimulation affects striated muscle. The therapy can cause hypertrophy
of skeletal muscle fibers, possibly by the recruitment of faster-conducting motor
units, which would not normally be recruited during voluntary efforts. In
addition, electrical stimulation can alter the expression of myosin isoforms,
favoring a conversion to type I muscle. Despite our incomplete understanding of
the mechanism of action of electrical stimulation, clinical devices have been
developed quickly. Case series have been reported throughout Europe. These were
followed by controlled clinical trials in the United States. There is good
evidence that the use of vaginal electrical stimulators can reduce the occurrence
of symptoms of overactive bladder in about half of the patients treated. Multiple
uses of nonimplanted stimulation, including thigh stimulation, anal stimulation,
and direct pelvic muscle stimulation, have been reported. In these trials, it is
common for objective findings to be poorly correlated with subjective reports of
improvements or cure. Patients frequently report that the urge-to-leak time
improves, but this is difficult to measure objectively. The use of nonimplanted
devices is effective and well tolerated, and should precede the use of implanted
devices. A direct comparison with other effective methods of treatment for
overactive bladder is warranted.
PMID- 10767447
TI - Biofeedback in overactive bladder.
AB - Biofeedback is a form of learning or re-education in which the participant is
retrained within a closed feedback loop. Information about one or more of the
patient's normally unconscious physiologic processes is made available to the
patient as a visual, auditory, or tactile signal. Objective responses are
recorded on a polygraph trace so that they can be easily observed. Subjective
responses are more difficult to monitor and it is often difficult to separate
these effects of biofeedback from the placebo effect. Biofeedback has been
successfully employed in cases of urinary incontinence due to detrusor
instability. Indeed, a recent report has shown that biofeedback-assisted
behavioral treatment is more effective than either oxybutynin or placebo in the
treatment of urge and mixed urinary incontinence in older, community-dwelling
women. Patients embarking on biofeedback need to be well motivated and
intelligent enough to understand what is expected of them. The treatment is time
consuming for both the patient and the operator, but the benefits of successful
treatment include a reduction in morbidity and side effects associated with other
therapies. Biofeedback can be employed as an adjunct to other forms of treatment,
such as drug therapy, and is particularly useful in children.
PMID- 10767449
TI - Questions and answers after linda brubaker, linda D. Cardozo, and magnus fall
PMID- 10767448
TI - Discussion: reactivation of bladder inhibitory reflexes-an underestimated asset
in the treatment of overactive bladder.
PMID- 10767450
TI - Muscarinic receptor antagonists in the treatment of overactive bladder.
AB - A wealth of clinical evidence supports the view that muscarinic receptor
antagonists are effective in the treatment of overactive bladder. However,
treatment-limiting adverse effects such as dry mouth, constipation, and blurred
vision have restricted the usefulness of previously available agents, such as
oxybutynin. A real need therefore existed for effective and well-tolerated agents
for the long-term management of the troublesome symptoms of overactive bladder.
This review outlines the various approaches that have been used in attempts to
overcome the tolerability problems of oxybutynin. It also describes how advances
in our understanding of muscarinic receptors and bladder function has led to the
potential development of either tissue- or subtype-selective antimuscarinic
agents with improved tolerability. Drugs that have been developed in this way
include tolterodine and darifenacin, each of which shows some bladder selectivity
in animal models. Unlike darifenacin, however, the bladder selectivity of
tolterodine has been confirmed by numerous clinical studies. Tolterodine's
improved tolerability compared with oxybutynin, along with its equivalent
therapeutic efficacy at recommended dosages, permits patients to experience the
beneficial effects of long-term treatment. Tolterodine therefore represents a
real alternative for the long-term management of overactive bladder. The results
of ongoing clinical studies with darifenacin are awaited before it can be
concluded that selective antagonism of M(3) receptors leads to improved
tolerability over existing agents in the treatment of overactive bladder.
Similarly, the potential improvements in tolerability associated with different
dosage formulations of oxybutynin, and the clinical utility of S-oxybutynin, are
yet to be conclusively demonstrated.
PMID- 10767452
TI - Questions and answers after christopher R. Chapple and yasuhiko igawa
PMID- 10767451
TI - Discussion: functional role of M(1), M(2), and M(3) muscarinic receptors in
overactive bladder.
PMID- 10767453
TI - Treatment of overactive bladder: other drug mechanisms.
AB - The well-known side effects of antimuscarinic drugs have focused interest on
other ways of treating overactive bladder. Targets for pharmacologic intervention
may be found in the central nervous system (CNS) or peripherally. Several CNS
transmitter systems can modulate voiding, but few drugs with a defined CNS site
of action have been demonstrated to be clinically useful. The mechanism of action
of imipramine, which may be effective in the treatment of overactive bladder, has
not yet been clarified. Like imipramine, duloxetine is an inhibitor of serotonin
(5-HT) and norepinephrine reuptake. Duloxetine has shown some promise in the
treatment of urinary incontinence, but, as with the selective serotonin reuptake
inhibitors, its effectiveness in the treatment of overactive bladder has not been
proven. Drugs affecting norepinephrine, dopamine or gamma-aminobutyric acid
(GABA) receptors and mechanisms may be useful. There is also evidence for a
central site of action of alpha(1)-adrenoceptor (AR) antagonists. Traditionally,
drugs for the treatment of overactive bladder have had a peripheral site of
action. Drugs acting on ARs or membrane channels, as well as prostaglandin
synthase inhibitors and several other agents, have been used with moderate
success. However, recent developments may lead to more effective drugs, including
potassium channel openers, prostaglandins, selective and nonselective inhibitors
of cyclooxygenase and those acting on the beta(3)-ARs in the human detrusor.
Drugs that reduce afferent activity represent an attractive therapeutic approach,
and transmitters of afferent nerves and their receptors are possible targets for
pharmacologic interventions.
PMID- 10767455
TI - Questions and answers after karl-erik andersson and Francois haab
PMID- 10767454
TI - Discussion: nitric oxide and bladder overactivity.
PMID- 10767456
TI - Intravesical treatment of overactive bladder.
AB - Intravesical agents for overactive bladder have mostly been used in patients with
neurogenic bladder disorders. The patients have usually had severe detrusor
hyperreflexia (DH) plus a disorder of bladder emptying, and because of residual
urine have been performing intermittent self-catheterization. Intravesical
medication has therefore been appropriate. Strategies for treating DH have been
either to lessen the parasympathetic efferent activity or to de-afferent the
bladder. Two types of treatment have been used: intravesical medications that
block pelvic nerve-detrusor smooth muscle cholinergic transmission, or agents
that block the afferent arm of the reflex that causes detrusor contraction.
Intravesical oxybutynin is thought to have some local anesthetic effect, although
its main mode of action is to block cholinergic transmission. It has been
demonstrated to be effective in resistant DH. Intravesical atropine has been
demonstrated to increase bladder capacity but its usefulness in the clinical
management of DH has yet to be demonstrated. Local anesthetics can increase
bladder capacity, but the effect is short-lived. Longer-acting agents may have a
selective neurotoxic effect on capsaicin-sensitive bladder afferents. Many
patients worldwide have now been treated with intravesical capsaicin.
Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that has the significant
advantage of being a nonirritant. Intravesical agents appear to be attractive
alternatives to oral medication and hold the exciting possibility of selectively
targeting end organs implicated in pathophysiologic responses.
PMID- 10767457
TI - Discussion: resiniferatoxin-preliminary data.
PMID- 10767458
TI - Questions and answers after clare J. Fowler and michael B. chancellor
PMID- 10767459
TI - Head and neck manifestations of Kawasaki disease.
AB - Kawasaki disease, also known as acute infantile febrile mucocutaneous lymph node
syndrome, is a self-limited vasculitic disease of infants and young children. The
cause of the disease remains uncertain. Within the constellation of signs and
symptoms, there are numerous otolaryngologic manifestations. The following
represents the largest series of patients in the otolaryngology literature,
involving 155 confirmed cases of Kawasaki disease as treated at our institution
during the last 10 years. The demographic data, clinical pictures of the typical
and atypical forms of the illness, as well as the laboratory values, therapy and
complications are discussed.
PMID- 10767460
TI - Variability of Eustachian tube function in children with secretory otitis media.
Evaluations at tube insertion and at follow-up.
AB - OBJECTIVE: Despite the variable clinical course of diseases related to Eustachian
tube function, the variability of tubal function has been less focused than
outcomes of single tests. This study aimed to compare the passive and active
tubal function and its variability in children with secretory otitis media (SOM)
at tube insertion and at follow-up. METHOD: Thirty-eight ears in 19 children aged
4-10 years (mean 7.0 years) with long-standing SOM were examined 4-6 h after tube
insertion, at 4 months and at 9 months. The pressure in the middle ear and the
nasopharynx were recorded while performing (1) forced opening test, (2)
equalization of +100 and -100 daPa, (3) Valsalva test, and (4) sniff test. The
procedure was repeated after 30 min. Relationships were analyzed by uni- and
multi-variate analysis of variance. RESULTS: From tube insertion to 4 months, the
mean forced opening pressure increased from 282+/-128 to 355+/-153 daPa (P<0.01),
and the mean closing pressure from 91+/-51 to 126+/-82 daPa (P<0.01). There was
no further change at 9 months. Female gender, serous effusion (in contrast to
mucoid), and more than three previous episodes of acute otitis media were related
to higher opening and closing pressures. At tube insertion, 60% and 16% equalized
+100 and -100 daPa, respectively, and 28% succeeded in performing Valsalva
inflation. The sniff test was positive in 32%, indicating a closing failure.
These rates did not change significantly over time. For individual ears, outcomes
of all tests varied considerably when retested after 30 min; P(o) changed by +/
12% and P(c) by +/-26%, and 9-29% of the ears changed from a positive to negative
response, or vice versa, in the equalization, Valsalva, and sniff tests.
CONCLUSIONS: The unexpected finding of weaker closing forces at the day of tube
insertion and increased tubal resistance at follow-up might be ascribed to
changes in the muco-adhesive forces related to the disease and tube treatment.
The pronounced intra-individual variability of test outcomes indicates that tubal
function is dynamic and variable in ears prone to SOM, which emphasizes that
results of single tubal function tests have very low prognostic value.
PMID- 10767461
TI - Intracranial complications of acute mastoiditis.
AB - OBJECTIVE: Oral antibiotic use may have changed the incidence and microbiology of
otitic intracranial complications. We reviewed cases of acute mastoiditis to
document: (1) incidence of intracranial complications; (2) risk factors; and (3)
identify pathologic organisms. METHODS: A retrospective study of children at a
tertiary care children's hospital with acute mastoiditis from July, 1986 through
June, 1998. RESULTS: 118 children with acute mastoiditis were identified. Eight
patients (6.8%), ages 20 months to 14 years, had intracranial complications
related to acute mastoiditis. Three children had a sigmoid sinus thrombosis, two
children had an epidural abscess, and two children had both complications of
sigmoid sinus thrombosis and epidural abscess, and a sigmoid sinus thrombosis and
meningitis was present in one child. Pre-admission oral antibiotics were
administered for an average of 10 days in seven of the eight patients. Persistent
otorrhea and/or otalgia were present in all patients. Intraoperative cultures
were negative in four cases (50%). Organisms isolated included: Streptococcus
pneumoniae (2); Proteus mirabilis (1); Pseudomonas aeruginosa (1); and coagulase
negative Staphylococcus (1). Multi-drug resistant organisms were documented in
only one case. All patients underwent a contrast enhanced CT of the temporal
bones and brain. Surgical management included complete mastoidectomy in all
patients and a pressure equalization tube in seven of the eight cases.
CONCLUSIONS: Our review did not document an increase in the incidence of otitic
intracranial complications. Persistent otalgia or otorrhea while on oral
antibiotics with associated neurologic symptoms are ominous signs suggestive of a
complication. Multi-drug resistant organisms are uncommon whereas negative
intraoperative cultures are common.
PMID- 10767462
TI - Acute mastoiditis: predictors for surgery.
AB - To estimate the incidence of acute mastoiditis and identify predictors for
mastoid surgery, a retrospective case record study of 38 children hospitalised
for acute mastoiditis in Oslo from 1989 to 1998 was performed. Median age at
diagnosis was 18 months and 13 (34%) of the children received mastoidectomy.
Compared to the period 1970-1979, the incidence of mastoidectomy was
significantly reduced. Only seven children (18%) had experienced acute otitis
media prior to the current episode. Symptom duration of 6 days or more prior to
hospitalisation and elevated white blood cell counts and C-reactive Protein were
predictive for mastoidectomy ((OR = 5.0 (1.0-22.8), (OR = 24.5 (2.5-240) and OR =
10.5 (1-108.8)). Furthermore, total time from symptom onset to hospital discharge
was significantly higher in children who received mastoidectomy. We suggest early
referral to an otolaryngologic department in children suspected of acute
mastoiditis.
PMID- 10767463
TI - Doxycycline sclerotherapy of benign lymphoepithelial cysts of the parotid: a
minimally invasive treatment.
AB - Benign lymphoepithelial cysts (BLCs) of the parotid gland are associated with
human immunodeficiency virus infections in both children and adults. These cysts
may become painful and unsightly, often initiating a request for therapeutic
intervention. There are several treatment options described in the literature. We
report the use of doxycycline sclerotherapy in the treatment of a child with BLCs
of the parotid.
PMID- 10767464
TI - Pseudoaneurysm of a lateral internal carotid artery in the middle ear.
AB - We report a case where a 7-year-old girl suffered significant aural bleeding
following myringotomy of the tympanic membrane. Investigations by computed
tomography scan, carotid angiography, and magnetic resonance angiography showed a
lateral aberrant internal carotid artery (LACI) with a little pseudoaneurysm in
the middle ear. The anomaly of the internal carotid artery was supposed to be
congenital, and the pseudoaneurysm was supposed to be traumatic, formed after
incision into the wall of the artery. Considerations about diagnosis, symptoms,
and treatment are discussed. The patient was treated by balloon embolization in
the internal carotid artery without sequelae.
PMID- 10767465
TI - Melanotic neuroectodermal tumor of infancy: report of two cases and review of
literature.
AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, distinctive neoplasm
containing melanin; it primarily affects the maxilla of the infants during the
first year of life. Approximately 150 instances of this tumor are reported in the
medical literature. Genesis of the tumor is obscure and the diagnosis is
challenging for the pathologist. Two cases operated by the first author are
presented, and the diagnostic features and treatment alternatives of MNTI
discussed.
PMID- 10767466
TI - Air gun dart injury in paranasal sinuses left alone.
AB - Patients with paranasal sinus foreign body are not commonly seen in
otolaryngological practice and papers dealing with this issue are rare in the
English literature. One case of penetrating sinus injury due to air gun dart is
presented to illustrate the potentially serious consequences of air gun injuries.
The clinical presentation, diagnostic pitfalls and the treatment aspects are
discussed.
PMID- 10767467
TI - Orbital rhabdomyosarcoma presenting as an apparent orbital subperiosteal abscess.
AB - We present a patient with acute sinusitis whose CT scan showed a ring-enhancing
lesion within the orbit typical of an orbital subperiosteal abscess. On
exploration of the orbit, there was no pus present but a tumour was found, which
on histological examination was found to be a rhabdomyosarcoma. The clinical
signs and CT characteristics of orbital subperiosteal abscesses and
rhabdomyosarcomas are discussed. A ring-enhancing lesion within the orbit on CT
scan should not be regarded as being pathognomonic for a subperiosteal abscess
and the possibility of other diagnoses should be considered.
PMID- 10767468
TI - Paecilomyces fungus infection of the paranasal sinuses.
AB - Fungal infections caused by Paecilomyces species are very rare and occur in adult
patients with impaired host defences or following foreign body implants. They are
found worldwide in soil and decaying vegetation. We describe a case of an 8 year
old child who came with complaints of left sided nasal obstruction and discharge,
telecanthus, diplopia and epiphora. On examination and investigation he had
pansinusitis caused by P. lilacinus. An endoscopic sinus surgery was done and the
patient was on oral Itraconazole for 6 months. To our knowledge, this is the
first case reported in the paediatric age group.
PMID- 10767469
TI - Sino-orbital foreign body in a child.
AB - Foreign bodies of the sinuses are uncommon. Few reports exist in the English
literature. Among these, the frontal and maxillary sinuses are most often
involved. Ethmoid and sphenoid foreign bodies are rare and tend to present with
chronic symptoms due to delayed diagnosis. We present a case of an acute
presentation of a foreign body involving the orbit and ethmoid sinus in a 12-year
old male.
PMID- 10767470
TI - Osteoma of the middle ear.
AB - Osteomas are benign pedunculated tumours of the lamellar bone, which commonly
originates from paranasal sinuses. Within the temporal bone they are seen
commonly in the external ear canal. Osteomas originating from the middle ear are
very rare. There are only 12 cases reported in the medical literature up to now.
Five of those cases caused conductive hearing loss and the others were
asymptomatic and diagnosed incidentally.
PMID- 10767471
TI - Spiral CT versus MRI in neonatal airway evaluation.
AB - Magnetic resonance imaging has become the standard means of imaging pediatric
airway obstruction due to vascular anomalies. However, magnetic resonance imaging
requires a long acquisition time and is prone to motion artifacts. The
development of spiral or helical computed tomography provides an alternative
imaging modality for evaluating pediatric airway obstruction. We present the case
of a neonate with a double aortic arch which initially was not identified on
magnetic resonance imaging but was visualized with spiral computed tomography. If
suspicion of an intra-thoracic abnormality is high, spiral computed tomography
may be a useful adjunct or replacement to magnetic resonance imaging.
PMID- 10767473
TI - Complexity: the new frontier in biomedical research.
PMID- 10767474
TI - Brain cysticercosis.
PMID- 10767475
TI - H(2)O(2) is an important mediator of physiological and pathological healing
responses.
AB - BACKGROUND: TGF-beta1 is a pleiotropic cytokine that plays a key role in wound
healing and organ fibrosis. We have recently demonstrated that, in part, some
fibrogenic actions of TGF-beta1 are mediated via formation of H(2)O(2). We have
also demonstrated that TGF-beta1 plays a key role in the accelerated healing
response induced by a peptidoglycan derived from some strains of Staphylococcus
aureus (SaPG). METHODS: To investigate further the role of H(2)O(2) in healing
responses, we implemented and improved a method to measure this reactive oxygen
species. Using this method, we quantified the production of H(2)O(2) by cultured
hepatic stellate cells-the main cells involved in type I collagen production in
the liver-and by saline- and SaPG-inoculated polyvinyl alcohol sponges that had
been surgically subcutaneously implanted in the dorsum of rats. RESULTS: We show
that cultured hepatic stellate cells produce significant amounts of H(2)O(2). We
show also that H(2)O(2) formation by saline- and SAPG-inoculated sponges is more
intense during the early inflammatory phase of the healing response and precedes
collagen deposition. Moreover, the production of H(2)O(2) is much higher in SaPG
inoculated sponges than in those inoculated with saline solution. CONCLUSIONS:
Based on these findings, and on the fact that H(2)O(2) is produced during TGF
beta-induced upregulation of the alpha1(I) procollagen gene, we conclude that
H(2)O(2) is one of the mediators of healing responses.
PMID- 10767476
TI - Protein kinase C activation reduces the function of the Na(+):K(+):2Cl(-)
cotransporter in Xenopus laevis oocytes.
AB - BACKGROUND: The basolateral isoform of the Na(+):K(+):2Cl(-) cotransporter is
expressed in several epithelial and non-epithelial cells, in which it is involved
in ion secretion processes and in cell volume regulation. In humans, this
cotransporter has been implicated in the development of primary hypertension. The
major goal of the present study was to characterize the effect of protein kinase
C activation on the function of the Na(+):K(+):2Cl(-) cotransporter isoform
present in Xenopus laevis oocytes. METHODS: Oocytes were surgically harvested
from adult female Xenopus laevis frogs, defolliculated by incubation in frog
ringer containing collagenase B (2 mg/mL) under vigorous shaking, and by hand
under the microscope. Only stage V-VI oocytes were used in the study. After
overnight incubation in regular frog Ringer, oocytes were switched to a Cl(-)
free ringer for at least 12 h before beginning uptake experiments. The function
of the Na(+):K(+):2Cl(-) cotransporter was determined by assessing tracer 22Na(+)
uptake in the control group as well as under several experimental conditions,
such as changes in extracellular osmolarity, absence of one of the cotransported
ions, or the presence of drugs such as the specific cotransporter inhibitor
bumetanide, phorbol esters (TPA, PDBu, or 4alphaPDD), and the PKC inhibitor
bisindolylmaleimide I. At the end of the uptake period, tracer Na(+) uptake was
counted by liquid scintillation of each individual oocyte previously dissolved in
SDS. RESULTS: Xenopus oocytes exhibited a bumetanide-sensitive Na(+):K(+):2Cl(-)
cotransporter in the plasma membrane activated by hypertonicity and inhibited by
hypotonicity. The bumetanide-sensitive fraction of Na(+) uptake was significantly
reduced by the addition of phorbol esters TPA or PDBu to the uptake media. This
inhibitory effect of PKC activators was dose- and time-dependent. Phorbol ester
4alphaPDD, which cannot activate PKC, exhibited no effect on Na(+):K(+):2Cl(-)
cotransporter function. In addition, pretreatment of oocytes with the PKC
inhibitor bisindolylmaleimide I partially abolished TPA-induced reduction in the
cotransporter function. CONCLUSION: In defolliculated Xenopus laevis oocytes,
phorbol esters reduce the function of the Na(+):K(+):2Cl(-) cotransporter by a
mechanism that includes the activation of an endogenous PKC.
PMID- 10767477
TI - Klebsiella pneumoniae 35 and 36 kDa porins are common antigens in different
serotypes and induce opsonizing antibodies.
AB - BACKGROUND: Klebsiella pneumoniae is a major cause of neonatal sepsis and
nosocomial infections in Mexico. Antibiotic therapy is the first choice for
treatment but the increase in multiple resistance strains has forced scientists
to look for alternative treatments, such as immunotherapy. In this work, we
propose that porins could be a common antigen among four different capsular
serotypes of Klebsiella pneumoniae for the production of immune sera with
opsonizing capacity. METHODS: The 35 and 36 kDa porins from four different
serotypes of the bacteria were isolated by the Nikaido method followed by
purification in Sephacryl column chromatography. The 36 kDa of serotype K8 was
further purified by electroelution. The 35 and 36 kDa porins were used to obtain
rabbit polyclonal antibodies (PolyAb) to the four serotypes and the 36 kDa from
K8 for the production of monoclonal antibodies (MoAb). Antigenic reactivity of
PolyAb and MoAb were analyzed by ELISA and WB and their opsonizing capacity for
human PMN was measured by chemiluminescence (CL) using capsulated and non
capsulated bacteria. RESULTS: Porins from the four strains showe electrophoretic
homology and cross reaction by ELISA and WB. CL assays indicated that PolyAb
opsonized heterologous strains and that MoAb perform this in the absence of
capsule. CONCLUSIONS: K.pneumoniae 35 and 36 kDa porins are common antigens for
the four serotypes studied and induce opsonizing antibodies.
PMID- 10767478
TI - Effect on acute rejection reaction and survival of the heart with the addition of
dextran 60 to conventional immunosuppressive therapy in an experimental model of
heterotopic heart transplantation.
AB - BACKGROUND: Rejection reaction is an important complication in heart
transplantation. Recent physiopathological findings suggest new immunosuppressive
alternatives such as the use of substances that block interaction between
leukocytes and endothelium or subsequent events. The objective of this work was
to evaluate the effect of the combination of dextran 60 and conventional
immunosuppressive therapy. METHODS: We used Sprague-Dawley rats, both sexes, with
mean weight of 317.3 +/- 31.3 g on which we carried out heterotopic heart
transplantation and then randomized into four groups. All groups received
cyclosporine (2 mg/kg/day) and prednisone (0.5 mg/day). Group I (n = 5) also
received 0.5 cc/kg/day of dextran 60, group II (n = 5) 1.0 cc/kg/day of dextran
60, group III (n = 5) 2 cc/kg/day, and group IV (n = 4) 0.9% saline solution 0.5
cc/kg/day. The incidence and severity of rejection reaction was evaluated as
survival of transplanted hearts. RESULTS: Significant differences were found
between groups III and IV for incidence of rejection reaction (p = 0.039).
However, there were no differences among groups (grade 3A or 3B) in the magnitude
of the rejection reaction. Survival of hearts was better in all groups receiving
dextran 60 (p = 0.031). CONCLUSION: It was concluded that dextran 60 improves
survival of transplanted hearts and decreases incidence of rejection reaction.
PMID- 10767479
TI - Lipoid pneumonia in children: clinical and imagenological manifestations.
AB - BACKGROUND: Oil-aspiration pneumonia is still a health problem in countries where
infants are forced to receive vegetable or animal oil due to traditional habits.
The aim of this paper is to present clinical and imagenological characteristics
of lipoid pneumonia (LP) in children and a review of the literature.
Distinguishing features of and differences between other series are presented.
METHODS: Series of cases. We retrospectively analyzed all records of children
with lipoid pneumonia between 1991 and 1996. RESULTS: We found 16 patients aged 1
19 months old with positive oil ingestion in 75% and history of recurrent or
persistent pneumonia in 81.2%. In almost 70% of patients, there were underlying
conditions known as risk factors of aspiration. Plain films and computed
tomography (CT) showed that the right lung was always involved. Fat density was
found in only two cases. Bronchoscopy with bronchial lavage was performed in 15
patients, with lipophages positive in each patient. CONCLUSIONS: Lipoid pneumonia
must be ruled out in the differential diagnosis in infants with persistent or
recurrent pneumonia with or without fever, especially in patients with aspiration
risk factors. Bronchoscopy with bronchial lavage and positive lipid-laden
alveolar macrophages proved a useful method for diagnosis of this condition. More
studies are needed to ascertain the clinical and imagenological evolution of this
condition.
PMID- 10767480
TI - Depression and body fat deposition in Mexican pregnant adolescents.
AB - BACKGROUND: The objective of this study was to assess the effect of maternal
depressive symptomatology on fat deposition in a group of pregnant adolescents.
METHODS: A case-control study was performed with 85 pregnant women (45
adolescents and 40 adults) who attended a prenatal care course at a teaching
hospital in Mexico City. During the second and third trimesters of gestation, a
test proposed by Zung was applied to measure depressive symptoms. Weight and
skinfolds (i.e., triceps, biceps, suprailiac, subscapular, and thigh) were
measured in all women beginning at week 20 of gestation through 4 weeks
postpartum. Monthly evaluations were performed. RESULTS: At the 28th week of
gestation, nearly 40% of pregnant adolescents showed scores above the cut-off
points in the depression test, while among the adults this proportion
corresponded to 15%. In the adolescents, depression status was related to self
esteem. Percentage of body fat in adult women tended to be relatively constant,
while in adolescents a tendency toward increased body fat was found. In
adolescents, depressive symptomatology and especially lack of self-esteem and
weight gain during pregnancy were the variables that better predicted the fat
increment pattern during gestation, while in adults no variable was found that
predicted fat deposition. CONCLUSIONS: Depression status is a risk factor for
excessive fat deposition during pregnancy in Mexican adolescents.
PMID- 10767481
TI - Characteristics of lymphocytes and granulocytes removed from whole blood by buffy
coat depletion. Comparison of an automated bottom-and-Top processing system and
the manual technique.
AB - BACKGROUND: Characteristics of lymphocyte and granulocyte removal were studied
during the processing of fresh human blood by buffy coat (BC) depletion. The
manual technique of BC depletion and that performed in a bottom-and-top (BAT)
semiautomated system were compared. Blood cells were counted in the resulting
components. RESULTS: Removal efficiency in lymphocytes and granulocytes
correlated to the loss of erythrocytes due to removal of the BC. Sigmoidal curves
showed good fit to experimental data. Variables of the equations differed
substantially concerning removal of lymphocytes and granulocytes. The bottom-and
top bag in the semiautomated system resulted in better efficiency in leukocyte
removal compared to the conventional manual technique.98% of lymphocytes may be
removed from whole blood in the semiautomated BAT system. Removal efficiency of
granulocytes is inferior compared to that of lymphocytes. Performance
characteristics of the semiautomated BAT technique appeared superior when
compared to the conventional manual technique. CONCLUSIONS: Substantial
variability was observed in granulocyte removal efficiency in both systems. The
present study may contribute to the production of erythrocyte preparations with
less contaminating leukocytes and to standardize semiautomated blood processing.
PMID- 10767482
TI - Diagnosis of bone marrow metastases in children with solid tumors and lymphomas.
Aspiration, or unilateral or bilateral biopsy?
AB - BACKGROUND: Malignancies are among the most common causes of death in children.
The present study was undertaken to evaluate and compare bone marrow aspiration
and unilateral biopsy to detect bone marrow metastases in pediatric patients,
using bilateral biopsy as the gold standard. METHODS: During a 6-month period, 63
consecutive newly diagnosed children with confirmed malignant diseases other than
leukemia were evaluated for bone marrow metastases or infiltration. Biopsies were
obtained from both right and left posterior iliac crests whereas aspiration was
performed only at the right crest. Interpretation to the right-side biopsy was
considered as the unilateral biopsy result, whereas the bilateral biopsy result
was as follows: positively was accepted if one or both of the two-side samples
were qualified as positive, while a negative result was considered only if both
sides were negative. The bilateral biopsy was considered the gold standard, and
sensitivity, specificity, positive and negative predictive value, and false
positive and negative rates were computed for the unilateral biopsy and
aspiration procedure. RESULTS: We identified bone marrow metastases in 11 (17.5%)
patients. The sensitivity was the only significant difference (p <0.05) observed
between unilateral biopsy and aspiration. Finally, of the 63 patients, unilateral
biopsy was reported as inadequate in one patient (1.6%), while aspiration was
inadequate in two (3.2%). CONCLUSION: Unilateral biopsy was better than bone
marrow aspiration. However, because bilateral biopsy is the gold standard, we
recommend using this and bone marrow aspiration simultaneously to evaluate a
pediatric patient with any malignancy potentially infiltrating bone marrow.
PMID- 10767483
TI - Absolute and relative predictor values of some non-invasive and invasive studies
for the outcome of anterior temporal lobectomy.
AB - BACKGROUND: There is controversy in the literature regarding the strategy used to
obtain better outcomes after performing an anterior temporal lobectomy (ATL).
Some investigators prefer to reduce the risks and costs of the predictor studies
despite the fact that the number of patients cured after ATL (no seizures with no
medication) is relatively small. Other investigators prefer to attempt a total
cure in all patients by using all available predictor studies regardless of risks
and costs. The latter strategy was the aim of the present work. METHODS: The
absolute (%) and relative (ratio differences) predictor values of non-invasive
and invasive studies for the outcome 24 months post-ATL were determined on 22
patients suffering from intractable non-lesional temporal lobe epilepsy. RESULTS:
Under these conditions, 11 (50%) patients had excellent outcomes (seizure-free,
no medication), 8 ( 36%), good outcomes (only auras with medication), and 3
(13.6%), poor ou tcomes (1 with >70%-seizure reduction and two no changes in
seizure frequency). Predictors of excellent (vs. poor outcome) include the
following: complex partial seizures (CXP) alone or associated with secondary
generalized tonic-clonic seizures; ictal motionless stare and postictal amnesia;
abnormal bitemporal spikes (prominent ipsilateral to ATL) and secondary bilateral
synchrony EEG activities; focal hippocampal ictal EEG activities, and the
presence of focal anterior temporal delta EEG activity 3 months after ATL.
Predictors of poor (vs. excellent) outcomes include the following: CXP associated
with other generalized seizure types; CTS, MRI, and EEG extratemporal
abnormalities, and generalized basotemporal ictal EEG activities and the presence
of seizures and focal anterior temporal spikes 3 months after ATL. CONCLUSIONS:
The present study corroborates that no single predictive study (including non
invasive MRI and invasive ictal EEG activity) is predictive of the success or
failure of ATL. Rather, a concordant combination of non-invasive and invasive
studies is more likely to be predictive of a high probability of success. The
high efficiency of ATL (86% of patients seizure-free) was accomplished by using
all available predictor studies.
PMID- 10767484
TI - Electrophysiological and behavioral methods in early detection of hearing
impairment.
AB - BACKGROUND: Recent advances in neonatal life-support systems have contributed to
the survival of high-risk newborns. However, protection of the auditory system
and the prevention of sequelae is still paramount in neonatal neurology. The aim
of this study was to compare auditory-evoked responses with a toy test and
acoustic reflex in the early detection of hearing loss in infants. METHODS: Three
groups were studied. The first was composed of infants showing less than a 30 dB
biaural threshold in the neurophysiological test. The second group was made up of
infants showing peripheral alterations on one side or both ears. The third group
was comprised of infants who showed no responses at 95 dB HL in both ears after
neurophysiological testing. The neurophysiological test, toy test, and acoustic
reflex were performed on the same day, with masked results given to each
investigator. Sensitivity and specificity for each toy test and acoustic reflex
were calculated afterward. RESULTS: Forty-five controls, 44 peripheral
alterations, and 8 non-response infants were studied. Most patients studied were
born prior to the 37(th) week of gestation with a birthweight of less than 2,250
g, received required administration of potential ototoxic drugs and mechanical
ventilation, and showed hyperbilirubinemia and hypoxia. Sensitivity for each toy
was as follows: drum 0.54; wooden rattle 1.0, and metallic ratle 0.88.
Specificity was 0.95, 1.0, and 1.0, respectively. Acoustic reflex sensitivity was
0.38 and specificity was 0.97. CONCLUSIONS: Results suggest that the wooden and
the metallic rattles of the toy test can be useful tools in the study of hearing
in the high-risk infant and deserve more attention in future studies.
PMID- 10767486
TI - Live varicella vaccine in both immunocompromised and healthy children.
AB - BACKGROUND: There is no information on the use of live varicella vaccine in
Mexican children. Our objective was to evaluate antibody response and safety of
the live varicella vaccine in both healthy and immunocompromised Mexican
children. METHODS: One hundred children with no history of varicella/zoster were
vaccinated with a live attenuated varicella vaccine. According to their immune
status, patients were divided into either a compromised (leukemia, solid tumors,
chronic renal failure, and cirrhosis) or a healthy children group. Serum IgG
antibodies against VZV were measured by ELISA at baseline and at 3 and 6 months
after vaccination. RESULTS: A positive VZV-ELISA at baseline was detected in 36
of 67 (53.7%) immunocompromised children and in 22 of 33 (66%) healthy children.
Among VZV-seronegative children, seroconversion at 6 months post-vaccination was
observed in 90.3% of compromised children and in 100% of healthy children.
Increases in serum antibody levels at 3 and 6 months post-vaccination was similar
in both groups. VZV vaccine-related adverse reactions, mostly mild and local,
were detected in 29% of the children. Three compromised children had a mild rash
symptomatic of varicella after vaccination. CONCLUSIONS: About 50% of
immunosuppressed children (mean age 8.8 +/- 3.6 years) with no varicella history
were VZV-seronegative. Almost all of these compromised VZV-seronegative patients
seroconverted 6 months after vaccine. In addition, antibody titers were similar
in both compromised and healthy children.
PMID- 10767485
TI - Protease inhibitor-associated hyperglycemia in Mexican patients with HIV
infection.
AB - BACKGROUND: The use of protease inhibitors has revolutionized the treatment of
HIV infection. These agents are well tolerated, although the Federal Drug
Administration (FDA) has warned U.S. doctors that protease inhibitors may
precipitate hyperglycemia and diabetes (DM), based on isolated reports from
physicians. METHODS: Sixty-one patients with HIV infection with criterion of non
DM from the onset of the protease inhibitor therapy participated in the study.
Plasma glucose levels were obtained every month during a 6-month period, with a
basal determination prior to protease inhibitor therapy. RESULTS: All Mexican
patients enrolled in this study had the same Hispanic-American ethnic origin.
Four patients (6.55%) developed hyperglycemia related with saquinavir. One had
family history of DM type II. These patients were controlled with diet.
CONCLUSIONS: Based on present data, we believe the benefits of these drugs to
patients suffering from HIV infection outweigh the various risks of taking
protease inhibitors. However, physicians who use these drugs have to be on the
alert for hyperglycemia in the Mexican population, while patients should know the
warning symptoms of hyperglycemia and diabetes.
PMID- 10767487
TI - Functional Xp disomy and hypomelanosis of Ito.
AB - BACKGROUND: Hypomelanosis of Ito (HI) is a neurocutaneous phenotype that reflects
different mosaicisms, including functional imbalances secondary to chromosome-X
inactivation patterns in certain X;autosome translocation carriers. METHODS: We
assessed X inactivation patterns by means of the human androgen receptor (HUMARA)
assay and BrdU labeling in affected and unaffected skin of a young female with HI
and a de novo t(X;13)(Xp13q;Xq13p). PCR analysis was carried out in DNA extracted
from uncultured and cultured skin, whereas the BrdU replication patterns were
sought in cultured fibroblasts. Parental DNA was also tested. Fluorescence in
situ hybridization (FISH) with X and 13/21 centromere probes (DXZ2 and
D13Z1/D21Z1) and a cosmid for the X inactivation center were also performed to
refine breakpoint assignments. RESULTS: An X inactivation pattern implying
functional Xpter-->q11 disomy was found in DNA extracted from uncultured
hypopigmented skin, whereas preferential inactivation of the normal X was
observed in uncultured normal skin as well as in cultured fibroblasts (after one
passage) from both affected and unaffected skin areas. PCR analysis also showed
paternal origin of the translocation. BrdU labeling of metaphases from
hypopigmented and normal skin primary cultures showed der(Xq13p) to be inactive
in about 25% of the cells. FISH revealed that der(Xp13q) had a compound
centromere, whereas der(Xq13p) retained 13 centromere repeats but lacked X
centromere sequences. Hence, breakpoints were assigned to Xq11 and 13q10. The X
inactivation center cosmid gave a signal on both normal X and der(Xp13q),
indicating that the inactivation center was not disrupted by the translocation.
CONCLUSIONS: These findings confirm that mosaic functional Xp disomy, rather than
disruption of X-linked genes, is associated with HI and involvement of the
central nervous system (CNS) in some carriers of a structurally balanced
X;autosome translocation.
PMID- 10767488
TI - Detection of respiratory syncytial virus in nasopharyngeal secretions by 24-well
plate precentrifugation assay using a monoclonal antibody against F protein.
AB - BACKGROUND: Respiratory syncytial virus (RSV) is responsible for 50% of all
bronchiolitis and 25% of pneumonia cases during the first month of life.
Detection of the RSV antigen by immunofluorescence in exfoliated nasal epithelium
or by other methods in nasopharyngeal swabs is useful in the potentially infected
patient because results are available within a few hours. In contrast, RSV
antigen detection in cell culture may require as much as 3 weeks. METHODS: Three
methods for detection of respiratory syncytial virus in 131 clinical respiratory
specimens from patients with acute respiratory disease and bronchiolitis were
compared utilizing the following: a precentrifugation immunofluorescence assay
using Hep-2 cells, indirect immunofluorescence assay, and conventional tube cell
culture using Hep-2 cells. RESULTS: Respiratory syncytial virus was identified in
36 specimens by the three methods previously described. The virus was recovered
in 41 (31.3%) samples by precentrifugation immunofluorescence assay, 40 (30.5%)
were identified by the immunofluorescence technique, and 38 (29.0%) cases were
positive by conventional cell culture. The sensitivity of the precentrifugation
assay in relation to the immunofluorescence technique was 90%, the specificity
94.5%, and the agreement, 96.2%. A positive predictive value of 90.2% was
obtained. Sensitivity, specificity, agreement, and positive predictive values
obtained by the precentrifugation assay variant compared to the conventional cell
were 90.8%, 94.5%, 93.1%, and 87.8%, respectively. CONCLUSIONS: The
precentrifugation immunofluorescence assay method was as sensitive as the
remainder of the methods used in our study and represents a valid alternative for
rapid detection of respiratory syncytial virus in clinical samples.
PMID- 10767489
TI - Detection of CFTR gene mutations in patients suffering from chronic bronchitis.
AB - BACKGROUND: The purpose of the study was to examine cystic fibrosis transmembrane
conductance regulator (CFTR) gene mutations in patients suffering from chronic
bronchitis. METHODS: Thirty-two patients admitted to the Department of
Pulmonology, Lublin School of Medicine, Lublin, Poland between 1995 and 1996 due
to chronic bronchitis were included in the study. Patients were analyzed for the
eight most common mutations of the CFTR gene (DeltaF508, G542X, N1303K, 1717
1(GoA)), W1282X, G551D, R553X, and DeltaI507 by the reverse-hybridization method.
RESULTS: CFTR gene mutations were found in five of 32 (16%) patients, all within
the DeltaF508 region of the CFTR gene. All positive samples were obtained from
patients heterozygous for the DeltaF508 mutation. The presence of the DeltaF508
mutation was considered statistically significant when our study group was
compared to the study of Poland's general population (p <0.05 Fisher's exact
test). CONCLUSION: Our results suggest there is an increased presence of the
DeltaF508 point mutation of the CFTR gene in Polish patients suffering from
chronic bronchitis.
PMID- 10767490
TI - Paradoxic response to diazepam in complex partial status epilepticus.
AB - BACKGROUND: Antiepileptics including benzodiazepines have long been recognized to
provoke seizures and precipitate status epilepticus occasionally. This has a
special clinical importance in the case of diazepam because of its use as first
choice medication in its management. This report is intended to highlight the
clinical importance of such a situation. METHODS: The clinical course of a 28
year old man with complex partial status, which lasted for two months, is
described in detail. RESULTS: Paradoxic response to diazepam was documented under
EEG monitoring. A similar response was also noted for midazolam, and had probably
contributed in exacerbating and prolonging the duration of status. CONCLUSION:
Paradoxic response to diazepam and midazolam is rare, but may be under
recognized. It should be considered in the setting of refractory status
epilepticus.
PMID- 10767493
TI - In this issue
PMID- 10767491
TI - Digging for pathogens
PMID- 10767494
TI - The resuscitation greats. The earliest records.
PMID- 10767495
TI - Alternative methods of mechanical cardiopulmonary resuscitation.
AB - Due to the relative ineffectiveness of standard resuscitation techniques,
alternative methods have been explored for many years. The aim of new methods is
to improve haemodynamics and increase survival rates. In spite of some
encouraging haemodynamic results, all but one study failed to show an increase in
long-term survival rates with an alternative method in a convincingly large group
of patients (hospital discharge without neurological damage, and 1-year
survival). In this study active compression-decompression resuscitation (ACD-CPR)
increased long-term survival compared to standard-CPR. The results from certain
individual studies, which showed a significant increase in short-term survival
rate, could not be reproduced in other trials. This may be attributed in part to
the fact that the alternative methods are not significantly superior, but also
due to logistical and statistical problems in the conduct of the studies and
differences in application within and between the study sites. ACD-CPR has been
the most studied method amongst the alternatives and can be recommended for
patients with asystole in centres with special training and where outcome quality
is regularly verified and evaluated.
PMID- 10767496
TI - Cardiac arrest outcomes at the Melbourne Cricket Ground and shrine of remembrance
using a tiered response strategy-a forerunner to public access defibrillation.
AB - The provision of medical, paramedical and first aid services at major public
events is an important concern for pre-hospital emergency medical care providers.
Patient outcomes of a cardiac arrest response strategy employed at the Melbourne
Cricket Ground (MCG) and the Shrine of Remembrance by St John Ambulance Australia
volunteers are reported. Twenty-eight consecutive events occurring between
December 1989 and December 1997 have been analysed. Included are three cardiac
arrests managed at ANZAC day parades utilising the same response strategy by the
same unit. The incidence of cardiac arrest at the MCG was 1:500000 attendances.
Of the 28 patients, 24 (86%) left the venue alive and 20 (71%) were discharged
home from hospital. In all cases the initial rhythm was ventricular fibrillation
(VF). All 26 patients (93%) who were defibrillated by St John teams had this
intervention within 5 min from the documented time of collapse. One patient in VF
spontaneously reverted during CPR. Of the eight fatalities, four died at the
scene. At major public venues and events, a co-ordinated emergency life support
provision strategy, tailor made for the venue, is necessary for the delivery of
prompt CPR, timely defibrillation and advanced life support.
PMID- 10767497
TI - Airway pressure with chest compressions versus Heimlich manoeuvre in recently
dead adults with complete airway obstruction.
AB - In a previous case report a standard chest compression successfully removed a
foreign body from the airway after the Heimlich manoeuvre had failed. Based on
this case, standard chest compressions and Heimlich manoeuvres were performed by
emergency physicians on 12 unselected cadavers with a simulated complete airway
obstruction in a randomised crossover design. The mean peak airway pressure was
significantly lower with abdominal thrusts compared to chest compressions, 26.4+/
19.8 cmH(2)O versus 40.8+/-16.4 cmH(2)O, respectively (P=0.005, 95% confidence
interval for the mean difference 5.3-23.4 cmH(2)O). Standard chest compressions
therefore have the potential of being more effective than the Heimlich manoeuvre
for the management of complete airway obstruction by a foreign body in an
unconscious patient. Removal of the Heimlich manoeuvre from the resuscitation
algorithm for unconscious patients with suspected airway obstruction will also
simplify training.
PMID- 10767498
TI - CPR '98: a practical multimedia computer-based guide to cardiopulmonary
resuscitation for medical students.
AB - This paper describes an initiative to build a multimedia computer-based teaching
package for cardiopulmonary resuscitation. The project resulted from a perceived
gap in the undergraduate medical curriculum allied to concern from medical
students. The software application was designed to be networked and used as an
adjunct to taught life support courses for undergraduate medical students. The
package comprises tutorials and test questions in basic and advanced life
support. It incorporates sound, video, graphics and animation to illustrate the
techniques involved and is distributed on CD ROM for the PC. The content is based
on the 'Advanced Life Support Manual', produced by the Resuscitation Council (UK)
and incorporates all changes to the guidelines made during 1997 and 1998. The
basic life support section has been networked locally, and has been tested on
more than 60 third year medical students attending a local basic life support
course. It was found that students who used the package performed significantly
better in theoretical assessments than those who did not.
PMID- 10767499
TI - Intra-aortic administration of epinephrine above an aortic balloon occlusion
during experimental CPR does not further improve cerebral blood flow and
oxygenation.
AB - Balloon occlusion of the descending aorta during cardiopulmonary resuscitation
(CPR) improves coronary and cerebral blood flow. In comparison with an equivalent
dose administered through a central venous catheter it has been suggested that
epinephrine administration above the aortic occlusion might produce a more rapid
increase in coronary perfusion pressure and a shorter time to restoration of
spontaneous circulation (ROSC). In a recent study, however, outcome was not
improved after intra-aortic epinephrine administration. We hypothesised that
epinephrine administered above the aortic occlusion could impose adverse effects
on cerebral blood flow and oxygenation, possibly because of an alpha-adrenergic
mediated vasoconstriction in the cerebral vascular beds. Twenty-six piglets
underwent 5 min of non intervention cardiac arrest followed by 8 min of closed
chest CPR. They were randomised to receive bolus doses of 45 microg/kg
epinephrine either above the aortic occlusion or through a central venous
catheter. Cerebral cortical blood flow was continuously measured using laser
Doppler technique. Cerebral tissue pH and PCO(2) were also measured using a multi
parameter fiberoptic device and cerebral oxygen extraction was calculated.
Balloon inflation resulted in an immediate enhancement of cerebral cortical blood
flow. Each of the epinephrine boluses through the central venous catheter
resulted in a transient increase in cerebral cortical blood flow. When
administered above the aortic balloon occlusion, epinephrine did not result in a
further increase in cerebral cortical blood flow, though a significant increase
in cerebral perfusion pressure was recorded throughout the CPR period. Cerebral
tissue pH monitoring revealed severe acidosis during CPR and long after ROSC,
which was refractory to buffering. No differences in the cerebral oxygen
extraction ratio were observed between the groups. In conclusion, epinephrine
administration above an aortic balloon occlusion was unable to improve cerebral
blood flow and oxygenation. In fact, it may even attenuate the beneficial effects
of aortic balloon occlusion on cerebral blood flow due to an alpha-adrenergic
mediated cerebral vasoconstriction. Further studies, including dose-response and
volumes of distribution, are needed to identify the effective beneficial dosage
of epinephrine during aortic occlusion with the least possible adverse effects.
PMID- 10767500
TI - Reduced metabolic rate accompanies the hemorrhage-induced hypothermia in
conscious rats.
AB - The mechanism for the hemorrhage-induced drop in body temperature is unknown.
This study determined the alterations in cutaneous heat exchange and metabolic
heat production caused by a moderate hemorrhage in conscious rats. Chronically
instrumented rats were subjected to a 16 ml/kg hemorrhage, followed by a 4-h
recovery period, while monitoring body core temperature and cutaneous
temperature. Cutaneous heat transfer was disrupted by housing the animals at an
elevated (28 degrees C) ambient temperature. A separate group of experiments
measured the change in oxygen consumption in the post-hemorrhage period. Moderate
hemorrhage caused a drop in body core temperature which stabilized at 0.7+/-0.3
degrees C below control in the second hour following hemorrhage. Disruption of
cutaneous heat exchange by reducing the thermal gradient did not diminish the
hemorrhage-induced hypothermia. Hemorrhage caused a significant decline of oxygen
consumption (-0. 21+/-0.05 ml O(2)/g per h). This 16% drop in resting oxygen
consumption was prevented by immediately retransfusing the aspirated blood back
into the rat. These data indicate that a decrease in metabolic heat production
mediates the drop in body core temperature caused by moderate hemorrhage in
conscious rats.
PMID- 10767501
TI - Corrigendum to "Waveforms of external defibrillators: analysis and energy
contribution".
PMID- 10767502
TI - Corrigendum to "Emergency medical services systems and HAZMAT major incidents".
PMID- 10767503
TI - Atrophie blanche.
PMID- 10767504
TI - Transvaginal ultrasonography examination of the uterine cervix in hospitalised
women undergoing preterm labour.
AB - OBJECTIVE: Our purpose was to assess the accuracy of cervical mensuration
(length, wedging) by transvaginal ultrasonography in the prediction of preterm
birth among hospitalised women undergoing preterm labour. METHOD: Evidence was
extracted from articles through a MEDLINE search from 1987 to 1997, followed up
by examining the references at the end of pertinent articles. The key words were:
pregnancy, cervix, ultrasonography, preterm labour, preterm delivery, cervical
length, cervical wedging or funnelling. Final criteria for the selection of the
studies were cervical length and/or wedging at internal os in hospitalised women
undergoing preterm labour without restriction on the study design. RESULTS: Nine
articles from 12 publications were analysed and incorporated in a discussion.
Study design and selection criteria vary among publications. Preterm delivery was
the principal outcome, but its definition is not the same according to the
authors. The best cut-off for cervical length varies from 18 to 30 mm. The size
of the samples is limited. The sensitivity for predicting preterm birth ranges
from 68 to 100%, and the specificity ranges from 30 to 78%. Cervical wedging has
a sensitivity varying from 23 to 100%, and a specificity ranging from 54 to 90%.
CONCLUSION: Ultrasonography of the cervix is an interesting technology as it is
cheap and easy to use. However this technique remains to be assessed before
implementing it in daily clinical practice. Finally, studies incorporating
transvaginal ultrasonography into interventional trials are needed to determine
the efficacy of measuring cervical length in the prevention of preterm birth.
PMID- 10767505
TI - Human umbilical cord blood banking and transplantation: a state of the art.
AB - Human umbilical cord blood has proven to be a feasible alternative source of
hematopoietic stem cells for pediatric and some adult patients with major
hematologic disorders. This has promoted the establishment of cord blood banks
for use in unrelated transplants worldwide. The banking of umbilical cord blood
offers many advantages: absence of donor risk, absence of donor attrition,
immediate availability, and the ability to expand available donor pools in
targeted ethnic and racial minorities currently underrepresented in all bone
marrow registries. Preliminary clinical experience suggests that, due to the
immunological immaturity of cord blood cells, graft versus host disease might be
lower than when using bone marrow from adult donors and HLA restrictions might be
less stringent. Techniques to improve the efficacy of blood banks are currently
under investigation. Closed cord blood collection methods have proven to be
superior to open in reducing the risk of microbial contamination. Efficient
banking requires volume reduction of cord blood units without significant loss of
progenitor cells, in order to decrease storage space and cost, and this may be
achieved by using the separation techniques. Cryopreservation and thawing
techniques have been established and do not seem to affect the viability and
progenitor cell recovery or the feasibility of CD34(+) selection and ex vivo
expansion. Nevertheless, many scientific, ethical, and social questions have
arisen in connection with cord blood banking that need to be addressed.
PMID- 10767506
TI - Prospective comparison study of levonorgestrel IUD versus Roller-Ball endometrial
ablation in the management of refractory recurrent hypermenorrhea.
AB - OBJECTIVE: To compare endometrial ablation and levonorgestrel-IUS for treatment
of refractory reccurrent hypermenorrhea. STUDY DESIGN: 30 patients with
refractory recurrent hypermenorrhea were included in a prospective controlled
comparative study. A transcervical Roller-Ball ablation was carried out in 15
patients after a 2-months GnRH analog pretreatment. A levonorgestrel IUD
(MIRENA(R), Schering AG Berlin, Germany) was inserted in 15 patients for the
treatment of hypermenorrhea. In a follow-up of the bleeding behavior over 12-24
months a reduction of bleeding was achieved in 14 of 15 patients after Roller
Ball ablation and in 11 of 15 patients after levonorgestrel IUD insertion. The
amenorrhea rates are roughly the same in both groups. Side effects of
levonorgestrel IUS were rare and mostly temporary. CONCLUSIONS: The insertion of
a levonorgestrel IUD for the local hormonal treatment of recurrent hypermenorrhea
refractory to oral treatment can be tried before endometrial ablation. The
MIRENA(R) device is particularly advantageous for younger patients who might wish
to have more children. The levonorgestrel IUD treatment can replace approx. 75%
of endometrial ablations.
PMID- 10767507
TI - Comparison of two procedures for laparovaginal hysterectomy: a randomized trial.
AB - OBJECTIVE: To compare peroperative parameters of two variants of a laparovaginal
hysterectomy in surgical management of gynecological conditions. METHODS: A
prospective randomized study of 70 laparovaginal hysterectomies performed by the
same two surgeons for disease of female pelvic organs. The following criteria
were studied: indication for surgery, previous surgery, duration of the
procedure, recovery, hospital stay, blood loss, tissue damage markers,
hysterectomy proportions and complication incidence. Statistical analysis was
performed using the non-parametric chi(2)-test and non-parametric Fischer's exact
probability test when appropriate, with a level of significance P=0.05. RESULTS:
Totals of 38 (54.3%) laparoscopy-assisted vaginal and 31 (45.7%) vaginally
assisted laparoscopic hysterectomies were performed for fibroma as the main
indication. Conversion to laparotomy was applied in only one patient. The VALH
group (P=0.01) showed both fewer procedures and shorter hospital stay with
insignificant blood loss. CONCLUSION: The two variants of a laparovaginal
hysterectomy appear to be safe and appropriate, effective procedures for women
with gynecological conditions. Furthermore, vaginally assisted laparoscopic
hysterectomy has been shown to be superior to laparoscopy-assisted vaginal
hysterectomy in terms of shorter operating time and greater palliative effect
upon the complex of uterosacral ligaments. Laparoscopic surgery can alter the
relationship between vaginal and abdominal hysterectomy.
PMID- 10767508
TI - Immunological markers in HIV-infected pregnant and non-pregnant women.
AB - OBJECTIVE: To assess the influence of pregnancy on the course of HIV infection by
comparing the behaviour of total lymphocyte counts and lymphocyte subsets (CD4(+)
and CD8(+) and their ratio) in a cohort of infected pregnant women. SETTING:
Tertiary referral centre for high risk obstetrics and infectious diseases in
pregnancy. PATIENTS AND METHODS: A prospective study was designed, HIV infected
women being enrolled at the beginning of pregnancy and sampled each trimester and
in the puerperium. As controls, a group of non-pregnant HIV-infected women, cross
matched for age, risk factors and stage of disease were included and similarly
evaluated in the same period. RESULTS: All the parameters, when longitudinally
evaluated, were stable during gestation. Compared with non-pregnant subjects,
patients had higher CD4(+) counts at the beginning and increased values of total
lymphocytes count and subsets during the puerperium. Antepartum and postpartum
risk factors such as drug abuse, smoking, antiretroviral therapy, length of
gestation, maternal complications and HIV status of the neonate were not
influential on the total lymphocytes counts and subsets. DISCUSSION: According to
this data, pregnancy per se seems to have a negligible influence over the course
of HIV infection, at least as far as immune parameters are concerned.
PMID- 10767509
TI - Congenital anomalies are an independent risk factor for neonatal morbidity and
perinatal mortality in preterm birth.
AB - OBJECTIVE: To determine whether congenital anomalies are associated with a high
rate of neonatal morbidity in preterm birth. STUDY DESIGN: 312 singletons (22-36
wk) with congenital anomalies that were delivered preterm were compared with a
random sample of 936 preterm singleton without congenital anomalies. Data was
obtained using the computerized birth discharge records. Statistical analysis
included univariate and multivariate logistic regression analyses. RESULTS: Three
thousand five hundred and seventy-eight (3578) women with preterm births met the
inclusion criteria (singleton with prenatal care). The prevalence of congenital
anomalies in the study population was 8.7% (312/3578). Gestational age at
delivery was significantly lower in the congenital anomaly group compared with
the control (32.0+/-3.7 SD vs. 34.4+/-2.7 SD; p<0.001). The following pregnancy
complications were higher in the group with congenital anomalies than in those
without anomalies: severe pregnancy induced hypertension (PIH), hydramnions,
oligohydramnion, intrauterine growth restriction (IUGR), fetal distress, cesarean
section, malpresentation and mal position, abruption placenta, meconium stained
amniotic fluid, 1 min Apgar score (<2), 5 min Apgar score (<7). Perinatal
mortality rates in 28-32 wk and 33-36 wk were significantly higher in the group
with congenital anomalies than in the control group. Neonatal morbidity data
(necrotizing enterocolitis, respiratory distress syndrome, bronchopulmonary
dysplasia, intraventricular hemorrhage, and sepsis) was available for 909
neonates (239 with congenital anomalies and 670 without congenital anomalies).
After adjusting for gestational age, the presence of congenital anomalies
remained strongly associated with neonatal morbidity (having one or more of the
above mentioned conditions) (adjusted OR: 5.3, 95% CI 3.4-9.2). When adjusting
for other confounding variables, congenital anomalies were strongly associated
with neonatal morbidity (OR: 6.44, 95% CI 3.94-10.51), and perinatal mortality
(OR: 3.08, 95% CI 2.04-4.65). In terms of attributable fraction in our population
of preterm births, the proportion of neonatal morbidity and the proportion of
perinatal mortality attributable to congenital malformation is 32% and 15%,
respectively. CONCLUSION: Congenital anomalies in preterm birth are associated
with a higher rate of pregnancy complications and are an independent risk factor
for neonatal morbidity and perinatal mortality.
PMID- 10767510
TI - Acardiac twinning where the pump twin dies in utero due to thrombosis in the
umbilical arteries.
AB - A case of acardiac twinning where the pump twin dies in utero due to massive
thrombotic occlusion of umbilical arteries at a site of umbilical cord stricture
of the intact twin. In acardiac twinning the morbidity and mortality of the pump
twin can be reduced by some invasive or medical approaches. The authors believe
that in this interesting case the death of the pump twin could not be prevented
by antenatal treatment.
PMID- 10767511
TI - Evaluation of the fetal kidney maturation by assessment of amniotic fluid alpha-1
microglobulin levels.
AB - OBJECTIVE: To evaluate the fetal renal maturation by assessment of amniotic fluid
microproteins and to show these proteins originate from fetal urine. STUDY
DESIGN: Amniotic fluid proteins (total protein, albumin, high molecular weight
protein-HMWP, low molecular weight protein-LMWP, alpha(1)-microglobulin and
beta(2)-microglobulin) were determined in 39 pregnant women at delivery and by
amniocentesis in 30 pregnant women. These values were compared with first urine
values of neonates with the same gestational age. RESULTS: Albumin was the
largest protein component in the amniotic fluid. LMWP showed an increase in the
amniotic fluid until the end of the second trimester; and as pregnancy advanced a
progressive decrease occurred in parallel to fetal renal maturation. After 26
weeks' gestation, a strong correlation was identified between LMWP levels and
alpha(1)-microglobulin, and between LMWP and beta(2)-microglobulin. No
significant difference was detected between LMWP levels in the first urine of the
neonates and in amniotic fluids. CONCLUSION: Microproteins in the fetal urine are
of fetal origin. Fetal renal maturation can be evaluated by measuring
microproteins in the amniotic fluid. Fetal renal maturation is best reflected by
alpha(1)-microglobulin.
PMID- 10767512
TI - Significance of success rate of external cephalic versions and vaginal breech
deliveries in counseling women with breech presentation at term.
AB - OBJECTIVE: To appreciate the role of success rates of external cephalic versions
and breech deliveries, in order to assess the risk reduction in women with breech
presentation at term. STUDY DESIGN: We reviewed the patient files of all women
with breech presentation whom had an attempt of external cephalic version (ECV)
at term. Most of the ECVs were performed under intravenous ritodrine infusion.
All women had a trial of labor (TOL) as long as they did not meet one or more of
the exclusion criteria of vaginal delivery. Success rates of ECV and TOL were
assessed, and statistical analysis was performed by using the student t-test for
continuous data, and the Chi-square and Fisher's exact tests for categorical
data. Statistically significant differences required a P value of <0.05. RESULTS:
Of all women with breech presentation at term and not in labor, who had no
contraindication for an ECV, 164 consented and were included in the study. The
success rate of ECV was 30% (22/74) and 67% (60/90) for nulliparae and
multiparae, respectively. Multiparity was the only significant positive
predicting variable for ECV success (OR=4.73, 95% CI 4.19-5.27, P=0.00001). Of
all the women that underwent a successful ECV, 18/22 primiparae (82%), and 52/60
multiparae (87%) had a vaginal delivery, compared to only 52% of the primiparae
and 63% of the multiparae that reached labor with a breech presentation. There
were no significant perinatal complications except for one case of mild placental
abruption. In the primiparous women, ECV decreased the chance of cesarean
delivery by only 9% (P=0.2), compared to a 16% decrease in the multiparae
(P=0.019). CONCLUSIONS: When counseling women with breech presentation at term,
complete information is needed for consent, and should take into account the
success rate of ECVs and of vaginal breech deliveries in the specific center.
PMID- 10767513
TI - Outcome of premature infants delivered after prolonged premature rupture of
membranes before 25 weeks of gestation.
AB - OBJECTIVE: To identify factors influencing the outcome of premature infants
delivered after prolonged premature rupture of membranes before 25 weeks'
gestation. DESIGN AND POPULATION: All premature infants with gestational age <34
weeks, either inborn or outborn, with history of rupture of membranes before 25
weeks' gestation, admitted to our NICU between January 1992 and July 1997, were
eligible for this retrospective study. Collected information included birth
weight, gestational age at rupture of membranes and at delivery, duration between
rupture of membranes and delivery (latency period), severity of oligohydramnios,
pre- and post-natal managements, and follow-up of survivors. RESULTS: A total of
28 neonates fulfilled the inclusion criteria. Despite new strategies of
ventilation and optimal management, the overall mortality rate was 43% (12/28).
Nonsurvivors were significantly less mature at rupture of membranes, and had
severe oligohydramnios (anamnios). We also noted less antenatal corticosteroids
and antibiotic therapy in this group. Nine of eleven infants (82%) following
rupture of membranes before 22 weeks' gestation died shortly after birth. The two
remaining infants developed severe bronchopulmonary dysplasia. Nine deaths
occurred in thirteen cases (69%) of anamnios. The major death causes were
refractory respiratory failure and neurologic complications. Half of all
survivors (8/16) developed bronchopulmonary dysplasia. CONCLUSION: The outcome of
premature infants following prolonged premature rupture of membranes before 25
weeks' gestation is influenced by gestational age at rupture, severity of
oligohydramnios, and antenatal antibiotics and corticosteroids. Neonates with
rupture of membranes before 22 weeks have a very low chance of survival at the
present time.
PMID- 10767514
TI - Maternal complications after caesarean section in HIV infected women.
AB - OBJECTIVE: To assess the intervention related risk in HIV-infected women,
undergoing caesarean section (CS). SETTING: Tertiary care center for high risk
obstetrics and infectious diseases in pregnancy. PATIENTS AND METHODS: Thirty
three HIV-positive women and one hundred and sixty-eight controls, cross matched
for age, weight, parity, obstetrical characteristics at delivery and indication
for CS, were prospectively recruited for the study. Infection related
characteristics, as mode of acquisition, drug abuse, immune status and stage of
disease were also recorded. Complications of the intervention were evaluated
according to infectious status and risk factors. RESULTS: Post-operative
complications were significantly more frequent among HIV-infected mothers. More
advanced disease and maternal age were the risk factors statistically related to
complications. DISCUSSION: According to our data, CS carries a higher chance of
post-operative complications in HIV-infected women, these complications being
also related with the severity of infection (stage and duration of the disease).
Given the characteristics of the population in the study (mode of acquisition,
prevalence of early stage of the disease), the rate of complication is still
relatively low compared to non-western, malnourished, drug-abusers groups.
PMID- 10767515
TI - Vaginal obliteration after total body irradiation and chemotherapy as treatment
for acute myeloid leukemia.
AB - Although radiotherapy is an integral part in the management of certain types of
hematological malignancies, its effect on the reproductive system has been well
documented. We report a rare complication where a patient had complete vaginal
obliteration after receiving a dose of total body irradiation (1575 cGy) as part
of her treatment for acute myeloid leukemia. A 37-year-old married woman, G3P2,
underwent high-dose cyclophosphamide accompanied by high dose (1575 cGy) total
body irradiation (TBI) as part of her treatment for acute myeloid leukemia (AML:
m1) when she was 35 years of age. After TBI, the patient developed ovarian
failure and amenorrhea, which was confirmed by hormonal evaluation. Nevertheless,
she did not receive any hormonal replacement therapy and stopped her sexual life
for two years. Fortunately, no recurrence of AML was noted. The patient visited
our clinic due to difficulty in performing coitus. Physical examination showed a
2-cm short and blinded vaginal pouch. She initially received hormonal replacement
therapy followed by surgical correction via vaginoplasty and two months of
dilatory replacement and frequent coitus with satisfactory result. To our limited
knowledge, vaginal obliteration as a complication of condition regimen has never
been reported before. In the present case report, it is unclear whether
spontaneous vaginal obliteration resulted from chemotherapy, total body
irradiation, or another unknown cause such as a concomitant leukemic infiltration
of the vaginal wall, severe bacterial and fungal infection before treatment, or
from any combination of the above. However, due to this case presentation, we
suggest that such patients must receive hormonal replacement therapy and be
encouraged to have a normal sexual life to avoid this possible problem.
PMID- 10767516
TI - Fast growing cervical carcinomas. A retrospective analysis of 20 IB-IIB FIGO.
AB - INTRODUCTION: Fast growing cervix carcinomas have a pejorative outcome: they may
occur quickly after cervical smears qualified as normal - within an interval from
12 to 18 months in women less than 50 years old, and involveing the endocervix.
This retrospective analysis is aimed at assessing 5-year outcomes. MATERIALS AND
METHODS: Twenty cases of fast-growing cancer of the uterine cervix classified
according to the FIGO clinical staging system as IB (n=14), IIA (3), and IIB (3),
have been reviewed and compared to a cohort of 160 cases not having this feature.
As regard to fast-growing carcinoma, the median age was 41 years (range 25-50),
and the median follow-up 22 months (8-213) as compared to 54 years (27-79) and 80
months (5-199) for the reference cohort. The comparison of the two cohorts shows
only a difference of breakdown which concerns the histological pelvic lymph nodes
status (P<0.05), more often positive in fast-growing forms. The treatment policy
was equally distributed between a radio-surgical approach, cesium 137
intracavitary irradiation followed by radical hysterectomy and lymphadenectomy,
or a definitive irradiation with pelvic external irradiation followed by cesium
137 intracavitary irradiation. RESULTS: Thirteen deaths are reported in the fast
growing series instead of 54 in the other series. The 5-year overall survival is,
respectively, 34 (13-55) vs. 74% (68-82) (P<0.001), the loco-regional-free
survival 58 (33-84) vs. 85% (79-81) (P<0.001), the 5-year metastasis-free
survival 61 (38-84) vs. 84% (78-90) (P=0. 004). CONCLUSION: These poor results
emphasize the need to intensify loco-regional therapy with a concurrent cisplatin
based chemotherapy within the framework of a multidisciplinary approach.
PMID- 10767517
TI - Malignant germ cell tumors of the ovary. Pregnancy considerations.
AB - OBJECTIVE: To study the pregnancy association and malignant germ cell tumors of
the ovary with regard to its effects on tumor prognosis. STUDY DESIGN: : Seventy
five patients with malignant germ cell tumors of the ovary treated at the King
Faisal Specialist Hospital-Research Center (KFSH-RC) Riyadh, Kingdom of Saudi
Arabia between January 1976 and December 1992, were reviewed. Data was retrieved
from the medical records and the database of ovarian tumor pathology. Patients
with tumor/pregnancy association were identified and correlation with obstetrical
outcome and tumor prognosis analyzed. Patients who conceived after treatment were
identified and their reproductive outcome described. RESULTS: Malignant germ cell
tumor was associated with pregnancy in a group of ten patients. Possible tumor
effects upon pregnancy in this group included operative delivery by caesarean
section (n=3), mid-trimester termination (n=2), spontaneous abortion (n=1). Four
patients had normal vaginal birth with no apparent tumor effects upon pregnancy.
Pregnancy did not seem to influence the tumor prognosis of pure dysgerminoma
(n=6), however, two patients with non-dysgerminomatous germ cell tumor (one
endodermal sinus tumor and one immature teratoma) died of rapidly progressive
disease during the second trimester. Two patients with advanced (stage IIIC)
disease concurrent with pregnancy (one pure dysgerminoma and one mixed germ cell
tumor), had normal fetal outcomes and achieved long-term survival. Amongst the 22
patients who planned to conceive after conservative surgery, with or without post
operative adjuvant chemotherapy, 12 conceived (12/22) and achieved a total of 20
pregnancies. Their outcomes included normal births (n=18) including one set of
twins and hydatidiform moles (n=2). CONCLUSIONS: Our findings suggest that, (1)
The association of pure dysgerminoma and pregnancy did not adversely affect the
tumor prognosis or fetal outcome. However, the question remains as to whether
pregnancy worsened the prognosis of non-dysgerminomatous germ cell tumors. (2)
Recent platinum-based regimens of multiagent chemotherapy for germ cell tumors
did not seem to affect fertility potential.
PMID- 10767518
TI - Poor clinical outcome in early stage cervical cancer with human papillomavirus-18
positive lymph nodes.
AB - Epidemiologic and molecular studies have proven that human papillomavirus (HPV)
plays an important role in the development of cervical cancer. However, the role
of the virus in the progression of the disease, i.e. in the development of lymph
node metastasis and in the adverse clinical outcome is poorly understood. We have
been using the polymerase chain reaction (PCR) to study the presence and typing
of human papillomavirus DNA since 1980 in cervical cancers and pelvic lymph nodes
from the same patients. Out of the series of 47 cervical cancer patients we
focused on four women (age: 41, 33, 35 and 56 years) in this article. The follow
up of these patients revealed early recurrences of the disease (7, 7, 17, 22
months) with very short survival (9, 10, 21, 24 months). Although we detected HPV
18 positivity both in the cervical tumors and in the regional lymph nodes too in
all four cases, lymph nodes were negative by routine hystology in case of the
three young patients (21, 33, 35 years of age). Our observations suggest that HPV
type 18 positive cervical cancer patients, despite negative histological findings
in the lymph nodes should be consider as a subpopulation for poor outcome
especially in the young age group (p=0,022, Fisher's exact test).
PMID- 10767519
TI - Effects on bone loss of manganese alone or with copper supplement in
ovariectomized rats. A morphometric and densitomeric study.
AB - OBJECTIVE: The aim of this study was to examine the effect of manganese (Mn)
alone and with the addition of copper (Cu) in the inhibition of osteopenia
induced by ovariectomy (OVX) in rats. STUDY CONDITIONS: Four lots of 100-day-old
female Wistar rats were divided into experimental groups of 15 each. One group
received a diet supplemented with 40 mg/kg of Mn per kilogram of feed (OVX+Mn).
The second group received the same diet as the first, but with an additional 15
mg/kg of copper (OVX+Mn+Cu). The third group of 15 OVX and the fourth group of 15
Sham-OVX received no supplements. At the conclusion of the 30-day experiment, the
rats were slaughtered and their femurs and fifth lumbar vertebrae were dissected.
Femoral and vertebral length were measured with caliper and bones were weighed on
a precision balance. The bone mineral content (BMC) and bone density (BMD) of the
femur (F-BMC, mg and F-BMD, mg/cm(2)) and the fifth lumbar vertebra (V-BMC, mg
and V-BMD, mg/cm(2)) were measured separately with dual energy X-ray
absorptiometry. RESULTS: The F-BMD, mg/cm(2) was lower in the OVX than in the
Sham-OVX group (P<0.0001) and in the other two groups receiving mineral
supplements (P<0.005 in both). F-BMC, mg was significantly lower in the OVX group
than in the other three (P<0.0001 in all cases). Calculations for V-BMC, mg and V
BMD, mg/cm(2) are similar to findings in the femur. CONCLUSIONS: These data show
that a Mn supplement is an effective inhibitor of loss of bone mass after OVX,
both on the axial and the peripheral levels, although this effect is not enhanced
with the addition of Cu.
PMID- 10767520
TI - Administration of L-thyroxine does not improve the response of the hypothalamo
pituitary-ovarian axis to clomiphene citrate in functional hypothalamic
amenorrhea.
AB - OBJECTIVE: To investigate the hypothalamo-pituitary-ovarian axis in women with
functional hypothalamic amenorrhea to determine whether the combination of L
thyroxine and clomiphene citrate produces a qualitative and quantitative increase
in induced ovulatory cycles. SETTING: Gynecological Endocrinology Research
Center, University of Siena (Italy). PATIENTS: 16 young women with functional
hypothalamic amenorrhea and 15 women with normal cycles in early follicular
phase. DESIGN: Administration of 50 microgram GnRH and 200 microgram TRH. The
women with functional hypothalamic amenorrhea were divided into groups A (n=8)
and B (n=8). Both groups were given 100 mg/day clomiphene for 5 days/month for 3
months. Women in group A were also given 75 mcg/day thyroid hormone (L-thyroxine)
for 3 months. MAIN OUTCOME MEASURES: Comparison of basal and stimulated levels of
gonadotropins, TSH and Prl, in groups A and B. Qualitative and quantitative
comparison of ovulatory cycles induced in the groups. RESULTS: Administration of
clomiphene and clomiphene plus L-thyroxine was evaluated in the second and third
months of treatment and was followed by a total of 11 ovulatory cycles, six in
group A and five in group B. No significant difference was found between groups.
Mean progesterone concentrations measured 16 days after the last clomiphene
tablet were 5.5+/-1.2 ng/ml in group A and 5.1+/-1.3 ngl/ml in group B.
CONCLUSIONS: Administration of L-thyroxine with clomiphene does not improve the
response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate or the
number of ovulatory cycles and does not reduce luteal phase defects.
PMID- 10767521
TI - Massive solitary metastasis of hepatocellular carcinoma in the ovary two years
after liver transplantation.
AB - Case report of a 47-year-old woman with a mass in the lower abdomen, was referred
to us by the surgeon, two years after orthotopic liver transplantation for
hepatocellular carcinoma (HCC). Serum alpha-fetoprotein (AFP), which was elevated
at the time of initial diagnosis, was in the normal range. Frozen section
examination during exploratory laparotomy showed appearances consistent with
metastatic HCC in the ovary. This was confirmed at the final pathological
examination. Definitive pathological conclusions were based on the findings of
tumor cells arranged in trabecular and papillary aggregates, and the presence of
bile-pigment, along with the patients history. This is the sixth case of
metastatic HCC in the ovary being described in literature and the first case in
which this metastasis was not accompanied by elevated AFP.
PMID- 10767522
TI - Microsporidia: accumulating molecular evidence that a group of amitochondriate
and suspectedly primitive eukaryotes are just curious fungi.
AB - Microsporidia are obligate intracellular parasites that have long been considered
to be primitive eukaryotes, both on the basis of morphological features and on
the basis of molecular, mainly ribosomal RNA-based, phylogenies. However,
accumulating sequence data and the use of more sophisticated tree construction
methods now seem to suggest that microsporidia share a common origin with fungi
and are therefore most probably just curious fungi. In this paper, we describe
the current views on the phylogenetic position of the microsporidia and present
additional evidence for a close relationship between fungi and microsporidia on
the basis of reanalyzed ribosomal RNA data. In this respect, the importance of
incorporating detailed knowledge of the substitution pattern of sequences into
phylogenetic methods is discussed.
PMID- 10767523
TI - Mechanisms of gene regulation by vitamin D(3) receptor: a network of coactivator
interactions.
AB - The vitamin D(3) receptor regulates transcription in direct response to its
cognate hormonal ligand, 1,25(OH)(2)D(3). Ligand binding leads to the recruitment
of coactivators. Many of these factors, acting in large complexes, have emerged
as chromatin remodelers partly through intrinsic histone modifying activities. In
addition, other ligand-recruited complexes appear to act more directly on the
transcriptional apparatus, suggesting that transcriptional regulation by VDR and
other nuclear receptors may involve a process of both chromatin alterations and
direct recruitment of key initiation components at regulated promoters.
PMID- 10767524
TI - Genetic and molecular roles of Otx homeodomain proteins in head development.
AB - Insights into the molecular mechanisms underlying neural development in
vertebrates come from the cloning and the functional analysis of genes which are
involved in the molecular pathways leading to neural induction, tissue
specification and regionalization of the brain. Among them, transcription factors
belonging to the orthodenticle family (Otx1, Otx2) play an important role during
early and later events required for proper brain development. To better
understand their functions, several mouse mutants have been generated by
homologous recombination. Their analysis clearly indicates that Otx1 is involved
in corticogenesis, sense organ development and pituitary functions, while Otx2 is
necessary earlier in development, for the correct anterior neural plate
specification and organisation of the primitive streak. A molecular mechanism
depending on a precise threshold of OTX proteins is necessary for the correct
positioning of the isthmic region and for anterior brain patterning. Finally,
vertebrate Otx genes share functional equivalence with the Drosophila homologue
otd, indicating that the genetic mechanisms underlying pattern formation in
insect and mammalian brain development are evolutionarily conserved.
PMID- 10767525
TI - New features of mitochondrial DNA replication system in yeast and man.
AB - In this review, we sum up the research carried out over two decades on
mitochondrial DNA (mtDNA) replication, primarily by comparing this system in
Saccharomyces cerevisiae and Homo sapiens. Brief incursions into systems of other
organisms have also been achieved when they provide new information.S. cerevisiae
and H. sapiens mitochondrial DNA (mtDNA) have been thought for a long time to
share closely related architecture and replication mechanisms. However, recent
studies suggest that mitochondrial genome of S. cerevisiae may be formed, at
least partially, from linear multimeric molecules, while human mtDNA is circular.
Although several proteins involved in the replication of these two genomes are
very similar, divergences are also now increasingly evident. As an example, the
recently cloned human mitochondrial DNA polymerase beta-subunit has no
counterpart in yeast. Yet, yeast Abf2p and human mtTFA are probably not as
closely functionally related as thought previously. Some mtDNA metabolism
factors, like DNA ligases, were until recently largely uncharacterized, and have
been found to be derived from alternative nuclear products. Many factors involved
in the metabolism of mitochondrial DNA are linked through genetic or biochemical
interconnections. These links are presented on a map. Finally, we discuss recent
studies suggesting that the yeast mtDNA replication system diverges from that
observed in man, and may involve recombination, possibly coupled to alternative
replication mechanisms like rolling circle replication.
PMID- 10767526
TI - Two attacin antibacterial genes of Drosophila melanogaster.
AB - Insects express a battery of potent antimicrobial proteins in response to injury
and infection. Recent work from several laboratories has demonstrated that this
response is neither stereotypic nor completely nonspecific, and that different
pathways are responsible for inducing the expression of antifungal and
antibacterial peptides. Here we report the cloning of two closely linked attacin
genes from Drosophila melanogaster. We compare their protein coding sequences and
find the amino acid sequences to be more highly conserved than the nucleotide
sequences, suggesting that both genes are expressed. Like other antimicrobial
peptides, attacin expression is strongly induced in infected and injured flies.
Unlike others, attacin transcription is uniquely sensitive to mutations in the 18
Wheeler receptor protein, and thus may be regulated by a distinct signaling
pathway. The number and organization of binding sites for kappaB and other
transcription factors in the promoter regions of both attacin genes are
consistent with strong and rapid immune induction. We demonstrate that these
promoter regions are sufficient to direct beta-galactosidase expression in
transformed Drosophila third-instar larval fat body in a bacterially inducible
manner. We present a comparison of the promoter regions of the two attacin genes
to those cloned from other antimicrobial peptide genes to assist a better
understanding of how antimicrobial genes are differentially regulated.
PMID- 10767527
TI - Genetic organization and heterogeneity of the iceA locus of Helicobacter pylori.
AB - The genetic organization and sequence heterogeneity of the iceA locus of
Helicobacter pylori was studied, and the existence of two distinct gene families,
iceA1 and iceA2, at this locus was confirmed. iceA1 has significant sequence
homology to nlaIIIR, encoding an endonuclease in Neisseria lactamica, but the
similarity at the protein level is limited, due to frameshift mutations of iceA1
in most H. pylori strains. In only five of the 19 iceA1 strains studied, a full
length open reading frame (ORF), capable of encoding a 228aa protein, with 52%
homology to NlaIII was observed. The region upstream of iceA2 is highly variable
in length, containing up to 15 copies of 8bp tandem repeats. iceA2 can encode
proteins of 24, 59, 94, or 129 amino acids, consisting of 14 and 10aa domains,
conserved in all iceA2 strains, flanking 0, 1, 2, or 3 copies of a 35aa cassette.
This 35aa cassette consists of domains of 13, 16 and 6aa, respectively. The 13aa
and 6aa domains are highly conserved, but the 16aa domain exists in two variants.
In total, five distinct iceA2 subtypes were defined. Database searches did not
reveal any homologous sequences. Recombinant IceA1 and IceA2 proteins were
expressed in Escherichia coli, confirming the predicted ORFs. Genotype-specific
PCR primers permitted iceA genotyping in 318 (99. 1%) of a worldwide collection
of 321 H. pylori strains. The conserved sizes of the amplification products
confirmed the worldwide distribution of discrete variants of iceA1 and iceA2.
PMID- 10767528
TI - Cloning and characterization of zebrafish smad2, smad3 and smad4.
AB - smad genes encode transcription factors involved in the signal transduction of
members of the TGFbeta superfamily. We report here the cloning, characterization
and genomic mapping of smad2, smad3 and smad4 from the zebrafish, Danio rerio. In
Xenopus, smad2 overexpression has been shown to interfere with gastrulation and
dorsal cell fate specification. However, full-length zebrafish smad2, although
functionally active in Xenopus explants, has no effect when overexpressed in
zebrafish embryos. In contrast, an N-terminally truncated, constitutively active
version of Smad2 protein causes severe dorsalization or partial secondary axis
formation, pointing to a role of Smad2 during mesoderm and axis formation. The
temporal and spatial expression patterns of zebrafish smad2, 3 and 4 were
investigated by developmental RT-PCR and whole mount in-situ hybridization. All
three genes show strong and ubiquitous maternal expression. Zygotic expression is
weak and ubiquitous in the case of smad2, and strong and ubiquitious in the case
of smad4, while smad3 shows a spatially restricted zygotic expression pattern. It
is expressed in migrating neural crest cells of the trunk and a subset of cells
in the diencephalon in close proximity to the expression domain of the Nodal
related protein Cyclops/Ndr2/Znr1, a potential signal upstream of Smad2/3
required for eye-field separation and floor plate specification. Overexpression
of truncated smad2 in cyclops mutant embryos leads to a rescue of the eye and
floorplate defects. These data suggest that Smad2 acts as a mediator of Nodal
signals during zebrafish midline signaling, while Smad3 might be involved in
later steps of eye field separation.
PMID- 10767529
TI - FePer 1, a gene encoding an evolutionarily conserved 1-Cys peroxiredoxin in
buckwheat (Fagopyrum esculentum Moench), is expressed in a seed-specific manner
and induced during seed germination.
AB - A cDNA corresponding to 1-Cys peroxiredoxin, an evolutionarily conserved thiol
specific antioxidant enzyme, was isolated from buckwheat (Fagopyrum esculentum
Moench), a dicotyledonous plant species belonging to the Polygonaceae family. The
cDNA, which we have designated as FePer1, contains a major open reading frame
capable of encoding a polypeptide of 219 residues with a predicted molecular mass
of 24.3kDa. The deduced primary structure of FePer1 polypeptide shows a high
level (about 70%) of sequence homology to other recently identified plant 1-Cys
peroxiredoxins. FePer1 also exhibits a significant level of sequence similarity
to non-plant 1-Cys peroxiredoxins, sharing 52 and 42% identities with mammalian
and fungal 1-Cys peroxiredoxins, respectively. As for all 1-Cys peroxiredoxins
identified from various organisms, the amino acid sequence proposed to constitute
the active site of the enzyme is highly conserved in FePer1 polypeptide. The gene
corresponding to FePer1 cDNA is a single-copy gene in the buckwheat genome. Its
expression is regulated in a seed-specific and temporal manner during seed
development. FePer1 gene is induced transiently for a short period immediately
after seed imbibition.
PMID- 10767530
TI - Transcription and proper splicing of a mammalian gene in yeast.
AB - The house mouse strain C57BL/6 harbours 64 copies of the multicopy gene Sp100-rs.
Three of these are contained in the yeast artificial chromosome (YAC) clone
yMm75. Four Sp100-rs transcripts of 3.0, 2.6, 1.6 and 1.3kb were detected by
Northern hybridization in the yMm75-harbouring line of Saccharomyces cerevisiae.
Additional and less abundant transcripts were detected by RT-PCR. With one
exception, the YAC-derived Sp100-rs transcripts were a subset of those found in
the C57BL/6 mouse. This indicates transcription and proper splicing of murine pre
mRNAs in yeast. Analysis of the splice sites shows that the yeast splicing
machinery accepts splice sites that deviate from the standard yeast consensus
sequences. It may be feasible, therefore, at least in a fair proportion of cases,
to exploit the mammalian mRNAs present in transgenic yeast for gene recognition
of YAC-inserts.
PMID- 10767531
TI - Molecular cloning and embryonic expression of dFKBP59, a novel Drosophila FK506
binding protein.
AB - A Drosophila cDNA encoding a structural homolog of mammalian FKBP59 (also
identified as FKBP52), a member of the FK506-binding protein (FKBP) class of
immunophilins, was isolated. The gene dFKBP59 corresponding to this cDNA has been
characterized and mapped to the 30D3-4 region. The predicted amino acid sequence
of this cDNA shows that the dFKBP59 protein contains one highly conserved FKBP12
like domain followed by two others with less conservation. Northern hybridization
reveals that the dFKBP59 mRNA is expressed throughout the Drosophila life-cycle.
In contrast to its mammalian homologs, in situ hybridization detected dFKBP59
expression in specific tissues: the lymph glands, Garland cells and oenocyte
cells, which are all specialized tissues in which intensive exocytic/endocytic
cycling takes place. Garland cells and oenocytes (also called Drosophila
nephrocytes) function in taking up waste material from the hemolymph. Finally, I
have mapped an enhancer trap element within the 5' region of dFKBP59 which may
help in future studies to address the question of its function during Drosophila
development.
PMID- 10767532
TI - Identification of a novel Reg family gene, Reg IIIdelta, and mapping of all three
types of Reg family gene in a 75 kilobase mouse genomic region.
AB - Regenerating gene (Reg), first isolated from a regenerating islet cDNA library,
encodes a secretory protein with a growth stimulating effect on pancreatic beta
cells that ameliorates the diabetes of 90% depancreatized rats and non-obese
diabetic mice. Reg and Reg-related genes have been revealed to constitute a
multigene family, the Reg family, which consists of three subtypes (types I, II,
III) based on the primary structures of the encoded proteins of the genes. We
have isolated three types of mouse Reg family gene (Reg I, Reg II, Reg IIIalpha,
Reg IIIbeta and Reg IIIgamma) [Unno et al. (1993) J. Biol. Chem. 268, 15974
15982; Narushima et al. (1997) Gene 185, 159-168]. In the present study, by
Southern blot analysis of a mouse bacterial artificial chromosome clone
containing the five Reg family genes in combination with PCR cloning of every
interspace fragment between adjacent genes, the Reg family genes were mapped to a
contiguous 75kb region of the mouse genome according to the following order: 5'
Reg IIIbeta-Reg IIIalpha-Reg II-Reg I-Reg IIIgamma-3'. In the process of ordering
the genes, we sequenced the 6.8kb interspace fragment between Reg IIIbeta and Reg
IIIalpha and encountered a novel type III Reg gene, Reg IIIdelta. This gene is
divided into six exons spanning about 3kb, and encodes a 175 amino acid protein
with 40-52% identity with the other five mouse Reg (regenerating gene product)
proteins. Reg IIIdelta was expressed predominantly in exocrine pancreas, but not
in normal islets, hyperplastic islets, intestine or colon, whereas both Reg I and
Reg II were expressed in hyperplastic islets and Reg IIIalpha, Reg IIIbeta and
Reg IIIgamma were expressed strongly in the intestinal tract. Possible roles of
Reg IIIdelta and the widespread occurrence of the Reg IIIdelta gene in mammalian
genomes are discussed.
PMID- 10767533
TI - Identification of two polyketide synthase gene clusters on the linear plasmid
pSLA2-L in Streptomyces rochei.
AB - The 200kb linear plasmid pSLA2-L was suggested to be involved in the production
of two macrolide antibiotics, lankamycin (Lm) and lankacidin (Lc), in
Streptomyces rochei 7434AN4. Hybridization experiments with the polyketide
synthase (PKS) genes for erythromycin and actinorhodin identified two eryAI
homologous regions and an actI-homologous region on pSLA2-L. The nucleotide
sequence of a 3.6kb SacI fragment carrying one of the eryAI-homologs revealed
that it codes for part of a large protein with four domains for ketoreductase,
acyl carrier protein, ketosynthase, and acyltransferase. Gene disruption
confirmed that the two eryAI-homologs are parts of a large type-I PKS gene
cluster for Lm. A 4.8kb DNA carrying the actI-homologous region contains four
open reading frames (ORF1-ORF4) as well as an additional ORF, i.e. ORF5, which
might code for a thioesterase. Deletion of the ORF2-ORF4 region showed that it is
not involved in the synthesis of Lm or Lc. Thus, it was confirmed that pSLA2-L
contains two PKS gene clusters for Lm and an unknown type-II polyketide.
PMID- 10767534
TI - First evidence of uncoupling protein-2 (UCP-2) and -3 (UCP-3) gene expression in
piglet skeletal muscle and adipose tissue.
AB - Uncoupling proteins (UCPs) facilitate proton transport inside the mitochondria
and decrease the proton gradient, leading to heat production. Until now, the
presence of UCP1 or other UCP homologs had not been detected in tissues of pig, a
species where evidence for the presence of brown adipose tissue has only been
provided in 2-3 month old animals. In the light of the improving knowledge on the
UCPs family, we decided to examine both UCP2 and UCP3 mRNA expression in piglet
skeletal muscle and adipose tissue. Using RT-PCR we have successfully cloned a
partial UCP2 sequence and a complete UCP3 cDNA. UCP3's open reading frame (936bp)
shares 90, 89 and 85% similarity with bovine, human and rat UCP3 nucleotide
sequences, respectively. In 3-5 day old piglets, these genes are expressed in
adipose tissue and in both longissimus thoracis (LT) and rhomboideus (RH)
muscles, without any effect of muscle metabolic type. This is in good agreement
with the measurement of the same membrane potential in mitochondria isolated from
both types of muscles. In triiodothyronine-treated piglets, UCP3 mRNA is more
expressed in LT than in RH muscle. These genes may be involved in the control of
the energy metabolism of the piglet.
PMID- 10767535
TI - Genomic organisation and characterisation of the neural sex-determination gene
fruitless (fru) in the Hawaiian species Drosophila heteroneura.
AB - There are several mechanisms for the determination of sex. Sexual behaviour is
part of the sex-determination cascade, and in Drosophila melanogaster male
courtship is controlled in part by the fruitless gene. As part of a study of
sexual behaviour in Hawaiian Drosophila, we have cloned the neural sex
determination gene fru from the Hawaiian picture-wing species Drosophila
heteroneura. The fru gene has at least seven exons covering a region of 18kb and
encodes three transcripts, fruA, fruB and fruC. Each transcript encodes a single
ORF of 841, 678 and 691aa, respectively. The FRUA and FRUB proteins have a BTB
protein-protein-binding domain and two zinc finger-like domains and are well
conserved with the D. melanogaster proteins. The FRUC protein has a BTB domain
but no zinc finger-like domains. The fru gene is expressed in 1-7 day old adult
males as a 5.1kb transcript. This transcript is not seen in adult females, so the
fru gene has a different pattern of sex-differential expression in the Hawaiian
Drosophila compared with D. melanogaster.
PMID- 10767536
TI - Candida glabrata shuttle vectors suitable for translational fusions to lacZ and
use of beta-galactosidase as a reporter of gene expression.
AB - The functionality of beta-galactosidase encoded by the E. coli lacZ gene as a
reporter of gene expression in C. glabrata was investigated. C. glabrata/E. coli
shuttle vectors were constructed, containing both a C. glabrata CEN-ARS cassette,
to allow regular segregation and episomal replication of the plasmids, and the
lacZ coding sequence of E. coli. The functionality of beta-galactosidase in C.
glabrata was verified by inserting the promoter and the 5' coding region of the
HIS3 gene from C. glabrata directionally upstream of the lacZ gene. By fusing the
promoter of the copper-controlled MTII gene to the lacZ reporter, we showed that
beta-galactosidase activity can be differentially induced in C. glabrata. beta
galactosidase reporter activities were detected qualitatively by an indirect
filter assay and quantitatively from permeabilized cells.
PMID- 10767537
TI - Genetic and molecular analysis in the 70CD region of the third chromosome of
Drosophila melanogaster.
AB - A collection of lethal and semi-lethal P-element insertions in the 70CD region of
chromosome 3 of Drosophila melanogaster was used to investigate genes and gene
arrangements by a combination of genetic, cytological, functional and molecular
methods. The 12 lethal insertions studied fall into seven complementation groups
of six genes. Lethal phases, expression patterns and other phenotypic aspects of
these genes were determined. The genes and additional available sequences were
placed on cloned genomic DNA fragments and arranged in an EcoRI map of 150kb that
covers approximately the bands 70C7-8 to 70D1. Determination of deficiency
breakpoints links the genetic, physical and molecular data. The sequences
adjacent to seven independent P-element insertions were established after plasmid
rescue or polymerase chain reaction. Similarity searches allowed the assignment
of the P-element insertions to known mutations, expressed sequence tags, sequence
tagged sites, or homologous genes of other species. Among these were identified a
putative transacylase, a putative cell cycle gene, and the gene responsible for
the dominant Polycomb-suppressor phenotype of devenir. The genomic sequence of
the l(3)70Ca/b gene reveals a novel heat shock protein (hsc70Cb). l(3)70Da was
identified as a member of the CDC48/PEX1 ATPase family and its coding sequence
was determined.
PMID- 10767538
TI - Phosphorylation of the insect immunophilin FKBP46 by the Spodoptera frugiperda
homolog of casein kinase II.
AB - Immunophilins are a family of conserved proteins found in both prokaryotes and
eukaryotes, that exhibit peptidylprolyl isomerase (PPIase) activity. Members of
this family bind to immunosuppressive drugs and on this basis are divided into
two classes: FKBPs bind to FK506 and rapamycin, while cyclophilins bind to
cyclosporin A. In this paper, we report on insect immunophilin FKBP46 and its
associated kinase. The insect FKBP46 belongs to the high-molecular-weight
immunophilins and shares many characteristic features with its mammalian
counterparts, but its functional role remains unclear. Here, we show that FKBP46
is phosphorylated by a protein kinase present in the nucleus of both insect
Spodoptera frugiperda (Sf9) and human Jurkat cells. This protein kinase is
immunoreactive with polyclonal antiserum raised against Drosophila melanogaster
casein kinase II (CKII). We have cloned, overexpressed and characterized a new
member of the CKII family derived from Spodoptera frugiperda cells. Recombinant
Sf9 CKII alpha subunit shares 75% identity to human, chicken and Drosophila
melanogaster homologs, whereas the Sf9 CKII beta subunit is 77% identical to rat,
chicken and human. Moreover, we demonstrate that the insect immunophilin FKBP46
can be phosphorylated by human and Sf9 casein kinase II. Finally, we show that
FKBP46 interacts with DNA, and this interaction is not prevented by
phosphorylation.
PMID- 10767539
TI - A novel multi-purpose cassette for repeated integrative epitope tagging of genes
in Saccharomyces cerevisiae.
AB - Gene tagging can be achieved by homologous recombination in yeast. The kan(r)
marker gene plays an important role in PCR-mediated gene disruption and PCR
mediated epitope tagging experiments. In this paper, new modules containing a tag
loxP-kanMX-loxP cassette are described that allow tagging of different genes by
using the kan(r) marker repeatedly.
PMID- 10767540
TI - Characterization of ywhE, which encodes a putative high-molecular-weight class A
penicillin-binding protein in Bacillus subtilis.
AB - The Bacillus subtilis genome sequencing project [Kunst et al., Nature 390 (1997)
249-256] identified ywhE as a gene that potentially encodes a high-molecular
weight class A penicillin-binding protein. Analysis of the expression of a
translational ywhE-lacZ fusion showed that ywhE expression is sporulation
specific, and is controlled predominantly by the forespore-specific sigma factor
sigma(F), and to a lesser extent by sigma(G). Primer extension analysis
identified two transcription start sites located 26 and 27 nucleotides upstream
of the ywhE translational initiation codon. Sequences located in the -10 and -35
regions relative to the transcription start sites showed good homology to the
consensus sequences for promoter elements of sigma(F)-dependent genes. An
insertional mutation in ywhE had no significant effect on growth, morphology, and
sporulation, and ywhE spores had normal heat-resistance, cortex structure, and
germination and outgrowth properties. However, overexpression of ywhE in
Escherichia coli resulted in cell lysis.
PMID- 10767541
TI - Genomic structure and expression of the murine Hmgi(y) gene.
AB - Mammalian HMGI proteins belong to the high mobility group (HMG) of small non
histone nuclear proteins, and function as architectural factors to mediate
structural changes in DNA. The HMGI family consists of three members: HMGI, HMGY
and HMGI-C. As pseudogenes have complicated the genomic analysis of murine
Hmgi(y), a mouse lambda FIX II genomic library was screened with an intron
specific probe to identify and characterize the authentic Hmgi(y) gene. The
murine Hmgi(y) gene is 7.2kb long and contains four protein coding exons and two
additional exons encoding part of the 5' untranslated region. Sequencing confirms
that an alternative splicing site within exon 3 results in the two protein
isoforms: Hmgi and Hmgy. Primer extension experiments revealed that at least
three transcription start sites exist in the 5' end of the gene. It has been well
established that the expression of both Hmgi-c and Hmgi(y) is readily detectable
throughout embryogenesis. Unlike Hmgi-c, whose expression is restricted to
embryogenesis, a Northern hybridization analysis showed low-level expression of
Hmgi(y) in adult mouse tissues. Similarly, when tissues from newborn animals were
examined, Hmgi(y) expression was readily detected at a level of intensity
intermediate between that found in embryos and adults. Understanding the gene
structure and expression pattern will provide important insights into the in-vivo
function of Hmgi(y).
PMID- 10767542
TI - Complex RNA processing of TDRKH, a novel gene encoding the putative RNA-binding
tudor and KH domains.
AB - The sequence from a human EST (IMAGE:259322) with homology to the nucleotide
sensitive chloride conductance regulator (ICln) was used to screen a human aortic
cDNA library. The probe sequence was from a region of the EST lacking homology to
ICln, and the goal was to isolate an ICln-like gene. A 2843bp cDNA clone with an
open reading frame coding for a 561 amino acid protein was isolated. This clone
had no homology to ICln. PROSITE analysis of the putative protein sequence
reveals one tudor and two K homology (KH) domains. The gene has therefore been
named TDRKH. Both KH and tudor motifs are involved in binding to RNA or single
strand DNA. PCR analysis demonstrated that TDRKH is alternatively spliced in
several ways and alternatively polyadenylated at multiple sites. Northern
analysis confirmed the presence of messages of multiple lengths with predominant
bands at 2.8 and 4.0 kb and also demonstrated that TDRKH is widely expressed in
human tissues. Within an intron of TDRKH, there is a region with 90% homology to
ICln. This sequence, which is incorporated into the alternatively spliced message
represented by IMAGE:259322, contains a 2 bp deletion that disrupts the ICln
reading frame and therefore represents an ICln pseudogene. The TDRKH gene was
mapped to the Epidermal Differentiation Complex (EDC) at chromosome 1q21 by
radiation hybrid mapping and STS content of genomic clones from that region. The
EDC contains a large cluster of related genes involved in terminal
differentiation of the epidermis. It remains to be determined whether TDRKH has a
specific role in epithelial function.
PMID- 10767544
TI - Cloning of CCRL1, an orphan seven transmembrane receptor related to chemokine
receptors, expressed abundantly in the heart.
AB - In an attempt to identify novel chemokine receptor genes, cDNA expressed sequence
tags (EST) were analyzed for a significant homology with mammalian chemokine
receptors. The sequence from one of the selected EST clones was used to generate
a full-length cDNA encoding a putative seven transmembrane receptor, CCRL1-CC
chemokine receptor like 1. The full-length receptor encodes a polypeptide of 350
amino acids and has about 35% homology to the chemokine receptors CCR6 and CCR7.
Northern blot analysis indicates predominant expression of about 5.0, 2.0 and
1.3kb mRNA forms in human heart tissue, while low-level expression of the 2.0 and
1.3kb forms was observed in lung, pancreas and spleen and in fetal tissues. In
situ hybridization confirmed the presence of CCRL1 mRNA in cardiac muscle cells.
Similar to the chemokine receptor CCR6, CCRL1 maps to chromosome 6 and has one
intron in the 5' untranslated region. Coupled transcription-translation of CCRL1
cDNA yielded a glycosylated polypeptide of about 45kDa.
PMID- 10767543
TI - Esr genes show different levels of expression in the same region of maize
endosperm.
AB - Esr genes share high homology among each other, code for small hydrophilic
proteins, and are expressed in a restricted region of maize endosperm surrounding
the embryo. We show here that not only Esr2 but also Esr1 and Esr3 are expressed
in maize, and that the relative contribution of Esr1, Esr2 and Esr3 to total Esr
mRNA is 17%, 55% and 28%, respectively. DNA sequence analysis of putative
promoter fragments ranging from 0.53 kb to 3.54 kb revealed the presence of
retrotransposons related to the Zeon and Cinful families in the distal parts of
the promoters. The proximal parts show high homology that extended over 504bp
between Esr2 and Esr3, and 265bp between Esr1 and the other two genes. The most
conspicuous potential cis element is a fully conserved tandem repeat of the
sequence CTACACCA close to the respective open reading frames (ORFs). By the
analysis of transgenic maize plants carrying promoter-Gus fusions, it was shown
that all three cloned upstream fragments contain functional promoters, that the
spatial activity of all three Esr promoters is identical, and that the cis
element(s) responsible for the expression in the embryo surrounding region reside
in the 265 bp upstream of the respective ORFs.
PMID- 10767545
TI - Gene conversion among chemokine receptors.
AB - It has been proposed that proteins which are involved in host defence and
susceptibility undergo accelerated evolution. Chemokine receptors have roles as
pro-inflammatory agents acting in response to infection, and in addition are
receptors for entry of viruses and other pathogens into cells. Consistent with
this, their rate of evolution is higher than that for other members of the seven
transmembrane domain receptor family. The pattern of evolution of the chemokine
receptors was examined in detail. Both chromosomal clusters of chemokine
receptors (CC and CXC) showed evidence of a number of gene conversions. These are
likely to have resulted in protein sequence changes, which could possibly alter
function. 45% of a control group of clustered genes also showed evidence of
conversion. Thus, the fixation of a gene conversion is not in itself sufficiently
unusual in tandemly repeated genes and cannot be taken as strong evidence of a
selection for a novel function. However, the degree of amino acid difference
between the chemokine receptors CCR1 and CCR3 was greater than that for any of
the control genes. Such changes could have functional implications for inter
species differences in chemokine receptor interactions with pathogens.
PMID- 10767546
TI - p53 splice acceptor site mutation and increased HsRAD51 protein expression in
Bloom's syndrome GM1492 fibroblasts.
AB - GM1492 human diploid skin fibroblasts derived from a patient with Bloom's
syndrome (BS), lack detectable p53 mRNA and protein as shown by Northern and
Western blotting, and express an increased RecA-like activity. Here we
demonstrate that the p53 gene is grossly intact in GM1492 cells according to
Southern blotting. DNA sequencing did not reveal any mutations in the promoter
region of p53. A highly sensitive RT-PCR produced a p53 cDNA fragment that was
shorter than expected. DNA sequence analysis of p53 cDNA showed that exon 6 was
missing, explaining the shorter PCR product. Furthermore, sequencing of genomic
DNA revealed a base substitution at the nucleotide preceding the AG splice
acceptor site of intron 5. The omission of exon 6 creates a frameshift at the
junction of exons 5 and 7, and a premature stop codon in exon 7. The aberrant
transcript is predicted to encode a truncated p53 protein containing 189 amino
acid residues. Moreover, Western blotting demonstrated elevated HsRAD51 protein
levels in GM1492 cells. The lack of sufficient levels of wild-type p53 and
increased levels of HsRad51 protein may contribute to the elevated RecA-like
activity in the GM1492 fibroblasts.
PMID- 10767547
TI - Identification and recombinant expression of glyceraldehyde-3-phosphate
dehydrogenase of Plasmodium falciparum.
AB - The gene coding for the cytosolic glyceraldehyde-3-phosphate dehydrogenase
(GAPDH; EC 1.2.1.12) was isolated from Plasmodium falciparum. The gene contains 1
intron and the A+T content is characteristic for the codon usage of P.
falciparum. The predicted open reading frame codes for 337 amino acids (36651Da)
and is 63.5% identical to the human erythrocytic GAPDH. GAPDH sequences from
several field isolates of P. falciparum displayed 100% conservation. Phylogenetic
analysis supports the hypothesis that dinoflagellates and Plasmodium are closely
related. The protein encoded by the pfGAPDH was expressed recombinantly in
Escherichia coli and exhibited enzymatic activity with NAD(+) but not with
NADP(+) as cofactor. Antiserum raised against the recombinantly expressed enzyme
detected specifically all developmental stages of cultured P. falciparum blood
stage parasites.
PMID- 10767549
TI - Characterization of the recombinase activating gene-1 and 2 locus in the Japanese
pufferfish, Fugu rubripes.
AB - The recombinase activating genes (RAG1 and RAG2) encode nuclear proteins that
directly mediate the mechanism V(D)J recombination process that occurs in T- and
B-lymphocytes. The expression of RAG1 and RAG2 is required for the proper
development of maturing lymphocytes. To identify evolutionary conserved
regulatory regions adjacent to both genes we isolated and sequenced a cosmid
clone containing 43kb of genomic DNA of the Japanese pufferfish, Fugu rubripes.
Fugu has a haploid genome of 400Mb and contains the same number of genes as the
genome of higher vertebrates. With low abundance of repetitive DNA, the genome of
the pufferfish has shown to be ideal for comparative genomics. We found three
complete genes, RAG1, RAG2 and ACS (a possible homologue of the plant 1
aminocyclopropane-carboxylate synthase gene). There is also the 5' exon of a
prohormone convertase gene, possibly PACE4. The genetic structure of both RAG1
and RAG2 is identical to that found in other fish, but the size of the intergenic
region is smaller in Fugu. Expression analysis by RT-PCR shows the presence of
RAG transcripts in kidney of adult Fugu. The human ACS was identified in a cosmid
assigned to chromosome 11p11, which is close to the location of the RAGs (11p12).
This indicates conservation of linkage between human and pufferfish.
PMID- 10767548
TI - Refining the DFNB7-DFNB11 deafness locus using intragenic polymorphisms in a
novel gene, TMEM2.
AB - The combined DFNB7-DFNB11 deafness locus maps to chromosome 9q13-q21 between
markers D9S1806 and D9S769. We have determined the cDNA sequence and genomic
structure of a novel gene, TMEM2, that maps to this interval and is expressed in
the cochlea. The mouse orthologue of this gene (Tmem2) maps to the murine dn
(deafness) locus on mouse chromosome 19. Screens for transmembrane helices reveal
the presence of at least one putative transmembrane domain in the TMEM2 protein.
To determine whether mutations in TMEM2 cause hearing loss at the DFNB7-DFNB11
locus, we screened the coding region of this gene in DFNB7-DFNB11 affected
families by direct sequencing. All DNA variants that segregated with the deafness
and changed the predicted amino acid sequence of TMEM2 were common polymorphisms,
as demonstrated by allele-specific amplification of pooled control DNA. Northern
blot analysis showed no difference in transcript size or expression level of
Tmem2 in dn/dn and control mice. The intragenic polymorphisms in TMEM2 represent
a novel centromeric boundary for the DFNB7-DFNB11 interval.
PMID- 10767550
TI - Cloning and characterization of dRFX, the Drosophila member of the RFX family of
transcription factors.
AB - The RFX family of transcription factors is characterized by a unique DNA binding
domain. Five genes have been isolated in mammals, one gene in Caenorhabditis
elegans and in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae.
Whereas the roles of the RFX genes are beginning to be understood in yeasts, no
clear function has been reported in multicellular organisms, except for RFX5, the
most divergent member of the family. To study the physiological role of RFX
transcription factors using an alternative multicellular model, we report the
isolation and characterization of the Drosophila RFX gene (dRFX). The fruit fly
protein shares highly conserved domains with the mammalian factors RFX1 to 3 and
is more closely related to this subgroup. It binds DNA with the same target
specificity as mammalian factors RFX1 to 3. dRFX is located on chromosome III and
we characterized the entire locus. dRFX expression was analyzed during
embryogenesis. dRFX mRNAs are detected only in the peripheral nervous system and
in the brain of the embryo.
PMID- 10767551
TI - Molecular cloning of profilin from Tetrahymena thermophila.
AB - The actin-binding protein profilin was isolated from Tetrahymena thermophila by
affinity chromatography, and the peptide sequence was determined for part of the
protein. The cDNA sequence was obtained by using the peptide sequence, reverse
transcription-PCR and 5' and 3' RACE. The cDNA coded for a profilin of 16680Da,
which made it among the largest known profilins, and it had a predicted
isoelectric point of 8.27. The deduced amino acid sequence was divergent from
other profilins, having more than 26% identity only with profilin from
Tetrahymena pyriformis. The sequence contained insertions that are also present
in profilins from Tetrahymena pyriformis and Trypanosoma brucei. There appeared
to be only a single profilin gene and one transcript from this gene.
PMID- 10767552
TI - The structure and expression of the human neuroligin-3 gene.
AB - The neuroligins are a family of proteins that are thought to mediate cell to cell
interactions between neurons. During the sequencing at an Xq13 locus associated
with a mental retardation syndrome in some studies, we discovered a portion of
the human orthologue of the rat neuroligin-3 gene. We now report the structure
and the expression of that gene. The gene spans approximately 30kb and contains
eight exons. Unlike the rat gene, it codes for at least two mRNAs and at least
one of which is expressed outside the CNS. Interestingly, the putative promoter
for the gene overlaps the last exon of the neighboring HOPA gene and is located
less than 1kb from an OPA element in which a polymorphism associated with mental
retardation is found. These findings suggest a possible role for the neuroligin
gene in mental retardation and that the role of the gene in humans may differ
from its role in rats.
PMID- 10767553
TI - HNF3beta and GATA-4 transactivate the liver-enriched homeobox gene, Hex.
AB - The orphan homeobox gene, Hex, has a limited domain of expression which includes
the developing and adult mouse liver. Hex is expressed in the developing liver
coincident with the forkhead/winged helix transcription factor, Hepatocyte
Nuclear Factor 3beta (HNF3beta). Although preliminary characterization of the
mouse Hex promoter has recently been reported, the identity of the molecular
regulators that drive liver expression is not known. We hypothesized that
putative HNF3beta and GATA-4 elements within the Hex promoter would confer liver
enriched expression. A series of Hex promoter-driven luciferase reporter
constructs were transfected in liver-derived HepG2 and fibroblast-like Cos
cells+/-HNF3beta or GATA expression plasmids. The Hex promoter region from nt
235/+22 conferred basal activity in both HepG2 and Cos cells, with the region
from -103/+22 conferring liver-enriched activity. HNF3beta and GATA-4
transactivated the promoter via response elements located within nt -103/+22,
whereas Sp1 activated the -235/+22 construct. Mutation of the HNF3 element
significantly reduced promoter activity in HepG2 cells, whereas this element in
isolation conferred HNF3beta responsiveness to a heterologous promoter.
Electrophoretic mobility shift assays were performed to confirm transcription
factor:DNA binding. We conclude that HNF3beta and GATA-4 contribute to liver
enriched expression of Hex.
PMID- 10767554
TI - PCR-mediated gene replacement in Escherichia coli.
AB - The hyper-recombinogenic properties of an E. coli strain in which the recBCD
genes have been replaced by lambda red recombination functions were exploited in
the development of a general PCR-mediated gene replacement scheme for Escherichia
coli. Linear DNA substrates generated by recombinant PCR are introduced by
electroporation into strains containing the recBCDDelta::red substitution. This
technique allows for gene replacement in E. coli without prior cloning of the
gene of interest. In addition, the counter-selectable marker sacB has been used
to construct unmarked precise gene deletions without the need to form sacB
containing plasmid integrates. In other experiments, electroporation of
recBCDDelta::red strains with high concentrations of linear DNA fragments
(derived from plasmid digests) gave linear transformation rates approaching 1% of
the survivors of electroporation. The placement of lambda red and gam at a locus
in the chromosome other than recBCD (galK) resulted in a strain that was as hyper
rec as one containing the lambda red for recBCD substitution. The gene
replacement technique described here has been used for the construction of
deletion-substitution alleles of lacZ and sulA, as well as six genes important
for general homologous recombination in E. coli. Three of these replacements were
performed without prior cloning of the genes.
PMID- 10767555
TI - Evolutionary relationships in Trypanosoma cruzi: molecular phylogenetics supports
the existence of a new major lineage of strains.
AB - For the purpose of investigating the evolutionary relationships among strains of
the human parasite Trypanosoma cruzi, we have determined the nucleotide sequence,
in 16 T. cruzi stocks, of a DNA fragment having approximately 1030 nucleotides in
length. Phylogenetic analyses show the presence of at least three major groups of
T. cruzi strains, a result that contradicts previous phylogenetic inferences
based on polymorphism data. We also performed an analysis of the relative extent
of nucleotide divergence among T. cruzi strains compared to the divergence
between Leishmania species, using the gene encoding pteridine reductase. The
results presented in this work show that the divergence among the most distant T.
cruzi strains is at least as high as the divergence between two different species
complexes of Leishmania, those containing L. major and L. mexicana.
PMID- 10767556
TI - cDNA cloning of acyl-CoA desaturase homologs in the silkworm, Bombyx mori.
AB - We have isolated two acyl-CoA desaturase clones from a pheromone gland cDNA
library by using the EST (expressed sequence tag) database of Bombyx mori. The
putative acyl-CoA desaturases encoded by the clones desat 1 (2029bp) and desat 2
(2341bp) have 98% identity, and both proteins show 61% identities to Trichoplusia
ni acyl-CoA Delta(11) desaturase. The deduced amino acid sequences conserve well
the histidine clusters that are catalytically essential for acyl-CoA desaturase
activity. Northern blot and RT-PCR analyses revealed that both transcripts of
desat 1 and desat 2 were expressed predominantly in the pheromone gland. Both
transcripts detected 3days before adult eclosion dramatically increased a day
before adult eclosion, keeping the mRNA levels high even after eclosion. These
results, combined with the fact that Delta(11) and Delta(10, 12) desaturation of
palmitate is a key step to synthesize pheromone in B. mori, suggest that the
desaturases encoded by desat 1 and desat 2 are involved in either or both of the
desaturation steps in the pheromone biosynthetic pathway of B. mori. The mRNA
levels of desat 1 and desat 2 were not affected by decapitation or injection of
the pheromone biosynthesis activating neuropeptide (PBAN) into the adult female
moth, suggesting that the transcription of desat 1 and desat 2 is not regulated
by PBAN. In addition to the clones in the pheromone gland, eight other clones
encoding the same Delta(9) desaturase homolog were found in an embryonic cDNA
library by searching from the EST database of B. mori. The deduced amino acid
sequence from one of the clones (desat 3) shows 79% identity to T. ni Delta(9)
desaturase but only 52% identity to the desaturases in the pheromone gland of B.
mori. Northern blot analysis showed that the mRNA corresponding to the desat 3
was detected in the ovary and fat body, but not in the pheromone gland. Abundance
of the Delta(9) desaturase clones (eight out of the 762 randomly sequenced
clones) in the library prepared from diapause-destined embryos (40h after
oviposition) suggests that the Delta(9) desaturase encoded by desat 3 plays an
important role in embryonic development in B. mori.
PMID- 10767557
TI - Molecular cloning of a novel human UDP-GalNAc:polypeptide N
acetylgalactosaminyltransferase, GalNAc-T8, and analysis as a candidate autosomal
dominant hypophosphatemic rickets (ADHR) gene.
AB - The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (ppGaNTase) family
of enzymes initiates mucin-like O-glycosylation of specific proteins. Using exon
prediction analysis on genomic sequence from human chromosome 12p13.3, we
identified novel exons that shared significant homology with the ppGaNTases. cDNA
library screening and RT-PCR produced the complete coding sequence of a novel
human ppGaNTase family member, designated GalNAc-T8. The open reading frame (ORF)
of GalNAc-T8 codes for a 637 amino acid, type-II membrane protein that is 45-60%
identical to the other mammalian ppGaNTases. GalNAc-T8 shares high homology
within the functional regions of the known ppGaNTases; however, the enzyme
possesses a novel residue substitution within a characteristic motif of the
catalytic domain. Northern analysis of multiple human tissue mRNAs demonstrated
that the 5.0 and 2.1kb GalNAc-T8 transcripts are widely expressed. The metabolic
disorder autosomal dominant hypophosphatemic rickets (ADHR) was previously mapped
to the region of chromosome 12p13.3 in which GalNAc-T8 resides. Using a
positional-candidate strategy for identifying the ADHR gene, GalNAc-T8 was
subjected to mutational analysis in DNA from ADHR individuals. We detected
multiple polymorphisms in the human GalNAc-T8 ORF, but did not find ADHR
mutations. In summary, these studies identified the human GalNAc-T8 gene, as well
as multiple genomic polymorphisms that will be useful for further understanding
the structure-function relations of the ppGaNTases.
PMID- 10767558
TI - Molecular evolution of growth hormone and receptor in the guinea-pig, a mammal
unresponsive to growth hormone.
AB - Growth in the guinea-pig is completely unresponsive to endogenous or exogenous
growth hormone, despite the fact that the guinea-pig produces normal to high
levels of growth hormone and receptor. In primates and artiodactyls, growth
hormone exhibits accelerated rates of evolution that appear to be correlated with
changes in function. Surprisingly, both guinea-pig growth hormone and receptor
exhibit slow rates of evolution similar to those seen in other mammals, implying
that both proteins are as functionally conserved in the guinea-pig as in other
mammals or that any loss or relaxation of functional constraint was very recent.
However, the guinea-pig growth hormone and receptor both exhibit a single amino
acid replacement at a site known to have functional significance. Nevertheless,
it is unclear whether the aberrant nature of the guinea-pig growth hormone-growth
hormone receptor axis is due to these replacements or whether it is due to a
defect in post-receptor signalling.
PMID- 10767559
TI - Positive and negative elements mediate control of alternative splicing in the
AMPD1 gene.
AB - The second exon of the AMP deaminase (AMPD) 1 gene is alternatively spliced in
response to stage-specific signals elaborated during myocyte differentiation.
Since inheritance of the mutation in exon 2 of the AMPD1 gene has been recently
shown to be associated with a better prognosis of congestive heart failure and
the alternative splicing of exon 2 modulates the residual activity of AMPD1 in
individuals with this mutant allele, the regulatory mechanism of alternative
splicing in the AMPD1 gene is clinically intriguing. Retention or exclusion of
exon 2 results from the interplay between negative and positive elements in the
primary transcript. Exon 2 is intrinsically defective and difficult to recognize.
Herein, we show that this property of exon 2 is the consequence of three defects;
a suboptimal 3' splice acceptor site, a suboptimal 5' splice donor site and the
small size of the exon. An improvement in any one of these defects relieves the
masking of this exon. Further, this defective exon can only be identified in the
presence of the adjacent downstream intron.
PMID- 10767560
TI - Mouse interferon-inducible RNA-dependent protein kinase Pkr gene: cloning and
sequence of the 5'-flanking region and functional identification of the minimal
inducible promoter.
AB - The RNA-dependent protein kinase (PKR) is implicated in the antiviral and
antiproliferative actions of interferon (IFN). As an extension of our structural
characterization of the exon-intron organization of the mouse Pkr gene, we now
have isolated and characterized the mouse Pkr promoter region required for IFN
inducible transcription. Transient transfection analyses, using reporter
constructs possessing various 5'-flanking fragments of the Pkr gene, led to the
identification of a functional IFN-inducible promoter. A single IFN-stimulated
response element (ISRE) was present in a minimal 44-nt TATA-less promoter
identified by deletion analysis; the 13-nt ISRE differed from previously
described ISRE elements in that the 3'-nt was a purine instead of a pyrimidine.
The sequence immediately upstream of the ISRE possessed the 15-nt KCS element
that was exactly conserved in sequence and position between the mouse and human
Pkr promoters. A single gamma IFN-activated sequence (GAS)-like element and
multiple recognition sites for factors including NF-kappaB and NF-IL6 involved in
responses to various cytokine and hormone signals in inflammatory responses were
also present in the 5'-flanking region. Northern blot analysis showed efficient
IFN-alpha induced accumulation of 2.4kb, 4.5kb and approx. 6kb Pkr transcripts,
but neither IFN-gamma nor IL-6 induced detectable Pkr mRNA accumulation in L
cells.
PMID- 10767561
TI - Isolation, characterization, and differential expression of the murine Sox-2
promoter.
AB - Sox proteins are expressed at many stages of development and in numerous tissues.
The transcription factor Sox-2 is first expressed throughout the inner cell mass
and subsequently becomes localized to the primitive ectoderm, developing central
nervous system, and the lens. Sox-2 is also highly expressed in F9 embryonal
carcinoma cells, but becomes undetectable following differentiation of these
cells. In this study, we have isolated, sequenced, and performed the first
characterization of the Sox-2 promoter of any species. Approximately 2kb of the
Sox-2 5'-flanking region has been sequenced and the primary transcription start
site mapped by primer extension analysis. Additionally, two positive regulatory
regions within the promoter region have been identified. We also show that
expression of Sox-2 promoter/reporter gene constructs is reduced in
differentiated EC cells as compared to their undifferentiated counterparts.
Furthermore, we have identified a consensus inverted CCAAT box motif present in
the Sox-2 promoter. Mutagenesis of this site significantly reduces the expression
of Sox-2 promoter/reporter constructs. We also demonstrate that this CCAAT box
motif can bind the trimeric transcription factor NF-Y.
PMID- 10767562
TI - NBP1 (Nap1 binding protein 1), an essential gene for G2/M transition of
Saccharomyces cerevisiae, encodes a protein of distinct sub-nuclear localization.
AB - Nap1p is identified in mammalian cell extract by its intrinsic activity to
facilitate nucleosome assembly in vitro in the physiological ionic condition. The
homologous proteins are present in most eukaryotes, and their functional analyses
in vitro have suggested that they are necessary to keep proper nucleosome
structures in transcription and replication. This protein is also identified for
its interaction with Clb2p in vitro. To address the function of Nap1p in vivo, we
have surveyed for proteins to interact with Nap1p by two-hybrid system and
obtained two genes, NBP1 and NBP2 (Nap1 Binding Protein 1 and 2). NBP1 is an
essential gene and encodes a novel protein consisting of 319 amino acids, with a
coiled-coil structure in the center of the predicted amino acid sequence. Several
A-kinase dependent phosphorylation sites and Cdc28p kinase-dependent sites are
also observed. By isolating the temperature-sensitive mutant, we demonstrate that
the nuclear division at a non-permissive temperature is delayed and that the
population of cells with a large bud carrying a single nucleus with a short
spindle are increased. This mutant also confers resistance against benomyl, a
microtubule-destabilizing agent. Judging from the green fluorescent protein (GFP)
signal fused with Nbp1p, this protein localizes in the nucleus as one or two tiny
dots.
PMID- 10767563
TI - Determination of baseline human nasal pH and the effect of intranasally
administered buffers.
AB - The nose is becoming a common route of drug administration, however, little is
known about the pH of the human nasal cavity. Local pH may have a direct effect
on the rate and extent of absorption of ionizable compounds and hence this study
was performed to investigate normal pH values and whether pH could be manipulated
by various buffers. Twelve healthy volunteers participated in a study to measure
pH in the anterior and posterior sites of the nasal cavity. Miniature pH
electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded
for 30 min once the pH had stabilized. One hundred microlitres of isotonic
solution was sprayed into the nostril and the pH was measured for 4 h post-dose.
The following five formulations were tested: formulation A--sodium chloride
(0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C-
Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens
phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but
adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a
taste marker for nasal clearance. The time at which each subject detected the
taste of saccharin was noted. The 30-minute baseline recording prior to
administration of the nasal spray formulation demonstrates that there was both
considerable intersubject and intrasubject variation in nasal pH. The average pH
in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from
H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18
S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for
posterior pH. Formulation A caused the pH in the anterior part of the nasal
cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14
(P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which
did not change over the recording period. Formulation B caused the anterior pH to
increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean
pH of 7.07 over the first hour which was still significantly above the baseline.
It remained at this value for the remainder of the recording period. The initial
average posterior pH was 6.32 and again this did not significantly change over
the recording period. Formulation C produced a sustained increase in anterior
nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed
in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established
within 15 min post dose. Formulation D significantly reduced anterior nasal pH
from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for
the remainder of the recording period. The posterior baseline pH was 6.3 and
introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6.
Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the
recording period. It had an insignificant effect on posterior nasal pH. The mean
(+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21,
14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was
no significant difference between the clearance times for the different
formulations. In conclusion, average baseline human nasal pH is approximately
6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are
used. Mildly acidic solutions produce an increase in pH presumably due to reflux
bicarbonate secretion. Posterior nasal pH was not altered by administration of
any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior
pH.
PMID- 10767564
TI - In vivo effects of highly purified docosahexaenoic acid on rectal insulin
absorption.
AB - The purpose of this study was to evaluate the effectiveness and the toxicity of
polyunsaturated fatty acid, such as oleic acid, eicosapentaenoic acid (DHA), as
potential absorption enhancer for rectal delivery of insulin, using a water-in
oil-in water (W/O/W) multiple emulsion. In a single administration study, rectal
insulin absorption was enhanced markedly, and marked hypoglycemia was induced by
the emulsion incorporating various fatty acids in an insulin dose-related
fashion. The pharmacological availability of the emulsion incorporating 2% oleic
acid, EPA and DHA was approximately 7.7, 11.0 and 25.4%, respectively. The
insulin absorption enhancement effect was not increased in proportion to the
amount of DHA in the emulsion, the mean T(max) value of the serum glucose-time
curve could be extended to twice that of the emulsion without PF 127. In a
multiple administration study, the mean AUC(glucose) values of the emulsion
incorporating DHA showed almost the same value on the first and the tenth day.
From the morphological appearance of the mucosal surface, the emulsion
incorporating DHA induced no or little mucosal damage. Our findings demonstrated
that DHA has a strong insulin permeability enhancement effect and little
toxicity. Thus, DHA is an attractive candidate as an absorption enhancer for
intestinal delivery of insulin.
PMID- 10767565
TI - Effect of matrix composition and process conditions on casein-gelatin beads
floating properties.
AB - Casein-gelatin beads have been prepared by emulsification extraction method and
cross-linked with D,L-glyceraldehyde in an acetone-water mixture 3:1 (v/v).
Casein emulsifying properties cause air bubble incorporation and the formation of
large holes in the beads. The high porosity of the matrix influences the bead
properties such as drug loading, drug release and floatation. These effects have
been stressed by comparison with low porous beads, artificially prepared without
cavities. The percentage of casein in the matrix increases the drug loading of
both low and high porous matrices, although the loading of high porous matrices
is lower than that of low porous matrices. As a matter of fact, the drug should
be more easily removed during washing and recovery because of the higher
superficial pore area of the beads. This can explain the drug release rate
increase, observed in high porous matrix, in comparison with beads without
cavities. This is due to the rapid diffusion of the drug through water filled
pores. The study shows that cavities act as an air reservoir and enable beads to
float. Therefore, casein seems to be a material suitable to the inexpensive
formation of an air reservoir for floating systems.
PMID- 10767566
TI - Structural relationship and desolvation behavior of cromolyn, cefazolin and
fenoprofen sodium hydrates.
AB - The hydrated crystal structures of cromolyn, cefazolin, and fenoprofen sodium
salts are reported. The former two compounds are non-stoichiometric hydrates,
whereas the fenoprofen lattice maintains its stoichiometry over a broad range of
relative humidity. The relationship between composition, lattice parameters, and
relative humidity is studied using a combination of moisture sorption isotherms
and variable humidity X-ray powder diffraction. The dehydration properties of the
sodium salts are related to the ion coordination and hydrogen bonding of the
water molecules in the structures. Anisotropic lattice contraction is observed
during dehydration of the cromolyn and cefazolin sodium and is related to the
closeness of intermolecular contacts in the hydrated structures.
PMID- 10767567
TI - The effect of terpene enhancer lipophilicity on the percutaneous permeation of
hydrocortisone formulated in HPMC gel systems.
AB - The percutaneous permeation of hydrocortisone (HC) was investigated in hairless
mouse skin after application of an alcoholic hydrogel using a diffusion cell
technique. The formulations contained one of 12 terpenes, the selection of which
was based on an increase in their lipophilicity (log P 1.06-5.36). Flux,
cumulative receptor concentrations, skin content, and lag time of HC were
measured over 24 h and compared with control gels (containing no terpene).
Furthermore, HC skin content and the solubility of HC in the alcoholic hydrogel
solvent mixture in the presence of terpene were determined, and correlated to the
enhancing activity of terpenes. The in vitro permeation experiments with hairless
mouse skin revealed that the terpene enhancers varied in their ability to enhance
the flux of HC. Nerolidol which possessed the highest lipophilicity (log P =
5.36+/-0.38) provided the greatest enhancement for HC flux (35.3-fold over
control). Fenchone (log P = 2.13+/-0.30) exhibited the lowest enhancement of HC
flux (10.1-fold over control). In addition, a linear relationship was established
between the log P of terpenes and the cumulative amount of HC in the receptor
after 24 h (Q(24)). Nerolidol, provided the highest Q(24) (1733+/-93
microg/cm(2)), whereas verbenone produced the lowest Q(24) (653+/-105
microg/cm(2)). Thymol provided the lowest HC skin content (1151+/-293 microg/g),
while cineole produced the highest HC skin content (18999+/-5666 microg/g). No
correlation was established between the log P of enhancers and HC skin content. A
correlation however, existed between the log P of terpenes and the lag time. As
log P increased, a linear decrease in lag time was observed. Cymene yielded the
shortest HC lag time, while fenchone produced the longest lag time. Also, the
increase in the log P of terpenes resulted in a proportional increase in HC
solubility in the formulation solvent mixture.
PMID- 10767568
TI - Effect of synthesized cyclohexanol derivatives using L-menthol as a lead compound
on the percutaneous absorption of ketoprofen.
AB - L-Menthol was selected as a lead compound to synthesize new candidates for
percutaneous absorption enhancers. In a previous study, O-ethylmenthol (MET) was
the most effective compound and caused relatively little skin irritation. To
develop more effective compounds, mono- or disubstitute groups of cyclohexane
with an O-ethyl group were synthesized. Some 35 compounds were synthesized and
evaluated for their promoting activity and effect on skin. An in vivo
percutaneous absorption study was performed using rats with hydrogel containing
ketoprofen and each of the synthesized compounds. The plasma concentration of
ketoprofen was determined after the application of hydrogel to the abdominal area
of rats. The apparent penetration rate (R(p)) was estimated based on the
pharmacokinetic model with a constant rate of penetration through the skin after
the lag time. The 2-compartment model was applied to the data obtained from the
iv administration. As an index to evaluate the promoting activity of each
enhancer, an enhancement factor (E(f)) was defined as follows: E(f) = R(p) (with
enhancer)/R(p) (without enhancer). Irritation to skin was pathologically
evaluated. The treated area of rat abdominal skin was excised after the in vivo
experiment using total irritation score (TIS). The compound having a C-3
positioned iso-butyl group on the chemical structure was the most effective and
caused relatively little irritation among mono-substituted compounds. In the case
of di-substituted compounds, all had the same effect as or a stronger effect than
MET. Furthermore, the promoting activity almost corresponded to irritation. To
estimate log P, one of the physicochemical properties of molecules, a computer
program 'CAChe' was employed. The log P was calculated using the atom typing
scheme. Multiple regression analysis revealed that the relations between E(f) or
TIS and log P were parabolic. It was suggested that the optimum logP value
reflects the promoting activity to enhance percutaneous absorption of ketoprofen.
PMID- 10767569
TI - Wettability studies of morphine sulfate powders.
AB - A capillary penetration technique was used to determine the wettability of
morphine sulfate powders by a range of wetting and partially wetting liquids.
Wetting rates were found to be dependent on both the properties of the wetting
liquid and the morphine sulfate batch. A number of liquids were established as
perfectly wetting, and the critical surface tension for morphine sulfate wetting
was estimated to be approximately 40 mN m(-1). Effective capillary radii for
packed beds of morphine sulfate powders were determined in the range 0.3-0.6
microm; these are compared with particle size, shape and surface area data. From
the Washburn approach, the advancing water-particle contact angles for the
different morphine sulfate samples were determined to be in the range 57-79
degrees, with errors less than +/-3 degrees. Sessile drop measurements on the
same samples were unable to determine reproducible equilibrium contact angles and
could not differentiate between the batches. The role of surface chemistry,
crystal morphology and crystal structure in controlling morphine sulfate powder
wettability was explored by X-ray photoelectron spectroscopy (XPS), scanning
electron microscopy (SEM) and X-ray diffraction. Contact angles were shown to
correlate with both the aspect ratio of the morphine sulfate crystals and the
nitrogen-to-oxygen surface atomic concentration ratio, determined by SEM and XPS,
respectively. The relative exposure of different crystal faces is considered to
play an important role in controlling the wettability of morphine sulfate
powders.
PMID- 10767570
TI - Formulation and characterisation of primaquine loaded liposomes prepared by a pH
gradient using experimental design.
AB - The effect of different formulation factors (lipid type, cholesterol, charge,
internal buffer capacity, drug-to-lipid incubation ratio) on the encapsulation
efficiency and size of primaquine liposomes (SUV's) in response to a pH gradient
was investigated by a fractional factorial screen ing design. Three of the
factors (charge, internal buffer capacity, drug -to-lipid incubation ratio) were
further studied in a Box--Behnken optimisation design. The lipid type was the
most important parameter followed by the drug-to-lipid incubation ratio, buffer
capacity, cholesterol and charge. Several of the interactions wer e important. In
the optimisation design a robust region with high encapsulation efficiency (>95%)
was obtained for DSPC: 33.33 mol% cholesterol-liposomes at high internal citrate
concentration (200 mM) by maintaining the drug-to-lipid incubation ratio below
0.15:1 (mol:mol) and varying the charge incorporation between 2 and 10%. In order
to achieve long-term stability and sterility, the liposomes were lyophilised
followed by gamma irradiation. The pH gradient was maintained during this
treatment with little chemical degradation of the substances. The final
preparation consisted of three separate vials with lyophilised liposomes, solid
state primaquine and hydration medium.
PMID- 10767571
TI - Membrane penetration enhancement of ibuprofen using supersaturation.
AB - Permeation enhancement of ibuprofen from supersaturated solutions formed using
the cosolvent technique was investigated using silicone as a model membrane.
Hydroxpropyl methyl cellulose and hydroxpropyl-beta-cyclodextrin were used to
stabilise the supersaturated states. Physical stability studies showed best
results for low drug concentrations in a 40:60 propylene glycol/water cosolvent
system. Variations in flux across model silicone membranes from saturated
solutions were observed as the PG content was increased. The flux of IBU
increased with the degree of saturation for solutions prepared in a 40:60
PG/water cosolvent mixture. HPMC and CD were found to be effective in enhancing
the stability of supersaturated solutions of IBU. The mechanisms of action are
different for the two additives and are discussed.
PMID- 10767572
TI - Salt form selection and characterization of LY333531 mesylate monohydrate.
AB - LY333531 is a potent protein kinase C(beta) (PKC(beta)) inhibitor currently under
development for the treatment of diabetic complications. Seven salts of LY333531
(hydrochloride, sulfate, mesylate, succinate, tartrate, acetate and phosphate)
were evaluated during the early phase of development. Physical property screening
techniques including microscopy, DSC, TGA, XRPD, hygroscopicity and solubility
were utilized to narrow the selection to two salts: the mesylate and
hydrochloride. Identification of the optimal salt form was based upon solubility,
bioavailability, physical stability and purity. During the evaluation process
three hydrated forms (anhydrate, monohydrate, and tetrahydrate) of the
hydrochloride salt were identified. The mesylate salt was found to give only one,
a monohydrate. Processing parameters (e.g. filtration rate, crystal form
stability) demonstrated that the anhydrate was the preferred form of the
hydrochloride salt. Bioavailability studies in dogs indicated that the C(max) and
area under the plasma concentration vs. time curve (AUC) for LY333531 and its
active metabolite, LY338522, following administration of the mesylate salt were
approximately 2.6 times those obtained after the LY333531 HCl dose. This
difference was presumed to be due primarily to the fact that the mesylate was
five times more soluble than the hydrochloride salt in water. These factors led
to selection and development of LY333531 mesylate monohydrate as the active
pharmaceutical ingredient for clinical evaluation.
PMID- 10767573
TI - When lysosomes get old.
AB - Changes in the lysosomes of senescent tissues and organisms are common and have
been used as biomarkers of aging. Lysosomes are responsible for the degradation
of many macromolecules, including proteins. At least five different pathways for
the delivery of substrate proteins to lysosomes are known. Three of these
pathways decline with age, and the molecular explanations for these deficiencies
are currently being studied. Other aspects of lysosomal proteolysis increase or
do not change with age in spite of marked changes in lysosomal morphology and
biochemistry. Age-related changes in certain lysosomal pathways of proteolysis
remain to be studied. This area of research is important because abnormalities in
lysosomal protein degradation pathways may contribute to several characteristics
and pathologies associated with aging.
PMID- 10767574
TI - G protein-dependent signalling and ageing.
PMID- 10767575
TI - Biochemistry of Indian summer: physiology of autumnal leaf coloration.
AB - The autumnal coloration of foliage in deciduous trees represents a most
spectacular phytogerontological phenomenon. It is primarily due to the
progressive loss of chlorophyll coinciding with the partial retention of
carotenoids. Leaf senescence is a developmental process that is aimed at the
recycling of nutrients to perennial parts of the tree for reuse upon the
production of new foliage in spring. The remobilization of protein in senescing
chloroplasts requires the dismantling of pigment-protein complexes and
concomitant photodynamic inactivation of chlorophyll. Detoxification of
chlorophyll is achieved by enzymic opening of the porphyrin macrocycle followed
by modifications of the resulting linear tetrapyrrole and storage of colorless
final catabolites in the vacuoles of degreening leaf cells. The polychromatic
beauty of autumnal trees is due to species-specific variations of the degree of
carotenoid retention, new synthesis of red anthocyanins and, upon cell death, the
formation of dark oxidation products of phenolics.
PMID- 10767576
TI - Age-dependent changes in B lymphocyte development in man and mouse.
AB - In recent years, detailed analyses of B cell development in both humans and mice
have revealed similar subsets of precursors along the same pathway of
differentiation. From these studies it also became clear that both species
undergo age related changes in this B lymphocyte development program. In this
review we summarize these findings and discuss, potential mechanisms underlying
these age related changes, and possible causative correlations between these
changes and age related B cell abnormalities.
PMID- 10767577
TI - Forward and reverse selection for longevity in Drosophila is characterized by
alteration of antioxidant gene expression and oxidative damage patterns.
AB - Patterns of antioxidant gene expression and of oxidative damage were measured
throughout the adult life span of a selected long-lived strain (La) of Drosophila
melanogaster and compared to that of their normal-lived progenitor strain (Ra).
Extended longevity in the La strain is correlated with enhanced antioxidant
defense system gene expression, accumulation of CuZnSOD protein, and an increase
in ADS enzyme activities. Extended longevity is strongly associated with a
significantly increased resistance to oxidative stress. Reverse-selecting this
long-lived strain for shortened longevity (RevLa strain) yields a significant
decrease in longevity accompanied by reversion to normal levels of its
antioxidant defense system gene expression patterns and antioxidant enzyme
patterns. The significant effects of forward and reverse selection in these
strains seem limited to the ADS enzymes; 11 other enzymes with primarily
metabolic functions show no obvious effect of selection on their activity levels
whereas six other enzymes postulated to play a role in flux control may actually
be involved in NADPH reoxidation and thus support the enhanced activities of the
ADS enzymes. Thus, alterations in the longevity of these Drosophila strains are
directly correlated with corresponding alterations in; 1) the mRNA levels of
certain antioxidant defense system genes; 2) the protein level of at least one
antioxidant defense system gene; 3) the activity levels of the corresponding
antioxidant defense system enzymes, and 4) the ability of the organism to resist
the biological damage arising from oxidative stress.
PMID- 10767578
TI - Subtractive hybridization of mRNA from early passage and senescent endothelial
cells.
AB - Regulation of cellular processes that eventually lead to a state of growth arrest
is an important manifestation of in vitro cellular senescence caused and
accompanied by variations of the gene expression pattern. Whereas these changes
at the mRNA level have been studied mainly in fibroblast cultures, we
concentrated on endothelial cells that represent an accepted model for vascular
systems and may be involved in the pathogenesis of diseases related to aging. To
isolate differentially expressed genes, we created a subtractive cDNA library
using mRNA from senescent (35 passages) and young (five passages) human umbilical
vein endothelial cells (HUVECs). Candidate clones were isolated from the cDNA
library, differential expression was confirmed by Northern blot analyses and
sequences were compared with a genbank data base. Because many mRNAs were below
the detection limit of Northern blot analysis, we were forced to establish a more
sensitive PCR based method (ATAC-PCR) to quantify and confirm altered levels of
gene expression. Several mRNAs were found to be upregulated in senescent HUVECs
including two components of the extracellular matrix (ECM): plasminogen activator
inhibitor and fibronectin. Elevated expression of both has already been described
in senescent cells. The mRNAs of TGF-beta-inducible gene H3 (beta-IG-H3; ECM
protein), insulin-like growth factor binding protein (IGFBP-3), p53-inducible
gene (PIG3) a protein involved in vesicular transport (SEC13R) and ribosomal
protein L28 have likewise been shown to be preferentially expressed in senescent
cells. Because studies support the involvement of ECM components, TGF-beta and
p53 in tumor suppressing mechanisms, our data supports the hypothesis that
cellular senescence and upregulation of ECM proteins may be associated with tumor
preventive functions.
PMID- 10767580
TI - Surface markers and transendothelial migration of dendritic cells from elderly
subjects.
AB - Age-related changes of immune functions have been extensively investigated in
both humans and animal models; nevertheless, the literature on potential
alterations of dendritic cells, potent antigen presenting cells responsible for
initiating immune responses, with aging is very scarce. We studied the immuno
phenotype of peripheral blood dendritic cells of elderly and young subjects by
three-color flow cytometry. In addition, the capacity of transendothelial
migration, an important step in inflammatory reactions, of peripheral blood
dendritic cells of elderly subjects was investigated in an in vitro model. The
expression of HLA-DR in the peripheral blood dendritic cells of the elderly
subjects was significantly decreased when compared to the young control subjects.
The expression of various other surface markers was similar in the young and
elderly subjects. The ability of transendothelial migration of dendritic cells
was found to be unimpaired in the elderly subjects. Both in the young and elderly
subjects a significantly higher expression of CD29, CD86, HLA-DR, and HLA-DQ in
the dendritic cells that had migrated through the endothelium in comparison to
nonadherent, nonmigrating cells was found. In the migrating dendritic cells of
the elderly subjects a significantly increased expression of CD11c was observed,
whereas the expression of CD54 was significantly enhanced in the migrating
dendritic cells of the young subjects only. In conclusion, our results
demonstrate intact functions and a normal immunophenotype of dendritic cells
derived from elderly subjects. Dendritic cells thus seem to be functional and
therefore are not responsible for the well-known decline of T cell functions with
aging.
PMID- 10767579
TI - Catalase expression in delayed and premature aging mouse models.
AB - The physiological decline that occurs with aging is thought to result, in part,
from accumulation of oxidative damage produced by reactive oxygen species (ROS)
generated during normal metabolism. Two genetic mouse models of aging, the Ames
dwarf and growth hormone (GH) transgenic, suggest that hormone levels may play a
role in antioxidative defense and aging. To explore this possibility, catalase
(CAT), an enzyme involved in elimination of ROS, was evaluated in long-lived
dwarf and short-lived transgenic mice. Catalase activity and/or protein was
significantly elevated in livers from dwarf mice at 3, 6, 13-15, and 24 months of
age when compared to age-matched wild type mice. In contrast, a 50 and 38%
reduction (P<0.05) in CAT protein was observed in 3 and 10 to 12 month old GH
transgenics respectively, when compared to wild type mice. Kidneys from old dwarf
mice exhibited significantly increased CAT activity (22%), protein (16%) and mRNA
expression (59%) compared to wild type mice. Conversely, kidneys from GH
transgenic mice showed reductions in CAT activity. The results of this study
suggest that hormonal status modulates antioxidative mechanisms and that CAT is
important in overall defense capacity with respect to lifespan in both
decelerated (dwarf) and accelerated (transgenic) mammalian models of aging.
PMID- 10767581
TI - Effect of aging on cytokine production in normal and experimental systemic lupus
erythematosus-afflicted mice.
AB - Aging mice of strains susceptible to the induction of experimental systemic lupus
erythematosus (SLE) develop a milder disease than young animals. To find out
whether the decrease in susceptibility to disease is due to age-associated
changes in cytokine profile, we first examined the secretion of cytokines by
healthy mice aged 2-15 months. A gradual age-related decline in the levels of
interleukin (IL)-2 and interferon (IFN) gamma, and an increase in IL-4, IL-10, IL
1, and tumor necrosis factor (TNF) alpha were observed. Experimental SLE was
induced in 2- and 10-month-old mice by immunization with the monoclonal anti-DNA
antibody bearing the 16/6 Id. Early increased production of pro-inflammatory
cytokines (TNFalpha and IL-1), followed by a peak of the Th1-type cytokines (IL
2, IFNgamma) were observed in young mice. The Th2-type cytokines (IL-4, IL-10)
peaked later. In contrast, only a mild increase in all of the above cytokines was
determined in 10-month immunized mice. It thus appears that the decline in
susceptibility to SLE induction in older mice may be related to changes in the
capacity to produce cytokines.
PMID- 10767582
TI - Decreased in vitro sensitivity to dexamethasone in corticotropes from middle-age
rats.
AB - A disregulation of the hypothalamic-pituitary-adrenal (HPA) axis due to a decline
of negative feedback regulation is a consistent feature of the aging process.
Hippocampus has been proposed to be a primary site responsible for this
alteration in the HPA axis in aging in rat. In this study an alternative
hypothesis that the decreased sensitivity of the HPA axis to glucocorticoids in
aging occurs directly in pituitary corticotropes has been tested. The sensitivity
of corticotropes isolated from 2- and 13-month old male Sprague-Dawley rats to
dexamethasone (DEX) in vitro was examined using a modification of the combined
DEX/CRH challenge test that was originally designed for investigation of relative
glucocorticoid resistance in vivo. No significant difference in basal ACTH
production by corticotropes from the two age groups was detected. Corticotropes
from middle-aged rats showed a diminished response of ACTH to CRH stimulation.
DEX treatment did not cause a significant inhibition of either basal or CRH
stimulated ACTH release in corticotropes from middle-aged rats. These findings
demonstrate an age-related decrease in the sensitivity of corticotropes to
glucocorticoids in vitro suggesting that there is a direct, pituitary-mediated
dysregulation of the HPA axis in rat starting as early as middle age.
PMID- 10767583
TI - The effect of rivastigmine on sleep in elderly healthy subjects.
AB - Previous research has shown that acetylcholinesterase inhibitors may affect REM
sleep, however, results are inconclusive. From the present findings it is
concluded that the effects of rivastigmine, a reversible acetycholinesterase
inhibitor, on REM sleep are more pronounced in the elderly where we found REM
latency to be significantly reduced. This may be explained by better
bioavailability and/or by reduced stability of the circadian rhythmicity in
elderly individuals. Because rivastigmine is used in the treatment of Alzheimer's
disease, further research investigating the relationship between the REM
enhancing properties of rivastigmine and cognitive functioning seems promising.
PMID- 10767584
TI - CT number variations due to different image acquisition and reconstruction
parameters: a thorax phantom study.
AB - A humanoid thorax phantom containing six compartments was scanned with two
different computed tomography (CT) scanners using various image acquisition and
reconstruction parameters. The differences of CT numbers were statistically
significant between the two CT scanners for each compartment (p<0.001) except for
the "air" compartment. The variabilities of the CT numbers are described for the
different parameters. The mean CT numbers of the "water" compartment, for
instance, ranged from 1 to 15HU (Hounsfield Units), those of the "air"
compartment varied from -962 to -990HU. Knowledge of these CT number
variabilities is necessary when CT numbers are used for tissue characterization.
PMID- 10767585
TI - Wavelet-based histogram equalization enhancement of gastric sonogram images.
AB - The gray levels of gastric sonogram images are usually concentrated at the zero
end of the spectrum, making the image too low in contrast and too dark for the
naked eye. Though histogram equalization can enhance the contrast by
redistributing the gray levels, it has the drawback that it reduces the
information in the processed image. In this paper, a wavelet-based enhancement
algorithm post-processor is used to further enhance the image and compensate for
the information loss during histogram equalization. Experimental results show
that the wavelet-based enhancement algorithm can enhance the contrast and
significantly increase the informational entropy of the image. Because the
combination of the histogram equalization and wavelet approach can dramatically
increase the contrast and maintain information rate in gastric sonograms, it has
the potential to improve clinical diagnosis and research.
PMID- 10767586
TI - How blurry is that border? An investigation into algorithmic reproduction of skin
lesion border cut-off.
AB - This paper describes an approach to algorithmically measuring the second of the
ABCD criteria [Stolz W, Braun-Falco O, Bilek P, Landthaler M, Cognetta AB. Color
atlas of dermatoscopy. Oxford: Blackwell Science Ltd, 1994], border cut-off. The
method measures the lightness gradient of the lesion at the boundary. Gradients
are assigned to "blurry" or "sharp cut-off" on the basis of a threshold obtained
by comparing dermatologists' opinions with the algorithm. The algorithm appears
to correlate quite well with dermatologists' opinions, although several concerns
are apparent, especially the distribution of the image set. This algorithm
presents a first step at measuring border cut-off and eventually, reproducing the
ABCD criteria [Stolz W, Braun-Falco O, Bilek P, Landthaler M, Cognetta AB. Color
atlas of dermatoscopy. Oxford: Blackwell Science Ltd, 1994].
PMID- 10767587
TI - Generation of fractal dimension images and its application to automatic edge
detection in brain MRI.
AB - We have developed four methods to generate a fractal dimension image and have
applied them to the brain MRI. We have adopted four types of scanning methods,
"CONVENTIONAL", "OVERLAPPING", "SYMMETRIC" and "FOLDED" to estimate the fractal
dimension. The first three methods show almost the same fractal dimension images
and their values were between two and three. In the "FOLDED" method, we were able
to obtain the images in which the edge of a narrow region including dura and
scalp surrounding the brain was selectively enhanced in the T1-weighted MRI. This
is found to be a new edge-enhancing filter. We could remove the surrounding
structure of the brain by using these filtered images and detect the edge of the
brain surface automatically. The brain surface data can be used for various
applications such as three-dimensional surface display and registration of inter
modal brain images.
PMID- 10767588
TI - Multi-level adaptive segmentation of multi-parameter MR brain images.
AB - MR brain image segmentation into several tissue classes is of significant
interest to visualize and quantify individual anatomical structures.
Traditionally, the segmentation is performed manually in a clinical environment
that is operator dependent and may be difficult to reproduce. Though several
algorithms have been investigated in the literature for computerized automatic
segmentation of MR brain images, they are usually targeted to classify image into
a limited number of classes such as white matter, gray matter, cerebrospinal
fluid and specific lesions. We present a novel model-based method for the
automatic segmentation and classification of multi-parameter MR brain images into
a larger number of tissue classes of interest. Our model employs 15 brain tissue
classes instead of the commonly used set of four classes, which were of clinical
interest to neuroradiologists for following-up with patients suffering from
cerebrovascular deficiency (CVD) and/or stroke. The model approximates the
spatial distribution of tissue classes by a Gauss Markov random field and uses
the maximum likelihood method to estimate the class probabilities and
transitional probabilities for each pixel of the image. Multi-parameter MR brain
images with T(1), T(2), proton density, Gd+T(1), and perfusion imaging were used
in segmentation and classification. In the development of the segmentation model,
true class-membership of measured parameters was determined from manual
segmentation of a set of normal and pathologic brain images by a team of
neuroradiologists. The manual segmentation was performed using a human-computer
interface specifically designed for pixel-by-pixel segmentation of brain images.
The registration of corresponding images from different brains was accomplished
using an elastic transformation. The presented segmentation method uses the multi
parameter model in adaptive segmentation of brain images on a pixel-by-pixel
basis. The method was evaluated on a set of multi-parameter MR brain images of a
twelve-year old patient 48h after suffering a stroke. The results of
classification as compared to the manual segmentation of the same data show the
efficacy and accuracy of the presented methods as well as its capability to
create and learn new tissue classes.
PMID- 10767589
TI - Universal interface for exchange of medical images via magneto-optical discs.
AB - Digital images are the ever-growing basis of modern medical imaging and
treatment. Despite the advent of the DICOM 3.0 standard for medical image
communication it still requires cumbersome efforts to export images from imaging
modalities to other computer systems. This is true especially for smaller
institutions, which often have limited resources for standardized image transfer.
To gain access even to these data we developed an exchange interface on the basis
of magneto-optical discs (MO-discs), as they are usually available in most of the
imaging modalities in use today. Unfortunately images on MO-discs are usually
stored in formats specific for each manufacturer. Therefore special routines to
access the data on MO-discs had to be developed for each company or even each
scanner. Over 10,000 CT and MRI images including their header information from
different General Electric and Siemens scanners were extracted successfully from
MO-discs. The interface proved to be reliable and easy to handle by technicians.
Support of additional manufacturers and of the DICOM 3.0 standard are work in
progress.
PMID- 10767590
TI - Renal cell carcinomas in von Hippel-Lindau disease; tumor detection and
management.
AB - Twenty-seven renal cell carcinomas (RCCs) found in one family affected with von
Hippel-Lindau disease were examined using ultrasound (US), CT, MRI and
angiography. The sensitivity of the tumor detection using different imaging
modalities was evaluated by macroscopic pathology (solid or cystic) and size
(exceeding 2cm in diameter or not). In 18 of the RCC's exceeding 2cm in diameter
(eight solid and ten cystic), all lesions were detected on US, CT, and MRI.
However, on angiography, solid RCCs were detected in 88%, and cystic RCCs were
detected in 60%. In nine RCCs less than 2cm in diameter (seven solid and two
cystic), solid RCCs were detected in 86% on US, 86% on CT, 80% on MRI, and 43% on
angiography, but cystic RCCs were detected in 50% on only CT and MRI. From the
pathologic correlation, even renal simple cystic lesions in VHL are considered
premalignant lesions and they had better be removed if the residual renal
function after surgery is preserved. In case of the observation, they should be
followed carefully using thin slice thickness dynamic CT to discover the wall
irregularity, septation and irregular contour.
PMID- 10767591
TI - The usefulness of 3D-CT angiography for the diagnosis of spontaneous vertebral
artery dissection-report of two cases.
AB - Spontaneous vertebral artery dissection (VAD) has been recognized as being more
common than was first thought, with the growing use of magnetic resonance imaging
(MRI). However, simple MRI alone is not always satisfactory for making an
accurate diagnosis. We experienced two cases of VAD in our clinic, in which three
dimensional computed tomographic angiography (3D-CTA) was performed. Our scanner
has the capability of examining a slice of 1mm thick, 0.5mm reconstruction pitch,
and a scan time of 1s/rotation. 3D-CTA clearly demonstrated the stenotic change
concomitant with the surrounding thrombus and was thought to be useful for making
an accurate diagnosis.
PMID- 10767593
TI - Oligonucleotide theme.
PMID- 10767592
TI - The advantages of MRI and MRA for diagnosing Behcet's disease and internal
jugular vein thrombosis.
AB - Behcet's disease is a multisystem disorder characterized by recurrent aphtous
ulcers of mucosal membranes, skin lesions, and vasculitis. The prevalence of
vascular involvement is about 25% and this is the leading cause of death in
Behcet's disease. Jugular vein involvement is an unusual manifestation of
Behcet's disease. Medical insertion of needles into veins or arteries can induce
thrombosis or aneurysms. Thus, diagnostic studies or therapy can aggravate the
disease and even be fatal. We report a patient with Behcet's disease and rare
internal jugular vein thrombosis. We also demonstrate the ability of noninvasive
magnetic resonance imaging and magnetic resonance angiography to aid in the
diagnosis and evaluation of vascular involvement in Behcet's disease, without
risking iatrogenic complications.
PMID- 10767594
TI - Physicochemical and biological characterisation of an antisense oligonucleotide
targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers.
AB - The aim of this study was to evaluate the use of cationic-hydrophilic copolymers
for self-assembly with antisense oligonucleotides targeted to the bcl-2 mRNA in
order to improve their biocompatibility and modulation of their pharmacokinetics
for greater therapeutic usefulness. Examination of the ability of
poly(trimethylammonioethyl methacrylate chloride)-poly[N-(2
hydroxypropyl)methacrylamide] (pHPMA-b-pTMAEM) block copolymers to condense the
oligonucleotide by fluorescence and electrophoresis techniques showed that
complexes were formed more efficiently than with copolymers containing
poly(ethylene glycol) blocks grafted onto the backbone of poly(L-lysine) (pLL-g
pEG). In addition, the copolymer pTMAEM-b-pHPMA produced oligonucleotide
complexes with the most favourable physicochemical properties appropriate for in
vivo applications. The complexes were small (approximately 36 nm in diameter),
with low surface charge as measured by zeta potential, relatively stable to
physiological salt conditions and could be formed at a DNA concentration of 500
microg/ml. Complex formation with the copolymer pTMAEM-b-pHPMA or pLL-g-pEG
reduced the urinary clearance of the oligonucleotide after intravenous injection
into mice. However after 30 min, the oligonucleotide complexes were cleared from
the bloodstream. These results indicate that for the systemic delivery of
oligonucleotides the polymer-derived complexes are not stable enough for
prolonged circulation. Instead, these complexes may be more suitable for
localised in vivo applications.
PMID- 10767595
TI - Distribution of (76)Br-labeled antisense oligonucleotides of different length
determined ex vivo in rats.
AB - Oligonucleotides may hybridize with high selectivity to an RNA sequence and can
be used for the monitoring of gene expression or for its inhibition in
experimental or therapeutic purposes. As part of the development of positron
emission tomography (PET) methods, different lengths (30, 20, 12 and 6 mer) of
antisense phosphorothioate oligonucleotides complementary to rat chromogranin A
were labeled with [(76)Br] using a prosthetic group. The (76)Br-oligonucleotides
were injected into rat's tail vein (1-2 MBq/rat), and the radioactivity
distribution was analyzed after 20 h using whole body autoradiography or by
measurement of organ radioactivity concentration. The whole body autoradiography
showed different distribution depending on the oligonucleotide length. The organs
with highest uptake changed from kidney cortex (with 6 or 12 mer), kidney cortex
and liver (with 20 mer), to liver and spleen (with 30 mer). With 20 or 30 mer
sequences, uptake could be observed in the adrenals. Kidneys and livers from rats
receiving 20 mer or 30 mer (76)Br-oligonucleotides were analyzed with respect to
subcellular distribution and DNA/RNA/protein fraction. 30%-45% of the
radioactivity was found in the nuclear fraction. More than 80% of the
radioactivity was recovered in the high molecular weight fraction (as proteins or
oligonucleotides longer than 10 mer) using size exclusion (NAP 5) gelfiltration
or cetylpyridinium bromide (CPB) precipitation. This work indicates the potential
to perform kinetic whole body studies of (76)Br-oligonucleotides using PET.
PMID- 10767596
TI - A lipid carrier with a membrane active component and a small complex size are
required for efficient cellular delivery of anti-sense phosphorothioate
oligonucleotides.
AB - Anti-sense oligonucleotides are potential therapeutic agents that are used to
block protein expression from mRNA. To assess the essential properties for an
efficient cellular delivery system of phosphorothioate oligonucleotides (PS
ODNs), different cationic carriers were compared. The carriers were complexed
with oligonucleotides at various +/- charge ratios in MES-Hepes buffer. Cationic
polymers, polylysines (PLL, mean MWs 4000, 20000, 200000 kDa), polyethyleneimines
(PEI, mean MWs 25 and 800 kDa) and fractured sixth-generation polyamidoamine
dendrimer (PAMAM) were tested for ODN delivery into a D 407 cell line (human
retinal pigment epithelial cells) with stably transfected luciferase gene. Anti
sense ODN was directed against the luciferase gene, and the anti-sense effect was
determined using a luminometric method. Lipid-based vehicles included DOTAP,
DOTAP/DOPE (1/1 by mol), DOTAP/Chol (1/1 by mol), DOTAP/DOPE/Chol (2/1/1 by mol),
DOGS and Cytofectin GS/DOPE (2/1 by mol). Additionally a membrane-active peptide
JTS-1 (NH(2) -GLFEALLELLESLWELLLEA-COOH) was added to the complexes containing
DOTAP, PEI or PLL. In D 407 and CV-1 cells, the anti-sense effect was seen only
with lipid-based carriers with a membrane-active component (DOPE or JTS-1). The
polymeric systems were ineffective. The effect of the complexation medium was
further studied on CV-1 cells. Complexes were prepared in either water, MES-Hepes
buffer or cell growth medium (DMEM). Complexes prepared in water were generally
most effective and the greater activity is probably due to the smaller complex
size. Complex sizes differed greatly in buffer and DMEM, especially in the case
of DOPE containing complexes. In conclusion, lipid carrier with a membrane active
component and small complex size are required for an efficient cellular delivery
of phosphorothioate oligonucleotides.
PMID- 10767597
TI - Optimized conditions for prediction of intestinal drug permeability using Caco-2
cells.
AB - The effects of various experimental conditions on in vitro drug permeability to
Caco-2 monolayers were investigated to determine the optimized conditions for the
prediction of intestinal drug absorption. Concerning the pH of the transport
medium in the Caco-2 study, two different pH values, 6.0 and 7.4, were tested for
the apical medium with the pH of the basolateral medium fixed to 7.4. The change
in the apical pH showed pronounced effects on the permeability of both passively
and actively transported drugs. It was found that the transport study under the
condition of an apical pH value of 6.0 showed a better prediction of in vivo drug
absorption in human. The appropriate conditions for determining the permeability
of poorly soluble drugs were also examined. First, the effects of bile acids,
surfactant and some agents used for solubilizing drugs on the permeability and
transepithelial electrical resistance (TEER) of Caco-2 monolayers were
investigated. Taurocholic and cholic acid showed no effects on the permeability
of 3H-Dexamethasone (DEX) and TEER at 10 mM concentration, suggesting the
possibility of use in the Caco-2 study. Polyethyleneglycol-400 and
dimethylsulfoxide reduced the permeability of DEX concentration dependently,
whereas ethanol induced no significant changes in the permeability. Furthermore,
it was demonstrated that the addition of plasma protein (bovine serum albumin) to
the basolateral medium apparently facilitated the transport of poorly soluble
drugs with high lipophilicity across Caco-2 monolayers. These findings clearly
suggest the importance of considering the physiological conditions of in vivo
drug absorption in optimizing the in vitro experimental conditions for transport
study using Caco-2 cells, in order to obtain a satisfactory in vitro-in vivo
correlation.
PMID- 10767598
TI - Evaluation of absorption enhancement for a potent cyclopeptidic alpha(nu)beta(3)
antagonist in a human intestinal cell line (Caco-2).
AB - Different absorption enhancing principles for a potent cyclopeptidic
alpha(nu)beta(3)-antagonist (EMD 121974) were investigated in monolayers of a
human intestinal cell line (Caco-2). Transepithelial transport was quantitated by
reversed-phase high-performance liquid chromatography. Cytotoxic effects were
characterized by determination of transepithelial electrical resistances (TEERs),
propidium iodide (PI)-influx, FITC-phalloidin staining and the release of
cytosolic lactate dehydrogenase (LDH). Medium chain fatty acids (MCFAs, NaC10,
NaC12) and taurocholate (NaTC) were the most efficient enhancers of cyclopeptide
and FITC-dextran 4400 permeability coefficients, displaying different time
profiles of activity. Whereas NaTC (15 mM) showed almost a constant permeation
enhancing effect from 20 min up to 120 min (ca. 12-fold), MCFA absorption
enhancement was markedly dependent on incubation time (NaC10, 20 min: 1.2-fold,
120 min: 17-fold; NaC12, 20 min: 4.3-fold, 120 min: 13-fold). All cytotoxicity
assays demonstrated that MCFAs were significantly more cytotoxic than NaTC. Ion
pairing with hydrophobic amino acids and heptane sulfonate distinctly increased
octanol-buffer partition coefficients of the cationic cyclopeptide but did not
enhance its transepithelial permeability. Nanoparticles as well as beta
cyclodextrin neither affected integrity of the cells nor transport properties of
the cyclopeptide. In summary, significant absorption enhancement was only
observed with NaTC or MCFAs. Increase in permeability coefficients using NaTC
occurred rapidly with acceptable cytotoxicities and merits further
investigations.
PMID- 10767599
TI - Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused
jejunum loop and in vivo: importance of drug ionisation in the in vitro
prediction of in vivo absorption.
AB - The aims of this study were (i) to compare the absorption of three closely
related inhibitors of angiotensin II, RU60018, RU60079 and HR720, in various in
vitro and in vivo models, and (ii) to explain the differences in the results and
to assess the importance of drug ionisation to predict absorption. Drug
absorption was investigated in Ussing chambers, Caco-2 cell monolayers, perfused
rat jejunum loops and in vivo after oral, intraduodenal or intravenous
administration. In Ussing chambers, the analogues showed the same site-related
absorption profile and a common mechanism involving the paracellular pathway. At
pH 7.4 in Ussing chambers, perfused jejunum loop or Caco-2 transport studies, the
three compounds exhibited low and comparable permeability values suggesting that
a similar level of oral absorption may be expected for all three compounds.
However, after oral or intraduodenal administration, only HR720 was significantly
absorbed. The in vivo results can be explained by the ionic distribution profile
which indicated that only HR720 possessed a significant amount of uncharged
species at pH values close to that found in the upper part of intestinal tract.
Hence, it is expected that in this part of the intestine, only HR720 absorption
is favoured. This is supported by Caco-2 transport studies performed when the pH
of the apical medium was lowered from 7.4 to 6.0, in which a dramatic increase in
permeability was observed for HR720 compared to those of the other analogues.
This study highlights the usefulness of different absorption models for drug
screening and demonstrates that ionisation profiles must be carefully considered
to avoid rejection of promising compounds.
PMID- 10767600
TI - Influence of neutron activation factors on matrix tablets for site specific
delivery to the colon.
AB - The impact of the neutron activation procedure, i.e. incorporation of samarium
oxide (Sm(2)O(3)) and neutron irradiation, on the compression properties
(including the crushing strength) and in vitro dissolution of potential colonic
delivery systems based on matrix tablets of amidated pectin (Am.P) or two types
of hydroxypropyl methylcellulose (HPMC) was investigated. The neutron activation
factors did not influence the compression properties of the tablets. Replacement
of magnesium stearate with samarium stearate in directly compressed Am.P tablets
to achieve both radiolabelling and lubrication resulted in a greater extent of
concentration-dependent reduction of the crushing strength. Dissolution tests
demonstrated that irradiation increased the release of the model drug ropivacaine
from the tablets. The extent of this increase was unexpectedly low considering
the previously observed degradation of the polymer expressed as an irradiation
induced viscosity reduction in solutions prepared from the polymers. Delayed
release coating with Eudragit L 100 protected the HPMC tablets against the
release-increasing effect of irradiation until the late phases of release.
Sm(2)O(3) retarded the release to a varying extent depending on particle
characteristics. Incorporation of Sm(2)O(3) in the coating layer did not
influence the release. However, one-third of the radioactivity leached from the
coating within 60 min in 0.1 M HCl.
PMID- 10767601
TI - Lipophilic methotrexate conjugates with antitumor activity.
AB - Lipophilic methotrexate (MTX)-lipoamino acid conjugates coupled with amide or
ester linkages (1a-1r) were synthesised. The inhibitory activity of the
conjugates was evaluated on bovine liver DHFR. The in vitro growth inhibitory
effect against MTX-sensitive human lymphoblastoid CCRF-CEM cells and an MTX
resistant sub-line (CEM/MTX), which displays defective intracellular transport of
MTX, was determined under short-term and continuous (120-h incubation) exposure
conditions. The alpha, gamma, or alpha,gamma amide conjugates showed different
activity in inhibiting the growth of parent cells. CEM/MTX cells were much less
susceptible than CCRF-CEM cells to inhibition by alpha or alpha,gamma-substituted
lipoamino acid conjugates, whereas both cell lines were almost equally sensitive
to the MTX-gamma conjugates. Although less potent than MTX, they could partially
circumvent the impaired transport system. These findings confirm that lipophilic
MTX conjugates may be good lead compounds on the drug development for the
treatment of some MTX-resistant tumors. Ester-type conjugates displayed an
interesting activity against parent CCRF-CEM cells, although they were less
potent against the transport-resistant sub-line. Stability studies on these
molecules indicated that they are not degraded into MTX in the culture medium,
thus suggesting that they are not able to over-cross cell resistance despite of
their lipophilicity.
PMID- 10767602
TI - The pattern and level of cytokines secreted by Th1 and Th2 lymphocytes of
syphilitic patients correlate to the progression of the disease.
AB - The results of our previous work indicated that cell-mediated immune response, of
importance in protection against Treponema pallidum, is distinctly inhibited at
certain periods of syphilitic infection. Considering that cytokines, produced by
Th1 lymphocytes, take part in this response and that their secretion may be
regulated by cytokines of Th2 lymphocytes, we examined if, and in which stages of
syphilis, such a regulation may exist. In this study we have examined the ability
of cells to produce IL-2, IFN and TNF (Th1 or Th1 like cytokines) as well as IL-6
and IL-10 (Th2 or Th2 like cytokines). It was found that cells of syphilitic
patients were able to produce IL-2, IFN, TNF, IL-10 and weakly IL-6 already in
primary seronegative syphilis. At the same stage of syphilis, but seropositive,
ability of Th1 lymphocytes to produce cytokines reached the highest values,
whereas the cells producing IL-10 lost this ability. The cells producing IL-6 and
MIF had the highest ability in secondary early syphilis. In this stage of
syphilis again slightly increased the ability of cells to secrete IL-10, which
reached the highest value in early latent syphilis. The growing ability to
produce IL-6 and IL-10 was accompanied with a diminished production of IL-2, IFN
and TNF nearly in all stages of syphilis. Only MIF, in contrast to other
cytokines, was produced in late syphilis without distinct changes. The greatest
suppression of Th1 lymphocytes to produce cytokines and cells to secretion of MIF
was found in early latent syphilis when the level of IL-10 in cell culture
supernates was the highest. High ability of Th2 lymphocytes to cytokines
secretion in late syphilis and low ability of Th1 ones, which are very important
for cell-mediated immune response, may be the reason for facilitating T. pallidum
multiplication and development of latent stages of disease despite presence of
immunologically competent cells.
PMID- 10767603
TI - Membrane attack complex formation on yeast as trigger of selective release of
terminal complement proteins from human polymorphonuclear leukocytes.
AB - It has recently been shown that measurable amounts of complement proteins, C6 and
in particular C7, are released from human polymorphonuclear leukocytes (PMNs).
The aim of the present study was to investigate the impact of opsonized Candida
albicans on this release. Stimulation with opsonized C. albicans led to a rapid
and sustained increase of C6 and C7 in the cell culture supernatant beginning
within 5 min of placing in co-culture, whereas co-culture with unopsonized C.
albicans or C. albicans mock-opsonized with inactivated human serum did not
affect the release. In contrast, even after stimulation employing opsonized C.
albicans, no release of the complement component C8 and only trace amounts of C9
were detected. The presence of the membrane attack complex (MAC) on C. albicans
after opsonization was demonstrated by indirect immunofluorescence. Opsonization
of C. albicans with human serum deficient in or depleted of a terminal complement
component resulted in only minor stimulation of C6 and C7 release, although C3
deposition on the surface of C. albicans was not affected as determined by direct
immunofluorescence. Detailed analyses with inactivated or deficient sera showed
that detection of C6 and C7 was not due to insufficient washing of the opsonized
yeast prior to co-culture and suggest that only a small proportion of these
proteins was derived from the membrane bound and then cleaved off MAC. Thus,
these findings imply that MAC on the fungal surface may represent an additional
trigger for the release of C6 and C7 from PMNs, suggesting a new role for the
terminal complement complex (TCC) on target membranes as modulator of PMN
functions locally at the site of inflammation.
PMID- 10767604
TI - Identification and characterization of mutants with increased expression of hilA,
the invasion gene transcriptional activator of Salmonella typhimurium.
AB - Induction of invasion gene transcription and expression of the invasive phenotype
of Salmonella strains are regulated by environmental conditions. Experimental
evidence indicates that oxygen, pH, and osmotic conditions need to closely
resemble those of the host intestinal lumen for invasion gene activation. The
hilA gene, encoded on Salmonella pathogenicity island 1 (SPI-1), is a
transcriptional activator which is required for invasion and whose expression is
modulated by oxygen, pH, and osmolarity. Additionally, hilA is regulated by
genetic elements encoded on SPI-1 (hilC/sirC/sprA and hilD), as well as by
elements which reside outside of SPI-1 (phoP/phoQ and sirA), although how
environmental signals modulate hilA is unknown. In an effort to further
characterize the Salmonella invasion gene regulon, we have created and
preliminarily characterized 18 Tn5 insertions which result in upregulation of a
hilA::lacZY fusion. We have classified the mutations based on location and
phenotype into three classes. Six class 1 and six class 2 mutants have insertions
in SPI-1 near the invasion gene orgA or the invasion gene regulator hilD,
respectively. Six class 3 mutants reside outside of SPI-1 in four different loci.
The class 2 and 3 mutations induce overexpression of an episomal hilA::lacZY
fusion and significantly increase S. typhimurium invasion of HEp-2 cells in a
standard invasion assay. These data implicate new regions of SPI-1 as being
involved in the regulation of invasion by S. typhimurium and identify new
invasion gene regulators located outside of SPI-1.
PMID- 10767605
TI - The role of cytotoxic necrotizing factor-1 in colonization and tissue injury in a
murine model of urinary tract infection.
AB - Cytotoxic necrotizing factor-1 (CNF1) is commonly found in Escherichia coli
isolates from patients with urinary tract infection (UTI). To determine whether
CNF1 is an important UTI virulence factor we compared the ability of a clinical
E. coli UTI isolate and a CNF1-negative mutant of that isolate to colonize and
induce histological changes in the urinary tract in a murine model of ascending
UTI. We found no evidence that the mutant strain was attenuated.
PMID- 10767606
TI - Presence of 22-kDa protein reacting with sera in piglets experimentally infected
with Brachyspira hyodysenteriae.
AB - In order to examine the effect of spectinomycin on outbreaks of swine dysentery,
experimental infection of piglets with Brachyspira hyodysenteriae was carried
out. Feed with and without spectinomycin (SP) was given to each piglet ad libitum
and the susceptibility of the piglets to infection with B. hyodysenteriae was
compared between SP-treated and untreated piglets. The results showed that the SP
treated piglets did not display clinical signs of swine dysentery unlike the
untreated piglets. The sera obtained from these piglets were examined by the
microscopic agglutination test and antibodies to B. hyodysenteriae in both groups
of experimentally infected piglets were detected and the reaction was serogroup
specific. The agglutination titers were very high in the untreated piglets with
dysentery while the titers in the SP-treated piglets were lower than those in the
untreated piglets. In addition, the immunoblotting technique was applied and the
results demonstrated that 22- and 17-kDa proteins in strain ATCC 31212 (serogroup
B) reacted strongly with the sera from the untreated piglets but not with the
sera from the SP-treated piglets. The 22- and 17-kDa proteins also reacted with
strain ATCC 27164 (serogroup A) which belongs to a different serogroup. The 22-
and 17-kDa proteins were also confirmed in six other strains of B. hyodysenteriae
which belong to six different serogroups. These proteins were sensitive to
proteinase K. These results indicate that the 22- and 17-kDa proteins are common
to eight strains of B. hyodysenteriae which differ serologically from each other.
PMID- 10767607
TI - Detection of peptidoglycan in human plasma using the silkworm larvae plasma test.
AB - Silkworm larvae plasma (SLP) reagent, which is prepared from the body fluid of
the silkworm, reacts with peptidoglycan (PG), a fragment of both the Gram
positive and Gram-negative bacterial cell wall, as well as with beta-glucan, a
component of fungi. We developed a quantitative method for the detection of PG in
human plasma from cases with bacterial infection using the SLP reagent. Tested in
this way, the SLP method showed 86.2% sensitivity, 90.6% specificity, 89.3%
positive predictive value, and 88.5% efficiency. The SLP method provides a
valuable tool for the diagnosis of systemic infection using patients' blood.
PMID- 10767608
TI - Atypical behaviour and survival of Streptococcus pyogenes L forms during
intraperitoneal infection in rats.
AB - Groups of rats were injected intraperitoneally with cell wall-deficient (L) forms
of Streptococcus pyogenes, with their parental (S) forms, as well as with a
combined inoculum of both forms (S+L). Peritoneal exudate samples were harvested
on days 1, 3, 7, 15 and 30 after challenge and were investigated by
microbiological, electron microscopic, cytometric and biochemical methods.
Parental S forms were isolated from peritoneal exudate samples up to day 15 post
infection, while L form cultures were isolated until the end of the examined
interval. Electron microscopic examination revealed continuous adhesion of L
forms on the macrophage surface as well as intracellular persistence inside them.
It was demonstrated that the intraperitoneal inflammatory response to L form
infection was higher than to the other infections and the monocyte-macrophage
populations were predominant. The established atypical behaviour and long
survival of S. pyogenes L forms in the rat's peritoneum could explain some of the
mechanisms of the pathogens' persistence as well as the reasons for chronic
streptococcal infections.
PMID- 10767609
TI - Heterogeneity in the immune response to serotype b LPS of Actinobacillus
actinomycetemcomitans in inbred strains of mice.
AB - We investigated the heterogeneity of the humoral immune responses to whole cells
and lipopolysaccharide (LPS) of Actinobacillus actinomycetemcomitans serotype b
and production of cytokines in inbred strains of mice. Nine such strains were
tested: A/J (H-2(a)), C57BL/6 (H-2(b)), BALB/c (H-2(d)), DBA/2 (H-2(d)), B10.BR
(H-2(k)), C3H/He (H-2(k)), C3H/HeJ (H-2(k)), DBA/1 (H-2(q)) and B10.S (H-2(s)).
Mice were immunized intraperitoneally with whole cells of A.
actinomycetemcomitans ATCC 43718 (serotype b) in phosphate buffered saline (PBS;
pH 7.2) emulsified with an equal volume of Freund's incomplete adjuvant. Serum
immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) levels
against A. actinomycetemcomitans were measured by an ELISA system. ELISA
analysis, using LPS fractions from serotype a, b or c strains of A.
actinomycetemcomitans as the coating antigens, revealed that mice strains C3H/He,
C3H/HeJ, B10.BR and B10.S had an extremely high-IgM response against serotype b
LPS. High-IgM titer sera contain also elevated levels of IgA antibodies to the
antigen. To compare the cytokine production among inbred mice, the amounts of
interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-6 (IL-6) released
from mouse splenocytes were measured using ELISA systems specific for these
cytokines. A. actinomycetemcomitans serotype b LPS stimulation induced IL-6
release from murine splenocytes of all tested strains. However, IL-4 and IL-5
were detected only in high-IgM/IgA responders to A. actinomycetemcomitans
serotype b LPS, not in low-IgM/IgA responders. Thus, we found a relationship
between the humoral immune response to LPS of A. actinomycetemcomitans serotype b
and production of type 2 cytokines by splenocytes.
PMID- 10767610
TI - Membrane surface of Mycobacterium microti-infected macrophages antigenically
differs from that of uninfected macrophages.
AB - Identification of the antigenic changes in mycobacteria-infected macrophage may
be important in understanding the mechanisms responsible for the intracellular
survival of the bacteria. In the present study, Mycobacterium microti-infected
macrophages were utilized to investigate the possibility of differentiating the
infected cells from normal cells, based on the antigenic changes occurring in the
membranes. Antisera were generated against bacterial extract, heat-killed
bacteria and crude preparation of M. microti-infected homologous macrophage
membrane. The reactivity of these antisera, towards in vitro infected
macrophages, was compared by flow cytometry. Unlike anti-bacterial extract
antiserum or anti-heat-killed bacterial antiserum, anti-infected macrophage
membrane antiserum reacted with infected macrophage surface. This reactivity
increased with the increase in post-infection time. However, it was not observed
with uninfected macrophages, PMA- or lipopolysaccharide-activated macrophages and
those harboring Mycobacterium tuberculosis H37Ra, heat-killed M. microti and
Leishmania donovani. Interestingly, anti-infected macrophage membrane antiserum
identified a 63-kDa antigen in M. microti-infected macrophage membranes which was
not present in the membranes of normal macrophages, activated macrophages and of
those infected with M. tuberculosis H37Ra, heat-killed M. microti and L.
donovani. Thus, membranes of M. microti-infected macrophages differ antigenically
from those of the normal macrophages and infected homologous macrophage membrane
antiserum provides a useful tool in studying such changes.
PMID- 10767611
TI - Meningococcal serogroup C-specific IgG antibody responses and serum bactericidal
titres in children following vaccination with a meningococcal A/C polysaccharide
vaccine.
AB - In the UK, a co-ordinated series of phase II studies is being undertaken with
meningococcal serogroup C conjugate (MCC) vaccines. The use of meningococcal A/C
polysaccharide (MACP) vaccines in control arms in young children has been avoided
because of the well recognised short comings of these vaccines. Following a
cluster of serogroup C disease centred on a day nursery, intervention by MACP
vaccination was performed as an outbreak control measure. Using this cohort,
serogroup C-specific IgG ELISA and serum bactericidal assays (SBA) were performed
using both de-O-acetylated (Oac(-)) and acetylated (Oac(+)) serogroup C antigen,
the measurement of primarily high avidity antibody and using baby rabbit or human
complement in the SBA. The effect of subject age (either less than or greater
than 2 years of age) was assessed for the different assays and significant
differences (P<0.05) were found using both antigen sources in the high avidity
ELISA and in the rabbit complement SBA but not in the standard ELISA. When
assessing results from different studies it is important that methodologies
utilised allow such comparisons since the choice of reagents can have a profound
influence. The importance of standardised assays is paramount at a time where
immunogenicity trials are replacing efficacy trials for the introduction of MCC
vaccines.
PMID- 10767612
TI - HIV-1 co-receptor CCR5 and CCR2 mutations among Greeks.
AB - The frequency of CCR5 and CCR2 alleles in human immunodeficiency virus (HIV)
positive and HIV-negative populations of Northern Greece was investigated. The
frequency of the CCR5Delta32 allele among the HIV-negative subjects was 0.052,
while it was approximately two-fold lower among the seropositives, suggesting
that the heterozygous genotype confers a partial resistance to the HIV infection.
No significant difference in CCR2 allele frequency between the two groups was
observed.
PMID- 10767613
TI - Evolutionary computation in medicine: an overview.
AB - The term evolutionary computation encompasses a host of methodologies inspired by
natural evolution that are used to solve hard problems. This paper provides an
overview of evolutionary computation as applied to problems in the medical
domains. We begin by outlining the basic workings of six types of evolutionary
algorithms: genetic algorithms, genetic programming, evolution strategies,
evolutionary programming, classifier systems, and hybrid systems. We then
describe how evolutionary algorithms are applied to solve medical problems,
including diagnosis, prognosis, imaging, signal processing, planning, and
scheduling. Finally, we provide an extensive bibliography, classified both
according to the medical task addressed and according to the evolutionary
technique used.
PMID- 10767614
TI - Evolutionary weighting of image features for diagnosing of CNS tumors.
AB - This paper concerns an application of evolutionary feature weighting for
diagnosis support in neuropathology. The original data in the classification task
are the microscopic images of ten classes of central nervous system (CNS)
neuroepithelial tumors. These images are segmented and described by the features
characterizing regions resulting from the segmentation process. The final
features are in part irrelevant. Thus, we employ an evolutionary algorithm to
reduce the number of irrelevant attributes, using the predictive accuracy of a
classifier ('wrapper' approach) as an individual's fitness measure. The novelty
of our approach consists in the application of evolutionary algorithm for feature
weighting, not only for feature selection. The weights obtained give quantitative
information about the relative importance of the features. The results of
computational experiments show a significant improvement of predictive accuracy
of the evolutionarily found feature sets with respect to the original feature
set.
PMID- 10767615
TI - Multi-objective optimization in radiotherapy: applications to stereotactic
radiosurgery and prostate brachytherapy.
AB - Treatment planning for radiation therapy is a multi-objective optimization
process. Here we present a machine intelligent scheme for treatment planning
based on multi-objective decision analysis (MODA) and genetic algorithm (GA)
optimization. Multi-objective ranking strategies are represented in the L(p)
metric under the displaced ideal model. Goal setting, protocol satisficing and
fuzzy ranking of objective importance can be incorporated into the decision
scheme to assimilate clinical decision making. For distance measures in the L(p)
metric, a dynamic gauge function is defined based on the state energy of the
decision system, which is assumed to undergo thermodynamic cooling with iteration
time. The MODA scheme interacts with a robust GA engine, which adaptively evolves
in the multi-modal landscape that defines the treatment plan quality. A
conventionally challenging case of stereotactic radiosurgery of a brain lesion
was selected for GA optimization. The resulting dose distributions are compared
to human-developed plans, which are commonly regarded as clinically relevant and
empirically optimal. The GA-optimized plans achieve substantially better sparing
of critical normal neuroanatomy surrounding the brain lesion while respecting the
preset constraints on tumor dose uniformity. In addition, machine optimization
tends to produce novel treatment strategies which complements expert knowledge.
The run time for producing an optimal plan is considerably shorter than the
typical planning time for human experts, thus GA can also be used to aid the
human treatment planning process. In prostate brachytherapy, MODA-GA was
specifically applied to non-ideal conditions in which typical surgical
uncertainties in seed implant positioning occur, where noisy objectives were
introduced into the optimization scheme. The noisy system is found to be
manageable by MODA-GA at uncertainty levels corresponding to reasonably
proficient surgery teams. In contrast, noisy objectives would be very difficult
to explore by human expert planners. Potential use of noisy optimization with
time series analysis is being explored for error-corrective computer guidance in
the operating room for prostate seed implantation. In conclusion, the combination
of MODA and GA optimization offers both a solution to practical treatment
planning tasks and the potential for real time applications in radiotherapy.
PMID- 10767616
TI - The learning classifier system: an evolutionary computation approach to knowledge
discovery in epidemiologic surveillance.
AB - The learning classifier system (LCS) integrates a rule-based system with
reinforcement learning and genetic algorithm-based rule discovery. This
investigation reports on the design, implementation, and evaluation of EpiCS, a
LCS adapted for knowledge discovery in epidemiologic surveillance. Using data
from a large, national child automobile passenger protection program, EpiCS was
compared with C4. 5 and logistic regression to evaluate its ability to induce
rules from data that could be used to classify cases and to derive estimates of
outcome risk, respectively. The rules induced by EpiCS were less parsimonious
than those induced by C4.5, but were potentially more useful to investigators in
hypothesis generation. Classification performance of C4.5 was superior to that of
EpiCS (P<0.05). However, risk estimates derived by EpiCS were significantly more
accurate than those derived by logistic regression (P<0.05).
PMID- 10767617
TI - Model-based spectral estimation of Doppler signals using parallel genetic
algorithms.
AB - Conventional spectral analysis methods use a fast Fourier transform (FFT) on
consecutive or overlapping windowed data segments. For Doppler ultrasound
signals, this approach suffers from an inadequate frequency resolution due to the
time segment duration and the non-stationarity characteristics of the signals.
Parametric or model-based estimators can give significant improvements in the
time-frequency resolution at the expense of a higher computational complexity.
This work describes an approach which implements in real-time a parametric
spectral estimator method using genetic algorithms (GAs) in order to find the
optimum set of parameters for the adaptive filter that minimises the error
function. The aim is to reduce the computational complexity of the conventional
algorithm by using the simplicity associated to GAs and exploiting its parallel
characteristics. This will allow the implementation of higher order filters,
increasing the spectrum resolution, and opening a greater scope for using more
complex methods.
PMID- 10767618
TI - Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation
spectra.
AB - During the past 25 years, ethenobases have emerged as a new class of DNA lesions
with promutagenic potential. Ethenobases were first investigated as DNA reaction
products of vinyl chloride, an occupational carcinogen causing angiosarcoma of
the liver (ASL). They were subsequently shown to be formed by several
carcinogenic agents, including urethane (ethyl carbamate), and more recently, to
occur in various tissues of unexposed humans and rodents. The endogenous source
of ethenobases in DNA is thought to be a lipid peroxidation (LPO) product.
Initial studies on metabolic activation, mutagenicity and carcinogenicity moved
to the analyses of the formation of ethenobases in vivo and to the determination
of their promutagenic properties. Quantification of etheno adducts in vivo became
possible with the development of ultrasensitive techniques of analysis. To study
the miscoding properties of ethenobases, the initial assays on the fidelity of
replication or of transcription were replaced by site-directed mutagenesis assays
in vivo. Ethenobases generate mainly base pair substitution mutations. With the
advent of new techniques of molecular biology, mutations were investigated in the
ras and p53 genes of tumors induced by vinyl chloride and urethane. In liver
tumors induced by vinyl chloride, specific mutational patterns were found in the
Ki-ras gene in human ASL, in the Ha-ras gene in hepatocellular carcinoma (HCC) in
rats, and in the p53 gene in human and rat ASL. In tumors induced by urethane in
mice, codon 61 of the Ha-ras gene (liver, skin) and of the Ki-ras gene (lung)
seems to be a characteristic target. These tumor mutation spectra are compatible
with the promutagenic properties of etheno adducts and with their formation in
target tissues, suggesting that ethenobases can be initiating lesions in
carcinogenesis. Another recent focus has been given to the repair of etheno
adducts, and DNA glycosylases able to excise these adducts in vitro have been
identified. The last two decades have brought ethenobases to light as potentially
important DNA lesions in carcinogenesis. More research is needed to better
understand the environmental and genetic factors that affect the formation and
persistence of ethenobases in vivo.
PMID- 10767619
TI - Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating
agents.
AB - Methylating agents are potent carcinogens that are mutagenic and cytotoxic
towards bacteria and mammalian cells. Their effects can be ascribed to an ability
to modify DNA covalently. Pioneering studies of the chemical reactivity of
methylating agents towards DNA components and their effectiveness as animal
carcinogens identified O(6)-methylguanine (O(6)meG) as a potentially important
DNA lesion. Subsequent analysis of the effects of methylating carcinogens in
bacteria and cultured mammalian cells - including the discovery of the inducible
adaptive response to alkylating agents in Escherichia coli - have defined the
contributions of O(6)meG and other methylated DNA bases to the biological effects
of these chemicals. More recently, the role of O(6)meG in killing mammalian cells
has been revealed by the lethal interaction between persistent DNA O(6)meG and
the mismatch repair pathway. Here, we briefly review the results which led to the
identification of the biological consequences of persistent DNA O(6)meG. We
consider the possible consequences for a human cell of chronic exposure to low
levels of a methylating agent. Such exposure may increase the probability that
the cell's mismatch repair pathway becomes inactive. Loss of mismatch repair
predisposes the cell to mutation induction, not only through uncorrected
replication errors but also by methylating agents and other mutagens.
PMID- 10767620
TI - Repair of O(6)-alkylguanine by alkyltransferases.
AB - The predominant pathway for the repair of O(6)-methylguanine in DNA is via the
activity of an alkyltransferase protein that transfers the methyl group to a
cysteine acceptor site on the protein itself. This review article describes
recent studies on this alkyltransferase. The protein repairs not only methyl
groups but also 2-chloroethyl-, benzyl- and pyridyloxobutyl-adducts. It acts on
double-stranded DNA by flipping the O(6)-guanine adduct out of the DNA helix and
into a binding pocket. The free base, O(6)-benzylguanine, is able to bind in this
pocket and react with the cysteine, rendering it an effective inactivator of
mammalian alkyltransferases. The alkylated form of the protein is rapidly
degraded by the ubiquitin/proteasomal system. Some tumor cells do not express
alkyltransferase despite having an intact gene. Methylation of key sites in CpG
rich islands in the promoter region are involved in this silencing and a change
in the nuclear localization of an enhancer binding protein may also contribute.
The alkyltransferase promoter contains Sp1, GRE and AP-1 sites and is slightly
inducible by glucocorticoids and protein kinase C activators. There is a complex
relationship between p53 and alkyltransferase expression with p53 mediating a
rise in alkyltransferase in response to ionizing radiation but having no clear
effect on basal levels. DNA adducts at the O(6)-position of guanine are a major
factor in the carcinogenic, mutagenic, apoptopic and clastogenic actions of
methylating agents and chloroethylating agents. Studies with transgenic mice in
which alkyltransferase levels are increased or decreased confirm the importance
of this repair pathway in protecting against carcinogenesis. Alkyltransferase
activity in tumors protects them from therapeutic agents such as temozolomide and
BCNU. This resistance is abolished by O(6)-benzylguanine and this drug is
currently in clinical trials to enhance cancer chemotherapy by these agents.
Studies are in progress to reduce the toxicity of such therapy towards the bone
marrow by gene therapy to express alkyltransferases with mutations imparting
resistance to O(6)-benzylguanine at high levels in marrow stem cells. Several
polymorphisms in the human alkyltransferase gene have been identified but the
significance of these in terms of alkyltransferase action is currently unknown.
PMID- 10767621
TI - DNA repair: counteragent in mutagenesis and carcinogenesis-- accomplice in cancer
therapy resistance.
AB - DNA-reactive carcinogens and anticancer drugs induce many structurally distinct
mutagenic and cytotoxic DNA lesions. The varying capability of normal and
malignant cells to recognize and repair specific DNA lesions influences both
cancer risk and the relative sensitivity or resistance of cancer cells towards
cytotoxic agents. Using monoclonal antibody-based immunoanalytical assays, very
low amounts of defined carcinogen-DNA adducts can be quantified in bulk genomic
DNA, in individual genes, and in the nuclear DNA of single cells. DNA repair
kinetics can, thus, be measured in a lesion-, gene-, and cell type-specific
manner, and the DNA repair profiles of malignant cells can be monitored in
individual patients. Even structurally very similar DNA lesions may be repaired
with strongly differing efficiency. The miscoding DNA alkylation products O(6)
methylguanine and O(6)-ethylguanine, for example, differ only by one CH(2) group.
These lesions are formed in DNA upon exposure to N-methyl-N-nitrosourea or N
ethyl-N-nitrosourea, both of which induce mammary adenocarcinomas in female rats
at high yield. Unrepaired O(6)-alkylguanines in DNA cause G:C-->A:T transition
mutations via mispairing during DNA replication. O(6)-methylguanines are repaired
at a similar slow rate in both transcriptionally active (H-ras, beta-actin) and
inactive genes (IgE heavy chain; bulk DNA) of the target mammary epithelia (which
express the repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) at a very
low level). In contrast, O(6)-ethylguanines are repaired approximately 20 times
faster than O(6)-methylguanines in both DNA strands of the transcribed genes
selectively via an AGT-independent, as yet unclarified excision mechanism.
Accordingly, G:C-->A:T transitions resulting from the misreplication of an O(6)
methylated guanine at the second position of codon 12 (GGA) of H-ras represent a
frequent "signature" mutation in rat mammary adenocarcinomas that develop after
exposure to N-methyl-N-nitrosourea. However, this mutation is not observed when
these tumors are induced by N-ethyl-N-nitrosourea, due to the fast repair of O(6)
ethylguanines in the H-ras gene. The key importance of "conventional" and
"conditional" gene knockout technology for resolving the intricacies of the
complex network of DNA repair pathways is briefly discussed.
PMID- 10767622
TI - Gene transfer to suppress bone marrow alkylation sensitivity.
AB - Alkylating agents represent a highly cytotoxic class of chemotherapeutic
compounds that are extremely effective anti-tumor agents. Unfortunately,
alkylating agents damage both malignant and non-malignant tissues. Bone marrow is
especially sensitive to damage by alkylating agent chemotherapy, and is a dose
limiting tissue when treating cancer patients. One strategy to overcome bone
marrow sensitivity to alkylating agent exposure involves gene transfer of the DNA
repair protein O(6)-methylguanine DNA methyltransferase (O(6)MeG DNA MTase) into
bone marrow cells. O(6)MeG DNA MTase is of particular interest because it
functions to protect against the mutagenic, clastogenic and cytotoxic effects of
many chemotherapeutic alkylating agents. By increasing the O(6)MeG DNA MTase
repair capacity of bone marrow cells, it is hoped that this tissue will become
alkylation resistant, thereby increasing the therapeutic window for the selective
destruction of malignant tissue. In this review, the field of O(6)MeG DNA MTase
gene transfer into bone marrow cells will be summarized with an emphasis placed
on strategies used for suppressing the deleterious side effects of
chemotherapeutic alkylating agent treatment.
PMID- 10767623
TI - Oxidative base damage to DNA: specificity of base excision repair enzymes.
AB - Base excision repair (BER) is likely to be the main mechanism involved in the
enzymatic restoration of oxidative base lesions within the DNA of both
prokaryotic and eukaryotic cells. Emphasis was placed in early studies on the
determination of the ability of several bacterial DNA N-glycosylases, including
Escherichia coli endonuclease III (endo III) and formamidopyrimidine DNA N
glycosylase (Fpg), to recognize and excise several oxidized pyrimidine and purine
bases. More recently, the availability of related DNA repair enzymes from yeast
and human has provided new insights into the enzymatic removal of several.OH
mediated modified DNA bases. However, it should be noted that most of the earlier
studies have involved globally modified DNA as the substrates. This explains, at
least partly, why there is a paucity of accurate kinetic data on the excision
rate of most of the modified bases. Interestingly, several oxidized pyrimidine
and purine nucleosides have been recently inserted into defined sequence
oligonucleotides. The use of the latter substrates, together with overexpressed
DNA N-glycosylases, allows detailed studies on the efficiency of the enzymatic
release of the modified bases. This was facilitated by the development of
accurate chromatographic and mass spectrometric methods aimed at measuring
oxidized bases and nucleosides. As one of the main conclusions, it appears that
the specificity of both endo III and Fpg proteins is much broader than expected a
few years ago.
PMID- 10767624
TI - Suppression of spontaneous mutagenesis in human cells by DNA base excision
repair.
AB - The chemical instability of the covalent structure of DNA, and in vivo exposure
of DNA to reactive oxygen species and endogenously produced alkylating agents,
has triggered the evolution of several specific DNA repair pathways. A major
strategy of repair involves the initial removal of an altered base from DNA by a
member of the enzyme family of DNA glycosylases. The currently known enzymes of
this type in mammalian cells are reviewed, and the subsequent base excision
repair (BER) steps that achieve restoration of the intact DNA structure are also
described. The specific problem of retaining high accuracy in this essentially
error-free repair process is discussed.
PMID- 10767625
TI - Thymine-DNA glycosylase and G to A transition mutations at CpG sites.
AB - About 23% of mutations in hereditary human diseases and 24% of mutations in p53
in human cancers are G to A transitions at sites of cytosine methylation
suggesting that these sites are either foci for DNA damage, or foci for damage
that is poorly repaired. Thymine produced at these sites by the hydrolytic
deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine
DNA glycosylase will also remove 3,N(4)-ethenocytosine and uracil from DNA. The
action of this enzyme is limited by its very low k(cat) and by tight binding to
the apurinic site produced when the thymine is removed. These properties of the
enzyme suggest that the inefficiency of the base excision repair pathway that it
initiates may be the underlying cause of the prevalence of these mutations.
PMID- 10767626
TI - Variability in nucleotide excision repair and cancer risk: a review.
AB - Cancer initiation is classically associated with the induction of mutations on
specific oncogenes or tumor suppressor genes, due to the presence of unrepaired
DNA lesions produced by endogenous or exogenous genotoxic agents. Among several
DNA repair pathways, the nucleotide excision repair (NER) is the most important
and versatile one in removing the bulky adducts induced by physical and chemical
carcinogens. Xeroderma pigmentosum (XP), characterized by a deficiency in NER and
an over 1000-fold increased risk of skin cancer, represents a paradigm to
understand the role of unrepaired lesion in the development of cancer. We
reviewed here several NER assays used in epidemiological studies investigating
the association between DNA repair efficiency and cancer risk. Reduced DNA repair
could contribute to the development of cutaneous basal cell carcinoma (BCC),
although discordant results have been reported. More consistent findings were
observed between cellular sensitivity towards genotoxic agents and smoking
related cancers.
PMID- 10767627
TI - The response of Parp knockout mice against DNA damaging agents.
AB - Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have
identified the various roles of Parp in cellular responses to DNA damage. The
partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant
mice indicates the participation of Parp in the repair of DNA strand break. Parp(
/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is
also thought to be involved in base-excision repair after DNA damage caused by
alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage
induced by reactive oxygen species implicates the contribution of Parp to cell
death through NAD depletion. Parp(-/-) mice with two different genetic
backgrounds also show enhanced sensitivity to the lethal effects of gamma
irradiation. Parp(-/-) mice show more severe villous atrophy of the small
intestine compared to the wild-type counterpart in a genetic background of
129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(
/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice
exhibit extensive hemorrhage in the glandular stomach and other tissues, such as
the testes, after gamma-irradiation. Severe myelosuppression is also observed in
both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive
extramedullary hematopoiesis in the spleen during the recovery phase of post
irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no
extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the
spleen is probably the underlying mechanism of hemorrhagic tendency in various
tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity
could contribute to post-irradiation tissue hemorrhage.
PMID- 10767628
TI - The ATM gene and breast cancer: is it really a risk factor?
AB - The genetic determinants for most breast cancer cases remain elusive. Whilst
mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer
risk, their contribution to sporadic breast cancer is low. In such cases genes
frequently altered in the general population, such as the gene mutated in Ataxia
telangiectasia (AT), ATM may be important risk factors. The initial interest in
studying ATM heterozygosity in breast cancer arose from the findings of
epidemiological studies of AT families in which AT heterozygote women had an
increased risk of breast cancer and estimations that 1% of the population are AT
heterozygotes. One of the clinical features of AT patients is extreme cellular
sensitivity to ionising radiation. This observation, together with the finding
that a significant proportion of breast cancer patients show an exaggerated acute
or late normal tissue reactions after radiotherapy, has lead to the suggestion
that AT heterozygosity plays a role in radiosensitivity and breast cancer
development. Loss of heterozygosity in the region of the ATM gene on chromosome
11, has been found in about 40% of sporadic breast tumours. However, screening
for ATM mutations in sporadic breast cancer cases, showing or not adverse effects
to radiotherapy, has not revealed the magnitude of involvement of the ATM gene
expected. Their size and the use of the protein truncation test to identify
mutations limit many of these studies. This latter parameter is critical as the
profile of mutations in AT patients may not be representative of the ATM
mutations in other diseases. The potential role of rare sequence variants within
the ATM gene, sometimes reported as polymorphisms, also needs to be fully
assessed in larger cohorts of breast cancer patients and controls in order to
determine whether they represent cancer and/or radiation sensitivity predisposing
mutations.
PMID- 10767629
TI - Regulation of p53 stability and activity in response to genotoxic stress.
AB - The p53 tumor suppressor is a universal sensor of genotoxic stress that regulates
the transcription of genes required for cell-cycle arrest and apoptosis. In
response to DNA damage, the p53 protein is phosphorylated at its amino-terminus
and becomes stabilized upon disruption of an interaction with its negative
regulator, MDM2. Subsequent phosphorylation and acetylation of p53 promote
different interactions with other proteins and with target gene regulatory
elements to facilitate cell-cycle arrest, apoptosis, or adaptation in response to
DNA damage. Downstream of p53, p21 is responsible for growth arrest in G1, but
other p53 target genes are responsible for G2 cell-cycle arrest. In response to
genotoxic insult, p53-induced apoptosis results from overlapping downstream
pathways that both suppress mitogenic and survival signaling and promote pro
apoptotic signaling. Adaptation to DNA damage is manifested by p53-mediated
expression of its negative regulator, MDM2. The frequency of observed mutations
in p53 predicts that its inactivation is a requisite step in tumorigenesis, as
p53 is mutated in approximately 50% of human tumors. Thus, it is likely that in
the remaining tumors, genetic aberrations will occur in pathways that regulate
p53 or in pathways directly downstream of p53. The advances in the understanding
of p53 signaling over the past few years point to many potential overlapping
signaling pathways, where mutations may occur as alternative modes to p53
mutation.
PMID- 10767630
TI - Cholesterol sulfate, an activator of protein kinase C mediating squamous cell
differentiation: a review.
AB - Activity of protein kinase C (PKC) depends on the interaction with polar head
groups of two membrane lipids, i.e., phosphatidylserine and diacylglycerol. We
demonstrated that cholesterol metabolism is directly involved in activation of
the eta isoform of protein kinase C (PKCeta), which is predominantly expressed in
epithelial tissues in close association with epithelial differentiation. We found
that PKCeta was activated by cholesterol sulfate (CS), a metabolite of
cholesterol formed during squamous cell differentiation. In the presence of CS,
phorbol ester only weakly enhanced the activity of PKCeta. CS also activated
PKCeta, PKCdelta and PKCepsilon in a dose-dependent manner, when assayed using
purified recombinant materials. However, when partially purified materials were
used from overexpressing normal human keratinocytes, only PKCeta was activated by
CS among the isoforms examined. All the existing lines of evidence, mainly
supplied from our laboratory, suggest that CS is involved in a signal
transduction of squamous cell differentiation and thereby modifying squamous cell
carcinogenesis.
PMID- 10767631
TI - Connexin gene mutations in human genetic diseases.
AB - Rapid advances in understanding the molecular biology of the gap junctional
proteins - connexins (Cx) - have revealed that these proteins are indispensable
for various cellular functions. Recent findings that mutational alterations of Cx
genes leads to several quite different human diseases provide additional evidence
that these proteins possess several not yet fully understood functions. Many
different mutations of Cx32 have been found in the hereditary peripheral
neuropathy - X-linked Charcot-Marie-Tooth syndrome and several mutations of Cx26
and Cx31 have been detected in deafness. Individual mutations of Cx46, Cx50 and
Cx43 have been found in cataract or heart malformations. In this review, we
analyzed the functional importance of mutations of different Cx described in
different human diseases. Topological comparison of mutations in different Cx
species has revealed several hot spots, where mutations are common for two
different Cx or diseases. The value of Cx mutations associated with diseases for
understanding Cx functions is discussed.
PMID- 10767632
TI - Early detection of carcinogenic substances and modifiers in rats.
AB - Over the past 20 years, we have been developing in vivo medium-term bioassay
systems in rats for detecting carcinogenic and modifying effects of test
compounds. The systems are based on the two-step hypothesis of carcinogenesis. In
a liver model, male F344 rats are initially given a single dose of
diethylnitrosamine (DEN, 200 mg/kg, i.p.) and starting 2 weeks later are treated
with test compounds for 6 weeks and then killed, all rats being subjected to two
thirds partial hepatectomy at week 3. Carcinogenic potential is scored by
comparing the numbers and areas per cm(2) of induced glutathione S-transferase
placental form (GST-P) positive foci in the livers of groups of about 15 rats
with those of corresponding control groups given DEN alone. A positive response
is defined as a significant increase in the quantitative values of GST-P-positive
foci, such a negative response as no change or a decrease. The results obtained
have been compared with reported Salmonella/microsome and long-term
carcinogenicity test findings for the same compounds. Of the liver carcinogens,
30 out of 31 (97%) mutagenic and 29 out of 33 (88%) non-mutagenic compounds gave
positive results. Carcinogens other than hepatocarcinogens gave a lower
proportion of positive results (9 out of 42, 21%). This bioassay also provides
information concerning inhibitory potential. The practical utility and benefits
of a multi-organ medium-term experimental protocol for early detection of
carcinogenic agents and modifiers acting at sites other than the liver are also
discussed.
PMID- 10767633
TI - Experimental prostate carcinogenesis - rodent models.
AB - A number of rodent models of prostate carcinoma development have been established
to study mechanisms and modifying potential. All except for transgenic mouse
models need long experimental periods for generation of a high yield of cancers.
Spontaneous prostate tumor models, while not practical in terms of time and tumor
incidences, allow the natural course of multistep neoplasia to be followed
without a need for chemical exposure. Carcinogens, especially in combination with
testosterone, can induce prostate carcinomas in rats, but none are prostate
specific, so that tumor development in other organs is a complicating factor.
Induction of invasive prostate carcinomas in the rat frequently requires long
term administration of a pharmacological dose of testosterone with or without
application of a chemical carcinogen. While there are several transgenic mouse
models, each also has strong and weak points, and it is therefore necessary to
select the best model for the purpose of any experimental study.
PMID- 10767634
TI - Milk and dairy products in cancer prevention: focus on bovine lactoferrin.
AB - Milk and dairy products constitute an important part of the western style diet. A
large number of epidemiological studies have been conducted to determine effects
of consumption on cancer development but the data are largely equivocal,
presumably reflecting the different included components. It has been proposed
that whereas fats in general could promote tumor development, individual milk
fats like conjugated linoleic acid could exert inhibitory effects. There is also
considerable evidence that calcium in milk products protects against colon
cancer, while promoting in the prostate through suppression of circulating levels
of 1,25-dihydroxyvitamin D3. Whey protein may also be beneficial, as shown by
both animal and human studies, and experimental data have demonstrated that the
major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the
post-initiation stage in male F344 rats treated with azoxymethane (AOM) without
any overt toxicity. The incidence of adenocarcinomas in the groups receiving 2%
and 0.2% bLF were thus 15% and 25%, respectively, in contrast to the 57.5%
control value (P<0.01 and P<0.05, respectively). Results in other animal models
have provided further indications that bLF might find application as a natural
ingredient of milk with potential for chemoprevention of colon and other cancers.
PMID- 10767635
TI - Genetic and epigenetic alterations in carcinogenesis.
AB - Precise and deliberate observations on tumors stand true for decades, and then
meet mechanistic explanations. The presence of genetic alterations in tumors is
now widely accepted, and explains the irreversible nature of tumors. However,
observations on tissue differentiation indicated that it shares something in
common with carcinogenesis, that is, "epigenetic" changes. Now, DNA methylation
in CpG sites is known to be precisely regulated in tissue differentiation, and is
supposed to be playing key roles. Many tumor suppressor genes are known to be
inactivated by the hypermethylation of their promoter regions. DNA methylation is
connected to histone deacetylation and chromatin structure, and regulatory
enzymes of DNA methylation are being cloned. Dedifferentiation,
dis(dys)differentiation and convergence of cancer cells were studied
phenotypically and biochemically, and are now explained from molecular aspects of
disturbances in tissue-specific transcription factors. Spontaneous regression of
malignant tumors enchanted researchers, and it is now noticed that genes
inactivated by hypermethylation are frequently involved in tumors that relatively
often undergo spontaneous regression. Carcinogenic mechanisms of some carcinogens
seem to involve modifications of epigenetic switch, and some dietary factors also
have the possibility to modify the switches. Based on the growing understanding
of the roles of DNA methylation, several new methodologies were developed to make
a genome-wide search for changes in DNA methylation. Now, a wave of new findings
is in sight.
PMID- 10767636
TI - Recurrent chromosome aberrations in cancer.
AB - Cytogenetic investigations of neoplastic cells during the past 25 years have
revealed more than 600 acquired, recurrent, balanced chromosome rearrangements,
and it has been established that every tumor type, studied in a sufficient number
to permit conclusions, may be subdivided on the basis of specific, and even
pathognomonic, abnormalities. At the molecular level, the balanced rearrangements
exert their action through one of two alternative mechanisms: Deregulation of one
gene by relocation to an immunoglobulin or T-cell receptor gene, or the creation
of a hybrid gene by the fusion of parts of two genes. At present, nearly 100
genes have been found to be involved in neoplasia-associated chromosomal
rearrangements, the great majority in hematological disorders. At the same time,
the clinical usefulness of various cytogenetic abnormalities as diagnostic and
prognostic aids has been increasingly appreciated. The identification of a
recurring chromosome abnormality can assist in the diagnosis and
subclassification of a malignant disease and, hence, in the selection of the
appropriate treatment. The karyotype is also an independent prognostic factor. In
hematological neoplasms, where the knowledge of chromosome abnormalities still is
much more complete than is the case with solid tumors, cytogenetic analysis now
plays an integral part in the diagnostic work-up of individual patients. Data
obtained during recent years strongly suggest that corresponding breakthroughs
will be achieved in solid tumors within a not-too-distant future.
PMID- 10767637
TI - Studies on biomarkers in cancer etiology and prevention: a summary and challenge
of 20 years of interdisciplinary research.
AB - Sensitive, specific methods have been developed that allow quantitative
measurements of the metabolites of carcinogen metabolites and of DNA and protein
adducts in humans exposed occupationally, environmentally and endogenously to
genotoxic agents. The interrelationship between exposure to carcinogens, host
risk factors and the responses of biomarkers has been examined in cross
sectional, ecological and case-control studies which provided new insights into
the causes of cancer and the mechanisms of carcinogenesis. The identification of
hitherto unknown DNA-reactive chemicals formed in the human body from dietary
precursors and of carcinogenic components of complex mixtures has increased the
possibility of establishing causal relationships in etiology. The identification
of individuals and subgroups heavily exposed to carcinogens has led to the
development of measures for avoiding or decreasing exposure to carcinogenic risk
factors. New, ultrasensitive methods for measuring DNA adducts allow the
quantification and structural elucidation of specific DNA damage in humans
arising from oxidative stress and lipid peroxidation (LPO), which have been found
to be the driving forces in several human malignancies. Background DNA damage in
"unexposed" individuals has been shown unequivocally to be due to LPO products,
and a significant interindividual variation in adduct levels has been shown in
individuals with comparable exposure to carcinogens. Thus, pharmacogenetic
variants with higher susceptibility to carcinogenic insults, due to genetic
polymorphism in xenobiotic-metabolizing enzymes, have been characterized by a
combination of genotyping and measurements of macromolecular adducts. Dosimetry
has been used in human studies to evaluate the efficacy of interventions with
chemopreventive agents like ascorbic acid, dietary phenols and green tea.
Advances in the application of selected biomarkers in human studies are reviewed
and illustrated by examples from the author's research conducted during the past
two decades.
PMID- 10767638
TI - The early detection of frameshift mutations induced by a food-borne carcinogen in
rats: a new tool for molecular epidemiology.
AB - The accumulation of genetic changes is considered as the main factor that
determines the development of cancer. Recent progresses in genetics and molecular
biology led to the discovery of many new molecular markers and to the development
of techniques able to monitor these markers. As a consequence, molecular
epidemiology has emerged as a powerful approach to study the ternary relationship
between the environment, the behaviour and the genetic predisposition of each
individual. Susceptibility to cancer is determined at different levels such as
the genetic polymorphism of enzymes involved in the activation and detoxification
of carcinogens, the polymorphism of genes that maintains the genome stability,
like those involved in DNA repair or recombination processes, and finally the
polymorphism in oncogenes or tumour suppressor genes. Consequently, the full
assessment of each individual's genetic predisposition is a long and difficult
task. As the accumulation of mutations in somatic cells integrates all these
parameters, its measurement would facilitate the evaluation of the individual
predisposition status, provided that a marker common to a large spectrum of
carcinogens could be found. Our current studies on the molecular mechanisms of
carcinogen-induced mutagenesis has revealed that G-rich repetitive sequences are
mutational hot spots for several major classes of environmental genotoxins such
as aromatic and heterocyclic amines, polycyclic hydrocarbons and oxidative
agents. We thus consider the possibility that these sequences form a new class of
biomarkers for carcinogen exposure. In order to validate this hypothesis, we
designed a sensitive PCR-based assay able to detect specific mutations induced by
a common food-borne carcinogen in the colon epithelium of rats exposed for a
short period to this carcinogen. This assay is sensitive enough to allow early
detection of induced mutations and therefore allows to differentiate between
unexposed animal and those exposed for a period as short as 1 week.
PMID- 10767639
TI - The yeast p53 functional assay: a new tool for molecular epidemiology. Hopes and
facts.
AB - The assumption of molecular epidemiology that carcinogens leave fingerprints has
suggested that analysis of the frequency, type, and site of mutations in genes
frequently altered in carcinogenesis may provide clues to the identification of
the factors contributing to carcinogenesis. In this mini-review, we revise the
development, and validation of the yeast-based p53 functional assay as a new tool
for molecular epidemiology. We show that this assay has some very interesting
virtues but also has some drawbacks. The yeast functional assay can be used to
determine highly specific mutation fingerprints in the human p53 cDNA sequence.
Discrimination is possible when comparing mutation spectra induced by
sufficiently different mutagens. However, we also reported that the same
carcinogen may induce distinguishable mutation spectra due to known influencing
factors.
PMID- 10767640
TI - Impact of polymorphisms in xeno(endo)biotic metabolism on pattern and frequency
of p53 mutations in bladder cancer.
AB - We have analyzed the tumor biopsies of 45 patients with bladder cancer for p53
mutations by direct sequencing. In addition to N-acetyltransferase-2 (NAT2) and
GSTM1 allelisms, which were examined previously, we have analyzed the genetic
polymorphisms of GSTT1, GSTP1, COMT, NQO1, TS-SULT and MPO in buffy coat DNA
using PCR-based methods. All subjects were interviewed through a questionnaire on
smoking, dietary habits and other risk factors. No specific pattern was evident
for p53 mutations. Eight out of ten mutations occurred in grade 3 tumors. All p53
mutations occurred in subjects with the COMT mutated allele (p=0.03). The
prevalence of cases with p53 mutations was 3.5-fold higher in subjects with wild
type than in those with variant GSTP1 alleles (p=0.03). The other polymorphisms
investigated were not associated with p53 mutations.
PMID- 10767641
TI - Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens.
AB - Mutations of the p53 tumor suppressor gene are found in about 50% of all human
cancers. The p53 mutation spectra in these cancers are providing clues to the
etiology and molecular pathogenesis of cancer. Recent studies indicate that the
p53 protein is involved in several vital cellular functions, such as gene
transcription, DNA synthesis and repair, cell cycle arrest, senescence and
programmed cell death. Mutations in the p53 gene can abrogate these functions and
may contribute to genomic instability and progression to cancer. Characteristic
p53 mutation spectra have been associated with dietary aflatoxin B(1) (AFB(1))
exposure and hepatocellular carcinoma (HCC); sunlight exposure and skin cancer;
and cigarette smoking and lung cancer. The mutation spectrum also reveals those
p53 mutants that provide cells with a selective clonal expansion advantage during
the multistep process of carcinogenesis. Although a number of different exogenous
carcinogens have been shown to selectively target p53, pieces of evidence
supporting the endogenous insult of p53 are accumulating. Furthermore, analysis
of a characteristic p53 mutation load in nontumorous human tissue can indicate
previous carcinogen exposure and may identify individuals at an increased cancer
risk.
PMID- 10767642
TI - Molecular epidemiology of breast cancer: genetic variation in steroid hormone
metabolism.
AB - The age-specific incidence rate of breast cancer in women rises until menopause,
levels off and then rises again at a much lower rate indicating a possible
hormonal influence on the disease risk. A large amount of evidence has implicated
hormones and other compounds with oestrogen activity in the pathogenesis of
certain endocrine cancers, particularly breast cancer. Widely dispersed hormone
like chemicals, capable of disrupting the endocrine system and interfering with
proliferation, have been described. Compounds such as dioxins, some
polychlorinated biphenyls and the plastic ingredient bisphenol-A have been shown
to interfere with human reproduction and hormonal regulation. The levels of these
foreign compounds as well as the levels of endogenous oestradiol may influence
the risk of breast cancer. Endogenous oestradiol is synthesised in the ovarian
theca cells of premenopausal women or in the stromal adipose cells of the breast
of postmenopausal women and minor quantities in peripheral tissue. These cells,
as well as breast cancer tissue, express all the necessary enzymes for this
synthesis: CYP17, CYP11a, CYP19, hydroxysteroid hydrogenase, steroid sulphatase
as well as enzymes further hydroxylating oestradiol such as CYP1A1, CYP3A4,
CYP1B1. Polymorphisms in these enzymes may have a possible role in the link
between environmental estrogens and hormone-like substances and the
interindividual risk of breast cancer.
PMID- 10767643
TI - Genetic steps in the development of squamous cell carcinoma of the esophagus.
AB - Esophageal squamous cell carcinoma (ESCC) is a frequent form of cancer that shows
striking variations in geographic distribution, reflecting exposure to specific
environmental factors that are still poorly defined. ESCC develops as the result
of a sequence of histopathological changes that typically involves esophagitis,
atrophy, mild to severe dysplasia, carcinoma in situ and finally, invasive
cancer. Genetic changes associated with the development of ESCC include mutation
of the p53 gene, disruption of cell-cycle control in G1 by several mechanisms
(inactivation of p16MTS1, amplification of Cyclin D1, alterations of RB),
activation of oncogenes (e.g., EGFR, c-MYC) and inactivation of several tumor
suppressor genes. Loss of heterozygosity on chromosome 17q25 has been linked with
tylosis, a rare autosomal dominant syndrome associated with high predisposition
to ESCC. Whether this locus is also involved in sporadic ESCC remains to be
elucidated. Chronic esophagitis is a frequent occurrence in populations at high
risk of ESCC. These lesions often show focal accumulation of p53 protein and in
some instances, patches of positive cells in esophagitis area at the margins of
tumors were found to contain a mutation in the p53 gene. This observation is
consistent with field cancerization in the esophagus and suggests that
esophagitis may represent an interesting target for early detection of ESCC as
well as for intervention strategies.
PMID- 10767644
TI - Alterations of oncogenes and tumor suppressor genes in esophageal cancer in
China.
PMID- 10767645
TI - A population at high risk for esophageal cancer in the north-east of Italy.
AB - Esophageal cancer is generally characterised by relatively low incidence and
mortality rates in Europe. However, a high-risk population for this tumour is
resident in the north-east of Italy. Several studies have been conducted on this
population of males confirming the major role of alcohol and tobacco consumption
alone and in combination. The inhabitants of this area of Italy constitute an
ideal target population for studies of molecular epidemiology aimed at
elucidating the natural history of the disease which is still ill-defined, and
the distribution of genetic alterations at a population level.
PMID- 10767646
TI - Overexpression of p53 protein is not directly related to hepatitis B x protein
expression and is associated with neoplastic progression in hepatocellular
carcinomas rather than hepatic preneoplasia.
AB - p53 mutations and binding of p53 to hepatitis B virus (HBV) x protein (HBx) have
been suggested as alternative mechanisms of development of hepatocellular
carcinomas (HCCs) in man, both processes resulting in intracellular accumulation
of the protein which is detectable by immunohistochemical approaches. We have
examined p53 expression in 149 explanted human livers, including 39 cases
infected with HBV and 35 bearing HCC. p53 was demonstrated immunohistochemically
in 51% of HCC samples (18/35), localized mainly in fast growing poorly
differentiated areas. Accumulation of mutant p53 was verified by
immunoprecipitation in most of the positive HCC samples (14/15), implying
occurrence of p53 mutations. No cells positive for p53 were found in 354
preneoplastic hepatocellular lesions examined. This indicates that p53 mutation
is associated with progression, rather than early development, of HCC in the low
aflatoxin B(1)-exposed region. The intracellular distribution patterns of p53 and
HBx were different, with the former within nuclei and the latter confined to
cytoplasmic compartment. HBx did not coimmunoprecipitate with p53. These data
indicate that p53-HBx binding is infrequent, if it really occurs, in HBV-infected
human liver, and that it cannot be a common mechanism of HBV-associated
hepatocarcinogenesis. In addition, p53 accumulation was also observed in some
parenchymal and ductular (oval) cells in cirrhotic livers and, more frequently,
in fulminant hepatitis, being independent of HBx expression, and seemingly
associated with the damage and/or regeneration of liver parenchyma, perhaps
merely reflecting a cellular stress response.
PMID- 10767648
TI - Perspectives in narcolepsy and hypocretin (orexin) research.
PMID- 10767647
TI - Primary prevention of hepatocellular carcinoma in developing countries.
AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with
80% of cases occurring in developing countries. The cancer is rapidly fatal in
almost all cases with survival generally less than 1 year from diagnosis. The
major risk factors for this cancer have been identified as chronic infection with
hepatitis B (HBV) and hepatitis C (HCV) viruses and dietary exposure to
aflatoxins. There is a safe and effective vaccine to prevent chronic HBV
infection. Given estimates that approximately 70% of HCC in developing countries
is attributable to HBV then vaccination could prevent more than 250,000 cases per
year in these areas of the world. A major challenge now is to ensure the
availability of vaccine in countries with endemic infection. Development of a
vaccine against HCV is more problematic due to the genetic heterogeniety of the
virus. However, with 24% of HCC in developing countries attributable to HCV
(approximately 93,000 cases per year) a vaccine would make a major contribution
to cancer prevention. Aflatoxins contaminate dietary staple foods (groundnuts,
maize), are potent animal hepatocarcinogens and are carcinogenic in humans with
particularly high risks in individuals with a concomitant infection with HBV.
Reduction of exposure can be addressed at the community level either pre- or post
harvest by limiting fungal contamination of crops; approaches may involve low
technology post-harvest measures to limit fungal growth or genetic engineering of
crops to be resistant to fungal infection or toxin biosynthesis. An alternative
measure is to modulate the metabolism of aflatoxins once ingested using
chemopreventive agents e.g., oltipraz. The resources available in countries with
endemic hepatitis infection and fungal contamination of foods are often severely
limited. Clearly HBV vaccination has to be the priority in the reducing the
incidence of HCC. However, there are currently 360 million chronic HBV carriers
worldwide and HBV vaccine is still not incorporated into many national
immunisation programs. Thus measures to reduce food spoilage by fungi and the
associated dietary exposure to aflatoxins is also a desirable public health goal.
PMID- 10767649
TI - Valerian for insomnia: a systematic review of randomized clinical trials.
AB - Objective: To systematically review the evidence for the effects of the herb
valerian (Valeriana officinalis) on insomnia, based on randomized, placebo
controlled, double-blind trials.Background: Valerian has long been advocated and
used for promoting sleep but until quite recently evidence was solely anecdotal.
However, during the last two decades a number of clinical trials have been
conducted.Materials and methods: Systematic literature searches were performed to
locate randomized, placebo-controlled, double-blind trials measuring the effect
of valerian monopreparations on sleep in human participants. Data were extracted
in a standardized manner and methodological quality was assessed by the Jadad
score.Results: Nine trials were located meeting the selection criteria. The
findings of the studies were contradictory and there was great inconsistency
between trials in terms of patients, experimental design and procedures and
methodological quality.Conclusion: The evidence for valerian as a treatment for
insomnia is inconclusive. There is a need for rigorous trials to determine its
efficacy.
PMID- 10767650
TI - Narcolepsy and the ability to resist sleep.
AB - We describe five patients who presented with irresistible daytime sleepiness and
who have the clinical and laboratory features of narcolepsy but differ from most
patients with narcolepsy in their ability to resist falling asleep during the
daytime. All of the patients described partial or complete remission of their
symptoms. Using an HLA marker, the expected haplotypes for narcolepsy were found,
but no specific genetic features were found associated with chromosome 6p that
differentiated this group from patients with typical narcolepsy. Problems are
discussed in the laboratory assessment of such patients using both the multiple
sleep latency test and the maintenance of wakefulness test.
PMID- 10767651
TI - A randomized trial of the long-term, continued efficacy and safety of modafinil
in narcolepsy.
AB - Objective: To assess the continued efficacy of modafinil in the treatment of
excessive daytime somnolence (EDS) of narcolepsy.Background: Modafinil has been
shown to be a safe and effective treatment for the EDS presented by patients with
narcolepsy. However, the duration of treatment has been relatively brief,
particularly considering the chronic nature of the disease.Methods: Sixty-nine
patients with narcolepsy, who completed a 6-week crossover study of modafinil
continued on modafinil for 16 weeks of open-label treatment (300+/-100 mg). This
was followed by 2 weeks during which patients were randomly and blindly allocated
to continue modafinil (M) at the same dose (n=30), or placebo (P; n=33).Results:
A mean dose of 330 mg of modafinil continued to produce a significant decrease in
EDS as measured by the Maintenance of Wakefulness Test (9.7+/-7.9 for P; 16.4+/
13.7 for M; P=0.009), the Epworth Sleepiness Scale (15.4+/-5.8 for P; 13.2+/-5.7
for M; P=0.023), and the number of episodes of severe somnolence and sleep
reported in patient diaries (8.2+/-7.2 for P; 4.2+/-5.2 for M; P=0.017).
Modafinil had no significant effects on nocturnal sleep, blood pressure, heart
rate, the electrocardiogram (ECG), weight, or mood.Conclusion: Modafinil
continues to be an effective and well-tolerated drug after 16 weeks of treatment.
PMID- 10767652
TI - Factors affecting sleep disturbances in children and adolescents.
AB - Objective: To determine factors affecting sleep disturbances in
children.Background: Factors affecting sleep disturbances have been studied
extensively in adults, but relatively few studies have been done in
children.Methods: As part of the twelfth survey of the Tucson Epidemiologic Study
of Obstructive Airways Disease (TESOAD, 1991-1992), children, ages 3-14, of adult
cohort members were administered a health questionnaire which contained items
related to sleep problems as well as items related to respiratory diseases and
symptoms. Participants were classified as having sleep disturbances if they
reported disorders of initiating and maintaining sleep (DIMS), excessive daytime
sleepiness (EDS) or snoring. Potential factors affecting sleep included age,
gender, obesity, asthma, other bronchial problems, cough and sputum production,
wheezing and rhinitis.Results: The overall prevalence rates were 16.8, 4 and
22.9% for DIMS, EDS, and snoring, respectively. We found a significantly higher
prevalence of DIMS in 11-14-year-old girls (30.4%) and snoring (32.3%) in 3-6
year-old boys. Certain respiratory factors were more prevalent in children with
sleep disturbances. Multivariate analysis revealed that risk factors for DIMS
included female gender, age 11-14 and wheezing. The risk for EDS was increased in
those children with cough and sputum production. Cough and sputum production also
were risk factors for snoring as was rhinitis and age 3-6.Conclusions: We
conclude that in children as in adults, respiratory symptoms are associated with
sleep disturbances. Further, the increased insomnia seen in adult women may begin
in early adolescence.
PMID- 10767653
TI - A standardized test for cataplexy.
AB - This study developed a standardized procedure for provoking cataplexy, which
facilitated observation of the physiologic changes occurring with cataplexy. Data
were obtained from narcoleptic patients recruited from a sleep disorder center.
Patients were asked to describe the nature and frequency of cataplexy, as well as
their typical emotional triggers. Referring clinicians were asked to assess the
likelihood, frequency, and severity of the patients' cataplexy. Nine patients
with multiple sleep latency test (MSLT)-confirmed narcolepsy were included in
this study. The subjects were then instructed to view a humorous videotape while
monitored with video-polysomnography including EEG, EMG, and EOG. In the event of
a spell, quadriceps reflexes were tested. The data were examined to determine the
occurrence of cataplexy in response to a standardized stimuli. Cataplexy was
successfully provoked in five patients (four women and one man). Areflexia of the
quadriceps muscle was the most sensitive marker of a cataplectic event. EMG tone
was mildly reduced in three patients with no other remarkable changes on
polysomnography. The narcoleptic patients' responses to the humorous videotapes
and other stimuli varied tremendously. This pilot study demostrates the
feasibility of a standardized procedure for provoking cataplexy, which permits
further study of these phenomena. Furthermore, a cataplexy test has considerable
potential as a diagnostic tool, especially in situations where an MSLT is
impractical.
PMID- 10767654
TI - Presumed REM sleep behavior disorder arising from cataplexy and wakeful dreaming.
AB - REM sleep behavior disorder (RBD) is an injurious parasomnia occasionally
associated with narcolepsy. RBD usually occurs within REM sleep. We report a case
of RBD in a narcoleptic patient arising from cataplexy and wakeful dreaming. The
problem of state boundary control inherent in narcolepsy together with the
pharmacological effects of tricyclic antidepressants used to treat cataplexy are
usually the reason of RBD in narcoleptics. By similar mechanism our patient has
presumed RBD out of REM intrusions into wakefulness.
PMID- 10767655
TI - Improvement in cluster headache after treatment for obstructive sleep apnea.
AB - A 60-year-old man with cluster headaches (CH), refractory to many different
medications for 9 years, was found to have obstructive sleep apnea (OSA).
Treatment with nasal continuous positive airway pressure (CPAP) was associated
with substantial reductions in the frequency and severity of cluster headaches.
These observations suggest that obstructive sleep apnea may trigger CH during
susceptible periods.
PMID- 10767656
TI - Arnold-Chiari malformation presenting as sleep apnea syndrome.
AB - Sleep apnea syndrome is a recognized manifestation of Arnold-Chiari malformation
that almost invariably has been described in association with other neurological
findings. We report a 39-year-old man who presented with severe daytime
hypersomnolence. A detailed neurological examination was completely normal.
Polysomnography revealed moderately severe mixed central and obstructive sleep
apnea and hypopnea with persistence of central apnea and hypersomnolence despite
nasal continuous positive airway pressure therapy. A history of severe headaches
precipitated by sustained laughter prompted the consideration of an Arnold-Chiari
malformation (ACM). A type I ACM with no evidence of syringomyelia or
hydrocephalus was confirmed by MRI and successfully decompressed by suboccipital
craniotomy and upper cervical laminectomies. Post-operatively the patient's
headaches and hypersomnolence disappeared and a repeat polysomnography showed
marked improvement in the sleep-disordered breathing. Physicians should be aware
that severe sleep- disordered breathing may be the initial and sole presenting
feature of Arnold-Chiari malformation.
PMID- 10767657
TI - Journal search and commentary.
PMID- 10767658
TI - Article reviewed: Hypocretin (orexin) deficiency in human narcolepsy.
PMID- 10767659
TI - Article reviewed: Impact of sleep dept on metabolic and endocrine function.
PMID- 10767660
TI - Article reviewed: The influence of sex, age and sleep/wake state on
characteristics of periodic leg movements in restless leg syndrome patients.
PMID- 10767661
TI - Article reviewed: Drug-induced arterial pressure elevation is associated with
arousal NREM from sleep in normal volunteers.
PMID- 10767662
TI - Article reviewed: Acute effects of paroxetine on genioglossus activity in
obstructive sleep apnea.
PMID- 10767663
TI - Article reviewed: Attenuated sensitivity to neuractive steroids in gamma
aminobutyrate type A receptor delta subunit knockout mice.
PMID- 10767664
TI - Periodic leg movements are not more prevalent in insomnia or hypersomnia but are
specifically associated with sleep disorders involving a dopaminergic impairment.
PMID- 10767666
TI - FDA: one nation under God, with limited access for all.
PMID- 10767667
TI - Nutritional strategies for treating chronic fatigue syndrome.
AB - Despite considerable worldwide efforts, no single etiology has been identified to
explain the development of chronic fatigue syndrome (CFS). It is likely that
multiple factors promote its development, sometimes with the same factors both
causing and being caused by the syndrome. A detailed review of the literature
suggests a number of marginal nutritional deficiencies may have etiologic
relevance. These include deficiencies of various B vitamins, vitamin C,
magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential
fatty acids. Any of these nutrients could be marginally deficient in CFS
patients, a finding that appears to be primarily due to the illness process
rather than to inadequate diets. It is likely that marginal deficiencies not only
contribute to the clinical manifestations of the syndrome, but also are
detrimental to the healing processes. Therefore, when feasible, objective testing
should identify them and their resolution should be assured by repeat testing
following initiation of treatment. Moreover, because of the rarity of serious
adverse reactions, the difficulty in ruling out marginal deficiencies, and
because some of the therapeutic benefits of nutritional supplements appear to be
due to pharmacologic effects, it seems rational to consider supplementing CFS
patients with the nutrients discussed above, along with a general high-potency
vitamin/mineral supplement, at least for a trial period.
PMID- 10767668
TI - Insulin resistance: lifestyle and nutritional interventions.
AB - Insulin resistance appears to be a common feature and a possible contributing
factor to several frequent health problems, including type 2 diabetes mellitus,
polycystic ovary disease, dyslipidemia, hypertension, cardiovascular disease,
sleep apnea, certain hormone-sensitive cancers, and obesity. Modifiable factors
thought to contribute to insulin resistance include diet, exercise, smoking, and
stress. Lifestyle intervention to address these factors appears to be a critical
component of any therapeutic approach. The role of nutritional and botanical
substances in the management of insulin resistance requires further elaboration;
however, available information suggests some substances are capable of positively
influencing insulin resistance. Minerals such as magnesium, calcium, potassium,
zinc, chromium, and vanadium appear to have associations with insulin resistance
or its management. Amino acids, including L-carnitine, taurine, and L-arginine,
might also play a role in the reversal of insulin resistance. Other nutrients,
including glutathione, coenzyme Q10, and lipoic acid, also appear to have
therapeutic potential. Research on herbal medicines for the treatment of insulin
resistance is limited; however, silymarin produced positive results in diabetic
patients with alcoholic cirrhosis, and Inula racemosa potentiated insulin
sensitivity in an animal model.
PMID- 10767669
TI - Oligomeric proanthocyanidin complexes: history, structure, and
phytopharmaceutical applications.
AB - Considerable recent research has explored therapeutic applications of oligomeric
proanthocyanidin complexes (OPCs), naturally occurring plant metabolites widely
available in fruits, vegetables, nuts, seeds, flowers, and bark. OPCs are
primarily known for their antioxidant activity. However, these compounds have
also been reported to demonstrate antibacterial, antiviral, anticarcinogenic,
anti-inflammatory, anti-allergic, and vasodilatory actions. In addition, they
have been found to inhibit lipid peroxidation, platelet aggregation, capillary
permeability and fragility, and to affect enzyme systems including phospholipase
A2, cyclooxygenase, and lipoxygenase. Based on these reported findings, OPCs may
be a useful component in the treatment of a number of conditions.
PMID- 10767670
TI - Antioxidants and cancer therapy II: quick reference guide.
AB - The previous lengthy review concerning the effects of antioxidant compounds used
concurrently with radiotherapy and chemotherapy has been reduced to a reference
guide. There are only three presently known examples in which any agent
classifiable as an antioxidant has been shown to decrease effectiveness of
radiation or chemotherapy in vivo. The vast majority of both in vivo and in vitro
studies have shown enhanced effectiveness of standard cancer therapies or a
neutral effect on drug action
PMID- 10767671
TI - The effect of bilberry nutritional supplementation on night visual acuity and
contrast sensitivity.
AB - PURPOSE: The purpose of this study was to investigate the effect of bilberry on
night visual acuity (VA) and night contrast sensitivity (CS). METHODS: This study
utilized a double-blind, placebo-controlled, crossover design. The subjects were
young males with good vision; eight received placebo and seven received active
capsules for three weeks. Active capsules contained 160 mg of bilberry extract
(25-percent anthocyanosides), and the placebo capsules contained only inactive
ingredients. Subjects ingested one active or placebo capsule three times daily
for 21 days. After the three-week treatment period, a one-month washout period
was employed to allow any effect of bilberry on night vision to dissipate. In the
second three-week treatment period, the eight subjects who first received placebo
were given active capsules, and the seven who first received active capsules were
given placebo. Night VA and night CS was tested throughout the three-month
experiment. RESULTS: There was no difference in night VA during any of the
measurement periods when examining the average night VA or the last night VA
measurement during active and placebo treatments. In addition, there was no
difference in night CS during any of the measurement periods when examining the
average night CS or the last night CS measurement during active and placebo
treatments. CONCLUSION: The current study failed to find an effect of bilberry on
night VA or night CS for a high dose of bilberry taken for a significant
duration. Hence, the current study casts doubt on the proposition that bilberry
supplementation, in the forms currently available and in the doses recommended,
is an effective treatment for the improvement of night vision in this population.
PMID- 10767672
TI - Berberine.
AB - Berberine is a plant alkaloid with a long history of medicinal use in both
Ayurvedic and Chinese medicine. It is present in Hydrastis canadensis
(goldenseal), Coptis chinensis (Coptis or goldenthread), Berberis aquifolium
(Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree
turmeric). The berberine alkaloid can be found in the roots, rhizomes, and stem
bark of the plants. Berberine extracts and decoctions have demonstrated
significant antimicrobial activity against a variety of organisms including
bacteria, viruses, fungi, protozoans, helminths, and chlamydia. Currently, the
predominant clinical uses of berberine include bacterial diarrhea, intestinal
parasite infections, and ocular trachoma infections.
PMID- 10767673
TI - A history of binocular vision quarterly
PMID- 10767674
TI - Aniseikonia symposium.
PMID- 10767676
TI - RE: Grand Rounds #56, persistent DVD in spite of elevation deficiency.
PMID- 10767675
TI - RE: Correlation of postoperative extraocular muscle suture adjustment with its
imediate effect on the strabismic deviation.
PMID- 10767677
TI - RE: Postoperatively adjustable suture techniques.
PMID- 10767678
TI - The 1999 Gunter K. von Noorden visiting professorship lecture. Monovsion: the
case for two binocular vision systems.
PMID- 10767679
TI - A three dimensional surgical dose-response schedule for lateral rectus resections
for residual congenital/infantile esotropia after large bilateral medial rectus
recessions.
AB - PROBLEM: A series of overcorrections after this surgical sequence. SUBJECTS &
METHODS: Forward stepwise multiple regression analysis of the effect of bilateral
lateral rectus resections, retrieved and tabulated retrospectively from the
clinical charts of 50 children with infantile esotropia who had significant
residual non- accommodative esotropia after bilateral medial rectus recessions.
Analysis allowed for selection among linear and quadratic forms of two relevant
predictor variables: the mm of previous bilateral medial rectus recession and the
prism diopters of residual esotropia. RESULTS: We found a correlation between the
effect of the second surgery (bilateral LR resections) and the two variables.
This relation could be expressed by a surgical dose-response schedule-surface
with the formula: [2.39 + 0.26 (mm MR recession) Squared + 0.41 (mm LR Resection)
Squared = prism diopters of effect]. A corresponding schedule (table) with these
two parameters was developed to facilitate clinical application. To test and
prove this schedule, we re-studied 19 of the 50 original cases who had had
surgery, fortuitously, +/-0.3 mm of our new surgical dose- response surface
schedule plus 10 new cases performed according to the new surface-schedule. For
these 29 cases there was only one "failure" at 6 months postop' (3%). As a
control, for the 31 cases of the original 50 whose surgery had not been within +/
0.3 mm of the new schedule, 7/31 (23%) were "failures", all overcorrections.
("Failure" vs. "success" - there were only two categories of outcome - was
defined as an esotropia over 8 PD or exophoria over 6 PD.) CONCLUSION: This
difference in results, expressed as "successes" of 28/29 vs 24/31, or 97% vs 77%
gave, on statistical analysis, a p=0. 053 of rejecting the null hypothesis, which
is considered a valid "trend" or marginally "statistically significant" and
definitely "clinically-medically significant". We have adopted the regular
application of our new surgical dose- response schedule in these cases and
recommend it for all such cases. binocular vision; complications, surgical; dose
response surgical schedule; esotropia, congenital/infantile; lateral rectus
muscle, resection; outcomes; overcorrections; strabismus surgery; study,
retrospective, clinical; surgery, strabismus.
PMID- 10767680
TI - Vertical transposition of the horizontal rectus muscles for congenital/early
onset "acquired" double elevator palsy: a retrospective long term study of 10
consecutive patients.
AB - BACKGROUND: Double elevator palsy (DEP) is a not uncommon congenital or acquired
clinical entity. Although a full tendon transposition of the horizontal rectus
muscles is the widely accepted treatment, the number of reports in the literature
is not great, and the techniques used are varied. This study reports on patients
with congenital or early onset "acquired" DEP submitted only to a transposition
of the horizontal rectus muscles according to Knapp, to add our experience to the
literature. SUBJECTS AND METHODS: Ten consecutive patients without complicating
factors had the horizontal rectus muscles transposed to the angle of the
insertion of the superior rectus. Patient ages ranged from 10 months to 7 years 4
months. The vertical deviation in primary position ranged for distance from 14 PD
to 50 PD (mean 30.6 PD) and at near from 12 PD to 50 PD (mean 27.4 PD). Five
patients had only a vertical deviation, and five also a horizontal deviation. The
first postsurgical evaluation was done between 7 and 39 days (mean 14.3) and the
last between one and 196 months (mean 102.1). The fusional status was assessed
using the Worth Four-Dot Test and Major Amblyoscope. RESULTS: Postoperatively,
3/10 patients had no vertical deviation for distance. Two were undercorrected (by
1 PD, 8 PD); and five were overcorrected (3 PD, 4 PD, 10 PD and two by 25 PD).
The mean correction for distance was 36. 4 PD. Three of the ten patients had no
vertical deviation at near; two were undercorrected (by 1 PD, 8 PD); and five
overcorrected (two by 4 PD, one each by 6 PD, 7 PD, and 9 PD). The mean
correction at near was 29.5 PD. Long term followup changes: The correction for
distance between the first and last postsurgical evaluation increased (the preop'
deviation decreased) in 8/10 patients (range 3 PD to 45 PD, mean 18.6 PD). At
near, 9/10 patients had an increase in the correction of the vertical deviation
over this period (range 4 PD to 24 PD, mean 13.8 PD). CONCLUSION: This
transposition procedure can reduce or eliminate the vertical deviation both for
distance and at near, and has an increased effect over time.
PMID- 10767681
TI - Selective management of double elevator palsy by either inferior rectus recession
and/or knapp type transposition surgery.
AB - BACKGROUND AND PURPOSE: Double elevator palsy (DEP) is a monocular elevation
deficiency in abduction and adduction characterized by hypofunction of the
superior rectus (SR) and inferior oblique muscles. Only a limited number of
studies are published on the management of this problem. Therefore, we studied
and report and add our experience with emphasis on the indications and types of
surgery for DEP. PATIENTS AND METHODS: The records of 18 patients with DEP out of
3612 strabismic cases (0.5%) were reviewed. Fourteen underwent surgery. Inferior
rectus (IR) recession was performed in cases with positive forced ductions (Group
1, n=6). In patients with negative forced duction test (Group 2, n=8) and in
patients whose vertical deviation was not corrected with IR recession,
transposition surgery (Knapp or modified Knapp procedure) was performed. A
hypotropia of less than 5 PD postoperatively was considered a "successful"
outcome. RESULTS: In Group 1, "IR recession only", the mean preoperative vertical
deviation was 29.2 PD +/-3.8 PD SD. The vertical deviation was adequately
corrected after IR recession in only one patient; the other 5 patients then
underwent transposition surgery at 6 months postop'. After the second operation,
the mean corrected deviation for Group 1 overall was 25.8 PD +/-5.6 PD with an
overall 33% surgical success rate. In Group 2, "primary transpositions", the mean
preoperative vertical deviation and the mean corrected deviation were 23.9 PD +/
6.7 PD and 18.6 PD +/-4.4 PD respectively, and the surgical "success" rate was
63%. The mean corrected deviation for all cases was 21.7 PD +/-4. 9 PD and the
overall surgical "success" rate was 57%. CONCLUSION: Surgical intervention should
be selective according to DEP clinical features. The surgical effect of
transposition surgery may be enhanced by IR recession.
PMID- 10767682
TI - Grand rounds #57: a case of torsional diplopia after three previous strabismus
surgical procedures.
PMID- 10767683
TI - Modified Kestenbaum surgery for correction of abnormal head posture in infantile
nystagmus: outcome in 63 patients with graded augmentaton.
AB - PURPOSE: To analyze the surgical effect of modified Kestenbaum surgery and show
how to determine the amount of appropriate augmentation for correction of
abnormal head posture in infantile nystagmus. METHODS: We reviewed the records of
63 patients with infantile nystagmus who required surgery for a significant face
turn and who were followed for at least five months after surgery. Group 1,
consisting of 29 patients, received Parks' modification of the standard
Kestenbaum procedure (the 5-6-7-8 mm procedure); Group 2, 32 patients, received a
20% augmentation of the original Parks recommendation; and Group 3, 2 patients,
received a 30% augmentation of the original Parks procedure. Pre-and
postoperative measurements with electro-oculography (EOG) using Nicolet Compact
Four/CA 2000 were made. RESULTS: The average preoperative face turn in the 63
patients with horizontal nystagmus was 31.9 degrees with an average postoperative
face turn of 5.2 degrees. The average net change in face turn was 26.7 degrees.
The average duration of time from surgery to final examination was thirteen
months. Fifty-six out of 63 patients (89%) achieved a straight head position or a
residual face turn of 10 degrees or less. CONCLUSION: A Parks' modified
Kestenbaum procedure, with appropriate graded augmentation up to 30% is effective
for the correction of abnormal head posture in infantile nystagmus without the
need for larger augmentations.
PMID- 10767685
TI - Comment/Critique of the issue
PMID- 10767684
TI - Automated cover testing for binocular misalignment in awake monkeys using
spectacle- mounted liquid crystal shutters.
AB - PURPOSE: In humans, pathologic misalignment of the eyes (strabismus, or hetero
tropia) is readily detected using a clinical technique in which the visual axis
of each eye is blocked briefly by a hand held occluder (i.e., the cover test, AKA
the single cover test, or unilateral cover test). This manual technique is
impractical for use in non-human primates. This paper reports the electronic
hardware and computer software we have devised and adapted to perform an
automated cover test in awake macaque monkeys (Macaca mulatta or rhesus, and
Macaca nemistrina or pigtail) to facilitate the study of strabismus in this
species. METHODS: Liquid crystal shutters (Displaytech LV2500OP-OEM) are mounted
in aluminum spectacle frames which are positioned in front of the monkey's eyes
by attaching the frame holder to an acrylic skull cap. The shutters are
electrically actuated alternately to an "open" (transparent) or "closed" (opaque)
state, occluding each eye in turn. The actuation signal (+/-5 volts) is generated
by a single logic chip. The chip is driven by commercial data control and
acquisition software (Spike 2, Cambridge Electronic Design) running on a
Macintosh computer. Eye position and movement during this cover tests is
monitored and recorded by the computer using surgically implanted scleral coils.
Monkeys are rewarded for fixating small, moveable targets so that binocular
misalignment can be measured with high precision at different or cardinal
positions of horizontal and vertical gaze. RESULTS: The shutters produced
occlusion of each eye as effective as that of an opaque plastic occluder used in
previous experiments that required monocular viewing. Heterotropias were detected
and recorded in monkeys and closely resembled those observed in human patients.
It was also possible to detect heterophorias by actuating the shutters
alternately. CONCLUSIONS: The shutters operated reliably, with negligible delay
and transition times, providing automated, repeatable cover tests that are, in
fact, in many respects superior to the standard clinical manual technique. In
addition, their application to humans, using infrared electro-oculography instead
of scleral coils to monitor eye position and movement, holds promise for future
applications.
PMID- 10767686
TI - Development of pemphigus vulgaris in a patient with pemphigus foliaceus:
antidesmoglein antibody profile shift confirmed by enzyme-linked immunosorbent
assay.
AB - We describe a patient with pemphigus foliaceus (PF) in whom pemphigus vulgaris
(PV) subsequently developed. The clinical change was accompanied by a shift of
autoantibody profile confirmed by enzyme-linked immunosorbent assay.
Antidesmoglein (Dsg) 1 antibodies alone were detected in the PF stage, whereas
both anti-Dsg3 and anti-Dsg1 antibodies were detected in the PV stage.
PMID- 10767687
TI - Abdominal nodules as a presentation of obstruction of the inferior vena cava and
factor V Leiden mutation.
AB - Abdominal nodular lesions are not usually considered a sign of deep venous
thrombosis. However, we have seen a patient with abdominal nodular lesions due to
venous thrombosis, that led to the diagnosis of factor V Leiden mutation, a
recently described cause of hypercoagulability.
PMID- 10767688
TI - Transepidermal migration of external cardiac pacing wire presenting as a
cutaneous nodule.
AB - Temporary epicardial pacing wires are used to control postoperative arrhythmias
in patients who have undergone open heart surgery. We present an interesting case
of a foreign body granuloma resulting from a retained epicardial pacing wire.
PMID- 10767689
TI - A painful cutaneous nodule as the presentation of metastatic transitional cell
carcinoma of the renal pelvis.
AB - We report a 43-year-old man with HIV who presented with a painful, vascular
appearing nodule as the initial manifestation of metastasis of a prior
transitional cell carcinoma of the renal pelvis. The transitional cell carcinoma
had been treated by nephroureterectomy 4 years before the appearance of the
nodule. Histopathologic comparison of the nodule with the prior transitional cell
carcinoma and immunoperoxidase staining with monoclonal antibodies confirmed that
the nodule was a metastasis of the original transitional cell carcinoma. In
general, metastasis of transitional cell carcinoma to the skin is quite uncommon.
This case is the first reported episode of transitional cell carcinoma of the
renal pelvis metastasizing to the skin in the form of a vascular-appearing
nodule. The significance of this unusual metastasis occurring in a person with
HIV is unknown.
PMID- 10767690
TI - Exogenous ochronosis.
AB - Ochronosis is an uncommon condition characterized by yellow-brown pigment
deposits in the dermis. It occurs in exogenous and endogenous forms. We report a
case of exogenous ochronosis in a Hispanic woman and discuss the different forms
of this condition. We treated the lesions with Q-switched ruby laser.
PMID- 10767691
TI - Solid facial edema preceding a diagnosis of retro-orbital B-cell lymphoma.
AB - Persistent solid facial edema is a rare condition of unknown cause. Although
acute facial edema has been associated with numerous disease processes such as
infections, neoplasms, immune disorders, inflammation, neuropathic processes,
drugs, mechanical obstructions, and trauma, solid facial edema has most often
been associated with acne vulgaris. We report the first case, to our knowledge,
of solid facial edema preceding a diagnosis of a subcutaneous scalp and
orbital/periorbital B-cell lymphoma.
PMID- 10767692
TI - Scleromyxedema: possible association with seminoma.
AB - Although scleromyxedema has been associated with neoplasm in rare instances, the
literature showed no evidence of association with seminoma. We report a 43-year
old man who presented with a scleromyxedema and relapsed seminoma. The skin
lesions of scleromyxedema cleared completely on treatment of seminoma with
chemotherapy.
PMID- 10767693
TI - Follicular contact dermatitis due to polyoxyethylene laurylether.
AB - Polyoxyethylene laurylether, an addition polymer of lauryl alcohol and ethylene
oxide, is used as an emulsifier in cosmetics. We report a case of follicular
contact dermatitis after the use of polyoxyethylene laurylether that was
contained in a cosmetic. A patch test with polyoxyethylene laurylether 1%
petrolatum showed a follicular papular reaction. A use test for polyoxyethylene
laurylether 1% petrolatum also produced follicular papules at 7 days.
PMID- 10767694
TI - An unusual hematopoietic proliferation seen in a nevus sebaceous.
AB - Nevus sebaceous is a tumor of primary epithelial germ cells that is generally
first noticed at birth. It is relatively quiescent until puberty when a variety
of benign and potentially malignant tumors may arise within it. We describe a
nevus sebaceous with immature fat cells, vascular ectasia, and extramedullary
hematopoiesis that was present at birth. At 4 months, the immature adipose and
hematopoietic elements, as well as the vascular changes, had resolved.
PMID- 10767695
TI - Fixed drug eruption due to fluconazole.
AB - We report a case of fixed drug eruption caused by fluconazole. A local
provocation with 10% fluconazole test in petrolatum applied at the site of a
previous lesion of fixed drug eruption reproduced the eruption clinically and
histopathologically.
PMID- 10767696
TI - Guttate psoriasis triggered by perianal streptococcal dermatitis in a four-year
old boy.
AB - Perianal streptococcal dermatitis (PSD) is a superficial bacterial infection
usually with group A beta-hemolytic streptococci. PSD is often misdiagnosed for
long periods and patients are subjected to treatments for a variety of
differential diagnoses without success. We report a 4-year-old boy with PSD who
presented to our clinic with guttate psoriasis for 2 reasons: first, to make
dermatologists aware of PSD and second, to emphasize the necessity to examine
patients, particularly pediatric patients, with guttate psoriasis very thoroughly
and swab both the pharynx and perianal and/or perigenital areas even when they
are, or seem to be, asymptomatic for bacterial infections. Once PSD has been
diagnosed, systemic antibiotic therapy with penicillin, erythromycin,
roxithromycin, or azithromycin (probably augmented by topical mupirocin ointment)
should be the treatment of choice. Therapy should be monitored by posttreatment
perianal and throat swabs as well as a urine analysis to monitor for
poststreptococcal glomerulonephritis.
PMID- 10767697
TI - Delayed-hypersensitivity granulomatous reaction induced by blepharopigmentation
with aluminum-silicate.
AB - Blepharopigmentation has been introduced during the last decade as a technique
for creating a permanent line along the eyelid margin, thus simulating a cosmetic
eyeliner. Complications related to this procedure are mostly reported in the
opthalmologic literature describing infectious, allergic, or technical problems.
We report a case of a woman who underwent blepharopigmentation with aluminum
silicate and in whom a delayed hypersensitivity granulomatous reaction developed.
PMID- 10767698
TI - Cowpox virus infection in an 11-year-old girl.
AB - We describe an 11-year-old girl with a cowpox virus infection, who presented with
a 14-day-old crusted, ulcerated nodule on the chin/neck and a 6-day-old eroded
blister on the left leg. The girl lived in a rural environment, had close contact
to several cats from the neighborhood, and had an atopic predisposition. The
presence of orthopox virus in the lesion on the left leg was demonstrated by
electron microscopy (negative staining, transmission electron microscopy) and
virus isolation. Classification as a cowpox virus was determined by polymerase
chain reaction (PCR), followed by restriction enzyme digestion of the PCR
product.
PMID- 10767699
TI - Pseudopelade of Brocq in beard area.
AB - Pseudopelade is a rare self-limited hair disorder, resulting in cicatricial
alopecia. It presents with skin-colored alopecic patches primarily involving the
parietal and vertex portions of the scalp. This is a case report of a patient
with pseudopelade that involves both his scalp and beard area.
PMID- 10767700
TI - A case of childhood epithelioid hemangioendothelioma.
AB - Epithelioid hemangioendothelioma (EHE) is a unique tumor, mainly of adults, which
is characterized by epithelioid or histiocytoid endothelial cells. It is a low
grade malignant vascular tumor first described as a distinctive entity in 1982 by
Weiss and Enzinger. An 8-year-old girl presented with an approximately 3-year
history of an erythematous plaque on the left frontal area of the scalp. The
diagnosis of EHE confined to the skin was made by clinicopathologic and
radiologic evaluation. To our knowledge, there are only 5 reported cases of EHE
with skin involvement, 2 of which showed concomitant systemic involvement, and
all occurred in adults. Our case is the fourth reported case of EHE confined to
the skin and the first to describe childhood onset of isolated cutaneous EHE.
PMID- 10767701
TI - Recurrent eosinophilic panniculitis associated with Fasciola hepatica infection.
AB - Eosinophilic panniculitis is characterized by a prominent infiltration of
subcutaneous fat with eosinophils. We report a case of Fasciola hepatica
infection presenting with eosinophilic panniculitis successfully treated with
bithionol. To our knowledge, this is the first report of recurrent eosinophilic
panniculitis associated with Fasciola hepatica infection.
PMID- 10767702
TI - Reactive angioendotheliomatosis in association with the antiphospholipid
syndrome.
AB - A 50-year-old woman with systemic lupus erythematosus developed extensive
necrotic skin lesions on her chest and abdomen after the discontinuation of
warfarin. The presence of antiphospholipid antibodies suggested a diagnosis of
antiphospholipid syndrome. Histopathology from a skin lesion demonstrated marked
expansion of the dermal microvasculature by intravascular cellular proliferation
and focal thrombosis. The intravascular cells stained positive for the
endothelial cell markers CD31 and factor VIII-associated antigen confirming
reactive angioendotheliomatosis (RAE). This report is the first to identify RAE
occurring in the context of the antiphospholipid syndrome. We suggest that
intravascular endothelial proliferation, in concert with thrombosis, contributed
to the angio-occlusive pathology.
PMID- 10767703
TI - Congenital and childhood dermatofibrosarcoma protuberans: a case report and
review of the literature.
AB - Dermatofibrosarcoma protuberans (DFSP) occurs most commonly on the trunk, affects
all races, and often develops between the second and fifth decades of life. It is
uncommon in childhood and is sometimes mistaken for a vascular lesion, as it
often presents as a blue macule or small nodule. Review of the English literature
revealed approximately 152 cases of DFSP developing before 16 years of age and
only 19 claimed congenital cases. A case of congenital dermatofibrosarcoma
protuberans is presented with a literature review and discussion of congenital
and childhood presentations of the tumor.
PMID- 10767704
TI - Anaplastic large-cell lymphoma associated with acquired ichthyosis.
AB - Anaplastic, CD30(+), large-cell lymphoma (ALCL) is a subtype of non-Hodgkin's
lymphoma that accounts for 2% to 8% of all lymphomas. Its most common form is a
classical systemic type, which involves multiple nodal and extranodal sites,
including the skin. Malignant lymphoproliferative disorders, especially Hodgkin's
disease, are known rarely to be associated with acquired ichthyosis, whereas only
1 case of ALCL has been reported to be associated with acquired ichthyosis. We
describe a 74-year-old Japanese man with ALCL, involving lymph nodes and the
skin, who exhibited acquired ichthyosis. The clinical and histopathologic
findings were recorded, and immunophenotyping, T-cell receptor (TCR), and
immunoglobulin gene rearrangement were determined. Clinically, right axillary and
bilateral inguinal lymph nodes were palpable. The cutaneous eruptions were
multiple pinkish and yellow colored, up to thumb-sized nodules, some of which
were ulcerated. Histologically, the right axillary lymph node showed
proliferation of anaplastic large cells in the paracortical and sinusoidal areas.
Both the lymph node and skin showed pleomorphic proliferation of lymphoid cells
with a mixture of mononuclear cells having oval, embryo-shaped, reniform, and
lobulated nuclei, binucleated Reed-Sternberg-like cells, and multinucleated
cells, with giant anaplastic and wreath-shaped nuclei. Immunophenotyping of the
neoplastic cells revealed that they were positive for CD30 (Ber-H2), CD15 (Leu
M1), CD45 (LCA), and CD45RO (UCHL-1). Southern blot analysis demonstrated clonal
rearrangement of the TCR beta region. In contrast, no novel bands were detected
with the immunoglobulin heavy chain JH probe. Several months after the detection
of the axillary nodes, an ichthyosiform, scaly eruption developed over almost the
entire body of the patient. Histologically, it showed orthokeratotic, slight
hyperkeratosis of the epidermis without a granular layer or with only a single
layer of cells in the granular layer. Several kinds of lymphoproliferative
diseases are associated with acquired ichthyosis, including Hodgkin's disease,
multiple myeloma, and lymphomatoid papulosis. This is the second case report of
acquired ichthyosis associated with ALCL. Although a common pathomechanism is
suspected of underlying the development of acquired ichthyosis in these diseases,
it is still unexplained.
PMID- 10767705
TI - Kaposi's varicelliform eruption of an elderly patient with multiple myeloma.
AB - Kaposi's varicelliform eruption (KVE) is characterized by disseminated
vesiculopustules and erosions due to a herpes virus infection superimposed on a
preexisting dermatosis such as atopic dermatitis. However, the occurrence of KVE
in patients with multiple myeloma seems to be very rare; to our knowledge, only
one such case has been reported. This report documents a second case of KVE in a
patient with multiple myeloma.
PMID- 10767706
TI - Cutaneous presentation of posttransplant lymphoproliferative disorder.
AB - Posttransplant lymphoproliferative disorder (PTLD) is a known complication of
solid organ and bone marrow transplantation. However, cutaneous manifestation is
an extremely rare phenomenon of this disorder. We describe a lung transplantation
patient with cutaneous PTLD who presented with bilateral extremity nodules and
fever.
PMID- 10767707
TI - Scleromyxedema with dermato-neuro syndrome.
AB - Scleromyxedema is a rare connective tissue disease of unknown cause characterized
by a generalized papular eruption, dermal fibroblast proliferation, and
monoclonal paraproteinemia. A paroxysmal triad consisting of high fever,
seizures, and coma with a flu-like prodrome can rarely occur in patients with
scleromyxedema and is termed "dermato-neuro syndrome." We describe a 41-year-old
patient with scleromyxedema in whom the dermato-neuro syndrome developed.
PMID- 10767708
TI - Trichosporon cutaneum (Trichosporon asahii) infection mimicking hand eczema in a
patient with leukemia.
AB - Trichosporon Cutaneum is a yeast-like fungus that causes white piedra and
onychomycosis. Recently, it has also been recognized as an opportunistic pathogen
in immunocompromised hosts. We describe a 64-year-old woman who developed a
superficial Trichosporon infection mimicking hand eczema during chemotherapy for
her chronic myelocytic leukemia. To our knowledge, no cases of superficial
infection like this one have previously been reported. This case suggests that
careful examination is required in diagnosing Trichosporon infection in
immunocompromised hosts, because the infection can be invasive or unusual in
appearance.
PMID- 10767709
TI - Sweet's syndrome in a patient with idiopathic progressive bilateral sensorineural
hearing loss.
AB - Acute febrile neutrophilic dermatosis, or Sweet's syndrome, was first described
in 1964 and consists of a triad of erythematous cutaneous plaques infiltrated by
neutrophils in association with fever and leukocytosis. Sweet's syndrome has been
reported to be associated with conditions ranging from upper respiratory tract
infections to inflammatory bowel disease to rheumatoid arthritis. We report a
patient with a 2-year history of Sweet's syndrome in whom idiopathic progressive
bilateral sensory neural hearing loss (IPBSNHL) developed. IPBSNHL is a suspected
immunologically mediated hearing loss first described by McCabe in 1979. On the
basis of this association, hearing evaluation should be considered in the initial
and subsequent examinations of the patient with Sweet's syndrome.
PMID- 10767710
TI - Melanocytic nevus with pregnancy-related changes in size accompanied by apoptosis
of nevus cells: a case report.
AB - Melanocytic nevi are commonly believed to undergo changes during pregnancy. This
is probably related to hormonal influences; however, few studies have been able
to prove it. We observed a case of a benign melanocytic nevus, which showed
significant enlargement during pregnancy and immediate postpartum regression
associated with increased apoptosis of nevus cells. Estrogen and progesterone
receptors were not found in our case, although the clinical course still
suggested a close association with hormonal influences.
PMID- 10767711
TI - Telepathology: a diagnostic tool for the millennium?
AB - Many developments in science have their origins in science fiction and
telepathology is no exception. The concept was first illustrated in 1924 in the
magazine 'Radio News'. It was not until 1980, however, that the first working
telepathology system was demonstrated. Although the system was shown to work, it
required special hardware, dedicated software and special microwave transmission
links to be installed. Little interest was shown worldwide because of the very
high cost and the inability of many people to replicate such a system. Ten years
later, the personal computer (PC) was able to provide more than adequate
performance at low cost for both image display quality and speed, and the
development of video technology had resulted in high quality images being
produced by television cameras that were now easily affordable. Microscopes were
also relatively cheaper. Thus, by 1993 or 1994, all the hardware necessary to
produce a telepathology system was available at reasonable cost. Telepathology
can now be used for remote primary diagnosis, remote referral to a specialist
pathologist, remote teaching, remote presentation of post-mortem or microscopic
findings, quality assurance image circulation and feedback, and consensus
diagnosis for pathological review in clinical trials. There are two residual
problems. The first concerns the speed of data transmission, commonly referred to
as the bandwidth. The second is that the software provided by most of the
manufacturers and suppliers of these systems is not entirely suitable to the task
and the systems are not interoperable. It is clear that the approach of the
manufacturers is at present unlikely to produce telepathology systems which
pathologists feel comfortable in using. A somewhat different approach is
illustrated by the accompanying article in this issue from the Berlin group,
where a relatively simple Java-based applet and the Internet are used to allow
single or multiple users to view slides on a robotic microscope. This could form
the basis for a truly useful system, but still needs modification for some
applications.
PMID- 10767712
TI - Telepathology by the Internet.
AB - A new concept for telemicroscopy has recently been introduced using the Internet
and conventional web browser, with Java support for microscope remote control as
well as image transfer and discussion (http://amba.charite.de/telemic/). The
system has two major components: the telemicroscopy server, which is a computer
with Internet access connected to the automatic microscope, and the
telemicroscopy client, who remotely operates the microscope. This simplified
telemicroscopy system allows any Internet user to become a consultant for
telepathology without the acquisition of specialized hardware or software. For
the inquirer seeking advice, however, this solution is still very expensive,
since it requires a fully automated microscope. The present study describes a
system that can be used for conventional microscopes. A video camera mounted on a
microscope with a photo tube is connected to the frame grabber of a PC. Java
based telemicroscopy software transforms the computer into an Internet server,
which automatically distributes new microscope images, after manual operations,
to all connected clients. Any Internet user can access the web page of the server
to become a telemicroscopy client. A Chat function allows for the online exchange
of written text and a Discuss function enables the mouse button to display an
arrow to all connected clients, which highlights distinct structures of the
images. The system was optimized for simplicity, while presenting all features
that are necessary to show and discuss difficult cases with any expert in the
field who has Internet access. It offers new perspectives for telepathology and
it is envisaged that many pathologists and scientists will use this facility to
connect their personal microscopes to the Internet, forming a network for
teleconsultation. To foster this development, the software described in this
paper is being made freely available. Hopefully, this development will promote
communication between pathologists and may thus increase the quality of
diagnosis. Information on inquiry and installation of the software is available
at the website mentioned above. Telemicroscopy sessions using the Telemic version
for conventional microscopes can be scheduled by contacting the authors by e-mail
(iver. petersen@charite.de).
PMID- 10767713
TI - Evidence for post-transcriptional down-regulation of the apoptosis-related gene
bcl-2 in human colorectal cancer.
AB - This retrospective study was undertaken to investigate the expression of bcl-2
protein and messenger RNA in colorectal cancer (CRC). Immunohistochemical
analysis using a monoclonal mouse antibody to the bcl-2 protein and in situ
hybridization using a digoxigenin-labelled bcl-2 cRNA probe were carried out on
formalin-fixed and paraffin-embedded specimens from 53 colorectal
adenocarcinomas, 27 liver secondaries, and 60 adenomas with various degrees of
dysplasia. Normal human tonsil sections were used as positive controls.
Expression of bcl-2 protein and of messenger RNA was evaluated
semiquantitatively. The expression of bcl-2 protein was gradually and
significantly lost during the progression from moderately dysplastic adenoma to
primary CRC (moderate/severe dysplasia: Mann-Whitney U-test, p=0.0001; severe
dysplasia/primary CRC: p=0.027), whereas the cellular expression of bcl-2 mRNA
was gradually increased during the dysplasia/adenoma-carcinoma neoplastic
sequence. These observations suggest that in a proportion of colorectal cancer
cases, the bcl-2 proto-oncogene expression may be down-regulated at a post
transcriptional level.
PMID- 10767714
TI - Keratin 20 is a specific marker of submicroscopic lymph node metastases in
colorectal cancer: validation by K-RAS mutations.
AB - Lymph node status has major prognostic importance in colorectal cancer and
greater precision in the diagnosis of lymph node metastases should provide better
prognostic and therapeutic guidance. Keratin 20 (K20) gene expression has been
used as a marker of lymph node metastases, but the evidence for this remains
circumstantial. This study has therefore sought to determine K20 specificity and
to correlate K20 expression with mutant K-RAS expression, in order to provide
direct evidence that K20 expression in lymph nodes of colorectal cancer patients
genuinely reflects metastatic disease. Specificity of K20 expression was
established against a range of tissue types and 289 lymph nodes from 41 non
cancer control patients. K20 expression was restricted to gastrointestinal
epithelia and was only present in one of the 289 control lymph nodes, giving a
calculated specificity of 97.6% (95% confidence limits: 87.1-99.9%). Forty-two
tumour samples were analysed for the presence of K-RAS codon 12 gene mutations
using a RT-PCR mutant allele-specific amplification (MASA) technique. Thirteen
tumours (31%) had codon 12 mutations detected by MASA and these were further
analysed to determine the exact nature of the mutation. MASA was then used to
screen the lymph nodes from these patients for the presence of the tumour
specific K-RAS transcript and the results were compared with K20 RT-PCR and
histopathology from the same samples. Whilst K-RAS MASA was not as sensitive as
K20 RT-PCR, there was substantial agreement between the assays. There were no K20
negative lymph nodes which were found to be K-RAS MASA-positive, whereas seven
nodes in four patients were K20-positive and K-RAS-negative, in keeping with the
differences in assay sensitivity. These results further validate K20 as a marker
by providing greater certainty that what is being detected represents occult
metastatic disease.
PMID- 10767715
TI - Identification of frequent chromosomal aberrations in ductal adenocarcinoma of
the pancreas by comparative genomic hybridization (CGH).
AB - Despite the continuous progress in molecular methodology, the genetic events
involved in the initiation and progression of ductal adenocarcinoma of the
pancreas remain largely unknown. In this study, 33 pancreatic ductal
adenocarcinomas were screened for genomic alterations by comparative genomic
hybridization (CGH). To date, most CGH studies of pancreatic cancer have been
based on cell lines. To emphasize genetic imbalances that are involved in the in
vivo development and progression of pancreatic carcinoma only fresh-frozen or
paraffin-embedded tumour samples were analysed in the present study. Twenty-two
tumours (67%) showed genomic alterations involving up to three (12%) or more
(55%) chromosomal regions. The number and nature of the genetic imbalances did
not, however, correlate with tumour stage or grade. Chromosome 18 was
preferentially altered in the tumours analysed. Frequent chromosomal losses were
found at 18q, 10q, 8p, and 13q. Commonly gained regions were located on 8q and
3q. Moreover, high copy number amplifications of the chromosomal regions 5p, 8q22
ter, 12p12-cen, 19q12-13.2, and 20q were identified. These data provide evidence
for the occurrence of characteristic genomic alterations which are of biological
relevance for the genesis of pancreatic cancer. The identified altered
chromosomal regions may harbour tumour genes which involved in the multistep
process of pancreatic carcinogenesis.
PMID- 10767716
TI - p53 and P-glycoprotein expression are significant prognostic markers in advanced
head and neck cancer treated with chemo/radiotherapy.
AB - The development of biological markers of response to chemo- and radiotherapy to
judge benefit to risk ratios for toxic treatments is still at an experimental
stage. Tumour cell death is largely by apoptosis and the p53 gene has a major
influence on this. P-glycoprotein (P-gp) accumulation has been correlated with
treatment failure in several types of cancer. p53 and P-gp expression were
studied in 111 advanced head and neck cancers treated with radiotherapy and up to
four courses of synchronous or sequential chemotherapy. The probability of
survival at 5 years for patients in the trial as a whole was 27.7%, while the
cohort used for this marker project was 29.4%. Among the subjects used for the
marker study at the time of analysis, 13 remained disease-free and 18 were alive.
Immunohistochemistry was used to assess p53 and P-gp expression; 27/111 (24%)
head and neck cancers demonstrated p53/P-gp expression and 33/111 (30%) were both
p53- and P-gp- negative. In univariate analysis, both p53 and P-gp expression
were associated with reduced disease-free and overall survival. Multivariate
analysis revealed tumour size, p53, and P-gp expression as the most powerful
pretreatment prognosticators in the study cohort. Long-term follow-up results
suggest that p53 and P-gp co-expression predicts the biological behaviour or the
outcome following chemo/radiotherapy in advanced head and neck cancer.
PMID- 10767717
TI - Relationship between expression of the KAI1 metastasis suppressor and other
markers of advanced bladder cancer.
AB - Expression of a newly described inhibitor of tumour metastasis, KAI1, was
examined in bladder cancer progression and compared with the expression of p53
and pRb, which are markers of advanced disease. KAI1 mRNA (by in situ
hybridization) and protein levels (by immunohistochemistry) were examined in 135
paraffin-embedded bladder tissue sections. Significant decreases in KAI1 mRNA and
protein levels were detected between normal and tumour tissue (p<0.001 and
p=0.026, respectively), and between non-invasive and invasive tumours (p=0.046
and p<0.001, respectively). Loss of KAI1 protein expression was accompanied by a
shift in staining pattern from a uniform distribution to a weaker, membranous or
heterogeneous pattern. Normal tissue and low-grade tumours showed little p53
protein staining. High level staining (indicative of mutant p53) was associated
with increased grade in non-invasive tumours (p=0.031) but was not significantly
higher in invasive tumours. Whilst p53 protein staining increased with malignant
progression and KAI1 mRNA expression decreased, there was no significant
correlation between the two patterns (p=0.33, adjusted for group, p=0.18) or when
only cancer samples were analysed (p=0.065, adjusted for group, p=0.26), even
when taking into account overexpression of MDM-2 protein as a pathway for
inactivation of p53. There was no correlation between loss of KAI1 mRNA
expression and gain of abnormal pRb staining (p=0. 30, or adjusted for tumour
samples only, p=0.59). These results suggest that loss of KAI1 expression is
associated with invasive bladder cancer, but is not related to mutation of p53 or
to loss of normal pRb expression.
PMID- 10767718
TI - Evaluation of the membrane attack complex of complement for the detection of a
recent myocardial infarction in man.
AB - The diagnosis of an acute myocardial infarction (MI) can be cumbersome for
pathologists. Even with a positive nitroblue tetrazolium (NBT) reaction,
haematoxylin and eosin (H&E) evaluation of the myocardial tissue can remain
inconclusive. Early signs presumed diagnostic for myocardial infarction, such as
hypereosinophilia, waviness, and contraction band necrosis, have to be considered
non-specific and are probably reversible signs of ischaemia. Several studies
implicate the complement system, and especially complement factor C9, as part of
the membrane attack factor (MAC), in cardiomyocyte damage during MI. In a post
mortem study on well-documented cardiological autopsies, we evaluated the use of
complement factor C9 immunostaining as a marker for the detection of very recent
MI. Forty-three tissue samples from 40 patients were obtained from the left
ventricular free wall only, a region that can be specifically attributed to one
corresponding coronary artery. As some patients presented with MIs of various
stages in that perfusion area, in total 57 observations were possible. C9
immunostaining specifically detected irreversibly damaged (=infarcted)
cardiomyocytes, as is implied by the lytic activity of C9/MAC binding to cell
membranes. Most interesting was the group of clinically suspected, NBT-positive
MIs resulting from very recent myocardial ischaemia. In this population, where
H&E evaluation by (cardio-) experienced pathologists was not conclusive, C9
immunostaining clearly pointed towards myocardial infarction in 47% of the cases.
In conclusion, C9 immunostaining, routinely practicable in the pathology
laboratory, has an additional value in discriminating between reversible
ischaemia and infarcted cardiomyocytes in very early MIs.
PMID- 10767720
TI - Inactive matrix metalloproteinase 2 is a normal constituent of human glomerular
basement membrane. An immuno-electron microscopic study.
AB - Remodelling of the extracellular matrix requires tight control not only of matrix
synthesis, but also of matrix degradation. Control of matrix degradation is
achieved mainly through the matrix metalloproteinase (MMP) enzymes. In the
glomerulus, MMP-2 and MMP-9 are believed to be particularly important, as they
have activity against type IV collagen. This study has demonstrated by immuno
electron microscopy that most of the immunoreactivity for MMP-2 in the normal
glomerulus is located within the glomerular basement membranes and mesangial
matrix. mRNA for MMP-2 is also detectable in normal glomeruli, but the other main
gelatinase, MMP-9, could not be localized by immuno-electron microscopy. In the
normal glomerulus, it seemed likely that MMP-2 is present in an inactive form. To
confirm this, in situ zymography was carried out using frozen sections of normal
kidney. Baseline activity of normal kidney was relatively weak, but this was
dramatically increased by chemical activation of metalloproteinases. The results
imply that MMP-2, in an inactive form, is a normal constituent of the
extracellular matrix and glomerular basement membranes. Activation would
presumably render the matrix 'self-degrading'; membrane-bound MMPs (MT-MMPs) seem
particularly likely to be involved in leukocyte penetration of basement membranes
in inflammation.
PMID- 10767719
TI - Expression of endothelial cell adhesion molecules on heart valves: up-regulation
in degeneration as well as acute endocarditis.
AB - Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor
alpha (TNF-alpha), as well as shear stress, cause endothelial cells (ECs), to
undergo not only functional alterations but also structural reorganizations,
which contribute to vascular leakage. Like ECs of the human aorta, ECs on heart
valves are exposed to extreme shear stress. However, while ECs expression of cell
adhesion molecules (CAMs) in large vessels has been widely studied, it seems that
there are no such studies on ECs of heart valves, although this knowledge might
be important for our understanding of the aetiological aspects of local
inflammatory responses. Using immunohistochemistry, this study characterized the
CAM expression of ECs on degenerative, mostly calcified heart valves and on heart
valves with florid endocarditis. As expected, the constitutively expressed
molecules (ICAM-1, CD34, CD31) were found both on degenerative and on inflamed
valves. Furthermore, marked expression of E-selectin and VCAM-1 was found not
only on inflamed valves, but also on larger portions of the degenerative valves
with no morphological evidence of inflammation. This striking finding might help
to explain why patients with fibrotic heart valves are susceptible to recurrent
endocarditis. Why the endothelial activation markers E-selectin and VCAM-1 are
expressed on degenerative heart valves requires further investigation.
PMID- 10767721
TI - Amniotic tissue in complete hydatidiform moles can be androgenetic.
AB - The purpose of this study was to determine whether amniotic tissue found
associated with cases of complete hydatidiform mole (CM) was genetically
identical to the CM, and therefore part of the molar pregnancy, or genetically
dissimilar to the CM, suggesting derivation from a twin pregnancy. DNA was
prepared from formalin-fixed, paraffin-embedded blocks of tissue containing both
CM and amnion. Maternal DNA was prepared from decidual tissue in the same blocks,
or from a maternal blood sample. Fluorescent microsatellite genotyping was
carried out to determine the origin of both the CM and the amniotic tissue. In
one of six cases examined, the amniotic tissue was genetically different from the
CM and was therefore likely to be derived from a twin pregnancy. In the five
remaining cases, the amniotic tissue was genetically identical to the CM and was
likely to be derived from the same conceptus. It is concluded that androgenetic
CM can support the development of amniotic tissue and that some early embryonic
development may occur in CM. The presence of amnion, or other fetal tissues,
associated with molar tissue should not therefore always be considered indicative
of a diagnosis of partial mole (PM).
PMID- 10767722
TI - Up-regulation of inducible nitric oxide synthase in fibroblasts parallels the
onset and progression of fibrosis in an experimental model of post-transplant
obliterative airway disease.
AB - The main cause of mortality following lung transplantation is chronic rejection,
manifesting morphologically as obliterative bronchiolitis (OB). It has been
suggested that damage to the respiratory epithelium initiates proliferation of
mesenchymal cells, leading to dense collagenous scarring in small airways.
Inducible nitric oxide synthase (iNOS) is strongly expressed in the damaged
epithelium in human OB, along with high levels of peroxynitrite, suggesting that
endogenous NO mediates the epithelial destruction. To examine further the role of
iNOS in this process, heterotopic airway implants were studied in rats, an
acknowledged disease model. Specimens of iso- or allografted trachea, collected 3
60 days after implantation, were processed for histology and immunocytochemistry
for iNOS and, as a marker of peroxynitrite formation, nitrotyrosine. In both iso-
and allografts at the earliest stage (day 3), ischaemia was associated with
severe epithelial damage or loss. These changes progressed until day 7 and were
accompanied by strong expression of iNOS and nitrotyrosine in epithelial cells.
In isografts, epithelial recovery was seen, with abundant iNOS immunoreactivity
but little nitrotyrosine. In contrast, the epithelium in allografts did not
regenerate and progressive inflammation and fibroproliferation occurred until
complete obliteration of the tracheal lumen at day 60. The fibroproliferation was
associated with changes in morphology of fibroblasts that were accompanied by
alterations in their iNOS expression. iNOS immunoreactivity was dense in the
plump fibroblasts of early lesions, in some cases as early as post-operative day
5, but very weak in elongated fibroblasts in totally occluded grafts. The
intensity of immunoreactivity for nitrotyrosine corresponded to that of iNOS.
These results indicate a dual role for NO in the airway obliteration that follows
transplantation, through destruction of epithelium and stimulation of fibroblast
activity.
PMID- 10767723
TI - Transplanted hepatocytes engraft, survive, and proliferate in the liver of rats
with carbon tetrachloride-induced cirrhosis.
AB - Repopulation of the cirrhotic liver with disease-resistant hepatocytes could
offer novel therapies, as well as systems for biological studies. Establishing
whether transplanted hepatocytes can engraft, survive, and proliferate in the
cirrhotic liver is a critical demonstration. Dipeptidyl peptidase IV-deficient
F344 rats were used to localize transplanted hepatocytes isolated from the liver
of syngeneic normal F344 rats. Cirrhosis was induced by administration of carbon
tetrachloride with phenobarbitone and these drugs were withdrawn prior to cell
transplantation. Cirrhotic rats showed characteristic hepatic histology, as well
as significant portosystemic shunting. When hepatocytes were transplanted via the
spleen, cells were distributed immediately in periportal areas, fibrous septa,
and regenerative nodules of the cirrhotic liver. Although some transplanted cells
translocated into pulmonary capillaries, this was not deleterious. At 1 week,
transplanted cells were fully integrated in the liver parenchyma, along with
expression of glucose-6-phosphatase and glycogen as reporters of hepatic
function. Transplanted cells proliferated in the liver of cirrhotic animals and
survived indefinitely. At 1 year, transplanted hepatocytes formed large clusters
containing several-fold more cells than normal control animals, which was in
agreement with increased cell turnover in the cirrhotic rat liver. The findings
indicate that the cirrhotic liver can be repopulated with functionally intact
hepatocytes that are capable of proliferating. Liver repopulation using disease
resistant hepatocytes will be applicable in chronic conditions, such as viral
hepatitis or Wilson's disease.
PMID- 10767724
TI - Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced
NOD mouse model by reducing beta-cell apoptosis.
AB - The development of diabetes in non-obese diabetic (NOD) mice, which normally
takes between 3 and 7 months, can be accelerated by cyclophosphamide (CY)
injections, with rapid progression to diabetes within only 2-3 weeks. This
insulin-dependent diabetes mellitus (IDDM) can be prevented or delayed in CY
treated NOD mice by nicotinamide (NA). The present study was undertaken to
determine the mode of cell death responsible for the development of IDDM in CY
treated male NOD mice and to investigate the effect of NA on beta-cell death.
Apoptotic beta cells were present within the islets of Langerhans in haematoxylin
and eosin-stained sections of the pancreata harvested from 3- and 12-week-old
male NOD mice, from 8 h until 14 days after a single intraperitoneal injection of
CY (150 mg/kg body weight). The maximum amount of beta-cell apoptosis in 3-week
old animals occurred 1-2 days after CY treatment (20 apoptotic cells per 100
islets), after which time levels of apoptosis declined steadily throughout the 14
day period studied. The incidence of beta-cell apoptosis in 12-week-old male NOD
mice occurred in two peaks; the first was recorded 8-24 h after CY treatment (30
apoptotic cells/100 islets), while the second, at 7 days (36 apoptotic cells per
100 islets), coincided with increased insulitis. Administration of NA 15 min
before CY treatment, and thereafter daily, substantially reduced the amount of
apoptosis and effectively eliminated (4 apoptotic cells per 100 islets) the
second wave of beta-cell apoptosis seen at day 7 in 12-week-old animals given CY
alone. These results show that apoptosis is the mode of beta-cell death
responsible for the development of CY-induced IDDM and that prevention of IDDM by
NA is associated with a reduction in beta-cell apoptosis.
PMID- 10767725
TI - Age-related amyloid beta protein accumulation induces cellular death and
macrophage activation in transgenic mice.
AB - In view of the importance of amyloid beta protein accumulation in Alzheimer's
disease, this paper examines age-related amyloid beta protein (Abeta) deposition
and accompanying cellular changes in a mouse model in vivo. Transgenic mice were
studied which expressed a gene encoding 18 residues of signal peptide and 99
residues of the carboxyl-terminal fragment (CTF) of the Abeta precursor, under
the control of the cytomegalovirus enhancer/chicken beta-actin promoter. In the
pancreas, Abeta accumulated in an age-dependent manner. Abeta deposits appeared
as early as 3 weeks of age and increased in size and number from 4 to 16 months
of age. The largest Abeta deposits were observed in the transgenic pancreas at 16
and 20 months of age. Haematoxylin and eosin staining, macrophage immunostaining,
and electron microscopy showed that the Abeta fibril deposits closely correlated
with degeneration of pancreatic acinar cells and macrophage activation. Abeta1-42
and Abetap3E-42 were predominant components of Abeta deposits among amino- and
carboxyl-terminal modified Abeta species. These findings suggest that
overproduction of Abeta causes age-related accumulation of Abeta fibrils, with
accompanying cellular degeneration and macrophage activation in vivo.
PMID- 10767727
TI - Author's reply
PMID- 10767726
TI - Ep-CAM in malignant liver tumours.
PMID- 10767728
TI - A randomised, double-blind comparison of the efficacy and safety of citalopram
compared to mianserin in elderly, depressed patients with or without mild to
moderate dementia.
AB - Depression is the most common psychiatric disorder among the elderly and in old
age may interact with emotional and cognitive functioning. Depression in old age
has been shown to be associated with degenerative changes in the brain. It is,
therefore, important that in this patient population antidepressants with a
favourable tolerability profile, such as the selective serotonin reuptake
inhibitors (SSRIs), are examined for both antidepressant efficacy and effect on
cognitive function and emotional impairment. This randomised, double-blind study
compared the efficacy and tolerability of citalopram and mianserin in 336
elderly, depressed patients with or without dementia. Patients received either
citalopram 20-40 mg/day or mianserin 30-60 mg/day for 12 weeks. The treatments
were equivalent with respect to change in Montgomery-Asberg Depression Rating
Scale (MADRS) total score; patients in both treatment groups responded well.
Patients with dementia showed a smaller decrease in total MADRS score than
patients without dementia. Both treatments were well tolerated with a relatively
low incidence of adverse events. Fatigue and somnolence were more frequent with
mianserin, while insomnia was more frequent with citalopram. Overall, this study
showed that the two treatments were equivalent in efficacy, and that citalopram
is an effective, well-tolerated and non-sedative treatment for elderly depressed
patients with or without dementia.
PMID- 10767729
TI - CT measurement of medial temporal lobe atrophy in Alzheimer's disease, vascular
dementia, depression and paraphrenia.
AB - OBJECTIVE: Measurement of medial temporal lobe atrophy (MTL) by computerised
tomography (CT) may be a useful adjunct to the diagnosis of AD. The aim of this
study was to assess the sensitivity, specificity, predictive values and
diagnostic accuracy of CT measurement of MTL thickness for patients with probable
AD, compared with a 'diseased' control group, and to correlate the measure with
neuropsychological test scores. DESIGN: Cross-sectional. METHODS: One hundred
subjects were prospectively recruited: 60 with probable AD (mean age 73.7 years,
mean Mini-Mental State Examination [MMSE] 19.6), 17 with probable vascular
dementia (VaD) (mean age 77.9 years, mean MMSE 20.9), 14 with depression (mean
age 73.2 years, mean MMSE 25.7) and nine with paraphrenia (mean age 74 years,
mean MMSE 25.4). Axial and temporal lobe-oriented CT brain was performed and the
minimum MTL thickness was measured electronically. RESULTS: The mean minimum MTL
thickness was significantly smaller in AD subjects compared to VaD (p<0.0001) and
psychiatric subjects (p<0.0001). For the clinical diagnosis of probable AD, the
sensitivity of the measure was 0.75, specificity 0.9, and diagnostic accuracy
0.81. For the mildest cases of AD (CDR 0.5), the sensitivity of the measure was
0.61, specificity 0.91, and diagnostic accuracy 0.81. No significant correlations
with neuropsychological test scores were found. CONCLUSIONS: Temporal lobe
oriented CT imaging is a non-invasive test with good discrimination for AD.
Potential uses of this technique include as an aid to diagnosis and possibly as a
means of monitoring disease progression.
PMID- 10767730
TI - Factor analysis supports the evidence of existing hyperactive and hypoactive
subtypes of delirium.
AB - OBJECTIVE: The aim of this study was to examine whether delirium has specific
clinical subtypes. METHOD: One hundred and eighty-three elderly subjects meeting
DSM-IIIR criteria for delirium were evaluated using a 19-item symptom check-list
assessing different dimensions of delirium symptomatology. Exploratory factor
analysis was conducted in order to examine which symptoms clustered. RESULTS:
Factor analysis confirmed the existence of two different clusters of symptoms:
first, symptoms of hyperalert/hyperactive features (agitation, hyper-reactivity,
aggressiveness, hallucinations, delusions); and second, symptoms of
hypoalert/hypoactive features (decreased reactivity, motor and speech
retardation, facial inexpressiveness). CONCLUSION: This preliminary study seems
to support the evidence of hypoactive and hyperactive subtypes of delirium, even
though their aetiology and prognostic values need to be further examined.
PMID- 10767731
TI - The clinical utility of the Hopkins Verbal Learning Test as a screening test for
mild dementia.
AB - OBJECTIVE: The purpose of this study was to determine whether the Hopkins Verbal
Learning Test (HVLT) could be used as a valid and reliable screening test for
mild dementia in older people, and to compare its performance to that of the Mini
Mental State Examination (MMSE). METHOD: Using a cross-sectional design, we
studied three groups of older subjects recruited from a district geriatric
psychiatry service: (1) 26 patients with DSM-IV dementia and MMSE scores of 18 or
better; (2) 15 patients with psychiatric diagnoses other than dementia; and (3)
15 normal controls. The relationship of each potential cutting point on the HVLT
and the MMSE was examined against the independently ascertained DSM-IV diagnoses
of dementia using a Receiver Operating Characteristic (ROC) analysis. RESULTS:
The subjects consisted of 21 (37.5%) males and 35 (62.5%) females with a mean age
of 74.7 (SD 6.1) years and a mean of 8.5 (SD 1.8) years of formal education. ROC
analysis indicated that the optimal cutting point for detecting mild dementia in
this group of subjects using the HVLT was 18/19 (sensitivity=0.96,
specificity=0.80) and using the MMSE was 25/26 (sensitivity=0.88,
specificity=0.93). CONCLUSIONS: The HVLT can be recommended as a valid and
reliable screening test for mild dementia and as an adjunct in the clinical
assessment of older people. The HVLT had better sensitivity than the MMSE in
detecting patients with mild dementia, whereas the MMSE had better specificity.
PMID- 10767732
TI - Demented patients' participation in a clinical trial: factors affecting the
caregivers' decision.
AB - Clinical trials for Alzheimer's disease take place in medical centers all over
the world. Patients and caregivers have to decide whether or not to agree to
participate in clinical trials. This study aimed to investigate the motivation
that determines the caregivers' choice. Nineteen caregivers of demented patients
who consented to participate in a clinical trial in our Memory Clinic and 10
caregivers who refused to participate were interviewed. The data were gathered by
a self-report questionnaire covering various aspects of the caregivers' decision
making process. Among the reasons for agreeing to participate in the clinical
trial were the respondents' belief that it would improve or help to maintain the
patients' condition. Most of the respondents of both groups indicated that
information regarding side effects and success probability was adequately
provided in advance. The primary reason for refusal was the potential side
effects of the drug. The implications of the findings are discussed.
PMID- 10767733
TI - Depression in holocaust survivors: profile and treatment outcome in a geriatric
day hospital program.
AB - The profile of depressive symptoms and the outcome of treatment in Holocaust
Survivors (HS) versus non-Holocaust Survivors (NS), attending a Psychiatric Day
Hospital Program for depression, were evaluated retrospectively using a clinical
database. Approximately 24% of the study population were Holocaust Survivors
(HS). The HS group was more likely to receive a diagnosis of major depressive
disorder or episode as one of their diagnoses. The HS group, in particular those
survivors who had been in ghettos or in concentration camps, were more likely to
be given a diagnosis of post-traumatic stress disorder. Both groups showed
improvement from baseline in their ratings of depression on the Hamilton
Depression Rating Scale (HDRS) and Geriatric Depression Scale at the time of
discharge (p<0.001). However, there were no significant differences between the
groups in terms of their ratings of depression either at admission, at discharge
or in their degree of improvement. Likewise, there was no significant difference
between the groups in the profile of their depression, as per the sub-scales of
the HDRS, with the exception that the HS group displayed more 'insight' than the
NS group (p=0.002). The NS group scored higher on the Mattis Dementia Rating
Scale compared to the HS group (119.1 versus 125.4, p<0.001), even when level of
education was covaried; however, language may be an important confound. In
conclusion, there was no significant difference in the profile or outcome of
depression between groups. However, the HS group was more likely to receive a
diagnosis of post-traumatic stress disorder, displayed more 'insight', and appear
to differ in their cognitive profile.
PMID- 10767734
TI - Donepezil for behavioural disorders associated with Lewy bodies: a case series.
AB - Dementia with Lewy bodies (DLB) has been associated with important behavioural
disturbances, such as psychotic symptoms. Unfortunately, neuroleptic sensitivity
in these patients limits effective pharmacological management of these symptoms.
Seven patients, five male and two female (mean age 75.3+/-4.7 years, range 68
81), diagnosed with DLB were treated with the acetylcholinesterase inhibitor
donepezil (5-10 mg once daily) to determine its effect on treating behavioural
disorders. Although the intended length of treatment was a minimum of 8 weeks,
only three patients completed 8 weeks of therapy, one patient completed 6 weeks,
two patients completed 4 weeks and one patient was discontinued after 5 days. The
primary outcome (behavioural disturbances) was measured prospectively by the
Neuropsychiatric Inventory (NPI), while other outcomes included cognition (Mini
Mental State Examination (MMSE)) and Clinical Global Impression. Three of the
seven subjects showed marked improvement in behaviour, with NPI scores dropping
significantly over time. Donepezil therapy was discontinued prematurely in three
of the cases due to insufficient response and/or adverse events. Overall, five of
the seven patients were rated at least minimally improved in behavioural
symptoms. Our experience with donepezil in this group of patients shows promise.
Given the limited experience with this agent in treating behavioural disorders
associated with DLB, further studies are warranted.
PMID- 10767735
TI - Psychiatric morbidity in elderly patients admitted to non-psychiatric wards in a
general/teaching hospital in Nigeria.
AB - OBJECTIVE: To determine the mental morbidity rate and types of disorders in
elderly patients admitted to non-psychiatric wards of a teaching hospital in
Nigeria; the ability of the non-psychiatrists to recognise the mental disorders
was also assessed. METHOD: All subjects aged 60 years and above who were admitted
into the medical, surgical and gynaecological wards were assessed with the Self
Reporting Questionnaire, Mini Mental State Examination and the Geriatric Mental
State Schedule. Diagnoses of mental disorders were made with the ICD-10
Diagnostic Criteria for Research. The patients' case records were then examined
to determine the medical and any mental disorder diagnoses made by the attending
physicians. The data were analysed by the SPSS/PC(+) computer package. RESULTS:
The mental morbidity rate was 45.3% with depression being the commonest disorder,
followed by organic disorders (delirium and dementia), adjustment disorder and
generalised anxiety disorder. There were also cases of alcohol and drug abuse.
The physicians recognised only 2.8% of the mental disorders and referred one
dementia patient to the mental health team. The negative predictive value for the
physicians was poor. CONCLUSION: Non-psychiatrist medical practitioners in
Nigeria need adequate training in mental health to enhance their ability to
recognise psychiatric disorders.
PMID- 10767736
TI - The pattern of psychiatric disorders among the aged in a selected community in
Nigeria.
AB - OBJECTIVE: To describe the common mental disorders in elderly Nigerians living at
home. METHOD: A house-to-house survey of a rural community was conducted to
identify subjects who were aged 60 years and above. The subjects were interviewed
with the Self-Reporting Questionnaire (SRQ-24) and the Geriatric Mental State
Schedule (GMS). Psychiatric syndromal diagnoses were made with the Clinical and
Research ICD-10 manuals (ICD-10/ICD-10, DCR). RESULTS: The overall rate of major
mental disorders was 23.1%, with depression constituting 79% of all the
diagnoses. Specific dementia disorders were not found in any of the subjects
(N=164), but 20.7% complained of forgetfulness. Use of tobacco (snuff), (local)
alcohol, and other substances were common. No subject with any identified
disorder was receiving any medical attention. CONCLUSION: The study reveals the
same range of mental disorders as in studies carried out elsewhere. This suggests
that if similar methodologies are used, the mental morbidity rates among the
elderly in different parts of the world may be about the same. There is a need
for adequate planning to accommodate the social security and mental health needs
of old Nigerians.
PMID- 10767737
TI - Course of objective memory impairment in non-demented subjects attending a memory
clinic and predictors of outcome.
AB - The aim of the study was to investigate the course of objective memory impairment
in non-demented subjects who attended a memory clinic and to test predictors of
outcome. Non-demented subjects (N=74) were included when they were older than 40
years and had a baseline score on the delayed recall of a word learning test
below the tenth percentile. Subjects with memory impairment due to known somatic
or neurological causes were excluded. The subjects were reassessed after 2 and 5
years. At the 5-year follow-up, 42% of the subjects had no memory impairment, 19%
of the subjects had memory impairment without dementia, and 39% of the subjects
had Alzheimer type dementia (AD). Predictors at baseline of reversible memory
impairment in a multivariate analysis were age, scores on the MMSE and delayed
recall, and the degree of functional impairment. Predictors at baseline of AD in
a multivariate analysis were age and the score on the MMSE. The apolipoprotein E
genotype and the presence of depression at baseline were not predictors of
outcome. The positive predictive value was 72% for reversible memory impairment
and 81% for AD. Memory impairment is often reversible and therefore its presence
alone is not sufficient to consider subjects as preclinically demented.
Predictive accuracy can be increased by including simple measures such as age,
the scores on the MMSE and delayed recall, and the degree of functional
impairment.
PMID- 10767738
TI - Interrater reliability of the short-memory questionnaire in a variety of health
professional representatives.
AB - A study was performed to assess interrater reliability of the Japanese version of
the Short-Memory Questionnaire (SMQ), which is an easily-administered, informant
based scale of cognitive function. The subjects were 18 consecutive patients with
Alzheimer's disease who were outpatients of Department of Neuropsychiatry in
Ehime University School of Medicine and their principal caregivers. One
neuropsychiatrist (NP) administered the SMQ, and all sessions were videotaped.
Then one nurse (Ns), one clinical psychologist (CP), one occupational therapist
(OT), and one neurologist (NL) from another institution viewed the videotape and
performed reassessments independently. Interrater reliability between the NP and
Ns, CP, OT, or NL were all extremely good. Interrater reliability between the Ns
and CP, between the Ns and OT, between the Ns and NL, between the CP and OT,
between the CP and NL, and between the OT and NL were also extremely good. The
SMQ is a convenient, quantitative scale, and in this study it showed good
interrater reliability between personnel from different fields. Therefore, it is
a very useful test for everyday medical consultations and for clinical research.
PMID- 10767739
TI - Cultural differences.
PMID- 10767741
TI - Foreword
PMID- 10767740
TI - Current awareness
AB - In order to keep subscribers up-to-date with the latest developments in their
field, John Wiley & Sons are providing a current awareness service in each issue
of the journal. The bibliography contains newly published material in the field
of geriatric psychiatry. Each bibliography is divided into 9 sections: 1 Books,
Reviews & Symposia; 2 General; 3 Assessment; 4 Epidemiology; 5 Therapy; 6 Care; 7
Dementia; 8 Depression; 9 Psychology. Within each section, articles are listed in
alphabetical order with respect to author. If, in the preceding period, no
publications are located relevant to any one of these headings, that section will
be omitted
PMID- 10767742
TI - Introduction to behavioural and psychological symptoms of dementia (BPSD).
PMID- 10767743
TI - Clinical issues in the behavioural and psychological symptoms of dementia.
PMID- 10767744
TI - Carer burden dementia.
PMID- 10767746
TI - Appendices
PMID- 10767745
TI - Control of aggression and agitation in patients with dementia: efficacy and
safety of risperidone.
PMID- 10767747
TI - The cancer patient with borderline personality disorder: suggestions for symptom
focused management in the medical setting.
AB - Medically ill cancer patients with borderline personality disorder (BPD) face
formidable emotional challenges as they cope with cancer diagnosis and treatment.
The anxiety and discomfort associated with medical treatment can lead them to
have difficulties with medical caregivers, distort reality for emotional
protection, or exhibit outright aggression and self-destructiveness. Co-morbid
substance abuse or a history of physical or sexual trauma may further complicate
cancer treatment. These patients may be in particular need of symptom-focused
psychotherapeutic management, which must include comprehensive assessment and
treatment of psychiatric symptoms, measures to limit aggression and self
destructiveness, and staff education and support. These interventions can reduce
patients' distress and maximize cancer treatment outcomes.
PMID- 10767748
TI - Involving family members in cancer care: focus group considerations of patients
and oncological providers.
AB - Family members are an integral part of a patient's cancer care from the moment
the diagnosis is delivered to the conclusion of treatment. Family members bring
with them a range of emotional reactions, interpersonal dynamics and expectations
for the care the patient receives. This study is part of a multi-institutional
project to continue to improve the process of cancer care. In this study, 19
focus groups (11 patient and 8 provider) were conducted concerning issues related
to doctor-patient communication in eight cancer centers in the United States. The
content of the conversations was analyzed and thematic categories emerged that
highlight the various strengths and difficulties associated with family
involvement. The focus groups' comments support the need for explicit
conversations between professional caregivers, patients and their loved ones, in
order to negotiate the expectations and needs of each team member. Implications
for clinical practice and strategies for working with family members are offered.
PMID- 10767749
TI - Social skills and psychological adjustment of child and adolescent cancer
survivors.
AB - Social skills and psychological adjustment for survivors of childhood cancer were
investigated. Cancer survivors included 42 children and adolescents ranging in
age at evaluation from 6 to 18 years with a mean age of 13.1 years. Measures
included teacher and parent ratings of social skills and adjustment and parent
ratings of family functioning. The findings showed that social skills and
psychological adjustment as rated by both parents and teachers were primarily
associated with academic functioning. In addition, family cohesiveness was found
to account for nearly one third of the variance in survivors' adjustment when
rated by teachers, and length of time off treatment accounted for a significant
percentage of the variance in children's adjustment when rated by parents. The
findings underscore the importance of a multi-informant approach to the
assessment of psychological adjustment of pediatric cancer survivors and
demonstrate the role of learning difficulties and family functioning in
influencing social skills and adjustment for these children and adolescents.
PMID- 10767750
TI - Physical exercise and quality of life in cancer patients following high dose
chemotherapy and autologous bone marrow transplantation.
AB - Preliminary evidence indicates that physical exercise may be an effective
strategy for the rehabilitation of cancer patients following high dose
chemotherapy (HDC) and bone marrow transplantation (BMT), but the focus of this
research has been on physical fitness and medical outcomes. In the present study,
we employed a prospective design to examine the relationship between physical
exercise and various quality of life (QOL) indices in 25 BMT patients.
Participants completed weekly self-administered questionnaires upon being
admitted to hospital, and monitored the frequency and duration of their exercise
during hospitalization. Statistical analyses indicated that exercise during
hospitalization was significantly correlated with almost all QOL indices,
including physical well-being, psychological well-being, depression, anxiety and
days hospitalized. Moreover, only some of the correlations were attenuated after
controlling for relevant demographic and medical variables. It was concluded that
physical exercise may be related to QOL in BMT patients, but that experimental
research is needed before any definitive conclusions can be drawn.
PMID- 10767751
TI - Young women's experience of breast cancer: defining young and identifying
concerns.
PMID- 10767752
TI - Communication styles in the cancer consultation: preferences for a patient
centred approach.
AB - OBJECTIVE: Although doctor-patient communication has been the focus of numerous
studies, there is a lack of empirical evidence on which to base a curriculum for
teaching effective communication skills for use in an oncology setting. Research
within the general practice area identifies patient-centred and doctor-centred
behaviours as the most important dimensions of doctor-patient communication. This
study examined patients and their relatives/friends' preferences for and
satisfaction with patient-centred and doctor-centred consulting styles. It was
argued that by determining patient preferences for consulting styles, specific
recommendations for improving communication in the oncology setting could be
formulated. PARTICIPANTS AND METHODS: One hundred and thirteen women who had been
treated for breast cancer and 48 of their relatives or friends watched videotaped
scenarios of an oncology consultation, using professional actors. Viewers were
randomly allocated to either a good prognosis or poor prognosis video, in which
the oncologist discussed the patient's diagnosis, treatment and prognosis. These
segments were presented in both styles to allow viewers to directly compare and
contrast the patient-centred and doctor-centred approach. Outcomes included style
preference and satisfaction. Demographic details, information and involvement
preferences, anxiety and depression levels were also obtained. RESULTS: Both
patients and their relatives or friends significantly preferred a patient-centred
consulting style across all aspects of the consultation (p<0.0001), except within
the treatment segment of the good prognosis video where there was no significant
difference. One third of the viewers preferred a doctor-centred style for the
treatment and prognosis segments. Predictors of a patient-centred style
preference in the treatment and prognosis segments included watching a poor
prognosis video (OR=2.45, 95% CI 1.04-5.81, p=0.04; OR=3.22, 95% CI 1.22-8.50,
p=0.02, respectively), and being employed in a professional occupation (OR=2.38,
95% CI 1.02-5.53, p=0.04 for the treatment segment only). Satisfaction ratings
varied within and across videos. CONCLUSION: Despite some methodological
limitations, this study provides empirical data indicating that patients and
their relatives or friends prefer a patient-centred approach to the consultation,
particularly when the patient has a poor prognosis. The fact that a substantial
minority of patients preferred a doctor-centred style emphasizes the need to
enhance physicians' abilities to recognize different patient needs throughout the
consultation.
PMID- 10767753
TI - Reproducibility of PET brain mapping of cancer patients.
AB - Twenty German cancer patients (56.9+/-12.7 years old) without brain metastasis
underwent neurological PET. The acquired brain data were compared to the data of
ten age and sex-matched controls (53.6+/-15. 7). Scores of Zung's Self-rating
Depression Scale (SDS) obtained from 15 out of the 20 patients suggested they
might be mildly depressed. Scores of Taylor's Manifest Anxiety Scale (MAS), used
for additional psychological evaluation, were close to normal distribution.
Hypometabolic areas in the German cancer patients were compared with those
demonstrated in our previous study in Japanese cancer patients. Common findings
in both studies were observed in the limbic structures, such as the anterior and
posterior cingulate gyri, the basolateral frontal cortices, as well as in the
basal ganglia (especially the caudate nucleus) and frontal cortex. These results
are in accordance with many previous PET studies on major depression. The results
show that the positron emission tomography and (18)F-fluoro-deoxyglucose ((18)FDG
PET) brain mapping results could be partially reproduced, and suggest that PET
brain mapping of cancer patients has a potential clinical application to the
field of psycho-oncology and cancer patient care.
PMID- 10767754
TI - An exploratory factor analysis of existential suffering in Japanese terminally
ill cancer patients.
AB - To determine an underlying factorial structure of existential distress in
Japanese terminally ill cancer patients, a principal components analysis was
performed on 162 Japanese hospice inpatients. Existential distress commonly
identified was dependency (39%), meaninglessness in present life (37%),
hopelessness (37%), burden on others (34%), loss of social role functioning
(29%), and feeling emotionally irrelevant (28%). By a factor analysis, three
primary components accounted for 66% of the variance. 'Dependency' and 'loss of
social role functioning' loaded highly on the first factor, which was interpreted
as 'loss of autonomy'. 'Burden on others' and 'feeling emotionally irrelevant'
loaded highly on the second component interpreted as 'lowered self-esteem', while
'hopelessness' loaded highly on the third factor. On the other hand,
'meaninglessness in present life' loaded equally on all three components, and was
significantly associated with other distress. In conclusion, existential
suffering of Japanese terminally ill cancer patients has three principal
components: loss of autonomy, lowered self-esteem, and hopelessness. It is also
suggested that meaninglessness in present life would be an underlying theme in
patients' spirituality.
PMID- 10767755
TI - Applicability of a Western-developed psychosocial group intervention for Japanese
patients with primary breast cancer.
AB - This paper examines the applicability of psychosocial group intervention for
Japanese patients with primary breast cancer. The study included two phases.
First, we examined the applicability for Japanese patients of an intervention
model developed in a Western country. The model, based on the work of Fawzy and
Fawzy (1994) on a structured psychosocial group intervention for cancer patients,
is a series of six 1.5-h sessions that incorporate health education, coping
skills training, relaxation training and psychological support. Second, we
formulated a Japanese version of the intervention model by modifying areas
identified as inappropriate by participants in the first-phase study. We then
evaluated this by conducting sessions of the modified model with 44 additional
breast cancer patients. Of the ten participants in the first-phase pilot study,
three (30%) dropped out and several inappropriate areas were reported. The areas
requiring significant change were the provision of medical information and
communication style with family members and doctors. No participants dropped out
of the modified version, and very few found any program areas to be
inappropriate. The findings suggests that psychosocial group intervention is
applicable for Japanese breast cancer patients when the model accounts for
cultural differences.
PMID- 10767756
TI - Clinical update
PMID- 10767757
TI - Laser mass spectrometry for environmental and industrial chemical trace analysis
AB - Resonant laser mass spectrometry is a promising method for chemical trace
analysis since it combines selectivity, sensitivity and rapidity of measurement.
It is a two-dimensional technique incorporating medium- or high-resolution UV
spectroscopy and time-of-flight mass spectrometry. No sample preparation and
chemical clean-up is necessary to reach detection limits in the sub-ppb range
even when highly complicated mixtures of chemical species are analyzed. After an
introduction to the principles of resonant laser mass spectrometry, illustrative
examples of applications are presented. Drawbacks, possibilities of overcoming
them, some interesting features and future developments of resonant laser mass
spectrometry are discussed.
PMID- 10767758
TI - Ion trap mass spectrometry of trimethylsilylamides following gas chromatography.
AB - Fatty acid amides are a class of compounds with newly discovered biological
activity. The ion trap mass spectrometric characteristics of silylated fatty acid
amides were examined. Silylation of primary fatty acid amides is required prior
to gas chromatography owing to thermal instability of the underivatized compound.
The trimethylsilylated amides do not yield a molecular ion under normal electron
ionization conditions (70 eV). With methane as a chemical ionization gas, the
[M+H]+ ion appears. The [M+H]+ ion also appears when the helium buffer gas
pressure is increased in the ion trap. There are three fragments other than the
[M+H]+ peak that are predominant in the ion trap mass spectra of these compounds.
Two of the fragments have been reported previously, namely the m/z 59 and the [M
71]+ fragments. The fragment of m/z 72 was identified and is the result of a
rearrangement. Isotopic labeling was used to confirm fragment identity and the
composition of the rearrangement products. Fragmentation patterns were affected
by the amide chain length and concentration.
PMID- 10767759
TI - Quadrupole ion trap studies of the structure and reactivity of transition metal
ion pair complexes
AB - Ion pairs are common species observed in the electrospray mass spectra of
transition metal coordination complexes. To understand the nature of these ion
pairs, a systematic study of the gas-phase chemistry of these species using ion
molecule reactions and collision-induced dissociation (CID) was carried out. Ion
pair complexes of the type MLnX+ (where M is Mn(II), Fe(II), Co(II), Ni(II),
Cu(II) or Zn(II), L is 1,10-phenanthroline, 2,2'-bipyridine, ethylenediamine,
diethylenetriamine or 1,4,8,11-tetraazacyclotetradecane and X is Cl-, NO3-,
acetylacetonate, ClO4-, acetate or SCN-) were studied. Ion-molecule reactions can
distinguish whether the counterion in an ion pair is an inner- or outer-sphere
ligand and can determine the coordination mode of the counterion. In addition,
CID and ion-molecule reactions reveal some interesting chemistry of these
complexes and unique coordination modes for some of the anions studied here were
inferred from the ion-molecule reactions. For example, the thiocyanate ion is
found to coordinate in a bidentate fashion in Zn(II) and Ni(II) complexes,
contrasting behavior typically observed in solution. Also, certain Co(II) and
Fe(II) ion pair complexes undergo oxidation reactions in which species such as
dioxygen and nitric oxide from the counterions ClO4- and NO3- are transferred to
the Co(II) and Fe(II) complexes, showing the inherent affinity of these metals
for these molecules. These complexes were also studied by ion-molecule reactions
and CID. Dioxygen in complexes formed by CID is demonstrated to be bidentate,
suggesting the formation of a peroxo ligand with concurrent oxidation of the
metal.
PMID- 10767760
TI - Characterization of iridoids by fast atom bombardment mass spectrometry followed
by collision-induced dissociation of
AB - Fast atom bombardment mass spectra of a series of naturally occurring and
synthetically modified iridoid glycosides were studied using lithium
cationization and collision-induced dissociation of the resulting [M+Li]+ ions.
Lithium cationization leads to the unambiguous determination of the molecular
masses of these compounds. Collision-induced dissociation of the lithiated
molecular ions give valuable structural information regarding the nature of the
substituent on both the aglycone and the sugar moieties. The characteristic
fragmentation pathways identified are (1) elimination of neutral molecules
comprising the substituents on either the aglycone or sugar moieties, (2)
formation of lithiated aglycone and their fragment ions, (3) formation of
lithiated sugar and their fragment ions, (4) fragmentation corresponding to the
cleavage of the aglycone or sugar ring and (5) fragmentation characteristic of
the substituents present in either the aglycone or sugar parts of the molecule.
Elimination of two acyloxy radicals from the lithiated molecular ion is a
characteristic fragmentation in the case of acyloxy derivatives.
PMID- 10767761
TI - Characterization of the atmospheric pressure ionization mass spectrometric
process obtained using a fused-silica emitter with the high voltage applied
upstream
AB - The atmospheric pressure ionization process obtained when a mixture of methanol
and water (90:10, v/v) also containing 50 microM sodium hydroxide is dispersed
from a fused-silica emitter was studied. A combination of a high electric field
and a nebulizer gas with the high voltage applied upstream in the liquid flow was
utilized to facilitate the spray process. By comparing the dependences of the
spray current and ion signals on the spray potential, it was found that
electrical corona discharges were obtained for potentials higher than about 2.6
kV, which resulted in a mixed electrospray and chemical ionization process. By
introducing vapour from a solvent, such as benzene or toluene, with a low
ionization energy into the nebulizing gas, it was found that the appearance of
the corresponding molecular ion was correlated with a change in the slope of the
spray current-potential curve. This indicates that the breakpoints in the spray
current-potential curves observed were correlated with the onsets of corona
discharges. It was shown that the mixed ionization process gives rise to
increased amounts of protonated solvent molecules and assists in the formation of
sodiated adduct ions from an uncharged fatty acid methyl ester.
PMID- 10767762
TI - Low-mass ions observed in plasma desorption mass spectrometry of high explosives
AB - The low-mass ions observed in both positive and negative plasma desorption mass
spectrometry (PDMS) of the high explosives HMX, RDX, CL-20, NC, PETN and TNT are
reported. Possible identities of the most abundant ions are suggested and their
presence or absence in the different spectra is related to the properties of the
explosives as matrices in PDMS. The detection of abundant NO+ and NO2- ions for
HMX, RDX and CL-20, which are efficient matrices, indicates that explosive
decomposition takes place in PDMS of these three substances and that a
contribution from the corresponding chemical energy release is possible. The
observation of abundant C2H4N+ and CH2N+ ions, which have high protonation
properties, might also explain the higher protein charge states observed with
these matrices. Also, the observation of NO2-, possibly formed by electron
scavenging which increases the survival probability of positively charged protein
molecular ions, completes the pattern. TNT does not give any of these ions and it
is thereby possible to explain why it does not work as a PDMS matrix. For NC and
PETN, decomposition does not seem to be as pronounced as for HMX, RDX and CL-20,
and also no particularly abundant ions with high protonation properties are
observed. The fact that NC works well as a matrix might be related to other
properties of this compound, such as its high adsorption ability.
PMID- 10767763
TI - Structure determination of soybean and wheat glucosylceramides by tandem mass
spectrometry.
AB - Glucosylceramide (GluCer) is a major sphingolipid of plant tissue and, thus,
abundant in nature and in dietary food sources. The lipid backbones of mammalian
GluCer (sphingosine, d18:1(delta4), and ceramide) induce cell death (apoptosis)
and inhibit colon carcinogenesis, it is critical to know the structures of GluCer
present in plants as a first step toward understanding this potential link
between diet and cancer. This study characterized the molecular species of GluCer
from soybean and wheat by low-resolution, high-resolution and tandem mass
spectrometry. Soybean GluCer was comprised primarily (>95%) of ceramide with 4,8
sphingadiene (d18:2(delta4,delta8)) and alpha-hydroxypalmitic acid (h16:0); the
remainder had the same backbone with h18:0, h20:0, h22:0 and h24:0 fatty acids.
Wheat GluCer had three major ceramide, d18:2(delta4,delta8) with h16:0,
d18:1(delta8) with h16:0 and d18: 2(delta4,delta8) with h20:0, and smaller
amounts of other homologs. These backbones differ from those of mammalian
sphingolipids, which often have a delta4-double bond (but rarely a delta8-double
bond), and have alpha-hydroxy fatty acids in only some cases. Previously
unexplained fragmentations that were diagnostic for the type of sphingoid base
backbone (i.e. by homolytic cleavage of the doubly allylic C-6-C-7 bond to yield
a stable distonic allylic radical cation and an allylic radical neutral) were
also identified. Hence this method should be useful in the identification of
double bonds in sphingolipids, and structure-function relationships between
sphingolipids and colon carcinogenesis.
PMID- 10767764
TI - Quantitative determination of SC-68328 in dog plasma using flow injection and
tandem mass spectrometry.
AB - A flow injection/tandem mass spectrometric assay was developed to quantitate SC
68328 in dog plasma using its stable isotopic analog [13C4]SC-68328 as an
internal standard (IS). Since SC-68328, a manganese-based superoxide dismutase
mimetic, is very unstable, very polar and adheres to silica-based high
performance liquid chromatographic columns, the analyte and IS were derivatized
to their bis-isothiocyanate forms followed by a liquid-liquid extraction with
methylene chloride and analyzed using positive ion electrospray mass
spectrometric detection. SC-68328 was quantitated using the peak-height ratio of
SC-68328 to its IS using MS/MS in the multiple reaction monitoring mode. The
lower limit of quantitation of the assay was 0.25 microg ml(-1) SC-68328 in dog
plasma with an inter-day precision of 11.8% and an accuracy of 113% (n = 12).
Acceptable precision and accuracy were also obtained for concentrations in the
calibration curve range (0.25-10 microg ml(-1) SC-68328 in dog plasma).
PMID- 10767765
TI - Confirmation of the structure of lipid A from Enterobacter agglomerans by
electrospray ionization tandem mass spectrometry
AB - Electrospray ionization (ESI) combined with tandem mass spectrometry (MS/MS) was
utilized for the structural confirmation of lipid A derived from Enterobacter
agglomerans, a Gram-negative bacterium commonly found in field cotton. Previous
ESI-MS studies conducted in our laboratory found that similarities exist between
the fatty acid side-chains in the lipid A of E. agglomerans and that of
Salmonella minnesota. It was noted that heterogeneity at the fatty acyl chain at
position 3' of the diglucosamine backbone of E. agglomerans can take the form of
either a myristyloxymyristyl group or, less commonly, a
hydroxymyristyloxymyristyl moiety. In this work, tandem mass spectra obtained
from heptaacyl and hexaacyl lipid A precursors derived from E. agglomerans and a
known standard S. minnesota were compared to assist in structural elucidation.
These ESI-MS/MS experiments confirmed the previously reported structure for lipid
A derived from E. agglomerans. Moreover, MS/MS data indicated that the additional
hydroxyl group of the 3'-position hydroxymyristyloxymyristyl moiety is present as
the alpha-isomer.
PMID- 10767766
TI - Capillary liquid chromatography interfaced to matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry using an on-line coupled
piezoelectric flow-through microdispenser
AB - A piezoelectric flow-through microdispenser interfacing capillary liquid
chromatography (LC) with matrix-assisted laser desorption/ionization time-of
fight mass spectrometry (MALDI-TOF MS) was developed for the identification of
biomolecules. The MALDI target plate was placed on a computer controlled high
resolution x-y stage, on to which the column effluent was deposited as discrete
spots, which thereby facilitated tracing of the chromatographic separation. The
entire target plate was sprayed with a homogeneous layer of alpha-cyano-4
cinnamic acid mixed with nitrocellulose by using an air-brush. Hence the tedious
manual handling of a micropipetter applying matrix solution on top of each
fraction collected spot was avoided. The pre-made target plates were stable for
at least 3 weeks if kept in darkness at room temperature, which easily allowed re
analysis of dispensed sample spots. The integrated microsystem was characterized
and optimized by means of fluidics, dispersion, operational stability and
sensitivity parameters. The dispensing unit was developed specifically to match
high-resolution capillary LC separations using a dispenser with an internal
volume from inlet to the ejecting nozzle of 250 nl. Minimizing dead volumes was
crucial in order to maintain the chromatographic resolution. The volume of the
ejected droplets was of the order of 60 pl. Successful separations of seven
immunoregulating peptides were made: ACTH 1-17, bradykinin, enkephalin,
angiotensin III, angiotensin II, angiotensin I and ACTH 18-39. On-line sample
dispensing on the target plate in combination with trace enrichment followed by
automated MALDI-TOF MS identification is demonstrated, reaching a sensitivity of
100 amol.
PMID- 10767767
TI - Quantitative determination of alpha-cyclodextrin in human plasma by liquid
chromatography/positive ion electrospray mass spectrometry.
AB - A sensitive and selective method for the determination of alpha-cyclodextrin in
human plasma is described using beta-cyclodextrin as an internal standard. After
protein precipitation with perchloric acid, the analytes were isolated from human
plasma by solid-phase extraction on Bond Elut C18 cartridges. The compounds were
chromatographed on a narrow-bore aminopropyl column (125 x 2 mm i.d., 5 microm)
and analyzed by electrospray ionization mass spectrometry in the positive
selected-ion mode using the [M+NH4]+ ion. The lower limit of quantitation was 5
ng ml(-1) of human plasma. Linear calibration curves were obtained over the
concentration range 5-1000 ng ml(-1) of human plasma. The intra- and inter-assay
precisions were <18% and the accuracy was <10.5% over the entire concentration
range. During the method development, the ionization efficiencies of the analytes
in plasma samples originating from different sources were examined to overcome
the matrix effect problems caused by co-eluting endogenous compounds. The method
was successfully applied to pharmacokinetic studies in human volunteers.
PMID- 10767768
TI - Signal suppression in electrospray ionization Fourier transform mass spectrometry
of multi-component samples
AB - The high resolution, mass range and sensitivity of Fourier transform mass
spectrometry (FTMS) suggest that it could be a valuable tool for the quantitative
analysis of biomolecules. To determine the applicability of electrospray
ionization combined with FTMS to the quantitation of biomolecules in multi
component samples, mixtures of varying compositions and concentrations of
cytochrome c, angiotensin II, insulin and chicken egg white lysozyme were
examined. The instrument used has an electrospray source with a hexapole trap to
accumulate ions for injection into an ion cyclotron resonance mass analyzer.
Linear responses for single component samples of angiotensin II and insulin were
in the range 0.031-3 microM and those of both cytochrome c and lysozyme were
between 0.031 and 1 microM. In examining various mixtures of the proteins with
angiotensin II, it was found that the presence of the large molecules suppresses
the signal of the smaller molecules. This is suggested to be a result of ion-ion
interactions producing selective ion loss from either the hexapole trap or the
ion cyclotron resonance mass analyzer trap. More massive, more highly charged
ions can collisionally transfer large amounts of translational energy to smaller,
less highly charged ions, ejecting the smaller ions from the trap. Mass
discrimination effects resulting from the trapping voltage were also examined. It
was found that relative signal intensities of ions of different masses depend on
trapping voltage for externally produced ions. The effect is most significant for
spectra including masses that differ by 30% or more. This suggests that for
quantitation all samples and standards be run at a constant trapping potential.
PMID- 10767769
TI - Hydrogen-deuterium exchange signature of porcine cerebroside sulfate activator
protein.
AB - Hydrogen-deuterium exchange can be a sensitive indicator of protein structural
integrity. Comparisons were made between cerebroside sulfate activator protein
(CSAct) in the native state and after treatment with guanidine hydrochloride plus
dithiothreitol. Native protein has three internal disulfide bonds and treated
protein has no internal disulfide bonds. The comparisons were made using hydrogen
deuterium exchange measured by electrospray ionization mass spectrometry,
percentage alpha-helical content measured by circular dichroism and biological
activity measured by the ability to support arylsulfatase A-catalyzed sulfate
hydrolysis from cerebroside sulfate. In acidic solvent native protein has 59
exchange refractory protons and treated protein has 20 exchange refractory
protons (44 and 14% of the exchangeable proton populations, respectively). In
native protein the size of the exchange refractory proton population is sensitive
to changes in pH, temperature and the presence of a ligand. It is uninfluenced by
the presence or absence of glycosyl groups attached to Asn21. Helical content is
virtually identical in native and treated protein. Biological activity is
significantly reduced but not obliterated in treated protein. The hydrogen
deuterium exchange profile appears to be a sensitive signature of the correctly
folded protein, and reflects a dimension of the protein structure that is not
apparent in circular dichroic spectra or in the ability of the protein to support
arylsulfatase A-catalyzed sulfate hydrolysis from sulfatide. The hydrogen
deuterium exchange profile will be a valuable criterion for characterizing mutant
forms of CSAct produced by recombinant and synthetic paradigms and also the
native and mutant forms of related proteins.
PMID- 10767770
TI - Equine metabolism of buspirone studied by high-performance liquid
chromatography/mass spectrometry.
AB - The metabolism and urinary excretion of a 100 mg dose of the non-sedating
anxiolytic drug buspirone was examined using high-performance liquid
chromatography/electrospray ionization mass spectrometry in the positive ion
mode. In addition to a significant proportion of unchanged buspirone we were able
to detect three major metabolite classes. These were identified as monohydroxy,
dihydroxy and dihydroxymethoxy products. Detection of the metabolites and the
parent drug was possible in all the urine samples collected (1-12 h) post
administration.
PMID- 10767771
TI - Characterizing DNA photo-oxidation reactions by high-resolution mass measurements
with matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry.
AB - High-resolution mass measurements by matrix-assisted laser desorption/ionization
time-of-flight (MALDI-TOF) mass spectrometry were employed to characterize laser
induced oxidation of guanine in a small synthetic deoxyoligonucleotide. The
oligonucleotide was exposed to high-intensity UV radiation at 266 nm to produce
modifications on the guanine base. The primary product showed a +16 Da mass shift
relative to the original strand, whereas secondary products showed mass shifts of
+32 and +34 Da. The mass shift of the primary product is consistent with an 8
oxoguanine modification. However, the reactivity of the primary product with hot
piperidine and other secondary oxidizing agents was different from that of a
synthetic oligonucleotide containing 7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxoG).
Based upon the results, a new reaction scheme involving the formation of an
epoxide ring across the C-4 and C-5 positions by UV laser-induced oxidation is
suggested. The results also illustrate the ability of MALDI to characterize
chemical reactivity rapidly at the a low picomolar level.
PMID- 10767772
TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
using an inorganic particle matrix for small molecule analysis
AB - Fine metal or metal oxide powder as an alternative to conventional organic
matrices in matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry (MALDI-TOFMS) has been utilized successfully for lower molecular
mass analytes, poly(ethylene glycol) 200 (PEG 200) and methyl stearate. Eleven
kinds of particle, Al, Mn, Mo, Si, Sn, SnO2, TiO2, W, WO3, Zn and ZnO, were
evaluated. The analyte was mixed with a metal or metal oxide powder (inorganic
matrix) with particle diameter of tens of micrometers and liquid dispersant,
followed by application to the sample target. Using a commercial MALDI-TOFMS
instrument equipped with an internal 337 nm pulsed nitrogen laser, the analytes,
PEG 200 and methyl stearate, were ionized as the alkali metal ion adducted
molecules [M+Na]+ or [M+K]+ when the inorganic matrices Mn, Mo, Si, Sn, TiO2, W,
WO3, Zn or ZnO were used. In the case of an Al matrix, PEG 200 was ionized as
[M+K]+, whereas methyl stearate was ionized as [M+H]+ and [M+Al]+. These
particles have potential as the matrix for MALDI. During our examination,
however, only SnO2 particles did not ionize either PEG 200 or methyl stearate.
Based on our protocol, when TiO2 powder was suspended with liquid paraffin, PEG
200 and methyl stearate gave their MALDI-TOF mass spectra with the lowest
background noise and highest intensity. TiO2 powder seemed to be a broad
potential matrix for low molecular mass polar or non-polar analytes. The results
suggested that bulk particles caused rapid heating/vaporization processes and
ionized analyte molecules under irradiation with a pulsed UV laser. The present
method can be readily applied to obtain the low background noise MALDI-TOF mass
spectra of small-sized compounds.
PMID- 10767773
TI - Atmospheric pressure ionization time-of-flight mass spectrometry coupled with
fast liquid chromatography for quantitation and accurate mass measurement of five
pharmaceutical drugs in human plasma.
AB - The quantitative determination and accurate mass measurement of five tricyclic
amine pharmaceutical drugs (doxepin, desipramine, imipramine, amitriptyline and
trimipramine) fortified in human plasma within a per sample run time of 18 s was
accomplished by atmospheric pressure ionization (API) time-of-flight (TOF) mass
spectrometry using a turboIonspray liquid chromatography/mass spectrometry
(LC/MS) interface coupled with high-performance liquid chromatography (HPLC). The
relatively short HPLC separation (18 s) was achieved using a short C18 column (15
x 2.1 mm i.d.) with a high aqueous mobile phase maintained at a flow-rate of 1.4
ml min(-1). An acquisition speed of 0.2 s per spectrum accommodates these fast
separation conditions. This method employs a one-step liquid-liquid extraction
procedure to isolate the five tricyclic amines from biological matrix components
The overall extraction recovery was 75% for desipramine and >90% for the other
four tricyclic amines. The lower level of quantitation was 1-2 ng ml(-1) for each
compound. The calibration curve was linear from 2 to 100 ng ml(-1) for
desipramine and from 1 to 50 ng ml(-1) for the other four tricyclic amines. A
deuterated internal standard, imipramine-d3, was used for all five tricyclic
amines. Acceptable intra- and inter-assay precision (1.0-17.7%) and accuracy (0.2
14.5%) were obtained. The linear dynamic range was extended to 200 based on a
software upgrade for correcting ion current detection saturation. The accurate
masses of the five tricyclic amines were determined by on-line LC/TOFMS analyses
of biological extracts using two-point internal mass calibration. This was done
by infusing a reference standard, Jeffamine D230, post-column into the HPLC
effluent. All results showed a mass error not greater than 9 ppm for all the
target compounds. These results were obtained from both synthetic mixtures when
as little as 100 pg were injected or extracts of spiked human plasma samples with
analytical concentration as low as 5 ng ml(-1). The factors influencing accurate
mass measurements are discussed.
PMID- 10767774
TI - Stereochemistry of norditerpenoid alkaloids by liquid chromatography/atmospheric
pressure chemical ionization mass spectrometry
AB - High-performance liquid chromatography/atmospheric pressure chemical ionization
mass spectrometry (HPLC/APCI-MS) is a very promising approach to structural
investigations of positional isomers and stereoisomers. This method was applied
successfully to stereoisomeric norditerpenoid alkaloids differing in
configuration at C-6. APCI-MS allowed the easy and precise control of energy
deposition by varying the drift voltage. Comparison of the breakdown curves,
observed by changing the potential difference between the first electrode and the
second electrode of the APCI ion source, revealed the stereochemical dependence
of different fragmentations. Comparison of the APCI spectra showed that the
abundance of fragment ions was significantly higher for C-6beta alkaloid than for
C-6alpha alkaloid. The axial positions of the corresponding substituents (6
methoxyl and 8-hydroxyl) strongly suggested a 1,3-diaxial interaction effect of
the fragmentation. The characteristic fragment ions were formed by the loss of
water or acetic acid at position 8, irrespective of the stereochemistry at
position 6. The possibility of distinct fragmentation mechanisms depending on the
stereochemistry of the precursor ion could be discerned by recording the spectra
in a deuterated solvent system of 0.05 M ammonium acetate in D2O-acetonitrile
tetrahydrofuran. Loss of D2O from the precursor ion gave the fragment ion. This
result indicated that the proton of protonation was included in the leaving water
molecule. The peak intensity ratio R = [M+H]+/[M+H-H2O]+ manifested the
stereochemical differentiation of alkaloids at position 6.
PMID- 10767775
TI - Determination of 21-hydroxydeflazacort in human plasma by high-performance liquid
chromatography/atmospheric pressure chemical ionization tandem mass spectrometry.
Application to bioequivalence study.
AB - A liquid chromatographic atmospheric pressure chemical ionization tandem mass
spectrometric method is described for the determination of 21-hydroxydeflazacort
in human plasma using dexamethasone 21-acetate as an internal standard. The
procedure requires a single diethyl ether extraction. After evaporation of the
solvent under a nitrogen flow, the analytes are reconstituted in the mobile
phase, chromatographed on a C18 reversed-phase column and analyzed by mass
spectrometry via a heated nebulizer interface where they are detected by multiple
reaction monitoring. The method has a chromatographic run time of less than 5 min
and a linear calibration curve with a range of 1-400 ng ml(-1) (r>0.999). The
between-run precision, based on the relative standard deviation for replicate
quality controls, was < or =5.5% (10 ng ml(-1)), 1.0% (50 ng ml(-1)) and 2.7%
(200 ng ml(-1)). The between-run accuracy was +/-7.1, 3.8 and 4.8% for the above
concentrations, respectively. This method was employed in a bioequivalence study
of two DFZ tablet formulations (Denacen from Marjan Industria e Comercio, Brazil,
as a test formulation, and Calcort from Merrell Lepetit, Brazil, as a reference
formulation) in 24 healthy volunteers of both sexes who received a single 30 mg
dose of each formulation. The study was conducted using an open, randomized, two
period crossover design with a 7-day washout interval. The 90% confidence
interval (CI) of the individual geometric mean ratio for Denacen/Calcort was 89.8
109.5% for area under the curve AUC(0-24 h) and 80.7-98.5% for Cmax. Since both
the 90% CI for AUC(0-24 h) and Cmax were included in the 80-125% interval
proposed by the US Food and Drug Administration, Denacen was considered
bioequivalent to Calcort according to both the rate and extent of absorption.
PMID- 10767776
TI - Mass spectrometric mapping of disulfide bonds in recombinant human interleukin
13.
AB - Interleukin 13 (IL-13), a member of the a-helical family of cytokines, has
approximately 30% primary sequence homology with IL-4 and shares a common
receptor component. The biologically active rhIL-13 is monomeric and non
glycosylated, and contains two disulfide bonds as determined by comparative
electrospray mass spectrometric (MS) analysis of the protein before and after
reduction with dithiothreitol-dithioerythritol. A trypsin-resistant core peptide
of rhIL-13 was isolated and analyzed by plasma desorption (PD) MS, identifying a
disulfide-linked core peptide. Subsequent digestion of this core peptide by
pepsin, followed by PDMS analysis of the resulting cystine-containing peptic
fragments, provided rapid determination of the existing disulfide bonds between
cysteine residues 28-56 and 44-70. This disulfide arrangement is similar to that
observed for the analogous four internal cysteine residues in hIL-4. The
conservation of disulfide bond arrangements between hIL-13 and hIL-4, coupled
with their alpha-helical structure and sequence homologies, confirms that IL-13
and IL-4 are structural homologues. It is also consistent with their reported
similarities in biological function and receptor binding kinetics.
PMID- 10767778
TI - Virtual freezing of the hemiacetal-aldehyde equilibrium of the aglycones of
oleuropein and ligstroside present in olive oils from Carolea and Coratina
cultivars by ionspray ionization tandem mass spectrometry
AB - The composition of the equilibrium between aldehydes and hemiacetals was
evaluated by ionspray ionization tandem mass spectrometry. The methanolic
extracts of virgin olive oil from Carolea and Coratina cultivars contain a
complex mixture of hydroxytyrosol (3) and tyrosol (4) derivatives (5, 6)
characterized by the presence of aldehyde moieties in equilibrium with their
hydrated form (8) or with the corresponding methanol hemiacetals 9 and 10. The
equilibrium was frozen by droplet evaporation, thus allowing the structure
determination of each component. The formation of the decarboxylated species 11
14, reported previously, was not observed.
PMID- 10767777
TI - Isolation from pig liver microsomes, identification by tandem mass spectrometry
and in vitro immunosuppressive activity of an SDZ-RAD 17,18,19,20,21,22-tris
epoxide.
AB - Macrolide immunosuppressive drugs such as tacrolimus (FK506) and sirolimus
(rapamycin) are compounds largely used in modern immunosuppressive therapy and
considered as powerful immunosuppressive agents. Some of these molecules are
still under clinical development as, for example, SDZ-RAD (40-O-(2
hydroxyethyl)rapamycin), an immunosuppressive drug closely related to rapamycin.
SDZ-RAD has a molecular mass of 957.57 Da (C53H83NO14) and shares the same common
intracellular receptor as tacrolimus, the FK-506 binding protein (FKBP-12). SDZ
RAD exerts its pharmacological effect by binding to a different effector protein,
inhibits the S6p 70-kinase and interrupts a different signal transduction pathway
than tacrolimus. Both SDZ-RAD and rapamycin are metabolized mainly by the
cytochrome P-450 3A4-dependent mixed function oxygenase enzyme system to
hydroxylated and demethylated metabolites. We describe here the isolation from
pig liver microsomes of a novel SDZ-RAD metabolite identified by electrospray
tandam mass spectrometry as a new SDZ-RAD 17,18,19,20,21,22-tris-epoxide
metabolite. The in vitro immunosuppressive activity as measured by the mixed
lymphocyte reaction is more or less comparable to that of SDZ-RAD, although its
pharmacological mode of action may be different from that classically described
for rapamycin.
PMID- 10767779
TI - Fate studies of the non-ionic surfactant alkyl glucamide by liquid
chromatography/electrospray mass spectrometry
AB - Alkyl glucamides (AGs) were analyzed by reversed-phase liquid chromatography (LC)
coupled to mass spectrometry with electrospray ionization (ESMS). Analytes were
separated according to the chain length of two homologs, C12- and C14-glucamide.
Mass spectrometric detection in the positive ion mode exhibited higher overall
sensitivity where, apart from fragments, different molecular and quasi-molecular
ions were obtained. However, application of the negative ion mode offered
advantages in terms of reproducibility and extent of information when analyzing
environmental samples. Therefore, a simple and sensitive analytical methodology
was developed for the determination of AGs in municipal sewage treatment plant
influent and effluent based on solid-phase enrichment, LC separation and negative
ion ESMS quantification. After preconcentration of 100 ml of aqueous sample, the
recoveries using polymeric LiChrolut EN cartridges exceeded 89%. A quantification
limit of 0.1 microg l(-1) was achieved. Studies on the biodegradability and
metabolic pathway of C10-glucamide were carried out on a laboratory-scale
microbial test unit under aerobic conditions. A postulated metabolism including
omega-oxidation of the alkyl chain followed by subsequent beta-oxidations was
checked by LC/ESMS. Identification and formation of 'C4-glucamide acid' as a
degradation intermediate was confirmed by mass spectrometric studies. Higher
homolog acids such as C10-, C8- and C6-glucamide acids, which should be predicted
precursors of C4-glucamide acid, and any other metabolites, were not detectable,
presumably owing to rapid breakdown.
PMID- 10767781
TI - Current literature in mass spectrometry
PMID- 10767780
TI - Mass spectrometric behaviour of 4-(arylimino)pentan-2-ones substituted with a
halogen atom in the aromatic ring
PMID- 10767782
TI - Heroes and friends.
PMID- 10767783
TI - Testing for hereditary breast and ovarian cancer in the southeastern United
States.
AB - OBJECTIVES: To detail characterization of mutations and uncharacterized variants
in the breast cancer susceptibility genes BRCA1 and BRCA2, as observed in a
population of breast cancer patients from the southeastern United States, and to
examine baseline characteristics of women referred for counseling and testing and
provide a preliminary look at how counseling and testing affected intentions
toward prophylactic surgery. BACKGROUND: Mutations in the BRCA1 and BRCA2 genes
give rise to a dramatically increased risk of developing breast or ovarian cancer
or both. There are many reports about special populations in which deleterious
mutations are present at a high frequency. It is useful to study these genes in
more heterogeneous populations, reflecting different geographic regions. Interest
in preventive surgery for gene carriers is high in women and their surgeons.
METHODS: Women were recruited through a prospective clinical trial of counseling
and free genetic testing. BRCA1 and BRCA2 were screened for mutations using
standard techniques, and results were given to participants. Baseline
questionnaires determined interest in preventive surgery at the beginning of the
study. Follow-up questionnaires for those who completed testing surveyed interest
in prophylactic surgery after counseling and receiving test results. RESULTS: Of
213 women who completed counseling and testing, 44 (20.6%) had 29 separate
mutations; there were 11 Jewish women carrying three founder mutations. Twenty
eight women (13.1%) had uncharacterized variants in BRCA1 or BRCA2; nine were not
previously reported. Women overestimated their chances of possessing a
deleterious gene mutation compared to a statistical estimate of carrier risk. A
number of women changed their intentions toward preventive surgery after genetic
counseling and testing. CONCLUSIONS: Hereditary breast cancer due to mutations in
BRCA1 and BRCA2 was a heterogeneous syndrome in the southeastern United States.
Most mutations were seen just once, and uncharacterized variants were common and
of uncertain clinical significance. In general, positive test results tended to
reinforce intentions toward prophylactic surgery. In contrast, women not
interested in surgery at the time of entry tended to remain reluctant after
testing and counseling.
PMID- 10767784
TI - Factors affecting morbidity, mortality, and survival in patients undergoing Ivor
Lewis esophagogastrectomy.
AB - OBJECTIVES: To examine the safety of transthoracic esophagogastrectomy (TTE) in a
multidisciplinary cancer center and to determine which clinical parameters
influenced survival and the rates of death and complications. SUMMARY BACKGROUND
DATA: Although the incidence of cancer at the gastroesophageal junction has been
rising rapidly in the United States, controversy still exists about the safety of
surgical procedures designed to remove the distal esophagus and proximal stomach.
Alternatives to TTE have been proposed because of the reportedly high rates of
death and complications associated with the procedure. METHODS: Data from 143
patients treated by TTE by one author (1989-1999) were entered into a
computerized database. Preoperative clinical parameters were tested for effect on
death, complications, and survival. RESULTS: The patient population consisted of
127 men and 16 women. One hundred twenty-one patients had a history of tobacco
abuse, and 118 reported the regular ingestion of alcohol. One hundred fifteen
patients had adenocarcinoma, 16 had squamous cell cancer, 6 had another form of
esophageal tumor, and 6 had high-grade dysplasia associated with Barrett
epithelia. Fifty-six patients had adenocarcinomas arising in Barrett epithelium.
Twenty-eight patients were treated with neoadjuvant chemoradiation before
surgery. Three patients died within 30 days of surgery (mortality rate 2.1%).
Five patients (3.5%) had a documented anastomotic leak; three died). Overall, 42
patients had complications (29%). Twenty-six had pulmonary complications (19%).
The mean length of stay in the intensive care unit was 3.35 days; the mean
hospital length of stay was 13.54 days. The overall 3-year survival rate was
29.6%. CONCLUSIONS: A high ASA score and the development of complications
predicted an increased length of stay. The presence of diabetes predicted the
development of complication and an increased length of stay. None of the other
parameters tested predicted perioperative death or complications. Only disease
stage, diabetes, and blood transfusion affected overall survival. From these
results with a large series of patients with gastroesophageal junction cancers,
TTE can be performed with a low death rate (2.1%), a low leak rate (3. 5%), and
an acceptable complication rate (29%).
PMID- 10767785
TI - Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and
metastasis: an additive strategy for cancer control.
AB - OBJECTIVE: To investigate the effect of a matrix metalloproteinase (MMP)
inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic
cancer. SUMMARY BACKGROUND DATA: Inhibitors of MMPs, enzymes that degrade
extracellular matrix, have been tested as single chemotherapeutic agents for
pancreatic cancer. METHODS: Capan1 and AsPC1 cell lines were studied. BB-94
cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and
MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro
effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic
metastases from pancreatic cancer were induced by intrasplenic injections of
Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver
metastases was evaluated by comparing animals receiving BB-94 treatment with
controls receiving vehicle alone. Variables measured included death rate and
tumor burden (liver-to-body weight ratio). RESULTS: BB-94 was not cytotoxic
between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by
both cell lines, with complete inhibition of these enzymes by BB-94 at 48 ng/mL.
Invasion chamber assays showed that BB-94 (48-400 ng/mL) impeded cell invasion in
vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced
the death rate from hepatic metastases in animals injected with Capan1 or AsPC1
cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden
compared with untreated controls. CONCLUSIONS: Inhibition of MMP reduces both
growth of pancreatic cancer metastases and the death rate. These actions do not
reflect cytotoxicity but rather result from impaired cancer cell attachment,
migration, and organ invasion. MMP inhibitors may provide an additive effect to
cytotoxic agents in multidimensional treatment regimens for pancreatic cancer.
PMID- 10767786
TI - Effect of reresection in extremity soft tissue sarcoma.
AB - OBJECTIVE: To determine whether reresection affects survival in patients with
inadequately resected, primary extremity soft tissue sarcoma. This study
correlates reresection with local recurrence-free survival, metastasis-free
survival, and disease-free survival. SUMMARY BACKGROUND DATA: Soft tissue
sarcomas are rare neoplasms, with an incidence of approximately 6,000 per year in
the United States. Because these tumors are rare and benign soft tissue tumors
are common, many are initially thought to be benign and are excised without wide
margins. METHODS: Patients who underwent treatment for primary tumors from July
1982 to June 1999 at a single institution were the subject of study. Two groups
of patients were analyzed: those who underwent one definitive resection (one
operation) and those whose tumors were previously resected and who were then
referred for subsequent reresection (two operations). Patients were given
adjuvant radiation or chemotherapy according to the standard of care. RESULTS: Of
1,092 patients with primary extremity soft tissue sarcoma underwent resection,
685 underwent definitive radical resection and 407 underwent reresection after
undergoing excisional resection elsewhere. Median follow-up was 4.8 years. The 5
year disease-free survival rate of the definitive resection (one operation) group
was 70%; that of the reresection (two operations) group was 88%. On multivariate
analysis, reresection was adjusted and controlled for age, grade, depth, size,
histology, and margins. Reresection remained a significant predictor of improved
disease-free survival, even after these adjustments. To determine whether this
difference was stage- or referral-biased, the patient population was divided by
AJCC stage. In all stages there was a trend toward improved outcome; this was
most marked for those with stage III disease (>5 cm, high-grade, and deep).
CONCLUSIONS: Patients with extremity soft tissue sarcoma who undergo reresection
with two "primary" operations have an improved survival compared with those who
undergo one operation. The most plausible explanation, referral and selection
bias, is questionable given the significance of reresection as a variable after
adjusting for stage and other risk factors. This suggests that where indicated
and possible, reresection should be liberally applied in patients with primary
extremity soft tissue sarcoma.
PMID- 10767787
TI - Human papilloma virus in melanoma biopsy specimens and its relation to melanoma
progression.
AB - OBJECTIVES: To evaluate melanoma biopsy specimens for human papilloma virus (HPV)
and determine the relation between the presence of HPV, in vitro growth, and
clinical progression of melanoma in the patients from whom the biopsy specimens
were derived. SUMMARY BACKGROUND DATA: Ultraviolet radiation from sun exposure
appears to be the primary causal agent in the development of cutaneous melanoma.
However, other agents, including HPV, as observed in different epithelial
carcinomas, may also play a role in melanoma development and progression.
METHODS: Twelve melanoma biopsy specimens obtained from 12 patients with AJCC
stage III and IV melanoma were stained with antibodies against gp-100 (HMB-45)
and S-100 protein to confirm melanoma diagnosis and with a polyclonal HPV
antibody. After mechanical dissociation, the melanoma specimen cells' ability to
grow in vitro was assessed. Patients were evaluated for melanoma progression with
physical examination, complete blood count, and liver function tests every 3
months and a chest radiograph every 6 months. RESULTS: All biopsy specimens were
positive for S-100, and nine (75%) were positive for gp-100. Seven of 12 (58%)
were positive for HPV by immunohistochemistry. In vitro, none of the HPV-negative
tumor cells grew from the tumor biopsies, whereas five of seven (71%) of the HPV
positive melanoma tumor cells grew very well. All patients with HPV-positive
tumor cells had recurrences and died of melanoma progression, whereas four of
five (80%) patients with HPV-negative tumor cells remained alive and without
melanoma recurrence. CONCLUSIONS: The presence of HPV was found in 58% of the
biopsy specimens obtained from patients with stage III and IV melanoma and
correlated with rapid melanoma progression. HPV may serve as a cofactor in the
development of melanoma and may modulate a more aggressive phenotype in HPV
containing melanoma cells.
PMID- 10767788
TI - The devastating potential of blunt vertebral arterial injuries.
AB - OBJECTIVE: To formulate management guidelines for blunt vertebral arterial injury
(BVI). SUMMARY BACKGROUND DATA: Compared with carotid arterial injuries, BVIs
have been considered innocuous. Although screening for BVI has been advocated,
particularly in patients with cervical spine injuries, the appropriate therapy of
lesions is controversial. METHODS: In 1996 an aggressive arteriographic screening
protocol for blunt cerebrovascular injuries was initiated. A prospective database
of all screened patients has been maintained. Analysis of injury mechanisms and
patterns, BVI grades, treatment, and outcomes was performed. RESULTS: Thirty
eight patients (0.53% of blunt trauma admissions) were diagnosed with 47 BVIs
during a 3.5-year period. Motor vehicle crash was the most common mechanism, and
associated injuries were common. Cervical spine injuries were present in 71% of
patients, but there was no predilection for cervical vertebral level or fracture
pattern. The incidence of posterior circulation stroke was 24%, and the BVI
attributable death rate was 8%. Stroke incidence and neurologic outcome were
independent of BVI injury grade. In patients treated with systemic heparin, fewer
overall had a poor neurologic outcome, and fewer had a poor outcome after stroke.
Trends associated with heparin therapy included fewer injuries progressing to a
higher injury grade, fewer patients in whom stroke developed, and fewer patients
deteriorating neurologically from diagnosis to discharge. CONCLUSIONS: Blunt
vertebral arterial injuries are more common than previously reported. Screening
patients based on injury mechanisms and patterns will diagnose asymptomatic
injuries, allowing the institution of therapy before stroke. Systemic
anticoagulation appears to be effective therapy: it is associated with improved
neurologic outcome in patients with and without stroke, and it appears to prevent
progression to a higher injury grade, stroke, and deterioration in neurologic
status.
PMID- 10767789
TI - Role of platelet-derived growth factor in allograft vasculopathy.
AB - OBJECTIVE: To test the hypothesis that platelet-derived growth factor (PDGF)
accelerates the formation of allograft vascular disease. SUMMARY BACKGROUND DATA:
Allograft vasculopathy, characterized by myointimal hyperplasia of the coronary
arteries in the transplanted heart, is the most common cause of late graft
failure and death in heart transplant recipients. The cause of the process is
unclear, and no treatment exists. PDGF has been implicated in alterations in
vascular endothelial biology and in vascular restenosis, but the role of PDGF in
allograft vasculopathy has not been explored. METHODS: An orthotopic heart
transplant model was established in the rat mismatched at one class II locus
using the PVGR8 and PVGR23 strains. No immunosuppressive regimen was used. Six
treatment groups (PDGF-A, PDGF-A antibody, and PDGF-A receptor antibody) using 10
rats per group were examined. An untreated group of 10 rats manifesting chronic
rejection as well as the native hearts were used as controls. PDGF-A at 1 ng/dL
(10 rats) or 10 ng/dL (10 rats) was administered intraperitoneally to each
transplant group. Similar groups were treated with PDGF-A antibody and PDGF-A
receptor antibody. The animals were killed after 50 days; transplanted and native
hearts were removed and coronary arteries were examined morphometrically. Smooth
muscle proliferation was confirmed by immunohistochemistry. Statistical analysis
was performed using multivariate analysis of variance. RESULTS: Coronary
myointimal hyperplasia was seen in the chronic rejection group. The PDGF-A groups
showed significant myointimal hyperplasia. Administration of PDGF-A antibody did
not attenuate the process. Administration of PDGF-A receptor antibody at 1 ng/dL
resulted in reduction of the hyperplasia, and 10 ng/dL significantly attenuated
the process. CONCLUSIONS: This study establishes a cause-and-effect relation
between PDGF-A and coronary myointimal hyperplasia in the rat transplant model.
Blockade of the PDGF-A receptor clearly attenuates the process, indicating a
potential mode of therapy to be explored.
PMID- 10767790
TI - Institutional and individual learning curves for focused abdominal ultrasound for
trauma: cumulative sum analysis.
AB - OBJECTIVE: To evaluate both institutional and individual learning curves with
focused abdominal ultrasound for trauma (FAST) by analyzing the incidence of
diagnostic inaccuracies as a function of examiner experience for a group of
trauma surgeons performing the study in the setting of an urban level I trauma
center. SUMMARY BACKGROUND DATA: Trauma surgeons are routinely using FAST to
evaluate patients with blunt trauma for hemoperitoneum. The volume of experience
required for practicing trauma surgeons to be able to perform this examination
with a reproducible level of accuracy has not been fully defined. METHODS: The
authors reviewed prospectively gathered data for all patients undergoing FAST for
blunt trauma during a 30-month period. All FAST interpretations were validated by
at least one of four methods: computed tomography, diagnostic peritoneal lavage,
celiotomy, or serial clinical evaluations. Cumulative sum (CUSUM) analysis was
used to describe the learning curves for each individual surgeon at target
accuracy rates of 85%, 90%, and 95% and for the institution as a whole at target
examination accuracy rates of 85%, 90%, 95%, and 98%. RESULTS: Five trauma
surgeons performed 546 FAST examinations during the study period. CUSUM analysis
of the aggregate experience revealed that the examiners as a group exceeded 90%
accuracy at the outset of clinical examination. The level of accuracy did not
improve with either increased frequency of performance or total examination
experience. The accuracy rates observed for each trauma surgeon ranged from 87%
to 98%. The surgeon with the highest accuracy rate performed the fewest
examinations. No practitioner demonstrated improved accuracy with increased
experience. CONCLUSIONS: Trauma surgeons who are newly trained in the use of FAST
can achieve an overall accuracy rate of at least 90% from the outset of clinical
experience with this modality. Interexaminer variations in accuracy rates, which
are observed above this level of performance, are probably related more to issues
surrounding patient selection and inherent limitations of the examination in
certain populations than to practitioner errors in the performance or
interpretation of the study.
PMID- 10767791
TI - A single-center 8-year experience with percutaneous dilational tracheostomy.
AB - OBJECTIVE: To determine surgical, postoperative, and postdischarge complications
associated with percutaneous dilational tracheostomy (PDT) in an 8-year
experience at the University of Kentucky. SUMMARY BACKGROUND DATA: There are
known risks associated with the transport of critically ill patients to the
operating room for elective tracheostomy, and less-than-optimal conditions may
interfere with open bedside tracheostomy. PDT has been introduced as an
alternative to open tracheostomy. Despite information supporting its safety and
utility, the technique has been criticized because advocates had not provided
sufficient information regarding complications. METHODS: A prospective database
was initiated on all patients who underwent PDT between September 1990 and May
1998. The database provided indication, procedure time, duration of intubation
before PDT, and intraoperative and postoperative complications. Retrospective
review of medical records and phone interviews provided long-term follow-up
information. RESULTS: In the 8-year period, 827 PDTs were performed in 824
patients. Two patients were excluded because PDT could not be completed for
technical reasons. There were 519 male and 305 female patients. Mean age was 56
years. Prolonged mechanical ventilatory support was the most common indication.
Mean procedure time was 15 minutes, and the average duration of intubation before
PDT was 10 days. The intraoperative complication rate was 6%, with premature
extubation the most common complication. The procedure-related death rate was
0.6%. Postoperative complications were found in 5%, with bleeding the most
common. With a mean follow-up of greater than 1 year, the tracheal stenosis rate
was 1.6%. CONCLUSIONS: On the basis of this large, single-center study, the
authors conclude that when performed by experienced surgeons, PDT is a safe and
effective alternative to open surgical tracheostomy for intubated patients who
require elective tracheostomy.
PMID- 10767792
TI - Does the additive risk of mitral valve repair in patients with ischemic
cardiomyopathy prohibit surgical intervention?
AB - OBJECTIVE: To assess the surgical risk of additional mitral valve repairs in
patients with ischemic cardiomyopathy. SUMMARY BACKGROUND DATA: Severe mitral
regurgitation in patients with ischemic cardiomyopathy increases the death rate
and symptomatic status. The 1-year survival rate for medical therapy in this
subset of patients is less than 20%. Transplantation is usually not feasible
because of donor shortage and death while on the waiting list. METHODS: To assess
additive risk, a retrospective chart review from 1993 to 1998 was performed
comparing patients with ischemic cardiomyopathy (ejection fraction [EF] <25%) and
severe mitral regurgitation undergoing mitral valve repair and coronary artery
bypass graft operations with patients with an EF of <25% undergoing coronary
artery bypass graft alone. These groups were also compared with 140 patients
receiving heart transplants since 1993 (group 3). RESULTS: The overall hospital
death rate for group 1 was 6.3%. The one death occurred 2 weeks after surgery
secondary to sepsis. This was not significantly different from the death rate of
4.1% in group 2. In group 1, there were two deaths at 1 year (87% survival rate),
one related to heart failure. One patient was New York Heart Association (NYHA)
class IV at 1 year; the remainder of patients were NYHA class I-II. These results
were not significantly different than the 8% death rate noted with
transplantation. There was no change in EF and minimal residual mitral
regurgitation in group 1 based on postoperative transesophageal echocardiography,
whereas group 2 had an average 11.7% improvement in EF. CONCLUSIONS: Previously,
severe mitral regurgitation in the setting of ischemic cardiomyopathy has been
associated with poor survival. In these authors' experience, repairing the mitral
valve along with coronary artery bypass grafting does not increase the surgical
risk, yields improvement in symptomatic status, and compares favorably to
coronary artery bypass grafting alone and cardiac transplantation. However, the
lack of change in EF in these patients probably represents an overestimation of
the EF before surgery secondary to severe mitral regurgitation.
PMID- 10767793
TI - Hand-assisted laparoscopic surgery (HALS) with the HandPort system: initial
experience with 68 patients.
AB - OBJECTIVE: To evaluate the feasibility and potential benefits of hand-assisted
laparoscopic surgery with the HandPort System, a new device. SUMMARY BACKGROUND
DATA: In hand-assisted laparoscopic surgery, the surgeon inserts a hand into the
abdomen while pneumoperitoneum is maintained. The hand assists laparoscopic
instruments and is helpful in complex laparoscopic cases. METHODS: A prospective
nonrandomized study was initiated with the participation of 10 laparoscopic
surgical centers. Surgeons were free to test the device in any situation where
they expected a potential advantage over conventional laparoscopy. RESULTS: Sixty
eight patients were entered in the study. Operations included colorectal
procedures (sigmoidectomy, right colectomy, resection rectopexy), splenectomy for
splenomegaly, living-related donor nephrectomy, gastric banding for morbid
obesity, partial gastrectomy, and various other procedures. Mean incision size
for the HandPort was 7.4 cm. Most surgeons (78%) preferred to insert their
nondominant hand into the abdomen. Pneumoperitoneum was generally maintained at
14 mmHg, and only one patient required conversion to open surgery as a result of
an unmanageable air leak. Hand fatigue during surgery was noted in 20.6%.
CONCLUSIONS: The hand-assisted technique appeared to be useful in minimally
invasive colorectal surgery, splenectomy for splenomegaly, living-related donor
nephrectomy, and procedures considered too complex for a laparoscopic approach.
This approach provides excellent means to explore, to retract safely, and to
apply immediate hemostasis when needed. Although the data presented here reflect
the authors' initial experience, they compare favorably with series of similar
procedures performed purely laparoscopically.
PMID- 10767794
TI - Preoperative lymphoscintigraphy for breast cancer does not improve the ability to
identify axillary sentinel lymph nodes.
AB - OBJECTIVE: To evaluate the role of preoperative lymphoscintigraphy in sentinel
lymph node (SLN) biopsy for breast cancer. SUMMARY BACKGROUND DATA: Numerous
studies have demonstrated that SLN biopsy can be used to stage axillary lymph
nodes for breast cancer. SLN biopsy is performed using injection of radioactive
colloid, blue dye, or both. When radioactive colloid is used, a preoperative
lymphoscintigram (nuclear medicine scan) is often obtained to ease SLN
identification. Whether a preoperative lymphoscintigram adds diagnostic accuracy
to offset the additional time and cost required is not clear. METHODS: After
informed consent was obtained, 805 patients were enrolled in the University of
Louisville Breast Cancer Sentinel Lymph Node Study, a multiinstitutional study
involving 99 surgeons. Patients with clinical stage T1-2, N0 breast cancer were
eligible for the study. All patients underwent SLN biopsy, followed by level I/II
axillary dissection. Preoperative lymphoscintigraphy was performed at the
discretion of the individual surgeon. Biopsy of nonaxillary SLNs was not required
in the protocol. Chi-square analysis and analysis of variance were used for
statistical comparison. RESULTS: Radioactive colloid injection was performed in
588 patients. In 560, peritumoral injection of isosulfan blue dye was also
performed. A preoperative lymphoscintigram was obtained in 348 of the 588
patients (59%). The SLN was identified in 221 of 240 patients (92.1%) who did not
undergo a preoperative lymphoscintigram, with a false-negative rate of 1.6%. In
the 348 patients who underwent a preoperative lymphoscintigram, the SLN was
identified in 310 (89.1%), with a false-negative rate of 8.7%. A mean of 2.2 and
2. 0 SLNs per patient were removed in the groups without and with a preoperative
lymphoscintigram, respectively. There was no statistically significant difference
in the SLN identification rate, false-negative rate, or number of SLNs removed
when a preoperative lymphoscintigram was obtained. CONCLUSIONS: Preoperative
lymphoscintigraphy does not improve the ability to identify axillary SLN during
surgery, nor does it decrease the false-negative rate. Routine preoperative
lymphoscintigraphy is not necessary for the identification of axillary SLNs in
breast cancer.
PMID- 10767796
TI - Survival after resection of multiple bilobar hepatic metastases from colorectal
carcinoma.
AB - OBJECTIVE: To define the long-term outcome and treatment complications for
patients undergoing liver resection for multiple, bilobar hepatic metastases from
colorectal cancer. METHODS: A retrospective analysis of 165 consecutive patients
undergoing liver resection for metastatic colorectal cancer was performed.
Patients were divided into a simple hepatic metastasis group, consisting of
patients with three or fewer metastases in a unilobar distribution, and a complex
hepatic metastases group, consisting of patients with four or more unilobar
metastases or at least two bilobar metastases. RESULTS: The 5-year survival rate
was 36% for the simple group and 37% for the complex group. Multivariate analysis
revealed that the number of hepatic segments involved by tumor and the maximum
diameter of the largest metastasis correlated significantly with the 5-year
survival rate. The surgical death rate was 4.9% for the simple group and 9.1% for
the complex group; this difference was not significant. Multivariate analysis
revealed that extended lobar resection and concomitant colon and hepatic
resection were significant and independent predictors of surgical death. The
combination of extended lobar resection and concomitant colon resection was used
significantly more frequently in the complex group than in the simple group.
CONCLUSIONS: Resection of complex hepatic metastases, as defined in this study,
results in a 5-year survival rate of 37% and confers the same survival benefit as
does resection of limited hepatic metastases. The surgical death rate for this
aggressive approach is significantly higher if extended lobar resections are
necessary and if concomitant colorectal resection is performed. Patients who have
complex hepatic metastases at the time of diagnosis of the primary colorectal
cancer and who would require extended hepatic lobectomy should have hepatic
resection delayed for at least 3 months after colon resection.
PMID- 10767795
TI - Effect of minimally invasive radioguided parathyroidectomy on efficacy, length of
stay, and costs in the management of primary hyperparathyroidism.
AB - OBJECTIVE: To compare the first 20 patients who underwent minimally invasive
radioguided parathyroidectomies (MIRPs) performed at the authors' institution
with 20 similar patients who underwent a more conventional surgical approach for
primary hyperparathyroidism. SUMMARY BACKGROUND DATA: The technique of
parathyroidectomy has traditionally involved a bilateral exploration of the neck
with the intent of visualizing four parathyroid glands and resecting enlarged
parathyroid glands. Parathyroid scanning using radioisotopes has evolved and now
can localize adenomas in 80% to 90% of patients. MIRP combines parathyroid
scanning with a hand-held intraoperative detector that guides the surgeon to the
adenoma. METHODS: Forty patients with documented primary hyperparathyroidism who
underwent surgery by a single surgeon between January 1998 and May 1999 were
included in this study. Twenty of these patients underwent MIRP. The technique
involved injecting 20 mCi technetium-99m sestamibi 2 hours before surgery and
performing a parathyroid scan. If the scan was considered positive for a single
adenoma, patients were taken to the operating room and given the choice of either
general anesthesia or intravenous sedation with local anesthesia. Using an
incision of 4 cm or less, the dissection down to the adenoma was guided by the
Navigator miniature hand-held probe. An additional 20 patients who underwent more
conventional bilateral or unilateral neck exploration were chosen to match the
MIRP patient population. Both groups included four patients undergoing repeat
surgery for persistent or recurrent primary hyperparathyroidism and one patient
with multiple endocrine neoplasia type 1 syndrome. Patient demographics,
preoperative calcium and parathyroid hormone levels, operative time, total time
in the operating room, time in the recovery room, complications, hospital charges
for the operating room, and total hospital charges were analyzed. RESULTS: There
were no differences in patient demographics, presenting symptoms, or preoperative
calcium level between patients undergoing the standard procedure versus MIRP.
Operative time, total time in the operating room, operative charges, and total
hospital charges were significantly reduced in the MIRP group. All 40 patients
were cured of primary hyperparathyroidism. There were no recurrent laryngeal
nerve injures in either group. The mean length of stay in the standard group was
1. 35 days; in the MIRP group, 65% of patients were discharged within 5 hours
after surgery. CONCLUSIONS: The MIRP technique resulted in excellent cure rates
for primary hyperparathyroidism while simultaneously decreasing operative time
and hospital stays. These resulted in significant cost reductions without
compromising patient safety. The technique may significantly change the
management of primary hyperparathyroidism.
PMID- 10767797
TI - Hepatic cryoablation, but not radiofrequency ablation, results in lung
inflammation.
AB - OBJECTIVE: To compare the effects of 35% hepatic cryoablation with a similar
degree of radiofrequency ablation (RFA) on lung inflammation, nuclear factor
kappaB (NF-kappaB) activation, and production of NF-kappaB dependent cytokines.
SUMMARY BACKGROUND DATA: Multisystem injury, including acute lung injury, is a
severe complication associated with hepatic cryoablation of 30% to 35% or more of
liver parenchyma, but this complication has not been reported with RFA. METHODS:
Sprague-Dawley rats underwent 35% hepatic cryoablation or RFA and were killed at
1, 2, and 6 hours. Liver and lung tissue were freeze-clamped for measurement of
NF-kappaB activation, which was detected by electrophoretic mobility shift assay.
Serum concentrations of tumor necrosis factor alpha and macrophage inflammatory
protein 2 were measured by enzyme-linked immunosorbent assay. Histologic studies
of pulmonary tissue and electron microscopy of ablated liver tissue were compared
among treatment groups. RESULTS: Histologic lung sections after cryoablation
showed multiple foci of perivenular inflammation, with activated lymphocytes,
foamy macrophages, and neutrophils. In animals undergoing RFA, inflammatory foci
were not present. NF-kappaB activation was detected at 1 hour in both liver and
lung tissue samples of animals undergoing cryoablation but not after RFA, and
serum cytokine levels were significantly elevated in cryoablation versus RFA
animals. Electron microscopy of cryoablation-treated liver tissue demonstrated
disruption of the hepatocyte plasma membrane with extension of intact hepatocyte
organelles into the space of Disse; RFA-treated liver tissue demonstrated
coagulative destruction of hepatocyte organelles within an intact plasma
membrane. To determine the stimulus for systemic inflammation, rats treated with
cryoablation had either immediate resection of the ablated segment or delayed
resection after a 15-minute thawing interval. Immediate resection of the
cryoablated liver tissue prevented NF-kappaB activation and lung injury; however,
pulmonary inflammatory changes were present when as little as a 15-minute thaw
interval preceded hepatic resection. CONCLUSIONS: Hepatic cryoablation, but not
RFA, induces NF-kappaB activation in the nonablated liver and lung and is
associated with acute lung injury. Lung inflammation is associated with the
thawing phase of cryoablation and may be related to soluble mediator(s) released
from the cryoablated tissue. These findings correlate the clinical observation of
an increased incidence of multisystem injury, including adult respiratory
distress syndrome (ARDS), after cryoablation but not RFA.
PMID- 10767799
TI - Laparoscopic donor nephrectomy with a 23-hour stay: a new standard for
transplantation surgery.
AB - OBJECTIVE: To determine the outcomes associated with laparoscopic donor
nephrectomy (LDN) performed as a 23-hour day surgery protocol. SUMMARY BACKGROUND
DATA: Living donor renal transplantation is associated with immediate graft
function and prolonged graft survival. The recent application of laparoscopic
technology to living renal donation has refocused attention on the advantages of
this donor source. LDN is associated with decreased donor pain, length of stay,
time out of work, and opportunity costs. The authors hypothesized that LDN would
be a viable 23-hour stay procedure. METHODS: All living donation procedures since
May 1998 have been performed with LDN. The 23-hour protocol was initiated in
January 1999. LDNs performed from May 1998 to December 1998 and traditional open
donor nephrectomy procedures from May 1996 to May 1998 served as historical
controls. The following variables were examined: donor sex, related versus
nonrelated donation, operative time, blood loss, length of stay, time out of
work, recipient and donor serum creatinine levels, hospital charges, and
complications. RESULTS: The 23-hour LDN protocol was associated with high degrees
of donor satisfaction. Thirty-six of the 41 donors were discharged within 23
hours; 1 was readmitted. Time out of work was equivalent to that of the control
group; graft function was identical among all three comparison groups. Hospital
charges were equivalent between the control group and the open nephrectomy group
and were significantly decreased in the 23-hour group. CONCLUSIONS: Laparoscopic
donor nephrectomy can be performed as a 23-hour stay procedure without incurring
additional complications or donor dissatisfaction. By further decreasing
opportunity costs and disincentives for donation, LDN may increase the number of
potential donors appearing for evaluation.
PMID- 10767798
TI - Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence
after liver resection in an animal model.
AB - OBJECTIVE: To evaluate the neoadjuvant use of a herpes simplex viral (HSV)
amplicon vector expressing the murine interleukin-12 (IL-12) gene. SUMMARY
BACKGROUND DATA: Surgery is the most effective therapy for hepatic malignancy.
Recurrences, which are common, most often occur in the remnant liver and are due
partly to growth of residual microscopic disease in the setting of postoperative
host cellular immune dysfunction. The authors hypothesized that engineering
tumors to secrete IL-12 in vivo would elicit an immune response directed at
residual tumor and would reduce the incidence of recurrence after resection.
METHODS: Solitary hepatomas were established in Buffalo rat livers and directly
injected with 106 particles of HSV carrying the gene for IL-12, lacZ (beta
galactosidase) or with saline. One week after injection, the animals were
challenged with an intraportal injection of 106 tumor cells, with subsequent
resection of the hepatic lobe containing the previously established macroscopic
tumor nodule, recreating the clinical scenario of residual microscopic cancer.
RESULTS: Hepatoma cells transfected with HSV-IL-12 produced high levels of IL-12
in vitro and in vivo. A significant local immune response developed, as evidenced
by a progressive increase in the number of CD4(+) and CD8(+) lymphocytes in the
tumor. Treatment of established hepatomas with HSV-IL-12 protected against growth
of microscopic residual cancer after hepatic resection. Sixty-four percent of the
animals treated with HSV-IL-12 had zero or one tumors compared with 30% of HSVlac
treated and 24% of saline-treated animals. CONCLUSIONS: This neoadjuvant immune
strategy may prove useful in reducing the incidence of cancer recurrence after
hepatic resection.
PMID- 10767800
TI - Anterior cervical foraminotomy for unilateral radicular disease.
AB - STUDY DESIGN: A clinical series of patients with unilateral radiculopathy treated
with the anterior cervical foraminotomy procedure. OBJECTIVE: To establish
procedural techniques and clinical and radiologic outcomes for the anterior
cervical foraminotomy procedure. SUMMARY OF BACKGROUND DATA: Cervical
radiculopathy is typically caused by unilateral disc herniation or uncovertebral
osteophytes that compress the ventral aspect of the nerve. Direct removal of a
cervical lesion causing radicular symptoms without concomitant fusion seems to be
an ideal treatment in selected patients. The indications for an anterior cervical
neural foraminotomy are limited to unilateral radicular symptoms at one or two
levels, with minimal neck pain. METHODS: Twenty-one patients were treated with
the anterior cervical neural foraminotomy procedure during a 3-year period with
follow-up from 6 to 36 months. There were 13 men and 8 women (age range, 27-58
years). Fourteen patients had symptomatic soft disc herniation, and 7 had
uncovertebral osteophytes confirmed by magnetic resonance imaging and/or
myelogram and computed tomography. Sixteen patients had a single anterior
cervical neural foraminotomy, and 5 had procedures at adjacent levels. RESULTS:
Nineteen patients (91%) had improved or resolved radicular symptoms, and 2 (9%)
had persistent radicular symptoms necessitating further surgery (one two-level
anterior cervical neural discectomy and fusion and one posterior foraminal
decompression). CONCLUSIONS: Patients treated with the anterior cervical neural
foraminotomy procedure have equivalent or better outcomes than those who undergo
current cervical procedures. It appears to be a good alternative procedure for
carefully selected patients with unilateral cervical radiculopathy and avoids a
fusion of the disc space.
PMID- 10767801
TI - Approaching the upper thoracic vertebrae without sternotomy or thoracotomy: a
radiographic analysis with clinical application.
AB - STUDY DESIGN: The distribution of the lowest vertebra tangential to the
suprasternal notch and the lowest intervertebral disc visualized above the
sternum was determined on magnetic resonance imaging (MRI) studies. The method is
illustrated in seven patients undergoing upper thoracic spinal reconstruction to
define a surgical approach without sternotomy or thoracotomy. OBJECTIVES: The
relation of the sternal notch to thoracic vertebrae was examined by MRI to
estimate the thoracic level approachable anteriorly without sternotomy. SUMMARY
OF BACKGROUND DATA: Upper thoracic spine (T1-T4) visualization is considered
difficult. The thoracic vertebrae that can be visualized anteriorly without
sternotomy is unknown. METHODS: The vertebral level tangential to the
suprasternal notch and the lowest intervertebral disc visualized in its entirety
above the sternum was determined from 106 consecutive midsagittal cervicothoracic
MRI studies. The method was evaluated in seven patients to illustrate application
of a low suprasternal, lateral extracavitary, or transpedicular approach to
performing upper thoracic reconstruction. RESULTS: The midportion of the T3
vertebra is often above the sternal notch, whereas the trajectory of the T1-T2
intervertebral disc is usually rostral to the sternum. All four patients with
disease above the sternal notch on MRI underwent a low left suprasternal
approach, whereas three others were treated with a lateral extracavitary or
transpedicular approach. No patient worsened neurologically and all ambulated
independently after surgery. CONCLUSIONS: Upper thoracic vertebrae can be exposed
without sternotomy or thoracotomy by a low left suprasternal approach.
Midsagittal cervicothoracic MRI can identify the thoracic vertebrae above the
sternum, thereby determining whether a low suprasternal approach is feasible.
Otherwise, a lateral extracavitary or transpedicular approach can be used to
avoid sternotomy or thoracotomy.
PMID- 10767802
TI - Posterior lumbar interbody fusion with restoration of lamina and facet fusion.
AB - STUDY DESIGN: To report the techniques and surgical results of posterior lumbar
interbody fusion with restoration of the lamina and facet fusion. OBJECTIVES: To
present a technique to reconstruct the posterior construct in posterior lumbar
interbody fusion. SUMMARY OF BACKGROUND DATA: Successful arthrodesis in posterior
lumbar interbody fusion requires both a large amount of graft and maximal graft
filling, it also requires an excessive distraction of neural structures and
excessive removal of the facet-lamina structure, which plays a significant
mechanical role, especially in rotatory stability. METHODS: This study consisted
of 36 surgery patients comprising 27 cases of chronic herniated lumbar disc, 4
caused by failed back surgery syndrome, 3 by recurrent lumbar disc herniation,
and 2 by apophysis fracture with disc avulsion. The facetolaminotomy was
performed by osteotomizing bilateral pars interarticularis with a Gigli saw.
Posterior lumbar interbody fusion was performed through the more widely exposed
intervertebral space by inserting a pair of carbon fiber cages and medial iliac
bone blocks between the cages. The facetolaminotomy flap was returned to the
previous site and fixed by translaminar and transisthmic screw fixation.
Bilateral facet arthrodesis was also performed. RESULTS: There were no neural
complications related to facetolaminotomy by using the Gigli saw, nor were there
any complications related to the screw fixation for the restoration of the
posterior construct. Of the 22 patients available for more than a 6-month
postoperative follow-up period, radiologic union at the interbody fusion site and
at both pars interarticularis was noted in 18. An incomplete union at unilateral
pars interarticularis was noted in the other 4 patients. CONCLUSIONS: The
technique of posterior lumbar interbody fusion with restoration of the lamina and
facet fusion not only provides a wide interspace for safe and effective posterior
lumbar interbody fusion but also restores the posterior constructs, thereby
preserving its important mechanical roles and often even achieving natural
circumferential arthrodesis.
PMID- 10767803
TI - Percutaneous vertebroplasty for pain relief and spinal stabilization.
AB - STUDY DESIGN: This was a retrospective review of 47 consecutive patients (1995
1998) in whom percutaneous intraosseous methylmethacrylate cement injection
(percutaneous vertebroplasty) was used to treat osteoporotic vertebral
compression fractures and spinal column neoplasms. OBJECTIVES: To present initial
results regarding pain relief, spinal stabilization, and complications after
treatment with percutaneous vertebroplasty. SUMMARY OF BACKGROUND DATA:
Percutaneous vertebroplasty was developed in France in the late 1980s. Several
European reports have described excellent results for treatment of compression
fractures and neoplasms. The procedure was not performed in the United States
until 1994. Only a single series of 29 patients treated in the United States has
been reported. METHODS: A retrospective review was conducted of 47 consecutive
patients with 84 vertebrae treated with percutaneous vertebroplasty. Thirty-eight
patients with 70 vertebrae had symptomatic, osteoporotic fractures and had failed
medical therapy. Eight patients with 13 vertebrae had primary or metastatic
neoplasms. One patient had a hemangioma. Immediate and long-term pain response,
spinal stability, and complications were evaluated. RESULTS: Among the 38
patients treated for osteoporotic fractures, 24 (63%) had marked to complete pain
relief, 12 (32%) moderate relief and 2 (5%) no significant change. Only 4 of the
8 patients with malignancies had significant pain relief. In 7 of these patients,
no further vertebral compression occurred, and spinal canal compromise was
prevented. The patient with the hemangioma had no significant pain reduction.
Minor complications occurred in 3 (6%) patients. CONCLUSIONS: Percutaneous
vertebroplasty provided significant pain relief in a high percentage of patients
with osteoporotic fractures. The procedure provided spinal stabilization in
patients with malignancies but did not produce consistent pain relief.
Complications were minor and infrequent. Percutaneous vertebroplasty is a
promising therapy for patients with osteoporotic fractures and for selected
vertebral column neoplasms.
PMID- 10767804
TI - Herniated lumbar disc material as a source of free glutamate available to affect
pain signals through the dorsal root ganglion.
AB - STUDY DESIGN: Combined prospective human cohort and prospective controlled animal
model. OBJECTIVES: To determine whether free glutamate is available in herniated
disc material in concentrations sufficient to diffuse to glutamate receptors and
affect the activity of neurons in the dorsal root ganglion that may transmit pain
information. SUMMARY OF BACKGROUND DATA: The severity of lumbar radicular pain
cannot be fully explained by physical pressure on nerve roots or ganglions. In
experimental models, inflammatory processes are relatively modest under
conditions of disc herniation. The hypothesis for the current study was that the
proteoglycan link and core proteins, which contain high fractions of acidic amino
acids, may be a source of glutamate when enzymatically degraded in an environment
without glutamate reuptake systems. Glutamate would be free to diffuse to the
dorsal root ganglion to affect glutamate receptors. METHODS: Disc material was
harvested during surgery from herniated and nonherniated portions in patients
undergoing elective lumbar disc surgery and subjected to immunohistochemistry and
high-performance liquid chromatography for assessment of the presence of
extracellular disc matrix glutamate. Miniosmotic pumps with differing
concentrations of radiolabeled glutamate based on human data were implanted in
the rat epidural space for 72 hours and dorsal root ganglion (DRG) in the region
were harvested. RESULTS: Densitometry of disc matrix demonstrated
immunohistochemical evidence for significant extracellular glutamate (P < 0.002).
High performance liquid chromatography showed significant concentrations of
glutamate in disc material and significantly more in herniated than in
nonherniated disc material (P < 0.05). Significant radiolabeling of the dorsal
root ganglion after epidural glutamate infusion was found at concentrations two
orders of magnitude below measured disc glutamate levels. Autoradiography
demonstrated radiolabeling of adjacent DRG. CONCLUSIONS: Glutamate originating
from degenerated disc proteoglycan may diffuse to the dorsal root ganglion and
effect glutamate receptors. Consideration may be given to treating disc
radiculopathy with epidural glutamate receptor antagonists.
PMID- 10767805
TI - The effect of age on inflammatory responses and nerve root injuries after lumbar
disc herniation: an experimental study in a canine model.
AB - STUDY DESIGN: An experimental investigation on the effect of age on pathologic
events surrounding the herniated disc and at the adjacent nerve root. OBJECTIVES:
To investigate the role of age on the inflammatory responses and nerve root
damage surrounding a sequestered lumbar disc fragment using a dog model. SUMMARY
OF BACKGROUND DATA: Lumbar disc herniation is manifested in patients by variable
clinical findings, natural history, and resorption phenomena in which the
variability is particularly noted among patients with different ages. There are
no previous reports on the effect of age on pathologic events induced by the
herniated disc. METHODS: Six beagle dogs, including two animals of each age group
of 6, 12, and 24 months (human equivalent ages of 10, 15, and 24 years), were
used in this study. The dogs underwent L4-L5, L5-L6, and L6-L7 laminotomy and
discectomy under general anesthesia. An autologous intervertebral disc from the
tail was divided into anulus fibrosus and nucleus pulposus fragments. The anulus
fibrosus and nucleus pulposus fragments were placed in the anterolateral epidural
space of L5-L6 and L6-L7, respectively. The L4-L5 discectomy site served as a
control. Dogs were killed at 12 weeks after surgery. The lumbar spine was removed
en bloc, and histologic sections were prepared consecutively and examined.
RESULTS: In the nucleus pulposus group at L6-L7, neovascularity, and intensive
infiltration of lymphocytes, macrophages, and fibroblasts were observed
surrounding the nucleus pulposus fragment in the 24-month-old group only.
Degenerative changes of the nerve root fibers were observed in the 24-month-old
group only. In the control and anulus fibrosus groups at L4-L5 and L5-L6, there
were no marked inflammatory reactions in all age groups. The nerve root fibers
around the anulus fibrosus were normal in all age groups. CONCLUSIONS: There is
an effect of age on the inflammatory response and nerve root injury caused by the
herniated disc. The apparent neuroprotective mechanism in the young animal, and
the apparent inflammatory and resorption changes of the nucleus pulposus fragment
in the older animal are quite intriguing.
PMID- 10767806
TI - Magnetic resonance imaging and histologic evidence of postoperative back muscle
injury in rats.
AB - STUDY DESIGN: Postoperative back muscle injury was evaluated in rats by magnetic
resonance imaging and histologic analyses. OBJECTIVE: To compare the magnetic
resonance imaging manifestation of back muscle injury with the histologic
findings in rats and to subsequently clarify the histopathologic appearance of
the high intensity regions on T2-weighted images in human postoperative back
muscles. SUMMARY OF BACKGROUND DATA: In a previous study, it was found that the
signal intensity on T2-weighted images of the postoperative back muscles was
increased in patients who had postsurgical lumbar muscle impairment, especially
in those with a prolonged surgery duration. However, the specific histopathologic
changes that cause the high signal intensity on T2-weighted images remain
unclear. METHODS: Rats were divided into three groups: sham operation group, 1
hour retraction group, and 2-hour retraction group. Magnetic resonance imaging
and histology of the multifidus muscles were examined before surgery and at 2, 7,
and 21 days after surgery. RESULTS: T2-weighted imaging was more useful than T1
weighted imaging to estimate back muscle injury. The high signal intensity of the
multifidus muscles on T2-weighted images remained 21 days after surgery only in
the 2-hour retraction group. Histologically, the regeneration of the multifidus
muscles was complete at 21 days after surgery in the 1-hour retraction group, but
the regenerated muscle fibers in the 2-hour retraction group had a small
diameter, and the extracellular fluid space remained large. CONCLUSION: The high
signal intensity on T2-weighted images of the postoperative multifidus muscles in
the regenerative phase may be due to an increased extracellular space and
incomplete muscle fiber regeneration.
PMID- 10767807
TI - Muscle response pattern to sudden trunk loading in healthy individuals and in
patients with chronic low back pain.
AB - STUDY DESIGN: A quick-release method in four directions of isometric trunk
exertions was used to study the muscle response patterns in 17 patients with
chronic low back pain and 17 matched control subjects. OBJECTIVES: It was
hypothesized that patients with low back pain would react to sudden load release
with a delayed muscle response and would exhibit altered muscle recruitment
patterns. SUMMARY OF BACKGROUND DATA: A delay in erector spinae reaction time
after sudden loading has been observed in patients with low back pain. Muscle
recruitment and timing pattern play an important role in maintaining lumbar spine
stability. METHODS: Subjects were placed in a semiseated position in an apparatus
that provided stable fixation of the pelvis. They exerted isometric contractions
in trunk flexion, extension, and lateral bending. Each subject performed three
trials at two constant force levels. The resisted force was suddenly released
with an electromagnet and electromyogram signals from 12 trunk muscles were
recorded. The time delay between the magnet release and the shut-off or switch-on
of muscle activity (reaction time) was compared between two groups of subjects
using two-factor analysis of variance. RESULTS: The number of reacting muscles
and reaction times averaged over all trials and directions showed the following
results: For healthy control subjects a shut-off of agonistic muscles (with a
reaction time of 53 msec) occurred before the switch-on of antagonistic muscles
(with a reaction time of 70 msec). Patients exhibited a pattern of co
contraction, with agonists remaining active (3.4 out of 6 muscles switched off)
while antagonists switched on (5.3 out of 6 muscles). Patients also had longer
muscle reaction times for muscles shutting off (70 msec) and switching on (83
msec) and furthermore, their individual muscle reaction times showed greater
variability. CONCLUSIONS: Patients with low back pain, in contrast to healthy
control subjects, demonstrated a significantly different muscle response pattern
in response to sudden load release. These differences may either constitute a
predisposing factor to low back injuries or a compensation mechanism to stabilize
the lumbar spine.
PMID- 10767808
TI - Anterior cervical fusion: a finite element model study on motion segment
stability including the effect of osteoporosis.
AB - STUDY DESIGN: Three-dimensional, nonlinear finite element models were used to
evaluate the stability of the mid cervical spine after anterior fusion in
patients with and without osteoporosis. OBJECTIVES: The objective of this study
was to compare the change in flexibility of C5-C6 after anterior discectomy with
both loose-fitting and tight-fitting fusion graft. SUMMARY OF BACKGROUND DATA:
Many factors such as surgical technique, osteoporosis, and excess neck motion
during the postoperative period may contribute to fusion failure. Knowledge about
changes in biomechanical properties after the surgical procedure is important for
selection of grafts with appropriate strength and for guiding patients in
postoperative care and rehabilitation. METHODS: Analyses with anterior fusion
models with both loose-fitting and tight-fitting graft were performed in a normal
and an osteoporotic spine. The motion of the C5 vertebra in relation to the C6
vertebra were calculated, after multidirectional moment loads of 0.5 Nm combined
with a compressive preload of 105 N. RESULTS: Loose-fitting graft produced both
an increase and a decrease in motion under various external moment loads, with
graft compressive stress below the compressive strength of the graft material. A
reduction in motion was observed under all moment loads when a tight-fitting
graft was used. The compressive stress in the tight-fitting graft was higher than
the strength of the graft material. Osteoporosis increased the principal motions
with both the loose-fitting graft and tight-fitting graft. Maximum increase in
motion with a loose-fitting graft construct was observed under extension and
axial torsion moment loads. CONCLUSIONS: Anterior discectomy and insertion of the
loose graft resulted in increased motion. A tight-fitting graft is beneficial in
reducing motion, but the stress within the graftincreases beyond the graft
strength. The presence of osteoporosis was nominally significant when the graft
was tight fitting.
PMID- 10767809
TI - Complications of pedicle screw fixation in reconstructive surgery of the cervical
spine.
AB - STUDY DESIGN: Retrospective evaluation of complications in 180 consecutive
patients with cervical disorders who had been treated by using pedicle screw
fixation systems. OBJECTIVES: To determine the risks associated with pedicle
screw fixation in the cervical spine and to emphasize the importance of
preoperative planning and surgical techniques in reducing the risks of this
procedure. SUMMARY OF BACKGROUND DATA: Generally, pedicle screw fixation in the
cervical spine has been considered too risky for the neurovascular structures.
There have been several reports describing the complications of lateral mass
screw-plate fixation. However, no studies have examined in detail the
complications associated with cervical pedicle screw fixation. METHODS: One
hundred eighty patients who underwent cervical reconstructive surgery using
cervical pedicle screw fixation were reviewed to clarify the complications
associated with the pedicle screw fixation procedure. Cervical disorders were
spinal injuries in 70 patients and nontraumatic lesions in 110 patients. Seven
hundred twelve screws were inserted into the cervical pedicles, and the locations
of 669 screws were radiologically evaluated. RESULTS: Injury of the vertebral
artery occurred in one patient. The bleeding was stopped by bone wax, and no
neurologic complication developed after surgery. On computed tomographic (CT)
scan, 45 screws (6.7%) were found to penetrate the pedicle, and 2 of 45 screws
caused radiculopathy. Besides these three neurovascular complications directly
attributed to screw insertion, radiculopathy caused by iatrogenic foraminal
stenosis from excessive reduction of the translational deformity was observed in
one patient. CONCLUSIONS: The incidence of the clinically significant
complications caused by pedicle screw insertion was low. Complications associated
with cervical pedicle screw fixation can be minimized by sufficient preoperative
imaging studies of the pedicles and strict control of screw insertion. Pedicle
screw fixation is a useful procedure for reconstruction of the cervical spine in
various kinds of disorders and can be performed safely.
PMID- 10767810
TI - Cervical and thoracic juxtafacet cysts causing neurologic deficits.
AB - STUDY DESIGN: Case reports and review of the literature. OBJECTIVES: To review
the clinical features, treatment, and outcome of juxtafacet cysts. SUMMARY OF
BACKGROUND DATA: There have previously been 4 reported cases of thoracic
juxtafacet cysts and 19 cases of cervical juxtafacet cysts. Cervical cysts have
usually originated from the cruciate ligament and caused myelopathy. Thoracic
cysts are usually signaled by myelopathy. METHODS: The records of the
Neurosurgery Department of Royal Adelaide Hospital from 1980 through 1995 were
reviewed for cases of intraspinal juxtafacet cysts. RESULTS: Eight cases of
intraspinal juxtafacet cysts were identified; six were in the lumbar spine. One
patient had a cervical cyst related to a facet joint and had unilateral
radiculopathy. A second patient with a thoracic cyst had the gradual onset of
myelopathy. Both patients had surgical excision of the cyst without resection of
the adherent dura. The symptoms and neurologic signs improved in each case.
CONCLUSIONS: Cervical and thoracic juxtafacet cysts are rare lesions that are
usually signaled by myelopathy. Results of surgery are excellent in most cases,
even if the cyst is not completely excised.
PMID- 10767811
TI - Low dose propofol as a supplement to ketamine-based anesthesia during
intraoperative monitoring of motor-evoked potentials.
AB - STUDY DESIGN: Motor-evoked potentials (MEPs) were analyzed using transcranial
electrical stimulation during spinal surgery in patients under ketamine-based
anesthesia, with and without propofol. OBJECTIVE: To investigate the effects of
propofol on MEPs and ketamine-induced adverse effects during spinal surgery in
patients under ketamine-based anesthesia. SUMMARY OF BACKGROUND DATA:
Intraoperative monitoring of transcranial motor-evoked responses provides a
method for monitoring the functional integrity of descending motor pathways.
However, because these responses are sensitive to suppression by most anesthetic
agents, anesthetic technique is limited during the monitoring of MEPs. Ketamine
has been reported to have little effect on MEPs but may produce adverse effects
such as psychedelic effect and hypertension. Recently, it has been reported that
propofol may be able to inhibit ketamine-induced adverse effects. METHODS:
Intraoperative monitoring of MEPs was performed in 58 patients who underwent
elective spinal surgery. Anesthesia was maintained with nitrous oxide-fentanyl
ketamine without or with low-dose (1-3 mg/kg/hr) of propofol (K group; n = 34, KP
group; n = 24, respectively). Transcranial stimulation with single or paired
pulses or a train of three or five pulses (interstimulus interval, 2 msec) were
delivered to the scalp, and compound muscle action potentials were recorded from
the left and right tibialis anterior muscles. To investigate the dose effects of
propofol on MEPs, propofol was administered at an infusion rate of 6, 4, and 2
mg/kg/hr and then discontinued in 14 patients. RESULTS: Results of MEPs were
comparable between the K and KP groups. The incidence of postoperative
psychedelic effect was significantly less in the KP group (14%) than in the K
group (41%). Although propofol inhibited MEPs dose dependently, the use of a
train of pulses for stimulation could overcome such inhibition. CONCLUSIONS: If a
train of pulses were used for transcranial stimulation, low-dose propofol can be
effectivelyused as a supplement to ketamine-based anesthesia during
intraoperative monitoring of myogenic MEPs. Addition of propofol significantly
reduced the ketamine-induced psychedelic effects.
PMID- 10767812
TI - Repeatability of pain drawings in a low back pain population.
AB - STUDY DESIGN: This is a prospective test-retest repeatability study. OBJECTIVE:
The primary purpose of this study was to determine the test-retest repeatability,
using a variety of scoring methods, of pain drawings in a group of chronic low
back pain patients. The intraevaluator repeatability for the methods requiring
subjective interpretation was also evaluated. SUMMARY OF BACKGROUND DATA: Pain
drawings have been used in a variety of applications, including documentation of
symptom location, as a tool for diagnosis and as a psychological screening tool.
Accordingly, there have been several methods described for interpreting the
drawings and several groups have investigated evaluators' abilities to replicate
their interpretation. However, there has been less investigation of patients'
consistency in completing the drawings. METHODS: The intraevaluator repeatability
was determined for the two scoring methods requiring subjective interpretation by
the evaluator rescoring the drawings 2 weeks after the initial scoring. To
determine repeatability, drawings were completed on two occasions by 75 patients.
Patients who indicated on a questionnaire that there had been no change in their
pain location since their first clinic visit (the day the first drawing was
completed) were included in the study. This subgroup consisted of 45 patients who
completed pain drawings on two occasions separated by a mean of 244.2 days
(range, 26-1197 days). Repeatability was assessed for several scoring methods
described in the literature: penalty point system, overall visual inspection,
body regions, and a grid method. RESULTS: Patients were consistent in completing
the drawings, assessed by the various scoring methods. The worst repeatability
values were for some of the sensation types. DISCUSSION: As reported by others,
the intraevaluator repeatability was high. The results of this study, finding
acceptable repeatability for most scoring methods for pain drawing completed on
occasions separated by a relatively long period of time, support that the pain
drawing is a stable instrument for use in chronic back pain patients.
PMID- 10767813
TI - The role of paraspinal muscle spindles in lumbosacral position sense in
individuals with and without low back pain.
AB - STUDY DESIGN: A two-group experimental design with repeated measures on one
factor was used. OBJECTIVES: To investigate the role of paraspinal muscle
spindles in lumbosacral position sense in individuals with and without low back
pain. SUMMARY OF BACKGROUND DATA: Proprioceptive deficits have been identified in
patients with low back pain. The underlying mechanisms, however, are not well
documented. METHODS: Lumbosacral position sense was determined before, during,
and after lumbar paraspinal muscle vibration in 23 young patients with low back
pain and in 21 control subjects. Position sense was estimated by calculating the
mean absolute error, constant error, and variable error between six criterion and
reproduction sacral tilt angles. RESULTS: Repositioning accuracy was
significantly lower in the patient group than in healthy individuals (absolute
error difference between groups = 2.7 degrees, P < 0.0001). Multifidus muscle
vibration induced a significant muscle-lengthening illusion that resulted in an
undershooting of the target position in healthy individuals (constant error =
3.1 degrees, P < 0.0001). Conversely, the position sense scores of the patient
group did not display an increase in negative directional error but a significant
improvement in position sense during muscle vibration (P < 0.05). No significant
differences in absolute error were found between the first and last trial in the
healthy individuals (P >/= 0.05) and in the patient group (P > 0.05).
CONCLUSIONS: Patients with low back pain have a less refined position sense than
healthy individuals, possibly because of an altered paraspinal muscle spindle
afference and central processing of this sensory input. Furthermore, muscle
vibration can be an interesting expedient for improving proprioception and
enhancing local muscle control.
PMID- 10767814
TI - A review of the association between cigarette smoking and the development of
nonspecific back pain and related outcomes.
AB - STUDY DESIGN: A structured review of the epidemiologic literature was performed.
Thirty-eight studies published in peer-reviewed journals were reviewed. The
methodologic strengths and weaknesses of the studies were described and assessed
qualitatively. Four studies were excluded because of difficulties in design or
interpretation. OBJECTIVES: To provide a systematic analysis of the literature to
assess the evidence as to whether smoking is associated with the prevalence and
incidence of nonspecific back pain and related outcomes. SUMMARY OF BACKGROUND
DATA: Evidence has been gathering regarding the association of smoking with
nonspecific back pain and other back disorders, but a comprehensive summary and
evaluation of the data have not been published. RESULTS: Positive associations
between current smoking and nonspecific back pain were found in 18 of 26 studies
in men and 18 of 20 studies in women. For sciatica and herniated discs, there
were four of eight and one of five positive studies in men and women,
respectively. The majority of these studies were cross-sectional (18 in men and
16 in women), with only a handful of prospective studies. Positive associations
between past smoking and nonspecific back pain were reported in five of nine
studies in men and five of six studies in women. In addition, increases in the
prevalence and/or incidence of nonspecific back pain were found in the majority
of studies in which level of consumption was analyzed and reported. An attempt
was made to assess whether these results could be artifactual arising from
selection bias, confounding bias, publication bias, or errors in measurement. As
well, the biologic mechanisms were summarized that have been suggested by various
investigators. CONCLUSIONS: The available data are consistent with the notion
that smoking is associated with the incidenceand prevalence of nonspecific back
pain, but there are too few studies to make any conclusions for the other end
points (e.g., sciatica, herniated discs). It cannot be ruled out that the
association is a statistical artifact arising from either selection or
confounding factors, because the evidence for nonspecific low back pain derives
mostly from cross-sectional studies. In addition, it cannot be stated
unequivocally that smoking preceded back pain. Long-term follow-up studies are
needed to eliminate the possibility that chronic back pain preceded smoking, to
better estimate dose-response correlations, and to perform biologic measurements
to elucidate possible mechanisms.
PMID- 10767815
TI - Early aggressive exercise for postoperative rehabilitation after discectomy.
AB - STUDY DESIGN: A randomized clinical trial of postoperative medical exercise
therapy in patients after operation for lumbar disc herniation with blind
assessment of clinical outcomes. OBJECTIVE: To assess the effect of an early
regimen of vigorous medical exercise compared with an ordinary care program.
SUMMARY OF BACKGROUND DATA: METHODS: Patients offered an operation for lumbar
disc herniation were consecutively randomized to a training group or to a control
group. The training consisted of an 8-week active rehabilitation program
including a regimen of vigorous lumbar stabilizing exercises. The control
subjects participated in a mild program of 2 to 3 back exercises at home, after
relaxing and resting their backs for 2 months after the surgery. The outcomes
were evaluated 6 and 12 months after the operation. The results are based on
intention-to-treat analyses. RESULTS: Sixty-three of 65 eligible patients agreed
to participate in the trial. Fifty-eight and 53 patients attended for evaluation
at 6 and 12 months, respectively. There was a significantly larger improvement in
the mean Roland's disability index (from 8.9 to 5.4 [P = 0.02] at 6 months and
from 8. 7 to 5.3 [P = 0.03] at 12 months) and in reported pain (from 3.7 to 2.0
[P = 0.04] at 6 months and from 3.2 to 1.8 [P = 0.09] at 12 months) in the
training group. A significantly (P = 0.05) higher proportion of the training
group reported that they participated in daily activities as usual. There were
more patients in the training group who reported improvement in self-evaluated
health after surgery at both 6 (P = 0.02) and at 12 months (P = 0.05). Finally,
no differences in clinical end points were observed between the groups.
CONCLUSIONS: Vigorous medical exercise therapy, started 4 weeks after surgery for
lumbar disc herniation, reduced disability and pain after surgery. Because no
differences in clinical end points were observed, there is hardly any danger
associated with early and vigorous training after operation for disc herniation.
PMID- 10767817
TI - Defining the pediatric spinal thoracoscopy learning curve: sixty-five consecutive
cases.
AB - STUDY DESIGN: Consecutive case prospective chart and radiographic review.
OBJECTIVES: The purpose of this study was to define the learning curve of spinal
thoracoscopy. SUMMARY OF BACKGROUND DATA: Thoracoscopy is an alternative to open
thoracotomy in the treatment of pediatric spinal deformity. The learning curve
for spinal thoracoscopy has not been described. METHODS: In this prospective
study 65 consecutive cases of thoracoscopic anterior release with discectomy and
fusion performed by one surgeon for the treatment of pediatric spinal deformity
were reviewed. The patients were, on average, 14 +/- 3 years old and had the
following diagnoses: idiopathic scoliosis (n = 13), Scheuermann's kyphosis (n =
9), neuromuscular spinal deformity (n = 35), congenital scoliosis (n = 4), and
tumor/syrinx (n = 4). RESULTS: The average operative time for the thoracoscopic
procedure was 161 +/- 41 minutes (range, 50-240 minutes). There was a slight
decrease in the average operative time as the series progressed. The average
number of discs excised was 6.5 +/- 1.5 (range, 3-10), and the number increased
as the series progressed. The average operative time per disc was 29.3 +/- 7.7
minutes in the first 30 patients compared with 22.3 +/- 4.7 minutes in the next
35 patients (P < 0.01). The average blood loss during the thoracoscopic procedure
was 301 +/- 322 mL (range, 25-2000 mL) and did not decrease as the series
progressed. Initial postoperative scoliosis and kyphosis corrections were 59% +/-
17% and 92% +/- 12%, respectively. Complications occurred in six patients (cases
4, 8, 17, 31, 39, and 46) and were evenly distributed throughout the series.
CONCLUSIONS: The learning curve for thoracoscopy is substantial, but not
prohibitive. This technique provides a safe and effective alternative to
thoracotomy in the treatment of pediatric spinal deformity.
PMID- 10767816
TI - Active treatment of chronic neck pain: a prospective randomized intervention.
AB - STUDY DESIGN: A randomized comparative study with single-blind outcome
assessments. OBJECTIVES: To compare the efficacy of a multimodal treatment
emphasizing proprioceptive training (ACTIVE) with activated home exercises (HOME)
and recommendation of exercise (CONTROL) in patients with nonspecific chronic
neck pain. SUMMARY OF BACKGROUND DATA: The efficacy of active exercises and
passive physiotherapy for neck trouble has been somewhat disappointing in the
previous few studies. METHODS: Seventy-six patients (22 men, 54 women) with
chronic, nonspecific neck pain participated. Sixty-two participated the 1-year
follow-up. Subjective pain and disability, cervical ranges of motion, and
pressure pain threshold in the shoulder region were measured at baseline, at 3
months, and at 12 months. The ACTIVE treatment consisted of 24 sessions of
proprioceptive exercises, relaxation, and behavioral support. The HOME regimen
included a neck lecture and two sessions of practical training for home exercises
and instructions for maintaining a diary of progress. The CONTROL treatment
included a lecture regarding care of the neck with a recommendation to exercise.
RESULTS: The average self-experienced total benefit was highest in the ACTIVE
group, and the HOME group rated over the CONTROL group (P < 0.001). Differences
between the groups in favor of the ACTIVE treatment were recorded in reduction of
neck symptoms and improvements in general health and self-experienced working
ability (P < 0.01-0.03). Changes in measures of mobility and pressure pain
threshold were minor. CONCLUSIONS: Regarding self-experienced benefit, the
multimodal treatment was more efficacious than activated home exercises that were
clearly more efficacious than just advising. No major differences were noted in
objective measurements of cervical function between the groups, but the content
validity of these assessments in chronic neck trouble can be questioned.
PMID- 10767818
TI - Intraosseous calcifying pseudotumor of the axis: a case report.
AB - STUDY DESIGN: A case report and review of the literature. OBJECTIVE: To present
the first case of intraosseous calcifying pseudotumor arising from the axis.
SUMMARY OF BACKGROUND DATA: Calcifying pseudotumor is a very rare disease. Only
24 cases have been previously reported. METHODS: A case of calcifying pseudotumor
involving the body, dens, and laminae of the axis in a 60-year-old male patient
was managed with total laminectomy of the axis and instrumented occipitocervical
fusion, followed by the curettage of the body and dens of the axis and autogenous
iliac bone graft. Medical records, imaging studies, microscopic findings, and
related literature are reviewed. RESULTS: Microscopic examination showed
amorphous, basophilic, and chondroid calcifying masses surrounded with palisading
histiocytes and foreign body-type giant cells. The findings were consistent with
those of calcifying pseudotumors previously reported in other sites of the body.
At 24 months after operation, a significant reduction of neck pain was achieved.
But there was evidence of local recurrence of the lesion in the body and dens of
the axis with a local progression of the preexisting lesion in the facet joints.
CONCLUSION: This is the first report of intraosseous calcifying pseudotumor
arising from the axis.
PMID- 10767820
TI - Imagery
PMID- 10767819
TI - Hepatic ischemia as a complication after correction of post-traumatic gibbus at
the thoracolumbar junction.
AB - STUDY DESIGN: This is a case report of hepatic ischemia secondary to celiac trunk
stenosis as a complication after correction of a preoperative 30 degrees gibbus
at the thoracolumbar junction. OBJECTIVES: A high index of suspicion is needed to
make a timely diagnosis of hepatic ischemia in any setting. After spinal
reconstruction involving lengthening, symptoms suggestive of an acute abdomen
accompanied by markedly elevated liver enzymes should be evaluated with an
angiogram to check for celiac trunk stenosis. SUMMARY OF BACKGROUND DATA: Review
of the literature showed no reported cases of hepatic ischemia or descriptions of
the status of celiac trunk stenosis after spinal surgery. Even in more commonly
associated settings, diagnosis of both phenomena is often delayed, with possible
morbid consequences. METHODS: A case is presented of a patient who underwent
gibbus correction and re-establishment of lost anterior intervertebral distance
at the thoracolumbar junction. After surgery, ischemic hepatitis, a perforated
gallbladder, and splenic infarction developed secondary to celiac trunk stenosis
a result of cephalad displacement of the celiac trunk and compression of the
artery by the diaphragmatic ligament. RESULTS: An emergent exploratory laparotomy
with cholecystectomy was performed followed by an angiogram, which demonstrated
stenosis of the celiac trunk. After release of the arcuate ligament, the
patient's condition improved rapidly, and he made a complete recovery.
CONCLUSIONS: The consequences of a delay in diagnosis of hepatic ischemia can be
disastrous. An awareness of the possibility of this complication after spinal
lengthening should facilitate a timely angiogram and operative intervention.
PMID- 10767821
TI - ACP. Best Practice No 155. Guidelines for handling oesophageal biopsies and
resection specimens and their reporting.
PMID- 10767822
TI - Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a
disease pathogenetically and clinically similar to that caused by the 654G-A
mutation (familial amyloidosis of the Finnish type).
AB - BACKGROUND: Familial amyloidosis of the Finnish type (FAF, Finnish hereditary
amyloidosis) is caused by a 654G-A mutation in the gelsolin gene on chromosome 9
resulting in the expression of mutant Asn-187 gelsolin which is abnormally
proteolytically processed generating amyloidogenic fragments that polymerize into
amyloid fibrils. We have recently shown that in a Danish and a Czech family with
a clinical syndrome similar to FAF, including corneal lattice dystrophy, cranial
neuropathy and skin changes, the disease is caused by another mutation at the
same position, namely 654G-T predicting a Try-for-Asp substitution at 187 in
secreted gelsolin. AIM: To undertake a closer examination of the Danish subtype
of FAF and report immunohistochemical and biochemical findings. RESULTS:
Immunostaining of plasma gelsolin isolated from heterozygous FAF of the Danish
subtype revealed a pattern similar to that found in FAF-Asn 187. The > 60 kDa
gelsolin species contain an epitope characteristic of the amyloid forming region
as revealed by an amyloid specific antibody, whereas the approximately 50 kDa
fragments are devoid of it. Compared with the wild-type gelsolin peptide (Asp
187), the corresponding mutant peptide (Tyr-187) showed dramatically increased
fibrillogenicity as revealed by quantitative thioflavine-T based fluorimetry;
ultrastructurally, amyloid-like fibrils were formed by the mutant peptide.
Immunohistochemistry showed that antibodies directed against residues 231-242 of
secreted gelsolin, representing the carboxy terminus of the sequence forming the
amyloid protein (residues 173-243) laid down in the tissues in a fibrillar form
in FAF, specifically labelled the amyloid deposited in rectum and skin in the
Danish (654G-T) subtype. CONCLUSIONS: The 654G-T mutation in the gelsolin gene
gives rise to an amyloid disease clinically and pathogenetically similar to that
caused by the 654G-A mutation.
PMID- 10767824
TI - Artefactual serum hyperkalaemia and hypercalcaemia in essential thrombocythaemia.
AB - AIM: To investigate possible abnormalities of serum potassium and calcium levels
in patients with essential thrombocythaemia and significant thrombocytosis.
METHODS: 24 cases of essential thrombocythaemia with significant thrombocytosis
(platelet count > 700 x 10(9)/litre) had serum potassium and calcium estimations
performed at the time of maximum thrombocytosis before treatment, and at the time
of low platelet count after treatment with cytoreductive drugs. Selected patients
were further investigated with plasma sampling and estimation of ionised calcium
and parathyroid hormone. RESULTS: At the time of maximum thrombocytosis six
patients had serum hyperkalaemia (> 5.5 mmol/litre) and five had serum
hypercalcaemia (> 2.6 mmol/litre). Following treatment and reduction of the
platelet count, hyperkalaemia resolved in all cases and hypercalcaemia in four of
the five cases. Mean serum potassium and calcium concentrations were raised (p <
0.0001) at maximum thrombocytosis compared with the values when the platelet
count was low. Serum potassium and calcium values were significantly correlated
at all stages. Measurements on plasma consistently corrected the hyperkalaemia
but not the hypercalcaemia. Serum hypercalcaemia was associated with raised
ionised calcium and normal parathyroid hormone concentrations. CONCLUSIONS:
Essential thrombocythaemia with significant thrombocytosis is associated with
serum hyperkalaemia and hypercalcaemia. The probable mechanism of hypercalcaemia
is the secretion of calcium in vitro from an excessive number of abnormally
activated platelets. It is thus likely that the hypercalcaemia is an artefact, as
is the hyperkalaemia.
PMID- 10767823
TI - Lack of mucin MUC5AC field change expression associated with tubulovillous and
villous colorectal adenomas.
AB - BACKGROUND: MUC5AC is a secreted mucin aberrantly expressed by polypoid
colorectal adenomas. It has been hypothesised that the "normal" surrounding
colorectal mucosa expresses MUC5AC as a field change phenomenon that can be used
to predict adenoma recurrence following resection. AIM: To determine if there is
a field change of de novo MUC5AC expression in histologically normal rectal
mucosa adjacent to villous and tubulovillous adenomas, and thus whether MUC5AC
expression can be used as a marker of early tumour recurrence. METHODS: In a
prospective cohort study paired mucosal biopsies of adenomatous and
macroscopically "normal" mucosa were obtained from 11 patients with villous and
11 patients with tubulovillous adenomas who underwent primary resection for
purpose of cure. The tissues were studied to determine MUC5AC gene expression by
immunohistochemistry and in situ hybridisation. Patients were followed up by
flexible sigmoidoscopy to detect the presence of early local recurrence. RESULTS:
10 villous adenomas showed mature MUC5AC glycoprotein and all 11 expressed MUC5AC
mRNA. Five tubulovillous adenomas showed mature MUC5AC glycoprotein and 10
expressed MUC5AC mRNA. Neoexpression of the MUC5AC mucin gene was not detected in
any of the mucosal biopsies taken adjacent to either villous or tubulovillous
adenomas, even in three patients with early, locally recurrent disease.
CONCLUSIONS: Aberrant MUC5AC gene expression is not a "field change" in the
colorectal mucosa in patients with rectal adenomas and therefore cannot be used
to predict local recurrence of villous and tubulovillous adenomas.
PMID- 10767825
TI - Strongyloides stercoralis: ultrastructural study of newly hatched larvae within
human duodenal mucosa.
AB - AIM: To investigate the ultrastructural features of the newly hatched larvae of
Strongyloides stercoralis in human duodenal mucosa. METHODS: Duodenal biopsies
from an AIDS patient were studied by transmission electron microscopy to
investigate morphology, location, and host-worm relations of newly hatched
larvae. RESULTS: Newly hatched larvae were found in the Lieberkuhn crypts within
the tunnels formed by migration of parthenogenic females. Delimiting enterocytes
were compressed. Release of larvae into the gut lumen was also documented. It was
shown that both a thin and a thick membrane surrounded the eggs and larvae, as a
tegument derived respectively from parasite and host. Segmentary spike-like
waves, caused by contractures of worm body musculature, were observed on the
surface of newly hatched larvae, and their intestinal lumen was closed and empty,
with no budding microvilli. Immaturity of the cuticle and some degree immaturity
of amphidial neurones were found, but there was no evidence of either immaturity
or signs of damage to other structures. CONCLUSIONS: Newly hatched larvae of S
stercoralis appear to be a non-feeding immature stage capable of active movement
through the epithelium, causing mechanical damage. The tegument resulting from
the thin and the thick membrane may protect the parasite and reduce any
disadvantage caused by immaturity.
PMID- 10767826
TI - Unlinked anonymous HIV study of hospital patients and general practice attenders
in Glasgow, 1991-1997.
AB - AIM: To determine whether HIV is spreading from injecting drug users and
homosexual/bisexual males into lower risk heterosexual populations in Glasgow,
Scotland, and to pilot a method of monitoring HIV prevalence which involves
testing routine biochemistry specimens. METHODS: An unlinked anonymous HIV
testing study of hospital patients and general practice attenders was conducted
during January 1992 to December 1997. Testing was performed on routine
biochemistry specimens from patients aged 16-49 years attending two hospitals
with catchment areas covering the north and the east of the city. RESULTS: 78,260
specimens were tested in the study period and no patient objected to their
samples being tested anonymously. HIV prevalence rates among male and female
subjects were 0.63% and 0.01%, respectively; the large difference in prevalence
resulted, in part, from the inclusion of HIV infected haemophiliac patients who
attended one of the hospitals. Prevalence among male general practice patients
ranged between 0.1% and 0.2%, while that for male patients attending surgical or
surgically related specialties was 0.1%. CONCLUSIONS: The prevalence data
indicate that HIV has not seeded from the high risk groups into the wider
heterosexual population, and that the risk of a surgeon acquiring HIV
occupationally is extremely low in a city which has an HIV prevalence similar to
or greater than that seen in most other parts of the United Kingdom. Large
numbers of residual specimens from busy biochemistry laboratories can be
processed for unlinked anonymous testing without interfering with the
laboratories' routine functions. This survey approach might be best suited to
monitoring HIV trends in developing countries with relatively high prevalence
rates and where transmission is principally heterosexual.
PMID- 10767827
TI - Epidemiology and molecular typing of an outbreak of tuberculosis in a hostel for
homeless men.
AB - AIM: To investigate a possible outbreak of tuberculosis in a hostel for homeless
men using IS6110 profiling, a polymerase chain reaction (PCR) based
fingerprinting technique. METHODS: Eight cases of tuberculosis were diagnosed in
residents of the hostel over a period of 28 months. To provide epidemiological
data, a heminested inverse PCR (HIP) assay targeting the insertion sequence
IS6110 together with its upstream flanking region was used to fingerprint the
eight isolates of M tuberculosis under investigation. RESULTS: The HIP technique
gave IS6110 profiles which showed that while three isolates were clearly
distinct, the remaining five strains were indistinguishable, suggesting the
latter were representatives of a single outbreak strain. CONCLUSIONS: The HIP
assay proved discriminatory and facilitated repeated testing for the direct
comparison of strains as more patients presented over the protracted course of
this outbreak.
PMID- 10767828
TI - Reliability of immunohistochemical demonstration of oestrogen receptors in
routine practice: interlaboratory variance in the sensitivity of detection and
evaluation of scoring systems.
AB - AIMS: To investigate interlaboratory variance in the immunohistochemical (IHC)
detection of oestrogen receptors so as to determine the rate of false negatives,
which could adversely influence the decision to give adjuvant tamoxifen
treatment. METHODS: To ensure that similar results are obtained by different
institutions, 200 laboratories from 26 countries have joined the UK national
external quality assessment scheme for immunocytochemistry (NEQAS-ICC).
Histological sections from breast cancers having low, medium, and high levels of
oestrogen receptor expression were sent to each of the laboratories for
immunohistochemical staining. The results obtained were evaluated for the
sensitivity of detection, first by estimating threshold values of 1% and 10% of
stained tumour cells, and second by the Quick score method, by a panel of four
assessors judging individual sections independently on a single blind basis. The
results were also evaluated using participants' own threshold values. RESULTS:
Over 80% of laboratories were able to demonstrate oestrogen receptor positivity
on the medium and high expressing tumours, but only 37% of laboratories scored
adequately on the low expressing tumour. Approximately one third of laboratories
failed to register any positive staining in this tumour, while one third showed
only minimal positivity. CONCLUSIONS: There is considerable interlaboratory
variability, especially in relation to the detection of breast cancers with low
oestrogen receptor positivity, with a false negative rate of between 30% and 60%.
This variability appears to be caused by minor differences in methodology that
may be rectified by fine adjustment of overall technique.
PMID- 10767829
TI - Temporal artery biopsy: is there any value in examining biopsies at multiple
levels?
AB - AIMS: To analyse the cost-effectiveness of three strategies for examining
temporal artery biopsies based on data from cases examined over the past 10
years. METHODS: Of a total of 172 temporal artery biopsies, five were unsuitable
for further analysis, 47 had already had levels cut, and 120 had levels cut as
part of the study. All the biopsies were examined blind before and after levels.
A tree with eventual diagnostic outcomes for different strategies was constructed
and economic and sensitivity analyses performed. Welcan units were used to assess
technical workload. RESULTS: Only one of the 132 initially normal cases and two
of 14 diagnosed with periarterial lymphocytic infiltration (PALI) revealed giant
cell arteritis after examining the tissue at multiple levels. Fifteen cases
(8.9%) showed PALI not previously observed. The marginal cost for each extra case
of giant cell arteritis detected was 83.5 Welcan units for a strategy of routine
levels on all sections, and 21 Welcan units for a strategy of only cutting levels
if PALI was present on the initial section. These costs were sensitive to the
frequency of giant cell arteritis in cases with PALI and to the relative extra
cost of moving from cutting single section to routine levels. CONCLUSIONS:
Routinely examining a temporal artery biopsy at multiple levels does not increase
the diagnostic yield of the test, although selective further examination may be
indicated in some cases. The significance of PALI is uncertain. The cost-benefit
of the different strategies in terms of clinical decision making revolve around
the perceived risk inherent in not making a diagnosis of giant cell arteritis.
PMID- 10767830
TI - The importance of skip lesions in temporal arteritis.
AB - AIM: To determine the frequency of skip lesions in an unselected series of
temporal artery biopsies and compare the results with other series. METHODS: The
study was a retrospective review of 102 consecutive temporal artery biopsies
taken in a five year period (1992-1997) in one large hospital. RESULTS: 35 cases
(34.3%) showed evidence of active cranial vasculitis with pathological evidence
of inflammation of the intima or media, with or without giant cells. Three of
these cases (8.5%) showed apparent skip lesions: normal intima, media, and
adventitia in one segment while in other segments there was clear evidence of
active vasculitis. Immunocytochemical stains for leucocyte common antigen (LCA)
and CD15 were helpful in identifying the absence of intimal or medial
inflammatory cell infiltrates within skip lesions. Skip lesions have been
described in up to 28.3% of cases in some series, while others have not found
evidence of skip lesions or have identified them in a much smaller percentage of
cases. CONCLUSIONS: In this series skip lesions were relatively rare, accounting
for 8.5% of cases of active vasculitis. The degree of inflammation in temporal
arteritis is discontinuous. Immunostaining for inflammatory cells, for example
LCA and CD15, may be helpful in identifying the presence of an inflammatory cell
infiltrate in skip lesion segments of the temporal artery.
PMID- 10767831
TI - A study of interval breast cancer within the NHS breast screening programme.
AB - AIM: To define the biological nature and malignant potential of interval cancers
presenting to a breast unit within the NHS breast screening programme. METHODS:
112 interval cancers were compared with matched, screen detected and symptomatic
cancers in terms of their radiographic, histopathological, and
immunohistochemical features. RESULTS: Interval cancers, strictly defined, showed
no characteristic radiographic pattern. In terms of size, vascular invasion,
lymph node status, and prognosis they were intermediate between screen detected
and symptomatic cancers. Within the interval cancers there was an excess of grade
1 and grade 3 tumours, and lesions with a high Ki67 index but
immunohistochemistry otherwise failed to discriminate between the three groups.
Inclusion of data from false negative "interval cancers" did not significantly
alter the results. CONCLUSIONS: Interval cancers are more aggressive than screen
detected cancers but in general less aggressive than symptomatic cancers.
However, within a heterogeneous group, occasional interval cancers are
exceptionally malignant.
PMID- 10767833
TI - Congenital acute T lymphoblastic leukaemia: report of a case with
immunohistochemical and molecular characterisation.
AB - A newborn infant with congenital T cell lymphoblastic leukaemia presented with
hepatosplenomegaly and pancytopenia at birth and died on the 21st day of multi
organ failure. Biopsy and necropsy examination showed extensive atypical lymphoid
infiltrates in the lungs, liver, spleen, kidneys, lymph nodes, and bone marrow.
Immunohistochemically, the lymphoid cells were TdT+, CD3+, CD45RO+, and CD10-,
CD79a-, CD20-. Genotypic analysis using polymerase chain reaction showed T cell
receptor gamma chain gene rearrangement and absence of immunoglobulin heavy chain
gene rearrangement. This appears to be the first documented case of congenital T
cell lymphoblastic leukaemia. The case had unusual histological and
immunogenotypic features, disseminated early, and pursued a highly aggressive
course. Consideration of the diagnosis is of paramount importance. The
immunophenotypic studies and molecular characterisation of such congenital
leukaemias are critical in arriving at a definite diagnosis.
PMID- 10767832
TI - Necropsy diagnosis of myocarditis: a retrospective study using CD45RO
immunohistochemistry.
AB - AIM: To use CD45RO immunohistochemistry to investigate the numbers of T
lymphocytes found in sections of myocardium from a routine necropsy series, and
to determine the incidence of myocarditis in this series. METHODS: Myocardial
sections from 163 routine hospital necropsies were stained with CD45RO and the
numbers of positive lymphocytes/mm2 were counted. The results were correlated
with the H/E opinion and the clinical context of the necropsy. RESULTS: Most
(143) cases showed low numbers (0-3) of CD45RO positive lymphocytes/mm2. Fifteen
cases showed 7-13 positive lymphocytes/mm2, comprising a wide variety of clinical
conditions, generally with no specific cardiac pathology. Five cases showed 14 or
more positive lymphocytes/mm2, comprising one case of active myocarditis, three
cases of cardiac transplant rejection, and one post-transplant
lymphoproliferative disorder, all conditions in which large numbers of
lymphocytes would be expected. CONCLUSIONS: The incidence of myocarditis in our
series was 0.6%. In most cases the normal myocardium has a low T lymphocyte count
(0-3/mm2). In some cases immunohistochemistry shows more positive cells than
would have been expected on light microscopy. Immunohistochemistry is a useful
and reliable means of confirming a diagnosis of myocarditis. The results support
the conclusion of the 1997 ISFC task force that 14 or more lymphocytes or
macrophages/mm2 of myocardium in the appropriate clinical context is a reliable
threshold for the diagnosis of chronic myocarditis.
PMID- 10767834
TI - Basal cell adenocarcinoma of the palate with squamous metaplasia.
AB - Basal cell adenocarcinoma is a rare salivary gland tumour, especially in minor
glands. The clinical, histological, and immunohistochemical features of a case
involving the palate are described. Formalin fixed, paraffin embedded sections of
the tumour were examined in haematoxylin and eosin (H&E) sections and also using
immunostaining for cytokeratins 7, 8, 13, 14, 18, 19, vimentin, muscle specific
actin (HHF35), and laminin. H&E sections showed that the tumour was composed
mainly of basaloid cells and a striking feature was the presence of squamous
metaplasia. Neural invasion was also conspicuous. Immunohistochemical reactions
indicated that cytokeratin 14 was expressed by all tumour cells and vimentin by
all cells except those in the areas of squamous metaplasia. The remaining
cytokeratins and actin were present in some of the tumour cells, while laminin
showed discreet positivity around cell arrangements. The foci of squamous
metaplasia and the immunohistochemical findings are helpful in distinguishing
basal cell adenocarcinoma from other salivary gland tumours which show basaloid
cells.
PMID- 10767835
TI - Recurrence of Kikuchi's lymphadenitis after 12 years.
AB - A 40 year old woman developed recurrent Kikuchi's disease 12 years after the
original episode. The recurrence affected the same site (axilla) and occurred
after the longest delay so far recorded in a European resident. Care must be
taken to avoid misdiagnosis of Kikuchi's disease as lymphoma.
PMID- 10767836
TI - Interaction of insulin with Burkholderia pseudomallei may be caused by a
preservative.
AB - AIM: To re-examine the previously reported in vitro interaction of insulin with
Burkholderia pseudomallei, in the light of a suggestion that the interaction may
have resulted from the presence of the preservative m-cresol in commercial
preparations. METHODS: Broth culture studies of B pseudomallei were performed
with and without the addition of m-cresol and various preparations of insulin.
RESULTS: Growth of B pseudomallei was inhibited by m-cresol at the concentrations
found in pharmaceutical insulin preparations, and by the insulin preparation
Humulin R, but not by pure insulin. CONCLUSIONS: The results of previous
experiments may have been confounded by the presence of the preservative m
cresol.
PMID- 10767837
TI - Paraovarian cystic endosalpingiosis in association with tamoxifen therapy.
AB - This report describes a case of macroscopically visible cystic endosalpingiosis
involving the paraovarian region in a woman who had been taking tamoxifen for
breast cancer. A 2.5 cm multicystic lesion was seen on the external surface of
the right ovary and histological examination showed a mass of dilated glands
lined by ciliated tubal-type epithelium and set in a fibrovascular stroma. Cystic
endosalpingiosis resulting in a tumour-like mass is a rarely described entity
which is probably not well recognised by histopathologists. Although unlikely to
be mistaken for malignancy, the lesion may result in diagnostic confusion. The
role of tamoxifen in the development of the lesion in the present case is not
clear but the oestrogenic effects of this drug may have contributed to its
formation.
PMID- 10767838
TI - Rationalised virological electron microscope specimen testing policy.
PMID- 10767839
TI - The new millennium: time for a change!
PMID- 10767840
TI - Reflections on the first issue of JCP. Microbiology.
PMID- 10767841
TI - Reflections on the first issue of JCP. Haematology.
PMID- 10767842
TI - On "Familial intestinal polyposis" by C E Dukes.
PMID- 10767843
TI - Giant cell arteritis at the millennium.
PMID- 10767844
TI - Chemical pathology: what has changed?
PMID- 10767845
TI - The pathologist in the 21st century--generalist or specialist?
PMID- 10767846
TI - Continuous professional development in pathology: a continental view.
PMID- 10767847
TI - The future of scientific communication in pathology.
PMID- 10767848
TI - Fear or favour? Statistics in pathology.
PMID- 10767849
TI - Molecular techniques: divide or share.
PMID- 10767851
TI - On mortuary assistants...
PMID- 10767850
TI - Robotics into the millennium.
PMID- 10767852
TI - Near patient testing and pathology in the new millennium.
PMID- 10767853
TI - Future directions in quantitative pathology: digital knowledge in diagnostic
pathology.
PMID- 10767854
TI - Is H&E morphology coming to an end?
PMID- 10767855
TI - Cervical cytology after 2000: where to go?
PMID- 10767856
TI - Xenotransplantation--2000.
PMID- 10767857
TI - Immunotherapy of AML: future directions.
AB - Immunotherapy in the form of allogeneic GvL has been curing AML patients for
nearly 30 years but our understanding of the mechanisms has been poor. Our
rapidly evolving understanding of the human immune system and the concomitant
technical developments in ex vivo cell manipulation, the vision of funding
bodies, the dedication of clinical and research staff, and above all the
commitment of our patients, promise substantial progress in the treatment of this
disease in the year 2000 and beyond.
PMID- 10767858
TI - Therapeutic trials in childhood ALL: what's their future?
PMID- 10767859
TI - Immunogenetics: changing the face of immunodeficiency.
AB - Tables 1 and 2 highlight the enormous advances that have been made in the
definition of the molecular defects underlying primary immunodeficiencies in the
past decade. The identification of SAP as the gene defective in XLP now completes
the molecular bases of all the recognised X linked syndromes. Of the autosomally
inherited syndromes, only the genes for DiGeorge syndrome, hyper-IgE, and perhaps
most importantly, common variable immunodeficiency remain to be elucidated. The
major clinical benefits of this information have primarily been in offering more
accurate and rapid molecular diagnoses. The ability to make a molecular diagnosis
also increases the options for earlier definitive treatments such as bone marrow
transplantation and somatic gene therapy. Finally, as illustrated by the studies
on the functions of WASP and the gamma c/JAK-3 pathway, identification of the
gene defect is the first step to understanding the molecular pathogenesis of the
immunological abnormalities.
PMID- 10767860
TI - Infection and antimicrobial prescribing control in the new millennium: nightmare
or nirvana?
PMID- 10767861
TI - Molecular bacteriology: a diagnostic tool for the millennium.
PMID- 10767862
TI - Quantitative molecular virology in patient management.
PMID- 10767863
TI - Candidal infection is uncommon in acute oesophagitis: evidence from a non
selected DGH population.
PMID- 10767865
TI - The risk of infection transmission by blood transfusion in England.
PMID- 10767864
TI - Dihydrate birefringent calcium oxalate or Weddellite calcification.
PMID- 10767866
TI - An assessment of the artefacts introduced by mounting two parallel sections from
each histological level of cervical punch biopsies.
PMID- 10767867
TI - Practice guideline for the treatment of patients with major depressive disorder
(revision). American Psychiatric Association.
PMID- 10767868
TI - [Physician errors].
PMID- 10767869
TI - [Prevention of endocarditis in Germany].
PMID- 10767870
TI - [Severe complications caused by inattention to endocarditis prevention during
dental procedures in adults with congenital heart abnormalities].
AB - BACKGROUND AND OBJECTIVE: Despite new guidelines on antibiotic prophylaxis to
prevent bacterial endocarditis there is still confusion about the forms of dental
procedures requiring antibiotic prophylaxis. Aim of this study was to determine
the incidence of bacterial endocarditis following dental procedures in adults
with congenital heart disease during a one-year period, and to assess connections
with prophylaxis. PATIENTS AND METHODS: The case notes of all adults with
congenital heart disease (CHD) treated in hospital during a one year period were
analyzed retrospectively to identify cases of endocarditis, and all adults with
CHD admitted to hospital for other reasons than endocarditis were interviewed
about their knowledge of antibiotic prophylaxis against bacterial endocarditis.
RESULTS: Among the 456 adults with CHD 351 (78%) knew about the need for
antibiotic prophylaxis against bacterial endocarditis. Three patients developed
endocarditis, in each case after a visit to the dentist. The disease started 11
16 days after dental descaling had been performed without antibiotic covering,
one patient developing a brain abscess. The patients had to be treated in the
hospital for 42-49 days. Despite presentation by the patient of a leaflet with
recommendations for prophylaxis, the dentist refused to give antibiotics.
CONCLUSIONS: Knowledge of adults with CHD is satisfactory but can still be
improved. Even more important is better training of dentists who treat patients
with CHD with special emphasis on the specific procedures including dental
descaling, which require antibiotic prophylaxis.
PMID- 10767871
TI - [Self-assessment by patients of impairment caused by obstructive sleep apnea
syndrome].
AB - BACKGROUND AND OBJECTIVE: The compliance of the nasal continuous positive airway
pressure treatment (nCPAP) of the obstructive sleep apnea syndrome (OSAS) depends
on the patients' awareness and improvement of the symptoms. Therefore, we studied
the relevance of OSAS in different aspects of the quality of life and important
aspects of daily life (driving performance, working place). METHODS: 352 patients
with OSAS filled in a questionnaire of sociodemographic data and impairment of
quality of life. The relevance of OSAS was evaluated with polysomnography and
parameters of daytime sleepiness. RESULTS: The number of women was lower than
expected from community related data. The apnea/hypopnea index was 29.9 +/-
23.4/h at baseline measurement and was reduced to 8.8 +/- 9.6/h with nCPAP (p <
0.001). The arousal index (baseline 26.6 +/- 15.3/h) fell with treatment
significantly (17.7 +/- 9.2 Arousals/h, p < 0.001). The error rate in the driving
simulator test was 7.8 +/- 8.9% (normal value 5.75 +/- 1.4). It was normalised
with nCPAP (5.8 +/- 9.5, p < 0.001). 42.3% of patients reported about sleep apnea
related symptoms for more than five years before diagnosis. The patients rated
their physical fitness on a scale (0 to 6) at 2.9 +/- 1.3. It increased
significantly with treatment to 3.4 +/- 1.3 an (p < 0.001). The mental activity
improved significantly, too. The daytime sleepiness improved from 3.4 +/- 1.5 to
3.1 +/- 1.5 (p < 0.001). 32.3% of the patients reported that they fell asleep
while steering at least once in the last month, 13.0% reported about more than
five episodes/month. 5.3% of the patients thought their job in danger because of
OSAS. 65.1% felt their performance in job to be impaired. CONCLUSION: OSAS
impairs patients in different aspects of daily life, especially in the working
place. The latency between the onset of symptoms and diagnosis is longer than
expected. NCPAP treatment improves the symptoms of OSAS significantly both in
criteria of polysomnography and self-assessment of the patients.
PMID- 10767872
TI - [Carbamazepine poisoning caused by confusing the drugs].
AB - HISTORY AND FINDINGS: By error a pharmacist had dispensed to a 41-year-old woman
Tegretal (carbamazepine; 400 mg retard tablets) instead of Trental
(pentoxifylline; 400 mg retard dragees). Similarly, a 76-year-old woman had been
prescribed carbamazepine-neuroxpharm (600 mg retard tablets) instead of piracetam
neuraxpharm (800 mg tablets) by her family doctor. Thirdly, a 79-year-old man
was, as an in-patient, by error given by a nurse Tegretal, 400 mg retard tablets
three times daily, presumably instead of 400 mg Trental retard. All 3 patients
developed mild cerebellar symptoms. The two elder patients showed additionally
wakefulness. After a fall the male in-patient, known to have a hemiparesis, also
developed myoclonus in the limbs: computed tomography demonstrated a mild left
temporal contusion. INVESTIGATIONS: Routine laboratory tests were unremarkable.
All 3 patients had raised carbamazepine levels (12-13 micrograms/ml [normal
range: 4-12 micrograms/ml]). DIAGNOSIS, TREATMENT AND COURSE: Because fast
carbamazepine saturation had been done in those three patients by error, all of
them showed symptoms of carbamazepine overdosage, but all symptoms fully
regressed within a few days without specific treatment. CONCLUSION: Adverse drug
events are not rare in routine medical practice and should be thought of in the
differential diagnosis of both in- and out-patients with unclear symptoms. In
addition to careful history-taking and consideration of the clinical symptoms,
toxicological screening can be of vital importance.
PMID- 10767873
TI - [Current therapy for stomach cancer].
PMID- 10767874
TI - [Physician's errors].
PMID- 10767875
TI - [Hygiene methods for patients with methicillin-resistant Staphylococcus aureus
(MRSA)].
PMID- 10767876
TI - The psychiatric interview in the emergency department.
AB - Psychiatric assessment of patients in the emergency department requires a
psychological and medical approach. Acute medical problems must be investigated
immediately, before a more nuanced exploration of emotional, cognitive, and
behavioral aspects of these patients is undertaken. A multidimensional,
nonreductive description then guides the treatment and disposition of patients in
the emergency department.
PMID- 10767877
TI - Medical clearance of psychiatric patients.
AB - Patients with primarily psychiatric complaints commonly present to emergency
departments. The challenges to emergency medicine physicians are to distinguish
functional from organic disease and to address any underlying medical
comorbidities. The key elements of this medical "clearance" evaluation of
psychiatric patients are discussed. The tremendous importance of the history and
physical examination are highlighted, as is judicious use of laboratory and
radiographic testing. Toxicology testing is specifically addressed.
PMID- 10767878
TI - Psychiatric manifestations of systemic illness.
AB - Many behavioral manifestations of systemic disease exist, including delirium,
psychosis, mania, catatonia, depression, and anxiety. The features and medical
causes of each of those manifestations are described. The indications from
history and physical examination that suggest underlying medical illness are
reviewed. The psychiatric presentations of several specific conditions are
discussed in detail.
PMID- 10767879
TI - New drugs in psychiatry.
AB - Recent years have witnessed the rapid expansion of new psychotropic agents and
psychotropic applications of primarily nonpsychiatric medications in nearly all
domains of psychopathology. Increasingly, patients in emergency departments may
be taking newer-generation antidepressants, antipsychotics, and mood-stabilizing
drugs, and individuals with treatment-resistant psychiatric disorders are often
prescribed complex, polypharmaceutical regimens. Current information on the use
of psychiatric medications that have entered widespread use in the past 5 to 10
years is reviewed, with focus on indications and dosing, comparisons with older
medications, management of patients with overdoses and toxicity states, and the
medical and psychiatric effects of newer drugs on patients who may present to
emergency departments.
PMID- 10767880
TI - Assessing capacity.
AB - Health care professionals often encounter patients who refuse a recommended
treatment plan. Overriding a patient's right to autonomy has ethical, legal, and
moral consequences. Incapacity is the determination by a physician that a patient
lacks the ability to make informed decisions about his or her health care. The
fundamentals needed for evaluating and documenting patients' capacity to make
decisions regarding their personal medical care are provided.
PMID- 10767881
TI - Delirium.
AB - Delirium is a true medical emergency that can masquerade as chronic dementia or
functional psychosis and obscure the causative underlying physical or toxic
disorder. In most cases, a well-focused history and thorough physical examination
can unmask the delirium and reveal the medical or toxic problem. Carefully
selected diagnostic testing can be required. Emergency management of the medical
or toxic disorder is the same as in nondelirious patients. Control of agitated or
aggressive behavior with pharmacologic or physical restraints and special support
measures are required to facilitate ED care. Delirious patients whose symptoms do
not totally resolve in the ED must be admitted.
PMID- 10767882
TI - Psychosis.
AB - Psychosis is the term used to describe a mental state of dysfunction in behavior
and thought processes. In patients with psychoses, mental capacity is grossly
distorted and thought is disorganized. These factors cause an inability to
recognize reality or relate to others in a meaningful way. A medical cause is
found in approximately 20% of patients with acute psychosis. Emergency medicine
physicians must differentiate psychotic symptoms caused by general medical
conditions from psychosis caused by a primary psychiatric disorder. A careful
evaluation must be performed to identify the cause of the psychosis. Correction
of reversible causes, sedation, and appropriate disposition are the keys to the
successful management of these patients.
PMID- 10767883
TI - Suicide and depression.
AB - Suicide is difficult to predict, has the potential for catastrophic outcome, and
is preventable. Although some persons admit freely to feelings of sadness and
wishes for their lives to be over, others offer little, if any, overt forecasting
of impending self-harm. Many of these same people seek help under other auspices.
Approximately two thirds of those who commit suicide had visited a physician
during the preceding month. Recognizing the signs and symptoms with which suicide
prone patients present to emergency departments is central to preventing
unnecessary death, injury, and disability caused by failed attempts. The common
presentations of patients at risk for suicide and some of the psychiatric
conditions that carry a risk for suicide are reviewed.
PMID- 10767884
TI - Withdrawal syndromes.
AB - The pathophysiology of substance withdrawal is elucidated by a review of classic
and cutting-edge research. The manifestation and evaluation of the associated
withdrawal syndromes from ethanol, sedative-hypnotics, opioids, and baclofen, are
compared. The general management of and pharmacotherapy for these patients are
discussed.
PMID- 10767885
TI - Recognition and acute management of patients with panic attacks in the emergency
department.
AB - Patients with panic attacks commonly present to emergency departments. If the
disorder is identified early, intervention can be begun, even during the
evaluation phase. Effective therapies significantly improve these patients'
health and quality of life.
PMID- 10767886
TI - The violent patient.
AB - Encounters with violent behavior are an inevitable part of working in emergency
departments. By adoption of a cohesive, multidisciplinary approach to behavioral
decompensation, as is done in preparation for airway compromise, the risk for
injury to patients and staff is minimized. As with airway compromise,
anticipation of and preparation for deterioration can avoid the necessity of the
most invasive measures and can ensure a calm, positive outcome. With the
appropriate knowledge, teamwork, and skills, even patients requiring the most
intensive intervention can be treated safely and professionally.
PMID- 10767887
TI - The neuroleptic malignant and serotonin syndromes.
AB - The neuroleptic malignant syndrome and the serotonin syndrome share many clinical
features and may exist on a spectrum of the same disorder. The neuroleptic
malignant syndrome, however, is an idiosyncratic drug reaction, whereas the
serotonin syndrome is an effect of drug toxicity. Both syndromes present with
varying degrees of mental status changes and autonomic instability. In general,
patients with the neuroleptic malignant syndrome have higher fevers and
pronounced extrapyramidal signs with muscle rigidity, whereas patients with the
serotonin syndrome have lower fevers, more gastrointestinal dysfunction, and
myoclonus. Treatment for both syndromes consists of removing the offending agent
and providing intensive supportive care. Syndrome-specific therapies are
controversial.
PMID- 10767888
TI - The use of hypnosis in emergency medicine.
AB - Hypnosis can be a useful adjunct in the emergency department setting. Its
efficacy in various clinical applications has been replicated in controlled
studies. Application to burns, pain, pediatric procedures, surgery, psychiatric
presentations (e.g., coma, somatoform disorder, anxiety, and posttraumatic
stress), and obstetric situations (e.g., hyperemesis, labor, and delivery) are
described. Negative effects are discussed.
PMID- 10767889
TI - Critical incident stress and challenges for the emergency workplace.
AB - A formal response to all levels of critical incidents that are potentially
psychologically disturbing is needed. This response is needed for small-scale and
large-scale incidents, such as natural or manmade disasters. Health care
providers at all levels should be encouraged to participate in wellness programs
and to understand workplace stressors. Critical incident stress debriefing teams
have a valuable role in preventing posttraumatic stress disorder. Procedures for
establishing response teams are presented, and future directions are discussed.
PMID- 10767890
TI - The question of herbal supplements: are they here to stay?
PMID- 10767891
TI - Herbal supplements and prescription drugs. A risky combination?
PMID- 10767892
TI - SAMe as a supplement: can it really help treat depression and arthritis?
PMID- 10767893
TI - Changing managed-care model offers opportunities for nutrition coverage.
PMID- 10767894
TI - Selenium status and the human immunodeficiency virus.
PMID- 10767895
TI - Consistent messages of nutrition education.
PMID- 10767896
TI - Keeping up with the increasing popularity of nonvitamin, nonmineral supplements.
PMID- 10767897
TI - The prevalence and impact of 'atypical' days in 4-day food records.
AB - OBJECTIVE: To understand how days with atypical food intake affect estimates of
usual nutrient intake from 4-day food records. PARTICIPANTS/SETTING: Secondary
analyses of 4-day food records (4DFRs) (n = 2,560) collected from 1,090 women,
aged 50 to 79 years, who participated in the Women's Trial Feasibility Study in
Minority Populations, a randomized dietary intervention trial. DESIGN: Food
records were classified as atypical if participants marked one or more day's food
intake as "more than usual" or "less than usual." Total amounts and nutrient
densities (percent of energy or grams per 1,000 kcal) were examined for all
macronutrients, fiber, vitamin C, beta carotene, and calcium. STATISTICAL
ANALYSIS: Contingency tables were used to examine associations of demographic
characteristics with the likelihood of completing a 4DFR with atypical intake
days. Analysis of variance was used to test whether nutrient intake differed
among records with and without atypical days. Student t tests were used to
identify any differences in total energy and percent energy from fat among
typical and atypical intake days. RESULTS: Approximately 16% of records included
at least 1 atypical day. Reporting less-than-usual intake was associated with
younger age, higher income, and higher body mass index. Black women were less
likely to report more-than-usual intake than whites and Hispanics. Records with
less-than-usual intake had lower intakes of all nutrients analyzed except
alcohol; however, there were no differences in nutrient densities. Records with
more-than-usual intake had higher intakes of alcohol and all nutrients except
beta carotene and vitamin C, with higher nutrient density measures of alcohol and
decreased nutrient density measures of protein, vitamin C, and fiber.
CONCLUSIONS: Atypical intake days are common in 4DFRs and they have a large
effect on mean total intakes of most nutrients. APPLICATIONS: It is important for
researchers to collect information on atypical intake days included in a 4-day
food record. Strategies are needed to incorporate information on atypical intake
days when analyzing and interpreting research results.
PMID- 10767898
TI - Caretaker-child interaction during children's 24-hour dietary recalls: who
contributes what to the recall record?
AB - OBJECTIVE: To describe patterns of caretaker-child communication during
children's caretaker-assisted dietary recall interviews. DESIGN: Data are from
transcriptions of audiotaped, caretaker-assisted, 24-hour dietary recalls.
Statements were coded to provide quantified measures of caretaker-child
interaction. SUBJECTS/SETTING: Thirty-four children aged 7 to 11 years who were
enrolled (with their caretakers) at the San Diego site of the Olestra Post
marketing Surveillance Study. STATISTICAL ANALYSES: Measures of participation for
caretaker-child pairs were compared using Mann-Whitney tests; chi 2 tests were
conducted to examine within-group differences. Mean numbers of statement types
were compared with t tests. Differences between contributions of caretakers and
children within caretaker-child pairs were examined using Wilcoxon signed rank
tests. RESULTS: Caretakers contributed primarily by adding food details and,
secondarily, by prompting children. Children rejected a notable proportion of
items added by caretakers, and children's knowledge of food details was
considerable. Gender made little difference, although the presence of a male
caretaker was associated with a reduced proportion of details contributed by
children. APPLICATIONS: In assessing children's dietary intake, questions should
be directed toward children, even when caretakers are present. Nutrition
professionals must clarify expectations for caretakers from the outset, intervene
as needed to limit caretaker participation, probe for children's disagreement
with caretakers' additions, and question the basis for caretakers' additions. If
feasible, caretakers should be excused toward the end of the interview so
children may privately make alterations to the record.
PMID- 10767899
TI - Dietary intake of vitamin D in premenopausal, healthy vegans was insufficient to
maintain concentrations of serum 25-hydroxyvitamin D and intact parathyroid
hormone within normal ranges during the winter in Finland.
AB - OBJECTIVE: To study vitamin D status and bone metabolism of premenopausal
vegetarians and omnivores during a 1-year period. DESIGN: Longitudinal,
observational study. Bone mineral density was measured, blood samples from
fasting subjects were obtained, and 24-hour urinary samples were collected in
February 1994, August 1994, and January 1995. Serum 25-hydroxyvitamin D [S
25(OH)D] and intact parathyroid hormone (S-iPTH) concentrations were measured and
intestinal calcium absorption was estimated. Dietary intakes of vitamin D and
calcium were calculated. SUBJECTS/SETTING: Six vegans, 6 lactovegetarians, and 16
omnivores living in Helsinki, Finland. STATISTICAL ANALYSES PERFORMED: Student
Newman-Keuls test; unbalanced, repeated-measures multiple analysis of variance;
analysis of covariance; Pearson correlation test; and linear regression analysis.
RESULTS: Dietary intake of vitamin D was significantly lower in vegans (P < .05,
yearly mean +/- standard deviation = 0.09 +/- 0.06 microgram/day) and in
lactovegetarians (P < .05, 0.7 +/- 0.4 microgram/day) compared with omnivores
(4.0 +/- 2.1 micrograms/day). Throughout the year S-25(OH)D (P = .01)
concentrations were lower and S-iPTH (P = .01) concentrations were higher in
vegans than in omnivores and lactovegetarians. Bone mineral density in the lumbar
region of the spine was lower in vegans (yearly mean +/- standard deviation =
1.034 +/- 0.174 g/cm2) than in omnivores (P = .05, 1.177 +/- 0.099 g/cm2) and
tended to be lower than that in lactovegetarians (P = .17, 1.138 +/- 0.06 g/cm2).
Bone mineral density in the neck of the femur tended to be lower in vegans (0.843
+/- 0.116 g/cm2) than in omnivores (P = .07, 0.999 +/- 0.138 g/cm2) and
lactovegetarians (P = .15, 0.961 +/- 0.059 g/cm2). No seasonal variation was
found in bone mineral density in the study groups. CONCLUSIONS: At northern
latitudes, dietary intake of vitamin D in vegans was insufficient to maintain S
25(OH)D and S-iPTH concentrations within normal ranges in the winter, which seems
to have negative effects on bone mineral density in the long run. APPLICATIONS:
An increase in vitamin D intake should generally be recommended for vegans at
least during winter, or selections of foodstuffs fortified with vitamin D should
be broadened in northern latitudes.
PMID- 10767900
TI - Bone ABCs and Ds in the elderly: a guide for practitioners.
PMID- 10767901
TI - Weight-loss practices, nutrition beliefs, and weight-loss program preferences of
urban American Indian women.
AB - OBJECTIVE: To describe health beliefs, weight concern, dieting practices, and
weight-loss program preferences of American Indian women residing in an urban
setting. DESIGN: Face-to-face interviews using a semistructured questionnaire
were conducted and height and weight were measured. SUBJECTS/SETTING: Subjects
were 203 American Indian adult women in an urban community setting. STATISTICAL
ANALYSIS: Frequency distributions and chi 2 analysis were performed using the
Statistical Analysis System software. RESULTS: About two-thirds of the subjects
were overweight. Most women were concerned about obesity and reported attempting
to manage their weight. Healthful weight-loss practices (e.g., eating more fruits
and vegetables, increasing physical activity) were used most frequently. However,
unhealthful practices, such as skipping meals/fasting, using laxatives/diuretics,
and self-induced vomiting were also mentioned. Regular bingeing was reported by
10% of respondents. APPLICATIONS: Weight-management intervention efforts should
focus on helping clients modify their diet and physical activity patterns. Low
cost programs offered in convenient locations would attract more participants, as
would the provision of child care. Education about the dangers and
ineffectiveness of unhealthful weight-loss practices will be necessary, given the
high rates of such behaviors in this population.
PMID- 10767903
TI - Focus groups as predictors of dietitians' roles on interdisciplinary teams.
PMID- 10767902
TI - Nonvitamin, nonmineral dietary supplements: issues and findings from NHANES III.
AB - The Commission on Dietary Supplement Labels encourages nutrition professionals to
become knowledgeable about all dietary supplements. The Dietary Supplement Health
and Education Act of 1995 (DSHEA) expanded the definition of dietary supplements
beyond essential nutrients while distinguishing them from drugs or food
additives. In order to give practical advice to consumers and policymakers,
dietetics professionals need to understand the implications resulting from this
less-restrictive regulatory environment for supplements. Dietetics professionals
must also become familiar with claims made by manufacturers, retailers, and
others regarding popular nonvitamin, nonmineral (NVNM) supplements, as well as
usage prevalence and trends. However, NVNM supplements currently are classified
inconsistently, and information on the prevalence of use is limited. Sales data
suggest that total intake is increasing, and garlic and ginseng are consistently
among the most popular supplements. Reported use of NVNM supplements in the third
National Health and Nutrition Examination Survey was highest for garlic and
lecithin. The data suggest associations of NVNM supplement use with age and more
healthful lifestyles; however, there is also a reported link with higher alcohol
consumption and obesity. Associations with education, income, region, and
urbanization are not evident from the sales data. Standardized survey procedures
regarding question phraseology, referent time period, and supplement
categorization--along with use of representative samples--will improve our
ability to assess supplement use, prevalence, and trends.
PMID- 10767904
TI - Change in body mass index does not predict change in body composition in
adolescent girls with anorexia nervosa.
PMID- 10767905
TI - Evaluation of efficiency and effectiveness measurements of a foodservice system
that included a spoken menu.
PMID- 10767906
TI - Questionable foods and the gluten-free diet: survey of current recommendations.
PMID- 10767907
TI - What clients need to know about sugar replacers.
PMID- 10767908
TI - The prevalence of anemia in a WIC population: a comparison by homeless
experience.
PMID- 10767909
TI - Case problem: medical nutrition therapy for a patient with Crohn's disease.
PMID- 10767911
TI - [Advanced stage vasculopathies of the lower extremities. Medical and management
aspects in amputees].
AB - AIM: The paper reports the experience of an operating unit for the rehabilitation
of amputees. The unit includes doctors and physiatrists working at the 6th
Division of Internal Medicine and the Centre for Motor Rehabilitation at the
"Ospedali Riuniti" in Trieste. METHODS: Subjects were selected on the basis of
their psychophysical characteristics and coexistent pathologies. All subjects
took part in a hospitalised rehabilitation programme lasting for 60-90 days. This
period was followed by outpatient controls that continued for one year after
discharge. Clinical conditions, self-sufficiency and quality of life were
monitored and studied using special questionnaires. RESULTS: Of a total of 45
amputees, 27 were not regarded as suitable and 9 died while in hospital. Eighteen
were selected for prosthesis; 14 completed the programme and 11 were followed-up
for one year as planned. One patient did not attend the follow-up, 1 patient had
a stroke and 1 patient died from myocardial infarction. CONCLUSIONS: Eleven of
the 45 amputees included in the study were successfully treated with prothesis.
The medical, nursing and economic commitment appears to have been considerable.
The expectations of all subjects were high and remained high during
rehabilitation in hospital, but deteriorated rapidly at home with the onset of
depressive type symptoms. This may have been due to disappointment following
their high expectations and the fact that post-discharge assistance was not
always appropriate. The high cost-benefit ratio underlines the importance of the
careful selection of candidates for rehabilitation.
PMID- 10767910
TI - [Spontaneous bacterial peritonitis (SBP): prevalence and characteristics in a
population of 314 cirrhotic patients evaluated at hospital admission].
AB - BACKGROUND: The aim of this study was to evaluate the incidence and the
characteristics of the infections of ascitic fluid in cirrhotic patients at the
moment of hospital admission. METHODS: A total of 314 patients consecutively
submitted to ascitic fluid tap within 3 days of hospital admission were studied.
Each patient was classified according to Child-Plugh classes. Neoplastic ascites
were excluded. The ascitic fluid was analyzed for PMN count, protein and albumin
content, cultural and cytological examinations. The patients with ascitic fluid
PMN > 250/ml were immediately treated with antibiotics. RESULTS: Out of 314
patients 11% had SBP (94% in class C patients according to Child-Plugh
classification), 17% CNNA and 3% MNNB. 15% of SBP patients were asymptomatic.
Total protein content in ascitic fluid was significantly lower in SBP and MNNB
compared to CNNA and sterile ascites. 56% of the isolated bacteria was Gram
negative, and the most frequently found were Streptococcus, Escherichia coli and
Staphylococcus. 80% of the patients with ascites infection underwent third
generation cephalosporin treatment. SBP mortality (29%) was significantly higher
than CNNA (9%), MNNB (10%) and sterile ascites (11%), also taking into account
the subgroup without ascites infection and class C group (14%). CONCLUSIONS: In
view of the high incidence (even in the absence of invasive procedures), of the
possibility of symptom free patients and of the high mortality of SBP, it is
advisable to carry out routine tap in all cirrhotics with ascites at hospital
admission.
PMID- 10767912
TI - [A health education program for the prevention of heart diseases carried out in a
population in Calabria].
AB - BACKGROUND: To evaluate the behaviour and knowledge of students on cardiovascular
risk factors and to programme a campaign for the prevention of cardiovascular
diseases. METHODS: All students attending the last year of the secondary school
of this province answered a questionnaire. An educational campaign followed the
analysis of the questionnaire. RESULTS: The analysis of 3675 questionnaires shows
that almost all students were between 18 and 20; 16% of males (m) and 7.4% of
females (f) were overweight; 1.5% and 0.4% respectively were obese; 88.8% of m
and 44% of were doing physical activity; 32.4% of m and 26.8% of f were cigarette
smokers. Knowledge about cardiovascular risk factors were poor. Development of
the prevention campaign. In the school districts four seminars were organized to
discuss about cardiovascular prevention with science teachers of the province,
using audiovisual materials. The same teachers devote 4-6 hours to the same
matters during school lessons. In the next months conferences destined to the
population of the province will be organized. CONCLUSIONS: This program allows to
promote health education in the whole population, through the students, with a
low cost.
PMID- 10767913
TI - [Syndrome of increased idiopathic capillary permeability (Clarkson's syndrome)].
AB - Idiopathic systemic capillary leak syndrome (Clarkson's disease) is characterized
by recurring attacks or increased capillary permeability, resulting in severe
hypovolemic shock due to plasma extravasation from the intravascular compartment.
Additional laboratory features include association with a monoclonal gammopathy,
extreme hemoconcentration and hypoalbuminemia. The underlying cause is not known
and there have been fewer than 40 cases reported. It affects people aged 30-40
years and has a high mortality, with only six of 25 patients surviving for more
than 5 years. Marked thirst is noted early in the attack and profound muscle
weakness, anorexia; nausea, and vomiting are present in all patients, especially
so during the course of an attack. Generally, oedema appeared several hours or
days before the onset of shock. The total duration of illness varied from six
months to seven years. An unknown trigger causes a temporary increase in the
macromolecular permeability in the capillary bed of skeletal muscle and
connective tissue. The syndrome of rhabdomyolysis includes myalgia, swelling and
weakness of the involved muscle groups, pigmenturia, and leakage of myoglobin and
CK into the serum. Different treatments have been tried, including
plasmapheresis, steroids, epoprostenol, salbutamol and Gingko biloba extract with
success in some cases. Treatment with corticosteroids should be considered for
prevention of attacks in the systemic capillary leak syndrome.
PMID- 10767914
TI - [The Alice in Wonderland syndrome].
AB - The "Alice in Wonderland syndrome includes an array of symptoms involving altered
perception of shape (meta-morphopsia) of objects or persons who appear to be
smaller (micropsia) or larger (macropsia) than normal, of impaired sense of
passage of time, of zooming of the environment. This unusual neurological picture
which can be confused with psychosis or drug intoxication has been found to
accompany cerebral lesions mainly temporo-occipital or parietal-occipital
temporal epilepsy and migraine. Todd gave the syndrome its literary name in his
report in 1955, describing a singular group of symptoms closely associated with
migraine and epilepsy. However the first description of the condition was made by
Lippman in 1952. This syndrome is so called because of the resemblance of its
symptoms to the fluctuations in size and shape that plague the main character in
Lewis Carrol's 1865 novel Alice in Wonderland. Cases of "Alice in Wonderland"
syndrome have been described associated with infectious mononucleosis. In each
clinical case, the classical infectious mononucleosis symptoms and diagnosis
followed the onset of visual aberration. Nuclear medicine techniques are able to
demonstrate changes in cerebral perfusion and may be used to detect abnormal
cerebral areas in patients with AIWS.
PMID- 10767915
TI - Highlights of the development of ENT in the 20th century.
PMID- 10767917
TI - Parental perceptions of grommet insertion in children with cleft palate.
AB - Otitis media with effusion is almost universal in children with cleft palate and
can delay speech, language and educational development by causing hearing loss.
Grommet insertion at the time of cleft palate repair is common. There is debate
about whether the benefits of grommets outweigh the risk of complications. A
postal questionnaire was used to investigate parental perceptions of middle-ear
ventilation via grommet insertion in children attending the multidisciplinary
cleft palate clinic. These children's case notes were reviewed. Many children had
speech and language delay, but parents thought this improved after grommet
insertion. Overall parents were pleased with the results. This confirms that
grommets have an important part to play in the management of children with cleft
palate.
PMID- 10767918
TI - Parental satisfaction with paediatric day-case ENT surgery.
AB - Day surgery is increasing to improve the efficient use of NHS resources and it is
vital that the quality of patient care is not compromised. The Audit Commission
has recommended that there should be a systematic appraisal of the patient's
views to monitor quality of day care. A survey of parental satisfaction with
paediatric day-case surgery provides valuable information for those providing day
surgery. A specific area of dissatisfaction previously identified is inadequate
pain control following discharge. It is also suggested that day surgery may incur
higher costs for the general practitioner. A retrospective study to investigate
parental satisfaction with 100 paediatric otorhinolaryngology cases was
performed. This study found 96 per cent of parents were happy with the treatment
their child received, 89 per cent were satisfied with self-administered simple
analgesia and no patients visited their general practitioner on the day following
surgery. It is concluded that with careful selection and adequate support the
degree of satisfaction with day surgery is high for a wide variety of procedures.
PMID- 10767916
TI - Prions and the ENT surgeon.
AB - Recent developments in our understanding of prion diseases have raised concerns
for the public health. There is now compelling evidence that the transmissible
agent for variant Creutzfeldt-Jakob disease (vCJD) in affected individuals is
accumulated in lymphoreticular tissues such as the appendix and tonsils. This
agent demonstrates a remarkable resistance to standard methods of sterilisation
used in hospital sterile services departments. The possible implications this has
on the safety of surgical instruments in ENT and other surgical practice is
discussed. This review also outlines the history of our understanding of prion
diseases and describes the development of a diagnostic test for vCJD in the
living patient by pharyngeal tonsil biopsy.
PMID- 10767919
TI - Tympanosclerosis: review of literature and incidence among patients with middle
ear infection.
AB - The aim of the study was to review the literature of tympanosclerosis especially
its pathogenesis, to study the general incidence of tympanosclerosis among
patients with chronic suppurative otitis media (CSOM), its association with
cholesteatoma and also the type of hearing loss as well as its relation to the
degree and site of tympanosclerosis. Seven hundred and seventy-five patients with
CSOM were studied retrospectively. A full history was taken and thorough ENT
examinations were carried out. Pure tone audiograms (PTA) of all patients were
done and analysed. The operative finding of tympanosclerosis as well as middle
ear status were inspected. The incidence of tympanosclerosis was found to be 11.6
per cent (90 patients out of 775 CSOM cases). Most tympanosclerosis cases had dry
ear, (85.6 per cent). Of the 57.8 per cent who had myringosclerosis, their PTA
showed an AB gap 20-40 dB. When sclerosis affect both the tympanic membrane and
middle ear, 61 per cent of patients had an AB gap > 40 dB. The association of
cholesteatoma and tympanosclerosis may be regarded as uncommon, 2.2 per cent. The
exact aetiology and pathogenesis of tympanosclerosis is as yet not well known.
Our study concentrated on the clinical picture of tympanosclerosis among patients
with CSOM. The majority of hearing loss associated with tympanosclerosis was of
the conductive type.
PMID- 10767920
TI - Acute mastoiditis in children: is surgical treatment necessary?
AB - Acute mastoiditis in children remains an otological problem. Although the
widespread use of antibiotics has reduced the need for surgical intervention,
surgery is frequently used in the treatment of acute mastoiditis and its
complications. The charts of 44 patients hospitalized with signs of acute
mastoiditis were reviewed. In 43.2 per cent of all patients, acute mastoiditis
was the presenting sign of acute middle-ear infection. Post-auricular erythema
and protrusion of the auricle were the most frequent signs at presentation. All
four signs (post-auricular erythema, oedema, tenderness, and protrusion of the
auricle) were present in 40.9 per cent of patients. No bacterial pathogen was
isolated in 45.5 per cent of ear cultures. Complicated acute mastoiditis was
diagnosed in 13.7 per cent of the patients. Eighty-seven per cent of patients
responded well to intravenous antibiotics and myringotomy, and in 11.4 per cent
mastoidectomy or abscess drainage were performed. We conclude that nearly all
patients with uncomplicated mastoiditis recover following intravenous antibiotics
and myringotomy. Mastoidectomy should be performed in selected cases, such as
cases of complicated acute mastoiditis.
PMID- 10767921
TI - Coagulation studies in patients admitted with epistaxis--current practice in
Scotland.
AB - Epistaxis remains the most common ENT emergency. The use of coagulation studies
in Scotland to manage these patients was investigated to determine current
practice. The study took the form of a postal questionnaire sent to all
practising ENT consultants and a telephone survey of ENT senior house officers
working in Scotland. Of the 60 questionnaires circulated amongst consultants, 55
responses were received (92 per cent). Thirty-eight consultants (70 per cent)
indicated that they did not routinely request a coagulation screen for their
patients, however, 30 per cent (16) did. Forty-three of the 45 junior staff were
available for interview, 22 (51 per cent) of whom routinely requested coagulation
studies. While the majority of consultants did not request routine coagulation
studies, there did not appear to be any consensus among the junior staff.
Although there is a paucity of scientific information with regard to this aspect
of epistaxis patient management, there is support in the literature for targeted
rather than blanket testing. There is perhaps a need to address this issue within
individual departments, to achieve uniformity of practice, and to improve
communication between junior and senior staff.
PMID- 10767922
TI - Early post-operative morbidity following tonsillectomy in children: implications
for day surgery.
AB - Adenotonsillectomy and tonsillectomy are amongst the most commonly performed
surgical procedures. In our prospective study we looked at early post-operative
morbidity (haemorrhage, vomiting and pyrexia) in 521 consecutive children
following tonsillectomy, adenotonsillectomy and adenoidectomy. While the
incidence of reactionary haemorrhage is low, pyrexia and vomiting are common. The
implications of this high early post-operative morbidity for day surgery are
discussed.
PMID- 10767923
TI - Pictorial assessment of the delivery of oropharyngeal rinse versus oropharyngeal
spray.
AB - Oral rinses/gargles and oral sprays are frequently used in the management of
oropharyngeal inflammation. This pictorial study, using methylene blue dye as a
marker of the distribution of these topical preparations in the oropharynx,
suggests that oral sprays are more effective in coating the oropharynx than oral
rinses, whilst oral rinses are better at staining the oral cavity and base of
tongue. The authors therefore suggest that oral rinses should be used to treat
disease in the oral cavity and oral sprays should be used to treat ailments in
the oropharynx.
PMID- 10767924
TI - A case of malignant otitis externa following mastoidectomy.
AB - We present a case of a 63-year-old diabetic male who developed malignant otitis
externa following mastoidectomy. Extensive skull base osteomyelitis caused
thrombosis of the jugular bulb and subsequent paralysis of cranial nerves VII,
IX, X and XII. He was treated aggressively with intravenous antibiotics and
debridement of granulation tissue in the mastoid bowl with full recovery of the
cranial nerve palsies associated with recanalization of the jugular bulb. We
believe this is the first reported case of malignant otitis externa to occur
following mastoidectomy with complete recovery of the cranial nerve paresis.
PMID- 10767925
TI - Langerhans' cell histiocytosis--a rare cause of sudden onset unilateral
sensorineural hearing loss.
AB - Langerhans' cell histiocytosis is a rare disorder of unknown aetiology in which
pathological Langerhans' cells accumulate and destroy local tissue. We report a
38-year-old female who presented with a sudden onset of left sensorineural
hearing loss. Magnetic resonance imaging (MRI) revealed a contrast-enhancing
lesion in the left mastoid and a second lesion in the hypothalamus. Following
left mastoid exploration and biopsy a definitive diagnosis of Langerhans' cell
histiocytosis was made and the patient was treated with external beam
radiotherapy. Subsequent right femur and right mastoid involvement were
successfully treated with steroids and cytotoxic chemotherapy. At one year follow
up the patient had residual left-sided sensorineural hearing loss with normal
hearing in the right ear. To our knowledge, Langerhans' cell histiocytosis has
not been previously reported as a cause of unilateral sudden onset sensorineural
hearing loss. It should be considered in the differential diagnosis of this
condition.
PMID- 10767926
TI - Meningioma of the internal auditory canal with extension into the vestibule.
AB - Meningiomas account for approximately 18 to 19 per cent of all brain tumours.
Although they can arise in numerous locations, meningiomas of the internal
auditory canal (IAC) are rare. Most tumours that originate in the IAC are
schwannomas of the VIIIth cranial nerve (acoustic neuromas). We report a case of
a meningioma which appears to originate from the IAC and extends into the
vestibule. The clinical findings and the radiographical features of meningiomas
of the IAC are similar to those of acoustic neuromas. Pre-operative
differentiation between acoustic neuromas and meningiomas of the IAC may be
difficult.
PMID- 10767927
TI - Alar haematoma.
AB - We present two cases of alar haematoma. This is a very rare complication of nasal
trauma, and only two cases have been described previously. One case presented
late and did not undergo surgical drainage and has a persistent cosmetic
deformity. We recommend early surgical drainage when possible.
PMID- 10767928
TI - Compartmentalized maxillary sinus mucocele.
AB - A rare case of compartmentalized maxillary sinus mucocele 12 years after a
Caldwell-Luc operation is reported. The two separate mucoceles were drained
intranasally by endoscopic sinus surgery. The clinical features of this mucocele
are presented and the incidence, presentation and theories on formation of post
operative mucoceles are reviewed.
PMID- 10767929
TI - Pituitary adenomas with infra-sellar extension into the nasopharynx.
AB - Three cases of pituitary adenomas with infra-sellar extension into the
nasopharynx and the nasal cavities are reported. The clinical signs were
epistaxis, nasal obstruction, painful sinuses and purulent rhinorrhoea. The
initial diagnostic hypothesis was that of a carcinoma of the nasopharynx or the
sinuses in all three cases. The diagnosis was made by histological examination
and measurement of plasma hormone levels. These cases highlight the difficulty in
the diagnosis of such tumours due to their misleading clinical, radiological and
histological features.
PMID- 10767930
TI - Trigeminal neurinoma presenting with trismus.
AB - We describe a patient with trigeminal neurinoma whose main presenting symptom was
trismus. This has not previously been reported in the literature. We review the
previously described symptoms and signs of trigeminal neurinoma.
PMID- 10767931
TI - Acute inspiratory stridor: a presentation of myasthenia gravis.
AB - We present a rare presentation of myasthenia gravis as acute inspiratory stridor
in a 16-year-old girl. Prompt diagnosis and medical treatment avoided the need
for tracheostomy. Although an uncommon cause, myasthenia gravis should be
included in the differential diagnosis of stridor.
PMID- 10767932
TI - Tracheal ring herniation following percutaneous dilatational tracheostomy and its
resection under endoscopic control.
AB - A 76-year-old patient had an elective percutaneous dilatational tracheostomy
(PDT) under endoscopic control in the intensive care unit. Twelve days later when
her general condition improved, two attempts at decannulation failed due to upper
airway obstruction above the tracheostomy site. Bronchoscopy showed herniation of
the anterior tracheal wall above the tracheostomy tube occluding 80 per cent of
the lumen. The herniated anterior segment was elevated and partially resected
under endoscopic guidance. The patient made a full recovery and was decannulated
on the first post-operative day. Pitfalls and possible complications of PDT are
discussed.
PMID- 10767933
TI - Non-cardiogenic pulmonary oedema due to foreign body aspiration.
AB - A patient who developed non-cardiogenic pulmonary oedema secondary to acute
airway obstruction caused by an aspirated foreign body is presented. The
literature is reviewed, discussing the theories regarding the formation of non
cardiogenic pulmonary oedema. The case highlights the importance of this rare
complication of foreign body aspiration and surgeons and anaesthetists should be
alert to continued respiratory symptoms following relief of acute airway
obstruction.
PMID- 10767934
TI - Spontaneous resolution of internal jugular vein thrombosis in a Salmonella neck
abscess patient.
AB - This article describes a rare case of Salmonella neck abscess complicated by
internal jugular vein thrombosis in a 51-year-old patient with previously
undiagnosed diabetes. The patient was discharged without any complications after
a combination of medical and surgical treatment. Also discussed here are the
clinical manifestations, imaging findings, and spontaneous resolution of the
internal jugular vein thrombosis. Being immunocompromised is a critical
predisposing factor for Salmonella neck abscess. Patient recovery is largely
determined by proper incision, drainage of pus and adequate intravenous
antibiotics according to bacterial sensitivity tests. Detection of an internal
jugular vein thrombosis does not signify a poor prognosis. Spontaneous resolution
of thrombosis is encountered after treating the infection.
PMID- 10767936
TI - ENT Clinical Audit meeting. Royal College of Surgeons (Eng) Meeting. 16th
September, 1999.
PMID- 10767935
TI - Bilateral secondary syphilis of the tonsil.
AB - A patient with bilateral tonsillar enlargement secondary to syphilis is
presented. Clinical appearance, histological findings and serological tests
permitted a correct diagnosis to be obtained, ruling out the suspicion of cancer.
PMID- 10767937
TI - Neurobiology of OB protein (leptin). Introduction.
PMID- 10767938
TI - Central mechanisms responsible for the actions of OB protein (leptin) on food
intake, metabolism and body energy storage.
PMID- 10767939
TI - Anatomic basis of leptin action in the hypothalamus.
PMID- 10767940
TI - Leptin and the neuroendocrinology of fasting.
PMID- 10767941
TI - Leptin regulation of proopiomelanocortin.
PMID- 10767943
TI - Perspectives on leptin's role as a metabolic signal for the onset of puberty.
PMID- 10767942
TI - Hypothalamic neuropeptide Y and its neuroendocrine regulation by leptin.
PMID- 10767944
TI - The brain is a source of leptin.
PMID- 10767945
TI - Screwworm turns heads in Florida.
PMID- 10767947
TI - Enrollment doubles for Cornell shelter medicine course.
PMID- 10767946
TI - Will nonrecovery surgery courses survive?
PMID- 10767948
TI - Thoughts on teaching complementary and alternative therapies.
PMID- 10767949
TI - Thoughts on teaching complementary and alternative therapies.
PMID- 10767950
TI - Thoughts on teaching complementary and alternative therapies.
PMID- 10767951
TI - Thoughts on teaching complementary and alternative therapies.
PMID- 10767952
TI - What is your diagnosis? Pleural effusion, pneumothorax, lung collapse and
bronchopleural fistula in a cat.
PMID- 10767953
TI - What is your neurologic diagnosis? Unilateral otitis externa or media, cerebellar
meningioma, and a solitary mammary adenoma.
PMID- 10767954
TI - Theriogenology question of the month. Pyometra, hydrometra, or mucometra.
PMID- 10767955
TI - Animal behavior case of the month. Persistent vomiting of food and gastric fluid.
PMID- 10767956
TI - Veterinary income per hour, 1997.
PMID- 10767957
TI - The revolution in horsemanship.
PMID- 10767958
TI - Equine welfare and emerging social ethics.
PMID- 10767959
TI - The role of the equine practitioner in disasters.
PMID- 10767960
TI - The pregnant mares' urine industry--management and research.
PMID- 10767961
TI - Equine welfare. Racing.
PMID- 10767962
TI - Animals in rodeo--a closer look.
PMID- 10767963
TI - The Horse Protection Act--a case study in industry self-regulation.
PMID- 10767964
TI - Equine slaughter transport--update on research and regulations.
PMID- 10767966
TI - Urban carriage horses 1999--status and concerns.
PMID- 10767965
TI - Who speaks for the horse--the sport of endurance riding and equine welfare.
PMID- 10767967
TI - Effect of the alpha-glucosidase inhibitor acarbose on control of glycemia in dogs
with naturally acquired diabetes mellitus.
AB - OBJECTIVE: To evaluate effect of acarbose on control of glycemia in dogs with
diabetes mellitus. DESIGN: Prospective randomized crossover controlled trial.
ANIMALS: 5 dogs with naturally acquired diabetes mellitus. PROCEDURE: Dogs were
treated with acarbose and placebo for 2 months each: in 1 of 2 randomly assigned
treatment sequences. Dogs that weighed < or = 10 kg (22 lb; n = 3) or > 10 kg (2)
were given 25 or 50 mg of acarbose, respectively, at each meal for 2 weeks, then
50 or 100 mg of acarbose, respectively, at each meal for 6 weeks, with a 1-month
interval between treatments. Caloric intake, type of insulin, and frequency of
insulin administration were kept constant, and insulin dosage was adjusted as
needed to maintain control of glycemia. Serum glucose concentrations, blood
glycosylated hemoglobin concentration, and serum fructosamine concentration were
determined. RESULTS: Significant differences in mean body weight and daily
insulin dosage among dogs treated with acarbose and placebo were not found. Mean
preprandial serum glucose concentration, 8-hour mean serum glucose concentration,
and blood glycosylated hemoglobin concentration were significantly lower in dogs
treated with insulin and acarbose, compared with insulin and placebo. Semisoft to
watery feces developed in 3 dogs treated with acarbose. CONCLUSIONS AND CLINICAL
RELEVANCE: Acarbose may be useful as an adjunctive treatment in diabetic dogs in
which cause for poor glycemic control cannot be identified, and insulin treatment
alone is ineffective.
PMID- 10767968
TI - Pentatrichomonas hominis infection in four kittens.
AB - Four purebred domestic cats examined because of diarrhea were found to have
Pentatrichomonas hominis, a rarely reported trichomonad parasite, in their feces.
Treatment with a combination of metronidazole and enrofloxacin tended to improve
consistency of the feces, whereas treatment with metronidazole alone reduced the
number of P hominis trophozoites in fecal smears but did not necessarily result
in an improvement in clinical signs. Two cats were euthanatized. Necropsy
revealed lymphoplasmacytic enterocolitis with eosinophils and eosinophilic
globular leukocytes, neutrophils in the mucosa of the colon and within
intraluminal contents of the cecum, and P hominis trophozoites in intraluminal
contents of the colon and cecum.
PMID- 10767969
TI - Association of high-speed exercise with racing injury in thoroughbreds.
AB - OBJECTIVE: To determine the association between high-speed exercise and risk of
injury while racing among Thoroughbreds in Kentucky. DESIGN: Matched case-control
study. ANIMALS: 206 Thoroughbreds that sustained a musculoskeletal injury while
racing and 412 Thoroughbreds that were not injured during the same races.
PROCEDURE: Data regarding official timed workouts and races and the Beyer's
numbers for the 3 races before the race during which injury occurred were
extracted from past performance charts and compared between injured horses and
control horses. RESULTS: For injured horses, cumulative distance of high-speed
exercise during the 1- and 2-month periods prior to the race in which injury
occurred was significantly less than that of control horses; for either period, a
difference of 10 furlongs was associated with approximately 2-fold greater risk
of injury. Beyer's numbers were significantly higher for injured horses than for
control horses. These effects remained significant after adjusting for age and
results of prerace physical inspection. CONCLUSIONS AND CLINICAL RELEVANCE: In
Kentucky, injured horses had significantly less cumulative high-speed exercise
than did control horses during the 1- and 2-month periods prior to the race in
which injury occurred. These results differ from those observed in California.
The association of injury with cumulative high-speed exercise appears to vary
among regions in the United States.
PMID- 10767970
TI - Gastric impaction and obstruction of the small intestine associated with
persimmon phytobezoar in a horse.
AB - Signs of mild colic, intermittent lethargy, and weight loss of 6 weeks' duration
in a 2-year-old Quarter Horse gelding were attributed to persimmon (Diospyros
virginiana) phytobezoar formation. Diagnosis of the phytobezoar was facilitated
by gastric endoscopy. Signs of gastrointestinal tract obstruction were associated
with a large phytobezoar in the lumen of the stomach, gastric ulceration, and
obstruction of the small intestine (as a consequence of fragmentation of the
primary bezoar). Conservative treatment, using mineral oil and dioctyl sodium
sulfosuccinate, was unsuccessful. A celiotomy was performed, and gastric
impaction and partial obstruction of the small intestine associated with
phytobezoar formation and fragmentation were identified. The horse made a
complete recovery following removal of all phytobezoars. Persimmon phytobezoar
should be considered in the fall and winter as a possible cause of lethargy,
colic, and weight loss in horses allowed access to persimmon fruit.
PMID- 10767972
TI - Efficacy of oxytetracycline for treatment of papillomatous digital dermatitis
lesions on various anatomic locations in dairy cows.
AB - OBJECTIVE: To evaluate efficacy of topical treatment with oxytetracycline
solution among dairy cows with papillomatous digital dermatitis (PDD) lesions on
the interdigital cleft, heels, or dewclaw. DESIGN: Clinical trial. ANIMALS: 70
dairy cows from a single herd. PROCEDURE: On the basis of anatomic location of
PDD lesions, cows were allocated into 1 of 3 groups (interdigital cleft [n = 14],
heels [30], or dewclaw [26]) and treated topically with oxytetracycline solution.
Cows were examined 14 and 30 days after initial treatment. During each
examination, pain and lesion size scores were recorded. RESULTS: On the basis of
pain and lesion size scores, oxytetracycline appeared significantly less
effective among cows with lesions on the interdigital cleft than for cows with
lesions on the heels or the dewclaw. Number of cows with signs of pain or visible
lesions after treatment was significantly higher for cows with lesions on the
interdigital cleft than for cows with lesions on heels or the dewclaw.
CONCLUSIONS AND CLINICAL RELEVANCE: Anatomic location of PDD lesions has an
effect on the efficacy of topical treatment with oxytetracycline solution in
dairy cows affected with PDD. Cows with lesions on the interdigital cleft were
less likely to respond to treatment, compared with cows with lesions on the heels
or the dewclaw.
PMID- 10767971
TI - Effects of pulmonary abscesses on racing performance of horses treated at
referral veterinary medical teaching hospitals: 45 cases (1985-1997).
AB - OBJECTIVE: To determine whether results of physical or radiographic examination
or biochemical analyses in adult racehorses with primary lung abscesses were
associated with ability to race following treatment. DESIGN: Multiple-center
retrospective study. ANIMALS: 25 Standardbreds and 20 Thoroughbreds. PROCEDURE:
Medical records of horses with a primary lung abscess that were admitted to any
of 4 veterinary teaching hospitals were reviewed. Results of physical
examination, laboratory testing, and thoracic radiography were reviewed. Racing
performance after treatment was compared with performance before illness and with
performance of the general population of racehorses of similar age, sex, and
breed. RESULTS: 23 of 25 Standardbreds and 13 of 20 Thoroughbreds raced after
diagnosis and treatment of a lung abscess. Most horses had a solitary abscess in
the dorsal to caudodorsal lung fields. Results of initial physical examination,
biochemical analyses, and culture and identification of the microbial isolate
were not associated with whether a horse returned to racing. For horses that had
raced prior to the illness, race performance after treatment of the lung abscess
was not significantly different from performance before the illness. CONCLUSIONS
AND CLINICAL RELEVANCE: On the basis of racing performance in those horses that
resumed racing after treatment, long-term residual lung damage did not develop in
horses with primary lung abscesses that were treated appropriately. It is not
known whether horses that recovered would be more likely to bleed from the site
of a prior infection when resuming strenuous exercise and whether lung abscesses
contributed to a failure to resume racing.
PMID- 10767973
TI - Long-bone fractures in llamas: six cases (1993-1998).
AB - OBJECTIVE: To determine clinical and radiographic findings, treatment, and
outcome for llamas with long-bone fractures. DESIGN: Retrospective study.
ANIMALS: 6 llamas. PROCEDURE: Medical records of llamas admitted between 1993 and
1998 because of long-bone fractures were reviewed. Data collected included age,
sex, type of fracture, method of fracture repair, and postoperative
complications. The Fisher exact test was used to compare age and sex of the
llamas with long-bone fractures with those of the hospital population of llamas.
All owners were contacted by telephone to determine perceived postoperative
problems and whether the llamas were able to perform as expected. RESULTS: Mean
age was 160.8 days (range, 23 to 365 days). There was 1 male and 5 females.
Fractures were more likely to occur in young llamas (< or = 1 year old) than in
adults. Five of the fractures were attributed to traumatic episodes. Long bones
affected included the tibia (n = 2), radius (2), femur (1), and humerus (1).
Internal fixation with lag screws, plating, or both was performed on fractures of
all llamas except 1; that llama was treated by use of confinement to a stall.
None of the llamas had intraoperative complications, but postoperative
complications were reported in 2 llamas. All fractures healed eventually, and
clients were pleased with outcomes. CONCLUSIONS AND CLINICAL RELEVANCE: Long-bone
fractures in llamas are uncommon. Several types of long bone fractures can be
successfully repaired by use of internal fixation, resulting in few complications
and minimal convalescent time.
PMID- 10767974
TI - Bone marrow transplantation for childhood hematological disorders: a global
pediatric approach in a twelve year single center experience.
AB - One hundred and 43 consecutive pediatric patients (June 1985-December 1996) with
at least 18 months of follow-up, were considered: most of the patients (111/143,
77.6%) underwent allogeneic BMT. The median follow-up was 5.7 years. Overall
survival and 5 years EFS were 48.6% and 46.9%, respectively. For patients who
underwent allogeneic BMT from HLA-identical siblings, the 5 years EFS for ALL was
75% in 1st CR, 60.4% in 2nd CR, 22.3% in > 2nd CR and 86.7% for AML in 1st CR.
The EFS for Allo-BMT in "good" and "poor" prognosis patients was 68.6% and 21.8%,
respectively (p value = 0.001). Early mortality in Allo-BMT patients was 17.7%
between 1985-1990 and 10.3% between 1991-1996. Early treatment-related organ
complications occurred mostly in patients who underwent BMT from an unrelated or
a mismatched family donor. Late toxicity was evaluated in 57 patients (median
follow-up of 82 months): none of the patients complained of significant late
cardiac or respiratory dysfunction. With regards to growth, 18/57 patients
(31.6%) lost more than two height centile channels. Three cases of thyroid
neoplasms were observed. Evaluation of psychosocial functioning, studied in 39
patients who had at least 2 years of follow-up in CR, did not reveal any evident
quality of life impairment. The possibility of curing childhood hematological
malignancies is based on a global pediatric and multidisciplinary approach. A
continuous need to improve results in terms of EFS and quality of life suggests
that further multicenter prospective studies should be carried out.
PMID- 10767975
TI - [Helicobacter pylori. Part II. Epidemiology, diagnosis, and treatment].
AB - In recent years, the diagnosis of Helicobacter Pylori (HP)-mediated infection has
become increasingly important not only in adults but also in children. Factors
such as residence in a country with low social and economic standards and the
presence of HP-positive family members underscore the widely-acknowledged fact
that the incidence of HP infection tends to increase with age both in children
(where the increase is roughly 1% per year) and in adults, where it reaches
values of 50% in the industrialized nations and 80% in developing countries. This
has led to research aimed at developing more accurate and less invasive
diagnostic techniques that can be used in children as well. Also, the development
of simple, cost-effective diagnosis is all the more important given the
widespread occurrence of HP infection, particularly in the developing countries.
The techniques employed range from the classical histological and culture
examination, which involves esophagogastroduodenoscopy (a rather invasive
technique), to serology and the Urea Breath Test with 13C. Also, the feasibility
of tracing HP antigens in the faeces, a non-invasive and simple technique, is
under investigation. As for therapy, there is as yet no unanimous agreement about
when to start treatment, about which antibiotics (beta-lactams, macrolides and
nitro-imidazoles) to use in association, about their effect on the gastric
mucosa, nor, indeed, about the treatment routines to be followed in adults and
children.
PMID- 10767976
TI - [Medical treatment of respiratory emergencies].
AB - Of the four treatments that can be used to treat respiratory insufficiency due to
laryngitis, two, nebulized adrenaline and O2 therapy, are undoubtedly effective.
The inhalation of water vapour appears to be increasingly useless and may be also
harmful. The use of steroids is still under debate. In recent literature,
however, the utility of steroids seems to be confirmed, especially if
administered per Os, and even at a relatively low single oral dose (1-2 mg/kg of
prednisone). According to the official organs (see Red Book) and according to the
Evidence Based Medicine (see Cochrane Library) the treatment of bronchiolitis
should be limited to an eventual support therapy, i.e. O2 therapy and
rehydration. However, the approach adopted by North American Hospitals and
European specialists in infectious diseases is in contrast and consists in the
use of beta 2 agonists and steroids in 90-100% and 40-80% of patients,
respectively. This contrast could be due to a deficiency in the researches of the
Evidenced Based Medicine which is obliged to retrieve studies done over 10-15
years in order to obtain a sufficient number of data for a statistically valid
investigation. These studies unfortunately are not updated with regard to the
dose of individual drugs and the immediate association of drugs. In particular,
with regard to nebulized beta 2 agonists, the absence of a positive effect could
be due to an excessively low dose in relation to the age of the patient.
According to the most recent knowledge, in fact, reduced doses are no longer
required for babies in consideration of age and weight. In reality an equal and
even higher dose than that used in adults would be best. The other reason for a
lack of response could be the absence of the association of a steroid with a beta
2 agonists at the right moment. The lack of timing in associating these two drugs
could also account for the absent response to the steroid. On the basis of these
considerations it would be a mistake to give up the use of beta 2 agonists and
steroids. Considering also the severity and frequency of a disease as
bronchiolitis. To follow the "fashion" of the Evidence Based Medicine. Recently,
magnesium sulphate, ketamine and the association elium-O2 have been suggested as
marginal and not revolutionary medical interventions for the treatment of asthma.
Among bronchodilators, the subordinate role of anticholinergics (for ex.
ipratropium bromide), and of adrenaline has been defined with respect to beta 2
agonists, in particular salbutamol. The optimisation of the administration by
nebulizers of the latter has been fundamental as it has a key role in the
treatment of acute severe asthma. In detail, traditional nebulizers tend to be
substituted by Metered Dose Inhaler + spacer with a ratio in the dose of 5/1. The
venous route is used only in very severe cases and is used late and in intensive
care although a single initial intravenous administration could determine a more
rapid reduction of bronchoconstriction and reduce the number of nebulized
bronchodilatators that can become extremely frequent in most severe cases. For
steroids, instead, the only safe therapeutic route is by PO, i.v., i.m.:
nebulized steroids although used with a definitely higher dose than that used for
chronic asthma, can be used only in the milder forms.
PMID- 10767977
TI - [Reflux nephropathy in absence of obvious vesicoureteral reflux].
AB - Although the majority of patients with vesicoureteric reflux presents DMSA scan
alterations, parenchimal renal scars are found also in children without
vesicoureteric reflux. Two clinical cases of reflux nephropathy without evidence
of reflux are presented. Several explanations could be advocated to justify this
picture, including haematogenous source of infection, inadequate timing and/or
procedure of cystouretrography, intermittency of reflux, ascending bacteria,
previous presence of reflux, and appearance of controlateral reflux during the
natural history of a monolateral documented reflux. Tailored diagnostic and
therapeutic strategy should discussed for each patient.
PMID- 10767978
TI - [Experience in the treatment of neonatal respiratory distress with nasal CPAP].
AB - Since the early 1970s, when continuous positive airways pressure (CPAP) was
introduced as a method of treatment of neonatal respiratory distress, many
technical approaches have been suggested. The Authors report their experience
with a new technique for nasal CPAP which has been developed to minimize
impedance to breathing and offering maximum airway pressure stability and
tolerance to leakage. Thirty-two newborns with symptoms of RDS were treated with
Infant Flow System, a new device for nasal CPAP with nasal prongs which resulted
inexpensive, simple to use and with lower risk for serious complications.
Furthermore, the results suggest that treatment by early CPAP with nasal prongs
in newborns presenting symptoms of RDS can be effective in reducing the number of
newborns transferred to the third level Unit.
PMID- 10767979
TI - [Idiopathic constipation in children: 10-year experience].
AB - Constipation is a frequent clinical disorder in pediatric age and it is often
difficult to resolve without a suitable diagnostic and therapeutic approach.
Parents and pediatrician often underestimate this pathology, reaching the
specialist only when it has already shown its complications. In the Department of
Pediatric Surgery of Siena, in the last 10 years, we have activated a study
centre on constipation in the pediatric age and we have developed a diagnostic
and therapeutic protocol to give indications on the type of constipation and the
consequent therapy. The Authors report their experience on 174 children with
chronic constipation. The patients underwent a scintigraphic colonic transit time
evaluation by radionuclides, an enema and an anorectal manometry. Such
examinations were able to divide patients into two groups: with colonic and
rectal constipation. The management consisted in common dietetic, behavioural and
pharmacological treatment at first and then of specific treatment (biofeedback,
prokinetic, emicolectomy), according to the type. The follow up showed recovery
or improvement in 83.53% cases, unchanged clinical condition in 8.57%,
aggravation in 1.9%. The Authors conclude emphasising the importance of
diagnostic techniques that allow to frame correctly the pediatric patient
affected by constipation. Particularly the anorectal manometry can be considered
a first level examination, able to identify rectal constipation; together with
scintigraphic colonic transit time that individualizes colonic constipation. The
right diagnosis will be able to give a suitable therapeutic treatment.
PMID- 10767980
TI - [Are urinary tract infections preventable in children? Importance of favorable
factors].
AB - The Authors asked themselves why in the last years they had observed a high
increment of urinary tractinfections and so they evidenced some favouring
factors.
PMID- 10767981
TI - [Health status of neonates born to immigrants at the University Polyclinic of
Messina in 1993-1998. A case-control study].
AB - The aim of the present case-control study was to verify the incidence and the
state of health of the neonates born of extracommunity parents (E.C.) in the our
hospital throughout the years 1993-1998. For every neonate born of E.C. we have
analyzed two italian neonates born immediately before and after. The parameters
analyzed were: nationality, age, and job of the parents, abortions, number of
ecography carried out during pregnancy, parity, delivery, gestational age (G.A.),
weight at birth, Apgar score, malformations, perinatal mortality and neonatal
morbidity. Statistical analyses were performed with the T Student test and the
chi-square test. Throughout the 1993-1998 years are born 9285 neonates. Of these
199 (2.4%) were E.C. The 45% of the E.C. derived from the Far East and only the
10% were nomad. The 86% of the E.C. had a job. In the E.C. group the multiparity
was significantly higher than in italian group. G.A., birth weight, number of
malformation, neonatal morbidity, and perinatal mortality were the same in the
E.C. and in the italian neonates. Our data, in disagreement with other Authors,
demonstrate that in our hospital the state of health of the E.C. and italian
neonates is not different. Because in the our analysis it results that the
greater number of E.C. parents had a job, it is likely that the non-observed
increased of perinatal mortality and morbidity in the neonates born of E.C.
depends on the social integration of E.C.
PMID- 10767982
TI - [Ovarian cysts diagnosed in utero: Report of 2 clinical cases].
AB - Two cases of ovarian cyst detected antenatally with complications are described.
The Authors enphatize the utility of graphic serial investigation for their
management.
PMID- 10767983
TI - [Infantile spasms: clinical course].
AB - The authors report on the factor which interferes on follow-up of children
affected by infantile spasm. On the basis of their series and on the data of
literature the factor more indicative for the clinical evolution are: type and
dosage of treatment, onset early or delayed, and the aetiology. While for the
first two factors the opinion of the expert are remarkable discordant, there is a
general agreement that the evolution of infantile spasm is mainly based on the
causes determining such kind of epilepsy.
PMID- 10767984
TI - [Transient erythroblastopenia in children: assessment of a hospital caseload].
AB - Transient erythroblastopenia of childhood (TEC) is an acquired, self-limiting,
uncommon disease, characterized by the temporary arrest of red cell production,
resulting in moderate to several anemia. We retrospectively evaluated four cases
of TEC, identified during an 8-year period of time in our Department of
Pediatrics, including one patient, who developed TEC during the course of
Kawasaki's syndrome. Clinical and hematological presentations of patients were
analyzed and the most recent data of literature were reviewed. In conclusion, we
suggest that a better knowledge of this rare and unique hematologic disorder of
childhood may help make a correct diagnosis, avoiding unnecessary laboratory
tests (e.g. bone marrow aspirate) and inappropriate therapeutic modalities.
PMID- 10767985
TI - Liver-specific and seasonal expression of transgenic Atlantic salmon harboring
the winter flounder antifreeze protein gene.
AB - We have analyzed the inheritance and expression of a line of transgenic salmon
harboring the antifreeze protein gene from the winter flounder. The genomic clone
2A-7 coding for a major liver-type antifreeze protein gene (wflAFP-6) was
integrated into the salmon genome. From a transgenic founder (#1469), an F3
generation was produced. In this study, southern blot analysis showed that only
one copy of the antifreeze protein transgene was integrated into a unique site in
F3 transgenic fish. The integration site was cloned and characterized. Northern
analysis indicated that the antifreeze protein mRNA was only expressed in the
liver and showed seasonal variation. All of the F3 offspring contained similar
levels of the antifreeze protein precursor protein in the sera and the sera of
these offspring showed a characteristic hexagonal ice crystal pattern indicating
the presence of antifreeze activity. In addition, the antifreeze protein
precursor protein level was found to vary with the season, being highest in the
month of November and lowest in May. This study had demonstrated a tissue
specific and stable expression of the antifreeze protein transgene in the F3
generation of the transgenic salmon 1469 line.
PMID- 10767986
TI - Production of recombinant human type I procollagen homotrimer in the mammary
gland of transgenic mice.
AB - The large scale production of recombinant collagen for use in biomaterials
requires an efficient expression system capable of processing a large (> 400 Kd)
multisubunit protein requiring post-translational modifications. To investigate
whether the mammary gland of transgenic animals fulfills these requirements,
transgenic mice were generated containing the alpha S1-casein mammary gland
specific promoter operatively linked to 37 Kb of the human alpha 1(I) procollagen
structural gene and 3' flanking region. The frequency of transgenic lines
established was 12%. High levels of soluble triple helical homotrimeric [(alpha
1)3] type I procollagen were detected (up to 8 mg/ml) exclusively in the milk of
six out of 9 lines of lactating transgenic mice. The transgene-derived human
procollagen chains underwent efficient assembly into a triple helical structure.
Although proline or lysine hydroxylation has never been described for any milk
protein, procollagen was detected with these post-translational modifications.
The procollagen was stable in milk; minimal degradation was observed. These
results show that the mammary gland is capable of expressing a large procollagen
gene construct, efficiently assembling the individual polypeptide chains into a
stable triple helix, and secreting the intact molecule into the milk.
PMID- 10767987
TI - Rice cell culture as an alternative production system for functional diagnostic
and therapeutic antibodies.
AB - We investigated the suitability of transformed rice cell lines as a system for
the production of therapeutic recombinant antibodies. Expression constructs
encoding a single-chain Fv fragment (scFvT84.66, specific for CEA, the
carcinoembryonic antigen present on many human tumours) were introduced into rice
tissue by particle bombardment. We compared antibody production levels when
antibodies were either secreted to the apoplast or retained in the endoplasmic
reticulum (ER) using a KDEL retention signal. Production levels were up to 14
times higher when antibodies were retained in the ER. Additionally, we compared
construct sencoding different leader peptides (plant codon optimised murine
immunoglobulin heavy and light chain leader peptides from mAb24) and carrying
alternative 5' untranslated regions (the petunia chalcone synthase gene 5' UTR
and the tobacco mosaic virus omega sequence). We observed no significant
differences in antibody production levels among cell lines transformed with these
constructs. The highest level of antibody production we measured was 3.8
micrograms g-1 callus (fresh weight). Immunological analysis of transgenic rice
callus confirmed the presence of functional scFvT84.66. We discuss the potential
merits of cell culture for the production of recombinant antibodies and other
valuable macromolecules.
PMID- 10767988
TI - Gene trap insertional mutagenesis in mice: new vectors and germ line mutations in
two novel genes.
AB - Insertional mutagenesis based on gene trap vectors that capture endogenous splice
sites is a promising tool for functional genomics. Several groups have proposed
large-scale gene trap screens, but questions remain as to the type of vectors and
their design. We report a set of plasmid-encoded gene trap vectors and the
disruption of two novel genes. Our results include a comparison of the relative
gene trapping efficiencies of two different splice acceptor sequences in ES cells
and an analysis of the structure of several gene trap insertions.
PMID- 10767989
TI - Transgenic animals with an altitude.
PMID- 10767990
TI - Stress in ASL: empirical evidence and linguistic issues.
AB - The study of signed languages provides an opportunity to identify those
characteristics of language that are universal and to investigate the effect of
production modality (signed vs. spoken) on the grammar. Over time, American Sign
Language (ASL) has accommodated itself to the production and perception
requirements of the manual/visual modality, resulting in a prosodic system that
is comparable in function to spoken languages but different in means of
expression. The present focus is on phrasal prominence in ASL. I review the
marking of stress and phrase boundaries in ASL, and discuss prominence assignment
at the phrasal level, with brief mention of lexical stress. At the kinematic
level, there is a modality effect in marking of linguistic prominence but no
modality effect with respect to marking phrase position. Of significance is the
fact that ASL lacks phrasal prominence plasticity, that is the ability to move
prominence to mark focus in a sentence location other than phrase final. I review
the typological implications of how ASL handles prominence as compared to other
languages.
PMID- 10767991
TI - Extrapolating from spoken to signed prosody via laboratory phonology.
AB - Laboratory phonology tests the predictions of phonological analyses through
experimental investigations of phonetic behavior. This paper describes how a
laboratory phonologist might investigate three issues in the analysis of the
prosody of signed languages: the internal structure, if any, of the signed
syllable, the realization of lexical and phrasal prominence, and the marking of
edges. The paper proposes to investigate the internal structure of the syllable
by adapting a variety of psycholinguistic techniques that have been extensively
used to study the phonetic packaging of phonological material in spoken
languages. Phonological and phonetic arguments are presented in support of the
hypothesis that signed languages will increase movement kinematics to convey
phrasal and perhaps lexical prominence, and an experiment is sketched that would
test this hypothesis. Finally, the paper suggests that the experimental study of
the edges of sign articulations might allow a clearer choice between competing
phonetic and phonological accounts of external sandhi in language in general.
PMID- 10767992
TI - Neuropsychological studies of linguistic and affective facial expressions in deaf
signers.
AB - For deaf users of American Sign Language (ASL), facial behaviors function in two
distinct ways: to convey affect (as with spoken languages) and to mark certain
specific grammatical structures (e.g., relative clauses), thus subserving
distinctly linguistic functions in ways that are unique to signed languages. The
existence of two functionally different classes of facial behaviors raises
questions concerning neural control of language and nonlanguage functions.
Examining patterns of neural mediation for differential functions of facial
expressions, linguistic versus affective, provides a unique perspective on the
determinants of hemispheric specialization. This paper presents two studies which
explore facial expression production in deaf signers. An experimental paradigm
uses chimeric stimuli of ASL linguistic and affective facial expressions
(photographs of right vs. left composites of posed expressions) to explore
patterns of productive asymmetries in brain-intact signers. A second study
examines facial expression production in left and right brain lesioned deaf
signers, specifying unique patterns of spared and impaired functions. Both
studies show striking differences between affective and linguistic facial
expressions. The data indicate that for deaf signing individuals, affective
expressions appear to be primarily mediated by the right-hemisphere. In contrast,
these studies provide evidence that linguistic facial expressions involve left
hemisphere mediation. This represents an important finding, since one and the
same muscular system is involved in two functionally distinct types of facial
expressions. For hearing persons, the right-hemisphere may be predominant in
affective facial expression, but for deaf signers, hemispheric specialization for
facial signals is influenced by the purposes those signals serve. Taken together,
the data provide important new insights into the determinants of the
specialization of the cerebral hemispheres in humans.
PMID- 10767993
TI - Signed and spoken language: a unique underlying system?
AB - Sign language has only recently become a topic of investigation in cognitive
neuroscience and psycholinguistics. In this paper, we review research from these
two fields; in particular, we compare spoken and signed language by looking at
data concerning either cortical representations or early acquisition. As to
cognitive neuroscience, we show that clinical neuropsychological data regarding
sign language is partially inconsistent with imaging data. Indeed, whereas both
clinical neuropsychology and imagery show the involvement of the left hemisphere
in sign language processing, only the latter highlights the importance of the
right hemisphere. We discuss several possible interpretations of these
contrasting findings. As to psycholinguistics, we survey research on the earliest
stages of the acquisition of spoken language, and consider these stages in the
acquisition of sign language. We conjecture that under favorable circumstances,
deaf children exploit sign input to gain entry into the language system with the
same facility as hearing children do with spoken input. More data, however, are
needed in order to gain a fuller understanding of the relation of different kinds
of natural languages to both the underlying anatomical representations and their
early acquisition.
PMID- 10767994
TI - [Expression and prognostic value of the drug resistance markers P-gp, Mrp1, Mrp2,
and Lrp in ovarian carcinoma].
AB - BACKGROUND: Intrinsic and/or acquired chemoresistance is the major obstacle to
overcome in the treatment of patients with ovarian carcinoma. The aim of the
present study was to investigate the prognostic value of drug resistance
associated proteins P-glycoprotein (P-gp), multidrug resistance related protein
(Mrp1), canalicular multispecific organic anion trans-porter (c-MOAT or Mrp2) and
lung resistance protein (Lrp) in ovarian carcinoma. METHODS: Expression of P-gp,
Mrp1, Mrp2 and Lrp was determined by immunohistochemistry of frozen tissue
sections of 115 ovarian carcinoma patients and associated to clinico-pathological
factors, response to chemotherapy and (progression free) survival. RESULTS:
Expression of P-gp was observed in 20 out of 115 (17%), Mrp1 in 51 out of 115
(44%), Mrp2 in 19 out of 115 (16%) and Lrp in 85 out 115 (74%) tumors. Expression
of Mrp1 was related to Mrp2 (p < 0.0001) and P-gp (p < 0.001) expression, while
Lrp expression was more frequently observed in patients with stage I/II versus
stage III/IV tumors (p < 0.01), grade I/II versus III tumors (p < 0.05) and
residual tumor < 2 cm versus > 2 cm after laparotomy (p < 0.05). Lower stage (p <
0.001), small residual tumor after first laparotomy (p < 0.001) and lower
differentiation grade (p < 0.05) were related to longer (progression free)
survival. P-gp, Mrp1, Mrp2, and Lrp expression was neither related to response to
first line chemotherapy (59 evaluable patients) nor to (progression free)
survival (all patients). On multivariate analysis only stage and residual tumor
after first laparotomy were independent prognostic factors for (progression free)
survival. CONCLUSIONS: In ovarian carcinoma Mrp1 expression is associated with
Mrp2 and P-gp expression, while Lrp expression is associated with favorable
clinicopathological characteristics. Assessment of P-gp, Mrp1, Mrp2 or Lrp does
not allow prediction of response to chemotherapy or (progression free) survival
in ovarian carcinoma.
PMID- 10767995
TI - [Osteoporosis: DEXA versus conventional radiography, comparison of 2 techniques.
Preliminary study].
AB - BACKGROUND: Osteoporosis is the most wide-spread metabolical illness in the
world, affecting from 30-40% of white women and 13% of white men over 50 years of
age. Recently, the DEXA technique (Dual Energy X-ray Absortiometry) has proven to
be a method, which is accurate, precise, low-cost, low-risk in terms of
exposition to radiation and fast in terms of execution times. METHODS: The
results obtained by comparing 54 DEXA examinations with the same number of
conventional X-ray examinations are presented. 54 women in menopause were
submitted to a computerized bone mineral evaluation with a 2.0 version DEXA
EUROMOX TBS at the level of the lumbar region (L1-L5) and the left femur, at the
Gynecology and Obstetrics Clinic of the University of L'Aquila. During the same
session the women were subjected to X-rays of the lumbar column, pelvis and
femurs. RESULTS: A diagnosis of osteoporosis was reported in 59% of the women in
both the lumbar and femoral regions with DEXA, while conventional radiography
showed osteoporosis in 33% of the examinations of the spinal column and in 51% of
the femurs. CONCLUSIONS: Thus, it was demonstrated that the presence of a
disorder at the level of the spinal column can lead to an interference in the
diagnosis, while the association of the femoral region, which is less subject to
related disorders leads to a more accurate diagnosis of osteoporosis in doubtful
cases.
PMID- 10767996
TI - [Innovations of the Stark method for cesarean section. Comparison of techniques].
AB - BACKGROUND: The evolution of surgical techniques for cesarean section have
improved the neonatal outcome as well as maternal morbidity and mortality. Aim of
this study is to compare the conventional technique with a personally modified
Stark's technique, in order to evaluate its effectiveness. METHODS: A prospective
study has been carried out on a group of patients submitted to cesarean section
by two different teams. A conventional technique for cesarean section was
performed by a team, while the other carried out a modified Stark's technique, at
the Obstetrics and Gynecology Department of the University of Parma from May 1997
to February 1998. A total of 105 cases underwent a modified Stark's technique,
while 99 were submitted to cesarean section with the conventional technique. In
order to get a better reliability of results, homogeneous cases for
epidemiological characteristics and indications have been enrolled in the study.
Statistical analysis was performed by using Student "t"-test, chi 2 test and
Wilcoxon test. The Stark's technique for cesarean section, modified by the
Authors, is described. RESULTS: The parameters concerning surgical procedure,
postoperative course and neonatal outcome showed statistically significant
differences in favour of the modified Stark's technique. CONCLUSIONS: The
conclusion is drawn that this technique leads to a remarkable reduction of blood
loss and urine bacteria. Surgical drainage was never required.
PMID- 10767997
TI - [Chemoresistance in ovarian cancer. State of the art and future prospects].
AB - Aim of this study was to provide a review of the basic mechanisms of drug
resistance in ovarian cancer and novel strategies to modulate drug resistance.
Relevant articles published through August 1999 were identified using the Medline
data base. Publications identified by the search were reviewed and evaluated
critically for their relevance to drug resistance in ovarian cancer. Ovarian
cancer patients have high response rates to initial chemotherapy after
cytoreductive surgery. However, most will develop resistance to chemotherapy
during the course of their treatment. There are multiple mechanisms resulting in
drug resistance. Strategies to modulate drug resistance include dose intensity,
various pharmacologic agents, and gene therapy.
PMID- 10767998
TI - [Buschke and Loewenstein tumors (giant condyloma acuminata). Immunologic
features].
AB - The Buschke-Loewenstein tumor, also called giant condyloma acuminatum, is
generally observed in male subjects, usually on the penis and rarely occurs in
women. A case of Buschke-Loewenstein tumor located on the vulva is reported. It
is a cauliflower-like tumor which behaves clinically in a malignant fashion,
although it shows no histomorphological criteria of malignancy. Histologically it
is a benign papillomatous growth characterized predominantly by epithelial
hyperplasia, hyperacanthosis and hyperkeratosis. The assessment of humoral and
cellular immunity demonstrated an unusual circulating increase of CD4+
lymphocytes suggesting their major role in the very slow progression of the
disease. Surgery remains the treatment of choice for this tumor.
PMID- 10767999
TI - [Prenatal diagnosis of osteogenesis imperfecta. Report of a case].
AB - Osteogenesis imperfecta is a heterogeneous group of connective tissue disorders;
it is characterized by blue scleras, bone fragility and deformity secondary to
recurring fractures. A case of osteogenesis imperfecta personally observed at the
21st week of gestation is presented.
PMID- 10768000
TI - [Meigs' syndrome with high blood levels of CA 125. Clinical case and review of
the literatureo].
AB - A case of Meigs' syndrome is reported. The patient presented with: hydrothorax,
ascites, benign ovarian tumor (thecoma) and increased serum levels of CA 125.
Ovarian thecoma is a rare tumor, accounting for less than 1% of all ovarian
tumors. When associated with Meigs' syndrome, it can produce a clinical picture
similar to that of ovarian carcinoma, but the prognosis is much more favourable.
The condition was managed by bilateral salpingo-oophorectomy and hysterectomy.
The ascites and hydrothorax disappeared spontaneously after removal of the
ovarian tumor and CA 125 level decreased.
PMID- 10768001
TI - [The use of FSH in adolescents and young adults with left idiopathic varicocele,
not submitted to surgery. Preliminary study].
AB - BACKGROUND: To study gonadal function in young patients suffering from left
varicocele. METHODS: DESIGN: prospective study. SETTING: university laboratory
and clinical services. patients: 20 boys (age range: 15-20 yrs; mean +/- DS: 17.9
+/- 1.48 yrs), affected by left idiopathic varicocele. INTERVENTION: high
purified urinary FSH s.c. (Metrodin HP 75, Ares-Serono), three times every week,
for three months. MAIN OUTCOME MEASURES: seminal fluid examination before and
after therapy (WHO). RESULTS: At the end of the study period a statistically
increase of sperm density/ml (38.45 x 10(6) vs 49.10 x 10(6)), total sperm
number/ejaculate with forward motility (37.41 x 10(6) vs 48.52 x 10(6)) and a
decrease of atypical forms (54.35% vs 49.60%) has been observed; the increase of
the total sperm number/ejaculate after FSH treatment greater than 50% compared
with basal values allows to define 9 patients as responders. CONCLUSIONS: In this
study the FSH treatment in young people with varicocele leads to a statistically
significant increase in the seminal fluid parameters and may characterize a group
of patients who may have a better prognostic outcome regarding the tubular
gonadal function and thus the fertility potential in adult life.
PMID- 10768002
TI - The type A botulinum toxin in the treatment of spasticity in evolutive age.
AB - BACKGROUND: Spastic hypertonia with or without athetosis is the main cause of
impairment of motor functions. In actual treatments to this condition, it is
provided the application of the type A botulinic toxin, which allows the decrease
of spasticity and, at the same time, the amelioration of the movement control,
reducing the incidence and gravity of contractures. METHODS: This work relates
about the treatment of spasticity with the use of type A botulinic toxin in a
group of 18 subjects in evolutive age. Before the treatment and during the follow
up, each clinical case had an objective general test, a neurologic test, a video
recording and, at the same time, the administration of the Physician Rating Scale
(PRS) to evaluate both pace and amplitude of the circular movement. RESULTS: Ten
subjects showed a prominent reduction of hypertonia and contractures,
amelioration in ambulating and grievous symptomatology. Eight cases presented a
light amelioration; only a case suffered of a temporary hyposthomia. The
sensibility of the subject to the toxin can ever since be researched, through the
toxin inoculation in a not jet involved distal muscle, and through a following
clinical or electromyographic evaluation on the caused effect. This allows to put
in evidence the increasing resistance to the toxin after repeated
administrations. CONCLUSIONS: It is interesting to evaluate the way in which the
lives of patients and their parents have been influenced by the disease, and how
the use of botulinic toxin may positively interfere on it.
PMID- 10768003
TI - Genetics and molecular biology of the GHRH-GH-IGF-I axis.
AB - In this paper, the genetics and molecular biology of the GHRH-GH-IGF-I (Growth
Hormone Releasing hormone-Growth Hormone-Insulin like Growth Factor I) axis
involved in the pathogenesis of short stature are reviewed. Short stature
associated with GH deficiency is estimated to occur in about 1/4000-10,000 live
births; 3-30% of cases affect first-degree relatives, suggesting a genetic
aetiology. Identification of such molecular defects is very recent and dependent
on new findings on the physiology of GHRH-GH-IGF-I axis: for example the
pituitary-specific transcription factors and their mutations have only been
described in the last few years. The epidemiological importance of the identified
molecular defect depends on the level of the axis involved, but the prevalence of
some of these genetic defects is probably underestimated. Time will tell what the
practical relevance of these findings is and what the clinical features of the
new mutations are; we will probably learn something more about the GHRH-GH-IGF-I
axis: to date, no mutations have been reported regarding the GHRH gene or the IGF
I receptor.
PMID- 10768004
TI - [Early relapse of herpes simplex encephalitis. Clinical and therapeutic
implications].
AB - A case of Herpes simplex virus encephalitis (HSVE) is reported in a 5 year old
boy, who relapsed twice during the acute phase of the disease. The second relapse
was completely cured by increasing the daily treatment with acyclovir to a dosage
of 60 mg/kg intravenously for two weeks and 30 mg/kg by mouth for a further week.
The full disappearance of the symptoms and the regression of cerebral lesions
could be correlated to a prompt diagnosis and to the dosage of acyclovir
employed, higher than that suggested for diseases caused that was by other
members of the Herpes virus family.
PMID- 10768005
TI - [Leukoencephalopathy with swelling, megalencephalopathy and surprisingly mild
course. A case report].
AB - Leukoencephalopathy with swelling and a discrepantly mild clinical course is a
recently identified syndrome described by van der Knaap et al. It is
characterised by macrocephaly occurring during the first year of life, initially
normal or nearly normal development, slowly progressive ataxia and spasticity
with initial preservation of intellectual functions. MRI shows diffuse
abnormality of signal intensity in the hemisphere white matter with subcortical
cyst-like spaces in the fronto-parietal and anterior temporal areas. The case of
a 5-year-old boy whose clinical and neuroimaging findings are consistent with
this syndrome is reported. The clinical and neuroimaging findings of this case
may provide further information about this new syndrome which could possibly be
useful also for genetic counselling.
PMID- 10768006
TI - [Evaluation of a new amino acid mixture for the treatment of phenylketonuria].
AB - BACKGROUND: To assess the acceptability and nutritional adequacy of a new
phenylalanine-free amino acid mixture (Phenylade-Dietetic Metabolic Food).
METHODS: Twenty PKU patients (aged 2.6-10 years) diagnosed and followed by our
Department. The children were given this product for a minimum of 4 and a maximum
of 12 months. The clinical control has been carried out before treatment and then
every 3 months. The biochemical parameters included: quantitative plasma amino
acids, hematologic measurements of nutritional adequacy folic acid and vitamin
B12. RESULTS: All patients (except one) found this new product to be an
acceptable alternatives as to taste and convenience to the previous low
phenylalanine protein substitutes. CONCLUSIONS: Normal growth was maintained.
PMID- 10768007
TI - [The newborn].
PMID- 10768008
TI - Alteration in alpha 2 integrin immunocytochemical expression on cultured human
gingival fibroblasts following nicotine exposure.
AB - BACKGROUND: Clinical epidemiologic studies carried out in smokers versus non
smokers support the concept that tobacco-related factor may affect the
periodontal tissues and wound healing. METHODS: In this study, the role of
nicotine on the integrin alpha 2 chain immunocytochemical expression, in human
gingival fibroblasts (HGF) was investigated in vitro. The kinetic induction of
this type of integrin on HGF in response to increasing percentage of nicotine was
been characterized. A human gingival fibroblast strain, derived from a healthy
individual with non-inflamed gingiva, was used in this study. The cells were then
grown on acetylated microscope slides and fixed with cold ethanol, samples were
then incubated for 16 to 19 hrs at 4 degrees C to anti-human alpha 2 integrin
chain monoclonal antibody. RESULTS: In control cultures and in HGF treated with
0.025 microM nicotine the initial higher expression of alpha 2 chain decreased
(grade 1 in both culture) while in HGF treated with 0.075 microM increased (grade
3). After 48 hours HGF exposed to 0.075 microM nicotine, increased further their
expression of alpha 2 chain. CONCLUSIONS: The results obtained demonstrate a dose
time dependent nicotine influence on immunocytochemical expression of alpha 2
integrin chain. These data suggest that nicotine may promote a collagene
breakdown via an increase of alpha 2 integrin chain expression.
PMID- 10768009
TI - Bacterial colonisation during GTR treatment. A longitudinal analysis.
AB - The purpose of the present study was to evaluate the long-term biological and
clinical effects of a controlled delivery system releasing tetracyclines during
the healing of interproximal periodontal defects treated by the technique of
guided tissue regeneration (GTR) using e-PTFE membranes. METHODS: Fifteen
patients, each with two comparable interproximal periodontal defects, underwent
surgical treatment with e-PTFE membranes in conjunction with tetracycline fibres
at the test site and e-PTFE membranes alone at the control site. Microbiological
specimens were taken from each site treated at baseline (T0) and one year after
surgery (T4). Plaque index (PI), gingival index (GI), pocket depth at probing
(PD) and attachment level at probing (PAL) were recorded at baseline (T0) and one
year after surgery (T4). The presence of selected pathogenic microbial species,
Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Fusobacterium
Nucleatum (Fn) and Actinobaccillus Actinomicetemcomitans (Aa), was investigated
and these species were identified by cultural methods. RESULTS: No statistically
significant difference in the level of periodontal pathogens was detected between
the test and control sites at time T4. Likewise, no significant clinical
difference between the test site and the control site was detected at time T4.
CONCLUSIONS: The results suggest that tetracycline fibres used in conjunction
with e-PTFE membranes do not provide and further clinical and microbiological
improvement or effect the healing of periodontal defects one year after GTR
treatment.
PMID- 10768010
TI - Bacterial adhesion to dental alloys. The role of the surface and composition.
AB - BACKGROUND: In the oral cavity, many bacteria can only survive by adhering to
hard surfaces. The roughness and free energy of these surfaces play an important
part in this process. Precision dental alloys may undergo corrosion, but findings
show that this does not seem to cause problems of biocompatibility. The release
of metallic ions into the oral cavity may both inhibit bacterial growth and
influence bacterial adhesion. The object of the present study was to bring to
light any possible correlation between corrosion and/or ionic release and
bacterial adhesion with regard to 18 different types of dental alloy, both before
and after polishing. METHODS: Electrochemical analyses were carried out (cyclic
potentiodynamic and potentiostatic polarisation tests). Corrodible elements were
analysed through Atomic Absorption Spectroscopy of specimens of each alloy. The
inhibition of bacterial adhesion and growth was determined using bacteria
specific to the oral cavity. RESULTS: All the alloys examined show a tendency
towards spontaneous passivation with low values of anodic current. The evaluation
of ionic release confirmed the biocompatibility of the tested materials and the
solutions conditioned with the alloys did not inhibit bacterial growth. There was
no significant bacterial adhesion after polishing. Bacteria adhere to unpolished
alloys in a specific manner and are inhibited from doing so in the presence of
alloys for gold-resin restorations containing silver and copper. CONCLUSIONS:
When polished, all the alloys are resistant to in vitro electrochemical corrosion
and bacterial adhesion. The possibility cannot be excluded that bacterial
adhesion occurs after the materials have been in place in the oral cavity for
some time. The alloys which were found to inhibit bacterial attack may be more
suitable, while not representing a biological risk for the surrounding tissues.
PMID- 10768011
TI - [Occlusion and posture: is there evidence of correlation?].
AB - The observation that the masticatory system and the postural body regulating
system are anatomically and functionally related, has led to postulate several
hypotheses of correlation between occlusal and postural disturbances. In the last
decade, these arguments have gained a great social impact, also because they have
been broadly spread by the mass-media. As a consequence, there has been a growing
number of patients seeking concomitant occlusal and postural treatments. The aim
of this study was to review critically the current evidence of correlation
between the two systems; this in order to address clinical issues for the
management of patients. Methodology of the studies reviewed has been evaluated
according to the criteria suggested by Storey and Rugh 20 rif. Although there are
some evidences of correlation between occlusion and posture, this appears limited
to the cranio-cervical tract of the column and tends to disappear when descending
in cranio-caudal direction. On the basis of this review of the literature, it's
not advisable to treat postural imbalance by means of occlusal treatment or vice
versa, particularly if the therapeutic modalities are irreversible.
PMID- 10768012
TI - Papillary carcinoma of the base of the tongue. Case clinic.
AB - Ectopic lingual thyroid tissue is an uncommon developmental anomaly. Tumours of
identical pathological characteristics as those arising in the eutropic thyroid
tissue, may be present in ectopic locations. There are very few cases of
malignant tumours reported in the literature. Here we report a review of this
pathology and we describe a case of a papillary carcinoma of the base of the
tongue, located in ectopic lingual thyroid tissue, in a 66 year-old white man,
complaining of dysphagia and oral bleeding. Surgical treatment was carried out,
consisting of radical resection of the right hemineck, tumour resection, right
hemiglossectomy and total thyroidectomy. Postoperative treatment with 131I and
substitutive thyroid hormonal therapy was prescribed.
PMID- 10768013
TI - [Benign cementoblastoma. A case report].
AB - Cementoblastoma is a benign odontogenic tumor of mesenchymal origin. It usually
presents as a distinct lesion with characteristic radiographic and
histopathologic appearances. The tumor is intimately associated with the roots of
teeth which are usually located in the posterior mandible. The purpose of this
report is to describe a case of cementoblastoma and discuss the clinical,
histopathological and therapeutic aspects of this tumor.
PMID- 10768014
TI - Metastases to the human mandible.
AB - Two clinical cases are reported of mandibular swelling caused by metastatic jaw
neoplasms. They analyse. The clinical characteristics of the swelling are
analysed and all laboratory and radiographic tests performed are examined. It is
concluded that metastatic localisations in the maxillofacial bone are very rare,
but that the mandible is certainly the most frequent site. The authors also
highlight the fact that the presence of metastatic lesions in the jaw may be the
first symptom of the neoplastic disease.
PMID- 10768015
TI - [Differential diagnosis in a case of brown tumor caused by primary
hyperparathyroidism].
AB - Fibrous-cystic osteitis is a bone metabolic disorder related to
hyperparathyroidism. This pathological condition shows a bone catabolism
enhancement, due to increased level of PTH. Brown tumour is a uni- or multi-focal
bone lesion, which represents the terminal stage of the hyperparathyroidism
dependent bone pathology. This focal lesion is not a real neoplasm showing itself
as a cellular reparative process, mainly interesting the jaws, specially the
mandible. Because of the similar radiological features (cyst-like radiolucency)
showed by other lesions, the diagnosis can be difficult. Histology cannot
guarantee a certain diagnosis, some lesions, such as giant cell tumour, giant
cell granuloma, aneurysmal bone cyst and cherubism, show a similar macroscopical
and microscopical features. Differential diagnosis is possible only by
comparative evaluation of clinical, radiological and biochemical evidences.
Personal experience with a patient affected by maxillary expansive lesion
previously diagnosed as GCT is reported. Radiological examinations showed another
cyst-like lesion involving the mandible. Clinical history and multifocality of
lesions were suggestive for the presence of a systemic disease, laboratory data
allowed a primary hyperparathyroidism diagnosis. Parathyroid scintigraphy was
performed and detected a parathyroid adenoma. In first instance the patient
underwent to surgical operation on the jaws in order to stop the rapid
progression of bone lesions, and then another operation for the removal of
parathyroid adenoma was performed.
PMID- 10768016
TI - [Evaluation of the efficacy of flurbiprofen in subjects undergoing extraction of
impacted 3d molar].
AB - INTRODUCTION: In this open controlled study the authors evaluated the anti
inflammatory, antalgic and antipyretic efficacy of flurbiprofen in 200 mg
capsules as a complementary treatment to antibiotic therapy following minor oral
surgery. METHODS: A total of 100 patients of both sexes, aged between 13 and 65,
were monitored after extraction of impacted 3rd molar. Patients were treated with
flurbiprofen SR 200 mg/day for five days and were controlled on the 2nd and 5th
day after surgery. The following parameters were evaluated: painful symptoms,
objective examination of mucosa and fever. RESULTS: The results showed the clear
efficacy of flurbiprofen SR in reducing all the parameters examined.
PMID- 10768017
TI - Light hazards from ophthalmic instruments. A clinical problem.
PMID- 10768018
TI - An appraisal of the disc-macula distance to disc diameter ratio in the assessment
of optic disc size.
AB - The disc-macula distance to disc diameter ratio (DM:DD ratio) has been advocated
as a method of supporting the diagnosis of optic nerve hypoplasia. A DM:DD ratio
of 3.00 has been claimed to be a satisfactory threshold value for this purpose.
This study has critically evaluated the above claim and found a value of 3.00 to
be too low. The threshold DM:DD ratio values for the diagnosis of unequivocal ONH
for an adult population, 5 and 2 years of age were found to be respectively 4.20,
3.93 and 3.70, the values for the diagnosis of mild ONH being 3.68, 3.44 and
3.23. Lower computed values reduce the predictive power. The method of
computation of the DM:DD ratio was modified to abolish potential error due to
disc rotation and foveal displacement. In an adult population, there was no
correlation between the DM:DD ratio and amblyopia or disc ovalness. There was a
trend of increasing DM:DD ratio towards myopia and decreasing DM:DD ratio towards
hypermetropia; the DM:DD ratio may therefore be falsely high in high myopia.
DM:DD ratio values below threshold should therefore be interpreted with care
until formal optic disc biometry can be performed.
PMID- 10768019
TI - The effect of target proximity on the aniso-accommodative response.
AB - Aniso-accommodation (unequal binocular accommodation) to lens-induced
anisometropia has been demonstrated by subjective and objective measurement
techniques (Marran and Schor, Vision Res. 38(22), 3601-3619). The gain of the
response was significantly reduced for some subjects when aniso-accommodation was
stimulated by a target at 1 m compared to a target at 20 cm, even when the
targets viewed were matched in retinal image size, convergence levels and aniso
accommodative stimuli. The two conditions did differ in both the accommodative
level and proximity of the target. Thus the higher gain of the response in the 20
cm condition could have arisen from either high proximity, high accommodative
level or a combination of both. In this investigation, target proximity and
accommodative level were manipulated independently while extra-retinal cues such
as absolute disparity and image size were held constant. The results show that
high target proximity alone rather than accommodative level or a combination of
the two was responsible for the distance dependent effect demonstrated by
subjects. Furthermore, accommodative level did not affect the response when
target proximity was held constant. Subjects who demonstrated invariant aniso
accommodation with changes in viewing distance also demonstrated invariant aniso
accommodation with experimental manipulation of target proximity at the target
distances tested, as would be expected. These results suggest that high level
processing, rather than a reflex blur response, is involved in aniso
accommodation. This conclusion is strengthened by the previous finding of long
reaction and response times, 11 and 15 s respectively, to step aniso
accommodative stimuli (Marran and Schor, Vision Res. 38(22), 3601-3619). Since
the experimental target provided subjects with visual feedback of the relative
blur of the dichoptically viewed letters, subjects had access to perceptual blur
information cues. Some subjects seemed to have required both aniso-blur and
proximity to exercise this volitional response. Those subjects who showed a
distance invariant aniso-accommodative response may have been able to use
perceived aniso-blur alone and their ability to disregard proximal cues may have
resulted from greater experience with the aniso-accommodative stimuli.
Alternatively, these subjects may have had a lower threshold to proximal stimuli
and experienced target proximity at the more distant (1 m) viewing condition.
PMID- 10768020
TI - The characteristics of near prism induced fixation disparity curve in Hong Kong
Chinese.
AB - The characteristics of prism induced fixation disparity curve at near were
studied in 56 asymptomatic young adult Hong Kong Chinese (average age 21 years).
The percentage distribution of types of fixation disparity curves was found to be
similar to some previous studies, with a higher prevalence of Type I curve
(64.3%), followed by Type II (28.6%) and Type III (7.1%) curves. No Type IV curve
was revealed from the sample. Two modified measurement approaches were applied to
study the effect of measurement techniques on the parameters of fixation
disparity curve obtained. A thorough description of the techniques was given.
Although a significant difference in the x- and y-intercepts was obtained between
different methods, the curve type and slope were not affected. The average y
intercepts (fixation disparity) were 2.72 min of arc and 3.54 min of arc from two
methods respectively. Forty-one subjects had x-intercept (associated phoria)
found from the curve. The average values were 2.42 delta base-out and 3.54 delta
base-out from two methods respectively.
PMID- 10768021
TI - The effect of surround luminance on measurements of contrast sensitivity.
AB - We investigated how the luminance of an immediate surround to a visual target
affects the measurement of contrast sensitivity. We examined four young, healthy,
subjects under typical lighting conditions for each test but varied the surround
luminance systematically by controlling a backlit surround. The effect of varying
the surround on contrast sensitivity measurements made with a Pelli-Robson chart
was minimal. The only statistically significant difference was between
measurements made with a 900 cd.m-2 surround compared to those made with 5.6, 9,
or 30 cd.m-2 surrounds when tested at a viewing distance of 4 m. The higher
luminance surround produced higher levels of contrast sensitivity. The effect of
the surround luminance was greater when measuring contrast sensitivity to
sinewave gratings using a method of constant stimuli. Optimum performance was
found using a surround luminance of 9 cd.m-2 (20% of the mean target luminance).
Statistically, a wide range of surround luminances (3-30 cd.m-2, or 7-67% mean
target luminance) gave similar levels of visual performance, but higher luminance
surrounds led to reduced contrast sensitivity. Possible reasons for the
difference in the effect of the surround depending upon the test are discussed.
Ophthalmic practitioners using contrast sensitivity measurements with letter
charts probably need not make special efforts to illuminate the test surround
appropriately. However, practitioners using sinewave gratings, especially
computer generated sinewave gratings, to measure contrast sensitivity, may have
their measurements affected by inappropriately lit task surrounds.
PMID- 10768022
TI - Effects of defocus and pupil size on human contrast sensitivity.
AB - Defocus lowers the contrast sensitivity function (CSF), producing a complex
function with local dips and peaks. Previously, we were able to predict the shape
of the CSF with large pupils from measured transverse aberrations with
hypermetropic defocus but not with myopic defocus (Atchison et al., 1998c, J.
Opt. Soc. Am. A. 15, 2536). As there is no reason that myopic defocus should be
more difficult to predict than hypermetropic defocus, we modified the procedure
to try to improve CSF predictions with myopic defocus. Also, we extended the
study to consider a range of pupil sizes. CSFs were measured for three subjects
at three defocus levels (in-focus, -2D and +2D) and three pupil sizes (2 mm, 4 mm
and 6 mm). Using a diffraction optics model, transverse aberration measures and
in-focus CSF measures, we predicted the defocused CSFs. The predicted defocused
CSFs were lower than the in-focus CSF as expected, and had complex shapes that
varied with defocus and pupil size and between subjects. While a few predictions
were poor, generally, the overall magnitude and shape of the defocused CSFs were
well predicted and similarly so for myopic and hypermetropic defocus. Some
further improvements in technique are indicated.
PMID- 10768023
TI - Visual perception of the Moire effect.
AB - The perception of Moire fringes is studied with two different tests for binocular
and monocular conditions. The results are negative for binocular conditions, and
positive for the monocular case when afterimages are used.
PMID- 10768024
TI - An Arabic letter distance visual acuity test chart for young children and
illiterate adults.
AB - This paper describes the design of a kinetic response Arabic letter distance
visual acuity test chart for young children and illiterate adults. An Arabic
letter ein which has previously been used in the design of Arabic alphabet VA
charts was employed. Four different orientations of the letter were constructed
on a 5 x 5 unit format and graded according to log MAR principle of acuity
scaling using an Apple computer. Inter-letter space in each row was made equal to
the width of each letter in the row, and inter-row space was made equal to the
height of letters in the next lower row. The chart has 14 acuity rows ranging
from 4/40 to 4/2 (6/60 to 6/3) (20/200 to 20/10) (log MAR 1.0 to -0.3) at 4
metres. To establish the validity of the chart, acuity values obtained using the
chart were compared with those from an existing Arabic log MAR distance VA chart
and the Bailey and Lovie distance VA chart. Test retest reliability of the chart
was also examined statistically. Results show that VA values from the new chart
were significantly similar with those from which it was compared, and that values
from the chart are reliable. The chart will be useful for evaluating vision,
especially for young children and illiterate adults.
PMID- 10768026
TI - Longitudinal spherical aberration and mass of bi-aspheric aphakic rigid contact
lenses.
AB - The purpose of this study is to calculate the longitudinal spherical aberration
and thickness, and consequently the mass of aphakic corneal contact lenses in air
to determine optimum lens designs. The longitudinal spherical aberration has been
calculated by the ray tracing method through the aspheric surfaces. The volume of
the lens was computed by solving integrations of rotationally symmetric bodies.
The results show that longitudinal spherical aberration can be made zero in
ellipsoid-ellipsoid designs for back vertex powers ranging from +8 to +20
dioptres (for a 4 mm marginal axial ray height). A reduction in mass of about 23%
was obtained when the anterior surface became ellipsoid and posterior surface
spherical for back vertex power +20 dioptres.
PMID- 10768025
TI - Refractive error changes in mixed astigmatism.
AB - The purpose of this note is to examine refractive error changes in children who
change from mixed astigmatism to myopic astigmatism. Data were collected for 16
children who changed from mixed astigmatism to simple myopic or compound myopic
astigmatism. Children with mixed astigmatism showed minimal refractive changes
until they converted to myopic astigmatism, at which time refractive changes
increased.
PMID- 10768027
TI - Phakic intraocular contact lenses--perversion of a profession?
PMID- 10768028
TI - A review of the management of 323 consecutive patients seen in a specific
learning difficulties clinic.
AB - Visual correlates of specific learning difficulties (SpLD) include: binocular
instability, low amplitude of accommodation, and Meares-Irlen Syndrome. Meares
Irlen Syndrome describes asthenopia and perceptual distortions which are
alleviated by using individually prescribed coloured filters. Data from 323
consecutive patients seen over a 15 month period in an optometric clinic
specialising in SpLD are reviewed. Visual symptoms and headaches were common. 48%
of patients were given a conventional optometric intervention (spectacles,
orthoptic exercises) and 50% were issued with coloured filters, usually for a
trial period. 40% of those who were given orthoptic exercises were later issued
with coloured overlays. 32% of those who were issued with coloured overlays were
ultimately prescribed Precision Tinted lenses. Approximately half the sample were
telephoned more than a year after the last clinical appointment. More than 70% of
those who were prescribed Precision Tints were still wearing them daily, and
results for this intervention compared favourably with data for non-tinted
spectacles. The data suggest that many people with SpLD need optometric care and
that the optometrist needs to be skilled in orthoptic techniques and cognisant of
recent research on coloured filters.
PMID- 10768029
TI - The EyeSys videokeratoscopic assessment of apical radius and p-value in the
normal human cornea.
AB - The EyeSys videokeratoscope was used to assess the corneal topography in 98
subjects. Scatterplots of distance squared versus radius squared were plotted for
the near horizontal and near vertical principal meridians of the two eyes. The
regression lines allowed calculation of the surface apical radius and the p
value. The group average apical radius was 7.93 mm (horizontal) and 7.78 mm
(vertical). The group average p-value was 0.76 (horizontal) and 0.82 (vertical).
Both apical radius and p-value were similar when comparing the two eyes for both
the horizontal and the vertical meridians. The two meridians in a single eye,
however, had different values for both apical radius and p-value. Male apical
radii were longer than those of females but the p-values were the same. There is
no apparent association between age and either apical radius or p-value for the
subjects used in this study. The asphericity of the cornea does not show any
apparent association with corneal curvature in this group of subjects.
PMID- 10768030
TI - The cornea swells in the posterior direction under hydrogel contact lenses.
AB - Two mathematical models were developed to describe the topographical corneal
swelling response to hydrogel contact lenses and the effect of these changes on
refractive error. In one, corneal thickness changes resulted in deformation of
the anterior corneal surface. In the other, the posterior surface only was
deformed. Refractive error, corneal thickness and corneal shape were monitored in
a sample of adapted contact lens wearers with one eye patched for 4 h while
wearing a soft contact lens. The experimental data were most consistent with the
model in which the posterior surface only was deformed.
PMID- 10768031
TI - Influence of age on the multifocal electroretinography.
AB - The influence of age on the amplitude density (nV/sq deg) of the multifocal
electroretinogram (ERG) was studied in 90 healthy subjects aged 18-52 years.
Subjects were divided into three separate age groups; (i) 18-22 years (ii) 33-37
years and (iii) 48-52 years. Amplitude density of first order kernel of the
multifocal ERG was measured for the three different age groups. When the whole
response of the retina is considered, analysis of variance showed no significant
differences in amplitude density between the three age groups. (ANOVA, df. 2, 87
F = 2.29, p = 0.11. However if the responses were segregated into a central area
and concentric rings around the central area, analysis of variance showed that
there were significant differences in responses between rings at different
eccentricities and between different age groups (Anova F = 76.19, df. 17, 522, p
= 0.00001). Post hoc analysis showed that the responses from the centre and the
second ring around the centre of fixation for 48-52 year olds were significantly
lower than those responses from the 33-37 year old and the 18-22 year old age
groups. The decline in the multifocal ERG in the central retina of the 48-52 year
olds could be associated with the decline of the number of photoreceptors as the
eye ages. Student t test revealed no significant differences in amplitude density
between males and females.
PMID- 10768032
TI - Ocular components values and their intercorrelations in Saudi Arabians.
AB - There are no previous studies on the dimensions of ocular components and their
intercorrelations in adult Saudi Arabians. In this study ocular components were
measured by ultrasonography and keratometry in 152 adult Saudis. Their ages
ranged from 16 to 50 years. The males had significantly longer anterior chamber
depth (ACD), vitreous chamber depth (VCD), axial length (AL) and axial
length/corneal radius ratio (AL/CR) than females. However, females had non
significantly steeper corneas than males. The AL/CR ratio had the highest
correlation with refractive error. Corneal radius of curvature was positively
correlated with VCD and AL. Lens thickness was negatively correlated with the
VCD, AL and AL/CR ratio. Myopes had significantly deeper ACD, VCD, and higher
AL/CR ratio than nonmyopes. Myopes had significantly thinner lenses than
hyperopes. The average values of the optical components and their
intercorrelations are similar to reported values obtained from subjects of other
races but with comparable refractive errors.
PMID- 10768033
TI - Chart construction and letter legibility/readability.
AB - Variation in legibility/readability between charts letters may be due to
differences in chart construction and/or examination protocols and/or subject
selection. An examination of legibility/readability of letters that are common to
two chart constructions was undertaken. Identical examination and subject
selection protocols for both charts were employed. It was found that ranking of
error frequencies for some letters varied between the Bausch & Lomb Compact
Acuity Projector and Bailey-Lovie charts. Despite many similarities in ranking,
the differences found for the letters D and E indicate that caution should be
observed before assuming that legibility/readability determined with one letter
chart would apply when using another. Lack of standardisation for chart
construction, as well as measurement methods and conditions of measurement,
invalidate inter-practice comparisons for visual acuity.
PMID- 10768034
TI - A logistics evaluation of visual acuity as applied to the Bailey-Lovie chart.
AB - AIMS: To discover whether as a result of the increasing use of the Bailey-Lovie
chart some classes of patients may not be affected by the crowding of the smaller
test characters, whose spacing is proportional to their size; and to determine
acuities with a logistic function so that all of a patient's responses may be
utilized. METHODS: 112 patients were tested both with the original chart and one
in which the horizontal distance is kept constant, i.e., the letters are arranged
in vertical columns. All of a patient's responses were recorded so that the
constants of the logistic function might be determined. RESULTS: No difference
was found for very high and very low acuity scores, but, for intermediate ones,
the vertical columns yielded acuity ratings increased by some 13%. CONCLUSION:
The use of the logistics function was successful in that the correlation between
stimulus and response was between 0.9 and 1 for some 80% of those examined. A
constant horizontal spacing may be of advantage to some patients with a
conventionally measured visual acuity of approximately 0.9.
PMID- 10768035
TI - A preliminary study on the ocular blood flow (OBF) of Hong Kong Chinese.
AB - The Ocular Blood Flow (OBF) Tonometer is an objective instrument to measure the
Pulsatile Ocular Blood Flow (POBF), Pulse Amplitude (PA) and Pulse Rate (PR). It
also provides the minimum intraocular pressure (IOPmin) simultaneously. This
preliminary study applied the OBF Tonometer on 74 Hong Kong Chinese. They had
their POBF measured followed by the Goldmann Applanation Tonometer (GAT). The OBF
tonometer overestimates the IOP slightly. The average POBF result was smaller
(661.2 microliters/min) than the previous studies. The effect of myopia of our
sample (mean spherical equivalent -4.27 D) could be one of the contributing
factors. Other factors include age and racial difference. Twenty-two subjects had
their POBF measured again by the same practitioner and different practitioner for
the reproducibility variation assessments. The POBF, PA and IOPmin were found to
be repeatable between sessions. The POBF "norm" in Hong Kong Chinese needs to be
established from a larger sample size and from a comparison on an age and
refraction matched Caucasian group.
PMID- 10768036
TI - Referrals to the Glaucoma Clinic of the Royal Infirmary of Edinburgh.
PMID- 10768037
TI - The development of hemispheric asymmetry in human motion VEPs.
AB - In six healthy adults we examined the sources underlying P1 and N2 of the motion
VEP. For this purpose was acquired, in addition to the VEP, MRI images and
patterns of regional cerebral blood flow with SPECT for three of the subjects.
With the same motion stimulus we also examined the spatial distribution of N2 in
children. In both adults and children left and right half-field responses were
compared. It was found that N2 is generated by extrastriate activity and that
motion stimuli are not equivalently processed in the two cerebral hemispheres. In
adults, N2 dominates in one hemisphere irrespective of the visual half-field used
for stimulation whereas children show an ipsilateral maximum for N2 upon half
field presentation.
PMID- 10768038
TI - Photoreceptor performance and the co-ordination of achromatic and chromatic
inputs in the fly visual system.
AB - White noise techniques are used to compare the two photoreceptor sub-types in
blowfly retina, the short visual fibres (R1-6) that code achromatic contrast, and
the long visual fibres (R7 and R8) that together code wavelength distribution and
polarisation plane. Measurements of signal and noise spectra and contrast gain,
taken across a broad intensity range, permit a detailed comparison of coding
efficiency under natural conditions of illumination. As a function of excitation
(effective photons per photoreceptor per second; h upsilon/rec per s), adaptive
changes in the long and short visual fibres are similar, suggesting that post
rhodopsin their phototransduction cascades are identical. Under identical natural
daylight conditions (photons per cm2 per second; h upsilon/cm2 per s) short
visual fibres catch more photons, thus operating with a higher signal to noise
ratio and faster response, to consistently outperform the long visual fibres.
Long visual fibres compensate for their poor quantum catch by having a higher
absolute gain (mV/h upsilon) which at low light intensities enables them to
achieve a level of contrast gain (mV/unit contrast) similar to the short visual
fibres. Differences in signal to noise ratios are related to known differences in
photoreceptor structure and synaptic frequency among visual interneurons. The
principles of matching sensitivity and synapse number to quantum catch described
here could explain analogous differences between chromatic and achromatic
pathways in mammalian and amphibian retinas.
PMID- 10768039
TI - Modulation of outgrowth from goldfish retinal explants by a 5-HT2 receptor
agonist and [3H]ketanserin binding sites in goldfish and rabbit retina.
AB - The binding of [3H]ketanserin to goldfish and rabbit retinal membrane
preparations and the possible role of 5-HT2A receptors in the in vitro outgrowth
from goldfish retina were evaluated. Saturation experiments indicated a high
affinity binding site, and positive cooperativity for both tissues. The 5-HT2A/2C
agonist (+/-)-2,5-dimetoxy-4-iodoamphetamine and serotonin inhibited outgrowth
from goldfish retinal explants. These effects were blocked by the 5-HT2
antagonists ketanserin and 1-(1-naphthyl)piperazine and by the 5-HT2C antagonist
mesulergine, respectively. Results make to suggest that [3H]ketanserin binds to 5
HT2A receptors in the rabbit and goldfish retina, but also to a monoamine
transporter in the latter tissue. Subtypes of 5-HT2 receptors might mediate the 5
HT modulatory role on in vitro outgrowth of the goldfish retina.
PMID- 10768040
TI - Monochromatic aberrations in the accommodated human eye.
AB - The wave-front aberration of the human eye was measured for eight subjects using
a spatially resolved refractometer (a psychophysical ray-tracing test). The eyes
were undilated and presented with accommodative stimuli varying from 0 to -6
diopters. Monochromatic wave-front aberrations tend to increase with increasing
levels of accommodation, although there are substantial individual variations in
the actual change in the wave-front aberration. While spherical aberration always
decreased with increasing accommodation, it did not change from positive to
negative for every observer. The direction and amount of change in fourth order
aberrations varied between observers. Aberrations with orders higher than fourth
are at a minimum near the resting state of accommodation. The accommodation
induced change in wavefront aberration was not strongly related to the total
amount of aberration in the eight eyes studied.
PMID- 10768041
TI - Estimating the time to collision with a rotating nonspherical object.
AB - We measured the precision (i.e. Weber fraction) and the accuracy with which the
time to collision (TTC) with a simulated approaching object is estimated. We
simulated a rigid spherical object and a rigid nonspherical object (an oblate
spheroid whose longer axis was vertical). We used the following viewing
conditions: that the available information about TTC was only monocular (M), only
binocular (B) and monocular plus binocular (M and B). In addition to the
approaching SPHERE condition, we used the following three simulation conditions
for the oblate spheroid: (2) a slow rotation through 90 degrees (SIDE-END); (3) a
slow rotation through 90 degrees (END-SIDE); (4) several complete rapid rotations
(RROT). Weber fractions for discriminating TTC were similar for all 12
combinations of viewing and simulation conditions. When only monocular
information was available, perceived TTC was longer in the M/SIDE-END condition
than in the M/SPHERE condition, and shorter in the M/END-SIDE condition than in
the M/SPHERE condition. As well, observers were strongly influenced by task
irrelevent variables in the M/SIDE-END condition so that they could not properly
perform the task. The addition of binocular information considerably improved the
accuracy of estimating TTC in simulation conditions SPHERE, END-SIDE and RROT,
and allowed reliably accurate estimations to be made in the SIDE-END simulation
condition. We suggest that, when binocular information is combined with monocular
information about TTC, the two kinds of information are weighted roughly equally
when the approaching object is a rigid sphere, but the binocular information is
weighted more heavily when the approaching object is nonspherical and rotating.
PMID- 10768042
TI - Asymmetries of saccadic eye movements in oriented-line-target search.
AB - Visual search for a line-element target differing sufficiently in orientation
from a background of line elements can be performed rapidly, effortlessly, and
without eye movements. There is, however, a response asymmetry: detection is
better with an oblique target element in vertical or horizontal background
elements than when these orientation are interchanged. If the underlying visual
mechanisms also provide an input to the oculomotor system, then a similar
asymmetry should be observed in eye-movement behaviour. To test this hypothesis,
an experiment was undertaken in which eye movements were recorded while subjects
searched for a line-element target in background of line elements; orientations
were chosen from the range 0 degree, 30 degrees, 60 degrees, and 90 degrees to
the vertical. Data from three subjects showed that (1) latencies for the initial
saccade, (2) angular errors in initial-saccade direction, and (3) manual response
times depended similarly on the combination of target- and background-element
orientations, performance being better for 30 degrees or 60 degrees targets in 0
degree or 90 degrees backgrounds than vice-versa. The early orientation-selective
mechanisms responsible for the rapid detection of oriented-line targets are
probably the same as those providing signals for saccadic eye movements.
PMID- 10768043
TI - Cuttlefish use polarization sensitivity in predation on silvery fish.
AB - Cephalopods are sensitive to the linear polarization characteristics of light. To
examine if this polarization sensitivity plays a role in the predatory behavior
of cuttlefish, we examined the preference of Sepia officinalis when presented
with fish whose polarization reflection was greatly reduced versus fish whose
polarization reflection was not affected. Cuttlefish preyed preferably on fish
with normal polarization reflection over fish that did not reflect linearly
polarized light (n = 24, chi 2 = 17.3, P < 0.0001), implying that polarization
sensitivity is used during predation. We suggest that polarization vision is used
to break the countershading camouflage of light-reflecting silvery fish.
PMID- 10768044
TI - The Ouchi illusion as an artifact of biased flow estimation.
AB - A pattern by Ouchi has the surprising property that small motions can cause
illusory relative motion between the inset and background regions. The effect can
be attained with small retinal motions or a slight jiggling of the paper and is
robust over large changes in the patterns, frequencies and boundary shapes. In
this paper, we explain that the cause of the illusion lies in the statistical
difficulty of integrating local one-dimensional motion signals into two
dimensional image velocity measurements. The estimation of image velocity
generally is biased, and for the particular spatial gradient distributions of the
Ouchi pattern the bias is highly pronounced, giving rise to a large difference in
the velocity estimates in the two regions. The computational model introduced to
describe the statistical estimation of image velocity also accounts for the
findings of psychophysical studies with variations of the Ouchi pattern and for
various findings on the perception of moving plaids. The insight gained from this
computational study challenges the current models used to explain biological
vision systems and to construct robotic vision systems. Considering the
statistical difficulties in image velocity estimation in conjunction with the
problem of discontinuity detection in motion fields suggests that theoretically
the process of optical flow computations should not be carried out in isolation
but in conjunction with the higher level processes of 3D motion estimation,
segmentation and shape computation.
PMID- 10768045
TI - Mechanisms of generalization in perceptual learning.
AB - Learning in many visual perceptual tasks has been shown to be specific to
practiced stimuli, while new stimuli have to be learned from scratch. Here we
demonstrate generalization using a novel paradigm in motion discrimination where
learning has been previously shown to be specific. We trained subjects to
discriminate directions of moving dots, and verified the previous results that
learning does not transfer from a trained direction to a new one. However, by
tracking the subjects' performance across time in the new direction, we found
that their speed of learning doubled. Therefore, we found generalization in a
task previously considered too difficult to generalize. We also replicated, in a
second experiment, transfer following training with 'easy' stimuli, when the
difference between motion directions is enlarged. In a third experiment we found
a new mode of generalization: after mastering the task with an easy stimulus,
subjects who have practiced briefly to discriminate the easy stimulus in a new
direction generalize to a difficult stimulus in that direction. This
generalization depends on both the mastering and the brief practice. The
specificity of perceptual learning and the dichotomy between learning of 'easy'
versus 'difficult' tasks have been assumed to involve different learning
processes at different cortical areas. Here we show how to interpret these
results in terms of signal detection theory. With the assumption of limited
computational capacity, we obtain the observed phenomena--direct transfer and
acceleration of learning--for increasing levels of task difficulty. Human
perceptual learning and generalization, therefore, concur with a generic
discrimination system.
PMID- 10768046
TI - The magnocellular deficit theory of dyslexia: the evidence from contrast
sensitivity.
AB - A number of authors have made the claim that dyslexia is the result of a deficit
in the magnocellular part of the visual system. Most of the evidence cited in
support of this claim is from contrast sensitivity studies. The present review
surveys this evidence. The result of this survey shows that the support for the
magnocellular deficit theory is equivocal. In the case of spatial contrast
sensitivity there clearly are results that are consistent with the magnocellular
deficit theory; however, these results are outnumbered both by studies that have
found no loss of sensitivity and by studies that have found contrast sensitivity
reductions that are inconsistent with a magnocellular deficit. Many of the
studies of temporal contrast sensitivity are also difficult to reconcile with a
magnocellular deficit. The evidence from studies of contrast sensitivity is
therefore highly conflicting with regard to the magnocellular system deficit
theory of dyslexia.
PMID- 10768047
TI - Low b-wave amplitudes in a strain of rabbits with a pigment epithelium defect.
AB - When preparing isolated rabbit retinas we found in some animals fundi which were
not uniformly dark but had abnormal areas of red coloration. The in situ
electroretinograms (ERG) of 82 rabbits recorded after 1 h of dark adaptation were
checked for abnormalities indicative of a degenerative disorder. The ERGs of
eight rabbits with small dark adapted b-waves (< or = 250 microV) were re
recorded and their b-waves found to decline with time. The greatest reduction, in
three rabbits, was > or = 150 microV over 2.5 years. After 1 year, however, the
light adapted b-waves were similar to those of rabbits with normal dark adapted b
waves. The majority of the progeny of these rabbits also had small b-waves, which
became still smaller in 2 years. Ultrastructural studies of two rabbit retinas of
the first generation showed pathological changes of the pigment epithelium
(Wrigstad, Hanitzsch & Nilsson, Ultrastructural and electrophysiological studies
of the retina and the retinal pigment epithelium in rabbits with low b-wave
amplitudes, in preparation). Evidently there is an inheritable defect in the
pigment epithelium which first impairs the rod pathway.
PMID- 10768049
TI - [The basics of catecholamine therapy. 2. A guide to clinical use].
AB - Myocardial function is determined by preload, afterload, contractility and heart
rate. Pathologic changes of these variables may result in decrease of blood
pressure, acute heart failure or cardiogenic shock. Hyperdynamic septic shock is
associated with systemic hypotension despite increased cardiac output. Mediators
of sepsis induce both myocardial depression and pulmonary arterial hypertension.
Moreover, sepsis is characterized by microcirculatory disturbances and dysbalance
in regional oxygen delivery and consumption. Severe systemic hypotension is a
symptom often requiring catecholamine therapy to restore systemic circulation and
to avoid organ damage. As the use of catecholamines is not a causal therapy
administration should be limited to an initial measure until correction of the
underlying abnormalities can be achieved. Different etiologies of shock as well
as diseases requiring specific interventions as pulmonary embolectomy, systemic
lysis or coronary angioplasty have to be considered. First line intervention
consists of optimizing preload by fluid resuscitation as appropriate and use of
dopamine (4-12 micrograms/kg.min) as primary catecholamine to increase
contractility and blood pressure. In acute left heart failure inotropic support
with dobutamine (4-12 micrograms/kg.min) or epinephrine (0.05-1 microgram/kg.min)
may be necessary, frequently combined with a vasodilator (sodium nitroprusside
0.2-5 micrograms/kg.min or nitroglycerine 0.5-2.5 micrograms/kg.min) or
phosphodiesterase-III-inhibitor (milrinone 0.3-0.8 microgram/kg.min). In right
heart failure norepinephrine is preferred to increase coronary perfusion
pressure. Hyperdynamic septic shock with decreased vascular resistance is treated
with norepinephrine to restore mean arterial pressure and to improve right
ventricular dysfunction induced by pulmonary hypertension.
PMID- 10768048
TI - [Catecholamines: its your choice].
PMID- 10768050
TI - [Clinical significance and effects of foreign body embolism during the use of
central venous catheters].
AB - An embolism caused by catheters or puncture devices is generally a rare
complication during the use of central venous catheters. Possible reasons are
either mistakes on the part of the user (e.g. shearing off or tearing of
catheters or Seldinger wires) or other accidental causes (e.g. faulty products,
material fatigue). As patients are at risk of suffering serious injuries
following an embolism, foreign bodies should be removed from the patient's cardio
circulatory system as quickly and as completely as possible. Two-dimensional echo
cardiography has proved to be very helpful for diagnostics, while interventional
radiology is most effective for the removal of intravascular foreign bodies.
PMID- 10768051
TI - The influence of airway pressure changes on intracranial pressure (ICP) and the
blood flow velocity in the middle cerebral artery (VMCA).
AB - OBJECTIVE: Due to the exponential shape of the intracranial volume-pressure
relation, simple measurement of epidural, parenchymal or intraventricular
intracranial pressure (ICP) in traumatic brain injury (TBI) often fails to early
recognize patients with a fulminant development of intracranial hypertension even
during recently available methods of tissue PO2 and microdialysis measurements.
One approach to this problem could be repetitive intracranial volume provocations
to evaluate a trend of the intracranial elastance. Several previously published
methods use invasive volume challenge through access to the cerebrospinal fluid
(CSF). This pilot study describes changes in intracranial pressure due to
variations of airway pressure with BIPAP ventilation maneuvers. PATIENTS AND
METHODS: Ten patients with severe TBI were enrolled and completed the study. The
inclusion was based on radiologic signs due to TBI in the first CT-scan and the
clinical indication for insertion of an ICP monitoring device. Patients with
elevated ICP above 20 mm Hg were excluded. The epidural ICP response together
with haemodynamic parameters in relation to defined airway pressure changes
(delta PAW) was detected. The influence of the duration of delta PAW was
evaluated additionally. Data of central venous pressure (CVP), ICP, mean arterial
pressure (MAP), cerebral perfusion pressure (CPP), airway pressure (PAW) and
blood flow velocity of the middle cerebral artery (VMCA) were analyzed on the
basis of differences between the maximum (inspiration) and minimum PAW values
(expiration). RESULTS: Elevations of PAW in the range of 20 to 35 cm H2O resulted
in changes of the ICPmean from 4.1 to 6.0 mm Hg (r = 0.9, p < 0.05). A
correlation was estimated for the changes of systolic arterial pressure (Part)
and CPPmean due to PAW variations which ranged between 4.5 and 11.6 mm Hg (r =
0.99, p < 0.05). Concerning the transcranial doppler measurements the data of
changes of the blood flow velocity of the middle cerebral artery (VMCA) revealed
a positive correlation to PAW with a r = 0.99, p < 0.05. CONCLUSIONS: Elevation
of the venous outflow resistance and a transient increase in cardiac output have
to be considered as mechanisms for transduction of transthoracic pressure changes
to intracranial pressure variations. We conclude, that trends of changes in
elastance can be derived from intermittent airway pressure variations. This can
be useful in easy and on line dynamic monitoring of ICP in traumatic brain
injury.
PMID- 10768052
TI - [Malignant hyperthermia].
PMID- 10768053
TI - [Risk and perioperative procedures in a patient under long-term lithium therapy].
PMID- 10768055
TI - [Thoracic epidural anesthesia an patients with Sturge-Weber-Krabbe disease].
PMID- 10768054
TI - [Snoring and postoperative pulmonary edema].
AB - After uneventful ENT surgery, two male patients developed acute upper airway
obstruction following extubation which progressed into negative pressure
pulmonary edema (NPPE). One of these two patients suffered from known obstructive
sleep apnoea syndrome, the other admitted to heavy snoring only after the
incident. The pathophysiology of NPPE and the anaesthesiological implications of
a patient's history of snoring are discussed.
PMID- 10768056
TI - [Combined preparations of semisynthetic penicillins and beta-lactamase
inhibitors: a method for overcoming resistance and the broadening of therapeutic
possibilities].
PMID- 10768057
TI - [A trial of using augmentin (amoxicillin/clavulanate) in surgical practice].
AB - The experience with the use of augmentin (amoxycillin/clavulane) in abdominal
surgery for prophylaxis of postoperative purulent complications was analyzed. The
drug was used in 44 patients after relatively pure operations, 37 of them having
various risk factors. In 2 patients (4.5 per cent) of that group postoperative
pyoinflammatory complications were recorded. For comparison the results of the
prophylactic use of cefoperazone, cefamandole or ceftazidime in the group of 78
patients after relatively pure operations on the abdominal cavity organs were
analyzed. Postoperative complications in the latter group amounted to 7.4 per
cent (4 patients). The results of the treatment of patients in two groups after
contaminated operations were also compared. The patients of one group (41
patients) were treated prophylactically with augmentin in a dose of 1200 mg
intraoperatively followed by the drug use in a dose of 600 mg thrice daily for 1
to 2 days after the operation. Postoperative pyoinflammatory complications were
recorded in 4 patients of that group (9.7 per cent). 78 patients of the other
group were treated prophylactically with ceftazidime or cefoperazone in a dose of
2 g and metronidazole intraoperatively or cefoperazone in a dose of 2 g twice
daily and metronidazole in a dose of 500 mg twice daily for 1 to 2 days after the
operation. Postoperative infectious complications were recorded in 8 patients of
that group (10 per cent). In the group of patients with acute cholecystitis
treated with ciprofloxacin in a dose of 400 mg in combination, with metronidazole
before the operation and for 1 to 2 days after the operation postoperative
complications were recorded in 4 patients (17 per cent).
PMID- 10768058
TI - [The augmentin (amoxicillin/clavulanate) prophylaxis of postoperative infectious
complications in patients with acute surgical diseases of the abdominal cavity
organs].
AB - Augmentin was used prophylactically in 25 patients with an account of the
infectious complication risk according to 4 regimens: ultrashort-term (1.2 g
intravenously with initial narcosis), short-term (1.2 g intravenously with
initial narcosis followed by intravenous administration in a dose of 600 mg in 8
and 16 hours), middle-term (1.2 g intravenously with initial narcosis followed by
intravenous administration in a dose of 600 mg every 8 hours for 2 days) and long
term (1.2 g intravenously with initial narcosis followed by intravenous
administration in a dose of 600 mg every 8 hours for 3 days). One complication
episode as wound suppuration was recorded. The routine approach to the use of
antibiotics in emergency abdominal surgery, when antibiotics are administered
every day for several days after the operation, should be revised.
PMID- 10768059
TI - [The clinical efficacy of augmentin (amoxicillin/clavulanate) in treating
inflammatory diseases of the urogenital organs].
AB - Augmentin (amoxycillin/clavulanate) was used in the treatment of 88 patients with
mild and moderate infections of the urogenital organs. The drug was administered
in a single dose of 375 mg thrice daily for 6 to 12 days. The renal function in
62 patients (70.5 per cent) was normal and in 26 patients (29.5 per cent) the
chronic renal insufficiency latent stage was stated (the decrease of the
glomerular filtration up to 55-70 ml/min). When augmentin was used before
lithotripsy in 35 patients for 6 days, all the laboratory and clinical indices
came to normal in 30 patients (85.7 per cent) and only in 4 patients (11 per
cent) leukocyturia and in 1 patient bacteriuria persisted. When augmentin was
used in 26 patients before adenomectomy or after transurethral resection for 7 to
9 days, all the indices came to normal in 13 patients (50 per cent) and in the
other 13 patients leukocyturia persisted, while no bacteriuria was recorded. When
augmentin was used in the treatment of 19 patients with pyelonephritis
exacerbation during the postoperative period for 7 to 12 days, all the clinical
and laboratory indices came to normal in 13 patients (68.4 per cent),
leukocyturia persisted in 6 patients and bacteriuria persisted in 2 patients.
When augmentin was used in the treatment of 8 patients with acute
orchiepididymitis for 7 to 10 days, the clinical effect was stated in all the
patients. As a rule, the drug was well tolerated by the patients.
PMID- 10768060
TI - [The use of augmentin (amoxicillin/clavulanate) in the postoperative period in
patients with infectious-inflammatory diseases of the ENT organs].
AB - Augmentin (SmithKline Beecham) was used in the treatment of 24 patients after
operations on the otorhinolaryngologic organs. The drug was administered orally,
intravenously or applied locally. After a radical operation on the maxillary
sinus the use of augmentin resulted in a marked decrease of the wound secretion
and soft tissue edema on the 6th-7th days. After tonsillectomy cleaning of the
tonsil niche from the fibrin patches and the epithelialization started on the 4th
5th days. After operations on the temporal bone cleaning of the postoperative
cavity and beginning of the epithelialization were observed on the 9th-10th days.
On the whole, the use of augmentin accelerated the cure which was recorded 3-4
days earlier.
PMID- 10768061
TI - [The structure and antibiotic sensitivity of the causative agents of community
acquired infectious diseases of bacterial origin in children].
AB - Four hundred and forty pediatric patients at the age of 7 days to 15 years with
various infections admitted to the Hospital within a month were examined. The
biological material was inoculated to blood agar on the first days of the patient
admittance to the Hospital and after the growth the organisms were isolated and
identified. Antibiotic susceptibility of the isolates was assayed with the disk
diffusion method. 479 strains in all were tested. The most frequent cases
requiring hospitalization and antibiotic therapy were those of respiratory tract
infections (54.09 per cent), urinary tract infections (26.36 per cent), cutaneous
and subcutaneous fat diseases, gastrointestinal diseases and others (about 25 per
cent of the cases in all). The main pathogens were Streptococcus viridans,
S.aureus and S.epidermidis, as well as Enterobacteriaceae (chiefly E.coli) whose
frequencies were practically equal (in 25-35 per cent of the cases). The
Pneumococcus isolates amounted to 6.3 per cent. Nonfermenting bacteria
(Pseudomonas aeruginosa and Acinetobacter) and some representatives of
Enterobacteriaceae (Citrobacter, Serratia, Morganella) were isolated from 7 per
cent of the patients. The frequency of Klebsiella and Enterobacter was about 11
per cent. The main pathogens were tested for their susceptibility to
amoxycillin/clavulanic acid, ampicillin, oxacillin and gentamicin. The least
active antibiotic was ampicillin. 88.8 per cent of the E.coli isolates and 100
per cent of the Klebsiella, P.mirabilis, Morganella, Citrobacter, Enterobacter
and Serratia isolates were resistant to it. 53.2 per cent of the Streptococcus
isolates including 64.5 per cent of the Pneumococcus isolates were as well
resistant to ampicillin. 59.5 per cent of the Streptococcus isolates (mainly
S.viridans and Enterococcus) was susceptible to oxacillin, 22.2 per cent of them
being moderately susceptible. 62.5 per cent of the Pneumococcus isolates and 78.1
per cent of the Staphylococcus isolates were also susceptible to oxacillin. The
highest susceptibility of the isolates was that to amoxycillin/clavulanic acid,
i.e. 90.1 per cent of the strains, 79.9 per cent of them being highly
susceptible. All the isolates of Citrobacter, Serratia and Morganella and some
isolates of P.aeruginosa, Acinetobacter, Enterobacter, Klebsiella and E.coli were
resistant to amoxycillin/clavulanic acid. As for the latter 5 organisms their
susceptibility to amoxycillin/clavulanic acid was comparable with that to
gentamicin. The susceptibility of the Streptococcus and Staphylococcus isolates
to amoxycillin/clavulanic acid was significantly much higher than that to
oxacillin, gentamicin and ampicillin: 93 per cent of the Streptococcus isolates
(62.7 per cent of the Pneumococcus isolates) and 90.7 per cent of the
Staphylococcus isolates.
PMID- 10768062
TI - [Microbiological monitoring for the causative agents of nosocomial infections
(exemplified by resuscitation and intensive therapy units)].
AB - More than 900 isolates from at least 1500 patients were tested within 1996-1998.
Gram-negative organisms were the main pathogens isolated from patients with
different forms of nosocomial complications such as late pneumonia, associated
with artificial ventilation of the lungs, and various secondary wound or urinary
tract infections. The prevalence of Pseudomonas aeruginosa was stated.
Antibioticograms showed that the most active drugs were imipenem (more than 90
per cent of the susceptible isolates) and ticarcillin/clavulanate (48-58 per cent
of the susceptible isolates). The activity of ticarcillin/clavulanate (Timentin)
was practically the same as that of imipenem against 21 strains of P.aeruginosa
isolated from the blood and cerebrospinal fluid of 21 patients with sepsis and 3
patients with secondary purulent meningitis.
PMID- 10768063
TI - [A trial of using timentin (ticarcillin/clavulanate) in treating abdominal
surgical infection].
AB - Efficacy of timentin was studied in the treatment of 19 patients with peritonitis
of various etiology and clinical and laboratory signs of systemic inflammatory
reaction characteristic of abdominal sepsis. The clinical and bacteriological
effects were recorded in 84.2 and 87.5 per cent of the cases respectively. The
drug was administered intravenously dropwise for 30 minutes in a dose of 3.1 g
every 4 hours. The treatment course was 4-11 days. The treatment failed in 3
patients. One of them had general peritonitis of gynecological etiology. In the
other no significant regression of abdominal sepsis was observed, Pseudomonas
aeruginosa strains were isolated from the abdominal cavity, the antibiotic was
changed, still incurable polyorganic insufficiency developed and the patient
died. The third patient had perforation of the large intestine due to tumor. No
adverse reactions to the use of timentin in any of the cases was observed.
PMID- 10768064
TI - [The clinical efficacy of ticarcillin/clavulanate in severe pneumonia].
AB - Efficacy of ticarcillin/clavulanate was studied in the treatment of 11 patients
with severe community- and hospital-acquired pneumonia in an open controlled
trial. The drug was administered in a dose of 3.1 g every 4 or 6 hours depending
on the infection severity. When pneumonia was due to Pseudomonas aeruginosa,
amikacin was additionally used. The positive clinical effect of
ticarcillin/clavulanate was stated in 73 per cent of the patients. The pathogen
eradication was stated in all the patients. However, in 2 cases superinfection
due to P.aeruginosa developed. Mild adverse effects were observed in 2 cases. It
is concluded that ticarcillin/clavulanate is highly efficient in the treatment of
patients with severe or complicated pneumonia. In cases with ventilator
associated pneumonia it is advisable to use ticarcillin/clavulanate in
combination with an aminoglycoside.
PMID- 10768065
TI - [A trial of the use of mupirocin in the nasal carriage of Staphylococcus aureus
in medical personnel].
AB - Many hospital-acquired purulent diseases and wound infections are due to
multiresistant hospital strains of Staphylococcus aureus. The role of S. aureus
nasal carriage in development of wound infections due to autoinfection is
confirmed. Not only inpatients but also hospital staff can be highly colonized
with coagulase positive staphylococci. The S. aureus persistence in hospital
personnel results in distribution of the microorganisms in the environment.
Therefore, detection of S. aureus carriers without signs of the infection among
the hospital personnel and eradication of the pathogen make it possible to
control outbreaks of S. aureus infection in hospitals. Clinical efficacy of nasal
ointment of mupirocin in the treatment of S. aureus carriers among the intensive
care personnel of the N. N. Blokhin Cancer Research Center was evaluated. S.
aureus nasal carriage was diagnosed in 17 (26 per cent) out of 65 persons. All
the isolates were susceptible to oxacillin. 5-7 days after discontinuation of the
mupirocin nasal ointment use eradication of S. aureus was stated in 100 per cent
of the cases. The effect was still observed in 94 per cent of the cases in 1
month, in 76 per cent of the cases in 5-6 months and in 60 per cent of the cases
in 8-9 months. It is believed that mupirocin nasal ointment (Bactroban) is
convenient to use, low toxic and highly active in the treatment of persons with
S. aureus nasal carriage.
PMID- 10768066
TI - The AIDS epidemic. Past and future.
AB - As we near the end of the second decade of AIDS, this global epidemic is
characterized by a widening gap between wealthier nations in North America and
Europe and the poorer nations of the world. In developed countries the epidemic
has stabilized and there are dramatic decreases in morbidity and mortality
resulting from the use of intensive but expensive therapies. This contrasts with
the experience of poorer nations, where the epidemic's spread is often unabated
and has devastating effects on communities, families, and individuals. A decrease
in transmission from mothers to their children is a possibility that still needs
to be realized in developing countries, although the potential now exists.
Adolescents and young adults are most at risk for contracting the infection, and,
recognizing that an effective vaccine is unlikely to be a reality for many years,
there is great need for culturally appropriate and innovative means of affecting
behavior to decrease the risk of transmission. Although the extent of children's
suffering through the loss of their parents has already been felt worldwide, the
extreme magnitude of this is still to come, particularly in those countries and
communities that have the least resources. The epidemic is a global problem, and
addressing the disease and its consequences on children and youth worldwide
requires an international response. The potential for complacency in developed
countries needs to be replaced by a determination to bridge existing gaps. This
requires the focus and support of governments, international agencies such as
UNAIDS, nongovernmental organizations, corporations (particularly those that
produce antiretroviral medications and artificial milk formulas), researchers
from many disciplines, and other individuals.
PMID- 10768067
TI - HIV infection in children. A new hope.
AB - A new understanding of the pathophysiology of HIV infection and recent advances
in the development of antiretroviral medications have led to dramatic changes in
the ways that children and adolescents are affected by their disease and has
provided new hope that did not exist in earlier years of the epidemic. These
advances and the changes they have produced, however, have posed new difficulties
and challenges to ensuring that each infected child and adolescent benefits
maximally. Although there will likely continue to be pauses in the pace of
progress, the future holds real promise, and the third decade of the AIDS
epidemic should see new developments that will continue to improve the lives of
those infected with the virus.
PMID- 10768068
TI - Children, adolescents, and families infected and affected by HIV and AIDS.
AB - An estimated 80,000 to 125,000 children in the United States will be orphaned by
the year 2000 as a result of an HIV related illness. Studies have found that the
support of a surviving parent is positively associated with the grieving child's
ability to cope with the loss of the other parent. HIV/AIDS affected children
often do not have another parent available to them. This article will review some
of the issues, struggles, and reactions of children and adolescents who have been
affected and infected by HIV. The material is illustrated by two cases, one of a
child and an adolescent affected by HIV and the second a child and an adolescent
infected and affected by HIV/AIDS.
PMID- 10768069
TI - Home-based treatment for children and families affected by HIV and AIDS. Dealing
with stigma, secrecy, disclosure, and loss.
AB - The compelling needs of HIV-affected children and families sometimes appear to
represent human struggles under the magnifying glass. The multiple assaults on
the healthy psychologic development of children through disruptions in
caregiving, loss, and abandonment require interventions that are mindful of their
mental health needs and longer-term developmental trajectories. An ongoing
relationship with a clinical team who can understand and respond to the
vicissitudes of the illness and provide calibrated psychotherapeutic and case
management services can aid both children and parents in the painful tasks that
AIDS presents. Whereas clinically informed case management services can offer
respectful and thoughtful concrete help, psychotherapy can offer the opportunity
for children to pull together the often fragmented narratives of their family
lives and integrate object loss to be free to continue on a normative
developmental path. Comprehensive, wraparound home-based services of the type
described in this article represent a mostly new tradition in psychiatry, but one
that ensures that mental health services are provided to the most vulnerable
children and families. For those affected by HIV or AIDS, home-based services can
be the key to healthcare and treatment compliance. In addition, when services are
well integrated within a community context, such that regular communication with
other healthcare providers (AIDS clinics, visiting nurse services, and AIDS care
agencies) is ongoing, what is provided constitutes continuity of care in the
truest sense.
PMID- 10768070
TI - An effective strategy for intervention with children and adolescents affected by
HIV and AIDS.
AB - With John's deep sorrow and grief and inability to express it adaptively, the
authors thought again about the children's therapeutic needs in group. What is
planned and expected from group often turns itself over to what children expect
and need. The program's wish for the children to verbally work out their
conflicts was idealistic and unrealistic. Instead, the authors needed to use
clinical skills creatively to re-establish safety for all the children and to
help John cope with his sorrow and anger. It was obvious to the leaders that his
anger regarding his mother's illness and death were escalated by the leader's
pregnancy. Support needed to be provided to John and the group as a whole by
understanding this psychologic struggle, and by providing a safe environment for
him to establish a language to express his rage and develop more adaptive coping
mechanisms. The example of John exemplifies many of the points made in this
article. Although John's experiences only speak of one member's experience within
a group, the power of the group is certain to be healing, not only for the
individual but also for all of its members. While John's healing is made clear in
the example, the other children also gained from these group experiences. They
all had their anger and resentment of loss of a leader (and metaphorically of
their mothers) expressed for them with a growing sense of safety in the
demonstration of pain and anger. They witnessed concretely that their rage and
sadness could be articulated and could not cause harm to others. Most
interestingly, they all began to talk about their mothers and their early
childhoods calmly, with a profound sense of connection with each other, even with
silliness and age-appropriate fun. They began to use each other as sources of
comfort in their sharing of their stories. The letters to and from John after his
departure from group allowed the group members to continue their powerful bond.
The current members remember John fondly. His angry outbursts and provocative
behavior have been integrated into the story of the group. As children need to
express rage they at times speak of John, using his ability to express this
feeling as an example to the safety of the group. Again this type of work is not
only powerful and intense, but needs to be unhurried. Children such as John and
his comembers need time to experience their grief and heal their pain. Thus,
groups are an effective strategy for work with HIV-affected children in helping
them deal with the losses within their families and continue to grow into healthy
adults.
PMID- 10768071
TI - Providing clinical opportunities for youths affected by HIV.
AB - Individual counseling, as invaluable as it is for HIV-affected youth, is just one
forum in which young people can receive clinical assistance. The youth-centered
programs noted previously and others carried out in various agencies around the
country offer HIV-affected youth an opportunity to receive clinical experiences
while focusing on their strengths and interests. A nonthreatening atmosphere in
which many children are invited to participate is essential for helping young
people feel comfortable and connected to the agency. When children develop
friendships through the agency, they can begin to feel less alone in their
situation and more willing to reach out to others--clinicians and peers--for
help. An increased trust in the agency can help HIV-affected young people
maintain an ongoing connection to services and open the door to traditional
counseling. As children become more engaged in the agency and begin to develop a
sense of ownership, they may want to take on more responsibility. Leadership
programs that focus on young people's skills and talents can help establish the
agency as a place that is safe for youths on their own terms. That may involve
activities such as older children serving as mentors for younger ones, performing
community projects in their neighborhoods, doing outreach to help connect more
people to the programs, or designing and running their own conferences for youth.
Collaboration with other agencies for special projects can help link children to
additional programs and to other youth, thus decreasing their isolation.
Childhood and adolescence is a time of rapid changes accompanied by emotional
fluctuations. Young people feel emotions intensely, but often lack the cognitive
ability necessary to articulate them. When a young person is coping with the
illness or death of a parent from AIDS in addition to all the pressures and
changes in life, the experience of growing up is even more difficult and
complicated. The emotional flux, confusion, and life transitions can lead to
impulsive and self-destructive behavior. But childhood and adolescence is also a
time of heightened energy, creativity, resilience, and hope. Programs for HIV
affected youth need to balance the attention paid to the challenges they face and
the strengths they possess. When allowed to grow and shine, affected young people
may begin to express some of their emotional needs. Caring workers can then help
them make sense of their experiences and mature into the successful adults they
all have the potential to become.
PMID- 10768072
TI - Relative caregiving. An effective option for permanency.
AB - Children affected by HIV/AIDS are at high risk for multiple placements as the
adults in their lives are often too incapacitated to provide stable, consistent
care for them. This article provides a historical overview of child caregiving,
describes the complex needs of HIV/AIDS affected children and their relative
caregivers, usually grandparents, and suggests that with necessary supports,
placement with relatives can be a thoughtful, realistic option for permanency.
PMID- 10768073
TI - Teaching young children about HIV and AIDS.
AB - AIDS education initiatives need to begin early, within the elementary grades, to
be effective. We should no longer underestimate the capacity of young children to
understand and benefit from this instruction. In addition, we should not
overestimate the impact of brief interventions, and should plan for continued
AIDS prevention instruction throughout the school years, involving sequential,
developmentally appropriate curricula that respond to the preadolescent's and
adolescent's changing cognitive capabilities, social skills, and expanding
exposure to sexual experiences. We should require that new approaches and
methodologies for AIDS prevention education be developed and evaluated rigorously
for efficacy with the same fervor required for the development and evaluation of
new drugs to combat this illness on the biologic front. New modalities and
approaches should be integrated with those that have already been shown to be
effective, creating multimodal and comprehensive educational initiatives
comparable to the multidrug treatment regimens. We should be skeptical of those
who are satisfied with the implementation of one interesting and simplistic
slogan for health promotion efforts for children (e.g., "Just say no"). Even if
such efforts were effective in the short term, sole reliance on this approach is
likely to result in the development of resistance. As the field of AIDS
prevention looks for novel approaches and theoretic constructs, it should borrow
ideas from other fields of study and foster interdisciplinary collaborations with
professionals from complementary fields. In this manner, educational
interventions can move beyond the individual context to begin to address the
social influences on sexual behaviors. Sexual behavior is interpersonal and
occurs in a social context. Programs must therefore address peer and social
pressures to engage in sexual activity. Although attempts are being made to
address the social network of children through such efforts as peer education, we
cannot ignore the broader social context (e.g., poverty) within which these
behaviors occur. For example, efforts to promote increased condom usage will be
ineffective until we learn more about why significant numbers of adolescents
practice unprotected sex. We are unlikely to affect behavioral change unless we
understand fully the motivation for such behavior. We must also recognize that
children are more than what they do and study outcomes other than behavior. There
is a need for further research on the development of attitudes, fears, stigma,
and coping in children, as well as means of promoting the development of healthy
sexual relationships.
PMID- 10768074
TI - School-based HIV prevention. A promising model.
AB - This article explores connections between the mental health and educational
systems by profiling the Redefining Actions and Decisions (RAD) curriculum, a
theory-based, developmentally informed HIV education program for middle and high
schools. RAD was developed by Deborah R. Schoeberlein and evaluated by Dr. John
Brett. RAD's public health approach, which has gained considerable attention at
the national level, argues that HIV prevention, either through risk-abstinence or
risk-reduction techniques, is an appropriate strategy for safeguarding community
health.
PMID- 10768075
TI - Guardianship as a therapeutic option.
AB - The HIV/AIDS epidemic has posed a significant challenge to our legal system,
demanding that it evolve to provide more flexible ways for parents to transfer
guardianship of their children to other caring adults in a timely and minimally
traumatic manner. Although a number of states have responded to the challenge,
adopting new guardianship options such as delegations of parental authority for
limited purposes, standby guardianship, co-guardianships, and subsidized
guardianships, the majority of states still do not provide this continuum of
options. Moreover, few states have established multidisciplinary programs that
help parents take full advantage of the new guardianship options. Few have even
begun to address the complex needs of the "second" families. Few have developed
plans to meet the needs of the older AIDS-affected youth. How well we ensure the
quality and continuity of parental care for children whose parents are living
with HIV and AIDS, or who later die of it, is one of the tests of our generation.
If we fail to meet this challenge, we are knowingly placing thousands of children
and youth at enormous, predictable, and potentially fatal risk.
PMID- 10768076
TI - National and state policies influencing the care of children affected by AIDS.
AB - The portrait of HIV-affected children and youth that emerges from this policy
overview is still one of children obscured from view by the shadow of their
parents' and siblings' illness and policies that only address the needs of HIV
infected individuals. In addition, the secrecy and stigma that still surround HIV
and AIDS make it difficult for HIV-affected children and youth to benefit as
fully as they might from policies and programs that provide more generic types of
care and assistance. Our failure as a nation to better illuminate the plight of
HIV-affected children and youth can only leave us with a generation of children
who are at greater risk of psychiatric illness, involvement with the criminal
justice system, substance abuse, and contracting HIV. To avoid these
consequences, both public and private sectors must place the spotlight on the
development of new policies and programs designed to specifically meet their
needs. Because the solutions defy traditional disciplinary and administrative
boundaries, we also need to become more skilled at interagency planning and
collaboration. No one system alone can be responsive to the many social, mental
health, legal, and support needs of these children and their caretakers. More
specifically, recommendations for improved systems of care to HIV-affected
children, youth, and their families are as follows: To promote and fund cross
disciplinary initiatives among agencies that administer child welfare services,
income supports, AIDS care, and children's mental health services at the
national, state, and local levels to specifically meet the mental health,
psychosocial, and permanency planning needs of HIV-affected children and youth.
To provide training opportunities for Ryan White Title I, II, and III case
managers on assessing the needs of HIV-affected children and youth, developmental
theories and concepts, principles of family-centered care, and child welfare
issues. To increase funding of the Ryan White CARE Act to permit a more family
centered approach to care across Titles. To establish clearer guidelines for
establishing a proportional basis for funding services to infants, children, and
women under the Ryan White CARE Act. To support legislative, educational, and
advocacy efforts to make managed care and welfare reform more responsive to the
needs of HIV-affected children, youth, and their families. To encourage states to
provide additional funding for mental health services specifically targeted to
HIV-affected children and youth that are sufficiently flexible and of a long
enough duration to adequately meet their needs. Surely, as we move into a new
millennium with the capacity to map the human genome and clearly view distant
galaxies, we should be able to marshal the will and resources necessary to
formulate a sufficiently focused effort to respond compassionately and
effectively to the needs of a generation of AIDS-affected children and youth.
PMID- 10768077
TI - Children affected by HIV. Clinical experience and research findings.
AB - This article describes the plight of HIV affected children, and the work of
mental health professionals with HIV affected children and their families, and
presents pertinent research findings on the topics. The concepts of prevention,
resilience, and family and child development are applied to the organizing of
mental health care for HIV affected children.
PMID- 10768078
TI - Severe sepsis and septic shock. Definitions, epidemiology, and clinical
manifestations.
AB - Severe sepsis and septic shock are frequently encountered conditions in today's
hospital environment. The incidence appears to be increasing despite our growing
armamentarium of antibiotics and our enhanced knowledge of the pathophysiologic
processes at play. The clinical presentation may take a variety of forms,
especially in patients at the extremes of age and in the immunocompromised
population. A high index of suspicion and prompt institution of appropriate
antimicrobial treatment is mandatory for a successful outcome. It is hoped that
adoption of uniform definitions will aid in research and in effective
communication concerning sepsis and its adverse sequelae.
PMID- 10768080
TI - Antibiotic selection for patients with septic shock.
AB - Early recognition of the sepsis syndrome, prompt administration of broad-spectrum
antibiotics, surgical intervention when indicated, and aggressive supportive care
in intensive care units remain the therapeutic strategies for patients with
sepsis. Antibiotic selection is based on many factors including the most probable
source of infection, the most likely pathogens, and knowledge of antibiotic
susceptibility patterns for community- and hospital-acquired infections.
Unfortunately, with this approach, mortality remains unacceptably high. Adjuvant
therapies such as antiendotoxin antibodies, cytokine antagonists, and anti
inflammatory agents aimed at blunting the host immune response to bacterial
infection have provided little clinical benefit to date. As our understanding of
the pathophysiology of sepsis progresses, perhaps newer modalities will improve
clinical outcome. At this time, preventive strategies, including optimal vaccine
use, effective infection control practices, judicious use and care of
intravascular lines and indwelling urinary catheters, and appropriate use of anti
infective agents to prevent microbial resistance should be used to decrease the
incidence of infection and subsequent sepsis.
PMID- 10768079
TI - Immunologic response to infection and its role in septic shock.
AB - In summary, the invasion of bacteria across mucosal surfaces is met with a
vigorous host response that includes complement, antibody formation (thymus
independent and eventually thymus-dependent), phagocytosis, production of
antibacterial peptides and proteins, the production of cytokines that result in
activation of phagocytes and endothelial cells to attract more phagocytes, and
the formation of fibrin to limit the spread of infection. The best summary of
immune response to infection was written by Lewis Thomas in 1974.
PMID- 10768082
TI - Myocardial dysfunction in septic shock.
AB - Over the last decade, it has become clear that myocardial depression, like
vascular dysfunction, is typical of human septic shock. Human septic myocardial
depression is characterized by reversible biventricular dilatation, decreased
ejection fraction, and decreased response to fluid resuscitation and
catecholamine stimulation (in the presence of overall hyperdynamic circulation).
A circulating myocardial depressant substance, not myocardial hypoperfusion, is
responsible for this phenomenon. This substance has been shown to represent low
concentrations of TNF-alpha and IL-1 beta acting in synergy on the myocardium
through mechanisms that include NO and cGMP generation. Despite major advances in
our understanding of the hemodynamics and pathogenesis of cardiac dysfunction in
sepsis, successful attempts to modulate these mechanisms to improve clinical
outcomes in human trials have not been demonstrated to date. For the moment, the
therapeutic approach to the patient with cardiac dysfunction in distributive or
septic shock must be primarily aimed at reestablishing adequate organ perfusion
and oxygen delivery by vigorous fluid resuscitation and vasopressor or inotropic
support. In the long term, however, only continued research regarding the
cellular mechanisms of organ dysfunction, including septic myocardial depression,
will lead to successful therapeutic strategies. These strategies will likely
involve direct manipulation of intracellular signaling processes that lead to
organ dysfunction as manifested by septic myocardial dysfunction and septic
shock.
PMID- 10768081
TI - Pharmacologic issues in the management of septic shock.
AB - Despite our increased understanding of the biochemistry and physiology of sepsis,
the treatment of septic shock remains a challenge. Initial management of septic
shock entails urgent and emergent stabilization of the patient followed by broad
spectrum, empiric antibiotic therapy. After volume resuscitation, vasopressors or
inotropic therapy or both may be necessary to restore perfusion. Adjunctive
therapies and monitoring strategies may be helpful in preventing complications in
the intensive care setting. Additional research and clinical trials are needed to
identify supportive interventions that may affect the outcome of the septic
patient.
PMID- 10768083
TI - Acute lung injury and acute respiratory distress syndrome in sepsis and septic
shock.
AB - Sepsis remains the leading cause of ARDS, and ARDS is still an often fatal
condition. With our expanding knowledge of the pathobiologic mechanisms and the
relationship between these two entities, early recognition, treatment, and
prevention of sepsis may prevent or hasten recovery from ARDS. Understanding the
biologic markers involved in the complex inflammatory response of sepsis and
acute lung injury offers the possibility of future investigations to target
treatment based on these mediators.
PMID- 10768084
TI - Metabolic derangements in sepsis and septic shock.
AB - This article examines the spectrum of metabolic alterations in sepsis and septic
shock. The clinical manifestations, neuroendocrine control, and bioenergetics of
the "ebb" and "flow" phases of sepsis are reviewed. Characteristic alterations in
carbohydrate, fat, and protein metabolism induced by sepsis are outlined.
Finally, the implications of these metabolic alterations for the nutritional
support of patients with sepsis are discussed.
PMID- 10768085
TI - Pathogenesis and management of multiple organ dysfunction or failure in severe
sepsis and septic shock.
AB - Organ system dysfunction is a common adverse sequelae of severe sepsis and septic
shock and has been reported to be the most common cause of death in the
noncoronary intensive care unit. The pathophysiology of the development of
multiple organ system dysfunction is likely multifactoral and may take several
different pathways. The frequency of specific organ system involvement is
dependent on the definition used to describe the organ dysfunction. The presence
of organ dysfunction has great clinical impact on the underlying disease process,
can prolong the hospital stay, increase the cost of care, and has been associated
with an increase in mortality rate. At present, there is no recognized specific
treatment for established organ failure, this primary attention has been directed
toward prevention.
PMID- 10768086
TI - Scoring systems for assessing organ dysfunction and survival.
AB - Sepsis is an ongoing disease process carrying a high risk of organ failure and
death. Scoring systems to determine disease severity and risk of mortality may be
useful in patient management and clinical trial enrollment, although the role of
either type of score in the determination of admission or discharge criteria or
in decisions relating to the continuation or withholding of treatment remains
controversial. General scoring systems have been developed to quantify the
severity of illness and the risk of mortality in ICU patients. Ideally, these
should be customized before use in patients with septic shock, but in general
noncustomized models are used, and this potential limitation should be
acknowledged. Prognostic scores are remarkably reliable at predicting outcome in
groups of patients and give an indication of severity of disease on admission,
but they are unable to provide detail on how a patient is responding to treatment
or on the disease progression. Organ function scores, however, can be assessed
repeatedly and used to define a patient's progress. This approach can thus be
used to evaluate individual patient care, to identify patients for enrollment in
clinical trials or epidemiologic analyses, and to assess morbidity measures in
clinical trials of new interventions. Organ dysfunction scores are just that,
descriptors of organ dysfunction, and although high values correlate well with
mortality, prognostication is not their prime aim; organ dysfunction scores and
outcome prediction scores should rather be viewed as complementary systems in the
description of ICU populations.
PMID- 10768087
TI - Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in
type II diabetes.
AB - Insulin is stored in secretory granules in the beta-cell and is secreted by
exocytosis. This process is precisely controlled to achieve blood glucose
homeostasis. Many forms of diabetes mellitus display impaired glucose-induced
insulin secretion. This has been shown to be the primary cause of the disease in
the various forms of maturity-onset diabetes of the young (MODY) and has also
been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus.
Glucose generates ATP and other metabolic coupling factors in the beta-cell
mitochondria. By plasma membrane depolarisation ATP promotes Ca2+ influx, which
raises cytosolic Ca2+ and triggers insulin exocytosis. Through hyperpolarisation
of the mitochondrial membrane glucose also increases the Ca2+ concentration in
the mitochondrial matrix activating Ca(2+)-sensitive dehydrogenases in the
tricarboxylic acid cycle. The resulting generation of glutamate participates in
Ca(2+)-stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the
polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead
to maternally inherited diabetes mellitus characterised by impaired insulin
secretion. The impact of altered mtDNA on insulin secretion has been shown in
mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin
secretion but retain a Ca(2+)-induced insulin secretion. A cellular model of
MODY3 expressing dominant-negative hepatocyte nuclear factor-1 alpha (HNF-1
alpha) also displayed deletion of glucose-induced but not Ca(2+)-induced insulin
secretion. Reduced mitochondrial metabolism explains this secretory pattern.
Thus, genetically manipulated beta-cell lines are essential tools in the
investigation of the molecular basis of beta-cell dysfunction in diabetes and
should explain the role of other transcription factors in the disease.
PMID- 10768088
TI - Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in
patients with type II diabetes.
AB - AIMS/HYPOTHESIS: The short-term efficacy, safety and tolerability of
rosiglitazone were compared with placebo in patients with Type II (non-insulin
dependent) diabetes mellitus in a dose-ranging study. METHODS: After a 2-week
placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment
with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. RESULTS: All
rosiglitazone doses significantly reduced fasting plasma glucose compared with
baseline. All rosiglitazone treatment groups showed significantly reduced peak
postprandial glucose concentrations compared with baseline (p < 0.001) and with
placebo (p < 0.0001) and reduced postprandial glucose excursion, without an
increase in the area under the postprandial insulin concentration-time curve.
Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA1c observed
in the placebo group. C peptide and serum insulin concentrations were
significantly reduced from baseline in all rosiglitazone treatment groups. In all
rosiglitazone treatment groups, nonesterified fatty acids decreased significantly
(p < 0.0001) and triglycerides did not change. Although total LDL and HDL
cholesterol increased significantly in the rosiglitazone treatment groups, total
cholesterol/HDL ratios did not change significantly. The proportion of patients
with one or more adverse event was similar in all four treatment groups. No
patient showed evidence of hepatotoxicity. CONCLUSION/INTERPRETATION:
Rosiglitazone given twice daily significantly reduced fasting and postprandial
glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type
II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of
rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice
daily should be the maximum clinical dose.
PMID- 10768089
TI - Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins.
AB - AIMS/HYPOTHESIS: To estimate the heritability of insulin sensitivity and insulin
secretion, both of which are considered to contribute to the development of Type
II (non-insulin-dependent) diabetes mellitus. METHODS: Intraclass correlation
coefficients and heritability estimates for insulin sensitivity (euglycaemic
clamp) as well as first-phase and late-phase insulin secretion (intravenous
glucose tolerance test) were calculated in 21 monozygotic and 20 dizygotic twin
pairs of the same sex between 54 and 72 years of age. RESULTS: Intrapair
correlations for all traits were consistently higher in monozygotic than in
dizygotic pairs. Insulin secretion correlated significantly only between
monozygotic (first-phase r = 0.55; p = 0.003 and late-phase r = 0.66; p < 0.001)
twins giving heritability estimates of 0.55 and 0.58, respectively. Insulin
stimulated glucose uptake showed a more modest correlation between monozygotic
twins (r = 0.46; p = 0.015). The heritability estimate was 0.37. The heritability
estimate for waist-to-hip ratio was 0.76 in female and 0.70 in male twins.
CONCLUSION/INTERPRETATION: Genetic variability seems to contribute to the
variance of insulin sensitivity as well as of insulin secretion. In the current
study, genetic variance accounted almost 60% for the variance in glucose
stimulated insulin secretion and almost 40% for the variance in insulin
stimulated glucose uptake. Our data is also compatible with findings in monogenic
forms of diabetes in which genetic defects in insulin secretion play a
predominant part in the pathogenesis of hyperglycaemia.
PMID- 10768090
TI - Engagement of the insulin-sensitive pathway in the stimulation of glucose
transport by alpha-lipoic acid in 3T3-L1 adipocytes.
AB - AIMS/HYPOTHESIS: A natural cofactor of mitochondrial dehydrogenase complexes and
a potent antioxidant, alpha-lipoic acid improves glucose metabolism in people
with Type II (non-insulin-dependent) diabetes mellitus and in animal models of
diabetes. In this study we investigated the cellular mechanism of action of alpha
lipoic acid in 3T3-L1 adipocytes. METHODS: We treated 3T3-L1 adipocytes with 2.5
mmol/l R (+) alpha-lipoic acid for 2 to 60 min, followed by assays of: 2
deoxyglucose uptake; glucose transporter 1 and 4 (GLUT1 and GLUT4) subcellular
localization; tyrosine phosphorylation of the insulin receptor or of the insulin
receptor substrate-1 in cell lysates; association of phosphatidylinositol 3
kinase activity with immunoprecipitates of proteins containing phosphotyrosine or
of insulin receptor substrate-1 using a in vitro kinase assay; association of the
p85 subunit of phosphatidylinositol 3-kinase with phosphotyrosine proteins or
with insulin receptor substrate-1; and in vitro activity of immunoprecipitated
Akt1. The effect of R (+) alpha-lipoic acid was also compared with that of S(-)
alpha-lipoic acid. RESULTS: Short-term treatment of 3T3-L1 adipocytes with R (+)
alpha-lipoic acid rapidly stimulated glucose uptake in a wortmannin-sensitive
manner, induced a redistribution of GLUT1 and GLUT4 to the plasma membrane,
caused tyrosine phosphorylation of insulin receptor substrate-1 and of the
insulin receptor, increased the antiphosphotyrosine-associated and insulin
receptor substrate-1 associated phosphatidylinositol 3-kinase activity and
stimulated Akt activity. CONCLUSION/INTERPRETATION: These results indicate that R
(+) alpha-lipoic acid directly activates lipid, tyrosine and serine/threonine
kinases in target cells, which could lead to the stimulation of glucose uptake
induced by this natural cofactor. These properties are unique among all agents
currently used to lower glycaemia in animals and humans with diabetes.
PMID- 10768091
TI - Distribution of peroxisome proliferator-activated receptors (PPARs) in human
skeletal muscle and adipose tissue: relation to insulin action.
AB - AIMS/HYPOTHESIS: To evaluate the tissue distribution and possible role of the
peroxisome proliferator-activated receptors (PPARs) in insulin action in fat and
muscle biopsy specimens from lean, obese and subjects with Type II (non-insulin
dependent) diabetes mellitus. METHODS: We measured PPAR alpha, PPAR beta (delta)
and PPAR gamma protein expression by western blot analysis. The PPAR gamma
protein was also measured in muscle before and after 3-h hyperinsulinaemic (300
mU.m-2.min-1) euglycaemic clamps. RESULTS: The PPAR alpha protein was expressed
preferentially in muscle relative to fat (more than sevenfold). The PPAR beta
protein was similar in fat and muscle. The amount of PPAR gamma protein found in
muscle was, on average, two-thirds of that present in fat. There was no
statistically significant difference between non-diabetic and diabetic subjects
in baseline (preclamp) muscle PPAR (alpha, beta or gamma) protein expression.
Subgroup analysis showed, however, significantly higher PPAR gamma protein in the
most insulin resistant diabetic subjects with glucose disposal rates of 3-6 mg.kg
1.min-1 compared with their age and weight matched counterparts with glucose
disposal rates of 6-9 (147 +/- 23 vs 88 +/- 10 AU/microgram protein, p < or =
0.01 in diabetic and vs 94 +/- 15, p < or = 0.04 in non-diabetic subjects).
Muscle PPAR gamma protein and glucose disposal rates were inversely correlated in
diabetic subjects (r = -0.47, p < or = 0.05). CONCLUSION/INTERPRETATION: All
PPARs (alpha, beta or gamma) are present in skeletal muscle and adipose tissue
with different relative distributions. The PPAR gamma protein is abundant in
skeletal muscle as well as adipose tissue. The altered expression of skeletal
muscle PPAR gamma is consistent with a role for this nuclear protein in the
impaired insulin action of Type II diabetes.
PMID- 10768092
TI - Glycation impairs high-density lipoprotein function.
AB - AIMS/HYPOTHESIS: To examine the effects of incubation of high-density lipoprotein
(HDL) under hyperglycaemic conditions on several functions of HDL in vitro.
METHODS: Human HDL (5 mg protein) was incubated for 1 week at 37 degrees C in the
presence or absence of 25 mmol/l glucose. Additional samples of human HDL were
incubated in butylated hydroxytoluene to control for oxidation. RESULTS: High
density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant
increases in the glycation product, fructoselysine and in the advanced glycation
end product, N epsilon-(carboxymethyl)-lysine. High-density lipoprotein
apolipoprotein AI and AII concentrations were not altered but glycated HDL had a
65% reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit
monocyte adhesion to human aortic endothelial cells in response to oxidised low
density lipoprotein in vitro (43 +/- 4 monocytes bound vs 21 +/- 2 monocytes for
control HDL, p < 0.0001). Hepatic lipase-mediated non-esterified fatty acid
release from HDL lipids was enhanced in glycated HDL compared with control HDL
(25 +/- 1 vs 16 +/- 1 nmol non-esterified fatty acid hydrolysed/min,
respectively, p < 0.0001). Direct glycation of purified paraoxonase protein by
incubation in 25 mmol/l glucose caused a 40% reduction in enzymatic activity.
This glycated paraoxonase did not inhibit monocyte adhesion to human aortic
endothelial cells in vitro (68 +/- 3 monocytes vs 49 +/- 2 monocytes bound for
control paraoxonase, respectively, p < 0.001). We also measured a 40% reduction
in paraoxonase activity in patients with Type II (non-insulin-dependent) diabetes
mellitus and documented coronary artery disease compared with non-diabetic
subjects, p < 0.0001. CONCLUSIONS/INTERPRETATION: Alterations in function of HDL
caused by exposure to hyperglycaemic conditions could contribute to the
accelerated atherosclerosis observed in Type II diabetes.
PMID- 10768093
TI - Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin
resistance: a novel variant with impaired insulin-stimulated lipid kinase
activity.
AB - AIMS/HYPOTHESIS: Phosphoinositide 3-kinase (PI 3K) plays a central part in the
mediation of insulin-stimulated glucose disposal. No genetic studies of this
enzyme in human syndromes of severe insulin resistance have been previously
reported. METHODS: Phosphoinositide 3-kinase p85 alpha regulatory subunit cDNA
was examined in 20 subjects with syndromes of severe insulin resistance by single
strand conformational polymorphism and restriction fragment length polymorphism
analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment
into phosphotyrosine complexes of variants of p85 alpha were studied in
transiently transfected HEK293 cells. Phosphopeptide binding characteristics of
wild-type and mutant p85 alpha-GST fusion proteins were examined by surface
plasmon resonance. RESULTS: The common p85 alpha variant, Met326I1e, was
identified in 9 of the 20 subjects. Functional studies of the Met326Ile variant
showed it to have equivalent insulin-stimulated lipid kinase activity and
phosphotyrosine recruitment as wild-type p85 alpha. A novel heterozygous
mutation, Arg409Gln, was detected in one subject. Within the proband's family,
carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l)
compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The
Arg409Gln p85 alpha subunit was associated with lower insulin-stimulated
phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15%, p
< 0.05, n = 5). The recruitment of Arg409Gln p85 alpha into phosphotyrosine
complexes was not significantly impaired. GST fusion proteins of wild-type and
mutant p85 alpha showed identical binding to phosphopeptides in surface plasmon
resonance studies. CONCLUSION/INTERPRETATION: Mutations in p85 alpha are uncommon
in subjects with syndromes of severe insulin resistance. The Met326Ile p85 alpha
variant appears to have no functional effect on the insulin-stimulated
phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase
activity of the Arg409Gln mutant suggests that it could contribute to the insulin
resistance seen in this family.
PMID- 10768094
TI - Diabetes and pancreatic tumours in transgenic mice expressing Pa x 6.
AB - AIMS/HYPOTHESIS: Both endocrine and exocrine cells of the pancreas differentiate
from epithelial cells of primitive pancreatic ducts, and four types of pancreatic
islet cells (alpha, beta, delta, and PP cells) are derived from the common
pluripotent precursor cells. Although Pa x 6 is expressed in all islet cells, Pa
x 4 is detected only in beta cells. In homozygous Pa x 4-null mice, beta cells
are absent, whereas the number of alpha cells is increased. Therefore, we
hypothesized that the balance of Pa x 4 and 6 is one of the determinants by which
the common progenitor cells differentiate into alpha or beta cells. METHODS: To
change this balance, we generated transgenic mice overexpressing Pa x 6 driven by
the insulin promoter or the PDX1 promoter. RESULTS: In both types of transgenic
mice, normal development of beta cells was disturbed, resulting in apoptosis of
beta cells and diabetes. In Insulin/Pa x 6-Tg mice, beta cells were specifically
affected, whereas in PDX/Pa x 6-Tg mice, developmental abnormalities involved the
whole pancreas including hypoplasia of the exocrine pancreas. Furthermore, PDX/Pa
x 6-Tg mice experienced proliferation of both ductal epithelia and islet cells
and subsequent cystic adenoma of the pancreas. CONCLUSION/INTERPRETATION: These
findings suggest that Pa x 6 promotes the growth of ductal epithelia and
endocrine progenitor cells and that the suppression of Pa x 6 is necessary for
the normal development of beta cells and the exocrine pancreas.
PMID- 10768096
TI - Different risk factors of microangiopathy in patients with type I diabetes
mellitus of short versus long duration. The EURODIAB IDDM Complications Study.
AB - AIMS/HYPOTHESIS: To identify factors associated with early development of and
late protection from microvascular complications in subjects with Type I (insulin
dependent) diabetes mellitus. METHODS: The frequency of microvascular
complications and their relation to risk factors were studied in 300 Type I
diabetic subjects with short duration of disease (< or = 5 years) compared with
1062 subjects with long duration (> or = 14 years). Microvascular disease was
defined as the presence of either retinopathy (assessed from centrally-graded
retinal photographs) or urinary albumin excretion rate of more than 20
micrograms/min. RESULTS: The prevalence of microvascular disease was 25% in the
short duration group. In the long duration group 18% had no evidence of
microvascular complications. In the short duration group factors associated with
early development of complications were cigarette smoking and a family history of
hypertension. Subjects free of microvascular complications in spite of long
duration of diabetes had better glycaemic control, lower blood pressure, better
lipid profile and lower von Willebrand factor levels. CONCLUSION/INTERPRETATION:
At the early stages of Type I diabetes, cigarette smoking and genetic
susceptibility to hypertension are important risk factors for microvascular
complications. At a later stage, additional risk factors are poorer glycaemic
control, higher blood pressure, and an unfavourable lipid profile possibly
associated with endothelial dysfunction. Many of these factors are amenable to
long-term intervention which should be started as soon as possible in the course
of the disease.
PMID- 10768095
TI - Gene transfer of endothelial nitric oxide synthase alters endothelium-dependent
relaxations in aortas from diabetic rabbits.
AB - AIMS/HYPOTHESIS: Cardiovascular disease is the leading cause of death in diabetes
mellitus. Abnormal endothelium-dependent relaxation is observed both in humans
and in animal models of diabetes mellitus and decreased bioavailability of nitric
oxide (NO) is thought to be involved in this defect. Therefore, the aim of this
study was to test whether adenovirus-mediated gene transfer of endothelial nitric
oxide synthase (eNOS) alters vascular reactivity of diabetic vessels. METHODS:
Vascular reactivity was first assessed in thoracic aortas and carotid arteries
from nine alloxan-induced diabetic (plasma glucose, 26.5 +/- 1.2 mmol/l; HbA1c,
6.4 +/- 0.3%) and nine control rabbits (plasma glucose, 11.1 +/- 1.3 mmol/l;
HbA1c, 2.1 +/- 0.1%). Vascular reactivity was next examined in thoracic aortas of
diabetic animals after ex vivo transduction with replication-deficient adenovirus
encoding gene for eNOS (AdeNOS) or beta-galactosidase (Ad beta gal). RESULTS:
After 10 weeks of hyperglycaemia, endothelium-dependent relaxation to
acetylcholine was impaired in diabetic aorta, but was normal in carotid arteries
from diabetic rabbits. In contrast, responses of both vessels to calcium
ionophore and nitric oxide donor were normal. Histochemical staining for beta
galactosidase and immunohistochemistry for eNOS showed transgene expression in
the endothelium and adventitia in Ad beta gal and AdeNOS transduced vessels,
respectively. During submaximum contractions with phenylephrine, relaxations to
low concentrations of acetylcholine (3 x 10(-8) to 10(-7) mol/l) were augmented
in AdeNOS transduced diabetic vessels. CONCLUSION/INTERPRETATION: These findings
suggest that adenovirus-mediated gene transfer of eNOS to diabetic aorta alters
vascular reactivity.
PMID- 10768097
TI - Regulation of gene expression during severe caloric restriction: lack of
induction of p85 alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of
patients with type II (non-insulin-dependent) diabetes mellitus.
AB - AIMS/HYPOTHESIS: Alterations in the regulation of gene expression could be
involved in the development of Type II (non-insulin-dependent) diabetes mellitus.
METHODS: We compared the mRNA concentrations of eight genes encoding proteins
involved in insulin action and intermediary metabolism in skeletal muscle of
healthy volunteers and Type II diabetic patients. The in vivo regulation of the
expression of these genes was investigated after 5 days of hypocaloric diet (1045
kJ/day). RESULTS: In the basal state, diabetic muscle showed reduced insulin
receptor (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein
lipase (-70%) mRNA expression. There was no difference in the mRNA abundances of
IRS-1, GLUT 4, p85 alpha phosphatidylinositol-3-kinase (p85 alpha PI3K) or Rad.
In both groups, caloric restriction induced weight loss, reduced glycaemia and
increased plasma ketone body concentrations. The diet also increased plasma
concentrations of fatty acids and decreased whole-body insulin sensitivity in
control subjects. In control subjects, the diet increased p85 alpha PI3K (+146%),
insulin receptor (+100%) and Rad (+40%) mRNA concentrations in muscle. In Type II
diabetic patients, the diet increased insulin receptor (+41%) and Rad (+31%)
mRNAs but the expression of p85 alpha PI3K was not modified.
CONCLUSION/INTERPRETATION: The regulation of the expression of p85 alpha PI3K is
altered during caloric restriction in skeletal muscle of Type II diabetic
patients. Because we have shown in an earlier study that there is also a
defective regulation of p85 alpha PI3K gene expression in response to insulin,
these data support the hypothesis that alterations in the regulation of gene
expression could be involved in the pathogenesis of Type II diabetes.
PMID- 10768098
TI - Analysis of the HNF4 alpha gene in Caucasian type II diabetic nephropathic
patients.
AB - AIMS/HYPOTHESIS: Linkage and association studies in Caucasian patients with Type
II (non-insulin-dependent) diabetes mellitus suggest that one or more diabetes
susceptibility gene(s) reside within human chromosome 20q12-13.1. This region of
chromosome 20 contains the maturity-onset diabetes of the young type 1 gene, HNF4
alpha. The purpose of this study was to assess the possible involvement of HNF4
alpha in Type II diabetes. METHODS: Mutation analysis was done on the 12 exons
and promoter regions of the HNF4 alpha gene in 182 Caucasian diabetic
nephropathic patients and 100 Caucasian control subjects. The functional
consequences of a novel promoter mutation were examined using a reporter system
in the HepG2 liver cell line and electrophoretic mobility shift assays. RESULTS:
We identified two novel mutations in the HNF4 alpha, an R323H missense mutation
in exon 8, and a 7 bp deletion (delta 7) in the proximal promoter region
resulting in deletion of a single putative Sp1 binding site. Using a reporter
assay system, the delta 7 sequence was found to exhibit a 51.2% (standard error
+/- 4.2%) reduction in promoter activity relative to the normal sequence. In
electrophoretic mobility shift assays using specific and non-specific
competitors, the delta 7 sequence had a 45.5% (range 40.4-46.6) reduction in
binding compared with the normal sequence. The delta 7 allele occurs in a family
with multiple cases of Type II diabetes in a pattern consistent with
coinheritance of the delta 7 allele and diabetes. CONCLUSION/INTERPRETATION:
Analysis of the HNF4 alpha gene revealed two possible mutations in 182 diabetic
patients which suggests that the HNF4 alpha gene does not make a large
contribution to diabetes susceptibility in the general population of Caucasian
diabetic nephropathic patients. Functional analysis of the delta 7 promoter
deletion suggests, however, that promoter mutations in otherwise normal genes
could contribute to diabetes susceptibility.
PMID- 10768099
TI - Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C
receptor gene and their association with obesity and type II diabetes.
AB - AIMS/HYPOTHESIS: Polymorphisms in the upstream region of the 5-HT2C receptor gene
could play a part in the development of obesity. METHODS: We screened the
upstream region from 27 men by the single strand conformational polymorphism
analysis and PCR-direct sequencing and then genotyped 466 non-obese (body mass
index < 28 kg/m2) and 123 obese (> or = 28 kg/m2) men including 138 patients with
Type II (non-insulin-dependent) diabetes mellitus. RESULTS: Three loci of single
nucleotide substitution (G-->A at -995, C-->T at -759, G-->C at -697) and a (GT)n
dinucleotide repeat polymorphism at -1,027 were identified. The frequency of
995/-759 and -697 variants was higher in non-obese subjects and that of -995/-759
variants in non-diabetic subjects. In the dinucleotide repeat locus, five alleles
were detected including Z containing 17 repeats. The Z - 6 allele was more common
in non-obese subjects and the Z + 2 allele in obese subjects. Haplotype 3 (Z - 6,
-995A, -759T, -697C) was associated with leanness (p = 0.02) and the absence of
diabetes (p = 0.033) and haplotype 9 (Z + 2, -995G, -759C, -697G) with obesity (p
= 0.007). Haplotype 2 (Z - 6, -995G, -759C, -697C) tended to be more common in
non-obese subjects. A luciferase reporter assay showed that haplotype 2 and
haplotype 3 had 1.44- or 2.58-fold higher promoter activities than the most
common haplotype 6 (Z, -995G, -759C, -697G). CONCLUSION/INTERPRETATION: The
haplotypes containing the nucleotide substitutions could be associated with
higher transcription levels of the gene and thereby with resistance to obesity
and Type II diabetes. Promoter polymorphisms of the 5-HT2C receptor gene may play
an important part in genetic predisposition to the disorders.
PMID- 10768100
TI - Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion
in cultured human adipocytes.
AB - AIMS/HYPOTHESIS: Increased plasma plasminogen activator inhibitor-1 (PAI-1)
concentrations are characteristic for subjects with insulin resistance and could
contribute to the increased cardiovascular risk in this state. In this study, we
investigated the effect of troglitazone, a ligand of the nuclear receptor
peroxisome proliferator activated receptor-gamma, on PAI-1 expression and
secretion in human adipocytes. METHODS: We used two models: in vitro
differentiated subcutaneous and omental adipocytes cultured under serum-free
conditions and isolated subcutaneous and omental fat cells kept in suspension
culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1
mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro
differentiated subcutaneous adipocytes from young normal-weight females to 1
microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by
29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In
cultures from severely obese subjects, troglitazone induced a decrease of PAI-1
antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p <
0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of
freshly isolated subcutaneous and omental adipocytes in suspension culture to
troglitazone induced a similar reduction of PAI-1 concentration in the culture
medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control,
respectively). CONCLUSION/INTERPRETATION: This study provides evidence that
troglitazone reduces PAI-1 production in human adipocytes, probably at the
transcriptional level. This observation could point to a new beneficial effect of
troglitazone, particularly in obese subjects, which could be associated with a
reduced cardiovascular risk.
PMID- 10768101
TI - Intermediate expansions of a X25/frataxin gene GAA repeat and type II diabetes:
assessment using parent-offspring trios.
PMID- 10768102
TI - Effects of metformin on androgens and insulin concentrations in type A insulin
resistance syndrome.
PMID- 10768103
TI - Measurement of T-cell autoreactivity in autoimmune diabetes.
PMID- 10768104
TI - Circulating hyaluronan and hyaluronidase are increased in diabetic rats.
PMID- 10768105
TI - [Value of the Stennert schema in therapy of sudden deafness].
PMID- 10768106
TI - [Categorical loudness scaling in ENT patient care. A temporary fad or essential
method?].
PMID- 10768107
TI - [Treatment of the hypertrophic inferior turbinate. 1].
AB - Chronic nasal obstruction is a common disorder, mostly caused by hypertrophied
inferior turbinates. If there is inadequate response to conservative medical
management, the inferior turbinates should be reduced. The choice of treatment is
mainly influenced by whether the nasal airway obstruction is due to hypertrophic
mucosa or to an enlarged turbinate bone. The first part of this review describes
the various surgical modalities for treatment of swelling of the turbinal mucosa.
The indications, advantages, disadvantages, complications, and controversies of
each modality (submucous diathermy, cryosurgery, infra-red coagulation, argon
plasma coagulation, radiofrequency, laser surgical techniques) are reviewed and
discussed.
PMID- 10768108
TI - [The Stennert antiphlogistic-rheologic infusion schema in treatment of
cochleovestibular disorders].
AB - The pathogenetic mechanisms of acute cochleo-vestibular lesions are still
unknown, but viral infections and vascular phenomena with impairment of
microvascular perfusion are thought to play a major role. Between 1 July, 1986
and 28 February 1998, 1501 patients were treated with an infusion protocol using
cortisone, dextrane 40 and pentoxifylline. Group 1 contained 1001 patients with
sudden hearing loss, group 2a 107 patients with isolated tinnitus and group 2b
393 patients with labyrinthine disorders (among which were 81 patients with
cochleovestibular dysfunction). The records were evaluated retrospectively. In
group 1 complete hearing recovery occurred in 44.8%, partially in 40.4%, no
change in 12.1% and worsened in 2.6%. In group 2a with isolated tinnitus 17.9%
had a complete recovery, 43.9% partial recovery, 35.5% no change and 2.8%
worsened symptoms. In group 2b vertigo disappeared in 56.8%, had partial recovery
in 21.0% and did not change in 7.4%. In the 1501 patients treated, no significant
side-effects were found to the medical interventions used. From these results we
conclude that the infusion protocol is safe and effective in the treatment of
cochleo-vestibular disorders.
PMID- 10768109
TI - [Categorical loudness scaling within the scope of hearing aid management].
AB - The loudness perception of patients with hearing aids was measured with a one
stage category loudness scaling procedure. Data were obtained from 102 ears and
were studied primarily in older patients who represented the majority of patients
with hearing disorders evaluated in our department. In all, 75% of the patients
were older than 45 years and had a mean age of 58 years. The reduction of
dynamics at high frequencies was considered to be typical for age-related hearing
disorders and was easily quantified with loudness scaling. Findings demonstrated
that prediction of recruitment was not possible from pure-tone thresholds or even
together with uncomfortable loudness levels, since the slopes of the level
loudness functions revealed a high interindividual variability. In contrast, the
desired compression ratio can be easily calculated with data from the loudness
scaling. In this study the loudness perception of patients with mainly non-linear
hearing aids fitted with customary procedures was evaluated. The benefit from the
hearing aids was proven with the outcome from the loudness scaling, with testing
also allowing for a better fitting of the aids.
PMID- 10768110
TI - [Effect of monaural deprivation on maturation of the auditory pathway in the
Mongolian gerbil (Meriones unguiculatus)].
AB - Several investigations prove that monaural acoustic deprivation induces
detrimental changes in the auditory pathway. So far the major interest focused on
degenerative processes on the deprived side, while effects on the contralateral
untreated side were not taken into consideration. This ontogenetic study
investigates effects of early monaural acoustic deprivation on the functional
development of the acoustically evoked auditory brainstem response (ABR) in the
Mongolian gerbil. Young gerbils were deafened by a single intracochlear
application of neomycin sulfate. The ABR development on the contralateral side
differed in a late developmental period from that of normally hearing animals.
These changes persisted until adulthood. Between day 55 and day 90 a significant
5 dB decrease of the ABR thresholds and a significant shortening of the interpeak
latency II-V occurred. The results confirm that a complete monaural deprivation
during the sensible or critical period leads on the contralateral side to plastic
or compensatory changes in the auditory brainstem.
PMID- 10768111
TI - [Standardized measurement of sound transmission of different middle ear
prostheses].
AB - The sound transmission properties of three different commercially available
middle ear implants and the prototype of a complete middle ear prosthesis (CoMEP)
were evaluated with a special measurement system that permits standardized
conditions. This system uses a mechanical middle ear model (MMM) which
approximates the impedances of the tympanic membrane and inner ear. The implants
were fitted under defined conditions into the MMM. Displacement of the artificial
stapes footplate of the MMM was measured with an optical probe. The measurements
of different middle ear prostheses showed that the mass of the implant was the
most important factor for optimum high frequency transmission. The lightest
implant (4 mg, titanium) showed the best results. The CoMEP revealed the highest
sensitivity because of a slight enlargement of the diameter of the artificial
tympanic membrane. These findings show that the CoMEP is able to restore sound
transmission to a normal range. In a second experiment one of the implants was
fitted into the MMM with different forces. The increase of stiffness produced a
slightly better high frequency transmission at the expense of low frequency
sensitivity. Hence, the fitting of the implant may not be too stiff because of
its loss of mobility within a significant frequency range.
PMID- 10768112
TI - [Using the Mongolian gerbil (Meriones unguiculatus) as an animal model in
ontogenetic cochlear implant research].
AB - One of the problems when providing prelingually deafened children with a cochlear
implant is to find the optimal moment for the implantation in order to make
optimal use of the sensitive phase in the maturation of the auditory system and
to achieve the maximum improvement of hearing. Ontogenetic questions can be
investigated in animal experiments under controlled conditions. In the present
study an animal model (gerbil, Meriones unguiculatus) was established to simulate
the situation of prelingually deafened children and to examine the influence of
chronic electrostimulation on the development of the auditory pathway. We used
species specific sounds for chronic stimulation to simulate significance of human
language in our animal modell. A daily two-hour electrostimulation during the
ontogenesis of early deafened animals lead to a partial compensation of the
functional degeneration of the auditory pathway, which can be observed in totally
deafened animals. This animal model provides an elaborate test design which can
be used in CI research for the investigation of numerous problems.
PMID- 10768113
TI - [Hearing screening of high risk newborn infants].
AB - OBJECTIVE: This prospective study reports on the prevalence of hearing impairment
in an at-risk neonatal intensive care unit (NICU) population. DESIGN: From 1990
to 1998, 1062 neonates were screened with the use of transitory evoked
otoacoustic emissions (TEOAE) and brainstem evoked response audiometry (BERA).
RESULTS: 934 infants passed the primary screen for both ears, 75 for one ear,
adding up to 95%. 17 infants (1.6%) were lost to follow-up. In fourteen infants
(1.3%), bilateral hearing impairment above 30 dB was confirmed. While all
children with hearing impairment belonged to the group of 862 children receiving
aminoglycosides, only one of them presented no other risk factors. In twelve of
the hearing impaired children other anamnestic factors, i.e. dysmorphism,
prenatal rubella or cytomegaly, family history of hearing loss or severe peri-
and postnatal complications seem to be more probable causes of the identified
hearing loss. In one of these children, delayed onset or progression of hearing
loss is suspected. CONCLUSIONS: From our data, aminoglycosides are not an
important risk factor for hearing impairment, when serum levels are continuously
monitored, as in our cohort. After adjustment for other risk factors, birth
weight between 1000 gr and 1500 gr and a gestational age between 29 and 31 weeks
were no predictive markers for hearing impairment. It might be speculated that
the improved medical treatment in a NICU reduces the probability of hearing
impairment for those two groups. Conductive hearing loss as a possible additional
cause for hearing impairment was not studied in detail, but the high percentage
of malformations detected (four out of fourteen hearing impaired infants) demands
further monitoring, close follow-up, adequate treatment and counselling.
PMID- 10768114
TI - [Chronic recurrent parotitis in childhood in monozygotic twins. Magnetic
resonance sialography].
AB - Recurrent parotitis is rare in childhood. Its occurrence is characterized by
recurrent episodes of swelling and pain in the parotid gland, which are usually
accompanied by fever and malaise. Inflammation usually resolves spontaneously
during adolescence. The disorder is a condition of unknown etiology. Sialectasis
and stricturing occurs in the distal ducts, whereas inflammation of the gland and
duct epithelium is probably caused by a low salivary flow rate. Which one can be
considered the primary event or secondary change remains unknown. The main-stay
of diagnosis is sialography, which depicts typical intraparotidal duct system
lesions as strictures or ectasias and excludes sialolithiasis. We here report two
10-year-old male monovular twins who suffered from recurrent swelling and pain in
only their left parotid glands. Symptoms were noted approximately every 6 weeks
in both patients strictly. Characteristic sialectasis of the distal ducts was
demonstrated by magnetic resonance-sialography. Our findings support the
hypothesis that recurrent parotitis is caused by a congenital abnormality of the
salivary gland ducts. Diagnostic imaging was performed by magnetic resonance
imaging during the acute phase of the disease. This technique helps to make the
diagnosis without retrograde application of a contrast agent.
PMID- 10768115
TI - [Chronic inflammation of the petrous bone with fatal outcome].
AB - We report the case of a 44-year-old woman, suffering from lethal cerebritis of
the temporal lobe caused by an unusual chronic otitis media with granulations. A
chronic inflammatory process of the left temporal bone had affected the patient
over a period of 4 years. This had started with mastoiditis accompanied by a
lesion of the dura mater, leading to labyrinthitis, encephalitis and cerebellar
abscess. The patient's symptoms persisted, especially vertigo and uncertainty,
and then deteriorated acutely. MRI showed otogenic cerebritis. Intracranial
bleeding from vasculitis had worsened the patient's condition, finally resulting
in the patient's death. This case impressively demonstrates that a cerebral
abscess can cause acute worsening of general complaints associated with ear
disease and results in a fatal outcome at any stage.
PMID- 10768116
TI - [The infection susceptible child].
PMID- 10768117
TI - [Axonotmesis].
PMID- 10768118
TI - [Discoloration of the external ear cartilage. Ochronosis (alkaptonuria)].
PMID- 10768119
TI - [Tampons and place holders in endonasal surgery].
PMID- 10768120
TI - The horse homolog of congenital aniridia conforms to codominant inheritance.
AB - Anterior segment dysgenesis syndrome occurs frequently in Rocky Mountain horses
and has two distinct ocular phenotypes: (1) large cysts originating from the
temporal ciliary body or peripheral retina and (2) multiple anterior segment
anomalies including ciliary cysts, iris hypoplasia, iridocorneal adhesions and
opacification, nuclear cataract, and megalocornea. To determine if anterior
segment dysgenesis syndrome is heritable in horses we performed ophthalmic
examinations and collected pedigree information on horses (n = 516) in an
extended Rocky Mountain horse pedigree. Logistic regressive segregation analysis
of a subset of animals (n = 337) in which the ocular phenotypes of progeny and
both parents were known indicated that the codominant inheritance model best fit
the data. This model predicted cyst phenotype expression in heterozygous animals
and multiple anterior segment anomalies in homozygous animals. Several cases of
nonpenetrance of the cyst phenotype were detected in one lineage. The close
resemblance between the inheritance and lesions observed in Small eye mice and
rats, humans with congenital aniridia or anterior segment malformation, and
horses with anterior segment dysgenesis syndrome supported the conclusion that
anterior segment dysgenesis syndrome in the horse may be homologous to similar
ophthalmic anomalies in other species.
PMID- 10768121
TI - Recombination, statistical power, and genetic studies of sexual isolation in
Drosophila.
AB - Genetic studies of sexual isolation in Drosophila have generally failed to fully
evaluate the effects of their sample size and recombination between markers on
their conclusions. In this study we evaluate recombinational distances between
markers in Drosophila pseudoobscura and D. persimilis, a species pair in which
numerous genetic mapping studies have been performed. We conclude that, contrary
to assertions, the inversions that distinguish these two species still allow for
much recombination within most of their chromosome arms in F1 hybrid females.
Such recombination may have caused previous mapping studies in these species to
miss (or grossly underestimate) the effects of several genomic regions. We also
evaluate the effects of sample size and recombination on genetic studies of
sexual isolation in other Drosophila species groups. We conclude that some of
these studies may have been heavily biased toward detecting only genes of large
effect. Future studies of sexual isolation should be preceded by detailed
statistical power analyses that determine the effects of recombination and sample
size in the species pair being studied to avoid these complications.
PMID- 10768122
TI - Single-locus complementary sex determination in Diadegma chrysostictos (Gmelin)
(Hymenoptera: Ichneumonidae).
AB - Following the establishment of isofemale lines and subsequent inbreeding, the
ichneumonid parasitoid wasp Diadegma chrysostictos (Gmelin) was shown by
segregation of polymorphic alloenzyme loci to have single-locus complementary sex
determination (sl-CSD). This and the biparental nature of diploid males was
confirmed using two independent Mendelian recessive phenotypic markers. The
existence of diploid males, sl-CSD, and the abrogation of diploid males following
outbreeding was further confirmed by flow cytometry, a potentially general method
that is independent of the maternal sex allocation or the need for genetic
markers. Estimates of the number of sex alleles in several British populations
demonstrated 17-19 alleles in Britain, with a decline toward the northerly limit
of the parasitoid's range, varying from 16 in the south of England to 4-5 in
central Scotland, in broad agreement with the rate of attainment of a male-biased
sex ratio when used to establish en masse laboratory cultures. These data
represent the second confirmation of the existence of sl-CSD in the Ichneumonidae
(and the first in the Campopleginae subfamily), lending further support to the
notion that sl-CSD was the ancestral condition in the Aculeata/Ichneumonoidea
clade (Cook 1993a; Periquet et al. 1993).
PMID- 10768123
TI - The impact of supplementation in winter-run chinook salmon on effective
population size.
AB - Supplementation of young raised at a protected site, such as a hatchery, may
influence the effective population size of an endangered species. A
supplementation program for the endangered winter-run chinook salmon from the
Sacramento River, California, has been releasing fish since 1991. A breeding
protocol, instituted in 1992, seeks to maximize the effective population size
from the captive spawners by equaling their contributions to the released
progeny. As a result, the releases in 1994 and 1995 appear not to have decreased
the overall effective population size and may have increased it somewhat.
However, mistaken use of non-winter-run chinook spawners resulted in artificial
crosses between runs with a potential reduction in effective population size, and
imprinting of the released fish on Battle Creek, the site of the hatchery,
resulted in limiting the contribution of the released fish to the target mainstem
population. Rapid genetic analysis of captured spawners and a new rearing
facility on the Sacramento River should alleviate these problems and their
negative effect on the effective population size in future years.
PMID- 10768124
TI - Cytogenetic analysis of the tamaraw (Bubalus mindorensis): a comparison of R
banded karyotype and chromosomal distribution of centromeric satellite DNAs,
telomeric sequence, and 18S-28S rRNA genes with domestic water buffaloes.
AB - The karyotype of the tamaraw (Bubalus mindorensis, 2n = 46) was investigated by
RBG-banding technique and compared with those of the river and the swamp
cytotypes of domestic water buffalo (B. bubalis). The tamaraw karyotype consisted
of 6 submetacentric and 16 acrocentric autosome pairs (NAA = 56), and X and Y
chromosomes. The RBG-banded karyotype of the three taxa had a high degree of
homology, and the tamaraw karyotype could be explained by a Robertsonian
translocation between chromosomes 7 and 15 and by a telomere-centromere tandem
fusion between chromosomes 4p and 12 of the standardized river buffalo cytotype
(2n = 50, NAA = 58). The buffalo satellite I and II DNAs were localized to the
centromeric regions of all the tamaraw chromosomes. The biarmed chromosome 2 of
the tamaraw resulting from the fusion between chromosomes 7 and 15 of the
standard contained much larger amounts of the satellite I DNA than the other
biarmed chromosomes, suggesting that this chromosome was formed by a relatively
recent Robertsonian fusion. The (TTAGGG)n telomeric sequence was specifically
localized to the telomeric region of all the buffalo chromosomes. The 18S + 28S
rDNA was localized to the telomeric regions of the chromosomes 5p, 7, 19, 21, and
22 of the tamaraw and of their homologous chromosomes in the river and swamp
buffalo cytotypes.
PMID- 10768125
TI - Mitochondrial DNA differentiation in the critically endangered Berg River redfin
(Pseudobarbus burgi).
AB - The Berg River redfin (Pseudobarbus burgi) is a critically endangered endemic
cyprinid from South Africa. We investigated mitochondrial DNA control region
variation among specimens representative of five populations drawn from two
adjacent river systems. Phylogenetic analyses, a minimum spanning network, and an
analysis of molecular variance underscore the pronounced genetic separation of
redfins originating from the geographically closely allied Verlorevlei and Berg
Rivers, two populations that may have remained isolated since the Pleistocene.
Despite a lack of geographic structuring within the Berg River, historic female
gene flow among the upper and middle/lower parts of the river appears to be
limited and the contemporary populations are probably isolated due to
deterioration of the mainstream of the river. Our results suggest that the Berg
and Verlorevlei populations should be managed as distinct conservation units. We
encourage the use of sanctuaries, particularly by private landowners within both
river systems, as this approach may contribute effectively to preserving genetic
diversity within the species.
PMID- 10768126
TI - Mosaic: a position-effect variegation eye-color mutant in the mosquito Anopheles
gambiae.
AB - The Mosaic (Mos) mutation, isolated in the F1 of 60Co-irradiated mosquitoes,
confers variegated eye color to third and fourth instar larvae, pupae, and adults
of the mosquito Anopheles gambiae. Mos is recessive in wild pink eye (p+)
individuals, but is dominant and confers areas of wild-type pigment in mutant
pink eye backgrounds. Mos is located 14.4 cM from pink eye on the X chromosome
and is associated with a duplication of division 2B euchromatin that has been
inserted into division 6 heterochromatin. Various combinations of Mos, pink eye
alleles, and the autosomal mutation red eye were produced. In all cases, the
darker pigmented regions of the eye in Mos individuals show the phenotypic
interactions expected if the phenotype of those regions is due to expression of a
p+ allele. Expression of Mos is suppressed by rearing larvae at 32 degrees C
relative to 22 degrees C. All of these characteristics are consistent with Mos
being a duplicated wild copy of the pink eye gene undergoing position-effect
variegation.
PMID- 10768127
TI - Genetic differentiation and structure of Hippocrepis valentina (Leguminosae)
populations.
AB - We present an analysis of isozyme variability in natural populations of the plant
species Hippocrepis valentina (Leguminosae), which is endemic to the eastern
Mediterranean coast of Spain and currently has endangered species status. Our
results, obtained by starch-gel electrophoresis of 15 loci, show normal levels of
variability for species with similar biology. The comparison with the patterns of
genetic variability of two closely related species, H. balearica and H. grosii,
confirms the taxonomic status of H. valentina as a proper species, independent of
H. balearica, as previously suggested. The analysis of population subdivision
shows that substantial variation among populations is present, and a hierarchical
analysis demonstrates that when zones are defined according to their geographic
location, a higher differentiation among populations within zones than among
zones is found. Indirect estimates of gene flow indicate that levels of migration
per generation are relatively low, except for a group composed of four
populations, three of which are in close proximity. For the remaining
populations, there is evidence of substantial differentiation. These results have
implications for the design of a conservation strategy for this species.
PMID- 10768128
TI - Genetics of isozymes in grasspea.
AB - We studied the inheritance and linkage of ACO-1, ACO-2, AAT-1, AAT-2, EST-3, EST
6, FDH, LAP-1, PGD-2, SKDH, and TPI-1 in four F2 populations of grasspea
(Lathyrus sativus L.) using horizontal starch-gel electrophoresis. Mendelian
inheritance was observed for all of the isozymes studied. All isozymes showed
codominant gene expression except for EST-3, which was expressed in a dominant
fashion due to the presence of a null allele. Monomeric quaternary structure was
observed for ACO-1, ACO-2, EST-6, LAP-1, and SKDH. Dimeric quaternary structure
was observed for AAT-1, AAT-2, FDH, PGD-2, and TPI-1. The isozyme loci Aat-2 and
Skdh were linked with a map distance of 28 cM.
PMID- 10768129
TI - Heteroplasmy of mitochondrial DNA in the ophiuroid Astrobrachion constrictum.
AB - We demonstrate the presence of mitochondrial heteroplasmy for the cytochrome
oxidase I (COI) gene of the brittle star (Astrobrachion constrictum). One of the
117 individuals analyzed contained two distinct single-strand conformation
polymorphism (SSCP) haplotypes differing by two substitutions; another showed
sequence evidence for heteroplasmy. We used polymerase chain reaction (PCR)
cloning, SSCP, and sequencing of a 480 bp region of the 5' end of COI to isolate
and characterize these haplotypes. This is the first properly substantiated case
of heteroplasmy in an echinoderm species and may have arisen from paternal
leakage.
PMID- 10768130
TI - X trisomy in an infertile bitch: cytogenetic, anatomic, and histologic studies.
AB - Three copies of the X chromosome were identified in a 5-year-old mixed breed
infertile bitch. One year after the cytogenetic examination, the bitch died due
to gastritis hemorrhagica, an inflammation of the mucus coat of the stomach.
Dental studies showed congenital lack of some premolar and molar teeth. Ovaries
were of normal shape and size. Also, histologic sections of the ovaries revealed
their normal structure, with two corpora lutea and primary follicles. Phenotypic
effects of X trisomy are discussed.
PMID- 10768131
TI - Trait association of a genetic marker near the IGF-I gene in egg-laying chickens.
AB - The insulin-like growth factor I (IGF-I) gene was screened for genetic variants
associated with trait means and trait correlations. Analysis of an unselected
randomly mated White Leghorn population revealed a PstI restriction fragment
length polymorphism (RFLP) in the 5' region of the gene which segregated at a
frequency of 0.83 for the PstI(+) allele (presence of a PstI restriction site). A
comparison of the three genotypic classes revealed that the PstI(-/-) genotype
was associated with a significantly lower egg weight measured in three different
time periods, while the PstI(+/-) genotype was significantly associated with a
higher eggshell weight estimated from the egg weight and egg specific gravity.
For eggshell weight, the effect was age dependent and significant only for the
last two periods of egg laying. No genotype associations were found for body
weight, feed consumption, and egg laying rates. Significant dominance effects of
the IGF-I genotype were observed for two of the egg weight measurements and three
of the eggshell weight estimates. Partial correlation analyses in the two most
frequent genotypic classes, PstI(+/+) and PstI(+/-), revealed the presence of a
regulatory loop between feed consumption, body weight, egg weight, and the rate
of egg laying. Several aspects of this regulatory loop were different between the
two genotypic classes. In particular, for the PstI(+/+) genotype, feed
consumption was positively associated with egg weight, while there was no
significant association for the PstI(+/-) genotype. Further, the degree of
association of body weight with egg weight decreased with age in the genotypic
class PstI(+/-), while it was constant for the PstI(+/+) genotype. The results
indicated that the marker in the IGF-I gene was not only associated with changes
in some trait means, but also with changes in the stability of the coordination
between feed intake, body weight, and egg production traits.
PMID- 10768132
TI - Neutrality tests on mtDNA: unusual results from nematodes.
AB - McDonald-Kreitman tests of neutrality on mitochondrial DNA (mtDNA) of
butterflies, Drosophila, and a variety of vertebrates usually show excess (over
the neutral expectation) intraspecific polymorphism at nonsilent sites. These
results are of great interest because they are the opposite of what is usually
found for nuclear genes, in which the neutral pattern or evidence of adaptive
divergence between species is usually observed. However, only vertebrates and
insects have been tested so far, so it is not clear whether this intriguing
pattern is typical for mtDNA in all taxa. Here I tested three pairs of nematode
species and found that they all show a deficit of replacement polymorphism. Taken
at face value, this result suggests that adaptive evolution proceeds more
efficiently in nematode mtDNA than in mtDNA of vertebrates or insects. An
alternate explanation is that the nematode pattern is an artifact of silent-site
saturation that results from the rapid and composition-biased way in which
nematode mtDNA evolves. Further studies are needed to distinguish between these
two hypotheses.
PMID- 10768133
TI - Possible genetic basis of pederin polymorphism in rove beetles (Paederus
riparius).
AB - In Paederus riparius, (+) females able to biosynthesize the unique hemolymph
toxin pederin and (-) females lacking this ability co-occur in natural
populations. Larvae descended from both types of females were reared in the
laboratory and the imagoes were crossed in order to get information about a
possible genetic basis of this polymorphism. The daughters of (+) mothers become
(+) females or (-) females, while the progeny of (-) mothers comprises only (-)
females. This suggests a matrilineal trait because pederin biosynthesis cannot be
inherited from the father. The rather stable proportion of nearly 90% (+) females
in collected females is not maintained, however, when the beetles are reared in
the laboratory. This observation is discussed with regard to artificial rearing
conditions, where individuals are kept separate and cannot prey on conspecifics.
PMID- 10768134
TI - Systematic implications of chromosomal data from two insular species of
Peromyscus from the Gulf of California.
AB - G- and C-banded karyotypes for two insular species of deer mice, Peromyscus
slevini and P. sejugis, are described and analyzed relative to the evolutionary
relationship of these species to and their inclusion within the P. maniculatus
species group. The chromosomal phenotype of P. slevini is unique among all banded
karyotypes reported for Peromyscus, and comparison with published karyotypes
suggests that P. slevini has systematic affinities with either the P. boylii or
P. mexicanus species groups. The karyotypic data for P. sejugis clearly align
these mice with P. maniculatus and provide a diagnostic character that supports
the specific distinction between these taxa.
PMID- 10768135
TI - The Rift Valley complex as a barrier to gene flow for Anopheles gambiae in Kenya:
the mtDNA perspective.
AB - Descriptions of A. gambiae population structure based on microsatellite loci and
mitochondrial DNA (mtDNA) were incongruent. High differentiation of populations
was measured across the Rift Valley by microsatellites, but no differentiation
was detected based on mtDNA. To resolve this conflict, we compared the old data
to new mtDNA data using the same specimen previously genotyped in microsatellite
loci. Analysis of a larger number of mtDNA sequences resulted in high and
significant differentiation between populations across the Rift Valley. We
developed a method to assess whether differentiation across the Rift Valley was
generated by pure drift rather than mutation-drift, based on DNA sequence data.
Applying this method to the mtDNA data suggested that pure drift was the primary
force generating differentiation between the populations across the Rift, while
mutation-drift generated differentiation across the continent. Given adequate
sample size, mtDNA provided congruent results with microsatellite loci.
PMID- 10768136
TI - Chromosome evolution of the blue sheep/bharal (Pseudois nayaur).
AB - A male dwarf blue sheep was collected 60 km south of Batang east to the Jinsha
Jiang river, and a male Subei blue sheep (Greater form) was collected from Gansu,
China, representing two geographically separated blue sheep forms. Chromosome
preparations were prepared from fibroblast cultures. The dwarf blue sheep has a
2n = 54 and a karyotype with three biarmed formations that resulted from
acrocentric chromosome fusions (based on the 2n = 60 Capra autosomal equivalents)
14p/5q, 27p/1q, and 29p/2q from the largest to the smallest biarmed chromosome,
respectively. The 14p/5q fusion is metacentric, whereas the 27p/1q and 29p/2q are
submetacentric. The Subei blue sheep had a 2n = 56, with only the 27p/1q and
29p/2q biarmed chromosome fusions. The remainder of the chromosomes in both blue
sheep are acrocentric; the X is the largest acrocentric chromosome and the Y is a
minute biarmed chromosome. Our observation is one evidence showing that
chromosome evolution within blue sheep has followed a series of centric fusions
resulting in the reduction of chromosome number, which is typical of all extant
genera within the tribe Caprini.
PMID- 10768137
TI - Genetics of rough seed coat texture in cowpea.
AB - Seed coat texture is an important trait in determining the acceptability of
cowpea varieties in different regions. A rough seed coat is preferred in western
and central Africa, since it permits easy removal of the seed coat which is
essential for indigenous food preparations. On the other hand, a smooth seed coat
is preferred in eastern and southern Africa as well as in parts of South America
where cowpea is consumed as boiled beans without removing the seed coats. This
study was undertaken to elucidate the inheritance of seed coat texture so that
cowpea breeders may adopt appropriate breeding strategy to develop cowpea
varieties with preferred seed types for different regions. The F1 plants between
smooth- and rough-seeded parents as well as between rough- and rough-seeded
parents produced smooth seeds, indicating a complementary gene action and
dominance for smooth seed coat. The F2 plants from the smooth x rough cross
segregated into a 3 smooth:1 rough seed coat ratio, but the F2 plants from rough
x rough crosses segregated into a 9 smooth:7 rough seed coat ratio. The F1 plants
from backcross to the smooth parent were all smooth, while the F1 plants from
backcross to rough parent segregated in a 1 smooth:1 rough seed coat ratio.
However, both the backcross populations in rough x rough crosses segregated into
1 smooth:1 rough seed coat ratio. These results indicate that two pairs of
independent recessive genes confer rough seed coat texture in cowpea and the
presence of at least one dominant gene at each of the two loci results into
smooth seed coat. The gene symbols rt1rt1 and rt2rt2 are being assigned for rough
seed coat texture in cowpea.
PMID- 10768138
TI - Polymorphism of alpha 1-antitrypsin in North American species of Canis.
AB - alpha 1-Antitrypsin (A1AT) is a major protease inhibitor present in all mammalian
sera that have thus far been investigated. A1AT is also highly polymorphic and is
therefore a useful genetic marker. Previously reported A1AT polymorphism in
domestic dogs consisted of two alleles designated as PiM and PiS which exhibited
frequencies of 0.72 and 0.28, respectively, in a group of randomly collected
mongrel dogs. North American species of Canis, which included gray wolves (n =
29), Mexican wolves (n = 20), coyotes (n = 24), wolf-dog crosses (n = 9), and red
wolves (n = 27) were tested for A1AT polymorphism. A1AT phenotypes were
determined by isoelectric focusing, followed by direct immunoblotting using a
specific antiserum. A1AT concentrations were determined by radial
immunodiffusion. Concentrations of A1AT were similar to those found in domestic
dogs (2.26 +/- 0.3, +/- SD mg/ml, +/- SD) and tended to be higher in females than
in males, possibly indicating that A1AT may be hormonally influenced in females.
Three phenotypic band patterns were observed (M, MS, S). The allele frequencies
for domestic dogs and gray wolves were very similar, 0.72 and 0.67 for PiM and
0.28 and 0.33 for PiS, respectively. The Mexican wolves had a significantly lower
frequency of PiS = 0.10. Coyotes and red wolves were all found to be monomorphic
for the PiS allele and were indistinguishable from each other in that respect.
PMID- 10768139
TI - Fragment length calculator: a Windows 95 program for calculating DNA fragment
length.
PMID- 10768140
TI - POPDIST, version 1.1.1: a program to calculate population genetic distance and
identity measures.
PMID- 10768141
TI - [GABA-ergic system and antiepileptic drugs].
AB - gamma-Aminobutyric acid (GABA) belongs to main inhibitory neurotransmitters in
the central nervous system and activates three types of specific receptors-
GABAA, GABAB i GABAC. At present, little is known about GABAC-mediated events.
GABAB receptors are metabotropic, whilst stimulation of ionotropic GABAA
receptors results in opening the chloride channel, followed by influx of chloride
ions and hyperpolarization. The GABAA receptor possesses also binding sites for
benzodiazepines and barbiturates which, via these sites, enhance GABAA-mediated
events. Another antiepileptic drug potentiating GABA-ergic inhibition is
valproate, which increases synthesis of GABA and reduces its metabolism. Among
new antiepileptic drugs associated with the GABA-ergic system are tiagabine,
vigabatrin, and to a certain degree--gabapentin. Tiagabine blocks neuronal and
glial uptake of GABA whilst vigabatrin increases the synaptic concentration of
GABA by inhibition of GABA aminotransferase. Gabapentin, probably through the
activation of glutamic acid decarboxylase, leads to the increase in synaptic
GABA. However, this antiepileptic drugs is also binds to specific sites within
voltage-dependent calcium channels, which results in the reduced intraneuronal
concentration of calcium ions. Presumably, tiagabine and vigabatrin possess only
one mechanism of action, associated with the increased GABA-ergic inhibition.
Although topiramate and felbamate were shown to enhance GABA-mediated events,
they have additional mechanisms of action, including blockade of voltage
dependent sodium channels and inhibition of glutamatergic neurotransmission.
PMID- 10768142
TI - [Stimulating amino acids in epilepsy: possibilities of treatment].
AB - Stimulating amino acids (glutamine and aspargine) play an essential role in
epileptogenesis. Activating receptors NMDA, AMPA, kainate and metabotropic
influence a conduction of ion canals and a beginning, duration and extinction of
epileptic discharges. Some of the new anti-epileptic drugs introduced in the
recent years modify functioning of glutamine receptors subtypes. It is expected
that they can also decrease a release of glutamines, amplify a GABA-ergic
suppression and block sodium channels. Most information about these drugs in
epileptogenesis was received in animal experiment which is an excuse for a lack
of certainty in a parallel referring their mechanisms to the central nervous
system in a man. Treatment resistant focal or general epilepsies and some
epileptic syndromes are the most often appearing indications for using agents
producing an effect on activating amino acids system. They are most often used in
an added therapy, more rarely in a monotherapy. Some negative comments concern
not very clear influence on cognitive functions, however some hope arises due to
a potential neuroprotective mechanism being a result of a decreased glutamine
release. The drugs blocking a stimulating transmission should be a good
supplement for a present possibilities of epileptic treatment.
PMID- 10768143
TI - [Epilepsy and hormones].
AB - The paper contains a review of reports concerned with how for hormones, epileptic
seizures and antiepileptic drugs can be influenced by one another. Hormones
influence brain excitability but, on the other hand, both epileptic seizures and
antiepileptic drugs may alter hormone secretion and metabolism. Effect of
hormones on seizures--Experimental studies revealed the properties which inhibit
or stimulate convulsive reactivity of different hormones. Progesterone,
testosterone, adrenocorticotropin and desoxycorticosterone are responsible for an
increase in seizure threshold, while estradiol, cortisol and thyroid hormones
cause a reduction. Effect of seizures on hormones--Epileptic seizures, chiefly
tonic-clonic, also complex partial and sometimes simple partial seizures, result
in "the hormonal storm". Immediately after an epileptic seizure, an increase is
found in serum concentrations of prolactin, cortisol, adrenocorticotropin,
triidothyronine, thyroxin, thyrotropin, luteotropin, follicular stimulating
hormone and growth hormone. These changes may persist for two hours, while
prolactin concentration even for 24 hours after a seizure. Effect of
antiepileptic drugs on hormones--Antiepileptic drugs may affect hypothalamus
pituitary function directly or indirectly through neurotransmitter system. By
induction of hepatic microsomal enzymes, some antiepileptic drugs cause
acceleration of hormone metabolism, reducing hormone serum concentrations.
Moreover, antiepileptic drugs enhance sex hormone binding globulin
SHBG/synthesis, increase binding of these hormones and reduce their active
fraction concentration in serum. Recognition of the relationship between epilepsy
and hormonal system is necessary to obtain better understanding of this disease.
PMID- 10768144
TI - [Intractable epilepsy of childhood and its treatment].
AB - This paper discusses the concept of epilepsy intractability as the criterium
qualifying for the administration of polytherapy, inclusion of new antiepileptic
drugs /AEDs/ and application of neurosurgical treatment. There were also
diagnostic criteria and complication discussed. To define the concept of epilepsy
intractability correctly and to administer appropriate treatment, it is necessary
to classify the kind of seizures and their possible reasons, to apply suitable
AEDs, their doses and to treat patients with them for a suitable period of time.
Intractable forms of epilepsy are diagnosed at about 20-30% of patients with
suitable treatment. The disease prevalence is different at particular age groups
and depends also on seizure type or epileptic syndrome. Therefore, Ohtahar
syndrome, West, Lennox and Gastaut syndromes, epilepsia partialis continua belong
to intractable epileptic syndromes at children. There is the biggest risk of
psychic disorders appearance among patients resistant to antiepileptic treatment.
Moreover, long-term application of AEDs may be associated with the induction of
epileptic seizures, occurrence of side and toxic symptoms. Great interest in
intractable epilepsy is connected with huge progress in treatment of this disease
which has resulted in introduction of many new AEDs for the last few years. Its
inclusion into treatment, first as add--on therapy, and then, due to clinical
examinations, also as a monotherapy, enables the improvement in seizure control
and in the quality of patients' life.
PMID- 10768145
TI - [Therapeutic antiepileptic drug monitoring: thirteen years of experience in the
Laboratory of Clinical Neuropharmacology in the Chair and Department of
Developmental neurology].
AB - Determining antiepileptic drug (AED) concentration in biological fluids and
calculating its dosage on this basis is a long-term method in the treatment of
epilepsy. This facilitates the treatment and increases the safety of patients in
the aspect of suitable seizure control and reduced risk of side effects. This
report presented the range and the number of antiepileptic drug concentration
determined during thirteen years activity of Laboratory of Clinical
Neuropharmacology in the Department of Developmental Neurology. There was also a
number of drug concentrations particularly often determined presented, compared
and discussed. Moreover, there were also analyses of subtherapeutic, therapeutic
and potentially toxic concentration decomposition presented for subsequent AEDs.
The frequency of conventional drug and of slow released forms for VPA and CBZ was
compared. VPA appeared to be the most frequently monitored drug and CBZ occurred
to be the next one. The concentrations of PHT, PB, PRM and ETH were more rarely
determined. In the observed period of time the number of LPP concentration
determined in the therapeutic range amounted to 69%, the least frequently the
potentially toxic levels were determined--11%. Normal concentrations i.e.
therapeutic ones were most often determined for CBZ (77%) and subtherapeutic
levels were determined mostly for PHT.
PMID- 10768146
TI - [Carbamazepine presence in plasma lipoproteins].
AB - The aim of this study was to define the disposition of carbamazepine (CBZ) in
serum lipoproteins. The examination was conducted using the serum of 51 patients
treated with carbamazepine the concentration of which was monitored 51 patients,
22 women and 29 men, 1.5-35 years old/mean 13.0 +/- 6.7 years/weighing 10.2-90.0
kg/mean 46.5 +/- 23.6/participated in the study. Every patient received
carbamazepine in an individual oral dose. Concentrations of cholesterol,
triglicerides, proteins and CBZ were determined. Lipoprotein fractions (VLDL,
LDL, HDL and LPDS) were separated by ultracentrifugation of serum. Carbamazepine
concentrations were measured by fluorescence polarization immunoassay technique
on a TD x analyzer. Cholesterol, triglicerides and proteins levels were measured
on Bayer--Technicon apparaturs. Carbamazepine is distributed in plasma
lipoproteins, mainly in HDL fraction (mean 45.2 +/- 9.0%) and in LPDS (mean 43.2
+/- 9.3%) fraction. Ratio of carbamazepine concentration to cholesterol (RcCH),
triglicerides (RcTG) and proteins concentration (RcP) and carbamazepine
concentration (%) to cholesterol (R% CH), triglicerides (R% TG) and proteins
concentration (%/R% P) are different in different fractions. The obtained results
suggest that the disposition of CBZ in lipoprotein fractions may have a
significant importance in the therapy and fat metabolism disorders make the
changes of drug dose urgent.
PMID- 10768148
TI - [The us of video-EEG in the diagnosis of epilepsy syndromes in the developmental
age].
AB - In the Department of Developmental Neurology, K. Marcinkowski University of
Medical Sciences in Poznan 120 video-EEG were performed in 1997-1998. Video-EEG
monitoring was executed by means of computer electroencephalograph "Ceegraph"
(Biologic--USA). A group of 20 patients between the age of 20 months up to 19
years, whose video-EEG was analysed, was hospitalised because of diagnostic
doubtful seizures. Stimultaneous EEG and clinical events recordings were
evaluated with the use of videotape at all children. In the investigated group,
13 patients with epileptic seizures (5 with nonepileptic seizures, 1 patient with
choreatic movements and 1 with nocturnal myoclonus) were recorded. There were 3
children classified with generalised absence seizures, 3 with partial seizures
and 1 patient with myoclonic seizure among the children with epilepsy. Moreover,
there were several different cases diagnosed: 3 patients presented Lennox-Gastaut
syndrome, 1 was classified with West's syndrome, 1 patient was characterised by
Alpers syndrome and 1 with tuberous sclerosis. Psychogenic pseudoepileptic
seizures were classified in 5 patients, in 3 of them both epileptic and
nonepileptic events occurred. Utility of video-EEG monitoring allows to
differentiate and classify seizures and epileptic syndromes in childhood,
especially absence seizures and psychogenic pseudoepileptic seizures. Its use
makes the introduction of appropriate treatment possible.
PMID- 10768147
TI - [Diagnostic value of sleep deprivation as the EEG activation method in diagnosis
of epilepsy in developmental age].
AB - The paper presented the significance of EEG activation in diagnosing epilepsy in
children and adolescents. EEG records of 108 patients between 3-19 years of age
with the occurrence of various types of paroxysmal disorders who were admitted to
Chair and Department of Developmental Neurology University of Medical Sciences in
Poznan were analysed. Standard EEG was administered to all children twice: the
first examination at rest with hyperventilation (HV) and photostimulation (FS)
and the second one after total or partial sleep deprivation (DS). At awaking
state normal records were stated in 57% of cases, in 15% paroxysmal changes in HV
or FS appeared, in the rest of cases (28%) generalised paroxysmal disorders,
localised changes, lateralised or diffused were noted. Among EEG activation
methods DS occurred to be the most effective after it, 52 patients (48%) were
diagnosed for generalised paroxysmal changes, 20% for localised, 3% lateralised
and for 6% for diffused changes. Normal EEG were recorded in 22% of examined
children and adolescents. The epilepsy were diagnosed in 59 (55%) of patients
mostly with generalised seizures (28) partial secondarily generalised (16) and
partially complex (11). In 49 (45%) children were diagnosed with other paroxysmal
disorders.
PMID- 10768150
TI - [The use of EEG polarization in the localization of epilepsy focus].
AB - Multiple spatio dipole structure of brain cortex has been developed to transform
the traditional scalp EEG into an image of source activities. Computer use of
complex calculation algorythms identify those brain regions which are active and
contribute to the epileptiform discharges. The Chair and Department of
Developmental Neurology at University of Medical Sciences in Poznan received a
new imaging technique Focus (Megis, Germany) for testing, which allows to obtain
maps of topographic EEG distribution at the instant chosen in time. Our research
was based on 32-channel EEG files recorded on Ceegraph SE (Bio-Logic, USA). The
purpose of the study was the comparison of traditional EEG evaluation and
automatic analysis made by computer programm "FOCUS". EEG records in patients
with simple partial and complex seizure were marked by a physician,
electroencephalographer. Digital EEG records were also analysed by a source
imaging Focus software. The best localisation of epileptic focus has been
obtained in baso-mesial temporal lobe. The new technique of dipole automatic
analysis is a non-invasive method providing information about seizure
localisation.
PMID- 10768149
TI - [Comparison of modern diagnostic methods in children with intractable focal
epilepsy].
AB - The basic aim of neuroimaging in children with intractable focal epilepsy is
stablishing localization of epileptogenic zone. In this study 34 children (age 11
17 years) with intractable focal epilepsy were examined including: clinical
history, physical examination, EEG, CT, MR, 99mTc-HMPAO SPECT. The hypoperfused
region in interictal SPECT was concordant with clinical seizure characteristics
in 22 children, with EEG in 13, with MR with 13 children. The localization of
hyperperfused region in ictal SPECT was concordant with the clinical seizure
characteristics in 9 from 10 examined children, with EEG in 7 and with MR in 8.
The diagnostic value of estimation of the localization of epileptogenic zone in
interictal SPECT (63 per cent) was comparable with the results of EEG (56 per
cent) and MR (59 per cent), but ictal SPECT offers more information (100 per
cent). In conclusion, performing both ictal and interictal SPECT studies may
provide data about both seizure origin and its relationship with structurally
abnormal regions of the brain.
PMID- 10768151
TI - [P300 event-related potential in epileptic children and adolescents].
AB - P300 is a manifestation of activity in a limited capacity system "whose use in
the service of different tasks is under relative control by instruction". It is
accepted as an objective correlate of mental processing involved in the
allocation of attentional resources when immediate memory is engaged. The aim of
this study was to evaluate cognitive function in epileptic children and
adolescents. We applied the "auditory oddball" paradigm to elicit event-related
potentials (ERPs) according to the IFCN recommendation standards. ERPs were
studied in fifteen patients with generalized epileptic seizures at matched age (8
18 years) (mean 13.8 +/- 2.4 y). 50 neurologically normal children were used as a
control group. ERP were averaged with a Multiliner (Toennies, Germany) equipment.
The method included two different tones for frequent and for rare stimuli
generated at random. The tones were presented binaurally through headphones. ERPs
were recorded at Fz, Cz and Pz according to the International 10-20 system. ERPs
for target and non-target stimuli were averaged separately. The major positive
peak between 250 and 500 ms for the rare tones was regarded as the cognitive
evoked potential (P300). Latency values were obtained from the intersection of
extrapolated lines from the ascending and descending slopes of each peak. The
latencies of the N1, P2, N2 and P300 waves were determined for each subject, as
well as peak to peak amplitudes of N1-P2, P2-N2, N2-P300. Auditory event related
potential may be helpful procedures used in objective evaluation of cognitive
function in patients with epilepsy.
PMID- 10768152
TI - [Bimodal evoked potentials during long-term therapy with conventional or slow
release preparations of carbamazepine and valproic acid in children and
adolescents with epilepsy].
AB - The measurement of evoked potentials (EPs) may be particularly useful in clinical
neuropharmacology for investigation of drug effects of afferent nerve conduction
within CNS. The study aims at estimating the long term effects of conventional or
slow release formulation (CR) of carbamazepine (CBZ) and valproid acid (VPA) on
visual (VPA) and brainstem auditory (BAEP) evoked potentials. Investigation
covered 125 patients 8 to 18 years old to whom both formulations of CBZ or VPA
were administered in monotherapy. Everyone received a drug dosage which gave an
adequate therapeutic plasma concentration and satisfactory seizure control.
Antiepileptic drugs (AEDs) plasma levels were measured by means of fluorescence
polarization immunoassay method aided of TDx Analyzer (Abbott, Diagnostic). EPs
were registered by means of Multiliner (Toennies, Germany). A pattern of reversal
stimulation for VEP was used. The latencies of N75, P100, N145 as well as
interpeak amplitudes of N75/P100, P100/N145 were evaluated. The following BAEP
parameters were considered: morphology of the potential, absolute latencies of
waves I, III, V and I-III, III-V, I-V. EP were always performed in the same
conditions and with the same equipment for the epileptic and control groups. The
obtained values were compared with age-matched control group. The following BAEP
abnormalities were observed: prolonged absolute latencies of waves I, III, V as
well as prolonged IPLs I-III. The BAEP V/I amplitude ratio and morphology of the
waves were normal in all patients. The VEPs abnormalities manifested as
prolongation of P100 or N145 latencies and reduction of amplitudes N75/P100,
P100/N145. Results of these electrophysiological studies with CBZ and VPA
demonstrate that EP are sensitive, noninvasive reflectors of AEDs effects within
the CNS.
PMID- 10768153
TI - [The use of lamotrigine monotherapy in children with newly diagnosed partial
epilepsy].
AB - Lamotrigine (Lamictal, Glaxo Wellcome) is a drug which is used as add-on therapy
in patients with refractory epilepsy. Several previous studies have demonstrated
the efficacy of lamotrigine monotherapy, but only few have been done in pediatric
patients. The aim of our study was the assessment of efficacy and tolerability of
lamotrigine monotherapy in children with newly diagnosed partial epilepsy.
Lamictal was used in 19 children (11 boys and 8 girls), aged 3-16 years. 17
patients demonstrated complex partial seizures (with or without secondarily
generalisation), 2 children had simplex partial seizures. Symptomatic epilepsy
was diagnosed in 10 patients and cryptogenic epilepsy in 9 cases. The drug was
administered at the dose of 3.87 +/- 1.02 mg/kg/day during 24 weeks. Three
children withdrew from the study because of adverse events: one patient developed
rash, two ones seizure exacerbation. Lamictal produced of at least 50% reduction
in seizure frequency in 12 (63.15%) children, included 10 seizure-free patients.
One third patients experienced EEG improvement. The most common adverse effects
were gastrointestinal and sleep disturbances, infections, dizziness, all of them
were mild and transient and observed more often in children under 12 years of
age. Lamotrigine monotherapy is effective and safe for treatment of newly
diagnosed cryptogenic and symptomatic epilepsy with partial seizures but further
studies are necessary specially in young children.
PMID- 10768154
TI - [Effectiveness and tolerance of adjunctive treatment of lamotrigine and
conversion to monotherapy in pediatric patients with epilepsy. Preliminary
studies].
AB - The examination concerned patients with intractable epilepsy aged 9-19 years with
partial seizures simple or complex, developing into generalized ones years,
treated with VPA (valproate) or CBZ (carbamazepine). They received VPA or CBZ for
at least 4 weeks and even with the therapeutic concentration of these drugs in
blood serum in the month preceding the examination they demonstrated seizures at
least twice. For a period of 8 weeks lamotrigine (LTG) was progressively added to
the therapy. Both drugs were administered for at least 8 weeks in a full dose. In
case of achieving a good therapeutic effect assessed on the basis of at least 50%
seizure reduction the use of VPA or CBZ was gradually discontinued. In the period
of 12-week observation an application of LTG monotherapy 2/3 of patients achieved
50-100% reduction of seizures. These patients improved reasoning dynamics and
memorizing ability. After LTG administration EEG showed normalization of
background activity and reduction of number and time of epileptic discharges.
PMID- 10768155
TI - [Neuropsychological aspects of cognitive functioning in epileptic children and
adolescents treated with lamotrigine].
AB - The aim of our study was to examine the influence of long term lamotrigine (LTG)
add-on therapy on higher nervous function in patients at the developmental age
with epilepsy and to analyse the correlation between changes in EEG and cognitive
parameters as a consequence of applying LTG in bi- or polytherapy with
conventional antiepileptic drugs (AEDs). There were 25 patients (pts), 8-18 years
of age with epilepsy stated as "difficult to treat" with partial (12 pts) and
generalised (13 pts) seizures. The frequency of seizures was estimated as one or
more per month last year (before LTG treatment). The mean age of the patients who
had the first seizure was 4.7 yrs. Doses of LTG were adjusted individually
(depending on conventional AEDs) according to the recommendation of the producer.
The serum levels of conventional AEDs were checked during LTG therapy.
Psychological examination was administered three times: before introduction of
LTG (as add-on drug) to the therapy, after 3- and after 16 months of the
treatment. We measured the level of intelligence, short-term memory, attention,
visuomotor integration and abilities of learning. EEG was recorded by Ceegraph
(Biologic, USA) after 3 and 12 months of LTG treatment. After the treatment no
statistically significant differences in Intelligence Quotient (IQ): global,
verbal, nonverbal were noticed. Statistical significance has been stated in
parameters of short-term memory. The number of seizures decreased more than 50%
in 12 pts. EEG records improved in 6 pts (normalisation of background activity),
minimising of epileptform discharges has been noticed in 3 pts. LTG introduced
into polytherapy of epilepsy in children and adolescents modified EEG and had
minimal influence on cognitive functions.
PMID- 10768156
TI - [Lamotrigine versus vigabatrin as an add-on therapy in refractory epilepsy:
prospective study].
AB - Lamotrigine (LTG) and Vigabatrin (VGB) has been licensed widely as adjunctive
therapy for partial and secondary generalized seizures. We compared the
efficiency of Lamotrigine and Vigabatrin as adjuvant therapy for 33 patients (16
male and 17 female) with drug-resistant partial epileptic seizures (simple and
complex) with secondary generalization receiving combination therapy
(carbamazepine--CBZ and valproic acid--VPA). Patients were enrolled if they had
experienced two partial seizures (simple or complex) and one secondary
generalization/month, despite combination therapy. Neurologic evaluation
including CT, MRI and EEG was performed every 3 months during observation. Blood
specimens for CBZ and VPA plasma concentration were obtained prior to the first
LTG or VGB dose and twice a year during the treatment. The assessment of LTG and
VGB effectiveness was performed in 2-month intervals during 2-3 years for
vigabatrin (mean daily dose 2.0 g) and 1-2 years for Lamotrigine (mean daily dose
0.3 g). The treatment (CBZ, VPA or both) with Vigabatrin or Lamotrigine as
adjunctive therapy was effective in about a half of patients with refractory
epilepsy. Findings suggest that the reduction in partial seizures (simple or
complex) frequency with Vigabatrin is greater than that with Lamotrigine. On the
other hand, Lamotrigine seems to be more effective in patients with partial
epileptic seizures with secondary generalization.
PMID- 10768157
TI - [Clinical analysis of the effectiveness and safety of vigabatrin].
AB - The efficacy and safety of vigabatrin (VGB) has been extensively evaluated in
preclinical and clinical studies but level of effectiveness in different type of
seizures has yet to be established. The aim of our study is the prospective
evaluation of anticonvulsant efficacy and toxicity of VGB. This long-term
observation mainly focusing on efficacy of VGB in partial vs. secondarily
generalized seizures were considered separately. In our study the criterion of
drug resistance is occurrence per month of at least 1 tonic-clonic seizure or at
least 2 complex partial seizures in 3 following months. The studies are based on
73 patients (39 F and 34 M), with average age of 26 years. After two weeks of
treatment with sabril the drug was withdrawn in 5 patients because of side
effects. The period of observation was 12 months. In group I--from total of 73
patients with partial seizures (including secondarily generalized)--31 (42%) of
patients suffered only from partial seizures. Complex partial seizures occurred
in 18 of patients; in this group were also 13 patients with simple partial
seizures. Group II consisted of 42 patients (58%) who suffered from secondarily
generalized tonic-clonic seizures. Number of seizures in group of patients with
tonic-clonic seizures was from 1 to 16 per month (average 3.4) and in group of
patients with complex partial seizures was from 1 to 70 per month (average
13.29). After titration period, Vigabatrin was given in doses of 500 to 3500 mg
daily. Mean monthly fit frequency was calculated for over 3 months prior to the
addition of vigabatrin and 12 months of therapy at the patient's maximum dose.
Monthly fit frequency expressed as mean +/- standard error of the mean, and this
statistical significance was determined using MANOVA for repeated measurement.
Average monthly fit frequency of partial seizures has been reduced from 13.29 to
6.96 (p < 0.0001) and of generalized seizures from 3.38 to 1.38 (p < 0.0001). The
percentage of patients achieving an increase of at least 75%--(Ratio < -0.6)--of
seizures was greater in generalized seizures (27.3) than in partial ones (21.3).
VGB is effective and well tolerated in refractory patients requiring add-on
antiepileptic treatment and it has shown efficacy both in therapy of refractory
partial seizures as well of secondarily generalized ones.
PMID- 10768158
TI - [Vigabatrin in the treatment of intractable focal epilepsy in children and
adolescents. Two-year study].
AB - Vigabatrin VGB is the drug of III generation applied for a long time to patients
in Poland. In Polish literature there were many reports published concerning the
efficacy of VGB, however, most are short-term examinations. The AIM OF THE STUDY
WAS: 1. the analysis of VGB efficacy in long term treatment of intractable focal
epilepsies in children and adolescents; 2. stating if efficacy of VGB treatment
depends on localization of epileptic focus; 3. answering if the effect of
tolerance is developed in relation to VGB. MATERIALS AND METHODS: There were 50
patients between 4 to 20 years of age (average 12.7 +/- 4.8) with intractable
focal epilepsy in the examined group. partial complex seizures were the dominant
type of seizures at 74% of the examined patients. Time of observation amounted to
24 months. The patients were administered with VGB as add-on therapy. 37 patients
(74%) were diagnosed with temporal lobe epilepsy, 11 (22%) with frontal lobe
epilepsy, 1 patient (2%) with parietal lobe epilepsy and 1 (2%) with occipital
lobe epilepsy. Patients who did not complain of seizures for a period of at least
one year were classified as those with "seizure free". RESULTS: The examination
was completed for 36 patients (76%). The treatment was discontinued in 12
patients (24%) as there was not a sufficient seizure control. One patient with
temporal lobe epilepsy stopped the drug as three occurred the epileptic state of
atypic generalised absence seizures induced by VGB. The final evaluation
comprised all 50 examined patients. 9 patients (18%) achieved complete seizure
control, 24 (48%) reduction to 50-99%. There was no change in 17 patients (34%).
The examined patients with frontal localisation of epileptic focus presented
significantly worse results of treatment, i.e. (reduction in the number of
seizures over 35.3-36.5%) than the patients with temporal lobe epilepsy
(reduction over 63.8 +/- 37.2%--p < 0.001). No significant difference in the
average number of seizures in the 5th and 24th month of treatment was reported in
the whole examined group. This contradicts the existence of the effect of
tolerance in relation to VGB. CONCLUSIONS: 1. Vigabatrin is a very efficient drug
in long-term treatment of patients with intractable focal epilepsies. 2. Patients
with temporal lobe epilepsy present statistically better treatment results than
patients with frontal lobe epilepsy. 3. No effect of tolerance to VGB was
recorded during a 2-year observation.
PMID- 10768159
TI - [Positive effect of falbamate therapy in a boy with refractory epilepsy].
AB - One of the most important achievement of contemporary epileptology has been a
concept of epileptic syndromes. According to the Commission on Classification and
Terminology of the International League Against Epilepsy there are many epileptic
syndromes which differ from each other not only by prognosis but also by reaction
to pharmacotherapy. Nevertheless the differentation between the some of epileptic
syndromes may be difficult in spite of quite precise clinical and
electrophysiological criteria. Good example of this problem may be the course of
disease of the boy who is now eleven years old. His refractory epilepsy which
started 7 years ago shares symptoms and signs of both epilepsy with myoclonic
astatic seizures (Doose Syndrome) and Lennox-Gastaut Syndrome. Felbamate therapy
was consider to be the turning-point in both therapeutic and diagnostic meaning.
PMID- 10768160
TI - [Preliminary assessment of felbamate effect on the cerebral bioelectrical
activity in children with refractory epilepsy].
AB - Influence Felbamate on the cerebral bioelectric activity (EEG) in the group of 31
children (18 with syndrome Lennox-Gastaut, 13 with partial epilepsy) with
refractory epilepsy was investigated. In the waking EEG was visually analysed: 1.
Abnormalities distribution and morphology with special consideration of slow
waves, sharp elements and paroxysmal character of discharges. 2. Influence of
Felbamate on the duration time of discharges. 3. Range dominant frequency and
length of segments (with non-disturbed topographic differentiation) of background
activity EEG. During therapy the results showed more often EEG improvement among
children with syndrome Lennox-Gastaut (near 70%) than in children with partial
refractory epilepsy (near 30%). The EEG results correlated positively with the
clinical improvement. In the both group of epilepsy background activity
improvement had a statistical significance. In sleep EEG any influence of
Felbamate on the sleep spindles was observed. No observation about increase beta
activity in waking and sleep EEG records was noted.
PMID- 10768161
TI - [Oxcarbazepine in the treatment of drug-resistant epilepsy in children and
adolescents: preliminary study].
AB - A comparative study was conducted to evaluate the efficacy and tolerability of
oxcarbazepine administration in patients with a diagnosed intractable epilepsy
with simple partially and complex seizures secondarily generalised. There were 12
patients aged between 2-23 treated in Outpatients' Neurological Department for
Children and Adolescents in Poznan. Oxcarbazepine was applied as an add-on
therapy in all patients. The drug was administered in 3 daily dose. The doses of
oxcarbazepine were evaluated as well as the occurrence of adverse effects was
recorded. Four patients presented over 50% reduction of seizures. During the
whole period of observation there was no occurrence of adverse effects associated
with the inclusion of oxcarbazepine as add-on drug.
PMID- 10768162
TI - [Tiagabine in drug-resistant epilepsy in children: preliminary study].
AB - The aim of the study was the presentation of our preliminary experiences and the
data concerning the efficacy and safety of tiagabine in patients below the 12-th
year of life. 4 cases of drug--resistant epilepsy--with partial complex attacks
in 3 and simple in 1 (frontal epilepsy from supplementary motor area) with
multiple seizures in the day were the subject of the study. Tiagabine add-one
therapy to CBZ or to VPA was used. Initial period--the dose titration lasted 4
weeks. The stable dosis period amounted to 5 months. The effective dosis of
tiagabine was 1 mg/kg/day. In 1 case the seizures completely disappeared and in 3
the frequency decreased to 2-4 times in comparison to frequency per day before
the treatment. There were not any side-effects reported which would be the cause
of the drug discontinuation. IN CONCLUSION: Tiagabine appeared to be an effective
and safe drug in resistant epilepsy in children below 12 years of age.
PMID- 10768163
TI - [Surgical treatment of clinical syndromes of intractable epilepsy in
developmental age].
AB - According to a longterm cathamnestic investigation in a series of 2400 patients
80% had favorably responded to medication, 60% are seizure free and in 20% there
was significant improvement. In further 20% any therapy has had failed. 200
children have been operated upon because of epilepsy resistant to pharmacological
treatment. In 80 classical methods (hemispherectomies, lobectomies topectomies
and disconnective techniques) have been performed. In further 120 cases
nosologically verified symptomatic epilepsy associated with the leading symptom
of untreatable fits due to aetiological lesions as neoplasms, scars, angiomas,
cysts lesionectomies extended by focectomies have been performed.
PMID- 10768164
TI - [Cerebral tumors as a cause of refractory epilepsy in children].
AB - Cerebral tumours are a cause of seizures in less than 1-2% of children epilepsy.
Seizure symptoms usually precede the diagnosis by several years and are often the
only symptoms of an ongoing process. The symptomatology of the seizures often
correlates with localization of a neoplastic lesion. The authors present six
children aged 3 to 18 in whom epileptic seizures not susceptible to treatment
were caused by cerebral tumours. The duration of epilepsy until the determining
of the aetiology was various--from half a year to 13 years. In each of our six
patients focal epilepsy occurred with simple or complex seizures with secondary
generalization. It was only one patient in whom the tomography of the head turned
out to be sufficient enough to establish the diagnosis of a brain tumour; in the
other ones MR was necessary. The final diagnosis in four of the children was
supported by histopathologic examination carried out during a neurosurgical
procedure, whereas in one of them--by means of biopsy of the brain.
PMID- 10768165
TI - [Phacomatoses: structural substare of epilepsy].
AB - AIM: Evaluation of frequency and characteristics of seizures in the most frequent
phacomatoses and assessment of relationship between fits and structural changes
in CNS. MATERIAL AND METHODS: 135 children with tuberous sclerosis (TS), 73 with
NF-1 and 30 with Sturge-Weber syndrome took part in the study. Except for careful
anamnesis in all patients with fits were done brain CT or MR studies. RESULTS:
Seizures were reported in 128 of 135 (95%) patients with TS, usually, between 3rd
and 6th month of life. Their early presentation was related to developmental
delay. Cortical and subcortical lesions detected in neuroimaging studies were
responsible for drug-resistant epilepsy in the children. 13 of 73 (18%) children
with NF-1 had seizures. In 9 of them CNS lesions were detected on neuroimaging.
In Sturge-Weber syndrome inherited meningo-encephalic lesions correlated with
hemilateral seizures, even in first months of life. Most children did not show
apparent developmental delay. CONCLUSIONS: Epileptic seizures in phacomatoses had
their own specificity. They were correlated with structural lesions in CNS.
PMID- 10768166
TI - [The evaluation of selected factors in the prognosis of drug-resistant epilepsy
in children with brain malformations].
AB - Brain malformations are important and frequent epilepsy reason in children and
adolescents. During the last six years in neurological department of Pediatrics
Clinic in Katowice were treated 106 children with brain malformations
demonstrated in magnetic resonanse imaging. The main clinical symptoms in these
patients were following: mental retardation, epilepsy, abnormalities in
neurological examinations, dysmorphic features. Epilepsy were observed in above
3/4 of patients (84 children). In most of them there was intractable epilepsy (55
children). The aim of study was evaluation of selected factors in prognosis of
epilepsy intractibility. The children with brain malformations and epilepsy were
divided into two groups: with intractable epilepsy and with good response for
pharmacotherapy. The type of malformation, the pre- i perinatal history, an age
at which the first seizures appeared, abnormalities in neurological examination
and IQ were compared in both groups. The differences weren't significant
statistically apart two data. Normal pre- and perinatal history and early
manifestation of seizures (during the first half of life) were confirmed
significant statistically more often in group of patients with intractable
epilepsy. There was limited value of most of the analysed parameters in prognosis
of epilepsy intractibility. Further accumulating of data and increasing of number
of the patients group with different types of malformations as well as progress
in diagnostics, particularly molecular genetics, may be helpful in correct
prognosis.
PMID- 10768167
TI - [Epileptic seizures in children and youth with cerebral palsy].
AB - An epidemiological analysis of the data recorded from a population of children
and youth from Zielona Gora in the age 0-18 years was made. Among 96 patients
with cerebral palsy (CP), the group of 29 children with epilepsy was separated.
Real relations between type and frequency of epileptic seizures in particular
clinical subtypes of CP was observed. Interdependences between mental development
and epilepsy were analysed. West or Lennox-Gastaut syndrome was more frequent
among children with severe or profound mental retardation when in other groups.
It was observed, that patients with severe motoric dysfunctions had epileptic
seizures in younger age than the other. In this group status epilepticus was
observed more frequent too. Effects of mono or politherapy in particular types of
seizures were analysed.
PMID- 10768168
TI - Heterogeneity of cerebral blood flow: a fractal approach.
AB - AIM: We demonstrate the heterogeneity of regional cerebral blood flow using a
fractal approach and single-photon emission computed tomography (SPECT). METHOD:
Tc-99m-labelled ethylcysteine dimer was injected intravenously in 10 healthy
controls and in 10 patients with dementia of frontal lobe type. The head was
imaged with a gamma camera and transaxial, sagittal and coronal slices were
reconstructed. Two hundred fifty-six symmetrical regions of interest (ROIs) were
drawn onto each hemisphere of functioning brain matter. Fractal analysis was used
to examine the spatial heterogeneity of blood flow as a function of the number of
ROIs. RESULTS: Relative dispersion (= coefficient of variation of the regional
flows) was fractal-like in healthy subjects and could be characterized by a
fractal dimension of 1.17 +/- 0.05 (mean +/- SD) for the left hemisphere and 1.15
+/- 0.04 for the right hemisphere, respectively. The fractal dimension of 1.0
reflects completely homogeneous blood flow and 1.5 indicates a random blood flow
distribution. Patients with dementia of frontal lobe type had a significantly
lower fractal dimension of 1.04 +/- 0.03 than in healthy controls. CONCLUSION:
Within the limits of spatial resolution of SPECT, the heterogeneity of brain
blood flow is well characterized by a fractal dimension. Fractal analysis may
help brain scientists to assess age-, sex- and laterality-related anatomic and
physiological changes of brain blood flow and possibly to improve precision of
diagnostic information available for patient care.
PMID- 10768169
TI - One-year follow-up of neuropsychology, MRI, rCBF and glucose metabolism (rMRGlu)
in cerebral microangiopathy.
AB - BACKGROUND: MRI shows lacunar infarctions (LI), deep white matter lesions (DWML)
and atrophy in cerebral microangiopathy, which is said to lead to vascular
dementia. In a first trial series on 57 patients with confirmed pure cerebral
microangiopathy (without concomitant macroangiopathy), neuropsychological
impairment and (where present) brain atrophy correlated with decreased rCBF and
rMRGlu. LI and DWML did not correlate with either neuropsychological impairment
or decreased rCBF/rMRGlu. This study was done one year later to detect changes in
any of the study parameters. METHODS: 26 patients were re-examined for rCBF,
rMRGlu, LI, DWML, atrophy and neuropsychological performance (7 cognitive, 3
mnestic, 4 attentiveness tests). Using a special head holder for exact
repositioning, rCBF (SPECT) and rMRGlu (PET) were measured and imaged slice by
slice. White matter/cortex were quantified using MRI-defined ROIs. RESULTS: After
one year the patients did not show significant decreases in rCBF or rMRGlu either
in cortex or in white matter (p > 0.05), nor did any patient show LI, DWML or
atrophy changes on MRI. There were no significant neuropsychological decreases (p
> 0.05). CONCLUSIONS: Cerebral microangiopathy ought to show progressive
neuropsychological, functional (rCBF, rMRGlu) and morphological deterioration
over periods > 1 year. It is unlikely that direct cortical damage (e.g.,
incomplete infarction) is responsible for neuropsychological impairment since one
year follow-up of our patients revealed no progression of brain atrophy or any
other cortical damage.
PMID- 10768171
TI - [Cortical blindness following heroin intoxication].
PMID- 10768170
TI - [Comparison of different methods for attenuation correction in brain PET: effect
on the calculation of the metabolic rate of glucose].
AB - AIM: There are several approaches for correcting the effects of photon scatter or
absorption by body tissues on positron emission tomography (PET). We examined the
influence of cold, hot and segmented transmission as well as of a mathematical
procedure on attenuation correction using regional cerebral glucose metabolism
(rMRGlu). METHODS: 6 patients with different cerebral diseases were examined
under resting conditions using an ECAT Exact 922/47. The attenuation-corrected
data (corrected by means of cold, hot and segmented transmission as well as a
mathematical procedure) were then quantified absolutely for assessment of
regional glucose metabolism in 16 regions of interest (ROIs). RESULTS: Using
absolutely quantified glucose metabolism in 16 ROIs, no significant differences
were found between cold transmission and the mathematical procedure except for
three regions (left and right temporal occipital and right parietal occipital).
Unlike the mathematical procedure, both hot and segmented transmission showed a
significantly lower value for regional glucose utilization in all 16 ROIs than
did cold transmission. The left and the right hemisphere both showed metabolic
values (rMRGlu) in the same decreasing order: cold transmission, the mathematical
procedure, hot or segmented transmission. There was no significant difference
between global cerebral glucose metabolism values for cold transmission and the
mathematical procedure (p = 0.25) while those for hot (p = 0.03) and segmented
transmission (p = 0.03) did show a significant difference. CONCLUSIONS: Except
for 3 regions (temporo-occipital left, temporo-occipital right and parieto
occipital right) attenuation correction procedures used for brain PET studies on
patients show no significant quantitative differences between cold transmission
and the mathematical procedure. rMRGlu of images corrected for attenuation using
hot and segmented transmission is significantly lower than of attenuation
corrected images where cold transmission was employed. For clinical routine
examinations, the mathematical procedure seems the best alternative to cold
transmission for a faster brain PET acquisition.
PMID- 10768172
TI - [Otobasal fistula as cause of recurring bacterial meningitis].
PMID- 10768173
TI - [Spontaneous intracranial hypotension syndrome in cervicothorackc cerebrospinal
fluid leak].
PMID- 10768174
TI - [Reduced antithyroid agents as a result of radioiodine therapy?].
PMID- 10768175
TI - Synthesis and resolution of a novel chiral diamine ligand and application to
asymmetric lithiation-substitution
AB - A short, efficient synthesis of chiral 1,5-diaza-cis-decalins (7) is presented.
In the lithiation of N-Boc pyrrolidine, the ligands with the smallest most
electron rich R groups (Me > Et > CH2tBu > CH2CF3 approximately Bn) were most
effective. In the asymmetric deprotonation/substitution of benzylic substrates,
(R,R)-7 (R = Me, R' = H) conferred modest selectivity. The ready availability of
both enantiomers of the 1,5-diaza-cis-decalins and the ability to tune steric and
electronic properties renders these compounds an attractive new class of diamine
ligands.
PMID- 10768176
TI - Pd(DIPHOS)2-catalyzed cross-coupling reactions of organoborons with free or
polymer-bound aryl halides.
AB - Bis[1,2-bis(diphenylphosphino)ethane]palladium(0) [Pd(DIPHOS)2] catalyzes cross
coupling reactions of free or polymer-bound aryl halides with organoboron
compounds to produce biaryls in overall yields of 60-96%.
PMID- 10768177
TI - High regio-, chemo-, and stereoselectivity via low-temperature 4 + 3
cycloadditions. Convergent synthesis of multifunctionalized vinylmetals (M = Si,
Sn) and S-vinyl benzenecarbothioates
AB - A series of enantiomerically pure 8-oxabicyclo[3.2.1]oct-6-en-3-ones
functionalized in the unsaturated two-carbon bridge has been prepared by the
title reaction. Carbocation reactivity has been fined-tuned at -95 degrees C and
adjusted to diene nucleophilicity. Conventional electrophilic substitution of 3
silylated and 3-stannylated furan is suppressed in favor of the rapid 4 + 3
cycloaddition mode. In the case of cycloadduct 13A, stereoselectivity (17:1) is
perfectly matched to regioselectivity (17:1). High stereoselection as well as
unprecedented regioselection and chemoselection is attributed to the low
temperature cycloaddition protocol and the design of chiral auxiliary and tether.
PMID- 10768178
TI - The first total synthesis of annonacin, the most typical monotetrahydrofuran
annonaceous acetogenins.
AB - The first total synthesis of annonacin (1) was achieved by a highly convergent
synthetic strategy. All the stereogenic centers were derived from three natural
hydroxy acids respectively, except that those at C19 and C20 were produced from a
Sharpless AD reaction.
PMID- 10768179
TI - Total synthesis of fully acetylated N-acetylneuraminic acid (Neu5Ac), 2-deoxy
beta-Neu5Ac, and 4-epi-2-deoxy-beta-Neu5Ac from D-glucose
AB - Sialic acid and its analogues have been synthesized using a salenCo(II) complex
catalyzed hetero Diels-Alder reaction and oxidative azidation (CAN/NaN3) of silyl
enol ether as the key steps.
PMID- 10768180
TI - Stereoselective alkylation of N-Boc-protected-5-substituted delta-lactams:
synthesis of alpha, delta-disubstituted delta-amino acids
AB - N-Boc-protected-5-substituted delta-lactams were readily prepared from the
corresponding beta 3-amino acids. Alkylation reactions of their Na enolates with
various electrophiles proceeded in high yields with high facial selectivity. The
structure of the alkylation products was confirmed by single-crystal X-ray
analysis. This method provides a fast access to optically active alpha, delta
disubstituted delta-amino acids.
PMID- 10768181
TI - A carbon-centered radical unreactive toward oxygen: unusual radical stabilization
by a lactone ring
AB - A lactone ring confers unusual stability to a diphenylmethyl-like radical that is
virtually unreactive toward oxygen. Thus, the radical derived from HP-136 is
about 10,000 times less reactive than typical carbon-centered radicals. A
reversible reaction with oxygen is proposed by analogy with triphenylmethyl;
however, the association constant is about 1000 times smaller for HP-136 than for
triphenylmethyl. While the lactone ring greatly influences the reactivity, the
spectroscopy of the HP-136-derived radical is in line with that expected for a
substituted diphenylmethyl radical.
PMID- 10768182
TI - X-ray crystal structures of conformationally biased flavin models.
AB - X-ray crystal structures of the oxidized form of three conformationally biased
flavin models are reported. Models 4 and 5 show significant distortion, which
contributes to their bias for the fully reduced form.
PMID- 10768183
TI - Solid-phase synthesis of beta-lactams via the ester enolate-imine condensation
route.
AB - The ester enolate-imine condensation route to beta-lactams via an immobilized
ester enolate has been achieved for the first time. The key reaction in the
synthesis is the cyclization of the resin bound ester dianion and an imine.
Traceless cleavage from the T1-triazene linker system yields the desired beta
lactams.
PMID- 10768184
TI - Recognition of flexible peptides in water by transition metal complexes.
AB - This paper describes the design, synthesis, and evaluation of transition metal
complexes capable of recognizing flexible histidine-containing peptides in
aqueous medium (25 mM HEPES buffer, pH = 7.0, 25 degrees C). When the pattern of
metal ions on a complex matches with the pattern of histidine moieties on the
peptide, strong interaction (K = 1.2 x 10(6) M-1) can be achieved. The complex
was highly selective (> 200:1) in discriminating similar flexible peptides
differing only by one glycine unit.
PMID- 10768185
TI - "Masterpiece" copolymer sequences by targeted equilibrium-shifting
AB - We describe an equilibrium model to determine whether a random population of
dynamic copolymer sequences could be driven by molecular recognition to a subset
of sequences that tightly bind a specific ligand. The model predicts that the
population's mean binding constant can be shifted, but because of competitive
binding, only to a limited degree (ca. 2 orders of magnitude larger than the
original mean). True chemical evolution will require a mechanism for selection
and amplification.
PMID- 10768186
TI - Relative and absolute configurations of ganefromycin alpha.
AB - The full structure of ganefromycin alpha has been determined. The relative
configurations were determined from 3JH,H coupling constants and NOE data, while
the absolute configurations in moleties A and B were determined separately by
difference CD of their acylate derivatives, which showed typical exciton
couplets. The configurations of the stereogenic centers in ganefromycin alpha are
8S, 9S, 11R, 12S, 13S, 21S, 22R, 23R, 24R, and 26S.
PMID- 10768187
TI - A diastereoselective switch in the access to isobenzofuran-derived alpha
selenoesters
AB - The cycloaddition of 1-phenylisobenzofuran (PIBF) with methyl acrylate yields, in
a moderate endo/exo ratio, the expected oxa-bridged adduct, which can be
deprotonated and condensed on diphenyl diselenide to provide, in a
stereoconvergent step, the "endo" alpha-selenoester. Its "exo" epimer is obtained
by reacting PIBF and methyl alpha-phenylselenoacrylate. These adducts can be
oxidized to give a common unsaturated bridged ester that can react with an
imminium ylide to provide the expected pyrrolidine stereoselectively.
PMID- 10768188
TI - Facile synthesis of O6-alkyl-, O6-aryl-, and diaminopurine nucleosides from 2'
deoxyguanosine
AB - The 3',5'-bis-O-TBDMS derivative of 2'-deoxyguanosine can be converted to its O6
alkyl and O6-aryl ethers as well as to N6-substituted diaminopurine nucleosides
in two simple steps. Also described is a novel, nonaqueous, one-step O6
desulfonylation method that leads to deprotection of the carbonyl moiety of 2'
deoxyguanosine.
PMID- 10768190
TI - A new catalytic and enantioselective desymmetrization of symmetrical methylidene
cycloalkene oxides
AB - Chiral copper complexes of C2-symmetrical phosphoroamidites were found to be
highly effective catalysts for both kinetic resolution and novel desymmetrization
reactions of new methylidene epoxycycloalkanes.
PMID- 10768191
TI - Enantioselective photoreduction of arylalkyl ketones via restricting the reaction
to chirally modified zeolite cages
AB - Obtaining a high enantiomeric excess during a photoreaction within a zeolite is
hampered by the statistical distribution of reactant and chiral inductor
molecules within the cages of a zeolite. By restricting the photoreactions to
only those cages that contain both the reactant and a chiral inductor, one should
be able to avoid reactions that yield racemic products. This approach is
illustrated with the photoreduction of an arylalkyl ketone by a chiral inductor
with an amino group.
PMID- 10768192
TI - Palladium-catalyzed cyclization reaction of allylic bromides with 1,2-dienyl
ketones. An efficient synthesis of 3-allylic polysubstituted furans
AB - 3-Allylic polysubstituted furans were synthesized via a palladium-catalyzed
cyclization reaction of allylic bromides with differently substituted 1,2-allenyl
ketones. This process may occur via the reaction of a furanyl palladium
intermediate with allylic bromide.
PMID- 10768193
TI - Total synthesis of (+)-amphidinolide P. [corrected].
AB - The convergent enantiocontrolled total synthesis of the 15-membered macrolactone
(-)-amphidinolide P is reported. Key transformations include a Sakurai
allylation, a Stille coupling for the formation of a fully functionalized acyclic
precursor, and intramolecular transesterification.
PMID- 10768194
TI - A new route to cyclopentenones via ruthenium-catalyzed carbonylative cyclization
of allylic carbonates with alkenes
AB - [RuCl2(CO)3]2/Et3N and (eta 3-C3H5)RuBr(CO)3/Et3N are highly effective catalyst
systems for carbonylative cyclization of allylic carbonates with alkenes to give
the corresponding cyclopentenones in high yields. For example, treatment of allyl
methyl carbonate (1a) with 2-norbornene (2a) in the presence of a catalytic
amount of [RuCl2(CO)3]2 (2.5 mol %) and Et3N (10 mol %) at 120 degrees C for 5 h
under 3 atm of carbon monoxide gave the corresponding cyclopentenone, exo-4
methyltricyclo[5.2.1.0(2,6)]dec-4-en-3-one (3a), in 80% yield with high
stereoselectivity (exo 100%).
PMID- 10768195
TI - A concise synthesis of physostigmine from skatole and activated aziridine via
alkylative cyclization.
AB - A concise synthetic route to physostigmine has been developed, where the key step
relies on the alkylative cyclization of 1,3-dimethylindole with (Z)-aziridine
catalyzed by Sc(OTf)3 and TMSCI in dichloromethane at -30 degrees C, to give 8 in
90% yield, which, in turn, can be readily converted into physostigmine.
PMID- 10768196
TI - Synthesis of the C16-C28 spiroketal subunit of spongistatin 1 (altohyrtin A): the
pyrone approach.
AB - The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has
been accomplished utilizing the addition of a metalated pyrone to an aldehyde and
subsequent acid-catalyzed spirocyclization. A stereoselective hydrogenation and
subsequent conformational inversion establish the C19 stereocenter and the axial
equatorial spiroketal center.
PMID- 10768197
TI - Perylene synthesis by the parallel cycloaromatization of adjacent enediynes
AB - As part of an investigation into new synthetic routes to poly(peri-naphthalene),
the synthesis and cycloaromatization of tetraethynylbiphenyls is described. The
temperature-dependent cyclization of biphenyls containing unsubstituted alkynes
provides the desired perylene in good yield.
PMID- 10768198
TI - Conversion of N-acyl-4-acyloxy-beta-lactams into 1,3-oxazin-6-ones: two
consecutive pseudopericyclic processes
AB - N-Acyl-4-acyloxy-beta-lactams are converted into 1,3-oxazin-6-ones under basic
conditions. This transformation is believed to proceed via N-acylazetones, which
rearrange to the final products by a sequence of two electrocyclic processes. The
calculated (RHF and B3LYP) transition structures of both concerted reactions are
shown to present characteristic pseudopericyclic orbital topologies.
PMID- 10768199
TI - Carbon networks based on dehydrobenzoannulenes. 3. Synthesis of graphyne
substructures
AB - This Letter describes the synthesis of the first macrobicyclic subunits of the
hypothetical all-carbon network graphyne. Key to synthetic success is an
intramolecular Sonogashira cross-coupling sequence.
PMID- 10768200
TI - Synthesis and antifungal activity of rhodopeptin analogues. 1. Modification of
the east and south amino acid moieties.
AB - Structure-activity relationships of the east and south amino acid modified
analogues of rhodopeptins, novel antifungal cyclic tetrapeptides isolated from
Rhodococcus species Mer-N1033, have been investigated. It was observed that a
basic amino acid moiety (lysine or ornithine) as the east amino acid and a
hydrophobic and bulky neutral amino acid (i.e., gamma-methylleucine) as the south
amino acid were indispensable structure motifs for antifungal activity of
rhodopeptin analogues.
PMID- 10768201
TI - Synthesis and antifungal activity of rhodopeptin analogues. 2. Modification of
the west amino acid moiety.
AB - Structure-activity relationships of the west amino acid modified analogues of
rhodopeptins, novel antifungal tetrapeptide isolated from Rhodococcus species Mer
N1033, have been investigated. Among the analogues synthesized, 2,2-difluoro and
2-hydroxy derivatives retained the antifungal activity with better physical
properties, i.e., solubility or acute toxicity.
PMID- 10768202
TI - Trifluoromethyl-substituted indenyl rhodium and iridium complexes are highly
selective catalysts for directed hydroboration reactions
AB - Rhodium and iridium catalysts containing trifluoromethyl-substituted indenyl
ligands (Ind'MCod, Ind' = C9H7, (1-CF3)C9H6, (2-CF3)C9H6, (1,3-CF3)2C9H5) have
been developed for the directed hydroboration of 4-(benzyloxy)cyclohexene to cis
3-(benzyloxy)cyclohexanol. Compared to unsubstituted complexes, trifluoromethyl
substitution yields a 3-10% increase in selectivity which is attributed to the
strong electron-withdrawing effect of the trifluoromethyl group. Rhodium
complexes give selectivities of 74-84%, and iridium complexes give high levels of
selectivity (93-98%).
PMID- 10768203
TI - Synthesis of biaryls by intramolecular radical aryl migration from silicon to
carbon
AB - A new method for the preparation of biaryls via intramolecular 1,5 aryl migration
reaction from silicon in silyl ethers to aryl radicals is presented. Various
readily available diphenylsilyl ethers can be used as substrates in this
reaction. Functionalized aryl groups can also be transferred. The analogous 1,4
aryl migration reaction is less efficient.
PMID- 10768204
TI - Efficient one-pot conversion of carbonyl compounds to their alpha,beta
unsaturated derivatives using a recoverable, minimally fluorous organoselenium
reagent
AB - A protocol for the preparation of a fluorous arylselenenyl chloride is described.
This selenenyl chloride may be used for the direct alpha-selenation of ketones
and, following oxidation and syn-elimination, formation of alpha,beta-unsaturated
carbonyl compounds. Treatment of the crude reaction mixtures with sodium
metabisulfite reduces the various selenium species to the diaryl diselenide,
which is then recovered in high yield by continuous fluorous extraction.
PMID- 10768205
TI - A new, more efficient, and effective process for the synthesis of a key
pentacyclic intermediate for production of ecteinascidin and phthalascidin
antitumor agents.
AB - An efficient process is described for the synthesis of 5, a key intermediate for
the synthesis of the potent antitumor agents ecteinascidin 743 (1) and
phthalascidin (2) from the readily available building blocks 3b and 4.
PMID- 10768206
TI - Metal-catalyzed acyl transfer reactions of enol esters: role of Y5(OiPr)13O and
(thd)2Y(OiPr) as transesterification catalysts
AB - Primary and secondary alcohols react with vinyl or isopropenyl acetate at room
temperature in the presence of catalytic amounts (0.05-1 mol %) of Y5(OiPr)13O to
give the corresponding esters. In selected cases, the yttrium catalyst promotes
the selective O-acylation of amino alcohols without the formation of the amide.
Enol esters also react with alpha-amino acid esters in the absence of a catalyst,
at room temperature, to give the corresponding amides.
PMID- 10768207
TI - Asymmetric ring opening of meso epoxides with TMSCN catalyzed by
(pybox)lanthanide complexes.
AB - The asymmetric ring opening of meso epoxides with TMSCN is catalyzed by
(pybox)YbCl3 complexes, yielding the beta-trimethylsilyloxy nitrile ring-opened
products with good enantioselectivities (83-92% ee). The reaction exhibits a
second-order kinetic dependence on catalyst concentration and a first-order
dependence on epoxide concentration, consistent with a bimetallic pathway
involving simultaneous activation of epoxide and cyanide.
PMID- 10768208
TI - Sulfinyl-directed diastereoselective
AB - Introduction of a homochiral p-tolylsulfinyl group at an appropriate position in
the alkene accelerates the thermal [5C + 2C] intramolecular cycloaddition to beta
silyloxy-gamma-pyrones and, most importantly, leads to excellent levels of
diastereodifferentiation. The resulting adducts can be easily desulfinylated to
give optically active 8-oxabicyclic[3.2.1]octane intermediates which by virtue of
their rich functionalization might be susceptible to elaboration into
enantiomerically pure natural products containing seven-membered carbocycles and
tetrahydrofurans.
PMID- 10768209
TI - Hopkins Lupus Cohort. 1999 update.
AB - The Hopkins Lupus Cohort is a decade-long prospective study, now numbering 800
patients with systemic lupus erythematosus. In this article, predictors of
disease activity, disease damage (including accelerated atherosclerosis and
antiphospholipid antibody syndrome) and health status are reviewed.
PMID- 10768210
TI - Apoptosis in systemic lupus erythematosus. Clinical implications.
AB - SLE is a heterogeneous and complex group of disorders of uncertain cause. Recent
studies have suggested that abnormalities in the apoptotic cell death process may
play an important role in the initiation and propagation of this spectrum of
disease by altering the generation and cleavage of antigens, and through
abnormalities in immunoregulation. The clustering and concentration of
autoantigens in and on the surface blebs of apoptotic cells, modifications of
antigen structure during certain forms of apoptotic death, and abnormalities in
apoptotic cell clearance in humans with SLE and in certain animal models are
reviewed and synthesized into a comprehensive model of systemic autoimmunity.
PMID- 10768211
TI - Genetics of systemic lupus erythematosus. Clinical implications.
AB - Rheumatic diseases have long been recognized as having complex inheritance
patterns. It has recently been estimated that over 100 genes may be implicated in
the SLE disease process. Identification of these genes has led to a greater
understanding of the etiopathogenesis of SLE and is beginning to lead to new
types of interventions directed at correcting aberrant biological processes.
PMID- 10768212
TI - Premature atherosclerosis in systemic lupus erythematosus.
AB - SLE is a multifaceted disease; over the past 20 years, as survival has improved
dramatically, new challenges have emerged. It is now clear from the results of
studies at several centers that SLE is associated with at least a fivefold
increased risk of CAD, which is accelerated at its onset and seems to abolish a
female premenopausal protection against CAD. Several groups have also found by
various techniques that subclinical disease occurs at a frequency of about 35% to
40%. The pathogenesis of atherosclerosis in this context seems to be a complex
interaction of factors associated with the disease, its therapy, and traditional
risk factors. Indeed, experimental models suggest a synergy of these different
dimensions in plaque formation. Hypercholesterolemia has been identified as
predictive of both future CAD events and sub-clinical disease. This is mainly the
case in those patients in whom hypercholesterolemia is a sustained phenomenon. In
addition, SLE itself seems to be a strong risk factor for CAD over and above the
effects of the known traditional CAD risk factors. There is a lot that is still
unknown about the pathogenesis of CAD in SLE. Current knowledge is sufficient to
justify the belief that an aggressive approach to management of traditional CAD
risk factors in patients with SLE is likely to have a major impact on morbidity
and mortality in this population. For this to happen, patients must be educated
about this issue and be encouraged to play an active role in lifestyle
modifications. In addition, clinicians who care for patients with SLE need to
assume a primary role in screening and coordinating the management of CAD risk
factors in these high-risk patients.
PMID- 10768213
TI - Management of osteonecrosis in systemic lupus erythematosus.
AB - Osteonecrosis is commonly found in patients with systemic lupus erythematosus.
The effects of this disease are magnified because these patients commonly have,
in addition to hip involvement, multiple other joints involved with the disease.
Early diagnosis is important for medical and surgical management to try to avoid
total joint replacements in this young patient population. There are many joint
salvaging procedures that have had moderate success in patients with this
disease. In the future, pharmacologic agents and growth and differentiation
factors may be effective in the early treatment of this disease and may lead to
more successful outcomes with surgical options.
PMID- 10768214
TI - Steroid-induced osteoporosis in systemic lupus erythematosus.
AB - The patient with SLE is at considerable risk of osteoporosis, because of the
inflammatory disease itself, its consequences, and its treatments. Because of
their extensive use, glucocorticoids are thought to be the most frequent cause of
drug-related osteoporosis and may be responsible for much of the bone loss in
lupus. This article focuses on the mechanisms of steroid-induced osteoporosis in
SLE and outlines strategies for prevention and treatment.
PMID- 10768215
TI - Antiphospholipid (Hughes) syndrome in systemic lupus erythematosus.
AB - APS is found in 20% to 35% of patients with SLE. PAPS and secondary APS have
similar features and aPL specificities. The clinical course of the secondary
syndrome is independent of the activity and severity of lupus, but the presence
of APS worsens the prognosis of patients with lupus. Some features of SLE may
result from thrombosis in patients with APS; thus, these patients require
anticoagulation rather than corticosteroids. Novel preliminary classification
criteria for APS were formulated during a postconference workshop held in
Sapporo, Japan, following the Eight International Symposium on Antiphospholipid
Antibodies. Treatment of APS remains empirical because of limited controlled
prospective data. There is strong evidence that patients with aPL-associated
thrombosis are subject to recurrences and require prophylactic therapy. APS is a
treatable cause of recurrent fetal loss in women with SLE. The treatment of
choice is anticoagulation with heparin, either standard unfractionated heparin or
LMWH. One of the main reasons for the improving outcomes in APS pregnancies is
closer obstetric surveillance.
PMID- 10768216
TI - Dehydroepiandrosterone in systemic lupus erythematosus.
AB - DHEA has shown promise for the treatment of SLE in three controlled and several
uncontrolled clinical trials, including one large multicenter study comprising
nearly 200 patients. The main benefits of DHEA seem to be a decrease in
corticosteroid requirements and improved overall symptomatology. Intriguing
aspects of DHEA treatment in SLE that require further study are a possible bone
protective effect and improvements in cognitive function. The most frequent side
effect is mild acneiform dermatitis, and long-term concerns include lowered HDL
cholesterol.
PMID- 10768217
TI - Update on cyclophosphamide for systemic lupus erythematosus.
AB - Over the past decade cyclophosphamide has come to assume an increasingly
prominent role in the management of severe, life-threatening manifestations of
SLE. Intermittent, intravenous pulse cyclophosphamide has become the standard of
treatment of diffuse proliferative lupus nephritis (WHO Class IV), and there is
now substantial clinical literature to suggest an indication for intermittent
cyclophosphamide therapy in most other forms of serious lupus affecting major
organ systems, in particular lupus vasculitis and acute central nervous system
manifestations. This update reviews the use of cyclophosphamide in the management
of lupus nephritis, expands on its role in other manifestations of SLE, and
discusses potential complications of the drug.
PMID- 10768218
TI - Hematopoietic stem cell transplantation for systemic lupus erythematosus.
AB - Many institutions worldwide are conducting clinical studies using immunoablative
therapy followed by hematopoietic stem cell transplantation for the treatment of
SLE. Interpretation of these studies will be complicated by the differences in
patient selection, conditioning regimens, and the method of stem cell collection.
A major concern with this approach is that autoreactive effector cells will be re
infused with the autologous graft. The recent demonstration that immunoablative
therapy (cyclophosphamide 200 mg/kg) can be safely delivered without the need for
stem cell rescue offers a potential way to circumvent this problem. Early results
employing immunoablative therapy, with or without stem cell rescue, are
encouraging; however, longer follow-up and additional patients are necessary to
validate this approach.
PMID- 10768219
TI - New therapies for systemic lupus erythematosus.
AB - New therapies for the treatment of SLE have gained increased attention, as
demonstrated by a growing number of new modalities being studied. These
modalities include novel biologic agents that target specific immunologic
responses and more traditional pharmaceutical agents. This article summarizes
these new therapies and briefly discusses their mechanisms of action and the most
recent research performed to characterize their safety and efficacy.
PMID- 10768220
TI - [Value of radiotherapy in urology].
PMID- 10768221
TI - [Value of radiotherapy in urology].
AB - Radiotherapy of patients with prostate cancer offers an alternative to radical
prostatectomy in early stages (T1-T2). In locally advanced prostate cancer a high
dose or combined radiotherapy is more effective than radical surgery with
concurrent lower morbidity and mortality. Recent developments in linear
accelerator technique, the progress in dose calculation and planning techniques
provide the means to apply higher doses to a given tumor volume while effectively
protecting the surrounding normal tissue at the same time. These improvements may
possibly reduce the rate of therapy related side effects or complications
significantly. The combination of external beam radiotherapy and interstitial
brachytherapy as well as the combination of hormone therapy and external beam
radiotherapy are most likely more effective than percutaneous irradiation alone.
In special cases with a very low risk of recurrent tumor an interstitial
permanent brachytherapy alone is indicated. Future developments (i.e. intensity
modulated radiotherapy-IMRT, combined thermo-radiotherapy, proton- or
neutrontherapy) may further increase the rate of curative treatments in patients
with prostate cancer.
PMID- 10768222
TI - [Value of radiotherapy in interdisciplinary management of testicular germ cell
tumors].
AB - Radiotherapy unequivocally has to be regarded as standard therapy in stage I and
IIA/B testicular seminoma. Using low dose abdominal irradiation tumour control
rates of 95-98% in stage I disease and 80-95% in stage IIA/B can be achieved.
Disease specific survival reaches 100%. Likewise, radiotherapy is treatment of
first choice in case of testicular intraepithelial neoplasia (TIN) in a solitary
testis or in case of a double-sided TIN yielding safe eradication of the in-situ
carcinoma of the testis. Objectives of further clinical research in radiotherapy
of testicular malignancies aim at reduction of treatment intensity in order to
minimize acute and late side effects of irradiation without compromising tumour
control rates.
PMID- 10768223
TI - [Radiotherapy of distant metastases of urological malignant tumors].
AB - The largest subgroup of patients with metastasised urological malignancies are
those with metastases of the bone. Lesions of bones frequently reduce the
patients quality of life. Therefore a sufficient therapy is crucial. First of all
the appropriate diagnostic procedure of the lesion/lesions is necessary because e
the right choice of diagnostic measures may already improve quality of life.
Besides the most frequently used local irradiation a systemic radiotherapy may be
the adequate therapy in patients with disseminated disease. Renal cell-, bladder
and penile cancer respectively are the urological malignancies frequently
metastasising into the brain. Adequate diagnostic procedures and therapy are
crucial to the patients quality of life for the remaining lifetime. Besides a
whole brain irradiation as standard therapy stereotactic radiotherapy is a high
precision tool to destroy intracerebral tumour. There are many other locations of
metastatic disease (i.e. lymph node or soft tissue metastasis, et cetera) where
palliative external beam irradiation may provide relief from symptoms such as
pain, lymph oedema or bleeding and thus increase quality of life. Psychological
and social care are of great value besides symptom oriented therapy (i.e.
radiotherapy, drugs, et cetera) to achieve an optimal palliation/quality of life.
PMID- 10768224
TI - [Treatment outcomes in primary and secondary retroperitoneal fibrosis].
AB - Retroperitoneal fibrosis (RPF) is an uncommon inflammatory disease of the
retroperitoneum leading to extensive fibrosis with consecutive obstruction of
adjacent organs, namely the ureters. Since no consensus on the standard therapy
exists, aim of the current study was to evaluate the outcome of 39 patients with
RPF. Between 1986 and 1997 39 cases of RPF were diagnosed: 21 cases had primary
RPF and 18 patients had secondary RPF after aortofemoral graft (n = 13),
radiation (n = 2), or prior retroperitoneal surgery (n = 2). 21 patients
demonstrated unilateral and 16 cases had bilateral hydronephrosis, in 2 patients
no dilatation was observed. In 28 cases (n = 12 primary RPF, n = 16 secondary
RPF) initial management consisted of DJ-stent placement, whereas in 11 cases (n =
9 primary RPF, n = 2 secondary RPF) percutaneous nephrostomy had to be placed.
All patients received oral immunosuppressive agents (prednisolone 1 mg/kg,
azathioprine 1 mg/kg/day) for 3 months before reevaluation was performed. In case
of complete remission, immunosuppressive medication was continued for another 3
months, in case of stable disease or progression surgery was performed. In 26
cases (n = 15 primary RPF, n = 11 secondary RPF) ureterolysis with
intraperitoneal displacement and omental wrapping was performed. 3 patients
demonstrated complete remission after oral prednisolone/azathioprine; in 2 cases
RPF presented as pelvic mass and was resected followed by immunosuppressive
therapy, in another 2 cases bilateral ileal replacement of the ureters had to be
performed and 4 cases remained on DJ-stents and nephrostomy, resp.
Postoperatively, all patients with primary RPF were continued on immunsuppressive
medication for another 3 months. After a follow-up of 6 to 120 months only 3
patients developed a retroperitoneal recurrence and were treated by unilateral
nephrectomy or DJ stent placement (n = 2). Our data suggest that the combination
of both immunosuppressive medication and surgical management results in an
excellent longterm outcome in idiopathic retroperitoneal fibrosis with a
recurrence rate of only 8%. Combination therapy should be considered as
therapeutic option early in the course of the disease. Primary reconstructive
surgery appears to be the most promising approach in secondary retroperitoneal
fibrosis with a recurrence rate of only 5%; short external compression of the
ureter might be managed by endoluminal balloon dilatation.
PMID- 10768225
TI - [Value of ultrasound in early diagnosis of renal cell carcinoma].
AB - The importance of ultrasonography in early detection of renal cell carcinoma was
analyzed for 1854 patients, who were operated from 1975 to 1997. The 5-year
survival rate of all patients amounts to 75%, the 10- and 20-year survival rate
was 68% and 64%. While from 1975 to 1986 tumor symptoms like hematuria (30%),
abdominal pain (19%) and palpable mass (3%) lead to diagnosis of renal cell
carcinoma in 56% of all cases, there were only 26% from 1987 to 1997. 83% of
asymptomatical tumors from 1987 to 1997 were accidentally detected by means of
ultrasonography in a kidney independent examination. These tumors are
significantly smaller (5.5 cm) than the tumors of symptomatical patients (7.8 cm)
and show often a significantly lower local tumor stage, a better tumor grade,
frequently lymph nodes, which are free of tumor infiltration and more rarely
distant metastasis. The 5-year survival rate of patients with incidental tumors,
detected by ultrasonography (82%) was significantly better (log rank < 0.001) in
comparison with the symptomatical patients (72%). These results verify 1. The
effectivity of ultrasonography in early diagnosis of renal cell carcinoma and 2.
The advantage of survival on patients with early tumor detection. That's why
asymptomatic patients, who selected under risk factors should be examinated by
ultrasonography consistently too.
PMID- 10768226
TI - [Lumbar radical nephrectomy. A retrospective analysis of 186 cases].
AB - 186 cases of nephrectomy for renal cell cancer are studied retrospectively. The
overall 5-year survival rate was 77.2%. According to the 4th edition of the "TNM"
classification system of UICC the survival rates of patients with T2-(n = 97),
T3a (n = 58) and T3b-tumors (n = 25) were 80.9%, 79.3% and 65.6%, respectively.
No patient with a stage T4 tumor (n = 6) survived longer than 20 months. The 5
year survival rate of patients with N1-lymph node metastases was 83.3% (n = 8);
without lymph node metastases 78.3% (n = 152), respectively. There was no
survival longer than 20 months in case of N2-lymph node metastases (n = 13).
According to the grading survival rates of 95.4% (G1, n = 46), 71.2% (G2, n =
130) and 71.4% (G3, n = 8) resulted.
PMID- 10768227
TI - [Central nervous system control of micturition in patients with bladder
dysfunctions in comparison with healthy control probands. An electrophysiological
study].
AB - PURPOSE: The pontine micturition center plays a central role in regulating the
micturition reflex, but the precise neural mechanisms are unclear. The cerebral
cortex is involved in coordinating micturition but there is little knowledge on
specific evolutionary higher brain regions. The present study aimed to
investigate whether cortical activation during micturition can be demonstrated by
EEG power spectra patterns and to explore whether specific cortical regions
involved in the interaction of inhibition and release during the micturition
reflex can be discerned. We also aimed to test whether intravesical
electrostimulation (IVES) therapy in patients with micturition disorders has an
effect on patterns of cortical activity. METHODS: The healthy control group was
divided into those who were able to void when requested (6 women, 12 men) and
those who were not (8 women, 10 men). These subgroups were compared separately
with the 14 patients before and after IVES for voiding dysfunction. Following
IVES all patients were able to void spontaneously. Mean age of the patients and
healthy volunteers was 52 and 30 years, respectively. At the beginning of the
study all subjects had a bladder volume of approximately 250 mL as measured by
sonography. The EEG was obtained at rest and during the attempt to void. In the
patients' group EEG was obtained before IVES treatment and at the day of the last
stimulation. The measurement period lasted about 6 minutes. At the beginning of
the recording the proband was asked to close his/her eyes. During the resting
period after 1 minute the patient was asked to open his/her eyes. After 10
seconds he/she was asked to close his/her eyes again. Then, with eyes still
closed, the patient was asked to void. During the entire EEG recording the
patient was seated in a comfortable, electrically isolated chair in a darkened
room and separated from the examiner by a partition. The subject was asked to
relax and not move his/her eyes. The EEG was recorded from the 19 standard points
(10-20 System) versus an averaged mastoid electrode with a gold-plated cup
electrode (Glass). An EOG was recorded simultaneously to register eye artefacts.
The amplification chain was calibrated with a 10-Hz 100-microVss sinus signal
generated with a biosignal amplifier. The transitional resistances of all EEG
channels were less than 5 kOhm and established as soon as possible. EEG and EOG
signals were amplified and recorded with a B.E.S.T. Brain Mapping System. The
recording frequency was 256 Hz and the resolution of the analog digital
conversion was 12 bit. A high pass and a low pass filter were set to 0.53 Hz and
70 Hz, respectively. All recordings were inspected visually before computer
analysis. Artefacts were marked and excluded from the further analysis. None of
the EEG recordings showed clinical abnormalities. As expected, the EEGs during
voiding attempts showed some muscle potentials and slow motion artefacts. For
each subject two artefact-free resting segments of about 20 seconds, one from the
resting phase and one from the voiding attempt, were defined by hand for
automated analysis. Relative power spectra (microV2) were calculated for the
defined segments. From the spectra the relative alpha band power (7.5-13.0 Hz)
was calculated for each subject for rest and voiding. Group (patients vs. voiding
probands vs. probands unable to void) and sex were independent variables. The
alpha power of the 17 electrode positions of the 10-20 system (without Fp1 and
Fp2) during rest and attempted voiding were repeated measurement variables. The
frontopolar electrode was not used because of its susceptibility to artefacts.
The number of dependent variables was due to the explorative nature of the study.
With interactions of variables with more than two factor levels a Greenhouse
Geisser correction was performed. Interactions were subjected to contrast
analysis and Newman-Keuls-Post tests. RESULTS: Significant effects were seen for
BEDINGUNG (
PMID- 10768228
TI - [Socioeconomic aspects of urinary calculi and metaphylaxis of urinary calculi].
AB - A calculation model was developed for the cost of stone therapy and metaphylaxis
in Germany based on estimates of stone incidence, types and recurrence rates,
actual costs for stone removal and metaphylaxis (based on data from a district of
the social health care system). There are 200,000 stone recurrences per year in
Germany. Cost for treatment of these stones amount to $687,000,000. Stone
metaphylaxis reduces the recurrence rate by some 40%. The annual cost for stone
removal could be lowered by $275,300,000. Metabolic evaluation/metaphylaxis
amount to $70,100,000 per year, resulting in an net saving of $205,200,000. In
1997, there were 96 days off-work per stone patient resulting in 5,800,000 days
off-work in Germany per year. Metaphylaxis in stone formers can lower health care
cost significantly. Although health care conditions may vary from country to
country, in principle this calculation model is applicable also to other
countries.
PMID- 10768229
TI - [Leiomyoma of the glans penis].
AB - Glans penis leiomyomas are uncommon as primary nonepithelial tumors of the
urogenital tract. Only 4 cases are described until today. We saw an other case of
an 12 years old boy with a leiomyoma of the glans penis. Clinically the lesion
presented as a yellow induration with no symptoms as pain, pruritus or bleeding.
The biopsy revealed histological a leiomyoma in the subcutis of the glans penis
with no symptoms of malignancy. Because of suspected functional and cosmetic
deficiency a total resection was not performed. None of the cases described in
the literature showed in the follow up malignancy or recurrency. 18 months
postoperatively our patient is furthermore well and without symptoms.
Nevertheless the leiomyoma of that localization is rare, this tumor should be
included in the differential diagnosis of the neoplasms of the glans penis.
PMID- 10768230
TI - [Mixed squamous epithelial and adenocarcinoma of the female urethra. A case
report].
AB - We report a case of mixed squamous-cell carcinoma with adenocarcinoma of the
female urethra. A 37 year old women who presented with a 3-month' history of
obstructive voiding symptoms. Clinical investigation showed a urethra tumor of
2.5 x 3.5 cm. Needle biopsy revealed a grade 3 carcinoma. Staging resulted in
local cancer disease, a 2.5 x 3.5 cm tumor surrounding the whole urethra with
protruding the trigonum. We performed urethrectomy with resection of the
bladderneck and cystoneostomy. During bladderneck resection we performed regional
staging lymphadenectomy of the obturator lymph nodes. Histological investigation
revealed a mixed squamous-cell carcinoma with adenocarcinoma and undifferentiated
carcinoma of the urethra. Periurethral tissue showed lymphangiosis carcinomatosa
with negative lymph nodes. To exclude involvement of regional superficial lymph
nodes we subsequently performed modified inguinal lymphadenectomy without
evidence of advanced cancer disease.
PMID- 10768231
TI - [Molecular biology diagnosis of bladder carcinoma].
PMID- 10768232
TI - [Ethics in medicine. Needs and forms].
PMID- 10768233
TI - Canine elbow dysplasia. The early radiographic detection of fragmentation of the
coronoid process.
AB - Ununited anconeal process, osteochondrosis, and fragmentation of the coronoid
process (FCP), separately or together, comprise canine elbow dysplasia.
Radiographic detection of ununited anconeal process or osteochondrosis is common,
whereas identification of an FCP is often inferred by finding joint incongruity
and secondary changes. Early identification of FCP can be improved by evaluating
the elbow joint for subtle changes visible early in the course of this disease.
Proper radiographic technique and positioning are essential in optimizing
identification of the changes associated with mild or early FCP.
PMID- 10768234
TI - Radiographic diagnosis of hip dysplasia in the young dog.
AB - Despite considerable research and the application of screening programs during
the past three decades, the incidence of canine hip dysplasia (CHD) remains
disturbingly high. Mild CHD is underdiagnosed by subjective evaluation of adult
dogs, and moderate CHD is underdiagnosed by subjective assessment of immature
dogs. Coxofemoral subluxation measurement methods hold promise for increasing the
accuracy of CHD assessment, especially in 4-month-old dogs. Many radiologists
have greater confidence in the PennHip method than in subjective hip assessment
alone for dogs 6 months of age or younger. The incidence of CHD is unlikely to be
dramatically reduced until CHD registries are open to the public and CHD
examination is required for purebred dog registration.
PMID- 10768235
TI - Radiographic features of feline joint diseases.
AB - Feline joint disorders are often overlooked, possibly because cats are extremely
agile and appear to cope with pathologic changes within their joints better than
their canine counterparts. There is a growing awareness that osteoarthritis
occurs more frequently than previously anticipated in cats, and recently we have
seen the emergence of hip dysplasia as an entity of concern in some purebred
cats. There are also several poorly understood conditions that affect the joints
of cats, such as synovial osteochondromatosis, that invite further study. In
recent years we have seen an expansion in the knowledge of immune-mediated and
infectious arthropathies and their inter-relationship with infective agents. This
article describes the radiographic changes seen in many of the currently
recognized joint disorders of domestic cats.
PMID- 10768236
TI - Myelographic artifacts.
AB - During myelography, injection of contrast outside the subarachnoid space can lead
to false-negative or false-positive studies by not contrasting lesions or
creating spurious signs. The production of high-quality myelograms and successful
interpretation depend on knowledge of meningeal anatomy and the appearance of
contrast material when injected between different meningeal layers. Opacification
of the subdural space is a recently described technical complication in
veterinary medicine, and increasingly is being recognized as a common problem
during myelography. The purpose of this article is to describe the appearance of
the different columns of contrast material that can be produced during
myelography and to correlate these findings to the relevant anatomy, especially
the subdural space.
PMID- 10768237
TI - Malignant versus nonmalignant bone disease.
AB - Diagnosis of bone lesions other than fractures is difficult from radiographs
alone because mixed patterns of lysis and bone proliferation are frequently
observed. It is important to evaluate whether the lesion is single (monostotic)
or involving multiple bones (polyostotic). Correlation of additional information
such as the patient signalment, sex, geographic habitat, history, clinical
findings, and prior therapy is useful to help establish the most accurate
differential diagnosis. The presence of intramedullary lesions with expansile
destructive pattern in the metaphyseal region of a middle-aged, large-breed dog
is supportive for a diagnosis of a primary bone tumor or an aggressive mycotic
osteomyelitis. Serial radiographic studies can be performed to evaluate
progression. Rapid bone change tends to occur with neoplasia, whereas slower
progression can occur with osteomyelitis. The location of change to the
vertebrae, such as spondylitis and diskospondylitis, often helps in the
understanding of the underlying disease process. Additional diagnostic
procedures, such as biopsies with appropriate lesion sampling and evaluation of
serum for fungal titers, should be considered to establish the diagnosis.
PMID- 10768238
TI - Effect of pharmaceuticals on radiographic appearance of selected examinations of
the abdomen and thorax.
AB - Pharmacologic agents may have a significant effect on the outcome of radiographic
interpretation in small animal imaging. Alterations in the abdomen and thorax may
represent artifactual or transient changes or changes reflecting cytotoxicity.
Examples of agents that may influence the appearance of radiographs include
anticonvulsants, sedatives, anesthetics, analgesics, antiinflammatories,
gastrointestinal prokinetic drugs, antineoplastics, and hormones such as
megestrol acetate. Radiographic studies may be part of a disease-monitoring
process. It is important to understand how pharmaceuticals (e.g.,
chemotherapeutics or therapy for an underlying medical condition) affect the
radiographic appearance. Caution should be exercised in the interpretation of
radiographic studies because the findings may relate to the drug therapy rather
than the underlying condition.
PMID- 10768239
TI - Vertebral scale system to measure heart size in radiographs.
AB - This article describes a method for measuring heart size relative to vertebral
length in radiographs. The lengths of the long and short axes of the heart are
scaled against the length of vertebrae dorsal to the heart beginning with the
fourth thoracic vertebra (v). The sum of the long and short axes of the heart is
the vertebral heart size (VHS). In 100 normal dogs, VHS was 9.7 v +/- 0.5 SD. The
differences between wide- and deep-chested dogs, males and females, and right or
left lateral recumbency were not significant. In 100 normal cats, the average VHS
was 7.5 v +/- 0.3. The short-axis dimension of the heart in ventrodorsal
radiographs of cats was 3.4 v +/- 0.25.
PMID- 10768240
TI - Radiography of feline cardiac disease.
AB - This article details the technique, pitfalls, and applications of radiography in
the management of feline cardiac disease. Radiographic differentiation of
pulmonary and cardiac disease is addressed. Specific cardiac diseases are
reviewed and discussed.
PMID- 10768241
TI - The diagnosis of urinary incontinence and abnormal urination in dogs and cats.
AB - No single technique allows one to diagnose all causes of urinary incontinence and
abnormal increased frequency of urination. Cystography is indicated for cases of
abnormal urinary bladder position, size, or shape. Ultrasonography is best for
mass effects, calculi, and extrinsic nonskeletal abnormalities. The combined
cystography and excretory urography technique is recommended for diagnosing
ectopic ureteral insertions. Computerized tomography and MR imaging are indicated
when the techniques described previously fail to elucidate the problem
sufficiently, but these methods are usually not selected as primary diagnostic
techniques.
PMID- 10768242
TI - Pros and cons of barium-impregnated polyethylene spheres in gastrointestinal
disease.
AB - Barium-impregnated polyethylene spheres are an alternative contrast agent for
radiographic studies of the gastrointestinal tract. The spheres are a practical,
efficient, and relatively inexpensive way to diagnose a number of relatively
common gastrointestinal conditions. They are most useful in the diagnosis of
chronic conditions. Radiographic interpretation relies on a thorough
understanding of the pathophysiology of gastrointestinal disease and how various
disease states influence gastrointestinal function.
PMID- 10768243
TI - Patients with dyspepsia benefit from eradication of Helicobacter pylori if other
organic causes for dyspepsia were carefully ruled out.
AB - AIM: In order to investigate the potential of Helicobacter pylori (HP) to induce
dyspepsia, we performed a randomized prospective study on the long-term effect of
HP-eradication on symptoms of HP-positive dyspeptic patients in whom other
organic causes for dyspepsia were carefully ruled out. PATIENTS: 201 patients
referred to our endoscopy unit with dyspeptic symptoms for at least six months
entered the study. Patients with previous peptic ulcer were excluded. METHODS:
After endoscopy of the upper alimentary tract and 13C-urea breath test, patients
with active peptic ulcer, hiatal hernia, macroscopic evidence for esophagitis and
negative HP-status were excluded. The remaining patients underwent abdominal
sonography, H2-exhalation test with lactose, and 24-h pH monitoring in order to
exclude other organic causes for dyspepsia. In 20 patients, dyspepsia was assumed
to be due to HP-gastritis. Patients received eradication therapy and were
controlled as assessed by the 13C-urea breath test six weeks and six months after
completion of the therapy. Dyspeptic symptoms were monitored by means of a
validated symptom score. RESULTS: Out of 20 patients with HP-gastritis the first
eradication treatment was successful in 13, while seven patients remained HP
positive after antibiotic treatment. Six months after completion of therapy the
symptoms of HP-eradicated patients improved considerably (score values 17.4 +/-
1.5 and 10.2 +/- 0.8, respectively, p < 0.01) whereas symptoms of patients with
persistent infection remained unchanged (21.1 +/- 1.7 and 20.4 +/- 1.5, n.s.) and
only improved after successful retherapy (20.4 +/- 1.5 and 11.7 +/- 2.1, p <
0.05). In total, 17 of 20 patients (85%) improved after successful eradication.
Also, neutrophil infiltration in the gastric mucosa correlated to both dyspeptic
symptoms before therapy (r = 0.85) and the decrease in symptom score after HP
eradication (r = 0.61). In contrast, the symptoms of eight patients with
gastroesophageal reflux disease were not improved after eradication (20.0 +/- 1.1
and 18.2 +/- 1.0, n.s.) CONCLUSIONS: HP-infection per se contributes to
dyspepsia. 17 of 20 (85%) HP-positive dyspeptic patients improved after HP
eradication, when other potential organic causes for dyspepsia had been ruled
out. However, many patients did not completely recover but the symptoms only
partly decreased which parallels the persistence of part of the inflammatory
infiltration in the gastric mucosa. This emphasizes the importance of HP
gastritis as an organic disease causing dyspeptic symptoms.
PMID- 10768244
TI - [Ultrasonically controlled percutaneous high frequency thermotherapy of liver
tumors with perfused needle electrodes].
AB - Percutaneous radiofrequency ablation (HFTT) is a new therapeutic technique for
the treatment of inoperable primary and secondary liver tumors. We report our
initial experience using a newly developed perfusion electrode. Twelve liver
tumors (11 metastases of colorectal tumors, 1 hepatocellular carcinoma) were
treated in 5 inoperable patients. The patients had 1 to 3 liver tumors. All
lesions were cytologically confirmed and measured 12-47 mm. The technique was
approved by the institutional review board and informed consent was obtained from
all patients. A 12-mm-needle electrode with a 15-mm-active tip was introduced
into the liver tumors under ultrasound guidance and tumors were coagulated with
radiofrequency energy of 350 kHz. The needle electrodes were perfused with 0.9%
saline during coagulation to increase the volume of coagulation necrosis without
tissue vaporization. The serial changes in tumor size after therapy were
evaluated with spiral CT imaging. Dynamic CT showed that unenhanced areas
indicative of coagulation necrosis developed in all tumors. In 8 of 12 tumors no
signs of recurrence appeared during the observation period of 7 (5-12) months. No
major complications were observed. Our preliminary experience suggests that
percutaneous radiofrequency coagulation can be a simple, safe and potentially
effective treatment for selected patients with inoperable liver tumors. The
results justify further studies to investigate the possible role in clinical
practice.
PMID- 10768245
TI - Antibiotic prophylaxis in percutaneous endoscopic gastrostomy (PEG)--results from
a prospective randomized multicenter trial.
AB - OBJECTIVE: To determine the efficacy of antibiotic prophylaxis in percutaneous
endoscopic gastrostomy (PEG) as a part of a standardized regimen. METHODS: An
open prospective randomised multicenter study in 216 patients. 106 received
ceftriaxone 1 g i.v. 30 min preinterventionally and 110 no study medication. A
standardized protocol was followed for PEG preparation, insertion, and aftercare;
all patients received a 15 French gastrostomy tube. Follow-up of local and
systemic infection and clinical course was continued to postintervention day 10.
An aggregate erythema and exudation score > 3 or the presence of pus was taken as
indicative of peristomal infection. The pharmacoeconomics of antibiotic use were
also examined. RESULTS: In no-prophylaxis patients, wound infection rates were
23.6% on day 4 and 24.5% on day 10 vs. 7.6% (p < 0.05) and 11.4% (p < 0.05),
respectively, in prophylaxis patients. Results were disproportionally better in
tumor patients in comparison with neurological patients. Patients systemic
infection rates were 11.8% vs. 1.9% in noprophylaxis vs. prophylaxis (p < 0.05),
and overall infection rates 36.3% vs. 13.3%, respectively (p < 0.05). Pneumonia
was more frequent in patients with underlying neurological disease and reduced in
the prophylaxis group. Antibiotic and application costs were similar in both
groups (p = 0.400). CONCLUSIONS: Single-dose ceftriaxone 1 g is a effective
prophylaxis against local and systemic infection after PEG and should be a part
of a standard regimen.
PMID- 10768246
TI - [Local injection of depot corticosteroids in endoscopic therapy of benign bile
duct strictures].
AB - BACKGROUND: Local injection of depot-corticosteroids into benign esophageal
strictures has been proven to maintain the effects of bougienage or balloon
dilation. METHODS: Eight consecutive patients with benign common bile duct (CBD)
strictures (postoperative, n = 6, primary-sclerosing cholangitis, n = 2) were
enrolled in this pilot trial. All had undergone initial balloon dilation and
insertion of a 10F-plastic prostheses without relevant effects on the stricture
diameter four to six weeks before. Than all patients underwent another balloon
dilation and insertion of a 10F-Tannenbaum-stent. In the same session injection
of 2 x 10 mg of triamcinolone (Volon A, Bristol-Myers Squibb, Munchen) into the
CBD-wall at the stricture site by means of a sclerotherapy needle was performed.
Four to six weeks later ERC was repeated and balloon dilation and/or stent
exchange was performed whenever indicated. RESULTS: The initial mean diameter of
the CBD-stenoses was 1.81 +/- 0.65 mm. The mean serum levels of the alkaline
phosphatase (AP) and of bilirubin were 455 +/- 188 U/L and 4.9 +/- 2.2 mg/dl,
respectively. After the initial balloon dilation and stent insertion no
significant improvement had been registered (1.9 +/- 0.7 mm). However, after
local triamcinolone injection and the second dilation/stent insertion the
diameter of the CBD-stenosis increased significantly to 3.68 +/- 0.96 mm (p <
0.01). No adverse affects were recognized. Three patients had complete recovery
of their CBD-stenosis after a third dilation, the remaining five patients were
cured after two or three additional balloon dilations with intermittent stent
exchange. Thereafter, no recurrence of a CBD-stenosis was observed during a
median follow-up of twelve months. At completion of the study the mean serum AP-
and bilirubin level were 195 +/- 87 U/L and 1.2 +/- 0.4 mg/dl, respectively.
CONCLUSION: Local application of depot corticosteroids is a feasible and safe
procedure for therapy of benign CBD-stenoses. The results of this pilot trial
justify a randomized study.
PMID- 10768247
TI - [Malignant fibrous histiocytoma of the liver].
AB - We report on a 43-year-old man with a primary sarcoma of the liver. The patient
was admitted to the hospital for evaluation of dyspnea, abdominal pain in the
right upper quadrant, diarrhea, and fever. Physical examination revealed
hepatomegaly. Increased laboratory values were found for gamma-GT, LDH, CA 125,
and NSE, but not for aspartate and alanine aminotransferase. Computed tomography
presented a tumor in the right lobe of the liver. Venous cavography revealed a
caval tumor thrombus reaching up to the right atrium. Major liver resection
combined with replacement of the vena cava inferior was proposed, but before
operation the patient complained about shortness of breath. Spontaneous
fragmentation of the tumor thrombus with consecutive embolization of the lungs
was suspected. Despite lysis therapy the patient died because of right
ventricular failure. Autopsy revealed a tumor measuring 8 cm in diameter, which
was located in the right lobe of the liver and invaded the inferior vena cava.
Because of multiple tumor aggregates seen in the left and right main pulmonary
arteries acute tumor embolization of the lungs was regarded as cause of death.
Histologically the tumor was composed of bizarre giant cells surrounded by
irregular spindle cells. The positive immunoreactivity pattern of the tumor cells
for vimentin, lysozym, and CD68 justified the diagnosis of a malignant fibrous
histocytoma (MFH) of the liver.
PMID- 10768248
TI - [Hepatitis E after travel to India--2 case reports].
AB - We report two cases of acute hepatitis E. The first case is a 21-year-old male
who had returned two weeks earlier from a three-month journey to India. He was
admitted into our clinic with nausea, stomach pain, vomiting, scleral icterus and
stool discoloration. After excluding other possible causes of the symptoms, we
made the diagnosis by testing for antibodies by EIA. No treatment was initiated
and despite a temporary increase of the icterus, the patient returned to a normal
state of health. The second case is a native of India who has lived in Germany
for ten years. He returned from a two-week visit to India with fever, nausea and
malaise. In follow-up, he was anticteric and a temporary thrombocytopenia was
detected. He was treated symptomatically, and recovered within a few days. The
patient had a secondary diagnosis of sinusitis, which was resolved with
antibiotics. In spite of a large spectrum of diagnostic possibilities, a part of
the liver diseases cannot be etiologically clarified. Following travel to India
and other endemic regions, hepatitis E should be considered in the differential
diagnosis. The course of hepatitis E is usually benign, further diagnostic
studies are rarely needed, and the treatment is usually symptomatic.
PMID- 10768249
TI - [Dysphagia as the leading symptom: presentation of a rare course in chronic
pancreatitis with formation of pseudocysts].
AB - Pancreatic pseudocysts are a common complication of pancreatitis. Although 20%
regress spontaneously, persistent pseudocysts may lead to various complications
such as infection, bleeding or compression of adjacent structures or organs. Due
to the barrier function of the diaphragm, infection of pancreatic pseudocysts
with posterior mediastinal extension represents a rare entity. Because of the
rareness and untypical symptoms of such events, a mediastinal extension of an
infected pancreatic pseudocyst often ist not recognized. In our case the
expansion of the infection to the mediastinum had led to a compression of the
distal esophagus. Preoperative diagnostic evaluation was highly suggestive for a
malignant distal esophageal tumor. A laparotomy was performed to further
elucidate the origin of the mass. Intraoperative findings showed a pancreatic
pseudocyst with infiltrative extension of an infection from retrogastral to the
lower mediastinum. After histologic preparations from intraoperative tissue
samples had ruled out malignancy, we performed a cystojejunostomy of the
pseudocyst and partial resection of the infected surrounding tissue. Mediastinal
masses with chronic pancreatitis should raise suspicion for extension of
pancreatitis to the mediastinum. In our opinion, for this course of chronic
pancreatitis operative intervention represent the standard for therapy.
PMID- 10768250
TI - [Antiviral therapy of hepatitis C].
AB - Hepatitis C is one of the world's leading infectious diseases. The interferon
ribavirin combination therapy is the new standard for the treatment of hepatitis
C in naive and relapse patients. Virological sustained response rates can be more
than doubled by the IFN-ribavirin combination therapy compared to IFN-monotherapy
and treatment duration can be reduced to six months in many cases. The IFN
ribavirin combination therapy has a high relative benefit in patients with
unfavorable predictive parameters like high viral load, HCV genotype-1 infection
and compensated liver cirrhosis. Anemia is the most important side effect of the
guanosin analogue ribavirin. There are no official therapeutic recommendations
for non-responder patients at present. These patients should be treated within
controlled clinical trials. Monotherapy with PEG(pegylated)-interferons and
combination therapies with PEG-interferons and ribavirin are the most promising
future therapeutic options.
PMID- 10768251
TI - [Antibiotic prophylaxis before percutaneous endoscopic gastrostomy (PEG
catheter)].
PMID- 10768252
TI - [Reliability of basic geriatric assessment].
AB - This study investigates the Geriatric Basis Assessment (GBA) in terms of its
reliability. Data from 1037 patients were collected. The reliability was
estimated relating to the lambda 2 coefficient. It is necessary to define the
items in different categories: the first variable means valuation 1 of each item
and not 2, 3, 4; the second variable means valuation 1, 2 against 3, 4; the third
variable means the valuation 1, 2, 3 and not 4. The table shows only little
difference concerning the lambda 2 coefficients. In conclusion, 80% of the
variability of the GBA items can be explained by differences in the patients
themselves, while 20% is due to the inaccurate assessment system. For 343
patients, data for both Barthel index and GBA were available. As presumed,
correlations between Barthel and connected GBA items were observed. However, the
correlations were too weak to predict the Barthel scores from the corresponding
GBA item accurately enough. The Barthel index appears to include similar, but not
exactly the same aspects as the GBA. The reliability of the Barthel index (lambda
2 = 0.89 for the first variable) is slightly higher compared to the GBA but it is
not suitable as a criterion of validity. Both the validity of the GBA and the
Barthel index can not be determined lacking an external measure. As an example, a
suitable criterion of validity could be the reintegration into the familiar
surroundings preceding the hospital stay. When developing the GBA, it was not
assumed that geriatric patients could be correctly diagnosed on the basis of an
overall score alone or to allocate them to adequate care using that score as a
sole indicator. Crucial for these purposes is the test profile as a whole,
including the impairments, disabilities handicaps, and last but not least the
diseases of the individual patient. Furthermore, the depiction of the GBA profile
at admission and discharge allows one to identify those items, on which therapy
has a significant influence and those which remain more or less stable. As
presumed, items with minor initial deficits (e.g., motivation, eyesight, hearing,
depression, capability of verbal expression, situative adaptability,
understanding) showed only small differences between admission and discharge. On
the other hand, items strongly influenced by geriatric treatment were, e.g.,
mobility (walking, transfer), functions of internal medicine, and domestic care.
Prognostically significant are those items which are crucial for reintegration
and describe a deficiency but cannot be altered reliably. Such items are the
person, to whom the patient relates most closely, situative adaptability,
motivation, orientation, capability of verbal expression, and possibly
depression. All of these parameters are more difficult to influence than the
activities of daily living assessed by the Barthel index. Further investigations
should clarify whether the GBA can be a reliable tool for allocating a patient to
adequate care. However, the requirement for such a criterion of validity is that
this allocation is truly optimal for the patient.
PMID- 10768253
TI - [Subjective memory loss--a sign of cognitive impairment in the elderly? An
overview of the status of research].
AB - According to the growing clinical interest in early indicators of dementia,
numerous studies have examined the association between subjective memory
complaints and cognitive performance in old age. Their results are contradictory.
In this paper, studies carried out over the last 10 years are compared with
regard to the study design and the assessment instruments used. The results are
discussed with particular reference to the diagnostic validity of subjective
memory complaints. The majority of case-control studies and cross-sectional
studies of non-representative samples could not demonstrate an association
between subjective memory complaints and cognitive performance. Most field
studies of larger representative population samples, however, have come to the
opposite conclusion. A consistent assessment of these statistically significant
associations against the background of diagnostic validity showed that memory
complaints cannot be taken as a clear clinical indicator for cognitive
impairment. Subjective memory complaints may reflect depressive disorders and a
multitude of other processes, of which an objective impairment of cognitive
performance is just one aspect. As a consequence, an inclusion of subjective
memory complaints as a diagnostic criterion for the diagnosis of "mild cognitive
disorder" according to ICD-10 is not justified.
PMID- 10768254
TI - [Need for psychosocial nursing care in a psychogeriatric nursing home].
AB - The aim of this study is to analyze the dimensions of psychosocial nursing
requirements in a psychogeriatric nursing home. In addition to biographical and
anamnestical data of nursing home residents, the psychosocial nursing
requirements are measured with the Nurses' Observations Scale for Geriatric
Patients (NOSGER). Data are compared with patients of a psychogeriatric
department of a state psychiatric hospital. Results show that psychogeriatric
nursing home residents have at least as much psychosocial restrictions as acutely
mentally ill patients in the psychiatric hospital. In some dimensions of the
NOSGER (memory, social behavior) residents show even higher scores than the
control group. By analyzing the rate of residents and psychogeriatric patients
who score above the cut-off points given by the NOSGER developers, it is shown
that the rate of residents with psychosocial nursing requirements is at least as
high as in the control group. Concerning the NOSGER dimensions Instrumental
Activities of Daily Living and Social Behavior, the rate of nursing home
residents above the cut-off points is significantly greater than the rate of the
acute psychogeriatric patients. It is concluded that budgets of psychogeriatric
nursing homes must be able to finance qualified psychiatric personnel to meet the
residents' special psychosocial requirements adequately.
PMID- 10768255
TI - [Success and variability of success of inpatient rehabilitation of the elderly:
an empirical study based on medical-psychiatric and psychosocial indicators].
AB - This study considers findings of psychological gerontology as particularly
important for geriatric rehabilitation research. Its concrete aim was to describe
the course and outcome of geriatric rehabilitation based on a wide range of
success criteria, to explore the influencing role of age, sex, and diagnosis as
well as to describe the variability pattern of success. The data were gathered
from a sample of 100 older adults who underwent treatment in a German inpatient
rehabilitation unit. Participants were assessed across five measurement occasions
by use of a state-of-the-art geriatric assessment and a psychological data
collection part. The results underline, for one, that significant improvements of
functional as well as psychological capacity were obtained. Second, age and sex
played practically no role concerning the course of the success criteria, whereas
diagnosis revealed some statistically meaningful effects. Third, it was found
that the variability of success was characterized by a relatively homogeneous
pattern of gain with regard to functional criteria; with respect to psychological
variables, heterogeneity was more pronounced and some participants show loss as
well, a chance for further improvement of the geriatric rehabilitation.
PMID- 10768256
TI - [Diagnosis and significance of psychiatric disorders in physically ill geriatric
patients].
AB - Psychic disorders were studied with a naturalistic design in 125 consecutive
patients of a medical-geriatric department in a general hospital. Based on the
clinical examination and the values of the Mini-Mental-State-Examination (2), 51
patients were classified as unable for diagnostic procedures concerning psychic
state. The other 74 patients underwent these diagnostic procedures including
clinical investigation and three screening-scales (Geriatric Depression Scale
(11); Hospital Anxiety and Depression-Scale (4)). If these examinations led to
the suspicion that a patient suffered from a psychic disorder, an interview was
performed by a psychotherapist with experience in gerontopsychosomatic treatment
and information was collected from the medical and nursing staff. Dementia was
detected or excluded by neuropsychological tests. Psychic disorders were found in
41 patients, mostly adaptation disorders and depressions. In more than half of
the patients, the disorder was estimated to be relevant for the whole hospital
therapy. The screening instruments turned out to be reliable, so they can be
recommended for further use. Difficult to answer remains the question, how the
treatment of the psychic disorders--in our sample necessary for each 5th to 6th
patient--can be implemented in a medical-geriatric department.
PMID- 10768257
TI - [Preventive home visits for elderly patients: development and pilot testing of a
multidimensional assessment instrument].
AB - Preventive home visits with multidimensional geriatric assessment have been shown
to delay or prevent the onset of disability and reduce nursing home admissions in
older people. The purpose of the present study was to develop and test a
multidimensional instrument for in-home preventive assessments in older persons.
In developing the instrument, we conducted a systematic literature review of risk
factors for functional status decline and of appropriate instruments for
measuring these risk factors. Based on an Expert Panel using a modified Delphi
process [1] the risk factor domains for functional status decline were chosen,
[2] the instruments for evaluating each of the included risk factor domains were
selected, and [3] the individual instruments were combined into one comprehensive
assessment instrument. A German language version of the original English version
of the instrument was developed based on translation, backtranslation, and
cultural adaptation. The feasibility of use of the new instrument was evaluated
in a field test in 150 people aged 75 years and older in Hamburg, Ulm, Germany,
and Bern, Switzerland. The instrument was well accepted by the older persons. The
prevalence of risk factors for functional status decline in these populations
(e.g., physical inactivity, urinary incontinence, vision impairment) was high.
There was also a high prevalence of underuse of preventive care measures (e.g.,
no pneumococcal vaccination in over 95 percent of persons). These preliminary
results support the possible usefulness of this instrument for conducting
preventive home visits or for epidemiological purposes (e.g., prevention
surveillance). In a next phase, the test-retest reliability of the instrument,
and the feasibility and reliability of self-administration as compared to
interviewer administration will be described in a separate paper.
PMID- 10768258
TI - [Significance of personality markers in Alzheimer dementia].
AB - Personality traits are of raising importance in the investigation of the causes
of Alzheimer's disease. The examination of possible correlations between
personality traits and the presence of dementia is complicated by some methodical
problems concerning the objective, reliable, and valid assessment especially of
premorbid personality style of demented persons. There is some evidence that a
higher level of education can not be considered as protective factors but seems
to delay the progression and modify the clinical manifestation of the disease.
How other premorbid personality traits influence the course of the disease is
still unresolved. A trend towards an uniform personality alteration in the course
of the disease seems to exist. Especially when selecting non-pharmacological
therapeutical or training strategies or even in the interaction with the
patients, it seems to be important to take personality change into consideration.
PMID- 10768259
TI - [Effect of a geriatric psychiatric center on quality of care for elderly
psychiatric patients].
AB - The goal of this evaluation study is to analyze the effects of a new
gerontopsychiatric institution, the gerontopsychiatric center (GC: a combination
of a home-based outpatient service, a day-hospital and a consulting office for
elderly with mental disorders) on the reorganization process of the treatment
system from intramural toward extramural structures, as experts of the government
of the FRG have been demanding for a long time. Based on data of cross-sectional
and longitudinal studies two regional catchment areas--the city of Bielefeld
(without GC, control region) and the district of Gutersloh (with GC)--are
compared and analyzed, whether changes within the gerontopsychiatric system
(subsystem A), the system of general medical treatment (subsystem B), or within
the elderly care system (subsystem C) occurred. Concerning subsystem A the
results are that the GC has a strong impact on the intended shift from intra- to
extramural structures, without selecting patients by diagnosis nor by severity
degrees of their mental disorders in extramural treatment facilities. The home
based outpatient treatment is especially successful for elderly with a functional
psychic disorder. These patients had the highest scores in improvement of
psychiatric symptoms as well as in reduction of their self-care deficits within
one year. Effects of the GC on subsystem B were evident soon after its
establishment, for example, by the increasing cooperation between the
gerontopsychiatric health services and general hospitals in the region with GC,
in which (hospitals) two fifths of all clinical gerontopsychiatric patients with
a mental disorder as the main diagnosis (ICD-9) are treated. An effect of the GC
on subsystem C is possibly the fact that in its region the rate of direct
transfers of patients from the clinical gerontopsychiatric department into homes
for the elderly is significantly lower than in the region without GC.
PMID- 10768260
TI - [Significance of the markers of aging].
AB - From its origin to its death the human organism is submitted to functional,
material and morphological changes that are perceptible. These changes permit
classifying an individual as young, adult, old, active or infirm. But this
estimation is not always correct. Some appear younger, some older than expected
from their chronological age. But what is ageing and how can it be measured? For
this, so-called markers or biological markers of ageing are used which are
measurable indicators of ageing in live organisms. A description of the
complexity, the asynchronous course and the biological variety and variability of
biological age is less successful with a single indicator than with the inclusion
of several markers in a multi-factorial measuring system, in a so-called test
battery. Various test batteries have already been applied in numerous studies
that consist of biochemical scans, mental and also social parameters in different
combinations. A more precise description of such a test battery can be seen in
the following discussion of the ILSE study.
PMID- 10768261
TI - [Can age and aging be measured?].
AB - Are age and aging measurable? Yes, of course they are, if all types of
quantification are included. Nevertheless, a lot of questions have to be
discussed with regard to different concepts of age, e.g., chronological age,
biological age, subjective age, mean age, life expectancy, etc. Even the question
when someone should be labeled old cannot be answered without reference to a
priori hypotheses and demographic development. Beyond that, aging is not a
standardized process. Aging is dependent on multiple individual and environmental
conditions and there is a large interindividual variability which is often
underestimated. Research on these aging processes is itself dependent on the
instruments used, e.g., the methods of a longitudinal or cross-sectional study.
Aging is a multifaceted and quite individual process.
PMID- 10768262
TI - [Age boundaries as social regulation of individual life organization: an
anachronism?].
AB - As part of the modern institutionalization of the life course, chronological age
boundaries have become highly salient even though they seem to contradict many of
the values and systemic requirements of modern societies. During the past few
decades, strict age boundaries have been increasingly criticized, and empirically
they have become somewhat more fluid. Are they today an anachronism? I treat this
question by focusing on the age boundary between work and retirement, and
distinguish two levels: its weight for structuring behavior and its meaning for
the actors. On both levels, the age boundary is still highly effective. As a last
step, I discuss whether the age boundary is (still) "reasonable", especially with
regard to the functional conditions of labor markets and social security systems.
PMID- 10768263
TI - [Cognitive prerequisites of geriatric rehabilitation].
AB - Rehabilitation aims at the restoration of maximal independence and autonomy after
functional loss due to illness or accident. In old age losses of independence in
daily life and autonomy are accounted for up to 60% by personal deficits in
cognitive abilities. Functional losses in cognitive abilities represent a higher
risk of having an accident or becoming ill. Cognitive performance proves to be
predictive for success of rehabilitation, independent of functional state. Using
the example of a fracture of the femur it can be shown that sensory and cognitive
deficits increase the risk of accidents and that executive abilities co-influence
long-term results. Strokes are more frequent if cognitive deficits have existed
before and the resulting damages are stronger. Long-term results generally depend
on complex abilities like everyday competence, reasoning and memory. Experiences
with patients with dementia undergoing a memory training show that learning
strategies are rarely generalized. Therefore in rehabilitation specific
disorders, as for example cortical or subcortical patterns, have to be treated by
different rehabilitation methods in the sense of differential rehabilitation. For
this an early neuro-psychological assessment of the geriatric rehabilitation
patient is needed. The cognitive-psychological findings only scarcely and
insufficiently enter diagnostics and therapy. The diverse cognitive disorders
have to be taken in account more frequently in education and differential
rehabilitation methods have to be developed for geriatric patients with cognitive
deficits.
PMID- 10768264
TI - [Does geriatric rehabilitation need a psychosocial foundation?].
AB - In view of the differentiality and multidimensionality of ageing, especially with
regard to geriatric rehabilitation, a look at psycho-social and also the
environmental context is indispensable. Above all there are mental and social
components that hide the physical consequences of acute incidents and that lead
to a reduction in the quality of life. Yet it is a widespread opinion that
expansion and the level of health care, in geriatry and in rehabilitation, are
nowadays oriented toward what is seen to be medically necessary and economically
feasible. Increasing mechanization, rationalization, standardization, and
economizing are unambiguous indicators. All the other mental and social needs are
problems ranking much lower in the health provision policy as well as in
geriatric rehabilitation, and are still far behind the medical and economic
requirements set by professional therapists, the health provision policy and the
question of who pays for the benefits. However, in consideration of the available
knowledge of gerontology, rehabilitation as well as health and nursing sciences
and--above all--for humanitarian reasons a psycho-social foundation for geriatric
rehabilitation seems to be indispensable.
PMID- 10768265
TI - [Basic principles of exercise therapy in geriatric rehabilitation].
AB - Physical therapy can support geriatric rehabilitation in contributing to better
health status, mobility, and quality of life. However, the central focus of this
contribution is not on illness-specific aspects of physical therapy but on power
and stamina training. These two training methods are of special importance for
geriatric rehabilitation since most patients are admitted due to related problems
and these two methods do imply specific risk factors for the rehabilitation
process. The spectrum of physical adaptation processes supported by power and
stamina training is described and scientifically evaluated. Even in higher age
groups positive training effects are possible. Adequate usage of these training
methods contributes to increased competence and a minimization of risks in daily
life.
PMID- 10768266
TI - [Fundamentals of dentistry for geriatric rehabilitation--an introduction to
geriatric dentistry].
AB - The percentage of aged and very old people in the total population is increasing
rapidly in industrialized countries. This is an important change which, in
particular, affects the areas of dentistry and oral medicine. The problems that
this older population group face need to be given more attention and need to be
brought more into the forefront of dental and oral medicine. The percentage of
the dentate population has increased in Germany, due to the high standard of the
dental care. The percentage of the edentulous population has therefore decreased.
It has become necessary for those who care for the elderly to adjust to caring
for the dentate patient, as opposed to edentulous patient. It is important for
all professions involved in the treatment and care of geriatric patients to have
an awareness of the basic fundamentals of geriatric dentistry within general
rehabilitation. Doctors in particular need to be given training in the detection
of caries, peridontal diseases, and denture problems. They should feel confident
working with the dentist and his team as partners in the rehabilitation
treatment. It is especially important that geriatric hospitals have experience in
dentistry and oral hygiene, so that damage to life-long well cared for teeth can
be prevented, and so that poor oral hygiene during a hospital stay does not
result in dental problems. Dentists and their teams will have to adjust to the
treatment of aged and multimorbidic patients. More discussion is also necessary
between dentists involved in all areas of geriatric medicine, geriatric
dentistry, and geriatric dental public health.
PMID- 10768267
TI - [The future of medical rehabilitation in accordance with SGB V and SGB XI in the
context of changes in the German Medical Care System].
AB - During recent years the German federal social welfare system has been subject to
several changes due to structural reforms. The hospital sector--as an element of
this system--has also been affected. Based on various legislation the financial
framework has been reduced which has led to tendencies of economic limitation and
rationalization. From this background considerable risk selection and changes in
emphasis might result. Cost intensive patients with a high need for treatment are
referred as quickly as possible and discharged to outpatient services despite
unknown domestic follow-up care. Mostly the elderly are affected. Medical
rehabilitation can be found in this system at the cut between SGB V and SGB XI.
However, this division raises problems and discussions concerning benefit payment
(rehabilitation before nursing, priority of home, etc.). Right in rehabilitation
the most important thing is an overlap of sectors. Various medical, nursing and
other social supplies have to be put into a network to achieve an integral
treatment of patients that focuses on the individual situation.
PMID- 10768268
TI - [Age limits from the legal perspective].
AB - In this article age limits in law are discussed. Two things first: Legal
commitments about old age are most commitments based on agreements which got
manifest in legislation. Second, age limits hold for typifying certain facts of
life, certain concerns of protection or other purposes. Therefore these age
limits by law will be shown by the right of state (legal participation,
citizenship and political participation, societal participation) and then
according to various phases of life. Age limits generally exist in two phases
during the life course: In the phase of childhood and youth, around the age of
six to twenty-one (upbringing and education) and the phase of the transition from
employment to retirement, around the age of sixty until seventy, at which age
limits of monetary provisions for one's old age represent an important part.
Furthermore, the legally achieved functions of age limits, like for example the
limits of ability and protection, will be discussed. Finally, it will be shown,
taking into account the comparison of legal aspects, if and how far age limits
are of discriminate character.
PMID- 10768269
TI - [Motivation or burden?--Illness and health in the elderly from the historical
perspective].
AB - Medical theories and practices concerning illness and health in old age as well
as several aspects of society that do influence the aging process are described
from a historical perspective integrating classical antiquity, middle ages, and
modern times. From the present state of research it is distinguished between
"primary illnesses in old age" and chronical diseases which might principally
also begin in younger ages but take a different course in old age. Even if the
frequency of disease and multimorbidity is increasing, negative stereotypes of
the aging process have to be invalidated. Advances in medical sciences are a good
pre-condition for increasing physical and mental health in old age.
PMID- 10768270
TI - [Aging, activity and longevity].
AB - From its origin to its death the human organism is submitted to functional,
material, and morphological changes that are perceptible. These changes permit
classifying an individual as young, adult, old, active or infirm. But this
estimation is not always correct. Some appear younger, some older than expected
from their chronological age. But what is aging and how can it be measured? For
this, so-called markers or biological markers of aging are used which are
measurable indicators of aging in live organisms. A description of the
complexity, the asynchronous course, and the biological variety and variability
of biological age is less successful with a single indicator than with the
inclusion of several markers in a multi-factorial measuring system, in a so
called test battery. Various test batteries have already been applied in numerous
studies that consist of biochemical scans, mental and also social parameters in
different combinations. A more precise description of such a test battery can be
seen in the following example of a discussion of the ILSE study.
PMID- 10768271
TI - [Changes in aging today and tomorrow--contributions of interventional
gerontology].
AB - This paper starts with the insight that today's intervention gerontology provides
a very broad scope of strategies with impact on the course of normal aging as
well as aging with competence losses. Also, it is assumed that this impact of
intervention gerontology will grow even further in the future. In the following,
current intervention gerontology research is discussed by particularly
highlighting its connection with basic gerontology findings, the contextual view
of aging, the interdisciplinary orientation, and the methodological standard.
With respect to the potential of gero-intervention in the future, three
prototypical domains are considered: (1) health and everyday competence, (2)
living environments, and (3) communication.
PMID- 10768272
TI - [Time, biography and life course].
AB - In this contribution implications of perspectives on the past and on the future
for the experience of the present and actual behavior are described. It is argued
that in a retrospective look on personal history (or selected periods of personal
history) people give meaning to events and processes--these events and processes
can be interpreted as "knots" around which other moments and periods (that are
subjectively judged as of less importance) do organize themselves. Subjectively
important aspects of the past are present in actual experiences and behavior:
Therefore, studying biography--subjects' interpretation of the life course--is a
pre-condition of understanding actual experiences and behavior. Moreover, people
are directed towards the future (e.g., in the sense of controllability vs. non
controllability). The perspectives on the past and future do constitute a human
time horizon. It is shown that the development of a time horizon and the
application of structure to the perception of time is a constructive performance
of human consciousness. Moreover, it is argued that the perception of time is a
basic antecendent of the experience of freedom. The contribution begins with the
analysis of a microsituation--the results of this analysis are then transferred
to the life course and biography. Life course and biography are analysed in the
context of the central theoretical positions that Ursula Lehr has developed and
tested empirically in her contributions to life span psychology.
PMID- 10768273
TI - [Patent foramen ovale: conservative or surgical therapy?].
AB - Notwithstanding the difficulties in definitely confirming paradoxical embolism,
the association between patent foramen ovale (PFO) and cryptogenic stroke has
repeatedly been demonstrated in clinical studies. Moreover, the recurrence rate
of cerebral ischemia in patients with PFO and an unexplained stroke was found to
be 3-4% per year in two recently published series. With the exception of right
atrial pressure elevation in the setting of major pulmonary embolism, a reliable
risk stratification of patients with PFO based on clinical or echocardiographic
findings is not yet possible. The presence of atrial septal aneurysm, a wide
opening of the defect during the cardiac cycle and a large atrial shunt have been
implicated as risk factors by some investigators. Long-term prevention of
paradoxical embolism with oral anticoagulants seems to be of questionable
benefit. Besides, these agents are poorly tolerated and carry the risk of
significant or fatal bleeding at a rate of 2-5% per year. Surgery of the atrial
septum has been performed for many decades in patients with atrial septal defect
and evidence accumulates that it is a safe and highly effective procedure in
patients with PFO. At present, surgical closure of the PFO appears to be the
treatment of choice for secondary prevention of paradoxical embolism. However,
further studies are needed to define the appropriate candidates for surgical
treatment. Devices for catheter-based sealing of PFO are also available and are
currently being evaluated in clinical trials. However, experience with their use
remains confined to specialized centers. Furthermore, further technical
improvements of these systems are needed in order to optimize successful delivery
and positioning, increase their long-term stability, and reduce periprocedural
complications.
PMID- 10768274
TI - [The 6 minute walking test: a cost-effective alternative to spiro-ergometry in
patients with chronic heart failure?].
AB - In contrast to the often debated NYHA classification, the determination of peak
oxygen uptake (peak VO2) by cardiopulmonary exercise testing allows an objective
assessment of the exercise capacity of patients with congestive heart failure
(CHF). However, cardiopulmonary exercise testing is a time consuming and costly
diagnostic tool, which requires sophisticated equipment and specially trained
personel. Exercise capacity can also be determined by the 6 minute walk test.
This test simply measures the distance covered by strong walking on a hallway
level within 6 minutes. The 6 minute walk test is a submaximal exercise test,
which is associated with much smaller increments in heart rate, blood pressure
and plasma catecholamines than cardiopulmonary exercise testing. It is
characterized by a very small intraindividual variance. Furthermore, it can be
easily performed and, due to low logistic and personal requirements, it is very
cost effective. The results of the 6 minute walk test--as well as of
cardiopulmonary exercise testing--are influenced by extracardial exercise
limiting disorders, such as pulmonary diseases. Independent from the etiology of
CHF, the results of the 6 minute walk test are closely related to peak VO2. In
serial exercise testing the distance covered within 6 minutes allow to predict
the individual peak VO2. Like peak VO2 the 6 minute walk test has been shown to
be a predictor of morbidity and mortality in CHF, with its predictive value being
independent from left ventricular ejection fraction and other potential
prognostic parameters. In CHF patients a walking distance < 300 m is associated
with a one-year-mortality of up to 50%, whereas the one-year-mortality in
patients reaching a walking distance > 450 m amounts to only a few percent. In
addition, the hospitalization rate of patients reaching a walking distance of <
300 m is several fold higher than in those with a walking distance > or = 450 m.
Like cardiopulmonary exercise testing, the 6 minute walk test allows to control
the efficiency of specific treatments and to monitor the natural course of the
disease. The 6 minute walk test is, thus, a cost effective alternative to
cardiopulmonary exercise testing in CHF patients. However, neither the 6 minute
walk test alone nor the results of cardiopulmonary exercise testing alone are
sufficient for selecting patients, e.g., for cardiac transplantation, as each
individual case requires a synopsis of all relevant facts and parameters.
PMID- 10768275
TI - Long-term safety of an early ACE-inhibitor treatment of patients with acute
myocardial infarction: results of the 3 year follow-up period on 696 Swiss
patients randomized to the ISIS-4 trial. ISIS-Switzerland Study Group.
AB - Several large scale clinical trials showed that early ACE inhibitor treatment in
patients with acute myocardial infarction reduced 30-day mortality. While the
short-term evidence of benefit and risks appears to be consistent among trials,
scarce data are available with respect to the long-term effects of short-term
treatments. This study shows that the early reduction in mortality rate observed
among patients treated with captopril persists for up to 3 years. This suggests
that the benefit achieved in the acute phase in not lost even after a long period
of time.
PMID- 10768277
TI - [Long-term management after heart transplantation--an assessment of current
status].
AB - Due to an improvement of results after heart transplantation, there is a
continuously growing number of long-term surviving patients. Aimed at a
characterization of established diagnostic and therapeutic protocols, the Working
Group of Thoracic Organ Transplantation within the German Society of Cardiology
performed a survey among all German heart transplantation centers. Based on the
experience of 1,500 patients, the clinical relevance as well as approaches for
prevention and treatment of rejection, infection, cardiac allograft vasculopathy,
malignancy, hypertension, renal insufficiency, and quality of life were assessed
by a questionnaire. As a result, a time dependency of expected complications
could clearly be shown. While early after HTX acute rejection and infection
episodes were judged as clinically important, later on cardiac allograft
vasculopathy, malignancy, and renal insufficiency predominate as relevant
complications. This spectrum was reflected by a differentiated diagnostic
protocol (early after HTX more frequent diagnostic procedures for rejection and
infection, later intensified examinations to identify cardiac allograft vascular
disease and malignancy) as well as by different intensities of immunosuppression
and concomittant medication. Regarding further improvement of survival rates and
quality of life, future clinical and scientific activities should be focused on
the prevention of late complications after heart transplantation.
PMID- 10768276
TI - [Correlation between cardiac autonomic activity and compromise of left
ventricular function in dilated cardiomyopathy].
AB - In recent years, evaluation of cardiac autonomic activity by means of heart rate
variability (HRV) determination and baroreflex sensitivity (BRS) testing has
become readily available. The results of the ATRAMI (Autonomic Tone and Reflexes
After Myocardial Infarction) study showed that both diminished HRV and baro
reflex sensitivity are associated with poor outcome in patients after myocardial
infarction. In contrast to patients with coronary disease little information is
available concerning cardiac autonomic activity in idiopathic dilated
cardiomyopathy (IDC). Therefore, HRV and BRS were assessed in 160 patients with
IDC and preserved sinus rhythm in order to investigate the relationship between
HRV, BRS, and left ventricular ejection fraction. Time domain indices of HRV were
computed from 24-hour digital Holter recordings. BRS testing was performed using
the noninvasive phenylephrine method. Mean standard deviation of all normal RR
intervals (SDNN) of the whole study population was 112 +/- 46 ms. A well
preserved HRV (SDNN > 105 ms) was found in 74 patients (46%), a moderately
decreased HRV (SDNN 70-105 ms) in 59 patients (37%), and a severely decreased HRV
(SDNN < 70 ms) in 27 patients (17%). Mean BRS was 7.5 +/- 5.0 ms/mm Hg. A well
preserved BRS (> 6 ms/mm Hg) was present in 78 patients (57%), a moderately
decreased BRS (3-6 ms/mm Hg) was present in 38 patients (28%), and a severely
decreased BRS (< 3 ms/mm Hg) in 21 patients (15%). There was only a weak
correlation between SDNN and BRS (r = 0.19; p < 0.05). A weak correlation was
found for SDNN and left ventricular ejection fraction (r = 0.29; p < 0.05). There
was no significant correlation between BRS and left ventricular ejection fraction
(r = 0.14). In summary, there was only a weak correlation between the HRV, BRS,
and left ventricular ejection fraction in patients with IDC suggesting that these
3 variables may be independent predictors of sudden death in IDC. The relative
prognostic value of these variables and other potential risk predictors including
the presence of arrhythmias on Holter, microvolt T wave alternans, QTc
dispersion, and signal-averaged ECG is currently under investigation in a large
prospective observational study (Marburg Cardiomyopathy Study (MACAS)) during 5
year follow-up at our institution.
PMID- 10768278
TI - Oxygen-mediated pulmonary vasodilation and plasma levels of endothelin-1, atrial
natriuretic peptide and cyclic GMP in patients with left-to-right shunt and
pulmonary hypertension.
AB - This study was performed to evaluate the role of endogenous endothelin-1 (ET-1),
atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in
patients with left-to-right shunt and pulmonary hypertension. Further objectives
were to study a possible feedback mechanism between ANP and ET-1 and to examine
the influence of ANP on cGMP plasma levels. Finally, the role of these hormones
in oxygen-mediated pulmonary vasodilation was examined. Plasma concentrations of
ET-1, ANP and cGMP were studied in 39 patients with congenital heart disease and
left-to-right shunt. Blood samples were taken from the pulmonary artery and
pulmonary vein at cardiac catheterization at baseline and after breathing oxygen
for 20 min. Patients were grouped according to the presence or absence of
pulmonary hypertension (defined as mean Pp/Ps > or = 0.5). Patients with
pulmonary hypertension (n = 18) were found to have significantly higher plasma
ANP (665 [59-1358] versus 267 [47-832] pg/ml) and cGMP (21.5 [3.6-82.2] versus
7.8 [0-14.6] nM/L) levels than patients without pulmonary hypertension (n = 21).
Pulmonary venous ET-1 plasma concentrations were above normal limits in one
patient only. ANP plasma levels were not related to ET-1 and cGMP concentrations.
There was no transpulmonary gradient for any of the factors. Pulmonary
vasodilation in response to oxygen was found in 7 of 18 patients with PH, but was
not associated with significant changes in ET-1, ANP or cGMP plasma
concentrations. Patients with congenital heart disease and PH show an increase
both in vasoconstrictive and vasodilating factors. The mechanism of oxygen
mediated vasodilation in these patients remains to be elucidated.
PMID- 10768279
TI - [Rupture of a congenital right coronary sinus of Valsalva aneurysm as etiology of
acute cardiac decompensation].
AB - A 54 year old woman was admitted to a hospital because of acute thoracal pain,
dyspnea, and clinical signs of overt right heart failure. Transthoracic and
multiplane echocardiography established the diagnosis of a ruptured aneurysm of
the right coronary sinus of valsalva into the right atrium which could be
confirmed by cardiac catheterization. During heart surgery, which was done
without complications, the defect was closed with a suture. Six months later
echocardiography showed a normal right ventricle; the function of the aortic
valve was regular. Acute heart failure may be due to a congenital structural
cardiac anomaly in spite of the age of 54. In such conditions transthoracic and
especially transesophageal echocardiography serve as noninvasive excellent tools
to make an exact diagnosis.
PMID- 10768280
TI - [Early postoperative dysfunction of a modified Blalock-Taussig shunt: successful
therapy with angioplasty and stent implantation in the subclavian artery].
AB - A newborn with pulmonary atresia with ventricular septal defect and transposition
of the great arteries was palliated with a modified Blalock-Taussig shunt at 5
days of age. Three days postoperatively arterial oxygen saturations dropped
significantly. Thrombosis of the shunt was suspected. Angiography revealed
stenosis of the proximal subclavian artery related to the creation of the shunt.
The patient was successfully treated with angioplasty and stent implantation into
the stenotic subclavian artery. Follow-up angiography 3 months after stent
deployment showed a completely patent subclavian artery and unobstructed blood
flow across the modified Blalock-Taussig shunt.
PMID- 10768281
TI - [Partial anomalous origin of the left pulmonary artery].
AB - The pulmonary sling or aberrant left pulmonary artery has an incidence of 3% to
6% of all anomalies of the aortic arch system. We report a boy with coexistence
of a normal and an anomalous left pulmonary artery. Associated congenital
anomalies were coarctation, mitral stenosis, and imperforate anus. Cardiac
catheterization and angiocardiography at the age of 5 months demonstrated an
inconspicuous pulmonary trunk dividing into left and right branches. There was a
normal right pulmonary artery, and a main left pulmonary artery supplying the
left upper lobe, lingula, and anterior segments of the left lower lobe. In
addition, an anomalous left lower lobe artery originated from the proximal right
pulmonary artery, passed inferior to the tracheal bifurcation to the left
supplying posterior segments of the left lower lobe. Chest X-rays and
bronchoscopy could not detect any malformation of the trachea and pulmonary
lobulation. There are only three reports of partial anomalous origin of the left
pulmonary artery, and only one had a similar course of the accessory artery. This
report is the first to present selective angiography and echocardiographic
findings of the partial anomalous left pulmonary artery. The development of the
partial anomalous pulmonary artery can be explained by the plexiform nature of
the primary pulmonary vascular bed and can help to understand the embryology of
the pulmonary arteries.
PMID- 10768282
TI - [Comment on the contribution by Wagdi Ph., Egloff L., Siebemann R., Tartini R.
"Catheter-induced dissection of the right coronary ostium and aortic root"].
PMID- 10768283
TI - Detection of Australian gill-associated virus (GAV) and lymphoid organ virus
(LOV) of Penaeus monodon by RT-nested PCR.
AB - A highly sensitive test based on reverse transcription followed by nested
polymerase chain reaction (RT-nPCR) was developed to detect the Australian yellow
head-like viruses, gill-associated virus (GAV) and lymphoid organ virus (LOV) of
Penaeus monodon. The RT-nPCR detected viral RNA in as little as 10 fg lymphoid
organ total RNA isolated from GAV-infected P. monodon. Amplification of serial
dilutions of a GAV cDNA clone showed that the nested PCR was sufficiently
sensitive to detect a single genome equivalent using a DNA template. The
specificity and sensitivity of the RT-nPCR was also demonstrated using
experimentally infected P. (Marsupenaeus) japonicus, where GAV sequences could be
amplified from lymphoid organ and haemocyte RNA as early as 6 h post infection
(p.i.), and from gills by 24 h p.i. In contrast, transmission electron microscopy
(TEM) identified nucleocapsids and virions in lymphoid organ cells and haemocytes
from Days 3 and 6 p.i., respectively, while there was no evidence of infection in
gill cells at any time. The practical application of the RT-nPCR was demonstrated
by screening healthy wild-caught P. monodon broodstock. The high prevalence
(>98%) of broodstock that were positive by RT-nPCR suggests that LOV is endemic
in northern Queensland. In addition, results with lymphoid organ, gill and
haemocyte RNA suggest that small gill biopsies may be best suited to the non
sacrificial testing of valuable broodstock. The speed and sensitivity of the RT
nPCR make it a useful adjunct to TEM for diagnosing LOV/GAV infection of P.
monodon, with the additional benefit that screening of gill biopsies may
facilitate selection of LOV-free broodstock.
PMID- 10768284
TI - Monodon baculovirus from Australia: ultrastructural observations.
AB - The cytopathology, virogenesis and replication of monodon baculovirus (MBV) in
Penaeus monodon from Australia are described. Electron-dense unenveloped
nucleocapsids, not previously described for MBV, are shown in the cytoplasm and
attached to the nuclear envelope of infected hepatopancreatocytes. These
nucleocapsids comprise a missing link in the published literature on the
replication cycle of MBV by providing evidence for the means by which the viral
genome travels from the plasma membrane of the hepatopancreatocyte to the
nucleus. Features similar to those of MBV from other areas, but not previously
reported for MBV from Australia include empty capsids attached to the nuclear
pore, central filaments in developing capsids, capsids partly filled with nucleic
acid, and filaments in subapical envelope expansions. A model for virogenesis and
replication is illustrated which takes into account the new observations as well
as previously described ultrastructural characteristics of the developing viral
particle.
PMID- 10768285
TI - A non-destructive method based on the polymerase chain reaction for detection of
hepatopancreatic parvovirus (HPV) of penaeid shrimp.
AB - Current methods to detect hepatopancreatic parvovirus (HPV) infection of penaeid
shrimp depend on invasive techniques that require dissecting the organs infected
by this virus. However, sacrificing valuable stocks in order to determine their
HPV status can be a drawback in the case of breeding programs. A method was
developed for HPV detection by applying a polymerase chain reaction (PCR) assay
to fecal samples collected from live HPV-infected shrimp Penaeus chinensis. A
pair of PCR primers, 1120F/1120R, which amplify a 592 base pair (bp) region from
the virus genome, was designed from previously known HPV sequence information
(HPV clone HPV8). PCR amplification with these primers generated a product of the
expected size directly from the crude feces of HPV-infected shrimp but not from
the feces of specific pathogen-free (SPF) shrimp. The HPV origin of the amplified
product was validated by means of an in situ hybridization assay where the
product of the amplification, labeled with digoxigenin (DIG)-11-dUTP, showed an
intense reaction within hepatopancreatic cells displaying characteristic HPV
lesions on HPV-infected shrimp. No reaction to this probe was observed when
reacted in situ with sections of the hepatopancreas of SPF specimens or to
sections of shrimp infected by the infectious hypodermal and hematopoietic
necrosis virus (IHHNV), another parvovirus of penaeid shrimp. These primers were
tested for specificity against homologous and nonhomologous viruses and no
product was amplified. A fragment of the expected size was obtained only when
purified HPV or purified HPV8 plasmid was used as template DNA. Under optimized
conditions, these primers detected as little as 1 fg of purified HPV8 plasmid
DNA, equivalent to approximately 300 HPV particles. Analysis of fecal samples by
PCR may prove useful for non-lethal screening of valuable shrimp of unknown HPV
status. This same strategy also might be used for detection of other enteric
viruses that infect penaeid shrimp.
PMID- 10768286
TI - Viremia-associated ana-aki-byo, a new viral disease in color carp Cyprinus carpio
in Japan.
AB - A new virus disease that displays dermal ulceration and high mortality has been
occurring since 1996 in color carp Cyprinus carpio reared in warm water in Japan.
In histological examinations, initial erosive lesions displayed necrosis,
hemorrhage and fibrin deposition in the dermal loose connective tissue and were
accompanied by the partial destruction of the epidermis. Developed ulcerative
lesions involved the lateral musculature with bacterial invasions. In visceral
organs, necrotic cells were observed in the hematopoietic tissue, the spleen and
the intestinal tissues as well as in cardiac muscle fibers which showed no signs
of bacterial invasion. Electron microscopy revealed corona-like virus particles
in these necrotic cells. The necrotic cells of the hematopoietic tissue and the
spleen were accompanied by the formation of tubular structures and crystalline
inclusions. The putative virus was isolated and cultured in epithelioma
papillosum cyprini (EPC) cells. Carp experimentally inoculated with the cultured
virus showed virus transmission, and the same pathological signs of the disease
and mortalities as in natural infections.
PMID- 10768287
TI - Epidermal lesions and mortality caused by vibriosis in deep-sea Bahamian
echinoids: a laboratory study.
AB - When significant mortality of the bathyal spatangoid echinoid Paleopneustes
cristatus occurred under laboratory conditions, we investigated the cause and
course of the disease by culturing and identifying internal pathogens, then
experimentally infecting healthy urchins with isolates of the suspected disease
organism. The pathogen was determined to be the gram-negative halophilic
bacterium Vibrio alginolyticus. This species was also recovered from frozen post
challenge specimens of P. cristatus and from moribund individuals of
Archaeopneustes hystrix, another spatangoid reared under similar in vitro
conditions. This is the first experimental study of bacterial disease in any deep
sea invertebrate.
PMID- 10768288
TI - Observations on the electron-dense bodies of the PKX parasite, agent of
proliferative kidney disease in salmonids.
AB - Ultrastructural observations on structures associated with the 'haplosporosome'
like electron-dense bodies (EDBs) of the primary cell of the extrasporogonic
stage of PKX are described. Observations made include formation of EDBs by the
trans-Golgi network, an additional membrane associated with EDB structure,
confronting cisternae, engulfment and presence of EDBs in multivesicular bodies,
fusion of EDBs with the plasmalemma, degeneration of EDBs in disintegrating
primary cells and endocytosis of PKX cytoplasm by adherent macrophages.
Immunogold localisation of a PKX-specific monoclonal antibody (MAb A3) suggests
that the EDBs contain periodate-sensitive carbohydrates on their membranes.
Tissues prepared for immunogold electron microscopy further suggest that some
contain a lipid-rich core. An interpretation is made on their possible function
and their relationship with the haplosporosomes and sporoplasmasomes found in
members of the Haplosporidea and Myxosporea respectively.
PMID- 10768289
TI - Mycobacteriosis in wild rabbitfish Siganus rivulatus associated with cage farming
in the Gulf of Eilat, Red Sea.
AB - Infection patterns of Mycobacterium marinum were studied over a period of 3 yr in
wild rabbitfish Siganus nivulatus populations associated with commercial
mariculture cages and inhabiting various sites along the Israeli Red Sea
coastline. Mycobacteriosis was first recorded from the Red Sea in 1990 in farmed
sea bass Dicentrarchus labrax and is absent from records of studies on parasites
and diseases of wild rabbitfish carried out in the 1970s and 1980s. A sharp
increase in the prevalence of the disease in cultured and wild fish in the region
has occurred since. A total of 1142 rabbitfish were examined over a 3 yr period
from inside mariculture net cages, from the cage surroundings and from several
sites along the coast. Histological sections of spleens were examined for
presence of granulomatous lesions. Overall prevalence levels of 50% were recorded
in the rabbitfish sampled inside the net cages and 39% at the cages' close
surroundings, 21% at a sandy beach site 1.2 km westwards, 35% at Eilat harbour 3
km to the south and 42% at a coral reef site about 10 km south of the cages. In
addition, 147 fish belonging to 18 native Red Sea species were sampled from 2
sites, the net cage farm perimeter and the coral reef area, and examined for
similar lesions. None of those from the coral reef were infected with
Mycobacterium; however, 9 of 14 species collected from the cage surroundings were
infected. An increase in prevalence of mycobacteriosis in the mariculture farm
area was noted from 1995 to 1997. At the same time, a significant increase in
prevalence was also apparent at the coral reef sampling site. Two M. marinum
isolates from rabbitfish captured at Eilat harbour and the coral reef site were
shown by 16S rDNA sequencing analysis to be identical to isolates from rabbitfish
trapped inside the mariculture cages as well as isolates from locally cultured
sea bass D. labrax. The implications of spreading of M. marinum infection in wild
fish populations in the Gulf of Eilat are discussed.
PMID- 10768290
TI - A study of sequential histopathology of Trypanoplasma borreli (Protozoa:
Kinetoplastida) in susceptible common carp Cyprinus carpio.
AB - The tissue response of common carp Cyprinus carpio to the kinetoplastid blood
parasite Trypanoplasma borreli Laveran & Mesnil, 1901 was investigated during a
laboratory infection of a highly susceptible carp line. With the development of
the parasitaemia an increased proliferation of the lymphoid renal interstitial
tissue was induced, which resulted in a progressive depression and deterioration
of renal tubules. In heavily infected carp at Days 20 to 28 post inoculation
(PI), a tubulonephrosis, a glomerulitis caused by a massive accumulation of
leukocytes in glomerular capillaries, and large numbers of trypanoplasms in blood
vessels and renal interstitium were observed. Corresponding with rising T.
borreli numbers in the peripheral blood, splenic lymphocytes showed increasing
proliferation rates, and the capillaries of the liver, gills, heart and intestine
were infiltrated with lymphocytes and trypanoplasms. In heavily infected carp,
congestion of liver sinusoids, focal necroses of hepatic tissue, extensive
accumulations of erythrocytes in the spleen and in the blood marked anaemia were
observed. These carp often showed abdominal distension, exophthalmus and swimming
disorders described as 'sleeping sickness of carp'. Proliferation of cells from
the interstitial lymphoid tissue of the kidney, which bears a close resemblance
to the bone marrow of higher vertebrates, is considered a normal immune response
of fish to antigen challenge. We here describe the unique case of a severe but
ineffective immune reaction which results in the destruction of excretory renal
structures. This has to be considered a severe disturbance of osmoregulation in
affected carp, which, together with a decrease in oxygen uptake due to anaemia,
is likely a major cause of death in these carp.
PMID- 10768291
TI - An antigen-capture enzyme-linked immunosorbent assay (ELISA) to detect
isometamidium chloride in Oncorhynchus spp.
AB - An antigen-capture enzyme-linked immunosorbent assay (ELISA) was developed to
detect and measure isometamidium chloride in the plasma of Oncorhynchus
tshawytscha and O. mykiss. Isometamidium-ovalbumin conjugate and anti
isometamidium antibodies were used to coat polystyrene plates. The peroxidase
saturation technique was used to optimize the coating antigen concentration; it
demonstrated low affinity of the isometamidium-ovalbumin conjugate but high
affinity of the anti-isometamidium antibodies for polystyrene surface sites. The
optimal conditions of antiisometamidium antibodies to coat plates was at pH 7.3
and a 1:1000 dilution (0.0012 mg ml(-1) protein). The ELISA was sensitive as it
detected 0.0006 mg ml(-1) of isometamidium in fish plasma. Isometamidium diluted
with saline could not be detected at concentrations less than 0.05 mg ml(-1). The
results indicate that this ELISA is much more sensitive when isometamidium is
bound to plasma than unbound isometamidium in saline.
PMID- 10768292
TI - An overview of the preclinical aspects of topiramate: pharmacology,
pharmacokinetics, and mechanism of action.
AB - In this overview, we discuss the discovery and development of topiramate (TPM) as
an anticonvulsant, including notable aspects of its chemical, biologic, and
pharmacokinetic properties. In particular, we highlight its anticonvulsant
profile in traditional seizure tests and animal models of epilepsy and the
results of recent electrophysiological and biochemical studies using cultured
neurons that have revealed a unique combination of pharmacologic properties of
TPM. Finally, we present a hypothesis for the mechanistic basis of the
anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane
ion channel proteins at phosphorylation sites and thereby allosterically
modulates channel conductance and secondarily inhibits protein phosphorylation.
PMID- 10768293
TI - Cellular actions of topiramate: blockade of kainate-evoked inward currents in
cultured hippocampal neurons.
AB - PURPOSE: This study was undertaken to evaluate the effects of topiramate (TPM) on
excitatory amino acid-evoked currents. METHODS: Kainate and N-methyl-D-aspartate
(NMDA) were applied to cultured rat hippocampal neurons by using a concentration
clamp apparatus to selectively activate the AMPA (alpha-amino-3-hydroxy-5
methylisoxazole-4-propionic acid)/kainate and NMDA receptor subtypes,
respectively. The evoked membrane currents were recorded by using perforated
patch whole-cell voltage-clamp techniques. RESULTS: TPM partially blocked kainate
evoked currents with an early-onset reversible phase (phase I) and a late-onset
phase (phase II) that occurred after a 10- to 20-min delay and did not reverse
during a 2-h washout period. Application of dibutyryl cyclic adenosine
monophosphate (cAMP; 2 mM) during washout after phase II block enhanced reversal,
with the kainate current amplitude being restored by approximately 50%. Phase II
but not phase I block was prevented by prior application of okadaic acid (1
microM), a broad-spectrum phosphatase inhibitor, suggesting that phase II block
may be mediated through interactions with intracellular intermediaries that alter
the phosphorylation state of kainate-activated channels. Topiramate at 100 microM
blocked kainate-evoked currents by 90% during phase II, but had no effect on NMDA
evoked currents. The median inhibitory concentration (IC50) values for phase I
and II block of kainate currents were 1.6 and 4.8 microM, respectively, which are
within the range of free serum levels of TPM in patients. CONCLUSIONS: The
specific blockade of the kainate-induced excitatory conductance is consistent
with the ability of TPM to reduce neuronal excitability and could contribute to
the anticonvulsant efficacy of this drug.
PMID- 10768294
TI - Topiramate modulates GABA-evoked currents in murine cortical neurons by a
nonbenzodiazepine mechanism.
AB - PURPOSE: These studies further investigate the ability of topiramate (TPM) to
enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a
benzodiazepine-insensitive pathway. METHODS: Topiramate (30 and 100 microM)
enhancement of GABA (1 microM)-evoked currents in primary cultures of mouse
cortical neurons was studied by using whole-cell electrophysiologic techniques.
Results obtained with TPM (30 microM) were compared with those obtained with
clonazepam (CZP; 1 microM). RESULTS: Topiramate enhanced GABA currents in a
subset of cortical neurons tested. In addition, TPM enhanced GABA-evoked currents
in CZP-insensitive neurons, and CZP was effective in a subset of TPM-insensitive
neurons. Related studies in vivo demonstrated that intraperitoneal (i.p.)
administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases
pentylenetetrazol (PTZ) seizure threshold. This effect of CZP, but not TPM, was
reversed by the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.).
CONCLUSIONS: These results indicate that GABA(A)-receptor sensitivity to TPM is
not dependent on the presence of BZD sensitivity. Enhancement of GABA-mediated
inhibition through a BZD-insensitive pathway may represent one mechanism through
which TPM exerts its anticonvulsant action.
PMID- 10768295
TI - Effects of topiramate on sodium-dependent action-potential firing by mouse spinal
cord neurons in cell culture.
AB - PURPOSE: The effects of topiramate (TPM) on sodium-dependent action potentials
were studied by using cultured mouse spinal cord neurons. METHODS: The ability of
TPM to limit (block) depolarization-induced spontaneous repetitive firing (SRF)
was determined and compared with corresponding effects of phenytoin (PHT) and
lamotrigine (LTG) in cultured mouse spinal neurons. RESULTS: Topiramate at
concentrations of > or =3 microM caused a voltage-sensitive and time-dependent
limitation of SRF that was associated with a decrease in the velocity of the
upstroke of the action potential. At high concentrations (30-600 microM), TPM
rapidly blocked SRF in about one third of the neurons tested and did not affect
SRF in about one third. In some neurons, TPM caused an intermittent limitation
(sputtering) of SRF (approximately 30% of the neurons) or blocked SRF only after
a delay of several seconds (approximately 10%). This complex pattern of effects
is distinctly different from that of PHT and LTG, in which the effect was always
a rapid limitation or complete blockade of SRF. Another difference between TPM
and the other anticonvulsants (AEDs) is that the effects of TPM were more
dependent on the length of time the neurons were exposed to the compound and the
intensity or duration of neuronal activity. CONCLUSIONS: The results of this
study do not support the concept that Na+ channel blockade is the primary
mechanism responsible for the anticonvulsant activity of TPM.
PMID- 10768296
TI - Differential sensitivity of recombinant GABA(A) receptors expressed in Xenopus
oocytes to modulation by topiramate.
AB - PURPOSE: This study evaluated the modulatory effects of topiramate (TPM) on
various subtypes of recombinant rat gamma-aminobutyric acid A (GABA(A)) receptors
expressed in Xenopus oocytes. METHODS: Specific subunits of GABA(A) receptors
were expressed in Xenopus oocytes. Voltage-clamp recordings of currents were
performed after application of TPM (1-100 microM) to these oocytes in the
presence or absence of GABA. RESULTS: In a concentration-dependent fashion, TPM
(1-100 microM) reversibly inhibited GABA-evoked Cl- currents in oocytes
expressing either alpha1beta2gamma2S and alpha2beta2gamma2S recombinant GABA(A)
receptors and reduced the current-fading rate in alpha1beta2gamma2S-expressing
oocytes. Topiramate was effective at GABA concentrations of 1-10 microM but not
at 100 microM. Topiramate (1-100 microM) potentiated GABA-evoked Cl- currents and
increased the fading rate in oocytes expressing the alpha6beta2gamma2S GABA(A)
receptor. It had no effect on Cl- currents mediated through the
alpha4beta2gamma2S receptor or through the mixed population of GABA(A) receptors
expressed from rat brain mRNA. In general, the observed effects of TPM were more
pronounced on fading rates than on peak Cl- currents. CONCLUSIONS: These results
indicate that TPM may affect desensitization of GABA(A) receptors as assessed by
changes in the fading rates of GABA-evoked Cl- currents, possibly by effects on
second-messenger systems.
PMID- 10768297
TI - Concentration-effect studies with topiramate on selected enzymes and
intermediates of the GABA shunt.
AB - PURPOSE: Topiramate (TPM) is a new antiepileptic agent with a multifactorial
mechanism of action. The drug potentiates responses to gamma-aminobutyric acid
(GABA) at the GABA(A) receptor and has inhibitory effects on neuronal sodium
channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase.
Recent evidence has, however, suggested that the drug also increases brain GABA
concentrations in humans. These studies were designed to investigate the
neurochemical basis of this observation. METHODS: Adult male mice were randomised
into two groups and administered TPM (0-1,000 mg/kg) intraperitoneally either as
a single dose or daily for 8 days. At 4 h after the final dose, brain tissues
were analysed for concentrations of GABA, glutamate, and glutamine and for the
activities of GABA-transaminase and glutamic acid decarboxylase. TPM levels in
brain also were determined. RESULTS: Single-dose and repeated TPM treatments were
without effect on all of the parameters investigated, although the drug was
detectable in the brain at doses of > or =10 mg/kg. CONCLUSIONS: These results
contradict the reported increase in brain GABA concentrations with TPM. More
detailed studies are required to determine the basis of this clinical observation
and the extent to which it contributes to the antiepileptic activity of the drug.
PMID- 10768298
TI - Topiramate as an inhibitor of carbonic anhydrase isoenzymes.
AB - PURPOSE: This study investigated the effectiveness of topiramate (TPM) as an
inhibitor of six isozymes of carbonic anhydrase (CA). METHODS: The inhibition
constants (Ki) of TPM and acetazolamide (AZM) for CA I, CA II, CA III, CA IV, CA
V, and CA VI were determined for human (HCA), rat (RCA), or mouse (MCA). The
activity of CA was studied by using purified isozymes, erythrocytes, subcellular
fractions of kidney or brain, and saliva, and was assayed at 37 degrees C or 25
degrees C by 18O mass spectrometry and/or by measuring the pH shift at 0 degrees
C. RESULTS: Topiramate Ki values for HCA I, HCA II, HCA IV, and HCA VI were
approximately 100, 7, 10, and >100 microM, respectively. TPM Ki values for RCA I,
RCA II, RCA III, RCA IV, and RCA V were approximately 180, 0.1 to 1, >100, 0.2 to
10 and 18 microM, respectively. For RCA II and RCA IV, the Ki values were
temperature dependent. TPM Ki values for MCA II and MCA IV ranged between 1 and
20 microM. CONCLUSIONS: These results indicate that TPM is more potent as an
inhibitor of CA II and CA IV than of CA I, CA III, and CA VI. In all three
species, AZM was usually 10 to 100 times more potent than TPM as an inhibitor of
CA isozymes.
PMID- 10768299
TI - Effects of topiramate on sustained repetitive firing and spontaneous recurrent
seizure discharges in cultured hippocampal neurons.
AB - PURPOSE: In this study, we examined the effects of topiramate (TPM) on the
electrophysiologic properties of cultured rat hippocampal pyramidal neurons.
METHODS: Whole-cell current-clamp recording techniques were used to determine the
effects of TPM on sustained repetitive firing (SRF), spontaneous epileptiform
burst firing, and spontaneous recurrent seizures (SRS). RESULTS: Topiramate at
therapeutic concentrations (10-100 microM) significantly decreased or abolished
SRF in a dose-dependent and partially reversible manner. When transiently exposed
to a medium in which Mg2+ is omitted, hippocampal neurons in culture develop SRS
("epilepsy") and epileptiform discharges. Application of TPM at concentrations
ranging from 10 to 100 microM to cells displaying seizure activity caused a
concentration-dependent decrease in the number of action potentials within a
burst and in the average duration of epileptiform activity. Both effects were
partially reversed during a 5- to 30-min drug washout period. CONCLUSIONS: These
effects on the electrophysiologic properties of cultured neurons are consistent
with the concept that TPM exerts modulatory effects on voltage-dependent Na+
and/or Ca2+ conductances responsible for the generation and propagation of action
potentials. Topiramate also may inhibit synaptic conductances responsible for
transmission of epileptiform discharges.
PMID- 10768300
TI - Topiramate blocks kainate-evoked cobalt influx into cultured neurons.
AB - PURPOSE: This study evaluated topiramate (TPM) antagonism of glutamate receptors
activated by kainate. METHODS: The ability of TPM (3-30 microM) to attenuate
kainate (300 microM)-activated cobalt (Co2+) flux through nonselective cation
channels permeable to Co2+, Mn2+, and Ca2+ into cultured cerebellar granule
neurons [9-14 days in vitro (div)] was investigated. Results were compared with
those obtained with the non-N-methyl-D-aspartate (non-NMDA) antagonist 6,7
dinitroquinoxalone-2,3-dione (DNQX) (10 microM). RESULTS: Topiramate produced a
concentration- and time-dependent inhibition of Co2+ uptake into cerebellar
granule cells cultured 9-11 div. Inhibition was evident at 10 microM, and
complete inhibition was observed at 30 microM. Maximal inhibition of Co2+ uptake
required pretreatment with TPM for > or =30 minutes before stimulation by
kainate. The effect of 30 microM TPM on Co2+ uptake was similar to that of 10
microM DNQX. However, TPM, unlike DNQX, did not affect kainate-evoked Co2+ uptake
into older neurons (i.e., 13-14 div). CONCLUSIONS: These results provide
additional support for an antagonistic effect of TPM on some types of alpha-amino
3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and/or kainate receptors,
and specifically suggest that TPM interacts with a Ca2+-permeable non-NMDA
receptor that is developmentally regulated. This observation may provide insight
into the molecular biology underlying the pathophysiology of seizure disorders
and antiepileptic drug resistance.
PMID- 10768301
TI - Effects of topiramate on kainate- and domoate-activated [14C]guanidinium ion flux
through GluR6 channels in transfected BHK cells using Cytostar-T scintillating
microplates.
AB - PURPOSE: This study was undertaken to test the hypothesis that topiramate (TPM)
exerts a negative modulatory effect on some types of alpha-amino-3-hydroxy-5
methylisoxazole-4-proprionic acid (AMPA)/kainate receptors by binding to the site
at which protein kinase A (PKA) phosphorylates the receptor-channel complex.
METHODS: The effect of TPM on kainate- or domoate-induced [14C]guanidinium ion
flux through iGluR6 channels expressed in baby hamster kidney (BHK) cells was
evaluated. Because the hypothesis predicts that TPM will bind only in the
dephosphorylated state, a variety of experimental conditions were used to either
promote or impede the phosphorylation of the receptor-channel complex. These
included the use of dibutyryl cyclic adenosine monophosphate (cAMP) and forskolin
to activate PKA, H-9 and H-89 to inhibit PKA, and okadaic acid to inhibit protein
phosphatases. RESULTS: Kainate (1 microM) induced a gradual accumulation of
[14C]guanidinium into the cells that plateaued approximately 30 min after
initiation of the reaction, whereas domoate (0.1 microM) caused a rapid
accumulation into the cells that peaked within 5 min; thereafter, the amount of
[14C]guanidinium in the cells declined gradually. Topiramate, at 0.1 and 100
microM, did not significantly affect the [14C]guanidinium accumulation under any
of the experimental conditions used. CONCLUSIONS: The results of this study are
not consistent with the hypothesis tested. However, the results must be
interpreted cautiously because iGluR6 receptors expressed in the BHK cells and
the functional state of proteins that regulate AMPA/receptors (e.g., PSD-95) may
not be sufficiently similar to the receptors and functional state in neurons to
serve as a true test of the hypothesis.
PMID- 10768302
TI - Modulation of high-voltage-activated calcium channels in dentate granule cells by
topiramate.
AB - PURPOSE: In this study, we assessed the effects of topiramate (TPM) on high
voltage-activated calcium channel (HVACC) currents in vitro. METHODS: HVACC
currents were recorded from rat dentate gyrus granule cells by using whole-cell
patch-clamp techniques. The biophysical properties of HVACCs were used to
separate voltage-activated Ca2+ currents into different subtypes. Three
concentrations of TPM were tested: 1, 10, and 50 microM. RESULTS: TPM inhibited L
type currents and was more effective at 10 microM than at 50 microM, suggesting
that there may be an optimal concentration at which TPM decreases L-type
currents. Non-L-type currents were transiently increased by TPM at a high
concentration (50 microM). CONCLUSIONS: Because the location of L-type calcium
channels on soma and proximal dendrites gives these channels a crucial role in
controlling dendritic excitability and in providing calcium for intracellular
effectors, the decrease in the L-type HVA Ca2+ currents may be an important
anticonvulsant mechanism of TPM.
PMID- 10768303
TI - Clinical pharmacology of topiramate: a review.
AB - Clinical success with an antiepileptic drug (AED) depends primarily on its
efficacy and tolerability. Clinicians also need to have a basic understanding of
an AED's pharmacokinetic characteristics, particularly those affecting the
potential for drug interactions such as hepatic enzyme inhibition or induction
and protein-binding displacement. Successful treatment may be complicated by
pharmacokinetic characteristics such as a short half-life, nonlinear kinetics,
and active metabolites. Pharmacokinetic characteristics that make a drug easy to
use may affect patient adherence. In general, newer AEDs such as topiramate (TPM)
are simpler to use than traditional AEDs because they have more favorable
pharmacokinetic characteristics and fewer drug interactions.
PMID- 10768304
TI - Topiramate as add-on therapy: pooled analysis of randomized controlled trials in
adults.
AB - PURPOSE: Six double-blind, placebo-controlled trials were conducted with
topiramate (TPM) initiated as adjunctive therapy in adults with treatment
resistant partial-onset seizures with or without secondary generalization.
METHODS: Because protocols and study populations were similar, data from the
studies were pooled and analyzed for 527 patients treated with TPM and 216
treated with placebo. RESULTS: Seizures were reduced > or =50% in 43% of TPM
treated patients and in 12% of placebo-treated patients (p < 0.001); 5% of TPM
treated patients, but no placebo-treated patients, were seizure free during 11-19
weeks of double-blind treatment (p < 0.001). The therapeutic effect was
consistent regardless of seizure type, age, gender, baseline seizure rate, or
concomitant antiepileptic drug (AED). With 100 mg/day TPM as a starting dosage
and weekly dosage increments of 100-200 mg/day added to maximally tolerated
dosages of AEDs, the most common treatment-emergent adverse events (TEAEs) were
dizziness, somnolence, fatigue, psychomotor slowing, nervousness, paresthesia,
ataxia, memory difficulty and speech problems. These central nervous system
effects were generally mild to moderate in severity, usually occurred early in
treatment, often during titration, and resolved with continued treatment. Other
notable TEAEs were weight loss and, in a small percentage of patients, renal
calculi.
PMID- 10768305
TI - Topiramate in the long-term management of refractory epilepsy. Topiramate YOL
Study Group.
AB - PURPOSE: A total of 292 adult patients (mean age, 33 years) with partial and/or
generalized seizures previously resistant to antiepileptic drug (AED) therapy
(median baseline seizure rate, 12 seizures/month) were treated with open-label
topiramate (TPM) in dosages of 100-1,600 mg/day. METHODS: The mean duration of
TPM treatment was 413 days (range, 84-804 days), and the mean TPM dosage was 503
mg/day (range, 100-1,600 mg/day; median TPM dosage, 300 mg/day). Seizure
reduction was calculated from seizure counts during the last 3 months and last 6
months of TPM therapy compared with baseline. RESULTS: Overall, >50% of patients
achieved > or =50% seizure reduction. More important, 11% of patients were
seizure-free for > or =3 months at the last visit; 10% of patients were seizure
free for > or =6 months at the last visit. This robust therapeutic response was
consistent for patients receiving TPM dosages >400 and <400 mg/day. The most
commonly reported adverse events were related to the central nervous system. Over
the 2.2-year treatment period, 19% of patients discontinued TPM therapy because
of inadequate seizure control; 32% discontinued because of adverse events.
Findings from this study show that TPM is a useful agent for long-term seizure
control, with some patients becoming seizure free for extended periods despite
failing previous AED therapy.
PMID- 10768306
TI - Nonfocal generalized tonic-clonic seizures: response during long-term topiramate
treatment. Topiramate YTC/YTCE Study Group.
AB - PURPOSE: A total of 131 adults and children (mean age, 27 years; range, 3-59
years) with generalized tonic-clonic seizures (GTCS) of nonfocal origin resistant
to other antiepileptic drugs (AEDs) were treated with open-label topiramate (TPM)
after completing double-blind placebo-controlled trials. RESULTS: The mean
duration of open-label TPM treatment was 387 days (range, 14-909 days); the mean
TPM dose was 7 mg/kg/day (range, 1-16 mg/kg/day). At the last study visit, the
frequency of GTCS was reduced > or =50% from baseline in 63% of patients and by >
or =75% in 44%. Among patients treated > or =6 months, 16% were GTCS free > or =6
months despite a pretreatment seizure frequency of one GTCS/week (median).
Treatment with TPM was being continued in 82% of patients (n = 107) at the last
visit. During treatment periods of up to 2.5 years, 11 (8%) patients discontinued
TPM because of adverse events and seven (5%) because of inadequate seizure
control. CONCLUSIONS: TPM therapy was well tolerated, and seizure control was
maintained with long-term, open-label therapy in patients with GTCS, leading to
prolonged seizure-free intervals in some patients with seizures previously
resistant to AED therapy.
PMID- 10768307
TI - Effectiveness, tolerability, and safety of topiramate in children with partial
onset seizures. Topiramate YP Study Group.
AB - PURPOSE: Children with partial-onset seizures, with or without secondary
generalization, participating in a double-blind, placebo-controlled trial of
topiramate (TPM) as adjunctive therapy were eligible to participate in an open
label, long-term extension study. METHODS: A total of 83 children (mean age, 9
years) continued long-term open-label TPM therapy in which the dosages of TPM and
concomitant antiepileptic drugs (AEDs) were adjusted according to clinical
response (mean TPM dosage, 9 mg/kg/day). RESULTS: Seizure frequency over the last
3 months of therapy was reduced > or =50% in 57% of children; 14% of children
were seizure-free > or =6 months at the last visit. During treatment periods up
to 2 1/2 years (mean, 15 months), 6% of children discontinued because of
treatment-emergent adverse events; 13% discontinued because of inadequate seizure
control. CONCLUSIONS: From these findings, TPM is well tolerated and provides
long-term seizure control in children with partial-onset seizures.
PMID- 10768308
TI - Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients
completing a randomized controlled trial. Topiramate YL Study Group.
AB - PURPOSE: The response to topiramate (TPM) as long-term adjunctive therapy was
evaluated in patients with Lennox-Gastaut syndrome (LGS) in a long-term, open
label extension to a double-blind, placebo-controlled trial. METHODS: In 97
patients with LGS (mean age, 11 years), dosages of TPM and concomitant
antiepileptic drugs (AEDs) were adjusted to optimal clinical response (mean TPM
dosage, 10 mg/kg/day). RESULTS: For those patients who had completed 6 months of
TPM therapy, drop attacks were reduced > or =50% in 55% of patients; 15% of
patients had no drop attacks for > or =6 months at the last visit. After
treatment up to 3+ years, 71% of patients who started open-label TPM were
continuing therapy at the last visit. CONCLUSIONS: During long-term therapy, TPM
is effective and well tolerated in controlling the treatment-resistant drop
attacks and seizures associated with LGS.
PMID- 10768309
TI - Long-term response to topiramate in patients with West syndrome.
AB - PURPOSE: The long-term effectiveness of topiramate (TPM) was evaluated in
children with West syndrome previously refractory to antiepileptic drug (AED)
therapy. METHODS: Children with infantile spasms who completed a pilot study were
eligible to enter a long-term extension phase in which the dosages of TPM and
other AEDs could be adjusted to optimal response (maximum, 50 mg/kg/day TPM). The
mean duration of long-term therapy was 18 months in the 11 children who were
followed; the mean TPM dosage was 29 mg/kg/day. RESULTS: Eight (73%) children
were continuing TPM therapy at the time data were analyzed; four (50%) children
were spasm free, seven (88%) had experienced a > or =50% reduction in spasms, and
three (38%) were able to achieve TPM monotherapy. CONCLUSIONS: TPM was well
tolerated in that no patients discontinued because of adverse events. The
response achieved with TPM during the pilot study was maintained in most
children.
PMID- 10768310
TI - Electrophysiological basis of QT dispersion measurements.
AB - Dispersion of ventricular repolarization is a now widely used term describing
nonhomogeneous recovery of excitability or heterogeneity of ventricular
repolarization. It is usually expressed as the difference or the range of various
repolarization measurements obtained from a heart. Experimentally, an increased
dispersion of ventricular repolarization was found to be tightly associated with
increased propensity for ventricular arrhythmias, and, therefore, is considered
an important arrhythmogenic mechanism. Noninvasively, this arrhythmogenic
substrate was approached using multilead body surface potential mapping, but also
QT interval dispersion (QTd) and similar electrocardiogram (ECG) variables from
the 12-lead surface ECG. Standard QTd from the ECG correlates significantly with
dispersion of repolarization measured from the myocardium. A causal relationship
is, however, still unclear, and there are 2 main hypotheses to explain the
electrophysiological basis of QTd. The local hypothesis explaining QTd with
spatial differences in action potential duration mirrored in the various QT
intervals competes with the global hypothesis explaining the variation in surface
ECG measurements with different projections of a common T-wave vector.
Notwithstanding the final explanation for QTd, and particularly for technical
reasons, new markers like advanced T-wave loop variables may best reflect the
abnormal repolarization substrate on the surface ECG.
PMID- 10768311
TI - Measurement and interpretation of QT dispersion.
AB - QT dispersion was proposed as an index of the spatial inhomogeneity of
ventricular recovery times. The results of studies that found significant
correlation between dispersion of ventricular recovery times measured with
monophasic action potentials and QT dispersion were interpreted as proof of the
direct link between QT dispersion and the dispersion of ventricular recovery
times. Later it was shown that QT dispersion is not a direct reflection of the
spatial variation of the recovery times and cannot be used for quantification of
this variation. The interlead variability of the QT intervals is a result of
different projections of the spatial T-wave loop into the various
electrocardiographic leads. The reliability of both manual and automatic
measurement of QT dispersion is low and is often of the order of the differences
of Qt dispersion between different patient groups. The measurement reliability is
influenced by intrinsic factors (e.g., amplitude of the T wave) and extrinsic
factors (e.g., noise, paper speed of recording, instruments for manual
measurements, and type of algorithm and interalgorithmic settings for automatic
measurement). There is very little to choose between the different indices of
expression of QT dispersion, as well as between the different lead configurations
used for its measurement. QT dispersion is not simply a result of measurement
error, but a crude measure of abnormalities during the whole course of
repolarization. Only grossly prolonged QT dispersion (e.g., > or =100 ms), must
be interpreted simply as a sign of the abnormal course of the repolarization, and
inferences about the actual dispersion of the ventricular recovery times should
not be made. Newer concepts of assessment of the morphology of the T wave are
already emerging and will probably be of higher clinical value.
PMID- 10768312
TI - Significance of QT dispersion in the long QT syndrome.
AB - The long QT syndrome (LQTS) has often been considered as a model to study the
abnormalities of cardiac repolarization in humans because it represents a pure
electrical disease with no evidence of cardiac structural abnormalities. The
arrhythmogenic potential of prolonged ventricular repolarization has been
extensively studied both in experimental models and at the clinical level in LQTS
patients, and many studies pointed to the pathogenetic role of the dispersion of
ventricular recovery times (i.e., dispersion of ventricular repolarization). In
the last few years, a new critical knowledge has been achieved thanks to the
molecular biology techniques that are unveiling the genetic bases of LQTS.
Indeed, the understanding of the genes and mutations that may cause the LQTS
opened the way to understanding the molecular determinants of the altered
ventricular repolarization that can be found in LQTS patients. From the clinical
standpoint, the traditional tools applied for the detection and quantification of
the dispersion of ventricular repolarization (monophasic action potential, QT
dispersion) showed their effectiveness but also their limitations. More recently,
the availability of new algorithms and the development of powerful computerized
supports allowed the evaluation of innovative techniques, which now represent
possible attractive alternatives intended to quantify the degree of
repolarization abnormalities in LQTS patients and possibly to noninvasively
quantify the risk of cardiac events.
PMID- 10768313
TI - Effect of coronary ischemia on QT dispersion.
AB - Over the last 5 to 8 years, numerous clinical studies have been conducted
evaluating the effects of coronary ischemia on disparity of ventricular
repolarization (VR) as assessed by determination of QT dispersion from the
surface electrocardiogram. From findings in patients with acute myocardial
infarction, stable coronary disease, and vasospastic angina there is convincing
evidence that acute coronary ischemia augments inhomogeneity in VR. In some
studies, this was associated with the occurrence of ventricular arrhythmias. In
general, therefore, these clinical observations confirm previous experimental
work. One should keep in mind, however, various problems inherent to the current
technology used to determine QT dispersion from the surface electrocardiogram.
Whereas some of these technological limitations can be overcome in carefully
designed and conducted clinical studies, these methodological shortcomings have
so far precluded the routine use of QT dispersion in taking care of patients with
acute coronary syndromes. It remains to be seen whether further refinements in
technology will enable clinicians to incorporate assessment of disparity of VR in
daily practice in an attempt to further improve care of patients with acute
coronary syndromes.
PMID- 10768314
TI - QT interval and mortality from coronary artery disease.
AB - Abnormalities in the QT interval can be divided into 3 types, prolongation of the
QT interval, increases in the dispersion of the QT interval, and abnormalities in
the heart rate dependent behavior of the QT interval. Abnormalities may be found
in short or long-term recordings. Prolongation of the QT interval may reflect
factors associated with an adverse prognosis in coronary disease and may in
itself be arrhythmogenic. The data to date suggest that there is an association
between adverse prognosis and QT interval prolongation in coronary disease, both
before and after acute myocardial infarctions. This relationship is weak,
however, and is not clinically useful. The data as to whether increased QT
dispersion postmyocardial infarction relates to adverse prognosis is weak because
there is no convincing evidence yet. If there is a relationship it is weak.
Abnormalities in the rate dependent behavior of the QT interval are widely found,
but as no large scale prospective study with mortality as an endpoint has yet
been undertaken the significance of rate dependent abnormalities is uncertain.
The widespread introduction of beat-to-beat QT analysis of 24 hour Holter tapes
may take QT intervalology into the realm of clinical practice.
PMID- 10768315
TI - Effects of antiarrhythmic drugs on QT interval dispersion--relationship to
antiarrhythmic action and proarrhythmia.
AB - Class IA, IC, and III antiarrhythmic drugs prolong ventricular repolarization
(VR) which is manifest as QT interval prolongation on the surface
electrocardiogram. These drugs may prolong VR in a spatially heterogeneous manner
which results in increased dispersion of VR. This may be manifest as increased QT
interval dispersion. Antiarrhythmic drug-induced decreases in QT interval
dispersion are associated with antiarrhythmic efficacy in patients with the long
QT syndrome and in patients with sustained ventricular tachycardia.
Antiarrhythmic drug-induced increases in QT interval dispersion are associated
with ventricular proarrhythmia secondary to torsades de points ventricular
tachycardia. A number of factors may modulate the effects of antiarrhythmic drugs
on dispersion of VR, including the disease state, transient ischemia, electrolyte
abnormalities, changes in autonomic tone, and hemodynamic stress.
PMID- 10768316
TI - Progression of diabetic retinopathy after endophthalmitis.
PMID- 10768317
TI - Phacotrabeculectomy: limbus-based versus fornix-based conjunctival flaps.
PMID- 10768318
TI - The "ice pack test" for diagnosing myasthenia gravis.
PMID- 10768319
TI - Potential acuity pinhole.
PMID- 10768320
TI - Trabeculotomy-trabeculectomy for early-onset glaucoma.
PMID- 10768321
TI - The mechanism of accommodation in primates.
PMID- 10768322
TI - The mechanism of accommodation in primates.
PMID- 10768323
TI - Target pressure--glaucomatologists' holey grail.
PMID- 10768324
TI - Two multicenter, randomized studies of the efficacy and safety of cyclosporine
ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study
Group.
AB - OBJECTIVE: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and
0.1% ophthalmic emulsions) to vehicle in patients with moderate to severe dry eye
disease. DESIGN: Multicenter, randomized, double-masked, parallel-group, 6-month,
vehicle-controlled. PARTICIPANTS: A total of 877 patients with defined moderate
to severe dry eye disease (292 to 293 in each treatment group). METHODS: Two
identical clinical trials; patients were treated twice daily with either CsA,
0.05% or 0.1%, or vehicle. The results of these two trials were combined for
analysis. MAIN OUTCOME MEASURES: EFFICACY: corneal and interpalpebral dye
staining, Schirmer tear test (with and without anesthesia), tear break-up time,
Ocular Surface Disease Index (OSDI), facial expression, patient subjective rating
scale, symptoms of dry eye, investigator's evaluation of global response to
treatment, treatment success, and daily use of artificial tears. SAFETY:
occurrence of adverse events, best-corrected visual acuity, intraocular pressure,
biomicroscopy, and blood trough CsA concentrations. RESULTS: Treatment with CsA,
0.05% or 0.1%, gave significantly (P < or = 0.05) greater improvements than
vehicle in two objective signs of dry eye disease (corneal staining and
categorized Schirmer values). CsA 0.05% treatment also gave significantly greater
improvements (P < 0.05) in three subjective measures of dry eye disease (blurred
vision, need for concomitant artificial tears, and the physician's evaluation of
global response to treatment). There was no dose-response effect. Both CsA
treatments exhibited an excellent safety profile, and there were no significant
topical or systemic adverse safety findings. CONCLUSIONS: The novel ophthalmic
formulations CsA 0.05% and 0.1% were safe and effective in the treatment of
moderate to severe dry eye disease yielding improvements in both objective and
subjective measures. Topical CsA represents a new pharmacologically based
treatment for dry eye disease that may provide significant patient benefits.
PMID- 10768325
TI - Avoiding serious corneal complications of laser assisted in situ keratomileusis
and photorefractive keratectomy.
AB - OBJECTIVE: To identify avoidable factors that can lead to serious complications
of laser refractive surgery (photorefractive keratectomy [PRK] and laser assisted
in situ keratomileusis [LASIK]). DESIGN: Noncomparative case series.
PARTICIPANTS: Twenty-seven eyes of 19 patients who had undergone either LASIK or
PRK with severe complications accrued retrospectively. INTERVENTION: Review of
clinical records. MAIN OUTCOME MEASURES: Symptoms, refractive outcome, and
assessment of avoidable factors contributing to the complication. RESULTS:
Patients were analyzed in four groups: group 1, scarring with ectasia; group 2,
unrecognized keratoconus; group 3, flap related LASIK complications; and group 4,
multiple retreatments. The 8 eyes with scarring and ectasia presented with the
worst vision, 20/400 uncorrected visual acuity and 20/200 best spectacle
corrected visual acuity, with avoidable factors considered as high or difficult
prescriptions with multiple retreatments. Four eyes in two patients with possible
forme fruste keratoconus showed worsening irregular astigmatism. Laser assisted
in situ keratomileusis flap complications included six eyes with partial laser
treatment under an incomplete flap with subsequent severe irregular astigmatism.
Six eyes in three patients who had undergone an average of three multiple
retreatments showed decreased vision with irregular astigmatism. CONCLUSIONS:
Certain severe complications of laser refractive surgery likely can be avoided by
using caution when treating high prescriptions, particularly with retreatments,
recognizing early keratoconus and avoiding laser treatment under a partial flap
in LASIK.
PMID- 10768326
TI - Laser in situ keratomileusis for high myopia with the VISX star laser.
AB - PURPOSE: To evaluate the results of laser in situ keratomileusis (LASIK) for
spherical and spherocylindrical myopia (range, 9-22 diopters [D]) with the VISX
Star laser, (VISX Inc., Santa Clara, CA). DESIGN: Non-comparative, single-surgeon
interventional case series. PARTICIPANTS: Two hundred ninety eyes of 175
patients. METHODS: Consecutive patients who underwent LASIK in the study range
with the VISX Star laser were evaluated for early (approximately 1 month) and
late (after 9 months) outcomes. Both single procedure outcomes and results after
reoperation for refractive enhancement were included. MAIN OUTCOME MEASURES:
Outcome measures included uncorrected visual acuity, manifest refraction,
refractive predictability, refractive stability, best spectacle-corrected visual
acuity (BSCVA), results of reoperations, and complications. RESULTS: At the early
postoperative examination, approximately 1 month after surgery, 285 of 290 eyes
(98.3%) were examined. Uncorrected visual acuity of 20/40 or better occurred in
209 of 285 (73.3%) eyes, and 198 of 285 (69.5%) eyes had a manifest
spheroequivalent between +/-1.00 D. Subsequently, 60 eyes (20.7%) underwent
reoperation for refractive enhancement. Late results, beyond 8 months from the
initial surgery and including reoperations, were available in 195 of 290 eyes
(67.2%). Uncorrected visual acuity results of 20/40 or better were found in 166
of 195 eyes (85.1%) and of 20/25 or better in 99 of 195 eyes (50.8%). Manifest
spheroequivalent results were +/-2.00 D in 187 of 195 eyes (95.9%) and +/-1.00 D
in 148 of 195 eyes (75.9%). In a paired-cohort analysis of 131 single-procedure
eyes seen at both intervals, refractive stability (change in manifest refractive
spheroequivalent of less than 1.00 D) was present in 101 of 131 eyes (77.1%)
between the two observation intervals. Overall, approximately 3.6% eyes lost 2
lines or more of BSCVA, and other complications (flap wrinkling and epithelial
ingrowth) were reported in 2% of eyes. Improvement in BSCVA of 1 line or more
occurred in 5.6% eyes. CONCLUSIONS: Laser in situ keratomileusis for high myopia
with the VISX Star laser provided satisfactory refractive and visual results that
compare well with other reports in the literature. Subjective results and other
measures of visual function need further evaluation.
PMID- 10768327
TI - Selective zonal ablations with excimer laser for correction of irregular
astigmatism induced by refractive surgery.
AB - OBJECTIVE: To demonstrate the safety and efficacy of selective zonal ablations
with excimer laser for the correction of irregular astigmatism induced by
refractive surgery. DESIGN: Thirty-one eyes of 26 patients. Retrospective and
noncomparative case series. METHODS: The authors reviewed the medical results of
the two series of consecutive cases of irregular astigmatism induced by
refractive surgery. One group showed a topography map with a defined pattern:
decentered ablation, decentered steep central island, central irregularity, and
peripheral irregularity. The other group showed an irregular astigmatism without
defined pattern. Selective zonal ablation was performed with a broad-beam excimer
laser. Laser ablations were adjusted according to the Munnerlyn formula. A
phototherapeutic keratectomy (PTK) mode was used in all cases without using
viscous masking solution. MAIN OUTCOME MEASURES: Uncorrected visual acuity, best
spectacle-corrected visual acuity (BCVA), and Holladay diagnostic summary (Eye
Sys 2.000) were considered before and after surgery to obtain the qualitative and
quantitative characteristics of the visual acuity and corneal topography. The
corneal uniformity index (CUI) was used to evaluate the corneal surface changes
induced by the selective zonal ablations in the correction of irregular
astigmatism. It proved to be a useful tool in the understanding of astigmatic
changes when it is not possible to apply the vector analysis. RESULTS: In group
1, the irregular astigmatism was significantly improved in 96.4% of cases. The
CUI was improved from 58+/-0.3% to 87+/-0.8%, P < 0.005 (Student's t-test). The
improvement of the BCVA was from 20/40+/-20/100 to 20/25+/-20/100, P < 0.005
(Student's t-test). The results obtained in group 2 were not clinically
significant in terms of improvement of CUI and BCVA. CONCLUSIONS: Using the
corneal topographic map as a guide, selective zonal ablations with excimer laser
can be used to create a more regular corneal surface, when a defined pattern of
topographic irregularities can be defined.
PMID- 10768328
TI - Videokeratography after excimer laser in situ keratomileusis for myopia.
AB - OBJECTIVE: The purpose of this study was to define qualitative patterns of
videokeratography after excimer laser in situ keratomileusis (LASIK) for myopia
and to identify associations of videokeratography patterns with clinical
variables. DESIGN: Single-center, retrospective, cohort study. PARTICIPANTS: One
hundred twenty-six eyes of 68 patients with myopia who desired surgical
correction of myopia ranging from -1.50 to -8.80 diopters. INTERVENTION: Myopia
was corrected with LASIK using a Summit OmniMed/Apex excimer laser. Computer
assisted videokeratography data were acquired at 3 months after primary LASIK,
and associations of videokeratography pattern with clinical variable were
assessed. MAIN OUTCOME MEASURES: Seven subgroup ablation zone patterns were
characterized using tangential curvature maps; these subgroups were combined into
pooled symmetric and asymmetric groups. Associations with age, attempted
correction, single-zone or multizone ablation, postoperative uncorrected and
spectacle-corrected visual acuity, predictability, astigmatism, corneal
uniformity, glare disability, and contrast sensitivity were analyzed. RESULTS:
Thirty-two eyes (25.4%) showed a uniform pattern, 14 eyes (11.1%) showed a bow
tie pattern, 22 eyes (17.5%) showed a peninsula pattern, 22 eyes (17.5%) showed a
semicircular pattern, 22 eyes (17.5%) showed an off-center blue spot pattern, 10
eyes (7.9%) showed an irregular pattern, and 4 eyes (3.2%) showed a central
island pattern. Spectacle-corrected visual acuity, astigmatism, corneal
uniformity, glare disability, and contrast sensitivity were significantly related
to videokeratography pattern, although the difference among videokeratography
groups was clinically small. Age, attempted correction, single- or multizone
ablation, and postoperative uncorrected visual acuity and predictability were not
predictive of videokeratography pattern. CONCLUSIONS: Most eyes in this study had
an asymmetric videokeratography pattern 3 months after LASIK. Small but
statistically significant differences were identified among the videokeratography
patterns that potentially may affect postoperative quality of vision.
PMID- 10768329
TI - Automated surgical equipment requires routine disinfection of vacuum control
manifold to prevent postoperative endophthalmitis.
AB - PURPOSE: Contamination of automated surgical equipment is a potential source of
postoperative endophthalmitis. The effect of disinfecting the unsterile vacuum
control manifold (VCM) on contamination of the aspiration fluid was studied.
DESIGN: Comparative prospective microbiologic contamination study. SPECIMENS AND
CONTROLS: The 37 aspiration fluid specimens studied or examined consisted of 25
from three automated evacuation systems equipped with an internal VCM
(experimental groups) and 12 from one system equipped with a modified external
VCM (control group). In addition, the tubings of two internal VCMs were
investigated. METHODS: We investigated aspiration fluid specimens from routine
cataract and vitrectomy operations performed with automated evacuation systems.
After tracing the source of contamination to the internal VCM, the system was
modified, creating an external VCM with the possibility for disinfection, and the
study was continued. Whereas no sterilizing rinsing procedures were applied to
the hidden internal VCM, the modified external VCM was regularly rinsed and
filled overnight with 70% isopropanol. All samples were collected under sterile
conditions, centrifuged, and cultured for bacterial growth on blood agar and
MacConkey agar for 24 to 48 hours at 37 degrees C. The samples of the two
internal VCMs were cultured for fungi as well. MAIN OUTCOME MEASURES: Bacterial
growth was quantified, and bacteria and fungi were isolated and identified
according to standard microbiologic procedures. RESULTS: In all aspiration fluid
specimens from internal VCM-systems, 2+ to 4+ bacterial growth was found.
Pseudomonas-related genera (Stenotrophomonas maltophilia, 17x; Comamonas
acidovorans, 8x; Chryseomonas spp., 3x), Agrobacterium radiobacter (1 3x),
Flavobacterium spp. (3x), and Micrococcus luteus (7x) were found most frequently.
The tubing of the two VCMs contained biofilms exhibiting several of these
bacteria and fungi. All specimens from the modified external VCM-system remained
sterile. There was a significant difference with regard to the frequency of
contamination of the aspiration fluid between the experimental and control groups
(chi-square: P = 0.0001). CONCLUSIONS: The technical modification described
herein allows facile hygienic measures, by which contamination of aspiration
fluid by the VCM can be eliminated, which otherwise can be a significant source
of contamination.
PMID- 10768331
TI - Changes in anterior chamber angle width and depth after intraocular lens
implantation in eyes with glaucoma.
AB - OBJECTIVE: To examine the changes in anterior chamber angle width and depth
induced by intraocular lens (IOL) implantation in eyes with angle-closure
glaucoma (ACG), in eyes with open-angle glaucoma (OAG), and in eyes with no
evidence of glaucoma or ocular hypertension. DESIGN: A comparative,
nonrandomized, interventional study. PARTICIPANTS: Seventy-seven eyes with ACG,
73 eyes with OAG, and 74 control eyes undergoing cataract extraction and IOL
implantation. INTERVENTION: All eyes underwent phacoemulsification and soft
acrylic IOL implantation. MAIN OUTCOME MEASURES: The angle width and depth of the
anterior chamber were measured using a Scheimpflug videophotography system before
surgery, and at 1 week and at 1, 3, 6, 9, and 12 months after surgery. RESULTS:
Before surgery, the mean anterior chamber angle width and depth in the ACG group
was less than that in either the OAG or control groups by approximately 10
degrees in angle width and 1.0 mm in depth (P < 0.0001). After cataract
extraction and IOL implantation, the angle width and depth increased
significantly in all three groups (P < 0.0001). Although the width and depth in
the ACG group were still smaller than that in the other groups, the differences
decreased to 2 degrees for angle width and 0.3 mm for depth. In addition, no
significant differences were found in these values between the OAG and control
groups before or after surgery. Furthermore, no significant changes were observed
in the angle width or depth in any of the three groups throughout the
postoperative observation period. As expected, the mean preoperative intraocular
pressure (IOP) in the ACG and OAG groups was higher than that in the control
group. After cataract surgery, however, the mean IOP decreased significantly and
was almost the same in all three groups at 1, 6, and 12 months after surgery.
CONCLUSIONS: The width and depth of the anterior chamber angle in eyes with ACG
increased significantly after cataract extraction and IOL implantation and became
similar to that in eyes with OAG and that in normal eyes, which may lead to the
decrease in IOP seen in the postoperative period. No significant changes were
observed in angle width and depth in any of the three groups after surgery.
PMID- 10768330
TI - Initial two years of experience with the AAO National Eyecare Outcomes Network
(NEON) cataract surgery database.
AB - PURPOSE: To report the results of the first 2 years of experience with an
American Academy of Ophthalmology (AAO) cataract surgery registry; to compare
patient characteristics, operative procedures, and patient outcomes observed in
the registry to those observed in the Cataract PORT study; and to discuss the
current shortcomings and potential benefits of a national cataract surgery
registry. DESIGN: Observational study of episodes of cataract surgery reported by
a self-selected sample of 249 ophthalmologists. PARTICIPANTS: Seven thousand six
hundred twenty-six patients undergoing cataract surgery during 1996 and 1997.
METHODS: Beginning in January 1996, participation in the AAO cataract surgery
registry was offered to all ophthalmologists. Participants could use software or
paper data collection forms to submit a common set of data regarding patients'
demographics, preoperative ophthalmologic history, physical examination and test
results, functional status and symptoms, intraoperative procedures and events,
and postoperative outcomes for all patients undergoing first or second eye
cataract surgery. Data were transmitted to a central database, where they were
aggregated and analyzed. Findings were compared with those observed in the
Cataract PORT study, which was conducted in 1991 and 1992. RESULTS: Between
January 1, 1996, and February 28, 1998, 249 ophthalmologists submitted data on at
least one patient who underwent cataract surgery. A total of 7626 patients
undergoing first or second eye surgery were enrolled, with all preoperative,
intraoperative, and postoperative data forms submitted for 3342 patients (44%).
The preoperative characteristics of patients reported to National Eyecare
Outcomes Network (NEON) were similar to those of patients enrolled in the
Cataract PORT study except for a higher reported prevalence of ocular comorbidity
in NEON patients. Use of retrobulbar anesthesia was reported far less commonly,
and use of topical anesthesia, phacoemulsification, and foldable intraocular
lenses was reported far more often for NEON than for Cataract PORT study
patients. Patient outcomes reported to NEON were similar to those observed in the
Cataract PORT study. MAIN OUTCOME MEASURES: Visual acuity, VF-14, Cataract
Symptom Score, surgical complications. CONCLUSIONS: During the first 2 years of
NEON, ophthalmologist participation in the NEON cataract surgery database was low
and consisted of a self-selected and likely nonrepresentative sample of
ophthalmologists. The representativeness of patients for whom data were reported
is unknown. In addition, complete data were submitted on only a minority of
patients who were enrolled. Even so, the preoperative characteristics of patients
on whom data were submitted to NEON were similar to those of patients enrolled in
the Cataract PORT study. The initial experience with NEON demonstrates that it is
technically possible to collect clinical data from, and report aggregated results
to, practicing clinicians' offices. In addition, at least some practicing
clinicians are willing to spend the time required to participate in the NEON
registry. The NEON cataract surgery database thus has the potential to provide a
practical means for tracking practice patterns and patient outcomes in real time.
If a representative sample of physicians was willing to contribute data
systematically and accurately over time, initiatives such as NEON could provide a
means for professional societies and physicians to play a leadership role in
defining and monitoring quality of care.
PMID- 10768332
TI - Optic nerve head appearance in juvenile-onset chronic high-pressure glaucoma and
normal-pressure glaucoma.
AB - OBJECTIVE: To evaluate the appearance of the optic nerve head in chronic high
pressure glaucoma and normal-pressure glaucoma. DESIGN: Clinic-based cross
sectional study. PARTICIPANTS: The study included 52 eyes with normal-pressure
glaucoma and 28 eyes with juvenile-onset primary open-angle glaucoma that served
as models for chronic high-pressure glaucoma. METHODS: Color stereo optic disc
photographs and wide-angle retinal nerve fiber layer photographs were
morphometrically examined. MAIN OUTCOME MEASURES: Localized retinal nerve fiber
layer defects; parapapillary chorioretinal atrophy; disc hemorrhages; optic cup
shape; retinal arteriole narrowing. RESULTS: Both study groups did not vary
significantly in count of localized retinal nerve fiber layer defects, size of
parapapillary atrophy, optic cup depth, steepness of disc cupping, rim/disc area
ratio, diameter of retinal arterioles, and frequency and degree of focal retinal
arteriole narrowing. In normal-pressure glaucoma versus juvenile open-angle
glaucoma, localized retinal nerve fiber layer defects were significantly broader,
disc hemorrhages were found significantly more often and were larger, and
neuroretinal rim notches were present more frequently and were deeper.
CONCLUSIONS: Chronic high-pressure glaucoma and normal-pressure glaucoma show
morphologic similarities in the appearance of the optic nerve head. The lower
frequencies of detected disc hemorrhages and rim notches in high-pressure
glaucoma may be due to a smaller size of hemorrhages and localized retinal nerve
fiber layer defects in high-pressure glaucoma. Both glaucoma types have
morphologic features in common, suggesting that they may possibly belong to a
spectrum of the same pathologic process.
PMID- 10768333
TI - Bleb reduction and bleb repair after trabeculectomy.
AB - OBJECTIVE: To describe methods and outcomes for repair of bleb-related
complications of trabeculectomy surgery. DESIGN: Retrospective, consecutive,
noncomparative case series. PARTICIPANTS: Thirty-one persons having bleb revision
by two surgeons at the Wilmer Institute from 1994 to the present. INTERVENTION:
One of two types of revision surgery was performed: bleb reduction to decrease
symptoms from large blebs or bleb repair to improve hypotony, using conjunctival
rotation flap or free conjunctival autograft. MAIN OUTCOME MEASURES: Visual
acuity, intraocular pressure (IOP), reported symptoms, complications, and number
of glaucoma medications at the final visit. RESULTS: The mean time from
trabeculectomy to bleb revision was 4.4 years. Bleb reduction was performed
because of symptomatic, high blebs in 11 eyes of 11 persons. Bleb repair was
performed to end bleb leakage in 13 eyes of 13 persons and to increase IOP in 8
eyes of 7 persons with hypotony. Median visual acuity improved from 20/50 before
revision to 20/30 at most recent follow-up. Mean IOP increased after treatment
from 7.7+/-4.9 to 12.4+/-4.0 mmHg (P < 0.001). Symptoms that caused the revision
surgery were eliminated in all cases. None of these eyes has lost IOP control,
none has required repeat trabeculectomy, and only 2 of the 32 (6%) require
topical glaucoma medication. More than one revision procedure was required in 8
of 32 (25%) eyes. CONCLUSIONS: Surgical bleb revisions for complications after
trabeculectomy surgery are safe and effective. Bleb reduction for large,
symptomatic blebs or bleb repair for leaking blebs and hypotony did not lead to
loss of IOP control.
PMID- 10768334
TI - Indications for and outcomes of repeat penetrating keratoplasty, 1989-1995.
AB - OBJECTIVE: To evaluate the indications for and outcomes of repeat penetrating
keratoplasty over a 7-year period and compare them to a similar study over the
prior 6-year period at the same institution. DESIGN: Retrospective noncomparative
case series. PARTICIPANTS: Two hundred twenty-three consecutive repeat corneal
transplants performed by one of five corneal surgeons between 1989 and 1995 were
studied. MAIN OUTCOME MEASURES: Reasons for primary and regraft failure,
indications for the initial corneal graft, graft clarity, and best-corrected
visual acuity were measured on each patient. RESULTS: Between 1989 and 1995, 16%
(271 of 1689) of transplants performed by our cornea group were regrafts compared
with 9% (165 of 1860) in the period from 1983 to 1988 (P < 0.01). The most common
indications for penetrating keratoplasty before regraft were pseudophakic bullous
keratopathy (27%, 61 of 223), failed graft (20%, 44 of 223), Fuchs' dystrophy
(11%, 24 of 223), aphakic bullous keratopathy (9%, 21 of 223), keratoconus (8%,
17 of 223), and herpes simplex keratitis (6%, 14 of 223). Compared with the prior
study period of 1983 to 1988, an increase was revealed in the incidence of failed
graft (11% to 20%, P = 0.03), and a decrease was revealed in the incidence of
aphakic bullous keratopathy (19% to 9%, P = 0.01). Of the 223 regrafts, 55 (25%)
failed during the study period (range, 1 month to 7.5 years; mean 2.1 years).
Eleven percent (6 of 55) of regraft failures occurred within 6 months, and 55%
(30 of 55) failed within 18 months. Of the 150 regrafts with 2 years follow-up
(mean, 3.9 years), 111 (74%) had clear grafts. A best-corrected visual acuity of
20/20 to 20/40 was achieved in 41% (46 of 111), 20/50 to 20/100 in 32% (36 of
111), 20/200 to 20/400 in 21% (23 of 111), and counting fingers to no light
perception in 5% (6 of 111). CONCLUSIONS: Failed grafts are increasing as an
indication for penetrating keratoplasty. Graft clarity and visual acuity results
continue to be very good, supporting the use of repeat corneal transplantation.
PMID- 10768335
TI - Endogenous endophthalmitis caused by Histoplasma capsulatum var. capsulatum: a
case report and literature review.
AB - OBJECTIVE: We report the first case of clinically diagnosed endogenous
endophthalmitis caused by Histoplasma capsulatum var. capsulatum in a patient
with the acquired immune deficiency syndrome. DESIGN: Interventional case report
and literature review. INTERVENTION: Pars plana vitrectomy and scleral buckling
procedure in the left eye with intravenous and intravitreal amphotericin in both
eyes. MAIN OUTCOME MEASURES: The clinical features, culture results, visual
outcome, and complications were studied. RESULTS: This case demonstrates a
bilateral endophthalmitis with severe subretinal exudation, choroidal granulomas,
and intraretinal hemorrhage leading to exudative bilateral retinal detachments.
Vitreous cultures grew H. capsulatum var. capsulatum. Treatment consisted of
intravenous amphotericin, intravitreal amphotericin (both eyes), pars plana
vitrectomy (left eye), and scleral buckling procedure (left eye) with resulting
counting fingers vision (right eye) and 20/300 (left eye). Four cases of
Histoplasma endophthalmitis have been reported previously, all of which had a
documented history of disseminated histoplasmosis and resulted in enucleation.
CONCLUSIONS: H. capsulatum should be considered a possible etiologic agent of
endophthalmitis, especially in patients with a history of disseminated
histoplasmosis and/or immune deficiency.
PMID- 10768336
TI - Visual loss from arterial steal in patients with maxillofacial arteriovenous
malformation.
AB - OBJECTIVE: To determine whether an arterial "steal" from the ophthalmic artery
accounts for the ocular manifestations associated with maxillofacial
arteriovenous malformation (AVM) outside the orbit. DESIGN: Retrospective
noncomparative case series. PARTICIPANTS: Seven patients with maxillofacial AVM
who had been previously treated, unsuccessfully, with proximal ligation of the
supplying external carotid artery branches were evaluated clinically and by
superselective cerebral angiography. No cases had intraorbital arteriovenous
shunting or abnormal venous drainage to the orbit. INTERVENTION: Endovascular
embolization. MAIN OUTCOME MEASURES: Signs and symptoms of ocular ischemia were
correlated with findings on cerebral/orbital angiography. RESULTS: Four of seven
patients had signs of ocular ischemia. By selective angiography, these four
patients were found to have a significant ophthalmic artery supply to the AVM. In
contrast, the three patients without signs of ocular ischemia had minimal or no
ophthalmic artery supply to the AVM. CONCLUSIONS: When the ophthalmic arterial
blood supply is recruited, ophthalmic artery "steal" phenomenon occurs in
patients with maxillofacial AVMs that do not directly involve the orbit. This
mechanism appears to be the cause of ocular ischemia. It is possible that this
"steal" is precipitated or worsened by previous surgical proximal ligation of
external carotid arterial branches that are potential collaterals with the
ophthalmic artery but fail to occlude the arteriovenous (AV) shunts.
PMID- 10768337
TI - Fibromuscular dysplasia: a rare cause of cilioretinal artery occlusion in
childhood.
AB - OBJECTIVE: To report a case of cilioretinal artery occlusion with angiographic
findings characteristic of the "string of beads" associated with renovascular
hypertension secondary to fibromuscular dysplasia of the renal artery in a child.
DESIGN: Case report. INTERVENTION: The patient underwent ex vivo renal artery
reconstruction with saphenous vein graft and reimplantation. MAIN OUTCOME
MEASURES: The main clinical outcomes were control of severe hypertension,
reversible hypertensive retinopathy, and improvement of vision. RESULTS:
Revascularization of the kidney improved renal function, and renovascular
hypertension was clearly improved. Visual acuity improved to 20/200. CONCLUSIONS:
A child with hypertensive retinopathy and arterial occlusion in the retina should
undergo investigation to rule out a surgically curable hypertension. Magnetic
resonance angiography of extrarenal vessels may reveal other sites of involvement
of fibromuscular dysplasia. Evaluation and early diagnosis of renovascular
hypertension will prevent severe end-organ damage.
PMID- 10768338
TI - Retinal choroidal anastomoses and occult choroidal neovascularization in age
related macular degeneration.
AB - OBJECTIVE: This study was designed to identify the incidence of retinal choroidal
anastomoses in patients with occult choroidal neovascularization (CNV) and focal
hot spots on indocyanine green (ICG) angiography, to identify the clinical and
angiographic features that would assist in their identification, and to determine
if the presence of these anastomotic lesions affect the outcome of laser therapy.
DESIGN: Combined prospective and retrospective cross-sectional study.
PARTICIPANTS: One hundred fifty consecutive patients with newly diagnosed occult
CNV secondary to exudative age-related macular degeneration and focal hot spots
on ICG angiography were evaluated prospectively. In addition, a retrospective
review was performed on 79 eyes previously reported to have undergone laser
photocoagulation treatment with ICG guidance. METHODS AND TESTING: In all cases,
stereo color and red-free photographs, and stereo fluorescein and digital ICG
angiograms were obtained for evaluation. MAIN OUTCOME MEASURES: Images obtained
by all four techniques were evaluated for the presence of a retinal choroidal
anastomosis. Associated clinical and angiographic findings were noted. In the
retrospective review, the success rate of laser treatment was correlated with the
presence or absence of a retinal choroidal anastomosis. RESULTS: Of the 150 eyes
evaluated prospectively, 31 (21%) were found to have a retinal choroidal
anastomosis. Retinal choroidal anastomoses were found in 27% of patients with
associated serous pigment epithelial detachment (PED), whereas 13% were found in
those without an associated elevation of the retinal pigment epithelium. Seventy
one percent of eyes had multiple anastomotic connections. Ninety percent of eyes
had at least one retinal vein involved in the anastomotic connection. Clinical
evidence of preretinal and intraretinal hemorrhage and cystic edema coupled with
angiographic evidence of intraretinal dye leakage were key features of retinal
choroidal anastomoses. In the retrospective review, seven patients were found to
have retinal choroidal anastomoses with associated serous PED and demonstrated a
very low (14%) success rate for laser treatment. CONCLUSIONS: Retinal choroidal
anastomoses can present as a primary manifestation of the exudative process in
age-related macular degeneration. They may be seen in eyes with and without
detachment of the retinal pigment epithelium. Specific clinical and angiographic
features have been identified that can aid in the diagnosis of these vascular
anomalies. Their presence represents a poor prognostic sign for successful ICG
guided laser treatment.
PMID- 10768339
TI - Entoptic perimetry screening for central diabetic scotomas and macular edema.
AB - OBJECTIVE: The aim of this study was to compare entoptic perimetry, using
conventional television, to Amsler grid and patient-reported visual loss for the
detection of functional diabetic maculopathy and macular edema. DESIGN:
Observational case series. PARTICIPANTS: A single eye from each of 104
consecutive patients with diabetes in an academic retina clinic. INTERVENTION:
Each eye was screened by Amsler grid, entoptic perimetry, and Humphrey 10-2
threshold visual field testing (HVF 10-2; Humphrey Instruments Inc., San Leandro,
CA) in random order. Eyes were then examined clinically. MAIN OUTCOME MEASURES:
The presence or absence of new visual decline since the patient's last clinical
examination, the presence or absence of central visual field abnormalities using
an Amsler grid, entoptic perimetry, HVF 10-2, and the presence or absence of
clinically significant macular edema (CSME). RESULTS: The sensitivities and
specificities for the detection of central diabetic scotomas as evidenced by HVF
10-2 abnormalities were: subjective impression, 31 of 90 eyes (34.4%) and 11 of
14 eyes (78.6%); Amsler grid, 29 of 90 eyes (32.2%) and 13 of 14 eyes (92.9%);
and entoptic perimetry, 58 of 90 eyes (64.4%) and 11 of 14 eyes (78.6%). Entoptic
perimetry was statistically more sensitive than both subjective impression (P <
0.001) and Amsler grid (P < 0.001), but the specificities were statistically
indistinguishable. The sensitivities and specificities for the detection of CSME
were: subjective impression, 6 of 24 eyes (25.0%) and 52 of 80 eyes (65.0%);
Amsler grid, 9 of 24 eyes (37.5%) and 59 of 80 eyes (73.8%); and entoptic
perimetry, 17 of 24 eyes (70.8%) and 44 of 80 (55.0%) eyes. These results are
also statistically significant, with entoptic perimetry being more sensitive and
less specific than both subjective impression (P = 0.007 and P = 0.011,
respectively) and Amsler grid (P = 0.008 and P < 0.001, respectively) in this
subset of patients. CONCLUSIONS: Entoptic perimetry is 87% more sensitive than
the subjective impression of visual decline (P < 0.001) and 100% more sensitive
than Amsler grid (P < 0.001) for the detection of central scotomas in diabetic
patients. For the detection of CSME, entoptic perimetry is 183% more sensitive
than subjective impression (P = 0.007) and 89% more sensitive than Amsler grid (P
= 0.008). Hence, entoptic perimetry, performed using conventional television, has
the potential to be an effective, inexpensive, and widespread adjunct to
surveillance examinations for the early detection of diabetic maculopathy.
PMID- 10768340
TI - Long-term incidence of reopening of macular holes.
AB - OBJECTIVE: To report the incidence of macular hole reopening after initial
successful surgery. DESIGN: A noncomparative retrospective case series.
PARTICIPANTS: From a series of 137 consecutive cases of idiopathic macular holes
operated on between August 1993 and May 1996, the authors analyzed the charts of
116 cases of successful surgery. SETTING: A single university-based ophthalmology
department. INTERVENTION: Pars plana vitrectomy, posterior hyaloid peeling, fluid
air and air-gas exchange with a nonexpansile 17% C2F6 mixture followed by face
down positioning. Eighty-eight patients (64%) received autologous platelets as a
biologic adjuvant. The anatomic success rate at the first postoperative month was
116 of 137 (85%). One hundred and six patients (91%) were followed up for more
than 2 years. MAIN OUTCOME MEASURE: Macular anatomic status. RESULTS: Mean follow
up was 27 months. Eleven eyes of 11 patients (9.5%) had reopening of the macular
hole. The mean period between hole surgery and reopening was 15.4 months (range,
8-29). In 8 of these 11 cases, reopening occurred after cataract extraction. In
two cases, an epiretinal membrane was noted. In another case cystoid macular
edema was present. The final anatomic success rate with one surgical procedure
was 105 of 137 (77%). Eight reopened holes were reoperated on and all were
anatomic successes at 1 month. However, four patients experienced a second
reopening. CONCLUSIONS: Macular hole reopening occurred in 9.5% of cases (11 of
116). The cause of reopening might have been any anatomic stress such as
epiretinal membrane formation or macular edema. However, in most of our reopened
cases, no definite cause was evident. Four patients experienced recurrent
reopening.
PMID- 10768341
TI - Polypoidal choroidal vasculopathy masquerading as central serous
chorioretinopathy.
AB - OBJECTIVE: To differentiate polypoidal choroidal vasculopathy (PCV) from central
serous chorioretinopathy (CSC). DESIGN: A retrospective, observational case
series. PARTICIPANTS: Thirteen patients originally diagnosed with CSC proved to
have PCV after more extensive evaluation and follow-up. METHODS: A clinical and
angiographic review of patients with manifestations of CSC, including macular
detachment. MAIN OUTCOME MEASURES: Demographic data, funduscopic examination, and
fluorescein and indocyanine green (ICG) angiographic findings. RESULTS: Thirteen
patients initially suspected of having CSC were ultimately diagnosed as having
PCV. These eyes had exudative macular detachments secondary to a small caliber,
polypoidal choroidal vascular abnormality or so-called polypoidal choroidal
neovascularization. The clinical manifestations in the fundus varied. They
included multiple, variably sized serous pigment epithelial detachments,
neurosensory retinal detachment, lipid deposition, patchy atrophy of the pigment
epithelium and indistinct staining from decompensation of the posterior blood
retinal barrier on fluorescein angiography. In reality, the suspected PEDs proved
to be polypoidal lesions of PCV when imaged with ICG angiography. CONCLUSIONS:
The clinical diagnosis of CSC or PCV generally poses little challenge to the
experienced retinal specialist. However, in CSC with persistent and/or recurrent
exudation, a myriad of retinal pigment epithelial changes may evolve that make it
difficult to differentiate these two entities. In such patients, ICG angiography
is useful in differentiating CSC from PCV. An accurate clinical diagnosis is
important since each of these entities, CSC and PCV, may differ in terms of their
risk factors, natural course, and visual prognosis.
PMID- 10768342
TI - De-misting condensation on intraocular lenses.
AB - BACKGROUND: Condensation occurs rapidly on intraocular lenses (IOLs),
particularly silicone IOLs, after vitrectomy and fluid-air exchange in the
presence of a posterior capsulotomy and severely limits the surgeon's view of the
retina. This study investigated the value of heating contact lens irrigation
fluid to prevent condensation on IOLs. DESIGN: An experimental in vitro study and
a noncomparative interventional case series. PARTICIPANTS: Five control eyes had
temperature measurements during fluid-air exchanges. Two patients with silicone
IOLs and posterior capsulotomies underwent a vitrectomy involving a fluid-air
exchange with heated contact lens fluid. METHODS: An in vitro model allowed
monitoring of temperature and humidity changes during condensation formation on
four different IOL materials. Adjusting variables to promote evaporation rather
than condensation was achieved in vitro. In vivo, intraocular temperatures were
measured at various stages of five vitrectomies involving a fluid-air exchange.
Finally, in two in vivo cases a blood warmer was used to heat the accessory
contact lens irrigation fluid during the vitrectomy and fluid-air exchange. MAIN
OUTCOME MEASURES: Successful prevention of condensation on the silicone IOL
during the fluid-air exchange. RESULTS: Anterior segment temperature influences
the IOL temperature, such that when it is higher than the posterior segment
temperature, condensation does not form and evaporation is promoted. In vivo the
temperatures in the eye are hypothermic throughout the vitrectomy. At fluid-air
exchange the posterior segment heats rapidly as irrigation ceases and low
specific heat gas enters. Finally, in two in vivo cases with silicone IOLs,
condensation was predicted then prevented by our intervention for the duration of
the fluid-air exchange. CONCLUSIONS: Heating the anterior segment by conduction
from warmed irrigation fluid flowing through the irrigating contact lens
represents a cheap, noninvasive, and safe means to prevent condensation on IOL
materials.
PMID- 10768343
TI - Correlation of visual acuity and ocular pigmentation with the 16-bp duplication
in the HPS-1 gene of Hermansky-Pudlak syndrome, a form of albinism.
AB - OBJECTIVE: Patients with the Hermansky-Pudlak syndrome (HPS), a form of albinism,
were studied. The first purpose of this investigation was to determine if visual
acuity was related to the presence or absence of the 16-bp duplication in the HPS
1 gene. The second was to study the correlation between the degree of ocular
pigmentation and visual acuity within the two genetic groups described above.
DESIGN: Cross-sectional study of a series of consecutive patients. PARTICIPANTS:
Forty-nine patients with HPS with or without the 16-bp duplication in HPS-1.
METHODS: Best corrected visual acuity (VA) using Early Treatment Diabetic
Retinopathy Study (ETDRS) charts, photographic gradings of iris transillumination
and of visibility of choroidal vessels in the macula (macular transparency). MAIN
OUTCOME MEASURES: Association between VA and the presence or absence of the 16-bp
duplication in HPS-1 and correlation between VA and the degree of iris
transillumination (iris score) and macular transparency (fundus score), as
determined by masked reading of photographs, with respect to the presence or
absence of the 16-bp duplication in HPS-1 were the main outcome measures.
RESULTS: The VA of the better eye did not differ between the two genetic groups
(P = 0.322, two-sided t test). Spearman's rank correlation between VA and iris
scores in 39 eyes of 20 patients with the duplication was not statistically
significant (P = 0.698) but was statistically significant in 36 eyes of 19
patients without the duplication (P < 0.001). Among all patients, the correlation
was statistically significant (r = -0.36 in RE and r = -0.51 in LE). Spearman's
rank correlation between VA and fundus scores in 36 eyes of 19 patients with and
34 eyes in 18 patients with and without the duplication was statistically
significant (P = 0.035 and P = 0.008, respectively). Among all patients, it was
also statistically significant (r = -0.39 in RE and r = -0.45 in LE).
CONCLUSIONS: The mean VA of the better eye did not differ in patients with the 16
bp duplication compared with those without the duplication. There were
statistically significant associations between VA and the iris score and the
fundus score except for the VA and iris scores in patients with the 16-bp
duplication. However, because of the variability of VA, these associations were
not large enough for useful prediction of VA based on the degree of ocular
pigmentation.
PMID- 10768344
TI - Progressive outer retinal necrosis caused by herpes simplex virus type 1 in a
patient with acquired immunodeficiency syndrome.
AB - OBJECTIVE/BACKGROUND: To identify the etiologic agent of rapidly progressive
outer retinal necrosis (PORN) in a 32-year-old man with acquired immunodeficiency
syndrome (AIDS), who had retinitis developed from cytomegalovirus (CMV). Multiple
yellowish spots appeared in the deep retina without evidence of intraocular
inflammation or retinal vasculitis, diagnosed clinically as PORN. Death occurred
after failure of multiple organs. DESIGN: Case report. METHODS: Both globes were
taken at autopsy, fixed in formalin, and examined histopathologically and
immunohistochemically to identify causative agents in the retinal lesions. MAIN
OUTCOME MEASURE: Immunohistochemistry. RESULTS: All layers of the retina were
severely damaged and contained focal calcification. Cytomegalic inclusion bodies
were found in cells in the damaged retina of the right eye. Immunohistochemical
studies for herpesviruses revealed the presence of CMV antigens in the right
retina at the posterior pole and herpes simplex virus type 1 (HSV-1)-specific
antigen in the periphery of both retinas. No varicella-zoster virus (VZV) antigen
was detected in either retina. CONCLUSIONS: PORN has been described as a variant
of necrotizing herpetic retinopathy, occurring particularly in patients with
AIDS. Although the etiologic agent has been reported to be VZV, HSV-1 can be an
etiologic agent.
PMID- 10768345
TI - Melanocytoma (magnocellular nevus) of the ciliary body: report of 10 cases and
review of the literature.
AB - PURPOSE: To describe the characteristics of melanocytoma (magnocellular nevus) of
the ciliary body, an unusual melanocytic tumor. DESIGN: Retrospective,
clinicopathologic case series. METHODS: Ten melanocytomas of the ciliary body
were examined histopathologically. Five tumors were also examined by transmission
electron microscopy. The clinical histories were abstracted from the patients'
medical records. We compared the clinical, histopathologic, and ultrastructural
findings of our 10 cases with those previously reported in the literature. MAIN
OUTCOME MEASURES: To define clinical and histopathologic parameters of this rare
tumor. RESULTS: A total of 40 cases were summarized, including our 10 and 30
previously reported cases. The mean age of the 40 cases was 47 years. Twenty-six
patients were female (65%), fourteen were male (35%). No laterality was observed.
Eighty percent of the patients were white and 10% were black. The most common
clinical presentation was an asymptomatic dark spot involving the iris and
ciliary body or the sclera. Involvement of chamber angle structures, with or
without intrascleral extension, was observed in 85% (34 of 40 patients); but only
12% (2 of the 17 patients for whom information about intraocular pressure and
local extension was available) had elevated preoperative intraocular pressure. By
electron microscopy, two distinct cell types were observed. CONCLUSIONS:
Melanocytomas can usually be distinguished from other pigmented lesions of the
ciliary body by histopathologic criteria, but may be difficult to differentiate
before surgery from other pigmented ciliary body tumors, including malignant
melanomas, adenomas, and adenocarcinomas of the pigmented ciliary epithelium.
Most tumors can be managed conservatively by iridocyclectomy.
PMID- 10768346
TI - Mucoepidermoid carcinoma of the conjunctiva: a series of three cases.
AB - OBJECTIVE: To detail the clinical presentation and outcomes of currently
available treatments for mucoepidermoid carcinoma of the conjunctiva (MCC).
DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Three patients
ranging from 40 to 63 years of age with MCC participated. INTERVENTION:
Excisional biopsies and various therapies were performed. MAIN OUTCOME MEASURES:
Clinical and surgical outcomes were measured. RESULTS: Patient 1 is a 55-year-old
man with right temporal MCC. He underwent two local excisions with adjuvant
cryotherapy and has had no recurrence at 31 months follow-up. Patient 2 is a 63
year-old man with right temporal MCC who underwent fractionated iodine 125 plaque
radiotherapy. He had a recurrence approximately 8 months after plaque treatment
and subsequently underwent enucleation of the right eye. Clinical follow-up
examinations revealed no further recurrence at 17 months. Patient 3 is a 40-year
old woman treated for right MCC with carbon dioxide laser with recurrence at 3
weeks. She subsequently underwent radiation treatment with the development of
regional lymph node metastases 16 months later. CONCLUSIONS: MCC is a rare
neoplasm that displays an extraordinary capacity for aggressive local invasion.
This series of three case reports demonstrates the high recurrence rate of MCC
and the response of this tumor to different current modalities of treatment.
Extended follow-up is required with this tumor because distant metastases can
occur very late.
PMID- 10768347
TI - Epithelioid hemangioma of the orbit.
AB - OBJECTIVE: To describe the histopathologic features of two cases of epithelioid
hemangioma occurring in the orbit and to distinguish this condition from Kimura's
disease and from other vascular lesions of proliferated endothelium. DESIGN: Two
interventional case reports. INTERVENTION: Treatment consisted of orbitotomy with
excision of the tumor. MAIN OUTCOME MEASURES: Histopathologic examination
including light microscopy, immunohistochemistry, and electron microscopy and
clinical follow-up. RESULTS: In one case, there was no local recurrence after 2
years of follow-up. In the other case, local recurrence required re-excision 2
years after surgery with no apparent recurrence 16 years later. Histopathologic
examination of both tumors disclosed an epithelioid hemangioma. A characteristic
finding was the presence of peculiar plump vacuolated endothelial cells lining
the vascular lumina. CONCLUSIONS: Epithelioid hemangioma is an uncommon benign
vascular tumor that can occur in the orbit, and surgical excision is usually
required. It is the same condition as angiolymphoid hyperplasia with
eosinophilia. There are distinct clinical and histopathologic characteristics to
distinguish epithelioid hemangioma from Kimura's disease and from other vascular
tumors.
PMID- 10768348
TI - Foraging ecology of the mountain monkey (Cercopithecus l'hoesti): implications
for its evolutionary history and use of disturbed forest.
AB - We present the first systematic field study on the feeding ecology of the
mountain monkey (Circopithecus l'hoesti), a semi-terrestrial guenon. We compare
our results with findings from a concurrent study of blue monkeys (C. mitis
doggetti, which have an overlapping home range) conducted over ten months in the
Nyungwe Forest Reserve, Rwanda. The mountain monkeys spent 35% of observation
time feeding on terrestrial herbaceous vegetation. Thirty-five fruit and seed
species comprised 42% of their diet, and invertebrates composed 9%. They spent
38% of observation time on the ground and 27% of observation time in canopy
trees. Individuals were observed for equivalent proportions of time foraging on
the ground for herbs and in canopy trees for fruits. Although mountain monkeys
primarily foraged in undisturbed open areas, they also used disturbed open
habitats for this purpose. Synthesizing our results with Pleistocene forest
history and C. l'hoesti evolutionary history, we suggest that, although these
monkeys readily use disturbed forest for herb foraging, they are a forest-adapted
species which has adopted a terrestrial lifestyle to exploit the abundant herb
layer common to montane forests.
PMID- 10768349
TI - Pituitary-adrenocortical responses to the first dyadic encounters in male rhesus
monkeys: effect of dominance relationship.
AB - Male rhesus monkeys unfamiliar with each other were paired in a cage, and blood
samples were collected before and a few hours after pair formation.
Adrenocorticotrophic hormone (ACTH) and cortisol levels in each blood sample were
measured. Dominant-subordinate status was ascertained through two rank tests, the
food competition test and the agonistic behavior test, which were performed
immediately after pair formation. As a result, the dominance relationship was
determined in seven pairs formed from five animals, and the differences in ACTH
and cortisol values between the dominant and subordinate animal in these pairs
were compared statistically. The day after the first encounter, a second
encounter was conducted in randomly selected pairs of monkeys. In the first
encounters, higher levels of both ACTH and cortisol were detected in dominant
animals in comparison to subordinate animals. Changing the animal's partner
altered the stress responses whenever the animal's dominant-subordinate status
changed. The elevated levels of ACTH and cortisol in dominant animals disappeared
on the day after the first encounter. In dominant animals, the pituitary
adrenocortical stress response reacts sharply to situational demands, whereas
subordinate animals have a weaker response. This acute stress response is
different from a chronic stress response. When the subordinate animal cannot
escape, its hypothalamic-pituitary-adrenocortical axis appears to be suppressed.
PMID- 10768350
TI - Sleeping site preferences in tufted capuchin monkeys (Cebus apella nigritus).
AB - The characteristics and availability of the sleeping sites used by a group of 27
tufted capuchin monkeys (Cebus apella nigritus) were studied during 17 months at
the Iguazu National Park, Argentina. We tested different hypotheses regarding
possible ultimate causes of sleeping-site selection. Most sleeping sites were
located in areas of tall, mature forest. Of the 34 sleeping sites the monkeys
used during 203 nights, five were more frequently used than the others (more than
20 times each, constituting 67% of the nights). Four species of tree (Peltophorum
dubium, Parapiptadenia rigida, Copaifera langsdorfii and Cordia trichotoma) were
the most frequently used. They constituted 82% of all the trees used, though they
represent only 12% of the trees within the monkeys' home range which had a
diameter at breast height (DBH) > 48.16 cm (1 SD below the mean DBH of sleeping
trees). The sleeping trees share a set of characteristics not found in other
trees: they are tall emergent (mean height +/- SD = 31.1+/-5.2 m) with large DBH
(78.5+/-30.3 cm), they have large crown diameter (14+/-5.5 m), and they have many
horizontal branches and forks. Adult females usually slept with their kin and
infants, while peripheral adult males sometimes slept alone in nearby trees. We
reject parasite avoidance as an adaptive explanation for the pattern of sleeping
site use. Our results and those from other studies suggest that predation
avoidance is a predominant factor driving sleeping site preferences. The patterns
of aggregation at night and the preference for trees with low probability of
shedding branches suggest that social preferences and safety from falling during
windy nights may also affect sleeping tree selection. The importance of other
factors, such as seeking comfort and maintaining group cohesion, was not
supported by our results. Other capuchin populations show different sleeping
habits which can be explained by differences in forest structure and by
demographic differences.
PMID- 10768351
TI - Seed dispersal by woolly monkeys (Lagothrix lagothricha) at Tinigua National
Park, Colombia: dispersal distance, germination rates, and dispersal quantity.
AB - The purpose of this study was to describe seed dispersal patterns of woolly
monkeys (Lagothrix lagothricha) in terms of dispersal quantity and two factors
related to dispersal quality: germination rates of dispersed seeds and the
distance of dispersal to parental trees. The possible influence of retention
time, travel distance, seed size, activity patterns, and fruit abundance on
dispersal distance was also analyzed. Observations on activity, diet, daily
movements, and seed dispersal were made on focal individuals of a group of woolly
monkeys at a tropical rain forest in Tinigua National Park (Colombia). Sixty
hours of focal samples per month were completed during 1 year. A total of 753
depositions were collected during the study. Each dropping contained seeds from
an average of 2.68 different species (range 0 to 9). Collected depositions
contained an underestimated total of 50,168 seeds (>1 mm). Given a population
density of 30 individuals/km2, the woolly monkeys in the study area disperse more
than 25,000 seeds/km2/day. These seeds belong to 112 different plant species.
Germination rates of dispersed seeds are usually similar or higher than those of
non-swallowed seeds. It was possible to determine dispersal distance in 264 cases
when the focal animal was continuously followed from ingestion at the parental
tree to deposition. Only 1% of these depositions landed in close proximity (<15
m) of the parental tree. It was very common that the droppings were deposited
between 100 and 500 m from the parent tree, and up to 1.5 km. Higher retention
times and longer travel distances were not correlated with increased dispersal
distance. Two main reasons for this result were the prolonged and variable
passage rates (avg=11.2 hr+/-6.5 SD.) and the circuitous routes of monkeys in
this forest.
PMID- 10768352
TI - LC method for the determination of assay and purity of sibutramine hydrochloride
and its enantiomers by chiral chromatography.
AB - Two isocratic liquid chromatography (LC) methods have been developed for the
purity estimation and quantitative determination of sibutramine HCl, using 4
chloro aniline and lovastatin as internal standards, respectively. The precision
has been checked in terms of F-test variance ratio using latter method as
reference. The ratio of variances of the two methods is close to unity,
confirming their good precision. The correlation coefficient for linear
regression is more than 0.999. The inter and intra-day precision is found to be <
1.3% RSD. The accuracy determined as relative mean error (RME) for the intra-day
assay is +/- 1.7%. The enantiomeric separation of sibutramine by chiral
chromatography method has been described also. This method is capable of
separating the two enantiomers with a selectivity of 1.4 and a resolution of 4.0.
Both methods are found to be stability indicating and useful in the quality
control of the bulk material.
PMID- 10768353
TI - A validated method for the determination and purity evaluation of benazepril
hydrochloride in bulk and in pharmaceutical dosage forms by liquid
chromatography.
AB - A gradient liquid chromatographic (LC) method has been developed for the
determination and purity evaluation of benazepril hydrochloride in bulk and
pharmaceutical dosage forms. The method is simple, rapid and selective. 5-Methyl
2-nitro phenol has been used as internal standard. The method is linear in the
range of 50-800 microg. The precision for inter and intra-day assay variation of
benazepril hydrochloride is below 1.6% RSD. The accuracy determined as relative
mean error (RME) for the intra-day assay is within +/- 2.0%. The method is
stability indicating, and is useful in the quality control of bulk manufacturing
and also in pharmaceutical formulations.
PMID- 10768354
TI - LC method for the quantitative determination of oxaprozin and its impurities in
the bulk drug.
AB - A reversed phase linear gradient liquid chromatographic method was developed for
the separation and quantitative determination of the seven known process related
impurities and one degraded product of oxaprozin in the bulk drug material. An
Inertsil-ODS 3V (150 x 4.6 mm), 5 microm column was operated with a phosphate
buffer acetonitrile gradient. Detection was carried out on a UV detector at 254
nm. This method has been proved to be accurate and sensitive. The limits of
detection (LOD) and limits of quantification (LOQ) of impurities were in the
order of 5-60 ng and 16-200 ng, respectively. In addition to its ruggedness and
robustness, this method offers identification of all eight impurities in a single
run.
PMID- 10768355
TI - Simultaneous determination of alpha, beta and gamma cyclodextrins by LC.
AB - Cyclodextrins (CDs) can be synthesized from starch by cyclodextrin
glycosyltransferase (CGTase). This enzyme produces alpha-, beta- and gamma-CDs in
varying proportions. In the production of cyclodextrins, purity as well as yield
are important factors. A precise and reproducible method was developed and
validated for the simultaneous determination of alpha-, beta-, and gamma-CDs.
Optimum separation between the three CDs was achieved using a Finepak amino
column with a mobile phase consisting of acetonitrile-water (70:30, v/v) at a
flow rate of 1 ml/min. Detection was carried out using a differential refractive
index detector. The developed method gave good chromatographic resolution of the
three components with retention times of 13.16, 16.83 and 21.74 min for alpha-,
beta- and gamma-CDs, respectively. The polynomial regression data for the
calibration plots exhibited good linear relationship (coefficient of correlation
r = 0.9987 for alpha, r = 0.9986 for beta and r = 0.9998 for gamma-CDs) over a
concentration range of 2-10 mg/ml. Statistical analysis proves that the proposed
LC method is precise, reproducible and accurate for the estimation of alpha-,
beta- and gamma-cyclodextrins. The method can be employed for determination of
percent purity as well as estimation of process yields of the cyclodextrins
during the enzymatic production.
PMID- 10768356
TI - Stability indicating HPTLC method for the estimation of estradiol.
AB - Estradiol (ESD) is widely used in post climacteric replacement therapy. Most of
the methods used for quantitation are expensive and time consuming. A rapid,
selective and precise stability indicating high performance thin layer
chromatography method was developed and validated for the estimation of ESD in
bulk and pharmaceutical dosage forms. The method employed TLC aluminium plate
precoated with silica gel 60F254 as the stationary phase. The solvent system
employed consisted of chloroform-acetone-isopropyl alcohol-glacial acetic acid
(9:1:0.4:0.1, v/v/v/v). Such a complex system was essential to obtain a dense and
compact spot of the drug at an Rf value of 0.40 +/- 0.02. The drug on intentional
degradation gave two products with Rf values of 0.52 +/- 0.01 and 0.58 +/- 0.01
respectively. Spectrodensitometric scanning-integration was performed on a Camag
system using a wavelength of 286 nm. The polynomial regression data for the
calibration plots exhibited good linear relationship (r = 0.9947) over a
concentration range of 1-8 microg. Recovery studies were also performed at three
experimental levels. The recovery data reveals that the RSD for intra-day and
inter-day analysis was found to be 1.27% and 1.75%, respectively. The proposed
method was found to be stability indicating. Statistical analysis proves that the
method is precise, accurate and reproducible, hence can be employed for the
routine analysis of the drug.
PMID- 10768357
TI - Stability indicating HPTLC determination of piroxicam.
AB - A rapid and sensitive HPTLC method was developed and validated for the estimation
of Piroxicam (PM). Spectrodensitometric scanning-integration was performed at an
absorbance wavelength of 360 nm. To justify the suitability, accuracy and
precision of the proposed method, recovery studies were performed at three
concentration levels. One of the degradation products of PM is 2-aminopyridine
(2AP). It becomes imperative to separate this compound as it is a precursor
during synthesis of the drug. A TLC aluminium plate precoated with silica gel 60F
254 was used as the stationary phase. The solvent system toluene-acetic acid (8:2
v/v) gave a dense and compact spot of PM with a Rf value of 0.58 +/- 0.01 which
was well separated from 2AP (Rf 0.23 +/- 0.01). The polynomial regression data
for the calibration plots exhibited good linear relationship (coefficient of
correlation r = 0.9982) over a concentration range of 400-800 ng. Statistical
analysis proves that the proposed method is accurate and reproducible. The method
is stability indicating and being economical can be employed for the routine
analysis in bulk drug as well as pharmaceutical formulations.
PMID- 10768358
TI - HPTLC determination of ketorolac tromethamine.
AB - A High Performance Thin Layer Chromatography (HPTLC) method for quantification of
ketorolac tromethamine, a non-narcotic and non-steroidal agent was developed. The
mobile phase composition was chloroform-ethyl acetate-glacial acetic acid
(3:8:0.1, v/v/v). Spectrodensitometric analysis of ketorolac tromethamine was
carried out at 323 nm. The calibration curve was linear in the range of 200-700
ng. The mean values of slope, intercept and correlation coefficient were, 2941,
749583, 0.99. The method was validated for method precision, system precision,
marketed sample analysis and recovery studies. The % CV for method precision
studies was 1.98 (n = 6) and system precision study was 1.83 (n = 6). The average
recovery was found to be 99.2%. Acid and base degraded products were adequately
separated from the drug. The method was successfully used for the determination
of drug from saliva. The results indicate that the method is simple, specific,
selective and reliable for quantitative analysis of ketorolac tromethamine as
bulk drug and from formulations. It can also be applied for the stability study
of the drug and analysis of drug in biological fluids.
PMID- 10768360
TI - Enantiomeric separation of a moxifloxacin intermediate by chiral liquid
chromatography using cellulose based stationary phases.
PMID- 10768359
TI - Simultaneous determination of lignocaine hydrochloride and phenylephrine
hydrochloride by HPTLC.
AB - A high performance thin layer chromatographic (HPTLC) method for the simultaneous
quantification of lignocaine hydrochloride (LIG) and phenylephrine hydrochloride
(PHE) is described. The mobile phase consisted of ethyl acetate-methanol ammonia
(4:1:0.4 v/v/v). The densitometric determination of LIG and PHE was carried out
at 262 nm and 291 nm, respectively. The calibration curves of LIG and PHE were
linear in the range of 8-18 microg and 4-9 microg, respectively. The method was
validated with respect to system precision, method precision, recoveries, intra
day and inter-day variation. The system was applied for the simultaneous
determination of LIG and PHE from a new drug delivery system. The results
indicate that the method is simple, specific, selective and reliable for
simultaneous quantitative determination of LIG and PHE as bulk drug and from
formulations.
PMID- 10768361
TI - Stability indicating reversed-phase liquid chromatographic determination of
ciprofloxacin as bulk drug and in pharmaceutical formulations.
PMID- 10768362
TI - LC analysis of hepatoprotective diterpenoids from Andrographis paniculata.
PMID- 10768363
TI - HPTLC determination of tryptophanase.
PMID- 10768364
TI - The use of micropolarization in the treatment of spinal cord lesions.
AB - Transdermal micropolarization of the spinal cord was performed in patients
suffering sequelae of spinal cord trauma and tuberculous spondylitis. Changes in
clinical and electrophysiological status were monitored. These studies
demonstrated that the use of local direct currents passed via skin electrodes
promoted improvements in motor and autonomic functions in these patients, leading
to positive changes in measures of the functional state of the spinal cord and
heart activity. The possible mechanisms of the action of direct currents acting
on the spinal cord are discussed, along with the potential for applying
micropolarization in the treatment of spinal cord lesions.
PMID- 10768365
TI - Indirect short-term influences of alternating magnetic fields on the brain in
epilepsy.
AB - Changes the bioelectrical activity of the cerebral hemispheres were studied in 20
patients with epilepsy and 18 healthy subjects subjected to local alternating
magnetic fields (MF) applied to the hand. MF produced increases in epileptic
activity in terms of the bioelectrical characteristics of foci and the level of
generalization. This suggests that alternating MF can be used to identify the
localization of epileptic foci. The most stable changes in response to
alternating MF were seen in the posterior parietal parts of the right hemisphere.
It is concluded that the effects of alternating MF are produced mainly by
processes in the right hemisphere.
PMID- 10768366
TI - Extraembryonic motor activity during the embryogenesis of higher vertebrates.
AB - Extraembryonic rhythmic motor activity in higher vertebrates, along with the
intrinsic motor activity of the embryo, is important for the normal development
of the embryo. This can have different natures in different classes of amniotes
(i.e., motor activities of the amnion, yolk sac, and uterus), but these have
similar functional importance. This activity changes reproducibly during the
process of embryogenesis, providing the optimum conditions for normal embryo
development. During embryogenesis, a system for controlling extraembryonic
rhythmic motor activity is also formed. There is a trend for the regulation of
this activity to become more complex in mammals as compared with birds. Reptiles
have received little study from this point of view. In addition to regular
changes in extraembryonic rhythmic motor activity during embryogenesis which
depend on the developmental stage of the embryo, motor activity can also change
in response to changes in a number of environmental factors (for example,
temperature and the gas composition of the air). This demonstrates the possible
involvement of embryo-associated extraembryonic motor activity in adapting the
embryo to changing environmental conditions and maintaining homeostasis for the
development of the embryo itself.
PMID- 10768367
TI - The endoplasmic reticulum and mitochondria as elements of the mechanism of
intracellular signaling in the nerve cell.
AB - Experimental data obtained in our laboratory from studies of intracellular
signals arising within nerve cells during excitation are summarized. Measurements
of transmembrane ion currents in conditions of fixed membrane potential and
intracellular free Ca ion concentrations, using fluorescent probes, yielded the
time and spatial characteristics of transient elevations in the Ca concentration
(the "calcium signal") in various types of mouse and rat neurons. These studies
showed that intracellular structures-the endoplasmic reticulum and mitochondria
had significant roles in forming these signals; these structures can take up Ca
from the cytosol and liberate Ca into the cytosol; the contribution of these
processes was extremely variable, depending on the internal organization of
different functional types of neurons.
PMID- 10768368
TI - Intracellular regulation of neuronal nicotinic cholinoreceptors.
AB - Experiments on isolated superior cervical ganglia from rats were used to study
the effects of substances affecting intracellular second messengers on membrane
currents evoked by iontophoretic application of acetylcholine (ACh currents) and
on excitatory postsynaptic currents (EPSC) induced by single discharges of
preganglionic nerve fibers. These studies showed that the adenylate cyclase
activator forskolin, the phosphodiesterase inhibitor isobutylmethylxanthine
(IMBX), and the protein kinase C activator phorbol ester decreased the amplitude
of the ACh current. Neither IMBX nor phorbol ester had any effect on the
amplitude or decay time constant of EPSC, while forskolin increased the amplitude
of EPSC without altering its decay time constant. Thapsigargin, which liberates
intracellular calcium, not only decreased the amplitude of the ACh current, but
also decreased EPSC amplitude without affecting its decay time constant. These
results suggest that intracellular signaling via protein kinases A and C may
affect neuronal nicotinic cholinoceptors (nAChR) only by altering receptor
desensitization and not affecting receptor sensitivity to transmitters released
from nerves or the kinetics of receptor ion channels. At the same time, neuronal
nAChR are influenced by intracellular calcium, which decreases their ability to
be activated by exogenous (perhaps acting via desensitization) and nerve-released
acetylcholine without affecting the kinetics of ion channel function.
PMID- 10768369
TI - Blockade of ion channels as an approach to studying AMPA receptor subtypes.
AB - This article reviews current progress in studies of the relationship between the
molecular structure of different subtypes of AMPA receptors and their functional
properties. Differences in the subunit composition of AMPA receptors involved in
glutamatergic synaptic inputs to efferent (main) neurons and interneurons are
discussed with reference to neurons isolated from the hippocampus, striatum, and
cerebellum. Data on the possibility of selective pharmacological actions on the
ion channels of different AMPA receptor subtypes are presented; this allows these
receptors to be identified and their functions to be studied in greater depth in
normal and pathological conditions.
PMID- 10768370
TI - The differentiation of dopaminergic neurons in situ, in vivo, and in transplants.
AB - This article summarizes results obtained from studies on the differentiation of
dopaminergic neurons in animal hypothalamus and human substantia nigra in situ,
in vitro, and in transplants, as well as the role of the microenvironment in
regulating this process. Four stages were identified in the differentiation of
dopaminergic neurons from rat hypothalamus: a) formation of neurons from
neuroepithelial precursor cells, b) expression of specific synthetic products
(enzymes and dopamine itself) and mechanisms for transmembrane dopamine transport
(reuptake and secretion in response to membrane depolarization), c) formation of
permanent and transient efferent connections, and d) formation of afferent
innervation and synaptogenesis. Along with dopaminergic neurons, rat fetuses
contained neurons expressing only one of the dopamine-synthesizing enzymes and
probably taking part in in situ dopamine synthesis. Differentiation of
dopaminergic neurons was sexually dimorphic in terms of the dynamics of neuron
formation and expression of enzymes involved in dopamine synthesis. A
neurotransplantation model showed that humoral factors of placental and maternal
origin had no significant effect on the differentiation of the dopaminergic
neurons of the hypothalamus. As regards the dopaminergic neurons of the
substantia nigra, expression of their specific phenotype in human fetuses started
with the synthesis of tyrosine hydroxylase and co-maturation of the specific
dopamine reuptake mechanism during the sixth week of development. During the next
four weeks, specific uptake increased, and this appears to be a measure of the
number of neurons and the growth of their processes. These data provide the basis
for regarding the period from week 6 to week 10 as optimal for transplantation of
dopaminergic neurons into the striatum of patients with Parkinson's disease.
Suspensions of fetal substantia nigra cells enriched with dopaminergic neurons
were introduced stereotaxically into a patient's striatum through a cannula.
Positron emission tomography studies showed that the transplanted neurons
survived within the host brain, underwent differentiation, and started to
synthesize dopamine. The results of clinical assessment performed in parallel
with these studies suggested that the transplanted dopaminergic neurons were
involved in regulating striatal target neurons.
PMID- 10768371
TI - Transmitter-dependent switching of respiratory interneurons to the locomotor
rhythm in the pulmonate mollusk Lymnaea.
AB - Cell RPeD1 of the pond snail Lymnaea stagnalis is a dopaminergic neuron known to
be involved in generating the respiratory rhythm. This report describes
conditions in which RPeD1 follows the rhythm of another central generator,
identified as the generator of muscular locomotion. This rhythmic activity of
RPeD1 developed in isolated CNS preparations treated with 0.05 mM serotonin (5
hydroxytryptamine, 5-HT) or 0.1 mM 5-hydroxytryptophan (5-HTP). It was
coordinated by cyclic synaptic currents with the activities of other pedal
neurons and with trains of spikes in the motor (pedal and columellar) nerves.
Only the pedal ganglia (both of them) retained the ability to generate 5-HT
dependent cyclic activity after complete isolation, indicating a pedal
localization and paired nature for the central generator. In intact animals,
injection of 100 microg/g of 5-HTP induced coordinated cyclic movements of the
foot and shell which had similar periods and resembled movements during
terrestrial (non-ciliary) locomotion. These results, along with the known role of
dopamine in generating the respiratory pattern, show that switching of RPeD1 from
one central rhythm to another is a transmitter-dependent phenomenon.
PMID- 10768372
TI - Cholinoreceptors of early (preneural) sea urchin embryos.
AB - Agonists of nicotinic cholinoreceptors (n-AChR) and 1-acetyl-4-methylpiperazine
(100 microM) had no effect on early embryogenesis in sea urchins, while in the
presence of phorbol-12-myristate-13-acetate (PMA) and various other protein
kinase C activators, these agents induced rapid lysis of oocytes or early
embryos, as a result of calcium shock. Many n-AChR ligands which do not penetrate
into the cytoplasm (not being antagonists of muscarinic cholinoreceptors)
protected against this cytotoxic effect. In the presence of PMA, acetylcholine
and carbachol had actions which were much weaker than those of nicotine, while
muscarine was completely inactive in these conditions. Thus, the surfaces of sea
urchin oocytes and early embryos bear receptor structures, presumably n-AChR,
which are functionally linked with second messengers which are endogenous protein
kinase C activators.
PMID- 10768373
TI - The neurotoxicity of environmental pollutants: the effects of tin (Sn2+) on
acetylcholine-induced currents in greater pond snail neurons.
AB - Inorganic and organic tin compounds present in aqueous ecosystems have diverse
effects on the behavior of living organisms. With the aim of identifying possible
correlates of these actions, we studied the effects of both types of Sn2+. The
effects of SnCl2 and Sn(CH3)2 on acetylcholine-activate currents were studied on
identified neurons of the mollusk Lymnaea stagnalis L. using a two-microelectrode
membrane potential clamping technique and by intracellular dialysis with
potential and ion concentration clamping. Experiments were performed on single
neurons after isolation and on whole ganglion preparations. SnCl2 decreased
acetylcholine-induced influx currents; the effect was dose-dependent. The
effective threshold concentration, measured by the two-microelectrode membrane
potential clamping method, was 0.1 microM, with saturation occurring at 5 microM
SnCl2. After a 10-min preapplication of SnCl2, the effect was stronger (20%) than
after treatment for 3 min (7%). Similar results were obtained after application
of tin using the intracellular dialysis method with potential and ion
concentration clamping. After preapplication of 10 microM SnCl2 for 1 min,
acetylcholine-induced influx currents decreased by 41%, we compared differences
in the effects induced by inorganic and organic tin compounds. Sn(CH3) induced a
decrease in the amplitude of acetylcholine-induced currents in the same way as
inorganic tin. The effect of Sn(CH3)2 was irreversible and stronger as the
preapplication time increased. These results support the previous conclusion that
agonist-activated channels are an important target for the actions of toxic
metals. It is concluded that direct actions on neuron membranes represent an
important component in the modulation of synaptic transmission and that this
should be considered in studies of the mechanisms of toxicity of tin.
PMID- 10768374
TI - The effects of the hormones of peripheral endocrine glands on the processes of
behavior, learning, and memory.
AB - The effects of systemic administration of thyroid, adrenal cortex, and sex
hormones on learning ability, memory trace retention, and behavior were compared
in male rats. These studies showed that thyroid, corticosteroid, and sex hormones
had no effect on passive learning. Excess quantities of sex hormones disrupted
active learning and subsequent reproduction of received information; an excess of
thyroid hormone improved the acquisition and retention of the active avoidance
habit. Increases in the levels of adrenal cortex hormones worsened active
learning and the retention of memory traces, and also increased the level of
behavioral activity.
PMID- 10768375
TI - The electrical characteristics of command and motor neurons during acquisition of
a conditioned defensive reflex and formation of long-term sensitization in
snails.
AB - The mechanisms of the acquisition of a conditioned defensive reflex and formation
of long-term sensitization were studied at the level of an analysis of the
electrical characteristics of defensive behavior command neurons and motor
neurons which open and close the pneumostoma. Significant decreases in membrane
and threshold potentials were seen in command neurons in response to acquisition
of the conditioned defensive reflex and formation of long-term sensitization,
along with further decreases in these parameters in snails which were trained
after long-term sensitization. Changes in the critical level of depolarization
and amplitude of action potentials were insignificant. The changes observed here
provide evidence for an increase in the membrane excitability of command neurons.
Similar changes were not seen in motor neurons.
PMID- 10768376
TI - Tangential segregation of simple and complex cells in the visual cortex and their
connections. A universal neocortical module.
AB - In the visual cortex of the guinea pig brain, the primary convergence zones for
afferents correspond to basal modules--columns which are about 200 microm in
diameter-and are separated by secondary convergence zones. The former are
characterized by their concentrations of neurons with simple receptive fields and
afferent inhibitory cells, and have a different organization of local
interneuronal connections as compared with secondary convergence zones, which
have an increased proportion of inhibitory influences, addressed excitatory
inputs, and more selectivity in their cellular reactions. The basal modules have
parameters similar to those of higher mammals; secondary convergence zones are
smaller in rodents, and have simpler organization.
PMID- 10768377
TI - Involvement of the cholinergic systems of the shell and core parts of the nucleus
accumbens in regulating operant behavior in dogs.
PMID- 10768378
TI - An expert system based on the principle of the functional asymmetry of the brain.
AB - A general concept for automating the secondary processing of data is proposed.
Starting information is accumulated in a database. During processing, a textual
description is generated for each object, and all further manipulations consists
of transformations of the database. The use of this approach allows different
types of information to be accumulated and analyzed efficiently using a single
scheme.
PMID- 10768379
TI - Projections of the substantia nigra, ventral tegmental area, and amygdaloid body
to the pallidum in the dog brain.
PMID- 10768380
TI - The topography and cellular organization of the reticular formation of the
thoracic part of the spinal cord in the cat.
PMID- 10768381
TI - The state and quantitative characterization of congested capillaries in the brain
in conditions of acute and chronic venous congestion.
PMID- 10768382
TI - The interaction of biological molecules with clay minerals: a scanning force
microscopy study.
AB - We have used the technique of scanning force microscopy (SFM) to investigate the
reaction of both amino acids and activated nucleotides in the presence of the
clay mineral Cu(II)-exchanged hectorite. Using simulated prebiotic heating and
wetting cycles, we have shown that the clay mineral acts to adsorb, concentrate,
and subsequently catalyze the polymerization of these biological monomers into
short peptides and oligonucleotides. The presence of the Cu(II) cations within
the clay intergallery regions, and at surface step edges and cracks, is crucial
for the observed reactions to occur. Clay minerals such as hectorite may have
thus played an important role in the evolution of biologically viable molecules
on the prebiotic earth.
PMID- 10768383
TI - Nanodissection and noncontact imaging of plasmid DNA with an atomic force
microscope.
AB - In this paper we report that a combination of noncontact and contact atomic force
microscopy is a convenient and reliable method for imaging and dissecting single
plasmid deoxyribonucleic acid (DNA) strands on mica at ambient conditions without
leaving feedback and without damage to the scanning tips. The width and thickness
measured at different points of the DNA strands agree with literature data and
are the same before and after dissection.
PMID- 10768384
TI - Glycoproteins and skin-core structure in Nephila clavipes spider silk observed by
light and electron microscopy.
AB - Microscopical imaging of natural, unstressed draglines or of untreated bulk
samples showed two types or threads with diameters of either approximately 1-2
microm or 4-5 microm, which could be identified as products of the minor or major
ampullate glands. The threads had a circular profile in serial cross sections and
are surrounded by a thin outer layer of a different material within the section.
Such fibrillar configurations were also found in untreated threads or in the same
serial sections of transmission electron microscopy (TEM) samples by means of the
special technique of laser scanning microscopy. In TEM slides, numerous cavities
with the same circular profile were detectable, and the length of these cavities
is variable from 40-300 nm. The threads are oriented parallel and twisted around
themselves to construct a double thread. In the interface between the two single
threads, bridge-like structures are prominent. The single untreated thread
consists of cylindrical fibers with a diameter of approximately 1-1.5 microm.
Apparently more than eight fibers are within a thread and each fiber is composed
of a great number of fibrils with a diameter of about 150 nm. The surface of
threads is coated with a characteristic layer approximately 150-250 nm thick that
contains glycoproteins. These were demonstrated for the first time by labeling
with concanavalin A lectin-gold complex and are dependent on the diameter and
length of the thread. The same substances could also be detected inside the
single thread. The skin can be removed completely or partially by mechanical
treatment, or by washing with phosphate-buffered saline or trypsin.
PMID- 10768385
TI - Microcratering within the lunar regolith--a theory and observation.
AB - Since the Apollo 11 mission to the moon, there has been substantial analysis of
the lunar rocks and soil grains, utilizing more recent advances in electron probe
technologies. It is the objective of this research to revisit the theories
concerning the microcratering within the lunar regolith. Recent theories have
included the idea that the microcratering phenomenon was caused by meteoric
impacting onto the lunar surface during early lunar history. Other theories have
suggested that the microcratering was a result of secondary ejector associated
with micrometeoric and meteoric impact. This research team suggests that
microcratering may have been associated with primordial dust during and before
the formation of our solar system.
PMID- 10768386
TI - The mechanism of G-banding detected by atomic force microscopy.
AB - The morphologic changes occurring in human chromosomes during G-banding by
trypsin treatment on the same metaphase were followed with the aid of an atomic
force microscope (AFM). It was found that trypsin treatment alone caused a
pattern of collapse in the chromosomes that was clearly dependent on the duration
of trypsinization. The progressive pattern of collapse first indicated the loss
of internal differentiation between chromatids, then bands, and finally all
internal structures, except for edges running around the chromosomes' perimeter.
When stained with Giemsa, the collapsed chromosomes partly regained their
original form, and transverse ridges appeared that correspond to G-positive band
regions. However, the treatment of fixed chromosomes with trypsin for 42 s
diminished the chromosomal edges, and the z-dimensions could not be measured even
with the subsequent application of Giemsa.
PMID- 10768387
TI - The remote electron beam-induced current analysis of grain boundaries in
semiconducting and semi-insulating materials.
AB - When no charge collecting p-n junction or Schottky barrier is present in the
specimen, but two contacts are applied, conductive mode scanning electron
microscope (SEM) observations known as remote electron beam-induced current
(REBIC) can be made. It was described as "remote" EBIC because the contacts to
the specimen can lie at macroscopic distances from the beam impact point. In
recent years, REBIC has been found to be useful not only for studies of grain
boundaries in semiconducting silicon and germanium, but also in semi-insulating
materials such as the wider bandgap II-VI compounds and electroceramic materials
like varistor ZnO and positive temperature coefficient resistor (PTCR) BaTiO3.
The principles of this method are outlined. Accounts are given of the five forms
of charge collection and resistive contrast that appear at grain boundaries (GBs)
in REBIC micrographs. These are (1) terraced contrast due to high resistivity
boundary layers, (2) peak and trough (PAT) contrast due to charge on the
boundary, (3) reversible contrast seen only under external voltage bias due to
the beta-conductive effect in a low conductivity boundary layer, (4) dark
contrast due to enhanced recombination, and (5) bright contrast apparently due to
reduced recombination. For comparison, the results of the extensive EBIC studies
of GBs in Si and Ge are first outlined and then the results of recent REBIC grain
boundary studies in both semiconducting and semi-insulating materials are
reviewed.
PMID- 10768388
TI - Hemodynamic role of the circle of Willis in stenoses of internal carotid
arteries. An analytical solution of a linear model.
AB - A mathematical model of blood flow through the circle of Willis was developed,
within a linear framework. Comprehensive analytical solutions, including a
remarkably small number of parameters, were derived in the cases of obstructive
lesions of extracranial carotid arteries. The influence of these lesions and the
role of anterior and posterior communicating arteries on the blood pressure at
the entry of the cerebral territories were quantified and analyzed emphasizing
that the responses of the system of Willis to obstructive carotid lesions are
extremely varied, depending on the communicating artery anatomy. Comparison with
numerical results obtained by using a non-linear model showed no physiologically
significant differences. Such a model might be an essential tool for an accurate
assessment of the cerebral hemodynamics in carotid diseases.
PMID- 10768389
TI - Mathematical modelling of interwound DNA supercoils.
AB - Small loops of DNA are affected by a variety of enzymes which remove turns of
twist relative to the underlying double-helical structure. The molecule adopts a
complex three-dimensional shape known as a supercoil in order to relieve the
resulting internal stresses. This article describes an approach to modelling the
overall shape of the supercoiled structure using elastic rod theory, which leads
to simple expressions for predicting the shape of the structure. Predictions on
the number of crossings in the balanced ply and the length of the end loops are
compared to data in the literature and show reasonable agreement. The effect of
the charged phosphate groups along the backbone of the DNA on the resulting
supercoiled shape are also examined, and it is shown that this shape is very
sensitive to the ionic concentration of the solution.
PMID- 10768390
TI - The influence of mechanical stimulus on the pattern of tissue differentiation in
a long bone fracture--an FEM study.
AB - 2D, coronal plane, finite elements models (FEMs) were developed from orthogonal
radiographs of a diaphyseal tibial fracture and its reparative tissue at four
different time points during healing. Each callus was separated into regions of
common tissue histology by computerised radiographic analysis. Starting point
values of tissue material properties from the literature were refined by the
model to simulate exactly the mechanical behaviour of the subject's callus and
bone during loading. This was achieved by matching measured inter-fragmentary
displacements with calculated inter-fragmentary forces. Stress and strain
distributions in the callus and bone were calculated from peak inter-fragmentary
displacements measured during natural walking activity, and were correlated with
the subsequently observed pattern of tissue differentiation and maturation of the
callus. The growth and stiffening of the external callus progressively reduced
the inter-fragmentary gap strain. Partial maturation of the gap tissue was
apparent only one week before fixator removal. Principal stresses in the callus
were compared with 'yield stresses' in corresponding tissue from the literature.
This indicated the presence of stress concentrations medial and lateral to the
fracture gap, which probably caused tissue damage during normal activity levels.
Tissue damage may also have precipitated partial structural failure of the
callus, both of which were believed to have delayed healing during the middle
third of the fixation period. Had the fixation device provided greater inter
fragmentary support during early healing, this may have prevented callus failure
and the consequent delay in healing. A further benefit of this would have been
the reduction of the initially high intra-gap tissue strains to a magnitude more
conducive to earlier maturation of the bridging tissue that united the bone.
PMID- 10768391
TI - Force and surface mechanomyogram frequency responses in cat gastrocnemius.
AB - Muscle surface displacement is a mechanical event taking place simultaneously
with the tension generation at the tendon. The two phenomena can be studied by
the surface mechanomyogram signal (MMG) (produced by a laser distance sensor) and
the force signal (from a load cell). The aim of this paper was to provide data on
the reliability of the laser detected MMG in muscle mechanics research. To this
purpose it was verified if the laser detected MMG was suitable to estimate a
frequency response in the cat medial gastrocnemius and its frequency response was
compared with the one retrieved by the force signal at the tendon level. The
force and MMG from the exposed medial gastrocnemius of four cats were analysed.
The frequency response was investigated by sinusoidally changing the number of
orderly recruited motor units, in different trials, in the 0.4-6 Hz range. It
resulted that it was possible to model the force and MMG frequency response by a
critically damped second-order system with two real double poles and a pure time
delay. On the average, the poles were at 1.83 Hz (with 22.6 ms delay) and at 2.75
Hz (with 38 ms delay) for force and MMG, respectively. It can be concluded that
MMG appears to be a reliable tool to investigate the muscle frequency response
during stimulated isometric contraction. Even though not statistically
significant. the differences in the second-order system parameters suggest that
different components of the muscle mechanical model may specifically affect the
force or MMG.
PMID- 10768392
TI - A computational model for the prediction of total knee replacement kinematics in
the sagittal plane.
AB - A computational model has been developed using a current generation computer
aided engineering (CAE) package to predict total knee replacement (TKR) kinematic
in the sagittal plane. The model includes friction and soft tissue restraint
varying according to the flexion angle. The model was validated by comparing the
outcomes of anterior-posterior (A-P) laxity tests of two contemporary knee
replacements against data obtained from a knee simulating machine. It was also
validated against predictions from a computer model reported in the literature.
Results show good agreement in terms of A-P displacements. Further tests were
performed to determined the influence of the soft tissue restraints varying with
flexion angle. This work represents the first attempt to use a sophisticated
commercial CAE package to predict TKR motions and the advantages of the modelling
procedure chosen are discussed.
PMID- 10768393
TI - Influence of stenosis morphology on flow through severely stenotic vessels:
implications for plaque rupture.
AB - Flow patterns and flow-related stresses contribute to the characterization of
health risks, particularly the risk of plaque rupture, posed by a particular
atherosclerotic stenosis. Blood flow in the presence of significant plaque
deposits is investigated, and the influence of factors such as stenosis
morphology and surface irregularity is evaluated. Solutions for three
dimensional, unsteady flow in these stenotic vessels are obtained for an
incompressible, Newtonian fluid. The equations of motion are solved numerically
using a finite volume formulation. The resulting flow patterns and shear and
normal stresses are interpreted with respect to diagnostic implications,
including the possibility of plaque rupture. The inadequacy of "percent stenosis"
to characterize the risks posed by a particular plaque is demonstrated. Surface
irregularity, stenosis aspect ratio, and the shape of the pulsatile waveform all
have considerable influence on the flow field and on the stresses on the plaque.
A measure of surface irregularity or plaque symmetry, in particular, may
complement percent stenosis in diagnosing the risk of plaque rupture.
PMID- 10768394
TI - Mechanical power in running: a comparison of different approaches.
AB - The purposes of the present study were: (1) to compare four different methods of
calculating mechanical power in running on the basis of comparable data over a
wide range of running velocity; (2) to examine the linearity of the relation
between mechanical power as calculated with the four methods and running
velocity. Eight runners participated in the investigation (height: 1.82 +/- 0.03
m, body mass: 81.05 +/- 4.69 kg). A Kistler force platform registered all
components of the ground reaction force (1000 Hz) during one foot ground contact,
which was additionally video taped using two high-speed video cameras running at
120 Hz. Four different methods were used to calculate mechanical power. Two
methods determined the mechanical power due to the work done on the athletes'
center of mass and two were calculated from the motion of the athletes' segments.
The four different methods provided different relations between mechanical power
and running velocity. The calculations on the basis of kinematic data cannot be
recommended to determine efficiency of movement. The methods based on ground
reaction force measurements revealed significant linear relations (r = 0.90, r2 =
0.84) between running velocity and mechanical power.
PMID- 10768395
TI - The components of passive knee movement are coupled to flexion angle.
AB - Movement of the unloaded knee has been described in several studies by an
"envelope of passive flexion", a description that does not describe or explain
the widely reported coupling of internal tibial rotation to flexion. The
objective of the current study was to show that the envelope of passive knee
flexion can be reduced to a coupled path. Two hypotheses were tested: (1) in
normal knees flexed passively, internal/external rotation, abduction/adduction
and all three components of translation are coupled to flexion angle, and (2) the
tibia rotates internally as the knee is flexed passively. Fifteen cadaver knees
were flexed in a rig designed to apply minimal resistance to knee movement while
three-dimensional kinematics of the femur relative to the tibia were measured
with an electromagnetic tracking system. Each specimen displayed internal tibial
rotation and posterior, proximal and medial displacement of a reference point
with flexion, while a range of ab/adduction behaviour was observed. Mean absolute
differences between the flexing and extending paths in normal specimens were
under 2 and 0.2 degrees for internal/external tibial rotation and ab/adduction,
respectively. Deviation from the movement path was resisted: when released after
being displaced, the femur of each normal joint sprang back to its original
position on the motion path. It was concluded that passive knee flexion can be
described by a coupled path. Although the exact shape of the path is very
sensitive to load and varies between knees, knee rotations and translations were
always coupled to flexion, and internal tibial rotation with flexion was always
observed.
PMID- 10768396
TI - Toward a biomechanical tool to evaluate rupture potential of abdominal aortic
aneurysm: identification of a finite strain constitutive model and evaluation of
its applicability.
AB - Knowledge of the wall stresses in an abdominal aortic aneurysm (AAA) may be
helpful in evaluating the need for surgical intervention to avoid rupture. This
must be preceded by the development of a more suitable finite strain constitutive
model for AAA, as none currently exists. Additionally, reliable stress analysis
of in vivo AAA for the purposes of clinical diagnostics requires patient-specific
values of the material parameters, which are difficult to determine
noninvasively. The purpose of this work, therefore, was three-fold: (1) to
develop a finite strain constitutive model for AAA; (2) to estimate the variation
of model parameters within a sample population; and (3) to evaluate the
sensitivity of computed stress distribution in AAA due to this biologic
variation. We propose here a two parameter, hyperelastic, isotropic,
incompressible material model and utilize experimental data from 69 freshly
excised AAA specimens to both develop the functional form of the model and
estimate its material parameters. Parametric analyses were performed via repeated
finite element computations to determine the effect of varying each of the two
model parameters on the stress distribution in a three-dimensional AAA model. The
agreement between experimental data and the proposed functional form of the
constitutive law was very good (R2 > 0.9). Our finite element simulations showed
that the computed AAA wall stresses changed by only 4% or less when both the
parameters were varied within the 95% confidence intervals for the patient
population studied. This observation indicates that in lieu of the patient
specific material parameters, which are difficult to determine the use of
population mean values is sufficiently accurate for the model to be reasonably
employed in a clinical setting. We believe that this is an important advancement
toward the development of a computational tool for the estimation of rupture
potential for individual AAA, for which there is great clinical need.
PMID- 10768397
TI - Determination of molecular changes in soft tissues under strain using laser Raman
microscopy.
AB - The paper presents a non-contact technique to examine the molecular changes in a
collagen fibre subjected to in vitro axial tension. Laser Raman microscopy was
employed to monitor the vibrational changes in specific assignments of the Raman
spectrum of collagen. Results were presented in the form of Raman wavenumber
shift as a function of applied tensile strain. Two distinct responses were
observed depending on whether the vibrations were axial to, or normal to, the
collagen backbone. The former response produced a decrease in wavenumber values,
indicating tension, whereas the latter produced an increase, indicating
compression. The rate of wavenumber shift with applied strain was non-linear in
form, with a marked increase at higher levels of applied strain, for example, a
strain 4% in the case of axial vibrations. This technique can prove to be a
powerful tool for examining deformation at the molecular level in collagenous
tissues.
PMID- 10768398
TI - A new kinematic model of pro- and supination of the human forearm.
AB - We introduce a new kinematic model describing the motion of the human forearm
bones, ulna and radius, during forearm rotation. During this motion between the
two forearm extrem-positions, referred to as supination (palm up) and pronation
(palm down), effects occur, that cannot be explained by the the established
kinematic model of R. Fick from 1904. Especially, the motion of the ulna is not
properly reproduced by Fick's model. During forearm rotation an evasive motion of
the ulna is observed by various authors, using magnetic resonance imaging MRI)
technology. Our new kinematic model also simulates this evasive motion.
Furthermore, the model is enlarged to include angulations of the forearm bones.
Using these results the influence of forearm fractures on the range of forearm
motion can be predicted. This knowledge can be used by surgeons to choose the
optimal therapy in re-establishing free forearm mobility.
PMID- 10768399
TI - Accuracy analysis for RSA: a computer simulation study on 3D marker
reconstruction.
AB - In this paper, error analysis of three-dimensional marker coordinates
reconstructed from noisy two-dimensional measurement in RSA was performed.
Mathematical models to predict error propagation of focus position and object
points were derived and computer simulations were performed to validate these
models. Two clinical calibration cages were compared by testing the error
propagation at each RSA step. The results revealed that errors of reconstructed
object points were related to the focus position error, two-dimensional
measurement error, position of focus and positions of object points, while errors
of reconstructed focus position were determined by the two-dimensional
measurement error, number of control points and location of the focus. The
maximum difference between the mathematical model and the simulation for the
assessment of errors of focus position was 14 microm and the maximum difference
of object point positions was 1.1 microm. These differences were small and judged
irrelevant, hence the simulations indicated that our models were accurate.
PMID- 10768400
TI - Relationships between femoral fracture loads for two load configurations.
AB - Studies of proximal femoral strength usually involve one of two types of loading
conditions, loading similar to joint loading during single-limb stance or loading
simulating impact from a fall. When interpreting the results of studies involving
only one of these load configurations, the question arises as to their
applicability to the other configuration. In addition, it is desirable to know
whether, for an individual bone, fracture load for one load configuration is
indicative of fracture load for the other configuration. In this study, the
relationship between proximal femoral fracture loads for single-limb stance
loading and loading simulating impact from a type of fall was determined from
mechanical testing of 17 matched pairs of human proximal femora. Fracture loads
for these two configurations were found to be linearly related (r = 0.901, p <
0.001). However, the correlation between fracture loads is not notably stronger
than correlations currently available between fracture load and measures of bone
density and geometry. In addition, the regression results indicate that 81% of
the variance in fracture load for one loading condition is accounted for by
fracture load for the other loading condition. Thus, 19% of the variance remains
unexplained, indicating that the results of studies involving only one load
configuration are not necessarily indicative of those that would be found for
another configuration.
PMID- 10768401
TI - Scattering of ultrasound in cancellous bone: predictions from a theoretical
model.
AB - An understanding of the interaction between acoustic waves and cancellous bone is
needed in order to realize the full clinical potential of ultrasonic bone
measurements. Scattering is likely to be of central importance but has received
little attention to date. In this study, we adopted a theoretical model from the
literature in which scattering was assumed to be proportional to the mean
fluctuation in sound speed, and bone was considered to be a random continuum
containing identical scatterers. The model required knowledge only of sound
speeds in bone and marrow, porosity, and scatter size. Predicted attenuation,
broadband ultrasonic attenuation (BUA) and backscatter coefficient were obtained
for a range of porosities and scatterer sizes, and were found to be comparable to
published values for cancellous bone. Trends in predicted BUA with porosity
agreed with previous experimental observations. All three predicted acoustic
parameters showed a non-linear dependence on scatterer size which was independent
of porosity. These data confirm the value of the scattering approach and provide
the first quantitative predictions of the independent influence of structure and
porosity on bone acoustic properties.
PMID- 10768402
TI - Comments on 'Hydrodynamics optimization in butterfly swimming: position, drag
coefficient and performance'.
PMID- 10768403
TI - Multiple regression analysis with optimal molecular descriptors.
AB - We consider construction of optimal molecular descriptors to be used for multiple
regression analysis of several properties of alcohols. The descriptors are
obtained by considering shorter paths with variable weight x for carbon-oxygen
bond in alcohol. In particular we consider as molecular descriptors paths of
length 1, 2 and 3. The multiple regression analysis of the following molecular
properties was examined: - log S (S = solubility), CSA (cavity surface area), log
P (P = octanol/water partition), and log gamma (gamma = infinite solution
activity coefficient). By minimizing the standard error of the regression for
each property we found optimal variable weight.
PMID- 10768404
TI - A general QSAR model for predicting the acute toxicity of pesticides to
Oncorhynchus mykiss.
AB - A Quantitative Structure-Activity Relationship (QSAR) model was derived for
estimating the acute toxicity of pesticides against Oncorhynchus mykiss under
varying experimental conditions. Chemicals were described by means of
autocorrelation descriptors encoding lipophilicity (H0 to H5) and the H-bonding
acceptor ability (HBA0) and H-bonding donor ability (HBD0) of the pesticides. A
three-layer feedforward neural network trained by the back-propagation algorithm
was used as statistical engine for deriving a powerful QSAR model accounting for
the weight of the fish, time of exposure, temperature, pH, and hardness.
PMID- 10768405
TI - Quantitative structure-activity studies of octopaminergic agonists and
antagonists against Locusta migratoria using similarity indexes.
AB - The quantitative structure-activity relationship of 39 octopamine (OA) agonists
and 12 antagonists against the thoracic nerve cord of the migratory locust,
Locusta migratoria L. was analyzed using atom based rigid fit method or flexible
fitting offered by PowerFit 1.0 from MicroSimulation. For OA agonists, the more
similar to reference compound NC (24) the structure of test compound, the higher
the activity, whereas for OA antagonists it was not the case. Antagonists may not
interact with the same part of the membrane with which the agonists interact.
Taken the part of the membrane with which the agonist interacts as the true
receptor, the antagonist may well interact with an area surrounding the receptor
including the ionophore.
PMID- 10768406
TI - On the topological sub-structural molecular design (TOSS-MODE) in QSPR/QSAR and
drug design research.
AB - A recently introduced graph-theoretical approach to the study of structure
property-activity relationships is presented. The theoretical approach and the
computational strategy for the use of the TOSS-MODE approach are given with
details. Several QSPR and QSAR applications are reviewed including the study of
physical properties of organic compounds, diamagnetic susceptibilities, and
biological properties. The applications of the TOSS-MODE approach to
discrimination of active/inactive compounds, the virtual screening of compounds
with a desired property from databases of chemical structures, identification of
active/inactive fragments and its relationships with 2D/3D pharmacophores, and to
the design of novel compounds with desired biological activities are also
reviewed.
PMID- 10768407
TI - Diet and disease during Europe's agricultural and industrial revolutions.
PMID- 10768408
TI - New nutrient intake recommendations are needed for childbearing.
AB - British recommendations (DRVs and RNIs) include hardly any increments for
pregnancy. British recommendations for protein are likely to cause unsatisfactory
birthweight. What is the normal nutrient intake in pregnancy of healthy women?
What evidence is there of special requirements for folate, iron, magnesium or
iodine? New recommendations for nutrient intakes in pregnancy should be the
responsibility of the Food Standards Agency and a survey of the diets of pregnant
women is needed.
PMID- 10768409
TI - Laboratory studies of the effects of carbohydrate consumption on wakefulness.
AB - Changes in wakefulness before and after exposure to carbohydrate intake were
tested in 30 test persons. Changes in wakefulness were tested via EEG and
subjective estimates. The intakes consisted of 400 ml glucose, 250 kcal (GI 100),
400 ml fructose, 209 kcal (GI 20), and 400 ml water. The study has indicated that
intake of fructose, glucose and water had a similar stimulating effect on
wakefulness in drowsy subjects immediately after intake. Our results also
indicate that intake of fructose can lead to a delay in the development of
drowsiness. Compared to water, a 20-30 minutes delay of the point in time when
high-degree drowsiness developed, took place. There was no significant difference
between glucose and water.
PMID- 10768410
TI - Optimum domestic processing and cooking methods for reducing the polyphenolic
(antinutrient) content of pigeon peas.
AB - Four high yielding and early maturing cultivars of pigeon pea (Cajanus cajan)
namely UPAS-120, ICPL-87, ICPL-151 and, especially, Manak, contained significant
amounts of polyphenols (1075 to 1328 mg/100g), which may limit their utilization.
The effectiveness of soaking (6, 12 and 18 h, 30 degrees C), soaking and
dehulling, ordinary cooking, pressure cooking and germination (24, 36, 48 h, 30
degrees C) in reducing the levels of polyphenols was investigated. A decrease in
the polyphenolic contents varying from 4 to 26 percent in different pigeon pea
cultivar was achieved. Pressure cooking of soaked-dehulled seeds was found to be
the most effective method, followed by sprouting for 48 h, ordinary cooking of
soaked-dehulled seeds, and pressure cooking of soaked whole seeds followed by
sprouting for 36 h.
PMID- 10768411
TI - A study of prevalence of protein energy malnutrition among 0-5 years in rural
Benue State, Nigeria.
AB - Three hundred and seventy pre-school children (181 males and 189 females) were
studied in order to document the prevalence of protein energy malnutrition and
factors that militate it. The prevalence of protein energy malnutrition among the
children was revealed to be 41.6% (154). One hundred and fiftyone (40.8%) of them
were found to have weight-for-height below -2SD indicating level of stunting
among the children. Most malnourished children belonged to mothers who were
illiterate 97 (54.8%) when viewed from the mothers' educational perspective. This
study also showed the following factors that were statistically significant with
PEM: educational status of mothers (p<0.05), marital status (p<0.05) of mothers,
occupational status of mothers (p=0.000), parental income per annum (p=0.000),
length of breastfeeding (p=0.000), water supply and regularity, type of housing
and toilet facilities. Intensification of health education aimed at encouraging
beneficial childhood feeding practices in the community is needed together with
further study on the subject, which will be directed at actual analysis of the
nutritive values of available local foodstuffs as a prerequisite for an effective
intervention programme.
PMID- 10768412
TI - Empowerment & reminiscence: possible tools in dietary health promotion in the
elderly.
AB - The COMA report "The Nutrition of Elderly People" recommended that elderly people
should be targeted for health education programmes in order to maintain
nutritional status in this group. Recent research indicates that interventions
which aim to influence nutritional behaviour are more likely to succeed if they
involve target populations at all stages of the process. This paper outlines a
preliminary action research project which attempted to identify some key issues
influencing eating behaviour in a group of elderly people based in the Halewood
area of Knowsley, Merseyside. An innovative methodology, combining empowerment
and reminiscence, was used to produce a nutritional advice leaflet which will be
used as a resource within the local community.
PMID- 10768413
TI - Anticonvulsion effect of acupuncture might be related to the decrease of neuronal
and inducible nitric oxide synthases.
AB - To measure the levels of hippocampal nitric oxide synthase isoforms in penicillin
induced epilepsy and to test the effect of electroacupuncture (EA) on changes of
these levels during epilepsy, we injected penicillin into rat hippocampus to make
an epilepsy model and performed electroacupuncture treatment on "Feng Fu" (DU 16)
and "Jin Suo" (DU 8) points in Wistar rats. Nitric oxide synthase (NOS) mRNA
levels of rat hippocampus were determined by reverse transcription-polymerase
chain reaction (RT-PCR). The neuronal nitric oxide synthase (nNOS) mRNA markedly
increased (p<0.01) and inducible nitric oxide synthase (iNOS) mRNA significantly
emerged during epilepsy, whereas no significant change in epithelial nitric oxide
synthase (eNOS) mRNA was observed. EA inhibited the epilepsy and decreased nNOS
(p<0.01) and iNOS (p<0.01) correspondingly but had no effect on the amount of
eNOS mRNA. The data suggest that penicillin-induced epilepsy caused an increase
in nNOS and iNOS, and the EA anticonvulsant effect might be related to the
decrease of these nitric oxide synthases.
PMID- 10768414
TI - Different analgesic effects of manual and electrical acupuncture stimulation of
real and sham auricular points: a blind controlled study with rats.
AB - Stimulation of the auricle is considered to be an effective analgesic technique.
The aim of the present study is to establish whether there is a correspondence
between somatic inflammation and the appearance of lower resistance points, and
moreover, whether the stimulation of such points has an analgesic effect. The
study has been conducted on 57 male Sprague-Dawley rats weighing between 120-140
g; 7 of them have been used to determine whether inflammation in the paw leads to
the formation of lower resistance points on the auricle. The 50 remaining animals
have been divided into 5 groups: Group 1 [12 animals], control were subjected to
all manipulations with the exception of the auricle stimulation; Group 2 [12] was
stimulated with manual acupuncture in the area corresponding to that observed in
the above-mentioned first group of 7 animals; Group 3 [12] was stimulated with 5
Hz and 5 mA; electroacupuncture (EAP) Group 4 [8] and group 5 [6] were treated
with acupuncture and with EAP respectively on points believed to be inactive in
areas diametrically opposite to the ones observed in the first group. After
acupuncture, 100 microg capsaicin in 50 microL of physiological solution were
injected subcutis in the dorsal surface of the paw. Edema response was monitored
for two hours, with measurement taken every 5 minutes. The results show a
reduction in the edema response, only in the group treated with EAP on the
appropriate points compared to the control group; no variation was observed in
the sham groups. To conclude, the hypothesis of a somatotopic division would seem
to be probable, and it would seem that the stimulation of the appropriate areas
and the use of an appropriate intensity constitute the two main variables
influencing the result.
PMID- 10768415
TI - The influence of acupuncture on the impedance measured by four electrodes on
meridians.
AB - The impedance on the pericardium merdian near Quze (P3) and control points in 12
cases was measured by a four electrodes impedance instrument. The amplitude of
impedance was recorded before, during and after needling the Neiguan. The result
showed that the mean impedance on the meridian and control points before the
needling were 52.8 +/- 11.0 (omega) and 61.7 +/- 10.3 (omega) respectively which
had significant difference (P<0.05). During the needling, impedance decreased
significantly on the meridian by 9.2 +/- 5.6 (omega) (P<0.001) while impedance
decreased by only 0.12 +/- 2.4 (omega) on control points without significance
(P>0.05). The impedance changed back to 51.1 +/- 11.3 (omega) and 59.9 +/- 11.0
(omega) on the meridian and control points respectively during the 5-10 minutes
after withdrawing the needling. In some cases, impedance changed intermittently
during the needling. The experiment implies that interstitial fluid increases
during the needling by axon reflection and blood capillary expanding which may be
one of the mechanisms of acupuncture regulation.
PMID- 10768416
TI - Clinical management of needle-phobia patients requiring acupuncture therapy.
AB - Both acupuncture and hypnosis have their distinct applications in the health
profession, but combining acupuncture therapy with hypnosis has rarely been done
for the purpose of therapeutic treatment, perhaps because few clinicians have
proper training in both disciplines. For needle phobic patients, acupuncture
treatment can be a dreadful experience, as multiple needles are usually used. It
is stressful for both clinicians and patients when the patients are put in an
extremely apprehensive state. Our research for combining both acupuncture and
hypnosis has revealed that synergy does exist in both, and that hypnosis does
augment the effect of acupuncture, resulting in better treatment outcomes. Since
many acupuncture patients who are needle phobic do not return for further
treatment even though acupuncture has rendered good therapeutic results for them,
stress reduction with hypnosis is, therefore, a welcome complimentary adjunct
that would enable them to return for further needed acupuncture treatment if and
when the factor of fear of the needle is removed.
PMID- 10768417
TI - The impact of the environment on height in Europe: conceptual and theoretical
considerations.
AB - PRIMARY OBJECTIVE: The purpose of this review is to assess whether information
available to evaluate the impact of the environment and, more specifically, socio
economic factors on height in European countries is sufficient. MAIN OUTCOMES AND
RESULTS: It is proposed that studies based on measurements taken 25 years ago or
more are unsatisfactory for assessing the current situation. There is a
widespread assumption that sufficient information is available for assessing the
issue. However, on inspection, there are very few environmental factors for which
sufficient material on their effects on height has been published. In many
studies to evaluate the effect of the environment an ecological design is used
and a post hoc interpretation is made. It is concluded that this type of study is
helpful only for generating hypotheses. When inspecting analytical studies on the
association between socio-economic factors and height it is observed that the
reports identified are only the tip of the iceberg of published reports on the
subject and include studies from less than half the European countries. In many
of these papers the independent variables are not defined in the same manner and
a formal comparison is difficult to make. CONCLUSIONS: Given the current
deficiencies, it is worthwhile to discuss in auxological epidemiology whether it
is relevant to tackle the issue proposed in this review. If the answer is yes, it
is necessary to identify the best course of action. Possible avenues to explore
are the potential and the barriers for harmonizing the investigation of socio
economic factors in growth studies, and the organization of a registry of reports
on growth and social factors. At a more modest level, a collaborative report
examining the availability of information and gaps on this topic among European
countries could be helpful.
PMID- 10768418
TI - Growth in some physical dimensions in relation to adolescent growth spurt among
rural Indian children.
AB - Measurements other than weight and height are rarely used in adolescent growth
assessment. It is necessary to examine changes in other physical dimensions
especially in relation to spurt in height as stature growth has a significance in
the assessment of adolescent growth. The present study, therefore, reports data
on four such measurements viz. foot length, sitting height, leg length and
shoulder width along with height in a semilongitudinal growth study carried out
over a 3 year period, on rural Indian boys (n = 587) and girls (n = 433), to
examine the occurrence of their maximum increments in relation to spurt in
height. Our analysis shows that the sequence of spurt in these physical
dimensions is the same in the case of boys and girls, viz. spurt in foot length
and leg length occurs before age at peak height velocity (14.3 yr--boys, 12.1 yr-
girls) while that for sitting height and shoulder width occurs after attaining
the peak height velocity. While foot length is the first one to reach peak (14 yr
-boys, 11 yr--girls), shoulder width is the last one (16 yr--boys, 14 yr--girls)
in this sequence. Thus the duration between the first spurt and the last spurt
was observed to be larger in case of girls (3 yr) as compared to boys (2 yr) and
apart from biological differences it could be partly due to the differential
treatment received by rural girls. Sitting heights and leg lengths of rural
children were significantly (p < 0.01) lower compared to Indian well-off and
British children suggest that undernutrition prevailing in rural community
affects all components of linear growth.
PMID- 10768419
TI - Variation in bone mineral density in adults in Poland: age and sex differences.
AB - The decline of mineral bone density with age can lead in more extreme cases to
osteopenia and osteoporosis, and is therefore one of the aspects of ageing with
great medical and social significance. With this idea in mind a study of age
changes in the trabecular and, separately, the cortical bone density of the
radius was carried out in 1218 females and 405 males, aged 22 to 60 years, all
occupationally active inhabitants of the city of Wroclaw, Poland. The technique
used was the peripheral Quantitative Computed Tomography (pQCT). It was found
that in females bone densities remain relatively stable throughout the period
between 22 and 40 years. They then begin to decline slowly, with a rapid decline
after the age of 55. A distinctly different pattern was found among males, with
bone densities reaching peak values, markedly higher than those in females, in
the third decade of life. After this age the bone density values begin to decline
at a rapid rate, so that by the age of 60 years mean trabecular and cortical
densities in males have decreased to levels almost equivalent to females of equal
age. In view of the small size of the male samples, especially in the older age
classes, the above results should be treated with caution and confirmed using
larger samples.
PMID- 10768420
TI - Analysis of sibling resemblance in anthropometric somatotype components.
AB - We analysed the Heath-Carter somatotype familial resemblance degree in a sample
of 1350 siblings (685 males and 665 females) from 634 nuclear families in the
province of Biscay (Basque Country, Spain). Sibling correlations were estimated
according to maximum likelihood procedures for endomorphy, mesomorphy, ectomorphy
and somatotypical attitudinal distance (SADi), after having adjusted for age, sex
and the two other components (Model I), and after taking into account several
environmental variables shared by all members of each sibship (Model II). All
sibling correlations of the somatotype components were significant, tending to be
higher in the case of mesomorphy than in the case of endomorphy. Same-sex
siblings (BB and SS) displayed significant mesomorphic and ectomorphic
resemblances, but in the case of endomorphy, sisters (SS) revealed relatively low
correlation compared with brothers (BB). The sex of sibs had a significant
influence on correlations of mesomorphy, but not on the other two components.
Further control of socio-familial variables such as the father's occupation and
education, and the sibship size, resulted in lower mesomorphy correlation
coefficients, but had no effect whatsoever on the other two components. SADi
correlations were very low and not significant, indicating high degrees of
dispersion in the individual somatotypes of the sample.
PMID- 10768421
TI - An analysis of consanguineous marriage in the Muslim population of India at
regional and state levels.
AB - Consanguineous marriage is widely favoured in a large majority of the world's
Islamic populations. According to recent estimates, the resident Muslim
population of India is over 100 million. However, apart from a few numerically
small or geographically defined surveys, little is known about their patterns of
marriage preferences since partition of the Indian Subcontinent in 1947. This
study seeks to determine the prevalence and patterns of consanguineous marriages
contracted among Indian Muslims at regional and state levels during the last two
generations. Data from the 1992/93 Indian National Family Health Survey (NFHS)
were used in the analysis. The NFHS was a nationally-representative survey of
ever-married women aged 13-49 years, conducted across 25 states of India. Of the
initial 9845 respondents, 8436 were included in the final weighted analysis
sample. Overall, 22.0% of marriages were found to be contracted between spouses
related as second cousins or closer, ranging from 15.9% in the eastern states to
32.9% in the western states of India. In all parts of the country first cousin
marriages were the preferred form of consanguineous union, and in four of the
five regions paternal first cousin marriages predominated. Despite predictions to
the contrary, there was no evidence of a significant change in the prevalence of
consanguineous unions over the course of the study period, which extended from
the late 1950s to the early 1990s.
PMID- 10768422
TI - Genetic variance of adolescent growth in stature.
AB - The aim of this study is to quantify the genetic and environmental variation in
biological parameters of the adolescent growth in stature in both sexes, using
structural equation models. Standing height was measured in 99 twin pairs from
the Leuven Longitudinal Twin Study. Subjects were seen at semi-annual intervals
between 10 and 16 years and at 18 years. Preece-Baines model I was fitted to the
individual data and biologically meaningful parameters were derived. Path models
were fitted to these parameters and a gender heterogeneity analysis was
performed. A model including additive genetic and specific environmental factors
(AE-model), allowing for a difference in total variance or in
genetic/environmental variance components in males and females best explains most
of the growth characteristics. For the timing and velocity of the adolescent
growth spurt, no gender heterogeneity was observed, and the genetic (0.89 to
0.93) and specific environmental (0.07 to 0.11) contributions were equal in both
sexes. For stature at take-off, stature at peak height velocity and for adult
stature, gender heterogeneity was observed and different models appeared to
result in the best fit for boys and girls. For height at PHV and adult stature,
the significant contribution of a common environmental (0.39 to 0.56) factor in
boys was noteworthy. For percentage of adult stature and distances between
relevant time points of the growth curve, a non-scalar effect was observed,
indicating that different genes affect these characteristics in boys and girls.
It is concluded that most characteristics of the growth spurt in stature are
under strong genetic control. Gender heterogeneity is present for stature and for
a number of derived growth characteristics.
PMID- 10768423
TI - Sex dimorphism in growth.
AB - While there is agreement that sex differences in height are small up to the onset
of the pubertal spurt in girls, there has been some debate about the question of
which, and to what extent, various growth phases contribute to the average adult
sex difference of about 13 cm. There has been no consistent agreement between
authors as to what extent this difference is due to the late onset of the
pubertal spurt (PS) for boys and to what extent it is due to their more intense
PS. In this paper, we investigate this question for the variables height, sitting
and leg height, arm length, bihumeral and biiliac width. Biiliac width is a
special case since both sexes have roughly the same adult size, but girls still
have a shorter growing period. The gains for boys, when compared to girls, show a
very different pattern across variables: for the legs, the additional growth due
to the later spurt is responsible for most of the adult sex difference (64%). On
the other hand, for bihumeral width and sitting height, the more intense PS
contributes almost 50% to the adult sex difference. An analysis across variables
indicates that increments from 1.5 to 6 years largely compensate for deviations
in infant morphology from adult morphology.
PMID- 10768425
TI - Science in society.
PMID- 10768424
TI - A prospective longitudinal study of urinary excretion of a bone resorption marker
in adolescents.
AB - In growing subjects, the rates of bone resorption and bone deposition are
substantially larger than in non-growing individuals. The purpose of this study
was to measure the urinary excretion of a specific bone resorption marker in
function of adolescent growth stages in a prospective longitudinal study. A
cohort of 60 adolescents (28 male and 32 female) was followed for 3.4 years
(range 1.7-4.6 years). Monthly measurements of height, weight and urinary
excretion of a bone resorption marker, collagen type I N-telopeptides (NTx), were
made. Changes in standing height were used to classify the adolescents into one
or more of six adolescent growth stages: pre-pubertal growth (continuous moderate
growth rate), ascending growth spurt (increasing growth rate), peak growth spurt
(growth rate higher than 7 cm/year for at least 6 months), descending growth
spurt (continuous decrease in growth rate), end of growth (growth rate between 0
and 2 cm/year), and no growth. An increase in NTx excretion from the pre-pubertal
to peak growth spurt of about 33% was found (44% and 27% for females and males
respectively). The decreasing growth rate after the pubertal growth spurt
coincided with a clear decrease in NTx excretion. These differences were
statistically significant, except between the prepubertal and ascending growth
stage. Individual mean NTx excretion during each growth stage was correlated with
the individual's growth rate during that time (r = 0.81). There was large inter
and intra individual variability. In non-growing adolescents (growth rate 0 cm/y)
NTx excretion levels were 4-7 times greater than in adults. In all females,
menarche was followed by a decrease in NTx excretion. In conclusion, the
excretion of a specific bone resorption marker, NTx, was correlated with the
changes in growth rate during adolescence, both for males and females. There were
large inter and intra-individual differences in NTx excretion during the
different growth stages. In adolescents who reached their adult height at the end
of the pubertal growth spurt. bone resorption decreased dramatically but remained
4-7 fold higher than in adults.
PMID- 10768426
TI - After Bezwoda.
PMID- 10768427
TI - Where next with stem-cell-supported high-dose therapy for breast cancer?
PMID- 10768428
TI - Cytochrome P450 enzymes in the heart.
PMID- 10768429
TI - Antibiotic policies in neonatal intensive-care units.
PMID- 10768430
TI - Medication errors, worse than a crime.
PMID- 10768431
TI - Rational decision-making about paediatric cardiac surgery.
PMID- 10768432
TI - Chemotherapy added to locoregional treatment for head and neck squamous-cell
carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative
Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.
AB - BACKGROUND: Despite more than 70 randomised trials, the effect of chemotherapy on
non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did
three meta-analyses of the impact of survival on chemotherapy added to
locoregional treatment. METHODS: We updated data on all patients in randomised
trials between 1965 and 1993. We included patients with carcinoma of the
oropharynx, oral cavity, larynx, or hypopharynx. FINDINGS: The main meta-analysis
of 63 trials (10,741 patients) of locoregional treatment with or without
chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI 0.85-0.94,
p<0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years
in favour of chemotherapy. There was no significant benefit associated with
adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to
radiotherapy gave significant benefits, but heterogeneity of the results
prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing
neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating
radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of
concomitant or alternating radiochemotherapy. Three larynx-preservation trials
(602 patients) compared radical surgery plus radiotherapy with neoadjuvant
chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy
in non-responders. The hazard ratio of death in the chemotherapy arm as compared
with the control arm was 1.19 (0.97-1.46). INTERPRETATION: Because the main meta
analysis showed only a small significant survival benefit in favour of
chemotherapy, the routine use of chemotherapy is debatable. For larynx
preservation, the non-significant negative effect of chemotherapy in the organ
preservation strategy indicates that this procedure must remain investigational.
PMID- 10768433
TI - Decision analysis and guidelines for anticoagulant therapy to prevent stroke in
patients with atrial fibrillation.
AB - BACKGROUND: Clinical guidelines are needed on whether or not to use anticoagulant
therapy to prevent stroke in patients with non-valvular atrial fibrillation. We
did a Markov decision analysis to model decision-making with regard to warfarin
treatment in patients with atrial fibrillation, and used the model to develop
evaluative guidelines. METHODS: The decision analysis involved a systematic
literature review supplemented by patients' estimates of the quality of life
associated with different states of health, secondary analysis of stroke-registry
data, and estimation of service costs; it also incorporated a sensitivity
analysis. The derived guidelines were subsequently applied to a cohort of
patients with atrial fibrillation. FINDINGS: We constructed decision tables for
12 age and sex groups. For most risk combinations, warfarin treatment would have
decreased health-care costs and increased quality-of-life years, although the
clinical decision was sensitive to patients' preferences and to the estimate of
warfarin's effectiveness. 97% of women with atrial fibrillation older than 75
years, and 69% aged 65-74 would have been recommended for treatment; for men, the
corresponding figures would have been 75% and 53%. With the upper quartile for
the loss of quality of life associated with being on warfarin treatment (1.00),
all but two of the 116 patients without contraindications would have been
treated, whereas with the lower quartile (0.92), only 27 of 116 would have been
treated. INTERPRETATION: Decision analysis is useful in the incorporation of
complex probabilistic data into informed decision-making, the identification of
factors influencing such decisions, and the subsequent development of evaluative
guidelines.
PMID- 10768434
TI - Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot
and hand warts: randomised double-blind trial.
AB - BACKGROUND: Photodynamic therapy (PDT) with topical 5-aminolaevulinic acid (ALA)
followed by irradiation with incoherent light (ALA-PDT) for recalcitrant warts
have had beneficial results. Therefore, we undertook a randomised, parallel,
double-blind clinical trial of ALA-PDT versus placeboPDT for recalcitrant foot
and hand warts. METHODS: Recalcitrant foot and hand warts were randomly assigned
to six repetitive ALA-PDT or placebo-PDT interventions combined with standard
treatment encompassing paring followed by a keratolytic (Verucid). Standardised
photographs of each wart were taken before, during (week 7) and after treatment
(weeks 14 and 18). The area of each wart compared with entry area was the primary
outcome variable, measured from photographs by an evaluator unaware of treatment
allocation for intervention. Pain intensity immediately and 24 h after each
intervention was assessed by a five-point scale. FINDINGS: A total of 232 foot
and hand warts in 45 patients were entered into the trial: 117 warts were
allocated to ALA-PDT and 115 warts to placebo-PDT. In week 14, the median
relative reduction in wart area was 98% in the ALA-PDT group (interquartile range
100%, 55%) versus 52% (100%, 0) in the placebo group (p=0.0006). In week 18, the
median relative reduction in wart area was 100% in the ALA-PDT group (100%, 57%)
versus 71% (100%, 0) in the placebo-PDT arm (p=0.008). Both the number of
vanishing warts and the difference in relative wart area of persisting warts at
week 14 and 18 were significant (p<0.05) in favour of ALA-PDT. Significantly more
ALA-PDT warts were graded at a higher pain intensity after treatment than placebo
PDT warts. INTERPRETATION: ALA-PDT is superior to placebo-PDT when both wart area
and number of vanishing warts are considered.
PMID- 10768435
TI - Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow
oleander: a randomised controlled trial.
AB - BACKGROUND: Severe cardiac glycoside cardiotoxicity after ingestion of yellow
oleander seeds is an important problem in rural areas of Sri Lanka. Currently,
patients must be transferred to the capital for temporary cardiac pacing. We did
a randomised controlled trial to investigate whether anti-digoxin Fab could
reverse serious oleander-induced arrhythmias. METHODS: After a preliminary dose
finding study, 66 patients who presented to hospital with a serious cardiac
arrhythmia were randomised to receive either 1200 mg of anti-digoxin Fab or a
saline placebo. A 12-lead electrocardiogram, 3 min rhythm strip, and blood sample
for measurement of electrolytes and cardiac glycosides were taken before
treatment and at 12 timepoints thereafter. FINDINGS: 34 patients received anti
digoxin Fab and 32 received placebo. The presenting arrhythmia had resolved
completely after 2 h in 15 antibody-treated patients and two controls (p<0.001);
24 and five patients, respectively, were in sinus rhythm at 8 h (p<0.001). Kaplan
Meier analysis of time to first reversal showed a significant response to anti
digoxin Fab. The heart rate increased in cases, from 49.1 per min at baseline to
66.8 at 2 h, but not in controls (50.6 per min at baseline to 51.5; p<0.001).
Mean serum potassium concentrations decreased from 4.9 mmol/L to 4.1 mmol/L at 2
h in cases; no such decrease occurred in controls. INTERPRETATION: Anti-digoxin
Fab fragments are a safe and effective treatment for serious cardiac arrhythmias
induced by yellow oleander. Their use in small rural hospitals in Sri Lanka
should minimise costly transfer of patients and reduce the numbers of deaths;
however, further study will be required to confirm this reduction.
PMID- 10768436
TI - An antibiotic policy to prevent emergence of resistant bacilli.
AB - BACKGROUND: Fear of infection in neonatal intensive care units (NICUs) often
leads to early use of empiric broad-spectrum antibiotics, a strategy that selects
for resistant bacteria. We investigated whether the emergence of resistant
strains could be halted by modifying the empiric antibiotic regimens to remove
the selective pressure that favours resistant bacteria. METHODS: Two identical
NICUs were assigned to different empiric antibiotic regimens. On unit A,
penicillin G and tobramycin were used for early-onset septicaemia, flucloxacillin
and tobramycin were used for late-onset septicaemia, and no broad-spectrum beta
lactam antibiotics, such as amoxicillin and cefotaxime were used. In unit B,
intravenous amoxicillin with cefotaxime was the empiric therapy. After 6 months
of the study the units exchanged regimens. Rectal and respiratory cultures were
taken on a weekly basis. FINDINGS: There were 436 admissions, divided equally
between the two regimens (218 in each). Three neonates treated with the
penicillin-tobramycin regimen became colonised with bacilli resistant to the
empirical therapy used versus 41 neonates on the amoxicillin-cefotaxime regimen
(p<.0001). The relative risk for colonisation with strains resistant to the
empirical therapy per 1000 patient days at risk was 18 times higher for the
amoxicillin-cefotaxime regimen compared with the penicillin-tobramycin regimen
(95% CI 5.6-58.0). Enterobacter cloacae was the predominant bacillus in neonates
on the amoxicillin-cefotaxime regimen, whereas Escherichia coli predominated in
neonates on the penicillin-tobramycin regimen. These colonisation patterns were
also seen when the units exchanged regimens. INTERPRETATION: Policies regarding
the empiric use of antibiotics do matter in the control of antimicrobial
resistance. A regimen avoiding amoxicillin and cefotaxime restricts the
resistance problem.
PMID- 10768437
TI - Gene expression in distinct regions of the heart.
AB - BACKGROUND: Cytochrome P450 mono-oxygenases bring about metabolism of many drugs,
including verapamil, but no information is available on the metabolism of such
drugs in the human heart. METHODS: We investigated the gene expression of major
human cytochrome P450 mono-oxygenases in the various regions of explanted hearts
from six patients with dilated cardiomyopathy and one with transposition of the
arterial trunk. For comparison we also studied samples of liver and lung from
three patients and two samples of normal heart. The biological significance of
tissue-specific cytochrome mono-oxygenase gene expression was further
investigated by study of the microsomal metabolism of verapamil in ventricular
tissue. FINDINGS: mRNA for the cytochromes 1A1, 2B6/7, 2C8-19, 2D6, and 4B1 was
predominantly expressed in the right ventricle; the unilateral expression of the
2D6 gene in right-venticular tissue is important because of its key role in the
metabolism of beta-blockers. A strong correlation between tissue-specific gene
expression and enzyme activity was found; microsomal metabolism of verapamil was
confined to the right ventricle. By contrast, cytochrome P450 3A genes (which are
the major drug-metabolising enzymes in the liver and the lung) were not expressed
in any of the human heart tissues, and mRNA transcripts for epoxide hydrolase,
cytochrome P450 2E1, and flavin-containing mono-oxygenases 2 and 5 were detected
in all regions of the human heart and the great vessels. INTERPRETATION: These
findings show that expression of genes for cytochrome P450 mono-oxygenases and
verapamil metabolism are found predominantly in the right side of the heart. This
finding may explain lack of efficacy of certain cardioselective drugs.
PMID- 10768438
TI - An unusual case of retinitis.
PMID- 10768439
TI - Waiting for coronary angiography: is there a clinically ordered queue?
AB - Among over 3000 patients undergoing coronary angiography in the absence of a
formal queue-management system, we found that a-priori urgency scores were
strongly associated with waiting times, prevalence of coronary-artery disease,
rate of revascularisation, and mortality. These data challenge the widely held
assumption that such waiting lists are not clinically ordered; however, the wide
variation in waiting times within urgency categories suggests the need for
further improvements in clinical queueing.
PMID- 10768440
TI - Imaging hypnotic paralysis: implications for conversion hysteria.
AB - In a single case study with positron emission tomography (PET) functional
imaging, hypnotic paralysis activated similar brain areas to those in conversion
hysteria, supporting the view that hypnosis and hysteria might share common
neurophysiological mechanisms.
PMID- 10768441
TI - Carbon-dioxide portography: an expanding role?
AB - We describe a new and inexpensive technique of imaging the portal vein in
patients with liver disease by use of carbon dioxide.
PMID- 10768442
TI - Infection of the fetus with hepatitis B e antigen via the placenta.
AB - Evidence that hepatitis B e antigen (HBeAg) can pass through the human placenta
has been questioned. We investigated 15 HBeAg-positive mothers who were hepatitis
B carriers and their newborn babies, and found that HBeAg does indeed cross the
human placenta.
PMID- 10768443
TI - Effect of 1997-98 El Nino on highland malaria in Tanzania.
AB - We compared the level of malaria infection in children from 22 communities in an
area of unstable transmission in the Usambara Mountains, Tanzania, immediately
before and after one of the strongest recorded El Nino southern oscillation
events. Although this event resulted in 2.4 times more rainfall than normal, we
found strikingly less malaria than in the preceding year.
PMID- 10768444
TI - Antibiotic cycling tested in nosocomial infections.
PMID- 10768445
TI - Second stories, sharp ends: dissecting medical errors.
PMID- 10768446
TI - Are Japan's medical sensei losing the public's respect?
PMID- 10768447
TI - Israelis divided over singer's AIDS secrecy.
PMID- 10768448
TI - High-dose chemotherapy for high-risk primary breast cancer: an on-site review of
the Bezwoda study.
AB - BACKGROUND: The efficacy of high-dose chemotherapy with progenitor-cell rescue
for women with breast cancer is a controversial issue. Although historically
controlled trials have suggested a survival advantage for high-dose chemotherapy,
several randomised studies have yet to confirm this advantage. Two studies,
however, by Bezwoda, of patients with high-risk and metastatic disease, seemed to
show a significant survival advantage for high-dose compared with conventional
dose chemotherapy for metastatic and high-risk primary breast cancer. METHODS: To
corroborate the study results before starting a large international confirmatory
study, a US team did an on-site review of records for patients in the high-risk
study. Limited numbers of records were made available for review, all of which
were for patients who received the high-dose-chemotherapy regimen. FINDINGS:
There was much disparity between the reviewed records and the data presented at
two international meetings. In addition, the reviewers saw no signed informed
consent, and the institutional review committee had no record of approval for the
investigational therapy. After the site visit, Bezwoda admitted scientific
misconduct by using a different control chemotherapy regimen from that described
in presented data. INTERPRETATION: The Bezwoda study should not be used as the
basis for further trials to test the efficacy of the cyclophosphamide,
mitoxantrone, etoposide regimen for high-dose chemotherapy in women with high
risk primary breast cancer. This review validates the essential nature of on-site
audits, especially in single-institution studies.
PMID- 10768449
TI - Mortality rates after surgery for congenital heart defects in children and
surgeons' performance.
AB - BACKGROUND: A public inquiry into surgery for paediatric congenital heart defects
in Bristol, UK, underscored the need for reliable data on overall mortality
rates, which would allow assessment of individual surgeons' performance. We aimed
to gather and report such data for 1 year to provide information for clinicians,
researchers, policy makers, and the general public. METHODS: We collected data on
all operations (1378) for congenital heart defects done by 11 surgeons in five
departments in the UK between April 1, 1997, and March 31, 1998. These operations
represented about 36% of all operations done in the UK during that time. Clearly
defined criteria were agreed to classify operations into subgroups. FINDINGS: The
overall mortality rate for all operations was 4.0% (95% CI 3.0-5.2). No deaths
occurred for 67 arterial-switch operations. Mortality rates for coarctation,
ventricular septal defect, atrioventricular septal defect, Fallot, and truncus
arteriosus operations were 1.1%, 0.6%, 3.6%, 2.3%, and 28.6%, respectively.
Although overall mortality rates between surgeons varied (1.6-6.9%), no surgeon's
were higher than the 95% CI. The numbers of operations done by individual
surgeons were small, which led to wide confidence intervals and made the
detection of differences in performance difficult. INTERPRETATION: The
participating departments seemed to reach high standards of care for children
with congenital heart defects, although more data would be needed to assess
performance of individual surgeons. The development of quality standards will be
difficult because of the complexity of defects, the different types of
operations, and few patients in each subgroup. Collection of larger sets of data
for more patients and centres are needed.
PMID- 10768450
TI - Thiazolidinediones: an update.
AB - Thiazolidinediones, which are being developed for the treatment of insulin
resistance and type 2 diabetes mellitus, bind and activate peroxisome
proliferator-activated receptor gamma, a nuclear receptor that regulates the
expression of several genes involved in metabolism. This receptor controls
adipocyte differentation, lipid storage, and insulin sensitisation. Besides
metabolic activities, thiazolidinediones have effects as diverse as the control
of host defence, cell proliferation, and tumorigenesis.
PMID- 10768451
TI - Scientific misconduct in a breast-cancer chemotherapy trial: response of
University of the Witwatersrand.
PMID- 10768452
TI - Semirecumbent position in intensive care patients.
PMID- 10768453
TI - Semirecumbent position in intensive care patients.
PMID- 10768454
TI - Semirecumbent position in intensive care patients.
PMID- 10768455
TI - Semirecumbent position in intensive care patients.
PMID- 10768456
TI - Prophylaxis against respiratory syncytial virus in premature infants. IMpact-RSV
Study Group.
PMID- 10768457
TI - Olfactory dysfunction in Alzheimer's disease.
PMID- 10768458
TI - Olfactory dysfunction in Alzheimer's disease.
PMID- 10768459
TI - Meningococcal vaccine and herd immunity.
PMID- 10768460
TI - Meningococcal vaccine and herd immunity.
PMID- 10768461
TI - Meningococcal vaccine and herd immunity.
PMID- 10768462
TI - Gail model and breast cancer.
PMID- 10768463
TI - Prenatal diagnosis of acute lymphoblastic leukaemia.
PMID- 10768464
TI - Mild cognitive impairment: further caution.
PMID- 10768465
TI - Cognitive impairment in temporal-lobe epilepsy.
PMID- 10768466
TI - Herb-drug interactions.
PMID- 10768467
TI - Medical evacuations from former Yugoslav Republic of Macedonia.
PMID- 10768468
TI - Dull journals.
PMID- 10768469
TI - The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude Elion (1918
99), and George H Hitchings (1905-98).
PMID- 10768470
TI - Microbiology of petroleum reservoirs.
AB - Although the importance of bacterial activities in oil reservoirs was recognized
a long time ago, our knowledge of the nature and diversity of bacteria growing in
these ecosystems is still poor, and their metabolic activities in situ largely
ignored. This paper reviews our current knowledge about these bacteria and
emphasises the importance of the petrochemical and geochemical characteristics in
understanding their presence in such environments.
PMID- 10768471
TI - Molecular ecology of hydrothermal vent microbial communities.
AB - The study of the structure and diversity of hydrothermal vent microbial
communities has long been restricted to the morphological description of
microorganisms and the use of enrichment culture-based techniques. Until recently
the identification of the culturable fraction required the isolation of pure
cultures followed by testing for multiple physiological and biochemical traits.
However, peculiar inhabitants of the hydrothermal ecosystem such as the
invertebrate endosymbionts and the dense microbial mat filaments have eluded
laboratory cultivation. Substantial progress has been achieved in recent years in
techniques for the identification of microorganisms in natural environments.
Application of molecular approaches has revealed the existence of unique and
previously unrecognized microorganisms. These have provided fresh insight into
the ecology, diversity and evolution of mesophilic and thermophilic microbial
communities from the deep-sea hydrothermal ecosystem. This review reports the
main discoveries made through the introduction of these powerful techniques in
the study of deep-sea hydrothermal vent microbiology.
PMID- 10768472
TI - Marine pharmacology.
AB - Marine organisms have provided a large proportion of the bioactive natural
products reported over the last 20 years, but none of these compounds have
reached the pharmaceutical marketplace. This review describes current progress in
the development of a selection of new antiinflammatory and anticancer agents,
discusses some difficulties encountered during the development process and
suggests how these difficulties may be overcome in the near future through
applications of recent advances in biotechnology.
PMID- 10768473
TI - Antimicrobial resistance among urinary tract infection (UTI) isolates in Europe:
results from the SENTRY Antimicrobial Surveillance Program 1997.
AB - The SENTRY Antimicrobial Surveillance Program was established to monitor the
occurrence and antimicrobial susceptibility of bacterial pathogens via an
international network of sentinel hospitals. Twenty European hospitals referred a
total of 887 urinary tract infection (UTI) isolates to the European SENTRY
reference laboratory during the period October-December 1997. Ninety percent of
the referred species were represented by Escherichia coli (52%), Enterococcus
spp. (12%), Klebsiella spp. (7%), Proteus spp. (7%), Pseudomonas aeruginosa (7%),
and Enterobacter spp. (5%). The susceptibility of E. coli isolates to penicillins
was less than 60%, while almost all of the isolates were susceptible to
piperacillin/tazobactam (98% susceptibility), cephalosporins (98%), and
carbapenems (100%). Amikacin was the best aminoglycoside (99.8% susceptibility).
The susceptibility to quinolones was only 88-89%, with highest levels of
resistance observed for isolates from Portugal, Italy, England, The Netherlands,
and some centers in France, Spain, and Poland. The susceptibility of Klebsiella
spp. to the newer generations of cephalosporins was 82-95% and to the carbapenems
100%. Amikacin was again the best aminoglycoside (94% susceptibility). The
susceptibility of Enterobacter spp. to any beta-lactam antibiotic was poor,
except for the carbapenems (100% susceptibility) and cefepime (90%
susceptibility), while the susceptibility to aminoglycosides was 80-89%. Proteus
spp. showed complete susceptibility to cefepime, ceftriaxone, the carbapenems,
and piperacillin/tazobactam, while the susceptibility of P. aeruginosa isolates
was poor, with best results for the carbapenems (susceptibility 89%),
piperacillin/tazobactam (susceptibility 84%), and amikacin and ticarcillin
(susceptibility to both 80%). Enterococcus spp. showed the highest susceptibility
to vancomycin (98%), teicoplanin (98%), and ampicillin (94%).
PMID- 10768474
TI - Cryptococcus adeliensis sp. nov., a xylanase producing basidiomycetous yeast from
Antarctica.
AB - Cryptococcus adeliensis sp. nov. (CBS 8351) is described based on phenotypic
characteristics and molecular sequence analysis of the D1/D2 large subunit and
internal transcribed spacer regions of the ribosomal DNA. Molecular comparisons
include species closely related to Cryptococcus albidus and several species
isolated from the Antarctic. C. adeliensis, which has a cold-adapted xylanase,
was isolated from Terre Adelie, Antarctica. ATCC 34633, which has a mesophilic
xylanase, was identified as Cryptococcus albidosimilis.
PMID- 10768475
TI - Reclassification of Pichia membranifaciens sensu Kurtzman.
AB - Forty strains which were stocked as Pichia membranifaciens sensu Kurtzman and 9
strains stocked as Candida valida, anamorphs of P. membranifaciens, in the
Institute for Fermentation, Osaka (IFO) were reclassified based on the data of
base composition of nuclear DNA, DNA/DNA hybridization, coenzyme Q system,
electrophoretic karyotype, and base sequence of 18S rDNA. P. membranifaciens
complex was assigned into 3 groups: (I) P. membranifaciens group, including 25
strains with high DNA homologies to the type strain of P. membranifaciens (72
98%); (II) P. manshurica group, including 18 strains with high DNA homology of 79
95% to the type strain of P. manshurica; and a group including the remaining 6
strains, which had low DNA homology to the above two species. GC content was 42.9
45.3 mol% for the P. membranifaciens group, 40.0-42.0 mol% for the P. manshurica
group, and 27.2-44.7 mol% for the remaining group. All three groups had
ubiquinone Co Q-7. Of the 6 anomalous strains, IFO 0162 was identified as Pichia
deserticola, and IFO 0839 and IFO 0840 were identified as Issatchenkia
occidentalis; but IFO 0842, IFO 0843, and IFO 1788 were thought to be unknown
strains.
PMID- 10768476
TI - Density gradient separation of active and non-active cells from natural
environments.
AB - We present a method for the selective, physical separation of active and non
active bacterial cells from natural communities. The method exploits the
reduction of tetrazolium salts to form insoluble formazan crystals
intracellularly in response to the addition of different oxidisable substrates.
The intracellular deposition of formazan alters the bouyant density of active
cells enabling them to be separated by density gradient centrifugation. The
method has been successfully applied to the fractionation and collection of large
whole cell sub-populations of active and non-active cells from sea-water samples.
Removal of the bands from the density gradient, followed by PCR amplification and
DGGE analyses showed distinct differences in the PCR amplicon diversity
associated with the active and non-active cell fractions; an indication of
changes in bacterial community structure in response to the addition of
oxidisable substrate. Thus, based on their in situ respiration potential, the
approach enables the cytochemical enrichment and molecular characterisation of
mixed bacterial populations in natural environments.
PMID- 10768477
TI - Ubiquinone systems in fungi. V. Distribution and taxonomic implications of
ubiquinones in Eurotiales, Onygenales and the related plectomycete genera, except
for Aspergillus, Paecilomyces, Penicillium, and their related teleomorphs.
AB - The ubiquinone (coenzyme Q) systems were determined for 176 teleomorphic
isolates, 14 anamorphic isolates, and three samples of fruit-bodies of
Dendrosphaera eberhardtii, which belonged to Eurotiales, Onygenales, and related
taxa. In Eurotiales, Ascosphaera had Q-9, whereas Bettsia had Q-10. All isolates
of Monascaceae had the Q-10 system, whereas those of four genera of
Pseudeurotiaceae had the Q-10(H2) system. The Q-10(H2) system was found in genera
of Trichocomaceae, except for Aspergillus, Penicillium, Paecilomyces, and their
related taxa. However, Thermoascus had the Q-9 system. In Onygenales, members of
Arthrodermataceae had Q-9, and those of Gymnoascaceae had Q-10(H2). Isolates of
Myxotrichaceae were characterized by Q-10(H2) with few exceptions, which had Q
10. The quinones of Onygenaceae belonged to complex systems, i.e., Q-9, 0-10 and
0-10(H2), and a combination of two systems. Families Onygenaceae and
Trichocomaceae are likely a phylogenetic heterogeneity. Ubiquinone analysis
provides a very useful criterion of great promise for classifying eurotialean
taxa and also for identifying their isolates.
PMID- 10768478
TI - Thiobacillus ferrooxidans response to copper and other heavy metals: growth,
protein synthesis and protein phosphorylation.
AB - Respirometric experiments demonstrated that the oxygen uptake by Thiobacillus
ferrooxidans strain LR was not inhibited in the presence of 200 mM copper. Copper
treated and untreated cells from this T. ferrooxidans strain were used in growth
experiments in the presence of cadmium, copper, nickel and zinc. Growth in the
presence of copper was improved by the copper-treated cells. However, no growth
was observed for these cells, within 190 h of culture, when cadmium, nickel and
zinc were added to the media. Changes in the total protein synthesis pattern were
detected by two-dimensional polyacrylamide gel electrophoresis for T.
ferrooxidans LR cells grown in the presence of different heavy metals. Specific
proteins were induced by copper (16, 28 and 42 kDa) and cadmium (66 kDa), whereas
proteins that had their synthesis repressed were observed for all the heavy
metals tested. Protein induction was also observed in the cytosolic and membrane
fractions from T. ferrooxidans LR cells grown in the presence of copper. The
level of protein phosphorylation was increased in the presence of this metal.
PMID- 10768479
TI - Dynamic surface tension and adsorption mechanisms of surfactants at the air-water
interface.
AB - Recent advances in understanding dynamic surface tensions (DSTs) of surfactant
solutions are discussed. For pre-CMC solutions of non-ionic surfactants,
theoretical models and experimental evidence for a mixed diffusion-kinetic
adsorption mechanism are covered. For micellar solutions of non-ionics, up to
approximately 100 x CMC, the DST behaviour can also be accounted for using a
mixed mechanism model. Finally, the first reported measurements of the dynamic
surface excess Gamma(t), using the overflowing cylinder in conjunction with
neutron reflection, are described.
PMID- 10768480
TI - Capillary interactions between particles bound to interfaces, liquid films and
biomembranes.
AB - This article is devoted to an overview, comparison and discussion of recent
results (both theoretical and experimental) about lateral capillary forces. They
appear when the contact of particles or other bodies with a fluid phase boundary
causes perturbations in the interfacial shape. The capillary interaction is due
to the overlap of such perturbations which can appear around floating particles,
vertical cylinders, particles confined in a liquid film, inclusions in the
membranes of lipid vesicles or living cells, etc. In the case of floating
particles the perturbations are due to the particle weight; in this case the
force decreases with the sixth power of the particle size and becomes immaterial
for particles smaller than approximately 10 microm. In all other cases the
interfacial deformations are due to the particle wetting properties; the
resulting 'immersion' capillary forces can be operative even between very small
particles, like protein globules. In many cases such forces can be responsible
for the experimentally observed two-dimensional particle aggregation and
ordering. An analogy between capillary and electrostatic forces enables one to
introduce 'capillary charges' of the attached particles, which characterize the
magnitude of the interfacial deformation and could be both positive and negative.
Moreover, the capillary interaction between particle and wall resembles the image
force in electrostatics. When a particle is moving bound to an interface under
the action of a capillary force, one can determine the surface drag coefficient
and the surface viscosity supposedly the magnitude of the capillary force is
known. Alternative (but equivalent) energy and force approaches can be used for
the theoretical description of the lateral capillary interactions. Both
approaches require the Laplace equation of capillarity to be solved and the
meniscus profile around the particles to be determined. The energy approach
accounts for contributions due to the increase of the meniscus area,
gravitational energy and/or energy of wetting. The second approach is based on
calculating the net force exerted on the particle, which can originate from the
hydrostatic pressure, interfacial tension and bending moment. In the case of
small perturbations, the superposition approximation can be used to derive an
asymptotic formula for the capillary forces, which has been found to agree well
with the experiment. Capillary interactions between particles bound to spherical
interfaces are also considered taking into account the special geometry and
restricted area of such phase boundaries. A similar approach can be applied to
quantify the forces between inclusions (transmembrane proteins) in lipid
membranes. The deformations in a lipid membrane, due to the inclusions, can be
described theoretically in the framework of a mechanical model of the lipid
bilayer, which accounts for its 'hybrid' rheology (neither elastic body nor
fluid). In all considered cases the lateral capillary interaction originates from
the overlap of interfacial deformations and is subject to a unified theoretical
treatment, despite the fact that the characteristic particle size can vary from 1
cm down to 1 nm.
PMID- 10768481
TI - Dielectric exclusion of ions from membranes.
AB - Dielectric exclusion is caused by the interactions of ions with the bound
electric charges induced by ions at interfaces between media of different
dielectric constants. It is considered as one of mechanisms of nanofiltration.
The transport properties of capillary model are expressed through ion
distribution and diffusion coefficients. Due to local equilibrium the
distribution coefficient is directly related to the excess solvation energy of
ion. First, this energy is considered for single ions in single neutral pores in
terms of pore size, ion charge, dielectric constants of solvent and membrane
matrix and pore geometry. The dielectric exclusion from pores with closed
geometry like circular cylinders is shown to be essentially stronger than that
from pores with relatively open geometry like slits. Furthermore, the role of
finite membrane porosity is analysed for the model of infinite slabs with
alternating dielectric constants. The presence of other ions is accounted for
within the scope of a mean-field approach, and the screening of dielectric
exclusion is thus introduced and considered in some detail. A fixed electric
charge is shown to cause additional screening. At the same time the dielectric
exclusion makes the Donnan exclusion of ions stronger. Therefore the interaction
between those two rejection mechanisms turns out to be non-trivial. Finally, the
effect of solvent molecular structure is considered within the scope of non-local
electrostatics. It is shown that the solvent non-locality typically results in
somewhat stronger dielectric exclusion, however, its most important effect is
slowing down the decline of dielectric exclusion with increasing bulk electrolyte
concentration.
PMID- 10768482
TI - Particle-bubble collision models--a review
AB - A critical review of the various models existing in the literature for the
calculation of the collision efficiency between particles and single, rising gas
bubbles is presented. Although all of these collision models predict that the
collision efficiency increases with particle size, their dependence on the latter
is different because of the various assumptions and hydrodynamic conditions used
in each model. Collision efficiencies of quartz particles with single bubbles
have been obtained from experimental flotation experiments under conditions where
the attachment and stability efficiencies were at, or near, unity. These
collision efficiencies were then used to test various collision models. Good
agreement between the experimental and calculated collision efficiencies was only
obtained with the Generalised Sutherland Equation. The differences in collision
efficiencies obtained between the various models were mainly explained in terms
of, firstly, the degree of mobility of the bubble surface and, secondly, a
consideration of the inertial forces acting on the particles.
PMID- 10768483
TI - Membrane-induced conformational change of proteins.
AB - Many proteins exhibit both a water-soluble and a membrane-bound state. The
proteins in the membrane-bound state obtain a distinct structure from that in the
bulk, which exists in many important biological processes. In the present paper
we would stress that the variation of the physical chemistry properties of the
microenvironment adjacent to the membrane-surface region play an important role
in the process of the membrane-induced conformational changes of the proteins.
PMID- 10768484
TI - Nonpigment components of the photochlorophyllide photoactive complex: studies of
low-temperature blue-green fluorescence spectra.
AB - Fluorescence spectra in the blue-green region and excitation fluorescence spectra
of green wheat leaves, etiolated wheat leaves and isolated inner etioplast
membranes (prolamellar bodies and prothylakoids) were compared to specify the
structure of the active protochlorophyllide pigment-protein complex of inner
etioplast membranes. Three bands in the blue region at 420, 443 and 470 nm and a
broader green band at 525 nm were found. Comparison of the emission and
excitation spectra suggests that the main components responsible for the blue
fluorescence of etioplast inner membranes are pyridine nucleotides and pterins.
The green fluorescence (525 nm) excitation spectra of etiolated samples were
identical to the excitation spectrum of flavin fluorescence. The fact confirms
the suggestion that flavins are the constituents of the active
protochlorophyllide-protein complex.
PMID- 10768485
TI - Correlation between the oscillatory and adhesion activities in erythroid cells.
AB - The attachment kinetics of erythroid cells, such as human erythrocytes, their
saponin ghosts, and erythroleukemic cells K562 to a glass surface has been
studied in the presence of substances inhibiting spontaneous fluctuations of cell
membranes. It has been shown that wheat germ agglutinin (WGA) slows down the
attachment kinetics of K562 cells, as is the case in intact erythrocytes.
Concanavalin A (Con A), which inhibits the attachment of erythrocytes to glass
does not affect the adhesion of K562 cells to glass due to the absence of band 3
proteins in the membranes of K562 cells. Both lectins slow down the adhesion rate
of saponin ghosts of human erythrocytes, as it takes place in intact
erythrocytes. Suramin and the anionic dye ANS bind specifically to the actin
protofilaments of the erythrocyte skeleton and also inhibit cell adhesion to
glass. At the same time, these substances do not affect the oscillatory and
adhesion activities of intact erythrocytes due to the impermeability of
erythrocyte membranes for these drugs. The results obtained allow the conclusion
that inhibition of erythrocyte adhesion by lectins is due to lectin binding to
different constituents of the erythrocyte membrane--sialic acid moieties of
glycophorin in the case of WGA and band 3 proteins in the case of Con A. The most
probable mechanism of erythrocyte and K562 cell attachment to glass is the
formation of the so-called local contacts between cells and the glass surface. It
is also suggested that the cell surface oscillations facilitate the formation of
cell contacts.
PMID- 10768486
TI - Mechanism of action of calcium ionophores on intact cells: ionophore-resistant
cells.
AB - Calcium ionophores are generally assumed to directly facilitate the transport of
Ca2+ across the plasma membrane. The ability of Ca2+ ionophores ionomycin and
A23187 to increase Ca2+ concentration in the cytosol ([Ca2+]i) in different cells
was analyzed in detail using fluorescent Ca2+ probes. In fura-2-loaded cells, the
dependence of the level of [Ca2+]i on ionomycin and A23187 concentrations had a
complex character and could not be explained by ionophoric properties only. The
Ca2+ signal induced by the Ca2+ ionophores consisted of three components. The
first component was due to the activation of Ca2+ influx through native Ca2+
channels and was sensitive to drugs which inhibited the receptor-operated Ca2+
influx. The second component originated from phospholipase C-dependent
mobilization of Ca2+ from intracellular stores. An additional influx of Ca2+ into
the cells was activated in this case by a store-regulated mechanism. The third
ionophoric component was very small at low concentrations of the ionophores. The
effect of the ionophores on Ca2+ influx and Ca2+ mobilization was demonstrated on
different cells such as Ehrlich ascites tumour cells, murine peritoneal
neutrophils, macrophages, and T-lymphocytes. Thymocytes, neutrophils, and Ehrlich
ascites tumour cells were more sensitive to the Ca2+ ionophores. Memory T-cells
and brown preadipocytes were ionophore-resistant. The insensitivity to Ca2+
ionophores correlated with the absence of Ca2+ in the intracellular Ca2+ stores
and the low activity of plasma membrane store-regulated Ca2+ channels.
PMID- 10768487
TI - Effect of bilirubin on the activity and thermokinetic characteristics of brain
(synaptosomal) membrane NO synthase.
AB - NO synthase activity was found in the plasma (synaptosomal) membrane particles
isolated from the homogenate of adult rat brain (without cerebellum) under
conditions preventing the protease attack and formation of reactive oxygen
species. The NO synthase discovered exhibited some properties of a neuronal
constitutive integral membrane enzyme and was inhibited by N-nitro-L-arginine. NO
synthase activity decreased when bilirubin entered the synaptosomal membrane in
vitro. Bilirubin caused the shift of the transition temperature in the
temperature dependence of NO synthase activity in Arrhenius plots. The
incorporation of bilirubin into synaptosomal membranes resulted in an increase in
the apparent activation energy for NO synthase within a temperature range of 10
30 degrees C. The membrane NO synthase was susceptible to the photodynamic effect
of membrane-bound bilirubin molecules. Monomeric human serum albumin without
organophilic ligands exerted a protective effect on NO synthase in bilirubin
containing membrane particles.
PMID- 10768488
TI - Effects of meconic and comenic acids on slow sodium channels of secondary
neurons.
AB - Effects of comenic and meconic acids on cultured dorsal root ganglion cells were
investigated by the whole-cell patch clamp technique. The acids, having a well
known antiinflammatory and antibacterial action, decreased effective charge
transfer in the activation gating system of TTX-resistant (slow) sodium channels
in a dose-dependent manner. The effects were described by Hill's equation. The
dissociation constant and Hill coefficient values were K(D) = 100 nM and X = 0.5
(for comenic acid) and K(D) = 10 nM and X = 0.34 (for meconic acid). The
nonspecific antagonist of opioid receptors naltrexone totally blocked the
effects. We suggest that the acids studied activate a subpopulation of opioid
receptors negatively coupled to TTXr sodium channels.
PMID- 10768490
TI - Structural and functional properties of Langmuir films of antibodies based on
amphiphilic polyelectrolytes.
AB - We optimized the procedure for the formation of Langmuir films of antibodies
based on amphiphilic polyelectrolytes and studied the physicochemical and
immunochemical properties of the films obtained. Their immunochemical properties
were compared with the immunochemical activity of antibodies in Langmuir films
without amphiphilic polyelectrolytes and with antibodies adsorbed on the surface
of polystyrene and graphite. The efficiency of immune adsorption by the films
based on amphiphilic polyelectrolytes was shown to be greater; the affinity of
antibodies and surface concentration of their active conformation depended on the
type of amphiphilic polyelectrolytes used to obtain the films. We investigated
the structure of these films at the surface of highly oriented pyrolytic graphite
using the method of atomic force microscopy. Changes in the structure of the
films under study caused by the increase of surface pressure were demonstrated.
PMID- 10768489
TI - The mechanism of potentiation of the glutamate-induced neurotoxicity by serum
albumin. A possible role of nitric oxide.
AB - Potentiation of the delayed (Glu)-induced neurotoxicity by serum albumin (SA) was
studied in experiments with cultured cerebellar granule cells. The delayed
neuronal death (DND) was evaluated by counting neurons containing or excluding
Trypan Blue 4 h after treatment with Glu. Cytoplasmic Ca2+ ([Ca2+]i) was measured
in individual Fura-2-loaded neurons. It was shown that a 15-min application of
bovine SA (4 mg/ml) together with Glu (100 microM, 10 microM glycine, Mg2+-free
solution) enhanced DND in the culture 1.7 times (43.1+/-3.1%) with respect to the
effect induced by Glu alone (24.6+/-0.6%). The bovine SA application did not
change the dynamics of [Ca2+]i response during a short-term (1 min) and long-term
(15 min) Glu-treatment. DND was prevented by simultaneous application of Glu and
inhibitor of NO-synthase N omega-nitro-L-arginine methyl ester (L-NAME), 100
microM) (10.8+/-1.0%) as well as by the application of Glu with SA and L-NAME
(9.8+/-1.2%). In order to evaluate the role of nitric oxide (NO) in the SA
effect, the cells were incubated for 15 min with the NO-donors sodium
nitroprusside (SNP, 10 and 100 microM) and sodium nitrite (NaNO2, 10 and 100
microM) together with SA and in its absence. SA also greatly enhanced the DND
induced by SNP and NaNO2. Thus, the DND after simultaneous treatment with SA and
SNP was 16.3+/-2.5% (10 microM) or 29.6+/-2.1% (100 microM), and 9.6+/-0.8% (10
microM) and 19.7+/-2.1% after treatment with SNP alone. Exposure to SA together
with NaNO2 led to the DND increase up to 26.5+/-1.9% (10 microM) and 37.7+/-3.5%
(100 microM) in comparison with 7.4+/-2.0% (10 microM) and 18.9+/-0.8% (100
microM) in experiments with NaNO2 alone. Taking into account the ability of NO
and NO2 to oxidize unsaturated fatty acids and the ability of SA to bind them
after their hydrolytic removal, we suggested that the SA-induced potentiation of
Glu neurotoxicity resulted from exacerbation of the toxic effects of NO and other
trace radicals on the neuronal membranes. This hypothesis was supported by the
finding that SA also enhanced the neurotoxicity of the lipid prooxidant FeCl2.
The simultaneous 15-min application of FeCl2 (10 microM) and SA caused a 51.5+/
4.0% increase in DND, which exceeded 2.4 times the effect produced by FeCl2 alone
(21.3+/-2.3%).
PMID- 10768491
TI - Two phases of gramicidin photoinactivation in bilayer lipid membranes in the
presence of a photosensitizer.
AB - The kinetics of the light-induced decrease in the gramicidin-mediated current
across a bilayer lipid membrane in the presence of a photosensitizer has been
shown to include a slow phase with a characteristic time of the order of 1 s and
a fast phase. Based on the dependence of the slow phase relative amplitude and
characteristic time on the gramicidin-mediated stationary conductance we
concluded that the slow phase reflected the establishment of an equilibrium
between gramicidin monomers and dimers in the membrane after the distortion of
this equilibrium resulting from modification of a portion of gramicidin molecules
by reactive oxygen species generated upon excitation of the photosensitizer. The
dependence of the fast phase contribution to the overall kinetics on the
stationary conductance allowed us to conclude that the fast phase is associated
with transition of gramicidin dimers into a nonconducting state. The
characteristic time of the fast phase measured with nanosecond laser excited
pulses is 1.5 ms. The slow phase of the decrease in the gramicidin-mediated
current was considerably decelerated in the presence of Rose Bengal. The results
obtained indicate that adsorption of Rose Bengal on the bilayer interface leads
to a reduction of the dipole potential drop at the membrane-solution boundary,
similarly to the action of phloretin.
PMID- 10768492
TI - Mathematical analysis of the effects of geometric parameters and mechanical
properties of erythrocytes on the filterability of nonuniform suspensions.
AB - Approaches to determination of the pattern of erythrocytes distribution with
regard to the rates of their passage through pores (3 microm in diameter) of a
membrane filter by processing the data on changes in the flow rates of
erythrocyte suspensions with time (filtration curves) are discussed. We
considered the case when the suspension consisted of two subpopulations of
erythrocytes differing in a single parameter. Using a model describing the
erythrocyte passage through a pore and a model describing filtration of a
nonuniform suspension, we analyzed the dependences of filtration kinetics of such
suspensions on the relative contents of the subpopulations and their rheological
characteristics. It has been shown that the filtration rates of the major
subpopulation and the minor abnormal subpopulation, and their relative contents
can be determined from the analysis of filtration curves. This can be done when
the filtration rate of cells from the minor subpopulation is at least one order
of magnitude lower than the filtration rate of cells from the major
subpopulation. Thus we can register the presence of the minor subpopulation in
the range of 0.5-1%. If filtration rates are recorded at different osmolalities,
their analysis makes it possible to determine the surface area, intracellular
viscosity, and membrane rigidity of cells of the major subpopulation and, in
certain cases, the same parameters for the cells of the minor subpopulation.
PMID- 10768493
TI - On the influence of pigment-protein interactions on the energy transfer processes
in photosynthetic membrane structures. 2. LH2 complex of Rhodobacter sphaeroides.
AB - Low-temperature heterogeneous absorption and circular dichroism spectra of the
Rb. sphaeroides LH2 complexes are calculated within the framework of the mini
exciton theory and diagonal static random disorder for the pure electronic
transitions of the monomeric Bchl molecules. The coupling of Bchl molecules with
the surrounding amino acid residues has been shown to change both the exciton
distribution between the pigment molecules in each of the exciton states. The
value of the delocalization index depends on the excitation wavelength and varies
between 2-6 Bchl molecules. The optical transitions occurring at 780-790 and 820
nm have been found to be strongly mixed so that all Bchl molecules of the LH2
complex predetermine absorption in these spectral regions. On the other hand,
absorption at 800 and 850 nm is mainly determined by the cycles of 9 and 18 Bchl
molecules, respectively. Thus, the light energy absorbed by the B800 molecules at
800 nm is transferred to the B850 molecules by the interlevel exciton relaxation
processes due to the population of the heavily mixed 820-nm exciton levels. The
width of the heterogeneous absorption band for the cyclic monomeric aggregate has
been shown to decrease as compared with the monomeric absorption band by square
root(Ndel) time, where Ndel is the mean number of pigments over which the exciton
is delocalized within the excited absorption band.
PMID- 10768494
TI - Determination of mobile phase effect on single-component adsorption isotherm by
use of numerical estimation.
AB - Numerical estimation was used to determine adsorption isotherm parameters of a
single-component in a normal-phase system. The distribution isotherm of methyl
deoxycholate was described between the mobile phase containing hexane, ethyl
acetate, methanol with varied concentration and a silica gel adsorbent. The
effect of the mobile phase composition on the isotherm parameters and the band
profiles was investigated. The results obtained were used to simulate the
overload gradient elution. The validity of the method proposed was verified by
comparison of the computer simulations with the experimental band profiles.
PMID- 10768495
TI - Screening for limonoid glucosides in Citrus tangerina (Tanaka) Tseng by high
performance liquid chromatography-electrospray ionization mass spectrometry.
AB - A screening method for limonoid glucosides in the peel of Citrus tangerina
(Tanaka) Tseng, which utilizes high-performance liquid chromatography (HPLC) with
diode-array detection and interfaced to electrospray ionization mass
spectrometry, has been developed. In this way, the UV-Vis spectra and the mass
spectra indicate the presence of limonoid glucosides without the necessity of
isolating the individual compounds. Two major limonoid glucosides--obacunone
glucoside (OG) and nomilin glucoside (NG)--were identified in the methanol
extract of the peel. The two limonoid glucosides were taken as the target and
isolated by means of preparative HPLC on a C18 reversed-phase column with an
acidic acetonitrile-water mobile phase. The structures of OG and NG were further
confirmed by nuclear magnetic resonance spectrometry.
PMID- 10768496
TI - Chromatographic resolution of tryptophan enantiomers with L-Leu-L-Leu-L-Leu
peptide effects of mobile phase composition and chromatographic support.
AB - Tryptophan enantiomers have been separated by zwitterion pair chromatography
using L-leucine-L-leucine-L-leucine peptide as the zwitterion pairing agent. The
peptide ligand is adsorbed onto an octadecylsilane support with excess ligand
present in bulk solution. This article examines the roles of the hydrophobic
matrix and the mobile phase components on tryptophan enantiomer binding and
resolution. Capacity factors and enantioselectivites are given for both
hydrophobic and hydrophilic matrices using mobile phases containing Leu-Leu-Leu
peptide and/or salt. A decrease in selectivity upon the addition of mobile phase
salt suggests that quadrupolar ion-pairing contributes to chiral recognition.
Results indicate that binding is significantly reduced and separation is not
achieved when Leu-Leu-Leu is coupled onto cross-linked or polymerized hydrophilic
resins as well as onto macroporous polystyrene resin. However, resin-immobilized
Leu-Leu-Asp-Leu-Leu-Leu, Leu-Leu-Glu-Leu-Leu-Leu, and Leu-Leu-Leu-Glu-Leu-Leu
peptides, with ion-pairing sites designed to mimic the Leu-Leu-Leu-saturated C18
support, also do not resolve tryptophan enantiomers. This suggests the Leu-Leu
Leu structure is critical for enantiomer resolution. Because D- and L-tryptophan
are separated in the absence of bulk Leu-Leu-Leu, chiral discrimination is
believed to occur at the surface of the octadecylsilane support.
PMID- 10768497
TI - Immobilised metal affinity chromatography of beta-galactosidase from unclarified
Escherichia coli homogenates using expanded bed adsorption.
AB - The development of an expanded bed process for the direct extraction and partial
purification of beta-galactosidase from unclarified Escherichia coli homogenates
using its natural affinity for metal loaded STREAMLINE Chelating is described.
Small packed beds were used to determine the effect of chelated metal ion (Cu2+,
Ni2+, Co2+ or Zn2+), loading pH and ionic strength on the selective binding
capacity, and recovery of beta-galactosidase from clarified homogenates. An
elution protocol was developed using the competitive displacer, imidazole, to
recover beta-galactosidase in 87% yield and 3.4-fold purification. These results
were then used to develop a separation for the recovery of beta-galactosidase
from unclarified homogenates in a 2.5-cm diameter expanded bed. Although Ni2+
loaded STREAMLINE Chelating had a 5% dynamic capacity for beta-galactosidase of
just 118 U ml(-1) (0.39 mg ml(-1)), the low capacity was thought to be due to the
large size of the target (464,000) relative to the exclusion limit of the
macroporous adsorbent. Despite this low capacity, Ni2 STREAMLINE Chelating was
used successfully to recover beta-galactosidase from an unclarified homogenate in
86.4% yield and at 5.95-fold purification. The degree of purification relative to
a commercial standard, as assessed using the purification factor and sodium
dodecyl sulphate-polyacrylamide gel electrophoresis was high suggesting that this
pseudo-affinity procedure compared favourably with alternative methods.
PMID- 10768498
TI - Separation of purines and pyrimidines by normal-phase high-performance liquid
chromatography using dimethyl sulfoxide in binary and ternary eluents.
AB - Chromatographic systems with a silica sorbent and mobile phases containing
dimethyl sulfoxide have been studied. It has been established that the
substitution of isopropanol by dimethyl sulfoxide in binary eluents results in a
specific selectivity of the chromatographic system and shows an improvement of
the peak shape for the solutes under study. When mobile phases consisting of
hexane, isopropanol and dimethyl sulfoxide (solvents with a limited mutual
solubility) are used, changes in retention characteristics and peak symmetry are
caused by a transition from adsorption to partition sorption mechanism. The
stationary liquid phase is generated dynamically in the pores of silica, even in
the mobile phases not saturated with a polar component. If the phase ratio of the
column reaches 0.1, partition dominates over adsorption and such mixed partition
adsorption (MPA) systems show very good peak symmetry for the solutes under
study. The investigation has shown that dimethyl sulfoxide-containing MPA systems
are applicable in analytical practice.
PMID- 10768499
TI - Speciation of selenium compounds with ion-pair reversed-phase liquid
chromatography using inductively coupled plasma mass spectrometry as element
specific detection.
AB - For selenium speciation analysis, the hyphenation of chromatographic separation
with element-specific detection has proved a useful technique. A powerful
separation system, which is capable of resolving several biologically and
environmentally important selenium compounds in a single column, is greatly
needed. However, that has been difficult to achieve. In this paper eight selenium
compounds, namely, selenite [Se(IV)], selenate [Se(VI)], selenocystine (SeCys),
selenourea (SeUr), selenomethionine (SeMet), selenoethionine (SeEt),
selenocystamine (SeCM) and trimethylselenonium ion (TMSe+), were separated by
using mixed ion-pair reagents containing 2.5 mM sodium 1-butanesulfonate and 8 mM
tetramethylammonium hydroxide as a mobile phase. The separation of these anionic,
cationic and neutral organic selenium compounds on a LiChrosorb RP18 reversed
phase column took only 18 min at a flow-rate of 1.0 ml/min with isocratic
elution, and baseline separation among the six organic Se compounds was achieved.
Inductively coupled plasma mass spectrometry (ICP-MS) was employed as element
specific detection. A comparison of ICP-MS signal intensity obtained with a
Barbington-type nebulizer and with an ultrasonic nebulizer (USN) was made.
Different signal enhancement factors were observed for the various selenium
compounds when a USN was used. The speciation technique was successfully applied
to the study on chemical forms of selenium in a selenium nutritional supplement.
Selenomethionine was found to be the predominant constituent of selenium in the
supplement.
PMID- 10768500
TI - Hindered amine stabilizers investigated by the use of packed capillary
temperature-programmed liquid chromatography. I. Poly((6-((1,1,3,3
tetramethylbutyl)-amino)-1,3,5-triazine-2,4- diyl)(2,2 ,6,6-tetramethyl-4
piperidyl)imino)-1,6-hexanediyl ((2,2,6,6-tetramethyl-4-piperidyl)imino)).
AB - Three different trademarks of a hindered amine stabilizer with the IUPAC name
poly((6-((1,1,3,3-tetramethylbutyl)-amino)-1,3,5-triazine-2,4-d iyl)(2,2,6,6
tetramethyl-4-piperidyl)imino)-1,6-hexanediyl(( 2,2 ,6,6-tetramethyl-4
piperidyl)imino)), have been analyzed and compared to each other by the use of
non-aqueous packed capillary temperature-programmed liquid chromatography and
light scattering detection. The analysis by this method has shown that the
products contained almost 40 different homologues and other components. This is
in contrast to what has been assumed earlier based on results achieved with size
exclusion chromatography. The method demonstrated significant differences between
the products from different manufacturers.
PMID- 10768501
TI - Comparative study on camphor enantiomers behavior under the conditions of gas
liquid chromatography and reversed-phase high-performance liquid chromatography
systems modified with alpha- and beta-cyclodextrins.
AB - The dependence of retention and selectivity parameters of camphor enantiomers on
the concentration of alpha- and beta-cyclodextrins were studied under conditions
of GLC (matrix solvent: Glycerol, 95 degrees C) and RP-HPLC (matrix solvent:
Aqueous methanolic, 20 degrees C). It has been found that beta-cyclodextrin forms
complex of 1:1 stoichiometry and does not recognize enantiomers of camphor. In
contrast alpha-CD forming complexes of 1:2 stoichiometry appeared to be very
efficient chiral selector of (+) and (-)-camphor. Relatively considerable
differences have been observed between stability constants determined by GLC and
RP-HPLC, what may be explained by the various natures of the matrix solvents and
the various temperatures of the measurements. On the contrary, the
enantioseparation factor alpha observed at higher concentrations of alpha
cyclodextrin stabilizes on the very similar value alpha+/-(GLC) approximately =
alpha-/+(HPLC) approximately = 1.6. Simple theoretical considerations focusing on
the differences in the mechanisms of the studied processes have been performed.
According to them the enantiomer forming the more stable complex with the
cyclodextrin should be eluted from the RP-HPLC column first and GLC column last.
This fact has been confirmed experimentally.
PMID- 10768502
TI - Trace analysis of pesticide residues in water by high-speed narrow-bore capillary
gas chromatography-mass spectrometry with programmable temperature vaporizer.
AB - A method for the rapid trace analysis of 17 residual pesticides in water by
narrow-bore capillary (I.D. 100 microm) gas chromatography-mass spectrometry (GC
MS) using a programmable temperature vaporizer (PTV) was discussed. The method
consisted of a large-volume injection (40 microl) by a PTV, high-speed analysis
using a narrow-bore capillary column and MS detection. The PTV with solvent vent
mode was very useful for large-volume injection into a narrow-bore capillary
column because the injected solvent volume could be reduced to less than 2
microl. The analysis time was 8.5 min [less than 50% of the analysis time using
conventional columns (I.D. 250 microm)]. A 10-ml volume of river water was
extracted by dichloromethane (4 ml), and then the extract was condensed to 1 ml.
This extract was analyzed. Mean recoveries for river water spiked at 100 pg/ml
ranged from 83.4 to 96.7%. The limit of detections of the 17 pesticides ranged
from 1 to 100 pg/ml.
PMID- 10768503
TI - Enantiomeric separation and discrimination of 2-hydroxy acids as O
trifluoroacetylated (S)-(+)-3-methyl-2-butyl esters by achiral dual-capillary
column gas chromatography.
AB - An efficient method is described for the simultaneous enantiomeric separation of
18 different racemic 2-hydroxy acids for the determination of their absolute
configurations. It involves the conversion of each enantiomer into a
diastereomeric O-trifluoroacetylated (S)-(+)-3-methyl-2-butyl ester for the
direct separation by achiral dual-capillary column gas chromatography with
subsequent identification and determination of its chirality by retention index
(I) library matching. The enantiomers of each acid were well separated with high
resolution values (R > or = 1.4) on DB-5 and DB-17 columns of different polarity.
When temperature-programmed I values of 2-hydroxy acid enantiomers as their
diastereomeric derivatives were measured on both columns, the I values were
characteristic of each enantiomer. Simple I matching with the reference values
was thus useful in cross-checking each acid enantiomer for the identification and
chiral discrimination. When applied to urine samples, the present method allowed
positive identification of most of the spiked 2-hydroxy acids from normal urine
and for endogenous (S)-lactic acid and (S)-2-hydroxybutyric acid from a clinical
urine specimen.
PMID- 10768504
TI - Quantitative analysis of 4-ethylphenol and 4-ethylguaiacol in red wine.
AB - 2,3,5,6-[2H4]-4-Ethylphenol (d4-4-ethylphenol) was synthesised for use as an
internal standard in a new, rapid and accurate analytical method, employing gas
chromatography-mass spectrometry to determine the concentration of the important
aroma compounds 4-ethylphenol and 4-ethylguaiacol in red wine. The concentrations
of both compounds in wine stored in 44 American and 47 French new and used oak
barrels from several suppliers were measured. Wine stored in shaved and refired
oak barrels contained up to 85% less 4-ethylphenol and 4-ethylguaiacol than wine
stored in normal barrels of the same age that were not shaved. The concentration
of 4-ethylphenol found in 61 bottled commercial Australian red wines of various
ages ranged from 2 microg/l in a Merlot up to 2660 microg/l in a Shiraz, with a
mean concentration of 795 microg/l. 4-Ethylguaiacol was also detected in every
red wine analysed, ranging in concentration from 1 microg/l (in a Pinot Noir) up
to 437 microg/l (in a Merlot) with a mean concentration of 99 microg/l.
PMID- 10768505
TI - Separation of polyphenols in Canary Islands wine by capillary zone
electrophoresis without preconcentration.
AB - A method for separation and determination of polyphenols in wine by capillary
zone electrophoresis (CZE) without any preconcentration step is described. The
sensitivity and limits of detection for gentisic and p-coumaric acid are better
than those previously published. The effect of a possible C18 solid-phase
extraction prior to the CZE analysis was examined. The developed optimized method
(without any extraction step) was applied to the analysis of wines from Tenerife,
Canary Islands.
PMID- 10768506
TI - Development and robustness testing of a nonaqueous capillary electrophoresis
method for the analysis of nonsteroidal anti-inflammatory drugs.
AB - Nine non steroidal anti-inflammatory drugs were simultaneously separated by
nonaqueous capillary electrophoresis with a methanol-acetonitrile (40:60, v/v)
mixture containing 20 mM ammonium acetate. The effect of solvent composition,
electrolyte nature and concentration on the electrophoretic behavior of the
selected drugs was systematically studied. Investigated electrolytes were
ammonium, lithium and sodium acetate. Modification of the solvent and/or the
electrolyte composition was found to alter the migration order of the
pharmaceutical drugs. Finally, to assess method robustness, three sensitive
electrophoretic parameters as well as their interactions were evaluated using a
full factorial design at two levels.
PMID- 10768507
TI - Analytical magnetapheresis of magnetically susceptible particles.
AB - Analytical magnetapheresis is a newly developed technique for analyzing magnetic
particles. The magnetically susceptible particles form deposition patterns after
flowing through a separation channel in a magnetic field. The separation channel
requirements for analytical magnetapheresis are an excellent seal for the carrier
flow and ease of disassembly after magnetapheresis. Previously used separation
channels often exhibit variable channel leakage and unstable flow velocities. We
improved the separation channel assembly to ensure stable, high flow velocities
and characterized the system with various magnetically susceptible and labeled
particles. Our new separation channel featured silicone sealant with embedded
nylon wires and met analytical magnetapheresis requirements. Characterization of
this system was performed using several magnetically susceptible particles, and
we studied a variety of diamagnetic sample labels with paramagnetic ions and
magnetically susceptible particles at different flow-rates and solution pH
values. The minimal labeling concentration for complete deposition was determined
to be approximately 2.50 x 10(10) ions per particle for test samples at a flow
velocity of 0.67 mm s(-1) and a magnetic field gradient of 2.8 T mm(-1). Silicas,
yeasts and blood cells were used for these studies. We determined that the
minimal difference in magnetic susceptibility (delta(chi)) for successful
separation was approximately 2.00 x 10(-6) [SI]. The magnetic susceptibilities of
Dynabeads M-450 at several separation distances and flow-rates were determined to
be 0.25 [SI], within 2% of values published by other workers. The magnetic
susceptibilities of various ion-labeled yeasts and cells were determined and most
varied by less than 5% at different flow-rates. The results of this study provide
very important references for analytical magnetapheresis applications.
PMID- 10768508
TI - Determination of silicate in water by ion exclusion chromatography with
conductivity detection.
AB - A novel method for the direct determination of silicate in water by ion exclusion
chromatography with conductivity detection is reported. The method is simple and
sensitive with good precision. The calibration graph was linear from 0.1000
micromol l(-1) to 1000.0 micromol l(-1) for silicate with a correlation
coefficient of 0.997 (n=6). The detection limit was 0.02 micromol l(-1). The
method was successfully applied to the determination of silicate in mineral
water, tap water, distilled water and seawater. The recovery was from 93 to 104%
and the relative standard deviation was in the range of 1.1 to 4.4%.
PMID- 10768509
TI - Trace analysis of ten chlorinated benzenes in water by headspace solid-phase
microextraction.
AB - Headspace solid-phase microextraction (SPME), as a simple, solvent-free method,
has been applied to the analysis of 10 chlorinated benzenes (CBs) present at
trace levels in water samples. An SPME fibre coated with 100-microm thick
poly(dimethylsiloxane) was used for extraction. The analytical data exhibited a
relative standard deviation (RSD) range of 1.19% (for pentachlorobenzene) to
8.19% (for hexachlorobenzene) for the 10 CBs; the RSD of most compounds was under
6%. The sensitivity of the method was enhanced with agitation and with addition
of salt to the sample solutions. With mass spectrometric detection, the limit of
detection was below 0.006 microg/l for all 10 CBs after a 30-min sampling time.
The linearity range was 0.02-20 microg/l for the compounds studied. Water samples
collected from a reservoir, and from the tap in a laboratory were analysed using
the optimised conditions.
PMID- 10768510
TI - Microbial ecology and treatment of Helicobacter pylori infections: review.
AB - The aims of the present study were to investigate the ecological disturbances
caused by four different anti-H. pylori regimens, to compare different methods
for diagnosing H. pylori, and to study the genetic variability of H. pylori. The
patients included in the study were all treated at the Center of
Gastroenterology, Huddinge University Hospital, Karolinska Institute. All
patients were H. pylori-positive before entering the study, confirmed by rapid
urease test, histology, culture and urea breath test or PCR. Treatment regimens
included in the study were omeprazole alone (OP), in combination with amoxicillin
(OA), in combination with amoxicillin and metronidazole (OAM) and in combination
with clarithromycin and metronidazole (OCM). Samples from the mouth (saliva and
dental plaque), stomach (biopsies from the gastric mucosa in the corpus and in
the antrum) and the intestine (feces) were collected before, during and after
treatment. The oral microflora was challenged by the three treatment regimens
including antimicrobial agents, with the emergence of resistant streptococci and
staphylococci in the OCM group. Bacterial strains in the gastric mucosa increased
in numbers during treatment in all treatment groups, probably due to the pH rise,
which provides a better environment for the commensal microflora. This overgrowth
was especially pronounced during treatment with omeprazole alone (OP), possibly
due to the fact that a concomitant suppression exerted by the antimicrobial
agents occurred in the other treatment groups. H. pylori was, on the other hand,
suppressed during treatment in all treatment groups, possibly due to a direct
effect of omeprazole and to the colonization resistance expressed by the normal
microflora. An emergence of resistant commensal strains in the gastric mucosa was
seen in the OCM and the OAM groups. The intestinal microflora was most altered in
the OAM and the OCM groups, with persistent disturbances in the OCM group 4 weeks
after treatment. The frequency of resistant Enterococcus spp. (OCM),
Enterobacteriaceae spp. (OA and OAM) and Bacteroides spp. (OCM) was increased
during and after treatment. Different detection methods for H. pylori were
compared and PCR was shown to have higher sensitivity than other routine
diagnostic tests. The patients in the present study seemed to be colonized with a
single strain of H. pylori. Treatment failures in patients treated with OAM were
caused by recrudescence. These four patients with relapsing H. pylori infection,
were shown to be reinfected with the original H. pylori strain, indicating that
H. pylori escapes treatment by a thus far unknown mechanism.
PMID- 10768511
TI - In vitro activity of cefepime and cefotaxime compared to six other agents against
350 penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae.
AB - From January 1996 to December 1997, we evaluated the in vitro activity of 8
antimicrobials (penicillin, amoxycillin, amoxycillin/clavulanate, cefuroxime,
ceftazidime, cefepime, cefotaxime, and imipenem) against 350 Streptococcus
pneumoniae clinical isolates collected from two hospitals. Imipenem, cefepime and
cefotaxime were the most active antibiotics against penicillin-intermediate (PI)
and highly penicillin-resistant (PR) S. pneumoniae with MICs 2- to 8-fold lower
than penicillin. Against PI and PR pneumococci amoxycillin and
amoxycillin/clavulanate were 2-times less active than cefepime and cefotaxime,
while cefuroxime was 4-8-times less active. The majority of strains of serotypes
6B, 23F, 14, 9 and 19 were penicillin-resistant, both intermediate (68%) and
highly resistant (32%).
PMID- 10768512
TI - A head-on comparison of the in vitro antifungal activity of conventional and
lipid-based amphotericin B: a multicenter study.
AB - A comparative study of conventional amphotericin B, Abelcet and AmBisome was
performed using a microdilution format of the NCCLS M27-A methodology for
susceptibility testing against 300 fungal isolates (152 yeasts, 148 filamentous
fungi) in both RPMI-1640 and antibiotic medium #3 (AB3). The clinical isolates
included Candida albicans (n=54), Candida glabrata (n=25), Candida parapsilosis
(n=23), Candida krusei (n=19), Candida lusitaniae (n=14), Cryptococcus neoformans
(n=5), Candida tropicalis (n=12), Aspergillus flavus (n=34), Aspergillus
fumigatus (n=46) and 68 other filamentous fungi encompassing 22 different genera.
The minimal inhibitory concentrations (MIC) for all drugs were defined as the
lowest concentrations in which there was no visible growth. MICs were determined
after 48 h for yeasts and 72 h for filamentous fungi. The mean MICs +/- standard
error (microg/ml) for yeasts and filamentous fungi, respectively, were: Abelcet,
0.51+/-0.21, 4.34+/-0.61; AmBisome, 1.28+/-0.24, 5.68+/-0.57; amphotericin B,
0.29+/-0.11, 1.12+/-0.19, respectively. Overall, against both yeasts and
filamentous fungi Abelcet proved to have more potent antifungal activity than
AmBisome. Using AB3 as opposed to RPMI-1640 generally produced lower MIC values
but did not have any effect on the order of relative activity with all of the
antifungal agents tested. In conclusion, our data shows that Abelcet is more
active than AmBisome against pathogenic yeast and filamentous fungi when assayed
in AB3 in vitro. Comparison of the activities of these antifungals in
experimental animal models is necessary to determine whether these in vitro
findings are correlated with in vivo efficacy.
PMID- 10768513
TI - Natural antibiotic susceptibility of Rahnella aquatilis and R. aquatilis-related
strains.
AB - A database is described of the natural susceptibilities of 70 Rahnella strains to
71 antibiotics. MIC values were determined by a microdilution procedure and
evaluated by a table calculation program. Rahnella aquatilis and R. aquatilis
related strains were naturally resistant to amoxycillin, ticarcillin, fosfomycin
and to antibiotics to which other species of Enterobacteriaceae are also
intrinsically resistant, i.e. macrolides (except azithromycin), benzylpenicillin,
oxacillin, rifampicin, fusidic acid, lincosamides and glycopeptides. Rahnella
strains were also naturally resistant or intermediate to cefazolin, cefuroxime
and loracarbef. All rahnellae were naturally sensitive or intermediate to
doxycycline, minocycline, aminoglycosides, some penicillins and cephalosporins,
carbapenems, aztreonam, quinolones, sulfamethoxazole, trimethoprim,
cotrimoxazole, chloramphenicol and nitrofurantoin. Bimodal or broad MIC
distributions were seen for several antibiotics, e.g. quinolones and
cephalosporins. With the exception of quinolones no differences in natural
antibiotic susceptibility were seen between reference strains of Rahnella
genomovar 1 (n=6) and 2 (n=7). Reference strains of genomovar 1 were pyrase
positive and more susceptible to quinolones than reference strains of genomovar
2, which were pyrase-negative. By discrimination of all rahnellae in the pyrase
positive and pyrase-negative strains the MIC distributions for quinolones became
smaller and unimodal. Under the conditions described pyrase might be a parameter
to differentiate strains of Rahnella genomovars 1 and 2.
PMID- 10768514
TI - Influence of five antianaerobic antibiotics on endotoxin liberation by gram
negative anaerobes.
AB - Endotoxin, a lipopolysaccharide (LPS), has for many years been recognized as a
key effector molecule in the pathogenesis of gram-negative sepsis and septic
shock. Seven strains of the Bacteroides fragilis group were studied for their
ability to liberate endotoxin upon exposure to five anti-anaerobic antibiotics,
trovafloxacin, cefoxitin, imipenem, meropenem and piperacillin/tazobactam, in an
in-vitro experiment. The minimum inhibitory concentrations (MICs) of the
antibiotics were determined by using the broth macrodilution technique.
Thereafter, endotoxin liberation was detected in the filtered broth cultures of
the anaerobic bacteria by the limulus amebocyte lysate (LAL) assay after exposing
the organisms to four different concentrations of the antibiotics in supplemented
Brucella broth. Aliquots of the broth cultures were also taken at intervals of 0,
6, 24 and 48 h for viable counts. All seven gram-negative anaerobic bacteria
investigated liberated induced cell-free endotoxin in filtered broth culture many
times higher than the control. There was noticeable variation in the propensity
of some antibiotics to induce endotoxin liberation. At four times the MICs,
cefoxitin and piperacillin/tazobactam induced negligible quantities of endotoxin
after 48 h exposure, whereas the others induced high levels of endotoxin release.
After exposure to all concentrations for 48 h, endotoxin activity in the test
system was many times higher with the Bacteroides fragilis sensu stricto than
with the rest of the species in the Bacteroides group. To varying degrees, all
five antibiotics had the capacity to induce endotoxin liberation by gram-negative
anaerobic bacteria. This differential endotoxin release by the B. fragilis group
may, in part, explain why B. fragilis sensu stricto, more than the other
Bacteroides spp., is usually associated with clinical infections and higher
morbidity.
PMID- 10768515
TI - The changing spectrum of Group B streptococcal (GBS) infection in infants of
Saudi Arabia.
AB - This study describes the incidence, clinical presentation and outcome of neonatal
Group B streptococcal (GBS) infection in a Saudi Arabian Hospital. Charts of all
neonates with GBS infection admitted to our hospital during a 5-year period (1990
1994) were reviewed retrospectively. Of the 29,601 live births, 23 neonates had
GBS infection, giving an overall incidence rate of 0.8 per 1000 live births. The
incidence rate appeared to increase from 0.2 per 1000 live births in 1990 to 1.2
per 1000 live births in 1994 (not statistically significant (P=0.07)). Of the 23
neonates with GBS infection, 16 (70%) were full term infants (gestation > or = 37
weeks). In contrast, 7 (30%) were preterm infants (gestation < 37 weeks). Ten
(44%) mothers had premature rupture of membrane. Intrapartum fever and/or urinary
tract infection was observed in 9% of the mothers. Nineteen (82%) of the neonates
had early onset GBS infection, whereas only 4 infants (18%) had late-onset
infection. Blood and CSF cultures were positive in 21 (91%) and 5 (21%),
respectively. Complications of GBS infection were as follows: sepsis without
focus of infection 15 (65%); meningitis 5 (22%); pneumonia 3 (13%); urinary tract
infection 2 (9%). None of these complications had any significant association
with the onset of infection (P>0.1). The overall case-fatality rate was 9%. The
incidence of GBS infection appears to be increasing in Saudi neonates and
measures to prevent perinatal transmission need to emphasized and implemented.
PMID- 10768516
TI - New insight into the clinical pharmacokinetics of cefaclor: tissue penetration.
AB - The serum pharmacokinetic data presented are generally in agreement with those
obtained by other authors with both the cefaclor IR (immediate release) and AF
(advanced formulation) or MR (modified release) formulations. With the new
sustained-release formulation, the time of peak (Tmax) and mean residence time
(MRT) values are significantly longer than those observed with the standard
cefaclor IR. For the first time the penetration of the MR formulation of cefaclor
was determined both in suction blister fluid (SBF) and alveolar epithelial lining
fluid (ELF). Cefaclor demonstrated a high tissue distribution, with a high
penetration index (PI) into blister fluid, which is at least representative of a
relatively large volume of fluid-filled spaces and in part of highly vascularized
tissues. SBF and ELF concentrations were higher than blood levels starting at the
4th-6th hour after dose, with longer elimination half-lives from the
extravascular compartment than from serum. Cefaclor has a favorable
pharmacokinetic profile, especially the new sustained-release formulation, which
maintains effective concentrations for a longer time than the IR preparation. The
MR formulation improves the kinetic properties of the cefaclor molecule with a
prolonged MRT which allows a daily dosage of 750 mg every 12 h.
PMID- 10768517
TI - A multicenter randomized trial of prophylaxis with intravenous cefepime +
metronidazole or ceftriaxone + metronidazole in colorectal surgery. The 230 Study
Group.
AB - We compared two prophylactic antimicrobial regimens in 615 patients undergoing
elective colorectal surgical procedures. Patients ranged in age from 19 to 92
years (median 66 years); the majority were male (54.0%) and most (77.7%) had
neoplastic disease. All underwent mechanical bowel preparation. Patients were
randomized to receive preoperative infusions of 2 g cefepime (n=307) or 2 g
ceftriaxone (n=308), followed by 500 mg metronidazole. Patients were followed for
up to 4 to 6 weeks after surgery. Antimicrobial prophylaxis was successful in
preventing primary site infections in 92.8% of patients in the cefepime +
metronidazole arm and 92.9% of patients in the ceftriaxone + metronidazole arm.
Both regimens were well tolerated. A single dose of cefepime + metronidazole thus
seems to be a very useful alternative to other regimens for prophylaxis in
patients undergoing colorectal surgery.
PMID- 10768518
TI - Differential costs and outcomes among pediatric oral antibiotic formulations
identified from a large prescription database.
AB - Differential performance of oral antibiotics continues to be a difficult
characteristic to measure. As payers make efforts to identify selected
antibiotics to place on their formularies or to reimburse, the challenge to these
decision-makers is to determine which agent will work best in their population.
Given the differences from one clinical trial to another, identifying performance
characteristics that might impact effectiveness in clinical practice is quite
challenging. This study's aim was to determine which beta-lactam and macrolide
antibiotic provided the best clinical and economic outcome when used in difficult
pediatric infections that previously experienced amoxicillin or cotrimoxazole
failure. The findings demonstrated that cefaclor, azithromycin, and
amoxicillin/clavulanate were associated with a decreased need for subsequent
antibiotic therapy. Total drug treatment costs for beta-lactams and macrolides
were lowest for cefaclor and azithromycin, respectively. These results are
consistent with previous published literature and seem plausible given potential
compliance advantages of these products as reported in studies of product
tolerability and taste.
PMID- 10768519
TI - Efficacy and safety of amoxycillin/clavulanate (Augmentin) twice daily versus
three times daily in the treatment of acute otitis media in children. The
Augmentin 454 Study Group.
AB - This multicenter, randomized, single-blind study compared the efficacy and safety
of a new, twice-daily formulation of amoxycillin/clavulanate (Augmenting) with
the standard three-times-daily formulation. Children with a clinical diagnosis of
acute otitis media, aged between 2 months and 12 years, received either
amoxycillin/clavulanate 45/6.4 mg/kg/day twice-daily (b.d.) (range 38.3/5.5
76.2/10.9 mg/kg/day) or amoxycillin/clavulanate 40/10 mg/kg/day three-times-daily
(t.d.s.) (range 25/6.25-56/14 mg/kg/day) for 7 or 10 days. Patients were
evaluated during therapy (Days 3-5), at the end of therapy (Days 7-12) and at
follow-up (Days 38-42). At the end of therapy, for the intent-to-treat and per
protocol populations, respectively, clinical success (cure) was achieved by
approximately 94% of patients in both treatment groups. A successful
bacteriological response at the end of therapy (Visit 3) was documented in 7/9
patients (77.8%) in the twice-daily group and in 11/13 patients (84.6%) in the
three-times-daily group. At follow-up (Visit 4), 93.3% of patients in the twice
daily group and 87.9% in the three-times-daily group continued to have a
clinically successful response. Both treatment regimens were well tolerated, with
most adverse events being of a mild-moderate and transient nature. The most
common treatment-related adverse event was diarrhea, occurring in 7.2% of
patients in the twice-daily group and in 10.7% of the three-times-daily group. In
total, 173 patients (82.8%) in the twice-daily group and 151 patients (73.3%) in
the three-times-daily group were compliant with medication. In conclusion, this
study confirms that b.d. amoxycillin/clavulanate is an effective treatment for
pediatric acute otitis media and demonstrates that the b.d. and t.d.s.
formulations of amoxycillin/clavulanate produce equivalent efficacy. Furthermore,
there was a trend towards a higher level of compliance and a lower incidence of
drug-related adverse events in the twice-daily compared with the three-times
daily treatment group.
PMID- 10768520
TI - Ceftazidime for outpatient parenteral antibiotic therapy (OPAT) of chronic
suppurative otitis media due to Pseudomonas aeruginosa.
AB - The number of patients receiving parenteral antibiotic therapy outside the
hospital (OPAT) is growing rapidly, not only because of financial considerations,
but also to limit the risk of nosocomial infections, hospitalization trauma, and
to improve the quality of life. The same benefits of OPAT have recently been
extended to pediatric patients. In the present study, the efficacy and safety of
OPAT was evaluated in 52 children (age range 6-12 years) affected by chronic
suppurative otitis media (CSOM) whose parents were deemed compliant.
Otorhinolaryngologists and infectious disease specialists (IDS) cooperated in
diagnosing, managing patients and being available 24 hours a day for family
consultation. Bacteriological examination of ear exudate was carried out before
antibiotic treatment. For all 52 children the infection was caused by Pseudomonas
aeruginosa in vitro sensitive to ceftazidime. Ceftazidime was administered at the
dosage of 500 mg b.i.d. i.m. at the patient's home according to a self
administration model for 7-10 days. All patients returned every other day during
the treatment course for clinical observation and cleansing of the ear, and 30
days after the end of the treatment (follow-up). Complete clinical cure and
bacteriological eradication were observed in 35 patients (67%), clinical
improvement in 12 (23%). No side-effects or hearing impairment were reported at
clinical and audiometric check-ups; compliance was absolute. Our data suggest
that children affected by CSOM can be managed as outpatients by a cooperative
team of otorhinolaryngologists and IDS.
PMID- 10768521
TI - Phenothiazine photosensitizers. III. Activity of methylene blue derivatives
against pigmented melanoma cell lines.
AB - The cytotoxicity and photocytotoxicity of methylene blue and several of its
derivatives against two pigmented melanoma cell lines (SK-23 murine melanoma and
SK-Mel 28 human melanoma) were investigated in culture. The derivatives were all
more effective photosensitizers than methylene blue in both cell lines over a
range of light doses (3.6-17.6 J cm(-2)). The increased activity correlated with
increased cellular uptake and inherent photosensitizing efficacy. The
photosensitizers also showed varying levels of interaction with the biopolymer
melanin and although this appeared to affect uptake and activity, there was no
direct correlation with toxicity.
PMID- 10768522
TI - Comparison of granisetron, ondansetron and tropisetron for control of vomiting
and nausea induced by cisplatin.
AB - Severe nausea and vomiting are common and one of the most feared side effects of
cisplatin-based chemotherapy. A total of 106 patients were randomized to receive
a single dose of 8 mg ondansetron or 3 mg granisetron or 5 mg tropisetron
intravenously as prevention of cisplatin-induced acute nausea and vomiting.
Antiemetic therapy was done within 30 minutes before initiating chemotherapy. A
questionnaire evaluating nausea, vomiting and retches was administered to
patients and the responses were categorized as complete, partial or failure. The
response determination was repeated in the first 24 hours, and within 24-72 hours
following cisplatin administration. The complete response rates for ondansetron,
granisetron and tropisetron in the first 24 hours were 51.4%, 65.7% and 61.1%
respectively. All three agents were highly effective against cisplatin-induced
acute and late vomiting and the results were statistically significant. This
study demonstrated no significant difference in effectiveness of these three
antiemetics. 5-HT3 (5-hydroxytryptamine 3) receptor antagonists have similar
efficacy in the prevention of nausea and vomiting due to cisplatin. Thus, we
recommend that drug choice be based on cost-benefit and patient tolerance.
PMID- 10768523
TI - Enterococcal nosocomial meningitis in children.
PMID- 10768524
TI - The rehabilitation of limb apraxia: a study in left-brain-damaged patients.
AB - OBJECTIVE: To assess the effectiveness of a rehabilitative training program for
patients with limb apraxia. DESIGN: Randomized, controlled trial. SETTING:
Neurologic rehabilitation unit of a university hospital. PATIENTS: Thirteen
patients with acquired brain injury and limb apraxia (lasting more than 2 months)
as a result of lesions involving the left cerebral hemisphere. Patients were
assigned to a study group or to a control group following a randomization scheme.
The study group underwent an experimental training for limb apraxia. The control
group received conventional treatment for aphasia. INTERVENTION: A behavioral
training program consisting of gesture-production exercises. The rehabilitative
program was made up of 3 sections dedicated to the treatment of gestures with or
without symbolic value and related or nonrelated to the use of objects. Thirty
five experimental sessions, each lasting 50 minutes, were given. MAIN OUTCOME
MEASURES: Neuropsychologic tests for assessment of aphasia, verbal comprehension,
"general intelligence," oral apraxia, constructional apraxia, and 3 tests
concerning limb praxic function (ideational apraxia, ideomotor apraxia, gesture
recognition). Scores related to each test were used to measure the outcome. Video
recordings of ideational and ideomotor apraxia tests allowed us to register type
and number of praxic errors. All outcome measures, except the aphasia test, were
recorded before and after the experimental (or control) treatment time interval.
RESULTS: The patients in the study group achieved a significant improvement of
performance in both ideational (p = .039) and ideomotor (p = .043) apraxia tests.
They also showed a significant reduction of errors in ideational (p = .001) and
ideomotor (p < .001) apraxia tests. A trend toward improvement was found in the
gesture comprehension test (p = .058), while other outcome measures did not show
any significant amelioration. Control patients did not show any significant
change in performance. CONCLUSIONS: The results show the possible effectiveness
of a specific training program for the treatment of limb apraxia.
PMID- 10768525
TI - Recovery of upper-extremity strength in complete and incomplete tetraplegia: a
multicenter study.
AB - OBJECTIVE: To examine upper-extremity motor recovery of subjects with tetraplegia
with both complete and incomplete injuries, to predict which patients and at what
time they would recover a motor level. DESIGN: Prospective, multicenter clinical
study of upper-extremity motor recovery in subjects with acute traumatic spinal
cord injury. SETTING: Three regional spinal cord injury centers. SUBJECTS: One
hundred sixty-seven individuals with acute traumatic tetraplegia (144 males
[86%], and 23 females [14%]) between the ages of 15 and 75 years (mean age, 35.5
yrs). METHODS: Subjects were examined and classified using sequential manual
muscle tests performed on admission, 72 hours, 1, 2, and 3 weeks, and 1, 2, 3, 6,
12, 18, and 24 months postinjury. C5 biceps, C6 extensor carpi radialis, C7
triceps, and C8 flexor digitorum profundus were evaluated using a 0-5 scale.
Analyses of the right motor levels used a series of logistic regression models,
and for multiple measurements on each subject, models were estimated using
generalized estimating equations. RESULTS: The analysis for recovery of the
biceps for the C4 group showed 70% of complete compared with 90% of incomplete
injuries recovered (p < .001); of the extensor carpi radialis in the C5 group,
75% complete and 90% incomplete recovered (p < .002); and of the triceps in the
C6 group, 85% of complete and 90% of incomplete injuries recovered (p < .16).
CONCLUSION: Predicting future potential for upper-extremity motor recovery and
for independence in self-care in groups of patients at a specific motor level is
possible within the first week of injury.
PMID- 10768526
TI - The measurement properties of fitness measures and health status for persons with
spinal cord injuries.
AB - OBJECTIVE: To assess the measurement properties of measures used to evaluate
fitness and health status in the spinal cord injury (SCI) population. DESIGN:
Inception cohort assessed during standardized exercise protocols at admission,
discharge, and 8-week follow-up from a SCI rehabilitation program. SETTING: Urban
tertiary care hospital. PATIENTS: One hundred two patients with SCI. RESULTS:
Measures at higher levels of physical exertion generally showed higher stability
between test and retest. Resting measures, blood lactates, and respiratory
exchange ratios were not stable. Heart rate, blood pressure, lactate levels,
ventilation rates, and activities of daily living measures did not reflect the
construct of aerobic fitness. The use of ratings of perceived exertion to predict
heart rate was found to be inaccurate in the SCI population. CONCLUSION: Power
output and VO2 at maximal workload, and ratings of perceived exertion at a
standard workload demonstrated stability and sensitivity to therapeutic change,
indicating acceptable measurement properties for the assessment of aerobic
fitness in SCI patients. Some other commonly used measures can be used with less
confidence.
PMID- 10768527
TI - Chair configuration and balance control in persons with spinal cord injury.
AB - OBJECTIVE: To study whether chair configuration influences sitting balance in
persons with spinal cord injury (SCI). DESIGN: Cross-sectional group study.
SETTING: Rehabilitation centers and hospital rehabilitation departments.
PATIENTS: Ten complete high thoracic SCI (level T2-T8) patients, 10 complete low
thoracic SCI (T9-T12) patients, and 10 matched able-bodied controls. SCI
participants had completed their active rehabilitation at least 6 months before
the study. INTERVENTIONS: A balance-changing (forward) reaching task while seated
in four differently configured chairs. Tilt angle (7 degrees and 12 degrees) and
reclination angle (22 degrees) were varied relative to a standard chair
configuration (10 degrees reclination). MAIN OUTCOME MEASURES: Maximal
unsupported reaching distance, center-of-pressure displacement and muscle
activity. RESULTS: Although no significant difference in actively controllable
reach was found in controls or in subjects with low SCI, sitting balance improved
in all chairs relative to the standard chair. Ability to control displacement of
arms and trunk during reaching improved. No apparent need for additional postural
muscle activity was found. Persons with high SCI did not improve their sitting
balance. They were unable to control a shift in body mass larger than the one
induced by arm movement. However, they had less muscle activity after backrest
reclination or tilting the chair backwards. CONCLUSIONS: The tested chairs had an
overall positive effect. However, for individually tailored chair configurations
factors other than those investigated should be considered.
PMID- 10768528
TI - Task-related circuit training improves performance of locomotor tasks in chronic
stroke: a randomized, controlled pilot trial.
AB - OBJECTIVE: To evaluate the immediate and retention effects of a 4-week training
program on the performance of locomotor-related tasks in chronic stroke. DESIGN:
Randomized, controlled pilot study with 2-month follow-up. SETTING:
Rehabilitation center. SUBJECTS: A convenience sample consisting of 12 chronic
stroke subjects was used. Subjects were randomly assigned to the experimental or
the control group. Three subjects withdrew from the study. INTERVENTION: Both
experimental and control groups participated in exercise classes three times a
week for 4 weeks. The exercise class for the experimental group focused on
strengthening the affected lower limb and practicing functional tasks involving
the lower limbs, while the control group practiced upper-limb tasks. MAIN OUTCOME
MEASURES: Lower-limb function was evaluated by measuring walking speed and
endurance, peak vertical ground reaction force through the affected foot during
sit-to-stand, and the step test. RESULTS: The experimental group demonstrated
significant immediate and retained (2-month follow-up) improvement (p < or = .05)
compared with the control group in walking speed and endurance, force production
through the affected leg during sit-to-stand, and the number of repetitions of
the step test. CONCLUSION: The pilot study provides evidence for the efficacy of
a task-related circuit class at improving locomotor function in chronic stroke.
PMID- 10768529
TI - Physiologic decrease of single thenar motor units in the F-response in stroke
patients.
AB - OBJECTIVE: To investigate the left-right difference and the reproducibility by
the F-wave motor unit number estimation and to compare the motor unit number
between the hemiplegic and unaffected side in stroke patients. SETTING: A
referral center and institutional practice providing outpatient care. SUBJECTS:
Seven healthy volunteers and 15 consecutive stroke patients. DESIGN: Diagnostic
statistical test and correlational study. METHOD: Submaximal stimuli were used to
evoke a sample of surface motor unit action potentials (S-MUAPs) in the F-waves
that are entirely representative of the relative numbers of detected S-MUAPs of
different sizes. The average S-MUAP amplitude was calculated from a selected
population of F-wave responses for each abductor pollicis brevis (APB) muscle.
The motor unit number was calculated by dividing the maximum M-potential negative
peak amplitude by the average S-MUAP negative peak amplitude. RESULT: There was
no statistical difference between motor unit numbers on either side and between
test and retest in this motor unit number estimation method among normal
subjects. The motor unit number on the hemiplegic side was significantly lower
than on the unaffected side (p < .05, Mann-Whitney test) among stroke patients.
CONCLUSION: The motor unit could decrease in the hemiplegic side after a moderate
to-severe hemiplegic stroke and this decrement might be due to the transsynaptic
degeneration secondary to an upper motor neuron lesion.
PMID- 10768530
TI - Neutral wrist splinting in carpal tunnel syndrome: a comparison of night-only
versus full-time wear instructions.
AB - OBJECTIVE: To compare the effects of night-only to full-time splint wear
instructions on symptoms, function, and impairment in carpal tunnel syndrome
(CTS). DESIGN: Randomized clinical trial with 6-week follow-up. SETTING: Veterans
Administration Medical Center, outpatient clinic. SUBJECTS: Outpatients with
untreated CTS were consecutively recruited from our electrodiagnostics lab.
Twenty-one patients (30 hands) were enrolled, and 17 patients (24 hands)
completed the study. INTERVENTIONS: Thermoplastic, custom-molded, neutral wrist
splints with subjects receiving either full-time or night-only wear instructions.
OUTCOME MEASURES: Symptoms and functional deficits were measured by Levine's self
administered questionnaire, and physiologic impairment was measured by median
nerve sensory and motor distal latency. COMPLIANCE AND CROSSOVER: Almost all
(92%) of the combined sample reported frequent splint use, but their adherence to
specific wearing instructions was limited. A majority (73%) of the full-time
group reported splint wear less than one half of waking hours, and some (23%) of
the night-only group reported occasional daytime wear. Despite this tendency for
treatment crossover, the two treatment groups differed in daytime wear as
intended (chi2 analysis, p = .004). RESULTS: The combined sample improved in
three of four outcome measures: sensory distal latency (mean = .28msec, standard
deviation [SD] = .37, p = .004), symptom severity (mean = .64, SD = .46, p =
.0001), and functional deficits (mean = .49, SD = .51, p = .0001). Severity of
CTS was a factor only in sensory distal latency improvement (more improvement in
severe CTS). Subjects receiving full-time wear instructions showed superior
distal latency improvement, both motor (.35 vs -.07msec, p = .04) and sensory
(.46 vs . 13msec, p = .05) when compared with subjects receiving night-only wear
instructions. CONCLUSIONS: This study provides added scientific evidence to
support the efficacy of neutral wrist splints in CTS and suggests that
physiologic improvement is best with full-time splint wear instructions.
PMID- 10768531
TI - Elevated detection thresholds for mechanical stimuli in chronic pain patients:
support for a central mechanism.
AB - OBJECTIVE: To investigate the relation between pain provoking cervical segments
identified by diagnostic dorsal root blockades and elevation of detection
thresholds in patients suffering from chronic cervicobrachialgia (CCB). DESIGN:
Quantitative sensory testing (light touch) of the cervical dermatomes using
Semmes-Weinstein monofilaments. SETTING: A university pain clinic. SUBJECTS:
Thirty-nine patients with CCB, with no clinical or diagnostic evidence of
radiculopathy or surgically treatable bony lesion and with one main pain
provoking cervical segment identified by diagnostic dorsal root blockades.
OUTCOME MEASURES: Detection thresholds with 95% confidence intervals (95% CI) of
pain-provoking segments, compared with surrounding and contralateral segments and
with normal values for cervical dermatomes. RESULTS: Patients' detection
thresholds were significantly (p < .001) higher than those for normal subjects:
3.51 (95% CI, 2.71-4.31) and 3.10 (95% CI, 2.34-3.86), respectively. No
significant differences existed between the segments. The elevations were
systematic. However, thresholds on the painful side were consistently, slightly
higher than those on the contralateral side. CONCLUSION: Supporting earlier
studies, results from CCB patients in the present study showed systematic
elevation of detection thresholds (low threshold mechanoreceptors), an adaptation
in contrast with, but not contradictory to, central sensitization of high
threshold neurons in chronic pain.
PMID- 10768532
TI - Predicting electrodiagnostic outcome in patients with upper limb symptoms: are
the history and physical examination helpful?
AB - OBJECTIVE: To determine the effectiveness of medical history and physical
examination in predicting electrodiagnostic outcome in patients with suspected
cervical radiculopathy. METHODS: Data on 183 subjects prospectively collected at
five different electrodiagnostic laboratories were analyzed (96 cervical
radiculopathies, 45 normal studies, and 42 abnormal electrodiagnostic findings
other than radiculopathy). The sensitivity, specificity, positive predictive
value, negative predictive value, and odds ratios were determined for symptoms
and neurologic signs. RESULTS: Symptoms of numbness, weakness, and tingling were
associated with twice the probability of having abnormal electrodiagnostic study
results in general, yet were not helpful in identifying a cervical radiculopathy.
All single and combined physical examination components had poor sensitivities,
with the exception of weakness, but much higher specificities. Patients with
either weakness or reduced reflexes on physical examination were up to five times
more likely to have abnormal electrodiagnostic findings. In subjects with any
abnormal neurologic sign, the sensitivity improved to 84%, the positive
predictive value was 79%, but the specificity was low (44%). Of those subjects
with normal physical examination results, almost one half had an abnormal
electrodiagnostic study result (negative predictive value 52%). CONCLUSIONS: In a
population of patients with suspected cervical radiculopathy, medical history and
physical examination are helpful yet not sufficient to predict the
electrodiagnostic outcome.
PMID- 10768533
TI - Comparative diagnostic sensitivities of orthodromic or antidromic sensory inching
test in mild carpal tunnel syndrome.
AB - OBJECTIVES: To compare the reliability, sensitivity, and specificity of the
"inching test" (IT) or "centimetric test," performed orthodromically (OIT) and
antidromically (AIT). METHODS: Incremental palmar study of the sensory fibers of
the median nerve was evaluated over 10cm across the wrist in 20 patients with
mild carpal tunnel syndrome (CTS) and in 20 controls. Mild CTS was defined as
clinical features of CTS with normal electrophysiologic findings by standard
methods. The CTS patients were preselected with abnormal orthodromic median-ulnar
latency difference of the fourth digit (mean .66+/-.21ms; nl < .40ms). RESULTS:
In controls, the mean conduction delay per centimeter (CD/cm) was .192ms for OIT
and .191ms for AIT; the mean maximum conduction delay per centimeter (MCD/cm) was
.250+/-.032ms for OIT and .344+/-.10ms for AIT. MCD/cm was located inside the
carpal tunnel in 85% of patients (OIT) versus 80% for AIT. No MCD/cm was greater
than .32ms (OIT) or .60ms (AIT). With corresponding pathologic thresholds of
.36ms (mean + 3.4 standard deviation [SD]) for OIT and .64ms (mean + 2.6 SD) for
AIT, IT was abnormal in 20 patients (100%) with OIT compared with only 4 patients
(20%) with AIT. CONCLUSIONS: The orthodromic method was superior to the
antidromic method in controls and in patients (chi2 = 23; p = 1.8 x 10(-6)).
These findings suggest that orthodromic IT should be used when standard
electrodiagnostic tests fail to reveal median nerve sensory abnormality in
persons with mild CTS.
PMID- 10768534
TI - Brain lesion size and location: effects on motor recovery and functional outcome
in stroke patients.
AB - OBJECTIVE: To investigate effects of brain lesion profiles that combined sizes
and locations on motor recovery and functional outcome after stroke in hemiplegic
patients. DESIGN: Delimiting sizes (a threshold lesion size) of 5 primary
locations were identified to establish brain lesion profiles based on magnetic
resonance imaging findings 1 month after stroke. Motor and functional outcome
were correlated with brain lesion profiles and other brain lesion factors to
identify the most dominant factor. SETTING: Medical center, rehabilitation
department. PARTICIPANTS: Fifty-five hemiplegic patients. MAIN OUTCOME MEASURES:
Brunnstrom's stages and Functional Independence Measure (FIM) scores were
assessed 1 and 6 months after stroke. RESULTS: With delimiting sizes for the
cortical, corona radiata, internal capsule, putaminal, and thalamic regions set
at 75, 4, .75, 22, and 12cm3, respectively, brain lesion profiles play a dominant
role in determining final Brunnstrom's stages (Spearman's rho = .861, p < .01)
and FIM score (Spearman's rho = .571, p < .01). Brunnstrom's and FIM scores had
no or only weak negative relationship with either absolute or relative lesion
size. CONCLUSIONS: These findings may suggest that motor and functional outcomes
after stroke correlate with brain lesion profiles (a combination of delimiting
sizes and primary locations) more than with absolute or relative lesion sizes
only. Delimiting sizes in determining final outcomes varied markedly according to
the primary lesion locations.
PMID- 10768535
TI - Functional impairment, depression, and life satisfaction among older hemodialysis
patients and age-matched controls: a prospective study.
AB - OBJECTIVE: To compare change over time in functional impairment, depression, and
life satisfaction among older dialysis patients and age-matched controls. DESIGN:
Prospective cohort study over 3 years. SETTING: Urban and rural communities
throughout Georgia. SUBJECTS: One hundred thirteen prevalent renal failure
patients on in-center hemodialysis and 286 controls. MAIN OUTCOME MEASURES:
Ordinal functional impairment index and life satisfaction rating, and Center for
Epidemiologic Studies Depression Scale. RESULTS: Dialysis patients, compared with
controls, reported significantly more functional impairment at baseline, and also
at follow-up after adjusting for baseline impairment and covariates. Dialysis
patients had higher depression scores at baseline, and also at follow-up after
adjusting for baseline depression and covariates. In contrast, dialysis patients
reported lower life satisfaction at baseline than did controls, but the two
cohorts were not significantly different on reported life satisfaction at follow
up, after adjusting for baseline life satisfaction and race. In both cohorts,
functional impairment and depression were significantly related. CONCLUSION:
Older dialysis patients' life satisfaction at a 3-year follow-up, which was
similar to life satisfaction among age-matched controls, indicates the value of
delivered dialysis care; the value of this care would be increased by reducing
excess functional impairment in these patients.
PMID- 10768536
TI - Self-care self-efficacy, quality of life, and depression after stroke.
AB - OBJECTIVE: To determine the relationship of self-care self-efficacy to functional
independence, quality of life, and depression after stroke. METHODS:
Longitudinal, descriptive correlational design. SETTING: Inpatient rehabilitation
facility at 1 month after stroke and home at 6 months after stroke. PARTICIPANTS:
Sixty-three stroke survivors. MAIN OUTCOME MEASURES: Four instruments: Strategies
Used by People to Promote Health, Quality of Life Index--Stroke Version, Center
for Epidemiologic Studies Depression Scale, and Functional Independence Measure.
RESULTS: Self-care self-efficacy increased after stroke and was strongly
correlated with quality of life measures and depression at both 1 and 6 months
after stroke. Functional independence and quality of life increased over time,
while depression decreased. Functional independence was modestly correlated with
quality of life at 6 months after stroke, but not at 1 month after stroke.
CONCLUSIONS: Self-care self-efficacy is strongly related to quality of life and
to depression. Clinicians and family may encourage stroke patients' self
confidence, expectations for self-care, and self-efficacy behaviors, thereby
improving patients' quality of life.
PMID- 10768537
TI - Pressure ulcer risk in spinal cord injury: predictors of ulcer status over 3
years.
AB - OBJECTIVE: To identify predictors of pressure ulcers in men with spinal cord
injury over a 3-year period. DESIGN: Longitudinal, two-panel, cohort. SETTING:
Community. PARTICIPANTS: One hundred eighteen men with spinal cord injury.
MEASURES: Interviews, questionnaires, and physical examinations were completed in
two phases, 3 years apart. Information obtained included demographic and spinal
cord injury characteristics; ulcer history; health beliefs and practices;
measures of impairment, disability, and handicap; and skin integrity. RESULTS:
Thirty-one percent of the participants reported having a pressure ulcer in the 12
months before Phase 2. Some Phase 1 predictors of self-reported ulcers in the
year before Phase 2 were a younger age at onset of spinal cord injury, previous
pressure ulcer surgery, and the presence of a pressure ulcer in the year before
Phase 1. On examination at Phase 2, 59% presented with an ulcer. Phase 1
predictors of ulcer presence at Phase 2 examination were similar to predictors
for self-reported ulcers. CONCLUSION: Individuals with the identified predictive
characteristics are at greater risk for developing pressure ulcers. These
individuals should receive additional interventions to reduce that risk.
Potential interventions include more systematic and frequent follow-up, frequent
review of pressure ulcer prevention and management strategies, and provision of
needed personal assistance and relevant equipment.
PMID- 10768538
TI - Pursed lips breathing improves ventilation in myotonic muscular dystrophy.
AB - OBJECTIVE: To determine the effects of pursed lips breathing on ventilation,
chest wall mechanics, and abdominal muscle recruitment in myotonic muscular
dystrophy (MMD). DESIGN: Before-after trial. SETTING: University hospital
pulmonary function laboratory. PARTICIPANTS: Eleven subjects with MMD and 13
normal controls. INTERVENTION: Pursed lips breathing. OUTCOME MEASURES:
Electromyographic (EMG) activity of the transversus abdominis, external oblique,
internal oblique, and rectus abdominis was recorded with simultaneous measures of
gastric pressure, abdominal plethysmography, and oxygen saturation. Self-reported
sensations of dyspnea, respiratory effort, and fatigue were recorded at the end
of each trial. RESULTS: Pursed lips breathing and deep breathing led to increased
tidal volume, increased minute ventilation, increased oxygen saturation, reduced
respiratory rate, and reduced endexpiratory lung volume. Dyspnea, respiratory
effort, and fatigue increased slightly with pursed lips breathing. EMG activity
of the transversus abdominis and internal oblique muscles increased in MMD only
and was associated with an increase in gastric pressure. CONCLUSIONS: Pursed lips
breathing and deep breathing are effective and easily employed strategies that
significantly improve tidal volume and oxygen saturation in subjects with MMD.
Abdominal muscle recruitment does not explain the ventilatory improvements, but
reduced end-expiratory lung volume may increase the elastic recoil of the chest
wall. Further clinical studies are needed to ascertain if the ventilatory
improvements with pursed lips breathing and deep breathing improve pulmonary
outcomes in MMD.
PMID- 10768539
TI - Functional outcome in knee osteoarthritis after treatment with hylan G-F 20: a
prospective study.
AB - OBJECTIVE: To assess functional change in patients with knee osteoarthritis (OA)
after treatment with intra-articular hyaluronic acid (Hylan G-F 20; Synvisc).
DESIGN: Prospective case series with 6-month follow-up. SETTING: Outpatient
community orthopedic practice. PARTICIPANTS: Eighty-four consecutive patients
referred to private orthopedic group with symptoms and radiographic evidence of
unilateral or bilateral knee OA who had either failed or could not tolerate the
side effects of conservative treatment. Sixty-one patients completed the study.
Nineteen patients were lost to follow-up. Four patients withdrew from study due
to subsequent knee arthroplasty. INTERVENTION: Three weekly injections of Hylan G
F 20 into one or both (if bilaterally symptomatic) knees (110 knees total).
OUTCOME MEASURE: SF-36 Health Survey was completed before treatment and 6 months
after treatment. RESULTS: Statistically significant improvement (p < .001) in
Physical Functioning, Role-Physical, Bodily Pain, Social Functioning, and Role
Emotional categories on 6-month follow-up survey. Age and percent above ideal
body weight were not significant predictors of functional change. CONCLUSION:
Efficacy of intra-articular injection of Hylan G-F 20 for knee OA 6 months after
injection is demonstrated in several categories of the SF-36, indicating a
measurable improvement in overall functioning in these patients.
PMID- 10768540
TI - Gait and postural stability in obese and nonobese prepubertal boys.
AB - OBJECTIVE: To examine differences in gait and postural stability of obese and
nonobese prepubertal boys. DESIGN: Percentage of gait cycle in double support was
examined to determine significant differences. Postural stability was compared
using temporal and frequency measures of the center of pressure in static stance.
SETTING: Gait was examined using videography on a 30-meter walkway. Postural
stability was examined using a measurement platform. PARTICIPANTS: Ten obese
(>95th percentile in body mass index) and 10 nonobese (15th to 90th percentile in
body mass index) prepubertal boys aged 8 to 10yrs. INTERVENTION: Participants
were examined at three walking cadences as determined by preferred gait cadence.
Full vision, darkness, and visually confused conditions were used to accentuate
static postural stability differences. MAIN OUTCOME MEASURES: In the presence of
dynamic stability differences (gait), static stability measures further
investigated stability differences. RESULTS: Obese boys spent significantly (p <
.02) greater percentage of gait cycle in dual stance. Obese boys showed
significantly (p < .01) greater sway areas, energy, and variability primarily in
the medial/lateral direction. CONCLUSIONS: Dual stance differences suggest
diminished dynamic stability in obese boys. Greater sway areas in medial/lateral
direction in obese boys and the absence of significant frequency measures suggest
that the instability observed in obese boys is caused by excess weight rather
than underlying postural instability.
PMID- 10768541
TI - User assessment of manual wheelchair ride comfort and ergonomics.
AB - OBJECTIVE: To examine wheelchair-user perceived ride comfort during propulsion
and to compare the ride comfort of ultralight and lightweight manual wheelchairs.
An ultralight wheelchair is defined as having a high degree of adjustability,
whereas a lightweight wheelchair has minimal adjustability. DESIGN AND
PARTICIPANTS: Repeated measures design of a sample of 30 community-dwelling
manual wheelchair users evaluating 7 different manual wheelchairs over an
activities of daily living course. SETTING: A rehabilitation engineering center.
MAIN OUTCOME MEASURES: Subject ratings of perceived ride comfort and basic
ergonomics while propelling over the activities of daily living course. Ratings
were recorded for each wheelchair on individual tasks and for the course overall.
RESULTS: The Invacare Action XT wheelchair was ranked best for both ride comfort
and basic ergonomics. The ride-comfort scores (p < .05) and wheelchair ergonomics
ratings (p < .05) for the ultralight wheelchair group were significantly
different from those for lightweight wheelchair group. CONCLUSION: There are
differences in perceived ride comfort and basic ergonomics between the designs of
the wheelchairs (lightweight vs ultralight). Subjects perceived that ultralight
wheelchairs were more comfortable and had better basic ergonomics than
lightweight wheelchairs.
PMID- 10768542
TI - Thermographic parameters in the diagnosis of secondary Raynaud's phenomenon.
AB - OBJECTIVE: To determine the major infrared thermographic parameters in
discriminating between patients with and without secondary Raynaud's phenomenon.
DESIGN: A cross-sectional study. SETTING: Outpatient clinic of a university
department of physical medicine and rehabilitation in Vienna. PATIENTS:
Consecutive sample of 86 patients (72 women, 14 men) referred from the Division
of Rheumatology for the clarification of a possible secondary Raynaud's
phenomenon. MAIN OUTCOME MEASURES: According to color changes induced by cold
exposure, clinical classification of Raynaud's phenomenon was performed as
follows: no, unlikely, probable, and definite Raynaud's phenomenon. The following
thermographic parameters were applied to a stepwise logistic regression analysis:
the absolute temperature of the fingertips before, 10, and 20 minutes after cold
challenge (Tpre, T10, T20); the longitudinal temperature difference before, 10,
and 20 minutes after cold challenge (LTDpre, LTD10, LTD20); the mean area under
the rewarming curve of the fingertips; the recovery index 20 minutes after cold
challenge (RI20); and the most rapid phase of rewarming of the fingertips of both
hands (Gmax right, Gmax left). The sensitivity of thermographic classification
into the 4 groups of clinical evaluation was assessed by discriminant analysis
using significant parameters from logistic regression analysis. RESULTS: Only
LTDpre reached the level of significance (p < .0001). Using LTDpre, 22 of 23
subjects without clinical Raynaud's phenomenon and 20 of 26 patients with
definite clinical Raynaud's phenomenon were classified correctly. Patients with
unlikely or probable Raynaud's phenomenon were classified as no Raynaud's
phenomenon or definite Raynaud's phenomenon. CONCLUSION: LTDpre is the major
thermographic parameter to discriminate between patients with and without
definite Raynaud's phenomenon by clinical history.
PMID- 10768543
TI - Biomechanical analysis of a weight-relief maneuver in C5 and C6 quadriplegia.
AB - OBJECTIVE: To determine the kinematics and kinetics of performing a weight-relief
maneuver in persons with C5 and C6 quadriplegia. STUDY DESIGN: A three
dimensional kinematic and kinetic analysis was performed on the upward phase of a
weight-relief maneuver with the use of a motion analysis system, two force
platforms, and an instrumented seat. Electromyography (EMG) data were collected
from the upper pectoralis, anterior deltoid, latissimus dorsi, and biceps brachii
muscles of the right upper limb. SETTING: Biomechanics laboratory. SUBJECTS:
Seven persons with C5 and C6 quadriplegia (ASIA A and B) with "flickers" (grade
1/5) or less in wrist flexor and triceps brachii muscles. MAIN OUTCOME MEASURES:
Angular displacements and associated moments of the shoulder, elbow, and wrist,
kinematic variables describing the position and displacement of the trunk and
upper limbs, and EMG data. RESULTS: Subjects lifted from a forward flexed posture
with their arms adducted against their trunks. During the course of lifting, they
flexed their shoulders and wrists and extended their elbows. They generated peak
mean (+/- SE) shoulder and elbow flexor moments of .65 (+/-.04) and .41 (+/-.06)
N x m x kg(-1), respectively. Shoulder adductor moments increased over the course
of the lift. The median (and interquartile range) mean EMG activity in the upper
pectoralis and the anterior deltoid muscles were 63% (35%-76%) and 44% (36%-49%)
of EMG obtained during maximal voluntary contractions, respectively. CONCLUSION:
Persons with quadriplegia with paralysis of the triceps brachii muscles lift
themselves by generating active shoulder flexor and adductor moments. They also
rely on wrist flexor moments that are generated by the stretch of the wrist
flexor muscles.
PMID- 10768544
TI - Cardiovascular consequences of loss of supraspinal control of the sympathetic
nervous system after spinal cord injury.
AB - Spinal cord injury (SCI) with resultant quadriplegia or high paraplegia is
associated with significant dysfunction of the sympathetic nervous system. This
alteration of sympathetic nervous system activity occurs as a consequence of loss
of supraspinal control of the sympathetic nervous system and is further
complicated by at least three subsequent phenomena that occur below the level of
SCI: reduced overall sympathetic activity, morphologic changes in sympathetic
preganglionic neurons, and peripheral alpha-adrenoceptor hyperresponsiveness.
Reduced sympathetic activity below the level of SCI appears to result in
orthostatic hypotension, low resting blood pressure, loss of diurnal fluctuation
of blood pressure, reflex bradycardia, and, rarely, cardiac arrest. Peripheral
alpha-adrenoceptor hyperresponsiveness likely accounts for some, if not the
majority, of the excessive pressor response in autonomic dysreflexia and may also
contribute to decreased blood flow in the peripheral microcirculation,
potentially increasing susceptibility to pressure sores. What has yet to be
established is whether this alpha-adrenoceptor hyperresponsiveness is a
consequence of receptor hypersensitivity or a failure of presynaptic reuptake of
noradrenaline at the receptor level. Better understanding of the pathophysiology
of sympathetic nervous system dysfunction after high-level SCI should allow
development of more effective measures to manage clinical complications.
PMID- 10768545
TI - The postpericardiotomy syndrome as a cause of pleurisy in rehabilitation
patients.
AB - Pleuritic chest pain in patients on a rehabilitation unit may be caused by
several conditions. We report 2 cases of postpericardiotomy syndrome (PPS) as a
cause of pleuritic pain. PPS occurs in 10% to 40% of patients who have coronary
bypass or valve replacement surgery. The syndrome is characterized by fever,
chest pain, and a pericardial or pleural friction rub. Its etiology is believed
to be viral or immunologic. The syndrome can be a diagnostic challenge, and an
increase in length of hospitalization because of it has been documented.
Identified risk factors for PPS include age, use of prednisone, and a history of
pericarditis. A higher incidence has been reported from May through July. Many
patients undergo a battery of expensive procedures before PPS is diagnosed. The
pain is sharp, associated with deep inspiration, and changes with position.
Pleural effusions may be present and tend to occur bilaterally. Pericardial
effusions are a documented complication. A pericardial or pleural rub may be
present and is often transient. Serial auscultation is important. Laboratory work
provides clues with a mild leukocytosis and an elevated erythrocyte sedimentation
rate. However, this does not provide the definitive diagnosis. Cardiac enzymes
are not reliably related to the syndrome. An electrocardiogram will show changes
similar to those associated with pericarditis. The patient may have a fever, but
it is rarely higher than 102.5 degrees F. Complications include pericardial
effusions, arrhythmias, premature bypass graft closure, and cardiac tamponade.
Treatment consists of a 10-day course of nonsteroidal anti-inflammatory drugs.
PMID- 10768547
TI - Phantom limb pain treated with therapeutic touch: a case report.
AB - Phantom limb pain is a widespread condition that responds poorly to conventional
medical and surgical treatments. A case report is presented of the successful
treatment of phantom leg pain in a 62-year-old man with peripheral vascular
disease using the complementary medical technique of Therapeutic Touch. The
clinical and research literature of Therapeutic Touch is briefly reviewed, with
regard to subjective outcome measures like pain and anxiety, as well as to
several objective measures of physiologic function. The possible role of
nonspecific factors like placebo responsiveness or hypnotic dissociation in this
case are considered, as are the applicability of complementary and alternative
medicine to phantom limb pain, the neurologic mechanisms that generate phantom
sensations, and the possible mechanism of action of Therapeutic Touch.
PMID- 10768546
TI - Lyme neuroborreliosis mimics stroke: a case report.
AB - Lyme neuroborreliosis is diagnostically challenging because of its diverse
manifestations. The well-documented neurologic spectrum includes lymphocytic
meningitis, cranial neuropathy, and radiculoneuritis in the early disseminated
stage; and peripheral neuropathy, chronic encephalomyelitis, and mild
encephalopathy in the late persistent stage. This case report describes a 74-year
old man who developed progressive left hemiparesis and facial palsy. The patient
was hospitalized to rule out a cerebral vascular accident. The diagnosis of Lyme
borreliosis was established with serologic studies. The patient was treated with
intravenous ceftriaxone and responded with rapid clinical and functional
recovery. Lyme neuroborreliosis presenting as hemiparesis has rarely been
reported. Prompt diagnosis and treatment appear to facilitate symptomatic relief
and prevent persistent neurologic deficits.
PMID- 10768548
TI - Gait in adolescent cerebral palsy: the effect of partial unweighting.
AB - OBJECTIVE: To determine the efficacy of partial unweighting in improving gait in
a patient with cerebral palsy. PATIENT: One medically stable 17-year-old female,
classified as having spasticity. METHODS AND MATERIALS: Heart rate, blood
pressure, and perceived exertion were recorded across increments in treadmill
gait speed as a function of nonsupported and partial unweighting conditions (30%
of body mass supported). Nonsupported and partial unweighting conditions were
administered 1 week apart. RESULTS: The partial unweighting condition resulted in
significantly lower physiologic (heart rate and blood pressure) indices and
perceived exertion across all increments in gait speed. Additionally, the subject
was able to ambulate at a faster rate of speed under the partial unweighting
relative to nonsupported conditions. CONCLUSIONS: These results suggest partial
unweighting improves gait efficiency across increments in gait speed, but only to
a certain point. For the subject in this report, gait efficiency declined as
speed increased beyond some critical threshold (about 2.72km/h), suggesting a
limit to partial unweighting during gait training as a function of endurance and
training.
PMID- 10768549
TI - The National Center for Medical Rehabilitation Research Institutional Training
Program, 1992 to 1997.
PMID- 10768550
TI - Osteoarthritis of the knee.
PMID- 10768551
TI - Hanford: study leaves questions about increased thyroid cancer rates unanswered.
PMID- 10768552
TI - Hanford "member of the public" speaks out.
PMID- 10768553
TI - On FDG PET metabolic imaging to assess myocardial viability.
PMID- 10768554
TI - Diagnosis of extensive coronary artery disease: intrinisic value of increased
lung 201 T1 uptake with exercise SPECT.
AB - Exercise lung 201 TI uptake calculated with planar imaging has an important
diagnostic and prognostic value in patients with coronary artery disease (CAD).
However, its value with SPECT imaging raises methodological concerns and is
controversial. We studied its value for the discrimination between extensive (E)
and limited (L) angiographic CAD with exercise SPECT. METHODS: Four methods of
lung-to-heart ratio quantification were calculated in patients with a low
likelihood (< 5%) of CAD (n = 62). Their dependent variables were defined, and
corresponding correction equations were derived. Receiver operating
characteristic (ROC) analysis was performed in a pilot group (L-CAD, n = 49; E
CAD, n = 126) to define the optimal method of calculation of the lung-to-heart
ratio. Its best threshold providing the best sensitivity for a specificity of 90%
was defined. After correction for dependent variables, the 4 methods were also
compared by ROC analysis and the optimal corrected method was compared with the
optimal uncorrected method using ROC analysis and the best threshold. The
consistency of these results in the validation group (L-CAD, n = 41; E-CAD, n =
122) and of the results of visual analysis of lung 201TI uptake were then
verified. RESULTS: On ROC analysis in the pilot group, the optimal method of
calculation of the lung-to-heart ratio was the mean activity in a region of
interest drawn at the base of the lungs to the mean activity over the heart
(Lb/H). For the best threshold, Lb/H presented a sensitivity of 34%. Corrected
Lb/H still remained the best method of calculation on ROC analysis compared with
the other corrected methods. On ROC analysis, there was no difference between
corrected and uncorrected Lb/H. For the best threshold, corrected Lb/H presented
a similar sensitivity of 37% compared with uncorrected Lb/H. When applied to the
validation group (L-CAD, n = 41; E-CAD, n = 122), the best-defined threshold in
the pilot group for corrected Lb/H presented a diagnostic value similar to that
in the pilot group (sensitivity, 41%; specificity, 90%), but uncorrected Lb/H
presented a higher sensitivity (47%; P < 0.04) and a slightly lower specificity
(80%). Results of lung 201TI uptake visual analysis were inconsistent between
pilot and validation groups (42% versus 58% sensitivity, P = 0.012; 86% versus
66% specificity, P = 0.023). CONCLUSIONS: For evaluation of E-CAD versus L-CAD,
quantification of the exercise lung-to-heart 201TI uptake ratio with SPECT is
feasible, reproducible, more discriminate than simple visual analysis, and best
calculated as Lb/H. It presents an intrinsic diagnostic value even after
correction for other clinically valuable dependent variables.
PMID- 10768555
TI - Cerebral metabolic response to passive audiovisual stimulation in patients with
Alzheimer's disease and healthy volunteers assessed by PET.
AB - Alzheimer's disease is associated with reductions in resting-state brain
metabolism, as measured by PET, progressing with dementia severity. The purpose
of this study was to see to what extent brain regions with reduced resting-state
metabolic rates in Alzheimer patients could be activated by a passive audiovisual
stimulation test and to compare the result with activation in age-matched healthy
volunteers. The extent of activation in Alzheimer's disease is considered to
reflect the integrity of synaptic function, or inherent viability, and the
potential responsiveness of the Alzheimer brain to drug therapy. METHODS:
Regional cerebral metabolic rates for glucose (rCMRglc, in mg/ 100 g tissue/min)
were measured in the resting state (eyes and ears covered) and during passive
audiovisual stimulation (watching a movie) in 15 otherwise healthy Alzheimer
patients of differing dementia severity (Mattis Dementia Rating Scale score, 23
128) and in 14 age-matched healthy volunteers (score, 141 +/- 3) using PET with 2
sequential injections of FDG. RESULTS: In the volunteers, audiovisual stimulation
caused significant rCMRglc increases in visual and auditory cortical areas but
significant decreases in frontal areas. In the mildly demented patients, rCMRglc
responses were within 2 SDs of the mean in volunteers. However, the magnitude of
the rCMRglc responses during stimulation declined significantly with dementia
severity in the right occipitotemporal, right and left occipital association, and
left calcarine cortical regions. CONCLUSION: Functional brain responsiveness,
evaluated by a passive audiovisual stimulation paradigm with PET, is within
normal limits in mildly demented Alzheimer patients but fails with worsening
dementia severity. Declining responsiveness may account for the limited success
of neurotransmitter replacement therapy in Alzheimer patients with moderate-to
severe dementia.
PMID- 10768557
TI - Quantitative analysis of technegas SPECT: evaluation of regional severity of
emphysema.
AB - The purpose of this study was to quantify the regional severity of emphysema by 3
dimensional fractal analysis of technegas (99mTc-carbon particle radioaerosol)
SPECT images. METHODS: Technegas SPECT was performed on 22 patients with
emphysema. The lungs were delineated using 4 cutoff levels (15%, 20%, 25%, and
30% of the maximal pixel radioactivity), and the total number of pixels was
measured in the areas surrounded by the contours obtained with each cutoff level.
We calculated fractal dimensions from the relationship between the total number
of pixels and cutoff levels transformed into logarithms. Fractal dimension for
total or regional lung was defined as the severity of emphysema. RESULTS: Total
lung fractal dimension (T-FD), upper lung fractal dimension (U-FD), and lower
lung fractal dimension (L-FD) for patients with emphysema were 1.84 +/- 0.46
(mean +/-SD), 2.22 +/- 0.61, and 1.77 +/- 0.49, respectively. U-FD was
significantly greater than was L-FD. Patients with the ratio of U-FD to L-FD of
<1.16 had a significantly greater percentage forced vital capacity (FVC) than did
patients with the ratio of >1.16. Patients with an L-FD of <1.8 had a
significantly greater forced expiratory volume in 1 s (FEV1)/FVC than did
patients with that of >1.8. No significant difference was found between patient
groups stratified by U-FD. CONCLUSION: The regional severity of emphysema was
well shown by these fractal dimensions.
PMID- 10768556
TI - Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson's
disease and in healthy volunteers.
AB - [99mTc]TRODAT-1 is a radiolabeled tropane that binds dopamine transporters. The
primary goal of this study was to determine whether its regional cerebral
distribution could differentiate between patients with Parkinson's disease and
healthy human volunteers. METHODS: The sample consisted of 42 patients with
Parkinson's disease, 23 age-matched controls, and 38 healthy adults younger than
40 y old. SPECT scans of the brain were acquired on a triple-head gamma camera 3
4 h after the intravenous injection of 740 MBq (20 mCi) [99mTc]TRODAT-1. Mean
counts per pixel were measured manually in subregions of the basal ganglia and
normalized to the mean background counts to give specific uptake values ([SUVs]
approximately k3/k4). Patient and control groups were also compared with
automated statistical parametric mapping techniques. Logistic discriminant
analyses were performed to determine the optimum uptake values for
differentiating patients from age-matched controls. RESULTS: Quantitative image
analysis showed that the group mean SUVs in patients were less than the mean
values in controls for all regions (all Ps < 0.000001). There was overlap in the
caudate as well as in the anterior-most portion of the putamen, but not in the
posterior putamen, even when the asymptomatic sides of 5 patients with clinically
defined hemi-Parkinson's disease were factored in. CONCLUSION: The findings
indicate that Parkinson's disease can be detected with [99mTc]TRODAT by simply
inspecting the images for uptake in the posterior putamen. Appropriate
asymmetries seem to be visible with quantification in patients with clinically
defined hemi-Parkinson's disease, even though changes in the putamen
contralateral to the clinically unaffected side in these patients appear to
precede the development of symptoms.
PMID- 10768558
TI - Effect of early emptying on quantitation and interpretation of liquid gastric
emptying studies of infants and young children.
AB - This study assesses the effect of emptying that occurs during feeding on
quantitation and interpretation of liquid gastric emptying studies of infants and
young children. METHODS: Forty-nine 99mTc-sulfur colloid liquid gastric emptying
studies of 44 children (22 boys, 22 girls; mean age, 20 mo; age range, 2-46 mo)
fed orally or by gastrostomy tubes were evaluated. Gastric residuals quantitated
by 2 commonly used methods, the first of which does not account for early
emptying and the second of which does, were compared. With the first method,
residual relative to activity in the stomach at the start of imaging (Rg) was
quantified by comparing activity in a region of interest (ROI) drawn about the
stomach on the final image to activity in an ROI drawn about only the stomach at
the start of imaging. With the second method, residual relative to total dose
(Rt) was quantified by comparing activity in the same final ROI to activity in an
ROI that included stomach and small bowel at the start of imaging. Studies were
interpreted independently for Rg and Rt considering a value >70% as evidence of
delayed emptying. RESULTS: Rt was lower than Rg by 15%-16% for the entire
population, for patients fed orally, and for patients fed by gastrostomy tube.
These differences reached statistical significance (P < 0.0001). In 31 of 49
studies, R1 was lower than Rg by > or =10%. In 8 studies, emptying classified as
delayed on the basis of Rg was classified as nondelayed on the basis of Rt.
Clinical decisions based on Rt did not require later management changes that
would have indicated that treatment of gastric dysmotility had been postponed in
any patient. CONCLUSION: Emptying that occurs during feeding should be factored
into quantitation of liquid gastric emptying in infants and young children. Not
recognizing and accounting for early emptying results in overestimated gastric
residuals and can lead to classification of emptying as delayed in children whose
residuals of the total administered dose are within a recognized range of normal.
PMID- 10768559
TI - Evaluation of portosystemic collaterals by SPECT imaging after endoscopic
variceal sclerotherapy: usefulness for predicting recurrence.
AB - Bleeding from esophageal varices is a major cause of morbidity and mortality in
cirrhotic patients. Identification of patients at high risk for bleeding is
particularly important. The aim of this study was to determine whether detection
of portosystemic collaterals by SPECT could predict the outcome of endoscopic
injection sclerotherapy of esophageal varices and be useful for selecting
appropriate therapy. METHODS: Sixty-two patients with liver cirrhosis who were
considered at high risk of bleeding were treated with endoscopic injection
sclerotherapy. Endoscopy was performed every 3 mo after therapy or until bleeding
occurred. Before and within 2 wk after therapy, tomographic images of intra
abdominal blood pool were constructed by SPECT. RESULTS: Before therapy, the
following portosystemic collateral routes were observed: coronary veins in 53
(85.5%) of 62 patients, short gastric veins in 8 patients (12.9%), splenorenal
shunts in 10 patients (16.1%), and paraumbilical veins in 6 patients (9.7%).
Patients positive for imaging of coronary veins were divided into 3 groups on the
basis of changes in images after therapy: complete responders (n = 17), whose
coronary vein images disappeared completely; partial responders (n = 18), whose
images became smaller; and nonresponders (n = 18), whose images did not change
significantly before or after therapy. The rates of recurrence after endoscopic
injection sclerotherapy until 6 mo in complete responders (4/17, 23.5%) and
partial responders (7/18, 38.9%) were significantly less (P < 0.05) than that in
nonresponders (11/13, 84.6%). The rate of recurrence of esophageal varices until
6 mo in nonresponders treated with additional submucosal injection sclerotherapy
(1/5, 20.0%) was significantly less (P < 0.05) than that in nonresponders without
additional submucosal injection sclerotherapy (11/13, 84.6%). CONCLUSION:
Abdominal blood-pool SPECT, a noninvasive method, is useful for evaluating the
therapeutic effectiveness of endoscopic sclerotherapy, for predicting the
recurrence of varices, and for selecting appropriate management after
sclerotherapy.
PMID- 10768560
TI - On-line measurement of exhaled [11C]CO2 during PET.
AB - The purpose of this study was to develop and evaluate a system for the continuous
on-line measurement of expired 11CO2 during 11C PET studies. METHODS: A detector
system was developed that allowed continuous sampling of expired air during PET.
Healthy volunteers (n = 4) underwent PET with [11C]CO2 during which expired air,
tomographic tissue activity, and blood data were collected. The measured expired
air 11CO2 radioactivity time courses were filtered, and an envelope was extracted
and compared with the time course of 11CO2/H11CO3 in blood. RESULTS: Good
agreement was found between the shapes of the expired-air envelope and the time
course in blood, enabling quantitative calibration against discrete blood
samples. CONCLUSION: A system for the continuous monitoring of expired
radioactivity during PET has been developed and evaluated with [11C]CO2. This
monitoring enables the quantitative continuous measurement of 11CO2/H11CO3- in
blood.
PMID- 10768561
TI - Comparison of voxel- and volume-of-interest-based analyses in FDG PET scans of
HIV positive and healthy individuals.
AB - Abnormal glucose metabolic patterns in the brain have been reported for HIV-1
seropositive (HIV+) patients when compared with seronegative healthy individuals.
The metabolic covariance pattern obtained from voxel- or volume-of-interest (VOI)
based multivariate data analysis techniques can be used to characterize disease
and potentially to detect and monitor disease progression in the early stage of
AIDS dementia complex. However, the arbitrary smoothing typically applied to PET
data during reconstruction and processing to reduce noise has an unknown effect
on the data, especially for the voxel-based analysis. METHODS: To investigate the
impact of smoothing on a discrimination task, we applied principal component
analysis with scaled subprofile-model preprocessing (SSM/PCA) followed by Fisher
discriminant analysis to FDG PET data that were reconstructed and processed with
different degrees of smoothing. Receiver operating characteristic curves were
used to compare the ability of derived metabolic covariance patterns to
discriminate HIV+ patients from healthy volunteers. RESULTS: For the voxel-based
analysis, we found that the spatial distribution of voxel weights from the
SSM/PCA analysis suggested edge effects along major tissue and cerebrospinal
fluid boundaries, indicative of a disease-specific pattern of cerebral atrophy
for the HIV+ patients. In terms of its discrimination performance, this metabolic
covariance pattern is stable and insensitive to a wide range of smoothing
kernels, except for ramp reconstruction and Hanning reconstruction with 7 x 7 x 7
block smoothing. In these reconstructions, the discrimination performance
decreased as a result of high image noise and excessive smoothing, respectively.
Our results also indicated that if sufficient variance from the VOI measurements
is included, the overall performance of a conventional VOI-based analysis can be
similar to that of the voxel-based analysis for the same discrimination task.
However, the VOI-based analysis performed poorly at low false-positive fraction
and is less tolerant to noise in the metabolic covariance pattern than the voxel
based analysis. CONCLUSION: We have obtained a unique covariance pattern of brain
glucose metabolism for HIV+ patients compared with healthy volunteers.
Discrimination based on this covariance pattern was found to be insensitive to a
wide range of image smoothness.
PMID- 10768562
TI - 99mTc-PEG liposomes for the scintigraphic detection of infection and
inflammation: clinical evaluation.
AB - Polyethyleneglycol (PEG) liposomes have been shown to be excellent vehicles for
scintigraphic imaging of infection and inflammation in various experimental
models. In this article we report on a series of patients with possible
infectious and inflammatory disease in whom the performance of 99mTc-PEG
liposomes was evaluated. The results of 99mTc-PEG liposome scintigraphy were
directly compared with those of 111In-immunoglobulin G (IgG) scintigraphy.
METHODS: Thirty-five patients (22 men, 13 women; mean age, 51 y; range, 20-76 y),
suspected of having infectious or inflammatory disease, received 740 MBq 99mTc
PEG liposomes intravenously. Imaging was performed at 4 and 24 h after injection.
Patients received 75 MBq 111In-IgG 24 h after administration of the liposomes.
The scintigraphic results were compared and verified by culture, biopsy, surgery,
and follow-up of at least 6 mo. RESULTS: Of the 16 proven infections and
inflammations, 15 were detected by 99mTc-PEG liposome scintigraphy: soft-tissue
infection (n = 3), septic arthritis (n = 3), autoimmune polyarthritis (n = 2),
infected hip prosthesis (n = 1), infected osteosynthesis (n = 1),
spondylodiscitis (n = 1), infected aortic prosthesis (n = 1), colitis (n = 1),
abdominal abscess (n = 1), and pneumonia (n = 1). 99mTc-PEG liposome and 111In
IgG scintigraphy both missed 1 case of endocarditis. In addition, an 111In-IgG
scan of a patient with mild soft-tissue infection was false-negative.
Concordantly false-positive scans were recorded from 2 patients, both with
uninfected pseudarthrosis and focal signs of sterile inflammation. During
liposomal administration, 1 patient experienced flushing and chest tightness,
which rapidly disappeared after lowering the infusion rate. No other adverse
events were observed. CONCLUSION: This clinical evaluation of 99mTc-PEG liposomes
shows that focal infection and inflammation can be adequately imaged with this
new agent. The performance of 99mTc-PEG liposomes is at least as effective as
that of 111In-IgG. With the simple and safe preparation and the physical and
logistic advantages of a 99mTc label, 99mTc-PEG liposomes could be an attractive
agent for infection or inflammation imaging.
PMID- 10768563
TI - 99mTc-sestamibi and 131I whole-body scintigraphy and initial serum thyroglobulin
in the management of differentiated thyroid carcinoma.
AB - 99mTc-sestamibi whole-body scanning has been used in the postoperative assessment
of differentiated thyroid carcinoma together with 131I whole-body scanning and
serum thyroglobulin (Tg) estimation. This study compared 99mTc-sestamibi whole
body scanning with 131I whole-body scanning in the context of initial serum Tg
levels of patients after total or near-total thyroidectomy who were taken off
thyroxine suppression therapy and who had no 131I ablation before surgery.
METHODS: A prospective study of 360 patients was undertaken. 99mTc-sestamibi
whole-body scintigraphy was performed at least 5 wk after thyroidectomy and was
followed by 131I whole-body scanning. The patients had no thyroxine suppression
for 5 wk, and Tg was measured thereafter. Radiologic studies (chest radiography,
CT, MRI, sonography, and bone scanning) and histopathologic examinations were
performed to clarify the presence of metastases with positive uptake on either
99mTc-sestamibi scans or 131I whole-body scans. Positive scans were defined as
those with the presence of thyroid remnants, lymph node disease, or metastases.
RESULTS: Two hundred fifty-nine (71.9%) of the 360 patients had initial serum Tg
levels < 30 ng/mL (group 1), whereas 101 (28.1%) had initial serum Tg levels > or
= 30 ng/mL (group 2). Of the 259 group 1 patients, 82 had positive 99mTc
sestamibi scans and 113 had positive 131I scans; 71.7% of patients with positive
1311 scans also had positive 99mTc-sestamibi scans, and 98.8% of patients with
positive 99mTc-sestamibi scans also had positive 131I scans. Of the 101 group 2
patients, 81 had positive 99mTc-sestamibi scans and 97 had positive 131I scans;
83.5% of patients with positive 131I scans also had positive 99mTc-sestamibi
scans, and all patients with positive 99mTc-sestamibi scans also had positive
131I scans. Of those with initial serum Tg levels > or = 30 ng/mL (group 2),
27.2% had thyroid remnants and 68.8% had lymph node disease or metastases. 131I
scanning detects more thyroid remnants and lung metastases than does 99mTc
sestamibi scanning. CONCLUSION: Our findings suggest that, compared with 131I
scanning, 99mTc-sestamibi scanning is less sensitive in detecting thyroid
remnants and lung metastases but appears to be more useful in the detection of
lymph node disease before initial 131I treatment.
PMID- 10768564
TI - 111In-DTPA-D-Phe1-octreotide binding and somatostatin receptor subtypes in
thyroid tumors.
AB - The purpose of this study was to evaluate the potential for therapy of thyroid
tumors using the radiolabeled somatostatin (SS) analog octreotide. METHODS:
Concentrations of 111In activity in human thyroid tumors and normal thyroid
tissue and blood samples were determined 1-15 d after intravenous injection of
111In-diethylenetriaminepentaacetic acid-Phe1-octreotide. The results were
compared with SS receptor (sstr subtype profile (by Northern blot analysis) and
the relative expression of the second subtype, sstr2 (by ribonuclease protection
assay, RPA). The true tumor volumes in lymph node metastases from 1 patient were
estimated. In total, tissues from 68 patients were included in the study.
RESULTS: The highest tumor-to-blood ratio (T/B) for medullary thyroid carcinoma
(MTC) was 360; for follicular adenoma (FA), 190; for Hurthle cell adenoma (HCA),
140; and for Hurthle cell carcinoma (HCC) and papillary carcinoma (PC), 70. The
corresponding value was 7-18 for normal thyroid tissue, with higher values for
colloid goiter (8-48) and thyroiditis (7-120). A high T/B was related to a large
fraction of tumor cells in lymph node metastases. T/Bs were higher for the tumor
samples with expression of sstr2 at Northern blot analysis than for those
without. All thyroid tumor types regularly expressed sstr1, sstr3, sstr4, and
sstr5. sstr2 was expressed in most MTC tumors but was not detected in FA or PC
and was irregularly expressed in HCA and HCC. However, RPA analysis detected
sstr2 in all tumors studied. CONCLUSION: Despite the lack of sstr2 at Northern
blot analysis in most of the thyroid tumors studied, high T/Bs were in general
found when compared with corresponding values for normal thyroid tissue. The
sometimes extremely high ratios are promising and indicate a possibility of using
radiolabeled octreotide for radiation therapy of sstr-positive tumors in the
future.
PMID- 10768565
TI - Follow-up regimen of differentiated thyroid carcinoma in thyroidectomized
patients after thyroid hormone withdrawal.
AB - For differentiated, nonmedullary thyroid carcinoma, postsurgical ablation of
thyroid remnants and treatment of residual tumor and metastases with 131I is a
potentially curative therapy. The aim of this study was to optimize the
diagnostic protocol for the follow-up of thyroidectomized patients. METHODS: Two
hundred fifty-four patients (187 females, 67 males; mean age, 45 y; range, 8-83
y) were studied retrospectively for a mean follow-up period of 2.7 y (range, 1
12.5 y). An evaluation study consisted of a low-dose 131I diagnostic procedure
under hyperthyroid conditions (thyroid-stimulating hormone > 30 MicroU/mL), 201TI
scintigraphy, and measurement of thyroglobulin (Tg) under hypothyroid conditions.
A total of 254 preablation studies (1 study per patient) and 586 follow-up
studies (average number of studies, 2.3 per patient) were evaluated. RESULTS:
Before ablation, low-dose 131I screening was useful to estimate the size of the
thyroid remnant. Low Tg levels (<10 pmol/L) indicated the absence of metastases.
After ablation, undetectable Tg levels indicated the absence of tumor recurrence.
When Tg levels were high (>10 pmol/L), local recurrence or metastases were always
observed, providing the basis for additional high-dose 131I therapy. In these
patients, 201TI imaging did not provide a significant contribution to patient
management. In the case of autoantibodies against Tg, both low-dose 131I
screening and 201TI scintigraphy may be advocated to allow an aggressive
diagnostic work-up. CONCLUSION: Tg plays a key role in follow-up and in making
decisions to treat patients with differentiated thyroid carcinoma. The role of
201TI imaging is very limited. In patients with negative low-dose 131I screening,
201TI scintigraphy can be considered when Tg is elevated or cannot be evaluated
because of autoantibodies against Tg. Under such circumstances, administration of
a therapeutic 131I dose without 201TI imaging can be considered.
PMID- 10768566
TI - Short- and long-term effects of 186Re-1,1-hydroxyethylidene diphosphonate in the
treatment of painful bone metastases.
AB - This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1
hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone
metastases and the influence of variables before therapy in determining the
characteristics of pain palliation. METHODS: Sixty patients with painful bone
metastases from different tumor types were treated with 1406 MBq 186Re-HEDP.
After treatment, the patients were followed up clinically at weekly intervals for
the first month and monthly thereafter up to 1 y, until death or pain relapse.
Pain response was graded as complete, partial, minimal, or absent using the
Wisconsin test scoring system. Duration of pain relief, performance status, tumor
markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic
bone progression were also evaluated. RESULTS: Overall, 80% of individuals
experienced prompt relief of pain, with 31% complete, 34% partial, and 15%
minimal responses. Transient World Health Organization grade 1-2 hematologic
toxicity was apparent, with a decrease in the mean platelet (32%) and mean
leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response
did not correlate with any pretreatment variable. The duration of pain relief
ranged from 3 wk to 12 mo and correlated positively with the degree of response
(P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline
phosphatase levels (P = 0.02). CONCLUSION: 186Re-HEDP is effective for fast
palliation of painful bone metastases from various tumors. The effect tends to
last longer if patients are treated early in the course of their disease.
PMID- 10768567
TI - Validation of an analytic method of calculating cerebral glucose metabolism using
PET.
AB - Quantitative modeling of cerebral metabolic rate for glucose (CMRglc) using PET
with the FDG method requires calculation of the integral of the time course of
radioactivity in arterial plasma. Numeric integration has typically been used but
requires 30 or more blood samples taken between 15 s and 100 min after injection
of the radiotracer. Our laboratory has developed an alternative integration
method that fits the values of the plasma samples to an analytically integrable
function using only 4-6 samples taken between 40 and 110 min after radiotracer
injection. METHODS: The plasma integrals were calculated by both the analytic and
the numeric methods with data from FDG PET studies that were not used in the
development of the analytic method. In 39 PET studies from 22 healthy volunteers,
30 plasma samples were taken over 110 min. RESULTS: The plasma integrals
determined by the analytic and numeric methods yielded a within-subject
correlation coefficient of >0.95 and differences of <10%. CONCLUSION: Because the
analytic method requires less blood sampling and does not require sampling
immediately after radiotracer injection, the experimental procedure is simplified
without loss of accuracy in CMRglc computation, and the effect of missing or
incorrect samples is reduced.
PMID- 10768568
TI - PET: the merging of biology and imaging into molecular imaging.
AB - PET and SPECT are molecular imaging techniques that use radiolabeled molecules to
image molecular interactions of biological processes in vivo. PET imaging
technologies have been developed to provide a pathway to the patient from the
experimental paradigms of biological and pharmaceutical sciences in genetically
engineered and tissue transplanted mouse models of disease. PET provides a novel
way for molecular therapies and molecular diagnostics to come together in the
discovery of molecules that can be used in low mass amounts to image the function
of a target and, by elevating the mass, to pharmacologically modify the function
of the target. In both cases, the molecules are the same or analogs of each
other. PET can be used to titrate drugs to their sites of action within organ
systems in vivo and to assay biological outcomes of the processes being modified
in the mouse and the patient. The goal is to provide a novel way to improve the
rates of discovery and approval of radiopharmaceuticals and pharmaceuticals.
Extending this relationship into clinical practice can improve drug use by
providing molecular diagnostics in concert with molecular therapeutics. Diseases
are biological processes, and molecular imaging with PET is sensitive and
informative to these processes. This sensitivity is exemplified by the detection
of disease with PET without evidence of anatomic changes on CT and MRI. These
biological changes are seen early in the course of disease, even in asymptomatic
stages, as illustrated by the metabolic abnormalities detected with PET and FDG
in Huntington's and familial Alzheimer's diseases 7 and 5 y, respectively, before
symptoms appear. Differentiation of viable from nonviable tissue is fundamentally
a metabolic question, as shown by the use of PET to differentiate patients with
coronary artery disease who will benefit from revascularization from those who
will not. Although beginning within a specific organ, cancer is a systemic
disease the most devastating consequences of which result from metastases. Whole
body PET imaging with FDG enables inspection of glucose metabolism in all organ
systems in a single examination to improve the detection and staging of cancer,
selection of therapy, and assessment of therapeutic response. In lung and
colorectal cancers, melanoma, and lymphoma, PET FDG improves the accuracy of
detection and staging from 8% to 43% over conventional work-ups and results in
treatment changes in 20%-40% of the patients, depending on the clinical question.
Approximately 65% are upstaged because unsuspected metastases are detected, and
35% are downstaged because a structural diagnosis of lesions is changed from
malignant to benign. Similar results are now being shown for other cancers. The
main difference between CT, sonography, MRI, and PET or SPECT is not technologic
but, rather, a difference between detecting and characterizing a disease by its
anatomic features as opposed to its biology. The importance and success of
developing new molecular imaging probes is increasing as PET becomes integral to
the study of the integrative mammalian biology of disease and as molecular
therapies targeting the biological processes of disease are developed.
PMID- 10768569
TI - Considerations in the selection of radiopharmaceuticals for palliation of bone
pain from metastatic osseous lesions.
AB - Bone pain is a common complication for terminal patients with bone metastases
from prostate, lung, breast, and other malignancies. A multidisciplinary approach
in treating bone pain is generally required, 1 which includes a combination of
analgesic drug therapy, radiation therapy, hormonal therapy, and chemotherapy.
Over the years, treatment of bone pain using bone-seeking radiopharmaceuticals
has been explored extensively. Pharmaceuticals labeled with energetic 1-particle
emitters such as 32p, 89Sr, 153Sm, and 186Re, in addition to the low-energy
electron emitter 117mSn, have been studied for this purpose. Bone-marrow toxicity
as a consequence of chronic irradiation by the energetic , particles is a general
problem associated with this form of treatment. It is therefore desirable to
identify radiochemicals that minimize the dose to the bone marrow and at the same
time deliver therapeutic doses to the bone. METHODS: New S values (mean absorbed
dose per unit cumulated activity) for target regions of human bone and marrow
were used to ascertain the capacity of various radiochemicals to deliver a high
bone dose while minimizing the marrow dose. The relative dosimetric advantage of
a given radiopharmaceutical compared with a reference radiochemical was
quantitated as a dosimetric relative advantage factor (RAF). Several
radionuclides that emit energetic 1 particles (32p, 89Sr, 153Sm, 186Re, and
177Lu) and radionuclides that emit low-energy electrons or beta particles (169Er,
117mSn, and 33p) were evaluated. For these calculations, ratios of the cumulated
activity in the bone relative to cumulated activity in the marrow alpha equal to
10 and 100 were used. RESULTS: When the radiopharmaceutical was assumed to be
uniformly distributed in the endosteum and alpha was taken as 100 for both the
reference and test radiochemicals, the RAF values compared with the reference
radionuclide 32p were 1.0, 1.2, 1.4, 1.6, 1.7, 1.9, and 2.0 for 89Sr, 186Re,
153Sm, 177Lu, 169Er, 117mSn, and 33P, respectively. In contrast, when the
radiopharmaceutical is assumed to be uniformly distributed in the bone volume,
the RAF values for these 7 radionuclides were 1.1, 1.5, 2.4, 3.2, 4.5, 5.1, and
6.5, respectively. CONCLUSION: These results suggest that low-energy electron
emitters such as 117mSn and 33P are more likely to deliver a therapeutic dose to
the bone while sparing the bone marrow than are energetic beta emitters such as
32p and 89Sr. Therefore, radiochemicals tagged with low-energy electron or beta
emitters are the radiopharmaceuticals of choice for treatment of painful
metastatic disease in bone.
PMID- 10768570
TI - Radionuclides for metastatic bone pain palliation: a need for rational re
evaluation in the new millennium.
PMID- 10768571
TI - Transmission scanning system for a gamma camera coincidence scanner.
AB - The goal of this research was to develop and evaluate a practical transmission
scanning system for attenuation correction on a 2-head gamma camera coincidence
scanner. METHODS: The transmission system operates in singles mode and uses point
sources of 137Cs that emit 662-keV gamma-radiation. Each point source is inserted
between existing septa that are normally used to provide an approximately 2
dimensional emission acquisition geometry. The sources are placed along a line
parallel to the axis of rotation near the edge of 1 camera. Data are acquired
with the opposing camera. The septa provide axial collimation for the sources so
that the transmission system operates in a 2-dimensional offset fanbeam geometry.
Camera energy and spatial resolution were measured at 511 and 662 keV.
Sensitivity was measured at 662 keV. The effects on axial resolution of adding
supplemental collimation to the septa were shown. The system was calibrated and
tested using a resolution (rod) phantom and a uniformity phantom. Torso phantom
data were acquired. Patient transmission and emission scans were obtained.
Postinjection transmission data were used to correct patient emission data.
RESULTS: The camera resolution at postinjection counting rates was 11.7% full
width at half maximum (FWHM) for 662-keV gamma-rays. Intrinsic spatial resolution
was 2.7 mm (FWHM) at 662 keV. The sensitivity of the system was 280 Hz/MBq using
five 74-MBq sources of 137Cs in the transmission geometry, with supplemental
collimation added to the septa to improve axial resolution. The transaxial
resolution of the system was such that the smallest rods (6-mm diameter and 12-mm
spacing) were well resolved in a reconstructed resolution-phantom image. The
corrected patient emission scans were free of attenuation-induced artifacts.
CONCLUSION: An easily implemented transmission system for a 2-head gamma camera
coincidence scanner that can be used for postinjection transmission scanning has
been developed.
PMID- 10768572
TI - Registration of planar emission images with reprojected CT data.
AB - Planar gamma-camera imaging is still widely used clinically. Alignment of planar
images with images from tomographic modalities, such as CT, or with other planar
images would be desirable. Here, we present and evaluate a method for such an
alignment, using planar transmission images acquired with the emission images and
reprojection of the 3-dimensional CT data. This method permits determination of
which CT slice corresponds to a particular row of pixels in the gamma-camera
image and which column of pixels in that CT slice corresponds to a particular
pixel in the emission data. METHODS: A method based on maximization of the
correlation coefficient, previously used for 3-dimensional datasets, was modified
to permit 2-dimensional registrations. Planar transmission measurements were
obtained using a collimated 99mTc flood source in conjunction with planar
emission studies. The CT data were first reprojected to permit the 2-dimensional
registration. The registration method was evaluated for its accuracy and
reproducibility. RESULTS: For phantom data, the registration errors were -0.1 +/-
1.0 mm for x-translations, 1.0 +/- 1.3 mm for y-translations, and -0.2 +/- 0.3
degrees for rotations. For patient data, the errors were 1.6 +/- 0.8 mm for x
translations, 1.3 +/- 1.0 mm for y-translations, and 0.5 +/- 0.5 degrees for
rotations. An examination of the need for rescaling of the attenuation data (to
compensate for the different photon energies used in the respective attenuation
measurements) showed no significant impact on registration error. When 5
different regions of interest were used for the correlation coefficient
calculation, the mean errors attributable to region-of-interest choice alone were
1.0 mm for x-translations, 2.0 mm for y-translations, and 1.2 degrees for
rotations. CONCLUSION: In almost all instances, translational registration errors
were kept to subpixel levels (pixel size, 2.6 mm) and rotational errors to 1
degrees or less. The 1 exception was in the easily avoidable case of "pitch"
rotations of the patient of 2 degrees or more. The modified registration method
provides a simple yet reliable way to provide cross-modality evaluation of planar
emission data.
PMID- 10768573
TI - A general method to correct PET data for tissue metabolites using a dual-scan
approach.
AB - This article presents and analyses a general method of correcting for the
presence of radiolabeled metabolites from a parent radiotracer in tissue during
PET scanning. The method is based on a dual-scan approach, i.e., parent scan
together with an independent supplementary scan in which the radiolabeled
metabolite of interest itself is administered. The method corrects for the
presence of systemically derived radiolabeled metabolite delivered to the tissues
of interest through the blood. METHODS: Data from the supplementary scan are
analyzed to obtain the tissue impulse response function for the metabolite. The
time course of the radiolabeled metabolite in plasma in the parent scan is
convolved with its tissue impulse response function to derive a correction term.
This is not a simple subtraction technique but 1 that takes account of the
different time-activity curves of the radiolabeled metabolite in the 2 scans.
RESULTS: The method, its implications, and its limitations are discussed with
respect to [11C]thymidine and its principal metabolite 11CO2. CONCLUSION: The
general method, based on a dual-scan approach, can be used to correct for
radiolabeled metabolites in tissues of interest during PET scanning. The
correction accounts for radiolabeled metabolites that are derived systemically
and delivered to the tissues of interest through the blood.
PMID- 10768575
TI - A new algorithm for the quantitation of myocardial perfusion SPECT. II:
validation and diagnostic yield.
AB - This study validates a new quantitative perfusion SPECT algorithm for the
assessment of myocardial perfusion. The algorithm is not based on slices and
provides fully 3-dimensional sampling and analysis independent of assumptions
about the geometric shape of the left ventricle. METHODS: Radiopharmaceutical-
and sex-specific normal limits and thresholds for perfusion abnormality in 20
segments of the left ventricle were developed for separate, dual-isotope rest
201Tl-exercise 99mTc-sestamibi SPECT in 36 patients with <5% before-scanning
likelihood of coronary artery disease (CAD) (group 1) and 159 patients with
perfusion abnormalities (group 2). These thresholds were validated in 131
patients (group 3) by comparison with expert visual interpretation. Thresholds
for automatic segmental scores were developed and validated for groups 2 and 3,
respectively. The accuracy of CAD detection was assessed in 94 patients, who
underwent coronary angiography (group 4). RESULTS: Overall sensitivity for
detection of stress and rest segmental perfusion abnormality was 91% and 96%,
respectively, for men and 89% and 79%, respectively, for women. Overall
specificity for stress and rest was 87% and 90%, respectively, for men and 88%
and 90%, respectively, for women. Agreement between automatic and visual scores
was good (weighted K of 0.71 and 0.60 for stress and rest images, respectively).
Sensitivity and specificity were 88% for the detection of > or =70% stenosis. For
the detection of left anterior descending, left circumflex, and right coronary
artery stenosis, sensitivity was 84%, 86%, and 88%, respectively, and specificity
was 84%, 88%, and 81%, respectively. CONCLUSION: The new quantitative perfusion
SPECT approach is highly sensitive and specific for the detection and
localization of CAD, provides accurate automatic scores for the assessment of
regional perfusion, and overcomes the low-specificity limitations of previous
quantitative algorithms.
PMID- 10768574
TI - A new algorithm for the quantitation of myocardial perfusion SPECT. I: technical
principles and reproducibility.
AB - We have developed a new, completely automatic 3-dimensional software approach to
quantitative perfusion SPECT. The main features of the software are myocardial
sampling based on an ellipsoid model; use of the entire count profile between the
endocardial and epicardial surfaces; independence of the algorithm from
myocardial shape, size, and orientation and establishment of a standard 3
dimensional point-to-point correspondence among all sampled myocardial regions;
automatic generation of quantitative measurements and 5-point semiquantitative
scores for each of 20 myocardial segments and automatic derivation of summed
perfusion scores; and automatic generation of normal limits for any given patient
population on the basis of data fractionally normalized to minimize hot spot
artifacts. METHODS: The new algorithm was tested on the tomographic images of 420
patients studied with a rest 201TI (111-167 MBq, 35 s/projection)-stress 99mTc
sestamibi (925-1480 MBq, 25 s/projection) separate dual-isotope protocol on a
single-detector camera, a dual-detector 90 degrees camera, and a triple-detector
camera. RESULTS: The algorithm was successful in 397 of 420 patients (94.5%) and
816 of 840 image datasets (97.1%), with a statistically significant difference
between the success rates of the 201TI images (399/ 420, or 95.0%) and the 99mTc
images (417/420, or 99.3%; P < 0.001). Algorithm failure was caused by
extracardiac uptake (10/24, or 41.7%) or inaccurate identification of the valve
plane because of low count statistics (14/24, or 58.3%) and was obviated by
simply limiting the image volume in which the software operates. Reproducibility
of measurements of summed perfusion scores (r = 0.999 and 1 for stress and rest,
respectively), global defect extent (r = 0.999 and 1 for stress and rest,
respectively), and segmental perfusion scores (exact agreement = 99.9%, kappa =
0.998 for stress and 0.997 for rest) was extremely high. CONCLUSION: Automatic 3
dimensional quantitation of perfusion from 201Tl and 99mTc-sestamibi images is
feasible and reproducible. The described software, because it is based on the
same sampling scheme used for gated SPECT analysis, ensures intrinsically perfect
registration of quantitative perfusion with quantitative regional wall motion and
thickening information, if gated SPECT is used.
PMID- 10768576
TI - Photon energy recovery for crosstalk correction in simultaneous 99mTc/201Tl
imaging.
AB - Simultaneous 99mTc sestamibi/201Tl imaging enables the acquisition of images of
myocardial stress perfusion and myocardial viability in a single process. One of
the major limits of this technique is the crosstalk of the 99mTc downscattered
photons into the 201Tl window. We propose using the spectral deconvolution
technique photon energy recovery (PER) for correcting this crosstalk. METHODS: A
planar line phantom made of 99Tc vertical lines and 201Tl horizontal lines and a
cardiac SPECT phantom including an anterior (2 mL) and an inferior (1.5 mL)
myocardial fixed defect were used. The phantoms were filled with an initial
99mTc/201Tl ratio of 5:1. Several successive acquisitions were made from time t =
0 to time t = 48 h (99mTc/201Tl ratio approximately 0) without moving the
phantoms. Total number of counts, contrast, and normalized SD (NSD) were
calculated on the Tl-raw and the Tl-PER planar images. SPECT datasets were
analyzed. The Tl-raw images recorded at 48 h were considered the reference
"virgin" 201Tl images. RESULTS: Total number of counts, contrast, and NSD ranged
from 336% to 201%, 15% to 29%, and 257% to 225% of the virgin 201Tl values,
respectively, for Tl-raw planar images; whereas values for Tl-PER images ranged
from 128% to 108%, 61% to 79%, and 154% to 108%, respectively. Anterior and
inferior defect contrasts ranged from 1.18 to 1.22 and 1.12 to 1.16 for Tl-raw
SPECT images, respectively; whereas for Tl-PER images, value ranges were 1.28
1.32 and 1.21-1.24, respectively. The corresponding reference virgin 201Tl values
were 1.31 and 1.25 respectively. Summed score, average defect severity, and
average defect extent ranges were 4-5, 0.4-0.52, and 4.7-5.9 for Tl-raw images,
respectively, and 8-9, 0.59-0.79, and 7.4-8.8 for Tl-PER images. The reference
virgin 201Tl values were 9, 0.73, and 8.7, respectively. CONCLUSION: PER is
quantitatively efficient to remove 99mTc crosstalk photons from 201Tl images for
99mTc/201Tl ratios ranging from 5:1 to 2:1.
PMID- 10768577
TI - Performance of ordered-subset reconstruction algorithms under conditions of
extreme attenuation and truncation in myocardial SPECT.
AB - We studied the bias and variance characteristics of the ordered-subset
expectation maximization (OSEM) and rescaled block-iterative EM (RBIEM) iterative
reconstruction algorithms in myocardial SPECT under extreme, but realistic,
conditions. METHOD: We used the 2-dimensional mathematic cardiac torso phantom to
simulate 2 patient anatomies: a large male with a raised diaphragm and a female
with large breast size, approximating extreme cases of attenuation conditions
found in the clinic. For each anatomy, realistic 201Tl projection data were
simulated for a 180 degrees acquisition arc. Three cases of truncation for a 90
degrees-configured dual detector system were simulated: no truncation, moderate
truncation, and extreme truncation. For each case, an ensemble of 250 noise
simulations was generated, and each noisy dataset was reconstructed with the OSEM
and RBIEM algorithms. The reconstructions modeled only the effects of nonuniform
attenuation and used a range of subset configurations. Over the ensemble, we
computed means and variances of activity in 8 regions of interest (ROIs) in the
heart as a function of iteration. RESULTS: Under conditions of no truncation and
moderate truncation, the results from OSEM and RBIEM were very close to those
from maximum-likelihood EM (MLEM); in all cases, the difference in ROI means was
<2.5%. For extreme truncation, the errors increased to as much as 11% with OSEM,
but these were no greater than the errors for MLEM under the same conditions. The
OSEM algorithm with 2 views per subset was found to result in much higher
variance of ROI estimates for the same bias as compared with RBIEM or OSEM with 4
or more views per subset. CONCLUSION: The OSEM and RBIEM algorithms are at least
as robust to highly attenuating patients and truncation as MLEM algorithm and can
be adequate substitutes for MLEM, even in extreme cases. Clinical users should
apply the smallest number of subsets that can be accommodated by allowable
processing time to reduce image noise and variance in quantitative estimates.
PMID- 10768578
TI - ROC and LROC analyses of the effects of lesion contrast, size, and signal-to
noise ratio on detectability in PET images.
AB - Image quality in PET is typically assessed using measures such as contrast
recovery, noise variation, and signal-to-noise ratio (SNR). However, these
criteria do not directly reflect performance in the clinical use of the images.
Lesion detection is a critical task in the clinical interpretation of many PET
studies. A receiver operating characteristic (ROC) study is an accepted method
for quantitatively evaluating detection performance with respect to factors that
influence image quality. ROC and localization ROC (LROC) analyses were conducted
to investigate the effects of lesion contrast, SNR, and size on detectability of
hot lesions in PET images. METHODS: A thorax phantom was imaged with spheres of 3
sizes simulating lesions (0.45, 1.0, and 1.9 mL). The relative activity in the
lesions and the total number of counts acquired were each varied by factors of 2
to ascertain the effects of contrast and SNR, respectively. Measured attenuation
correction and a standard reconstruction protocol were used. Three nuclear
medicine physicians and 6 medical physicists participated as readers, rating each
image and indicating the suspected lesion location. The area under the calculated
ROC and LROC curves (Az and Az,LROC) were used as measures of detection
performance. RESULTS: Detection performance was shown to increase from virtually
random (Az approximately 0.5, Az,LROC approximately 0.2) to superior (Az > 0.9,
Az,LROC > 0.9) as lesion contrast was increased by 50% and as lesion SNR was
doubled. Detection performance was not seen to vary when comparison was made
using image-based measures alone. CONCLUSION: This study quantitatively shows
that moderate increases in the image-based measures of lesion contrast and SNR
give a relatively large increase in the task-based measure of lesion detection as
measured by ROC and LROC analyses. Thus, techniques that give modest increases in
lesion contrast or SNR are expected to improve detection. Results will be useful
in evaluating improvement in detection for various reconstruction, acquisition,
and data analysis methods that enhance contrast or noise performance.
PMID- 10768580
TI - Uptakes and images of 38K in rabbit heart, kidney, and brain.
AB - The purpose of this study was to evaluate the kinetics and image quality of
positron-emitting 38K (half-life, 7.6 min) and high-resolution small-animal PET
in the heart, kidney, and brain of rabbits. METHODS: Studies were performed with
18 closed-chest anesthetized rabbits at baseline and during infusions of
adenosine (0.2 mg/kg/min) and propranolol (0.5-1.0 mg/kg intravenously) using
high-resolution small-animal PET. 38K was injected intravenously and dynamic PET
imaging of the heart, kidney, or brain was performed for 3 min. Colored
microspheres were injected into the left ventricle to measure organ blood flow.
Arterial blood was withdrawn directly from the femoral artery, and, after the
animals were killed, 38K activities in each organ were measured directly with a
well counter. Uptake of 38K was calculated by dividing the 38K activities in each
organ by the integral of the input function. The extraction fraction of 38K was
estimated by dividing the uptake of 38K in each organ by the organ blood flow,
measured by microspheres. RESULTS: The left ventricular myocardium and kidney
were clearly visualized, but there was no visual 38K uptake in the brain. For the
heart, kidney, and brain, respectively, average blood flow was 2.91 +/- 1.29,
5.49 +/- 0.71, and 0.57 +/- 0.11 mL/min/g, and the extraction fraction of 38K at
baseline was 0.55 +/- 0.13, 0.48 +/- 0.13, and 0.022 +/- 0004. The Renkin-Crone
model fit the relation between myocardial extraction and flow under a wide range
of myocardial blood flow (r = 0.89). CONCLUSION: 38K is a suitable tracer for
noninvasively showing the potassium kinetics of the heart, kidney, and brain by
PET imaging.
PMID- 10768579
TI - Pharmacokinetics of 111In- and 125I-labeled antiTac single-chain Fv recombinant
immunotoxin.
AB - The use of immunotoxins for cancer therapy is an attractive strategy that
exploits the targeting specificity of monoclonal antibodies and their fragments
as well as the exquisite toxicity of the toxins. However, few studies of
immunotoxins have evaluated their biodistribution in vivo. Previous studies have
used 125I for tracing immunotoxin biodistribution in mice. Because the
immunotoxin works only when it is internalized and because of known problems with
quick dehalogenation after internalization of antibodies, we decided to use
111In, which has greater intracellular retention than iodine. METHODS: To trace
the in vivo pharmacokinetics of the immunotoxin in mice, we labeled the
antiTac(Fv)-PE38 with 111ln and compared it with 125I-labeled antiTac(Fv)-PE38.
We successfully labeled antiTac(Fv)-PE38 with 111In at up to 2.96 GBq/mg. A 3- to
4-fold decrease in cytotoxicity was observed for both radiolabeled preparations.
We evaluated the internalization of 111In- and 125I-labeled antiTac(Fv)PE38 into
ATAC4 cells (Tac-positive) as well as their biodistribution and pharmacokinetics
in vivo in mice. In addition, some mice receiving these reagents were co-infused
with 30 mg L-lysine to inhibit renal accumulation. RESULTS: Significantly more
111In- than 125I-labeled antiTac(Fv)-PE38 accumulated in the ATAC4 cells (20%
versus 5% of initial surface-bound radioactivity; P < 0.001). In vivo,
significantly more 111In- than 125I-labeled antiTac(Fv)-PE38 accumulated in the
kidney (119 versus 31 percentage injected dose per gram [%ID/g]; P < 0.001). The
tumor accumulation of 111In-labeled antiTac(Fv)-PE38 at 96 h was 13-fold greater
than that of 125I-labeled antiTac(Fv)-PE38 (1.4 versus 0.1 %ID/g; P < 0.001). No
antiTac(Fv)-PE38 was excreted into the urine in its intact form unless lysine was
co-infused. Co-injected lysine reduced the renal accumulation of 111In-labeled
antiTac(Fv)-PE38 by 62%. CONCLUSION: We evaluated the biodistribution,
pharmacokinetics, and catabolism of 111In-labeled antiTac(Fv)-PE38 and found that
it differed from 125I-labeled antiTac(Fv)PE38. These studies suggest that 111In
labeled antiTac(Fv)-PE38 can be used to trace the fate of antiTac(Fv)-PE38 in
humans.
PMID- 10768581
TI - Nursing research publications on older adults.
PMID- 10768582
TI - Influence of practice environment and nurse characteristics on perinatal nurses'
responses to ethical dilemmas.
AB - BACKGROUND: Previous research on nurses' responses to ethical dilemmas has
focused either on nurse characteristics or on practice environment
characteristics, but has not examined both influences concurrently. OBJECTIVE: To
explore the relative contributions of practice environment characteristics and
nurse personal and professional characteristics to perinatal nurses' willingness
to be involved in activities to resolve clinical ethical dilemmas. METHODS: A
descriptive correlational design and hierarchical multiple regression were used
to examine responses of 127 perinatal nurses to three instruments: the Nursing
Ethical Involvement Scales (NEIS), Perinatal Values Questionnaire (PVQ), and
Demographic Data Sheet (DDS). RESULTS: The organizational variable, nursing
influence, accounted for the greatest amount of variance in nurses' reported
resolution actions, with nurses' concern about ethics and consequentialist values
also contributing significantly. The three predictors together accounted for 31%
(24% adjusted) of the variance in actions to resolve clinical ethical dilemmas.
Level of nursing education was not a statistically significant influence.
CONCLUSIONS: These results suggest that nurses are more likely to be involved in
dilemma resolution activities when they perceive themselves to have higher levels
of influence in their practice environments and higher levels of concern about
the ethical aspects of clinical situations. Nurses who emphasize consideration of
morally relevant aspects of individual patient situations (consequentialist value
orientation) and deemphasize adherence to abstract standards, rules, and policies
also are more likely to be involved in dilemma resolution.
PMID- 10768583
TI - Spiritual activities as a resistance resource for women with human
immunodeficiency virus.
AB - BACKGROUND: Few studies have investigated the role that spiritual activities play
in the adaptational outcomes of women with human immunodeficiency virus (HIV)
disease. OBJECTIVE: To examine the role of spiritual activities as a resource
that may reduce the negative effects of disease-related stressors on the
adaptational outcomes in HIV-infected women. METHODS: A theoretically based
causal model was tested to examine the role of spiritual activities as a
moderator of the impact of HIV-related stressors (functional impairment, work
impairment, and HIV-related symptoms) on two stress-related adaptational outcomes
(emotional distress and quality of life), using a clinic-based sample of 184 HIV
positive women. RESULTS: Findings indicated that as spiritual activities
increased, emotional distress decreased even when adjustments were made for HIV
related stressors. A positive relationship between spiritual activities and
quality of life was found, which approached significance. Findings showed that
HIV-related stressors have a significant negative effect on both emotional
distress and quality of life. CONCLUSIONS: The findings support the hypothesis
that spiritual activities are an important psychological resource accounting for
individual variability in adjustment to the stressors associated with HIV
disease.
PMID- 10768584
TI - Workplace access, negative proscriptions, job strain, and substance use in
registered nurses.
AB - BACKGROUND: Both occupational conditions and individual factors have been shown
as contributors to the likelihood of substance use among health professionals.
OBJECTIVES: To assess the use of Winick's (1974) model for explaining nurses'
substance use, which asserts that groups with access to substances, freedom from
negative proscriptions, and role strain have an increased likelihood of drug
dependence. METHODS: Data were analyzed from the 3,600 working nurses
participating in the Nurses Worklife and Health Study, a nationally
representative survey of registered nurses in the United States. A structural
equation model was tested fitting workplace access to substances (availability,
frequency of administration, and knowledge), freedom from negative proscriptions
(internal: religiosity; external: social network), and role strain (job demands
and depressive symptoms) to the frequency of past year alcohol,
marijuana/cocaine, and prescription-type drug use. RESULTS: Nurses were more
likely to use substances when workplace access to substances increased (p <
0.001), with social networks containing more drug users, and when religiosity
decreased (p < 0.001). Role strain (measured through job demands and depressive
symptoms) also was related to substance use. Depressive symptoms were related
directly and negatively to substance use (p < 0.01), whereas job demands were
related indirectly to substance use through depressive symptoms. CONCLUSIONS:
Winick's model has use in explaining nurses' substance use. Research and
preventive initiatives should consider the multidimensional aspects of substance
use in nurses.
PMID- 10768585
TI - The energy costs of a modified form of T'ai Chi exercise.
AB - BACKGROUND: Alternative strategies for exercises that provide both training and
relaxation benefits are optimal for persons with very low functional capacities
who also are at high risk for complications. T'ai Chi C'hih, a modified form of
traditional T'ai Chi, is a series of slow balanced movements and breathing
promoted to increase energy levels and induce relaxation. OBJECTIVES: To estimate
the energy costs and cardiovascular effects of T'ai Chi C'hih. Measured energy
costs of specific activities can assist with safe exercise prescription for
individuals with very low energy reserves. METHODS: A convenience sample (n = 26)
of healthy adults participated in this study, which involved completion of
surveys to estimate functional capacity and exercise participation, training in a
select series of nine T'ai Chi C'hih movements, and oxygen consumption testing
while movements are performed. Movements involving front to back and lateral
moves of the lower extremity, full shoulder range of motion of upper extremity,
and deep forced inhalation and stepped exhalations were performed at slow to fast
cadences in sitting and standing positions. The Human Activity Profile was used
to estimate lifestyle energy consumption. Exercise participation was quantified
as Kcal/Kg(1) expended per week. RESULTS: Metabolic equivalents (METs) for
sitting T'ai Chi C'hih movements were estimated to be 1.5 +/- 0.17 and 2.3 +/-
0.34 for slow standing, and 2.6 +/- 0.47 for fast standing. Mean maximum heart
rates ranged from 43% to 49% of predicted maximum heart rates. Mean increases in
both systolic and diastolic blood pressures over resting were 8%. Mean METs of
breathing exercises ranged from 3 to 3.6. There were no differences in responses
to the movements by gender or experience with T'ai Chi exercise. CONCLUSION: The
movements used to perform T'ai Chi C'hih require energy expenditure comparable
with that for activities of daily living and for low level exercises currently
recommended for persons with low exercise tolerance. Therefore, T'ai Chi C'hih
may be an alternative approach to health promotion in many populations with
chronic disease.
PMID- 10768586
TI - Validity of the nursing diagnosis of relocation stress syndrome.
AB - BACKGROUND: There have been no reports of validation studies on the nursing
diagnosis of relocation stress syndrome (RSS). OBJECTIVES: To validate the
presence of some defining characteristics of RSS in a group of long-term care
residents relocated en masse to a new facility. METHODS: This study measured the
effects of relocation on 106 elderly residents moved from one long-term care
facility to another. The presence of five characteristics defining the nursing
diagnosis of RSS (dependency, confusion, anxiety, depression, and withdrawal)
were measured using the Multidimensional Observation Scale for Elderly Subjects
(MOSES) scale, a tool previously validated for use among similar groups of
individuals. Using the Chenitz model of relocation, measures were taken twice
before and twice after the move to examine changes in these characteristics over
time. No extraordinary efforts were made to alleviate RSS. RESULTS: Repeated
measures analysis of variance indicated no differences in the mean scores (p <
0.05) on these factors overall or from one measurement period to another.
CONCLUSION: On the basis of the findings from this research and supporting
literature, the appropriateness of anticipating RSS during mass moves is
questioned. Additional research with other measurement tools should be conducted
to verify these results.
PMID- 10768588
TI - Factors differentiating dropouts from completers in a longitudinal, multicenter
clinical trial.
AB - BACKGROUND: Subject dropout from a prospective, longitudinal trial can produce
biases in the remaining sample that affect study findings and their
interpretation, yet little is known about factors contributing to dropout.
OBJECTIVE: To determine characteristics differentiating those who complete from
those who drop out of a longitudinal multicenter clinical trial. METHODS: In this
study, 578 parents and other caretakers of infants at risk for cardiopulmonary
arrest enrolled in a longitudinal trial investigating the psychosocial impact of
cardiopulmonary resuscitation training. In this secondary analysis, the baseline
sociodemographic, emotional, psychosocial, and infant characteristics of those
who dropped from the trial were compared with those who completed the study.
RESULTS: The study was completed by 60% (n = 347) of the participants. Those most
likely to drop out were fathers or other caretakers (vs. mothers) employed
outside the home who spoke English (vs. Spanish); were assigned to an
experimental group (vs. a control group); had higher levels of depression,
hostility, and overall psychosocial distress; and held negative views about
health care. CONCLUSION: Although a few sociodemographic characteristics
differentiated dropouts from completers, personal, emotional and psychosocial
factors were the predominant predictors of dropouts. Other reputed sources of
retention difficulties (e.g., income, education, minority status, lack of social
support, or problems with family functioning) did not predict dropout.
PMID- 10768587
TI - Fecal incontinence in hospitalized patients who are acutely ill.
AB - BACKGROUND: Information about fecal incontinence experienced by patients in acute
care settings is lacking. The relationship of fecal incontinence to several well
known nosocomial or iatrogenic causes of diarrhea has not been determined.
OBJECTIVES: To determine the cumulative incidence of fecal incontinence in
hospitalized patients who are acutely ill, and to ascertain the relationship
between fecal incontinence and stool consistency, and between diarrhea and two
well-known nosocomial or iatrogenic etiologies of diarrhea: Clostridium difficile
and tube feeding. The relationship of fecal incontinence and risk factors for
diarrhea associated with C. difficile and tube feeding in hospitalized patients
was examined. METHODS: Fecal incontinence, stool frequency and consistency,
administration of tube feeding and medications, severity of illness, and
nutritional data were prospectively recorded in 152 patients on acute or critical
care units of a university-affiliated Veterans' Affairs Medical Center. Rectal
swabs and stool specimens from patients were obtained weekly for C. difficile
culture. C. difficile culture and cytotoxin assay were performed on diarrheal
stools. HindIII restriction endonuclease analysis (REA) was used for typing of C.
difficile isolates. RESULTS: In this study, 33% (50/152) of the patients had
fecal incontinence. The proportion of total surveillance days with fecal
incontinence in these patients was 0.50 +/- 0.06. A greater percentage of
patients with diarrhea had fecal incontinence than patients without diarrhea
(23/53 [43%] vs. 27/99 [27%]; p = 0.04). Incontinence was more frequent in
patients with loose/liquid stool consistency than in patients with hard/soft
stool consistency (48/50 [96%] vs. 71/100 [71%]; p < 0.001). The proportion of
surveillance days with fecal incontinence was related to the proportion of
surveillance days with diarrhea (r = 0.69; p < 0.001) and the proportion of
surveillance days with loose/liquid stools (r = 0.64; p < 0.001). Multivariate
risk factors for fecal incontinence were unformed/loose or liquid consistency of
stool (RR = 11.1; 95% confidence interval [CI] = 2.2, 56.7), severity of illness
(RR = 5.7; CI = 2.6, 12.3), and age (RR = 1.1; CI = 1, 1.1). CONCLUSIONS: Fecal
incontinence is common in hospitalized patients who are acutely ill, but the
condition was not associated with any specific cause of diarrhea. Because loose
or liquid stool consistency is a risk factor for fecal incontinence, use of
treatments that result in a more formed stool may be beneficial in managing fecal
incontinence. However, treatments that slow intestinal transit should be avoided
in patients with C. difficile-associated diarrhea.
PMID- 10768589
TI - Auditing research studies.
AB - BACKGROUND: Recognizing the increasing attention being given to reports of
misconduct, fraud, and unethical behavior in biomedical research, it appears
timely for nurse researchers to engage in an organized method of peer review.
OBJECTIVES: To describe an auditing process for funded research grants, the
guidelines used to conduct the research audit, and the results to date. METHODS:
The audit encompassed National Institutes of Health (NIH)-funded projects and
their respective research teams, 12 faculty auditors using an audit worksheet
developed by the Center for Nursing Research. RESULTS: Overall, auditing of
research grants was viewed positively by both investigators and faculty auditors.
Minor problems were identified that could be corrected. Only one grant required a
second review. CONCLUSIONS: Specific guidelines are proposed for future audits
that include level of funding and timing of audits.
PMID- 10768590
TI - Renal cell carcinoma: progress against an elusive tumor.
PMID- 10768591
TI - Epidemiologic aspects of renal cell cancer.
AB - Renal cell cancer accounts for about 2% of cancers worldwide. It has been
increasing in incidence in North America and northern Europe, but not in other
areas of the world. In the United States the rate of increase has been about 3%
per year, with the highest rates now seen among blacks. Survival has improved,
with the 5-year relative survival rate increasing from 30% to 40% in the 1960s to
between 50% and 60% in the 1990s. A large number of epidemiologic studies,
particularly case-control investigations, have searched for clues to the
etiology. Cigarette smoking is a causal factor in the development of renal cell
cancer. Virtually every study has identified obesity or high relative weight as
another major determinant, particularly among women. High blood pressure or its
medications may also play a role, although the mechanism is unknown. Occupational
exposures such as asbestos, coke oven emissions, gasoline, and solvents have been
related to an excess risk, but no convincing evidence exists regarding these or
any other occupational factor. An inverse association between risk and intake of
fruits and vegetables has been seen in a number of studies and remains one of the
few consistent dietary findings. A relation with coffee, alcohol, or any other
beverage has not been demonstrated for renal cell cancer and is unlikely to
exist. Genetic susceptibility plays a significant role in an unknown portion of
cases, likely through a number of mechanisms. Future etiologic studies should
focus on the mechanism by which obesity increases risk, the role of high blood
pressure and its medications, and the reasons for the remarkedly rapid increase
in incidence among blacks in the United States.
PMID- 10768592
TI - Contemporary approach to the classification of renal epithelial tumors.
AB - Our understanding of the morphologic and genetic features of renal epithelial
neoplasia has brought about profound changes in the classification of these
tumors. It is clear that they represent a heterogeneous group of tumors with
distinct histopathologic, genetic, and clinical features ranging from benign to
high-grade malignant. "Granular" and "sarcomatoid" carcinomas are not distinct
entities, since tumors with granular or spindle cell features may be seen in many
tumor-types. Using conventional pathologic tools such as hematoxylin and eosin
staining, histochemistry, immunohistochemistry, and electron microscopy, we are
able to properly classify the majority of these tumors. Nevertheless,
approximately 6% to 7% of cases are impossible to classify in this fashion, thus
requiring molecular genetic studies for proper characterization.
PMID- 10768593
TI - Genetic and clinical aspects of familial renal neoplasms.
AB - Genetic studies of families at high risk for developing malignant and benign
renal neoplasms led to cloning of genes whose alteration results in tumor
formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes
(MET). Their significance in understanding oncogenesis extends far beyond the
familial syndromes. The identification of these genes and the elucidation of
their biochemical functions are likely to facilitate (1) our understanding of the
full clinical spectrum of the corresponding diseases, (2) genetic counseling, and
(3) rational design of effective strategies to prevent and/or treat familial and
sporadic forms of these neoplasms.
PMID- 10768594
TI - Imaging of renal cell carcinoma.
AB - Today, a large proportion of patients diagnosed with renal cancer are those with
small tumors discovered incidentally on imaging studies. Radiologic studies
should be tailored to enable further characterization of renal masses, so that
nonmalignant lesions can be differentiated from malignant ones. Intravenous
urography (IVU) is often obtained as the first imaging study to evaluate the
urinary tract in patients with symptoms that may indicate the presence of renal
cell carcinoma Ultrasound scanning, computed tomography (CT), magnetic resonance
imaging (MRI), and imaging-guided percutaneous biopsy techniques should be used
appropriately to achieve maximum accuracy in the detection and staging of renal
carcinoma. Diagnostic angiography, largely supplanted by less invasive radiologic
techniques, may be useful in selected situations. After surgical removal of renal
cell carcinoma, follow-up imaging is especially important in the first 2 years,
when recurrence is most likely, especially in patients with stage III or IV
tumors. The clinical presentation will determine choices of specific imaging
"algorithms" for detection and staging of renal cell cancer.
PMID- 10768595
TI - Renal cell carcinoma: presentation, staging, and surgical treatment.
AB - The widespread availability of abdominal ultrasound, magnetic resonance imaging
(MRI), and computed tomography (CT) scanning has increased the diagnosis of
incidental renal tumors, which now comprise the vast majority of the new cases
diagnosed each year. With the detection of renal tumors at an earlier stage,
partial nephrectomy and nephron-sparing surgery have evolved as effective
alternatives to radical nephrectomy. The poor prognostic findings of involved
regional lymph nodes or ipsilateral adrenal metastases has led to more selective
operations on those sites in the face of incidental tumor detection.
Technological advances have allowed for the development by committed surgical
investigators of techniques of laparoscopic and laparoscopically assisted
nephrectomy. Although not widely employed, further improvements in technology may
widen the appeal of these approaches to selected renal tumors. Advances in
cardiovascular surgical techniques have made resection of renal cell carcinoma
(RCC) with tumor thrombi involving the inferior vena cava (IVC) possible,
although this approach is still associated with significant perioperative
mortality depending on the degree of caval involvement. In highly selected cases,
resection of limited metastatic disease is recommended, particularly if the
disease-free interval is greater than 12 months and there is a only a single site
of metastatic disease. Whether metastectomy is therapeutic or fits within the
realm of the often long and unpredictable natural history of RCC is not known.
Strategies for follow-up are based primarily on the pathologic stage of the
operated tumor. Small incidental tumors have an excellent prognosis and require
little in the way of postoperative imaging. As the pathologic stage increases,
the likelihood of developing metastatic disease increases, necessitating biannual
chest x-ray in addition to history and physical examination. Symptom-directed
bone scans and CT scans are effective in identifying most recurrences in patients
with large, poorly differentiated tumors. Patients requiring specialized follow
up programs include those treated by partial nephrectomy, and those with end
stage renal disease, acquired cystic disease of the kidney, or von Hippel-Lindau
(VHL) disease.
PMID- 10768596
TI - Chemotherapy for renal cell carcinoma.
AB - Renal cell carcinoma is highly resistant to systemic chemotherapy, and no agent
should be considered standard in the treatment of metastatic disease. At this
time, it is appropriate for patients with advanced local or metastatic renal cell
carcinoma to be offered new therapeutic investigational experimental options,
since clearly there are limited therapies presently available. The experience
with chemotherapy is reviewed.
PMID- 10768597
TI - Interferon in metastatic renal cell carcinoma.
AB - Metastatic renal cell carcinoma (MRCC) represents an immunoresponsive malignancy
in individual patients. Interferons (IFNs) have thus been broadly investigated in
this cancer type, with the most commonly used being recombinant IFN-alpha. The
average response rate is 15%, with a response duration of 4 to 6 months. Complete
responses are rare (< or =5%), but may be long-lasting. Responses are seen
predominantly in lung and lymph node metastases. Subcutaneous (SC) or
intramuscular (IM) doses of 9 to 10 x 10(6) U/d or 9 to 18 x 10(6) U thrice
weekly are most often used. Flu-like symptoms (fever, myalgia, asthenia) occur in
almost all patients treated with IFN-alpha and may be dose-limiting. The
combination of IFN-alpha with vinblastine is not superior to IFN monotherapy.
Phase III studies have demonstrated a modest survival benefit for IFN-alpha
therapy as compared with placebo-equivalent treatment, with a survival gain of 3
to 7 months. Predictive for beneficial outcome are an excellent performance
status, low sedimentation rate, no weight loss, and long interval between initial
diagnosis and start of IFN treatment. The significance of nephrectomy is
currently being investigated in phase III studies. IFN-gamma has no major
therapeutic role in MRCC. IFN-beta and "natural IFN" are equally effective as IFN
alpha. In conclusion, IFN-alpha represents the standard treatment in patients
with MRCC who are candidates for systemic therapy. Any IFN-alpha-containing
combination treatment is investigational (eg, with interleukins or retinoids).
PMID- 10768598
TI - Interleukin-2 in the treatment of renal cancer.
AB - Interleukin-2 (IL-2) administered in pharmacologic doses to renal cancer patients
with intact organ function and good performance status induces durable complete
responses in about 5% of patients and partial responses in an additional 10% to
15%. The mechanism of antitumor efficacy of IL-2 is closely related to its
ability to expand and activate cytotoxic lymphocytes of the natural killer (NK)-
and thymic (T)-cell subsets that express IL-2 receptors (IL-2R). There is also
accumulating evidence that local or generalized effector cell dysfunction, which
is characteristic of patients with advanced cancer, can be reversed with IL-2
exposure. The toxicities of IL-2 are mediated by cytokines and other small
molecules secreted by IL-2R-expressing cells responding to the binding of this
ligand. The common mechanism for IL-2-induced multiorgan dysfunction appears to
be a capillary leak syndrome directly mediated by local production of nitric
oxide by cells of the monocyte-macrophage lineage. To date, efforts to improve on
the antitumor activity of IL-2 by the addition of IL-2-activated peripheral blood
mononuclear cells (lymphokine-activated killer [LAK] cells) or cell subsets
selected for proximity or potential antigen-specificity (tumor-infiltrating
lymphocytes [TIL]) have not led to improved therapeutic outcomes. Attempts to
reduce the risks of IL-2 therapy (which could potentially allow for increased IL
2 administration) by blocking one or more of the known mediators of toxicity have
also been disappointing. Current research is directed at developing combination
regimens with additive or synergistic antitumor effects and incompletely
overlapping toxicities, as well as the identification of tumor antigens that may
be the target of more focused cellular therapies. The role of high-dose IL-2 in
the adjuvant therapy of resected renal cancer at high risk of relapse is also
under investigation.
PMID- 10768599
TI - Cytokine combinations: therapeutic use in patients with advanced renal cell
carcinoma.
AB - Treatment of metastatic renal cell carcinoma (RCC) remains unsatisfactory. To
enhance the antitumor effects of various cytokines, combinations of these agents
have been investigated. Interleukin-2 (IL-2) and interferon-alfa (IFN-alpha) have
been combined based on data from preclinical studies suggesting synergism. A
review of available phase I and II trials in more than 1,400 patients indicates
that response rates are approximately 20%. Complete regressions are seen in 3% to
5% of patients. To demonstrate that this combination increases overall response
rates, randomized trials were required. The results of a phase III study
demonstrate a significantly improved response rate (18.6%) and 1-year event-free
survival (20.9%) for patients treated with continuous infusion recombinant (r) IL
2 and subcutaneous IFN-alpha compared with either cytokine alone. The toxicity of
rlL-2 and IFN-alpha is related to cytokine dose and schedule, but appears less
than that reported with high-dose rIL-2. Analysis of prognostic factors and
surrogate marker changes have been conducted. Performance status and number of
disease sites predict response. rIL-2 and IFNalpha were then combined with
fluorouracil, with initial reports suggesting response rates greater than 40%.
Recent reports indicate 1% to 39% of patients responding. In a group of 836
patients with metastatic RCC receiving this therapy, 25.3% responded. Randomized
trials comparing chemoimmunotherapy to rIL-2 and/or IFN-alpha are now required.
The biologic basis and rationale for utilization of cytokines are strong.
Clinical results are consistent with improved response rates in patients
receiving rIL-2 and IFN-alpha. Continued investigation of novel and new treatment
approaches remains a priority.
PMID- 10768600
TI - Prognostic factors in renal carcinoma.
AB - Identification of tumor-, patient-, or treatment-related prognostic factors in
renal carcinoma (RC) would allow the most appropriate application of current and
future therapy to patients with this poorly responsive malignancy. Stage,
including degree of lymph node and venous involvement, and grade remain the most
powerful predictors of patient outcome. Performance status (PS) of patients also
influences prognosis, as it relates to tumor aggressiveness and ability to
receive adequate treatment. Newer techniques of measuring tumor proliferation and
the application of cytogenetics to RC are currently being explored and may add to
prognostication. Lastly, characteristics of tumor metastases and the appropriate
application of surgical and chemotherapeutic treatment modalities allow for
identification of patient subgroups with different survival times. This review
explores various characteristics as they impact on overall survival in patients
with RC.
PMID- 10768601
TI - Adoptive cellular therapy.
AB - We provide a current review of adoptive cellular therapy in the management of
metastatic renal cell carcinoma. A comprehensive literature review of peer
reviewed articles on the development and use of adoptive cellular immunotherapy
was performed. Renal cell carcinoma is a highly immunogenic tumor that has proven
resistant to standard cytotoxic chemotherapy, but has shown reproducible response
to immune-based therapy. In an effort to improve responses, a variety of adoptive
cellular strategies have been devised and tested in the setting of metastatic
disease. Among the techniques developed, the use of lymphokine-activated killer
(LAK) cells, autolymphocyte therapy (ALT), and tumor-infiltrating lymphocytes
(TIL) have been the best studied. While further trials are ongoing, thus far,
these approaches have not consistently shown benefit in comparison to standard
immune-based treatment with biologic response modifiers, most importantly, high
dose bolus interleukin-2 (IL-2). Future approaches, including the use of
dendritic cells (DC) to facilitate the development of tumor vaccines, are
encouraging. Advanced renal cell carcinoma continues to inspire research of
promising new cellular immunotherapeutics. The experience with LAK, ALT, and TIL
has greatly increased our understanding of tumor immunobiology, and has led to
the ongoing development of new technology, including DC, vaccine, and antibody
therapy.
PMID- 10768602
TI - Novel investigative approaches for advanced renal cell carcinoma.
AB - Metastatic renal cell carcinoma remains one of the most treatment-resistant
malignancies in humans. As such, long-term survival is limited to a minority of
patients. Interferon-alpha and interleukin-2 induced major responses in some
patients with renal cell carcinoma, and in so doing generated a great deal of
interest and hope. However, clinical benefit is limited to relatively few
patients. Here, we briefly discuss the management of metastatic renal cell
carcinoma, and then elaborate on several novel treatment approaches in
development, including retinoids, monoclonal antibodies, and antiangiogenesis
strategies.
PMID- 10768603
TI - Symposium introduction: antibodies in clinical neurology.
PMID- 10768604
TI - Antibodies to calcium channel and synaptotagmin in Lambert-Eaton myasthenic
syndrome.
AB - In the Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease that is
often associated with lung cancer and characterized by reduced quantal release of
acetylcholine from the motor nerve terminal, our studies to search for the target
of LEMS antibodies have brought the voltage-gated calcium channel (VGCC) into
relief. Among multiple types of VGCCs, the P/Q-type was highly recognized by LEMS
antibodies. Using synthetic peptides or recombinant proteins as antigens, the
study specified the S5-S6 linker regions in 3 of 4 domains as immunodominant
sites in the molecular structure of P/Q-type VGCC alpha1 subunit. Synaptotagmin,
one of the functionally VGCC-associated synaptic proteins, was also found to be
an immunogen in the pathogenesis of LEMS.
PMID- 10768605
TI - Acquired neuromyotonia: a new autoantibody-mediated neuronal potassium
channelopathy.
AB - Neuromyotonia (Isaacs syndrome) is a rare and heterogenous syndrome of continuous
motor unit activity of peripheral nerve origin that manifests as various
combinations of muscle stiffness, cramps, twitching, weakness, and delayed muscle
relaxation. Although neuromyotonia may accompany an assortment of inherited
diseases, most cases are acquired. The observation that the acquired form is
often associated with an autoimmune disorder, and the demonstration that some
cases improve after plasma exchange, has led to a search for an immune-mediated
etiology. This review summarizes the recent immunological and
electrophysiological evidence that autoantibodies to voltage-gated potassium
channels produce the peripheral motor nerve hyperexcitability that characterizes
neuromyotonia and thus establishes acquired neuromyotonia as an autoantibody
mediated disorder. In the nervous system, ion channels and neurotransmitter
receptors that function as ligand-gated ion channels seem to be favored targets
for autoantibody attack, and neuromyotonia can now be added to the growing list
of autoimmune channelopathies.
PMID- 10768606
TI - Autoantibodies in paraneoplastic neurological syndrome.
AB - Paraneoplastic neurological syndrome is a rare disorder caused by the secondary
effects of cancer and is thought to be immune-mediated. A high titer of
autoantibodies in the patient's serum and cerebrospinal fluid, directed against
both neurons and tumor, have been detected in some forms of this syndrome. These
autoantibodies are considered the result of an immunological response to tumor
and may cross-react with cells of the nervous system, causing neuronal damage.
Specific forms of this syndrome are often associated with specific antineuronal
antibodies and tumors. The onset of neurological symptoms and detection of these
antibodies often precede the diagnosis of the tumor; therefore, detection of
these antibodies greatly assists the diagnosis of this syndrome and prompts
investigations for the underlying tumor. The pathogenicity of these antineuronal
antibodies has been proven in only a few cases, such as that of anti-voltage
gated calcium-channel antibodies in Lambert-Eaton myasthenic syndrome. The
selective involvement of specific types of neurons has not been fully elucidated.
The target spectrum of some of these antineuronal antibodies correlates well with
the neurological symptoms, but that of others is wider than expected from the
symptoms. Interesting evidence has suggested that these antionconeuronal
antibodies can suppress tumor growth. The discovery of new antibodies and
characterization of target molecules have been reported with advances in the
field of molecular biology. A more detailed understanding of the relationship
between the cancer and the neural involvement from the molecular biological
standpoint may lead to rational tumor therapy and elucidation of the mechanism of
neuronal death. Here, major clinical forms with well-known antineuronal
antibodies and specific tumors are reviewed; for each antineuronal antibody, the
target antigens and its putative role in the pathogenesis of this syndrome are
described.
PMID- 10768607
TI - Autoantibodies in inflammatory myopathies.
PMID- 10768608
TI - Antiglycolipid antibodies in Guillain-Barre syndrome and autoimmune neuropathies.
PMID- 10768610
TI - Developing theoretical constructs for outcomes research.
AB - BACKGROUND: In March of 1998, The Advisory Commission on Consumer Protection and
Quality in Health Industry released a report in response to the US Presidential
Executive Order that recommended increasing funding for outcomes research. This
report indicated that outcomes research was critical to assessing the
effectiveness of treatment and the quality of care. METHODS: A systematic review
was conducted of the pertinent English literature that describes the development,
methods, and limitations of outcomes research to identify methods for minimizing
its limitations. RESULTS: Current evidence indicates that approximately 80% of
commonly used medical treatments have not been shown to be efficacious, primarily
because the necessary randomized controlled trials have not been conducted
because of methodological problems, the time required for their execution, the
expense, or ethical reasons. Therefore, physicians disagree on the value of many
common clinical practices, which is reflected in the large variation in medical
care prescribed for different populations. Outcomes research, which is conducted
under actual clinical practice conditions using effectiveness studies, offers an
efficient approach for investigating the link between medical care and outcomes.
However, the major limitation of past outcomes research has been its limited
ability to link medical care with outcomes, because of the lack of theory
development to guide the research process, inadequate data sources, or both.
CONCLUSIONS: The literature review suggests that the use of pertinent theoretical
constructs to guide the outcomes research process will generate the results
needed to assess the effectiveness of treatment and the quality of care.
PMID- 10768609
TI - The urine/plasma electrolyte ratio: a predictive guide to water restriction.
AB - Patients with hypotonic hyponatremia are encountered commonly in the general
practice of medicine. Nearly all strategies for the management of subacute or
chronic hyponatremia call for some amount of water restriction. The
considerations for such a prescription have not been addressed in the literature.
We describe therefore a simple approach grounded in the physiology of electrolyte
free water clearance that can be used at the bedside.
PMID- 10768611
TI - Sternal osteomyelitis caused by mycobacterium tuberculosis: case report and
review of the literature.
AB - Sternal osteomyelitis caused by Mycobacterium tuberculosis is rare; since the
advent of modern antituberculous therapy, a limited number of detailed cases have
been reported. Most patients were relatively young, free of underlying disease,
and lived in a country in which tuberculosis is endemic. The disease presented
indolently with sternal pain and swelling. Extrasternal disease is detectable in
less than half. Diagnosis was based on histologic examination of infected tissues
and mycobacterial cultures. Most patients recovered after surgical debridement
and combination drug therapy. Tuberculous sternal osteomyelitis should be
considered in patients with sternal pain and swelling.
PMID- 10768612
TI - Primary meningococcal pneumonia in elderly patients.
AB - Neisseria meningitidis infection in humans usually manifests as meningitis and
septicemia with skin manifestations. Infections of the respiratory tract with N
meningitidis have been documented in the past, but often this organism is not
routinely considered in the differential diagnosis of pneumonia. The pathogenic
role of N meningitidis in lower respiratory tract infections may be
underestimated because its isolation is difficult, particularly when
oropharyngeal flora are present. We profile 2 elderly patients with primary
meningococcal pneumonia to show the importance of Gram stain and culture in early
diagnosis. These modalities helped guide treatment and prophylactic measures.
PMID- 10768613
TI - Chronic myelomonocytic leukemia with t(1;3)(p36;q21) and a synchronous gastric
cancer.
AB - The translocation t(1;3)(p36;q21) has been reported previously in patients with
the myelodysplastic syndrome and with acute nonlymphocytic leukemia. It has been
reported in only 5 cases of chronic myelomonocytic leukemia and t(1;3)(p36;q21).
We observed a case of chronic myelomonocytic leukemia with t(1;3)(p36;q21)
complicated by a gastric cancer at the time of diagnosis.
PMID- 10768614
TI - Transient diabetes insipidus and hypopituitarism after pituitary apoplexy: a rare
association with pericardial effusion and painless thyroiditis.
AB - Pituitary apoplexy in a 38-year-old male patient with acromegaly who presented
with pericardial effusion, anterior pituitary dysfunction, and diabetes insipidus
is described. With corticosteroid therapy, there was good initial recovery of
pituitary function and regression of pericardial effusion. On withdrawal of
corticosteroids, he developed painless thyroiditis, with transient
thyrotoxicosis. Subsequently, the pituitary function tests remained normal for a
year, but later he gradually developed hypogonadotropic hypogonadism,
hypocortisolism, growth hormone deficiency, and progressive pituitary atrophy,
resulting in empty sella syndrome.
PMID- 10768615
TI - Internal carotid artery occlusion in a patient with malignant peritoneal
mesothelioma: is it a sign of malignancy-related thrombosis?
AB - To our knowledge, the occlusion of arteries and platelet hyperaggregation have
not been reported in patients with malignant mesothelioma. However, venous
thromboembolism, especially in the pulmonary vasculature in association with
thrombocytosis and hyperfibrinogenemia, are commonly noticed in this disorder.
Furthermore, we detected enhanced platelet aggregation in a case of malignant
peritoneal mesothelioma with internal carotid artery occlusion in whom there were
postsplenectomy thrombocytosis and hyperfibrinogenemia. The possible mechanisms
of ICA occlusion in this patient, including the role of MPM and postsplenectomy
state, thrombocytosis, platelet functional changes, and other factors were
investigated and discussed.
PMID- 10768616
TI - Rapid communication: the human FEM1B gene maps to chromosome 15q22 and is
excluded as the gene for Bardet-Biedl syndrome, type 4.
AB - We have identified a novel human gene, FEM1B, that encodes a protein virtually
identical to that encoded by the mouse gene Fem1b. These mammalian proteins are
homologs of the FEM-1 protein of Caenorhabditis elegans, which acts as a signal
transduction component within the nematode sex-determination pathway. We report
here the mapping of FEM1B to chromosome 15q22, a region that is homologous to the
region of mouse chromosome 9, where Fem1b resides. The BBS4 locus, one of the
loci causing the autosomal recessive Bardet-Biedl syndrome, maps to this region
of chromosome 15. Therefore, we sought to determine whether the FEM1B gene might
be involved in this disorder. Radiation hybrid mapping demonstrates that FEM1B
does not reside within the interval of chromosome 15 containing the BBS4 locus.
PMID- 10768617
TI - Prospects for pharmacological intervention in Alzheimer disease.
AB - Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic
transmission in the cerebral cortex and hippocampus in areas of the brain
particularly associated with memory and higher intellectual functioning. Other
neurotransmitter deficits also occur, but the mechanisms underlying the
widespread impairment of synaptic functions remain uncertain. Research on the
molecular basis of AD has elucidated a pathogenic pathway from which a range of
rational pharmacological interventions has emerged. Although at least 3
cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine
tartrate) are now available and provide patients with modest relief, the most
promising strategy involves approaches to retarding, halting, or preventing the
formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed
to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy
in women with menopause is associated with a reduced risk or delayed onset of AD.
The association between nonsteroidal anti-inflammatory drugs and a reduced risk
of AD has not yet been confirmed, but these agents may protect the brain from the
reactive glial and microglial responses associated with Abeta deposition. Also,
recent studies suggested that antioxidants, such as vitamin E taken alone or in
combination with selegiline hydrochloride, can delay the progression of AD.
Despite these encouraging results, no current therapy has been shown to halt or
reverse the underlying disease process. The proof of the principle that anti
Abeta drugs will work in the transgenic models of AD is eagerly awaited with the
expectation that they will eventually prove successful in humans.
PMID- 10768618
TI - Subthalamic stimulation in Parkinson disease: a multidisciplinary approach.
AB - BACKGROUND: High-frequency stimulation of the subthalamic nucleus constitutes a
therapeutic advance for severely disabled patients with Parkinson disease.
OBJECTIVE: To evaluate the efficacy and safety of continuous bilateral high
frequency stimulation of the subthalamic nucleus in patients with Parkinson
disease. DESIGN: A prospective study of patients with Parkinson disease treated
at a university hospital. PATIENTS AND METHODS: Electrodes were implanted
bilaterally in the subthalamic nucleus of 23 consecutive patients with Parkinson
disease who responded well to levodopa but had severe motor complications. There
were 16 men and 7 women (mean +/- SEM age, 53 +/- 2 years) who had a mean +/- SEM
disease duration of 14.7 +/- 1.0 years. Targets were determined by 3-dimensional
magnetic resonance imaging, combined with intraoperative electrophysiologic
recordings and stimulation. RESULTS: Six months after surgery, motor disability,
levodopa-induced motor fluctuations, dyskinesias, and the daily dose of levodopa
equivalent decreased significantly by 67%, 78%, 77%, and 61%, respectively,
compared with the preoperative state. No significant morbidity was observed,
except transient depression in 4 patients. CONCLUSIONS: The beneficial effects of
subthalamic stimulation depend on (1) the criteria used for patient selection,
(2) the precision with which the subthalamic nucleus is targeted (dependent on
the 3-dimensional magnetic resonance imaging and the intraoperative
electrophysiologic and clinical assessments), and (3) the long-term postoperative
adjustment of stimulation variables.
PMID- 10768619
TI - Cognitive impairment and the brain dopaminergic system in Parkinson disease:
[18F]fluorodopa positron emission tomographic study.
AB - OBJECTIVE: To investigate the role of the brain dopaminergic system in cognitive
impairment in patients with Parkinson disease (PD). DESIGN: We studied 28
patients with PD and 16 age-matched healthy control subjects using [18F]
fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD
showed a variable degree of cognitive impairment, which was assessed using the
Mini-Mental State Examination and detailed neuropsychologic assessment, including
tests sensitive for frontal lobe function. RESULTS: [18F] Fluorodopa uptake was
reduced in the putamen (to 36% of the control mean; P<.001), the caudate nucleus
(to 61% of the control mean; P<.001), and the frontal cortex (to 45% of the
control mean; P<.001) in patients with PD compared with controls. There was no
significant association between the degree of overall cognitive impairment of
patients and [18F] fluorodopa uptake values. The influx constant (Ki(occ)) in the
caudate nucleus had a negative association with performance in the attention
demanding Stroop interference task, especially with the interference time. The
Ki(occ) in the frontal cortex had a positive correlation with performance in the
digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus,
the better the patient performed in tasks demanding immediate and working memory
and executive strategies, the better the [18F] fluorodopa uptake in the frontal
cortex. In the putamen, no significant correlation was seen between the Ki(occ)
value and any of the cognitive tests. The severity of the motor symptoms of PD
and [18F]fluorodopa uptake showed a negative correlation in the putamen (r =
0.38; P = .04), and in the caudate nucleus a similar trend was seen (r = -0.36; P
= .06). CONCLUSIONS: Reduced [18F]fluorodopa uptake in PD in the caudate nucleus
(and frontal cortex) is related to impairment in neuropsychologic tests measuring
verbal fluency, working memory, and attentional functioning reflecting frontal
lobe function. This indicates that dysfunction of the dopamine system has an
impact on the cognitive impairment of patients with PD. However, our results do
not exclude the possibility of more generalized cognitive impairment in PD, the
pathophysiology of which is probably different and more generalized.
PMID- 10768620
TI - Aspiration subsequent to a pure medullary infarction: lesion sites, clinical
variables, and outcome.
AB - BACKGROUND: Aspiration as a symptom of dysphagia and its apparent sequela,
aspiration pneumonia, are common consequences of a stroke in the medulla.
Previous reports that focused on dysphagia due to a medullary lesion were studies
of single cases or a relatively small number of patients with multiple lesion
loci. Moreover, the interval between the onset of stroke and the evaluation time
of swallowing was not controlled and varied largely among patients. Thus,
prediction of the swallowing status of patients with a medullary lesion has not
been tenable. OBJECTIVES: To investigate the relation between the loci of pure
medullary lesions and aspiration, to examine swallowing function over time, and
to explore clinical variables that can predict aspiration. METHODS: We
investigated 23 patients with pure medullary infarctions using the
videofluoroscopic swallowing study and compared the airway status findings with
the lesion location as determined with magnetic resonance imaging. The patients
were classified by 6 medullary lesion-level categories (lower, lower-middle,
middle, lower-middle-upper, middle-upper, and upper) and by 5 intralevel lesion
loci (inferior-dorsal, large inferior-dorsolateral, para-median, midlateral, and
dorsolateral). From the results of the videofluoroscopic swallowing studies, 2
patient groups were formed: one with aspiration and the other without aspiration.
The clinical variables related to aspiration and outcome measures were also
explored. RESULTS: Ten (44%) of the 23 patients manifested aspiration on
swallowing: 9 (69%) of 13 with only middle-level lesions or lesions in
multilevels, including the middle level; 1 (33%) of 3 with only upper-level
lesions; and 0 (0%) of 7 with only lower-level medullary lesions. A lesion
running the length of the middle and the lower medullary levels always resulted
in aspiration. When an upper-level lesion was additionally involved, the
incidence of aspiration depended on the horizontal extension of the lesion. We
were able to discriminate the 2 patient groups with 95.7% accuracy using such
variables as dysphonia, soft palate dysfunction, and facial hypesthesia. Most of
the patients with aspiration symptoms due to a pure medullary infarction
recovered rather quickly. CONCLUSIONS: Medullary infarctions often cause
aspiration, but the occurrence may depend on the levels along the neuraxis and
intralevel lesion loci. When different lesion levels and loci and their related
clinical findings are considered as possible variables, aspiration becomes
predictable. The outcome data prove that systematic control of evaluation time of
swallowing was critical as we engaged in this study, since many aspirators with
pure medullary infarctions resolve their swallowing difficulties rather quickly.
PMID- 10768621
TI - A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer
disease.
AB - BACKGROUND: Pathogenic mutations in the presenilin 1 (PS1) gene leading to early
onset Alzheimer disease have been described in various populations. The different
mutations are not distributed randomly in the PS1 protein but are clustered in
some PS1 exons. OBJECTIVE: To screen the PS1 gene in search of a potential
mutation in a Spanish family with early-onset Alzheimer disease. METHODS: Single
stranded conformational polymorphism and heteroduplex analyses of all exons were
used to search for a potential mutation. Subsequent sequencing of the DNA samples
with an abnormal heteroduplex pattern was performed to identity the mutation in
the sense strand and in the complementary strand. RESULTS: We found a novel
mutation in exon 6 of the PS1 gene at a site that, so far, had not been described
as a cluster of mutations. The mutation (an A to C change) causes a substitution
of leucine for arginine at position 166 of the PS1 protein and is located
adjacent to the transmembrane domain III, where few mutations have been found. In
this family, the disease follows an autosomal inheritance pattern with early
onset (range, 32-44 years). CONCLUSION: A novel missense mutation (Leu166Arg) at
an atypical site associated with early-onset Alzheimer disease has been
identified in a Spanish family.
PMID- 10768622
TI - Visuoperceptual impairment in dementia with Lewy bodies.
AB - BACKGROUND: In dementia with Lewy bodies (DLB), vision-related cognitive and
behavioral symptoms are common, and involvement of the occipital visual cortices
has been demonstrated in functional neuroimaging studies. OBJECTIVES: To
delineate visuoperceptual disturbance in patients with DLB in comparison with
that in patients with Alzheimer disease and to explore the relationship between
visuoperceptual disturbance and the vision-related cognitive and behavioral
symptoms. DESIGN: Case-control study. SETTING: Research-oriented hospital.
PATIENTS: Twenty-four patients with probable DLB (based on criteria of the
Consortium on DLB International Workshop) and 48 patients with probable Alzheimer
disease (based on criteria of the National Institute of Neurological and
Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders
Association) who were matched to those with DLB 2:1 by age, sex, education, and
Mini-Mental State Examination score. MAIN OUTCOME MEASURES: Four test items to
examine visuoperceptual functions, including the object size discrimination, form
discrimination, overlapping figure identification, and visual counting tasks.
RESULTS: Compared with patients with probable Alzheimer disease, patients with
probable DLB scored significantly lower on all the visuoperceptive tasks (P<.04
to P<.001). In the DLB group, patients with visual hallucinations (n = 18) scored
significantly lower on the overlapping figure identification (P = .01) than those
without them (n = 6), and patients with television misidentifications (n = 5)
scored significantly lower on the size discrimination (P<.001), form
discrimination (P = .01), and visual counting (P = .007) than those without them
(n = 19). CONCLUSIONS: Visual perception is defective in probable DLB. The
defective visual perception plays a role in development of visual hallucinations,
delusional misidentifications, visual agnosias, and visuoconstructive disability
charcteristic of DLB.
PMID- 10768623
TI - Is ictal recording mandatory in temporal lobe epilepsy? Not when the interictal
electroencephalogram and hippocampal atrophy coincide.
AB - OBJECTIVE: To investigate the concordance between scalp electroencephalogram
(EEG) lateralization and side of hippocampal atrophy in patients with temporal
lobe epilepsy (TLE). METHODS: We studied 184 consecutive patients with TLE
without lesions other than those compatible with mesial temporal sclerosis. In
this study, we studied specifically hippocampal atrophy and the results of scalp
EEG investigation. Patients were classified according to the localization of
interictal epileptiform discharges as unilateral, bilateral asymmetric, and
bilateral symmetric. The EEG seizure onsets were also classified separately as
unilateral, bilateral asymmetric, and bilateral symmetric. The hippocampal
atrophy was determined by volumetric measurements using high-resolution magnetic
resonance imaging (MRIVol). RESULTS: Only 3% of patients had discordance between
the ictal and interictal EEG lateralizations; however, none of these had
unilateral interictal EEG abnormalities. Interictal EEGs were considered
unilateral in 62.0% of patients, bilateral asymmetric in 31.5%, and bilateral
symmetric in 6.5%. Ictal EEGs were considered unilateral in 63.5% of patients,
bilateral asymmetric in 30.0%, and bilateral symmetric in 6.5%. The MRIVol showed
unilateral hippocampal atrophy in 60.9% of patients, bilateral asymmetric
hippocampal atrophy in 19.0%, symmetric hippocampal atrophy in 3.8%, and normal
volumes in 16.3%. There was a significant concordance between MRIVol
lateralization and both interictal and ictal EEG lateralization (P<.001). All
patients with unilateral hippocampal atrophy had concordant interictal and ictal
EEG lateralization. Six (18.2%) of the 33 patients with bilateral asymmetric
hippocampal atrophy had MRI lateralization discordant with EEG lateralization.
CONCLUSIONS: We found a strong concordance between EEG and MRIVol lateralization
in patients with TLE. Unilateral hippocampal atrophy predicted ipsilateral
interictal epileptiform abnormalities and ipsilateral seizure onsets with no
false lateralization. Previous studies in addition to the present series support
that a concordant outpatient EEG evaluation in patients with TLE and unilateral
hippocampal atrophy would obviate the need for inpatient EEG monitoring.
PMID- 10768624
TI - The alpha-synuclein gene and Parkinson disease in a Chinese population.
AB - OBJECTIVE: To study the Ala53Thr and Ala30Pro mutations of the alpha-synuclein
gene in a large number of Chinese patients with Parkinson disease (PD) as well as
controls. METHODS: We recruited 183 Chinese patients with sporadic PD, 17 with
younger-onset PD (onset age <50 years), and 7 with PD and a positive family
history as well as 227 unaffected Chinese control subjects from the outpatient
departments of 2 major hospitals in Hong Kong. All subjects were assessed for the
the diagnosis of PD by a consultant neurologist or geriatrician. Subjects were
interviewed with a standard questionnaire that also questioned for family
history. Venous blood samples were obtained from the subjects and genomic DNA was
extracted and studied for the presence of Ala53Thr mutation in exon 4 and
Ala30Pro mutation in exon 3 of the alpha-synuclein gene using a polymerase chain
reaction restriction fragment length polymorphism method. RESULTS: None of the
Chinese PD patients or controls had either the Ala53Thr (exon 4) or Ala30Pro
(exon 3) mutation of the alpha-synuclein gene. CONCLUSION: We failed to discover
Ala53Thr or Ala30Pro mutations in a large number of Chinese patients with PD and
control subjects, adding to the emerging consensus that variations in the alpha
synuclein gene are associated with PD in few families worldwide.
PMID- 10768625
TI - Parkinson disease survival: a population-based study.
AB - OBJECTIVE: To evaluate whether the survival of patients with Parkinson disease
(PD) is shorter than that of the general population. DESIGN: Survival was
investigated in a cohort of patients with PD previously identified during a
population-based prevalence study (prevalence day, November 1, 1987, reference
follow-up date, October 31, 1995). The survival of patients with PD was compared
with that of a control sample randomly selected from the same population (2
controls for each case, matched for age, sex, and study municipality). The causes
of death in the 2 groups were also compared. Both univariate and multivariate
survival analyses were performed to investigate the association with disease
related variables. SETTING: A door-to-door 2-phase prevalence survey performed in
3 Sicilian municipalities. PATIENTS: Fifty-nine patients with PD and 118
controls. RESULTS: Patients with PD showed a high risk of death (relative risk,
2.3; 95% confidence interval, 1.60-3.39). Greater age at November 1, 1987, high
Hoehn-Yahr score, and lack of levodopa therapy were associated with a lower
survival on univariate analysis. Multivariate analysis confirmed the association
between shorter survival among patients with PD and greater age on November 1,
1987. One-way analysis of variance indicated a different effect of levodopa
therapy according to age. Multivariate analysis did not confirm this finding.
Pneumonia was the cause of death most frequently associated with PD. CONCLUSION:
This study indicates that patients with PD have a shorter survival time than the
general population.
PMID- 10768626
TI - Motor strokes sparing the leg: different lesions and causes.
AB - BACKGROUND: A considerable number of patients develop stroke without involvement
of the lower limb. However, there are few reports about the motor syndrome when
the leg is spared. OBJECTIVE: To study clinical findings, causative factors, and
lesion topography in stroke patients with a motor deficit sparing the leg.
PATIENTS AND METHODS: We studied 895 patients with paresis sparing the leg from
the 3,901 patients enrolled in the Lausanne Stroke Registry. They were compared
with 1,644 stroke patients with paresis involving the leg, by means of univariate
and multivariate analysis. RESULTS: Eight hundred forty-four infarcts (94.3%) and
51 hemorrhages (5.7%) led to weakness sparing the leg. Different sites of lesion
were found, but the majority were caused by superficial infarcts. Almost half of
the lesions were confined to superficial branches of the middle cerebral artery
territory, with 276 (30.8%) in the anterior (superior) and 138 (15.4%) in the
posterior (inferior) middle cerebral artery. More than half of the infarcts had a
presumed embolic source from large-artery disease or from the heart. In
comparison with patients with paresis involving the leg, patients without leg
involvement had a lower prevalence of small-artery disease (P<.001), but a higher
prevalence of migraine (P<.001), transient ischemic attack (P = .001),
atherosclerosis without stenosis (P = .005), large-artery disease (P<.001), and
left hemispheric strokes (P<.001). They also had a lower frequency of hemorrhagic
stroke. CONCLUSIONS: Patients without leg involvement had different stroke
lesions and causes and were characterized by more superficial infarcts mainly
caused by emboli from large-artery disease and atherosclerosis without stenosis.
PMID- 10768627
TI - Presence of diarrhea and absence of tendon xanthomas in patients with
cerebrotendinous xanthomatosis.
AB - BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive
disorder of bile acid synthesis. A diagnosis of CTX should be considered in
patients with premature bilateral cataracts, intractable diarrhea, neurological
signs and symptoms, and tendon xanthomas, especially in the Achilles tendons. The
prevalence of these signs and symptoms increases with age. OBJECTIVES: To
investigate signs and symptoms, age at onset, and age at diagnosis in 32 patients
with biochemically and genetically confirmed CTX, and to compare this clinical
spectrum with reports in the literature. METHODS: Retrospective analysis of
records of all patients with CTX at our hospital (27 adults and 5 children).
After a MEDLINE search in the English, French, and German literature, 181
patients with CTX (165 adults and 16 children) were identified worldwide.
RESULTS: Of our 32 patients with CTX, 31 (97%) had cataracts and neurological
signs and symptoms, predominantly pyramidal signs (26 [81%]); 21 (66%) had low
intelligence and 18 (56%) had cerebellar signs. Only 13 (41%) had visible or
palpable tendon xanthomas at the time of diagnosis. In total, 16 patients (50%)
had chronic, intractable diarrhea that started in childhood. These findings were
in contrast with the literature, where tendon xanthomas were reported in 89% and
diarrhea in only 2 patients. CONCLUSIONS: We believe that CTX is underdiagnosed
worldwide. We recommend that the presence of 2 of the 4 clinical hallmarks of CTX
prompt thorough metabolic screening, including determination of urine bile
alcohol excretion and serum cholestanol level, because CTX is a treatable
disease.
PMID- 10768628
TI - Autoantibodies in thymoma-associated myasthenia gravis with myositis or
neuromyotonia.
AB - BACKGROUND: About 50% of patients with thymoma have paraneoplastic myasthenia
gravis (MG). Myositis and myocarditis or neuromyotonia (NMT) will also develop in
some. Patients with thymoma-associated MG produce autoantibodies to a variety of
neuromuscular antigens, particularly acetylcholine receptor (AChR), titin,
skeletal muscle calcium release channel (ryanodine receptor [RyR]), and voltage
gated potassium channels (VGKC). OBJECTIVE: To examine whether neuromuscular
autoantibodies in patients with thymoma correlate with specific clinical
syndromes. METHODS: Serum and plasma samples from 19 patients with thymoma
associated MG, of whom 5 had myositis and 6 had NMT, underwent testing for
antibodies to AChR, titin, RyR, and VGKC. RESULTS: Antibodies to AChR and titin
were found in 19 and 17 patients, respectively. Antibodies to RyR correlated with
the presence of myositis (P = .03); they were found in all 5 patients with
myositis and in only 1 patient with NMT, but also in 4 of 8 patients with neither
disease. Antibodies to VGKC were found in 4 patients with NMT, 1 of 3 patients
undergoing testing for myositis, and 2 of 7 patients undergoing testing with
neither comorbidity. Presence of RyR antibodies correlated with high levels of
titin antibodies. CONCLUSIONS: The results appear to distinguish partially
between 3 groups of patients with thymoma-associated MG: the first with RyR
antibodies and myositis or myocarditis, the second with NMT without RyR
antibodies, and the third without RyR antibodies, myositis, or NMT. Differences
in the thymoma may underlie these pathologic associations.
PMID- 10768629
TI - Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat
expansion in patients with hereditary spinocerebellar ataxia from Chinese
kindreds.
AB - OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2,
SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and
DRPLA (dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions
[(CAG)n] among persons diagnosed with hereditary SCA from Chinese families.
PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7,
and DRPLA (CAG)n mutation were detected with the polymerase chain reaction,
highly denaturing polyacrylamide gel electrophoresis, and silver staining
technique in 167 patients with autosomal dominant SCA from 85 Chinese families
and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n
mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats.
Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds
(5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado
Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was
expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and
37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD,
SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the
number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically,
dementia and hyporeflexia were more frequent in patients with SCA2, while
spasticity, hyperreflexia, and Babinski signs were more frequent in patients with
SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish
patients with SCA3/MJD and SCA2 from others with different types of SCA.
CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1
and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are
non-Portuguese. Clinical expressions of the various types of SCAs overlap one
another; therefore, for clinical study it is important to make a gene diagnosis
and genetic classification for patients with SCA.
PMID- 10768630
TI - Adhesion molecules in multiple sclerosis: relation to subtypes of disease and
methylprednisolone therapy.
AB - OBJECTIVES: To determine levels of adhesion molecules in blood and cerebrospinal
fluid (CSF) samples from patients with different subtypes and activities of
multiple sclerosis (MS) and to assess the effect of intravenous
methylprednisolone sodium succinate treatment on the levels of soluble adhesion
molecules. DESIGN: The expressions of very late activation antigen 4 (VLA-4),
lymphocyte function associated antigen 1 (LFA-1), vascular cell adhesion molecule
1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) were determined
immunocytochemically, and levels of soluble VCAM-1, ICAM-1, and E-selectin, by
means of enzyme immunoassay technique. The volumes of T2- and T1-weighted MS
plaques and brain atrophy were determined by means of the semiautomatic magnetic
resonance imaging (MRI) segmentation technique. SETTING: A university hospital in
Finland. PATIENTS: One hundred subjects (71 patients with MS and 29 healthy
control subjects). The subtypes of MS were relapsing-remitting (RRMS [n = 26]),
secondary progressive (SPMS [n = 20]), and primary progressive (PPMS [n = 25]).
RESULTS: In patients with RRMS and SPMS, the expressions of VLA-4 and LFA-1 on
immune cells from blood were at least 1.5- to 3-fold higher than in controls
(RRMS, P = .002 and P<.001, respectively; SPMS, P = .03 and P =.001,
respectively). In RRMS, LFA-1 and ICAM-1 expression in blood was more up
regulated than in SPMS (P = .03 and P = .01, respectively). The expressions of
adhesion molecules on CSF lymphocytes in RRMS and SPMS were of similar magnitude,
but the proportions of CSF VLA-4- and LFA-1-expressing lymphocytes were 3- to 4
fold higher than in controls (P = .04 and P = .008, respectively). The levels of
serum soluble VCAM-1 were higher in SPMS than in RRMS (P = .005) or PPMS (P =
.04). Intravenous methylprednisolone treatment of patients with RRMS in
exacerbation caused a significant reduction in the serum levels of soluble VCAM-1
and E-selectin (P<.001). In SPMS, the volumes of T2-weighted plaques correlated
with the serum level of soluble ICAM-1 (r = 0.64; P = .03). CONCLUSIONS: Up
regulated adhesion molecules in blood and CSF indicate sustained potential for
inflammation in the CNS throughout the clinical spectrum of MS. Therapies
interfering with cell adhesion may be of key importance in suppressing MS.
PMID- 10768631
TI - Cerebrospinal fluid oligoclonal IgG bands in patients with spinal arteriovenous
malformation and structural central nervous system lesions.
AB - OBJECTIVE: To investigate the incidence and characteristics of patients with
structural central nervous system (CNS) lesions and cerebrospinal fluid
oligoclonal IgG bands. DESIGN: A retrospective study. METHOD: The medical records
of patients with cerebrospinal fluid oligoclonal IgG bands were evaluated for the
presence of structural CNS lesions, their location and cause, and for clinical
characteristics. SETTING: Cerebrospinal fluid oligoclonal IgG bands were examined
in the Neuroimmunology Laboratory, Hadassah University Hospital, Jerusalem,
Israel. PATIENTS: Two hundred seventy of 570 patients with positive cerebrospinal
fluid oligoclonal IgG bands were available for analysis. Twenty patients had
structural CNS lesions. RESULTS: Twenty (7.5%) of the 270 patients had structural
CNS lesions: 3 patients had spinal arteriovenous malformation; 5 patients had
tumors; 9 patients had compressive cervical myelopathy. Traumatic leukomalacia,
Arnold-Chiari malformation type 1, and CNS hemosiderosis were present in 1
patient each. In 2 patients (1 patient with recurrent meningioma and 1 patient
with posttraumatic encephalomalacia) the presence of a structural CNS lesion was
followed by the development of multiple sclerosis. In all 3 patients with spinal
arteriovenous malformation, oligoclonal IgG identification prolonged the time to
diagnosis and therapy, which varied from a few weeks to 3 years. CONCLUSIONS:
Structural CNS lesions, responsible for the neurological disorder, were present
in 20 patients (7.5%) with cerebrospinal fluid oligoclonal IgG bands. The
mechanism underlying oligoclonal IgG presence in spinal arteriovenous
malformation and the coexistence of multiple sclerosis and structural CNS lesions
is unknown, but may be related to recurrent tissue damage with repeated
presentation of CNS antigens to the immune system.
PMID- 10768632
TI - Visual hallucinations in recovery from cortical blindness: imaging correlates.
AB - OBJECTIVE: To investigate the cerebral metabolic and functional patterns during
recovery from cortical blindness. DESIGN: Follow-up study with serial clinical,
metabolic, and functional imaging and visual evoked potentials. CASE
PRESENTATION: A 24-year-old woman suffered from cortical blindness after cardiac
arrest and recovered over a 6-month period. During recovery, she experienced
complex visual hallucinations that could be initiated by visual imagery. RESULTS:
Initially, the regional cerebral metabolic rate of glucose was severely reduced
in the visual and parieto-occipital cortex bilaterally but recovered almost
completely. Visual hallucinations led to significant increases of the regional
cerebral blood flow in the initially severely hypometabolic parieto-occipital and
temporo-lateral cortex. CONCLUSIONS: Recovery of vision was related to
normalization of the postlesionally dysfunctional cortex. Visual hallucinations
appeared as the clinical correlate of the electrophysiological hyperexcitability
of the recovering partially damaged visual cortex.
PMID- 10768633
TI - Dystonia in a patient treated with propranolol and gabapentin.
AB - We present a 68-year-old patient with essential tremor who was treated with
propranolol hydrochloride (80 mg daily) and gabapentin (900 mg daily) after a
history of mild success of gabapentin alone in relieving his symptoms. The
patient had several daily episodes of paroxysmal dystonic movements in both
hands. After reducing the propranolol dose to 40 mg daily, the dystonic movements
resolved. This case suggests a synergistic effect between propranolol and
gabapentin.
PMID- 10768634
TI - Hemimasticatory spasm associated with localized scleroderma and facial
hemiatrophy.
AB - OBJECTIVES: To report a case and discuss the mechanism of hemimasticatory spasm.
DESIGN: Case report. PATIENT: A 37-year-old woman had a 3-year history of
involuntary spasms of the right masseter muscle in association with localized
scleroderma and facial hemiatrophy. Electrophysiological studies revealed a
normal blink reflex. However, the masseter reflex and silent period were absent
on the affected side. Distal latency and compound muscle action potential of the
masseter nerve were normal. Needle electromyography demonstrated irregular bursts
of motor unit potentials similar to those described in hemifacial spasm. A
magnetic resonance imaging scan of the head showed mild hypertrophy of the
masseter muscle and atrophy of subcutaneous fatty tissues on the affected side.
Local injection of botulinum toxin A into the masseter muscle resolved the
patient's symptoms. CONCLUSION: On the basis of clinical and electrophysiological
findings, focal demyelination of motor branches of the trigeminal nerve owing to
deep tissue changes is suggested as the cause of abnormal excitatory electrical
activities resulting in involuntary masticatory movement.
PMID- 10768635
TI - Deterioration of giant cell arteritis with corticosteroid therapy.
AB - BACKGROUND: Failure of response of giant cell arteritis (GCA) to corticosteroid
therapy has invariably been attributed to the delay in diagnosing the disease or
the use of inadequate corticosteroid dosage. Following our observation of
progressive deterioration following the introduction of prednisolone use in a
patient, we examined the possibility that worsening of the condition might be due
to corticosteroid therapy rather than coincidence. OBJECTIVE: To determine
whether corticosteroid therapy may exacerbate GCA. DESLGN: Case report and an
analysis of similar cases reported in the medical literature. PATIENT: A 64-year
old man had a 3-month history of headache, night sweats, malaise and general
weakness, and anorexia and weight loss and a more recent history of jaw
claudication, dysphagia, and hoarseness. Clinical findings included prominent
temporal arteries with absent pulsation, abnormal saccades to the right, and
eyelid retraction. Laboratory findings included an elevated erythrocyte
sedimentation rate and platelet count. Results of a biopsy of the temporal artery
confirmed GCA. Magnetic resonance imaging scans showed ischemic cerebellar
lesions and a mature infarct in the left anterior occipital, posteroparietal
region. Following corticosteroid therapy commencement, the patient's condition
deteriorated steadily for 5 days with clinical signs suggestive of an evolving
vertebrobasilar stroke. Following treatment with high-dose intravenous
dexamethasone sodium phosphate and heparin sodium, his symptoms improved. DATA
SOURCES: The review included analysis of autopsy-based reports in which clinical
details are provided and clinical reports in which major visual or cerebral
complications are described. Significant complications occurred in many cases
shortly following the introduction of corticosteroid therapy. In many of these
cases, the symptoms indicated that GCA had been present for a significant period
prior to corticosteroid therapy. CONCLUSIONS: Progressively evolving occlusive
strokes may occur following corticosteroid therapy in patients with GCA. In
cerebrovascular complications, vascular occlusion occurs at sites of active
vasculitis, usually within the vertebrobasilar system. It is not certain that the
worsening of the condition following corticosteroid therapy is always
coincidental, and an alternative possibility, namely a functional relationship
between the initiation of corticosteroid therapy and clinical deterioration,
should be borne in mind.
PMID- 10768636
TI - Mixed gangliocytoma/pituitary adenoma.
PMID- 10768637
TI - Whiplash: the evidence for an organic etiology.
PMID- 10768638
TI - Chronic whiplash syndrome as a functional disorder.
PMID- 10768639
TI - Manganese intoxication.
AB - Manganese plays an important role as a cofactor in many enzymatic reactions in
humans but in excess amounts can cause irreversible nervous system damage.
Although manganism is a rare condition, it can be the cause of complex nervous
system symptoms, especially in the setting of environmental exposure.
Specifically, manganese is a well-known cause of dystonic parkinsonism. This
article highlights several historical descriptions of the clinical
manifestations, pathological changes, and attempted therapeutic intervention in
manganese intoxication.
PMID- 10768640
TI - Organophosphorus intoxication.
AB - In every period of history, military leaders have wrestled between a desire to
gain victory by using every possible means and a revulsion from resorting to
poison. During the First World War, a European country cast aside the
humanitarian tradition of its poets and philosophers and attacked its enemies
with a wave of chlorine gas; the same nation, 30 years later, put to death 6
million human beings in gas chambers. But out of the industry of war gases, a few
organophosphorus compounds, notably tabun and sarin, later underwent large-scale
development. These compounds are nowadays used primarily as insecticides. Several
early citations on organophosphate compounds place this chemical class in
neurological context. However, as evidenced by events during the Gulf War of 1991
and the United Nations' arsenal inspections during that war, military interests
in organophosphates are medically very pertinent today, beyond just historical
allusions.
PMID- 10768641
TI - The history of tabes dorsalis and the impact of observational studies in
neurology.
AB - It is common for a particular aspect of scientific knowledge to undergo a great
advance in a brief period of time after the discovery of new investigational
procedures that broaden research horizons. Knowledge of neurosyphilis increased
markedly during the second half of the 19th century. As revealed by the example
of tabes dorsalis, this progress was not related to new research methods but
instead to the impetus of careful clinical observations.
PMID- 10768642
TI - Nutritionally independent B12 deficiency and Alzheimer disease.
PMID- 10768643
TI - Effectiveness of infliximab in the treatment of refractory perineal cutaneous
Crohn disease.
PMID- 10768644
TI - The mission of sex-based professional societies should be to become unnecessary.
PMID- 10768645
TI - Utility of step sections: demonstration of additional pathological findings in
biopsy samples initially diagnosed as actinic keratosis.
AB - OBJECTIVES: To discover additional diagnostic findings on step sections of biopsy
samples showing features of actinic keratosis on the initial section and to
correlate such findings with clinical and histological variables. DESIGN:
Prospective study comparing initial histological findings with those noted on
deeper tissue levels. SETTING: University-based dermatopathology practice.
PATIENTS: Fifty-seven patients (36 men and 21 women) with biopsy samples from 69
skin lesions. MAIN OUTCOME MEASURES: Identification of additional pathological
diagnoses in step sections and correlation with clinical diagnosis, size and
location of lesion, history of skin cancer or immunosuppression, size and
handling of specimen, and presence of ulceration on the initial level. RESULTS:
Additional diagnostic findings were present on step sections in 23 specimens
(33%), including 9 (13%) with squamous cell carcinoma in situ, 3 (4%) with basal
cell carcinoma, and 2 (3%) with invasive squamous cell carcinoma. Three variables
were significantly correlated with the discovery of cancer on step sections: (1)
ulceration on the first level, (2) clinical diagnosis of skin cancer, and (3)
history of skin cancer diagnosed by biopsy examination. The latter 2 variables
were also correlated with the discovery of any additional finding, whether benign
or malignant, on step sections. CONCLUSIONS: In biopsy samples initially
diagnostic of actinic keratosis, examination of step sections contributes
clinically important information. Step sections are particularly useful when a
clinical diagnosis of skin cancer is present. The results of this study confirm
the pathogenetic importance of actinic keratosis as a precursor to fully evolved
malignant neoplasia and suggest that such lesions merit thorough histological
study.
PMID- 10768646
TI - Acne keloidalis is a form of primary scarring alopecia.
AB - OBJECTIVE: To better define the pathogenesis of acne keloidalis (AK). DESIGN:
Prospective, blinded study of histologic material collected from 10 patients with
clinically typical AK. SETTING: Outpatient dermatology clinic of a military
tertiary care medical center. PATIENTS: Ten male volunteers 18 years or older
with early AK lesions (1- to 4-mm firm papules on the lower occipital/nuchal
region). DATA SOURCE: Biopsy specimens from small, early lesions and from
clinically uninvolved skin, studied histologically with transverse sectioning.
INTERVENTION: Three separate 4-mm punch biopsy specimens of the scalp (lesional,
perilesional, and "normal" scalp) were obtained from each volunteer. The
specimens were processed using transverse sectioning. MAIN OUTCOME MEASURES: The
primary variables for data analysis were the presence or absence of the following
histologic features: premature loss of the inner root sheath; eccentric placement
of shaft, with thinning of the outer root sheath; lamellar fibroplasia
surrounding the follicle; loss of sebaceous glands; evidence of follicular
destruction or scarring; inflammation; and intrafollicular or perifollicular
microorganisms. The number and type of hairs were also recorded. RESULTS: The
most common findings in the 19 histologically abnormal specimens were
perifollicular, chronic (lymphocytic and plasmacytic) inflammation, most intense
at the level of the isthmus and lower infundibulum; lamellar fibroplasia, most
marked at the level of the isthmus; complete disappearance of sebaceous glands,
associated with inflamed or destroyed follicles; thinning of the follicular
epithelium, most marked at the level of the isthmus; and total epithelial
destruction (superficial and deep), with residual "naked" hair fragments. Even
some "normal" specimens contained true follicular scars, demonstrating that
normal-appearing scalp skin had previously been affected by the disease.
CONCLUSIONS: Acne keloidalis is a primary form of scarring alopecia, and many of
the histologic findings closely resemble those found in certain other forms of
cicatricial alopecia. Extensive subclinical disease may be present in patients
with AK and can account for some of the permanent hair loss. Overgrowth of
microorganisms does not appear to play an important role in the pathogenesis of
the disease. There is no etiologic relationship between AK and pseudofolliculitis
barbae. Therapies found to be useful in other forms of inflammatory scarring
alopecia are useful in the treatment of early AK.
PMID- 10768647
TI - Lower relapse rate of botulinum toxin A therapy for axillary hyperhidrosis by
dose increase.
AB - BACKGROUND: Primary focal hyperhidrosis is a common condition that gives rise to
functional and emotional problems and may disturb professional and social life.
Recently, low-dose intracutaneous injections of botulinum toxin A have been shown
to induce a temporary anhidrosis, with relapses occurring usually after 4 to 6
months. OBJECTIVE: To evaluate the short- and long-term effectiveness and
possible adverse effects of high-dose botulinum toxin therapy in the treatment of
axillary hyperhidrosis. DESIGN: In an open study, patients with focal
hyperhidrosis were treated with intracutaneous injections of botulinum toxin A
(Botox; Allergan Inc, Irvine, Calif). A total dose of 200 U of botulinum toxin A
was used once per axilla. Patients were observed for up to 15 months. SETTINGS:
University medical center. PATIENTS: Twenty-four patients with axillary
hyperhidrosis were treated. Their ages ranged from 19 to 58 years (mean +/- SD,
34.8 +/- 12.4 years). MAIN OUTCOME MEASURES: Reduction of sweating as assessed by
the Minor iodine-starch test and planimetry of hyperhidrotic areas. Patients were
interviewed at the end of follow-up about their satisfaction with this treatment.
RESULTS: Within 6 days, all patients reported cessation of excessive sweating.
The mean +/- SD area of excessive sweating identified by the Minor iodine-starch
test decreased from 19.27 +/- 11.95 cm2 to 0.25 +/- 0.61 cm2 (P<.001). The mean
follow-up was 10.0 +/- 2.8 months (range, 5-15 months). Four patients (17%)
reported a return of axillary hyperhidrosis after 7 to 10 months. All patients
who experienced relapse showed an excellent response to a second treatment. The
only adverse effects reported were temporary pain and burning during the
injections. No muscular weakness, insensitivity, or systemic reactions were
observed. CONCLUSIONS: High-dose botulinum toxin A seems to be as safe as low
dose botulinum toxin A in the treatment of axillary hyperhidrosis. The
preliminary data suggest a lower rate of relapse.
PMID- 10768648
TI - Accuracy, concordance, and reproducibility of histologic diagnosis in cutaneous T
cell lymphoma: an EORTC Cutaneous Lymphoma Project Group Study. European
Organization for Research and Treatment of Cancer.
AB - OBJECTIVE: To assess the level of observer variability in the histologic
identification of cutaneous T-cell lymphoma (CTCL) and its discrimination from
diseases with similar histologic features. DESIGN: Cutaneous T-cell lymphoma
specimens and randomly mixed controls were evaluated twice by 3 examiners.
SETTINGS: The European Organization for Research and Treatment of Cancer (EORTC)
Cutaneous Lymphoma Project Group. PATIENTS: The study was conducted with
histologic specimens from 32 patients with mycosis fungoides (MF). In addition,
13 specimens of spongiotic, lichenoid, or psoriasiform simulators of MF were
blindly and randomly mixed with the CTCL specimens as controls. MAIN OUTCOME
MEASURES: To evaluate the accuracy and concordance among and individual
reproducibility of raters of histologic diagnoses. RESULTS: Overall, the
concordance among raters was fair to moderate (range, 0.283-0.562; weighted
overall kappa, 0.412). Individual reproducibility of examiners ranged from
moderate to almost perfect (range, 0.473-0.896; weighted overall kappa, 0.709)
and was not significantly different for the definite lymphoma (range, 0.551
0.921; overall kappa, 0.802) and nonlymphoma (range, 0.368-0.950; overall kappa,
0.793) categories. Accuracy was similarly variable among raters: sensitivity
ranged from 49.3% to 78.1% (overall kappa, 0.654), and specificity (control
series) ranged from 46.2% to 69.2% (overall kappa, 0.595). Adding the diagnoses
of probable lymphoma to those of definite lymphoma, sensitivity ranged between
73.5% and 84.9%. Although for each examiner there was a trend toward a lower
sensitivity in the detection of early lesions compared with later lesions, the
difference in sensitivity between the 2 groups was not statistically significant.
CONCLUSIONS: The levels of concordance and reproducibility found in this
investigation were similar to those obtained with comparable studies in the most
varied fields of pathology, confirming that the identification of CTCL for our
observers did not cause particular problems. Our findings also revealed that
pitfalls in CTCL identification are not only limited to early lymphomatous
lesions, as commonly postulated.
PMID- 10768650
TI - Lymphedema after sentinel lymph node biopsy for cutaneous melanoma: a report of 5
cases.
AB - BACKGROUND: Sentinel lymph node (SLN) biopsy has rapidly become the procedure of
choice for assessing the lymph node status of patients with 1992 American Joint
Committee on Cancer stages I and II melanoma. The procedure was designed to be
less invasive and, therefore, less likely to cause complications than a complete
lymph node dissection. To our knowledge, this is the first report in the
literature documenting extremity lymphedema following SLN biopsy. OBSERVATION: We
report 5 cases of lymphedema after SLN biopsy in patients being routinely
followed up after melanoma surgery at the Massachusetts General Hospital Melanoma
Center, Boston. Three cases were mild, and 2 were moderate. Potential
contributing causes of lymphedema were present in 4 patients and included the
transient formation of hematomas and seromas, obesity, the possibility of occult
metastatic melanoma, and the proximal extremity location of the primary melanoma
excision. Four of the patients underwent an SLN biopsy at our institution. We
used the total number of SLN procedures (N = 235) that we have performed to
calculate a 1.7% baseline incidence of lymphedema after SLN biopsy. CONCLUSIONS:
Sentinel lymph node biopsy can be complicated by mild and moderate degrees of
lymphedema, with an incidence of at least 1.7%. Some patients may have
contributing causes for lymphedema other than the SLN biopsy, but many of these
causes are difficult to modify or avoid.
PMID- 10768649
TI - Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients.
AB - OBJECTIVES: To determine the disease course of Dutch patients with mycosis
fungoides and to define factors related to disease progression and survival.
DESIGN: A multicenter, 13-year, retrospective cohort analysis. SETTING: Eight
dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group.
PATIENTS: Three hundred nine patients with mycosis fungoides registered between
October 1985 and May 1997, including 89 patients with limited patches or plaques
(stage Ia), 135 with generalized patches or plaques (stage Ib), 46 with skin
tumors (stage Ic), 18 with enlarged but uninvolved lymph nodes (stage II), 18
with lymph node involvement (stage III), and 3 with visceral involvement (stage
IV). MAIN OUTCOME MEASURES: Response to initial treatment, sustained complete
remission, actuarial disease progression, and overall and disease-specific
survival per clinical stage. RESULTS: The median follow-up was 62 months (range,
1-113 months). For the entire group, the actuarial overall and disease-specific
survival was 80% and 89% at 5 years, and 57% and 75% at 10 years, respectively.
The actuarial 5-year disease-specific survival of patients with stage Ia, Ib, and
Ic disease was 100%, 96%, and 80%, respectively, and only 40% for patients with
stage III disease. Using multivariate analysis, the presence of extracutaneous
disease, the type and extent of skin involvement, the response to initial
treatment, and the presence of follicular mucinosis were independently associated
with higher disease progression and mortality rates. The calculated risks of
disease progression at 5 and 10 years gradually increased from 4% to 10% for
those with stage Ia disease, from 21% to 39% for those with stage Ib disease, and
from 32% to 60% for those with stage Ic disease; for those with stage III
disease, the risk remained at 70% at 5 and 10 years. The overall risk of disease
progression at 5 and 10 years was 24% and 38%, respectively, for the total study
group. CONCLUSION: At least within the first 10 years after diagnosis, disease
progression and mycosis fungoides-related mortality occur in only a subset of
patients generally presenting with advanced disease.
PMID- 10768651
TI - Bullous pemphigoid and amyotrophic lateral sclerosis: a new clue for
understanding the bullous disease?
AB - BACKGROUND: Bullous pemphigoid (BP) occurs in many patients with multiple
sclerosis. Isolated cases of BP in patients with other neurological disorders
further support a pathogenic association between cutaneous and neurological
diseases. Any description of BP in patients with amyotrophic lateral sclerosis is
lacking. OBSERVATIONS: We studied a French population of 168 patients with
typical amyotrophic lateral sclerosis. Among these, 3 had clinical and
histological features of BP. The mean age of the patients was 54 years. None was
known to have autoimmune disorders. Results of immunoblot analysis disclosed both
anti-BP antigen 1 and anti-BP antigen 2 antibodies. CONCLUSIONS: Bullous
pemphigoid seems to be unexpectedly associated with amyotrophic lateral
sclerosis. On the basis of the cases presented herein, we discuss the
epidemiological significance of the association and the possible interrelation
between BP antigen 1 and neurofilaments in the pathogenesis of both disorders.
PMID- 10768652
TI - Bullous pemphigoid of childhood: autoantibodies target the same epitopes within
the NC16A domain of BP180 as autoantibodies in bullous pemphigoid of adulthood.
AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering
disease of the elderly that rarely occurs in children. Most adult BP serum
samples react with epitopes within the NC16A domain of BP180, a glycoprotein of
the cutaneous basement membrane zone. OBJECTIVES: To characterize the autoimmune
response in childhood BP using recombinant forms of BP180 and to determine the
subclass distribution of autoantibodies and their correlation with disease
activity. OBSERVATIONS: Serum samples from 2 infants with BP, aged 4 and 5
months, reacted by immunoblot analysis with 4 epitopes clustered within the N
terminal 45 amino acids of the NC16A domain. The same 4 epitopes have previously
been shown to be the target in adult BP. Childhood BP antibodies to BP180 NC16A
belonged to IgG1, IgG2, IgG3, and IgG4 immunoglobulin subclasses. IgE reactivity
was not detected. Serum levels of antibodies targeting BP180 NC16A paralleled
disease activity as detected by enzyme-linked immunosorbent assay. CONCLUSIONS:
The fine specificity of autoantibodies to BP180 is the same in BP of childhood
and adulthood. Childhood BP is a true variant of BP.
PMID- 10768653
TI - Accurate diagnosis of cutaneous keratinocytic neoplasms: the importance of
histological step sections (and other factors)
PMID- 10768654
TI - Botulinum toxin: beyond cosmesis.
PMID- 10768655
TI - Can dermatopathologists reliably make the diagnosis of mycosis fungoides? If not,
who can?
PMID- 10768656
TI - Verrucous plaques on the face. North American blastomycosis.
PMID- 10768657
TI - An ulcerating verrucous plaque on the foot. Verrucous carcinoma (epithelioma
cuniculatum).
PMID- 10768658
TI - Extensive bluish gray skin pigmentation and severe arthropathy. Endogenous
ochronosis (alkaptonuria).
PMID- 10768659
TI - Grouped papules on the arm of an infant. Eccrine nevus.
PMID- 10768660
TI - Sex-based professional societies are by no means obsolete--yet.
PMID- 10768661
TI - Fecal porphyrin measurements are crucial for adequate screening for
porphyrinopathy.
PMID- 10768662
TI - A controlled trial, LSE vs killed LSE, is needed.
PMID- 10768664
TI - Treatment of cutaneous warts with squaric acid dibutylester: a decade of
experience.
PMID- 10768663
TI - Etanercept-associated injection-site reactions.
PMID- 10768665
TI - Lack of hypocomplementemia in chronic urticaria.
PMID- 10768666
TI - Relation between skin temperature and location of facial lesions in seborrheic
dermatitis.
PMID- 10768667
TI - The potential role of an adult mentor in influencing high-risk behaviors in
adolescents.
AB - BACKGROUND: While mentorship programs, which connect adolescents with adults to
whom they can turn to for help and advice, are proliferating in an attempt to
prevent high-risk behaviors in teenagers, there are few data to show that
mentorship actually makes a difference. OBJECTIVE: To determine if there is an
association between having an adult mentor and high-risk behaviors in
adolescents. HYPOTHESIS: Adolescents who have an adult mentor would be less
likely to engage in high-risk behaviors than those without an adult mentor.
DESIGN: Cross-sectional study. A self-administered, anonymous questionnaire was
developed to assess demographics, involvement in risk behaviors, and the
prevalence of a mentor in the life of a young person. PARTICIPANTS: A convenience
sample of 294 adolescents, seen consecutively (93% of those approached),
receiving outpatient medical care. Participants were predominantly female (68%),
of mixed race/ethnicity, aged between 12 and 23 years (mean +/- SD age, 16.9 +/-
2.4), and from diverse socioeconomic backgrounds. SETTING: An adolescent health
service in a suburban community-based teaching hospital. MAIN OUTCOME MEASURES:
Adolescent smoking, alcohol and drug use, sexual practices, and weapon carrying.
RESULTS: Adolescents with mentors were significantly less likely to participate
in 4 of the 5 measured risk behaviors: ever carrying a weapon (odds ratio, 0.41;
P< or =.01), illicit drug use in the past 30 days (odds ratio, 0.44; P< or =.01),
smoking more than 5 cigarettes per day (odds ratio, 0.54; P< or =.05), and sex
with more than 1 partner in the past 6 months (odds ratio, 0.56; P< or =.05). No
significant difference was found with alcohol use (> or =3 drinks in the past 30
days). CONCLUSION: A strong positive relationship was found between adolescents
having an adult mentor and decreased participation in 4 of the 5 risk behaviors
evaluated.
PMID- 10768668
TI - The adolescents training and learning to avoid steroids program: preventing drug
use and promoting health behaviors.
AB - BACKGROUND: Use of alcohol and other illicit drugs by adolescent male athletes is
a significant problem. Participation in sports may encourage use of drugs that
enhance athletic performance, especially anabolic steroids (AS). Because, to our
knowledge, no other intervention has successfully altered substance abuse by
athletes, we developed and assessed the efficacy of a team-centered, sex-specific
education program designed to reduce adolescent athletes' intentions to use and
use of AS and alcohol and other illicit drugs. METHODS: We studied 31 high school
football teams that comprised 3207 athletes in 3 successive annual cohorts (1994
1996). The intervention included interactive classroom and exercise training
sessions given by peer educators and facilitated by coaches and strength
trainers. Program content included discussion of sports nutrition, exercise
alternatives to AS and sport supplements, and the effects of substance abuse in
sports, drug refusal role-playing, and the creation of health promotion messages.
Questionnaires assessing AS, the use of sport supplements and alcohol and other
illicit drugs, and potential risk and protective factors were administered before
and after the intervention (before and after the football season) and up to 1
year after the program. RESULTS: At season's end, intentions to use (P<.05) and
actual AS use (P<.04) were significantly lower among students who participated in
the study. Although AS reduction did not achieve significance at 1 year (P<.08),
intentions to use AS remained lower (P = .02). Illicit drug use (marijuana,
amphetamines, and narcotics) was reduced at 1 year, whether alcohol was included
(P = .04) or excluded (P = .02) from the index. Other long-term effects included
fewer students reporting drinking and driving (P = .004), less sport supplement
use (P = .009), and improved nutrition behaviors (P<.02). CONCLUSIONS: Use of
alcohol and other illicit drugs and associated harmful activities can be
prevented with a sex-specific, team-centered education. School athletic teams
provide an optimal environment in which to provide drug prevention and health
promotion education.
PMID- 10768669
TI - Renal function 16 to 26 years after the first urinary tract infection in
childhood.
AB - OBJECTIVE: To evaluate renal function in a population-based cohort with
urographic renal scarring after childhood urinary tract infection (UTI). DESIGN:
Follow-up investigation 16 to 26 years after the first recognized UTI. SETTING:
Outpatient university clinic for children with UTI serving the local area.
PATIENTS: From the original cohort of 1221 consecutive children with first UTI
diagnosed during 1970 to 1979, 57 (41 females and 16 males; mean age, 24.5 years)
of 68 with nonobstructive renal scarring participated as well as 51 (38 females
and 13 males; mean age, 24.9 years) matched subjects without scarring. MAIN
OUTCOME MEASURE: Glomerular filtration rate (GFR) measured by chromium 51-EDTA
clearance, expressed as milliliters per minute per 1.73 square meters. RESULTS:
Median GFR was 99 in both those with and without renal scarring. In patients with
unilateral scarring, the total GFR remained unchanged over the years whereas the
individual GFR of the scarred kidneys declined significantly from 46 to 39. In 7
patients with bilateral scarring, the GFR declined from 94 to 84 (P = .14);
compared with those with unilateral scarring, the GFR was significantly lower at
follow-up (P = .007). Median urinary albumin-creatinine ratio was 1.2 and 0.6
mg/mmol in those with scarring and those without, respectively (P = .30).
CONCLUSIONS: The GFR 2 decades after the first recognized UTI in childhood was
well preserved. However, a significant reduction of individual renal GFR in the
unilaterally scarred kidneys indicates that further follow-up is required.
Although there were few patients with bilateral scarring, a more serious
prognosis can be expected among them.
PMID- 10768670
TI - Pediatric acetaminophen overdose: risk factors associated with hepatocellular
injury.
AB - OBJECTIVES: To characterize demographic and clinical factors associated with
pediatric acetaminophen overdose and identify risk factors for hepatocellular
injury. DESIGN: Retrospective 10-year chart review. SETTING: Two regional
children's hospitals. MATERIALS AND METHODS: Records of patients examined because
of acetaminophen ingestion from January 1, 1988, through December 31, 1997, were
reviewed. Hepatocellular injury was defined as elevation of serum
aminotransferase levels greater than 2 times the reference values. Severe
hepatotoxic effect was defined as hepatotoxic effect with evidence of
encephalopathy and/or coagulopathy. RESULTS: Data from 322 patients (208 girls
and 114 boys, aged 1-17 years) were obtained. Ingestions were intentional in 140
patients (median age, 14 years) and unintentional in 172 (median age, 2 years).
Another 10 cases represented dosing errors with therapeutic intent (median age,
3.5 years). Twenty-seven patients had hepatocellular injury; of these, 4 had
severe hepatotoxic effects and 1 died. Hepatocellular injury occurred in 10.0% of
the dosing error group, 17.9% of the intentional group, and 0.6% of the
unintentional group. No patients underwent liver transplantation. Hepatocellular
injury was associated with presentation longer than 24 hours after ingestion
(odds ratio [OR], 335.0; 95% confidence interval [CI], 40.8-275.0), age 10 to 17
years (OR, 36.9; 95% CI, 4.9-275.4), intentional overdose (OR, 37.2; 95% CI, 5.0
278.2), dose greater than 150 mg/kg (OR, 17.9; 95% CI, 2.3-139.2), and white race
(OR, 2.8; 95% CI, 1.1-7.2). CONCLUSIONS: Intentional and unintentional
acetaminophen overdoses occurred with similar frequency. Therapeutic misadventure
was relatively uncommon, as was hepatocellular injury. Practitioners should have
greater suspicion of acetaminophen-associated hepatocellular injury in patients
who present more than 24 hours after ingestion, older children, and those who
have intentional ingestion.
PMID- 10768671
TI - Tykes and bikes: injuries associated with bicycle-towed child trailers and
bicycle-mounted child seats.
AB - OBJECTIVES: To describe the incidence, type, and severity of injuries related to
the use of bicycle-towed trailers for transporting children and to compare them
with injuries associated with the use of child seats mounted on adult bicycles.
DESIGN: A retrospective analysis of data from the National Electronic Injury
Surveillance System of the US Consumer Product Safety Commission for 1990 to
1998. RESULTS: There were 49 injuries to children during the 9-year study period
(estimated 2338 injuries; 95% confidence interval [CI], 1121-3555): 6 were
associated with the use of bicycle-towed trailers (an estimated 322 injuries; 95%
CI, 158-486) and 43 were related to the use of bicycle-mounted child seats (an
estimated 2015 injuries; 95% CI, 988-3042). The mean age of injured children was
2.4 years and 51% were male. A collision with a motor vehicle accounted for 2
(33%) of the injuries associated with bicycle-towed trailers; 3 (50%) of the
injuries were the result of falls. A motor vehicle was involved in 4 injuries
(9%) related to the use of bicycle-mounted child seats (Fisher exact test, P<.13
vs bicycle-towed trailers); 31 (72%) were the result of falls (Fisher exact test,
P<.26 vs bicycle-towed trailers). Contact with a bicycle wheel or spokes was the
mechanism of 1 injury associated with the use of a bicycle-towed trailer (17%)
and the mechanism for 8 (19%) of the injuries associated with the use of a
bicycle-mounted child seat (Fisher exact test, P<.69). The head or face was the
most common site of injury, accounting for 5 (83%) injuries among those riding in
bicycle-towed trailers and 21 (49%) injuries among children in bicycle-mounted
child seats (Fisher exact test, P<.12). All 6 children injured in bicycle-towed
trailers had contusions/ abrasions or lacerations; 22 (51%) children injured
using bicycle-mounted child seats had contusions/abrasions or lacerations and 9
(21%) had fractures. Two children (33%) injured in bicycle-towed trailers and 2
(5%) injured in bicycle-mounted child seats were admitted to the hospital (Fisher
exact test, P<.06). CONCLUSIONS: When compared with bicycle-mounted child seats,
there were fewer reported injuries to children associated with the use of bicycle
towed trailers. Motor vehicle involvement and need for hospital admission were
similar among injured children in both groups, and the head or face was the most
common site of injury. These data imply that ongoing surveillance efforts to
identify injuries associated with use of bicycle-towed child trailers are
warranted and that bicycle helmets should be worn by children riding in bicycle
towed child trailers and in bicycle-mounted child seats.
PMID- 10768672
TI - Appropriateness of urgent referrals by nurses at a hospital-based pediatric call
center.
AB - OBJECTIVES: To evaluate (1) the appropriateness of the after-hours referral
(AHR), (2) clinical characteristics of urgently referred patients, and (3)
parental compliance with disposition recommendations by the After-Hours Call
Center of the Children's Hospital, Denver, Colo. SUBJECTS: Patients of Denver,
Colo, pediatricians who called after office hours were triaged by nurses using a
computerized triage system, and were referred for after-hours evaluation to 1 of
5 urgent care sites (N = 409). DESIGN: Data were collected at each site for 2
week periods every 3 months, from October 1996 to October 1997 (total study
period, 10 weeks). Appropriateness of AHRs (diagnoses, clinical interventions,
and final dispositions) were determined by a questionnaire that was completed by
the evaluating physician. Parental compliance with the AHR was assessed by review
of the after-hours site patient database and by telephone survey. RESULTS: Of the
referred patients, 339 (82.9%) complied with the recommendation for AHR and, of
these, physician questionnaires were completed for 332 (97.9%). The mean
percentage of evaluated patients judged appropriate was 90.7% and did not differ
statistically by site or by physician training. A history indicating a
potentially serious condition was the most common reason for judging a referral
appropriate (80.1%), followed by patient discomfort (53.3%), findings from a
physical examination (42.5%), parental anxiety (41.5%), and an urgent need for
diagnostic test or therapy (34.7%). Of evaluated patients, 37.0% had a diagnostic
test, and in 43.5% of cases, the evaluating physician thought a therapeutic
intervention was necessary that night. Of the total sample, 93.4% were discharged
and 6.6% were admitted to the hospital. The major reasons given by families for
noncompliance were lack of understanding of the disposition recommendation and
disagreement with the need for urgent referral. CONCLUSIONS: Approximately 90% of
patients who complied with a referral for urgent evaluation by the After-Hours
Call Center were judged by the evaluating physician to have been appropriately
referred. The appropriateness rate for all referrals may be lower if there is
significant self-selection in those families who do not comply.
PMID- 10768673
TI - Adolescents who use the emergency department as their usual source of care.
AB - OBJECTIVE: To examine the factors associated with use of the emergency department
(ED) as the only source of health care among adolescents. DESIGN: Analyses of the
1997 Commonwealth Fund Survey of the Health of Adolescent Girls, a nationally
representative sample of 6748 in-school male and female adolescents in 5th
through 12th grade. The X2 statistics and logistic regression analyses were
computed with the use of SUDAAN. RESULTS: Overall, 4.6% of the adolescents in the
survey, or 1.5 million adolescents in the United States, reported that the ED was
their usual source of health care. In multivariate models, factors associated
with the use of the ED included male sex, African American ethnicity, fewer
financial resources, and living in a rural area. Adolescents with higher levels
of risky behaviors, a history of physical or sexual abuse, and higher depression
scores were all more likely to use the ED as their usual source of care.
Adolescents who reported using the ED as their usual care source were also less
likely to have had regular well visits and were more likely to report having
missed needed care than those with other sources of primary care. CONCLUSIONS:
Adolescents who use the ED as their usual source of care are often from
vulnerable populations. Many have special mental or physical needs that are
unlikely to be met with ED visits only, and they are likely to have missed care
they needed. Creating linkages between EDs and other services could help at-risk
adolescents identify and use more appropriate sources of primary care.
PMID- 10768674
TI - Actions without consequences: injury-related messages in children's programs.
AB - OBJECTIVE: To characterize children's television programs in terms of their
unintentional injury-related messages. DESIGN: Content analysis. Episodes
representing a total of 216 unique television programs were coded for the
presence of imitable unsafe behaviors without consequences. SETTING: A census of
all children's programming airing in a northeastern city during the first week of
December 1996. RESULTS: Exactly 47.0% of children's programming depicted at least
1 instance of unsafe, imitable behavior without consequences; one third had more
than 3 instances. Exactly 51.0% of the programs targeted to school-age children
and 33.4% of the programs targeted to preschoolers contained these unsafe
behaviors. The majority (56.8%) of children's programs on basic cable television
depicted unsafe behavior as compared with 23.1% of programs shown on public
television. Cartoon programs depicted the most unsafe behaviors (60.3%), as
compared with live-action programs (33.4%) and other genres (23.3%). CONCLUSIONS:
Children's television programs depict too many unsafe behaviors without
consequences. Future work should explore the role of these programs in the
development of unsafe behaviors in children.
PMID- 10768675
TI - Are signs and symptoms associated with persistent corneal abrasions in children?
AB - BACKGROUND: Corneal abrasions are common eye injuries in children. Most are
treated with antibiotic drops or ointment, patching of the affected eye, and
follow-up within 24 hours to confirm resolution by fluorescein examination.
OBJECTIVE: To determine if signs and symptoms at follow-up were associated with
the presence of a persistent corneal abrasion or abnormal visual acuity. DESIGN:
Retrospective case series. SETTING: A children's hospital. PATIENTS: Children who
were aged 4 years or older with the diagnosis of corneal abrasion between May
1992 and December 1996 and who had a follow-up examination. RESULTS: Seventy
seven patients (57% male) were enrolled (median age, 7 years). The respective
sensitivities, specificities, positive predictive values, and negative predictive
values of selective signs and symptoms for persistent abrasions were as follows:
for pain, 53%, 93%, 80%, and 80%; for photophobia, 57%, 100%, 100%, and 80%; for
redness, 100%, 46%, 44%, and 100%; for pain and redness, 40%, 96%, 80%, and 80%;
and for at least 1 sign or symptom, 95%, 48%, 47%, and 95%. Twenty-six patients
had persistent corneal abrasions at follow-up. Six of these 26 patients were
symptom free at follow-up, and 15 patients had only redness as a persistent sign.
Five patients had abnormal visual acuity, one of whom was asymptomatic. All 3
patients with complications were symptomatic. CONCLUSIONS: Signs and symptoms are
inconsistently associated with persistent corneal abrasions. Asymptomatic
patients may have persistent corneal abrasions, suggesting the need for selective
follow-ups.
PMID- 10768676
TI - T-lymphocyte subsets in HIV-infected and high-risk HIV-uninfected adolescents:
retention of naive T lymphocytes in HIV-infected adolescents. The Adolescent
Medicine HIV/AIDS Research Network.
AB - BACKGROUND: The capacity of the immune system of adolescents to generate and
repopulate naive and memory cell populations under conditions of normal
homeostasis and human immunodeficiency virus (HIV) infection is largely unknown.
OBJECTIVE: To assess lymphocyte subsets in HIV-infected and high-risk HIV
negative adolescents. DESIGN: The Reaching for Excellence in Adolescent Care and
Health Project of the Adolescent Medicine HIV/AIDS Research Network recruits a
cohort of HIV-infected and high-risk HIV-uninfected adolescents, aged 13 to 18
years 364 days, into a study of biomedical and behavioral features of HIV
infection as seen in the context of full availability of primary care and HIV
related consultative services. Lymphocyte phenotypes were determined using
standard 3-color flow cytometry. SETTING: The Reaching for Excellence in
Adolescent Care and Health Project is carried out at 16 clinical sites in 14
urban areas. PARTICIPANTS: T-lymphocyte subsets are reported in 192 HIV-positive
and 78 HIV-negative youths. RESULTS: For HIV-positive subjects, the total CD4+
cell count and the percentage of CD4+ cells are decreased when compared with
those of the HIV-negative controls (P<.001). The reduction in total CD4+ cells
reflects a loss of naive, and memory, CD4+ cells compared with HIV-negative
youths. Human immunodeficiency virus-infected adolescents, many of whom have been
infected recently (ie, those with CD4+ cell counts > or =0.500 x 10(9)/L
[500/microL]), have a significant increase in naive CD8+ cells compared with HIV
negative youths (P<.01). There also is a significant increase in memory CD8+
cells at all strata of total CD4+ cells compared with HIV-negative youths
(P<.01). The increase in naive CD8+ cells in those subjects with CD4+ cell counts
of 0.500 x 10(9)/L or greater is a unique finding in this cohort. CONCLUSIONS:
This study demonstrates high levels of naive CD8+ cells in response to HIV
infection in adolescents with CD4+ cell counts of 0.500 X 10(9)/L or greater. The
presence of high levels of naive CD8+ cells suggests functioning thymic tissue in
some adolescents infected with HIV. Furthermore, the normal level of naive CD4+
cells in adolescents with CD4+ levels of 0.500 x 10(9)/L or greater provides
additional support for the concept of a more robust immune system in HIV-infected
adolescents compared with HIV-infected adults. These observations suggest that
the immune system of HIV-infected adolescents may be capable of better responses
to neoantigens and cytotoxic T-lymphocyte responses to HIV than the immune system
of infected children or adults. Human immunodeficiency virus-infected adolescents
may have an immune system that is capable of reconstitution following highly
active antiretroviral therapy.
PMID- 10768678
TI - Clinical decision rule to identify febrile young girls at risk for urinary tract
infection.
AB - OBJECTIVE: To develop a clinical prediction rule to identify febrile young girls
needing urine culture for evaluation of urinary tract infection (UTI). DESIGN:
Prospective cohort study. SETTING: Urban children's hospital emergency
department. PATIENTS: All girls younger than 2 years (N = 1469) presenting to the
emergency department with fever (temperature > or =38.3 degrees C) and without an
unequivocal source of fever during a 12-month period. MAIN OUTCOME MEASURES: The
outcome of interest was UTI, defined as a catheterized urine culture with pure
growth of 10(4) colonies/mL or greater. Candidate predictors included
demographic, historical, and physical examination variables. Clinical prediction
rules were developed using multiple logistic regression after screening variables
for univariate association and reliability. RESULTS: The presence of 2 or more of
the following 5 variables-less than 12 months old, white race, temperature of
39.0 degrees C or higher, fever for 2 days or more, and absence of another source
of fever on examination-predicted UTI with a sensitivity of 0.95 (95% confidence
interval, 0.85-0.99) and a specificity of 0.31 (95% confidence interval, 0.28
0.34). In the study population, with an overall prevalence of UTI of 4.3%, the
positive predictive value of a score of 2 or more was 6.4% and the negative
predictive value of a score of less than 2 was 0.8%. CONCLUSION: Using this
clinical decision rule, a strategy of obtaining urine cultures from girls younger
than 2 years with a score of 2 or more would lead to identification of 95% of
children with UTI and elimination of 30% of unnecessary urine cultures.
PMID- 10768677
TI - The influence of maternal smoking during pregnancy on the toddler's negativity.
AB - OBJECTIVE: To extend previous studies by looking at the effect of the mother's
smoking during pregnancy on her toddler's negative behavior. DESIGN: A survey
consisting of a structured questionnaire was administered to the mothers of 2
year-old toddlers. SETTING: The subjects were drawn from a community sample, as
part of a larger study of mothers and their children. SUBJECTS: The subjects were
99 toddlers and their mothers taken from a community sample. Fifty-two of the
mothers smoked throughout pregnancy, while 47 either stopped smoking during
pregnancy or started smoking after childbirth. MEASURES: The measures consisted
of scales with adequate psychometric properties, which, for the most part, were
adapted from the literature. Measures included assessment of smoking behavior,
the mother's personality/behavior, perinatal variables, demographic variables,
and aspects of the mother-child relationship. RESULTS: Using logistic regression
analyses, maternal smoking during pregnancy was found to be related to negativity
in the child, controlling for demographic factors, perinatal factors, maternal
personality attributes, and the mother-child relationship. CONCLUSIONS: The
findings suggest that maternal smoking during pregnancy has an adverse effect on
the child's negativity, and that a decrease in maternal smoking during pregnancy
might be expected to lead to a decrease in the child's negativity. The
relationship of maternal smoking during pregnancy and early childhood negativity
to other problem behaviors remains to be explored.
PMID- 10768679
TI - Accuracy of clinical judgment in neonatal jaundice.
AB - CONTEXT: Recommendations for management of jaundice in newborns presume
thatjaundice is a reliable clinical finding and that the pattern and intensity of
jaundice reflects the degree of elevation of the serum bilirubin level.
OBJECTIVES: To determine whether experienced observers agree in describing the
extent of jaundice and to evaluate the reliability of visual assessment as an
indication for the measurement of serum bilirubin levels. DESIGN: Comparison of
independent judgments of the extent of jaundice between examiners and with actual
serum bilirubin measurements. SETTING: Well-newborn nursery in an urban public
hospital. PARTICIPANTS: A convenience sample of 122 healthy term newborns whose
bilirubin concentration was measured in the course of standard newborn care.
Observers were experienced pediatric nurse practitioners, pediatric house staff,
and pediatric attending physicians. RESULTS: Agreement was moderately good for
whether an infant's skin was darkly pigmented (K = 0.56). However, agreement
between observers regarding the presence of jaundice at each specific body site
was poor (0%-23% agreement beyond chance); correlation between estimated
bilirubin concentrations was similarly poor (Pearson correlation coefficient,
0.37). Correlation between estimated and actual bilirubin values was slightly
better (Pearson correlation coefficient, 0.43-0.54). CONCLUSIONS: Clinical
examination with visual assessment for jaundice in newborns is neither reliable
nor accurate. The decision to perform serum bilirubin testing should be based on
additional factors.
PMID- 10768680
TI - Antimicrobial use in defined populations of infants and young children.
AB - BACKGROUND: Antimicrobial overprescribing contributes to bacterial resistance,
but data on use in infants and young children are limited. OBJECTIVES: To assess
antimicrobial use in a defined population of infants and young children and to
determine diagnosis-specific prescribing rates for common infections. DESIGN AND
SETTING: Retrospective cohort study of children served by 44 practices affiliated
with 2 managed care organizations. PATIENTS: Children aged 3 months to 72 months
enrolled in either health plan between September 1, 1994, and August 31, 1996.
ANALYSIS: Rates of antimicrobial use were calculated as the number of pharmacy
dispensings divided by the number of person-years of observation contributed to
the cohort in 2 age groups (3 to <36 months and 36 to <72 months). Other outcomes
included the distribution of diagnoses associated with antimicrobial dispensing
and population-based rates of diagnosis of common acute respiratory tract
illnesses. RESULTS: A total of 46477 children contributed 59710 person-years of
observation across the 2 health plans. Rates of antimicrobial dispensing for
children aged 3 to 36 months were 3.2 and 2.1 dispensings per person-year in the
2 populations. A substantial fraction of younger children (35% in population A
and 23% in population B) received 4 or more antimicrobial prescriptions in a
single year. For children aged 36 to 72 months, the dispensing rates for the 2
populations were 2.0 and 1.5 antimicrobials per person-year. We found significant
differences in rates between the populations studied and a decrease in use at all
sites from 1995 to 1996. The diagnosis of otitis media accounted for 56% of
antimicrobial drugs dispensed to children aged 3 to 36 months and 40% of those
dispensed to children aged 36 to 72 months. Antimicrobial prescribing for colds
and upper respiratory tract infections, bronchitis, and sinusitis was less
frequent than previously reported but accounted for 10% to 14% of antimicrobial
drugs dispensed. CONCLUSIONS: In these populations, otitis media accounted for
the largest number of antimicrobial agents dispensed to children younger than 6
years. Clearly inappropriate indications such as cold, upper respiratory tract
infection, and bronchitis accounted for smaller fractions of antimicrobial use
but may be most amenable to change. However, interventions that encourage use of
strict criteria for diagnosis and treatment of otitis media will likely have the
greatest impact on overall antimicrobial exposure. Monitoring defined populations
longitudinally will allow assessment of the effectiveness of such national and
local initiatives.
PMID- 10768681
TI - Chiropractic care for children.
AB - OBJECTIVE: To describe the practice characteristics and pediatric care of
chiropractors. STUDY DESIGN: Cross-sectional, descriptive survey. SETTING:
Chiropractic practices in the Boston, Mass, metropolitan area. PARTICIPANTS: One
hundred fifty licensed chiropractors. MAIN OUTCOME MEASURES: Demographics,
practice characteristics, and fee structure. Practitioners were also asked about
their approach to childhood immunizations and a clinical scenario. Data were
analyzed using simple descriptive statistics. RESULTS: Ninety (60%) chiropractors
responded. All were white and 65% were men. Respondents had on average 122
patient visits weekly, of which 13 (11%) were from children and adolescents.
Typical visit frequency ranged from 1 to 3 times weekly. Average visit fees were
$82 and $38 (initial and follow-up) and 49% of the fees were covered by
insurance. Seventy percent of the respondents recommended herbs and dietary
supplements. For pediatric care, 30% reported actively recommending childhood
immunizations; presented with a hypothetical 2-week-old neonate with a fever, 17%
would treat the patient themselves rather than immediately refer the patient to a
doctor of medicine, doctor of osteopathy, or an emergency facility. CONCLUSIONS:
Children and adolescents constitute a substantial number of patients in
chiropractics. An estimated 420000 pediatric chiropractic visits were made in the
Boston metropolitan area in 1998, costing approximately $14 million. Pediatric
chiropractic care is often inconsistent with recommended medical guidelines.
National studies are needed to assess the safety, efficacy, and cost of
chiropractic care for children.
PMID- 10768682
TI - Clinical and cardiorespiratory assessment in children with Down syndrome without
congenital heart disease.
AB - OBJECTIVE: To assess the clinical and functional status of a young Down syndrome
(DS) population without congenital heart disease. DESIGN: Prospective study of
children with DS and control subjects. SETTING: Bambino Gesu Children's Hospital,
Rome, Italy. PARTICIPANTS AND METHODS: Forty-two children with DS (mean +/- SD
age, 9.8 +/- 3.6 years) underwent genetic, clinical, neuropsychological (IQ), and
cardiorespiratory evaluation. Cardiorespiratory fitness was assessed with a
treadmill test and a lung function test to determine forced vital capacity, first
second forced expiratory volume, and peak expiratory flow. Data were expressed as
a percentage of the predicted values for control children. To assess cooperation
during exercise testing, we devised a compliance scale assigning a score
according to the subjects' ability to understand instructions, ability to walk
and run as required, and need for vocal encouragement. RESULTS: Eighteen (43%) of
42 children with DS were obese, 10 (24%) were short, and 17 (40%) had
microcephaly. On the Leiter International Performance Scale, 2 of 35 subjects had
a normal IQ score (80-120); all others had low IQ scores (79 to <40). Five
subjects did not undergo cardiorespiratory assessment. Eighteen of 37 subjects
completed lung function tests: the results for 10 were unremarkable, and results
from 8 revealed reduced forced vital capacity because of poor compliance. The
subjects tested had low exercise tolerance (mean +/- SD tolerance percentage, 61%
+/- 12%), mild tachycardia (maximal heart rate, 91% +/- 4%), and a mild
hypertensive response (maximal blood pressure, 89% +/- 8%). Compliance scores
correlated significantly with exercise time and age but not with IQ. CONCLUSIONS:
Clinical and cardiorespiratory assessment is feasible in subjects with DS without
congenital heart disease and should be useful in gauging their fitness level for
safe physical activity.
PMID- 10768683
TI - Pediatric resident and faculty knowledge of the Denver II.
AB - OBJECTIVE: To assess knowledge of the Denver II, the revised developmental
screening tool recommended by the American Academy of Pediatrics, in residents
and faculty, and to evaluate a teaching intervention for incoming postgraduate
year 1 (PGY-1) trainees. DESIGN: A cross-sectional test of knowledge for all
subjects and pretesting and posttesting of the incoming PGY- 1 trainees. SETTING:
University of Texas-Houston Medical School Department of Pediatrics.
PARTICIPANTS: Faculty (n = 9) and residents (n = 78), including an intervention
group (n = 45), of incoming PGY-1 trainees over 2 years. INTERVENTIONS:
Postgraduate year 1 trainees in both 1994 through 1995 and 1995 through 1996
viewed the Denver II training videotape on entry into a continuity clinic.
Trainees were encouraged to perform Denver II evaluations on at least 1
appropriate patient at each pediatric clinic session and had access to Denver II
support materials. MAIN OUTCOME MEASURES: Scores on the Denver II Proficiency
Written Test, self-reported measures of comfort, and number of Denver II
evaluations performed. RESULTS: The mean (SD) test scores for incoming,
preintervention PGY-1 trainees (n = 45) (41.3 [9.6]) did not differ from scores
for outgoing PGY-1 trainees (n = 13) (38.5 [10.4]) who had not received the
intervention. Postintervention PGY-1 test results were significantly improved
(59.4 [10.6]) (P<.001). Test scores for upper-level residents who had
participated in the developmental pediatrics rotation (n = 14) were better (55.3
[9.31), but all scored below passing. Residents who had not yet participated in
the developmental pediatrics rotation (n = 19) and members of the general
pediatric faculty (n = 9) had scores similar to those of PGY-1 trainees (40.9
[13.4] and 39.0 [15.1], respectively). CONCLUSIONS: Residents had a greater
knowledge of the Denver II after completing a developmental pediatrics rotation.
Our intervention produced significant improvement in PGY-1 trainees' knowledge,
raising it to levels similar to those of upper-level residents exposed to
developmental pediatrics. Faculty were not expert in using the Denver II.
PMID- 10768684
TI - Radiological case of the month. Spinal epidural abscess.
PMID- 10768685
TI - Picture of the month. Neonatal adrenal hemorrhage.
PMID- 10768686
TI - Pathological case of the month. Sertoli cell tumor.
PMID- 10768687
TI - Symptom reduction and suicide risk in patients treated with placebo in
antidepressant clinical trials: an analysis of the Food and Drug Administration
database.
AB - The assumption that depressed patients who are assigned to placebo in
antidepressant clinical trials are exposed to substantial morbidity and mortality
is not based on research data. We assessed suicides, suicide attempts, and
depressive symptom reduction in studies of 7 new antidepressants using the Food
and Drug Administration database. Among 19,639 participating patients, 34
committed suicide (0.8% per year), and 130 attempted suicide (2.9% per year).
Rates of suicide and attempted suicide did not differ significantly among the
placebo- and drug-treated groups. Annual rates of suicide and attempted suicide
were 0.4% and 2.7% with placebo, 0.7% and 3.4% with active comparators, and 0.8%
and 2.8% with investigational antidepressants, respectively. Symptom reduction
was 40.7% with investigational drugs (n = 4,510), 41.7% with active comparators
(n = 1,416), and 30.9% with placebo (n = 2,805). These data may help inform
discussions about the use of placebo in antidepressant clinical trials.
PMID- 10768688
TI - Placebo controls: no news is good news.
PMID- 10768689
TI - The placebo problem remains.
PMID- 10768690
TI - What conditions are necessary to assess antidepressant efficacy?
PMID- 10768691
TI - Suicide and antidepressant treatment.
PMID- 10768692
TI - Statistical analysis to settle ethical issues?
PMID- 10768693
TI - Placebo protects subjects from nonresponse: a paradox of power.
PMID- 10768694
TI - Abnormal ventral temporal cortical activity during face discrimination among
individuals with autism and Asperger syndrome.
AB - BACKGROUND: Recognition of individual faces is an integral part of both
interpersonal interactions and successful functioning within a social group.
Therefore, it is of considerable interest that individuals with autism and
related conditions have selective deficits in face recognition (sparing nonface
object recognition). METHOD: We used functional magnetic resonance imaging (fMRI)
to study face and subordinate-level object perception in 14 high-functioning
individuals with autism or Asperger syndrome (the autism group), in comparison
with 2 groups of matched normal controls (normal control group ] [NC1] and normal
control group 2 [NC2]) (n = 14 for each). Regions of interest (ROIs) were defined
in NC1 and then applied in comparisons between NC2 and the autism group. Regions
of interest were also defined in NC2 and then applied to comparisons between NC1
and the autism group as a replication study. RESULTS: In the first set of
comparisons, we found significant task x group interactions for the size of
activation in the right fusiform gyrus (FG) and right inferior temporal gyri
(ITG). Post hoc analyses showed that during face (but not object) discrimination,
the autism group had significantly greater activation than controls in the right
ITG and less activation of the right FG. The replication study showed again that
the autism group used the ITG significantly more for processing faces than the
control groups, but for these analyses, the effect was now on the left side.
Greater ITG activation was the pattern found in both control groups during object
processing. CONCLUSIONS: Individuals with autism spectrum disorders demonstrate a
pattern of brain activity during face discrimination that is consistent with
feature-based strategies that are more typical of nonface object perception.
PMID- 10768695
TI - Exploring the neurofunctional organization of face processing in autism.
PMID- 10768696
TI - Structural abnormalities of subicular dendrites in subjects with schizophrenia
and mood disorders: preliminary findings.
AB - BACKGROUND: Postmortem studies of the subiculum from subjects with schizophrenia
have detected smaller pyramidal cell bodies and diminished immunoreactivity for
the dendritic protein, microtubule-associated protein 2. While these findings
suggest that subicular pyramidal cell dendrites may be structurally altered in
subjects with schizophrenia, this possibility had not been tested directly.
METHODS: Rapid Golgi impregnation of archival brain specimens was used to compare
the morphologic characteristics of subicular dendrites in subjects with
schizophrenia (n = 13) and mood disorders (n = 6) with subjects without
psychiatric disease (n = 8). The specimens were processed and analyzed by
physicians blind to diagnosis. The extent of dendritic trees in the subiculum and
fusiform gyrus was examined by Sholl analysis. Spine density on apical dendrites
of subicular pyramidal cells was determined at a fixed distance from the cell
body. RESULTS: Spine density and arborization of subicular apical dendrites were
significantly related to diagnostic group. Spine density was significantly lower
in the schizophrenia and mood disorder groups than in the nonpsychiatric group.
Among the mood disorder cases, diminished spine density was apparently related to
a strong family history of major psychiatric diseases. There were no significant
effects of diagnostic group on Sholl analysis of nonapical subicular dendrites
nor on Sholl analysis of dendrites of neocortical pyramidal cells in the fusiform
gyrus. CONCLUSIONS: We have observed an association between schizophrenia and
major mood disorders and structural abnormalities of subicular apical dendrites.
Further studies are needed to test this association in a larger sample and to
evaluate the potential role of family history and of confounding factors, such as
medications and chronic institutionalization.
PMID- 10768697
TI - A family study of obsessive-compulsive disorder.
AB - BACKGROUND: The causes of obsessive-compulsive disorder (OCD) are as yet unknown.
Evidence of familial aggregation is one approach for investigating the role of
genetics in the etiology of this condition. The current study was conducted to
determine ifOCD is familial and to investigate possible familial subtypes.
METHODS: Eighty case probands were identified in 5 specialty OCD clinics and 73
community control probands were identified by random-digit dialing. These
probands and their first-degree relatives (343 case and 300 control relatives)
were blinded to group and evaluated by psychiatrists and doctoral-level clinical
psychologists using semistructured instruments. Final diagnoses were assigned by
a blinded-consensus procedure. The results were analyzed using logistic
regression by the method of generalized estimating equations. RESULTS: The
lifetime prevalence of OCD was significantly higher in case compared with control
relatives (11.7% vs 2.7%) (P<.001). Case relatives had higher rates of both
obsessions and compulsions; however, this finding is more robust for obsessions.
Age at onset of obsessive-compulsive symptoms in the case proband was strongly
related to familiality (odds ratio, 0.92; confidence interval, 0.85-0.99) (P =
.05); no case of OCD symptoms was detected in the relatives of probands whose age
at onset of symptoms was 18 years or older. Probands with tics or obsessive
compulsive personality disorder were not more likely to have relatives with OCD
than those without these features. CONCLUSIONS: Obsessive-compulsive disorder is
a familial disorder. Obsessions are more specific to the phenotype than are
compulsions. Age at onset of OCD is valuable in characterizing a familial
subtype.
PMID- 10768698
TI - Preliminary findings of antistreptococcal antibody titers and basal ganglia
volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity
disorders.
AB - BACKGROUND: Previous studies have provided preliminary serological evidence
supporting the theory that symptoms of tic disorders or obsessive-compulsive
disorder (OCD) may be sequelae of prior streptococcal infection. It is unclear,
however, whether previously reported associations with streptococcal infection
were obscured by the presence of diagnostic comorbidities. It is also unknown
whether streptococcal infection is associated in vivo with anatomical alterations
of the brain structures that have been implicated in the pathophysiology of these
disorders. METHODS: Antistreptococcal antibody titers were measured in 105 people
diagnosed as having CTD, OCD, or attention-deficit/hyperactivity disorder (ADHD)
and in 37 community controls without a disorder. Subjects were unselected with
regard to their history of streptococcal exposure. Basal ganglia volumes were
measured in 113 of these subjects (79 patients and 34 controls). RESULTS: A DSM
IV diagnosis of ADHD was associated significantly with titers of 2 distinct
antistreptococcal antibodies, antistreptolysin O and anti-deoxyribonuclease B.
These associations remained significant after controlling for the effects of CTD
and OCD comorbidity. No significant association was seen between antibody titers
and a diagnosis of either CTD or OCD. When basal ganglia volumes were included in
these analyses, the relationships between antibody titers and basal ganglia
volumes were significantly different in OCD and ADHD subjects compared with other
diagnostic groups. Higher antibody titers in these subjects were associated with
larger volumes of the putamen and globus pallidus nuclei. CONCLUSIONS: These
findings suggest that the prior reports of an association between
antistreptococcal antibodies and either CTD or OCD may have been confounded by
the presence of ADHD. They also support the hypothesis that in susceptible
persons who have ADHD or OCD, chronic or recurrent streptococcal infections are
associated with structural alterations in basal ganglia nuclei.
PMID- 10768700
TI - Synchrony of change in depression and disability: what next?
PMID- 10768699
TI - Psychosocial disability during the long-term course of unipolar major depressive
disorder.
AB - BACKGROUND: The goal of this study was to investigate psychosocial disability in
relation to depressive symptom severity during the long-term course of unipolar
major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major
life functions and social relationships were obtained during an average of 10
years' systematic follow-up of 371 patients with unipolar MDD in the National
Institute of Mental Health Collaborative Depression Study. Random regression
models were used to examine variations in psychosocial functioning associated
with 3 levels of depressive symptom severity and the asymptomatic status.
RESULTS: A progressive gradient of psychosocial impairment was associated with a
parallel gradient in the level of depressive symptom severity, which ranges from
asymptomatic to subthreshold depressive symptoms to symptoms at the minor
depression/dysthymia level to symptoms at the MDD level. Significant increases in
disability occurred with each stepwise increment in depressive symptom severity.
CONCLUSIONS: During the long-term course, disability is pervasive and chronic but
disappears when patients become asymptomatic. Depressive symptoms at levels of
subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent
a continuum of depressive symptom severity in unipolar MDD, each level of which
is associated with a significant stepwise increment in psychosocial disability.
PMID- 10768701
TI - Income differences in persons seeking outpatient treatment for mental disorders:
a comparison of the United States with Ontario and The Netherlands.
AB - BACKGROUND: Variations in the relationships among income, use of mental health
services, and sector of care are examined by comparing data from 3 countries that
differ in the organization and financing of mental health services. METHODS: Data
come from the 1990-1992 National Comorbidity Survey (n = 5,384), the 1990-1991
Mental Health Supplement to the Ontario Health Survey (n = 6,321), and the 1996
Netherlands Mental Health Survey and Incidence Study (n = 6031). Analysis of the
association between income and use of mental health services was carried out for
the population that was between ages 18 and 54 years. Differential use of mental
health treatment was examined in 3 sectors: the general medical sector, the
specialty sector, and the human services sector. RESULTS: No significant
association between income and probability of any mental health treatment was
observed for persons with psychiatric disorders in any of the 3 countries.
However, there were significant differences among countries in the association
between income and sector of mental health care treatment. In the United States,
income is positively related to treatment being received in the specialty sector
and negatively related to treatment being received in the human services sector.
In the Netherlands, patients in the middle-income bracket are less likely to
receive specialty care, while those in the high-income bracket are less likely to
be seen in the human service sector. Income is unrelated to the sector of care
for patients in Ontario. CONCLUSIONS: Future research should examine whether
differential access to the specialty sector for low-income people in the United
States is associated with worse mental health outcomes.
PMID- 10768703
TI - On the nature of civility.
PMID- 10768704
TI - Health care reform and undergraduate medical education: implications for
surgeons.
PMID- 10768702
TI - Methadone dose increase and abstinence reinforcement for treatment of continued
heroin use during methadone maintenance.
AB - BACKGROUND: Although methadone maintenance is an effective therapy for heroin
dependence, some patients continue to use heroin and may benefit from therapeutic
modifications. This study evaluated a behavioral intervention, a pharmacological
intervention, and a combination of both interventions. METHODS: Throughout the
study all patients received daily methadone hydrochloride maintenance (initially
50 mg/d orally) and weekly counseling. Following baseline treatment patients who
continued to use heroin were randomly assigned to 1 of 4 interventions: (1)
contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2)
methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined
contingent vouchers and methadone dose increase (n = 32 patients); and (4)
neither intervention (comparison standard; n = 28 patients). Methadone dose
increases were double blind. Vouchers had monetary value and were exchangeable
for goods and services. Groups not receiving contingent vouchers received
matching vouchers independent of urine test results. Primary outcome measure was
opiate-negative urine specimens (thrice weekly urinalysis). RESULTS: Contingent
vouchers and a methadone dose increase each significantly increased the
percentage of opiate-negative urine specimens during intervention. Contingent
vouchers, with or without a methadone dose increase, increased the duration of
sustained abstinence as assessed by urine screenings. Methadone dose increase,
with or without contingent vouchers, reduced self-reported frequency of use and
self-reported craving. CONCLUSIONS: In patients enrolled in a methadone
maintainence program who continued to use heroin, abstinence reinforcement and a
methadone dose increase were each effective in reducing use. When combined, they
did not dramatically enhance each other's effects on any 1 outcome measure, but
they did seem to have complementary benefits.
PMID- 10768705
TI - Impact of laparoscopic staging in the treatment of pancreatic cancer.
AB - HYPOTHESIS: Staging laparoscopy in patients with pancreatic cancer identifies
unsuspected metastases, allows treatment selection, and helps predict survival.
DESIGN: Inception cohort. SETTING: Tertiary referral center. PATIENTS: A total of
125 consecutive patients with radiographic stage II to III pancreatic ductal
adenocarcinoma who underwent staging laparoscopy with peritoneal cytologic
examination between July 1994 and November 1998. Seventy-eight proximal tumors
and 47 distal tumors were localized. INTERVENTIONS: Based on the findings of
spiral computed tomography (CT) and laparoscopy, patients were stratified into 3
groups. Group 1 patients had unsuspected metastases found at laparoscopy and were
palliatedwithout further operation. Group 2 patients had no demonstrable
metastases, but CT indicated unresectability due to vessel invasion. This group
underwent external beam radiation with fluorouracil chemotherapy followed in
selected cases by intraoperative radiation. Patients in group 3 had no metastases
or definitive vessel invasion and were resection candidates. MAIN OUTCOME
MEASURE: Survival. RESULTS: Staging laparoscopy revealed unsuspected metastases
in 39 patients (31.2%), with 9 having positive cytologic test results as the only
evidence of metastatic disease (group 1). Fifty-five patients (44.0%) had
localized but unresectable carcinoma (group 2), of whom 2 (3.6%) did not tolerate
treatment, 20 (36.4%) developed metastatic disease during treatment, and 21
(38.2%) received intraoperative radiation. Of 31 patients with potentially
resectable tumors (group 3), resection for cure was performed in 23
(resectability rate, 74.2%). Median survival was 7.5 months for patients with
metastatic disease, 10.5 months for those receiving chemoradiation, and 14.5
months for those who underwent tumor resection (P = .01 for group 2 vs. group 1;
P<.001 for group 3 vs group 1). CONCLUSIONS: Staging laparoscopy, combined with
spiral CT, allowed stratification of patients into 3 treatment groups that
correlated with treatment opportunity and subsequent survival. Among the 125
patients, laparoscopy obviated 39 unnecessary operations and irradiation in
patients with metastatic disease not detectable by CT. Laparoscopic staging can
help focus aggressive treatment on patients with pancreatic cancer who might
benefit.
PMID- 10768706
TI - Mechanisms of the salutary effects of dehydroepiandrosterone after trauma
hemorrhage: direct or indirect effects on cardiac and hepatocellular functions?
AB - BACKGROUND: Dehydroepiandrosterone (DHEA) is the most abundant adrenal hormone in
man and has been shown to improve immune functions after trauma-hemorrhage.
However, it remains unknown whether this agent has any salutary effects on the
depressed organ functions under such conditions. HYPOTHESIS: Administration of
DHEA after trauma-hemorrhage attenuates depressed cardiac and hepatocellular
functions, and beneficial effects are mediated via the estrogen receptors.
DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Male rats underwent laparotomy
and were then bled to and maintained at a mean arterial pressure of 40 mm Hg
until 40% of the maximal bleed-out volume was returned in the form of Ringer
lactate (RL) solution. The animals were then resuscitated with 4 times the
maximum bleed-out volume with RL for 60 minutes. Subcutaneous administration of
DHEA (30 mg/kg of body weight) or vehicle occurred after resuscitation. At 24
hours after resuscitation, cardiac output was measured by a dye-dilution
technique. Hepatocellular function, ie, the maximum velocity of indocyanine green
clearance (Vmax) and the efficiency of the active transport (Km), was determined
using an in vivo hemoreflectometer. Plasma levels of DHEA, sex hormone binding
globulin, 17beta-estradiol, and testosterone were also determined. Moreover,
additional groups of animals received a high-affinity estrogen receptor
antagonist (ICI 182,780) with or without DHEA treatment. RESULTS: Cardiac output
decreased by 12.9% at 24 hours after trauma-hemorrhage; however, it was similar
to shams in DHEA-treated animals. Moreover, hepatocellular function was
significantly depressed after hemorrhage (Vmax, -74.4%; Km, -62.3%), whereas DHEA
treatment restored those values to sham levels. Plasma levels of 17beta-estradiol
and testosterone were not significantly altered in animals receiving DHEA. The
hemorrhage group treated with DHEA and ICI 182,780 showed markedly depressed
cardiac and hepatocellular functions. CONCLUSIONS: Since DHEA treatment after
trauma-hemorrhage restored the depressed cardiac and hepatocellular functions, it
appears that DHEA is a safe and inexpensive adjunct to fluid resuscitation for
restoring the depressed cardiac and hepatocellular responses after severe
hemorrhagic shock in male subjects. Furthermore, since ICI 182,780 administration
with DHEA abolished the salutary effects of DHEA, it appears that these effects
on cardiac and hepatocellular functions after trauma-hemorrhage are mediated via
the estrogen receptors.
PMID- 10768707
TI - Do female sex steroids adversely or beneficially affect the depressed immune
responses in males after trauma-hemorrhage?
AB - HYPOTHESIS: Administration of female sex steroids in males after trauma
hemorrhage has salutary effects on the depressed immune responses. DESIGN:
Randomized laboratory experiment. INTERVENTIONS: Male C3H/HeN mice were subjected
to midline laparotomy and hemorrhagic shock (35+/-5 mm Hg for 90 minutes, then
resuscitation) or sham operation and received subcutaneous 17beta-estradiol (40
microg/kg body weight) or corn oil vehicle at the beginning of resuscitation.
MAIN OUTCOME MEASURES: At 24 hours after hemorrhage, the animals were killed and
plasma 17beta-estradiol and IL-6, splenocyte interleukin (IL) 2, IL-3, and IL-10
production as well as splenic and peritoneal macrophage IL-1beta, IL-10, and IL-6
release were measured. RESULTS: Splenocyte IL-2 and IL-3 release were
significantly depressed after hemorrhage in vehicle-treated mice (P<.05, analysis
of variance). Treatment with 17beta-estradiol after hemorrhage led to the
restoration of splenocyte IL-2 and IL-3 release. The depressed proinflammatory
cytokine (IL-1 and IL-6) release seen in splenic and peritoneal macrophages was
restored in the 17beta-estradiol-treated hemorrhage group. In contrast, the
sustained release of the anti-inflammatory cytokine IL-10 by splenocytes and
splenic and peritoneal macrophages in vehicle-treated mice after hemorrhage was
decreased in 17beta-estradiol-treated mice. The increase in circulating IL-6
levels after hemorrhage was significantly attenuated in 17beta-estradiol-treated
mice. Although administration of 17beta-estradiol increased plasma 17beta
estradiol levels by approximately 100% in sham as well as hemorrhage groups,
improved immune responses were seen only in posthemorrhage 17beta-estradiol
treated mice. There was no adverse effect of 17beta-estradiol treatment in the
sham or posthemorrhage groups. CONCLUSION: Since administration of a single dose
of 17beta-estradiol in males after trauma-hemorrhage restores the immune
functions and decreases circulating levels of IL-6, hormones with estrogenic
properties should be considered as safe and novel therapeutic agents for
restoring the immune responsiveness in male trauma victims.
PMID- 10768708
TI - Experience with endoluminal colonic wall stents for the management of large bowel
obstruction for benign and malignant disease.
AB - HYPOTHESIS: To assess the applicability and efficacy of endoluminal colonic wall
stents (ECWSs) in the management of large bowel obstruction (LBO). DESIGN:
Inception cohort study. SETTING: University-based tertiary medical center.
PATIENTS: Eleven consecutive patients with LBO in the absence of peritonitis.
INTERVENTION: Placement of ECWS under endoscopic and fluoroscopic guidance. MAIN
OUTCOME MEASURES: The success rate in ECWS placement, the efficacy in
decompressing the obstruction, and the patency rate of the ECWS. RESULTS:
Successful placement of ECWSs was obtainable in 10 of 11 patients. Once placed,
all 10 patients achieved immediate decompression of their LBO. Eight patients had
malignant obstructions associated with distant spread of disease; 3 patients had
diverticular disease. Among those with malignant obstruction, 6 patients had
successful and lasting palliation without colostomy, 1 patient underwent 1-stage
resection 1 month later with no evidence of obstruction, and 1 patient could not
be stented so diversion was done. None of the patients with diverticular disease
required diversion: 2 had complete bowel preparation followed by resection with
primary anastomosis, whereas the third declined surgery. Four of the 10 patients
required overlapping ECWSs to bridge the stricture. One patient required a second
ECWS secondary to recurrence of obstruction after stent migration and has
continued palliation of his stage 4 rectal cancer for the last 11 months. No
other complications were encountered. CONCLUSIONS: Urgent surgery with colostomy
for LBO was avoided in 10 of 11 patients because of successful placement of
ECWSs. We believe that endoscopic colonic stenting is safe, effective, and
lasting, and should be considered as initial nonoperative management in all
patients seen with LBO in the absence of peritonitis.
PMID- 10768709
TI - Surgical resident research in New England.
AB - HYPOTHESIS: This study sought to determine the attitudes of general surgery
residents in New England toward research and the factors that affect their
research participation and productivity. DESIGN: Survey. SETTING: Eighteen of the
20 general surgery residency programs in New England. PARTICIPANTS: Four hundred
fifty-nine surgical residents taking the American Board of Surgery In-Training
Examination in 1999. MAIN OUTCOME MEASURES: Rationale for and amount of time
spent in research and the number of publications. RESULTS: A majority of
residents (61%) participated in research. Rationales for research participation
included initiating an academic career (82%) and enhancing fellowship application
prospects (83%). Personal debt was substantial, but had little influence on
decisions regarding research. Gender was not a factor in the decision to
participate in research, although women were more likely to cite a break from
residency as a positive influence in their decision for doing research. Residents
from larger programs (>25 residents) were more likely to participate in research,
spend more time in research, and to publish an article than those from programs
with fewer than 25 residents. CONCLUSIONS: Most surgical residents in New England
plan to or participate in research and publish their work. Significant
differences in the type, duration, and productivity of research exist between
larger and smaller programs, and may reflect differing priorities among
residents, or differences in the variety of research opportunities available.
PMID- 10768710
TI - Spinal anesthesia for preterm infants undergoing inguinal hernia repair.
AB - HYPOTHESES: Use of spinal anesthesia is safe and effective in an outpatient
population of preterm infants undergoing inguinal hernia repair (IHR) and
eliminates routine postoperative hospital admission for apnea monitoring.
METHODS: From October 1982 through October 1997, all preterm (gestational age
[GA], < or =37 weeks), high-risk (preterm infants whose postconceptual age at
surgery [PCAS] is <60 weeks) infants undergoing IHR with spinal anesthesia were
studied prospectively. No exclusions were made for preexisting conditions.
Elective IHRs and incarcerated hernias were both considered. A postoperative
apnea rate was calculated and compared with published postoperative apnea rates
in preterm infants after receiving general anesthesia. RESULTS: For 269 IHRs
performed, 262 spinal anesthetic placements (97.3%) were successful in 259
infants; 246 placements were achieved on the first attempt and 16 on the second.
The mean GA was 32 weeks (GA range, 24-37 weeks); mean PCAS, 43.7 weeks (PCAS
range, 33.4-59.3 weeks); and mean birth weight, 1688 g (weight range, 540-3950
g). Two hundred six patients (78.6 %) did not require supplemental anesthesia; 56
(21.4%) did: 34 received intravenous anesthesia; 6, general; 12, local; and 4,
other regional. One hundred fifty-three infants had a history of apnea. Thirteen
episodes of apnea were noted in 13 infants (4.9%) following the 262 procedures;
all 13 were inpatients undergoing concomitant therapy for apnea (mean GA, 28
weeks; PCAS, 42.9 weeks). Four of these infants received supplemental anesthesia.
This apnea rate is significantly lower than the published rate (10%-30%) (P =
.01). One hundred three infants underwent IHR on an outpatient basis, 39 of whom
had a history of apnea. None of these developed apnea postoperatively. The mean
birth weight of this group was 2091 g (weight range, 710-3693 g); mean GA, 33
weeks (GA range, 25-37 weeks); and mean PCAS, 44.3 weeks (PCAS range, 35.4-59.2
weeks). All 103 patients were discharged home the day of surgery. Average time
from room entry to incision was 26.3 minutes, which is similar to anesthesia
induction time for patients receiving general anesthesia. Average time from
bandaging to leaving room was 1 minute, less than usual time for patients
receiving general anesthesia. CONCLUSIONS: Spinal anesthesia is safe, effective,
and eliminates the need for postoperative hospital admission in an outpatient
population of preterm infants undergoing IHR. This results in considerable cost
savings without compromising quality of care.
PMID- 10768711
TI - Lower extremity revascularization in diabetes: late observations.
AB - HYPOTHESIS: Despite the success of infrainguinal arterial bypass in diabetic limb
and foot salvage, optimism remains guarded because of purported high late
mortality and limb loss in patients with diabetes. DESIGN: Inception cohort, with
minimum 5-year follow-up. SETTING: Tertiary referral center. PATIENTS: Eight
hundred forty-three consecutive patients undergoing lower extremity arterial
reconstruction from July 1, 1990, through July 31, 1993. INTERVENTION:
Infrainguinal arterial bypass with vein graft. MAIN OUTCOME MEASURES: Graft
patency, limb salvage, and survival. RESULTS: A total of 962 vein grafts (843
patients) were performed; 795 grafts (82.6%) were performed in patients with
diabetes (DM group) and 167 (17.4%) in nondiabetic patients (NDM group). Average
age was 68.4 years, and was lower in the DM group (66.2 [range, 27-92 years] vs.
70.5 years [range, 37-96 years]) (P = .005). Inhospital 30-day perioperative
mortality was 1.4%, lower in the DM group (0.9% vs. 4.2%) (P = .005). The target
vessel was more frequently infrageniculate in the DM group (87% vs. 77%; P =
.002). Five-year primary and secondary graft patencies were 74.7% (DM group,
75.6%; NDM group, 71.9%; P = .80) and 76.2% (DM group, 77.0%; NDM group, 73.6%; P
= .90), respectively. The 5-year overall limb salvage rate was 87.1%, also
unaffected by diabetes (DM group, 87.3%; NDM group, 85.4%; P = .80). Survival at
5 years was 58.1% overall and virtually identical in the DM (58.2%) and NDM
groups (58.0%). CONCLUSIONS: Diabetes mellitus does not influence late mortality,
graft patency, or limb salvage rates after lower extremity arterial
reconstruction. Concern for longterm mortality and limb loss in diabetic patients
is unwarranted and should not prevent aggressive attempts at limb salvage.
PMID- 10768712
TI - Variation in the use of laparoscopic cholecystectomy for elderly patients with
acute cholecystitis.
AB - HYPOTHESIS: There is regional variation in the use of laparoscopic
cholecystectomy (LC) for acute cholecystitis in the New England (Maine, New
Hampshire, Vermont, Massachusetts, Rhode Island, and Connecticut) Medicare
population. DESIGN: Population-based, cross-sectional study. SETTING: Hospital
service areas (HSAs), small geographic areas reflecting local hospital markets,
in New England. PATIENTS: We identified from the claims database 21 570 Medicare
patients undergoing cholecystectomy between 1995 and 1997. Patients with acute
calculous cholecystitis but no bile duct stones (n = 6156) were then identified
using International Classification of Diseases, Ninth Revision diagnostic codes.
To reduce variation by chance, we excluded patients residing in HSAs with fewer
than 26 cases, leaving 5014 patients in 77 HSAs. MAIN OUTCOME MEASURES: For each
HSA, we assessed the rate of cholecystectomies performed laparoscopically,
mortality, and hospital length of stay. RESULTS: Overall, 53.5% of patients with
acute cholecystitis underwent LC. There was wide regional variation in the rate
of patients undergoing laparoscopic surgery, from 30.3% in the Salem, Mass, HSA
to 75.5% in the Hyannis, Mass, HSA. Seventeen HSAs had rates below 40%, while 9
had rates above 70%. The average length of stay (7.6 days) was approximately 1
day shorter in HSAs with high rates of patients undergoing LC than in other HSAs.
There was no correlation between regional use of laparoscopic surgery and 30-day
mortality (3.1% overall). CONCLUSIONS: The likelihood of elderly patients with
acute cholecystitis receiving LC depends strongly on where they live. Efforts to
reduce regional variation should focus on disseminating techniques for safe LC in
this high-risk population.
PMID- 10768713
TI - Ileoanal pouch operation: long-term outcome with or without diverting ileostomy.
AB - HYPOTHESIS: Avoiding a diverting ileostomy does not influence the long-term
overall morbidity and functional outcome of patients after ileoanal pouch
operation (IAP). DESIGN: All patients undergoing IAP were prospectively entered
into a database, and those undergoing operation from October 1, 1989, through
January 31, 1996, were contacted by mail questionnaire. SETTING: Tertiary
referral center. PATIENTS: One hundred thirty unselected sequential patients.
INTERVENTIONS: The IAP was completed by a stapled method without diverting
ileostomy, provided the patient agreed, and there were no other complicating
factors. MAIN OUTCOME MEASURES: Need for reoperation, fecal leakage, pouch
frequency, ability to defer evacuation, pouchitis, and overall quality of life.
RESULTS: Of 102 patients (78.5%) who initially underwent IAP without diverting
ileostomy, 10 (9.8%) developed an anastomotic leak and required a diverting
ileostomy. Additional surgery was required in 12 (9.2%) of the 130 patients for
bowel obstruction and in 3 (2.3%) for pouch excision. Two patients died of
unrelated causes, leaving 125 functioning pouches (96.2%). Questionnaires were
completed in 111 (88.8%) of the 125; 75 patients (67.6%) reported perfect
continence for gas and stool, 10 patients (9.0%), regular nighttime leakage, and
24 patients (21.6%), occasional fecal leakage. Pouch evacuation frequency (+/-SD)
per 24 hours was 7.8+/-2.4 (range, 4-12), and 95.5% of patients could defer pouch
evacuation. Of the 111 patients, 42.3% reported pouchitis, with 7.2% receiving
long-term antibiotic therapy. Of the patients, 74.8% reported total satisfaction,
and 84.7% regarded themselves as being in perfect health. CONCLUSION: Long-term
outcome after IAP remains favorable with or without diverting ileostomy.
PMID- 10768714
TI - The necessity for a thoracic approach in thyroid surgery.
AB - HYPOTHESIS: A thoracic approach is commonly required in certain subsets of
patients with a mediastinal thyroid mass. DESIGN: A retrospective review.
SETTING: A tertiary referral center. PATIENTS: Nine hundred seventy-six
consecutive patients who underwent thyroid surgery by a single surgeon from June
1, 1991, to March 30, 1999. Symptoms of airway compression, including respiratory
distress, dyspnea, hoarseness, dysphagia, and persistent cough, were the most
common presenting symptoms. The patients ranged in age from 27 to 89 years (mean,
63 years). RESULTS: Patients in whom the computed tomographic scan and operative
findings revealed that at least 50% of the thyroid mass was below the thoracic
inlet were considered to have a mediastinal mass. These strict criteria
identified 94 patients with a mediastinal thyroid mass. Twenty-seven (29%) of
these patients required a thoracic approach. The thoracic approach consisted of
21 partial sternotomies, 5 full sternotomies, and 1 right posterolateral
thoracotomy. Fifteen patients had a malignant neoplasm. Fourteen patients had a
papillary carcinoma, and 3 of these patients had a multifocal microscopic
papillary carcinoma within a multinodular colloid goiter. One patient had a
follicular carcinoma. Seven patients underwent reoperative surgery, 5 for a
malignant tumor and 2 for a benign tumor. Five patients had a posterior tumor,
and 2 had an aberrant mediastinal thyroid mass. Twenty-two (81%) of the 27
patients who underwent a thoracic approach fell into one of the following
categories: malignant neoplasm, reoperation, or aberrant or posterior mediastinal
thyroid mass. CONCLUSIONS: Subsets of patients with a mediastinal thyroid mass
are at considerably increased risk for requiring a thoracic surgical approach.
These subsets include patients with malignant mediastinal tumors, patients
undergoing reoperative thyroid surgery, and patients with posterior or aberrant
mediastinal thyroid masses. Surgeons should be prepared for the increased
likelihood of a thoracic approach in these subsets of patients.
PMID- 10768715
TI - Interval hepatic resection of colorectal metastases improves patient selection.
AB - HYPOTHESIS: Interval reevaluation for resectability of hepatic colorectal
metastases aids patient selection. DESIGN: A retrospective review. SETTING: A
tertiary care medical center. PATIENTS AND METHODS: From January 1, 1985, to July
1, 1998, 318 patients with colorectal hepatic metastases were identified.
Resectable lesions (N = 73) were divided into synchronous (n = 36) or
metachronous (n = 37) and retrospectively reviewed for immediate resection or
interval reevaluation. Kaplan-Meier survival curves of treatment groups were
compared by the log-rank test. RESULTS: Survival curves of patients with
synchronous and metachronous lesions undergoing interval reevaluation vs.
immediate resection were not significantly different (P = .74 and P = .65,
respectively). No lesions from patients who underwent interval reevaluation
became unresectable due to growth of the initial metastases. After interval
reevaluation, 8 (29%) of 28 patients with synchronous metastases were spared the
morbidity of laparotomy because of distant or an increased number of metastases
and 10 (36%) of 28 patients were spared the morbidity of hepatic resection at the
time of interval laparotomy. Actuarial median and 5-year survival of patients
after delayed hepatic resection (51 months and 45%, respectively) were
significantly improved compared with those of all other patients with resectable
metastases (23 months and 7%, respectively) (P = .02). For patients with
metachronous lesions who underwent interval reevaluation, 4 (29%) of 14 patients
were spared the morbidity of laparotomy because of an increased number of hepatic
or distant metastases. CONCLUSIONS: Delaying hepatic resection for metastatic
colorectal cancer does not impair survival. Potentially, two thirds of patients
can avoid maj or hepatic surgery. For synchronous metastases, delaying hepatic
resection appears to select patients who will benefit from hepatic resection.
PMID- 10768717
TI - A time to remember.
PMID- 10768716
TI - Minimally invasive surgery for primary hyperparathyroidism: systematic review.
AB - HYPOTHESIS: Use of minimally invasive parathyroidectomy techniques, either
unilateral or endoscopic, will result in the same or improved safety and efficacy
outcomes as those of the bilateral open neck exploration technique in patients
with primary hyperparathyroidism. DATA SOURCES: Studies on minimally invasive
parathyroid surgery were identified using MEDLINE (January 1984 to August 1998),
EMBASE (January 1974 to August 1998), and Current Contents (week 1 of 1993 to
week 34 of 1998). The search terms were as follows: ((endoscop* or (minimal* and
invasive) or unilateral) and parathyroid). The Cochrane Library was searched from
issue 1 of 1966 to issue 3 of 1998, using the search terms "parathyroidectomy or
parathyroid resection." STUDY SELECTION: Human studies of patients with primary
hyperparathyroidism using unilateral or endoscopic exploration were included.
Animal studies describing minimally invasive technique development were also
included. A surgeon (R.F.P.) and researcher (W.J.B.) independently assessed the
retrieved articles for their inclusion in the review. DATA EXTRACTION: Studies
directly comparing the unilateral method with bilateral open neck exploration
were used to analyze outcomes. DATA SYNTHESIS: Analysis of data using odds ratios
and 95% confidence intervals indicated a tendency to favor the unilateral
technique. However, these individual studies generally had large confidence
intervals; therefore, preference to the unilateral procedure cannot be espoused
with certainty. There is also a selection bias due to the strict enrollment
criteria for unilateral surgery. CONCLUSIONS: The proposed role of minimally
invasive parathyroid surgery is for patients with primary hyperparathyroidism who
have unilateral parathyroid pathological features. To assess the safety and
efficacy of minimally invasive techniques, it is suggested that their
introduction be monitored as part of a trial in Australia, from which data should
be accrued to a register.
PMID- 10768718
TI - Mary Edwards Walker.
PMID- 10768719
TI - Complete denture wearers: electromyography of mastication and texture perception
whilst eating meat.
AB - This study was undertaken to evaluate the sensitivity of denture wearers to
different food textures and to follow masticatory pattern adaptation with
variation in texture using electromyography (EMG) recordings. Nine patients with
complete dentures and 9 dentate control patients without any oro-dental pathology
were studied. Six different samples of beef were obtained from the same muscle by
altering the state of the muscle fibres and by variation of the cooking
temperature. The variations in texture were mechanically controlled.
Electromyographic activity was recorded during chewing. The patients' subjective
appreciation of texture was reported using a 10-cm non-structured analogue scale.
The following parameters were analysed: muscle work, number of masticatory
cycles, number of rejected samples, initial tenderness, overall tenderness,
juiciness, and duration of chewing for each sample in the mouth. Muscle activity
was less for the edentulous group, particularly that of the masseter muscles. The
masticatory pattern of complete denture wearers was less adapted to each sample
texture than was that of the control group. Both groups perceived differences in
texture of the samples. It was concluded that although texture perception is
little altered, muscular adaptation to the bolus is reduced in patients with
complete dentures.
PMID- 10768720
TI - Clinical and radiographic judgement of occlusal caries in adolescents.
AB - In this study, the clinical and radiographic material of two groups of 17- and 20
yr-old adolescents, born either in 1970 or in 1976, was compared to study changes
in the prevalence of occlusal dentine caries and to determine the additional
value of the bitewing radiographs. The first and second molars of 478
participants were included. Clinical data were derived from an epidemiological
project. Two examiners judged the bitewing radiographs, of which about 10% was
examined by both. The overall Cohen's kappa for interexaminer agreement was 0.87.
The prevalence of occlusal caries had not changed for the two age groups; after
clinical and radiographic examination, around 33% of the occlusal surfaces of the
17 yr olds and around 25% of the 20 yr olds exhibited dentine caries. The
clinical prevalence of occlusal caries in first and second molars was highly
underestimated when compared with the radiographs. In the 1976 group, more
sealants were recorded during the clinical examination. On the bitewing
radiographs, radiolucencies were found underneath one-half of the sealants of the
17 yr olds and underneath one quarter of the sealants present in the 20 yr olds.
PMID- 10768721
TI - Effect of gender on acute pain prediction and memory in periodontal surgery.
AB - Pain is a complex experience that is affected by factors such as gender, stress,
anxiety and cognitions. The purpose of this study was to investigate the inter
relationship between gender and acute pain prediction and memory under
periodontal surgery treatment. The study was conducted on 15 male and 22 female
dental patients (mean age 34 yr, mean education level 14.7 yr), who were
scheduled for periodontal surgery. Patients were evaluated during four
consecutive appointments: at initial check-up, immediately pre-operatively, 1 wk
post-operatively, and at 4 wk post-operative follow-up. Patients were requested
to complete questionnaires concerning their anxiety at each appointment and to
indicate their subjective evaluations concerning pain (on a visual analogue
scale). Evaluations concerning expectation to experience pain during the planned
surgery (pain prediction) were made at the first two appointments and evaluations
of the experienced pain as remembered from the surgery (pain memory) were made at
the last two appointments. Gender had a significant effect on pain prediction and
pain memory. Men expected to experience more pain pre-operatively than women but
remembered less pain post-operatively. It was concluded that cognitive pain
perception in clinical situations differs between genders.
PMID- 10768722
TI - Dental erosion in Cuban children associated with excessive consumption of
oranges.
AB - Marked erosion at the mesial edges of upper front teeth was observed during an
examination of Cuban children. The preferential erosion of mesial edges produced
characteristic V-shaped defects on upper central incisors, and the aim of the
present study, carried out on 12-yr-old children (N = 1010) in 10 communities in
the Province of Havana was to establish the frequency of dental erosion and
explain its occurrence. The symmetrical erosion of teeth 11 and 21 (excluding
crown injuries and attrition) were clinically classified into four grades: 0.5 =
objectionable; 1 = abnormal mesial shortening of incisal edges; 2 = V-shaped
defect of cutting edges; 3 = exposure of dentine and extension of the erosive
defect to the lateral incisors. In four of the communities, children did not show
or rarely showed incisal erosion. In the other six communities, the frequency was
surprisingly high (16.6-40.9%). Overall, 17.4% of children exhibited erosion, and
the occurrence was significantly higher in girls (20.7%) than in boys (15.0%).
The typical V-shaped pattern of erosion seems to be a consequence of the manner
in which citrus fruits are eaten. There was also a positive correlation between
the frequency of dental erosion and the proximity of citrus plantations, which
presumably related to the extent of (daily) orange consumption.
PMID- 10768723
TI - A comparison of the erosive potential of different beverages in primary and
permanent teeth using an in vitro model.
AB - The aim of this study was to compare the erosive potential of different beverages
and foodstuffs in primary and permanent teeth. Sixty primary and 60 permanent
human teeth were immersed for 3 min in the solution under study (5 teeth per
treatment group). Surface microhardness was measured before and after exposure.
Initial (baseline) surface microhardness was lower for primary teeth than for
permanent teeth. In both primary and permanent teeth, Sprite showed the highest
decrease in surface microhardness, whereas yogurt showed an increase in surface
microhardness in the primary teeth. Overall decrease was 27.2 +/- 17.5 KHN (mean
+/- SD) for primary and 25.9 +/- 15.6 KHN for permanent teeth. The comparison of
the erosive susceptibility in this in vitro model showed that primary teeth were
not more susceptible to erosion compared to permanent teeth.
PMID- 10768724
TI - Effects of hypothalamic-pituitary-adrenal axis reactivity on periodontal tissue
destruction in rats.
AB - The aim of this study was to test the hypothesis of an association between
hypothalamic-pituitary-adrenal (HPA) axis reactivity and progression of
periodontal disease. Histocompatible Lewis and Fischer 344 rats respond to
stressful stimuli with low and high HPA axis reactivity, respectively.
Experimental periodontitis was induced by tying a silk ligature around the neck
of maxillary 2nd right molar teeth in 10 Lewis and 10 Fischer 344 rats with
contralateral non-manipulated teeth as controls. Twenty non-manipulated animals
were included. Also, experimental periodontitis was induced in 10
adrenalectomized Wistar rats and in 10 sham-operated rats. Furthermore,
corticosterone pellets were subcutaneously implanted in 9 Lewis rats, while
placebo pellets were implanted in 8 animals. Disease progression was evaluated
histometrically and radiographically. The low-responding Lewis rats developed
significantly less periodontal breakdown than did the high-responding Fischer 344
rats. Administration of corticosterone increased the disease development. while
adrenalectomy reduced the disease severity. Our findings demonstrate the
importance of genetic factors in the development of periodontal disease, and
suggest that HPA axis hyper-activation is one mechanism by which periodontal
disease susceptibility may be increased.
PMID- 10768725
TI - Effects of chlorpromazine on alveolar bone loss in experimental periodontal
disease in rats.
AB - Chlorpromazine (CPZ), a phenothiazine derivative, possesses anti-inflammatory
properties, inhibition of tumor neurosis factor-alpha (TNF-alpha) synthesis and
bone resorption. TNF-alpha promotes inflammatory changes and bone resorption in
periodontitis. We have studied the effect of CPZ in experimental periodontitis.
Wistar rats were subjected to a ligature placement around the cervix of the right
second upper molars. Alveolar bone loss was evaluated by the sum of the distances
between the cusp tip and the alveolar bone along the axis of each molar root,
which was subtracted from the contralateral side. Histopathological analysis of
the periodontium was based on cell influx, osteoclast number, and alveolar bone
and cementum integrity. Animals were weighed daily and total and differential
peripheral white blood cell counts were performed 6 h and 1, 7 and 11 d after
periodontitis induction. Groups were treated with CPZ 1 h before and daily up to
the 11th d of periodontitis. Alveolar bone loss was inhibited 46%, 55.4%, and
76.5% by CPZ at 1, 3 and 9 mg/kg, respectively. Histological analysis showed a
significant reduction of cell influx and osteoclast number, as well as
preservation of the alveolar process and cementum. CPZ reversed leukocytosis but
not weight loss. In conclusion, CPZ reduces bone loss in experimental
periodontitis, probably via TNF-alpha blockade.
PMID- 10768726
TI - Superoxide release and superoxide dismutase expression by human gingival
fibroblasts.
AB - Oxygen reactive intermediates released from phagocytic cells are important for
microbicidal activity, but they may also be harmful to surrounding cells and
matrix components at the inflammation site. In different forms of inflammatory
periodontal disease, peripheral and crevicular polymorphonuclear leukocytes, as
well as mononuclear phagocytes and gingival fibroblasts, are exposed to bacterial
cell wall components and cytokines. The aim of this study was to evaluate if some
bacterial components and cytokines induce superoxide release and superoxide
dismutase (SOD) expression in gingival fibroblasts. Lipopolysaccharide (LPS),
streptococcal cell walls (SCW), and formyl-methionyl-leucyl-phenylalanine were
found to stimulate O2- release from gingival fibroblasts, which increased when
Ca2+ was added. Phorbol myristate acetate, a potent activator of respiratory
burst in phagocytes, was found to be a weak stimulator of O2- release in gingival
fibroblasts. Of the cytokines tested, tumor necrosis factor (TNF)-alpha was found
to activate superoxide release in gingival fibroblasts. Gene expression for
manganese superoxide dismutase (MnSOD), but not for copper/zinc superoxide
dismutase (CuZnSOD), was demonstrated in fibroblasts exposed to LPS, SCW and TNF
alpha using Northern blot analysis. The production of MnSOD may be protective for
these cells. We conclude that bacterial cell wall components and cytokines
modulate O2- release by gingival fibroblasts which may contribute to periodontal
pathology.
PMID- 10768727
TI - Anaerobic neutrophil-dependent killing of Actinobacillus actinomycetemcomitans in
relation to the bacterial leukotoxicity.
AB - The effect of leukotoxin on the interaction of Actinobacillus
actinomycetemcomitans with human polymorphonuclear leukocytes (PMNL) was studied
under anaerobic conditions with strains able to produce high or low amounts of
leukotoxin. PMNL morphology, phagocytosis and killing were examined by
transmission electron microscopy and bioassays, respectively. At ratios of > or
=25 bacteria/PMNL, a highly toxic A. actinomycetemcomitans strain completely
destroyed the PMNL within 7 min, resulting in bacterial survival. Lowering the
bacteria/PMNL-ratio enabled phagocytosis and killing of this highly toxic strain.
A. actinomycetemcomitans strains with low leukotoxicity were effectively killed
by PMNL under any condition. Presence of specific antibodies against A.
actinomycetemcomitans or of anti-leukotoxin serum protected PMNL from being
injured and allowed phagocytosis to occur. Pre-incubation of the leukotoxic
strain with Porphyromonas gingivalis, a bacterium that destroys leukotoxin,
abolished lysis of PMNL and inhibited phagocytosis of A. actinomycetemcomitans.
The results show that leukotoxin may protect A. actinomycetemcomitans against
phagocytosis by human PMNL. The protection occurs at a population level and in
relation to the bacterial load. The size of the bacterial population required to
counteract phagocytosis is dependent on the leukotoxin production of the strain.
PMID- 10768728
TI - Total IgA and Porphyromonas gingivalis-reactive IgA in the saliva of patients
with generalised early-onset periodontitis.
AB - Generalised early-onset periodontitis (GEOP) is characterized by acute
inflammatory bursts, resulting in rapid destruction of the periodontal apparatus
in young adults. An impaired host defense seems to play an important role as
etiological factor of periodontitis, especially in the development of GEOP. As
the gram-negative Porphyromonas gingivalis has been identified as one of the
causative anaerobic bacteria, the humoral immune response to this micro-organism
is of particular interest in patients with GEOP. To evaluate the local immune
status, we measured total and P. gingivalis-reactive salivary IgA in GEOP
patients and in age- and gender-matched periodontally normal controls. We found a
significantly lower concentration and secretion rate of total salivary IgA in the
GEOP group. Although no differences were detected in the concentration or
secretion of P. gingivalis-reactive IgA between groups, the specific fraction of
P. gingivalis-reactive IgA of the total IgA was significantly higher in the GEOP
group. These findings indicate an inhibition of total secretory IgA in GEOP,
while the P. gingivalis-reactive humoral immune system in saliva is, however,
activated. P. gingivalis seems to selectively activate IgA lymphocyte clones and
induces a switch in the fraction of specific IgA.
PMID- 10768729
TI - Effects of fluoride- and chlorhexidine-containing varnishes on plaque composition
and on demineralization of dentinal grooves in situ.
AB - The aim of the study was to compare the effects of Cervitec, containing 1%
chlorhexidine (CHX) and 1% thymol, Fluor Protector, containing 0.1% fluoride,
their 1:1 mixture, and a placebo varnish on the percentage of mutans streptococci
and lactobacilli in plaque and on the underlying dentin demineralization, as
assessed by microradiography. Bovine dentine discs, fitted with three parallel
grooves, received one of the varnish treatments into the first groove and on the
adjacent part of the dentin surface. Volunteers (n = 23) wore the discs fixed to
their partial dentures for four consecutive 3 wk periods. Microbiological
analysis of plaque accumulated in the grooves showed no difference between
groups. Fluoride varnishes (Fluor Protector and mixed varnish) had a
significantly larger inhibitory effect on mineral loss in the treated groove than
Cervitec or placebo. All treatment varnishes had more pronounced effect in
panelists (n = 14) with higher degree of demineralization (mineral loss in
placebo group > or = 1,200 vol% x microm). In these panelists, CHX-containing
varnishes showed an inhibitory effect on demineralization in all grooves, also in
the two non-varnished grooves. As fluoride varnishes had the largest localized
effect on demineralization, and CHX varnishes were showing a peripheral effect, a
combined treatment could be the preferred method to obtain an optimal caries
preventive effect in caries-prone individuals.
PMID- 10768730
TI - Culture conditions for the detection of allergen-specific T-cell reactivity in
cord blood: influence of cell number.
AB - Raised T-cell proliferation of cord blood mononuclear cells (CBMC) in response to
various ingestant and inhalant allergens has been reported in newborns,
suggesting a prenatal allergen contact. In general, for in vitro proliferation
assays a concentration of 50 x 10(3) or 100 x 10(3) cells/well are used. The aim
of this study was to analyze whether cell concentration influences T-cell
reactivity in cord blood cells and to study differences of T-cell reactivity
triggered by inhalant and ingestant allergens. CBMC from 51 neonates (34 females:
22 with and 29 without a family history of allergy, i.e. FH+ or FH-) were
incubated with interleukin-2 (IL-2), beta-lactoglobulin (beta-LG), ovalbumin
(OVA), house dust mite allergen Dermatophagoides pteronyssinus (Der p 1), and
timothy grass allergen Phleum pratense (Ph1 p 1) for 7 days. The cell
concentration ranged from 6.25 x 10(3) to 100 x 10(3) cells/well. Proliferation
was assessed by incorporation of [3H]-thymidine and was expressed as counts per
minute (c.p.m.). In unstimulated cells, a decreasing cell concentration
paralleled a steep drop of background activity. In response to IL-2, a decreasing
cell concentration led to a slow decrease of c.p.m. The corresponding mean
stimulation indices (SI) were 9, 32, 77, 47, and 21 for 100 x 10(3), 50 x 10(3),
25 x 10(3), 12.5 x 10(3), and 6.25 x 10(3) cells/well, respectively. In addition,
the highest number of positive proliferative responses to specific allergens were
obscured at lower cell concentrations. For beta-LG, the maximal number of
positive responses were obtained between 25 x 10(3) (n = 44) and 12.5 x 10(3) (n
= 46) cells/well, for OVA at 25 x 10(3) (n = 3) cells/well, for Der p 1 at 50 x
10(3) (n = 5) cells/well, and for Ph1 p 1 between 25 x 10(3) and 12.5 x 10(3) (n
= 5) cells/well. Positive proliferation in at least one of the tested assays was
observed in 100% of samples in response to beta-LG, in 22% in response to Ph1 p
1, and in 14% in response to OVA and Der p 1. T-cell reactivity did not differ
between samples of newborns with or without a family history of atopy. Therefore,
sensitivity of T-cell proliferation measurement is highly influenced by
background proliferation of unstimulated cells. Hence, proliferation assays with
lower cell numbers unmask T-cell reactivity in response to ingestant and inhalant
allergens. We suggest the use of concentrations of 12.5 x 10(3)-50 x 10(3)
cells/well in proliferation experiments.
PMID- 10768731
TI - Determination of T-cell subpopulations and intracellular cytokine production
(interleukin-2, interleukin-4, and interferon-gamma) by cord blood T-lymphocytes
of neonates from atopic and non-atopic parents.
AB - This report describes the results of a prospective study on immunological markers
in cord blood for the prediction of allergic diseases in children. First we
evaluated methodological aspects of the flow cytometric technique on cord blood
cytokine measurements. Subsequently, the T-cell subsets and percentage of
cytokine-producing cord blood T-helper (Th) and T-suppressor/cytotoxic
lymphocytes of neonates from atopic and non-atopic parents were compared. A group
of 33 healthy, full-term newborn infants of whom 23/33 were at risk for atopy
(i.e. having at least one parent with one or more atopic symptoms and positive
specific immunoglobulin E [IgE] to at least one common inhalant allergen) was
studied. A flow cytometric technique was used to analyze cord blood T-cell
subsets and to determine the percentage of interleukin (IL)-2-, IL-4-, and
interferon-gamma (IFN-gamma)-producing cord blood Th and T-suppressor/cytotoxic
lymphocytes following stimulation with phorbol 12-myristate 13-acetate (PMA) and
ionomycin. The percentage of CD3 (T lymphocytes), CD3+ CD4+ (Th lymphocytes),
CD3+ CD8+ (T-suppressor/cytotoxic lymphocytes), CD19+ (B lymphocytes), CD3+ CD4+
CD45RO+ (memory Th lymphocytes), and CD3+ CD4+ CD45RA+ (naive Th lymphocytes)
cells was unrelated to parental atopic status. PMA stimulation augmented the
percentage of IL-2- and IFN-gamma-producing Th and T-suppressor/cytotoxic
lymphocytes, whereas the number of IL-4-producing T lymphocytes remained very low
or undetectable. No differences in the percentage of TL-2-, IL-4- and IFN-gamma
producing Th and T-suppressor/cytotoxic lymphocytes were found between neonates
from atopic and non-atopic parents. These results will be re-evaluated when the
atopic status of the children at the age of 1 and 2 years can be assessed.
PMID- 10768732
TI - Low levels of interferon-gamma in nasal fluid accompany raised levels of T-helper
2 cytokines in children with ongoing allergic rhinitis.
AB - The T-helper 2 (Th2) cytokines interleukin-(IL-) 4, IL-5, IL-6, IL-10 and the Th1
cytokine IFN-gamma and their associations with eosinophil, eosinophil cationic
protein (ECP) and immunoglobulin (Ig) E were studied in nasal lavage fluid from
60 school children with allergic seasonal rhinitis and 36 nonatopic healthy
controls, before and during the pollen season. Eosinophil differential counts and
IgE increased significantly in the patients during the pollen season. The
eosinophil differential counts, ECP and IgE were all significantly higher during
the season than in specimens simultaneously obtained from the nonatopic controls.
Before season, the levels of ECP and IgE, but not eosinophils, were significantly
higher in the patients than in the controls. During the season the nasal lavage
fluid levels of IFN-gamma were significantly lower and the IL-4/IFN-gamma
quotients significantly higher in the allergic than in the control children. In
the allergic children, but not in the controls, the nasal fluid levels of the Th2
cytokines IL-4, IL-5 and IL-10 increased during the season, and together with IL
6, were correlated with the differential counts of eosinophils, and with the
levels of ECP and IgE. These findings are compatible with the hypothesis that a
deficient release of the Th1 cytokine IFN-gamma plays an important role in the
pathogenesis of allergic inflammation. Regardless of whether the defective IFN
gamma secretion is primary or a consequence of suppression by other cytokines, it
will in the atopic subjects enhance the release of Th2 cytokines, which in turn
will facilitate the development of allergic inflammation.
PMID- 10768733
TI - Human milk polyunsaturated long-chain fatty acids and secretory immunoglobulin A
antibodies and early childhood allergy.
AB - The possible protective effect of breast milk against atopic manifestations in
infancy, i.e. atopic eczema and food allergy, has been controversial for the last
decades. Besides the methodological problems, differences in the composition of
human milk could explain these controversies. The aim of this study was to
investigate the composition of polyunsaturated fatty acids (PUFA) and secretory
immunoglobulin A (S-IgA) levels to food proteins (ovalbumin and beta
lactoglobulin) and an inhalant allergen (cat) in milk from mothers of allergic
and non-allergic children. Blood samples were obtained at birth and at 3 months
from 120 children. Skin prick tests were performed at 6, 12 and 18 months, and
the development of atopic diseases was assessed in the children. Breast milk
samples were collected from their mothers at birth and monthly during the
lactation period. Milk PUFA composition was measured by gas chromatography, and
enzyme-linked immunosorbent assay (ELISA) was used to measure total S-IgA, anti
cat S-IgA, anti-ovalbumin S-IgA, and anti-beta-lactoglobulin S-IgA. Allergic
disease developed in 44/120 children (22/63 children of allergic mothers and
22/57 children of non-allergic mothers). Lower levels of eicosapentaenoic acid,
C20:5 n-3 (EPA), docosapentaenoic acid C22:5 n-3 (DPA), and docosatetraenoic acid
C22:4 n-6 (DHA) (p < 0.05 for all) were found in mature milk from mothers of
allergic as compared to milk from mothers of non-allergic children. The total n
6:total n-3 and the arachidonic acid, C20:4 n-6 (AA):EPA ratios were
significantly lower in transitional and mature milk from mothers of allergic
children, as compared to milk from mothers of non-allergic children. The PUFA
levels in serum of allergic and non-allergic children were largely similar,
except for higher levels of C22:4 n-6 and C22:5 n-6 (p < 0.05 for both) and a
higher AA:EPA ratio in serum phospholipids in the former group (p < 0.05).
Changes in the levels of milk PUFA were reflected in changes in PUFA serum
phospholipids, particularly for the n-6 PUFA. The AA: EPA ratio in maternal milk
was related, however, to the AA:EPA only in serum from non-allergic children,
while this was not the case in allergic children. The levels of total S-IgA, anti
cat S-IgA, anti-ovalbumin S-IgA, and anti-beta-lactoglobulin S-IgA in milk from
mothers of allergic, as compared to non-allergic, children were similar through
the first 3 months of lactation. Low levels of n-3 PUFA in human milk, and
particularly a high AA:EPA ratio in maternal milk and serum phospholipids in the
infants, were related to the development of symptoms of allergic disease at 18
months of age. The milk PUFA composition influenced the composition of PUFA in
serum phospholipids of the children. We also showed that the lower levels of
colostral anti-ovalbumin S-IgA and lower total S-IgA in mature milk from atopic
mothers did not influence the development of allergic disease in the children up
to 18 months of age. The findings indicate that low alpha-linolenic acid, C18:3 n
3 (LNA) and n-3 long-chain polyunsaturated fatty acids (LCP) 20-22 carbon chains,
but not the levels of S-IgA antibodies to allergens, are related to the
development of atopy in children.
PMID- 10768734
TI - Asthma and allergy among schoolchildren in a mountainous, dry, non-polluted area
in Norway.
AB - The aim of this study was to assess prevalence of asthma and allergy in the non
polluted mountain area of Upper Hallingdal, Norway. All schoolchildren (7-16
years) who in a previous questionnaire survey (n = 1177) reported 'sometime'
asthma were enrolled in group I (n = 80), the 59 who reported asthma-like
symptoms in the past 12 months formed group II, and 77 of the healthy controls
were randomly selected as group III. All 216 children underwent clinical
examination, skin prick test, spirometry, bronchial provocation (PD20
metacholine) and treadmill exercise test. Subsequently they were reclassified as
(1) healthy, never had asthma or symptoms, (2) symptoms not confirmed as asthma,
(3) previous asthma, now healthy, (4) current asthma. Lifetime asthma prevalence
was 10.2%. Based upon clinical examination, the specificity and sensitivity of
the questionnaire for asthma diagnosis were 88 and 74%, respectively. Forced
vital capacity was significantly higher among the asthmatics (group 4 versus 1),
whereas forced expiratory volume in one second (FEV1) and forced expiratory flow
at 50% of vital capacity were similar in all groups. More than 10% reduction in
FEV1 following treadmill-run was found in 20% of children. Children with current
asthma compared to controls had significantly; lower mean values of PD20 (9.1
versus 16.5 micromol), higher eosinophil cationic protein (13.4 versus 7.7
micromol) and more frequent sensitization to animal dander (56% versus 10%). In
conclusion, despite a favorable climate, little mite sensitization and low
outdoor pollution, asthma prevalence was surprisingly high in Upper Hallingdal.
Sensitization to animal dander was the most important contributing factor for
current asthma.
PMID- 10768735
TI - Treatment preferences of adolescent patients with asthma.
AB - The study objective was to assess whether asthmatic adolescents who were regular
users of inhaled corticosteroids preferred treatment with zafirlukast tablets or
inhaled beclomethasone dipropionate (BDP), and, secondarily, to assess
adolescents' inhaler technique and their opinions about treatment. An open-label,
randomized, two-period, crossover study was conducted in 18 centres (primary care
to specialist asthma centres) in South Africa, the UK, Finland and the Czech
Republic. One hundred and thirty-two adolescents aged 12-17 years with asthma for
at least 1 year and FEV1 > or = 75% of predicted, treated with short-acting
bronchodilators and inhaled corticosteroids, entered the study. Patients received
oral zafirlukast tablets (Accolate) 20 mg b.i.d. or inhaled BDP 100 or 200 microg
b.i.d., provided by a standard pressurized metered-dose inhaler, for 4 weeks
each. One questionnaire was used to determine preference (the primary outcome
measure) and a second questionnaire was used to determine patients' likes and
dislikes of treatment. Investigators also scored inhaler technique. Of 113
adolescents, 79 (70%) preferred zafirlukast compared with 31 (27%) who preferred
the BDP inhaler (p < 0.001); three had no preference. Only 35 (29%) of 122
adolescents could use their inhaler correctly at study entry. Seventy-six
patients (65%) rated zafirlukast tablets as 'very easy' to use, compared with 35
(30%) for the BDP inhaler. Both treatments were well-tolerated. This study shows
that asthmatic adolescents prefer zafirlukast tablets by a ratio of 2.6:1 over
inhaled BDP, and these results may have implications for improving adolescent
patient compliance with asthma therapy.
PMID- 10768736
TI - A new dipstick test (Allergodip) for in vitro diagnosis of latex allergy-
validation in patients with spina bifida.
AB - While there is established data on the value of various assays for determining
specific immunoglobulin E (IgE) in serum, little has been reported about semi
quantitative dipstick methods. Therefore, in a pilot study we compared a new
dipstick assay (Allergodip) with a well-evaluated commercial assay (Pharmacia CAP
system), in terms of sensitivity and specificity, in sensitized and
nonsensitized, symptomatic and non-symptomatic patients with spina bifida. One
hundred and thirty-five patients with spina bifida (median age 10.8 years) were
included in this study. Sixty-nine patients (51.1%) were positive in the CAP
system, 61 patients (45.2%) were positive in the Allergodip assay, and 67
patients (49.6%) were positive in a skin prick test with natural rubber latex
milk. The concordance between the CAP-system and Allergodip was good. Forty-seven
patients (34.8%) showed a positive response to the provocation test. The
sensitivity of Allergodip was 85.1% compared with 91.5% for the CAP-system.
Specificity was 75.0% for the Allergodip assay and 70.5% for the CAP-system. We
conclude that the new dipstick test is a useful screening test for diagnosing
sensitization to latex, e.g. when planning surgical interventions. However, in
instances of doubtful reactions, discrepancies with clinical features or for
scientific work it does not replace quantitative determination of specific IgE.
PMID- 10768737
TI - Multislice MR perfusion imaging and regional myocardial function analysis:
complimentary findings in chronic myocardial ischemia.
AB - PURPOSE: The purpose of this study is to assess the reliability of multislice MR
perfusion imaging in comparison to regional wall function and nuclear medicine
and to test different qualitative and quantitative parameters for perfusion
assessment. MATERIAL AND METHODS: 15 patients with chronic myocardial ischemia
underwent CINE and first-pass perfusion MR imaging. Functional myocardial imaging
was performed using a segmented CINE FLASH sequence and systolic myocardial wall
thickening was assessed after semiautomated segmentation. MR first-pass perfusion
studies were performed using a multislice saturation recovery TurboFLASH
sequence. Different parameters were calculated for assessment of hypoperfused
segments and results of MR imaging compared to 99mTc-SestaMIBI SPECT. RESULTS: MR
perfusion imaging showed a sensitivity of 72% and a specificity of 98%. In
combination with MR CINE imaging and wall thickening analysis we calculated a
sensitivity of 100% and a specificity of 93%. Qualitative and quantitative
perfusion parameter analysis showed significant differences between normal and
hypoperfused segments for the signal intensity increase (p < 0.001), the signal
intensity upslope (p < 0.001) as well as for the myocardial mean transit time (p
< 0.001). CONCLUSION: The combination of systolic wall thickening analysis and
myocardial perfusion can markedly improve the sensitivity of MRI in depiction of
LV myocardial perfusion abnormalities. For assessment of hypoperfusion, different
quantitative and qualitative parameters can be calculated showing significant
differences between normal state and hypoperfusion.
PMID- 10768738
TI - Cine MR imaging after myocardial infarction--assessment and follow-up of regional
and global left ventricular function.
AB - Myocardial infarction often leads to regional wall motion defects and in case of
large defects to remodeling of the left ventricle. With this study, changes in
regional and global myocardial function of 12 patients 3 weeks after myocardial
infarction and after revascularization therapy were determined using MRI. Cine
MRI was performed at study entry at rest and during low-dose dobutamine
stimulation. All patients were re-examined at rest 3 and 6 months after the
revascularization, including analysis of wall thickening and of left ventricular
end-diastolic volume index (LVEDVI), end-systolic volume index (LVESVI), ejection
fraction (LVEF), and mass index. After revascularization. 6 patients with stress
induced improvement of regional wall thickening recovered, 4 patients without
improvement did not, but 2 patients without stress-induced improvement of wall
thickening also recovered. Concerning global cardiac function, patients with
mainly improved regional wall motion also showed a lower LVESVI and a higher LVEF
than patients without improvement of regional contractility 6 months after
revascularization in comparison to study entry. In conclusion, improvement of
global myocardial function after revascularization is higher in patients with
improved contractility in the infarcted region. The extent of the response of
regions with wall motion defects to dobutamine stress correlates with the actual
improvement after revascularization, and, therefore, dobutamine stress MRI may be
helpful in selecting patients that will have a higher benefit from a
revascularization therapy.
PMID- 10768739
TI - Cardiac phase contrast gradient echo MRI: measurement of myocardial wall motion
in healthy volunteers and patients.
AB - A number of methods have been proposed for the noninvasive measurement of
myocardial wall motion. The paper describes a strategy for assessing myocardial
motion based on the sensitivity of the phase of the MR-signal to motion using a
breath-hold phase contrast technique. A motion-sensitized and a motion
compensated MR-signal are measured during successive scans. The difference
between the two MR-signals is used to calculate myocardial velocity in all three
spatial dimensions. Postprocessing includes the transformation of the measured
velocities into an internal coordinate system of the left ventricle. Also various
presentation modes and further processing of the received velocity information
are provided including calculation of global motion parameters. We examined 20
patients suffering from myocardial infarction. The overall left ventricular
motion can be characterized by appropriate parameters describing the rotation and
contraction or expansion, respectively. Regional motional disturbances are
visualized using parametric images. Contrary to the highly consistent
interindividual data in normal volunteers, patients showed significant localized
motion deficits.
PMID- 10768740
TI - Direct comparison of an intravascular and an extracellular contrast agent for
quantification of myocardial perfusion. Cardiac MRI Group.
AB - A direct comparison of extracellular and intravascular contrast agents for the
assessment of myocardial perfusion was carried out in a porcine model (N = 5)
with a flow-limiting occluder on the left anterior descending coronary artery.
Rapid imaging during the first pass of an extracellular or intravascular contrast
agent with a saturation-recovery-prepared TurboFLASH sequence showed comparable
peak contrast-to-noise enhancements in myocardial tissue regions with flows
averaging 1.1 +/- 0.2 at baseline to 4.8 +/- 0.6 ml/min/g during hyperemia. The
coefficient of variation between the MR estimates of blood flow with Gadomer-17
and the microsphere blood flow measurements was 11 +/- 11%, while the
corresponding co-efficient of variation for blood flow estimates with the
extracellular CA was 23 +/- 11%. Blood volume differences between rest and
hyperemia observed with the intravascular tracer were significant (Vvasc(rest) =
0.078 +/- 0.013 ml/g, versus Vvasc(hyperemia) = 0.102 +/- 0.019 ml/g; p < 0.05).
The effects of water exchange were minimized through the choice of pulse sequence
parameters to provide blood volume estimates consistent with the changes expected
between rest and hyperemia. This study represents the first application of
multiple indicators in first pass imaging studies for the assessment of
myocardial perfusion. The use of an intravascular instead of an extracellular
contrast agent allows a reduction of the degrees of freedom for modeling tissue
residue curves and results in improved accuracy of blood flow estimates.
PMID- 10768741
TI - A novel technique using biplane cine magnetic resonance imaging to evaluate left
ventricular volume in children.
AB - The purpose of the study is to determine the feasibility of a novel simplified
technique using cine magnetic resonance imaging (MRI) to assess left ventricular
(LV) volume and ejection fraction (EF) validated by comparison with biplane LV
angiography. Previous MRI studies to assess LV volumes have used multiple axial
planes, which are compromised by partial volume effects and are time consuming to
acquire and analyze. Accordingly, we developed a simplified imaging approach
using biplane cine MRI and imaging planes aligned with the intrinsic cardiac axes
of the LV. We studied 20 children (aged 4 months to 10 years) with various heart
diseases. The accuracy of cine MRI was compared with that of LV angiography in
all patients. LV volumes were calculated using Simpson's rule algorithm, for both
MRI and LV angiography. LV volumes determined from MRI were slightly
underestimated but correlated reasonably well with angiographic volumes (LVEDV: Y
= 0.88X + 1.58, r = 0.99, LVESV: Y = 0.73X + 1.03, r = 0.98). Most importantly,
even in patients who had abnormal ventricular curvature such as in tetralogy of
Fallot, MRI determined LV volumes correlated well with angiographic values. The
MR study was completed within 35 min in all patients. In conclusion, simplified
biplane cine MRI, using the intrinsic LV axis planes, permits noninvasive
assessment of LV volumes in views comparable to standard angiographic projections
and appears practical for clinical use in childhood heart disease since the scan
and analysis times are relatively short.
PMID- 10768742
TI - Evaluation of pulmonary blood supply by multiplanar cine magnetic resonance
imaging in patients with pulmonary atresia and severe pulmonary stenosis.
AB - The purpose of this study was to assess the capability of multiplanar cine
magnetic resonance imaging (MRI) for evaluating pre- and post-operative pulmonary
circulation in patients with pulmonary atresia and severe pulmonary stenosis.
Seventy-three multiplanar cine MRIs were performed in 30 patients, aged 1 month
to 7 years (mean age, 27 months). The morphology and size of the central
pulmonary arteries (PA), source of the major aortopulmonary collateral arteries
(MAPCA), patency of Blalock-Taussig (BT) shunt vessels, and the post-operative
pulmonary circulation were assessed. The accuracy of cine MRI was compared with
that of angiography in all patients. The PA was visualized to the first hilar
branch in 21 patients, but not in 8 patients in whom the central PA was absent.
On follow-up MRI, PA growth was measured, and the results showed excellent
correlation with the results obtained by angiography. In 17 patients who had
undergone 23 BT shunt operations, cine MRI correctly demonstrated all patient
shunts and 5 of 6 stenotic lesions. Multiplanar cine MRI provided excellent
detail of the peripheral PA in all patients, 7 of 8 peripheral pulmonary
stenoses, 3 of 4 nonconfluent pulmonary arteries, and 2 of 3 PA obstructions.
Although the sources of MAPCA were identified in 7 of 9 patients, the distal
connection of the MAPCA was not detected in all patients. Seven patients were
reexamined after pulmonary plasty; they exhibited normal pulmonary flow patterns.
Multiplanar cine MRI provides high-resolution imaging of PA with dynamic
visualization of flow and is an effective noninvasive technique for evaluating
pre- and post-operative patients with pulmonary atresia and severe pulmonary
stenosis.
PMID- 10768743
TI - Stenosis quantification from post-stenotic signal loss in phase-contrast MRA
datasets of flow phantoms and renal arteries.
AB - In this study a semi-automated and observer-independent algorithm for quantifying
post-stenotic signal loss (PSL) in 3D phase-contrast (PC) magnetic resonance
angiography (MRA) of patients with renal artery stenosis is presented. This
algorithm was developed on MRA datasets of stenotic phantoms, which were included
in a flow circuit with stationary flows. The length and the severity of the PSL
(incorporating both length and degree of PSL) in the maximum intensity
projections (MIPs) of MRA datasets were proposed for quantifying stenoses. The
algorithm was tested in renal arteries of ten patients with renal artery stenosis
and seven healthy volunteers. Digital subtraction angiography (DSA) was performed
in the patients and served as the gold standard. Stenosis severity showed better
correlation with the severity of the PSL than with the length, both for in vitro
as in vivo. Spearman correlation coefficients (rS) showed statistically
significant correlations between the severity of the PSL and parameters
determined by DSA, i.e. percent diameter stenosis (rS = 0.90). The length of the
PSL showed no correlation with the diameter stenosis (rS = 0.37).
PMID- 10768744
TI - Biplane X-ray angiograms, intravascular ultrasound, and 3D visualization of
coronary vessels.
AB - The technology for determination of the 3D vascular tree and quantitative
characterization of the vessel lumen and vessel wall has become available. With
this technology, cardiologists will no longer rely primarily on visual inspection
of coronary angiograms but use sophisticated modeling techniques combining images
from various modalities for the evaluation of coronary artery disease and the
effects of treatment. Techniques have been developed which allow the calculation
of the imaging geometry and the 3D position of the vessel centerlines of the
vascular tree from biplane views without a calibration object, i.e., from the
images themselves, removing the awkwardness of moving the patient to obtain 3D
information. With the geometry and positional information, techniques for
reconstructing the vessel lumen can now be applied that provide more accurate
estimates of the area and shape of the vessel lumen. In conjunction with these
developments, techniques have been developed for combining information from
intravascular ultrasound images with the information obtained from angiography.
The combination of these technologies will yield a more comprehensive
characterization and understanding of coronary artery disease and should lead to
improved and perhaps less invasive patient care.
PMID- 10768745
TI - Quantitative measurements in IVUS images.
AB - IntraVascular UltraSound (IVUS) is a catheter-based technique which provides real
time high resolution tomographic images of both the lumen and arterial wall of a
coronary segment, this in contrast to X-ray arteriography that provides a shadow
image (luminogram) of the entire lumen. Nowadays the lumen and vessel parameters
are measured manually, which is very time consuming and suffers from high inter-
and intra-obser variability. With the continuing improvement in IVUS imaging, it
is now feasible to develop and clinically apply automated methods of three
dimensional quantitative analysis of the coronary vessel morphology in an
objective and reproducible way with automated contour detection techniques (QCU).
Quantification, in 2D and 3D, as well as volume rendering for visualization of
the IVUS images requires segmentation of the images (contour detection). The 3D
contour detection system described in this article is based on the combination of
contour detection in the transversal and sagital view. This article provides some
of the basic principles of IVUS, the IVUS image quantification, the three
dimensional reconstruction and the contour detection and quantification in three
dimensional IVUS images.
PMID- 10768746
TI - The seismocardiogram as magnetic-field-compatible alternative to the
electrocardiogram for cardiac stress monitoring.
AB - Seismocardiography (SCG) is a methodology derived from the field of seismology to
measure non-invasively compression waves generated by myocardial motion. The use
of SCG is proposed here as method to monitor cardiac function during stress
testing and magnetic resonance imaging (MRI). It is shown that recording of the
seismocardiogram in subjects undergoing an MRI study is not compromised by flow
induced electrical voltages that can severely distort the electrocardiogram.
Electromagnetic compatibility of the seismocardiograph device with the MRI
scanner hardware was tested. Experiments in an animal model proved that changes
in the SCG waveform during different levels of LAD stenosis correlate with the
changes seen in LV function with cine MRI. The changes in the SCG waveform
characteristic for the onset of ischemia were observed almost immediately after
the creation of a flow-limiting stenosis. This novel application of SCG to
monitor changes in peak acceleration from cardiac blood flow and wall motion may
represent a solution to the long-standing and important problem of monitoring
patients for signs of myocardial ischemia during MRI.
PMID- 10768747
TI - Usefulness of coronary MR angiography prior to angioplasty.
AB - The range of indications for percutaneous transluminal coronary angioplasty
(PTCA) has increased greatly since the procedure was initially introduced. The
success rate depends on the anatomy and length of the occlusion and on the state
of the distal vessel. We present a case where the use of magnetic resonance
angiography (MRA) allowed to evaluate the length of a subtotal occlusion prior to
PTCA, and thus could have had an impact on therapeutic decisions. Coronary MR
angiography is one of the many applications of breathhold MRI, where
breathholding and segmented k-space acquisition are combined to provide
anatomical images of coronary vessels. Coronary MR angiography allows
reproducible visualization of coronary vessels. Even under adverse circumstances
(poor cardiac triggering) the images are sometimes of sufficient quality to help
make a diagnosis. This capability may increase the as yet limited clinical use of
MR technology in the practice of cardiology.
PMID- 10768748
TI - Involvement of neutrophilic granulocytes in the uptake of biodegradable non
stealth and stealth nanoparticles in guinea pig.
AB - The in vivo behavior of monomethoxypoly(ethylene oxide)-poly(lactic acid) (MPEO20
PLA45/PLA (75/25)) nanoparticles in comparison with PLA ones was studied in
guinea pig. Indeed, the aim of this study was to bring to the fore the in vivo
stealth character of these copolymer nanoparticles and to identify the phagocytic
circulating cells involved in their uptake. After the intravascular
administration of fluorescent nanoparticles (rubrene), their phagocytosis by
granulocytes and monocytes was assayed by flow cytometry. At the same time, the
evolution of the number of these phagocytic cells was realized in order to
identify their function in the nanoparticle uptake. Finally, a histological study
of the spleen (30 h after the nanoparticle administration) was investigated to
highlight the splenic trapping of these stealth nanoparticles. This study has
shown that the phagocytic circulating cells involved in the nanoparticle uptake
were mainly neutrophilic granulocytes and some of them were found in the spleen.
PMID- 10768749
TI - Release of adsorbed fibronectin from temperature-responsive culture surfaces
requires cellular activity.
AB - We have previously developed a temperature-responsive cell culture surface by
grafting poly(N-isopropylacrylamide) that changes its surface hydrophobicity in
response to temperature. While this surface shows similar hydrophobicity to that
of commercial polystyrene cell culture surfaces and facilitates cell adhesion and
proliferation at 37 degrees C, grafted polymer becomes hydrophilic below 32
degrees C and releases spread cultured cells without trypsin. Temperature
regulated cell detachment requires cell metabolic activity requiring ATP
consumption, signal transduction, and cytoskeleton reorganziation. Precoating
these surfaces with fibronectin (FN) improves spreading of less adhesive cultured
hepatocytes and reducing culture temperature releases cultured cells from FN
adsorbed grafted surfaces. Immunostaining with anti-FN antibody revealed that
only FN located beneath cultured cells is removed from culture surfaces after
reducing temperature. FN adsorbed to surface areas lacking direct cell attachment
remained surface-bound after reducing temperature. A novel concept of active cell
detachment is also discussed.
PMID- 10768750
TI - Effect of an immobilization matrix and capsule membrane permeability on the
viability of encapsulated HEK cells.
AB - The effect of inclusion of an immobilization matrix and the capsule membrane
permeability on the viability, metabolic activity, and proliferation of
encapsulated HEK cells was investigated in vitro. In the absence of a matrix, a
particular transfected HEK cell line formed a single aggregate in the core of the
poly(hydroxyethyl methacrylate-co-methyl methacrylate) (HEMA-MMA) capsule, and
the number of live cells decreased significantly with the passage of time. In
contrast, co-encapsulation with a 1% (w/v) ultralow gelling temperature agarose
matrix promoted the proliferation of the encapsulated cells. The initial number
of approximately 200 live cells/capsule doubled 14 d after encapsulation and
reached a plateau of approximately 500 live cells/capsule 28 d after
encapsulation. The agarose matrix provided uniform distribution of the cells
within the capsule core giving rise to multiple aggregates upon proliferation.
Reduction of the polymer solution concentration, and hence the increase of the
permeability of the capsule membrane, did not have an effect on the extent or
rate of proliferation of cells co-encapsulated with agarose, and did not improve
the viability of cells that were encapsulated without a matrix. These cells
(transfected with the cDNA for human hepatic lipase) served as a model as part of
a program evaluating the use of encapsulated cells for gene therapy.
PMID- 10768751
TI - Wet spun chitosan-collagen fibers, their chemical N-modifications, and blood
compatibility.
AB - Based on an in vitro test for an improvement of the blood compatibility of chitin
by blending with tropocollagen, we prepared a novel biocompatible blended fiber
and its chemically N-modified fibers. Each (1 g/30 ml) of a clear mixed solution
of chitosan with tropocollagen or collagen and a clear solution of chitosan
itself in aqueous 2% acetic acid-methanol (2:1, v/v) was spun through a viscose
type spinneret into an aqueous 5% ammonia solution containing 40-43% ammonium
sulfate at room temperature to afford a white fiber of chitosan-tropocollagen
blends (1.08-1.65 g/denier for the tenacity and 10.9-43.2% for the elongation).
The tropocollagen content up to 50% by weight) in the blended fiber affected
little their tenacity and elongation values. The blended fiber was chemically N
modified at the fiber state by treatment with a series of carboxylic anhydrides
and aldehydes to afford the corresponding N-modified fiber (0.86-1.31 g/denier
for the tenacity and 8.0-12.1% for the elongation). A transparent blended
hydrogel of N-acetylchitosan (chitin) with tropocollagen was produced from the
above mixed solution by treatment with acetic anhydride, and its membrane and
sponge sheet were also prepared from the hydrogel.
PMID- 10768752
TI - Production of TNF-alpha and bone resorbing activity by macrophages in response to
different types of bone cement particles.
AB - We have compared the capacity of clinically relevant wear debris from seven
different cement types to activate macrophages to produce TNF-alpha, IL-1beta, IL
6 and bone resorbing activity in vitro. The bone cements were: CMW 1 original
(PMMA only); CMW 1RO (1 microm BaSO4; 9.2%); CMW copolymer bone cement 1 (10
microm BaSO4; 10%); CMW copolymer bone cement 2 (1 microm BaSO4; 10%); Palacos R
(10 microm ZrO2; 15.6%); CMW Calcium phosphate cement 20% (10 microm tri-calcium
phosphate; 20%) and CMW calcium phosphate cement 30% (10 microm tri-calcium
phosphate; 30%). Cement debris was produced aseptically using a simple
configuration wear test. The majority of particles were in the size range 0.1-0.5
microm for each cement type. The cement particles were co-cultured with the U937
macrophage cell line at ratios of 10 and 100 microm3 particle volumes to
macrophage cell numbers for 24 h. At the 10:1 ratio the particles had no effect
on the cells. At the 100:1 ratio, the major cytokine produced was TNF-alpha and
there were no statistical differences between the different types of cement
debris. The bone resorption activity of the co-culture supernatants was
significantly greater than the control (U937 cells without particles) for
particles of CMW 1RO, CMW copolymer bone cement 1, CMW copolymer bone cement 2
and Palacos R (P < 0.05, ANOVA). However there were no statistical differences
between the levels of bone resoprtion evoked by these four cement types. The CMW1
original and CMW calcium phosphate containing cements failed to induce the
macrophages to elaborate bone resorption activity at the 100:1 ratio. These data
suggest that the addition of radio-opaque additives to bone cement may increase
the capacity of the debris to induce osteolysis.
PMID- 10768753
TI - A finite element analysis of the stress at the restoration-tooth interface,
comparing inlays and bulk fillings.
AB - A finite element investigation comparing bonded inlays and directly placed
restorations is presented. The stress build-up due to the contraction of the
restorative composite and the composite luting cement was computed using a finite
element model accounting for the time-dependent, elasto-visco-plastic behaviour
of the composite. In addition, the stresses generated in the restoration due to
occlusal loading were computed. It was found that inlays, in general, generate
higher stresses during curing, particularly along the interface between the
cement and the dentine at the base of the cavity. This is probably due to a
reduced capacity for stress relief through viscous flow during the early stages
of the curing reaction. Under occlusal load, restorations placed using both
techniques perform similarly, from a purely mechanical point of view.
PMID- 10768754
TI - Polydimethylsiloxane/polyether-mixed macrodiol-based polyurethane elastomers:
biostability.
AB - A series of four thermoplastic polyurethane elastomers were synthesized with
varying proportions of poly(hexamethylene oxide) (PHMO) and
poly(dimethylsiloxane) (PDMS) macrodiols. The macrodiol ratios (by weight)
employed were (% PDMS:% PHMO) 100:0, 80:20, 50:50 and 20:80. The weight fraction
of macrodiol in each polymer was fixed at 60%. The mixed macrodiols were reacted
with 4,4'-methylenediphenyl diisocyanate (MDI) and 1,4-butanediol (BDO) chain
extender. The biostability of these polymers was assessed by strained
subcutaneous implantation in sheep for three months followed by microscopic
examination. Pellethane 2363-80A and 2363-55D were employed as control materials.
The mechanical properties of the polymers were tested and discussed along with
the biostability results. The results showed that soft, flexible PDMS-based
polyurethanes with very promising biostability can be successfully produced using
the mixed macrodiol approach. The formulation with 80% PDMS macrodiol produced
the best result in terms of a combination of flexibility, strength and
biostability.
PMID- 10768755
TI - Activation of the cyclic AMP pathway in cells adhering to biomaterials:
regulation by vitronectin- and fibronectin-integrin binding.
AB - Our previous studies have shown that cells adhering to biomaterials in serum-free
conditions increase their content of cyclic AMP (cAMP) and become aggregated. In
cells on an acrylonitrile membrane (AN69), these biochemical and morphological
changes are prevented by adding 10% foetal calf serum (FCS) to the medium; cells
on the cellulose membrane Cuprophan (CU) remain unaffected. The present study
examines the roles of vitronectin (VN)- and/or fibronectin (FN)-integrin binding
in this inhibition. Competitively blocking VN- and FN-receptors with echistatin
increased intracellular cAMP significantly and caused cells on AN69 to aggregate,
but did not modify cAMP-dependent cell aggregation on CU. VN or FN adsorbed onto
CU also inhibited cAMP production by attached cells and prevented their
aggregation, whereas adsorbed BSA had no effect. Therefore, the binding of VN or
FN to cell-surface integrins seems to limit the activation of the cAMP pathway
initiated by the substratum itself.
PMID- 10768756
TI - Non-adhesive cyanoacrylate as an embolic material for endovascular neurosurgery.
AB - Endovascular neurosurgery is now becoming available as one of strategies for the
treatment of cerebro-spinal arterio-venous malformations and aneurysms. For this
treatment, a microcatheter is advanced into or close to a lesion and then an
embolic material is administered through it to obliterate the lesion. N-butyl-2
cyanoacrylate (NBCA) has preferentially been used as an embolic material in
Europe and America. However, its exceptionally strong adhesive force sometimes
causes adhesion between the tip of the microcatheter and the artery. In this
study, a new non-adhesive cyanoacrylate, isostearyl-2-cyanoacrylate (ISCA), was
developed. It carries a long hydrophobic side isostearyl group with lower
reactivity and adhesion than other cyanoacrylates. Its polymerization rate is,
however, too low to obliterate a vascular lesion with a rapid blood flow. To
increase the polymerization rate. ISCA was mixed with NBCA. As a result, the
adhesive force of the mixture became extremely low, compared with that of NBCA.
The viscosity of the mixture was low enough to allow its' use as an embolic
material. Tissue reactions against the mixture was milder than those against
NBCA. Radio-angiography became possible by mixing further with Lipiodol. The
evaluation of this new embolic material with a rabbit renal artery showed that
the obliteration effect of the mixture of ISCA and NBCA was excellent to use as
an embolic material for clinical applications.
PMID- 10768757
TI - Secretion of IL-1 and H2O2 by human mononuclear cells in vitro.
AB - The secretion of hydrogen peroxide (H2O2) and interleukin-1alpha (IL-1alpha) was
evaluated during in vitro culturing of human monocytes. The oxidative metabolism
and cytokine secretion were correlated to the cell distribution (number of
surface-associated cells), the DNA content and their integrity, evaluated by
lactate dehydrogenase (LDH) assay. The differentiation of cultured monocytes was
determined by the expression of CD14, 27E10 and RM3/1. After 24 h cultivation,
unstimulated cells had a low production of H2O2 and IL-1alpha. A four-fold
increase in the production of H2O2 was detected with 5 and 10 microg/ml of
lipopolysaccharide (LPS) and polystyrene (PS) particles. PS particles induced a
concentration-dependent increase in IL-1alpha after 24 h. In contrast,
cultivation for 48 h, did not result in any measurable production of H2O2,
irrespective of the type of stimulus. A decreased viability of monocytes was
shown after stimulation with PS particles in high concentrations. Our results
indicate that the phenotype expression, adhesion, integrity and secretory pattern
of human monocytes is dependent on the culture time and the type and
concentration of stimulus.
PMID- 10768758
TI - Surface modification of polyethylene balloon catheters for local drug delivery.
AB - Local drug delivery is an attractive approach to the associated problems of
percutaneous transluminal coronary angioplasty (PTCA), including arterial injury.
The objective of the present research was to deliver a high concentration of a
potent anti-thrombin agent, argatroban (ARG), to the vessel wall in order to
reduce arterial injury. Local delivery was accomplished by the ionic attachment
of drug particles to a modified balloon surface. Surface graft polymerization of
ionic monomers to a high-density poly(ethylene) (PE) substrate was performed
utilizing ultra-violet (UV) methods. Acrylic acid (AAc) and 2(dimethylamino)
ethyl methacrylate (DMAEMA) were successfully grafted onto PE surfaces. Surface
grafting was verified by contact angle, X-ray photoelectron spectroscopy, and
zeta potential measurements. The amount of ARG adsorbed onto the modified PE
surface was highly dependent on the pH of the drug media for both anionic and
cationic grafted monomers. The efficacy of local drug delivery to the arterial
wall was analyzed using drug-immobilized PE balloon catheters in the rabbit
common carotid artery model. High concentrations of ARG (280 nmol/g tissue) were
found within the ballooned arterial segment immediately after angioplasty,
followed by a decrease after blood flow was restored.
PMID- 10768759
TI - Scanning electron microscopical analysis of laser-treated titanium implant
surfaces--a comparative study.
AB - Design and surface qualities of titanium implants are of vital importance for
long-term stability following implantation. Four different implant surfaces
treated individually were analyzed with special attention focused on laser
surface treatment. Surfaces with machine roughness, titanium spray coating,
treated by aluminum oxide and treated by laser were examined individually.
Evaluation of the surface was carried out by electron microscope examination and
mechanical profilometry. The EDS analysis determined the degree of contamination
of the implant surface. Electron microscope examination showed that the titanium
plasma spray as well as the laser-treated implants have optimum surface
qualities: a secondary and tertiary structure with micro-roughness of 10 mm and
roughness ranging from 0.5 to 4 mm. The least contamination was found for machine
rough surfaces as well as those treated by laser. The other implants showed
contamination corresponding to the method of surface treatment. In summary the
optimal surface structure with the least contamination was found for the laser
treated titanium surface. Similar surface purity was found for the machine rough
surfaces. An optimal structure was also achieved by the titanium plasma spray
method, however, at the cost of surface purity.
PMID- 10768760
TI - Adsorption of plasma proteins on polyethylene oxide-modified lipid bilayers
studied by total internal reflection fluorescence.
AB - Distearoylphophatidylcholine (DSPC) mixed with various mole percentages of
polyethylene oxide (number average molecular weight 2000)-grafted
distearoylphosphatidylethanolamine (PEO2000-DSPE) were deposited on DSPE-coated
quartz surfaces by the Langmuir-Blodgett deposition. Structural transitions in
PEO2000 from pancake to mushroom, and from mushroom to brush conformations were
revealed from film balance experiments. Adsorption kinetics of proteins from 1%
platelet-poor plasma (PPP) on the supported lipid bilayers were studied using
intrinsic total internal reflection fluorescence. All the supported lipid
bilayers exhibited over a magnitude reduction in adsorbed plasma proteins,
compared with the quartz substrate. The increase of PEO2000-DSPE density in the
mixed bilayers slightly increases the amount of adsorbed proteins on the
bilayers.
PMID- 10768761
TI - An up-date of Verster's (1969) 'Taxonomic revision of the genus Taenia Linnaeus'
(Cestoda) in table format.
AB - The paper 'A taxonomic revision of the genus Taenia Linnaeus, 1758 s. str.'
(Verster, 1969) gives concise characterisations, together with drawings of
rostellar hooks and the terminal genital organs, of the 32 Taenia species and
three subspecies which this author found to be valid. Yet, it is hardly possible
to quickly identify a questionable species or to readily access information on
their hosts, geographical range and synonyms. The present paper compiles these
data and additional information on larval characteristics into tables.
Measurements and numbers of hooks are shown using a graph. Additional data are
included from authors not mentioned by Verster and for seven new species (T.
dinniki, T. jaipurensis, T. kotlani, T. madoquae, T. saigoni and T. simbae), two
re-validated species (T. krepkogorski, T. retracta) and two subspecies (T.
polyacantha arctica and T. saginata asiatica) described since 1969. Reasons for
rejecting one new species and one new subspecies are given. A table of definitive
hosts and the Taenia species occurring in them is also included, as is one of
synonyms from 1850 onwards. A good procedure for the staining and mounting of
cestodes is described.
PMID- 10768762
TI - Pseudoterranova decipiens species A and B (Nematoda, Ascaridoidea): nomenclatural
designation, morphological diagnostic characters and genetic markers.
AB - Five genetically distinct and reproductively isolated species have been detected
previously within the morphospecies Pseudoterranova decipiens from the Arctic
Boreal, Boreal and Antarctic. Morphological analysis was carried out on male
specimens identified by genetic (allozyme) markers, allowing the detection of
significant differences at a number of characters between two members of the P.
decipiens complex, namely P. decipiens A and B. On the basis of such differences,
the nomenclatural designation for the two species is discussed. The names
Pseudoterranova krabbei n. sp. and P. decipiens (sensu stricto) are proposed for
species A and B, respectively. Morphological and genetic differentiation between
the two species is shown using multivariate analysis. Allozyme diagnostic keys
for routine identification of the four members of the P. decipiens complex,
namely P. decipiens (s.s.), P. krabbei, P. bulbosa and P. azarasi, irrespective
of sex and life-history stage, are provided.
PMID- 10768764
TI - Description and morphometric variability of Paranoplocephala serrata n. sp.
(Cestoda: Anoplocephalidae) in collared lemmings (Dicrostonyx spp., Arvicolinae)
from Arctic Siberia and North America.
AB - We describe Paranoplocephala serrata n. sp. (Cestoda, Anoplocephalidae) from
collared lemmings Dicrostonyx torquatus and D. groenlandicus (Arvicolinae,
Rodentia) in Arctic Siberia and North America. The new species was recorded from
the Yamal Peninsula (type-locality), Yana Delta, Kolyma Delta, Wrangel Island,
Alaska and Victoria Island/Kent Peninsula (Northwest Territories). P. serrata n.
sp. is characterised by a long, ribbon-like strobila, distinctly serrated
segments, a small scolex, unilateral or infrequently alternating genital pores
and testes confined to the antiporal part of the segment. It differs from the
related species (Andrya bairdi, Parandrya feodorovi and Paranoplocephala manseri)
by several morphological features, including the distribution of testes (several
testes antiporal to ventral longitudinal osmoregulatory canal), structure of the
cirrus-sac and vagina, and large eggs (0.053-0.068 mm in the type-material). The
material of P. serrata n. sp. from North America differs from the Siberian
material by the shorter cirrus-sac, smaller dimensions of the female reproductive
organs, larger seminal receptacle and larger eggs. However, the statistical
differences in the dimensions of reproductive organs mainly reflect the larger
size of mature segments in Siberian specimens compared with North American
specimens. The main diagnostic features, i.e. the size and form of scolex and
suckers, number and distribution of testes, position of female glands,
vagina/cirrus-sac ratio and morphology of reproductive organs, do not differ
markedly between the Palaearctic and Nearctic specimens. According to the
structure of the early-stage uterus, A. bairdi Schad, 1954 belongs to the genus
Paranoplocephala. Parandrya Gulyaev & Chechulin, 1996 is probably a synonym of
Paranoplocephala. A redescription is provided for Paranoplocephala bairdi n.
comb.
PMID- 10768763
TI - The life-cycle of Echinostoma friedi n. sp. (Trematoda: Echinostomatidae) in
Spain and a discussion on the relationships within the 'revolutum' group based on
cercarial chaetotaxy.
AB - The morphology of the different stages and life-cycle of Echinostomna friedi n.
sp. are described and figured. The freshwater snail Lymnaea peregra (Gastropoda:
Lymnaeidae) serves as the natural and experimental first intermediate host and L.
corvus and Gyraulus chinensis (Gastropoda: Planorbidae) as experimental first
intermediate hosts. These, and Physella acuta (Gastropoda: Physidae), also serve
as second intermediate hosts. Adult worms, possessing 37 collar spines, were
obtained from naturally infected Rattus norvegicus and experimentally from albino
rats, golden hamsters and chickens. Mice were not suitable experimental
definitive hosts. E. friedi differs from the most closely related species in the
'revolutum' group mainly in terms of several morphological and biological
features of the life-cycle stages and in its cercarial chaetotaxy. The chaetotaxy
patterns of the species of the 'revolutum' group are analyzed and the results
show that a taxonomic comparison of these species may be carried out on the basis
of the number of sensilla in the clusters CIII VI, CIII V2 (or CIII V1 + CIII
V2), CIV DL and UVb. These clusters appear adequate to establish taxonomic
relationships between different species within the 'revolutum' group.
PMID- 10768765
TI - An exactly solvable Ogston model of gel electrophoresis. V. Attractive gel
analyte interactions and their effects on the Ferguson plot.
AB - We examine the effect of attractive analyte-gel interactions within the framework
of our recently developed lattice model of gel electrophoresis. We show that it
is possible to take into account such interactions and still calculate exact
mobilities for various analytes and gel structures. Our study then focuses on two
main issues: (i) the effect of these interactions on the separation efficiency of
the Ogston regime; and (ii) the presence of inflection points (changes of
curvature) in Ferguson plots. We establish some general principles, and we
describe the results for selected two- and three-dimensional model systems.
Numerous practical problems, such as chiral separations and affinity
electrophoresis, can be treated using this approach.
PMID- 10768766
TI - Ultrathin-layer sodium dodecyl sulfate gel electrophoresis of proteins: effects
of gel composition and temperature on the separation of sodium dodecyl sulfate
protein complexes.
AB - This paper discusses the effects of gel composition and separation temperature on
the migration properties of fluorescein-5-isothiocyanate-labeled protein
molecular mass markers (ranging from 20 100 to 205 000 Da) in automated ultrathin
layer sodium dodecyl sulfate (SDS) gel electrophoresis. The separation mechanism
with the agarose and composite agarose - linear polyacrylamide, agarose -
hydroxyethyl cellulose, and agarose - polyethylene oxide matrices were all found
to comply with the Ogston sieving model in the molecular mass range of the
protein molecules investigated. Our temperature studies revealed that
electrophoretic separation of SDS protein complexes is an activated process and,
in pure agarose and in composite agarose hydroxyethyl cellulose and agarose -
polyethylene oxide matrices that the separation requires increasing activation
energy as a function of the molecular mass of the separated proteins. On the
other hand, when linear polyacrylamide was used as composite additive, the
activation energy demand of the separation decreased with increasing solute
molecular mass. The sensitivity of the laser-induced fluorescent detection of the
automated ultrathin-layer electrophoresis system was evaluated by injecting a
series of dilutions of the markers and was found to be less than 2.5 ng/band for
the fluorophore-labeled protein.
PMID- 10768767
TI - Direct Blue 71 staining of proteins bound to blotting membranes.
AB - A sensitive staining method for protein blots using Direct Blue 71 is described.
It is based on the selective binding of dye molecules to proteins in acidic
solution and produces bluish violet colored bands. It is a simple and rapid
procedure, involving only staining and rinsing steps that occur within 7 min. The
sensitivity of this method is 5-10 ng of protein on nitrocellulose (NC) and 10-20
ng on polyvinylidene difluoride (PVDF), which is tenfold better than that of the
commonly used Ponceau S staining. Moreover, the staining is reversible for
subsequent immunostaining, without impairing immunoreactivity. To remove the dye
from the developed bands, changes in pH and hydrophobicity of the solvent are
required. Due to its sensitivity, rapidity, simplicity, and low cost, this stain
may be more practical than other dye-based stains or metal-based stains for
routine laboratory purposes.
PMID- 10768768
TI - Electroelution of nonfluorescent stacked proteins detected by fluorescence optics
from gel electrophoretic bands for transfer into mass spectrometry.
AB - The extreme accuracy of spectrometrically determined masses of proteins has
opened the possibility to identify proteins separated as gel electrophoretic
bands in the absence of specific immunologic ways of identification. For the
purpose of protein transfer from gel electrophoretic bands to mass spectrometer,
electroelution from the intact gel has advantages, in particular when apparatus
with capacity for fluorescent scanning allows one to direct the electroelution
cell over the band under computer control. To avoid fluorescent labeling of the
protein which is incompatible with mass spectrometric identification, it is
proposed to selectively stack the unlabeled protein and detect it by comigrating
tracking dye prior to electroelution. The feasibility of the approach is
exemplified in case of a single protein, but still remains to be demonstrated in
conjunction with the selective stacking or unstacking of a single protein from a
mixture of several proteins.
PMID- 10768769
TI - Heat-induced conformational transition of cytochrome c observed by temperature
gradient gel electrophoresis at acidic pH.
AB - Temperature-gradient gel electrophoresis (TGGE) has been used to study the
thermal unfolding of ferricytochrome c in low and high concentrations of acetic
acid. It has been observed that the mobility of cytochrome c is a linear function
of temperature when the system is characterized by a homogeneous population of
conformation-state, single molecular species. Within the transition temperature
range, the mobility clearly displays the characteristic sigmoidal shape
describing the transitions of protein unfolding. The data obtained by TGGE were
used to estimate the apparent thermodynamic parameters (enthalpy change deltaHvh
and transition temperature Tm), associated with the transition of unfolding. The
accuracy of the apparent thermodynamic parameters obtained by this method agrees
within error limits with the values obtained by direct calorimetric measurements
using differential scanning calorimetry (DSC).
PMID- 10768770
TI - Unlimited increase in the resolution of DNA ladders.
AB - Fractionation of DNA ladders by gel electrophoresis is limited by the progressive
compressing of the long DNA end of a ladder. Improvement in the resolution of
this DNA is achieved by use of the following two-step electrophoresis. Initially,
the DNA ladder is fractionated by conventional constant field agarose gel
electrophoresis. Subsequently, gel electrophoresis is performed in the reverse
direction by pulsing the electrical field (PFGE). A newly developed type of
pulsing is used, which causes inversion of a double-stranded DNA ladder: the
distance migrated increases as the length of the DNA molecule increases. Thus,
the resolution of DNA bands continues to increase during the PFGE. These two
stages of electrophoresis are serially repeated. Eventually, both the short and
the long DNA ends of the ladder migrate out of the gel while a selected region of
the ladder undergoes progressive increase in resolution during back-and-forth
migration. Improved resolution of DNA bands is achieved, without a known limit.
PMID- 10768771
TI - Characterization of the selective staining of DNA on gels using two
fluorochromes.
AB - Ethidium bromide (EB) and 4'-6-diamidino-2-phenylindole (DAPI) are both well
known fluorochromes for detecting DNA fragments. EB binds to DNA by intercalation
and DAPI binds in the DNA minor groove. We previously developed a staining method
using both EB and DAPI that is selective for AT-rich DNA fragments. Using this
double-staining method, AT-rich DNA fragments are visualized as bluish-white
fluorescent bands. To further characterize this method, a series of synthetic DNA
fragments were designed with systematic variations in the length, AT content, and
DNA sequence pattern. The staining properties of these fragments were determined
in the presence of DAPI and EB, and the following results were obtained. (i) In a
series of fragments with three AT base pairs followed by one GC base pair, the
stained DNA fragments exhibited different fluorescent colors and varied from
bluish (more DAPI staining) to pinkish (less DAPI staining) in the order 5'-AAA
3', 5'-AAT-3', 5'-ATA-3', 5'-TTA-3'. (ii) In fragments with constant AT content,
the blue fluorescent color increased with increasing number of A (or T)
nucleotides, due to increased DAPI binding. The blue color was saturated when the
number of A (or T) nucleotides was 12 or greater. (iii) The fluorescent color of
the stained DNA fragments changed in the order of red-orange, pink, pinkish
white, white, bluish-white, blue as the AT content increased from 0 to 100%.
Thus, the fluorescent color of DNA fragments stained with DAPI and EB depends on
base composition and nucleotide sequence, suggesting that individual stained DNA
fragments may have characteristic and specific fluorescent colors. The
fluorescent color emitted by specific stained DNA fragments in the presence of EB
and DAPI can be analyzed with a high degree of sensitivity and resolution using
the XYZ colorimetric system.
PMID- 10768772
TI - Quality of assurance considerations for use of the Fluorlmager SI and fragmeNT
analysis software.
AB - The Fluorlmager SI (FSI) from Molecular Dynamics is one of several scanning
instruments available for the detection of fluorescent emissions associated with
DNA samples in a variety of matrices (agarose and polyacrylamide gels, membranes
and microplates). In our laboratory, we measured the electrophoretic mobility of
randomly amplified polymorphic DNA (RAPD) fragments stained with ethidium bromide
in agarose using the FSI to scan gels and the associated Molecular Dynamics
software (ImageQuaNT, and FragmeNT Analysis) for analysis. Initial scans and
analyses resulted in inconsistent band detection across the same gel and across
several scans of the same gel. To determine the best types of calibration for the
instrument, several factors were considered and then evaluated. Tests of
calibration acceptability were also evaluated. Band detection by FragmeNT
Analysis was improved following optimization of matrices and parameters used in
calibration and experimental scans. In addition, use of software templates for
analysis and modifications in the staining procedure, which have resulted in
decreased instrument associated variance, are discussed.
PMID- 10768773
TI - Microsatellite structures in the context of human evolution.
AB - Six microsatellite - or short tandem repeat (STR) - systems with uniform
repetitive sequences (HumTH01, HumCD4, HumFES/FPS, HumF13B, HumTPO, HumLPL) and
three compound repeat systems (HumVWA, HumFIBRA, D21S11) were used, including
data from the literature, to determine genetic distances among eight populations
worldwide. The TH01- and VWA homologous loci in nonhuman primates (chimpanzees,
gorillas, orangutans, rhesus monkeys, ring-tailed lemurs) were compared and found
to be shorter than in humans. Microsatellites of lower complexity were most
efficient for the separation of major ethnic groups. The loci of higher
complexity showed a leveling of the diversity differences among populations,
which could be attributed to higher mutation rates.
PMID- 10768774
TI - Cloning and characterization of a novel caprine genomic repetitive element that
hybridizes with papillomavirus DNA.
AB - A goat genomic library was screened by Southern blot hybridization at reduced
stringency with a bovine papillomavirus type 5 (BPV 5) DNA probe in order to
identify potential cellular and viral sequences related to the papillomavirus
genome. A recombinant clone with an 8.5 kb genomic insert was found to contain a
1.3 kb PstI subfragment (designated as P1-1) that hybridized with the DNA of BPV
5, two murine papillomaviruses and human papillomavirus types 5 and 8, but not
with DNA from another eight human and bovine papillomavirus types. Southern blot
hybridization of the goat P1-1 DNA probe was restricted to a single 1.0 kb
subfragment within the E1 open reading frame (ORF) of BPV 5 but produced multiple
bands ranging between 1.0 and 9.0 kb when hybridized under stringent conditions
with PstI-digested DNA obtained from different goat tissues. The genomic sequence
of P1-1 has direct repeats of 10 and 13 nucleotides flanking 153 nucleotides, and
889 nucleotides of sequence, respectively, and an inverted repeat sequence of 11
nucleotides flanking a major ORF potentially coding for 244 residues. Potential
splice acceptor and donor sites capable of joining with upstream and downstream
exons are present within the major ORF. Sequence similarity between P1-1 and BPV
5 DNA at the nucleotide and amino acid level was limited to a stretch of 58
nucleotides which includes an oligopurine/pyrimidine tract. This region of
similarity contains a predicted glutamic acid-rich domain. The P1-1 sequence is a
novel repetitive element within the goat genome that is unrelated in sequence to
papillomavirus DNA and to genomic sequences of mouse and man.
PMID- 10768775
TI - Quantitative DNA methylation analysis by fluorescent polymerase chain reaction
single-strand conformation polymorphism using an automated DNA sequencer.
AB - A novel DNA methylation assay technique, termed bisulfite single-strand
conformation polymorphism (bisulfite-SSCP), is a combination of sodium-bisulfite
modification and fluorescence-based polymerase chain reaction (PCR)-SSCP. After
bisulfite treatment followed by PCR amplification, methylated and unmethylated
alleles can be simultaneously separated in a nondenaturing gel using an automated
DNA sequencer. Using bisulfite-SSCP, methylation of hMLH1 was detected in a
quantitative manner. This method is not only simple, quick, accurate, and
quantitative, but detailed information about methylation is also available with
less work. Methylation analysis of large numbers of samples for multiple loci
will be facilitated by bisulfite-SSCP.
PMID- 10768776
TI - New adsorbed coatings for capillary electrophoresis.
AB - New acrylic polymers bearing oxirane groups were synthesized to be used in the
production of coated capillaries. A fully automated coating procedure was devised
based on the use of diluted water solutions of these polymers. The whole
procedure required less than 30 min. The new polymers rapidly adsorbed from water
onto the capillary wall, thus suppressing electroosmotic flow (EOF) to a
negligible value. The adsorbed coatings were stable for hundreds of hours at high
pH, temperature, and in the presence of 8 M urea. Efficient separations of acidic
and basic proteins were achieved in the new phases.
PMID- 10768777
TI - Investigation of capillary electrochromatography with brush-type chiral
stationary phases.
AB - Fused-silica capillaries (100 microm ID) were packed with the (3R, 4S)-Whelk-O
chiral stationary phase (CSP) bonded on 3.0 microm silica particles. The
enantiomers of 41 neutral analytes containing stereogenic centers, axes or planes
were examined by packed capillary electrochromatography. More than 30 of these
were cleanly resolved, owing to the selectivities and efficiencies afforded by
this CSP. High reproducibility with no indication of diminished performance was
observed using the same capillary for hundreds of runs (including intermediate
change of the buffer system) over a period of several weeks. Acetate, 2-(N
morpholino)ethanesulfonic acid, or phosphate buffers, each modified with either
acetonitrile or methanol, were used as mobile phases. The influence of buffer
concentration, modifier amount, temperature, applied voltage, and pH on
performance of the brush-type CSP was investigated.
PMID- 10768778
TI - A new method of quantification of pipemidic-acid by capillary zone
electrophoresis with end-column amperometric detection.
AB - Capillary zone electrophoresis was employed for the determination of pipemidic
acid using an end-column amperometric detection with a carbon fiber microdisk
array electrode, at a constant potential of -1.10 V vs. saturated calomel
electrode. The optimum conditions of separation and detection were 1.2 x 10(-4)
mol/LNaOAc - 8.8 x 10(-4) mol/ LHOAc for the buffer solution, 20 kV for the
separation voltage, 5 kV and 10 s for the injection voltage and the injection
time. The limit of detection was 1.05 x 10(-7) mol/L or 189 amol (S/N=3). The
relative standard deviation was 0.31% for the migration time and 2.0% for the
electrophoretic peak current. The method was applied to determining pipemidic
acid in human serum.
PMID- 10768779
TI - Capillary electrophoresis of nonprotein and protein amino acids without
derivatization.
AB - An efficient separation of eleven nonprotein amino acids (NPAAs) and three
protein amino acids containing aromatic moieties was achieved by capillary
electrophoresis without derivatization. The fourteen amino acids were well
separated with a 100 mM sodium phosphate run buffer (pH 2.0) using a 57 cm fused
silica capillary (50 microm ID, 50 cm effective length) at 20 degrees C. With an
electric field of 351 V/cm, the time needed for the separation was less than 20
min. Under optimum conditions, excellent linear responses were obtained in the
concentration range of 5-100 microM, with the linear correlation coefficient
ranging from 0.9785 or greater. The relative standard deviations of the migration
times and the corrected peak areas were found to be 1.5-3.9% and 8.0-11.5%,
respectively. In order to improve the limit of detection (LOD), simple stacking
and large volume stacking using an EOF pump (LVSEP) methods were used. Improved
LODs were about 300 nM in stacking and below 15 nM for five small NPAAs in LVSEP.
PMID- 10768780
TI - Mapping and identification of Mycobacterium tuberculosis proteins by two
dimensional gel electrophoresis, microsequencing and immunodetection.
AB - Mycobacterium tuberculosis is the infectious agent giving rise to human
tuberculosis. The entire genome of M. tuberculosis, comprising approximately 4000
open reading frames, has been sequenced. The huge amount of information released
from this project has facilitated proteome analysis of M. tuberculosis. Two
dimensional polyacrylamide gel electrophoresis (2-D PAGE) was applied to
fractions derived from M. tuberculosis culture filtrate, cell wall, and cytosol,
resulting in the resolution of 376, 413, and 395 spots, respectively, in silver
stained gels. By microsequencing and immunodetection, 38 culture filtrate
proteins were identified and mapped, of which 12 were identified for the first
time. In the same manner, 23 cell wall proteins and 19 cytosol proteins were
identified and mapped, with 9 and 10, respectively, being novel proteins. One of
the novel proteins was not predicted in the genome project, and for four of the
identified proteins alternative start codons were suggested. Fourteen of the
culture filtrate proteins were proposed to possess signal sequences. Seven of
these proteins were microsequenced and the N-terminal sequences obtained
confirmed the prediction. The data presented here are an important complement to
the genetic information, and the established 2-D PAGE maps (also available at:
www.ssi.dk/publichealth/tbimmun) provide a basis for comparative studies of
protein expression.
PMID- 10768781
TI - Reference map of soluble proteins from Streptococcus thermophilus by two
dimensional electrophoresis.
AB - Streptococcus thermophilus is a lactic acid bacterium widely used for the
production of fermented dairy products. The two-dimensional electrophoresis (2
DE) protein profile was obtained from three independent analyses of 2-DE gels of
soluble proteins of the strain PB18. About 270 spots were detected by silver
staining and the average molecular weight and isoelectric point of each protein
spot were calculated to be 41 600 and 5.2, respectively. Twelve proteins were
purified by chromatographic techniques because their concentration was too low
for direct sequencing from blots. Eleven were located in the PB18 2-DE profile
after silver staining. These preliminary results contribute to the setting up of
a two-dimensional image (or reference map) of the proteins from S. thermophilus
in order to identify and compare strains of various origin or to follow metabolic
process such as stress. Bidimensional autoradiographs of two strains (PB18 and
ST105) of S. thermophilus grown in exponential phase at 42 degrees C with
[35S]methionine were compared with an image analysis system. Among the eleven
located proteins in the 2-DE silver-stained profile, nine were found in PB18 and
eight in ST105 autoradiographs. One protein was specific to PB18. The eight
proteins could play the role of internal 2-D PAGE markers of p/ and Mr for S.
thermophilus.
PMID- 10768782
TI - Cell surface proteins of Candida albicans: preparation of extracts and improved
detection of proteins.
AB - We have reexamined the detection of the components in a beta-mercaptoethanol and
ammonium carbonate buffer extract of surface proteins of Candida albicans and the
effects of postextraction manipulation of the extract on recovery of extract
components. Following sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE), preferential staining of some moieties was observed when bands
detected by a commercial silver staining method or a Coomassie Brilliant Blue
(CBB) staining method were compared. Additional protein bands that were either
not detected or poorly detected by a single method alone were readily observed by
a combined silver-CBB staining method. This method also detected alterations in
the profile of extracted proteins from organisms grown in the presence of
galactose or hemoglobin rather than glucose. Two-dimensional electrophoresis (2
DE) gel analysis by double stain showed better detection of several acidic and
basic protein spots. Less than 10% of the extract as determined by a dye-binding
assay was lost following either or both lyophilization and dialysis. These
manipulations of the extract did not change the protein profile following SDS
PAGE as determined by the combined staining or Western blot analysis of a 70 kDa
protein. These observations suggest that soluble cell wall proteins are not
unusually sensitive to procedures routinely used in protein purification. In
addition, these studies suggest that a modified staining method that combines
both silver stain and CBB stain provides improved detection of cell wall proteins
compared to either method alone.
PMID- 10768783
TI - Serum protein immunogenicity: implications for liver xenografting.
AB - The objectives of this study were threefold: (i) assess immunogenicity of donor
plasma proteins following hepatic xenotransplantation, (ii) identify potential
immunogens, and (iii) consider the implications of antibody formation against
these plasma proteins in xenograft survival. We studied liver and heart
xenografts in a concordant combination, hamster to rat. All grafts were examined
at necropsy for evidence of rat immunoglobulin G (IgG) deposition. Cardiac
xenografts were placed in recipients who had, or had not, been sensitized with
hamster serum. Hepatic xenografts were placed in naive recipients to see if
antibodies to hamster serum proteins could be eluted from the rejecting organ.
Sera of immunized rats were examined for the presence of anti-hamster antibodies
by immunoelectrophoresis and by Western blotting following sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS-PAGE) separation of hamster serum.
Antibodies in sera of immunized rats were compared with those eluted from
rejecting livers. Candidate antigens were identified by tandem mass spectrometry,
sequence analysis, and reference to protein databases. Results showed that sera
of immunized rats recognized a minimum of four different antigens in hamster
serum by immunoelectrophoresis, and a minimum of seven by the more sensitive SDS
PAGE Western blot. IgG eluted from rejecting livers bound three of seven
candidate antigens recognized by sera of the immunized animals. Sequence analysis
searches revealed proteinase inhibitors in each of the three SDS-PAGE bands
common to the above samples. All of these candidate proteinase inhibitor
immunogens share a common catabolic fate, uptake via the lipoprotein-related
protein (LRP/alpha 2-macroglobulin receptor (CD91). Sensitization to hamster
serum proteins hastened cardiac xenograft rejection in 30-50% of recipients
(depending on sensitization protocol). Vascular deposition of rat IgG occurred in
all rejecting xenografts. Antibody binding to proteinase inhibitors could disturb
their functional activity and contribute to the pathogenesis of delayed xenograft
rejection.
PMID- 10768784
TI - Proteomic analysis of the renal effects of simulated occupational jet fuel
exposure.
AB - We analyzed protein expression in the cytosolic fraction prepared from whole
kidneys in male Swiss-Webster mice exposed 1 h/day for five days to aerosolized
JP-8 jet fuel at a concentration of 1000 mg/m3, simulating military occupational
exposure. Kidney cytosol samples were solubilized and separated via large-scale,
high-resolution two-dimensional electrophoresis (2-DE) and gel patterns scanned,
digitized and processed for statistical analysis. Significant changes in soluble
kidney proteins resulted from jet fuel exposure. Several of the altered proteins
were identified by peptide mass finger-printing and related to ultrastructural
abnormalities, altered protein processing, metabolic effects, and paradoxical
stress protein/detoxification system responses. These results demonstrate a
significant but comparatively moderate JP-8 effect on protein expression in the
kidney and provide novel molecular evidence of JP-8 nephrotoxicity. Human risk is
suggested by these data but conclusive assessment awaits a noninvasive search for
biomarkers in JP-8 exposed humans.
PMID- 10768785
TI - Separation efficiency in protein zone electrophoresis performed in capillaries of
different diameters.
AB - R-phycoerythrin (PHYCO, Mr 240 000), glucose-6-phosphate dehydrogenase (GPD, Mr
104 000) and two charge isomers of recombinant green fluorescent protein (GFP-1
and GFP-2, Mr 27 000) were subjected to capillary zone electrophoresis (CZE) in
capillaries of 50, 100 and 150 microm inner diameter at various sample
concentrations, electric field strengths, and lengths of the initial zone with
the purpose of testing the hypothesis that protein - capillary wall interactions
rather than thermal effects are predominantly responsible for the peak spreading
of proteins in CZE. The efficiency of CZE was expressed in terms of the number of
theoretical plates, N, or the plate height corrected by subtracting the
contribution from initial zone length, H'. The latter has the advantage of solely
reflecting contributions to the separation efficiency arising from intracolumn
peak spreading in capillaries of different diameters. The separation efficiency
measured varied widely, by two orders of magnitude, for these proteins under
identical conditions, with GPD exhibiting the highest and PHYCO the lowest values
of N. H' was found to be independent of sample concentrations within the
concentration ranges studied, 1-100 microg/mL for PHYCO and 100-1000 microg/mL
for GPD, while exhibiting a decrease with sample concentration for GFP,
especially in 150 microm diameter capillaries, within the concentration range 1
100 microg/mL. H'was also found to be independent of electric field strength up
to 300-400 V/cm for PHYCO and GFP. In all experiments, the CZE of proteins in 100
microm diameter capillaries provided a higher or, at least, equal efficiency,
compared to that in 50 or 150 microm diameter capillaries. It may be concluded
that the protein - capillary wall interactions and protein microheterogeneity are
the dominant sources of peak spreading and their specific combinations are
thought to be responsible for the wide variation in separation efficiency between
proteins in CZE observed under identical conditions.
PMID- 10768786
TI - A comparison of three commercially available isoelectric focusing units for
proteome analysis: the multiphor, the IPGphor and the protean IEF cell.
AB - We tested and compared three different commercially available instruments for
isoelectric focusing for proteome analysis by two-dimensional protein
electrophoresis. These instruments, the Multiphor, the IPGphor, and the Protean
IEF cell, were used with 18 cm immobilized pH gradient strips and run under
various conditions. The total number of spots and features was obtained by
Melanie software (Bio-Rad Laboratories) and separately by visual inspection. The
Multiphor consistently resulted in the highest number of spots detected per gel
independent of sample type, immobilized pH gradient (IPG) and method to calculate
the number of spots. The Protean IEF cell had the next highest number of spots
detected per gel. In the experiments performed, the IPGphor afforded good
reproducibility in the total number of Melanie-detected spots from gel to gel
while the Protean IEF cell offered better reproducibility in the total number of
manually detected spots from gel to gel. Among gels run with the different
instruments, differences in the quality of the ammoniacal silver stain were also
observed. A measure of quantitative reproducibility suggests that the Protean IEF
cell, which was the easiest instrument to use, performs better than the other
instruments, although all three instruments had demonstrated good quantitative
reproducibility in the experiments performed.
PMID- 10768787
TI - Preparative electrochromatography of proteins in various types of porous media.
AB - The performance of commercial and enzymatically modified size-exclusion (SE) gels
in electrochromatography was compared for preparative protein separations.
Dextran and agarose-based SE gels were subjected to enzymatic digestion under
mild conditions. This treatment partially hydrolyzed the gel matrix modifying its
pore size distribution. Enzymatic treatment of agarose-based SE gels was found to
increase the resolution of the separation. Successful separation of preparative
amounts of the A and B forms of beta-lactoglobulin (difference in electrophoretic
mobility of 8.5%) was achieved with a high degree of purity using agarose-based
SE gels. The four major whey proteins, beta-lactoglobulin, alpha-lactalbumin, BSA
and immunoglobulins, were purified from an acid whey preparation. The degree of
retention of a protein in electrochromatography followed their free-solution
electrophoretic mobility (mu) when the protein was able to enter the gel pores
and the ratio of diffusion/mu when the protein was excluded.
PMID- 10768788
TI - Separation of different physical forms of plasmid DNA using a combination of low
electric field strength and flow in porous media: effect of different field
gradients and porosity of the media.
AB - The retention of different physical forms of DNA by an electric field in a
chromatography system was studied. We were able to effectively separate the
supercoiled and the open circular forms of plasmid DNA using this type of
electrochromatography system. Chromatography columns were packed with porous
beads, and an axial electric field was applied so that convective buffer flow
opposed the direction of electrophoresis of the DNA. A model system composed of
approximately equal amounts of the super-coiled and open circular forms of the
plasmid pBR 322 (4322 base pairs) was used to test the separation. Chromatography
beads (agarose-based) with different porosities were used to determine the effect
of the stationary phase on the separation. The porous media did not have a major
effect on the separation, but the best separations were obtained using porous
chromatography media made with the highest agarose concentration (10% agarose).
Selective elution of plasmid DNA with different forms was obtained by either
increasing the flow rates or decreasing the electric field strength (by steps or
a gradient). In all the separations, the more compact supercoiled form of the
plasmid was retained less strongly than either the open circular form (nicked) or
the linear form. High molecular weight host genomic DNA was more strongly
retained than the plasmid DNA. Increasing the ionic strength of the buffer
improved resolution and capacity. The capacity of the separation was determined
by injecting increasing amounts of plasmid DNA. Satisfactory separation was
obtained at sample loading of up to 360 microg of total DNA on a column with
dimensions of 2.5 by 11 cm (bed volume of 54 mL). The retention of DNA depends
upon a counter-current flow of electrophoresis and convective flow and could be
regarded as a type of field flow fractionation. The retention of the DNA by the
electric field and flow is discussed in relation to the diffusion coefficients of
the DNA.
PMID- 10768789
TI - The role of Joule heating in dispersive mixing effects in electrophoretic cells:
hydrodynamic considerations.
AB - The analysis described in this contribution is focused on the effect of Joule
heating generation on the hydrodynamics of batch electrophoretic cells (i.e.,
cells that do not display a forced convective term in the motion equation). The
hydrodynamics of these cells is controlled by the viscous forces and by the
buoyancy force caused by the temperature gradients due to the Joule heating
generation. The analysis is based on differential models that lead to analytical
and/or asymptotic solutions for the temperature and velocity profiles of the
cell. The results are useful in determining the characteristics of the
temperature and velocity profiles inside the cell. Furthermore, the results are
excellent tools to be used in the analysis of the dispersive-mixing of solute
when Joule heating generation must be accounted for. The analysis is performed by
identifying two sequentially coupled problems. Thus, the "carrier fluid problem"
and the "solute problem" are outlined. The former is associated with all the
factors affecting the velocity profile and the latter is related to the
convective-diffusion aspects that control the spreading of the solute inside the
cell. The analysis of this contribution is centered on the discussion of the
"carrier fluid problem" only. For the boundary conditions selected in the
contribution, the study leads to the derivation of an analytical temperature and
a "universal" velocity profile that feature the Joule heating number. The Grashof
number is a scaling factor of the actual velocity profile. Several
characteristics of these profiles are studied and some numerical illustrations
have been included.
PMID- 10768790
TI - Role of Joule heating in dispersive mixing effects in electrophoretic cells:
convective-diffusive transport aspects.
AB - This contribution addresses the problem of solute dispersion in a free convection
electrophoretic cell for the batch mode of operation, caused by the Joule heating
generation. The problem is analyzed by using the two-problem approach originally
proposed by Bosse and Arce (Electrophoresis 2000, 21, 1018-1025). The approach
identifies the carrier fluid problem and the solute problem. This contribution is
focused on the latter. The strategy uses a sequential coupling between the
energy, momentum and mass conservation equations and, based on geometrical and
physical assumptions for the system, leads to the derivation of analytical
temperature and velocity profiles inside the cell. These results are subsequently
used in the derivation of the effective dispersion coefficient for the cell by
using the method of area averaging. The result shows the first design equation
that relates the Joule heating effect directly to the solute dispersion in the
cell. Some illustrative results are presented and discussed and their implication
to the operation and design of the device is addressed. Due to the assumptions
made, the equation may be viewed as an upper boundary for applications such as
free flow electrophoresis.
PMID- 10768791
TI - Pediatric human immunodeficiency virus and acquired immunodeficiency syndrome: an
overview.
AB - This article covers the epidemiological manifestations of human immunodeficiency
virus and acquired immunodeficiency syndrome (HIV/AIDS) in children, demographic
statistics, and information on the three modes of virus transmission. The various
opportunistic diseases and neurological dysfunction that characterize pediatric
HIV are described. The Center for Disease Control pediatric HIV classification
system is presented, and the developmental disorders often found in children with
HIV are discussed. The Universal Disease Precautions of the American Speech and
Hearing Association (ASHA) for clinicians is also presented.
PMID- 10768792
TI - Language and oral-motor development and disorders in infants and young toddlers
with human immunodeficiency virus.
AB - There are only a few studies on the preverbal and language development of infants
and toddlers with human immunodeficiency virus (HIV). However, the available
literature indicates that HIV infection appears to compromise language
development. No studies could be found on the oral-motor development of such
children. This article reviews current research on the preverbal and language
development of children with HIV from birth to 3 years of age and provides
recommendations for future research. Information on several virus-related
pathologies that can interfere with oral-motor integrity and development is also
presented. Proper intervention to remediate language disorders and support oral
motor development of these children requires their comprehensive assessment, and
a dynamic assessment strategy is recommended.
PMID- 10768793
TI - Language development and assessment in children with human immunodeficiency
virus: 3 to 6 years.
AB - Young children infected or exposed, or both to the human immunodeficiency virus
(HIV) present with a variety of speech, language, and communication problems. The
purpose of this article is to provide an overview of the impact that HIV has on
young children from 3 to 6 years of age. Issues concerning medically related
problems are discussed, along with assessment criteria and descriptions of
communication disorders among HIV-infected and -exposed children.
PMID- 10768794
TI - Development and assessment of school-age and adolescent children with human
immunodeficiency virus.
AB - This article presents a review of the literature regarding the communication
problems of school-age children with HIV-infection and the impact of the
psychosocial and emotional reactions of these children on their social
relationships. An overview of the effects of HIV infection on the central nervous
system is followed by descriptions of how hearing, oral motor function, speech,
language, reading and written language may be affected.
PMID- 10768795
TI - Communication intervention and therapeutic issues in pediatric human
immunodeficiency virus.
AB - This article provides an overview of treatment strategies that target
communicative disorders exhibited by children exposed to human immunodeficiency
virus (HIV). The myriad of communicative disorders presented by these children is
discussed in relationship to the complex needs of culturally diverse families.
Rehabilitation considerations, the impact of health status on treatment outcomes,
and the need to work collaboratively with other health care professionals in
meeting children's needs from a family-focused perspective are further discussed.
PMID- 10768796
TI - Psychosocial issues in pediatric human immunodeficiency virus.
AB - This article discusses the psychosocial issues associated with pediatric human
immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS). Using a
psychosocial model instead of the usual medical or rehabilitation model will
challenge speech-language pathologists to incorporate an understanding of the
psychosocial stresses that affect a child's progression through HIV/AIDS and
ensure that they receive adequate consideration in a total treatment model. A
case study illustrates the relationship between communication disorders and
HIV/AIDS.
PMID- 10768797
TI - Process evaluations of the 5-a-day projects.
AB - Process evaluation is an important, but infrequently conducted, component of
evaluating the impact of health promotion interventions. The process evaluation
results from the nine 5-a-Day projects were overviewed. Process evaluation helped
explain some of the weaker aspects of program performance, process indicators
occasionally declined over time and varied by demographic characteristics, and
some process measures were related to mediating variables and program outcomes.
Future development of process evaluation must include further development of
concepts, more consistent and thorough conduct of process evaluation, appropriate
methodological work, and assessment of the relations among the process evaluation
components and the program mediators and outcomes. Further development in this
area promises refinement in understanding how and why interventions achieve their
effects, how best to conduct intervention programs to maximize effects, and
enhancement of the internal and external validity of the studies.
PMID- 10768798
TI - Gimme 5 fruit and vegetables for fun and health: process evaluation.
AB - Gimme 5 (Georgia) was a school-based nutrition education effectiveness trial to
help fourth- and fifth-grade students eat more fruit, 100% juice, and vegetables
(FJV). Process evaluation assessed fidelity of implementation, reach, and use of
intervention materials and environmental mediators: teacher training, curriculum
delivery, participation in family activities, attendance at evening point-of
purchase grocery store activities, and availability and accessibility of FJV at
home. Approximately half of the curriculum activities were implemented in fourth
and fifth grades. The lowest proportion completed were those most pertinent to
behavior change. Eighty-seven percent of parents reported participating in
homework activities with their fourth grader, 66% with fifth graders. Sixty-five
percent of parents reported viewing a video with their child in both grades. Ten
percent attended evening point-of-purchase grocery store activities. The low
level of implementation and modest level of participation in family activities
suggest that higher levels of behavior change may have occurred if exposure to
the intervention had been higher.
PMID- 10768799
TI - Methods, results, and lessons learned from process evaluation of the high 5
school-based nutrition intervention.
AB - This article describes the process evaluation of High 5, a school-based
intervention targeting fruit and vegetable consumption among fourth graders and
their families. The outcome evaluation involved 28 schools randomized to
intervention or control conditions. The intervention included classroom, family,
and cafeteria components. Process evaluation was completed on each of these
components by using observations, self-report checklists, surveys, and other
measures. Results indicated high implementation rates on the classroom
activities. Moderate family involvement was attained, perhaps diminishing
intervention effects on parent consumption. Cafeterias provided environmental
cues, and fruit and vegetable offerings as directed by the program. A lower dose
of the intervention was delivered to schools with larger African American
enrollments and lower-income families. This article provides insights into the
effective elements of a school-based dietary intervention and provides
suggestions for process evaluation in similar studies.
PMID- 10768800
TI - 5-a-day Power Plus: process evaluation of a multicomponent elementary school
program to increase fruit and vegetable consumption.
AB - The 5-a-Day Power Plus program targeted multiethnic fourth- and fifth-grade
students in 10 intervention and 10 control urban elementary schools in St. Paul,
Minnesota, to increase fruit and vegetable consumption. The intervention included
behavioral curricula in classrooms, parental involvement, school food service
changes, and food industry support. Process evaluation was conducted by using
surveys and classroom and lunchroom observations to assess the characteristics of
teachers and food service staff, the degree the intervention was implemented as
intended, and exteral factors that may have affected the program results. Results
showed high levels of participation, dose, and fidelity for all of the
intervention components, with the exception of parental involvement. The process
evaluation findings help explain why the increase in fruit and vegetable
consumption occurred mostly at school lunch and not at home. Future intervention
research should focus on creating new and potent strategies for parental
involvement and for increasing the appeal and availability of vegetables.
PMID- 10768801
TI - Process of conducting a 5-a-day intervention with high school students: Gimme 5
(Louisiana).
AB - Gimme 5: A Fresh Nutrition Concept for Students (Gimme 5) was a 4-year
intervention targeting increased fruit and vegetable consumption by high school
students. Twelve schools were randomized to intervention or control conditions.
The cohort (2,213 students; 56% female, 84% Euro-American) were followed from 9th
to 12th grade. Interventions were composed of a school-based media campaign,
classroom workshops, school meal modification, and parental involvement. For each
of the four Gimme 5 intervention components, process evaluation measures were
developed to assess program dose, penetration, and utilization, as well as
external competing factors. Process evaluation results are presented to
illustrate the various functions of process evaluation data. These include, but
are not limited to, describing program implementation, quality control and
monitoring, and explaining study outcomes. The implementation of process
evaluation systems to complement the outcome measures in a high school-based
intervention provides useful strategies for a more comprehensive approach to
program evaluation.
PMID- 10768802
TI - Seattle 5-a-Day Work-Site Project: process evaluation.
AB - The Seattle 5-a-Day Work-Site Project developed a community-based intervention to
increase fruit and vegetable intake, using both environmental (including
cafeteria and work-site-wide events) and individual strategies. The Employee
Advisory Board developed its own protocol from a common skeleton and a minimum
set of activities. Small work sites and work sites with fewer female employees
delivered more displays, posters, and table tents per employee (p < .01 and p <
.05, respectively). Dose was neither related to use of the intervention nor to
change in fruit and vegetable intake. Use of informational materials increased
fruit and vegetable intake in the cohort of employees with both baseline and
follow-up data (p = .05). The intervention was associated both with increased
employee use of the intervention (activities and materials) and with increased
intake of fruit and vegetables. Work sites with medium average baseline intake
were the most responsive. These findings can guide the development of more
efficient community-based dietary interventions.
PMID- 10768803
TI - Results of employee involvement in planning and implementing the Treatwell 5-a
Day work-site study.
AB - When work-site health promotion programs incorporate theories of community
organization, it is likely that employee ownership and participation are
enhanced. This article reports quantitative indicators of involvement of Employee
Advisory Board (EAB) members in the Treatwell 5-a-Day work-site study and
examines relationships between EAB member time spent on project activities and
work-site size, with indicators of the extent of implementation and variables
associated with behavior change and work-site support. The results reported here
indicate that a greater number of EAB member hours spent on program activities
was associated with a greater number of events implemented. Smaller work-site
size was associated with greater employee awareness of the program and greater
participation in project activities as reported on the employee survey. These
results suggest that the number of hours employee representatives devote to
project activities might be an important consideration in planning employee
involvement in work-site health promotion programming.
PMID- 10768804
TI - Implementing a 5-a-day peer health educator program for public sector labor and
trades employees.
AB - Peer education in the Arizona 5-a-Day project achieved lasting improvements in
fruit and vegetable intake among multicultural employees. Measures monitored
implementation of peer education from peer educators' logs, the program's reach
from employee surveys, and employees' use in terms of employees' dietary change.
Peer educators logged 9,182 coworker contacts. Contacts averaged 10.9 minutes,
according to coworkers. Coworkers read an average of 4.7 booklets and 2.23
newsletters. Many employees talked with peer educators (59%) and read materials
(54%) after the program finished. Employee reports of peer educator contact were
positively associated with fruit and vegetable intake. Peereducation was
implemented as intended and reached many coworkers. It continued after program
completion, reached into coworkers' families, and was used by employees to
improve intake. This method can be used with employees who rely on informal
sources and whose work presents barriers to wellness activities.
PMID- 10768805
TI - The North Carolina Black Churches United for Better Health Project: intervention
and process evaluation.
AB - The North Carolina Black Churches United for Better Health project was a 4-year
intervention trial that successfully increased fruit and vegetable (F&V)
consumption among rural African American adults, for cancer and chronic disease
prevention. The multicomponent intervention was based on an ecological model of
change. A process evaluation that included participant surveys, church reports,
and qualitative interviews was conducted to assess exposure to, and relative
impact of, interventions. Participants were 1,198 members of 24 intervention
churches who responded to the 2-year follow-up survey. In addition, reports and
interviews were obtained from 23 and 22 churches, respectively. Serving more F&V
at church functions was the most frequently reported activity and had the highest
perceived impact, followed by the personalized tailored bulletins, pastor
sermons, and printed materials. Women, older individuals, and members of smaller
churches reported higher impact of certain activities. Exposure to interventions
was associated with greater F&V intake. A major limitation was reliance on church
volunteers to collect process data.
PMID- 10768806
TI - Uses of process evaluation in the Maryland WIC 5-a-day promotion program.
AB - Using a crossover design, the authors conducted a 6-month intervention program
aimed at increasing fruit and vegetable consumption among women served by the
Women, Infants, and Children program in Baltimore City and six Maryland counties.
The theoretical framework for the interventions was the Transtheoretical Model of
Change. At 2 months postintervention, mean daily consumption had increased
significantly more in intervention participants than in control participants.
Extensive process evaluation data were collected to assess the quantity and
quality of program services delivered. These included participant nutrition
session evaluation forms and attendance logs, focus groups of attenders and
nonattenders of sessions, information about peer educators, and postintervention
surveys. Many lessons were learned about program delivery, factors affecting
attendance, and the obstacles to dietary change. Strategies to increase
participants' consumption of fruits and vegetables were modified based on these
lessons and the process evaluations.
PMID- 10768807
TI - Transendothelial migration of monocytes in rat aorta: distribution of F-actin,
alpha-catnin, LFA-1, and PECAM-1.
AB - To determine changes in the distribution of cell adhesion molecules during
diapedesis of monocytes in situ, we labeled aortic whole mounts from
hypercholesterolemic rats with Texas red-phalloidin and antibodies to LFA-1,
PECAM-1, or alpha-catenin, and analyzed them by laser scanning confocal
microscopy. Monocytes transmigrated through circular openings (transmigration
passages) formed by pseudopodia that penetrated between adjacent endothelial
cells. Transmigrating monocytes remained spherical above the endothelium, while
spreading beneath it. The transmigration passage was lined by F-actin and
partially by alpha-catenin, suggesting cadherin-mediated heterotypic
interactions. LFA-1 was present in clusters at the monocyte cell surface
throughout diapedesis, but was concentrated at the margin of the transmigration
passage. PECAM-1 was enriched in the endothelial contact regions where the
monocytes transmigrated. PECAM-1 was barely detectable in monocytes before and
after diapedesis, but appeared during diapedesis at the cell surface in the parts
of the monocyte located above the endothelium. PECAM-1 was enriched near the
endothelial cell-cell junctions, but was not detected in parts that spread
beneath the endothelium. Our results suggest a major role for LFA-1 during
diapedesis and reveal dynamic changes in the distribution of PECAM-1, the actin
cytoskeleton, and alpha-catenin during monocyte diapedesis in situ.
PMID- 10768808
TI - Fluorescence tracing of intracellular proteins.
AB - Developments in fluorescence microscopy and the availability of fluorescently
labeled antibodies and probes for localization of molecules and organelles have
made the microscope an indispensable tool with which one can map specific
molecules to subcellular loci allowing deep insight into cell and organelle
biology. Furthermore, confocal microscopy permits analysis of the three
dimensional architecture of cells that could not be accomplished by conventional
light microscopy. The goal of fluorescence protein tracing by microscopy is to
visualize cellular constituents and general cytoarchitecture as close to native
organization as possible. To achieve this, and to preserve cellular structure in
the best possible manner, the specimen is usually fixed chemically. Here I review
several standard fixation, permeabilization and labeling schemes followed by
examples of several standard imaging techniques.
PMID- 10768810
TI - Pneumococcal vaccine for infants, toddlers licensed.
PMID- 10768809
TI - Stains for the differential diagnosis of degenerative dementias.
AB - Our understanding of the structural substrates underlying the dementia syndrome
has been transformed by the introduction of the Gallyas silver stain and the
application of immunostains for tau, ubiquitin, and alpha-synuclein.
Visualization of sequential changes in Alzheimer's disease and the recognition of
a new substrate for dementia and dementia with argyrophilic grains, are two of
the advances related to the application of the Gallyas method. The specificity of
alpha-synuclein for recognizing Lewy bodies enables the unequivocal diagnosis of
dementia with Lewy bodies. The diverse entities that constitute the Pick complex
can be identified by applying immunostains for tau and ubiquitin in addition to
the Gallyas silver stain.
PMID- 10768811
TI - Interaction between indinavir and St. John's wort reported.
PMID- 10768812
TI - Federal actions for error reduction outlined.
PMID- 10768813
TI - JCAHO selects core performance measures. Joint Commission on Accreditation of
Healthcare Organizations.
PMID- 10768814
TI - Breast-cancer risk: higher with estrogen-progestin than estrogen alone.
PMID- 10768815
TI - Medicare should extend coverage of nutrition therapy, other services, report
says.
PMID- 10768816
TI - State efforts to ensure hospital quality highlighted.
PMID- 10768817
TI - Medicaid cites persistent problems with pharmacy claims.
PMID- 10768818
TI - Internet pharmacies.
PMID- 10768819
TI - Pathophysiology and treatment of psoriasis.
AB - The pathogenesis and treatment of psoriasis are reviewed. Psoriasis is
characterized by defects in the normal cycle of epidermal development that lead
to epidermal hyperproliferation, altered maturation of skin cells, and vascular
changes and inflammation. The condition typically manifests as areas of
thickened, flaky, silvery white and reddened skin that may hurt, itch, and bleed.
Biochemical markers of psoriasis are changes in levels of keratins, keratinocyte
transglutamase, migration inhibitory factor-related protein, skin-derived
antileukoproteinase, involucrin, small protein rich protein 2, filaggrin, and
cytokines. Types of psoriasis that may be clinically encountered include plaque
psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis.
Psoriasis is believed to be genetically linked but can also be triggered by
mechanical, ultraviolet, and chemical injury; various infections; prescription
drug use; psychological stress; smoking; and other factors. Topical treatment of
psoriasis is usually the first line of therapy. Topical treatments consist of
emollients and keratolytic agents, anthralin, coal tar, corticosteroids, vitamin
D3 analogues, topical retinoids, and topical psoralens plus ultraviolet A (UVA)
light. In patients who do not respond adequately to topical therapy, oral or
injectable therapy, such as oral retinoids, methotrexate, cyclosporine,
tacrolimus, and oral psoralens plus UVA light, may be warranted. Patients
receiving systemic treatments should be carefully monitored for adverse effects
and drug-drug interactions. Drug therapy is the mainstay of the treatment of
psoriasis. The potential adverse effects and interactions necessitate vigilant
monitoring.
PMID- 10768820
TI - Pharmacotherapy of acute sinusitis in children.
AB - The pharmacotherapeutic options for acute sinusitis in children are reviewed.
Acute sinusitis occurs more frequently in children than in adults. The diagnosis
is based primarily on clinical signs and symptoms. Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis are the organisms most
frequently implicated. A variety of antimicrobials have FDA-approved labeling for
use in the treatment of sinusitis. In randomized, controlled clinical trials
identified in a MEDLINE search for the period from 1966 to 1999, amoxicillin had
efficacy similar to that of amoxicillin-clavulanate, azithromycin, cefuroxime,
and clarithromycin in treating acute sinusitis in children. Azithromycin was
effective as a three-day course of treatment. Amoxicillin and cefuroxime are
better tolerated than most antibiotics; azithromycin and clarithromycin are also
well tolerated. Amoxicillin-clavulanate tends to cause more gastrointestinal
symptoms than amoxicillin and is more expensive. Azithromycin is more expensive
than amoxicillin but less expensive than other broad-spectrum antimicrobials.
Amoxicillin remains the drug of first choice for treating acute sinusitis in
children. It has been found to be as effective as other broad-spectrum agents,
better tolerated, and less expensive.
PMID- 10768821
TI - Pharmacy database for tracking drug costs and utilization.
AB - A pharmacy database for tracking drug costs and physician prescribing trends is
described. Accuracy problems plagued data systems used to make drug-use-policy
decisions at a tertiary care teaching hospital because of structural deficiencies
within the systems and their nonclinical orientation. To resolve these problems,
a programmer analyst, a clinical supervisor, and a clinical pharmacist developed
a hierarchical database of drug costs. The database was designed to be valid for
tracking drug costs according to patterns of clinical use. Internal controls were
created that could identify and correct cost-tabulation errors arising within the
ordering, order-entry, and billing processes. The database was able to tabulate
drug costs according to the clinical service on which the patient was being
treated at the time so that reports could compare aggregate prescribing trends
from one time period to another for the same service. Similarly, the database
could track and report drug use by disease or financial classification. Flagging
elements were introduced to the database for cancer chemotherapy and
antimicrobial drug products to enable reporting by these categories and by
therapeutic subcategories within the antimicrobial category. Routine monthly
reports were distributed to end users. Development of a database for tracking
drug costs and utilization allowed a teaching hospital to derive the cost of
medications from billing-charge information and to report data to health care
professionals on the basis of important factors like clinical services.
PMID- 10768822
TI - Hospital pharmacy service provision in Australia--1998.
AB - The results of a 1998 national survey of pharmaceutical services in hospitals
throughout Australia are reported. A self-administered questionnaire was sent to
all directors of hospital pharmacy services and senior hospital pharmacy managers
to determine the extent of clinical and nonclinical pharmacy services provided by
hospitals in Australia. Respondents chose the services their departments provide
from a list of 26 commonly provided services. The response rate was 58.5%.
Respondents were fairly evenly divided between teaching and nonteaching
hospitals, but most of the respondents were from public (versus nongovernment)
hospitals. The five most commonly provided services were imprest (a wordstock of
frequently used medications that are regularly restocked by the pharmacy
department), informal drug education for hospital staff, review of medication
charts, control of drug purchasing, and inpatient dispensing. Review of
medication charts and provision of drug education for the hospital staff were the
most widely provided clinical pharmacy services. The most common services
available from hospital pharmacies throughout Australia were imprest, informal
drug education for hospital staff, review of medication charts, control of drug
purchasing for the hospital, and inpatient dispensing.
PMID- 10768823
TI - New perspectives on preventing medication errors and adverse drug events.
PMID- 10768824
TI - More on disruptions in dialysis patients' drug therapy.
PMID- 10768825
TI - Spot glucose measurement in epidermal interstitial fluid--an alternative to
capillary blood glucose estimation?
AB - Capillary blood glucose estimation is an essential but inconvenient prerequisite
in the current management of diabetes mellitus. Spot glucose measurement in
epidermal interstitial fluid appears to be a promising alternative to capillary
blood glucose estimation, and due to its near non-invasive properties it might be
a tool for improving the lives of people with diabetes in the near future. The
present status of epidermal interstitial fluid glucose determination, the first
clinical results, and some open questions regarding this new technology are
reviewed here.
PMID- 10768826
TI - Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocortical system
activity and anxiety behaviour.
AB - Natriuretic peptides (ANP, BNP and CNP) comprise a family of structurally related
peptides, which are derived from three different genes and which share a 17-amino
acid internal ring. Besides their peripheral involvement in diuresis and blood
pressure regulation these peptides, their bioactive fragments and their
corresponding receptors (natriuretic peptide receptors NPR-A, NPR-B and NPR-C)
are found throughout the central nervous system (CNS): NPR-A and NPR-C are found
on neurons and astrocytes, while NPR-B is located mainly on neurons and partially
colocalizes with NPR-A. In the CNS of man and rodents NPR-A is found mainly in
cortex and hippocampus, whereas NPR-B is present in the amygdala and several
brainstem regulatory sites. NPR-C is found widely within the CNS i.e. in
neocortex, limbic cortex, the hippocampal area and the amygdala. These peptides
and their receptors represent an important neuromodulatory system within the CNS,
which is involved not only in the regulation of fluid homeostasis but also
directly influences emotional behaviour, such as anxiety and arousal, and the
sequelae of stress hormone release and autonomic nervous system activation.
Natriuretic peptides are specifically involved in the regulation of the
hypothalamo-pituitary-adrenocortical (HPA) system: in man and rodents ANP
inhibits the HPA system at all regulatory levels, while CNP stimulates the
release of cortisol. Complementarily, the anatomic structure of natriuretic
peptide systems within the CNS supports an important role for these in normal and
pathologic emotional behaviour (e.g. anxiety and panic): in rodents ANP was found
to reduce anxiety levels, whereas CNP induced the opposite effect. In patients
with panic disorder basal ANP plasma levels are lower in comparison to healthy
volunteers, but ANP secretion is faster and more pronounced during experimentally
induced panic attacks. The inhibitory potency of ANP could explain the unexpected
and so far unresolved failure of autonomic and HPA system activation during panic
attacks. Moreover, panic anxiety and concomitant ACTH and cortisol secretion
elicited by stimulation with the panicogen cholecystokinin-tetrapeptide were also
attenuated by ANP infusions in patients as well as in healthy volunteers. Hence,
it may be surmised that in man and rodents ANP reduces anxiety and terminates
panic attacks and their neuroendocrine sequelae.
PMID- 10768827
TI - Influence of streptozotocin-induced diabetes and insulin treatment on the
pituitary-testicular axis during sexual maturation in rats.
AB - Effects of streptozotocin (STZ)-diabetes and insulin treatment on the functioning
of pituitary-testicular axis during sexual maturation was studied. Prepubertal
(30 days old) and pubertal (50 days old) male Wistar rats were made diabetic by a
single injection of STZ. A group of diabetic rats was given insulin (3U/100 g
b.wt./day in 2 equally divided doses), 3 days after STZ treatment. Prepubertal
and pubertal rats of all groups were killed on postnatal days 51 and 71,
respectively. STZ-diabetes caused marked reduction in serum LH, FSH, prolactin,
testosterone and testicular interstitial fluid testosterone as well as the
activities of Leydig cellular steroidogenic enzymes (3beta-and 17beta
hydroxysteroid dehydrogenases). Insulin treatment to diabetic rats maintained
these changes at control range except FSH and prolactin in prepubertal rats. The
results indicate that (i) diabetes-induced steroidogenic lesions in Leydig cells
represent a direct consequence of dysfunctioning of pituitary-testicular axis,
(ii) the adverse effects of diabetes on pituitary-testicular functions are
influenced by age of its induction and (iii) optimum insulin level is essential
for the acquisition of Leydig cellular steroidogenic efficacy during sexual
development.
PMID- 10768828
TI - Insulin action in primary hyperaldosteronism before and after surgical or
pharmacological treatment.
AB - The relationship between arterial hypertension and insulin resistance has long
been established. We used primary hyperaldosteronism as a model of the
relationship between secondary hypertension and insulin sensitivity. Our group
consisted of 9 patients with arterial hypertension caused by primary
hyperaldosteronism. Five of these patients with aldosterone producing adenoma
were operated on and four patients with idiopathic hyperaldosteronism were
treated with spironolactone. Hyperinsulinaemic euglycaemic clamp technique was
performed before and at least 6 months following the treatment to evaluate the
insulin action. Significantly lower glucose disposal rate (M), insulin
sensitivity index (M/I) and decreased metabolic clearance rate of glucose
(MCR(G)) were found in patients before treatment as compared to healthy controls.
In both treated groups the blood pressure and plasma potassium concentrations
returned to normal values, whereas plasma aldosterone levels were normalised only
after surgical removal of the adenoma. Significantly improved insulin action
(M/I: 30.2 +/- 5.9 vs. 51.4 +/-12.2 micromol.kg(-1).min(-1) per mU.l(-1) x 100, p
= 0.017) was observed in patients after operation of aldosterone producing
adenoma. In contrast, spironolactone treatment of patients with idiopathic
hyperaldosteronism did not significantly influence insulin action (M/I: 24.5 +/-
7.3 vs. 18.7 +/- 7.6 micromol.kg(-1).min(-1) per mU.l(-1) x 100, p = 0.198).
Since plasma aldosterone concentrations have been normalised only in patients
after removal of the adenoma whereas they remained increased in spironolactone
treated group, we suppose that aldosterone itself could play a role in the
development of impaired insulin action.
PMID- 10768829
TI - Regulation of subcellular distribution of GLUT4 in cardiomyocytes: Rab4A reduces
basal glucose transport and augments insulin responsiveness.
AB - Members of the Rab subfamily of small-GTP binding proteins have been suggested to
be involved in insulin-regulated translocation of the glucose transporter GLUT4.
To directly study this process in muscle tissue, we have established an insulin
sensitive cardiac cell line (H9K6) stably overexpressing GLUT4, which was derived
from H9c2 cardiac myoblasts. H9K6-cells were transiently transfected with rab4A
and rab3C with an efficiency of 65% and glucose uptake and the cellular
distribution and expression of the transporter isoforms GLUT1 and GLUT4 was
subsequently determined. Rab3C-overexpression caused no significant change in
both basal and insulin-stimulated 2-deoxyglucose uptake compared to control cells
transfected with the blank vector. Rab4A was barely detectable in membranes of
H9K6 cells. However, after transient transfection this protein was expressed at a
level comparable to adult cardiomyocytes. This resulted in a reduction of basal
glucose uptake by 31% compared to control cells. Under these conditions insulin
was able to stimulate 2-deoxyglucose uptake by 120%. Total expression of GLUT1
and GLUT4 was not affected by Rab4-overexpression. Cell surface biotinylation was
used to quantify the abundance of GLUT1 and GLUT4 in the plasma membrane. A
decrease of cell surface GLUT4 by about 40% compared to control cells was found
in Rab4-overexpressing cells Insulin treatment increased cell surface-GLUT4 by
100% compared to only 26% in control cells. Distribution of GLUT1 was not
affected under these conditions. Our data show that Rab4A but not Rab3C is able
to reduce basal glucose uptake and cell surface content of GLUT4 in cardiac
muscle cells. This results in an increased stimulation of glucose uptake by
insulin which can be fully explained by enhanced translocation of GLUT4. We
suggest that Rab4A participates in the redistribution of GLUT4 to intracellular
pools and represents an essential determinant of the insulin responsiveness of
GLUT4 translocation in cardiac muscle cells.
PMID- 10768830
TI - Long-term anticonvulsant therapy leads to low bone mineral density--evidence for
direct drug effects of phenytoin and carbamazepine on human osteoblast-like
cells.
AB - Anticonvulsant therapy causes changes in calcium and bone metabolism and may lead
to decreased bone mass with the risk of osteoporotic fractures. The two widely
used antiepileptic drugs phenytoin and carbamazepine are recognized to have
direct effects on bone cells. The aim of our study was to measure the influence
of long-term treatment with antiepileptic drugs on bone mineral density (BMD) and
to look on direct effects of carbamazepine and phenytoin on human osteoblast-like
cells. BMD was measured by dual-energy X-ray absorptiometry. Markers of bone
formation and bone resorption were determined in serum and urine. Data of 59
patients were compared to 55 age and sex matched controls. Direct effects of
phenytoin and carbamazepine on human osteoblast-like cells were investigated in
experimental studies. BMD in the lumbar spine region (L2 through L4) was
significantly lower in the patient group as compared to controls (p < 0.0004). At
femoral sites BMD was lower in patients, but this difference did not reach
statistical significance. The decrease in BMD at both sites was dependent on the
duration of therapy. Excretion of pyridinoline crosslinks was markedly increased
in the patients. 25-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 were
significantly decreased in patients. Proliferation rate of human osteoblast-like
cells was increased by phenytoin in low doses. Both, phenytoin and carbamazepine
inhibited cell growth at concentrations equivalent to therapeutic doses for the
treatment of epileptic diseases. Our clinical and experimental data indicate that
long-term treatment with anticonvulsant drugs leads to a lower BMD. The
experimentally observed decrease in bone cell proliferation might be clinically
associated with impaired new bone formation. Beside alterations in calcium and
vitamin D homeostasis leading to osteomalazia, direct effects of anticonvulsant
drugs on bone cells may contribute to the damaging effects on the skeletal
system.
PMID- 10768831
TI - Effects of testosterone, FSH, and LH on oestradiol and progesterone secretion by
preovulatory cumulus oophorus complexes of the rat.
AB - Female Wistar rats exhibiting a regular 4-day oestrous cycle were included in
this study. They were killed in succession on the day of pro-oestrus at 11.00,
18.00, and 22.00 h. From ovarian preovulatory follicles cumulus oophorus
complexes (COCs) were isolated and subsequently cultured with or without
testosterone (T), T plus FSH, or T plus LH. In control cultures COCs isolated at
all investigated hours released similar amounts of oestradiol. T stimulated this
basal secretion and the effect was usually enhanced in the presence of FSH or LH.
In control cultures the amount of released progesterone was greatest when
expanded COCs were isolated (22.00 h). T present in culture media diminished the
amount of secreted progesterone. However, when T was added with FSH or LH a
distinct stimulatory effect was observed, except in cultures with T plus FSH set
up at 22.00 h. Previously, gonadotrophins alone did not effect progesterone
secretion. The results suggest that T can regulate steroid, and especially
progesterone secretion by COCs. Until the preovulatory gonadotrophin surge T can
inhibit luteinization of COCs, while afterwards, acting synergestically with
gonadotrphins (especially with LH), T can stimulate progesterone production in
the cumulus granulosa cells.
PMID- 10768832
TI - Absence of H- and K-ras oncogene mutations in sporadic medullary thyroid
carcinoma.
AB - Medullary thyroid carcinoma (MTC) occurs sporadically (sMTC) or as part of the
inherited cancer syndrome, multiple endocrine neoplasia type 2 (MEN 2). While the
occurence of the MEN 2 syndrome is associated with mutations in the RET
protooncogene, the reason for carcinogenesis in sMTC still remains unclear. Ras
is a frequently mutated oncogene in a broad spectrum of human tumors and has been
found in about 50% of follicular, papillary or anaplastic thyroid carcinomas. The
purpose of this study was to determine, whether mutations in the ras oncogene
could play a possible role in the carcinogenesis of sMTC. In this study we
analyzed 15 sMTC for mutations in the hotspots codon 12, 13 and 61 of the H- and
K-ras oncogene. We used the direct sequencing technique. In none of the examined
tumors we were able to detect a mutation in the codon 12, 13 and 61 of the H-ras
and K-ras oncogene. Based upon these results, we conclude that H- and K-ras do
not play an important role in the carcinogenesis of sMTC.
PMID- 10768833
TI - Diabetes insipidus in a patient with a highly malignant B-cell lymphoma and
stomatitis.
AB - A 37-year-old male patient with a diffuse pleomorphic B-cell-lymphoma, which has
been diagnosed two month earlier with the primary site at the pterygopalatine
fossa on both sides with infiltration of the clivus and cavernous sinus was
referred to our hospital for continuation of the third course of CHOP
chemotherapy. At admission he reported about a recent history of painful
swallowing and intermittent substernal chest pain. Alleviation of the pain on
swallowing and the chest pain was apparently only possible by drinking 10 to 15 l
of cold coca cola throughout the day and night, a regimen that resulted in
polyuria. Physical examination revealed extensive thrush stomatitis and soor
esophagitis. Despite successful treatment with fluconazole, polydipsia continued
unabated. The classic osmotic test of dehydration and exogenous vasopressin
revealed hypothalamic diabetes insipidus (DI). Basal hormones and stimulated
endocrine function tests of the adenohypophysis were found to be normal. MRI-scan
revealed lymphoma infiltration of the neurohypophysis. After the third course of
CHOP chemotherapy the patient surprisingly recovered completely from his
excessive thirst. The present report shows that clinical disorders such as thrush
stomatitis can mask diabetes insipidus caused by an early relapsing lymphoma.
PMID- 10768834
TI - Decreased expression of corticotropin-releasing factor-binding protein mRNA in
ACTH-secreting pituitary adenomas.
AB - This study was designed to analyze the sequence and the expression of CRF-BP mRNA
in ACTH-secreting pituitary adenomas. Direct sequencing analysis revealed no
apparent mutations in the CRF-BP mRNA. Thus, we conclude that mutations in the
coding region of the CRF-BP gene are not involved in the pathogenesis of
Cushing's disease. However, using a semiquantitative PCR approach coamplifying
the house-keeping gene GAPDH we detected a reduced expression of CRF-BP mRNA in
ACTH-secreting pituitary adenomas when compared with normal pituitaries. We
suggest that the decreased CRF-BP gene expression in ACTH-secreting pituitary
adenomas is most likely an effect due to high cortisol levels in Cushing
patients.
PMID- 10768835
TI - Clinical significance of autoimmune thyroid disease in myasthenia gravis.
AB - We investigated thyroid function and autoimmunity in 74 (61% females) consecutive
patients with MG. 30 of these patients were tested twice: the time between the
investigations ranging from 1 to 4 years. MG was diagnosed on the basis of
typical clinical symptoms, a positive tensilone-test, and/or detectable
acetylcholine antibodies and/or repetetive stimulation tests. Eye involvement was
present in 86%, concurrent thymomas in 56%. The following parameters were
measured in the serum of these patients by commercially available kits: free and
total T4, TSH, TSH-Receptor-Antibodies ("TRAB"), antibodies against thyroglobulin
(Tg-Ab), against thyroid microsomes (M-Ab) and against acetyl-choline-receptors .
An age matched group of 50 patients (54% females) with no known thyroid disease
from a cardiological ward and from the neurological outpatient department served
as control. There was only 1 MG patient with overt thyroid dysfunction (iodine
induced thyrotoxicosis in a patient with autonomous adenoma and no circulating
thyroid autoantibodies detected at the second investigation). There were,
moreover, 1 euthyroid MG-patient on L-thyroxine therapy with a history of
Hashimoto's disease and positive thyroid autoantibodies and 1 other MG-patient
with mildly elevated TSH without elevated thyroid antibodies, who has had
subtotal thyroidectomy without substitution therapy years before for unknown
reasons. Tg-Ab were positive (>360 IU/ml) in 5%, M-Ab were positive (>154 IU/ml)
in 15% of the MG patients. The control group had 4% Tg-Ab and 6% M-Ab. TRAB
levels were normal in all patients and controls. The relative increase in M-Ab
frequency was not statistically significant (x-square test). We conclude from our
results, that autoimmune thyroid disease may be associated with MG but that the
occurrence of thyroid dysfunction induced by autoimmunity is a very rare
phenomenon in MG.
PMID- 10768836
TI - Construction and characterization of a novel recombinant single-chain variable
fragment antibody against Western equine encephalitis virus.
AB - A novel recombinant single-chain fragment variable (scFv) antibody against
Western equine encephalitis virus (WEE) was constructed and characterized. Using
antibody phage display technology, a scFv was generated from the WEE specific
hybridoma, 10B5 E7E2. The scFv was fused to a human heavy chain IgG1 constant
region (CH1-CH3) and contained an intact 6 His tag and enterokinase recognition
site (RS10B5huFc). The RS10B5huFc antibody was expressed in E. coli and purified
by affinity chromatography as a 70-kDa protein. The RS10B5huFc antibody was
functional in binding to WEE antigen in indirect enzyme-linked immunosorbent
assays (ELISAs). Furthermore, the RS10B5huFc antibody was purified in proper
conformation and formed multimers. The addition of the human heavy chain to the
scFv replaced effector functions of the mouse antibody. The Fc domain was capable
of binding to protein G and human complement. The above properties of the
RS10B5huFc antibody make it an excellent candidate for immunodetection and
immunotherapy studies.
PMID- 10768837
TI - Differential expression of murine CD81 highlighted by new anti-mouse CD81
monoclonal antibodies.
AB - We describe the use of a soluble CD81-Fc fusion protein to screen for novel
monoclonal antibody (MAb) reactive with the extracellular loops of murine CD81
(TAPA-1). Two such MAbs, Eat1 and Eat2 (for Extracellular Anti-TAPA1), were used
to assess the expression and function of CD81 on murine lymphocytes. Although
CD81 is expressed uniformly on all human lymphocytes, murine CD81 was found to be
expressed at much higher levels on resting B cells than on resting T cells. This
was particularly evident when staining with the new MAbs, Eat1 and Eat2. The
molecule is also functionally active on B cells, as Eat1 and Eat2 induce
homotypic adhesion of B lymphocytes. Stimulated B cells undergo early apoptotic
events in the presence of Eat2, as shown by binding of Annexin V-fluorescein
isothiocyanate (FITC). Polyclonal activation of murine T cells also induces
higher level CD81 expression, and many immortalized murine T-cell lines express
high levels of the protein. In contrast to human CD81, which is expressed equally
on all thymocytes, murine CD81 is induced during thymic development, being
expressed at high levels on CD4+CD8+ thymocytes, in contrast to other subsets of
thymocytes. Finally, murine dendritic cells, splenic macrophages, and non-killer
(NK) cells all express high levels of CD81. We conclude that CD81 is
differentially expressed in the murine immune system, and is involved in
regulating the adhesion and activation of murine B cells.
PMID- 10768838
TI - Selection of an immunogenic and protective epitope of the PsaA protein of
Streptococcus pneumoniae using a phage display library.
AB - Streptococcus pneumoniae is an important pathogen that causes disease in young
and elderly individuals. The currently available polysaccharide vaccines have
limited efficacy in those age groups most susceptible to pneumococcal infections.
This study focuses on mapping the epitopes of a surface protein of S. pneumoniae
by biopanning a 15 mer phage display library using 5 different monoclonal
antibodies (MAbs) against the Pneumoccal surface adhesin A (PsaA). PsaA is a
component of the bacterial cell wall that is highly species specific and is
involved in bacterial adherence and virulence. Biopanning of the phage display
library reveals three distinct epitopes on the PsaA protein. The sequence
homology of these epitopes ranges from two to six amino acids when compared to
the native PsaA protein type 2. Two of these epitopes have been evaluated for
their immunogeneicity in mice. The peptide selected by the MAbs 8G12, 6F6, and
1B7 is referred to as the consensus peptide and is immunogenic in mice. Optimal
anti-PsaA response is observed in mice immunized with 50microg of the consensus
peptide complexed to proteosomes in 1:1 ratio. The anti-PsaA response is
significantly lower than the response to the PsaA native protein. The peptide
selected by monoclonal antibody 4E9 in its lipidated form is significantly
protective in mice challenged with S. pneumoniae serotype 2 when compared to mice
immunized with the native protein. These results show that the selected epitopes
of PsaA protein are immunogenic and protective in mice. These epitopes need to be
evaluated further as alternatives to currently available vaccines.
PMID- 10768839
TI - Development and characterization of a bispecific single-chain antibody directed
against T cells and ovarian carcinoma.
AB - Bispecific antibodies with specificity for tumor antigen and CD3 have been shown
to redirect the cytotoxicity of T cells against relevant tumor. Our objective was
to generate single-chain bispecific antibodies (bsSCA) that could retarget mouse
cytotoxic T lymphocytes (CTL) to destroy human ovarian carcinoma in a xenogeneic
setting. A bsSCA, 2C11 x B43.13, was constructed by genetic engineering and
expressed in mammalian cells. Molecular characteristics, binding properties, and
ability to retarget CTL were studied. Western blot analysis showed that the
product is a 65-kDa protein. Purification of antibodies could be done by single
step affinity chromatography using protein L-agarose with an unoptimized yield of
200 microg/L. BsSCA 2C11 x B43.13 was capable of binding to mouse CD3 and human
CA125 as detected by FACS analysis of EL4 and OVCAR Nu3H2 cells, respectively. It
could also bridge activated splenic T cells and human ovarian carcinoma as
demonstrated by a bridge FACS assay. Redirected mouse CTL could mediate human
target cell lysis in a 20-h 51Cr release assay despite that they are xenogeneic.
Prolonged incubation of redirected CTL and tumor targets resulted in a dramatic
reduction in tumor cell number. CD28 co-stimulation enhanced redirected CTL
function in both types of assays. BsSCA 2C11 x B43.13 thus can be used as a
preclinical immunotherapeutic model for human ovarian cancer in a xenogeneic
setting.
PMID- 10768840
TI - Characterization of the CD30L binding domain on the human CD30 molecule using
anti-CD30 antibodies.
AB - CD30 and its counter-receptor CD30 ligand (CD30L) are members of the TNF
receptor/TNFalpha superfamily and function to regulate lymphocyte survival and
differentiation. Several monoclonal antibodies (MAbs) have been developed against
CD30 and, based on mutual inhibition assays, are grouped into three
nonoverlapping serologic clusters. However, the relationship between the epitopes
recognized by the antibodies comprising each cluster and the binding domain for
CD30L is not known. Using a soluble CD30L/CD8alpha chimeric protein, we assessed
the ability of anti-CD30 MAb to inhibit the binding of CD30L to CD30 expressed by
the CD30+ Karpas 299 cell line. CD30L binding by CD30 is blocked by MAb that
recognize epitopes belonging to cluster Group A (like Ber-H2, Ber-H8, and HRS-4)
as well as cluster Group C (like HeFi-1 and M44). Cluster Group B antibodies,
including M67 and Ki-1, do not affect CD30L binding to CD30. The pattern of CD30L
binding inhibition shows only limited correspondence to the functional capacity
of some anti-CD30 MAb to trigger CD30 signaling. Finally, we demonstrate that the
anti-CD30L MAb M81 also completely inhibits CD30/CD30L interaction. This
information is useful for applying these MAbs in functional studies to further
investigate the CD30/CD30L system and for designing assays for soluble CD30L.
PMID- 10768841
TI - Generation and characterization of a monoclonal antibody that recognizes an
activation antigen expressed by a majority of adherent lymphokine-activated
killer cells.
AB - In an attempt to generate murine natural killer (NK) cell-specific monoclonal
antibodies (MAbs) by immunizing Balb/c mice with C57BL/6 (B6) A-LAKs, we have
isolated a hybridoma, CS/NicT.2, which secretes an IgM that recognizes a majority
of B6 and B6 Rag-1-/- A-LAKs. The CS/NicT.2 antigen is highly expressed by A
LAKs, but only at extremely low levels on resting splenocytes, suggesting that
its expression is tightly associated with IL-2 activation. Among the cell lines
examined, only CTLL-2 expresses the CS/NicT.2 antigen at relatively high levels.
A low level of CS/NicT.2 staining is also detected on resting allo-specific
cytotoxic T lymphocytes (CTL) clones, AB.1 and C11. In addition, a similar low
level of CS/NicT.2 staining is detected on the T-helper cell line HT-2. The
CS/NicT.2 antigen is upregulated by ionomycin but not by phorbol 12-myristate 13
acetate (PMA). For the CTL clones examined, CS/NicT.2 staining is also
dramatically increased by anti-TCRbeta or anti-CD3epsilon stimulation. Protease
treatments of CTLL-2 show that this antigen is proteinase K sensitive, but
relatively resistant to trypsin digestion. Furthermore, the CS/NicT.2 antigen
exhibits a relatively fast turnover rate as assessed by proteinase K and
cycloheximide treatments of CTLL-2, suggesting that the CS/NicT.2 antigen may
have a short half-life on the cell surface.
PMID- 10768842
TI - Monoclonal antibody probes for p21WAF1/CIP1 and the INK4 family of cyclin
dependent kinase inhibitors.
AB - Inhibition of cyclin dependent kinases (cdk) by proteins of two families of cdk
inhibitors (CKIs) represents one of the key modes of cell-cycle control. Although
not fully understood at present, the functions of the individual members of the
Cip/Kip and INK4 families of CKIs have been implicated in fundamental biological
processes as diverse as cellular proliferation, responses to genotoxic stress,
regulation of cellular differentiation, and senescence. In addition, the seven
currently known CKIs qualify as either established or candidate tumor suppressors
whose loss or inactivation contribute to molecular pathogenesis of a wide range
of tumor types. In this study, we report the isolation and characterization of a
panel of 10 mouse monoclonal antibodies (MAbs) that specifically recognize
p21WAF1/CIP1 (p21) or the individual members of the INK4 family of CKIs: p15INK4b
(p15), p16INK4a (p16), p18INK4c (p18), or p19INK4d (p19). These antibodies are
proving to be invaluable molecular probes for analyses of protein abundance,
subcellular localization, interacting cellular proteins, and ultimately the
function(s) of these cell cycle regulators. Epitopes targeted by the antibodies
were mapped by peptide enzyme-linked immunoadsorbent assay (ELISA), and
performance of the MAbs assessed in a range of immunochemical techniques.
Individual MAbs of our series recognize distinct pools of the respective CKIs, a
feature reflected by their differential applicability in immunoblotting,
immunoprecipitation, and immunostaining including immunohistochemistry on
archival paraffin-embedded tissue sections. Together, these antibodies represent
useful reagents to study CKIs in cells and tissues, a set of tools that should
help elucidate the physiological roles played by the individual CKIs, and better
understand the molecular mechanisms of loss or inactivation of these (candidate)
tumor suppressors in human malignancies.
PMID- 10768843
TI - Characterization and gene cloning of monoclonal antibody specific for the
hepatitis B virus X protein.
AB - The hepatis B virus X protein (HBx) has been thought to be implicated in the
development of hepatocellular carcinoma. Although many functions of HBx have been
reported, it is not clear which of HBx functions is important in hepatocellular
carcinogenesis. To study HBx function, we produced a monoclonal anti-HBx Ab
secreted by hybridoma cell clone H7 and mapped its epitope to a region of HBx
between amino acids 29 and 48 by Western blot with truncated forms of HBx and by
enzyme-linked immunoadsorbent assay (ELISA) with synthetic HBx peptides. The
variable regions of H7 anti-HBx Ab were cloned by polymerase chain reaction using
the degenerate-primers and by the 5' rapid amplification-cDNA end method. The
sequence analyses revealed that the variable gene segments of the heavy and light
chains are the members of mouse heavy chain variable gene 1 family and kappa
light chain variable gene 2 family, respectively. In addition, J(H)2 or Jkappa4
gene segment at the end of the heavy-chain or light-chain variable region and
DSP2.x gene segment in the CDR 3 of heavy chain were identified.
PMID- 10768844
TI - Generation of sheep X (sheep X mouse) heterohybridoma cell line expressing the
beta-1 integrin membrane molecule.
AB - Sheep are an important biological model in such diverse areas as immunology and
reproductive biology. The limitation of sheep as an experimental model is the
absence of reliable cell lines. To establish cell lines that express functional
sheep membrane molecules, we produced a sheep x mouse heterohybridoma by fusion
of sheep efferent lymph T cells with the murine myeloma cell line NS1. A cloned
heterohybridoma fusion partner was selected by treatment with 8-azaguanine. The
resulting cell line HL1/385 was selected for hypoxanthine/aminopterin/thymidine
(HAT) sensitivity and growth efficiency. The HL1/385 cell line was used as a back
fusion partner into lectin-stimulated efferent T lymphocytes. The back-fusion
approach produced more than 50 heterohybrid cell lines with high growth
efficiency. The expression of physiological levels of the sheep beta-1 integrin
cell surface molecule on the HT4/6 cell line was stable for months in culture.
These results suggest that somatic heterohybrids may provide a reliable source of
cell lines for sheep studies in vitro.
PMID- 10768845
TI - Monoclonal antibodies against the major coat protein of filamentous phage as a
useful analytical tool for bacteriophage peptide/protein display.
AB - Four mouse monoclonal antibodies (MAbs) that react with filamentous M13KO7 and
R408 phage were obtained. Three of these MAbs (two IgG2a and one IgG3) recognize
linear sequences of the p8 main structural coat protein, and one (IgG2a)
identifies a putatively conformational epitope, as suggested by Western blot.
These MAbs also react with recombinant phage expressing peptide antigens fused to
p8, and are though useful reagents for peptide/protein phage display screening
based methods. The latter was shown in an enzyme-linked immunoadsorbent assay
(ELISA) and a visual immunoassay where one of the anti-p8 MAbs was used to
capture recombinant phages displaying a peptide characteristic of the Hepatitis B
virus surface antigen or a Dengue virus-related peptide antigen.
PMID- 10768846
TI - Preparation and cDNA sequence analysis of two novel monoclonal antibodies against
magaininII.
AB - By using intrasplenic immunization and the conventional B lymphocyte hybridoma
technique, we have established two novel hybridoma cell lines stably secreting
specific monoclonal antibodies (MAbs) to magaininII, termed as 2D1 and 3F8,
respectively. The two cell lines were then subjected to RNA extraction and the VH
and VL segments were obtained by reverse transcription of RNA followed by
polymerase chain reaction (RT-PCR) and characterized by nucleotide sequence
analysis. The VH segments of 2D1 and 3F8 belong to the VH5 family and the VL
segments of 2D1 and 3F8 belong to VK10 and VK1 groups, respectively. The two MAbs
utilize different VL segments and have disparities in their HCDR3 regions, which
may contribute to the different epitope recognition of the two antibodies.
PMID- 10768847
TI - Apoptosis in the gastric mucosa: molecular mechanisms, basic and clinical
implications.
AB - Apoptosis a programmed cell death, is an essential mechanism of eliminating
damaged or aged cells and thus to maintain tissue integrity. There are two
central pathways that lead to apoptosis: a) the positive induction by ligands
(death factors) binding to plasma membrane receptors (death factor receptors) and
b) negative induction by the loss of suppressor activity. The common execution
mechanisms of apoptosis consist of the activation of cytosolic aspartate-specific
proteases (ICE-proteases) termed caspases, which can be activated via various
intracellular pathways. In the stomach, mucosal surface epithelial cells are
constantly exfoliating to the gastric lumen and completely replaced within 3-5
days under physiological conditions. Apoptosis has been reported to take place in
all regions of the stomach with apoptotic cells occurring predominantly in the
superficial parts of the gastric glands, at a rate of 2-3% for all cells.
Following mucosal injury (e.g. ulcer development), apoptosis rapidly increases
and remains elevated for 2-3 months. In a 3-month old ulcer scar, the apoptosis
rate of mucous, parietal, chief and endocrine cells was found to be similar to
that of normal gastric mucosa. Helicobacter pylori (H. pylori) infection induces
apoptosis in the gastric mucosa and this action appears to be independent of VacA
cytotoxin of H. pylori strains. Nonsteroidal anti-inflammatory drugs (NSAIDs),
especially cyclooxygenase-2 (COX-2) inhibitors are potent inductors of gastric
epithelial cell apoptosis. However, they can abrogate apoptosis or proliferation
effects induced by H. pylori. Many details of the exact intracellular and
molecular mechanisms regulating apoptosis in gastric mucosa remain to be
elucidated.
PMID- 10768848
TI - Mechanisms underlying the regulation of motor unit contraction in the skeletal
muscle.
AB - The control of movements is made posible thanks to the activity of motor units in
skeletal muscles. In the present paper the influence of frequency and pattern of
motoneuronal firing on the tension of contraction and the tension-time area is
presented and discussed. The most resistant to fatigue slow-twitch motor units
are low susceptible to changes in a pattern of impulses and therefore they are
well prepared to participate in long-lasting movements at low but rather stable
levels of tension. Moreover, their contraction is very effective and it is
performed at a low metabolic charge. Fast-twitch units have lower resistance to
fatigue and they have higher tension but they have high susceptibility to a
pattern of pulses and their tension can be effectively regulated by an increase
or a decrease in the interpulse interval. Therefore, fast motor units are
specialized to participate in the regulation of the movement force. The existence
of different functional groups of motor units in skeletal muscles enables the
performance of different motor tasks very effectively and at possibly low
metabolic costs.
PMID- 10768849
TI - The adrenal renal vascular connection plays an essential role in the pathogenesis
of renovascular hypertension in the rat.
AB - The adrenal renal portal circulation (ARPC) contributes to decrease in renal
blood flow occurring after renal artery clipping. The aim of present study was to
determine the role of the ARPC in the development of the renovascular
hypertension in 1-kidney 1-clip model in the rat. Experiments were performed on
male Wistar rats. In the control group (A) the right nephrectomy and
adrenalectomy were done. In the experimental groups renovascular hypertension was
produced by clipping the left renal artery (silver clip ID 0.40 mm). In the first
of the experimental groups (B) the right nephrectomy and adrenalectomy were done.
In the second experimental group (C), for elimination of the ARPC, the right
kidney and the left adrenal gland were removed. In the half number of rats from
each group plasma renin activity was measured 48 hours after surgery. An increase
in SBP was significantly higher in the group B (ARPC intact) than in the group C
(ARPC eliminated) (172 +/- 4 vs 144 +/- 2 mmHg, p.<0.01). PRA was significantly
higher in the group C than in the group B (39.0 +/- 1.4 vs 31.2 +/- 2.0
mmol/l/min, p.<0.05). In the control group (A) PRA was significantly lower as
compared to the both experimental group (2.0 +/- 1.6 mmol/l/min, p.<0.05).
PMID- 10768850
TI - Influence of acute cerebellar lesions on somatosensory evoked potentials (SEPs)
in cats.
AB - We studied the effect of acute unilateral cerebellar lesions on the cerebello
thalamo-cortical projection in cats. The lesions were classified into two groups
according to their extent. In group I the lesion only covered the cerebellar
cortex, while in group II both the cerebellar cortex and deep cerebellar nuclei
were removed. Early (short-latency) and late (long-latency) waves, evoked by an
electrical stimulation of a forelimb, were collected contralateral to the
stimulated leg hemisphere. Pre- and postsurgery recordings from primary and non
primary (motor and parietal) cortices were compared. Cerebellar impairment had a
strong influence on discharges of all the considered cortical areas. Early non
primary and primary responses increased in group I and remained unchanged in
group II. Late somatosensory evoked potentials components were suppressed in both
groups. An inhibitory influence of the cerebellar cortex on the thalamo-cortical
projection was confirmed. Changes within the primary sensory cortex may suggest
an engagement of that area in the compensation process of cerebellar dysfunction
shortly after cerebellar lesion. An alteration in the unaffected hemisphere
activation indicate that the spino-cerebellar and cerebello-cortical inputs,
responsible for somatosensory evoked potentials generation, are regulated through
contralateral and ipsilateral pathways. These pathways are unmasked by cerebellar
lesion.
PMID- 10768851
TI - Expression of endothelin-1, and endothelin A and B receptors in portal
hypertensive esophagus of rats.
AB - Nitric oxide synthase is overexpressed in the portal hypertensive (PHT)
esophagus, suggesting that expression of other vasoactive mediatora could also be
affected. Therefore, in the present study we determined the expression of
endothelin-1 (ET-1) and endothelin receptors, which could contribute to the
regulation of the vascular tone in PHT esophagus. In esophageal specimens of PHT
and sham operated rats, expression of ET-1 and its receptors A and B (ET(A)R and
ET(B)R) mRNAs was studied by reverse transcription-polymerase chain reactions. ET
1 protein expression was assessed by immunostaining and enzyme immunoassay. In
PHT esophagus, expression of ET-1, ET(A)R and ET(B)R mRNAs was significantly
increased by 2.2-, 2.5- and 1.5-fold, respectively, compared with sham operated.
The ET-1 protein was significantly increased by 2.2-fold vs. controls as measured
by enzyme immunoassay. ET-1 protein was predominantly localized to endothelia of
submucosal veins. Thus, portal hypertension induces over-expression of ET-1 in
endothelia of esophageal submucosal vessels. Since ET-1 and its receptors could
promote vascular proliferation and induce mucosal damage, the overexpressed ET-1
may play an important role in the development and rupture of esophageal varices
in portal hypertension.
PMID- 10768852
TI - Role of interleukin-4 in down-regulation of endothelin-1 during gastric ulcer
healing: effect of sucralfate.
AB - BACKGROUND: The course of events associaed with healing gastric mucosal injury
involves an orderly interplay between the array of signaling molecules that exert
their influence on the processes leading to the restoration of the mucosal
integrity. In this study, we investigated the effect of antiulcer agent,
sucralfate, on the mucosal apoptotic processes during gastric ulcer healing by
analyzing the expression of interleukin-4 (IL:4), endothelin-1 (ET-1), tumor
necrosis factor-alpha (TNF-alpha), and the mucosal activity of capase-3, and
constitutive (cNOS) and inducible nitric oxide synthase (NOS-2). METHODS: Rats
with experimentally induced chronic gastric ulcers were administered twice daily
for 14 days either sucralfate at 100 mg/kg or vehicle, and at different stages of
treatment their stomachs were used for macroscopic and biochemical assessments.
RESULTS: The ulcer onset was characterized by a massive epithelial apoptosis
associated with a 33-fold increase in caspase-3 activity, 5.7-fold increase in
TNF-alpha, 17.5-fold increase in NOS-2 and a 3.9-fold increase in ET-1, while the
mucosal expression of cNOS activity showed a 7.6-fold drop and IL-4 expression
fell by 37.2%. The healing was reflected in a rapid recovery in IL-4, and a
decrease in apoptosis, caspase-3, TNF-alpha, ET-1 and NOS-2, and a slow recovery
in cNOS activity, and the process was accelerated in the sucralfate-treated
group. While in the absence of sucralfate the expression of IL-4 returned to that
of the normal mucosa by the 7th day of healing and that of ET-1 and TNF-alpha by
the 14th day, an accelerated ulcer healing with sucralfate treatment was
associated with IL-4 recovery by the 4th day and that of ET-1 and TNF-alpha by
the 10th day when the ulcer heated, while recovery in cNOS activity required 14
days. Yet, in both groups of animals the apoptotic DNA fragmentation rate,
caspase-3 and the expression of NOS-2 activity remained significantly elevated
even after the ulcer healed. CONCLUSIONS: The results suggest that a decrease in
the mucosal expression of the regulatory cytokine IL-4 at the ulcer onset may
well be a key factor causing dysregulation of ET-1 production, induction of TNF
alpha, and triggering the apoptotic events that affect the efficiency of mucosal
repair process. We also show that accelerated ulcer healing by sucralfate may be
the result of a rapid mucosal IL-4 generation that leads to the suppression of
the mucosal apoptotic events.
PMID- 10768853
TI - Protective role of endogenous nitric oxide (NO) in lipopolysaccharide--induced
pancreatic damage (a new experimental model of acute pancreatitis).
AB - Lipopolysaccharide (LPS) derived from the bacterial cell wall activates the
inflammatory response in the tissue but the role of LPS in the pathogenesis of
pancreatic damage and in the activation of NO system in the pancreas has not been
fully explained. The aim of this study was to investigate the effect of repeated
administration of LPS to the rats on the integrity of the pancreas, on the
ability of isolated pancreatic acini to secrete the amylase and on the plasma
level of tumor necrosis factor alpha (TNFalpha). The role of NO in the pancreatic
resistance to the damage was assessed in animals subjected to repeated
administration of LPS. To induce pancreatic damage one group of rats received
intraperitoneal (i.p.) injection of LPS (from E. coli) every day during 5
consecutive days (10 mg/kg--day). Another groups of animals were given N(G)-nitro
L-arginine (L-NNA), an inhibitor of NO synthase (NOS) (20 mg/kg i.p.) alone or in
combination with L-arginine (100 mg/kg i.p.), 30 min prior to each LPS injection.
Plasma level of TNFalpha was determined by ELISA kit. Repeated administration of
LPS produced mild pancreatic inflammation that was most pronounced at day 5 of
LPS treatment and manifested as edema, neutrophil infiltration and hemorrhage of
the pancreas. The survival rate after 5 days treatment with LPS was 87.5%.
Pancreatic weight, plasma levels of TNFalpha and amylase, pancreatic blood flow
(PBF) and NO generation by pancreatic acini were markedly increased in rats
subjected to repeated administration of LPS whereas the amylase response of
isolated pancreatic acini to pancreatic secretagogues was significantly
attenuated. Suppression of NOS by L-NNA resulted in a dramatic increase in the
mortality of the animals reaching 50% and significantly increased inflammatory
changes in the pancreatic tissue, decreased PBF, abolished the ability of
pancreatic acini to release NO and to secrete amylase. Pancreatic weight and
plasma levels of amylase and TNFalpha significantly increased in the group of
rats treated with combination of LPS+L-NNA as compared to the animals received
LPS alone. Addition of L-arginine to L-NNA+LPS administration reversed all
harmful effects produced by L-NNA in the pancreas. We conclude that repeated
administration of high doses of bacterial LPS to the rats could induce pancreatic
tissue damage by itself, however, it is not able to produce severe pancreatitis.
Suppression of NO generation significantly aggravates the pancreatic lesion
produced by LPS leading to the dramatic mortality in treated rats. The rise of
plasma level of TNFalpha corresponds to the severity of pancreatic inflammation.
PMID- 10768854
TI - Effect of triiodothyronine on phospholipid metabolism in skeletal muscles of the
rat.
AB - The aim of the present study was to examine the effect of treatment with
triiodothyronine (T3) on certain aspects of phospholipid metabolism in skeletal
muscles. Rats were injected with triiodothyronine (T3) daily (10 microg x 100 g(
1) b.w., s.c.) for six days. Saline-treated rats served as controls. 24 h after
the last dose of T3, 14C palmitic acid suspended in the serum of a donor rat, was
administered intravenously. Thirty min later, samples of the soleus, white and
red section of the gastrocnemius and blood from the abdominal aorta were taken.
The muscle phospholipids were extracted and separated into different fractions by
means of thin layer chromatography. The following fractions were obtained:
shingomeylin, phosphatidylcholine phosphatidylethanolamine, phosphatidylinositol,
phosphatidylserine and cardiolipin. The phospholipids were quantified and their
radioactivity was measured. The plasma free fatty acid concentration and
radioactivity was also determined. Treatment with T3 reduced the content of
phosphatidylinositol and phosphatidylserine in each muscle type, whereas the
concentration of other phospholipids remained stable. T3 increased markedly
incorporation of the blood-borne fatty acids into each phospholipid fraction in
the muscles. It is concluded that an excess of T3 influences the metabolism of
phospholipids in skeletal muscles.
PMID- 10768855
TI - The role of adrenoreceptors in the regulation of oxytocin and vasopressin release
after superior cervical ganglionectomy.
AB - In male rats under anaesthesia, dialysis of the venous blood from sella turcica
region was carried out. Vasopressin and oxytocin content was determined in the
dialysates by radioimmunoassay. The obtained results indicate that: 1. Electrical
stimulation of the superior cervical ganglion causes an increase in vasopressin
and oxytocin release. 2. 20 days after superior cervical ganglionectomy the
vasopressin and oxytocin release increased. 3. Superior cervical ganglionectomy
immediately before the dialysis evoked a several times increase in vasopressin
and oxytocin release. 4. Application of alpha1-blocker, prazosin, as well beta
blocker, propranolol, has partially prevented the increase in vasopressin release
which was found immediately after superior cervical ganglionectomy. 5. Contrary
to vasopressin, the increase in oxytocin release after superior cervical
ganglionectomy is completely prevented by the beta-blocker, propranolol, and only
partially by the alpha1-blocker, prazosin.
PMID- 10768856
TI - Dose-and-time dependent effect of 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) on
progesterone secretion by porcine luteal cells cultured in vitro.
AB - In the current study, to characterize TCDD action during luteal phase of the
ovarian cycle, the direct effect of TCDD was investigated in vitro using a system
of monolayer cell culture. Luteal cells isolated from mid-developing corpora
lutea were cultured with four different doses of TCDD (0.1, 1.0, 10.0 and 100
nM). The dose of 0.1nM TCDD had no effect on progesterone (P4) secretion by
luteal cells while the doses of 10nM and 100nM in the same, statistically
significant manner decreased P4 secretion (p <0.05). The inhibitory effect of
TCDD was dependent not only on doses by also on experimental conditions. In cells
treated every day for 72 hrs of culture with 0.1nM TCDD, P4 secretion was 71% of
basal secretion. 100nM TCDD added only at the beginning of the culture and nor
repeated when medium was changed every 24 hrs decreased P4 secretion to 81.8% of
basal secretion. The most inhibitory effect was observed in experiments in which
100nM TCDD was added at the beginning of the culture and medium was not changed
for 72 hrs. Secretion of P4 was only 33.9% of that by control cultures. In order
to show the time-dependent response to TCDD in terms of P4 secretion, luteal
cells were cultured for 24,48, 72 hrs with 0.1 and 100nM TCDD. 85%, 75% and 72%
of basal progesterone secretion was noted after 24, 48 and 72h respectively in
0.1nM TCDD-treated cells. In 100nM TCDD treated cells the decrease of
progesterone secretion was 57%, 67% and 82% of basal secretion after 24, 48 and
72 hrs of culture. These experiments suggest that TCDD by suppressing
progesterone secretion by corpora lutea can cause adverse reproductive effects
such as early pregnancy failure. Endocrine disrupters that interfere with
progesterone production can act as abortifacients.
PMID- 10768857
TI - Partial purification and identification of cardiodepressant factor from the
posterior pituitary lobe in rats.
AB - It has been demonstrated previously that the cardiodepressant activity is present
in the bovine hypothalamic extract and in the medium incubating the rat's
posterior pituitary lobe "in situ". In this study medium incubating the posterior
pituitary lobe was fractionated by a low pressure gel filtration procedure and
the cardiodepressant fractions were pooled and further purified by the HPLC
technique on C8 and TSK 3000 SW columns. It was shown, on the basis of mass
spectrometry, that cardiodepressant activity is associated with substance(s) with
molecular mass of about 500 d. Application of this fraction into the fluid used
for incubation of isolated right auricle of the right heart atrium of a two-day
old rat, strongly decreased the frequency of spontaneous discharge of the
pacemaker tissue.
PMID- 10768858
TI - Usefulness of thoracic electrical bioimpedance in detection of ejection fraction
changes.
AB - The aim of this study was to evaluate a usefulness of thoracic electrical
bioimpedance (TEB) in following adaptive haemodynamic adjustments to postural
change and isometric exercise. Sixteen subjects with intact cardiovascular system
took part in this study. Haemodynamic parameters were obtained in recumbency and
after taking up erect posture. Besides, TEB was performed during handgrip test
and the results were compared with baseline resting data. Each time the
radionuclide ventriculography (RV) was performed concurrently with TEB to obtain
an independent measurement of ejection fraction (EF). Active orthostasis was
associated with a change in stroke volume, cardiac output and total vascular
resistance by -29.7%, -3.4%, +3.9%, respectively. The handgrip produced a
significant increase in cardiac output by 16.3%, however it was not associated
with an enhancement of stroke volume. Although there was a moderate correlation
between EF calculated by TEB and RV in supine position (r=0.66; p < 0.001), TEB
failed to reflect changes of EF in orthostasis and isometric exercise. In
conclusion, our results suggest that TEB offers in subjects with normal
cardiovascular function a valuable alternative to cardiovascular monitoring of
stroke volume and cardiac output, but calculation of EF is associated with a risk
of serious error.
PMID- 10768859
TI - Hypotensive effect of angiotensin II after AT1-receptor blockade with losartan.
AB - Recent data suggest that hypotensive effect of losartan may not be attributed
solely to AT1-receptor blockade, but also to excessive AT2 or other receptors
stimulation by elevated angiotensin II and its derivative peptides. Therefore in
the present study we examined the effect of angiotensin II on mean blood pressure
after AT -receptor blockade with losartan. Male Wistar rats were anaesthetised
and received injection of either losartan (30 mg/kg, 1 ml/kg, i.v.) or saline
(the same volume and route) followed by bolus injection of angiotensin II (100,
300 or 1,000 ng/kg; 1 ml/kg, i.v.) or 1-hour infusion of angiotensin II (200
ng/kg/min; 2.5 ml/kg/h, i.v.). Control animals received saline instead.
Angiotensin II, given either as the injection or the infusion, caused an evident
increase in mean blood pressure (p ranged from 0.05 to 0.001 depending on the
experimental group). Losartan caused a rapid drop in mean blood pressure and
blunted the hypertensive effect of angiotensin II (p < 0.01). Moreover, in the
losartan-pretreated animals the hypotensive phase was enhanced by the infusion,
but not single injection of angiotensin II, which was most evident from the 30 th
minute of observation (p < 0.05 vs control). In conclusion, hypotensive effect of
losartan may be amplified by simultaneous increase in angiotensin II level, the
situation observed during chronic AT1-receptor blockade.
PMID- 10768860
TI - Isolation of morphologically and functionally intact gastric mucosal microvessels
rapid communication.
AB - Gastric mucosal microvessels were isolated after arterial perfusion of the rat
stomach with magnetized iron oxide suspension. After homogenization of scrapped
gastric mucosa, microvessels were initially separated with a high power magnet
and further separated and purified by using a nylon sieve. Aliquots of purified
microvessels were assessed for viability, histologic appearance, ultrastructure
and generation of prostacyclin. Microvessels were plated on Matrigel and cultured
in DMEM with high glucose and 10% FBS for 1, 3 or 5 days. After 1, 3 and 5 days
of culturing, endothelial viability was assessed with Fast green exclusion, and
the basal and stimulated (with calcium ionophore) generation of prostacyclin was
determined by assaying aliquots of the incubating medium for 6-keto PGF(1alpha).
At 1 and 3 hrs after isolation, microvessels demonstrated intact morphologic
structures as reflected by transmission EM and 92+/-4% of viable endothelial
cells. The microvessels plated on Matrigel maintained good viability for at least
5 days and generated prostacyclin at the baseline and following ionophore
stimulation. These data demonstrate that isolated microvessels cultured under
optimal conditions are fully viable and functional.
PMID- 10768861
TI - Role of the basic helix-loop-helix transcription factor p48 in the
differentiation phenotype of exocrine pancreas cancer cells.
AB - The majority of human pancreatic adenocarcinomas display a ductal phenotype;
experimental studies indicate that tumors with this phenotype can arise from both
acinar and ductal cells. In normal pancreas acinar cells, the pancreas
transcription factor 1 transcriptional complex is required for gene expression.
Pancreas transcription factor 1 is a heterooligomer of pancreas-specific (p48)
and ubiquitous (p75/E2A and p64/HEB) basic helix-loop-helix proteins. We have
examined the role of p48 in the phenotype of azaserine-induced rat DSL6 tumors
and cancers of the human exocrine pancreas. Serially transplanted acinar DSL6
tumors express p48 whereas DSL6-derived cell lines, and the tumors induced by
them, display a ductal phenotype and lack p48. In human pancreas cancer cell
lines and tissues, p48 is present in acinar tumors but not in ductal tumors.
Transfection of ductal pancreas cancers with p48 cDNA did not activate the
expression of amylase nor a reporter gene under the control of the rat elastase
promoter. In some cell lines, p48 was detected in the nucleus whereas in others
it was cytoplasmic, as in one human acinar tumor. Together with prior work, our
findings indicate that p48 is associated with the acinar phenotype of exocrine
pancreas cancers and it is necessary, but not sufficient, for the expression of
the acinar phenotype.
PMID- 10768862
TI - Role and regulation of p53 during an ultraviolet radiation-induced G1 cell cycle
arrest.
AB - p53 can play a key role in response to DNA damage by activating a G1 cell cycle
arrest. However, the importance of p53 in the cell cycle response to UV radiation
is unclear. In this study, we used normal and repair-deficient cells to examine
the role and regulation of p53 in response to UV radiation. A dose-dependent G1
arrest was observed in normal and repair-deficient cells exposed to UV.
Expression of HPV16-E6, or a dominant-negative p53 mutant that inactivates
wildtype p53, caused cells to become resistant to this UV-induced G1 arrest.
However, a G1 to S-phase delay was still observed after UV treatment of cells in
which p53 was inactivated. These results indicate that UV can inhibit G1 to S
phase progression through p53-dependent and independent mechanisms. Cells
deficient in the repair of UV-induced DNA damage were more susceptible to a G1
arrest after UV treatment than cells with normal repair capacity. Moreover, no G1
arrest was observed in cells that had completed DNA repair prior to monitoring
their movement from G1 into S-phase. Finally, p53 was stabilized under conditions
of a UV-induced G1 arrest and unstable when cells had completed DNA repair and
progressed from G1 into S-phase. These results suggest that unrepaired DNA damage
is the signal for the stabilization of p53, and a subsequent G1 phase cell cycle
arrest in UV-irradiated cells.
PMID- 10768863
TI - Brachyury is expressed by human teratocarcinoma cells in the absence of
mesodermal differentiation.
AB - Reverse transcription-PCR and Northern and Western blot analyses indicate that
mRNA and protein encoded by the Brachyury gene are expressed by the pluripotent
human embryonal carcinoma cell line NTERA2 and are only modestly down-regulated
during retinoic acid-induced differentiation. This differentiation occurs along a
neural lineage, with no obvious evidence of the formation of mesodermal
derivatives. Several other human embryonal carcinoma cell lines that do not
differentiate, a yolk sac carcinoma cell line and two choriocarcinoma cell lines,
also express readily detectable levels of Brachyury mRNA and protein. Thus, in
human teratocarcinomas, Brachyury expression is not necessarily an indicator of
commitment to mesodermal differentiation.
PMID- 10768864
TI - Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse.
AB - We have determined the expression pattern of the A-raf proto-oncogene in the
embryonic and adult mouse. Western blot analysis of protein lysates from tissues
of adult mice show that p69A-raf is ubiquitously expressed, but that levels of
expression vary among different tissues. To determine the cell-specific
expression pattern of A-raf, we generated transgenic mice expressing the beta
galactosidase reporter gene from the A-raf promoter. We show that A-raf
expression is highly specific within a given tissue, and we identify cell types
expressing this gene in the adult testis, epididymis, vas deferens, seminal
vesicle, ovary, oviduct, bladder, kidney, intestine, heart, spleen, thymus, and
cerebellum. In the embryo, ubiquitous expression of the reporter gene is
observed, but the highest levels of expression are specifically detected in the
embryonic heart at stages 9.5-11.5 days post-coitum.
PMID- 10768865
TI - Blocking HER-2/HER-3 function with a dominant negative form of HER-3 in cells
stimulated by heregulin and in breast cancer cells with HER-2 gene amplification.
AB - Amplification and overexpression of the HER-2 (neu/ erbB-2) gene in human breast
cancer are clearly important events that lead to the transformation of mammary
epithelial cells in approximately one-third of breast cancer patients.
Heterodimer interactions between HER-2 and HER-3 (erbB-3) are activated by neu
differentiation factor/heregulin (HRG), and HER-2/HER-3 heterodimers are
constitutively activated in breast cancer cells with HER-2 gene amplification.
This indicates that inhibition of HER-2/HER-3 heterodimer function may be an
especially effective and unique strategy for blocking the HER-2-mediated
transformation of breast cancer cells. Therefore, we constructed a bicistronic
retroviral expression vector (pCMV-dn3) containing a dominant negative form of
HER-3 in which most of the cytoplasmic domain was removed for introduction into
cells. By using a bicistronic retroviral vector in which the antibiotic
resistance gene and the gene of interest are driven by a single promoter, we
attained 100% coordinate coexpression of antibiotic resistance with the gene of
interest in target cell populations. Breast carcinoma cells with HER-2 gene
amplification (21 MT-1 cells) and normal mammary epithelial cells without HER-2
gene amplification from the same patient (H16N-2 cells) were infected with pCMV
dn3 and assessed for HER-2/ HER-3 receptor tyrosine phosphorylation, p85PI 3
kinase and SHC protein activation, growth factor-dependent and -independent
proliferation, and transformed growth in culture. Dominant negative HER-3
inhibited the HRG-induced activation of HER-2/HER-3 and signaling in H16N-2 and
21 MT-1 cells as well as the constitutive activation of HER-2/HER-3 and signaling
in 21 MT-1 cells. Responses to exogenous HRG were strongly inhibited by dominant
negative HER-3. In contrast, the proliferation of cells stimulated by epidermal
growth factor was not apparently affected by dominant negative HER-3. The growth
factor-independent proliferation and transformed growth of 21 MT-1 cells were
also strongly inhibited by dominant negative HER-3 in anchorage-dependent and
independent growth assays in culture. Furthermore, the HRG-induced or growth
factor-independent proliferation of 21 MT-1 cells was inhibited by dominant
negative HER-3, whereas the epidermal growth factor-induced proliferation of
these cells was not: this indicates that dominant negative HER-3 preferentially
inhibits proliferation induced by HER-2/HER-3.
PMID- 10768866
TI - Effect of IL-6 elevation in malignant pleural effusion on hyperfibrinogenemia in
lung cancer patients.
AB - BACKGROUND: The involvements of interleukin-6 (IL-6) and fibrinogen in cancer
development were elucidated independently, irrespective of IL-6 activity to
induce fibrinogen. This study was undertaken to clarify the clinicopathological
association of these molecules in lung cancer patients with malignant pleurisy.
METHODS: IL-6, fibrinogen and the related molecules in blood and pleural effusion
of 38 patients were assayed at 3-day intervals. RESULTS: IL-6 levels were
elevated in sera of 27 cases (71.1%) and in all the effusions with mean values of
20.5 and 9970.5 pg/ml, respectively. Their correlation in 22 cases who were
examined on the same day was statistically strong (r = 0.902, p < 0.0001).
Occasional elevations of tumor necrosis factor-alpha were independent of IL-6
elevation. Levels of plasma fibrinogen, fibrin(ogen) degradation products (FDP)
and C-reactive protein (CRP) were more frequently elevated in the IL-6-elevated
cases than those without IL-6 elevation. In all pleural effusions, fibrinogen
levels were significantly decreased to <150 mg/dl with large elevations of FDP
level. Immunocytologically, IL-6 was detected in cancer cells in 16 cases of
adenocarcinoma in addition to host pleural cells, but its cellular positivity was
not reflected in the IL-6 level in each pleural effusion. CONCLUSION: Compared
with lung cancer patients without malignant pleurisy, IL-6, fibrinogen, FDP and
CRP levels in patients with malignant pleurisy were increased more frequently in
their peripheral blood. These were basically attributed to systemic leakage of IL
6 from the affected pleural cavity, in which plasma fibrinogen induced in
response to serum IL-6 was exudated and degraded predominantly to FDP.
PMID- 10768867
TI - Phase II trial of daily low-dose carboplatin and thoracic radiotherapy in elderly
patients with locally advanced non-small cell lung cancer.
AB - BACKGROUND: The purpose of this study was to investigate the feasibility of
concurrent thoracic radiotherapy (TRT) and daily low-dose carboplatin (CBDCA) in
elderly patients with locally advanced non-small cell lung cancer (NSCLC) and to
estimate tumor response, toxicity and survival. METHODS: Forty patients were
entered in a multicenter phase II study. All were patients with pathologically
documented unresectable stage IIIA or IIIB or medically inoperable stage I, II
NSCLC. CBDCA 30 mg/m2 was given on days 1-5 in weeks 1-4 concurrently with TRT,
mainly for radiosensitization. TRT was started 1 h after CBDCA (30 min infusion)
was given. TRT was given in 2 Gy/fraction/day, 5 days a week for a total of 50
60Gy. RESULTS: Thirty-eight patients were assessable for treatment response and
toxicity. One patient had a CR and 18 patients PRs with a response rate of 50%
(95% CI, 33.4-66.6%). The main toxicities were hematological toxicity. Other
toxicities were grade > or =2 esophagitis in one patient, grade 3 nausea/vomiting
in one and grade > or =3 pulmonary toxicity in two. There was one treatment
related death due to pulmonary toxicity. For stage IIIA + IIIB patients, the
median survival time was 15.1 months and 1-and 2-year actuarial survival rates
were 52.6 and 20.5%, respectively. For stage I + II patients, 1- and 3-year
actuarial survival rates were 90.9 and 69.3%, respectively. CONCLUSIONS: The data
suggest that TRT with daily low-dose CBDCA in elderly patients is effective and
feasible because of its low toxicity and survival.
PMID- 10768868
TI - Ultrasound-guided core needle biopsy for breast cancer: preliminary report.
AB - BACKGROUND: Ultrasound-guided automated percutaneous core needle biopsy (US-CNB)
for breast tumors has been introduced into clinical practice, but it has not yet
been used routinely. We evaluated its usefulness, especially in terms of
histological accuracy. METHODS: Thirty-one consecutive patients underwent
mammography followed by breast biopsy with the automated core needle biopsy
device. RESULTS: Mammography was highly suggestive of malignancy or suspicious
abnormalities in 17 cases whose histological findings from US-CNB specimens were
invasive ductal carcinoma without exception. The other 14 cases with benign or
probably benign mammography findings showed no malignancy histologically in the
US-CNB specimens. In cases of malignancy, the accuracy rates of histological
findings for the specimens obtained by US-CNB were 94.1% in histological type,
100% in direct infiltration, 82.4% in lymphatic infiltration, 82.4% in venous
infiltration, 94.1% in histological grading and 82.4% in intraductal spread.
CONCLUSION: US-CNB was useful for making reliable preoperative histopathological
diagnosis and may substitute fine needle aspiration biopsy and surgical biopsy.
PMID- 10768869
TI - The surgical approach to the adrenal gland: a comparison of the retroperitoneal
and the transabdominal routes in 326 operations on 284 patients.
AB - BACKGROUND: To compare the results of adrenalectomy using a retroperitoneal and a
transabdominal approach, especially for adrenal carcinoma and pheochromocytoma.
METHODS: A retrospective study was carried out at the Leiden University Medical
Center. Charts of 284 patients who had undergone 326 adrenal operations between
1947 and 1995, including 44 patients with adrenal cancer and 60 patients with
pheochromocytoma, were reviewed. The main outcome measures were operation time,
blood loss, hospital stay and intra- and post-operative complications. RESULTS:
In patients who underwent adrenalectomy (ADX) using a retroperitoneal (RP)
approach, duration of operation, intra-operative blood loss, hospital stay and
post-operative morbidity compared favourably with those undergoing a
transabdominal approach (TA-ADX). However, most of these differences could be
explained by the more frequently benign nature and smaller size of the lesions in
patients undergoing RP-ADX. However, blood loss remained lower after correction
for confounding in all patients undergoing RP-ADX. In patients with larger
adrenal lesions, adrenal cancer and pheochromocytoma, that would nowadays be held
unsuitable for laparoscopic adrenalectomy, RP-ADX was associated with shorter
operation time, less blood loss and less intra-operative complications.
CONCLUSION: Although laparoscopic adrenalectomy is the treatment of choice for
small and benign adrenal lesions, larger lesions and/or adrenal malignancy
require open adrenalectomy. In these cases the retroperitoneal approach is the
preferred route.
PMID- 10768870
TI - What patients can survive disease free after complete resection for
hepatocellular carcinoma?: A multivariate analysis.
AB - BACKGROUND: Although there have been extensive studies to determine risk factors
affecting survival after resection for hepatocellular carcinoma (HCC), we still
do not know which patients can survive disease free after curative resection.
This study was undertaken to determine independent risk factors affecting the
length of disease-free survival. METHODS: 171 patients, who survived disease free
more than 1 year after curative resection, were divided into four groups
according to the disease-free period: Group I (n = 96) for the patients with
intrahepatic recurrence between 1 and 3 postoperative years, Group II(n = 27) for
those between 3 and 5 years, Group III (n = 40) for those between 5 and 10 years
and Group IV (n = 8) for those without recurrence within 10 years. The 37
variables (host factors, tumor factors, non-tumor liver factors, surgical
factors) were compared among the four groups. Activity of hepatitis and hepatic
fibrosis was scored by the Histological Activity Index (HAI). In a multivariate
study, possible prognostic variables with a statistical difference in the disease
free survival rate among each category were preliminarily selected from the 37
variables and the independent variables were finally selected using a
proportional hazard analysis. RESULTS: The patients' age, indocyanine green
retention rate, microscopic tumor capsular invasion and portal invasion, cell
differentiation, extent of hepatectomy, aggressiveness of chronic hepatitis and
inflammatory activity assessed by HAI score were significantly different among
the four groups. In the multivariate analysis, the following variables were
selected as the independent determinants favorable for achieving a longer disease
free period: younger age, lower indocyanine green retention rate, solitary HCC
with expansive growth, no microscopic portal invasion and lower activity of co
existing hepatitis. CONCLUSIONS: The importance of inflammatory activity in
addition to aging, hepatic reserve and tumor characteristics was confirmed as a
risk factor for recurrence by multivariate analysis. To achieve better disease
free survival, not only early detection but also suppression of co-existing
hepatitis is necessary.
PMID- 10768871
TI - The relationship between frequencies of extracolonic manifestations and the
position of APC germline mutation in patients with familial adenomatous
polyposis.
AB - BACKGROUND: Familial adenomatous polyposis (FAP) patients develop various
extracolonic lesions; however, the relationship between germline mutation of the
APC gene and extracolonic manifestations is mostly unknown. To examine the
genotype-phenotype relationship, we compared the APC mutation and clinical data.
METHODS: Germline mutations from codon 157 to 1465 of the APC gene were
identified in 39 families of FAP and clinical data were collected from 80
patients of these families. Germline mutations were classified into two groups:
mutations from exon 4 to 9 (codon 157 to 416, Group 1) and those from exon 10 to
15H (codon 564 to 1465, Group 2). The complication rates of extracolonic
manifestations were compared between these two groups. RESULTS: Frequencies of
duodenal polyps and gastric adenomas in Group 2 were higher than those in Group 1
(p < 0.0001 and p < 0.0004, respectively) and development of osteoma was more
frequent in Group 2 (p = 0.01). The number of colorectal polyps and retinal
pigments also correlated with the germline mutation, which was consistent with
previous reports. However, such correlations were less obvious with regard to
gastric fundic polyps, desmoid tumors, soft tissue tumors and colorectal cancer.
CONCLUSION: There are two types with regard to extracolonic manifestations of
FAP: one is more severely affected according to the position of germline mutation
of the APC gene and the other is not affected.
PMID- 10768873
TI - Screening for prostate cancer using prostate-specific antigen alone as a first
line checkup parameter: results of the health checkup system.
AB - BACKGROUND: The incidence of prostate cancer in Japan is not very high but it is
the most increasing malignant tumor form. To decrease the mortality from cancer,
detection of early cancer and early treatment are most effective. As a primary
screening for prostate cancer, measurement of serum prostate-specific
antigen(PSA) added to the health checkup system has not been assessed. METHODS:
Among males who received a health checkup during a 30-month period, serum PSA
levels were measured in males who desired prostate cancer screening. The cut-off
value for PSA was 4.0 ng/ml. Males with serum PSA levels exceeding this value
were referred for further screening by digital rectal examination (DRE) and
transrectal ultrasonography (TRUS). In secondary screening, in all males with PSA
levels of 10.0 ng/ml or more and in males in whom PSA levels were within the gray
zone (4.0-10.0 ng/ml) and either DRE or TRUS showed abnormal findings, systematic
prostate sextant needle biopsy was performed. RESULTS: Of 24528 males who
received a health checkup, 1125 (4.6%) underwent prostate cancer screening. In 60
(5.3%) of these males, PSA levels exceeded the cut-off value. In 34 of 50 males
who received further screening, prostate biopsy was performed. Seventeen males
were diagnosed as having prostate cancer. Detection rates of prostate cancer were
1.53% (17/1125) in males overall and 2.1% (17/819) in males > or =50 years old.
In 16 of 17 males, clinically localized cancer was suggested. In 12 of these
patients, radical prostatectomy was performed. No lymph node metastasis was
detected in any patient. CONCLUSIONS: These results suggest that prostate cancer
screening using PSA as a primary screening parameter during general health
checkups is very useful for efficiently detecting early-stage prostate cancer.
PMID- 10768872
TI - Clinical significance of MUC1 and MUC2 mucin and p53 protein expression in
colorectal carcinoma.
AB - BACKGROUND: Up-regulation of MUC1, down-regulation of MUC2 and p53 overexpression
are seen in colorectal carcinomas. However, there have been few reports about the
associations between MUC1, MUC2 and p53 expression and metastatic potential. The
aim of this study was to investigate MUC1, MUC2 and p53 expression in colorectal
carcinoma with special reference to regional and distant metastasis. METHODS:
Eighty-six colorectal carcinomas were collected from patients undergoing tumor
resection. Sections were used for MUC1, MUC2 and p53 immunostaining. Cancers were
regarded as MUC1 or MUC2 positive when the positive cells were beyond 30% of
cancer cells. Cancers with diffuse or nested patterns were regarded as having p53
overexpression. RESULTS: Of 86 cancers, 37 (43%) were MUC1 positive, 28 (33%)
were MUC2 positive and 59 (69%) showed p53 overexpression. A difference was
observed only in the frequency of MUC1 positivity with respect to depth of tumor
invasion. Neither depth of tumor invasion nor histological differentiation had a
positive correlation with MUC1, MUC2 and p53 overexpression. The frequency of
MUC1 positive cells in Dukes' C and D tumors was significantly higher than that
in Dukes' A and B tumors. The frequency of MUC1 positivity in tumors with hepatic
involvement was significantly higher than that in tumors without hepatic
involvement (100 vs 39%; p < 0.01). There was no difference in the frequency of
MUC2 or p53 positivity in Dukes' stage or hepatic metastasis. MUC1
immunoreactivity of the surface was identical with that of the whole tumor in 81%
(70/86) of carcinomas, MUC 2 in 87% and p53 in 100%. CONCLUSIONS: The results
suggest that up-regulation of MUC1 is involved in the progression from the non
metastatic to the metastatic stage and that p53 abnormality is not directly
involved in it. The data also imply that immunostaining of preoperative biopsy
samples is useful for evaluating the immunoreactivity of the whole tumor.
PMID- 10768874
TI - Chromophobe renal cell carcinoma with osseous metaplasia: a case report.
AB - A 60-year-old Japanese male with a chromophobe cell carcinoma of his left kidney
is reported. The tumor, 18 x 27 mm in size, was incidentally found by abdominal
ultrasonography. Computed tomography and magnetic resonance imaging demonstrated
a well-demarcated solid tumor arising from the lower pole of the left kidney.
Histopathological examination of the surgically removed tumor revealed that it
was composed of solid sheets of cancer cells having abundant and slightly
eosinophilic reticular cytoplasm with accentuated cell membranes making up a
plant cell-like appearance. Electron microscopic examination demonstrated
numerous intracytoplasmic microvesicles. Although the tumor cells were positive
for cytokeratin and epithelial membrane antigen, they did not show vimentin
immunoreactivity. The unique histological finding of this tumor from other
reported renal chromophobe carcinomas was that it had a peripheral fibrotic area
with a focus of metaplastic ossification.
PMID- 10768875
TI - Simultaneous development of a pineal tumor and an intradural spinal mass during
remission of acute lymphocytic leukemia.
AB - A small percentage of children with acute lymphocytic leukemia experience relapse
in the central nervous system in spite of prophylaxis. Diffuse leptomeningeal
infiltration is common but an intracranial leukemic mass or spinal cord
involvement is a rare manifestation. We report a child with acute lymphocytic
leukemia who simultaneously developed a pineal tumor and an intradural spinal
cord mass as her first relapse. She was successfully managed by comprehensive
combined treatment including peripheral blood stem cell transplantation. She
remains in continuous complete remission for more than 5 years without further
evidence of neurological sequelae.
PMID- 10768876
TI - CT-assisted transbronchial brachytherapy for small peripheral lung cancer.
AB - Transbronchial brachytherapy for small peripheral lung cancer was developed with
the use of the CT-guided bronchoscopy technique. Under CT guidance, an applicator
carrying a dummy source was introduced into a lesion and stabilized. A
radioactive source was then delivered through the applicator using a high dose
rate remote afterloading system. For multiple radiation fractions, a marker was
placed immediately under the pleura in a peripheral bronchus penetrating the
lesion using the CT-guided barium marking technique. During brachytherapy, an
applicator with a dummy source was inserted under fluoroscopic guidance up to the
marker. A radioactive source was subsequently delivered. CT-assisted
transbronchial brachytherapy allows radiation to be delivered from inside a
lesion. This minimizes radiation damage to noncancerous tissue and offers
distinct advantages over conventional radiation techniques.
PMID- 10768878
TI - The Anthropology of Religion and the Quarrel between Poetry and Philosophy.
PMID- 10768877
TI - Mortality rates by prefectures in Japan.
PMID- 10768879
TI - The Language of Classic Maya Inscriptions1.
AB - Recent decipherments of Classic Maya hieroglyphs (ca. a.d. 250 to 850) reveal
phonological and morphological patterns that, through epigraphic and historical
analyses, isolate a single, coherent prestige language with unique and widespread
features in script. We term this language "Classic Ch'olti'an" and present the
evidence for its explicable historical configuration and ancestral affiliation
with Eastern Ch'olan languages (Ch'olti' and its still-viable descendant,
Ch'orti'). We conclude by exploring the possibility that Ch'olti'an was a
prestige language that was shared by elites, literati, and priests and had a
profound effect on personal and group status in ancient Maya kingdoms.
PMID- 10768880
TI - Genes, Tribes, and African History.
AB - Over the past 40 years, traditional perspectives on the constitution of human
groups have been subjected to stringent critique within anthropology. This began
with the dismantling of accepted "race" divisions after World War II and
continued with analyses of the meaning and reality of African "tribal"
distinctions from the 1960s until the present. Archaeologists, ethnographers,
linguists, and historians of Africa now work within a research milieu where
social interactions, cultural exchange, and the dynamic nature of group
identifications are accepted as a normal part of the human experience. At the
same time, new techniques have been developed for the examination of human
history, techniques based upon an expanding repertoire of tools for the analysis
of genetic variability in human populations. Perhaps the most striking result of
this research has been Cavalli-Sforza, Menozzi, and Piazza's The History and
Geography of Human Genes. Rather less attention has been paid, however, to the
conceptual relationships between the human groups defined through such analyses,
in Africa and elsewhere, and those defined through other kinds of research. This
paper is a preliminary examination of the fit between genetic, archaeological,
and ethnographic data on the African past.
PMID- 10768881
TI - The Evolution of Human Homosexual Behavior.
AB - Homosexuality presents a paradox for evolutionists who explore the adaptedness of
human behavior. If adaptedness is measured by reproductive success and if
homosexual behavior is nonreproductive, how has it come about? Three
adaptationist hypotheses are reviewed here and compared with the anthropological
literature. There is little evidence that lineages gain reproductive advantage
through offspring care provided by homosexual members. Therefore, there is little
support for the hypothesis that homosexuality evolved by kin selection. Parents
at times control children's reproductive decisions and at times encourage
children in homosexual behavior. There is therefore more support for the
hypothesis of parental manipulation. Support is strongest, however, for the
hypothesis that homosexual behavior comes from individual selection for
reciprocal altruism. Same-sex alliances have reproductive advantages, and sexual
behavior at times maintains these alliances. Nonhuman primates, including the
apes, use homosexual behavior in same-sex alliances, and such alliances appear to
have been key in the expanded distribution of human ancestors during the
Pleistocene. Homosexual emotion and behavior are, in part, emergent qualities of
the human propensity for same-sex affiliation. Adaptationist explanations do not
fully explain sexual behavior in humans, however; social and historical factors
also play strong roles.
PMID- 10768883
TI - On Evolutionary Ecology and Evolutionary Archaeology: Some Common Ground?
PMID- 10768882
TI - Essential Differences: National Homogeneity and Cultural Representation in Four
Recent Works on Greek Macedonia.
PMID- 10768884
TI - On "Virgin Birth" and a Paradox of Procreation.
PMID- 10768885
TI - Tastes of Chimpanzee Plant Foods.
PMID- 10768886
TI - Killing of Captured Enemies: A Cross-cultural Study.
PMID- 10768887
TI - "The Worst Hassle Is You Can't Play Rugby": Haemophilia and Masculinity in New
Zealand.
PMID- 10768888
TI - Maasai Gummivory: Implications for Paleolithic Diets and Contemporary Health.
PMID- 10768889
TI - Prehistoric Maize Evolution in the Tehuacan Valley.
PMID- 10768890
TI - Coronary angioplasty is like going to the dentist.
PMID- 10768891
TI - Assessment of left ventricular systolic function in research and in clinical
practice.
PMID- 10768892
TI - Cardiovascular risks and outcomes: ethnic variations in hypertensive patients.
PMID- 10768894
TI - Intravascular radiotherapy: restenosis and more?
PMID- 10768895
TI - Fatal unruptured myocardial abscesses.
PMID- 10768896
TI - Left ventricular free wall rupture: clinical presentation and management.
PMID- 10768897
TI - Survival of patients with a new diagnosis of heart failure: a population based
study.
AB - OBJECTIVE: To describe the survival of a population based cohort of patients with
incident (new) heart failure and the clinical features associated with mortality.
DESIGN: A population based observational study. SETTING: Population of 151 000
served by 82 general practitioners in west London. PATIENTS: New cases of heart
failure were identified by daily surveillance of acute hospital admissions to the
local district general hospital, and by general practitioner referral of all
suspected new cases of heart failure to a rapid access clinic. INTERVENTIONS: All
patients with suspected heart failure underwent clinical assessment, and chest
radiography, ECG, and echocardiogram were performed. A panel of three
cardiologists reviewed all the data and determined whether the definition of
heart failure had been met. Patients were subsequently managed by the general
practitioner in consultation with the local cardiologist or admitting physician.
MAIN OUTCOME MEASURES: Death, overall and from cardiovascular causes. RESULTS:
There were 90 deaths (83 cardiovascular deaths) in the cohort of 220 patients
with incident heart failure over a median follow up of 16 months. Survival was
81% at one month, 75% at three months, 70% at six months, 62% at 12 months, and
57% at 18 months. Lower systolic blood pressure, higher serum creatinine
concentration, and greater extent of crackles on auscultation of the lungs were
independently predictive of cardiovascular mortality (all p < 0.001).
CONCLUSIONS: In patients with new heart failure, mortality is high in the first
few weeks after diagnosis. Simple clinical features can identify a group of
patients at especially high risk of death.
PMID- 10768898
TI - Abnormal cardiopulmonary exercise variables in asymptomatic relatives of patients
with dilated cardiomyopathy who have left ventricular enlargement.
AB - BACKGROUND: Left ventricular enlargement with normal systolic function is common
in asymptomatic relatives of patients with familial dilated cardiomyopathy, many
of whom progress to overt dilated cardiomyopathy at follow up. OBJECTIVE: To
examine maximal and submaximal gas exchange variables of cardiopulmonary exercise
testing in asymptomatic relatives with left ventricular enlargement. DESIGN AND
SETTING: Controlled evaluation of metabolic exercise performance of patients with
dilated cardiomyopathy and asymptomatic relatives with left ventricular
enlargement identified through prospective family screening in a cardiomyopathy
outpatient clinic. METHODS: 23 relatives with left ventricular enlargement, 33
normal controls, 29 patients with dilated cardiomyopathy, and 10 elite athletes
with echocardiographic criteria of left ventricular enlargement ("physiological"
enlargement) underwent symptom limited upright cycle ergometry using a ramp
protocol. RESULTS: Peak oxygen consumption (pVO(2); mean (SD)) was significantly
reduced in relatives with left ventricular enlargement (78 (16.3)%) v normal
controls (96%, p < 0.01) and athletes (152%, p < 0.001), but was higher than in
patients with dilated cardiomyopathy (69%, p < 0.01). pVO(2) was less than 80% of
predicted in 75% of patients, 58% of relatives, 22% of controls, and none of the
athletes. Oxygen pulse (pVO(2)/heart rate) was less than 80% of predicted in 69%
of patients, 35% of relatives, 6% of controls, and none of the athletes. The
slope of minute ventilation v CO(2) production (DeltaVE/DeltaVCO(2)) was > 30 in
68% of patients, 50% of relatives, and in none of the controls or athletes.
Anaerobic threshold, occurring in relatives at 37 (14)% of the predicted VO(2),
was higher than in the patients (32%, p < 0.01) and lower than in the controls
(45%, p < 0.05) or in the athletes (55%, p < 0.001). CONCLUSIONS: Maximal and
submaximal cardiopulmonary exercise test variables are abnormal in asymptomatic
relatives with left ventricular enlargement, in spite of normal systolic
function. This provides further evidence that left ventricular enlargement
represents subclinical disease in relatives of patients with dilated
cardiomyopathy. Metabolic exercise testing can complement echocardiography in
identifying relatives at risk for the development of dilated cardiomyopathy.
PMID- 10768899
TI - Mid-ventricular HOCM with apical asynergy.
PMID- 10768900
TI - Comparison of myocardial contrast echocardiography with NC100100 and (99m)Tc
sestamibi SPECT for detection of resting myocardial perfusion abnormalities in
patients with previous myocardial infarction.
AB - OBJECTIVE: To determine whether myocardial contrast echocardiography (MCE)
following intravenous injection of perfluorocarbon microbubbles permits
identification of resting myocardial perfusion abnormalities in patients who have
had a previous myocardial infarction. PATIENTS AND INTERVENTIONS: 22 patients
(mean (SD) age 66 (11) years) underwent MCE after intravenous injection of
NC100100, a novel perfluorocarbon containing contrast agent, and resting (99m)Tc
sestamibi single photon emission computed tomography (SPECT). With both methods,
myocardial perfusion was graded semiquantitatively as 1 = normal, 0.5 = mild
defect, and 0 = severe defect. RESULTS: Among the 203 normally contracting
segments, 151 (74%) were normally perfused by SPECT and 145 (71%) by MCE. With
SPECT, abnormal tracer uptake was mainly found among normally contracting
segments from the inferior wall. By contrast, with MCE poor myocardial
opacification was noted essentially among the normally contracting segments from
the anterior and lateral walls. Of the 142 dysfunctional segments, 87 (61%)
showed perfusion defects by SPECT, and 94 (66%) by MCE. With both methods,
perfusion abnormalities were seen more frequently among akinetic than hypokinetic
segments. MCE correctly identified 81/139 segments that exhibited a perfusion
defect by SPECT (58%), and 135/206 segments that were normally perfused by SPECT
(66%). Exclusion of segments with attenuation artefacts (defined as abnormal
myocardial opacification or sestamibi uptake but normal contraction) by either
MCE or SPECT improved both the sensitivity (76%) and the specificity (83%) of the
detection of SPECT perfusion defects by MCE. CONCLUSIONS: The data suggest that
MCE allows identification of myocardial perfusion abnormalities in patients who
have had a previous myocardial infarction, provided that regional wall motion is
simultaneously taken into account.
PMID- 10768901
TI - Long term outcome of infective endocarditis in patients who were not drug
addicts: a 10 year study.
AB - OBJECTIVE: To determine the clinical features and long term prognosis of
infective endocarditis in patients who were not drug addicts. DESIGN: Prospective
case series. SETTING: A university hospital that is both a referral and a primary
care centre. PATIENTS: 138 consecutive cases of infective endocarditis diagnosed
and treated from January 1987 to March 1997. RESULTS: Mean patient age was 44
(20) years old. 95 patients (69%) had native valve endocarditis and 43 (31%) had
prosthetic valve endocarditis. Staphylococci were the causal microorganisms in
34% of cases and streptococci in 33%. Severe complications occurred in 83% of
patients and 51% of patients underwent surgery during the active phase (22% was
emergency surgery). Inpatient mortality was 21%. During a follow up of 56 (44)
months, 10 patients (9%) needed late cardiac surgery and seven (5% of the whole
series) died. Overall 10 year survival was 71%. There were no significant
differences in survival depending on the type of treatment received during the
hospital stay (medical or combined medical-surgical). CONCLUSIONS: A high early
surgery rate is related to good long term results and does not increase in
hospital mortality. Medical treatment, however, also offers favourable long term
results in cases of responsive infective endocarditis where poor prognostic
factors are absent.
PMID- 10768902
TI - Heart rate variability and baroreflex sensitivity in idiopathic dilated
cardiomyopathy.
AB - OBJECTIVE: To examine the relation between cardiac autonomic tone, assessed by
baroreflex sensitivity and heart rate variability, and left ventricular function,
arrhythmias on Holter monitoring, and clinical variables in patients with
idiopathic dilated cardiomyopathy. DESIGN: A prospective observational study.
PATIENTS: 160 patients with idiopathic dilated cardiomyopathy and preserved sinus
rhythm in the absence of antiarrhythmic drug treatment. Measures of heart rate
variability obtained by digital 24 hour Holter recordings included the mean of
all coupling intervals between normal beats (RRm), the standard deviation of the
mean of normal RR intervals (SDNN), and the square root of the mean of the
squared differences between adjacent normal RR intervals (rMSSD). Baroreflex
sensitivity testing was performed using the phenylephrine method. RESULTS: Mean
SDNN (SEM) was 112 (46) ms, and baroreflex sensitivity was 7.5 (5.0) ms/mm Hg.
SDNN showed a weak correlation with baroreflex sensitivity (r = 0.19, p < 0.05)
and with left ventricular ejection fraction (r = 0.29, p < 0.05). SDNN showed no
significant correlation with age (r = -0.07), the presence of non-sustained
ventricular tachycardia (r = -0.13), or left ventricular end diastolic diameter
(r = -0.07). In addition, baroreflex sensitivity showed no significant
correlation with age (r = -0.13), non-sustained ventricular tachycardia (r =
0.08), left ventricular end diastolic diameter (r = 0.09), or ejection fraction
(r = 0.14). CONCLUSIONS: The weak correlation between baroreflex sensitivity and
heart rate variability suggests that these two indices explore different aspects
of cardiac autonomic control in patients with idiopathic dilated cardiomyopathy.
The weak or absent correlation between baroreflex sensitivity, heart rate
variability, and other potential non-invasive risk predictors, including left
ventricular ejection fraction, left ventricular end diastolic diameter, and non
sustained ventricular tachycardia on Holter monitoring, indicate that these
variables may have independent prognostic value in idiopathic dilated
cardiomyopathy.
PMID- 10768903
TI - Left atrial volume assessed by transthoracic three dimensional echocardiography
and magnetic resonance imaging: dynamic changes during the heart cycle in
children.
AB - OBJECTIVE: To assess the dynamic changes in left atrial volume by transthoracic
three dimensional echocardiography and compare the results with those obtained by
magnetic resonance imaging (MRI). DESIGN AND PATIENTS: 30 healthy children (15
boys and 15 girls, aged 8 to 13 years) underwent examination by three dimensional
echocardiography and MRI. METHODS: Three dimensional echocardiography of the left
atrium was performed using rotational acquisition of planes at 18 degrees
intervals from the parasternal window with ECG gating and without respiratory
gating. Volume estimation by MRI was performed with a slice thickness of 4-8 mm
and ECG triggering during breath holding in deep inspiration. A left atrial time
volume curve was reconstructed in each child. RESULTS: Left atrial maximum and
minimum volumes averaged 24.0 ml/m(2) and 7. 6 ml/m(2) by three dimensional
echocardiography, and 22.1 ml/m(2) and 11.9 ml/m(2) by MRI. The greater left
atrial minimum volume in the latter was at least in part a result of breath
holding. Dynamic changes in left atrial volume during the heart cycle were
detectable by both methods. The higher temporal resolution of three dimensional
echocardiography allowed a more precise evaluation of different phases.
CONCLUSIONS: Three dimensional echocardiography and MRI were both useful methods
for studying the physiological volume changes in the left atrium in children.
These methods may be used for further study of the systolic and diastolic
function of the heart.
PMID- 10768904
TI - Distal end of the atrioventricular nodal artery predicts the risk of
atrioventricular block during slow pathway catheter ablation of atrioventricular
nodal re-entrant tachycardia.
AB - OBJECTIVE: To search for a reliable anatomical landmark within Koch's triangle to
predict the risk of atrioventricular (AV) block during radiofrequency slow
pathway catheter ablation of AV nodal re-entrant tachycardia (AVNRT). PATIENTS
AND METHODS: To test the hypothesis that the distal end of the AV nodal artery
represents the anatomical location of the AV node, and thus could be a useful
landmark for predicting the risk of AV block, 128 consecutive patients with AVNRT
receiving slow pathway catheter ablation were prospectively studied in two
phases. In phase I (77 patients), angiographic demonstration of the AV nodal
artery and its ending was performed at the end of the ablation procedure, whereas
in the subsequent phase II study (51 patients), the angiography was performed
immediately before catheter ablation to assess the value of identifying this new
landmark in reducing the risk of AV block. Multiple electrophysiologic and
anatomical parameters were analysed. The former included the atrial activation
sequence between the His bundle recording site (HBE) and the coronary sinus
orifice or the catheter ablation site, either during AVNRT or during sinus
rhythm. The latter included the spatial distances between the distal end of the
AV nodal artery and the HBE and the final catheter ablation site, and the
distance between the HBE and the tricuspid border at the coronary sinus orifice
floor. RESULTS: In phase I, nine of the 77 patients had complications of
transient (seven patients) or permanent (two patients) complete AV block during
stepwise, anatomy guided slow pathway catheter ablation. These nine patients had
a wider distance between the HBE and the distal end of the AV nodal artery, and a
closer approximation of the catheter ablation site to the distal end of the AV
nodal artery, which independently predicted the risk of AV block. In contrast,
none of the available electrophysiologic parameters were shown to be reliable.
When the distance between the distal end of the AV nodal artery and the ablation
target site was more than 2 mm, the complication of AV block virtually never
occurred. In phase II, all 51 patients had successful elimination of the slow
pathways without complication when the ablation procedure was guided by preceding
angiography with identification of the distal end of the AV nodal artery.
CONCLUSIONS: The distal end of the AV nodal artery shown by angiography serves as
a useful landmark for the prediction of the risk of AV block during slow pathway
catheter ablation of AVNRT.
PMID- 10768905
TI - Strangulated gastric volvulus: an unusual cause of cardiac compression resulting
in electromechanical dissociation.
PMID- 10768906
TI - Intracoronary dipyridamole reduces the incidence of abrupt vessel closure
following PTCA: a prospective randomised trial.
AB - OBJECTIVES: To investigate the effect of intracoronary dipyridamole on the
incidence of abrupt vessel closure, myocardial infarction, necessity for bypass
grafting, and death following percutaneous transluminal coronary angioplasty
(PTCA). PATIENTS: Patients were randomly allocated to receive either conventional
pretreatment (heparin 15 000 IU and aspirin 500 mg intravenously) or additional
intracoronary dipyridamole (0.5 mg/kg bodyweight). Dipyridamole was administered
in 550 PTCA procedures (455 interventions in men, mean (SD) age 59.2 (8.4) years;
74 acute coronary syndromes), while conventional pretreatment was administered in
544 interventions (444 interventions in men 58.3 (7.9) years old; 81 acute
coronary syndromes). In 53 interventions bail out stenting was performed for
threatened abrupt vessel closure. RESULTS: Intracoronary dipyridamole
significantly reduced the incidence of abrupt vessel closure (odds ratio 0.42.
95% confidence interval (CI) 0.22 to 0.79). While abrupt vessel closure occurred
in 6.1% of interventions following conventional pretreatment, dipyridamole
reduced the incidence to 2.5%. Restricting the analysis to balloon angioplasty,
this reduction was observed in patients with stable angina (odds ratio 0.49, 95%
CI 0.23 to 0.96) as well as in those with acute coronary syndromes (odds ratio
0.29, 95% CI 0.09 to 0.87). Reduction of secondary end points in the dipyridamole
treated patients failed to reach significance in the PTCA group. CONCLUSIONS:
Intracoronary dipyridamole before PTCA reduces the incidence of abrupt vessel
closure following PTCA for stable angina and acute coronary syndromes.
PMID- 10768907
TI - Effusive-constrictive pericarditis.
PMID- 10768908
TI - Triage of patients for short term observation after elective coronary
angioplasty.
AB - OBJECTIVE: To evaluate triage of patients for short term observation after
elective percutaneous transluminal coronary angioplasty (PTCA), as appropriate
selection of patients for short term observation after angioplasty may facilitate
early discharge. METHODS: 1015 consecutive patients scheduled for elective PTCA
were prospectively included for short term observation. Patients with unstable
angina Braunwald class III were excluded. There were no angiographic exclusion
criteria. Patients were discharged from the interventional centre when considered
stable during 4 hours of observation after PTCA. It was left to the operator's
discretion whether to prolong the observation period. Procedural complications
were defined as death, coronary bypass surgery, early repeat PTCA, and myocardial
infarction. OUTCOME MEASURES: The need for prolonged observation (> 4 hours) and
the occurrence of complications. Predictors for prolonged observation and the
occurrence of complications after the 4 hours observation were assessed by
univariate and multivariate analysis. RESULTS: Two patients died, including one
of six patients who underwent emergency bypass surgery. In all, 922 patients
(90.8%) were triaged to short term observation and had an uncomplicated three day
follow up. Observation was prolonged in 87 patients (8.6%), and 40 patients had a
complicated course. Independent predictors of procedural complications were acute
closure (odds ratio (OR) 9.7; 95% confidence interval 4.4 to 21.4), side branch
occlusion (OR 8.9; 3.4 to 23.7), no angiographic success (OR 5.1; 2.4 to 11.0),
female sex (OR 3.1, 1.7 to 5.7), any unplanned stent (OR 2.8, 1.4 to 5.9), and
ostial lesion (OR 2.2, 1.0 to 4.7). CONCLUSIONS: A 4 hour observation period is
safe after elective coronary angioplasty. As procedural variables are the
strongest predictors of postprocedural complications, the immediate procedural
results allow effective triage of patients for short term or prolonged
observation in order to anticipate complications.
PMID- 10768909
TI - Potentially fatal atrial pacemaker lead disruption detected by fluoroscopic
surveillance.
PMID- 10768910
TI - The Newcastle protocols for head-up tilt table testing in the diagnosis of
vasovagal syncope, carotid sinus hypersensitivity, and related disorders.
PMID- 10768911
TI - Evaluation of in vivo biocompatibility of different devices for interventional
closure of the patent ductus arteriosus in an animal model.
AB - OBJECTIVE: To evaluate the in vivo biocompatibility of three different devices
following interventional closure of a patent ductus arteriosus (PDA) in an animal
model. MATERIALS AND METHODS: A medical grade stainless steel coil (n = 8), a
nickel/titanium coil (n = 10), and a polyvinylalcohol foam plug knitted on a
titanium wire frame (n = 11) were used for interventional closure of PDA in a
neonatal lamb model. The PDA had been maintained by repetitive angioplasty.
Between one and 278 days after implantation the animals were killed and the
ductal block removed. In addition to standard histology and scanning electron
microscopy, immunohistochemical staining for biocompatibility screening was also
undertaken. RESULTS: Electron microscopy revealed the growth of a cellular layer
in a cobblestone pattern on the implant surfaces with blood contact, which was
completed as early as five weeks after implantation of all devices.
Immunohistochemical staining of these superficial cells showed an endothelial
cell phenotype. After initial thrombus formation causing occlusion of the PDA
after implantation there was ingrowth of fibromuscular cells resembling smooth
muscle cells. Transformation of thrombotic material was completed within six
weeks in the polyvinylalcohol plug and around the nickel/titanium coil, and
within six months after implantation of the stainless steel coil. An implant
related foreign body reaction was seen in only one of the stainless steel coil
specimens and in two of the nickel/titanium coil specimens. CONCLUSION: After
implantation, organisation of thrombotic material with ingrowth of fibromuscular
cells was demonstrated in a material dependent time pattern. The time it took for
endothelium to cover the implants was independent of the type of implant. Little
or no inflammatory reaction of the surrounding tissue was seen nine months after
implantation.
PMID- 10768912
TI - Inhibition of angiotensin converting enzyme cannot prevent increases in
angiotensin II production in coronary circulation.
AB - OBJECTIVE: To determine whether inhibition of angiotensin converting enzyme (ACE)
can prevent angiotensin II production in the coronary circulation induced by
percutaneous transluminal coronary angioplasty (PTCA) in patients with myocardial
ischaemia. DESIGN, PATIENTS: 41 patients who underwent elective PTCA and six
control subjects who received diagnostic coronary angiography were studied.
Patients were divided into two groups according to the chronic administration of
ACE inhibitors (group A, 15 patients treated with ACE inhibitors; group B, 26
patients without ACE inhibitors). Blood samples were drawn through catheters
placed in the aorta and coronary sinus before and 24 hours after PTCA. RESULTS:
Mean levels of ACE activity in the aorta were significantly lower in patients in
group A than in group B. However, mean angiotensin II concentrations in the aorta
were not significantly different between the two groups. Differences in basal
angiotensin II concentrations between the coronary sinus and aorta, which
reflected basal angiotensin II production in the coronary circulation, were not
significant among group A, group B, and control subjects. The production of
angiotensin II in the coronary circulation was significantly increased 24 hours
after PTCA in both group A and group B to the same extent. No significant changes
were observed in control subjects 24 hours after diagnostic coronary angiography.
CONCLUSIONS: This study revealed that inhibition of ACE activity by ACE
inhibitors could not prevent increases in angiotensin II production in the
coronary circulation induced by PTCA.
PMID- 10768913
TI - Plasma fibrinogen, soluble P-selectin, and von Willebrand factor in aortic valve
disease: evidence for abnormal haemorheology, platelet activation, and
endothelial dysfunction.
PMID- 10768914
TI - Raised interleukin 6 concentrations as a predictor of postangioplasty restenosis.
PMID- 10768915
TI - Late aortic homograft valve endocarditis caused by Cardiobacterium hominis: a
case report and review of the literature.
AB - An unusual case of Cardiobacterium hominis endocarditis involving an aortic
homograft valve is presented. Although the patient was young (a 17 year old man)
and showed few of the characteristic features of the disease, the report does
illustrate a number of the problems associated with this illness and highlights
the need for the careful assessment of apparent culture negative endocarditis.
The organism itself is susceptible to most antibiotics but further treatment,
including surgery, may be necessary. Patients must therefore be examined
repeatedly and assessed for haemodynamic deterioration, valve destruction or
embolic phenomena. Homograft valve replacement may offer some benefits in the
setting of aortic valve endocarditis and is therefore an attractive option in
this situation.
PMID- 10768916
TI - Onset and termination of atrial fibrillation.
PMID- 10768917
TI - Arrhythmogenic right ventricular cardiomyopathy: diagnosis, prognosis, and
treatment.
PMID- 10768918
TI - Epidemiology, aetiology, and prognosis of heart failure.
PMID- 10768919
TI - Non-transplant surgery for heart failure.
PMID- 10768920
TI - Transient appearance of antegrade conduction via an AV accessory pathway caused
by atrial fibrillation in a patient with intermittent Wolff-Parkinson-White
syndrome.
AB - A 55 year old man with intermittent Wolff-Parkinson-White (WPW) syndrome had an
episode of atrial fibrillation (AF) that lasted for 117 days. After interruption
of the AF a Delta wave appeared that lasted for two days and then disappeared.
Exercise stress and isoprenaline infusion could not reproduce the Delta wave, but
after another episode of AF which lasted for seven days a persistent Delta wave
appeared that lasted for six hours. In an electrophysiological study performed on
a day without a Delta wave, neither antegrade nor retrograde conduction via an
accessory pathway was seen, but after atrial burst pacing (at 250 ms cycle
length) for 10 minutes, a Delta wave appeared lasting for 16 seconds. Atrial
electrical remodelling-that is, the shortening of the atrial effective refractory
period caused by AF, is a possible mechanism of the appearance of the Delta wave.
PMID- 10768921
TI - Coronary arteries from a single coronary ostium in the right coronary sinus: a
previously unreported anatomy.
AB - The coronary circulation originating from a single coronary ostium is rare. All
possible anatomical variations were the basis of a recent classification. This
case report describes a previously unreported IID(1) pattern, comprising a
solitary coronary ostium in the right coronary sinus with an anatomical course of
the right coronary artery. The left circumflex coronary artery arises from the
proximal right coronary artery coursing behind the aorta to the left. The left
anterior descending coronary artery arises from the proximal right coronary
artery coursing to the left side anterior to the right ventricle.
PMID- 10768922
TI - Immune destruction of larval taenia crassiceps in mice.
AB - Immune destruction of larval Taenia crassiceps was examined by first injecting
BALB/cJ mice subcutaneously with larval buds and 30 to 60 days later challenging
the mice with larvae injected into the peritoneal cavity. The larvae injected
intraperitoneally (i.p.) secondarily are killed by host cells that completely
encase the larvae in a thick sheath. The peritoneal exudate cells and the
cytokines they produced were characterized by flow cytometry, enzyme-linked
immunosorbent assays (ELISAs), and reverse transcription PCR (RT-PCR). No changes
in percentage of CD4(+) T cells, CD8(+) T cells, B1 cells, or macrophages were
detected in the peritoneal cavities of mice that were killing larvae compared to
mice with a primary 7-day infection i.p. Both RT-PCR and ELISA demonstrated a
decrease in cytokines including gamma interferon (IFN-gamma), interleukin-4 (IL
4), and IL-10 in mice that were killing the larvae compared to control mice
infected for 30 to 60 days i.p. alone, although there was little difference
compared to mice infected for 7 days i.p. alone. Serum cytokine levels in mice
that were killing the larvae showed a decrease in IFN-gamma and IL-4, an increase
in IL-10 when compared to mice infected for 30 to 60 days i.p. alone, and
increases in all cytokines compared to mice infected for 7 days i.p. alone.
Inhibition of nitric oxide production did not significantly affect the number or
the viability of larvae in the peritoneal cavity of mice that were killing larvae
during secondary infection.
PMID- 10768923
TI - Binding to and opsonophagocytic activity of O-antigen-specific monoclonal
antibodies against encapsulated and nonencapsulated Klebsiella pneumoniae
serotype O1 strains.
AB - The high mortality of nosocomial infections caused by Klebsiella spp. has acted
as a stimulus to develop immunotherapeutic approaches targeted against surface
molecules of these bacteria. Since O-antigen-specific antibodies may add to the
protective effect of K antisera, we tested the functional and binding capacity of
O-antigen-specific monoclonal antibodies (MAbs) raised against different
Klebsiella O antigens. The MAbs tested were specific for the O-polysaccharide
partial antigens D-galactan II (MAb Ru-O1), D-galactan I (MAb IV/4-5), or core
oligosaccharide (MAb V/9-5) of the Klebsiella serogroup O1 antigen. In enzyme
linked immunosorbent assay binding experiments, we found that all MAbs recognized
their epitopes on intact capsule-free bacteria; however, binding to encapsulated
wild-type strains belonging to different K-antigen serotypes was significantly
reduced. The K2 antigen acted as the strongest penetration barrier, while the K7
and K21 antigens allowed some, though diminished, antibody binding. In vitro
phagocytic killing experiments showed that MAb Ru-O1 possessed significant
opsonizing activity for nonencapsulated O1 serogroup strains and also, to a much
lesser extent, for encapsulated strains belonging to the O1:K7 and O1:K21
serotypes. MAbs or antisera specific for the D-galactan II antigen may thus be
the most promising agents for further efforts to develop a second-generation
Klebsiella hyperimmune globulin comprising both K- and O-antigen specificities.
PMID- 10768924
TI - Lipopolysaccharide-binding protein and phospholipid transfer protein release
lipopolysaccharides from gram-negative bacterial membranes.
AB - Although animals mobilize their innate defenses against gram-negative bacteria
when they sense the lipid A moiety of bacterial lipopolysaccharide (LPS),
excessive responses to this conserved bacterial molecule can be harmful. Of the
known ways for decreasing the stimulatory potency of LPS in blood, the binding
and neutralization of LPS by plasma lipoproteins is most prominent. The
mechanisms by which host lipoproteins take up the native LPS that is found in
bacterial membranes are poorly understood, however, since almost all studies of
host-LPS interactions have used purified LPS aggregates. Using native Salmonella
enterica serovar Typhimurium outer membrane fragments (blebs) that contained (3)H
labeled lipopolysaccharide (LPS) and (35)S-labeled protein, we found that two
human plasma proteins, LPS-binding protein (LBP) and phospholipid transfer
protein (PLTP), can extract [(3)H]LPS from bacterial membranes and transfer it to
human high-density lipoproteins (HDL). Soluble CD14 (sCD14) did not release LPS
from blebs yet could facilitate LBP-mediated LPS transfer to HDL. LBP, but not
PLTP, also promoted the activation of human monocytes by bleb-derived LPS.
Whereas depleting or neutralizing LBP significantly reduced LPS transfer from
blebs to lipoproteins in normal human serum, neutralizing serum PLTP had no
demonstrable effect. Of the known lipid transfer proteins, LBP is thus most able
to transfer LPS from bacterial membranes to the lipoproteins in normal human
serum.
PMID- 10768925
TI - Transforming growth factor-beta inhibits lipopolysaccharide-stimulated expression
of inflammatory cytokines in mouse macrophages through downregulation of
activation protein 1 and CD14 receptor expression.
AB - The septic shock that occurs in gram-negative infections is caused by a cascade
of inflammatory cytokines. Several studies showed that transforming growth factor
beta1 (TGF-beta1) inhibits this septic shock through suppression of expression of
the lipopolysaccharide (LPS)-induced inflammatory cytokines. In this study, we
investigated whether TGF-beta1 inhibition of LPS-induced expression of
inflammatory cytokines in the septic shock results from downregulation of LPS
stimulated expression of CD14, an LPS receptor. TGF-beta1 markedly inhibited LPS
stimulation of CD14 mRNA and protein levels in mouse macrophages. LPS-stimulated
expression of CD14 was dramatically inhibited by addition of antisense, but not
sense, c-fos and c-jun oligonucleotides. Since TGF-beta1 pretreatment inhibited
LPS-stimulated expression of c-fos and c-jun genes and also the binding of
nuclear proteins to the consensus sequence of the binding site for activation
protein 1 (AP-1), a heterodimer of c-Fos and c-Jun, in the cells, TGF-beta1
inhibition of CD14 expression may be a consequence of downregulation of AP-1. LPS
stimulated expression of interleukin-1beta and tumor necrosis factor alpha genes
in the cells was inhibited by addition of CD14 antisense oligonucleotide. Also,
TGF-beta1 inhibited the LPS-stimulated production of both inflammatory cytokines
by the macrophages. In addition, TGF-beta1 inhibited expression of the two
cytokines in several organs of mice receiving LPS. Thus, our results suggest that
TGF-beta1 inhibition of LPS-stimulated inflammatory responses resulted from
downregulation of CD14 and also may be a possible mechanism of TGF-beta1
inhibition of LPS-induced septic shock.
PMID- 10768926
TI - Interleukin-4 and interleukin-10 are involved in host resistance to
Staphylococcus aureus infection through regulation of gamma interferon.
AB - Our previous study showed that gamma interferon (IFN-gamma), a T-helper 1 (Th1)
type cytokine, plays a detrimental role in Staphylococcus aureus infection in
mice. In this study, the role of Th2-type cytokines such as interleukin-4 (IL-4)
and IL-10 in S. aureus infection was investigated. IL-10 mRNA was induced in
parallel with IFN-gamma in the spleens and kidneys of mice during S. aureus
infection, whereas IL-4 mRNA was induced in the spleens but not in the kidneys of
these animals. Spleen cells obtained from S. aureus-infected mice produced lower
titers of IFN-gamma and higher titers of IL-4 and IL-10 in response to heat
killed S. aureus than did those from uninfected mice. Administration of anti-IL-4
monoclonal antibody (MAb) or anti-IL-10 MAb inhibited the elimination of S.
aureus cells from the kidneys of mice. IFN-gamma mRNA expression was enhanced in
the spleens of anti-IL-4 MAb- or anti-IL-10 MAb-treated mice and also in the
kidneys of anti-IL-4 MAb-treated animals. Next, we evaluated the role of IFN
gamma in S. aureus infection in IFN-gamma(-/-) mice. An increase in survival
rates, a decrease in bacterial numbers in the kidneys, and an amelioration of
histologic abnormalities in these organs were observed in IFN-gamma(-/-) mice
compared with those in IFN-gamma(+/+) mice. Administration of MAb against IL-4 or
IL-10 failed to affect bacterial growth in the spleens and kidneys of IFN-gamma(
/-) mice irrespective of the expression of Th2 response. These results suggest
that S. aureus infection induced a Th2 response and that IL-4 and IL-10 might
play a protective role through the regulation of IFN-gamma in S. aureus
infection.
PMID- 10768927
TI - Are B lymphocytes of importance in severe Staphylococcus aureus infections?
AB - To investigate the role of B cells in experimental, superantigen-mediated
Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell
deficient mice. The mice were inoculated intravenously with a toxic shock
syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and
thus agamma-globulinemic mice showed striking similarities to the wild-type
control animals with respect to the development of arthritis, the mortality rate,
and the rate of bacterial clearance. Surprisingly, we found that the levels of
gamma interferon in serum were significantly lower (P < 0. 0001) in B-cell
deficient mice than in the controls, possibly due to impaired superantigen
presentation and a diminished expression of costimulatory molecules. In contrast,
the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both
groups. Our findings demonstrate that neither mature B cells nor their products
significantly contribute to the course of S. aureus-induced septic arthritis.
PMID- 10768928
TI - Cloning and sequencing of the Klebsiella pneumoniae O5 wb gene cluster and its
role in pathogenesis.
AB - One representative recombinant clone encoding Klebsiella pneumoniae O5-antigen
lipopolysaccharide (LPS) was found upon screening for serum resistance in a
cosmid-based genomic library of K. pneumoniae KT769 (O5:K57) introduced into
Escherichia coli DH5alpha. A total of eight open reading frames (wb(O5) gene
cluster) were necessary to produce K. pneumoniae O5-antigen LPS in E. coli K-12.
The enzymatic activities proposed for the wb(O5) gene cluster are in agreement
with the activities proposed for the biosynthesis of K. pneumoniae O5-antigen
LPS. Using the complete DNA sequence of the K. pneumoniae wb(O5) gene cluster, we
obtained (by single or double recombination) genetically well-characterized
mutants devoid only of this O5-antigen LPS. Finally, using these O5(-) mutants
and the corresponding wild-type strains or complemented mutants with the wb(O5)
gene cluster (O5(+) strains), we found that the presence of K. pneumoniae O5
antigen LPS is essential for some pathogenic features like serum resistance,
adhesion to uroepithelial cells, and colonization (experimental infections) of
the urinary tract in rats.
PMID- 10768929
TI - Characterization of an isogenic mutant of Streptococcus pyogenes Manfredo lacking
the ability to make streptococcal acid glycoprotein.
AB - An isogenic mutant of Streptococcus pyogenes Manfredo that lacks the ability to
make streptococcal acid glycoprotein (SAGP) has been constructed by inserting a
deletion in the sagp gene using the method of allelic exchange. An assay of cell
extracts (CE) prepared from the wild-type and mutant Manfredo strains for the
enzyme arginine deiminase (AD) showed that significant activity was present in
wild-type CE but none could be detected in mutant CE. These findings confirm our
earlier conclusion that SAGP has AD activity (B. A. Degnan, J. M. Palmer, T.
Robson, C. E. D. Jones, M. Fischer, M. Glanville, G. D. Mellor, A. G. Diamond, M.
A. Kehoe, and J. A. Goodacre, Infect. Immun. 66:3050-3058, 1998). Wild-type CE
but not mutant CE potently inhibited human peripheral blood mononuclear cell
proliferation in response to phytohemagglutinin, and this inhibition was overcome
by the addition of L-arginine to proliferation assay mixtures. Invasion assays
showed that the isogenic mutant organisms lacking SAGP, and thus AD activity,
were between three and five times less able to enter epithelial cells (Hep-2C and
A549) than were the wild-type streptococci. Both wild-type and mutant S. pyogenes
bacteria were extremely sensitive to low pH. However, L-arginine (1 mM or above)
significantly increased the viability of the wild type but not the isogenic
mutant organisms under acidic conditions. The difference in acid susceptibility
between wild-type and mutant bacteria may explain the reduced capacity of the
isogenic mutant bacteria to invade and survive intracellularly.
PMID- 10768930
TI - Potentiality of interleukin-18 as a useful reagent for treatment and prevention
of Leishmania major infection.
AB - Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role
in natural killer cell activation and the T helper 1 (Th1) cell response,
particularly in collaboration with IL-12. Since Th1 cells play a pivotal role in
the host defense against infection with intracellular microbes, such as
Leishmania major, we investigated whether IL-18 is critically involved in
protection against L. major infection by activation of Th1 cells. We administered
IL-12 and/or IL-18 daily to L. major-susceptible BALB/c mice. Neither IL-12 (10
ng/mouse) nor IL-18 (1,000 ng/mouse) induced wound healing, while daily injection
of IL-12 and IL-18 during the first week after infection strongly protected the
mice from footpad swelling by induction and activation of Th1 cells. Furthermore,
these mice acquired protective immunity. We also investigated a protective role
of endogenous IL-18 by using anti-IL-18 antibody-treated C3H/HeN mice (an L.
major-resistant strain) or IL-18 deficient (IL-18(-/-)) mice with a resistant
background (C57BL/6). We found that in the absence of endogenous IL-18, these
mice showed prolonged footpad swelling as well as diminished nitric oxide
production. However, daily injection of IL-18 into IL-18(-/-) mice corrected
their deficiencies, suggesting that these mice have Th1 cells that produce gamma
interferon (IFN-gamma) in response to IL-18. Indeed, these mice had normal levels
of Th1 cells. Thus, IL-18 is not responsible for inducing Th1 cells but
participates in host resistance by its action in stimulating Th1 cells to produce
IFN-gamma. Our results also indicate the high potentiality of IL-18 as a useful
reagent for treatment as well as prevention against reinfection.
PMID- 10768931
TI - The sigA gene which is borne on the she pathogenicity island of Shigella flexneri
2a encodes an exported cytopathic protease involved in intestinal fluid
accumulation.
AB - In this study, the sigA gene situated on the she pathogenicity island of Shigella
flexneri 2a was cloned and characterized. Sequence analysis showed that sigA
encodes a 139.6-kDa protein which belongs to the SPATE (serine protease
autotransporters of Enterobacteriaceae) subfamily of autotransporter proteins.
The demonstration that SigA is autonomously secreted from the cell to yield a 103
kDa processed form and possesses a conserved C-terminal domain for export from
the cell were consistent with the autotransporter pathway of secretion.
Functional analysis showed that SigA is a secreted temperature-regulated serine
protease capable of degrading casein. SigA was cytopathic for HEp-2 cells,
suggesting that it may be a cell-altering toxin with a role in the pathogenesis
of Shigella infections. SigA was at least partly responsible for the ability of
S. flexneri to stimulate fluid accumulation in ligated rabbit ileal loops.
PMID- 10768933
TI - pH-induced conformational changes in Clostridium difficile toxin B.
AB - Toxin B from Clostridium difficile is a monoglucosylating toxin that targets
substrates within the cytosol of mammalian cells. In this study, we investigated
the impact of acidic pH on cytosolic entry and structural changes within toxin B.
Bafilomycin A1 was used to block endosomal acidification and subsequent toxin B
translocation. Cytopathic effects could be completely blocked by addition of
bafilomycin A1 up to 20 min following toxin treatment. Furthermore, providing a
low extracellular pH could circumvent the effect of bafilomycin A1 and other
lysosomotropic agents. Acid pH-induced structural changes were monitored by using
the fluorescent probe 2-(p-toluidinyl) naphthalene-6-sulfonic acid, sodium salt
(TNS), inherent tryptophan fluorescence, and relative susceptibility to a
specific protease. As the toxin was exposed to lower pH there was an increase in
TNS fluorescence, suggesting the exposure of hydrophobic domains by toxin B. The
change in hydrophobicity appeared to be reversible, since returning the pH to
neutrality abrogated TNS fluorescence. Furthermore, tryptophan fluorescence was
quenched at the acidic pH, indicating that domains may have been moving into more
aqueous environments. Toxin B also demonstrated variable susceptibility to
Staphylococcus aureus V8 protease at neutral and acidic pH, further suggesting pH
induced structural changes in this protein.
PMID- 10768932
TI - Candida albicans and Candida krusei differentially induce human blood mononuclear
cell interleukin-12 and gamma interferon production.
AB - Protection against Candida infection involves both innate and acquired immune
responses, and cytokines produced by monocytes during the innate response may
modify the acquired immune response by T cells. We hypothesized that Candida
species which differ in pathogenicity can differentially induce production of
immunoregulatory cytokines by human monocytes, which in turn modify T cells for
immune responses to Candida. To test this hypothesis, we examined the effects of
Candida albicans and Candida krusei on immunoregulatory cytokine production by
human monocytes and gamma interferon (IFN-gamma) production by peripheral blood
mononuclear cells (PBMC). Purified monocytes were incubated with live or heat
killed strains of C. albicans and C. krusei at the optimal Candida/monocyte ratio
of 0.5. Cytokines in the supernatants were measured by enzyme-linked
immunosorbent assay. Our data demonstrated that live C. albicans and C. krusei
significantly induced interleukin-10 (IL-10), monocyte chemotactic factor 1, IL
1beta, and tumor necrosis factor alpha production by monocytes relative to
unstimulated monocytes. In contrast, unlike C. krusei, pathogenic live strains of
C. albicans induced no or only a minimal level of IL-12. The expression of IL-12
p40 mRNA levels by reverse transcription-PCR corroborated the IL-12 protein (p70)
findings. In human PBMC, human blood monocytes were the major source of both IL
10 and IL-12 production in response to C. albicans and C. krusei. Upon activation
of T cells in the presence of Candida-modified monocytes and antigen-presenting
cells, IL-12 production by PBMC treated with Candida organisms correlated
strongly with the level of IFN-gamma production by T cells. These results
indicate that the virulence of C. albicans may be related to its ability to
induce the monocytic type II cytokine IL-10, with a selective inhibition of IL-12
production, which may be responsible for the observed lack of T-cell IFN-gamma
and may restrain an effective type I immune response to Candida.
PMID- 10768934
TI - Purification, characterization, and molecular analysis of the gene encoding
glucosyltransferase from Streptococcus oralis.
AB - Streptococcus oralis is a member of the oral streptococcal family and an early
colonizing microorganism in the oral cavity of humans. S. oralis is known to
produce glucosyltransferase (GTase), which synthesizes glucans from sucrose. The
enzyme was purified chromatographically from a culture supernatant of S. oralis
ATCC 10557. The purified enzyme, GTase-R, had a molecular mass of 173 kDa and a
pI of 6.3. This enzyme mainly synthesized water-soluble glucans with no primer
dependency. The addition of GTase markedly enhanced the sucrose-dependent resting
cell adhesion of Streptococcus mutans at a level similar to that found in growing
cells of S. mutans. The antibody against GTase-R inhibited the glucan
synthesizing activities of Streptococcus gordonii and Streptococcus sanguis, as
well as S. oralis. The N-terminal amino acid sequence of GTase-R exhibited no
similarities to known GTase sequences of oral streptococci. Using degenerate PCR
primers, an 8.1-kb DNA fragment, carrying the gene (gtfR) coding for GTase-R and
its regulator gene (rgg), was cloned and sequenced. Comparison of the deduced
amino acid sequence revealed that the rgg genes of S. oralis and S. gordonii
exhibited a close similarity. The gtfR gene was found to possess a species
specific nucleotide sequence corresponding to the N-terminal 130 amino acid
residues. Insertion of erm or aphA into the rgg or gtfR gene resulted in
decreased GTase activity by the organism and changed the colony morphology of
these transformants. These results indicate that S. oralis GTase may play an
important role in the subsequent colonizing of mutans streptoccoci.
PMID- 10768935
TI - Yersinia enterocolitica invasin protein triggers differential production of
interleukin-1, interleukin-8, monocyte chemoattractant protein 1, granulocyte
macrophage colony-stimulating factor, and tumor necrosis factor alpha in
epithelial cells: implications for understanding the early cytokine network in
Yersinia infections.
AB - Yersinia enterocolitica infection of epithelial cells results in interleukin-8
(IL-8) mRNA expression. Herein we demonstrate that besides IL-8, increased mRNA
levels of five other cytokines, IL-1alpha, IL-1beta, monocyte chemoattractant
protein 1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and
tumor necrosis factor alpha (TNF-alpha), can be detected upon infection of HeLa
cells with Yersinia. Yersinia-triggered cytokine production was not affected by
blocking phosphatidylinositol-3-phosphate kinase with wortmannin, which inhibited
bacterial invasion. Comparable cytokine mRNA responses were triggered by
Escherichia coli expressing Yersinia inv, while no response was triggered by an
inv-deficient Yersinia mutant. Moreover, cytokine responses were independent from
metabolic activity of the bacteria, as killed bacterial cells were sufficient for
triggering cytokine responses in HeLa cells. Semiquantitative reverse
transcription-PCR analysis was used to assess the kinetics of cytokine mRNA
expression in infected HeLa cells. IL-8, IL-1alpha, IL-1beta, MCP-1, GM-CSF, and
TNF-alpha mRNA expression increased within 1 h postinfection, reached a maximum
after 3 to 4 h, and then declined to preinfection levels within 3 h. IL-8, MCP-1,
and GM-CSF were secreted by HeLa cells, whereas IL-1alpha and IL-1beta were not
secreted and thus were found exclusively intracellularly. TNF-alpha protein could
not be detected in cell lysates or supernatants. Stimulation of HeLa cells with
IL-1alpha was followed by increased IL-8 mRNA expression, whereas stimulation
with IL-8 did not induce cytokine production. Likewise, MCP-1 and GM-CSF did not
induce significant cytokine responses in HeLa cells. Our results implicate that
the initial host response to Yersinia infection might be sustained by IL-8, MCP
1, and GM-CSF produced by epithelial cells.
PMID- 10768936
TI - RpmA is required for nonopsonic phagocytosis of Pseudomonas aeruginosa.
AB - Pseudomonas aeruginosa causes severe respiratory tract infections in patients
with cystic fibrosis (CF). We have been examining nonopsonic phagocytosis of P.
aeruginosa by macrophages. To study the P. aeruginosa-macrophage interaction at
the molecular level, we have constructed a transposon Tn5G bank in a clinical
isolate of P. aeruginosa (strain 4020) and identified mutants resistant to
nonopsonic phagocytosis. Phagocytosis-resistant mutants were enriched by
passaging the transposon bank over 18 macrophage monolayers. Of 900 individual
mutants isolated from this enriched pool in a nonopsonic phagocytosis assay, we
identified 85 putative mutants that were resistant to phagocytosis. In this
study, we have characterized one of these transposon mutants, P. aeruginosa 4020
H27A, which was poorly ingested. H27A possessed a Tn5G insertion in a gene
encoding a protein with homology to the MotA proteins of several species of
bacteria. We have called this gene rpmA for required for phagocytosis by
macrophages. RpmA is one of two MotA paralogs in P. aeruginosa. This rpmA::Tn5G
mutant was motile both on agar plates and in visual examination of wet mounts.
The phagocytosis defect was partially complemented by providing the rpmA gene in
trans and fully complemented when both rpmA and rpmB were provided. A rpmA null
mutant was ingested by macrophages similar to the H27A transposon mutant. These
data suggest that the rpmA and rpmB gene products are required for the efficient
ingestion of P. aeruginosa by macrophages.
PMID- 10768937
TI - Tetanus toxin fragment C expressed in live Salmonella vaccines enhances antibody
responses to its fusion partner Schistosoma haematobium glutathione S
transferase.
AB - Tetanus toxoid has been used widely as an adjuvant. The atoxic fragment C from
tetanus toxin (TetC) is potently immunogenic when expressed in Salmonella vaccine
strains and has been used as a fusion partner for antigens (Ag). However, there
has been no formal comparison of the immunomodulatory impact of TetC on its
fusion partners. In this study, we have addressed this important issue. The
protective 28-kDa glutathione S-transferase (GST) from Schistosoma haematobium
(Sh28GST) was expressed either as a fusion to TetC or as the full-length Sh28GST
alone in a nonvirulent aroA-attenuated strain of Salmonella enterica serovar
Typhimurium. The Sh28GST proteins were soluble and stably expressed in
Salmonella, as evaluated by Western blotting with TetC and/or Sh28GST antisera.
Mice were immunized orally with a single dose of the live recombinant Salmonella.
The constructs were stable in mice but, dramatically, only the strain expressing
the TetC-Sh28GST fusion elicited significant antibody (Ab) responses directed
against Sh28GST as determined by enzyme-linked immunosorbent assay. An analysis
of the isotype profiles showed that these mice also produced anti-Sh28GST
immunoglobulin A and GST-neutralizing assays revealed high levels of neutralizing
Abs in sera. These are important correlates of protection in schistosomiasis. In
addition, stimulation of spleen cells from immunized mice with Sh28GST Ag showed
that both strains, expressing Sh28GST alone or the TetC-Sh28GST fusion, were able
to stimulate the secretion of Th1-related cytokines (gamma interferon and
interleukin 2) to comparable levels. Thus, TetC has modulated the immune
responses generated against its fusion partner, Sh28GST, by markedly enhancing
the Ab responses elicited. These results have important implications in the
rational development of live vaccines.
PMID- 10768938
TI - Interleukin-5 is essential for vaccine-mediated immunity but not innate
resistance to a filarial parasite.
AB - The study of protective immune mechanisms effective against filarial nematodes
has been hampered by the inability of these important human pathogens to infect
laboratory mice. Recently, Litomosoides sigmodontis, a natural parasite of rats,
has been developed as a valuable model for the study of filarial infection.
BALB/c mice are fully susceptible to infection with L. sigmodontis third-stage
larvae and develop patent infection. In contrast, mice on the C57BL background
are resistant, and parasites undergo only a single molt and do not mature to
adulthood. We used interleukin-5 (IL-5)-deficient mice on the C57BL/6 background
to address the role of IL-5 and eosinophils in the innate resistance of C57BL/6
mice. We found no differences in parasite survival between IL-5-deficient and
C57BL/6 mice. However, when these mice were used for the analysis of vaccine
mediated immunity, a critical role for IL-5 was elucidated. Mice genetically
deficient in IL-5 were unable to generate a protective immune response when
vaccinated with irradiated larvae, whereas C57BL/6 mice were fully protected from
challenge infection. These studies help to clarify the highly controversial role
of eosinophils in filarial infection.
PMID- 10768939
TI - rpoS gene function is a disadvantage for Escherichia coli BJ4 during competitive
colonization of the mouse large intestine.
AB - The ability of Escherichia coli to survive stress during growth in different
environments is, in large part, dependent on rpoS and the genes that comprise the
rpoS regulon. E. coli BJ4 and an isogenic BJ4 rpoS mutant were used to examine
the influence of the rpoS gene on E. coli colonization of the streptomycin
treated mouse large intestine. Colonization experiments in which the wild-type E.
coli BJ4 and its rpoS mutant were fed individually as well as simultaneously to
mice suggested that E. coli BJ4 does not face prolonged periods of nutrient
starvation in the mouse large intestine and that the rpoS regulon is not
expressed during long-term colonization after adaptation of the bacteria to the
gut environment.
PMID- 10768940
TI - Identification of a Haemophilus influenzae 5'-nucleotidase protein: cloning of
the nucA gene and immunogenicity and characterization of the NucA protein.
AB - We report on the identification of a surface-exposed, highly conserved,
immunogenic nontypeable Haemophilus influenzae (NTHi) protein, which elicits
cross-reactive bactericidal antibodies against NTHi. The protein was extracted
from NTHi strain P860295 with KSCN and purified; it migrated as a single band on
a sodium dodecyl sulfate-polyacrylamide gel with an apparent molecular mass of 63
kDa. Mouse antiserum generated against the purified protein was reactive on whole
cell enzyme-linked immunosorbent assay (ELISA) with seven NTHi strains and type b
Eagan and Whittier strains and exhibited bactericidal activity to homologous and
heterologous NTHi strains. However, the protein is made in small amounts in NTHi
as corroborated by immunoelectron microscopy. To further study this protein, we
cloned, sequenced, and expressed it recombinantly in Escherichia coli. The
recombinant protein is localized in the periplasm of E. coli and has been
purified to homogeneity. Both the recombinant and native proteins possess 5'
nucleotidase activity; hence, the protein has been called NucA. Mouse antiserum
directed against the recombinant NucA protein was reactive on Western immunoblots
and whole-cell ELISA with all H. influenzae strains tested including Eagan and
was bactericidal for two heterologous strains tested. The antiserum also resulted
in a log reduction in bacteremia, in an infant-rat protection study with H.
influenzae type b as the challenge strain. These features suggest that NucA is a
potential subunit vaccine candidate against NTHi disease.
PMID- 10768941
TI - Identification of murine B-cell and T-cell epitopes of Escherichia coli outer
membrane protein F with synthetic polypeptides.
AB - The major pore-forming outer membrane proteins (Omps) of gram-negative bacteria
demonstrate numerous immunomodulating properties and are involved in the
virulence of pathogenic strains. Because Escherichia coli OmpF is the best
characterized porin in terms of structural and functional characteristics, in
vitro B-cell and T-cell responses to this porin in six different strains of mice
were analyzed. Mice were immunized with purified OmpF trimers or overlapping
synthetic polypeptides (20-mers) spanning the entire 340-amino-acid sequence of
the OmpF monomer. T-cell proliferative responses and immunoglobulin G antibody
responses to native OmpF and the peptide analogues were determined. For each
strain, patterns of T-cell proliferation were similar regardless of whether
native OmpF or synthetic peptides were inoculated, although all strains
recognized one or more cryptic determinants. Mice exhibited several haplotype
specific responses, but genetically permissive epitopes were also identified.
Four peptides (75-94, 265-284, 295-314, and 305-324) elicited strong T-cell
proliferative responses from all strains of mice when mice were presensitized
with native OmpF or a homologous peptide. In general, 10 or fewer peptides were
recognized by sera from mice immunized with native OmpF or synthetic peptides,
and most sera from peptide-immunized mice reacted poorly with the native protein.
Four peptides spanning amino acids 45 to 64, 95 to 114, 115 to 134, and 275 to
294 were recognized by sera from all strains immunized with native OmpF but not
by sera from peptide-immunized mice. Peptides 245-264 and 305-324 were
universally recognized by sera from peptide-immunized mice, but these sera
reacted weakly or were negative when tested against the native protein. Based on
the pattern of cytokine secretion by proliferating T cells, immunization with
native OmpF polarizes T helper cells toward development of a TH1 response. T-cell
and B-cell responses have been investigated based on the assumption that
differences in epitope specificity could influence protective or pathologic host
reactions. Because of the high level of structural homology of OmpF to porins
isolated from other enteric pathogens, the identification of T- and B-cell
stimulatory determinants of E. coli OmpF may have broader application.
PMID- 10768942
TI - Nitric oxide participation in the fungicidal mechanism of gamma interferon
activated murine macrophages against Paracoccidioides brasiliensis conidia.
AB - Paracoccidioidomycosis, a systemic mycosis restricted to Latin America and
produced by the dimorphic fungus Paracoccidioides brasiliensis, is probably
acquired by inhalation of conidia produced by the mycelial form. The macrophage
(Mphi) represents the major cell defense against this pathogen; when activated
with gamma interferon (IFN-gamma), murine Mphis kill the fungus by an oxygen
independent mechanism. Our goal was to determine the role of nitric oxide in the
fungicidal effect of Mphis on P. brasiliensis conidia. The results revealed that
IFN-gamma-activated murine Mphis inhibited the conidium-to-yeast transformation
process in a dose-dependent manner; maximal inhibition was observed in Mphis
activated with 50 U/ml and incubated for 96 h at 37 degrees C. When Mphis were
activated with 150 to 200 U of cytokine per ml, the number of CFU was 70% lower
than in nonactivated controls, indicating that there was a fungicidal effect. The
inhibitory effect was reversed by the addition of anti-IFN-gamma monoclonal
antibodies. Activation by IFN-gamma also enhanced Mphi nitric oxide production,
as revealed by increasing NO(2) values (8 +/- 3 microM in nonactivated Mphis
versus 43 +/- 13 microM in activated Mphis). The neutralization of IFN-gamma also
reversed nitric oxide production at basal levels (8 +/- 5 microM). Additionally,
we found that there was a significant inverse correlation (r = -0.8975) between
NO(2)(-) concentration and transformation of P. brasiliensis conidia.
Additionally, treatment with any of the three different nitric oxide inhibitors
used (arginase, N(G)-monomethyl-L-arginine, and aminoguanidine), reverted the
inhibition of the transformation process with 40 to 70% of intracellular yeast
and significantly reduced nitric oxide production. These results show that IFN
gamma-activated murine Mphis kill P. brasiliensis conidia through the L-arginine
nitric oxide pathway.
PMID- 10768943
TI - Superantigen YPMa exacerbates the virulence of Yersinia pseudotuberculosis in
mice.
AB - Yersinia pseudotuberculosis, a gram-negative bacterium responsible for enteric
and systemic infection in humans, produces a superantigenic toxin designated YPMa
(Y. pseudotuberculosis-derived mitogen). To assess the role of YPMa in the
pathogenesis of Y. pseudotuberculosis, we constructed a superantigen-deficient
mutant and compared its virulence in a mouse model of infection to the virulence
of the wild-type strain. Determination of the survival rate after intravenous
(i.v.) bacterial inoculation of OF1 mice clearly showed that inactivation of
ypmA, encoding YPMa, reduced the virulence of Y. pseudotuberculosis. Mice
infected i.v. with 10(4) and 10(5) wild-type bacteria died within 9 days, whereas
mice infected with the ypmA mutant survived 12 and 3 days longer, respectively.
This decreased virulence of the ypmA mutant strain was not due to an impaired
colonization of the spleen, liver, or lungs. In contrast to i.v. challenge,
bacterial inoculation by the intragastric (i.g.) route did not reveal any
difference in virulence between wild-type Y. pseudotuberculosis and the ypmA
mutant since the 50% lethal doses were identical for both strains. Moreover,
inactivation of ypmA gene did not affect the bacterial growth of Y.
pseudotuberculosis in Peyer's patches, mesenteric lymph nodes (MLNs), and spleen
after oral infection. Histological studies of spleen, liver, lungs, heart,
Peyer's patches, and MLNs after i.v. or i.g. challenge with the wild type or the
ypmA mutant did not reveal any feature that can be specifically related to YPMa.
Our data show that the superantigenic toxin YPMa contributes to the virulence of
Y. pseudotuberculosis in systemic infection in mice.
PMID- 10768944
TI - Immunization with recombinant Helicobacter pylori urease in specific-pathogen
free rhesus monkeys (Macaca mulatta).
AB - Immunization with urease can protect mice from challenge with Helicobacter
pylori, though results vary depending on the particular vaccine, challenge
strain, and method of evaluation. Unlike mice, rhesus monkeys are naturally
colonized with H. pylori and so may provide a better estimate of vaccine efficacy
in humans. The purpose of this study was to examine the effectiveness of H.
pylori urease as a vaccine in specific-pathogen (H. pylori)-free rhesus monkeys.
Monkeys raised from birth and documented to be free of H. pylori were vaccinated
with orogastric (n = 4) or intramuscular (n = 5) urease. Two control monkeys were
sham vaccinated. All monkeys were challenged with a rhesus monkey-derived strain
of H. pylori, and the effects of vaccination were evaluated by use of
quantitative cultures of gastric tissue, histology, and measurement of serum
immunoglobulin G (IgG) and salivary IgA. Despite a humoral immune response, all
monkeys were infected after H. pylori challenge, and there were no differences in
the density of colonization. Immunization with urease therefore does not fully
protect against challenge with H. pylori. An effective vaccine to prevent H.
pylori infection will require different or more likely additional antigens, as
well as improvements in the stimulation of the host immune response.
PMID- 10768945
TI - Outer membrane protein A, peptidoglycan-associated lipoprotein, and murein
lipoprotein are released by Escherichia coli bacteria into serum.
AB - Complexes containing lipopolysaccharide (LPS) and three outer membrane proteins
(OMPs) are released by gram-negative bacteria incubated in human serum and into
the circulation in an experimental model of sepsis. The same OMPs are bound by
immunoglobulin G (IgG) in the cross-protective antiserum raised to Escherichia
coli J5 (anti-J5 IgG). This study was performed to identify the three OMPs. The
35-kDa OMP was identified as outer membrane protein A (OmpA) by immunoblotting
studies using OmpA-deficient bacteria and recombinant OmpA protein. The 18-kDa
OMP was identified as peptidoglycan-associated lipoprotein (PAL) based on peptide
sequences from the purified protein and immunoblotting studies using PAL
deficient bacteria. The 5- to 9-kDa OMP was identified as murein lipoprotein
(MLP) based on immunoblotting studies using MLP-deficient bacteria. The studies
identify the OMPs released into human serum and into the circulation in an
experimental model of sepsis as OmpA, PAL, and MLP.
PMID- 10768946
TI - Antigen specificity in experimental bovine tuberculosis.
AB - This report describes the kinetics of T-cell responses to a panel of
mycobacterial antigens (PPD-M, PPD-A, ESAT-6, Ag85, 38kD, MPB64, MPB70, MPB83,
hsp16.1, hsp65, and hsp70) following experimental infection of cattle with
Mycobacterium bovis. Increased antigen-specific lymphocyte proliferation, gamma
interferon, and interleukin-2 responses were observed in all calves following
infection. Positive lymphocyte proliferation and cytokine responses to PPD-M and
ESAT-6 were observed throughout the infection period studied. In contrast,
responses to all other antigens were more variable and were not constantly
present, suggesting that antigen cocktails rather than individual antigens should
be used for immunodiagnosis. The detection of cytokine responses in the absence
of lymphocyte proliferation, particularly during the early stages of infection,
suggests a role for antigen-specific cytokine readout systems in the early
identification of M. bovis infection in cattle.
PMID- 10768947
TI - Effects of Enterococcus faecalis fsr genes on production of gelatinase and a
serine protease and virulence.
AB - Three agr-like genes (fsrA, fsrB, and fsrC, for Enterococcus faecalis regulator)
were found upstream of the previously reported gelatinase gene (gelE) and a
downstream putative serine protease gene (sprE; accession number Z12296) of
Enterococcus faecalis OG1RF. The deduced amino acid sequence of fsrA shows 26%
identity and 38% similarity to Staphylococcus aureus AgrA (the response regulator
of the accessory gene regulator system in the agr locus), FsrB shows 23% identity
and 41% similarity to S. aureus AgrB, and FsrC shows 23% identity and 36%
similarity to S. aureus AgrC (the sensor transducer of Agr system). Northern blot
analysis suggested that gelE and sprE are cotranscribed and that fsrB and fsrC
are also cotranscribed in OG1RF. Northern blot analysis of fsrA, fsrB, fsrC,
gelE, and sprE insertion mutants showed that fsrB, fsrC, gelE, and sprE are not
expressed in fsrA, fsrB, and fsrC mutants, while insertion in an open reading
frame further upstream of fsrA did not effect the expression of these genes,
suggesting that agr-like genes may be autoregulated and that they regulate gelE
and sprE expression, as further confirmed by complementation of fsr gene
mutations with a 6-kb fragment which contains all three fsr genes in the shuttle
vector, pAT18. Testing of 95 other isolates of E. faecalis showed that 62%
produced gelatinase (Gel(+)), while 91% (including all Gel(+) strains) hybridized
to a gelE probe; 71% (including all Gel(+) strains) hybridized to an fsr probe,
corroborating the conclusion that both gelE and fsr are necessary for gelatinase
production. Testing of fsrA, fsrB, and sprE mutants in a mouse peritonitis model
showed that sprE and agr-like gene mutants resulted in highly significantly
prolonged survival compared to the parent strain OG1RF, a finding similar to what
we had previously shown for a gelE mutant. These results suggest that sprE and
agr-like genes contribute to the virulence of E. faecalis OG1RF in this model.
PMID- 10768948
TI - Inhibition of vesicular secretion in both neuronal and nonneuronal cells by a
retargeted endopeptidase derivative of Clostridium botulinum neurotoxin type A.
AB - Clostridial neurotoxins potently and specifically inhibit neurotransmitter
release in defined cell types by a mechanism that involves cleavage of specific
components of the vesicle docking/fusion complex, the SNARE complex. A derivative
of the type A neurotoxin from Clostridium botulinum (termed LH(N)/A) that retains
catalytic activity can be prepared by proteolysis. The LH(N)/A, however, lacks
the putative native binding domain (H(C)) of the neurotoxin and is thus unable to
bind to neurons and effect inhibition of neurotransmitter release. Here we report
the chemical conjugation of LH(N)/A to an alternative cell-binding ligand, wheat
germ agglutinin (WGA). When applied to a variety of cell lines, including those
that are ordinarily resistant to the effects of neurotoxin, WGA-LH(N)/A conjugate
potently inhibits secretory responses in those cells. Inhibition of release is
demonstrated to be ligand mediated and dose dependent and to occur via a
mechanism involving endopeptidase-dependent cleavage of the natural botulinum
neurotoxin type A substrate. These data confirm that the function of the H(C)
domain of C. botulinum neurotoxin type A is limited to binding to cell surface
moieties. The data also demonstrate that the endopeptidase and translocation
functions of the neurotoxin are effective in a range of cell types, including
those of nonneuronal origin. These observations lead to the conclusion that a
clostridial endopeptidase conjugate that can be used to investigate SNARE
mediated processes in a variety of cells has been successfully generated.
PMID- 10768950
TI - Evaluation of an isogenic major outer membrane protein-deficient mutant in the
human model of Haemophilus ducreyi infection.
AB - Haemophilus ducreyi expresses 2 OmpA homologs, designated MOMP and OmpA2, whose
genes are arranged in tandem on the chromosome. Northern blot analysis indicated
that momp and ompA2 are transcribed independently. Sequences of the momp open
reading frame (ORF) lacking the transcriptional start site were amplified by PCR,
and an Omega-Km2 cassette was ligated into the ORF. A plasmid containing this
construction was electroporated into H. ducreyi 35000HP, and an isogenic MOMP
deficient mutant (35000HP-SMS2) was generated by allele exchange. In Southern
blotting, 35000HP-SMS2 contained one copy of the Omega-Km2 cassette in momp.
35000HP and 35000HP-SMS2 had similar outer membrane protein (OMP) and
lipooligosaccharide profiles and growth rates except for up-regulation of a
putative porin protein in the mutant. Five subjects were inoculated with three
doses of live 35000HP-SMS2 on one arm and two doses of live 35000HP and one dose
of a heat-killed control on the other arm in a double-blind escalating dose
response trial. Pustules developed at 7 of 10 sites inoculated with 35000HP and
at 6 of 15 sites inoculated with 35000HP-SMS2 (P = 0.14). 35000HP and 35000HP
SMS2 were recovered at similar rates from daily surface cultures and
semiquantitative cultures. The data suggest that expression of MOMP is not
required for pustule formation by H. ducreyi in the human model of infection.
PMID- 10768949
TI - The galE gene of Campylobacter jejuni is involved in lipopolysaccharide synthesis
and virulence.
AB - Lipopolysaccharide (LPS) is one of the main virulence factors of gram-negative
bacteria. The LPS from Campylobacter spp. has endotoxic properties and has been
shown to play a role in adhesion. We previously cloned a gene cluster (wla) which
is involved in the synthesis of the Campylobacter jejuni 81116 LPS molecule.
Sequence alignment of the first gene in this cluster indicated similarity with
galE genes. These genes encode a UDP-glucose 4-epimerase, which catalyzes the
interconversion of UDP-galactose and UDP-glucose. A Salmonella galE mutant was
transformed with the galE gene from C. jejuni. The LPS analysis of wild-type,
galE, and complemented galE Salmonella strains showed that the C. jejuni galE
gene could restore the smooth wild-type Salmonella LPS. A UDP-glucose 4-epimerase
assay was used to demonstrate that the galE gene from C. jejuni encoded this
epimerase. We constructed a C. jejuni galE mutant which expressed a lipid A-core
molecule of reduced molecular weight that did not react with antiserum raised
against the parental strain. These results show an essential role for the galE
gene in the synthesis of C. jejuni LPS. The galE mutant also showed a reduction
in its ability to adhere to and invade INT407 cells. However, it was still able
to colonize chickens to the same level as the wild-type strain. The serum
resistance and hemolytic activity of this mutant were not changed compared to the
parent strain. The ability of the mutant to take up DNA and integrate it in its
genome was reduced 20-fold. These results show that LPS of C. jejuni is an
important virulence factor.
PMID- 10768951
TI - Characterization and formulation of multiple epitope-specific neutralizing
monoclonal antibodies for passive immunization against cryptosporidiosis.
AB - The coccidian parasite Cryptosporidium parvum causes diarrhea in humans, calves,
and other mammals. Neither immunization nor parasite-specific pharmaceuticals
that are consistently effective against this organism are available. While
polyclonal antibodies against whole C. parvum reduce infection, their efficacy
and predictability are suboptimal. We hypothesized that passive immunization
against cryptosporidiosis could be improved by using neutralizing monoclonal
antibodies (MAbs) targeting functionally defined antigens on the infective
stages. We previously reported that the apical complex and surface-exposed zoite
antigens CSL, GP25-200, and P23 are critical in the infection process and are
therefore rational targets. In the present study, a panel of 126 MAbs generated
against affinity-purified CSL, GP25-200, and P23 was characterized to identify
the most efficacious neutralizing MAb formulation targeting each antigen. To
identify neutralizing MAbs, sporozoite infectivity following exposure to
individual MAbs was assessed by enzyme-linked immunosorbent assay. Of 126 MAbs
evaluated, 47 had neutralizing activity. These were then evaluated individually
in oocyst-challenged neonatal mice, and 14 MAbs having highly significant
efficacy were identified for further testing in formulations. Epitope specificity
assays were performed to determine if candidate MAbs recognized the same or
different epitopes. Formulations of two or three neutralizing MAbs, each
recognizing distinct epitopes, were then evaluated. A formulation of MAbs 3E2
(anti-CSL [alphaCSL]), 3H2 (alphaGP25-200), and 1E10 (alphaP23) provided highly
significant additive efficacy over that of either individual MAbs or combinations
of two MAbs and reduced intestinal infection by 86 to 93%. These findings
indicate that polyvalent neutralizing MAb formulations targeting epitopes on
defined antigens may provide optimal passive immunization against
cryptosporidiosis.
PMID- 10768952
TI - Cytophilic immunoglobulin responses to Plasmodium falciparum glutamate-rich
protein are correlated with protection against clinical malaria in Dielmo,
Senegal.
AB - The goal of this study was to analyze antibody responses to Plasmodium falciparum
glutamate-rich protein (GLURP) using clinical data and plasma samples obtained
from villagers of Dielmo, Senegal. This molecule was chosen because it is
targeted by human antibodies which induce parasite growth inhibition in antibody
dependent cellular inhibition (ADCI) assays. The results showed a strong
correlation between protection against malaria attacks and levels of
immunoglobulin G2 (IgG2) and IgG3 against GLURP(94-489) (R0) and IgG3 against
GLURP(705-1178) (R2) when corrected for the confounding effect of age-related
exposure to malaria. Thus, GLURP may play a role in the induction of protective
immunity against P. falciparum malaria.
PMID- 10768953
TI - Characterization of recombinant, ureolytic Streptococcus mutans demonstrates an
inverse relationship between dental plaque ureolytic capacity and cariogenicity.
AB - Dental caries results from prolonged plaque acidification that leads to the
establishment of a cariogenic microflora and demineralization of the tooth.
Urease enzymes of oral bacteria hydrolyze urea to ammonia, which can neutralize
plaque acids. To begin to examine the relationship between plaque ureolytic
activity and the incidence of dental caries, recombinant, ureolytic strains of
Streptococcus mutans were constructed. Specifically, the ureABCEFGD operon from
Streptococcus salivarius 57.I was integrated into the S. mutans chromosome in
such a way that the operon was transcribed from a weak, cognate promoter in S.
mutans ACUS4 or a stronger promoter in S. mutans ACUS6. Both strains expressed
NiCl(2)-dependent urease activity, but the maximal urease levels in ACUS6 were
threefold higher than those in ACUS4. In vitro pH drop experiments demonstrated
that the ability of the recombinant S. mutans strains to moderate a decrease in
pH during the simultaneous metabolism of glucose and urea increased
proportionately with the level of urease activity expressed. Specific-pathogen
free rats that were infected with ACUS6 and fed a cariogenic diet with drinking
water containing 25 mM urea and 50 microM NiCl(2) had relatively high levels of
oral urease activity, as well as dramatic decreases in the prevalence of smooth
surface caries and the severity of sulcal caries, relative to controls. Urease
activity appears to influence plaque biochemistry and metabolism in a manner that
reduces cariogenicity, suggesting that recombinant, ureolytic bacteria may be
useful to promote dental health.
PMID- 10768954
TI - Identification and genetic characterization of Haemophilus influenzae genetic
island 1.
AB - The type b capsule of pathogenic Haemophilus influenzae is a critical factor for
H. influenzae survival in the blood and the establishment of invasive infections.
Other pathogenic factors associated with type b strains may also play a role in
invasion and sustained bacteremia, leading to the seeding of deep tissues. The
gene encoding haemocin is the only noncapsular gene found to be specific to type
b strains until now. Here we report the discovery of an approximately 16-kb
genetic locus, HiGI1, that is present primarily in type b strains. Pulsed-field
gel electrophoresis and Southern hybridization were used to map this new locus
between secG (HI0445) and fruA (HI0446), which are contiguous in Rd, a
nonpathogenic derivative of a serotype d strain. It is inserted at the 3' end of
tRNA(4)(Leu) and has regions whose G+C content differs from the average genomic
G+C content of H. influenzae. An integrase gene, which encodes a CP4-57 like
integrase, is located downstream of tRNA(4)(Leu). Hybridization probes based on
the sequences within the HiGI1 locus have been used to screen 61 H. influenzae
strains (2 type a, 22 type b, 2 type c, 1 type d, 3 type e, 7 type f, and 21
nontypeable H. influenzae [NTHi]) from our collection. This HiGI1 locus exists in
all 22 type b strains and two NTHi strains and is likely to have been acquired by
an ancestral type b strain.
PMID- 10768955
TI - Functional flexibility of the FimH adhesin: insights from a random mutant
library.
AB - Type 1 fimbriae are surface organelles of Escherichia coli which mediate D
mannose-sensitive binding to different host surfaces. This binding is conferred
by the minor fimbrial component FimH. Naturally occurring variants of the FimH
protein have been selected in nature for their ability to recognize specific
receptor targets. In particular, variants that bind strongly to terminally
exposed monomannose residues have been associated with a pathogenicity-adaptive
phenotype that enhances E. coli colonization of extraintestinal locations such as
the urinary bladder. In this study we have used random mutagenesis to
specifically identify nonselective mutations in the FimH adhesin which modify its
binding phenotype. Isogenic E. coli clones expressing FimH variants were tested
for their ability to bind yeast cells and model glycoproteins that contain
oligosaccharide moieties rich in either terminal monomannose, oligomannose, or
nonmannose residues. Both the monomannose- and the oligomannose-binding capacity
of type 1 fimbriae could be altered by minor amino acid changes in the FimH
protein. The monomannose-binding phenotype was particularly sensitive to changes,
with extensive differences in binding being observed in comparison to wild-type
FimH levels. Different structural alterations were able to cause similar
functional changes in FimH, suggesting a high degree of flexibility to target
recognition by this adhesin. Alteration of residue P49 of the mature FimH
protein, which occurs within the recently elucidated carbohydrate-binding pocket
of FimH, completely abolished its function. Amino acid changes that increased the
binding capacity of FimH were located outside receptor-interacting residues,
indicating that functional changes relevant to pathogenicity are likely to be due
to conformational changes of the adhesin.
PMID- 10768956
TI - Protection elicited by native outer membrane protein Oms66 (p66) against host
adapted Borrelia burgdorferi: conformational nature of bactericidal epitopes.
AB - Oms66 is a Borrelia burgdorferi outer membrane porin protein whose role in Lyme
disease pathogenesis and immunity has not been well established. Oms66 was
solubilized from whole-cell lysates of strain B313 (which is derived from B31 but
lacks OspA, -B, -C, and -D) and purified to homogeneity by fast-protein liquid
chromatography. Purified native Oms66 (nOms66), which retained the ability to
form large channels in a planar lipid bilayer model membrane system, and
denatured Oms66 (hOms66) were used to immunize New Zealand White rabbits. The
resulting Oms66 antisera were tested in a complement-dependent borreliacidal
assay in parallel with basal serum and with serum from rabbits immune to
reinfection with B. burgdorferi (IRS). IRS showed high-titer complement-dependent
killing of both strains B31 and B313. Sera from animals immunized with nOms66
showed high-titer complement-dependent killing activity against strain B313 but
exhibited no killing of B31. By comparison, serum generated from immunizations
with hOms66 showed no killing activity against either strain. Following
adsorption of antiserum to nOms66 with recombinant Oms66 (rOms66), the serum
antibodies no longer bound to rOms66 or to nOms66 that had been denatured with 8
M urea. However, the antibodies still bound to nOms66 and killing activity
against B313 was retained, thus suggesting that native, conformational epitopes
are targets of this bactericidal activity. Six C3H HeJ mice were immunized with
nOms66 and were challenged using "host-adapted" B. burgdorferi B31 by skin
implantation of infected mouse ear tissue. Four of the six mice were protected
against both localized and disseminated infection. These findings indicate that
native Oms66 can elicit potent bactericidal activity and significant protective
immunity against host-adapted organisms.
PMID- 10768957
TI - Pathogenic mycobacteria disrupt the macrophage actin filament network.
AB - Phagosomes with pathogenic mycobacteria retain fusion and intermingling
characteristics of early endosomes indefinitely. The time course of acquisition
of newly endocytosed tracers becomes, however, atypical (lag instead of immediate
acquisition) starting from day 1 postinfection (p.i.), thereby suggesting that
additional factors affect this process. Disruption of the actin filament (F
actin) network by cytochalasin D perturbs the movement of early endosomes and
probably fusion events among early endosomes and phagosomes. Here we compare, by
immunofluorescence microscopy, the morphology and distribution of F-actin in
macrophages infected with virulent Mycobacterium avium, in uninfected
macrophages, or in macrophages after phagocytosis of nonpathogenic bacteria
(Mycobacterium smegmatis or Bacillus subtilis) or hydrophobic latex particles. In
uninfected cells, F-actin appeared as a network of small filaments distributed
throughout the cell; about 80% of the cells also displayed one or two small
patches of F-actin at the cell periphery. Virulent M. avium caused a marked
disorganization of the F-actin network starting from day 1 p.i. The most salient
features were the formation of several large patches, the progressive
disappearance of the small filaments, and the appearance of large numbers of tiny
punctate structures starting from day 2 p.i. With the three other particles, the
F-actin network was unmodified compared to that in uninfected cells. The atypical
lag in acquisition of newly endocytosed tracers by M. avium-containing
phagosomes, therefore, seems to coincide with the disorganization of the F-actin
network.
PMID- 10768958
TI - Eradication of Cryptosporidium parvum infection by mice with ovalbumin-specific T
cells.
AB - CD154 is necessary for mice to clear a Cryptosporidium parvum infection, but
whether this ligand has to be expressed on T cells with specificity for C. parvum
has not been determined. We infected DO11.10 (ovalbumin specific) T-cell receptor
transgenic mice that had been bred to a RAG(-/-) background with C. parvum and
found that the infection was cleared within 6 weeks, while RAG(-/-) controls were
unable to clear C. parvum infection. Recovery was accompanied by an increase in
the number of splenic T cells with the CD44(high) phenotype that characterizes
memory cells. To determine whether a C. parvum-infected environment sufficed to
activate transgenic T cells, we reconstituted C. parvum-infected BALB/c SCID mice
with DO11.10 RAG(-/-) splenocytes. Fecal excretion of C. parvum antigen ceased in
the 12 weeks following the adoptive transfer, unless the mice were also injected
with tolerizing doses of ovalbumin. DO11.10 T cells were found in the submucosa
of C. parvum-infected, but not uninfected, BALB/c SCID hosts within 48 h of
injection. The transferred DO11.10 T cells divided and acquired a CD44(high)
memory phenotype in C. parvum-infected, but not uninfected, recipients. DO11.10
splenocytes from CD154 knockout donors failed to clear a C. parvum infection,
confirming a requirement for CD154 in recovery. In vitro, the DO11.10 cells did
not proliferate in response to C. parvum antigen, and a tBlast GenBank search
revealed no matches between the ovalbumin peptide and C. parvum DNA sequences. C.
parvum-infected SCID mice given RAG(-/-) CD8(+) T cells with a Listeria-specific
transgene did not recover from C. parvum infection. Our data suggest that antigen
nonspecific CD4(+) T-cell effector mechanisms in combination with the innate arm
of the immune system are sufficient for the eradication of C. parvum infection.
PMID- 10768959
TI - Deviant expression of Rab5 on phagosomes containing the intracellular pathogens
Mycobacterium tuberculosis and Legionella pneumophila is associated with altered
phagosomal fate.
AB - The intracellular human pathogens Legionella pneumophila and Mycobacterium
tuberculosis reside in altered phagosomes that do not fuse with lysosomes and are
only mildly acidified. The L. pneumophila phagosome exists completely outside the
endolysosomal pathway, and the M. tuberculosis phagosome displays a maturational
arrest at an early endosomal stage along this pathway. Rab5 plays a critical role
in regulating membrane trafficking involving endosomes and phagosomes. To
determine whether an alteration in the function or delivery of Rab5 could play a
role in the aberrant development of L. pneumophila and M. tuberculosis
phagosomes, we have examined the distribution of the small GTPase, Rab5c, in
infected HeLa cells overexpressing Rab5c. Both pathogens formed phagosomes in
HeLa cells with molecular characteristics similar to their phagosomes in human
macrophages and multiplied in these host cells. Phagosomes containing virulent
wild-type L. pneumophila never acquired immunogold staining for Rab5c, whereas
phagosomes containing an avirulent mutant L. pneumophila (which ultimately fused
with lysosomes) transiently acquired staining for Rab5c after phagocytosis. In
contrast, M. tuberculosis phagosomes exhibited abundant staining for Rab5c
throughout its life cycle. To verify that the overexpressed, recombinant Rab5c
observed on the bacterial phagosomes was biologically active, we examined the
phagosomes in HeLa cells expressing Rab5c Q79L, a fusion-promoting mutant. Such
HeLa cells formed giant vacuoles, and after incubation with various particles,
the giant vacuoles acquired large numbers of latex beads, M. tuberculosis, and
avirulent L. pneumophila but not wild-type L. pneumophila, which consistently
remained in tight phagosomes that did not fuse with the giant vacuoles. These
results indicate that whereas Rab5 is absent from wild-type L. pneumophila
phagosomes, functional Rab5 persists on M. tuberculosis phagosomes. The absence
of Rab5 on the L. pneumophila phagosome may underlie its lack of interaction with
endocytic compartments. The persistence of functional Rab5 on the M. tuberculosis
phagosomes may enable the phagosome to retard its own maturation at an early
endosomal stage.
PMID- 10768960
TI - Characterization of conserved T- and B-cell epitopes in Plasmodium falciparum
major merozoite surface protein 1.
AB - Vaccines for P. falciparum will need to contain both T- and B-cell epitopes.
Conserved epitopes are the most desirable, but they are often poorly immunogenic.
The major merozoite surface protein 1 (MSP-1) is currently a leading vaccine
candidate antigen. In this study, six peptides from conserved or partly conserved
regions of MSP-1 were evaluated for immunogenicity in B10 congenic mice.
Following immunization with the peptides, murine T cells were tested for the
ability to proliferate in vitro and antibody responses to MSP-1 were evaluated in
vivo. The results showed that one highly conserved sequence (MSP-1#1,
VTHESYQELVKKLEALEDAV; located at amino acid positions 20 to 39) and one partly
conserved sequence (MSP-1#23, GLFHKEKMILNEEEITTKGA; located at positions 44 to
63) contained both T- and B-cell epitopes. Immunization of mice with these
peptides resulted in T-cell proliferation and enhanced production of antibody to
MSP-1 upon exposure to merozoites. MSP-1#1 stimulated T-cell responses in three
of the six strains of mice evaluated, whereas MSP-1#23 was immunogenic in only
one strain. Immunization with the other four peptides resulted in T-cell
responses to the peptides, but none of the resulting peptide-specific T cells
recognized native MSP-1. These results demonstrate that two sequences located in
the N terminus of MSP-1 can induce T- and B-cell responses following immunization
in a murine model. Clearly, these sequences merit further consideration for
inclusion in a vaccine for malaria.
PMID- 10768961
TI - Mucosal immune responses to meningococcal group C conjugate and group A and C
polysaccharide vaccines in adolescents.
AB - Previous studies in children have shown that Haemophilus influenzae type b (Hib)
polysaccharide conjugate vaccines can reduce nasopharyngeal carriage of H.
influenzae and provide herd immunity and suggest that this effect is mediated
through mucosal antibodies. As this phenomenon may operate in other invasive
bacterial infections which are propagated by nasopharyngeal carriage, mucosal
antibody responses to meningococcal C conjugate and A/C polysaccharide vaccines
were investigated. A total of 106 school children aged 11 to 17 years were
randomized to receive a single dose of either conjugate or polysaccharide vaccine
in an observer-blind study. Before and at 1, 6, and 12 months after immunization,
samples of unstimulated saliva were collected and assayed by enzyme-linked
immunosorbent assay for group C polysaccharide-specific immunoglobulin A (IgA),
IgA1, IgA2 and secretory component, IgG antibodies, and total IgG and IgA. A
subset of serum samples were also assayed for specific IgA and IgG antibodies.
The concentrations of specific IgA and IgG in saliva were expressed both as
nanograms per milliliter and as nanograms per microgram of total IgA or IgG. One
month after immunization, significant increases in antibody titers (both IgA and
IgG) were observed in saliva in both groups. There were significant subsequent
falls in antibody titers by 6 months. Anti-meningococcal C-specific secretory
component and IgA antibody titers were closely correlated (r = 0.85, P < 0.001),
but there was no significant correlation between salivary and serum IgA titers,
suggesting that IgA antibodies are locally produced. Significant correlation was
found between salivary and serum IgG titers (r = 0.52, P < 0.01), suggesting that
salivary IgG may be serum derived. Compared with polysaccharide vaccine, the
conjugate vaccine induced significantly higher salivary IgG responses (P < 0.05),
although there were no significant differences between salivary IgA responses to
the two vaccines. The conjugate vaccine induced greater salivary IgG responses
than a polysaccharide vaccine. Both vaccines induced significant salivary IgA
antibodies. Further studies are needed to establish the functional significance
of these mucosal responses.
PMID- 10768962
TI - Coimmunization with complementary glucosyltransferase peptides results in
enhanced immunogenicity and protection against dental caries.
AB - Peptide constructs from the catalytic (CAT) and glucan-binding (GLU) regions of
the mutans streptococcal glucosyltransferase enzymes (GTF) can provide immunity
to dental caries infection. A strategy of coimmunization was tested to determine
whether protection could be enhanced. Rats were immunized with one of the
previously described peptide constructs from the CAT or GLU region of the GTF of
mutans streptococci or coimmunized with a combination of these constructs (CAT
GLU). Coimmunized animals demonstrated significantly higher serum immunoglobulin
G (IgG) and salivary IgA antibody levels to CAT or GTF than rats immunized with
either construct alone. To assess the functional significance of coimmunization
with these constructs, animals were immunized as above or with Streptococcus
sobrinus GTF and then infected with S. sobrinus to explore the effects of
immunization on immunological, microbiological, and disease (dental caries)
parameters. Serum antibody from the communized group inhibited S. sobrinus GTF
mediated insoluble glucan synthesis in vitro above that of the individual
construct-immunized groups. Immunization with CAT or GLU constructs resulted in
significantly reduced dental caries after infection with S. sobrinus compared
with sham-immunized animals. Coimmunization produced greater reductions in caries
than after immunization with either CAT or GLU. Also, significant elevations in
lymphocyte proliferative responses to CAT, GLU, and GTF were observed after
coimmunization with CAT-GLU compared with the responses after immunization with
the individual constructs. The results suggested that increased numbers of memory
T cells, which could proliferate to CAT, were generated by coimmunization. The
experiments support the functional significance of these GTF domains in dental
caries pathogenesis and present coimmunization as a simple alternative to intact
GTF to enhance protective immunity against cariogenic microorganisms.
PMID- 10768963
TI - Serum immunoglobulin G (IgG) and IgG subclass responses to the RgpA-Kgp
proteinase-adhesin complex of Porphyromonas gingivalis in adult periodontitis.
AB - Serum immunoglobulin G (IgG), IgM, and IgG subclass responses to the RgpA-Kgp
proteinase-adhesin complex of Porphyromonas gingivalis were examined by enzyme
linked immunosorbent assay using adult periodontitis patients and age- and sex
matched controls. Twenty-five sera from subjects with adult periodontitis
(diseased group) and 25 sera from healthy subjects (control group) were used for
the study. Sera and subgingival plaque samples from 10 sites were collected from
each patient at the time of clinical examination. The level of P. gingivalis in
the plaque samples was determined using a DNA probe. Highly significant positive
associations between the percentage of sites positive for P. gingivalis and
measures of disease severity (mean pocket depth, mean attachment loss, and
percentage of sites that bled on probing) were found. The diseased group had
significantly higher specific IgG responses to the RgpA-Kgp complex than did the
control group, and the responses were significantly associated with mean probing
depths and percentage of sites positive for P. gingivalis. Analysis of the IgG
subclass responses to the RgpA-Kgp complex revealed that the subclass
distribution for both the diseased and control groups was IgG4 > IgG2 > IgG3 =
IgG1. The IgG2 response to the complex was positively correlated with mean
probing depth, whereas the IgG4 response was negatively correlated with this
measure of disease severity. Immunoblot analysis of the RgpA-Kgp complex showed
that sera from healthy subjects and those with low levels of disease, with high
IgG4 and low IgG2 responses, reacted with the RgpA27, Kgp39, and RgpA44 adhesins;
however, sera from diseased subjects with low IgG4 and high IgG2 responses
reacted only with the RgpA44 and/or Kgp44 adhesins. Epitope mapping of the RgpA27
adhesin localized a major epitope recognized by IgG4 antibodies in sera from
subjects with high IgG4 and low IgG2 responses to the RgpA-Kgp complex which was
not recognized by sera from diseased subjects with low IgG4 and high IgG2
responses.
PMID- 10768964
TI - Host resistance and immune deviation in pigeon cytochrome c T-cell receptor
transgenic mice infected with Toxoplasma gondii.
AB - Resistance to Toxoplasma gondii has been shown to be mediated by gamma interferon
(IFN-gamma) produced by NK, CD4(+), and CD8(+) T cells. While studies of SCID
mice have implicated NK cells as the source of the cytokine in acute infection,
several lines of evidence suggest that IFN-gamma production by CD4(+) T
lymphocytes also plays an important role in controlling early parasite growth. To
evaluate whether this function is due to nonspecific as opposed to T-cell
receptor (TCR)-dependent stimulation by the parasite, we have examined the
resistance to T. gondii infection of pigeon cytochrome c transgenic (PCC-Tg) Rag
2(-/-) mice in which all CD4(+) T lymphocytes are unreactive with the protozoan.
When inoculated with the ME49 strain, PCC-Tg animals exhibited only temporary
control of acute infection and succumbed by day 17. Intracellular cytokine
staining by flow cytometry revealed that, in contrast to infected nontransgenic
controls, infected PCC-Tg animals failed to develop IFN-gamma-producing CD4(+) T
cells. Moreover, the CD4(+) lymphocytes from these mice showed no evidence of
activation as judged by lack of upregulated expression of CD44 or CD69.
Nevertheless, when acutely infected transgenic mice were primed by PCC injection,
the lymphokine responses measured after in vitro antigen restimulation displayed
a strong Th1 bias which was shown to be dependent on endogenous interleukin 12
(IL-12). The above findings argue that, while T. gondii-induced IL-12 cannot
trigger IFN-gamma production by CD4(+) T cells in the absence of TCR ligation,
the pathogen is able to nonspecifically promote Th1 responses against nonparasite
antigens, an effect that may explain the immunostimulatory properties of T.
gondii infection.
PMID- 10768965
TI - The shdA gene is restricted to serotypes of Salmonella enterica subspecies I and
contributes to efficient and prolonged fecal shedding.
AB - Little is known about factors which enable Salmonella serotypes to circulate
within populations of livestock and domestic fowl. We have identified a DNA
region which is present in Salmonella serotypes commonly isolated from livestock
and domestic fowl (S. enterica subspecies I) but absent from reptile-associated
Salmonella serotypes (S. bongori and S. enterica subspecies II to VII). This DNA
region was cloned from Salmonella serotype Typhimurium and sequence analysis
revealed the presence of a 6,105-bp open reading frame, designated shdA, whose
product's deduced amino acid sequence displayed homology to that of AIDA-I from
diarrheagenic Escherichia coli, MisL of serotype Typhimurium, and IcsA of
Shigella flexneri. The shdA gene was located adjacent to xseA at 52 min, in a 30
kb DNA region which is not present in Escherichia coli K-12. A serotype
Typhimurium shdA mutant was shed with the feces in reduced numbers and for a
shorter period of time compared to its isogenic parent. A possible role for the
shdA gene during the expansion in host range of S. enterica subspecies I to
include warm-blooded vertebrates is discussed.
PMID- 10768966
TI - Heterologous expression of Trypanosoma cruzi trans-sialidase in Leishmania major
enhances virulence.
AB - Earlier studies showed that mice primed for a few hours with the trans-sialidase
(TS) of Trypanosoma cruzi, the agent of Chagas' disease, become highly
susceptible to trypanosomal infection. These studies suggest that TS affects
parasite virulence independent of antigenic stimulation. Potentially, TS could
enhance or reduce the virulence of heterologous microbes depending on the
mechanism of TS action and on the type of immune response elicited by the
particular parasite. We tested this hypothesis by expressing heterologous TS in
Leishmania major, a protozoan parasite that causes cutaneous leishmaniasis and
lacks TS and the TS product alpha2-3-linked sialic acid. Leishmania cells
transfected with a T. cruzi TS expression construct made high levels of active
enzyme, which was present in the promastigotes and shed into the extracellular
milieu. TS expression did not affect L. major binding to and entry into cultured
macrophages or its tropism for macrophage infection in vivo. However, TS
expressing L. major exhibited elevated virulence in BALB/c mice, as determined by
lesion progression, parasite numbers, and macro- and microscopic examination of
cutaneous lesions. Several genetic tests proved that the enhanced virulence was
directly attributable to TS expression. The results are consistent with TS
functioning to sabotage the mouse immune system to confer a growth advantage on
T. cruzi and transgenic L. major. These data suggest that heterologous expression
of T. cruzi virulence factors in Leishmania may provide a new approach for
dissecting their function in vivo.
PMID- 10768967
TI - The flagellar sigma factor FliA (sigma(28)) regulates the expression of
Salmonella genes associated with the centisome 63 type III secretion system.
AB - One of the essential features of all pathogenic strains of Salmonella enterica is
the ability to enter into nonphagocytic cells. This pathogenic property is
mediated by the Salmonella pathogenicity island 1 (SPI-1)-encoded type III
secretion system. Expression of components and substrates of this system is
subject to complex regulatory mechanisms. These mechanisms include a number of
specific and global transcriptional regulatory proteins. In this study we have
compared in S. enterica serovars Typhimurium and Typhi the effect of mutations in
flagellar genes on the phenotypes associated with the SPI-1 type III protein
secretion system. We found that serovar Typhi strains carrying a null mutation in
either of the flagellar regulatory genes flhDC or fliA were severely deficient in
entry into cultured epithelial cells and macrophage cytotoxicity. This defect
could not be reversed by applying a mild centrifugal force, suggesting that the
effects of the mutations were not due to the absence of motility. In contrast,
the same mutations had no significant effect on the ability of serovar
Typhimurium to enter into cultured Henle-407 cells or to induce macrophage cell
death. Consistent with these observations, we found that the mutations in the
flagellar regulatory proteins significantly reduced the expression of components
of the SPI-1-encoded type III system in serovar Typhi but had a marginal effect
in serovar Typhimurium. Our results therefore indicate that there is an overlap
between regulatory mechanisms that control flagellar and type III secretion gene
expression in Salmonella serovar Typhi.
PMID- 10768968
TI - Detection of Chlamydia pneumoniae DNA and antigen in the circulating mononuclear
cell fractions of humans and koalas.
AB - Chlamydia pneumoniae is a common respiratory pathogen of humans which, in
addition to causing disease at the respiratory site, has recently been linked to
disease at other body sites. If C. pneumoniae does contribute to disease at
nonrespiratory sites, then it must have a mechanism by which it reaches these
sites. We analyzed the peripheral blood mononuclear cell (PBMC) fractions from 60
healthy human blood donors for the presence of C. pneumoniae DNA (by ompA PCR)
and chlamydial antigens (by genus- and species-specific monoclonal antibody
staining). Ten of the sixty (16. 7%) blood donors were C. pneumoniae positive by
PCR, and all 10 of these PCR-positive individuals' samples demonstrated specific
staining with anti-C. pneumoniae monoclonal antibodies. The only other host
naturally infected with C. pneumoniae is the koala, in which the bacterium also
causes respiratory infections. We demonstrated the presence of C. pneumoniae DNA
and antigens in the PBMC fractions of 30% of 20 koalas tested. Our finding of C.
pneumoniae-infected PBMCs in koalas as well as humans suggests that the ability
to infect PBMCs and to disseminate from the respiratory site is not restricted to
the human biovar of C. pneumoniae but is a general characteristic of this
chlamydial species.
PMID- 10768969
TI - Bactericidal activity of mammalian cathelicidin-derived peptides.
AB - Endogenous antimicrobial peptides of the cathelicidin family contribute to innate
immunity. The emergence of widespread antibiotic resistance in many commonly
encountered bacteria requires the search for new bactericidal agents with
therapeutic potential. Solid-phase synthesis was employed to prepare linear
antimicrobial peptides found in cathelicidins of five mammals: human
(FALL39/LL37), rabbit (CAP18), mouse (mCRAMP), rat (rCRAMP), and sheep (SMAP29
and SMAP34). These peptides were tested at ionic strengths of 25 and 175 mM
against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and
methicillin-resistant Staphylococcus aureus. Each peptide manifested activity
against P. aeruginosa irrespective of the NaCl concentration. CAP18 and SMAP29
were the most effective peptides of the group against all test organisms under
both low- and high-salt conditions. Select peptides of 15 to 21 residues, modeled
on CAP18 (37 residues), retained activity against the gram-negative bacteria and
methicillin-sensitive S. aureus, although the bactericidal activity was reduced
compared to that of the parent peptide. In accordance with the behavior of the
parent molecule, the truncated peptides adopted an alpha-helical structure in the
presence of trifluoroethanol or lipopolysaccharide. The relationship between the
bactericidal activity and several physiochemical properties of the cathelicidins
was examined. The activities of the full-length peptides correlated positively
with a predicted gradient of hydrophobicity along the peptide backbone and with
net positive charge; they correlated inversely with relative abundance of anionic
residues. The salt-resistant, antimicrobial properties of CAP18 and SMAP29
suggest that these peptides or congeneric structures have potential for the
treatment of bacterial infections in normal and immunocompromised persons and
individuals with cystic fibrosis.
PMID- 10768970
TI - Passive transfer of antiserum specific for immunogens derived from a nontypeable
Haemophilus influenzae adhesin and lipoprotein D prevents otitis media after
heterologous challenge.
AB - We recently determined that passive transfer of serum directed against a
synthetic peptide called LB1 or a recombinant fusion protein immunogen [LPD
LB1(f)(2,1,3)] could prevent otitis media after challenge with a homologous
nontypeable Haemophilus influenzae (NTHI) isolate. NTHI residing in the
nasopharynx was rapidly cleared from this site, thus preventing it from ascending
the eustachian tube and inducing otitis media in chinchillas compromised by an
ongoing viral upper respiratory tract infection. While LB1 is based solely on one
NTHI adhesin, the latter immunogen, LPD-LB1(f)(2,1,3), was designed to
incorporate two NTHI antigens shown to play a role in the pathogenesis of otitis
media; lipoprotein D (LPD) and the P5-homologous fimbrin adhesin. The design of
LPD-LB1(f)(2,1,3) also accommodated for the recently demonstrated existence of
three major groupings, based on amino acid sequence diversity, in the third
surface-exposed region of P5-fimbrin. LPD-LB1(f)(2,1,3) was thus designed to
potentially confer broader protection against challenge by diverse strains of
NTHI. Chinchillas were passively immunized here with serum specific for either
LB1 or for LPD-LB1(f)(2,1,3) prior to challenge with a member of all three groups
of NTHI relative to diversity in region 3. The transferred serum pools were also
analyzed for titer, specificity, and several functional activities. We found that
both serum pools had equivalent ability to mediate C'-dependent killing and to
inhibit adherence of NTHI strains to human oropharyngeal cells. When passively
transferred, both serum pools significantly inhibited the signs and incidence of
otitis media (P I>IIB for the men
and I>IIA>IIB for the women. These data establish normative values for the
mATPase-based fiber type distribution and sizes in untrained young men and women.
PMID- 10769047
TI - Distribution and cellular localization of prostacyclin synthase in human brain.
AB - Prostacyclin (PGI(2)) is a labile, lipid-derived metabolite of arachidonic acid
synthesized through the sequential action of cyclo-oxygenase (COX) and
prostacyclin synthase (PGIS). In addition to its well-characterized vasodilatory
and thrombolytic effects, an increasing number of studies report an important
role of PGI(2) in nociception in various animal species. In this study we
investigated the regional distribution of PGIS in human brain by
immunohistochemistry and in situ hybridization. PGIS-immunoreactive (ir) protein
was localized to blood vessels throughout the brain. Neuronal cells and glial
cells, such as microglia and oligodendrocytes, also showed intense labeling. The
strongest expression of PGIS was seen in large principal neurons, such as
pyramidal cells of the cortex, pyramidal cells of the hippocampus, and Purkinje
cells of the cerebellum. Abundance of PGIS mRNA was observed in blood vessels and
large neurons and correlated well with the immunohistochemical findings. The
expression of PGIS in human brain was further demonstrated by immunoblotting and
detection of 6-keto-PGF (1alpha), the stable degradation product of prostacyclin
in human brain homogenate. These results demonstrate a widespread expression of
PGIS in the central nervous system and suggest a potentially important role of
prostacylin in modulating neuronal activity in human brain.
PMID- 10769048
TI - Tracking micrometastasis to multiple organs with lacZ-tagged CWR22R prostate
carcinoma cells.
AB - Metastasis to organs other than lung is rarely observed in animal model systems
of human prostate carcinoma (PCA), with the exception of already metastatic
isolates of human PCA cultured for long periods of time. To analyze more directly
the evolution of metastatic variants from primary PCA tumor isolates, the lacZ
histochemical marker gene was transfected into the CWR22Rv1 cell line isolated
from the CWR22R xenograft (primary tumor). Three clones of varying lacZ
expression stability were analyzed for tumorigenicity and progression in athymic
nude mice. Clones B and D were highly tumorigenic in the subcutis; however, lacZ
expression was highly unstable. In contrast, clone H demonstrated highly stable
lacZ expression for >25 passages in culture or in animals. Clone H, injected sc
in a PBS vehicle, gave a 15-40% tumorigenic take. All primary tumor-bearing
animals exhibited micrometastases in lung and other organs. Clone H injected in a
Matrigel vehicle gave 100% tumorigenicity, with all animals displaying
micrometastases in lung, liver, and/or bone (lower frequency in brain and
kidney). Overall, the relative frequency of micrometastasis to multiple organs
was lung>liver=bone>>brain>kidney. Overt metastases were never observed in the
lung or bone but were occasionally found in liver. lacZ-transfected clone H
CWR22Rv1 cells represent a much more accurate model of metastasis of PCA to the
organs normally involved in progression of the human disease. Use of marker gene
tagged cells and other high-resolution molecular techniques will now permit
analyses of the earliest events in PCA progression and micrometastasis.
PMID- 10769049
TI - Seven-color fluorescence imaging of tissue samples based on Fourier spectroscopy
and singular value decomposition.
AB - Seven-color analyses of immunofluorescence-stained tissue samples were
accomplished using Fourier spectroscopy-based hyperspectral imaging and singular
value decomposition. This system consists of a combination of seven fluorescent
dyes, three filtersets, an epifluorescence microscope, a spectral imaging system,
a computer for data acquisition, and data analysis software. The spectra of all
pixels in a multicolor image were taken simultaneously using a Sagnac type
interferometer. The spectra were deconvolved to estimate the contribution of each
component dye, and individual dye images were constructed based on the
intensities of assigned signals. To obtain mixed spectra, three filter sets,
i.e., Bl, Gr, and Rd for Alexa488 and Alexa532, for Alexa546, Alexa568, and
Alexa594, and for Cy5 and Cy5.5, respectively, were used for simultaneous
excitation of two or three dyes. These fluorophores have considerable spectral
overlap which precludes their separation by conventional analysis. We resolved
their relative contributions to the fluorescent signal by a method involving
linear unmixing based on singular value decomposition of the matrices consisting
of dye spectra. Analyses of mouse thymic tissues stained with seven different
fluorescent dyes provided clear independent images, and any combination of two or
three individual dye images could be used for constructing multicolor images.
PMID- 10769050
TI - Modified basement membrane composition during bronchopulmonary tumor progression.
AB - During tumor progression, the extracellular matrix (ECM) and particularly the
basement membrane (BM) appear to be dynamic structures that are not only degraded
but also deposited around tumor clusters. In this study we examined by
immunohistochemistry the localization of three chains of Type IV collagen
(alpha1, alpha3 and alpha5), Type VII collagen, and laminin 5 at different stages
of bronchopulmonary cancers. In normal tissues, alpha1(IV) chain was detected in
all BMs (bronchial, vascular, alveolar, and glandular), alpha5(IV) chain was
present only in vascular BM, and laminin 5 and Type VII collagen were co
localized in bronchial and glandular BMs, whereas alpha3(IV) immunolabeling was
totally absent from normal bronchi. In well-differentiated carcinomas, alpha3(IV)
chain staining was found in some neosynthetized BMs interfacing the tumor cell
and the stromal compartment, contrasting with the total absence of labeling in
normal tissues. alpha1(IV) chain showed strong reactivity in all BM. Laminin 5
and Type VII collagen were also detected in neosynthetized BM. In poorly
differentiated invasive cancers, alpha3(IV) chain and Type VII collagen were not
found, whereas laminin 5 and alpha1(IV) chain persisted. The most important
modifications in BM composition during tumor progression therefore appear to be
the appearance of the alpha3 (IV) chain in well-differentiated carcinomas and its
subsequent disappearance in poorly differentiated carcinomas, together with the
loss of type VII collagen. alpha5(IV) chain distribution was restricted in
vascular BM of well- and poorly differentiated carcinomas. These results show
that the composition of BM is modified during the progression of bronchopulmonary
tumor, emphasizing that the BM represents a dynamic element in tumor progression
and has an important role in tumor cell invasiveness.
PMID- 10769051
TI - A new cat Fos antibody to localize the immediate early gene c-fos in mammalian
visual cortex after sensory stimulation.
AB - We developed a novel antibody against cat Fos by immunizing rabbits with a 26
amino-acid peptide. Immunocytochemistry on visual cortex of cats undergoing
different visual manipulations was applied to test the reliability and the
efficacy of this antiserum. One hour of light stimulation after an overnight dark
adaptation resulted in strongly induced Fos expression in supra- and
infragranular layers of cat primary visual cortex. Short-term monocular
deprivation changed the Fos expression profile into a columnar immunostaining
related to ocular dominance columns. Fos expression has also been analyzed in
cats in which visual input was confined to the right hemisphere by sectioning the
left optic tract and the corpus callosum. In the right hemisphere, visual
stimulation elicited Fos induction, whereas in the contralateral hemisphere a
very low Fos signal was observed. The specificity of this newly synthesized
antibody was confirmed by Western blotting. To further establish the
applicability of this Fos antiserum, we performed immunostaining on monkey and
rat visual cortex. This new cat Fos antibody appears to be excellent for study of
Fos expression as a marker for mapping neuronal activity in mammalian brain.
PMID- 10769052
TI - Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase
(PDE5) in rat tissues.
AB - We raised a polyclonal antibody against maltose binding protein fusion human cGMP
binding, cGMP-specific phosphodiesterase (PDE5) produced in E. coli. This
antibody immunoreacted specifically with recombinant human and rat PDE5 proteins
expressed in transfected COS-7 cells and with a native form of PDE5 in extracts
of rat platelets, lung, and cerebellum. Immunohistochemical analysis showed that
the anti-PDE5 antibody detected immunoactive materials in Purkinje cell layers of
the cerebellum, proximal renal tubules, collecting renal ducts, and epithelial
cells of pancreatic ducts in rats. Reverse transcriptase-polymerase chain
reaction analysis demonstrated that PDE5 transcripts are also present in rat
cerebellum, kidney, and pancreas. Here we described a cell-specific localization
of PDE5 in various rat tissues, suggesting the possibility of the presence of a
cGMP/PDE5 pathway in these tissues.
PMID- 10769053
TI - Morphological aspects of the postnatal development of submandibular glands in
male rats: involvement of apoptosis.
AB - We studied the involvement of the apoptotic mechanism(s) in cell differentiation
in the developing male rat submandibular gland using the TUNEL (terminal
deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick
labeling) assay in combination with light and electron microscopy. Whereas the
proacinar cells were completely transformed into acinar cells within 2 weeks
after birth, starting on postnatal Day 21, the terminal tubule cells formed
vacuoles that disappeared by postnatal Day 35. During this period, positive TUNEL
reactivity was seen in the terminal tubule cells, and electron microscopic
analysis showed that certain morphological features of apoptosis, including
fragmentation of nuclei and the presence of apoptotic bodies in the cytoplasm,
were present in and restricted to the terminal tubule cells. These results
indicate that, in addition to an autophagocytosis-mediated mechanism, apoptosis
may also be involved in reducing the number of terminal tubule cells during
postnatal development in the submandibular gland.
PMID- 10769054
TI - Fluctuating gene expression and localized cellular distribution of vasoactive
intestinal contractor (VIC) in mouse uterus.
AB - To understand the physiological roles of vasoactive intestinal contractor (VIC)
and endothelin-2 (ET-2) in the uterus, we examined the expression levels of VIC
mRNA by real-time quantitative reverse transcription-linked polymerase chain
reaction (RT-PCR) and characterized the cellular distribution of VIC peptide and
mRNA by immunostaining and in situ hybridization in mouse uterus. In pregnant
mouse uterus, VIC mRNA expression changed considerably between Days 10.5 and 12.5
of pregnancy. The expression levels were significantly (p<0.05) higher
(approximately fivefold) in the later stage of pregnancy (Days 12.5-17.5) than in
the earlier stage (Days 7.5-10.5). In nonpregnant uterus, VIC mRNA expression was
significantly (p <0.05) higher (approximately threefold) in proestrus and estrus
than in diestrus. Immunohistochemical studies demonstrated the presence of VIC
peptide in endometrial epithelial cells, myometrial cells, and vascular smooth
muscle cells during the estrous cycle and pregnancy and after parturition.
Notably, myometrial cells showed dominant immunostaining in proestrus and estrus,
in the later pregnancy stage, and in the early postpartum period, analogous to
the expression pattern of VIC mRNA. In situ hybridization confirmed localization
of VIC mRNA in myometrial cells. These findings suggest that VIC may play an
important role in the function of myometrial cells.
PMID- 10769055
TI - AgarCyto: a novel cell-processing method for multiple molecular diagnostic
analyses of the uterine cervix.
AB - In diagnostic cytology, it has been advocated that molecular techniques will
improve cytopathological diagnosis and may predict clinical course. Ancillary
molecular techniques, however, can be applied only if a sufficient number of
preparations are made from a single cell sample. We have developed the AgarCyto
cell block procedure for multiple molecular diagnostic analyses on a single
scraping from the uterine cervix. The optimized protocol includes primary
fixation and transport in ethanol/carbowax, secondary fixation in Unifix, and
embedding in 2% agarose and then in paraffin according to a standard protocol for
biopsies. More than 20 microscopic specimens were produced from a single AgarCyto
cell block, and standard laboratory protocols have been successfully applied for
H&E staining, immunohistochemistry for Ki-67 and p53, and in situ hybridization
for the centromere of human chromosome 1 and human papilloma virus Type 16. In
addition, single AgarCyto sections yielded sufficient input DNA for specific HPV
detection and typing by LiPA-PCR, and the protocol includes an option for DNA
image cytometry. The AgarCyto cell block protocol is an excellent tool for
inventory studies of diagnostic and potentially prognostic molecular markers of
cervical cancer.
PMID- 10769056
TI - Affinity imaging of red blood cells using an atomic force microscope.
AB - We used an atomic force microscope (AFM) to produce an image of a mixed layer of
group A and O red blood cells with a contrast based only on the measured strength
of a specific receptor-ligand pair. The image was obtained by measuring and
plotting for each image pixel the adhesion force between the mixed RBC layer and
the AFM tip functionalized with Helix pomatia lectin. The high specificity of
that lectin for the N -acetylgalactosamine-terminated glycolipids present in the
membrane of group A RBCs enabled us to discriminate between the two cell
populations and to produce an image based on affinity contrast. The rupture force
of the adhesion events leading to the image formation were quantitatively
analyzed and compared to rupture forces measured with the same AFM tip on N
acetylgalactosamine tethered to agarose beads. The mean rupture force was found
to be 65 pN when measured on the group A RBCs and 35 pN on the agarose beads.
These results show that the adhesion, mediated by only a few receptor-ligand
pairs, produces sufficient contrast for the affinity image formation.
PMID- 10769057
TI - High genetic variability of the group-specific a-determinant of hepatitis B virus
surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in
chronic virus carriers lacking detectable HBsAg in serum.
AB - Chronic carriers of hepatitis B virus (HBV) usually show hepatitis B surface
antigen (HBsAg) in their sera, which is considered the best marker for acute and
chronic HBV infection. In some individuals, however, this antigen cannot be
detected by routine serological assays despite the presence of virus in liver and
peripheral blood. One reason for this lack of HBsAg might be mutations in the
part of the molecule recognized by specific antibodies. To test this hypothesis,
the HBV S gene sequences were determined of isolates from 33 virus carriers who
were negative for HBsAg but showed antibodies against the virus core (anti-HBc)
as the only serological marker of hepatitis B. Isolates from 36 HBsAg-positive
patients served as controls. In both groups, a considerable number of novel
mutations were found. In isolates from individuals with anti-HBc reactivity only,
the variability of the major hydrophilic loop of HBsAg, the main target for
neutralizing and diagnostic antibodies, was raised significantly when compared
with the residual protein (22. 6 vs 9.4 mutations per 1000 amino acids; P<0.001)
and with the corresponding region in the controls (22.6 vs 7.5 exchanges per 1000
residues; P<0.001). A similar hypervariable spot was identified in the reverse
transcriptase domain of the viral polymerase, encoded by the same nucleotide
sequence in an overlapping reading frame. These findings suggest that at least
some of the chronic low-level carriers of HBV, where surface antigen is not
detected, could be infected by diagnostic escape mutants and/or by variants with
impaired replication.
PMID- 10769058
TI - Cytokine profile of draining lymph node lymphocytes in mice grafted with
syngeneic keratinocytes expressing human papillomavirus type 16 E7 protein.
AB - Studies on the immune response to human papillomaviruses are compromised by the
extreme host and tissue specificity of these viruses. To circumvent this, a mouse
model system has been used in which antigen is presented via a differentiated,
syngeneic keratinocyte graft expressing human papillomavirus type 16 (HPV-16) E7
protein. Using this model, previous studies have shown that animals grafted with
a high cell inoculum (1x10(7) NEK 16 cells) exhibit a delayed-type
hypersensitivity response that is E7-specific and CD4(+)-mediated, but those
receiving a low cell inoculum (5x10(5) NEK 16 cells) are rendered unresponsive to
subsequent and repeated antigen challenge. To investigate the mechanisms
underlying this phenomenon, we have analysed the early changes in the cytokine
profile of the graft-draining lymph node (GDLN) after high- or low-dose grafts.
At 4 days post-grafting, there was a peak secretion of IL-2 associated with a
decreased secretion of IL-4 by gammadelta-TCR(+) cells in the group receiving
1x10(7) NEK 16 cells. At 5 days post-grafting, there was a peak secretion of IL
10 by CD8(+) cells in both the high- and low-dose graft groups compared with
controls. In contrast, low dose-grafted animals showed an increase in IL-4
production by CD8(+) cells at this time-point. Low antigen challenge in this
model system is associated with the appearance of a CD8(+) population in the GDLN
that secretes both IL-4 and IL-10. This population may represent a Tc2 or Ts
subset that could induce further unresponsiveness.
PMID- 10769060
TI - Evolution of human polyomavirus JC.
AB - More than 20 near full-length genome sequences have been reported for human
polyomavirus JC (JCV). These have previously been classified into seven
genotypes, and additional subtypes, which exhibit geographical associations. One
of these genotypes, Type 4, has been suggested to be a recombinant of Types 1 and
3. We have investigated the pattern of diversity, and evolutionary relationships,
among these sequences. In direct contradiction of a recent report, we found that
different phylogenetic methods gave consistent results for the phylogenetic
relationships among strains. The single known strain representing Type 5 was
shown to be a mosaic of sequences from Types 2 and 6, although whether this
recombination occurred in vivo or in vitro is not clear. In contrast, there was
no substantial evidence that Type 4 strains are recombinant; rather they seem to
be simply divergent examples of Type 1. On the assumption that the major
genotypes of JCV diverged with human populations, the rate of synonymous
nucleotide substitution was estimated to be around 4x10(-7) per site per year,
about 10 times higher than a previous estimate for primate polyomaviruses.
PMID- 10769059
TI - Agnoprotein 1a and agnoprotein 1b of avian polyomavirus are apoptotic inducers.
AB - Avian polyomavirus (APV) causes an acute fatal disease in a variety of avian
species. DNA laddering indicating apoptosis was demonstrated in APV-infected
chicken embryo (CE) cells. DNA laddering, however, was not observed in Vero cells
infected with mammalian polyomavirus simian virus 40. Expression of APV
agnoprotein 1a and agnoprotein 1b induced apoptosis in insect cells and CE cells.
An APV full-length plasmid transfected in CE cells induced apoptosis, and
infectious virus was produced. After transfection of CE cells with a plasmid
containing a mutated initiation codon for agnoprotein 1a and agnoprotein 1b,
however, a considerably lower number of apoptotic cells was observed, and no
infectious progeny was produced.
PMID- 10769061
TI - Neuronal pathways for the propagation of herpes simplex virus type 1 from one
retina to the other in a murine model.
AB - Herpetic retinitis in humans is characterized by a high frequency of bilateral
localization. In order to determine the possible mechanisms leading to bilateral
retinitis, we studied the pathways by which herpes simplex virus type 1 (HSV-1)
is propagated from one retina to the other after intravitreal injection in mice.
HSV-1 strain SC16 (90 p.f.u.) was injected into the vitreous body of the left eye
of BALB/c mice. Animals were sacrificed 1, 2, 3, 4 and 5 days post-inoculation
(p.i.). Histological sections were studied by immunochemical staining. Primary
retinitis in the inoculated eye (beginning 1 day p.i.) was followed by
contralateral retinitis (in the uninoculated eye) starting at 3 days p.i.
Infected neurons of central visual pathway nuclei (lateral geniculate nuclei,
suprachiasmatic nuclei and pretectal areas) were detected at 4 days p.i. Iris and
ciliary body infection was minimal early on, but became extensive thereafter and
was accompanied by the infection of connected sympathetic and parasympathetic
pathways. The pattern of virus propagation over time suggests that the onset of
contralateral retinitis was mediated by local (non-synaptic) transfer in the
optic chiasm from infected to uninfected axons of the optic nerves. Later,
retinopetal transneuronal propagation of the virus from visual pathways may have
contributed to increase the severity of contralateral retinitis.
PMID- 10769062
TI - Detection of lymphocytes productively infected with Epstein-Barr virus in non
neoplastic tonsils.
AB - Epstein-Barr virus (EBV) persists for life in the infected host. Little is known
about EBV reactivation and regulation of virus persistence in healthy
individuals. We examined tonsils of chronic tonsillitis patients to detect EBV
transcripts, EBV genomes and lytic proteins. LMP1 transcripts were observed in 11
of 15 specimens and BZLF1 transcripts were detected in six. Multiple copies of
EBV genome equivalents per cell, and ZEBRA- and viral capsid antigen-positive
cells were also detected in tonsillar lymphocytes. These results indicate that
EBV productively infected cells may survive in the face of immune surveillance in
the tonsils. Thus, EBV replication may occur in tonsillar lymphocytes, and
tonsillar lymphoid tissues may play a role in the maintenance of EBV load in
vivo.
PMID- 10769063
TI - Molecular characterization of Kaposi's sarcoma-associated herpesvirus/human
herpesvirus-8 strains from Russia.
AB - We report the molecular characterization, with subtyping of both K1 and K14.1/K15
genomic regions, of seven new human herpesvirus-8 (HHV-8) strains from Russian
patients with classical Kaposi's sarcoma. Phylogenetic studies, based on the
complete K1 gene/protein analysis, indicate that six of these strains belong to
the A subtype, with one belonging to the A4 group and exhibiting a unique
deletion of 19 amino acids in the VR2 region at position 186-204. PCR-based
studies of the K14.1/K15 genomic region indicate that four of the new strains
were of the M subtype while three belonged to the P subtype. Our study indicates
an important genetic diversity of the HHV-8 strains currently present in Russia,
including a new peculiar strain possessing a unique deletion in the VR2 segment,
and confirms the absence of correlation between the K1 and K14.1/K15 molecular
subtypes, as M and P genotypes can be observed in the A K1 subtype.
PMID- 10769064
TI - Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding
proteins.
AB - Interleukin-18 (IL-18) is a proinflammatory cytokine that plays a key role in the
activation of natural killer and T helper 1 cell responses principally by
inducing interferon-gamma (IFN-gamma). Human and mouse secreted IL-18-binding
proteins (IL-18BPs) have recently been described which block IL-18 activity but
have no sequence similarity to membrane IL-18 receptors. Several poxvirus genes
encode proteins with sequence similarity to IL-18BPs. Here we show that vaccinia,
ectromelia and cowpox viruses secrete from infected cells a soluble IL-18BP (vIL
18BP) that may modulate the host antiviral response. The ectromelia virus protein
was found to block NF-kappaB activation and induction of IFN-gamma in response to
IL-18. The highly attenuated vaccinia virus modified virus Ankara encodes IL-18
binding activity, and thus deletion of the vIL-18BP may improve further the
safety and immunogenicity of this promising human vaccine candidate. We confirm
that molluscum contagiosum virus, a molluscipoxvirus that produces small skin
tumours in immunocompetent individuals and opportunistic infections in
immunodeficient AIDS patients, also encodes a related, larger vIL-18BP (gene
MC54L). This protein may contribute to the lack of inflammatory response
characteristic of molluscum contagiosum virus lesions. The expression of vIL
18BPs by distinct poxvirus genera that cause local or general viral
dissemination, or persistent or acute infections in the host, emphasizes the
importance of IL-18 in response to viral infections.
PMID- 10769065
TI - The punctate sites of accumulation of vaccinia virus early proteins are
precursors of sites of viral DNA synthesis.
AB - Several vaccinia virus early proteins (encoded by genes B1R, H5R and I3L)
synthesized in the presence of an inhibitor of DNA synthesis localize, at least
in part, to punctate inclusions that are visible by immunofluorescence in the
cytoplasm of poxvirus-infected cells. It is shown that these inclusions contain
DNA (visualized by DAPI staining of the infected cells) and that the number of
inclusions is proportional to the amount of input virus. Their mean diameter
(about 680 nm) was larger than that of purified vaccinia virus particles. When
the inhibition of DNA synthesis was reversed, incorporation of BrdU into the B1R
particles was demonstrated after labelling for 30 min, suggesting that these
cytoplasmic focal sites correspond to viral DNA replication complexes that have
initiated normally but are inhibited at the step of DNA chain elongation. These
experiments suggest strongly that these inclusions are the precursors of the
virosomes.
PMID- 10769066
TI - Simian rhesus rotavirus is a unique heterologous (non-lapine) rotavirus strain
capable of productive replication and horizontal transmission in rabbits.
AB - Simian rhesus rotavirus (RRV) is the only identified heterologous (non-lapine)
rotavirus strain capable of productive replication at a high inoculum dose of
virus (>10(8) p.f.u.) in rabbits. To evaluate whether lower doses of RRV would
productively infect rabbits and to obtain an estimate of the 50% infectious dose,
rotavirus antibody-free rabbits were inoculated orally with RRV at inoculum doses
of 10(3), 10(5) or 10(7) p.f.u. Based on faecal virus antigen or infectious virus
shedding, RRV replication was observed with inoculum doses of 10(7) and 10(5)
p.f.u., but not 10(3) p.f.u. Horizontal transmission of RRV to one of three mock
inoculated rabbits occurred 4-5 days after onset of virus antigen shedding in RRV
infected rabbits. Rabbits infected at 10(7) and 10(5), but not 10(3), p.f.u. of
RRV developed rotavirus-specific immune responses and were completely (100%)
protected from lapine ALA rotavirus challenge. These data confirm that RRV can
replicate productively and spread horizontally in rabbits. In attempts to
elucidate the genetic basis of the unusual replication efficacy of RRV in
rabbits, the sequence of the gene encoding the lapine non-structural protein NSP1
was determined. Sequence analysis of the NSP1 of three lapine rotaviruses
revealed a high degree of amino acid identity (85-88%) with RRV. Since RRV and
lapine strains also share similar VP7s (96-97%) and VP4s (69-70%), RRV might
replicate efficiently in rabbits because of the high relatedness of these three
gene products, each implicated in host range restriction.
PMID- 10769067
TI - Properties of a neutralizing antibody that recognizes a conformational form of
epitope ERDRD in the gp41 C-terminal tail of human immunodeficiency virus type 1.
AB - The possibility that epitopes from the C-terminal tail of the gp41 transmembrane
protein of human immunodeficiency virus type 1 (HIV-1) are exposed the surface of
the virion has long been contentious. Resolution of this has been hampered by the
absence of any neutralizing monoclonal antibodies, but we have recently epitope
purified a neutralizing polyclonal IgG specific for one of the putative gp41 tail
epitopes, (746)ERDRD(750). This was obtained from mice immunized parenterally
with a plant virus chimera expressing residues 731-752 from the gp41 tail. The
ERDRD epitope is highly conformational and is conserved in 81% of B clade
viruses. Here, it is shown that this polyclonal ERDRD-specific IgG is highly
potent, with an affinity of 2.2x10(8) M(-1), and a neutralization rate constant (
K(neut)) of 7.8x10(4) M(-1) s(-1) that exceeds that of nearly all other known HIV
1-neutralizing antibodies. ERDRD-specific IgG gave 50% neutralization at 0.1-0.2
microg/ml and 90% neutralization at approximately 3 microg/ml. It also
neutralized virus that was already attached to target cells, and this and other
data suggest that it neutralized by inhibiting a virion event that precedes the
fusion-entry process. Consistent with this conclusion was the finding that
neutralizing amounts of ERDRD-specific IgG did not inhibit the attachment of free
virus to target cells. ERDRD-specific IgG was also cross-reactive and neutralized
all but one of six B clade T cell line-adapted strains tested.
PMID- 10769068
TI - CD8(+) cell noncytotoxic anti-human immunodeficiency virus response inhibits
expression of viral RNA but not reverse transcription or provirus integration.
AB - CD8(+) T cells from human immunodeficiency virus (HIV)-infected individuals can
suppress HIV replication in CD4(+) cells by a noncytotoxic mechanism that
inhibits the expression of viral RNA. The present study examined whether other
step(s) in the virus replicative cycle could be affected by the CD8(+) cells.
Culturing HIV-infected CD4(+) T cells with antiviral CD8(+) T cells did not
significantly reduce the amounts of (i) early HIV DNA reverse transcripts
(detected by LTR-U3/R), (ii) total nuclear HIV gag DNA, or (iii) integrated
proviral DNA. However, exposure to the CD8(+) T cells did cause a reduction in
the amount of multiply spliced tat and full-length gag mRNA expressed by the
infected CD4(+) T cells, confirming previous observations. The levels of
glyceraldehyde-3-phosphate dehydrogenase and interleukin-2 receptor-alpha mRNA
were not affected. The results support the conclusion that the noncytotoxic anti
HIV response of CD8(+) T cells, demonstrable in vitro, does not affect any of the
virus replication steps leading to the integration of proviral HIV, but
specifically interrupts the expression of viral RNA.
PMID- 10769069
TI - Suboptimal splice sites of equine infectious anaemia virus control Rev
responsiveness.
AB - The Rev protein of equine infectious anaemia virus (EIAV) was shown previously to
stimulate the expression of a heterologous CAT reporter gene when the 3' half of
the EIAV genome was present downstream in cis. However, computer analysis could
not reveal the existence of a stable RNA secondary structure that could be
analogous to the Rev-responsive element of other lentiviruses. In the present
study, the inhibitory RNA element designated the cis-acting repressing sequence
(CRS) has been localized to the centre of the EIAV genome. The inhibition exerted
by this element could be overcome by supplying Rev in trans. The ability of the
EIAV CRS to function in a heterologous context suggests that it does not require
interactions with other viral proteins. Site-directed mutagenesis showed that the
various centrally located suboptimal splice sites of the EIAV genome function as
CRS and confer Rev-dependence on the CRS-containing transcripts. In addition, the
data suggest that in canine Cf2Th cells, which are highly permissive for EIAV
replication, CRS prevents nuclear export of CRS-containing transcripts and the
supply of Rev relieves this suppression.
PMID- 10769070
TI - Homologous and heterologous glycoproteins induce protection against Junin virus
challenge in guinea pigs.
AB - Tacaribe virus (TACV) is an arenavirus that is genetically and antigenically
closely related to Junin virus (JUNV), the aetiological agent of Argentine
haemorrhagic fever (AHF). It is well established that TACV protects experimental
animals fully against an otherwise lethal challenge with JUNV. To gain
information on the nature of the antigens involved in cross-protection,
recombinant vaccinia viruses were constructed that express the glycoprotein
precursor (VV-GTac) or the nucleocapsid protein (VV-N) of TACV. TACV proteins
expressed by vaccinia virus were indistinguishable from authentic virus proteins
by gel electrophoresis. Guinea pigs inoculated with VV-GTac or VV-N elicited
antibodies that immunoprecipitated authentic TACV proteins. Antibodies generated
by VV-GTac neutralized TACV infectivity. Levels of antibodies after priming and
boosting with recombinant vaccinia virus were comparable to those elicited in
TACV infection. To evaluate the ability of recombinant vaccinia virus to protect
against experimental AHF, guinea pigs were challenged with lethal doses of JUNV.
Fifty per cent of the animals immunized with VV-GTac survived, whereas all
animals inoculated with VV-N or vaccinia virus died. Having established that the
heterologous glycoprotein protects against JUNV challenge, a recombinant vaccinia
virus was constructed that expresses JUNV glycoprotein precursor (VV-GJun). The
size and reactivity to monoclonal antibodies of the vaccinia virus-expressed and
authentic JUNV glycoproteins were indistinguishable. Seventy-two per cent of the
animals inoculated with two doses of VV-GJun survived lethal JUNV challenge.
Protection with either VV-GJun or VV-GTac occurred in the presence of low or
undetectable levels of neutralizing antibodies to JUNV.
PMID- 10769071
TI - Genetic analysis of the compatibility between polymerase proteins from human and
avian strains of influenza A viruses.
AB - In order to determine how efficiently the polymerase proteins derived from human
and avian influenza A viruses can interact with each other in the context of a
mammalian cell, a genetic system that allows the in vivo reconstitution of active
ribonucleoproteins was used. The ability to achieve replication of a viral-like
reporter RNA in COS-1 cells was examined with heterospecific mixtures of the core
proteins (PB1, PB2, PA and NP) from two strains of human viruses (A/Puerto
Rico/8/34 and A/Victoria/3/75), two strains of avian viruses
(A/Mallard/NY/6750/78 and A/FPV/-Rostock/34), and a strain of avian origin
(A/Hong Kong/156/97) that was isolated from the first human case of H5N1
influenza in Hong Kong in 1997. In accordance with published observations on
reassortant viruses, PB2 amino acid 627 was identified as a major determinant of
the replication efficiency of heterospecific complexes in COS-1 cells. Moreover,
the results showed that replication of the viral-like reporter RNA was more
efficient when PB2 and NP were both derived from the same avian or human virus or
when PB1 was derived from an avian virus, whatever the origin of the other
proteins. Furthermore, the PB1 and PB2 proteins from the A/Hong- Kong/156/97
virus exhibited intermediate properties with respect to the corresponding
proteins from avian or human influenza viruses, suggesting that some molecular
characteristics of PB1 and PB2 proteins might at least partially account for the
ability of the A/Hong Kong/156/97 virus to replicate in humans.
PMID- 10769072
TI - Evolutionary characterization of the six internal genes of H5N1 human influenza A
virus.
AB - The entire nucleotide sequences of all six internal genes of six human H5N1
influenza A viruses isolated in Hong Kong in 1997 were analysed in detail from a
phylogenetic point of view and compared with the evolutionary patterns of the
haemagglutinin and neuraminidase genes. Despite being isolated within a single
year in the same geographical location, human H5N1 viruses were characterized by
a variety of amino acid substitutions in the ribonucleoprotein complex [PB2, PB1,
PA and nucleoprotein (NP)] as well as the matrix (M) proteins 1 and 2 and
nonstructural (NS) proteins 1 and 2. The presence of previously reported amino
acid sequences specific for human strains was confirmed in the PB2, PA, NP and M2
proteins. Nucleotide and amino acid sequence identities of the six internal genes
of H5N1 viruses examined here were separated into at least two variant groups. In
agreement with the above result, phylogenetic trees of the six internal genes of
human H5N1 viruses were generally composed of two minor clades. Additionally,
variable dendrogram topologies suggested that reassortment among viruses
contributed further to the genetic variability of these viruses. As a result, it
became clear that human H5N1 viruses are characterized by divergent gene
constellations, suggesting the possible occurrence of genetic reassortment
between viruses of the two evolutionary lineages.
PMID- 10769073
TI - Filamentous particle formation by human parainfluenza virus type 2.
AB - Some paramyxoviruses form long filamentous virus particles: however, the
determinants of filament formation and the role of such particles in virus
transmission and pathogenicity are not clearly defined. By using conventional
immunofluorescence microscopy, we found that human parainfluenza virus type 2
(HPIV2) forms filamentous particles ranging from 5 to 15 microm in length in
virus-infected, polarized epithelial cells. The formation of filamentous
particles was found to be virus type-specific and was not observed when the same
cell types were infected with parainfluenza virus type 3 or Sendai virus,
suggesting that different paramyxovirus genera exhibit distinct morphological
properties. HPIV2 filamentous particle formation was found to be inhibited by
cytochalasin D (CD) or jasplakinolide treatment in a dose-dependent manner. In
the presence of 4 microg/ml CD or 1 microM jasplakinolide, the formation of
filamentous particles was completely abolished, although similar
haemagglutination and p.f.u. titres of virus were found to be released into the
culture medium at 24 h post-infection. These observations indicate that host cell
components, including the actin microfilament network, are important determinants
of the morphology of parainfluenza viruses. The predominance of filamentous
particles in polarized epithelial cells may reflect specific pathogenic roles of
these particles in infection of human epithelial tissues.
PMID- 10769074
TI - A novel sensitive approach for frequency analysis of measles virus-specific
memory T-lymphocytes in healthy adults with a childhood history of natural
measles.
AB - Measles virus (MV), a single-stranded negative-sense RNA virus, is an important
pathogen causing almost 1 million deaths annually. Acute MV infection induces
immunity against disease throughout life. The immunological factors which are
responsible for protection against measles are still poorly understood. However,
T-cell-mediated immune responses seem to play a central role. The emergence of
new single-cell methods for quantification of antigen-specific T-cells directly
ex vivo has prompted us to measure frequencies of MV-specific memory T-cells. As
an indicator for T-cell activation IFN-gamma production was measured. PBMC were
analysed by intracellular staining and ELISPOT assay after stimulation with MV
infected autologous B-lymphoblastoid cell lines or dendritic cells. T-cell
responses were exclusively seen with PBMC from MV-seropositive healthy adults
with a history of natural measles in childhood. The median frequency of MV
specific T-cells was 0.35% for CD3(+)CD4(+) and 0.24% for the CD3(+)CD8(+) T-cell
subset. These frequencies are comparable with T-cell numbers reported by other
investigators for persistent virus infections such as Epstein-Barr virus,
cytomegalovirus or human immunodeficiency virus. Hence, this study illustrates
that MV-specific CD4(+) and CD8(+) T-cells are readily detectable long after the
acute infection, and thus are probably contributing to long-term immunity.
Furthermore, this new approach allows efficient analysis of T-cell responses from
small samples of blood and could therefore be a useful tool to further elucidate
the role of cell-mediated immunity in measles as well as in other viral
infections.
PMID- 10769075
TI - DNA vaccination with both the haemagglutinin and fusion proteins but not the
nucleocapsid protein protects against experimental measles virus infection.
AB - Plasmids that expressed the nucleocapsid, haemagglutinin and fusion proteins of
measles virus (MV) were used to immunize cotton rats (Sigmodon hispidus) against
intranasal MV infection. After immunization with all three plasmids, T cell
responses and MV-specific antibodies were induced. A reduction in virus titre was
observed in lung tissue from animals immunized with plasmids expressing the viral
glycoproteins. Histologically, however, a moderate peribronchitis was observed
after immunization with the plasmid expressing the fusion protein whereas, after
immunization with plasmids expressing haemagglutinin or both glycoproteins, only
mild or focal peribronchitis was seen. Immunization with the nucleocapsid did not
reduce virus titres, probably because of the failure to induce neutralizing
antibodies. A disadvantage of plasmid immunization was its inefficacy in the
presence of MV-specific 'maternal' antibodies. This indicates that genetic
immunization has to be improved to be a useful alternative vaccine against
measles.
PMID- 10769076
TI - Effect of cellular changes and onset of humoral immunity on the replication of
porcine reproductive and respiratory syndrome virus in the lungs of pigs.
AB - Twenty-two 4- to 5-week-old gnotobiotic pigs were intranasally inoculated with
10(6.0) TCID(50) of porcine reproductive and respiratory syndrome virus (PRRSV)
(Lelystad) and euthanized at different time intervals post-inoculation (p.i.).
Bronchoalveolar lavage (BAL) cell populations were characterized, together with
the pattern of virus replication and appearance of antibodies in the lungs. Total
BAL cell numbers increased from 140x10(6) at 5 days p.i. to 948x10(6) at 25 days
p.i. and remained at high levels until the end of the experiment. The number of
monocytes/macrophages, as identified by monoclonal antibodies 74-22-15 and 41D3,
increased two- to fivefold between 9 and 52 days p.i. with a maximum at 25 days
p.i. Flow cytometry showed that the population of differentiated macrophages was
reduced between 9 and 20 days p.i. and that between the same time interval, both
74-22-15-positive and 41D3-negative cells, presumably monocytes, and 74-22-15-
and 41D3-double negative cells, presumably non-phagocytes, entered the alveolar
spaces. Virus replication was highest at 7 to 9 days p.i., decreased slowly
thereafter and was detected until 40 days p.i. Anti-PRRSV antibodies were
detected starting at 9 days p.i. but neutralizing antibodies were only
demonstrated in one pig euthanized at 35 days and another at 52 days p.i. The
decrease of virus replication in the lungs from 9 days p.i. can be attributed to
(i) shortage of susceptible differentiated macrophages, (ii) lack of
susceptibility of the newly infiltrated monocytes and (iii) appearance of anti
PRRSV antibodies in the lungs. Neutralizing antibodies may contribute to the
clearance of PRRSV from the lungs.
PMID- 10769077
TI - Enzymatic properties of hepatitis C virus NS3-associated helicase.
AB - The hepatitis C virus non-structural protein 3 (NS3) possesses a serine protease
activity in the N-terminal one-third, whereas RNA-stimulated NTPase and helicase
activities reside in the C-terminal portion. In this study, an N-terminal
hexahistidine-tagged full-length NS3 polypeptide was expressed in Escherichia
coli and purified to homogeneity by conventional chromatography. Detailed
characterization of the helicase activity of NS3 is presented with regard to its
binding and strand release activities on different RNA substrates. On RNA double
hybrid substrates, the enzyme was shown to perform unwinding activity starting
from an internal ssRNA region of at least 3 nt and moving along the duplex in a
3' to 5' direction. In addition, data are presented suggesting that binding to
ATP reduces the affinity of NS3 for ssRNA and increases its affinity for duplex
RNA. Furthermore, we have ascertained the capacity of NS3 to specifically
interact with and resolve the stem-loop RNA structure (SL I) within the 3'
terminal 46 bases of the viral genome. Finally, our analysis of NS3 processive
unwinding under single cycle conditions by addition of heparin in both helicase
and RNA-stimulated ATPase assays led to two conclusions: (i) NS3-associated
helicase acts processively; (ii) most of the NS3 RNA-stimulated ATPase activity
may not be directly coupled to translocation of the enzyme along the substrate
RNA molecule.
PMID- 10769078
TI - Isolation and complete nucleotide sequence of a Chinese Sindbis-like virus.
AB - Infection with alphaviruses is common in the Chinese population. Here we report
the isolation of a Sindbis-like virus from a pool of Anopheles mosquitoes
collected in Xinjiang, China during an arbovirus survey. This virus, designated
XJ-160, rapidly produced cytopathic effects on mosquito and hamster cells. In
addition, it was lethal to neonatal mice if inoculated intracerebrally.
Serologically, XJ-160 reacted with and was neutralized by an anti-Sindbis
antibody. Anti-XJ-160 antibodies were found in several cohorts of Chinese
subjects. The complete 11626-base nucleotide sequence of XJ-160 was determined.
XJ-160 has diverged significantly from the prototype Sindbis virus, with an 18%
difference in nucleotide sequence and an 8.6% difference in amino acids; there
are 11 deletions and 2 insertions, involving 99 nucleotides in total. XJ-160 is
most closely linked to Kyzylagach virus isolated in Azerbaijan. Both belong to
the African/European genetic lineage of Sindbis virus, albeit more distantly
related to other members.
PMID- 10769079
TI - Genome structure of Sagiyama virus and its relatedness to other alphaviruses.
AB - Sagiyama virus (SAG) is a member of the genus Alphavirus in the family
Togaviridae, isolated in Japan from mosquitoes in 1956. We determined the
complete nucleotide sequence of the SAG genomic RNA from the original stock virus
which formed a mixture of plaques with different sizes, and that from a full
length cDNA clone, pSAG2, infectious RNA transcripts from which formed uniform
large plaques on BHK-21 cells. The SAG genome was 11698 nt in length exclusive of
the 3' poly(A) tail. Between the complete nucleotide sequences of the full-length
cDNA clone, pSAG2, and the consensus sequence from the original stock virus,
there were nine amino acid differences; two each in nsP1, nsP2 and E1, and three
in E2, some of which may be responsible for plaque phenotypic variants in the
original virus stock. SAG was most closely related to Ross River virus among
other alphaviruses fully sequenced, with amino acid sequence identities of 86% in
the nonstructural proteins and of 83% in the structural proteins. The 3' terminal
280 nt region of SAG was 82% identical to that of Barmah Forest virus, which was
otherwise not closely related to SAG. Comparison of the nucleotide sequence of
SAG with partial nucleotide sequences of Getah virus (GET), which was originally
isolated in Malaysia in 1955 and is closely related to SAG in serology and in
biology, showed near identity between the two viruses, suggesting that SAG is a
strain of GET.
PMID- 10769080
TI - Molecular epidemiology and evolution of coxsackievirus A9.
AB - Genetic relationships between 35 clinical isolates of coxsackievirus A9 (CAV9),
collected during the last five decades from different geographical regions, were
investigated by partial sequencing. Analysis of a 150 nucleotide sequence at the
VP1/2A junction region identified 12 CAV9 genotypes. While most of the strains
within each genotype showed geographical clustering, the analysis also provided
evidence for long-range importation of virus strains. Phylogenetic analysis of a
longer region around the VP1/2A junction (approximately 390 nucleotides) revealed
that the designated genotypes actually represented phylogenetic lineages. The
phylogenetic grouping pattern of the isolates in the analysis of the VP4/VP2
region was similar to that obtained in the VP1/2A region whereas analysis of the
3D region indicated a strikingly different grouping, which suggests that
recombination events may occur in the region encoding the nonstructural proteins.
Analysis of the deduced amino acid sequences of the VP1 polypeptide demonstrated
that the RGD (arginine-glycine-aspartic acid) motif, implicated in the
interaction of the virus with integrin, was fully conserved among the isolates.
PMID- 10769081
TI - Inhibition of cap-dependent gene expression induced by protein 2A of hepatitis A
virus.
AB - The viral protein 2A of hepatitis A virus (HAV) lacks the conserved 18 aa
sequence found in other picornavirus proteases; hence, it is unclear whether the
induction of CPE by culture-adapted HAV strains is due to 2A-mediated activity.
Moreover, the cleavage sites and actual borders of HAV 2A are not known.
Accordingly, a nested series of cDNA sequences encoding the segment of the HAV
polyprotein (aa 760-1087) were linked to the 5'-UTR of poliovirus type 2 (Lansing
strain) and inserted downstream of the gene encoding human growth hormone (GH).
Following transfection of COS-1 cells, levels of GH (translation of which was
entirely cap dependent) were determined in culture supernatants. Expression of
HAV peptides extending from aa 764, 776 or 791 to 981 strongly inhibited cap
dependent translation of GH, whereas cap-independent expression of a reporter
gene (CAT) directed by the poliovirus RNA 5'-UTR was unaffected. The inhibitory
effect was absent in constructs expressing either the short peptide encompassing
aa 760-836 or proteins initiated downstream of the putative cleavage site 836
837, suggesting that the boundaries of a functional HAV 2A may extend from the
Gln/Ser junction 791-792 to residue 981, while peptides initiated at the Gln/Ala
pair 836-837 may result from alternative cleavage. Point mutations that
substituted members of the triad Ser(916), His(927) and Asp(931) abolished the
inhibitory effect on cap-dependent translation, suggesting that the HAV-induced
CPE may be mediated by 2A protein.
PMID- 10769082
TI - Foot-and-mouth disease virus is a ligand for the high-affinity binding
conformation of integrin alpha5beta1: influence of the leucine residue within the
RGDL motif on selectivity of integrin binding.
AB - Field isolates of foot-and-mouth disease virus (FMDV) use RGD-dependent integrins
as receptors for internalization, whereas strains that are adapted for growth in
cultured cell lines appear to be able to use alternative receptors like heparan
sulphate proteoglycans (HSPG). The ligand-binding potential of integrins is
regulated by changes in the conformation of their ectodomains and the ligand
binding state would be expected to be an important determinant of tropism for
viruses that use integrins as cellular receptors. Currently, alphavbeta3 is the
only integrin that has been shown to act as a receptor for FMDV. In this study, a
solid-phase receptor-binding assay has been used to characterize the binding of
FMDV to purified preparations of the human integrin alpha5beta1, in the absence
of HSPG and other RGD-binding integrins. In this assay, binding of FMDV resembled
authentic ligand binding to alpha5beta1 in its dependence on divalent cations and
specific inhibition by RGD peptides. Most importantly, binding was found to be
critically dependent on the conformation of the integrin, as virus bound only
after induction of the high-affinity ligand-binding state. In addition, the
identity of the amino acid residue immediately following the RGD motif is shown
to influence differentially the ability of FMDV to bind integrins alpha5beta1 and
alphavbeta3 and evidence is provided that alpha5beta1 might be an important FMDV
receptor in vivo.
PMID- 10769083
TI - Echovirus infection of rhabdomyosarcoma cells is inhibited by antiserum to the
complement control protein CD59.
AB - A number of echoviruses use decay accelerating factor (DAF) as a cellular
receptor or attachment protein for cell infection. Binding of echovirus 7 to DAF
at the cell surface, but not to soluble DAF in solution, triggers the formation
of virus particles exhibiting an altered sedimentation coefficient ('A'
particles) which are considered indicative of the particle uncoating process. We
have previously demonstrated that antibodies to beta(2)-microglobulin block cell
infection at a stage prior to 'A' particle formation and suggested that this
reflects the involvement of beta(2)-microglobulin (or the associated MHC-I) in a
virus-receptor complex that forms at the cell surface. We demonstrate here that
antiserum to CD59 specifically blocks infection of rhabdomyosarcoma cells by a
range of echoviruses, including viruses that bind DAF (e. g. echovirus 7) and
those that use currently unidentified receptors other than DAF. The block occurs
prior to 'A' particle formation and is cell-type specific. The potential role of
CD59 as an active member, or passive participant, in the virus-receptor complex
is discussed.
PMID- 10769084
TI - Mutagenesis of the active site coding region of the Autographa californica
nucleopolyhedrovirus chiA gene.
AB - The chitinase of Autographa californica nucleopolyhedrovirus (AcMNPV) is required
for the characteristic liquefaction of baculovirus-infected insect larvae.
Alignments of the putative active sites of a range of chitinases revealed two
highly conserved residues, glutamate and aspartate, which have been proposed to
constitute the catalytic residues of the active site. These residues were mutated
in the AcMNPV chitinase. Three recombinant viruses were generated, AcchiA(D311G),
AcchiA(E315G) and AcchiA(D311G E315G), which contained mutations at either the
glutamate, the aspartate or both. It was demonstrated that chitinase protein
production was unaffected by the mutation of these residues. However, mutation of
both residues resulted in the attenuation of chitinolytic activity and the
cessation of liquefaction of Trichoplusia ni larvae infected with AcchiA(D311G
E315G). Mutagenesis of the glutamate residue led to a reduction in exochitinase
activity and a delay in the appearance of endochitinase activity. In addition,
larvae infected with this virus, AcchiA(E315G), liquefied more slowly than those
larvae infected with wild-type AcMNPV. Mutagenesis of the aspartate residue
resulted in a reduction of exochitinase activity but an unexpected enhancement of
endochitinolytic activity. Liquefaction of AcchiA(D311G)-infected larvae was
observed at the same time as that of AcMNPV-infected larvae.
PMID- 10769085
TI - Is CT angiography sufficient for prediction of resectability of periampullary
neoplasms?
AB - The optimal preoperative evaluation of periampullary neoplasms remains
controversial. The aim of this study was to analyze the accuracy of helical
computed tomography (CT) and CT angiography with three-dimensional reconstruction
in predicting resectability. Between March 1996 and May 1999, a total of 100
patients with periampullary neoplasms were prospectively staged by helical CT and
CT angiography with three-dimensional reconstruction. Vascular involvement was
graded from 0 to 4, with grade 0 representing no vascular involvement and grade 4
total encasement of either the superior mesenteric vein or artery. Patients with
grade 4 lesions were considered unresectable. Sixty-eight patients underwent
surgical exploration with intent to perform a pancreaticoduodenectomy. Forty-four
lesions were grade 0, five were grade l, eight were grade 2, and 11 were grade 3.
Resectability for grades 0 to 3 was 96%, 100%, 50%, and 9%, respectively, for an
overall resectability rate of 76%. Resectability in patients with vascular
encroachment (grade 2) is usually determined by the extent of local disease
rather than the presence of extrapancreatic disease. Resection is rarely possible
in patients with evidence of vascular encasement (grade 3). Additional imaging
modalities such as diagnostic laparoscopy are superfluous in patients with no
evidence of local vascular involvement on CT angiography (grades 0 and 1) because
of the high resectability rate and infrequency of unsuspected distant metastatic
deposits.
PMID- 10769086
TI - Therapy for microcirculatory disorders in severe acute pancreatitis: comparison
of delayed therapy with ICAM-1 antibodies and a specific endothelin A receptor
antagonist.
AB - Many of the complications in severe acute pancreatitis result from the amplifying
effects of microcirculatory disruption. The pathogenesis of these
microcirculatory disorders is multifactorial and involves various vasoactive
mediators. Thus questions arise as to which vasoactive mediators are most
important and how long after the onset of disease vasoactive mediator blockade
may be effective. The present study compares the effect of delayed therapy with
two vasoactive mediator antagonists, previously tested with promising results in
other studies in a well-established rodent model of severe acute pancreatitis.
Twelve hours after induction of acute pancreatitis, rats were randomized to
therapy with intracellular adhesion molecule-1 (ICAM-1) antibody (2 mg/kg IA-29),
endothelin A receptor antagonist (ET-RA) (40 mg/kg LU 135252), or saline solution
(volume equivalent). After 12 hours of fluid resuscitation, animals underwent
repeat laparotomy for intravital microscopic determination of capillary blood
flow, leukocyte rolling, and capillary permeability in the pancreas and colon.
Other measurements included cardiorespiratory parameters, hematocrit, pleural
effusions, ascites, urine production, and survival. Compared to saline treatment,
both ICAM antibody and ET-RA significantly enhanced capillary blood flow in the
pancreas and colon, reduced leukocyte rolling, and stabilized capillary
permeability. These beneficial effects on microcirculation were associated with
decreased fluid loss into the third space and improved renal function and
survival. Although both antagonists likewise enhanced capillary blood flow and
reduced leukocyte rolling, ET-RA was significantly more effective than ICAM
antibody in counteracting capillary leakage, thereby further reducing fluid
sequestration. The present study confirms the beneficial effects of endothelin
and ICAM antagonists in severe acute pancreatitis, even with delayed therapy,
suggesting that both compounds are candidates for further clinical testing.
Selective endothelin A receptor blockade appears to be especially attractive for
clinical use not only because it was superior to ICAM antibody in the present
study but also because of its favorable pharmacologic properties and
(preliminary) positive results in clinical phase 2 studies currently underway for
other diseases.
PMID- 10769087
TI - Temporal correlation of tumor necrosis factor-alpha release, upregulation of
pulmonary ICAM-1 and VCAM-1, neutrophil sequestration, and lung injury in diet
induced pancreatitis.
AB - Lung injury is a major cause of patient morbidity in acute pancreatitis. The
purpose of this study was to examine the mechanism of pulmonary infiltration and
lung injury in acute pancreatitis. Mice were fed a choline-deficient/ethionine
supplemented (CDE) diet for 144 hours to induce severe acute pancreatitis. Serum
samples were collected for measurement of biochemical markers of disease and for
the detection of tumor necrosis factor-alpha (TNF-alpha). Cell surface adhesion
molecule expression was quantified by the sensitive radiolabeled dual monoclonal
antibody technique. Neutrophil sequestration in lung tissue was measured by the
myeloperoxidase assay. Lung injury was determined histologically and lung edema
was assessed by wet/dry ratios. Pancreatic injury was demonstrated to occur in
all CDE-fed mice, which developed significant hyperamylasemia and hypoglycemia by
48 hours (P <0.0001). Serum TNF-alpha levels increased significantly by 48 hours
over baseline values (P <0.02). Expression of intracellular adhesion molecule
(ICAM-1) in pulmonary endothelia was significantly increased above baseline by
30% at 48 hours (P <0.02) and peaked at 120 hours by 100% (P <0.0001). Vascular
cellular adhesion molecule (VCAM-1) was constitutively expressed at baseline and
was upregulated threefold by 48 hours (P <0.0001). Neutrophil infiltration
increased gradually 24 hours after ICAM-1 and VCAM-1 were upregulated with
significant elevation of myeloperoxidase activity over baseline at 72 hours (7.2
+/- 1.2 vs. 18.1 +/- 2.2 activity units/gram tissue; P <0.05). Neutrophil
infiltration peaked at 144 hours (26.24 +/- 10.49 activity units/gram tissue P
<0.0001), and its kinetics correlated with the onset and progression of
morphologic injury as well as increased lung edema. These results show that acute
pancreatitis is associated with a systemic release of inflammatory cytokines,
followed by increased expression of pulmonary ICAM-1 and VCAM-1, neutrophil
infiltration, and histologic lung injury. The adhesion molecule axis may be a
potential target for practical intervention to ameliorate lung injury and
morbidity in acute pancreatitis.
PMID- 10769088
TI - Do preoperative biliary stents increase postpancreaticoduodenectomy
complications?
AB - It has been suggested that the placement of endoscopic or percutaneous biliary
stents prior to pancreaticoduodenectomy increases postoperative morbidity. A
retrospective review of a prospectively collected database was performed.
Patients undergoing preoperative biliary stenting were compared with patients who
did not undergo stenting. In addition, outcomes after endoscopic and percutaneous
stenting were compared. Patients who had undergone operative biliary bypass prior
to pancreaticoduodenectomy were excluded from the analysis. Between January 1994
and December 1997, 567 patients underwent pancreaticoduodenectomy without prior
operative biliary bypass. Preoperative biliary stenting was performed in 408
patients (72%), whereas the remaining 159 patients (28%) did not undergo biliary
stenting. In the stented group, 64% had stents placed via a percutaneous approach
and 36% had stents placed endoscopically. The stented patients were older (mean
63.1 years vs. 61.4 years; P = 0.05) and were more likely to be white (92% vs.
82%; P = 0.005). Those who had stents placed were more likely to have jaundice
(67% vs. 38%; P <0.0001) and fever (5% vs. 1%; P = 0.03) as presenting symptoms.
There were no differences in multiple intraoperative parameters when the two
groups were compared. Patients who had stents placed had a perioperative
mortality rate of 1.7% compared to 2.5% in those who did not (P = 0.3). Although
the overall complication rates were 35% in those who had stents placed and 30% in
those who did not (P = NS), patients with stents experienced a significantly
increased incidence of pancreatic fistula (10% vs. 4%; P = 0.02) and wound
infection (10% vs. 4%; P = 0.02). The incidences of other postoperative
complications were similar between the stented and unstented groups. Eight
patients (3%) in the percutaneously stented group developed significant hemobilia
after stent placement, whereas none of the patients undergoing endoscopic stent
placement developed hemobilia (P = 0.03). There were no statistical differences
in other complications between the percutaneously and endoscopically stented
groups. Preoperative biliary stenting did not increase the overall complication
rate or mortality rate in patients undergoing pancreaticoduodenectomy. Stenting
does appear to increase the rate of pancreatic fistula formation, possibly as a
result of pancreatic inflammation related to the stenting procedure. Stenting
also increases the rate of wound infection, likely secondary to contaminated bile
(bactibilia) after instrumentation of the biliary tree. Preoperative biliary
stenting is safe but should be used selectively because of the above-mentioned
risks. The method of stenting should be based on local expertise.
PMID- 10769089
TI - Ontogeny of activin B and follistatin in developing embryonic mouse pancreas:
implications for lineage selection.
AB - Activin, a member of the transforming growth factor-beta superfamily, has been
shown to be a critical regulator in exocrine and endocrine pancreas formation.
The purpose of our study was to describe the ontogeny of activin B and its
inhibitor, follistatin, in developing pancreas and to elucidate potential
mechanisms for exocrine and endocrine lineage selection. Mouse embryonic
pancreata were dissected at various ages (day 10 [E10.5] to birth [E18.5]),
sectioned, and immunostained for activin B (one of two existing isomers, A and
B), follistatin, insulin, and glucagon. In addition, reverse transcriptase
polymerase chain reaction was employed to determine the messenger RNA expression
of follistatin in isolated pancreatic epithelia and mesenchyme of various ages.
Activin B was first detected at E12.5 in epithelial cells coexpressing glucagon.
At E16.5 these coexpressors appeared as clusters in close proximity to early
ducts. By E18.5 activin B was localized to forming islets where cells coexpressed
glucagon and were arranged in the mantle formation characteristic of mature alpha
cells. Follistatin was found to be ubiquitous in pancreatic mesenchyme at early
ages by immunohistochemical analysis, disappearing sometime after E12.5.
Follistatin reappeared in E18.5 islets and remains expressed in adult islets.
Follistatin messenger RNA was first detected in epithelium at E11.5, preceding
its protein expression in islets later in gestation. We propose that mesenchyme
derived follistatin inhibits epithelium-derived activin at early embryonic ages
allowing for unopposed exocrine differentiation and relative suppression of
endocrine differentiation. At later ages the decrease in the amount of mesenchyme
relative to epithelium and the subsequent drop in follistatin levels liberates
epithelial activin to allow differentiation of endocrine cells to form mature
islets by the time of birth.
PMID- 10769090
TI - Gastroesophageal reflux after intact vertical banded gastroplasty: correction by
conversion to Roux-en-Y gastric bypass.
AB - Symptomatic gastroesophageal reflux disease is common in our experience after
vertical banded gastroplasty. Our aim was to determine the safety and efficacy of
Roux-en-Y gastric bypass in the treatment of symptomatic gastroesophageal reflux
disease complicating vertical banded gastroplasty. We evaluated prospectively
collected data on 25 patients who underwent revisional bariatric surgery because
of severe gastroesophageal reflux disease after vertical banded gastroplasty.
Only 4 of 25 patients had gastroesophageal reflux disease symptoms prior to
vertical banded gastroplasty. Endoscopic findings in 24 patients included
esophagitis (58%), Barrett's esophagus (28%), pouchitis (29%), and gastritis
(21%);7 (28%) of 25 patients had evidence of stenosis at the pouch outlet. Mean
follow-up (complete in all 25) after Roux-en-Y gastric bypass was 37 +/- 7 months
(range 3 to 102 months). There were no deaths. Postoperative complications
occurred in six patients: pneumonia in two, wound infection in two, prolonged
drainage of the defunctionalized stomach via gastrostomy in one, and fever in
one. Median hospitalization was 7 days (range 5 to 43 days). At follow-up (37 +/-
7 months), 24 (96%) of 25 are completely or almost completely symptom free. Body
mass index was 33 +/- 2 kg/m(2) before and 28 +/- 2 kg/m(2) after Roux-en-Y
gastric bypass (P = 0. 001). Symptoms of gastroesophageal reflux disease are
common after vertical banded gastroplasty. Conversion to Roux-en-Y gastric bypass
is safe, relieves gastroesophageal reflux disease, and promotes further weight
loss. Moreover, maladaptive eating (vomiting, and so forth) induced by vertical
banded gastroplasty is relieved.
PMID- 10769091
TI - Treatment of esophageal achalasia with laparoscopic Heller myotomy and Dor
partial anterior fundoplication: prospective evaluation of 100 consecutive
patients.
AB - In this article we report our experience in 100 consecutive achalasia patients
who were treated with laparoscopic Heller myotomy and Dor antireflux
fundoplication, with particular regard to the technical problems encountered, the
learning curve, and the long-term follow-up. The operation was completed
laparoscopically in 94 patients, with a median operative duration of 150 minutes,
and a continuous steady reduction in the operating time from the first patients
to the last. In six patients the operation was completed through "open" access.
Postoperative complications were recorded in six cases. Follow-up was completed
in all 100 patients, with a median follow-up of 24 months. Overall, actuarial
life-table analysis showed a probability of 90% that patients would be symptom
free over a 5-year period. Radiologic assessment showed a significant reduction
in the esophageal diameter, and manometry showed a significant reduction in the
lower esophageal sphincter resting pressure and residual pressure. Twenty-four
hour pH monitoring showed postoperative reflux in 6.9% of the patients.
Persistent dysphagia or chest pain was reported by eight patients, which
constituted treatment failures. Seven of these eight patients were eventually
treated with multiple pneumatic dilatations, which were successful in six cases.
It was concluded that laparoscopic Heller myotomy with Dor fundoplication is a
feasible and effective treatment for achalasia, with an actuarial success rate of
90% at 5 years.
PMID- 10769092
TI - Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53
disruption.
AB - We studied tumorigenesis and p53 immunostaining in a murine transgenic model
introducing E1A/E1B under the control of the mouse mammary tumor virus-long
terminal repeat (MMTV-LTR) promoter in which adenocarcinoma occurs at the
squamocolumnar junction in the foregut, predominantly in males, and at no other
site. Mutations of p53 are frequent in human esophageal adenocarcinoma and the
E1B gene product interferes with p53-mediated apoptosis, inhibiting tumor
suppression at the G(1)/S checkpoint. Transgenic animals were generated utilizing
a purified linear 6.7 kb fragment of plasmid DNA containing MMTV-LTR/E1A/E1B and
were confirmed by dot blot hybridization of tail DNA to (32)P-labeled E1A/E1B
probe and polymerase chain reaction (PCR) amplification of E1A. Transgenic and
control animals were observed for morbidity and weight changes. Eleven of 45
animals were transgenic (24% efficiency) with an estimated 5 to 57 copies of the
gene per genome. Profound weight loss (>20%) led to sacrifice or death of one of
five females (at 12 weeks) and four of six males (at 16 to 17 weeks). Grossly
visible tumors (2 to 10 mm) were noted in the forestomach at the visible margin
between the proximal (squamous-lined) stomach and the distal glandular stomach.
Histologic sections confirmed adenocarcinoma arising in each case at the
squamocolumnar junction with glandular formation, pleomorphism, and frequent
mitotic figures. Immunostaining was positive for p53 indicating accumulation of
mutated or altered p53 protein. E1A/E1B transgenic animals developed macroscopic
and microscopic adenocarcinoma at the squamocolumnar junction, which corresponds
to adenocarcinoma at the human esophagogastric junction. Disruption of p53 was
present in the transgenic model as in the human cancer.
PMID- 10769093
TI - Standard Roux-en-Y gastrojejunostomy vs. "uncut" Roux-en-Y gastrojejunostomy: a
matched cohort study.
AB - Roux-en-Y gastrojejunostomy is a common method of reconstruction after subtotal
gastrectomy. Maintaining myoneural continuity has been proposed to decrease the
incidence of Roux stasis syndrome, with an "uncut" Roux-en-Y reconstruction. The
aim of our study was to compare the clinical results in patients who have
undergone uncut Roux-en-Y gastrojejunostomy with those in patients who have
undergone a standard Roux-en-Y gastrojejunostomy. Eleven patients underwent
gastrectomy and uncut Roux-en-Y gastrojejunostomy and were compared with a cohort
of 14 patients who underwent gastrectomy and standard Roux-en-Y
gastrojejunostomy. Patients were contacted and charts were reviewed for Visick
grade, early and late morbidity and mortality, and incidence of staple line
dehiscence. Early postoperative morbidity was 18% in patients undergoing uncut
Roux gastrojejunostomy and 28% in patients undergoing standard Roux
reconstruction. There were no early postoperative deaths in either group. In the
patients undergoing the uncut Roux procedure, no cases of staple line dehiscence
were detected clinically (mean follow-up 9 months, range 1 to 48 months). Visick
grade improved following the uncut Roux procedure, but changed little after
standard Roux reconstruction. Uncut Roux-en-Y gastrojejunostomy can be performed
safely with improvement in symptoms. The uncut Roux procedure may provide an
alternative for reconstructive gastric surgery.
PMID- 10769094
TI - Surgical resection improves survival in the treatment of early gastric lymphomas.
AB - Gastric lymphomas are a relatively rare form of malignancy and controversy about
their optimum treatment still exists. To date, there have been no studies
directly comparing results of medical therapy alone versus a combination of
surgery plus medical therapy. We reviewed our experience in the three teaching
hospitals of the University of Massachusetts Medical School to determine the role
of surgery in the management of early gastric lymphoma. Statistics were evaluated
by means of chi-square, log-rank, and Kaplan-Meier curve analysis where
appropriate. Using tumor registry data, 39 patients were treated for early
disease at our medical school from 1980 to 1998. Patients treated with surgery
plus chemotherapy and radiation had a 90% 5-year survival compared to patients
who received chemotherapy and radiation alone (55% 5-year survival; P <0.01).
When we compared all patients on an intention-to-treat basis (patients
preoperatively thought to have early-stage disease), there was still a
significant survival benefit with the addition of surgery to their management.
Because this is an uncommon disease, there are no large prospective studies
examining treatment. Based on our retrospective experience, surgical resection
should be considered an important adjunct in the treatment of gastric lymphomas
in early-stage disease.
PMID- 10769096
TI - Role of transforming growth factor beta-1 in peritonitis-induced adhesions.
AB - Peritonitis is a major cause of intra-abdominal adhesion formation. The
overexpression of transforming growth factor beta-1 (TGF-Beta1), a potent
mitogen, chemoattractant, and stimulant for collagen synthesis by fibroblasts,
has been linked to tissue fibrosis at various sites throughout the body including
peritoneal adhesion formation. Hence we hypothesized that the mechanism(s)
involved in peritonitis-induced adhesion formation may be mediated through the
upregulation of TGF-Beta1 expression. Peritonitis was induced in rats by cecal
ligation and puncture, while a control group underwent sham operation. Adhesions
were scored and harvested from both groups at 0, 6 and 12 hours and at 1, 2, 4,
7, and 28 days. Tissue expression of TGF-Beta1 mRNA was determined by
quantitative reverse transcription-polymerase chain reaction and TGF-Beta1
protein was localized by immunohistochemical analysis. Serum and peritoneal fluid
TGF-Beta1 concentrations were quantified by enzyme-linked immunosorbent assay.
Compared with sham operation, peritonitis was associated with a significantly
greater incidence of abdominal adhesions and a significant increase in the levels
of TGF-Beta1 mRNA expression at days 2, 4, and 7. Immunostaining intensity of TGF
Beta1 in adhesions from the peritonitis group also steadily rose through day 7.
In peritoneal fluid, the ratio of active:total TGF-Beta1 was significantly
increased in the peritonitis group on days 1, 2, and 4 compared with the sham
group. These results suggest that peritonitis is associated with the upregulation
of TGF-Beta1, a mechanism that may exacerbate adhesion formation.
PMID- 10769095
TI - Role of a hyaluronate-based membrane in the prevention of peritonitis-induced
adhesions.
AB - Adhesions remain a significant postoperative complication of abdominal surgery;
however, recent evidence suggests that physical barriers may reduce their
incidence. Although these adhesion prevention barriers are efficacious when used
under aseptic conditions, little is known about their use in the presence of
peritonitis, which is associated with an increased incidence of abdominal
adhesions. A sodium hyaluronate and carboxymethylcellulose bioresorbable membrane
(HA membrane) has been shown recently to reduce postoperative adhesions in
several animal models and in two clinical trials. To investigate the efficacy of
HA membrane in the presence of peritonitis, generalized peritonitis was induced
in rats by either cecal ligation and puncture (CLP) or cecal ligation (CL) alone.
The ceca were resected after 12 hours, and animals were randomly assigned to
receive or not receive HA membrane applied to the cecum. At day 7, abdominal
adhesions and abscesses were scored. In the presence of peritonitis, HA membrane
did not significantly reduce the number or tenacity of adhesions. A trend toward
increased abscess formation was associated with HA membrane in the CL group.
Although HA membrane has been shown to reduce the incidence and severity of
abdominal adhesions under aseptic conditions, this study demonstrates that it is
not efficacious in preventing abdominal adhesions in the presence of peritonitis.
The association between HA membrane and abscess formation in the presence of
experimental peritonitis requires further investigation.
PMID- 10769098
TI - Toward individualized quality-of-life assessment.
PMID- 10769097
TI - Hospital procedure volume and teaching status do not influence treatment and
outcome measures of rectal cancer surgery in a large general population.
AB - A clear benefit of increased hospital procedure volume or teaching hospital
status on outcomes of rectal cancer surgery has yet to be shown. Few have
examined treatment differences that may lead to varying outcomes. This study
assessed the impact of hospital procedure volume and teaching status on both
treatment and outcome measures of rectal cancer surgery in a large general
population. Data were obtained for 1072 incident cases of rectal adenocarcinoma
diagnosed in 1990 from Ontario, Canada, and treated with a major resection.
Hospitals were classified by teaching status and procedure volume. Pathology
reports were examined for 418 procedures. Abdominoperineal resections accounted
for 31.0% of all procedures. There were no clinically significant differences in
treatment measures, operative mortality, and long-term survival among the
hospital groups according to both univariate and multivariate analyses. In
conclusion, the absence of a hospital volume or teaching status effect on
treatment and outcome measures suggests that for rectal cancer surgery in
Ontario, centralization of procedures into high-volume or teaching centers is
unlikely to improve surgical quality.
PMID- 10769099
TI - Numb chin syndrome.
AB - Numb chin syndrome reflects an abnormality in the mental nerve or inferior
alveolar nerve, or occasionally in a nervous structure located higher up in the
body. It manifests as objective and/or subjective sensory disorders in the
distribution of the mental nerve or inferior alveolar nerve, represented
primarily by half of the lower lip and chin. Although numb chin syndrome falls
mainly within the province of dentists and stomatologists, it can reveal a number
of neoplastic or other diseases seen by rheumatologists. This article provides
background information on numb chin syndrome, discusses its causes (including
those seen mainly by dentists and stomatologists), and reviews numb chin syndrome
due to generalized malignancies based on 144 cases from the literature and two
personal cases.
PMID- 10769100
TI - Arthritis, tenosynovitis, fasciitis, and bursitis due to sea urchin spines. A
series of 12 cases in Reunion Island.
AB - Arthritis, tenosynovitis, and bursitis due to sea urchin spine injuries have
unique pathological features and run a chronic course until the spines are
removed. Of the 40 cases of sea urchin spine-related clinical symptoms published
to date, only 12 had osteoarticular symptoms. PATIENTS AND METHODS: We studied 12
cases with osteoarticular symptoms seen in Reunion Island from 1994 to 1998.
There were nine cases of arthritis and one case each of tenosynovitis, fasciitis,
and bursitis. The nine males and three females had an age range of 9 to 50 years.
RESULTS: The injury was at the knee in six cases, the foot in three, and the hand
in three. The time from injury to lesion development ranged from two days to two
and a half months. Laboratory tests were normal apart from evidence of mild
inflammation in three of the arthritis cases. The spine was visible on plain
radiographs in eight cases. Histology was done in seven patients and consistently
showed a typical foreign body granuloma. Removal of the spine with synovectomy
was performed in 11 cases and consistently ensured a full recovery. DISCUSSION:
The clinical manifestations and management in our patients were compared to those
in earlier reports. The differential diagnosis of laboratory test, radiographic,
and histologic findings is reviewed. Pathogenic hypotheses and the immunogenic
effect of the protein sheath that surrounds sea urchin spines are discussed.
CONCLUSION: The diagnosis of these frequently under-recognized lesions rests on a
careful history and on converging histologic, radiologic, and clinical findings.
PMID- 10769101
TI - Comparison of two modes of administration of a personalized quality of life scale
in a longitudinal study of total hip arthroplasty.
AB - Quality of life scales are being increasingly used to evaluate patients. The
earliest scales were standardized questionnaire that did not necessarily provide
an optimal evaluation of the quality of life of each individual patient. A number
of personalized scales are now available, including the SEIQoL, in which the
patients nominate the five quality of life areas most important to them. The
SEIQoL has been validated. We tested the SEIQoL in patients treated by total hip
arthroplasty, a procedure that is expected to improve quality of life. OBJECTIVE:
To compare two methods of administration of the SEIQoL several months after total
hip arthroplasty. METHODS: The SEIQoL was administered before and after the
arthroplasty. During the postoperative test session, the SEIQoL was administered
twice, once using the items nominated preoperatively and once after allowing the
patient to repeat the nomination procedure. RESULTS: With both methods,
significant improvements in quality of life were demonstrated (P < 0.05). There
was no significant difference between the two methods. CONCLUSION: Changing the
items of the SEIQoL during prospective studies does not modify the overall
quality of life score. Keeping the same items throughout the study is
nevertheless warranted.
PMID- 10769102
TI - Comparison of clinical, laboratory, radiographic, and scintigraphic findings in
erosive and nonerosive hand osteoarthritis. Results of a two-year study.
AB - OBJECTIVES: The primary objective was to compare the clinical, radiologic,
laboratory, and scintigraphic features in 28 patients with erosive hand
osteoarthritis and in 24 with non-erosive hand osteoarthritis. Other objectives
were to evaluate clinical, radiographic, and scintigraphic progression in the two
groups over a two-year period and to estimate the value of bone scintigraphy for
predicting clinical and radiographic progression. METHOD: Prospective two-year
study of 52 patients with hand osteoarthritis, of whom 28 had at least three
subchondral erosions and 24 patients had no erosions. RESULTS: The group with
erosive disease had higher serum immunoglobulin G levels (14.53 +/- 3.79 mg/L vs.
12.03 +/- 4.01 mg/L; P < 0.05) and a higher radiographic index (91.81 +/- 3.67
vs. 25.88 +/- 12.81; P < 0.001), whereas the group with non-erosive disease had a
higher rate of paresthesia (66.7% vs. 39.3%; P < 0.05) and higher values for the
erythrocyte sedimentation rate (25.21 +/- 20.86 vs. 13.21 +/- 12.85; P < 0.05)
and serum C-reactive protein level (8.82 +/- 6.08 vs. 3.25 +/- 6.92; P < 0.01).
None of the other study parameters showed any significant differences, and both
age and sex distribution were also similar in the two groups. At completion of
the two-year follow-up, no changes versus baseline were found in any of the study
parameters in the overall study population or in either of the two groups. The
baseline scintigraphic index was significantly correlated with the radiographic
index at baseline (r = 0.497; P < 0.01) and at study completion (r = 0.550; P <
0.001). Joints with a positive baseline scintigram were significantly more likely
to show radiographic progression (21.09%, vs 6.68% in negative joints; P < 0.001)
and joint tenderness exacerbation (21.22% vs. 13.73%; P < 0.001). CONCLUSION:
These data suggest that bone scintigraphy may be useful for predicting clinical
and radiographic progression of hand osteoarthritis with or without erosions.
PMID- 10769104
TI - Glucocorticoid-induced osteoporosis: is the bone density decrease the only
explanation?
AB - BACKGROUND: Glucocorticoids may increase bone fragility via mechanisms
independent from their bone mass reducing effect. OBJECTIVE: To study
relationships between osteoporotic fractures and bone mineral density in patients
on long-term glucocorticoid therapy. PATIENTS AND METHODS: We studied 121 women
with a mean age of 60.4 +/- 14.3 years on long-term glucocorticoid therapy
(cumulative dose > or = 1 g of prednisone equivalent, duration > or = 6 months)
for rheumatoid arthritis (n = 38), polymyalgia rheumatica or giant cell arteritis
(n = 26), connective tissue disease (n = 15), asthma (n = 14), another
inflammatory joint disease (n = 14), or another condition (n = 14). The control
group was composed of 125 subjects who had the same mean age and met the same
exclusion criteria as the case group. Bone mineral density was measured at the
lumbar spine and femoral neck using a Hologic QDR 4500 unit. In subjects with
back pain, radiographs of the thoracic and lumbar spine were obtained to look for
fractures. RESULTS: The odds ratio for a bone mineral density decrease of one
standard deviation at the femoral neck was 1.68 (1.20-2.35) in patients with a
cumulative glucocorticoid dose of 10 g of prednisone equivalent and 1.67 (1.22
2.29) in those with a glucocorticoid therapy duration of 2 years. Sixty-eight
fractures were recorded in 56 patients (46% of the overall patient group). Even
after adjustment on age, glucocorticoid therapy duration, and dose, mean bone
mineral density values at the lumbar spine and femoral neck were significantly
lower in the subgroup of patients with fractures than in the subgroup without
fractures. Sensitivity and specificity of bone mineral density at the femoral
neck and/or lumbar spine for the diagnosis of vertebral fracture and/or
peripheral fracture were 73% and 51%, respectively. In the stepwise logistic
regression model, factors explaining the presence of fractures were as follows,
in hierarchical order: age; absence of calcium/vitamin D supplementation, femoral
neck T-score, and glucocorticoid dose. CONCLUSION: Our data are compelling
evidence that bone mineral density is a major determinant of the fracture risk in
patients with glucocorticoid-induced osteoporosis.
PMID- 10769103
TI - Efficacy of nerve root versus interspinous injections of glucocorticoids in the
treatment of disk-related sciatica. A pilot, prospective, randomized, double
blind study.
AB - STUDY OBJECTIVES: Pilot study comparing the short-term efficacy on pain and
functional impairment of nerve root sheath versus interspinous glucocorticoid
injections in patients admitted to a French rheumatology department for disk
related sciatica or femoral neuralgia. PATIENTS AND METHODS: Thirty patients with
refractory nerve root pain (sciatica, n = 29; femoral neuralgia, n = 1) for a
mean of four months were randomized to nerve root injection (n = 17) or
interspinous injection (n = 13) of the same mixture of 0.10 g of lidocaine
hydrochloride and 3.75 mg of cortivazol. Both injection methods were performed
under analgesia and benzodiazepine sedation to maintain double blinding. Each
patient was evaluated daily during the first seven days of bed rest in the
hospital, then after discharge on postinjection day 28. RESULTS: Prompt pain
relief was obtained in both groups. On day 1, the mean pain scale score (0-100)
fell from 70 +/- 3.9 to 26 +/- 5.6 in the nerve root group and from 63 +/- 4 to
23 +/- 4.7 in the interspinous group. These results were sustained on D7 and D28.
CONCLUSIONS: The unusually high level of efficacy of glucocorticoid injection in
our study may be ascribable in part to strong placebo and Hawthorne effects and
in part to the intrinsic effects of the injections. Whether nerve root injection
is superior over interspinous injection remains unproven.
PMID- 10769105
TI - Ulnar nerve compression at the wrist by a synovial cyst successfully treated with
percutaneous puncture and corticosteroid injection.
AB - A case of ulnar nerve palsy due to a conduction block in the deep motor branch at
the wrist is reported. The cause was a rapidly growing synovial cyst.
Ultrasonography and computed tomography were performed to determine the exact
location of the cyst, which was punctured and injected with corticosteroid.
Function promptly returned to normal after this procedure.
PMID- 10769106
TI - Secondary amyloidosis: a severe complication of ankylosing spondylitis. Two case
reports.
AB - STUDY OBJECTIVE: To report two cases of amyloidosis secondary to ankylosing
spondylitis. PATIENTS AND RESULTS: Of the 47 ankylosing spondylitis patients who
have received follow-up at our department over the last few years, two have
developed AA amyloidosis. Both have extremely severe, long-standing joint
disease, with virtually complete spinal ankylosis and destructive peripheral
arthritis of the hips and wrists; one also has tarsal joint destruction. Renal
dysfunction was the first manifestation of amyloidosis in both cases. One patient
required chronic hemodialysis and developed peritonitis due to colonic
perforation, probably at a site of amyloid deposition. CONCLUSIONS: Secondary
amyloidosis is a rare complication of ankylosing spondylitis that can cause
severe renal and gastrointestinal complications. No treatment capable of clearing
established amyloid deposits is available to date.
PMID- 10769108
TI - [Raloxifene, selective estrogen receptor modulator (SERM). Introduction and
conclusion].
PMID- 10769107
TI - Antiphospholipid syndrome and factor V Leiden. Three cases with recurrent venous
thrombosis.
AB - Recurrent thrombosis is a common complication of various rheumatic disorders and
is part of the definition of antiphospholipid syndrome. We report three cases of
recurrent venous thrombosis due not only to antiphospholipid syndrome with a
normal activated partial thromboplastin time but also to resistance to activated
protein C caused by the factor V Leiden mutation. These three cases confirm that
thrombotic disease is frequently multifactorial and suggest that resistance to
activated protein C should be looked for routinely in patients with suggestive
clinical manifestations, particularly when standard clotting tests are normal.
PMID- 10769110
TI - [Clinical results of selective estrogen receptor modulators (SERM)].
AB - The SERMs (selective estrogen receptor modulators) are a new class of molecules
that bind to the estrogen receptor, resulting in an estradiol agonist or
antagonist response according to the target tissue. Raloxifene, a new SERM, has
been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral
fractures in osteoporotic women, to decrease serum cholesterol and its LDL
fraction, and to reduce significantly the risk of breat cancer. Raloxifene is
available in France for the prevention of post-menopausal osteoporosis.
PMID- 10769109
TI - [Physiopathology of bone loss and pharmacologic approach of selective estrogen
receptor modulators].
AB - Osteoclastic resorption increases at menopause and remains high during aging. The
complex mechanism responsible for this increase involves cytokines and growth
factors secreted by stromal cells and/or by osteoblasts and cells in the
hematopoietic microenvironment. Although estrogen receptors have been found
mainly on osteoblasts and their precursors, the stromal cells, they have also
been demonstrated on osteoclast precursors. Raloxifene is a selective estrogen
receptor modifier (SERM) that has the beneficial effects of estrogens on bone
tissue but no estrogen agonist effects on the breast and uterus. Although recent
data have established that the mechanism of action of estrogens and SERMs is far
more complex than was previously thought, the reason for the tissue selectivity
of these molecules remains unknown.
PMID- 10769111
TI - Determination of the mechanism of orotidine 5'-monophosphate decarboxylase by
isotope effects.
AB - Orotidine 5'-monophosphate shows a (15)N isotope effect of 1.0036 at N-1 for
decarboxylation catalyzed by orotidine 5'-monophosphate decarboxylase. Picolinic
acid shows a (15)N isotope effect of 0.9955 for decarboxylation in ethylene
glycol at 190 degrees C, while N-methyl picolinic acid shows a (15)N isotope
effect of 1.0053 at 120 degrees C. The transition state for enzymatic
decarboxylation of orotidine 5'-monophosphate resembles the transition state for
N-methyl picolinic acid in that no bond order changes take place at N-1. This
rules out enolization to give a quaternary nitrogen at N-1 in the enzymatic
mechanism and suggests a carbanion intermediate stabilized by simple
electrostatic interaction with Lys-93. The driving force for the reaction appears
to be ground-state destabilization resulting from charge repulsion between the
carboxyl of the substrate and Asp-91.
PMID- 10769112
TI - Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by
human DNA polymerase eta.
AB - Platinum anticancer agents form bulky DNA adducts which are thought to exert
their cytotoxic effect by blocking DNA replication. Translesion synthesis, one of
the pathways of postreplication repair, is thought to account for some resistance
to DNA damage and much of the mutagenicity of bulky DNA adducts in dividing
cells. Oxaliplatin has been shown to be effective in cisplatin-resistant cell
lines and less mutagenic than cisplatin in the Ames assay. We have shown that the
eukaryotic DNA polymerases yeast pol zeta, human pol beta, and human pol gamma
bypass oxaliplatin-GG adducts more efficiently than cisplatin-GG adducts. Human
pol eta, a product of the XPV gene, has been shown to catalyze efficient
translesion synthesis past cis, syn-cyclobutane pyrimidine dimers. In the present
study we compared translesion synthesis past different Pt-GG adducts by human pol
eta. Our data show that, similar to other eukaryotic DNA polymerases, pol eta
bypasses oxaliplatin-GG adducts more efficiently than cisplatin-GG adducts.
However, pol eta-catalyzed translesion replication past Pt-DNA adducts was more
efficient and less accurate than that seen for previously tested polymerases. We
show that the efficiency and fidelity of translesion replication past Pt-DNA
adducts appear to be determined by both the structure of the adduct and the DNA
polymerase active site.
PMID- 10769113
TI - Contribution of the hydrogen-bond network involving a tyrosine triad in the
active site to the structure and function of a highly proficient ketosteroid
isomerase from Pseudomonas putida biotype B.
AB - Delta(5)-3-Ketosteroid isomerase from Pseudomonas putida biotype B is one of the
most proficient enzymes catalyzing an allylic isomerization reaction at rates
comparable to the diffusion limit. The hydrogen-bond network (Asp99...
Wat504...Tyr14...Tyr55...Tyr30) which links the two catalytic residues, Tyr14 and
Asp99, to Tyr30, Tyr55, and a water molecule in the highly apolar active site has
been characterized in an effort to identify its roles in function and stability.
The DeltaG(U)(H2O) determined from equilibrium unfolding experiments reveals that
the elimination of the hydroxyl group of Tyr14 or Tyr55 or the replacement of
Asp99 with leucine results in a loss of conformational stability of 3.5-4.4
kcal/mol, suggesting that the hydrogen bonds of Tyr14, Tyr55, and Asp99
contribute significantly to stability. While decreasing the stability by about
6.5-7.9 kcal/mol, the Y55F/D99L or Y30F/D99L double mutation also reduced
activity significantly, exhibiting a synergistic effect on k(cat) relative to the
respective single mutations. These results indicate that the hydrogen-bond
network is important for both stability and function. Additionally, they suggest
that Tyr14 cannot function efficiently alone without additional support from the
hydrogen bonds of Tyr55 and Asp99. The crystal structure of Y55F as determined at
1.9 A resolution shows that Tyr14 OH undergoes an alteration in orientation to
form a new hydrogen bond with Tyr30. This observation supports the role of Tyr55
OH in positioning Tyr14 properly to optimize the hydrogen bond between Tyr14 and
C3-O of the steroid substrate. No significant structural changes were observed in
the crystal structures of Y30F and Y30F/Y55F, which allowed us to estimate
approximately the interaction energies mediated by the hydrogen bonds
Tyr30...Tyr55 and Tyr14...Tyr55. Taken together, our results demonstrate that the
hydrogen-bond network provides the structural support that is needed for the
enzyme to maintain the active-site geometry optimized for both function and
stability.
PMID- 10769114
TI - Evolution of enzymatic activities in the enolase superfamily: crystallographic
and mutagenesis studies of the reaction catalyzed by D-glucarate dehydratase from
Escherichia coli.
AB - D-Glucarate dehydratase (GlucD) from Escherichia coli catalyzes the dehydration
of both D-glucarate and L-idarate as well as their interconversion via
epimerization. GlucD is a member of the mandelate racemase (MR) subgroup of the
enolase superfamily, the members of which catalyze reactions that are initiated
by abstraction of the alpha-proton of a carboxylate anion substrate. Alignment of
the sequence of GlucD with that of MR reveals a conserved Lys-X-Lys motif and a
His-Asp dyad homologous to the S- and R-specific bases in the active site of MR.
Crystals of GlucD have been obtained into which the substrate D-glucarate and two
competitive inhibitors, 4-deoxy-D-glucarate and xylarohydroxamate, could be
diffused; D-glucarate is converted to the dehydration product, 5-keto-4-deoxy-D
glucarate (KDG). The structures of these complexes have been determined and
reveal the identities of the ligands for the required Mg(2+) (Asp(235), Glu(266),
and Asn(289)) as well as confirm the expected presence of Lys(207) and His(339),
the catalytic bases that are properly positioned to abstract the proton from C5
of L-idarate and D-glucarate, respectively. Surprisingly, the C6 carboxylate
group of KDG is a bidentate ligand to the Mg(2+), with the resulting geometry of
the bound KDG suggesting that stereochemical roles of Lys(207) and His(339) are
reversed from the predictions made on the basis of the established structure
function relationships for the MR-catalyzed reaction. The catalytic roles of
these residues have been examined by characterization of mutant enzymes, although
we were unable to use these to demonstrate the catalytic independence of Lys(207)
and His(339) as was possible for the homologous Lys(166) and His(297) in the MR
catalyzed reaction.
PMID- 10769115
TI - Cooperative thermal denaturation of proteins designed by binary patterning of
polar and nonpolar amino acids.
AB - We previously reported a combinatorial strategy for designing alpha-helical
proteins by assigning only the binary patterning of polar or nonpolar residues
[Kamtekar, S., Schiffer, J. M., Xiong, H. Y., Babik, J. M., and Hecht, M. H.
(1993) Science 262, 1680-1685]. Here we describe the finding that approximately
half of the proteins in the original collection display some level of
cooperativity in their thermal denaturation profiles. Many are monomeric in
solution, demonstrating that the observed cooperativity is not merely a
consequence of oligomerization. These findings demonstrate that although the
combinatorial nature of the design strategy precludes explicit design of side
chain packing, binary patterning incorporates sufficient sequence information to
generate de novo proteins with cooperatively folded structures. As binary
partitioning of polar and nonpolar amino acids is an intrinsic part of the
genetic code, these findings may bear on the early evolution of native proteins.
PMID- 10769116
TI - Structures of the N(omega)-hydroxy-L-arginine complex of inducible nitric oxide
synthase oxygenase dimer with active and inactive pterins.
AB - Nitric oxide synthases (NOSs) catalyze two mechanistically distinct,
tetrahydrobiopterin (H(4)B)-dependent, heme-based oxidations that first convert L
arginine (L-Arg) to N(omega)-hydroxy-L-arginine (NHA) and then NHA to L
citrulline and nitric oxide. Structures of the murine inducible NOS oxygenase
domain (iNOS(ox)) complexed with NHA indicate that NHA and L-Arg both bind with
the same conformation adjacent to the heme iron and neither interacts directly
with it nor with H(4)B. Steric restriction of dioxygen binding to the heme in the
NHA complex suggests either small conformational adjustments in the ternary
complex or a concerted reaction of dioxygen with NHA and the heme iron.
Interactions of the NHA hydroxyl with active center beta-structure and the heme
ring polarize and distort the hydroxyguanidinium to increase substrate
reactivity. Steric constraints in the active center rule against superoxo-iron
accepting a hydrogen atom from the NHA hydroxyl in their initial reaction, but
support an Fe(III)-peroxo-NHA radical conjugate as an intermediate. However, our
structures do not exclude an oxo-iron intermediate participating in either L-Arg
or NHA oxidation. Identical binding modes for active H(4)B, the inactive
quinonoid-dihydrobiopterin (q-H(2)B), and inactive 4-amino-H(4)B indicate that
conformational differences cannot explain pterin inactivity. Different redox
and/or protonation states of q-H(2)B and 4-amino-H(4)B relative to H(4)B likely
affect their ability to electronically influence the heme and/or undergo redox
reactions during NOS catalysis. On the basis of these structures, we propose a
testable mechanism where neutral H(4)B transfers both an electron and a 3,4-amide
proton to the heme during the first step of NO synthesis.
PMID- 10769118
TI - New reactions in the crotonase superfamily: structure of methylmalonyl CoA
decarboxylase from Escherichia coli.
AB - The molecular structure of methylmalonyl CoA decarboxylase (MMCD), a newly
defined member of the crotonase superfamily encoded by the Escherichia coli
genome, has been solved by X-ray crystallographic analyses to a resolution of
1.85 A for the unliganded form and to a resolution of 2.7 A for a complex with an
inert thioether analogue of methylmalonyl CoA. Like two other structurally
characterized members of the crotonase superfamily (crotonase and dienoyl CoA
isomerase), MMCD is a hexamer (dimer of trimers) with each polypeptide chain
composed of two structural motifs. The larger N-terminal domain contains the
active site while the smaller C-terminal motif is alpha-helical and involved
primarily in trimerization. Unlike the other members of the crotonase
superfamily, however, the C-terminal motif is folded back onto the N-terminal
domain such that each active site is wholly contained within a single subunit.
The carboxylate group of the thioether analogue of methylmalonyl CoA is hydrogen
bonded to the peptidic NH group of Gly 110 and the imidazole ring of His 66. From
modeling studies, it appears that Tyr 140 is positioned within the active site to
participate in the decarboxylation reaction by orienting the carboxylate group of
methylmalonyl CoA so that it is orthogonal to the plane of the thioester carbonyl
group. Surprisingly, while the active site of MMCD contains Glu 113, which is
homologous to the general acid/base Glu 144 in the active site of crotonase, its
carboxylate side chain is hydrogen bonded to Arg 86, suggesting that it is not
directly involved in catalysis. The new constellation of putative functional
groups observed in the active site of MMCD underscores the diversity of function
in this superfamily.
PMID- 10769117
TI - Discovering new enzymes and metabolic pathways: conversion of succinate to
propionate by Escherichia coli.
AB - The Escherichia coli genome encodes seven paralogues of the crotonase (enoyl CoA
hydratase) superfamily. Four of these have unknown or uncertain functions; their
existence was unknown prior to the completion of the E. coli genome sequencing
project. The gene encoding one of these, YgfG, is located in a four-gene operon
that encodes homologues of methylmalonyl CoA mutases (Sbm) and acyl CoA
transferases (YgfH) as well as a putative protein kinase (YgfD/ArgK). We have
determined that YgfG is methylmalonyl CoA decarboxylase, YgfH is propionyl
CoA:succinate CoA transferase, and Sbm is methylmalonyl CoA mutase. These
reactions are sufficient to form a metabolic cycle by which E. coli can catalyze
the decarboxylation of succinate to propionate, although the metabolic context of
this cycle is unknown. The identification of YgfG as methylmalonyl CoA
decarboxylase expands the range of reactions catalyzed by members of the
crotonase superfamily.
PMID- 10769119
TI - Peroxynitrite-mediated nitration of the stable free radical tyrosine residue of
the ribonucleotide reductase small subunit.
AB - Ribonucleotide reductase activity is rate-limiting for DNA synthesis, and
inhibition of this enzyme supports cytostatic antitumor effects of inducible NO
synthase. The small R2 subunit of class I ribonucleotide reductases contains a
stable free radical tyrosine residue required for activity. This radical is
destroyed by peroxynitrite, which also inactivates the protein and induces
nitration of tyrosine residues. In this report, nitrated residues in the E. coli
R2 protein were identified by UV-visible spectroscopy, mass spectrometry (ESI
MS), and tryptic peptide sequencing. Mass analysis allowed the detection of
protein R2 as a native dimer with two iron clusters per subunit. The measured
mass was 87 032 Da, compared to a calculated value of 87 028 Da. Peroxynitrite
treatment preserved the non-heme iron center and the dimeric form of the protein.
A mean of two nitrotyrosines per E. coli protein R2 dimer were obtained at 400
microM peroxynitrite. Only 3 out of the 16 tyrosines were nitrated, including the
free radical Tyr122. Despite its radical state, that should favor nitration, the
buried Tyr122 was not nitrated with a high yield, probably owing to its
restricted accessibility. Dose-response curves for Tyr122 nitration and loss of
the free radical were superimposed. However, protein R2 inactivation was higher
than nitration of Tyr122, suggesting that nitration of the nonconserved Tyr62 and
Tyr289 might be also of importance for peroxynitrite-mediated inhibition of E.
coli protein R2.
PMID- 10769120
TI - Two critical cysteine residues implicated in disulfide bond formation and proper
folding of Kir2.1.
AB - Inwardly rectifying potassium channels are important in cellular repolarization
of many excitable tissues. Amino acid sequence alignment of different mammalian
inward rectifier K(+) channels revealed two absolutely conserved cysteine
residues in the putative extracellular face, suggesting a possible disulfide
bond. Replacement of these cysteine residues in the Kir2.1 channel (i.e., C122
and C154) with either alanine or serine abolished current in Xenopus laevis
oocytes although Western blotting established that the channels were fully
expressed. The digestion pattern of channels treated with V8 protease combined
with Western blotting under reducing and nonreducing conditions confirmed
intrasubunit cross-linking of C122 and C154. Whole-cell and single channel
current recordings of oocytes expressing tandem tetrameric constructs with one or
two of the mutant subunits suggested that insertion of one mutant subunit is
sufficient to eliminate channel function. Coexpression studies confirmed that the
cysteine mutant channels eliminate wild-type Kir2.1 currents in a dominant
negative manner. Despite these results, sulfhydryl reduction did not alter the
functional properties of Kir2.1 currents. Molecular modeling of Kir2.1 with the
two cysteines cross-linked predicted that the extracellular loop between the
first transmembrane domain and the pore helix contains a beta-hairpin structure.
Distinct from the KcsA structure, the disulfide bond together with the beta
hairpin structure is expected to constrain and stabilize the P-loop and
selectivity filter. Taken together, these results suggest that intramolecular
disulfide bond exists between C122 and C154 of Kir2.1 channel and this cross-link
might be required for proper channel folding.
PMID- 10769121
TI - Tryptophan phosphorescence study of enzyme flexibility and unfolding in
laboratory-evolved thermostable esterases.
AB - Directed evolution of p-nitrobenzyl esterase (pNB E) has yielded eight
generations of increasingly thermostable variants. The most stable esterase, 8G8,
has 13 amino acid substitutions, a melting temperature 17 degrees C higher than
the wild-type enzyme, and increased hydrolytic activity toward p-nitrophenyl
acetate (pNPA), the substrate used for evolution, at all temperatures. Room
temperature activities of the evolved thermostable variants range from 3.5 times
greater to 4.0 times less than wild type. The relationships between enzyme
stability, catalytic activity, and flexibility for the esterases were
investigated using tryptophan phosphorescence. We observed no correlation between
catalytic activity and enzyme flexibility in the vicinity of the tryptophan (Trp)
residues. Increases in stability, however, are often accompanied by decreases in
flexibility, as measured by Trp phosphorescence. Phosphorescence data also
suggest that the N- and C-terminal regions of pNB E unfold independently. The N
terminal region appears more thermolabile, yet most of the thermostabilizing
mutations are located in the C-terminal region. Mutational studies show that the
effects of the N-terminal mutations depend on one or more mutations in the C
terminal region. Thus, the pNB E mutants are stabilized by long-range,
cooperative interactions between distant parts of the enzyme.
PMID- 10769123
TI - Conformational studies of human milk oligosaccharides using (1)H-(13)C one-bond
NMR residual dipolar couplings.
AB - 1H-(13)C one-bond dipolar coupling values were measured for natural abundance
samples of the human milk oligosaccharides "lacto-N-fucopentaose" (LNF-1 LNF-2,
and LNF-3), "lacto-N-difucohexaose" (LND-1), "lacto-N-tetraose" (LNT), and "lacto
N-neo-tetraose" (LNnT), four of which have Lewis blood group epitopes. Each
oligosaccharide was dissolved in a 7.5% solution of 1, 2-dimyristoyl-sn-glycero-3
phosphocholine/1, 2-dihexanoyl-sn-glycero-3-phosphocholine (DMPC/DHPC) bicelle
liquid crystals oriented in the NMR magnetic field. The dipolar coupling data and
NOE were fitted to conformational models with calculations of an optimum
orientation tensor which best represents the dipolar coupling values for a
fragment hypothesized to adopt a single conformation. In the case of LNF-1, LNF
2, LNF-3, and LND-1, the models confirm previous conformational models for the
Lewis epitopes based on NOE and molecular dynamics simulations. Extensions of the
model provided new structural data for the remaining residues. In all cases,
upper limits for the errors in the glycosidic angles of the models were
estimated. Since residual dipolar coupling provides information on long-range
order, it is a valuable complement to other types of NMR data such as NOE and
scalar coupling for exploring conformations of complex oligosaccharides.
PMID- 10769122
TI - Functional effects of periodic tryptophan substitutions in the alpha M4
transmembrane domain of the Torpedo californica nicotinic acetylcholine receptor.
AB - Previous amino acid substitutions at the M4 domain of the Torpedo californica and
mouse acetylcholine receptor suggested that the location of the substitution
relative to the membrane-lipid interface and perhaps to the ion pore can be
critical to the channel gating mechanism [Lasalde, J. A., Tamamizu, S., Butler,
D. H., Vibat, C. R. T., Hung, B., and McNamee, M. G. (1996) Biochemistry 35,
14139-14148; Ortiz-Miranda, S. I., Lasalde, J. A., Pappone, P. A., and McNamee,
M. G. (1997) J. Membr. Biol. 158, 17-30; Tamamizu, S., Lee, Y. H., Hung, B.,
McNamee, M. G., and Lasalde-Dominicci, J. A. (1999) J. Membr. Biol. 170, 157
164]. In this study, we introduce tryptophan substitutions at 12 positions
(C412W, M415W, L416W, I417W, C418W, I419W, I420W, G421W, T422W, V423W, S424W, and
V425W) along this postulated lipid-exposed segment M4 so that we can examine
functional consequences on channel gating. The expression levels of mutants
C412W, G421W, S424W, and V425W were almost the same as that of the wild type,
whereas other mutants (M415W, L416W, C418W, I419W, I420W, T422W, and V423W) had
relatively lower expression levels compared to that of the wild type as measured
by iodinated alpha-bungarotoxin binding ([(125)I]-alpha-BgTx). Two positions
(L416W and I419W) had less than 20% of the wild type expression level. I417W gave
no detectable [(125)I]BgTx binding on the surface of oocyte, suggesting that this
position might be involved in the AChR assembly, oligomerization, or transport to
the cell membrane. The alphaV425W mutant exhibited a significant increase in the
open channel probability with a moderate increase in the macroscopic response at
higher ACh concentrations very likely due to channel block. The periodicity for
the alteration of receptor assembly and ion channel function seems to favor a
potential alpha-helical structure. Mutants that have lower levels of expression
are clustered on one side of the postulated alpha-helical structure. Mutations
that display normal expression and functional activity have been shown previously
to face the membrane lipids by independent labeling studies. The functional
analysis of these mutations will be presented and discussed in terms of possible
structural models.
PMID- 10769124
TI - Rational design of selective submicromolar inhibitors of Tritrichomonas foetus
hypoxanthine-guanine-xanthine phosphoribosyltransferase.
AB - All parasitic protozoa lack the ability to synthesize purine nucleotides de novo,
relying instead on purine salvage enzymes for their survival. Hypoxanthine
guanine-xanthine phosphoribosyltransferase (HGXPRT) from the protozoan parasite
Tritrichomonas foetus is a rational target for antiparasitic drug design because
it is the primary enzyme the parasite uses to salvage purine bases from the host.
The study presented here is a continuation of our efforts to use the X-ray
structure of the T. foetus HGXPRT-GMP complex to design compounds that bind
tightly to the purine pocket of HGXPRT. The goal of the current project was to
improve the affinity and selectivity of previously identified HGXPRT inhibitor
TF1 [4-(3-nitroanilino)phthalic anhydride]. A virtual library of substituted 4
phthalimidocarboxanilides was constructed using methods of structure-based drug
design, and was implemented synthetically on solid support. Compound 20 [(4'
phthalimido)carboxamido-3-benzyloxybenzene] was then used as a secondary lead for
the second round of combinatorial chemistry, producing a number of low-micromolar
inhibitors of HGXPRT. One of these compounds, TF2 [(4'-phthalimido)carboxamido-3
(4-bromobenzyloxy)benzene], was further characterized as a competitive inhibitor
of T. foetus HGXPRT with respect to guanine with a K(I) of 0.49 microM and a 30
fold selectivity over the human HGPRT. TF2 inhibited the growth of cultured T.
foetus cells in a concentration-dependent manner with an ED(50) of 2.8 microM,
and this inhibitory effect could be reversed by addition of exogenous
hypoxanthine. These studies underscore the efficiency of combining structure
based drug design with combinatorial chemistry to produce effective species
specific enzyme inhibitors of medicinal importance.
PMID- 10769125
TI - Regulation of tryptophan synthase by temperature, monovalent cations, and an
allosteric ligand. Evidence from Arrhenius plots, absorption spectra, and primary
kinetic isotope effects.
AB - To investigate the linkage between enzyme conformation and catalysis, we have
determined the effects of temperature on catalytic properties of the tryptophan
synthase alpha(2)beta(2) complex and beta(2) subunit in the absence or presence
of different monovalent cations (Cs(+), Na(+), and GuH(+)) and of an allosteric
ligand, alpha-glycerol 3-phosphate. Arrhenius plots of the activity data between
5 and 50 degrees C are nonlinear in the presence of certain ligands but not
others. The conditions that yield nonlinear Arrhenius plots also yield
temperature-dependent changes in the equilibrium distribution of enzyme-substrate
intermediates and in primary kinetic isotope effects. The results provide
evidence that the nonlinear Arrhenius plots are caused by a temperature-dependent
conformational change that precedes the rate-limiting step in catalysis.
Thermodynamic analysis of the data associated with the conformational change
shows that the activation energies are much higher at low temperatures than at
high temperatures. We correlate the results with a model in which the enzyme is
converted by increased temperature under certain conditions from a low-activity
"open" conformation to a high-activity "closed" conformation. The allosteric
ligand and different monovalent cations, including GuH(+), which also acts as a
chaotropic agent, affect the equilibrium between the open and closed forms. The
large positive entropy changes in the conformational conversion suggest that the
closed conformation results from tightened hydrophobic interactions that exclude
water from the active site of the beta subunit.
PMID- 10769126
TI - The role of enzyme isomerization in the native catalytic cycle of the ATP
sulfurylase-GTPase system.
AB - ATP sulfurylase, from E. coli Kappa-12, is a GTPase.target complex that
conformationally couples the free energies of GTP hydrolysis and activated
sulfate (adenosine 5'-phosphosulfate, or APS) synthesis. Energy coupling is
achieved by an allosterically driven isomerization that switches on and off
chemistry at specific points in the catalytic cycle. This coupling mechanism is
derived from the results of model studies using analogue complexes that mimic
different stages of the native catalytic cycle. The current investigation extends
the analogue studies to the native catalytic cycle. Isomerization is monitored
using the fluorescent, guanine nucleotide analogues mGMPPNP (3'-O-(N
methylanthraniloyl)-2'-deoxyguanosine 5'-[beta, gamma-imido]triphosphate) and
mGTP [3'-O-(N-methylanthraniloyl)-2'-deoxyguanosine 5'-triphosphate]. The
isomerization is shown to be initiated by an allosteric interaction that requires
the simultaneous occupancy of all three substrate-binding sites. Stopped-flow
fluorescence and single-turnover studies were used to define and quantitate the
isomerization mechanism, and to show that the isomerization precedes and rate
limits both GTP hydrolysis and APS synthesis. These findings are incorporated
into a model of the energy-coupling mechanism.
PMID- 10769127
TI - Mixed disulfide with glutathione as an intermediate in the reaction catalyzed by
glutathione reductase from yeast and as a major form of the enzyme in the cell.
AB - Glutathione reductase catalyzes the reduction of glutathione disulfide by NADPH.
The FAD of the reductase is reduced by NADPH, and reducing equivalents are passed
to a redox-active disulfide to complete the first half-reaction. The nascent
dithiol of two-electron reduced enzyme (EH(2)) interchanges with glutathione
disulfide forming two molecules of glutathione in the second half-reaction. It
has long been assumed that a mixed disulfide (MDS) between one of the nascent
thiols and glutathione is an intermediate in this reaction. In addition to the
nascent dithiol composed of Cys(45) and Cys(50), the enzyme contains an acid
catalyst, His(456), having a pK(a) of 9.2 that protonates the first glutathione
(residue numbers refer to the yeast enzyme sequence). Reduction of yeast
glutathione reductase by glutathione and reoxidation of EH(2) by glutathione
disulfide indicate that the mixed disulfide accumulates, in particular, at low
pH. The reaction of glutathione disulfide with EH(2) is stoichiometric in the
absence of an excess of glutathione. The equilibrium position among E(ox), MDS,
and EH(2) is determined by the glutathione concentration and is not markedly
influenced by pH between 6.2 and 8.5. The mixed disulfide is the principal
product in the reaction of glutathione with oxidized enzyme (E(ox)) at pH 6. 2.
Its spectrum can be distinguished from that of EH(2) by a slightly lower thiolate
(Cys(50))-FAD charge-transfer absorbance at 540 nm. The high GSH/GSSG ratio in
the cytoplasm dictates that the mixed disulfide will be the major enzyme species.
PMID- 10769128
TI - Probing the catalytic mechanism of prephenate dehydratase by site-directed
mutagenesis of the Escherichia coli P-protein dehydratase domain.
AB - The Escherichia coli bifunctional P-protein, which plays a central role in L
phenylalanine (Phe) biosynthesis, contains distinct chorismate mutase (CM) and
prephenate dehydratase (PDT) domains as well as a regulatory (R) domain for
feedback control by Phe. To elucidate the catalytic mechanism of PDT in the P
protein, 24 mutations of 15 conserved residues in the PDT domain were created,
expressed in the pheA(-)E. coli strain NK6024, and studied for their effect on
PDT activity. Fourteen mutant enzymes were purified to homogeneity, tested for
feedback inhibition by Phe, and characterized by kinetic analysis and circular
dichroism spectroscopy. Selected mutant enzymes were further studied by gel
filtration, fluorescence emission, and microcalorimetry. In addition, a
monofunctional PDT domain (PDT20, residues 101-285) was cloned and overexpressed
in plasmid pET with expression levels up to 200-250 mg/L. PDT20 retained full PDT
activity, lacked CM activity, and was insensitive to feedback inhibition by Phe.
Four residues (T278, N160, Q215, and S208) were shown to be important for PDT
catalysis. The values of k(cat)/K(m) for the S208A/C and T278S mutant enzymes
were 100-fold lower, and 500-fold lower for the N160A and Q215A mutant enzymes
than the wild-type (WT) protein. The T278A and T278V mutant enzymes displayed no
measurable catalytic activity, yet bound both prephenate and a competitive
inhibitor (S-DNBA) comparably to the WT protein. These data, taken together with
the normal CD spectra of the mutant enzymes, strongly suggested that T278 was
involved in the catalytic mechanism. To establish whether acidic residues were
involved in catalysis, all the conserved Glu and Asp residues in the PDT domain
were mutated to Ala. None of these mutations significantly reduced PDT activity,
indicating that the acidic residues of the PDT domain are not directly involved
in catalysis. However, two mutant enzymes (E159A and E232A) displayed higher
levels of PDT activity (2.2- and 3.5-fold, respectively), which was due to
enhanced substrate binding. For the double mutant enzyme (E159A-E232A),
k(cat)/K(m) was ca. 7-fold higher than for the WT enzyme, while its K(m) was 4.6
fold lower.
PMID- 10769129
TI - Expression, purification, and characterization of HMWP2, a 229 kDa, six domain
protein subunit of Yersiniabactin synthetase.
AB - The six domain, 229 kDa HMWP2 subunit of the Yersinia pestis yersiniabactin (Ybt)
synthetase has been expressed in soluble, full-length form in E. coli as a C
terminal His8 construct at low growth temperatures and with attenuated induction.
All six domains of this nonribosomal peptide synthetase subunit, three
phosphopantetheinylatable carrier protein domains (ArCP, PCP1, PCP2), one
adenylation (A) domain, and two cyclization domains (Cy1, Cy2), have been assayed
and are functional. Mutants that convert the phosphopantetheinylatable serine
residue to alanine in each of the carrier protein domains accumulate acyl-S
enzyme intermediates upstream of the blocked apo carrier protein site. The ArCP
mutant cannot be salicylated by the adenylation protein YbtE; the PCP1 mutant
releases salicyl-cysteine from thiolysis of the Sal-S-ArCP intermediate; and the
PCP2 mutant releases hydroxyphenyl-thiazolinyl-cysteine from the HPT-S-PCP1 acyl
enzyme intermediate, all of which demonstrates processivity and directionality of
chain growth. Restoration of the ArCP mutant's function was accomplished with the
native ArCP fragment added in trans. The wild-type HMWP2 subunit accumulates
hydroxyphenyl-4, 2-bithiazolinyl-S-enzyme at its most downstream PCP2 carrier
site, presumably for transfer to the next subunit, HMWP1. The A domain was found
to activate and transfer to PCP1 and PCP2 not only the natural L-Cys but also S-2
aminobutyrate, L-beta-chloroalanine, and L-Ser, enabling testing of the substrate
specificity of the Cy domain. Probes of Cy domain function include mutagenesis of
the Cy1 domain's conserved signature motif DX(4)DX(2)S to show that both D
residues but not the S are crucial for both amide bond formation and
heterocyclization. Also the Cy1 domain would accept an alternate upstream
electrophilic donor substrate (2,3-dihydroxybenzoyl-S-ArCP) but would not process
any of the three alternate downstream nucleophilic acceptors in place of Cys-S
PCP1, even for the amide bond-forming step in chain elongation.
PMID- 10769130
TI - Epsilon amino caproic acid inhibits streptokinase-plasminogen activator complex
formation and substrate binding through kringle-dependent mechanisms.
AB - Lysine side chains induce conformational changes in plasminogen (Pg) that
regulate the process of fibrinolysis or blood clot dissolution. A lysine side
chain mimic, epsilon amino caproic acid (EACA), enhances the activation of Pg by
urinary-type and tissue-type Pg activators but inhibits Pg activation induced by
streptokinase (SK). Our studies of the mechanism of this inhibition revealed that
EACA (IC(50) 10 microM) also potently blocked amidolytic activity by SK and Pg at
doses nearly 10000-fold lower than that required to inhibit the amidolytic
activity of plasmin. Different Pg fragments were used to assess the role of the
kringles in mediating the inhibitory effects of EACA: mini-Pg which lacks
kringles 1-4 of Glu-Pg and micro-Pg which lacks all kringles and contains only
the catalytic domain. SK bound with similar affinities to Glu-Pg (K(A) = 2.3 x
10(9) M(-1)) and to mini-Pg (K(A) = 3.8 x 10(9) M(-)(1)) but with significantly
lower affinity to micro-Pg (K(A) = 6 x 10(7) M(-)(1)). EACA potently inhibited
the binding of Glu-Pg to SK (K(i) = 5.7 microM), but was less potent (K(i) = 81.1
microM) for inhibiting the binding of mini-Pg to SK and had no significant
inhibitory effects on the binding of micro-Pg and SK. In assays simulating
substrate binding, EACA also potently inhibited the binding of Glu-Pg to the SK
Glu-Pg activator complex, but had negligible effects on micro-Pg binding. Taken
together, these studies indicate that EACA inhibits Pg activation by blocking
activator complex formation and substrate binding, through a kringle-dependent
mechanism. Thus, in addition to interactions between SK and the protease domain,
interactions between SK and the kringle domain(s) play a key role in Pg
activation.
PMID- 10769131
TI - Endogenously expressed apolipoprotein E has different effects on cell lipid
metabolism as compared to exogenous apolipoprotein E carried on triglyceride-rich
particles.
AB - Apolipoprotein E (apoE) on model triglyceride-rich particles (TGRP) increases
triglyceride (TG) utilization and cholesteryl ester (CE) hydrolysis, independent
of its effect on enhancing particle uptake. We questioned whether, under
physiological concentrations, endogenously expressed apoE has similar effects on
cellular lipid metabolism as compared to exogenous apoE. J774 macrophages, which
do not express apoE, were engineered to express endogenous apoE by transfection
of human apoE3 cDNA expression constructs (E(+)) or control vectors (E(-)) into
the cells. To compare the effects of exogenous apoE and endogenous apoE on TGRP
uptake, cells were incubated with or without apoE associated with (3)H
cholesteryl ether-labeled TGRP. Exogenous apoE enhanced TGRP uptake in both E(-)
and E(+) cells. E(-) cells displayed significantly higher TGRP uptake than E(+)
cells. Sodium chlorate, which inhibits cell proteoglycan synthesis, markedly
diminished differences in TGRP uptake between E(-) and E(+) cells, suggesting
that endogenous apoE-proteoglycan interaction contributes to differences in
uptake between the two cell types. Particle uptake by the LDL receptor, by the
LDL receptor related protein, or by scavenger receptors were similar between E(-)
and E(+) cells indicating that endogenous apoE expression does not have a general
effect on endocytic pathways. Exogenous apoE carried on TGRP stimulated TG
utilization and CE hydrolysis in both cell types. However, TG utilization and CE
hydrolysis were not affected by endogenous apoE expression. In conclusion,
macrophage expression of apoE has very different effects on TGRP metabolism than
exogenously supplied apoE. The fluorescence microscopy results in this study
showing that exogenous apoE and endogenous apoE were confined in separate
cellular compartments support the hypothesis that these differences resulted from
distinct intracellular trafficking pathways followed by exogenous apoE bound to
TGRP as compared to endogenous cell-expressed apoE.
PMID- 10769132
TI - Structure of an atypical O-antigen polysaccharide of Helicobacter pylori
containing a novel monosaccharide 3-C-methyl-D-mannose.
AB - Lipopolysaccharides (LPS) were isolated by hot phenol-water extraction from
Danish Helicobacter pylori strains D1, D3, and D6, which were nontypeable using a
variety of anti-Lewis and anti-blood-group monoclonal antibodies. An atypical O
chain polysaccharide (PS) was liberated from the LPS of the three strains by acid
under mild conditions and found to contain D-rhamnose (D-Rha), L-rhamnose (L
Rha), and a branched sugar, 3-C-methyl-D-mannose (D-Man3CMe). The last sugar,
which has not hitherto been found in Nature, was identified using GLC-MS of the
derived alditol acetate and the partially methylated alditol acetate, and (1)H
and (13)C NMR spectroscopy, including NOESY and (1)H,(13)C HMBC experiments. The
following structure of the trisaccharide repeating unit of the PS was
established: -->2)-alpha-D-Manp3CMe-(1-->3)-alpha-L-Rhap-(1-->3)-alpha-D- Rhap-(1
- >. In contrast to the pathogenic importance of the Lewis antigen mimicry
exhibited by the PS of H. pylori strains previously investigated, the biological
relevance of the atypical PS for H. pylori pathogenesis is unclear. The
production of a differing surface PS may represent a form of antigenic variation
by these particular H. pylori strains and/or may reflect the adaptation of these
strains to a particular human population.
PMID- 10769133
TI - Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis:
a role for cyclooxygenase-2 and lipoxins in periodontal disease.
AB - The potential involvement of the inducible cyclooxygenase isoform (COX-2) and the
role of novel lipid mediators were investigated in the pathogenesis of
periodontal disease. Crevicular fluids from localized juvenile periodontitis
(LJP) patients contained prostaglandin (PG)E(2) and 5-lipoxygenase-derived
products, leukotriene B(4), and the biosynthesis interaction product, lipoxin
(LX)A(4). Neutrophils from peripheral blood of LJP patients, but not from
asymptomatic donors, also generated LXA(4), suggesting a role for this
immunomodulatory molecule in periodontal disease. To characterize host responses
of interest to periodontal pathogens, Porphyromonas gingivalis was introduced
within murine dorsal air pouches. In the air pouch cavity, P. gingivalis elicited
leukocyte infiltration, concomitant with elevated PGE(2) levels in the cellular
exudates, and upregulated COX-2 expression in infiltrated leukocytes. In
addition, human neutrophils exposed to P. gingivalis also upregulated COX-2
expression. Blood borne P. gingivalis gave significant increases in the murine
tissue levels of COX-2 mRNA associated with both heart and lungs, supporting a
potential role for this oral pathogen in the evolution of systemic events. The
administration of metabolically stable analogues of LX and of aspirin-triggered
LX potently blocked neutrophil traffic into the dorsal pouch cavity and lowered
PGE(2) levels within exudates. Together, these results identify PMN as an
additional and potentially important source of PGE(2) in periodontal tissues.
Moreover, they provide evidence for a novel protective role for LX in
periodontitis, limiting further PMN recruitment and PMN-mediated tissue injury
that can lead to loss of inflammatory barriers that prevent systemic tissue
invasion of oral microbial pathogens.
PMID- 10769134
TI - Protease nexin II interactions with coagulation factor XIa are contained within
the Kunitz protease inhibitor domain of protease nexin II and the factor XIa
catalytic domain.
AB - Protease nexin II, a platelet-secreted protein containing a Kunitz-type domain,
is a potent inhibitor of factor XIa with an inhibition constant of 250-400 pM.
The present study examined the protein interactions responsible for this
inhibition. The isolated catalytic domain of factor XIa is inhibited by protease
nexin II with an inhibition constant of 437 +/- 62 pM, compared to 229 +/- 40 pM
for the intact protein. Factor XIa is inhibited by a recombinant Kunitz domain
with an inhibition constant of 344 +/- 37 pM versus 422 +/- 33 pM for the
catalytic domain. Kinetic rate constants were determined by progress curve
analysis. The association rate constants for inhibition of factor XIa by protease
nexin II [(3.35 +/- 0.35) x 10(6) M(-1) s(-1)] and catalytic domain [(2.27 +/- 0.
25) x 10(6) M(-1) s(-1)] are nearly identical. The dissociation rate constants
are very similar, (9.17 +/- 0.71) x 10(-4) and (7.97 +/- 1.1) x 10(-4) s(-1),
respectively. The rate constants for factor XIa and catalytic domain inhibition
by recombinant Kunitz domain are also very similar: association constants of
(3.19 +/- 0.29) x 10(6) and (3.25 +/- 0.44) x 10(6) M(-1) s(-1), respectively;
dissociation constants of (10.73 +/- 0.84) x 10(-4) and (10.36 +/- 1.3) x 10(-4)
s(-1). The inhibition constant (K(i)) values calculated from these kinetic
parameters are in close agreement with those measured from equilibrium binding
experiments. These results suggest that the major interactions required for
factor XIa inhibition by protease nexin II are localized to the catalytic domain
of factor XIa and the Kunitz domain of protease nexin II.
PMID- 10769135
TI - Subsite mapping of the human pancreatic alpha-amylase active site through
structural, kinetic, and mutagenesis techniques.
AB - We report a multifaceted study of the active site region of human pancreatic
alpha-amylase. Through a series of novel kinetic analyses using malto
oligosaccharides and malto-oligosaccharyl fluorides, an overall cleavage action
pattern for this enzyme has been developed. The preferred binding/cleavage mode
occurs when a maltose residue serves as the leaving group (aglycone sites +1 and
+2) and there are three sugars in the glycon (-1, -2, -3) sites. Overall it
appears that five binding subsites span the active site, although an additional
glycon subsite appears to be a significant factor in the binding of longer
substrates. Kinetic parameters for the cleavage of substrates modified at the 2
and 4' ' positions also highlight the importance of these hydroxyl groups for
catalysis and identify the rate-determining step. Further kinetic and structural
studies pinpoint Asp197 as being the likely nucleophile in catalysis, with
substitution of this residue leading to an approximately 10(6)-fold drop in
catalytic activity. Structural studies show that the original pseudo
tetrasaccharide structure of acarbose is modified upon binding, presumably
through a series of hydrolysis and transglycosylation reactions. The end result
is a pseudo-pentasaccharide moiety that spans the active site region with its N
linked "glycosidic" bond positioned at the normal site of cleavage.
Interestingly, the side chains of Glu233 and Asp300, along with a water molecule,
are aligned about the inhibitor N-linked glycosidic bond in a manner suggesting
that these might act individually or collectively in the role of acid/base
catalyst in the reaction mechanism. Indeed, kinetic analyses show that
substitution of the side chains of either Glu233 or Asp300 leads to as much as a
approximately 10(3)-fold decrease in catalytic activity. Structural analyses of
the Asp300Asn variant of human pancreatic alpha-amylase and its complex with
acarbose clearly demonstrate the importance of Asp300 to the mode of inhibitor
binding.
PMID- 10769136
TI - A novel approach to serine protease inhibition: kinetic characterization of
inhibitors whose potencies and selectivities are dramatically enhanced by
Zinc(II).
AB - Serine proteases play a role in a variety of disease states and thus are
attractive targets for therapeutic intervention. We report the kinetic
characterization of a class of serine protease inhibitors whose potencies and
selectivities are dramatically enhanced in the presence of Zn(II). The structural
basis for Zn(II)-mediated inhibition of trypsin-like proteases has recently been
reported [Katz, B. A., Clark, J. M., Finer-Moore, J. S., Jenkins, T. E., Johnson,
C. R., Ross, M. J., Luong, C., Moore, W. R., and Stroud, R. M. (1998) Nature 391,
608-612]. A case study of the kinetic behavior of human tryptase inhibitors is
provided to illustrate the general phenomenon of Zn(II)-mediated inhibition.
Tryptase, Zn(II), and the inhibitor form a ternary complex which exhibits classic
tight-binding inhibition. The half-life for release of inhibitor from the
tryptase-Zn(II)-inhibitor complex has been measured for a number of inhibitors.
Consistent with tight-binding behavior, potent tryptase inhibitors are
characterized by extremely slow rates of dissociation from the ternary complex
with half-lives on the order of hours. A model of human serum, designed to
reproduce physiological levels of Zn(II), has been employed to evaluate the
performance of Zn(II)-potentiated tryptase inhibitors under physiological
conditions. We demonstrate that Zn(II)-mediated inhibition can be achieved at
physiological Zn(II) levels.
PMID- 10769137
TI - Oleyl sulfate reveals allosteric inhibition of soybean lipoxygenase-1 and human
15-lipoxygenase.
AB - Inhibition of lipoxygenase (LO) is currently an important goal of biomedical
research due to its critical role in asthma, atherosclerosis, and cancer
regulation. Steady-state kinetic data indicate that oleic acid (OA) is a simple
competitive inhibitor for soybean lipoxygenase; however, kinetic isotope effect
(KIE) data suggest a more complicated inhibitory mechanism. To investigate the
inhibitory effects of fatty acids on lipoxygenase more thoroughly, we have
synthesized a novel inhibitor to lipoxygenase, (Z)-9-octadecenyl sulfate (oleyl
sulfate, OS), which imparts kinetic properties that are inconsistent with simple
competitive inhibition for both SLO-1 and 15-HLO. The KIE exhibits a hyperbolic
rise with addition of OS, indicating the formation of a catalytically active
ternary complex with K(D) values of 0.6 +/- 0.2 and 0.4 +/- 0.05 microM for SLO-1
and 15-HLO, respectively. The steady-state kinetics show that SLO-1 proceeds
through a hyperbolic mixed-type inhibition pathway, where OS binding (K(i) = 0.7
+/- 0.3 microM) causes an approximate 4-fold increase in the K(m)(app) (alpha =
4.6 +/- 0.5) and a decrease in the k(cat) by approximately 15% (beta = 0.85 +/-
0.1). 15-HLO also exhibits a hyperbolic saturation of k(cat)/K(m) consistent with
the observed rise in its KIE. Taken together, these findings indicate the
presence of an allosteric site in both SLO-1 and 15-HLO and suggest broad
implications regarding the inhibition of LO and the treatment of LO-related
diseases.
PMID- 10769138
TI - 13C and deuterium isotope effects suggest an aldol cleavage mechanism for L
ribulose-5-phosphate 4-epimerase.
AB - On the basis of (13)C and deuterium isotope effects, L-ribulose-5-phosphate 4
epimerase catalyzes the epimerization of L-ribulose 5-phosphate to D-xylulose 5
phosphate by an aldol cleavage to the enediolate of dihydroxyacetone and
glycolaldehyde phosphate, followed by rotation of the aldehyde group and
condensation to the epimer at C-4. With the wild-type enzyme, (13)C isotope
effects were 1.85% at C-3 and 1.5% at C-4 at pH 7, with the values increasing to
2.53 and 2.05% at pH 5.5, respectively. H97N and Y229F mutants at pH 7 gave
values of 3.25 and 2.53% at C-3 and 2. 69 and 1.99% at C-4, respectively.
Secondary deuterium isotope effects at C-3 were 2.5% at pH 7 and 3.1% at pH 5.5
with the wild-type enzyme, and 4.1% at pH 7 with H97N. At C-4, the corresponding
values were 9.6, 14, and 19%. These data suggest that H97N shows no commitments,
while the wild-type enzyme has an external commitment of approximately 1.4 at pH
7 and an internal commitment independent of pH of approximately 0.6. The Y229
mutant shows only the internal commitment of 0.6. The sequence of the epimerase
is similar to those of L-fuculose-1-phosphate and L-rhamnulose-1-phosphate
aldolases for residues in the active site of L-fuculose-1-phosphate aldolase,
suggesting that Asp76, His95, His97, and His171 of the epimerase may be metal ion
ligands, and Ser44, Gly45, Ser74, and Ser75 may form a phosphate binding pocket.
The pH profile of V/K for L-ribulose 5-phosphate is bell-shaped with pK values of
5.94 and 8.24. The CD spectra of L-ribulose 5-phosphate and D-xylulose 5
phosphate differ sufficiently that the epimerization reaction can be followed at
300 nm.
PMID- 10769139
TI - Role of metal ions in the reaction catalyzed by L-ribulose-5-phosphate 4
epimerase.
AB - H97N, H95N, and Y229F mutants of L-ribulose-5-phosphate 4-epimerase had 10, 1,
and 0.1%, respectively, of the activity of the wild-type (WT) enzyme when
activated by Zn(2+), the physiological activator. Co(2+) and Mn(2+) replaced
Zn(2+) in Y229F and WT enzymes, although less effectively with the His mutants,
while Mg(2+) was a poorly bound, weak activator. None of the other eight
tyrosines mutated to phenylalanine caused a major loss of activity. The near-UV
CD spectra of all enzymes were nearly identical in the absence of metal ions and
substrate, and addition of substrate without metal ion showed no effect. When
both substrate and Zn(2+) were present, however, the positive band at 266 nm
increased while the negative one at 290 nm decreased in ellipticity. The changes
for the WT and Y229F enzymes were greater than for the two His mutants. With
Co(2+) as the metal ion, the CD and absorption spectra in the visible region were
different, showing little ellipticity in the absence of substrate and a weak
absorption band at 508 nm. With substrate present, however, an intense absorption
band at 555 nm (epsilon = 150-175) with a negative molar ellipticity approaching
2000 deg cm(2) dmol(-1) appears with WT and Y229F enzymes. With the His mutants,
the changes induced by substrate were smaller, with negative ellipticity only
half as great. The WT, Y229F, H95N, and H97N enzymes all catalyze a slow aldol
condensation of dihydroxyacetone and glycolaldehyde phosphate with an initial
k(cat) of 1.6 x 10(-3) s(-1). The initial rate slowed most rapidly with WT and
H97N enzymes, which have the highest affinity for the ketopentose phosphates
formed in the condensation. The EPR spectrum of enzyme with Mn(2+) exhibited a
drastic decrease upon substrate addition, and by using H(2)(17)O, it was
determined that there were three waters in the coordination sphere of Mn(2+) in
the absence of substrate. These data suggest that (1) the substrate coordinates
to the enzyme-bound metal ion, (2) His95 and His97 are likely metal ion ligands,
and (3) Tyr229 is not a metal ion ligand, but may play another role in catalysis,
possibly as an acid-base catalyst.
PMID- 10769140
TI - Spin labeling analysis of structure and dynamics of the Na(+)/proline transporter
of Escherichia coli.
AB - With respect to the functional importance attributed to the N-terminal part of
the Na(+)/proline transporter of Escherichia coli (PutP), we report here on the
structural arrangement and functional dynamics of transmembrane domains (TMs) II
and III and the adjoining loop regions. Information on membrane topography was
obtained by analyzing the residual mobility of site-specifically-attached
nitroxide spin label and by determination of collision frequencies of the
nitroxide with oxygen and a polar metal ion complex using electron paramagnetic
resonance (EPR) spectroscopy. The studies suggest that amino acids Phe45, Ser50,
Ser54, Trp59, and Met62 are part of TM II while Gly39 and Arg40 are located at a
membrane-water interface probably forming the cytoplasmic cap of the TM. Also
Ala67 and Glu75 are at a membrane-water interface, suggesting a location close to
the periplasmic ends of TMs II and III, respectively. Ser71 between these
residues is clearly in a water-exposed loop (periplasmic loop 3). Spin labels
attached to positions 80, 86, and 91 show EPR properties typical for a TM
location (TM III). Leu97 may be part of a structured loop region while Ala107 is
clearly located in a water-exposed loop (cytoplasmic loop 4). Finally, spin
labels attached to the positions of Asp33 and Leu37 are clearly on the surface of
the transporter and are directed into an apolar environment. These findings
strongly support the recently proposed 13-helix model of PutP [Jung, H.,
Rubenhagen, R., Tebbe, S., Leifker, K., Tholema, N., Quick, M., and Schmid, R.
(1998) J. Biol. Chem. 273, 26400-26407] and suggest that TMs II and III of the
transporter are formed by amino acids Ser41 to Gly66 and Ser76 to Gly95,
respectively. In addition to the topology analysis, it is shown that binding of
Na(+) and/or proline to the transporter alters the mobility of the nitroxide
group at the positions of Leu37 and Phe45. From these findings, it is concluded
that binding of the ligands induces conformational alterations of PutP that
involve at least parts of TM II and the preceding cytoplasmic loop.
PMID- 10769141
TI - Purification and characterization of neutral sphingomyelinase from Helicobacter
pylori.
AB - Phospholipase activities of human gastric bacterium, Helicobacter pylori, are
regarded as the pathogenic factors owing to their actions on epithelial cell
membranes. In this study, we purified and characterized neutral sphingomyelinase
(N-SMase) from the superficial components of H. pylori strains for the first
time. N-SMase was purified 2083-fold with an overall recovery of 37%. The
purification steps included acid glycine extraction, ammonium sulfate
precipitation, CM-Sepharose, Mono-Q, and Sephadex G-75 column chromatography.
Approximate molecular mass for the native N-SMase was around 32 kDa. When N-omega
trinitrophenylaminolauryl sphingomyelin (TNPAL-SM) was used as a substrate, the
purified enzyme exhibited a K(m) of 6.7 microM and a V(max) of 15.6 nmol of TNPAL
sphingosine/h/mg of protein at 37 degrees C in 50 mM phosphate-buffered saline,
pH 7.4. N-SMase reaches optimal activity at pH 7.4 and has a pI of 7.15. The
enzyme activity is magnesium dependent and specifically hydrolyzed sphingomyelin
and phosphatidylethanolamine. The enzyme also exhibits hemolytic activity on
human erythrocytes. According to Western blot analysis, a rabbit antiserum
against purified N-SMase from H. pylori cross-reacted with SMase from Bacillus
cereus. Sera from individuals with H. pylori infection but not uninfected ones
recognizing the purified N-SMase indicated that it was produced in vivo. In
enzyme-linked immunosorbent assays, the purified N-SMase used as an antigen was
as effective as crude protein antigens in detecting human antibodies to H.
pylori.
PMID- 10769142
TI - Consequences of hydrophobic mismatch between lipids and melibiose permease on
melibiose transport.
AB - The structural and functional consequences of a mismatch between the hydrophobic
thickness d(P) of a transmembrane protein and that d(L) of the supporting lipid
bilayer were investigated using melibiose permease (MelB) from Escherichia coli
reconstituted in a set of bis saturated and monounsaturated phosphatidylcholine
species differing in acyl-chain length. Influence of MelB on the midpoint gel-to
liquid-phase transition temperature, T(m), of the saturated lipids was
investigated through fluorescence polarization experiments, with 1,6-diphenyl
1,3,5-hexatriene as the probe, for varying protein/lipid molar ratio. Diagrams in
temperature versus MelB concentration showed positive or negative shifts in T(m)
with the short-chain lipids DiC12:0-PC and DiC14:0-PC or the long-chain lipids
DiC16:0-PC and DiC18:0-PC, respectively. Theoretical analysis of the data yielded
a d(L) value of 3.0 +/- 0.1 nm for the protein, similar to the 3.02 nm estimated
from hydropathy profiles. Influence of the acyl chain length on the carrier
activity of MelB was investigated in the liquid phase, using the monounsaturated
PCs. Binding of the sugar to the transporter showed no dependence on the acyl
chain length. In contrast, counterflow and Deltapsi-driven experiments revealed
strong dependence of melibiose transport on the lipid acyl chain length. Similar
bell-shaped transport versus acyl chain length profiles were obtained, optimal
activity being supported by diC16:1-PC. On account of a d(P) value of 2.65 nm for
the lipid and of various local constraints which would all tend to elongate the
acyl chains in contact with the protein, one can conclude that maximal activity
was obtained when the hydrophobic thickness of the bilayer matched that of the
protein.
PMID- 10769143
TI - Kinetics and structural requirements for the binding protein of the Di-tripeptide
transport system of Lactococcus lactis.
AB - The gene (dppA) encoding the binding protein of the di-tripeptide ABC transporter
of Lactococcus lactis (DppA) was cloned under the control of the nisin promoter.
Amplified expression ( approximately 200-fold increase) of the protein fused to a
carboxyl-terminal six-histidine tag allowed the purification of DppA-(His)(6) by
nickel-chelate affinity and anion-exchange chromatography. Ligand binding to DppA
(His)(6) elicited an electrophoretic mobility shift, a decrease in the intrinsic
fluorescence, and a blue shift of the emission maximum. Each of these parameters
detected conformational changes in the protein that reflect ligand binding, and
these were used to determine the structural requirements of DppA-(His)(6) for
binding peptides. The major features of peptide binding include (i) high affinity
for di- and tripeptides, (ii) requirement of a free N-terminal alpha-amino group
and an alpha-peptide bound contiguous with the N-terminal amino group, (iii)
stereospecificity for L-isomers, and (iv) preference for dipeptides containing
methionine or arginine, followed by hydrophobic tripeptides consisting of leucine
or valine residues. Maximal binding affinity was detected at pH 6.0, and the K(d)
for binding increased 1 order of magnitude for every unit increase in pH. This
suggests that the ionization of protein residues (pK > 6.0) in or in close
proximity to the binding site is critical in the binding mechanism.
PMID- 10769144
TI - CRE-transcription factor decoy oligonucleotide inhibition of MCF-7 breast cancer
cells: cross-talk with p53 signaling pathway.
AB - The CRE, 5'-TGACGTCA-3', has been described as the consensus sequence for the cis
element that directs cAMP-regulated gene expression. Many transcription factors
bind to this element and regulate the expression of a wide variety of cellular
and viral genes. We have shown that CRE-transcription factor decoy
oligonucleotide restrains the growth of cancer cells in vitro and in vivo [Park,
Y. G., Nesterova, M., Agrawal, S., and Cho-Chung, Y. S. (1999) J. Biol. Chem.
274, 1573-1580]. The growth inhibition was accompanied by changes in cell
morphology and apoptosis. To elucidate the molecular mechanism(s) of the growth
inhibition by the CRE-decoy oligonucleotide, we investigated the p53 signaling
pathway. Herein, we report that CRE-decoy oligonucleotide treatment results in an
increase in the p53 protein level in MCF-7 human breast cancer cells that express
wild-type p53. The p21WAF1/Cip1 protein levels were also increased in the CRE
decoy oligonucleotide treated cells accompanying a reduction in Cdk2- and cyclin
E-dependent kinase activity and pRb phosphorylation. Pulse-chase experiments
reveal that the p53 upregulation was due to increased stability of the protein.
The decoy oligonucleotide treatment also enhanced the p53 promotor-directed
transcription in vivo along with the increase in p53-CBP (CREB-binding protein)
complex formation. Thus, the stabilization and activation of p53 may have
contributed to the growth inhibition induced by CRE-transcription factor decoy
oligonucleotide in MCF-7 breast cancer cells. This decoy oligonucleotide approach
offers great promise as a tool for defining cellular regulatory processes and
treating cancer and other diseases.
PMID- 10769145
TI - Participation of the amino-terminal domain in the self-association of the full
length yeast TATA binding protein.
AB - The association of monomeric TATA binding protein with promoter DNA is an
essential first step in many current models of eukaryotic transcription
initiation. This step is followed by others in which additional transcription
factors, and finally RNA polymerase, assemble at the promoter. Here we
characterize the quaternary interactions of the Saccharomyces cerevisiae TATA
binding protein (yTBP), in the absence of other proteins or DNA. The data reveal
a robust pattern in which yTBP monomers equilibrate with tetramers and octamers
over a broad span of temperatures (4 degrees C [Fe(2)-P](Z) +
4H(+), where P(Z) is the apoprotein of net charge Z and [Fe(2)-P](Z) represents a
diferrous ferroxidase complex. The slower phase 2 reaction corresponds to the
oxidation of this complex by molecular oxygen according to the net equation:
[Fe(2)-P](Z) + (1)/(2)O(2) --> [Fe(2)O-P](Z) where [Fe(2)O-P](Z) represents an
oxidized diferric ferroxidase complex, probably a mu-oxo-bridged species as
suggested by UV-visible and EPR spectrometric titration data. The third phase
corresponds to mineral core formation according to the net reaction: 4Fe(2+) +
O(2) + 6H(2)O --> 4FeO(OH)((core)) + 8H(+). Iron oxidation is inhibited by the
presence of Zn(2+) ions. The patterns of phase 2 and phase 3 inhibition are
different, though inhibition of both phases is complete at 48 Zn(2+)per 24mer,
i.e., 2 Zn(2+) per ferroxidase center.
PMID- 10769152
TI - Unusual spectroscopic and electrochemical properties of the 2[4Fe-4S] ferredoxin
of Thauera aromatica.
AB - A reduced ferredoxin serves as the natural electron donor for key enzymes of the
anaerobic aromatic metabolism in the denitrifying bacterium Thauera aromatica. It
contains two [4Fe-4S] clusters and belongs to the Chromatium vinosum type of
ferredoxins (CvFd) which differ from the "clostridial" type by a six-amino acid
insertion between two successive cysteines and a C-terminal alpha-helical amino
acid extension. The electrochemical and electron paramagnetic resonance (EPR)
spectroscopic properties of both [4Fe-4S] clusters from T. aromatica ferredoxin
have been investigated using cyclic voltammetry and multifrequency EPR. Results
obtained from cyclic voltammetry revealed the presence of two redox transitions
at -431 and -587 mV versus SHE. X-band EPR spectra recorded at potentials where
only one cluster was reduced (greater than -500 mV) indicated the presence of a
spin mixture of S = (3)/(2) and (5)/(2) spin states of one reduced [4Fe-4S]
cluster. No typical S = (1)/(2) EPR signals were observed. At lower potentials
(less than -500 mV), the more negative [4Fe-4S] cluster displayed Q-, X-, and S
band EPR spectra at 20 K which were typical of a single S = (1)/(2) low-spin [4Fe
4S] cluster with a g(av) of 1.94. However, when the temperature was decreased
stepwise to 4 K, a magnetic interaction between the two clusters gradually became
observable as a temperature-dependent splitting of both the S = (1)/(2) and S =
(5)/(2) EPR signals. At potentials where both clusters were reduced, additional
low-field EPR signals were observed which can only be assigned to spin states
with spins of >(5)/(2). The results that were obtained establish that the common
typical amino acid sequence features of CvFd-type ferredoxins determine the
unusual electrochemical properties of the [4Fe-4S] clusters. The observation of
different spin states in T. aromatica ferredoxin is novel among CvFd-type
ferredoxins.
PMID- 10769153
TI - The dynamic impact of CpG methylation in DNA.
AB - Solid-state deuterium NMR is used to investigate perturbations of the local,
internal dynamics in the EcoRI restriction binding site, -GAATTC- induced by
cytidine methylation. Methylation of the cytidine base in this sequence is known
to suppress hydrolysis by the EcoRI restriction enzyme. Previous solid-state
deuterium NMR studies have detected large amplitude motions of the phosphate
sugar backbone at the AT-CG junction of the unmethylated DNA sequence. This study
shows that methylation of the cytidine base in a CpG dinucleotide reduces the
amplitudes of motions of the phosphate-sugar backbone. These observations suggest
a direct link between suppression of the amplitudes of localized, internal
motions of the sugar-phosphate backbone of the DNA and inhibition of restriction
enzyme cleavage.
PMID- 10769154
TI - Hammerhead cleavage of the phosphorodithioate linkage.
AB - Under standard reaction conditions, a hammerhead ribozyme with a
phosphorodithioate linkage at the cleavage site cleaved to the expected products
with a rate about 500-fold slower than the corresponding phosphodiester linkage.
When the greater stability of the dithioate linkage to nonenzymatic nucleophilic
attack is taken into account, the hammerhead is remarkably effective at cleaving
the dithioate linkage considering that the R(P)-phosphoromonothioate linkage is
virtually inactive. On the basis of experiments determining the Mg(2+)
concentration dependence of the cleavage rate and the stimulation of cleavage by
thiophilic Cd(2+) ion, the lesser catalytic rate enhancement of the dithioate
linkage is primarily due to the loss of a single Mg(2+) ion bound near the
cleavage site. These results are qualitatively similar to, but quantitatively
different from, similar experiments examining the hammerhead cleavage properties
of the R(P)-phosphoromonothioate linkage. The dithioate linkage thus promises to
be a valuable alternative phosphate analogue to the monothioate linkage in
studying the mechanisms of RNA catalysis.
PMID- 10769155
TI - pH jump studies of the folding of the multidomain ribosomal protein L9: the
structural organization of the N-terminal domain does not affect the anomalously
slow folding of the C-terminal domain.
AB - The folding kinetics of the multidomain ribosomal protein L9 were studied using
pH jump stopped-flow fluorescence and circular dichroism (CD) in conjunction with
guanidine hydrochloride (GdnHCl) jump stopped-flow CD experiments. Equilibrium CD
and 1D (1)H NMR measurements demonstrated that the C-terminal domain unfolds
below pH 4 while the N-terminal domain remains fully folded. Thus, the N-terminal
domain remains folded during the pH jump experiments. The folding rate constant
of the C-terminal domain was determined to be 3.5 s(-1) by pH jump experiments
conducted in the absence of denaturant using stopped-flow CD and fluorescence. CD
detected GdnHCl jump measurements showed that the N- and C-terminal domains fold
independently each by an apparent two-state mechanism. The folding rate constant
for the N-terminal domain and the C-terminal domain in the absence of denaturant
were calculated to be 760 and 4. 7 s(-1), respectively. The good agreement
between the pH jump and the denaturant concentration jump experiments shows that
the folding rate of the C-terminal domain is the same whether or not the N
terminal domain is folded. This result suggests that the slow folding of the C
terminal domain is not a consequence of unfavorable interactions with the rest of
the protein chain during refolding. This is an interesting result since contact
order analysis predicts that the folding rate of the C-terminal domain should be
noticeably faster. The folding rate of the isolated N-terminal domain was also
measured by stopped-flow CD and was found to be the same as the rate for the
domain in the intact protein.
PMID- 10769156
TI - Turbidite Megabeds in an Oceanic Rift Valley Recording Jokulhlaups of Late
Pleistocene Glacial Lakes of the Western United States.
AB - Escanaba Trough is the southernmost segment of the Gorda Ridge and is filled by
sandy turbidites locally exceeding 500 m in thickness. New results from Ocean
Drilling Program (ODP) Sites 1037 and 1038 that include accelerator mass
spectrometry (AMS) 14C dates and revised petrographic evaluation of the sediment
provenance, combined with high-resolution seismic-reflection profiles, provide a
lithostratigraphic framework for the turbidite deposits. Three fining-upward
units of sandy turbidites from the upper 365 m at ODP Site 1037 can be correlated
with sediment recovered at ODP Site 1038 and Deep Sea Drilling Program (DSDP)
Site 35. Six AMS 14C ages in the upper 317 m of the sequence at Site 1037
indicate that average deposition rates exceeded 10 m/k.yr. between 32 and 11 ka,
with nearly instantaneous deposition of one approximately 60-m interval of sand.
Petrography of the sand beds is consistent with a Columbia River source for the
entire sedimentary sequence in Escanaba Trough. High-resolution acoustic
stratigraphy shows that the turbidites in the upper 60 m at Site 1037 provide a
characteristic sequence of key reflectors that occurs across the floor of the
entire Escanaba Trough. Recent mapping of turbidite systems in the northeast
Pacific Ocean suggests that the turbidity currents reached the Escanaba Trough
along an 1100-km-long pathway from the Columbia River to the west flank of the
Gorda Ridge. The age of the upper fining-upward unit of sandy turbidites appears
to correspond to the latest Wisconsinan outburst of glacial Lake Missoula. Many
of the outbursts, or jokulhlaups, from the glacial lakes probably continued
flowing as hyperpycnally generated turbidity currents on entering the sea at the
mouth of the Columbia River.
PMID- 10769157
TI - Stratigraphic Analysis of Upper Cretaceous Rocks in the Mahajanga Basin,
Northwestern Madagascar: Implications for Ancient and Modern Faunas.
AB - Upper Cretaceous strata of the Mahajanga Basin, northwestern Madagascar, yield
some of the most significant and exquisitely preserved vertebrate fossils known
from Gondwana. The sedimentology of these strata and their stratigraphic
relations have been the focus of renewed geological investigations during the
course of five expeditions since 1993. We here designate stratotypes and
formalize the terrestrial Maevarano Formation, with three new members (Masorobe,
Anembalemba, Miadana), and the overlying marine Berivotra Formation. The
Maevarano Formation accumulated on a broad, semiarid alluvial plain bounded to
the southeast by crystalline highlands and to the northwest by the Mozambique
Channel. The Berivotra Formation was deposited in an open marine setting that
evolved from a clastic- to a carbonate-dominated shelf, resulting in deposition
of the overlying Betsiboka limestone of Danian age. New stratigraphic data
clearly indicate that the Maevarano Formation correlates, at least in part, with
the Maastrichtian Berivotra Formation, and this in turn indicates that the most
fossiliferous portions of the Maevarano Formation are Maastrichtian in age,
rather than Campanian as previously reported. This revised age for the Maevarano
vertebrate assemblage indicates that it is approximately contemporaneous with the
vertebrate fauna recovered from the Deccan basalt volcano-sedimentary sequence of
India. The comparable age of these two faunas is significant because the faunas
appear to be more similar to one another than either is to those from any other
major Gondwanan landmass. The revised age of the Maevarano Formation, when
considered in the light of our recent fossil discoveries, further indicates that
the ancestral stocks of Madagascar's overwhelmingly endemic modern vertebrate
fauna arrived on the island in post-Mesozoic times. The basal stocks of the
modern vertebrate fauna are conspicuously absent in the Maevarano Formation.
Finally, the revised age of the Maevarano Formation serves to expand our global
perspective on the K/T event by clarifying the age of a diverse, and arguably the
best preserved, sample of Gondwanan vertebrates from the terminal Cretaceous.
PMID- 10769158
TI - Growth and Deformation of the Ladakh Batholith, Northwest Himalayas: Implications
for Timing of Continental Collision and Origin of Calc-Alkaline Batholiths.
AB - The calc-alkaline Ladakh batholith (NW Himalayas) was dated to constrain the
timing of continental collision and subsequent deformation. Batholith growth
ended when collision disrupted subduction of the Tethyan oceanic lithosphere, and
thus the youngest magmatic pulse indirectly dates the collision. Both U-Pb ages
on zircons from three samples of the Ladakh batholith and K-Ar from one
subvolcanic dike sample were determined. Magmatic activity near Leh (the capital
of Ladakh) occurred between 70 and 50 Ma, with the last major magmatic pulse
crystallizing at ca. 49.8+/-0.8 Ma (2sigma). This was followed by rapid and
generalized cooling to lower greenschist facies temperatures within a few million
years, and minor dike intrusion took place at 46+/-1 Ma. Field observations, the
lack of inherited prebatholith zircons, and other isotopic evidence suggest that
the batholith is mantle derived with negligible crustal influence, that it
evolved through input of fresh magma from the mantle and remelting of previously
emplaced mantle magmatic rocks. The sedmimentary record indicates that collision
in NW Himalaya occurred around 52-50 Ma. If this is so, the magmatic system
driven by subduction of Tethys ended immediately on collision. The thermal
history of one sample from within the Thanglasgo Shear Zone (TSZ) was determined
by Ar-Ar method to constrain timing of batholith internal deformation. This is a
wide dextral shear zone within the batholith, parallel to the dextral, N 30
degrees W-striking crustal-scale Karakoram Fault. Internal deformation of the
batholith, taken up partly by this shear zone, has caused it to deviate from it
regional WNW-ESE trend to parallel the Karakoram Fault. Microstructures and
cooling history of a sample from the TSZ indicate that shearing took place before
22 Ma, implying that (1) the history of dextral shearing on NW-striking planes in
northern Ladakh started at least 7 m.yr. before the <15 Ma Karakoram Fault, (2)
shearing was responsible for deviation of the regional trend of the Ladakh
batholith, and (3) dextral shearing occured within a zone apporximately 100 km
wide that includes the Ladakh batholith and portions of the younger Karakoram
batholith.
PMID- 10769159
TI - Precise U-Pb Zircon Constraints on the Earliest Magmatic History of the Carolina
Terrane.
AB - The early magmatic and tectonic history of the Carolina terrane and its possible
affinities with other Neoproterozoic circum-Atlantic arc terranes have been
poorly understood, in large part because of a lack of reliable geochronological
data. Precise U-Pb zircon dates for the Virgilina sequence, the oldest exposed
part, constrain the timing of the earliest known stage of magmatism in the
terrane and of the Virgilina orogeny. A flow-banded rhyolite sampled from a
metavolcanic sequence near Chapel Hill, North Carolina, yielded a U-Pb zircon
date of 632.9 +2.6/-1.9 Ma. A granitic unit of the Chapel Hill pluton, which
intrudes the metavolcanic sequence, yielded a nearly identical U-Pb zircon date
of 633 +2/-1.5 Ma, interpreted as its crystallization age. A felsic gneiss and a
dacitic tuff from the Hyco Formation yielded U-Pb zircon dates of 619.9 +4.5/-3
Ma and 615.7 +3.7/-1.9 Ma, respectively. Diorite and granite of the Flat River
complex have indistinguishable U-Pb upper-intercept dates of 613.9 +1.6/-1.5 Ma
and 613.4 +2.8/-2 Ma. The Osmond biotite-granite gneiss, which intruded the Hyco
Formation before the Virgilina orogeny, crystallized at 612.4 +5.2/-1.7 Ma.
Granite of the Roxboro pluton, an intrusion that postdated the Virgilina orogeny,
yielded a U-Pb upper intercept date of 546.5 +3.0/-2.4 Ma, interpreted as the
time of its crystallization. These new dates both provide the first reliable
estimates of the age of the Virgilina sequence and document that the earliest
known stage of magmatism in the Carolina terrane had begun by 633 +2/-1.5 Ma and
continued at least until 612.4 +5.2/-1.7 Ma, an interval of approximately 25
m.yr. Timing of the Virgilina orogeny is bracketed between 612.4 +5.2/-1.7 Ma and
586+/-10 Ma (reported age of the upper Uwharrie Formation). The U-Pb systematics
of all units studied in the Virgilina sequence are simple and lack any evidence
of an older xenocrystic zircon component, which would indicate the presence of a
continental-type basement. This observation, together with the juvenile Nd
isotopic character of the Virgilina volcanic arc sequence, suggests that the
oldest part of the Carolina terrane was built on oceanic crust away from a
continental crustal influence.
PMID- 10769160
TI - Bulge Migration and Pinnacle Reef Development, Devonian Appalachian Foreland
Basin.
AB - Detailed stratigraphic analyses of Late Emsian and Early Eifelian (Lower to
Middle Devonian) carbonate-dominated strata in the northern Appalachian Basin
indicate anomalous, locally varying relative sea level changes and inversions of
topography. The distribution of a major basal-bounding unconformity, basinal
pinnacle reefs, local absence of parasequences, and eastward migration of shallow
marine carbonate lithofacies and related biofacies in the Onondaga Limestone and
underlying strata mark the retrograde migration of an elongate, northeast
southwest-trending area of positive relief, bordered on its cratonward side by a
similarly migrating basin of intermediate depth. These features are thought to
represent the forebulge and back-bulge basin of the Appalachian foreland basin
system as it developed during a time of relative quiescence within the Acadian
Orogeny. However, the relatively small size of the bulgelike feature (ca. 80-100
km-wide, 20-50-m positive relief), its great distance from the probable
deformation front (>400 km), and the lack of a well-developed foredeep
immediately adjacent to the bulgelike feature may indicate that it represents a
smaller-scale flexural high ("flexural welt") superposed over the cratonward edge
of the larger-scale classical forebulge of the basin. Development of shallow
water reefs on the crest of the bulge during sea level lowstand, followed by
migration of the bulge and widespread transgression, permitted growth of
economically significant pinnacle reefs in the deep basin center. Further
subsurface reef exploration should concentrate along the projected position of
the bulge during the basal Onondaga lowstand.
PMID- 10769161
TI - Contrasting Metamorphic Record of Heat Production Anomalies in the Penokean
Orogen of Northern Michigan.
AB - It is proposed that the contrasting metamorphic mineral assemblages of the
isolated amphibolite facies metamorphic highs in the Penokean orogen of northern
Michigan may be caused by different heat production rates in the Archean
basement. This hypothesis is based on concentrations of K, U, and Th in the
Archean basement gneisses and Paleoproterozoic metasediments that indicate
significant contribution of radiogenic heating during Penokean metamorphism. Heat
production was anomalously high ( approximately 10.6 uWm-3) where andalusite
bearing mineral assemblages indicate that high temperatures were attained at
shallow crustal levels ( approximately 550 degrees -600 degrees C at
approximately 3 kbar). In contrast, where exposed metamorphic rocks indicate peak
temperatures of 600 degrees -650 degrees C at 6-7 kbar, heat production in the
Archean basement was lower ( approximately 3.7 uWm-3). The effect of heat
production rates on the metamorphic pressure-temperature paths was tested with
numerical thermal models. The calculations show (1) that if the heat production
rate, where andalusite-bearing assemblages formed, was significantly <6.0 uWm-3,
the estimated pressure at peak temperatures (PTmax) would be much higher and lie
in the sillimanite or kyanite stability fields; and (2) differences between PTmax
estimates for the metamorphic highs based on thermobarometry can be reproduced if
thermal history involved significant crustal thickening as well as moderate
unroofing rates.
PMID- 10769162
TI - Role of lipids in the translocation of proteins across membranes.
AB - The architecture of cells, with various membrane-bound compartments and with the
protein synthesizing machinery confined to one location, dictates that many
proteins have to be transported through one or more membranes during their
biogenesis. A lot of progress has been made on the identification of protein
translocation machineries and their sorting signals in various organelles and
organisms. Biochemical characterization has revealed the functions of several
individual protein components. Interestingly, lipid components were also found to
be essential for the correct functioning of these translocases. This led to the
idea that there is a very intimate relationship between the lipid and protein
components that enables them to fulfil their intriguing task of transporting
large biopolymers through a lipid bilayer without leaking their contents. In this
review we focus on the Sec translocases in the endoplasmic reticulum and the
bacterial inner membrane. We also highlight the interactions of lipids and
proteins during the process of translocation and integrate this into a model that
enables us to understand the role of membrane lipid composition in translocase
function.
PMID- 10769163
TI - Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor
gp600/megalin.
AB - gp600/megalin, an endocytic receptor, belongs to the low-density lipoprotein
receptor family. It is most abundant in the renal proximal tubular cells, where
it is implicated in the reabsorption of a number of molecules filtered through
the glomerulus. The cytoplasmic tail (CT) of gp600/megalin contains a number of
sequence similarities, which indicate that gp600/megalin might be involved in
signal transduction. To find intracellular proteins that would interact with the
gp600/megalin CT, a human kidney cDNA library was screened by using the yeast two
hybrid system. The phosphotyrosine interaction domain (PID) of the Disabled
protein 2 (Dab2), a mammalian structural analogue of Drosophila Disabled, was
found to bind to the gp600/megalin CT in this system. The interaction between
these two proteins was confirmed by a binding assay in vitro and by the co
immunoprecipitation of both proteins from renal cell lysates. The gp600/megalin
CT contains three PsiXNPXY motifs (in which Psi represents a hydrophobic residue)
that are potentially able to interact with PID. Analysis of the CT deletion and
point-mutation variants of gp600/megalin by the two-hybrid system revealed that
the third PsiXNPXY motif is most probably involved in this interaction. Dab2 is a
mitogen-responsive phosphoprotein thought to be an adaptor molecule involved in
signal transduction, and a suggested negative regulator of cell growth. Dab2 is
the first intracellular ligand identified for gp600/megalin; gp600/megalin is the
first known transmembrane receptor that interacts with the cytosolic protein
Dab2. We speculate that their interaction might involve gp600/megalin in signal
transduction pathways or might mediate the intracellular trafficking of this
receptor.
PMID- 10769164
TI - The human vasoactive intestinal peptide/pituitary adenylate cyclase-activating
peptide receptor 1 (VPAC1) promoter: characterization and role in receptor
expression during enterocytic differentiation of the colon cancer cell line Caco
2Cl.20.
AB - The basic organization of the human vasoactive intestinal peptide/pituitary
adenylate cyclase-activating peptide receptor (VPAC) 1 promoter was investigated
after cloning the 5'-flanking region (1.4 kb) of the VPAC1 gene from a human
genomic library. Subsequent functional analysis of various deletions of the 5'
flanking sequence, subcloned upstream of a luciferase reporter gene, was carried
out in HT-29 cells. The minimal promoter region identified encompasses the
205/+76 sequence and contains a crucial CCAAT box (-182/-178) and a GC-rich
sequence. Moreover a region (-1348/-933) containing a silencer element was
identified. We previously showed that the expression of the VPAC1 receptor
binding site is strictly dependent upon the enterocytic differentiation of human
colon cancer Caco-2 cells [Laburthe, Rousset, Rouyer-Fessard, Couvineau,
Chantret, Chevalier and Zweibaum (1987) J. Biol. Chem. 262, 10180-10184]. In the
present study we show that VPAC1 mRNA increases dramatically when Caco-2Cl.20
cells differentiate, as measured by RNase protection assays and reverse
transcriptase-PCR. A single transcript species of 3 kb is detected in
differentiated cells by Northern-blot analysis. Accumulation of VPAC1 receptor
mRNA is due to a 5-fold increase of transcription rate (run-on assay) without a
change in mRNA half-life (9 h). Stable transfections of various constructs in
Caco-2Cl.20 cells and subsequent analysis of reporter gene expression, during the
enterocytic differentiation process over 25 days of culture, further indicated
that the -254/+76 5'-flanking sequence is endowed with the regulatory element(s)
necessary for transcriptional regulation of VPAC1 during differentiation.
Altogether, these observations provide the first characterization of the basic
organization of the human VPAC1 gene promoter and unravel the crucial role of a
short promoter sequence in the strict transcriptional control of VPAC1 expression
during differentiation of human colon cancer Caco-2 cells.
PMID- 10769165
TI - Large-scale synthesis and functional elements for the antimicrobial activity of
defensins.
AB - Human neutrophil defensins, and their analogues incorporating anionic,
hydrophobic or cationic residues at the N- and C-termini, were synthesized by
solid-phase procedures. The synthetic defensins were examined for their
microbicidal activity against Candida albicans, two Gram-negative bacteria
(Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis) and two Gram
positive bacteria (Streptococcus gordonii and Streptococcus mutans). The human
neutrophil peptide 1 (HNP1) and HNP2 were found to be potent candidacidal agents.
HNP3, which differs by one amino acid at the N-terminus of its sequence, was
totally inactive. The Gram-negative bacteria A. actinomycetemcomitans and P.
gingivalis and the Gram-positive bacteria S. gordonii and S. mutans were
insensitive to human defensins. However, the insertion of two basic residues,
such as arginine, at both the N-terminus and the C-terminus of HNP2 significantly
enhanced antifungal and antibacterial activity. The addition of anionic residues,
such as aspartic acid, at the N- and C-termini rendered the molecule totally
inactive. The presence of two hydrophobic amino acids, such as valine, at the N
terminus of HNP2 and of two basic arginine residues at its C-terminus resulted in
molecules that were optimally active against these oral pathogens. The results
suggest that the N- and C-terminal residues in defensin peptides are the crucial
functional elements that determine their microbicidal potency. The three
dimensional structure of all defensins constitutes the same amphiphilic beta
sheet structure, with the polar face formed by the N- and C-terminal residues
playing an important role in defining microbicidal potency and the antimicrobial
spectrum. The enhanced microbicidal activity observed for defensin peptides with
two basic residues at both the N- and C-termini could be due to optimization of
the amphiphilicity of the structure, which could facilitate specific interactions
with the microbial membranes.
PMID- 10769166
TI - Differential adrenergic regulation of the gene expression of the beta
adrenoceptor subtypes beta1, beta2 and beta3 in brown adipocytes.
AB - In brown adipocytes, fundamental cellular processes (cell proliferation,
differentiation and apoptosis) are regulated by adrenergic stimulation, notably
through beta-adrenergic receptors. The presence of all three beta-receptor
subtypes has been demonstrated in brown adipose tissue. Due to the significance
of the action of these receptors and indications that the subtypes govern
different processes, the adrenergic regulation of the expression of the beta(1)
(,) beta(2)- and beta(3)-adrenoceptor genes was examined in murine brown-fat
primary cell cultures. Moderate levels of beta(1)-receptor mRNA, absence of
beta(2)-receptor mRNA and high levels of beta(3)-receptor mRNA were observed in
mature brown adipocytes (day 6 in culture). Noradrenaline (norepinephrine)
addition led to diametrically opposite effects on beta(1)- (markedly enhanced
expression) and beta(3)-gene expression (full cessation of expression, as
previously shown). beta(2)-Gene expression was induced by noradrenaline, but only
transiently (<1 h). The apparent affinities (EC(50)) of noradrenaline were
clearly different (7 nM for the beta(1)-gene and200 kDa) and
single polypeptides folded with internal S-S cross-links (<41 kDa) have been
detected by SDS/PAGE in particulate membranes and soluble extracts of developing
cotyledons of nasturtium (Tropaeolum majus L.). When first prepared from fruit
homogenates, these polypeptides were found to bind reversibly to UDP-Gal
(labelled with [(14)C]Gal or [(3)H]uridine), and to co-precipitate specifically
with added xyloglucan from solutions made with 67% ethanol. Initially, the bound
UDP-[(14)C]Gal could be replaced (bumped) by adding excess UDP, or exchanged
(chased) with UDP-Gal, -Glc, -Man or -Xyl. However, this capacity for turnover
was lost during incubation in reaction media, or during SDS/PAGE under reducing
conditions, even as the glycone moiety was conserved by autoglycosylation to form
a stable 41 kDa polypeptide. Polyclonal antibodies raised to a similar product
purified from Arabidopsis bound to all the labelled nasturtium polypeptides in
immunoblotting tests. The antibodies also inhibited the binding of nasturtium
polypeptides to UDP-Gal, the uptake of UDP-[(14)C]Gal into intact nasturtium
membrane vesicles and the incorporation of [(14)C]Gal into nascent xyloglucan
within these vesicles. This is the first direct evidence that these polypeptides
facilitate the channelling of UDP-activated sugars from the cytoplasm through
Golgi vesicle membranes to lumenal sites, where they can be used as substrates
for glycosyltransferases to synthesize products such as xyloglucan.
PMID- 10769193
TI - Epoxyalkyl glycosides of D-xylose and xylo-oligosaccharides are active-site
markers of xylanases from glycoside hydrolase family 11, not from family 10.
AB - A series of omega-epoxyalkyl glycosides of D-xylopyranose, xylobiose and
xylotriose were tested as potential active-site-directed inhibitors of xylanases
from glycoside hydrolase families10 and 11. Whereas family-10 enzymes
(Thermoascus aurantiacus Xyn and Clostridium thermocellum Xyn Z) are resistant
toelectrophilic attack of active-site carboxyl residues, glycosidehydrolases of
family 11 (Thermomyces lanuginosus Xyn and Trichoderma reesei Xyn II) are
irreversibly inhibited. Theapparent inactivation and association constants (k(i),
1/K(i)) are one order of magnitude higher for thexylobiose and xylotriose
derivatives. The effects of the aglycone chainlength can clearly be described.
Xylobiose and n-alkyl beta-D-xylopyranosides are competitive ligands and provide
protectionagainst inactivation. MS measurements showed 1:1 stoichiometries inmost
labelling experiments. Electrospray ionization MS/MS analysisrevealed the
nucleophile Glu(86) as the modified residue inthe T. lanuginosus xylanase when
2,3-epoxypropyl beta-D-xylopyranoside was used, whereas the acid/base catalyst
Glu(178) was modified by the 3,4-epoxybutyl derivative. The active-site residues
Glu(86) and Glu(177) in T. reesei Xyn II are similarly modified, confirming
earlier X-raycrystallographic data [Havukainen, Torronen, Laitinen and Rouvinen
(1996)Biochemistry 35, 9617-9624]. The inability of the omega-epoxyalkyl
xylo(oligo)saccharide derivatives to inactivate family-10enzymes is discussed in
terms of different ligand-subsiteinteractions.
PMID- 10769194
TI - Polyamines directly induce release of cytochrome c from heart mitochondria.
AB - Cytochrome c release from mitochondria to the cytosol represents a critical step
in apoptosis, correlated to the activation of the caspase cascade. In this
report, we show that addition of micromolar concentrations of polyamines to
isolated rat heart mitochondria induces the release of cytochrome c. Spermine,
which is effective at concentrations of 10-100 microM, is more potent than
spermidine, whereas putrescine has no effect up to 1 mM. The release of
cytochrome c caused by spermine is a rapid, saturable and selective process that
is independent of mitochondria damage. Spermine, unlike polylysine, is able to
release a discrete amount of cytochrome c from intact, functional mitochondria.
The cytochrome c-releasing power of spermine is not affected by cyclosporin A,
differently from the effect of permeability transition inducers. In a cardiac
cell-free model of apoptosis, the latent caspase activity of cytosolic extracts
from cardiomyocytes could be activated by cytochrome c released from spermine
treated heart mitochondria. These data indicate a novel mechanism of cytochrome c
release from the mitochondrion, and suggest that prolonged and sustained
elevation of polyamines, characteristic of some pathologies such as heart
hypertrophy, could be involved in the development of apoptosis.
PMID- 10769195
TI - Heteroduplex DNA and ATP induced conformational changes of a MutS mismatch repair
protein from Thermus aquaticus.
AB - ATP hydrolysis by MutS homologues is required for the function of these proteins
in mismatch repair. However, the function of ATP hydrolysis in the repair
reaction is not very clear. We have examined the role of ATP hydrolysis in
oligomerization of Thermus aquaticus (Taq) MutS protein in solution. Analytical
gel filtration and cross-linking of MutS protein with disuccinimidyl suburate
suggest that TaqMutS is a dimer in the presence of ATP. ATP binding and
hydrolysis by TaqMutS reduces the heteroduplex-DNA binding by the protein. Using
limited proteolysis we detected extensive conformational changes of the TaqMutS
protein in the presence of ATP and heteroduplex DNA. Heteroduplex-DNA binding is
necessary for the observed conformational changes since F39A mutant protein
defective in DNA binding does not display ATP-induced conformational changes. The
implications of the observed conformational changes in the MutS protein are
discussed with respect to two different models proposed for the role of ATP
hydrolysis by MutS in DNA mismatch repair.
PMID- 10769196
TI - The nuclear pore complex: mediator of translocation between nucleus and
cytoplasm.
AB - The enclosure of nuclear contents in eukaryotes means that cells require sites in
the boundary that mediate exchange of material between nucleus and cytoplasm.
These sites, termed nuclear pore complexes (NPCs), number 100-200 in yeast, a few
thousand in mammalian cells and approximately 50 million in the giant nuclei of
amphibian oocytes. NPCs are large (125 MDa) macromolecular complexes that
comprise 50-100 different proteins in vertebrates. In spite of their size and
complex structure, NPCs undergo complete breakdown and reformation at cell
division. Transport through NPCs can be rapid (estimated at several hundred
molecules/pore/second) and accommodates both passive diffusion of relatively
small molecules, and active transport of complexes up to several megadaltons in
molecular mass. Each pore can facilitate both import and export. The two
processes apparently involve multiple pathways for different cargoes, and their
transport signals, transport receptors and adapters, and the molecules (and their
regulators) that underpin the transport mechanisms. Over the past few years there
has been an increasing interest in the pore complex: structural studies have been
followed by elucidation of the biochemical aspects of nuclear import, and
subsequent investigations into nuclear export. The current challenge is to
understand the interactions between the structural elements of the pore complex
and the mechanisms that drive the physical processes of translocation through it.
PMID- 10769197
TI - The p53/p63/p73 family of transcription factors: overlapping and distinct
functions.
AB - The p53 gene is the most frequently mutated gene in human cancer. The
identification of two homologues, p63 and p73, revealed that p53 is a member of a
family of related transcription factors. Given that they share amino acid
sequence identity reaching 63% in the DNA-binding domain, p53, p63 and p73 should
have redundant functions in the regulation of gene expression. Indeed, p73 can
activate p53-regulated genes and suppress growth or induce apoptosis. Moreover,
p53 and p73 are both induced by DNA damage - albeit through distinct mechanisms.
Other evidence, however, suggests that p63 and p73 are important for regulation
of normal development. An extended C-terminal region, not found in p53, is
alternatively spliced in p63 and p73. Within this C-terminal extension is a
sterile &agr; motif (SAM) previously found in other proteins that regulate
development. The p63-deficient mice showed developmental abnormalities.
Interestingly, the human p63 gene is mutated in children who have the disease
Ectrodactyly, Ectodermal dysplasia and facial Clefts (EEC) syndrome, and the
disease phenotype is similar to the one of p63-deficient mice. The p63 and p73
genes are rarely mutated in human cancer, although p73 loss is observed in
neuroblastoma and a subtype of T-cell lymphoma. p53, p63 and p73 appear to have
overlapping and distinct functions: p53 regulates the stress response to suppress
tumors; p63 is essential for ectoderm development; and p73 might regulate both
the stress response and development. Because p53 and p73 are linked to different
upstream pathways, this family of transcription factors might regulate a common
set of genes in response to different extracellular signals and developmental
cues.
PMID- 10769198
TI - Rising behind NO: cGMP-dependent protein kinases.
AB - Over the past few years, a wealth of biochemical and functional data has been
gathered on mammalian cGMP-dependent protein kinases (cGKs). In mammals, three
different kinases are encoded by two genes. Mutant and chimeric cGMP kinase
proteins generated by molecular biology techniques have yielded important
biochemical knowledge, such as the function of the N-terminal domains of cGKI and
cGKII, the identity of the cGMP-binding sites of cGKI, the substrate specificity
of the enzymes and structural details of the catalytic center. Genetic approaches
have proved to be especially useful for the analysis of the biological function
of cGKs. Recently, some of the in vivo targets and mechanisms leading to smooth
muscle relaxation have been identified. In vivo targets are the myosin-binding
subunit of myosin phosphatase (PP1M), a member of the protein phosphatase 1, the
calcium-activated maxi K(+) channel and a new protein named IRAG that forms a
complex with the inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) receptor and cGKI.
Phosphorylation of PP1M by cGKI(alpha) activates myosin phosphatase, whereas
phosphorylation of IRAG by cGKI(beta) decreases Ins(1,4, 5)P(3)-induced calcium
release. cGKII regulates in vivo intestinal fluid secretion by phosphorylation of
the cystic fibrosis transmembrane conductance regulator (CFTR), bone growth and
renal renin secretion by phosphorylation of unknown proteins.
PMID- 10769199
TI - Cell adhesion and motility depend on nanoscale RGD clustering.
AB - Integrin adhesion receptors play a crucial role in regulating interactions
between cells and extracellular matrix (ECM). Integrin activation initiates
multiple intracellular signaling pathways and results in regulation of cell
functions such as motility, proliferation and differentiation. Two key
observations regarding the biophysical nature of integrin-mediated cell-matrix
interactions motivated the present study: (1) cell motility can be regulated by
modulating the magnitude of cell-substratum adhesion, by varying cell integrin
expression level, integrin-ECM binding affinity or substratum ECM surface
density; and (2) integrin clustering enables assembly of multiple cytoplasmic
regulatory and structural proteins at sites of aggregated integrin cytoplasmic
domains, activating certain intracellular signalling pathways. Here, using a
minimal integrin adhesion ligand, YGRGD, we test the hypothesis that ligand
clustering can affect cell migration in a manner related to its modulation of
cell-substratum adhesion. We employ a synthetic polymer-linking method, which
allows us to independently and systematically vary both the average surface
density and the local (approx. 50 nm scale) spatial distribution of the YGRGD
peptide, against a background otherwise inert with respect to cell adhesion. In
this system, the ligand was presented in three alternative spatial distributions:
singly, in clusters with an average of five ligands per cluster, or in clusters
with an average of nine ligands per cluster; for each of these spatial
distributions, a range of average ligand densities (1,000-200,000
ligands/micrometer(2)) were examined. Cluster spacing was adjusted in order to
present equivalent average ligand densities independently of cluster size. The
murine NR6 fibroblast cell line was used as a model because its migration
behavior on ECM in the presence and absence of growth factors has been well
characterized and it expresses integrins known to interact with the YGRGD
peptide. Using time-lapse videomicroscopy and analysis of individual cell
movement paths, we find that NR6 cells can migrate on substrata where adhesion is
mediated solely by the YGRGD peptide. As previously observed for migration of NR6
cells on fibronectin, migration speed on YGRGD is a function of the average
surface ligand density. Strikingly, clustering of ligand significantly reduced
the average ligand density required to support cell migration. In fact, non
clustered integrin ligands support cell attachment but neither full spreading nor
haptokinetic or chemokinetic motility. In addition, by quantifying the strength
of cell-substratum adhesion, we find that the variation of cell speed with
spatial presentation of YGRGD is mediated via its effect on cell adhesion. These
effects on motility and adhesion are also observed in the presence of epidermal
growth factor (EGF), a known motility-regulating growth factor. Variation in
YGRGD presentation also affects the organization of actin filaments within the
cell, with a greater number of cells exhibiting stress fibers at higher cluster
sizes of YGRGD. Our observations demonstrate that cell motility may be regulated
by varying ligand spatial presentation at the nanoscale level, and suggest that
integrin clustering is required to support cell locomotion.
PMID- 10769200
TI - Association of human ubiquitin-conjugating enzyme CDC34 with the mitotic spindle
in anaphase.
AB - Present in organisms ranging from yeast to man, homologues of the Saccharomyces
cerevisiae ubiquitin-conjugating enzyme CDC34 have been shown to play important
roles in the regulation of cell cycle progression and checkpoint function. Here
we analyze the expression and intracellular localization of endogenous CDC34
during mammalian cell cycle progression. We find that CDC34 protein is
constitutively expressed during all stages of the cell cycle. Immunofluorescence
experiments reveal that during interphase, endogenous CDC34 is localized to
distinct speckles in both the nucleus and the cytoplasm. The presence of CDC34 in
these compartments has also been established by biochemical fractionation
experiments. Interestingly, nuclear localization depends on the presence of
specific carboxy-terminal CDC34 sequences that have previously been shown to be
required for CDC34's cell cycle function in Saccharomyces cerevisiae. Finally, we
find that in anaphase and not during early stages of mitosis, CDC34 colocalizes
with (beta)-tubulin at the mitotic spindle, implying that it may contribute to
spindle function at later stages of mitosis. Taken together, these results
support a model in which CDC34 ubiquitin-conjugating enzyme functions in the
regulation of nuclear and cytoplasmic activities as well as in the process of
chromosome segregation at the onset of anaphase in mammalian cells.
PMID- 10769201
TI - The S. pombe orthologue of the S. cerevisiae mob1 gene is essential and functions
in signalling the onset of septum formation.
AB - We have isolated the Schizosaccharomyces pombe orthologue of the Saccharomyces
cerevisiae MOB1 gene in a screen designed to enrich for septation mutants. The
gene is essential, and cells lacking it display a phenotype typical of septation
signalling network mutants. mob1p is located on both spindle pole bodies
throughout mitosis. In addition it is also co-localised with the medial ring
later in mitosis, and flanks the septum as the medial ring contracts. We also
demonstrate that mob1p can be precipitated from cells in a complex with the
septation regulating kinase sid2p.
PMID- 10769202
TI - Intracellular targeting and retention of the glucose transporter GLUT4 by the
perinuclear storage compartment involves distinct carboxyl-tail motifs.
AB - The mechanisms by which the insulin-sensitive glucose transporter, GLUT4, is
targeted and retained in a storage compartment near to the Golgi complex are
poorly understood. Here we report that removal of the carboxyl-terminal acidic
Pro(505)AspGluAsnAsp(509) sequence prevents the storage of GLUT4 in the VAMP-2
positive compartment adjacent to the Golgi complex (GSC), and results in its
targeting to GLUT4-positive vesicles and Rab7-positive late endosomes. Storage of
the truncated GLUT4 in the GSC is restored by substitution of Phe for the
Tyr(502) residue adjacent to Pro(505) or by treatment of cells with the tyrosine
kinase inhibitor genistein. Ablation of the Leu(489)Leu(490)-based motif prevents
the targeting of GLUT4delta5 to GLUT4-positive-vesicles and late endosomes as
well as the retention of GLUT4delta5Phe(502 )by the GSC. These results are
consisting with a model of GLUT4 transport in which the targeting of the protein
from the TGN to the GSC is mediated by the Leu(489)Leu(490)-based motif and its
release from the GSC involves Tyr(502 )and the adjacent carboxyl-terminal
Pro(505)AspGluAsnAsp(509) sequence.
PMID- 10769203
TI - Adhesion-dependent tyrosine phosphorylation of (beta)-dystroglycan regulates its
interaction with utrophin.
AB - Many cell adhesion-dependent processes are regulated by tyrosine phosphorylation.
In order to investigate the role of tyrosine phosphorylation of the utrophin
dystroglycan complex we treated suspended or adherent cultures of HeLa cells with
peroxyvanadate and immunoprecipitated (beta)-dystroglycan and utrophin from cell
extracts. Western blotting of (&bgr;)-dystroglycan and utrophin revealed adhesion
and peroxyvanadate-dependent mobility shifts which were recognised by anti
phospho-tyrosine antibodies. Using maltose binding protein fusion constructs to
the carboxy-terminal domains of utrophin we were able to demonstrate specific
interactions between the WW, EF and ZZ domains of utrophin and (beta)
dystroglycan by co-immunoprecipitation with endogenous (beta)-dystroglycan. In
extracts from cells treated with peroxyvanadate, where endogenous (beta)
dystroglycan was tyrosine phosphorylated, (beta)-dystroglycan was no longer co
immunoprecipitated with utrophin fusion constructs. Peptide 'SPOTs' assays
confirmed that tyrosine phosphorylation of (beta)-dystroglycan regulated the
binding of utrophin. The phosphorylated tyrosine was identified as Y(892) in the
(beta)-dystroglycan WW domain binding motif PPxY thus demonstrating the
physiological regulation of the (beta)-dystroglycan/utrophin interaction by
adhesion-dependent tyrosine phosphorylation.
PMID- 10769204
TI - The G(2) DNA damage checkpoint targets both Wee1 and Cdc25.
AB - The onset of mitosis is controlled by the cyclin dependent kinase Cdc2p. Cdc2p
activity is controlled through the balance of phosphorylation and
dephosphorylation of tyrosine-15 (Y15) by the Wee1p kinase and Cdc25p
phosphatase. In the fission yeast Schizosaccharomyces pombe, detection of DNA
damage in G(2) activates a checkpoint that prevents entry into mitosis through
the maintenance of Y15 phosphorylation of Cdc2p, thus ensuring DNA repair
precedes chromosome segregation. The protein kinase Chk1p is the endpoint of this
checkpoint pathway. We have previously reported that overexpression of Chk1p
causes a wee1(+)-dependent G(2) arrest, and this or irradiation leads to
hyperphosphorylation of Wee1p. Moreover, Chk1p directly phosphorylates Wee1p in
vitro. These data suggested that Wee1p is a key target of Chk1p action in
checkpoint control. However, cells lacking wee1(+) are checkpoint proficient and
sustained Chk1p overexpression arrests cell cycle progression independently of
Wee1p. Therefore, up-regulation of Wee1p alone cannot enforce a checkpoint
arrest. Chk1p can also phosphorylate Cdc25p in vitro. These phosphorylation
events are thought to promote the interaction with 14-3-3 proteins the
cytoplasmic retention of the 14-3-3/Cdc25p complexes. However, we show here that
the G(2) DNA damage checkpoint is intact in cells that regulate mitotic entry
independently of Cdc25p. Further, these cells are still sensitive to Chk1p
mediated arrest, and so down-regulation of Cdc25p is also insufficient to
regulate checkpoint arrest. Conversely, inactivation of both wee1(+) and cdc25(+
)abolishes checkpoint control. We also show that activation of the G(2) DNA
damage checkpoint induces a transient increase in Wee1p levels. We conclude that
the G(2) DNA damage checkpoint simultaneously signals via both up-regulation of
Wee1p and down-regulation of Cdc25p, thus providing a double-lock mechanism to
ensure cell cycle arrest and genomic stability.
PMID- 10769205
TI - The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for
desmoglein 2.
AB - beta-catenin and plakoglobin are members of the armadillo family of proteins and
were first identified as components of intercellular adhering junctions. In the
adherens junction beta-catenin and plakoglobin serve to link classical cadherins
to the actin-based cytoskeleton. In the desmosome plakoglobin links the
desmosomal cadherins, the desmogleins and the desmocollins, to the intermediate
filament cytoskeleton. beta-catenin is not a component of the desmosome.
Previously we have shown that the central armadillo repeat region of plakoglobin
is the site for desmosomal cadherin binding. We hypothesized that the unique
amino- and/or carboxyl-terminal ends of beta-catenin may regulate its exclusion
from the desmosomal plaque. To test this hypothesis we used chimeras between beta
catenin and plakoglobin to identify domain(s) that modulate association with
desmoglein 2. Chimeric constructs, each capable of associating with classical
cadherins, were assayed for association with the desmosomal cadherin desmoglein
2. Addition of either the N- or C-terminal tail of beta-catenin to the armadillo
repeats of plakoglobin did not interfere with desmoglein 2 association. However,
when both beta-catenin amino terminus and carboxyl terminus were added to the
plakoglobin armadillo repeats, association with desmoglein 2 was diminished.
Removal of the first 26 amino acids from this construct restored association. We
show evidence for direct protein-protein interactions between the amino- and
carboxyl-terminal tails of beta-catenin and propose that a sequence in the first
26 amino acids of beta-catenin along with its carboxyl-terminal tail decrease its
affinity for desmoglein and prevent its inclusion in the desmosome.
PMID- 10769206
TI - Dictyostelium DdCP224 is a microtubule-associated protein and a permanent
centrosomal resident involved in centrosome duplication.
AB - A cDNA encoding a 224-kDa Dictyostelium discoideum centrosomal protein (DdCP224)
was isolated by immunoscreening. DdCP224 was detected at the centrosome and, more
weakly, along microtubules throughout the entire cell cycle. Centrosomal
localization does not require microtubules, suggesting that DdCP224 is a genuine
centrosomal component. DdCP224 exhibits sequence identity to a weakly conserved
class of microtubule-associated proteins including human TOGp and yeast Stu2p.
Stu2p has a size of only approximately 100 kDa and corresponds to the N-terminal
half of DdCP224. The functions of the N- and C-terminal halves of DdCP224 were
investigated in the corresponding GFP-fusion mutants. Surprisingly, the N
terminal construct showed only cytosolic localization, whereas the C-terminal
construct localized exclusively to the centrosome. This is unexpected because
Stu2p is localized at the spindle pole body. Full-length DdCP224-GFP was present
both at centrosomes and along microtubules. Furthermore, it bound to microtubules
in vitro, unlike the two truncated mutants. Thus centrosome binding is determined
by the C-terminal half and microtubule binding may require the interaction of the
N- and C-terminal halves. Interestingly, cells expressing full-length DdCP224-GFP
exhibit supernumerary centrosomes and show a cytokinesis defect, suggesting that
DdCP224 plays an important role in centrosome duplication. These features are
unique among the known centrosomal proteins.
PMID- 10769208
TI - Tight junctions are membrane microdomains.
AB - Tight junctions (TJ) of polarized epithelial cells regulate barrier function at
mucosal surfaces. Structural proteins of TJs include hyperphosphorylated occludin
(HO) and the peripheral membrane protein, ZO-1. Since TJs are dynamically
regulated, and lipid-modified signal transduction proteins localize to TJs, we
considered the possibility that the TJ itself is composed of microdomains with
unique structure. Differential detergent extraction and isopycnic sucrose density
gradients were utilized to isolate TJ-enriched membranes from a polarized
intestinal epithelial cell line, T84. Here we report that major pools of
hyperphosphorylated occludin (HO) and ZO-1 are found in raft-like membrane
microdomains with characteristics of the previously described detergent-insoluble
glycolipid rafts (DIGs). Properties of such gradient fractions included Triton X
100 (TX-100) insolubility, light scattering at 600 nm, buoyant density of
approximately 1.08 g/cm(3) and increased cholesterol content compared to high
density fractions. Similar results were obtained using natural epithelium. Unlike
the TJ proteins HO and ZO-1, other basolateral transmembrane proteins including E
cadherin, c-met and &bgr; 1 integrin were not increased in DIG-like fractions.
Immunoprecipitation studies revealed coprecipitation of a pool of occludin with
caveolin-1, a scaffolding protein abundant in DIGs. Coprecipitation results were
supported by immunofluorescence and immunogold labeling studies demonstrating
caveolin-1 localization in the apical membrane and focal colocalization with
occludin in TJs. TJ disassembly by calcium chelation resulted in displacement of
TJ proteins from the 'raft-like' compartment. Our findings suggest that raft-like
compartments play an important role in the spatial organization of TJs and
probably in regulation of paracellular permeability in epithelial cells.
PMID- 10769207
TI - A beta-catenin/engrailed chimera selectively suppresses Wnt signaling.
AB - beta-catenin plays an integral role in cell-cell adhesion by linking the cadherin
complex of the adherens junction to the underlying actin cytoskeleton. In
addition, beta-catenin transduces intracellular signals within the Wnt
developmental pathway that are crucial to the proper establishment of embryonic
axes and pattern formation of early mesoderm and ectoderm. For example, in the
context of a defined dorsal 'organizer' region of early Xenopus embryos, beta
catenin enters the nucleus and associates with transcription factors of the HMG
(High Mobility Group) Lef/Tcf protein family. Consequently, genes such as
siamois, a homeobox gene contributing to the specification of the dorsoanterior
axis, are activated. To further examine the role that beta-catenin plays in Wnt
signaling, we generated a chimeric protein, beta-Engrailed (beta-Eng), in which
the C-terminal trans-activation domain of beta-catenin is replaced with the
transcriptional repression domain of Drosophila Engrailed. Dorsal overexpression
of this mRNA in early Xenopus embryos leads to suppression of organizer-specific
molecular markers such as siamois, Xnr-3 and goosecoid, corresponding with the
dramatic morphological ventralization of embryos. Ventralized embryos further
exhibit reduced activity of the Wnt pathway, as indicated by the loss of the
notochord/organizer marker, chordin. Importantly, beta-Eng associates and
functions normally with the known components of the cadherin complex, providing
the experimental opportunity to repress beta-catenin's signaling function apart
from its role in cadherin-mediated cell-cell adhesion.
PMID- 10769210
TI - Expression of Eph receptors and ephrins is differentially regulated by E
cadherin.
AB - E-cadherin is the main cell adhesion molecule of early embryonic and adult
epithelial cells. Downregulation of E-cadherin is associated with epithelial
mesenchymal transition during embryonic mesoderm formation and tumor progression.
To identify genes whose expression is affected by the loss of E-cadherin, we
compared mRNA expression patterns between wild-type and E-cadherin null mutant
embryonic stem (ES) cells. We found that expression of several Eph receptors and
ephrins is dependent on E-cadherin. Rescue of E-cadherin null ES cells with E
cadherin cDNA restores the wild-type expression pattern of Eph family members.
Rescue of E-cadherin null ES cells with N-cadherin cDNA does not restore the wild
type expression pattern, indicating that the regulation of differential
expression of Eph family members is specific to E-cadherin. Constitutive ectopic
expression of E-cadherin in non-epithelial NIH3T3 cells results in the production
of the EphA2 receptor. In epithelial cells, E-cadherin is required for EphA2
receptor localization at cell-cell contacts; in the absence of functional E
cadherin, EphA2 localizes to the perinuclear region. Our results indicate that E
cadherin may be directly or indirectly required for the membrane localization of
Eph receptors and their membrane-bound ligands.
PMID- 10769209
TI - Disassembly of membrane-associated NSF 20S complexes is slow relative to vesicle
fusion and is Ca(2+)-independent.
AB - N-ethylmaleimide-sensitive fusion protein (NSF) and its co-factor soluble NSF
attachment protein (alpha)-SNAP) are essential components of the synaptic vesicle
fusion machinery and form part of a structurally-conserved 20S protein complex.
However, their precise function, relative to fusion itself, is not clear. Using a
UV-activated cross-linking approach, we have measured the rate at which a single
round of NSF-driven ATP hydrolysis leads to 20S complex disassembly within
synaptic membranes. Although this rate is substantially faster than previous
estimates of NSF-dependent ATP hydrolysis, it remains much lower than published
rates for fusion of synaptic vesicles. Furthermore, the stability of 20S
complexes is unaffected by Ca(2+) at concentrations that elicit rapid membrane
fusion. We conclude that the ATPase activity of NSF does not contribute directly
to vesicle fusion, but more likely plays an earlier role in the synaptic vesicle
cycle.
PMID- 10769211
TI - Different effects of dominant negative mutants of desmocollin and desmoglein on
the cell-cell adhesion of keratinocytes.
AB - Desmosomes contain two types of cadherin: desmocollin (Dsc) and desmoglein (Dsg).
In this study, we examined the different roles that Dsc and Dsg play in the
formation of desmosomes, by using dominant-negative mutants. We constructed
recombinant adenoviruses (Ad) containing truncated mutants of E-cadherin,
desmocollin 3a, and desmoglein 3 lacking a large part of their extracellular
domains (EcaddeltaEC, Dsc3adeltaEC, Dsg3deltaEC), using the Cre-loxP Ad system to
circumvent the problem of the toxicity of the mutants to virus-producing cells.
When Dsc3adeltaEC Ad-infected HaCaT cells were cultured with high levels of
calcium, E-cadherin and beta-catenin, which are marker molecules for the adherens
junction, disappeared from the cell-cell contact sites, and cell-cell adhesion
was disrupted. This also occurred in the cells infected with EcaddeltaEC Ad. With
Dsg3deltaEC Ad infection, keratin insertion at the cell-cell contact sites was
inhibited and desmoplakin, a marker of desmosomes, was stained in perinuclear
dots while the adherens junctions remained intact. Dsc3adeltaEC Ad inhibited the
induction of adherens junctions and the subsequent formation of desmosomes with
the calcium shift, while Dsg3deltaEC Ad only inhibited the formation of
desmosomes. To further determine whether Dsc3adeltaEC directly affected adherens
junctions, mouse fibroblast L cells transfected with E-cadherin (LEC5) were
infected with these mutant Ads. Both Dsc3adeltaEC and EcaddeltaEC inhibited the
cell-cell adhesion of LEC5 cells, as determined by the cell aggregation assay,
while Dsg3deltaEC did not. These results indicate that the dominant negative
effects of Dsg3deltaEC were restricted to desmosomes, while those of Dsc3adeltaEC
were observed in both desmosomes and adherens junctions. Furthermore, the
cytoplasmic domain of Dsc3adeltaEC coprecipitated both plakoglobin and beta
catenin in HaCaT cells. In addition, beta-catenin was found to bind the
endogenous Dsc in HaCaT cells. These findings lead us to speculate that Dsc
interacts with components of the adherens junctions through beta-catenin, and
plays a role in nucleating desmosomes after the adherens junctions have been
established.
PMID- 10769212
TI - Molecular mechanism of myosin-II assembly at the division site in
Schizosaccharomyces pombe.
AB - Schizosaccharomyces pombe cells divide by virtue of the F-actin-based contractile
ring (F-actin ring). Two myosin-II heavy chains, Myo2 and Myp2/Myo3, have been
localized to the F-actin ring. Here, we investigated the mechanism of myosin-II
assembly at the division site in S. pombe cells. First, we showed that Cdc4, an
EF-hand protein, appears to be a common myosin light chain associated with both
Myo2 and Myo3. Loss of function of both Myo2 and Myo3 caused a defect in F-actin
assembly at the division site, like the phenotype of cdc4 null cells. It is
suggested that Myo2, Myo3 and Cdc4 function in a cooperative manner in the
formation of the F-actin ring during mitosis. Next, we investigated the dynamics
of myosin-II during mitosis in S. pombe cells. In early mitosis when accumulation
of F-actin cables in the medial region was not yet observed, Myo2 was detected
primarily as dots widely located in the medial cortex. Myo2 fibers also became
visible following the appearance of the dots. The Myo2 dots and fibers then fused
with each other to form a medial cortical network. Some Myo2 dots appeared to be
localized with F-actin cables which are also accumulated in the medial region.
Finally these structures were packed into a thin contractile ring. In mutant
cells that cannot form the F-actin ring such as cdc3(ts), cdc8(ts) and cdc12(ts),
Myo2 was able to accumulate as dots in the medial cortex, whereas no accumulation
of Myo2 dots was detected in cdc4(ts) cells. Moreover, disruption of F-actin in
the cell by applying latrunculin-A did not affect the accumulation of Myo2 dots,
suggesting that F-actin is not required for their accumulation. A truncated Myo2
which lacks putative Cdc4-binding sites (Myo2dIQs) was able to rescue myo2 null
cells, myo3 null cells, cdc4(ts) mutant cells and cdc4 null cells. The Myo2dIQs
could assemble into a normal-shaped ring in these cells. Therefore, its assembly
at the division site does not require the function of either Cdc4 or Myo3.
PMID- 10769213
TI - Requirement for C-terminal end of fibroblast growth factor receptor 4 in
translocation of acidic fibroblast growth factor to cytosol and nucleus.
AB - The ability of COS cells to bind and internalise acidic fibroblast growth factor
(aFGF) was studied after transient transfection of the cells with wild-type and
mutated fibroblast growth factor receptor 4. In one case the tyrosine kinase of
the receptor was inactivated by a point mutation in the active site, whereas in
other cases parts of the receptor were deleted to remove various parts of the
cytoplasmic domain. In all cases the receptors were expressed at the cell surface
at a high level and the cells bound labelled growth factor efficiently and
internalised it by endocytosis. Translocation of externally added aFGF across
cellular membranes to reach the cytosol and nucleus was measured as transport of
labelled growth factor to the nuclear fraction obtained by centrifugation, by
farnesylation of growth factor modified to carry a CAAX motif, and by
phosphorylation of the growth factor at a site specific for protein kinase C.
Whereas both full-length receptors (with and without an active kinase domain)
facilitated translocation of the growth factor to the cytosol and nucleus, as
assessed by these methods, the mutants of the receptor where the C terminus was
deleted, were unable to do so. In contrast, a receptor containing only the 57
most C-terminal amino acids of the cytoplasmic domain in addition to the
juxtamembrane, transmembrane and extracellular domains, was in fact able to
mediate translocation of aFGF to the cytosol. These data indicate that
information contained in the C terminus of the receptor is required for
translocation.
PMID- 10769214
TI - Surface oxidase and oxidative stress propagation in aging.
AB - This report summarizes new evidence for a plasma-membrane-associated hydroquinone
oxidase designated as CNOX (constitutive plasma membrane NADH oxidase) that
functions as a terminal oxidase for a plasma membrane oxidoreductase (PMOR)
electron transport chain to link the accumulation of lesions in mitochondrial DNA
to cell-surface accumulations of reactive oxygen species. Previous considerations
of plasma membrane redox changes during aging have lacked evidence for a specific
terminal oxidase to catalyze a flow of electrons from cytosolic NADH to molecular
oxygen (or to protein disulfides). Cells with functionally deficient mitochondria
become characterized by an anaerobic metabolism. As a result, NADH accumulates
from the glycolytic production of ATP. Elevated PMOR activity has been shown to
be necessary to maintain the NAD(+)/NADH homeostasis essential for survival. Our
findings demonstrate that the hyperactivity of the PMOR system results in an NADH
oxidase (NOX) activity capable of generating reactive oxygen species at the cell
surface. This would serve to propagate the aging cascade both to adjacent cells
and to circulating blood components. The generation of superoxide by NOX forms
associated with aging is inhibited by coenzyme Q and provides a rational basis
for the anti-aging activity of circulating coenzyme Q.
PMID- 10769215
TI - Transport properties of cultured branchial epithelia from freshwater rainbow
trout: a novel preparation with mitochondria-rich cells.
AB - A new double-seeded insert (DSI) technique is described for culture of branchial
epithelial preparations from freshwater rainbow trout on filter supports. DSI
epithelia contain both pavement cells and mitochondria-rich (MR) cells (15.7+/
2.5 % of total cell numbers). MR cells occur singly or in clusters, are
voluminous, open apically to the 'external environment' and exhibit
ultrastructural characteristics similar to those found in the 'chloride cells' of
freshwater fish gills. After 6-9 days in culture with Leibovitz's L-15 medium on
both surfaces (symmetrical conditions), transepithelial resistance (TER)
stabilized at values as high as 34 k capomega cm(2), indicative of electrically
'tight' epithelia. The density of MR cells, the surface area of their clusters
and transepithelial potential (TEP; up to +8 mV basolateral positive, mean +1.9+/
0.2 mV) were all positively correlated with TER. In contrast, preparations
cultured using an earlier single-seeded insert (SSI) technique contained only
pavement cells and exhibited a negligible TEP under symmetrical conditions.
Na(+)/K(+)-ATPase activities of DSI preparations were comparable with those in
gill filaments, but did not differ from those of SSI epithelia. Replacement of
the apical medium with fresh water to mimic the in vivo situation (asymmetrical
conditions) induced a negative TEP (-6 to -15 mV) and increased permeability to
the paracellular marker PEG-4000. Under symmetrical conditions, unidirectional
Na(+) and Cl(-) fluxes were in balance, and there was no active transport by the
Ussing flux ratio criterion. Under asymmetrical conditions, there were large
effluxes, small influxes and evidence for active Cl(-) uptake and Na(+)
extrusion. Unidirectional Ca(2+) fluxes were only 0.5-1.0 % of Na(+) and Cl(-)
fluxes; active net Ca(2+) uptake occurred under symmetrical conditions and active
net extrusion under asymmetrical conditions. Thus, DSI epithelia exhibit some of
the features of the intact gill, but improvements in culture conditions are
needed before the MR cells will function as true freshwater 'chloride cells'.
PMID- 10769216
TI - Dynamic mechanical characterization of a mutable collagenous tissue: response of
sea cucumber dermis to cell lysis and dermal extracts.
AB - The dermis of the holothurian Cucumaria frondosa is a mutable collagenous tissue
(MCT). In this study, the inner and outer regions of the dermis were separated
and used to make two different tissue extracts. These extracts were applied to
intact pieces of dermis, one invoking a stiff mechanical state and the other
invoking a compliant state. The extracts were effective on tissues incubated in
artificial sea water (ASW) and in those incubated in Ca(2+)-chelated ASW.
Furthermore, the extracts were effective on both fresh tissues and tissues in
which the cells had been lysed by freeze-thawing, indicating that the sites of
action are in the extracellular matrix. Dynamic oscillatory shear tests and
analyses were used to measure both the dynamic shear stiffness (G*) and the
relative damping (tan delta ) of the tissue. These two parameters proved to be
inversely related to each other (i.e. when G* increased, tan delta decreased). A
theoretical viscoelastic model is constructed to interpret the results of these
tests. It is concluded that changes in the mechanical state of the tissue involve
interactions between elastic elements within the tissue rather than an alteration
of its viscous components.
PMID- 10769217
TI - Hagfish (Myxine glutinosa) red cell membrane exhibits no bicarbonate permeability
as detected by (18)O exchange.
AB - The bicarbonate permeability of the plasma membrane of intact hagfish (Myxine
glutinosa) red blood cells and the intracellular carbonic anhydrase activity of
these cells were determined by applying the (18)O exchange reaction using a
special mass spectrometric technique. When the macromolecular carbonic anhydrase
inhibitor Prontosil-Dextran was used to suppress any extracellular carbonic
anhydrase activity, the mean intracellular acceleration of the CO(2)
hydration/HCO(3)(-) dehydration reaction over the uncatalyzed reaction (referred
to as intracellular carbonic anhydrase activity A(i)) was 21 320+/-3000 at 10
degrees C (mean +/- s.d., N=9). The mean bicarbonate permeability of the red
blood cell membrane (P(HCO3)-) was indistinguishable from zero. It can be
concluded that CO(2) transport within hagfish blood does not follow the classical
scheme of CO(2) transport in vertebrate blood. It is suggested that the
combination of considerable intraerythrocytic carbonic anhydrase activity and low
P(HCO3)- may serve to enhance O(2) delivery to the tissue in the exceptionally
hypoxia-tolerant hagfish.
PMID- 10769218
TI - The energetic cost of short flights in birds.
AB - Many small birds perform short flights, for which take-offs, ascents and descents
form a large component of the total flight time and which are characterised by
low airspeeds. Using the doubly-labelled water technique, zebra finches
Taeniopygia guttata engaging in repeated short flights were found to expend 13.65
kJ more than 'non-flying' controls, which equated to a flight expenditure of 27.8
times their basal metabolic rate. This is over three times the predicted flight
expenditure derived from existing aerodynamic models. These data were used to
determine a coefficient (0.11) for converting the mechanical power derived from
aerodynamic models into metabolic power. An equation is presented, based on body
mass, which can be used to predict the costs of short flights in ecological and
behavioural studies of birds.
PMID- 10769219
TI - Behaviour-locked signal analysis reveals weak 200-300 Hz comb vibrations during
the honeybee waggle dance.
AB - Waggle-dancing honeybees produce vibratory movements that may facilitate
communication by indicating the location of the waggle dancer. However, an
important component of these vibrations has never been previously detected in the
comb. We developed a method of fine-scale behavioural analysis that allowed us to
analyze separately comb vibrations near a honeybee waggle dancer during the
waggle and return phases of her dance. We simultaneously recorded honeybee waggle
dances using digital video and laser-Doppler vibrometry, and performed a
behaviour-locked Fast Fourier Transform analysis on the substratum vibrations.
This analysis revealed significantly higher-amplitude 200-300 Hz vibrations
during the waggle phase than during the return phase (P=0.012). We found no
significant differences in the flanking frequency regions between 100-200 Hz
(P=0.227) and 300-400 Hz (P=0.065). We recorded peak waggle phase vibrations from
206 to 292 Hz (244+/-28 Hz; mean +/- s. d., N=11). The maximum measured signal -
noise level was +12.4 dB during the waggle phase (mean +5.8+/-2.7 dB). The
maximum vibrational velocity, calculated from a filtered signal, was 128 microm
s(-)(1) peak-to-peak, corresponding to a displacement of 0.09 microm peak-to-peak
at 223 Hz. On average, we measured a vibrational velocity of 79+/-28 microm s(
)(1) peak-to-peak from filtered signals. These signal amplitudes overlap with the
detection threshold of the honeybee subgenual organ.
PMID- 10769220
TI - Comb-wax discrimination by honeybees tested with the proboscis extension reflex.
AB - We used the proboscis extension reflex of honeybees to test their ability to
discriminate between comb waxes of different ages (wax scales, 1-week-old wax, 2-
to 3-year-old wax, 8- to 10-year-old wax). Such waxes differ in their chemical
composition, and an ability to discriminate between them may aid the orientation
of the bees in the nest. To train the bees, we used whole extracts of waxes and
four different fractions of the whole extract based on different elutions of
solid-phase extractions (extract I, fraction A eluted with hexane and fraction B
with diethylether; extract II, fraction B further subdivided into fraction C by
elution with isopropylchloride and fraction D by elution with diethylether). In a
differential training regime (six learning and six test trials) with whole
extracts or with the different fractions, we paired one type of wax with a reward
and another with no reward. The bees learned to discriminate between all tested
pairs of whole extracts. The two subfractions (fractions A and B) gave different
results: the bees could discriminate between waxes of different ages when
fraction B was used but not when fraction A was used. A further subdivision of
fraction B into fractions C and D showed that only fraction D contained the
elements that enabled bees to discriminate between old and new wax. Fraction D
makes up only 5?8 % of the total wax mass and contains hydroxy alkyl esters (5?6
% of the total wax mass), primary alcohols (0.3?0.5 % of the total wax mass) and
acids (0.06?1. 0 % of the total wax mass). Fractions A and C (together forming
62?64 % of the total wax mass), which consist of unbranched and branched
aliphatic hydrocarbons and alkyl esters, could not be discriminated by the bees.
The remaining wax mass (25?29 %) was eluted with a mixture of chloroform,
methanol and water (13:5:1) as fraction E.
PMID- 10769222
TI - A tubular network associated with the brush-border surface of the Aedes aegypti
midgut: implications for pathogen transmission by mosquitoes.
AB - The mosquito Aedes aegypti is capable of transmitting a variety of pathogens to
man and to other vertebrates. The midgut of this insect has been well-studied
both as the tissue where the first contact occurs between ingested pathogens and
the insect host, and as a model system for blood meal digestion in blood-sucking
insects. To understand better the nature of the midgut surface encountered by
parasites or viruses, we used scanning electron microscopy to identify the most
prominent structures and cell morphologies on the luminal midgut surface. The
luminal side of the midgut is a complex and layered set of structures. The
microvilli that are found on most, but not all, cells are covered by a network of
fine strands that we have termed the microvilli-associated network (MN). The MN
strands are membranous, as shown by a membrane bilayer visible in cross sections
of MN strands at high magnification in transmission electron micrographs. The MN
is found in blood-fed as well as unfed mosquitoes and is not affected by
chitinase treatment, suggesting that it is not related to the chitinous
peritrophic membrane that is formed only after blood feeding. The cells in the
midgut epithelium have two distinct morphologies: the predominant cell type is
densely covered with microvilli, while cells with fewer microvilli are found
interspersed throughout the midgut. We used lectins to probe for the presence of
carbohydrates on the midgut surface. A large number of lectins bind to the
luminal midgut surface, suggesting that a variety of sugar linkages are present
on the structures visualized by electron microscopy. Some of these lectins
partially block attachment of malaria ookinetes to the midgut surface in vitro.
Thus, the mosquito midgut epithelium, like the lining of mammalian intestines, is
complex, composed of a variety of cell types and extensively covered with surface
carbohydrate that may play a role in pathogen attachment.
PMID- 10769221
TI - Desensitisation of chromaffin cell nicotinic receptors does not impede
catecholamine secretion during acute hypoxia in rainbow trout (Oncorhynchus
mykiss).
AB - Experiments were performed on adult rainbow trout (Oncorhynchus mykiss) in vivo
using chronically cannulated fish and in situ using a perfused posterior cardinal
vein preparation (i) to characterise the desensitisation of chromaffin cell
nicotinic receptors and (ii) to assess the ability of fish to secrete
catecholamines during acute hypoxia with or without functional nicotinic
receptors. Intra-arterial injection of nicotine (6.0x10(-)(7 )mol kg(-)(1))
caused a rapid increase in plasma adrenaline and noradrenaline levels; the
magnitude of this response was unaffected by an injection of nicotine given 60
min earlier. Evidence for nicotinic receptor desensitisation, however, was
provided during continuous intravenous infusion of nicotine (1.3x10(-)(5 )mol kg(
)(1 )h(-)(1)) in which plasma catecholamine levels increased initially but then
returned to baseline levels. To ensure that the decline in circulating
catecholamine concentrations during continuous nicotine infusion was not related
to changes in storage levels or altered rates of degradation/clearance, in situ
posterior cardinal vein preparations were derived from fish previously
experiencing 60 min of saline or nicotine infusion. Confirmation of nicotinic
receptor desensitisation was provided by demonstrating that the preparations
derived from nicotine-infused fish were unresponsive to nicotine (10(-)(5 )mol l(
)(1)), yet remained responsive to angiotensin II (500 pmol kg(-)(1)). The in situ
experiments demonstrated that desensitisation of the nicotinic receptor occurred
within 5 min of receptor stimulation and that resensitisation was established 40
min later. The ability to elevate plasma catecholamine levels during acute
hypoxia (40-45 mmHg; 5.3-6.0 kPa) was not impaired in fish experiencing nicotinic
receptor desensitisation. Indeed, peak plasma adrenaline levels were
significantly higher in the desensitised fish during hypoxia than in controls
(263+/-86 versus 69+/-26 nmol l(-)(1); means +/- s.e.m., N=6-9). Thus, the
results of the present study demonstrate that activation of preganglionic
sympathetic cholinergic nerve fibres and the resultant stimulation of nicotinic
receptors is not the sole mechanism for eliciting catecholamine secretion during
hypoxia.
PMID- 10769223
TI - The scaling of carbon dioxide release and respiratory water loss in flying fruit
flies (Drosophila spp.).
AB - By simultaneously measuring carbon dioxide release, water loss and flight force
in several species of fruit flies in the genus Drosophila, we have investigated
respiration and respiratory transpiration during elevated locomotor activity. We
presented tethered flying flies with moving visual stimuli in a virtual flight
arena, which induced them to vary both flight force and energetic output. In
response to the visual motion, the flies altered their energetic output as
measured by changes in carbon dioxide release and concomitant changes in
respiratory water loss. We examined the effect of absolute body size on
respiration and transpiration by studying four different-sized species of fruit
flies. In resting flies, body-mass-specific CO(2) release and water loss tend to
decrease more rapidly with size than predicted according to simple allometric
relationships. During flight, the mass-specific metabolic rate decreases with
increasing body size with an allometric exponent of -0.22, which is slightly
lower than the scaling exponents found in other flying insects. In contrast, the
mass-specific rate of water loss appears to be proportionately greater in small
animals than can be explained by a simple allometric model for spiracular
transpiration. Because fractional water content does not change significantly
with increasing body size, the smallest species face not only larger mass
specific energetic expenditures during flight but also a higher risk of
desiccation than their larger relatives. Fruit flies lower their desiccation risk
by replenishing up to 75 % of the lost bulk water by metabolic water production,
which significantly lowers the risk of desiccation for animals flying under xeric
environmental conditions.
PMID- 10769224
TI - The emetic reflex in a reptile (Crocodylus porosus).
AB - The emetic (vomiting) reflex in a crocodilian, Crocodylus porosus, was
characterised for the first time using the plant alkaloid veratrine (5 mg kg(
)(1) i.v. or i.p.) as an emetic stimulus. The latency to the onset of vomiting
was 8.0+/-0.9 min (mean +/- s.e.m., N=5 animals). Vomiting was preceded by a
clearly defined set of prodromal behaviours including, in temporal sequence,
rhythmic contraction of the pharynx, sneezing and jaw snapping. Expulsion of
vomitus was not particularly forceful and was accompanied by lateral shaking of
the head. Physiological studies revealed that vomiting was accompanied by
oscillatory (9.1+/-0.7 oscillations over 29.7+/-3. 6 s, N=9 episodes in three
animals) increases in intraperitoneal pressure (7.0+/-0.9 kPa, cf. 0.7+/-0.1 kPa
during respiration). The significance of these results is discussed in the
context of the role(s) of vomiting as a protective reflex and as a mechanism for
removal of indigestible food residues (e.g. fur, claws) from the gut.
PMID- 10769225
TI - Axon pathfinding proceeds normally despite disrupted growth cone decisions at CNS
midline.
AB - Axons in the bilateral brain of Drosophila decide whether or not to cross the
midline before following their specific subsequent pathways. In commissureless
mutants, the RP3 and V motoneuron axons often fail to cross the midline but
subsequently follow the mirror-image pathways and innervate corresponding muscle
targets on the ipsilateral side. Conversely, in roundabout mutants, the RP2 and
aCC motoneuron axons sometimes cross the midline abnormally but their subsequent
pathways and synaptic targeting are the perfect mirror images of those seen in
wild type. Furthermore, within a single segment of these mutants, bilateral pairs
of motoneuron axons can make their midline decisions independently of each other.
Thus, neither the growth cones' particular molecular experience nor the decision
at the midline caused by these mutations affects their ability to respond
normally to subsequently presented cues.
PMID- 10769226
TI - Induction of inner ear fate by FGF3.
AB - Loss-of-function experiments in avians and mammals have provided conflicting
results on the capacity of fibroblast growth factor 3 (FGF3) to act as a secreted
growth factor responsible for induction and morphogenesis of the vertebrate inner
ear. Using a novel technique for gene transfer into chicken embryos, we have
readdressed the role of FGF3 during inner ear development in avians. We find that
ectopic expression of FGF3 results in the formation of ectopic placodes which
express otic marker genes. The ectopically induced placodes form vesicles which
show the characteristic gene expression pattern of a developing inner ear.
Ectopic expression of FGF3 also influences the formation of the normal orthotopic
inner ear, whereas another member of the FGF family, FGF2, shows no effects on
inner ear induction. These results demonstrate that a single gene can induce
inner ear fate and reveal an unexpectedly widespread competence of the surface
ectoderm to form sensory placodes in higher vertebrates.
PMID- 10769227
TI - The Arabidopsis floral homeotic gene PISTILLATA is regulated by discrete cis
elements responsive to induction and maintenance signals.
AB - PISTILLATA is a B-class floral organ identity gene required for the normal
development of petals and stamens in Arabidopsis. PISTILLATA expression is
induced in the stage 3 flowers (early expression) and is maintained until
anthesis (late expression). To explore in more detail the developmentally
regulated gene expression of PISTILLATA, we have analyzed the PISTILLATA promoter
using uidA (beta)-glucuronidase gene) fusion constructs (PI::GUS) in transgenic
Arabidopsis. Promoter deletion analyses suggest that early PISTILLATA expression
is mediated by the distal region and that late expression is mediated by the
proximal region. Based on the PI::GUS expression patterns in the loss- and gain
of-function alleles of meristem or organ identity genes, we have shown that LEAFY
and UNUSUAL FLORAL ORGANS induce PISTILLATA expression in a flower-independent
manner via a distal promoter, and that PISTILLATA and APETALA3 maintain
PISTILLATA expression (autoregulation) in the later stages of flower development
via a proximal promoter. In addition, we have demonstrated that de novo protein
synthesis is required for the PISTILLATA autoregulatory circuit.
PMID- 10769228
TI - FOG acts as a repressor of red blood cell development in Xenopus.
AB - Members of the GATA family of zinc-finger transcription factors have critical
roles in a variety of cell types. GATA-1, GATA-2 and GATA-3 are required for
proliferation and differentiation of several hematopoietic lineages, whereas GATA
4, GATA-5 and GATA-6 activate cardiac and endoderm gene expression programs. Two
GATA cofactors have recently been identified. Friend of GATA-1 (FOG-1) interacts
with GATA-1 and is expressed principally in hematopoietic lineages, whereas FOG-2
is expressed predominantly in heart and brain. Although gene targeting
experiments are consistent with an essential role for FOG-1 as an activator of
GATA-1 function, reporter assays in transfected cells indicate that FOG-1 and FOG
2 can act as repressors. We have cloned a Xenopus laevis homologue of FOG that is
structurally most similar to FOG-1, but is expressed predominantly in heart and
brain, as well as the ventral blood island and adult spleen. Ectopic expression
and explant assays demonstrate that FOG proteins can act as repressors in vivo,
in part through interaction with the transcriptional co-repressor, C-terminal
Binding Protein (CtBP). FOG may regulate the differentiation of red blood cells
by modulating expression and activity of GATA-1 and GATA-2. We propose that the
FOG proteins participate in the switch from progenitor proliferation to red blood
cell maturation and differentiation.
PMID- 10769229
TI - Caenorhabditis elegans twist plays an essential role in non-striated muscle
development.
AB - The basic helix-loop-helix (bHLH) transcription factor Twist plays a role in
mesodermal development in both invertebrates and vertebrates. In an effort to
understand the role of the unique Caenorhabditis elegans Twist homolog, hlh-8, we
analyzed mesodermal development in animals with a deletion in the hlh-8 locus.
This deletion was predicted to represent a null allele because the HLH domain is
missing and the reading frame for the protein is disrupted. Animals lacking
CeTwist function were constipated and egg-laying defective. Both of these defects
were rescued in transgenic mutant animals expressing wild-type hlh-8. Observing a
series of mesoderm-specific markers allowed us to characterize the loss of hlh-8
function more thoroughly. Our results demonstrate that CeTwist performs an
essential role in the proper development of a subset of mesodermal tissues in C.
elegans. We found that CeTwist was required for the formation of three out of the
four non-striated enteric muscles born in the embryo. In contrast, CeTwist was
not required for the formation of the embryonically derived striated muscles.
Most of the post-embryonic mesoderm develops from a single lineage. CeTwist was
necessary for appropriate patterning in this lineage and was required for
expression of two downstream target genes, but was not required for the
expression of myosin, a marker of differentiation. Our results suggest that
mesodermal patterning by Twist is an evolutionarily conserved function.
PMID- 10769231
TI - OOC-3, a novel putative transmembrane protein required for establishment of
cortical domains and spindle orientation in the P(1) blastomere of C. elegans
embryos.
AB - Asymmetric cell divisions require the establishment of an axis of polarity, which
is subsequently communicated to downstream events. During the asymmetric cell
division of the P(1) blastomere in C. elegans, establishment of polarity depends
on the establishment of anterior and posterior cortical domains, defined by the
localization of the PAR proteins, followed by the orientation of the mitotic
spindle along the previously established axis of polarity. To identify genes
required for these events, we have screened a collection of maternal-effect
lethal mutations on chromosome II of C. elegans. We have identified a mutation in
one gene, ooc-3, with mis-oriented division axes at the two-cell stage. Here we
describe the phenotypic and molecular characterization of ooc-3. ooc-3 is
required for the correct localization of PAR-2 and PAR-3 cortical domains after
the first cell division. OOC-3 is a novel putative transmembrane protein, which
localizes to a reticular membrane compartment, probably the endoplasmic
reticulum, that spans the whole cytoplasm and is enriched on the nuclear envelope
and cell-cell boundaries. Our results show that ooc-3 is required to form the
cortical domains essential for polarity after cell division.
PMID- 10769230
TI - The Xenopus homologue of Bicaudal-C is a localized maternal mRNA that can induce
endoderm formation.
AB - In Xenopus, zygotic transcription starts 6 hours after fertilization at the
midblastula transition and therefore the first steps in embryonic development are
regulated by maternally inherited proteins and mRNAs. While animal-vegetal
polarity is already present in the oocyte, the dorsoventral axis is only
established upon fertilization by the entry of the sperm and the subsequent
rotation of the egg cortex. In a screen for maternal mRNAs whose stability is
regulated by this cortical rotation, we isolated the Xenopus homologue of the
Drosophila gene Bicaudal-C (xBic-C). It encodes a putative RNA-binding molecule
expressed maternally and localized predominantly to the vegetal half of the egg.
Upon fertilization and cortical rotation, xBic-C mRNA is displaced together with
the heavy yolk towards the future dorsal side of the embryo. In UV-ventralized
embryos, xBic-C is polyadenylated less than in untreated embryos that undergo
cortical rotation. Overexpression of xBic-C by injection of synthetic mRNA in
whole embryos or in ectodermal explants leads to ectopic endoderm formation. This
endoderm-inducing activity is dependent on the presence of the RNA-binding domain
of the protein. In contrast to the two other known maternally encoded endoderm
inducers, Vg1 and VegT, xBic-C ectopic expression leads specifically to endoderm
formation in the absence of mesoderm induction.
PMID- 10769232
TI - Shh and Wnt signaling pathways converge to control Gli gene activation in avian
somites.
AB - The regulation of the Gli genes during somite formation has been investigated in
quail embryos. The Gli genes are a family encoding three related zinc finger
transcription factors, Gli1, Gli2 and Gli3, which are effectors of Shh signaling
in responding cells. A quail Gli3 cDNA has been cloned and its expression
compared with Gli1 and Gli2. These studies show that Gli1, Gli2 and Gli3 are co
activated at the time of somite formation, thus providing a mechanism for
regulating the initiation of Shh signaling in somites. Embryo surgery and
paraxial mesoderm explant experiments show that each of the Gli genes is
regulated by distinct signaling mechanisms. Gli1 is activated in response to Shh
produced by the notochord, which also controls the dorsalization of Gli2 and Gli3
following their activation by Wnt signaling from the surface ectoderm and neural
tube. This surface ectoderm/neural tube Wnt signaling has both negative and
positive functions in Gli2 and Gli3 regulation: these signals repress Gli3 in
segmental plate mesoderm prior to somite formation and then promote somite
formation and the somite-specific activation of Gli2 and Gli3. These studies,
therefore, establish a role for Wnt signaling in the control of Shh signal
transduction through the regulation of Gli2 and Gli3, and provide a mechanistic
basis for the known synergistic actions of surface ectoderm/neural tube and
notochord signaling in somite cell specification.
PMID- 10769233
TI - Zebrafish no isthmus reveals a role for pax2.1 in tubule differentiation and
patterning events in the pronephric primordia.
AB - Pax genes are important developmental regulators and function at multiple stages
of vertebrate kidney organogenesis. In this report, we have used the zebrafish
pax2.1 mutant no isthmus to investigate the role for pax2.1 in development of the
pronephros. We demonstrate a requirement for pax2.1 in multiple aspects of
pronephric development including tubule and duct epithelial differentiation and
cloaca morphogenesis. Morphological analysis demonstrates that noi(- )larvae
specifically lack pronephric tubules while glomerular cell differentiation is
unaffected. In addition, pax2.1 expression in the lateral cells of the pronephric
primordium is required to restrict the domains of Wilms' tumor suppressor (wt1)
and vascular endothelial growth factor (VEGF) gene expression to medial podocyte
progenitors. Ectopic podocyte-specific marker expression in pronephric duct cells
correlates with loss of expression of the pronephric tubule and duct-specific
markers mAb 3G8 and a Na(+)/K(+) ATPase (&agr;)1 subunit. The results suggest
that the failure in pronephric tubule differentiation in noi arises from a
patterning defect during differentiation of the pronephric primordium and that
mutually inhibitory regulatory interactions play an important role in defining
the boundary between glomerular and tubule progenitors in the forming nephron.
PMID- 10769234
TI - The zebrafish unplugged gene controls motor axon pathway selection.
AB - En route to their targets, motor axons encounter choice points at which they
select their future path. Experimental studies predict that at each choice point
specialized cells provide local guidance to pathfinding motor axons, however, the
identity of these cells and their signals is unknown. Here, we identify the
zebrafish unplugged gene as a key component for choice point navigation of
pioneering motor axons. We show that in unplugged mutant embryos, motor neuron
growth cones reach the choice point but make inappropriate pathway decisions.
Analysis of chimeric embryos demonstrates that unplugged activity is produced by
a selective group of mesodermal cells located adjacent to the choice point. As
the first motor growth cones approach the choice point, these mesodermal cells
migrate away, suggesting that unplugged activity influences growth cones by a
contact-independent mechanism. These data suggest that unplugged defines a somite
derived signal that elicits differential guidance decisions in motor growth
cones.
PMID- 10769235
TI - Fate and function of the ventral ectodermal ridge during mouse tail development.
AB - In the mouse embryo, the body axis continues to develop after gastrulation as a
tail forms at the posterior end of the embryo. Little is known about what
controls outgrowth and patterning of the tail, but it has been speculated that
the ventral ectodermal ridge (VER), a morphologically distinct ectoderm on the
ventral surface near the tip of the tail, is a source of signals that regulate
tail development (Gruneberg, H. (1956). Nature 177, 787-788). We tested this
hypothesis by ablating all or part of the VER and assessing the effects of such
ablations on the development of tail explants cultured in vitro. The data showed
that the VER produces signals necessary for somitogenesis in the tail and that
the cells that produce these signals are localized in the middle and posterior
region of the VER. Dye labeling experiments revealed that cells from these
regions move anteriorly within the VER and eventually exit it, thereby colonizing
the ventral surface ectoderm anterior to the VER. In situ hybridization analysis
showed that the genes encoding the signaling molecules FGF17 and BMP2 are
specifically expressed in the VER. Assays for gene expression in VER-ablated and
control tails were performed to identify targets of VER signaling. The data
showed that the VER is required for expression of the gene encoding the BMP
antagonist noggin in the tail ventral mesoderm, leading us to speculate that one
of the major functions of the VER in tail development is to regulate BMP
activity.
PMID- 10769236
TI - Regulation of proliferation and differentiation in spermatogonial stem cells: the
role of c-kit and its ligand SCF.
AB - To study self-renewal and differentiation of spermatogonial stem cells, we have
transplanted undifferentiated testicular germ cells of the GFP transgenic mice
into seminiferous tubules of mutant mice with male sterility, such as those
dysfunctioned at Steel (Sl) locus encoding the c-kit ligand or Dominant white
spotting (W) locus encoding the receptor c-kit. In the seminiferous tubules of
Sl/Sl(d) or Sl(17H)/Sl(17H) mice, transplanted donor germ cells proliferated and
formed colonies of undifferentiated c-kit (-) spermatogonia, but were unable to
differentiate further. However, these undifferentiated but proliferating
spermatogonia, retransplanted into Sl (+) seminiferous tubules of W mutant,
resumed differentiation, indicating that the transplanted donor germ cells
contained spermatogonial stem cells and that stimulation of c-kit receptor by its
ligand was necessary for maintenance of differentiated type A spermatogonia but
not for proliferation of undifferentiated type A spermatogonia. Furthermore, we
have demonstrated that their transplantation efficiency in the seminiferous
tubules of Sl(17H)/Sl(17H) mice depended upon the stem cell niche on the basement
membrane of the recipient seminiferous tubules and was increased by elimination
of the endogenous spermatogonia of mutant mice from the niche by treating them
with busulfan.
PMID- 10769237
TI - Role of dHAND in the anterior-posterior polarization of the limb bud:
implications for the Sonic hedgehog pathway.
AB - dHAND is a basic helix-loop-helix (bHLH) transcription factor essential for
cardiovascular development. Here we analyze its pattern of expression and
functional role during chick limb development. dHAND expression was observed in
the lateral plate mesoderm prior to emergence of the limb buds. Coincident with
limb initiation, expression of dHAND became restricted to the posterior half of
the limb bud. Experimental procedures that caused mirror-image duplications of
the limb resulted in mirror-image duplications of the pattern of dHAND expression
along the anterior-posterior axis. Retroviral overexpression of dHAND in the limb
bud produced preaxial polydactyly, corresponding to mild polarizing activity at
the anterior border. At the molecular level, misexpression of dHAND caused
ectopic activation of members of the Sonic hedgehog (Shh) pathway, including Gli
and Patched, in the anterior limb bud. A subset of infected embryos displayed
ectopic anterior activation of Shh. Other factors implicated in anterior
posterior polarization of the bud such as the most 5' Hoxd genes and Bmp2 were
also ectopically activated at the anterior border. Our results indicate a role
for dHAND in the establishment of anterior-posterior polarization of the limb
bud.
PMID- 10769238
TI - Processing of the Drosophila Sog protein creates a novel BMP inhibitory activity.
AB - Structurally unrelated neural inducers in vertebrate and invertebrate embryos
have been proposed to function by binding to BMP4 or Dpp, respectively, and
preventing these homologous signals from activating their receptor(s). In this
study, we investigate the functions of various forms of the Drosophila Sog
protein using the discriminating assay of Drosophila wing development. We find
that misexpression of Drosophila Sog, or its vertebrate counterpart Chordin,
generates a very limited vein-loss phenotype. This sog misexpression phenotype is
very similar to that of viable mutants of glass-bottom boat (gbb), which encodes
a BMP family member. Consistent with Sog selectively interfering with Gbb
signaling, Sog can block the effect of misexpressing Gbb, but not Dpp in the
wing. In contrast to the limited BMP inhibitory activity of Sog, we have
identified carboxy-truncated forms of Sog, referred to as Supersog, which when
misexpressed cause a broad range of dpp(-) mutant phenotypes. In line with its
phenotypic effects, Supersog can block the effects of both misexpressing Dpp and
Gbb in the wing. Vertebrate Noggin, on the other hand, acts as a general
inhibitor of Dpp signaling, which can interfere with the effect of overexpressing
Dpp, but not Gbb. We present evidence that Sog processing occurs in vivo and is
biologically relevant. Overexpression of intact Sog in embryos and adult wing
primordia leads to the developmentally regulated processing of Sog. This in vivo
processing of Sog can be duplicated in vitro by treating Sog with a combination
of the metalloprotease Tolloid (Tld) plus Twisted Gastrulation (Tsg), another
extracellular factor involved in Dpp signaling. In accord with this result,
coexpression of intact Sog and Tsg in developing wings generates a phenotype very
similar to that of Supersog. Finally, we provide evidence that tsg functions in
the embryo to generate a Supersog-like activity, since Supersog can partially
rescue tsg(-) mutants. Consistent with this finding, sog(- )and tsg(-) mutants
exhibit similar dorsal patterning defects during early gastrulation. These
results indicate that differential processing of Sog generates a novel BMP
inhibitory activity during development and, more generally, that BMP antagonists
play distinct roles in regulating the quality as well as the magnitude of BMP
signaling.
PMID- 10769239
TI - The expression of the homeobox gene Msx1 reveals two populations of dermal
progenitor cells originating from the somites.
AB - Experimental manipulation in birds has shown that trunk dermis has a double
origin: dorsally, it derives from the somite dermomyotome, while ventrally, it is
formed by the somatopleure. Taking advantage of an nlacZ reporter gene integrated
into the mouse Msx1 locus (Msx1(nlacZ) allele), we detected segmental expression
of the Msx1 gene in cells of the dorsal mesenchyme of the trunk between embryonic
days 11 and 14. Replacing somites from a chick host embryo by murine Msx1(nlacZ
)somites allowed us to demonstrate that these Msx1-(beta)-galactosidase positive
cells are of somitic origin. We propose that these cells are dermal progenitor
cells that migrate from the somites and subsequently contribute to the dorsalmost
dermis. By analysing Msx1(nlacZ) expression in a Splotch mutant, we observed that
migration of these cells does not depend on Pax3, in contrast to other migratory
populations such as limb muscle progenitor cells and neural crest cells. Msx1
expression was never detected in cells overlying the dermomyotome, although these
cells are also of somitic origin. Therefore, we propose that two somite-derived
populations of dermis progenitor cells can be distinguished. Cells expressing the
Msx1 gene would migrate from the somite and contribute to the dermis of the
dorsalmost trunk region. A second population of cells would disaggregate from the
somite and contribute to the dermis overlying the dermomyotome. This population
never expresses Msx1. Msx1 expression was investigated in the context of the
onset of dermis formation monitored by the Dermo1 gene expression. The gene is
downregulated prior to the onset of dermis differentiation, suggesting a role for
Msx1 in the control of this process.
PMID- 10769240
TI - Regulation of cell proliferation and patterning in Drosophila oogenesis by
Hedgehog signaling.
AB - The localized expression of Hedgehog (Hh) at the extreme anterior of Drosophila
ovarioles suggests that it might provide an asymmetric cue that patterns
developing egg chambers along the anteroposterior axis. Ectopic or excessive Hh
signaling disrupts egg chamber patterning dramatically through primary effects at
two developmental stages. First, excess Hh signaling in somatic stem cells
stimulates somatic cell over-proliferation. This likely disrupts the earliest
interactions between somatic and germline cells and may account for the frequent
mis-positioning of oocytes within egg chambers. Second, the initiation of the
developmental programs of follicle cell lineages appears to be delayed by ectopic
Hh signaling. This may account for the formation of ectopic polar cells, the
extended proliferation of follicle cells and the defective differentiation of
posterior follicle cells, which, in turn, disrupts polarity within the oocyte.
Somatic cells in the ovary cannot proliferate normally in the absence of Hh or
Smoothened activity. Loss of protein kinase A activity restores the proliferation
of somatic cells in the absence of Hh activity and allows the formation of
normally patterned ovarioles. Hence, localized Hh is not essential to direct egg
chamber patterning.
PMID- 10769241
TI - The zebrafish young mutation acts non-cell-autonomously to uncouple
differentiation from specification for all retinal cells.
AB - Embryos from mutagenized zebrafish were screened for disruptions in retinal
lamination to identify factors involved in vertebrate retinal cell specification
and differentiation. Two alleles of a recessive mutation, young, were isolated in
which final differentiation and normal lamination of retinal cells were blocked.
Early aspects of retinogenesis including the specification of cells along the
inner optic cup as retinal tissue, polarity of the retinal neuroepithelium, and
confinement of cell divisions to the apical pigmented epithelial boarder were
normal in young mutants. BrdU incorporation experiments showed that the
initiation and pattern of cell cycle withdrawal across the retina was comparable
to wild-type siblings; however, this process took longer in the mutant. Analysis
of early markers for cell type differentiation revealed that each of the major
classes of retinal neurons, as well as non-neural Muller glial cells, are
specified in young embryos. However, the retinal cells fail to elaborate
morphological specializations, and analysis of late cell-type-specific markers
suggests that the retinal cells were inhibited from fully differentiating. Other
regions of the nervous system showed no obvious defects in young mutants. Mosaic
analysis demonstrated that the young mutation acts non-cell-autonomously within
the retina, as final morphological and molecular differentiation was rescued when
genetically mutant cells were transplanted into wild-type hosts. Conversely,
differentiation was prevented in wild-type cells when placed in young mutant
retinas. Mosaic experiments also suggest that young functions at or near the cell
surface and is not freely diffusible. We conclude that the young mutation
disrupts the post-specification development of all retinal neurons and glia
cells.
PMID- 10769243
TI - Dorsoventral axis determination in the somite: a re-examination.
AB - We have repeated classic dorsoventral somite rotation experiments (Aoyama and
Asamoto, 1988, Development 104, 15-28) and included dorsal and ventral gene
expression markers for the somitogenic tissue types, myotome and sclerotome,
respectively. While the histological results are consistent with those previously
published, gene expression analysis indicates that cells previously thought to be
'sclerotome' no longer express Pax1 mRNA, a sclerotome marker. These results,
together with recent quail-chick transplantation experiments indicating that even
very late sclerotome tissue fragments are multipotential (Dockter and Ordahl,
1998, Development 125, 2113-2124), lead to the conclusion that sclerotome tissue
remains phenotypically and morphogenetically plastic during early embryonic
somitogenesis. Myotome precursor cells, by contrast, appear to be determined
within hours after somite epithelization; a finding consistent with recent
reports (Williams and Ordahl, 1997, Development 124, 4983-4997). Therefore, while
these findings support a central conclusion of Aoyama and Asamoto, that axis
determination begins to occur within hours after somite epithelialization, the
identity of the responding tissues, myotome versus sclerotome, differs. A simple
model proposed to reconcile these observations supports the general hypothesis
that determinative aspects of early paraxial mesoderm growth and morphogenesis
occur in early and late phases that are governed principally by the myotome and
sclerotome, respectively.
PMID- 10769242
TI - The zebrafish slow-muscle-omitted gene product is required for Hedgehog signal
transduction and the development of slow muscle identity.
AB - Hedgehog proteins mediate many of the inductive interactions that determine cell
fate during embryonic development. Hedgehog signaling has been shown to regulate
slow muscle fiber type development. We report here that mutations in the
zebrafish slow-muscle-omitted (smu) gene disrupt many developmental processes
involving Hedgehog signaling. smu(-/-) embryos have a 99% reduction in the number
of slow muscle fibers and a complete loss of Engrailed-expressing muscle
pioneers. In addition, mutant embryos have partial cyclopia, and defects in jaw
cartilage, circulation and fin growth. The smu(-/-) phenotype is phenocopied by
treatment of wild-type embryos with forskolin, which inhibits the response of
cells to Hedgehog signaling by indirect activation of cAMP-dependent protein
kinase (PKA). Overexpression of Sonic hedgehog (Shh) or dominant negative PKA
(dnPKA) in wild-type embryos causes all somitic cells to develop into slow muscle
fibers. Overexpression of Shh does not rescue slow muscle fiber development in
smu(-/-) embryos, whereas overexpression of dnPKA does. Cell transplantation
experiments confirm that smu function is required cell-autonomously within the
muscle precursors: wild-type muscle cells rescue slow muscle fiber development in
smu(-/-) embryos, whereas mutant muscle cells cannot develop into slow muscle
fibers in wild-type embryos. Slow muscle fiber development in smu mutant embryos
is also rescued by expression of rat Smoothened. Therefore, Hedgehog signaling
through Slow-muscle-omitted is necessary for slow muscle fiber type development.
We propose that smu encodes a vital component in the Hedgehog response pathway.
PMID- 10769244
TI - Regulation of meristem organization and cell division by TSO1, an Arabidopsis
gene with cysteine-rich repeats.
AB - In higher plants, meristem organization and cell division regulation are two
fundamentally important and intimately related biological processes. Identifying
and isolating regulatory genes in these processes is essential for understanding
higher plant growth and development. We describe the molecular isolation and
analyses of an Arabidopsis gene, TSO1, which regulates both of these processes.
We previously showed that tso1 mutants displayed defects in cell division of
floral meristem cells including partially formed cell walls, increased DNA
content, and multinucleated cells (Liu, Z., Running, M. P. and Meyerowitz, E. M.
(1997). Development 124, 665-672). Here, we characterize a second defect of tso1
in influorescence meristem development and show that the enlarged influorescence
in tso1 mutants results from repeated division of one inflorescence meristem into
two or more influorescence meristems. Using a map-based approach, we isolated the
TSO1 gene and found that TSO1 encodes a protein with cysteine-rich repeats
bearing similarity to Drosophila Enhancer of zeste and its plant homologs. In
situ TSO1 mRNA expression pattern and the nuclear localization of TSO1-GFP are
consistent with a regulatory role of TSO1 in floral meristem cell division and in
influorescence meristem organization.
PMID- 10769245
TI - TSO1 is a novel protein that modulates cytokinesis and cell expansion in
Arabidopsis.
AB - Previous analyses of tso1 mutants revealed a loss of control of directional
cellular expansion and coordination of growth of adjacent cells, and defects in
karyokinesis and cytokinesis. We isolated TSO1 using a map-based approach, and
show that it is a member of a family of at least three genes in Arabidopsis.
Consistent with the mutant phenotype, TSO1 transcript was most abundant in
flowers, where it accumulated to the highest levels in developing ovules and
microspores. The putative TSO1 protein has two cysteine-rich regions that are
similar to the CXC domains of a variety of proteins from plants and animals,
including a class of kinesins involved in chromosome segregation, and enhancer of
zeste-type proteins. Visualization of TSO1-fusion proteins indicated that TSO1 is
a nuclear protein. The tso1 mutant phenotypes and the novelty of the TSO1
sequence suggest the existence of previously unknown participants in regulation
of directional processes in eukaryotic cells.
PMID- 10769246
TI - Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via
Dishevelled, but not through the canonical Wnt pathway.
AB - Gastrulation in the amphibian embryo is driven by cells of the mesoderm. One of
the genes that confers mesodermal identity in Xenopus is Brachyury (Xbra), which
is required for normal gastrulation movements and ultimately for posterior
mesoderm and notochord differentiation in the development of all vertebrates.
Xbra is a transcription activator, and interference with transcription activation
leads to an inhibition of morphogenetic movements during gastrulation. To
understand this process, we have screened for downstream target genes of
Brachyury (Tada, M., Casey, E., Fairclough, L. and Smith, J. C. (1998)
Development 125, 3997-4006). This approach has now allowed us to isolate Xwnt11,
whose expression pattern is almost identical to that of Xbra at gastrula and
early neurula stages. Activation of Xwnt11 is induced in an immediate-early
fashion by Xbra and its expression in vivo is abolished by a dominant-interfering
form of Xbra, Xbra-En(R). Overexpression of a dominant-negative form of Xwnt11,
like overexpression of Xbra-En(R), inhibits convergent extension movements. This
inhibition can be rescued by Dsh, a component of the Wnt signalling pathway and
also by a truncated form of Dsh which cannot signal through the canonical Wnt
pathway involving GSK-3 and (beta)-catenin. Together, our results suggest that
the regulation of morphogenetic movements by Xwnt11 occurs through a pathway
similar to that involved in planar polarity signalling in Drosophila.
PMID- 10769247
TI - Intermodal selective attention in monkeys. I: distribution and timing of effects
across visual areas.
AB - This study quantified the magnitude and timing of selective attention effects
across areas of the macaque visual system, including the lateral geniculate
nucleus (LGN), lower cortical areas V1 and V2, and multiple higher visual areas
in the dorsal and ventral processing streams. We used one stimulus configuration
and behavioral paradigm, with simultaneous recordings from different areas to
allow direct comparison of the distribution and timing of attention effects
across the system. Streams of interdigitated auditory and visual stimuli were
presented at a high rate with an irregular interstimulus interval (mean of 4/s).
Attention to visual stimuli was manipulated by requiring subjects to make
discriminative behavioral responses to stimuli in one sensory modality, ignoring
all stimuli in the other. The attended modality was alternated across trial
blocks, and difficulty of discrimination was equated across modalities. Stimulus
presentation was gated, so that no stimuli were presented unless the subject
gazed at the center of the visual stimulus display. Visual stimuli were diffuse
light flashes differing in intensity or color and subtending 12 degrees centered
at the point of gaze. Laminar event-related potential (ERP) and current source
density (CSD) response profiles were sampled during multiple paired penetrations
in multiple visual areas with linear array multicontact electrodes. Attention
effects were assessed by comparing responses to specific visual stimuli when
attended versus when visual stimuli were looked at the same way, but ignored.
Effects were quantified by computing a modulation index (MI), a ratio of the
differential CSD response produced by attention to the sum responses to attended
and ignored visual stimuli. The average MI increased up levels of the lower
visual pathways from none in the LGN to 0.0278 in V1 to 0.101 in V2 to 0.170 in
V4. Above the V2 level, attention effects were larger in ventral stream areas (MI
= 0. 152) than in dorsal stream areas (MI = 0.052). Although onset latencies were
shortest in dorsal stream areas, attentional modulation of the early response was
small relative to the stimulus-evoked response. Higher ventral stream areas
showed substantial attention effects at the earliest poststimulus time points,
followed by the lower visual areas V2 and V1. In all areas, attentional
modulation lagged the onset of the stimulus-evoked response, and attention
effects grew over the time course of the neuronal response. The most powerful,
consistent, and earliest attention effects were those found to occur in area V4,
during the 100-300 ms poststimulus interval. Smaller effects occurred in V2 over
the same interval, and the bulk of attention effects in V1 were later. In the
accompanying paper, we describe the physiology of attention effects in V1, V2 and
V4.
PMID- 10769248
TI - Intermodal selective attention in monkeys. II: physiological mechanisms of
modulation.
AB - Of all areas studied in the accompanying study, attention effects were most
consistent and well resolved in V4. In this study, to define some of the
anatomical circuits and neural processes underlying the influence of attention,
we examined the laminar distribution and physiology of attention effects in V4
and in two lower areas, V1 and V2. Laminar event-related potential (ERP), current
source density (CSD) and multiunit activity (MUA) profiles allowed identification
of processes occurring in the local ensembles, as well as their sequence and
laminar distribution. These methods also permitted us to analyze the brain
processes reflected in attention-sensitive components of the surface ERP. As
outlined in the previous study, the first robust modulation by attention occurred
in V4 during the 100-300 ms poststimulus interval. This is the time frame of the
net refractoriness which follows the net local excitatory response to luminance
increment. Over this interval, attention reduced CSD amplitudes and increased
action potential firing rates, findings consistent with disinhibition as a
mechanism for attention in V4. Similar effects were observed during the 100-300
ms time frame in V2. In V4, attention had no effect on the initial excitatory
response at the depth of lamina 4, but it did produce large modulations in
supragranular and deep laminae, origins of both feedforward and feedback
projections. Attentional modulation in V2 was later than in V4 and concentrated
in extragranular laminae, with no modulation of the initial layer 4 response.
Attentional modulation in V1 was smaller and still later than that in V2 and was
focused in the supragranular laminae. In this paradigm, attention did not
modulate either the response in lateral geniculate nucleus (LGN) or the initial
excitation in lamina 4C of V1. The timing of effects across areas and the laminar
distribution of effects within areas indicate that attention effects are mediated
by feedback projections. Moreover, our findings suggest that attention may
increase the perceptual salience of stimuli by reducing stimulus-evoked
refractoriness and/or inhibition in cortical ensembles. Finally, attentional
modulation of transmembrane current flow in V4 produced a sustained negative
deflection in the laminar ERP profile, that was manifested in the ERP over the
occipital surface. This posits a mechanism for the 'selection negativity', a
scalp ERP effect noted under similar experimental conditions in human subjects.
PMID- 10769249
TI - Cortical connections of the insular and adjacent parieto-temporal fields in the
cat.
AB - We present a comprehensive analysis of the cortical connections of the insular
and adjacent cortical areas in the domestic cat by using microinjections of wheat
germ agglutinin conjugated to horseradish peroxidase. We examined the identity
and extent of the cortical fields connected to each area, the relative anatomical
weights of the various connections, their laminar origin, and their paths across
the cerebral commissures. Our main finding is that despite their relatively small
size and close apposition, the connections of the insular and adjacent areas are
far more widespread and more specific to each area than previously realized,
suggesting that each area is involved in disparate aspects of cortical
integration. The granular insular area is linked to a constellation of
somatosensory, motor, premotor and prefrontal districts. The dysgranular insular
area is chiefly associated with lateral prefrontal and premotor, lateral
somatosensory and perirhinal cortices. The dorsal agranular insular area is
connected with limbic neocortical fields, while the ventral agranular insular
area is associated with an array of olfactory allocortical fields. The anterior
sylvian area is associated with visual, auditory and multimodal areas, with the
dorsolateral prefrontal cortex, and with perirhinal area 36. The parainsular area
is linked to non-tonotopic auditory and ventromedial frontal areas. Trajectories
followed by the callosal axons of each of the investigated areas are extremely
divergent. As a whole, the picture of the insular region that emerges from this
and a parallel study (Clasca et al., J Comp Neurol 384:456-482, 1997) is that of
an extreme heterogeneity, both in terms of histological architecture and neural
connections. Comparison with earlier published reports on primates suggests that
most, but not all, of the areas we investigated in cats may have an direct
counterpart within the insula of Old World monkeys.
PMID- 10769250
TI - Cellular mosaics in the rat marginal zone define an early neocortical
territorialization.
AB - We describe a novel neuronal group of the neocortical primordium that is formed
by the pioneer neurons, unlike the Cajal-Retzius cells and the subplate component
of the preplate. These pioneer neurons of the preplate and the marginal zone send
transient axonal projections into the nascent internal capsule, preceding the
formation of the axonal projection from the subplate neurons. In wholemount
preparations, the pioneer neurons of the preplate and the marginal zone cover the
prospective neocortical territory from embryonic day (E) 12 to E17. Two
subpopulations of pioneer neurons (defined by differential expression of calcium
binding proteins) group into well-defined cell clusters, separated by spaces
containing a lower packing density of cells immunoreactive to the corresponding
calcium-binding protein. In both cases, cell clustering was concomitant with
fasciculation of their axons. Although both subpopulations cohabit in the same
areas of the marginal zone, their clustering occurs in specific, well-delineated
territories, giving a mosaic appearance to the surface of the neocortical
primordium before the arrival of thalamocortical axons. We hypothesize that the
fascicles of descending axons arising from defined territories of the marginal
zone may intervene in the initial guidance of the subcortical projection from the
subplate.
PMID- 10769251
TI - Speed selectivity for optic flow in area 7a of the behaving macaque.
AB - Area 7a, in the inferior parietal lobe, has been implicated in optic flow
processing to obtain spatial information about the environment. Optic flow, angle
of-gaze and center-of-motion dependencies are already documented, but the
selectivity of area 7a to speed is unknown. Such information is crucial as area
7a provides the final step in visual motion analysis that begins at the lateral
geniculate nucleus and passes through MT, MST and LIP/VIP. Macaque area 7a
neurons were tested with optic flows with speeds of 0.5-128 degrees /s. Of 161
neurons tested in four hemispheres of two adult male macaques, 53% (86/161) were
speed selective at either the time of stimulus onset, at the end of the trial, or
at both times. Speed selec- tivities resembling the basic filter types (band
pass, band-reject, high-pass, low-pass, broadband) were found. Area 7a neurons
exhibited two novel properties not previously reported elsewhere. Speed
selectivity was found to be dynamic in that many cells gained, lost or changed
speed tuning over the course of a trial. In addition, speed dependence and optic
flow selectivity interacted. For example, a cell could preferentially respond to
one type of naviga- tional optic flow at a slow speed and a different
navigational optic flow at a fast speed. The presence of speed selectivity
combined with other properties of area 7a neurons indicates that these neurons
may have a role in the concurrent representation of heading as well as multiple
object speeds and directions.
PMID- 10769271
TI - April 18, 2000
PMID- 10769252
TI - Distribution of the receptor-anchoring protein gephyrin in the rat dentate gyrus
and changes following entorhinal cortex lesion.
AB - We analyzed the distribution of the receptor-anchoring protein gephyrin in the
normal and deafferented rat dentate gyrus to investigate whether the expression
of this postsynaptic protein is altered in response to the formation of new
synaptic contacts. Confocal microscopy and digital image analysis revealed that
in normal dentate gyrus immunolabeling was most prominent in the outer molecular
layer and decreased successively in the direction of the granule cell layer.
Simultaneous immunolabeling for gephyrin and cell-specific markers showed that
granule cells and parvalbumin-positive interneurons express gephyrin. Large,
intensely stained, gephyrin-positive clusters were distributed along distinct
dendrites, and most of them were positive for parvalbumin. Calbindin
immunostained dendrites were associated with smaller, gephyrin-positive clusters.
Lesion of the medial entorhinal cortex leads to deafferentiation of the middle
molecular layer which resulted in an increased gephyrin immunoreactivity. These
changes were due to a significantly increased concentration of the very small
gephyrin-positive clusters. Parvalbumin-positive dendrites did not display any
increase in co-localizing gephyrin-positive structures. The altered
immunolabeling pattern persisted until 12 weeks after lesion, a time when the
process of synaptic reorganization is complete. Our findings suggest that
synaptogenesis following deafferentiation results in a cell-specific
redistribution of gephyrin immunoreactivity at specific inhibitory synapses.
PMID- 10769253
TI - Volumetry of hippocampus and amygdala with high-resolution MRI and three
dimensional analysis software: minimizing the discrepancies between laboratories.
AB - Within the medial temporal lobe, both the hippocampus and amygdala are frequently
targeted by researchers and clinicians for volumetric analysis based on magnetic
resonance imaging (MRI). However, different data acquisition techniques, analysis
software and anatomical boundaries have in the past made it difficult to compare
results of MRI studies from different laboratories. In order to reduce these
differences, a segmentation protocol was established with 40 healthy normal
control subjects recently scanned in our laboratory. Data acquisition was
performed with a three-dimensional gradient echo technique, and scans were
corrected for non-uniformity and registered into standard stereotaxic space prior
to segmentation. Volumetric analysis was performed manually using three
dimensional software that allows simultaneous analysis of sagittal, coronal and
horizontal images. Intra- and inter-rater coefficients yielded correlation
coefficients comparable with other protocols. The hippocampal volume was larger
in the right hemisphere (3324 versus 3208 mm(3)), while no interhemispheric
differences for the amygdala (1154 versus 1160 mm(3)) could be observed. Most
importantly, results from recent segmentation protocols for hippocampus and
amygdala seem to approach each other with regard to mean volumes and
interhemispheric differences. This indicates that the advances in scanning
technique, volume preparation and segmentation protocols allow a more precise
definition of medial temporal lobe structures with MRI, and that results for mean
volumes for hippocampus and amygdala from different laboratories will eventually
become comparable.
PMID- 10769272
TI - Circulating markers of inflammation for vascular risk prediction: are they ready
for prime time.
PMID- 10769273
TI - Hydroxymethylglutaryl coenzyme A reductase inhibitors modify the inflammatory
response of human macrophages and endothelial cells infected with Chlamydia
pneumoniae.
AB - BACKGROUND: In patients with atherosclerosis, hepatic hydroxymethylglutaryl
coenzyme A reductase (CSE) inhibitors may reduce the activation of inflammation.
Because Chlamydia pneumoniae infection has been linked to coronary artery disease
through the induction of plaque inflammation, we investigated whether
cerivastatin affects the infection rate of human macrophages and endothelial
cells (ECs) and their proinflammatory activation after chlamydial infection.
METHODS AND RESULTS: Macrophages were collected from the alveolar compartment of
6 volunteers and 10 patients with chronic bronchitis. ECs were obtained from 10
umbilical cords. The C. pneumoniae strain CWL was incubated with macrophages or
ECs in the presence and absence of the CSE inhibitor cerivastatin. The infection
rate was determined by immunofluorescence microscopy. The release of monocyte
chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and tumor necrosis
factor (TNF)-alpha was quantified by ELISA. The release of oxygen radicals was
determined by ferricytochrome assay. Infection rates were tendentially lower
after the preincubation of macrophages with CSE inhibitors (17.2% versus 9. 3%
and 18.2% versus 10.4%, respectively; P=NS). The secretion of MCP-1, IL-8, and
TNF-alpha by infected macrophages from volunteers increased. Coincubation with
cerivastatin resulted in significantly lower MCP-1 and IL-8 production, whereas
the release of TNF-alpha remained unaffected. Similar effects regarding chemokine
release were observed in ECs. CONCLUSIONS: CSE inhibitors modify the inflammatory
response of human immune cells to C. pneumoniae. This finding could be relevant
for the therapeutic potential of CSE statins in patients with atherosclerosis and
C. pneumoniae infection.
PMID- 10769274
TI - The value of magnetic resonance imaging of the left ventricular outflow tract in
patients with hypertrophic obstructive cardiomyopathy after septal artery
embolization.
AB - BACKGROUND: We tested the value of magnetic resonance imaging (MRI) in the follow
up of patients with hypertrophic obstructive cardiomyopathy after septal artery
embolization. MRI provides a noninvasive visualization of transplanar turbulent
flow in order to quantify left ventricular outflow tract obstruction. METHODS AND
RESULTS: We followed 10 patients who were treated with septal artery embolization
for 12 months. We used gradient echo sequences to document continuous improvement
of the outflow tract area and T1- and T2-weighted spin echo sequences to
visualize myocardial infarction. A continuous, but not linear, improvement of the
outflow tract area occurred after septal artery embolization during the 12-month
follow-up period. The improvement of the outflow tract area correlated well with
the amelioration of symptoms (r(2)=0.86). CONCLUSIONS: We conclude that MRI
reliably detects the degree of obstruction in patients with hypertrophic
obstructive cardiomyopathy. This modality may be especially useful for follow-up
after septal artery embolization.
PMID- 10769275
TI - Plasma concentration of interleukin-6 and the risk of future myocardial
infarction among apparently healthy men.
AB - BACKGROUND: Interleukin-6 (IL-6) plays a central role in inflammation and tissue
injury. However, epidemiological data evaluating the role of IL-6 in
atherogenesis are sparse. METHODS AND RESULTS: In a prospective study involving
14 916 apparently healthy men, we measured baseline plasma concentration of IL-6
in 202 participants who subsequently developed myocardial infarction (MI) and in
202 study participants matched for age and smoking status who did not report
vascular disease during a 6-year follow-up. Median concentrations of IL-6 at
baseline were higher among men who subsequently had an MI than among those who
did not (1.81 versus 1. 46 pg/mL; P=0.002). The risk of future MI increased with
increasing quartiles of baseline IL-6 concentration (P for trend <0.001) such
that men in the highest quartile at entry had a relative risk 2.3 times higher
than those in the lowest quartile (95% CI 1.3 to 4.3, P=0.005); for each quartile
increase in IL-6, there was a 38% increase in risk (P=0.001).This relationship
remained significant after adjustment for other cardiovascular risk factors, was
stable over long periods of follow-up, and was present in all low-risk subgroups,
including nonsmokers. Although the strongest correlate of IL-6 in these data was
C-reactive protein (r=0.43, P<0.001), the relationship of IL-6 with subsequent
risk remained after control for this factor (P<0.001). CONCLUSIONS: In apparently
healthy men, elevated levels of IL-6 are associated with increased risk of future
MI. These data thus support a role for cytokine-mediated inflammation in the
early stages of atherogenesis.
PMID- 10769277
TI - Endothelial dysfunction is detectable in young normotensive first-degree
relatives of subjects with type 2 diabetes in association with insulin
resistance.
AB - BACKGROUND: Endothelial dysfunction (ED) is regarded as an early step in the
development of atherosclerosis. Among the pathogenetic factors leading to
atherosclerosis, the role of insulin resistance and hyperinsulinemia as
independent risk factors is still under debate. In this study, we examined the
association between ED and insulin resistance in normotensive and normoglycemic
first-degree relatives (FDRs) of patients with type 2 diabetes mellitus (DM).
METHODS AND RESULTS: Endothelium-dependent and -independent vasodilation of the
brachial artery was measured with high-resolution ultrasound (13 MHz) in 53
normotensive FDRs (21 men, 32 women; mean age, 35 years) with normal oral glucose
tolerance, 10 age- and sex-matched normal control subjects, and 25 DM patients
(mean age, 57 years). According to the tertiles of the clamp-derived glucose
metabolic clearance rate (MCR), the FDRs were further classified as insulin
resistant with an MCR or =7.8 mL. kg(-1). min(-1), and borderline with an MCR of 5.9 to 7.7
mL. kg(-1). min(-1). Flow-associated dilation was 4.1+/-0.9% in insulin-resistant
FDRs, 6.7+/-1.1% in borderline FDRs, 9.0+/-1.2% in insulin-sensitive FDRs
(P=0.002), 7.7+/-2.9% in control subjects (P=NS versus FDRs), and 3.8+/-1.0% in
DM patients (P=0.03). In multiple regression analysis, low MCR was significantly
correlated with ED independent of age, sex, smoking, body mass index, percent
body fat, serum insulin, and lipids. CONCLUSIONS: There is a significant
association between ED and insulin resistance in young FDRs of DM subjects
independent of the classic cardiovascular risk factors.
PMID- 10769276
TI - Ciprofibrate therapy improves endothelial function and reduces postprandial
lipemia and oxidative stress in type 2 diabetes mellitus.
AB - BACKGROUND: Exaggerated postprandial lipemia (PPL) is a factor in atherogenesis,
involving endothelial dysfunction and enhanced oxidative stress. We examined the
effect of ciprofibrate therapy on these parameters in type 2 diabetes mellitus.
METHODS AND RESULTS: Twenty patients entered a 3-month, double-blind, placebo
controlled study. Each subject was studied fasting and after a fatty meal, at
baseline, and after 3 months of treatment. Glucose and lipid profiles were
measured over an 8-hour postprandial period. Endothelial function (flow-mediated
endothelium-dependent vasodilatation [FMD]) and oxidative stress (electron
paramagnetic resonance spectroscopy) were measured after fasting and 4 hours
postprandially. At baseline, both groups exhibited similar PPL and deterioration
in endothelial function. After ciprofibrate, fasting and postprandial FMD values
were significantly higher (from 3.8+/-1. 8% and 1.8+/-1.3% to 4.8+/-1.1% and
3.4+/-1.1%; P<0.05). This was mirrored by a fall in fasting and postprandial
triglycerides (3. 1+/-2.1 and 6.6+/-4.1 mmol/L to 1.5+/-0.8 and 2.8+/-1.3 mmol/L,
P<0. 05). Fasting and postprandial HDL cholesterol was also elevated (0. 9+/-0.1
and 0.8+/-0.1 mmol/L and 1.2+/-0.2 and 1.2+/-0.1 mmol/L, P<0. 05). There were no
changes in total or LDL cholesterol. Fasting and postprandial triglyceride
enrichment of all lipoproteins was attenuated, with cholesterol depletion of VLDL
and enrichment of HDL. There were similar postprandial increases in oxidative
stress in both groups at baseline, which was significantly attenuated by
ciprofibrate (0.3+/-0.6 versus 1.5+/-1.1 U, P<0.05). CONCLUSIONS: This study
demonstrates that fibrate therapy improves fasting and postprandial endothelial
function in type 2 diabetes. Attenuation of PPL and the associated oxidative
stress, with increased HDL cholesterol levels, may be important.
PMID- 10769278
TI - Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor
induction by C-reactive protein: relationship with age, sex, and hormone
replacement treatment.
AB - BACKGROUND: Elevated plasma levels of C-reactive protein (CRP) in population
studies and in patients with unstable coronary syndromes are predictive of future
adverse events, including cardiac death and myocardial infarction, implicating
inflammation in pathogenesis. Although CRP is considered a marker of
inflammation, it induces monocyte tissue factor (TF) and may play a prothrombotic
role in atherosclerosis and its complications. METHODS AND RESULTS: Peripheral
blood mononuclear cells (PBMCs) from 79 healthy men and women aged 26 to 83 years
and 21 healthy postmenopausal women taking hormone replacement therapy (HRT) were
stimulated with CRP, lipopolysaccharide (LPS), interferon-gamma (IFN), or their
combination. Levels of CRP in the normal range (1 to 5 microg/mL) increased basal
monocyte TF 4- to 6-fold and 40-fold at higher concentrations (25 microg/mL).
Coincubation of LPS with CRP produced a greater-than-additive response. IFN did
not induce TF but synergized with CRP to approximately double activity. There was
a striking positive correlation between age and monocyte TF induction, with a
dramatic rise on monocytes from postmenopausal women that was not apparent on
cells from women taking HRT. CONCLUSIONS: Synergy between CRP and inflammatory
mediators may play a direct prothrombotic role in the pathogenesis of coronary
atherosclerosis and its acute complications by increasing monocyte/macrophage TF.
This may contribute to age and sex differences in coronary events and to the
protective effects of HRT.
PMID- 10769279
TI - Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in
human vascular smooth muscle and transcriptional effects.
AB - BACKGROUND: Estrogens have vascular effects through the activation of estrogen
receptors (ERs). In addition to ERalpha, the first ER to be cloned, a second
subtype called ERbeta has recently been discovered. METHODS AND RESULTS: Using a
reverse-transcriptase polymerase chain reaction assay that employs the same
primer pair to simultaneously amplify ERalpha and ERbeta transcripts, we found
that ERbeta is the ER form that is predominantly expressed in human vascular
smooth muscle, particularly in women. The transcriptional effects of the 2 ERs in
transfected HeLa cells differed. In response to 17beta-estradiol, ERalpha is a
stronger transactivator than ERbeta at low receptor concentrations. However, at
higher receptor concentrations, ERalpha activity self-squelches, and ERbeta is a
stronger transactivator. Tamoxifen has partial agonist effects with ERalpha but
not with ERbeta. CONCLUSIONS: The protective effects of estrogens in the
cardiovascular system of women may be due to the genomic effects of ERbeta in
vascular tissue.
PMID- 10769280
TI - Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell
activation, foam cell transformation, and proliferation.
AB - BACKGROUND: Enzymatic, nonoxidative modification transforms LDL to an atherogenic
molecule (E-LDL) that activates complement and macrophages and is present in
early atherosclerotic lesions. METHODS AND RESULTS: We report on the atherogenic
effects of E-LDL on human vascular smooth muscle cells (SMC). E-LDL accumulated
in these cells, and this was accompanied by selective induction of monocyte
chemotactic protein-1 in the absence of effects on the expression of interleukin
(IL)-8, RANTES, or monocyte inflammatory proteins-1alpha and -beta). Furthermore,
E-LDL stimulated the expression of gp130, the signal-transducing chain of the IL
6 receptor (IL-6R) family, and the secretion of IL-6. E-LDL invoked mitogenic
effects on SMC through 2 mechanisms. First, an autocrine mitogenic circuit
involving platelet-derived growth factor and fibroblast growth factor-beta was
induced. Second, upregulation of gp130 rendered SMC sensitive to transsignaling
through the IL-6/sIL-6R activation pathway. Because E-LDL promoted release of
both IL-6 and sIL-6R from macrophages, application of macrophage cell
supernatants to prestimulated SMC provoked a pronounced and sustained
proliferation of the cells. CONCLUSIONS: E-LDL can invoke alterations in SMC that
are characteristic of the evolving atherosclerotic lesion.
PMID- 10769281
TI - Evolution of the volume-outcome relation for hospitals performing coronary
angioplasty.
AB - BACKGROUND: Hospitals performing more surgical procedures tend to yield better
outcomes. This study examines the evolution of this volume-outcome relation over
time. METHODS AND RESULTS: The relation between the number of percutaneous
transluminal coronary angioplasty (PTCA) procedures performed at hospitals
(volume) and in-hospital bypass surgery and death for 353 488 patients treated in
California between 1984 and 1996 was examined. Descriptive statistics and
logistic regression were used to compare outcomes for 3 periods: 1984 to 1987,
1988 to 1992, and 1993 to 1996. The in-hospital mortality rate was 2.5% for
hospitals performing <200 PTCA procedures per year but only 1.3% for hospitals
performing >400 procedures per year in 1984 to 1987. By 1993 to 1996, mortality
rates in these 2 volume categories narrowed to 1.7% and 1.3%, respectively.
Bypass surgery rates also narrowed and fell in low-volume (<200 procedures)
versus high-volume (>400 procedures) hospitals from 12.4% versus 6.9% in 1984 to
1987 to 4.6% versus 3.3% in 1993 to 1996. In a logistic regression, PTCA
procedures significantly predicted in-hospital mortality and bypass surgery rates
in all 3 time periods. However, coefficient estimates indicate that improvements
over time in outcomes for hospitals performing <200 procedures were comparable to
the predicted benefits of increasing volume above 400 procedures within time
periods. CONCLUSIONS: Over time, the disparity in outcomes between low- and high
volume hospitals has narrowed, and outcomes have improved significantly for all
hospitals. Given these improvements, lower minimum volume standards may be
advisable in less populated areas, where the alternative is no angioplasty at
all.
PMID- 10769282
TI - Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that
maps to 6q23-24.
AB - BACKGROUND: Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL)
are prevalent disorders that occur alone or as components of complex multisystem
syndromes. Multiple genetic loci have been identified that, when mutated, cause
DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been
previously recognized. METHODS AND RESULTS: Clinical evaluations of 2 kindreds
demonstrated autosomal-dominant transmission and age-related penetrance of both
SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss
was evident by late adolescence, whereas ventricular dysfunction produced
progressive congestive heart failure after the fourth decade. DNA samples from
the larger kindred (29 individuals) were used to perform a genome-wide linkage
study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the
disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease
locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a
location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not
cause cardiomyopathy. The epicardin gene, which encodes a transcription factor
expressed in the myocardium and cochlea, was assessed as a candidate gene by
nucleotide sequence analysis; no mutations were identified. CONCLUSIONS: A
syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at
6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder
allows for the identification of young adults at risk for serious heart disease,
thereby enabling early intervention. Definition of the molecular cause of this
syndrome may provide new information about important cell physiology common to
both the ear and heart.
PMID- 10769283
TI - Assessment of aortic line of elasticity using polynomial regression analysis.
AB - BACKGROUND: The aim of this study was to assess the sigmoid line of elasticity in
the human aorta. METHODS AND RESULTS: The pressure-diameter relation was measured
in the descending aorta in 120 subjects. In an additional group of 6 subjects,
transient vena caval occlusion produced 5 sets of pressure-diameter data. We
found that the best fit curve of the pooled pressure-diameter data was a third
order polynomial. A polynomial equation was used to calculate the sigmoid line of
elasticity in the entire population and after the administration of diltiazem (15
patients) or enalaprilat (10 patients). The sigmoid line of elasticity was
significantly different with respect to age (P<0.001), history of hypertension
(P<0.004), and hypercholesterolemia (P<0.02). The difference between the
transition point and the peak systolic pressure was increased in normal subjects
compared with patients (P<0.0001). The sigmoid line shifted leftward and upward
with diltiazem, but it remained unchanged with enalaprilat. During an average of
3 years of follow-up, 19 of 88 patients developed stroke (n=4), unstable angina
(n=8), acute myocardial infarction (n=4), or acute pulmonary edema (n=3).
CONCLUSIONS: This approach provides a quantitative evaluation of the aortic line
of elasticity, which can differentiate the intrinsic from the extrinsic aortic
elastic properties. Furthermore, it is a powerful and independent risk factor for
cardiovascular events.
PMID- 10769284
TI - Early and intermediate outcomes after repair of pulmonary atresia with
ventricular septal defect and major aortopulmonary collateral arteries:
experience with 85 patients.
AB - BACKGROUND: Pulmonary atresia with ventricular septal defect (VSD) and major
aortopulmonary collaterals (MAPCAs) is a complex lesion with marked heterogeneity
of pulmonary blood supply. Traditional management has involved staged
unifocalization of pulmonary blood supply. Our approach has been to perform early
1-stage complete unifocalization in almost all patients. METHODS AND RESULTS:
Since 1992, 85 patients with pulmonary atresia, VSD, and MAPCAs have undergone
unifocalization (median age, 7 months). Complete 1-stage unifocalization and
intracardiac repair were performed through a midline approach in 56 patients,
whereas 23 underwent unifocalization in a single stage with the VSD left open,
and 6 underwent staged unifocalization through sequential thoracotomies. There
were 9 early deaths. During follow-up (1 to 69 months), there were 7 late deaths.
Actuarial survival was 80% at 3 years. Among early survivors, actuarial survival
with complete repair was 88% at 2 years. Reintervention on the neo-pulmonary
arteries was performed in 24 patients. CONCLUSIONS: Early 1-stage complete
unifocalization can be performed in >90% of patients with pulmonary atresia and
MAPCAs, even those with absent true pulmonary arteries, and yields good
functional results. Complete repair during the same operation is achieved in two
thirds of patients. There remains room for improvement; actuarial survival 3
years after surgery is 80%, and there is a significant rate of reintervention.
These results must be appreciated within the context of the natural history of
this lesion: 65% of patients survive to 1 year of age and slightly >50% survive
to 2 years even with surgical intervention.
PMID- 10769286
TI - Pressure-derived fractional flow reserve to assess serial epicardial stenoses:
theoretical basis and animal validation.
AB - Background-Fractional flow reserve (FFR) is an index of stenosis severity
validated for isolated stenoses. This study develops the theoretical basis and
experimentally validates equations for predicting FFR of sequential stenoses
separately. Methods and Results-For 2 stenoses in series, equations were derived
to predict FFR (FFR(pred)) of each stenosis separately (ie, as if the other one
were removed) from arterial pressure (P(a)), pressure between the 2 stenoses
(P(m)), distal coronary pressure (P(d)), and coronary occlusive pressure (P(w)).
In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary
artery, FFR(pred) was compared with FFR(app) (ratio of the pressure just distal
to that just proximal to each stenoses) and to FFR(true) (ratio of the pressures
distal to proximal to each stenosis but after removal of the other one) in case
of fixed distal and varying proximal stenoses (n=15) and in case of fixed
proximal and varying distal stenoses (n=20). The overestimation of FFR(true) by
FFR(app) was larger than that of FFR(true) by FFR(pred) (0.070+/-0.007 versus
0.029+/-0.004, P<0.01 for fixed distal stenoses, and 0.114+/-0.01 versus 0.036+/
0. 004, P<0.01 for fixed proximal stenoses). This overestimation of FFR(true) by
FFR(app) was larger for fixed proximal than for fixed distal stenoses.
Conclusions-The interaction between 2 stenoses is such that FFR of each lesion
separately cannot be calculated by the equation for isolated stenoses (P(d)/P(a)
during hyperemia) applied to each separately but can be predicted by more
complete equations taking into account P(a), P(m), P(d), and P(w).
PMID- 10769285
TI - Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the
heart.
AB - BACKGROUND: Matrix metalloproteinases (MMPs) contribute to collagen degradation
and remodeling of the extracellular matrix after myocardial infarction; however,
their role in myocardial dysfunction immediately after ischemia and reperfusion
is unknown. METHODS AND RESULTS: We measured the release of MMPs into the
coronary effluent of isolated, perfused rat hearts during aerobic perfusion and
reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP
2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were
also detected in the coronary effluent. After 20 minutes of global no-flow
ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that
peaked within the first minute of reperfusion. The release of pro-MMP-2 into the
coronary effluent during reperfusion was enhanced with increasing duration of
ischemia and correlated negatively with the recovery of mechanical function
during reperfusion (r(2)=0.99). MMP-2 antibody (1.5 to 15 microg/mL) and the
inhibitors of MMPs doxycycline (10 to 100 micromol/L) and o-phenanthroline (3 to
100 micromol/L) improved whereas MMP-2 worsened the recovery of mechanical
function during reperfusion. CONCLUSIONS: These results show that acute release
of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical
dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for
the treatment of ischemia-reperfusion injury.
PMID- 10769288
TI - Impaired endothelium-dependent regulation of ventricular relaxation in pressure
overload cardiac hypertrophy.
AB - BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial
relaxation and may benefit diastolic function. Left ventricular hypertrophy (LVH)
is characterized by abnormal myocardial relaxation and endothelial dysfunction.
We investigated endothelium-dependent regulation of LV relaxation in moderate
pressure-overload LVH induced by aortic banding in guinea pigs. METHODS AND
RESULTS: Isolated ejecting hearts of banded or sham-operated animals (shams) were
studied. The specific agonists for endothelial release of NO, bradykinin (10
nmol/L), and substance P (100 nmol/L) both induced earlier onset of LV relaxation
in shams (time to LV dP/dt(min) [tdP/dt(min)], -13.4+/-3.0 and -10.4+/-2.5 ms,
respectively) without altering peak LV pressure or LV dP/dt(max). Neither agent
altered tdP/dt(min) in banded animals. The ACE inhibitor captopril (1 micromol/L)
also selectively reduced tdP/dt(min) in shams via a bradykinin/NO-dependent
mechanism but had no effect in banded animals. An exogenous NO donor, sodium
nitroprusside (0.1 micromol/L), selectively reduced tdP/dt(min) to a similar
extent in both shams and banded animals. Endothelial-type NO synthase (eNOS)
protein expression in whole LV homogenate was unaltered in banded animals.
CONCLUSIONS: Endothelium-dependent enhancement of LV relaxation is impaired in
moderate pressure-overload LVH, despite a preserved response to exogenous NO.
This is not accounted for by altered eNOS expression. These abnormalities may
contribute to diastolic dysfunction in LVH.
PMID- 10769287
TI - Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and
resistance coronary vessels in conscious dogs: comparison with B(2) receptor
stimulation.
AB - BACKGROUND: Constitutive bradykinin B(1) receptors have been identified in dogs;
however, their physiological implications involving the coronary circulation
remain to be determined. This study examined, in conscious dogs, the coronary
response to des-Arg(9)-bradykinin (a B(1) receptor agonist) and the mechanisms
involved. METHODS AND RESULTS: Eleven dogs were instrumented with a left
ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a
Doppler flow probe, and ultrasonic crystals to measure coronary blood flow
velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg(9)-bradykinin
(3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic
hemodynamics but dose-dependently increased CBFv and CD. Des-Arg(9)-bradykinin
was less potent than bradykinin. Hoe 140 (a B(2) antagonist, 10 microg/kg)
abolished the effects of bradykinin but did not influence the effects of des
Arg(9)-bradykinin. When CBFv increase was prevented by the cuff occluder, CD
responses to bradykinin and des-Arg(9)-bradykinin were maintained. Intracoronary
lisinopril (0. 75 mg) increased the CD response to bradykinin, with only minimal
effect on CBFv, and extended the duration of the effect. Lisinopril did not alter
des-Arg(9)-bradykinin responses. Intracoronary N(omega)-nitro-L-arginine (2
mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD
effects of des-Arg(9)-bradykinin. The relaxing effect of des-Arg(9)-bradykinin on
isolated coronary rings was prevented by des-Arg(9), [Leu(8)]-bradykinin.
CONCLUSIONS: In the conscious dog, B(1) receptors are present in coronary
vessels, and their stimulation produces vasodilation in conductance and
resistance vessels, which is mediated essentially by NO but not modulated by
angiotensin-converting enzyme. However, the coronary vasodilation induced by B(1)
receptor stimulation is not as great as that produced by B(2) receptor
stimulation.
PMID- 10769289
TI - Role of the Na(+)/H(+) exchanger in short-term atrial electrophysiological
remodeling.
AB - BACKGROUND: The pathophysiology underlying electrophysiological remodeling (ER)
from rapid atrial rates is unknown. We tested the hypothesis that activation of
the Na(+)/H(+) exchanger (NHE) by ischemia contributes to ER. METHODS AND
RESULTS: Twenty-eight dogs were studied under autonomic blockade. In 15 closed
chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm
over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of
the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective
refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from
143+/-7 to 118+/-5 ms (1 hour) and to 122+/-17 ms (5 hours). Shortening of AERP
was prevented in the pace/NHEI group (P=0.02 compared with pace/controls). At
baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP
(physiological rate adaptation), which was lost at 5 hours in pace/controls. In
pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing
(P=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and
after occlusion of the right coronary artery. Five received HOE642
(ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In
ischemia/controls, AERP(400) decreased (156+/-30 to 130+/-32 ms). Shortening of
AERP was not prevented by glibenclamide (180+/-20 to 153+/-33 ms) but was
prevented in ischemia/NHEI dogs (169+/-12 to 184+/-19 ms, P=0.001 compared with
ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in
ischemia/controls and preserved in ischemia/NHEI dogs (P=0. 02). CONCLUSIONS:
Activation of the NHE is one mechanism underlying short-term ER.
PMID- 10769290
TI - Endothelial cell activation by pore-forming structures: pivotal role for
interleukin-1alpha.
AB - BACKGROUND: Interaction of complement with endothelial cells (ECs) underlies the
development of inflammation and coagulation in disease. Assembly of the membrane
attack complex (MAC) of complement on EC membrane, like stimulation with
cytokines, upregulates tissue factor and cyclooxygenase-2 but does so via the
intermediary action of IL-1alpha. We asked whether the MAC activates porcine
aortic and microvascular ECs in a global manner by this mechanism and whether
this mechanism is used by membrane pore-forming structures. METHODS AND RESULTS:
Exposure of ECs to complement caused upregulation of mRNAs for E-selectin,
intracellular adhesion molecule-1, vascular cell adhesion molecule-1, Ikappa
Balpha, interleukin (IL)-1alpha, IL-1beta, IL-8, and plasminogen activator
inhibitor-1 over a period of 6 hours. The expression of these genes was not a
primary response to stimulation, however, because IL-1 receptor antagonist
inhibited expression of these genes. Activation of ECs by complement depended on
the autocrine action of IL-1alpha, because complement-mediated EC activation was
inhibited by anti-IL-1alpha antibodies. Melittin and mastoparan, amphiphilic pore
forming peptides like the MAC, induced E-selectin through intermediary action of
IL-1. CONCLUSIONS: These findings suggest that transmembrane pore-forming
proteins, as a class of molecules, activate ECs through the autocrine effects of
IL-1alpha.
PMID- 10769291
TI - Homage to James B. Herrick: a contemporary look at myocardial infarction and at
sickle-cell heart disease: the 32nd Annual Herrick Lecture of the Council on
Clinical Cardiology of the American Heart Association.
PMID- 10769292
TI - Images in cardiovascular medicine. Exclusion of an aneurysmal segment of the
thoracic aorta with covered stents.
PMID- 10769293
TI - Three-dimensional reconstruction of a large venous bypass graft aneurysm
supplying 2 coronary arteries.
PMID- 10769294
TI - Medicare trust fund solvency.
PMID- 10769295
TI - Cancer in veterinarians.
AB - OBJECTIVES: Veterinarians come into contact with several potentially carcinogenic
exposures in the course of their occupation. These exposures include radiation,
anaesthetic gases, pesticides (particularly insecticides), and zoonotic
organisms. This review aims to summarise what is known about the carcinogenic
risks in this profession. METHODS: The levels of exposure to potential
carcinogens in the veterinary profession are examined and evidence is reviewed
for carcinogenesis of these substances in humans at doses similar to those
experienced by veterinarians. The few published studies of cancer in
veterinarians are also summarised. RESULTS: Veterinarians have considerable
potential for exposure to several known and potential carcinogens. Risks may be
posed by work in clinics with poorly maintained x ray equipment, by use of
insecticides, and from contact with carcinogenic zoonotic organisms. The few
studies available suggest that veterinarians have increased mortality from
lymphohaematopoietic cancers, melanoma, and possibly colon cancer. CONCLUSIONS:
The exposures examined in this review are not unique to the veterinary
profession, and, as a consequence, information gathered on the carcinogenic risks
of these exposures has implications for many other occupations such as veterinary
nurses, animal handlers, and some farmers, as well as dentists, radiographers,
and anaesthetists.
PMID- 10769297
TI - Occupational exposures and pancreatic cancer: a meta-analysis.
AB - OBJECTIVES: Consolidation of epidemiological data on pancreatic cancer and
worksite exposures. METHODS: Publications during 1969-98 were surveyed. Studies
without verified exposures were excluded. Meta-analyses were conducted on data
from 92 studies covering 161 populations, with results for 23 agents or groups of
agents. With a standard format, five epidemiologists extracted risk estimates and
variables of the structure and quality of each study. The extracted data were
centrally checked. Random meta-models were applied. RESULTS: Based on 20
populations, exposure to chlorinated hydrocarbon (CHC) solvents and related
compounds was associated with a meta-risk ratio (MRR) of 1.4 (95% confidence
interval (95% CI) 1.0 to 1.8). Nickel and nickel compounds were considered in
four populations (1.9; 1.2 to 3.2). Excesses were found also for chromium and
chromium compounds (1.4; 0.9 to 2.3), polycyclic aromatic hydrocarbons (PAHs)
(1.5; 0.9 to 2.5), organochlorine insecticides (1.5; 0.6 to 3.7), silica dust
(1.4; 0.9 to 2.0), and aliphatic and alicyclic hydrocarbon solvents (1.3; 0.8 to
2.8). Evidence on pancreatic carcinogenicity was weak or non-positive for the
following agents: acrylonitrile (1.1; 0.0 to 6.2); arsenic (1.0; 0.6 to 1.5);
asbestos (1.1; 0.9 to 1.5); diesel engine exhaust (1.0; 0.9 to 1.3);
electromagnetic fields (1.1; 0.8 to 1.4); formaldehyde (0. 8; 0.5 to 1.0); flour
dust (1.1; 0.3 to 3.2); cadmium and cadmium compounds (0.7; 0.4 to 1.4); gasoline
(1.0; 0.8 to 1.2); herbicides (1.0; 0.8 to 1.3); iron and iron compounds (1.3;
0.7 to 2.5); lead and lead compounds (1.1; 0.8 to 1.5); man-made vitreous fibres
(1.0; 0.6 to 1.6); oil mist (0.9; 0.8 to 1.0); and wood dust (1.1; 0.9 to 2.5).
The occupational aetiological fraction of pancreatic cancer was estimated at 12%.
In a subpopulation exposed to CHC solvents and related compounds, it was 29%; to
chromium and chromium compounds, 23%; to nickel and nickel compounds, 47%; to
insecticides, 33%; and to PAHs, 33%. CONCLUSION: Occupational exposures may
increase risk of pancreatic cancer. High quality studies are called for on
interactions between occupational, environmental, and lifestyle factors as well
as interactions between genes and the environment.
PMID- 10769296
TI - Reactivity and recovery from different types of work measured by catecholamines
and cortisol: a systematic literature overview.
AB - OBJECTIVES: To review occupational health, laboratory, and sports literature on
neuroendocrine reactivity and recovery from mental, combined mental and physical,
or physical tasks. METHODS: A systematic literature search was performed in eight
databases. Studies with catecholamines or cortisol as effect variables measured
in blood, urine, or saliva were included. RESULTS: After application of inclusion
and exclusion criteria, 77 studies from the initial 559 identified were taken
into account. In occupational settings it was found that relatively few studies
were conclusive about recovery, which formed a contrast with sports research. For
reactivity and recovery up to 1 hour after performing the task, half of the
studies considered physical tasks and more than two thirds showed incomplete
recovery compared with baseline excretion of catecholamines and cortisol.
Recovery extending to 3 days after the task was performed was often incomplete
for cortisol after combined mentally and physically demanding tasks, and less
often after solely mental or physical tasks. This type of recovery was more often
incomplete for adrenaline (epinephrine) than for noradrenaline (norepinephrine),
which was the case after mental as well as combined mental and physical tasks.
CONCLUSIONS: The results from laboratory and sports research may be transferable
to some occupations, but more research is needed on the course of recovery
relative to health effects in occupational settings.
PMID- 10769298
TI - Workplace exposures and oesophageal cancer.
AB - OBJECTIVES: To describe the relation between oesophageal cancer and many
occupational circumstances with data from a population based case-control study.
METHODS: Cases were 99 histologically confirmed incident cases of cancer of the
oesophagus, 63 of which were squamous cell carcinomas. Various control groups
were available; for the present analysis a group was used that comprised 533
population controls and 533 patients with other types of cancer. Detailed job
histories were elicited from all subjects and were translated by a team of
chemists and hygienists for evidence of exposure to 294 occupational agents.
Based on preliminary results and a review of literature, a set of 35 occupational
agents and 19 occupations and industry titles were selected for this analysis.
Logistic regression analyses were adjusted for age, birthplace, education,
respondent (self or proxy), smoking, alcohol, and beta-carotene intake. RESULTS:
Sulphuric acid and carbon black showed the strongest evidence of an association
with oesophageal cancer, particularly squamous cell carcinoma. Other substances
showed excess risks, but the evidence was more equivocal-namely chrysotile
asbestos, alumina, mineral spirits, toluene, synthetic adhesives, other paints
and varnishes, iron compounds, and mild steel dust. There was considerable
overlap in occupational exposure patterns and results for some of these
substances may be mutually confounded. None of the occupations or industry titles
showed a clear excess risk; the strongest hints were for warehouse workers, food
services workers, and workers from the miscellaneous food industry. CONCLUSIONS:
The data provide some support for an association between oesophageal cancer and a
handful of occupational exposures, particularly sulphuric acid and carbon black.
Many of the associations found have never been examined before and warrant
further investigation.
PMID- 10769299
TI - Exposure-response relations for self reported asthma and rhinitis in bakers.
AB - OBJECTIVES: To explore relations between two estimates of exposure to inhalable
flour dust, and the incidence rates (IRs) of asthma and rhinitis in bakers.
METHODS: This was a retrospective cohort study among 2923 bakers. A posted
questionnaire registered the disease and work history. For every year, each baker
was assigned an estimate of the exposure concentration to inhalable flour dust
derived from reported job-tasks and dust measurements. Exposure at onset of
disease was expressed as current dust exposure concentration, and as cumulative
dose of exposure to dust. A multiple Poisson regression analysis assessed the
impacts of the exposure estimates on the IRs of asthma and rhinitis. RESULTS: IRs
of asthma and rhinitis increased by dust concentration at onset of disease. The
IR of asthma for the bakers with highest exposure (dough makers) was 7. 3/1000
person-years in men and 6.5 in women and for rhinitis 43.4 and 38.5,
respectively. There was a significant association between the dust concentration
at onset of disease and the risk for asthma or rhinitis, but not of the
cumulative exposure. CONCLUSION: The risk of asthma seemed to be increased at
inhalable dust concentrations >/=3 mg/m(3) (dough making or bread forming),
whereas the risk of rhinitis was increased at all concentrations >/=1 mg/m(3),
indicating an increased risk in all bakery job-tasks. The risks seemed to be less
dependent on the cumulative exposure dust than the inhalable dust concentrations.
PMID- 10769300
TI - Vibration exposure, smoking, and vascular dysfunction.
AB - OBJECTIVES: Vibration white finger (VWF), also known as "occupational Raynaud's
phenomenon", is marked by arterial hyperresponsiveness and vasoconstriction
during cold stimulation. The impact of tobacco use, and by extension stopping
smoking, on the long term course of the disease has been inconclusively
characterised. The objectives of this study included assessment of the impact of
tobacco use on symptoms and on objective tests in shipyard workers exposed to
vibration, and in gauging the natural history of the disorder after stopping
exposure and changing smoking patterns. METHODS: In a cross sectional
investigation, 601 current and former users of pneumatic tools were evaluated
subjectively for cold related vascular symptoms, and tested by cold challenge
plethysmography. There was follow up and subsequent testing of 199 members of the
severely effected subgroup of smokers and non-smokers, many of whom had stopped
smoking in the interval between tests. Effects of smoking and stopping smoking on
symptoms and plethsymographic results were assessed. RESULTS: Symptoms and
measured abnormal vascular responses related to cold were more severe in smokers
than in non-smokers. Follow up of 199 severely effected members of the cohort,
all removed from exposure for 2 years, indicated that smokers were almost twice
as likely to have more severe vasospasm (test finger/control finger systolic
blood pressure% (FSBP%) <30) than were non-smokers (-32.2% v 17.4%). 53 Subjects
who stopped smoking during the interval between tests improved, and were
indistinguishable from non-smokers similarly exposed to vibration. Additional
physiological benefits of stopping smoking were still apparent at further follow
up examination, 1 year later. Improvements evident on plethysmography were not
accompanied by improvements in symptoms, which were unaffected by smoking.
CONCLUSIONS: Smoking seems to delay physiological improvement in response to cold
challenge in workers with VWF, after the end of exposure to vibration. Symptoms
were less likely to improve over time than digital blood pressure, and were less
affected by smoking.
PMID- 10769301
TI - Haematological and spermatotoxic effects of ethylene glycol monomethyl ether in
copper clad laminate factories.
AB - OBJECTIVES: To investigate the effects of ethylene glycol monomethyl ether (EGME)
on haematology and reproduction in exposed workers. METHODS: 53 Impregnation
workers from two factories that make copper clad laminate with EGME as a solvent
were recruited as the exposed group. Another group of 121 lamination workers with
indirect exposure to EGME was recruited as the control group. Environmental
monitoring of concentrations of EGME in air and biological monitoring of urinary
methoxyacetic acid (MAA) concentrations were performed. Venous blood was
collected for routine and biochemical analyses. Semen was collected from 14
workers exposed to EGME for sperm analysis and was compared with 13 control
workers. RESULTS: Results of haematological examination showed that the
haemoglobin, packed cell volume, and red blood cell count in the male workers
exposed to EGME were significantly lower than in the controls. The frequency of
anaemia in the exposed group (26.1%) was significantly higher than in the control
group (3.2%). However, no differences were found between the female workers
exposed and not exposed to EGME. After adjustment for sex, body mass index, and
duration of employment, red blood cell count was significantly negatively
associated with air concentrations of EGME, and haemoglobin, packed cell volume,
and red blood cell count were significantly negatively associated with urinary
concentrations of MAA. The pH of semen in the exposed workers was significantly
lower than in the control workers, but there were no significant differences in
the sperm count or sperm morphology between the exposed and control groups.
CONCLUSION: It can be concluded that EGME is a haematological toxin, which leads
to anaemia in the exposed workers. However, the data from this study did not
support the theory of a spermatotoxic effect of EGME.
PMID- 10769302
TI - Fatigue among working people: validity of a questionnaire measure.
AB - OBJECTIVES: To evaluate the validity of the checklist individual strength
questionnaire (CIS) in the working population. This 20 item self reported
questionnaire has often been used in patients with chronic fatigue. To date, no
research has focused on the validity of the CIS in occupational groups. METHODS:
To evaluate the discriminant validity the CIS was filled out by five groups of
employees with expected differences in fatigue. The convergent validity was
evaluated by comparing the results of the CIS with the results of three related
measures: measured unidimensional fatigue, burnout, and need for recovery.
RESULTS: The CIS was able to discriminate between fatigued and non-fatigued
employees in occupational groups. The expected agreement between the results of
the CIS and related measures was confirmed. CONCLUSIONS: The CIS seems to be an
appropriate instrument for measuring fatigue in the working population.
PMID- 10769303
TI - Asbestosis and lobar site of lung cancer.
AB - OBJECTIVE: To assess the evidence for the hypothesis that lung cancer has a
predilection for the lower lobes in workers with asbestosis. METHOD: A review of
the available literature with relevant information. RESULTS: Six published
reports were analysed. In four studies limited to series of cases with diagnoses
of asbestosis, three showed lower lobe predominance of lung cancer whereas the
fourth study included cases in which the radiographic readings did not meet the
usual criterion of profusion for asbestosis. One cohort study showed lower lobe
predominance; the other reported only 33% lower lobe cancers compared with 20% in
unexposed controls. CONCLUSION: There is some support for the hypothesis but more
studies are needed.
PMID- 10769304
TI - Imaging cognition II: An empirical review of 275 PET and fMRI studies.
AB - Positron emission tomography (PET) and functional magnetic resonance imaging
(fMRI) have been extensively used to explore the functional neuroanatomy of
cognitive functions. Here we review 275 PET and fMRI studies of attention
(sustained, selective, Stroop, orientation, divided), perception (object, face,
space/motion, smell), imagery (object, space/motion), language (written/spoken
word recognition, spoken/no spoken response), working memory (verbal/numeric,
object, spatial, problem solving), semantic memory retrieval (categorization,
generation), episodic memory encoding (verbal, object, spatial), episodic memory
retrieval (verbal, nonverbal, success, effort, mode, context), priming
(perceptual, conceptual), and procedural memory (conditioning, motor, and
nonmotor skill learning). To identify consistent activation patterns associated
with these cognitive operations, data from 412 contrasts were summarized at the
level of cortical Brodmann's areas, insula, thalamus, medial-temporal lobe
(including hippocampus), basal ganglia, and cerebellum. For perception and
imagery, activation patterns included primary and secondary regions in the dorsal
and ventral pathways. For attention and working memory, activations were usually
found in prefrontal and parietal regions. For language and semantic memory
retrieval, typical regions included left prefrontal and temporal regions. For
episodic memory encoding, consistently activated regions included left prefrontal
and medial temporal regions. For episodic memory retrieval, activation patterns
included prefrontal, medial temporal, and posterior midline regions. For priming,
deactivations in prefrontal (conceptual) or extrastriate (perceptual) regions
were consistently seen. For procedural memory, activations were found in motor as
well as in non-motor brain areas. Analysis of regional activations across
cognitive domains suggested that several brain regions, including the cerebellum,
are engaged by a variety of cognitive challenges. These observations are
discussed in relation to functional specialization as well as functional
integration.
PMID- 10769305
TI - Activation in human MT/MST by static images with implied motion.
AB - A still photograph of an object in motion may convey dynamic information about
the position of the object immediately before and after the photograph was taken
(implied motion). Medial temporal/medial superior temporal cortex (MT/MST) is one
of the main brain regions engaged in the perceptual analysis of visual motion. In
two experiments we examined whether MT/MST is also involved in representing
implied motion from static images. We found stronger functional magnetic
resonance imaging (fMRI) activation within MT/MST during viewing of static
photographs with implied motion compared to viewing of photographs without
implied motion. These results suggest that brain regions involved in the visual
analysis of motion are also engaged in processing implied dynamic information
from static images.
PMID- 10769306
TI - Specialized neural systems underlying representations of sequential movements.
AB - The ease by which movements are combined into skilled actions depends on many
factors, including the complexity of movement sequences. Complexity can be
defined by the surface structure of a sequence, including motoric properties such
as the types of effectors, and by the abstract or sequence-specific structure,
which is apparent in the relations amongst movements, such as repetitions. It is
not known whether different neural systems support the cognitive and the
sensorimotor processes underlying different structural properties of sequential
actions. We investigated this question using whole-brain functional magnetic
resonance imaging (fMRI) in healthy adults as they performed sequences of five
key presses involving up to three fingers. The structure of sequences was defined
by two factors that independently lengthen the time to plan sequences before
movement: the number of different fingers (1-3; surface structure) and the number
of finger transitions (0-4; sequence-specific structure). The results showed that
systems involved in visual processing (extrastriate cortex) and the preparation
of sensory aspects of movement (rostral inferior parietal and ventral premotor
cortex (PMv)) correlated with both properties of sequence structure. The number
of different fingers positively correlated with activation intensity in the
cerebellum and superior parietal cortex (anterior), systems associated with
sensorimotor, and kinematic representations of movement, respectively. The number
of finger transitions correlated with activation in systems previously associated
with sequence-specific processing, including the inferior parietal and the dorsal
premotor cortex (PMd), and in interconnecting superior temporal-middle frontal
gyrus networks. Different patterns of activation in the left and right inferior
parietal cortex were associated with different sequences, consistent with the
speculation that sequences are encoded using different mnemonics, depending on
the sequence-specific structure. In contrast, PMd activation correlated
positively with increases in the number of transitions, consistent with the role
of this area in the retrieval or preparation of abstract action plans. These
findings suggest that the surface and the sequence-specific structure of
sequential movements can be distinguished by distinct distributed systems that
support their underlying mental operations.
PMID- 10769307
TI - Output units of motor behavior: an experimental and modeling study.
AB - Cognitive approaches to motor control typically concern sequences of discrete
actions without taking into account the stunning complexity of the geometry and
dynamics of the muscles. This begs the question: Does the brain convert the
intricate, continuous-time dynamics of the muscles into simpler discrete units of
actions, and if so, how? One way for the brain to form discrete units of behavior
from muscles is through the synergistic co-activation of muscles. While this
possibility has long been known, the composition of potential muscle synergies
has remained elusive. In this paper, we have focused on a method that allowed us
to examine and compare the limb stabilization properties of all possible muscle
combinations. We found that a small set (as few as 23 out of 65,536) of all
possible combinations of 16 limb muscles are robust with respect to activation
noise: these muscle combinations could stabilize the limb at predictable,
restricted portions of the workspace in spite of broad variations in the force
output of their component muscles. The locations at which the robust synergies
stabilize the limb are not uniformly distributed throughout the leg's workspace,
but rather, they cluster at four workspace areas. The simulated robust synergies
are similar to the actual synergies we have previously found to be generated by
activation of the spinal cord. Thus, we have developed a new analytical method
that enabled us to select a few muscle synergies with interesting properties out
of the set of possible muscle combinations. Beyond this, the identification of
robustness as a common property of the synergies in simple motor behaviors will
open the way to the study of dynamic stability, which is an important and
distinct property of the vertebrate motor-control system.
PMID- 10769308
TI - Functional anatomy of high-resolution visual mental imagery.
AB - This study had two purposes. First, in order to address the controversy regarding
activation of the primary visual area (PVA) during visual mental imagery,
regional cerebral blood flow (rCBF) was recorded while subjects performed a task
that required high-resolution visual mental imagery. Second, in order to discover
whether verbal descriptions can engage visual mechanisms during imagery in the
same way as visual stimuli, subjects memorized 3D scenes that were visually
presented or were based on a verbal description. Comparison of the results from
the imagery conditions to a non-imagery baseline condition revealed no activation
in PVA for imagery based on a verbal description and a significant decrease of
rCBF in this region for imagery based on visual learning. The pattern of
activation in other regions was very similar in the two conditions, including
parietal, midbrain, cerebellar, prefrontal, left insular, and right inferior,
temporal regions. These results provide strong evidence that imagery based on
verbal descriptions can recruit regions known to be engaged in high-order visual
processing.
PMID- 10769309
TI - Anatomical segregation of component processes in an inductive inference task.
AB - Inductive inference underlies much of human cognition. The essential component of
induction is hypothesis selection based on some criterion of relevance. The
purpose of this study was to determine the neural substrate of inductive
inference, particularly hypothesis selection, using fMRI. Ten volunteers were
shown stimuli consisting of novel animals under two task conditions, and asked to
judge whether all the animals in the set were the same type of animal. In one
condition, subjects were given a rule that specified the criteria for "same type
of animal". In the other condition, subjects had to infer the rule without
instruction. The two conditions were further factored into easy and difficult
components. Rule inference was specifically associated with bilateral hippocampal
activation while the task by difficulty interaction was associated with
activation in right lateral orbital prefrontal cortex. We interpret the former in
terms of semantic encoding of novel stimuli and the latter in terms of hypothesis
selection. Thus, we show an anatomical dissociation between task implementation
and task difficulty that may correspond to a critical psychological distinction
in the processes necessary for inductive inference.
PMID- 10769310
TI - An event-related neuroimaging study distinguishing form and content in sentence
processing.
AB - Two coordinated experiments using functional Magnetic Resonance Imaging (fMRI)
investigated whether the brain represents language form (grammatical structure)
separately from its meaning content (semantics). While in the scanner, 14 young,
unimpaired adults listened to simple sentences that were either nonanomalous or
contained a grammatical error (for example, *Trees can grew.), or a semantic
anomaly (for example, *Trees can eat.). A same⁄different tone pitch
judgment task provided a baseline that isolated brain activity associated with
linguistic processing from background activity generated by attention to the task
and analysis of the auditory input. Sites selectively activated by sentence
processing were found in both hemispheres in inferior frontal, middle, and
superior frontal, superior temporal, and temporo-parietal regions. Effects of
syntactic and semantic anomalies were differentiated by some nonoverlapping areas
of activation: Syntactic anomaly triggered significantly increased activity in
and around Broca's area, whereas semantic anomaly activated several other sites
anteriorly and posteriorly, among them Wernicke's area. These dissociations
occurred when listeners were not required to attend to the anomaly. The results
confirm that linguistic operations in sentence processing can be isolated from
nonlinguistic operations and support the hypothesis of a specialization for
syntactic processing.
PMID- 10769311
TI - Functional changes in brain activity during priming in Alzheimer's disease.
AB - Patients with Alzheimer's disease (AD) are often impaired on certain forms of
implicit memory, such as word-stem completion priming (WSCP). Lesion data suggest
that deficient WSCP may be associated with abnormal functioning in the posterior
neocortex. Using positron emission tomography (PET), we here provide direct
support for this view. Compared with normal old adults, AD patients showed
reduced priming on a word-stem completion task. The normal old showed decreased
activity in right occipital cortex (area 19), whereas the AD patients showed
increased activity in this region during priming. To the extent that decreased
activity during priming reflects an experience-dependent reduction of the
neuronal population involved, these results indicate that shaping of the relevant
neurons is slower in AD, possibly as a result of inadequate initial stimulus
processing.
PMID- 10769312
TI - Contrasting cortical and subcortical activations produced by attentional-set
shifting and reversal learning in humans.
AB - Much evidence suggests that lesions of the prefrontal cortex (PFC) produce marked
impairments in the ability of subjects to shift cognitive set, as exemplified by
performance of the Wisconsin Card Sorting Test (WCST). However, studies with
humans and experimental primates have suggested that damage to different regions
of PFC induce dissociable impairments in two forms of shift learning implicit in
the WCST (that is, extradimensional (ED) shift learning and reversal shift
learning), with similar deficits also being apparent after damage to basal
ganglia structures, especially the caudate nucleus. In this study, we used the
same visual discrimination learning paradigm over multidimensional stimuli, and
the H215O positron emission tomography (PET) technique, to examine regional
cerebral blood flow (rCBF) changes associated with these subcomponent processes
of the WCST. In three conditions, subjects were scanned while acquiring visual
discriminations involving either (i) the same stimulus dimension as preceding
discriminations (intradimensional (ID) shifts); (ii) different stimulus
dimensions from previous discriminations (ED shifts) or (iii) reversed stimulus
reward contingencies (reversal shifts). Additionally, subjects were scanned while
responding to already learnt discriminations ('performance baseline'). ED shift
learning, relative to ID shift learning, produced activations in prefrontal
regions, including left anterior PFC and right dorsolateral PFC (BA 10 and
9⁄46). By contrast, reversal learning, relative to ID shift learning,
produced activations of the left caudate nucleus. Additionally, compared to
reversal and ID shift learning, ED shift learning was associated with relative
deactivations in occipito-temporal pathways (for example, BA 17 and 37). These
results confirm that, in the context of visual discrimination learning over
multidimensional stimuli, the control of an acquired attentional bias or'set',
and the control of previously acquired stimulus-reinforcement associations,
activate distinct cortical and subcortical neural stations. Moreover, we propose
that the PFC may contribute to the control of attentional-set by modulating
attentional processes mediated by occipito-temporal pathways.
PMID- 10769313
TI - Large scale neurocognitive networks underlying episodic memory.
AB - Large-scale networks of brain regions are believed to mediate cognitive
processes, including episodic memory. Analyses of regional differences in brain
activity, measured by functional neuroimaging, have begun to identify putative
components of these networks. To more fully characterize neurocognitive networks,
however, it is necessary to use analytical methods that quantify neural network
interactions. Here, we used positron emission tomography (PET) to measure brain
activity during initial encoding and subsequent recognition of sentences and
pictures. For each type of material, three recognition conditions were included
which varied with respect to target density (0%, 50%, 100%). Analysis of large
scale activity patterns identified a collection of foci whose activity
distinguished the processing of sentences vs. pictures. A second pattern, which
showed strong prefrontal cortex involvement, distinguished the type of cognitive
process (encoding or retrieval). For both pictures and sentences, the
manipulation of target density was associated with minor activation changes.
Instead, it was found to relate to systematic changes of functional connections
between material-specific regions and several other brain regions, including
medial temporal, right prefrontal and parietal regions. These findings provide
evidence for large-scale neural interactions between material-specific and
process-specific neural substrates of episodic encoding and retrieval.
PMID- 10769314
TI - Age differences in the frontal lateralization of verbal and spatial working
memory revealed by PET.
AB - Age-related decline in working memory figures prominently in theories of
cognitive aging. However, the effects of aging on the neural substrate of working
memory are largely unknown. Positron emission tomography (PET) was used to
investigate verbal and spatial short-term storage (3 sec) in older and younger
adults. Previous investigations with younger subjects performing these same tasks
have revealed asymmetries in the lateral organization of verbal and spatial
working memory. Using volume of interest (VOI) analyses that specifically
compared activation at sites identified with working memory to their homologous
twin in the opposite hemisphere, we show pronounced age differences in this
organization, particularly in the frontal lobes: In younger adults, activation is
predominantly left lateralized for verbal working memory, and right lateralized
for spatial working memory, whereas older adults show a global pattern of
anterior bilateral activation for both types of memory. Analyses of frontal
subregions indicate that several underlying patterns contribute to global
bilaterality in older adults: most notably, bilateral activation in areas
associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal
sites (DLPFC; greater left activation for spatial and greater right activation
for verbal). We consider several mechanisms that could account for these age
differences including the possibility that bilateral activation reflects
recruitment to compensate for neural decline.
PMID- 10769315
TI - Age differences in behavior and PET activation reveal differences in interference
resolution in verbal working memory.
AB - Older adults were tested on a verbal working memory task that used the item
recognition paradigm. On some trials of this task, response-conflict was created
by presenting test-items that were familiar but were not members of a current set
of items stored in memory. These items required a negative response, but their
familiarity biased subjects toward a positive response. Younger subjects show an
interference effect on such trials, and this interference is accompanied by
activation of a region of left lateral prefrontal cortex. However, there has been
no evidence that the activation in this region is causally related to the
interference that the subjects exhibit. In the present study, we demonstrate that
older adults show more behavioral interference than younger subjects on this
task, and they also show no reliable activation at the same lateral prefrontal
site. This leads to the conclusion that this prefrontal site is functionally
involved in mediating resolution among conflicting responses or among conflicting
representations in working memory.
PMID- 10769316
TI - Age-related differences in neural activity during item and temporal-order memory
retrieval: a positron emission tomography study.
AB - Positron emission tomography (PET) was used to investigate the hypothesis that
older adults' difficulties with temporal-order memory are related to deficits in
frontal function. Young (mean 24.7 years) and old (mean 68.6 years) participants
studied a list of words, and were then scanned while retrieving information about
what words were in the list (item retrieval) or when they occurred within the
list (temporal-order retrieval). There were three main results. First, whereas
the younger adults engaged right prefrontal regions more during temporal-order
retrieval than during item retrieval, the older adults did not. This result is
consistent with the hypothesis that context memory deficits in older adults are
due to frontal dysfunction. Second, ventromedial temporal activity during item
memory was relatively unaffected by aging. This finding concurs with evidence
that item memory is relatively preserved in old adults and with the notion that
medial temporal regions are involved in automatic retrieval operations. Finally,
replicating the result of a previous study (Cabeza, R., Grady, C. L., Nyberg, L.,
McIntosh, A. R. , Tulving, E., Kapur, S., Jennings, J. M., Houle, S., and Craik,
F. I. M., 1997), the old adults showed weaker activations than the young adults
in the right prefrontal cortex but stronger activations in the left prefrontal
cortex. The age-related increase in left prefrontal activity may be interpreted
as compensatory. Taken together, the results suggest that age-related changes in
brain activity are rather process- and region-specific, and that they involve
increases as well as decreases in neural activity.
PMID- 10769317
TI - A crosslinguistic PET study of tone perception.
AB - In studies of pitch processing, a fundamental question is whether shared neural
mechanisms at higher cortical levels are engaged for pitch perception of
linguistic and nonlinguistic auditory stimuli. Positron emission tomography (PET)
was used in a crosslinguistic study to compare pitch processing in native
speakers of two tone languages (that is, languages in which variations in pitch
patterns are used to distinguish lexical meaning), Chinese and Thai, with those
of English, a nontone language. Five subjects from each language group were
scanned under three active tasks (tone, pitch, and consonant) that required
focused-attention, speeded-response, auditory discrimination judgments, and one
passive baseline as silence. Subjects were instructed to judge pitch patterns of
Thai lexical tones in the tone condition; pitch patterns of nonspeech stimuli in
the pitch condition; syllable-initial consonants in the consonant condition.
Analysis was carried out by paired-image subtraction. When comparing the tone to
the pitch task, only the Thai group showed significant activation in the left
frontal operculum. Activation of the left frontal operculum in the Thai group
suggests that phonological processing of suprasegmental as well as segmental
units occurs in the vicinity of Broca's area. Baseline subtractions showed
significant activation in the anterior insular region for the English and Chinese
groups, but not Thai, providing further support for the existence of possibly two
parallel, separate pathways projecting from the temporo-parietal to the frontal
language area. More generally, these differential patterns of brain activation
across language groups and tasks support the view that pitch patterns are
processed at higher cortical levels in a top-down manner according to their
linguistic function in a particular language.
PMID- 10769318
TI - A twin MRI study of size variations in human brain.
AB - Although it is well known that there is considerable variation among individuals
in the size of the human brain, the etiology of less extreme individual
differences in brain size is largely unknown. We present here data from the first
large twin sample (N=132 individuals) in which the size of brain structures has
been measured. As part of an ongoing project examining the brain correlates of
reading disability (RD), whole brain morphometric analyses of structural magnetic
response image (MRI) scans were performed on a sample of adolescent twins.
Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which
at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither
member had RD. We first factor-analyzed volume data for 13 individual brain
structures, comprising all of the neocortex and most of the subcortex. This
analysis yielded two factors ("cortical" and "subcortical") that accounted for
64% of the variance. We next tested whether genetic and environmental influences
on brain size variations varied for these two factors or by hemisphere. We
computed intraclass correlations within MZ and DZ pairs in each sample for the
cortical and subcortical factor scores, for left and right neocortex, and for the
total cerebral volume. All five MZ correlations were substantial (r's=.78 to.98)
and significant in both samples, as well as being larger than the corresponding
DZ correlations, (r's=0.32 to 0.65) in both samples. The MZ-DZ difference was
significant for 3 variables in the RD sample and for one variable in the smaller
control sample. These results indicate significant genetic influences on these
variables. The magnitude of genetic influence did not vary markedly either for
the 2 factors or the 2 hemispheres. There was also a positive correlation between
brain size and full-scale IQ, consistent with the results of earlier studies. The
total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with
full-scale IQ in the RD sample; there was a similar trend in the smaller control
sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found
between the subcortical factor and full-scale IQ, whereas the results for the
cortical factor (r=.16 and.13) were smaller and not significant. In sum, these
results provide evidence for the heritability of individual differences in brain
size which do not vary markedly by hemisphere or for neocortex relative to
subcortex. Since there are also correlations between brain size and full-scale IQ
in this sample, it is possible that genetic influences on brain size partly
contribute to individual differences in IQ.
PMID- 10769319
TI - Dynamics of encoding in neuron populations: some general mathematical features.
AB - The use of a population dynamics approach promises efficient simulation of large
assemblages of neurons. Depending on the issues addressed and the degree of
realism incorporated in the simulated neurons, a wide range of different
population dynamics formulations can be appropriate. Here we present a common
mathematical structure that these various formulations share and that implies
dynamical behaviors that they have in common. This underlying structure serves as
a guide toward efficient means of simulation. As an example, we derive the
general population firing-rate frequency-response and show how it may be used
effectively to address a broad range of interacting-population response and
stability problems. A few specific cases will be worked out. A summary of this
work appears at the end, before the appendix.
PMID- 10769320
TI - Local and global gating of synaptic plasticity.
AB - Mechanisms influencing learning in neural networks are usually investigated on
either a local or a global scale. The former relates to synaptic processes, the
latter to unspecific modulatory systems. Here we study the interaction of a local
learning rule that evaluates coincidences of pre- and postsynaptic action
potentials and a global modulatory mechanism, such as the action of the basal
forebrain onto cortical neurons. The simulations demonstrate that the interaction
of these mechanisms leads to a learning rule supporting fast learning rates,
stability, and flexibility. Furthermore, the simulations generate two
experimentally testable predictions on the dependence of backpropagating action
potential on basal forebrain activity and the relative timing of the activity of
inhibitory and excitatory neurons in the neocortex.
PMID- 10769321
TI - Nonlinear autoassociation is not equivalent to PCA.
AB - A common misperception within the neural network community is that even with
nonlinearities in their hidden layer, autoassociators trained with
backpropagation are equivalent to linear methods such as principal component
analysis (PCA). Our purpose is to demonstrate that nonlinear autoassociators
actually behave differently from linear methods and that they can outperform
these methods when used for latent extraction, projection, and classification.
While linear autoassociators emulate PCA, and thus exhibit a flat or unimodal
reconstruction error surface, autoassociators with nonlinearities in their hidden
layer learn domains by building error reconstruction surfaces that, depending on
the task, contain multiple local valleys. This interpolation bias allows
nonlinear autoassociators to represent appropriate classifications of nonlinear
multimodal domains, in contrast to linear autoassociators, which are
inappropriate for such tasks. In fact, autoassociators with hidden unit
nonlinearities can be shown to perform nonlinear classification and nonlinear
recognition.
PMID- 10769322
TI - No free lunch for noise prediction.
AB - No-free-lunch theorems have shown that learning algorithms cannot be universally
good. We show that no free funch exists for noise prediction as well. We show
that when the noise is additive and the prior over target functions is uniform, a
prior on the noise distribution cannot be updated, in the Bayesian sense, from
any finite data set. We emphasize the importance of a prior over the target
function in order to justify superior performance for learning systems.
PMID- 10769323
TI - Self-organisation of symmetry networks: transformation invariance from the
spontaneous symmetry-breaking mechanism.
AB - Symmetry networks use permutation symmetries among synaptic weights to achieve
transformation-invariant response. This article proposes a generic mechanism by
which such symmetries can develop during unsupervised adaptation: it is shown
analytically that spontaneous symmetry breaking can result in the discovery of
unknown invariances of the data's probability distribution. It is proposed that a
role of sparse coding is to facilitate the discovery of statistical invariances
by this mechanism. It is demonstrated that the statistical dependences that exist
between simple-cell-like threshold feature detectors, when exposed to temporally
uncorrelated natural image data, can drive the development of complex-cell-like
invariances, via single-cell Hebbian adaptation. A single learning rule can
generate both simple-cell-like and complex-cell-like receptive fields.
PMID- 10769324
TI - Geometric analysis of population rhythms in synaptically coupled neuronal
networks.
AB - We develop geometric dynamical systems methods to determine how various
components contribute to a neuronal network's emergent population behaviors. The
results clarify the multiple roles inhibition can play in producing different
rhythms. Which rhythms arise depends on how inhibition interacts with intrinsic
properties of the neurons; the nature of these interactions depends on the
underlying architecture of the network. Our analysis demonstrates that fast
inhibitory coupling may lead to synchronized rhythms if either the cells within
the network or the architecture of the network is sufficiently complicated. This
cannot occur in mutually coupled networks with basic cells; the geometric
approach helps explain how additional network complexity allows for synchronized
rhythms in the presence of fast inhibitory coupling. The networks and issues
considered are motivated by recent models for thalamic oscillations. The analysis
helps clarify the roles of various biophysical features, such as fast and slow
inhibition, cortical inputs, and ionic conductances, in producing network
behavior associated with the spindle sleep rhythm and with paroxysmal discharge
rhythms. Transitions between these rhythms are also discussed.
PMID- 10769325
TI - An accurate measure of the instantaneous discharge probability, with application
to unitary joint-even analysis.
AB - We present an estimate for the instantaneous discharge probability of a neurone,
based on single-trial spike-train analysis. By detecting points where the neurone
abruptly changes its firing rate and treating them specially, the method is able
to achieve smooth estimates yet avoid the blurring of significant changes. This
estimate of instantaneous discharge probability is then applied to the method of
unitary event analysis. We show that the unitary event analysis as originally
conceived is highly sensitive to firing-rate nonstationarities and covariations,
but that it can be considerably improved if calculations of statistical
significance use an instantaneous discharge probability instead of a firing-rate
estimate based on averaging across multiple trials.
PMID- 10769326
TI - Impact of correlated inputs on the output of the integrate- and-fire model.
AB - For the integrate-and-fire model with or without reversal potentials, we consider
how correlated inputs affect the variability of cellular output. For both models,
the variability of efferent spike trains measured by coefficient of variation
(CV) of the interspike interval is a nondecreasing function of input correlation.
When the correlation coefficient is greater than 0.09, the CV of the integrate
and-fire model without reversal potentials is always above 0.5, no matter how
strong the inhibitory inputs. When the correlation coefficient is greater than
0.05, CV for the integrate-and-fire model with reversal potentials is always
above 0. 5, independent of the strength of the inhibitory inputs. Under a given
condition on correlation coefficients, we find that correlated Poisson processes
can be decomposed into independent Poisson processes. We also develop a novel
method to estimate the distribution density of the first passage time of the
integrate-and-fire model.
PMID- 10769327
TI - Weak, stochastic temporal correlation of large scale synaptic input is A major
determinant of neuronal bandwidth.
AB - We determine the bandwidth of a model neurone to large-scale synaptic input by
assessing the frequency response between the outputs of a two-cell simulation
that share a percentage of the total synaptic input. For temporally uncorrelated
inputs, a large percentage of common inputs are required before the output
discharges of the two cells exhibit significant correlation. In contrast, a small
percentage (5%) of the total synaptic input that involves stochastic spike trains
that are weakly correlated over a broad range of frequencies exert a clear
influence on the output discharge of both cells over this range of frequencies.
Inputs that are weakly correlated at a single frequency induce correlation
between the output discharges only at the frequency of correlation. The strength
of temporal correlation required is sufficiently weak that analysis of a sample
pair of input spike trains could fail to reveal the presence of correlated input.
Weak temporal correlation between inputs is therefore a major determinant of the
transmission to the output discharge of frequencies present in the spike
discharges of presynaptic inputs, and therefore of neural bandwidth.
PMID- 10769328
TI - Second-order learning algorithm with squared penalty term.
AB - This article compares three penalty terms with respect to the efficiency of
supervised learning, by using first- and second-order off-line learning
algorithms and a first-order on-line algorithm. Our experiments showed that for a
reasonably adequate penalty factor, the combination of the squared penalty term
and the second-order learning algorithm drastically improves the convergence
performance in comparison to the other combinations, at the same time bringing
about excellent generalization performance. Moreover, in order to understand how
differently each penalty term works, a function surface evaluation is described.
Finally, we show how cross validation can be applied to find an optimal penalty
factor.
PMID- 10769329
TI - Quality versus quantity: the case for the very old.
PMID- 10769330
TI - Heat waves: their impact on the health of elders.
AB - A trend toward more hot and humid summers in the United States raises concern for
the health of our elderly population. Older adults are more vulnerable to heat
illness than younger people because of dysfunctional thermoregulatory mechanisms,
chronic dehydration, medications, and diseases involving the systems that
regulate body temperature. Heat exhaustion, if untreated, will lead to heat
stroke, which is fatal if body temperature is not quickly lowered, and research
shows that survivors may suffer long-term disabilities. Prevention requires
strong knowledge and application of measures necessary to keep elders healthy in
extreme heat. Should illness occur, careful monitoring and assessment will ensure
early detection and prompt treatment. This article provides information for
caregivers that will enable them to protect their patients from heat illness. It
also discusses age-related changes in the thermoregulatory system's response to
heat, risk factors, assessment criteria, preventive measures, and first aid for
victims of heat exhaustion and heat stroke.
PMID- 10769331
TI - Chronic constipation management for institutionalized older adults.
AB - Bran's effectiveness in reducing the need for bowel medication for intermediate
care patients was examined at a VA medical center in New York. Twelve older men
with chronic constipation and bowel medication use were matched and randomized to
receive either bran treatment or usual care (controls). After baseline
assessment, six patients were given gradually increasing daily doses of a bran
mixture. Results over a 4-month period showed that these patients completely
discontinued oral laxative use and had an 80% reduction in total bowel medication
use without adversely affecting bowel frequency. The six men who received usual
care (controls) experienced no changes.
PMID- 10769332
TI - Dehydration: hazards and benefits.
AB - Dehydration is a serious risk for elders because total body water decreases with
age, aging kidneys are less able to concentrate urine, and the sensation of
thirst decreases. Geriatric nurses traditionally have assessed for dehydration,
but its signs are difficult to detect in many patients. Instead, nurses,
assistive personnel, and family members must work to prevent dehydration in
elders. In contrast, dehydration may be beneficial to patients during the final
stage of a terminal illness, although the decision to withhold or withdraw
medical hydration may present a legal and ethical dilemma for nurses.
PMID- 10769333
TI - End-of-life ethical issues in Japan.
AB - This article discusses the end-of-life ethical issues of disclosure of
information to the terminally ill patient, informed consent, and overtreatment
for the elderly people of Japan. These issues are placed within the cultural
context of Japan, which is discussing and developing ways to deal with them. The
ethical problems that nurses confront when they work clinically with elderly
patients also are outlined. No consensus has been reached about the ethics of
health care in Japan.
PMID- 10769334
TI - Cognitive evaluation in care planning for people with Alzheimer disease and
related dementias.
AB - Caring for people with Alzheimer disease or related dementias can be a
challenging task. Anxiety, wandering, agitation, and aggressive behaviors can be
frustrating for both resident and care providers. With creative programming,
these symptoms can be lessened or even eliminated. Cognitive evaluation can
provide a roadmap for successful and creative care planning for these
individuals. Knowing the person's abilities and limitations can create a positive
environment and enhance his or her quality of life. The program described in this
article uses cognitive evaluation in the care delivery process.
PMID- 10769335
TI - NGNA Launches Research Grant Program.
PMID- 10769336
TI - Wandering problems need ongoing nursing planning. A case study.
PMID- 10769337
TI - The relationship between severity of physical impairment and costs of care in an
elderly population.
AB - The cost-effective use of long-term care options in a resource-scarce environment
depends on targeting services to people who could be cared for most efficiently
in specific settings. This study identified subgroups with a high potential for
reduced costs of care in different settings by using some measures of physical
impairment. The findings indicated that, for elderly people with physical
impairment scores below 12 (possible range of 0 to 14), the cost of care was
lower with home care than in the nursing home setting. However, for elderly
people with physical impairment scores above 12, the cost of care was higher with
home care than in a nursing home.
PMID- 10769338
TI - Medicate with caution to prevent problems in frail elders.
PMID- 10769339
TI - Philosophical perspectives in home care: the ontology of aging.
PMID- 10769340
TI - Nutritional anemia.
PMID- 10769341
TI - Occupational asthma: "the big picture".
AB - With more than 200 agents inducing occupational asthma, an organized approach to
identify the impact of both low- and high-molecular-weight agents is important.
In this report, our goal is to explain the general categories of the sensitizing
agents, present guidelines regarding what might be expected when exposures and
sensitization occur, and present a number of references that can be explored to
find information regarding the outcome of those with these illnesses.
PMID- 10769342
TI - How much asthma is occupationally related?
AB - Asthma is a chronic respiratory disease that is increasing in both prevalence and
mortality in developed countries around the world. Occupational exposures to
sensitizers and irritants are causes of both asthma cases and asthma
exacerbations in adults. The determination of how many cases of asthma may be
caused or worsened by occupational exposures is highly dependent on how asthma is
defined, what constitutes work-relatedness, and what specific methodology is
employed. Surveillance-based methods generally have found the lowest proportion
of work-related asthma, ranging from 1-8% of cases. Other types of studies, using
exposed-unexposed methodology or interviews of incident asthma cases, have
determined that 10-25% of cases are occupationally related. Ultimate
determination of how much asthma may be related to occupational or environmental
exposures will require better surveillance of asthma, along with a better
understanding of this disease and its natural history.
PMID- 10769343
TI - Why are some low-molecular-weight agents asthmagenic.
AB - The chemical structure of low-molecular-weight substances (LMW) that cause
occupational asthma (OA) determines their reactivity and hence their OA hazard.
LMW agents that can form at least two bonds with native human macromolecules
carry a higher OA hazard. Thus bi- or polyfunctional LMW agents such as
diisocyanates and aliphatic or cyclic amines, as well as dicarboxylic acid
anhydrides and dialdehydes, rank highly among organic LMW substances, while some
transition metal ions or their complexes also are OA hazards. More subtle effects
arise from diverse reactive groups or unsaturation. Quantitative structure
activity relationships show increasing promise in predicting the OA hazard of
these LMW substances.
PMID- 10769344
TI - Is specific antibody determination diagnostic for asthma attributable to low
molecular-weight agents?
AB - It is important to understand a medical testis performance characteristics, so
that it can be used appropriately. Performance characteristics of tests for
antibodies specific to low-molecular-weight (LMW) agents in predicting asthma
caused by these agents differ in the study population. In general, currently
published data supporting the use of tests to detect specific IgE and IgG to LMW
agents in the diagnosis of occupational asthma is limited and inconclusive.
However, a few general statements can be made. The most promising results have
been achieved for agents such as acid anhydrides and platinum salts, where
specific IgE responses appear to play a significant pathogenic role in causing
occupational asthma. Results have been less promising for agents such as
isocyanates and plicatic acid, for which antibody responses do not appear to
underlie the development of asthma in most individuals. In the case of
isocyanates, determination of antigen-specific IgG might have some utility as a
biomarker of exposure.
PMID- 10769345
TI - Can We protect workers from developing the adverse respiratory effects of
isocyanate exposure?
AB - In this review, the authors have attempted to present the difficulty in defining
a permissible exposure limit (PEL) to agents that act as sensitizers and may
induce asthma-even at exposure levels less than the PEL. One approach to this
relatively unaddressed problem may be to define the separate aspects of exposure
to the specific sensitizing agent. The first effect is an accelerated rate of
decline in lung function in nonsensitized individuals who are exposed to the
agent (in this case the model used is isocyanates). The second effect is
sensitization. Rules for developing a PEL might take this sensitizing effect into
account, and this group of agents with such dual effects may be defined as
"sensitizers." Exposure to agents with this designation would require special
educational and surveillance initiatives to facilitate early detection. The
elimination of sensitization may be a greater challenge. An important form of
prevention is medical screening of exposed workers, yet it is unclear which
screening approach best identifies workers with early isocyanate asthma.
PMID- 10769346
TI - Beyond the peak flow meter: newer technologies for determining and documenting
changes in lung function in the workplace.
AB - There are many potential problems with the use of serial peak expiratory flow
(PEF) measurement to investigate potential occupational asthma. Among these are
inaccurate and incomplete recording of results. However, PEF meters will continue
to be used because of their relatively low cost and the availability of improved
graphing methods and computer-assisted interpretation (OASYS-2). New technologies
that automatically record PEF values and the time at which the maneuver was
performed have improved the reliability of serial PEF measurements. Further, new
hand-held spirometers not only record the test time but also the FEV&inf1; and
FEV&inf6;, in addition to PEF. Automated assessment of maneuver quality with
immediate feedback to the worker may improve test quality. The storage of raw
volume-time or flow-volume curves, not yet widely available, can be used by
reviewers to evaluate the quality of the maneuver on which PEF and FEV&inf1;
values are based-further improving the reliability of serial measurements.
Mechanical stimulators and testing waveforms are available to thoroughly test
these new devices and insure that they meet the minimum ATS requirements for
monitoring devices.
PMID- 10769347
TI - Couriers of asthma: antigenic proteins in natural rubber latex.
AB - Natural rubber latex (NRL) is a milky, white liquid containing the polymer cis
1,4-polyisoprene, derived from the laticifer cells of the rubber tree, Hevea
brasiliensis. Reports of allergic reactions to NRL, ranging in severity from skin
rashes to anaphylaxis and death, have been increasing. High rates of latex
allergy are seen in children with spina bifida. Healthcare workers, especially
those who frequently use powdered latex medical gloves, can develop NRL allergy
and asthma, often resulting in considerable disability. Atopy and, possibly, pre
existing dermatitis predispose to sensitization and allergic symptoms. NRL
protein antigens are found in many NRL products and also have been shown to bind
to cornstarch glove-donning powders. Of the approximately 240 polypeptides in
NRL, nearly 60 are antigenic, and nine have been identified and registered (Hev b
1&ndash9). Many natural latex antigens share epitopes with structural proteins
and enzymes from other plant species. Current knowledge indicates that proposed
reductions in total glove protein and limitations on the use of powder on NRL
gloves are likely to result in a decline in the prevalence and severity of NRL
allergies among healthcare workers.
PMID- 10769348
TI - Determinants of whether occupational agents cause early, late, or dual asthmatic
responses.
AB - Early asthmatic responses to aeroallergens can be predicted from skin prick tests
and the level of airway responsiveness. High-molecular-weight occupational agents
ought to behave in the same way, but this has not been established sufficiently
to allow challenge tests to be avoided. Responses to low-molecular-weight agents
are difficult to predict because of the absence of a good measure of
sensitization. Late responses appear more common with these agents, but this may
be in part a consequence of the single-dose challenge protocol that is commonly
used. The pattern of response also is likely to be influenced by the length of
time from the last exposure, and the use of medication.
PMID- 10769349
TI - Why does airway obstruction persist in asthma due to low-molecular-weight agents?
A Pathologistis view.
AB - The pathology of occupational asthma, which is similar to that of nonoccupational
asthma, is characterized by airway infiltration of eosinophils, mast cells, and T
lymphocytes associated with thickening of the subepithelial reticular basement
membrane. Since occupational asthma is caused by exposure to a sensitizing agent
present in the working environment, it might be expected that cessation of
occupational exposure leads to complete recovery from the disease. Unfortunately,
this fa orable prognosis is observed in only a small percentage of patients with
occupational asthma; in most of them, symptoms and bronchial hyperresponsiveness
persist, although often at a decreased level. The few longitudinal studies
performed on airway pathology in subjects with occupational asthma have shown
that, after cessation of exposure to the sensitizing agent, some of the
pathologic alterations (such as the subepithelial collagen deposition) improve,
whereas others (such as the airway eosinophilia) persist. This latter finding
suggests a role for eosinophils in the persistence of symptoms and bronchial
hyperresponsiveness in the majority of asthmatic subjects even several months
after removal from exposure.
PMID- 10769350
TI - Immunologic versus toxicologic mechanisms in airway responses.
AB - There is now considerable evidence that T lymphocytes play an important role in
generating the IgE-mediated immune response of classical allergic asthma. An
immune response can be generated by other routes, including IgG- and cell
mediated mechanisms, as well. Regardless of the mechanism, it is clear that
allergic asthma is an inflammatory disease, with activated T lymphocytes,
eosinophils, mast cells, and other leucocytes all playing a role. Recently, an
irritant asthma called reactive airway dysfunction syndrome also has emerged. It
appears to be due to direct irritant or toxic effects, but shares many features
of allergic asthma. Thus, several different pathways lead to the inflammatory
changes and nonspecific airway responsiveness underlying asthma.
PMID- 10769351
TI - Workplace respiratory irritants and asthma.
AB - Workplace respiratory irritants can have a variety of effects in relation to
asthma. Very high exposures can cause new-onset asthma (reactive airways
dysfunction syndrome or irritant-induced asthma) with or without concurrent
sensitization, e.g., to diisocyanate. Aggravation of underlying asthma can result
from moderate exposures. Adjuvant or other effects enhancing the risk of
sensitization to high molecular weight allergens have occurred with chronic low
moderate exposures. Enhancement of airway responsiveness on a short-term basis
can be produced by ozone and biological irritants such as endotoxin and beta 1-3
glucans. Production of nonasthmatic responses such as hyperventilation and vocal
cord dysfunction can mimic asthma symptoms. Controversy exists as to whether
moderate irritant exposures can cause asthma or long-term worsening of underlying
asthma.
PMID- 10769352
TI - [Virtual public health library].
PMID- 10769353
TI - [Schoolchildren statural deficit cartography in Paraiba State, Brazil].
AB - OBJECTIVE: The study is part of a project financed by the United Nations (FAO)
and the Ministry of Education of Brazil (Fundacao de Assistencia ao Escolar)
which intends to evaluate the nutritional status of public schools students in
order to estimate, giving emphasis to geographical aspects, the magnitude and
distribution of statural deficit of this population in the Paraiba State,
Northeastern Brazil. METHODS: Schoolchildren, aged 6-9 years and enrolled in the
first grade inall municipalities of Paraiba state went through a height survey.
We consider as statural deficit values below -2 standard deviations according to
the anthropometric pattern of National Center of Health Statistics. RESULTS: A
frequency of 14. 5% of statural deficit was found in the whole state, as well as
18. 7% in the semidesertic region (sertao), 13.8% in Agreste area, 11. 9% in
Borborema region and 10.9% in Mata zone. In rural area, the prevalence of
statural deficit was higher (17.8%) than for those living in urban area (11.8%).
CONCLUSIONS: The results reveal a process of inlanding of statural deficit, which
contrasts with historical descriptions of the geographical distribution of this
problem in the Northeastern region of Brazil
PMID- 10769354
TI - [Ocular health beliefs among teachers in the public educational system of the
city of Sao Paulo, SP, Brazil].
AB - OBJECTIVE: With the purpose of collecting information for training programs
targeted to teachers, ocular health beliefs were assessed concerning eyeglasses
wear, visual problems and damages while reading in different settings. METHODS: A
survey was carried out among first-grade teachers of public elementary schools
located in the Southern region of S. Paulo city, state of S. Paulo, Brazil. The
study population included 545 subjects from 120 different schools. A self
administered structured questionnaire was developed based on a previous
exploratory study. RESULTS: Average age in this population was 37.8 years and
they have been working as educators for an average of 13.2 years; most of them
(67.4%) have not received orientation on ocular health for the last three years;
almost all of them (99.4%) believed that eyeglasses should be wore constantly;
62. 3% considered the fact of a constant vision straining as an aggravating
factor for eye disorders; 95% of the teachers admitted that there could be
damaging consequences when someone watches television at a distance of less than
2 meters; 59.9% of them believed that watching TV with the lights off could
damage one's vision; 45.6% considered reading in a moving vehicle a cause for
visual problems. CONCLUSIONS: Popular beliefs related to eye health reveal a need
for orientation programs for teachers in order to implement preventive actions
related to eye health within elementary schools.
PMID- 10769355
TI - [Seroprevalence of Triatoma infestans Chagas disease after vector control
measures].
AB - INTRODUCTION: The study is part of a project intended to retrieve information
about the serology of the American trypanosomiasis in the state of Sao Paulo,
Brazil, during the period when there was a state effort to control the vector.
Data from the municipality of Taquarituba, administrative region of Sorocaba,
which was then important in the epidemiology of Chagas disease in that region,
were analyzed. Despite the government efforts started in the 1950s, domiciliary
triatomines were still being captured in that region during the 1970s. METHODS:
Population samples were selected from five localities of Taquarituba. Age, sex,
birthplace, and time of residence in the house being occupied at the time of the
interview, were recorded. It is used Probit analysis to assess a possible
relationship between age and seropositivity, the latter taken as indicative of
the risk of transmission. RESULTS: Blood from Taquarituba native people
represented 62.9% of the samples examined (n = 2.784) and 62.4% of all
seropositives (n = 380). Overall proportion of seropositives was 13.6% with no
significant difference between genders (p = 0.538). Children under 6 years of age
were not seropovitive, Seropositivity increased from 2.7% in the age group 6-9
years to 30.6% in the age group 30-39 years. By using probit analysis, an age
seropositivity relationship was found within these groups. CONCLUSIONS: The
results of serological tests pointed to an association between the actions taken
against Triatoma infestans and the decline and eventual control of the
transmission of Chagas disease in the late 1960s.
PMID- 10769356
TI - [Equivalence between revisions of the International Classification of Diseases:
causes of death].
AB - OBJECTIVE: To evaluate the comparability of the underlying cause and multiple
causes of death identified according to the ninth and tenth revisions of the
International Classification of Diseases. METHODS: Study data was obtained by a
random sample of 3,313 death certificates of individuals living in the State of
S. Paulo and whose death was registered during the year of 1992. They
corresponded to 1.6% of the total deaths of that year. The corresponding file was
processed by the Automated Classification of Medical Entities system, and codes
were assigned to all mentioned conditions. The underlying cause of death had been
evaluated and revised according to the ninth revision. All the conditions
mentioned on the medical form of the corresponding death certificates were coded
according to the tenth revision and the codes were introduced in the original
file in order to assess the causes of death by the Declaracoes de Obito de S.
Paulo system to obtain the underlying cause of death. Multiple causes of death
tabulations for both ninth and tenth revisions codes were produced by the
respective versions of the Multiple Causes of Death Tabulator software. The
comparisons of causes of death are circumscribed to the chapters of both
revisions. RESULTS/CONCLUSIONS: The most important changes with the underlying
causes of death occurred in chapters I, III and VIII of the ninth revision and
the corresponding chapters I, IV and X of the tenth revision of the International
Classification of Diseases. They were due to the displacement of deaths related
to the human immunodeficiency virus disease and the dismissal of pneumonias as a
cause of death. Regarding multiple causes of death, it was observed an increase
ofrespiratory diseases and a corresponding reduction of causes included in the
chapter of ill-defined affections due to recoding of respiratory failure.
PMID- 10769357
TI - [Radiosensitivity of Vibrio cholerae O1 incorporated in oysters, to (60)CO].
AB - OBJECTIVE: Evaluate the effect of ionizing irradiation by 60Co on Vibrio cholerae
O1, El-Tor, Ogawa, non-toxigenic, incorporated in live oysters Crassostrea
brasiliana. METHODS: Samples of oysters were selected from Cananeia town in the
South coast of S. Paulo state, Brazil, contaminated with Vibrio cholerae and
irradiated with 60Co at 0.5 and 1.0 kGy dosages. RESULTS: Showed significant
reductions of the initial number of V. cholerae, ranging from 3.4 x10(7) to 10(3)
and 10(2), respectively. The D10 values related with the respective doses of
irradiation were 0.173 and 0.235. CONCLUSION: Considering a 6 value as safety
factor, it is concluded that 1.41 kGy irradiation dosage is necessary to
eliminate a high number of V. cholerae viable cells in oysters. Controls were
used in the experiment.
PMID- 10769358
TI - [Parity and ovarian development of Anopheles albitarsis l.s.in irrigated
agroecosystem field].
AB - INTRODUCTION: To determine the parity, ovarian development and survival rates of
Anopheles albitarsis species, in order to estimate the potential of malaria
transmission. METHODS: Two populations of Anopheles albitarsis A and B in an
Experimental Farm of S. Paulo State, Brazil were captured during the crepuscular
sunset, between 5PM and 8PM, using Shannon traps. Dissections were performed
using Polovodova's technique, and the evaluation of follicular development was
according to Christophers and Mer's criterion. The Vercruysse method was used to
estimate daily survival and we applied Davidson method to determine the duration
of the gonotrophic cycle. RESULTS: A total of 2,612 specimens was dissected, of
these, 237 of population A and 2,375 of population B. The daily survival rates
were 0.5339+/-0.047 and 0.5566+/-0.015, respectively, for the populations A and
B. The duration of the gonotrophic cycle for population A was 1,990 days and for
population B 2,046 days. CONCLUSIONS: The results help to estimate the malaria
transmission potential in the region.
PMID- 10769359
TI - [Effects of environmental tobacco smoke on lower respiratory system of children
under 5 years of age].
AB - OBJECTIVE: To determine the effects of second-hand smoke in the respiratory
system of children under 5 years old. METHODS: A cross sectional study of a total
of 1,104 children under 5 years old. Information about respiratory symptoms and
illness, family history of respiratory diseases, smoking habits of household
members and housing conditions were assessed by home interviews with the
children's parents. RESULTS: We studied 546 boys and 558 girls. Among 611
children exposed to second-hand smoke, 82% had respiratory problems (odds ratio =
1.64; 95% confidence interval: 1.21-2.20). Children whose parents were smokers at
the time of the survey were more likely to experience wheezing than children of
nonsmoking parents (odds ratio = 1.66; 95% confidence interval: 1.21-2.27),
shortness of breath (odds ratio = 1.91; 95% confidence interval: 1. 36-2.67),
morning and day time or night coughs (odds ratio = 1.58; 95% confidence interval:
1.09-2.28). The odds ratio for asthma, bronchitis and pneumonia was greater for
children exposed to second-hand smoke (odds ratio = 1.60; 95% confidence
interval: 1. 11-2.31). CONCLUSIONS: Maternal smoking, paternal smoking, family
history of respiratory diseases, and housing conditions are considered risk
factors for respiratory diseases in children.
PMID- 10769360
TI - [Social inequalities and health services use: evidences from a stratified
household survey].
AB - OBJECTIVE: The study aims to identify children who are not benefited by local
health programs, looking for to characterize the excluded segment of the
population in order to broaden the access to and use of the main actions provided
by local health programs. METHODS: A sample of 465 children aged less than 1 year
was studied, living in the year of 1996 in Embu, a city of the metropolitan area
of S. Paulo, Brazil. Our hypothesis was that there is a higher availability of
private health care resources among families who haven't been using the local
health program. The statistical analysis consisted of stratified association
analysis to study the heterogeneity between and intra four strata of families
defined by different socioeconomic conditions. RESULTS: Although only 85.4% of
the study children were enrolled in local health services, 91.2% of them were
being benefited by main health care actions. The analysis of differences intra
strata revealed that our hypothesis was only corroborated in one stratum. It is
in the stratum 3, which concentrates the peripheral population, where we could
find children who have not been using the local health program in Embu city.
CONCLUSIONS: In the same social segment it was detected some inner heterogeneity
among families related to the availability of private resources for their
children health care.
PMID- 10769361
TI - [Dietary fiber consumption in an adult population].
AB - OBJECTIVE: The dietary fiber has emerged as a leading dietary factor in the
prevention and treatment of chronic diseases. I was estimated the average
consumption of total dietary fiber (DF), insoluble fiber (IF) and soluble fiber
(SF) in the meals of both sex adults from the town of Cotia, a metropolitan area
in S. Paulo State, Brazil. METHODS: A population sample of Cotia country, S.
Paulo (Brazil), consisted of 559 adults older than 20 years old, was studied.
Food consumption was assessed by the dietary history habits. The amount of
dietary fiber in each meal (breakfast, lunch and dinner) was estimated by the
serving size. The foods were classified according to their fiber content in Very
High (7 g or more), High (4.5 to 6.9), Moderate (2.4 to 4.4) and Low (<2.4).
RESULTS: The average population's consumption of dietary fiber was of 24 g/day,
with an average consumption of insoluble fiber of 17 g/day and soluble of 7
g/day. Among women, the average consumption was 20 g/day and among men 29 g/day
(p<0.01). Most of the foods in their diet were classified as having a low content
of dietary fiber. Beans were the most important dietary fiber source in the
population diet. Lunch and dinner were the meal with a higher content of dietary
fiber. CONCLUSIONS: A low consumption of dietary fiber in the population sample
could be detected. Their usual sources of dietary fiber were poor.
PMID- 10769362
TI - [Prevalence and risk factors for anemia in Southern Brazil].
AB - OBJECTIVE: To measure the prevalence and evaluate the risk factors of anemia.
METHODS: Cross sectional populational based study of the urban area of Criciuma
town, in the state of Santa Catarina, Southern Brazil. The study population was a
probabilistic sample of 476 children aged under three years. RESULTS: The
prevalence of anemia found in the sample was 60.4% for children aged 0 to 35.9
months according to the Brault-Dubuc criteria and 54% for children aged 6 to 35.9
months according to the OMS criteria. The prevalence of anemia increases with age
up to 18 months-old and then decreases. It is less prevalent in families where
the father has a higher education level and where there is a higher total family
income. Nevertheless, even within the 25% higher income group 40% of the children
are anemic. The prevalence of anemia is higher among children living in
unfinished and overcrowded houses, where the toilet is not equipped with flush,
and among children who have two or more older brothers. It is also higher among
teenager mothers (<20 years), and 35 years old or older mothers. The prevalence
of anemia is lower among women who had 5 to 9 prenatal visits during pregnancy.
Low weight at birth was associated with iron deficiency. The nutritional
condition was associated with anemia only according to weight/age criteria.
Hospitalizations in the last 12 months were not associated with the disease. In
the hierarchical multivariate analysis children age, family income, and crowded
house were the only significant variables. Reproductive health history, health
service visits, birth weight, breast-feeding, anthropometry, and morbidity did
not characterize a risk factor of anemia in the multivariate analysis.
CONCLUSIONS: The study makes it evident that social inequality is a strong
determinant of anemia. The risk imposed by anemia to children in regard to their
health and intellectual development requires immediate action.
PMID- 10769363
TI - [Female mortality in reproductive age in the State of Sao Paulo, Brazil, 1991
1995: underlying causes of death and maternal mortality].
AB - OBJECTIVE: To describe female mortality in the reproductive age (15 to 49 years
old) in the State of S. Paulo, Brazil, from 1991 to 1995, according to the age
and underlying causes of death. METHODS: Underlying causes of death, according to
the International Classification of Diseases, 9th Revision, were determined in
the program Automated Classification of Medical Entities (ACME), developed by
"Fundacao Seade", which provided us data files and estimated women population by
age groups and numbers of live births during the 1991 - 1995 period. Specific
rates were calculated per 100,000 women and maternal mortality rates were given
per 100,000 live births. Percentages of death were calculated for sub-groups. The
median of the rates for a five-year-period was calculated to allow the comparison
among the leading underlying causes of death. RESULTS: "Cellular immunity
deficiency" increased from 1991 to 1995 in women aged 25 or more which seems to
be concomitant to the spreading of the AIDS epidemic among women. Lesions and
poisonings were the leading causes of death in younger women, but after the age
of 35 cardiovascular diseases and neoplasms became the chief causes. Infectious
and parasitic diseases were rated in the 7th or 8th positions in all ages.
Accidents and homicides were high. Maternal mortality rates ranged from 43.7 to
49.6 per 100,000 live births, their leading causes were presented and discussed.
CONCLUSIONS: Women in the reproductive age were exposed to external factors,
chronic diseases and AIDS. The majority of maternal causes of death are
preventable diseases. There is a lack of adequate and extensive antenatal care as
well as in delivery and postpartum care.
PMID- 10769364
TI - [Birth weight and hospital mortality among liveborn infants, 1975-1996].
AB - OBJECTIVE: To assess the trend of birth weight and hospital mortality rate of
newborns, in a maternity hospital of Campinas, SP. METHODS: A total of 215,435
births of a maternity hospital in Campinas, S. Paulo State, Brazil, was studied
between 1976 and 1996. Information was collected from registration files and
annual reports of medical care. All the newborns from that period were included.
The causes of death that occurred before the discharge, regardless the age, were
analyzed. For data analysis, Epi info 6.01 method was used. RESULTS: Birth weight
distribution remained the same for the 22 years period studied. Low birth weight
was seen in about 9% of newborns, and accounted for 82% of hospital deaths in
1996. Below average weight was observed in about 24% of the newborns. We could
notice an improvement in survival for those who had a birth weight between 1,000
g and 1,999 g. In 1975, 13.3% of those with weights between 1,000 g and 1,499 g
survived and 73.8% of those who weighed between 1,500 g and 1,999 g. In 1996,
survival rates increased to 69. 1% and 87.7% respectively. Hospital mortality
rate among infants whose weight was below 1,000 g remained high, between 78.9%
and 100%, even in the 90's. There was a reduction of hospital mortality rates
from 17 to 11 per thousand live births. CONCLUSIONS: There was not any change in
the distribution of birth weight despite improvements in life conditions of
Campinas population. The decrease in mortality rates is due to improvement in
health care which is very expensive. There is a need of other studies to allow
why birth weight distribution remained the same.
PMID- 10769365
TI - [Mite contamination in polished rice and beans sold at markets].
AB - OBJECTIVE: To evaluate mite contamination rate in grains commercialized in nine
municipal markets of the city of Sao Paulo, in the period from November 1989 to
November 1990. METHODS: 23 samples of polished rice and 53 samples of beans were
microscopically examined after sieving, once a week and during 42 days at air
temperature. Other sample fractions were kept in an incubator at 25 degrees C and
75% Relative Humidity (RH) during 28 days. RESULTS: Samples were negative for
mites in the first day of analysis and were detected after incubation. Samples
incubated revealed a higher percentage of positive examinations for mites
(incidence): 31.7% (and 1,845 mites); while samples kept at air temperature
showed only 6.9% (and 45 mites). Samples of polished rice were more contaminated
in comparison to the ones of beans. There was a larger amount of mites when the
mean monthly temperature of the laboratory was between 21.5 degrees C to 22.5
degrees C (37. 8%) and humidity between 73.5% to 74.5% (31.1%). CONCLUSIONS: The
predominant species was Tyrophagus putrescentiae and other identified species
were Blomia tropicalis, Cheyletus spp., Blattisocius tarsalis, and others. Mite
population had a higher proliferation rate during spring, summer and in the
beginning of autumn, due to highest temperature and humidity. These results
confirm the importance of improving grains storage, to avoid mites proliferation.
PMID- 10769366
TI - [Cutaneous larva migrans in children in a school of center-western Brazil].
AB - This paper reports an outbreak of cutaneous larva migrans in children of a school
located in Campo Grande, MS. Six out of the 16 students (37.5%) acquired this
parasitic dermatitis in two playgrounds contaminated by cat feces, in which
ancylostomid larvae were found. The serpiginous lesions and/or papules were
located in the hands, feet, buttocks, thighs, vulva and scrotum. Control measures
of this parasitosis are discussed.
PMID- 10769367
TI - [Importance of the diagnoses and treatment of phenylketonuria].
AB - Phenylketonuria is the most common inborn error of amino acid metabolism. It is
due to a deficiency of phenylalanine hydroxylase, which normally converts
phenylalanine to tyrosine. A diet low in phenylalanine starting in the first
month of life can significantly reduce mental retardation, the most important
feature of the disease. The aim of the review is to discuss the difficulties
found in the diagnosis of PKU and its variants, ranging from classic
phenylketonuria to mild hyperphenylalaninaemia, and the effects of dietary
restriction of phenylalanine on the growth and development of children. Also, we
present the current controversies about the age of discontinuing the dietary
treatment. This review summarizes the benefits and problems emerging from a
prolonged therapy taking into account dietary compliance in different age groups,
and discusses dietary alternatives to the synthetic amino acid mixtures free of
phenylalanine, based on low phenylalanine protein hydrolysates. In addition, we
show some information about the effects of maternal phenylketonuria on pregnancy
outcome and infant development, if exposed to high phenylalanine levels intra
uterineo.
PMID- 10769368
TI - [The concept of disability].
PMID- 10769369
TI - [National Health Policy on Food and Nutrition].
PMID- 10769370
TI - The fruits of fly research.
PMID- 10769371
TI - Can current fMRI techniques reveal the micro-architecture of cortex?
PMID- 10769372
TI - Reply to "Can current fMRI techniques reveal the micro-architecture of cortex?"
PMID- 10769373
TI - Preassembly and transport of nerve terminals: a new concept of axonal transport.
PMID- 10769374
TI - Sodium channels develop a tyrosine phosphatase complex.
PMID- 10769375
TI - Locating an error correction signal for adult birdsong.
PMID- 10769376
TI - Anterior cingulate and prefrontal cortex: who's in control?
PMID- 10769377
TI - Deus ex genomix.
PMID- 10769378
TI - Exceptions that prove the rule
PMID- 10769379
TI - A sensitive mechanism for cation modulation of potassium current.
PMID- 10769380
TI - The merging of the senses: integration of subthreshold taste and smell.
PMID- 10769381
TI - Neuroscience training at the turn of the century: a summary report of the third
annual ANDP survey.
PMID- 10769382
TI - A sodium channel signaling complex: modulation by associated receptor protein
tyrosine phosphatase beta.
AB - Voltage-gated sodium channels in brain neurons were found to associate with
receptor protein tyrosine phosphatase beta (RPTPbeta) and its catalytically
inactive, secreted isoform phosphacan, and this interaction was regulated during
development. Both the extracellular domain and the intracellular catalytic domain
of RPTPbeta interacted with sodium channels. Sodium channels were tyrosine
phosphorylated and were modulated by the associated catalytic domains of
RPTPbeta. Dephosphorylation slowed sodium channel inactivation, positively
shifted its voltage dependence, and increased whole-cell sodium current. Our
results define a sodium channel signaling complex containing RPTPbeta, which acts
to regulate sodium channel modulation by tyrosine phosphorylation.
PMID- 10769383
TI - Assembly of presynaptic active zones from cytoplasmic transport packets.
AB - Little is known about presynaptic assembly during central nervous system
synaptogenesis. Here we used time-lapse fluorescence imaging, immunocytochemistry
and electron microscopy to study hippocampal neuronal cultures transfected with a
fusion construct of the presynaptic vesicle protein VAMP and green fluorescent
protein. Our results suggest that major cytoplasmic and membrane-associated
protein precursors of the presynaptic active zone are transported along
developing axons together as discrete packets. Retrospective electron microscopy
demonstrated varied vesicular and tubulovesicular membrane structures. Packets
containing these heterogeneous structures were stabilized specifically at new
sites of dendrite- and axon-initiated cell-cell contact; within less than one
hour, evoked vesicle recycling was observed at these putative nascent synapses.
These observations suggest that substantial membrane remodeling may be necessary
to produce the uniform vesicles typical of the mature active zone, and that many
presynaptic proteins may be united early in their biogenesis and sorting
pathways.
PMID- 10769384
TI - Large-scale oscillatory calcium waves in the immature cortex.
AB - Two-photon imaging of large neuronal networks in cortical slices of newborn rats
revealed synchronized oscillations in intracellular Ca2+ concentration. These
spontaneous Ca2+ waves usually started in the posterior cortex and propagated
slowly (2.1 mm per second) toward its anterior end. Ca2+ waves were associated
with field-potential changes and required activation of AMPA and NMDA receptors.
Although GABAA receptors were not involved in wave initiation, the developmental
transition of GABAergic transmission from depolarizing to hyperpolarizing (around
postnatal day 7) stopped the oscillatory activity. Thus we identified a type of
large-scale Ca2+ wave that may regulate long-distance wiring in the immature
cortex.
PMID- 10769385
TI - Amyloid beta interacts with the amyloid precursor protein: a potential toxic
mechanism in Alzheimer's disease.
AB - Amyloid beta protein (Abeta) deposition in the brain is a hallmark of Alzheimer's
disease (AD). The fibrillar form of Abeta is neurotoxic, although the mechanism
of its toxicity is unknown. We showed that conversion of Abeta to the fibrillar
form markedly increased binding to specific neuronal membrane proteins, including
amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Abeta
bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of
cultured APP-null neurons to Abeta neurotoxicity suggested that Abeta
neurotoxicity involves APP. Thus Abeta toxicity may be mediated by the
interaction of fibrillar Abeta with neuronal membrane proteins, notably APP. An
Abeta-APP interaction reminiscent of the pathogenic mechanism of prions may thus
contribute to neuronal degeneration in AD.
PMID- 10769387
TI - The two thyroid hormone receptor genes have opposite effects on estrogen
stimulated sex behaviors.
AB - The two genes coding for thyroid hormone receptors (TR) alpha 1 and beta have
opposite effects on female sex behaviors. Deletion of TRalpha 1 reduced them,
whereas deletion of TRbeta actually increased them. These results could not be
attributed to altered levels of hormones in the blood, general alterations in
estrogen responsiveness or altered general activity. Instead, they indicate a
previously unknown molecular mechanism upon which the two TR genes exert opposite
influences.
PMID- 10769386
TI - Mice lacking the norepinephrine transporter are supersensitive to
psychostimulants.
AB - The action of norepinephrine (NE) is terminated, in part, by its uptake into
presynaptic noradrenergic neurons by the plasma-membrane NE transporter (NET),
which is a target for antidepressants and psychostimulants. Disruption of the NET
gene in mice prolonged the clearance of NE and elevated extracellular levels of
this catecholamine. In a classical test for antidepressant drugs, the NET
deficient (NET-/-) animals behaved like antidepressant-treated wild-type mice.
Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine.
These responses were accompanied by dopamine D2/D3 receptor supersensitivity.
Thus altering NET expression significantly modulates midbrain dopaminergic
function, an effect that may be an important component of the actions of
antidepressants and psychostimulants.
PMID- 10769388
TI - Functional changes at periphery and cortex following dorsal root lesions in adult
monkeys.
AB - Chronic peripheral nerve injuries produce neural changes at different levels of
the somatosensory pathway, but these responses remain poorly defined. We
selectively removed cutaneous input from the index finger and thumb in young
adult macaque monkeys by lesioning dorsal rootlets to examine both immediate and
long-term systemic responses to this deficit. Corresponding digit representations
within somatosensory cortex (SI) were initially silenced, but two to seven months
later again responded to cutaneous stimulation of the 'deafferented' digits. We
remapped cutaneous receptive fields (RFs) within adjacent intact dorsal rootlets
two to four months after lesioning. RF distributions had greatly expanded, so
that rootlets previously innervating adjacent hand regions now responded to
stimulation of the index finger and/or thumb. Thus our results demonstrate
peripherally mediated central reorganization.
PMID- 10769389
TI - Slow NMDA-EPSCs at synapses critical for song development are not required for
song learning in zebra finches.
AB - Birdsong, like human speech, is learned via auditory experience during a
developmentally restricted sensitive period. Within projection neurons of two
avian forebrain nuclei, NMDA receptor-mediated EPSCs (NMDA-EPSCs) become fast
during song development, a transition posited to limit learning. To discover
whether slow NMDA-EPSCs at these synapses are required for learning, we delayed
song learning beyond its normal endpoint, post-hatch day (PHD) 65, by raising
zebra finches in isolation from song tutors. At PHD45, before learning, isolation
delayed NMDA-EPSC maturation, but only transiently. By PHD65, NMDA-EPSCs in
isolates were fast and adult-like, yet isolates presented with tutors readily
learned song. Thus song learning did not require slow NMDA-EPSCs at synapses
critical for song development.
PMID- 10769390
TI - Changing objects lead briefly flashed ones.
AB - Continuous, predictable events and spontaneous events may coincide in the visual
environment. For a continuously moving object, the brain compensates for delays
in transmission between a retinal event and neural responses in higher visual
areas. Here we show that it similarly compensated for other smoothly changing
features. A disk was flashed briefly during the presentation of another disk of
continuously changing color, and observers compared the colors of the disks at
the moment of flash. We also tested luminance, spatial frequency and pattern
entropy; for all features, the continuously changing item led the flashed item in
feature space. Thus the visual system's ability to compensate for delays in
information about a continuously changing stimulus may extend to all features. We
propose a model based on backward masking and priming to explain the phenomenon.
PMID- 10769391
TI - Undercounting features and missing features: evidence for a high-level deficit in
strabismic amblyopia.
AB - Abnormal visual development in strabismic amblyopia drastically affects visual
perception and properties of neurons in primary visual cortex (V1). To test the
notion that amblyopia also has consequences for higher visual areas, we asked
humans with amblyopia to count briefly presented features. Using the amblyopic
eye, strabismic amblyopes counted inaccurately, markedly underestimating the
number of features. This inaccuracy was not due to low-level considerations
(blur, visibility, crowding, undersampling or topographical jitter), as they also
underestimated the number of features missing from a uniform grid. Rather,
counting deficits in strabismic amblyopes reflected a higher-level limitation in
the number of features the amblyopic visual system can individuate.
PMID- 10769392
TI - Anterior cingulate activity during routine and non-routine sequential behaviors
in macaques.
AB - Anterior cingulate cortex is important in monitoring action for new challenges.
We recorded neuron activity in the anterior cingulate sulcus of macaques while
they performed a sequential problem-solving task. By trial and error, animals
determined the correct sequence for touching three fixed spatial targets. After
the sequence was repeated three times, we then changed the correct solution
order, requiring a new search. Irrespective of component movements or their
kinematics, task-related neurons encoded the serial order of the sequence.
Neurons activated with sequence components (68%) differed in activity between
search and repetition. Search-related activity occurred when behavioral
flexibility was required and ended as soon as the animal accumulated enough
information to infer the solution, but had not yet tested it. Repetition-related
activity occurred in a regime of memory-based motor performance in which
attention to action is less necessary.
PMID- 10769393
TI - Isolating the neural mechanisms of age-related changes in human working memory.
AB - Working memory (WM), the process by which information is coded into memory,
actively maintained and subsequently retrieved, declines with age. To test the
hypothesis that age-related changes in prefrontal cortex (PFC) may mediate this
WM decline, we used functional MRI to investigate age differences in PFC activity
during separate WM task components (encoding, maintenance, retrieval). We found
greater PFC activity in younger than older adults only in dorsolateral PFC during
memory retrieval. Fast younger subjects showed less dorsolateral PFC activation
during retrieval than slow younger subjects, whereas older adults showed the
opposite pattern. Thus age-related changes in dorsolateral PFC and not
ventrolateral PFC account for WM decline with normal aging.
PMID- 10769394
TI - Prefrontal-cingulate interactions in action monitoring.
AB - We found that medial frontal cortex activity associated with action monitoring
(detecting errors and behavioral conflict) depended on activity in the lateral
prefrontal cortex. We recorded the error-related negativity (ERN), an event
related brain potential proposed to reflect anterior cingulate action monitoring,
from individuals with lateral prefrontal damage or age-matched or young control
participants. In controls, error trials generated greater ERN activity than
correct trials. In individuals with lateral prefrontal damage, however, correct
trial ERN activity was equal to error-trial ERN activity. Lateral prefrontal
damage also affected corrective behavior. Thus the lateral prefrontal cortex
seemed to interact with the anterior cingulate cortex in monitoring behavior and
in guiding compensatory systems.
PMID- 10769397
TI - Physiology and pathophysiology of calcium homeostasis.
AB - This review summarizes the physiology and pathophysiology of calcium homeostasis.
The calcium balance and how it is controlled by various hormones and by Ca2+
itself will be discussed in the first section. The second section deals with the
predominant role of cytosolic Ca2+ as a second messenger controlling cell
function.
PMID- 10769398
TI - Calcium ions as extracellular, first messengers.
AB - Ca2+ concentration in the extracellular fluids ([Ca2+]o) is essential for a
number of vital processes from bone formation to blood clotting. For this reason,
it is necessary that [Ca2+]o must be strictly controlled. Mammalian species have
developed a complex homeostatic system that includes parathyroid glands, kidney
and bone. The extracellular Ca(2+)-sensing receptor (CaR) is an essential
component of this system, regulating parathyroid hormone secretion, calcium
excretion by the kidney and bone remodeling. Initially identified from bovine
parathyroid glands (1), within the five years following its identification CaR
presence has rapidly been extended to organs where the link with mineral ion
metabolism has not been elucidated (i.e., brain, stomach, eye, skin, and many
other epithelial cells) (see 2 for review). This review will address the
discovery of a novel class of ionsensing receptors, receptor-effector coupling,
and the roles of the CaR inside and outside the Ca2+o homeostatic system.
PMID- 10769399
TI - Ca2+ channels, Ca2+ sparks, and regulation of arterial smooth muscle function.
AB - In cardiac, skeletal, and arterial muscle, transient, spatially localized
elevations in [Ca2+]i, termed "Ca2+ sparks", have been observed using confocal
laser scanning microscopy. Ca2+ sparks are thought to represent "elementary" Ca2+
release events, which arise from one or more ryanodine receptor (RyR) channels in
the sarcoplasmic reticulum (SR). In striated muscle, Ca2+ sparks are thought to
be key elements of excitation-contraction coupling. In arterial smooth muscle,
Ca2+ sparks have been suggested to oppose myogenic vasoconstriction and to
influence vasorelaxation. Using a developmental model, we have investigated
whether RyRs causing Ca2+ sparks and activation of Ca(2+)-activated K+ (KCa)
channels (STOCs) function as "elementary" Ca2+ release units that regulate
arterial myogenic tone. Whereas increases in the global [Ca2+]i induce sustained
constriction of arterial smooth muscle, Ca2+ sparks induce vasodilation through
the local activation of KCa channels. In cerebral arteries, the global bulk
[Ca2+]i and a Ca2+ spark frequency < 10(-2) Hz/cell do not cause sufficient KCa
channel activity to regulate membrane potential of smooth muscle cells and
myogenic tone. The frequency of Ca2+ sparks and STOCs is regulated by agents that
modulate protein kinase G and protein kinase A activity. Our findings suggest
that "elementary" Ca2+ release units may represent novel, important therapeutic
targets for regulating function of the intact arterial smooth muscle tissue.
PMID- 10769400
TI - Role of pericytes in vascular calcification: a review.
AB - Pericytes are defined by their location in vivo; the pericyte partially surrounds
the endothelial cell of the microvessel and shares a common basement membrane
with it. As an integral part of the microvasculature, pericytes play a
fundamental role in maintaining local and tissue homeostasis. Current evidence
also suggests that pericytes function as progenitor cells capable of
differentiating into a variety of different cell types including osteoblasts,
chondrocytes and adipocytes. It is now apparent that cells resembling
microvascular pericytes, and termed 'pericyte-like' cells, have a widespread
distribution in vivo. Pericyte-like cells have been identified in the inner
intima, the outer media, and in the vasa vasora of the adventitia of large,
medium and small human arteries (1, 2). Moreover, recent studies have suggested
that these cells may be responsible, at least in part, for mediating the
calcification commonly associated with atherosclerosis (1, 3, 4). In this review,
we a) examine the evidence that microvascular pericytes deposit a bone-like
mineralised matrix in vitro, b) compare the morphological and biochemical
properties of microvascular pericytes, calcifying vascular cells (CVCs) and
'classical' smooth muscle cells (SMCs) isolated from bovine aorta, c) demonstrate
that microvascular pericytes deposit a well-organised matrix of bone, cartilage
and fibrous tissue in vivo, and d) discuss recent studies designed to gain a
better understanding of how pericyte differentiation is regulated.
PMID- 10769401
TI - Natural history of calcium deposits in atherosclerosis progression and
regression.
AB - Calcium deposits emerge in young people as granules of microscopic size in
atherosclerotic lesions defined histologically are type IV. Granules are found
among the vast quantity of extracellular lipid droplets and cell remnants that
form the core of this lesion type, and intracellularly within smooth muscle cells
that have been disrupted and impaired by the accumulated extracellular material.
Extracellular calcium granules are, in part, granules that formed intracellularly
and were set free through cell death, and in part they represent extracellular
calcification of cell remnants. Extracellular granules combine and grow to form
large structures until, in adults past the fourth decade of life, the greater
part of a lesion core may be calcified (type VII lesion). Organization of calcium
deposits into bone (osseous metaplasia) may occur as a late step. The fate of
human lesion components subsequent to therapeutic lowering of high blood
cholesterol is not known. In rhesus monkeys, 3 1/2 years of drastic reduction of
high blood cholesterol resulted in complete loss of macrophages, macrophage foam
cells, and lymphocytes and loss or reduction of extracellular accumulations of
lipid and cell remnants from advanced lesions. Calcium deposits, however,
remained in the arterial wall and were not visibly changed. Osseous metaplasia of
calcium deposits did not occur in monkeys over a 9-year period of lesion
progression and regression.
PMID- 10769402
TI - Atherosclerotic carotid arteries--calcification and radio-morphological findings.
AB - OBJECTIVES: Are there any predictable factors influencing the process of
calcification in carotid arteries? BACKGROUND: The carotid arteries and
especially the carotid bifurcation are one of the predisposed regions of
atherosclerotic disease. Whether topography of the carotid sinus, flow patterns
or different patient characteristics (e.g., diabetes mellitus, age, sex) are a
factor determining calcification of atherosclerotic lesions is still hardly
understood. METHODS: Morphological and morphometrical analysis including
radiographic classification of different degrees of calcification on postmortal
carotid arteries (90 men and 19 women) and 306 surgical samples after intramural
desobliterations of carotid arteries (202 patients with diabetes, 104 patients
without diabetes). RESULTS: Most common localization of radiographically
identified calcified deposits are the carotid bulb (76%) especially on the
lateral wall opposite the flow divider and the internal carotid artery (55%)
especially the proximal 1 cm section. No difference in degree of calcification
was found when comparing patients with and without diabetes (intermediate
calcification in 59% of patients with diabetes and 50% without diabetes). More
female patients with diabetes show calcification when compared to the group of
patients without diabetes. Females produce calcification in atherosclerotic
carotid lesions at an older age compared to male patients. CONCLUSIONS:
Calcification is a frequent finding in advanced atherosclerotic carotid lesions.
There is no difference in regard to degree, pattern of calcification or age
distribution when comparing patients with and without diabetes mellitus.
Atherosclerotic lesions more frequently found in female patients with diabetes
may be due to less vasoprotection by estrogens.
PMID- 10769403
TI - Coronary calcification: insights from sudden coronary death victims.
AB - We studied 108 cases of sudden coronary death at autopsy. Any calcification was
present in 55% of men and women under 40 years; all hearts showed some
calcification by age 50 in men, and by age 60 in women. The only risk factor
independently associated with increased calcification was diabetes mellitus, in
women only. The degree of calcification was greatest for acute and healed plaque
ruptures, and the least for plaque erosion. Calcification in coronary
atherosclerosis appears to be delayed in women, is greatest in women diabetics,
and is associated with one type of plaque instability, namely plaque rupture.
PMID- 10769404
TI - Vascular smooth muscle and arterial calcification.
AB - Smooth muscle cultures can calcify under certain circumstances. As a model system
these cultures therefore provide information on why calcification occurs in
atherosclerotic plaques. Whether all smooth muscle cells (under certain
conditions), or only specific populations, can produce this mineralization has
not been resolved. Demer's group has cloned calcifying vascular cells from
subcultured bovine aorta and studied them in detail. They have speculated on
whether the cells are smooth muscle which have altered in phenotype, or whether
they are derived from a stem cell population within the artery wall. The article
argues that while the normal process of smooth muscle phenotypic modulation seen
in arterial repair could account for the observations, this view may be two
simplistic considering the complex nature of the artery wall. Certainly there is
evidence for heterogeneity of smooth muscle cells in the artery wall and recent
evidence suggests that stem cells can circulate in the blood and repopulate
tissues. Further studies are required to resolve the important question as to the
origin of cells which produce mineralization in atheroma.
PMID- 10769405
TI - Expression of mineralisation-regulating proteins in association with human
vascular calcification.
AB - OBJECTIVES: These studies aim to investigate the expression and function of
mineralisation-regulating proteins in association with human vascular
calcification focussing on the similarities and differences between the two major
calcification pathologies in man: atherosclerotic, intimal calcification and
Monckeberg's sclerotic medial calcification. BACKGROUND: A number of studies have
documented expression of mineralisation-regulating proteins in association with
human atherosclerotic calcification leading to the suggestion that human vascular
calcification may be a regulated process with similarities to developmental
osteogenesis. METHODS: In situ hybridisation, immunohistochemistry and semi
quantitative RT-PCR analysis were used to determine the temporal and spatial
expression patterns of mineralisation-regulating proteins within human calcified
vascular lesions. Additionally, the expression and regulation of bone-associated
proteins was analysed during spontaneous calcification of human VSMCs in vitro.
RESULTS: In association with both medial and intimal calcification, the temporal
changes in expression of mineralisation-regulating proteins are similar. Some
constitutively expressed bone-associated proteins, including matrix Gla protein
(MGP), are down-regulated in association with calcification while expression of a
number of bone-associated proteins, not normally expressed in the vessel wall,
are induced including alkaline phosphatase (ALK), bone sialoprotein (BSP) and
bone Gla protein (BGP). In medial calcification the source of expression of these
mineralisation-regulating proteins is VSMCs while in intimal lesions both VSMCs
and macrophages express them. Furthermore, these bone-associated proteins are
spontaneously expressed by VSMCs in vitro suggesting that human VSMCs are capable
of simultaneously exhibiting smooth muscle and osteogenic-like properties.
CONCLUSIONS: These studies imply that both medial and intimal vascular
calcification are regulated processes; however the aetiology of each pathology
differs.
PMID- 10769406
TI - Cell differentiation in vascular calcification.
AB - Ectopic tissue formation is commonly found in calcified atherosclerotic plaques.
This suggests that cell differentiation plays an important role in vascular
calcification, even though the origin of the cells involved is unclear.
Calcifying vascular cells (CVCs), derived from bovine aortic media, have been
used as an in vitro model for vascular calcification. CVCs have many
characteristics in common with bone cells, but there are also differences
suggesting mechanisms that may be applicable to the problem of osteoporosis in
the setting of vascular calcification. Matrix GLA protein (MGP) deficient mice
develop severe vascular calcification and die prematurely from heart failure
and/or aortic rupture. The molecular mechanism of MGP is unknown. It has been
hypothesized that MGP acts as a calcification inhibitor by binding calcium,
preventing mineral deposition in extracellular fluids near the saturation point
for calcium and phosphate. Alternatively, MGP expression may be an attempt to
regulate cell differentiation in the vascular wall, possibly by acting as an
inhibitor to a factor able to induce cartilage and bone such as bone
morphogenetic proteins (BMPs).
PMID- 10769407
TI - Mechanism of atherosclerotic calcification.
AB - Calcification is almost invariably associated with atherosclerotic plaque
lesions. Recent data suggest that plaque calcification is an active, regulated
process similar to osteogenesis. In order to clarify the mechanism of plaque
calcification, we developed an in vitro model of vascular calcification by
utilizing bovine vascular smooth muscle cells (BVSMCs). This model is useful in
that diffuse and massive calcification can be induced within 2 weeks and thereby
biochemical analyses of vascular calcification can be performed. We have analyzed
several aspects of vascular calcification by using this model and demonstrated as
follows: 1) in vitro calcification of BVSMCs is regulated by calciotropic
hormones and BVSMCs are equipped with a unique autocrine and/or paracrine system
regulating calcium metabolism. 2) Sodium-dependent phosphate cotransport plays a
crucial role in BVSMC calcification as well as in mineralization of skeletal
tissues. 3) BVSMCs acquire osteoblastic phenotype under certain conditions.
Finally, we discuss the roles of macrophages in the development of
atherosclerotic calcification. Interferon-gamma (IFN-gamma) induces gene
expression of 25-hydrovitamin D-1 alpha-hydroxylase (1 alpha OHase) and its
activity in macrophages. Since 1 alpha OHase can locally convert 25
hydroxyvitamin D into 1 alpha, 25-dihydroxyvitamin D (1,25(OH)2D), an active
metabolite of vitamin D, it is suggested that local production of 1,25(OH)2D by
macrophages may promote atherosclerotic calcification. Moreover, macrophages may
be involved in the phenotypic changes of vascular smooth muscle cells (VSMCs) to
acquire calcifying capacity. Therefore, the phenotypic changes of VSMCs in
atherosclerotic plaque may contribute to the development of atherosclerotic
calcification.
PMID- 10769408
TI - Atherosclerotic lesion mechanics versus biology.
AB - The world-wide importance of acute vascular syndromes is increasing. Acute events
are usually triggered by fibrous cap disruption and subsequent thrombus
formation. Histological studies have established specific structural features
common among unstable plaques. The eccentric, lipid-laden plaque has to bear
remarkably high mechanical stresses at the "shoulder regions". These internal
stresses can reach thousands of millimeters of mercury. In addition, weakening of
the extracellular matrix at these sites leads to fibrous cap rupture. Dynamic
interactions between inflammatory mediators and matrix cause weakening of the
plaque at these high stress locations, and it is likely that lowering cholesterol
reduces both mechanical stresses and the inflammation that promotes fibrous cap
weakening. Understanding the interplay of plaque architecture, mechanical
properties, and matrix biology is critical in the future development of therapies
to stabilize lesions.
PMID- 10769409
TI - Mechanical behavior of calcified plaques: a summary of compression and stress
relaxation experiments.
AB - This paper summarizes the results from mechanical testing of atherosclerotic
plaques performed in the Cardiovascular Mechanics Laboratory and the Laboratory
for Implantable Materials at UMBC. The motivation for our work is that balloon
angioplasty, stenting, and roto-ablation are mechanical processes that are
designed to permanently alter the shape of an occluded arterial lumen. The
mechanisms of permanent plaque deformation are not known. Therefore, to study the
mechanical behavior of plaques, we performed mechanical tests on atherosclerotic
lesions with different compositions and investigated differences in the
materials' mechanical responses. Atherosclerotic plaque specimens were subjected
to two main types of loading: multiple cyclic compression and stress-relaxation.
The multiple-cycle test protocol was two fifteen-cycle loading phases that were
separated by a 10-15 minute unloaded "rest" period. The compressive stress
relaxation test protocol was a series of three consecutive loadings (called
phases I, II, and III). Each phase consisted of a 25% compression that was
achieved in less than 1 second, a 10 minute relaxation period, and a 10 minute
unloaded "rest" period between loadings. In the multiple cycle compressive
loading, plaques exhibited three distinct types of behavior, which corresponded
to the plaque compositions. Calcified plaques showed behaviors distinct from
other plaque types and healthy vessels. In contrast to the cyclic compression
results, plaque types could not be distinguished solely on the basis of stress
relaxation behavior. Calcified and fibrous plaques had similar behavior, and
therefore histology was used for definite identification. Calcified plaques have
unique mechanical properties, and therefore interventions like angioplasty, roto
ablation, and stenting may require protocols specific for calcified lesions. The
optimum protocols for calcified plaques may be quite different from plaques with
other compositions. It is essential to learn more about the mechanical behavior
of all plaque types to increase the success rate of occlusive atherosclerosis
treatments.
PMID- 10769410
TI - Vascular mechanics of the coronary artery.
AB - This paper describes our research into the vascular mechanics of the coronary
artery and plaque. The three sections describe the determination of arterial
mechanical properties using intravascular ultrasound (IVUS), a constitutive
relation for the arterial wall, and finite element method (FEM) models of the
arterial wall and atheroma. METHODS: Inflation testing of porcine left anterior
descending coronary arteries was conducted. The changes in the vessel geometry
were monitored using IVUS, and intracoronary pressure was recorded using a
pressure transducer. The creep and quasistatic stress/strain responses were
determined. A Standard Linear Solid (SLS) was modified to reproduce the non
linear elastic behavior of the arterial wall. This Standard Non-linear Solid
(SNS) was implemented into an axisymetric thick-walled cylinder numerical model.
Finite element analysis models were created for five age groups and four levels
of stenosis using the Pathobiological Determinants of Atherosclerosis Youth
(PDAY) database. RESULTS: The arteries exhibited non-linear elastic behavior. The
total tissue creep strain was epsilon creep = 0.082 +/- 0.018 mm/mm. The
numerical model could reproduce both the non-linearity of the porcine data and
time dependent behavior of the arterial wall found in the literature with a
correlation coefficient of 0.985. Increasing age had a strong positive
correlation with the shoulder stress level, (r = 0.95). The 30% stenosis had the
highest shoulder stress due to the combination of a fully formed lipid pool and a
thin cap. CONCLUSIONS: Studying the solid mechanics of the arterial wall and the
atheroma provide important insights into the mechanisms involved in plaque
rupture.
PMID- 10769411
TI - Medial arterial calcification and diabetes mellitus.
AB - Medial arterial calcification (MAC) is a frequent vascular finding in patients
with type II diabetes mellitus. Morphologically distinct from focal
calcifications of atherosclerosis its radiographically distinct tramline pattern
is frequently encountered in the arteries of the lower extremities. MAC is
inconsistently related to age, duration and therapy of diabetes. In contrast, a
strong association with diabetic polyneuropathy and familial aggregation have
been documented. Although initially considered benign MAC is now recognized as a
strong predictor of cardiovascular morbidity and mortality in diabetic patients.
Investigations into MAC pathogenes and into its role in vascular pathophysiology
are underway.
PMID- 10769412
TI - Quantification of plaque volume, shear stress on the endothelium, and mechanical
properties of the arterial wall with intravascular ultrasound imaging.
AB - Present intravascular echographic imaging (IVUS) is based on either the
mechanically rotated single element catheter or the multi-element phased array
catheter principle. In both methods the ultrasonic beam is rotated through 360
degrees and the cross-sectional echo image of plaque and wall structures is
visualised. A new development based on intravascular ultrasound is calculation of
mechanical properties of the arterial wall. In this so-called elastographic
approach, high frequency information obtained at identical positions in the
arterial wall is compared under systolic and diastolic pressures. Minute shifts
in the echo data indicate local compressibility. It thus becomes possible to
indicate areas of high or low strain, which correspond to soft and hard material.
Three-dimensional information can be obtained if the position of cross sectional
slices is recorded with a pull-back device and slices are united into a 3D image.
On the basis of such information it has become possible to view stents in 3D, and
with interactive software, to calculate automatically plaque volume. With pull
back information only, the artery is reconstructed as a "straight pipe". Only
when the biplane X-ray information is combined with the intravascular pull-back
echo information can the true 3D reconstruction of the artery be constructed.
Given the true geometric lumen information, it becomes possible, under certain
assumptions, to derive the luminal fluid dynamics. From this, shear stress values
close to the arterial wall can be calculated. Under the assumption that low
values for local shear stress are areas prone to restenosis, predictions of
endangered areas can be made.
PMID- 10769413
TI - Coronary calcification: assessment by intravascular ultrasound imaging.
AB - The role of intralesional coronary calcification is not only an important
prognostic factor with respect to interventions, but can be extremely important
with respect to diagnostic classification of lesion subsets. Intravascular
ultrasound details the relationship between plaque and vessel wall in real time
throughout the coronary arterial tree. This provides the opportunity to exactly
define not only the quantity but also the distribution of calcium within the
vessel wall. This is particularly important from a diagnostic standpoint, as
plaque-containing calcification can often lead to ambiguous or erroneous
angiographic information. Being able to classify different plaque substructures
with intravascular ultrasound can help not only to clarify the ambiguous
angiogram but delineate the exact nature of luminal encroachment. From a
treatment standpoint, the identification of calcification patterns, particularly
those on the superficial intimal surface, can alert the operator to change the
compliance prior to definitive therapy. High-speed rotational atherectomy is a
technique that provides significant de-calcification in preparation for
optimizing the stent geometry within such lesion subsets. Although electron beam
computed tomography can accurately locate calcification patterns within the
coronary tree in a non-invasive manner, it's often difficult to know the extent
of calcification and the relationship to fibrofatty plaques. Intravascular
ultrasound albeit invasive, provides the opportunity to delineate these plaque
substructures and potentially identify lesion subsets that may have an important
natural history in the development of coronary atherosclerosis.
PMID- 10769414
TI - Intravascular ultrasound insights into plaque composition.
AB - Previous studies correlating histomorphology with 20-30 MHz-derived intravascular
ultrasound (IVUS) images showed that IVUS provides to some extent qualitative
information on plaque composition. IVUS imaging proved to define calcifications
with high sensitivity and specificity but was found to be less accurate in the
assessment of soft components. Nevertheless previous studies on atherosclerotic
plaque characterization were limited by use of low-frequency transducers that did
not define accurately soft components. Our goal was to test the effectiveness of
high frequency IVUS transducers in the identification of lipid/necrotic pools in
atherosclerotic plaques. METHODS: Forty MHz transducers were used for in vitro
IVUS assessment of 12 arterial segments (10 coronary arteries and 2 carotid
arteries dissected from 5 different autopsy cases). IVUS acquisition was
performed at a 0.5 mm/s speed after ligature of the branching points to generate
a closed system. Lipid necrotic areas were defined by IVUS as large echolucent
intraplaque areas surrounded by tissue with higher echodensity. To obtain
histopathologic sections corresponding to IVUS cross sections, vessels were
divided into consecutive 3 mm-long segments using the most distal recorded IVUS
image as the starting reference. Then, samples were fixed with 10% buffered
formalin, processed for histopathologic study, serially cut, and stained with the
Movat penthacrome method. RESULTS: One hundred twenty-two sections were analyzed.
Lipid pools were observed by histology in 30 cross sections (25%). IVUS revealed
the presence of lipid pools in 19 of 122 cross sections with a sensitivity and
specificity of 67% and 94%, respectively. CONCLUSIONS: High frequency transducers
accurately identify lipid/necrotic pools and open new perspectives on future IVUS
characterization of atherosclerotic plaques.
PMID- 10769415
TI - Assessment of atherosclerotic arterial changes in the carotid artery with
noninvasive ultrasound.
AB - Atherosclerotic changes of the carotid tree comprise changes of the wall
structure, the wall stiffness, and local blood flow properties. They are
associated with atherosclerotic changes in other arterial beds such as the
coronary and cerebral arteries and with manifest atherosclerotic diseases. It has
also been shown that they are at least in part potent predictors for future
cardiovascular disease. Transcutaneous ultrasound of the carotid tree offers the
possibility of detecting atherosclerotic changes on a noninvasive basis. In the
following, the different methods for the assessment of atherosclerotic changes of
the carotid wall structure, wall stiffness, and local hemodynamics with
noninvasive ultrasound are briefly reviewed. The combined assessment of all these
arterial properties may increase the predictive value of non-invasive ultrasound
in detecting early atherosclerosis in other arterial beds. However, more
prospective studies are necessary to examine the possible value of increased wall
stiffness, altered local hemodynamics, and the combined assessment of these
parameters together with the assessment of arterial wall structure in this
respect. Therefore, the current ultrasound methods for the measurement of
structure, function, and hemodynamics has yet to be optimized for usage in
routine medical examinations.
PMID- 10769416
TI - Electron beam computed tomography: calcification and lipid lowering
interventions.
AB - Over 50% of myocardial infarctions lead to sudden death without any prior warning
signs or previously known coronary disease (1). Thus, persons with preclinical
atherosclerosis must be identified prior to the onset of angina, MI, stroke or
death. It has been estimated that primary prevention can avert more than 100,000
premature deaths each year in the United States alone and 10 times that worldwide
(2). new modalities are being investigated to look for atherosclerotic plaque
burden, plaque morphology, and endothelial function. Multiple trials on
cholesterol reduction have reproducibly demonstrated a positive mortality benefit
in primary (3, 4) and secondary (5-6) prevention combining diet with statins.
Newer therapies, including antibiotics, anti-oxidants, and angiogenesis
medications are being introduced for the possible prevention or treatment of
coronary artery disease. The ability to track the progression or regression of
atherosclerosis non-invasively would allow better evaluation of these therapies.
PMID- 10769417
TI - Regression of calcified coronary artery plaque assessed by electron beam computed
tomography.
AB - Lipid lowering therapies and aggressive life style modifications can induce
regression of coronary artery disease as demonstrated by several angiographic
studies. Such regression has also been associated with greatly reduced
cardiovascular event rates. However, coronary angiography is invasive and
expensive and other non-invasive diagnostic approaches would be preferable.
Electron beam computed tomography imaging is used to detect coronary artery
calcification, it is non-invasive and considerably less expensive than
angiography. This tool provides an opportunity to serially monitor the
effectiveness of medical therapy for coronary artery disease via the follow-up of
a surrogate marker of disease such as vascular calcification. We review the
current status of the literature on the use of electron beam computed tomography
as a tool to follow progression of disease.
PMID- 10769418
TI - Calcium antagonists and vascular smooth muscle cell reactivity.
AB - OBJECTIVES: To determine the mechanisms whereby calcium channel blockers (CCBs)
control the reactivity of vascular smooth muscle cells (VSMCs). BACKGROUND:
Although CCBs are known to play an important role in the calcium homeostasis of
VSMCs, they are suspected to exert additional effects in this cell type. Thus,
the possibility that CCBs could affect VSMC growth/proliferation through a
mechanism distinct from the inhibition of calcium channels was investigated.
METHODS: VSMCs were isolated from rat aortae and cultured. The influence of
nifedipine and amlodipine on basic fibroblast growth factor (bFGF)-stimulated DNA
synthesis and proliferation was studied by measuring bFGF-induced BrdU
incorporation into VSMCs and cell counts, respectively. The influence of
amlodipine (and of isradipine) on the mobilization of intracellular Ca2+ stores
was determined by studying the fluorescence of thapsigargin-stimulated VSMCs pre
labeled with the fluoroprobe Fura-2. RESULTS: Both nifedipine and amlodipine
inhibited bFGF-induced VSMC growth/proliferation. In the case of nifedipine but
not in that of amlodipine, this inhibitory effect could be accounted for by the L
type Ca(2+)-channel antagonist property of the drug. On the other hand,
amlodipine but not isradipine, diltiazem, and verapamil, did inhibit thapsigargin
induced Ca2+ mobilization. CONCLUSIONS: These findings suggest that in addition
to its L-type Ca(2+)-channel antagonist property, amlodipine also exerts a
"thapsigargin-like" activity which, together with its particular antioxidant
property, might participate in its antiatherogenic potency.
PMID- 10769419
TI - [SAPHO syndrome: clinico-rheumatologic and radiologic differentiation and
classification of a patient sample of 86 cases].
AB - Synovitis (inflammatory arthritis), acne (pustulosa), pustulosis (psoriasis,
palmoplantar pustulosis), hyperostosis (acquired), and ostitis (bland
osteomyelitis) are symptoms forming the acronym SAPHO, which is a syndrome of
nosologic heterogeneity. All entities forming the SAPHO syndrome are connected by
a non-obligate dermatoskeletal association with an aseptic pustulous character.
86 cases were analyzed clinically, radiologically and by
histology/histopathology. 31 adult patients showed the typical triad of
pustulosis palmo-plantaris (psoriatica, PPP), sterno-costo-clavicular
hyperostosis (SCCH), and "productive" spondylopathy, which we define as entity I.
spondarthritis hyperostotica pustulopsoriatica (Spond.hyp.pp). Twelve adolescent
and 13 adult patients showed entity no. II: chronic recurrent multifocal
osteomyelitis (CRMO), being characterized by non-purulent osteomyelitis of plasma
cell sclerotic type, potentially being a reactive inflammatory process. 50% of
the adult patients with CRMO showed PPP. Differentiation between these two
entities is possible by detection of ossifying enthesiopathy in cases of Spond.
hyp.pp and primarily chronic osteomyelitis in cases of CRMO. Two more entities or
abortive forms of group I and II are III: the inflammatory syndrome of the
anterior chest-wall (ACW syndrome) and IV: the more productive form of isolated
sterno-costoclavicular hyperostosis (SCCH). Both are connected quite frequently
to HLA-B-27-independent forms of spondarthritis and to pustulous dermatosis. More
rarely we find osteo-articular symptoms in cases of acne pustulosa, which form
group V: acne-associated spondarthritis and CRMO in the case of acne. Adult forms
of CRMO with different forms of appearance (lumosacro-iliac hyperostosis with
retroperitobeal fibrosis, pelvic type with affection of the hip-joint) are
described. The immunologic theory of a "reactive osteomyelitis" potentially
triggered by saprophytes is described. The inverse acne triad is brought in a
context of skin symptoms. A case of intercurrent postpartum symptoms together
with ulcerative colitis is described. Three cases of patients with Crohn's
disease are described. Clinical features, radiological findings, and
histopathological elements are brought together to determine the connections
between the different entities and the possibilities of differentiation. With
these elements together with bone-scan, it is often not necessary to obtain a
bone specimen. Therapeutical possibilities, especially concerning CRMO, are
discussed. "SAPHO syndrome" is more a sign-post on the way to a more subtle
diagnosis when it comes to hyperostotic, skin-associated diseases, and it needs
interdisciplinary work to clear the situation.
PMID- 10769420
TI - Corticotropin releasing hormone (CRH) promoter polymorphisms in various ethnic
groups of patients with rheumatoid arthritis.
AB - The regulatory region of the corticotropin releasing hormone (CRH) is highly
conserved and plays a crucial role in the response of the organism to stress.
Release of CRH initiates a cascade of events leading to the release of cortisone
and the regulation of inflammatory and immune events. OBJECTIVE: Since it has
been postulated that the impaired corticotropin releasing hormone (CRH) response
to stress in patients with rheumatoid arthritis (RA) has a genetic basis, we
investigated the distribution of CRH alleles in a cohort of UK patients as well
as in South African RA patients. METHODS: Restriction fragment length
polymorphism of PCR amplified DNA products of the CRH promoter. We compared the
allele frequencies in the RA patients with the respective healthy control
population described previously. RESULTS: As in the control populations we found
two biallelic polymorphic sequences (named A1 and A2 and B1 and B2, respectively)
in the CRH promoter which could be assigned to compound alleles. The A2B1
compound allele was protective against development of RA in a large group of UK
Caucasoid patients (p = 0.03; odds ratio 0.43, 95% confidence interval 0.21
0.88). In contrast, A1B1 was positively associated with RA in a cohort of black
South African RA patients (p = 0.05; odds ratio 1.78, 95% confidence interval
1.01-3.15). CONCLUSION: Taken together, these findings support the hypothesis
that CRH promoter polymorphism represents a new genetic marker for RA
susceptibility and may prove useful for the prediction of RA risk in the future
when further genetic and environmental risk factors are determined.
PMID- 10769421
TI - [Quality assurance of clinical studies on the course, diagnosis and therapy of
rheumatic diseases].
PMID- 10769422
TI - [Evidence-based medicine--from evidence production to its implementation].
AB - Evidence-based medicine (EBM) and evidence-based health care (EBHC) is one answer
to the increasing need for quality and transparency in the care of individual
patients as well as health care services. Using explicit and sound methodological
criteria, EBM and EBHC question current management strategies for their
effectiveness and usefulness to individual patients and patient groups. This
approach therefore supports the implementation of rational patient-oriented care.
PMID- 10769423
TI - [Goals and methods of clinical studies].
AB - The validity of clinical patient-oriented research is always threatened by the
influence of bias, confounding factors or random effects that might distort the
results. However, the susceptibility to distortion varies between different study
designs. The best protection against spurious relationships or distorted results
are specific focused research questions and rigorous integration of sound study
methodology during the design and performance phase.
PMID- 10769424
TI - [Effect size in clinical studies of patients with rheumatoid arthritis. EULAR
guidelines and OMERACT core-sets].
AB - Clinical trials in rheumatology are confronted with new challenges. The
pharmaceutical industry must be more efficient in identifying and marketing new
drugs, regulatory authorities require additional evidence about the effectiveness
of new compounds, and the consumer including physicians require more transparency
in the selection and use of appropriate outcomes in clinical trials. These
challenges find their common denominator in a further standardization of clinical
trials that extends beyond the application of Good Clinical Practice. For years,
national and international organizations have developed recommendations for the
selection of appropriate outcomes in RA clinical trials. However, these
recommendations have rarely been data driven or evidence based. The international
informal collaboration Outcome Measures in Rheumatoid Arthritis Clinical Trials
(OMERACT) has contributed enormously towards the application of a standardized
methodology in the development of recommendations to enhance the quality of
research in clinical rheumatology. The scope of this initiative goes now far
beyond rheumatoid arthritis and now covers all major rheumatic conditions.
PMID- 10769425
TI - [Concept for nationwide cooperation in planning and implementing multicenter
studies].
AB - In Germany, good clinical multicenter studies that are not supported by
pharmaceutical companies are rarely performed. Good supranational industry
sponsored studies are usually aimed at the registration of new (expensive) drugs.
The preconditions for co-operation in conducting industry-independent studies
which are of interest for the scientific community have been improved
substantially in Germany by instituting the working group of co-operating
arthritis centers, the so-called core documentation where 32,000 patients with
rheumatic conditions were documented in 1997 and the institution of a
sophisticated information system ("RheumaNet"). The executive board of the German
Rheumatology Association has set up an "ad hoc commission" that agreed to
institute a "Committee for the Coordination of Clinical Studies in Rheumatic
Diseases". In this committee rheumatologists subspecialized from medicine,
orthopedic, pediatrics working in universities, hospitals and private practice as
well as specialists in statistics and epidemiology shall be represented. In
principle this committee is independent of the co-operating arthritis centers and
the RheumaNet. All members of the German Rheumatology Association are invited to
cooperate with this committee by contributing to the clinically important
questions and participating in clinical studies. The committee has to define key
questions in rheumatology and shall plan and organize multicenter studies to
answer these questions. In addition, study protocols of pharmaceutical companies
may be examined as to their importance, quality, and feasibility.
PMID- 10769426
TI - [Documentation concepts in MedNet-Rheuma (competence network "Inflammatory
rheumatic systemic diseases")].
AB - Concepts of documentation rely not only on the contents required and technical
demands, but the procedures covered and in medical applications especially
security aspects are also matters of critical concern. Even though the need for
effective documentation (i.e., adequate in content, availability, feasibility and
easy to retrieve analysis) is not a question, tasks and aims (for example,
quality of patient care) deserve attention and establishing efforts have to be
analyzed regarding their structural and personal prerequisites and implications
before particular tools for documentation can be developed.
PMID- 10769427
TI - [Leipzig Center for Therapy Studies--a cooperative structure for realizing
clinical studies].
AB - The most important aim of the center is the development of an innovative
structure for organizing clinical research in order to define quickly a large
number of patients and include them in special studies that will be carried out
with high clinical quality and competence. To this end, special competence
networks in which clinical doctors of the university and private doctors will be
organized to cooperate in the field of clinical studies.
PMID- 10769428
TI - Age-related changes in bone mass, structure, and strength--effects of loading.
AB - The incidence of vertebral fracture has increased three- to fourfold for women
and more than fourfold for men during the last 30 years. These data are age
adjusted and therefore highlight the decrease in bone mass or bone quality from
generation to generation. To arrest or reverse these increases in osteoporotic
fractures, effective preventive regimens must be established. However, in order
to do so, a basic understanding of age-related changes in the quality and
strength of vertebral bone is crucial. In this study, the normal age-related
changes in human bone have been investigated by using a combination of different
techniques: normal histomorphometry, structural analyses, scanning electron
microscopy (SEM), and biomechanical testing. It has been demonstrated that age by
itself is the major determinant of vertebral bone strength, mass, and
microarchitecture. When the sex-related differences are investigated, three
different factors are disclosed: Men have, at the age of 20-30 years, a higher
peak bone mass and strength than women. Men show an age-related compensatory
increase in bone size (cross-sectional area of the vertebral bodies) which can
not be found in women. There is, after the age of 50 years (menopause), a higher
tendency for disconnection of the trabecular network in women than in men.
Furthermore, it was shown that loading plays an important role in the maintenance
of trabecular connectivity (through the remodeling process) and in the periosteal
apposition and thereby increase in cross-sectional area (through the modeling
process). Loading affects bone mass, microarchitecture, and size throughout life.
Loading is therefore important for the maintenance of bone strength during normal
aging--and exercise plays an important role in the prevention of osteoporotic
fractures.
PMID- 10769429
TI - [Osteoporosis in rheumatoid arthritis--significance of alfacalcidol in prevention
and therapy].
AB - Besides localised osteopenia, patients with rheumatoid arthritis (RA) with or
without corticosteroids develop in 30-50% osteoporosis induced by several factors
and thus a higher risk of fractures. Bone loss appears very early and correlates
directly with disease activity and also later with the negative effects of
restrictive mobility. Corticosteroids reduce as a pathogenetic co-factor
intestinal calcium absorption and increase renal calcium excretion resulting in
compensatory increased PTH-release and increased sensitivity of bone to PTH. In
addition, corticosteroids inhibit osteoblast function as well as the favourable
effects of growth factors and sex hormones on bone. It has recently been
recognised that the expression of D-hormone receptors (VDRs) is suppressed by
these medications and that corticosteroids probably induce VDR disorders. The
negative influence of corticosteroids on muscle strength (indirectly--via
increased PTH-levels, lowered IGF-1-levels or reduced D-hormone activity) is a
feature which has been underestimated. The demonstrated drop in 1,25(OH)2D3 (D
hormone) levels in patients with RA in correlation with C-reactive protein (CRP)
is of significance in the pathogenesis of RA-induced osteoporosis and could
further promote the process of inflammation. There is a general consensus that
cytokines (e.g. IL-1, IL-6, IL-12, TNF-alpha) induce bone resorption in
inflammatory rheumatic diseases. There are, however, new findings which show that
cytokines like TNF-alpha also interfere with bone formation by promoting
apoptosis of osteoblasts and reduce the muscle strength, too. D-hormone
preparations (alfacalcidol, calcitriol) possess immunoregulatory effects in vitro
and in vivo by inhibiting the cytokines IL-1, IL-6, TNF-alpha and particularly IL
12. At the cellular level, D-hormone reduces the expression of Th1 helper cells
directly or indirectly by inhibition of IL-12 from monocytes. Therapy with
alfacalcidol or calcitriol results in increased production of Th2 helper cells
which produce bone protective cytokines like IL-4 and IL-10. It is important to
know that D-hormone protects osteoblasts against TNF-alpha-induced cell death.
After conversion to D-hormone in the liver and bone, alfacalcidol antagonises the
above described pathogenetic factors of the corticosteroids. D-hormone is one of
the body's own immunoregulators, which is produced in macrophages in cases of
need to reduce immunological overreactions in a feed-back loop. Improved
understanding of the pathogenesis of corticosteroid-induced osteoporosis and of
the pharmacological effects of alfacalcidol in this type of iatrogenic bone loss
as well as the results of specific animal models simulating bone loss in
inflammatory diseases explain the favourable effects of alfacalcidol in this
indication. Various clinical studies have demonstrated clearly that alfacalcidol
retards corticosteroid-induced bone loss in contrast to plain vitamin D. Due to
its immunomodulating properties, alfacalcidol is particularly suitable for RA
induced bone loss and for the prevention of transplantation osteoporosis, and an
adjuvant contribution to the disease-modifying therapy of RA and to the
immunosuppressive therapy after transplantation can not be excluded.
PMID- 10769430
TI - [Inflammation mediated osteopenia (IMO): therapeutic effect of D-hormone and the
role of cytokines].
AB - Inflammation-mediated osteopenia is an animal model for bone mass reduction
following chronic inflammation. We found a reduction of calcitriol serum
concentrations during the inflammatory process, in addition cytokines are
increased. Treatment of the animals with calcitriol is able to prevent bone mass
reduction and to preserve bone formation.
PMID- 10769431
TI - 1,25-Dihydroxyvitamin D3--a hormone with immunomodulatory properties.
AB - The active vitamin D metabolite, 1,25-dihydroxyvitamin D3[1,25-(OH)2D3], exerts
immunosuppressive activity. At a cellular and molecular level, the hormone
preferentially targets helper T cell activity (Th1) by inhibiting the secretion
of both IL-2 and IFN-gamma by Th1 and by suppressing the secretion pro-Th1
cytokine IL-12 by antigen-presenting cells. The active metabolite further
inhibits class II antigen expression and enhances suppressor cell activity. In
animal models of autoimmunity, 1,25-(OH)2D3 prevents the development of
experimental autoimmune encephalomyelitis, reduces the incidence of diabetes, and
attenuates murine lupus. The hormone also prolongs graft survival in animal
models of transplantation. In humans, non-classical use of 1,25-(OH)2D3 has led
to an anti-proliferative effect in psoriasis, antineoplastic effect in prostate
cancer, and immunomodulatory effect in scleroderma. The development of less
hypercalcemic analogs might open a new therapeutic area for vitamin D3.
PMID- 10769432
TI - [Vitamin D metabolites in rheumatoid arthritis: findings--hypotheses-
consequences].
AB - Active vitamin D metabolites are not only involved in the regulation of bone
metabolism but exerts immunomodulatory effects important in the regulation of
inflammatory processes. The purpose of the present study was to evaluate the
effects of a short-time treatment with 1 alpha-hydroxycholecalciferol on both
disease activity and bone metabolism in patients with rheumatoid arthritis (RA).
The effects of an adjuvant therapy with 1 microgram 1 alpha
hydroxycholecalciferol over eight weeks on conventional parameters of disease
activity (Ritchie index, duration of morning stiffness, C-reactive protein, ESR),
serum levels of cytokines and soluble cytokine receptors (TNF-alpha, IL-6, IL-4,
sIL-2R, sIL-6R) and parameters of bone metabolism (bone-specific alkaline
phosphatase, osteocalcin, renal excretion of pyridinolin- and desoxypyridinolin
collagen-crosslinks, serum levels of parathormon, 1,25-dihydroxycholecalciferol
and calcium, daily urinary calcium excretion) were investigated in 20 patients
with RA. The treatment with 1 alpha-hydroxycholecalciferol resulted in an
insignificant decrease in the number of swollen and tender joints, morning
stiffness, CRP and ESR. Furthermore, a non-significant decrease in serum levels
of TNF-alpha and IL-6 and an increase in IL-4 was observed. The treatment led to
a significant decrease of bone-specific alkaline phosphatase (p = 0.001),
osteocalcin (p = 0.04) and renal excretion of pyridinolin-crosslinks (p = 0.022)
and to an increase of both serum calcium (p = 0.01) and daily urinary calcium
excretion (p = 0.004). The results of this pilot study in a small group of RA
patients indicate that an adjuvant therapy with active vitamin D metabolites may
not only have preventive effects on systemic bone loss but also may inhibit the
inflammatory and destructive process in RA in a limited degree.
PMID- 10769433
TI - Rheumatoid arthritis and osteoporosis.
AB - Some controversial issues in the current literature in relation to osteoporosis
and rheumatoid arthritis are updated and discussed. Because most studies agree
that osteoporosis in postmenopausal women and in men with RA is more evident at
the hip and radius than at the spine, and that the most important determinants of
bone loss are disability, local disease activity, and cumulative corticosteroid
dose, osteoporosis is not a common systemic extra-articular manifestation of RA.
In early arthritis, periarticular osteoporosis does indeed reflect disease
activity because it is closely related to the acute phase reactants, but once
periarticular osteoporosis is established it is no longer a marker of disease
severity. The threshold dose for corticosteroid-induced osteoporotic fractures is
the cumulative rather than the actual dose. Statements based on quantitative
tomography concerning the acute effects (and their reversal) of corticosteroids
on bone have to be interpreted with care because of important body composition
changes, in particular in bone marrow fat, during corticosteroid treatment. At
present there is no evidence that anti-resorbing drugs can change the progress of
RA erosions, probably because erosions are the result of non-osteoclast mediated
mechanisms. Stress fractures in RA are underdiagnosed and are often confused with
synovitis, and therefore it is likely that they are more frequent than commonly
thought, especially in the lower limbs. Methotrexate osteopathy is known in
oncological practice. Whether low dose methotrexate is toxic for bone is not
clear, but a number of clinical observations suggest that the occurrence of
spontaneous fractures and lower extremity pain is more frequent in methotrexate
treated patients than expected. Prospective studies are necessary to confirm
these impressions.
PMID- 10769434
TI - Relationship between muscle strength and vitamin D metabolites: are there
therapeutic possibilities in the elderly?
AB - To test the hypothesis that muscle weakness associated with aging is in part due
to low serum levels of vitamin D, we investigated the relationship between muscle
strength and serum levels of vitamin D metabolites in ambulatory elderly people
who were not receiving vitamin D supplementation. We enrolled 319 ambulatory
elderly subjects (103 women: mean age 74.2, age range 65-86; 216 men: mean age
76.6, age range 66-95) between April and August 1995. The study design was cross
sectional. Muscle strength was measured as leg extension power in watts (LEP).
Mean 25-hydroxyvitamin D serum concentrations were higher in male participants at
36.2 ng/ml (range 3.0-85.0) versus 27.4 ng/ml (range 5.0-88.0) in female subjects
(p = 0.008). We found 12 percent of female and 18 percent of male subjects with
25-hydroxyvitamin D values below the lower threshold (< 12 ng/ml). Mean 1,25
dihydroxyvitamin D levels were similar in both sexes: 39.8 pg/ml (range 15.0
73.0) in women and 37.9 pg/ml (range 13.0-69.0) in men. LEP declined with age in
women and men (f: r = -0.35, p = 0.001; m: r = -0.48, p < 0.0001). Men were
significantly stronger than women (p < 0.0001). In men both 25-hydroxyvitamin D
and 1,25-dihydroxyvitamin D showed pairwise correlation with LEP (r = 0.24; p =
0.0004/r = 0.14; p = 0.045). In women only 1,25-hydroxyvitamin D was
significantly correlated with LEP (r = 0.22; p = 0.03). In ANCOVA, including all
participants, explaining LEP by sex (p < 0.0001), age (p < 0.0001), BMI (p =
0.013), 1,25-dihydroxyvitamin D (p = 0.02), 25-hydroxyvitamin D (p = 0.18) and
iPTH (p = 0.82), all factors showed significant effects except 25-hydoxyvitamin D
and iPTH (r2 of the whole model: 0.41). In conclusion our results support the
view that, in concert with other factors, deficiency of both 25-hydroxyvitamin D
and 1,25-hydroxyvitamin D contributes to the age-related decline in muscle
strength. Modest, but significant relationships between 1,25-dihydroxyvitamin D
and muscle strength in both sexes, and 25-hydroxyvitamin D in male participants
could be documented. Whether the impact of vitamin D on calcium homeostasis and
bone mineral density or directly on the muscle tissue level is more important for
prevention of hip fractures remains unclear. Further prospective and comparative
treatment studies should be performed, in order to evaluate whether and in which
dose requirements, vitamin D supplementation can improve muscle strength in the
elderly.
PMID- 10769435
TI - The diagnosis and management of osteoporosis.
AB - Osteoporosis is a prevalent disease, which can cause considerable morbidity due
to osteoporotic fractures. Knowledge of the cause of osteoporotic bone loss would
help implementation of the appropriate treatment. There are two pathogenic
mechanisms involved in the development of osteoporosis: 1) achievement of a
relatively low peak bone density in young adulthood which increases the risk of
osteoporosis because only a modest bone loss later in life results in bone
densities in the osteoporotic range, and 2) a rapid bone loss rate at menopause
and/or later in life. Most patients exhibiting osteoporosis have some combination
of these two pathogenic mechanisms. There are basically two causes for
osteoporosis: 1) a normal peak bone mass with rapid bone loss, and 2) low peak
bone mass with a normal bone loss rate. Proper management of osteoporosis
involves early diagnosis of the disease and appropriate treatments. With respect
to diagnosis of osteoporosis, we now have two important diagnostic tools: a)
instruments that measure bone density with high precision, and b) serum and urine
biochemical markers of bone formation and resorption assays that allows rapid and
frequent monitoring of bone turnover rates. Bone density measurements allow the
diagnosis of osteoporosis before fractures occur. Biomarkers can identify
patients with a high bone turnover, a situation that leads to rapid bone loss.
These two diagnostic tools together can help identify osteoporosis in its
earliest form so that preventative measures can be instituted. With respect to
treatment of osteoporosis, we now have several forms of effective therapies, such
as estrogens, bisphosphonates, calcitonins, and vitamin D (and/or active vitamin
D metabolites), that are approved for the use in the prevention and/or treatment
of osteoporosis. Consequently, most patients with osteoporosis can now be treated
with effective therapies that will have a positive impact on the disease.
PMID- 10769436
TI - Corticosteroid osteoporosis.
AB - Corticosteroids are widely used in the treatment of patients with chronic
inflammatory diseases. Since the most rapid bone loss occurs in the first 12-24
months after commencing high dose corticosteroids, it is important to consider
two different therapeutic situations, (a) prevention in patients starting
corticosteroids and (b) treatment of patients on chronic corticosteroids who will
already have some significant degree of corticosteroid related bone loss. An
adequate calcium intake is recommended and any contributing factors to
osteoporosis should be treated. A bone density will give information about the
future risk of osteoporotic fracture and the need for active pharmacological
treatment. Patients commencing high dose long-term corticosteroid therapy should
be treated prophylactically with a bisphosphonate and/or active vitamin D
metabolites (alphacalcidol or calcitriol) and the treatment may need to be
continued for 1-2 years. Patients on chronic corticosteroids may improve their
bone density by treatment with bisphosphonates and vitamin D metabolites
(including the calciferols). In postmenopausal women, concomitant use of estrogen
replacement therapy is also appropriate. It is important in a patient on long
term therapy to review the need for continuing treatment or the possibility of
dosage reduction.
PMID- 10769437
TI - Prevention of corticosteroid-induced osteoporosis by alfacalcidol.
AB - We studied the effect of alphacalcidol (1-alpha-hydroxycholecalciferol) on bone
metabolism in patients who were placed on glucocorticoid therapy. We selected 41
women (age: 32-52 yrs) who were recently diagnosed with systemic lupus
erythematodes, multiple sclerosis, rheumatoid arthritis or asthma bronchiale.
Patients did not have other disease or take drugs known to influence bone
metabolism. Patients were randomly enrolled into two groups and were given 5-25
mg prednisone daily. After 4 weeks, group A (n = 21) received 0.5-1.0 microgram
(mean = 0.54 +/- 0.03 microgram) alphacalcidol and group B (control; n = 20) was
given 500 mg calcium daily for three years. There were no significant differences
in age and steroid doses between groups. Serum calcium (Ca), osteocalcin (OC),
collagen I C-terminal propeptide (PICP), parathyroid hormone (PTH), and urinary
calcium and deoxypyridinoline crosslink excretion (DPD) were measured before
corticosteroid administration, and before alphacalcidol or calcium treatment as
well as 6 weeks, 6 months, and 1, 2, and 3 years later. Bone mineral density
(BMD) was examined before treatment and 6 months, 1, 2, and 3 years later by DEXA
and SPA. OC and PICP decreased significantly after 4 weeks on steroid in both
groups and increased in group A but not in group B after 6 weeks of treatment
with alphacalcidol and remained unchanged for 3 years. Serum PTH increased in
both groups after 4 weeks of glucocorticoid treatment and was reduced in group A,
but not in group B, after 6 weeks on alphacalcidol. Serum Ca, urinary Ca, and DPD
did not change significantly in either group during the study period. Lumbar
spine and femoral neck BMD were significantly reduced in group B after 6 months
and 1 year, respectively, and continued to decrease during the study, while no
significant change in group A was observed. BMD of the radius did not change in
either group for 2 years but there was a significant reduction by the third year
in group B. Based on these results, alphacalcidol treatment appears to be
effective in preventing glucocorticoid-induced bone loss in these patients by
reducing secondary hyperparathyroidism and stimulating bone formation.
PMID- 10769438
TI - Transplantation osteoporosis and corticosteroid-induced osteoporosis in
autoimmune diseases: experience with alfacalcidol.
AB - The effect of alfacalcidol therapy on bone mineral density at the spine and
proximal femur was evaluated in 112 transplant recipients (59 heart, 26 liver and
27 lung); 45 transplant cases served as controls (included in a randomised way in
a placebo group) and in 42 rheumatoid arthritis cases. Liver and lung
transplantation cases had before transplantation a lower bone density at the
spine and femur compared to heart transplant cases. Heart transplant cases lost
considerably more bone immediately after transplantation than liver and lung
transplant recipients. A positive effect of 2 years alfacalcidol treatment (0.5-1
microgram/day) on bone loss was observed in all treated groups. Alfacalcidol was
particularly effective against trabecular bone loss at the spine in rheumatoid
arthritis patients and transplant recipients. There is a manifest difference in
evolution between organ transplant groups and bone sites measured. Liver and lung
transplant recipients respond better to therapy than cardiac recipients.
PMID- 10769439
TI - [Carotid surgery].
PMID- 10769440
TI - [The modern surgery of face lift: indications and results].
AB - In this retrospective study with a group of 55 patients aged 47.7 +/- 8.3 years,
surveyed for a period of 16 months, the results of different face lift techniques
-subcutaneous face lift combined with imbrication of the SMAS-Platysma complex
versus sub-SMAS-dissection with transposition of the SMAS-Platysma complex--were
compared in order to evaluate risks and complication rates of these two
techniques. Various indications and different techniques including special
features were discussed. A slightly higher complication rate is evident in the
patient group treated with the sub-SMAS face lift technique, mainly referring to
temporary asthenia of the nervus facialis, which regressed in all cases after 7
months. The post op bleeding rate was 2.3%, within the range given in the
literature. Concludingly, the pure subcutaneous face lift with imbrication of the
SMAS-Platysma complex still is an established method in modern rhytidectomy
treatment.
PMID- 10769441
TI - [Natural history and indications for surgery in carotid stenosis].
AB - Atherosclerotic stenoses of the internal carotid artery are often the underlying
cause for ischemic stroke. Several studies show a strong correlation between the
grade of stenosis and stroke risk. When cerebral symptoms occur in patients with
a carotid artery stenosis of 60% or more the risk of stroke within the following
12 months is over 10%. Large randomised studies show that patients with a high
grade carotid artery stenosis benefit clearly from carotid endarterectomy.
Surgical treatment reduces stroke risk by more than 70% in these patients.
Symptomatic patients with stenoses less than 40% do not benefit by endarterectomy
even when surgical complication rate is low. The benefit of carotid
endarterectomy is proven for asymptomatic stenoses, too. In asymptomatic
patients, however, an operative procedure is justified only when surgical
complication rate is 3% or less.
PMID- 10769442
TI - [Conventional thrombendarterectomy with carotid patch plasty vs. eversion
endarterectomy: technique, indications and results].
AB - We report our experience with carotid surgery during the past 11 years and a
prospective randomized study on 600 patients with conventional thromb
endarterectomy (TEA) versus eversion-endarterectomy (EEA). First results gave EEA
a slight advantage, which could not be proved in the following years. Both
methods are equivalent in terms of postoperative and long-term results. Follow-up
showed one difference between the two methods: Restenosis occurred more often in
the TEA-group (14.7% TEA versus 6.5% EEA). The frequency of symptomatic
restenosis was the same in both groups (3.8% TEA versus 3.9% EEA). EEA did not
show late restenosis. We attribute this to the avoidance of patch-suture and the
introduction of patch material, as was observed by other authors. No ruptures of
venous patches occurred in our study after primary implantation, while two venous
grafts ruptured after substitution of an infected Dacron patch. Infection rate
for the Dacron patch was below 0.2% and is therefore negligible. Duplex
ultrasound is indispensable in evaluating plaque-morphology, although sensitivity
is low in the detection of dangerous atherosclerotic lesions (73.4% for the soft
plaque, 31.9% for ulcerations). In view of these results and a critical analysis
of the current literature, we see slight advantages for EEA over TEA inspite of
equivalent operative results. However, EEA is a suitable procedure only in
connection with subtile intraoperative control and in the hand of an experienced
surgeon.
PMID- 10769443
TI - [Eversion endarterectomy--out?].
AB - Carotid eversion endarterectomy has become a well established alternative to
conventional carotid endarterectomy. Similar perioperative morbidity and
mortality results have been documented in several large clinical series. Our
experience with carotid reconstructive surgery consists of 12,596 operations
between 8/84 and 12/97, some 60% of which were performed using the eversion
technique. Transient or permanent neurologic deficit was observed in 2.0%; 0.8%
died after the procedure. Eversion endarterectomy should only be performed under
suitable anatomic conditions. It is a challenging technique which requires
advanced surgical skills and sound clinical judgement. The long-term rate of
restenosis seems to be influenced favourably after eversion endarterectomy.
PMID- 10769444
TI - [Cerebral ischemia during carotid clamping: diagnosis and prevention].
AB - A serious complication in carotid endarterectomy (CEA) is the occurrence or
aggravation of neurological deficits caused by insufficient collateral cerebral
blood flow during cross-clamping. At the moment, patients with failure of
collateral circulation at this point cannot be identified preoperatively. Thus,
intraoperative monitoring and methods to prevent clamping-related cerebral
ischemia are required. To put this strategy into clinical practice there are
several methods of monitoring cerebral function (e.g. surgery performed in awake
patients, electroencephalography, somatosensory evoked potentials), changes of
hemodynamic (e.g. carotid stump pressure, transcranial Doppler ultrasonography)
or metabolic parameters (e.g. jugular bulb oximetry or transcranial oximetry).
One technique that meets nearly all requirements of an ideal monitoring under
general anesthesia is the use of somatosensory evoked potentials (SEPs).
Registration of SEPs is simple to perform and indicates with a high sensitivity
and specificity critical cerebral hypoperfusion during cross-clamping. Thus, SEPs
monitoring indicates the necessity of shunt placement. As a result, the use of an
indwelling shunt as the most effective method to prevent clamping ischemia can be
limited to selected cases, avoiding the risks of shunting in patients with
sufficient collateral flow. In addition, correct shunt function is immediately
indicated by recovering potentials. Whether a combination of SEPs with
transcranial Doppler measurements will be successful to provide additional
information about cerebral embolisation should be determined.
PMID- 10769445
TI - [Intraoperative quality control in carotid surgery].
AB - The intraoperative quality control in carotid surgery is performed by different
methods: angiography, duplex-ultrasonography, transcranial Doppler
ultrasonography, cw-Doppler, B-mode ultrasonography, pulsed Doppler with spectral
analysis, angioscopy and flow-measurements. In Germany these measures are used
only in one third of the carotid reconstructions. Especially with angiography and
duplex-ultrasonography technical defects can be detected and differentiated if
they were without clinical relevance like low-grade stenoses, small intima-flaps
and residual plaques or needed to be reexplored. These are high-grade stenoses,
acute thrombus-formations of the endarterectomised area and large intima-flaps.
Abnormalities were detected in a mean of 17% of all carotid reconstructions by
intraoperative control methods. In 5% severe irregularities lead to an immediate
revision. Despite that there does not exist clear evidence whether the use of
quality control methods reduces the perioperative neurological complication rate.
It is not necessary to perform intraoperative quality control if meticulous
operative technique with shunting and patch angioplasty is applied and a low
perioperative complication rate is reached. For the documentation of the surgical
result angiography can be recommended.
PMID- 10769446
TI - [Urgent and emergency carotid TEA].
AB - Restoration of blood flow to reperfuse ischemic but not infarcted areas of the
brain (ischemic penumbra) and the removal of an ongoing embolic source are the
therapeutic aims of emergency and urgent carotid endarterectomy (CEA), both in
patients with an acute or progressive ischemic stroke and in patients in the
early period after a carotid-related stroke. Based on poor results in the 60ies
and 70ies, many centers traditionally perform CEA four to six weeks after a
carotid-related stroke at the earliest interval. Since natural history is
associated with a high risk of an disabling and/or recurrent stroke in several
subgroups of patients, some reports were able to show that urgent and emergency
CEA could be worthwhile in well-selected patients.
PMID- 10769447
TI - [Treatment of restenosis].
AB - Carotid restenosis after endarterectomy is observed in up to 24.1% of patients
with long-term follow up. Indication for reintervention in asymptomatic patients
however should be reserved for greater than 80% stenosis. Treatment options
include repeat surgical reconstruction as well as intraoperative or percutaneous
balloon angioplasty +/- stenting. We compared our past experience with 66
operative reconstructions in 64 patients with a recent series of 60 patients who
underwent intraoperative balloon-dilatation and stenting. After conventional
surgery 2 patients (3.1%) suffered a permanent neurological deficit, one patient
developed a TIA (1.5%). After intraoperative dilation and stenting 8 patients
(13.3%) suffered a stroke; 2 patients died after surgery (one stroke, one
myocardial infarction) (mortality 3.3%). When compared to conventional operative
repair intraoperative carotid balloon angioplasty and stenting of restenosis is
complicated by a substantial increase in morbidity and mortality and cannot be
recommended as routine therapy.
PMID- 10769448
TI - [Primary bacterial aortitis].
AB - Primary bacterial aortitis represents a rare disease with a high lethality. From
June 1997 to April 1999 5 patients with an abdominal aortic infection were
treated by resection of the infected aorta and in-situ reconstruction or by extra
anatomic bypass. There was no treatment in one case because of the infaust
prognosis. 3 patients survived, one with a paraparesis as a result of spinal
ischemia. On the basis of our patients the pathogenesis, clinical symptoms with
diagnosis and the therapeutic options are discussed.
PMID- 10769449
TI - [Late results after below-knee revascularization of the popliteal artery with
thin-wall InterGard vascular prosthesis].
AB - We report on our clinical experience with a knitted Dacron prosthesis: thin
walled, spirally reinforced InterGard prosthesis. Between 1993 and 1996, 81
prostheses were implanted in 72 patients with an infrainguinal connection. We
describe the special features of the prosthesis. The entire group of patients was
analyzed. Indications for operation were disabling claudication in 42 cases
(51.8%) and critical limb ischemia in 39 (48.0%) cases. The angiographic run-off
was poor in 71 (87.9%) implantations. The perioperative mortality rate was 1.2%
(1 patient). The primary cumulative patency rate calculated by the life-table
method was 70% at 69 months. Our results suggest that PTFE offers no clear
advantage over Dacron and the preferential use of PTFE needs to be reassessed.
PMID- 10769450
TI - [Manifestation of popliteal aneurysm during pulse spray thrombolysis (PST)].
AB - We report the case of a 32-year-old woman presenting with acute extremity
ischemia due to thrombosis of a previously undetected popliteal artery aneurysm.
The popliteal artery aneurysm was revealed by PST which was indicated for the
treatment of thrombosis of the superficial femoral artery. PST was complicated by
a peripheral embolism with subsequent severe extremity ischaemia. Immediate
embolectomy and reconstructive vascular surgery led to a successful result. This
case illustrates the diagnostic problems of a thrombosed popliteal artery
aneurysm and warns of embolic complications during PST.
PMID- 10769451
TI - [Endoscopic obesity surgery: gastric banding. A new trend without scientific
basis?].
AB - Indication for operation in morbid obesity is a body mass index greater than 40
kg/m2. Various operative procedures such as vertical banded gastroplasty and
gastric bypass are used for therapy. Since 1994 the laparoscopic performed
gastric banding is an alternative to conventional techniques. The mortality rate
of this technique is below 1%, summarizing data from the literature of 905
patients the complication rate ranged to 24%. These results are comparable to
conventional operations. Regarding the weight loss the results are comparable to
the vertical banded gastroplasty. 80% of the patients loss 60% of their excess
weight at 12 months. The rate of conversion to open procedure is low and ranges
to 2.4%. Especially in obese patients the laparoscopic approach offers the well
known advantages of endoscopic procedures. Open questions are the long-term
effects and complications of laparoscopic gastric banding.
PMID- 10769452
TI - [Obesity: when does the internist recommend surgery?].
AB - Obesity is a chronic disease with a poor therapeutical outcome. Well-defined
education of the patient and conservative treatment are the basics of therapy.
Nevertheless, one should always be aware of the possibility of surgical
intervention. In the following, the diagnostical and therapeutical procedures
concerning obesity will be described in order to allow a reasonable indication of
surgical intervention.
PMID- 10769453
TI - [Experience in the use of propofol in surgical interventions in children].
AB - The adequacy of anesthesia with propofol is evaluated in 48 children aged 3
months to 7 years (ASA I-III) subjected to abdominal and urological
interventions. The children were divided into groups administered different
general anesthesias: 9 children aged 3-7 years operated under total intravenous
anesthesia (TIVA) with propofol and fentanyl and 39 children aged 3 months to 6
years operated under TIVA with propofol, ketamine, and fentanyl. The efficiency
of anesthesia was evaluated by electroencephalography and hemodynamic monitoring.
TIVA with propofol, fentanyl, and ketamine did not notably decrease arterial
pressure during induction; the course of anesthesia and recovery ran a smooth
course; the doses of propofol and fentanyl were appreciably decreased. Use of
this protocol in children aged under 3 years ensured adequate anesthesia with the
minimum risk of hemodynamic disorders.
PMID- 10769454
TI - [Reaction of the sympathoadrenal system in young children with congenital heart
defects during cardiopulmonary bypass surgery].
AB - Reactions of the sympathoadrenal system were studied during surgical
interventions in children aged 1.5-3 years with congenital heart disease operated
under conditions of artificial circulation and hypothermia. The state of the
sympathoadrenal system was different in uneventful and complicated course of the
operation, which may indicate a different efficiency of the neurovegetative
blocking and antistress protection from surgical trauma.
PMID- 10769455
TI - [State of the sympathoadrenal system and hemodynamics in children during
congenital heart defect surgery with high thoracic epidural anesthesia using
lidocaine-clofelin].
AB - Effects of high thoracic epidural anesthesia (HTEA) on the hemodynamics and
sympathoadrenal system were studied in patients during cardiopulmonary bypass
surgery. In 55 patients aged 1-14 years, HTEA was used in combination with oxygen
air-halothane anesthesia. In one group lidocaine and fentanyl were used for HTEA
and in another clonidine and lidocaine. In the control, standard intravenous
fentanyl-diazepam anesthesia was combined with oxygen-air-halothane anesthesia.
In the clonidine-lidocaine group the endocrine stress response was decreased in
comparison with other groups even without narcotics; hemodynamics was stable even
in patients with NYHA class III-IV.
PMID- 10769456
TI - [Characteristics of general anesthesia in video thoracoscopic surgery in
children].
AB - Videothoracoscopic operations were carried out in 54 patients aged 6 months to 14
years. Two variants of general anesthesia were used: bolus injection of fentanyl
in combination with calypsol and infusion of fentanyl in combination with
subnarcotic doses of fluothane. One-lung ventilation was carried out in all
children. Hemodynamic status, gaseous composition of the blood, and cerebral
bloodflow were monitored during general anesthesia.
PMID- 10769457
TI - [Comparative characterization of changes in visual perception after ketamine and
brietal anesthesia in children].
AB - Visual perception is disordered in children aged 10-15 years subjected to surgery
under ketamine and brietal anesthesia in an outpatient setting. Psychological
testing was carried out during 24 h after intervention. Results of the
Rorschach's test indicate that ketamine impairs the quality of visual perception
(inadequate evaluation of the size, shape, velocity, etc.). Brietal disorders
mainly the integrity of visual image. Visual perception did not normalize 24 h
after both anesthesias. Disorders typical of each drug persisted.
PMID- 10769459
TI - [Experience in tube feeding of children in intensive care].
AB - Tube feeding was used in 97 children aged 0 to 8 years hospitalized in intensive
care wards. Daily rations were calculated on the basis of daily requirements. The
feeding was carried out continuously or intermittently. Algorithms of the methods
are presented. If requirements to tube feeding are strictly adhered to, the
incidence and severity of complications are minimal.
PMID- 10769458
TI - [State of central hemodynamics in various kinds of anesthesia during short-term
ENT surgery in children].
AB - The study was carried out in 124 children aged 4-10 years with ASA risk I or II.
Group 1 consisted of 40 patients operated on under combined anesthesia with
midazolam, fentanyl, and N2O, group 2 were 30 children operated on under mask
anesthesia with fluothane, and nitric oxide + oxygen, group 3 patients were
operated on under combined anesthesia with ketamine, midazolam, and N2O + CO2,
and group 4 patients were operated on under thiopental and N2O + CO2.
Cardiovascular function was evaluated by the NCCOM3-R-7 device (BoMed) by the
bioimpedance method. Satisfactory cardiovascular function was observed in all
groups, but the best stability was noted in the midazolam-fentanyl group. Hence,
midazolam-fentanyl combination can be the method of choice in short-term ENT
operations.
PMID- 10769460
TI - [New aspects of the activities of pediatric intensive care unit].
AB - A model of regional network of pediatric resuscitation has been created in the
Sverdlovsk region. The model is based on evaluation of hazards, is staged,
standard, and makes use of a universal information space. The unifying structure
is a pediatric resuscitation consultation center. Its main tasks are therapy and
counseling in the region and introduction of overall training in reanimation and
intensive care of children, with improvement of the level of urgent care at
therapeutic institutions of the region. The activities of the resuscitation care
network promoted a significant decrease in neonatal mortality by 29.5% and of
infant mortality by 28.7%.
PMID- 10769461
TI - [Significance of hereditary factors in multiple organ dysfunction syndrome in
children with infections].
AB - In order to elucidate the contribution of hereditary factor (dose of ribosome
genes) to the realization of organ dysfunction syndromes in children with
surgical infection, the total size of silver nitrate-stained nucleoli-forming
regions (Ag-NFR) of acrocentric chromosomes in karyotypes was assessed in 22
patients aged from 14 months to 12 years, 17 of these with appendicular
peritonitis, 4 with destructive pneumonia, and 1 with acute hematogenic
osteomyelitis. Pyoseptic diseases involved no organ dysfunction in 10 patients,
and in 12, multiple organ dysfunction was diagnosed. Our findings indicate that
the carriers of low-copy variants of ribosome genes are characterized by
hereditary predisposition to lowered individual resistance of the organism.
Therefore, children with surgical infection with a decreased size of Ag-NFR (low
dose of ribosome genes) in the karyotype potentially represent a group at risk of
multiple organ dysfunction realization.
PMID- 10769462
TI - [Role of cyclic nucleotides in formation of pathologic reactions in the immediate
postoperative period].
AB - Effects of anesthesia and surgery on the level of cyclic nucleotides (CN) and
their role in the formation of pathological reactions are little studied. We
measured plasma concentrations of CN for evaluating the quantitative and
qualitative changes in adenylate-guanylate cyclase metabolism under the effect of
operation and for elucidating the role of these changes in postoperative
disorders of hemodynamics and gas exchange. The findings in patients with
surgical diseases of the lungs (168 pts), with acquired and congenital heart
diseases (193 pts), and with atherosclerotic involvement of the aorta (63 pts)
were analyzed. The CN system is responsible for the pre-, intra-, and
postoperative status of surgical patients, which manifests by a hypermetabolic
reaction leading to an increase in the blood concentrations of cAMP and cGMP. At
the initial stages this reaction is compensatory, while in the immediate
postoperative period CN are involved in the pathological mechanisms leading to
hemodynamic disorders.
PMID- 10769463
TI - [Characteristics of the strategy of intensive care of unconscious children].
AB - Three major groups can be distinguished among children hospitalized in
resuscitation and intensive care wards in a state of unconsciousness: patients
with bacterial meningitis and meningoencephalitis, viral meningoencephalitis, and
noninfectious involvement of the NCS. Common strategy of treatment of these
patients is characterized by some specific features: etiotropic antibiotic
therapy in group 1 patients, antiviral drugs in group 2, and mainly symptomatic
measures in group 3. Immunotherapy used in each of these groups is substitute in
group 1, immunomodulating and immunostimulating in group 2 and even more so in
group 3. Better results in group 1 are due to highly effective etiotropic
antibiotics and drugs.
PMID- 10769464
TI - [Intensity of basal metabolism and ratio of oxidized energy substrates in
children with craniocerebral trauma].
AB - Twenty-five children aged 2-14 years with isolated and combined craniocerebral
injury were examined. Some of them underwent urgent neurosurgical interventions.
Mechanical injury and intervention were regarded as aggressive factors. The basic
methods were indirect calorimetry and intravenous prolonged glucose and fat
tolerance test. The results indicate that in general, the intensity of basal
metabolism and the ratio of oxidized energy substrates in children with
craniocerebral injury correspond to the course of standard postaggressive
reaction. Time course of changes in RQ, structure and share of basic energy
substrates in the total energy produced confirm a general biological regularity
of postaggressive metabolism: fat is oxidized predominantly during the initial
period, while on day 5 inversion of fat and glucose oxidation values is observed.
PMID- 10769465
TI - [Use of noninvasive assisted lung ventilation in children in intensive care
units].
AB - Thirty-six patients aged 2 months to 14 years were observed. Noninvasive assisted
ventilation of the lungs (NAVL) was performed through Respironix Inc. masks (USA)
with Puritan-Bennet 7200, Bear 1000, and Bear 750 respirators in the SIMV + PS,
CPAP + PS modes with manual regulation of the supporting pressure level.
Respiratory rate, heart rate, respiratory volume, pO2, pCO2, SpO2, stroke volume,
and minute volume of the heart were evaluated. During development of central
respiratory failure in the early postoperative period or in case of forced deep
medicamentous neuroplegia NAVL normalized the external respiration function and
promoted adequate ventilation of the lungs; in the majority of cases with
development of restrictive respiratory failure (RF) it improved ventilation of
the lungs and therefore no intubation of the trachea and transfer to forced
ventilation was needed. NAVL is indicated as a component of multiple-modality
treatment for obstructive RF.
PMID- 10769466
TI - [Relations between several parameters of respiratory mechanics after radical
correction of congenital heart defects].
AB - The results of this study are at variance with highly prevalent opinion that an
increase in Vinsp leads to a parallel growth of Cst. A different degree of
relationship between Vinsp and Cst was observed in the studied groups (from 0.33
to 0.92). These relationships in children with congenital heart disease are
determined by the state of pulmonary circulation and lung parenchyma before
surgery and after correction and depend on the form of the defect and patient's
age. Such a variety of values is due to specificity of changes in the lungs
depending on the pathomorphology of congenital heart disease and progress of
these changes with age.
PMID- 10769467
TI - [Use of assisted forced ventilation of the lungs in patients during prolonged
respiratory therapy].
AB - A total of 338 patients were treated by prolonged forced ventilation of the lungs
(AVL). The adult respiratory distress syndrome was detected in 78 patients.
Control group consisted of 260 patients in need of prolonged AVL because of
respiratory discomfort. Central hemodynamics was assessed by the Swan-Ganz
balloon catheter. The advantages of assisted AVL are decreased resistance of the
patient to the respirator, no suppression of muscular activity, decreased
intrathoracic pressure, a lower probability of respiratory alkalosis or acidosis,
and possibility of inspiration end positive pressure during spontaneous
respiration. The shortcomings are poor reaction of trigger mechanisms to the
beginning of a spontaneous act and rapid exhaustion of respiratory muscles in
grave weak patients.
PMID- 10769468
TI - [Early respiratory support in anti-shock therapy of children with severe thermal
trauma].
AB - Search for effective method for decreasing the mortality of children with severe
thermal injuries and approaches to preventing and treating multiorgan dysfunction
in severe thermal injury is a pressing problem of reanimatology. The majority of
scientists consider disorders in the ventilation-perfusion function of the lungs
the main factor in the pathogenesis of burn shock. Lung injury is most often the
first manifestation of multiple organ dysfunction. The depth of disorders in the
gas exchange function of the lungs clearly correlates with the severity of burn
injury and the terms of the beginning of respiratory support. The severity of
burn shock, preclinical diagnosis of acute respiratory distress syndrome and
disseminated intravascular blood coagulation, depth of hemodynamic disorders and
disorders in the oxygen transporting system can serve as a criterion of the
compensatory stress and be an indication for active respiratory therapy.
Comparison of the main and control groups demonstrated the efficiency of early
respiratory therapy in children with severe burns, because such therapy
normalizes the blood oxygen transporting function and hemodynamic parameters
sooner and with less strain for the compensatory potential of the organism.
PMID- 10769469
TI - [New conditions for evaluating static compliance].
AB - Static compliance (Cst), time course and clinical and diagnostic significance of
relationship between Cst and Vinsp were studied in 97 patients with congenital
heart diseases aged over 3 years after open-heart surgery for correction of the
defect during uneventful immediate postoperative period. Three groups of patients
were distinguished: 1) patients operated on for Fallot's tetralogy without a
previous aortopulmonary anastomosis (TF-1); 2) patients with Fallot's tetralogy
with a previous systemic pulmonary anastomosis (TF-2); 3) patients operated on
for atrioventricular septal defects and incomplete atrioventricular
communication. Age subgroups of 3-5, 6-8, 9-11, and 12-15 years were singled out
in each group. The proposed modified method for measuring Cst in children aged
over 3 years operated on for congenital heart disease more accurately and
reliably characterized the status of lung parenchyma. As a result, the
correlation (r) between Cst and Vinsp in all nosological groups and age subgroups
was much higher than was previously reported.
PMID- 10769470
TI - [Method for determining the position of the catheter end in the central vein].
AB - The position of the catheter end in the central vein was studied by the x-ray,
ultrasonic, and electrometric methods during catheterization of 69 veins in 66
patients. The position was incorrect in 64% cases. Electrometric method for
detecting the position of the end of venous catheter is the most available for
intensive care wards of municipal hospitals, because no special equipment or
staff is needed, the method is simple, can be used directly during
catheterization, and is cheap.
PMID- 10769471
TI - [Centralized delivery of anesthetic gases: advantages and hazards].
PMID- 10769472
TI - [Methemoglobin-forming agent poisoning in children].
PMID- 10769473
TI - [Fatal outcome caused by lysthenon in a child at the early stage of primary
myopathy].
AB - A child aged 3 years 10 months with latent early stage of primary myopathy died
during surgery for left-side cryptorchidism after injection of lysthenon.
Asystole, the immediate cause of death, was caused by release of potassium ions
from skeletal muscles into the blood. Myopathy was diagnosed at autopsy by
histological examination of the diaphragm and mm. pectoralis major and
gastrocnemius.
PMID- 10769474
TI - [Immunological aspects of postoperative sepsis].
PMID- 10769475
TI - [Intensive therapy of acute kidney failure in children].
PMID- 10769476
TI - [Synchronization of the child with the respirator is the most important condition
in preventing complications of artificial ventilation of the lungs in newborn
infants].
PMID- 10769477
TI - [Building hygiene between the past and the present].
PMID- 10769478
TI - [Influenza surveillance in a town of northern Italy in 1994-1997].
PMID- 10769480
TI - [Exposure to airborne bacteria in a waste water treatment plant].
PMID- 10769479
TI - [Activities of the Antirabies Center of Rome: analysis and proposals].
PMID- 10769481
TI - [Chronic diseases of nutritional origin and their prevention].
PMID- 10769482
TI - [Water quality control of 2 swimming pools in Rome. Evaluation of the
bacteriophage parameter].
PMID- 10769483
TI - [Study of the association between air pollution and hospital admissions for
respiratory diseases in the city of Novara].
PMID- 10769484
TI - [Problem of removing dust in an ancient book library. Microbiological study: the
experience at Lancisiana Library].
PMID- 10769485
TI - [DRG analysis in general surgery departments of 3 hospitals and a private clinic
in the Local Health Unit of Chieti, 1997].
PMID- 10769486
TI - [Height of rooms: changes after the Ministerial Decree of June 9, 1999].
PMID- 10769487
TI - Lassa fever imported to England.
PMID- 10769488
TI - MRSA with intermediate resistance to teicoplanin.
PMID- 10769489
TI - Monkeys with herpes B virus culled at a safari park.
PMID- 10769490
TI - [Examination of silane ceramic systems by differential thermoanalysis].
AB - In the present study two silane adhesive agents (Silicoup, Heraeus/Kulzer, and
Monobond-S, Vivadent) and one type ceramic (VITA VKM 68) and their interface
reactions were tested by thermo-analysis. The ceramic powder is thermally
inactive. Using the two different silane solutions with the same ceramic type
different thermical characteristics were found despite the same base material
(gamma-methacryloxi-propyl-trimethoxi-silane). This can probably be attributed to
the different configurations of the polycondensates.
PMID- 10769491
TI - [Effect of conditioning on the circulation of rat teeth].
AB - Materials employed in "adhesive filling technique" often lack informative
instructions concerning the depth of cavities which require lining. Etching
materials directly placed on the dentin can adversely influence the pulp leading
to changes in local microcirculation which can be an early sign of the
pathological changes in the pulp. Therefore, it is worth examining the effect of
these materials on the diameters of pulpal vessels. In the present study we
examined wether acid etching (test1: 15 s and test2: 60 s) alters the blood
circulation of the pulp lower incisors, by applying it directly onto a thin layer
of pulpal wall (40-50 microns) without any liner, and following the instructions
provided by the manufacturer. Twenty male Sprague-Dawley rats (weighing 330 +/-
51 g) and the technique of vitalmicroscopy was used for this investigation. The
left lower incisors of the rats were prepared for vitalmicroscopy. Changes in
vessel diameter were recorded prior to and 5, 15, 30 and 60 minutes after
investigated materials or saline (control) were administered on dentin. In
control and test1 group the vessel diameter was unchanged during the experiment.
However, in group test2 an intense vasoconstriction was registered. There were
significant (p > 0.05, ANOVA) differences in diameter changes between the control
group and those treated with acid etching for 60s. Our results suggest that
extended etching time may affect the circulatory system in the dental pulp, when
applied onto very thin layer of dentin.
PMID- 10769492
TI - [Clinical experience with the use of benzylalcohol and amyl-m-cresol (Strepsils)
in stomatological diseases].
AB - The results gained with the treatment of benzylalcohol and amyl-m-cresol tablets
in oral inflammatic diseases (153 cases) and in the prophylaxis of possible
infections (119 cases) accompanied with surgical interventions has been
summarised. It was concluded that, the average healing process shortened by 30%
in time, and the quality parameters (pain, function etc.) showed 30% better
results in 78.4% of the cases treated with Strepsils. 88.3/ of patients preferred
to get the tablets, the tolerability was excellent. The two third of the patients
suffering from inflammatory diseases reported reduction of the pain within the
first 60 minutes after the very first tablet application. The experience gained
with 272 patients showed very good effectivity especially in the cases aphtha,
gingivostomatitis herpetica, stomatitis mycotica, gingivitis, denture stomatitis,
erythema exsudativum multiforme, stomatopharyngitis, periodontitis. The drug has
showed of remarkable result in the prophylaxis of periodontal, dentoalveolar,
implant, soft tissue, maxillofacial surgical interventions.
PMID- 10769493
TI - [Diagnosis and staging using spiral computed tomography of an endobronchial
carcinoid tumor].
AB - The authors emphasize the effectiveness of spiral CT in the diagnosis of typical
endobronchial carcinoid. The tumor was found in a 25-year-old man referred for
evaluation of steroid-resistant asthma. Successful diagnosis and complete local
staging of the right intermediate bronchus tumor were obtained by two successive
single apnea spiral acquisitions: a high resolution series (HRCT) with
Multiplanar Reconstruction (MPR) and 3D virtual endoscopic views was completed by
a dynamic angiographic series (angio-CT) with multiplanar Maximal Intensity
Projections (MIP). The CT findings are compared with macroscopic anatomic views
and major features of bronchial carcinoid are shortly addressed.
PMID- 10769494
TI - Pseudo-occlusion of the external iliac artery after stenting.
AB - A patient with an unknown thoracic aortic coarctation underwent angiography for
calf claudication. Percutaneous angioplasty and stenting of an external iliac
artery (EIA) stenosis produced flow reversal in the EIA, mimicking occlusion on
the angiogram. This aberrant situation resulted from a haemodynamic disbalance
between the iliac flow and a dominant compensatory collateral flow through the
inferior mammary-epigastric channel produced by the coarctation.
PMID- 10769495
TI - Unusual localization of craniopharyngioma.
PMID- 10769496
TI - Synovial cyst of the lumbar spine.
PMID- 10769497
TI - Synovial osteochondromatosis.
PMID- 10769498
TI - Lymphoma of mucosa-associated lymphoid tissue.
PMID- 10769499
TI - Metastatic tumor of the heart.
PMID- 10769500
TI - Hunter syndrome.
PMID- 10769501
TI - Tuberous sclerosis.
PMID- 10769502
TI - Fibromatosis colli of infancy.
PMID- 10769503
TI - Agenesis of the corpus callosum.
PMID- 10769504
TI - Moyamoya disease.
PMID- 10769505
TI - Giant lymph node hyperplasia.
PMID- 10769506
TI - Basilar artery occlusion.
PMID- 10769507
TI - Marfan syndrome.
PMID- 10769508
TI - Mucocele of the appendix.
PMID- 10769509
TI - Spinal arteriovenous malformation.
PMID- 10769510
TI - Intraabdominal desmoid tumor.
PMID- 10769511
TI - Pulmonary interstitial gas.
PMID- 10769512
TI - Schizencephaly.
PMID- 10769513
TI - Emphysematous pyelonephrits.
PMID- 10769514
TI - Poland's syndrome.
PMID- 10769515
TI - Ureteral pseudodiverticulosis.
PMID- 10769516
TI - Cystadenolymphoma of the parotid gland.
PMID- 10769517
TI - Chronic avulsive injury of the hip.
PMID- 10769518
TI - Intracranial ganglioglioma.
PMID- 10769519
TI - Langerhans cell histiocytosis.
PMID- 10769520
TI - Lipoproteins and coronary artery disease.
PMID- 10769521
TI - Lipoprotein(a) status in coronary heart disease.
AB - OBJECTIVE: To compare the magnitude of lipid, and lipoproteins, especially the
lipoprotein(a) [Lp(a)], in controls and patients with coronary heart disease
(CHD). METHODS: Serum total cholesterol, triglyceride, HDL-C, LDL-C, VLDL-C, apo
A1, apo B, and Lp(a) levels were determined in 37 patients with CHD and 25 age
matched control subjects. RESULTS: A significant difference (P < 0.001) in lipid
and apolipoprotein ratios were found. Lp(a) and other lipid parameters were found
significantly high (P < 0.001) with the exception of HDL-C and apo B which were
significantly low (P < 0.001) in CHD patients. CONCLUSIONS: Elevated levels of
Lp(a) suggest not only its role in atherogenesis, leading to CHD, but also that
Lp(a) should be given due consideration while assessing CHD risk.
PMID- 10769522
TI - Ultrasound guided percutaneous drainage of abdominal abscesses.
AB - OBJECTIVE: To see yield of ultrasound guided percutaneous drainage of abdominal
abscesses. SETTING: Department of General Surgery Unit I, Lahore General Hospital
and North Surgical Unit, Mayo Hospital, Lahore. DESIGN: A prospective case
controlled study. SUBJECTS: Patients with spontaneous or post operative abdominal
abscesses. RESULTS: Overall success rate was 96.2%, major complications 11.5%,
minor complications 26.9% and mortality 3.8%. In simple abscesses (20 patients),
the success rate was 100% and in complex abscesses (six patients) 83.4%, with
respective mortality 0.0% and 16.6%. Mean hospital stay was 10.7 days (range 3
25). CONCLUSION: Ultrasound guided percutaneous drainage of abdominal abscesses
is an effective and safe method, suited particularly for simple abscesses.
PMID- 10769523
TI - The effect of grandmultiparity on pregnancy related complications: the Aga Khan
University experience.
AB - BACKGROUND: Grandmultiparity has been associated with complications for both
mother and the fetus. OBJECTIVE: To evaluate if grandmultiparity is a risk factor
in the presence of adequate antenatal care. SETTING: A tertiary care teaching
hospital. METHODS: It was a retrospective study conducted in the department of
Obstetrics & Gynecology at The Aga Khan University Hospital in Karachi. During
this period 9253 women were delivered, out of these 143 booked grandmultiparas
(GMP) served as cases. The outcome of these women was compared with 430 non
grandmultiparas (NGMP). Logistic regression model was used to adjust for
potential confounders. RESULTS: Grandmultiparas had almost three times increased
risk of having postpartum hemorrhage compared to NGMP group. Similarly, there
were significantly low five-minute apgars in the GMPs compared to the NGMP group.
Although the neonatal intensive care admissions were three times more in the GMPs
but this did not reach statistical significance due to small number of cases in
both groups. CONCLUSION: Our study indicates that grandmultiparity is a risk
factor for pregnancy in this part of the world, even in the presence of
reasonable antenatal care. This may be explained on the basis of the increased
age of these women. Finally, we also recommend that an age-matched study needs to
be undertaken in order to determine if age is an important determinant for risk
factors in grandmultiparas.
PMID- 10769524
TI - Antibiotic susceptibility of Streptococcus pneumoniae in Karachi.
AB - OBJECTIVE: To evaluate, record and analyse the comparative activity of a range of
oral antibiotics against Streptococcus pneumoniae. SETTING: Specimen collected at
a private laboratory and some received from different hospitals and clinics.
MATERIALS: The specimen comprised of Sputum, Throat Swabs, C.S.F., Pus, Pleural
fluid, Ear Swabs, Eye Swabs, Bronchial Wash, Prostatic discharge and Antral
Secretions. METHODS: The isolates were tested for their antibiotic susceptibility
using the E-test by the methods described in the study protocol. The groups of
antibiotics tested were Amoxicillin--Clavulanate, Clarithromycin, Cefaclor,
Cefuroxime, Ceftriaxone and Penicillin. RESULTS: A total of 116 strains of
Streptococcus pneumoniae were isolated and susceptibility to Amoxicillin
Clavulanate was 100%, 99.1% strains were susceptible to Cefuroxime and 0.9% were
intermediate. Susceptibility to Penicillin was 80.2% and 19.8% of the strains
were in intermediate category, while susceptibility to Clarithromycin was 89.7%,
1.7% were in intermediate region and 8.6% of the strains were resistant to this
antibiotic. The susceptibility pattern of Cefaclor was not calculated as there is
no current NCCLS--97 Cefaclor breakpoints available. CONCLUSION: The percentage
of drug resistant Streptococcus pneumoniae was negligible in Karachi during the
study period, however it is important to monitor the susceptibility pattern to
keep a check on an increase in the number of DRSP as reported at different
centres in Turkey, Saudi Arabia, Singapore, Thailand, Hong Kong and Indonesia.
PMID- 10769525
TI - Comparison of thiopentone sodium and propofol for electro convulsive therapy
(ECT).
AB - OBJECTIVE: For safe conduct of electro convulsive therapy (ECT), general
anaesthesia is administered to the patients. In this study we compared
thiopentone sodium and propofol as induction agents for ECT. PATIENTS AND
METHODS: Twenty five patients each undergoing at least 2 sessions of ECT at the
psychiatry department were included in the study. Each patient either received
thiopentone or propofol for induction of sleep in a randomized manner. Drugs were
evaluated regarding their effects on ECT induced haemodynamic changes (Blood
pressure, Heart rate), seizure duration related to the procedure and recovery
from sleep. Any side effects during the procedure and recovery were also noted.
RESULTS: Propofol offered a superior haemodynamic stability during the procedure
and a quick recovery from sleep. CONCLUSION: Propofol was found to be a better
induction agent for ECT compared to thiopentone sodium.
PMID- 10769526
TI - Gender and schizophrenia.
PMID- 10769527
TI - Disseminated bipolaris infection in an immunocompetent host: an atypical
presentation.
PMID- 10769528
TI - Diagnosis and management of the neonatal cloaca.
PMID- 10769529
TI - Perceptions about female sexuality among young Pakistani men presenting to family
physicians at a teaching hospital in Karachi.
AB - OBJECTIVE: To study the perceptions about female sexuality among young Pakistani
men, presenting to family physicians at a teaching hospital in Karachi, Pakistan.
STUDY DESIGN: A questionnaire based prevalence study. SETTING: Questionnaire
administered to 188 young Pakistani men, between the ages 18-30 years, who
presented to family physicians, at the outpatient department of the Aga Khan
University Hospital, Karachi, Pakistan. MAIN OUTCOME MEASURES: Perception among
Pakistani young men about enjoyment of sexual experiences in women, whether women
stop to enjoy sexual experiences during stress, menstruation, pregnancy and after
menopause. Whether they are aware about "orgasm" in women and their belief in who
can initiate sexual experiences, husband, wife or both. RESULTS: The age of the
study population was uniformly distributed between 18-30 years. The majority of
the respondents were professionals, with a high school or a higher level
education and belonged to the middle socioeconomic group. Well over 40% of the
respondents thought that sexual experiences in women in comparison to men are
less enjoyable. 22% believed that women cannot enjoy sex during pregnancy while
20% thought they can't enjoy after menopause. 58% of the respondents were aware
of the phenomenon of orgasm in women. 6.4% believed that the initiation of sexual
experience lies with husband only. CONCLUSION: We have found a high prevalence of
misconceptions about female sexuality among Pakistani young men in our study
sample. We expect the situation to be more adverse in the society where education
is less and people belong to the lower socio-economic class. We strongly
recommend sex education of our youth.
PMID- 10769530
TI - Emergency patient care.
PMID- 10769531
TI - [When and how to anticoagulate a patient undergoing auricular fibrillation?].
PMID- 10769532
TI - [Atrial fibrillation and stroke].
AB - BACKGROUND: Atrial fibrillation (AF) is a known risk factor for stroke.
Furthermore, it has been suggested that the severity of the stroke is increased
in these patients. We studied the clinical characteristics, radiologic findings,
in-hospital outcome and prognosis of stroke in patients with AF. METHODS: All
patients who were admitted due to an stroke in our Hospital since March 1, 1995
from May 15, 1997 have been analysed. They were divided in two groups, according
to the presence or not of AF and we analysed: vascular risk factors, clinical
characteristics, radiologic findings, in-hospital outcome and Barthel index and
Canadian score on admission and at discharge. RESULTS: 747 patients were
analysed, 205 (27.4%) with AF and 542 without it. The mean age was higher in
patients with AF (p < 0.001). The ischemic stroke/cerebral hemorrhage ratio was
higher in patients with AF than in those without it (OR: 3.91). We found in 3/4
of patients with AF, clinical data supporting the embolic etiology. In the AF
group, Barthel index on admission and at discharge and Canadian score on
admission were significantly lower. Patients with AF had more complications, a
higher mortality rate, longer hospital stays and lower discharge rate to their
own home. CONCLUSIONS: AF is independently related with a greater severity and
worse outcome in patients suffering acute stroke. These findings emphasize the
importance of stroke prevention in patients with AF.
PMID- 10769533
TI - [Spinal meningiomas].
AB - OBJECTIVE: Meningiomas account for 15 to 45% of spinal cord tumors. They are more
frequent in females and have low recurrence rate due both to their low tendency
for regrowth and to their prevalence in the aged population. METHODS: We reviewed
retrospectively the clinical records of 37 patients operated on for spinal
meningioma in our Neurosurgical Service from 1982 to 1998. Duration and type of
symptoms, radiological and surgical results are analyzed. RESULTS: Our spinal
meningiomas account for about 26% of all spinal cord tumors operated on during a
19-year period. They accounted for 11% of all meningiomas operated during the
same period. We observed a higher prevalence in females between 50 to 70 years of
age. Weakness and localized pain were the most common presenting symptoms. The
tumors were located in the thoracic region in 33 patients and only one case was
found to be completely extradural. All the patients were operated on by
laminectomy and total removal was achieved in all cases. CONCLUSIONS: The use
magnetic resonance to make an early diagnosis and microsurgical techniques
appeared as the most relevant factors for further improvement of the surgical
results.
PMID- 10769534
TI - [Acquired dyslexias and dysgraphias under the prism of cognitive neuropsychology:
a model for the Spanish language].
AB - The present paper discusses the different clinical manifestations of acquired
disorders of reading and writing from a neurocognitive viewpoint. Based on a
specific functional architecture of reading and writing--a cognitive model;
presented as well--the different syndromes of acquired dyslexias and dysgraphias,
that have been described in the specialized literature during the last 25 years,
will be reviewed. The different pathologies are distributed along three different
functional axes: a plurimodal component, including the semantic system, for the
description of peripheric disorders of reading and writing; a lexical block which
is justified by the findings in patients with surface dyslexia/dysgraphia; and a
third, sublexical component, in order to illustrate the different functional
impairments in phonological dyslexia/dysgraphia. Following the description of
syndromes due to selective "functional lesions", we discuss deep
dyslexia/dysgraphia, a syndrome due to multiple functional lesions. All of the
syndromes will be justified and discussed with respect to the different
components of the functional architecture presented and are based on cases of the
literature and personal observations. Concluding remarks will evaluate the new
insights gained by the presented functional arquitecture in relation to other
cognitive models for the analysis of reading aloud and writing to dictation of
single words.
PMID- 10769535
TI - [Contraction fasciculations].
PMID- 10769536
TI - [Cerebral ischemia in Rendu-Osler-Weber disease].
AB - Neurologic manifestations occur in 8-12% of the patients with Rendu-Osler-Weber
disease or hereditary hemorrhagic telangiectasia (HHT), principally infectious
and hemorrhagic and, less frequently, ischemic ones. More than a half of these
neurologic complications are associated with pulmonary arterio-venous
malformations (PAVM). The diagnosis of HHT is based on the presence of
telangiectases, hemorrhagic events and a family history with an autosomal
dominant pattern. We report a case of a patient diagnosed as having HHT with
transient ischemic attacks and a PAVM, which was occluded by the use of
embolotherapy. Cerebral ischemia in HHT is related to the existence of a PAVM and
results from three mechanisms: 1) secondary poliglobulia and hyperviscosity
because of the hypoxemia due to a right-left shunt; 2) communication between the
airway and the pulmonary circulation during cough access, which produces gas
embolism and hemoptysis; 3) and, finally, paradoxical embolism trough the PAVM,
the same mechanism proposed to the infectious neurologic manifestations of the
disease. When the diagnosis of HHT is suspected, early search and treatment of
PAVM, with embolotherapy or surgery, are necessary in order to avoid respiratory
problems (hemoptysis, exertional dyspnea, cianosis, clubbing) and neurologic
complications.
PMID- 10769537
TI - [A case of multiple malignant schwannoma as the only disease in a 40-year-old
patient: is this a new type of neurofibromatosis?].
AB - We present the case of a 40-year-old man that presented a fast growing tumour on
the external side of the left elbow. The tumour was extirpated by means of
marginal exerectomy. The microscopic study corresponded to epithelioid malignant
schwannoma, and the patient received radiotherapy and adjuvant chemotherapy.
During the following years two local recidives and two new malignant schwannomas,
one in the left sciatic common trunk and another paraspinal one, appeared and
were extirpated. Radiotherapy and chemotherapy were again administered. In the
last year, four new tumours have appeared: in the supraclavicular space, right
posterior costofrenic, left costovertebral, and in the inferior abdominal wall,
none of them has been extirpated or has hystologic diagnosis at the moment,
however radiologic findings suggest malignant schwannomas. In this moment there
is no neurologic deficiency except for the secondary ones to surgical procedures,
and no neurofibromatosis types I to VII signs have been observed. So, the
possibility of a new neurofibromatosis type is appointed.
PMID- 10769538
TI - [The use of corticosteroids in the treatment of neuropathic pain of acute herpes
zoster].
PMID- 10769539
TI - [Hemichorea of ischemic origin aggravated by hyperosmolar non-ketosic
hyperglycemia].
PMID- 10769540
TI - [Did Hitler's parkinsonism have an impact on the development of World War II?].
PMID- 10769541
TI - [Subacute polyneuropathy as the initial manifestation of sarcoidosis].
PMID- 10769542
TI - [Hematopoietic stem cell transplantation in the treatment of autoimmune
diseases].
AB - Stem cell transplantation is a new possibility to treat autoimmune diseases.
Animal data and early clinical trials highlight that rebuilding the completely
destroyed immune system leads to the remission of several immune-mediated
diseases. The aim of this review was to summarize experimental and clinical
results as well as recommendations for the protocol of stem cell transplantation
and its complications.
PMID- 10769543
TI - [Trends of premature mortality from cardiovascular diseases in Hungary and the
European Union, 1970-1997].
AB - It is a well known fact that in Hungary--as in the European Countries, in general
-the trends of premature mortality are mainly determined by the trends of
mortality caused by cardiovascular diseases. The timeliness of our present study
on changes in trends of early cardiovascular mortality in the period of 1970-1997
in Hungary in comparison with trends of EU countries is underlined by the
upcoming access of Hungary to the European Union. The evaluation is based on WHO
data, the relative risk of premature mortality due to different forms of
cardiovascular diseases for different sex and age groups of the Hungarian
population is expressed as a ratio between standardized mortality rates of
Hungarian groups and that of EU-average and of countries specified. Detailed data
demonstrate that the risk of early death caused by cardiovascular--especially
ischaemic heart and cerebrovascular--diseases, in contrast with EU countries, is
significantly increased in Hungary, most significantly in age groups of 35-44 and
45-64 years for both sexes. The authors' results draw the attention to the
possible shortcomings of health care systems and the lack of comprehensive health
promotion (including prevention) programs in Hungary.
PMID- 10769544
TI - [Nephropathy in non-insulin-dependent (type-2) diabetes mellitus].
AB - There is a dramatic increase in the incidence of end-stage renal disease in non
insulin dependent diabetes mellitus (NIDDM) requiring renal replacement therapy.
The most important risk factors of the onset of nephropathy in NIDDM are genetic
predisposition (history of diabetes, hypertension and cardiovascular events in
first-degree relatives), hypertension, quality of glycaemic control and smoking.
These risk factors play an important role also in the progression of diabetic
nephropathy. In about 20-25% of NIDDM patients nondiabetic renal diseases cause
the renal damage (other primary nephropathies, ischaemic nephropathy). NIDDM is
mainly the part of metabolic x syndrome (hypertension, obesity, dyslipidaemia,
impaired glucose tolerance or NIDDM) and, for this reason, all members of
metabolic x syndrome has to be involved in treatment strategies e.g. blood
pressure "subnormalization", aggressive glycaemic control, cessation of smoking,
the treatment of obesity and dyslipidaemia with diet, physical activity and
antilipidaemic drugs, as well as restriction of dietary protein and salt intake.
The successful prevention and treatment of diabetic nephropathy needs the
development of an interdisciplinary interaction that involves general
practitioners, diabetologists and nephrologists.
PMID- 10769545
TI - [Right bundle branch block and ST-segment elevation in right precordial leads: a
marker for sudden cardiac death].
AB - The authors present a patient with a specific ECG pattern and a history of
syncope and malignant ventricular arrhythmias. Patients without demonstrable
structural heart disease and an ECG pattern of RBBB and ST segment elevation in
leads V1 through V3 are at risk for sudden cardiac death. They demonstrate the
role of cardiac electrophysiology study including programmed ventricular
stimulation and pharmacological testing in evaluation of patients with possible
Brugada syndrome. The authors emphasize the role of implantable cardioverter
defibrillator (ICD) therapy in treatment of patients with Brugada syndrome.
PMID- 10769546
TI - [The anatomist Davidas: Leo Davida (1852-1929); Jen"o Davida (1884-1929)].
PMID- 10769547
TI - [Dr. Dezs"o Miskolczy and Dr. Nandor Hun (records of an era)].
PMID- 10769548
TI - [About the prophylaxis of pertussis, with special consideration for the spread of
tuberculosis. 1899].
PMID- 10769549
TI - [The Hungarian connections of R. Nissen].
PMID- 10769550
TI - [Anti-inflammatory analgesics COX-2. Therapeutic perspectives].
PMID- 10769551
TI - [Publications derived from free communications at the XX Congress of the
Anesthesiology and Resuscitation Spanish Association (Anesthesia 92)].
AB - OBJECTIVES: To analyze the publication in MEDLINE-indexed journals of articles
derived from free presentations at the Twentieth Congress of the Spanish Society
of Anesthesiology (SEDAR) (Anestesia 92) held in 1992. MATERIAL AND METHODS: Two
of the authors independently investigated the publication of research presented
at Anestesia 92 in MEDLINE-indexed journals, carrying out a search of authors'
names between 1990 and 1998 with no restrictions on language or type of
publication. We obtained year of publication and names of journals and extracted
the abstracts, then analyzing the number and order of authors, content and time
elapsing between the congress and publication. RESULTS: Eighty-four articles
(17.1%) were published based on 491 congress presentations, with a mean time to
publication of 1.8 years (range -2 to 6). Journals specializing in anesthesiology
published 79.8%, and Revista Espanola de Anestesiologia y Reanimacion published
59.5%. Different authors were listed for published articles and congress
presentations in 92.9% and the first author had changed in 35.7%. The content of
a published article was similar to that of the congress presentation in 46% and
scope was reduced for publication in 35.7%. CONCLUSIONS: Few publications were
derived from free presentations at Anestesia 92 and major changes were made in
authors and content between congress presentation and publication.
PMID- 10769552
TI - [The administration of 20 ppm of inhaled nitric oxide produces a faster response
than the inhalation of 5 ppm in adult respiratory distress syndrome].
AB - OBJECTIVES: To compare the effects of 5 and 20 ppm of nitric oxide, evaluating
time until response for each dose, in patients with adult respiratory distress
syndrome (ARDS). PATIENTS AND METHODS: The study was prospective, controlled and
random. Fifteen patients assigned to two groups received either 5 ppm (8
patients) or 20 ppm (7 patients) from November 96 to July 97. The main variables
analyzed were PaO2/FiO2 and pulmonary vascular resistance index. We also studied
etiology, severity of pulmonary damage as reflected by the Lung Injury Score,
age, sex, Apache II prognostic score and exitus. Outcome was considered good if
PaO2/FiO2 increased and/or pulmonary vascular resistance index decreased by more
than 30% from the initial level (before inhalation of nitric oxide). RESULTS: The
mean lung injury score was 2.9 +/- 0.4 and the two groups were homogeneous. Time
until response to nitric oxide was significantly less in the 20 ppm group. Both
PaO2/FiO2 and pulmonary vascular resistance index improved significantly in both
groups whereas Qs/Qt improved only in the 20 ppm group. We also found that
cardiac index and oxygen transport increased, the latter significantly only in
the 20 ppm group. NO2 formation was less than 2 ppm and methemoglobin levels did
not rise above 2%. CONCLUSIONS: Inhaled nitric oxide significantly improves
oxygenation and decreases pulmonary vascular resistance without altering systemic
vascular resistance during treatment of ARDS. The final outcomes were similar for
both doses, but the 20 ppm dose produced a significantly faster response as well
as a significant decrease in Qs/Qt.
PMID- 10769553
TI - [Use of the anesthetic cream EMLA in arterial punction].
AB - INTRODUCTION: Arterial puncture is a painful procedure requiring prior local
anesthesia. Various products are available for pain relief, among them EMLA
anesthetic cream. OBJECTIVE: To compare pain from simple puncture of the radial
artery performed with or without application of EMLA anesthetic cream and after
infiltration of mepivacaine. PATIENTS AND METHODS: A prospective, random double
blind study of 153 patients in three groups: group A, 51 patients who were
applied 1 g of EMLA cream; group B, 52 patients who were applied 1 g of placebo
cream; and group C, 50 patients who received infiltration of 0.2 ml of 1%
mepivacaine. Pain was assessed on a 10 cm visual analog scale (0, absence of
pain; 10, greatest imaginable pain). RESULTS: Pain intensity reported by the
patients was 2.6 +/- 1.8 in group A, 2.9 +/- 1.8 in group B and 1.6 +/- 1.8 in
group C. The results for group C were statistically different from those for
groups A and B. The difference between groups A (EMLA) and B (placebo), however,
was not statistically significant. CONCLUSIONS: Mepivacaine infiltration is the
more effective method for minimizing pain from puncture of the radial artery.
EMLA anesthetic cream is not effective against pain caused by this procedure.
PMID- 10769554
TI - [Immune response in the surgical patient: effect of anesthesia and blood
transfusion].
AB - Anesthesiology has progressed spectacularly over the last two decades, largely
parallel to developments in basic and clinically applied sciences such as
immunology. The anesthesiologist's involvement now extends to all matters
involved in perioperative care. Surgery, anesthetic procedures themselves, and
other associated techniques such as blood transfusion all alter the patient's
immune response and all fall within the range of procedures monitored by the
anesthesiologist. The repercussions on the patient are important, given that
alterations suppose increased risk of postoperative infection and increased
recurrence of neoplastic disease. The present article reviews available knowledge
on how and to what extent the patient's immune status is affected in the
perioperative period. Generally, surgery and anesthesia induce immune system
depression. It is possible to demonstrate a decrease in the number and activity
of circulating immune cells and alterations of various types in interleukins and
in protein synthesis during acute phase response. Research in this field is
complex given that the individual effect of each factor involved is difficult to
measure and experimental or clinical designs usually yield only biased views.
Replacement of lost red blood cells is another factor leading to immunological
changes. New anesthetic techniques, the optimization of methods already in use,
and the development of modern, less immunodepressant drugs and of alternatives to
homologous blood transfusion are all solutions that have been proposed. This is
an exciting field of study in which today, perhaps more than ever, the
anesthesiologist has a critical role to play.
PMID- 10769555
TI - [Postoperative nausea and vomiting. Controversies, evidence and new drugs].
AB - In spite of the availability of drugs to control postoperative nausea and
vomiting, emesis remains an unresolved problem for the anesthesiologist. The
etiology of postoperative nausea and vomiting is multifactorial: some causes are
well-defined whereas others continue to be the object of debate. Statistical
methods applying logistical regression have proven valuable for assessing the
risk of emesis in individual patients. Taking a preanesthetic case history to
investigate the presence of factors that might lead to emesis allows the
anesthesiologist to establish with a certain degree of credibility that a
patient, a priori, is likely to experience nausea or vomiting. Various strategies
for preventing or treating emesis can then be established in function of risk.
Meta-analysis has been applied to the large body of literature that evaluates
and/or compares a variety of drugs and anesthetic techniques, thus facilitating
evidence-based decision-making. The therapeutic options available for
postoperative nausea and vomiting are moderately effective and are
distinguishable by their side effects and prices. Clinical trials with a new
group of drugs (neurokinin receptor antagonists) are currently underway. With
their wider spectrum of action and absence of side effects, these drugs may
represent a qualitative advance in the treatment of postoperative nausea and
vomiting.
PMID- 10769556
TI - [Erotic hallucinations associated with the use of propofol].
AB - A 42-year-old woman underwent outpatient surgery to remove vocal cord polyps. She
had a history of depressive syndrome and had previously undergone surgery without
complications. Before surgery she received 3.5 mg of midazolam orally. General
anesthesia was provided with propofol: one initial bolus of 1 mg/kg followed by
an infusion of 6 mg/kg/h. Surgery was uneventful. Upon arrival in the
postanesthetic recovery ward, the patient, greatly agitated, accused the
orderlies pushing the gurney of forcing her to touch his genitals. Twenty-four
hours after surgery she did not remember the incident. Since 1987 various cases
of postoperative sexual hallucination have been associated with the use of
propofol. Usually the patients are women undergoing minor gynecological
procedures and involve male health-care providers in the surgical area. The
incidents are characteristically followed by amnesia. This clinical picture has
also been described for midazolam and nitrous oxide, but the frequency is higher
for propofol owing to its pharmacodynamic and pharmacokinetic properties (rapidly
recovered awareness and lowering of inhibition). Given the legal implications,
the presence of someone of the same sex as the patient is recommended when the
patient awakens.
PMID- 10769557
TI - [Anesthesia in Goodpasture syndrome].
PMID- 10769558
TI - [Transitory radicular irritation syndrome after the use of hyperbaric lidocaine].
PMID- 10769559
TI - [Intradural anesthesia in a case of carcinoid syndrome].
PMID- 10769560
TI - [The tendency to incorrectly shorten scientific papers].
PMID- 10769561
TI - [Management of the airway in an infant with Apert syndrome].
PMID- 10769562
TI - [Middle ear physiology].
AB - The middle ear forms part of the sound transformer mechanism, together with the
outer ear and the conducting system of the inner ear. An intermediate sensory
organ, sensitive to acoustic vibration, and linked to the inner ear, the middle
ear made its appearance during the period of adaptation of marine creatures to a
terrestrial habitat; its presence is therefore a phylogenetic requirement. It is
classical to ascribe three functions to the middle ear: the transmission of
acoustic vibrations from the tympanic membrane to the cochlea, impedance matching
between the air in the external auditary meatus and the labyrinthine fluids, and
protection of the inner ear by means of the acoustic reflex. If the classical
mechanical explanation has been able to explain its function, the
conceptualization of its physiology in terms of energy allows an even better
understanding, as well as providing and explanation for the paradoxes which arise
in clinical practice when the classical model is used.
PMID- 10769563
TI - [The definition of acoustic impedance and its application to the human hearing
organ].
AB - Acoustic impedance measurement at the point of entry into the external auditory
meatus provides a rapid means to detect malfunctions of the middle ear in the
region of the tympanic membrane, without having recourse to perforating the
tympanic membrane. In this article we define acoustic impedance and provide a
brief reminder of its physical properties. In the last part, we review the
possibilities offered by measurement of the impedance to acoustic stimuli, not
only for clinical diagnosis, but also in the understanding ot the physical
phenomena occurring within the hearing organ.
PMID- 10769564
TI - [Multi-frequency tympanometry in experimentally-induced cochlear lesions in
chinchillas and guinea pigs].
AB - OBJECTIVES: To establish that susceptance-conductance tympanograms at a probe
tone frequency of 2 kHz reflects the status of the annular ligament (AL) and
through it of the cochlea. METHODS: Experimental study in 5 chinchillas and 22
guinea pigs. Six validating experiments were used: blockages of the stapes and of
the round window membrane (RWM), fistula of the RWM, fluid removal from the
cochlea, injection of saline in the scala tympani (ST) and acoustic trauma (AT).
Quantitative data (mean values of Y226, FR, Y2000, G2000 and B2000) and shape of
the curves were analyzed before and immediately after lesions were done. RESULTS:
Guinea pig was the most convenient provided bulla was vented and the same tip was
used along the experiments. Only the shape of the curves are discriminant: 1/a
supplementary sharp peak, centered around negative pressures, is observed in Y/G
tympanograms in every case of RWM fistulas and in some case of AT. 2/injection of
saline into ST induces immediate and reproducible Y2000, G2000, et B2000 curves
modifications. 3/RWM and stapes blockages provoke foreseeable stiffening and
sharpening of the tympanograms at 2 kHz. 4/on the contrary, fluid removal from
the cochlea induces multiple peaks curves. CONCLUSIONS: Experimentally-induced
modifications at the AL either direct (stapes blockage) or indirect by AT or
decrease/increase of pressure load at the cochlear interface at the footplate
result in noticeable, constant, reproducible changes of curves registered at 2
kHz. The stapes behaves both as the plotter of the curves and the interpreter of
the inner ear pressure.
PMID- 10769565
TI - [Multi-frequency impedance measurement and Meniere's disease. Analysis of the
results of TEFLAG].
AB - We present today our preliminary results of the TEFLAG test performed on 58
patients suffering from Meniere's disease. This test completed in 1993 has
already led to a 4-stage classification of noise induced hearing losses. On the
one hand, it is based on the morphological study of susceptance B curves, and on
the other hand, on the study of the resonant frequency (RF) of the annular
ligament of the stapes, provided by a multifrequential impedancemeter. The
endolymphatic hydrops coming with the Meniere's disease practically always
cohabits in the intercritical period with the decrease of the perilymphatic
pressure of the scala vestibuli, which is shown in the morphology of Stage IV
curves especially, and the decrease of the annular ligament rigidity. Inversely,
during the vertigo or around, we mainly have stage I curves, and an increase of
the stapes annular ligament resonant frequency (RF), testifying the labyrinthic
hydrops, which is the physiopathological essence of the Meniere's disease.
PMID- 10769566
TI - [Comparison: tinnitus pain].
AB - After having recalled the different physiologic hypothesis of the tinnitus and
those more documented of the pain, the authors noted certain parallelious in the
therapeutical approaches of these tow subjectives sensations. They put the
emphasis on the necessity, like with pain, to treat the tinnitus as fast as
possible in order to avoid a centralisation by actionning of neuronal autonomized
circuits.
PMID- 10769567
TI - Endoscopic sinus surgery in the isolated paranasal sinus aspergilloma.
AB - Fungal infections of the paranasal sinuses are in four clinical forms. Beside the
acute fulminating form, chronic invasive form, allergic fungal sinusitis and
fungus ball. Fungus ball is mostly encountered in only one paranasal sinus of an
otherwise healthy person. Ten fungus balls of the paranasal sinuses are presented
with their management and results.
PMID- 10769568
TI - Epidemiological study of salivary gland tumours.
AB - Tumours located in the salivary glands form the most heterogeneous group in all
human oncological pathology. They show various epidemiological, clinical and
evolutionary characteristics which separate them from other neoplasms of the head
and neck. In this paper, we have carried out a study on their epidemiological
aspects, collecting 80 cases diagnosed in the ENT Service of the University
Hospital Complex of Santiago over 17 years. The incidence was 1.22 cases per
100,000 inhabitants per year. The frequency was higher in males (58.75%) and in
the 7th decade of age. A predominance was noticed in females under 40 years of
age and in males over this age, but the differences were not statistically
significant. The most frequent site was the parotid gland, and we could not find
any case in the sublingual gland. In 52.5% of cases the tumour was benign,
pleomorphic adenoma being the most prevalent. Among malignant tumours, the
epidermoid carcinoma stood out in our series. The prevalence of benign tumours in
females and of malignant tumours in males was clear, with significant
differences. We compare our results with the data published in the literature.
PMID- 10769569
TI - [Sebaceous carcinoma of the parotid gland].
AB - Sebaceous carcinoma is a rare tumor, from the adnexal epithelium of the sebaceous
glands. Usually, lesions arise in meibonian glands of the eyelid. However,
extraocular lesions within head and neck have been reported. We report a case of
recurrent sebaceous carcinoma of the parotid gland without metastases.
PMID- 10769570
TI - [Nasal localization of the Crohn's disease].
AB - Crohn's diseases is a chronic granulomatous inflammatory disease of the
gastrointestinal tract. Any part of the gastrointestinal tract may be affected,
and 9% of cases have oral lesions (1). Nasal involvement is exceptionally rare.
We report a case of nasal involvement revealed by chronic atrophic rhinitis in a
patient with known Crohn's disease.
PMID- 10769571
TI - [Extramedullary plasmocytoma of the nasal cavity: a case report].
AB - PURPOSE OF STUDY: To establish a diagnosis and therapeutic management in patients
with extramedullar plasmocytomas. METHOD: There is no consensus concerning
extramedullar plasmocytoma treatment. One patient with a nasal cavity tumor
location and a review of literature are reported. RESULTS: Extramedullar
plasmocytoma is a rare tumor that occurs most frequently in the upper respiratory
tract. The most common location is the nasal cavity. Diagnosis can only be made
after histological and immunohistochemical examinations. Localized tumors are
treated by radiation therapy, combined or not with surgery. Disseminated diseases
are treated by chemotherapy. CONCLUSION: Diagnosis can only be confirmed after
the exclusion of a systemic disease (multiple myeloma).
PMID- 10769572
TI - [Epidemiological aspects, risk factors, and detection of pancreatic cancer].
AB - The incidence of pancreatic cancer (PC) is increasing in developing countries.
Smoking, reduced consumption of fruits and vegetables, chronic pancreatitis
appear to be the best established risk factors. PC is often diagnosed at a late
stage. We have to look for it when dyspepsia with weight loss, pancreatic pain or
impaired glucose tolerance occurs. Tumor markers are briefly exposed and we
discuss the place of endoscopic retrograde cholangiopancreatography (ERCP) after
non invasive imaging techniques.
PMID- 10769573
TI - [Endoscopic ultrasonography in the diagnosis and staging of pancreatic and
ampullary cancer: influence on patient management].
AB - Accurate preoperative staging is now more prerequisite in the management of
cancer of the pancreas and ampulla in order to orientate the patient toward the
best selected treatment: either a curative or a palliative surgery associated or
not with a pre- or postoperative multimodal therapy, or an endoscopic palliative
technique which does not require surgery. Endoscopic ultrasonography (EUS)
appears to be a highly accurate diagnostic procedure in the assessment of local
resectability because it enables detailed visualization of the pancreatic gland,
the depth of infiltration into the surrounding tissue and organs and
visualisation of regional lymph nodes involvement. EUS-guided fine needle
aspiration for cytology will provide a tissue diagnosis. The likelihood of
successful resection for palliative or cure can be predicted before surgery. The
following overview will point out the clinical impact of EUS on diagnosis,
staging and management of these tumors.
PMID- 10769574
TI - [State of the art of pancreatic cancer imaging].
AB - Ultrasonography and CT-scanner remain the first choice nowadays concerning
detection and preoperative work-up of pancreatic cancer. MRI offers interesting
options for the detection of liver metastases, and high quality of ductal and
vascular examination. Actually, while we await a larger diffusion of MR systems
and radiological expertise this technique is preferentially indicated as a third
step procedure when ultrasonography and CT-scanner are normal despite a real
suspicion. Otherwise, MRI permits with a single non-invasive examination a
complete work-up useful to prepare palliative therapy in case of unresectable
tumor.
PMID- 10769575
TI - [18FDG-PET imaging of pancreatic adenocarcinoma].
AB - FDG-PET imaging non invasively studies the glucose metabolism which is usually
increased in malignant lesions. We evaluated the clinical performance of PET for
detecting pancreatic cancer and its recurrence. In our series of 24 studies, PET
appears to complement other imaging modalities. As compared to CT, in particular,
it demonstrated fewer false positive results in the pancreas and it was also more
sensitive. Moreover, whole-body FDG-PET allows for the entire staging of the
disease.
PMID- 10769576
TI - [Adenocarcinoma of the pancreas. Preoperative staging].
AB - The authors assess the value of laparoscopy in the preoperative staging of the
adenocarcinoma of the pancreas to prevent unnecessary pancreatic resections in a
disseminated disease. By laparoscopy, a macroscopic evaluation, a peroperative
liver and pancreas ultrasonography as well as biopsies are possible and are more
accurate in assessing the extent of the disease than other means.
PMID- 10769577
TI - [Image of the month. A case of atrial septal aneurysm].
PMID- 10769578
TI - [How I treat ... particular endometrial lesions by hydro-thermo-ablation].
AB - The hydro-thermo-ablation is a new technique of ablation of the endometrium, that
uses a small quantity of saline solution at 90 degrees C, perfused under
hysteroscopic control at a pressure of 50 to 55 mmHg and that allows uterus
distention and uniform dispersion of the warm liquid. The endometrium prepared by
Gn-RH analogues is then destructed at 4 mm depth and won't regenerate. This
technique is safe because realized at low pressure and without possibility of
extravasation of the used liquid, and can even be used under local anesthesia. In
the future, this technique may take the place of some of our indications of
hysterectomy.
PMID- 10769579
TI - [Clinical case of the month. A new case of nephropathia epidemica due to Puumala
virus].
AB - Nephropathia epidemica due to Puumala virus has already been described in
Belgium. Its evolution is usually favourable. The main symptoms are fever, a
decrease platelet count, proteinuria and acute renal insufficiency, which, in an
epidemiological context, quickly point the correct diagnosis. Acute and
transitory myopia is typical. Nevertheless, the clinical presentation, including
multisystemic symptoms may lead to the false diagnosis of an acute bacterial or
immune disease.
PMID- 10769580
TI - [Antioxidant vitamins in the prevention of cardiovascular diseases. 2nd part:
results of clinical trials].
AB - Various epidemiological studies suggested that individuals with high intake of
antioxidant vitamins (E, A and C) have a better cardiovascular prognosis than
subjects with relative deficiencies in such vitamins. However, placebo-controlled
randomized clinical trials did not demonstrate that a specific supplementation in
either alpha-tocopherol (vitamin E) or beta-carotene (vitamin A) allows to reduce
the incidence of major cardiovascular events, in the general population or even
in various subgroups at high risk, and there is no such controlled trials with
vitamin C alone. Some studies suggested that combined supplements of several
antioxidant vitamins might be more efficacious, and these observations led to
initiate several large controlled studies. Thus, until now, there is no
convincing arguments in the literature in favour of artificial supplements of
antioxidant vitamins. It seems preferable to encourage a well-balanced healthy
diet while awaiting the results of the large prospective ongoing trials with
combined supplementation.
PMID- 10769581
TI - [Towards obsolete senescence. Everything wanes ... Old age no longer exists!].
AB - Skin ageing is the global result of the influence of numerous factors. Oxidative
stress through the intervention of free radicals is one of the most important
biological mechanisms solicited by ageing promotors. Prevention of skin
senescence relies on several approaches. The main ones are sun protection,
tobacco avoidance and limitation of sustained mechanical stress to the skin. Free
radical scavengers in adequate combinations might slow down the ageing process.
In cosmetology, retinol fulfills its claims. Vitamins E and C, as well as
selenium and some plant extracts also show some interest. In the search for
increased efficacy, tretinoin is the single topical drug available. Its biologic
activity boosts the epidermal growth and the collagen synthesis while inhibiting
some metalloproteinases responsible for dermal degradation. Clinical proofs of
its efficacy are beyond doubt.
PMID- 10769582
TI - [Pharmacy clinics. Medication of the month. Topiramate (Topamax)].
AB - Topiramate is a new antiepileptic drug that has now become available for
prescription in Belgium. In vitro and in vivo preclinical studies have indicated
that topiramate has several mechanisms of action that may contribute to its
anticonvulsivant activity. A broad antiepileptic spectrum could be suspected that
has been confirmed on a clinical basis. Topiramate has favorable pharmacokinetic
properties: rapid absorption, long half-life and little interaction with other
AED. Several meta-analysis have confirmed its efficacy, particularly as
adjunctive therapy for partial onset seizures, refractory to other AED. It is
actually reimbursed only for these patients but its indications will probably be
widened in the future.
PMID- 10769583
TI - [Pharmacy clinics. Medication of the month. Cerivastatin (Lipobay, Cholstat)].
AB - Cerivastatin, commercialized under the trade names of Lipobay by Bayer and
Cholstat by Fournier Pharma, is a new synthetic statin. Because of its high
affinity for HMG-CoA reductase enzyme that it specifically and selectively
inhibited in the hepatocytes, cerivastatin exerts its cholesterol-lowering effect
at very low doses, between 0.1 and 0.3 mg/day. Cerivastatin is indicated, after
diet failure, in the treatment of primary forms of isolated hypercholesterolaemia
or combined hyperlipidaemia. It is presented by the two pharmaceutical companies
as 0.1, 0.2 and 0.3 mg filmed tablets. Usual dose is 0.3 mg, once daily, to be
reduced in presence of renal failure. Cerivastatin is metabolised within the
liver by two different families of cytochrome P450, which limits the risk of drug
interferences. Besides this potential advantage as compared with some other
statins, its pharmacodynamic activity and safety profile seem to be similar to
those of other agents of the same pharmacological family.
PMID- 10769584
TI - [Clinical study of the month. The HOPE study, a two-by-two factorial clinical
trial with contrasted results].
AB - The results of the HOPE ("Heart Outcomes Prevention Evaluation") study, recently
published in the New England Journal of Medicine, demonstrated a highly
significant cardiovascular protection by an angiotensin converting enzyme
inhibitor, ramipril at a dose of 10 mg/day, after a mean follow-up of 4.5 years,
but not of vitamin E supplements at a dose of 400 UI/day in high-risk patients (>
55 years old) who had evidence of vascular disease (secondary prevention) or
combined diabetes mellitus and another cardiovascular risk factor (primary
prevention).
PMID- 10769585
TI - [The cleaning and obturation of the root canal system without conventional
instruments. A position definition].
PMID- 10769586
TI - [Holistic dentistry: mere faith or scientific medicine?].
PMID- 10769587
TI - [Organization and methodological activities of Russian Center for Forensic
Medical Expert Evaluations Ministry of Health of the Russian Federation].
AB - Analyzes the organization and methodological activities of Russian Center for
Forensic Medical Expert Evaluations in 1996-1998. Informs about the federal law
on forensic medical expert evaluations and norm-setting acts aimed at improvement
of forensic medical service in the Russian Federation, which have been developed
at the Center. Offers recommendations on improving the quality control of expert
evaluations at territorial centers and continuous education of experts.
Formulates the main tasks of the Center fort the nearest future.
PMID- 10769588
TI - [Organization and procedure of forensic medical expert evaluation of professional
working capacity loss].
AB - Sixty-one forensic medical expert conclusions on the loss of professional working
capacity are analyzed and typical errors are characterized. The procedure of
forensic medical expert evaluation of the degree of loss of professional working
capacity in accordance with the Civil Code and Civil Judicial Procedure Code of
the Russian Federation and the actual norm-setting documents is described.
PMID- 10769589
TI - [Evaluation of medical care quality in cases with health damage infliction
leading to unfavorable outcomes].
AB - Discusses modern approaches to evaluation of the quality of medical care in cases
when civil action is brought against medical people for inflicting damage to
health leading to unfavorable outcomes. Emphasizes the need in developing a
special organization model of medical care quality and efficacy control system,
which should be based on universal principles, notions, and adequate tests and
evaluations.
PMID- 10769590
TI - [Content of macro- and trace elements in human body and environmental factors].
AB - Evaluations of the mean normal, increased, or decreased concentrations of macro-
and trace elements in human body and biological media (e.g. hairs) are discussed.
It is proposed that the element composition in an individual (mean normal,
increased, or decreased) be evaluated by comparison with the mean level for the
region, which depends on the biological, geological, and chemical (soil, water,
etc.), ecological, climatic, and geographical factors. The efficiency of such an
approach is demonstrated by forensic medical and clinical physiological findings.
PMID- 10769591
TI - [Chemical and toxicological studies in mushroom poisoning].
AB - Two accessory diagnostic tables reflecting the relationship between toxic effect
of mushrooms and the nature and chemical structure of toxin have been developed
for improving the diagnosis of mushroom poisoning. New color tests have been
developed and conditions for isolation and chromatography in a thin adsorbent
layer determined. The Schiff's test is specific for Amanita phalloides. This
mushroom's toxins can be detected in the viscera after the maximal survival of 50
h, other mushrooms' toxins after 26-30 h.
PMID- 10769592
TI - [Double descending aorta (congenital developmental defect)].
PMID- 10769593
TI - [Risk lethal outcome in patients with febrile schizophrenia].
PMID- 10769594
TI - [Mechanical asphyxia caused by thymus tumor].
PMID- 10769595
TI - [Determination of ABO blood groups in bone tissue].
PMID- 10769596
TI - [Canine blood admixture as cause of probable errors in practical forensic medical
expert evaluation of material evidences].
PMID- 10769597
TI - [Case of poisoning by intravenous carbophos injections].
PMID- 10769598
TI - [Detection of phenolphthalein and diphenhydramine in forensic chemical analysis
of cadaveric material].
PMID- 10769599
TI - [Psychological and pedagogical aspects in organization and management of
individual student's work in class and out of class].
PMID- 10769600
TI - [Closed spinal cord injuries].
PMID- 10769601
TI - Hepatology in India--sailing without a mast.
PMID- 10769602
TI - Liver resection: an opaque organ made transparent.
PMID- 10769603
TI - A trial of Phyllanthus amarus in acute viral hepatitis.
AB - The study was done to know whether the powders of Phyllanthus amarus plants
favourably influence the duration of disease in patients with acute viraus B
hepatitis when compared to placebo. The powders of the plant were given in
capsule form (300 mg capsules--3 capsules--3 capsules thrice daily) and an
antacid powder in similar capsule was used as placebo. Persons with
encephalopathy, preexisting medical conditions or serum bilirubin above 350 iu/l
were excluded from the study. Fifty seven patients were randomized to receive
either the placebo (28 cases) or the drug (28 cases). The two groups were
comparable at the time of entry. Two cases from the placebo and one from the
placebo and one from the drug group dropped out of the study. The duration of
disease (time taken for bilirubin to come to below 2 mg%) was taken as the
outcome measure. The duration of disease in the two groups was compared by Cox's
proportional hazards analysis after adusting for the variables that influence the
duration of jaundice. Only initial serum bilirubin was an independent predictor
of duration of jaundice. The an analysis showed that Phyllanthus amarus powders
did not significantly reduce the duration of jaundice in persons with virus B
hepatitis.
PMID- 10769604
TI - Aetiological spectrum of obstructive jaundice and diagnostic ability of
ultrasonography: a clinician's perspective.
AB - BACKGROUND: A vast array of invasive and non invasive diagnostic tests are
available to diagnose and establish the etiology of surgical obstructive jaundice
(SOJ). Invasive tests may cause cholangitis and imaging techniques like computed
tomography(CT) scan and MRI are expensive. The aim of the present study was to
test ultrasonography as the primary investigation in patients with SOJ and to
elucidate the aetiological spectrum of obstructive jaundice as seen at a tertiary
referral center. METHODS: 429 patients diagnosed as having obstructive jaundice
on the basis of either CT, endoscopic retrograde cholangiopancreatography(ERCP),
fine needle aspiration cytology(FNAC) or surgery underwent real time sonography
over a 10 year period from May 1988 to Dec 1997. The diagnostic accuracy of
ultrasonography for SOJ was established. RESULTS: Sonography correctly
established the presence of obstructive jaundice in 380 of 429 patients. Of 429
patients (mean age 62.5 +/- 34.2 yrs, 229 males and 194 females) the sensitivity
of ultrasound to correctly diagnose and establish the site of etiology of
obstruction was 94% with a specificity of 96%. Malignant SOJ was much more common
than benign causes (75.3% Vs. 24.7%). Carcinoma (Ca) of the gallbladder (28.7%)
was the commonest aetiology followed by Ca pancreas (26.5%), choledocholithiasis
(12.4%), cholangio Ca (10.8%) benign stricture (10.8%) and ampullary Ca (9.8%). A
total of 167 subjects (44%) had high block while 213 (56%) had low block. Block
at the porta hepatis was due to gallbladder Ca in 91% of patients. Ca pancreas
was the cause of lower end block in 76% of patients. CONCLUSION: SOJ, as seen in
this large series of patients was most often due to malignant cause and
gallbladder Ca was the commonest cause in North Indian patients. The clinician
should utilize the ability of the ultrasound to diagnose the presence of
obstructive jaundice and its location.
PMID- 10769605
TI - Gastro-intestinal effects of Indian spice mixture (Garam Masala).
AB - Spices are a part of diet all over the world but the variety and quantity
consumed in tropical countries is particularly significant. The intestinal
transit time of Indians is shorter, and their stool weight larger than that of
Europeans on a comparable fibre intake. Ingestion of chilli is associated with a
faster whole gut transit time. There is hardly any human work on the effects of
spices on intestinal transit or gastric emptying. To explore the effects of
spices on gastro intestinal transit this study was conducted on 18 well nourished
healthy human adult volunteers using Radiolabelled Idli with or without Garam
Masala. On gastric scintigraphy the gastric emptying time was much faster in
subjects when spicy meal was given. The t1/2 of the spicy meal, 40.09 +/- (p <
0.05) thus implying a faster transit through the stomach. In 17 out of the 18
subjects t1/2 of the spicy meal was consistently lower than that of spicefree
meal. The lag phase of gastric emptying showed no significant difference. There
was a tendency towards slower gastrocolic transit with Spicefree meal but more
subjects need to be done to confirm this.
PMID- 10769606
TI - Prevalence of Helicobacter pylori infection in patients with reflux oesophagitis.
AB - In this prospective study 30 patients of reflux esophagitis were studied to
detect if there was any association between presence of esophagitis and H. pylori
infection. 30 patients of non-ulcer dyspepsia acted as controls. In both the
groups esophageal and antral biopsies were studied for the presence of H. pylori
infection. None of the esophageal biopsies showed H. pylori infection in either
group. H. pylori positivity was similar in the antrum of the patients with
esophagitis (20 out of 30) and non ulcer dyspepsia (19 out of 30) (p > 0.05).
There was no significant association between presence of H. pylori infection in
antrum and severity of esophagitis (p > 0.05). In conclusion, this study has
shown that H. pylori did not colonise esophagus in patients of esophagitis or
patients of non-ulcer dyspepsia. There was no significant association between H.
pylori colonization in the antrum and esophagitis and the grade of esophagitis
with H. pylori infection.
PMID- 10769607
TI - Unusual causes of gastrointestinal bleeding following thermal injury.
PMID- 10769608
TI - A case of multicentric angio-follicular lymph node hyperplasia (Castleman's
disease).
PMID- 10769609
TI - Acute on chronic phenomenon in hepatic IVC obstruction: a case report.
AB - Hepatic IVC obstruction though common is usually misdiagnosed because of lack of
appreciation of the disease. Patient with chronic disease may develop acute
exacerbation, which may be precipitated by surgery or endoscopic procedures. It
is a report of a case of chronic IVC disease with acute development of ascites
following gallbladder surgery.
PMID- 10769610
TI - Prophylactic gastric bypass for unresectable periampullary cancer.
PMID- 10769611
TI - Duodenum preserving head resection for chronic pancreatitis.
PMID- 10769612
TI - Functional outcome of overlapping sphincter repair for anal incontinence.
PMID- 10769613
TI - A case of large oesophageal mucocele after surgical isolation.
PMID- 10769614
TI - Small bowel leiomyoma: an unusual presentation.
AB - Dual pathology having similar symptomatology is uncommon. We present a patient
whose symptoms, although not absolutely typical of inguinal hernia, were
attributed to bilateral irreducible inguinal hernias and were treated surgically.
He remained symptomatic and later, was found to have an intraluminal leiomyoma of
the jejunum, which was then removed. We suggest that the presence of any unusual
clinical features should prompt further investigation to detect an alternative
causative pathology.
PMID- 10769615
TI - [To live happily, we live secretly. The knowledge of virus reservoirs is
essential for the fight against infectious diseases].
AB - The concept of virusreservoir is defined and illustrated. It corresponds to the
site where the microorganisms survive "caches et heureux". The definite control
of infectious diseases consists, whenever possible, of the elimination of the
responsible organisms from their reservoir. Frequently the virusreservoir was
originally thought to be located in the proximity of man, but later
investigations showed many reservoirs to be situated at much greater ecological
distance. In many situations the phenomenon of latency plays an important role.
This phenomenon is badly understood and a better understanding of its mechanisms
could offer means to combat the microorganisms and the diseases they cause.
PMID- 10769616
TI - Molecular methods in the diagnostic microbiology laboratory: when to start and
where to stop?
AB - The introduction of molecular diagnostic methods in the microbiologic diagnostic
laboratory is subject to a number of practical and financial constraints
requiring the elaboration of a sound strategy. Validation of the tests may
require the use of an expanded gold standard or the application of novel
statistical methods such as latent class analysis. The procedures should be
constantly evaluated for false positive an false negative results. The
introduction of molecular methods will not only depend on their performance for
each individual microorganism, but also on the clinical relevance of the
diagnostic question asked, the prevalence of the clinical problem and whether the
new methods are added to the procedures in use or will replace them. Therefore no
general rules can be proposed, strategies have to be elaborated for each
infectious agent or clinical syndrome. Strategies concerning the use of molecular
diagnostic techniques for the diagnosis of Mycobacterium tuberculosis, Chlamydia
trachomatis, meningo-encephalitis syndrome and respiratory infections, are
discussed. Their role in typing of microorganisms and the detection of previously
unknown infectious agents are mentioned.
PMID- 10769617
TI - Gene targeting and gene transfer to unravel the molecular basis of the formation
and disorders of blood vessels.
AB - Novel gene technologies have allowed to manipulate the genetic balance of
candidate molecules in mice in a controllable manner. Homologous or site-specific
recombination in embryonic stem cells allows to study the consequences of
deficiencies, mutations, conditional or tissue specific expression of gene
products in transgenic mice. These technological breakthroughs have significantly
advanced biomedical research and our understanding of the pathophysiological role
of candidate disease genes. In addition, gene transfer allows to test the
possible therapeutic use of gene products for gene therapy. With the advent of
genome sequencing programs, these gene technologies provide means to study gene
function in a conclusive manner. Furthermore, disease models can be generated
which can be used as testmodels for (gene) therapy or for discovery of novel
genes using differential gene profiling techniques. The present review will focus
on the use of these technologies to study the molecular basis of how blood
vessels form (angiogenesis) and how vessels can become affected by disorders. A
selected number of molecules that have been studied in our laboratory will be
reviewed in particular.
PMID- 10769618
TI - [Staphylokinase for a better thrombolytic treatment of heart and platelet
diseases].
AB - Staphylokinase is a plasminogen activator of bacterial origin with pronounced
fibrin specificity. The first clinical studies suggest that recombinant
staphylokinase (Sak) constitutes an effective thrombolytic agent in the treatment
of patients with myocardial infarction or peripheral arterial occlusion. Also in
an animal ischemic stroke model Sak has produced promising results. Despite its
fibrin specificity life-threatening bleeding still may occur. Sak induces
neutralizing antibodies that may interfere with renewed administration.
Therefore, recombinant variants have been engineered that are less antigenic
while preserving thrombolytic properties.
PMID- 10769620
TI - Nursing, art and science: revisiting the two cultures.
AB - I begin this paper by setting out the importance of the Two Cultures debate,
given that many nurse authors would agree with Closs's position that the art
versus science debate should be closed finally. I suggest that issues are every
bit as present and urgent in our current era as they were in the past. A brief
tracing of the history of the Two Cultures debate highlights the relevance of the
central features of the debate for nursing. I then focus on nursing's current
understanding of science and art and attempt to defend science from some of the
accusations levelled at it, while also questioning some of the claims made on
behalf of the arts. In the latter sections of the paper, I make a case for the
development of 'nursing humanities' and argue the vital importance of overcoming
the Two Cultures divide for the everyday practices of nurses and midwives.
PMID- 10769619
TI - A midwife-public-health nurse's work in northern Finland, 1950-87.
AB - This paper describes the work of Jouki Nykanen, a midwife public-health nurse in
northern Finland during the years 1950-87. The material for the study was
collected by a biographical interview. On the basis of content analysis, the work
of the interviewee consisted of the following phases: (i) midwife-public-health
nurse in the district of Sevettijarvi (1950-58); (ii) municipal midwife in
Pyhanta (1958-60); and (iii) midwife-public-health nurse in the rural district of
Karunki (1962-87). In Sevettijarvi, Jouki's work emphasised independent planning
and implementation. In Pyhanta, her health-care clinics were well organised. In
Karunki, another midwife-public-health nurse working with Jouki made conditions
flexible, with personal districts for the two nurses. During home visits, Jouki
took care of the whole family, from the grandfather to the baby. The Finnish
Public Health Act (1972) changed the character of Jouki's work. The number of
home visits decreased and clinics, fragmented into several fields of health care,
took the place of home visits, requiring efficiency and results. The results of
the study showed the core of a midwife-public-health nurse's work in Finland in a
changing historical and social context, as well as showing the changes in a
midwife-public-nurse's work since the post-war years.
PMID- 10769621
TI - Family issues in home-based care.
AB - In Australia, home-based care for the chronically ill is increasing.
Technological advances and increased economic constraints are often cited as the
reasons for the increase in home-based treatments. Exploring the development of
home-based care, in particular home-based dialysis, using a case-study approach
provided an opportunity to identify the issues of families involved in home care.
Issues that emerged included: (i) the development of the home-based clinic; (ii)
the role of women; (iii) social isolation; (iv) and the lack of effective support
from general practitioners and health services.
PMID- 10769622
TI - Locked up: researching in an unfamiliar environment.
AB - This paper describes the personal experiences of three nurse researchers who
entered a new field, one they would not normally encounter. The experiences
occurred during a research project involving detainees in Juvenile Justice
Centres in New South Wales, Australia. The Healthy Lifestyle Check computerized
health screening program was used to seek responses regarding the detainees'
health behaviours, knowledge of health services and health education needs.
Physical assessment was conducted and counselling and referral was provided. The
researchers' best endeavours to prepare for the field were not enough for the
reality of the controlled environment, fears for personal safety and the stamina
required to complete the project. The researchers' completion of the project
enriched their professional lives with a sense of achievement and a new
confidence in their ability to work in uncharted fields. Implications for future
nursing research that incorporates fieldwork in this environment include: (i)
ensuring adequate knowledge of security protocols; (ii) securing access to
participants; and (iii) ensuring adequate physical assistance for fieldworkers to
enter.
PMID- 10769623
TI - Measuring outcomes from the patients' perspective.
AB - This descriptive study examines the outcomes of care from the perspective of
patients following a recent orthopaedic admission at a teaching hospital in
Sydney. Results were extracted and analysed from transcripts of audio-taped focus
groups. Participants identified five nursing activities that made a positive
difference to patient outcomes. These activities were: (i) patient-controlled
analgesia; (ii) water-filled gloves placed under patients' heels; (iii) cream
rubbed into patients' heels; (iv) an explanation, at pre-admission clinic, of the
impending operation; and (v) being informed about the details of their treatment
while in hospital. Three activities that participants felt made a negative
difference to their outcome were also identified, as were seven activities not
performed by nursing staff that participants felt would have made a positive
difference to their outcome. The results from this study reinforce the importance
of basic nursing care, and the value of measuring outcomes, not only from the
professional perspective, but also from the patients' viewpoint.
PMID- 10769624
TI - Smoking: rates and attitudes among nursing staff in central Sydney.
AB - The objectives of this study were to determine the prevalence and predictors of
smoking and attitudes to smoking-related issues among nurses employed by the
Central Sydney Area Health Service in Sydney, Australia. A self-administered
questionnaire, was distributed via the internal mail system of the Central Sydney
Area Health Service in November 1997 to 610 randomly selected nursing staff.
Twenty-one per cent (n = 127) of respondents smoked. Smokers were significantly
younger than non-smokers and were more likely to speak mainly English at home.
There were clear differences between smokers and non-smokers in response to all
attitude statements. Interventions specifically directed at nurses who smoke to
assist them to stop and maintain cessation are indicated. Future health service
workplace tobacco control programmes should address deficits in knowledge about
the health effects of passive smoking, should raise awareness among nurses who
smoke about their potential to affect the behaviours of others through modelling,
and should provide all nurses with the skills required to be smoking educators
and advocates for tobacco control.
PMID- 10769625
TI - Family member as a hospital patient: sentiments and functioning of the family.
AB - The aim of this pilot study was to find out how families experience the
hospitalization of one family member and to chart the participation of the family
in the treatment of the hospitalized family member. A questionnaire was used to
gather data for the study and the three open-ended questions in the questionnaire
were interpreted using content analysis. The study population (n = 70) was the
family members of patients in the neurological wards of Tampere University
Hospital. The study demonstrated a variety of negative sentiments in the
families, such as worry, fear, shock, anxiety and depression at the
hospitalization of their family member. The families also expressed neutral and
positive sentiments, such as approval, relief and faith in the help given. Nearly
80% of the families' statements dealt with emotional responses. Changes in the
everyday life of the family caused by the hospitalization of a family member were
also reported, with most changes affecting the immediate family. Hospital visits
gave a rhythm to family life. There were changes in the sharing of housework and
taking care of affairs, as well as in relationships within the family. Family
members spoke of their loneliness, fear and longing. External changes in family
life were present in 13% of statements. Helping the patient in hospital involved
functions like participation in nursing care, taking the patient to the cafeteria
and rehabilitation. Only 20% of statements dealt with emotional support for the
patient. Future research could broaden the perspective to include the views of
patients, nurses and doctors on the reality of family nursing.
PMID- 10769626
TI - Telephone nursing: calls and caller satisfaction.
AB - To understand the function of telephone nursing, every call to the Medical Call
Centre in Stockholm was recorded during one week (n = 2866). Every tenth caller
(n = 203) was asked to answer a mailed questionnaire about consultation and
satisfaction. The most common reason for calling was symptoms of infection. The
predominant outcome was self-care advice (49%). In the mailed questionnaire 85%
of respondents stated that they had followed the advice and 95% were satisfied
with their consultation. Compared to earlier studies of calls to health-care
centres and accident and emergency departments, a larger proportion of the
callers were advised to see a physician. The Call Centre we examined proved to be
more inclined to give self-care advice than other health-care settings.
PMID- 10769627
TI - Phosphorylation status and function of P53 are inversely related to protein
kinase C activation.
AB - The role of phosphorylation in the regulation of p53 protein function is little
understood. We have addressed the role of protein kinase C (PKC) in the
phosphorylation. Exposure to the protein kinase inhibitor, 1-(5
isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), increased the
phosphorylation of wild type p53 protein, whereas exposure to the tumor promoter
phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), decreased it in vivo
following 3 hours incubation with mouse epidermal JB6 cells. Exposure to the c
AMP dependent protein kinase (PKA) activator, forskolin, did not decrease the
phosphorylation of p53 protein. In the transient transfection/luciferase reporter
transactivation assay, H7 modestly increased the mouse double minute (MDM) 2
reporter transactivation activity of p53 protein after 24 hours treatment, and
TPA completely blocked it. These results suggest that the accelerated
phosphorylation of wild type p53 protein is inversely related to PKC activation,
and that p53 phosphorylation may have some relation to transcription factor
function.
PMID- 10769628
TI - Overexpression of manganese superoxide dismutase gene suppresses spontaneous
apoptosis without a resultant alteration in in vivo growth of the mouse
fibrosarcoma, FSa-II.
AB - The relationship between spontaneous apoptosis and overexpression of manganese
superoxide dismutase (MnSOD) gene was examined in vivo. The mouse fibrosarcoma
cells expressing high MnSOD activities due to transfection with the human MnSOD
cDNA (SOD-H), or the fibrosarcoma cells transfected with the selectable marker
alone (NEO), were transplanted into immune-deficient Fox Chase SCID C.B-17/Icr
scid Jcl mice. Apoptosis in tumors was visually quantified by the in situ end
labeling method. The number of apoptotic cells in the SOD-H tumors was
significantly less than that in the NEO tumors. The tumor growth time of the SOD
H tumors to grow from 34 to 500 mm3 in one-half of the mice was slightly longer
than that of the NEO tumors, but the difference was not statistically
significant. These results suggest that overexpression of MnSOD gene is involved
in the suppression of spontaneous apoptosis, without a resultant alteration in
the tumor growth.
PMID- 10769629
TI - 17 beta-estradiol-regulated expression of protein tyrosine phosphatase gamma gene
in cultured human normal breast and breast cancer cells.
AB - BACKGROUND: Protein tyrosine phosphatase gamma (PTP gamma) has been implicated as
a potential tumor suppressor gene in kidney and lung adenocarcinomas. We have
previously shown that PTP gamma mRNA expression levels are lower in DES-induced
kidney tumors than in normal kidneys of Syrian hamsters. The goals of the present
study were to determine if PTP gamma mRNA is present in both normal and cancerous
human breast cells, and to investigate the estrogenic regulation of PTP gamma
mRNA expression in these cell types. METHODS: Primary cultured human breast cells
derived from surgical specimens of mammoplasty and breast cancer patients, as
well as human breast cancer cell lines were used for the study. RT-PCR and RNase
protection assay was utilized to detect and quantify levels of PTP gamma mRNA
among the cell types used and between control and 17 beta-estradiol (E2)-treated
cells. Transient transfection of human estrogen receptor (ER) into MDA-MB-231
human breast cancer cells was performed to establish the role of ER in the
regulation of PTP gamma mRNA expression. RESULTS: The results show that PTP gamma
mRNA is expressed in primary cultured human breast cells isolated from
mammoplasty and breast cancer patients, as well as in human cancer cell lines,
and that E2 significantly inhibits PTP gamma expression in ER-positive human
breast cancer cells via an ER-mediated mechanism. We show that PTP gamma mRNA
levels are lower in human breast cancer cells than in normal human breast cells.
Furthermore, we report that PTP gamma mRNA expression is inhibited by E2 in a
dose-dependent manner in primary cultured breast cells. After treatment with 20
nM E2 for 24 hours, PTP gamma mRNA was significantly suppressed in primary
cultured cancerous and non-cancerous cells from breast cancer patients, as well
as in the ER-positive MCF-7 cell line by 50%, 85%, and 66%, respectively. In
contrast, the PTP gamma mRNA expression levels did not change in similarly
treated ER-negative MDA-MB-231 cells. Sensitivity to E2-induced suppression could
be restored (94% inhibition) by transfecting MDA-MB-231 cells with an ER
expression plasmid. CONCLUSIONS: Our results are the first to suggest that PTP
gamma is a potential estrogen-regulated tumor suppressor gene in human breast
cancer which may play an important role in neoplastic processes of human breast
epithelium.
PMID- 10769630
TI - Cell-surface expression of complement restriction factors and sialyl Lewis
antigens in oral carcinoma: relevance to chemo-immunotherapy.
AB - Oral squamous cell carcinomas overexpress tumor-associated antigens, yet these
antigens do not induce an immune-mediated anti-tumor response. The absence of an
anti-tumor immune response may be due to poor immunogenicity of the tumor
antigens or due to presence of factors that restrict immune functions. We have
analyzed the expression of the tumor-associated sialyl LewisA (sLeA) and sialyl
LewisX (sLeA) antigens, the complement restriction factors (CD59, CD46 and CD55)
and the apoptosis associated factors Fas and Fas Ligand. Sialyl Lewis antigens
(sLeA and sLeX), are immunogenic in that they elicit complement-fixing IgM
antibodies. These antigens are associated with aggressive invasive behavior,
tumor progression and poor disease-free survival of patients with human
carcinomas. Human oral squamous carcinoma cell lines, SCC12 and SCC71, were
analyzed for the density of Sialyl Lewis antigens, CD59, CD46, CD59, Fas and FasL
on the cell surface. Expression of these antigens on the cell surface was
determined employing a cell-suspension ELISA with monospecific monoclonal
antibodies. In both oral carcinoma cell lines, the density of expression of sLeX
was higher than that of sLeA and SCC71 had a very low level of sLeA expression.
Both cell lines expressed a high density of CD59 and slightly lower levels of
CD46 and CD55 on the cell surface, suggesting that even if host antibodies are
accessible to the target antigens such as sLeX, they could not mediate complement
dependent cytotoxicity. The SCC lines expressed very low levels of Fas and FasL
indicating that there maybe a lack of these signaling molecules for apoptosis.
Our data suggests that passive immunotherapy or tumor killing by antibody
complement interaction may require downregulation of complement restriction
factors.
PMID- 10769631
TI - Correlation of chemopreventive efficacy data from the human epidermal cell assay
with in vivo data.
AB - Continuous exposure to low doses of potentially mutagenic and carcinogenic
chemicals over the human lifetime makes the identification of agents, which could
reduce the ensuing risk of cancer, beneficial. The Human Epidermal Cell (HEC)
Assay includes multiple exposures to low, non-toxic doses of propane sultone,
which increases cellular growth and inhibits differentiation, and co-exposure to
potential chemopreventive agents to determine their ability to inhibit the
increased growth or increase differentiation. Original data are presented on the
efficacy of twenty potential cancer chemopreventive agents were screened for
efficacy in the HEC Assay. Efficacy was determined by the ability of agents, at
nontoxic concentrations, to reverse either of the propane sultone-induced
biomarkers, enhanced growth and reduced involucrin expression. Based on the
number of positive concentrations and the lack of toxicity, 1,2-dithiol-3-thione,
oltipraz, and a synthetic retinoid, Ro 16-9100, were the most active. Eleven of
seventeen positive agents were active for both endpoints. S-Allylcysteine was
only active for the growth inhibition endpoint, and DFMO, Iycopene, perillyl
alcohol, ursodiol, and black tea polyphenols were only active for the involucrin
endpoint. The three agents that have been shown to be negative in animal models,
diphenhydramine, d-mannitol, and nordihydroguaiaretic acid, were correctly
identified as negative by the assay. When the data from previous studies (Elmore
et al, Anticancer Res, 19: 909-918, 1999) are included, a positive response in
one or more endpoints of the HEC Assay correlates 100% (26/26) with a positive
response in one or more of the animal cancer prevention models (8). The available
data suggest that the HEC Assay response is highly predictive of efficacy in
animals in vivo with an overall accuracy of 90%. Future studies will include data
with additional negative agents. The correlation of the HEC Assay data with data
from in vivo studies in animal models, which utilize multiple carcinogens and
multiple target organs, would suggest that this in vitro assay has the ability to
identify agents with the potential to prevent carcinogen-induced cancer. While
our ultimate goal is to identify agents with potential efficacy for preventing
human cancer, sufficient human data are not yet available to make this
correlation.
PMID- 10769632
TI - Medroxyprogesterone acetate increases anthracyclines uptake in chronic lymphatic
leukemia cells: role of nitric oxide and lipid peroxidation.
AB - Anthracyclines are one of the most used drugs in the therapy of several malignant
tumors. Unfortunately, its use is still limited by their cardio-toxicity and by
the presence of cancer cells resistant to these drugs. In the present study we
evaluated the ability of a chemo-sensitizer agent, MPA (Medroxyprogesterone
Acetate), to modify anthracyclines intranuclear uptake in normal leukocytes (NL)
and in chronic lymphatic leukemia leukocytes (CLL). Moreover we evaluated the
role of lipid peroxidation and nitric oxide (NO) production on antracyclines
activity and on their combination with MPA. Our data show that MPA significantly
increases anthracyclines uptake only in CLL cells and decreases anthracyclines
induced lipid peroxidation.
PMID- 10769633
TI - Differential expression of transforming growth factor beta receptors in human
pancreatic adenocarcinoma.
AB - BACKGROUND: Many cancer cells show resistance to transforming growth factor beta
(TGF-beta)-mediated growth inhibition. This resistance to TGF-beta is associated
with an increased tumorigenic phenotype. OBJECTIVE: In this study, we determined
whether a loss in expression of TGF-beta receptors or DPC4, an important down
stream target of TGF-beta signaling, might account for this lack of TGF-beta
sensitivity in pancreatic adenocarcinoma. MATERIALS AND METHODS: To accomplish
this, six established pancreatic cancer cell lines, twenty-six surgically
resected tumor specimens of pancreatic adenocarcinoma and ten non-tumor pancreas
tissues were analyzed for the mRNA expression of the three TGF-beta receptors
(RI, RII, and RIII) and DPC4. RESULTS: We report here that five of six pancreatic
cancer cell lines were not sensitive to TGF-beta. All the ten non-tumor specimens
of pancreas showed expression of RI, and DPC4; while nine of ten showed
expression of RIII and eight of ten showed expression of RII. Five of six
pancreatic cancer cell lines and 23 of 26 tumor specimens showed expression of
RI. Two cell lines and about half (46%) of the tumor specimens did not express
RII. Only two cell lines showed appreciable levels of RIII expression; while ten
of 26 (38%) tumor specimens did not show expression of RIII. DPC4 expression was
observed in three of the six (50%) cell lines and 19 of 24 (79%) tumor specimens.
CONCLUSION: This study indicates that apart from the functional loss of DPC4 due
to mutations or homozygous deletion, a lack of the TGF-beta receptors,
particularly RII and RIII, may contribute to a loss of TGF-beta signaling in a
population of pancreatic cancers.
PMID- 10769634
TI - Relevant genomics of neurotensin receptor in cancer.
AB - The expressed sequence tag (EST) databases are an attractive starting point for
gene discovery for diseases like cancer. Validation of gene targets from these
sequences (both known and novel) in cancers requires a comprehensive expression
profiling. We identified from the Cancer Gene Anatomy Project database (CGAP), a
hit called neurotensin receptor (NT-r) that was expressed in the pancreatic
cancer cDNA libraries. Neurotensin (NT), a neuroendocrine peptide, exerts trophic
effects in vivo and stimulates the growth of cancer-derived cell lines in vitro.
High affinity neurotensin receptors (NT-r) are expressed in cancer-derived cell
lines and in some primary tumors. To date, a comprehensive expression profile of
the NT-r in diverse cancers and normal tissues has not been reported. A cancer
selective expression of NT-r, if demonstrable, may provide a basis for a
diagnostic and potential therapeutic utility. We demonstrate that the NT-r is
expressed in a variety of cancer-derived cell lines as well as primary tumors,
but only in a select few normal tissues. The expression of NT, on the other hand,
was detected in many normal tissues, but not in the cancer-derived cell lines.
The NT expression however, was detected in the primary tumors. We further
demonstrate that NT expression is stimulated by androgen deprivation in the
prostate cancer models. These results demonstrate the usefulness of a panel of
cDNA repository for rapid validation of potential cancer targets.
PMID- 10769635
TI - Modulation of the connexin26 tumor suppressor gene expression through methylation
in human mammary epithelial cell lines.
AB - BACKGROUND: Normal mammary epithelial cells express mainly gap junction connexin
26 (Cx26) that is either reduced or absent in breast cancers. Since connexin gene
mutations are rare we examined if Cx26 gene repression is related to
hypermethylation. MATERIALS AND METHODS: Five breast epithelial cell lines were
examined for Cx26 mRNA expression and hypermethylation. Treatment with a DNA
methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (5-Aza-CdR), was carried out
to determine if Cx26 gene expression could be upregulated. RESULTS: Cx26
expression was easily detectable in an immortalized human mammary epithelial cell
line (MCF-10) and markedly diminished (MDA-MB231) or undetectable in (MCF-7, BT
20, T47-D) breast cancer cell lines. Hypermethylation of the Cx26 5' region was
observed in MCF-10 and MCF-7 cells. Treatment with 5-Aza-CdR resulted in slight
or no induction in Cx26 expression in breast cancer cell lines. CONCLUSIONS:
Hypermethylation is unlikely to be a major mechanism for Cx26 gene repression in
human mammary cancer cell lines.
PMID- 10769636
TI - Cytogenetic and molecular genetic abnormalities in primitive neuroectodermal
tumors of the central nervous system.
AB - Primitive neuroectodermal tumors constitute a large class of pediatric brain
tumors. Despite notable recent advances in improving treatment and survival, the
pathogenesis and the molecular genetic bases of these malignancies remain poorly
understood. Combined cytogenetic and molecular genetic approaches have been used
to identify genomic alterations in different histologic tumor types. Translation
of these advances from basic science to clinical application is currently
underway. Goals for the future include the development of more efficacious
treatment strategies while simultaneously lessening toxicity. The most important
cytogenetic and molecular genetic abnormalities documented to date together with
their potential prognostic significance are reviewed.
PMID- 10769637
TI - Downregulation of mitogen-activated protein kinases in human colon cancers.
AB - BACKGROUND: Activation of the mitogen-activated protein kinases (MAPKs) appears
to play an important role in both proliferation and transformation of various
cells; the role of MAPK activation in colorectal cancers has not been clearly
defined. The purpose of our study was to determine whether MAPK activity and
protein levels were increased in colorectal cancers. METHODS: Colorectal cancers
and adjacent normal mucosa from 21 patients were extracted for protein.
Expression levels and activity of the MAPKs (ERK1/2, JNK1, p38 and ERK3) were
assessed by immunoblot analysis and in vitro kinase assays, respectively. In
addition, changes in myelin basic protein (MBP) kinase activity and
autophosphorylation were determined by in-gel kinase assays. RESULTS: The
activities of ERK1/2, JNK1 and p38 were downregulated in the majority of cancers;
ERK3 kinase activity was increased in 10 of 21 cancers. The presence of proteins
displaying increased MBP phosphorylation and autophosphorylation was identified
specifically in the cancers by in-gel kinase assays. CONCLUSIONS: Our findings
demonstrate that the constitutive activation of ERK1/2, JNK1 and p38 is not a
feature of colorectal cancers. Moreover, our in-gel kinase results suggest that
protein kinases, other than the MAPKs assessed, may play a more crucial role in
colon carcinogenesis.
PMID- 10769638
TI - Response to 5-fluorouracil of orthotopically xenografted human colon cancers with
a microsatellite instability: influence of P53 status.
AB - Response to 5-FU of 5 different human colon cancers (hCC) with a DNA
microsatellite instability (MSI), xenografted into nude mice, was analysed
according to their p53 status. Two hCC (TC82 and TC71) had a mutated p53
(mutp53), while two others (TC33 and LoVo) had a wild type p53 (wtp53); the fifth
tumour (X17LoVo) originated from the stable transfection of LoVo cells with a
dominant mutp53 (273his) vector. All tumours were implanted onto the caecum of
nude mice to induce orthotopic growth of hCC. 5-FU was administered at 40 mg/kg
per day for 5 consecutive days. A significant growth inhibition of TC82 and TC71
tumours (of 68 and 60%, p < 0.05 and < 0.01 respectively) was observed, whereas 5
FU had no effect on TC33 and LoVo. Moreover, the mutp53 transfected tumour,
X17LoVo, displayed significant sensitivity to 5-FU (p < 0.05). This suggests that
distinct genetic alterations influence differently the response of hCC to this
antimetabolite.
PMID- 10769639
TI - Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and
epiregulin in androgen-independent prostate cancer cell lines.
AB - BACKGROUND: The proliferation of androgen-independent prostate cancer cell lines
has previously been shown to be influenced by an autocrine loop of the epidermal
growth factor (EGF) system. This observation has alerted us to study the
expression of ligands and receptors from the EGF-system in prostate cell lines.
METHODS: The expression of the EGF system was determined by quantitative RT-PCR
and ELISA in the normal prostate epithelial cell line (PNT1A), in the androgen
sensitive-(LNCaP), and the androgen-independent (DU145 and PC3) prostate cancer
cell lines. RESULTS: The expression of mRNA for the ligands TGF alpha,
amphiregulin, HB-EGF and epiregulin were increased 10 to 100 fold in androgen
independent cells, as compared to LNCaP and PNT1A cells. Expression of mRNA for
the ligands EGF and betacellulin and of the receptors HER1 and HER2 were similar
in all lines investigated, except LNCaP cells which exhibit low expression of
HER1. Similar results were obtained by ELISA. CONCLUSIONS: The data indicates a
selective up-regulation of a subclass of ligands of the EGF-system in androgen
independent prostate cancer cell lines. We suggest this could be a mechanism to
escape androgen dependence in prostate cancer.
PMID- 10769640
TI - Benefits of complete polyamine deprivation in hormone responsive and hormone
resistant MCF-7 human breast adenocarcinoma in vivo.
AB - Polyamines are ubiquitous cellular compounds which are required for estradiol
induced proliferation in breast cancer. Complete polyamine deprivation, using 2
alpha-difluoromethyl-ornithine (DFMO, Eflornithine), a specific inactivator of
ornithine decarboxylase (key-enzyme of the polyamine biosynthesis) combined with
inhibition of the bacterial production of gastrointestinal polyamine and a
polyamine free regimen, was demonstrated to exhibit a cytostatic effect and a
decrease of the three tumoral polyamine concentrations in a MCF-7 tumor model. In
this experiment, complete polyamine deprivation has been tested on a standard MCF
7 tumor and on a variant MCF-7 tumor (i.e. with a tamoxifen acquired resistance).
Polyamine deprivation was effective on the tumor growth, both on standard and
variant sub-types. The polyamine contents of two types of tumor were similar, and
identically, polyamine deprivation has caused a decrease of putrescine,
spermidine and also spermine tumoral concentrations measured by the HPLC method
in standard and variant MCF-7 tumors. Acquired tamoxifen resistance is common in
patients undergoing hormonal therapy for advanced breast cancer. It has been
hypothesized that the direct stimulation of polyamine pathway without estradiol
involvement could be one of the mechanisms responsible for the tamoxifen
resistance. The ability of polyamine deprivation to inhibit the growth of tumors
becoming tamoxifen resistant could offer a therapeutic advantage in case of tumor
with acquired tamoxifen resistance and could be tested to prevent or delay the
hormonal responsiveness to breast cancer.
PMID- 10769641
TI - Involvement of p21Waf1 in mediating inhibition of paclitaxel-induced apoptosis by
epidermal growth factor in MDA-MB-468 human breast cancer cells.
AB - Paclitaxel (Taxol) is currently one of the most widely used anti-cancer drugs for
human breast cancer. In this study, we investigated how epidermal growth factor
(EGF) modulated paclitaxel-induced apoptosis in MDA-MB-468 human breast
adenocarcinoma cells. Pulse-exposure of the cells to paclitaxel resulted in cell
death through apoptosis. When EGF was present during the post-paclitaxel culture
period, this paclitaxel-induced apoptosis was inhibited in an EGF dose-dependent
manner. The induction of apoptosis by paclitaxel was accompanied by an elevated
level of p34cdc2 kinase activity, which was inhibited in the presence of EGF
during the post-paclitaxel culture period. Exposure of MDA-MB-468 cells to EGF
induced expression of the cyclin-dependent kinase inhibitor p21Waf1. Incubation
of paclitaxel-treated MDA-MB-468 cell extracts with EGF-treated MDA-MB-468 cell
extract, which exhibited elevation of p34cdc2 activity, inhibited the kinase
activity. This inhibition was not observed with p21Waf1-immunodepleted EGF
treated cell extract. Transfection of the cells with p21Waf1 antisense
oligonucleotide abolished the induction of p21Waf1 and also significantly reduced
inhibition by EGF of paclitaxel-induced apoptosis. These studies demonstrate that
p21Waf1 plays a key role in the inhibition of paclitaxel-induced apoptosis by EGF
in MDA-MB-468 cells.
PMID- 10769642
TI - Anti-metastatic effect of an autooxidation-resistant and lipophilic ascorbic acid
derivative through inhibition of tumor invasion.
AB - The invasion of human fibrosarcoma HT-1080 cells through Matrigel was shown to be
inhibited by pretreatment with ascorbic acid (Asc) or its four derivatives, such
as Asc-6-O-palmitate (Asc6Plm), Asc-2-O-phosphate (Asc2P), Asc-2-O-phosphate-6-O
palmitate (Asc2P6Plm), and Asc-5,6-benzylidene (Asc5,6Bz) of non-cytotoxic
concentrations for 1 or 18 hr. Two lipophilic derivatives such as Asc6Plm and
Asc2P6Plm exerted an invasiveness-inhibitory activity more markedly with 1-hr
pretreatment, being a more practical index in terms of the plasma half-life, than
Asc, Asc5,6Bz or Asc2P being less lipophilic. Considerably less cytotoxicity (a >
3.3-fold higher IC50 for 1-hr pretreatment) of Asc2P6Plm sufficiently compensated
a slightly lower invasiveness-inhibitory activity (a < 1.8-fold higher EC50) as
compared with Asc6Plm. Pulmonary metastasis of mouse melanoma B16BL6 cells
injected into the tail vein was also inhibited by intravenous administration with
Asc2P6Plm dose-dependently. Thus Asc2P6Plm, a lipophilicity-hydrophilicity
balanced molecule protectively blockd in the autooxidation-prone moiety, is
anticipated as a potent anti-metastatic agent via inhibition of tumor invasion.
PMID- 10769643
TI - Expression of the mismatch repair protein hMSH2 in carcinoma in situ and invasive
cancer of the breast.
AB - BACKGROUND: Dysregulations in the mechanism of DNA-repair are contributed to
tumorgenesis and tumorprogression in human cancer. The mismatch repair gene hMSH2
encodes a protein, which recognizes and binds to mismatch-sequences of the DNA.
METHODS: Using immunohistochemical techniques hMSH2 expression was analyzed in
invasive cancer (n = 85) and in situ carcinoma (n = 34) of the breast. RESULTS:
The percentage of hMSH2 positive cases was significantly (p = 0.0001) decreased
in invasive cancer as compared to in situ carcinomas. There was an association of
hMSH2 expression with parameters of unfavorable prognosis, such as lymph node
involvement (p = 0.03), higher degree of malignancy (p = 0.05) and higher
proliferative activity (p = 0.05). CONCLUSIONS: During development from in situ
to invasive cancer of the breast, hMSH2 expression seems to be downregulated.
However, in invasive cancer, hMSH2 expression seems to be associated with tumor
progression. This could be explained by the fact that enhanced proliferation of
tumor cells results in increased mistakes within DNA replication procedures.
PMID- 10769644
TI - Down-regulation of nerve growth factor in poorly differentiated and advanced
human esophageal cancer.
AB - BACKGROUND: Binding of nerve growth factor (NGF) to its receptor TrkA leads to
intracellular tyrosine kinase activation and regulates the growth and
differentiation of various non-neuronal tumours. PATIENTS AND METHODS: In the
present study NGF and TrkA were analysed by Northern blot analysis, in situ
hybridisation and immunohistochemistry in 41 esophageal cancer samples in
comparison to normal controls. RESULTS: NGF mRNA (P < 0.01), but not TrkA mRNA
was down-regulated in esophageal cancer samples compared with normal tissues. In
the normal esophagus, NGF mRNA and protein was present in epithelial cells of the
entire epithelial layer and TrkA mRNA and protein was present in epithelial cells
of the basal layer. In esophageal cancer NGF and TrkA mRNA and protein were
present in the cancer cells. Down-regulation of NGF correlated with poor
differentiation (P < 0.01) and advanced tumour stage (P < 0.01). Low TrkA
expression was related to advanced tumour stage (P < 0.05). CONCLUSION: A loss of
activation of the NGF/TrkA pathway occurs during tumour progression and may
contribute to loss of tumour differentiation in esophageal cancer.
PMID- 10769645
TI - Hydroxyurea and trimidox enhance the radiation effect in human pancreatic
adenocarcinoma cells.
AB - BACKGROUND: Pancreatic cancer remains the most lethal of all common human
malignancies with a 5-year survival rate of lower than 5%. Adjuvant and
neoadjuvant preoperative and postoperative chemo-radiotherapy using 5
fluorouracil, have reduced local relapse rate and slightly increased the median
survival. Testing new and more potent radiation-sensitising drugs in human
pancreatic cancer cells can provide the basis for a more effective chemo
radiation regimen and may consequently improve treatment outcome. MATERIALS &
METHODS: The present study was performed to evaluate the efficacy of two potent
ribonucleotide reductase (RR) inhibitors: hydroxyurea and trimidox in radio
sensitising Panc-1 human pancreatic cancer cells in an attempt to identify a more
effective chemo-radiotherapy regimen with minimal side effects. RESULTS:
Treatment of Panc-1 cells with hydroxyurea or trimidox alone for 2 hours was
associated with a dose-dependent decrease in their cloning efficacy to similar
extent. The IC50 of trimidox, hydroxyurea or radiation alone were 2.5 + 0.3
microM, 39.0 + 0.4 microM and 3.2 + 0.2 Gy, respectively. Treatment with 39.0
microM non-cytotoxic IC50 dose of hydroxyurea for two hours before or immediately
after radiation reduced the IC50 of radiation to only 1.1 + 0.14 or 1.0 + 0.1 Gy,
respectively. Treatment with 2.5 microM non-cytotoxic IC50 dose of trimidox for
two hours before or immediately after radiation reduced the IC50 of radiation to
only 1.2 + 0.16 or 1.4 + 0.12 Gy, respectively. The mean radiation enhancement
ratios were 2.9 and 3.2 for hydroxyurea before and immediately after radiation.
The greater radio-sensitising effect of hydroxyurea compared to trimidox or
gemcitabine could be due to its unique double action by synchronising the cancer
cells into the radiosensitive G1/S border and inhibiting DNA damage repair.
CONCLUSIONS: The present study demonstrates the superiority of hydroxyurea at non
cytotoxic doses compared to the other two recent RR inhibitors: gemcitabine and
trimidox in radio-sensitising human pancreatic cancer cells. Hydroxyurea combined
with radiation has significantly improved progression-free survival of advanced
cervical cancer and glioblastoma patients and showed clinical benefit in
combination with other chemotherapy drugs in advanced pancreatic cancer. The
present results suggest the clinical use of hydroxyurea as a radiosensitiser in
both pre- and post-operative chemo-radiotherapy in pancreatic cancer patients.
Given the demonstrated potent radio-sensitising effect of hydroxyurea at non
cytotoxic doses when administered before or immediately after radiation and its
low clinical toxicity, it should be feasible to administer hydroxyurea both
before and after radiation in pancreatic cancer patients.
PMID- 10769647
TI - Use of the monoclonal antibody M30 for detecting HSG cell apoptosis.
AB - An immunocytochemical method using a monoclonal antibody (MoAb), M30, which
reacts with the product resulting from the cleavage of cytokeratin 18 by
activated caspase, was applied to detect the apoptosis of human salivary gland
tumor (HSG) cells induced by epigallocatechin gallate (EGCG), gallic acid (GA)
and sodium ascorbate (SA). EGCG, GA and SA dose-dependently induced HSG cell
death. Immunoreactive products were significantly observed in the cytoplasm of
HSG cells after treatment with all these compounds. The reactions occurred with
lower concentrations of these agents and after shorter treatment times, in
comparison with DNA fragmentation detected by the terminal deoxynucleotidyl
transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. These results
suggest that immunocytochemical staining with the MoAb M30 may be useful for
detecting the apoptosis-inducing activities of various chemical compounds.
PMID- 10769646
TI - Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral
sensitivity to other classes of anti-leukemic drugs.
AB - The major limitation of treatment with antimetabolite drugs is that they produce
resistant clones both in vitro and in patients who either do not respond to
treatment or relapse soon after response has been documented. To better
understand the phenomenon of cross-resistance, we developed seven CEM/ara-C
resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from
4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using
this model, we determined IC50 concentrations to several chemotherapeutic agents
and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2)
proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related
protein (MRP). The cell viability assays showed that these clones were cross
resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to
8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x
10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from
1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree
of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments
from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with
ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C
from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell
line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more
sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2
protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant
clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10
microM ara-C for 48 hours showed increased p53 protein expression in most of
these lines. No increase in bcl-2 protein expression was seen in the wt cell line
after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara
C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl
2 protein after treatment with 1 microM ara-C, but not after 10 microM. This
alteration may lead to resistance to apoptosis and enhanced cell survival. The
ratio of bcl-2 to p53 was increased significantly in these three clones, thus
favoring an anti-apoptotic drive. All of the cell lines examined were negative
for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for
MRP functional activity. However, three ara-C resistant cell clones, CEM/ara
C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and
functional activity. It is apparent that selection for ara-C resistance confers
cross-resistance to many other classes of drugs and gamma radiation, probably due
to bcl-2 protein overexpression or P-gp and MRP expression, as independent
mechanisms.
PMID- 10769648
TI - Suppression of ascites formation and re-accumulation associated with human
ovarian cancer by an anti-VPF monoclonal antibody in vivo.
AB - Ascites formation is often observed in ovarian cancer patients. Vascular
permeability factor (VPF) may induce ascites formation. We established an animal
model of ascites formation and re-accumulation by i.p. transplantation of a human
ovarian adenocarcinoma cell line, NOS2, into nude mice. The formation of ascites
was observed after 10 days of tumor inoculation and continued for up to 4 weeks.
In the ascitic fluid, biologically active VPF was detected. The repeated i.p.
administration of an immunoneutralizing monoclonal antibody (MAb) to VPF, MV833,
significantly inhibited the formation of ascites throughout the experiments. Re
accumulation of ascites occurred quickly in control mice after aspiration of
ascites and these mice died within 20 days. MV833 again inhibited the re
accumulation of ascites and significantly prolonged the life span of mice without
any side effect. These results indicate that VPF plays an important role in the
accumulation of ascites induced by ovarian cancer and an anti-VPF MAb is a new
specific drug to suppress the formation and re-accumulation of ascites. This MAb
may contribute to ameliorating quality of life of cancer patients as well as
prolong their survival.
PMID- 10769649
TI - SCID mouse lymphogenous metastatic model of human lung cancer constructed using
orthotopic inoculation of cancer cells.
AB - An animal model of metastasis with features similar to those of lung cancer
metastasis in humans is required for an understanding of the cellular and
molecular mechanisms of human lung cancer metastasis. Ma-44 cell lines derived
from human squamous cell lung cancer were percutaneously injected (2-3 x 10(4))
into the left lung of SCID mice. After orthotopic implantation, Ma-44 cell lines
formed tumors in the left lung at a high rate (17/25, 68%), and many of those
metastasized to mediastinal lymph nodes (13/17, 76%) by the 14th day, but not to
other organs. After the ectopic implantation, the Ma-44 cell line inoculated
subcutaneously (2-3 x 10(5)) formed a tumor at the inoculation site by the 28th
day (all mice), but did not metastasize to any organs. The Ma-44 cell line
inoculated intravenously (2-3 x 10(5)) formed metastases in the lungs (37/50,
74%), and these pulmonary metastases metastasized to the mediastinal lymph nodes
at low rate (3/37, 8%) by the 14th day. The orthotopic sites of implantation are
critical for the metastatic ability of transplanted tumors in SCID mice. Since
non-small cell lung cancer (NSCLC) grows at the primary site in humans,
lymphogenous metastasis occurs frequently, and blood-born metastasis occurs at
moderate rate, our orthotopic SCID mice model was similar to the metastatic
behavior of NSCLC in humans. Thus, this model may be useful for elucidating the
mechanism of lymphogenous metastasis in human lung cancer, and testing the anti
metastatic efficacy of therapeutic agents in vivo.
PMID- 10769651
TI - Immunohistochemical and DNA sequencing analysis on human mismatch repair gene
MLH1 in cervical squamous cell carcinoma with LOH of this gene.
AB - BACKGROUND: The human MLH1 gene (hMLH1) is one of the DNA mismatch repair genes.
Defects in these genes are believed to be the underlying cause of microsatellite
instability (MSI). MSI has been demonstrated in many human cancers such as colon
cancer and some female-specific tumors. The hMLH1 gene can be inactivated by
genetic mutation or by hypermethylation of its promoter region, which often
causes cessation of hMLH1 protein production. We were prompted by our previous
finding of 43% of cervical cancers and their precursors with a loss of
heterozygosity (LOH) of the hMLH1 gene to investigate whether it is inactivated
during the carcinogenesis of cervical cancer. MATERIALS AND METHODS: hMLH1
protein production was assessed by immunohistochemistry, and nucleotide sequence
analysis were performed on all exons of the hMLH1 gene. RESULTS: In 11 cases of
invasive cervical cancer, among which 7 had LOH of the hMLH1 gene,
immunohistochemistry provided no evidence for cessation of hMLH1 protein
production. In addition, no mutations were found in any of the 19 hMLH1 gene
exons. CONCLUSIONS: The activity of hMLH1 gene might not be disturbed in the
development of cervical cancer although a proportion of the cases had lost one of
its hMLH1 gene copies.
PMID- 10769650
TI - Experimental induction of apoptosis by a combination of etoposide and radiation
treatment.
AB - The present study was undertaken to investigate cell death (particularly
apoptosis) induced by etoposide, radiation, and both, and to examine p53 protein
expression in relation to cell death. Nude mice transplanted with a human tumor
(ependymoblastoma) were treated with etoposide (5-40 mg/kg) or 1-2 Gy X-ray
irradiation or both. The tumor was excised at different points after treatment,
and tumor tissue specimens were used to check for apoptosis and p53 protein
expression by TUNEL, p53 protein staining, etc. Induction of p53-dependent
apoptosis was observed in the etoposide treatment group, the X-ray irradiation
group, and the combined (etoposide + X-ray irradiation) group. Etoposide 10 mg/kg
was found to be approximately equivalent to 1 Gy X-ray irradiation in ability to
induce apoptosis. When etoposide treatment was combined with X-ray irradiation at
intervals of 3-6 hours, an approximately additive effect was observed.
PMID- 10769652
TI - Topoisomerase II alpha expression in squamous cell carcinomas of the head and
neck.
AB - The aim of the present study was to examine topoisomerase II alpha (topo II
alpha) expression in cancers of the head and neck and to establish a correlation
with clinicopathological parameters and survival. Paraffin embedded tissue
specimens (studied by immunohistochemistry), from 103 consecutive patients with
squamous cell carcinoma of the head and neck regions, were examined on the
primary tumor (96 patients) and on recurrence (7 patients). Immunostaining
evaluation was quantified by examining at least 1,000 neoplastic cells and
counting the percentage of positively stained nuclei. Topoisomerase II alpha
expression was correlated with age, gender, stage, site of the disease, tumor
differentiation, response to chemotherapy, disease-free survival and overall
survival. More than half of the specimens had a high expression of topoisomerase
II alpha (> or = 15% positive neoplastic cells). Topoisomerase II alpha
expression was significantly higher in tumors of low and moderate differentiation
versus tumors of high differentiation (P = 0.00001). There was also a significant
difference in topo II alpha in specimens of responders to chemotherapy versus non
responders (P = 0.02), although the cytotoxic drugs used do not belong to
topoisomerase II alpha antagonists. The correlation of high topoisomerase II
alpha expression and stage of disease, age, gender, primary site, recurrence,
disease-free survival and overall survival was not statistically significant. In
conclusion, topoisomerase II alpha is highly expressed in histological specimens
of the majority of patients with head and neck cancers; mainly, it is related to
a significant degree to low and moderately differentiated tumors versus highly
differentiated ones. High expression of topoisomerase II alpha is also
significantly related to response to chemotherapy.
PMID- 10769653
TI - Prevention of bladder tumor formation in mice by a novel bone marrow-derived
factor, reptimed.
AB - BACKGROUND: Reptimed is a novel, species-conserved, bone marrow-derived molecule
which possesses anti-neoplastic activity. Previously, we established an
orthotopic murine bladder tumor (MBT-2) model and reported accurate documentation
of the presence and the extent of intravesical involvement of bladder tumor
implants using magnetic resonance imaging (MRI) (1). Herein, we investigated the
activity of exogenously administered Reptimed in the MBT-2 model. MATERIALS AND
METHODS: Intravesicular and intraperitoneal administration of Reptimed
concurrently with and following transurethral tumor cell implantation was
performed and MBT-2 tumor response was assessed at several time points post tumor
implant. RESULTS: Serial MRI scans of Reptimed-treated mice at days 14 to 33 post
tumor transplant revealed significant inhibition of bladder tumor growth with no
significant tumor growth observed by MRI on day 33 post-implant. The
corresponding histological examination of the whole mount bladder sections
revealed similar inhibitory effects of Reptimed with respect to the topography
and depth of intravesical tumor involvement. In contrast, control, untreated
bladders revealed extensive exophytic tumors with deeply invasive transitional
cell carcinoma. CONCLUSIONS: These studies demonstrate the anti-tumor effect of
Reptimed and highlight its importance as a potential therapy for cancer.
PMID- 10769654
TI - In vitro growth of TS/A adenocarcinoma and of the gene transfected TS/A-IL4 line
on biological substrates.
AB - The growth capacity and adaptation of TS/A and TS/A-IL4 lines on laminin,
fibronectin, collagens I and IV and matrigel compared to plastics were studied by
flow cytometry. On plastic plates, TS/A-IL4 grows in vitro more slowly than the
TS/A line and shows a more differentiated phenotype. TS/A-IL4 cells loose the
capacity to bind lymphocytes and peroxidase positive cells obtained from mice
implanted with the same tumour. The ratio between fibroblast- and epithelial-like
cells of TS/A adenocarcinoma is subjected to marked modifications depending on
the substrate on which the two cell lines are grown. IL4 release per cell unit is
increased by collagen I as is the number of CD54 positive cells, suggesting that,
at least in part, the in vivo rejection of TS/A-IL4 tumor might be ascribed to
the stimulatory effect of the tissue on the IL4 release by tumor cells. The
overall result is that gene modified TS/A-IL4 line shows marked changes of
behaviour, most of them depending on the substrate on which tumor cells are
growing.
PMID- 10769655
TI - Fate of the antimetastatic ruthenium complex ImH [trans-RuCl4(DMSO)Im] after
acute i.v. treatment in mice.
AB - The content of ruthenium in blood and different organs of healthy CBA mice was
determined by AAS after single i.v. treatment of 200 mg kg-1 of NAMI-A, a new
antimetastatic ruthenium compound. Ruthenium concentration in blood falls 5 min
after i.v. treatment. In the kidney, ruthenium concentration is markedly higher
than in any other analysed tissue. No ruthenium was detected in brains.
Pharmacokinetic parameters for a mono- or a bi-compartment model are
identifiable: t1/2 is 10.45 h vs 12.02 (t1/2 alpha 0.023 h + t1/2 beta 12 h) with
Cltot of 1.60 ml*h-1 vs 1.59); Vd is 24.15 vs 27.48 ml and (model dependent) AUC
is 689 vs 694 mg*L-1*h. AUC(0-->infinity) calculated by noncompartmental method
(linear trapezoidal rule) is 719.77 mg*L-1*h. NAMI-A is rapidly cleared from the
blood compartment immediately after i.v. administration. Apparently, there is no
differential accumulation of ruthenium in the lungs which might account for a
selective antimetastatic effect caused by a cytotoxic concentration in this site,
nor in any other specific organ examined.
PMID- 10769656
TI - Correlation of chemosensitivity to anticancer drugs and telomere length,
telomerase activity and telomerase RNA expression in human ovarian cancer cells.
AB - BACKGROUND: We examined the correlations among telomere length (TRF), telomerase
activity (TA) and the steady-state level of telomerase RNA expression (hTR) of
human ovarian cancer cells with different phenotypes and investigated whether the
cells' sensitivities to anticancer agents correlate with TRF, TA or hTR.
MATERIALS AND METHODS: The TRF, TA and hTR of 11 human ovarian cancer cell lines
and 2 cisplatin-resistant ovarian cancer cell lines were determined by genomic
Southern blotting, a telomeric repeat amplification protocol and reverse
transcription-polymerase chain reaction. The chemosensitivities of the cell lines
to cisplatin (CDDP), paclitaxel (TAX), etoposide (ETO), CPT-11 (CPT),
cyclophosphamide (CYC), ifomide (IFO) and doxorubicin (DOX) were decided as IC50
values by calorimetric assay. RESULTS: All 11 cell lines presented shorter mean
TRFs (5.0 kb) than normal control tissue (8.0 kb); 10 cell lines presented a 3.2
fold higher mean TA than the control and all 11 cell lines expressed hTR.
Quantitatively, the steady-state levels of hTR correlated with the TRF (p <
0.05). Significant positive correlations between hTR and CDDP sensitivities (at
24 hours of exposure), ETO (72 hours), CPT (48 hours) and CYC/IFO (24-72 hours)
were observed. The same was true for TRF and the CDDP sensitivities (at 24
hours). TAX and DOX did not have any impact on these factors. The TRF, TA and hTR
values in the two CDDP-resistant cell lines were generally reduced, compared to
their parent cell lines. CONCLUSIONS: Alkylating agents (CDDP, CYC and IFO) and
topoisomerase inhibitors (ETO, CPT) may have the potential to influence the
structural alteration of hTRs and telomeres and thus, the down-regulation of the
TA in ovarian cancer cells.
PMID- 10769657
TI - Microsatellite instability in squamous cell carcinomas and dysplasias of the
esophagus.
AB - Microsatellite instability (MSI) caused by the defective functions of mismatch
repair genes plays an important role in the carcinogenesis of gastrointestinal
tumors. However, little is known about the role of MSI in esophageal
carcinogenesis. In the present study, we conducted microsatellite assays on 41
esophageal carcinomas and also on 44 dysplasias of the esophagus with 7 separate
microsatellite loci. MSI was detected in 17 cases (42%) among 41 esophageal
carcinomas. MSI negative cases revealed greater lymph node metastasis, metastasis
at a more advanced stage, a higher recurrence level and a poorer prognosis
(statistically not significant). In the analysis of dysplasias, MSI was detected
in 26 lesions (59%) among 44 lesions. Interestingly, MSI was detected in 21
lesions (78%) from the mutator phenotype dysplasias, but detected in only 5
lesions (29%) from the non-mutator phenotype cases. Although the significance of
MSI in esophageal carcinoma was not clear, these results indicate that MSI occurs
in the early stage of esophageal carcinogenesis.
PMID- 10769658
TI - The effects of Brassica oleraceae var capitata on epidermal glutathione and lipid
peroxides in DMBA-initiated-TPA-promoted mice.
AB - BACKGROUND: The objective of the present study was to determine if modulation of
GSH-dependent antioxidant protective system by Brassica oleraceae var capitata
might inhibit the molecular mechanism of skin tumor promotion. MATERIALS AND
METHODS: In a two stages skin carcinogenesis model, the protocol used included a
single topical application of 200 nmol of the initiator 7,12-dimethyl-benz(a)
anthracene (DMBA) to the backs of mice, followed 1 week later by promotion with
10 nmol of 12-O-tetradecanoyl-phorbol-13 acetate (TPA) twice weekly for 30 weeks.
In addition to this regimen, 0.1 g/L brassica extract was added water week prior
to the initiating dose of DMBA in the treatment group. Tissue glutathione (GSH)
contents and levels of lipid peroxidation products (measured as thiobarbituric
acid (TBA)-reactive substances) were quantitated in the skin tumors generated by
the initiation-promotion protocol. RESULTS: It was observed that the tumor
incidence and tumor multiplicity in the treatment group was highly significantly
low compared to the first group of mice (p < 0.001 and p < 0.001, respectively).
In the treatment group, GSH content in the papillomas was higher than in the non
involved skin surrounding the papillomas. CONCLUSIONS: We suggest that the
anticarcinogenicity of Brassica may be linked to its ability to facilitate or
enhance the activity of the natural GSH-dependent antioxidant protective system
of the epidermal cells during the later stages of skin tumor promotion.
PMID- 10769659
TI - Grape-derived chemopreventive agent resveratrol decreases prostate-specific
antigen (PSA) expression in LNCaP cells by an androgen receptor (AR)-independent
mechanism.
AB - Trans-resveratrol, a polyphenol present in red wines and various human foods,
inhibited the proliferation of LNCaP cells and the expression of a prostate
specific gene, PSA. A 4-day treatment with resveratrol reduced the levels of
intracellular and secreted PSA by approximately 80%, as compared to controls. To
test whether this decrease was coordinated with changes in AR expression, levels
of AR were assayed by Western blot analysis, using the cognate antibody, or by
binding with the radioactive ligand methyltrienolone [3H]R1881. With either
assay, little or no change in AR expression could be detected between control and
resveratrol-treated cells. Thus, it would appear that the prostate tumor marker
PSA is down regulated by resveratrol, by a mechanism independent of changes in
AR.
PMID- 10769660
TI - Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in
an experimental murine colon adenocarcinoma.
AB - The di-sodium phosphate pro-drug of combretastatin-A4(combA-4P) is undergoing
Phase 1 clinical trial in the USA and UK. Its mechanism of action is thought to
be related to tubulin-binding properties that result in rapid, tumour endothelial
cell damage, neovascular shutdown and subsequent haemorrhagic necrosis. Drugs
that work by this mechanism are unlikely to eradicate the tumour as a single
agent but should potentiate standard chemotherapy. This study demonstrates that
extensive necrosis occurred in a treated refractory murine colon adenocarcinoma
but the damage was not accompanied by any measurable effect on tumour growth.
Tumours continued to grow from the viable rim that remained. Combination
chemotherapy with 5-fluorouracil (5-FU) resulted in significant (p < 0.01) anti
tumour effects. Measurement of 5-FU concentrations suggested that this was true
synergism and not simply a pharmacokinetic interaction due to the vascular
mechanism of combA-4P. The study suggests that if an antivascular mechanism can
be demonstrated in humans, combination chemotherapy should be rapidly assessed in
a clinical setting.
PMID- 10769661
TI - Sensitization and caffeine potentiation of cisplatin cytotoxicity resulting from
introduction of wild-type p53 gene in human osteosarcoma.
AB - The present study was performed to investigate whether the introduction of a wild
type p53 gene into human osteosarcoma cells could alter the growth rate and
enhance the cytocidal effect of cisplatin (CDDP) and the synergistic antitumor
effect of caffeine. The lipofection method was used to transfect a wild-type p53
expression plasmid into the human osteosarcoma cell line, Saos2, which has both
p53 alleles deleted. The transfected cells, Saos2/p53, had a reduced growth rate
compared with the parental cell line. The colorimetric WST-1 assay demonstrated
that Saos2/p53 cells were twice as sensitive to CDDP alone at a 50% inhibition
concentration than the parental Saos2 cells. Caffeine significantly potentiated
the cytocidal effect of CDDP in the Saos2/p53 cells. Furthermore, the TUNEL assay
revealed that following treatment both with CDDP alone and with CDDP combined
with caffeine, a higher percentage of the Saos2/p53 cells underwent apoptosis
than did the parental Saos2 cells. Therefore the cytocidal effect of CDDP and the
synergistic antitumor effect of caffeine are enhanced by the introduction of a
wild-type p53 gene into a human osteosarcoma cell line null for p53. This raises
the possibility that gene therapy using the p53 gene may prove efficatious for
human osteosarcomas lacking p53 and which are resistant to standard chemotherapy.
PMID- 10769662
TI - Induction of apoptosis by dopamine in human oral tumor cell lines.
AB - Dopamine dose-dependently reduced the viable cell number of both human salivary
gland tumor HSG and oral squamous cell carcinoma HSC-2, HSC-4, and NA cells.
CoCl2 significantly reduced both the cytotoxic activity and radical intensity of
dopamine (determined by ESR spectroscopy). Dopamine produced DNA fragments
(demonstrated by TUNEL method) and induced degradation of cytokeratin by
activated caspase in HSG cells (detected by an immunocytochemical method, using a
specific M30 monoclonal antibody). FACS analysis demonstrated that dopamine
induced DNA fragmentation, a biochemical hallmark of apoptosis, in human
promyelocytic leukemia HL-60 cells. The addition of catalase did not prevent the
apoptosis-inducing activity of dopamine, reducing the possibility of the
involvement of H2O2 for dopamine-induced apoptosis. Dopamine transiently induced
p38 mitogen-activated protein kinase (MAP kinase) phosphorylation. However, an
inhibitor of p38 MAP kinase phosphorylation, SB203680, failed to inhibit the
dopamine-induced apoptosis. These data suggest that p38 phosphorylation at an
early stage may not be a causative event for apoptosis.
PMID- 10769663
TI - Uptake of 14C- and 11C-labeled glutamate, glutamine and aspartate in vitro and in
vivo.
AB - To explore their potential use as in vivo tracers, the uptake of the amino acids
glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in
tumor cell aggregates, in vivo in rats and a few pilot studies with positron
emission tomography (PET) in patients. The uptake in aggregates increased
linearly with time, and was competitively inhibited by the same amino acids. The
uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not
by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L
norleucine (a glutamine analogue) and Substance P had different effect on the
uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was
evaluated with protein separation and with HPLC. The in vivo distribution in rats
showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and
kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas
had the highest uptake followed by kidney with 11C-glutamate, and followed by
spleen with 11C-aspartate. A primary pancreas tumour and metastases in liver were
difficult to identify except in one case.
PMID- 10769664
TI - Metallothionein immunoreactivity in head and neck carcinomas; special reference
to clinical behaviors and chemotherapy responses.
AB - Metallothionein (MT), has selectively binding affinity for heavy metal ions and
over expression of MT has a potential against resistance for CDDP anticancer
agents and radiation treatment. The role of MT immunoreactivity of squamous cell
carcinoma in oral and pharyngeal regions (n = 28) and in the maxillary sinus
region (n = 3) was evaluated for distribution patterns of MT and
clinicopathologic behaviors. All the sections were examined in 400x and counted
for MT positive cells over 5 fields of tumor growing foci. MT immunoreactivity
was expressed in both tumor cell cytoplasm and nuclei, and showed heterogeneous
localization in tumor epithelial cells and in the stroma. Immunohistochemical
localizations showed mosaic patterns as the highest MT staining tumor cells
intermingled with negative or low staining cells in neoplastic foci, and in
stromal cells. Histiocytic and fibrocytic cells in both peripheral and
interstitial stromas were also not stained homogeneously. In oral and pharyngeal
carcinomas (n = 28), MT positive cell index in treated cases (n = 11) was 17.85%
and that in non treated tumors (n = 17) was 25.19%. In maxillary sinus carcinomas
(n = 3), MT positive index was 4.56% and showed lowers levels as compacted to
other SCC sites. Among histological grading in oral and pharyngeal SCCs, MT index
of well differentiated SCC (n = 9) was 17.04%, of moderately differentiated SCC
(n = 13) 21.92% and poorly differentiated SCC (n = 6) was 31.06%. There is no
significant correlation of positive index of metallothionein between treated and
untreated samples taken in oral and pharyngeal SCCs.
PMID- 10769665
TI - Changes in intracellular concentrations of amino acids and polyamines during the
apoptosis of HL-60 cells.
AB - Possible changes in the intracellular concentrations of amino acids and
polyamines were investigated during the apoptosis of human promyelocytic leukemic
HL-60 cells. Treatment of HL-60 cells with sodium 5,6-benzylidene-L-ascorbate
(SBA) or sodium ascorbate induced apoptotic cell death characterized by chromatin
condensation, nuclear fragmentation, loss of microvilli, and production of
numerous vacuoles and apoptotic bodies. The apoptosis was accompanied by a
significant increase in the intracellular concentration of almost all neutral and
basic amino acids (regardless of their polarity). On the other hand, the
concentration of glutamic acid, the most abundant amino acid in the cells, was
significantly reduced. These data suggest the reduced amino acid utilization and
possible membrane impairment, especially in SBA-treated cells. Among three major
polyamines, the intracellular concentration of putrescine rapidly declined,
whereas that of spermidine and spermine was almost unchanged during apoptosis.
Conversely, the concentration of putrescine, but not that of spermidine and
spermine, was significantly increased during the chemically-induced
carcinogenesis of mouse liver tissue. The present study demonstrates that the
putrescine level is the most sensitive to the proliferation capability of the
cells, among three polyamines, and provides an early marker for apoptosis and
proliferation.
PMID- 10769666
TI - Induction of apoptosis by flavones, flavonols (3-hydroxyflavones) and isoprenoid
substituted flavonoids in human oral tumor cell lines.
AB - Various flavones, flavonols (3-hydroxyflavones) and isoprenoid-substituted
flavones (flavonols) were investigated for their cytotoxic activity. Most of
these compounds were more cytotoxic against human oral squamous cell carcinoma
and salivary gland tumor cell lines than human gingival fibroblasts. The
cytotoxic activity of flavonoids was generally higher than that of tannin-related
compounds. Flavonoids induced apoptotic cell death characterized by DNA
fragmentation (as identified by TUNEL method) and activation of caspase(s) (as
identified by degradation products of cytokeratin 18 with M30 monoclonal
antibody). ESR spectroscopy revealed that higher concentrations of flavonoids
produced radicals under alkaline conditions. However, not all of them enhanced
the radical intensity of sodium ascorbate, suggesting that the redox potential of
flavonoids differs considerably from samples to samples. Catalase failed to
eliminate the cytotoxic activity of flavonoids, reducing the possibility of the
involvement of hydrogen peroxide for the cytotoxicity induction by them.
PMID- 10769667
TI - Polyadenylation signal facilitates the expression of foreign gene that is driven
by an internal promoter located in the reverse orientation to long terminal
repeat of retrovirus.
AB - We examined whether the presence of a polyadenylation [poly(A)] signal in a
retrovirus vector could affect the expression level of exogenous gene(s) that was
controlled by an internal promoter. Three suicide genes were placed under a
promoter of the human midkine gene, whose expression is elevated in lung cancer
cells. Orientation of the internal transcriptional unit was designed to be
opposite to the viral long terminal repeat. Expression of each suicide gene was
greater in ecotropic packaging cells transfected with a retrovirus vector without
a poly(A) signal than in those with a poly(A)-containing vector. Sensitivity to
ganciclovir, a prodrug that becomes an active drug by herpes simplex virus
thymidine kinase, was significantly improved in retrovirally transduced lung
cancer cells compared with wild-type cells. However, the sensitivity was much
greater in the cells transduced with poly(A)-containing vector than in those with
poly(A)-deleted construct. The presence of a poly(A) signal downstream of
exogenous gene(s) therefore favors the expression of foreign gene(s) driven by an
internal promoter.
PMID- 10769668
TI - Peritoneal macrophages from 17 alpha-ethinylestradiol-treated NMRI mice secrete
transformation-specific low molecular weight proteins.
AB - Analysis of protein secretion was performed for a macrophage-like cell line,
which was established from the peritoneal cells of NMRI mice treated with 17
alpha-ethinylestradiol. The protein secretion pattern was investigated by
computerized analysis of high resolution two-dimensional gel electrophoresis (2-D
PAGE) and compared to that of control macrophages, intraperitoneally activated by
bacterial lipopolysaccharide. The transformed cells encode a number of low
molecular weight proteins (10-20 kDa), which were not observed in control cells
under identical experimental conditions. In conclusion the transformation of
peritoneal macrophages by 17 alpha-ethinylestradiol leads to an upregulation of
polypeptides, in particular of low molecular weight proteins. A high similarity
between the induced low molecular weight protein secretion by macrophages of 17
alpha-ethinylestradiol-treated and that of 2,3,7,8-tetrabromodibenzo-p-dioxin
treated mice was found.
PMID- 10769669
TI - A novel polypeptide p10 expressed in tumor-promoter-treated murine epidermis and
in untreated neonatal murine epidermis.
AB - 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) has been shown to induce a broad
variety of morphological and metabolic changes in mouse skin. These include gross
changes in cell growth as well as subtle changes regarding gene expression.
Changes in the induction of specific proteins have been described, but it is not
yet clear, if there exists a strict causal correlation between the induction of
expression of specific proteins and the phenomenon of tumor promotion. At least
some of these proteins might also be correlated with an accompanying
hyperproliferative effect. This has been shown for protein p10, a 10 kDa protein
not found in untreated adult mouse epidermis. The expression of this protein can
be induced de novo after the topical administration of TPA. It is also shown,
that p10 is expressed in untreated neonatal murine epidermis. Due to the
induction of this protein by irritation, hyperproliferation-causing tumor
promoters and due to the observable abundance in neonatal epidermis, this protein
seems not strictly related to tumor promotion, but rather to proliferation and
differentiation.
PMID- 10769670
TI - Telomerase assay as a possible predictor of the response to anticancer
chemotherapy.
AB - BACKGROUND: The correlation between telomerase activity and antitumor effects was
investigated in cell lines of human gastric (MKN-28, MKN-45, and MKN-74) and
breast (T-47D, MCF-7, ZR75-1) cancers to evaluate the possibility of utilizing
this enzyme to predict tumor response to chemotherapy. MATERIALS AND METHODS:
After culture with various concentrations of 5-fluorouracil (5-FU) or doxorubicin
(DOX) for 3 days, cell viability (trypan blue exclusion), cell cycle distribution
(flow cytometry), and telomerase (TRAP-EZE) were measured. RESULTS: Telomerase
activity correlated significantly with the number of viable cells. After drug
exposure, this activity decreased rapidly in a dose-dependent fashion in most
cell lines. There was no correlation between telomerase activity and the
distribution of cells in the cell cycle. CONCLUSIONS: As the assay for telomerase
activity is extremely sensitive and is virtually specific to cancer cells, this
method may prove useful for the sensitivity testing of small specimens of human
tumors.
PMID- 10769671
TI - Expression of nitric oxide synthase isozymes (NOS I-III) by immunohistochemistry
and DNA in situ hybridization. Correlation with macrophage presence, vascular
endothelial growth factor (VEGF) and oedema volumetric data in 220 glioblastomas.
AB - BACKGROUND: Nitric oxide (NO) is synthesized from arginine by three different
isozymes of nitric oxide synthase (NOS I-III). NO has been identified as a
powerful metabolite of vascular smooth muscle cell function, cerebral blood
circulation and oedema induction. NOS induction by different cytokines has been
shown previously in glioblastoma cell cultures and NOS III expression due to
astrocytoma grading has been shown in several tumors recently. The aim of the
present study was to study the coexpression of NOS I-III, macrophage and
capillary presence with VEGF, EGF and their receptors and to investigate a
possible mechanism in peritumoral oedema generation. MATERIALS AND METHODS: We
have investigated the expression (4-grade values, blinded assay by two observers)
of NOS I-III together with those of VEGF, VEGF- R (Flt-1), EGF-R1, von-Willebrand
factor (VWF) and a pan-macrophage marker (Ki-M1P) immunohistochemically in tumor
specimens from 220 patients and performed tumor volume morphometry by image
analysis in a subgroup of 32 cases to test for any correlation with the
peritumoral oedema volumes. Inducible NOS II was further investigated by in situ
labelling with a DNA oligonucleotide probe cocktail. RESULTS: All of the
specimens revealed some NOS expression, NOS II was expressed in macrophages,
microglia and endothelial cells, NOS III and I was localized in glioblastoma
cells, NOS III in endothelial cells as well. The highest degrees of expression
were observed in 46% (NOS I), 22% (NOS II) and 75% (NOS III) of all specimens.
Inducible NOS II in any expression grade was observed in 47.5% of the specimens.
Significant correlations were observed for the expression of the macrophage
marker Ki-M1P with NOS II (p = 0.024), endothelial NOS III with NOS I (p =
0.0003), VEGF-R1 with NOS II (p = 0.0008) and NOS III (p = 0.011) The oedema
volumes could not be correlated significantly with NOS or VEGF-R1 expression
values but with those of endothelial staining (p = 0.02). We observed a trend
towards higher Ki-M1P expression values together with higher oedema volume
extensions. In situ hybridization demonstrated reaction products in endothelial
and perivascular regions and sometimes scattered throughout the specimens
revealing the labelling of macrophages. CONCLUSIONS: The main source of NO is NOS
I and NOS III. The latter is located in endothelial cells and glioblastoma cells.
The expression of NOS II in glioblastomas is restricted to infiltrating
macrophages. NOS II and III expressions were observed significantly together with
that of VEGF-R1. Neither NOS I-III nor VEGF-R expression could be correlated with
the extension of the peritumoral oedema.
PMID- 10769673
TI - Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid
diseases.
AB - BACKGROUND: Immunohistochemical expression of the transcription factor Pax-8 in
human thyroid diseases has never been investigated. The relationship between Pax
8, bcl-2 and p53 in thyroid neoplasms is also matter of interest. MATERIALS AND
METHODS: Seventy-three thyroid tissue samples were evaluated for the expression
of Pax-8, p53 and bcl-2 using the immunoperoxidase technique. The series included
11 follicular adenomas, 11 goitres, 23 papillary carcinomas, 16 follicular
carcinomas, 6 undifferentiated carcinomas and 6 medullary carcinomas. RESULTS:
The percentage of Pax-8 positive cells ranged from 14.9 to 27.1% and 10.1 to 39%
in goitres and follicular adenomas, respectively. Among differentiated
carcinomas, follicular histotype showed a Pax-8 immunoreactivity ranging from 0
to 26.5% of the neoplastic cells whereas in papillary carcinomas the percentage
of positive cells ranged from 0 to 16.8%. None out of the six undifferentiated
carcinomas showed Pax-8 immunoreactivity. The same negative pattern was noticed
in medullary carcinomas. A statistically significant difference in Pax-8
expression was observed between non-malignant and malignant diseases (p <
0.0001). A different reactivity for Pax-8 was also noticed between differentiated
carcinomas and undifferentiated carcinomas (p = 0.07). None of the benign tissues
stained for p53 whereas among malignant specimens different percentages of p53
expression were observed with all undifferentiated carcinomas expressing the
highest positivity (range 24.1-88.6%). Finally, when a combined analysis of bcl-2
and Pax-8 reactivity was carried out, some carcinomas proved to be Pax-8 negative
and bcl-2 positive whereas others showed a similar immunoreactive pattern for
both Pax-8 and bcl-2. CONCLUSIONS: Pax-8 is mainly expressed in benign rather
than in malignant thyroid diseases and, among neoplasms, differentiated
carcinomas express Pax-8 more frequently than undifferentiated carcinomas. An
inverse pattern was observed for p53. Bcl-2 seems to be partially related to Pax
8 expression. However, a Pax-8 independent bcl-2 expression is also evident.
PMID- 10769672
TI - Oedema extension in cerebral metastasis and correlation with the expression of
nitric oxide synthase isozymes (NOS I-III).
AB - BACKGROUND: The development of a peritumoral oedema is a common radiological sign
in preoperative CT- and MRI scans of patients with cerebral metastasis. Large
tumours can be accompanied by a marginally extended oedema and vice versa.
Several cytokines (VEGF) have been identified as mediators of vascular induction
and permeability. Transmitters such as nitric oxide (NO) have been identified as
specific mediators of vascular dilation and tumour blood flow in primary brain
tumours in which different NOS isozymes (NOS I and III) are induced as a result
of the latent hypoxic metabolic scenery. Other authors have considered NO as an
endothelial stabilising metabolite. Inducible NOS II is expressed by microglia
and macrophages invading during tumour growth. At present, no data exist on NO
synthesising enzymes in cerebral metastasis. MATERIALS AND PATIENTS: Cryosections
(N = 96) of metastatic resections were investigated immunohistologically using a
4-step grading evaluation for the expression of NOS I-III, VEGF-receptor FLT-1, a
pan-macrophage marker Ki-M1P, and capillary vessel presence by endothelial Von
Willebrand-Factor staining. The tumour and oedema extension was measured in
preoperative MRI scans by an image processing device (Kontron) and calculated for
the ratios of oedema volumes to total tumour volumes. The data were analysed
statistically (Pearson Chi2 and Kruskal-Wallis analysis of variances) and
correlated with the clinical data. Inducible NOS II was further investigated by
in situ hybridization with a (4x30 mer) DNA oligoprobe cocktail. RESULTS: Between
1987 and 1996 289 patients in our department suffered from a metastatic disease
in the brain or spinal cord. In 96 cases resected tumour material was processed
for the immunohistological investigation. The age distribution ranged from 14 to
85 years with a median age of 58 years. The mean duration of symptoms before
diagnosis was estimated as 53 days. The expression of NO synthase was frequently
observed. NOS I was detected in 83.6%, gradings 2 and 3 in 40.5% of them. NOS
III, the endothelial isoform, was observed in 39.4% (gradings 2 and 3), inducible
NOS II in 29.4% (grading 2 and 3) of the specimens. The VEGF receptor FLT-1 could
be detected in 70% of them, 24% in higher expression 2 and 3. The pan macrophage
marker Ki-M1P was observed in 72% of all cases. Fifty seven percent of the
specimens exhibited strong labelling with antibodies against VWF. Coexpressions
were statistically significant for the VEGF receptor and NOS I-III (p < 0.01), Ki
M1P and NOS I and II (p < 0.05). A negative correlation was detected for the
oedema index (oedema volume/total volume) and the labelling data for NOS III (r =
-0.44, p = 0.13) and VEGF-R (r = -0.42, p = 0.022). No correlation existed for Ki
M1P, VWF and NOS I. CONCLUSIONS: The objective of the study was to investigate
oedema morphometry, expression of NOS I-III and VEGF-R, presence of capillary
vessels and macrophages in cerebral metastasis. A further aim was to investigate
a putative oedema induction by NO producing isozymes. Nitric oxide synthase
expression was statistically significantly correlated with the expression of the
VEGF receptor and the presence of macrophages and microglia. There was a negative
correlation between oedema extension and the presence of NOS III and VEGF-R. The
results seem to indicate a specific oedema modulating role of NO in cerebral
metastasis.
PMID- 10769674
TI - TNF alpha, IL-1 beta and IL-6 production by peripheral blood monocytes in
patients with renal cell carcinoma.
AB - Renal cell carcinoma (RCC) has been shown to be immunologically more labile than
other types of cancer. In this study, we examined tumor necrosis factor alpha
(TNF alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) production
of peripheral blood monocytes in 38 RCC patients. Monocytes were isolated from
peripheral blood mononuclear cells by adherence to a plastic dish and cultured
with lipopolysaccharide for 24 hours. The culture supernatant was obtained, and
the production of TNF alpha, IL-1 beta and IL-6 was measured by ELISA. As a
result, TNF alpha and IL-1 beta production was significantly higher in the high
stage patients compared to the control subjects and low stage patients. When the
patients were divided according to serum C-reactive protein (CRP), TNF alpha, IL
1 beta and IL-6 production was significantly higher in the CRP-positive patients
compared to the control subjects and the CRP-negative patients. Overexpression of
these cytokines may therefore induce a hypermetabolic status that may be a cause
of malnutrition and cancer cachexia.
PMID- 10769675
TI - Expression of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid
receptor in primary lung carcinomas.
AB - We examined the immunohistochemical distribution of 11 beta-hydroxysteroid
dehydrogenase type 2 (11 beta HSD2) and mineralocorticoid receptor (MR) in 63
primary lung carcinomas. Immunoreactivity of 11 beta HSD2 and MR was detected in
37 cases and in 32 cases of 42 adenocarcinomas, respectively. There was a
significant correlation between 11 beta HSD2 and MR immunoreactivity. In three
adenosquamous carcinomas, both 11 beta HSD2 and MR were detected only in
adenocarcinomatous components. Neither 15 squamous cell carcinomas, 2 small cell
carcinomas nor 1 large cell carcinoma expressed 11 beta HSD2 or MR. In papillary
and acinar adenocarcinomas, both 11 beta HSD2 and MR immunoreactivity was
significantly correlated with the grade of histological differentiation. The
patterns of 11 beta HSD2 and MR expression in 10 lymph-node metastases were
similar to those determined in the primary lesions. These data suggest that the
patterns of 11 beta HSD2 and MR expression may reflect cellular origin and
differentiation status of primary lung adenocarcinomas and serve as a new useful
marker of differentiation.
PMID- 10769676
TI - Exogenous mutant p53 DNA enhanced cisplatin-induced apoptosis in TSGH-8301 human
bladder cancer cells.
AB - BACKGROUND: The influence of tumor suppressor gene p53 on the apoptosis of
bladder cancer cells is not completely understood. In this study, the requirement
for p53 in the cisplatin-induced apoptosis of human bladder cancer cells TSGH
8301 was investigated. MATERIALS AND METHODS: TSGH-8301 cells, which contain
endogenous wild type p53 genes, were transfected with expression vectors
containing p53 cDNA mutated at codon 173. Stable mutant p53 transfectant clones
were confirmed by Southern blotting and Western blotting. The cellular response
to cisplatin was determined on the basis of (a) cells viability, (b) apoptotic
DNA fragmentation, and (c) nuclear condensation. RESULTS: Cells containing an
exogenous mutant p53 sequence had increased sensitivity to cisplatin by
undergoing apoptosis compared with parental TSGH8301 cells. In contrast, no
difference was observed in those clones with rearranged or undetectable exogenous
mutant p53 cDNA. However, analysis of p53 mRNA with RT-PCR sequencing indicated
that none of the transfectant clones expressed exogenous mutant p53 mRNA.
CONCLUSION: The transfectants had lost the expression of mutant p53 during
selection; however, they could still enhance the expression of wild-type p53,
which conferred sensitivity to cisplatin. IMPLICATION: Transient expression of
mutant p53 protein in TSGH8301 cells may induce an irreversibly stabilization of
p53 and increase the steady state of p53 expression.
PMID- 10769677
TI - Expression and clinical significance of the G1-S modulators in carcinoma of the
extrahepatic bile duct.
AB - Expression of cell cycle modulators at the G1-S boundary, the retinoblastoma gene
product (pRb), p21, p16, p27, p53, cyclin D1 as well as Ki-67 was investigated
with 39 extrahepatic bile duct carcinomas (BDC). The Ki-67 labeling index (LI)
was higher in cases with poor differentiation, lymph node metastasis and stage
III or IV. Cyclin D1 overexpression was seen in 14 cases (35.8%). This phenomenon
could be observed more frequently in cases of hilar carcinoma and with poor
differentiation, perineural invasion, lymphatic invasion and lymph node
metastasis. Furthermore, Ki-67 LI was higher in cyclin D1 overexpressing cases.
p27 expression showed inverse relationships with Ki-67 LI, lymph node metastasis
and aberrant p53 expression. Although p16 and p21 expression significantly
correlated with lymph node metastasis and cyclin D1 overexpression, respectively,
they were not related to Ki-67 LI. pRb expression was observed in all cases.
Although the LI was lower in carcinoma of upper and middle bile ducts, no
correlation was established between pRb expression and other clinicopathological
parameters including Ki-67 LI. Aberrant p53 expression was observed in 13 cases
(33.3%) and Ki-67 LI was significantly higher in these cases. These findings
suggest that p27 and cyclin D1 strongly correlate with BDC proliferation and
reflect the biological aggressiveness of this carcinoma.
PMID- 10769678
TI - An immunohistochemical study of p16, pRb, p21 and p53 proteins in human
esophageal cancers.
AB - BACKGROUND: Cell cycle-associated proteins, p16, pRb, p21 and p53 are important
in regulating the G1-S checkpoint in the cell cycle, and their functional
alterations play key roles in carcinogenesis and cell proliferation. MATERIALS
AND METHODS: We immunohistochemically examined the expression of p16, pRb, p21
and p53 proteins by using surgically resected tissues from 35 patients with
primary esophageal cancers. RESULTS: In 35 esophageal cancers, the expressions of
p16, pRb, p21 and p53 proteins were detectable in 4(11.4%), 25(71.4%), 11(31.4%)
and 20(57.1%) respectively. Interestingly, 24 of 25 pRb positive cancers (96.0%)
had negative p16, whereas three of ten pRb-negative cancers (30.0%) had high
levels of p16 (p < 0.05). In 11 cases of p21 positive immunostaining, there was
lymph node metastasis (pN1) in 9 (81.8%). CONCLUSIONS: These results suggest that
abnormalities of p16 protein may be closely associated with the carcinogenesis or
cell proliferation of esophageal cancers.
PMID- 10769679
TI - The relationship between p53 status and anticancer drugs-induced apoptosis in
nine human bladder cancer cell lines.
AB - To study the relationship between the p53 status and chemotherapeutic drug
induced apoptosis, we have assessed the extent of apoptosis in nine bladder
cancer cell lines during the treatment of adriamycin, cisplatin and methotrexate.
Apoptosis was measured by the DNA fragmentation and merocyanine 540 (MC540)
staining methods. Among the nine human bladder cancer cell lines, both wt-p53-
and mut-p53-expressing cell lines (p53+/-) underwent apoptosis in response to
anticancer drugs treatment. While the J82 (p53-/-) and TCCSUP (p53+/+) cell lines
showed little or no apoptosis to these agents. Similar results were obtained when
subjected to low doses of anticancer drug treatment. Interestingly, our results
suggested that bladder cancer cells heterozygous for mutant p53 (+/-) seem to be
most susceptible to chemotherapeutic drug. We therefore postulate that p53
mutations do not always provide a selective advantage in the development of
chemoresistance, at least in bladderer tumor cell lines.
PMID- 10769680
TI - Anti-tumor effect of N-beta-alanyl-5-S-glutathionyldihydroxyphenylalanine (5-S
GAD), a novel anti-bacterial substance from an insect.
AB - PURPOSE: We examined the anti-tumor effect of 5-S-GAD, a novel potent inhibitor
of protein tyrosine kinases, isolated from the flesh fly in order to investigate
the potential use of this compound as an anti-tumor agent. METHODS: In vitro
growth inhibition was evaluated using the alamarBlue assay kit. In vivo anti
tumor activity was evaluated by i.p. treatment of 5-S-GAD against xenografted
melanoma (LOX-IMV1) and breast carcinoma (MDA-MB-435S) in nude mice. RESULTS: Of
38 human cancer cell lines examined, this compound showed significant
cytotoxicity toward two estrogen-negative breast carcinomas (MDA-MB-231 and MDA
MB-435S) and one malignant melanoma (LOX-IMV1) in vitro, indicating that it
exhibits selective cytotoxicity to certain tumor cell lines. In accordance with
its in vitro anti-tumor effect, 5-S-GAD was shown to significantly repress the
growth of sensitive tumor cells in nude mice. CONCLUSION: These results indicate
that 5-S-GAD is potentially useful to treat certain human cancer.
PMID- 10769681
TI - Kinetics of cytokine gene expression during the in vitro CTL induction against a
murine nonimmunogenic tumor.
AB - BACKGROUND: The study of the local environment around tumors, including cellular
and endogenous cytokine kinetics may improve our understanding of the biological
process occurring during the CTL induction. MATERIALS AND METHODS: The expression
kinetics of ten cytokine genes and immune cell subsets were examined by a RT-PCR
and immunohistochemistry using a nonimmunogenic murine tumor and its immunogenic
variant (A7). RESULTS: In a mixed lymphocyte-parent tumor cell culture (MLTC)
using in vivo A7-immunized spleen cells, where CTL induction was confirmed on day
5 of cultivation, IL-6 gene expression was promptly activated at 12 h, IL-2 and
IL-4 gene expression was prominently up-regulated on days 1 and 2, and then IL-10
and TGF-beta gene expression was down-regulated from day 2 onward. In contrast,
in a MLTC using non-immunized spleen cells (a CTL non-induction model), no
prominent upregulation of the IL-6, IL-2 or IL-4 gene was detected, and
expression of the IL-10 and TGF-beta genes increased steadily. Although numerous
dendritic cells were observed in the A7 immunized spleen tissue, lower numbers of
dendritic cells were evident in the non-immunized spleen tissue. CONCLUSIONS: A
cellular environment that includes the presence of dendritic cells and a cytokine
environment that involves the timely production of IL-6, IL-2, and IL-4, and
subsequent inhibition of the immunosuppressive cytokines IL-10 and TGF-beta,
appear to play an important role in induction of CTL in this model.
PMID- 10769682
TI - 3,5-diacetyl-1,4-dihydropyridines: synthesis and MDR reversal in tumor cells.
AB - Eleven 4-phenyl-3,5-diacetyl-1,4-dihydropyridines (AcDHPs) [G1-11] substituted at
the phenyl ring were synthesized and compared for their cytotoxic activity and
multidrug resistance (MDR)-reversing activity in in vitro assay systems. Among
them, compound [G7] showed the highest cytotoxic activity against human
promyelocytic leukemia HL-60 and human squamous cell carcinoma HSC-2 cells.
However, no compounds tested produced radicals at pH 7.4-12.5. The activity of P
glycoprotein (Pgp) responsible for MDR in tumor cells was reduced by compounds
[G2, 3, 6, 5, 8, 1, 11], verapamil [VP] and nifedipine [NP]. However, compounds
[G4, 7, 10] were hardly active while G9 did not show a MDR reversing effect at
2.0-20.0 micrograms/mL. These data show a relationship between chemical
structures and MDR-reversing effect on tumor cells.
PMID- 10769684
TI - Response of the spleen of Balb/c and p53-transgenic mice to low doses of
carcinogen and to polyclonal antibodies generated against the soluble 53 kDa
protein.
AB - BACKGROUND: We have previously reported that p53-transgenic mice are highly
sensitive to low doses of a carcinogen and to vaccination with soluble 53 kDa
antibodies, compared to normal mice. The splenic manifestation of this strain
dependent hypersensitivity was investigated immunohistochemically and
morphometrically. METHODS: The spleen was obtained from Balb/c and human p53
promoter-CAT transgenic mice. Mice had either been treated with the carcinogen
dimethylhydrazine (DMH), vaccinated before DMH treatment with polyclonal IgG
generated against the soluble 53 kDa protein, or left untreated. RESULTS:
Significant differences in the splenic structures were found between the strains
compared, including the area occupied by the white and red pulps, the
periarterial lymphoid sheath (PALS) and the marginal zone, and in the number of
lymphoblasts and lymphocytes. Exposure to DMH stimulated the immune response, but
in transgenic mice the number of B and T lymphocytes and especially helper T
lymphocytes was significantly lower than in Balb/c mice. Vaccination followed by
DMH injections did not improve the insufficiency of the immune response in
transgenic mice. In transgenic mice, the number of B lymphocytes in follicles was
almost half and the total number of cells in PALS and the number of T lymphocytes
were only 71% and 60% respectively in BALB/c mice. In the marginal zone,
macrophages proliferated as lymphocytes decreased. CONCLUSIONS: Insufficiency of
the immune system after exposure to a carcinogen is more pronounced in transgenic
mice, and is mainly related to the B-cell system. It may stem from defects in B
lymphocytes or from inherent differences in their maturation and regulation. The
increase in the number of macrophages, dendritic cells and neutrophils
illustrates the compensatory processes that can remedy this developing immune
insufficiency.
PMID- 10769683
TI - Metallothionein expression in transplantable mouse mammary tumors.
AB - BACKGROUND: The metal binding protein, metallothionein (MT) is involved in
various physiological processes. In various human tumors, moreover, MT is
reported to play an important role in carcinogenesis. MATERIALS AND METHODS: MT
expression was investigated immunohistochemically and chromatographically in a
transplantable pregnancy-dependent mouse mammary tumor (TPDMT-4) and related
autonomous tumor sublines (T4-OI320 and -OI320CY). RESULTS: All tumor lines
showed MT expression in the nucleus and/or cytoplasm of tumor cells. However,
adenoacanthomatous T4-OI320 whose structure was different histopathologically
from the remaining adenocarcinomas showed over-expression of MT in the basal
layer of squamous metaplastic nodules. Cell proliferation activity estimated by
the BrdU labeling method (BrdU index) was highest in the squamous nodules and
correlated with the degree of MT expression (r = 0.96). By contrast, the BrdU
index in T4-OI320CY was inversely correlated with the MT index (r = -0.91).
CONCLUSIONS: The present investigation suggests expression of isotype MT in the
transplantable mouse mammary tumors which may be involved in the carcinogenesis.
PMID- 10769685
TI - Potentiated antitumor effects of interleukin 12 and matrix metalloproteinase
inhibitor batimastat against B16F10 melanoma in mice.
AB - The application of antiangiogenic agents in cancer therapy has been studied
extensively. Combination of agents with antiangiogenic properties could possibly
enhance antitumor effects. Interleukin 12 is a cytokine with potent antitumor
activity mediated also via antiangiogenic mechanisms. These effects are
attributed to IFN-gamma production stimulated by IL-12. Since IFN-gamma has been
reported to augment antitumor effects when combined with one of the
metalloproteinase inhibitors--batimastat (BB-94), we have examined a combined
treatment with IL-12 and BB-94 in a murine melanoma model. The administration of
both agents showed potentiated antitumor activity. Furthermore, we have shown in
a tumor-induced angiogenesis model that the combined application of IL-12 and
batimastat inhibits the formation of new blood vessels to a greater extent than
either agent alone. Our observations show that antiangiogenic effects are at
least partly responsible for the enhanced antitumor effects of the combined
treatment with IL-12 and BB-94.
PMID- 10769686
TI - Nafoxidine modulates the expression of matrix-metalloproteinase-2 (MMP-2) and
tissue inhibitor of metalloproteinases-1 (TIMP-1) in endothelial cells.
AB - During angiogenesis, proteases and their inhibitors interact in the remodelling
of the basement membrane. It has been demonstrated that nafoxidine has
antiangiogenic activity in the chick egg chorioallantoic membrane assay, but the
precise mechanism of action is unknown. We have analyzed the effect of the
partial estrogen antagonist nafoxidine on human umbilical vein endothelial cells
(HUVEC). Our data indicated that in nafoxidine-treated endothelial cells MMP-2
was activated. Nafoxidine upregulated, in a dose-dependent manner, the secretion
of a 66 kDa TIMP-1 dimer, that lacks anti-MMP activity and inhibited angiogenesis
in the endothelial cord formation assay. We can postulate that nafoxidine induces
an increase in TIMP-1, which has antiangiogenic activity in the late stages of
tube formation, independent of its capacity to inhibit MMPs.
PMID- 10769687
TI - Radiation enhancement of gemcitabine in two human squamous cell carcinoma cell
lines.
AB - BACKGROUND: Gemcitabine (dFdC) is a new nucleoside analogue with promising
activity in different solid tumors. We investigated whether dFdC enhances the
effect of irradiation in human squamous carcinoma cells of the oropharynx (#4197)
and of the uterine cervix (HeLa) with special regard to the time-dose
relationship concerning dFdC and the dependence upon the timing of irradiation.
MATERIALS AND METHODS: Under standardized conditions monolayers of cells were
exposed to various dFdC concentrations (0.003-10 mumol/l) for different times (4
24 h). Irradiation (0-6 Gy) followed immediately or 12 h after dFdC exposure
(0.003-0.03 mumol/l; 4-24 h). RESULTS: The cytotoxic effect of dFdC depends on
its concentration and the exposure duration. Exposed to non and/or slightly
cytotoxic concentrations (> or = 0.003-0.03 mumol/l) for 4, 8, 16 and 24 h and
followed by immediate irradiation the radiation enhancement ratio (RER) is 1.03
1.67 in #4197 cells and 1.04-2.47 in HeLa cells, respectively. Irradiated 12 h
after 24 h exposure (dFdC 0.01-0.03 mumol/l) the RER is reduced to 1.10-1.17
(#4197) and 1.18-1.72 (HeLa). CONCLUSIONS: Depending on the drug concentration,
exposure duration, and timing of irradiation, dFdC enhances the irradiation
effect on human squamous cell carcinoma cell lines (#4197, HeLa).
PMID- 10769688
TI - Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis.
AB - The AKT oncogenes are amplified or AKT kinase activity is constitutively elevated
in several types of human malignancy. We sought to determine whether AKT might
play a role in the development of resistance to apoptosis induced by
chemotherapy. We showed that ovarian cancer cells either overexpressing
constitutively active Akt/AKT1 or containing AKT2 gene amplification were highly
resistant to paclitaxel than cancer cells express low AKT levels. The Akt/AKT1
clones also contained higher levels of phospho-Bad protein than parental cells.
Further, the complexes between the endogenous proapoptotic protein, Bad, and the
anti-apoptotic protein, BC1-XL were undetectable in Akt/AKT1 clones. These
results suggest that Akt/AKT1 expressed in these clones can phosphorylate Bad and
prevent it from binding to Bcl-XL. Furthermore, overexpression of Akt/AKT1 can
inhibit the release of cytochrome c induced by paclitaxel. Therefore, our
findings provide evidence that aberrant expression or activation of AKT in cancer
cells may confer resistance to paclitaxel.
PMID- 10769689
TI - Development of a new plasmid vector with PSA-promoter and enhancer expressing
tissue-specificity in prostate carcinoma cell lines.
AB - Differential expression of the desired gene product in the target tissue is
central to the concept of gene therapy. One approach is to use a tissue-specific
promoter to drive therapeutic genes, such as the p53 tumor suppressor gene. To
determine the feasibility of tissue-specific gene therapy for prostate cancer
using prostate specific antigen (PSA) promoter and/or enhancer, in this study, we
developed a tissue specific expression vector using a PSA promoter and enhancer.
Our results showed that the cloned PSA promoter actively drives gene expression
in the PSA-producing prostate cancer cell line (LNCaP). However, barely any
promoter activity was detected in the non-PSA producing prostate cancer cell
lines (DU145, PC-3) or the non-prostate cell lines (HEK-293, SAOS-2). The wild
type p53 gene driven by this PSA-promoter efficiently suppressed the growth of
LNCaP. Moreover, p53 driven by the PSA enhancer-promoter cassette more
efficiently suppressed the growth of the PSA-producing prostate cancer cell line
(LNCaP) in vitro. This suggest that we were able to manage the tissue specificity
by PSA enhancer and promoter. Additionally, the juxtaposed enhancer-promoter
cassette showed great enhancement of p53 expression and apoptosis in vitro. Taken
together, these results show that PSA enhancer-promoter may be a potential tool
for gene therapy for prostate cancer.
PMID- 10769690
TI - Selective cytotoxic activity of grape peel and seed extracts against oral tumor
cell lines.
AB - Grape seed extracts were more cytotoxic than grape peel extracts. Methanol and
70% methanol extracts of grape seed selectively killed two human oral tumor cell
lines, more efficiently than human gingival fibroblasts. ESR spectroscopy
revealed that these extracts produced radicals under alkaline conditions and
enhanced the radical intensity of sodium ascorbate at higher concentrations. On
the other hand, lower concentration of these extracts slightly reduced the
radical intensity of sodium ascorbate, and scavenged superoxide anion, generated
by hypoxanthine and xanthine oxidase reaction. These properties of grape seed
extracts suggest their possible application for cancer prevention.
PMID- 10769691
TI - I-FISH control of CGH-detected gain of DNA sequence copy number in oral squamous
cell carcinomas (OSCC).
AB - Interphase fluorescence in situ hybridization (I-FISH) was used to control the
gain of genomic material in 21 human oral squamous cell carcinomas (OSCC) which
had been detected by comparative genomic hybridization (CGH). DNA probes for
3q27, for 5p15.2, and for the protooncogenes c-myc (8q24) and c-abl (9q34), were
used for I-FISH examination of the interphase nuclei of paraffin sections of the
tumors. The corresponding alphoid DNA probes for the centromeric regions of the
respective chromosomes and a probe on 5q served as controls of aneusomy. Previous
examinations with int2 (11q13) and erbB2 (17q11.2-13) were included for
comparison. I-FISH analysis detected a gain of 3q27 in 17, of 5p15.2 in 7, of c
myc in 14, of c-abl in 10, and formerly, of int2 in 12 and of erbB2 in 10 of the
examined tumors. There was an overall confirmation of the CGH findings by the I
FISH data in 63% (36-83% depending on the studied chromosomal site), and vice
versa of 76% of the I-FISH results by the CGH data. Based on these results it is
recommended to use a combination of both I-FISH and CGH for the detection of
genomic changes in human solid tumors as the data obtained by both techniques
ideally complete each other. For this reason both techniques have now enriched
the spectrum of molecular histopathology.
PMID- 10769692
TI - Regulation of telomerase activity by gamma-radiation in nasopharyngeal carcinoma
cells.
AB - Since telomerase has been suggested to play a role in radiation response, the
effect of radiation on the regulation of telomerase activity was studied on two
NPC cell lines, CNE1 and 915. In order to investigate the correlation between
cell survival and telomerase activity, three low doses (0.25, 0.5 and 1 Gy) and
three high doses (2, 4 and 8 Gy) of gamma-radiation were used. We found that low
doses of radiation induced telomerase activity (up to 250% of untreated controls)
followed by a cell cycle G1 arrest, suggesting that the up-regulation of
telomerase may play a role in initiating radiation induced cell cycle arrest.
High doses of radiation resulted in decreased telomerase activity (down to 30% of
untreated controls) and this was followed by an increased cell death. Our results
indicate that the up-regulation of telomerase activity is an important response
to radiation induced sub-lethal DNA damage. Our results also suggest that
inhibition of telomerase activity by high doses of radiation may play a role
radiation-induced cell death.
PMID- 10769693
TI - Enhancement of chemotherapeutic agents induced-apoptosis associated with
activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected
gastric cancer cells.
AB - Apoptois is an important determinant in the sensitivity to chemotherapeutic
agents in gastric cancer cells. In this study, we examined whether the
introduction of the bax gene into MKN45 gastric cancer cells could enhance the
sensitivity to chemotherapeutic agents in association with apoptosis. Apoptosis
in the bax-transfected gastric cancer cells was enhanced following the treatment
of various chemotherapeutic agents including adriamycin (ADM), cisplatin (CDDP),
etoposide (VP-16) and taxotere (TXT) as compared to those of neo gene-transfected
cells. The enhancement of apoptosis was coincident with the increase of
sensitivity in the ratio of IC50 value, that was 1.3-fold in ADM, 4.4-fold in
CDDP, 4.6-fold in VP-16 and 2.5-fold in TXT, respectively. Further, the
enhancement of apoptosis in the bax-transfected gastric cancer cells was
associated with the activation of c-Jun N-terminal kinase 1 (JNK 1) and caspase 3
(CPP32). The increases of sensitivities to these agents in the bax-transfected
cells were also demonstrated in in vivo experiments using the tumor cells
transplanted into nude mice. The tumor growth in the bax-transfected cells was
significantly suppressed following the treatment of CDDP or VP-16 compared to
that of neo-transfected cells (p < 0.05). These results indicated that, the bax
gene might play a critical role in determination of sensitivity to
chemotherapeutic agent in gastric cancer cells in vivo, and that the activation
of JNK 1 and CPP32 might be involved in the signal transduction pathways leading
to apoptosis.
PMID- 10769694
TI - Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds.
AB - BACKGROUND: The anticancer activity of cisplatin derives from its ability to
crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide
excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic
notch at the damage site, which can be specifically bound by damage-recognition
proteins, thus shielded from NER-activity. We aimed at preventing resistance by
enhancing this mechanism using more hydrophobic platinum compounds. METHODS: We
synthesized three platinum analogs with increased hydrophobic characteristics.
Performing MTT-assays, the efficacy of cisplatin and the novel agents was
compared in a fibroblast and eight brain tumour cell lines. RESULTS: Among the
novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most
cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the
second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 =
2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x
10(-6) M). CONCLUSIONS: Comparison of the novel compounds supports the hypothesis
that increased hydrophobicity contributes to higher antitumour-activity. Other
advantageous characteristics of cisplatin might relate to its remaining highest
efficacy.
PMID- 10769695
TI - Autocrine regulation of TPA-induced apoptosis in monoblastic cell-line U-937:
role for TNF-alpha, MnSOD and IL-6.
AB - The present studies were undertaken to analyse the factors regulating TPA-induced
apoptosis. Treatment of the monoblastic U-937 cells with the phorbol ester, TPA,
was found to induce apoptosis in two distinct phases. In phase I (from 0 to 72
hours following TPA induction), apoptotic cells appeared, despite the expression
of high levels of the anti-apoptotic Bcl-2 protein. After 96 h. of TPA treatment
(phase II), the percentage of apoptotic cells increased as did the cell
differentiation stage. The first phase apoptotic response could be significantly
reduced (70%) by treatment with anti-tumor necrosis factor-alpha (TNF-alpha)
antibody. TNF-alpha protein required de novo RNA and protein synthesis and was
found to be mediated by protein kinase and protein tyrosine kinases. Manganese
superoxide dismutase (MnSOD) inhibited, whereas IL-6 increased TPA-induced
apoptosis. These findings suggest that both TPA, via TNF-alpha synthesis, exerts
its protective function intracellularly by inducing MnSOD production and IL-6 may
be an effective adjunct to TNF-alpha in the clinic, increasing the antitumor
potency of this cytokine.
PMID- 10769696
TI - Radioimmunotherapy of nude mice with intraperitoneally growing ovarian cancer
xenograft utilizing 211At-labelled monoclonal antibody MOv18.
AB - The aim of this study was to investigate the therapeutic efficacy of 211At
labelled monoclonal antibody given intraperitoneally to nude mice with
intraperitoneal growth of a human ovarian cancer cell line. Female nude mice were
inoculated intraperitoneally with 1 x 10(7) cells of the human ovarian cancer
cell line NIH:OVCAR 3. After about two weeks they were injected with the 211At
labelled specific monoclonal antibody MOv18 intraperitoneally. For comparison,
other groups of mice were given the same labelled antibody intravenously, 211At
labelled unspecific antibody C242 intraperitoneally or unalbelled MOv18
intraperitoneally. Six weeks later the animals were sacrificed and the occurrence
of tumour and ascites was determined. When the mice were treated with 211At
labelled MOv18 intraperitoneally 9 out of 10 were apparently free of both ascites
and tumour compared to none of the mice given unlabelled antibody. 211At-labelled
MOv18 given intravenously or 211At-labelled unspecific antibody given
intraperitoneally were less effective. Regional radioimmunotherapy with the alpa
emitter 211Astatine seems to be an effective treatment of nude mice with
intraperitoneally growing human ovarian cancer. Hopefully this treatment can be
given in an adjuvant setting to women with minimal residual ovarian cancer in the
future.
PMID- 10769697
TI - Peripheral benzodiazepine receptor in human endometrium and endometrial
carcinoma.
AB - Since elevated concentrations of peripheral benzodiazepine (PBZr) have been
reported in some tumors it was of interest to study the distribution PBZr in the
endometrium and endometrial carcinoma. A specific ligand or PK 11195 was used to
measure PBZr in the mitochondria (m-fraction) and the microsomal fraction (p
fraction). Density of binding sites and binding affinity (KD) was computed from
Scatchard analysis. Binding in both m- and p-fractions from endometrium and
endometrial carcinoma were saturable and of high affinity. The PBZr density in p
fraction from endometrium was slightly higher than in m-fraction, whereas the
binding in m-fraction in endometrial carcinoma was more than 2-fold higher than
in p-fraction. The difference between the densities in m-fraction from
endometrial cancer and endometrium was highly significant (p < 0.005). There was
no significant difference in the binding affinities (KD values) for PK 11195 in
the various fractions. The selective increase in the density of PBZr in
mitochondria of tumors suggests an association with energy demand and utilization
and could be of diagnostic and/or therapeutic value in endometrial cancer. The
role of a relatively high density of PBZr in microsomal fractions remains to be
elucidated.
PMID- 10769698
TI - Effects of the immunomodulator tilorone on the acetylation of 2-aminofluorene and
DNA-2-aminofluorene adducts in the rats.
AB - The present studies were undertaken to determine the effect of tilorone
dihydrochloride (a synthetic interferon inducer) on the in vivo acetylation of 2
aminofluorene and DNA-2-aminofluorene adducts. For in vivo examination,
pretreatment with tilorone dihydrochloride (50 mg/kg) 48 hr prior to the
administration of 2-aminofluorene (50 mg/kg) resulted in a 35% and 29% increase
in the fecal and urinary recovery of N-acetyl-2-aminofluorene and a 52% increase
in the metabolic clearance of 2-aminofluorene to N-acetyl-2-aminofluorene.
Following the exposure of rats to the 2-aminofluorene with or without
pretreatment with tilorone dihydrochloride, DNA-2-aminofluorene adducts were
determined in liver, bladder, lung and also in circulating leukocytes. The DNA-2
aminofluorene adducts in liver were increased by pretreatment with tilorone
dihydrochloride. This is the first demonstration of tilorone-induced increasing
in N-acetylation of carcinogens and DNA-carcinogen adducts in vivo.
PMID- 10769700
TI - Clinical significance of angiogenesis, proliferation and apoptosis in renal cell
carcinoma.
AB - BACKGROUND: The prognostic significance of angiogenesis, proliferation and
apoptosis after interferon (IFN) was investigated in 96 patients with renal cell
carcinoma (RCC). MATERIALS AND METHODS: Microvessel density in the tumor(MVD),
proliferative index(PI) and apoptotic index(AI) were quantified using
immunohistochemical staining of factor VIII-related antigen and Ki-67 antigen for
the former two parameters and the TUNNEL technique for AI. RESULTS: MVD and PI
were correlated with the M criteria and histological grade. AI was not correlated
with either criteria. Analysis using PI, AI, MVD and the classical prognostic
factors revealed that PI was the most significant prognostic factor and that
patients with high MVD values and those with low AI values had a poor prognosis.
Of the high MVD group and high PI group among patients with metastasis, IFN
treated patients showed a tendency for a better prognosis than nontreated
patients (p = 0.067 and 0.020, respectively). CONCLUSIONS: It is speculated that
proliferation, angiogenesis and apoptosis play a complex role in the prognosis of
patients with RCC. It is suggested that IFN treatment is likely to have an
inhibitory effect on proliferation and angiogenesis.
PMID- 10769699
TI - Effect of E-2-(4'-methoxybenzylidene)-1-benzosuberone on the 7,12
dimethylbenz[alpha]anthracene-induced onco/suppressor gene action in vivo. I: A
24-hour experiment.
AB - The cyclic chalcone analogue, E-2-(4'-methoxybenzylidene)-1-benzosuberone (MBB),
was found to show outstanding in vitro antineoplastic activity against P388,
L1210, Molt 4/C8 and CEM cells as well as against a panel of human tumor cell
lines. In order to determine whether this promising antineoplastic activity would
extend to anticarcinogenic properties, the effects of MBB on the 7,12
dimethylbenz[alpha] anthracene (DMBA)-induced expression of c-myc, Ha-ras and p53
genes in isolated RNA from liver, lung, kidney, spleen, thymus, lymph nodes and
bone marrow of CBA/Ca inbred mice was investigated. DMBA is a well-known chemical
carcinogen, which can act as an initiator by causing point mutations in certain
oncogenes and tumor suppressor genes. Elevated expression of oncogenes after
treatment with DMBA and other carcinogenic chemicals has been noted previously.
Administration of MBB simultaneously with DMBA, 24 hours prior to or 24 hours
after the DMBA treatment characteristically modified the DMBA-induced expression
of the three genes in the 24-hour experiments. The most pronounced suppression
effect of MBB could be observed in almost all the investigated tissues when it
was administered simultaneously with DMBA. These "short-term" in vivo results
support our previous conclusion that MBB can serve as a model molecule for
subsequent structural modifications in searching for new effective
anticarcinogenic agents.
PMID- 10769701
TI - Do the expression of CD44, apoptosis and thymidylate synthase inhibition rate
correlate with the efficacy of chemotherapy in colorectal cancer?
AB - BACKGROUND: Tegafur-uracil(UFT;TAIHO Pharmaceutical Co.Ltd, Tokyo, Japan) is
commonly used to treat digestive cancers. However, the inhibitors of metastasis
in this agent have not been fully examined. To investigate a cell adhesion
molecule, CD44, which may very well contribute to the pathogenesis of metastasis,
we examined the association of CD44 and the thymidylate synthase inhibition
rate(TSIR) with prognosis, and examined the expression of apoptosis in patients
who were administrated tegafur-uracil before surgery for colorectal cancer.
MATERIALS AND METHODS: This study included 66 patients who underwent curative
resection of colorectal cancer. In these patients, tegafur-uracil(600 mg) was
orally administered every day for 3 to 7 days before surgery, and Tegafur-uracil
(400 mg) was orally administered every day for 2 years after surgery. CD44 and
apoptosis were detected immunohistochemically and by the TUNNEL method,
respectively. The TSIR was calculated from the total TS level, and free TS levels
by modified Spears' method using fresh tumor tissue specimens. RESULTS: The TSIR
of non-recurrent patients was significantly higher than that of recurrent
patients(p < 0.05). The 5-year survival rate in CD44-low grade positive/negative
patients (81.6%) was significantly higher than that in CD44-high grade positive
patients (46.4%) (p < 0.005). The 5-year survival rate in apoptosis-high grade
positive patients (89.7%) was significantly higher than that in apoptosis-low
grade positive/negative patients(46.4%) (p < 0.001). With respect to the
relationship between CD44 and apoptosis, the proportion of apoptosis-high grade
positive patients among CD44-low grade positive/negative patients (55.3%) was
significantly higher than that among CD44-high grade positive patients(28.6%) (p
< 0.05). In the multivariate analysis, the CD44 expression was suggestive of an
independent prognostic factor. CONCLUSION: Based on our results for TSIR, Tegafur
uracil may induce apoptosis of tumor cells in patients by the inhibition of
thymidylate synthase. It was suggested that CD44 expression could be used as a
possible independent predictor of survival. In addition, it was suggested that
UFT, via the inhibition of CD44 expression caused the inhibition of distant
metastasis.
PMID- 10769703
TI - Response of MHC class-1 antigen on rat glioma cells to cytokines.
AB - BACKGROUND: Enhanced MHC class-1 expression has potentially been correlated with
the increased susceptibility of tumor cells to a T cell-mediated immune response.
We examined the immunomodulatory effects of some cytokines on MHC class-1
expression in rat glioma cell lines. MATERIALS AND METHODS: Using three rat
glioma cell lines (RG2, C6, 9L), the immunomodulatory effects of cytokines (rhIL
2, rmIL-4, rmGM-CSF, rrIFN-gamma) on the expression of MHC class-1 antigen were
evaluated using immunohistochemical and flow cytometric analyses. RESULTS:
Varying baseline levels of MHC class-1 antigen were confirmed in each glioma cell
line. Stimulation with rrIFN-gamma consistently increased the expression of MHC-1
antigen in all three of the rat glioma cell lines. On the other hand, MHC class-1
expression was not affected by stimulation with rhIL-2, rmIL-4 or rmGM-CSF, even
in combination. CONCLUSIONS: rrIFN-gamma can upregulate MHC class-1 expression in
rat glioma cells. Our data suggest that rrIFN-gamma may be able to exert
antitumor activity against gliomas in vivo.
PMID- 10769702
TI - TNP-470 inhibits growth and the production of vascular endothelial growth factor
of uterine carcinosarcoma cells in vitro.
AB - BACKGROUND: Carcinosarcoma is the most aggressive neoplasm among the known
uterine malignancies. Most patients who are affected with this biphasic neoplasm
hardly show any response to common anti-cancer drugs or radiotherapy and thus
they tend to show an extremely poor prognosis. This is the first study to examine
the inhibitory and anti-angiogenic effects of angiogenesis inhibitor TNP-470, a
synthetic analogue of fumagillin, for human uterine carcinosarcoma in vitro.
MATERIALS AND METHODS: The direct growth-inhibitory effect of TNP-470 was
examined by an MTT assay in vitro. The levels of vascular endothelial growth
factor (VEGF) in the culture supernate of TNP-470 treated FU-MMT-1 cells were
also analyzed by an enzyme-linked immunosorbent assay (ELISA). The VEGF
expression of TNP-470 treated FU-MMT-1 cells was also immunohistochemically
examined using an anti-VEGF antibody. RESULTS: TNP-470 inhibited the growth of FU
MMT-1 cells in vitro. The level of VEGF in the culture supernatant of TNP-470
treated FU-MMT-1 cells was significantly lower than that of the control (TNP-470
untreated FU-MMT-1 cells) in vivo. The expression of VEGF in TNP-470 treated FU
MMT-1 cells immunocytochemically decreased in comparison to that of the control
TNP-470 untreated FU-MMT-1 cells). CONCLUSIONS: Our in vitro findings suggest
that this angiogenesis inhibitor, TNP-470, might be a novel therapeutic agent for
uterine carcinosarcoma. However, further in vivo experimental studies using TNP
470 for this tumor will be necessary before any definitive conclusions can be
made.
PMID- 10769704
TI - Correlation of the expression of nuclear factor-kappa B, tumor necrosis factor
receptor type 1 (TNFR 1) and c-Myc with the clinical course in the treatment of
malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha
(TNF-SAM2).
AB - We present our experience with a combination chemotherapy regimen consisting of
ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF
SAM2) for malignant astrocytomas. We also investigated the expression of nuclear
factor-kappa B (NF-kappa B), tumor necrosis factor receptor type 1 (TNFR1), and c
Myc in human astrocytoma tissues in vivo in patients treated with TNF-SAM2 by RT
PCR and immunohistochemical analysis to examine whether there is any correlation
between the prognosis of these patients after TNF-SAM2 treatment and the
expression of these factors. The initial regimens were prescribed as adjuvant
therapy in conjunction with radiotherapy following standard surgical treatment.
Newly diagnosed patients were treated with up to four cycles of this regimen (TNF
SAM2, MCNU, and radiotherapy: TMR group). Four patients with anaplastic
astrocytomas and 13 patients with glioblastomas (11 men and 6 women) aged 24 to
68 years (median 55.7 years) were eligible and evaluated for response and
toxicity. The estimated median survival time was 354 weeks with anaplastic
astrocytomas, and 79 +/- 10.8 weeks with glioblastomas. One- and 2-year survival
rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 30.8% with
glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None
of the patients experienced a treatment delay due to toxicity. All other acute
toxicities were anticipated and manageable. Two of the 4 patients with anaplastic
astrocytomas were positive for the expression of NF-kappa B, TNFRl and c-Myc. The
expression of NF-kappa B, TNFR1 and c-Myc was investigated in 10 of the 13
patients with glioblastoma, and c-Myc, TNFRl and NF-kappa B were detected in 9,
7, and 8 of these 10 patients' surgical specimens, respectively. Despite the
small number of patients, these clinical results suggest that combined
chemotherapy with mutant TNF-alpha (TNF-SAM2) was safe and well tolerated, and
may confer a survival benefit for patients with malignant astrocytomas in
comparison to our historical controls. Its effectiveness as an adjuvant therapy
deserves a properly stratified randomized trial. Although there was no
significant correlation between the efficacy of TNF-SAM2 treatment and the
expression of NF-kappa B, our results suggest that the constitutive activation of
NF-kappa B subunits in malignant astrocytomas, especially in glioblastoma, could
be associated with resistance to TNF-alpha immunotherapy. These results could
offer new insight to help establish a new chemotherapeutic strategy for malignant
astrocytomas.
PMID- 10769705
TI - Pharmacokinetics of isolated hepatic perfusion with high dose tumor necrosis
factor in rat model.
AB - BACKGROUND: Although the application of an isolation procedure with tumor
necrosis factor (TNF) to the liver is quite attractive, an animal model is not
yet available to evaluate antitumor effects by TNF in isolated hepatic perfusion
(IHP). To establish the rat model in IHP, the pharmacokinetics of TNF, both in a
perfusate and in a systemic circuit should be examined. METHODS: All rats
underwent IHP with TNF. After a 10 min perfusion, a washout procedure was
performed for 5 min, after which isolation was terminated. Throughout the
procedure and afterward, blood samples were obtained from the systemic blood and
concentrations of TNF were assayed by L-929 cytotoxicity. RESULTS: After the
administration of 240 micrograms of TNF in the circuit, TNF reached a plateau at
about 12.7 micrograms/ml of perfusion fluid, lasting until the end of IHP. As a
result of the washout procedure, regional TNF concentrations declined from 12.7
micrograms/ml to 1.5 micrograms/ml. At the beginning of the IHP, all rats
exhibited no detectable level of TNF activity in the systemic circulation (< 100
pg/ml). With time, TNF plasma levels quickly increased to reach a plateau of
about 0.2 microgram/ml at 15 min. Systemic leakage of TNF is calculated as less
than 2% of the total TNF in perfusate during perfusion. CONCLUSION: Rat IHP
models with TNF showed that systemic leakage of TNF was higher than that of pig
models, although a large enough amount of TNF in perfusate was achieved without
death. Rat models might be feasible to evaluate antitumor effect of IHP against
liver metastatic tumors.
PMID- 10769706
TI - Reduction of hepatotoxicity of tumor necrosis factor in isolated hepatic
perfusion by administration of glucocorticoid as well as lipopolysaccharide.
AB - BACKGROUND: The application of an isolation procedure with tumor necrosis factor
(TNF) to the liver is quit attractive, however, one of problems to overcome is
reducing the toxicity to the liver caused by high doses of TNF. MATERIALS AND
METHODS: Rats underwent isolated hepatic perfusion (IHP) with TNF and pre
treatment of subcutaneous administration of dexamethasone (4 mg/kg) and/or
intradermal administration of LPS (50 micrograms/rat). After a 10 min perfusion,
a washout procedure was performed for 5 min, after which isolation was
terminated. RESULTS: SD or Wister rats and F344 rats tolerated up to 120 mg/rat
or 4 micrograms/rat, respectively. Dexamethasone and/or LPS was tolerated at 40
micrograms/rat of TNF in F344 rat and showed a significant reduction of
hepatotoxicity, and indicated histologically the suppression of ballooning and of
necrosis during and after perfusion by TNF. CONCLUSION: We propose new a protocol
for IHP as follows: 1. the intradermal administration of LPS for protection
against toxicity of TNF, 2. IHP with TNF-SAM2, a mutain of TNF-alpha, having less
toxicity than conventional TNF-alpha, and 3. simultaneous perfusion with
chemotherapeutic agents such as 5-fluorouracil (5-FU).
PMID- 10769707
TI - Relationship between microvessel quantification and inducibility of endogenous
tumor necrosis factor in colorectal adenocarcinoma.
AB - BACKGROUND: Although we have reported that the inducibility of endogenous tumor
necrosis factor (en-TNF) by tumor cells is an independent prognostic factor in
Dukes stage C colorectal cancer patients, the mechanism by which the patients
having high inducibility of en-TNF show better prognosis is still unclear. We
hypothesize that the inducibility of en-TNF by colorectal tumor cells affects the
prognosis of patients through the modulation of angiogenesis. Thus, the aim of
this study is to clarify the relationship between inducibility of en-TNF and
tumor vascularity in colorectal cancer. PATIENTS AND METHODS: Histological
sections from 62 Dukes stage C colorectal cancer patients who received curative
operation were immunostained for CD34 antigen. Microvessels were counted in the
photograph of x200 fields (0.298 mm2). The average count of five most vascular
areas was determined as a microvessel density of each case. RESULTS: Two of 62
cases were excluded from the analysis, because of insufficient staining. A total
of 60 patients were dichotomized by a median vessel count of 34 into two groups:
30 patients with lower microvessel density (Low MVD group) and 30 patients with
higher microvessel density (High MVD group). There was no significance in the
distribution of all clinicopathological factors among these two groups. Regarding
en-TNF inducibility, no difference was shown between the two groups. The five
year survival rate of Low MVD group and High MVD group were 58.7% and 68.0%,
respectively. And, the 5 year relapse-free survival rate of Low MVD group and
High MVD group were 59.7% and 52.2%, respectively. No significant difference was
demonstrated between Low MVD group and High MVD group. CONCLUSION: Intratumoral
microvessel density did not influence on the prognosis of colorectal cancer
patients in Dukes stage C after curative operation. The inducibility of en-TNF
showed no correlation with intratumoral microvessel density in Dukes stage C
patients after curative operation.
PMID- 10769708
TI - Serum levels of interleukin-12 in patients with gastrointestinal cancer.
AB - Interleukin 12(IL-12) is a heterodimeric cytokine that has potent anti-tumor and
anti-metastatic activities. Although clinical trials of recombinant human IL-12
have begun in patients with several advanced malignancies, very few studies have
investigated the preoperative serum levels of IL-12 in patients with gastric or
colorectal cancer. The purpose of the present study was to investigate the
relationships between the preoperative serum levels of IL-12 and
clinicopathological factors in patients with gastric or colorectal cancer. Blood
was obtained before surgery from 14 patients with gastric cancer and 15 patients
with colorectal cancer. Serum levels of IL-12 was assessed using the quantitative
sandwich enzyme immunoassay technique. Although not statistically significantly,
low serum levels of IL-12 tended to be associated with gastric cancer patients
who were node-positive, CEA positive, had tumors that penetrated the serosa, had
tumors greater than 5 cm in diameter, were more than 60 years-old, or were more
advanced than stage IIIA(TNM) or stage IIIa(Japanese Research Society for Gastric
Cancer). Patients with colorectal cancer who were node-positive, had tumors that
penetrated the serosa, were more than 60 years-old, or were more advanced than
stage III(TNM), stage IIIa(Japanese Society for Cancer of the Colon and Rectum)
and Dukes' C also tended to have low serum IL-12 levels. These results suggest
that low serum levels of IL-12 may be observed in more advanced gastric and
colorectal cancer patients. Thus, patients with low serum levels of IL-12 in
gastric or colorectal cancer may require additional immunochemotherapy after
surgery.
PMID- 10769709
TI - Neuro-psychological discorders and renal cell carcinoma: a case report and a
psychological study of urological cancer patients.
AB - Several pathways for immunodepression induced by stress and injury have been
speculated, with precise analysis regarding out correlations between sympathetic
nerve system and immunodepressive cytokines. Here, we show an interesting case
and a clinical study of psychological disorders of urological advanced cancer
patients. In the case report, a male renal-cell cancer patient whose disease
disappeared following interferon therapy is presented whose disease relapsed five
years after therapy and eight months after a traffic injury. Careful observation
of the history suggests that severe pain could destruct patient's own anti-cancer
mechanisms. In the clinical study on psychological disorders of the 131 patients,
a higher rate (28%) of disorders was recognised in renal-cell cancer patients
than in other cancer patients. Serum CRP values of the renal-cell cancer patients
with the disorders was significantly higher than those of the same cancer
patients without the disorders. A complicated inter-relationship between the
central nercous system, various external forces, the cancer itself and the immune
system may exist and have an influence on the efficacy of biotherapy.
PMID- 10769710
TI - Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a
phase II study of the Italian Sarcoma Group (ISG).
AB - BACKGROUND: Doxorubicin remains one of the few drugs with consistent single agent
activity in advanced Soft Tissue Sarcomas (STS), with a demonstrated dose
response relationship. Liposomal-encapsulated Doxorubicin (LED) has been shown to
be at least as active as free doxorubicin in experimental models, and phase I and
II human studies indicate that this novel strategy of drug delivery my have less
myocardial toxicity. Few clinical trials in adult STS have been published until
now, with disappointing and often contrasting results. PATIENTS AND METHODS:
Twenty-five consecutive patients with measurable advanced and/or metastatic STS,
previously pretreated with anthracycline-based chemotherapy, were enrolled into
the trial. LED (Caelyx) was administered over 1-hour intravenous infusion at the
dose of 30 mg/m2 in the first 5 patients, then at the fixed dose of 50 mg/m2 in
the subsequent 20 patients. Treatment was given on ambulatory basis, at 3-week
intervals. Antiemetics were generally not required and only used if indicated.
RESULTS: A total of 98 courses of chemotherapy were given (median 4 per patient,
range 2 to 5). Amongst the 25 evaluable patients, there were 3 partial responses
(12%, 95% confidence interval 4.2% to 29.9%) lasting 3-9+ months and all
occurring in patients treated at 50 mg/m2/cycle. In addition, 2 minor responses
(4+ months) and 17 stable disease (2-7+ months) were observed; the remaining 3
patients progressed while on therapy. The median delivered drug dose-intensity
was 13.3 mg/m2/week (range 10 to 16.6 mg/m2/week). Treatment was well tolerated,
with no patient requiring dose reduction or therapy delay because of toxicity.
Only 2 cases of WHO grade 3 toxicity occurred, consisting of neutropenia and
scrotal skin toxicity; respectively; no cardiotoxicity was seen. CONCLUSIONS:
This study shows that Caelyx has some activity in advanced, anthracycline
pretreated STS, with favourable toxic profile. From the analysis of available
experiences it emerges that liposomal doxorubicin has not been tested at doses
adequate to exploit the antitumor effects of the drug, being the reached dose
intensity being even lower than those deemed critical for obtaining optimal
responses to free doxorubicin. We suggest that further and better addressed
studies be performed in STS, including patients with less advanced stages of
disease, focused on attempting to delivery the drug at optimal doses.
PMID- 10769711
TI - Relationship between the expression of caspase-3 and the clinical outcome of
patients with non-small cell lung cancer.
AB - This study examined whether a relationship exists between the expression of
caspase-3 in 135 non-small cell lung carcinomas and clinical outcome.
Immunohistochemistry and Western blot analyses were used to analyze the
expression of caspase-3 in solid tumors and cell lines. A significant correlation
was observed between the expression of caspase-3, survival and metastasis.
Caspase-3 expression correlated with a lower incidence of lymph node involvement
(p = 0.0007). The median survival was longer for patients with caspase-3 positive
carcinomas than for those with caspase-3-negative tumors (41 vs 87 weeks, p =
0.038).
PMID- 10769712
TI - Selective lymph node dissection in patients with intermediate thickness melanoma:
our experience.
AB - The role of elective lymph node dissection (ELND) for the treatment of cutaneous
melanoma has been debated for many years. Actually, the value of ELND is
seriously questioned because an increasing of overall survival rates has not been
demonstrated. The lymphatic mapping technique, initially performed by an
intradermic injection of vital blue dye, subsequently improved by the use of
radioguided surgery (RGS), proved effective for the detection of clinical occult
lymph node metastasis. We performed a sentinel node biopsy on 71 patients with
stage pT2/T3N0M0 melanoma. Vital blue dye mapping alone was performed on 39
patients; the remaining 32 patients had a combined lymphatic mapping with both
blue dye and RGS. The sentinel node (SN) was complexively identified in 69/71
(97.2%) patients. Sixteen patients (23.2%) were found to have metastatic melanoma
cells in their SN(s); all these patients underwent lymph node dissection of the
affected basin. Our experience confirmed that the intraoperative detection of
sentinel nodes using both blue dye and radio-guided surgery is an effective and
reliable technique for selecting patients to be submitted to lymph node
dissection.
PMID- 10769713
TI - Advanced colorectal cancer: quality of life and toxicity in patients after weekly
24-hour continuous infusions of biomodulated 5-fluorouracil.
AB - It is generally agreed that chemotherapy prolongs survival and relieves symptoms
more than the best supportive care in advanced colorectal cancer. Since its
introduction over 35 years ago, 5-fluorouracil (5-FU) has been the only effective
chemotherapeutic option available for the treatment of advanced colorectal
cancer. Efforts have focused on the use of various 5-FU-based regimens. A
commonly used regimen, frequently extolled as the "gold standard" for clinical
trials in advanced colorectal cancer, is the Mayo Clinic regimen; this option
has, however, been associated with considerable dose-limiting toxicity. Another
approach has involved 5-FU administration by continuous intravenous infusion. In
this paper we present our experience on 10 Dukes D colorectal cancer patients
treated with 24-hour continuous infusion of biomodulated 5-FU delivered in an
ambulatory setting with an intravenous infusional pump. The number of treated
patients was admittedly not sufficient to evaluate the clinical response of this
5-FU chemotherapeutic regimen. This is not the goal of our work; however, other
rationale for adopting this approach is justified: the regimen has a favourable
toxicity profile and can provide considerable benefit in terms of improved
quality of life while at the same time the health care costs are alleviated since
hospitalization is generally not required.
PMID- 10769714
TI - Evaluations of p53 immunoreactivity, nucleolar organizer regions, and
proliferating cell nuclear antigen in non-small cell lung carcinoma.
AB - We examined p53 protein expression, proliferating cell nuclear antigen (PCNA),
and argyrophilic nuclear organizer regions (AgNOR), in 102 patients with
surgically-treated non-small cell lung cancer (NSCLC). p53 positive cases with DO
1 were defined when more than 10% of the tumor cell nuclei were stained. Mean
AgNOR count and PCNA LI were 2.80 and 40.7 and there were no significant
differences of AgNOR count and PCNA LI between p53 positive and negative cases.
We assessed the relationship between the p53 immunoreactivity and various
clinical or pathological parameters. p53 positive rate of stage III disease
(46.3%) was significantly higher than that of stage II disease (28.6%). The p53
positive rate of squamous cell carcinoma (42.1%) tended to be higher than that of
adenocarcinoma (33.9%). In the survival curves of patients with NSCLC according
to the p53 immunoreactivity, there was no significant difference between p53
positive and negative cases. Eight potential prognostic parameters (p53
immunoreactivity, AgNOR count, PCNA LI, sex, age, year of operation, histology,
and stage) were also estimated, using univariate and multivariate analysis. In
univariate analysis, PCNA LI and AgNOR count, and stage were significantly
related to shortened survival. In multivariate analysis, PCNA LI, Age, and stage
were independently associated with shortened survival of NSCLC patients. PCNA
staining may be more useful than p53 and AgNOR staining in assessing the
aggressiveness of surgically-treated NSCLC, although the most useful clinical
prognostic parameter should be achieved by the combined analysis of several
prognostic indicators.
PMID- 10769715
TI - Case report: natural development of osteosarcoma from precancerous lesion.
AB - We encountered a very rare case that suggested the natural development of
osteosarcoma from a precancerous lesion. The patient presented with a huge
osteosarcoma in the distal femur on the initial consultation to our hospital. He
had undergone X-ray examination twice previously, due to a knee injury. The
findings of the lesion detected by the first X-ray examination were similar to a
fibrous cortical defect (FCD), differing from those of an osteosarcoma lesion
detected by second and last X-ray examinations. We retrospectively estimated the
growth rate of the FCD-like and osteosarcoma lesions and found that FCD-like
lesion was not osteosarcoma, but might have been a precancerous lesion. We also
speculated that this osteosarcoma lesion might have appeared 18 months before the
patient consulted our hospital.
PMID- 10769716
TI - A sequential chemo-radiotherapeutic treatment for patients with malignant
gliomas: a phase II pilot study.
AB - BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of
a sequential chemo-radiotherapeutic treatment on the basis of an earlier report
by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients
with histologically diagnosed malignant gliomas entered the study. Fifteen
patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin
(40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks.
Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on
the preoperative volume. RESULTS: Thirteen patients had measurable disease and
were evaluable for response. After chemotherapy we obtained 3 CRs (complete
remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were
converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13).
The median duration of response was 10 months. The median survival of the entire
patients population was 9 months with 33% survival rates at 1 year. Hematological
toxicity grade 4 in one patient and grade 3 in two patients were the major
complications due to chemotherapy. CONCLUSIONS: Our sequential chemo
radiotherapeutic regimen appears to have significant activity in adults with
newly diagnosed high-grade gliomas.
PMID- 10769717
TI - Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450
1A1, 2E1, and glutathione-S-transferase M1 enzymes.
AB - Chemical carcinogens generally require metabolic activation in order to be able
to bind to DNA and contribute to cancer causation. Most of the human metabolizing
enzymes are genetically polymorphic, and these polymorphisms may affect the
enzyme activity or inducibility. In our present study we investigated the
connection between genetic polymorphism of cytochrome P450 1A1, 2E1 (phase I
enzymes) and glutathione-S-transferase M1 (a phase II enzyme) and colorectal
cancer occurrence in a Hungarian population. The CYP 2E1 c2 allele proved to be
in significant association with colorectal cancer (OR: 1.91, 95% CI: 1.05-3.52),
the CYP 1A1 Val allele was also overrepresented among colon cancer patients (OR:
1.57, 95% CI: 0.90-2.74), and the frequency of GSTM1 homozygous 0 genotype showed
only minor difference (OR: 1.19, 95% CI: 0.75-1.35). Combined analysis of the
polymorphisms showed that individuals carrying all the three "high-risk" alleles
have a strikingly increased risk for sporadic colorectal cancer (OR: 4.62, 95%
CI: 1.23-25.68).
PMID- 10769718
TI - Biliary carcinoembryonic antigen levels can predict metachronous liver metastasis
of colorectal cancer.
AB - We set out to determine whether carcinoembryonic antigen (CEA) levels in
gallbladder bile and serum can predict metachronous liver metastasis of
colorectal cancer. At the time of surgery, gallbladder bile and serum were
sampled for enzyme immunoassays of CEA. Upper limit (mean +/- 2SD) of the normal
range for CEA in bile was established from samples at surgery for nonneoplastic
gallbladder disease. In 11 patients with synchronous liver metastases, biliary
CEA levels correlated with the size of hepatic lesions. In 49 patients without
evident liver metastases at the time of surgery, elevated biliary CEA levels
predicted subsequent emergence of metachronous liver metastases with 75%
sensitivity, 85% specificity, and 84% accuracy; serum CEA levels were not a
reliable predictor. In conclusion, determination of biliary CEA level at the time
of colorectal resection shows promise as a way to identify patients at high risk
for hepatic recurrence.
PMID- 10769719
TI - Disseminated metastasis of neuroblastomatous component in immature mediastinal
teratoma: a case report.
AB - A 17-year-old man with high levels of serum AFP and hCG was diagnosed as having
primary mediastinal GCT. Cisplatin-based chemotherapy decreased the biomarkers,
but the mass showed further growth. Pathological examination of the resected mass
revealed a mixture of immature and mature teratomas. Six months after the
surgery, the patient died of a dissemination of neuroblastomatous cells, which
were similar to those in the immature neural component of the primary tumor. A
disseminated metastasis of neuroblastoma in immature mediastinal teratoma is a
rare complication. Serum NSE can be a useful marker in detecting the metastasis.
PMID- 10769720
TI - Detection of 20q13 gain by dual-color FISH in breast cancers.
AB - An increase in the 20q13 copy number has been reported in a wide range of solid
tumors including breast cancers. However, the biological significance of this
20q13 gain has not yet been defined. We examined the 20q13 gain in breast cancer
cells by dual-color FISH using two different DNA probes specific for the region
of 20q13 and chromosome 20 centromere to investigate the relationship between
20q13 gain and the clinicopathological features of breast cancers. DNA
measurement by LSC revealed DNA diploidy in 14 tumors and DNA aneuploidy in 24
tumors. Although the modal number of chromosome 20 was 2 in most of the tumors,
the average fraction of cells with the modal chromosomal number was significantly
different in the diploid and aneuploid tumors (p < 0.01). A gain in the 20q13
copy number was detected in 9 of 38 breast cancers, 2 of which showed a high
level gain. The gain in 20q13 was associated with negative expression for the
progesterone receptor, but it was not linked to estrogen receptor expression. A
20q13 gain tended to be seen in DNA aneuploid and/or scirrhous carcinomas, but
the increase in the 20q13 copy number did not affect either the nodal state or
the disease stage in this series.
PMID- 10769721
TI - Cathepsin H expression distinguishes oncocytomas from renal cell carcinomas.
AB - BACKGROUND: Because the differential diagnosis of oncocytoma and renal cell
carcinoma lacks specificity, new methods supporting correct diagnostic decisions
are welcome. MATERIAL AND METHODS: Sixteen cases of renal oncocytoma, and 16 sex
, age-, and stage- matched controls of renal cell carcinoma (T1-2N0M0) were
studied. The minimum follow up exceeded ten years. There were no deaths due to
neoplasm among oncocytomas, but 4 patient died with metastatic disease among
cancer patients. Immunohistochemical staining for cathepsin H was quantified by 3
histoscores. The histoscores evaluated: 1) even cytoplasmic staining of
neoplastic cells, 2) granular staining, or 3) total staining. RESULTS: 100%
distinction was possible with the even cytoplasmic staining score. Total staining
distinguished 87.5%, and granular staining 25% of neoplasms. CAM 5.2 cytokeratin,
or vimentin distinguished 84.4% or 56.6% of these tumors, respectively.
CONCLUSIONS: Cathepsin H histoscore on even cytoplasmic immunostaining is an
excellent method for the distinction of oncocytomas and renal cell carcinomas.
PMID- 10769722
TI - Immunomodulatory treatment with low-dose interferon-alpha and oral retinoic acid
in lymphangioma-like Kaposi's sarcoma.
AB - BACKGROUND: The presence of lymphangiectasis without the characteristic spindle
cell proliferation may lead to diagnostic difficulties in Kaposi's sarcoma.
Although the literary data mention that the lymphangioma-like tumors may occur in
Kaposi's sarcoma, there have been few specific reports and case presentations
published. OBSERVATIONS: A case of lymphangioma-like Kaposi's sarcoma in
association with IgG/lambda type paraproteinaemia is reported in a 60-year-old
man. The HSV8 DNA sequence could be detected by PCR analysis from lesional skin.
CONCLUSION: The beneficial effect of alpha-2 interferon (4.5 million units per
week) combined with retinoic treatment (0.5 mg/body weight of isotretinoin)
caused the regression of the skin rashes while improving the values of
immunological tests (T cell function, quantity of paraproteins). The patient's
improved general condition and the ameliorating immunological parameters were due
to the combination of two regimens applied in a low-dose the alpha-2 interferon
(tumor regression) and the oral isotretinoid (antitumor activity, reduction of IL
6 receptor display) treatment.
PMID- 10769723
TI - Interpretation guidelines of DNA histograms from tissue sections of breast
cancer.
AB - BACKGROUND: Evaluation of nuclear DNA staining intensity from histological breast
cancer sections has not always been accepted, because of the difficulties in
interpreting the histograms. One reason for this is the lack of evidence based
interpretation guidelines. MATERIALS AND METHODS: The DNA staining intensity of
140 breast cancer samples was measured with flow cytometry (FCM) and image
cytometry (ICM). The methods were compared by using grading efficiency (GE).
RESULT: First, the ICM histograms were evaluated with a computer assisted image
cytometry system using different cut off points for aneuploidy. The GE results
varied from 67.9-76.4%. Subjective interpretation and evaluation according two
previously published interpretation methods did not improve the GE. Secondly, we
excluded histograms which showed clearly different cell clones in FCM and ICM.
The GE of remaining histograms was 77.9%. Comparison of these histograms allowed
formulation of interpretation guidelines which improved the GE to 85.3%.
CONCLUSIONS: This study suggests that efficient interpretation guidelines of
section-based DNA histograms can be created.
PMID- 10769724
TI - Locally advanced breast carcinoma: evaluation of mammography in the prediction of
residual disease after induction chemotherapy.
AB - BACKGROUND: We aimed to assess the mammographic features of locally advanced
breast carcinoma treated with neoadjuvant chemotherapy and to evaluate
morphological criteria that determine the value of mammography in therapy
monitoring. MATERIALS AND METHODS: We reviewed the pre- and post-therapeutic
mammograms of 44 patients with stage III-breast carcinoma with regard to tumor
characteristics and malignant calcifications and compared to histopathological
results. RESULTS: Delineation of the tumor proved to be the most significant
criterion. In 34 tumors more than 50% of the lesion was defined; these showed a
high correlation between the mammographically determined tumor diameter and that
determined on histopathological examination (r = 0.77). Less than 50% of the mass
was definable in 14 tumors; here the correlation between mammographically and
histopathologically determined tumor diameter was low (r = -0.19). CONCLUSIONS:
The diagnostic value of mammography in the evaluation of tumor response to
induction chemotherapy depends primarily on the extent to which the tumor can be
delineated from the adjacent breast tissue. For tumors whose margins can be
defined by more than 50% on the baseline mammogram, the diagnostic reliability of
mammography is high. Ill-defined masses should preferably be assessed with other
imaging procedures such as ultrasonography or magnetic resonance imaging.
PMID- 10769725
TI - Incidence of BRCA1 and BRCA2 mutations in Ashkenazi colorectal cancer patients:
preliminary study.
AB - BACKGROUND: Mutations in BRCA genes are associated with an elevated incidence of
colorectal cancer (CRC). While 20% of CRC patients have a familial history of
colonic malignancies, in only 5% is the genetic setting understood. Thus, a
majority of these patients lack any known genetic marker. Our aim was to explore
the relevance of BRCA mutations to serve as such markers in the genetic screening
and counseling of CRC patients. PATIENTS AND METHODS: 136 consecutive Israeli
Jewish patients with sporadic CRC were screened for BRCA "Ashkenazi mutations":
185delAG, 5382insC and 6174delT. Carrier status was evaluated employing PCR,
restriction analysis, SSCP and a Pronto BRCA kit. RESULTS: We found one 185delAG
and two 6174delT carriers, altogether three Ashkenazi carriers out of 87
Ashkenazi patients tested, 3.5%. No carriers were found among the Arabs and non
Ashkenazi Jews surveyed. CONCLUSIONS: Our preliminary results show elevated rates
of BRCA "Ashkenazi mutations" in Ashkenazi CRC patients, suggesting their
involvement in CRC carcinogenesis. An implementation of a wider study will
establish the role of these mutations as genetic markers for CRC.
PMID- 10769726
TI - Treatment modality affects long-term quality of life in gynaecological cancer.
AB - In order to survey the side effects after cancer treatment, quality of life data
were collected from females in clinical remission. MATERIALS AND METHODS: The
study was cross-sectional; every patient that visited the outpatient clinic
during a period of three months was asked to anonymously complete the EORTC QLQ
C30 questionnaire and five additional specific questions related to
gynaecological cancer. RESULTS: In total, 235 patients (90%) returned the
questionnaire. In general, both the levels of functioning and symptomatology were
time-dependent. Patients with short treatment-free intervals reported more
problems than the others. When using treatment modality as an independent
variable in the statistical calculations, a treatment-related effect on
functioning and symptomatology was demonstrated (p < 0.05 to p < 0.001). Patients
previously treated with chemotherapy had poorer role- and cognitive functioning
and more problems with fatigue, nausea, vomiting, dyspnoea, constipation and
financial problems, compared with those not treated with chemotherapy (p < 0.05
to p < 0.01). Those patients who had been treated with external radiotherapy
and/or brachytherapy had significantly more problems with flatulence and
diarrhoea (p < 0.05 to p < 0.001). In conclusion, patients who underwent
treatment for gynaecological cancer reported long-term side effects also many
years after finishing treatment. The problems where related to treatment modality
which should be considered, especially when planning adjuvant treatment.
PMID- 10769727
TI - Predictive value of uPA, PAI-1, HER-2 and VEGF in the serum of ovarian cancer
patients.
AB - BACKGROUND: Tissue levels of uPA, PAI-1, HER-2 and VEGF are known to have
prognostic value in different malignant tumors. The prognostic potential of serum
concentrations of these markers is less clear and was investigated. PATIENTS AND
METHODS: The response to 2nd line chemotherapy was studied in 61 patients with
recurrent ovarian cancer. Marker analyses were performed using specific and
sensitive ELISA tests and the response to therapy was evaluated using multiple CA
125 determinations and including these values in a simple and comprehensive
formula. RESULTS: Correlations were observed between VEGF and CA 125, HER-2
(inversely) as well as PAI-1, and between uPA and PAI-1. However, no marker
showed a significant relation to the overall survival of patients, nor to
treatment response. CONCLUSIONS: Serum levels of uPA, PAI-1, HER-2 and VEGF do
not have enough predictive potential in recurrent ovarian cancer. Most likely
additional sources contribute to the serum levels of the markers studied so that
their levels are not only tumor specific.
PMID- 10769728
TI - Significance of surgical resection for the treatment of multiple brain
metastases.
AB - BACKGROUND: We investigated the role of surgery in the treatment of multiple
brain metastases when performed with radiation therapy. PATIENTS AND METHODS: One
hundred and thirty-eight patients who underwent resection for brain metastases
and received 30 Gy or more of adjuvant radiation therapy were entered into this
study. Seventy-seven of the 138 patients (56%) had single brain metastases
(Single Group), while the remaining 61 patients (44%) had multiple foci (Multiple
Group). The 138 patients were divided into four subgroups; patients in Single
Group treated with total or subtotal resection (Group A), those in Multiple Group
who underwent total or subtotal resection and had remaining tumors smaller than 2
cm (Group B), those in Single Group treated with partial resection (Group C), and
the other patients in Multiple Group (Group D). RESULTS: The median survival was
8.7 and 9.2 months for the Single Group and the Multiple Group, respectively (not
statistically different). The median survival was 9.6, 12.4, 3.7, and 4.5 months
for Groups A, B, C, and D, respectively. Survival duration differed significantly
between Groups A/B and Groups C/D (p < 0.05). CONCLUSIONS: Surgical reduction of
tumor volume which is approximately larger than 2 cm improves the efficacy of
adjuvant radiation therapy and contributes to survival even in the patients with
multiple brain metastases.
PMID- 10769729
TI - Recurrent liposarcomas of the abdomen and retroperitoneum: three case reports.
AB - We report three cases of patients with liposarcomas of the abdomen who had been
treated during the last 13 years (1980-1993). Two patients were men, aged 29 and
51 years, with tumors of the retroperitoneal space and the third patient was a
woman aged 64 years with a tumor in the peritoneal cavity. Therapeutic treatment
was as aggressive as possible excision of the tumor. In the case of the first
male patient, the histological examination revealed a retroperitoneal myxoid
liposarcoma which recurred 5 times within 13 years. In the second male patient,
it revealed a well differentiated retroperitoneal liposarcoma of the sclerosing
type which recurred 5 times within 5 years since the first treatment. Finally,
the one female patient had 2 recurrences of myxoid liposarcoma of the abdomen 9
years after the first operation, presented with an infected mass and has been
well since then.
PMID- 10769730
TI - A comparison of Web page and slide/tape for instruction in periapical and
panoramic radiographic anatomy.
AB - Self-guided slide/tape (ST) and web page (WP) instruction in normal radiographic
anatomy of periapical and panoramic images is compared using objective test
performance and subjective preference of freshman dental students. A class of
seventy-four students was divided into a group studying anatomy in periapical
images using WP and a group studying similar ST material. In a modified cross
over design the groups switched presentation technologies to learn anatomy in
panoramic images. Students completed self-administered on-line quizzes covering
WP materials and conventional quizzes for ST material. Students also completed a
voluntary survey. Mean quiz performance identifying matched anatomic features in
PA (n = 26) and panoramic images (n = 35) was excellent (96.9%) and not different
between image types (p = 0.12) or presentation technologies (p = 0.81). Students
preferred WP for accessibility, ease of use, freedom of navigation, and image
quality (p < .01). Student comfort level with the quiz formats of the two
technologies was not different (p = 0.11). Students experienced a higher rate of
mechanical and logistical problems with ST than with WP technology. While 71
percent of the students preferred WP technology, this preference appears to be
related to ease of use and facilitation of flexible learning styles rather than
improved didactic performance.
PMID- 10769731
TI - Management of patients needing antibiotic prophylaxis in a dental education
setting.
AB - The management of antibiotic prophylaxed (ABX) patients at an educational
institution was evaluated to identify areas for improvement. Management criteria,
reflecting guidelines to prevent oral-induced hematogenous microbial seeding,
were pretested and applied to 1,225 record entries of eighty-five patients
needing ABX for dental treatment between 1991 and 1996. Seven hundred twenty-two
of the visits had 857 management or documentation problems, including no
documentation indicating whether or not patients premedicated (n = 281);
incomplete, insufficient, or repeated treatment (n = 214); and preventive
concerns (n = 172), among others. The proportion of providers' patient visits
with one or more management problems differed significantly (p < 0.001) by
provider type, as did the distribution of problem categories (documentation,
treatment, preventive, and scheduling concerns p < 0.001; compliance issues p <
0.005). Fifty-one percent of postgraduates' and 39 percent of faculty's record
entries omitted patients' ABX status. Improved documentation, outcome measures,
and patient, faculty and student education are indicated.
PMID- 10769732
TI - A corpus-linguistic investigation of dental English.
AB - This article begins by presenting corpus linguistics and explaining how the
corpus approach to language analysis can be used to investigate the language of
dentistry. It then reports findings from an analysis that was carried out with
readily available software and a corpus of 1,400 dental research abstracts.
Included is information about word frequency in dental abstracts and also about
how certain words tend to co-occur in sentences and form regular patterns. The
article concludes with a discussion of ways that corpus-based findings can be
applied to the teaching of English to non-native speakers of the language, many
of whom will need English skills for their future careers in dentistry.
PMID- 10769733
TI - The use of gaming in a dental hygiene review course.
PMID- 10769734
TI - A revisitation of dental student's attitudes toward individuals with AIDS.
PMID- 10769735
TI - Prosthodontic Olympics: gaming to aid students gain proficiency.
PMID- 10769736
TI - Simplified AFLP protocol: replacement of primer labeling by the incorporation of
alpha-labeled nucleotides during PCR.
PMID- 10769737
TI - Rapid quantification of cell numbers using computer images.
PMID- 10769738
TI - Sequencing difficult DNA templates using membrane-mediated loading with hot
sample application.
PMID- 10769739
TI - Mix of sequencing technologies for sequence closure: an example.
PMID- 10769740
TI - Rapid, high-yield method for the bulk purification of fibronectin from human
plasma.
PMID- 10769741
TI - Isolating PCR-quality DNA from human feces with a soil DNA kit.
PMID- 10769742
TI - Ethylene as a gaseous reporter molecule for monitoring gene expression in
cultured cells.
PMID- 10769743
TI - Efficient DNA subcloning through selective restriction endonuclease digestion.
AB - Described here is a selective restriction endonuclease digestion method that
eliminates the electrophoresis step that is usually used during the subcloning of
new DNA sequences into typical E. coli-based plasmids. The method increases yield
while decreasing laboratory resource and time utilization. By using donor and
acceptor sequences that contain unique restriction sites found only outside of
the intended recombination sequences, the initial digestion products can be
directly combined without electrophoresis if the ligation step is followed by a
selective digestion using the unique restriction enzymes before transformation.
This system is based on the several order of magnitude decrease in transformation
efficiency of linearized compared to circular plasmids. As an example, this
method was used to obtain recombinants between a 3.6 kb acceptor plasmid and 3.0
kb insert following one ligation reaction after the failure of nine standard
reactions using similar amounts of input DNA. It is particularly applicable to
situations in which low subcloning efficiencies are expected. The technique can
be extended to a large percentage of planned recombinations by using nonidentical
compatible cohesive or blunt-ended fragments, or site-directed mutagenesis.
PMID- 10769744
TI - DNA extraction method for screening yeast clones by PCR.
AB - A simple procedure for isolating yeast DNA suitable for use as a template for PCR
amplification is described. SDS treatment alone is sufficient for extraction of
chromosomal DNA from yeast cells. Cells of a yeast colony are suspended in a
small volume (about 20 microL) of a 0.25% SDS solution, mixed vigorously and
centrifuged. The supernatant can be directly used as a template after dilution to
give an SDS concentration of less than 0.01% in the final PCR mixture.
PMID- 10769745
TI - Heteroduplex resolution using T7 endonuclease I in microbial community analyses.
AB - Microbial community analyses using molecular techniques, such as PCR followed by
genomic library construction, have been helpful in better understanding microbial
communities. This is especially critical in ecological systems where most of the
microbes present cannot be cultured using traditional techniques. Unfortunately,
there are problems associated with the use of such molecular techniques for the
analysis of microbial community structure, primarily from the frequent formation
of PCR artifacts. Multitemplate PCR is often subject to errors such as
heteroduplex formation that is generated during the amplification of a particular
gene from a mixed community of DNA. Based on work in this laboratory,
heteroduplexes may be resolved before carrying out genomic library construction
by including a digestion step with T7 endonuclease I. Here, the 18S rDNA gene of
fungi was amplified from soil community DNA and digested with T7 endonuclease I
to resolve any heteroduplexes present in the PCR product before cloning. These
samples were compared with replicates that did not receive the T7 endonuclease I
treatment. Digestion of the amplified community 18S rDNA with 10 U T7
endonuclease I/microgram DNA prior to cloning eliminated heteroduplexes, leaving
only the desired clones. Without the T7 endonuclease I treatment, heteroduplexes
were produced in approximately 10% of the recombinants screened. The addition of
this step may eliminate heteroduplexes from PCR products and ensure that
subsequent genomic library construction is not compromised.
PMID- 10769746
TI - Relative quantitative RT-PCR protocol for TrkB expression in neuroblastoma using
GAPD as an internal control.
AB - An RT-PCR protocol for the relative quantitative measurement of TrkB transcripts
using glyceraldehyde-3-phosphate-dehydrogenase (GAPD) transcripts as an internal
control is described. Both TrkB and GAPD sequences were co-amplified in the
exponential phase of amplification using 5'-biotinylated primers. The PCR
products were subjected to PAGE, electro-transferred to nylon membrane and
detected by a chemiluminescent procedure using alkaline phosphatase conjugated
with avidin. Signals detected on X-ray film were analyzed by densitometry. The
ratio between TrkB and GAPD expression levels was determined to normalize the
expression levels of TrkB transcripts. Initially, strong signals of GAPD
transcripts led to overexposure of X-ray film compared to those of TrkB, which
causes difficulties in the accurate determination of the TrkB/GAPD ratio. To
circumvent this problem, uniformly biotinylated GAPD primers were replaced with a
mixture of biotinylated and non-biotinylated GAPD primers of the same sequence
and concentration. GAPD signals detected on X-ray film were proportionally
decreased as the amount of biotin-labeled primers was reduced in the total GAPD
primers. This modification enabled both GAPD and TrkB signals to be analyzed
within the linear range of X-ray film detection without affecting the
amplification efficiency of TrkB sequence. Use of composite primers may have a
wide range of applicability in quantitative analysis of nucleic acids.
PMID- 10769747
TI - Sensitive single-stage PCR using custom-synthesized internal controls.
AB - A new approach for an internally controlled PCR was developed using a custom
synthesized oligonucleotide as the internal control. Three different PCR setups
demonstrated the usefulness of this approach: (i) the addition of the respective
internal control to samples containing ssDNA virus Parvo B19; (ii) the co
extraction of plasma samples and the respective internal control for the
detection of the ssDNA virus TTV; and (iii) the addition of the respective
internal control to a crude lysate of tail pieces for the genotyping of FVIII
knockout mice, demonstrating that this approach is also applicable for dsDNA.
PMID- 10769748
TI - Q vectors, bicistronic retroviral vectors for gene transfer.
AB - We have developed a retroviral vector that incorporates unique features of some
previously described vectors. This vector includes: 3' long terminal repeats
(LTRs) of the self-inactivating class; a 5' LTR that is a hybrid of the
cytomegalovirus (CMV) enhancer and the mouse sarcoma virus promoter; an internal
CMV immediate early region promoter to drive expression of the transduced gene
and the neomycin phosphotransferase selectable marker; an expanded multiple
cloning site and an internal ribosome entry site. An SV40 ori was introduced into
the vector backbone to promote high copy number replication in packaging cell
lines that express the SV40 large T antigen. We demonstrate that these retroviral
constructs, designated Q vectors, can be used in applications where high viral
titers and high level stable or transient gene expression are desirable.
PMID- 10769749
TI - Electrophoretic detection of single-nucleotide polymorphisms.
AB - Single-nucleotide polymorphisms (SNPs) represent the most prevalent class of
genetic markers available for linkage disequilibrium or cladistic analyses. PCR
primers may be labeled with fluorescent dyes and used to rapidly and accurately
differentiate among alleles that are defined by a single-nucleotide differences.
Here, we describe the primer-mediated detection of SNPs based on primer mismatch
during allele-specific amplification of preamplified target sequences. Primers
are labeled with different fluors at their 5' nucleotides, with their 3' termini
at the transition mutation that defines allelic variation at the target locus.
Each primer perfectly matches one of the two available alleles for each locus.
Electrophoretic detection permits characterization of the product both by size
and fluor. This report demonstrates some of the capabilities of this assay,
including heterozygote determination and multiplexed analysis.
PMID- 10769750
TI - Optimized multiplex IgH/ras PCR: a tool for quantitative monitoring of B
lymphoproliferative disorders.
AB - The use of quantitative PCR is recommended to monitor the level of residual
hematological malignancies. The proposed multiplex IgH/ras PCR uses a co
amplification of the clonal CDR3 rearrangement of the immunoglobulin heavy chain
gene (IgH) as a disease marker and a segment of the Hras 1 gene containing codon
61 (ras) as a control gene. Serial dilutions of stored diagnostic DNAs are
examined together in the same PCR at a sub-plateau phase and, after analysis by
densitometry, the amount of CDR3 product is related to the ras product. An
increase of this ratio at comparable amounts of DNA is viewed as an increase of
malignant cells. This endpoint PCR quantifying approach appears to be applicable
in monitoring B-lymphoproliferative disorders as was shown to be true in B-cell
non-Hodgkin's lymphoma and may provide information on disease activity and
treatment outcome.
PMID- 10769751
TI - Analysis of fast dynamic processes in living cells: high-resolution and high
speed dual-color imaging combined with automated image analysis.
AB - The generation of spectral mutants of the green fluorescent protein (GFP) set the
stage for multiple-color imaging in living cells. However, the use of this
technique has been limited by a spectral overlap of the available GFP mutants
and/or by insufficient resolution in both time and space. Using a new setup for
dual-color imaging, we demonstrate here the visualization of small, fast moving
vesicular structures with a high time resolution. Two GFP-fusion proteins were
generated: human chromogranin B, a secretory granule matrix protein, and phogrin,
a secretory granule membrane protein. They were tagged with enhanced yellow
fluorescent protein (EYFP) and enhanced cyan fluorescent protein (ECFP),
respectively. Both fusion proteins were cotransfected in Vero cells, a cell line
from green monkey kidney. EYFP and ECFP were excited sequentially at high time
rates using a monochromator. Charged coupled device (CCD)-based image acquisition
resulted in 5-8 dual-color images per second, with a resolution sufficient to
detect transport vesicles in mammalian cells. Under these conditions, a fully
automated time-resolved analysis of the movement of color-coded objects was
achieved. The development of specialized software permitted the analysis of the
extent of colocalization between the two differentially labeled sets of cellular
structures over time. This technical advance will provide an important tool to
study the dynamic interactions of subcellular structures in living cells.
PMID- 10769752
TI - Homogeneous scoring of single-nucleotide polymorphisms: comparison of the 5'
nuclease TaqMan assay and Molecular Beacon probes.
AB - Homogeneous assays based on real-time fluorescence monitoring during PCR are
relevant alternatives for large-scale genotyping of single-nucleotide
polymorphisms (SNPs). We compared the performance of the homogeneous TaqMan 5'
nuclease assay and the Molecular Beacon assay using three SNPs in the human
estrogen receptor gene as targets. When analyzing a panel of 90 DNA samples, both
assays yielded a comparable power of discrimination between the genotypes of a C
to-T transition in codon 10 and a G-to-A transition in codon 594 of the estrogen
receptor gene. The Molecular Beacon probes distinguished better than the TaqMan
probes between homozygous and heterozygous genotypes of a C-to-G transversion in
codon 325. The sensitivity of detecting one allele, present as a minority in a
mixed sample, varied between the SNPs and was similar for both assays. With the
Molecular Beacon assay, the measured signal ratios were proportional to the
amount of the minor allele over a wider range than with the TaqMan assay at all
three SNPs.
PMID- 10769753
TI - Use of denaturing HPLC to map human and murine genes and to validate single
nucleotide polymorphisms.
AB - Linkage mapping has been extensively applied in the murine and human genomes. It
remains a powerful approach to mapping genes and identifying genetic variants. As
genome efforts identify large numbers of single-nucleotide polymorphisms, it will
be critical to validate these polymorphisms and confirm their gene assignment and
chromosomal location. The presence of pseudogenes can confuse such efforts. We
have used denaturing HPLC to identify polymorphisms in human genes and to
genotype individuals in selected CEPH pedigrees. The same approach has been
applied to the mapping of murine genes in interspecies backcross animals. This
strategy is rapid, accurate and superior in several respects to other
technologies.
PMID- 10769754
TI - Scanning by DOVAM-S detects all unique sequence changes in blinded analyses:
evidence that the scanning conditions are generic.
AB - The [detection of virtually all mutations]-SSCP (DOVAM-S) is a highly sensitive
variant of single strand conformation polymorphism (SSCP). Mutations in the
factor IX gene were used to find a set of five SSCP conditions that detects
virtually all mutations. A blinded analysis of the factor IX gene in patients
with hemophilia B detected 82 of 82 unique mutations. Since the method was
developed and tested on the factor IX gene, it is possible that the conditions
selected work more efficiently in the factor IX gene than in other genes. To test
the general applicability of the conditions under which DOVAM-S detected all
mutations in this gene, blinded analyses were performed in the human factor VIII
and ataxia-telangiectasia (ATM) genes. Segments were amplified individually,
combined into groups of 16 to 18 amplified segments and electrophoresed in five
different nondenaturing conditions of varying matrices, buffers, temperatures and
additives. Blinded analyses were performed in 92 samples from patients with
hemophilia A (factor VIII gene) and 19 samples from A-T patients (ATM gene).
Combined with an earlier blinded analysis in the factor IX gene, all of the 250
mutations and polymorphisms (180 of which are unique) were detected in both
analyses. For two, three and four joint conditions, the average detection
frequency ranged from 77%-97%, 91%-100% and 95%-100%, respectively. For each of
the genes, one mutation may have been missed if only four conditions were used.
With DOVAM-S, approximately 500 kb of autosomal sequence can be scanned in five
gels with virtually 100% detection of mutations within the scanned region. The
detection of 180 out of 180 unique sequence changes implies that DOVAM-S detects
at least 96.5% (P = 0.03) of mutations. Blinded analyses that detect 400 unique
sequence changes are required to determine that a scanning method detects at
least 98.5% of mutations.
PMID- 10769755
TI - Using the fluorogenic 5' nuclease assay for high-throughput detection of (CA)n
repeats in radiation hybrid mapping.
AB - Here, the power of the 5' nuclease assay to detect PCR products containing (CA)n
repeats was compared with that of the classical electrophoretic analysis. This
assay, which relies on the use of a unique (CA)10 energy transfer-labeled probe
and the 5' nuclease activity of Taq DNA polymerase, was used to construct a dog
radiation hybrid map consisting of microsatellite markers. Data from over 7000
PCRs were analyzed in parallel by the fluorogenic assay and the conventional
ethidium bromide-stained, agarose gel-based assay. We show that the fluorogenic
assay provides a sensitive, reliable and specific method for detecting (CA)n
amplimers. Moreover, as no processing is required after the PCR, the risk of
carryover contamination and the time required for sample analysis are greatly
reduced. All radiation hyrid (RH) assays can be performed using a single PCR
protocol, and a standard analysis method has been developed that enables
numerically automated data processing. On the whole, using this strategy greatly
enhanced the rapidity, throughput and accuracy of the RH mapping of
microsatellite markers.
PMID- 10769756
TI - Comparison of two PCR techniques used in amplification of microdissected plant
chromosomes from rice and wheat.
AB - Linker adaptor-mediated PCR (LAM-PCR) and degenerate oligonucleotide primed PCR
(DOP-PCR) are major ways to generate chromosome-specific libraries. In this
study, these two PCR techniques were used to amplify the microdissected mitotic
and meiotic chromosomes from rice and wheat. The results of amplifications were
compared, and the advantages and limitations between the two techniques are
presented.
PMID- 10769757
TI - General method for HPLC purification and sequencing of selected dsDNA gene
fragments from complex PCRs generated during gene expression profiling.
AB - Gene expression profiling using an AFLP-based technique generates a large number
of gene fragments that require identification by sequencing. The DNA fragments
vary in length from about 50-500 bp. Ion-pair reversed-phase HPLC can be used to
purify selected double-stranded DNA fragments that represent differentially
expressed genes. The gene fragments are sequenced directly after vacuum drying of
the collected HPLC fractions.
PMID- 10769758
TI - New positive selection system based on the parD (kis/kid) system of the R1
plasmid.
AB - The use of vectors that are designed to allow positive selection of recombinants
facilitates cloning experiments in E. coli. Using kid, a lethal gene of the R1
plasmid parD locus, we generated pKID vectors leading to high selective
efficiency of recombinants (greater than 90%). The E. coli bacterial host used to
propagate these vectors produces the Kis protein, the natural antagonist of Kid.
This new positive-selection system exhibits the same efficiency as the original
ccdB-based selection vectors, pKIL (4). We also show that the ccdB and kid
systems are independent. This property increases the potential of plasmidic
poison-antidote systems for genetic applications and opens the door to a
generation of new vectors containing the two selection systems.
PMID- 10769759
TI - Multiple epitope tagging of expressed proteins for enhanced detection.
AB - Three FLAG epitopes have been incorporated into the mammalian expression vector
pCMV-5 to create a transient expression vector, p3XFLAG-CMV-7. The vector was
designed to express FLAG fusion proteins that can be detected at tenfold lower
expression levels than the current FLAG fusion protein expression system. The
usefulness of this expression and detection system was demonstrated by expression
of bacterial alkaline phosphatase in COS-7 cells. In addition, 3XFLAG bacterial
alkaline phosphatase was expressed in Escherichia coli, purified on anti-FLAG M2
affinity gel, and detection of 500 pg of purified protein by Western blot
analysis is demonstrated.
PMID- 10769760
TI - Ion pair-reversed phase HPLC approach facilitates subcloning of PCR products and
screening of recombinant colonies.
AB - The isolation of a single DNA molecule for cloning is technically difficult, and
the subsequent screening of colonies for recombinant DNA clones is time
consuming. Ion pair-reversed phase HPLC (IP-RP-HPLC) analysis of nucleic acids
improves the resolution and isolation of PCR products to be cloned. We
demonstrate that PCR products analyzed and collected using the IP-RP-HPLC
approach (WAVE DNA Fragment Analysis System) can be cloned directly into a
plasmid vector. In addition, we demonstrate that when IP-RP-HPLC analysis is
extended to the colony screening process, the time required for these procedures
is reduced.
PMID- 10769761
TI - Perception is reality.
PMID- 10769762
TI - Work force oversupply not a problem.
PMID- 10769763
TI - Strongyle resistance to fenbendazole in horses.
PMID- 10769764
TI - An ethicist's commentary on rabies vaccinations of raccoons.
PMID- 10769765
TI - Equine orbital neoplasia: a review of 10 cases (1983-1998).
AB - The clinical manifestations, laboratory findings, and survival times of 10 horses
with orbital neoplasms are reported. In all cases, orbital neoplasms were
malignant and locally invasive with no defined surgical circumscribed edges. It
was often difficult to identify the primary cell type of the neoplasia in
histologic specimens due to the poorly differentiated, anaplastic nature of the
majority of cases. All except one horse were eventually euthanized 2 mo to 5 y
after diagnosis due to poor response to treatment, metastasis, or unrelenting
orbital neoplasia. Mean survival time increased with surgical treatment, but no
significant difference was found among no treatment, chemotherapy, surgical mass
removal, or exenteration/enucleation. Equine practitioners should be aware of the
marked difference in prognosis of orbital neoplasms compared with ocular or
localized eyelid neoplasia.
PMID- 10769766
TI - Clinical efficacy and tolerance of meloxicam in dogs with chronic osteoarthritis.
AB - A clinical trial was conducted to evaluate the safety and efficacy of the
nonsteroidal anti-inflammatory drug meloxicam in dogs with chronic
osteoarthritis. Forty clinical cases were enrolled in the 2-phase study. Phase 1
compared therapeutic efficacy and tolerance of meloxicam or placebo for 1 week.
Phase 2 involved a 4-week evaluation of the drug's clinical efficacy and
tolerance. Clinical efficacy was evaluated by using a scoring system that
assessed specific lameness, general stiffness, painful rise, exercise
intolerance, and behavior. Evaluations demonstrated significant reductions (P <
0.05) in clinical signs of osteoarthritis following 4 weeks of drug therapy. Side
effects were minimal in extent and duration. The drug was accepted without
problems in the majority of cases. The findings of this investigation suggest
that the efficacy, tolerance, and formulation of meloxicam oral suspension make
it well suited for the treatment of chronic osteoarthritis in the dog.
PMID- 10769767
TI - Cross-sectional study of the association of abomasal displacement or volvulus
with serum electrolyte and mineral concentrations in dairy cows.
AB - The objective of this study was to evaluate serum mineral and electrolyte
concentrations at the time of on-farm diagnosis of left displaced abomasum, right
displaced abomasum, or abomasal volvulus in dairy cows. Data were collected from
104 affected cows and 96 control cows matched with cases, based on herd, parity,
and stage of lactation. Cows with abomasal displacement or volvulus had
significantly lower calcium, phosphorous, magnesium, potassium, and chloride
concentrations and increased anion gap at the time of diagnosis compared with
control cows from the same herds. The percentages of cases and controls with
total serum calcium concentrations below the lower limit of the laboratory
reference range (2.08 mmol/L [8.3 mg/dL]) were 70% and 23%, respectively. Based
on the large percentage of cases with hypocalcemia, administering calcium salts
at the time of treatment of field cases of abomasal displacement or volvulus may
be beneficial.
PMID- 10769768
TI - The effect of tilmicosin administered to ewes prior to lambing on incidence of
clinical mastitis and subsequent lamb performance.
AB - The effect of tilmicosin on the incidence of clinical mastitis and subsequent
lamb performance was studied in 9 sheep flocks in Ontario. Ewes were treated
randomly with either tilmicosin or placebo approximately one month prior to
lambing. Outcome was assessed by comparing rates of clinical mastitis, palpable
udder abnormalities, and preweaning (50-day) lamb weights between the 2 treatment
groups, while controlling for other important variables. Lambs raised by
multiparous ewes treated with tilmicosin were significantly heavier than lambs
from placebo-treated multiparous ewes at 50 days. Lambs from tilmicosin-treated
ewes were on average 0.52 kg heavier than lambs in the placebo group. There was
no difference between treatment groups in the weight of lambs from first parity
ewes. Tilmicosin treatment resulted in a 43% decrease in palpable udder
abnormalities. Incidence of clinical mastitis did not differ between experimental
groups. The administration of tilmicosin prelambing, at the time of routine
clostridial disease vaccination, may be a beneficial and convenient way to reduce
mastitis infection and improve the preweaning gain of lambs.
PMID- 10769769
TI - Incursion of bluetongue virus into the Okanagan Valley, British Columbia.
AB - Bluetongue virus was isolated from a sentinel herd in British Columbia. Virus
isolation was by intravenous inoculation of embryonated chicken eggs and
subculture in BHK-21 cells. The cytopathic agent was identified as bluetongue
virus by electron microscopy and the immunoperoxidase test. The serotype was
identified as serotype 11 by virus neutralization.
PMID- 10769770
TI - An unusual presentation of enzootic bovine leukosis.
AB - A 6-year-old, Holstein x Simmental cow diagnosed with pyelonephritis had
increasing difficulty rising and became recumbent, despite treatment with
antibiotics. A serological test for the bovine leukemia virus was positive; at
necropsy, the left kidney and ureter and the myocardium showed lesions of
lymphosarcoma, confirmed by histology.
PMID- 10769771
TI - Renal infestation with Parvicapsula minibicornis in wild sockeye salmon from the
Harrison and Adams rivers in British Columbia.
PMID- 10769772
TI - Preliminary results from the Canadian Veterinary Urolith Centre.
PMID- 10769773
TI - Seroprevalence of leptospirosis in lynx and bobcats from Quebec.
PMID- 10769774
TI - Successful treatment of vaginal occlusion in a mare.
PMID- 10769775
TI - Did you plan ahead? If not, at least plan now!
PMID- 10769776
TI - Diagnostic ophthalmology. Bullous spectaculopathy++ in a king snake.
PMID- 10769777
TI - The effect of particle morphology on the physical stability of pharmaceutical
powder mixtures: the effect of surface roughness of the carrier on the stability
of ordered mixtures.
AB - The effect of particle morphology of the components on the physical stability of
ordered mixtures was determined for a model system comprised of a mixture of
micronized aspirin and a monodisperse carrier. Spray-dried lactose, crystallized
lactose, microcrystalline cellulose, and dextrate were used as carriers. The
surface texture of the carriers was quantified in terms of the ratio of the
perimeter of the particles to that of an idealized shape at a constant
magnification. Mixtures containing highly textured carriers segregated to a
lesser extent than those containing smoother textured carriers. This was
postulated to be due to the presence of a higher concentration of surface
asperities on the coarse carriers that can constitute potentially strong adhesion
sites for the fine component because of their higher energy relative to adjacent
areas on the surface. The effect of the addition of a ternary component,
magnesium stearate, on the stability of the above mixtures was studied. The
observed differences in the segregation response were attributed to electrostatic
charge effects.
PMID- 10769778
TI - Aqueous solubility of diclofenac diethylamine in the presence of pharmaceutical
additives: a comparative study with diclofenac sodium.
AB - Aqueous solubility of diclofenac diethylamine (DDEA), a nonsteroidal anti
inflammatory drug currently formulated as a topical emulgel, was studied in the
presence of pharmaceutical additives and compared with diclofenac sodium (DS).
Electrolytes at low concentrations exhibited a salting-in effect on DDEA with
peak solubility that was attributed to the association of DDEA into micelles,
followed by a salting-out effect at higher concentrations, by which structure
formation by DDEA molecules increased and precipitation occurred. For DS, which
is not capable of forming micelles, the salting-out effect was dominant due to
the common ion effect. Cosolvents displayed significant enhancement in solubility
of both salts except glycerol, which showed a slight increase in solubility of
DDEA and a decrease in solubility of DS due to transformation into the less
soluble hydrate form. Ethanol and polyethylene glycol (PEG) 400 cosolvent systems
at all concentrations showed positive deviations from the log-linear solubility
equation. In the case of propylene glycol (PG) cosolvent systems, negative
deviations were observed at low volume fractions of cosolvent, while positive
deviations were observed at high volume fractions of cosolvent for DS and DDEA.
The parent drug, being less ionizable and highly nonpolar, showed negative
deviations up to 90% PG content. Thus, the positive deviations for DS and DDEA
could be attributed to the more ionizable carboxylic group and its higher ability
for hydrogen bonding at higher fractions of cosolvent. Polyvinylpyrrolidone (PVP)
and PEG4000 or PEG6000 enhanced the solubility of DS and DDEA, with PVP exerting
higher solubilizing efficiency and DS showing better solubility than DDEA.
Solubilities of DS in Tween 80 (T80) and Pluronic F-127 (PF127) aqueous solutions
were almost similar, while the solubility of DDEA in the presence of T80 was
higher than the solubility in the presence of PF127. DS appeared to be located
more in the polyoxyethylene mantle of the micelles, while DDEA was located more
in the core of the micelles.
PMID- 10769779
TI - The effect of the membrane fluidity on pharmacokinetics for lipid A analog E5531.
AB - The effect of the dispersing procedure on the aggregate size, membrane fluidity
and the pharmacokinetics were evaluated for the lipid A analog E5531. The size of
the aggregates prepared by the pH-jump method (pH 11.0-->7.3) was decreased,
reaching 20 nm with increasing dispersing time in 0.003 N NaOH (pH 11.0). The
membrane fluidity of the aggregates increased with increasing dispersing time.
When prepared by the normal dilution method (pH 7.3-->7.3), the size of the
aggregates remained constant at 150 nm and the membrane fluidity was smaller
compared to samples prepared by the pH-jump method. Using samples with different
degrees of hydration and different membrane fluidities prepared by the pH-jump
method, the pharmacokinetics after intravenous administration into rats were
evaluated, and the data obtained confirmed that the membrane fluidity was
correlated with the pharmacokinetics in rat. In addition, E5531 vials were stable
for 24 months at room temperature when used within 24 hr after reconstitution.
PMID- 10769780
TI - A stability study of ticlopidine products from 18 countries.
AB - The results of the stability study of ticlopidine formulations (250 mg and 100
mg) show that products available in many countries worldwide exhibit different
stability characteristics. Stability testing under the International Conference
on Harmonization (ICH) accelerated test conditions (40 degrees C/75% relative
humidity [RH], 3 and 6 months) was performed on a total of 43 products obtained
from 18 countries. The samples were visually examined for physical change and
analyzed for their content of degradation products, remaining ticlopidine, and in
vitro dissolution characteristics (in the case of tablets). Only 6 (16%) of all
the samples submitted to this study had a good stability profile. Their
appearance remained unchanged during the study; assay results were between 95%
and 100%; their impurity content did not exceed 0.25%; and in the dissolution
test, at least 75% of ticlopidine was dissolved after 30 min. Three samples had
excellent dissolution properties and showed a very high purity level (viz. 21,
40, and 43) over the course of the study.
PMID- 10769781
TI - Solubility and dissolution properties of generic rifampicin raw materials.
AB - Rifampicin shows polymorphism; therefore, it is necessary to select a suitable
crystal form at an early stage of development to ensure optimum solubility and
dissolution rates. This study was an investigation into the crystal properties of
several rifampicin raw materials currently being used by manufacturers of generic
rifampicin raw materials in South Africa. Powders were characterized by X-ray
diffraction (XRD), infrared (IR) spectroscopy, and differential scanning
calorimetry (DSC). The solubility in water and dissolution properties in water,
buffer pH 7.4 and 0.1 M HCl, were also measured. The main difference between the
powders was the amorphous content. XRD, IR, and DSC methods could detect the
presence of amorphous rifampicin. In contrast to expectations, an increase in
amorphous content significantly reduced the dissolution rate of the powders in
water and buffer pH 7.4. This behavior was attributed to the electrostatic
properties of the very fine particles in the amorphous powders. The results of
this study showed that the physical properties of rifampicin raw materials varied
not only among manufacturers, but also among batches from the same manufacturer.
PMID- 10769782
TI - In vitro release studies of piroxicam from oil-in-water creams and hydroalcoholic
gel topical formulations.
AB - The importance of piroxicam, a therapeutic anti-inflammatory drug, is well known.
Because of gastrointestinal disorders, dermatological dosage forms are
recommended most. In our first studies, oil-in-water (O/W) creams of piroxicam
(1% concentration) were prepared using glyceryl monostearate (GMS), stearic acid,
and triethanolamine as additive ingredients. In our second studies,
hydroalcoholic transparent gel formulations of this drug in a 0.5% concentration
were prepared using hydroxypropylcellulose (HPC) as the gelling agent. The
release of piroxicam from all formulations via dialysis through a cellulose
membrane into phosphate buffer pH 6.8 at 37 degrees C was studied. The effects of
additives such as propylene glycol and 2-propanol on the drug release were also
investigated. The release profiles from the standpoint of diffusion-controlled
processes, as well as zero-order and first-order kinetics, were evaluated, and
relevant parameters, such as diffusion coefficient, permeability coefficient, and
partition coefficient, were calculated. The release obeys both the diffusion
mechanism and first-order kinetics. The drug release from gel formulations
containing 10%, 20%, and 30% propylene glycol was decreased due to the
enhancement of viscosity. However, the limpidity of these formulations was
improved. Moreover, the release of drug from gel formulations containing 15% and
20% of 2-propanol was increased. These results show that a hydroalcoholic gel
formulation with HPC is a more suitable preparation of piroxicam when compared
with an O/W cream formulation.
PMID- 10769783
TI - Comparative studies with Kollicoat MAE 30 D and Kollicoat MAE 30 DP in aqueous
spray dispersions and enteric coatings on highly swellable caffeine cores.
AB - A film formulation containing Kollicoat MAE 30 D, Kollidon 30, Sicovit Rot 30,
titanium dioxide, talc, and a plasticizer for the aqueous manufacture of enteric
coatings was studied for the coagulations occurring with certain plasticizers and
for differences in resistance on highly swellable caffeine cores. Also included
in these investigations were the latices Kollicoat MAE 30 DP and Eudragit L 30 D
55. The coagulations occurring with all three film latices can be attributed to
the presence of Kollidon 30 together with certain excipients. Preparations with
Kollidon 30, but without color pigments, showed no tendency to coagulate. The
advantage of propylene glycol (PG) compared to other plasticizers such as
triethyl citrate (TEC) is that no coagulations occurred, even in the presence of
Kollidon 30 and color pigments. Among the Kollidon 30-free film formulations
examined, a plasticizer content of 10-15% PG or TEC gave the best results.
Optimal pigment distribution in the coat originally produced by Kollidon 30 can
optionally be achieved by prolonged stirring of the pigment suspension. The
resistance can be further improved by inclusion of a subcoating with Kollidon VA
64. Kollicoat MAE 30 D and MAE 30 DP and Eudragit L 30 D-55 showed identical
behavior in this study.
PMID- 10769784
TI - Low-level (PPB) determination of cisplatin in cleaning validation (rinse water)
samples. I. An atomic absorption spectrophotometric method.
AB - Suitable analytical methods are required for quantitative determination of trace
levels of ingredients in samples obtained for purposes of cleaning validation. We
describe below an atomic absorption method for the quantitation of cisplatin, an
antineoplastic agent, in aqueous samples. Cisplatin was reacted with
diethyldithiocarbamic acid (DDTC), sodium salt, to yield a platinum-DDTC (Pt
DDTC) complex. The Pt-DDTC chelate was extracted into methylene chloride, the
extract was mixed with acetonitrile, and the platinum content was then determined
using a Zeeman atomic absorption (AA) spectrophotometer. The extraction
conditions and AA experimental conditions were set up such that the detection
level could be extended to 0.5 ng/ml. Reproducible results were obtained at a
quantitative working standard concentration of 5 PPB. The absorbance response was
found to be a linear function of cisplatin concentration in the region between
0.5 PPB and 20 PPB, which is about 10% to 400% of the target analyte
concentration of 5 PPB. The target analyte concentration was set at 5 PPB such
that it was at least 10 times the detection limit of about 0.5 PPB.
PMID- 10769785
TI - Low-level (PPB) determination of cisplatin in cleaning validation (rinse water)
samples. II. A high-performance liquid chromatographic method.
AB - A high-performance liquid chromatographic (HPLC) method is described for the
determination of residual levels of cisplatin from extracts of surfaces with very
low surface area; from extracts of surfaces of coupons made of Teflon
(polytetrafluoroethylene, PTFE), stainless steel, and glass; and in aqueous
solution collected after rinsing equipment and parts. Initially, the method was
developed to determine cisplatin at concentrations ranging from 20 to 200 ng/ml
by direct injection. Retaining the same method conditions, the scope of the
method was expanded by the addition of a sample preconcentration step, allowing
analyses at levels ranging from 0.5 ng to 20 ng/ml. Preconcentration is necessary
for the determination of cisplatin in rinse waters at a quantifiable
concentration of about 2 PPB. Under these conditions, the detection limit is
about 0.2 to 0.3 ng/ml. Residual cisplatin on different types of surfaces,
including surfaces with very low surface area, can be determined by swabbing each
test surface with a derivatizing solution. The cisplatin recovered in the
swabbing solution can be analyzed by HPLC using direct injection or
preconcentration, depending on the expected level of cisplatin in the sample.
Initial methods were developed to quantitate at a cisplatin concentration of
about 100 PPB or higher in solution extracted from surfaces. However, when
surface areas are limited because of the size of the parts, solution
concentration becomes very low as a result of the minimum volume required for
extraction. To support the application of swabbing techniques to surface
analysis, stainless steel, Teflon, and glass surfaces were spiked with cisplatin
at 2.5 to 20 ng/cm2. Satisfactory overall recoveries of 90% +/- 10% were obtained
from all surfaces. Cisplatin has no ultraviolet/visible (UV/Vis) spectral-active
functional group that can be used to detect low levels of cisplatin. Hence,
diethyldithiocarbamate (DDTC) was used as a derivatizing agent to increase
sensitivity to UV absorption at 340 nm. Diethyldithiocarbamate forms complexes
with the platinum in cisplatin to yield a platinum-DDTC (Pt-DDTC) complex with a
high molar-extinction coefficient. The Pt(DDTC)2 complex thus formed was
chromatographically separated and the quantitated by comparison of its detector
response to that of a similarly derivatized standard preparation. DDTC also has
application as a cleaning agent for cisplatin (e.g., for production equipment
cleaning, spill cleanup). Destruction of cisplatin can be affected by the
reaction of cisplatin with this cleaning agent. Derivatization of cisplatin will
convert active cisplatin to platinum-DDTC on surfaces or in solution. Final
cleaning can be accomplished using a water-for-injection rinse. After such a
cleaning process, the rinse water, when collected and analyzed, showed levels of
free cisplatin less than the detection concentration of 0.2 PPB and a total
platinum concentration less than 10 PPB as Pt-DDTC complex.
PMID- 10769786
TI - Response surface analysis applied to the preparation of tablets containing a high
concentration of vegetable spray-dried extract.
AB - This work relates to the formulation of tablets containing a high proportion of
spray-dried extracts (SDEs) from Passiflora edulis leaves. The tablets were
prepared by direct compression. Colloidal silicon dioxide was selected as a
glidant and moisture adsorbent, cross-linked carboxymethycellulose was used as
the disintegrant, microcrystalline cellulose was the filler/binder, and
tricalcium phosphate as a spray-drying adjuvant. The colloidal silicon dioxide
and cross-linked carboxymethycellulose quantities and their influences on the
tablet hardness and disintegration time were studied by a central composite
design. The model equations were fitted to the experimental data and then
validated. It could be concluded that the colloidal silicon dioxide proportion
increased the hardness, and the cross-linked carboxymethycellulose proportion
determined a linear decrease of the disintegration time. The optimal values
chosen were 2.0% Aerosil 200 and 2.5% Ac-Di-Sol. The tablets showed a hardness of
85.02 N and a disintegration time of 7.35 min.
PMID- 10769787
TI - Possible mechanism for drug retardation from glyceryl monostearate matrix system.
AB - Lipophilicity was evaluated as a possible mechanism for drug retardation from a
glyceryl monostearate matrix system. Lipophilicity of the glyceryl monostearate
matrix system was studied using contact angle measurement of water droplets on
the surface of compressed disks, extrudate ascension of water, and movement of
water through a powder mixture packed in a high-performance liquid
chromatographic (HPLC) column. Increase in glyceryl monostearate content resulted
in an increase in water droplet contact angle, decrease in the rate of water
ascending the extrudate, and increase in the pressure values as a function of
flow rate of water moving through the powder mixture. These could be due to the
increase in lipophilicity of the matrix, rendering the matrix less wettable. As a
result, the rate of water penetration into the matrix decreased, and the drug
release could be sustained.
PMID- 10769788
TI - Diclofenac sodium: oxidative degradation in solution and solid state.
AB - The formation of two oxidative degradates of diclofenac in solution and the solid
state was demonstrated.
PMID- 10769789
TI - A new method for quality control of zinc pyritione pharmaceutical and cosmetic
forms.
AB - A simple high-performance liquid chromatographic (HPLC) method was developed to
determine zinc pyritione in pharmaceutical and cosmetic products. Reversed-phase
chromatography was conducted using a C18 column with an isocratic mobile phase
consisting of a suitable mixture of methanol, acetonitrile, and water
(30:2.5:20). The effluent was monitored on a ultraviolet (UV) detector at 243 nm.
The method was validated following International Conference on Harmonisation
(ICH) suggestions and proved accurate, precise, and specific.
PMID- 10769790
TI - Self-assembled carbohydrate-stabilized ceramic nanoparticles for the parenteral
delivery of insulin.
AB - The insulin-bearing aquasomes were fabricated by first preparing the nanosize
calcium phosphate dihydrate core. The calcium phosphate dihydrate core was
prepared by colloidal precipitation and sonication of disodium hydrogen phosphate
solution and calcium chloride solution at low temperature. This core was coated
with cellobiose, pyridoxal-5-phosphate, or trehalose under sonication and was
further loaded with the drug at low temperature by a partial adsorption
mechanism. The prepared systems were characterized for size, shape, size
distribution, drug loading efficiency, and in vivo performance. The in vivo
performance of the formulated aquasome was compared with standard porcine insulin
solution, and better results were observed compared to insulin solution.
PMID- 10769791
TI - Study of load capacity of Avicel PH-200 and Cellactose, two direct compression
excipients, using experimental design.
AB - The load capacity of two excipients, a large particle size grade of
microcrystalline cellulose (Avicel PH-200) and a coprocessed material composed of
lactose and pulverized cellulose (Cellactose) was determined using a model mix
with Dipyrone (metamizol sodium) and experiments planned by design of
experiments. A multiple-regression model was proposed, and as a result, a new
parameter, called specific load capacity SLC was obtained. This constant can be
determined for other excipients and drugs; it depends only on the excipient and
the drug used.
PMID- 10769792
TI - Transdermal delivery of propranolol using mixed grades of Eudragit: design and in
vitro and in vivo evaluation.
AB - A matrix-dispersion-type transdermal drug delivery system of propranol was
developed using different ratios of mixed polymeric grades of Eudragit.
Formulations were evaluated for in vitro dissolution characteristics using a
Cygnus' sandwich patch holder. Selected formulations followed zero-order release
kinetics. In vivo evaluation was carried out on healthy human volunteers
following a balanced incomplete block design (BIBD). In vitro dissolution rate
constant k and pharmacokinetic parameters generated from plasma and urine were
evaluated statistically. Statistically excellent correlation was found between
percentages of drug absorbed from patch versus Cmax, AUC0-24, and AUC0-alpha. A
highly significant difference was observed when Cmax and AUC0-alpha generated
from plasma and urine data were compared, but when ke, t1/2e, ka, and t1/2a were
compared, the difference was not significant. Urinary excretion data are
suggested as a simpler alternative to blood-level data in studying the kinetics
of absorption and deriving the absorption parameter.
PMID- 10769793
TI - [Clinical studies on renal pelvic and ureteral tumors].
AB - Clinical studies were performed on 35 patients with renal pelvic and/or ureteral
cancer treated at Kitano Hospital between 1988 and 1997. They consisted of 17
renal pelvic cancers, 17 ureteral cancers and 1 renal pelvic and ureteral cancer.
Twenty-nine patients were males and six were females, and their age ranged from
41 to 82 years old (average: 62.2). Histologically, 34 were transitional cell
carcinoma and 1 was adenocarcinoma. Pathological stage of the tumor was pTa in
34.3%, pT1 in 14.3%, pT2 in 11.4%, pT3 in 37.1%, and pT4 in 2.9%, and grade of
the tumor G1 in 11.8%, G2 in 58.8% and G3 in 29.4%. Eighteen patients (51%) had
or developed bladder cancer, which preceded the diagnosis of cancer of upper
urinary tract in 2 cases, coexisted in 4 cases and developed subsequently in 12
cases. The overall cause-specific survival rate was 91.3% at 1 year, 83.8% at 3
years and 79.4% at 5 years. Tumor stage, grade, lymph node metastasis and
vascular invasion had impact on survival.
PMID- 10769794
TI - [Clinical profiles of prostate cancer in our hospital: association between
primary symptoms and clinical stage].
AB - We analyzed the primary symptoms and clinical stage before and after 1988 when
the prostate specific antigen (PSA) measurement was introduced in 491 patients
with prostate cancer diagnosed in our hospital between 1976 and 1996. Most
primary symptoms were related to problems with urination both before and after
1988. However, after PSA measurement became available, the number of patients
referred to our hospital by non-urologists increased significantly. In contrast,
the frequency of patients with stage D2 disease decreased significantly and the
frequency of patients with early prostate cancer (stage A and B) did not
increase. Few patients with prostate cancer had PSA levels of 4 to 10 ng/ml. We
suggest that general use of PSA for prostate cancer screening by non-urologists
does not contribute to the early detection of prostate cancer, most likely
because few patients with prostate cancer have low PSA levels.
PMID- 10769795
TI - [Evaluation of varicocele by ultrasonography through a water bag in the supine
position].
AB - Recently, ultrasonography has been widely used to evaluate varicocele. However,
it is difficult to obtain reproducible scrotal images with a hand probe in the
standing position. We, therefore, applied the water bag technique during
ultrasonographic examination of the scrotal contents in the supine position. The
ultrasonographic images thus obtained were compared with physical findings and
scrotal scintigraphic findings. Forty-five varicocele patients diagnosed by
palpation and ultrasonography were enrolled in this study. An ultrasonographic
examination through a water bag in the supine position has the following
advantages 1) it is easy to perform and stable images are obtained, 2)
varicoceles that are not palpable can be detected and 3) examinations can be
repeated both pre- and postoperatively. Of the 45 patients, 39 and 41 had
positive findings on the ultrasonographic images and physical examinations,
respectively. Four patients had negative findings on physical examination but
positive findings on the ultrasonographic images. Thus, ultrasonographic images
through a water bag in the supine position proved to be a useful method of
confirming the hemodynamics in varicoceles.
PMID- 10769796
TI - [A case of unilateral and metachronous occurrence of renal tubulopapillary
adenoma and renal cell carcinoma].
AB - A 50-year-old male underwent a nephron-sparing surgery for a small renal
incidentaloma, which was atypical for renal cell carcinoma in diagnostic images.
The tumor was pathologically diagnosed as renal tubulopapillary adenoma. Three
years later, another tumor was pointed out in the ipsilateral kidney, and he
underwent a radical nephrectomy. The latter was diagnosed as clear cell
carcinoma. We report this very rare case of unilateral and metachronous
occurrence of renal tubulopapillary adenoma and renal cell carcinoma.
PMID- 10769797
TI - [Multicentric Castleman's disease found by a renal sinus lesion: a case report].
AB - A 79-year-old man complained of anorexia and weight loss. Computed tomography and
magnetic resonance imaging showed a solitary mass in the left renal sinus. Left
nephrectomy was carried out under a clinical diagnosis of renal pelvic tumor. The
pathological diagnosis was plasma cell type of Castleman's disease. The patient
suffered from lymph node swelling in the right neck at age 75 and the lymph node
was resected. The pathological diagnosis was lymphadenitis but it proved to be
plasma cell type of Castleman's disease. The patient also had had a
lymphadenectomy in the supraclavicular fossa and in the supraorbital area at age
76. Both had been diagnosed as lymphadenitis pathologically but they proved to be
plasma cell type of Castleman's disease. The final diagnosis was multicentric
Castleman's disease. We reviewed multicentric Castleman's disease.
PMID- 10769798
TI - [A case of cadaveric kidney transplantation from a heart-beating donor].
AB - We experienced a case of cadaveric kidney transplantation from a heart-beating
donor, a 23-year-old man who became brain dead after a traffic accident. The
recipient, a 39-year-old man, had been receiving regular hemodialysis since 1990,
was admitted to our hospital on June 14, 1999. The number of human lymphocyte
antigen mismatches was 3. The left kidney of the donor was transplanted to the
right iliac fossa of the recipient 6 hours 28 minutes after the start of in situ
cooling of the kidney. For the purpose of immunosuppressive induction,
tacrolimus, azathioprine, antilymphocyte globulin, methylpredonisolone and
deoxyspergualin were administered. Immediate function was obtained, moreover, the
serum creatinine level of the recipient was normalized without hemodialysis. The
histopathological examination of the transplant kidney biopsied 1 hour after
transplantation revealed little damage of renal tubules. Since no rejection
episode was recognized, the patient was discharged on the 48th day after
transplantation. This is the third case of cadaveric kidney transplantation from
a heart-beating donor after enforcement of the law concerning organ
transplantations in Japan.
PMID- 10769799
TI - [A case of infected renal cyst extending to leg abscess].
AB - A 45-year-old woman was referred to our hospital with the chief complaint of left
flank pain, left leg pain and loss of appetite. Computed tomography scan and
magnetic resonance imaging demonstrated a large cystic mass in the left kidney,
which we diagnosed as an infected renal cyst. Under ultrasonic guidance,
percutaneous puncture and drainage of the renal cyst were performed. After her
leg pain worsened, computed tomography revealed abscesses in the left leg,
suggesting an infected renal cyst extending to the leg through the obturator
foramen. Under general anesthesia, incision and drainage were performed. Cultures
from the cyst and abscess fluid showed Klebsiella pneumoniae. Our case is the
82nd case of an infected renal cyst in the Japanese literature.
PMID- 10769800
TI - [A case of renal tuberculosis following bacillus Calmette-Guerin instillation
therapy for bladder cancer].
AB - A rare case of histopathologically revealed renal tuberculosis caused by
intravesical bacillus Calmette-Guerin (BCG) therapy is reported. A 67-year-old
man was admitted complaining of fever and micturition pain. He had been
undergoing prophylactic BCG instillation therapy for recurrent superficial
bladder tumor. Physical examination was unremarkable. The tuberculin skin test
was negative. Mycobacterium tuberculosis (MT) was not demonstrated by acid-fast
staining and culture of urine. However, MT was isolated by the polymerase chain
reaction method. In the following 7 days, symptoms were dissolved with
administration of isoniazid, rifampicin and piperacillin. Two months later,
nephroureterectomy was performed because of left renal pelvic tumor. Tuberculomas
were also found in the renal parenchyma which showed no MT by Ziehl-Neelsen's
method. Anti-tuberculous medication was not given postoperatively. Two months
after operation, he is free of disease with normal urine examination and positive
tuberculin skin test measuring 12 x 10 mm.
PMID- 10769801
TI - [A case of synchronous ipsilateral renal cell carcinoma and ureteral transitional
cell carcinoma].
AB - A 62-year-old man was admitted to our hospital with the chief complaint of right
flank pain. Abdominal computed tomographic scan revealed a right hydronephrosis
and intrapelvic tumor. Ultrasound revealed a renal mass lesion. Ultrasound guided
renal biopsy and laparotomy of intrapelvic tumor was performed. The
histopathological diagnosis was renal cell carcinoma and ureteral transitional
cell carcinoma.
PMID- 10769802
TI - [Choriocarcinoma of the renal pelvis: a case report].
AB - A 68-year-old male presented to our hospital complaining of gross hematuria.
Intravenous pyelography subsequently demonstrated a left non-visualized kidney,
and he was admitted for further evaluation. Cystoscopy revealed a bladder tumor
around the left ureteral orifice and retrograde pyelography showed a filling
defect in the left renal pelvis. The urinary cytology from the left renal pelvis
indicated class IV, and the microscopic findings of a bladder biopsy demonstrated
grade 1 transitional cell carcinoma. We performed transurethral resection of
bladder tumor (TUR-BT) followed by left nephroureterectomy with bladder cuff. The
pathological diagnosis was high grade transitional cell carcinoma with
choriocarcinomatous component. After the operation, the serum human chorionic
gonadotropin-beta (hCG-beta) level was slightly elevated, and the combination
chemotherapy with methotrexate, vinblastine and cisplatin (MVC) was administered.
Although the serum hCG-beta level fell to 0.1 ng/ml, after two courses of MVC
chemotherapy, bilateral pulmonary metastases appeared in the chest X-ray with
increasing hCG-beta levels. Salvage chemotherapy with cisplatin, etoposide and
bleomycin (PEB) was performed. After two courses of PEB chemotherapy, the serum
hCG-beta level fell to within the normal range and all pulmonary metastases
disappeared.
PMID- 10769803
TI - Geriatric ureteropelvic junction obstruction: the possible role of an
arteriosclerotic lower pole branch of renal artery: report of two cases.
AB - An 83-year-old woman presented with left flank pain and high grade fever. After
left ureteral catheterization and intensive chemotherapy with hemoperfusion,
surgical exploration revealed the lower pole branches of the renal vessels were
obstructing the ureteropelvic junction (UPJ), and dissection of the vessels
released the obstruction. An 82-year-old man presented with right flank pain.
Angiography demonstrated UPJ obstruction caused by the lower pole branch of the
renal artery. Arterial dissection with dismembered pyeloplasty resulted in
improvement of obstruction. In both cases, the patients had a long history of
hypertension with mild to severe arteriosclerosis. Arteriosclerosis associated
with fixation of the UPJ, may be one of the important factors leading to
progressive hydronephrosis in geriatric patients.
PMID- 10769804
TI - [Stage pT1 signet ring cell carcinoma of the urinary bladder: a case report].
AB - A case of primary signet ring cell carcinoma of the urinary bladder is described.
A 59-year-old man presented with microscopic hematuria, and cystoscopy revealed a
white nonpapillary tumor. Histopathological examination of the resected tumor
revealed signet ring cell carcinoma and transitional cell carcinoma. Histological
depth of invasion was pT1. No adjuvant therapy was performed. Primary signet ring
cell of the urinary bladder is a rare tumor with 37 cases reported to date in
Japan. We investigated previously reported cases and discussed adjuvant therapies
of superficial signet ring cell carcinoma of the urinary bladder.
PMID- 10769805
TI - [Primary paraganglioma of the urinary bladder with high serum CA19-9 level: a
case report].
AB - A case of primary paraganglioma of the urinary bladder with a high serum CA19-9
level is reported. A 44-year-old woman visited our hospital with the chief
complaint of lower abdominal pain. Magnetic resonance imaging (MRI) examination
incidentally revealed a cystic bladder tumor. Cystoscopy disclosed a broad-based
non-papillary tumor on the posterior wall of the urinary bladder. With the
diagnosis of a bladder submucosal cystic tumor transurethral needle puncture and
biopsy were performed. The solution sampled with puncture was bloody. The patient
suddenly complained of headache and blood pressure was elevated to 215/120 mmHg
when we held the tumor with a cold cup biopsy forceps. Catecholamine levels of
the solution in the tumor were abnormally elevated. The serum CA19-9 level was
also raised. Ten days later, she underwent partial cystectomy. Histological
findings of the removed specimen showed primary paraganglioma of the urinary
bladder. The serum CA19-9 level decreased to normal limits on the 28th
postoperative day. Our experience suggests that the level of serum CA19-9 may
serve as a useful index for observing the clinical course of a patient with this
disease.
PMID- 10769807
TI - [Vesicovaginal fistula due to a vaginal foreign body: a case report].
AB - An 18-year-old female consulted a clinic complaining of pollakisuria and urinary
incontinence. She was referred to our department for operation under the
diagnosis of vesicovaginal fistula due to a vaginal foreign body confirmed by
intravenous pyelography and cystoscopic examination. About 7 months earlier, she
inserted a hair spray can into the vagina but could not remove its cap. The
vaginal foreign body was transvaginally removed. After 2 months, transabdominal
repair of the vesicovaginal fistula was performed. After operation, dysuria and
urinary incontinence were not observed. Few cases of vesicovaginal fistula due to
a foreign body in the vagina have been reported, and there have been only 6
reported cases in Japan including ours.
PMID- 10769806
TI - [Recurrent spontaneous rupture of the urinary bladder: a case report].
AB - The patient was a 67-year-old woman who had undergone radical hysterectomy and
postoperative radiotherapy for cervical cancer at the age of 46 years.
Spontaneous rupture of the urinary bladder occurred twice in 1997, and
conservative treatment was performed on each occasion. She was admitted to our
hospital for the third time of spontaneous rupture of the urinary bladder. She
underwent bilateral cutaneous ureterostomy because of panperitonitis and
paralytic ileus. A review of 11 cases of recurrent rupture of the urinary bladder
reported in Japan including the present case revealed that, patients who had been
conservatively treated tended to be subject to recurrence. However, the risk of
recurrence remains when a partial cystectomy is performed. Therefore, especially
in recurrent cases, augmentation cystoplasty or urinary diversion should be
considered as the treatment for spontaneous rupture of the urinary bladder due to
radiation cystitis.
PMID- 10769808
TI - [Statistics of the operations at the Department of Urology, Tone Chuo Hospital
during a six-year period (June 1993-May 1999)].
AB - A clinical statistic survey was made on the operations performed at the
Department of Urology, Tone Chuo Hospital between June 1993 and May 1999. The
total number of operations was 1296, consisting of 97 (7.5%) operations of the
kidney, 67 (5.2%) operations of the ureter, 190 (14.7%) operations of the
bladder, 454 (35.0%) operations of the prostate, 63 (4.9%) operations of the
urethra, 92 (7.1%) operations of the penis, 149 (11.5%) operations of the scrotum
and 184 (14.2%) other operations. With the aging society, the number of
operations for those over 60 years old has exceeded 60%.
PMID- 10769809
TI - Relationship between cerebrospinal fluid and extracranial lymph.
PMID- 10769810
TI - Thoracic duct lymph flow and its driving pressure in anesthetized sheep.
AB - We examined the relationship between thoracic duct lymph flow (TDF) and its
driving pressure (DP) in six anesthetized sheep. DP was determined as the
thoracic duct pressure (TDP) minus the innominate vein pressure (VP). TDF was
measured using an ultrasound transit-time flow meter, placing a flow probe beside
the caudal mediastinal lymph node. TDP was measured with a fine needle inserted
near the flow probe. TDP increased linearly together with an increase in VP after
balloon inflation in the cranial vena cava with a TDP/VP ratio of 0.79. DP
decreased, therefore, with an increase in VP and this decrease in DP correlated
directly with a fall in TDF. After rapid i.v. fluid infusion, TDF increased but
DP varied among the six sheep. Nonetheless, after balloon inflation with expanded
volume (i.e., i.v. fluid infusion), DP and TDF were positively correlated. We
conclude that DP is the main factor determining TDF when VP rises in conjunction
with increased lymph production.
PMID- 10769811
TI - Electromagnetic diathermia: a lymphoscintigraphic and light reflection
rheographic study of leg lymphatic and venous dynamics in healthy subjects.
AB - Because electromagnetic diathermia (ED) has been reported to reduce lymphedema,
we opted to examine the effects of ED on leg venous and lymph dynamics in healthy
subjects. To examine lymph flow, we performed lymphangioscintigraphy (LAS) in 10
subjects without leg edema and used static images at the injection site and at
the inguinal region for "control data." Later, we applied ED (2450 MHz, 200W) and
then repeated the LAS using the same dosage and volume. Differences between the
first and second sessions were examined using two way ANOVA and the differences
between the scores with or without ED were analyzed by a Student's t-test. To
examine venous flow, we first tested the left lower leg of 15 healthy subjects on
two occasions using light reflection rheography (LRR). Venous refill time was
recorded after each individual performed 10 dorsiflexions with the left foot on
three occasions with an interval of 3 minutes between each recording. Thereafter,
20 minutes ED (2450 MHz, 200 W) was applied and using the same protocol venous
refill time was recorded and repeated after an interval of one week. The 20%
level and the declination angle of the refill time was determined and differences
between the experimental and control groups analyzed by ANOVA. The results
between the first and second sessions were consistent and reproducible with or
without the electromagnetic application, with no change of radiotracer transport
from the injection site or arrival at the inguinal nodes. There was also a high
correlation between the scores for the 50% level and declination angle (r = 0.97)
after LRR. Thus, after ED there was an accelerated venous refill time. In
conclusion, after ED there was no increase in lymph flow but there was
accelerated venous return.
PMID- 10769812
TI - Effect of complex decongestive physiotherapy on gene expression for the
inflammatory response in peripheral lymphedema.
AB - Complex decongestive physiotherapy (CDP), consisting of manual lymph drainage,
compression bandaging, remedial exercises and skin care, mobilizes accumulated
edema fluid and increases lymph flow. On the other hand, it also has a beneficial
therapeutic effect on fibrosclerosis. Because little is known of its possible
mode of action on a molecular level, this preliminary study evaluated CDP in
patients with peripheral leg lymphedema as to the potential role of gene
expression in the inflammatory response. The quantitative expression of genes for
CD14, interferon-gamma receptor (IFN gamma R), tumor necrosis factor-alpha (TNF
alpha), integrin alpha 4 beta 1 (VLA-4), tumor necrosis factor receptor p55
(TNFR1) and CD44 (standard form) was examined in 9 patients with primary or
secondary leg lymphedema before and after phase 1 of CDP. Overall, there was a
decrease of expression of these pro-inflammatory genes after CDP, suggesting that
biologic mechanisms implicated in the inflammatory cascades in other disorders
are also involved in the fibrosclerotic reactivity in lymphedema. However,
whereas each patient acted as his or her own control before and after CDP, gene
expression in normal patients and normal limbs before and after CDP needs to be
examined before the full meaning of these observations can be understood.
PMID- 10769813
TI - Eicosanoid production and lymphatic responsiveness in human cigarette smokers
compared with non-smokers.
AB - Leg lymphatic segments were isolated from 10 patients (4 cigarette smokers and 6
non-smokers) undergoing conventional lymphography. Prostaglandin (PG) levels and
PG synthesis in the lymphatics and in a variety of body fluids and the effects of
eicosanoids on lymphatic contractility were determined. Leg lymphatics from 4
smokers generated less PGI2 and contained more 8-epi-PGF2 alpha when compared
with leg lymphatics in 6 non-smokers. Similarly, levels of 8-epi-PGF2 alpha in
smokers compared with non-smokers were higher in plasma (28.6 cf 19.7 pg/ml), leg
lymph (146.7 cf 65.3 pg/ml), serum (299.0 cf 204.1 pg/ml), and urine (473.4 cf
241.0 pg/mg creatinine). Lymphatics from smokers also showed a higher contractile
response, less 14C-arachidonic acid conversion to PGI2 and less PGI2-formation
with various stimuli compared with non-smokers. Together these findings suggest
that smoking induces oxidation injury, promotes altered (iso-)eicosanoid
production and impacts on the function and dysfunction of peripheral lymphatics
under normal circumstances and in a variety of clinical disorders.
PMID- 10769814
TI - Light microscopy of the human thoracic duct.
PMID- 10769815
TI - Neurostimulation.
PMID- 10769816
TI - Future prospects of brain stimulation.
AB - Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has
replaced thalamotomy as a treatment of tremor of various origins and was extended
to two other targets (Subthalamic nucleus (STN) and the medial pallidus (GPi)),
since 1993 based on recent experimental data in rats and monkeys. STN appears to
be a target of major interest, able to control the three cardinal symptoms and to
allow the decrease or suppression of levodopa treatment, which then suppresses
also levodopa induced dyskinesias. The mechanisms of action of HFS are not fully
understood, but are definitely related to high frequency and are probably
different depending on the target. Inhibition of cellular activity or of network
functions could be induced, by jamming of a retroactive loop for tremor, or by
shutdown of neurotransmitter release in STN. All cardinal symptoms are alleviated
from tremor to akinesia and rigidity. The effects remain stable over more than
five years chronic HFS of STN, as the method of choice when a surgical procedure
is indicated for the treatment of Parkinson's disease and even more when a
bilateral procedure is necessary. Recent data show that STN stimulation could be
useful in the treatment of dystonia as well as some forms of epilepsies. It is
therefore possible that DAS in STN as well as in other targets could become a
potent therapeutic tool in the future for neurological disorders. The future of
brain stimulation will depend on new technologies (new circuits, electrodes, web
based programmers), waveforms (alternatives to square waves, random
distribution), targets (hypothalamic nuclei, locus coeruleus) and indications
(dystonia, epilepsy, eating disorders.
PMID- 10769817
TI - Advances in neurostimulation for movement disorders.
AB - In just 12 years since its introduction, deep brain stimulation (DBS) has become
well established as a safe and effective therapy in the treatment of medically
refractory movement disorders. Ventralis intermedius (Vim) DBS has virtually
replaced thalamotomy in the routine clinical treatment of essential tremor,
affording relief to thousands of patients who previously would not have undergone
surgery, and there is increasing usage of Vim DBS in other tremors of intention
(e.g., multiple sclerosis). Subthalamic nucleus (STN) and globus pallidus
internus (GPi) DBS have revolutionized the treatment of advanced stage
Parkinson's disease, improving all cardinal disease features and increasing 'on'
time without dyskinesias. Finally, DBS of various sub-cortical structures is
being developed and tested in other less prevalent movement disorders such as
dystonia. Future developments in this rapidly advancing area will no doubt
include widening indications for this relatively safe surgical procedure,
elucidation of the mechanisms of action of electrical stimulation, and
technological advancements improving effectiveness and convenience.
PMID- 10769818
TI - Mechanisms of deep brain stimulation and future technical developments.
AB - Possible mechanisms underlying the therapeutic effect of deep brain stimulation
(DBS) are reviewed, particularly the notion that DBS is inhibitory. Computer
simulations are described that model the effect of different frequencies and
regularity of neuronal activity (target neuron), either spontaneous or
stimulated, on information transfer between two other neurons. Most simulations
resulted in a loss of information. These were the least with high frequency and
regular activity or stimulation of the target neuron with regularity having the
least deleterious effect on information transfer. The simulations suggest that
irregular activity in neurons converging with other neurons can result in a loss
of information transfer. This may explain why increased irregularity in globus
pallidus activity associated with Parkinson's disease, dystonia and hemiballismus
may result in symptoms. Further, the therapeutic effect of DBS may be due to
driving neurons at higher and perhaps more importantly, regular frequencies.
There were simulations in which information transfer was augmented suggesting the
presence of stochastic resonance. This most often occurred with low frequency
activity in the target neuron. It is hypothesized that low frequency activity,
either spontaneous or stimulated, could account for involuntary movements,
including tremor. Future directions and challenges to DBS are also discussed.
PMID- 10769819
TI - A neuromodulation strategy for rational therapy of complex brain injury states.
AB - We review initial efforts at neuromodulation in the vegetative state and organize
several aspects of recent studies of the underlying neurobiology of catastrophic
brain injuries. An innovative strategy for patient and target selection for
neuromodulation of impaired cognitive function is outlined. Scientific and
ethical issues that will attend future efforts to appropriately risk-stratify
patients and initiate interventions with therapeutic intent are considered.
PMID- 10769820
TI - A proposed ethical framework for interventional cognitive neuroscience: a
consideration of deep brain stimulation in impaired consciousness.
AB - Advances in neuromodulation techniques offer the promise of new therapeutic
interventions for patients with neuropsychiatric maladies. Several complex
social, ethical and policy issues will attend developments in this area. In this
paper an ethical framework for clinical research in interventional cognitive
neuroscience is advanced. Deep brain stimulation in traumatic brain injury is
considered as a paradigm case to examine ethical obligations in human subject
research. These include balancing access to novel therapies versus protection of
vulnerable study populations, rational evaluation of study design and research
strategies, informed consent, and the importance of achieving societal consensus
for this line of scientific inquiry.
PMID- 10769821
TI - Future trends in spinal cord stimulation.
AB - Spinal cord stimulation (SCS) has been available for about 30 years, but only in
the past five years has it met with widespread acceptance and recognition by the
medical community. Traditionally performed by neurosurgeons, SCS is being
increasingly utilized by anesthesiologists, orthopedic surgeons and physiatrists.
Pain management continues to be the most widespread application of SCS. More
sophisticated technology has allowed the implanters to successfully address more
complex pain syndromes such as widespread reflex sympathetic dystrophy and the
failed back syndrome. Other applications are being developed, combining the
ability to stimulate the spinal cord, the nerve roots and the peripheral nerves.
Examples include angina pectoris, urinary incontinence and occipital neuralgia.
Computer-interactive programming is gaining popularity, especially due to the
extreme complexity of the implanted stimulation devices. The ability to stimulate
independently multiple channels as well as multiple arrays of electrodes is today
a reality. This has increased greatly the efficacy, safety and reliability of the
modality. In the future, SCS will undoubtedly move several steps up in the
treatment ladder of chronic pain conditions, while new applications will be
discovered. The future of neural implantable technologies is bright, with an
increasingly important role in the medical management of chronic conditions
affecting the nervous system.
PMID- 10769822
TI - Mechanisms of spinal cord stimulation in neuropathic pain.
AB - The understanding of the mode of action of spinal cord stimulation (SCS) as
treatment of neuropathic pain is still fragmentary. SCS evolved from the gate
control theory postulating a spinal modulation of noxious inflow, but there is
little evidence that SCS influences nociceptive pain; pain relief in peripheral
vascular disease and angina pectoris is presumably secondary to other SCS
effects. In man, SCS may effectively abolish both continuous and evoked pain
(tactile/thermal allodynia) whereas induced, acute nociceptive pain is
unaffected. Recent SCS studies performed on rat models of mononeuropathy have
demonstrated a preferential effect on A beta fiber mediated functions, and the
hyperexcitability of wide-dynamic-range dorsal horn neurons was attenuated. These
effects were coupled to increased release of GABA and reduced glutamate and
aspartate release in the dorsal horn. Intrathecal administration of GABA,
baclofen and adenosine enhanced the SCS effect on tactile allodynia even in
previously non-responsive rats. Preliminary results indicate that gabapentin may
have a similar effect. GABAergic and adenosine-related mechanisms conceivably
represent only examples of a number of putative receptor systems involved in SCS.
Clinical trials have been initiated exploring the possibility to improve the
efficacy of SCS by concomitant pharmacotherapy.
PMID- 10769823
TI - Spinal cord stimulation for ischemic heart disease.
AB - An increasing number of patients are suffering from angina pectoris that is
chronically refractory to standard anti-ischemic treatment such as
pharmacological and surgical strategies. To improve the quality of life of these
severely disabled patients, without adversely affecting their prognosis, a number
of adjunct therapies are available. One of the most promising appears to be
spinal cord stimulation. We will review the literature and discuss the efficacy,
safety and mechanisms of neuromodulation as an adjuvant therapy for chronic
refractory angina pectoris.
PMID- 10769824
TI - The future of peripheral nerve neurostimulation.
AB - Electrical stimulation of selected peripheral nerves for treatment of intractable
pain has been used inconsistently over the past 30 years due to difficulties in
clarifying appropriate indications, utilizing approved device technology, and
standardizing the surgical techniques. Circumferential electrodes treating
mononeuropathies have given way to paddle electrode techniques and, most
recently, the application of percutaneous wire electrode methods will allow for
minimally invasive peripheral nerve stimulation for certain intractable CRPS and
other painful monoeuropathies.
PMID- 10769826
TI - The neural circuitry of pain as explored with functional MRI.
AB - Since the discovery in the early 1990s that magnetic resonance imaging (MRI) can
be used for functional imaging of the human brain, the technique has been used to
examine the contribution of thalamic and cortical areas to the human pain
experience. In a series of studies in this laboratory, functional MRI (fMRI) of
noxious heat-, cold-, and median nerve stimulation-evoked activations
demonstrated the involvement of the thalamus and multiple cortical areas in pain.
The cortical areas identified included the primary and secondary somatosensory
cortex (S1, S2), the anterior insula and the anterior cingulate cortex. The data
also revealed a significant intersubject variability in the activation of any one
of these regions, particularly during heat- and cold-evoked pain. These findings
revealed the widespread cortical regions that are recruited by a noxious stimulus
and provide clues to the neural circuitry of pain that undoubtedly include
sensory, motor and cognitive components.
PMID- 10769825
TI - Functional brain imaging of movement disorders.
AB - Functional brain imaging techniques such as positron emission tomography (PET)
have contributed to our understanding of the pathophysiology of Parkinson's
disease (PD) and other movement disorders. PET employs small amounts of positron
emitting radioligands to produce quantitative measures of physiological and
biochemical processes in the brain and other organs. In a PET experiment, a
subject is given a compound of biological interest. The spatial and temporal
distribution of the radiotracer is measured quantitatively in the course of the
PET study, providing a tomographic representation of regional radioactivity
concentration. In this review, we focus on the potential application of PET in
the selection of suitable candidates and the assessment of surgical interventions
such as pallidotomy, thalamotomy, and deep brain stimulation.
PMID- 10769827
TI - Neurostimulation and functional brain imaging.
AB - Recent advancements in functional neuroimaging have furthered our understanding
of the normal and pathological brain. These non-invasive imaging modalities have
allowed us to study the human brain in vivo. Concurrently, the revival of
neurostimulation in the treatment of pain, movement disorders, and epilepsy has
allowed the synergistic combination of these two technologies. Several studies
focusing on the use of functional imaging in patients with implanted
neurostimulation devices are reviewed. The anticipated roles of these two
disciplines are discussed.
PMID- 10769828
TI - [Anatomical and surgical notes: Seishu Hanaoka and neurosurgery].
PMID- 10769829
TI - [Treatment of intracranial dural arteriovenous fistula].
PMID- 10769830
TI - [Infratemporal fossa approach for mid-skull base lesion: its usefulness, surgical
anatomy, and intraoperative device].
AB - The usefulness of the infratemporal fossa type C approach is reported through a
presentation of a case of clival chordoma, which was successfully treated by this
approach. Although it is complicated and includes some demerits, this approach
gives a shorter and wider access to mid-skull base pathology than other
approaches. Among the demerits, deformity of the temporal region caused by
extensive drilling of the bone could be minimized by cosmetic mastoidectomy,
which was first applied during this approach by the authors. The surgical anatomy
for this approach is demonstrated using a cadaver specimen.
PMID- 10769831
TI - [Diffusion-weighted MRI in patients with occlusive cerebrovascular disease: the
initial DWI findings within 6 hours after onset].
AB - We performed this study to evaluate the accuracy of diffusion-weighted imaging
(DWI) in detecting focal ischemia, and to predict the role of DWI in the
management of patients with ischemia in the superacute phase. 99 patients with
clinically diagnosed acute occlusive cerebrovascular disease were studied with
DWI within 6 hours after onset of symptoms. In 88 of 99 patients, early ischemic
lesions were identified on initial DWI as hyperintensity areas. The initial DWI
findings were classified into 4 types according to the location and extent of the
hyperintensity area. The patients with type 1 (no hyperintensity area) were
clinically diagnosed as TIA or complete stroke within 2 hours after the onset. 28
patients out of the patients with type 2 (hyperintensity area in the perforator's
territory) were diagnosed with lacunar infarction, and the remaining 13 patients
were diagnosed as victims of stroke caused by main trunk occlusion. Except for 2
patients with TIA, the patients with type 3 (scattered hyperintensity areas in
the cortex) had main trunk occlusion and showed a more extended ischemic area on
SPECT than hyperintensity area on DWI. All the patients with type 4 (extended
hyperintensity area) had main trunk occlusion and showed severe hypoperfusion in
the affected area on SPECT, and the area of hypoperfusion was well matched with
the hyperintensity area on DWI. Comparing DWI findings with rCBF on SPECT, a
significant difference was noted in rCBF between hyperintensity and non
hyperintensity area. We considered that emergence of hyperintensity on DWI was
related to both the time of duration and the degree of hypoperfusion, and the
reduced perfusion area where DWI showed no hyperintensity was thought to be the
"ischemic penumbra". Our study indicated DWI had high diagnostic accuracy in
superacute occlusive cerebrovascular disease and could furnish useful information
to reveal the pathologic condition. In addition, DWI is expected to be available
for selection as a therapeutic strategy.
PMID- 10769832
TI - [Treatment of peripheral aneurysms of the posterior circulation].
AB - Peripherally located aneurysms of the posterior circulation are extremely rare.
The outcome of patients with peripherally located aneurysms has been poor, and
the treatment of such aneurysms has been surgically challenging. We report a
consecutive series of peripherally located ruptured aneurysms in the posterior
circulation, and discuss in this article the optimal treatment strategy for such
lesions. Clinical presentation, neuroradiological findings, treatment method, and
the outcome were reviewed retrospectively. Two cases with distal posterior
cerebral artery aneurysm, two with distal posterior inferior cerebellar artery
aneurysm, two with anterior inferior cerebellar aneurysm, and one with superior
cerebellar artery aneurysm were included in this study (mean age, 59.3 +/- 16.0,
M:F = 1:6). Three patients with good neurological status on admission who
underwent clipping of the aneurysmal neck via craniotomy showed a favorable
outcome. In contrast, four patients with poor neurological status on admission
who underwent endovascular proximal occlusion of the parent artery showed an
unfavorable outcome. Although the outcome of patients who underwent endovascular
surgery was poor, endovascular proximal occlusion was effective in preventing re
rupture of the aneurysms. Proximal occlusion of the parent artery has several
shortcomings such as cerebral infarction, but proximal occlusion at the very
distal area of the parent arteries would not be critical because of good
collateral circulation. Thus, endovascular proximal occlusion may provide us
another option in the treatment of peripherally located aneurysms especially in
patients with poor neurological status. Further data is needed to discover the
optimal treatment for patients with peripherally located cerebral aneurysms.
PMID- 10769833
TI - [Rerupture mechanism of ruptured intracranial dissecting aneurysm in the
vertebral artery following proximal occlusion].
AB - Proximal occlusion is commonly employed to prevent rebleeding of intracranial
dissecting aneurysms of the vertebral artery (VA), but rebleeding sometimes
occurs. To determine the cause of such rebleeding we reviewed nine cases,
including eight reported in the literature and one treated at our hospital. We
classified the techniques used to proximally occlude the VA into two types. In
Type I, occlusion is performed immediately proximal to the aneurysm so that there
are no perforating arteries or the posterior inferior cerebellar artery (PICA)
between the clip and the aneurysm. In Type II, occlusion is performed proximal to
the PICA so postoperative retrograde flow persists from the contralateral VA
through the aneurysm into the ipsilateral PICA. Among the four Type I cases
reviewed, it was found that the interval between occlusion and rebleeding was
very short: three developed rebleeding within four hours of occlusion, and the
fourth showed rebleeding on the fourth day. In the five Type II patients,
rebleeding occurred more than four days (mean 15.2 days) after occlusion. It is
thought that in Type I occlusion, retrograde flow into the aneurysm immediately
after occlusion may raise the intraaneurysmal pressure enough to cause rerupture
within just a few hours of occlusion. In Type II occlusion, postoperative
retrograde flow through the aneurysm into the ipsilateral PICA exists, so the
intraaneurysmal pressure is not likely to rise as rapidly, with the result that
rebleeding occurred after more than four days probably due to recurrence of
dissection. The short interval between proximal occlusion and rebleeding,
especially in Type I cases, suggests that postoperative angiography is only of
limited usefulness in evaluating the possibility of rebleeding. The mortality
rate reported for cases with reruptured vertebral dissecting aneurysms after
proximal occlusion is very high (55.6%). These data indicate that surgical
trapping or endovascular intraluminal occlusion, which is difficult to perform in
some patients, should be considered the most suitable procedure from the view
point of preventing postoperative rebleeding.
PMID- 10769834
TI - [Suprasellar primary malignant rhabdoid tumor in an adult: a case report].
AB - Malignant rhabdoid tumor (MRT), described for the first time in 1978 in the
kidney, has rarely been reported in other organs including the brain and has
involved adults in only 3 cases. We described a case of MRT in a 32-year-old
woman who presented with severe headache, nausea and sudden onset of visual
disturbance. MRI showed a well-enhanced mass at the suprasellar region. Subtotal
removal of the tumor was performed. However, tumor regrowth occurred after the
operation (doubling time, 8.36 days) and spinal dissemination was detected.
Therefore, chemotherapy and radiotherapy were administered focusing on the
suprasellar lesion and the spinal cord. Pathologically, light micrographs showed
rhabdoid cells with large, round, single or double nuclei with one prominent
nucleolus and eosinophilic cytoplasmic inclusions. Electron micrographs were made
of typical rhabdoid cells displaying bundles of intermediate filaments within the
perikaryon. In immunohistochemical studies, EMA, vimentin, cytokeratin and SMA
were positive. Pathological findings were consistent with those of MRT. Optimal
treatment for this tumor has not been established. Our case may be useful in
defining treatment for MRT.
PMID- 10769835
TI - ["Adenoid" glioblastoma].
AB - A surgical case of glioblastoma which showed a pronounced "adenoid" (or
"epithelioid") appearance was reported. The patient was an 81-year-old woman, who
presented with unsteady gait. Neuroradiological examination revealed three
discrete mass lesions located in the 1-frontal, 1-parieto-occipital, and r
occipito-temporal lobes. Despite the subtotal removal of two of the three lesions
and postoperative chemotherapy and radiotherapy, the patient died 21 months after
the onset of illness. Histopathological examination of the resected tumors
revealed typical features of glioblastoma in the peripheral region of the tumor.
In the central region, the tumor cells were arranged in a papillary fashion or
formed solid, sheet-like cell nests and were surrounded by fibrous connective
tissue septa. Although the histopathological appearance of the tumor closely
resembled metastasis of adenocarcinoma, the immunohistochemical and
ultrastructural studies of the tumor failed to detect evidence of a definite
differentiation towards epithelial cells.
PMID- 10769836
TI - [The use of a modified vertical mandibular osteotomy for exposure of a distal
cervical internal carotid artery].
AB - We report herein the case of a 56-year-old woman who presented with repeated
transient ischemic attacks (TIAs). Cerebral angiography revealed that the left
redundant internal carotid artery (ICA) uncharacteristically curved medially.
These findings were highly suggestive of an internal carotid artery aneurysm at
the level between the first and second cervical vertebral bodies. The lesion was
presumed to be difficult to access by the surgical procedure usually adopted in
carotid endarterectomy. Thus, we decided to employ a modified vertical mandibular
osteotomy. The operative view revealed that the lesion was atherosclerotic
stenosis with ulceration, so carotid endarterectomy was indicated. This
mandibular osteotomy not only provided us with wide, satisfactory exposure of the
distal cervical internal carotid artery but also afforded good mandibular
stability during the postoperative period.
PMID- 10769837
TI - [A case of adult moyamoya disease progressed after vascular reconstructive
surgery].
AB - We report an adult onset patient with moyamoya disease showing acute progress
after contralateral vascular reconstructive surgery. A 47-year-old female
developed cerebral infarction in the left corona radiata. A magnetic resonance
(MR) angiography and a cerebral angiogram revealed severe stenosis extending from
the terminal portion of left internal carotid artery (ICA) to the M1 portion. The
right ICA showed slight stenosis. We performed direct bypass surgery (STA-MCA
anastomosis) on the affected left side. MR angiography 1 month after surgery
revealed the progressive stenosis of the C1 portion of the right ICA. While
measurement of cerebral blood flow (CBF) showed a slight impairment of vascular
reactivity to acetazolamide loading in the region of the right MCA, we continued
without vascular reconstructive surgery for the right side because there was no
ischemic attack. The patient had a transient sensory disturbance of the left
upper extremity 16 months after surgery. MR angiography and a cerebral angiogram
revealed more progressive stenosis extending from the right ICA to the M1
portion. CBF study showed a low CBF at rest and a negative response to
acetazolamide loading in the region of the right MCA. Direct bypass surgery was
performed on the right hemisphere. Follow-up study revealed an increment of rest
CBF and improvement of vascular reactivity. We underlined the necessity for
careful postoperation observation of progressive contralateral arterial stenosis
using MR angiography and CBF study in adult onset patients with moyamoya disease.
PMID- 10769838
TI - [The stenoses at the terminal portion of the internal carotid artery improved
after initiation of antithyroid therapy: a case report].
AB - We reported the case of a 19-year-old female complicated with Basedow disease.
She was admitted, complaining of headache and endocrine function tests showed
hyperthyroidism. CT scan revealed left intraventricle hemorrhage and angiography
revealed the stenoses at the terminal portion of the bilateral internal carotid
arteries (ICA) without basal moyamoya vessels. During the angiography, a thyroid
crisis occurred and we initiated the antithyroid therapy. Bilateral CAG a month
after the onset revealed that the stenoses had improved partially and the
stenosis was thought to be vasospasm caused by the intraventricle hemorrhage. But
as the collateral circulation had already been established soon after the
hemorrhage, we suspected that the stenoses at the terminal portion of the ICA had
existed before the intraventricle hemorrhage. Angiography was performed one year
after the onset and bilateral CAG revealed that the stenoses at the terminal
portion of the ICA had also improved. As some investigators have mentioned that
Basedow disease might be associated with the causal genesis of Moyamoya disease,
we suspected that Basedow disease might have played an important role in
vasospasm after hemorrhage and that the stenoses at the terminal portion of the
ICA might have existed before the hemorrhage took place.
PMID- 10769839
TI - [Functional alteration of mitochondrial enzymes in Alzheimer's brain].
PMID- 10769840
TI - [Sex hormones as putative risk factors].
PMID- 10769841
TI - [Cerebral ischemia and vascular factors].
PMID- 10769842
TI - [Aluminum as a risk factor of Alzheimer's disease].
PMID- 10769844
TI - [Neuroimaging features of intraventricular neurocytoma].
AB - We presented the clinicopathological features of 8 cases of intraventricular
neurocytoma, which was a rare, benign tumor of neuronal origin and affected young
patients. In each case the intraventricular tumor existed near the foramen of
Monro and/or body of the lateral ventricle, and was associated with ventricular
dilatation. A CT scan demonstrated a well-circumscribed iso- or hyperdense mass
with some calcification, intratumoral cysts of various sizes and a heterogeneous
enhancement. MRI, which was performed in 4 cases, confirmed a mass of isointense
or slightly hyperintense on T 1-weighted images, and with multiple sites of
attachment (mainly to the septum pellucidum and the head of the caudate nucleus).
While these neuroimaging features are helpful in eliminating alternative
diagnosis such as ependymomas, choroid plexus papillomas, subependymal giant cell
astrocytomas and meningiomas, age of the patient and the tumor location within
the lateral ventricle are important features for differential diagnosis.
PMID- 10769843
TI - [Regional cerebral blood flow of the basal ganglia and thalamus measured using Xe
CT].
AB - Cerebral blood flow (CBF) images obtained using Xe-CT have a much higher spatial
resolution than SPECT or PET images. The regional CBF (rCBF) of deep brain
regions, the basal ganglia and thalamus, was able to be measured using Xe-CT in 6
subjects. Average rCBF was 87.1 +/- 20.7 ml/100 g/min in the caudate nucleus,
83.5 +/- 15.8 ml/100 g/min in the putamen, 50.0 +/- 8.7 ml/100 g/min in the
globus pallidus and 88.9 +/- 12.4 ml/100 g/min in the thalamus. The average rCBF
value of the globus pallidus was lower than the values of the caudate nucleus,
putamen and thalamus. These observations may be explained by reduced cellularity
of the globus pallidus in comparison to the other regions. SPECT and PET are not
able to clearly demonstrate the globus pallidus on CBF images. However, precise
rCBF values can be measured in the globus pallidus using Xe-CT.
PMID- 10769845
TI - [A case of cardiogenic cerebral embolism with successful recanalization: apparent
diffusion coefficient analysis for prediction of reversible cerebral ischemia].
AB - A 54-year-old woman complaining of left hemiplegia was transferred to our
hospital. Computed tomography on admission demonstrated normal. Electrocardiogram
showed atrial fibrillation. Cerebral blood flow (CBF) was decreased in both the
cortex and the perforator territory of the right middle cerebral artery (MCA),
whereas the apparent diffusion coefficient (ADC) in the cortex was normal.
Digital subtraction angiography (DSA) revealed an occlusion of the right MCA (M 1
proximal) with collateral flow from the right anterior cerebral artery (ACA) to
the territory of the right MCA. After intra-arterial injection of tissue
plasminogen activator (t-PA), DSA showed partial recanalization, and the symptoms
of the patient improved considerably. Five days after that, the patient
deteriorated again and showed disturbance of consciousness and left hemiplegia.
In this episode, both CBF and ADC in the cortex of the right MCA were decreased.
DSA revealed an occlusion of the right internal carotid artery (ICA) and
collateral flow from the right ACA to the territory of the right MCA disappeared.
After intra-arterial injection of t-PA, DSA showed partial recanalization with
collateral flow from the right ACA, and the symptoms of the patient improved. DSA
5 weeks after onset showed complete recanalization of both the right MCA and the
ICA. The patient was diagnosed as both mitral and aortic stenosis and
regurgitation (MSR + ASR) and underwent an operation for both mitral and aortic
value replacement. She was discharged with no neurological deficit 4 months after
onset. ADC analysis is especially useful for the prediction of reversible
ischemic damage and the prevention of hemorrhagic transformation and fatal edema
in acute ischemic stroke.
PMID- 10769846
TI - [A case of brain stem infarction with bilateral hearing loss].
AB - The study case was a 66-year-old man who had bilateral neurosensory hearing
impairment due to brain stem infarctions. He noticed mild hearing loss, frequent
vertigo and tinnitus. About one month later, his hearing took a sudden turn for
the worse, and he suffered from dysarthria, dysphagea and abasia. Neurological
examination revealed pseudobulber palsy, left hemiparesis, cerebeller ataxia,
disturbance of pain and temperature sensation on the right face and left side of
the body. Brain stem auditory evoked potentials (BAEPs) showed a delayed small
wave V with the abscence of previous waves on the right side and no significant
waves on the left side. Brain magnetic resonance images (MRI) revealed
infarctions in the bilateral middle cerebellar peduncles, including in the right
lateral portions of pons, and the right lower pontine base. We believe that not
only peripheral, but also central auditory pathways adjacent to infarctions were
damaged. Magnetic resonance angiography (MRA) showed severe stenosis or occlusion
of left vertebral artery and basilar artery. We concluded that hypoperfusion of
the vertebrobasilar artery territories caused ischemia of the cochlear nerve and
the auditory tracts in the brain stem, which resulted in bilateral hearing loss.
PMID- 10769847
TI - [A case of a pituitary mass in association with sarcoidosis].
AB - We report a case of a pituitary mass associated with sarcoidosis. Natural
regression of the mass was demonstrated after the replacement of corticosteroid
hormone. A seventy-one-year old man presented with blurred vision and general
fatigability, and admitted to our hospital. He was diagnosed to have ophthalmic
and pulmonary sarcoidosis. Two months later, he consulted our hospital again,
with complaints of fatigability and vomiting. Laboratory data showed
hyponatremia, and CT scan revealed a suprasellar mass. He had no neurological
deficits. Diabetes insipidus was not observed. Magnetic resonance image showed a
heterogeneously enhanced intrasellar and suprasellar dumbbell shaped mass and
thickening of the pituitary stalk. Hormonal examination revealed corticosteroid
insufficiency and hypothyroidism, possibly caused by the pituitary mass.
Replacement of corticosteroid hormone significantly improved his fatigability.
Two months later, follow-up MRI showed regression of the pituitary mass. Based on
the clinical and radiological findings, pituitary mass was strongly suggested to
be caused by sarcoidosis. We recommend prompt steroid treatment for such a
pituitary mass and strict follow-up MRI study.
PMID- 10769848
TI - [Two cases of acute aortic disease complicated by ischemic cerebrovascular
disease].
AB - Ischemic cerebrovascular diseases are commonly induced by atherosclerosis and
cardiogenic embolization but rarely they occur in association with Takayasu's
arteritis and aortic lesion such as aortic dissection and aneurysm. Here we
experienced two cases of acute aortic disease complicated by ischemic
cerebrovascular disease (CVD). Patient 1 was a 77-year-old male. He complained of
dyspnea and left hemiparesis. He was brought to our hospital by ambulance. Left
hemiparesis and dyspnea improved soon. The patient only complained of left lower
extremity pain and physical examination revealed hypotension. Brain CT showed no
abnormality but chest CT revealed aortic dissection. The resection of the intimal
tear and replacement of ascending aorta and aortic arch with 28 mm Hemashield
graft were performed under hypothermia and selective cerebral perfusion. The
postoperative course was uneventful and he has been doing well. Patient 2 was a
67-year-old female. She was found lying unconscious and brought to our hospital
by ambulance. Physical examination revealed right hemiparesis and hypotension.
Brain CT demonstrated low density area in the left corona radiata and ruptured
aortic aneurysm was seen in abdominal CT. Just after the examination, the patient
suddenly complained of severe back pain and died despite cardiopulmonary
resuscitation. Aortic lesions can manifest ischemic symptom involving multiple
organs following their vascular disorder. Aortic dissection rarely occurs in
association with ischemic CVD and in that case it is likely to be seen by
neurologists. Aortic dissection and aneurysm deteriorate so suddenly that
immediate diagnosis and proper treatment are needed.
PMID- 10769849
TI - [Cerebellar atrophy associated with phenytoin intoxication].
PMID- 10769850
TI - [A 77-year-old man with gait and gaze disturbance].
AB - We report a 77-year-old Japanese man with progressive gait disturbance. He was
well until his 71 years of the age (1992), when he noted an onset of disturbance
in his speech, which was followed by difficulty in using his left hand. He did
not attempt to use his left hand afterwards. He started to fall down in the
spring of 1994. He was admitted to our service on October 6, 1994. Neurologic
examination revealed an alert and oriented man. He showed limb-kinetic apraxia in
his left hand with anosognosia for his apraxia. Vertical gaze was impaired. He
walked in small steps. He had moderate axial and limb rigidity. He had no
weakness, ataxia, or tremor. Deep tendon reflexes were normal. Plantar response
was flexor. Sensation was intact. His gait had progressively become worse and he
was admitted to another hospital in April of 1996. At that time he was
disoriented to time. He was only able to walk a few steps with support. He
continued to show limb-kinetic apraxia in his left hand. He developed dementia
and dysphagia and he expired on October 27, 1998. He was discussed in a
neurological CPC, and the chief discussant arrived at the conclusion that the
patient had corticobasal degeneration. Most of the participants agreed with this
diagnosis, but a few of them thought that progressive supranuclear palsy would be
more likely. Post-mortem examination revealed no gross cortical atrophy. The
right hemisphere was kept frozen for future biochemical analysis. The left
precentral gyrus showed spongy changes, neuronal loss and gliosis. The pallidum,
putamen, and the subthalamic nucleus were unremarkable, however, neurofibrillary
tangles were seen in the subthalamic nucleus. The substantia nigra showed only
slight neuronal loss; neuronal pigments were well retained. A few neurofibrillary
tangles were seen in the remaining neurons. The cerebellar dentate nucleus showed
grumose degeneration. Gallyas-Braak staining revealed many tuft-shaped astrocytes
in the precentral gyrus. Pathologic diagnosis was progressive supranuclear palsy.
Some participants thought that this diagnosis was unacceptable, because the
pathologic changes in the substantia nigra, globus pallidus, and the subthalamic
nucleus, which were usually severely involved in PSP, did not show typical
changes of PSP. In addition, the predominant clinical feature was limb-kinetic
apraxia, although he showed vertical gaze paresis and parkinsonian gait, which
could also be seen in corticobasal degeneration. There was a big discussion among
participants with regard to the diagnosis.
PMID- 10769851
TI - Great expectations.
PMID- 10769852
TI - Odontogenic bacteremia following tooth cleaning procedures in children.
AB - PURPOSE: This study was designed to investigate the prevalence and intensity of
odontogenic bacteremia from tooth cleaning procedures in children and
adolescents. METHODS: One hundred and fifty five children receiving dental
treatment under general anesthesia at The Great Ormond Street Hospital for
Children and Guy's Hospital were recruited. Each child was randomly allocated to
one of three tooth cleaning groups. These were (1) toothbrushing, (2)
professional cleaning with a rubber cup and (3) scaling. RESULTS: There was no
significant difference in the prevalence of positive blood cultures or intensity
of bacteremia between the three groups. The bacterial species isolated were
similar to those reported by other workers. These were S. mitis, S. sanguis and
Coagulase--negative staphylococci, all of which are implicated in the
pathogenesis of Bacterial Endocarditis. CONCLUSIONS: Patients at risk are as
likely to develop odontogenic bacteremia from toothbrushing at home as from
professional scaling and polishing of the teeth at dental surgery.
PMID- 10769853
TI - Fluoridated light-activated bonding resin adhesion to enamel and dentin: primary
vs. permanent.
AB - PURPOSE: This study compared fluoridated bonding resin adhesion to primary enamel
(Group 1), primary dentin (Group 2), permanent enamel (Group 3), and permanent
dentin (Group 4). METHODS: The buccal surfaces of 24 primary molars and 24
premolars were used. The bonding system and resin composite used in this study
were Imperva Fluorobond and Lite-Fil IIA (Shofu Inc., Kyoto, Japan). Effects of
tooth surface conditioning by FB primer were observed using SEM (N = 2/group).
Shear bond strengths (SBS) were tested, and the test surfaces of enamel, dentin,
and resin specimens were observed using SEM (N = 10/group). Data was
statistically analyzed using one-way ANOVA with subsequent post hoc Duncan's new
multiple range test at P < 0.05. RESULTS: Effects of tooth surface conditioning
by FB primer were appropriate to dentin but low to enamel. Means and standard
deviations of the SBS for each group were: Group 1 (16.34, 5.53 MPa), Group 2
(15.06, 7.02 MPa), Group 3 (14.39, 6.52 MPa) and Group 4 (15.45, 5.35 MPa). There
was no significant difference of SBS among Groups 1, 2, 3, and 4. CONCLUSION:
Imperva Fluorobond system gave the same level of bond strength to primary enamel,
primary dentin, permanent enamel, and permanent dentin.
PMID- 10769854
TI - A retrospective study of chloral hydrate, meperidine, hydroxyzine, and midazolam
regimens used to sedate children for dental care.
AB - PURPOSE: The purpose of this retrospective study was twofold: a) to examine the
behavior and physiology of pre-school children each sedated with 1 of 3 drug
regimens based on patient age, dental needs, and pre-operative clinical
impression; and b) to determine the association between pre-operative behaviors
to the behavior and physiology of the sedated children. METHOD: Records of more
than 600 patients sedated at Columbus Children's Hospital dental clinic over a
two-year period were culled for patients who ranged in age from 2 to 5 years of
age and had received one of three different drug regimens: a) chloral hydrate and
hydroxyzine (CH-H), b) chloral hydrate, meperidine, and hydroxyzine (CH-D-H), or
c) midazolam (M). A minimum of 300 patients (100/drug regimen) were randomly
selected. The standard sedation sheet used in all sedations at the clinic
included, among other factors, pre-operative assessments of patient behavior,
interaction, and cooperation. Physiological and behavioral variables during the
intraoperative sedation periods were also available. These periods included
initial baseline vitals, vitals following drug administration, topical and local
drug administration, rubber, dam placement, and a minimum of the first 15 minutes
of restorative procedures. The three drug regimens were compared for these
variables. Data were entered into SPSS for data analysis using one-way ANOVA, Chi
square, regression analysis, and descriptive statistics. RESULTS: The results
indicated significant mean differences in patient age, weight, and duration by
drug regimen (F = 20.3, P < 0.001; 16.2, P < 0.001; and 48.7, P < 0.001,
respectively). ANOVA indicated a significant difference among drug regimens for
percent of quiet, sleeping, and struggling behaviors. Quiet behavior accounted
for 26%, 41%, and 67% of all behaviors for CH-H, CH-D-H, and M, respectively.
Sleep accounted for 50%, 43%, 0.4% and struggling 11%, 8%, and 19% for CH-H, CH-D
H, and M, respectively. Pre-operative behaviors were also significantly different
and patient cooperation was the only variable found minimally predictable of
intra-operative behaviors (R = 0.32, P < 0.001). Significant differences among
drug regimens were found for heart rate (HR) and mean arterial blood pressure
(MAP) during certain procedures (e.g., CH-H produced lower MAP compared to the
other drug regimens); however, all physiological variables were within normal
limits for the children. CONCLUSION: Significant differences were found for
behavioral and physiological variables among the drug regimens (e.g., CH-D-H
produced significantly more quiet and sleeping behaviors than M). Prospective
studies are needed to confirm these findings.
PMID- 10769855
TI - Intravenous sedation in pediatric dentistry using midazolam, nalbuphine and
droperidol.
AB - PURPOSE: The purpose of this pilot investigation was to study the efficacy,
physiologic responses, and safety of a multi-drug intravenous conscious sedation
technique in an outpatient setting in children who demonstrated uncooperative
behavior when comprehensive restorative dental treatment was attempted. METHODS:
Using a time-based sedation record, the physiologic responses of 153 healthy
children, age range 23 months to 14.5 years, were measured after they had
received midazolam (Versed), nalbuphine (Nubain), and droperidol (Inapsine), each
administered intravenously, and nitrous oxide and oxygen administered by nasal
mask, while each child received comprehensive restorative or surgical dental
care. Each patient was monitored according to the American Academy of Pediatrics
Sedation Guidelines. Heart rate and rhythm, blood pressure, respiratory rate,
hemoglobin oxygen saturation, end-tidal CO2, level of sedation, and behavioral
responses were recorded preoperatively, at 5 minute intervals during treatment
and in recovery until discharge. Sedation was titrated to Level 2 or 3 during
treatment as defined by the American Academy of Pediatric Dentistry Reference
Manual. RESULTS: For each child, the sedation level was judged to be either
acceptable or optimal for the completion of all planned dental treatment. There
were no sedation failures. Children under 20 kg required significantly higher
dosages of each sedative medication than children more than 20 kg to achieve the
same level of sedation (P < 0.001, ANOVA). There were no episodes of
intraoperative vomiting, hypotension, cardiac arrhythmias, respiratory depression
requiring respiratory support, or dysphoria during treatment, in the recovery
period, or after discharge. CONCLUSION: This multi-drug intravenous conscious
sedation technique is a safe and effective method to control the behavior of
uncooperative children who require comprehensive dental treatment.
PMID- 10769856
TI - Monitoring pediatric dental patients with nasal mask capnography.
AB - PURPOSE: The purpose of this study was to evaluate the potential of using
capnography to analyze respiratory samples taken from a scavenging nitrous oxide
nasal hood during routine pediatric dental procedures. METHODS: Twenty-two
subjects, aged 60-116 months, were administered alternately either 40% nitrous
oxide/60% oxygen or 100% oxygen during two sequential restorative appointments.
All subjects were monitored continuously for end-tidal carbon dioxide and
respiratory rate using a capnograph whose sampling line was attached directly to
the nitrous oxide nasal hood. The subject's breath sound, displayed behavior,
type of dental procedure being performed, and presence of rubber dam isolation
were recorded every minute throughout the two appointments. RESULTS: Values for
end-tidal carbon dioxide and respiratory rate were displayed on the capnograph
when administering either oxygen or a combination of nitrous oxide/oxygen
inhalation through the nasal hood. These respiratory values were lowered
significantly when comparing 40% nitrous oxygen-60% oxygen to 100% oxygen
inhalation. They were not significantly altered by the type of breath sound,
patient behavior, dental procedure, or presence of rubber dam isolation, with the
exception of some dental procedures which significantly lowered end-tidal carbon
dioxide. The apnea alarm on the capnograph occurred during 5% of the total
treatment time, but its occurrence represented a 97% false positive rate. The
occurrence of the apnea alarm was significantly associated with the type for
breath sound, patient behavior, and dental procedure. When used in this manner,
the capnograph was effective in alerting the practitioner to potential apneic
events, but likely has limited value in monitoring valid end-tidal carbon dioxide
levels due to limitations in the sampling technique. CONCLUSIONS: This study
demonstrated the potential of the capnograph as a respiratory monitor for
pediatric dental patients when the sampling line was attached to a scavenging
nitrous oxide nasal hood.
PMID- 10769857
TI - The physiological effects of supplemental oxygen versus nitrous oxide/oxygen
during conscious sedation of pediatric dental patients.
AB - PURPOSE: This study was performed to compare the effects of nitrous oxide/oxygen
(N2O/O2) versus oxygen (O2) as adjuncts to an oral narcotic regimen for pediatric
conscious sedation. METHODS: Using a randomized double-blind crossover design, 19
children (mean age 41 +/- 8.6 months) were sedated with chloral hydrate (50
mg/kg), meperidine (1.5 mg/kg) and hydroxyzine pamoate (25 mg) for two
appointments. Patients were assigned randomly to receive 100% O2 at one visit and
50% N2O/O2 at the other. Physiologic parameters were measured in five-minute
intervals, including respiratory rate, pulse rate (PR), oxyhemoglobin saturation
(SpO2) and end-tidal carbon dioxide. Data analyses focused on true desaturations
and apnea, level of sedation and sedation outcomes. RESULTS: There were no
differences in PR, SpO2 and risk of desaturation between the inhalation agents.
The level of sedation was deeper and the sedation outcomes were better in the
N2O/O2 group. CONCLUSION: N2O/O2 deepened the sedation while improving its
success with minimal alteration in physiologic parameters.
PMID- 10769859
TI - Management of children with hereditary angioedema: a report of two cases.
AB - Dentists must take extreme care in treating patients with Hereditary Angioedema
(HAE). Physical trauma, emotional stress, or anxiety during dental treatment
could lead to an acute attack that may lead to a laryngeal obstruction. This
article reviews clinical signs and symptoms, disease classification,
pathophysiology, and treatment recommendations for HAE. Management of 2 patients
with HAE is also presented.
PMID- 10769858
TI - Pediatric emergency room visits for nontraumatic dental disease.
AB - PURPOSE: This study described the incidence and predisposing, enabling, and need
factors of outpatients in a pediatric ER who sought care for nontraumatic
preventable dental disease and analyzed treatment rendered by attending
physicians and associated hospital charges for treatment. METHODS: Chart review
of outpatients discharged from the ER of a children's hospital during 1996-97,
using ICD-9 diagnostic codes for dental caries, periapical abscess and facial
cellulitis yielded the data for this investigation. RESULTS: During 1996-97, 149
patients made 159 ER visits. The most common diagnoses were ICD-9 codes 521.0 for
dental caries (48%) and 522.5 for periapical abscess (47%). Medicaid recipients
used the ER at an intermediate level between patients with no payor source and
those with private insurance. Almost one-half of the accounts changed status
during the billing process, with the majority being entered as private pay upon
admission, but changing to bad debt or charity after the registration records
were processed and collection was attempted. Most patients were treated
empirically by the ER physicians according to their presenting signs/symptoms.
CONCLUSION: This study confirmed that parents utilize the ER as their child's
primary dental care source.
PMID- 10769860
TI - Treatment of the avulsed tooth.
PMID- 10769861
TI - Detection of dens invaginatus in a one-year old infant.
PMID- 10769862
TI - Complete intrusion of a maxillary right primary central incisor.
AB - This clinical article presents a rare presentation of complete intrusion of a
maxillary right primary central incisor. Routine examination of a 29-month old
female patient revealed an intrusion injury where the primary central incisor was
displaced through the floor of the nasal cavity. The traumatic impaction was
erroneously diagnosed as an avulsion injury by the attending emergency room
physician and later discovered by the dental team during routine care. The injury
was documented with radiographs. The intruded incisor was removed through the
right naris utilizing general anesthesia to manage behavior and surgical access.
This article emphasizes the importance of radiographs and demonstrates the need
to involve the dental professional in initial assessment of dental trauma.
PMID- 10769863
TI - Focal epithelial hyperplasia: a multifocal oral human papillomavirus infection.
AB - Widespread, slightly elevated and confluent nodules are observed throughout the
oral mucosa in a young Hispanic girl. Repeated irritation of the soft tissues
from a compromised occlusion is an aggravating factor for the spread of these
lesions. A diagnosis of focal epithelial hyperplasia, a human papillomavirus
infection, is made following histopathologic diagnosis and viral typing.
Recognition of this specific type of warts is important in order to avoid the
mistaken identification of condyloma acuminata, which may have significant
repercussions in the life of a young child.
PMID- 10769864
TI - Treatment of mucus retention phenomena in children by the micro-marsupialization
technique: case reports.
AB - The purpose of the present study was to emphasize the technique of micro
marsupialization as an alternative for the treatment of mucus retention
phenomena. Out of 41 patients, 14 were selected for treatment by the micro
marsupialization technique on the basis of clinical criteria. Patient age ranged
from 5-9 years. The technique was performed as follows: the area was disinfected
with 0.1% iodine; a topical anesthetic was applied to cover the entire lesion for
approximately 3 min; a 4.0 silk suture was passed through the internal part of
the lesion along its widest diameter; and a surgical knot was made. Of the
original 14 patients treated by the micro-marsupialization technique, 12
presented full regression one week after treatment. Recurrence occurred in two
cases. It was possible to conclude that the micro-marsupialization technique is
an alternative to be considered, especially in pediatric dentistry.
PMID- 10769865
TI - Pemphigus vulgaris in adolescence: case report.
AB - Pemphigus vulgaris is an uncommon mucocutaneous disease caused by autoantibodies
against desmosomal antigens. It affects mainly middle-aged adults, and juvenile
cases are rare. The authors present a case of pemphigus vulgaris in adolescence
and review the literature. A 16-year-old girl showed oral and cutaneous lesions
suggestive of pemphigus vulgaris. Histopathology and direct immunofluorescence of
the oral mucosa confirmed the diagnosis and systemic steroid therapy was
efficient in controlling the disease. The recognition of the oral lesions of
pemphigus by the clinician, its early diagnosis, and prompt therapy are essential
for a favorable prognosis.
PMID- 10769866
TI - The age one dental visit: information on the web.
AB - As consumers increasingly turn to the Internet as a health resource it is likely
that parents may seek information on the recommended age for a first dental
visit. A meta-search engine was used to determine whether a parent would find
available, accessible, and authoritative information when seeking this
recommendation. Of 47 "hits" on the phrase "first dental visit", only 2 were
associated with major national health professional associations. Information
obtained through this search technique was readily available and accessible but
not authoritative. Individual searches on sites of leading dental and pediatric
organizations revealed that all major dental organizations that provide consumer
information and the Bright Futures consortium of child healthcare providers site
all advocate the age 1 visit. The American Academy of Pediatrics, however
suggests age 3 for the first visit. Information obtained from selected sites is
available and authoritative but not particularly accessible unless the names of
leading organizations are known.
PMID- 10769867
TI - Projecting retirement income of future retirees with panel data: results from the
modeling income in the near-term (MINT) project.
AB - Cross-sectional data capture only a point in time and miss individual changes in
earnings, labor force participation, marriage, fertility, and health. Because
panel data follow individuals over time, they do not have this problem. The
problems or concerns with cross-sectional data may be compounded when these data
are used to make projections. Iams and Sandell (1997) found that using panel data
on earnings explained much more variation in future earnings than using cross
sectional survey data. Panel data are also needed to estimate Social Security
benefits, especially for women. Because of auxiliary benefits paid to spouses, ex
spouses, and widow(er)s of entitled workers, an individual's Social Security
retirement benefit depends not only on his or her earnings history, but also on
his or her marital history and the earnings histories of current and previous
spouses. When we compare projected unreduced Social Security benefits with what
they would be if we didn't have marital history or earnings history data for men,
we find that: Benefits computed using only earnings histories are not very
different from benefits computed using both earnings and marital histories.
Benefits computed using only current earnings and marital histories underestimate
benefits for those in earlier birth cohorts and overestimate benefits for those
in the most recent birth cohort. Benefits computed without either marital or
earnings histories underestimate benefits for all birth cohorts, but by much more
for earlier cohorts than for more recent cohorts. For women we find that benefits
computed without marital or earnings histories underestimate benefits in all
birth cohorts. The largest differences are for women in earlier birth cohorts.
Using both marital and earnings histories to estimate unreduced Social Security
benefits, we find that men are projected to continue receiving higher benefits
than women, although the gap is expected to narrow as the baby boomers near
retirement age. We also look at the composition of projected total income
available at retirement for those with incomes in the 45th-55th percentiles of
the income distribution and find that: Total income at retirement is projected to
be larger for men than for women in every birth cohort. Women are projected to
receive the largest share of their total income from Social Security benefits.
Men are projected to receive the largest share of their total income from other
income sources, although this share declines as the baby boomers near retirement
age.
PMID- 10769868
TI - Identifying the race or ethnicity of SSI recipients.
AB - The Social Security Administration (SSA) has, from its beginnings, recorded the
race and ethnicity provided by those who apply for a Social Security card.
Although some of these data are eventually used in published tabulations when
persons file for benefits, problems with the data prevent a larger selection of
published tables. These problems stem from: incomplete internal SSA computer
processing; changes in the racial coding schemes over time; and missing codes for
younger cohorts of applicants. In spite of these problems, more data can be
shared with the public. This article shows how matching administrative files and
using statistical techniques make it possible to associate a race/ethnicity code
with the great majority of persons receiving a payment under the Supplemental
Security Income (SSI) program, a means-tested program for persons who are aged or
disabled. The article follows a 1-percent sample of SSI recipients through
several steps in an attempt to develop a race code. This approach can provide
data for the next several years on the race of all SSI recipients, as well as
data on race and ethnicity for recipients under age 40. Beyond the next few
years, these techniques will become less useful, and other methods will be
needed. SSA is in the process of revising its standards for classification of
federal data on race and ethnicity. The census for year 2000 will include coding
changes. Other federal agencies will be given as long as January 2003 to comply
with the new guidelines.
PMID- 10769870
TI - Summary of the 1999 Technical Panel report on assumptions and methods.
PMID- 10769869
TI - Collecting information on disability in the 2000 Census: an example of
interagency cooperation.
AB - The United States Constitution requires that an enumeration (or census) of the
population be conducted every 10 years to apportion seats in the House of
Representatives. Census information is also used to allocate funds and to plan
and manage programs. Census 2000 occurs on April 1, 2000, when one-sixth of all
American households will be mailed the "long form," containing disability,
demographic, economic, and housing questions. Although no short set of commonly
accepted questions on disability existed, one was developed for Census 2000 by a
collaborative, federal interagency work group on disability, convened by the
Office of Management and Budget. The work group consisted of staff from the
Social Security Administration (SSA), the Department of Health and Human
Services, the U.S. Census Bureau, and other agencies. They reviewed questions
initially proposed by the Census Bureau, developed an alternative proposal,
tested both versions in the Census Bureau's cognitive questionnaire lab, and on
the basis of testing, derived a consensus version for Census 2000. In many ways,
the six questions now contained on Census 2000 are an improvement over previous
efforts. Disability is ascertained for children as well as for adults, and
information will be collected separately for several domains of disability (for
example, sensory, mental, physical). The need for a brief set of disability
measures goes beyond Census 2000. If such data were collected regularly on
national surveys, critical policy and program concerns across agencies could be
addressed because better information could be gathered on changes in disability
prevalence and on the characteristics of persons with disabilities. Other similar
efforts include the former Disability Evaluation Study, now known as the National
Study of Health and Activity--a national sample survey on working-age disability
to be conducted by SSA--and the President's Task Force on the Employment of
Adults with Disabilities (Executive Order 13078).
PMID- 10769871
TI - Ultrasound-enhanced reactivity of calcium in the reduction of aromatic
hydrocarbons
AB - Reductions of aromatic hydrocarbons by calcium in ethylenediamine-n-alkylamine
mixture were investigated under ultrasonic conditions. Using an ultrasonic probe,
with naphthalene as test molecule, it has been demonstrated that under ultrasonic
action the reactions proceed faster (x10) and require a lower metal quantity
(0.5) than the reactions conducted with an efficient mechanical stirrer. In
addition, at ambient temperature and depending on the specific alcohol addition,
selective naphthalene reduction can be performed using ultrasound. 1,2
Dihydronaphthalene (88% yield) results from the reaction in the presence of 2
propanol, and 1,4,5,8-tetrahydronaphthalene (88% yield) is obtained with tert
butanol. Investigation of the metal surface points out the characteristics of the
calcium ultrasonic activation. The procedure was efficiently tested with several
aromatic hydrocarbons.
PMID- 10769872
TI - Sonication of chitin-glucan, preparation of water-soluble fractions and
characterization by HPLC.
AB - A water-insoluble chitin-glucan complex, isolated from the mycelium of
Aspergillus niger, was swollen in various aqueous media and treated subsequently
by high-energy sonication. The concentration of the resulting water-soluble
polysaccharide fractions was dependent on the swelling medium, the amount of the
chitin-glucan complex in the suspension, and on the time of sonication. The
yields of water-soluble chitin-glucan were within the range 13.6 to 24.4%
relative to the mass of the original chitin-glucan. The nitrogen content obtained
for the samples of water-soluble chitin-glucan indicated a higher content of
chitin (3.45% of nitrogen in high-molecular fraction) than in the original water
insoluble chitin-glucan sample (1.8%). The distribution of the molecular weights
of the water-soluble fractions prepared was determined by high-performance liquid
chromatography.
PMID- 10769873
TI - Sonoelectrochemical recovery of silver from photographic processing solutions
AB - This paper describes the effect of ultrasound upon the electrochemical recovery
of silver from photographic processing solutions using a newly designed
electrochemical cell--SonoEcoCell. Rates of deposition of silver (obtained
potentiostatically) were studied in the model 'fix' solutions (dilute aqueous
Na2S2O3/NaHSO3 at a stainless steel cylinder electrode in both the absence and
the presence of ultrasound. Under silent conditions, the magnitude of the
cathodic potential is a major factor in the removal of silver. Under 20 kHz
sonication, the rate of deposition of silver increases with increasing ultrasonic
intensity. The cathode efficiency is also enhanced under insonation. The position
of the ultrasonic probe with respect to the rotating cylinder electrode (RCE) was
studied. It was found that for a 'face-on' geometry (probe parallel to the
electrode) led to higher rate constants compared with a 'side-on' geometry (probe
perpendicular to the electrode). The effect of coupling an RCE with ultrasound
upon these rate constants employing the two geometry was also investigated. It
was found that, employing either the face-on or the side-on geometry alone,
improved rate constants were obtained below approximately 1500 and 2000 rpm,
respectively.
PMID- 10769874
TI - Influence of continuous phase viscosity on emulsification by ultrasound
AB - Power ultrasound is one means among others of mechanically producing emulsions.
In spite of numerous publications on the basic principles of this technique,
there is insufficient knowledge of continuous ultrasound emulsification processes
and the main parameters of practical relevance. A comparison of this system with
other continuous mechanical emulsifying devices is made. The effect of continuous
phase viscosity on droplet disruption due to ultrasound is the subject of a more
detailed investigation. Continuous phase viscosity is varied by means of water
soluble stabilizers (o/w systems) and different oils (w/o systems). At constant
energy density, droplet size decreases when adding stabilizers, whereas the
viscosity of the oil in w/o emulsions has no effect. Qualitative investigations
of the local distribution of cavitation have shown very small penetration depths
of cavitation into the liquid. This emphasizes the need for improvement of
apparatus design to optimize the emulsification process.
PMID- 10769875
TI - Sonolysis of fluoro-, chloro-, bromo- and iodobenzene: a comparative study
AB - The sonolysis at 520 kHz of the four monohalogenated benzenes, fluoro- (FB),
chloro- (CB), bromo- (BB) and iodobenzene (IB) at different initial
concentrations, 0.5, 1 and 2 mM, was studied. The sonolysis rate of all four
compounds depends on the initial concentration. During sonolysis of FB, CB, BB
and IB analogous apolar organic degradation products were determined, indicating
that all four monohalogenated benzenes degrade following a similar degradation
mechanism. The relative yield of the different degradation products was
different, as was shown for the degradation product benzene. A previously
developed kinetic model was applied to the sonolysis of the monohalogenated
benzenes and a good correlation between experimental and simulated concentration
versus time profiles was obtained for all four compounds. By comparing the
influence of the different monohalogenated benzenes on their own sonolysis rate,
it could be deduced that the proportionality between their concentration in the
cavitation bubbles and their concentration in the bulk solution depends on their
aqueous diffusion coefficient rather than on their Henry's law coefficient.
PMID- 10769876
TI - The role of object violation in the development of visual analysis.
AB - The present study investigated whether sensitivity to object violations in
perception as well as in action would vary with age. Five-, 6-, and 11-yr.-old
children and adults solved tasks which involved perception only, motoric
indication of parts, actual assembly of parts, and drawing of a violated figure.
In perception, object violation was the only factor showing change across age
groups, with violations being increasingly noticed. In composition tasks
involving motor components, object violation was just one factor besides quantity
of parts and type of segmentation contributing to task difficulty and showing
increase in performance across age groups. Analysis of object violations in
visual structure required abilities similar to those needed when analysing shape
interference. Improved visual detection and graphic construction of object
violation seemed not to occur because segmentation increased quantitatively but
more likely because fast perceptual processes came under scrutiny.
PMID- 10769877
TI - Cattell 16 personality profiles of patients following closed-head injuries.
AB - The personality scores from Cattell's 16 PF for 188 patients who had been
referred for neuropsychological assessment following motor vehicle incidents were
analyzed as a function of the severity of neuropsychological impairment (Halstead
Reitan Index) and time since the injury. Patients who were impaired (Index > 0.4)
exhibited lower scores on Factor B (moe concrete thinking), Factor E (more
submissive), and Factor F (more cautious) than patients who were not impaired.
The presence of impairment accommodated only 10% of the variance in Factor E
scores, associated with the largest group difference. There were no significant
differences between scores on any of the personality factors, verbal
intelligence, or standardized reading ability as a function of time since the
injury.
PMID- 10769878
TI - Attribution of meaning from movement of simple objects.
AB - Many researchers claim that attribution of meaning to movement is based
prevalently on the properties of the kinetic pattern. Using a constant kinetic
pattern, the present study examined the possible influence of shape, size,
luminance, and hue of the moving objects on the attribution of meaning. A
significant influence of the shape and luminance of the moving objects on the
expressivity of the kinetic pattern was found. This influence is probably due to
the fact that the kinetic conditions were not unequivocal and specific and so
easily influenced by some figural properties. The hue and size of the moving
objects seemed instead to have little importance in the attribution of meaning to
movement. The need for further investigation to assess the influence of the
properties of the kinetic pattern on the perception of a mechanical, intentional,
or expressive event is suggested.
PMID- 10769879
TI - Relationship between years of training and judged performance in Shotokan karate
black-belts.
AB - The relation between length of training and Dan rank was significant for 110 male
black-belts, although the complication of tied ranks was noted.
PMID- 10769880
TI - Subjective improvement following treatment with carbamazepine (Tegretol) for a
subpopulation of patients with traumatic brain injuries.
AB - Over a 3-yr period, 19 patients who had sustained brain traumas during motor
vehicle incidents and who exhibited abnormal scores for a dichotic word-listening
task and Roberts' Epileptic Spectrum Disorder Inventory more than one year after
the injury were recommended for treatment with carbamazepine (Tegretol). The
psychiatric profile of these patients, as defined by the Minnesota Multiphasic
Personality Inventory, was similar to the profile of patients from other studies
who had displayed more objective improvement following this treatment. Of the 14
patients 12 who followed the recommendation retrospectively reported that within
a few weeks after treatment they experienced marked reductions in the incidence
of sudden confusion and depression, increased attention and focus, and either
elimination or attenuation of an aversive sensed presence. Such results suggest
that many of the debilitating symptoms that persist for months to years after a
traumatic brain injury may be electrical in nature rather than due to
"psychological responses" and might be treatable by appropriate dosages of
carbamazepine or other, e.g., Gabapentin (Neurontin) antiepileptic compounds.
PMID- 10769882
TI - Electropalatographic and spectrographic descriptions of allophonic variants of
/1/.
AB - Prevocalic and postvocalic /1/ were investigated in three adult subjects
utilizing a combination of electropalatographic and acoustic techniques. Results
indicated that prevocalic /1/ was characterized by both alveolar and lateral
lingua-palatal contact, while postvocalic /1/ was primarily alveolar contact
only. Acoustically, prevocalic /1/ had a lower first formant and higher second
formant than postvocalic /1/. In addition, the second and third formants were
often weak or absent for prevocalic but not postvocalic /1/. Vowel context had a
greater effect on the electropalatographic and acoustic characteristics of
prevocalic than postvocalic /1/. Models that relate physiological and acoustical
aspects of speech were utilized to account for the observed results.
PMID- 10769881
TI - Equipment malfunctions and attribution of causality.
AB - The purpose of this study was to test whether individuals would be more likely to
attribute the cause for the malfunction of a new piece of equipment as a
manufacturing problem in the equipment or as an inability on their part to
properly work with the equipment. The subjects were 600 residents of Florida,
selected by a stratified random sample and interviewed in a statewide telephone
survey. Subjects were more likely to attribute the cause to themselves rather
than the machine. Overall, 71% attributed the cause to themselves, while only 24%
said the machine was at fault. There was also an interaction effect in terms of
income, with middle-income users more likely to blame the machine and upper
income users more likely to blame themselves. Further, there was also a
significant relationship between attribution of cause and age, with older
respondents being more likely to attribute cause to themselves. These results
imply that attribution may differ when the potential object of attribution is a
machine rather than another person.
PMID- 10769883
TI - Severity of injuries due to accidental fall across the life span: a retrospective
hospital-based study.
AB - This retrospective study investigated injuries due to accidental fall across the
life span for which 19,593 patients were admitted to the Emergency Unit of the
Groningen University Hospital during the period 1990 through 1997. 64% of the
accidental falls were found for those in the age range between 10 years and 59
years; however, the proportion of accidental falls with regard to other causes of
injuries by age group were the highest in youngsters (infants up to 9 years old)
and in elderly persons (over 60 years old), 43% or more of these patients having
falls with injuries. The clinically treated patients had on the average a
statistically greater Injury Severity Score (7.2) than the outpatients (2.4). The
highest percentages of medically treated inpatients were the patients of 60 years
and over. Their mean ISS score was about the same for elderly inpatients, but the
percentage of clinical treatment increased with age as well as the mortality. 30%
of the injuries were found in the lower extremities and 30% in the upper
extremities. Bone fracture was statistically significantly the major (36%) injury
followed by contusion (20%). 34% of the accidental falls occurred at home, and
statistically significantly more females, 50 years of age and older, were injured
than males.
PMID- 10769884
TI - Effects of types of featural information on interpretation by young children of
novel words at the superordinate level.
AB - In this experiment with a Novel Label Task, 48 children ages 5 to 6 years were
given a novel word for a target item, e.g., a dog. They were also given one of
two types of featural information for the target item, a feature naturally common
to animals, i.e., "This has a heart inside," or an accidental feature uncommon to
animals, i.e., "This gets a splinter." As a result, the number of children who
interpreted the novel word at the superordinate level (animal) increased
significantly when they were given the feature naturally common to animals. On
the other hand, there was no significant increase for an accidental feature.
Further, the children were given the instruction that all animal items in this
task had the same features as the target item. As a result, although the number
of children who interpreted the novel word at the superordinate level (animal)
increased significantly when they were given both the feature naturally common to
animals and also the accidental feature, there were more when the instruction was
with the feature naturally common to animals than with the accidental feature.
The findings were discussed in relation to the factors corresponding to young
children's interpretation of a novel word at the superordinate level.
PMID- 10769885
TI - Effects of word spacing on reading Chinese text from a video display terminal.
AB - This study investigated the effects of designing space between words in Chinese
text, i.e., whether using a "word" instead of a "character" as a presentation
unit, will facilitate the performance of reading from a video display terminal.
Experimental results indicated that the main effect of word spacing significantly
affected the reading time and the number of questions answered correctly.
Subjects spent less time on the text with half-character word spacing or with
whole-character word spacing than with conventional type (without word spacing).
We also discovered that the number of questions answered correctly for stimuli
with half-character spacing is significantly greater than that for stimuli with
whole-character spacing, while both are smaller than for stimuli with
conventional type. The additional variables, such as text difficulty and display
control have significant effects as well. Our results suggested that the optimal
word spacing in Chinese text should be greater than that in the traditional
layout and less than a whole-character spacing. Apparently, in Chinese text,
using a "word" as a presentation unit is more favorable than the traditional
layouts that do not have any explicit word boundaries. The word spacing design
may benefit in reading difficult or unfamiliar materials and further apply in
emergency situations or in reading ambiguous sentences.
PMID- 10769886
TI - Comparative analysis of different correction methods for measuring Rod-and-Frame
Test performance.
AB - A comparative analysis was conducted of five different methods for scoring the
Rod-and-Frame Test to examine the convergent validities of each of the five
methods with performance on the Embedded Figures Test for a sample of 408 13- to
16-yr.-olds. The scoring methods included the absolute error, the algebraic
error, the absolute value of the algebraic error, the frame effect, and an
assessment of relative field dependence. Correlations obtained among the five
methods and the Embedded Figures Test indicated different patterns for boys and
girls. In general, the method which employed the absolute value of the algebraic
error yielded the strongest convergent validity coefficients with scores on the
Embedded Figures Test and Group Embedded Figures Test for boys (.62 and -.54,
respectively), although, for girls, the absolute algebraic error and absolute
error both yielded coefficients of .50 with Embedded Figures Test scores and -.46
with Group Embedded Figures Test scores.
PMID- 10769887
TI - From unidentified to 'misidentified' newborn: male bias in recognition of sex.
AB - Our study tests in newborns the perceptual bias described in 1979 by Hildebrandt
and Fitzgerald in recognizing the sex of infants, using videorecords instead of
still photographs. Analysis showed a tendency for young adults to perceive
newborn infants as male immediately after birth, and this perceptual bias
diminished if the babies smile.
PMID- 10769888
TI - Effects of sex composition by class and instructor's sex on physical self
efficacy of college men.
AB - The relationship of sex composition of class and instructor's sex to Physical
Self-efficacy has yielded conflicting results in several studies. This study
examined the relationship of sex composition of class and instructor's sex to
scores on Physical Self-efficacy, Perceived Physical Ability, and Physical Self
presentation Confidence of 80 male students enrolled in one of four sections of a
strength training class. Analysis indicated no significant difference on Physical
Self-efficacy between male students who were enrolled in all male classes or in
coeducational classes; improvements in scores on Physical Self-efficacy were not
specific to the sex composition of the class or sex of the instructor and no
significant difference on Perceived Physical Ability and Physical Self
presentation Confidence between male students who joined an all male class or a
coeducational class. Perceived Physical Ability improved from the pretest to the
posttest in all classes; and no improvement in scores for Physical Self
presentation Confidence was found in all classes. In conclusion, the analysis
showed sex composition of the class and sex of the instructor were not
significantly related to scores for self-efficacy.
PMID- 10769889
TI - Coactivation, pop-out, and symmetry affect line discrimination.
AB - 17 college students discriminated between vertical and horizontal target lines
flanked by vertical and horizontal distractors. Large displays with 3.0-cm lines
and small displays half this size were used. The distractors were positioned
above and below the target or to the left and right of it, forming vertical and
horizontal global orientations. The number of flankers sharing the target's
orientation was varied. Vertical targets and small display sizes were processed
more quickly. Speed of responding did not differ for the two global orientations.
There was no advantage for target lines consistent with global orientation. The
results were replicated in Exp. 2 with diagonal flankers. This supports an
explanation using stimulus compatibility, since diagonal lines do not correspond
to either of the response options and cannot induce a tendency to respond more to
one target than another. Displays with multiple symmetry were responded to faster
than those with a single symmetry which were faster than asymmetrical displays,
supporting the idea that symmetrical axes parallel and perpendicular to the
target orientation provide a facilitative frame of reference. Coactivation from
same-oriented flankers, pop-out from differences in orientation, and symmetry all
influenced responding in these patterns.
PMID- 10769890
TI - A lower incidence of left-handed writing among young adults in Bulgaria than in
the USA.
AB - The incidence of left-handed writing among 590 young Bulgarian adults was 6.4%,
significantly lower than that reported in two studies of students in the United
States. Of those writing with the right hand, 10.8% stated that they had been
forced to change their preferred hand for writing. The parents of the Bulgarian
sample had a similar low incidence of left-handed writing (5.9%). Left-handed
writing was almost three times more likely if one or both of the parents wrote
with the left hand.
PMID- 10769891
TI - Additional study of the Youth-Depression Adjective Check List.
AB - Replicated and extended aspects of determinations of reliability and validity for
the State version of the Youth-Depression Adjective Check List. Students from
Grades 9 through 12 (64 girls and 41 boys) completed the State version and the
Adolescent Activities Checklist on each of 12 consecutive days and completed the
Trait version, the Reynolds Adolescent Depression Scale, the Multiple Affect
Adjective Check List--Revised Grade 6, and the Adolescent Activities Checklist at
the beginning and the end of the study. Good reliability and validity of the
State version were confirmed and extended, and preliminary information on
characteristics of the Trait version of the Youth-Depression Adjective Check List
also was presented. The State version seems suitable for use in research with
adolescents and preadolescents. More study of the Trait version is recommended.
PMID- 10769892
TI - Implicit memory for auditorily presented threatening stimuli: a process
dissociation approach.
AB - The investigation of unconscious cognition involves especially problems with the
methodology of measuring implicit and explicit proportions of different task
performances. In this study the process dissociation procedure of Jacoby and its
modification within the multinomial modelling framework for an indirect word
nonword-discrimination task is applied to a sample of 45 healthy students. The
paradigm includes acoustically presented stimuli. During a learning phase,
subjects listened to a series of neutral and threatening words. Performance was
tested by letting subjects decide whether a presented stimulus (masked with white
noise at signal-noise ratio of -17 dB or unmasked) had been a word or a nonword.
Within this paradigm, implicit cognition occurs when (a) a word is more probably
correctly recognized as "word" after presentation during the learning phase
(typical priming effect) or when (b) a nonword derived from a word is more
probably falsely recognized as "word" after its corresponding word had been
presented during the learning phase (effect of implicit cognition given
perceptual fluency). Frequencies for hits and false alarms were analyzed within
the multinomial model which allows estimating parameters for the correct
discrimination of words (c), the response bias (b), the classical priming effect
(u1), and the parameter for the priming effect of "old" nonwords (u2). Under
masked stimuli the multinomial model showed implicit cognition, an effect not
equally found for neutral and threatening words. Threatening words exhibited a
significantly higher portion of implicit cognition than neutral ones. Given the
statistical complexity of multinomial models, the application of this method was
explained in detail.
PMID- 10769893
TI - Evidence for a third factor on the Positive and Negative Affect Schedule in a
college student sample.
AB - The Positive and Negative Affect Schedule (PANAS) was originally developed to
measure two orthogonal dimensions of affect. The present study examined the
factor structure of the PANAS in a sample of 302 undergraduates. maximum
Likelihood factor analysis was used to compare two- and three-factor solutions to
self-rated affect. The two-factor solution resulted in confirmation of the two
factors of Positive and Negative Affect hypothesized to underlie the schedule.
When, however, a three-factor solution was specified, the Positive Affect factor
was retained, while the Negative Affect factor split into two lower-order factors
generally consistent with the Upset and Afraid factors described by Mehrabian in
1997. These findings highlight the need for research to consider the possible
influence of a third affective dimension, such as Dominance-Submissiveness on
self-rated affective experience.
PMID- 10769894
TI - Benefits of interhemispheric integration on the Japanese Kana script-matching
tasks.
AB - We tested Banich's hypothesis that the benefits of bihemispheric processing were
enhanced as task complexity increased, when some procedural shortcomings in the
previous studies were overcome by using Japanese Kana script-matching tasks. In
Exp. 1, the 20 right-handed subjects were given the Physical-Identity task
(Katakana-Katakana scripts matching) and the Name-Identity task (Katakana
Hiragana scripts matching). On both tasks, a pair of Kana scripts was
tachistoscopically presented in the left, right, and bilateral visual fields.
Distractor stimuli were also presented with target Kana scripts on both tasks to
equate the processing load between the hemispheres. Analysis showed that, while a
bilateral visual-field advantage was found on the name-identity task, a
unilateral visual-field advantage was found on the physical-identity task,
suggesting that, as the computational complexity of the encoding stage was
enhanced, the benefits of bilateral hemispheric processing increased. In Exp. 2,
the 16 right-handed subjects were given the same physical-identity task as in
Exp. 1, except Hiragana scripts were used as distractors instead of digits to
enhance task difficulty. Analysis showed no differences in performance between
the unilateral and bilateral visual fields. Taking into account these results of
physical-identity tasks for both Exps. 1 and 2, enhancing task demand in the
stage of ignoring distractors made the unilateral visual-field advantage obtained
in Exp. 1 disappear in Exp. 2. These results supported Banich's hypothesis.
PMID- 10769895
TI - Future time perspective and positive health practices among young adolescents: a
further extension.
AB - A sample of 139 young adolescents attending a middle school responded to the
Future Time Perspective Inventory and the Personal Lifestyle Questionnaire in
classrooms. A statistically significant correlation of .46 was found between
their scores on future time perspective and ratings for the practice of positive
health behaviors. This correlation was larger than those previously reported for
middle and late adolescents but smaller than that found for young adults.
PMID- 10769896
TI - Color discrimination under chronic hypoxic conditions (simulated climb "Everest
Comex 97").
AB - Hypoxia is known to alter visual functions. In the present study, the effects of
chronic hypobaric hypoxia upon visual color discrimination were studied in 8
subjects participating in a simulated climb from sea level (PO2 = 210 hPa) to
8,848 m (PO2 = 70 hPa) over a 31-day period of confinement in a decompression
chamber ('Everst-Comex 97'). During these investigations, the subjects were
required to discriminate between colors of different hue in the red, blue, and
green ranges. Alterations in color discrimination increased slightly but
significantly as altitude increased. Impairments occurred mainly in the red and
blue ranges. In addition, our results further indicate that color discrimination
would be affected only when a minimum threshold of difference between color
stimuli is not present. Methodological and physiological implications are
discussed.
PMID- 10769897
TI - Implications of the symbol figure representations: information from the direction
and spatial location used by Japanese students.
AB - Meanings of physical distance, spatial location, and direction of symbolic figure
in the Doll Location Test were investigated with 283 normal college students in
Japan. They were asked to indicate eight symbolic figures of hypothetical people
such as reliable father, unreliable mother on a recording sheet. The physical
dyadic distance from the self, spatial location, and direction of symbolic
figures were analyzed. Positive persons were placed twice as close as a negative
person. Analysis of direction showed that more than 90% of the positive people
were represented in either the same direction as or facing self, whereas a
negative person was represented either in the opposite or in an unrelated
direction from the self. Spatial location of the symbolic figures did not yield
evaluative values.
PMID- 10769898
TI - Comparison of the Trail Making and Color Trails Tests in a Chinese context: a
preliminary report.
AB - The Color Trails Test developed as a culturally fair analogue of the Trail Making
Test, was used to examine the relationship between the two tests with 35
undergraduate Chinese in Hong Kong recruited as the subjects. The scores on these
two tests of the 12 men and 23 women were significantly correlated .71. The
equivalence of the Trail Making and Color Trails Tests when applied to Chinese in
Hong Kong was discussed.
PMID- 10769899
TI - Happiness and self-actualization under conditions of strain: a sample of homeless
men.
AB - Maslow's contention that happiness includes striving and is more than a
hedonistic construct was tested in a sample of 146 homeless men. Since all
participants were homeless, environmental experiences can be considered as
largely held constant, allowing an examination of personality and happiness under
conditions of strain. Principal axis factor analysis with promax and oblique
rotations placed scores from the measures Unhappy-Happy and the Brief Index of
Self-actualization on the same factor which supported Maslow's idea. Humanistic
existential psychology has interest in the happiness construct particularly
regarding the development of human potential.
PMID- 10769900
TI - Group exercise reduces depression in obese women without weight loss.
AB - Given participation in a 6-mo. exercise and relaxation training 8 obese women
showed significant change in scores on the Beck Depression Inventory over the 6
mo. interval, but not on Body Mass Index or Medical Outcome Study Short-Form-36.
PMID- 10769901
TI - Relationship of visual motor development and academic performance of young
children in Hong Kong assessed on the Bender-Gestalt test.
AB - This study compared the Qualitative Scoring System for the Modified Version of
the Bender-Gestalt test and the Developmental Scoring System for the Bender
Gestalt test in predicting performance on the Standardized Attainment Test of
young children in Hong Kong. The study was done in two phases. First, 748 middle
class children ages 4 to 8 years from 6 kindergartens and 6 primary schools were
given the Bender-Gestalt test individually in kindergarten and in groups for
older children, respectively. Both scoring systems were used to measure the
children's visual motor development. Second, among the participants' protocols,
257 Primary 1 to Primary 3 children ages 6 to 8 years were selected to compare
the Qualitative Scoring System for the 6 designs of the Modified Version of the
Bender-Gestalt test and the Developmental Scoring System for the 9 designs of the
Bender-Gestalt test in predicting performance on the Standardized Attainment
Test. Results indicated that the Qualitative Scoring System differentiates better
than the Developmental Scoring System in evaluating visual-motor development
among young Chinese children from Hong Kong. Results also indicated that the
Qualitative Scoring System correlated significantly with achievement in Chinese
and English at all three levels. Scores on the Developmental Scoring System
correlated significantly with only marks for Primary 1 and Primary 2 Chinese.
PMID- 10769902
TI - Use of subjective estimation in motor skill tests of young children: judgment
based on observation of behavior in daily life.
AB - This study assessed what motor skill tests were appropriate by observing 636
young children's behavior in daily life (low-aged classes, M = 3.7 yr.; middle
aged classes, M = 4.7 yr.; high-aged classes, M = 5.7 yr.). A homeroom teacher
and an assistant teacher estimated motor achievement as pass-or-fail, and then
judged pass-or-fail based on practical testing. Estimate-re-estimate agreement,
interrater agreement, and agreement between estimated values and measured values
were examined for 27 items, e.g., skipping, bouncing a ball, and turning on one
leg. Estimate-re-estimate agreement was high on the whole. Interrater agreement
ranged from 34% to 100% for 3-yr.-olds, 21% to 100% for 4-yr.-olds, and 89% to
100% for 5-yr.-olds. Agreement between estimated values and measured values
greater than 80% was found in most items for 5-yr.olds (14 items). After
examining the above-mentioned agreements, 26 items were selected as possible
tests to judge motor development, using a pass-or-fail, from the observation of
young children's behavior in daily life.
PMID- 10769903
TI - Relationship of laboratory and on-road tests for driving-school students and
experienced drivers.
AB - There is a pressing need to evaluate driving ability without an actual driving
test but no reliable, standardised procedure is available. This study
investigated the resulting distortion performance evaluation for different driver
groups in on-road tests due to driving skills and driving style. Two groups, 15
female driving school students and 25 experienced male drivers were examined
using cognitive and psychomotor tests and standard personality questionnaires as
well as an on-road driving test. The students made significantly fewer errors on
the driving test than the experienced drivers. The former group's driving
performance could be predicted by errors on the laboratory tests, along with
personality factors, while experienced drivers' driving errors were best
predicted by slowness on laboratory tests. This study suggests that, when a
series of standard cognitive and psychomotor tests are considered, different
measures may apply in predicting young people's ability to drive safely based on
assessing driving ability of experienced drivers, assumed lowered due to
distorted driving style.
PMID- 10769904
TI - Positive and negative stimuli in relation to tennis players' reaction time.
AB - Research has indicated that negative and positive thoughts may affect sport
performance. The purpose of this analogue study was to assess whether negative
and positive stimuli influenced tennis performance similar to positive and
negative thought. The reaction time (RT) of 40 competitive tennis players was
measured during a timed response to a tennis ball rotating in a topspin,
sidespin, or backspin direction on the computer screen. Immediately prior to the
ball presentation, a phrase (accessory stimulus) was presented visually or
aurally. The accessory stimulus provided either positive (e.g., 'nice shot') or
negative information (e.g., 'bad shot') followed by the subject's name. Analysis
showed a main effect only for the type of spin. The slowest RT occurred when
responding to a tennis ball rotating in a backspin direction. A significant
interaction was found for the sensory modality (audition vs vision) and polarity
(positive vs negative) of the accessory stimulus. RT to negative stimuli was
slowest when the accessory stimulus was presented aurally. The quickest RT to
positive stimuli occurred when the accessory stimulus was presented aurally.
These results indicated that negative and positive stimuli, when presented
aurally, affected performance as positive and negative thoughts measured in other
studies. Not measured was whether negative and positive stimuli actually produce
the negative and positive thoughts, respectively, that have been reported to
affect performance.
PMID- 10769905
TI - Discrimination of rotation from linear motion: influence of interference gratings
and dichoptic viewing.
AB - Observers viewed a screen on which a number of patches containing horizontally
moving pixels were presented. Target patches consisted of pixels whose motion
simulated the rotation of a cylinder around its Y-axis; distractors, of pixels
whose motion was linear. The task was to assess whether a display contained a
target patch. Exp. 1 showed that the superposition of the displays with drifting
sine-wave gratings interfered with rotation detection in a spatial- and temporal
frequency specific manner. In Exp. 2, dichoptic presentation greatly reduced the
interference of the drifting gratings. It is argued on various grounds that the
process(es) responsible for the detection and discrimination of rotating
structure in depth exists at a low level of the visual system.
PMID- 10769906
TI - Usefulness of assessment techniques in assessing classification for emotional
disturbance and generating classroom recommendations.
AB - A national survey of specialist school psychologists examined the perceived
usefulness of assessment techniques in making decisions regarding eligibility for
the educational classification of emotional disturbance and in generating
classroom recommendations. Analysis showed measures rated as most useful were
interviews with the parent, teacher, and student, observations of the student,
and norm-referenced rating scales. Projective techniques were least useful. These
findings are important in the context of "best practices" for the
multidimensional assessment of emotional disturbance which promotes a more direct
link between assessment and intervention.
PMID- 10769907
TI - Minimizing error in measurement of error: a proposed method for calculation of
error in a two-dimensional motor task.
AB - Traditional one-dimensional error scores are still consistently used in research
on motor learning to quantify two-dimensional error; however, the inherent
differences in two-dimensional tasks render that application inappropriate and
often misleading. Consequently, the purpose of this paper was to propose a novel
method of presenting errors, which more precisely represents the accuracy,
direction, and variability of error in two-dimensional settings. Although closely
related to several alternatives for representing errors, the methodology used and
the results obtained provide a more accurate procedure for pinpointing critical
trends in what have been commonly referred to as AE (absolute error), VE
(variable error), CE (constant error), and E (total variability). The proposed
measurements of AVE (adjusted variable error), DE (directional error), TSE (total
spread of error), and RE (radial error) provide composite error scores carrying a
variety of information about performance on two-dimensional tasks. Formulas and
examples are provided to facilitate computation and enhance understanding of the
proposed scores.
PMID- 10769908
TI - Use of photic feedback as an adjunct treatment in a case of Miller Fisher
syndrome.
AB - Photic Feedback treatment of a patient diagnosed with Miller Fisher syndrome has
resulted in the rapid and permanent remission of symptoms. During Photic Feedback
treatment, the CD20 appeared to be slightly increased. This may have been
associated with changes in humoral immunity. The present clinical observation of
a single patient suggests that Photic Feedback treatment should be investigated
as a possible adjunct therapy for patients who suffer from polyneuropathies, such
as Miller Fisher syndrome, within a carefully controlled clinical trial.
PMID- 10769909
TI - Evaluating architectural design review.
AB - Architectural design review is a method of environmental management which is
widely used by governmental agencies in both the United States and in Great
Britain. Because design review is a governmental function, there is a major need
to assess how well it works. Research covering over 29,000 respondents and 5,600
environmental scenes suggests that scientific protocols can be adapted to provide
an accurate and efficient design review protocol. The protocol uses preference
experiments to find the standardized mean difference [formula: see text] between
a proposed project and a random sample of existing projects. Values of d will
indicate whether the project will increase, maintain, or diminish the aesthetic
merit of the sampled area. The protocol is illustrated by applying it to the case
of design review for a single residence. Implications for further implementations
are discussed.
PMID- 10769910
TI - Absence of a numerical memory span advantage in Japanese Kanji.
AB - Research suggests that people's memory span for Arabic numerals is consistently
greater than that for digit words written in an alphabet, even when these stimuli
have been matched for word length, lexicality, and semantics. It is not clear
whether this "numeral advantage" holds true for other scripts. The present study
tested this possibility in the case of Japanese kanji (the Chinese characters
used in Japanese). 23 Japanese adults responded to stimuli comprised of two sets
of random number sequences, one set presented in Arabic numerals and the other in
digit word kanji. Each set began with three two-item sequences followed by three
three-item sequences and so on, until three 12-item sequences were presented.
Consecutive repetition of stimuli was avoided. Memory span was measured as the
length of the last correctly recalled item sequence. Results indicated no numeral
advantage effect, as there was no significant difference between people's recall
of numerals and digit words. Memory strategy in dealing with kanji appears to
bear more resemblance to numerals than to words in English.
PMID- 10769911
TI - Grip-strength performances by 6- to 19-yr.-old children with and without hearing
impairments.
AB - 86 children and youth enrolled at a residential school for the deaf were matched
with 86 children and youth with normal hearing (by age, sex, height, weight, and
hand preference) from four public schools. Each participant's grip strength was
tested with a calibrated hydraulic dynamometer set at the second position. No
significant between-group differences were observed. The authors attributed the
similar between-group performances to the equal opportunities for participation
in sport and physical education in this residential school.
PMID- 10769912
TI - Perceived relative importance of psychological and physical factors in successful
athletic performance.
AB - Ratings of the perceived relative importance of psychological and physical
factors for successful athletic performance were obtained from 29 men and 53
women in sports of track, swimming, soccer, volleyball, basketball, gymnastics,
baseball or softball, tennis, diving, and golf, by level of competition (high
school, college, and professional), and sex of athlete. The over-all rating of
the relative importance of psychological factors was 39%. Significant differences
in the ratings of the relative importance of psychological factors were found for
sport, level, sex, sport x level, and level x sex. Ratings of the relative
importance of psychological factors for successful performance in various sports
increased in the order listed above. The significant effect for level and
interaction of sport x level were accounted for primarily by the higher ratings
given to professional golf. The significant effect of sex and the interaction of
sex x level were attributable to higher ratings of the importance of
psychological variables for high school women athletes as compared to high school
men athletes.
PMID- 10769913
TI - Emotion space as a predictor of binocular rivalry.
AB - In our 1999 report, we examined robustness of a two-dimensional structure of
facial expressions of emotion under the condition of some perceptual ambiguity,
using a stereo-scope. The current study aimed to replicate and extend the
previous work by adding facial photographs of different persons and by measuring
participants' perception of stereoscopically presented faces. Multidimensional
scaling provided a two-dimensional configuration of facial expressions comparable
with the previous studies. Although binocular rivalry was a less frequent
phenomenon, it was suggested that the distances between facial expressions in the
derived space were a contributing factor in eliciting binocular rivalry.
PMID- 10769914
TI - Human movement-related brain potentials preceding voluntary movements in
different arousal states monitored with skin potential level.
AB - The present study investigated the readiness potential (RP) preceding a brisk
extension of the right middle finger during different arousal states as monitored
by skin potential level (SPL). The late component of the readiness potential in
the medium arousal state was significantly larger than those in the low and high
arousal states. This finding indicates that the RP waveform may vary as a
function of arousal states, suggesting the inverse U-shaped relationship proposed
in studies of the contingent negative variation.
PMID- 10769915
TI - Effects of music on mood during bench stepping exercise.
AB - This study evaluated the effect of music on the mood of women during exercise. 16
middle-aged women, aged 49.9 +/- 7.53 yr., performed 60-min. bench stepping
exercise while listening to Japanese traditional folk song, aerobic dance music,
or nonmusic. The subjects reported significantly less fatigue with aerobic dance
music and Japanese traditional folk song than with nonmusic. Aerobic dance music
was associated with significantly more vigor and less confusion than nonmusic.
PMID- 10769916
TI - Local muscular fatigue and attentional processes in a fencing task.
AB - Study of the effects of brief exercise on mental processes by Tomporowski and
Ellis (1986) has shown that moderate muscular tension improves cognitive
performance while low or high tension does not. Improvements in performance
induced by exercise are commonly associated with increase in arousal, while
impairments are generally attributed to the effects of muscular or central
fatigue. To test two hypotheses, that (1) submaximal muscular exercise would
decrease premotor time and increase would increase the attentional and
preparatory effects observed in premotor time 9 men, aged 20 to 30 years,
performed an isometric test at 50% of their maximum voluntary contraction between
blocks of a 3-choice reaction-time fencing task. Analysis showed (1) physical
exercise did not improve postexercise premotor time, (2) muscular fatigue induced
by isometric contractions did not increase motor time, (3) there was no effect of
exercise on attentional and preparatory processes involved in the postexercise
choice-RT task. The invalidation of hypotheses was mainly explained by disparity
in directional effects across subjects and by use of an exercise that was not
really fatiguing.
PMID- 10769917
TI - Injuries due to school sports accidents in 4 to 13-yr.-old children.
AB - 505 kindergarten and primary school children from 4 to 13 years of age were
treated for school sports injuries during the period 1990-1997. The incidence of
injuries increased statistically significantly from .5 per 1,000 children 4- to 5
yr.-old to 4.8 injured children per 1,000 in 12- to 13-yr.-old. 59% of the
injuries involved upper extremities; 35% of these were in the wrist region. 33.5%
of the injuries were of the lower extremities, with 50% being of the feet and
36.4% of the ankle. Accidental falls were the main situation (53%) in which
school sport accidents occurred. Nearly 65% of these accidental falls occurred at
the ground level; the remaining accidents (35%) occurred when the child was
working on an apparatus, e.g., parallel bars, balancing beam, side horse. The 4-
to 5-yr.-old children were the most vulnerable to accidental fall (67%). A
statistically significant increase in injuries in ball sports was observed from 4
to 5-yr.-olds (0%) to the 12- to 13-yr.-olds (28%).
PMID- 10769918
TI - Pencil lead diameter affects response sheet completion time.
AB - The effect of pencil lead diameter on the completion time of a multiple-choice
response sheet was examined. Participants used three pencil lead diameters (.5
mm, .9 mm, and a standard No. 2 pencil) to fill in "bubbles" on response sheets
in one experiment; a .7-mm pencil was substituted for the No. 2 pencil in Exp. 2.
Participants using a .5-mm pencil completed response sheets more slowly than when
using a .7-mm, .9-mm, or a No. 2 pencil.
PMID- 10769919
TI - Evaluation of physical activity measured via accelerometry in rural fourth-grade
children.
AB - Interest in the benefits of exercise has prompted increased research examining
the relationship between physical activity and health status in adults. More
recently, considerable research effort has been directed toward the role of
physical activity in young children as a precursor to adult physical fitness. The
purpose of this study was to estimate the relationship between physical activity
measured via accelerometry and body mass index, body mass, body composition, and
physical fitness in fourth-grade boys and girls during physical education
lessons. 54 fourth-grade students in rural Pennsylvania (28 girls, M age 9.6, SD
= .56; 26 boys, M age 9.5, SD = .51) were subjects. Girls were significantly less
active during all lessons measured (p < .001). The results of linear regression
analyses indicated that physical activity was negatively associated with body
mass index, body mass, and body fat percentage (p < .05), and positively
associated with physical fitness (VO2max) (p < .01). These data indicate the need
for curricular intervention to motivate girls to increase their activity during
structured physical education lessons and demonstrate the efficacy of the body
mass index as a screening tool within the schools.
PMID- 10769920
TI - External motivators of self-touching behavior.
AB - Previous research has shown that nonverbal self-touching behaviors can be induced
by external motivators such as videos and literary passages about insects. This
study investigated whether the number of self-touching behaviors differed between
presentation of what was assumed to be an anxiety-inducing stimulus (listening to
the reading of a passage about leeches and answering questions) or a nonanxiety
inducing stimulus (a passage about canaries). It also investigated whether there
was a difference in frequency of self-touching when subjects were passively
listening to passages or actively answering questions. The difference in
frequency of self-touching between men and women was also observed. Over-all,
subjects did not perform significantly more self-touching gestures during the
anxiety-inducing stimulus than during the nonanxiety-inducing, as previous
research had indicated. Subjects did touch themselves significantly more,
however, while answering questions than while listening to the passage. Over-all,
men performed significantly more self-touching behaviors than women. And, women
touched themselves significantly more during the active anxiety-inducing cell
than in any other condition.
PMID- 10769921
TI - Field dependence versus field independence of students with and without learning
disabilities.
AB - The Group Embedded Figures Test of Oltman, Raskin, and Witkin was administered to
60 high school students (30 with learning disabilities and 30 without learning
disabilities) to measure their cognitive styles of field dependence versus field
independence. The analysis showed that the students with learning disabilities
scored as more field dependent than those without learning disabilities.
PMID- 10769922
TI - Influence of aerobic and stretching exercise on anxiety and sensation-seeking
mood state.
AB - This study randomly assigned participants to either an aerobic, non-aerobic, or
lecture group to assess whether one bout of exercise would alter mood state.
Regardless of experimental condition, changes in mood state were found on the
Sensation Seeking and Anxiety State Tests, where sensation-seeking scores
increased and anxiety state decreased from pre- to posttest.
PMID- 10769923
TI - Overestimation of the effectiveness of cardiopulmonary resuscitation as a
function of CPR certification level.
AB - 67 college students holding three different levels of certification in CPR
estimated the survival rates of people given this procedure. Students not
certified in CPR estimated the survival rate to be 51.2%, those previously
certified estimated 43.8%, and those currently certified estimated 27.0%.
Although knowledge of CPR was associated with greater accuracy, all three groups
significantly overestimated the actual survival rate of 10%.
PMID- 10769924
TI - Effect of acute hepatic encephalopathy on [3H]dopamine release from rat cerebral
cortex and striatum in vitro: role of Ca2+.
AB - Hepatic encephalopathy (HE) is characterized by motor symptoms associated with
disturbed functions of the dopaminergic systems, but the underlying mechanisms
are not clear. A previous study from our laboratories revealed that HE, induced
in rats by repeated treatment with thioacetamide, enhanced the 50 mM potassium
(KCl)-stimulated release of newly loaded [3H]dopamine in both striatal and
frontal cerebral cortical slices in the presence of Ca2+. In the present study we
compared the effects of HE on dopamine release in striatal and frontal cerebral
cortical slices and synaptosomes in the presence and absence of Ca2+. HE enhanced
the KCl-stimulated [3H]dopamine release from striatal and frontal cortical
synaptosomes in the presence of Ca2+ to the same extent as in slices prepared
from the respective brain regions. In the absence of Ca2+ a slight reduction in
dopamine release was observed in frontal cortical synaptosomes from HE rats when
compared to control rats, while no effect of HE on the release was discernible in
frontal cortical and striatal slices and striatal synaptosomes. We conclude that
in both brain regions studied HE stimulates dopamine exocytosis triggered by Ca2+
influx without affecting the release mediated by means of plasma membrane
transporters or exocytosis involving intraterminal Ca2+.
PMID- 10769926
TI - Categorization of unilaterally presented emotional words: an ERP analysis.
AB - This study is intended to clarify the functional role of different ERP components
as indicators of the processing of emotions. The effect of emotional connotation
of words on hemispheric lateralization is also explored. Visual ERPs were
recorded to unilaterally presented positive, negative, and neutral words that
should be categorized according to their emotional connotation. The P2 amplitude
was larger to positive than to negative words whereas P3 amplitude was larger to
positive words compared with neutral ones. The slow positive wave (SPW) was
influenced by words emotionality at anterior and posterior sites differently. The
amplitude of the N1 component was larger in the left hemisphere to
contralaterally presented words. The P2 and P3 components were larger over the
left hemisphere whereas the N3 and N4 components were larger over the right
hemisphere to ipsilateral stimulation. The results support our hypotheses on the
functional role of positive ERP components in the processing of an affective
words connotation: the P2 wave reflects a general evaluation of emotional
significance, the P3 a task-related decision, and the SPW an additional decision
control in the context of the emotional experience of an individual. Neither the
"right hemisphere hypothesis" nor "valence hypothesis" on lateralization of the
processing of emotions were confirmed. Each hemisphere seems to exert its effect
on emotion through specific hemispheric resources that are unequally allocated
along the different stages of task processing and may cause alternation of
hemispheric dominance.
PMID- 10769925
TI - Light activation of phospholipase A2 in the photoreceptor of the crayfish
(Procambarus clarkii).
AB - Retinal lipids of crayfish, kept at 4 degrees C under continuous darkness for 3
weeks, consisted mainly of phosphatidylcholine (PC) and phosphatidylethanolamine
(PE); sphingomyelin (SM), phosphatidylinositol (PI) and phosphatidylserine (PS)
were minor contributors. PI, involved in the phototransduction cascade, never
reached greater concentrations than 7% of the total. High concentrations of
polyunsaturated fatty acids (PUFA) such as 20:4n-6, 20:5n-3 and 22:6n-3 (DHA,
docosahexaenoic acid) were present in PC, PE and PS, but scarce in SM and PI. In
retinae of crayfish kept at 4 degrees C in darkness for 3 weeks and then exposed
to white light (6 h; ca. 4,500 lx), SM and PS remained seemingly unaffected. PC,
however, significantly decreased within 10 min to 65% of the initial value and
50% at 180 min. To study the reduction of PC, lipids of retinae suspended in
physiological solution with/without phospholipase C (PLC) and phospholipase A2
(PLA2) inhibitors such as DMDA (= DEDA), manoalide, ET-18-OCH3, and U-73122 were
measured. Only free fatty acids (FFA) of retinae with inhibitors of PLA2 like
DMDA and manoalide decreased. Retinae irradiated by white light for 3 h displayed
a significant reduction of PC, compared with those that had remained in
continuous darkness. However, the PC of retinae with PLA2-inhibitors was not
decreased by light. Our results provide evidence that not only photoreceptor cell
PLC, but also PLA2 is activated by light.
PMID- 10769927
TI - The role of mounts and intromissions in triggering ejaculation in rats.
AB - Eight male rats copulated with an estrus female with an open vagina (NF) and an
estrus female with the vagina covered by adhesive tape (CF). Experimental
sessions were composed of two phases. During Phase 1 the males copulated with NF
or with CF females until 4 intromissions or 4 mount bouts were displayed
respectively. In Phase 2 the males copulated alternately with NF or CF according
to three schedules: (1) a sequence two mount bouts with a CF female followed by
one intromission, (2) a sequence one intromission followed by two mount bouts
with a CF female, and (3) a sequence one intromission followed by four mount
bouts with a CF female. All of these sequences were repeated until ejaculation.
Ejaculation occurred in 95.8% of cases within one minute after the last
intromission during copulation with the CF female. The results of this study
indicate that: (1) the number of intromissions displayed during Phase 2 does not
depend on the character of the copulatory behaviour displayed during Phase 1, (2)
at least two intromissions are displayed before ejaculation, and (3) the tactile
stimulation of the glans of penis plays a crucial role in the ejaculatory seminal
reflex.
PMID- 10769928
TI - Senescence and learning in honeybee (Apis mellifera) workers.
AB - Foraging by honeybee workers was investigated from the moment of the first
foraging flight until death. To minimise the influence of factors other than
senescence the foragers were trained to collect food from an artificial flower
close to their hive. During each foraging trip the workers repeatedly visited an
artificial flower, collecting one microlitre of 50% sugar solution per visit.
During the first 50 flights the mean time taken to collect one portion of food
decreased significantly and the number of visits to the artificial flower per
flight increased significantly. During flights following the 50th flight, the
mean time taken to collect one portion of food increased significantly and the
number of visits to the artificial flower per flight decreased significantly. The
results confirm earlier observations that the foraging behaviour of honeybee
workers is not only influenced by learning, but also by the effects of
senescence.
PMID- 10769929
TI - NADPH-diaphorase in the cat carotid body.
PMID- 10769930
TI - Detecting oscillations in cortical and subcortical structures.
PMID- 10769931
TI - Oscillatory cortical activities in the gamma band in the human EEG induced by
visual stimuli--representation of the stimulus?
AB - The present work presents three experiments investigating cortical activities in
the gamma band in humans. On the basis of theoretical models and animal
experiments, synchronized oscillatory neuronal activity is discussed as the key
mechanism by which the brain binds information processesed in different cortical
areas to form a percept. Using an identical stimulation design--the same as used
in animal studies--it was shown that induced gamma band responses in the EEG
resemble the same features as those found in the intracortical recordings of
animals. In addition, the present work demonstrates that these cortical
activities are not higher harmonics of the alpha band and that they are sensitive
to the features of the stimulus. These results support the notion that gamma band
activity is not just a by-product of neuronal activity and that alpha- and gamma
band activities most certainly represent different cortical functional states.
PMID- 10769932
TI - In vitro recorded theta-like activity in the limbic cortex: comparison with
spontaneous theta and epileptiform discharges.
AB - The generation of EEG theta rhythm in the mammalian limbic cortex is a prime
example of rhythmic activity that involves central mechanisms of oscillations and
synchrony. This EEG pattern has been extensively studied since 1938, when Jung
and Kornmuller (1938) demonstrated the first theta recordings in the hippocampal
formation of rabbits. In 1986 in collaboration with Drs. B.H. Bland, S.H. Roth
and B.M. MacIver we demonstrated for the first time that bath perfusion of
hippocampal slices with the cholinergic agonist, carbachol, resulted in theta
like oscillations. Since this initial demonstration of in vitro theta-like
activity, we have carried out a number of experiments in an attempt to answer the
basic question: what are the similarities between cholinergic-induced in vitro
theta-like activity and theta rhythm which naturally occurs in the in vivo
preparation. Thus far, our studies have provided strong evidence that theta-like
activity recorded in vitro shares many of the physiological and pharmacological
properties of theta rhythm observed in vivo. The question whether in vitro theta
like oscillations reflect features of epileptiform activity is also addressed in
this review.
PMID- 10769933
TI - EEG analysis with nonlinear deterministic and stochastic methods: a combined
strategy.
AB - We describe nonlinear deterministic versus stochastic methodology, their
applications to EEG research and the neurophysiological background underlying
both approaches. Nonlinear methods are based on the concept of attractors in
phase space. This concept on the one hand incorporates the idea of an autonomous
(stationary) system, on the other hand implicates the investigation of a long
time evolution. It is an unresolved problem in nonlinear EEG research that
nonlinear methods per se give no feedback about the stationarity aspect. Hence,
we introduce a combined strategy utilizing both stochastic and nonlinear
deterministic methods. We propose, in a first step to segment the EEG time series
into piecewise quasi-stationary epochs by means of nonparametric change point
analysis. Subsequently, nonlinear measures can be estimated with higher
confidence for the segmented epochs fulfilling the stationarity condition.
PMID- 10769934
TI - Nonlinearity in human resting, eyes-closed EEG: an in-depth case study.
AB - The question of nonlinearity in the human electroencephalogram (EEG) is
important, since linear methods of EEG analysis are more well-developed and
computationally faster than nonlinear methods. Furthermore, the presence or
absence of nonlinearity has important theoretical implications for understanding
the nature of the brain's oscillatory activity. Using a linear summary measure as
a control, we report a failure to reject the null hypothesis of a (largely)
stationary linear-Gaussian process for normal, resting, eyes-closed EEG from a
single participant. We found significant evidence of nonlinearity at two
occipital sites (O1 and O2) where the 8-12.5 Hz alpha rhythm was prominent.
However, this element of nonlinear structure appeared trivial, as (1) we found no
evidence of time irreversibility at these loci, and (2) best-fitting linear
models accounted on-average for over 94% of the variance in the data with
nonlinear modeling doing no better. Half of the remaining variance could be
accounted for by nonstationarity. While our findings technically apply only to
the one individual tested, his EEG was typical of those seen under the conditions
that we employed.
PMID- 10769935
TI - The role of the thalamic reticular neurons in alpha- and gamma-oscillations in
neocortex: a mechanism for selective perception and stimulus binding.
AB - The long-term objective is to understand how large masses of neurons in the brain
process information during various learning and memory paradigms. Both time- and
space-dependent processes have been identified in animals through computer-based
analytic quantifications of event-related extracellular potentials. New nonlinear
analyses have been introduced that presume that the fine-grain variation in the
signal is determined and patterned in phase-space. Some neurons in the primary
visual cortex manifest gamma-band oscillations. These cells show both a
nonspecific phase-alignment (response synchrony) and a specific tuning
(orientation tuning) when stimuli are presented to their receptive fields. This
dual regulation of the sensory cells is proposed to underlie stimulus binding, a
theoretical mechanism for "object" perception. Nonlinear analytic results from
gamma-activities in a simple model neuropil (olfactory bulb) suggest that
neuroplasticity may arise through self-organization, a process in which a
nonlinear change in the dynamics of the oscillatory field potentials is the
hallmark. This self-organization may follow simple dynamical laws in which global
cooperativity among the neurons is transiently brought about that, over trials,
results in enduring changes in the nonlinear dynamics of some neurons. In
conclusion, the sculpturing of the synaptic throughput in the sensory cortex
(stimulus binding) may be associated with the irregular phases of the gamma
activities and may result from both specific and nonspecific systems operating
together in a nonlinear self-organizing manner.
PMID- 10769936
TI - Optimal number of response categories in rating scales: reliability, validity,
discriminating power, and respondent preferences.
AB - Using a self-administered questionnaire, 149 respondents rated service elements
associated with a recently visited store or restaurant on scales that differed
only in the number of response categories (ranging from 2 to 11) and on a 101
point scale presented in a different format. On several indices of reliability,
validity, and discriminating power, the two-point, three-point, and four-point
scales performed relatively poorly, and indices were significantly higher for
scales with more response categories, up to about 7. Internal consistency did not
differ significantly between scales, but test-retest reliability tended to
decrease for scales with more than 10 response categories. Respondent preferences
were highest for the 10-point scale, closely followed by the seven-point and nine
point scales. Implications for research and practice are discussed.
PMID- 10769937
TI - A system for investigating 3-D form perception.
AB - This paper describes a noninvasive, relatively inexpensive, and simple to use
system developed by the authors for monitoring the visual inspection behavior of
someone free to select any viewing angle of an object by moving about it while at
the same time being able to rotate it. A demonstration experiment verifies the
potential of the system to study 3-D form perception.
PMID- 10769938
TI - Sensorimotor synchronization: the impact of temporally displaced auditory
feedback.
AB - When subjects are asked to tap in synchrony to a regular sequence of stimulus
events (e.g., clicks), performance is not perfect in that, usually, an
anticipation of the tap is observed. The present study examines the influence of
temporally displaced auditory feedback on the size of this anticipatory error.
Whereas earlier studies have shown that this asynchrony exhibits a linear
increase in size as a function of an increasing delay in such additional auditory
feedback, this study compared the impact of shifting feedback forward in time
(i.e., feedback presented before the tap) with that of delayed auditory feedback.
Results showed that the impact of feedback displacement on the amount of
asynchrony differed for positive and negative displacements. Delayed feedback led
to an increase in asynchrony, whereas negative displacements had (almost) no
effect. This finding is related to a model assuming that the various feedback
components arising from the tap (tactile, kinesthetic, auditory) are integrated
to form one central representation, and that the timing of this central
representation arises from a linear combination of the components involved.
PMID- 10769939
TI - Implicit and explicit learning of event sequences: evidence for distinct coding
of perceptual and motor representations.
AB - Event-related brain potentials (ERPs) of 21 subjects were recorded in a choice
reaction time task with a repeating eight-element long stimulus sequence. The
regular event sequence was sometimes interrupted by 'perceptual' or by 'motor
deviants' which both replaced an expected stimulus but either preserved or
violated the sequence of motor responses. Response times confirmed that all
subjects had acquired some knowledge of the sequential dependencies. By means of
a post-experimental free recall and recognition test, subjects were classified as
having either explicit or implicit knowledge of the event sequence. The ERPs
showed different effects for different types of stimuli and the two groups. In
the group of explicit learners, a larger N200 component was evoked by both types
of deviants and a larger P300 by motor deviants only. In the group of implicit
learners these 'perceptual components' remained unaffected. In contrast, in both
groups of subjects the lateralized readiness potential (LRP) which accompanied
motor deviants revealed a partial activation of the to be expected but incorrect
response, i.e. motor learning. These results suggest that explicit learners
acquire knowledge about both, stimulus and response dependencies while implicit
learners acquire knowledge about response dependencies only.
PMID- 10769940
TI - The effect of cognitive load on saccadic eye movements.
AB - The present study tested the hypothesis that, unlike prosaccades, antisaccades
require controlled processing, due to the prepotent response that needs to be
inhibited. The effect of the Random time Interval Generation (RIG) task
(Vandierendonck, A., De Vooght, G., & Van der Goten, K. (1998). European Journal
of Cognitive Psychology, 10, 413-444) on these saccade latencies and errors was
studied. This task has the advantage that it loads executive processes, with only
minimal interference with verbal or visuo-spatial components. A first experiment
compared saccade performance within the prosaccade and the antisaccade task,
executed alone and in combination with the RIG task and fixed tapping (added to
exclude possible motor component interference explanations). A second experiment
investigated the influence of task characteristics on the effects found. Although
it was shown that antisaccades are more prone to interference of an executive
interference task, it seems that prosaccades are also vulnerable. Interference on
prosaccades could originate from a controlled execution of these saccades. A
third experiment confirmed that endogenously generated prosaccades are
susceptible to dual-task interference and showed that controlled saccade
execution, without the need to inhibit a prepotent response, is sufficient to
produce interference.
PMID- 10769941
TI - The weighing of pathological and non-pathological information in clinical
judgment.
AB - On the basis of the classic data of Meehl (1959), I examine how clinical
psychologists use the MMPI scales to judge the degree of pathology of psychiatric
patients by comparing linear models of the judgment to a linear model of the
criterion (the actual diagnosis of the patients). This comparison reveals that
excessively heavy weight is assigned to pathological information in comparison to
non-pathological information. Additional analyses reveal that this biased
weighing also influences the actual diagnosis and that it is a major determinant
of the accuracy of clinical judgment. It is suggested that these effects arise
from a confirmation bias associated with the hypothesis that a patient has
severe, rather than mild, pathology.
PMID- 10769942
TI - Target velocity effects on manual interception kinematics.
AB - Participants generated manual interception movements toward a target cursor that
moved across a computer screen. The target reached its peak velocity either
during the first third, at the midpoint, or during the last third of the
movement. In Experiment 1 the view of the target was available for either the
first 316, 633, 950, or 1267 ms, after which it disappeared. Results showed that
for all viewing conditions, the timing of the interception velocity was related
to the temporal properties of the target's trajectory. In Experiment 2, when the
portion of the target trajectory that was viewed was reversed (such that
participants did not see the first 316, 633, 950, or 1267 ms of the trajectory,
but instead saw only the later portions of the trajectory), there was no clear
relationship between the target trajectory and the timing of the aiming
trajectory. These results suggest that participants use visual information early
in the target's trajectory to form a representation of the target motion that is
used to facilitate manual interception.
PMID- 10769944
TI - WHO position paper on hepatitis A vaccines.
PMID- 10769943
TI - When complexity helps: an electrophysiological analysis of multiple feature
benefits in object perception.
AB - Fournier, L. R., Eriksen, C. W. and Bowd, C. (1998. Multiple feature
discrimination faster than single feature discrimination within the same object?
Perception & Psychophysics 60, 1384-1405) found that judging the presence of
multiple features within an object is faster than judging the presence of the
least discriminable of these features alone (multiple feature benefits, MFBs).
When an 'absent' response is required, responses are slower when some of the
relevant (target) features are present (multiple feature costs, MFCs). The
present study utilized psychophysiological measures (of the event-related brain
potential and the electromyogram) to determine the contributions of response
priming and stimulus evaluation processes (P300 latency) to these effects. P300
latency and reaction time (RT) both showed evidence of MFBs and MFCs. These
findings suggest that MFBs and MFCs can be attributed to processing that occurs
prior to response selection. No dissociations between P300 latency and RT
measures were found for 'present' responses across the single and multiple
feature judgements. However, for 'absent' responses, partial dissociations were
found between these measures, and partial errors and longer response execution
intervals were observed more often when an object contained some target features.
These findings suggest that response priming contributes to MFCs, but may not
contribute to MFBs.
PMID- 10769945
TI - Meningococcal infection in pilgrims returning from the Haj.
PMID- 10769946
TI - Two hepatitis C lookback exercises--national and in London.
PMID- 10769947
TI - [Neuronal organization of the olfactory bulb of the olfactory center].
PMID- 10769948
TI - Relative effectiveness of electrically- vs mechanically-elicited EMGs in
detecting pedicle wall perforation and surgically-induced nerve root damage.
AB - Electrical stimulation of a pedicle hole and screw with recording EMGs from the
lower extremities has been used as an indicator in detecting perforations of the
pedicle. Mechanically-elicited EMGs are reported to be sensitive to mechanical
irritation of nerve roots. This study analyzed the sensitivity of the data
elicited by two EMG monitoring methods in the presence of a neurologic deficit
caused by a malpositioned screw to determine the relative effectiveness of
electrically- vs mechanically-elicited EMGs in detecting pedicle wall
perforations and nerve root damage in patients undergoing spinal surgery
utilizing transpedicular instrumentation. One hundred and four surgeries were
monitored using the two EMG methods. Six hundred and fifty-four pedicle holes
were prepared and 650 placed pedicle screws were electrically tested.
Mechanically-elicited EMGs were monitored from a total of 618 muscles.
Electrically-elicited EMGs showed a 62% true-positive rate and a 0.2% false
negative rate in detecting pedicle wall perforations. None of the patients who
initially demonstrated abnormal electrically-elicited EMGs demonstrated any post
operative neurologic problems due to an incorrect screw placement. Only one
patient who had abnormal mechanically-elicited EMGs during the procedures related
to instrumentation developed new L4 radiculopathy immediately post-operatively
which was consistent with the level of mechanically-elicited EMGs. Mechanically
elicited EMGs showed a 100% true-positive rate for nerve root irritation and a
3.5% false-negative rate in detecting pedicle wall perforations by malpositioned
screw. In conclusion, although mechanically-elicited EMGs were an insensitive
technique in detecting a perforation of the pedicle, mechanically-elicited EMGs
were more beneficial than electrically-elicited EMGs in detecting the risk of
nerve root irritation.
PMID- 10769949
TI - A case of multiple myeloma which developed into multiple extramedullary
involvement in the terminal stage.
AB - A 69-year-old man with a diagnosis of multiple IgG class myeloma received
combination chemotherapy. He achieved a partial response with an undetected M
spike. However, he demonstrated new lytic bone lesions and multiple
extramedullary involvement 10 months after the initial presentation. Polymerase
chain reaction (PCR) analysis using a framework 3 (Fr3) V-region primer clarified
a discrete band in the extramedullary tumor, while it yielded 4 bands including
the same size as the extramedullary tumor produced in the bone marrow sample
obtained before the chemotherapy. These findings suggest that a resistant and non
secretory clone was selected by the combination chemotherapy.
PMID- 10769950
TI - [The All-Russian Research Institute of Railway Hygiene].
PMID- 10769951
TI - [Railway hygiene in the 21st century].
PMID- 10769952
TI - [Present-day problems in organization of medical aid in railway wrecks].
AB - The paper deals with the results and efficiency of organizing emergency medical
aid to victims in railway accidents, crashes, and other emergencies in the past
years. It presents the data of researches, which characterizes the specific
features of railway injury, which should be taken into account in planning and
organizing a medical aid to suffered passengers and railway workers. The authors
have developed and proposed guidelines for improving health care to emergency
victims by railway therapeutical and prophylactic and sanitary facilities.
PMID- 10769953
TI - [Land and space hygienic monitoring of environment quality].
AB - Monitoring of changes occurring in the environment and human health is a basic
way of solving the problem of the optimal society-biosphere interaction. The
initiated ecological and hygienic studies using the space facilities and
techniques of remote probing of the Earth's surface create prerequisites for the
land and space monitoring of biospheric solution, for the assessment of the
anthropoecological situation and for the prediction environment-related diseases
in the population.
PMID- 10769954
TI - [Hygienic and antiepidemic provision of the utilization of solid waste from long
distance trains].
AB - Based on the hygienic analysis of the currently available methods for
decontamination and processing of solid waste from long-distance trains, the
authors have developed a system for its collection and utilization. The hygienic
aspects of the reconstruction and construction of railway objects are presented
by taking into account the proposed system for refuse collection and processing.
PMID- 10769955
TI - [Current tasks of hygienic provisions of metro design and construction].
AB - A new part of the existing document on sanitary norms and metro design is
proposed to present as a separate section "Hygienic and Ecological Requirements".
Its structure should be determined by current views on the regulated
environmental factors (physical, chemical, biological, ergonomic). Requirements
should be systematized by hygienic criteria of the duration and rate of the human
influence of these factors by taking into account of the functional purpose of
premises and erections.
PMID- 10769956
TI - [Hygienic evaluation of the effectiveness of the use of impulse ultraviolet
radiation sources in railway transport].
AB - The paper covers the use of impulse ultraviolet radiation sources for
disinfecting the air and inside surfaces of the premises of railway station
buildings and the water of long-distance passenger trains.
PMID- 10769957
TI - [Hygienic evaluation of polymer materials for new carriages].
AB - The paper presents the data of the hygienic studies made at the All-Russian
Research Institute of Railway Hygiene to examine the materials for carriage
building. Some materials (such as designing, finishing, and heat insulating ones)
are recommended for their industrial use.
PMID- 10769958
TI - [Problems in establishing special pensions for locomotive team workers].
AB - The paper deals with a physiological rationale for fixing pensions for locomotive
drivers within the ranges of age and length of service. The study is based on the
fact that the nature and conditions of their work accelerate their ageing and
decrease their working capacity.
PMID- 10769959
TI - [Practical introduction of "Sanitary Requirements for the design and operational
use of diagnostic cars and trolleys"].
AB - The practical introduction of "Sanitary Requirements for the Design and
Operational Use of Diagnostic Cars and Trolleys" indicates that the stock of
diagnostic cars does not meet the present requirements. To put this document into
practice has determined specific measures for meeting sanitary specifications for
diagnostic cars and trolleys.
PMID- 10769960
TI - [Clinical testing of hygienic criteria for assessing working conditions].
AB - Occupational morbidity in railway transport is discussed. The rates of
occupational morbidity are compared with that due to temporary working
incapacity. There were no direct correlations between the incidence of major
nosological entities of occupational diseases, the magnitude and rate of
influence of industrial factors, which provides evidence for their further
testing and correction.
PMID- 10769961
TI - [Emotional disorders in railway workers and their rehabilitation].
AB - The paper discusses whether industrial factors can influence the emotional sphere
of railway workers. It outlines the basic trends of recreative measures and the
principle of their use in emotional disorders.
PMID- 10769962
TI - [Organization of a medical occupational rehabilitation system for locomotive team
workers].
AB - The paper deals with the setting up of a system for early diagnosis of
premorbidity and for medical professional rehabilitation of locomotive teams. Non
drug preventive measures are shown to have a high rehabilitative effect.
PMID- 10769963
TI - [Health status of railway workers using magnetic powder flaw detectors].
AB - The rates of morbidity with temporary working incapacity (TWI) of magnetic-powder
defectoscopic operators are discussed. The incidence of diseases with TWI and the
days of disability in the study group of workers are greater than the average
industrial rates. A comprehensive physical examination detected asthenic
vegetative syndrome. This shows it necessary to improve methodological approaches
to medical examinations of workers exposed to electromagnetic waves.
PMID- 10769964
TI - [Methods of nondrug prevention of diminished work capacity and impaired health in
railway workers].
AB - The paper deals with the physiological assessment of some biologically active
food additives (BAFA). The authors formulate principles in selecting BAFA to
prevent fatigability and premorbidity associated with safe railway traffic.
PMID- 10769965
TI - [Experience in hygienic and ergonomic design of an inter-regional high-speed
electric train "Sokol"].
AB - The fundamental hygienic principles in the design of a high-speed Sokol electric
train and its ergonometric approach cause one to anticipate a new rolling stock
with high convenience for passengers, which will be an analogue of the world's
best ones to appear.
PMID- 10769966
TI - [New approaches to hygienic assessment of machines used in the construction of
railways].
AB - The stock of railway machines has been greatly replaced by that new-generation
ones that have a high capacity and can themselves move at high speeds. This
changes the working conditions of the staff and the conditions of their driving.
The new conditions promotes the development of new standard requirements and the
methods of tests and assessing the indices of unfavorable working conditions.
PMID- 10769967
TI - [Efficiency of the use of locomotive cab heating systems].
AB - The paper describes the efficiency of the heating, thermal insulating, and air
tightness systems in the cabs of a railway rolling stock.
PMID- 10769968
TI - [Hygienic assessment of new technology of tank cars].
AB - A washing and steaming station built by Finnish specialists in 1997 operates at
the Ryazan petroleum processing plant. The process is completely automatic and
hermetic, excludes the workers' contact with harmful industrial factors. There is
a whole set of special clothes and individual protective means. The plant's gas
fighting and rescue service monitors the air environment every 3 months. There is
a closed rinsing water regeneration system at the plant.
PMID- 10769969
TI - [A comparative study of sun-protective glasses for locomotive team workers].
AB - Solar flashes of 1500 to 9000 kd/m2 have been ascertained to have an adverse
impact on the functional status of a visual analyzer. Comparing Russian and
foreign sun-proof filters has indicated that a HC-9 neutral light-proof filter
and a NIIOOIK film have the optimum light-protective properties, which may be
recommended for use in the sun-proof glasses for locomotive workers.
PMID- 10769970
TI - [State of occupationally significant visual function in locomotive team personnel
working in radioactive pollution areas].
AB - Long exposure to small radio activity doses have no impact on the acuity of
photopic and mesopic vision, on the resistance of eyes to glare, and on the
rapidity of color differentiation, which remain to be at the high level that
meets medical requirements for the professional abilities of locomotive workers.
PMID- 10769971
TI - [Development and practical introduction of sanitary rules for improving work
conditions of railroad workers].
AB - To develop and introduce sanitary regulations will promote increased current and
preventive sanitary surveillance in railway transport, which will in turn improve
the working conditions, promotes health in railway personnel, and increase
railway traffic safety in Russia.
PMID- 10769972
TI - [Clinical and hygienic aspects of asbestos-induced lung diseases].
AB - The outcomes of 31 operations made in patients with asbestos-induced lung cancer
and mesothelioma are considered; the relationships of age, lengths of services,
and occupation to the occurrence of diseases are analyzed. A phenomenological
concept of development of asbestos-induced cancer diseases is proposed. The
functional and morphological features of the course of the disease have been
established. Recommendations on the prevention and treatment of abnormalities are
given.
PMID- 10769973
TI - [Progress and prospects in the development of catastrophe medicine in the
prevention and cleaning up of accidents caused by hazardous cargo].
AB - Progress in emergency medicine in the prevention and liquidation of hazardous
cargo-induced accidents is analyzed. The results of development of theoretical
aspects, search for adequate individual protective means and methods for chemical
decontamination of hazardous cargo residues are summarized.
PMID- 10769974
TI - [Planning and implementation of protective measures in emergencies during railway
transportation of radioactive cargo].
AB - Protective measures in emergencies during railway transportation of radioactive
cargoes must be planned in advance, by obligatorily taking into account many
factors that influence the scope, nature, specific features and consequences of
radiation transport accidents. Of great importance are radiation monitoring,
protective regimens, and requirements for decontamination of various objects in
liquidating the consequences of a radiation transport accident.
PMID- 10769976
TI - [New organizational and methodological approaches to prophylactic check-ups of
railway workers].
PMID- 10769975
TI - [Principles of public health pricing].
AB - The development of various organizational and legal enterprises, including those
in medicine and public health makes it necessary for medical and sanitary workers
to know basic pricing. Their knowledge will assist in making correct managerial
decisions.
PMID- 10769978
TI - [Improved method for hygienic area ranging].
PMID- 10769979
TI - The status of hypnosis as an empirically validated clinical intervention: a
preamble to the special issue.
AB - In his introductory remarks to this Journal's special issue on the status of
hypnosis as an empirically supported clinical intervention, the editor briefly
describes the dawn of clinical hypnosis research, the logic of the natural
science model, the importance of an inspired but tough-minded clinical science,
and the auspicious confluence of practice and research purpose in this
enterprise. The progenitor of this effort was indeed the Report of the Royal
Commission coauthored by Benjamin Franklin and Antoine Lavoisier, among others,
more than 215 years ago--a report noted as one of the most important documents in
the history of human reason. The ethos and logic of this special issue is
grounded on the legacy of that document. Eschewing the conflicting mental health
agendas of managed-care, government, patient rights, and professional guild
interests, this special issue seeks to present a frank, evenhanded, informed, and
dispassionate assessment of what science knows and does not know about clinical
hypnosis.
PMID- 10769977
TI - [Possibilities of the use of space survey data in hygienic studies (review of the
literature)].
PMID- 10769980
TI - Clinical hypnosis with children: first steps toward empirical support.
AB - A review of controlled studies on the efficacy of clinical hypnosis with children
reveals promising findings, particularly for reduction of acute pain,
chemotherapy-related distress, and enuresis. However, no child hypnosis
interventions currently qualify as "efficacious" according to criteria for
empirically supported therapies (EST). A major limitation of the existing
literature relative to EST guidelines is the lack of treatment specification via
a manual or its equivalent.
PMID- 10769981
TI - A meta-analysis of hypnotically induced analgesia: how effective is hypnosis?
AB - Over the past two decades, hypnoanalgesia has been widely studied; however, no
systematic attempts have been made to determine the average size of
hypnoanalgesic effects or establish the generalizability of these effects from
the laboratory to the clinic. This study examines the effectiveness of hypnosis
in pain management, compares studies that evaluated hypnotic pain reduction in
healthy volunteers vs. those using patient samples, compares hypnoanalgesic
effects and participants' hypnotic suggestibility, and determines the
effectiveness of hypnotic suggestion for pain relief relative to other
nonhypnotic psychological interventions. Meta-analysis of 18 studies revealed a
moderate to large hypnoanalgesic effect, supporting the efficacy of hypnotic
techniques for pain management. The results also indicated that hypnotic
suggestion was equally effective in reducing both clinical and experimental pain.
The overall results suggest broader application of hypnoanalgesic techniques with
pain patients.
PMID- 10769982
TI - Research on hypnosis as an adjunct to cognitive-behavioral psychotherapy.
AB - There is a growing body of research evaluating the use of hypnosis with cognitive
behavioral techniques in the treatment of psychological disorders. The central
question for research is whether the addition of hypnosis enhances the efficacy
of cognitive-behavioral treatments. Overall, studies demonstrate a substantial
benefit from the addition of hypnosis; however, the number of published studies
is relatively small, and many of them have methodological limitations. For
cognitive-behavioral hypnotherapies to be recognized as empirically supported
treatments, a number of well-designed, randomized clinical trials are necessary.
Currently, the efficacy of hypnosis as an adjunctive treatment remains
unresolved.
PMID- 10769983
TI - Empirical findings on the use of hypnosis in medicine: a critical review.
AB - Recent changes in health care have been characterized by an increased demand for
empirically supported treatments in medicine. Presently, there is moderate
support for the integration of hypnotic techniques in the treatment of a number
of medical problems. This critical review of the research literature focuses on
the empirical research on the effectiveness of hypnotic treatments as adjuncts to
medical care for anxiety related to medical and dental procedures, asthma,
dermatological diseases, gastrointestinal diseases, hemorrhagic disorders, nausea
and emesis in oncology, and obstetrics/gynecology. Wider acceptance of hypnosis
as an intervention to assist with medical care will require further research.
PMID- 10769984
TI - Hypnosis and suggestion-based approaches to smoking cessation: an examination of
the evidence.
AB - This article reviews 59 studies of hypnosis and smoking cessation as to whether
the research empirically supports hypnosis as a treatment. Whereas hypnotic
procedures generally yield higher rates of abstinence relative to wait-list and
no-treatment conditions, hypnotic interventions are generally comparable to a
variety of nonhypnotic treatments. The evidence for whether hypnosis yields
outcomes superior to placebos is mixed. In short, hypnosis cannot be considered a
specific and efficacious treatment for smoking cessation. Furthermore, in many
cases, it is impossible to rule out cognitive/behavioral and educational
interventions as the source of positive treatment gains associated with hypnotic
treatments. Hypnosis cannot, as yet, be regarded as a well-established treatment
for smoking cessation. Nevertheless, it seems justified to classify hypnosis as a
"possibly efficacious" treatment for smoking cessation.
PMID- 10769985
TI - Hypnosis in the treatment of trauma: a promising, but not fully supported,
efficacious intervention.
AB - Hypnotic techniques for the treatment of posttraumatic conditions were often used
by the clinical pioneers of the end of the 19th century and by military
therapists treating soldiers during the 20th century's conflagrations. More
recently, hypnosis has also been used with survivors of sexual assault,
accidents, and other traumas, and with various groups, including children and
ethnic minorities. Nonetheless, there have been almost no systematic studies on
the efficacy of hypnosis for posttraumatic disorders. This state of affairs is
especially disappointing considering that: hypnosis can be easily integrated into
therapies that are commonly used with traumatized clients; a number of PTSD
individuals have shown high hypnotizability in various studies; hypnosis can be
used for symptoms associated with PTSD; and hypnosis may help modulate and
integrate memories of trauma. Hypnotic techniques may indeed be efficacious for
posttraumatic conditions, but systematic group or single-case studies need to be
conducted before reaching that conclusion.
PMID- 10769986
TI - Hypnosis as an empirically supported clinical intervention: the state of the
evidence and a look to the future.
AB - Drawing on the literature reviews of this special issue of the International
Journal of Clinical and Experimental Hypnosis (2000), this article summarizes the
evidence for the effectiveness of hypnosis as an empirically supported clinical
intervention. As a whole, the clinical research to date generally substantiates
the claim that hypnotic procedures can ameliorate some psychological and medical
conditions, as judged against the Chambless and Hollon methodological guidelines.
In many cases, these clinical procedures can also be quite cost-effective. It is
probable that with some key empirical refinement a number of other hypnosis
treatment protocols will have sufficient empirical documentation to be considered
"well-established." However, it is noted that the Chambless and Hollon guidelines
are not particularly well-suited for assessing hypnosis' impact when used
adjunctly with other interventions. The article concludes with recommendations
regarding the efficacy questions that need to be more fully addressed empirically
and offers methodological guidelines for researchers and practitioners.
PMID- 10769987
TI - Results from surgical treatment for thymoma. 43 years of experience.
AB - OBJECTIVE: The biological behavior of thymoma and its prognosis after surgical
intervention remain still controversial. The efficacy of surgical treatment for
thymoma was investigated by examining long-term follow-up data. SUBJECTS AND
METHODS: Follow-up data for patients undergoing surgical resection of
histopathologically-confirmed thymoma between 1954 and 1997 were obtained and
were retrospectively analyzed. Clinical staging was based on Masaoka's staging
system, and histological classification on Rosai's proposed criteria. RESULTS:
Data for 140 patients were collected. Sixty-four patients had stage I, 32 had
stage II, 28 had stage III, and 16 had stage IV thymoma. There were significant
differences in survival between patients with stage I and stage III, stage I and
stage IV and stage II and stage III disease, but not between those with stage I
thymoma and stage II thymoma. No significant difference in survival was observed
between the 56 patients with myasthenia gravis (MG) and the 84 without MG. The 38
patients classified as having a predominantly-epithelial thymoma had a poorer
prognosis than the 41 with a predominantly-lymphocytic thymoma. Until 1975, there
were four patients with stage I thymomas who later showed recurrence, compared
with 21 among those with stage II, III and IV diseases. Since 1976, extended
thymectomy with thymomectomy under median sternotomy has been adopted as the
standard operation for a thymoma, and there has been no recurrence in stage I
patients. CONCLUSIONS: Patients with stage III or IV invasive thymoma have a
poorer prognosis and a higher recurrence rate than those with encapsulated
thymoma, and patients with a predominantly-epithelial thymoma have a poorer
prognosis than those with a predominantly-lymphocytic thymoma. Extended
thymectomy with thymomectomy under median sternotomy can be considered as
adequate treatment for a stage I thymoma. Myasthenia gravis does not appear to
affect the prognosis of patients with a thymoma.
PMID- 10769988
TI - Coronary artery bypass grafting in patient with malignant neoplasm. Efficacy of
coronary artery bypass grafting on beating heart.
AB - OBJECTIVE: Coronary artery bypass grafting (CABG) prior to noncardiac major
surgery has effectively decreases short- and long-term mortality related to
coronary ischemia. Coronary artery bypass on the beating heart is conducted to
avoid the risk of cardiopulmonary bypass and it has contribute to shorten
recovery time. METHODS: Subjects were 19 patients with malignant neoplasm for
whom a retrospective chart review was made between Jan. 1, 1992 and July 31,
1998. In the early phase of this study, between Jan. 1, 1992, and Dec. 31, 1997,
CABG was performed using cardiopulmonary bypass, and late phase, between Jan. 1,
1998, and July 1, 1998, CABG was done on the beating heart without
cardiopulmonary bypass. RESULTS: Conventional CABG was performed in 12 patients
with neoplasms (10 male and 2 female, age 64.7 +/- 6.1 years), and CABG on the
beating heart was performed in 7 patients (6 male and 1 female, age 68.0 +/- 7.5
years). Fewer number of bypass grafts were made in the beating-heart CABG group
(1.3 +/- 0.5 in beating-heart CABG versus 3.9 +/- 1.1 in conventional CABG). No
cardiac events occurred in either group during the surgery for malignant tumors.
The operative interval between CABG and cancer surgery was significantly shorter
in the beating-heart CABG group (21.8 +/- 17.9 days in beating-heart CABG versus
53.5 +/- 42.9 days in conventional CABG, p < 0.05). CONCLUSION: Patients with
severe coronary artery disease and malignant neoplasms should undergo coronary
artery revascularization before the neoplasm is treated. CABG on the beating
heart was safe and effective procedure in those with malignant neoplasms.
PMID- 10769989
TI - Safety and efficacy of blood donation prior to elective cardiac surgery in anemic
patients.
AB - OBJECTIVE: To determine the safety and effectiveness of blood donation in anemic
patients, we harvested blood from cardiac patients with baseline hemoglobin
levels below 11.0 g/dl. METHODS: Subjects were 118 patients who underwent
elective cardiac surgery between January 1994 and October 1997. We assigned
patients to 1 of 2 groups based on their entry hemoglobin level: an anemic group
(hemoglobin < 11.0 g/dl, n = 20) and a nonanemic group (hemoglobin > or = 11.0
g/dl, n = 98). All patients received subcutaneous administration of recombinant
human erythropoietin, and autologous blood was collected once a week for at least
3 weeks before the scheduled surgery date if the hemoglobin level exceeded 10.5
g/dl. RESULTS: No statistically significant differences were seen between the 2
groups in patient profiles or surgical data. The estimated hemoglobin increase
did not differ significantly between groups at any time point. The total
collected blood volume per patient was greater in the nonanemic group than in the
anemic group (1098 +/- 224 ml vs. 712 +/- 334 ml), but the difference in volume
was not statistically significant. The percentage of patients who received
allogeneic blood did not differ significantly between groups. No side effects
were associated with hemoglobin level prior to donation because the incidence of
side effects was similar across hemoglobin levels. CONCLUSIONS: This study
suggests that autologous blood donation reduces the need for allogeneic blood in
patients with baseline hemoglobin levels below 11.0 g/dl.
PMID- 10769990
TI - Nafamostat mesilate modulates the release of platelet-activating factor during
left ventricular assistance with hemofiltration in canine heart failure.
AB - OBJECTIVE: The enhanced generation of various chemical mediators is regarded as
one of the mechanisms by which severe heart failure progresses to multiple organ
failure. Platelet-activating factor is a phospholipid mediator which plays an
important role in inflammatory reactions and circulatory shock. We studied the
changes in platelet-activating factor levels in a canine heart failure model
treated with a left ventricular assist device and hemofiltration, and assessed
the effect of a protease inhibitor, nafamostat mesilate. METHODS: Twenty dogs
underwent multiple coronary ligations, and at 2 hours after the ligations they
were maintained on left ventricular assist device support with continuous
hemofiltration. The animals were divided into two groups: a nafamostat group (n =
10) that received nafamostat mesilate (2 mg/kg/hr), and a control group (n = 10)
that received vehicle only. RESULTS: The blood platelet-activating factor level,
before coronary ligations, in the control and nafamostat groups was 2.3 +/- 0.4
and 2.0 +/- 0.7 ng/ml, respectively, and the coronary ligations had little effect
on the platelet-activating factor. However, after the initiation of left
ventricular assist device, the platelet-activating factor in the control group
(5.6 +/- 2.2) was significantly higher (p < 0.05) than that in the nafamostat
group (1.1 +/- 0.3). Nafamostat administration was also effective in controlling
the increase in the blood lactate level. Hemofiltration did not change the
platelet-activating factor. CONCLUSIONS: We concluded that platelet-activating
factor may play a critical role in the development of severe heart failure with
left ventricular assistance, and nafamostat administration is likely to be
beneficial in such a critical condition by suppressing the platelet-activating
factor level.
PMID- 10769991
TI - Ulnar artery graft for myocardial revascularization.
AB - We present a 60-year-old man who underwent coronary artery bypass grafting using
an ulnar artery as one of the grafts intended to release angina pectoris.
Previously, his right leg had been amputated following a traffic accident. The
blood supply of his left leg was reduced due to atherosclerotic stenotic change
(left ankle pressure index 0.6). He had been under treatment for severe diabetes
mellitus for 4 years. Coronary angiography revealed severe stenosis in the triple
coronary artery system. Immediate myocardial revascularization was considered
necessary. We considered that saphenous vein grafts and bilateral internal
thoracic artery grafts were unsuitable for this patient. Moreover, Allen's test
was positive in the bilateral forearms. Coronary artery bypass surgery consisted
of left internal thoracic artery grafting to the left anterior descending artery,
right gastroepiploic artery grafting to the right coronary artery, and left ulnar
artery grafting to the diagonal branch. No myocardial or hand complications were
observed after surgery. Following a review of the Japanese literature, we
conclude that our case is the first report of an ulnar artery graft for coronary
artery bypass grafting in Japan.
PMID- 10769992
TI - Oblique plication for repair of the atrialized ventricle and tricuspid
incompetence of Ebstein's anomaly.
AB - An 8-year-old girl who weighed 42 kg presented Ebstein's anomaly with severe
tricuspid incompetence, and mild systemic cyanosis during exercise. A new
reconstructive procedure for this complex anomaly was used. Oblique transference
of the displaced posterior leaflet was performed, which resulted in plication of
the atrialized ventricle and reduction in the tricuspid annular diameter. This
procedure requires neither detachment nor closure of the tricuspid valve.
PMID- 10769993
TI - Video-assisted mediastinoscopic resection of a thymic cyst by sternum lifting.
AB - We performed mediastinoscopic surgery on two patients with a thymic cyst using a
new instrument by sternum-lifting with tape. The merits of this technique are
that a resection of the thymus and cyst can be achieved without a midline
sternotomy, and under bilateral ventilation, and in cases with pleural adhesion.
This technique can be applicable to most benign thymic lesions including
thymectomy for myasthenia gravis and to selected cases with a malignant thymic
tumor.
PMID- 10769994
TI - Pseudoaneurysm of a septal perforator in beating heart coronary bypass grafting.
AB - A 46-year-old man with unstable angina underwent beating heart coronary bypass
grafting for a left anterior descending coronary artery. Postoperative
angiography showed intramuscular extravasation (6 x 8 mm) distal to the
anastomosis, which was most likely the result of a needle injury caused by a
snare during the operation. Follow-up angiography 2 weeks later revealed no
extravasation.
PMID- 10769995
TI - Acute aortic thrombosis after intra-aortic balloon pumping.
AB - Acute aortic occlusion is a rare but devastating complication of intra-aortic
balloon pumping. Prompt diagnosis of aortic occlusion and immediate therapeutic
decision making are keys for saving patients in such cases. We describe a 72-year
old man who underwent emergency surgical removal of a thrombus and aortoiliac
bifurcated grafting for acute aortic occlusion after withdrawal of the intra
aortic balloon pumping catheter. The presence of a small unrecognized abdominal
aortic aneurysm was considered to be the cause of thrombosis in this patient.
Ultrasonographic screening for an abdominal aortic aneurysm is recommended for
patients who require intra-aortic balloon pumping support.
PMID- 10769997
TI - Mitral valve replacement in a patient with idiopathic thrombocytopenic purpura.
AB - Reports of a cardiac operation in a patient with idiopathic thrombocytopenic
purpura are scarce. Here we present a case of successful mitral valve replacement
in a patient with idiopathic thrombocytopenic purpura. Preoperative treatment
with high-dosage gamma-globulin successfully increased the platelet count from
50,000/microliter to 80,000/microliter. Twenty units of platelet-rich plasma were
administered during and after the operation. No other blood products were used.
The postoperative convalescence was uneventful. Perioperative management for
patients with idiopathic thrombocytopenic purpura undergoing open-heart surgery
is discussed.
PMID- 10769996
TI - Surgical excision of malignant pheochromocytoma in the left atrium.
AB - We present a rare case of malignant pheochromocytoma in the left atrium and its
surgical treatment. The patient was a 39-year-old male who presented a low-grade
fever with perspiration. A large tumor was first detected in the left atrium by
chest CT, and was confirmed by ultrasonic echo cardiogram and chest MRI. A left
adrenal tumor was indicated also by abdominal echography. To prevent the risk of
its embolization, surgical excision was performed on a subemergency basis. The
patient developed near Shock State on the operative day, presumably due to
catecholamine depletion. The preoperative urinary levels of norepinephrine and
dopamine were abnormally high. Bilateral adrenal tumors also, confirmed
postoperatively by abdominal MRI, were developing rapidly. The pathological
examination revealed that the tumor was a pheochromocytoma.
PMID- 10769998
TI - Papillary fibroelastoma on the mitral valve.
AB - A 78-year-old woman was admitted with transient unknown fever and old cerebral
infarction. An echocardiogram demonstrated mild mitral valve regurgitation and
high echogenic mass on the mitral posterior leaflet. Surgery was performed with
the diagnosis of a healed infective endocarditis. A sea anemone-like appearance
tumor, 8 mm in diameter, was located on the mitral posterior leaflet.
Annuloplasty was performed following removal of the tumor. A pathological
examination confirmed the lesion was a papillary fibroelastoma. No evidence of
infective endocarditis was seen. The cause of the fever remained unknown. The
tumor was very fragile. Surgical removal was mandatory for preventing embolism
despite the advanced age.
PMID- 10769999
TI - Modified trap-door thoracotomy for mediastinal metastasis of thyroid carcinoma
invading the right brachiocephalic vein.
AB - The patient was a 65-year-old female with metastasis of thyroid papillary
carcinoma at the right upper mediastinum. The tumor, which invaded almost the
entire length of the right brachiocephalic vein, was resected via a modified trap
door thoracotomy. The modification was the additional resection of the first rib
from inside the thorax, which provided a sufficient exposure from the distal side
of the brachiocephalic and subclavian vein. Because the subclavian and internal
jugular veins could be clamped under this thoracotomy, the entire right
brachiocephalic vein could be reconstructed by graft without excessive
difficulty. Modified trap-door thoracotomy is a useful approach in the resection
of malignancies which invade the brachiocephalic and subclavian vein.
PMID- 10770000
TI - Ductal aneurysm of adult patients.
AB - A ductal aneurysm is very rarely diagnosed in adults. We experienced 2 cases of
adult ductal aneurysm. Both cases developed hoarseness and computed tomographic
scanning demonstrated a typical 'triple star sign' at the aortopulmonary window
level. They underwent surgical repair with successful results. During the same
period, we experienced 38 operations for true thoracic aneurysm. The ductus
origin was found in 5.2% of these patients. The ductal aneurysm may no longer be
considered a 'rare' vascular disease with more careful diagnostic procedure.
PMID- 10770001
TI - Penetrating knife injury to the heart.
AB - A 39-year-old man attempted to kill himself using a small knife to penetrate the
left anterior chest wall because of trouble at work and with his girlfriend. On
arrival at the emergency room, his consciousness was not clear and vital signs
were unstable. The knife remained vertically located in the left anterior chest
wall. A large left hemothorax was identified by chest X-ray, and moderate cardiac
tamponade was detected by echocardiography. Left-sided chest drainage was
performed by inserting a chest drainage tube, and about 2500 ml of hemorrhagic
effusion was drained. An emergency operation was performed to relieve the cardiac
tamponade and repair the penetrating cardiac injury. About an hour after arrival
at the emergency room, a median sternotomy was performed in the operating room.
The knife had injured the surface of the right ventricular outflow tract, the
left lung, and the 3rd intercostal artery and vein. Cardiopulmonary bypass was
immediately prepared for the repair of the cardiac injury. The wounds were
successfully repaired with pledgeted sutures under cardiac beating. The
postoperative course was uneventful with no sign of infection. The patient was
discharged at 9 days after the operation. Here we have reported a case of
successful surgical repair of a penetrating knife injury to the heart, which was
managed by immediate resuscitation and emergency surgery.
PMID- 10770002
TI - Those who can, do.
PMID- 10770003
TI - Facial hematoma.
PMID- 10770004
TI - Treating bruxism and clenching.
PMID- 10770005
TI - Study suggests aspirin can help fight periodontitis.
PMID- 10770006
TI - Patients being treated for HIV should avoid St. John's Wort: NIH.
PMID- 10770007
TI - Oral pharyngeal cancer prevention and early detection. Dentists' opinions and
practices.
AB - BACKGROUND: The five-year survival rate for patients in the United States
diagnosed with oral pharyngeal cancer is 52 percent, which suggests that these
cancers are diagnosed at late stages. The authors conducted this study to
determine U.S. dentists' opinions and practices regarding oral cancer prevention
and early detection. METHODS: The authors mailed a pretested survey to 7,000
randomly selected general practitioners. A total of 3,200 dentists provided
information on how they conduct oral cancer examinations, their use of health
history questions to assess patients' oral cancer risks and their oral cancer
training and practices. The authors carried out analyses using unweighted data;
both bivariate and logistic analytical techniques at a P < or = .01 level of
significance were used. RESULTS: On average, dentists assessed about five of the
eight health history items on the survey. Eighty-six percent indicated that they
did not conduct oral cancer examinations on edentulous patients 18 years of age
or older; 81 percent, however, reported that they conducted oral cancer
examinations for 100 percent of their patients 40 years of age or older on their
initial appointment. CONCLUSIONS: The reported practices of these dentists
regarding oral cancer, in conjunction with their opinions about key aspects of
these practices and their training, point to a need for systematic educational
updates in oral cancer prevention and early detection. CLINICAL IMPLICATIONS:
Dentists need to determine their patients' risks for oral cancers and provide
routine and comprehensive oral cancer examinations.
PMID- 10770008
TI - Assessing the effectiveness of direct digital radiography barrier sheaths and
finger cots.
AB - BACKGROUND: Effective cross-contamination prevention is critical for direct
digital radiography, or DDR, sensors, which are not sterilizable; however,
current manufacturers' recommendations for standard precautions are limited to
the use of plastic barrier sheaths, which are commonly known to tear or leak. The
authors sought to determine the incidence of digital radiography barrier-sheath
leakage, with and without additional latex finger cot protection, as measured by
a water pressure test. METHODS: Four hundred plastic barrier sheaths were
randomly assigned to four groups based on intraoral radiograph positioning device
use and supplemental barrier protection with a latex finger cot. Sheaths were
carefully placed to cover DDR sensors for a single intraoral use, gently removed
from the sensors and tested for leakage through a water pressure technique.
RESULTS: Perforations occurred in 44 to 51 percent of plastic sheaths after a
single radiographic exposure. However, only up to 6 percent of the plastic
sheaths that were covered by a latex finger cot leaked during the water pressure
test. CONCLUSIONS: At least 44 percent of the plastic barrier sheaths leaked
after a single intraoral radiographic exposure. Use of a latex finger cot over
the plastic sheath significantly reduced leakage to no more than 6 percent.
CLINICAL IMPLICATIONS: Latex finger cots used in conjunction with the standard
plastic sheaths that cover DDR sensors may more effectively prevent cross
contamination than do plastic sheaths alone. Dentists who use DDR sensors during
highly invasive dental procedures such as dental implant surgery are encouraged
to consider supplemental barrier protection for these delicate, expensive and
nonsterilizable sensors to prevent patient cross-contamination.
PMID- 10770009
TI - Efficacy of bonded and nonbonded amalgam in the treatment of teeth with
incomplete fractures.
AB - BACKGROUND: This clinical study compared the efficacy of adhesive-retained vs.
pin-retained complex amalgam restorations in the treatment of molars with
incomplete fractures. Both relief of chewing pain and cold sensitivity were
evaluated at two weeks, three months and one year. METHODS: The authors treated
38 patients with a chief complaint of chewing sensitivity on vital molar teeth
(40 teeth in the study). A random-number generator determined the treatment
method for each tooth. Twenty teeth received bonded amalgam restorations. Twenty
teeth received amalgapins or threaded pins to retain the amalgam. Teeth were
evaluated for postoperative chewing sensitivity. A visual analog pain scale was
used to evaluate cold response to a skin-refrigerant-soaked cotton pellet at each
visit. After 12 months, all 40 teeth were available for evaluation. RESULTS:
Chewing pain was completely eliminated in all but one tooth. A Student's t-test
found no significant difference (P > .05) in preoperative cold sensitivity
between the bonded and nonbonded groups. A paired t-test comparison indicated
that the teeth in the bonded group were significantly less sensitive to cold
after three months and 12 months than they were at the time of the baseline
measurements (P < .0001). A paired t-test indicated no significant difference
between preoperative and postoperative cold sensitivity scores for teeth in the
nonbonded group (P > .05). CONCLUSIONS: Both adhesively bonded and mechanically
retained complex amalgam restorations were successful in resolving chewing
sensitivity in cracked molars. For 39 of 40 teeth, chewing sensitivity did not
return during the one-year follow-up period. At three months and 12 months, cold
sensitivity was reduced in the bonded restorations. At all three time periods,
cold sensitivity remained similar to baseline levels for the mechanically
retained restorations. CLINICAL IMPLICATIONS: Incomplete tooth fracture in molars
can be successfully treated by covering fractured cusps with amalgam
restorations. This study excluded teeth with prolonged sensitivity to a cold
stimulus or those with periodontal evidence of root fracture. With these
exclusions, elimination of chewing sensitivity was predictable. Teeth restored
with bonded restorations experienced a decrease in sensitivity to a cold stimulus
at three months and at 12 months, but not at two weeks. The cold sensitivity of
teeth restored with nonbonded restorations was similar at baseline, two weeks,
three months and one year.
PMID- 10770010
TI - The role of computerized tomography in the diagnosis and therapy of parotid
stones: a case report.
AB - BACKGROUND: Small, semi-calcified parotid stones are difficult to diagnose as
imaging can be extremely difficult. Understanding how to diagnose parotid stones
is important to dentists, however, because people with this condition develop
parotid swellings and may seek routine dental care. CASE DESCRIPTION: The authors
describe a classic case of parotid sialadenitis secondary to a small lucent stone
in Stensen's duct. They discovered the stone only because of the keen sensitivity
of computerized tomography, or CT, to minimal amounts of calcific salts. The CT
scan's ability to accurately locate the stone and its position within 1
centimeter of the orifice facilitated a successful intraoral surgical approach.
CLINICAL IMPLICATIONS: CT can be a significant aid in early diagnosis and therapy
of patients with parotid stones, who eventually develop sialadenitis. With early
intervention, further gland degeneration and parotidectomy will be prevented.
PMID- 10770011
TI - A practical approach to the diagnosis and treatment of periodontal disease.
AB - BACKGROUND: Both nonsurgical and surgical periodontal therapies are important in
the control of most forms of periodontal disease. Sometimes, nonsurgical therapy
is adequate to control the disease in mild cases and to slow progression and
maintain periodontal stability in more advanced cases. Other times, both
therapies may be indicated to obtain satisfactory results. The author presents
treatment guidelines and recommendations for periodontal therapy. METHODS: The
author searched the dental literature for information pertaining to periodontal
therapy. RESULTS: The author found evidence-based data to support the
effectiveness of nonsurgical and surgical periodontal therapy in controlling
periodontal disease. Nonsurgical periodontal therapy requires time, effort, and
good diagnostic and clinical skills to obtain satisfactory results. The results
are determined by evaluating the patient's periodontal disease after active
therapy, at which time additional surgical or nonsurgical treatment may be
recommended. Evaluation should continue throughout the lifelong supportive phase
of periodontal therapy. CONCLUSION: Clinicians should continue to develop and
enhance their diagnostic skills, assess factors that affect diagnosis and
prognosis, formulate a comprehensive treatment plan, render appropriate
treatment, evaluate the outcome and determine when periodontal care is indicated.
CLINICAL IMPLICATION: Failure to comply with monitoring the patient's periodontal
status may lead to uncontrolled disease and eventually premature tooth loss.
Premature tooth loss can be prevented through patient education and application
of evidence-based nonsurgical and surgical therapy.
PMID- 10770012
TI - Treating internal resorption using a syringeable composite resin.
AB - BACKGROUND: Internal resorption is a pathological process initiated within the
pulp space with the loss of dentin. It often is described as an oval shaped
enlargement of the root canal space and usually is asymptomatic and detectable by
routine radiographs. Treatment of internal resorption has included several
materials--gutta-percha, zinc oxide eugenol and amalgam alloy. These materials do
not provide strength to the tooth structure. CASE DESCRIPTION: A 29-year-old
woman was referred to a dental clinic for treatment of a large internal
resorptive defect in the coronal and middle one-third of the maxillary left
central incisor root with no apparent periapical pathosis, as well as a large
periapical radiolucency at the apex of the maxillary left lateral incisor that
was associated with a necrotic pulp. The authors used a dual-cure syringable
composite resin in conjunction with a bonding agent within the defect to treat
it. CLINICAL IMPLICATIONS: This technique seals the dentinal tubules and
strengthens the remaining tooth structure. It also improves the outcome of
resorptive defects and reduces operators' chair time.
PMID- 10770013
TI - Assessing the effect of composite formulation on polymerization stress.
AB - BACKGROUND: In this study, the authors measured the magnitude of the
polymerization stress of a variety of dental composite materials and explored the
effect of a novel monomer, a methacrylated derivative of styrene-allyl alcohol,
or MSAA, in reducing polymerization stress. METHODS: Eleven commercially
available composites and a series of experimental composites were evaluated in a
mechanical testing machine to measure the maximum stress generated during
placement in a confined setting. RESULTS: A significant relationship between
higher filler volume and increased polymerization stress was found among the
commercial materials. Introduction of MSAA produced a 30 percent reduction in
polymerization stress in an experimental composite material. CONCLUSIONS:
Composites that contain lower levels of inorganic filler particles are less
likely to produce high levels of polymerization stress during placement.
Modifications to traditional composite chemistry can result in materials that
produce lower polymerization stress levels. CLINICAL IMPLICATIONS: The
polymerization stress produced by dental composite materials during light-curing
is a leading reason for bond failures in adhesive restorations, resulting in
postoperative sensitivity, marginal staining and recurrent caries.
PMID- 10770014
TI - Building up tooth preparations for full crowns--2000.
AB - Many factors influence whether teeth planned for crowns or fixed prosthesis
abutments need to be built up. Teeth may now be treated more conservatively with
minimal fillers because of the greater strength of current cements, including
hybrid ionomers and resins. Teeth planned as fixed prosthesis abutments require
more remaining tooth structure and greater buildup strength than those designed
for single full crowns. It appears that crown buildup is still necessary, but
this procedure is needed less frequently than it was in previous years. Fillers
can be used to fill holes left when previous restorations were removed, and are
more commonly placed than build-ups.
PMID- 10770015
TI - Compassion, communication and craniofacial orodental trauma: opportunities
abound.
PMID- 10770016
TI - Optical coherence tomography: a new imaging technology for dentistry.
AB - BACKGROUND: Optical coherence tomography, or OCT, is a new diagnostic imaging
technique that has many potential dental applications. The authors present the
first intraoral dental images made using this technology. METHODS: The authors
constructed a prototype dental OCT system. This system creates cross-sectional
images by quantifying the reflections of infrared light from dental structures
interferometrically. RESULTS: We used our prototype system to make dental OTC
images of healthy adults in a clinical setting. These OCT images depicted both
hard and soft oral tissues at high resolution. CONCLUSIONS: OCT images exhibit
microstructural detail that cannot be obtained with current imaging modalities.
Using this new technology, visual recordings of periodontal tissue contour,
secular depth and connective tissue attachment now are possible. The internal
aspects and marginal adaptation of porcelain and composite restorations can be
visualized. CLINICAL IMPLICATIONS: There are several advantages of OCT compared
with conventional dental imaging. This new imaging technology is safe, versatile,
inexpensive and readily adapted to a clinical dental environment.
PMID- 10770017
TI - Age discrimination.
PMID- 10770018
TI - Wet-field resin bandage for fractured anterior teeth.
PMID- 10770019
TI - Postoperative care for patients with implant prostheses.
PMID- 10770020
TI - Current status of artificial hearts and ventricular assist devices.
AB - Currently available approaches for patients with refractory heart failure include
intravenous inotropic therapy, partial left ventriculectomy, dynamic
cardiomyoplasty, mechanical circulatory support, and heart transplantation. Heart
transplantation is limited by the availability of donor organs, which is never
expected to meet the increasing demand. Numerous devices have been developed for
circulatory support. Currently available devices differ in configuration,
anatomic location, flow characteristics, and durability. Many devices are
currently available for mechanical support, and they can generally be categorized
as follows: 1) pulsatile or continuous blood flow; 2) internal (implantable) or
external (extracorporeal); 3) pneumatically or electrically powered; and 4) for
short-term or long-term support. Proper selection of patients for a given therapy
has a major impact on clinical outcome. Early implantation of implantable
devices, before the onset of multiple or irreversible end-organ failure, is
essential. Short-term devices are indicated if myocardial recovery is
anticipated, as in cases of postcardiotomy shock and acute myocarditis. Long-term
devices are indicated for transitioning patients with end-stage myocardial
failure to heart transplantation. Long-term assist devices may, in some selected
cases, serve as an alternative to heart transplantation. This alternative will
benefit both patients in chronic heart failure competing for a limited donor
supply and patients with contraindications to transplantation, such as advanced
age, previous malignancies, and renal dysfunction. The next generation of blood
pumps to be applied clinically is likely to be axial pumps, which are valveless,
miniaturized, intraventricular left ventricular assist devices.
PMID- 10770021
TI - Impact of developmental biology on medicine.
AB - How a single zygote develops into a complex organism is the greatest mystery in
biomedical science. The discipline of studying this developmental process is
called "developmental biology". With advances in genetics, molecular biology, and
genomics and judicious use of various model organisms, modern developmental
biologists are gradually unveiling the mystery of the developmental process.
During this process, embryonic cells proliferate and differentiate to form
various tissues and organs. Eventually, a fully functioning organism results. The
embryo possesses the mysterious power to give rise to all kinds of new cells and
tissues. If we can harness the power of embryogenesis, the lost function of a
diseased organ might be restored. To demonstrate the potential impact of
developmental research on future medical care, we cite major progress in several
areas such as 1) the search for human disease genes and the study of gene
function using model organisms; 2) the power of stem cells; and 3) bioartificial
organs. Medical researchers in the 21st century should have an ample knowledge of
developmental biology and an ability to use various model organisms to study gene
function. Through this, new treatments using the power of embryogenesis may
evolve.
PMID- 10770022
TI - Recent advances in the study, prevention, and treatment of infectious diseases.
AB - Along with the rapid progress in molecular biology and computer technology, many
changes have occurred in the diagnosis, treatment, prevention, and understanding
of infectious diseases. Molecular techniques are taking a more important role
both in the diagnosis and in the discovery of etiologic agents. The associations
of Helicobacter pylori with gastroduodenal disorders and Chlamydia pneumoniae
with atherogenesis have revised contemporary thinking about the pathogenesis of
chronic organ and tissue diseases. Vaccination, once a privilege of children, is
now being used in adults and is also being tried as a therapeutic modality for
chronic diseases. Acquired immunodeficiency syndrome (AIDS) has become pandemic
and its toll is devastating. The study of AIDS has not only benefited patients
living with human immunodeficiency virus (HIV) infection, but has also delivered
a strong boost to antiviral research. Structure-based drug design was proven
useful through the successful development of HIV protease inhibitors and an
influenza neuraminidase inhibitor. In the future, the integration of structure
based drug design and combinatorial chemistry should expedite the pace of new
drug development. Finally, dissection of human genes related to susceptibility to
infectious diseases is a task to be completed in our fight against infectious
microorganisms.
PMID- 10770023
TI - Impact of assisted reproductive technology on modern medicine.
AB - A surge in knowledge and interest in reproductive biology has occurred since the
advent of assisted reproductive technology (ART) in the 1960s. These innovative
medical advances soon challenged societies and invited criticism. Nevertheless,
ART has superseded older therapies and serves as a back-up when all else fails.
There are currently 61 ART clinics in Taiwan. Thanks to a group of young
physicians and scientists who have devoted great effort in catching up with the
modern advances in assisted reproduction, most of the important advances in ART
have been introduced to Taiwan promptly and resulted in good success rates. The
complications of multifetal pregnancies as well as controversies regarding
gestational surrogacy and new technologies such as intracytoplasmic sperm
injection, preimplantation genetic diagnosis, and cloning have challenged
conventional wisdom, ethics, laws, and religions. Society now faces a dilemma in
striking a balance among science, ethics, and human rights. It is, thus,
advisable that we stand back once in a while and carefully consider where we
should go next.
PMID- 10770024
TI - Impact of human genome research on medicine--the initial Taiwan experience.
AB - The human genome contains at least 80,000 genes, and each carries out its unique
biologic function in the human body. Gene mutation and variation may result in
hereditary disease, cancer, hypertension, and even susceptibility to infectious
diseases. A complete compilation of all human genes (the human genome) should
allow a better understanding of the role of specific genes in diseases and,
consequently, better design of effective treatments. The human genome project
(HGP) is scheduled to be completed in 2003. This article reviews the novel
technology used in the HGP and the new information that will be generated. The
results will influence medical practice greatly. Indeed, as in the forthcoming
era of genomic medicine, a battery of gene tests is likely to be as routine as
blood chemistry tests are today. The impacts are to be felt soon and medical
professionals should be ready to grasp and apply new knowledge as it becomes
available to better serve their patients. We also describe how the findings from
the HGP might be used to solve locally important medical problems, using the
examples of genomic research in liver and nasopharyngeal cancers. Finally,
because the HGP has raised many new ethical, legal, and social challenges that
should often take precedence over the problems of technology, an overview of
these issues is also provided.
PMID- 10770025
TI - Significance of nitrogen removal mass in uremic patients on different modalities
of dialysis therapy.
AB - BACKGROUND AND PURPOSE: While most nephrologists use Kt/V values for dialysis
prescriptions, some researchers are beginning to view the role of solute removal
mass as an indicator of adequate dialysis. This study, using nitrogen as a
surrogate for solute removal, probed whether solute removal mass can be used as
the target of adequate dialysis. Mathematical formulas for easy bedside
calculation of nitrogen removal mass were used to avoid the problems associated
with direct measurement. METHODS: The weekly removal mass of urea nitrogen (M)
and the urea generation rate (G) of 32 conventional hemodialysis (HD) and 21
continuous ambulatory peritoneal dialysis (CAPD) patients were calculated. All
the patients were anuric, clinically stable, and under adequate dialysis pursuant
to either the criterion of the urea index, Kt/V, or clinical requirements.
RESULTS: The difference in MHD (MHD = 41.9 +/- 9.5 g/week, MCAPD = 38.8 +/- 11.9
g/week) and G (GHD = 3.90 +/- 1.02 mg/min, GCAPD = 3.85 +/- 1.21 mg/min) between
the two groups was statistically insignificant (p = 0.119 and p = 0.868,
respectively). When protein nitrogen leaking through the peritoneal membrane was
considered and added to MCAPD, nitrogen removal in CAPD patients (M'CAPD = 42.3
+/- 13.0 g/week) approached that in HD patients (p = 0.886). There was no
correlation between dialysis dosage and urea removal mass in either the CAPD or
HD groups. CONCLUSIONS: Urea nitrogen removal mass is similar to the protein
catabolic rate (PCR) in stable patients. It is meaningful in dialysis evaluation
only when it is used simultaneously with blood urea nitrogen measurement.
However, because M changes at the inception of dialysis, it more significant than
PCR in the evaluation of unstable patients.
PMID- 10770026
TI - Pulmonary infection in human immunodeficiency virus-infected patients in Taiwan.
AB - BACKGROUND: Pulmonary infection is a major cause of morbidity and mortality in
human immunodeficiency virus (HIV)-infected patients. METHODS: We conducted a
retrospective analysis of the pathogens causing pulmonary infection in 272 HIV
infected patients admitted to a university hospital from January 1993 through
December 1998. RESULTS: A total of 158 (58%) patients had pulmonary
complications, all but two of whom had acquired immunodeficiency syndrome (AIDS).
There were 156 episodes of pulmonary infection, involving 124 patients. The most
common pulmonary infection was Pneumocystis carinii pneumonia (PCP): 66 patients
had 77 episodes of PCP, all of which occurred in patients with CD4+ lymphocyte
counts below 0.2 x 10(9)/L (200/microL). Pulmonary tuberculosis (TB), diagnosed
in 47 patients, was the second most common pulmonary infection. Twenty TB
patients had open TB. HIV-infected patients who were immigrants from Southeast
Asia (9/23, 39%) had a higher risk of developing pulmonary TB than nonimmigrants
(38/249, 15%) (p = 0.004). Only one of 17 episodes of community-acquired
bacterial pneumonia was caused by Streptococcus pneumoniae. Less common
opportunistic pulmonary pathogens included cytomegalovirus (5 cases), Aspergillus
species (3), Cryptococcus neoformans (3), Mycobacterium avium complex (2),
Penicillium marneffei (1), Nocardia species (1), and Rhodococcus equi (1).
CONCLUSIONS: PCP and pulmonary TB are the two leading pulmonary infections in
Taiwanese HIV/AIDS patients. These findings should be taken into consideration
when developing management strategies and public health policies.
PMID- 10770027
TI - Survey of infectious skin diseases and skin infestations among primary school
students of Taitung County, eastern Taiwan.
AB - BACKGROUND: There are no complete records on the prevalence of childhood skin
diseases in Taiwan. We conducted a survey of infectious skin diseases and skin
infestations among primary school children in Taitung County, which is located in
southeastern Taiwan. METHODS: From March 1998 through October 1998, a total of
3,029 students from four rural districts (Changbin, Yanping, Lanyu, and Dawu) and
one urban area (Taitung City of Taitung County) were examined by dermatologists.
Treatment and instructions for disease care were given immediately after the
diagnosis of dermatoses, when appropriate. RESULTS: The most common infectious
skin diseases and infestations were pediculosis capitis (12.9%), verruca vulgaris
(5.1%), tinea versicolor (4.4%), tinea pedis (4.1%), verruca plantaris (1.8%),
and scabies (1.4%). Most skin diseases, including pediculosis capitis, scabies,
verruca vulgaris, verruca plantaris, folliculitis, pyoderma, tinea pedis, and
tinea versicolor, were significantly more common in rural areas than in the urban
area (p < 0.05 for all). Pediculosis capitis was more common among girls (p <
0.001), but tinea pedis and tinea versicolor were more common among boys (p <
0.05). CONCLUSIONS: The prevalence of most skin infections and infestations are
much higher in rural Taitung County than in Taitung City. Prevention and
treatment of these skin diseases should be reemphasized in the education of
teachers, as well as students and their families. Adequate dermatologic training
of nurses and physicians and the development of teleconsultation and
teledermatology in rural areas might decrease the prevalence of these skin
diseases in school children.
PMID- 10770028
TI - Treatment of poisonous snakebites in northern Taiwan.
AB - PURPOSE: We evaluated the epidemiology and outcomes of snakebites in northern
Taiwan, and the effect of local antivenom injection to speed neutralization and
reduce the spread of venom. METHODS: We retrospectively reviewed the medical
records of 130 venomous snakebite patients treated in a general hospital in
northern Taiwan during a 3-year period (1991-1994). Patients received either
combined local and intravenous injection of antivenom or intravenous
administration only, according to the physicians' decision. The species of snake
involved, time of bite, and outcome of the patient were recorded. The effect sof
local and systemic antivenom administration were analyzed using the duration of
emergency department (ED) stay among patients discharged from the ED with medical
approval as a treatment index. RESULTS: Most (76.1%) venomous snakebites were
attributed to the green habu (68 patients) and the Taiwan habu (31 patients). All
bites were to the extremities: 74 (57%) to the feet and 56 (43%) to the hands or
arms. Most bites (n = 70, 53.9%) occurred between 2 PM and 9 PM. The peak months
for snakebites were June through October (n = 84, 64.6%). Eighteen patients
(13.8%) were admitted for further treatment after being cared for in the ED. The
other 112 patients were discharged from the ED (86.2%), although three of these
were admitted later because of infection. No patients died, but eight developed
wound infections. Of the 93 patients discharged from the ED with medical
approval, 26 (28.0%) received local injection plus systemic administration of
antivenom. The duration of ED stay did not differ significantly between patients
with local plus systemic administration and those who received systemic
administration alone (23.7 +/- 19.5 hours vs 27.0 +/- 12.5 hours, p = 0.19).
CONCLUSIONS: Most snakebites in northern Taiwan were due to habus and caused mild
symptoms. Local antivenom injection plus intravenous administration of antivenom
had no benefit over intravenous administration alone.
PMID- 10770029
TI - Effects of continuous calcitonin treatment on osteoclasts derived from cocultures
of mouse marrow stromal and spleen cells.
AB - BACKGROUND: Continuous calcitonin (CT) treatment for bone diseases associated
with increased bone resorption may be followed by prolonged depression of
osteoclast response to CT. The mechanisms of this "escape" phenomenon remain
unclear. METHODS: We examined the effects of continuous CT treatment on cell
formation, calcitonin receptor (CTR) expression, response to CT, and bone
resorption of osteoclasts in a coculture of mouse marrow stromal and spleen cells
in the presence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Cells were cocultured
and treated with salmon CT (sCT) for 7, 14, or 21 days. The effects of continuous
CT treatment on osteoclast formation was determined by quantitation of tartrate
resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs). CTR
expression in osteoclasts was determined by binding of [125I]sCT in
autoradiography. Bone resorption and CT responsiveness were assessed by examining
the formation of resorption pits and by enumerating osteoclast reattachment on
dentine slices after sCT rechallenge. RESULTS: TRAP-positive MNCs appeared in
cocultures treated with sCT and were similar in number and morphology to those in
control cultures, regardless of the concentration and duration of sCT treatment.
A decrease in CTR expression was identified as a loss of silver grains from the
TRAP-positive cells in cocultures receiving sCT treatment for 14 or 21 days.
Partial recovery of CTR expression in TRAP-positive cells was evident in
cocultures treated with sCT for only the first 7 days of coculture. TRAP-positive
MNCs in cocultures treated with sCT for 14 or 21 days were resistant to the
rechallenge with sCT. They attached to dentine slices and caused numerous
resorption pits compared with control cells and cells treated with sCT for the
first 7 days of coculture (p < 0.01). CONCLUSION: These findings suggest that the
escape phenomenon that develops after continuous CT treatment may be due, at
least in part to: 1) loss of responsiveness to CT in existing osteoclasts; and 2)
development of new osteoclasts that are CTR-deficient and, therefore, refractory
to CT rechallenge.
PMID- 10770030
TI - Circadian variations in plasma neutral and basic amino acid concentrations in
young men on an ordinary Taiwanese diet.
AB - BACKGROUND AND PURPOSE: Plasma levels of circulating free amino acids reflect the
net status of protein breakdown and synthesis, and may be linked to various
disease states. We studied circadian variations in plasma concentrations of
neutral and basic amino acids during a 24-hour period in healthy young men who
consumed ordinary Taiwanese test meals. METHODS: Ten subjects ingested the test
diet (protein intake, 1.5 g.kg-1.d-1) which was offered in three meals and two
light snacks during the day. Thirteen heparinized blood samples were collected
from each subject to analyze plasma amino acid concentrations during the
experimental period, at 1- to 3-hour intervals. RESULTS: The plasma
concentrations of all neutral amino acids, including the large neutral amino
acids (leucine, isoleucine, valine, tryptophan, tyrosine, and phenylalanine) and
methionine, as well as the small neutral amino acids (glycine, serine, threonine,
and proline) and the basic amino acids (histidine, arginine, lysine), varied
significantly as a function of the time of day (p < 0.001). Except for glycine
and proline, all of the neutral amino acids exhibited a marked evening elevation
after dinner, with the highest plasma concentration at 23:00. Proline showed peak
concentrations at 09:00, while glycine and the basic amino acids exhibited peak
concentrations at 21:00. Most of the plasma amino acids exhibited the lowest
concentrations at 12:00. CONCLUSION: Plasma neutral and basic amino acid
concentrations exhibited significant circadian variations. The present study also
provided the mean fasting plasma levels of amino acids in healthy young men
consuming an ordinary Taiwanese diet.
PMID- 10770031
TI - Childhood mixed connective tissue disease.
AB - Two girls with mixed connective tissue disease (MCTD) were treated in our
hospital in the past 5 years. Patient 1, a 10-year-old girl presenting with
migratory arthralgia, had an initial diagnosis of juvenile rheumatoid arthritis.
Muscle weakness with elevated levels of creatine kinase and liver enzymes,
sclerodactyly, Raynaud's phenomenon and heliotrope sign developed subsequently in
the following 3 years. Patient 2, a 13-year-old girl, had been treated for
suspected systemic lupus erythematosus since 9 years of age. She presented with
lymphadenopathy, arthralgia, pericardial effusion, and paralytic ileus. The
symptoms waxed and waned. Sclerodactyly, Raynaud's phenomenon, proteinuria, and
hypertension were also noted. Both patients had high serum titers of antinuclear
antibody (speckled pattern, 1:5120) and were seropositive for antiribonuclear
protein antibody. Intravenous immunoglobulin, prednisolone, cyclosporine A, and
nonsteroidal anti-inflammatory drugs (NSAIDs) were given to patient 1. Patient 2
received cyclosporine A, prednisolone, and methylprednisolone pulse therapy. The
disease has been well controlled for 2 years by low-dose immunosuppressants and
NSAIDs. MCTD is a rare juvenile rheumatic disease: early identification and
appropriate treatment can improve the disease outcome.
PMID- 10770032
TI - Parvovirus B19 infection in a human immunodeficiency virus-infected patient with
anemia.
AB - Anemia is generally attributed to zidovudine therapy in human immunodeficiency
virus (HIV)-infected patients, although parvovirus B19 infection has been
reported as a rare cause. We report on a 24-year-old homosexual man infected with
HIV who presented with anemia. He had received aggressive daily antiretroviral
therapy (zidovudine 600 mg, lamivudine 300 mg, and saquinavir 1,800 mg) for 2
years. At the time of admission, his CD4+ count was 10 x 10(6) cells/L. A bone
marrow aspirate smear showed a marked decrease in erythropoiesis and
immunocytochemical staining for parvovirus B19 was positive. Parvovirus B19 viral
DNA was detected in the peripheral blood using a polymerase chain reaction-based
assay. Serologic studies were positive for parvovirus B19 immunoglobulin (Ig)M
antibodies, but negative for IgG antibodies. The patient was treated with packed
red blood cell transfusion. Zidovudine was stopped and replaced with zalcitibine
2.25 mg daily after anemia occurred. He did not receive intravenous Ig therapy
because of its cost. After discontinuation of zidovudine for 1 year, anemia
persisted and the patient depended on regular blood transfusions to control the
anemia. This case emphasizes that, in addition to drug-related causes, parvovirus
B19 infection should be included in the differential diagnosis of chronic anemia
in HIV-infected individuals.
PMID- 10770033
TI - Arcobacter butzleri bacteremia in a patient with liver cirrhosis.
AB - Invasive Arcobacter butzleri infection in humans has been rarely described. We
report a 60-year-old man with liver cirrhosis who presented with high fever and
esophageal variceal bleeding. Two aerobic blood cultures grew Campylobacter-like
organisms. The biochemical reactions of the isolate were inconclusive, while
sequence analysis of the 16S rRNA gene definitively identified the organism as A.
butzleri. The patient's bleeding stopped after endoscopic sclerosing therapy.
Although the organism appeared to be resistant to cephalosporins on the basis of
the minimum inhibitory concentrations determined with the E test, the fever
resolved with parenteral cefuroxime. Whether the clinical improvement was related
to cephalosporin therapy or to the self-limited nature of Arcobacter bacteremia
is not known.
PMID- 10770034
TI - Composite graft tear and aortico-left ventricular tunnel after aortic root
replacement using Cabrol's technique.
AB - Woven graft tera is a very rare complication after aortic root replacement using
Cabrol's technique. In this report, we present a 40-year-old man with aortic
annular ectasia and severe aortic regurgitation who underwent four revisional
aortic valve operations because of recurrent paravalvular leakage after valve
repair and/or replacement. The Bentall operation with translocated aortic valve
and Cabrol's coronary artery anastomosis were performed in the fifth operation,
because of progressive dilatation of the aortic root and ascending aorta.
Unfortunately, aortico-ventricular tunnel developed 2 years after aortic root
replacement using Cabrol's technique. Graft tear and proximal anastomotic leakage
were found to be the cause of the tunnel during the sixth operation. The patient
died of myocardial failure 8 days after the seventh aortic root replacement
operation. The devastating result of this complication should alert
cardiovascular surgeons to the possibility of graft failure after the Bentall
operation.
PMID- 10770035
TI - Late-onset holocarboxylase synthetase deficiency with homologous R508W mutation.
AB - Holocarboxylase synthetase (HCS) is responsible for the biotinylation of pyruvate
carboxylase, propionyl coenzyme A (CoA) carboxylase, beta-methylcrotonoyl CoA
carboxylase, and acetyl CoA carboxylase. We report on a patient with HCS
deficiency resulting in a rare metabolic disease. The patient, a 2-year-old boy,
presented with vomiting, consciousness disturbance, and dyspnea. Laboratory
examinations showed hyperglycemia, hyperammonemia, lactic acidosis, and excretion
of large amounts of beta-hydroxyisovalerate and beta-methylcrotonylglycine in the
urine. After 10 days of treatment with biotin 5 mg.kg-1.day-1, the abnormal
organic acids in his urine had almost completely disappeared. There were no
subsequent attacks, and his growth and development remained normal during 1 year
of follow-up. Nucleotide sequence analysis of the HCS cDNA of the patient
revealed a homozygous 1809C-->T (R508W) mutation. The R508W mutation is found
worldwide, and might be associated with higher residual HCS activity than other
mutations. Late-onset HCS deficiency cannot be differentiated clinically from
biotinidase deficiency. Prompt and correct diagnosis is important for these
biotin-responsive disorders.
PMID- 10770036
TI - Characterization of the first clinical isolate of vancomycin-resistant
Enterococcus faecalis, AH803, in Taiwan.
AB - We previously isolated a vancomycin-resistant strain of Enterococcus faecalis,
designated AH803, from the sputum of a patient with pneumonia and bacteremia in
Taiwan. AH803 was resistant to vancomycin (minimal inhibitory concentration, MIC
= 512 micrograms/mL) but susceptible to teicoplanin (MIC = 8 micrograms/mL), and
harbored the vanA gene but not the vanB gene. In this study, we further
characterized E. faecalis AH803 and the plasmid it was found to contain. DNA from
AH803 was analyzed for the presence of vanA and vanB resistance genes by
polymerase chain reaction. The vancomycin resistant phenotype was transferable
from AH803 to E. faecalis JH2-2, at a frequency of 4.8 x 10(-2). AH803 was also
resistant to gentamicin and chloramphenicol, and these antibiotic resistance
phenotypes cotransferred with vancomycin resistance. The genes responsible for
resistance to all three antibiotics were located on a 42-kb conjugative plasmid
(pBL101). This plasmid had the same restriction enzyme digestion patterns as
Tn1546, found in pIP816 of E. faecalis BM4147. Epidemiologic studies of
glycopeptide resistance should perhaps combine phenotypic and genotypic methods,
rather than using phenotypic methods alone.
PMID- 10770037
TI - Role of pathologists in the new millennium.
PMID- 10770038
TI - Virus through gene therapy.
PMID- 10770039
TI - The use of intra aortic baloon pump in patients undergoing coronary artery bypass
grafting at the Aga Khan University Hospital, Karachi.
AB - OBJECTIVE: To review the experience in the use of Intra Aortic Balloon Pump
(IABP) in patients undergoing Coronary Artery Bypass Grafting (CABG) at a
tertiary care hospital with a new Open Heart surgery program. DESIGN:
Retrospective study. SETTING: The Aga Khan University Hospital, Karachi.
PATIENTS: Medical records of all patients undergoing CABG between November 1994
and July 1997 were reviewed and those in whom IABP device was used, were included
in this study. RESULTS: A total of 15 patients had IABP support during the study
period. Four surgeries were done urgently while two were emergencies. There were
three mortalities. Ejection fractions in all but one patient were impaired. Among
the surviving patients, the average pre-IABP Cardiac Index was 2.6
litres/min/meter2 which registered an average increase of 21.15% after the
initiation of the IABP. The Pulmonary Artery Wedge Pressure also showed an
average reduction of 29.11% from the pre IABP levels reflecting an increase in
the cardiac output with the use of the IABP. CONCLUSION: This series represents
the early experience of a new cardiac surgery center in Pakistan in the use of
IABP. Although the numbers in this study are too small to derive any conclusions,
the overall morbidity and mortality in this short series are within acceptable
limits in the high risk patients included.
PMID- 10770040
TI - Decline in breast feeding, who is to be blamed?!! A study of knowledge, attitude
and practice of breast feeding amongst nurses.
AB - OBJECTIVES: Breast-feeding is on the decline. Very often the first introduction
to bottle-feeding is facilitated in the maternity units. This reduces the chances
for the mother to breast feed successfully. The objective of the study was to
evaluate the knowledge, attitude and practices of breast-feeding amongst the
nurses working in the maternity units. SUBJECTS: Nurses working in the maternity
units of North Nazimabad, Karachi. DESIGN/METHODOLOGY: A cross-sectional study
was conducted in the maternity units of North Nazimabad, Karachi. The Nurses were
interviewed through a structured questionnaire. RESULTS: Out of 110 nurses
working in the units, interviews of 70 nurses were obtained. The survey reveals
that out of 70 nurses only 16 were qualified. The result shows that the nurses
know little about successful lactation management and their role in the promotion
and support of breast-feeding. There was a significant difference (P < 0.00)
between qualified and non-qualified nurses as regards management of different
aspects of breast-feeding. CONCLUSION: There is a huge gap between what is
desired and what is available. Intensive training programs should be organized to
enhance nursing activities for the required services in order to promote and
support breast-feeding.
PMID- 10770041
TI - Ultrasonographic renal size in individuals without known renal disease.
AB - OBJECTIVE: In order to establish some preliminary data of our population, we
determined the ultrasonographic kidney dimensions in individuals without known
renal disease. We assessed whether age, sex, side, body mass index (BMI) and
presence or absence of diabetes mellitus and hypertension affect the renal size.
METHODS: Ultrasonographic kidney measurements were performed on 194 adult
patients without known kidney lesions. Measurements included length, width,
cortical thickness and estimation of renal size which was obtained by multiplying
the first three variables. The effect of age, gender, side, height, weight, BMI,
hypertension and diabetes mellitus was statistically analyzed. RESULTS: The mean
kidney length was 10.4 +/- 0.8 cm, mean with 4.5 +/- 0.6 cm and mean cortical
thickness 1.6 +/- 0.2 cm. The estimated mean renal size was 76 +/- 22 cm3. Kidney
length did not significantly differ between right and left, however, kidney
width, cortical thickness and size did (p < 0.05). Right kidneys were smaller
than the left ones. In univariate analysis, the mean renal size correlated with
age, sex, side, BMI and absence or presence of hypertension and diabetes
mellitus. In a multivariate analysis, however, the only significant factors
affecting renal size were sex and BMI. CONCLUSION: We conclude that renal size is
related to age, side, sex and the individual's height and weight. Population
based studies are needed to establish the normal values for the Pakistani
population.
PMID- 10770042
TI - In vitro differentiation of human endometrial stromal cells: effect of
transforming growth factor beta 1 on prolactin secretion.
AB - OBJECTIVE: To investigate the role of Transforming Growth Factor beta 1 on
differentiation of human endometrial stromal cells. STUDY DESIGN: A prospective
study. MATERIAL AND METHODS: Human endometrial cells obtained from 9 women were
cultured in DMEM-HAMs F12 media to adequate cell confluence and then the flasks
were cultured in the presence and absence of TGF b 1. The influence of TGF beta 1
were measured by prolactin production expressed as nanograms of prolactin/mg of
total DNA in cells measured by diphenylamine reaction. RESULTS: The levels of
prolactin in the culture medium with and without TGF beta 1 were 0.16 +/- 0.27
ng/microgram DNA/day and 0.24 +/- 0.41 ng/microgram DNA/day respectively. There
was no significant difference between groups. CONCLUSION: There is no direct
effect of TGF beta 1 on differentiation of human endometrial stromal cells.
However it may involve in more complex relationship in this process.
PMID- 10770043
TI - Learning approaches and academic performance of undergraduate medical students in
Pakistan.
AB - OBJECTIVE: To classify undergraduate medical students according to their learning
approaches and to correlate the learning approaches with their academic
achievements. MATERIALS AND METHODS: A questionnaire to appraise learning
approaches of undergraduate medical students was administered and collected at
the end of the regular certifying examinations. The responses were analysed
through the principal component factor analysis. RESULTS: The results did not
depict formation of demonstrable learning approaches during academic years.
However, increased self-awareness about the approaches was indicated by the
responses of final year students as compared to the third year students. The
correlation of the learning approaches with the scores of the certifying
examination and a mock test (consisting of specially developed integrated
questions), through multivariate analysis depicted statistically insignificant
results. CONCLUSION: There was a non-significant relationship between the
learning approaches and academic performances and a weak statistical significance
between achievement, orientation and performance in certifying examination. It is
essential that along with changes in the instructional and assessment strategies
awareness should be created in students about various learning approaches.
PMID- 10770044
TI - Human cost of political violence.
AB - OBJECTIVE: To evaluate the cost of political violence in terms of human life and
its influence on social, psychological and financial aspects of community.
DESIGN: Retrospective study conducted from 1987 to 1989. SETTING: Department of
Accident and Emergency, Jinnah Postgraduate Medical Centre, Karachi. SAMPLE SIZE:
Nine hundred and fifty four victims including two hundred and fifty seven dead.
RESULTS: The mean age of the victims was 27.29 +/- 9.46 years with a male to
female ratio of 33:1. All ethnic groups suffered to some extent. No case of
violence on religious differences was reported during this period. Firearms were
frequently used. Most of the deaths (92.2%) occurred due to firearm injuries.
Landhi, Korangi, Malir and Shah Faisal Colony were the worst affected areas.
There was however no significant difference between them. The projected loss of
life for the dead was approximately 3.15 million days. The same was difficult to
assess for the injured because of multifactorial reasons. Six thousand four
hundred and ninety two close family members suffered from Psychological and
Physical Trauma. The number of distant members affected psychologically was
estimated to be 0.566 million. Schooling of approximately five thousand four
hundred thirty seven children of the victims suffered. CONCLUSION: Political
violence has significant short and long term effects on the society in terms of
physical and psychological trauma, financial losses, poor schooling and health,
biased pattern of child development, migration of families and further division
of society into identifiable communities which may prolong the conflict.
PMID- 10770045
TI - Setting the agenda for change in the new millennium: an open invitation from the
International Poverty and Health Network to all health professionals.
PMID- 10770046
TI - Risk of imported filariasis in Pakistan.
PMID- 10770047
TI - Multiple cerebral hydatid cysts: a surgical challenge.
PMID- 10770048
TI - Immunosuppressive drug therapy as a potentiator of anal carcinoma in a patient
with relapsing lymphoma.
PMID- 10770049
TI - Sexuality during pregnancy in Pakistani women.
AB - OBJECTIVE: We investigated the patterns of sexual activity during pregnancy and
explored all beliefs related to coitus during pregnancy in women with the
objective of promoting awareness and assisting health care providers in
understanding and dispelling fears/misconceptions prevalent in our culture.
METHODS: A cross-sectional, KAP (Knowledge, Attitude, Practice) study was
conducted using questionnaires to interview 150 healthy pregnant women attending
antenatal clinics at Aga Khan University Hospital (AKUH) and Lady Dufferin
Hospital, both located in Karachi, Pakistani. Data was analysed using Epi Info 6
statistical package. RESULTS: The mean frequency of intercourse during pregnancy
(1.6 times/week) was less than before pregnancy (3.5 times/week). Husbands were
the main initiators of sexual activity (44%) while the wives only rarely did so
(0.7%). Some (13.3%) women felt it served to keep husbands around. Coitus during
pregnancy was gratifying in 64.7% and painful in 37.3% of respondents. Most
(45.4%) believed coitus was harmful for the foetus. Others (28.7%) thought it did
not make any difference whereas 4.7% believed that it made a difference if the
foetus was female by gender. 22.7% women believed that coitus during pregnancy
caused abortions early in pregnancy and 6.7% that it induced pre-term labour. 26%
did not know the means by which the harmful effects were produced but still
maintained their beliefs. Some (10.7%) thought it could actually help widen the
birth canal and facilitate labour. Majority (85.3%) believed that frequency
should be lowered during pregnancy, 10% thought that it should be continued as
before and 4% that it should be stopped completely. CONCLUSION: This study
suggests a mixed attitude towards sexuality in pregnancy with a tilt towards the
belief that it is harmful and should therefore be decreased during pregnancy,
specially during the last trimester. It is the responsibility of health care
providers to dispel fears and clarify any misconceptions regarding such matters.
PMID- 10770050
TI - [Pathology of xenograft, allograft and autograft cardiac valves].
AB - Histopathological changes in xenograft, allograft and autograft heart valves
after implantation are discussed. Collagen is the most important structural
element in all these valves. In xenograft, there is no synthetic or renewal
mechanism to replace the collagen that is gradually broken down, either because
of proteolysis or the mechanical stresses to which the cusps are subjected. Thus,
the cumulative effect of this breakdown can lead to the formation of cuspal tears
and perforations. Collagen in implanted xonografts tends to undergo a time
dependent process of focal calcification, which may result in stenosis and/or
regurgitation and loss of mobility of the cusps. In cryopreserved allograft, the
viability of donor cells is usually not sufficient to maintain the structure of
the cusps. The durability of allograft is influenced by the degree of
preservation of collagen and elastic fibers in the graft, attenuation of
immunologic reaction and extent of fibrous sheathing. Pulmonary autografts keep
their cellular population and structure after implantation, and may have growth
potential. Progressive root dilatation is the most important cause of valvular
failure after the Ross procedure.
PMID- 10770051
TI - [Midterm results of total aortic root replacement with pulmonary autograft (Ross
operation)].
AB - Between February 1995 and December 1999, 18 patients underwent Ross operation.
Age at the operation ranged from 2 to 31 years. Diagnosis includes congenital
aortic stenosis and/or regurgitation in 15, and adult aortic regurgitation in 3.
In all cases autograft was implanted by the method of total aortic root
replacement, associated with annuloplasty for the dilated aortic annulus in 2 and
aortoventriculotomy by the Konno procedure in 3 (Ross-Konno). Right ventricular
outflow tract was reconstructed by a pulmonary homograft in 12, a xenopericardial
conduit in 3, or the other reconstructive procedures with autologous tissue and
outflow patch in 3. There was no operative and late death. Reoperation was needed
in 1 patient due to stenosis of pericardial conduit 4 years after the initial
operation. Pressure gradient across implanted autograft valve was negligible (4.8
+/- 0.5 mmHg), and echocardiography revealed no aortic regurgitation in 12 cases
and trivial to mild in 6, over a mean follow-up period of 23 +/- 18 months (range
2 to 60 months), signifying excellent durability of implanted autograft. Right
ventricular outflow tract reconstruction with the homograft resulted in excellent
mid-term performance as showing pressure gradient of 9.0 +/- 4.6 mmHg and no
regurgitation in 11 of 12 cases, whereas pressure gradient was 17.9 +/- 13.1 mmHg
in the patients underwent the other reconstructive procedures. We conclude that
Ross procedure associated with the concomitant procedures to adjust the size
discrepancy between the native aortic annulus and autograft has provided good
midterm results with excellent autograft durability. And this procedure was
thought to be a preferable method for children as well as young adults with
congenital aortic stenosis.
PMID- 10770052
TI - [An experience with the Ross operation utilizing cryopreserved pulmonary
homografts procured by and stored in our homograft valve bank].
AB - Eight patients, 4 males and 4 females ranging in age from 10 to 54 years (mean 27
+/- 13 years) underwent the Ross operation using a cryopreserved pulmonary
homograft harvested by and cryopreserved in our institutional "Tissue Bank".
Seven patients had a congenital bicuspid aortic valve and 3 patients had had
healed infective endocarditis of the aortic valve. Four young female patients
wanted to have a baby after operation. The Ross procedure was carried out
utilizing aortic root replacement techniques in all patients. All patients
survived and are currently in NYHA class 1, but 2 cardiac events occurred in 2
patients during the mean follow-up term of 29 +/- 19 months. The one was the
anastomic stenosis between the homograft and distal pulmonary artery treated by
balloon dilatation and the other was ventricular tachycardia eventually managed
by the insertion of an ICD. Pulmonary autograft valve regurgitation is present in
3 patients, but it is not progressive up to the present time. Pulmonary homograft
valves function well in all patients. The Ross operation for adolescents and
young adults should become more popular along with more easy availability of
homograft valves based upon the establishment of the "Homograft Valve Bank"
system in Japan.
PMID- 10770053
TI - [Recent donation and clinical results of homograft tissue].
AB - Between August 1995 and July 1999, we have experienced 14 donors for allografts
(mean age: 39.8 +/- 15.8, M/F = 10/4, mean warm ischemic time: 359 minutes).
Donated tissues were included 12 aortic valves and 12 pulmonary valves,
respectively. Since February 1994, clinical diagnoses of 14 patients included 7
congenital heart disease, 5 infective heart disease, 1 artificial graft
infection, and 1 thrombosed valve. There was no graft-transmitted disease. In
congenital heart disease, 3 patients (HLHS: 1, Truncus: 1, TOF + PA: 1) died
(early mortality, 42%) and 1 with TGA had residual conduit stenosis. However, in
infective heart disease, all patients survived without recurrent infection and
did not need reoperation (early mortality, 0%). Our clinical results of homograft
implantation for infective heart disease were excellent, but more careful
consideration will be needed for congenital heart disease in neonates and/or
patients with poor preoperative condition.
PMID- 10770054
TI - [Valve replacement with cryopreserved allograft].
AB - Allograft valves have several advantages such as 1) the absence of thromboembolic
complications without anticoagulation, 2) superior durability to bioprosthetic
valves, 3) good resistance to infection, 4) excellent hemodynamic performance
especially in small sizes. Surgeons in western countries, therefore often use
these valves and have reported good long-term results. In Japan, there have been
only a small number of case reports on such valve replacement. We experienced
five cases of valve replacement with cryopreserved allografts, four men and one
woman. Four of them had formerly received AVR or Cabrol operation, and the
prosthetic valve (graft) infection or aortitis syndrome was the main reason of
reoperation. One 15 year-old woman suffering from congenital aortic stenosis
underwent Ross operation with pulmonary allograft. Although one case with PVE
received re-re-AVR 2 years and 4 months after the allograft replacement because
of the recurrence of infection, the other four cases are in good condition long
after the surgery. We hope that the use of allograft valves will become common in
Japan.
PMID- 10770055
TI - [Early experience with the freestyle stentless xenograft].
AB - We performed aortic valve replacement with the Freestyle stentless xenograft in 9
patients. There were 6 men and 2 women, whose ages ranged from 44 to 76 years.
The modified subcoronary implantation was used in 6 patients and the completely
subcoronary implantation was used in 2 patients. The full root replacement was
used in 1 patient with bicuspid aortic valve. In a patient who underwent root
replacement, postoperative cineangiogram revealed just proximal right coronary
artery stenosis. The patient underwent coronary artery bypass grafting to right
coronary artery by use of the right internal mammary artery. One in-hospital
death occurred on the 46th postoperative day in a patient with severe aortic
stenosis and renal failure. 5 patients were investigated by doppler
echocardiography at 2 weeks, 3, 6, and 12 months after operation. Peak pressure
gradient 1 year after implantation was 11.7 +/- 3.9 mmHg for all valves. No
patient had postoperative significant aortic regurgitation.
PMID- 10770056
TI - [Aortic valve replacement with a stentless porcine aortic root bioprosthesis].
AB - From April, 1999 to November, 1999, 8 patients underwent the aortic valve
replacement using Medtronic Freestyle aortic root bioprosthesis. Mean age was
67.8 years old. Aortic valve etiology was as follows, AS: 1 case, AR: 2 cases,
ASR: 3 cases, IE: 1 case, mechanical valve malfunction due to subvalvular pannus:
1 case. The implanted valve size was 25: 2 cases, 23: 3 cases, 21: 1 cases, 19: 2
cases. Surgical technique was subcoronary: 7 cases, full-root: 1 case. Post-op 2D
echo revealed tribial aortic valve incompetence in two cases because of size
discrepancy between the aortic annulus and the ascending aorta. Pacemaker
implantation was needed in 1 case because of the complete A-V block. In
comparison with 5 cases of aortic valve replacement with Hancock II performed in
same period, there were no significant differences about the implanted valve size
and mean systolic pressure gradient, but the effective orifice area in Freestyle
cases was significantly larger than Hancock II cases.
PMID- 10770057
TI - [Aortic valve/root replacement using a stentless bioprosthesis (Medtronic
Freestyle valve)].
AB - BACKGROUND: The purpose of the study is to assess the clinical and hemodynamic
performance of aortic valve replacement (AVR) with the Freestyle bioprosthesis.
METHODS: Twenty-one patients received AVR with a Freestyle aortic root bio
prosthesis between May 1998 and October 1999. Eighteen patients underwent AVR
with subcoronary method and three patients with aortic root (full root) method.
Patients were evaluated postoperatively at discharge by clinical examination and
color Doppler echocardiography. RESULTS: There was one death due to multi-organ
failure. No patients experienced valve deterioration, paravalvular leak,
unacceptable hemodynamic performance, nor thromboembolic event. Excellent
function is demonstrated by very low gradient (mean gradient 7.2 +/- 4.7 mmHg)
through aortic valve and no significant aortic regurgitation (none: 11,
trivial/mild: 10). All patients had been in New York Heart Association Functional
Class III and IV preoperatively, and after surgery, 17 patients were in Class I,
and 3 were in Class II. CONCLUSION: The Freestyle bioprosthesis has good clinical
and hemodynamic performance without Coumadin. Further follow-up is required to
evaluated valve durability.
PMID- 10770058
TI - [Aortic valve replacement with stentless bioprosthesis: operative methods and
pitfalls].
AB - Operative methods and pitfalls of aortic valve replacement using either Toronto
SPV and Freestyle prosthesis were described. Precise transverse aortotomy,
straight inflow-suture line, and outflow suture not obstructing coronary orifices
are the points for the standard procedure. For bicuspid aortic valves, care
should be taken for the anomaly of coronary orifices. Our experience with 24
consecutive cases indicated that oversizing of the prosthesis was possible in
stentless bioprosthesis.
PMID- 10770059
TI - [Aortic valve replacement using Medtronic Freestyle stentless porcine xenograft].
AB - We analyzed the left ventricular hemodynamic changes after aortic valve
replacement using Medtronic Freestyle stentless valve. Doppler echocardiograms
were performed at three weeks and three months after operation in twelve
patients. Both left ventricular end-diastolic volume (index) and left ventricular
end-systolic volume (index) were decreased respectively. Fractional shortening
were markedly increased from 21.4 +/- 7% to 31.8 +/- 3.8%, and left ventricular
mass index were markedly decreased from 194.3 +/- 25.3 g/m2 to 182.3 +/- 24.4
g/m2. Transvalvular pressure gradient measured by cardiac catheterization were
almost zero mmHg at three weeks after operation. No aortic regurgitation were
found in all cases. Good left ventricular remodeling were obtained so that we
believe this valve could be acceptable alternative for many surgeons. These
excellent results justify wider use of stentless valve.
PMID- 10770060
TI - [Efficacy of aortic valve replacement with freestyle stentless valve in patients
with aortic valve disease].
AB - Stentless porcine aortic bioprosthesis has several potential advantages over
conventional stented bioprosthesis. The Medtronic Freestyle aortic bioprosthesis,
a stentless design analogous to an aortic allograft, has zero-pressure-fixed
leaflets treated with an antimineralization agent, and has been shown to have
benefits of superior effective orifice area, excellent flow characteristics and
durability. To evaluate the early results for its efficacy in view of post
operative performance. The valve was implanted using the cylinder method, with
subcoronary, root-inclusion techniques or full root techniques. No patients
experienced any significant valvular regurgitation on echocardiography. The post
operative data of EDVI, ESVI and LVPWD decreased significantly as compared with
the pre-operative data while ejection fraction remained unchanged. The average
peak pressure gradient was 16.5 mmHg, and the average effective orifice area was
2.45 cm2. In conclusion, Freestyle stentless aortic bioprosthesis showed
excellent hemodynamic function. It seems to be suited for the older patient with
a small aortic annulus.
PMID- 10770061
TI - [Successful aortic root replacement for prosthetic valve endocarditis using the
freestyle stentless bioprosthesis: report of two cases].
AB - We report two cases of prosthetic valve endocarditis which were successfully
treated with aortic root replacement using the freestyle stentless bioprosthesis.
Prosthetic valve endocarditis occurred in two patients after aortic valve
replacement and modified Bentall operation, respectively. The aortic annulus was
severely damaged and left ventriculo-aortic discontinuity was found in both
cases. We used the freestyle stentless bioprosthesis, which fits well to the
destroyed aortic annulus with left ventriculo-aortic discontinuity, because of
its flexibility. Postoperative echocardiography revealed excellent hemodynamic
results in both cases. Although the long-term results obtained with the freestyle
stentless bioprosthesis, such as resistance to bacterial infection, have not been
reported, this prosthesis appears to be very useful for treatment of prosthetic
valve endocarditis. We expect that this prosthesis might be a option for PVE as
an alternative to a homograft.
PMID- 10770062
TI - [Hemodynamic assessment of the Carpentier-Edwards pericardial valve compared with
the St. Jude Medical valve in the aortic position using dobutamine-stress
echocardiography].
AB - To assess the hemodynamic performance of the prosthetic valve in the aortic
position, we examined dobutamine-stress echocardiography (DSE) to the patients
underwent AVR with CEP valve or SJM valve. In 23 mm size, there were no
significant differences between CEP group and SJM group in Peak velocity of the
aortic jet (PV), peak pressure gradient (PPG) and effective orifice area (EOA).
On the other hand, in 21 mm size, PV and PPG of the CEP group were significantly
lower than those of the SJM group after DSE. The EOA of the CEP group was
significantly larger than that of the SJM group after DSE. Our results suggest
that the hemodynamic function of the CEP valve is superior to that of the SJM
valve especially in small aortic annuli.
PMID- 10770063
TI - [Aortic valve reconstruction of aortic root repair].
AB - We report the choice of aortic valve reconstruction, surgical results and
postoperative results in 22 patients who underwent aortic root replacement
between June 1996 and October 1999. We chose the replacement using bio-prosthesis
in six patients over 65 years of age and valve preservation or replacement using
mechanical prosthesis in sixteen patients under 65 years of age. Ten patients
underwent valve replacement using mechanical prosthesis. There was one hospital
death and one late death. Six patients underwent valve replacement using bio
prosthesis. There was no hospital death and no late death. Six patients underwent
valve preservation. There was one hospital death. There was no event among five
patients in the mid-term follow-up, although a longer follow-up must be
necessary.
PMID- 10770064
TI - [Necessity of permanent anticoagulant therapy for isolated mitral valve
replacement with bioprosthetic heart valve to prevent the postoperative
thromboembolic complications].
AB - One hundred fifty four patients underwent isolated mitral valve replacement with
bioprosthetic heart valve at Hyogo Medical College Hospital from November 1973 to
December 1998. A porcine bioprosthetic valve was replaced in 82 patients (Hancock
43, Carpentier-Edwards 26, Hancock II 13) and pericardial bioprosthetic valve in
72 patients (Ionescue-Shiley 39, Carpentier-Edwards 33) with a mean follow-up of
1,410 patients-years. Their thromboembolism rates were also analyzed in linear
and actuarial term over the 15-year period. The incidence of thromboembolism rate
was 2.5%/pt.yr. Thromboembolic free rates for patients with anticoagulant therapy
were significantly decreased for patients without therapy. Thromboembolic free
rates for patients with atrial fibliration were also were significantly decreased
for patients with sinus rhythm because the patients with sinus rhythm were not on
anticoagulant therapy. In conclusion, it is necessary for the all patients to be
on anticoagulant therapy after mitral valve replacement with bioprosthetic
valves, even though patients with sinus rhythm.
PMID- 10770065
TI - [A case of right B2 hillar lung cancer treated by sleeve segmentectomy].
AB - A 47-year-old male, a heavy smoker, was referred to our hospital after Class IV
was detected by screening of sputum cytology. His chest X-ray film showed no
abnormalities, but bronchoscopy revealed a small nodular lesion at the orifice of
right B2. Squamous cell carcinoma was diagnosed by transbronchial biopsy. The
clinical stage was I (T1N0M0), and S2 sleeve segmentectomy with lymph node
dissection (R 2 b) was performed. The pathological stage was I (T1N0M0), and it
was confirmed as early hilar lung cancer. There were no post operative
complications and he is well without any evidence of recurrence 5 months after
surgery. It may well be considered that this segmental bronchoplastic procedure
is useful for cases with early stage squamous cell carcinoma of the segmental
bronchus to preserve pulmonary function.
PMID- 10770066
TI - [Primary mediastinal germ cell tumor: report of a case].
AB - Fourty-seven years old male was admitted to this hospital with the symptoms of
worsening cough and chest pain. An anterior mediastinal tumor, 13 cm in diameter,
was pointed out on chest X-ray. The tumor was diagnosed as primary mediastinal
germ cell tumor with mixed seminomatous and non-seminomatous elements due to
elevated serum AFP and beta HCG, and the pathological finding of needle biopsy
specimen. He underwent 3 courses of chemotherapy with BEP regimen, and following
surgical resection of the tumor, left upper lobectomy and partial resection of
pericardium via median sternotomy. Pathological diagnosis of the resected tumor
was mature cystic teratoma. For 9 months no recurrence of the tumor has been
observed.
PMID- 10770067
TI - Children are born as information seekers, "bright and dark sides of multimedia
for child development". Introduction.
PMID- 10770068
TI - Expanding concept of learning to learn.
PMID- 10770069
TI - Children in Japan and multimedia.
AB - Many parents in Japan today are very concerned and have daily problems with their
children over the following kind of issues concerning video games, multimedia,
and similar devices. 1) Is children's enthusiasm for video games actually harming
their growth (physically or mentally)? 2) Is there any way that video games can
help children in the future? For example, will playing these games help children
learn to use computers or develop their power of thought? 3) Will excessive
enthusiasm for TV games undermine our basic lifestyle? Is the time they spend
studying at home or playing outside actually decreasing? 4) Will the methods of
communication brought about by computers, pagers, and cellular phones weaken
human relations among children? 5) Will being immersed in a virtual world created
by computers result in a diminished sense of reality? The causes of this
uneasiness may be traced to parents' own anxieties and concerns about the
exceedingly rapid growth of the "information society" of today, together with the
fact that their children are directly caught up in the deluge of this information
and multimedia society. The development of media has coincided with the growth of
today's adults, but children are immersed in a media-filled environment from the
day they are born. In Japan, there are now children who can play video games
before even learning to write. No one can predict what kind of adults these
children will grow to be in the future, and it is fair to say that the most
parents and children in Japan are being tossed about on the waves of this
information explosion. At this international symposium, we hope to hear the many
views that are held around the world concerning children and multimedia.
PMID- 10770070
TI - Country report: Singapore.
PMID- 10770071
TI - Education in Australia.
AB - School-based adoption of Multimedia: An Australian Perspective. This paper will
look first at the work of Young Media Australia--a national community-based,
information, research, training and advocacy organization working in the field of
children, young people and mass media. The adoption rate of multi-media,
including information technologies, in school systems across Australia will then
be examined. Issues relating to the use of school-based multimedia, including the
internet, will also be identified.
PMID- 10770072
TI - Country report on multimedia and Internet for children and youth in Taiwan.
AB - The actions of Taiwan government for promoting information education have being
carried out since 1996. The main goal is to educate students of primary school
and high school about the basic information knowledge and the internet. The
actual actions will be described. There are many kind of multimedia CD titles in
Taiwan market right now. The major types of multimedia CD titles will be
discussed. And the difficulties of developing materials of CD titles will be
discussed.
PMID- 10770073
TI - Multimedia and children in Turkey.
AB - Multimedia will be regarded as essential tools for children to create their new
world. The effects of television on young children's life have been well studied.
Television differs, however, from other media, including the movies, in its
pervasive impact on children. Children spend more time watching television than
any other activity except sleeping. Overall 31% of children spent at least 4
hours a day watching television during weekday and 71.7% during weekend in
Turkey. Television's influence on children is a function of the length of time
they spend watching and the cumulative effect of what they see. Television may be
a cause as well as a solution for many serious childhood problems. Excessive
viewing of television has also been linked to aggressive behavior, violence,
childhood obesity. On the other hand, television may act as a socializing agent
and as a learning tool if the recommendations of American Academy of Pediatrics
is learned by pediatricians, parents and broadcasters. The use of home personal
computers in urban residence increased from 3.2% in 1993 to 6.5% by January 1998
in Turkey. Around 20% of computer households reported owing a modem. Internet has
been using only for 5 years in Turkey. Nearly 40% of computer households also
used CD-ROM equipment. The percentage of schools that have a computer laboratory
is only 2.64%. On the other hand, multimedia allows students to move away from a
uniform education for everyone to assert individual identity, liberalize
education and management. It seems likely that, within the next few years, most
of the countries with substantial internet infrastructure will use the internet
as the major medium for disseminating information, including information on
children. To prepare students for such a world demands that educational systems
make the best possible use of all knowledge and technologies currently available.
PMID- 10770074
TI - Introducing the Internet to primary schools in Japan: 100-School Networking
Project, NTT Konet Plan, and related projects.
PMID- 10770075
TI - The use of multimedia in the Childwatch International research network.
AB - The article describes the background and the activities in the Childwatch
International research network in using electronic communication. The network has
a core of 30 institutions world-wide that work together to establish Childwatch
International as a tool for international cooperation and for mutual support in
capacity enhancing within child research. One of the main objectives of
Childwatch is to develop overviews of the activities of central research
institutions within child research and to facilitate the flow of information
between the institutions. The information strategy of Childwatch has explicitly
aimed at taking advantage of the opportunities represented by modern electronic
communication technology. Childwatch launched the idea of establishing Children's
House in Cyberspace. Which is an electronic meeting place for those working for
and with children at the professional level, whether within research,
programming, planning, advocacy, legislation or policy-making.
PMID- 10770076
TI - Social indicators of child well-being and the World Wide Web: considering youth
as users.
PMID- 10770077
TI - Multimedia for edu-tainment of children in Asia: the case of television in seven
Asian countries.
PMID- 10770078
TI - Virtual reality in a children's hospital.
AB - We used virtual reality technology to improve the quality of life and amenity of
in-patients in a children's hospital. Children in the hospital could enjoy a zoo,
amusement park, and aquarium, in virtual. They played soccer, skiing and horse
riding in virtual. They could communicate with persons who were out of the
hospital and attend the school which they had gone to before entering hospital.
They played music with children who had been admitted to other children's
hospitals. By using this virtual technology, the quality of life of children who
suffered from psychological and physiological stress in the hospital greatly
improved. It is not only useful for their QOL but also for the healing of
illness. However, these methods are very rare. Our systemic in our children's
hospital is the first to be reported in Japan both software and hardware of
virtual reality technology to increase the QOL of sick children need further
development.
PMID- 10770079
TI - Virtual reality--current multimedia--the world of virtual reality for children.
AB - Some people go as far to say that the invention of virtual technology is
comparable to Columbus' discovery of the American continent. Nowadays, computers
are regarded as essential tools for children to explore their new world. It will
be interesting to observe and guide the growth of these children who have entered
into such a world filled with many possibilities.
PMID- 10770080
TI - Digital kids of the Heisei era: experiment at Toyonaka Bunka Kindergarten.
AB - I wonder what most people think when they hear of small children playing on
computers in kindergarten. One can almost hear the responses: "Why should
kindergarten children have to use computers?" Small children are using computers?
It's much too earlyl" "At kindergarten children should be singing, playing games,
and making mud pies!" A computer is the epitome of the artificial. If we really
make a mess of things, humans will become slaves to computers. What can they be
thinking, putting such things in kindergartens as a child's toy? Many people who
think in this way have never touched a computer, and it often seems the case that
these "emotional opponents" are opposed to them only because of their own
preconceptions. There is still a preconception that" a computer = a square
machine like a TV with lots of difficult-looking keys". Computers are now in
virtually all of the electronic appliances we use every day, refrigerators,
washing machines, vacuums and televisions, and we think nothing of it. We live
each day using computers, but only the "square" computer invites such contempt.
Why is this the case? On the other side, there are the "proactive endorsers", who
think "Computers have spread thus far in society and schools, so we must let
children become familiar with them from a very young age!" These people often
seem to want to teach everyone everything. There is much to know about the image
and use of computers. They seem to think that if adults don't teach them,
children won't understand anything. On this point, they are at the same level as
the "emotional opponents", in that they conceive of computers as being something
out of the ordinary.
PMID- 10770081
TI - Introduction of "Shinkenzemi 84 Net" project.
PMID- 10770082
TI - Multimedia unplugged: a workshop on learning designs at the neoMuseum, Japan.
AB - In Japan, we have a growing field called 'Information Education,' but people are
paying too much attention to computers and the internet. That's why I am
proposing unplugging the computer and thinking about the more essential aspects
of learning and information design. 'Unplugged' means that technology and
multimedia need not be limited to digital forms. Pencil-and-paper and traditional
'by hand' media also have important roles to play. In the Multimedia Unplugged
workshop, participants use different forms of expression and media, including
paper and styrofoam cubes, freeform construction kits and a wide variety of
everyday objects, like bamboo leaves and post-it papers. Through this workshop,
participants can understand that each medium has its own constraints and
opportunities, and have a change to rethink the roles of multimedia from new
perspectives. They can then replug and thus be able to choose appropriate media-
digital or physical or both--to express their ideas.
PMID- 10770083
TI - Designing, constructing and utilizing of new learning spaces: space as a place to
think with.
PMID- 10770084
TI - New tools for learning.
AB - In the last twenty-five years more has been learned about the human brain than in
the past history of mankind. Through the use of new technologies such as PET and
CAT scans and functional MRI's, it is now possible to see and learn much about
the human brain while it is in the process of thinking. The research of
neuroscientists, such as Marian Diamond, has demonstrated that the brain changes
physiologically as a result of learning and experience--for better or worse--and
that plasticity can continue throughout the lifespan. It appears that there are
particular kinds of environments that are most conducive to the development of
good mental equipment. They are positive, nurturing, stimulating, and encourage
action and interaction. Many of the most effective schools and training programs
have created such high-challenge low-threat environments. It is also very clear
that intelligence is not a static structure, but an open, dynamic system that can
continue to develop throughout life. This understanding is being utilized not
only in school systems but in the workplace, where training programs show that
even at the adult level people are able to develop their intelligence more fully.
Corporations such as Motorola have implemented programs in which they are
training their employees, managers, and executives to think, problem-solve and
create more effectively using strategies developed by such educational innovators
as Reuven Feurstein, J.P. Guilford, and Edward de Bono. A most recent development
is in the new kinds of technology that make it possible for people to take
responsibility for their own learning as they access and process information
through the internet, communicate with experts anywhere in the world, and use
software that facilitate higher order thinking and problem-solving. Computers are
in no way replacing teachers, but rather these new tools allow them to spend more
time being facilitators, mentors, and guides. As a result, teachers and students
are able more often to collaborate on creating new knowledge as well as mastering
the basics. As technology becomes more ubiquitous, there is growing recognition
of the importance of the arts in humanizing the curriculum. "More high-tech, more
need for high-touch" is becoming the by-word of many schools. They recognize that
the arts are not only culturally important and civilizing influences, but they
can facilitate the learning of almost any subject. I believe that these four
concepts--the plasticity of the brain, the modifiability of intelligence, the use
of technology as a powerful new tool for learning, and the renaissance of the
arts in education--have major implications specifically for educational systems
and generally for the future of our world. In this time of rapid change, leading
edge educational systems are equipping people with the ability to learn, unlearn,
and relearn continually. They are giving students meaningful opportunities to
apply what they have learned in order to turn information into knowledge. And--of
critical importance if any of this is to lead to a healthy future--they are
helping students to learn to use knowledge responsibly, ethically, and with
integrity. Furthermore, they are involving students in experiences that develop
compassion and altruism in the process of their education. Our complex world
urgently needs more people who have developed their fullest potential in mind,
body, and spirit.
PMID- 10770085
TI - Implications for the future.
PMID- 10770086
TI - Awareness of the earth and possibilities for new science education in the
Internet age.
AB - The internet as "the nervous system of global size" and multimedia technology
have changed our global experience radically and suggests possibilities of
entirely new approaches to the conventional education of sciences and the
environment. They are not merely the changes where printed text books are
converted into dynamic things with vivid appeal to our senses and information
about the world's museums and art galleries, digitalized and shared by all. If
the seismic activities occurring every day in various parts of the world can be
seen in real form directly through the internet by all the people of the world,
how will children's views of the earth change and how will their scientific
understanding improved? If there was a system whereby one could monitor, in real
time, how one member or others of the world net surf the global home pages, and
if one could follow the "moving" process on the internet, children would
certainly appreciate the presence of the internet as a global network of
information. The web site "Sensorium" (http://www.sensorium.org) was created by
us in an effort to put these live experiences of the internet into design.
Sensorium is not a site merely to digitalize and list the existing knowledge and
data. It is an experiment for the Digital Museum as a new "forum" where we may
experience and share a moment. It is also an attempt to create tools for science
and environment education which are only available on the network.
PMID- 10770087
TI - A quick overview of present technology in Japan.
PMID- 10770088
TI - Results of the Turkish congenital malformation survey.
AB - In order to acquire data about the incidence of congenital malformations in the
Turkish population, we recorded all livebirths and stillbirths at 22 university
hospitals between July 1993-July 1994. Congenital malformation incidence was 3.65
percent. Incidence of individual malformations were compatible with that reported
from other populations, with the exception of neural tube defects and cleft
palate which were found to be significantly frequent. Abnormal ultrasonographic
findings and disorders such as hypertension, diabetes mellitus and vaginal
bleeding during pregnancy were found to be valuable indicators for the presence
of congenital malformations in the fetus. Incidence of congenital malformations
was lower in the western Anatolian region. Variables such as maternal age,
education and employment were found to be risk factors for congenital
malformations.
PMID- 10770089
TI - Neural tube defects in Turkey: prevalence, distribution and risk factors.
AB - The aim of the study was to determine the prevalence rate and risk factors
relevant to neural tube defects (NTDs) in Turkey. All livebirths and stillbirths
recorded at the university hospitals throughout Turkey between July 1993-June
1994 were evaluated with respect to congenital anomalies. For each birth,
information was recorded about the child, the mother, the pregnancy and risk
factors. A total of 66 cases with a NTD were recorded in 21,907 births.
Prevalence rate of NTDs was 30.1 per 10,000 births. Of these 66 cases, 29 (43.9%)
were male and 37 (56.1%) female. Female/male ratio was 1.27. The ratio of spina
bifida/anencephaly is 1.20 for Turkey. Maternal illiteracy, maternal advanced age
and residence in northern or eastern regions of Turkey are shown to be risk
factors for having a baby with a NTD. The prevalence rate of NTDs is very high
for Turkey. Geographical distribution of NTDs in this country confirms a
relationship between the socioeconomic status and environmental factors for the
development of a NTD. The results of this study point to the importance
establishing a health policy to prevent neural tube defects in Turkey.
PMID- 10770090
TI - Psychiatric symptoms among Turkish adolescents.
AB - This research was planned to investigate psychiatric symptoms in a normal
adolescent population. Four hundred and thirty-four students were selected
randomly from three schools of different socioeconomic status. Symptom Check List
90-R was used to evaluate the psychiatric symptoms. The results were analyzed
considering the effects of age, gender and socioeconomic status. It was concluded
that being female, 15-16 years of age and having a lower socioeconomic status are
risk factors for developing psychiatric symptoms.
PMID- 10770091
TI - The impact of the sexual maturation stage on body mass index in adolescent girls.
AB - Body mass index (BMI) is used in the clinical assessment of adiposity in children
and adolescents. Population-based, race-specific and age-specific curves of BMI
for children and adolescents exist, but there are noknown sexual maturation-based
BMI curves. The aim of this study was to investigate the effects of pubertal
development (assessed according to the Tanner breast stage) on BMI in adolescent
girls in a cross-sectional study. The study group comprised 167 healthy girls,
between the ages of nine and 16 years, attending school near a hospital in
Gerede, Bolu. A significant positive correlation was found between the Tanner
stage of breast development and BMI (r = 0.79, p < 0.001). Age also had a
significant influence on BMI (r = 0.69, p < 0.001). After controlling the effects
of age, BMI was highly correlated with weight (r = 0.82, p < 0.001) and the
Tanner breast stage (r = 0.49, p < 0.001), but not with height. The correlation
between BMI and the sexual stage was also found to increase with increasing age.
But when breast development was taken as a control parameter, BMI was not
statistically associated with age or height. As a result, there was a significant
variation in BMI with the Tanner breast stage in addition to the well known
change with increasing age in adolescent girls. Developmental differences
occurring in the same age may require that BMI be evaluated only within the same
sexual stages in adolescence. This study indicates that the curves of BMI need to
take into account the sexual maturation stage of adolescents.
PMID- 10770092
TI - Changes of hemostatic factors in patients with hemoglobinopathies.
AB - In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII),
prothrombin fragment 1+2(PF1,2), thrombin-antithrombin III complex (TAT), von
Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 13 patients
with beta thalassemia intermedia (TI) not requiring transfusion, six patients
with sickle cell disease (SCD), and seven patients with HbS-beta thalassemia (S
BT) who were not in crisis. These hemostatic parameters were also studied in 12
healthy children assigned as a control group. Protein C and Protein S (PC-PS)
were found to be decreased in TI patients and normal in S-BT patients. PC was
decreased in SCD patients. In the patients with TI and SCD, the mean PF1,2 level
was elevated, whereas the TAT level was not statistically different from that of
the control group. These results suggested that in patients with
hemoglobinopathies: a) decreased natural anticoagulants and b) enhanced
procoagulant activation have been encountered. Other unexpected and interesting
results of this study are the decreased vWF and elevated HCFII levels in all
three patient groups.
PMID- 10770093
TI - Profile of bone marrow iron stores in childhood iron deficiency anemia.
AB - To demonstrate the importance of bone marrow iron stores, we examined the
complete hemogram, serum iron (SI), serum iron-binding capacity (SIBC),
transferrin saturation (TS), serum ferritin and bone-marrow-stored iron in 31
children with iron deficiency (ID). The ages of the patients ranged from one to
14 years (mean 3.7 +/- 3.9). Laboratory findings of the 31 patients were as
follows: hemoglobin (Hb) 8.5 +/- 2.4 g/dl, hematocrit (Hct) 27.8 +/- 6.3 percent,
mean corpuscular volume (MCV) 58.6 +/- 8.6 fl, red blood cell count (RBC) 4 +/-
0.8 10(12)/L, red cell distribution width (RDW) 19.3 +/- 4.9, SI 17.2 +/- 9.3
microg/dl, SIBC 311 +/- 50.5 microg/dl, TS 5.5 +/- 2.8 percent and ferritin 6.7
+/- 7.3 ng/dl. In the bone marrow smears with iron stains, all patients' scores
were zero for iron stores, which shows that bone-marrow-stored iron in childhood
is easily affected. Because of the traumatic effect of bone marrow aspiration, it
is recommended that it not be done routinely. The diagnosis of ID could be
especially difficult in patients with low SI levels but normal SIBC levels and in
patients with chronic inflammatory diseases. In those conditions, illustration of
bone marrow stores could be of particular assistance for diagnosis of iron
deficiency.
PMID- 10770094
TI - Increased gastric juice leukotriene B4, C4 and E4 concentrations in children with
Helicobacter pylori colonization.
AB - During recent years, the role of inflammatory lipid mediators in the
pathophysiology of Helicobacter pylori (H. pylori) infections has been
investigated in several studies. The concentrations of leukotrienes (LTs) in
gastric juice from H. pylori positive (n = 13) and negative (n = 18) children
with recurrent abdominal pain were studies in order to determine whether these
lipid inflammatory mediators are involved in local and systemic biological
actions. Gastric juice samples and biopsy specimens of mucosa were obtained
endoscopically from 31 patients with recurrent abdominal pain for assessment of
LTs and histopathological examination. In this study, all children with recurrent
abdominal pain were investigated by rapid urease test and histological assessment
for H. pylori colonization. Leukotriene levels were measured by high performance
liquid chromatography (HPLC) and radioimmunoassay (RIA) in gastric juice samples.
Gastric juice LTB4, LTC4, and LT4 levels were significantly higher in patients
with H. pylori colonization than in children without H. pylori colonization.
These results indicate that increased gastric content of proinflammatory
mediators (LTB4, LTC4, and LT4) may be related to the pathogenesis of H. pylori
associated gastritis.
PMID- 10770095
TI - Percutaneous transvenous balloon mitral valvuloplasty: mid-term results in
adolescents.
AB - Six patients with mitral valve stenosis underwent percutaneous balloon mitral
valvuloplasty (PBMV) in our department between November 1992 and December 1997.
Five patients had rheumatic mitral valve stenosis and one had congenital mitral
valve stenosis and Eisenmenger's syndrome with patent ductus arteriosus (PDA).
Functional status before PBMV was class IV in two patients, class III in two
patients, and class II-III in two patients, as classified by the New York Heart
Association (NYHA). The mean diastolic pressure gradient across the mitral valve
measured during heart catheterization before and immediately after PBMV was 18.8
+/- 10.42 and 9.4 +/- 7.7 mmHg, respectively (p < 0.01). The patients were
followed for a mean period of 36.6 +/- 8.5 months (range 12 to 72 months) after
the procedure. During follow-up, post PBMV mean diastolic transmitral gradient
measured by color Doppler echocardiography decreased from 19.3 +/- 11.16 to 7.43
+/- 7.3 mmHg (p < 0.01) and the mitral valve area increased from 1.09 +/- 0.7 to
3.1 +/- 0.9 cm2 (p < 0.002). Functional capacity showed improvement to NYHA class
I in four patients, to class II-III in the patient with congenital mitral valve
stenosis and Eisenmenger's syndrome with PDA and to class II in one patient with
severe mitral valve calcification in whom restenosis occurred three years after
PBMV. Percutaneous balloon mitral valvuloplasty PBMV can achieve very good short-
and mid-term results in relieving symptomatic rheumatic mitral valve stenosis.
PMID- 10770096
TI - The accuracy of antenatal fetal echocardiography.
AB - The purpose of this study was to evaluate our experience with a group of patients
who were either selected by us or referred by an obstetrician or geneticist with
the indication of fetal echocardiography. This prospective study was done on 128
cases between 1996-1998. Maternal age range was between 16 and 41 years (mean:
28.79). Gestational age range was between 15 and 37 weeks (mean: 26). In the
postnatal period the newborn babies were reevaluated for cardiovascular system
abnormalities by physical examination, ECG, telecardiogram and, if it was
necessary, by echocardiography, cardiac catheterization and angiography. By
comparing prenatal and postnatal findings, sensitivity and specificity of fetal
echocardiographic diagnosis were determined. Among the total cases studied, nine
had major congenital heart disease in postnatal evaluation. Two cases had false
negative; there were no false positive prenatal diagnoses. Sensitivity of
echocardiographic diagnosis was 100 percent and specificity 78 percent. Three
patients had paroxysmal atrial tachycardia and two atrioventricular block We
concluded that the fetal echocardiography is a very useful technique in the
evaluation of the fetal cardiovascular system. However, awkward fetal position,
severe maternal obesity, and technologic insufficiency of the echo machine may
result in unfavorable scanning conditions. Minuteness of anomaly may also result
in a false negative prenatal evaluation.
PMID- 10770097
TI - Ultrastructural findings of bone marrow in a case with malignant osteopetrosis
following successful allogeneic bone marrow transplantation.
AB - A nine-month-old female patient suffering from malignant osteopetrosis was
evaluated by light and transmission electron microscopic study before and
following allogeneic bone marrow transplantation (BMT). Bone marrow specimens
were obtained from iliac crest biopsies. Before BMT, the bone marrow had an
irregular appearance and was filled with bridging bony trabeculae devoid of
cells. Following BMT, the marrow had an almost normal appearance with no
myelofibrosis and a relatively regular distribution of hematopoletic cells. The
osteocytes were visible in their lacunae in the bone matrix. Presence of bone
resorbing and bone forming cell together demonstrated that the bone was beginning
to gain its normal dynamic structure. These findings were in accordance with the
clinical, laboratory and radiological data which showed the beneficial effect of
the therapy.
PMID- 10770099
TI - Benign rheumatoid nodules of childhood.
AB - The nodules associated with rheumatoid arthritis and rheumatic fever appear with
other signs of active rheumatic disease. Rheumatoid nodule-like lesions
irrelevant to rheumatoid disease occasionally occur in children who are well and
have no complaints associated with rheumatoid diseases. Laboratory tests are
normal. Children with benign rheumatoid nodule are not at increased risk for
rheumatic disease. No therapy or prophylaxis is required. We present a two-year
old girl with a subcutaneous nodule on the right pretibial region who was
diagnosed with clinical and histological findings.
PMID- 10770098
TI - Fatal acidosis in a neonate with Pearson syndrome.
AB - We report a neonate who presented with hypotonia, hypoglycemia, and severe lactic
acidosis. The patient's acidosis did not respond to bicarbonate replacement and
dialysis. Postmortem liver samples revealed portal dilatation, fibrosis,
canalicular proliferation, cholestasis, and hepatocellular hemosiderosis.
Vacuolization of bone marrow precursors suggested a diagnosis of Pearson
syndrome. A common mitochondrial DNA deletion of 4,978 bp was found. We emphasize
that Pearson syndrome should be considered in neonates with lactic acidosis
despite absence of anemia.
PMID- 10770100
TI - Gastric antral stricture in a patient with chronic granulomatous disease.
AB - Chronic granulomatous disease (CGD) is a rare disorder of phagocytic cell
oxidative metabolism. Patients have recurrent infections with catalase-positive
organisms and granulomatous lesions throughout the body. Gastric antrum can be an
occult site of involvement. We describe a four-year old boy with chronic
granulomatous disease who was admitted with the complaints of persistent vomiting
and weight loss. Gastric antral narrowing was diagnosed according to radiological
findings. Treatment with steroid and antibiotics yielded a good clinical response
in 15 days with a relief of the obstruction. This case report emphasizes the
beneficial effect of this form of therapy in preventing life-threatening
obstruction of vital organs in CGD.
PMID- 10770101
TI - Tumoral calcinosis: a case report.
AB - Tumoral calcinosis is a rare disorder with the calcified masses in subcutaneous
tissues. We report herein a nine-year-old girl, in whom the calcified lesions
bilaterally involved the soft tissues in the anterior part of the knee joint.
Serum calcium and phosphorus levels were in normal ranges and there was no family
history. Surgical excision was performed and recurrence was not observed in early
follow-up. Review of the literature shows that only clinical and radiological
appearance of tumoral calcinosis are generally agreed while its epidemiology,
etiology and treatment are still under discussion.
PMID- 10770102
TI - Eosinophilic fasciitis--progression to linear scleroderma: a case report.
AB - Eosinophilic fasciitis is a rare disease in children. Although changes similar to
linear scleroderma have been reported, the outcome is usually good. In this
report, a 10-year-old boy who developed eosinophilic fasciitis without a good
response to steroids is presented. He progressed to linear scleroderma within
months. Our case reinforces the hypothesis that eosinophilic fasciitis may be an
early manifestation or a variant of localized scleroderma similar to the other
cases in the literature.
PMID- 10770103
TI - Sacroiliitis in familial Mediterranean fever: an unusual presentation in
childhood.
AB - Familial Mediterranean fever (FMF) is an autosomal recessively transmitted
disease characterized by attacks of fever and serositis. The course of arthritis,
which is a common manifestation of FMF, is generally benign. Sacroiliitis due to
FMF has been reported by several authors, but all the patients described so far
had roentgenographic abnormalities, and most of them were adult cases. Here we
report the youngest FMF patient with sacroiliitis without any abnormality on
sacroiliac x-ray. She is also the first FMF patient in whom sacroiliac
involvement was diagnosed by computed tomography (CT) in childhood. It is
concluded that CT is a useful technique for the early diagnosis of destructive
arthritis in FMF patients even in early childhood.
PMID- 10770104
TI - Respiratory distress due to esophageal perforation caused by ball point
ingestion.
AB - A 15-month-old girl who developed respiratory distress which persisted for three
days prior to admission demonstrated pleural effusion on the chest x-ray which
was determined to be due to esophageal perforation caused by the ingestion of a
ball point. A gastrotomy was performed to extract the ball point. A gastrostomy
was performed and a chest tube was inserted. The esophagus was normal
radiologically within one month. Foreign body ingestion may cause esophageal
perforation in childhood. If it goes unnoticed and a diagnosis is delayed, there
is danger of the more hazardous development of mediastinitis. It is important
that a child with respiratory distress also be evaluated for esophageal foreign
body ingestion.
PMID- 10770105
TI - Torsade de pointes associated with encephalitis.
AB - Torsade de pointes is a polymorphic ventricular tachycardia. Causes of torsade de
pointes are well described. Although intracranial disease can produce dramatic
electrocardiographic (ECG) changes, we are not aware of previous cases with
torsade de pointes and encephalitis. We report a case with encephalitis who
developed torsade de pointes, and was treated with temporary ventricular pacing
and magnesium infusion.
PMID- 10770106
TI - Scimitar syndrome with absence of the right pulmonary artery: a case report.
AB - We report a two-year-old female child with scimitar syndrome associated with
absent pulmonary artery but with normal pulmonary artery pressure although
several collaterals originated from the abdominal aorta to the right lung. To our
knowledge, this is the fifth case with an absent pulmonary artery. Our case also
had microphthalmia, an association not previously described in scimitar syndrome.
PMID- 10770107
TI - Vascular ring formed by right aortic arch with aberrant left subclavian artery
and left ligamentum arteriosum: a rare cause of respiratory distress in newborn
infants.
AB - Vascular ring, in which the trachea and esophagus are completely surrounded by
vascular structures, is one of the causes of respiratory distress in children.
Right aortic arch with aberrant left subclavian artery is a common aortic arch
anomaly; however, respiratory distress due to vascular ring is seldom associated
with this anomaly. We report herein a newborn infant treated surgically because
of severe respiratory distress caused by vascular ring formed by right aortic
arch with aberrant left subclavian artery and left ligamentum arteriosum. As
laryngomalacia was first thought to be the reason for respiratory distress, we
suggest that patients with respiratory distress diagnosed with laryngomalacia be
evaluated for possible vascular ring.
PMID- 10770108
TI - Prevalence of asthma symptoms among Turkish Cypriot schoolchildren.
AB - We assessed the prevalence of symptoms suggestive of asthma in Turkish Cypriot
schoolchildren and the associated risk factors using a slightly modified version
of the ISAAC (International Study of Asthma and Allergies in Childhood)
questionnaire. The questionnaire and questions regarding risk factors were issued
to the parents of 2,822 children aged six to 14 years. The response rate was 89.6
percent. The cumulative and 12-month prevalence of wheezing were 14.7 and 4.8
percent, respectively. The prevalence of physician-diagnosed asthma was 11.4
percent. Family history of atopy was the strongest risk factor for "ever
wheezing" (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.52-1.92) and
physician-diagnosed asthma (OR 1.71, CI 1.53-1.93). This study demonstrates that
symptoms suggestive of asthma are quite common and constitute a major health
problem in Northern Cyprus.
PMID- 10770109
TI - Safety, tolerability and immunogenicity of a Haemophilus influenzae type b
vaccine containing aluminum phosphate adjuvant administered at 2, 3 and 4 months
of age.
AB - The primary aim of this study was to assess the tolerability and immunogenicity
of a new Haemophilus influenzae type b (Hib)/AlPO4 (CHIRON, SpA) vaccine, in two
month-old healthy infants. Twenty-three subjects were enrolled and administered
the new Hib vaccine containing AlPO4 adjuvant at two, three and four months of
age concomitantly with diphtheria-pertussis-tetanus (DPT) and hepatitis B
vaccines according to the local program. Children were observed for 30 minutes
after each immunization for any immediate local and systemic reactions. An active
surveillance for side effects was performed on the 2nd and 7th days following
each immunization by telephone. Families also filled out diaries for the first
seven days. From the 2nd day to the next immunization only data about adverse
events necessitating a physician's visit or about serious adverse events were
collected. Blood samples were obtained before the first immunization and one
month after the third dose for evaluation of anti-polyribosylribitol phosphate
(PRP) antibody response. Local reactions at the Hib site were mild and less
frequent compared to those observed at the DPT site. Systemic reactions noted
after the three immunizations were fever in 70 percent, irritability in 48
percent, persistent crying in 26 percent, change in eating habits in 22 percent,
diarrhea in 17 percent, sleepiness in 17 percent, vomiting in 9 percent, and
unusual crying in 4 percent of the cases. There was no serious adverse event. One
hundred percent and 95 percent of children achieved an anti-PRP antibody response
over 0.15 microg/ml and 1.0 microg/ml, respectively. The geometric mean titer was
15 microg/ml and the geometric mean ratio 84. It was concluded that the new
(Hib)/AlPO4 vaccine is safe and well tolerated, and induced a good PRP antibody
response in healthy two-month-old infants.
PMID- 10770110
TI - Neonatal outcome following early onset preterm premature rupture of the membranes
-a case controlled study.
AB - A case-controlled study was performed to determine whether preterm premature
rupture of the membranes (PPROM), particularly if occurring in the second
trimester, increased the duration of ventilatory support or hospital admission.
Infants born after membrane rupture of at least 24 hours duration and prior to 37
weeks of gestation were identified. It was possible to match for gestational age
and birthweight 40 PPROM infants, 15 of whom had onset of rupture of the
membranes (ROM) prior to 27 weeks of gestation, with a control (an infant whose
mother had not suffered PPROM). A greater proportion of the mothers of the PPROM
infants had received antenatal steroids (p<0.01), had an antepartum hemorrhage
(p=0.06) or delivered vaginally (p<0.02). More PPROM infants had pulmonary
hypoplasia (p<0.03) or infection (p<0.01). Overall, however, and if only those
matched pairs where membrane rupture had occurred prior to 27 weeks of gestation
were considered, there were no statistically significant differences in the
duration of ventilatory support or hospital admission. Step-wise regression
analysis confirmed that in the study population overall and in the matched pairs
where membrane rupture had occurred at less than 27 weeks of gestation, neither
the duration of ventilation nor hospital admission significantly related to
PPROM. These findings have implications when counselling parents.
PMID- 10770111
TI - Relationship between high leukocyte count and cell size in childhood acute
myeloblastic leukemia.
AB - In order to determine the significance of cell size together with high leukocyte
count (>30x10(9)/L) in acute myeloblastic leukemia (AML), we evaluated the
percentages of small, medium and large cells in 33 children with AML. All of the
10 patients with a high leukocyte count and 14 of the 23 patients with a low
leukocyte count (<30x10(9)/L) died or experienced a relapse within the first
year. The mean small cell percentage of patients with high leukocyte counts was
significantly lower than that of patients with low leukocyte counts (p<0.05). The
percentages of small, medium and large cells of patients with high leukocyte
counts and of patients with low leukocyte counts who died or experienced a
relapse within the first year were similar. The percentage of medium cells of
patients with high leukocyte counts was significantly higher than that of
surviving patients with low leukocyte counts (p<0.05). The mean percentages of
small, medium and large cells were similar in patients who died or experienced a
relapse and surviving patients with low leukocyte count. We conclude that cell
size has prognostic significance when the leukocyte count at admission is over
30x10(9)/L, although confirmation seems necessary with a larger population of
patients.
PMID- 10770112
TI - Serum leptin levels during childhood and adolescence: relationship with age, sex,
adiposity and puberty.
AB - We studied serum leptin levels in 189 healthy children to evaluate related
factors during childhood and adolescence. Leptin correlated with body mass index
(BMI), triceps skinfold thickness (p<0.001) and body weight (p<0.01). Obese
children and girls had higher leptin levels than non-obese children and boys,
respectively (p<0.001). In girls, leptin correlated positively with age, skinfold
thickness and BMI (p<0.001). In boys, leptin correlated negatively with age
(p<0.001) and positively with skinfold thickness (p<0.05). Prepubertal boys had
higher leptin levels than prepubertal girls and pubertal boys (p<0.05). Pubertal
girls had higher leptin levels than prepubertal girls and pubertal boys
(p<0.001). Leptin levels in girls were higher at Tanner stages 4 and 5 than at
stage 1 (p<0.001). In conclusion, serum leptin levels are related with adiposity,
have obviously age-related gender differences during childhood and adolescence,
and may be involved in the maturation of reproductive capacity.
PMID- 10770113
TI - Blood levels of leukotrienes (LTC4, D4, E4, B4) and synthesis of leukotriene B4
by peripheral leukocytes in children with acute A and B hepatitis.
AB - Leukotrienes (LTs) are cell-membrane derived lipid inflammatory mediators,
synthesized and eliminated by the liver. LTs have effects on liver cells in some
pathological conditions. In this study, we measured plasma endogenous and
liberated leukotriene (LT) concentration in peripheral blood leukocytes
stimulated in vitro by the calcium ionophore (CaA23187) and platelet-activating
factor (PAF). Production of LTs was measured in type A (n=37) and type B (n=10)
acute hepatitis patients and control subjects (n=10). LTs levels were measured by
high performance liquid chromatography (HPLC) and radioimmunoassay (RIA). The
concentration of LTB4 measured in plasma and stimulated peripheral blood
leukocyte supernatants of children with hepatitis A infection was found to be
statistically elevated and in positive correlation with serum alanine
aminotransferase (ALT) levels. In plasma samples of hepatitis B patients, LTC4
and LTE4 were measured in significantly elevated concentrations. These results
suggest that LTB4 may be a critical mediator of hepatitis A virus-induced
hepatocellular injury.
PMID- 10770114
TI - Autoimmune hemolytic anemia with warm antibodies in children: retrospective
analysis of 51 cases.
AB - In this paper, research based on 51 children with a positive antiglobulin test is
presented. Eighteen of the children had acute anemia and 33 had chronic anemia.
Two clinical patterns were distinguished: an acute transient type and a prolonged
chronic type. Corticosteroid therapy was effective in all acute cases but its
results were variable in the chronic cases. The acute form was more frequent in
young children, while chronic autoimmune hemolytic anemia (AIHA) occurred mainly
among children at puberty. In the chronic form of the disease, it was sometimes
necessary to add immunosuppressive drugs and in two cases to perform a
splenectomy.
PMID- 10770115
TI - CEA, CA125 and CA19-9 levels in congenital gastrointestinal anomalies.
AB - Preoperative and postoperative serum samples of 35 patients with different
congenital gastrointestinal anomalies were analyzed for the markers CEA, CA 125
and 19-9 by immunoradiometric assay during a period of three years. The majority
of the anomalies were aganglionic megacolon and hypertrophic pyloric stenosis. CA
125 and CA 19-9 were likely to indicate logistic model probabilities for babies
with anomalies, while CEA was not (F=35.78, p<0.05 for CA CA 125 and F=4.36,
p<0.05 for CA 19-9). Probability of no congenital anomaly for babies was: p
(Normal)=e4.41-0.13CA125 - 0.05CA19-9/1+e4.41-0.13CA125- 0.05CA19-9 Using CA 125
as a marker, babies with congenital anomalies were determined with 83.3 percent
probability (F= 11.33, p<0.05). On the other hand, it was not possible to predict
the type of anomaly with these three markers. CEA, CA 125 and CA 19-9 seem to be
prognostic variables associated with congenital anomalies. These biological
markers provide information that can be incorporated into the diagnosis of
anomalies but without doubt results of markers should be supported by clinical
findings.
PMID- 10770116
TI - Four different hernias are encountered in the anterior part of the diaphragm.
AB - A retrospective clinical study was performed to evaluate the hernias encountered
in the anterior part of the diaphragm. Twenty patients (14 males, 6 females; aged
7 days-7 years) with hernias located in the anterior part of the diaphragm who
were treated surgically formed the study group. The exact locations, contents and
additional malformations were evaluated. The locations were parasternal in 14 and
retrosternal in six. Parasternal locations were the right side in 11, left side
in two and bilateral in one patient. Three patients had trisomy 21 syndrome. A
sac was presented in all cases and included the colon in 12 patients. A patient
with retrosternal location also had trisomy 21 syndrome. The patients with
retrosternal hernias also presented with sacs, and the colon was the most
commonly included viscus. In the presented series, no intrapericardial
herniations or anteromedial defects were encountered. Comparison of previously
reported patients and the present series suggests that the anterior part of the
diaphragm hosts various hernias of congenital origin in its different locations.
According to the exact location and the presence or absence of sacs, four
different types of hernias occur in this area: retrosternal hernias with a sac,
intrapericardial herniation, and parasternal and anteromedial hernias with either
unilateral or bilateral involvements. Since four different hernias were
distinguished, the term Morgagni hernia does not include or define all the
hernias of the anterior part of the diaphragm. We believe they should, therefore
be designated according to the location and presence or absence of a sac.
PMID- 10770117
TI - Hemostatic system in early respiratory distress syndrome: reduced fibrinolytic
state?
AB - Previous studies suggest that there is a systemic activation of clotting and
fibrinolysis in preterm infants with advanced respiratory distress syndrome
(RDS). However, there are no data on the hemostatic status in the early stages of
the disease; therefore, we studied some of the hemostatic parameters in these
patients and made several studies at different times in preterm infants who did
or did not develop RDS, using similar protocols. We found normal plasma
fibrinogen, protein C, protein S, C4b-binding protein, thrombomodulin,
antithrombin III, thrombin-antithrombin III complex, prothrombin fragment 1.2,
plasminogen, tissue plasminogen activator, alpha-1 antitrypsin, alpha-2
macroglobulin and protein Z. However, lower D-dimer and higher plasminogen
activator inhibitor and von Willebrand factor antigen levels were found within
six hours of life in infants who later developed RDS compared to the control
group. These findings suggest that disseminated intravascular coagulation is not
prominent in the early stages of RDS. Moreover, reduced D-dimer and increased
plasminogen activator inhibitor and von Willebrand factor antigen levels are
probably related to the abnormalities in the fibrinolytic mechanism due to lung
damage in RDS, but further studies are needed to show their pathogenic
significance in RDS.
PMID- 10770119
TI - Neurological crisis mimicking acute pancreatitis in tyrosinemia type I.
AB - Hereditary tyrosinemia results from an inborn error in the final step of tyrosine
metabolism. Neurological manifestations have been reported in nearly half of
patients during illness to have characteristics of altered consciousness,
weakness, anorexia, vomiting, and pain in the extremities and abdomen. His
physical findings and laboratory results pointed out acute pancreatitis. There
have been some reports of acute and chronic pancreatitis in patients with
metabolic diseases; however, this is the first case with tyrosinemia type I who
exhibited clinical and biochemical findings of acute pancreatitis during
neurological crisis. The presented case suggests the possibility that the
pancreas is affected in neurological crisis. The determination of amylase
concentration both in serum and urine samples of further cases will clarity the
association between pancreatitis and neurological crisis.
PMID- 10770118
TI - Congenital microvillus atrophy in a 4-month-old girl.
AB - Congenital microvillus atrophy is a severe generalized enteropathy with
ultrastructural abnormalities of the intestinal brush border. It is a rather new
clinicopathological entity which needs to be differentiated from other
enteropathies within the spectrum of intractable diarrhea of infancy. The
presented case was a four-month-old girl with a chronic, intractable diarrhea,
beginning at birth. The diagnosis was established only after the electron
microscopic examination of small intestinal mucosa which revealed the
characteristic features of the disease. Congenital microvillus atrophy is a rare
autosomal recessively inherited disorder and bowel transplantation becomes a
realistic option of treatment. Therefore, it should be specifically considered in
the differential diagnosis of chronic intractable diarrhea of infancy.
PMID- 10770120
TI - MRI of fibromatosis colli.
AB - Magnetic resonance imaging (MRI) appearance of fibromatosis colli has been
reported in only two cases in the literature. We herein describe the MRI findings
in a case of fibromatosis colli: the signal intensity of the fusiform mass on T2
weighted images was slightly less than on T1 weighted images, consistent with the
presence of some fibrous tissue within the muscle mass.
PMID- 10770121
TI - A case with acute leukemia presenting with cardiac tamponade.
AB - Pericardial effusions and cardiac tamponade are rare and severe complications of
leukemia. They often develop during the radiation therapy, chemotherapy, or
infections in the course of leukemia. However, some cases present with
pericardial effusion and tamponade. We report a three-year-old girl who was
admitted with cardiac tamponade and needed urgent pericardiocentesis. Clinical
evaluation and laboratory results revealed myeloid markered-T cell acute
lymphoblastic leukemia (ALL) and pericardial invasion. She is the youngest
patient with cardiac tamponade who was diagnosed acute lymphoblastic leukemia in
the English-language literature.
PMID- 10770122
TI - A case of hemophilia A associated with Hodgkin's disease.
AB - Lymphoreticular malignancies are more common in patients with hemophilia, but it
is usually attributed to human immunodeficiency virus (HIV) infection associated
with repeated use of blood products. However, there are a couple of hemophiliac
patients with malignancies but without HIV infection in the literature. We report
a case of a hemophiliac patients who had Hodgkin's disease at 2.3 years old
without any congenital or acquired immunodeficiency and without use of any blood
products. This patient showed that malignancy can develop in hemophiliacs without
HIV infection, but further studies are needed to clarify whether hemophiliacs are
more susceptible to malignancies.
PMID- 10770124
TI - Bronchiectasis due to ciliary aplasia in Turner's syndrome.
AB - A seven-year-old girl with Turner's syndrome, who suffered from recurrent
respiratory system infections since birth, was investigated to determine the
etiology of bronchiectasis. Electron microscopy of recurrent nasal biopsy
specimens revealed ciliary aplasia. Ciliary aplasia in Turner's syndrome, has not
previously been reported.
PMID- 10770123
TI - Cardiac dysrhythmia that simulates seizure disorder in two children.
AB - Cardiac dysrhythmia can present signs and symptoms of a seizure disorder and
sometimes they are clinically indistinguishable. We present two children with a
presumed seizure disorder but also with an underlying and associated cardiac
problem. Therefore, we suggest that both conditions must be considered
concomitantly, and that each patient with a newly diagnosed seizure disorder
requires both neurological and cardiological evaluation.
PMID- 10770125
TI - Two female siblings from Turkey with Langer mesomelic dysplasia (homozygous Leri
Weill dyschondrosteosis syndrome).
AB - Leri-Weill dyschondrosteosis is an autosomal dominant syndrome of which the
characteristic features are mild-to-moderate shortness of stature and Madelung
deformity of the wrist. The homozygous state of the gene for Leri-Weill syndrome
causes Langer mesomelic dysplasia which is characterized mainly by shortening of
the long tubular bones, more markedly in the middle than in the proximal and
distal segment of the extremities. In this paper, we present two sisters with
Langer mesomelic dysplasia (12 years and 6 months of age, respectively), from
consanguineous parents. The mother of our cases had Madelung deformity. Father,
mother and grandmother also had a slight deformity of both forearms.
Unfortunately, despite the well documented case of the older sister with Langer
mesomelic type dysplasia, the first and second trimester ultrasonographies of the
younger sister were performed by inexperienced staff of a local urban hospital
and the prenatal diagnosis of this case was not made. In this paper, we also
discuss the prenatal diagnosis of Langer type mesomelic dysplasia.
PMID- 10770126
TI - Hepatitis as the presenting symptom of childhood systemic lupus erythematosus.
AB - We report in this article a girl with an initial diagnosis of autoimmune
hepatitis who developed full-blown systemic lupus erythematosus (SLE) at her two
years follow-up. She was formerly considered as HBV-related chronic active
hepatitis but due to the persistence of elevated liver enzymes, the reversal of
the albumin and globulin ratio and abnormal HBV serology, she was later diagnosed
as autoimmune hepatitis. With the clinical findings of arthritis, arthralgia and
malar rash and supported by results of laboratory tests, she was diagnosed as a
case of unusual SLE presenting with autoimmune hepatitis. We conclude, therefore,
that each patient with a diagnosis of autoimmune hepatitis in childhood who
exhibits abnormal HBV serology must be evaluated for a possible diagnosis of SLE.
PMID- 10770127
TI - Psoriasis in a patient with neurofibromatosis.
AB - A seven-year-old boy with neurofibromatosis who developed scalp psoriasis is
presented. The clinical evaluation of the patient revealed multiple cafe au lait
spots, axillary freckling, bilateral Lisch nodules and a psoriatic plaque on his
scalp. Though there is no known direct relationship between neurofibromatosis and
psoriasis, one is suggested in this patient, possibly related to a common genetic
defect.
PMID- 10770128
TI - The old man's friend.
PMID- 10770129
TI - Effects of mental stress in patients with coronary artery disease: evidence and
clinical implications.
PMID- 10770130
TI - Microbicides: ideas flourish, money to follow?
PMID- 10770131
TI - Statins help--if they're used.
PMID- 10770132
TI - Merits, flaws of live virus flu vaccine debated.
PMID- 10770133
TI - From the Surgeon General. Food safety: a growing global health problem.
PMID- 10770134
TI - From the Centers for Disease Control and Prevention. Preliminary Foodnet data on
the incidence of foodborne illnesses--selected sites, United States, 1999.
PMID- 10770135
TI - From the Centers for Disease Control and Prevention. Rubella among Hispanic
adults--Kansas, 1998, and Nebraska, 1999.
PMID- 10770136
TI - Dietary fiber and weight gain.
PMID- 10770137
TI - Dietary fiber and weight gain.
PMID- 10770138
TI - Adenoidectomy and adenotonsillectomy for recurrent otitis media.
PMID- 10770139
TI - Adenoidectomy and adenotonsillectomy for recurrent otitis media.
PMID- 10770140
TI - Assessing patients' views of clinical changes.
PMID- 10770141
TI - Assessing patients' views of clinical changes.
PMID- 10770142
TI - Increased bioavailability of sildenafil in Mexican men.
PMID- 10770143
TI - Can meningococcal C conjugate vaccine overcome immune hyporesponsiveness induced
by previous administration of plain polysaccharide vaccine?
PMID- 10770144
TI - Association of sleep-disordered breathing, sleep apnea, and hypertension in a
large community-based study. Sleep Heart Health Study.
AB - CONTEXT: Sleep-disordered breathing (SDB) and sleep apnea have been linked to
hypertension in previous studies, but most of these studies used surrogate
information to define SDB (eg, snoring) and were based on small clinic
populations, or both. OBJECTIVE: To assess the association between SDB and
hypertension in a large cohort of middle-aged and older persons. DESIGN AND
SETTING: Cross-sectional analyses of participants in the Sleep Heart Health
Study, a community-based multicenter study conducted between November 1995 and
January 1998. PARTICIPANTS: A total of 6132 subjects recruited from ongoing
population-based studies (aged > or = 40 years; 52.8% female). MAIN OUTCOME
MEASURES: Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas
per hour of sleep, with apnea defined as a cessation of airflow and hypopnea
defined as a > or = 30% reduction in airflow or thoracoabdominal excursion both
of which are accompanied by a > or = 4% drop in oxyhemoglobin saturation)
[corrected], obtained by unattended home polysomnography. Other measures include
arousal index; percentage of sleep time below 90% oxygen saturation; history of
snoring; and presence of hypertension, defined as resting blood pressure of at
least 140/90 mm Hg or use of antihypertensive medication. RESULTS: Mean systolic
and diastolic blood pressure and prevalence of hypertension increased
significantly with increasing SDB measures, although some of this association was
explained by body mass index (BMI). After adjusting for demographics and
anthropometric variables (including BMI, neck circumference, and waist-to-hip
ratio), as well as for alcohol intake and smoking, the odds ratio for
hypertension, comparing the highest category of AHI (> or = 30 per hour) with the
lowest category (< 1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03
1.83; P for trend = .005). The corresponding estimate comparing the highest and
lowest categories of percentage of sleep time below 90% oxygen saturation (> or =
12% vs < 0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified
analyses, associations of hypertension with either measure of SDB were seen in
both sexes, older and younger ages, all ethnic groups, and among normal-weight
and overweight individuals. Weaker and nonsignificant associations were observed
for the arousal index or self-reported history of habitual snoring. CONCLUSION:
Our findings from the largest cross-sectional study to date indicate that SDB is
associated with systemic hypertension in middle-aged and older individuals of
different sexes and ethnic backgrounds.
PMID- 10770145
TI - Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a
randomized controlled trial.
AB - CONTEXT: Despite the high prevalence, chronicity, and associated comorbidity of
posttraumatic stress disorder (PTSD) in the community, few placebo-controlled
studies have evaluated the efficacy of pharmacotherapy for this disorder.
OBJECTIVE: To determine if treatment with sertraline hydrochloride effectively
diminishes symptoms of PTSD of moderate to marked severity. DESIGN: Twelve-week,
double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo
lead-in period, conducted between May 1996 and June 1997. SETTING: Outpatient
psychiatric clinics in 8 academic medical centers and 6 clinical research
centers. PATIENTS: A total of 187 outpatients with a Diagnostic and Statistical
Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a
Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of
at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years;
73% were women; and 61.5% experienced physical or sexual assault). INTERVENTION:
Patients were randomized to acute treatment with sertraline hydrochloride in
flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or
placebo (n=93). MAIN OUTCOME MEASURES: Baseline-to-end-point changes in CAPS-2
total severity score, Impact of Event Scale total score (IES), and Clinical
Global Impression-Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared
by treatment vs placebo groups. Results Sertraline treatment yielded
significantly greater improvement than placebo on 3 of the 4 primary outcome
measures (mean change from baseline to end point for CAPS-2 total score, -33.0 vs
-23.2 [P =.02], and for CGI-S, -1.2 vs -0.8 [P=.01]; mean CGI-I score at end
point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing
a trend toward significance (mean change from baseline to end point, -16.2 vs
12.1; P=.07). Using a conservative last-observation-carried-forward analysis,
treatment with sertraline resulted in a responder rate of 53% at study end point
compared with 32% for placebo (P=.008, with responder defined as >30% reduction
from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much
improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for
sertraline from week 2 on the CAPS-2 total severity score. Sertraline had
significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of
avoidance/numbing (P=.02) and increased arousal (P=.03) but not on
reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia
the only adverse effect reported significantly more often than placebo (16.0% vs
4.3%; P=.01). CONCLUSIONS: Our data suggest that sertraline is a safe, well
tolerated, and effective treatment for PTSD.
PMID- 10770146
TI - Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart
disease events after menopause.
AB - CONTEXT: Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor
for coronary heart disease (CHD) events. However, few data exist on the clinical
importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen
has been found to lower Lp(a) levels in women. OBJECTIVE: To determine the
relationships among treatment with estrogen and progestin, serum Lp(a) levels,
and subsequent CHD events in postmenopausal women. DESIGN AND SETTING: The Heart
and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo
controlled secondary prevention trial conducted from January 1993 through July
1998 with a mean follow-up of 4.1 years at 20 centers. PARTICIPANTS: A total of
2763 postmenopausal women younger than 80 years with coronary artery disease and
an intact uterus. Mean age was 66.7 years. INTERVENTION: Participants were
randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus
medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical
placebo (n = 1383). MAIN OUTCOME MEASURES: Lipoprotein(a) levels and CHD events
(nonfatal myocardial infarction and CHD death). RESULTS: Increased baseline Lp(a)
levels were associated with subsequent CHD events among women in the placebo arm.
After multivariate adjustment, women in the second, third, and fourth quartiles
of baseline Lp(a) level had relative hazards (RHs) (compared with the first
quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85
2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the
lowest quartile (P for trend = .03). Treatment with estrogen and progestin
reduced mean (SD) Lp(a) levels significantly (-5.8 [15] mg/dL) (-0.20 [0.53]
micromol/L) compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] micromol/L)
(P<.001). In a randomized subgroup comparison, women with low baseline Lp(a)
levels had less benefit from estrogen and progestin than women with high Lp(a)
levels; the RH for women assigned to estrogen and progestin compared with placebo
were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67
1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth
quartiles, respectively (P for interaction trend = .03). CONCLUSIONS: Our data
suggest that Lp(a) is an independent risk factor for recurrent CHD in
postmenopausal women and that treatment with estrogen and progestin lowers Lp(a)
levels. Estrogen and progestin therapy appears to have a more favorable effect
(relative to placebo) in women with high initial Lp(a) levels than in women with
low levels. This apparent interaction needs confirmation in other trials.
PMID- 10770147
TI - The accuracy of patient history, wheezing, and laryngeal measurements in
diagnosing obstructive airway disease. CARE-COAD1 Group. Clinical Assessment of
the Reliability of the Examination-Chronic Obstructive Airways Disease.
AB - CONTEXT: The accuracy of the clinical examination in detecting obstructive airway
disease (OAD) is largely unknown because of a paucity of methodologically
rigorous studies. OBJECTIVE: To determine the accuracy of patient history,
wheezing, laryngeal height, and laryngeal descent in the diagnosis of OAD.
DESIGN: Comparison study conducted from November 3, 1998, to December 4, 1998,
evaluating 4 clinical examination elements for diagnosis of OAD vs the gold
standard of forced expiratory volume in 1 second (FEV1) and FEV1-forced vital
capacity (FVC) ratio less than the fifth percentile (adjusted for patient height,
age, and sex). SETTING: Twenty-five sites, including primary care and referral
practices, in 14 countries. PARTICIPANTS: A total of 309 consecutive patients
were recruited (mean age, 56 years; 43% female), 76 (25%) with known chronic OAD,
114 (37%) with suspected chronic OAD, and 119 (39%) with neither known nor
suspected OAD. MAIN OUTCOME MEASURES: Sensitivity, specificity, and likelihood
ratios (LRs) for each of the 4 elements of the clinical examination compared with
the gold standard. RESULTS: Mean FEV1 and FVC values were 2.1 L/s and 2.9 L; 52%
had an FEV1 and FEV1-FVC ratio less than the fifth percentile. The LR for
wheezing was 2.7 (95% confidence interval [CI], 1.7-4.2) and was not
statistically significant in the multivariate model. The LR for laryngeal descent
ranged from 0.9 (95% CI, 0.5-1.4) to 1.2 (95% CI, 0.4-3.4), depending on the cut
point chosen, and did not enter the multivariate model. Only 4 of the history or
physical examination elements we tested were significantly associated with the
diagnosis of OAD on multivariate analysis: smoking for more than 40 pack-years
(LR, 8.3), self-reported history of chronic OAD (LR, 7.3), maximum laryngeal
height of 4 cm [corrected] or less (LR, 2.8), and age at least 45 years (LR,
1.3). Patients having all 4 findings had an LR of 220 (ruling in OAD); those with
none had an LR of 0.13 (ruling out OAD). The area under the receiver operating
characteristic curve for the model incorporating these 4 factors was 0.86.
CONCLUSIONS: Further research is needed to validate our model, but in the
meantime, our data suggest that less emphasis should be placed on the presence of
individual symptoms or signs (such as wheezing or laryngeal descent) in the
diagnosis of OAD.
PMID- 10770148
TI - Physician manipulation of reimbursement rules for patients: between a rock and a
hard place.
AB - CONTEXT: Health plan utilization review rules are intended to enforce insurance
contracts and can alter and constrain the services that physicians provide to
their patients. Physicians can manipulate these rules, but how often they do so
is unknown. OBJECTIVE: To determine the frequency with which physicians
manipulate reimbursement rules to obtain coverage for services they perceive as
necessary, and the physician attitudes and personal and practice characteristics
associated with these manipulations. DESIGN, SETTING, AND PARTICIPANTS: A random
national sample of 1124 practicing physicians was surveyed by mail in 1998; the
response rate was 64% (n = 720). MAIN OUTCOME MEASURE: Use of 3 different tactics
"sometimes" or more often in the last year: (1) exaggerating the severity of
patients' conditions; (2) changing patients' billing diagnoses; and/or (3)
reporting signs or symptoms that patients did not have to help the patients
secure coverage for needed care. RESULTS: Thirty-nine percent of physicians
reported using at least 1 tactic "sometimes" or more often in the last year. In
multivariate models comparing these physicians with physicians who "never" or
"rarely" used any of these tactics, physicians using these tactics were more
likely to (1) believe that "gaming the system" is necessary to provide high
quality care today (odds ratio [OR], 3.67; 95% confidence interval [CI], 2.54
5.29); (2) have received requests from patients to deceive insurers (OR, 2.44;
95% CI, 1.72-3.45); (3) feel pressed for time during patient visits (OR, 1.69;
95% CI, 1.21-2.37); and (4) have more than 25% of their patients covered by
Medicaid (OR, 1.60; 95% CI, 1.08-2.38). Notably, greater worry about prosecution
for fraud did not affect physicians' use of these tactics (P = .34). Of those
reporting using these tactics, 54% reported doing so more often now than 5 years
ago. CONCLUSIONS: A sizable minority of physicians report manipulating
reimbursement rules so patients can receive care that physicians perceive is
necessary. Unless novel strategies are developed to address this, greater
utilization restrictions in the health care system are likely to increase
physicians' use of such manipulative "covert advocacy" tactics.
PMID- 10770149
TI - The public release of performance data: what do we expect to gain? A review of
the evidence.
AB - CONTEXT: Information about the performance of hospitals, health professionals,
and health care organizations has been made public in the United States for more
than a decade. The expected gains of public disclosure have not been made clear,
and both the benefits and potential risks have received minimal empirical
investigation. OBJECTIVE: To summarize the empirical evidence concerning public
disclosure of performance data, relate the results to the potential gains, and
identify areas requiring further research. DATA SOURCES: A literature search was
conducted on MEDLINE and EMBASE databases for articles published between January
1986 and October 1999 in peer-reviewed journals. Review of citations, public
documents, and expert advice was conducted to identify studies not found in the
electronic databases. STUDY SELECTION: Descriptive, observational, or
experimental evaluations of US reporting systems were selected for inclusion.
DATA EXTRACTION: Included studies were organized based on use of public data by
consumers, purchasers, physicians, and hospitals; impact on quality of care
outcomes; and costs. DATA SYNTHESIS: Seven US reporting systems have been the
subject of published empirical evaluations. Descriptive and observational methods
predominate. Consumers and purchasers rarely search out the information and do
not understand or trust it; it has a small, although increasing, impact on their
decision making. Physicians are skeptical about such data and only a small
proportion makes use of it. Hospitals appear to be most responsive to the data.
In a limited number of studies, the publication of performance data has been
associated with an improvement in health outcomes. CONCLUSIONS: There are several
potential gains from the public disclosure of performance data, but use of the
information by provider organizations for quality improvement may be the most
productive area for further research.
PMID- 10770150
TI - Users' guides to the medical literature: XXI. Using electronic health information
resources in evidence-based practice. Evidence-Based Medicine Working Group.
PMID- 10770151
TI - Is untreated sleep apnea a contributing factor for chronic hypertension?
PMID- 10770152
TI - Fidelity and deceit at the bedside.
PMID- 10770153
TI - Public release of performance data: a progress report from the front.
PMID- 10770154
TI - JAMA Patient Page: lung disease.
PMID- 10770155
TI - Radiation safety role in institutional disaster planning.
AB - United States Nuclear Regulatory Commission (NRC) materials license applicants
(non-nuclear power) must submit spill procedures with their application. While
our counterparts in the nuclear power industry historically have concerned
themselves with disaster drills and evacuation plans as a result of fire,
explosion, or an act of terrorism, other licensees are looking only at minor
spills of unsealed radioactive material and only at tile radiation hazard. Beyond
NRC regulations, various oversight and accrediting organizations require, or at a
minimum encourage, a written disaster plan outlining actions to be taken for
events likely to occur in the region of the institution. Some of these
organizations require drills to practice implementation of the written plan. On 5
May 1999, Mayo Clinic performed a wide-scale disaster drill involving Rochester
City and Olmsted County response organizations, and several Mayo Clinic
departments. Planning took several months; the drill took approximately three
hours. Participants gathered at several meetings post-drill for "debriefing"
sessions to discuss successes, areas for improvement, and lessons learned. There
were three overriding lessons learned: critical responders need special
identification to allow access to the disaster site; initial victim surveys are
for gross contamination only; and access to the potentially contaminated disaster
site might take weeks or months following a real event.
PMID- 10770156
TI - Estimating the administrative cost of regulatory noncompliance: a pilot method
for quantifying the value of prevention.
AB - Routine regulatory inspections provide a valuable independent quality assurance
review of radiation protection programs that ultimately serves to improve overall
program performance. But when an item of non-compliance is noted, regardless of
its significance or severity the ensuing notice of violation (NOV) results in an
added cost to both the permit holder and the regulatory authority. Such added
costs may be tangible, in the form of added work to process and resolve the NOV,
or intangible, in the form of damage to organizational reputation or worker
morale. If the portion of the tangible costs incurred by a regulatory agency for
issuing NOVs could be quantified, the analysis could aid in the identification of
agency resources that might be dedicated to other areas such as prevention.
Ideally, any prevention activities would reduce the overall number of NOVs issued
without impacting the routine inspection process. In this study, the
administrative costs of NOV issuance and resolution was estimated by obtaining
data from the professional staff of the Texas Department of Health, Bureau of
Radiation Control (TDH-BRC). Based a focus group model, the data indicate that
approximately $106,000 in TDH-BRC personnel resources were expended to process
and resolve the 6,800 NOVs issued in Texas during 1997 inspection activities. The
study's findings imply that an incremental decrease in the number of NOVs issued
would result in corresponding savings of agency resources. Suggested prevention
activities that might be financed through any resource savings include the
dissemination of common violation data to permit holders or training for
improving correspondence with regulatory agencies. The significance of this
exercise is that any savings experienced by an agency could enhance permittee
compliance without impacting the routine inspection process.
PMID- 10770158
TI - Steam generator hand hole shielding.
AB - Seabrook Station is an 1198 MWE Pressurized Water Reactor (PWR) that began
commercial operation in 1990. Expensive and dose intensive Steam Generator
Replacement Projects among PWR operators have led to an increase in steam
generator preventative maintenance. Most of this preventative maintenance is
performed through access ports in the shell of the steam generator just above the
tube sheet known as secondary side hand holes. Secondary side work activities
performed through the hand holes are typically performed without the shielding
benefit of water in the secondary side of the steam generator. An increase in
cleaning and inspection work scope has led to an increase in dose attributed to
steam generator secondary side maintenance. This increased work scope and the
station goal of maintaining personnel radiation dose ALARA led to the development
of the shielding concept described in this article. This shield design saved an
estimated 2.5 person-rem (25 person-Smv) the first time it was deployed and is
expected to save an additional 50 person-rem (500 person-mSv) over the remaining
life of the plant.
PMID- 10770157
TI - Ultraviolet light hazards from transilluminators.
AB - Ultraviolet (UV) light boxes ("transilluminators") are commonly used in molecular
biology laboratories for visualizing ethidium bromide-intercalated nucleic acids
separated under electric current in electrophoretic gels. These devices typically
have peak outputs at 254 or 312 nm, well within the UV-C and -B regions that are
biologically active and capable of damaging skin. Field evaluations of laboratory
transilluminators under actual conditions of use indicate that the UV light
emitted from transilluminators is an identifiable and potentially significant
occupational hazard for many laboratory workers, as is the high frequency of
workstation surface contamination with ethidium bromide, a known mutagen.
Fortunately, these hazards can be relatively easily controlled through worker
training and the regular use of basic personal protective equipment.
PMID- 10770159
TI - Elements of a portable radiation detector calibration program.
AB - The Department of Environmental Health & Safety at San Diego State University
(SDSU) calibrates portable radiation detectors as a service to the university's
research community. SDSU's calibration program was developed and implemented
based on selected recommendations provided by the American National Standards
Institute and the National Council on Radiation Protection and Measurements. This
paper outlines the elements of the calibration program including, technical
references and the rationale for program development. Covered under the
provisions of this paper include those instruments used to evaluate the dose
rates from radioactive materials and those instruments used to determine
radioactive contamination or uptake. Those detectors specifically not addressed
are liquid scintillation counters, semi-conductors, neutron dose rate
instruments, and instruments intended for quantifying dose rates due to beta
emission.
PMID- 10770160
TI - Apparent high tritium intake by a radiation worker at the University of
Rochester.
AB - On 20 September 1999, a urine sample submitted by a University of Rochester
radiation worker was noted to have a count rate of about 759,500 disintegrations
per minute (dpm) per milliliter as analyzed on the Radiation Safety Unit (RSU)
Packard liquid sintillation counter. The sample was recounted that day with
variable results but each time indicating several hundred thousand dpm of
activity present. Calculations indicated this corresponded to a whole-body uptake
of about 518 MBq (14 nmCi) and a whole-body dose of about 10 msv (1 rem). An
investigation indicated it was unlikely for these analytical results to indicate
an actual uptake of tritium and suggested the results were most likely due to
chemical luminescence in the sample. Accordingly, no dose was assigned to this
worker from the exposure.
PMID- 10770161
TI - Managing a sound portable gauge radiation safety program.
AB - At some construction engineering companies, individuals with no background in
radiation safety sometimes are assigned the not always welcome title of Radiation
Safety Officer (RSO). With this new title comes the responsibility of ensuring
that portable gauges are used safely at their facilities and in tile field. These
newly appointed RSOs sometimes lack the knowledge and experience needed to manage
a radiation safety program. This article was developed to provide the basic
information needed to work confidently and safely around these instruments and to
discuss licensing requirements and other information pertaining to the management
of a portable gauge radiation safety program.
PMID- 10770162
TI - The Pennsylvania computerized tomography study.
AB - This study was conducted to identify areas of concern not adequately addressed in
the Pennsylvania Code Title 25 regulations regarding computerized tomography
(CT). These areas of concern are now presented in the Bureau of Radiation
Protection's CT regulations/guidelines.
PMID- 10770163
TI - UVA, UVB, and UVC and their possible effects.
PMID- 10770164
TI - The application of ALARA for occupational exposures NCRP Statement No. 8, issued
June 8, 1999. National Council on Radiation Protection.
PMID- 10770165
TI - Clinical review 113: Hypopituitarism secondary to head trauma.
PMID- 10770166
TI - Genes influencing variation in serum osteocalcin concentrations are linked to
markers on chromosomes 16q and 20q.
AB - Osteocalcin (OC) is an important constituent of bone that is synthesized by
osteoblasts. Serum levels of OC have been used as a biochemical marker of bone
turnover. To identify the genes influencing variation in serum OC levels, we
conducted a genome-wide scan in 429 individuals comprising 10 large
multigenerational families. OC levels were measured by immunoassay, and genetic
markers were typed at approximately 10-cM intervals across the genome.
Quantitative trait linkage was tested using a multipoint analysis based on
variance component methodology, adjusting for the effects of age, sex, and oral
contraceptive use. Significance levels for linkage were obtained empirically, by
Monte Carlo simulation. The heritability of OC levels in this population was 62
+/- 8%. We detected significant evidence for linkage between a quantitative trait
locus influencing serum OC levels and markers on chromosome 16q, and suggestive
evidence for linkage of OC levels with markers on chromosome 20q. The multipoint
lod scores peaked at 3.35 on chromosome 16 and 2.78 on chromosome 20,
corresponding to P values of 0.00004 and 0.00017, respectively. A potential
candidate gene for bone formation in the linked region on chromosome 20 is CDMP1,
which encodes cartilage-derived morphogenetic protein 1. Future studies should
evaluate whether variation in CDMP1 or in other genes in the linked regions on
chromosomes 16 and 20 influence the rate of bone turnover.
PMID- 10770167
TI - Urinary iodine concentration follows a circadian rhythm: a study with 3023 spot
urine samples in adults and children.
AB - Our overall aim is to monitor iodine supply in a prospective study before and
after the September 1998 increase of salt iodide content in Switzerland. Because
iodide is supplied by alimentation, we moreover wondered whether urinary iodine
concentration (UI) is governed by circadian rhythmicity. Forty-two subjects (18
males and 24 females, including 13 children) collected 3023 urine spots between
May 1996 and May 1998, at a rate of three to five samples per month, at any time
of the day. The results show that circadian rhythmicity of UI in adults and
children was found independent of the individual subject, age, gender, and
season. Lowest UI levels were found between 8-11 h. A curve increasing
progressively between 12 and 24 h was obtained. UI returned to base-line levels
between 21 and 22 h in children only. UI peaks occurred 4-5 h after main meals;
children's peaks occurred later than that of adults. Although the existence of a
circadian rhythm of UI is probably universal, its profile, however, depends on
alimentation. Because nadir of UI is represented by morning spots, this might
seem an appropriate collecting period. In view of the significant circadian
rhythmicity of UI, studies with restriction of sampling time to morning hours,
for example, cannot be directly compared with studies in which urine is sampled
all over the day.
PMID- 10770168
TI - Hypothalamo-pituitary abnormalities in adult patients with langerhans cell
histiocytosis: clinical, endocrinological, and radiological features and response
to treatment.
AB - Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous
deposits occur at multiple sites within the body, but which often involves the
hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well
recognized complication, the frequency of anterior pituitary and other
nonendocrine hypothalamic (NEH) involvement has not been well defined,
particularly in adult patients with the disease. We have evaluated the frequency
and progression of LCH-related anterior pituitary and other NEH dysfunction and
their responses to treatment in 12 adult patients with histologically proven LCH
and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the
diagnosis of DI was made. Study evaluations comprised clinical (including formal
psychometric assessment where appropriate), basal and dynamic pituitary function
tests, and radiology with computed tomography and/or magnetic resonance imaging
scanning. Eleven patients received systemic treatment, and 5 patients received
external beam radiotherapy confined to the HPA. The median age at diagnosis of DI
was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients,
whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the
diagnosis of LCH. Eight patients developed one or more anterior pituitary
hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis
of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr),
FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH
deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr),
respectively; five patients developed panhypopituitarism. In addition, seven
patients with anterior pituitary dysfunction also developed symptoms of other NEH
dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body
mass index, >35), five short term memory deficits, four sleeping disorders, two
disorders of thermoregulation, and one adipsia. All patients developed disease
outside of the hypothalamus during the course of the study, and no fluctuation of
disease activity in the HPA region was noted. Radiological examination of the HPA
was abnormal in each of the eight patients with anterior pituitary involvement
and in the seven patients with NEH dysfunction (one or more abnormalities): seven
had thickening of the infundibulum, and one had hypothalamic and thalamic signal
changes. All patients who had a magnetic resonance imaging scan had absence of
the bright spot of the posterior pituitary on the T1-weighted sequences, and in
four patients with DI and normal anterior pituitary function this was the only
abnormality. The five patients who received radiotherapy to the HPA achieved a
partial or complete radiological response, and there was no evidence of tumor
progression in this region. No form of therapy, including chemotherapy, improved
any established hormonal deficiencies or symptoms of NEH. In summary, in our
adult patients with hypothalamic LCH and DI, anterior pituitary hormonal
deficiencies developed in 8 of 12 patients; these occurred over the course of 20
yr. They were frequently accompanied by structural changes of the HPA, although
these were often subtle in nature. In addition, symptoms of NEH dysfunction
developed in up to 90% of such patients and complicated management. Radiotherapy
may be useful in achieving local control of tumor, but established anterior,
posterior pituitary, and other NEH dysfunctions do not improve in response to
current treatment protocols. Patients with LCH and DI, particularly those with
multisystem disease and a structural lesion on radiology, should undergo regular
and prolonged endocrine assessment to establish anterior pituitary deficiency and
provide appropriate hormonal replacement.
PMID- 10770169
TI - Human oviductal gonadotropin-releasing hormone: possible implications in
fertilization, early embryonic development, and implantation.
AB - The oviduct is host to gametes and early embryos at a critical point in their
lives. It is clear that the interactions of gametes/early embryo with the
maternal oviduct in an autocrine and paracrine manner provide a microenvironment
that enhances fertilization, early embryonic development, and implantation.
Moreover, there is considerable evidence that an extrahypothalamic GnRH may play
a substantial role as a molecular autocrine/paracrine regulator in these events.
Gametes and preimplantation embryos express GnRH and GnRH receptor at both
messenger ribonucleic acid (mRNA) and protein levels. However, whether GnRH is
produced by the human oviduct has not yet been demonstrated. We used RT-PCR and
immunohistochemical techniques to investigate GnRH mRNA and protein expression in
human fallopian tubes throughout the menstrual cycle of premenopausal fertile
patients. Our results, at both the mRNA and protein levels, revealed cycle
dependent production of an oviductal GnRH with expression during the luteal
phase. Moreover, GnRH immunostaining was localized in the tubal epithelium during
the luteal phase. On the basis of these data, we suggest that during reproductive
life, oviductal GnRH may play a substantial paracrine/autocrine role in human
fertilization, early embryonic development, and implantation.
PMID- 10770170
TI - Regulation of protein metabolism in middle-aged, premenopausal women: roles of
adiposity and estradiol.
AB - The age-related loss of fat-free mass (FFM) is accelerated in women during the
middle-age years and continues at an increased rate throughout the postmenopausal
period. Because protein is the primary structural component of fat-free tissue,
changes in FFM are largely due to alterations in protein metabolism. Knowledge of
the hormonal and physiological correlates of protein metabolism in middle-aged
women, therefore, has important implications for understanding the mechanisms
underlying changes in FFM. We measured leucine kinetics (expressed relative to
FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47
+/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic
hyperinsulinemia (40 mU/m2/min) using a 5.5-h infusion of [1-13C]leucine.
Additionally, we measured insulin-stimulated glucose disposal by euglycemic
hyperinsulinemic clamp, body composition by dual energy x-ray absorptiometry,
abdominal fat distribution by computed tomography, and hormone levels by RIA as
possible correlates of protein metabolism. Under basal conditions, stepwise
regression analysis showed that leucine appearance (i.e. protein breakdown) was
related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine
oxidation was related to serum estradiol and percent body fat (r2 = 26%; P <
0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with
the percent change in leucine appearance. The percent change in leucine oxidation
was related to intraabdominal adipose tissue area and glucose disposal rate (r2 =
48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e.
protein synthesis) under basal and euglycemic hyperinsulinemic conditions were
similar to those observed for leucine appearance. From these results, we conclude
that adiposity and/or serum estradiol may contribute to the regulation of protein
metabolism and FFM in middle-aged, premenopausal women.
PMID- 10770171
TI - Effects of variations in physiological cortisol levels on thyrotropin secretion
in subjects with adrenal insufficiency: a clinical research center study.
AB - Although pharmacological doses of glucocorticoids suppress TSH secretion, less is
known regarding the effects of physiological variations in cortisol levels on
TSH. To study this issue, seven subjects with primary adrenal insufficiency each
underwent four studies. In the first study subjects received infusions of saline
for 48 h (baseline study). In the second study subjects received infusions of
hydrocortisone for 48 h in a pulsatile and diurnal pattern that replicated serum
cortisol levels in healthy subjects (physiological study). In most cases, the
dose of hydrocortisone was 19 mg/24 h, but this was adjusted as necessary until
the resulting serum cortisol levels reproduced those seen in healthy, nonstressed
control subjects. In the third study subjects received the same total dose of
hydrocortisone as in the physiological study, but with pulses of equal magnitude
spaced evenly throughout the time period (constant study). In the fourth study
subjects received the same total dose of hydrocortisone, but with the diurnal
pattern shifted 12 h from the physiological infusion (reversed study). TSH levels
were measured every 15 min during the final 24 h of each study. During the
baseline study, the 24-h mean TSH level was 2.87 +/- 0.56 mU/L and did not
exhibit any diurnal variation. During the physiological study, daytime TSH levels
decreased 39% compared to those during the baseline study due to decreased TSH
pulse amplitude, and the normal TSH diurnal rhythm was reestablished. The
constant and reversed studies did not lead to significant changes in serum TSH
levels compared to baseline. These results suggest that the normal circadian
variation in endogenous cortisol levels may control TSH secretion, with maximal
TSH suppression seen during the time when cortisol levels are highest. However,
changing the diurnal pattern of hydrocortisone infusion did not lead to
reciprocal changes in TSH levels, and the specific nature of the interactions
between cortisol and TSH within the physiological range remains to be fully
elucidated.
PMID- 10770172
TI - Insulin, androgen, and gonadotropin concentrations, body mass index, and waist to
hip ratio in the first years after menarche in girls with regular menstrual
cycles, irregular menstrual cycles, or oligomenorrhea.
AB - Data on changes in hormone concentrations during the first years after menarche
are scarce. We studied the relation between gynecological age (age minus age at
menarche), hormone concentrations, and body measurements from the lst to the 6th
yr after menarche in 229 observations of girls with regular menstrual cycles, 157
observations of girls with irregular menstrual cycles, and 104 observations of
girls with oligomenorrhea. Body Mass Index, waist circumference, hip
circumference, LH, androstenedione, testosterone, and dehydro-epiandrosterone
sulphate increased significantly (linear regression, P < 0.05) by gynecological
age in all menstrual cycle pattern groups. For PRL and estradiol a significant
increase with gynecological age was only documented in the regular menstrual
cycle group and for waist to hip ratio only in the irregular menstrual cycle
group. No significant correlation could be documented between gynecological age
and overnight fasting insulin concentrations or glucose to insulin ratio. We
found no significant correlation between insulin concentrations or glucose to
insulin ratio and androgen concentrations. Significant positive correlations were
found between LH and androgens. LH and androgen levels increase during the first
years after menarche, and reference values should be adjusted for gynecological
age. In these years, no significant correlation between hyperinsulinemia and
hyperandrogenemia could be documented.
PMID- 10770173
TI - Insulin resistance early in adulthood in subjects born with intrauterine growth
retardation.
AB - In a case-control study that investigated the effect of intrauterine growth
retardation (IUGR) on glucose homeostasis, 20-yr-old adults born with IUGR were
shown to be hyperinsulinemic in an oral glucose tolerance test, suggestive of
insulin resistance. The aim of this study was to ascertain the decreased insulin
sensitivity in young IUGR-born adults compared to that in controls. We studied 26
IUGR-born subjects and 25 controls, aged 25 yr. Insulin sensitivity was assessed
by peripheral glucose uptake and monitoring free fatty acid (FFA) concentrations
under euglycemic hyperinsulinemic clamp. The percent body fat was significantly
higher in the IUGR group (27.2 +/- 7.6% vs. 22.0 +/- 7.3%; P = 0.02), contrasting
with comparable body mass index in both groups. Insulin-stimulated glucose uptake
was significantly lower in IUGR-born subjects than in controls (6.7 +/- 2.9 vs.
8.0 +/- 1.9 mg/kg fat-free mass x min; P = 0.05), and the difference remained
significant after adjustment for body mass index, total body fat, or waist to hip
ratio. In IUGR-born subjects, insulin-stimulated FFA suppression correlated
significantly with peripheral glucose uptake (r2 = 0.23; P = 0.02). First phase
insulin release in the iv glucose tolerance test, adjusted for insulin
sensitivity, did not significantly differ between IUGR and control groups (442 +/
284 vs. 391 +/- 209 pmol/L; P = 0.86). In conclusion, IUGR subjects have
decreased insulin-stimulated glucose uptake as early as 25 yr of age without
major impairment of insulin secretion. Low glucose uptake is associated with a
lesser degree of FFA suppression in adipose tissue, which suggests a role of
adipose tissue at an early stage of insulin resistance in these subjects.
PMID- 10770174
TI - Effects of insulin-like growth factor I (IGF-I) therapy on body composition and
insulin resistance in IGF-I gene deletion.
AB - We have recently reported a patient with a homozygous partial deletion of the
insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin
resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been
shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I
deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition,
bone mineral density (BMD), insulin sensitivity, and linear growth in this
patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a
starting dose of 40 microg/kg daily, increasing after 3 months to 80 microg/kg
daily. Body composition, BMD, markers of bone mineralization, and auxological
parameters (height, weight) were measured at 0, 6, and 12 months after start of
therapy. Si, acute insulin response to glucose, and glucose effectiveness were
determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy,
body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies
(dual-energy x-ray absorbtiometry) revealed an initial decrease in total body
fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy,
this had reversed, with an increase to 21.8%. Si, calculated using Bergman's
minimal model, was substantially reduced at baseline at 1.45 x 10-4 min-1
(microU/mL) [normal value, 5.1 x 10-4 min 1 (lean adult male)]. rhIGF-I therapy
resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I
dose: 40 microg/kg x day, Si = 2.06 x 10-4 min-l; rhIGF-I dose: 80 microg/kg x
day, Si = 4.39 x 10-4 min-1). Baseline reduction in Si was accompanied by
elevated acute insulin response to glucose, which also fell in a dose-dependent
manner. Baseline BMD was severely reduced when compared with age-matched controls
(-4.88 SD); however, calculation of bone mineral apparent density indicated that
the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and
bone mineral apparent density by 7%, indicating that IGF-I has a greater effect
on bone growth than bone mineralization. Bone turnover markers also increased on
rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6
months of rhIGF-I (NR for adult male, 3.4-9.1 ng/mL); mean bone specific alkaline
phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for
adult male, 15-41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3
cm/yr on 80 microg/kg.day of rhIGF-I. In this patient with severe insulin
resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body
composition, bone size, and linear growth. These results have implications for
IGF-I therapy in a variety insulin resistant states.
PMID- 10770175
TI - Effects of growth hormone treatment in obese prepubertal boys.
AB - Childhood obesity is associated with several abnormalities of the GH axis,
including decreased spontaneous secretion, decreased response to exogenous
secretagogues, and altered pulsatile pattern of secretion. In adults, GH
treatment reduces abdominal obesity and improves insulin sensitivity, as well as
blood lipid profiles. Whether GH has similar effects in obese children has not
been investigated previously. In this study, seven prepubertal severely obese
boys aged 10-12 yr were treated with GH for 6 months and followed for an
additional 6 months. No diet or exercise modifications were initiated. Body fat
percentage decreased from 51.3% to 46.1% after treatment (P = 0.03). Frequently
sampled iv glucose tolerance tests revealed an increased responsivity of the
acute insulin secretion (P = 0.04) and a nonsignificant trend toward improved
insulin sensitivity. In isolated adipocytes, the maximum isoprenaline- and
terbutaline-induced lipolysis were increased approximately 2.5-fold (P = 0.02).
The sensitivity of the adipocytes to isoprenaline was unchanged, whereas the
sensitivity to terbutaline was increased (P = 0.04). No effect was observed on
basal or insulin-stimulated lipogenesis. In conclusion, GH treatment for 6 months
of obese prepubertal boys reduces body fat, possibly, via stimulation of
catecholamine-induced lipolysis, without negative effects on glucose homeostasis.
PMID- 10770176
TI - Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and
mortality.
AB - The objective of the present study was to determine the incidence of pituitary
adenomas (PAs) and the associated rates and causes of mortality in a large
population. The study population comprised 2279 patients (1010 women and 1269
men) of all individuals (n = 3321) with pituitary tumors included in the Swedish
Cancer Registry between 1958 and 1991. The mean age (+/-SD) at diagnosis was 52.3
+/-15.7 yr. The age-standardized incidence of PA increased significantly from
approximately 6 cases/million inhabitants in 1958 to 11 cases/ million in 1991.
The age-specific incidence peaked between 60-70 yr of age in both sexes. Excess
mortality was found in the study population. The total number of deaths was 842.
The standardized mortality ratio (SMR) for the study population was 2.0. The SMR
for women (2.3) was significantly (P < 0.01) higher than that for men (1.9).
Cardiovascular diseases were the most common cause of mortality among patients,
accounting for 346 deaths (SMR, 1.6). The difference between the sexes was
significant (men, 1.4; women, 1.8; P < 0.05). Cerebrovascular death occurred in
97 patients (SMR, 2.4), with no significant difference between men (SMR, 2.5) and
women (SMR, 2.2). Excess mortality was also observed for tumors, endocrine
diseases, and gastrointestinal diseases. These findings suggest that the annual
incidence of PA is increasing. Possible explanations are improved diagnostic
skill and/or increased awareness of pituitary diseases among physicians. However,
a real increase in the incidence of PA cannot be ruled out.
PMID- 10770177
TI - Cardiac effect of thyrotoxicosis in acromegaly.
AB - Cardiac structure and function are affected both by acromegaly and
hyperthyroidism. Whereas the former is mainly characterized by ventricular
hypertrophy as well as diastolic and systolic impairment, the latter frequently
leads to increased heart rate and enhancement of contractility and cardiac
output. To further investigate this issue, we designed this two-arm study. In the
first cross-sectional study, we compared echocardiography and radionuclide
angiography results obtained in eight hyperthyroid acromegalic patients, eight
hyperthyroid nonacromegalic patients, and eight healthy subjects. All acromegalic
patients were receiving treatment for acromegaly at the onset of hyperthyroidism.
In the second longitudinal study, performed in the group of acromegalic patients,
we compared the cardiovascular results obtained during hyperthyroidism with the
retrospective data obtained at the initial diagnosis of acromegaly and after 1-yr
treatment for this disease and those prospective data obtained during the
remission of hyperthyroidism. In the cross-sectional study, hyperthyroid
acromegalic patients showed an increase in the left ventricular (LV) mass index
(LVMi) compared to healthy and hyperthyroid controls (P < 0.05), with evidence of
LVMi hypertrophy in five of them (62.5%). A significant correlation was found
between LVMi and GH levels (r = 0.785; P < 0.05). The LV ejection fraction (LVEF)
at rest was higher in the control hyperthyroid population than in healthy
controls (P < 0.05), whereas the LVEF response to exercise was reduced in
acromegalic patients (P < 0.05 vs. healthy controls). In acromegalics, the
exercise-induced change in LVEF was significantly reduced compared to that in
healthy controls (P < 0.001), but not to that in hyperthyroid controls (P <
0.07), being abnormal (<5% increase vs. baseline values) in six patients. Four of
these six patients (66%) had elevated GH and insulin-like growth factor I levels
during the treatment of acromegaly. An inverse correlation between GH and LVEF at
rest (r = -0.896;P < 0.05) and at peak exercise (r = -0.950; P < 0.001) was
recorded. The peak filling rate was reduced in hyperthyroid acromegalic patients
compared to those in both control populations (P < 0.05). In the longitudinal
study, acromegalic patients showed an increased LVMi during hyperthyroidism
compared to that observed after successful treatment of acromegaly (P < 0.05);
resting LVEF was increased compared to both basal (P < 0.001) and posttreatment
values (P < 0.05). However, the exercise-induced change in LVEF was reduced (P <
0.05 vs. previous follow-up values). Remission of hyperthyroidism led to
significant reduction of LVMi (P < 0.05) and resting LVEF (P < 0.05) and an
increase in exercise-induced LVEF (P < 0.05). In light of these findings,
hyperthyroidism produces a detrimental effect on the cardiovascular system of
acromegalic patients, particularly in those with uncontrolled disease. Thus,
control of GH and insulin-like growth factor I should be a major objective, as
cardiovascular risk persists in patients with ineffective hormonal suppression,
and constant endocrine and cardiovascular surveillance remain crucial steps in
patient follow-up.
PMID- 10770178
TI - Integrity of the growth hormone/insulin-like growth factor system is maintained
in patients with chronic fatigue syndrome.
AB - GH deficiency states and chronic fatigue syndrome (CFS) share several
characteristics, and preliminary studies have revealed aspects of GH dysfunction
in CFS. This study assessed indexes of GH function in 37 medication-free CFS
patients without comorbid psychiatric illness and 37 matched healthy controls. We
also assessed GH function before and after treatment with low dose
hydrocortisone, which has been shown recently to reduce fatigue in CFS. We
measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF
binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH
excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH
test and an insulin stress test using 0.15 U/kg BW insulin. There were no
differences between patients and controls in basal levels of IGF/IGFBP or in
urinary GH excretion. GH responses to both the GHRH test and the insulin stress
test were no different in patients and controls. CFS patients did have a
marginally reduced suppression of IGFBP-1 during the insulin stress test.
Hydrocortisone treatment had no significant effect on any of these parameters.
There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone
treatment appears to have little impact on GH function.
PMID- 10770179
TI - Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical
and biochemical features.
AB - Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions,
often arbitrarily considered as nonfunctioning tumors. Recent studies, however,
have reported increasing evidence that subtle cortisol production and
abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent
than previously thought. The purpose of this study was to investigate the
clinical and hormonal features of patients with incidentally discovered adrenal
adenomas, in relation to their clinical outcome. Fifty consecutive patients with
incidentally detected adrenal adenomas, selected from a total of 65 cases of
adrenal incidentalomas, were prospectively evaluated. All of them underwent
abdominal computed tomography scan and hormonal assays of the HPA axis function:
circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17
hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2
mg) dexamethasone test. The patients were reevaluated at regular intervals (6,
12, and 24 months) for a median period of 38 months. Subtle hypercortisolism,
defined as abnormal response to at least 2 standard tests of the HPA axis
function in the absence of clinical signs of Cushing's syndrome (CS), was defined
as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%)
patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50
(12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass
index, determined as weight/height2, > 25), and 14 patients (28%) had serum lipid
concentration abnormalities (cholesterol > or = 6.21 mmol/L, low-density
lipoprotein cholesterol > or = 4.14 mmol/L and/or triglycerides > or = 1.8
mmol/L). Compared with a healthy population, bone mineral density Z-score,
determined by the DEXA technique, tended to be slightly (but not significantly)
lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared
with 107 sex- and age-matched controls, and patients with adenomas were found to
have heterogeneous hormonal abnormalities. In particular, significantly higher
serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and
impaired cortisol suppression by dexamethasone (P < 0.001) were observed.
Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and
androstenedione responses to corticotropin were significantly increased (P <
0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly
lower at baseline, with blunted response to corticotropin (P < 0.001, both).
However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of
these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension,
5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids.
The clinical and hormonal features improved in all patients treated by
adrenalectomy, but seemed unchanged in all those who did not undergo surgery
(follow-up, 9 to 73 months), except for one, who was previously found as having
nonfunctioning adenoma and then revealed to have subclinical CS. In conclusion,
an unexpectedly high prevalence of subtle autonomous cortisol secretion,
associated with high occurrence of hypertension, diabetes mellitus, elevated
lipids, and diffuse obesity, was found in incidentally discovered adrenal
adenomas. Although the pathological entity of a subclinical hypercortisolism
state remained mostly stable in time during follow-up, hypertension, metabolic
disorders, and hormonal abnormalities improved in all patients treated by
adrenalectomy. These findings support the hypothesis that clinically silent
hypercortisolism is probably not completely asymptomatic.
PMID- 10770180
TI - A genotypic and histopathological study of a large Dutch kindred with
hyperparathyroidism-jaw tumor syndrome.
AB - Familial primary hyperparathyroidism is the main feature of 2 familial endocrine
neoplasia syndromes: multiple endocrine neoplasia type 1 (MEN 1) and
hyperparathyroidism-jaw tumor syndrome (HPT-JT). The latter is a recently
described syndrome that has been associated with ossifying fibroma of the jaw and
various types of renal lesions, including benign cysts, Wilms' tumor, and
hamartomas. To further illustrate the natural history of this syndrome, we
describe a large, previously unreported Dutch kindred in which 13 affected
members presented with either parathyroid adenoma or carcinoma; in 5 affected
individuals, cystic kidney disease was found. Additionally, pancreatic
adenocarcinoma, renal cortical adenoma, papillary renal cell carcinoma,
testicular mixed germ cell tumor with major seminoma component, and Hurthle cell
thyroid adenoma were also identified. Linkage analysis of the family using MEN1
linked microsatellite markers and mutation analysis excluded the involvement of
the MEN1 gene. Using markers from the HPT-JT region in 1q2531, cosegregation with
the disease was found, with a maximum logarithm of odds score of 2.41 obtained
for 6 markers using the most conservative calculation. Meiotic telomeric
recombination between D1S413 and D1S477 was identified in 3 affected individuals,
and when combined with previous reports, delineated the HPT-JT region to 14
centimorgan. Combined comparative genomic hybridization and loss of
heterozygosity data revealed complex genetic abnormalities in the tumors,
suggesting different possible genetic mechanisms for the disease. In conclusion,
we report a family with hyperparathyroidism linked to chromosome 1q, and
exhibiting several types of renal and endocrine tumors that have not been
previously described.
PMID- 10770181
TI - Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated
with birth weight and serum triglyceride concentration in preschool aged
children.
AB - The Leu7Pro gene variant of the signal peptide part of neuropeptide Y (NPY), has
been shown to affect cholesterol metabolism in obese adults. This study
investigates whether the Leu7Pro polymorphism in the prepro-NPY has an impact on
serum lipid concentrations in preschool-aged children at 5 and 7 yr of age. As
birth weight may influence future lipid values, we also investigated whether
Leu7Pro polymorphism is associated with birth weight. The study comprised 688
children participating in the Special Turku Coronary Risk Factor Intervention
Project. Fasting lipid concentrations were determined first at the age of 5 yr
and again at the age of 7 yr. The Leu7Pro polymorphism was not associated with
serum total or low density lipoprotein cholesterol values in boys or in girls.
However, Pro7 substitution in prepro-NPY was constantly associated with 14-17%
higher mean serum triglyceride values in the boys at the ages of 5 and 7 yr (P =
0.023). In addition, boys with the Pro7 substitution had, on the average, a 193-g
higher birth weight than boys homozygous for Leu7 (P = 0.03). The Leu7Pro
polymorphism may thus be linked with serum triglyceride concentrations, but not
with serum cholesterol concentrations, in gender-specific manner in preschoolers.
PMID- 10770182
TI - Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new
onset synovitis/rheumatoid arthritis: relations with indices of inflammation.
AB - To determine whether alterations in adrenocortical function occur early in the
development of inflammatory joint disease, we examined patients with new onset
synovitis (<1 yr) prior to treatment with corticosteroids or other disease
modifying antirheumatic drugs. Thirty-two patients with new onset synovitis,
including 15 fitting criteria for rheumatoid arthritis (RA), taking no
medications, were referred for study by local rheumatologists; 32 age- and sex
matched healthy individuals were recruited as controls. Patients and controls had
blood drawn under identical conditions between 0900 and 1100 h. Plasma ACTH,
cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, free and total
testosterone, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid
factor were measured. Compared with controls, patients had higher inflammatory
indices (erythrocyte sedimentation rate, C-reactive protein) and lower basal
morning levels of free testosterone (lower in males age > or =45 yr), but similar
levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In
addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and
cortisol-DHEA, observed in the normal controls, were weakened or abolished in the
patients (both total and RA subset). No positive relations between inflammatory
indices and ACTH or cortisol were noted, yet an inverse correlation between these
indices and DHEA and testosterone was observed. Moreover, a steeper age
associated decline in DHEA was observed in our cross-sectional sample of patients
with new onset synovitis. We conclude that patients with synovitis (including
those fitting criteria for RA) have adrenocortical hormone alterations within a
year of disease onset. Paradoxically, these patients have no positive relation
between indices of inflammation and ACTH or cortisol, but rather serum androgen
levels are inversely correlated with these indices. In addition, the relations
between ACTH, the classic stimulus of cortisol and adrenal androgens, and these
hormones are weakened or abolished, whereas the negative relation between age and
zona reticularis function is steeper than that of controls.
PMID- 10770183
TI - Diagnosis of growth hormone (GH) deficiency in adults with hypothalamic-pituitary
disorders: comparison of test results using pyridostigmine plus GH-releasing
hormone (GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia as GH
secretagogues.
AB - The insulin tolerance test (ITT) is widely accepted as the method of choice to
evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders.
However, the test is not suitable in the elderly or in patients with
cardiovascular disease or seizure disorders. In recent years alternatives to the
ITT have been introduced. The purpose of the present study was to investigate the
diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test,
the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I)
in an unselected group of patients with hypothalamic-pituitary disease. An
evaluation of the reproducibility of the different stimulation tests was included
in the study. Based on repeated testing with the various GH stimulation tests in
healthy adult males and females, the lower limits of normality for the ITT, the
PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L,
respectively. A consecutive group of 26 unselected patients with hypothalamic
pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested
twice with all stimulation tests, except that only 10 patients were tested once
with the CLO+GHRH test due to side-effects related to clonidine. The peak GH
responses between test 1 and test 2 correlated significantly in both the ITT and
the PD + GHRH test (P < 0.02), and no significant difference was observed in the
median peak response to repeated testing. In addition, no sex difference was
observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH),
but in the majority of patients low values were repeatedly low. The peak GH
response was significantly higher during the PD+GHRH test than during the ITT (P
= 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was
no significant difference in the peak GH response (P = 0.398). When the test
specific cut-off values were used, no significant difference in diagnostic
outcome was observed between the various tests (P > 0.3). In contrast, the
diagnosis obtained with IGF-I differed significantly from all GH stimulation
tests (P < 0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH
deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients
with multiple pituitary failure (>2 hormones affected), GH deficiency was present
in more than 90% regardless of the type of stimulation test used. The IGF-I
levels were only subnormal in 42% of the patients and did not correlate with the
peak GH responses in any of the stimulation tests (P > 0.05). Except for 1
patient all patients with subnormal IGF-I were GH deficient in all stimulation
tests. It is concluded that in patients with hypothalamic-pituitary disease and a
normal IGF-I level 2 stimulation tests should be performed to establish a
diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH
stimulation test should be sufficient to confirm the presence of GH deficiency.
PMID- 10770184
TI - A simple test for growth hormone deficiency in adults.
AB - GH deficiency (GHD) in adults is a well recognized clinical syndrome that results
in significant metabolic and psychological morbidity. GH replacement therapy not
only reverses these changes but improves the quality of life and results in a
significant improvement in well being. There is no single simple and safe test to
assess GHD. GHD in adults is diagnosed biochemically by provocative testing of GH
secretion, and the insulin tolerance test (ITT) is accepted to be the test of
choice. However, the ITT has many contraindications, needs multiple blood
samples, and is potentially dangerous, requiring regular monitoring of patients
in a specialized investigation unit. The aim of our study was to evaluate the GH
releasing effect of a combination of the hypothalamic secretagogue GHRH with a
small dose of the synthetic peptide GHRP-2, to diagnose GHD. We have compared the
GH response to ITT and GHRH/GHRP in a large group of adults with
hypothalamic/pituitary disease (n = 36; 22 males and 14 females; age, 18 -59 yr)
and in healthy volunteers (n = 30; 15 males and 15 females; age, 22-66 yr). The
GHRH/GHRP test produces a measurable GH secretory response in normal,
hypopituitary and GH-deficient patients. The test has no side effects. Using the
ITT as our 'gold standard' with a GH response of 9 mU/L as our cut-off to define
GHD, we compared the clinical efficacy of these two tests. Choosing an arbitrary
cut-off of 17 mU/L to define GHD in the GHRH/GHRP test, this new test proved to
have 78.6% sensitivity and 100% specificity even when we only used the 30-min
datum point.
PMID- 10770185
TI - Older men manifest multifold synchrony disruption of reproductive neurohormone
outflow.
AB - Under a working clinical hypothesis that aging putatively disrupts neuroendocrine
control mechanisms, here we test a specific corollary notion that transitions in
sleep stage, oscillations in nocturnal penile tumescence (NPT; a neurogenically
organized signal), and the rates of instantaneous secretion of LH and/or
testosterone are jointly synchronous in healthy young, but not older, men. To
this end, we evaluated 10 young (aged 21-31 yr) and 8 older (aged 65-74 yr) men
by intensive overnight multisite monitoring, viz. simultaneous electro
encephalogram and NPT recordings (every 30 s) and remote blood sampling (every
2.5 min) to quantitate LH and testosterone release. Waveform-independent
deconvolution and cross-correlation analyses of these neurohormone outflow
measures revealed that healthy young men sustain four salient physiological
linkages overnight: 1) a strong inverse (confirmatory) relationship between sleep
stage and NPT activity, such that deeper sleep is accompanied by suppression of
NPT; 2) consistent coupling between NPT and testosterone secretion, wherein
heightened NPT activity respectively precedes and follows increased testosterone
secretion by 12.5-32.5 and 50-60 min; 3) evident synchrony between sleep stage
and testosterone secretion, in which testosterone secretion increases over a 30
min window (-2.5 to 25 min) while sleep deepens; and 4) a close temporal linkage
between instantaneous LH release and NPT oscillations, whereby LH secretion
increases 55-62.5 min before and again 5-30 min after NPT declines. In contrast,
older men manifested global loss of expected young adult synchrony; namely, 1)
abolition of the inverse relationship between sleep stage and NPT, 2)
decorrelation of NPT oscillations and testosterone secretion, 3) decoupling of
testosterone release and deep sleep, and 4) abrogation of the linkage between LH
secretion and penile detumescence. In summary, high intensity overnight
monitoring of multiple reproductive neuroendocrine outflow measures
simultaneously in young men delineates prominent neurophysiological coupling
among sleep transitions and NPT activity, LH and testosterone secretion or NPT
oscillations, and testosterone secretion and deepening sleep stage. In contrast,
healthy older men exhibit near-universal disruption of physiological young adult
synchronicity. Thus, we conclude that male reproductive aging is marked by
erosion of coordinate regulation among sleep transitions, central nervous system
directed NPT activity, and hypothalamically driven episodic GnRH/LH (and thereby
Leydig cell testosterone) secretion. Whether analogous multifold uncoupling of
neurohormone signals emerges in the course of reproductive aging in women or in
nonhuman species is not yet known.
PMID- 10770186
TI - Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a
slow release formulation of the somatostatin analog lanreotide.
AB - Somatostatin analogs have been shown to be effective for the treatment of TSH
secreting pituitary adenomas. However, their use in this indication is limited by
the fact that available analogs require several daily sc injections. The present
study was performed to evaluate the effects of a slow release formulation of the
somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size
and to assess the tolerance in a series of thyrotropinomas treated for 6 months.
Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary
adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a
basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1
month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18
patients were injected twice monthly, and 7 of 18 patients received SR-L every 10
days for 5 additional months. One patient was dismissed from the study in month 1
of the study for side-effects and another in month 3 for noncompliance to the
protocol. Clinical and biological evaluations (plasma TSH, free alpha-subunit,
fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6
of treatment. Pituitary magnetic resonance imaging and gallbladder
ultrasonography were performed both at entry and at the end of the study.
Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable
patients. Mean (+/- SEM) plasma lanreotide levels reached 1.11 +/- 0.43 and 1.69
+/- 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then
remained stable until the end of the study. During therapy, the plasma TSH level
decreased from 2.72 +/- 0.32 to 1.89 +/-0.27 mU/L (P < 0.01), with parallel
significant changes in free alpha-subunit. During the same period, plasma fT4 and
fT3 levels decreased from 37.9 +/- 2.9 to 19.7 +/- 2.3 pmol/L (P < 0.01) and from
14.6 +/- 1.1 to 8.3 +/- 0.8 pmol/L (P < 0.01), respectively. No statistically
significant change in mean adenoma size was observed after 6 months of treatment.
Side-effects, including pain at the injection point, abdominal cramps, and
diarrhea, were mild and transient and did not lead to interruption of the
treatment. No gallstones occurred during the study. SR-L appears to be able to
suppress clinical signs of hyperthyroidism in our series of patients with TSH
secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid
hormone levels, which were normalized in 13 of 16 cases. The effect was
maintained throughout the treatment using 2 or 3 SR-L injections monthly without
any problem of tolerance. We conclude that SR-L is a safe and effective treatment
of thyrotropinomas and avoids the drawbacks of the modes of administration of
other somatostatin analogs, given three times daily.
PMID- 10770187
TI - Alendronate in early postmenopausal women: effects on bone mass during long-term
treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.
AB - We studied the effect on bone mass of alendronate treatment for 5 yr and its
withdrawal. Four hundred and forty-seven postmenopausal women with normal bone
mass entered a 3-yr randomized trial followed by a 2-yr open label extension.
Three hundred and eleven women completed the first 3 yr, and 263 consented to
continue and completed the extension. We are reporting data from groups using the
dose of alendronate currently approved for osteoporosis prevention (5 mg) or from
the group in which alendronate treatment was withdrawn: 52 women received
alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by
alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2
yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg)
increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P <
0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs.
baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine,
hip, and total body in groups I and III. The 3-yr decrease in BMD after
withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs.
baseline) and similar to the 3-yr decrease in BMD in group II during the initial
3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr
followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal
of alendronate (20 mg), bone loss resumed at the normal early postmenopausal
rate.
PMID- 10770188
TI - Effects of 10 days of endurance exercise training on the suppression of whole
body and regional lipolysis by insulin.
AB - The aim of this study was to evaluate in premenopausal women (10 sedentary obese
women) the effects of 10 days of exercise on the suppression of whole body and
regional lipolysis by insulin. Lipolysis was determined using 2H5-glycerol
infusion and microdialysis of sc adipose tissue during a two-stage
hyperinsulinemic-euglycemic clamp [10 (LO) and 20 (MO) mU/m x min]. Microdialysis
probes were positioned in abdominal and femoral sc adipose tissue to monitor
interstitial glycerol and blood flow. Basal plasma glycerol was 86.7 +/-17.0 and
100.3 +/- 19.8 micromol/L before and after training, respectively (P < 0.05).
Plasma glycerol was suppressed to a greater extent after [to 47 +/- 5% (LO) and
42 +/- 5% (MO) of basal] than before [to 62 +/- 8% (LO) and 55 +/- 8% (MO) of
basal] training. The rate of appearance of glycerol was suppressed to 49 +/- 7%
and 40 +/- 5% of basal during LO and to 38 +/- 5% and 30 +/- 4% of basal during
MO (P < 0.05) before and after training, respectively. There were no differences
in the suppression of lipolysis in abdominal as well as femoral sc adipose tissue
as evidenced by similar reductions in dialysate glycerol levels before and after
training in each of these tissues. The results indicate that the antilipolytic
response to insulin can be improved through endurance exercise training.
Intraabdominal adipose tissue or skeletal muscle may be the site of improved
antilipolytic response to insulin after training, as improvement was not evident
in abdominal or femoral sc adipose tissue.
PMID- 10770189
TI - Growth hormone (GH) effects on bone and collagen turnover in healthy adults and
its potential as a marker of GH abuse in sports: a double blind, placebo
controlled study. The GH-2000 Study Group.
AB - The effects of GH on bone remodeling in healthy adults have not been
systematically investigated. An analysis of these effects might provide insights
into GH physiology and might yield data useful for the detection of GH doping in
sports. The aim of this study was to evaluate the effects of GH administration on
biochemical markers of bone and collagen turnover in healthy volunteers. Ninety
nine healthy volunteers of both sexes were enrolled in a multicenter, randomized,
double blind, placebo-controlled study and assigned to receive either placebo (40
subjects) or recombinant human GH (0.1 IU/kg day in 29 subjects and 0.2 IU/kg x
day in 30 subjects). The treatment duration was 28 days, followed by a 56-day
wash-out period. The biochemical markers evaluated were the bone formation
markers osteocalcin and C-terminal propeptide of type I procollagen, the
resorption marker type I collagen telopeptide, and the soft tissue marker
procollagen type III. All variables increased on days 21 and 28 in the two active
treatment groups vs. levels in both the baseline (P < 0.01) and placebo (P <
0.01) groups. The increment was more pronounced in the 0.2 IU/kg-day group and
remained significant on day 84 for procollagen type III (from 0.53 +/- 0.13 to
0.61 +/- 0.14 kU/L; P < 0.02) and osteocalcin (from 12.2 + 2.9 to 14.6 +/- 3.6
UG/L; P < 0.02), whereas levels of C-terminal propeptide of type I procollagen
and type I collagen telopeptide declined after day 42 and were no longer
significantly above baseline on day 84 (from 3.9 +/- 1.2 to 5.1 +/-1.5 microg/L
and from 174 +/- 60 to 173 +/- 53 microg/L, respectively). Gender-related
differences were observed in the study; females were less responsive than males
to GH administration with respect to procollagen type III and type I collagen
telopeptide (P < 0.001). In conclusion, exogenous GH administration affects the
biochemical parameters of bone and collagen turnover in a dose- and gender
dependent manner. As GH-induced modifications of most markers, in particular
procollagen type III and osteocalcin, persist after GH withdrawal, they may be
suitable markers for detecting GH abuse.
PMID- 10770190
TI - The changing incidence and spectrum of thyroid carcinoma in Tasmania (1978-1998)
during a transition from iodine sufficiency to iodine deficiency.
AB - Exposure to ionizing radiation, changing levels of iodine nutrition, and
increased pathologic diagnosis of clinically unimportant thyroid neoplasia have
all been proposed as explanations for a worldwide rise in the incidence of
thyroid carcinoma (TC) over the past 6 decades. Tasmania is geographically an
area of endemic iodine deficiency. In this report, we describe the spectrum of TC
in a population averaging 450,000 persons during a 21-yr period that spans the
communities transition from iodine sufficiency to iodine deficiency after
discontinuation of universal iodine prophylaxis in the mid 1980s. The Tasmanian
Cancer Register was used to ascertain all cases of TC diagnosed in Tasmania
between 1978 and 1998. Histopathological and demographic data were reviewed. A
total of 289 cases of TC were identified. Papillary TC (PTC), follicular TC,
medullary TC, and other species accounted for 62%, 23%, 4%, and 11% of cases,
respectively. The age standardized incidence rate for total TC increased from
2.45 to 5.33 per 100,000 for females and 0.75 to 1.76 per 100,000 for males
between 1978 and 1984 and 1992 and 1998, respectively. A rise in the incidence of
PTC by 4.5-fold (P < 0.05) in females and 2.1-fold in males (not significant) was
the dominant change over this period. In parallel, the proportion of follicular
TC relative to PTC fell from 0.35 to 0.17 during these years (P < 0.05). The rise
in PTC incidence was, in part, due to an increase in the occurrence of tumors 1cm
or less in diameter. Nonetheless, a 3-fold rise in incidence of larger lesions
was also observed during the study period. Forty-three (24%) PTC cases had
multifocal disease, 17 (40%) of whom had bilateral tumors. Familial (autosomal
dominant) PTC was identified in nine (5%) total PTC cases. Prior studies have
linked iodine prophylaxis to a rise in the proportion of differentiated TC,
particularly PTC. Our data suggest a complex relationship between iodine
nutrition and thyroid tumorigenesis. Factors such as a long latency between
changes in iodine nutrition and thyroid tumorigenesis, a dose threshold for the
effect of iodine nutrition on thyroid tumorigenesis, and an interaction between
iodine nutrition and thyroidal sensitivity to ionizing radiation may all play a
role.
PMID- 10770191
TI - The combination of insulin-like growth factor I and insulin-like growth factor
binding protein-3 reduces insulin requirements in insulin-dependent type 1
diabetes: evidence for in vivo biological activity.
AB - Insulin-like growth factor-I (IGF-I) enhances insulin action in normal subjects
and in patients with both type 1 and 2 diabetes; however, its administration is
associated with significant side effects in a high percentage of patients. The
coadministration of IGF binding protein-3 (IGFBP-3, the predominant IGF binding
protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not
attenuate the ability of IGF-I to enhance protein synthesis and bone accretion;
therefore, we determined whether IGF-I/IGFBP-3 would retain biological activity
in type 1 DM and limit side effects associated with free IGF-I administration.
Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg-day) by
continuous sc infusion for 2 weeks. Each subject served as his own control; and,
during a paired 2-week period, each received a placebo infusion. The order of the
treatments was randomized. Subjects were placed on a constant caloric intake but
were allowed to adjust insulin doses to maintain appropriate levels of glycemic
control. Subjects measured blood glucose four times per day at home and kept a
log of their insulin use. Frequent sampling for glucose, insulin, and GH was
conducted during four inpatient study periods, one at the beginning and one at
the end of each 2-week study interval. During IGF-I/IGFBP-3, insulin doses were
reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels
obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared
with control, but showed no change with placebo. Concomitant glucose measurements
did not differ in the two treatment groups. There was no change in body weight.
Fructosamine levels decreased by 12%, but this was not significant (P < 0.1).
Fasting triglyceride was unchanged, but cholesterol declined from 170 +/- 24 to
149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable)
rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze
the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the
change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48
to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated
subjects had minor hypoglycemic episodes at home that required adjustment of
insulin doses. No episode was classified as severe. In contrast to previous
studies with free IGF-I, there were no cases of edema, headache, jaw pain,
retinal edema, or Bell's palsy. No subject withdrew because of drug
complications. These findings indicate that IGF-I/IGFBP-3 is biologically active
on carbohydrate metabolism, as measured by a decrease in insulin requirements in
patients with type 1 diabetes. Further studies will be required to determine the
long-term safety and efficacy of this combination in patients with insulin
resistance and diabetes.
PMID- 10770192
TI - Bilateral inferior petrosal sinus sampling in the differential diagnosis of
adrenocorticotropin-dependent Cushing's syndrome: a comparison with other
diagnostic tests.
AB - To compare bilateral inferior petrosal sinus sampling (IPSS) with high dose
dexamethasone (HDD) and CRH testing (using recently proposed stringent response
criteria) in the differential diagnosis of ACTH-dependent Cushing's syndrome, we
reviewed 53 consecutive cases. The main analysis was limited to 45 cases with
confirmed diagnosis: 44 with pituitary dependency, proven by confirmatory
histology and/or significant biochemical improvement after pituitary surgery, and
1 with ectopic ACTH syndrome. After HDD (2 mg every 6 h for 48 h), 21 of the 44
pituitary cases met the stringent more than 90% suppression criterion. Twenty
three of the 44 pituitary cases also underwent CRH testing; 16 of 23 met a
stringent response criterion of a more than 50% serum cortisol rise. For HDD and
CRH testing combined, 8 of 23 fulfilled both stringent criteria, 10 of 23 had
discordant results, and 5 of 23 failed to fulfil either of the stringent criteria
for pituitary dependency. IPSS was performed in all 44 of the proven pituitary
cases; 36 had petrosal/peripheral ACTH ratios of 2.0 or more without CRH
stimulation. Thus, in patients with proven pituitary disease, stringent response
criteria to HDD and CRH testing were fulfilled by only 48% and 70%, respectively.
IPSS, which gave direct evidence of pituitary ACTH secretion in 82% of the cases,
is therefore considered necessary in a significant proportion of cases.
PMID- 10770193
TI - The severity of chronic heart failure due to coronary artery disease predicts the
endocrine effects of short-term growth hormone administration.
AB - Treatment with human recombinant GH has yielded conflicting results in patients
with heart failure. As GH sensitivity may be important for treatment effects, the
present study evaluated GH secretion and sensitivity in noncachectic patients
with ischemic heart failure. Twenty clinically stable, male patients with
moderate heart failure (mean New York Heart Association class, 2.0 +/- 0.8; mean
ejection fraction, 30.0 +/- 8.4%) due to coronary artery disease were randomly
assigned single blind to a low dose (group A; n = 10) and a high dose (group B; n
= 10) group, receiving either 5 microg/kg x day recombinant human GH for 4 days
followed by 10 microg/kg x day GH for another 4 days or 10 and 20 microg/kg x day
GH, respectively. Cardiac function was assessed by echocardiography. Serum
insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and 24-h
urinary GH excretion as a measure of pituitary GH secretion were determined at
baseline and on days 5 and 9. Baseline IGF-I and IGFBP-3 levels and GH excretion
were significantly diminished compared to those in age-matched controls. There
was a dose-dependent increase in IGF-I and IGFBP-3 during GH treatment. The
increase in IGF-I induced by 10 microg/kg x day GH correlated positively to left
ventricular ejection fraction (r = 0.59; P = 0.006) and inversely to left
ventricular end-diastolic and end-systolic dimensions (r < -0.6 and P < 0.01 for
both). In conclusion, GH secretion and serum levels of IGF-I and IGFBP-3 are
diminished in patients with moderate ischemic heart failure. Left ventricular
function determines the sensitivity of the GH/IGF-I system, measured as the IGF-I
response to GH application. This finding suggests that individual dose
adjustments may be an indispensable prerequisite for successful GH therapy in
heart failure.
PMID- 10770194
TI - Effects of short-term glucocorticoid deprivation on growth hormone (GH) response
to GH-releasing peptide-6: studies in normal men and in patients with adrenal
insufficiency.
AB - There are no data in the literature about the effects of glucocorticoid
deprivation on GH-releasing peptide-6 (GHRP-6)-induced GH release. The aims of
this study were to evaluate GH responsiveness to GHRP-6 1) after metyrapone
administration in normal men, and 2) in patients with chronic hypocortisolism
after glucocorticoid withdrawal for 72 h. In normal subjects, metyrapone
ingestion did not alter significantly GH responsiveness to GHRP-6 [n = 8; peak,
39.3 +/-7.1 microg/L; area under the curve (AUC), 1958.8 +/- 445.7 microg/min x
L; mean +/- SE] compared to placebo (n = 8; peak, 21.9 +/- 4.5; AUC, 1131.0 +/-
229.6). In patients with chronic hypocortisolism (n = 8), GH responses to GHRP-6
were similar both during replacement therapy (peak, 11.8 +/- 3.9; AUC, 563.2 +/-
208.7) and after withdrawal of prednisone (peak, 14.4 +/- 4.5; AUC, 695.6 +/-
272.9) and did not differ from those in controls. Interestingly, after
glucocorticoid withdrawal, GH responsiveness to GHRP-6 in patients with chronic
hypocortisolism was significantly lower than that in normal subjects pretreated
with metyrapone. Our data suggest that short term glucocorticoid deprivation does
not have a major impact on GHRP-6-dependent GH-releasing mechanisms. However, in
long standing hypocortisolism, subtle changes in GHRP-6 secretory pathways may be
present.
PMID- 10770195
TI - The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with
Graves' disease in African Americans.
AB - Information on genetic susceptibility to Graves' disease in African Americans is
limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4
polymorphisms in 49 African American patients with adult onset Graves' disease
and 47 racially-matched controls using PCR-based sequence-specific priming
methods. There were no significant differences in DRB1 or DQB1 allelic
frequencies or CTLA-4 polymorphisms between patients and controls. However, we
found that the frequency of DRB3 was significantly increased in the patients
(75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype
(53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in
concordance with our previous observations in Caucasian patients with adult-onset
Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P
= 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or
DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 =
7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202,
particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s)
for Graves' disease in adult African Americans. Considering these data with those
in Caucasian patients, our results would suggest that the primary Graves
susceptible locus is likely DRB3 and not DRB1.
PMID- 10770196
TI - Changes in energy expenditure and substrate oxidation resulting from weight loss
in obese men and women: is there an important contribution of leptin?
AB - The aim of the present study was to determine the impact of weight loss and its
related metabolic and hormonal changes on resting energy expenditure (REE) and
substrate oxidation. Forty subjects (16 men and 24 women) took part in a 15-week
weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or
placebo coupled to an energy restriction (-700 Cal/day). Subjects were asked to
come to the laboratory after an overnight fast for an indirect calorimetry
measurement before and after weight loss. Fasting blood samples were also drawn
and were analyzed for plasma glucose, insulin, leptin, and free fatty acid
determinations. This program reduced body weight by 11% and 9% (P < 0.01) in men
and women, respectively. Fat mass (FM) and fat-free mass (FFM) were also
significantly reduced in both sexes. A significant decrease in REE (13%; P <
0.01) and fat oxidation (11%; P = 0.08) was observed in men in response to this
program, whereas no significant differences were noted for these variables in
women. In men, positive correlations were found between changes in FFM and energy
related variables, whereas the best predictor of changes in REE and substrate
oxidation was the change in FM in women. The most important finding of this study
is that in men, the association between changes in fasting plasma leptin and
changes in REE (r = 0.50; P < 0.01) and fat oxidation (r = 0.63; P < 0.01)
persist after correction for changes in body composition. These results suggest
that a comparable weight loss is accompanied by a greater decrease in REE and
substrate oxidation in men than in women, and that these changes are better
explained by changes in leptinemia in men and by changes in FM in women.
PMID- 10770197
TI - Insulin-like growth factor I (IGF-I) replacement during growth hormone receptor
antagonism normalizes serum IGF-binding protein-3 and markers of bone formation
in ovariectomized rhesus monkeys.
AB - Previous work from this laboratory has shown that the constant sc infusion of
insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a
sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP
3), whereas the acute administration of IGF-I to monkeys pretreated with a GH
receptor antagonist produces a brief, but significant, elevation in serum IGFBP
3. The present study tested the hypothesis that the constant infusion of IGF-I
would normalize serum concentrations of IGFBP-3 in females treated with the GH
receptor antagonist. To assess the biological significance of these effects,
serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation,
osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five
female rhesus monkeys were studied over 21 consecutive days involving 7 days of
baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week,
sc), and 7 days of treatment with the GH receptor antagonist supplemented with
IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of
the initiation of treatment with the GH receptor antagonist, serum IGF-I and
IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels
continued to decline through the remainder of treatment. However, within 48 h of
the initiation of IGF-I administration during GH receptor antagonist treatment,
both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values.
Serum concentrations of ALS were also decreased by GH antagonism, but levels
increased in some (n = 2), but not all, subjects upon administration of IGF-I.
Size exclusion ultrafiltration indicated that the amount of IGF-I found in the
high molecular mass complex (>100 kDa) decreased significantly during GH
antagonism, but was similar during the baseline and IGF-I infusion phases.
Finally, treatment with the GH receptor antagonist also significantly reduced
serum levels of osteocalcin and collagen type I C-terminal propeptide, an effect
reversed by the addition of IGF-I. These data support the hypothesis that IGF-I
increases serum concentrations of IGFBP-3 when endogenous GH action is
compromised and that such treatment produces biologically active IGF-I, as
evidenced by normalization of biomarkers for bone formation. These results
indicate that IGF-I administration during GH receptor antagonism restores
circulating levels of IGFBP-3 and the amount of IGF-I found in the high molecular
mass complex to levels observed during baseline conditions. It remains to be
determined whether IGF-I directly affects hepatic synthesis and secretion of
IGFBP-3 and what role IGF-I has in the direct regulation of ALS in the monkey.
PMID- 10770198
TI - Differential regulation by troglitazone of plasminogen activator inhibitor type 1
in human hepatic and vascular cells.
AB - Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma
activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic
patients such as women with polycystic ovary syndrome and patients with type 2
diabetes mellitus. However, underlying mechanisms have not yet been fully
elucidated. Human hepatic and vascular cells, the main sources of circulating PAI
1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in
conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone
(P = 0.001). The accumulation depended on the concentration of troglitazone, but
not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human
aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1
expression by 23% (P = 0.037) and decreased transforming growth factor-beta
induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue
type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial
cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen
activator was unaffected. The results suggest that the reduction in plasma
activity of PAI-1 induced by troglitazone in patients may reflect both directly
mediated diminution of its elaboration from vessel walls and indirectly mediated
reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia
(known to increase the hepatic synthesis of PAI-1).
PMID- 10770199
TI - Glucose and lactate kinetics in children with severe malaria.
AB - Children with severe malaria often present with lactic acidosis and hypoglycemia.
Although both complications independently predict mortality, mechanisms
underlying their development are poorly understood. To study these metabolic
derangements we sequentially allocated 21 children with falciparum malaria and
capillary lactate concentrations of 5 mmol/L or more to receive either quinine or
artesunate as antimalarial therapy, and dichloroacetate or saline placebo for
lactic acidosis. We then administered a primed infusion (90 min) of L-[3
13C1]sodium lactate and D-[6,6-D2]glucose to determine the kinetics of these
substrates. The mean (SD) glucose disposal rate in all patients was 56 (16)
micromol/kg x min, and the geometric mean (range) lactate disposal rate was 100
(66-177) micromol/kg x min. Glucose and lactate disposal rates were positively
correlated (r = 0.62; P = 0.005). Artesunate was associated with faster parasite
clearance, lower insulin/glucose ratios, and higher glucose disposal rates than
quinine. Lactate disposal was positively correlated with plasma lactate
concentrations (r = 0.66; P = 0.002) and time to recovery from coma (r = 0.82; P
< 0.001; n = 15). Basal lactate disposal rates increased with dichloroacetate
treatment. Elevated glucose turnover in severe malaria mainly results from
enhanced anaerobic glycolysis. Quinine differs from artesunate in its effects on
glucose kinetics. Increased lactate production is the most important determinant
of lactic acidosis.
PMID- 10770200
TI - Effects of the menopause, gender, and estrogen replacement therapy on vascular
nitric oxide activity.
AB - Changes in vascular nitric oxide (NO) activity may contribute to cardiovascular
risk. We determined the effect of the menopause, gender, and estrogen replacement
therapy on arterial vascular NO activity. Vascular NO activity and sensitivity
were determined in 15 healthy premenopausal women (mean age, 48 yr), 12
postmenopausal women (51 yr), and 14 men (51 yr). The effects of 14 days of
estrogen replacement therapy (625 microg conjugated estrogens) were studied in 20
healthy postmenopausal women (60 yr). Forearm blood flow responses to brachial
arterial infusions of L-NG-monomethyl-arginine (L-NMMA), norepinephrine, glyceryl
trinitrate (GTN), and serotonin were determined using venous occlusion
plethysmography. Constrictor responses to L-NMMA were reduced in postmenopausal
women (82 +/- 14, summary response, mean +/- SEM) and men (89 + 6) compared to
premenopausal women (118 + 10; P < 0.05). Constrictor responses to norepinephrine
were increased in males (125 +/- 13) compared to premenopausal (81 +/- 8) and
postmenopausal (88 +/- 16) women (P < 0.05). No differences were observed in GTN
or serotonin responsiveness. Constrictor responses to L-NMMA increased after
estrogen replacement (132 +/- 7 vs. 89 +/- 14; P < 0.05), with no change in
norepinephrine, GTN, or serotonin responses. The menopause and male gender were
associated with reduced arterial NO activity. Two weeks of estrogen replacement
therapy restored vascular NO activity to premenopausal levels. Changes in
vascular NO activity may contribute to changes in cardiovascular risk associated
with male gender, postmenopausal status, and estrogen replacement therapy.
Increased alpha-adrenoceptor responsiveness may contribute to increased
cardiovascular risk in males.
PMID- 10770201
TI - Impaired insulin-stimulated expression of the glycogen synthase gene in skeletal
muscle of type 2 diabetic patients is acquired rather than inherited.
AB - To examine whether defective muscle glycogen synthase (GYS1) expression is
associated with impaired glycogen synthesis in type 2 diabetes and whether the
defect is inherited or acquired, we measured GYS1 gene expression and enzyme
activity in muscle biopsies taken before and after an insulin clamp in 12
monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control
subjects. The effect of insulin on GYS1 fractional activity, when expressed as
the increment over the basal values, was significantly impaired in diabetic (15.7
+/- 3.3%; P < 0.01), but not in nondiabetic (23.7 +/- 1.8%; P = NS) twins
compared with that in control subjects (28.1 +/- 2.3%). Insulin increased GYS1
messenger ribonucleic acid (mRNA) expression in control subjects (from 0.14 +/-
0.02 to 1.74 +/- 0.10 relative units; P < 0.01) and in nondiabetic (from 0.24 +/-
0.05 to 1.81 +/- 0.16 relative units; P < 0.01) and diabetic (from 0.20 +/- 0.07
to 1.08 + 0.14 relative units; P < 0.01) twins. The effect of insulin on GYS1
expression was, however, significantly reduced in the diabetic (P < 0.003), but
not in the nondiabetic, twins compared with that in control subjects. The
postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r
= -0.61; P < 0.001). Despite the decrease in postclamp GYS1 mRNA levels, the GYS1
protein levels were not decreased in the diabetic twins compared with those in
the control subjects (2.10 +/- 0.46 vs. 2.10 +/- 0.34 relative units; P = NS). We
conclude that 1) insulin stimulates GYS1 mRNA expression; and 2) impaired
stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes
is acquired and most likely is secondary to chronic hyperglycemia.
PMID- 10770202
TI - Expression and regulation of P2U-purinergic receptor in human granulosa-luteal
cells.
AB - The P2U purinoceptor (P2UR) has been identified pharmacologically in the ovary.
However, the expression and regulation of the P2UR messenger RNA (mRNA) in human
ovarian cells are still poorly characterized. The present study was designed to
examine the expression and regulation of the P2UR in human granulosa-luteal cells
(hGLCs) by RT-PCR and Northern blot analysis. A PCR product corresponding to the
expected 599-bp P2UR complementary DNA was obtained from hGLCs. Molecular cloning
and sequencing of the PCR product revealed an identical sequence to the reported
P2UR complementary DNA. Two mRNA transcripts of 2.0 kb and 4.6 kb were identified
in hGLCs using Northern blot analysis. The expression of the P2UR mRNA was down
regulated by human CG in a dose- and time-dependent manner. Treatment with 8
bromo-cAMP and forskolin also attenuated P2UR mRNA levels. Calcium signaling
following the activation of the P2UR in single hGLCs was studied using
microspectrofluorimetry. It revealed that, like ATP, uridine triphosphate (UTP)
also induced cytosolic calcium mobilization in a dose-dependent manner. These
results demonstrate for the first time that the P2UR mRNA is expressed in hGLCs
and that P2UR mRNA is regulated by human CG, cAMP, and forskolin. The P2UR
expressed in hGLCs functional because activation of the P2UR by ATP or UTP
resulted in rapid and transient mobilization of cytosolic calcium at the single
cell level. These findings further support a potential role of this
neurotransmitter receptor in the human ovary.
PMID- 10770203
TI - Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein
I in polycystic ovary syndrome.
AB - The objective of the present study was to investigate whether metformin affected
plasma concentrations of insulin-like growth factor (IGF) I and IGF-binding
protein I (IGFBP-I) in polycystic ovary syndrome (PCOS) patients. This was an
open study conducted by the Department of Obstetrics and Gynecology at the
University of Siena, Italy. Seventeen women with PCOS participated in the study
and were administered metformin at a dose of 500 mg three times a day. Treatment
was continued for 30-32 days, after which the pretreatment evaluation was
repeated. Plasma concentrations of LH, FSH, estradiol, free testosterone, IGF-I,
IGFBP-I, sex hormone-binding globulin, and insulin were evaluated. Metformin led
to a significant reduction in areas under the insulin curves (9310 +/- 1509 vs.
6520 +/-1108 mU/mL x min; P < 0.05) and was associated with a decrease in plasma
free testosterone levels (12.7 +/- 1.7 vs. 10.3 +/- 2 pg/mL; P < 0.05) and an
increase in plasma sex hormone-binding globulin concentrations (62 +/- 8 vs. 94
+/- 13 nmol/L; P < 0.05). A nonsignificant increase in plasma IGF-I levels was
observed after metformin (276 +/-48 vs. 291 +/- 71 mcg/L), with a significant
increase in plasma IGFBP-I levels (0.56 +/- 0.2 vs. 0.98 +/- 0.38 mcg/L; P <
0.05). The IGF-I/IGFBP-I ratio was significantly lower (492.8 +/- 117 vs. 296.9
+/- 82; P < 0.05) at the end of therapy than before treatment. In conclusion, it
seems to be appropriate to intervene with an insulin-sensitizing agent such as
metformin in an attempt to break the pathogenetic link between hyperinsulinemia
and hormonal perturbations in PCOS.
PMID- 10770204
TI - Identification of wild-type and exon 5 deletion variants of estrogen receptor
beta in normal human mammary gland.
AB - We have examined messenger RNA (mRNA) expression of estrogen receptor (ER) alpha,
wild-type ERbeta (mRNA and protein), and ERbeta exon 5 deletion variants (ERbeta
delta5) in samples of normal human mammary gland obtained from 37 premenopausal
subjects undergoing reduction mammoplasty. Comparing individual expression,
ERbetaP mRNA predominated, expressed in 34 of 37 samples (91%), whereas ERalpha
was found in 21 of 37 cases (57%). Receptor combinations were then analyzed and
compared. Most samples either coexpressed ERalpha with ERbeta (54%) or expressed
just ERbeta (38%). Immunohistochemical analysis revealed that ERbeta mRNA
expression mirrored that of protein. Immunoreactivity was observed in the nucleus
with additional evidence of cytoplasmic staining in those epithelial cells lining
the breast ducts. Sporadic immunoreactivity was also detected in stromal cells.
Expression of wild type and ERbeta delta5 was analyzed, and their association
with ERalpha was compared. Most samples coexpressed wild-type ERbeta and the
splice variant (62%; P = 0.05), with 30% exclusively expressing wild-type ERbeta.
Although samples coexpressing wild type and variant ERbeta showed no statistical
association with ERalpha, those samples expressing only wild-type ERP, showed a
trend toward associations with ERalpha (P = 0.07). In conclusion, our data would
support a role for ERbeta in the normal human mammary gland, where we propose it
may be the dominant receptor.
PMID- 10770206
TI - Progesterone exposure prevents matrix metalloproteinase-3 (MMP-3) stimulation by
interleukin-1alpha in human endometrial stromal cells.
AB - Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to
maintain tissue stability during the invasive events of implantation and
placental development. Several laboratories have shown that inflammatory
cytokines, including interleukin-lalpha (IL-1alpha), can oppose progesterone
suppression of MMPs in the human endometrium. Furthermore, we have recently
demonstrated colocalization of epithelial cell IL-1alpha and MMP-7 expression at
sites of ectopic pregnancy. The current study extends these findings, revealing a
previously unrecognized interrelationship between progesterone and IL-1alpha in
regulation of MMP-3. Although IL-1alpha is a potent stimulator of MMP-3 in
proliferative phase endometrium in organ culture, we demonstrate that
progesterone exposure in vivo reduces IL-1alpha stimulation of MMP-3 in secretory
phase tissue. This loss of sensitivity to IL-1alpha was duplicated in isolated
stromal cells treated with progesterone in vitro, and IL-1alpha stimulation of
MMP-3 returned in a dose-dependent manner with progesterone withdrawal. The
antiprogestin, onapristone, partially blocked the ability of progesterone to
prevent stimulation of MMP-3 by IL-1alpha. These data suggest a novel mechanism
by which progesterone may preserve tissue integrity during the establishment and
maintenance of pregnancy by limiting stimulation of MMPs by inflammatory
cytokines such as IL-1a.
PMID- 10770205
TI - Studies of the variability of the genes encoding the insulin-like growth factor I
receptor and its ligand in relation to type 2 diabetes mellitus.
AB - Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of
growth, differentiation, and development, and as low birth weight has been
associated with impaired glucose tolerance and overt type 2 diabetes in adult
life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR)
as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here
we report the mutational analysis of the coding regions of the IGF-I and IGF-IR
performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No
mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR
genes were detected, but several silent and intronic polymorphisms were found.
The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was
evaluated in a population-based sample of 349 young healthy subjects, where the
variant had an allele frequency of 0.44 (95% confidence interval, 0.40-0.48). No
significant relationships between this variant and birth weight, birth length, or
insulin sensitivity index were detected. In addition, we did not observe any
significant differences in allelic frequencies of the codon 1013 variant between
395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval,
0.49-0.55) and 238 matched glucose-tolerant control subjects (allelic frequency,
0.47; 95% confidence interval, 0.43-0.50). In conclusion, variability in the
coding regions of IGF-I and the IGF-IR does not associate with reduced birth
weight, insulin sensitivity index, or type 2 diabetes in the Danish population.
PMID- 10770207
TI - Gonadotropins and cytokines affect luteal function through control of apoptosis
in human luteinized granulosa cells.
AB - The luteal phase in the normal human menstrual cycle is known to be about 14
days. The physiological mechanisms that regulate the corpus luteum remain to be
clarified, although apoptosis is reported to be involved. This study was
undertaken to investigate the regulation of luteal function by gonadotropins,
cytokines, and PGs, concentrating attention on the incidence of apoptosis and its
molecular mechanisms in cultured human luteinized granulosa cells collected at
oocyte pick-up from patients undergoing in vitro fertilization and embryo
transfer. Clusters of granulosa cells were pipetted in 0.1% hyaluronidase in
phosphate-buffered saline. After cell separation by centrifugation using Ficoll
Paque, 1 x 104 viable cells/mL in RPMI 1640 medium with 10% FCS were used for
experimentation. Substances added were FSH (100 ng/mL), hCG (100 ng/mL), LH (100
ng/mL), interleukin-1beta (IL-1beta; 10 ng/mL), transforming growth factor-beta1
(TGFbeta1; 10 ng/mL), macrophage colony-stimulating factor (MCSF; 10 ng/mL),
tumor necrosis factor-alpha (TNFalpha; 10 ng/mL), and PGF2alpha (10 ng/mL). After
24-h culture at 37 C under 5% CO2 and air, cells were fixed with 4% neutral
buffered formalin and stained with Hoechst 33258. Apoptotic bodies were counted
under a fluorescence microscope, and immunostaining was performed using anti-Fas,
Fas ligand, Bcl-2, Bax, and p53 antibodies. Incidences of apoptotic bodies in the
group without substance addition were 0.7 +/- 0.2% (0 h), 5.9 +/-0.6% (24 h), and
7.9 +/- 1.2% (48 h); spontaneous increase was significant at the latter time
points. Defining the incidence at 24 h as 100%, values after treatment were: FSH,
57%; LH, 84%; hCG, 44%; IL-1beta, 76%; TGFbeta1, 52%; M-CSF, 50%; TNFalpha, 177%;
and PGF2alpha, 147%. Significant suppression was observed with FSH, hCG,
TGFbeta1, and M-CSF (P < 0.01). On the other hand, significant induction occurred
with TNFalpha and PGF2alpha (P < 0.01). On immunostaining, the incidence of
stained cells with anti-Fas, Fas ligand, Bax, and p53 antibody was increased
after 24-h incubation without addition. This was reduced by hCG, TGFbeta1, and M
CSF. No stained cells were observed with anti-Bcl-2 antibody before or after
incubation. In conclusion, our results suggest that both gonadotropins (FSH and
hCG) and cytokines (TGFbeta1 and M-CSF) may be involved in the support of luteal
function via suppression of apoptosis, and that TNFalpha and PGF2alpha may
contribute to ovarian dysfunction and/or luteal regression via its induction in
human luteinized granulosa cells. Our results also suggest that Fas, Fas ligand,
p53, and Bax may play roles in this apoptosis controlled by hCG, TGFbeta1, and M
CSF.
PMID- 10770208
TI - Testosterone and insulin-like growth factor (IGF) I interact in controlling IGF
binding protein production in androgen-responsive foreskin fibroblasts.
AB - The growth of the male external genitalia is primarily regulated by androgens.
However, human genital fibroblast growth is also stimulated by insulin-like
growth factor (IGF) I. In this study, we report that IGF-binding protein (IGFBP)
production in human foreskin fibroblasts is regulated by androgens and IGF-I.
Human foreskin fibroblasts secrete IGFBP-3, IGFBP-4, and IGFBP-5. IGF-I increased
the abundance of both intact IGFBP-3 and -5 in the culture medium. Testosterone
increased IGFBP-3, and the combination of IGF-I and testosterone had an additive
effect. Following its secretion, IGFBP-5 was degraded, but the effect of IGF-I on
IGFBP-5 peptide abundance in conditioned media did not seem to be due to
inhibition of proteolysis. Testosterone had no effect on IGFBP-5 degradation.
Intact IGFBP-4 was decreased by IGF-I, and the combination resulted in a similar
reduction. The mechanism seemed to be decreased synthesis, since IGFBP-4
messenger RNA was also decreased. The increase in IGFBP-5 synthesis was
associated with an increase in the abundance of intact IGFBP-5 in the
extracellular matrix. The combination of testosterone and IGF-I resulted in a
synergistic stimulation of total protein synthesis by the fibroblast cultures,
suggesting that a maximum anabolic response requires both hormones. These
observations suggest that combined exposure to androgen and IGF-I altered the
abundance of some forms of IGFBPs and that the IGFBPs that are regulated may play
a role in modulating the effects of IGF-I on the anabolic response.
PMID- 10770209
TI - Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent
girls and adult women: relation to age, stage of puberty, menstrual cycle,
follicle-stimulating hormone, luteinizing hormone, and estradiol levels.
AB - Biochemical assessment of gonadal function during maturation in girls and in
adult women can be troublesome. With the recent advent of specific assays for the
gonadal peptides inhibin A and inhibin B, it might be possible to achieve a
clearer picture of events. We therefore determined serum levels of inhibin A,
inhibin B, FSH, LH and estradiol in a cross-sectional study of 403 healthy
schoolgirls (aged 6 -20 yr) in relation to age and stage of puberty and in 181
healthy nonpregnant women (aged 20-32 yr) in relation to stage of the menstrual
cycle. In addition, inhibin A and inhibin B were measured daily throughout the
menstrual cycle in 10 healthy adult women. Levels of inhibin B are low or
undetectable in prepubertal girls (median, 26.5 pg/mL; 95% prediction interval,
<20-100 pg/mL), increase sharply through pubertal stage II to peak in stage III
(median, 84 pg/mL; 95% prediction interval, 28-227 pg/mL) and thereafter decline
through pubertal stages IV and V. These changes presumably reflect increasing
ovarian stimulation through early puberty, resulting in an increased number of
developing follicles, follicles reaching a later stage of development before
undergoing atresia, or both. Declining levels in late puberty and adulthood
probably reflect the onset of the menstrual cycle and the subsequent appearance
of the luteal phase, where inhibin B levels are low. Inhibin A levels are
undetectable or very low in early puberty (median, <7 pg/mL; 95% prediction
interval, <7-14) pg/mL), increasing gradually through pubertal stages to reach
their highest values in adult women (median, 21.5 pg/mL; 95% prediction interval,
<7-129 pg/mL). Levels of inhibin A greater than 19 pg/mL are only seen in
postmenarcheal girls in puberty and in adult women, again consistent with inhibin
A being primarily produced by the corpus luteum. Determining cut-off levels of
serum inhibin B regarding whether a girl had entered puberty resulted in similar
(low) sensitivities and specificities as those found for cut-off levels of LH or
estradiol due to the large overlap between serum values in Tanner stages I and
II. Correlations between inhibin A and inhibin B and FSH, LH, and estradiol
within pubertal stages are presented. In early puberty both inhibin A and inhibin
B correlated positively with LH and FSH. In late puberty inhibin A correlated
negatively with FSH and did not correlate with LH; inhibin B still correlated
positively with both FSH and LH, now most strongly with FSH. In adult women
during the menstrual cycle, serum inhibin B levels increased during the
follicular phase, indicating the greatest production by follicles in early stages
of development. In contrast, serum inhibin A levels peaked during the luteal
phase, indicating the greatest production by the corpus luteum. In conclusion,
serum inhibin A and inhibin B levels in normal puberty in girls show consistency
with our knowledge of the manner in which these hormones are secreted within the
menstrual cycle in adult women. The presented reference values may be of use in
the clinical evaluation of pubertal development in girls.
PMID- 10770210
TI - Cloning and characterization of the novel thyroid and eye muscle shared protein
G2s: autoantibodies against G2s are closely associated with ophthalmopathy in
patients with Graves' hyperthyroidism.
AB - Serum autoantibodies against eye muscle antigens are closely linked with thyroid
associated ophthalmopathy (TAO), although their significance is unclear. The two
antigens that are most often recognized are eye muscle membrane proteins with
molecular masses of 55 and 64 kDa, as determined from immunoblotting with crude
human or porcine eye muscle membranes. We cloned a fragment of the 55-kDa protein
by screening an eye muscle expression library with affinity-purified anti-55 kDa
protein antibody prepared from a TAO patient's serum. A complementary DNA (cDNA)
encoding a novel protein, which we have called G2s, was sequenced on both
strands, and its size was 411 bp. The open reading frame of G2s corresponded to a
121-amino acid peptide with a size of 1.4 kb. Using the rapid amplification of 5'
cDNA ends technique we were able to clone an additional 0.3 kb of the protein.
G2s did not share significant homologies with any other entered protein in
computer databases and had one putative transmembrane domain. Using the 1.4 kb
cDNA as probe in Northern blotting of a panel of messenger ribonucleic acids
prepared from human tissues, the parent protein was shown to correspond to a
large molecule of about 5.8 kb with a calculated molecular mass of approximately
220 kDa, consistent with earlier immunoblot studies performed in the absence of
reducing agents. G2s was strongly expressed in eye muscle, thyroid, and other
skeletal muscle and to a lesser extent in pancreas, liver, lung, and heart
muscle, but not in kidney or orbital fibroblasts. We tested sera from patients
with Graves' hyperthyroidism with and without ophthalmopathy and from control
patients and subjects for antibodies against a G2s fusion protein by
immunoblotting and enzyme-linked immunosorbent assay. In immunoblotting,
antibodies reactive with G2s were identified in 70% of patients with TAO of less
than 3 yr duration, 53% with TAO of more than 3 yr duration, 36% with Graves'
hyperthyroidism without evident ophthalmopathy, 17% with Hashimoto's thyroiditis,
3% with type 1 diabetes, 23% with nonimmunological thyroid disorders, and 16% of
normal subjects. The prevalences, compared to normal values, were significant for
the two groups of patients with TAO, but not for the other groups. Tests were
positive in 54% of patients with active TAO, 33% with chronic ophthalmopathy, 36%
with Graves' hyperthyroidism, 54% with Hashimoto's thyroiditis, 23% with type 1
diabetes, and in 11% of normal subjects using enzyme-linked immunosorbent assay.
The antibodies predicted the development of the ocular myopathy subtype of TAO in
six of seven patients and the congestive ophthalmopathy subtype in seven of eight
patients, respectively, with Graves' hyperthyroidism studied prospectively during
and after antithyroid drug therapy. Antibodies reactive with G2s may be early
markers of ophthalmopathy in patients with Graves' hyperthyroidism. Because G2s
is expressed in both thyroid and eye muscle, immunoreactivity against a shared
epitope in the two tissues may explain the well known link between thyroid
autoimmunity and ophthalmopathy.
PMID- 10770211
TI - In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin
levels in humans.
AB - The female predominance in several autoimmune diseases suggests a role for sex
steroid hormones in disease susceptibility. We therefore investigated to what
extent sex hormones would influence immune responsiveness. We analyzed T helper
type 1 (TH1) and type 2 cytokine patterns, chemokine receptor expression (n = 2 x
10), and Ig levels (n = 2 x 25) in transsexual men and women before and after 4
months of cross-sex hormone administration. Antithyroperoxidase levels were
compared between 186 transsexual males (treated >5 yr with estrogens) and 186
male controls. In men, estrogens plus antiandrogens increased free cortisol
levels in 24-h urine samples, decreased natural killer cell numbers, and slightly
inhibited the mitogen-induced interferon-gamma/interleukin-4 ratio, but up
regulated the expression of TH1-associated chemokine receptors, CCR1, CXCR3, and
CCR5. Conversely, in women, androgens slightly decreased free cortisol levels in
24-h urine samples and enhanced the mitogen-induced interferon-gamma/interleukin
4 ratio and tumor necrosis factor-alpha production. At the single cell level no
TH 1/TH2 shifts were found. Remarkably, up-regulation of TH1 cytokines was
accompanied by down-regulation of CCR1, CXCR3, and CCR5 expression. Neither CD4+
lymphocyte numbers nor IgG, IgM, and antithyroperoxidase levels, although higher
in women then in men, were affected by cross-sex hormonal treatment. These
results demonstrate that the capacity to develop a TH1 phenotype of peripheral
blood lymphocytes is stimulated by androgens and is slightly inhibited by
estrogens. These changes may be direct or indirect through the effects on other
hormones.
PMID- 10770212
TI - Expression and biological effects of endothelin-1 in human gonadotropin-releasing
hormone-secreting neurons.
AB - In a previous report, we demonstrated that in FNC-B4 cells, derived and
characterized from a human fetal olfactory epithelium, both sex steroids and
odorants regulate GnRH secretion. We now report the presence and biological
activity of endothelin (ET)-1 in this GnRH-secreting neuronal cell. By in situ
hybridization and immunohistochemistry, we found gene and protein expression of
ET-1 and its converting enzyme ECE-1 in both fetal olfactory mucosa and FNC-B4
cells. The presence of authentic ET-1 in the conditioned media of FNC-B4 cells
was further supported by combined RIAs and high-performance liquid chromatography
studies. Experiments with radiolabeled ET-1 and ET-3 strongly indicated the
presence of two classes of binding sites, corresponding to the ETA (16,500
sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using
selective analogs, indicated that these two classes of receptors subserve
distinct functions in human GnRH-secreting cells. The ETA receptor subtype
mediated an increase in intracellular calcium and GnRH secretion. Conversely,
stimulation of the ETB subtype induced DNA synthesis and mitogen-activated
protein kinase p44ERK1 expression. This is the first demonstration, in a human in
vitro model, of a neuroendocrine role for ET-1 as regulator of GnRH-secreting
neuron activity.
PMID- 10770213
TI - Vitamin D receptor gene polymorphism is associated with birth height, growth to
adolescence, and adult stature in healthy caucasian men: a cross-sectional and
longitudinal study.
AB - Vitamin D receptor (VDR) polymorphism has been associated with bone mineral
density (BMD), but recent data indicate association to parameters of body
constitution and growth. We investigated VDR gene polymorphism, defined by BsmI
and TaqI, in 90 healthy Caucasian males and any relation with parameters of body
constitution at birth, and to parameters of body constitution, BMD and bone area,
at age 16.9 +/- 0.3 yr (mean +/- SD) and at age 19.2 +/- 0.7. Using PCR and the
restriction enzyme BsmI and TaqI, the allelic variants BB, Bb, and bb, and TT,
Tt, and tt were identified. Height (cm) and weight (kg) were measured using
standardized equipment, and BMD of the total body, lumbar spine, and femoral
neck, and bone area (cm2) of the total body, humerus, femur was measured using
dual-energy x-ray absorptiometry. BsmI and TaqI genotypes were related in 89 of
the 90 cases; hence, the same associations were found for both genotypes. Boys
with the BB genotype were shorter at birth (P = 0.01) and grew less from birth to
age 16.9 +/- 0.3 (P = 0.01) than their Bb and bb counterparts. Both during
puberty (age 16.9 +/- 0.3) and after puberty (age 19.3 +/- 0.7), the BB boys were
shorter (P = 0.005-0.008) and had lower bone area of the humerus, femur, and
total body (P < 0.05) than the Bb and bb boys. The allelic variants were not
related to BMD at any site. A prediction model including parental height, birth
height, birth weight, and VDR alleles could predict up to 39% of the total
variation in adult height in our population. The VDR allelic variants alone
contributed to 8% of the total variation.
PMID- 10770214
TI - Changes in insulin-like growth factor-binding protein-3 messenger ribonucleic
acid in endothelial cells of the human corpus luteum: a possible role in luteal
development and rescue.
AB - In the human menstrual cycle, extensive angiogenesis accompanies luteinization;
and the process is physiologically important for corpus luteum (CL) function.
During luteolysis, the vasculature collapses, and the endothelial cells die. In a
conceptual cycle, the CL persists both functionally and structurally beyond the
luteoplacental shift. Although luteal rescue is not associated with increased
angiogenesis, endothelial survival is extended. Despite the central role of the
luteal vasculature in fertility, the mechanisms regulating its development and
demise are poorly understood. There is increasing evidence that insulin-like
growth factors (IGFs) and their binding proteins (IGFBPs) may be important
effectors of luteal function. Here, we have found that IGFBP-3 messenger RNA is
expressed in the endothelium of the human CL and that the levels of message
change during luteal development and rescue by human CG. The signal was strong
during the early luteal phase, but it showed significant reduction during the mid
and late luteal phases. Interestingly, administration of human CG caused a
marked increase in the levels of IGFBP-3 messenger RNA in luteal endothelial
cells that was comparable to that observed during the early luteal phase. We
conclude that endothelial cell IGFBP-3 expression is a physiological property of
the CL of menstruation and pregnancy. These observations raise the intriguing
possibility that the regulated expression of endothelial IGFBP-3 may play a role
in controlling angiogenesis and cell responses in the human CL by
autocrine/paracrine mechanisms.
PMID- 10770215
TI - Characterization of two novel homozygous missense mutations involving codon 6 and
259 of type II 3beta-hydroxysteroid dehydrogenase (3betaHSD) gene causing,
respectively, nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder.
AB - We identified two homozygous missense mutations in the human type II 3beta
hydroxysteroid dehydrogenase (3/betaHSD) gene, the first in codon 6 of exon II
[CTT (Leu) to TTT (Phe)] in a male infant with hyperpigmented scrotum and
hypospadias, raised as a male and no apparent salt-wasting since neonatal age,
and the second in codon 259 of exon IV [ACG (Thr) to ATG (Met)] in a male
pseudohermaphrodite with labial scrotal folds, microphallus, chordee, and fourth
degree hypospadias, raised as a female and with salt-wasting disorder since
neonatal age. In vitro transient expression of mutant type II 3betaHSD
complementary DNAs of L6F, T259M, as well as T259R for comparison was examined by
a site-directed mutagenesis and transfection of construct into COS-1 and COS-7
cells. Northern blot analysis revealed expression of similar amounts of type II
3betaHSD messenger ribonucleic acid from the COS-1 cells transfected by L6F,
T259M, T259R, and wild-type (WT) complementary DNAs. Western immunoblot analysis
revealed a similar amount of L6F mutant protein compared to WT enzyme from COS-1
cells, but neither L6F from COS-7 cells nor T259M or T259R mutant protein in COS
1 or COS-7 cells was detectable. Enzyme activity in intact COS-1 cells using 1
micromol/L pregnenolone as substrate in the medium after 6 h revealed relative
conversion rates of pregnenolone to progesterone of 46% by WT enzyme, 22% by L6F
enzyme, and 8% by T259M enzyme and less than 4% activity by T259R enzyme. Using 1
micromol/L dehydroepiandrosterone as substrate, the relative conversion rate of
dehydroepiandrosterone to androstenedione after 6 was 89% by WT enzyme, 35% by
L6F enzyme, 5.1% by T259M enzyme and no activity by T259R enzyme. However, the
L6F mutant 3betaHSD activity, despite its demonstration in the intact cells, was
not detected in homogenates of COS-1 cells or in immunoblots of COS-7 cells,
suggestive of the relatively unstable nature of this protein in vitro, possibly
attributable to the decreased 3betaHSD activity. In the case of T259M and T259R
mutations, consistently undetectable proteins in both COS cells despite
detectable messenger ribonucleic acids indicate severely labile proteins
resulting in either no or very little enzyme activity, and these data further
substantiate the deleterious effect of a structural change in this predicted
putative steroid-binding domain of the gene. In conclusion, the findings of the
in vitro study of mutant type II 3betaHSD enzyme activities correlated with a
less severe clinical phenotype of nonsalt-wasting and a lesser degree of genital
ambiguity in the patient with homozygous L6F mutation compared to a more severe
clinical phenotype of salt-wasting and severe degree of genital ambiguity in the
patient with homozygous T259M mutation in the gene.
PMID- 10770216
TI - Insulin-like growth factor I and growth hormone (GH) treatment in GH-deficient
humans: differential effects on protein, glucose, lipid, and calcium metabolism.
AB - We examined the effects of recombinant human (rh) insulin-like growth factor I
(IGF-I) vs. rhGH in a variety of metabolic paths in a group of eight severely GH
deficient young adults using an array of contemporary tools. Protein, glucose,
and calcium metabolism were studied using stable labeled tracer infusions of L-[1
13C]leucine, [6,6-2H2]glucose, and 42Ca and 44Ca; substrate oxidation rates were
assessed using indirect calorimetry; muscle strength was determined by isokinetic
and isometric dynamometry of the anterior quadriceps, as well as growth factors,
hormones, glucose, and lipid concentrations in plasma before and after 8 weeks of
rhIGF-I (60 microg/kg, sc, twice daily), followed by 4 weeks of washout, then 8
weeks ofrhGH (12.5 microg/kg-day, sc); the treatment order was randomized. In the
doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased
the percent fat mass, with a more robust decrease in the percent fat mass after
rhGH; both were associated with an increase in whole body protein synthesis rates
and a decrease in protein oxidation. Neither hormone affected isokinetic or
isometric measures of skeletal muscle strength. However, rhGH was more potent
than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid
profiles. Both hormones increased hepatic glucose output, but rhGH treatment was
also associated with decreased carbohydrate oxidation and increased glucose and
insulin concentrations, indicating subtle insulin resistance. Neither hormone
significantly affected bone calcium fluxes, supporting the concept that these
hormones, by themselves, are not pivotal in bone calcium metabolism. In
conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium
metabolism, yet have divergent effects on lipid and carbohydrate metabolism in
the GH-deficient state. These differences may allow for better selection of
treatment modalities depending on the choice of desired effects in
hypopituitarism.
PMID- 10770217
TI - A large homozygous or heterozygous in-frame deletion within the calcium-sensing
receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant
hypocalcemia.
AB - Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense
activating mutations of the calcium-sensing receptor (CaSR) gene, a G-protein
coupled receptor playing key roles in mineral ion metabolism. We now describe an
ADH kindred of three generations caused by a novel CaSR mutation, a large in
frame deletion of 181 amino acids within its carboxylterminal-tail from S895 to
V1075. Interestingly, the affected grandfather is homozygous for the deletion but
no more severely affected than heterozygous affected individuals. Functional
properties of mutant and wild-type (WT) CaSRs were studied in transiently
transfected, fura-2-loaded human embryonic kidney (HEK293) cells. The mutant
receptor exhibited a gain-of-function, but there was no difference between cells
transfected with mutant complementary DNA alone or cotransfected with mutant and
WT complementary DNAs, consistent with the similar phenotypes of heterozygous and
homozygous family members. Therefore, this activating deletion may exert a
dominant positive effect on the WT CaSR. The mutant receptor's cell surface
expression was greater than that of the WT CaSR, potentially contributing to its
gain-of-function. This novel mutation in the CaSR gene provides the first known
examples of a large naturally occurring deletion within a G-protein-coupled
receptor's carboxylterminal-tail and of a homozygous, affected individual with
ADH.
PMID- 10770218
TI - Functional characterization of the molecular defects causing nephrogenic diabetes
insipidus in eight families.
AB - X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder
characterized by the excretion of abnormal large volumes of diluted urine mainly
caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI
patients for mutations within the AVPR2 gene we have identified three novel
(I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In
addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was
identified in a female patient with autosomal recessive NDI associated with
sensorineural deafness. Selected clinical data of the NDI patients were compared
with the results from the in vitro studies. Functional analysis of I46K and I130F
revealed reduced maximum agonist-induced cAMP responses as a result of an
improper cell surface targeting. In contrast, the F105V mutation is delivered to
the cell surface and displayed an unchanged maximum cAMP response, but impaired
ligand binding abilities of F105V were reflected in a shifted concentration
response curve toward higher vasopressin concentrations. As the extracellularly
located F105 is highly conserved among the vasopressin/oxytocin receptor family,
functional analysis of this residue implicates an important role in high affinity
agonist binding.
PMID- 10770219
TI - Localization and signaling of the prolactin receptor in the uterus of the common
marmoset monkey.
AB - This study investigated the expression and signaling pathway of PRL and its
receptor in the non-pregnant uterus of the common marmoset monkey.
Immunohistochemistry localized PRL expression to the stromal compartment of the
endometrium. Expression was minimal during the proliferative phase and was up
regulated during the mid to late secretory phase of the ovulatory cycle. In situ
hybridization and immunohistochemistry localized expression of the PRL receptor
to the glandular epithelium of the endometrium. Similar to that of PRL, PRL
receptor expression was minimal during the proliferative phase and was
dramatically up-regulated during the secretory phase. The temporal pattern of PRL
receptor gene expression in the marmoset uterus across the cycle was further
confirmed by ribonuclease protection assay. The roles of Janus kinase-2 (JAK2)
and signal transducer and activator of transcription-1 (STAT1) in the
intracellular signaling pathway of PRL were also assessed in the mid to late
secretory phase. JAK2/STAT1 proteins were localized in the glandular epithelial
compartment, and both proteins were temporally phosphorylated in response to PRL.
Finally, the pattern of expression of the interferon regulatory factor-1 (IRF-1)
gene and the effect of PRL on transcription of IRF-1 were investigated during the
mid to late secretory phase. IRF-1 expression in the marmoset uterus was encoded
by a protein of 48 kDa and was localized to the glandular epithelial compartment,
as was observed for the PRL receptor and JAK2/STAT1 proteins. Moreover,
incubation of mid to late secretory uterine tissue with PRL for 1 and 3 h
resulted in 0.4 +/- 0.2- and 2.4 +/-0.5-fold (P < 0.05) inductions of the IRF-1
gene, respectively. These studies confirm the expression of both PRL and its
receptor in the uterus of the marmoset monkey. Expression of both genes is up
regulated during the mid to late secretory phase of the ovulatory cycle. PRL
function in the marmoset uterus is linked to the JAK/STAT signaling pathway,
leading to the regulation of expression of PRL-responsive genes such as IRF-1.
The site of expression of PRL, PRL receptors, and IRF-1 in the marmoset uterus
suggest that PRL may influence glandular epithelial function and direct gene
transcription in these cells in a paracrine fashion.
PMID- 10770220
TI - Somatostatin receptor subtypes in human thymoma and inhibition of cell
proliferation by octreotide in vitro.
AB - Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1-5, are
heterogeneously expressed in the normal human thymus. This suggests their
involvement in controlling the immune and/or neuroendocrine functions in this
organ. Moreover, recently a high in vivo uptake of [111In-DTPA-D-Phe1]octreotide
has been reported in patients bearing thymoma. The present study characterizes in
vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake
of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with
myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11] SS
14 was found on a membrane preparation of the surgically removed thymoma.
Scatchard analysis showed high affinity binding sites (Kd, 47.5 +/- 2.5 pmol/L)
with low maximum binding capacity (23.5 +/- 2.5 fmol/mg membrane protein). RT-PCR
analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA
(mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed
sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By
immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly
expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A
immunoreactivity was found in the stromal compartment of the tumor, particularly
on the endothelium of small intratumoral blood vessels. In primary cultured tumor
cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine
incorporation by 40.6% and 43.2%, respectively. The following conclusions were
reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the
cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype
involved in the inhibition of epithelial tumor cell proliferation by octreotide
in vitro. 2) A loss of endogenous SS production in this thymoma might be
implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a
role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS
receptor scintigraphy.
PMID- 10770221
TI - Modulation of cortisol metabolism by low-dose growth hormone replacement in
elderly hypopituitary patients.
AB - 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net
reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in
a shift in cortisol metabolism favoring cortisone, an observation that may have
significance in patients with ACTH deficiency who are unable to compensate for
such changes. We have studied the effect of three doses of GH replacement (0.17,
0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol
metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were
receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I
levels rose in a dose-dependent manner over the course of the study. Fat mass
decreased significantly at 24 weeks (P = 0.02), a change that was maintained at
36 weeks. Fasting serum insulin levels did not change significantly over the
course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em)
fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at
baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the
dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks
(GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH
dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did
not correlate with serum insulin-like growth factor I, fat mass, or fasting
insulin levels at any time during the study. This study confirms the inhibitory
effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at
very low GH doses and is not mediated indirectly by change in circulating
insulin. Patients with partial or total ACTH deficiency, in whom cortisol
replacement is suboptimal, may be at risk of the clinical manifestations of
cortisol deficiency when they are commenced on GH therapy.
PMID- 10770222
TI - The -238 and -308 G-->A polymorphisms of the tumor necrosis factor alpha gene
promoter are not associated with features of the insulin resistance syndrome or
altered birth weight in Danish Caucasians.
AB - Recently, two G-->A polymorphisms at positions -308 and -238, in the promoter of
the tumor necrosis factor alpha (TNF-alpha) gene, have been identified. These
variants have, in different ethnic groups, been linked to estimates of insulin
resistance and obesity. The objective of the present study was to investigate
whether these genetic variants of TNF-alpha were associated with features of the
insulin resistance syndrome or alterations in birth weight in two Danish study
populations comprising 380 unrelated young healthy subjects and 249 glucose
tolerant relatives of type 2 diabetic patients, respectively. All study
participants underwent an iv glucose tolerance test with the addition of
tolbutamide after 20 min. In addition, a number of biochemical and anthropometric
measures were performed on each subject. The subjects were genotyped for the
polymorphisms by applying PCR restriction fragment length polymorphism. Neither
of the variants was related to altered insulin sensitivity index or other
features of the insulin resistance syndrome (body mass index, waist to hip ratio,
fat mass, fasting serum lipids or fasting serum insulin or C-peptide). Birth
weight and the ponderal index were also not associated with the polymorphisms. In
conclusion, although the study was carried out on sufficiently large study
samples, the study does not support a major role of the -308 or -238
substitutions of the TNF-alpha gene in the pathogenesis of insulin resistance or
altered birth weight among Danish Caucasian subjects.
PMID- 10770223
TI - The role of the CAG repeat polymorphism in the androgen receptor gene and of
skewed X-chromosome inactivation, in the pathogenesis of hirsutism.
AB - The human androgen receptor (AR) gene contains a variable number of CAG repeats
within exon 1. Shorter AR alleles, by increasing transactivation, may result in
augmented AR-mediated sensitivity of the hair follicle. We have evaluated whether
the number of CAG repeats, or if skewed inactivation of X-chromosome, favoring
the presence of shorter AR alleles, influence hirsutism in women with and without
hyperandrogenemia. Twenty-eight women with idiopathic hirsutism (normal serum
androgens), 34 women with hyperandrogenic hirsutism (increased serum androgens),
and 15 healthy control women were analyzed by evaluating the number of CAG
repeats in genomic DNA, as well as the methylation pattern (after DNA digestion
with HpaII), which allows identification of which allele is inactive. Despite
marked differences among the groups in serum androgens, which were markedly
increased in women with hyperandrogenic hirsutism as compared with women with
idiopathic hirsutism and to controls, there were no significant differences among
the groups in the number of CAG repeats. Moreover, skewed X-chromosome
inactivation was found in 10 subjects (3 with idiopathic hirsutism, 5 with
hyperandrogenic hirsutism, and 2 controls; P = 0.746) of the 67 women (14.9%) who
were heterozygous for the AR gene. In several of these subjects, it was the
shorter allele that was preferentially inactivated. In conclusion, neither the
CAG repeat polymorphism in the AR gene, nor skewed X-chromosome inactivation,
seem to play a significant role in the pathogenesis of hirsutism.
PMID- 10770224
TI - Complications of inferior petrosel sinus sampling.
PMID- 10770225
TI - Penicillin fermentation: mechanisms and models for industrial-scale bioreactors.
AB - Even after many years of research and industrial practice, the production of
penicillin G in fed-batch fermentation by Penicillium crysogenum continues to
attract research interest. There are many reasons: the commercial and therapeutic
importance of penicillin and its derivatives, the complexity of cell growth, and
the impact of engineering variables, the last of which are significant in large
bioreactors but are not yet fully understood. Extensive research has generated
new information on the mechanisms of cellular reactions and morphological
features of the mycelia and their role in the synthesis of the product. Given a
choice of mechanisms, models of different degrees of complexity, for both
cellular differentiation and bioreactor performance, have been proposed. The more
complex models require and provide more information. They are also more difficult
to evaluate and apply in automatic control systems for production-scale
bioreactors. The present review considers the evolution of recent knowledge and
models from this perspective.
PMID- 10770226
TI - Growth of filamentous fungi in submerged culture: problems and possible
solutions.
AB - Filamentous fungi are important organisms industrially and continue to attract
research interest as microbiologists attempt to overcome the problems associated
with their behavior in submerged culture. This review critically examines the
literature describing these problems and where available suggests possible
solutions to them. The influence of the chemical and physical environment on
culture morphology, the process engineering challenges presented by different
fungal morphologies, and the relationship between fungal morphology and
metabolite production are all discussed.
PMID- 10770227
TI - Biotechnological production of plant-based insecticides.
AB - The demand for natural and nonpersistent insecticides is increasing day by day.
Plant cell cultures could be an alternative to conventional methods of production
of insecticides from field-grown plants. In vitro cultured plant cells produce a
wide array of insecticides as a part of their secondary metabolism. Their ability
to synthesize key enzymes and the manipulation of these could lead to the
enhanced production of many insecticides of industrial importance. The
development of a high-yielding hairy root culture system for thiophenes,
nicotine, and phytoecdysones is of considerable interest. In this article, the
current literature on various factors that influence the growth, production, and
secretion of six insecticidal compounds, namely, pyrethrins, azadirachtin,
thiophenes, nicotine, rotenoids, and phytoecdysones which have been prospects for
the scale-up of cell cultures, genetic engineering to obtain transgenic plants,
and metabolically engineered plants for increased production of bio-molecules,
has been discussed. Environmental safety clearance and the future prospects of
application of biomolecules for plant-derived insecticides are presented.
PMID- 10770228
TI - Speaking modifies voice-evoked activity in the human auditory cortex.
AB - The voice we most often hear is our own, and proper interaction between speaking
and hearing is essential for both acquisition and performance of spoken language.
Disturbed audiovocal interactions have been implicated in aphasia, stuttering,
and schizophrenic voice hallucinations, but paradigms for a noninvasive
assessment of auditory self-monitoring of speaking and its possible dysfunctions
are rare. Using magnetoencephalograpy we show here that self-uttered syllables
transiently activate the speaker's auditory cortex around 100 ms after voice
onset. These phasic responses were delayed by 11 ms in the speech-dominant left
hemisphere relative to the right, whereas during listening to a replay of the
same utterances the response latencies were symmetric. Moreover, the auditory
cortices did not react to rare vowel changes interspersed randomly within a
series of repetitively spoken vowels, in contrast to regular change-related
responses evoked 100-200 ms after replayed rare vowels. Thus, speaking primes the
human auditory cortex at a millisecond time scale, dampening and delaying
reactions to self-produced "expected" sounds, more prominently in the speech
dominant hemisphere. Such motor-to-sensory priming of early auditory cortex
responses during voicing constitutes one element of speech self-monitoring that
could be compromised in central speech disorders.
PMID- 10770229
TI - Lesion segmentation and manual warping to a reference brain: intra- and
interobserver reliability.
AB - The study of subjects with acquired brain damage has been an invaluable tool for
exploring human brain function, and the description of lesion locations within
and across subjects is an important component of this method. Such descriptions
usually involve the separation of lesioned from nonlesioned tissue (lesion
segmentation) and the description of the lesion location in terms of a standard
anatomical reference space (lesion warping). The objectives of this study were to
determine the sources and magnitude of variability involved in lesion
segmentation and warping using the MAP-3 approach. Each of two observers
segmented the lesion volume in ten brain-damaged subjects twice, so as to permit
pairwise comparisons of both intra- and interobserver agreement. The segmented
volumes were then warped to a reference brain using both a manual (MAP-3) and an
automated (AIR-3) technique. Observer agreement between segmented and warped
volumes was analyzed using four measures: volume size, distance between the
volume surfaces, percentage of nonoverlapping voxels, and percentage of highly
discrepant voxels. The techniques for segmentation and warping produced high
agreement within and between observers. For example, in most instances, the
warped volume surfaces created by different observers were separated by less than
3 mm. The performance of the automated warping technique compared favorably to
the manual technique in most subjects, although important exceptions were found.
Overall, these results establish benchmark parameters for expert and automated
lesion transfer, and indicate that a high degree of confidence can be placed in
the detailed anatomical interpretation of focal brain damage based upon the MAP-3
technique.
PMID- 10770230
TI - Image registration using a symmetric prior--in three dimensions.
AB - This paper describes a Bayesian method for three-dimensional registration of
brain images. A finite element approach is used to obtain a maximum a posteriori
estimate of the deformation field at every voxel of a template volume. The priors
used by the MAP estimate penalize unlikely deformations and enforce a continuous
one-to-one mapping. The deformations are assumed to have some form of symmetry,
in that priors describing the probability distribution of the deformations should
be identical to those for the inverses (i.e., warping brain A to brain B should
not be different probablistically from warping B to A). A gradient descent
algorithm is presented for estimating the optimum deformations.
PMID- 10770231
TI - Gender differences in regional cerebral activity during sadness.
AB - Functional magnetic resonance imaging and echo-planar-imaging were used to
investigate affect related gender differences in regional cerebral activity. The
experiment was conducted using a standardized mood induction procedure. Blood
oxygen-level-dependent effect was measured in 13 male and 13 female healthy
subjects, during both moods of happiness and sadness, respectively. Parallel to
earlier neuroimaging findings, our results show brain activity in the amygdala of
males during negative affect. Females failed to demonstrate a similar activation
pattern despite matched subjective ratings of negative affect to males. Results
point to differential regional cerebral correlates of emotional experience in
males and females, which is suggestive of a more focal and subcortical processing
of sadness in men.
PMID- 10770232
TI - Continuities of separation anxiety from early life into adulthood.
AB - The study investigates whether a putative diagnosis of separation anxiety
disorder can be identified in adulthood and whether there are continuities
between juvenile and adult forms of the disorder. Seventy patients with
conventional adult diagnoses of panic disorder and generalized anxiety disorder
attending an anxiety clinic were administered an interview and checklist to
assess separation anxiety (SA) symptoms in adulthood. Memories of early SA were
assessed using the Separation Anxiety Symptom Inventory (SASI). A subsample (n =
31) was used to calibrate the checklist against assignment to a category of adult
separation anxiety disorder (ASAD) based on the structured interview. In an
expanded sample (n = 70), patients assigned to the ASAD category returned
statistically higher scores on the SASI, with the severity of juvenile SA
symptoms accounting for 33% of the variance of adult SA scores (p < .001).
Assignment of subjects to the putative ASAD category was not associated with any
conventional adult anxiety diagnosis and symptoms of SA appeared to predate the
onset of the other anxiety disorders. One possible explanation for the data is
that, in some individuals, early onset separation anxiety disorder may persist
into adulthood, but the symptoms may either be overlooked or, alternatively,
obscured by secondary features such as panic.
PMID- 10770233
TI - Nosological insertion of axis I disorders in the etiology of obsessive-compulsive
disorder.
AB - This study explores the prevalence of developing Axis I disorders at various time
points within an obsessive-compulsive disorder (OCD) population. A sample of 409
patients diagnosed as OCD according to the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (American Psychiatric Association, 1994)
participated. Of the 409 patients, 132 (32.2%) developed at least one other Axis
I disorder. Odds ratio data indicates that an anxiety disorder, mood disorder,
eating disorder, or tic disorder is likely to occur first. Second disorder is
likely to be another anxiety disorder, mood disorder, eating disorder, somatoform
disorder (tic disorders fall out of the continuum). The third disorder is likely
to be a mood disorder, or anxiety disorder (all other disorders fall out of the
continuum). Demographic data including gender, religion, occupation, marital
status, and family psychiatric history is similar to the data reported in other
studies of primary OCD. It is suggested that although OCD may present with
additional comorbid conditions, other distinct pathology may emerge (be inserted)
independently over time. This supports the conceptualization of OCD as a
continuum, where additional diagnoses may be expected to occur in the time course
of the condition.
PMID- 10770234
TI - Generalized anxiety disorder publications: so where do we stand?
AB - Although generalized anxiety disorder (GAD) has traditionally been understudied,
several authors have stated that interest in GAD has recently increased. However,
no data exist to confirm or refute this assertion. The present study investigates
publication rates for the anxiety disorders from 1980 to 1997 in two extensive
databases: PsycLIT and MEDLINE. GAD publications were examined in two ways.
First, the annual percentage of anxiety disorder publications devoted to GAD was
calculated. Second, GAD publications were classified into one of four categories:
descriptive, process, treatment, and review. The results show that GAD is
considerably less studied than panic disorder/agoraphobia, posttraumatic stress
disorder and obsessive-compulsive disorder. Though the percentage of anxiety
disorder publications devoted to GAD increased considerably during the 1980s, it
has generally remained stable in the 1990s. The results also show that
descriptive and treatment issues account for the vast majority of GAD
publications. The author concludes that the paucity of research into process
issues is unfortunate because intensified investigation of the specific processes
involved in GAD may lead to new breakthroughs in our understanding and treatment
of this anxiety disorder.
PMID- 10770235
TI - The effects of target and distractor familiarity on visual search in anxious
children: latent inhibition and novel pop-out.
AB - Children and adolescents (ages 6-17 years) diagnosed as having an anxiety
disorder were compared to matched controls on a two-stage serial visual search
task in which they identified presence or absence of a unique shape presented
with homogeneous distractors. Response time was examined as a function of prior
experience with either target, distractor, or both, allowing for a within-subject
assessment of latent inhibition (LI: slower responding to a target that was
formerly a distractor against a background of distractors that were formerly
targets as compared to a novel target with distractors that were formerly
targets) and novel pop-out effects (NPO: faster responding to a novel target
against a background of familiar former targets as compared to the condition in
which both the target and distractors were novel). There were robust LI and NPO
effects for both anxious and control children. However, the predicted interaction
between diagnosis and LI condition was not obtained. In general, the results
suggest that children with diagnosed anxiety disorder do not differ from controls
on basic information processing as assessed by this visual search task.
PMID- 10770236
TI - Gender role orientation and fearfulness in children with anxiety disorders.
AB - Research on gender differences in children's fears has generally shown that girls
are more fearful than boys. A common hypothesis offered for this finding is that
gender role orientations or expectations may be operating. However, this
hypothesis has not been directly investigated in child samples. The present study
examined the relation between a self-report measure of gender role orientation
(i.e., masculinity/femininity) and the intensity of self-reported fears in a
clinic sample of children (N = 66; ages 6-11; 41 boys and 25 girls) with anxiety
disorders. Results revealed that masculinity was negatively related to overall
levels of fearfulness as well as specific fears of failure and criticism, medical
fears, and fears of the unknown. In contrast, no relation was found between
femininity and fearfulness. These findings suggest that gender role orientation,
especially masculinity, may play a role in the development and/or maintenance of
fearfulness in children.
PMID- 10770237
TI - Future directions in anxiety disorders: profiles and perspectives of leading
contributors.
AB - Eight of the most influential clinicians and researchers in the study and
treatment of anxiety disorders were identified by polling professional members of
the Anxiety Disorders Association of America. These eight individuals are (in
alphabetical order): James C. Ballenger, David H. Barlow, Aaron T. Beck, David M.
Clark, Edna B. Foa, Rick G. Heimberg, Donald F. Klein, and Isaac M. Marks. Each
offered their thoughts on a set of questions concerning the current and future
status of the anxiety disorders field. Profiles and perspectives of these
individuals are presented.
PMID- 10770238
TI - Personal toll of trichotillomania: behavioral and interpersonal sequelae.
AB - Patients suffering from trichotillomania are at risk for significant mood and
interpersonal problems. Using a clinical sample, this study sought to clarify the
nature and types of problems experienced by patients and to examine how these
problems might be interrelated. The charts of 67 patients who sought treatment
for trichotillomania were reviewed. The majority of patients reported problems
with affect and interpersonal relationships. Public and social activities (e.g.,
haircuts, sexual activities) were avoided by a large number of patients. Self
esteem, shame, feelings of unattractiveness, depressed affect, and secretiveness
were all interrelated, suggesting that these issues might best be conceptualized
as a cluster that needs to be considered in the etiology, effects, and treatment
of trichotillomania.
PMID- 10770239
TI - Children with congenital diaphragmatic hernia are at risk for lower levels of
cognitive functioning and increased emotional and behavioral problems.
AB - The physical, psychological, and social functioning of 11 children aged 8 to 12
years with Congenital Diaphragmatic Hernia (CDH) was assessed with several
standardized assessment procedures. Physically, most children functioned well at
follow-up with half of the children showing minor physical problems such as
bronchial hyperreactivity. The mean IQ of the children was 15 points (1 SD) below
the norm of 100. Only 6 children were at expected school level. The children
showed more emotional and behavioral problems than in the general population as
reported by parents and teachers. The children themselves reported more
depressive problems, but not a lower self-esteem than children in the general
population. These results were confirmed by the results of interviews with
parents and children concerning psychosocial functioning. It is concluded that
children with CDH show more cognitive and learning problems and increased rates
of emotional and behavioral problems compared to children in the general
population. Since no children treated with Extra Corporeal Membrane Oxygenation
(ECMO) were involved in this study, the earlier reports that lower cognitive
functioning is limited to children with CDH treated with ECMO can not be
confirmed by this study. Considering the results of this study, there is a need
for further follow-up studies concerning the long-term psychological and social
functioning of children with CDH.
PMID- 10770240
TI - Surgical treatment of diaphragmatic agenesis by transposition of a muscle flap:
report on 15 cases.
AB - Between 1987 and 1996 the transposition of a muscle flap using the anterolateral
abdominal wall (the internal oblique and transversus abdominus muscle) has been
used for the surgical treatment of fifteen cases of diaphragmatic agenesis. There
are several advantages of this technique: a more accurate reconstruction of the
diaphragmatic dome, a better adapted muscle flap, good tolerance and evolution as
a result of the use of autologous material with thus less risk of recurrence
and/or infection. The disadvantages are represented by the nine cases of
abdominal herniation at the site of the muscle flap, three of which necessitated
secondary surgical treatment. Nine children survived this treatment, six died
following severe cardio-pulmonary complications associated with this
malformation.
PMID- 10770241
TI - Diagnostic significance of pancreas divisum in early life.
AB - Pancreas divisum (PD) is a congenital anomaly in which the ventral and dorsal
pancreatic ducts fails to fuse in the early fetal period. This anomaly has been
known to rarely cause recurrent pancreatitis and to require surgical
intervention. With the recent advances in image diagnostic procedures, an
increasing incidence of this anomaly has been recognized in the pediatric age
group. Seven cases of PD were encountered in our institution between 1978 and
1998. Six were female and one was male, with a mean age of 8 years. All cases
were diagnosed to have PD by endoscopic retrograde pancreatography (ERCP) or
operative pancreatography. One case (14.3%) had PD associated with a bout of
pancreatitis and was operated on by transduodenal papilloplasty, but recurrent
bouts of pancreatitis led to the performance of longitudinal
pancreaticojejunostomy (Puestow procedure). Six cases (85.7%) were found to have
PD as an incidental finding during operation for congenital dilatation of the
bile ducts (CDBD), however, 2 cases (33.3%) out of the 6 developed pancreatitis
in a later stage and ERCP was effective in their follow-up assessment. One
benefited from conservative treatment while the other needed transduodenal
papilloplasty along with pancreatoductoplasty. Imaging procedures (ERCP or
operative pancreatography) revealed complete PD in 3 cases (42.9%), and
incomplete PD in 4 cases (57.1%), however, there was no clinically significant
difference between the groups.
PMID- 10770242
TI - Clinical long-term follow-up results in intestinal neuronal dysplasia (IND).
AB - Commonly available information on intestinal neuronal dysplasia (IND) is sparse.
Especially well documented long-term courses are lacking. The aim of this study
was to correlate defecation as a clinical parameter of the long-term course in
malformations of the enteric nervous system with the morphological diagnosis. 57
children with intestinal neuronal dysplasia (IND) or aganglionosis with cranial
intestinal dysganglionosis (agIND), diagnosed between 1983 and 1992, were
analysed including histomorphological classification, collection of clinical data
and evaluation of the defecation mode by questionnaire as a parameter of the long
term course. Of 29 dysganglionic (IND) patients, 9/29 cases (31 %) had been
treated conservatively, 18/29 cases surgically (62.1%), in two children (6.9%) no
therapy had been necessary. All 28 patients with Hirschsprung's disease and
cranial IND (agIND) underwent resection. 46 of the children could be followed up
3.64 years after the end of the main therapeutic period and with a mean age of
6.7 years at the time of follow-up; 43.5% of the analysed children still showed
severe constipation. 23.9% only were really cured; 15.2% had normal defecation
still using conservative treatment and 17.4% had diarrhea. No significant
difference was found between both groups, IND and agIND, and the results were
independent of treatment modality. The results were much worse than in idiopathic
constipation as reported in the literature and even worse in comparison to
unselected Hirschsprung collectives. It has to be concluded that in IND with
chronic constipation intensive long-term care is necessary and it is crucial that
treatment algorithms should be outlined urgently together by pediatric
gastroenterologists and pediatric surgeons. AgIND seems to need more extended
resection following an exact histomorphological mapping by biopsies taken during
enterostomy procedure.
PMID- 10770243
TI - Incontinence and constipation after low anorectal malformations in a boy.
AB - BACKGROUND: Low anorectal malformations are considered to be a benign type of
anorectal malformations. Their treatment is simple in the neonatal period and
gives good results as far continence is concerned. METHODS: We studied a group of
55 boys with low anorectal malformations which had been surgically treated
between the 1st January 1975 and the 31st December 1992. We studied the initial
treatment and the associated anomalies, 5 patients have died. 27 were seen for an
interview and a clinical examination. Extra investigations (anorectal manometry
or electromyography of external sphincter) were only offered to consenting
patients with an ongoing problem. RESULTS: 3 to 20 years had passed since their
operations. Associated anomalies had been found in 11 children. The initial
treatment was a perineal procedure in 20 cases and a colostomy in 8 cases.
Dilatations were carried out on 11 children. Faecal and urinary continence had
been acquired before 30 months of age. 13 children (48%) had problems of soiling
and/or chronic constipation. There was no difference between these children and
the 14 continent ones regarding the type of malformation, the initial treatment
and the follow-up. Anorectal manometry (performed on 9 cases) showed 4 anorectal
dyssynergies. It was normal in 3 cases. The Recto Anal Inhibitory Reflex was
always present. CONCLUSION: Problems of continence are not rare in the evolution
of low anorectal malformations. We suggest therefore a long-term clinical follow
up for those children, with one anorectal manometry control being performed after
continence is acquired.
PMID- 10770244
TI - Enterocystoplasty complications in children. A study of 30 cases.
AB - BACKGROUND/PURPOSE: Bladder augmentation for small vesical capacity represents an
important aid to these patients, but the appearance of complications is not rare.
We analysed the complications of the enterocystoplasty techniques used in our
Department. METHODS: From 1983 to 1997 sixteen girls and fourteen boys were
treated. We performed 28 bladder augmentations (in 13 cases using small bowel, in
one case using ileum and caecum and in 14 cases using sigmoid colon) and 2
bladder substitutions (in one case with ileum and sigmoid colon and in the second
using a colonic segment). RESULTS: Twelve children present recurrent urinary
infections. In five children bladder stones were formed (among them a case of
familial cystinuria-lysinuria). Two children presented intestinal volvulus and
another one a caecal volvulus. In two children a perforation of the augmented
bladder was treated operatively. An 11-years-old child presented severe
electrolyte disturbances. CONCLUSIONS: The complications presented in our
patients confirm the view that they are associated with intestinal mucosa in the
bladder and our study proves, once more, the current necessity to seek
alternative tissues for bladder augmentation.
PMID- 10770245
TI - Widely meshed autograft associated with cultured autologous epithelium for the
treatment of major burns in children: report of 12 cases.
AB - This is a retrospective study of the combination of widely meshed autograft and
autologous cultured keratinocytes. We used this method faced with the lack of
allogenic skin, as an alternate to the Cuono method. Twelve children suffering
extensive burn injury (deep burns of 60%+/-16 of the total body surface)
underwent this grafting procedure. The surgical treatment consisted of an early
surgical excision, with an immediate coverage by autografts as much as possible.
When cultured epithelium was available, a large mesh autograft was applied and
covered with cultured epidermis sheets during the same operative procedure. The
rate of take was of 84% (+/- 12). No secondary graft loss was observed. This
means of coverage appeared reliable and resistant. On average, this method
allowed the epidermization of 30% (+/-9) of the total body surface of the
children. The average hospital stay of the children was 64+/-20 days. All the
children recovered to lead a normal life. The school delay after rehabilitation
is one year. This technique is an alternative to Cuono's method when allografts
are missing. The combination of autograft and autologous cultured epidermis
sheets appeared more effective than one of these techniques applied alone, as if
the suggested coupling induced a synergy.
PMID- 10770246
TI - Posttraumatic dural sinus thrombosis in children.
AB - Posttraumatic dural sinus thrombosis (DST) in children has rarely been described
in the literature. Over a period of two years (1994-1996) we treated 131 children
(n=131) with minor or severe head injury requiring a cranial computed tomography
(CT) scan. DST was found in eight patients (6.1%), five with mild and three with
severe cranial trauma. Diagnosis was suspected either because of a skull fracture
crossing over a dural sinus or because of a hyperdensity at a dural sinus in the
noncontrast CT scan. Enhanced CT scan was used to confirm DST. No specific
symptoms related to DST were observed. DST was managed conservatively in all
patients and recovery was uneventful. Recanalization of the sinus was documented
to occur within three weeks to six months in six children. One patient showed a
residual clot after five months and another did not have a follow-up CT scan.
Based on our data we conclude that neither surgical nor medical intervention is
indicated in traumatic DST in children.
PMID- 10770247
TI - Adenocarcinoma of the stomach with tumor-thrombotic microangiopathy in an 11-year
old male patient.
AB - The majority of malignancies in childhood are represented by leukemias, lymphomas
or other reticuloendothelial neoplasms, tumors of the central nervous system,
nephroblastomas and sarcomas. Gastrointestinal tumors represent less than 5% of
pediatric neoplasms and carcinomas within this subgroup have been very rarely
described, especially those arising in the stomach. In this study, we report a
case of an 11-year-old boy with a signet-ring carcinoma of the stomach. The
patient initially presented with respiratory symptoms which were caused by
massive pulmonary lymphangiosis carcinomatosa and a peculiar microangiopathy,
recently addressed as pulmonary tumor thrombotic microangiopathy. To our
knowledge, this constellation has not been reported so far.
PMID- 10770248
TI - Cholecystokinin administration in congenital diaphragmatic hernia--a case report
and review of the literature.
AB - Deterioration in the respiratory function of a newborn infant with a repaired
diaphragmatic hernia and respiratory insufficiency followed administration of
cholecystokinin for cholestatic jaundice. The possible mode of action is
discussed and a vasoactive/bronchoactive effect is proposed.
PMID- 10770249
TI - Thoracic wall lipoblastoma: a case report and review of histopathology and
cytogenetics.
AB - A rare case of a successfully excised intra- and extrathoracic lipoblastoma of
the anterior chest wall in a 13-month-old female infant is reported.
Histopathology and cytogenetical analysis established the diagnosis of a
lipoblastoma. The differential diagnosis, histology and cytogenetical evaluation
of lipomatous neoplasms are discussed. Karyotypic analysis may be of use in
diagnostically difficult cases owing to the characteristic alterations in 18q11
13. A complete resection of lipoblastomas is feasible and advantageous with no
need for a mutilating radical excision.
PMID- 10770250
TI - Delayed cure of an omphalocele requiring abdominosternoplasty, right hepatectomy
and partial splenectomy.
AB - A large ventral hernia resulting from the primary treatment of an omphalocele
according to the Gross technique was repaired at age 16. The girl presented with
extra-abdominal development of the liver and the spleen along with hypotrophy of
the abdominal and thoracic cavities. The operation included enlargement
sternoplasty, liver and spleen-size reduction and prosthetic abdominal closure.
The cosmetic and functional results are good and stable on 7-year follow-up.
Surgical issues and blood transfusion policy are discussed. A multi-disciplinary
pediatric surgical approach is advocated.
PMID- 10770251
TI - An ileostomy at the aganglionic ileum for total colon aganglionosis.
AB - For the initial management of total colon aganglionosis (TCA), an ileostomy is
usually created at the distal end of the ganglionic bowel, which is associated
with profuse diarrhea resulting in a water and electrolyte imbalance as well as
malnutrition during the ileostomy period. An ileostomy at the aganglionic ileum
several centimeters toward the anal side of the transition for TCA is thus
expected to cause bowel retention without any bowel obstruction and to facilitate
water reabsorption in the small bowel. We performed this procedure in 2 babies
with TCA. The length of the aganglionic ileum was 50 cm and 10 cm, respectively.
The ileostomies were made 5 cm distal to the transition at 1 month and 1 day
after birth, respectively. Oral feedings were well tolerated, resulting in
adequate weight gain and the stools were semisolid during the ileostomy periods.
Definitive operations using the Duhamel procedure with a right colon patch graft
without the creation of a new ileostomy were successfully performed at 7 and 3
months of age, respectively. The postoperative courses were satisfactory. An
ileostomy at the aganglionic ileum appears to be the method of choice as initial
management for patients with TCA.
PMID- 10770252
TI - Paraurethral cysts in newborn: a case report and review of literature.
AB - Paraurethral cysts are uncommonly reported in the newborn. Twenty-eight cases
have been reported in the English literature until now. These lesions generally
resolve spontaneously. For this reason, a conservative approach is recommended,
especially in paraurethral cysts of newborn without complications and symptoms.
In this paper, we describe a female neonate who had a paraurethral cyst that
spontaneously resolved one month after birth and review the literature.
PMID- 10770253
TI - Priapism in a sickle cell prepuberal child.
AB - Between 1985 and 1995, six sickle cell children listed SS were hospitalized in
our department for priapism persisting after 24 hours of medical treatment. Two
cases regressed after 6 hours of treatment follow-up. Four children were treated
by a corpus cavernosum puncture, through the gland, leading to priapism
detumescence in 3 cases. In one of our cases, the persistence of priapism induced
us to perform a spongiocavernous anastomosis at the 72nd hour. One of the
children developed a cerebrovascular accident 10 days after the beginning of the
priapism. The other children have been re-examined. They have not presented any
reccurence and have normal erection after puberty. Starting from a literature
review, we explain the principles we adopted. The physiopathology of priapism in
sickle cell patients remains unclear, for both high and low flows do exist. In
addition to the risks related to blood products, the treatment by transfusional
exchange involves neurological risks and must not delay any surgery. Analgesic
treatment is often required. Corpus cavernosum puncture is efficient, with no
fibrosis risk. In case of failure, a cavernospongious shunt, with a biopsy
needle, can be performed at the same time. Surgical anastomoses are then proposed
in case of priapism persistence. General evolution is satisfactory. But the
sickle cell patient's priapism needs a long-term follow-up in order to recognise
any minor recurrences. The latter could be the principal cause of fibrosis and
impotency.
PMID- 10770254
TI - Post-traumatic arterial priapism in the child: a study of four cases.
AB - The authors report four cases of arterial priapism in the child, a rare condition
since only 13 cases are described in the literature. High-flow priapism follows
perineal or penile injury with damage to a cavernosal artery and formation of an
arteriosinusoidal fistula. The onset may be immediate but more often occurs after
a few days. Arterial priapism is painless, as the corpora cavernosa are less
tumescent in the anterior third of the penis. The clinical appearance and
circumstances of onset suggest the diagnosis. Doppler ultrasound is the
complementary investigation of choice, confirming and localising the fistula.
Various methods of treatment have been proposed. Injections of alphastimulant
seem ineffective in most cases and are not without danger. Surgery, which is
potentially damaging, has been used only in the adult. Most authors propose
embolising with resorbable material the artery which feeds the fistula. However,
priapism may resolve spontaneously in less than three weeks, as occurred in our
cases, without recurrence or subsequent erectile dysfunction. We thus consider
the condition may initially be managed by observation alone, with recourse to
embolisation if priapism does not resolve after a period of time which however
remains to be defined.
PMID- 10770255
TI - Tyrosine-kinase dependent TGF-beta and extracellular matrix expression by
mechanical stretch in vascular smooth muscle cells.
AB - Vascular hypertrophy, which is characterized by proliferation of vascular smooth
muscle cells (VSMC) and accumulation of extracellular matrix (ECM), is a major
pathological change in blood vessels after chronic exposure to hypertension.
Blood pressure is transmitted to the arterial walls and counterbalanced by
mechanical stress, leading to stretching of circumferentially oriented VSMC,
which may play some role in the pathogenesis of vascular hypertrophy. The present
study was designed, therefore, to investigate the effect of mechanical stretch on
the expression of ECM components and transforming growth factor-beta (TGF-beta),
a potent stimulator for ECM production, and to examine the signal transduction
mechanisms of the induction of TGF-beta in cultured rat VSMC. VSMC were subjected
to cyclic stretch to provide a maximal elongation of 20% at a rate of 60 cycles
per minute for up to 24 h. Mechanical stretch stimulated TGF-beta1 mRNA
expression in a time- and elongation-dependent manner. Indeed, the secretion of
TGF-beta proteins into the culture media was increased after stretch. Stretch
also stimulated mRNA expression of the ECM components, type I and type IV
collagen, and fibronectin, which was largely inhibited by addition of
neutralizing antibody against TGF-beta. The tyrosine kinase inhibitors genistein
and herbimycin A blocked the induction of TGF-beta1 and type I collagen by
stretch, while protein kinase C inhibitors, the calcium channel blockers
nitrendipine and gadolinium, or Ca removal from the media had no effect. These
results suggest that stretch-induced, tyrosine kinase-mediated
autocrine/paracrine production of TGF-8 may play a critical role in the
progression of vascular remodeling associated with high blood pressure.
PMID- 10770256
TI - Effects of the Chinese medicine, TSJN on insulin resistance and hypertension in
fructose-fed rats.
AB - The aim of this study was to determine the effect of Tang-Shen-Jiao-Nang (TSJN),
a Chinese medicine used to treat diabetes mellitus, on insulin resistance and
hypertension in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats
were fed either normal rat chow (control) or a fructose-rich chow (FFR) for 6 wk.
For the last 2 or 4 wk of a 6-wk period of either diet, the rats were treated by
gavage with gum arabic solution as a vehicle (control or FFR) or TSJN (800
mg/kg/d; FFR+TS), and then we performed the euglycemic hyperinsulinemic glucose
clamp technique to estimate insulin sensitivity. Systolic blood pressure was
measured weekly for 6 wk. At the end of the glucose clamp, the soleus muscle was
dissected out for determination of muscle fiber composition by ATPase methods.
Systolic blood pressure was elevated at 2 wk after the start of the fructose-rich
chow feeding and persisted thereafter throughout the study. Systolic blood
pressure during the glucose clamp in the FFR group was significantly higher than
that in the control group. Although there was no effect on systolic blood
pressure in rats treated with TSJN for the last 2 wk of their 6-wk diet, those
treated with TSJN for the last 4 wk of their 6-wk diet had lower systolic blood
pressure than did the rats in the FFR group. The average rate of glucose infusion
during the glucose clamp, as a measure of insulin sensitivity (M value), was
significantly lower in the FFR than in the controls (10.9 +/- 0.6 and 15.4 +/-
0.4, mg/kg/min, for FFR and controls, respectively; p< 0.01). Treatment with TSJN
for 2 wk significantly improved the M value compared to that of the control level
(15.1 +/- 0.5 mg/kg/min). The composite ratio of type I fibers in the soleus
muscle was significantly decreased in the FFR compared to controls (75.0 +/- 1.7
and 81.7 +/- 1.5%, for FFR and controls, respectively; p< 0.01), and treatment
with TSJN for 2 wk led to a recovery composite ratio of type I fiber to the same
level as that of the control group (78.7 +/- 1.7% in FFR + TS). The M value was
significantly correlated with the compositions of type I and type II fibers (for
type I fibers, r= 0.45, p < 0.01, for type II fibers, r= -0.44, p< 0.05). These
results suggest that the Chinese medicine TSJN may improve insulin resistance,
lower the systolic blood pressure, and modulate muscle fiber composition in
hypertensive and insulin-resistant fructose-fed rats.
PMID- 10770257
TI - Blockade of angiotensin receptors in the anterior hypothalamic preoptic area
lowers blood pressure in DOCA-salt hypertensive rats.
AB - It has been established that deoxycorticosterone acetate (DOCA)-salt hypertensive
rats have an overactive brain angiotensin-system. The purpose of the present
study was to identify the brain sites showing enhanced angiotensin-system
activity responsible for the pathogenesis of hypertension in DOCA-salt
hypertensive rats. The angiotensin receptor antagonist, losartan, was injected
into brain ventricles or into tissues around the rostral parts of the third
ventricle in conscious DOCA-salt hypertensive rats. Losartan (1 microg) injection
into the lateral ventricle or into the rostral parts of the third ventricle
produced a depressor response, whereas the agent did not affect blood pressure
when injected into the caudal parts of the third ventricle or into the fourth
ventricle. Losartan (0.1 microg) injection into the anterior hypothalamic
preoptic area, anterior (AHA) produced a depressor response. Angiotensin II (0.1
1 ng) injection into the AHA produced a pressor response in sham-operated and
DOCA-salt hypertensive rats, and the pressor response to angiotensin II (1 ng)
was greater in DOCA-salt hypertensive rats than that in sham-operated rats.
Release of angiotensin peptides in the AHA was greater in DOCA-salt hypertensive
rats than that in sham-operated rats. These findings suggest that the angiotensin
system in the AHA is enhanced, and that this enhancement is involved in the
maintenance of hypertension in DOCA-salt hypertensive rats. Both increased
pressor reactivity to angiotensin II and increased release of angiotensin
peptides in the AHA appear to be related to this enhancement of the angiotensin
system in DOCA-salt hypertensive rats.
PMID- 10770258
TI - Contribution of cardiovascular hypersensitivity to orthostatic hypertension and
the extreme dipper phenomenon.
AB - We report the case of a 68-yr-old woman who, upon standing, experienced dizziness
in association with increased blood pressure (BP) and heart rate (HR). We made a
diagnosis of orthostatic hypertension and examined the BP response to postural
change using the head-up tilt test. Positional change resulted in a 20-mmHg
increase in systolic BP and a 15-bpm increase in HR. A 24-h ambulatory BP
recording showed daytime hypertension that decreased at night, along with a
nocturnal decrease in HR. Based on these post-diagnostic results, the patient was
rediagnosed as an extreme dipper with silent lacunar infarction as the only
complication of orthostatic hypertension. We suggest that, in our patient, the
mechanism of orthostatic hypertension was hypersensitivity of cardiovascular
responsiveness to endogenous vasoconstrictors. This was evidenced by increased
pressure sensitivity to isoproterenol as well as phenylephrine. We thus selected
carvedilol, a beta-blocker with slight alpha-blocking action, and were more
effective in abolishing the hypertension.
PMID- 10770259
TI - Incidence and long-term prognosis of initial stroke and acute myocardial
infarction in Okinawa, Japan.
AB - We performed a cross-sectional survey of the incidence of stroke and acute
myocardial infarction (AMI) in Okinawa, Japan, with a census population of about
1.2 million. A total of 3,644 cases of first-ever stroke and 898 cases of initial
AMI were detected. The age-adjusted annual incidence rate of stroke was 105 per
100,000 of the standard population of Japan based on census population taken in
1985, and that of AMI was 26 per 100,000. The case-fatality rate of stroke within
28 days of onset was 12.8%, and that of AMI was 22.2%. Of the stroke cases, 51.4%
were diagnosed as brain infarctions, 38.7% as brain hemorrhages, and 9.3% as
subarachnoid hemorrhages. The diagnoses of stroke subtypes were confirmed by
computed tomography or magnetic resonance imaging in 98.4% of all stroke cases.
The long-term prognosis of patients with stroke and AMI was studied by examining
their 10-yr survival rates (follow-up rate 89.8%). The cumulative survival rate
was 38.2% in brain infarction cases, 40.4% in brain hemorrhage cases, and 38.2%
in AMI cases. The 50% reduction of survival had occurred at 2,880 days after
onset in brain infarction cases, at 2,764 days in brain hemorrhage cases, and at
2,658 days in AMI cases. In Okinawa, the incidence rate of AMI was still
considerably lower than that in the Western population, and the rate of stroke
was similar to that in the Western population. The ten-year survival rates were
quite similar in AMI and stroke, and both were unexpectedly high.
PMID- 10770260
TI - Functional analysis of cardiovascular renin-angiotensin system using a gain or
loss of function approach.
AB - The study of the effect of autocrine-paracrine vasoactive modulators on
cardiovascular biology is very difficult in vivo, because in vivo studies are
limited. In particular, characterization of the role of components of the renin
angiotensin system (RAS) in vivo is limited by the difficulty in manipulating
individual components of the RAS as well as by methodological limitations in
studying the function of a local RAS in the absence of any contribution by the
circulatory system. Recent progress in in vivo gene transfer technologies has
provided us with the opportunity to study cellular responses to the manipulation
of the individual components (i.e., by overexpression or inhibition). Many
researchers have recently developed various in vivo gene transfer techniques for
cardiovascular applications. Using in vivo gene transfer approaches, the roles of
various tissues in the RAS, such as cardiac angiotensin, have been identified.
Such an approach may increase our understanding of the biology and pathobiology
of the autocrine-paracrine system. This review discusses the potential utility of
in vivo gene transfer methods.
PMID- 10770261
TI - Comparison of the effect of blood pressure on the development of stroke, acute
myocardial infarction, and end-stage renal disease.
AB - Hypertension is a known risk factor for cardiovascular disease, but few
epidemiological studies have examined simultaneously the effect of baseline blood
pressure on the development of stroke, acute myocardial infarction (AMI), and end
stage renal disease (ESRD). In 1983, a large, community-based mass screening
covered about 14% of the adult population in Okinawa, Japan. The total number of
people screened was 107,192 (51,122 men, 56,070 women). We had access to two
independent registries of end-organ damage: the Co-operative Study Group of
Morbidity and Mortality of Cardiovascular Diseases in Okinawa (COSMO) registry
for stroke and AMI, and the Okinawa Dialysis Study (OKIDS) registry for ESRD. The
total number of people registered was 4,756 with stroke, 1,059 with AMI, and 641
with ESRD during the study period from April 1, 1988, to March 31, 1991. By using
the name, sex, birth date, and ZIP code of registrants, we identified those
registrants who were screened in 1983 and had developed stroke, AMI, or ESRD.
Hypertension was defined as systolic blood pressure (SBP) of 140 mmHg or higher
or diastolic blood pressure (DBP) of 90 mmHg or higher. Other readings were
regarded as normotensive. The prevalence of hypertension was 35.8% (N=37,299).
The cumulative incidence of stroke, AMI, and ESRD was 154, 21, and 19 subjects
among those with SBP < or = 119 mmHg, and 1933, 315, and 71 subjects among those
with SBP > or = 160 mmHg. Similarly, the incidence of stroke, AMI, and ESRD was
234, 44, and 25 subjects among those with DBP < or = 69 mmHg and 1980, 381, and
364 subjects among those with DBP > or = 110 mmHg. Hypertension was prevalent in
the adult population in Okinawa, Japan, and was a significant predictor of
stroke, AMI, and ESRD. However, the effect of blood pressure on target organs
differed and was more evident in those with stroke than in those with AMI and
ESRD.
PMID- 10770262
TI - Twenty-four hour urinary sodium and 3-methylhistidine excretion in relation to
blood pressure in Chinese: results from the China-Japan cooperative research for
the WHO-CARDIAC Study.
AB - We examined the associations between sodium and blood pressure (BP), and between
3-methylhistidine (3MH) (a marker of animal protein intake) and BP in four
Chinese population samples (Guiyang, Guangzhou, Shanghai and Shijiazhuang). This
work was a constituent part of the World Health Organization (WHO) Cardiovascular
Disease and Alimentary Comparison (CARDIAC) Study. Each population sample
consisted of 100 men and 100 women aged 48-56 yr and randomly selected using a
cross-sectional study design. Twenty-four hour urine samples were collected.
Urinary sodium and potassium excretion levels were measured by the flame
photometry method, and 3MH was measured using a Hitachi Amino Acid Analyzer 835
(Hitachi, Ibaraki, Japan). After excluding subjects who did not complete the 24-h
urine collection (as assessed by urinary creatinine excretion in relation to
weight), the total study group included 314 men and 355 women. The results showed
that (1) Sodium was positively, and 3MH negatively associated with systolic and
diastolic BP (SBP, DBP) in both the total sample and in those who were not
administered anti-hypertensive drugs; these associations were all significant (p<
0.05), and remained so after adjustment for age, sex, body mass index [BMI,
weight (kg)/height (m2)], alcohol intake and potassium excretion. Sodium and 3MH
were also observed to exert a combined effect on BPs. In general, subjects who
had higher sodium and lower 3MH levels had higher mean SBP and DBP. This combined
effect was particularly clear on SBP. (3) A positive association between sodium
and BP, and a negative association between 3MH and BP were also shown in subjects
who had BMI less than 26 kg/m2. In conclusion, the study confirmed and further
extended previous observations on the study of salt and animal protein intake in
relation to BP in middle-aged Chinese. The results support recommendations for a
reduction in high salt intake for the control of high BP in the general
population and in those with lower BMI. The results also provide important
evidence that adequate animal protein intake may have a favorable effect on BP.
PMID- 10770263
TI - Control of blood pressure and prevention of end-organ damage in patients with
accelerated hypertension by combination with arotinolol and extended release
nifedipine.
AB - In patients with accelerated (malignant) hypertension, end-organ damage is the
determinant factor for prognosis. Although recent advances in antihypertensive
therapy have improved the outcome of patients with accelerated hypertension, the
effectiveness of antihypertensive therapy still remains less convinced. In this
study, we followed 13 patients clinically diagnosed with accelerated hypertension
(defined as diastolic blood pressure > 130 mmHg, retinopathy with K-W IV and
accelerated renal impairment) for 3 yr. One patient died due to acute myocardial
infarction arising from poor compliance with antihypertensive therapy. One
patient was maintained on hemodialysis for 3 yr. One patient was introduced for
continuous ambulatory peritoneal dialysis (CAPD) for a year and then lived
without dialysis therapy. The remaining 10 patients were followed for 3 yr. All
patients were initially treated with intravenous administration of calcium
antagonist for reduction of blood pressure, followed by hemodialysis therapy if
needed. After stabilization of blood pressure, combination therapy with extended
release nifedipine (40 to 80 mg daily) and arotinolol (20 mg daily) was started.
The targets for blood pressure control were a systolic pressure of 135 mmHg and a
diastolic pressure of 80 mmHg. If blood pressure control was unsatisfactory,
guanabenz (2 to 4 mg before bedtime), a central acting drug, was added. At
presentation, the mean diastolic blood pressure (mDBP) among the 10 remaining
patients was 134 +/- 2 mmHg, the mean serum creatinine (mScr) was 4.5 +/- 0.7
mg/dl and the left ventricular mass index (LVMi) as measured by echocardiography
was 150 +/- 9 g/m2. At 1 yr, the mDBP was reduced to 90 +/- 3 mmHg, the mScr to
2.9 +/- 0.9 mg/dl and the LVMi to 140 +/- 9 g/m2. At 3 yr, the mDBP was
stabilized at 79 +/- 3 mmHg, the mScr maintained at 2.2 +/- 0.4 mg/dl, and the
LVMi reduced to 128 +/- 9 g/m2. These results indicate that appropriate blood
pressure control is important for improvement of renal impairment and cardiac
damage in patients with accelerated hypertension. Moreover, combination therapy
with arotinolol and extended release nifedipine may be beneficial for this
purpose.
PMID- 10770264
TI - Adrenomedullin amidation enzyme activities in hypertensive patients.
AB - Adrenomedullin (AM) is a potent vasodilating peptide secreted from the
vasculature of various organs. It is biologically active when its C-terminus is
amidated. Recently, an RIA method was developed for measurement of the active
form of AM, or mature AM. We here employed this method to investigate the
significance of amidation of AM in controlling cardiovascular function. Thirty
six patients under hemodialysis were recruited and divided into hypertensive (n =
25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM,
immature AM and blood pressure were monitored during hemodialysis in all
patients. There was a significant reduction in blood pressure during hemodialysis
in both groups, although after hemodialysis blood pressure was still higher in
hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/-
5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives
than normotensives and it decreased in both groups. Although mature AM decreased
more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the
end point, its level was still higher in normotensives. The ratio of mature
AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained
stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in
ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level
in hypertensives may have contributed to the higher blood pressure in this group.
The attenuation of AM amidation in normotensives indicates that an unspecified
amidative enzyme of AM was regulated in order to normalize blood pressure.
PMID- 10770265
TI - An insertion/deletion polymorphism in intron 18 of the type B human natriuretic
peptide receptor gene is not associated with cerebral infarction.
AB - The natriuretic peptide (NP) system may play a crucial role in the development of
cardiovascular and renal diseases. C-type NP dilates arteries and lowers blood
pressure, and it inhibits the proliferation of vascular smooth muscle cells via
the type B NP receptor (NPRB). We determined and analyzed the structure of the
NPRB gene and found an insertion/deletion (I/D) polymorphism in intron 18. In
this experiment, we studied this I/D polymorphism in the NPRB gene in 241
subjects, including 118 patients with cerebral infarction (the CI group) and 123
control subjects (the non-CI group). Our goal was evaluate the association of
this polymorphism with cerebral infarction. Our findings showed that genotype
frequencies of the I/D polymorphism were in Hardy-Weinberg equilibrium. The
frequencies for the II, ID, and DD alleles were 0.569, 0.374, and 0.057,
respectively, in the non-CI group and 0.576, 0.356, and 0.068, respectively, in
the CI group. No association was found between this polymorphism and cerebral
infarction. These results suggest that this polymorphism in the NPRB gene is not
linked to a pathogenic CI gene.
PMID- 10770266
TI - 24-hour blood pressure in Uygur, Kazakh and Han elderly subjects in China.
AB - The Uygur in Hotan (Xinjiang, China) are reported to have a long life expectancy.
The purpose of this study was to clarify the relationship between variations in
blood pressure (BP) and longevity. Cross-sectional surveillance was carried out
in both Hotan and Barkol. The subjects were divided into five groups: 1. Uygur
longevity subjects in Hotan (103 subjects, age >90 yr); 2. Uygur elderly subjects
in Hotan (107 subjects, age 65-70 yr); 3. Han elderly subjects in Hotan (41
subjects, age 65-70 yr); 4. Kazakh elderly subjects in Barkol (117 subjects, age
65-70 yr); 5. Han elderly subjects in Barkol (50 subjects, age 65-70 yr). BP was
monitored and analyzed using the fourteen devices of ambulatory BP monitoring.
The prevalence of hypertension was lowest in the Uygur (16.2% in Uygur elderly
subjects in Hotan; 23.7% in Uygur longevity subjects in Hotan; 27.0% in Han
elderly subjects in Hotan; 42.0% in Han elderly subjects in Barkol; 50.0% in
Kazakh elderly subjects in Barkol). The ratio of dips in BP was largest in the
Han (57% in Han elderly subjects in Barkol; 50% in Han elderly subjects in Hotan;
50% in Uygur longevity subjects in Hotan, 49% in Uygur elderly subjects in Hotan;
17% in Kazakh elderly subjects in Barkol). The 24-h mean systolic BP in Uygur
longevity subjects in Hotan was not different from those in Uygur elderly
subjects and Han elderly subjects in Hotan, nor did the 24-h mean diastolic BP
differ from those in Uygur elderly subjects and Han elderly subjects in Hotan
respectively. In conclusion, Uygur subjects seem to be less hypertensive,
compared to Kazakh subjects. Uygur longevity subjects had more dipping in their
BP variation than did the Kazakh subjects in Xinjiang, China.
PMID- 10770267
TI - Direct effects of statins on cells primarily involved in atherosclerosis.
AB - Statins are lipid-lowering agents which act by inhibition of 3-hydroxy-3
methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme is responsible for the
conversion of HMG-CoA to mevalonate. Products of mevalonate metabolism are
critical for several cellular processes of eukaryotic cells, and inhibition of
the mevalonate pathway by statins has pleiotropic effects. It has been reported
that statins inhibit the migration and proliferation of vascular smooth cells
(VSMCs) and macrophages, decrease interleukin-6 and inducible nitric oxide
synthase expression in VSMCs, improve endothelial function and up-regulate
endothelial nitric oxide synthase expression. The above effects of statins are
independent of plasma cholesterol levels, and are completely blocked by exogenous
mevalonate and some isoprenoids. These findings suggest that, in addition to
their effects on plasma lipids, statins exert direct antiatherosclerotic effects
on the cells primarily involved in atherosclerosis.
PMID- 10770268
TI - Immunomodulation of experimental autoimmune diseases via oral tolerance.
AB - The concept of oral tolerance refers to a form of peripheral tolerance in which
mature lymphocytes in the peripheral lymphoid tissues are rendered nonfunctional
or hyporesponsive by prior oral administration of an antigen. The primary
mechanisms mediating oral tolerance include deletion, anergy of antigen-specific
T cells and active cellular suppression, the primary determining factor being the
dose of fed antigen. Low doses favor active suppression, whereas high doses favor
deletion and anergy. Active cellular suppression is mediated by the induction of
regulatory T cells in the gut-associated lymphoid tissue, which migrate to the
systemic immune system. One of the primary mechanisms of active cellular
suppression is via secretion of suppressive cytokines such as TGF-beta, IL-4, and
IL-10 following antigen-specific triggering. TGF-beta is produced both by CD4+
and CD8+ GALT-derived T cells and is an important mediator of the active
suppression component of oral tolerance. CD4+ cells that primarily produce TGF
beta appear to be a unique T-cell subset and termed Th3 cells. Oral tolerance was
successfully studied in a variety of experimental models for autoimmune diseases,
among them experimental autoimmune encephalomyelitis, experimental arthritis,
experimental anti-phospholipid syndrome, experimental autoimmune uveoretinitis,
experimental insulin dependent diabetes mellitus (IDDM), and experimental
autoimmune myasthenia gravis. The results obtained in experimental animal models
have led to the conduction of several clinical trials of oral tolerance in
patients with multiple sclerosis, rheumatoid arthritis, uveitis, and IDDM.
Conflicting results were obtained, and although some improvement has been noted
in some of the patients, broad ranging clinical improvement has not yet been
observed. A more accurate choice of antigens, as well as more precise dosing and
timing of antigen-administration might lead to better results in the future.
PMID- 10770269
TI - CD4+ T cells in adoptive immunotherapy and the indirect mechanism of tumor
rejection.
AB - Tumor-specific CD4+ effector T cells often play a decisive role in immunologic
tumor rejection, in some cases without evident co-participation of CD8+ T cells.
During such CD4+ T-cell-mediated rejection there is often no detectable direct
contact between T cells and tumor cells. Optimally prepared, adoptively
transferred CD4+ T cells can reject established tumors with great efficiency even
when targeted tumor cells express no MHC Class II molecules, implying that
recognition of tumor antigen (Ag) occurs via MHC Class II-expressing host antigen
presenting cells (APC) within the tumor. Because consequent rejection also
excludes Ag-specific contact between CD4+ T cells and MHC Class IIneg tumor
cells, the most critical CD4+ T-cell-mediated event is likely cytokine release,
resulting in an accumulation and activation of accessory cells such as
tumoricidal macrophages and lymphokine-activated killer cells. Although such an
indirect rejection mechanism may appear antithetical to popular strategies
centered on CD8+ cytotoxic T cell (CTL), current evidence suggest that even CD8+
T-cell-mediated recognition/rejection often bypasses direct tumor cell contact
and is largely cytokine mediated. While CTL are likely to participate prominently
in many models of tumor rejection, indirect mechanisms of recognition/rejection
have the theoretical advantage of remaining operative even when individual tumor
cells evade direct contact by down-regulating MHC and/or Ag expression.
PMID- 10770270
TI - Human TCR as antigen: homologies and potentially cross-reactive HLA-DR2
restricted epitopes within the AV and BV CDR2 loops.
AB - The major function of the T-cell receptor is to confer antigen specificity to T
cells. However, nascent TCR proteins that are not assembled into functional
heterodimers may be processed and displayed with self MHC molecules on the T-cell
surface, and are thought to be the genesis of autoregulatory T cells that can
limit inflammatory responses through T-T network interactions. In previous work,
we and others have exploited this natural regulatory system using TCR peptides to
amplify regulatory T cells that potentially can treat human autoimmune diseases
such as multiple sclerosis (MS) and arthritis. The development of this approach
is limited by the diversity of human TCR V gene sequences, and by lack of
knowledge of exactly which regions of the V gene proteins are immunogenic in
association with various MHC alleles. To identify similar amino acid sequences
within and among human V gene families that might have immunologic cross
reactivity, we aligned 74 known AV and 109 known BV protein sequences into
homologous groups using the ClustalX program. Moreover, with a focus on CDR2
peptides that have previously been used to induce regulatory T cells in clinical
trials, we established homologous peptide groups, and then identified the optimal
amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that
have been associated with susceptibility to MS. From this analysis, > 75% of AV
and BV CDR2 sequences were predicted to bind with at least moderate avidity to
each of the DR2 alleles, thus enhancing the likelihood that they could be
antigenic. Further ordering of putative TCR contact residues revealed a different
set of homology groupings, including many intrafamily sequence matches and some
interfamily matches that might allow immunological cross reactivity. Particularly
striking were DRB1*1501-restricted IH-S and IY-S motifs shared by BV11, BV12, and
BV13 and BV3, BV12, BV13, and BV17 family members, respectively, and DRB5*0101
restricted RL-H and RL-Y motifs shared by BV11, BV12, and BV13 and BV13 and BV17
family members, respectively. This analysis may be useful in designing an array
of clinically useful homologous peptides with optimal MHC binding properties and
highly cross-reactive TCR binding motifs.
PMID- 10770271
TI - Chronic allograft rejection associated vasculopathy and synthetic biodegradable
vascular grafts: a lesson to learn?
AB - In chronic allografts, graft vessels eventually develop so-called "transplant
vascular sclerosis" or "intimal hyperplasia". A major question is whether the
cells in the neointima are donor or recipient derived. The process of transplant
vascular sclerosis closely resembles the remodeling of the vascular wall as seen
when synthetic biodegradable small caliber vascular grafts are implanted. In this
model, the cells in the newly developing neointima as well as neomedia are, by
definition, recipient derived. By using cardiac allografts as well as aortic
allografts exchanged between a female donor and a male recipient (rats), the
origin of the neointimal vascular smooth muscle cells could be traced by looking
for the Y-chromosome in isolated (alpha-actin positive) intimal cells using PCR.
In both models these intimal cells were found to be of recipient-origin. It is
proposed, that, basically, this remodeling process is part of a normal healing
process. Whereas in biodegradable grafts this "healing process" appears to be
self limiting, in allografts the process goes on beyond the needs of functional
repair, eventually, in some cases, leading to total vascular occlusion. Future
therapeutic protocols might try and aim at controlling this essentially normal
repair process.
PMID- 10770272
TI - Membrane processing of fruit juices and beverages: a review.
AB - Membrane technology for the processing of fruit juices and beverages has been
applied mainly for clarification using ultrafiltration and microfiltration, and
for concentration using reverse osmosis. The effects of product preparation,
membrane selection, and operating parameters are important factors influencing
filtration rate and product quality. Technological advances related to the
development of new membranes, improvement in process engineering, and better
understanding of fruit beverage constituents have expanded the range of membrane
separation processes. Developments in novel membrane processes, including
electrodialysis and pervaporation, increased the array of applications in
combination with other technologies for alternate uses in fruit juices and
beverages.
PMID- 10770273
TI - Modeling microbial survival during exposure to a lethal agent with varying
intensity.
AB - Traditionally, the efficacy of preservation and disinfection processes has been
assessed on the basis of the assumption that microbial mortality follows a first
order kinetic. However, as departures from this assumed kinetics are quite
common, various other models, based on higher-order kinetics or population
balance, have also been proposed. The database for either type of models is a set
of survival curves of the targeted organism or spores determined under constant
conditions, that is, constant temperature, chemical agent concentration, etc.
Hence, to calculate the outcome of an actual industrial process, where conditions
are changing, as in heating and cooling during a thermal treatment or when the
agent dissipates as in chlorination or hydrogen peroxide application, one has to
integrate the momentary effects of the lethal agent. This involves mathematical
models based on assumed mortality kinetics, and simulated or measured history,
for example, temperature-time or concentration-time relationships at the
"coldest" point. It is shown that the survival curve under conditions where the
agent intensity increases, decreases, or oscillates can be constructed without
assuming any mortality kinetics and without the use of the traditional D and Z
values, which require linear approximation, and without thermal death times,
which require extrapolation. The actual survival curves can be compiled from the
isothermal survival curves provided that growth and damage repair do not occur
over the pertinent time scale and that the mortality rate is a function of only
the momentary agent intensity and of the organism's or spore's survival fraction
(but not of the rate at which this fraction has been reached). The calculation is
greatly facilitated if both the "isothermal" survival curves and the time
dependent agent intensity can be expressed algebraically. The differential
equation derived from these considerations can be solved numerically to produce
the required survival curve under the changing conditions. The concept is
demonstrated with simulated survival curves during heating at different rates,
heating and cooling cycles, oscillating temperature, and exposure to a
dissipating chemical agent. The simulated thermal processes are based on
published data of Clostridium botulinum spores, whose semilogarithmic survival
curves have upward concavity and on a hypothetical "Listeria-like" organism whose
semilogarithmic curves have downward concavity.
PMID- 10770274
TI - Immunity to Salmonella typhimurium.
PMID- 10770276
TI - Immune response to infection with Salmonella typhimurium in mice.
AB - Infection of mice with Salmonella typhimurium results in systemic infection and a
disease similar to that seen in humans after infection with S. typhi. The innate
immune system can restrict replication of S. typhimurium to a certain degree, but
for effective control and eradication of bacteria, acquired immunity is
essential. Salmonella infection induces the generation of specific CD4+ and CD8+
T cells, and both T cell populations are important for protection during primary
and secondary responses, although the mechanisms underlying T cell-mediated
protection are not yet completely understood. Infection with S. typhimurium also
results in a strong antibody response to Salmonella antigens and, in contrast to
most other intracellular bacteria, this antibody response participates in
protection. In summary, the response to S. typhimurium involves both T and B cell
mediated immunity, and mechanisms mediated by both lymphocyte populations are
important for control of primary infection and protection against secondary
infection.
PMID- 10770275
TI - Toll-like receptors: a growing family of immune receptors that are differentially
expressed and regulated by different leukocytes.
AB - Toll is a Drosophila gene essential for ontogenesis and antimicrobial resistance.
Several hortologues of Toll have been identified and cloned in vertebrates,
namely Toll-like receptors (TLR). Human TLR are a growing family of molecules
involved in innate immunity. TLR are structurally characterized by a cytoplasmic
Toll/interleukin-1R (TIR) domain and by extracellular leucine-rich repeats. TLR
characterized so far activate the MyD88/IRAK signaling cascade, which bifurcates
and leads to NF-kappaB and c-Jun/ATF2/TCF activation. Genetic, gene transfer, and
dominant-negative approaches have involved TLR family members (TLR2 and TLR4) in
lipopolysaccharide recognition and signaling. Accumulating evidence suggests that
some TLR molecules are also involved in signaling receptor complexes that
recognize components of gram-positive bacteria and mycobacteria. However, the
definitive role of other TLR is still lacking. A systematic approach has been
used to determine whether different human leukocyte populations selectively or
specifically expressed TLR mRNA. Based on expression pattern, TLR can be
classified as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5), and specific
(TLR3). Expression and regulation of distinct though overlapping ligand
recognition patterns may underlie the existence of a numerous, seemingly
redundant, TLR family. Alternately, the expression of a TLR in a single cell type
may indicate a specific role for this molecule in a restricted setting.
PMID- 10770277
TI - Exploitation of host cell signaling machinery: activation of macrophage
phosphotyrosine phosphatases as a novel mechanism of molecular microbial
pathogenesis.
AB - Intracellular pathogens, particularly those that target host mononuclear
phagocytes, have evolved strategies to either evade or inhibit cellular
mechanisms of host defense. Mycobacterium tuberculosis and Leishmania donovani
exemplify a diverse group of microorganisms that have developed the ability to
invade and replicate within host macrophages, leading to disease expression.
Recent studies have suggested that the pathogenesis of intracellular infection
may involve interference with host cell signaling. Drawing upon examples from in
vitro models that focused on M. tuberculosis and L. donovani, we review evidence
that activation of host cell phosphotyrosine phosphatases may contribute to
pathogenesis. A leading candidate appears to be the Src homology 2 domain
containing phosphotyrosine phosphatase SHP-1, the activation of which may
contribute to the development of infection and disease progression.
PMID- 10770279
TI - Does innate immune privilege exist?
AB - Immune privilege in the eye is believed to originate from the eye's need to avoid
the sight-destroying consequences of inflammation. Over the past 25 years, many
of the anatomical, cellular, and molecular mechanisms by which the eye avoids
inflammation secondary to adaptive immune responses have been elucidated. In the
recent past, it has become increasingly clear that innate immune responses play a
critical role in activating the adaptive immune response. Moreover, innate
immunity itself carries a heavy burden of inflammation, thereby posing a threat
to vision if it should occur intraocularly. Ocular immunologists have now begun
to inquire into the extent to which the eye regulates the expression of innate
immunity in oculi. Evidence is presented which indicates that factors found in
normal aqueous humor (1) prevent NK cells from lysing their targets, (2) inhibit
neutrophil activation by CD95 ligand, (3) suppress nitric oxide production by
activated macrophages, and (4) interfere with complement activation via the
alternative pathway. These factors include transforming growth factor-beta2,
alpha-melanocyte-stimulating hormone, calcitonin gene-related peptide, and
migration inhibitory factor. The ability of the eye to prevent intraocular
activation of innate immune effectors spares the corneal endothelium (which
expresses CD95 ligand constitutively, but low levels of MHC class I molecules)
from destruction by NK cells and neutrophils, and protects the visual axis from
distortion by macrophage and complement-mediated inflammation. Thus, privilege
exists in the eye for both adaptive and innate immunity.
PMID- 10770278
TI - The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC
chemokines with divergent roles in early neutrophil regulation.
AB - The recruitment of neutrophil granulocytes to sites of tissue injury is one of
the earliest events during host defense. Several chemotactic cytokines belonging
to the CXC subfamily of chemokines are thought to be implicated in this kind of
response. Especially those CXC chemokines that are stored in blood platelets and
become immediately released upon activation are likely to dominate neutrophil
dependent host defense at the onset of inflammation. The major platelet-derived
CXC chemokines are the beta-thromboglobulins and platelet factor 4 (PF-4), which
are both released into the blood at micromolar concentrations. The availability
as well as the functional activity of these mediators appear to be subject to
tight control by diverse regulatory mechanisms. These include proteolytic
processing of chemokine precursors, oligomer formation, and the differential
usage of neutrophil-expressed receptors. Herein we review our work on early
neutrophil regulation by PF-4, the beta-thromboglobulin neutrophil-activating
peptide 2 (NAP-2) and its major precursor connective tissue-activating peptide
III (CTAP-III). We moreover propose a model to assess the contribution by either
of these chemokines to coordinated recruitment and activation of neutrophils in
response to acute tissue injury.
PMID- 10770280
TI - Regulation of adaptive immune responses by innate cells expressing NK markers and
antigen-transporting macrophages.
AB - A continuing theme of work done in our laboratory involves regulation of adaptive
immune response by innate cells, in general, and immuneregulation by natural
killer (NK) and NKT cells, in particular. Studies include work with the lung and
the eye. In addition to immune surveillance of tumor cells, the NK cell is often
associated with secreting cytokines that contribute to the creation of
microenvironments conducive to Th1 responses and with defense mechanisms that
lessen the initial infecting viral load. Reported studies show that the NKT cells
support both T helper cell responses (type 1 and 2), as well as their being
absolutely central to the development of antigen-specific T-regulatory cells
involved in peripheral tolerance. Because of the multifunctional capabilities of
the NKT cell, we propose that yet another cell, such as the antigen-presenting
cell (APC), may influence the effector pathway of the NKT cell. We postulate that
the APC that transports the antigen from the entry environment provides both
trafficking and activation signals for innate cells in the secondary lymphoid
organs. Evidence is presented that macrophage-derived signals selectively recruit
NKT cells and bias their cytokine synthesis. Data imply that, just as occurs in
immune inflammation, a collection of innate and adaptive immune cells interact
within the secondary lymphoid tissue to generate antigen-specific tolerance in
the periphery.
PMID- 10770281
TI - Regulation of phagocytic leukocyte activities by C-reactive protein.
AB - The classic acute phase reactant C-reactive protein (CRP) is classified as an
effector of innate host resistance because it activates the classical complement
cascade and is opsonic. The latter action occurs via specific CRP receptors (CRP
R) that have recently been identified as both FcgammaRI and FcgammaRII on human
phagocytic leukocytes. New findings also suggest an anti-inflammatory role for
CRP because it modulates endotoxin shock and inhibits chemotaxis and the
respiratory burst of neutrophils. CRP inhibited phorbol myristate acetate-induced
superoxide (O2-) production more efficiently than the fMLP-triggered response. An
examination of the inhibition of the protein kinase C (PKC)-dependent assembly of
the NADPH oxidase complex revealed that both phosphorylation and translocation of
PKC-beta2 to the membrane were inhibited by a threshold acute phase dose of
approximately 50 microg/mL CRP. Translocation to the membrane and serine
phosphorylation of the major cytosolic p47-phox component of the NADPH oxidase
complex was inhibited by CRP. CRP also inhibited membrane localization of
activated Rac2, the small G protein regulator of the assembly of the oxidase
components in activated neutrophils as well as the cytoskeleton during
chemotactic movement. CRP-mediated regulation occurs via the CRP-R because an IgM
mouse mAb to the human CRP-R mimicked CRP-induced inhibition of O2- production
and chemotaxis. CRP may serve as an antiinflammatory regulator of activities at
sites of tissue damage where it selectively accumulates and thus influences
neutrophil infiltration and polymorphonuclear neutrophil activities. By contrast,
CRP activates cells of the monocyte/macrophage lineage, suggesting differential
regulation of these two leukocyte populations at the level of signaling. CRP
appears to be a multifunctional protein with the capability of exerting both
effector functions for innate host resistance, as well as exerting specific anti
inflammatory effects.
PMID- 10770282
TI - A negative autoregulatory link between Nramp1 function and expression.
AB - Nramp1 (natural resistance-associated macrophage protein) controls resistance to
infection by intracellular pathogens in mice. Nramp1 regulates the
microenvironment of the invading pathogen by increasing the luminal iron that
participates in the Haber-Weiss reaction, producing radicals that attack the
pathogen. We have studied the effect of inflammatory stimuli, iron, and sodium
nitroprusside on Nramp1 expression in bone marrow macrophages. Investigations
show all three up-regulate Nramp1 expression with a parallel increase in
immunoreactivity to an amino-terminal antibody and Nramp1 mRNA. Growth rates are
reduced in macrophage cell lines expressing Nramp1. This is through a decrease in
iron availability, shown by an increase in IRP2 activity and a reciprocal
decrease in conventional protein kinase Cbeta-1 expression. We propose that
Nramp1 activity may control its own expression via a negative autoregulatory loop
that is important for iron homeostasis and maintenance of low cytoplasmic redox
active iron levels in the macrophage.
PMID- 10770283
TI - The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for
pro-inflammatory interleukins and microbial products.
AB - The interleukin-1 (IL-1) receptor/Toll-like receptor (TLR) superfamily is a
recently defined and expanding group of receptors that participate in host
responses to injury and infection. The superfamily is defined by the Toll/IL-1
receptor (TIR) domain, which occurs in the cytosolic region of family members,
and is further subdivided into two groups based on homology to either the Type I
IL-1 receptor or Drosophila Toll receptor extracellular domain. The former group
includes the receptor for the important Th1 cytokine IL-18, and T1/ST2, which may
have a role in Th2 cell function. The latter group includes six mammalian TLRs,
including TLR2 and TLR4, that largely mediate the host response to gram-positive
and gram-negative bacteria, respectively. Whether bacterial products are actual
ligands for TLRs, or whether they generate ligands via as yet unidentified
pattern recognition receptors, has yet to be determined. Signaling pathways
activated via the TIR domain trigger the activation of downstream kinases, and
transcription factors such as NF-kappaB, and involve the adaptor protein MyD88,
which itself contains a TIR domain.
PMID- 10770285
TI - Activation of cAMP-dependent protein kinase is necessary for actin rearrangements
in human neutrophils during phagocytosis.
AB - We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in
neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG
dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity
measurements of phalloidin-stained actin in neutrophils showed a reduced amount
of filamentous actin (F-actin) in pseudopods and around the phagosome in cells
treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount
of phosphotyrosine-containing proteins was also reduced in pseudopods and around
the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin
reorganization during receptor-mediated phagocytosis, particularly triggered by
IgG-FcR interaction. Our results support the hypothesis that active subcortical
reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is
less important during CR3-mediated ingestion.
PMID- 10770284
TI - Scorpion venom-induced neutrophilia is inhibited by a PAF receptor antagonist in
the rat.
AB - A dramatic blood neutrophilia is an important feature of the severe envenoming
caused by the Brazilian scorpion Tityus serrulatus and may contribute to the
development of lung injury in children. We examined the effects of an intravenous
injection of T. serrulatus scorpion venom (TsV) on the total number of leukocytes
and neutrophils in the blood of anesthetized rats. Injection of TsV (250
microg/kg) induces a significant leukocytosis 2 and 3 h after its injection,
explained by an increase in the number of neutrophils. The release of
catecholamines and action on adrenoceptors is responsible for most of the
systemic manifestations of TsV. However, pretreatment with the beta-adrenoceptor
antagonists metoprolol and propranolol or the alpha1-adrenoceptor antagonist
prazosin (0.25 mg/kg) did not prevent TsV-induced neutrophilia. Blood
neutrophilia induced by TsV occurred simultaneously with a significant reduction
of mature neutrophils in bone marrow. Pretreatment with the platelet-activating
factor (PAF) receptor antagonists UK-74505 or WEB-2086 prevented TsV-induced
increase in blood neutrophils and reduction in the number of neutrophils in the
bone marrow. It is concluded that scorpion venom induces blood neutrophilia in
rats, explained by a PAF receptor-dependent mobilization of neutrophils from the
bone marrow.
PMID- 10770286
TI - Theophylline induces neutrophil apoptosis through adenosine A2A receptor
antagonism.
AB - This study was designed to determine whether theophylline would augment
granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A
selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most
efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to
19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival.
A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity
of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil
apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil
apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the
following pattern of potency for inducing neutrophil apoptosis competing with CGS
21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >>
enprofylline. This pattern is consistent with the affinity established for A2A
receptors. Theophylline demonstrated an additive effect to that of anti-Fas
antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of
adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM),
suggesting conflicting effects on the receptor antagonism. These findings suggest
that theophylline has an immunomodulatory action on neutrophil apoptosis via a
mechanism of A2A antagonism.
PMID- 10770287
TI - A flow cytometric immune function assay for human peripheral blood dendritic
cells.
AB - CD11c+ and CD11c- (CD123+) dendritic cells (DCs) have been described in blood.
Both cell types express high levels of HLA-DR and lack the lineage markers CD3,
CD14, CD19, CD20, CD16, and CD56. These immunophenotypic properties were used
along with analysis of activation-related surface antigens and intracellular
staining of cytokines to characterize functional responses of these DC subsets to
stimuli in whole human blood (WB). Samples from healthy donors were activated
with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate plus ionomycin
(PMA+I). The only distinct response in CD11c- DCs was the expression of CD25 upon
PMA+I activation. CD11c+ cells responded to LPS stimulation by producing high
levels of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF
alpha), and lower levels of IL-6, IL-1Ra, and IL-8 and an increased expression of
accessory molecules (CD25, CD40, CD80, CD86, HLA-DR, and HLA-DQ). PMA+I
activation of CD11c+ cells resulted in high levels of IL-1beta and lower levels
of IL-8, IL-1Ra, and TNF-alpha and up-regulation of CD80, CD86, HLA-DR, and HLA
DQ. Our data support prior observations of functional differences between
peripheral blood DC subsets and demonstrate the power of multiparameter flow
cytometry to characterize the pleiotropic responses of these cells to various
stimuli.
PMID- 10770288
TI - Lack of IL-10 synthesis by murine alveolar macrophages upon lipopolysaccharide
exposure. Comparison with peritoneal macrophages.
AB - The central role of alveolar macrophages in the establishment of
lipopolysaccharide (LPS)-induced lung inflammation is well demonstrated. They
produce and release numerous proinflammatory molecules, among which is tumor
necrosis factor alpha (TNF-alpha), a cytokine responsible in part for the
neutrophilic alveolitis. Interleukin-10 (IL-10) produced by LPS-activated
mononuclear phagocytes is a major anti-inflammatory cytokine that down-regulates
TNF-alpha synthesis. We studied the ability of murine alveolar macrophages to
produce IL-10 in vivo and in vitro, in response to LPS. Unexpectedly, the IL-10
protein was not detected in the whole lung and airspaces after LPS intranasal
instillation. In addition, no IL-10 protein was found in supernatants of isolated
and LPS-stimulated alveolar macrophages. The lack of IL-10 synthesis was
confirmed by the absence of specific RNA transcripts. By contrast and as
expected, autologous peritoneal macrophages produced IL-10 upon LPS challenge.
Drugs that usually modify the TNF-alpha/IL-10 balance in favor of IL-10 were used
without success. Thus, maneuvers allowing an increase in intracellular cAMP
concentrations did not reverse this unexpected phenotype. Moreover, direct
activation of protein kinase C with PMA was unable to trigger IL-10 formation by
alveolar, by contrast to peritoneal, macrophages. The current findings describe a
specific phenotype for murine alveolar macrophages during LPS-induced
inflammation.
PMID- 10770289
TI - Neurotransmitters of the sympathetic nerve terminal are powerful chemoattractants
for monocytes.
AB - Macrophages in lymphoid organs are in close contact to nerve terminals of the
sympathetic nervous system. Hence, these cells could be targets of neuronal
modulation. We studied sympathetic neurotransmitters as chemoattractants enabling
the aggregation of macrophages and nerve terminals. Norepinephrine (NE),
neuropeptide Y (NPY), isoproterenol (beta-adrenergic), p-aminoclonidine (alpha2
adrenergic), methoxamine (alpha1-adrenergic), and adenosine triphosphate (ATP)
were used to study human monocyte and macrophage migration in 48-well Boyden
chambers. NE stimulated chemotaxis of monocytes and macrophages at an optimal
concentration of 10-(10) M (P < 0.025). Isoproterenol, but not p-aminoclonidine
or methoxamine, induced chemotaxis of monocytes (10(-10) M, P < 0.05). In these
studies, elevation of cAMP is a critical step in NE-induced chemotaxis of
monocytes. NPY (10(-11) M, P < 0.05) stimulated monocyte chemotaxis as well. ATP
at 10(-4) and 10(-5) M stimulated undirected cell mobility (P < 0.05). All tested
neurotransmitters of the sympathetic nerve terminal were potent chemoattractants.
These findings may explain the close association of nerves and macrophages in
tissue and lymphoid organs and may thus be of functional relevance in
neuroimmunomodulation.
PMID- 10770290
TI - Specific association of increased cyclin-dependent kinase 5 expression with
monocytic lineage of differentiation of human leukemia HL60 cells.
AB - Hematopoietic cell differentiation takes place in phenotypically recognizable
stages characterized by morphology as well as by the expression of enzymes and
surface markers. It is recognized that differentiation results from an
interaction of environmental cues, such as cytokines and hormones, with internal
cellular programs, but the precise mechanisms are not entirely clear. HL60 cells,
a human acute myeloid leukemia (AML) cell line with promyelocytic features,
provide a model for such studies because they behave like stem cells, which can
differentiate into two different lineages, granulocytic or monocytic/macrophage,
depending on the inducer. Protein levels and kinase activity of cyclin-dependent
kinase 5 (Cdk5) were reported [F. Chen and G. P. Studzinski (1999) Exp. Cell Res.
249, 422, 1999] to increase in HL60 cells induced to monocytic differentiation by
1alpha,25-dihydroxyvitamin D3 (1,25D3), but the specificity of the association of
Cdk5 with the monocytic phenotype has not been established. We show here that up
regulation of Cdk5 does not occur in granulocytic differentiation, whereas
inhibition of Cdk5 activity by olomoucine, or its expression by a plasmid
construct expressing antisense Cdk5, switches the 1,25D3-induced monocytic
phenotype (a combination of positive nonspecific esterase reaction, expression of
the CD14 marker, and morphology) to general myeloid phenotype (positive nitro
blue tetrazolium reaction, CD11b marker and morphology). The transcriptional up
regulation of Cdk5 by 1,25D3 was not inhibited by olomoucine. These findings show
that in human myeloid cells up-regulation of Cdk5 is specifically associated with
the monocytic phenotype.
PMID- 10770291
TI - Identification of a new murine eosinophil major basic protein (mMBP) gene:
cloning and characterization of mMBP-2.
AB - We have identified a new eosinophil major basic protein gene family member in the
mouse and have given it the designation murine major basic protein-2 (mMBP-2).
The gene was initially characterized as a unique expressed sequence tag (EST)
clone having significant identity to the previously recognized member of this
gene family, mMBP-1. The EST was used to screen and isolate mMBP-2 from a bone
marrow cDNA library. In addition, a genomic clone of mMBP-2 was isolated and this
gene was shown to be physically linked to within 100 kb of mMBP-1 on the central
region of mouse chromosome 2. Progressive similarity alignment of the deduced
mMBP-2 open reading frame demonstrates the apparent conservation of the "pre-pro
mature" protein structure found in the other known mammalian MBPs. Mature mMBP-2
maintains the cationic nature associated with these proteins with a predicted pI
of 9.95. However, unlike the human MBPs, which display a three orders of
magnitude charge difference [hMBP-1 (pI 11.4) vs. hMBP-2 (pI 8.7)], mMBP-2 is
only slightly less cationic than mMBP-1 (pI 10.5). Expression studies demonstrate
that transcription of the mMBP-2 gene parallels mMBP-1 and is confined to
hematopoietic compartments engaged in eosinophilopoiesis. Moreover, using mMBP-1
knockout mice and immunohistochemistry with an antisera that recognizes both mMBP
1 and -2, we demonstrate that mMBP-2 protein expression is restricted to
eosinophil lineage-committed cells.
PMID- 10770292
TI - NF-kappaB-dependent fractalkine induction in rat aortic endothelial cells
stimulated by IL-1beta, TNF-alpha, and LPS.
AB - Fractalkine is an endothelial cell-derived CX3C chemokine that is chemotactic
mainly to mononuclear cells. Fractalkine was induced in rat aortic endothelial
cells (RAEC) by interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF
alpha), and lipopolysaccharide (LPS) transcriptionally and translationally. This
induction correlated with increased NF-kappaB DNA binding activity as determined
by gel mobility shift assay. Supershift assays revealed that the NF-kappaB
subunits p50 and p65 were responsible for kappaB binding. Accordingly, we
examined the role of NF-kappaB in fractalkine induction in RAEC through the use
of an adenovirus-mediated mutant IkappaB as a specific inhibitor. Delivery of a
dominant-negative form of IkappaBalpha in RAEC dramatically reduced the induction
of fractalkine by these stimuli, suggesting a role for NF-kappaB activation in
fractalkine induction. The inhibition of fractalkine expression by two potent NF
kappaB inhibitors, sulfasalazine and sanguinarine, further supported the central
role of NF-kappaB in fractalkine transcription regulation and suggested a novel
therapeutic target aimed at modulating leukocyte endothelial cell interaction.
PMID- 10770293
TI - Chymase is a potent chemoattractant for human monocytes and neutrophils.
AB - Chymase is a major chymotrypsin-like serine protease expressed in the secretory
granules of mast cells in many mammalian species. In this study, we revealed the
chemotactic activity of chymase for human mononuclear cells and neutrophils with
a 48-well microchemotaxis chamber technique. Human chymase showed the potent
chemotactic activity for monocytes and neutrophils dose-dependently in a
concentration range from 0.1 to 10 microg/mL, corresponding to about 4-400
microM. The activity was as potent as that of N-formyl-methionyl-leucyl
phenylalanine. Chymase also stimulated cell migration of lymphocytes and purified
T cells, but checkerboard analysis revealed that the effect was chemokinetic
rather than chemotactic. Inhibition of chymase activities with chymase
inhibitors, such as antileukoprotease and Bowman-Birk soybean trypsin inhibitor,
significantly inhibited the chemotactic activity of chymase, suggesting that the
proteolytic activity of chymase participates in the chemotactic activity. Our
results suggest that mast cell chymase acts as a chemoattractant, and may play a
role in the accumulation of inflammatory cells in development of the chronic
inflammatory responses of allergic and nonallergic diseases.
PMID- 10770294
TI - Resisting smoke and spin.
PMID- 10770295
TI - Pathophysiology and treatment of microscopic-colitis syndrome.
PMID- 10770296
TI - Blood or marrow?
PMID- 10770297
TI - G-protein polymorphisms and maternal/neonatal metabolism: still a weight for the
answer.
PMID- 10770298
TI - Minimally invasive approach to management of irritable hip in children.
PMID- 10770299
TI - Suicide in women.
PMID- 10770300
TI - Stroke-distance measurement after acute myocardial infarction.
PMID- 10770301
TI - Low molecular-weight heparin versus aspirin in patients with acute ischaemic
stroke and atrial fibrillation: a double-blind randomised study. HAEST Study
Group. Heparin in Acute Embolic Stroke Trial.
AB - BACKGROUND: Patients with acute ischaemic stroke and atrial fibrillation have an
increased risk of early stroke recurrence, and anticoagulant treatment with
heparins has been widely advocated, despite missing data on the balance of risk
and benefit. METHODS: Heparin in Acute Embolic Stroke Trial (HAEST) was a
multicentre, randomised, double-blind, and double-dummy trial on the effect of
low-molecular-weight heparin (LMWH, dalteparin 100 IU/kg subcutaneously twice a
day) or aspirin (160 mg every day) for the treatment of 449 patients with acute
ischaemic stroke and atrial fibrillation. The primary aim was to test whether
treatment with LMWH, started within 30 h of stroke onset, is superior to aspirin
for the prevention of recurrent stroke during the first 14 days. FINDINGS: The
frequency of recurrent ischaemic stroke during the first 14 days was 19/244
(8.5%) in dalteparin-allocated patients versus 17/225 (7.5%) in aspirin-allocated
patients (odds ratio=1.13, 95% CI 0.57-2.24). The secondary events during the
first 14 days also revealed no benefit of dalteparin compared with aspirin:
symptomatic cerebral haemorrhage 6/224 versus 4/225; symptomatic and asymptomatic
cerebral haemorrhage 26/224 versus 32/225; progression of symptoms within the
first 48 hours 24/224 versus 17/225; and death 21/224 versus 16/225. There were
no significant differences in functional outcome or death at 14 days or 3 months.
INTERPRETATION: The present data do not provide any evidence that LMWH is
superior to aspirin for the treatment of acute ischaemic stroke in patients with
atrial fibrillation. However, the study could not exclude the possibility of
smaller, but still worthwhile, effects of either of the trial drugs.
PMID- 10770302
TI - Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies
in the UK.
AB - BACKGROUND: Flat and depressed colorectal tumours were originally thought to be
unique to the Japanese population. Recently there have been reports of flat and
depressed lesions in western countries but they have been thought to be uncommon.
METHODS: In this prospective study, 1000 consecutive patients attending for
routine colonoscopy were examined for flat or depressed lesions. The examinations
were done by one European colonoscopist using methods developed in Japan.
FINDINGS: 321 adenomas were found: 202 (63%) were polypoid, 36% (117) were flat
and 2 (0.6%) appeared depressed. Most adenomas contained areas of mild or
moderate dysplasia but 10% (31) were severely dysplastic. Six Dukes' A
adenocarcinomas were identified together with 25 more advanced adenocarcinomas.
The likelihood of Dukes' A cancer or severe dysplasia increased from 4% (3/70) in
small flat lesions, to 6% (9/154) in small polyps, 16% (8/50) in larger polyps,
29% (14/49) in large flat lesions, and 75% (3/4) in depressed lesions. 54%
(20/37) lesions containing severe dysplasia or Dukes' A carcinoma were flat or
depressed. INTERPRETATION: The polyp-carcinoma hypothesis prompts colonoscopists
to search only for polypoid lesions when screening for cancer, and many early
colorectal neoplasms may therefore be missed. Colonoscopists require training in
the recognition of flat and depressed lesions to detect colorectal tumours in the
early stages.
PMID- 10770303
TI - Mortality among lone mothers in Sweden: a population study.
AB - BACKGROUND: An increasing number of lone mothers are experiencing financial and
health disadvantages. Our aim was to assess mortality among lone mothers compared
with mothers with partners. METHODS: In this population-based study, overall and
cause-specific mortality, between 1991 and 1995, was estimated for 90,111 lone
mothers and 622,368 mothers with partners from data collected in the Swedish
Population and Housing Census 1990. We estimated relative risks by Poisson
regression, adjusted for socioeconomic status, and, to handle health-selection
effects, we adjusted for previous inpatient history from 1987 to 1990. FINDINGS:
Lone mothers showed an almost 70% higher premature risk of death than mothers
with partners. The excess risk remained significantly increased (relative risk
1.2 [95% CI 1.1-1.4]) after adjustments for socioeconomic status and previous
severe somatic and psychiatric inpatient history. Increased mortality was
especially pronounced for suicides (2.2 [1.5-3.1]), violence (3.0 [0.9-10.6]),
and alcohol-related mortality (2.4 [1.4-4.1]) among mothers who were without a
partner in 1985 and in 1990. INTERPRETATION: The increase of lone mothers in
society shows financial, social, and health disadvantages. Nevertheless, the
increased mortality risk of lone mothers seems to be partly independent of
socioeconomic status and health selection into lone motherhood. For long-term
lone mothers the risks may be underestimated when adjusting for selection bias by
taking hospital discharge history into account, since these events may be part of
the consequences of the stress of lone motherhood.
PMID- 10770304
TI - Injury-related deaths among women aged 10-50 years in Bangladesh, 1996-97.
AB - BACKGROUND: Few studies have examined injury-related deaths among women in
Bangladesh. We did a case-finding study to identify causes and the impact of
intentional and unintentional injury-related deaths among women aged 10-50 years
in Bangladesh. METHODS: Between 1996 and 1997, health care and other service
providers at 4751 health facilities throughout Bangladesh were interviewed about
their knowledge of deaths among women aged 10-50 years. In addition, at all
public facilities providing inpatient service, medical records of women who died
during the study period were reviewed. The reported circumstances surrounding
each death were carefully reviewed to attribute the most likely cause of death.
FINDINGS: 28,998 deaths among women aged 10-50 years were identified in our
study, and, of these, 6610 (23%) were thought to be caused by intentional or
unintentional injuries. About half (3317) of the injury deaths were attributable
to suicide, 352 (5%) to homicide, 1100 (17%) to accidental injuries, and the
intent was unknown for 1841 (28%) deaths. The unadjusted rate of suicides were
higher in the Khulna administrative division (27.0 per 100,000) than the other
four administrative divisions of Bangladesh (range 3.5-11.3 per 100,000).
Poisoning (n=3971) was the commonest cause of injury-related death--60% of all
injury deaths (6610) and 14% of all deaths (28,998). Other common causes of
injury deaths in order of frequency were hanging or suffocation, road traffic
accidents, burns, drowning, physical assault, firearm or sharp instrument injury,
and snake or animal bite. INTERPRETATION: Intentional and unintentional injuries
are a major cause of death among women aged 10-50 years in Bangladesh. Strategies
to reduce injury-related deaths among women need to be devised.
PMID- 10770305
TI - Aetiology, outcome, and risk factors for mortality among adults with acute
pneumonia in Kenya.
AB - BACKGROUND: Despite a substantial disease burden, there is little descriptive
epidemiology of acute pneumonia in sub-Saharan Africa. We did this study to
define the aetiology of acute pneumonia, to estimate mortality at convalescence,
and to analyse mortality risk-factors. METHODS: We studied 281 Kenyan adults who
presented to two public hospitals (one urban and one rural) with acute
radiologically confirmed pneumonia during 1994-96. We did blood and lung-aspirate
cultures, mycobacterial cultures, serotype-specific pneumococcal antigen
detection, and serology for viral and atypical agents. FINDINGS: Aetiology was
defined in 182 (65%) patients. Streptococcus pneumoniae was the most common
causative agent, being found in 129 (46%) cases; Mycobacterium tuberculosis was
found in 26 (9%). Of 255 patients followed up for at least 3 weeks, 25 (10%) died
at a median age of 33 years. In multivariate analyses, risk or protective factors
for mortality were age (odds ratio 1.51 per decade [95% CI 1.04-2.19]),
unemployment (4.42 [1.21-16.1]), visiting a traditional healer (5.26 [1.67
16.5]), visiting a pharmacy (0.30 [0.10-0.91]), heart rate (1.64 per 10 beats
[1.24-2.16]), and herpes labialis (15.4 [2.22-107]). HIV-1 seropositivity, found
in 52%, was not associated with mortality. Death or failure to recover after 3
weeks was more common in patients with pneumococci of intermediate resistance to
benzylpenicillin, which comprised 28% of pneumococcal isolates, than in those
infected with susceptible pneumococci (5.60 [1.33-23.6]). INTERPRETATION: We
suggest that tuberculosis is a sufficiently common cause of acute pneumonia in
Kenyan adults to justify routine sputum culture, and that treatment with
benzylpenicillin remains appropriate for clinical failure due to M. tuberculosis,
intermediate-resistant pneumococci, and other bacterial pathogens. However,
interventions restricted to hospital management will fail to decrease mortality
associated with socioeconomic, educational, and behavioural factors.
PMID- 10770306
TI - Allogeneic blood and bone-marrow stem-cell transplantation in haematological
malignant diseases: a randomised trial.
AB - BACKGROUND: Autologous transplantation with peripheral blood stem cells (PBSC)
results in faster haematopoietic-cell repopulation than with bone marrow. We
prospectively compared bone marrow and PBSC for allogeneic transplantation.
METHODS: Adult HLA-identical sibling donors provided bone marrow and lenograstim
mobilised PBSC. 39 patients with malignant haematological disorders were infused
with either bone marrow (n=19) or PBSC (n=20) after standard conditioning
regimens in a double-blind, randomised fashion. The identity of the infused
products for all patients remained masked until 1 year after the last patient had
received transplantation. FINDINGS: The PBSC group had significantly faster
neutrophil recovery to 0.5x10(9)/L (median 17.5 vs 23 days, p=0.002), and
platelet recovery to 20x10(9)/L (median 11 vs 18 days, p<0.0001) and to
50x10(9)/L (median 20.5 vs 27 days, p=0.02) than the bone-marrow group. PBSC
patients were discharged from hospital earlier than were bone-marrow patients
(median 26 vs 31 days, p=0.01). At 4 weeks after transplantation, absolute
lymphocytes (0.48 vs 0.63, p=0.08) and CD25 cells (0.04 vs 0.08, p=0.007) were
higher in the PBSC group, and the proportion of patients with absolute
lymphopenia (74% vs 33%, p=0.03) and CD4 lymphopenia (59% vs 24%, p=0.05) was
significantly higher in the bone-marrow group. There was no significant
difference in the occurrence of acute or chronic graft-versus-host disease and
overall survival. The probability of relapse was significantly higher in the bone
marrow group than in the PBSC group (p=0.01); all five relapses occurred among
bone-marrow recipients. INTERPRETATION: Our small study indicates that PBSCs are
better than bone marrow for allogeneic transplantation from HLA-identical
siblings in terms of faster haematopoietic and immune recovery, and have the
potential to reduce disease recurrence.
PMID- 10770307
TI - A man with a leaky drain.
PMID- 10770308
TI - Bowel wall thickness measured by ultrasound as a marker of Crohn's disease
activity in children.
AB - Non-invasive procedures are desirable for assessing disease activity in the
follow-up of children with Crohn's disease. We show that bowel wall thickness
measured by ultrasound is related to clinical and histological assessment of
disease activity and could represent an easy method for monitoring the intestinal
inflammatory process in Crohn's disease.
PMID- 10770309
TI - G protein beta3 subunit 825 TT genotype and post-pregnancy weight retention.
AB - Primiparous homozygous carriers of the G protein beta3 825T allele, a thrifty
genotype, are at high risk of obesity and post-pregnancy weight retention if they
do not exercise regularly.
PMID- 10770310
TI - Association of maternal G protein beta3 subunit 825T allele with low birthweight.
AB - Weight at birth has been associated with an increased risk for cardiovascular
disease and type 2 diabetes in adult life. We found an association between the
maternal G protein beta3 subunit 825T allele and low birthweight in babies born
to women without other risks for reduced fetal growth.
PMID- 10770311
TI - Endosymbiotic bacteria in worms as targets for a novel chemotherapy in
filariasis.
AB - Endosymbiotic bacteria living in plasmodia or worm parasites are required for the
homoeostasis of their host and should be excellent targets for chemotherapy of
certain parasitic diseases. We show that targeting of Wolbachia spp bacteria in
Onchocerca volvulus filariae by doxycycline leads to sterility of adult worms to
an extent not seen with drugs used against onchocerciasis, a leading cause of
blindness in African countries.
PMID- 10770312
TI - Discrete neurophysiological correlates in prefrontal cortex during hysterical and
feigned disorder of movement.
AB - The clinical distinction between hysterical symptoms and those that are feigned
awaits objective validation. We used functional neuroimaging to examine the
neural correlates of these two disorders.
PMID- 10770313
TI - WHO's blood-safety initiative: a vain effort?
PMID- 10770314
TI - Warsaw conference on emerging infections in central and eastern Europe.
PMID- 10770315
TI - Look to the bones for clues to human disease.
PMID- 10770316
TI - Chaos greets birth of insurance system for Japan's elderly.
PMID- 10770317
TI - UK nuclear power station under threat from international pressure.
PMID- 10770318
TI - Tobacco industry efforts subverting International Agency for Research on Cancer's
second-hand smoke study.
AB - Scientific reports on second-hand smoke have stimulated legislation on clean
indoor air in the USA, but less so in Europe. Recently, the largest European
study, by the International Agency for Research on Cancer (IARC), demonstrated a
16% increase in the point estimate of risk in lung cancer for nonsmokers, a
result consistent with earlier studies. However, the study was described by
newspapers and the tobacco industry as demonstrating no increase in risk. To
understand the tobacco industry's strategy on the IARC study we analysed industry
documents released in US litigation and interviewed IARC investigators. The
Philip Morris tobacco company feared that the study (and a possible IARC
monograph on second-hand smoke) would lead to increased restrictions in Europe so
they spearheaded an inter-industry, three-prong strategy to subvert IARC's work.
The scientific strategy attempted to undercut IARC's research and to develop
industry-directed research to counter the anticipated findings. The
communications strategy planned to shape opinion by manipulating the media and
the public. The government strategy sought to prevent increased smoking
restrictions. The IARC study cost $2 million over ten years; Philip Morris
planned to spend $2 million in one year alone and up to $4 million on research.
The documents and interviews suggest that the tobacco industry continues to
conduct a sophisticated campaign against conclusions that second-hand smoke
causes lung cancer and other diseases, subverting normal scientific processes.
PMID- 10770319
TI - Red cells II: acquired anaemias and polycythaemia.
AB - Iron deficiency affects 30% of the world's population. Iron metabolism is tightly
regulated, with both gut transport and storage being coordinated. Hereditary
haemochromatosis due to mutations in the HFE gene leads to increased absorption
of iron and multiple end-organ damage. Myelodysplastic disorders are acquired
clonal stem-cell disorders that cause ineffective erythropoiesis. Aplastic
anaemia is caused by an intrinsic defect of haemopoietic stem cells; both
inherited and acquired forms occur. Primary polycythaemia is a myeloproliferative
disorder, a non-malignant stem-cell disease.
PMID- 10770320
TI - Financing of vaccines.
PMID- 10770321
TI - Hypertension and ascorbic acid.
PMID- 10770322
TI - Hypertension and ascorbic acid.
PMID- 10770323
TI - Hypertension and ascorbic acid.
PMID- 10770324
TI - Hypertension and ascorbic acid.
PMID- 10770325
TI - Hypertension and ascorbic acid.
PMID- 10770326
TI - Antenatal corticosteroids: is more better?
PMID- 10770327
TI - Increased body-mass index in patients with narcolepsy.
PMID- 10770328
TI - STD research and policy formulation.
PMID- 10770329
TI - STD research and policy formulation.
PMID- 10770330
TI - Association studies of genetic polymorphisms and complex disease.
PMID- 10770331
TI - Association studies of genetic polymorphisms and complex disease.
PMID- 10770332
TI - Association studies of genetic polymorphisms and complex disease.
PMID- 10770333
TI - Association studies of genetic polymorphisms and complex disease.
PMID- 10770334
TI - Reforming the borderline personality diagnosis.
PMID- 10770335
TI - Swedish cancer register: corrected data.
PMID- 10770336
TI - Thiomersal in vaccines.
PMID- 10770337
TI - Hazards of translation of non-English medical publications in Medline.
PMID- 10770338
TI - The Nobel chronicles. 1990: Joseph Edward Murray (b 1919) and E Donnall Thomas (b
1920).
PMID- 10770339
TI - A regional task force on traditional medicine and AIDS.
PMID- 10770340
TI - An indicator cell assay for T-cell tropic, macrophage-tropic, and primary
isolates of HIV-1 based on green fluorescent protein.
AB - Quantitation of HIV-1 in blood is now widely used by clinicians to manage
antiviral therapy. Current methods to detect viral RNA are expensive, have slow
turnaround times, and do not directly quantitate infectious particles. Indicator
cell assay (ICA) methods for titering HIV-1 rely on the activation of HIV-1 long
terminal repeat (LTR)-driven expression of a reporter gene by the viral tat gene
product, which is expressed early in the course of infection. The Aequorea
victoriana green fluorescent protein (GFP) has proven to be a useful reporter
gene for detecting tat-mediated HIV-LTR activation. A general approach to
developing a clinically useful ICA required a method of introducing the LTR-GFP
expression cassette into various HIV1-infectable cell lines. The LTR-GFP
expression cassette was inserted into the LXSN retrovector in a reverse
orientation with respect to transcription from the 5' LTR. In cells transduced by
the RH5 retrovector, GFP expression was tightly dependent on expression of HIV-1
tat. The PM1 human T-cell line was transduced with RH5 and was further engineered
to express the CCR5 HIV-1 CD4 coreceptor constitutively. The resulting cell line,
D5-R5, was susceptible to infection by primary HIV-1 strains, macrophage-tropic
(M-tropic) and T-cell tropic (T-tropic) laboratory strains, and syncytium
inducing (SI) and and non-SI (NSI) variants. Four days after HIV-1 infection of
the indicator cells, GFP expression was detected and quantitated by fluorescence
activated cell sorter (FACS), without any false-positive signals. This GFP-based
ICA method is of potential use in clinical management of HIV-1, especially in the
detection and recovery of drug-resistant virus and the direct determination of
antiviral drug sensitivities.
PMID- 10770341
TI - Monoclonal antibodies to an HIV-1 group O envelope recombinant.
AB - Monoclonal antibodies were developed to a recombinant HIV-I group O envelope
protein derived from the isolate HAM112. These monoclonal antibodies were
characterized for reactivity to a series of overlapping synthetic peptides (29-30
mers) covering gp120 C-terminal and gp41 ectodomain regions of the HIV-1 group O
envelope protein. Most of these monoclonal antibodies reacted with peptides
spanning sequences analogous to HIV-1 group M epitopes identified from studies in
mice and humans. However, several of the antibodies that were nonreactive to
individual peptides did react to a mixture of longer peptides from the N-terminal
and C-terminal helical regions of the gp41 ectodomain. The monoclonal antibodies
described in this study are valuable tools for characterization of antigenic
differences between HIV-1 group O and group M viruses.
PMID- 10770342
TI - Cytomegalovirus retinitis in advanced HIV-infected patients treated with protease
inhibitors: incidence and outcome over 2 years.
AB - We prospectively studied the incidence of cytomegalovirus (CMV) retinitis in 93
patients treated with highly active antiretroviral therapy (HAART) containing a
protease inhibitor (PI), during a median follow-up period of 24 months. The
median initial CD4+ count was 22 cells/microl (range, 1-311 cells/microl), and
the median plasma HIV viral load was 5.1 log10 copies/ml (range, 2.4-6.4 log10
copies/ml). The fundus was examined monthly in patients with a history of CMV
retinitis or an initial CD4+ count <50 cells/microl and every 3 months in the
other patients. Of patients with previously controlled CMV retinitis, 1 of 7
relapsed. In addition, 6 of 59 patients with a CD4+ count <50 cells/microl and no
history of CMV retinitis before starting PI therapy developed CMV retinitis. Of
them, 3 had at least one relapse during follow-up. CD4+ counts were <40
cells/microl at the time of primary or recurrent CMV retinitis, except in two
cases (147 cells/microl and 203 cells/microl). In conclusion, the incidence of
CMV retinitis was 0.091 per patient-year among study subjects with advanced HIV
infection who were receiving HAART (95% confidence interval [CI], 0.037-0.145).
The time to progression of CMV retinitis (mean, 215 days; 95% CI, 113-317 days)
was longer than reported before widespread use of PIs.
PMID- 10770343
TI - Treatment of AIDS-related cutaneous Kaposi's sarcoma with topical alitretinoin (9
cis-retinoic acid) gel. Panretin Gel North American Study Group.
AB - BACKGROUND: Kaposi's sarcoma (KS) is the most frequent malignancy in patients
with HIV. Given the promise that retinoids show in the treatment of various
hyperproliferative skin disorders and in vitro evidence of inhibition of
proliferation of KS cells, a randomized, controlled clinical trial was conducted.
METHODS AND RESULTS: A 12-week, multicenter, randomized, double-blind, vehicle
controlled safety and efficacy evaluation of topical alitretinoin 0.1% gel
applied to cutaneous KS lesions was conducted in HIV-infected patients. The
primary efficacy endpoint was the patient's response rate, as determined by
evaluating six index lesions representative of the patient's overall KS cutaneous
disease using AIDS Clinical Trials Group (ACTG) response criteria applied to
topical therapy. Of 268 patients entered in the blinded treatment phase of the
study (alitretinoin group, n = 134; vehicle group, n = 134), 47 patients (35%)
treated with alitretinoin 0.1% gel had a positive response, compared with 24
patients (18%) treated with vehicle gel. Of 184 patients receiving open-label
alitretinoin treatment following the blinded phase of the trial, 90 patients
(49%) met criteria for a positive response. This superior efficacy of
alitretinoin gel over vehicle gel was maintained when the data were adjusted or
analyzed for age, race, Kamofsky scores, baseline CD4+ lymphocyte counts, number
of raised lesions at baseline, and aggregate area of index lesions. Alitretinoin
0.1% gel was superior to vehicle gel regardless of the number of concurrent
antiretroviral therapies. Most adverse events were mild to moderate in severity,
limited to the application site, and reversible on reduction in frequency or
suspension of application. Relatively few patients (7%) discontinued alitretinoin
therapy because of to related adverse events. CONCLUSIONS: The results show that
alitretinoin gel application is safe and generally well tolerated, and they
indicate the superiority of alitretinoin 0.1% gel over vehicle gel in the
treatment of cutaneous AIDS-related KS lesions.
PMID- 10770344
TI - Adherence to colposcopy among women with HIV infection.
AB - In the general population, nonadherence to the recommendation to have colposcopy
in women with abnormal cytologic smears is estimated at 30% to 80%, but studies
have failed to identify consistent risk factors for nonadherence. The purpose of
this analysis is to assess adherence to colposcopy in a subset of participants in
the Women's Interagency HIV Study (WIHS), an ongoing multisite longitudinal study
of HIV infection in women in the United States and determine factors associated
with nonadherence. Identification of such predictors would be useful in designing
strategies to improve adherence in this group. METHODS: Adherence to colposcopy
was examined in a cohort of 462 women with, or at risk for, HIV infection with
abnormal cervical cytology on entry into WIHS. Adherence was defined as having
colposcopy done within 6 months of an abnormal cytology result. RESULTS: Overall
adherence to colposcopy was 65% (302 of 462). A multivariate logistic regression
model revealed that the odds of adherence were significantly lower for the women
who were HIV-infected (p = .011), current crack/cocaine users (p = .040), ever
too ill to get medical care (p = .033), not recruited by WIHS study staff (p =
.004), and less concerned about the care of their children (p = .037). Among HIV
seropositive women, low CD4 counts, high viral loads, and presence of AIDS
defining illness were not predictive of nonadherence. DISCUSSION: Adherence to
colposcopy among WIHS participants was at the upper limit of the reported range
in the United States. Chemical dependency and domestic violence may negatively
impact on colposcopy adherence whereas supportive study personnel, having health
insurance, and concerns about raising one's children appear to be motivators for
adherence to colposcopy in this study. HIV infection was a risk factor for
nonadherence, but markers of advanced disease were not predictive of
nonadherence.
PMID- 10770345
TI - Randomized, controlled trial of caloric supplements in HIV infection. Terry Beirn
Community Programs for Clinical Research on AIDS.
AB - OBJECTIVE: To compare the efficacy of three nutritional regimens in the
prevention of weight loss. DESIGN: A three-arm randomized controlled trial with
primary outcome measure percent change in weight over four months. PATIENTS: A
total of 536 patients with CD4 count <200 cells/mm3 and stable weight, defined as
<5% weight loss as determined by a weight measurement 3 to 6 months before
randomization were recruited at fourteen administrative units in the United
States, each unit consisting of multiple primary care sites. INTERVENTION: The
three arms were 500 kcal daily of caloric supplement with peptides and medium
chain triglycerides plus a multivitamin and mineral supplement, 500 kcal of a
caloric supplement with whole protein and long-chain triglycerides plus a
multivitamin and mineral supplement, and a multivitamin and mineral supplement
only. RESULTS: There were no significant differences among the three regimens in
the percent change in weight (p = .74) and body cell mass (p = .63). On average,
65% of the recommended 500 kcal/day of caloric supplements containing peptides
with medium-chain triglycerides and 82% of the 500 kcal/day of the caloric
supplement containing whole protein and long-chain triglycerides were consumed.
CONCLUSIONS: Caloric supplements do not promote increases in average weight or
body cell mass in weight-stable, HIV-infected adults beyond that offered by a
multivitamin and mineral supplement.
PMID- 10770346
TI - Meta-analysis of two randomized controlled trials comparing combined zidovudine
and didanosine therapy with combined zidovudine, didanosine, and nevirapine
therapy in patients with HIV. INCAS study team.
AB - OBJECTIVES: To extend the range of CD4 counts in which a plasma viral load nadir
(pVL) <20 copies/ml was known to be predictive of the duration of virologic
response. To determine whether baseline pVL is predictive of virologic response
during the study periods. METHODS: A meta-analysis was conducted of the original
individual patient data from two randomized controlled trials comparing
zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP). RESULTS: In
total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects
on triple therapy with baseline pVL <100,000 copies/ml were more likely to
achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml
(OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000
copies/ml. Among triple therapy patients, the relative risk of virologic failure
was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10
copies/ ml; p = .01), after controlling for compliance and pVL nadir. The
relative risks of virologic failure associated with pVL nadir <20 copies/ml and
between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26),
respectively, compared with patients with a pVL nadir >400 copies/ml.
CONCLUSIONS: We have extended our earlier results that achieving a pVL nadir <20
copies/ml is important for maintaining virologic suppression. In particular, we
have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more
protective against virologic failure than achieving a pVL nadir between 20 and
400 copies/ml. Baseline pVL is significantly associated with the probability of
achieving and sustaining virologic suppression.
PMID- 10770348
TI - Evaluation of a statewide non-name-based HIV surveillance system.
AB - Recent advances in AIDS-related therapies have delayed the onset of AIDS-defining
illnesses and reduced the usefulness of AIDS surveillance in assessing the
incidence of early HIV disease and estimating future needs of the HIV-infected
population. These changes have prompted renewed interest in expanding
surveillance to include HIV and have engendered national debate on whether an HIV
surveillance system should be based on reports of the names of infected
individuals or employ non-name-based data codes. In 1994, the state of Maryland
implemented a program to require HIV surveillance by unique identifier (UI)
patient code. This evaluation of Maryland's program found that when complete, the
12-digit UI number provided a virtually unduplicated count 99.8% unique, was
99.9% unique with only the last four digits of the U.S. government Social
Security Number (SSN), date of birth (DOB), and race, and 77.7% unique if the
last four digits of the SSN were missing. Health care providers were willing to
create the UI, with DOB and gender present 98.3% and 98.8% of the time, race was
complete 84.1% and last four digits of SSN were complete 72.4%. The overall
completeness of reporting for HIV tests was 87.8%.and 84.8%, respectively, using
different methodologies. Evidence from the Maryland UI evaluation demonstrates
that a non-name-based system can provide accurate, timely and valid data
concerning the scope of the HIV epidemic, without the creation of state-wide name
based registry.
PMID- 10770347
TI - CCR2B-64I chemokine receptor allele and mother-to-child HIV-1 transmission or
disease progression in children. French pediatric HIV infection study group.
AB - The beneficial role of a variant of the chemokine receptor CCR2B (CCR2B-641) in
the evolution of HIV-1 infection in adults is still controversial. Furthermore,
no studies have been performed in HIV-1-infected children. A multicenter and
prospective study of 745 infants born to HIV-1-seropositive mothers was
performed. The CCR2B-641 allele was studied in 525 non-African children among
whom 523 had been previously genotyped for the CCR5delta32 allele and 220 African
children. Of the 745 total, 376 children were infected and 369 were uninfected.
In the complete population studied, the children homozygous for the CCR2B-64I
allele and the heterozygous children were found distributed equally in the
infected (respectively, 1.6% and 21%) and uninfected (respectively, 1.9% and
26.3%) groups (p < .22). Among 376 infected children, the incidence of stage C
symptoms (U.S. Centers for Disease Control and Prevention [CDC] classification)
or the progression of severe immune deficiency (CD4 <15%, CDC stage 3) was not
significantly different in heterozygous infected children or children homozygous
for the normal allele (p < .17 and p < .75, respectively). The same lack of
protective effect was obtained when a separate analysis was performed in the non
African and African HIV-1-infected children.
PMID- 10770349
TI - Modeling HIV risk.
AB - OBJECTIVE: To provide HIV risk estimates for specific local population subgroups
using an HIV risk index combining HIV risk behaviors, prevalence rates, and
transmission probabilities. METHODS: A sample of 270 individuals was studied.
Respondents described sexual and injection risk behaviors and partners in the
previous 30 days. An HIV risk index was computed for each individual, combining
reported sexual and injecting risk behaviors, HIV prevalence estimates for
partners and HIV transmission probabilities for each of the risk behaviors.
Partner HIV prevalence rates were estimated from a national sample, and HIV
transmission probabilities were obtained from previously published studies.
RESULTS: Projected risk estimates were found to differ a great deal within major
demographic categories. Highest 10-year risk was found among African-American
male gay injectors (72%) and the lowest among white male heterosexual
noninjectors (<.01%). CONCLUSIONS: The method used here for estimating HIV risk
can be calculated for specific at-risk population subgroups of any size and
composition, including individuals. By understanding which specific
subpopulations are at risk, specific interventions and public health campaigns
may be better targeted.
PMID- 10770350
TI - HIV-1 subtyping in Salvador, Bahia, Brazil: a city with African sociodemographic
characteristics.
AB - To investigate the prevalence of the HIV-1 subtypes in different populations from
Salvador, Bahia, Brazil, blood samples from 72 HIV-1-seropositive injecting drug
users (IDUs) and 62 individuals infected sexually were analyzed using the
heteroduplex mobility assay (HMA). In the IDU group, 89.5% were classified as
subtype B, 3% as subtype F, and 7.5% showed a B/F HMA profile. In the sexual
transmission (ST) group, 95% were identified as B subtype, 3.4% showed a B/F
profile, and 1.6% a B/C/E HMA profile. All Brazilian samples that showed multiple
reactivities in the HMA analysis clustered on sequencing with B North American/
European HIV-1 isolates in the phylogenetic analysis, whereas the F subtypes
clustered with F Brazilian HIV-I isolates. Serologic reactivities of IDU's sera
were examined using a panel of synthetic V3 loop peptides representative of the
different HIV-1 subtypes. No difference in serologic reactivity between F and B
subtype plasma could be observed. Predominance of HIV-I subtype B was identified
in both study groups, whereas subtype F was detected only among IDUs in a
frequency lower than described for other Brazilian regions.
PMID- 10770351
TI - Sexual behaviors and other HIV risk factors in circumcised and uncircumcised men
in Uganda.
AB - OBJECTIVE: To study the differences in sexual practices, hygienic behaviors, and
other HIV risk factors between circumcised and uncircumcised men. DESIGN: A cross
sectional study of men >17 years of age selected by single stage cluster sampling
in the Industrial Borough, Mbale, Uganda. METHODS: Using a structured
questionnaire, 188 circumcised and 177 uncircumcised consenting Ugandan men were
interviewed in one of four native languages during April and May, 1997. RESULTS:
Among non-Muslims, circumcised men had a higher risk profile than uncircumcised
men in that they were more likely to drink alcohol in conjunction with sex (odds
ratio [OR], 1.86: 95% confidence interval [CI], 1.09-3.16), to have sexual
contacts with women on the first day of meeting (OR, 2.37; 95% CI, 1.39-4.04), to
have had sexual contacts in exchange for money or gifts (OR, 2.08; 95% CI, 1.21
3.09), to have experienced episodes of pain on urination or to have experienced
penile discharge (OR, 1.68; 95% CI, 1.07-2.64), had an earlier age at sexual
debut (15.7 versus 16.9 years), and had more extramarital sex partners in the
last year (1.13 versus 0.62). Circumcised men also reported a preference for
nonwet sex. Muslims generally had a lower risk profile than other circumcised men
except they were less likely to have ever used a condom (OR, 0.34; 95% CI, 0.15
0.78) or to have used a condom during the last sex encounter (OR, 0.37; 95% CI,
0.14-0.87). CONCLUSIONS: These results suggest that differences between
circumcised and uncircumcised men in their sex practices and hygienic behaviors
do not account for the higher risk of HIV infection found among uncircumcised
men. Further consideration should be given to male circumcision as a prevention
strategy in areas of high prevalence of HIV and other sexually transmitted
diseases. Studies of the feasibility and acceptability of male circumcision in
traditionally noncircumcising societies are warranted.
PMID- 10770352
TI - Gender difference in skin reactivity to purified protein derivative among
carriers of HTLV-I in Japan.
AB - The incidence of malignancies due to oncogenic virus infections tends to be
higher in men than in women. Gender-related differences in cell-mediated
immunity, which plays a role in viral pathogenesis, may explain this observation.
To explore this possibility in the context of HTLV-I infection, we examined skin
reactivity to purified protein derivative (PPD) among 128 residents of an HTLV-I
endemic area in Japan, who were born before 1921 and are assumed to have been
exposed to M. tuberculosis bacilli. The odds ratio (OR) for reduced PPD
reactivity (erythema <10 mm in diameter) was calculated by multiple logistic
regression analysis. Men were significantly less likely than women to have
reduced PPD reactivity among HTLV-I-negative individuals (26% versus 59%; p <
.01); whereas this gender difference was not apparent among HTLV-I carriers (63%
versus 62%; p = .87). HTLV-I positivity was strongly associated with reduced PPD
reactivity in men, but not in women (odds ratio [OR], 7.3 versus 1.2; p = .05).
Although this observation may be due, in part, to a longer average duration of
HTLV-I infection in men compared with women, the finding also raises the
possibility that men may be inherently more susceptible to loss of PPD reactivity
by HTLV-I infection.
PMID- 10770353
TI - Interferon plus ribavirin in HIV-infected patients with chronic hepatitis C.
PMID- 10770354
TI - Effects of high-dose intravenous immunoglobulin on virus load in HIV-infected
children.
PMID- 10770355
TI - Risk of HHV-6A primary and recurrent infections during the course of AIDS.
PMID- 10770356
TI - Substantial decrease in numbers and rates of AIDS deaths over the last decade.
PMID- 10770357
TI - Seroprevalence of HTLV-I/II antibodies in blood donors and different groups at
risk in Tunisia.
PMID- 10770358
TI - Esophageal pharmacology and treatment of primary motility disorders.
AB - Swallowing is a complex mechanism based on the coordinated collaboration of
tongue, pharynx and esophagus. Disturbances of this interplay or disorders of one
or several of these components lead to dysphagia, non-cardiac chest pain or
regurgitation. The major primary esophageal motility disorders--achalasia,
diffuse esophageal spasm, hypercontractile esophagus ('nutcracker esophagus') and
non-specific motility disorder--are of unknown etiology. Other esophageal
diseases, such as cervical diverticula or gastroesophageal reflux disease, might
also be caused by a primary esophageal motility disorder. Medical treatment of
esophageal disorders with esophageal hyper- or dysmotility requires agents that
reduce esophageal contractile force (anticholinergic agents, nitrates, calcium
antagonists). Despite the beneficial effect of the various drugs on esophageal
motility parameters, the clinical benefit of medical treatment of esophageal
motility disorders is rather disappointing. Calcium channel antagonist, alone or
in combination with anticholinergics or nitrates, can be used as a medical trial,
especially in mild achalasia. However, medical therapy is clearly inferior to
pneumatic balloon dilation therapy. Recently, botulinum toxin injection was
suggested as a therapeutic option in achalasia patients with good results on
lower esophageal sphincter pressure (LESP) and symptom scores that were similar
to the results achieved by pneumatic balloon dilation. Hypercontractile esophagus
shows a good manometric response to calcium channel antagonists, but only little
clinical effect in terms of improvement of symptoms. Diffuse esophageal spasm is
a relatively rare disease and few clinical studies are available. The use of
calcium channel antagonists can be beneficial, at least in some patients with
diffuse esophageal spasm. From clinical and epidemiological studies, there is
some evidence of a 'psychological' component in the pathogenesis or perception of
esophageal symptoms. There is some clinical benefit from centrally acting drugs
such as benzodiazepines or antidepressants. With the exception of botulinum toxin
for achalasia, medical therapy of primary esophageal motility disorders is rather
limited and the clinical results are poor. Further understanding of esophageal
pathophysiology as well as development of new receptor-selective drugs might
increase our chances of a successful treatment of primary esophageal motility
disorders.
PMID- 10770359
TI - Endosonographic staging of 100 consecutive patients with esophageal carcinoma:
introduction of the 8-mm esophagoprobe.
AB - Endoscopic ultrasound of esophageal carcinoma is conventionally performed using
the 13-mm fiberoptic/ultrasound echoendoscope. However, the large diameter
results in an inability to negotiate the primary tumor in 25% of patients. The
aim of this study was first to determine whether use of the 8-mm esophagoprobe
would overcome this problem and second to evaluate the accuracy of the smaller
diameter instrument. One hundred consecutive patients with esophageal cancer
underwent initial gastroscopy. Based upon the degree of luminal stenosis,
patients were staged with either the conventional echoendoscope (luminal diameter
> or = 15 mm) or the esophagoprobe (luminal diameter < 15 mm). The primary tumor
was successfully negotiated in all subjects (echoendoscope 30, esophagoprobe 70)
so that T- and N-staging was accomplished in every patient. Esophageal dilatation
was performed in 12 patients (12%). The procedure was well tolerated and there
were no complications, in particular no patient suffered esophageal perforation.
The accuracy of the esophagoprobe for T-staging was 90% (19 out of 20) and that
for N-staging was 75% (15 out of 20). This was similar to the accuracy of staging
with the conventional echoendoscope, 90% (9 out of 10) for T-stage and 90% (9 out
of 10) for N-stage. The esophagoprobe can safely and accurately stage patients
with esophageal carcinoma, including those with high-grade stenoses.
PMID- 10770360
TI - Cervical esophagogastric anastomosis: results following esophagectomy for
carcinoma.
AB - We reviewed our experience with 262 consecutive two-layer, hand-sewn cervical
esophageal anastomoses in patients undergoing surgery for esophageal carcinoma.
Anastomotic leak rates were determined for the entire group and the frequency of
post-operative esophageal dilatations was obtained for the first 101 patients. It
was assumed that the frequency of dilatations would reflect the frequency of
anastomotic strictures. The overall leak rate was 0.8% (two patients). Overall
hospital mortality was 2.7%. No patient died as a result of anastomotic leakage.
In our series, 26% of patients required at least one dilatation. If a dilatation
was needed, the majority occurred within the first 6 months. We conclude that
using a standardized, two-layer hand-sewn anastomotic technique cervical
esophageal anastomoses may be performed safely with results similar to those
reported using intrathoracic techniques.
PMID- 10770361
TI - Intraoperative radiotherapy for the abdominal lymphatic system in patients with
esophageal carcinoma.
AB - We applied intraoperative radiotherapy (IORT) to the esophageal carcinoma in an
attempt to prevent abdominal lymph node recurrence, and retrospectively studied
patterns of failure and controllability of abdominal lymph nodes in patients
treated with or without IORT. Between July 1986 and October 1997, 81 patients
with radically resected esophageal carcinoma, aged 42-76 years (mean 61), were
divided into two groups, the IORT group (39 patients) and the non-IORT group (42
patients). All patients except two, who received transhiatal esophagectomy for
superficial carcinoma, underwent subtotal esophagectomy with thoracic and
abdominal with/without cervical lymphadenectomy. Fourteen patients underwent only
surgical resection, and the remaining 67 patients received radiotherapy to the
mediastinum post-operatively (40-50 Gy/20-25 Fr/4-5 W) in 37 and preoperatively
(44 Gy/40 Fr/4 W) in 30 patients. Preoperative irradiation was performed as a
neoadjuvant chemoradiotherapy consisting of two courses of cisplatin (each
patient received 80-100 mg, mean 60 mg m(-2), day 1, bolus injection) and 5
fluorouracil (each patient received 500-1000 mg day(-1), mean 400 mg m(-2), days
1-4, continuous infusion). The target volume of IORT encompassed the upper
abdominal lymph node area including lymph node groups of right/left cardia, left
gastric artery, celiac artery and abdominal para-aorta. A single dose of high
energy electrons (9-12 MeV) of 20-23 Gy, prescribed to the 90% isodose curve, was
delivered. Treatment for the abdominal lymphatic system was classified into four
categories: surgery alone in 30 patients, surgery with chemotherapy in 12,
surgery with IORT in 15, surgery with chemotherapy and IORT in 24. There were no
complications related to IORT. Forty patients (49%) had recurring carcinoma: in
the lymph nodes (36%), in distant organs (27%) and locally (6%). The incidence of
lymph node metastasis was 29% in the neck, 32% in the mediastinum, and 27% in the
abdomen. Abdominal lymph node recurrence in the IORT group was less frequent than
in the non-IORT group (p=0.048). In particular, 24 patients treated with a
combination of surgery, chemotherapy and IORT had no recurrence in the abdominal
lymphatic system. The overall median survival was 46 months, the survival at 1,
3, and 5 years being 85%, 52%, and 44% respectively. However, there was no
difference in survival between the IORT group and the non-IORT group. The IORT
for the abdominal lymphatic system was feasible for reduction of the rate of
abdominal lymphatic recurrence without survival benefit in this study. This
retrospective finding should be confirmed by a prospective randomized study.
PMID- 10770362
TI - Motility across esophageal anastomoses after esophagectomy or gastrectomy.
AB - The esophageal motility of 23 patients who underwent esophagectomy or gastrectomy
for carcinoma of the esophagus or gastroesophageal junction was recorded daily
during the immediate post-operative period for high-pressure transients or other
motility disturbances. Patients were divided into three subgroups according to
the level of the esophageal anastomosis: group 1, neck (n = 4); group 2, thoracic
(n = 14); group 3, diaphragmatic hiatus (n = 5). Peristalsis was absent in all
patients studied during ventilation and sedation in the intensive care unit (five
patients). Early post-operative esophageal motility after esophageal anastomosis
varied somewhat with the length of residual esophagus. With short lengths of
residual esophagus, no consistent motility pattern emerged. With longer lengths,
early peristaltic activity was evident, but diminished over the first few post
operative days. Esophageal resection and anastomosis is associated with loss of
peristalsis in the initial post-operative period, consistent with the concept of
an esophageal ileus.
PMID- 10770363
TI - The use of an anabolic steroid (nandrolone decanoate) to improve nutritional
status after esophageal resection for carcinoma.
AB - Anabolic steroids increase appetite and muscle mass. This randomized, double
blind trial investigates any nutritional benefits of anabolic steroid in patients
after surgery for esophageal cancer. Forty patients were recruited: 19 patients
had five injections of 50 mg nandrolone decanoate and 21 patients received
placebo over 3 months, starting 1 month after surgery. Measurements of body
weight, mid-arm muscle circumference (MAMC) and appetite were taken over a 6
month period. Nutrition was optimized by dietary advice and by esophageal
dilatation if required. Percent ideal weight, percent ideal MAMC and appetite
score did not show significant differences between steroid and placebo groups,
but there was a trend to an increase over 6 months for percent ideal MAMC in the
test group. With this protocol, we have experienced minimal side-effects.
However, we have not demonstrated any therapeutic benefit with low-dose steroid.
An increased dose schedule over a longer period might produce a significant
response.
PMID- 10770364
TI - Improvement of oral ingestion in patients with inoperable esophageal cancer
treated with radiotherapy, chemotherapy and insertion of a self-expanding nitinol
stent.
AB - Radiotherapy, chemotherapy and self-expanding nitinol stent insertion were
performed in patients with inoperable esophageal cancer to improve oral
ingestion. Twelve patients underwent radiotherapy and chemotherapy. A stent was
inserted in patients with dysphagia after radiotherapy and chemotherapy.
Patients' capacity for oral ingestion was classified into three categories: grade
I patients were able to ingest enough food; grade II patients could ingest food
but required nutritional support; and grade II patients found it impossible to
ingest anything. After radiotherapy and chemotherapy, the number of grade I
patients increased from three to five but seven patients remained in grades II
and III. Four grade II and III patients were treated with stents, after which
dysphagia was reduced to grade I. In the grade I patients after treatment with
radiotherapy and chemotherapy, the duration of grade I was on average 167 days
and survival was 191 days. In the patients subjected to stent insertion, grade I
lasted 65 days and survival was 149 days. Before the introduction of the stent,
grade II patients died, on average, after 91 days. After the introduction of self
expanding nitinol stents, all patients could ingest enough food and were
discharged.
PMID- 10770365
TI - Endoscopic palliation of esophageal and cardial cancer: neodymium-yttrium
aluminum garnet laser therapy.
AB - The aim of this study was to evaluate the impact of laser palliation on symptoms
such as dysphagia and bleeding in patients with esophageal and cardial
carcinomas. From November 1992 to October 1997, 174 patients with unresectable
esophageal and cardial carcinomas were treated with neodymium-yttrium aluminum
garnet laser therapy. The indications for palliative treatment were advanced
tumor in 96 patients and high surgical risk in 78. The tumor involved the
esophagus and cardia in 107 and 67 patients respectively. The mean length of the
tumors was 6 cm. Two laser sessions (range 1-4) were necessary for
recanalization. During the follow-up, the average interval between the laser
sessions was 2 months. Overall, no early and late complications or hospital
mortality occurred. The quality of palliation was excellent or good in 82%, of
the patients. The mean survival time was 6 months, and mortality was not related
to the procedure. Endoscopic laser therapy in patients with vegetant or
hemorrhagic carcinomas may represent the best therapy, with acceptable morbidity
and mortality rates and satisfactory functional results.
PMID- 10770366
TI - Esophageal body length, lower esophageal sphincter length, position and pressure
in health and disease.
AB - We compared esophageal dimensions in control subjects and patients with differing
motility disorders and severities of reflux disease. Patients (1108) and healthy
controls (36) underwent manometry and 24-h pH monitoring. Subjects were grouped
according to pH and manometry data into seven groups. Mean (s.e.m.) esophageal
body length is greatest in achalasia [22.41 (0.27) cm] and least in reflux
disease [20.06 (0.13) cm, p < 0.05]. Lower esophageal sphincter (LES) pressure is
greatest in achalasia [17.46 (1.06) mmHg] and least in reflux disease [6.57
(0.24) mmHg, p < 0.05]. LES length is least in achalasia patients and control
subjects. The ratio of intra-abdominal to intrathoracic LES is greatest in
achalasia (1.29), no reflux and normal motility group, and controls and least in
reflux disease (1.04, p < 0.05). In conclusion, esophageal body length is
greatest in achalasia and least in reflux disease. This is associated with caudal
movement of the LES in achalasia and cranial movement of the LES in reflux
disease, relative to the diaphragm.
PMID- 10770367
TI - Reflux evaluation: correlation between pH results, esophagitis, esophageal
dysmotility, patient age, and esophageal caliber.
AB - The purpose of this study was to correlate gastroesophageal reflux evaluated by
24-h pH study to esophageal motility, diameter of the esophagus and diaphragmatic
hiatus, and patient age. We recorded radiographic findings from barium
esophagrams in 91 patients (47 women, 44 men) with a mean age of 52 years (range
17-18 years), who had 24-h pH monitoring of the esophagus. All patients had one
or more symptoms related to the upper aerodigestive system, and both studies were
performed within 2 days of each other. The average diameters of the esophagus and
hiatus were 24 mm and 19 mm respectively. The correlation coefficient (r) between
patient age and diameter of the esophagus was -0.22. No correlation was found
between the diameter of the hiatus and the size of the esophagus or patient age.
Esophageal diameter is significantly wider in patients with esophagitis than in
patients who have no esophagitis. Thirteen of 27 patients with absent primary
peristalsis had abnormal pH results. The diameter of the esophagus may be
affected by aging, but was not affected by the presence of dysmotility. The
caliber of the hiatus was stable and was narrower than the diameter of the
esophagus. The hiatus tended to be wider when esophagitis existed.
PMID- 10770368
TI - Cola drinks consumption and oesophagitis.
AB - For oesophageal epithelial changes to develop from gastro-oesophageal reflux
disease (GORD), the character of the refluxate must be acid enough to cause
injury. Experimentally, copious perfusion of the oesophagus with weak acid is
quite harmless. However, hydrochloric acid alone with a pH below 3.0 may cause
oesophageal injury. Cola drinks are strongly acidic (pH 2.5). This study analyses
the influence of and possible interaction between cola consumption and
oesophagitis. Twenty rats were divided into two groups of 10. The animals
received saline (pH 7.0) or cola (pH 2.6) per OS with 24 h free access to these
solutions. After the experiment the oesophagus was dissected. The mucosa was
macroscopically and histopathologically examined, and flow cytometric analysis
was used to look for proliferative activity. The histopathological analysis
showed that there is no difference between saline and cola. But the findings of
cell cycle analysis showed that the effects of cola and saline in inducing
oesophageal mucosal damage are different. In the cola group the values were
G0/G1, 7.33 +/- 2.88; S, 29.88 +/- 2.88; G2/M, 0.10 +/- 0.01; PI (proliferative
regenerative index), 29.76 +/- 2.88. The rat cell population g0/g1 phases were
found to be low (p < 0.01), and the cell population S and PI phases were found to
be significantly elevated compared with the control group (p < 0.01). (G0/G1,
79.30 +/- 5.97; S, 16.06 +/- 8.27; G2/M, 4.66 +/- 4.03; PI, 20.03 +/- 6.01).
These results were reflected in the proliferative index, which is used as a
measure of the regeneration index. The data show that cola has proliferative and
regenerative effects on the oesophageal mucosa, and it is possible that its
regenerative effect is caused as a result of an irritant effect.
PMID- 10770369
TI - Esophageal lichen planus: the Mayo Clinic experience.
AB - Lichen planus (LP) is an inflammatory papulosquamous disease which may affect the
squamous epithelium of the esophagus. We reviewed six patients with esophageal
lichen planus (ELP) seen at Mayo Clinic Rochester between 1984 and 1998. The
presenting symptoms were dysphagia (in all six patients) and odynophagia (two
patients). Cervical esophageal strictures were seen in four patients; average
number of esophageal dilatations required was 15 (range, 10-18). Esophageal
biopsies demonstrated the classical histologic findings of ELP in two patients,
and a lymphocytic infiltrate in the other four. Concomitant lichen planus (LP)
was seen at other sites in five patients: all five had oral LP preceeded by ELP
symptoms in all five; three had genital LP preceeded by ELP symptoms in all
three; two had dermal LP, preceeded by ELP symptoms in one. Proton pump
inhibitors were tried unsuccessfully in all patients. Four patients were started
on systemic steroid medication; three had resolution of symptoms within 1 month.
PMID- 10770370
TI - Simultaneous transhiatal esophagectomy and coronary artery bypass grafting
without cardiopulmonary bypass.
AB - A 69-year-old patient underwent simultaneous transhiatal esophagectomy for
carcinoma of the esophagogastric junction and benign spindle cell gastric tumor
and coronary artery bypass grafting without cardiopulmonary bypass. A standard
technique of transhiatal esophagectomy was used. The long saphenous vein was
grafted to the left anterior descending artery and to the distal circumflex
artery. The total theatre time was 6.5 h and the total ischemic time was 19 min.
The patient made a good recovery and was discharged on day 18. He is enjoying an
active lifestyle 6 months post-operatively.
PMID- 10770371
TI - Extended esophagolaryngeal resection with parathyroid autotransplantation.
AB - Esopharyngolaryngeal resection for carcinoma of the cervical esophagus must be
accompanied by resection of the thyroid gland, parathyroid bodies, and regional
lymph nodes. In order to reduce long-term morbidity associated with the
procedure, we performed parathyroid autotransplantation in two patients who
underwent esophagolaryngeal resections. Grafting of the upper two parathyroid
glands into the sternocleidomastoid muscle was carried out successfully in both
cases. Graft function was rapidly restored. During the third postoperative week,
blood levels of intact parathormone (PTH) reached 20 pg ml(-1) in the first case
and 15 pg ml(-1) in the second, and the patients were successfully weaned off
calcium and vitamin D supplementation. Parathyroid autotransplantation should be
attempted in all cases of esophagolaryngeal resections provided that parathyroid
glands are free of malignancy.
PMID- 10770372
TI - Case of spontaneous regression of metastatic lesions of leiomyosarcoma of the
esophagus.
AB - A rare case of spontaneous regression of esophageal leiomyosarcoma is reported. A
63-year-old woman underwent esophagectomy and reconstruction at our hospital
after diagnosis of leiomyosarcoma. Nineteen months after esophagectomy, a coin
lesion was detected in the right lung and right thoracotomy revealed pleural
dissemination. The lesion in the right lung was resected and was confirmed
histologically as recurrence of leiomyosarcoma. During further surgery,
metastatic lesions were found in the spleen and pleura. However, all metastatic
lesions were found to decrease without any anti-cancer therapy.
PMID- 10770373
TI - A paraesophageal bronchogenic cyst with esophageal communication.
AB - Paraesophageal bronchogenic cysts are a rare developmental anomaly of the upper
digestive tract. Although often asymptomatic, their growth can cause severe
symptoms and complications because of the location. The diagnosis is difficult
and is mostly by histopathologic findings after extirpation of the cyst. The
authors present a case of a paraesophageal bronchogenic cyst, of typical
histologic structure (ciliated epithelium and hyaline cartilage) connected with
the esophageal lumen by a narrow canal composed of stratified squamous
epithelium. According to the available literature, only three cases of
bronchogenic paraesophageal cysts with esophageal communication have been
reported.
PMID- 10770374
TI - Esophagobronchial fistula after thoracoscopic resection of an epiphrenic
diverticulum.
AB - We report a case of a 54-year-old man presenting with recurrent epiphrenic
diverticulum and esophagobronchial fistula 3 years after thoracoscopic
diverticulectomy. Surgical correction required transhiatal stapling of the pouch
combined with distal esophageal myotomy and Dor fundoplication.
PMID- 10770375
TI - Fungal ball of the oesophagus.
AB - Candidal colonization of the gastrointestinal tract is common, but localized
complications are rare. A case of an oesophageal fungal ball is described.
PMID- 10770376
TI - Esophageal carcinoma in a patient with bleeding esophageal varices.
AB - More than 20 cases of esophageal carcinoma have been reported to develop after
endoscopic injection sclerotherapy (EIS), and this technique is implicated in the
pathogenesis of esophageal cancer. We report a case of esophageal carcinoma
presenting as a superficial ulcer in a patient with esophageal varices with no
prior EIS. Whether the development of esophageal carcinoma in patients with
previous EIS is coincidental or consequential is controversial. Such carcinoma
might have already existed before EIS in some reported cases. A causal
relationship between EIS and esophageal carcinoma cannot be established without
further clarification by a well-designed study.
PMID- 10770377
TI - Involvement of endogenous nitric oxide and c-kit-expressing cells in chronic
intestinal pseudo-obstruction.
AB - BACKGROUND/PURPOSE: Chronic intestinal pseudo-obstruction (CIP) in infants and
children is a motility disorder without apparent mechanical cause. Nitric oxide
(NO), an inhibitory neurotransmitter and c-kit cells, essential for the
intestinal pacemaker activity, both play a key role in the intestinal motility
function. In the current study, the authors investigated the distributive change
in the intestinal nitric oxide synthase (NOS) and c-kit cells of patients with
CIP. METHODS: Tissues were obtained from 4 patients undergoing bowel resection or
biopsy for CIP at laparotomy. For controls, the intestinal specimens were
obtained from 4 age-matched cases of intestinal stricture, intussusception, and
autopsy with no evidence of gastrointestinal disease. Immunohistochemical studies
were performed on paraffin-embedded tissue cross sections with neuronal NOS and
inducible NOS monoclonal antibody as well as a rabbit polyclonal antibody against
the human c-kit receptor. RESULTS: Under immunohistochemical staining, a greatly
increased density of neuronal NOS immunoreactivity and an evidently increased
number of intense NOS immunoreactive nerve fibers were observed in the myenteric
plexus and circular muscle layers compared with the control sections. In the
submucosal plexus and longitudinal muscle layer, there was no change in NOS
immunoreactivity. Inducible NOS immunoreactivity was not detected in the control
cases. However, in tissues of CIP, almost all the epithelial cells were
positively and strongly labeled for inducible NOS immunoreactivity. For c-kit
cells staining, the number of c-kit-positive cells in the myenteric plexus and
circular muscle layers were greatly less than that in the controls, especially in
the myenteric plexus region. CONCLUSION: These findings suggest that sustained
production of NO by an increased NOS activity and a deficiency of c-kit cells in
the intestine may be related to the pathogenesis of CIP.
PMID- 10770378
TI - The role of endoscopic retrograde cholangiopancreatography in infants with
cholestasis.
AB - BACKGROUND/PURPOSE: Endoscopic retrograde cholangiopancreatography (ERCP) was
assessed in the diagnosis of cholestatic liver disease in infants. METHODS: ERCP
was performed in 50 infants who had prolonged cholestasis. Their ages ranged from
25 to 274 days (mean, 69 days), and their weight ranged from 2.6 to 6.7 kg (mean,
4.7 kg). Incomplete visualization of the biliary tree or visualization of only
the pancreatic duct was followed by exploratory laparotomy. In those in whom the
biliary tree was visualized completely, the caliber of the bile duct was compared
with that of the pancreatic duct. RESULTS: ERCP was completed in 43 patients
(success rate, 86%) without complications. In the 7 patients in whom ERCP failed,
6 had biliary atresia (BA) diagnosed by exploratory laparotomy. The other patient
had congenital biliary dilatation (CBD). In 29 of the 43 patients, the biliary
tree was seen partially or only the pancreatic duct was visualized. These
patients had BA diagnosed by laparotomy. Complete visualization of the biliary
tree was obtained in 14 patients. Of these, 9 had neonatal hepatitis (NH), 2 had
a paucity of intrahepatic bile ducts (PIBLD), and 3 had CBD. In all of the
patients with NH, cholestasis improved spontaneously. The 2 patients with PIBLD
had biopsy-proven disease. The caliber of the bile duct was larger than that of
the pancreatic duct in NH. This relationship was not observed in PIBLD.
CONCLUSIONS: ERCP is safe in infants. It is useful in the diagnosis of prolonged
cholestasis.
PMID- 10770379
TI - Pediatric chest wall Ewing's sarcoma.
AB - BACKGROUND: Chest wall tumors of primitive neuroectodermal origin (PNET, Ewing's
sarcoma [ES]) are rare and have a poor prognosis. Multimodality therapy has
improved survival results, and long-term survival is possible. Whether adjuvant
radiation therapy is uniformly beneficial remains unclear. METHODS: A
retrospective analysis of the authors' institutional experience between 1979 and
1998 was performed. RESULTS: Twenty consecutive patients with PNET-ES of the
chest wall were identified. The median age was 12 years (range, 2.5 to 21 years).
Median follow-up was 3 years (range, 7 months to 19.4 years). Seven patients
presented with a mass, 12 with pain, 1 with respiratory distress, and 1 with a
neuropathy. Initial therapy consisted of biopsy and neoadjuvant chemotherapy
followed by chest wall resection in 12 patients. Of the remaining 8 patients, 6
underwent biopsy, followed by chest wall resection and adjuvant chemotherapy, 1
underwent biopsy, chemotherapy, and resection of a lung nodule, and 1 underwent
biopsy, chemotherapy, and a laminectomy and decompression procedure. All 20
patients were included in institutional-based trials using multiagent
chemotherapy. Fifteen patients received radiation therapy with a median dose of
3,000 cGy. At last follow-up, 11 patients are alive and disease free, with a
median survival of 7.5 years (range, 7 months to 19.4 years). Seven of 11 (64%)
survivors had neoadjuvant therapy followed by chest wall resection. Seven of 11
(64%) survivors had radiation therapy. There was no surgical mortality. Twelve
patients had treatment-related complications, 3 of which were related to surgical
resection. There were no survivors among patients with recurrent disease. Three
of the patients who died of disease had both local and distant recurrences, 4
patients had distant recurrence only, and one patient had local recurrence only.
Only 4 of 9 (44%) patients who died were treated initially with chemotherapy
followed by chest wall resection. All but 1 of those that died (89%) received
initial radiation therapy. All 9 patients who did not survive received additional
salvage radiotherapy as well. CONCLUSIONS: Long-term survival is possible with ES
PNET after complete chest wall resection. This may be facilitated by neoadjuvant
chemotherapy. Long-term survival without radiation therapy is possible, and
consideration of radiation therapy should be made on a case-by-case basis.
PMID- 10770380
TI - Anterior urethral valves: a rare cause of infravesical obstruction in children.
AB - PURPOSE: The aim of this study was to report the clinical presentation, mode of
diagnosis, and treatment of patients with anterior urethral valves (AUV), a rare
congenital anomaly causing infravesical obstruction in children. METHODS: Three
patients with anterior urethral valves were admitted in the Pediatric Urology
Unit at The Children's Hospital, Lahore, Pakistan, during the period 1997 through
1998. Main clinical features included difficulty in voiding, dribbling of urine,
incontinence, poor urinary stream, hematuria, and urinary tract infections. The
diagnosis was confirmed by voiding cysto-urethrogram (VCUG) in 2 patients and
retrograde urethrogram in 1 patient. A total of 4 valves were found; 1 patient
had 2 valves. Two patients had associated vesico-ureteric reflux. Endoscopic
resection was performed in all patients. RESULTS: Postoperatively, all patients
were able to pass urine with good stream. At 9 to 24 months' follow-up, all
patients remain well and asymptomatic. CONCLUSIONS: Although rare, AUV must be
considered in the differential diagnosis of lower urinary tract obstruction. They
present with all degrees of severity depending on the age of patient and the
degree of obstruction. A properly performed and carefully interpreted VCUG is
essential for diagnosis. Transurethral resection is the treatment of choice.
PMID- 10770381
TI - Intraabdominal pressure: a parameter helpful for diagnosing and predicting a
complicated course in children with appendicitis.
AB - BACKGROUND/PURPOSE: The intraabdominal pressure (IAP) of children presenting with
acute, perforated, or suspected appendicitis were determined and compared to
define if the IAP has any diagnostic value or helps to predict a complicated
course. METHODS: Eighty-four patients with a initial diagnosis of appendicitis
were evaluated. In addition to preoperative measurements, IAP of each patient was
determined repeatedly on the postoperative first, second, and third days. The
patients were grouped according to the final diagnoses as acute, perforated, or
suspected appendicitis or negative exploration. The preoperative and
postoperative IAP of the patients were compared among the groups. Postoperative
complications were recorded, and IAP of those patients were additionally compared
with the others in the same group. RESULTS: Whereas a normal appendix was found
in 4 of the operated patients, 27 and 38 patients had acute and perforated
appendicitis, respectively. The mean preoperative values of IAP for acute,
perforated, or suspected appendicitis and negative exploration were 6.2 +/- 0.4,
9 +/- 0.3, 0.3 +/- 0.4, and 3 +/- 0.4 cm H2O, respectively (P< .001).
Postoperative first day and second day values of the IAP for acute appendicitis,
perforated appendicitis, and negative laparotomy groups were 2 +/- 0.2 and 0.6 +/
0.1,3 +/- 0.1 and 1.5 +/- 0.1,0.5 +/- 0.6 and -0.2 +/- 0.6 cm H2O, respectively.
The difference between acute and perforated appendicitis groups was significant
(P< .05). Wound infection was encountered in 7 among 38 patients with perforated
appendicitis. The preoperative and first postoperative day IAP values of patients
with perforated appendicitis who experienced a wound infection and who were
without a wound infection have been 11.8 +/- 0.4 and 4.8 +/- 0.2, and 8.4 +/- 0.2
and 3.1 +/- 0.3 cm H2O (P< .001). Discriminant analysis has shown that 93.3%,
70.4%, and 73.3% of patients with suspected, acute, and perforated appendicitis
have been within the expected groups. IAP less than 1.39 cm H2O has excluded
appendicitis with a 95% confidence interval. Although the interval has been
between 5.40 and 7.04 cm H2O for acute appendicitis, it has varied between 8.46
and 9.70 cm H2O for perforated appendicitis. CONCLUSIONS: Although the IAP does
not increase in conditions mimicking appendicitis, it increases among children
with appendicitis. A further increase is encountered among children with
perforated appendicitis. Complicated course is encountered among children with
highest IAP values. Therefore, IAP may be used both as a diagnostic parameter and
a predictor of a complicated course associated with appendicitis in children.
PMID- 10770382
TI - A comparative histopathologic evaluation of the effects of three different
solutions used for whole bowel irrigation: an experimental study.
AB - PURPOSE: Although whole bowel irrigation (WBI) is a widely used method of bowel
preparation in daily surgical practice, almost nothing is known about the
histopathologic alterations caused by WBI and whether these differences have any
detrimental effect on the outcome of gastrointestinal surgical procedures.
Therefore, an experimental study has been conducted to evaluate and compare the
effects of WBI with various solutions on the histology of gastrointestinal tract.
METHODS: During the experimental procedures animals were divided into 4 groups
consisting of 8 animals each as follows: group A, WBI performed by using isotonic
saline solution; group B, WBI performed by using an isoosmolar solution
containing polyethylene glycol (PEG); group C, WBI performed by using Lactated
Ringer's solution; group D, Animals that were not irrigated but sham operations
that were performed served as controls. Four hours after WBI the animals
underwent laparotomy and a segment of transverse colon with intact vascular
peduncle was prepared. After waiting for 30 minutes, specimens from duodenum,
small intestine, large bowel, colonic segment, and liver were obtained from each
animal. Histopathologically, all of the specimens were evaluated and graded by 3
parameters including congestion, edema, and inflammation. RESULTS: Although
varying degrees of congestion, edema, and inflammation were encountered from all
of the specimens of group A, B, and C, only slight congestion was noted in all
specimens of group D. The difference between group D and other groups was
statistically very significant (P < .001). When the sections from duodenums of
groups were evaluated, the degree of congestion, edema, and inflammation were
found to be moderate in group B, mild-moderate in group A, and mild in group C.
Histopathologic examinations of specimens of the small, large bowel, and isolated
colonic segment showed severe congestion, edema, and inflammation in group A,
moderate-mild in group B, and mild in group C. The difference between A and B, A
and C, and A and D was statistically significant (P < .01). Although severe
congestion was encountered in liver specimens of group A, only mild congestion
was encountered in groups B and C (P= .0001). The matched durations of
irrigations and total volume of irrigation solutions were found to be not related
with the difference in histopathologic findings. CONCLUSIONS: WBI has induced
varying degrees of histopathologic alterations from mild to severe in the rat
gastrointestinal tract. Lactated Ringer's solution and PEG solution have induced
the least alterations. Therefore, WBI with Lactated Ringer's solution and PEG
solution seem to be safe alternatives of mechanical bowel preparation before
elective large bowel surgery. Because saline solution has caused detrimental
alterations in distal gastrointestinal tract histology, WBI with saline solution
seems to be unadvisable.
PMID- 10770383
TI - Renal expression of monocyte chemotactic protein-1 and epidermal growth factor in
children with obstructive hydronephrosis.
AB - BACKGROUND/PURPOSE: The authors studied the potential role of ureteropelvic
junction obstruction (UPJ-O) in causing progressive renal damage in children
through the renal expression of epidermal growth factor (EGF) and monocyte
chemotactic protein-1 (MCP-1) mRNA. METHODS: Renal tissues were harvested from 11
children with UPJ-O and from 10 normal kidneys to study the renal expression of
EGF and MCP-1 detected by means of in situ hybridization. Five of the patients
were found to have a history of urinary tract infection (UTI). RESULTS: Children
with UPJ-O had marked reduction of EGF gene expression when compared with
controls. Interstitial expression of MCP-1 mRNA was present in all UPJ-O cases.
Both EGF and MCP-1 expression did not correlate with age, with differential renal
function, and with renal thickness measured through MAG3 renal scan. Children
with a history of UTI had a more severe reduction of the renal thickness of the
affected kidney compared with those without UTI. MCP-1 expression was higher and
EGF more reduced in children with a history of UTI. CONCLUSIONS: Our results
suggest a potential role of EGF and MCP-1 in the pathogenesis of renal damage and
growth failure in UPJ-O, especially in children with UTI. These important
functional changes begin early in life, possibly during fetal life.
PMID- 10770384
TI - Nissen fundoplication in the management of gastroesophageal reflux occurring
after repair of esophageal atresia.
AB - BACKGROUND/PURPOSE: Gastroesophageal reflux is a major cause of complications
after esophageal atresia repair. The suitability of the Nissen fundoplication in
these patients is still disputed. Therefore, the authors evaluated the results of
their prospective treatment protocol in those patients who underwent a Nissen
fundoplication. METHODS: From 1984 to 1996, 125 patients underwent anastomosis
for esophageal atresia. A Nissen fundoplication was later performed in 29
patients. The prospective protocol included x-ray after 10 days, 6 weeks, 12
weeks, 6 months, and 12 months. Forty-eight-hour pH measurements were performed
between 6 and 12 weeks. Mean postfundoplication follow-up was at least 5 years
(range, 2 to 13 years). RESULTS: Two of the 29 patients died after the Nissen
fundoplication from unrelated causes. A third patient was excluded from the study
group. Nineteen of the remaining 26 patients showed severe stricture. pH-metry
succeeded in 18 patients, showing pathological reflux in 17. In 24 patients the
fundoplication was performed between 1 and 24 months (median, 4 months), in the
other 2 patients much later. In 4 of the 26 patients(15%) the Nissen proved to be
insufficient and had to be redone. The remaining 22 patients had no short-term or
long-term complications. CONCLUSION: The authors' findings in this group of
patients, comparing them with the results reported in the literature, indicate
that there is no reason to change their prospective treatment protocol nor their
policy to perform Nissen fundoplications at an early stage.
PMID- 10770385
TI - Ureterocystoplasty: an alternative reconstructive procedure to enterocystoplasty
in suitable cases.
AB - PURPOSE: The objective of the report is to present the results of
ureterocystoplasty in 6 children with megaureters and low-capacity, high-pressure
bladders. METHODS: Of the 6 patients, 2 had valve bladders, 1 had Hinmann's
syndrome, 1 had neuropathic bladder, and the remaining 2 with ureterocutaneostomy
were mainly diverted because of refluxing megaureters. Nephrectomy was performed
in both of the boys with posterior urethral valve because of vesicoureteral
reflux dysplasia (VURD) syndrome, and the ipsilateral ureter was used for the
augmentation. In 2 patients with ureterocutaneostomy and in 1 with Hinmann's
syndrome, a transureteroureterostomy was carried out, and the distal part of the
ureter was used to perform augmentation. The patient with neuropathic bladder had
a nonfunctioning crossed ectopic left kidney with an associated ipsilateral,
refluxing megaureter, and the ureter was used for augmentation after the
nephrectomy. RESULTS: All of the patients are continent, and 4 patients who are
neurologically normal void spontaneously without requiring clean intermittent
catheterization (CIC). The average increase in bladder capacity is 263% (range,
190% to 340%). CONCLUSIONS: Ureterocystoplasty is the bladder augmentation of
choice for patients with a nonfunctioning kidney with an associated ipsilateral,
refluxing megaureter and for patients with kidneys both in good function and
megaureters suitable for a transureteroureterostomy.
PMID- 10770386
TI - Treatment of facial dog bite injuries in children: a retrospective study.
AB - PURPOSE: The authors assess their approach to immediate surgical repair with
general anesthesia of facial dog bites in children over a 10-year period in their
pediatric department. METHODS: The authors reviewed a series of 100 children (59
boys, 41 girls) who required immediate surgical intervention during the first
hours after admission between 1985 and 1995. Strict disinfection was always used
to preclude the risk of rabies, and parenteral antibiotherapy was used to avoid
aero-anaerobic infections. RESULTS: A total of 68% of children were below 5 years
of age. The most frequent injury was to the midface. Associated injuries or death
were not observed. One case of postoperative wound infection was noted. Four
surgical revisions were performed because of unsightly scars, but in most
children the scar had attenuated 1 year after injury. CONCLUSIONS: The aim of
immediate surgical repair is to obtain a satisfactory cosmetic result and to
avoid infections. Better cosmetic results (4 cases of scar revisions) with a
minimal risk of wound infections (1 cheek wound infection) are obtained.
PMID- 10770387
TI - Esophageal atresia in Bremen, Germany--evaluation of preoperative risk
classification in esophageal atresia.
AB - BACKGROUND/PURPOSE: The current study enrolled 113 patients with esophageal
atresia (EA) accompanying tracheoesophageal fistula (TEF) (Vogt type IIIb) who
were treated at the Central Hospital St. Jurgen Strasse, Department of Pediatric
Surgery in Bremen, Germany between 1978 and 1997. METHODS: These EA patients were
classified into patients preoperatively complicated by respiratory distress
syndrome (RDS) or pneumonia and those without complications. In each group, risk
factors were classified according to the risk classification described by Spitz
et al, and the prognoses and therapeutic problems were evaluated. Based on these
results, a new preoperative risk classification consisting of risk factors
described by Spitz et al supplemented with RDS and pneumonia was evaluated.
RESULTS: When the prognoses of EA were evaluated, the survival rate was markedly
decreased when RDS or pneumonia alone or more than 2 of 3 factors including major
cardiac anomalies and low birth weight were present as preoperative risk factors.
Concerning therapeutic problems, the necessity of treatment with delayed primary
repair tended to increase when RDS or pneumonia was present as risk factors.
However, it was suggested that secure and safe blockage of TEF was still
difficult during the initial surgery. CONCLUSIONS: During selection of
therapeutic strategies for EA, RDS and pneumonia are still considered to be
essential as preoperative risk factors for EA. Our new preoperative risk
classification consisting of risk factors described by Spitz et al supplemented
with RDS and pneumonia appears to clearly reflect the prognoses and therapeutic
problems of EA.
PMID- 10770388
TI - Cost-effectiveness of neonatal surgery: a review.
AB - BACKGROUND/PURPOSE: Technological developments have revolutionized both diagnosis
and treatment in neonatal surgery. However, it has been increasingly recognized
that financial resources might become insufficient to provide all the medical
care that is technically feasible or that patients and families might desire. The
purpose of this study is to apply the theory of health economics to neonatal
surgery and to explore the extent and the kind of economic evaluation done in
neonatal surgery. METHODS: To explore the work done so far, the authors undertook
a literature search aimed at costs and effects of surgical interventions in
newborns with Ravitch' surgical index diagnoses of congenital anomalies. Common
keywords in cost-effectiveness analysis were used to search Medline. RESULTS:
Evidence about the cost effectiveness of neonatal surgery is largely lacking.
This is probably because of difficulties in long-term tracking of the patients
and to the problem that most generic quality-of-life measures are not applicable
in children yet. CONCLUSIONS: Further cost-effectiveness research in neonatal
surgery is warranted to settle priority discussions in health care when neonatal
surgery is part of such discussions. Methodology for generic quality-of-life
measurement in children is badly needed.
PMID- 10770389
TI - Initial response to portoenterostomy determines long-term outcome in patients
with biliary atresia.
AB - PURPOSE: The aim of this study was to assess the efficacy of portoenterostomy in
biliary atresia and determine factors that predict outcomes. METHODS: The
outcomes after portoenterostomy for biliary atresia from 1976 to 1996 were graded
into 3 defined groups: G (good, jaundice free); I (intermediate, progressive
liver disease with liver transplant if needed after 3 years of age); P (poor,
liver transplant or death at less than 3 years of age). RESULTS: Twenty-seven of
49 children (55%) who underwent portoenterostomy responded. Of these, 13 (26%)
were jaundice free (G). Of 14 children (28%) in I, 6 underwent liver transplant
after 3 years of age. Of 22 children (44.8%) in P, 14 (28%) died before 3 years
and 8 underwent liver transplant before 3 years. Thus, 42% of the children in
this series are surviving with native liver. Age at operation in P was
significantly different compared with G. Preoperative values of bilirubin and
alanine transaminase were comparable in the 3 groups. Postoperative values of
bilirubin and alanine transaminase were lower in G and I compared with P
Complications were significantly lower in group G. CONCLUSIONS: Portoenterostomy
alone in biliary atresia is beneficial in 40% of cases. Factors associated with
the outcome include age at operation, postoperative cholangitis, and change in
values of bilirubin and alanine transaminase. A classification based on decline
of bilirubin and enzyme levels 3 months after portoenterostomy is proposed to
predict the long-term outcome of an individual case of biliary atresia. It is
particularly relevant in the intermediate group in which timing of referral may
preclude or compromise liver transplant.
PMID- 10770390
TI - Transabdominal amnioinfusion to avoid fetal demise and intestinal damage in
fetuses with gastroschisis and severe oligohydramnios.
AB - BACKGROUND/PURPOSE: Despite dramatic improvement in survival rate for neonates
with gastroschisis, significant postoperative morbidity and a low mortality rate
still occur. Furthermore, even in recent publications, some fetal death has been
reported. Does this mean that antenatal diagnosis of gastroschisis is a missed
opportunity? In fact, decreased amniotic fluid (AF) volume is observed in some
fetuses with gastroschisis. However, oligohydramnios is associated with an
increased risk of fetal suffering. When severe oligohydramnios is observed,
intrapartum amnioinfusion, to restore AF volume, may help avoid fetal
complications. METHODS: Two fetuses with gastroschisis and severe oligohydramnios
were treated antenatally with amnioinfusion of saline solution. In one case,
fetal heart beat decelerations were observed at 27 weeks' gestation among with
the oligohydroamnios and serial transabdominal amnioinfusions were performed. In
the second case, severe oligohydramnios was observed at 31, weeks and an
amnioinfusion was performed. The 2 babies were delivered at 31 and 34 weeks,
respectively. RESULTS: In both cases, exteriorized bowel was nearly normal at
birth, and primary closure could be performed. Outcome was favorable, and they
were discharged home on day 43 and day 54, respectively. CONCLUSIONS: Because
fetuses with gastroschisis and oligohydramnios are part of a particular high-risk
group, serial ultrasound examination and computerized fetal heart beat monitoring
are necessary during the third trimester. In selected cases of gastroschisis
associated with severe oligohydramnios, serial amnioinfusion may be required.
PMID- 10770391
TI - What have we learned about traumatic diaphragmatic hernias in children?
AB - BACKGROUND/PURPOSE: Diaphragmatic injuries have been reported to be a predictor
of serious associated injuries in trauma and a marker of severity. The aim of
this retrospective study was to identify pitfalls in the diagnosis and treatment
of these injuries in children. METHODS: Data were collected from all patients
admitted to the trauma service with traumatic diaphragmatic hernias for the
period of January 1977 to August 1998. The authors evaluated 15 cases of
traumatic diaphragmatic rupture (6 girls and 9 boys). RESULTS: Mean age was 7.5
years (range, 3 weeks to 15 years). Thirteen patients suffered from blunt trauma,
and 2 patients suffered from penetrating trauma. The right and left
hemidiaphragms were injured equally (7 patients each), with 1 additional patient
suffering from bilateral injuries. All but 1 patient had laparotomies for trauma
(n = 14). The diagnosis was made preoperatively in 8 patients (53%) with just a
chest radiograph. Computed tomography (CT) scan, magnetic resonance imaging
(MRI), and oral contrast studies were used as ancillary tests to diagnose
traumatic diaphragmatic rupture. There were 3 missed injuries. Associated
injuries included liver lacerations (47%), pelvic fractures (47%), major vessels
tear (40%), bowel perforations (33%), long bone fractures (20%), renal
lacerations (20%), splenic lacerations (13%), and closed head injuries (13%). The
mean hospital stay was 20 days (range, 7 to 60 days). Complications were observed
most commonly in those patients with multiple injuries and included postoperative
ileus (40%), pneumonia (30%), pancreatitis (20%), wound infection (20%),
intestinal obstruction (20%), cholestasis (10%), and renal failure (6%). Five
deaths (33%) were caused by hemorrhagic shock, respiratory failure, coagulopathy,
and refractory acidosis. CONCLUSIONS: Traumatic diaphragmatic hernias usually are
associated with serious injuries in children. It is important to combine a high
index of suspicion with radiological diagnostic tests in patients at risk.
Palpation and/or visualization of both diaphragms at laparotomy is extremely
important in detecting these injuries when they are not suspected preoperatively.
PMID- 10770392
TI - Paratesticular rhabdomyosarcoma in a neonate.
AB - A 13-day-old boy presented with left scrotal tumor and coronary hypospadias. Left
radical orchiectomy was performed. Histological diagnosis was embryonal-type
paratesticular rhabdomyosarcoma. To the authors' knowledge, this is the first
reported case of paratesticular rhabdomyosarcoma in a neonate in English-language
literature. Also, the association of a testicular tumor with hypospadias has not
been noted.
PMID- 10770393
TI - The factor V Leiden mutation: a possible contributor to the hepatic artery
thrombosis encountered after liver transplantation in a child.
AB - A 10-year-old girl has experienced 3 recurrences of hepatic artery thrombosis
(HAT) after a liver transplantation. She responded to intraarterial
administrations of urokinase after the first 2 attacks. However, the restoration
of the arterial flow was not possible after the third attack. The child and her
father were both heterozygous for factor V Leiden mutation. In addition to the
technical factors, the factor V Leiden mutation should be considered as a factor
that plays a role in HAT.
PMID- 10770394
TI - Use of "Gore-Tex surgical membrane" to minimize surgical adhesions in multistaged
extrathoracic esophageal elongation for esophageal atresia.
AB - The procedure of choice in the surgical correction of "long gap" esophageal
atresia should, when possible, preserve the native esophagus. We present a
modification of "the multistaged extrathoracic esophageal elongation method,"
designed to facilitate esophageal elongation and use of a Gore-Tex (W.L. Gore and
Associates, Flagstaff, AZ) surgical membrane to minimize surgical adhesions. We
used this technique to successfully treat a 1-kg infant, with type A esophageal
atresia, associated aortic coartation, and severe necrotizing enterocolitis with
multiple perforations. Multistaged extrathoracic esophageal elongation was begun
at the age of 9 months and concluded at 17 months.
PMID- 10770395
TI - Anterior rectal duplication: a diagnostic challenge.
AB - The authors present an anterior rectal cyst in a 14-month-old girl. This rare
variant of rectal duplications presented with recurrent urinary infections. The
diagnosis was challenging in view of the multiple differential diagnoses to be
considered. Magnetic resonance imaging appeared to be the most accurate
preoperative investigation. The cyst was removed uneventfully by partial excision
and mucosal ablation. An awareness of this variant can lead to early diagnosis
and curative resection.
PMID- 10770396
TI - Diaphragmatic plication in the extremely low birth weight infant.
AB - A case of acquired diaphragmatic paralysis in an extremely low birth weight
infant complicated by respiratory failure, recurrent atelectasis, and pneumonia
is described. Diaphragmatic plication led to a rapid improvement in pulmonary
function and allowed for discontinuation of mechanical ventilation in less than 1
week. Therapeutic options for acquired diaphragmatic paralysis, including the
rationale for early operative intervention, in this patient population are
discussed.
PMID- 10770397
TI - Duplication of the vermiform appendix.
AB - In this brief report, the authors present a case of duplication of the vermiform
appendix with appendicitis occurring in both appendices and causing small bowel
obstruction.
PMID- 10770398
TI - Obstructive jaundice caused by placement of a nasoenteric feeding tube.
AB - Nasoenteric feeding tubes are a safe and effective means for providing
nutritional support to the critically ill patient. Serious complications have
been reported, but usually are the result of an improper path of the tube during
placement. The authors report a case of ampullary obstruction and jaundice caused
by a nasoenteric feeding tube, presumably caused by coiling of the tube in the
duodenum. This report represents the first such case in the literature.
PMID- 10770399
TI - Hearing loss in infants with congenital diaphragmatic hernia treated without
extracorporeal membrane oxygenation: report of two cases.
AB - The authors report the cases of 2 infants with congenital diaphragmatic hernia
(CDH) treated without extracorporeal membrane oxygenation (ECMO) therapy who were
discovered to have hearing loss at 1 year of age. Both boys had been diagnosed as
having CDH antenatally and were treated with surgery and high-frequency
oscillatory (HFO) therapy. The patterns of hearing loss were consistent with
sensorineural deafness and believed to be associated with HFO therapy, prolonged
mechanical ventilation, and a high pH.
PMID- 10770400
TI - Maximizing ovarian salvage when treating idiopathic adnexal torsion.
AB - Idiopathic adnexal torsion threatens ovarian function. The best ways to maximize
ovarian salvage have not been stressed widely. The authors describe 2 girls who
illustrate the benefit of untwisting the torsion, limiting resection and
performing bilateral gonadopexy to prevent both ipsilateral recurrence and
contralateral occurrence.
PMID- 10770401
TI - Fungal sepsis in a patient with duodenal hematoma.
AB - A 4-year-old boy presented with a duodenal hematoma and was admitted for
conservative management including nasogastric tube drainage and parenteral
nutrition. Within 2 days, the child became fungemic and went on to require urgent
laparotomy. This previously undescribed life-threatening complication of duodenal
hematoma is discussed in the context of standard treatment of this injury.
PMID- 10770402
TI - Liver transplantation in patients with homozygotic familial hypercholesterolemia
previously treated by end-to-side portocaval shunt and ileal bypass.
AB - Familial hypercholesterolemia is the result of mutations in the gene that encodes
the synthesis of the cellular receptor for low density lipoprotein (LDL). In the
homozygous form of the disease (HFHC), cellular LDL receptors either do not form,
or, when present, cannot bond LDL and mediate its cellular uptake LDL, and the
cholesterol that it transports accumulate in plasma, producing severe premature
atherosclerosis and death from coronary artery disease usually before the age of
20. Currently, the only effective treatment is liver transplantation, which,
alone or in association with medications, normalizes plasma cholesterol levels.
The authors report the cases of 2 siblings with HFHC who underwent portocaval
shunt at the ages of 2.5 and 1.5 years, respectively. Portocaval shunt produced
an immediate, but insufficient decrease in cholesterol (by 40% and 35%,
respectively), leaving them with cholesterol concentrations of about 500 mg/dL.
One year later they each underwent ileal bypass without obtaining any significant
response. Liver transplantation at the ages of 18 and 16 years, respectively,
reduced plasma cholesterol concentrations to 129 and 225 mg/dL, respectively. The
earlier operations seriously increased the technical difficulty of liver
transplantation and did not produce a favorable effect on the natural course of
the disease, so portocaval shunt and ileal bypass are not indicated in HFHC, not
even for the purpose of delaying liver transplantation.
PMID- 10770403
TI - Appendico-ileal fistula in cystic fibrosis.
AB - This report describes a young woman with cystic fibrosis presenting with small
bowel obstruction. Intraoperatively, an appendix with a wide lumen was found with
a fistula to the distal ileum.
PMID- 10770404
TI - Congenital small bowel diverticulosis and intestinal atresia: a rare association.
AB - An unusual case of multiple intestinal atresias with multiple small bowel
diverticulae is presented. To the best of our knowledge this is the first
reported case of its kind in the literature.
PMID- 10770405
TI - Isolated rupture of the cisterna chyli after blunt trauma.
AB - An 8-year-old boy was evaluated for blunt abdominal trauma after a motor vehicle
crash. In the course of his workup, a computed tomography (CT) scan of the
abdomen was suspicious for a duodenal injury. At surgery, the duodenum was found
to be normal; however, a rupture of the cisterna chyli was identified. This
injury was repaired, and the boy made an uneventful recovery. This report is one
of few in the literature describing isolated injury to the cisterna chyli after
blunt abdominal trauma.
PMID- 10770406
TI - Gastric volvulus associated with wandering spleen in a child.
AB - Wandering spleen is an uncommon entity in childhood and has been described only
rarely in association with gastric volvulus. Wandering spleen and gastric
volvulus were diagnosed in a 5-year-old boy who presented with acute abdominal
pain and distension. Intraoperatively, normal ligamentous connections between the
stomach, spleen, and posterior abdominal wall were absent. Developmental
anomalies that result in wandering spleen may lead to hypermobility of the
stomach and a predisposition to gastric volvulus. In such patients, prophylactic
gastropexy should be considered.
PMID- 10770407
TI - Solitary intestinal fibromatosis as a cause of bile vomiting in a neonate.
AB - The authors describe a 3-day-old newborn admitted with signs of intestinal
obstruction caused by solitary intestinal fibromatosis (SIF). This is a very rare
lesion, which has an excellent prognosis. The differential diagnosis of bilious
vomiting in a neonate caused by other than tumorous processes in the neonatal
intestine is extensive. Probably this kind of lesion is more frequent in the
neonatal period than thought until now but underdiagnosed because of the
difficulty of diagnosis. Therapy of choice is wide local excision, and prognosis
is excellent.
PMID- 10770409
TI - Progressive biliary pathology associated with common pancreato-biliary channel.
AB - A female infant who presented with transient obstructive jaundice and who was
shown to have mild fusiform dilatation of the common bile duct at the age of 18
months was followed up with hepatobiliary ultrasound scans over a period of 17
years. Enlarging gallbladder polyps were identified during the last 2 years of
follow-up, and endoscopic retrograde cholangio-pancreatography (ERCP) showed a
common pancreato-biliary channel with minimal bile duct dilatation. A high
concentration of pancreatic amylase was detected in the bile. Hepaticojejunostomy
and cholecystectomy were performed. Histologically, the resected common bile duct
showed fibrous thickening of the wall and loss of surface epithelium. Muscular
hypertrophy and polypoid lesions, which were foci of cholesterosis, were
identified in the gallbladder. There was a minimal lymphocytic infiltrate in the
subepithelial connective tissue. This report documents a progressive change in
the ultrasound appearances of the gallbladder and histological changes in the
extrahepatic ducts secondary to a common pancreato-biliary channel and pancreato
biliary reflux.
PMID- 10770408
TI - Primary idiopathic chylopericardium in a 2 month old successfully treated without
surgery.
AB - The authors report a case of primary idiopathic chylopericardium in a previously
healthy 2-month-old infant. He was treated with continuous pericardial drainage
and low-fat total parenteral nutrition. He remains asymptomatic after 14 months
of follow-up. This is the first report of primary idiopathic chylopericardium
successfully treated nonoperatively.
PMID- 10770410
TI - Granular cell tumor of the biliary tree in a pediatric patient.
AB - Granular cell tumor of the biliary tree is a rare benign tumor that occurs most
commonly in young African-American girls. Granular cell tumor rarely is included
in the differential diagnosis of biliary obstruction, yet complete surgical
excision is curative. The authors report a case of granular cell tumor of the
biliary tree in a pediatric patient that required a pancreaticoduodenectomy for
cure.
PMID- 10770411
TI - Patent ductus venosus with a hypoplastic intrahepatic portal system presenting
intrapulmonary shunt: a case treated with banding of the ductus venosus.
AB - A case of patent ductus venosus (PDV) presenting intrapulmonary shunting is
described. Although retrograde venography of ductus venosus showed few
intrahepatic branches, banding of PDV resulted in increased intrahepatic portal
branches and disappearance of symptoms 10 months after the operation. Banding of
the ductus venosus may be effective in PDV even with hypoplastic intrahepatic
portal system.
PMID- 10770412
TI - Kasai-type dissection for biliary atresia in 39 patients.
PMID- 10770413
TI - Therapeutic drug monitoring of sirolimus: correlations with efficacy and
toxicity.
AB - We sought to examine the potential benefits of therapeutic drug monitoring of
sirolimus, a potent immunosuppressive agent that displays a pleiotropic array of
side effects. METHODS: A high-performance liquid chromatography (LC) procedure
combined with ultraviolet detection (UV) was used to measure serial
concentrations of parent compound sirolimus in 150 renal transplant recipients
over a period of 4 yr. Drug concentrations in whole blood at trough time, as well
as within pharmacokinetic profiles, were correlated with clinical events using
contingency tables, logistic regression analysis, and receiver operating
characteristic (ROC) curves. RESULTS: The LC/UV method showed an excellent
correlation with detection of LC-resolved components by tandem mass spectrometry,
demonstrating that the LC/UV method selectively detected parent compound.
Sirolimus displayed the characteristics of a critical-dose drug: Its
concentration could not be predicted by a standard body or demographic measure,
or by dose, and it showed high degrees of intra- and inter-individual
variability. However, there was a good correlation between trough and area-under
the-curve measurements. There was a significant association between trough values
expressed as either observed ( < 5 ng/mL) or dose-corrected parameter ( < 1.7
ng/mL per mg administered drug) and the occurrence and severity of acute
rejection episodes - despite the low overall incidence of 23 episodes among the
cohort of 150 patients. Similarly, ROC functions showed a correlation of the
occurrence of hypertriglyceridemia, thrombocytopenia, and leukopenia, but not
hypercholesterolemia, with trough concentrations above 15 ng/mL. CONCLUSION: Due
to its behavior as a critical-dose drug, therapeutic monitoring to measure
sirolimus concentrations by a LC/UV method may provide clinicians with a tool to
optimize outcomes.
PMID- 10770414
TI - Plasma homocysteine levels in renal transplanted patients on cyclosporine or
tacrolimus therapy: effect of treatment with folic acid.
AB - Hyperhomocysteinemia, an independent risk cardiovascular factor, has been
reported in renal transplanted patients (RTP). The aim of the present study was
to evaluate homocysteine levels in RTP treated with cyclosporine or tacrolimus,
and the changes observed in the two groups of patients after treatment with folic
acid. Forty-two RTP with stable function (21 treated with cyclosporine and 21
with tacrolimus, matched by gender and age) were studied. Forty healthy control
subjects were matched by age and gender with the patients. In RTP, homocysteine
was increased compared with the controls (16.4 +/-5.2 vs 8.0 +/- 1.8 micromol/L;
p < 0.001), but there was no difference in vitamin B12 and folic acid levels.
Thirty-three patients and one control showed hyperhomocysteinemia (78.5 vs 2.5%;
p < 0.001). Homocysteine correlated negatively with creatinine clearance in the
patients (p = 0.04), but no correlation was found with vitamin B12, folic acid
and lipoproteins. By univariate analysis, patients treated with cyclosporine had
higher homocysteine than those treated with tacrolimus (p = 0.03), but
multivariate analysis did not confirm these results. In 21 patients with
hyperhomocysteinemia and folate levels similar to those of the controls, folic
acid (5 mg/d for 3 months) was administered. Homocysteine decreased significantly
(19.1 +/- 4.8 vs 13.2 +/- 3.4 micromol/L; p < 0.001), with a median reduction of
31% and with no differences observed in patients treated with either cyclosporine
or tacrolimus. We concluded that hyperhomocysteinemia is very frequent in RTP,
but homocysteine levels are not different in patients treated with cyclosporine
or tacrolimus. Folic acid therapy produces a significant decrease in homocysteine
concentrations, in the absence of clear folate deficiency, without differences in
relation to immunosuppressant therapy.
PMID- 10770415
TI - Comparing quality of life following liver transplantation for Laennec's versus
non-Laennec's patients.
AB - The overall success of orthotopic liver transplantation (OLTX) includes not only
survival, but quality of life (QOL) as well. We studied one controversial group
of OLTX recipients, patients transplanted for alcoholic liver disease
(Laennec's), to determine if their post-OLTX QOL was similar to that of patients
transplanted for non-alcoholic liver disease (non-Laennec's). Over a 10-yr
period, patients undergoing OLTX at our institution were asked to complete a QOL
questionnaire addressing a wide range of topics from demographics and employment
to symptom distress/frequency, activities of daily living, and effect of loss of
health on daily life. Twenty-four Laennec's and 100 non-Laennec's OLTX recipients
completed the questionnaire at both their 2- and 5-yr follow-up visits at our
institution. Both groups were well-matched in age, race, and patient location
status at the time of OLTX. No significant differences could be detected between
Laennec's and non-Laennec's scores regarding overall QOL, including one's ability
to function, health perception, and self-perception at 2 and 5 years post-OLTX,
and between 2 and 5 years post-OLTX. Although not between groups, a significant
difference was noted regarding patients' satisfaction with life, with less
satisfaction reported at the 5-yr versus the 2-yr time point post-OLTX. Rates of
current/recent employment between both groups were also similar at 2 years post
OLTX, and again at 5 years post-OLTX. We conclude that overall QOL and employment
levels appear similar between patients transplanted for alcoholic and non
alcoholic liver disease. This similarity appears to extend to 5 years post-OLTX.
PMID- 10770416
TI - Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone
marrow transplant patients.
AB - Mycophenolate mofetil (MMF), a new immunosuppressive drug successfully used in
renal and heart transplant recipients, was used in combination with cyclosporin A
(CsA), methotrexate (MTX) and prednisolone for the prophylaxis of acute graft
versus-host disease (aGVHD) after bone marrow transplantation (BMT) and
peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen
(HLA)-mismatched, unrelated (n = 9) and related donors (n = 4) in an open single
centre phase II study. Thirteen patients, transplanted from HLA-mismatched donors
of 18-57 yr of age, received 1 g MMF daily, starting at day 10, in addition to
CsA and prednisolone for aGVHD prophylaxis. All patients were engrafted between
days 13 and 15. Four of the 13 patients experienced aGVHD grade I/II (n = 2) and
grade III (n = 2). All patients except 3 were alive on day 100 post
transplantation. No severe adverse effects of MMF were recorded. In our pilot
study, we demonstrated that MMF can be used safely for the prophylaxis of aGVHD.
PMID- 10770417
TI - Erythropoiesis and renal transplant pregnancy.
AB - OBJECTIVE: To examine erythropoiesis in renal transplant pregnancies. METHODS:
Retrospective cohort study of 30 renal transplant cases and 30 age, smoking and
parity-matched healthy controls with normal index pregnancy. Retrospective chart
review and assay of frozen antenatal serum (for serum erythropoietin
concentration [serum EPO]), transferrin receptor protein [TfR], ferritin, folate
and B12) were performed. The linear regression equation for normal pregnancy
controls was used to calculate predicted [serum EPO] and the observed/predicted
(O/P) log [serum EPO] was plotted. The relationship between [serum EPO] and
haemoglobin (Hb) among transplant cases was considered to be different from that
among controls if the slope of the O/P log [serum EPO] versus Hb regression was
significantly different from zero. RESULTS: The transplant (14 cadaveric) to
conception interval was (median [range]) 33.5 [4, 189] months. Immunosuppressants
were azathioprine (n = 25), cyclosporine (n = 22) and/or prednisone (n = 25).
Cases were more often primiparous (20 vs. 7 [controls]; p = 0.01), had pre
existent hypertension (20 vs. 0 [controls]; p < 0.001), developed new/increased
hypertension or pre-eclampsia (28 vs. 0 [controls]; p < 0.001) and an antenatal
rise in creatinine (14 vs. 2 [controls]; p < 0.001). In early pregnancy, cases
had similar EPO (15.2 [2.6, 84.6] vs. 15.7 [6.4, 41.0] [controls] U/L) but lower
Hb (101 [65, 129] vs. 116 [106, 150] g/L; p < 0.001). Twenty-two (73%) cases had
Hb < 100 g/L (vs. 4 [controls]; p < 0.0001); Hb was comparable at 6 wk
postpartum. With advancing gestational age (GA), Hb remained stable and serum EPO
increased in both groups. The slope of the O/P log [serum EPO] versus Hb for
transplant cases was significantly different from zero within both the 17-28 wk
(slope +/- SEM: 0.010 +/- 0.002; p < 0.0001) and the 29-42 wk GA categories
(0.006 +/- 0.003; p = 0.02). Cases showed smaller rises in serum TfR (change 481
[- 1471, 2780]) vs. 1119 [- 698, 4195] [controls] ng/mL; p = 0.005). CONCLUSIONS:
Anaemia frequently complicates renal transplant pregnancies, in which serum EPO
is inappropriately low and the rate of erythropoiesis blunted.
PMID- 10770418
TI - Mycophenolate mofetil increases cytomegalovirus invasive organ disease in renal
transplant patients.
AB - The impact of cytomegalovirus (CMV) infection post-transplantation is in part
influenced by the degree of immunosuppression. While mycophenolate mofetil (MMF)
does not increase the overall incidence of CMV infection, we have questioned
whether or not it increases its severity. Using a case control study design in
which 29 renal transplant patients developed CMV disease [17 (59%) of which
received azathioprine (AZA) and 12 (41%) received MMF], increases in the
frequency of organ involvement with CMV (58 vs. 18%; p = 0.03) and in the number
of organs involved with CMV were noted in the MMF versus the AZA group (2.0 vs.
1.0; p = 0.015). These results indicate that the increased immunosuppressive
activity of MMF impacts the morbidity of CMV infection, thus warranting the use
of effective anti-CMV preventive regimens while patients are treated with MMF.
PMID- 10770419
TI - Are lipid-dependent indicators of cardiovascular risk affected by renal
transplantation?
AB - Hyperlipoproteinemia has been reported to frequently occur in kidney transplanted
patients, thus possibly explaining, at least in part, the increased incidence of
cardiovascular disease in this population. To evaluate the impact of renal
transplantation (Tx), and related immunosuppressive therapy, on plasma
lipoprotein and Lp(a) profile, we selected a cohort of kidney transplanted
patients (36 M/14 F; age 33.8 + 12.0 yr, range 13-62) lacking significant causes
of hyperlipidemia. All patients received a triple immunosuppressive regimen and
showed a stable renal function after Tx (plasma creatinine: 1.36 +/- 0.35 mg/dL).
One year after Tx, we found a significant increase of total cholesterol (TC),
LDL, HDL, ApoB and ApoA-I (p < 0.005), while plasma triglyceride levels remained
unmodified. Lp(a) plasma levels after Tx were within the normal range and
displayed a significant inverse relationship with apo(a) size. Noteworthy,
LDL/HDL ratio and ApoB/ ApoA-I ratio in kidney transplanted patients were almost
superimposable with those of normal controls. Specifically, LDL/HDL ratio
significantly decreased in 64% of patients after Tx, due to a prevalent increase
of HDL, and was associated with a moderate amelioration of plasma TG. In a
multiple linear regression model, post-Tx HDL level was significantly related to
recipient's age, gender, BMI and cyclosporine (CyA) trough levels (Adj-R2 = 0.35,
p = 0.0002), with gender and CyA trough levels being the better predictors of
HDL. In conclusion, immunosuppressive regimens, in themselves, do not appear to
significantly increase the atherogenic risk related to lipoproteins. Rather,
other factors can affect the lipoprotein profile and its vascular effects in
renal transplant recipients.
PMID- 10770420
TI - The use of flow cytometry for the detection of CMV-specific antigen (pp65) in
leukocytes of kidney recipients.
AB - Flow cytometric assay (FCA) was used to detect a cytomegalovirus (CMV) specific
antigen (pp65) in CMV-infected fibroblast cells and in leukocytes of kidney
recipients. FCA distinguished clearly between the infected and non-infected
fibroblast cells. Regarding transplant patients, the FCA was positive when the
number of antigenemia assay (AA) positive cells was five or more per 5 x 10(4).
Moreover, the percentage of antigenemia-positive cells by FCA correlated well
with symptomatic CMV infections.
PMID- 10770421
TI - Extracorporeal membrane oxygenation support of donor abdominal organs in non
heart-beating donors.
AB - Both family consent and legal consent were required for organ/tissue donation
from non-heart-beating donors (NHBD) in Taiwan. A district attorney had to come
to the bedside to confirm the donor's asystole, confirm the family consent, and
complete some legal documents before a legal consent was issued for organ
donation. The resultant warm ischemic time would be unpredictably long and in
fact precluded the organ donation from NHBD in Taiwan. We developed a method of
using extracorporeal membrane oxygenation (ECMO) to maintain NHBD for a longer
time and prevent warm ischemic injury of the donor abdominal organs. After
ventilator disconnection in NHBD, phentolamine and heparin were injected and
mannitol infusion was given. After the donor's asystole was confirmed by the
electrocardiogram (EKG) strip recording, the ECMO support was set up through the
right femoral veno-arterial route, an occlusion balloon catheter was inserted
through the left femoral artery to occlude the thoracic aorta, and bilateral
femoral arteries were ligated. Usually, the ECMO could begin within 10 min after
the donor's asystole. The ECMO, combined with a cooler, provided cold oxygenated
blood to the abdominal visceral organs, and prevented their warm ischemic
injuries. Under the ECMO support (range: 45-70 min), eight renal grafts were
procured from 4 NHBD. With the exception of the first two renal grafts with
delayed function, all others had immediate function postoperatively and dialysis
was no longer needed. In conclusion, by our ECMO technique, NHBD could be
maintained for a longer time and the renal grafts had better immediate
postoperative function than those reported by other methods.
PMID- 10770422
TI - Excellent long-term graft survival in low risk, primary renal allografts treated
with prednisolone-avoidance immunosuppression.
AB - Primary avoidance of oral corticosteroids for renal transplant recipients is
uncommon. The South Australian renal transplant service used a double therapy
(DT) regimen of cyclosporin and azathioprine from August 1986 to July 1996 for
low risk (first graft, PRA < 50%) allografts. Oral corticosteroid, prednisolone
(P), was reserved for severe rejection or two mild rejection episodes, but could
be later withdrawn at the physician's discretion. This regimen is associated with
more early acute rejection (Russ et al., Clin Transplant 1990: 4: 26). We have
now analysed long-term patient survival (PS) and graft survival (GS) for this
group. Of 448 transplants in South Australia between August 1986 and July 1996,
295 commenced DT regimen. Ninety-four (31.8%) never received P at any stage post
transplantation (group 1), 96 (32.5%) were placed on P and later weaned (group
2), and 97 (33%) remained on long-term P (group 3). Technical losses, eight
(2.7%), within 30 d of transplantation, were excluded from sub-group analysis. PS
for the total DT cohort at 1, 5 and 9 yr post-transplantation was 97, 88 and 74%,
respectively. GS over the same time period was 88, 75 and 55%, respectively.
There was no statistically significant difference in survival compared to other
'low risk' grafts in the rest of Australia during the same time period. Mean
serum creatinine concentration (CrC) for the DT group at 3 and 6 months and 1, 3,
5 and 10 yr was not significantly different to the rest of the Australian 'low
risk' grafts. In the DT cohort, there were 334 acute rejections ( < 90 d) in 206
patients (70%), but only 42 (12.5%) required anti-lymphocyte antibody therapy
(OKT3 or ATG) for rejection. PS at 9 yr was not statistically significantly
different between groups 1 and 2, but both groups survived better than group 3 (p
< 0.0043). GS for group 1 at 1, 5 and 9 yr post-transplantation was 90, 81 and
73%, respectively; for group 2, 98, 87 and 66%, respectively; and for group 3,
84, 63 and 29%, respectively. Statistical significance was reached in group 1
versus 3 (p < 0.001) and group 2 versus 3 (p < 0.001). In summary, a DT regimen
in low risk, first renal allografts gives excellent long-term patient and GS and
minimises long-term P, despite a high rate of early acute rejection.
PMID- 10770423
TI - Prophylactic photopheresis and chronic rejection: effects on graft intimal
hyperplasia in cardiac transplantation.
AB - BACKGROUND: Despite the decreased incidence of acute rejection episodes and
improvements in short and intermediate term graft survival with current
immunosuppressive agents, there has been little progress in decreasing the
morbidity and mortality from chronic rejection. This phenomenon may, in part, be
related to the development of a humoral immune response with increases in anti
HLA antibodies, which presents as accelerated graft arteriopathy with intimal
hyperplasia. METHODS: Based on prior experimental work, a pilot, prospective,
randomized study was performed in 23 primary cardiac transplant recipients to
determine whether the addition of prophylactic photopheresis to a cyclosporine,
azathioprine and prednisone regimen was safe and resulted in decreased levels of
panel reactive antibodies (PRA) and transplant arteriopathy. RESULTS: There was
no difference between the two groups in regard to infection or acute rejection
incidence. The photopheresis group had a significant reduction in PRA levels at
two time points within the first 6 postoperative months. Coronary artery intimal
thickness was significantly reduced in the photopheresis group at 1-yr (0.23 vs.
0.49 mm, p < 0.04) and 2-yr (0.28 vs. 0.46 mm, p < 0.02) follow-up compared with
the control group. CONCLUSION: In this small pilot study, photopheresis is a
safe, well-tolerated immunomodulatory technique that is capable of decreasing the
severity of chronic rejection manifesting as post-transplant graft intimal
hyperplasia.
PMID- 10770424
TI - Flow cytometry crossmatching as a predictor of acute rejection in sensitized
recipients of cadaveric renal transplants.
AB - Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than
the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the
detection of anti-donor antibodies, that mediate hyperacute rejection and graft
loss in the early post-transplant period in renal transplant recipients. The role
of FCXM in predicting long-term clinical outcome in renal allograft recipients is
unclear. This study examines the role of FCXM in predicting long-term clinical
outcome in highly sensitized recipients of cadaveric renal transplants. All
patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who
received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our
institution, were divided into FCXM + and FCXM - groups. The incidence of acute
rejection was determined for each group during the first yr after transplant.
Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared
between groups. FCXM + patients experienced a higher incidence of acute rejection
during the first yr after transplant (69 vs. 45%), and a higher percentage of
FCXM + patients had more than one episode of acute rejection during the first yr
after transplant (34 vs. 8%) when compared to FCXM - patients. There was no
statistically significant difference in 1-, 2-, or 3-yr graft survival between
FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively).
These results suggest that sensitized FCXM + cadaveric renal transplant
recipients have a higher incidence of acute rejection episodes in the first yr
after transplant. Given the association of multiple rejection episodes with poor
long-term allograft survival, FCXM may be a useful predictor of long-term
clinical outcome in this sub-group of renal transplant recipients.
PMID- 10770426
TI - No worlds left to conquer?
PMID- 10770425
TI - Graft-versus-host disease after liver transplantation: documentation by
fluorescent in situ hybridisation and human leucocyte antigen typing.
AB - Graft-versus-host disease (GVHD) after liver transplantation is uncommon and the
outcome is often fatal. A firm diagnosis of GVHD is difficult because the
clinical triad of skin rash, marrow failure and diarrhoea can be
indistinguishable from drug reaction or viral infection, and the presence of
donor lymphocyte chimerism is not specific. We describe a case of severe GVHD in
a female patient after liver transplantation from a male cadaveric donor. Skin
biopsy showed characteristic changes of GVHD. Using Y-chromosome-specific
fluorescent in situ hybridisation (FISH), male lymphocytes were demonstrated in
10% of marrow cells and in 90% of lymphocytes infiltrating the dermal epidermal
junction. Donor human leucocyte antigens (HLAs) were detected in the peripheral
blood, buccal mucosa and skin by polymerase chain reaction. The GVHD subsided
with steroid and anti-thymocyte globulin, but recurred on tailing off of
treatment. Despite maximum supportive therapy, including random donor leucocyte
infusion, and marrow infusion from a HLA-identical sibling, the patient succumbed
to sepsis. Our results showed the utility of combining morphological features
with molecular techniques using FISH and HLA typing in confirming a diagnosis of
GVHD.
PMID- 10770427
TI - Malignant eccrine spiradenoma (spiradenocarcinoma): a clinicopathologic study of
12 cases.
AB - Malignant eccrine spiradenoma is a very rare tumor. The clinicopathologic
features of 12 cases are reported herein. Six patients were men, six were women,
and the average patient age was 62 years. Seven tumors were located on the trunk,
three on the extremities, and two in the head and neck region. All tumors were
large (average size-7.5 cm). Lesions had been present from 7 months to 30 years
before surgical removal. In all cases, continuity between benign eccrine
spiradenoma and areas with malignant change was observed. Malignancy was
evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, and
hyperchromasia, loss of nested and trabecular growth patterns, and absence of a
dual cell population. In most cases (8 of 12), the malignant component comprised
the bulk of the lesion. Two distinctive histologic patterns were observed. Five
of 12 tumors exhibited abrupt transition between a benign eccrine spiradenoma and
a high-grade carcinoma component. The others lacked a clear-cut transition
between benign and malignant components and were diagnostically challenging.
Diagnosis in such cases was established based on the loss of two cell
populations, increased nuclear to cytoplasmic ratio, hyperchromasia, and marked
mitotic activity. Two tumors showed focal squamous differentiation. Five of seven
patients on whom there was follow-up information were free of disease (average
duration of follow-up = 3.4 years). One patient developed metastases to local
lymph nodes 5 years after the primary tumor was resected. This patient had no
evidence of disease 16 months after resection of her lymph node metastases.
PMID- 10770428
TI - p53 expression in two cases of spiradenocarcinomas.
AB - p53 protein is a nuclear 53-kDa phosphoprotein that acts as a suppressor protein.
There are several studies on the expression of p53 in skin tumors, but few deal
with adnexal malignant tumors because of their rarity. We performed
immunohistochemistry for the detection of p53 and Ki-67 in two cases of malignant
spiradenomas and six cases of spiradenomas retrieved from our files. In our
cases, p53 was expressed only in the malignant areas of the lesions, whereas the
benign areas of the spiradenocarcinomas and all the spiradenomas were negative
(nuclear positivity <10%). These results seem to support the idea that p53 is
implicated in the malignant transformation of adnexal tumors.
PMID- 10770429
TI - Trichoblastoma is the most common neoplasm developed in nevus sebaceus of
Jadassohn: a clinicopathologic study of a series of 155 cases.
AB - Nevus sebaceus of Jadassohn is a hamartoma that combines epidermal, follicular,
sebaceous, and apocrine gland abnormalities. Classically, several types of
cutaneous neoplasms have been associated with this hamartoma, with basal cell
carcinoma being the most frequently described malignancy. We studied a series of
155 examples of nevus sebaceus of Jadassohn with clinicopathologic correlation.
Several histopathologic changes related to the age of the patients were found. In
our series, we could not identify any cases of authentic basal cell carcinoma. In
contrast, several examples of primitive follicular induction and of
trichoblastomas were seen. Other cutaneous hamartomas, hyperplasias, and
neoplasms found in our series of nevus sebaceus of Jadassohn included
syringocystadenoma papilliferum, sebomatricoma, apocrine gland cyst, poroma,
different histopathologic variants of warts (classic warts, tricholemmoma, and
desmoplastic tricholemmoma), primitive follicular induction, and ductal
induction. In our series, no examples of malignant neoplasms were identified. On
the basis of these findings, the classically recommended treatment for this
hamartoma, which consists of early excision to prevent the development of
malignancy, seems to be inappropriate.
PMID- 10770430
TI - Syndecan-1 expression is decreased with increasing aggressiveness of basal cell
carcinoma.
AB - Syndecans, a family of cell-surface proteoglycans of which syndecan-1 is the
prototypical member, play an important role in limiting tumor growth and invasive
capacity through their actions as receptors for growth factors and extracellular
matrix. Cutaneous biopsy specimens of basal cell carcinoma, including
superficial, nodular, infiltrative, and morpheic subtypes, were assessed
regarding the pattern of syndecan-1 expression. We found that with increasing
aggressiveness of basal cell carcinomas, syndecan-1 expression is lost from the
surface of the neoplastic cells. However, within the dermis, which is normally
devoid of syndecan-1 expression, immunopositivity for syndecan-1 is present in
areas adjacent to aggressive tumors. This pattern of staining indicates that
syndecan-1 expression is produced by stromal cells rather than being shed by the
carcinoma cells into the stroma.
PMID- 10770431
TI - Incidence of perineural invasion in histologically aggressive types of basal cell
carcinoma.
AB - Basal cell carcinoma is generally an indolent form of skin cancer. Morpheaform,
infiltrative, and sclerosing types are more aggressive tumors. The incidence of
perineural invasion in aggressive types of basal cell carcinoma has not been
previously described. We studied aggressive basal cell carcinomas for the
presence of perineural invasion. Between 1995 and 1998, the histopathologic
diagnosis of basal cell carcinoma was made on 5,097 specimens at Dartmouth
Hitchcock Medical Center. Of this total, 507 were classified as sclerosing,
infiltrative, or morpheaform. Perineural invasion was found in 15 of the 507
cases. Of these 15 cases, 12 were from the face, and 3 from the back; 13 were
recurrent, and 2 were primary lesions. The mean age of patients at diagnosis was
71 years. We found 9.9% of all basal cell carcinomas at our institution to be
aggressive types. We found an incidence of perineural invasion of 3% in the
aggressive basal cell carcinoma types. This incidence approaches that reported by
others for cutaneous squamous cell carcinomas.
PMID- 10770432
TI - Lipidized fibrous histiocytoma: clinicopathologic analysis of 22 cases.
AB - We report the clinicopathologic analysis of 23 tumors from 22 patients with
lipidized fibrous histiocytoma (FH), which has been an underrecognized variant of
cutaneous FH. The 16 men and 6 women patients (male/female ratio, 2.7:1) ranged
in age from 21 to 82 years (median, 50 years). The location of the tumor was
concentrated strikingly in the lower limb, especially around the ankle, hence the
alternative informal designation of "ankle-type" FH. The tumors showed relatively
large size compared with those of conventional FH, ranging up to 8 cm in greatest
dimension (median, 2.5 cm), and tended to be polypoid and yellowish in color.
Hyperlipidemia was only a rare and perhaps incidental association in two cases.
Histologically, lipidized FH was characterized by accumulation of numerous foam
cells, smaller numbers of siderophages, and stromal hyalinization typically
appearing "wiry," keloidlike, or osteoidlike, although focal features of ordinary
FH almost always coexisted and were identified as a focal storiform or curlicue
pattern of spindle tumor cells, epidermal hyperplasia, and peripheral "entrapped"
dermal collagen. Although follow-up data are limited, the prognosis appears to be
good with no recurrence, even after incomplete excision. These clinicopathologic
features highlight lipidized FH as a distinctive variant, which can be
distinguished from ordinary or other variants of FH, as well as from other foam
cell-rich cutaneous lesions, especially xanthoma.
PMID- 10770433
TI - Angiomatoid Spitz nevus: a distinct variant of desmoplastic Spitz nevus with
prominent vasculature.
AB - Five cases of a distinctive variant of desmoplastic Spitz nevus are reported. To
the best of our knowledge, this tumor has never been described previously.
Clinically, it presents itself as a solitary papule on the extremities of young
adults. Microscopically, it shows predominance of solitary melanocytes with
epithelioid appearance over cell nests. They are embedded in a prominent fibrous
stroma with many densely arranged, small blood vessels with plump endothelia not
seen in other Spitz nevi. Because of its resemblance to a vascular tumor, the
name angiomatoid Spitz nevus is proposed for this lesion. Absence of recurrences
or metastases after complete excision in all cases supports the benign nature of
the tumor.
PMID- 10770434
TI - Angiogenesis in cutaneous lymphoproliferative disorders: microvessel density
discriminates between cutaneous B-cell lymphomas and B-cell pseudolymphomas.
AB - The role of angiogenesis in neoplastic disorders is supported by the evidence
that tumor growth beyond a certain size requires induction of new blood vessels.
The extent of tumor-associated angiogenesis, measured as microvessel density
(MVD), has shown to correlate with aggressiveness and the prognostic outcome in
several malignant neoplasms. Few data have been reported on the angiogenic
response in lymphoproliferative diseases. In this study, the MVD has been
assessed in benign and malignant primary cutaneous B-cell lymphoproliferative
disorders. MVD was determined in formaldehyde-fixed, paraffin-embedded specimens
of primary cutaneous B-cell lymphomas (CBCL; n = 18) and cutaneous B-cell
pseudolymphomas (B-PSL; n = 22) according to previously described protocols but
was performed using computer-aided microscopic morphometry. The endothelial cells
of microvessels were identified by immunohistochemical staining for factor VIII
related antigen and CD31. The MVD was 99 dots/mm2 for CBCL and 68 dots/mm2 for
PSL, and a MVD of 115 dots/mm2 for CBCL and 73 dots/mm2 for PSL by using an
antibody against factor VIII-related antigen and CD31 antigen, respectively.
Univariate analysis revealed statistically highly significant differences in MVD
between CBCL and B-PSL (P = 0.0036 with staining for factor VIII-related antigen
and P = 0.0002 with staining for CD31 antigen). This study analyzes for the first
time the angiogenic response in CBCL compared with that of B-PSL and demonstrates
that MVD discriminates between CBCL and B-PSL. However, because of an overlap in
the ranges of MVD in CBCL and PSL, the MVD is not useful as a diagnostic tool in
individual cases.
PMID- 10770435
TI - Herpes incognito.
AB - Can a microscopist suspect that telltale histopathologic changes of infection by
herpesvirus (varicella, zoster, or simplex) are nearby even when no diagnostic
epithelial changes are present in the sections being studied? Punch-biopsy
specimens from three patients are presented; in two of those cases herpesvirus
infection was not even a clinical consideration. The initial histopathologic
sections from these patients did not show changes of herpesvirus infection, but
step sections revealed focal diagnostic changes. Atypical lymphocytes were
present in each of these cases. When atypical lymphocytes are found in concert
with a pattern of an inflammatory-cell infiltrate that does not conform precisely
to any well-defined entity, a microscopist should consider that the findings may
represent changes near infection by herpesvirus. In addition, we reviewed every
case we diagnosed as herpesvirus infection over an 18-month period and found that
in just over two thirds of those specimens (32 out of 45 cases), atypical
lymphocytes accompanied the characteristic epithelial changes induced by
herpesvirus.
PMID- 10770436
TI - Benign lymphangioendothelioma of the thigh simulating a low-grade angiosarcoma.
AB - Benign lymphangioendothelioma (BL) is a rare vascular neoplasm that can
histopathologically mimic a low-grade angiosarcoma or the patch stage of Kaposi
sarcoma. We report on the case of a 49-year-old man with a benign
lymphangioendothelioma on the right thigh that evolved on a vascular birthmark
after a trauma. Because of constant pain and the slow but progressive growth of
the lesion, we decided to excise the tumor. Three stages of surgery were needed
to obtain negative margins. We review the reports of BL to date, with special
attention to those that developed after trauma and those that had a preexistent
vascular lesion, and expound on the histopathologic differential diagnosis with
low-grade angiosarcoma.
PMID- 10770437
TI - Sebaceous neoplasms in Muir-Torre syndrome.
AB - A 59-year-old Japanese woman presented with two sebaceous neoplasms on the chest
wall and on the left cheek. The patient had a history of ascending colon cancer,
and her mother had died of gastric cancer. The histopathologic features of both
sebaceous neoplasms were vaguely in accordance with those of sebaceous adenoma
and sebaceoma. Based on these findings, we diagnosed the patient as having Muir
Torre syndrome. The sebaceous neoplasm on the chest wall exhibited features of a
sebaceous adenoma with a unique cystic appearance, namely cystic sebaceous
adenoma, which has been reported as a specific marker for Muir-Torre syndrome
(MTS). However, histopathologically, both the sebaceous adenoma and sebaceoma had
relatively large, vesicular or heterochromous and crowded nuclei with some
pleomorphism and distinct nucleoli associated with some mitotic figures, casting
doubt on their benignancy. We show that some or most benign sebaceous neoplasms
in MTS might have a high potential for malignant transformation or may be well
differentiated sebaceous carcinomas with low-grade malignancy, mimicking
sebaceous adenoma/sebaceoma. This results in difficulties in classification
regarding sebaceous neoplasms in MTS.
PMID- 10770438
TI - Gianotti-Crosti syndrome presenting as lichenoid dermatitis.
AB - Papular acrodermatitis of childhood (Gianotti-Crosti syndrome) is an uncommon,
self-limited disease characterized by an erythematous papular eruption
symmetrically distributed on the face and limbs and mild lymphadenopathy, thought
to be of viral origin. The histopathologic findings are nonspecific and include
focal parakeratosis, mild spongiosis, superficial perivascular infiltrate,
papillary dermal edema, and extravasated red blood cells. Interface changes with
some basal vacuolization may be present, but are not a conspicuous feature. We
present a 2 1/2-year-old boy with multiple papules and plaques on the face and
extremities and cervical lymphadenopathy. Histopathologic analysis showed compact
orthokeratosis, focal parakeratosis, hypergranulosis, psoriasiform epidermal
hyperplasia, and a dense lichenoid lymphohistiocytic infiltrate with extensive
exocytosis of mononuclear cells. Immunoperoxidase staining with CD 1 a revealed
clusters of Langerhans cells in the epidermis and in the papillary dermis. In
view of the clinical findings, a diagnosis of Gianotti-Crosti syndrome was made.
Although there are a few reports describing a lichenoid pattern of infiltration
in Gianotti-Crosti syndrome, this histologic pattern is not widely known. This
case is presented to illustrate the fact that Gianotti-Crosti syndrome can
present as lichenoid dermatitis, and, especially in children, should be added to
the differential diagnoses of lichenoid infiltrates.
PMID- 10770439
TI - Primary mucinous carcinoma of the skin.
AB - Primary mucinous carcinomas of the skin are very rare. To date, 120 cases have
been described in the literature. This tumor is a histologic subtype of sweat
gland carcinoma. Because of the histopathologic appearance, primary mucinous
carcinoma of the skin can be mistaken for metastasis from extracutaneous sites.
We report on the cases of two elderly women with mucinous carcinomas arising in
the scalp. Immunohistochemical staining of both tumors was positive for low
molecular-weight cytokeratin and epithelial membrane antigen. Carcinoembryonic
antigen was positive in Case 2. Neuroendocrine features represented by neuron
enolase-specific positivity were also observed in both cases, and Grimelius and
chromogranin A positivity were observed in Case 2. In both cases, there was
strong positivity for estrogen receptor and progesterone receptor. Image analysis
cytometry showed a diploid DNA content with a low rate of proliferative cells and
negativity for p53 and c-erbB-2 proteins in agreement with the low aggressiveness
of these neoplasms.
PMID- 10770440
TI - Eccrine syringofibroadenoma (Mascaro): an immunohistochemical study.
AB - Eccrine syringofibroadenoma is an uncommon benign eccrine tumor, which was first
described by Mascaro in 1963. It usually develops on the extremities of elderly
persons. We report on a 74-year-old man who presented with a 2-year history of a
slowly growing lesion on his face. A detailed histologic and immunohistochemical
study was performed on the biopsy material. The tumor consisted of epidermal
derived anastomosing thin epithelial cords embedded in a fibrovascular stroma.
The epithelial cords contained ductal and cystic structures lined by luminal
cells, which were decorated by antibodies against carcinoembryonic antigen,
keratin K19, K8, and K18. Antibody to keratin K6 decorated the luminal walls of
the acrosyringia. Antibodies to filaggrin decorated the superficial luminal
structures. These results suggest dual acrosyringial and dermal duct
differentiation in syringofibroadenoma.
PMID- 10770441
TI - Epidermotropic xanthoma mimicking balloon cell melanoma.
AB - Xanthomas of the skin may mimic balloon cell melanoma because 1) both lesions may
exhibit a diffuse dermal proliferation of cytologically similar large vacuolated
or clear cells with distinct cytoplasmic membranes, 2) dermal maturation (smaller
deep dermal nuclei) is absent in both lesions, 3) melanin pigment is usually
absent in balloon cell melanoma, 4) cellular atypia may be minimal in balloon
cell melanoma, and 5) mitoses may be absent or rare in balloon cell melanoma. We
report a unique xanthoma, which further simulated melanoma by exhibiting
epidermotropism and a pseudonesting pattern at the dermal-epidermal junction. The
correct diagnosis was made with an immunohistochemical panel revealing tumor cell
positivity for CD68 and negativity for S-100 protein and MART-1.
Immunohistochemical studies may be required in the critical differential
diagnosis of epidermotropic xanthoma and amelanotic balloon cell melanoma.
PMID- 10770442
TI - Proliferation of eccrine sweat ducts associated with heterotopic neural tissue
(nasal glioma).
AB - The term "nasal glioma" refers to the presence of heterotopic neural tissue,
mainly glial in nature, at or near the root of the nose. We describe a case in
which all three components of neural tissue, that is, leptomeninges, glia, and
neurons, were present, associated with sweat-duct hyperplasia. Proliferation of
sweat ducts is a reactive process in some benign and malignant neoplasms,
hamartomas, and cysts. This is the first documented case of hyperplasia of
eccrine ductal epithelium induced by nasal glioma.
PMID- 10770443
TI - Proliferating trichilemmal cyst with focal invasion: report of a case and a
review of the literature.
AB - Proliferating trichilemmal cyst (PTC) is a rare but morphologically distinctive
tumor that usually occurs in the scalp of elderly women. Furthermore, only 30
well-documented examples of so-called malignant PTC have been reported.
Alternatively, some authors have recently proposed that PTC is squamous cell
carcinoma. We describe a case of PTC with focal invasion that was
indistinguishable from squamous cell carcinoma in areas, and we review the
literature. This debate should be considered in PTCs to provide adequate
treatment (wide local excision) and follow-up (long term), particularly in large
and long-standing lesions.
PMID- 10770444
TI - A lymphomatoid papule, but not lymphomatoid papulosis!
PMID- 10770445
TI - Histopathologic diagnosis of superficial soft tissue tumors, related lesions, and
simulators: an algorithmic approach based on colors: tumors with predominance of
pink.
AB - An algorithmic approach based on colors for histopathologic diagnosis of soft
tissue tumors and their simulators is proposed. At scanning magnification, in
specimens stained with hematoxylin and eosin, mesenchymal tumors can be
classified according to their color. The color of a tumor is basically determined
by density, morphology, and distribution of neoplastic cells, and by density and
quantity of the stroma. The basic colors that can be observed by neoplasms
stained with hematoxylin and eosin are white, pink, red, and blue. Colors may be
used as a first step in choosing the algorithm for specific diagnosis of a given
mesenchymal neoplasm. Furthermore, colors may be helpful in understanding the
histogenesis of a tumor, and this is especially important in soft tissue
pathology, because criteria for benignancy and malignancy vary according to the
nature of the neoplasm. In this article, tumors with a predominance of pink are
analyzed. Pink tumors are composed of cells with abundant eosinophilic cytoplasm
and sparse chromatin in their nuclei, such as leiomyoma. In other cases, the pink
color in a tumor is determined by abundant fibrous stroma rather than by
characteristics of neoplastic cells, such as sclerotic fibroma.
PMID- 10770446
TI - Pestilence narratives in classical literature: a study in creative imitation: I.
Homer, Sophocles, Thucydides, and Lucretius.
PMID- 10770447
TI - Contraceptive effectiveness: cytochromes and induction.
PMID- 10770448
TI - Evaluation of sexual functioning in depressed outpatients: a double-blind
comparison of sustained-release bupropion and sertraline treatment.
AB - Sexual dysfunction is a frequently reported side effect of many antidepressants,
including serotonin reuptake inhibitors. Bupropion, an antidepressant of the
aminoketone class, is relatively free of adverse sexual effects. In a randomized,
double-blind, multicenter trial, sustained-release bupropion (bupropion SR) and
sertraline, a selective serotonin reuptake inhibitor, were found to be similarly
efficacious in the treatment of outpatients with moderate to severe depression.
This report describes the results of a double-blind comparison of the sexual side
effect profiles of bupropion SR and sertraline. Two hundred forty-eight patients
who had received a diagnosis of moderate to severe major depression were randomly
assigned to receive treatment with bupropion SR (100-300 mg/day) or sertraline
(50-200 mg/day) for 16 weeks. Eligible patients were required to be in a stable
relationship and to have normal sexual functioning. Sexual functioning was
assessed by the investigator at each clinic visit using investigator-rated
structured interviews. A significantly greater percentage of sertraline-treated
patients (63% and 41% of men and women, respectively) developed sexual
dysfunction compared with bupropion SR-treated patients (15% and 7%,
respectively). Sexual dysfunction was noted as early as day 7 in sertraline
treated patients at a dose of 50 mg/day and persisted until the end of the 16
week treatment phase. Four patients, all of whom were treated with sertraline,
discontinued from the study prematurely because of sexual dysfunction. Given the
similar efficacy of the two drugs in treating depression, bupropion SR may be a
more appropriate antidepressant choice than sertraline in patients for whom
sexual dysfunction is a concern.
PMID- 10770449
TI - Nefazodone treatment of major depression in alcohol-dependent patients: a double
blind, placebo-controlled trial.
AB - Depression is the most common comorbid psychiatric illness in patients with
alcohol dependence. This double-blind study tested the efficacy of nefazodone
versus placebo for the treatment of depression in actively drinking alcohol
dependent patients who were also participating in weekly group treatment for
alcoholism. Sixty-four subjects with major depression disorder and alcohol
dependence with a history of at least one prior episode of depression when not
drinking were randomly assigned to receive 12 weeks of either nefazodone or
placebo and participated in a weekly psychoeducational group on alcoholism.
Subjects were assessed every 2 weeks for depression, anxiety, side effects, and
drinking frequency. Subjects taking nefazodone were significantly more likely to
complete the study (62%) than those taking placebo (34%). Analyses of covariance
using drinks per week as a time-dependent covariate showed lower Hamilton Rating
Scale for Depression scores at week 8 for end-point analysis and at weeks 8 and
12 for completers. The endpoint analysis demonstrated a significantly greater
response in the nefazodone group (48%) than in the placebo group (16%). Both
groups showed a similarly significant decrease in the average number of alcoholic
drinks consumed per day over the course of the study. Although the number of
adverse effects was significantly greater for the nefazodone group, there were no
severe adverse events, and nefazodone was well tolerated. Nefazodone is a safe
and effective antidepressant to use in a population of alcohol-dependent patients
with depression who have a high degree of comorbidity. Nefazodone treatment was
superior to placebo in alleviating depression in these patients but did not add
any advantage over the psychoeducational group in terms of drinking outcomes.
PMID- 10770450
TI - Evaluation of platelet activation in depressed patients with ischemic heart
disease after paroxetine or nortriptyline treatment.
AB - This study investigated the effects of antidepressant treatment on platelet
activation in depressed patients with ischemic heart disease (IHD). Plasma levels
of platelet alpha-granule release products beta-thromboglobulin (BTG) and
platelet factor 4 (PF4) were measured in 17 depressed patients with IHD who were
treated in a 6-week, double-blind trial with either paroxetine (10 patients) or
nortriptyline (7 patients). Baseline measurements of BTG and PF4 were
significantly elevated in both drug treatment groups before the initiation of
antidepressant therapy compared with those of healthy control subjects. In the
paroxetine group, mean PF4 and BTG levels significantly decreased from these
elevated baseline values within 1 week of treatment and remained low at 3- and 6
week measurements. In contrast, the nortriptyline group did not exhibit a
significant decrease in PF4 or BTG plasma levels after 1, 3, or 6 weeks of
treatment. Therefore, platelet activation in depressed patients with IHD seems to
be inhibited by the selective serotonin reuptake inhibitor paroxetine. The effect
of paroxetine on PF4 and BTG plasma levels suggests that it may reduce platelet
aggregation in vivo and may positively impact IHD-related mortality in this
population.
PMID- 10770451
TI - Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in
Japanese patients: impact of CYP2D6 genotype on the hydroxylation of
nortriptyline.
AB - The authors investigated the impact of the CYP2D6 genotype on steady-state
concentrations of nortriptyline (NT) and its metabolites, trans-10
hydroxynortriptyline (EHNT) and cis-10-hydroxynortriptyline in a Japanese
population of psychiatric patients. Forty-one patients (20 men and 21 women) were
orally administered nortriptyline hydrochloride. The allele frequencies of the
CYP2D6*5 and CYP2D6*10 were 4.9% and 34.1%, respectively. Significant differences
in NT concentrations corrected for dose and weight were observed between the
subjects with no mutated alleles and those with one mutated allele (mean +/- SD
for no mutated alleles vs. one mutated allele: 70.3 +/- 25.4 vs. 98.4 +/- 36.6
ng/mL x mg(-1) x kg(-1); t = 2.54, dcf = 33, p < 0.05) and between the subjects
with no mutated alleles and two mutated alleles (no mutated alleles vs. two
mutated alleles: 70.3 +/- 25.4 vs. 147 +/- 31.1 ng/mL x mg(-1) x kg(-1); t =
5.87, df = 19, p < 0.0001). Also, a significant difference in the NT/EHNT ratio,
which is representative of the hydroxylation ratio of NT, was observed between
the subjects with no mutated alleles and those with two mutated alleles (no
mutated alleles vs. two mutated alleles: 0.82 +/- 0.30 vs. 2.71 +/- 0.84; t =
7.86, df = 19, p < 0.0001). Multiple regression analysis showed that the number
of mutated alleles of CYP2D6, which was the only significant factor, accounted
for 41% and 48% of the variability in log(NT corrected for dose and weight) and
log(NT/EHNT), respectively.
PMID- 10770452
TI - Dose-response evaluation of the interaction between sertraline and alprazolam in
vivo.
AB - In vitro data show the inhibition of alprazolam metabolism by sertraline via
CYP3A4; therefore, using a randomized, double-blind, placebo-controlled design,
the authors conducted this study to assess the potential for similar in vivo
inhibition in humans. Ten healthy volunteers participated in two test sessions
(placebo/alprazolam 1 mg orally) before the initiation of sertraline treatment.
Blood samples were obtained over a 32-hour period and pharmacodynamic measures
(sedation, psychomotor performance, memory function) were obtained over an 8-hour
period. After a minimum of 2 weeks of daily sertraline self-administration (50,
100, or 150 mg/day), test sessions were repeated. Alprazolam concentrations (N =
6, 4, and 6 at sertraline doses of 50, 100, and 150 mg/day, respectively) showed
no significant changes based on peak concentration (Cmax), time to maximum
concentration (Tmax), elimination half-life (t1/2[beta]), and area under the
concentration-time curve (AUC(0-8)), with the exception of a reduced Cmax in the
50 mg/day group. Similarly, dynamic data showed no significant variations based
on peak effect, Tmax, and AUC(0-infinity), with the exception of increased peak
impairment in one measure of psychomotor performance. No differences were
detected between placebo alone and placebo plus sertraline. These findings
suggest that sertraline (50-150 mg/day) does not alter the single-dose kinetics
or dynamics of alprazolam; therefore, the combination may be prescribed without
an increased risk of alprazolam toxicity.
PMID- 10770453
TI - Nefazodone treatment for chronic posttraumatic stress disorder: an open trial.
AB - Currently, there is no standard treatment for posttraumatic stress disorder
(PTSD) because of a deficit of systematic treatment trials. The symptom overlap
with other mood and anxiety disorders that respond to antidepressants and the
results of a limited number of antidepressant trials indicate promise for
psychopharmacologic treatment. Several open trials and one controlled trial with
selective serotonin reuptake inhibitors have reported improvement in the
symptomatology of PTSD. In this study, a relatively new serotonergic
antidepressant, nefazodone, was tested as a treatment for PTSD. Veterans with
chronic PTSD (N = 36) were enrolled in an 8-week open-label trial of nefazodone.
The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS).
Thirty-one patients completed at least 4 weeks of treatment, which was considered
to be an adequate trial, and 26 patients completed the 8-week study. During
treatment, there was a significant decrease in the total CAPS score and in each
of three CAPS subscale scores, with most of the improvement occurring during the
first 4 weeks. Comparable improvements were also seen on the Hamilton Rating
Scales for Anxiety and for Depression. Nefazodone treatment was well tolerated by
this patient population, with only four patients discontinuing because of adverse
effects. In summary, nefazodone treatment improved the symptoms of PTSD,
including the core symptoms. Placebo-controlled studies should be undertaken to
further elucidate the efficacy of nefazodone in the treatment of PTSD.
PMID- 10770454
TI - Increased sensitivity to stress in spontaneous recurrence of methamphetamine
psychosis: noradrenergic hyperactivity with contribution from dopaminergic
hyperactivity.
AB - The significance of increased sensitivity to stress associated with noradrenergic
hyperactivity involving dopaminergic change in spontaneous recurrences of
methamphetamine (MAP) psychosis (flashbacks) was examined. Plasma monoamine
metabolite levels were assayed in 18 subjects with flashbacks who had been
exposed to stressful events plus MAP-induced frightening psychotic symptoms (N =
11) or frightening psychotic symptoms alone (N = 7) during previous MAP use, in
15 nonflashbackers with a history of MAP psychosis, in 8 subjects with persistent
MAP psychosis, and in 27 control subjects. Monoaminergic values were subjected to
a square-root transformation, rendering the distribution normal. The numbers of
stressful events (mostly threatening events) and frightening psychotic symptoms
were significantly higher in the flashbackers than in the nonflashbackers.
Factors triggering flashbacks were mild psychosocial stressors (mostly a mild
fear of other people). During flashbacks, plasma norepinephrine levels increased,
and the flashbackers, 11 of whom had experienced stressful events plus
frightening psychotic symptoms, had an additional small increase in plasma levels
of 3-methoxytyramine, which is indicative of dopamine release. Thus, threatening
stressful events, together with MAP use, may induce noradrenergic hyperreactivity
to subsequent mild stressors. Threatening, stressful events plus frightening
psychotic symptoms may further induce increased dopamine release in response to
mild stressors. Increased sensitivity to stress associated with noradrenergic
hyperactivity involving increased dopamine release may have elicited memories of
MAP psychosis related to frightening, stressful experiences. The increased
sensitivity may be critical for the development of flashbacks.
PMID- 10770455
TI - Interindividual variation in bromperidol metabolism and relationship to
therapeutic effects.
AB - Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were
determined in 31 patients with schizophrenia who were administered BRP for their
psychiatric symptoms. Activities of carbonyl reductase in red blood cells were
assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged
from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP
ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values
notably lower than the previously reported values of reduced haloperidol to
haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP
reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood
cells, which was at approximately the same level as that of HAL reductase.
Patients with positive responses to BRP treatment were evaluated using the Brief
Psychiatric Rating Scale. We found that the number of patients who had a positive
response to BRP did not increase after BRP plasma levels had reached the level of
12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy
of schizophrenia occurs, and there is no advantage to raising the dose once this
plateau is reached.
PMID- 10770456
TI - Pharmacologic profile of perphenazine's metabolites.
AB - The authors have previously reported that in elderly patients treated with low
doses of perphenazine, few extrapyramidal symptoms (EPS) developed in those who
were not poor CYP2D6 metabolizers. The authors hypothesized that this atypical
side effect profile is due to perphenazine's principal metabolite, n
dealkylperphenazine (DAPZ), which is usually present in vivo at concentrations
1.5 to 2 times that of the parent drug. Perphenazine, DAPZ, and 7
hydroxyperphenazine affinities were examined in vitro by competition-binding
analysis to isolated human receptors expressed in transfected cell lines.
Perphenazine and metabolite effects were examined in vivo in 54 older patients
who were treated with perphenazine, at a target dose of 0.1 mg/kg, for 10 to 17
days. Drug concentrations were determined by high-performance liquid
chromatography with electrochemical detection. In in vitro binding studies, DAPZ
demonstrated a higher affinity for serotonin-2A receptors than for dopamine-2
receptors to an extent comparable to that of some atypical neuroleptic agents. In
contrast, perphenazine and 7-hydroxyperphenazine demonstrated a higher affinity
for dopamine-2 receptors than for serotonin-2A receptors. The mean +/- SD
concentrations in the 54 subjects were the following: perphenazine, 1.5 +/- 1.4
ng/mL; DAPZ, 2.0 +/-1.6 ng/mL; and 7-hydroxyperphenazine, 0.8 +/- 1.9 ng/mL. The
mean +/- SD quotient for the DAPZ/perphenazine concentration was 1.7 +/- 1.1 and
for the 7-hydroxyperphenazine/perphenazine was 0.54 +/-1.6. EPS onset was not
correlated with the perphenazine concentration, the metabolite concentrations,
the DAPZ/perphenazine quotient, or the 7-hydroxyperphenazine/perphenazine
quotient. Despite a moderately atypical receptor-binding profile, DAPZ does not
seem to moderate perphenazine effects in vivo in older patients. This outcome
likely reflects the low potency of DAPZ for dopamine-2 and serotonin-2A receptors
relative to the potency of perphenazine for these receptors. Further exploration
of atypical properties of DAPZ should include de novo administration of this
metabolite in animal models.
PMID- 10770457
TI - Tardive dyskinesia associated with higher mortality in psychiatric patients:
results of a meta-analysis of seven independent studies.
AB - This article reports a meta-analysis of seven independent studies on the
association of tardive dyskinesia with all-cause mortality in psychiatric
patients. Most of the studies included provide either small sample sizes or
follow-up periods too short to reach a substantive conclusion on their own. In
the meta-analysis, the overall odds ratio (OR) was significant when calculated
either by the fixed-effects model (OR = 1.4, 95% confidence interval [CI] = 1.2
1.7, p < 0.005) or the random-effects model (OR = 1.4, 95% CI = 1.1-1.8, p <
0.005). There was no overall heterogeneity (Q test = 8.1, df = 7,p = 0.32). The
overall estimate changed within study designs (OR = 1.4,p = 0.002 in three
prospective controlled studies; OR = 2.2, p = 0.02 in two prospective
uncontrolled studies; and OR = 0.9, p = 0.80 in two retrospective controlled
studies). It was modified upward when the two most influential studies (one
prospective and one retrospective) were removed from the overview (OR = 2.2, 95%
CI = 1.4-3.5,p = 0.001; Q test = 0.81, df = 4,p = 0.94). The conclusion of the
meta-analysis was that tardive dyskinesia must be considered a weak risk factor
in terms of mortality. It remains to be elucidated whether it is a risk factor on
its own or just a surrogate for any unknown organic liability.
PMID- 10770458
TI - Valproate as an adjunct to neuroleptic medication for the treatment of acute
episodes of mania: a prospective, randomized, double-blind, placebo-controlled,
multicenter study. European Valproate Mania Study Group.
AB - To compare the efficacy of sodium valproate administered as adjunct to
neuroleptic medication for patients with acute mania with the efficacy of
neuroleptics alone, the authors conducted a 21-day, randomized, double-blind,
parallel-group, placebo-controlled trial. The study design closely reflected a
clinical psychiatric setting in Europe where patients with acute mania commonly
receive neuroleptic medication. In this trial, 136 hospitalized patients met the
ICD-10 criteria for acute manic episodes; these patients received a fixed dose of
20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH,
Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably
haloperidol and/or perazine. The primary outcome measure was the mean dose of
neuroleptic medication (after conversion into haloperidol-equivalents) for the 21
day study period. Severity of symptoms was measured using the Young Mania Rating
Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression
Scale. Intent-to-treat analysis was based on 69 patients treated with valproate
and 67 patients who received placebo. Groups were comparable with regard to
demographic and clinical baseline data. Premature discontinuations occurred in
only 13% of the patients. The mean neuroleptic dose declined continuously in the
valproate group, whereas only slight variations were observed in the placebo
group; the difference was statistically significant (p = 0.0007) for study weeks
2 and 3. The combination of neuroleptic and valproate proved superior to
neuroleptics in attempts to alleviate manic symptoms. The proportion of
responders (a 50% improvement rate shown on the YMRS) was higher for the
combination with valproate than for the group receiving only neuroleptics (70%
vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or
neuroleptics; the only adverse event was asthenia, which occurred more frequently
with the combination therapy. Valproate represents a useful adjunct medication
for the treatment of acute manic symptoms. Valproate is beneficial because it
allows the administration of fewer neuroleptic medications and produces improved
and quicker remission of manic symptoms.
PMID- 10770459
TI - Thyroid function and psychiatric morbidity in patients with manic disorder
receiving lithium therapy.
AB - Euthyroid hyperthyroxinemia as a result of a transient increase in thyroid
stimulating hormone (TSH) levels may contribute to the development of manic
disorder. Lithium has a potent short-term antithyroidal effect that may account
for its antimanic action. The thyroid function and psychiatric morbidity of 46
adult patients with manic disorder were assessed prospectively before and 1 and 6
months after lithium treatment. At baseline, the free thyroxine level (FT4, 16.23
+/- 3.11 pmol/L) was at the high end of the normal range, whereas the free
triiodothyronine (FT3, 4.24 +/- 0.65 pmol/L) and TSH (1.47 +/- 0.73 mIU/L) levels
were within the normal range. All patients were clinically euthyroid, but five of
them (11%) had elevated FT4 levels. Baseline FT3 and FT4 levels were positively
correlated with past psychiatric morbidity. The FT4 level at baseline and after 1
month of treatment was positively correlated with scores on the Brief Psychiatric
Rating Scale (p < 0.02) and negatively correlated with scores on the Global
Assessment Scale (p < 0.005). During the first month of treatment, the reduction
of FT3 and FT4 levels was significantly correlated with a decrease in psychiatric
symptoms. By 6 months, the FT3 level was no longer significantly different from
that at the baseline, but FT4 levels remained significantly lower. The TSH level
increased progressively from baseline to 6 months. Multilevel models showed that
FT4 and serum lithium levels were positively and negatively associated with
psychiatric symptoms, respectively. The findings of the study lend support to the
notion that euthyroid hyperthyroxinemia contributes to acute mania and suggest
that lithium's short-term antimanic action may be mediated by its antithyroid
effect.
PMID- 10770460
TI - Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in
schizophrenic patients: no relationship with clinical variables during short-term
treatment.
AB - In an open clinical trial, serum concentrations of haloperidol pyridinium
(C(HP+)) and reduced haloperidol pyridinium (C(RHP+)), as well as haloperidol
(CH) and reduced haloperidol (C(RH)), were measured in 57 schizophrenic and
schizoaffective inpatients during 6 weeks of short-term treatment.
Psychopathology was monitored with the Brief Psychiatric Rating Scale (BPRS), and
extrapyramidal adverse effects were assessed with the Extrapyramidal Symptom
Rating Scale (EPS). Significantly linear relationships were found between
haloperidol dose (D) and pyridinium metabolite serum concentrations, as well as
between C(H) and the pyridinium metabolite serum concentrations. C(HP+) (range,
0.2-4.9 ng/mL) and C(RHP+) (range, 0.03-6.23 ng/mL) were low compared with C(H)
and C(RH), being as mean values approximately 7% and 14% of C(H) and C(RH),
respectively. Additionally, the values of C(RHP+) and the slope of the
correlation of C(H) with the C(RHP+)/C(HP+) ratio were considerably lower than in
a previous report of long-term treatment with haloperidol. This is explained by
the shorter time of treatment of the present study. Carbamazepine comedication
was found to not influence relative pyridinium metabolite serum concentrations
C(HP+)/D and C(RHP+)/D. However, the aromatization ratios of haloperidol
(C(HP+)/C(H)) and reduced haloperidol (C(RHP+)/C(RH)) were increased by
concomitant carbamazepine. As the main result, no relationships between the
pyridinium metabolite serum concentrations and clinical variables (BPRS change,
EPS, dose of biperiden) were detected. For instance, the aromatization ratios
C(HP+)/C(H) and C(RHP+)/C(RH) did not predict clinical improvement or
extrapyramidal adverse effects. Therefore, no confirmation of the "pyridinium
hypothesis," which suggests haloperidol pyridinium metabolites to be the origin
of adverse effects and decreased therapeutic effect, can be derived from this
study. However, the authors emphasize that pyridinium metabolites cannot be
excluded as the origin of decreased therapeutic effect in long-term treatment and
of adverse effects not investigated in the present study, such as tardive
dyskinesia. Finally, it is concluded that the serum concentration of the parent
drug remains the main variable of interest in the therapeutic drug monitoring of
haloperidol during short-term treatment.
PMID- 10770461
TI - Olanzapine pharmacokinetics in pediatric and adolescent inpatients with childhood
onset schizophrenia.
AB - Well-designed studies investigating how pediatric or adolescent patients with
mental disorders respond to and metabolize the newer antipsychotic drugs are
practically nonexistent. Without such data, clinicians have difficulty designing
appropriate dosage regimens for patients in these age groups. The results from a
study of olanzapine pharmacokinetics in children and adolescents are described.
Eight inpatients (ages 10-18 years) with treatment-resistant childhood-onset
schizophrenia received olanzapine (2.5-20 mg/day) over 8 weeks. Blood samples,
collected during dose titration and at a steady state provided pharmacokinetic
data. The final evaluation (week 8) included extensive sampling for 36 hours
after a 20-mg dose. Olanzapine concentrations in these eight pediatric patients
were of the same magnitude as those for nonsmoking adult patients with
schizophrenia but may be as much as twice the typical olanzapine concentrations
in patients with schizophrenia who smoke. Olanzapine pharmacokinetic evaluation
gave an apparent mean oral clearance of 9.6 +/- 2.4 L/hr and a mean elimination
half-life of 37.2 +/- 5.1 hours in these young patients. The determination of the
initial olanzapine dose for adolescent patients should take into consideration
factors such as the patient's size. In general, however, the usual dose
recommendation of 5 to 10 mg once daily with a target dose of 10 mg/day is likely
a good clinical guideline for most adolescent patients on the basis of our
pharmacokinetics results.
PMID- 10770462
TI - Effects of lorazepam on emotional reactivity, performance, and vigilance in
subjects with high or low anxiety.
AB - This study examined the hypothesis that low doses of lorazepam modify emotional
response. In accord with the results of prior studies that suggest a differential
effect of benzodiazepines according to the subjects' anxiety level, the authors
tested the effect of lorazepam (0.5 mg twice daily) on 2 groups of 32 subjects:
those with high anxiety (HA) and those with low anxiety (LA). These groups were
formed a priori on the basis of their scores on the Cattell Anxiety Scale and the
Hamilton Rating Scale for Anxiety. The two groups were evaluated for psychomotor
function and vigilance (visual analog scales [VAS], digit-symbol substitution
test [DSST], and choice reaction time [CRT]), as well as emotional reactivity.
Six emotions (fear, anger, disgust, sadness, joy, and neutral state) were induced
by the presentation of six movie excerpts, and subjects' emotional responses were
measured using the Differential Emotions Scale. The results suggest that at the
doses studied, lorazepam led to an increase in negative emotions and a decrease
in positive emotions, compared with placebo. This shift of emotional reactivity
toward more negative emotions was slightly stronger with the HA than with the LA
subjects. However, no reliable differences in the levels of performance and
vigilance (CRT, DSST, and VAS) were observed as a function of either treatment or
subject group. These findings suggest a possible relationship between
benzodiazepine effects and subjects' anxiety level.
PMID- 10770463
TI - Oxidative and nonoxidative benzodiazepines and the risk of femur fracture. The
Systematic Assessment of Geriatric Drug Use Via Epidemiology Study Group.
AB - Benzodiazepine use is a well-identified risk factor for falls and the resulting
femur fractures in elderly adults. Benzodiazepines not requiring hepatic
biotransformation may be safer than agents undergoing oxidation because oxidative
activity has been shown to decline with age. The association between the use of
either oxidative or nonoxidative benzodiazepines and the risk of femur fracture
among elderly adults living in nursing homes was studied. A nested case-control
study was conducted using the Systematic Assessment of Geriatric drug use via
Epidemiology (SAGE) database; the records of 9,752 patients hospitalized for
incident femur fracture during the period 1992 to 1996 were extracted, matching
by age, gender, state, and index date to the records of 38,564 control patients.
Conditional logistic regression models were conducted to estimate the odds ratios
(ORs) for femur fracture with adjustment for potential confounders. The adjusted
OR for the overall use of benzodiazepines was 1.10 (95% confidence interval [CI],
0.98-1.20); the risk seemed of only slightly greater magnitude for exposure to
nonoxidative agents (1.18; 95% CI, 1.03-1.36) than to oxidative benzodiazepines
(1.08; 95% CI, 0.95-1.23). Among the latter, the effect was mainly accounted for
by the use of agents with a long elimination half-life. A dose relationship was
observed exclusively among users of long half-life oxidative benzodiazepines. The
risk associated with the use of nonoxidative benzodiazepines showed no
relationship to the age of the patients. In contrast, patients aged 85 years or
older receiving oxidative benzodiazepines at high dosages or as needed had a two-
to three-fold increased risk of femur fracture than did patients in the younger
age group. Among older individuals, the use of benzodiazepines slightly increased
the risk of femur fracture, mainly irrespective of the metabolic fate of the
drug. Our results suggest that the use of nonoxidative benzodiazepines does not
carry a lower risk for femur fracture than does the use of oxidative
benzodiazepines. However, the latter agents may be associated with a somewhat
higher risk of side effects among the oldest old, especially at higher dosages.
PMID- 10770464
TI - Subject selection for the placebo- and comparator-controlled trials of
neuroleptics in schizophrenia.
AB - It has been suggested that inclusion of a placebo treatment arm in controlled
clinical trials might bias the selection of study subjects. Presumably, patients
in the placebo-controlled studies are more stable, but there are no data
available to support such an assumption. The authors tested the hypothesis in a
set of randomized trials of neuroleptics in treating schizophrenia by comparing
placebo-controlled (PCTs) and comparator-controlled trials (CCTs) in terms of
basic patient characteristics. The results, based on a total of 296 studies,
showed that the patients in PCTs, compared with those in CCTs, were older (p <
0.002), had a longer duration of illness (p < 0.001), and a lower initial symptom
severity (p < 0.02). No difference was found in the number of subjects per
treatment arm or in the proportion of female subjects. However, investigation of
studies which used same-gender study subjects revealed that female-only
populations were more likely to be tested in PCTs (p < 0.03) than in CCTs. To
investigate current trends in psychopharmacologic research, the authors tested
separately a subset of trials of new atypical antipsychotics. The results
indicated a significantly smaller number of females participating in the latest
PCTs (p < 0.0003). Moreover, our findings suggest that the characteristics of
patients in the current controlled trials are rather uniform; thus, the
generalizability of new study findings for certain groups of patients with
schizophrenia (e.g., with early or late onset or brief duration of illness) may
be compromised.
PMID- 10770465
TI - Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on
outcome and costs associated with severe mental illness.
AB - The influence of cytochrome P450 2D6 (CYP2D6) genetic variability was examined in
psychiatric inpatients by evaluating adverse drug events (ADEs), hospital stays,
and total costs over a 1-year period in an extension of a previously published
brief report. One hundred consecutive psychiatric patients from Eastern State
Hospital in Lexington, Kentucky, were genotyped for CYP2D6 expression. ADEs were
evaluated by a neurologic rating scale, modified Udvalg for Kliniske
Undersogelser Side Effect Rating Scale, or chart review. Information on total
hospitalization days and total costs were gathered for a 1-year period. Forty
five percent of the patients received medications that were primarily dependent
on the CYP2D6 enzyme for their elimination. When the analysis was restricted to
just those patients in each group receiving medication heavily dependent on the
CYP2D6 enzyme, the following were observed: (1) a trend toward greater numbers of
ADEs from medications as one moved from the group with ultrarapid CYP2D6 activity
(UM) to the group with absent CYP2D6 activity (PM); (2) the cost of treating
patients with extremes in CYP2D6 activity (UM and PM) was on average $4,000 to
$6,000 per year greater than the cost of treating patients in the efficient
metabolizer (EM) and intermediate metabolizer (IM) groups; and (3) total duration
of hospital stay was more pronounced for those in CYP2D6 PM group. Variance of
hospital stays and costs calculated from these preliminary data suggests that
1,500 to 2,000 patients must be evaluated over at least a 1-year period to
determine whether the CYP2D6 genetic variation significantly alters the duration
of hospital stay and costs.
PMID- 10770466
TI - High-dose treatment with haloperidol: the effect of dose reduction.
AB - High doses of antipsychotic medications are sometimes prescribed in clinical
practice, although the efficacy and safety of such treatment have not been
established. The purpose of this study was to determine whether high-dose, long
term antipsychotic treatment prescribed on the basis of clinical judgment can be
justified. Patients who were receiving high doses of haloperidol were screened,
and those patients whose plasma levels were at least 15 ng/mL were randomly
assigned to an experimental group (N = 11) or to a control group (N = 12). The
experimental group underwent a dose reduction to achieve the target plasma level
of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control
group treatment was maintained at the original level. Both groups were then
followed up for another 16 weeks, during which the plasma levels of haloperidol
were kept constant. The study used double-blind procedures. Both groups showed an
average slight symptom reduction. There was no significant difference in the
severity of symptoms between the two groups at any time point. The dose reduction
had no apparent adverse effects. Thus, the results of this study did not provide
justification for high-dose, long-term antipsychotic treatment. However, these
results must be interpreted with caution because the sample studied here was
small and biased.
PMID- 10770467
TI - Residual catatonic state following neuroleptic malignant syndrome.
AB - Neuroleptic malignant syndrome (NMS) is usually a self-limited disorder, with
most cases resolving within 2 weeks after antipsychotic drug discontinuation.
However, the course of NMS may not always be short-lived. In this report, the
authors describe five patients who developed a residual catatonic state that
persisted after acute hyperthermic symptoms of NMS had subsided and compare them
with 27 similar cases in the literature. Two of our patients recovered gradually
with supportive treatment. Three patients were treated with electroconvulsive
therapy (ECT). Of these, two showed a positive response, although one died later
of intercurrent pneumonia. A third patient did not respond to ECT, but recovered
gradually thereafter. Although dopamine agonists or benzodiazepines have been
advocated for the treatment of residual symptoms in previous case reports, ECT
was the treatment most often associated with a rapid response and no mortality,
even in patients refractory to pharmacotherapy. In conclusion, catatonic and
parkinsonian symptoms of NMS may persist as a residual state lasting for weeks to
months after more fulminant acute symptoms abate. These residual symptoms may be
more likely to develop in patients with pre-existing structural brain disorders.
Although patients may improve gradually with supportive care or pharmacotherapy,
ECT can often be highly effective in treating the residual catatonic state that
follows NMS.
PMID- 10770468
TI - Hypercalcemia, arrhythmia, and mood stabilizers.
AB - Recent findings in a bipolar patient receiving maintenance lithium therapy who
developed hypercalcemia and severe bradyarrhythmia prompted the authors to
conduct a retrospective study of bipolar patients with lithium-associated
hypercalcemia. A printout of all cases of hypercalcemia that presented during a 1
year period was generated. After eliminating spurious hypercalcemias or those
associated with intravenous fluids, the authors identified 18 non-lithium-treated
patients with hypercalcemias related to malignancies and other medical conditions
(group A) and 12 patients with lithium-associated hypercalcemia (group B).
Patients in group B were not comparable to those in group A, as the latter were
medically compromised and were receiving multiple pharmacotherapies. Thus, two
control groups were generated: group C1, which included age- and sex-comparable
lithium-treated bipolar normocalcemic patients, and group C2, which included
bipolar normocalcemic patients treated with anticonvulsant mood stabilizers. The
electrocardiographic (ECG) findings for patients in group B were compared with
those of patients in groups C1 and C2. It was found that these groups did not
differ in their overall frequency of ECG abnormalities; however, there were
significant differences in the frequency of conduction defects. Patients with
hypercalcemia resulting from medical diseases and bipolar patients with lithium
associated hypercalcemia had significantly higher frequencies of conduction
defects. Patients in group A had significant mortality at 2-year follow-up (28%),
in contrast to zero mortality in the other three groups. The clinical
implications of these findings are discussed.
PMID- 10770469
TI - Mirtazapine for depression in patients with human immunodeficiency virus.
PMID- 10770470
TI - Treatment-refractory depression successfully treated with the combination of
mirtazapine and lithium.
PMID- 10770471
TI - Benztropine for venlafaxine-induced night sweats.
PMID- 10770472
TI - Tranylcypromine abuse associated with delirium and thrombocytopenia.
PMID- 10770473
TI - Unilateral facial numbness and visual blurring associated with paroxetine
discontinuation.
PMID- 10770474
TI - Naturalistic study of the weight effects of amitriptyline, fluoxetine, and
sertraline in an outpatient medical setting.
PMID- 10770475
TI - Pramipexole augmentation of a selective serotonin reuptake inhibitor in the
treatment of depression.
PMID- 10770476
TI - Nafazodone-induced palinopsia.
PMID- 10770477
TI - Correlation of valproate plasma concentrations and dose in bipolar affective
disorder.
PMID- 10770478
TI - Olanzapine: safe during clozapine-induced agranulocytosis.
PMID- 10770479
TI - Neuroleptic malignant syndrome after antipsychotic drug administration during
benzodiazepine withdrawal.
PMID- 10770480
TI - Seizures caused by possible interaction between olanzapine and clomipramine.
PMID- 10770481
TI - Update on "open study of the catechol-O-methyltransferase inhibitor tolcapone in
major depressive disorder".
PMID- 10770482
TI - Risperidone distribution and excretion into human milk: case report and estimated
infant exposure during breast-feeding.
PMID- 10770483
TI - Alprazolam, citalopram, and clomipramine for stuttering.
PMID- 10770484
TI - Lithium augmentation in treatment-resistant depression: meta-analysis of placebo
controlled studies.
PMID- 10770485
TI - Functional role of transmembrane helix 7 in the activation of the heptahelical
lutropin receptor.
AB - A member of the G protein-coupled receptor superfamily, the LH receptor (LHR),
and the two other glycoprotein hormone receptors are distinguished from the other
members by the presence of a relatively large N-terminal extracellular domain
that is responsible for high-affinity ligand binding. Transmembrane helix (TMH) 7
of LHR is amphipathic, with an extended face containing only hydrophobic side
chains and another containing both hydrophobic and polar side chains with
potential hydrogen bond donor and acceptor functions. Since several reports have
shown the importance of this helix in ligand-mediated signaling, we have used Ala
scanning mutagenesis to study eight amino acid residues of rat LHR that are
invariant in the three glycoprotein hormone receptors, Leu586, Val587, Asn593,
Ser594, Cys595, Asn597, Phe604, and Thr605. The wild type (WT) and mutant cDNAs
were transiently transfected into COS-7 cells for characterization by human CG
(hCG) binding and cAMP production. No differences were detected in dissociation
constants (K(d)S) or basal cAMP production relative to WT LHR, but three
categories of LHR mutants were distinguished from WT LHR based upon their
expression levels and responsiveness to hCG: 1) comparable or higher expression
but reduced ligand responsiveness (N593A and C595A), 2) reduced expression and
ligand responsiveness (N597A and T605A), and 3) comparable expression and
responsiveness (L586A, V587A, S594A, and F604A). Three other mutants, C595M,
F604Y, and T605Y, were comparable to WT LHR in ligand responsiveness. To provide
more information on Asn593 and Asn597, a total of 12 replacements were
investigated. Of considerable interest and potential significance was the finding
that many of the replacements in LHR resulted in either loss of function (N593A,
Q, S; N597R) or gain of function (N593R and N597Q), this being the first evidence
of a position in LHR that, depending upon the nature of the amino acid residue,
can result in constitutive activation and/or diminished responsiveness to ligand.
The results of molecular modeling and energy minimization of TMHs 6 and 7, based
on a postulated interaction between Asp556 (TMH 6) and Asn593/Asn597 (TMH 7),
indicated that, while there is not a correlation between function and predicted
energies of WT LHR and the mutants, reorientation of one or both helices is
responsible for the functional changes observed. Possible interactions of TMHs 3
and 4 and of 5 and 6 were suggested by molecular modeling. Ten mutants were
prepared of two amino acid residues that are invariant in the glycoprotein
hormone receptors and have side chain hydrogen bond donor and acceptor function,
Glu429 in TMH 3 and Asn513 in TMH 5. Expression levels and hCG-mediated signaling
were reduced in most of the LHR mutants, but none of these exhibited constitutive
receptor activation. We conclude that Glu429 is not critical for receptor
function, while Asn513 appears to be particularly important in receptor folding
and/or trafficking. The results reported herein indicate an important role for
TMH 7, and particularly Asn593 and Asn597, in the process of receptor activation.
Moreover, these two asparagines, although in close proximity to each other in TMH
7, are quite distinct in function as evidenced by certain replacements that can
lead to loss of function in one and gain of function in the other.
PMID- 10770486
TI - Divergent and composite gonadotropin-releasing hormone-responsive elements in the
rat luteinizing hormone subunit genes.
AB - GnRH pulses regulate gonadotropin subunit gene transcription in a frequency
dependent, subunit-specific manner. The alpha-subunit gene is stimulated by
constant GnRH and by rapid to intermediate pulse frequencies, while stimulation
of LHbeta subunit gene transcription requires intermediate frequency pulses. We
have defined the GnRH-responsive elements of the rat LH subunit gene promoters by
deletion/mutation analysis and transfection studies in rat pituitary cells and
two clonal gonadotrope cell lines. The alpha-subunit gene GnRH-responsive region
lies between -411 and -375 bp. The region contains two Ets-domain protein binding
sites, and mutating either site obliterates the response. DNA protein binding
studies demonstrate the two sites are not equivalent, and that Ets-1 does not
mediate this response. Studies of the LHbeta promoter reveal a major GnRH
responsive region between -456 and -342 bp. Within this region, two Sp1 binding
sites contribute to the GnRH response, and the 3'Sp1 site is also critical for
basal expression. The 5'Sp1 site partially overlaps a CArG box, and mutating the
CArG element specifically eliminates the response to pulsatile GnRH. DNA
containing this mutation cannot form intermediate mobility complexes with nuclear
proteins, but retains Sp1 binding. Mutation of the 3'Sp1 site and either the
5'Sp1 or CArG element partially restores GnRH stimulation, suggesting a
downstream element contributes to the full GnRH response. These studies
demonstrate that unique composite elements and transcription factors are
responsible for GnRH stimulation of the LH subunit genes and may contribute to
their differential responses to GnRH pulses.
PMID- 10770487
TI - Transforming growth factor-beta1 down-regulation of major histocompatibility
complex class I in thyrocytes: coordinate regulation of two separate elements by
thyroid-specific as well as ubiquitous transcription factors.
AB - Transforming growth factor (TGF)-beta1-decreased major histocompatibility complex
(MHC) class I gene expression in thyrocytes is transcriptional; it involves trans
factors and cis elements important for hormone- as well as iodide-regulated
thyroid growth and function. Thus, in rat FRTL-5 thyrocytes, TGF-beta1 regulates
two elements within -203 bp of the transcription start site of the MHC class I 5'
flanking region: Enhancer A, -180 to -170 bp, and a downstream regulatory element
(DRE), -127 to -90 bp, that contains a cAMP response element (CRE)-like sequence.
TGF-beta1 reduces the interaction of a NF-kappaB p50/fra-2 heterodimer (MOD-1)
with Enhancer A while increasing its interaction with a NF-kappaB p50/p65
heterodimer. Both reduced MOD-1 and increased p50/p65 suppresses class I
expression. Decreased MOD-1 and increased p50/p65 have been separately associated
with the ability of autoregulatory (high) concentrations of iodide to suppress
thyrocyte growth and function, as well as MHC class I expression. TGF-beta1 has
two effects on the downstream regulatory element (DRE). It increases DRE binding
of a ubiquitously expressed Y-box protein, termed TSEP-1 (TSHR suppressor element
binding protein-1) in rat thyroid cells; TSEP-1 has been shown separately to be
an important suppressor of the TSH receptor (TSHR) in addition to MHC class I and
class II expression. It also decreases the binding of a thyroid-specific trans
factor, thyroid transcription factor-1 (TTF-1), to the DRE, reflecting the
ability of TGF-beta1 to decrease TTF-1 RNA levels. TGF-beta1-decreased TTF-1
expression accounts in part for TGF-beta1-decreased thyroid growth and function,
since decreased TTF-1 has been shown to decrease thyroglobulin, thyroperoxidase,
sodium iodide symporter, and TSHR gene expression, coincident with decreased MHC
class I. Finally, we show that TGF-beta1 increases c-jun RNA levels and induces
the formation of new complexes involving c-jun, fra-2, ATF-1, and c-fos, which
react with Enhancer A and the DRE. TGF-beta1 effects on c-jun may be a pivotal
fulcrum in the hitherto unrecognized coordinate regulation of Enhancer A and the
DRE.
PMID- 10770488
TI - 5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific:
differential regulation of variant transcripts by early-life events.
AB - Glucocorticoid receptor (GR) gene expression is regulated in a complex tissue
specific manner, notably by early-life environmental events that program tissue
GR levels. We have identified and characterized several new rat GR mRNAs. All
encode a common protein, but differ in their 5'-leader sequences as a consequence
of alternate splicing of, potentially, 11 different exon 1 sequences. Most are
located in a 3-kb CpG island, upstream of exon 2, that exhibits substantial
promoter activity in transfected cells. Ribonuclease (RNase) protection analysis
demonstrated significant levels of six alternate exons 1 in vivo in rat, with
differences between liver, hippocampus, and thymus reflecting tissue-specific
differences in promoter activity. Two of the alternate exons 1 (exons 1(6) and
1(10)) were expressed in all tissues examined, together present in 77-87% of
total GR mRNA. The remaining GR transcripts contained tissue-specific alternate
first exons. Importantly, tissue-specific first exon usage was altered by
perinatal environmental manipulations. Postnatal handling, which permanently
increases GR in the hippocampus, causing attenuation of stress responses,
selectively elevated GR mRNA containing the hippocampus-specific exon 1(7).
Prenatal glucocorticoid exposure, which increases hepatic GR expression and
produces adult hyperglycemia, decreased the proportion of hepatic GR mRNA
containing the predominant exon 1(10), suggesting an increase in a minor exon 1
variant. Such tissue specificity of promoter usage allows differential GR
regulation and programming.
PMID- 10770489
TI - Subnuclear trafficking of estrogen receptor-alpha and steroid receptor
coactivator-1.
AB - We have analyzed ligand-dependent, subnuclear movements of the estrogen receptor
alpha (ERalpha) in terms of both spatial distribution and solubility
partitioning. Using a transcriptionally active green fluorescent protein-ERalpha
chimera (GFP-ERalpha), we find that 17beta-estradiol (E2) changes the normally
diffuse nucleoplasmic pattern of GFP-ERalpha to a hyperspeckled distribution
within 10-20 min. A similar reorganization occurs with the partial antagonist 4
hydroxytamoxifen; only a subtle effect was observed with the pure antagonist ICI
182,780. To examine the influence of ligand upon ERalpha association with nuclear
structure, MCF-7 cells were extracted to reveal the nuclear matrix (NM). Addition
of E2, 4-hydroxytamoxifen, or ICI 182,780 causes ERalpha to partition with the NM
bound fraction on a similar time course (10-20 min) as the spatial reorganization
suggesting that the two events are related. To determine the effects of E2 on the
redistribution and solubility of GFP-ERalpha, individual cells were directly
examined during both hormone addition and NM extraction and showed that GFP
ERalpha movement and NM association were coincident. Colocalization experiments
were performed with antibodies to identify sites of transcription (RNA pol Ilo)
and splicing domains (SRm160). Using E2 treated MCF-7 cells, minor overlap was
observed with transcription sites and a small amount of the total ERalpha pool.
Experiments performed with bioluminescent derivatives of ERalpha and steroid
receptor coactivator-1 (SRC-1) demonstrated both proteins colocalize to the same
NM-bound foci in response to E2 but not the antagonists tested. Deletion
mutagenesis and in situ analyses indicate intranuclear colocalization requires a
central SRC-1 domain containing LXXLL motifs. Collectively, our data suggest that
ERalpha transcription function is dependent upon dynamic early events including
intranuclear rearrangement, NM association, and SRC-1 interactions.
PMID- 10770490
TI - Impaired steroidogenic factor 1 (NR5A1) activity in mutant Y1 mouse
adrenocortical tumor cells.
AB - Mutants isolated from the Y1 mouse adrenocortical tumor cell line (clones 10r-9
and 10r-6) are resistant to ACTH because they fail to express the melanocortin-2
receptor (MC2R). In this study, we show that a luciferase reporter plasmid driven
by 1,800 bp of the proximal promoter region of the MC2R was expressed poorly in
the mutant cells compared with parent Y1 cells. The differential expression of
the MC2R in parent and mutant cells resulted from impaired activity of the orphan
nuclear receptor NR5A1 (SF1) on the promoter as determined by 5'-deletion
analysis. Furthermore, the activity of an SF1 expression plasmid on an SF1
dependent reporter plasmid was compromised in mutant clones. The site-specific
DNA binding properties of SF1 from parent and mutant cells did not differ as
determined in electrophoretic mobility shift assays, and the addition of the
activation domain of VP16 to the amino terminus of SF1 restored the
transcriptional activity of the protein. In addition, the levels of SF1 and other
cofactors including WT1, CBP/p300, and steroid receptor coactivator 1 did not
differ appreciably between parent and mutant cells. Taken together, these results
suggest that ACTH resistance in the mutant clones resulted from a defect that
affected the activation properties of SF1 rather than its DNA binding activity.
Consistent with the observed impairment in SF1 function, other SF1-dependent
genes, including Cyp11b1 and steroidogenic acute regulatory protein (StAR), were
poorly expressed and global steroidogenesis, as evidenced by the metabolism of
22(R)-hydroxycholesterol to steroid products, was impaired. Interestingly, MC2R,
Cyp11a, Cyp11b1, and StAR transcripts were not affected to the same degree,
suggesting that each of these genes may have a different absolute requirement for
SF1. These mutants thus provide an experimental paradigm to identify factors that
influence SF1 function and to evaluate the relative importance of SF1 in the
expression of genes essential for adrenal steroidogenesis.
PMID- 10770491
TI - Activation of estrogen receptor-alpha by the heavy metal cadmium.
AB - Previous studies from this laboratory have shown that the heavy metal cadmium
(Cd) mimics the effects of estradiol in estrogen-responsive breast cancer cell
lines. To understand the mechanism by which cadmium activates estrogen receptor
alpha (ER-alpha), the ability of cadmium to bind to and activate wild-type and
various mutants of ER-alpha was examined. When tested in transient cotransfection
assays in COS-1 cells, cadmium concentrations as low as 10(-11) M activated ER
alpha. Scatchard analysis employing either purified human recombinant ER-alpha or
extracts from ER-containing MCF-7 cells demonstrated that l09Cd binds to the ER
with an equilibrium dissociation constant of approximately 4 to 5 x 10(-10) M.
Cadmium also blocks the binding of estradiol to ER-alpha in a noncompetitive
manner (K(i) = 2.96 x 10(-10) M), suggesting that the heavy metal interacts with
the hormone-binding domain of the receptor. To study the role of the hormone
binding domain in cadmium activation, COS-1 cells were transiently cotransfected
with GAL-ER, a chimeric receptor containing the DNA-binding domain of the
transcription factor GAL4 and the hormone-binding domain of ER-alpha, and a GAL4
responsive reporter gene. Treatment of the transfected cells with either 10(-6) M
cadmium or 10(-9) M estradiol resulted in a 4-fold increase in reporter gene
activity. The effect of cadmium on the chimeric receptor was blocked by the
antiestrogen, ICI-164,384, suggesting that cadmium activates ER-alpha through an
interaction with the hormone-binding domain of the receptor. Transfection and
binding assays with ER-alpha mutants identified C381, C447, E523, H524, and D538
as possible interaction sites of cadmium with the hormone-binding domain of ER
alpha.
PMID- 10770492
TI - Involvement of SOCS-1, the suppressor of cytokine signaling, in the prevention of
prolactin-responsive gene expression in decidual cells.
AB - The cells forming the rat decidua produce PRL and PRL-related proteins and
express both the long and short forms of the PRL receptor. Yet, only a defined
subpopulation, the mesometrial cells, express the PRL-dependent alpha2
macroglobulin gene. This gene is silenced in vivo in the antimesometrial cells
and in the GG-AD cell line, derived from antimesometrial cells. To examine
whether the lack of alpha2-macroglobulin expression is due to defective
components in the PRL signaling pathway, we compared the relative expression of
Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 a and b
(Stat5 a and b), suppressor of cytokine signaling-1 (SOCS-1), and the tyrosine
phosphatase SHP-2 mRNA in mesometrial and antimesometrial decidua on days 12 and
13 of pseudopregnancy, the time of maximal alpha2-macroglobulin expression. We
found no significant differences in the relative expression of either Jak2, Stat5
(a and b), or SHP-2 in the two cell populations. However, we discovered a
profound difference in the expression of SOCS-1, an inhibitor of the Jak/Stat
pathway. This gene was highly expressed in the antimesometrial cells and in the
GG-AD cells, which do not produce alpha2-macroglobulin. Immunoprecipitation
experiments with GG-AD cells revealed that although Jak2 and Stat5 coprecipitate
in response to PRL stimulation, no phosphorylation of Jak2 and Stat5 could be
observed. To examine whether SOCS-1 plays a role in silencing the alpha2
macroglobulin gene, we cultured GG-AD cells in the presence of either a SOCS-1
antisense oligonucleotide or an irrelevant oligonucleotide for 4, 12, and 28 h.
Cells were also treated with PRL. Within 4 h of SOCS-1 antisense treatment,
alpha2-macroglobulin mRNA expression was initiated. After 28 h, only cells
treated with PRL and SOCS-1 antisense oligonucleotide retained the ability to
express the alpha2-macroglobulin gene. In summary, results of this study reveal
that constitutive expression of SOCS-1 can prevent PRL signaling and that the
lack of PRL-induced expression of alpha2-macroglobulin in a defined decidual cell
population is largely due to SOCS-1 expression in these cells.
PMID- 10770493
TI - Prolactin (PRL)-PRL receptor system increases cell proliferation involving JNK (c
Jun amino terminal kinase) and AP-1 activation: inhibition by glucocorticoids.
AB - PRL receptor (PRLR) signal transduction supports PRL-induced
growth/differentiation processes. While PRL is known to activate Jak2-Stat5
(signal transducer and activator of transcription 5) signaling pathway, the
mechanism by which cell proliferation is stimulated is less known. We show that
PRL induces proliferation of bovine mammary gland epithelial cells and AP-1 site
activation. Using PRLR mutants and the PRLR short form, we have found that both
homodimerization of PRLR wild type and the integrity of box-1 and C-distal
tyrosine of PRLR intracellular domain are needed in PRL-induced proliferation and
AP-1 activation. The effect of PRL has been assayed in the presence of
dexamethasone (Dex), insulin, and alone. We found that Dex negatively regulates
PRL-induced proliferation and AP-1 site activation. We demonstrate that PRL
exerts activation of AP-1 transcriptional complex, and the mechanism by which
this activation is produced is also studied. We show that PRL induces an increase
in the c-Jun content of AP-1 transcriptional complexes. The PRL-induced c-Jun of
AP-1 transcriptional complex diminishes in the presence of Dex in a dose
dependent manner. Dex inhibition was reversed by the higher concentration of PRL
added to cells. Despite the fact that the regulation of the AP-1 site is complex,
we found that PRL activates the c-Jun amino terminal kinase (JNK), while
glucocorticoid prevents this JNK activation. These data support a regulation of
cellular growth by PRL-PRLR system by increasing AP-1 transcriptional complex
activity via JNK activation. JNK activation can be repressed by glucocorticoid in
a DNA-binding-independent manner.
PMID- 10770495
TI - Horner syndrome with equal-sized pupils in a case with underlying physiologic
anisocoria.
AB - A case is presented in which Horner syndrome occurred on the side of the larger
pupil in underlying physiologic anisocoria. The unusual coincidence resulted in
ipsilateral ptosis, but with clinically equal-sized and normally reactive pupils.
PMID- 10770494
TI - Induction of relaxin messenger RNA expression in response to prolactin receptor
activation requires protein kinase C delta signaling.
AB - The ability of PRL or rat placental lactogen (rPL)-1 to induce relaxin mRNA
expression was analyzed in a luteinized rat granulosa cell culture model. PRL
receptor activation induced relaxin mRNA expression in a concentration- and time
dependent manner. High concentrations of PRL receptor agonist, equivalent to
those of the second half of pregnancy in rats, were required to elicit relaxin
mRNA expression. A 40-fold induction of relaxin mRNA was observed in cells
treated 24 h with 1 microg/ml of rPL-1. Estrogen enhanced relaxin expression
induced by PRL but did not affect relaxin expression on its own. PRL/rPL-1
induction of relaxin expression was independent of the extracellular regulated
kinase (ERK) members of the mitogen-activated protein kinase (MAPK) pathway,
based on the inability of the ERK kinase inhibitor PD98059 to block induction of
relaxin expression. PRL/rPL-1 induction of relaxin expression required protein
kinase C (PKC) delta, based on the ability of the preferential PKC delta
inhibitor rottlerin to abolish induction of relaxin expression. Direct activation
of PKC by phorbol myristate acetate, however, was not sufficient to promote
induction of relaxin mRNA expression. Stats (signal transducers and activators of
transcription) 3 and 5 DNA binding activities were induced by PRL/rPL-1 treatment
of luteinized granulosa cells but only Stat 3 DNA binding was reduced by
rottlerin. PRL/rPL-1 treatment of luteinized granulosa cells resulted in
increased phosphorylation on tyrosine-705 and serine-727 of Stat 3, and these
responses were reduced and blocked, respectively, by rottlerin. Tyrosine and
serine phosphorylations of Stat 3 in the corpus luteum were also increased in the
second half of pregnancy when PL levels are highest. Stat 3, but not Stat 1 or 5,
coimmunoprecipitated with luteal PKC delta during pregnancy; Stat 3 transiently
coimmunoprecipitated with PKC delta from luteinized granulosa cells in response
to PRL receptor activation; and Stat 3/PKC delta complex formation required PKC
delta kinase activity. Taken together, these results show that PKC delta is
obligatory for PRL/rPL-1-dependent relaxin expression, that PKC delta complexes
with Stat 3 in response to PRL receptor activation, and that PKC delta is
involved in the regulation of Stat 3 phosphorylation downstream of the PRL
receptor. These results demonstrate that PRL/rPL-1 promotes relaxin expression in
luteal cells and that this event is mediated, at least in part, via PKC delta.
PMID- 10770496
TI - Optic nerve head hemangioma.
PMID- 10770497
TI - Accommodative and vergence findings in ocular myasthenia: a case analysis.
AB - Myasthenia gravis (MG) is a neuromuscular disorder that affects skeletal muscles,
in particular, the extraocular muscles. Response variability is a hallmark sign.
Detailed findings are described in a patient with MG in which the presenting sign
was accommodative insufficiency. Objective accommodative findings were recorded 3
years before the onset of myasthenia, soon after the initial diagnosis was made,
and then after the treatment commenced with pyridostigmine. In addition, clinical
measurements were obtained periodically at different times of the day for various
binocular motor functions, including near point of convergence, phoria, fusional
and accommodative amplitudes, and relative accommodation. The disease adversely
affected all accommodative and vergence findings, with fatigue being the primary
disturbance. The therapeutic administration of pyridostigmine improved static
measurements of accommodation and vergence and reduced asthenopia. The objective
dynamic measurements of accommodation, vergence, and versions were less affected.
These findings provide a clear demonstration that both intrinsic and extrinsic
ocular muscles may be affected in the prepresbyopic myasthenic patient.
PMID- 10770498
TI - Magnetic resonance venography in idiopathic pseudotumor cerebri.
AB - OBJECTIVE: To inform clinicians about the use of magnetic resonance (MR)
venography in idiopathic pseudotumor cerebri. MATERIALS AND METHODS: A
prospective study to evaluate for the presence or absence of dural sinus
thrombosis using MR imaging and MR venography of the brain in 22 consecutive
young, female, overweight patients with typical pseudotumor cerebri. RESULTS:
None of the 22 MR imaging and MR venography studies showed venous sinus
thrombosis. CONCLUSION: Magnetic resonance venography might not add significantly
to the evaluation of typical idiopathic pseudotumor cerebri but may be indicated
in atypical cases (e.g., male, thin, or elderly patients).
PMID- 10770499
TI - Hemangioma of the mandibular branch of the trigeminal nerve in the Meckel cave
presenting with facial pain and sixth nerve palsy.
AB - In a 25-year-old woman with episodic periorbital-temporal pain who eventually
developed a sixth nerve palsy, magnetic resonance imaging revealed a lesion
predominantly in the Meckel cave that was found to be a capillary hemangioma
arising from the mandibular division of the trigeminal nerve. Hemangiomas of the
Meckel cave must be considered in cases of facial pain with a sixth nerve palsy.
even if there are no clinical findings of trigeminal neuropathy.
PMID- 10770500
TI - Arteriovenous communication in the orbit.
AB - Arteriovenous malformations (AVMs) are anomalous communications between arterial
and venous systems without interposed capillaries. These lesions are rarely
entirely intraorbital. A case of an arteriovenous communication between branches
of the internal and external carotid arterial circulations and the ophthalmic
veins located within the orbit is reported. Treatment with embolization resulted
in a branch retinal artery occlusion. Attempted direct arterial occlusion of a
dural-based fistula of the eye is a risky procedure. If embolized, AVMs should
probably be approached from the venous side, if at all.
PMID- 10770501
TI - Third nerve palsy as the presenting manifestation of esthesioneuroblastoma.
AB - A 52-year-old patient experienced unilateral third nerve palsy because of
cavernous sinus involvement of biopsy-proven esthesioneuroblastoma. The patient
experienced resolution of diplopia after surgical debulking of the tumor.
Clinicians should be aware of the neuro-ophthalmologic manifestations of
esthesioneuroblastoma.
PMID- 10770502
TI - The blind beautiful eye.
AB - Master Jehan Yperman, a medieval surgeon, observed that when the optic nerve is
injured, the eye becomes blind and beautiful. This is an attempt to trace the
footsteps of this forgotten surgeon and to track the history of the cosmetic use
of the belladonna herb, as well as the concept of amaurotic mydriasis.
PMID- 10770503
TI - Anomalous optic disc elevation associated with ultrasonographic evidence of
increased subarachnoid fluid.
AB - The presence of increased subarachnoid fluid around the optic nerve as measured
by ultrasound has been shown to be associated with elevated intracranial
pressure, as well as a number of other conditions. This finding has proved useful
for distinguishing optic disc elevation secondary to papilledema from disc
elevation attributable to other causes. This report describes a patient with
anomalous optic disc elevation and increased subarachnoid fluid around the optic
nerve.
PMID- 10770504
TI - Bilateral optic neuropathy associated with diffuse cerebral angiomatosis in
Sturge-Weber syndrome.
AB - Visual loss in patients with encephalotrigeminal angiomatosis or Sturge-Weber
syndrome usually results from secondary glaucoma or from damage to the
retrogeniculate pathways by the angiomatous lesions. Optic neuropathy has not
been reported as a component of this syndrome. This report describes a patient
who developed bilateral optic neuropathy with progressive visual loss associated
with diffuse cerebral angiomatosis in the setting of Sturge-Weber syndrome.
PMID- 10770505
TI - Visual loss and central venous catheterization: cortical blindness and
hemianopsia after inadvertent subclavian artery entry.
AB - A case of presumed embolic transient ischemic episodes and multifocal infarcts to
the occipital and parietal cortices and the cerebellum of a young woman with
ulcerative colitis is reported. These episodes were manifested by multifocal
neurologic deficits including cortical blindness, visual hallucinations, and
homonymous hemianopsia. They correlated with parenteral nutrition via a central
line, presumed venous, but found to be in the subclavian artery. The
complications of central venous lines are reviewed. The need for attention to
neighborhood structures and unexpected symptoms, in view of the less well
recognized arterial embolic complications is emphasized.
PMID- 10770506
TI - Adrenal cortical carcinoma metastatic to the brain in a child.
AB - A 9-year-old girl presented with profoundly decreased vision in both eyes and
bilateral optic disc swelling. Magnetic resonance imaging showed a large
intraventricular mass. Excisional biopsy diagnosed metastatic adrenal cortical
carcinoma (ACC). This is, to the best of our knowledge, the first reported case
of ACC metastatic to the brain in a child. It also illustrates the importance of
differentiating optic neuritis from papilledema in children.
PMID- 10770507
TI - Transient visual loss after licorice ingestion.
AB - The authors present a spectrum of clinical presentations of transient visual
loss/aberrations and show that these occurrences were attributable to ingestion
of significant amounts of licorice. A case series of five patients was seen at
Geisinger Medical Center between October 1986 and May 1996. Details of patient
presentation, treatment, and outcome are discussed. The literature on the effects
of licorice derivatives on vascular smooth muscle function is reviewed. Of the
five patients, two had documented visual loss by visual acuity testing and visual
fields. All patients reported a recent ingestion of significant amounts of
licorice (1/4-2 lbs.). All patients had resolution of their visual symptoms; the
aid of hyperbaric oxygen was required for one patient. Thorough review of the
literature shows recent in vitro and in vivo evidence of glycyrrhetinic acid (the
active component of licorice) and carbenoxolone (the hemisuccinate derivative of
glycyrrhetinic acid) directly and indirectly enhancing vasoconstrictor action in
vascular smooth muscle. It is believed that licorice derivatives can cause
retinal or occipital vasospasm, giving rise to transient monocular or binocular
visual loss/aberrations. This has not been described before in the literature. It
is important to ask about licorice ingestion with patients who present with these
visual symptoms.
PMID- 10770508
TI - Spontaneous resolution of pituitary adenoma after apoplexy.
AB - A patient with typical pituitary apoplexy with documented intralesional
hemorrhage and spontaneous resolution is presented. There was no evidence of a
tumor at a 3-month follow-up.
PMID- 10770509
TI - Magnetic resonance imaging enhancement of cranial nerves in inflammatory bulbar
polyneuropathy.
AB - A patient with generalized inflammatory polyneuropathy and facial diplegia was
studied with magnetic resonance imaging. Multiple cranial nerves showed signal
enhancement without sensory or motor dysfunction.
PMID- 10770510
TI - Annual update of systemic disease--1999: emerging and re-emerging infections
(Part II).
PMID- 10770511
TI - Cysticercosis of the optic nerve.
AB - Cysticercosis of the optic nerve has been reported only twice in the literature.
A case of optic nerve cysticercosis in a 50-year-old woman with atypical optic
neuritis is reported. Computerized tomography showed a thickened left optic nerve
with a ring-enhancing lesion containing an eccentric nodule. An enzyme-linked
immunosorbent assay test for cysticercosis further established the diagnosis. The
patient was treated with oral prednisolone and albendazole, with no improvement
in vision.
PMID- 10770512
TI - Acute onset of a bilateral areflexical mydriasis in Miller-Fisher syndrome: a
rare neuro-ophthalmologic disease.
AB - Miller-Fisher syndrome (MFS) is characterized by variable ophthalmoplegia,
ataxia, and tendon areflexia. It seems to be a variant of Guillain-Barre syndrome
(GBS), but unlike in GBS, there is a primitive involvement of the ocular motor
nerves, and in some cases there is brainstem or cerebellum direct damage. The
unusual case of MFS in the current study started with a bilateral areflexical
mydriasis and a slight failure of accommodative-convergence. Ocular-movement
abnormalities developed progressively with a palsy of the upward gaze and a
bilateral internuclear ophthalmoplegia to a complete ophthalmoplegia. In the
serum of this patient, high titers of an IgG anti-GQ1b ganglioside and IgG anti
cerebellum. anti-Purkinje cells in particular, were found. The former
autoantibody has been connected to cases of MFS, of GBS with associated
ophthalmoplegia, and with other acute ocular nerve palsies. The anti-cerebellum
autoantibody could explain central nervous system involvement in MFS. The role of
these findings and clinical implications in MFS and in other neuro-ophthalmologic
diseases are discussed.
PMID- 10770513
TI - Pregeniculate afferent visual system: part II
PMID- 10770514
TI - From cortical plasticity to unawareness of visual field defect.
PMID- 10770515
TI - An anisocoria produces a small relative afferent pupillary defect in the eye with
the smaller pupil.
PMID- 10770516
TI - Homocysteine concentrations and methionine loading in patients on antiepileptic
drugs.
AB - OBJECTIVES: A few reports have shown elevated fasting total plasma homocysteine
(tHcy) in patients taking antiepileptic drugs (AEDs). In this study we determined
the influence of AEDs on plasma tHcy levels prior to and following methionine
loading. MATERIAL AND METHODS: Thirty-four patients on different AEDs and 34
matched controls were recruited. Blood samples were drawn prior to and 6 h post
methionine loading (6h-PML). RESULTS: The patients on AEDs inducing the
cytochrome P450 (carbamazepine, phenytoin, phenobarbital, primidone), had higher
fasting and 6h-PML plasma tHcy concentrations than the controls (P = 0.01 and
P<0.001). Patients on AED inhibiting the cytochrome P450 (valproate [VPA]), had
lower 6h-PML p-tHcy concentrations than controls (P = 0.01). CONCLUSIONS: Our
data indicate that not only fasting but also 6h-PML tHcy levels should be
determined in order to identify hyperhomocysteinemia among patients on AEDs.
Inducer AEDs seem to have an opposite effect than the inhibitor VPA on plasma
tHcy, erythrocyte folate and serum folate levels.
PMID- 10770517
TI - Absence of HHV-6 and HHV-7 in cerebrospinal fluid in relapsing-remitting multiple
sclerosis.
AB - OBJECTIVE: To contribute to clarifying the controversy on the association between
Human Herpesviruses 6 and 7 (HHV-6, HHV-7) and multiple sclerosis (MS) studying
patients with relapsing-remitting MS (RRMS) with or without evidence of disease
activity (clinically or radiologically evaluated). MATERIAL AND METHODS: In 25
RRMS patients, 7 suspected MS patients and 9 patients with other neurological
diseases, the following parameters were analysed: i) antibody titers (IgM and
IgG) against HHV-6 by indirect immunofluorescence both in serum and cerebrospinal
fluid (CSF) samples; ii) PCR-detection of HHV-6 DNA and HHV-7 DNA in CSF and HHV
6 DNA in peripheral blood mononuclear cells (PBMCs). MS patients in remission
underwent a gadolinium-enhanced magnetic resonance imaging in proximity of sample
collections. RESULTS: No viral DNA was found in any CSF sample, HHV-6 DNA
frequency in PBMCs of MS patients and controls was not statistically different.
Antibody titers against HHV-6 were comparable to those of the general population.
Some 30.4% of MS patients were seronegative to HHV6. CONCLUSION: Our data suggest
that there is no relationship between HHV-6 or HHV-7 and MS.
PMID- 10770518
TI - Molecular characterization of HERV-H variants associated with multiple sclerosis.
AB - Our objective was to characterize retroviral sequences by RT-PCR with gag and env
primers on RNA from RT-positive retroviral particles produced by multiple
sclerosis (MS) derived B-lymphoblastoid cell lines. Sequence variants with high
homology to the potentially functional subgroup RGH of the human endogenous
retrovirus RTVL-H/HERV-H family were found. The same sequences were also
specifically found in the particulate fraction of a series of MS patient plasma
samples and were absent in controls. South-Western blots demonstrate the presence
of a nucleic acid binding protein, corresponding in size and function to the
nucleocapsid protein, Gag NC, of other retroviruses. We also present indications
for transmission of the retrovirus to PHA-stimulated lymphocytes from healthy
individuals.
PMID- 10770519
TI - Evaluation of the clinical utility of cerebrospinal fluid (CSF) indices of
inflammatory markers in multiple sclerosis.
AB - OBJECTIVES: Accumulating evidence indicates significant heterogeneity in MS and
soluble (s) adhesion molecules are postulated as markers of disease activity. We
sought to evaluate intrathecal production of these and other molecules across the
clinical spectrum of MS. METHODS: CSF indices of IgG, sICAM-1, sVCAM-1, sE
selectin and sCD30 were calculated in 17 primary progressive (PPMS) patients, 15
secondary progressive patients (SPMS), 28 relapsing-remitting patients in relapse
(RRMSR) and 14 RRMS patients in remission (RRMSNR) using commercially available
ELISA kits. Patients had not received any immunomodulating therapy within the
previous 6 months. MS patients were compared with 44 patients with non
inflammatory neurological diseases (NINDs). RESULTS: The most sensitive CSF index
at a 90% level of specificity was for IgG which had 93% sensitivity in RRMSR and
92% sensitivity in RRMSNR. Corresponding sensitivity in PPMS and SPMS was 71% and
73% respectively. None of the other indices had sensitivity >50% apart from sVCAM
1 (64% in RRMSR and 52% RRMSNR) and sCD30 (53% in PPMS). CONCLUSIONS:
Unsurprisingly the strongest association in MS was with the intrathecal
production of IgG. Similar results in PPMS and SPMS may reflect comparable rates
of progression in these 2 groups. Of the other molecules only intrathecal sVCAM-1
production is significantly associated with MS and only in relapsing-remitting
disease.
PMID- 10770520
TI - Effect of baclofen on gait in spastic MS patients.
AB - OBJECTIVES: To measure gait and postural stability by objective methods in
spastic MS patients and to evaluate the effect of baclofen on gait and postural
stability. PATIENTS AND METHODS: Fourteen spastic MS patients were examined in a
placebo controlled double-blind, cross-over trial of oral baclofen treatment. The
gait was measured on a computerized treadmill and postural stability was measured
on a computer assisted force-plate. RESULTS: Only insignificant improvements in
the clinical measurements during baclofen treatment were found. At baseline gait
was characterized by low speed, short steps and unsteadiness. Postural stability
was severely impaired. During baclofen treatment only vertical unsteadiness of
gait diminished significantly. DISCUSSION: We conclude that patients primarily
with spasticity, concomitant with hampering or painful spasms and co-contractions
should be offered treatment with baclofen. Only some will experience improvement
of their gait disorders, when treated with baclofen.
PMID- 10770521
TI - Diagnostic value of electrophysiological tests in patients with sciatica.
AB - OBJECTIVES: To assess the diagnostic value of electrophysiological tests in
patients with sciatica. MATERIALS AND METHODS: The diagnostic value of
electrophysiological tests were evaluated in 25 patients with monoradicular
sciatica. The electrophysiological study included dermatomal somatosensory evoked
potentials, electromyography, F-wave latencies, H-reflexes and motor and sensory
nerve conduction determinations. The results of the electrophysiological
examinations were evaluated blindly, and the test results were analysed
separately by a receiver operating characteristic (ROC) analysis. Furthermore,
the 5 modalities were evaluated jointly and analysed by a decision-analytic
regret function. RESULTS: A high predictive value was found for the H-reflex
examination, but low for the other modalities. When the 5 modalities were
evaluated jointly, a non-significant decrease in expected regret from the pre
test situation of 0.96 to a value of 0.93 in post-test situation was revealed.
CONCLUSION: Electrophysiological testing is not sufficient as stand-alone
examination in patients with sciatica.
PMID- 10770522
TI - OXPHOS and mtDNA alterations in a family with spastic paraparesis.
AB - OBJECTIVE: To study muscle biopsies in hereditary spastic paraparesis (HSP).
METHODS: We analyzed oxidative phosphorylation activities and mtDNA in 3
individuals from an HSP family. RESULTS: We found histochemical evidence for
mitochondrial proliferation and cytochrome c oxidase negative fibers.
Biochemically, there was an important reduction of the activities of complexes I
and IV in 3 patients. In addition, multiple mtDNA deletions (ranging 4.0-7.0 kb)
were found in 2 cases by PCR but not by Southern blot. CONCLUSION: We suggest the
use of a muscle biopsy when examining HSP patients. HSP can represent a disorder
of nuclear-mitochondrial intercommunication.
PMID- 10770523
TI - Is there any change of stroke incidence during Ramadan?
AB - Ramadan is a special month for Muslims, as fasting during Ramadan is a religious
duty. In this study we investigated whether stroke incidence differs during
Ramadan compared to other months. All patients with stroke admitted to any
hospital in the Isparta Province between 1991-1995 were included in this study.
Patients were divided into 2 groups according to the month of onset of stroke.
The first group included patients with strokes that occurred in Ramadan and the
second group strokes with onset in other months. The stroke incidence of Isparta
has been found to be 137 per 100,000 for people older than 25 years. There were
no statistically significant differences between the age and sex distribution of
patients and the incidences of strokes in both groups. We concluded that fasting
during Ramadan has no affect on stroke occurrence in the Isparta Province.
PMID- 10770524
TI - Neurological findings in complex regional pain syndromes--analysis of 145 cases.
AB - Early diagnosis is a prerequisite for a successful treatment of complex regional
pain syndrome (CRPS). In order to describe neurological symptoms which
characterize CRPS, we evaluated 145 patients prospectively. Two-thirds of these
were women, the mean age at time of investigation was 50.4 years. CRPS followed
limb trauma, surgery and nerve lesion. Employing the current IASP criteria 122
patients were classified as CRPS I and 23 as CRPS II. All patients were assessed
clinically pain was quantified using the McGill pain questionnaire, skin
temperature was measured by an infrared thermometer and a subgroup of 57 patients
was retested in order to determine thermal thresholds (QST). Of our patients 42%
reported stressful life events in a close relationship to the onset of CRPS and
41% had a history of chronic pain before CRPS. The latter group of patients gave
a higher rating of CRPS pain (P<0.05). The major symptoms were pain at rest in
77% and hyperalgesia in 94%. Typical pain was deep in the limb having a tearing
character. Patients getting physical therapy had significantly less pain than
those without (P<0.04). Autonomic signs were frequent (98%) and often changed
with the duration of CRPS. Skin temperature was warmer in acute and colder in
chronic stages (P<0.001). Likewise edema had a higher incidence in acute stages
(P<0.001). We found no correlation between pain and autonomic dysfunction. Motor
dysfunction (present in 97%) included weakness, tremor, exaggerated tendon
reflexes, dystonia or myoclonic jerks. QST revealed increased warm perception
thresholds (P<0.02) and decreased cold pain thresholds (P<0.03) of the affected
limb. The detailed knowledge of clinical features of CRPS could help physicians
early to recognize the disease and thus to improve therapy outcome.
PMID- 10770525
TI - Decreased stability of alpha2-macroglobulin purified from patients with multiple
sclerosis.
AB - OBJECTIVES: To investigate conformational properties of alpha2-macroglobulin from
multiple sclerosis patients. MATERIALS AND METHODS: alpha2-macroglobulin was
purified to homogeneity from plasma of 4 multiple sclerosis patients and 5
healthy controls. The plasma and the purified alpha2-macroglobulin from each
individual were investigated using polyacrylamide gel electrophoresis. RESULTS:
Impaired stability of purified alpha2-macroglobulins from multiple sclerosis
patients was demonstrated with spontaneous conversion to an electrophoretic
"fast" form upon purification and following storage not ascribable to bait region
cleavage. CONCLUSION: alpha2-macroglobulin from multiple sclerosis patients
displays altered stability. Possible functional impairments of proteinase
inhibition mechanisms are discussed.
PMID- 10770526
TI - Hippocampal and temporal lobe atrophy and age-related decline in memory.
AB - OBJECTIVES: To evaluate the relationship of memory decline that accompanies aging
with structural changes in the medial temporal lobe, in healthy middle-aged and
older subjects. MATERIAL AND METHODS: A sample of 35 neurologically non-diseased
subjects, between 55 and 70 years of age, were examined in a 5-year follow-up
study. Neuropsychological investigation included tests of learning, verbal
memory, and visual memory. MRI was performed with a superconducting MRI system
operating at 1.0 T, using coronal slices of T1-weighted images. Medial temporal
lobe atrophy was rated separately in the neocortical, entorhinal and hippocampal
regions. RESULTS: We did not find any statistically significant relationship
between mild hippocampal or temporal atrophy and memory test performance. Nor did
the longitudinal decline in memory show a relationship with temporal lobe
atrophy. CONCLUSIONS: The main outcome of our study was that age-related memory
decline was not related to mild temporal lobe atrophy in healthy subjects without
mild cognitive impairment. There could be other factors influencing memory
functions besides age-related structural changes in temporal lobes.
PMID- 10770527
TI - Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's
dementia.
AB - INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in
the neurodegenerative and repair processes of the nervous system, and the
deposition of the same protein together with beta amyloid peptide was found as
cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND
METHODS: Because of the differential diagnostic importance, serum and
cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented
(AD) and 16 ischemic type of vascular demented (VD) probands were compared with
17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were
found in the normal range in all groups. The ischemic VD probands had the
tendency to have higher cystatin C levels than the AD. No correlation has been
found with the severity and duration of dementia and with the other measured
parameters. CONCLUSION: These results indicate that lower than normal CSF
cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.
PMID- 10770528
TI - Pleural fibrosis associated with dihydroergocryptine treatment.
AB - OBJECTIVES: This is the first report of a histologically confirmed
pleuropulmonary fibrosis (PPF) associated with the dopamine agonist
dihydroergocryptine. CASE REPORT: A 67-year-old male patient with Parkinson's
disease developed a severe restrictive pulmonary disorder with dyspnea and
nonproductive cough after a daily intake of 45 mg dihydroergocryptine for 2
years. After changing the dopamine agonist to the non-ergoline substance
pramipexole, marked improvement of the clinical symptoms of PPF occurred, while
radiological signs showed only a moderate decrease. CONCLUSION: PPF is a possibly
fatal complication. Chest X-rays and specific pneumological diagnostics should be
done if typical symptoms or nonspecific signs of PPF occur while a patient is on
treatment with an ergoline dopamine agonist.
PMID- 10770529
TI - Hypersomnia in Wilson's disease: an unusual symptom in an unusual case.
AB - Wilson's disease (WD) shows a wide heterogeneity in symptoms. In this case report
we present hypersomnia as a symptom of WD. The male patient's complaints as
fatigue, decreased level of concentration, and highly increased demand of
sleeping started at his age of 21 years. No abnormality was found at physical
examination. A moderate elevation in liver function tests was found, but all the
other laboratory findings were within the normal range. The marked hypersomnia
was verified by 24-h cassette EEG polisomnographic monitoring. No abnormality was
found at physical examination. EEG, brain CT and MRI were normal. Neither toxic
nor infectious disease was detectable. The diagnosis of WD was based on decreased
coeruloplasmin level, increased baseline and forced urinary excretion of copper,
and decreased level of serum copper. Kayser-Fleischer ring was not detectable. D
penicillamine (DPA) was introduced. At 8-10 months after the initiation of the
therapy the patient's complaints gradually resolved. The control sleep record 14
months after the initiation of the DPA therapy was normal. Five years later the
patient is currently on penicillamine treatment and he is free of any symptom.
PMID- 10770530
TI - Sexual behavior changes and protease inhibitor therapy. SEROCO Study Group.
AB - OBJECTIVE: To examine changes in sexual activity and unprotected sexual
intercourse among HIV-infected patients before and after the initiation of
protease inhibitor therapy. DESIGN: An analysis of data from the SEROCO Study, a
French prospective cohort. METHODS: All 191 patients who initiated protease
inhibitor therapy after 1 January 1996, who were interviewed within one year
before the initiation of therapy (Time 1), and who had at least 6 months of
follow-up after therapy initiation (Time 2) were included. Patients provided
information about sex partner characteristics and unprotected sexual intercourse.
RESULTS: Eighty-one (42%) were gay or bisexual men, 46 (24%) were heterosexual
men, and 64 (34%) were women. No significant increases were found in either the
number of patients reporting anal or vaginal sex or the number reporting
unprotected sexual intercourse after protease inhibitor initiation. However, in
matched pair analysis, gay or bisexual men were three times more likely to report
having had unprotected sexual intercourse with partners who were of HIV-negative
or unknown serostatus after protease inhibitor initiation [relative risk (RR) =
3.0, 95% confidence interval (CI) = 1.2-7.6]. Non-significant decreases in
unprotected sexual intercourse among both heterosexual men and women were also
observed. No relationship between plasma viral load after protease inhibitor
initiation and unprotected sexual intercourse was found in these data.
CONCLUSIONS: A relapse in sex risk practices among some HIV-infected gay or
bisexual men cannot be ruled out and requires both continued monitoring and
immediate secondary preventative intervention.
PMID- 10770531
TI - Lack of mother-to-child HIV-1 transmission is associated with elevated serum
levels of 90 K immune modulatory protein.
AB - BACKGROUND: 90 K is a secreted human serum glycoprotein with immune modulatory
activity. METHODS: Serum 90 K levels were determined by an enzyme-linked
immunosorbent assay in 19 HIV-1-infected mothers at the time of delivery, in
their new-borns (11 HIV-1 infected and eight uninfected), in 26 HIV-1-uninfected
mothers and in 86 new-borns of HIV-1-uninfected mothers. RESULTS: 90 K levels in
HIV-1-infected transmissive mothers (22.4 +/- 13.9 microg/ml) were similar to
those of HIV-1-uninfected mothers (21.1 +/- 7.6 microg/ml; P = 0.715), but lower
than those of HIV-1-infected non-transmissive mothers (45.5 +/- 24.8 microg/ml; P
= 0.019). The levels were higher in HIV-1-uninfected (47.6 +/- 22.4 mg/ml) than
HIV-1-infected (23.7 +/- 15.6 microg/ml; P = 0.014) new-borns of HIV-1-infected
mothers. The new-borns of HIV-1-uninfected mothers had lower levels (11.7 +/- 5.3
microg/ml) than both HIV-1-infected and HIV-1-uninfected new-borns of HIV-1
infected mothers (all differences, P < 0.001). CONCLUSION: These results suggest
that high 90 K protein serum levels in HIV-1-infected mothers and their new-borns
are associated with lack of mother-to-child HIV-1 transmission.
PMID- 10770532
TI - Sexual risk behaviors among heterosexual HIV serodiscordant couples in the era of
post-exposure prevention and viral suppressive therapy.
AB - OBJECTIVES: To describe awareness and use of antiretroviral treatments, viral
load monitoring, and post-exposure prevention; to assess changing concerns about
HIV transmission; and to examine the effect of these advances on sexual behavior
in HIV-serodiscordant heterosexual couples. METHODS: Cross-sectional analysis of
a baseline sample of 104 couples (n = 208 individuals) from the California
Partners Study II, an intervention trial for HIV-serodiscordant couples in
California. Questions on sexual practices, viral load testing, HIV treatment,
post-exposure prevention, and their effect on sexual behaviors, risk taking and
transmission concerns were measured at intake. RESULTS: Over two-thirds of couple
members surveyed reported unprotected sex with their partner in the past 6
months. Among seropositive respondents, 37% were taking protease inhibitor
therapy, 92% had undergone viral load testing, and of those, 40% said it had ben
undetectable at their most recent test. Most respondents, regardless of
serostatus, said that viral load testing and awareness of post-exposure
prevention had no effect on their condom use. In addition, perceiving that their
partner had an undetectable viral load was associated with having protected sex
among seronegative subjects (P < 0.05). Seropositive respondent taking protease
inhibitors were 2.4 times less likely to report unprotected sex compared with
those not taking protease inhibitors (P = 0.05). However, up to 33% of
seropositive and 40% of seronegative respondents acknowledged decreased
transmission concerns in the light of the new HIV treatments. In comparison with
their seropositive partners, seronegative individuals were more likely to
acknowledge increased risk taking and decreased HIV transmission concerns (P <
0.05). CONCLUSIONS: New medical advances were not associated with unprotected sex
in HIV-serodiscordant couples. However, new treatment options may decrease
concerns about HIV transmission, particularly among seronegative partners.
Providers should discuss the effect of antiretroviral treatments on sexual
transmission risk with their patients. The inclusion of seronegative partners in
counseling interventions may decrease risk taking in serodiscordant couples.
PMID- 10770533
TI - Progressive specific immune attrition after primary, secondary and tertiary
immunizations with bacteriophage phi X174 in asymptomatic HIV-1 infected
patients.
AB - BACKGROUND: Antibody responses to immunization are often compromised in patients
infected by HIV-1, and the use of childhood immunization in affected children is
controversial. We investigated whether multiple immunizations with a T cell
dependent neoantigen, bacteriophage phiX174, induce selective immune attrition
and post-vaccination viremia. METHODS: Seventeen asymptomatic, antiretroviral
therapy-naive HIV-1-infected patients with a CD4 cell count of 450 cells/microl
or greater were immunized in 1990/1991 with three intravenous doses of
bacteriophage phiX174. Group 1 received zidovudine (ZDV) during the primary and
secondary immunization. Group 2 received ZDV exclusively during the tertiary
immunization. Bacteriophage-specific antibodies of the IgM and IgG class,
lymphocyte phenotypes (CD4+, CD8+, CD4+DR+, CD8+DR+, CD4+CD45RO+ and CD4+45RA+,
CD4+CD45RO+DR+) and HIV-1 plasma viremia were measured sequentially. RESULTS: In
both patient groups the primary, secondary and tertiary antibody responses, as
expressed by geometric mean antibody titres and IgM to IgG switch, were impaired.
Booster immunizations resulted in a progressive attrition of specific antibody
responses to bacteriophage. Antibodies to tetanus toxoid remained stable. The HIV
1 viral loads, which were evaluated in archived specimens from eight patients,
increased after immunization but returned to baseline approximately 4 weeks
later. The humoral immune attrition and increases in plasma viremia were blunted
by concomitant short courses of ZDV. DISCUSSION: Multiple boosters of
immunizations in asymptomatic treatment-naive HIV-1-infected patients may result
in a specific immune attrition and vaccine-induced viremia. Short-term
monotherapy with ZDV may have blunted these adverse effects. Hyperimmunization of
HIV-1-infected patients may be detrimental unless accompanied by antiretroviral
therapy.
PMID- 10770534
TI - Accelerated bone mineral loss in HIV-infected patients receiving potent
antiretroviral therapy.
AB - BACKGROUND: The use of highly active antiretroviral therapy (HAART) has been
associated with multiple metabolic complications whose pathogenesis is poorly
understood at the present time. METHODS: We performed a cross-sectional analysis
of whole-body, lumbar spine (L1-L4) and proximal femur bone mineral density in
112 male subjects (HIV-infected patients on HAART that included a protease
inhibitor, HIV-infected patients not receiving a protease inhibitor and healthy
seronegative adults) using dual energy x-ray absorptiometry. RESULTS: Men
receiving protease inhibitors had a higher incidence of osteopenia and
osteoporosis according to World Health Organization definitions: relative risk =
2.19 (95% confidence interval 1.13-4.23) (P = 0.02). Subjects receiving protease
inhibitors had greater central: appendicular adipose tissue ratios than the other
two groups (P < 0.0001). There was no relationship between the central:
appendicular fat ratio and the lumbar spine or proximal femur bone mineral
density t- or z- scores, suggesting that osteoporosis and body fat redistribution
are independent side effects of HAART. CONCLUSIONS: Osteopenia and osteoporosis
are unique metabolic complications associated with protease inhibitor-containing
potent antiretroviral regimens, that appear to be independent of adipose tissue
maldistribution.
PMID- 10770535
TI - Plasma RNA viral load predicts the rate of CD4 T cell decline and death in HIV-2
infected patients in West Africa.
AB - OBJECTIVE: To examine whether the levels of plasma RNA and DNA provirus predict
the rate of CD4 cell decline and patient death. DESIGN: Retrospective analysis of
HIV-2 cohort subjects. METHODS: Fifty-two subjects were recruited between January
1991 and December 1992. HIV-2 RNA levels in plasma and DNA levels in peripheral
blood mononuclear cells (PBMC) were measured using in-house quantitative PCR
assays. The annual rate of CD4 cell decline was calculated using the least
squares method. The survival data on 31 December 1997 were used. RESULTS: The
mean percentage of CD4 cells at baseline was 30.7 (SD, 9.5). In a linear
regression model, the annual rate of CD4 cell decline was 1.76 CD4% faster for
every increase in one log10 RNA copies/ml [95% confidence interval (CI), 0.81
2.7; P = 0.0006; r = 0.46; n = 52] and 1.76 CD4% faster for every increase in
log10 DNA copies/10(5) PBMC (95% CI 0.46-3.1; P = 0.01; r = 0.33; n = 42). In a
multiple linear regression model, RNA load was related to CD4 decline
independently of DNA load (P = 0.02). The overall mortality rate was 7.29/100
person-years. In a Cox regression model, the hazard rate increased by 2.12 for
each log10 increase in RNA load (95% CI, 1.3-3.5; P = 0.0023) but only by 1.09
for each log10 increase in DNA load (95% CI, 0.64-1.87; P = 0.8). CONCLUSION:
This longitudinal study shows for the first time that a baseline HIV-2 RNA load
predicts the rate of disease progression. HIV-2-infected patients with a high
viral load may need to be treated as vigorously as HIV-1 patients.
PMID- 10770536
TI - Deregulation of the CD95/CD95L system in lymphocytes from patients with primary
acute HIV infection.
AB - OBJECTIVE: To analyze the role of CD95/CD95 ligand (CD95L) expression and
functionality in peripheral blood lymphocytes (PBL) during primary, acute HIV
syndrome (AHS) and in the subsequent period. PATIENTS: Twelve patients were
studied during the acute phase of the viral infection and most were followed for
some months. METHODS: Cell culture and cytotoxicity assays based upon 51Cr
release and flow cytometry were used to evaluate cell killing via CD95 molecule,
flow cytometry to assess surface antigens, enzyme-linked immunosorbent assay
(ELISA) for the determination of soluble CD95 and CD95L plasma levels,
quantitative competitive (QC) reverse transcription polymerase chain reaction (RT
PCR) with an original RNA competitor for the analysis of CD95L mRNA expression
and QC RT-PCR for determining plasma viral load. RESULTS: The analysis of PBL
during this phase revealed that almost all cells, including CD8 T cells with a
virgin phenotype, B lymphocytes and natural killer cells displayed CD95 molecules
on the plasma membrane. Activation of CD95 on the surface of isolated lymphocytes
by anti-CD95 monoclonal antibodies or binding to CD95L induced rapid apoptosis.
However, CD95L mRNA was not expressed in PBL from these patients and was poorly
inducible. Soluble CD95 was found in the plasma of all patients, but only in a
few at high levels, even some months after seroconversion. In contrast, soluble
CD95L was detected in only one patient, this occurring after the symptomatic
period. For 10 of the 12 patients, expression of CD95 on the cell membrane or in
the plasma did not correlate with the plasma viral load, which varied widely from
patient to patient. Further, plasma levels of soluble CD95 were not altered by
decreased lymphocyte activation or by efficient antiretroviral therapy.
CONCLUSIONS: In patients experiencing an acute, primary HIV infection, a
prolonged deregulation of the CD95/CD95L system may exist, which is probably not
entirely related to virus production but may contribute to the pathogenesis of
the disease. The hypothesis can be put forward that a complex balance exists
between proapoptotic events (increase in CD95 expression), probably triggered by
the host as a method to limit viral production, and antiapoptotic events
(decrease in CD95L expression) probably triggered by the virus as a way to
increase its production and survival.
PMID- 10770537
TI - Adherence to protease inhibitors, HIV-1 viral load, and development of drug
resistance in an indigent population.
AB - OBJECTIVE: To examine the relationship between adherence, viral suppression and
antiretroviral resistance in HIV-infected homeless and marginally housed people
on protease inhibitor (PI) therapy. DESIGN AND SETTING: A cross-sectional
analysis of subjects in an observational prospective cohort systematically
sampled from free meal lines, homeless shelters and low-income, single-room
occupancy (SRO) hotels. PARTICIPANTS: Thirty-four HIV-infected people with a
median of 12 months of PI therapy. MAIN OUTCOMES: Adherence measured by periodic
unannounced pill counts, electronic medication monitoring, and self-report; HIV
RNA viral load; and HIV-1 genotypic changes associated with drug resistance.
RESULTS: Median adherence was 89, 73, and 67% by self-report, pill count, and
electronic medication monitor, respectively. Thirty-eight per cent of the
population had over 90% adherence by pill count. Depending on the measure,
adherence explained 36-65% of the variation in concurrent HIV RNA levels. The
three adherence measures were closely related. Of 20 genotyped patients who
received a new reverse transcriptase inhibitor (RTI) when starting a PI, three
had primary protease gene substitutions. Of 12 genotyped patients who received a
PI without a new RTI, six had primary protease gene substitutions (P < 0.03).
CONCLUSION: A substantial proportion of homeless and marginally housed
individuals had good adherence to PI therapy. A strong relationship was found
between independent methods of measuring adherence and concurrent viral
suppression. PI resistance was more closely related to the failure to change RTI
when starting a PI than to the level of adherence.
PMID- 10770538
TI - AVANTI 2. Randomized, double-blind trial to evaluate the efficacy and safety of
zidovudine plus lamivudine versus zidovudine plus lamivudine plus indinavir in
HIV-infected antiretroviral-naive patients.
AB - OBJECTIVES: To investigate the effect of combination antiretroviral therapy on
plasma HIV-1 RNA as measured by HIV RNA PCR and to assess their safety and
tolerability. DESIGN: A randomized, multicentre, double-blind, placebo-controlled
trial. SETTING: Multicentre study in eight European countries, Australia and
Canada. PATIENTS: Antiretroviral naive patients (n = 103) with CD4 cell counts
between 150 and 500 x 10(6)/l. INTERVENTION: Patients were randomly assigned to
zidovudine (ZDV; 200 mg three times per day) plus lamivudine (3TC; 150 mg twice
per day) or to ZDV + 3TC + indinavir (IND; 800 mg q8h) for 52 weeks. MAIN OUTCOME
MEASURES: Degree and duration of reduction of plasma HIV-1 RNA as measured by RNA
PCR; Development of drug-related toxicities sufficiently severe to warrant dose
modification, interruption or permanent discontinuation. RESULTS: ZDV + 3TC + IND
reduced plasma HIV-1 RNA (P < 0.001) and increased CD4 cell count significantly
(P = 0.01) more than ZDV + 3TC. The addition of IND to ZDV + 3TC as initial
therapy markedly increased the proportion of patients with plasma HIV-1 RNA
values < 500 copies/ml (31/52, 60%) or 20 copies/ml (24/52, 46%) as compared with
ZDV + 3TC (9/50, 18% or 2/50, 4% respectively) at week 52 in an intention-to
treat, missing = failure analysis. Assessment of time to virological rebound (>
0.5 log10 copies/ml above nadir) showed that patients who attained a minimum
plasma HIV-1 RNA of < or = 20 copies/ml were less likely to rebound than those
who did not reach this threshold. The addition of IND to ZDV + 3TC did not result
in any significant increase in adverse experiences. CONCLUSION: ZDV + 3TC + IND
resulted in a considerable improvement compared with the double combination, in
reduction in plasma HIV-1 RNA, increase in CD4 cell count and proportion of
patients with HIV RNA below the limit of detection. Despite an average 3 log10
decrease in plasma HIV-1 RNA on triple therapy, however, maximal suppression (<
or = 20 copies/ml) was only attained in about one-half of the patients in an
intent-to-treat analysis.
PMID- 10770539
TI - Comparison of clinical features, CD4 and CD8 responses among patients with acute
HIV-1 infection from Geneva, Seattle and Sydney.
AB - OBJECTIVE: To compare the clinical features and T-cell subsets among 160 patients
with acute HIV-1 infection not treated with antiretroviral agents from three
different locations (Geneva, Seattle and Sydney). DESIGN: Patients with
documented acute HIV-1 infection were enrolled in four prospective studies: one
randomized placebo controlled trial (RCT) and three observational cohort studies.
SETTING: All patients were diagnosed and followed in three university affiliated
tertiary clinical care centers. METHODS: The chi-square test was used for
comparing proportions and one way analysis of variance (ANOVA) for comparing
continuous variables among these groups. Multiple regression analysis was used to
identify the variables independently associated with the duration of acute HIV-1
infection. The differences in mean CD4 and CD8 load between centers were assessed
using the random-effect models for the longitudinal data. RESULTS: Minor
differences were noted in the frequency of symptoms among subjects enrolled at
different locations. RCT patients reported a longer duration of symptoms (31
days) compared with that for observational patients (15 days; P < 0.0001). For
the most common symptoms such as fever, skin rash, arthralgia, myalgia, and
headaches, a longer duration was observed in the RCT group compared with that for
observational patients (P range, 0.001 to < 0.0001). T-cells subsets within 100
days of seroconversion did not statistically differ by centre or by mode of
recruitment. CONCLUSIONS: These results suggest a selection bias toward patients
with longer symptomatic acute HIV-1 infection enrolled in the RCT. Data collected
from RCT are not comparable to that collected in observational studies. However,
data from collaborative international studies can be combined.
PMID- 10770540
TI - Discontinuation of secondary prophylaxis for opportunistic infections in HIV
infected patients receiving highly active antiretroviral therapy.
AB - BACKGROUND: Immune reconstitution following the introduction of highly active
antiretroviral therapies (HAART) has lead to a remarkable reduction in the
incidence of opportunistic infections (OI) in subjects with advanced HIV disease.
Moreover, discontinuation of primary prophylaxis for some OI can be attempted
without risk in patients experiencing a favourable response to treatment.
However, data on the feasibility of discontinuing secondary prophylaxis are much
more scarce, and restricted mainly to the withdrawal of maintenance treatment for
cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS: Retrospective review of
the clinical outcome at 18 months in HIV-infected patients in whom
discontinuation of secondary prophylaxis, for different OI, was recommended 3
months after the introduction of HAART, if both CD4 counts > 100 x 10(6) CD4
lymphocytes/l and plasma HIV-RNA < 500 copies/ml had been achieved. RESULTS:
Fifty-three subjects were analysed. Secondary chemoprophylaxis was discontinued
for the following OI: Pneumocystis carinii pneumonia (PCP) (n = 29), cerebral
toxoplasmosis (n = 9), disseminated Mycobacterium avium complex infection (n =
7), CMV retinitis (n = 5), recurrent oroesophageal candidiasis (n = 5), Visceral
leishmaniasis (n = 2), recurrent herpes zoster (n = 2), and chronic mucocutaneous
herpes simplex infection (n = 1). In six individuals, OI prophylaxis was
discontinued for two or more entities. Only two episodes of OI were recorded in
these individuals during 18 months of follow-up. One developed tuberculous
lymphadenitis despite having a good response to treatment, and another suffered a
new episode of PCP after voluntary treatment interruption for 6 weeks.
CONCLUSION: Secondary prophylaxis for OI can be attempted without major risk in
HIV-infected patients experiencing a favourable response to HAART. The benefit of
this intervention should reduce costs, drug side-effects and pharmacologic
interactions, and indirectly will improve patient's quality of life and adherence
to antiretroviral treatment.
PMID- 10770541
TI - Phase III study of granulocyte-macrophage colony-stimulating factor in advanced
HIV disease: effect on infections, CD4 cell counts and HIV suppression.
Leukine/HIV Study Group.
AB - OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony
stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM
CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA,
and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III
randomized, double-blind, placebo-controlled trial enrolled subjects with CD4
cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS
defining illness on stable antiretroviral therapy. Subjects were stratified by
baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive
subcutaneous injections of GM-CSF 250 microg or placebo three times per week for
24 weeks. Subjects were permitted to continue on blinded drug for up to 20
months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte
counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three
hundred and nine subjects received at least one dose of study drug, 70% completed
24 weeks of therapy. Groups were well matched at baseline. Significant increases
in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM
CSF group. GM-CSF significantly reduced the incidence of overall infections (78%
placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days
placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative
opportunistic infections was observed between groups; however, among subjects
without an opportunistic infection prior to study, the GM-CSF group demonstrated
a trend towards fewer subjects with an opportunistic infection on study (26%
placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly
different between groups, but significantly fewer GM-CSF subjects with baseline
viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased
viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA
levels below the limit of detection at baseline, more GM-CSF patients maintained
an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02).
GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell
count and decreased virological breakthrough and overall infection rate in
subjects with advanced HIV disease.
PMID- 10770542
TI - Structured treatment interruption in chronically HIV-1 infected patients after
long-term viral suppression.
AB - OBJECTIVE: To investigate the virological and immunological impact of a
structured treatment interruption (STI) in a cohort of HIV-1 chronically infected
patients with a further long-lasting effective virus suppression. METHODS: Twelve
HIV-1 chronically infected adults who had maintained viral suppression (< 20
copies/ml) for more than 2 years, as well as a CD4:CD8 ratio > 1 for a median
time of 22 months, were included in the study. Participants interrupted their
antiretroviral treatment during a maximum period of 30 days or until a viral load
rebound > 3000 copies/ml was detected. The same prior antiretroviral regimen was
resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days
during the treatment interruption period. Flow cytometry and cell proliferation
assays were performed before and after STI. Genotypic resistance was assessed at
the time of treatment resumption. RESULTS: No adverse events occurred during the
interruption period. In two patients no viral rebound was detected after 30 days
of treatment interruption. In the remaining 10 patients, viral load became
detectable (> 20 copies/ml) at a median time of 14 days after treatment
interruption. Afterwards, viral load increased exponentially with a mean t1/2 of
1.6 days. Treatment was successfully resumed in all patients. No resistance
conferring mutations associated with the pre-interruption antiretroviral regimen
were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the
STI period; however, the level of expression of T-cell activation antigen CD38 on
CD8 T cells increased significantly in response to viral rebound. Four patients
gained T-helper cell responses to recall antigens (tuberculin and tetanus
toxoid), two of who developed an HIV-specific response to p24. CONCLUSIONS: STI
in chronically HIV-1-infected patients is not associated with reductions in CD4 T
lymphocytes or to clinical complications in this group of patients after 2 years
of effective plasma viral suppression. Viral load rebounds in most but not all
patients, without evidence of selection of resistance-conferring mutations.
Thereafter, viraemia can be effectively controlled by antiretroviral agent
reintroduction. HIV-specific T-helper cell responses may be achieved after one
cycle of treatment interruption suggesting some degree of immune-stimulation.
These data do not discard consecutive cycles of STI as a therapeutic strategy to
boost HIV-specific immunity in order to maintain viral replication under
effective control.
PMID- 10770543
TI - The effect of treatment intensification in HIV-infection: a study comparing
treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine.
Prometheus Study Group.
AB - OBJECTIVE: To evaluate the effect of treatment with ritonavir (RTV)/saquinavir
(SQV)/6 stavudine (D4T) or RTV/SQV alone, with treatment intensification if
needed, in protease inhibitor- and D4T-naive HIV-1-infected individuals. DESIGN:
Multicentre, open-label, randomized controlled trial. Two-hundred and eight
patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice
daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study
medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA
remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was
48 weeks. RESULTS: In a strict intention-to-treat analysis, counting all dropouts
as virological failures, 63% [95% confidence interval (CI), 54-73%] of subjects
in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week
48, as compared with 69% (95% CI, 60-78%) in the RTV/SQV/D4T group (n = 104; P =
0.379). In the on-treatment analysis these percentages were 88 and 91%
respectively. Thirty-one patients intensified their study medication according to
the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty
out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow
up visit. Ten per cent of patients discontinued study medication due to adverse
events. CONCLUSION: The concept of starting with a simple, potent regimen, that
could be intensified if necessary, showed good virological results after 48 weeks
in this study, comparable to starting with more drugs from the beginning. Longer
follow-up is needed to determine the long-term efficacy of this treatment
strategy.
PMID- 10770544
TI - Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA.
AB - OBJECTIVES: To determine the frequency of cervicovaginal lavage and plasma HIV-1
RNA levels that are below detectable levels (< 400 copies/ml) among women on
highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To
compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in
the blood plasma and genital tract among antiretroviral-naive women. METHODS:
Data were obtained from 205 HIV-infected women with paired plasma and
cervicovaginal lavage viral load measurements. Seven antiretroviral-naive women
starting HAART had viral load measurements performed daily for one week, at 2
weeks and at 1 month after initiating therapy. Viral load quantification was
carried out by nucleic acid sequence-based amplification assay. The lower limit
of detection was 400 copies/ml. RESULTS: Plasma and cervicovaginal HIV-1 RNA was
detectable in 71 and 26% of the women, respectively. Among women with plasma
viral loads less than 400, 400-9999, and 10,000 copies/ml or over, genital tract
HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per
cent of the women with CD4 cell counts of less than 200/mm3 had detectable
cervicovaginal viral loads compared with 18% among women with CD4 cell counts of
200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml
in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no
therapy (P < 0.045). In seven antiretroviral-naive women initiating HAART,
cervicovaginal HIV-1 RNA decreased by 0.7-2.1 log10 within 1-14 days of starting
therapy. CONCLUSION: The cervicovaginal HIV-1 RNA level was positively correlated
with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART
was significantly associated with below-detectable levels of HIV-1 RNA in both
plasma and the genital tract. HIV-1 RNA suppression in the genital tract may
occur rapidly after initiating therapy.
PMID- 10770545
TI - Syringe exchange not associated with social network formation: results from
Baltimore.
AB - OBJECTIVE: To examine possible formation of new social contacts at the Baltimore
Syringe Exchange Program (SEP). DESIGN: Systematic sub-sample of new SEP
participants recruited into evaluation cohort for biannual interviews. This
analysis used 6-month interview data. METHODS: Participants were interviewed for
behavioral and network characteristics, and number of new social contacts formed
at the SEP. Variables were cross-tabulated using chi2 statistics. RESULTS: Of 413
participants interviewed, 32 (8%) said they had made at least one social contact
at the SEP. These 32 individuals were more likely to have engaged in commercial
sex (16 versus 3%, P = 0.005) and, among active injectors, were more likely to
have used syringes obtained from other drug users (22 versus 8%, P = 0.026).
CONCLUSIONS: Findings argue against the formation of new social networks (and
therefore new disease transmission networks) in the context of syringe exchange
participation.
PMID- 10770546
TI - Seven-year trends in HIV-1 infection rates, and changes in sexual behaviour,
among adults in rural Uganda.
AB - OBJECTIVE: To assess trends in HIV-1 infection rates and changes in sexual
behaviour over 7 years in rural Uganda. METHODS: An adult cohort followed through
eight medical-serological annual surveys since 1989-1990. All consenting
participants gave a blood sample and were interviewed on sexual behaviour.
RESULTS: On average, 65% of residents gave a blood sample at each round. Overall
HIV-1 prevalence declined from 8.2% at round 1 to 6.9% at round 8 (P = 0.008).
Decline was most evident among men aged 20-24 years (11.7 to 3.6%; P < 0.001) and
women aged 13-19 (4.4% to 1.4%; P = 0.003) and 20-24 (20.9% to 13.8%; P = 0.003).
However, prevalence increased significantly among women aged 25-34 (13.1% to
16.6%; P = 0.04). Although overall incidence declined from 7.7/1000 person-years
(PY) in 1990 to 4.6/1000 PY in 1996, neither this nor the age-sex specific rates
changed significantly (P > 0.2). Age-standardized death rates for HIV-negative
individuals were 6.5/1000 PY in 1990 and 8.2/1000 PY in 1996; corresponding rates
for HIV-positive individuals were 129.7 and 102.7/1000 PY, respectively. There
were no significant trends in age-adjusted death rates during follow-up for
either group. There was evidence of behaviour change towards increase in condom
use in males and females, marriage at later age for girls, later sexual debut for
boys and a fall in fertility especially among unmarried teenagers. CONCLUSIONS:
This is the first general population cohort study showing overall long-term
significant reduction in HIV prevalence and parallel evidence of sexual behaviour
change. There are however no significant reductions in either HIV incidence or
mortality.
PMID- 10770547
TI - Maternal HIV-1 and HIV-2 infection and child survival in The Gambia.
AB - OBJECTIVE: To compare the survival of children born to HIV-1 or HIV-2
seropositive mothers with that of children born to HIV-seronegative mothers and
to evaluate risk factors for mortality. DESIGN: Physician-blinded prospective
study. METHODS: One hundred and one HIV-1-seropositive, 243 HIV-2-seropositive
pregnant women, and 468 HIV-seronegative women (control group) matched by age,
parity, and health centre, were followed up in a study of mother-to-child
transmission of HIV. Mothers and children were seen at 2 and 6 months of age and
subsequently followed at 3-monthly intervals up to 18 months of age. HIV
infection in children was diagnosed by polymerase chain reaction at 2, 9 or 18
months and by antibody assays at 18 months. RESULTS: Fifteen per cent of children
born to HIV-1-infected mothers died compared with 7% of children born to HIV-2
infected mothers [hazard ratio, 2.3; 95% confidence interval (CI), 1.1-4.7; P =
0.02], and 6% of HIV-seronegative mothers (hazard ratio, 2.6; 95% CI, 1.4-5.0; P
= 0.003). Six of the 17 children known to be HIV-1 infected died compared with
none among the eight HIV-2-infected children (P = 0.13). High proviral load in
the babies, high antenatal maternal RNA plasma viral load, and maternal death
increased child mortality significantly. CONCLUSIONS: More children born to HIV-1
infected mothers died in comparison with those born to HIV-2-infected mothers or
to mothers from the control group. This effect was due to excess death in HIV-1
infected infants which was associated with a high viral load in the affected
mother and child.
PMID- 10770548
TI - Maternal plasma viral RNA levels determine marked differences in mother-to-child
transmission rates of HIV-1 and HIV-2 in The Gambia. MRC/Gambia
Government/University College London Medical School working group on mother-child
transmission of HIV.
AB - OBJECTIVES: To determine the rates of, and risk factors for, mother-to-child
transmission (MCT) of HIV-1 and HIV-2 infection in The Gambia. DESIGN: A blinded,
prospective, community-based cohort study of 29.549 pregnant women attending the
eight largest antenatal clinics in The Gambia. METHODS: Women were tested for HIV
1 and HIV-2 infection. Infected subjects and a group of HIV-seronegative women
were followed with their babies until 18 months after delivery. Maternal CD4 cell
count percentages were measured before and 18 months after delivery, and the
antenatal plasma viral load was determined. Babies were tested for HIV by the
polymerase chain reaction and/or serology at 2, 9 and 18 months of age. RESULTS:
The study enrolled 144 women positive for HIV-1 and 294 for HIV-2 plus 565
seronegative pregnant women: the mean antenatal percentage CD4 cell counts of 96
HIV-1-positive, 223 HIV-2-positive and 125 HIV-seronegative mothers were 31% [95%
confidence interval (CI) 28-33], 41% (95% CI 39-42) and 47% (95% CI 45-49),
respectively. The geometric mean antenatal plasma viral load of 94 HIV-1-infected
women was 15,100 copies x 10(3) ml (95% CI 10,400-19,000) which was much higher
than that of 60 randomly selected HIV-2-infected women, which was 410 copies x
10(3) ml (95% CI 150-910) (P < 0.001). The estimated transmission rate of HIV-1
was 24.4% (95% CI 14.6-33.9) and that of HIV-2 was 4.0% (95% CI 1.9-7.4). Five of
17 HIV-1-positive and three of eight HIV-2-positive babies were infected after 2
months of age. Birth in the rainy season [odds ratio (OR) 2.9; 95% CI 1.2-7.2], a
low postnatal CD4 cell percentage (OR for a 10% fall 2.4; 95% CI 1.1-5.1) and a
high maternal plasma viral load (OR for a 10-fold increase 2.9; 95% CI 1.1-7.8)
were risk factors for transmission that applied equally to both viruses.
CONCLUSION: Low maternal HIV-2 RNA levels, which on average are 37-fold less than
in HIV-1 infection, relate to the low MCT rate of HIV-2.
PMID- 10770549
TI - Allelic frequencies of host genetic variants influencing susceptibility to HIV-1
infection and disease in South African populations.
AB - OBJECTIVES: Limited information is available on the prevalence in African
populations of host genetic polymorphisms conferring resistance to HIV-1
infection and disease. The objective of this study was to determine the allelic
frequencies in South African populations of the chemokine receptor gene variants
CCR5delta32, CCR5m303 and CCR2b-641 and the CXCR4 ligand gene variant SDF1-3'A.
METHOD: Cross-sectional study to determine the prevalence of these gene variants
in South African subjects of African and European descent. RESULTS: The
CCR5delta32 genetic variant is rare in individuals of African origin, having an
allelic frequency of 0.1% (n = 1247) compared with 9.8% (n = 144) in Caucasians.
The CCR5m303 mutation was not detected in Africans (n = 687), whereas an allelic
frequency of 0.9% (n = 145) was identified in Caucasians. The frequency of CCR2b
641 allele was 13.1% (n = 180) in Africans, which was significantly higher that
the 7.2% (n = 146) detected in Caucasians. Finally the allelic frequency of the
SDF1-3'A gene variant was only 1.0% (n = 198) in Africans compared with 19.8% (n
= 145) in Caucasians. CONCLUSIONS: These results indicate that genetic
polymorphisms conferring resistance to HIV-1 infection are rare in the South
African Black population. Except for the CCR2b-641 gene variant, individuals of
African origin also had a much lower prevalence of genetic variants associated
with prolonged disease progression.
PMID- 10770550
TI - Association of HIV-1 load and CD4 lymphocyte count with mortality among untreated
African children over one year of age.
AB - OBJECTIVE: To examine the association of viral load and CD4 lymphocyte count with
mortality among HIV-infected children over one year of age. DESIGN: A prospective
study. HIV-infected children were enrolled during the first year of life and
followed for more than 2 years at the Queen Elizabeth Central Hospital in
Blantyre, Malawi (southeast Africa). METHODS: Morbidity and mortality information
was collected every 3 months, and physical examination and blood testing (for
viral level and CD4 cell percentage) were performed every 6 months. Kaplan-Meier
analyses and proportional hazards models were used to estimate survival and to
examine the association of primary predictors with mortality. RESULTS: Of 155 HIV
infected children originally enrolled, 115 (74%) had viral load testing and 82
(53%) had both viral load and CD4 cell percentage testing after their first year.
Among children over one year of age, significant associations were found between
mortality and the log10 viral load and CD4 cell percentage in both univariate and
multivariate models. Independent of the CD4 cell value, a one unit log10 increase
in HIV RNA level increased the hazard of child mortality by more than twofold.
Children with low CD4 cell counts (< 15%) and high viral loads (> or = 250,000
copies/ml median value) had the worst survival; children with high CD4 cell
counts (> or = 15%) and low viral loads (< 250,000 copies/ml) had the best
survival. CONCLUSION: As in developed countries, viral load and CD4 cell count
are the main predictors of mortality among African children. Making these tests
available adds to the challenges to be considered if antiviral therapies were to
be adopted in these countries.
PMID- 10770551
TI - Carriage of Pneumocystis carinii by immunosuppressed patients and molecular
typing of the organisms.
PMID- 10770552
TI - The impact of co-infection with hepatitis C virus and HIV on the tolerability of
antiretroviral therapy.
PMID- 10770553
TI - Reversible acute haemolysis associated with indinavir.
PMID- 10770554
TI - Failure of a ritonavir plus saquinavir-based rescue regimen precludes the use of
protease inhibitors.
PMID- 10770555
TI - The development of lipodystrophy on a protease inhibitor-sparing highly active
antiretroviral therapy regimen.
PMID- 10770556
TI - Patient HIV-1 strains carrying the multiple nucleoside resistance mutations are
cross-resistant to abacavir.
PMID- 10770557
TI - Heterosexual transmission of Kaposi's sarcoma-associated herpes virus between two
patients developing AIDS-Kaposi's sarcoma.
PMID- 10770558
TI - L-Carnitine as a treatment of life-threatening lactic acidosis induced by
nucleoside analogues.
PMID- 10770559
TI - Peripheral blood natural killer cell reconstitution after highly active
antiretroviral therapy.
PMID- 10770560
TI - Telemedicine comes of age.
PMID- 10770561
TI - Resection of synchronous liver metastases from colorectal cancer.
AB - BACKGROUND: The prognosis for patients with liver metastases from colorectal
cancer is still poor. Thus, patient selection for hepatic resection is essential
to improve the poor results of the procedure. Some reports have shown that the
prognosis for patients with synchronous liver metastases is worse than that for
those with metachronous liver metastases. Therefore, determination of the factors
that influence outcome after resection of synchronous liver metastases is more
important than with metachronous liver metastasis. METHOD: We studied patients
who had been followed for more than 5 years after undergoing resection of
synchronous liver metastases from colorectal cancer. RESULTS: Among the 12
prognostic factors studied (age, gender, adjuvant chemotherapy, tumor site, CEA
level, tumor differentiation, tumor size, regional lymph node metastatic status,
distribution of liver metastases, number of liver metastases, tumor size and
pathological margin), regional lymph node metastatic status and pathological
margin were significant prognostic factors by univariate analysis (p = 0.0002 and
0.005, respectively). Regional lymph node metastatic status was a significant
prognostic factor by multivariate analysis (p = 0.031). The survival curve of
patients with six or more regional lymph node metastases was similar to that of
patients with non-resectable liver metastasis. CONCLUSION: The resection of
synchronous liver metastases in patients with six or more regional lymph node
metastases is relatively contraindicated. For these patients, other treatment
modalities should be considered.
PMID- 10770562
TI - Preoperative carcinoembryonic antigen level as an independent prognostic factor
in colorectal cancer: Taiwan experience.
AB - BACKGROUND: Preoperative carcinoembryonic antigen (CEA) level is considered as a
factor predictive of survival in colorectal cancer patients. Patients with normal
(<5 ng/ml) or lower preoperative CEA levels were reported to have significantly
longer survival. This study was carried out in an effort to evaluate the
prognostic significance of preoperative CEA levels of patients with colorectal
cancer in Taiwan. METHODS: Between 1990 and 1994, 218 patients with
histologically confirmed colorectal cancers were evaluated retrospectively at the
Veterans General Hospital-Taipei. All the patients had undergone potentially
curative surgery. Patients with metastatic diseases were not included. 5
Fluorouracil-based adjuvant chemotherapy was administered if the patients had
Dukes' C disease. Reference to the Dukes' classification was according to the
classical criteria described in 1932 for carcinoma of the rectum and adapted for
use in colonic tumors. Data on gender, age, degree of tumor differentiation,
location of the tumor, tumor size, lymph node metastasis, penetration of the
bowel wall and preoperative CEA levels were analyzed to determine their
association with survival. Blood samples for CEA measurement were taken a few
days before operation and were analyzed using the radioimmunoassay method.
Multivariate analysis by Cox's proportional hazards regression model was
performed to determine the most important predictors of survival among all of the
possible variables. RESULTS: By univariate analysis, the size of the tumor (p =
0.012), lymph node metastases (p = 0.007), penetration of the bowel wall (p <
0.001) and preoperative CEA levels (p < 0.001) were found to be significant
prognostic factors, while gender, age, degree of tumor differentiation and
location of the tumor were not significant. By multivariate Cox analysis, lymph
node metastases (p = 0.003), penetration of the bowel wall (p = 0.0001) and
preoperative CEA levels (p = 0.0001) were found to be independent prognostic
factors in colorectal cancer patients. CONCLUSIONS: The data from our study
indicate that in addition to lymph node metastases and penetration of the bowel
wall, the preoperative CEA levels are also an independent prognostic factor in
non-metastatic colorectal cancer patients after curative surgery. This could
serve as an appropriate modification to the initial Dukes' scheme in colorectal
cancer.
PMID- 10770563
TI - Multidisciplinary approach to Wilms' tumor: 18 years of experience.
AB - BACKGROUND: The aim was to evaluate the characteristics of Wilms' tumor and the
results of combined modality treatment obtained in our center in Turkey. METHODS:
From January 1978 to December 1996, 106 patients with Wilms' tumor were
diagnosed. Of these 106 patients, 61 were male and 45 were female (M/F = 1,35);
the median age at diagnosis was 39 months. The distribution of the 106 patients
according to clinical stage was stage I 10%, stage II 42%, stage III 35%, stage
IV 9% and stage V 4%. Histologically, 102 of the cases could be evaluated:
favorable histology was diagnosed in 88.2% and unfavorable histology in 11.8% of
the patients. Ninety-eight patients were treated according to NWTS and eight
patients according to SIOP protocols. RESULTS: The EFS and overall survival rates
at 2 years were 74.2 and 79.5% respectively, and at 5 years 72.4 and 76.6%
respectively. CONCLUSION: As a developing country we evaluated our survival rates
and report an improvement in treatment in recent years.
PMID- 10770564
TI - A pilot study of intermittent androgen ablation in advanced prostate cancer in
Japanese men.
AB - BACKGROUND: Permanent androgen ablation has been the mainstay of treatment for
advanced prostate cancer. However, the favorable outcome seen in recent pilot
studies of intermittent androgen ablation raises the possibility of
overtreatment. METHODS: This study included 35 Japanese men with advanced
prostate cancer. Initial androgen ablation continued for 2 months after PSA
levels decreased to <4.0 ng/ml, then was withdrawn. Androgen ablation was
reinstituted 2 months after PSA reached levels >10 ng/ml, when indicated
clinically or on patient request. Cycling continued until androgen independence
was reached. RESULTS: Mean follow-up was 21.0 months, representing an average of
2.5 cycles. Nine patients developed androgen independence at an average of 16.0
months following androgen ablation; three of these have died. Six of the nine
patients with early biochemical progression had elevated alkaline phosphatase
levels at entry; five of these exhibited a flare in alkaline phosphatase activity
after initiation of androgen ablation. Mean bone mineral density (BMD) in the
lumbar spines of 17 patients was 81.5 mg/cm3 at 23 months following therapy. The
BMD of 10 of these patients was normal for their age. Four patients suffered bone
fractures, none pathological. CONCLUSIONS: Intermittent androgen ablation may be
an option for patients with advanced prostate cancer and may be especially
beneficial for those with initially low BMD levels. Patients with elevated
alkaline phosphatase levels at entry or a flare in its activity may not be ideal
candidates. Whether prolonging time to androgen independence will provide benefit
remains to be investigated in a randomized, prospective study.
PMID- 10770565
TI - Follicular thyroid cancer presenting initially with soft tissue metastasis.
AB - Follicular thyroid cancer rarely manifests itself as a distant metastatic lesion.
We report a case of an otherwise asymptomatic 58-year-old woman with follicular
thyroid cancer who initially presented with a soft tissue mass on the right
scapular region. An incisional biopsy specimen of soft tissue metastasis showed
thyroid follicular neoplasm. Upon this diagnosis, the thyroid gland was re
evaluated by ultrasound, which demonstrated a solitary, hypoechoic nodule in the
right lobe. Ultrasonography guided fine-needle aspiration biopsy of the thyroid
nodule confirmed follicular neoplasm and the diagnosis of metastatic follicular
thyroid cancer was established. The patient refused any type of treatment and
left hospital against medical advice. 2.5 years later the patient was admitted to
the hospital with giant, sarcoma-like multiple soft tissue masses. On this
admission, the serum thyroglobulin level was extremely elevated (3500 ng/ml) and
she only accepted to receive chemotherapy. Epirubicin and cyclophosphamide were
administered. She received three courses of chemotherapy and is alive with a
stable disease after 3 months of follow-up. This case of follicular thyroid
cancer is reported because of its uncommon initial presentation with soft tissue
metastasis which spread to multiple areas as giant soft tissue masses during
follow-up.
PMID- 10770566
TI - Atypical medullary carcinoma of the breast with cartilaginous metaplasia in a
patient with a BRCA1 germline mutation.
AB - We examined a 34-year-old premenopausal woman who had noticed a left-breast lump
a month previously. She had no past history of malignancies but had a family
history of breast and ovarian cancers. Her mother had suffered from ovarian
cancer when aged 47 years and had died of the disease at age 52. The younger two
of the patient's four aunts had developed breast cancer when they were 37 and 48
years old. A physical examination showed an ill-defined mass, 1.5 cm in diameter,
located in the upper outer quadrant of the patient's left breast. Mammography
revealed diffuse microcalcification in both breasts but ultrasonography revealed
an irregular tumorous lesion only in the left breast. Aspiration breast cytology
revealed adenocarcinoma of the left breast. Modified radical mastectomy of the
left breast and excision of a biopsy specimen from the right breast were carried
out simultaneously. Histopathologically the left-breast tumor was an atypical
medullary carcinoma with cartilaginous metaplasia, of histological grade 3, and
the right-breast specimen showed fibrocystic changes with atypical ductal
hyperplasia. Estrogen receptors were positive, but progesterone receptor was not
detected on the tumor cells, which were immunopositive for nuclear p53 although c
erbB-2 overexpression was not observed. A nonsense germline mutation of the BRCA1
gene (exon5) was detected. The patient has been well since the operation (10
months). These findings may provide useful information about the carcinogenesis
and biological behavior of BRCA1-associated breast cancers.
PMID- 10770567
TI - Three cases of malignant lymphoma of the breast.
AB - We report three cases of malignant lymphoma (ML) of the breast and discuss
diagnosis and management. The first case is a 35-year-old woman who had a left
breast tumor. Fine needle aspiration cytology (FNAC) showed ML. Mastectomy was
performed without any adjuvant chemotherapy. Histology revealed diffuse large B
cell lymphoma of REAL classification. Seventy one months after surgery, lesions
indicating relapse were detected in nodes of the right axilla, mediastinum and
para-aorta. She underwent eight cycles of CHOP regimen, but 1 month after the
chemotherapy a brain metastasis was detected. The patient then received a high
dose methotrexate regimen with whole-skull irradiation. The second case is a 47
year-old woman who had anterior neck swelling and bilateral breast tumors.
Histology of the tumor revealed diffuse large B-cell lymphoma. The patient
underwent eight cycles of CHOP regimen and high-dose chemotherapy (HDC) with
peripheral blood stem cell transplantation (PBSCT). Forty eight months after the
PBSCT, there is no evidence of disease. The third case is a 38-year-old woman who
had a right breast tumor. FNAC of the breast tumor showed ML and a CT scan of the
chest revealed lymphadenopathy at the crus of the diaphragm. Histology of the
tumor revealed low-grade B-cell lymphoma of MALT type. The patient underwent six
cycles of CHOP regimen and HDC supported by PBSCT. Eighteen months after the
PBSCT, relapse lesions were detected in nodes of the neck, mediastinum and renal
hilum. The patient received nine cycles of a THP-COP regimen.
PMID- 10770568
TI - Pulmonary lymphangitic sarcomatosis from cutaneous angiosarcoma: an unusual
presentation of diffuse interstitial lung disease.
AB - Pulmonary lymphangitic sarcomatosis (PLS) is not much recognized clinically
although it shows similar pathological patterns and diagnostic features to
pulmonary lymphangitic carcinomatosis (PLC). We report a case with hand
angiosarcoma whose chest X-ray findings revealed a diffuse interstitial pattern
consistent with lymphangitic spreading. The final diagnosis was made by open lung
biopsy. The clinical, diagnostic and pathological features of this disease
process are reviewed.
PMID- 10770569
TI - Multiple pulmonary infarctions associated with lung cancer.
AB - We present a case of right lung adenosquamous cell carcinoma that had obstructed
the main pulmonary artery and superior pulmonary vein, causing multiple pulmonary
infarctions in the right upper and middle lobes. Multiple peripheral pulmonary
nodules showed clinical features that are characteristic of pulmonary infarction:
rapid appearance and gradual reduction in size, pleural-based parenchymal density
with a truncated apex and a round nodular shadow with a blurred margin and a
centrally directed linear shadow. The nodules were more intense than the primary
tumor in both T1- and T2-weighted magnetic resonance imaging (MRI). We conclude
that pulmonary infarction can look like a nodule when lung cancer invades both
the pulmonary artery and vein and that such cases can be distinguished from
pulmonary metastasis by MRI, computed tomography and a series of radiological
examinations.
PMID- 10770570
TI - Minute squamous cell carcinoma of the gallbladder: a case report.
AB - Following a simple cholecystectomy, a 63-year-old woman with gallstones was
histologically diagnosed as having minute squamous cell carcinoma of the
gallbladder. A laparotomy revealed a small, firm nodule that appeared to be an
adenoma, which was palpated in the fundus of the gallbladder. The resected
gallbladder contained 37 small stones and a small and firm mass (0.4 x 0.4 x 0.3
cm in size) on the mucosal side. Histologically, a pure type of well
differentiated squamous cell carcinoma of the gallbladder was diagnosed. To our
knowledge, this is the first case of a minute and pure type of squamous cell
carcinoma in the gallbladder. This case may have implications for the
histogenesis of squamous cell carcinoma of the gallbladder.
PMID- 10770571
TI - Positive resection margins in gastric cancer do not necessarily mean negative
thinking.
PMID- 10770572
TI - All cancer mortality in Japan.
PMID- 10770573
TI - Genetic profiling for cancer surfaces slowly in the clinic.
PMID- 10770574
TI - Applications of SPECT imaging of dopaminergic neurotransmission in
neuropsychiatric disorders.
AB - Single photon emission computed tomography (SPECT) tracers selective for pre- and
post-synaptic targets have allowed measurements of several aspects of
dopaminergic (DA) neurotransmission. In this article, we will first review our DA
transporter imaging in Parkinson's disease. We have developed the in vivo
dopamine transporter (DAT) imaging with [123I]beta-CIT ((1R)-2beta-Carbomethoxy
3beta-(4-iodophenyl)tropane). This method showed that patients with Parkinson's
disease have markedly reduced DAT levels in striatum, which correlated with
disease severity and disease progression. Second, we applied DA imaging
techniques in patients with schizophrenia. Using amphetamine as a releaser of DA,
we observed the enhanced DA release, which was measured by imaging D2 receptors
with [123I]IBZM (iodobenzamide), in schizophrenics. Further we developed the
measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)
induced unmasking of D2 receptors. Finally, we expanded our techniques to the
measurement of extrastriatal DA receptors using [123I]epidepride. The findings
suggest that SPECT is a useful technique to measure DA transmission in human
brain and may further our understanding of the pathophysiology of
neuropsychiatric disorders.
PMID- 10770575
TI - Detection of coronary artery disease by iodine-123-labeled iodophenyl-9-methyl
pentadecanoic acid SPECT: comparison with thallium-201 and iodine-123 BMIPP
SPECT.
AB - To evaluate the ability to detect coronary artery disease (CAD) with a new iodine
123 labeled branched fatty acid analog, iodophenyl-9-methyl pentadecanoic acid
(9MPA), we performed 9MPA, iodine-123 BMIPP and thallium-201 SPECT in patients
with CAD. Twenty-four patients (11 with effort angina and 13 with myocardial
infarction) were studied. In all patients, 9MPA SPECT was obtained at 15 min
after injection. Twenty-three patients underwent stress-redistribution 201Tl
SPECT and 9 patients also underwent BMIPP myocardial fatty acid imaging. The
regional uptakes of 9MPA, BMIPP and 201Tl were scored semiquantitatively and the
segmental agreements were compared among them. In the segment-to-segment
comparison, 9MPA showed reduced activity in comparison to stress-redistribution
201Tl imaging. The defect score of 9MPA was significantly greater than that of
redistribution 201Tl images (p < 0.001). In addition, segmental 9MPA uptake was
lower than BMIPP and its defect score was significantly greater than that of
BMIPP (p < 0.05). When coronary angiography was used as the criterion, 9MPA
showed higher sensitivity and lower specificity than stress-redistribution 201Tl
(p < 0.01). In conclusion, fatty acid metabolic imaging with 9MPA is a sensitive
but nonspecific detector of CAD.
PMID- 10770576
TI - Impact of radiotherapy on normal brain tissue: semi-automated quantification of
decrease in perfusion.
AB - PURPOSE: We attempted to ascertain the impact of Co-60 conventional external
radiotherapy (cRT) on the perfusion of normal brain tissue in relation to the
radiation doses delivered to the tumors in patients with primary brain tumors.
MATERIALS AND METHODS: After surgery 18 patients (pts) were due to undergo cRT
with a total dose of 5400- 6400 cGy. All the patients had a Tc-99m-HMPAO SPECT
study prior to cRT (basal), 15th and 30th days of cRT as well as 1 (in 6 pts), 3
(in 9 pts), and 6 (in 3 pts) months after cRT. For quantitative evaluation, the
entire set of transverse slices were divided into 4 regions as frontal, parietal,
occipital and temporal regions by means of a computer software program. Semi
automated quantification was performed on a total of 1392 regions in 87 studies
to determine left to right ratios. An interregional difference of at least 10%
was considered abnormal. RESULTS: After elimination of tumor sites, 80 normal
brain regions showed decreased perfusion after cRT. The percent decrease in
perfusion was (mean 22.5+/-9.9) significantly higher in areas irradiated with
doses > 3000 cGy (p < 0.05). CONCLUSION: cRT has adverse effects on the perfusion
of normal brain tissue for doses > 500 cGy. Our findings justify treating
patients with small and limited lesions with stereotactic radiotherapy in order
to minimize the adverse effects of cRT on normal tissues.
PMID- 10770577
TI - Early and delayed Tc-99m ECD brain SPECT in SLE patients with CNS involvement.
AB - We compared early and delayed Tc-99m ECD SPECT scans in 32 SLE patients (Group 1,
definite neuropsychiatric disorders; Group 2, minor neurologic symptoms or
normal) with those of normal controls by visual inspection and semi-quantitative
evaluation. With visual interpretation, 13 out of 14 patients in Group 1 (93%)
and 7 out of 18 patients in Group 2 (39%) had diffuse uneven decrease in early
scans. Seven patients in Group 2 (39%) who had normal early scans demonstrated
focal decrease in the medial frontal lobe in delayed scans. With cerebral region
to cerebellar ratios, in early scans, the medial frontal lobe in Group 1 and
Group 2 was significantly lower than in normal controls, and lateral frontal lobe
and occipital lobes in Group 1 were significantly lower than in normal controls.
Nevertheless, in delayed scans, every cortical region except for the parietal
lobe in Groups 1 and 2 was significantly lower than in normal controls. The
retention rates in all regions in SLE patients were significantly lower than in
normal controls. No case showed SPECT improvement on follow-up studies in either
group in spite of clinical improvement. Delayed Tc-99m ECD brain SPECT of high
sensitivity might be useful in detecting CNS involvement. Although the SPECT
findings did not correlate with the neuropsychiatric symptoms, early and delayed
Tc-99m ECD SPECT seems to provide useful objective diagnostic information in SLE
patients.
PMID- 10770578
TI - Characteristics of myocardial 18F-fluorodeoxyglucose positron emission computed
tomography in dilated cardiomyopathy and ischemic cardiomyopathy.
AB - Myocardial 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) has
been used to assess myocardial ischemia and viability, but few studies have
conducted on FDG-PET for dilated cardiomyopathy (DCM). We investigated myocardial
FDG uptake in patients with DCM in comparison with ischemic cardiomyopathy (ICM).
Twenty-four patients with heart failure were included in this study. Fourteen of
them were diagnosed as DCM and the other 10 were ICM. All of them underwent
myocardial FDG-PET at fasting and after glucose loading the same day. FDG uptake
was quantified by the ratio of the counts at the heart to those at the liver (H/L
ratio). Left ventricular (LV) function was measured by echocardiography. We
classified FDG distribution patterns in the myocardium in the fasting state into
3 types (faint uptake, regional uptake and diffuse uptake). In DCM patients, 5
had faint uptake, 7 had regional uptake, and the other 2 had diffuse uptake. On
the other hand, all ICM patient had regional uptake (p < 0.05). In DCM, there
were no significant relationships between the patterns and LV functions. On the
other hand, there were close correlation between the H/L ratio after glucose
loading and the left ventricular ejection fraction (r = 0.680, p < 0.01). The
changes in PET images caused by glucose loading were classified into 2 types (non
reversing and reversing patterns). DCM significantly showed a non-reversing
pattern (86%, 12 of 14 patients) whereas ICM showed mainly a reversing pattern
(70%, 7 of 10 patients; p < 0.05). In conclusion, myocardial FDG uptake after
glucose loading may indicate a myocardial viable mass although FDG uptake at
fasting was not evidently related to LV function. The change in the pattern of
the FDG image from fasting to glucose loading may be useful in differentiating
DCM from ICM.
PMID- 10770579
TI - The comparison of dual phase Tc-99m MIBI and tc-99m MDP scintimammography in the
evaluation of breast masses: preliminary report.
AB - The aim of this prospective study was to determine the diagnostic value of Tc-99m
MDP scintimammography (SMG) for the detection of breast cancer in patients with
breast masses and to compare the results with Tc-99m MIBI scintimammography.
Twenty patients, categorized as suspicious, positive or benign for breast cancer
according to the mammographic findings were included in the study. Dual phase Tc
99m MIBI and Tc-99m MDP SMG were performed in the prone lateral position within 5
days of each other. Although early and late Tc-99m MIBI SMG showed equal (90.4%)
sensitivity, the specificity of late Tc-99m MIBI (87.5%) was found superior to
early (62.5%) imaging. The overall sensitivity and specificity of early Tc-99m
MDP SMG were 71.4% and 62.5%, respectively. Although late Tc-99m MDP imaging
showed 100% specificity, its sensitivity was only 23.8%. In the patients with
palpable masses, both early Tc-99m MDP and Tc-99m MIBI showed equal sensitivity
(100%), but the sensitivity of early Tc-99m MIBI (37.5%) was found slightly
higher than Tc-99m MDP (25.0%) for nonpalpable breast lesions. The sensitivity of
Tc-99m MIBI and Tc-99m MDP SMG in detecting metastatic axillary involvement was
66.6% and 50%, respectively. High sensitivity and specificity together with its
low cost, easy availability and the possibility of detecting bone metastases
seems to make Tc-99m MDP a contributive agent in the evaluation of breast lesions
as an alternative to Tc-99m MIBI.
PMID- 10770580
TI - Usefulness of cerebral blood flow (CBF) measurements to predict the functional
outcome for rehabilitation in patients with cerebrovascular disease (CVD).
AB - PURPOSE: The objectives of this study were to (1) elucidate the relationship
between the mean CBF in the whole brain (Av.mCBF) before rehabilitation of CVD
patients and the BI score before and after rehabilitation, (2) determine whether
the efficacy of rehabilitation can be predicted by measurement of the Av.mCBF,
and (3) investigate what part of the brain was most important to improving the BI
score. MATERIALS AND METHODS: The Av.mCBFs in 160 patients with CVD were
calculated by Patlak plots with 99mTc-HMPAO before rehabilitation, and we
determined the BI score before and after rehabilitation. Based on the BI scores
before and after rehabilitation, patients were divided into four groups: Group A,
BI = 100; Group B, 80 < or = BI < or = 99; Group C, 60 < or = BI < or = 79; Group
D, 0 < or = BI < or = 59. We evaluated the relationship between the Av.mCBF and
BI score before and after rehabilitation. RESULTS: The Av.mCBF before
rehabilitation showed a tendency to be more correlated with the BI score after
rehabilitation (r = 0.414, p < 0.0001) than before rehabilitation (r = 0.272, p =
0.0006). After rehabilitation, there was a tendency for the Av.mCBF value to
increase in direct proportion to the BI score of the group: it was highest in
Group A and lowest in Group D. The strongest correlation was found between the
frontal lobe regional CBF before rehabilitation and the BI score after
rehabilitation (r = 0.343, p < 0.0001). CONCLUSIONS: Measurement of the Av.mCBF
before rehabilitation of CVD patients will permit prediction of the efficacy of
rehabilitation. Also the regional CBF of the frontal lobe is most important for
improving the BI score.
PMID- 10770581
TI - Demonstration of Achilles tendon rupture by three phase bone scintigraphy and
MRI.
AB - A man with complaint of soreness in the right medial ankle underwent three-phase
bone scintigraphy; the results of the study suggested chronic active
osteomyelitis or cellulitis, he was on antibiotics and was not experiencing any
improvement. MR imaging confirmed Achilles tendon rupture. This case illustrates
that a positive three-phase study is non-specific disease entity.
PMID- 10770582
TI - Impaired myocardial accumulation of 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic
acid in a patient with hypertrophic cardiomyopathy and exercise-induced ischemia
due to vasospasm.
AB - We encountered a patient with hypertrophic cardiomyopathy complicated with
exercise-induced myocardial ischemia. Exercise-stress 99mTc-tetrofosmin imaging
demonstrated reversible ischemia in the lateral wall, whereas resting fatty acid
imaging with a new beta-methyl branched fatty acid analogue, I-123-15-(p
iodophenyl)-9-(R,S)-methylpentadecanoic acid (123I-9-MPA), showed impaired uptake
and accelerated washout kinetics in the inferoapical and posteroseptal walls but
not in the ischemia-related region. These findings suggest that the metabolic
derangement is closely related to cardiomyopathy per se rather than exercise
induced myocardial ischemia in this patient with hypertrophic cardiomyopathy and
a spastic coronary lesion so that myocardial perfusion and 123I-9-MPA imagings
may contribute to clarifying the etiological background of impaired myocardial
fatty acid metabolism.
PMID- 10770583
TI - Reverse redistribution: revisited with myocardial contrast echocardiography.
AB - The aim of this study is to better understand the pattern and nature of reverse
redistribution (RR) in myocardial perfusion imaging. In 20 consecutive acute
myocardial infarction (MI) patients, frequency of RR was correlated with that of
subendocardial MI that was detected by myocardial contrast echocardiography
(MCE). RR was judged to be present when there was more than one grade of
worsening in perfusion on 24 hr delayed images compared with the initial rest
images. MCE evaluated no opacification in the subendocardial myocardium to
suggest subendocardial MI. Kendall's nonparametric correlation coefficiency was
calculated. Concordant cases were 15 of 20 (75%) and correlation was
statistically significant (p = 0.0285). Our results suggested that RR was
correlated with MCE-detected nontransmural MI.
PMID- 10770584
TI - Preliminary evaluation of [1-11C]octanoate as a PET tracer for studying cerebral
ischemia: a PET study in rat and canine models of focal cerebral ischemia.
AB - Octanoate is taken up into the brain and is converted in astrocytes to glutamine
through the TCA cycle after beta-oxidation. We speculate that [1-11C]octanoate
may be used as a tracer for astroglial functions and/or fatty acid metabolism in
the brain and may be useful for studying cerebral ischemia. In the present study
we investigated brain distribution of [1-11C]octanoate and compared it with
cerebral blood flow (CBF) by using rat and canine models of middle cerebral
artery (MCA) occlusion and a high resolution PET. In rats brain distribution of
[15O]H2O measured 1-2 h and 5-6 h after insult was compared with that of [1
11C]octanoate measured 3-4 h after insult. Radioactivity ratios of lesioned to
normal hemispheres determined with [15O]H2O were lower than those determined with
[1-11C]octanoate. These results were confirmed by a study on a canine model of
MCA-occlusion. Twenty-four hours after insult, CBF decreased in the MCA-territory
of the occluded hemisphere, whereas normal or higher accumulation of [1
11C]octanoate was observed in the ischemic regions. The uptake of [1
11C]octanoate-derived radioactivity therefore increased relative to CBF in the
ischemic regions, indicating that [1-11C]octanoate provides functional
information different from CBF. In conclusion, we found that [1-11C]octanoate is
a potential radiopharmaceutical for studying the pathophysiology of cerebral
ischemia.
PMID- 10770586
TI - Morphology and functional roles of synoviocytes in the joint.
AB - The joint capsule exhibits a unique cellular lining in the luminal surface of the
synovial membrane. The synovial intimal cells, termed synoviocytes, are believed
to be responsible for the production of synovial fluid components, for absorption
from the joint cavity, and for blood/synovial fluid exchanges, but their detailed
structure and function as well as pathological changes remain unclear. Two types
of synoviocytes, macrophagic cells (type A cells) and fibroblast-like cells (type
B cells) have been identified. Type A synoviocytes are non-fixed cells that can
phagocytose actively cell debris and wastes in the joint cavity, and possess an
antigen-presenting ability. These type A cells, derived from blood-borne
mononuclear cells, can be considered resident macrophages (tissue macrophages)
like hepatic Kupffer cells. Type B synoviocytes are characterized by the rich
existence of rough endoplasmic reticulum, and dendritic processes which form a
regular network in the luminal surface of the synovial membrane. Their complex
three-dimensional architecture was first revealed by our recent scanning electron
microscopy of macerated samples. The type B cells, which are proper synoviocytes,
are involved in production of specialized matrix constituents including
hyaluronan, collagens and fibronectin for the intimal interstitium and synovial
fluid. The proliferative potentials of type B cells in loco are much higher than
type A cells, although the transformation of subintimal fibroblasts into type B
cells can not be excluded. In some mammals, type B cells show features suggesting
endocrine and sensory functions, but these are not recognized in other species.
The synoviocytes, which form a discontinuous cell layer, develop both fragmented
basement membranes around the cells and junctional apparatus such as desmosomes
and gap junctions. For an exact understanding of the mechanism of arthritis, we
need to establish the morphological background of synoviocytes as well as their
functions under normal conditions.
PMID- 10770585
TI - Unique and multifunctional adhesion junctions in the testis: ectoplasmic
specializations.
AB - In this paper, we review the structure and function of a unique type of actin
related intercellular adhesion junctions in the testis. Based on their
ultrastructure, the junctions are divided into five distinct domains. The
currently identified molecular components of each domain are summarized. In
addition, the architecture of the mammalian system is compared with that of non
mammalian vertebrates. Functionally, the junctions are related to the turnover of
adhesion between Sertoli cells, to the attachment of spermatids to the
seminiferous epithelium, and to sperm release. They also are part of the
mechanism by which spermatids are moved through the epithelium. Evidence
consistent with adhesion and motility related functions is discussed. Control,
both of junction turnover and of microtubule-based transport, is identified as an
important avenue for future research.
PMID- 10770587
TI - The expression and cellular localization of the sperm flagellar protein MC31/CE9
in the rat testis: possible posttranscriptional regulation during rat
spermiogenesis.
AB - We isolated the MC31 cDNA clone coding the antigen specifically recognized by the
monoclonal antibody mMC31, and found that MC31 was identical to rat CE9.
Therefore, this molecule is called MC31/CE9. MC31/CE9, a member of the
immunoglobulin superfamily molecules, was localized on the rat sperm flagellar
plasma membrane. We analyzed the expression and cellular localization of MC31/CE9
mRNA and protein in the adult rat testis by use of Northern hybridization, in
situ hybridization, and immunohistochemical analyses. In the course of
spermatogenesis, MC31/CE9 mRNA first appeared in type B spermatogonia. The mRNA
signal intensity increased progressively to pachytene spermatocytes and remained
constantly at a considerable level throughout the subsequent phases of
spermatocytes and round spermatids, and then decreased gradually from step-11
spermatids to disappear in step-15 spermatids. On the other hand, MC31/CE9
protein expression showed a bimodal pattern. Immunohistochemical analysis for the
MC31/CE9 protein revealed its most intense immunoreactivity on the flagella of
step-8 to step-19 elongated spermatids. The cytoplasmic immunoreactivity of the
MC31/CE9 protein also appeared in preleptotene to early pachytene spermatocytes
and elongated spermatids, with particularly intense immunoreactivity in the Golgi
complexes of zygotene and early pachytene spermatocytes (stage XIII to III) as
well as step-8 to step-13 spermatids. Between these two phases, the MC31/CE9
protein proved undetectable in the cytoplasm of any spermatogenic cells. Sertoli
cells and Leydig cells were devoid of MC31/CE9 mRNA and its protein. Therefore,
the production of MC31/CE9 is thought to be posttranscriptionally regulated
during spermiogenesis.
PMID- 10770588
TI - Effects of different types of injury to the inferior alveolar nerve on the
behavior of Schwann cells during the regeneration of periodontal nerve fibers of
rat incisor.
AB - The present study reports on different regeneration patterns of axons and Schwann
cells in the periodontal ligament of the rat incisor using immunohistochemistry
of protein gene product 9.5 (PGP 9.5) and S-100 protein. Three kinds of injury
(transection, crush and segmental resection) were applied to the inferior
alveolar nerve. In normal animals, PGP 9.5- and S-100-immunoreactivities were
detected in the axons and Schwann cell elements of periodontal Ruffini endings,
respectively. They were restricted to the alveolus-related part, occurring only
rarely in the tooth-related part and in the shear zone (the border between the
alveolus-related and tooth-related parts). Both transection and segmental
resection caused the complete disappearance of PGP 9.5-immunoreactive nerve
fibers in the periodontal ligament, while a small number of them could be found
following the crush injury. Regenerating PGP 9.5-reactive nerve fibers appeared
at 5 days and 21 days following the transection and segmental resection,
respectively. The regeneration of periodontal nerve fibers completed in a period
of 21-28 days and 14-21 days following the transection and crush, respectively,
but was not completed even at 56 days following the segmental resection. The
behavior of Schwann cells during regeneration was similar after the different
nerve injuries; spindle-shaped S-100-immunoreactive cells, presumably Schwann
cells, appeared in the shear zone and the tooth-related part. These cells
disappeared 5-7 days prior to the completion of the regeneration of axonal
elements of the periodontal ligament following the transection and crush.
Following the segmental resection, in contrast, spindle-shaped S-100-positive
cells disappeared from the tooth-related part at 42 days, although the axonal
regeneration of periodontal Ruffini endings proceeded even until 56 days. We thus
conclude that the duration of the migration of Schwann cells depends on the state
of the regeneration of axons.
PMID- 10770589
TI - Oral sensory papillae, chemo- and mechano-receptors, in the snake, Elaphe
quadrivirgata. A light and electron microscopic study.
AB - The oral sensory papillae of the snake (Elaphe quadrivirgata), comprising a
compound sensory system located along the tooth rows, were studied by light
microscopy, immunohistochemistry for neuron specific enolase and S 100 protein,
and scanning and transmission electron microscopy. Each sensory papilla exhibited
a single taste bud and free nerve endings in the epithelium, and Meissner-like
corpuscles, branched coiled terminals, and lamellated corpuscles in the
connective tissue. The taste buds consisted of four types of cells; the type III
cells, exclusively synapsing onto intragemmal nerves, were identified as
gustatory in function. The gustatory cells included dense-cored and clear
vesicles in the cytoplasm. These vesicles were accumulated both in the
presynaptic and infranuclear regions, suggesting dual functions: the synaptocrine
and paracrine/endocrine release of signal substances. The free nerve endings
constantly contained mitochondria and frequent clear vesicles. The Meissner-like
corpuscles were located in the uppermost zone of the connective tissue. These
corpuscles consisted of nerve fibers and lamellar cells. The nerve fibers, rich
in mitochondria, were folded and layered on each other. The branched coiled
terminals were localized in the connective tissue along the side wall of the
papillae. Nerve fibers, free from a Schwann-cell covering, swelled up to make
terminals which accumulated mitochondria and glycogen particles. The lamellated
corpuscles were associated with the nerve-fiber bundles in the connective tissue.
Consisting of a central nerve axon and lamellar cells encircling it, these
corpuscles resembled mammalian Vater-Pacini corpuscles, except that they lacked a
capsule. These findings demonstrated that the snake sensory papilla represents
one of the most specialized, compound sensory systems among vertebrates, which
may play an important role in receiving chemical and mechanical information on
prey.
PMID- 10770590
TI - Type I collagen is a non-adhesive extracellular matrix for macrophages.
AB - Macrophages adhere to a variety of substrata including plastic, glass or an
extracellular matrix either in a highly specific manner or through less specific
mechanisms. We investigated the effect of type I collagen, the most abundant
protein in animal tissues, on the adhesion of macrophages derived from a human
monoblastic cell line U937. Macrophages were observed to adhere very weakly to
type I collagen and aggregate, whereas they adhered firmly and spread on plastic,
bovine serum albumin or fibronectin. On the adhesive substratum, the lower
surface of the macrophages was flat and closely apposed to the substratum. In
contrast, macrophages adhered on type I collagen at the tip of cell processes.
The adhesion of macrophages to plastic, bovine serum albumin or fibronectin was
associated with the induction of tyrosine phosphorylation of a variety of
proteins including a major protein band at 66 kDa. In contrast, the induction of
tyrosine phosphorylation was markedly reduced when the macrophages were cultured
on type I collagen. Two members of the src family, Lyn and Hck, were tyrosine
phosphorylated in firmly adhered macrophages but not in macrophages cultured on
type I collagen. These results suggest that the adhesion of macrophages is
associated with the tyrosine phosphorylation of a variety of proteins including
Lyn and Hck, and that type I collagen serves as a non-adhesive substratum for
macrophages, resulting in an altered signal transduction.
PMID- 10770591
TI - The presence of specialized epithelial cells on the bronchus-associated lymphoid
tissue (BALT) in the mouse.
AB - The aggregation of lymphoid cells in the bronchial mucosa has been named the
bronchus-associated lymphoid tissue (BALT) and investigated in comparison with
the gut-associated lymphoid tissue (GALT). To elucidate precisely the structure
and function of the BALT, the present study examined the age-related change in
the mouse BALT by light microscopy. We also observed the characteristics of the
overlying epithelium, especially the lectin-binding properties of the epithelial
cells, by the combined use of light microscopy (LM), scanning electron microscopy
(SEM) and transmission electron microscopy (TEM). By LM, lymphoid aggregates were
not recognizable in the bronchial mucosa of young (8-10 week-old) mice, while
they were commonly found at the second to fourth branching portions of the
bronchial tree in older (32-40 week-old) mice. The epithelium overlying the
lymphoid aggregates of the mature mice often contained a large number of
mononuclear cells. Lectin cytochemistry revealed that UEA1 (Ulex europaeus
agglutinin 1) positive cells were not only restricted to the overlying epithelium
of the BALT in the older mice but also found in a cell group in the mucous
epithelium at the branching portions in the young mice. Comparison between the LM
and SEM images of the UEA1-stained whole mount specimens clarified the surface
morphology of the lectin-stained epithelial cells, showing them to be non
ciliated cells with a large number of short microvillous projections on the
apical surface. TEM studies further demonstrated that the UEA1 reaction products
appeared on the plasma membrane of the non-ciliated cells which often enfolded
lymphocytes in the old mice. Latex microbeads, which were administrated
intratracheally, were selectively taken up by the UEA1-positive cells of the
BALT. These results indicate that the mouse BALT has specialized epithelial cells
similar to the UEA1 positive M cells in the GALT and probably functions as a part
of the mucosal immune system. This study also showed the possibility that the
UEA1 positive cells appear in the mucous epithelium before the formation of the
BALT.
PMID- 10770592
TI - Combination of continuous intravenous infusion using a mixture of guaifenesin
ketamine-medetomidine and sevoflurane anesthesia in horses.
AB - The anesthetic and cardiovascular effects of a combination of continuous
intravenous infusion using a mixture of 100 g/L guaifenesin-4 g/L ketamine-5 mg/L
medetomidine (0.25 ml/kg/hr) and oxygen-sevoflurane (OS) anesthesia (GKM-OS
anesthesia) in horses were evaluated. The right carotid artery of each of 12
horses was raised surgically into a subcutaneous position under GKM-OS anesthesia
(n=6) or OS anesthesia (n=6). The end-tidal concentration of sevoflurane (EtSEV)
required to maintain surgical anesthesia was around 1.5% in GKM-OS and 3.0% in OS
anesthesia. Mean arterial blood pressure (MABP) was maintained at around 80 mmHg
under GKM-OS anesthesia, while infusion of dobutamine (0.39+/-0.10 microg/kg/min)
was necessary to maintain MABP at 60 mmHg under OS anesthesia. The horses were
able to stand at 36+/-26 min after cessation of GKM-OS anesthesia and at 48+/-19
minutes after OS anesthesia. The cardiovascular effects were evaluated in 12
horses anesthetized with GKM-OS anesthesia using 1.5% of EtSEV (n=6) or OS
anesthesia using 3.0% of EtSEV (n=6). During GKM-OS anesthesia, cardiac output
and peripheral vascular resistance was maintained at about 70% of the baseline
value before anesthesia, and MABP was maintained over 70 mmHg. During OS
anesthesia, infusion of dobutamine (0.59+/-0.24 microg/kg/min) was necessary to
maintain MABP at 70 mmHg. Infusion of dobutamine enabled to maintaine cardiac
output at about 80% of the baseline value; however, it induced the development of
severe tachycardia in a horse anesthetized with sevoflurane. GKM-OS anesthesia
may be useful for prolonged equine surgery because of its minimal cardiovascular
effect and good recovery.
PMID- 10770593
TI - Effects of adjuvants on the immune response of staphylococcal alpha toxin and
capsular polysaccharide (CPS) in rabbit.
AB - This study was performed to isolate a vaccine strain of S. aureus from clinical
or subclinical mastitis and to choose the most optimal adjuvant for immune
response of alpha toxin and capsular polysaccharide (CPS) of field strain. Of
thirty strains of S. aureus isolated from milk of clinical or subclinical
mastitis, V112 strain isolated from milk of gangrenous mastitis was used in this
vaccine. Twenty one of rabbits were allocated into 5 groups based on adjuvants
and immunized twice every 2 weeks for 8 weeks. This vaccine was composed of alpha
toxin (10 hemolytic units) and formalinized whole cells (1 x 10(11) cells/ml.
Five rabbits received PBS solution as a control group. The highest antibody
titers against alpha toxin and CPS were observed in dextran sulfate- and
aluminium hydroxide-adjuvant group at 8 weeks after immunization, respectively.
These results of the study showed that one adjuvant could not induce strong and
long-term immune response of alpha toxin and CPS antigens. Therefore, the use of
combined adjuvants in subunit vaccine may be useful and feasible.
PMID- 10770594
TI - Plasma LH and progesterone levels before and after ovulation and observation of
ovarian follicles by ultrasonographic diagnosis system in dogs.
AB - Recently, canine frozen semen has been attracting attention for breeding
purposes, and methods of judging ovulation and optimum timing for insemination
have become important. As methods of predicting the canine ovulation, vaginal
smear, plasma sex hormone levels and ultrasonographic diagnosis system (US) have
been investigated in combination, but a standard technique has not yet been
established. Therefore, we investigated a method of predicting canine ovulation
in dogs by US, and by measuring plasma LH and progesterone (P) levels three times
a day. Ovulation could be observed by detecting irregularly shaped ovarian
follicles by US in six of 11 dogs (54.5%). In these dogs, the time between the LH
peak and ovulation was 24-48 hr, 38.0 hr on average. The P level on the ovulation
day was 1.88-2.81 ng/ml, 2.34 ng/ml on average. A value of 1.88 ng/ml was
detected in one dog, but the other five dogs showed P levels of 2 ng/ml or
higher. The P level on the day before ovulation was 0.8-1.56 ng/ml, 1.12 ng/ml on
average. Assuming that ovulation occurred two days after the LH peak in the 11
experimental dogs, the P level was 2.12-4.06 ng/ml, 2.78 ng/ml on average. The
period of a high LH level, not less than 10 ng/ml, continued for 12 hr around the
LH peak. Based on these findings, to predict ovulation using US and LH level, it
would be necessary for the tests to be performed several times a day. In
contrast, it was shown that the day on which a plasma P level of 2 ng/ml or
higher was detected by the test performed once a day corresponded to the
ovulation day.
PMID- 10770595
TI - Botulinum C3 enzyme changes the lactate dehydrogenase isozyme pattern of primary
culture of neurons.
AB - Changes in the lactate dehydrogenase (LDH) isozyme pattern of primary culture of
neurons treated with botulinum C3 enzyme were examined in order to elucidate the
functional changes accompanying the morphological change that follows ADP
ribosylation of Rho protein. Primary neurons were prepared from the cerebrum of
ICR mouse embryos on day 15. Neurons were cultured in MEM with 10% fetal calf
serum at 37 degrees C. In the neurons treated with C3 enzyme, a typical
morphological change was observed after 24 hr, and the LDH isozyme pattern was
changed after 72 hr. The ratio of H-subunit to M-subunit in LDH was decreased by
C3 treatment, suggesting the induction of a state of lower intracellular oxygen
consumption in neurons in the primary cultures.
PMID- 10770596
TI - Isolation of liver oval cells from hamsters treated with diethylnitrosamine and 2
acetyl aminofluorene.
AB - Recently, cholangiocellular carcinoma (CCC) was successfully induced in the
hamster by infecting with Clonorchis sinensis following hepatocarcinogen
treatment and has been proposed as a suitable model to study the pathogenesis of
human CCC. In this hamster model, oval cells are suggested to be cells of origin
of CCC. More direct analysis of histogenesis of CCC would become possible if
large numbers of highly purified oval cells of hamster origin are obtained. In
this study, we describe successful isolation of highly purified oval cells from
hamsters. Oval cells were induced by diethylnitrosamine and 2-acetylaminofluorene
treatment under choline deficient diet and isolated by centrifugal elutriation
method. This isolated cells were highly homogenous in size (10.9+/-1.1 microm in
diameter) and had a high nuclear to cytoplasmic ratio, an oval-shaped nucleus and
a few cytoplasmic organelles. Immunocytochemically, 85.4+/-1.6%, 75.1+/-2.0%,
62+/-1.5% and 25.6+/-2.7% of the isolated cells were positive for cytokeratin 19,
OV-6, albumin and alpha-fetoprotein, respectively, indicating that these cells
had phenotypic characteristics of both hepatocytes and bile duct epithelium. The
isolated cells were therefore considered to be hamster oval cells.
PMID- 10770597
TI - Establishment and characterization of a cell line from a chemically-induced mouse
hepatoblastoma.
AB - We established a cell line (MHB-2) from a hepatoblastoma (HB) induced by
diethylnitrosamine (DEN) and sodium phenobarbital (PB) in male B6C3F1 mice and
examined the biological characteristics of MHB-2. MHB-2 cells grew as monolayers
in culture and showed a spindle or polygonal shape. Immunohistochemically, the
original tumor cells and MHB-2 cells were negative for keratin, alpha-fetoprotein
and albumin. Electron microscopically, MHB-2 cells had irregular-shaped nuclei
with prominent nucleoli, abundant free ribosomes, myelinosomes, desmosomes and
surface microvilli. Growth of this cell line was significantly accelerated by
hepatocyte growth factor (HGF) and expression of its receptor c-met was confirmed
by the reverse transcription-polymerase chain reaction (RT-PCR). MHB-2, however,
was not found to be tumorigenic when transplanted into the subcutaneous tissue of
syngeneic, nude or scid mice. To our knowledge, this is the first report on the
establishment of a cell line derived from a mouse HB. MHB-2 would be useful for
further studies to clarify the biological characteristics of mouse HB.
PMID- 10770598
TI - The effect of GnRH supplement of FSH and PMSG treatments for prepubertal swamp
buffalo calves (Bubalus bubalis).
AB - The objective of the experiment was to improve the multifollicle stimulation
technique and the ovarian response examination in prepubertal swamp buffalo
calves. Six animals were stimulated by gonadotropin hormone 7 days after a
progesterone ear-implant. The first stimulation was done by giving 24 mg FSH +
100 microg GnRH (FSH+GnRH) and the second, one month after by giving 2,000 IU
PMSG + 100 microg GnRH (PMSG+GnRH). Twenty-four hours after GnRH, the ovarian
responses were checked using rectal palpation and real-time B mode
ultrasonography. Five out of six animals (83.3%) responded to both treatments and
were selected for oocyte collection. The oocytes were aspirated directly
following a caudal midline laparotomy. The results of ovarian responses to
FSH+GnRH and PMSG+GnRH averaged 17.6+/-12.1 (L-9.8+/-8.7, R=7.8+/-6.2) and 17.4+/
5.6 (L-9.4+/-2.9, R=8.0+/-3.7), respectively. The average number of recovered
oocytes per animal was 9.0+/-6.4 and 8.4+/-1.1, respectively which represented a
recovery rate of 56.3 (+/- 9.2)% and 51.9 (+/- 10.3)%. More than eighty percent
of the recovered oocytes were in an immature stage with more than 2-3 layers of
compact cumulus mass. The present study showed that the oocytes were collected
successfully in prepubertal buffalo calves after the FSH+GnRH or PMSG+GnRH
stimulation and most of the recovered oocytes were immature, which made them
suitable for in vitro maturation and fertilization.
PMID- 10770599
TI - Prevalence of Bartonella henselae, Bartonella clarridgeiae and the 16S rRNA gene
types of Bartonella henselae among pet cats in Japan.
AB - The authors investigated bacteriologically the prevalence of Bartonella infection
among 690 pet cats derived from 10 private animal hospitals in six cities
(Sapporo, Hokkaido Prefecture; Sendai, Miyagi Prefecture; Joetsu, Niigata
Prefecture; Fujisawa, Kanagawa Prefecutre; Kyoto, Kyoto Prefecture; Sanda, Hyogo
Prefecutre) and 4 counties (Mishima, Osaka Prefecture; Hikawa, Shimane
Prefecture; Aira, Kagoshima Prefecture; Shimajiri, Okinawa Prefecture) located
from the north to the south of Japan. Bartonella species were isolated from 7.2%
(50/690) of all the cats examined. No Bartonella species were isolated from the
cats in Sapporo or Sendai. The isolation rate varied from 2% in Joetsu and Sanda
to 20% in Shimajiri. Bartonella clarridgeiae was isolated from two of 50 cats in
Kyoto, three of 50 in Mishima and one of 50 in Shimajiri, but not in cats from
the other cities or counties. Though the cats of Joetsu, Fujisawa, Kyoto, Sanda,
Aira and Shimajiri were infected with either B. henselae or B. clarridgeiae, one
of eight infected cats in Mishima was harboring both Bartonella species. Type I
of 16S rRNA gene was the predominant type among the isolates of B. henselae, but
only one isolate derived from Shimajiri was found to be of type II. Prevalence of
B. clarridgeiae and the 16S rRNA gene type of B. henselae among cats in Japan was
demonstrated for the first time in this investigation.
PMID- 10770600
TI - Consideration of the role of antigenic keratan sulphate reacting to a 1/14/16H9
antibody as a molecular marker to monitor cartilage metabolism in horses.
AB - The role of keratan sulphate (KS) as a marker of cartilage metabolism was
evaluated by using an in vitro model of equine articular cartilage. Articular
cartilage was harvested from clinically healthy 6-month-old foals (n=3).
Chondrocytes were centrifuged and cultured as pellets. Chondrocyte pellets were
stimulated by insulin-like growth factor (IGF)-Ialpha or interleukin (IL)-1alpha
for 2 weeks. The sulfated glycosaminoglycans (GAG) and antigenic KS
concentrations in the culture media were measured by a 1,9-dimethyl-methylene
blue (DMMB) colorimetric assay and an inhibition ELISA using a 1/14/16H9
antibody, respectively. Concentration of GAG was significantly increased in the
media of pellets stimulated by both IGF-Ialpha and IL-1alpha. Antigenic KS
concentration was significantly increased in those stimulated by IL-1alpha, while
no significant change was found in those stimulated by IGF-Ialpha. A high
correlation between GAG and antigenic KS concentrations was found in the media of
pellets stimulated by IL-1alpha (r=0.87), but not in those stimulated by IGF
Ialpha (r=0.43). The results suggest that the concentration of antigenic KS
reacting to 1/14/16H9 mirrors the GAG concentration during the stage of cartilage
catabolism, but not during the cartilage anabolic stage. The concentration of
antigenic KS reacting to 1/14/16H9 antibody in biological fluids could therefore
be a useful marker to further understand principally the catabolic and slightly
the anabolic process of articular cartilage metabolism.
PMID- 10770601
TI - Difference in the meq gene between oncogenic and attenuated strains of Marek's
disease virus serotype 1.
AB - Serotype 1 strains of Marek's disease virus (MDV1), except attenuated vaccine
strains, are known to cause lymphomas in visceral organs of infected chickens. To
know additional genetic differences between oncogenic and nononcogenic MDV1,
polymerase chain reaction (PCR) was performed to amplify the meq gene of the
viral genome. In addition to the 1,062-bp band including the native meq open
reading frame (ORF), a 1.2-kb band was amplified from the DNA sample prepared
from chick embryo fibroblast infected with an attenuated strain, CVI988, but not
with oncogenic strains. Sequence analysis of the 1.2-kb band showed that a 178-bp
sequence was inserted to the meq ORF of CVI988. This ORF could encode for the Meq
protein with a different transactivator domain. Southern blot analysis also
confirmed the insertion of the 178-bp sequence in the meq ORF of CVI988. This
insertion of 178-bp sequence may explain the reason why CVI988 is not oncogenic.
PMID- 10770602
TI - Histological disorders related to the focal disappearance of the epiphyseal
growth plate in rats induced by high dose of vitamin A.
AB - The histological disorders related to the focal disappearance of the epiphyseal
growth plate were examined histochemically in the proximal tibia of rats
administered a high dose of vitamin A. Animals were given 100,000 IU/100 g body
weight/day of vitamin A for 5 days from 4 weeks after birth (VA rats) or given
deionized water as control and sacrificed on Day 12 and 19 of the experiment.
Tibiae were examined by immunohistochemistry for type I, II and X collagens,
lectin-histochemistry for Helix pomatia and backscattered electron imaging. On
Day 12, the abnormally developed calcified cartilage matrix was detected within
the epiphyseal growth plate in VA rats. The uncalcified cartilage matrix
contained type I collagen but lacked type II collagen. In addition, the eroded
regions accompanied with numerous osteoclasts and osteoblasts were detected in
the epiphyseal growth plate. On day 19, eroded regions penetrated the epiphyseal
growth plate to result in its focal disappearances with the eroded surfaces
entirely covered with bone tissue in VA rats. These findings suggested that the
cartilage matrix of the epiphyseal growth plate was abnormally calcified and
showed the phenotypes like bone matrix. The eroded regions of the epiphyseal
growth plate seemed to be caused by the invasion of osteoclasts into the altered
cartilage matrix and might develop to the focal disappearances by the modeling or
remodeling due to action of osteoclasts and osteoblasts.
PMID- 10770603
TI - Cloning and expression of the M5 RNA segment encoding outer capsid VP5 of
epizootic hemorrhagic disease virus Japan serotype 2, Ibaraki virus.
AB - The complete nucleotide sequence of a cDNA clone representing the M5 RNA segment
of epizootic hemorrhagic disease virus Japan serotype 2 (EHDV-2), Ibaraki virus,
was determined. The M5 segment is 1641 base pairs long with the single open
reading frame which predicts a polypeptide of 527 amino acids. The comparison of
the amino acid sequence of the VP5 with those of EHDV-1, bluetongue virus
serotype 10, and African horse sickness virus serotype 4 revealed that the
protein shared 67%, 57% and 42% homologies, respectively. In addition, the VP5
protein was expressed in insect cells by recombinant baculovirus, which could be
recognized by the mouse anti-EHDV-2 sera at a position of the expected 59 kDa on
immunoblot analysis.
PMID- 10770604
TI - The quality and maturation of bitch oocytes recovered from ovaries by the slicing
method.
AB - Oocytes were recovered from bitch ovaries at various stages of the estrous cycle
by the slicing method. The proportion of Grade A oocytes (darkly pigmented and
surrounded in part, or whole, by dense layers of cumulus cells) were counted.
Only Grade A oocytes were cultured in TCM199 supplemented with 5% fetal calf
serum for evaluation of meiotic competence. There were no significant differences
in the total number of oocytes or the proportion of Grade A oocytes that were
recovered from bitches at various stages of the estrous cycle. Only 11% of the
oocytes reached metaphase II (MII) at 72 hr after initiation of maturation
culture. However, the proportions of oocytes reaching MII did not increase with
culturing for up to 120 hr.
PMID- 10770605
TI - Fecal estrone sulfate profile of a sow showing abnormal pregnancy with fetal
mummification.
AB - Fecal and plasma E1S of a sow with mummified fetuses, was compared with normal
delivery cases. Fecal and plasma fluctuation patterns in E1S were similar. In the
sow with fetal mummification both fecal and plasma E1S concentration rapidly
decreased after day 80-90 compared to normal farrowing sows. This coincided with
the estimated time of fetal death.
PMID- 10770606
TI - An occurrence of Salmonella typhimurium infection in sika deer (Cervus nippon).
AB - Seven sika deer (Cervus nippon) in a herd of 30 deer in a park died. Upon
examination of three dead deer, Salmonella Typhimurium was isolated from the
organs and intestinal contents. Histopathological examination revealed catarrhal
enteritis and focal necroses in the liver. Immunohistochemically, Salmonella
antigen of O4 was detected in the enteric lesions. The case was diagnosed as S.
Typhimurium infection in the sika deer. Because of the importance of Salmonella
in public health, fecal and soil samples were continuously collected from the
paddock. However, no Salmonella was isolated from any samples collected after
medication of the deer and thorough disinfection of the immediate environment.
PMID- 10770607
TI - The complete nucleotide sequence of segment L2 of Ibaraki virus encoding for the
antigen recognized by neutralizing antibodies.
AB - The complete nucleotide sequence of cDNA clones representing the L2 dsRNA from
Japan isolate of epizootic hemorrhagic disease serotype 2 (EHDV-2JPN) was
determined. The EHDV-2JPN L2 gene is 3002 base pairs long with a single open
reading frame of 2949 bp which predicts a polypeptide of 982 amino acid residues.
Comparison of VP2 sequence between Japan and North American Isolates of EHDV-2
showed a 72% homology in spite of the same serotype, although those among the
North American isolates showed a high genetic identity (>97%).
PMID- 10770608
TI - Protein analysis of Babesia caballi merozoites by two-dimensional polyacrylamide
gel electrophoresis and western blotting.
AB - Babesia caballi merozoites were prepared by combining two improved methods of
cultivation and purification of merozoites using Percoll-gradiation, and the
protein compositions of merozoites were analyzed by two-dimensional sodium
dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. The
relative molecular masses of the major proteins and protein masses separated by
electrophoresis were >94, 80-70, 50-45, 34-30, 30-28 and 18 kDa. By Western
blotting, twelve proteins or protein groups were recognized by pooled sera from
two horses experimentally infected with B. caballi. Among twelve proteins, five
new proteins (54, 30-26, 24, and two 18 kDa) were identified, and the 48 kDa
protein was revealed to consist of 2 components in the B. caballi merozoite. One
protein (54 kDa) of B. caballi was also recognized by the pooled sera from two
horses experimentally infected with B. equi.
PMID- 10770610
TI - Detection of porcine epidemic diarrhea virus by immunohistochemistry with
recombinant antibody produced in phages.
AB - Several diagnostic methods including immunofluorescence, enzyme-linked
immunosorbent assay, polymerase chain reaction and immunohistochemistry have been
developed for the detection of porcine epidemic diarrhea virus (PEDV). An
immunohistochemical method using a new recombinant antibody produced by a phage
antibody system (PAS16) kit was investigated and compared with that using a
monoclonal antibody for PEDV detection in PEDV-infected piglets. In both the
immunohistochemical methods, PEDV antigens were detected in the cytoplasm of
villous enterocytes and in the macrophages infiltrated in the lamina propria at
18 to 110 hr post inoculation. The positive signals with the recombinant PAS16
antibody were similar to those with the monoclonal antibody. This result suggests
that the recombinant PAS16 antibody can be applicable for the rapid
immunohistochemical diagnosis of PEDV infection.
PMID- 10770609
TI - Infection of bovine immunodeficiency virus and bovine leukemia virus in water
buffalo and cattle populations in Pakistan.
AB - A survey of antibodies to bovine immunodeficiency virus (BIV) known as bovine
lentivirus and bovine leukemia virus (BLV) was conducted with samples from water
buffalo and cattle populations in Pakistan. A total of 370 water buffaloes and 76
cattle were tested, and 10.3% and 15.8%, respectively, were found positive for
anti-BIV p26 antibodies determined by Western blotting, while 0.8% of water
buffaloes and no cattle were positive for anti-BLV antibodies determined by
immunodiffusion test. BIV-seropositive water buffaloes and cattle were found to
have BIV proviral DNA in the peripheral blood mononuclear cells determined by
nested polymerase chain reaction. This is the first report of BIV infections in
water buffaloes.
PMID- 10770611
TI - In vitro developmental potential of bovine nuclear transfer embryos derived from
primary cultured cumulus cells.
AB - The in vitro development and the quality of blastocysts produced from the nuclear
transfer (NT) embryos reconstituted from primary cultured cumulus cells (NT
cumulus) were examined compared to in vitro fertilized embryos (IVF) and NT
embryos reconstituted from the embryonic blastomeres (NT-blastomere). The
cleavage rate, and the development to blastocyst were the same for all three sets
of embryos. The time required for blastocoel formation starting from the time of
the initial cleavage was shorter for NT embryo groups than IVF ones. All
experimental groups produced morphologically similar and normal blastocysts
containing the same cell number. The percentage of the blastocysts with normal
chromosomal complements were the same for NT-cumulus and IVF.
PMID- 10770612
TI - Desmin as a possible immunohistochemical marker for feline hypertrophic
cardiomyopathy.
AB - Desmin has been suggested as a possible histopathological marker for hypertrophic
cardiomyopathy (HCM) in humans. To test whether a similar pattern of desmin
staining applies to HCM in cats, we conducted an immunohistochemical study on
myocardial samples from 13 cats (HCM 4, other cardiomyopathies (OCM) 4, and
control 5). The pattern of staining for desmin in HCM cats was not the same as
that reported in humans, but was weaker than in OCM cats and controls. This
suggested that desmin may be a possible histochemical marker for feline HCM, but
our data was insufficient to clearly confirm this.
PMID- 10770613
TI - The inhibitory effect of interferon gamma and tumor necrosis factor alpha on
intracellular multiplication of Neospora caninum in primary bovine brain cells.
AB - Primary culture of bovine brain cells was examined for its susceptibility to
Neospora caninum infections, and this model was used to investigate the effects
of bovine interferon gamma (IFN-gamma) and tumor necrosis factors alpha (TNF
alpha) on tachyzoite growth. Tachyzoites of N. caninum grew well in this culture,
and tachyzoite growth in astroglia and microglia were confirmed by
immunocytochemical staining. IFN-gamma inhibited the tachyzoite growth, and this
inhibition was not reversed by the addition of nitric oxide antagonist. TNF
alpha, to a lesser extent, also inhibited the tachyzoite growth. Th-1 type
cytokines may play an important role in host defense mechanisms in N. caninum
infection.
PMID- 10770614
TI - Evaluation of intracranial pressure by transcranial Doppler ultrasonography in
dogs with intracranial hypertension.
AB - Transcranial Doppler ultrasonography (TCD) has been used to confirm changes in
cerebral hemodynamics. In this study, we investigated whether the parameters for
the basilar artery measured by TCD were correlated with the intracranial and
cerebral perfusion pressures in extreme intracranial hypertension. An
intracranial hypertension model was produced in seven dogs by inflating a balloon
inserted into the epidural space. The resistance index was compared with the
corresponding intracranial pressure and cerebral perfusion pressure values during
intracranial hypertension. A significant correlation was recognized between the
resistance index and cerebral perfusion pressure. Therefore, measurement of the
basilar artery by TCD in the dog with intracranial hypertension is useful in
estimating the intracranial circulation in cases where the measurement of
intracranial pressure is not available or not indicated.
PMID- 10770615
TI - Biotin-labeled proteins of Eimeria tenella sporozoite.
AB - To identify surface proteins of eimerian sporozoite, Eimeria tenella sporozoites
were labeled with biotin-LC-hydrazide, and analyzed by two-dimensional
polyacrylamide gel electrophoresis (2D-PAGE) and Western blotting. More than 200
sporozoite proteins were recognized with silver staining after 2D-PAGE. Among
them, 7 biotin-labeled proteins were detected as surface molecules after Western
blotting and reaction with horseradish peroxidase conjugated streptavidin. Their
molecular masses ranged from 23 to 117 kilo daltons and their isoelectric points
from 4.3 to 6.3. It appears that the biotin-labeling technique can be used to
analyze of surface proteins of eimerian parasites.
PMID- 10770616
TI - Pathogenesis of nonimmune hydrops fetalis caused by intrauterine B19 infection.
AB - Intrauterine human parvovirus B19 infection is related to non-immune hydrops
fetalis and fetal death. First, we performed epidemiological studies to determine
the critical period during which maternal infection led to hydrops fetalis. The
studies showed that the hepatic period of hematopoietic activity was correlated
with the critical period of maternal infection, which suggested that B19 might
have affinity for erythroid lineage cells at the stage of hematopoiesis. We next
established an in vitro infection experimental system of B19 using erythroid
lineage cells derived from fetal liver cells. We demonstrated that the erythroid
lineage cells proved to be appropriate targets for B19 virus and that B19
infection could induce apoptosis of infected cells. The massive destruction of
erythroid lineage cells through apoptosis seems to cause severe anemia and to
result in heart failure of the fetus. To analyze the cytotoxic mechanism in more
detail, we established a stringent regulatory expression system of the NS1
protein encoded by the B19 genome and indicated that the apoptosis induced by B19
was directly caused by the NS1 protein. Experiments using mutations engineered in
the ATP-binding domain of NS1 indicated that this domain played a critical role
for the apoptosis induction. The present studies may contribute to a better
understanding of the pathogenesis of hydrops fetalis associated with B19
infection during pregnancy.
PMID- 10770617
TI - Comparative studies on the cysteine proteinase inhibitory capacity of mammalian
blood.
AB - The inhibition of cysteine proteinase (papain) by human, bovine, horse, rabbit,
guinea pig, rat, hamster, and mouse plasma, and pig, sheep, goat, and dog sera
was investigated. The rat and mouse plasma and the pig serum showed such high
inhibitory capacity as 813, 380, and 508%, respectively, of the human plasma. On
the other hand, the horse, guinea pig, and rabbit plasma indicated 36, 40, and
54%, respectively, of the human plasma. A cysteine proteinase inhibitor (s) was
separated from alpha-macroglobulin by Sephacryl S-300, and the inhibitory
activity of all of the mammalian plasma/sera except for the guinea pig plasma
appeared at around the 50-150-kDa region. The guinea pig plasma exhibited well
resolved two peaks of 100 and 200 kDa.
PMID- 10770618
TI - Time course of the size of the dark area in macular holes by scanning laser
ophthalmoscopy.
AB - To investigate the time course of idiopathic macular hole development by scanning
laser ophthalmoscopy (SLO), we examined 28 eyes of 25 patients with macular
holes. Cases included four eyes with stage 1-B disease (foveal detachment), 3
with stage 2 (break at the fovea), 13 with stage 3 (full-thickness macular hole),
and 8 with stage 4 (hole with pseudo-operculum, posterior vitreous detachment),
according to Gass's classification. The diameter of the dark area around the
macular holes was recorded by SLO using a helium-neon laser. We compared the
percent difference of dark area recorded between initial findings and these after
three months. The size of the dark area increased after three months in eyes with
stages 1, 2, and 3 disease. The size of the dark area in stage 4 disease
decreased after 3 months. In the stage before posterior vitreous detachment
(PVD), the dark areas increased. Once PVD occurred, these areas decreased. These
findings suggested that the time course of the dark area may be related to the
development of PVD.
PMID- 10770619
TI - Bile acid metabolism, bacterial bowel flora and intestinal function following
ileal pouch-anal anastomosis in dogs, with reference to the influence of
administration of ursodeoxycholic acid.
AB - The pathophysiology following a total colectomy with ileal pouch-anal anastomosis
(IPAA) has not been sufficiently clarified yet. We investigated bile acid
metabolism, bacterial bowel flora and transit of the alimentary tract after IPAA,
with reference to administration of ursodeoxycholic acid (UDCA) in dogs
undergoing IPAA. Ten adult beagle dogs underwent IPAA at one stage, and were
observed for 12 months. UDCA (100 mg/day) was administered orally to five dogs,
and the other five did not. In the UDCA(+) group, UDCA replaced other bile acids,
especially cholic acid, accounting for 16.5% of gallbladder bile at 12 months
after surgery. Both plasma levels and postprandial increase of total bile acids
remained unchanged in the UDCA(+) group, but decreased in the UDCA(-) group at 12
months. Fecal excretion of bile acids tended to be smaller in the UDCA(+) group,
and the ratio of secondary to primary bile acids was larger in the UDCA(-) group.
Almost all the bile acids were in free form in stool, and UDCA constituted 19% in
the UDCA(+) group. The transit time of the whole alimentary tract was elongated
by administering UDCA, especially at an early period after IPAA. Although both
anaerobic and aerobic bacteria decreased after IPAA, the latter decreased more in
stool, resulting in an increase in the ratio of total anaerobes/total aerobes,
especially in the UDCA(-) group. The decrease in Bacteroidaceae and Lactobacillus
after IPAA was slightly smaller in the UDCA(+) group. Administration of UDCA
following IPAA was efficient to induce rapid intestinal adaptation and also to
keep the bile acid fraction in the ileal pouch less harmful.
PMID- 10770620
TI - Rapid, sensitive and simple detection of candida deep mycosis by amplification of
18S ribosomal RNA gene; comparison with assay of serum beta-D-glucan level in
clinical samples.
AB - We evaluated the clinical usefulness of a polymerase chain reaction (PCR) assay
amplifying the 18S ribosomal RNA gene of fungi for the diagnosis of deep
candidiasis, compared with that of the beta-glucan test or Cand-Tec test. Thirty
critically ill patients who had received prolonged care with intravenous
hyperalimentation and endotracheal intubation in the intensive care unit and were
suspected of having deep fungal infections were examined. Twenty-one were fungi
positive in the PCR assay (70%). Among 24 samples in which the PCR assay, beta
glucan test and Cand-Tec test were performed simultaneously, 75% of the samples
(18/24) were fungi positive in the PCR assay, whereas only 54% (13/24) had
positive reactions in the beta-glucan test and 21% (5/24) in the Cand-Tec test.
The results of the Cand-Tec test showed no relationship with those of the PCR or
beta-glucan test. The lower limit of detection in the PCR assay was 4-5 CFU/ml of
C. albicans in blood. No fungal organism was amplified from the serum of 20
healthy individuals. The results of the PCR assay and beta-glucan test showed a
significant correlation in this study, but the PCR assay proved to be more
sensitive than the beta-glucan test (p < 0.05), and to be more useful for the
clinical diagnosis and monitoring of deep Candidiasis.
PMID- 10770621
TI - The vasocontractive action of norepinephrine and serotonin in deep arterioles of
rat cerebral gray matter.
AB - To examine the direct effects of norepinephrine (NE) and serotonin (5-HT) on the
contractility of arterioles in the gray matter of the rat cerebrum, we micro
perfused arterioles in vitro and observed the changes in luminal diameter under
the stop-flow condition with constant intraluminal pressure. While the average
diameter of the lumen of arterioles was 39.9 +/- 9.7 microm (n=7) in Hepes
buffered saline, the average in 10(-7) M NE in the extraluminal solution changed
into smaller in saline by 21.1 +/- 5.4% (n=7). The contractile effect of NE shows
a dose-dependent curve between the 10(-7) and 10(-5) M. The contractile response
to 10(-6) M NE was significantly reduced by yohinbin, an alpha2 blocker. 10(-6) M
NE applied to the lumen also caused contraction of arterioles by 12.4 +/- 5.3% in
diameter (n=5). 5-HT at 10(-7) M in the extraluminal solution caused contraction
of arterioles by 10.9 +/- 4.4% in diameter (n=7). 5-HT in the extraluminal
solution caused contraction of arterioles in a dose dependent manner between 10(
10) and 10(-6) M. The contractile effect of 5-HT at 10(-6) M was strongly reduced
by 10(-6) M ketanserin, a 5-HT2 receptor antagonist. 5-HT applied to the lumen
had no effect at all (n=6), however NE applied to the lumen caused contraction.
These results strongly suggest that 5-HT plays a significant role in arteriolar
contractility only from the cerebrospinal fluid (CSF) side, while NE is an
important regulator of arteriolar contractility from both the CSF and blood
circulation sides.
PMID- 10770622
TI - A preliminary study on the knowledge and attitudes of physicians at two
university hospitals towards the medical insurance system of Japan.
AB - In this preliminary study, we surveyed the physicians at two academic hospitals
on their knowledge of and attitudes toward the medical insurance system in Japan.
Most of the physicians had not read the "Ministerial Ordinance on Insurance
Medical Institutions' and Insurance Medical Doctors' Medical Treatment under
Health Insurance." Of the 433 physicians who filled out the questionnaire
completely, 34% had either not read or rarely read the "Medical Fee Point List."
Most (89.1%) of the physicians knew that there is a stepwise reduction in the
hospitalization fee as the length of a patient's hospital stay increases.
However, approximately 30% did not know the stipulation of obtaining an informed
consent from the patient prior to blood transfusion. As for the right of patients
to see their medical care remuneration statements, which was decided by the
government in 1997, 26.8% of the physicians did not know this rule. Physicians
who had read the "Ministerial Ordinance on Medical Treatment," were more likely
to read the "Medical Fee Point List" frequently; were more likely to know the
stipulation about diminishing hospitalization fee; were more likely to know that
an informed consent must be obtained prior to blood transfusion; and were more
likely to know that patients had a right to see their medical care remuneration
statements. The longer the clinical experience of the physician, the more likely
that the physician had read the "Ministerial Ordinance on Medical Treatment" and
know the other stipulations well. In these two academic hospitals, it is
important to establish educational seminars for physicians on the guidelines of
the medical insurance system so that physicians will become familiar with the
medical insurance system quickly.
PMID- 10770623
TI - Effects of nasal continuous positive airway pressure on awake ventilatory
responses to hypoxia and hypercapnia in patients with obstructive sleep apnea.
AB - This study was aimed to examine the short- and long-term effects of nasal
continuous positive airway pressure (CPAP) on the chemosensitivity to hypoxia and
hypercapnia in the patients with obstructive sleep apnea (OSA). Awake ventilatory
responses to hypoxia and hypercapnia were examined in 28 patients (3 female) with
moderate to severe OSA. All these tests were examined before and after 2 weeks of
nasal CPAP. In 10 patients these tests were repeated after 3-6 months of nasal
CPAP. All were also tested for spirometry and arterial blood gas analysis.
Patients were middle-aged (48.9 +/- 9.9 years) and their mean apnea-hypopnea
index was 58.3 +/- 20.4/hour. After 2 week of nasal CPAP, PaO2 significantly
increased (77.7 +/- 11.8 vs. 84.6 +/- 9.8 mmHg) and PaCO2 significantly decreased
(44.9 +/- 3.8 vs. 42.3 +/- 3.7 mmHg). The ventilatory response to hypoxia
significantly decreased (0.80 +/- 0.51 vs. 0.61 +/- 0.51 liter/min/%) whereas the
ventilatory response to hypercapnia significantly increased after 2 weeks (1.47
+/- 0.73 vs. 1.80 +/- 0.76 liter/min/mmHg). Similar findings were also observed
after 3-6 months of nasal CPAP in 10 OSA patients. Nasal CPAP treatment can alter
the ventilatory responses in patients with OSA.
PMID- 10770624
TI - Interleukin-2 gene-transduced human leukemic cells induce major
histocompatibility complex-restricted and -unrestricted anti-leukemic effectors
in mixed lymphocyte-tumor cultures.
AB - To explore the feasibility of designing vaccination protocols in acute leukemia
patients with cytokine gene-transduced leukemic cells, we studied in vitro the
growth potential of human leukemic cells transduced with the interleukin-2 (IL
2), IL-7, or IL-7 plus IL-2 genes, as well as the capacity of generating both
autologous and allogeneic cytotoxic lymphocytes directed against the parental
cells. A lymphoblastic T-cell line, ST4, obtained from a patient in long-lasting
complete remission, was retrovirally engineered with the IL-2, IL-7, and IL-7
plus IL-2 genes; in addition, clones releasing different amounts of the cytokines
were obtained by limiting dilution. Mixed lymphocyte-tumor cultures (MLTCs) were
set up with parental or transduced leukemic cells as stimulators and with
autologous or allogeneic lymphocytes as responders. When nonirradiated ST4
parental cells or clones producing <50 international units (IU)/mL/10(6) cells/72
hours of IL-2 were used as stimulators, leukemic overgrowth was observed in MLTCs
within 16 days of culture. When clones producing >80 IU/mL/10(6) cells/72 hours
of IL-2 were used as stimulators, the proliferation of leukemic cells was blocked
and the transduced leukemic cells were completely cleared from the cultures by
day 16; repeated restimulations with IL-2-producing leukemic cells were required
to sustain long-term lymphocyte survival. On the contrary, when IL-7- or IL-7-IL
2-producing cells were used as stimulators, only a delay in leukemic cell
overgrowth was observed, and lymphocytes were completely cleared from the
cultures after day 60. IL-7 production by the different clones ranged between 11
and 36 ng/mL/10(6) cells/72 hours, whereas the highest IL-2-producing IL-7-IL-2
clone released 50 IU/mL/10(6) cells/72 hours of IL-2. When the stimulator
efficacy of the highest IL-2-producing clone (ST4/IL-2#A7) was compared with that
of exogenous IL-2 plus parental cells, a 7-fold higher amount of exogenous IL-2
was required to achieve the same results obtained with IL-2-producing leukemic
cells. Autologous and allogeneic long-term MLTCs (up to 35 days) with ST4/IL-2#A7
as the stimulator were capable of generating cytotoxic effectors equally endowed
with both major histocompatibility complex (MHC) class I-unrestricted and
restricted activity against parental ST4 cells. By day 18 of both autologous and
allogeneic cultures, a substantial proportion of CD56+ cells was consistently
recorded; this was coupled to a predominantly MHC-unrestricted cytotoxic activity
directed against parental ST4 cells. CD56+ cells decreased considerably at the
end of the different MLTCs, together with the unrestricted cytotoxic activity. At
this time, >50% of the cells were CD8+, and 55% of the activity could be blocked
by an anti-MHC class I monoclonal antibody. The results of this study demonstrate
that IL-2 gene-transduced human acute leukemia cells cocultured with both
autologous and allogeneic lymphocytes are capable of inducing a strong MHC
unrestricted anti-leukemic activity and subsequently "educating" MHC class I
restricted anti-leukemic effectors. The evidence that the immunogenic potential
of human leukemic blasts can be boosted after transfer of the IL-2 gene suggests
that the possibility of using leukemic cells engineered to release IL-2 as a
therapeutic vaccine needs to be explored further.
PMID- 10770625
TI - Enhanced antitumoral effect of adenovirus-mediated cytosine deaminase gene
therapy by induction of antigen-presenting cells through stem cell
factor/granulocyte-macrophage colony-stimulating factor gene transfer.
AB - Suicide gene therapy has been studied intensively for the treatment of cancer. A
limited antitumoral effect was obtained by intratumoral injection of adenovirus
harboring Escherichia coli cytosine deaminase gene (AdCD) in tumor-bearing mice
followed by continuous administration of 5-fluorocytosine (5FC). To address the
drawbacks of the limited potential for the induction of antitumoral immunity by
CD suicide gene therapy, we hypothesized that antigen-presenting cells (APCs)
might contribute to the efficient induction of an antitumoral immune response in
tumor-bearing mice undergoing suicide gene therapy. We preinjected the mice with
murine stem cell factor (SCF)-encoding adenovirus (AdSCF) and murine granulocyte
macrophage colony-stimulating factor (GM-CSF)-encoding adenovirus (AdGM-CSF);
after 7 days, the mice were inoculated with CT26 colon adenocarcinoma. AdCD was
injected intratumorally into tumor-bearing mice followed by 5FC administration.
The results showed that AdSCF/AdGM-CSF treatment could increase the number,
surface molecule expression, and function of APCs efficiently. A more significant
growth inhibition of established tumors and a prolongation of the survival period
were observed in tumor-bearing mice after AdSCF/AdGM-CSF pretreatment in
combination with AdCD/5FC therapy when compared with mice treated with AdSCF or
AdGM-CSF in combination with AdCD/5FC, or AdCD/5FC alone (P < .01). Cytotoxic T
lymphocyte activity was induced efficiently after the combined therapy, and mRNA
of tumor necrosis factor-alpha, interleukin-4, interferon-gamma, and interleukin
2 was present in the tumor mass after combined therapy, suggesting that a more
potent antitumoral response was induced by enhanced APCs. Our results
demonstrated that AdSCF/AdGM-CSF pretreatment could activate APCs, and that these
APCs could present the tumor antigens released from AdCD/5FC-killed tumor cells
and activate the antitumoral response of the host, thus increasing the
therapeutic efficiency of suicide gene therapy.
PMID- 10770626
TI - Bystander-mediated regression of osteosarcoma via retroviral transfer of the
herpes simplex virus thymidine kinase and human interleukin-2 genes.
AB - Current treatment of osteosarcoma produces disappointing outcomes, and innovative
therapies must be investigated. We have used retroviral vectors to transfer the
herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human
osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene
effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A
strong bystander effect was observed in vitro, whereby nontransduced tumor cells
in proximity to transduced cells acquired susceptibility to GCV killing. Human
osteosarcoma cells were used to develop a series of experiments in athymic nude
mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of
tumor cells and HSVtk vector producer cells developed into tumors that completely
regressed upon administration of GCV. Subcutaneously implanted mixtures of
transduced and wild-type cells showed a potent bystander effect upon
administration of GCV, with complete tumor ablation when as little as 10% of the
cells were HSVtk+. A significant (P < .05) antitumoral response was seen against
primary tumors composed of unmodified cells when a secondary tumor of transduced
cells was implanted at a distance of 1 cm, suggesting a diffusible bystander
factor. The presence of interleukin-2-transduced cells improved the efficacy of
treatment. A significant (P < .03) antitumoral response was seen in the treatment
of established osteosarcomas by the injection of HSVtk vector producer cells.
PMID- 10770627
TI - Purging of human breast cancer cells from stem cell products with an adenovirus
containing p53.
AB - Tumor cell contamination of stem cell products can contribute to tumor relapse
following high-dose chemotherapy and stem cell rescue. Numerous techniques have
been used to remove the tumor cells from stem cell products with the objective of
prolonging relapse-free survival. However, to date these techniques have been
relatively ineffectual and/or toxic to hematopoietic stem and progenitor cells.
The differential infectivity of adenovirus (Adv) vectors for breast cancer cells,
compared with hematopoietic cells, has suggested that Adv-p53 might provide an
effective purging strategy. To facilitate the use of Adv-p53 as a clinical
strategy, we undertook studies to determine the parameters necessary for optimal
stem cell product purging. The parameters studied were the particle number to
nucleated cell ratio, the duration of coincubation, the incubation volume, and
the presence or absence of hematopoietic progenitor cells. We have found that
these parameters are interdependent and conclude that a 4-hour coincubation with
an Adv-p53 particle to nucleated cell ratio of 2000:1 with 2 x 10(8) nucleated
cells/mL is optimal for tumor cell purging. Furthermore, this appeared to be a
safe procedure, with total loss of clonogenic growth of breast cancer cells as
well as no significant effect on progenitor cell function as determined by
granulocyte-macrophage colony-forming unit assays.
PMID- 10770628
TI - Local versus systemic interleukin-2: tumor formation by wild-type and B7-1
positive murine melanoma cells.
AB - Modification of murine K1735 melanoma cells to express the immune costimulator B7
1 had no effect on tumor formation in syngeneic mice. In contrast, <40% of mice
inoculated with K1735 cells modified to secrete murine interleukin-2 (IL-2)
formed tumors, and no tumors formed when the K1735 cells coexpressed both murine
IL-2 and B7-1. However, administration of systemic recombinant human IL-2 had no
detectable effect on the formation of tumors by the B7-1-expressing K1735 cells.
By contrast, admixtures of IL-2-secreting and B7-1-expressing K1735 cells formed
fewer tumors than either cell type alone. Murine IL-2 was effective only when
secreted locally, because the IL-2-secreting cells inoculated into the right
flank did not affect the growth of the B7-1-expressing cells inoculated into the
opposite flank.
PMID- 10770629
TI - Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2'
deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-beta-D
arabinofuranosyluracil (BVaraU), against tumor cells expressing either the
Varicella zoster or the Herpes simplex virus thymidine kinase.
AB - The inhibitory effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and its
arabinosyl derivative (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil
(BVaraU) on the growth of both MDA-MB-435 human breast carcinoma and 9L rat
gliosarcoma cells expressing the thymidine kinase (tk)-encoding gene of the
Varicella zoster virus (VZV) or the Herpes simplex virus (HSV) were evaluated. In
vitro, BVDU and BVaraU effectively killed both cell types expressing VZVtk, with
50% inhibitory concentration values ranging from 0.06 to 0.4 microM, whereas
ganciclovir (GCV) lacked activity. On HSVtk+ cells, BVDU had high cytotoxic
activity, with 50% inhibitory concentration values that were similar to those of
GCV, whereas BVaraU was inactive. In vivo, BVDU applied intraperitoneally caused
a 50% tumor growth inhibition in nude mice inoculated subcutaneously with VZVtk+
as well as HSVtk+ mammary tumor cells. In mice and at variance with the in vitro
results, BVaraU had very little activity against the VZVtk+ mammary cells; GCV
had the highest activity on the HSVtk+ cells, resulting in a 50% eradication of
the tumors. With the 9L rat gliosarcoma model, the VZVtk/BVDU system completely
failed to inhibit the development of VZVtk+ glioma tumors induced subcutaneously
in syngeneic rats, although BVDU had a similar 45-minute half-life in both rats
and mice. Factors other than degradation of the prodrug and related to the mode
of action of these analogs are possibly involved in the observed discrepancies
between the in vitro and in vivo results.
PMID- 10770630
TI - Adenovirus-mediated overexpression of Fas induces apoptosis of gliomas.
AB - Gliomas express a higher amount of Fas than normal brain tissue. It is of
interest to know whether expression of the Fas receptor is unfavorable to the
antiapoptotic pathways in gliomas. In this study, we introduced the Fas gene via
an adenovirus vector (Adeno-Fas) into the A-172, U251, and U-373 MG glioma cell
lines, each of which expresses Fas on the cell surface. Infection of Adeno-Fas
induced apoptosis in each glioma cell line. In U251 cells and A-172 cells that
express the same level of Fas as a result of infection with Adeno-Fas, a much
higher percentage of U251 cells underwent apoptosis than did A-172 cells. This
suggests that each glioma cell line has its own threshold of Fas expression,
above which apoptosis is induced, and that the constitutive expression of Fas is
below the level of this threshold. It was found that the constitutive expression
of the anti-apoptotic gene Bcl-X(L) is higher in A-172 cells than in U251 cells.
Adenovirus-mediated transduction of the Bcl-X(L) gene into U251 cells effectively
suppressed Adeno-Fas-mediated apoptosis. These data indicate that the Bcl-X(L)
gene is one of the important determinants of the threshold for Fas-mediated
apoptosis. When U251 and U-373 MG cells were transduced with the Fas gene
controlled by the myelin basic protein promoter, which had been shown to be
active in gliomas but not in neural tissues, the cells underwent markedly
enhanced apoptosis. Taken together, these results indicate that the
overexpression of Fas alone induced apoptosis in each glioma cell line. The
degree of Fas-mediated apoptosis was attenuated by the expression of an anti
apoptotic gene, Bcl-X(L). The adenovirus-mediated induction of Fas gene
controlled by a tissue-specific promoter (e.g., myelin basic protein promoter)
would be a promising therapeutic approach for malignant glioma.
PMID- 10770631
TI - Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical
use of mitozolomide.
AB - Retroviral gene transfer was used to achieve expression in mouse bone marrow of a
mutant form of the DNA repair protein O6-alkylguanine-DNA alkyltransferase
(hATPA/GA), which exhibits resistance to inactivation by O6-benzylguanine (O6
beG). After reconstitution of mice with transduced bone marrow, approximately 50%
of the bipotent granulocyte-macrophage colony-forming cell (GM-CFC) and
multipotent spleen colony-forming unit (CFU-S) hemopoietic populations showed
expression of the transgene; this expression was associated with resistance to
either mitozolomide or to a combination of O6-beG and mitozolomide, relative to
mock-transduced controls. Thus, at a dose of mitozolomide in vivo that allowed
only 70% and 62% survival of mock-transduced GM-CFC and CFU-S, respectively, the
hATPA/GA CFC were totally resistant to the same dose of mitozolomide (P < .05 and
.001, respectively). In the presence of O6-beG, the toxicity of mitozolomide was
greatly potentiated. Only 24% and 18%, respectively, of mock-transduced GM-CFC
and CFU-S survived combination treatment, whereas 45% (P < .05) and 37% (P < .01)
of GM-CFC and CFU-S, respectively, from hATPA/GA mice survived the same
combination of doses. Furthermore, as a result of transgene expression, the
number of micronucleated polychromatic erythrocytes induced by mitozolomide was
significantly reduced (P < .05) by 40% relative to mock-transduced controls,
indicating the potential of this approach to reduce the frequency of mutation
associated with chemotherapy exposure. The protection against the toxic and
clastogenic effects of mitozolomide in both primitive and more mature hemopoietic
cells suggests that the severe myelosuppression that halted further clinical
investigation of this drug could be substantially ameliorated by the exogenous
expression of O6-alkylguanine-DNA alkyltransferase. Therefore, these data raise
the prospect for the reinvestigation of mitozolomide and other proscribed drugs
in the context of genetically protected hemopoiesis.
PMID- 10770632
TI - Ganciclovir-mediated cell killing and bystander effect is enhanced in cells with
two copies of the herpes simplex virus thymidine kinase gene.
AB - Delivery and expression of the herpes simplex virus thymidine kinase (HSVtk) gene
in combination with the prodrug ganciclovir is currently being evaluated for the
treatment of many types of cancer. After initial phosphorylation by HSVtk,
cellular kinases generate the toxic triphosphate form of ganciclovir (GCV). To
further define the role of GCV metabolism in cells expressing HSVtk, two human
tumor cell lines, UMSCC29 and T98G, were transduced with HSVtk and screened for
insertion of one or two copies of the viral transgene by Southern blot analysis.
Both the relative capacities for incorporating labeled GCV and the levels of GCV
metabolites were determined for each of the parental cell lines and their
derivatives containing either one or two copies of the HSVtk gene. The efficiency
of GCV killing and the magnitude of the bystander effect were compared for the
single- and double-copy HSVtk cell lines. Consistently, cells that expressed two
copies of HSVtk metabolized GCV more efficiently, were more sensitive to GCV, and
demonstrated improved bystander killing relative to single-copy HSVtk cells. The
implications of these results for future and current therapies employing HSVtk
and GCV are discussed.
PMID- 10770633
TI - Protective immunity is induced in murine colon carcinoma cells by the expression
of interleukin-12 or interleukin-18, which activate type 1 helper T cells.
AB - We investigated the antitumor effects induced by the production of interleukin-12
(IL-12) or IL-18, which influence the function of T helper type 1 cells, in
murine colon carcinoma cells (Colon 26). Retrovirally transduced cells with IL-12
genes that encoded both p35 and p40 (Colon 26/IL-12) lost their tumorigenicity
when inoculated subcutaneously or intraperitoneally into syngeneic
immunocompetent mice. Moreover, the mice that had rejected the Colon 26/IL-12
cells generated protective immunity to wild-type (wt) cells when subsequently
challenged. Colon 26 cells transduced with the IL-18 gene (Colon 26/IL-18) could
not form subcutaneous tumors in immunocompetent mice, and the mice became
resistant to inoculated wt cells. Immunohistochemical analysis revealed that the
numbers of blood vessels in Colon 26/IL-12 or Colon 26/IL-18 tumors were markedly
reduced, and that the expression of adhesion molecules such as intercellular
adhesion molecule-1 and vascular cell adhesion molecule-1 increased on the
endothelium in the stroma of Colon 26/IL-12 tumors. The loss of tumorigenicity of
Colon 26/IL-12 or Colon 26/IL-18 cells was not observed in immunocompromised
mice. However, the survival days of the immunocompromised mice inoculated with
Colon 26/IL-12 but not Colon 26/IL-18 cells were significantly longer than those
inoculated with wt cells. The secretion of cytokines that stimulate T helper type
1 cells from tumor cells can thereby induce an antitumor response. However, the
effector cells involved in these antitumor effects could differentially migrate
to the tumors, and the inhibition of angiogenesis may partially contribute to the
antitumor responses observed.
PMID- 10770634
TI - Transduction of murine colon carcinoma cells with interleukin-15 gene induces
antitumor effects in immunocompetent and immunocompromised hosts.
AB - We examined the antitumor effects caused by murine colon carcinoma cells (Colon
26) transduced with interleukin-15 (IL-15) gene. Although the in vitro
proliferation rate of IL-15-secreting Colon 26 (Colon 26/IL-15) cells was not
different from that of wild-type (wt) cells, small subcutaneous tumors of Colon
26/IL-15 cells that developed in syngeneic immunocompetent mice regressed
spontaneously in contrast to tumors of wt cells. The mice that had eliminated
tumors of Colon 26/IL-15 cells rejected wt cells when subsequently challenged.
The survival of the mice that had been inoculated intraperitoneally with Colon
26/IL-15 cells was significantly prolonged compared with that of the mice
injected with wt cells. However, in an experimental lung metastasis model, the
survival of the mice inoculated with Colon 26/IL-15 cells remained the same as
that of the mice inoculated with wt cells. The inoculation of Colon 26/IL-15
cells into immunocompromised nude or severe combined immunodeficient mice
produced tumors, but the survival of the immunocompromised mice was significantly
longer than that of the mice inoculated with wt cells. The nude mice inoculated
with Colon 26/IL-15 cells also survived longer than the severe combined
immunodeficient mice with Colon 26/IL-15 cells. Depletion of natural killer cells
in nude mice with anti-asialo GM1 antibody did not influence the survival of the
mice injected with Colon 26/IL-15 cells. Immunohistological examination revealed
that CD31+ cells migrated into tumors of Colon 26/IL-15 cells that developed in
immunocompetent and immunocompromised mice. Taken together, our results indicate
that an inoculation of IL-15-producing tumor cells can produce antitumor effects
that are mediated by a variety of immunocompetent cells.
PMID- 10770635
TI - Gene delivery by an epidermal growth factor/DNA polyplex to small cell lung
cancer cell lines expressing low levels of epidermal growth factor receptor.
AB - In the present study, we wanted to determine whether efficient gene delivery
using an epidermal growth factor (EGF)/DNA polyplex could be accomplished in
small cell lung cancer (SCLC) cell lines expressing low EGF receptor (EGFR)
levels. EGFR expression levels and transduction efficiencies with polyplexes were
examined in five SCLC cell lines and two controls. EGFR expression was examined
by binding assays and demonstrated low EGFR levels ranging from 3.6 to 87.4
fmol/mg protein. The SCLC cell lines exhibited high sensitivity to adenovirus
infection, which was an important determinant for transduction efficiency when
adenovirus was used as an endosomolytic agent. The transduction efficiencies with
EGF/DNA polyplexes ranged from 41% +/- 3.5% to 73% +/- 4.6% in the EGFR-positive
SCLC cell lines. In the controls lacking EGFRs, only 5% +/- 1.0% and 8% +/- 1.8%
of the cells were transduced. Furthermore, the transduction efficiency could be
reduced from 50% +/- 4.9% to 18% +/- 1.1% when excess EGF was added to compete
with the EGF/DNA polyplexes. In the present study, receptor-targeted gene
delivery to SCLC cell lines has been demonstrated for the first time. Our results
indicate that even low receptor expression levels in the target cells are
sufficient for efficient and specific in vitro gene delivery with EGF/DNA
polyplexes.
PMID- 10770636
TI - Bifidobacterium longum as a delivery system for cancer gene therapy: selective
localization and growth in hypoxic tumors.
AB - A fundamental obstacle in gene therapy for cancer is the specific delivery of an
anticancer gene product to a solid tumor, and yet no systemic delivery system
that specifically targets solid tumors currently exists. A strain of domestic
bacteria, Bifidobacterium longum, which is nonpathogenic and anaerobic,
selectively localized and proliferated in several types of mouse solid tumors
after systemic application. In this report, we further describe a novel approach
to cancer gene therapy in which genetically engineered Bifidobacterium is used as
a tumor-specific vector. Similarly to wild-type B. longum, genetically engineered
B. longum could be detected in tumor tissue only and was not found in a large
survey of normal mouse tissues after intravenous injection. This finding strongly
suggests that obligate anaerobic bacteria such as Bifidobacterium can be used as
highly specific gene delivery vectors for cancer gene therapy.
PMID- 10770637
TI - Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against
epithelial ovarian cancer but not normal mesothelium and is suitable for
intraperitoneal oncolytic therapy.
AB - Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the
infected cell product (ICP)34.5 region lose their neurovirulence and replicate
more efficiently in dividing tumor cells than stationary cells, becoming
replication-selective oncolytic agents. Additional mutation of the ICP6 gene,
which encodes ribonucleotide reductase, further impairs the ability of HSV-1
mutants to replicate in normal cells, enhancing tumor selectivity. The present
study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5
and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse
xenograft model. To assess the selectivity of multimutated HSV-G207 against
malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against
normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207
infected both EOC cells and mesothelial cells; however, unlike EOC cells,
mesothelial cells provided a poor substrate for replication of HSV-G207. In
contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC
cells but spared normal mesothelial cells in vitro. Primary EOC cells were more
sensitive to the virus than established EOC cell lines. A single intraperitoneal
injection of HSV-G207 resulted in a significant reduction in tumor volume and
tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules
and caused no apparent intraperitoneal toxicity. Oncolytic therapy with
multimutated replication-restricted HSV may offer a novel approach in the
treatment of EOC.
PMID- 10770638
TI - Recognition of human colon cancer by T cells transduced with a chimeric receptor
gene.
AB - Transduction with chimeric T-cell receptor genes can be used to redirect primary
T lymphocytes to recognize specific antigens (Ags), including ovarian and breast
cancer Ags. To extend this approach to colon cancer we report here redirection of
T cells using a chimeric receptor recognizing the colon cancer-associated Ag
EGP40. Chimeric T cell receptors were constructed by ligating single-chain genes
of either of two EGP40-specific monoclonal antibodies (CO17.1 A, GA733) to the Fc
receptor gamma-signaling chain. Retroviral vectors incorporating these constructs
were used to transduce a murine T-cell line and human peripheral blood
lymphocytes. These modified T cells were analyzed for specific recognition of
colon cancer lines by measuring cytokine release and lytic activity against tumor
targets. Murine lymphocytes transduced with the chimeric receptor based on GA733,
but not CO17.1A, released cytokine specifically in response to EGP40-expressing
colon cancer cell lines. Recognition of colon cancer targets by murine
lymphocytes was blocked by the addition of GA733 antibody or soluble EGP40 Ag,
confirming that colon cancer recognition is based on specific chimeric receptor
Ag interaction. Human lymphocytes transduced with chimeric GA733 specifically
recognized colon carcinoma cells in cytokine release assays and lysed EGP40
expressing tumor cells. Genetic modification of T cells can be used to redirect T
cells against EGP40-expressing tumor cells. The expression of chimeric GA733 in
the autologous lymphocytes of patients may provide a source of tumor-reactive
cells with therapeutic application against colon cancer.
PMID- 10770639
TI - Reduction of breast carcinoma tumor growth and lung colonization by
overexpression of the soluble urokinase-type plasminogen activator receptor
(CD87).
AB - The serine protease urokinase-type plasminogen activator, uPA, when bound to its
specific receptor, uPAR (CD87), plays a significant role in tumor cell invasion
and metastasis. In breast cancer, enhanced uPA antigen in the primary tumor is
correlated with poor prognosis of the patient. In an in vivo nude mouse model, we
tested tumor growth and metastasis of human breast carcinoma cells that had been
transfected with an expression plasmid encoding a soluble form of uPAR (suPAR).
We explored, whether suPAR/uPA interaction reduces the binding of uPA to cell
surface-associated uPAR, and, as a consequence, could suppress tumor growth and
metastasis of the human breast cancer cell line MDA-MB-231 BAG. Overexpressed,
secreted suPAR was shown to bind and thus scavenge the uPA secreted by the
transfected lines suPAR3 and suPAR10. In vitro, an overexpression of suPAR did
not alter the proliferation rate of the transfected tumor cells, nor did it
affect the expression of uPA. Overexpression of suPAR led to a reduction in the
plasminogen activation-related proteolytic activity of breast carcinoma cells.
Primary tumor growth in the mammary fat pad of nude mice was followed up for 52
days. Overexpression of suPAR correlated with a reduction in tumor growth (from
day 21, reaching 30% by day 34) as well as lung colonization (lung metastasis
positive mice in suPAR3: 4 of 17; suPAR10: 3 of 10; parental MDA-MB-231 BAG: 13
of 18). We conclude that suPAR overexpression leading to effective scavenge of
uPA impairs proteolysis as well as the tumor growth and metastatic potential of
breast carcinoma cells in vivo.
PMID- 10770640
TI - Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of
the wild-type p53 gene in human lung cancer cells.
AB - The aim of the present study is to identify the optimal anticancer agents for use
in combination with gene therapy using wild-type (wt) p53 gene transfer. We used
adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects
of wt p53 gene transfer in combination with 12 anticancer agents on a human
pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary
large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents
at various concentrations were added followed by the addition of recombinant
adenovirus solutions; after a 5-day incubation period, the anticancer activity
was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5
carbo xanilide assay. Each 50% inhibitory concentration was calculated based on
the dose-response curves. The agents showing a high degree of effectiveness on
NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7
ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT
11); conversely, cyclophosphamide and paclitaxel showed a low degree of
effectiveness. Based on these data, an isobologram was performed to investigate
the interaction between AdCAp53 and some anticancer agents. A supra-additive
effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect
was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI
H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299
cells. No drug showed any subadditive or protective effects. These findings
suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for
use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11
had a significant antitumoral effect on H157 cell xenografts of nude mice in
vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for
the combination of chemotherapy and gene therapy for non-small cell lung cancer.
PMID- 10770641
TI - Construction of a recombinant adeno-associated virus (rAAV) vector expressing
murine interleukin-12 (IL-12).
AB - IL-12 is a heterodimeric cytokine that is known to induce tumor regression and
long-term antitumor immunity. Recombinant adeno-associated virus (rAAV) vectors
are advantageous for gene therapy in that they lack pathogenicity in humans,
infect dividing as well as nondividing cells, and show a broad range of
infectivity. We constructed an rAAV vector expressing interleukin-12 (IL-12) for
cancer immunotherapy studies in a mouse model by inserting murine IL-12 (mIL-12)
p35 and p40 cDNAs into the plasmid pRep4 and inserting the encephalomyocarditis
virus internal ribosomal entry site between the p35 and p40 cDNAs. The mIL-12
expression cassette containing the Rous sarcoma virus promoter and a simian virus
40 polyadenylation signal was subcloned into the AAV plasmid p008Sub/NeoR, which
contains two AAV inverted terminal repeat sequences and the NeoR gene driven by
the thymidine kinase promoter. rAAV virions (10(4) infectious particles/ml) were
generated by cotransfection of rAAV-mIL-12 and a helper plasmid (pAAV/Ad) into
293 cells previously infected with adenovirus 5. After infection of D6
fibroblasts with rAAV-mIL-12, G418-resistant clones were isolated. Each of the 1D
D6 clones isolated produced up to 5.2 ng/10(6) cells/48 hours of mIL-12 as
determined by enzyme-linked immunosorbent assay. Induction of interferon-gamma,
enhanced lymphocyte proliferation, and cytotoxicity assays confirmed biologically
functional IL-12 production by the vector. This is the first report indicating
that an rAAV vector expresses mIL-12, which can be used to model the effects of
mIL-12 alone and/or in combination with other antitumor agents.
PMID- 10770642
TI - Newcastle disease virus infection induces B7-1/B7-2-independent T-cell
costimulatory activity in human melanoma cells.
AB - Viral oncolysates of Newcastle disease virus (NDV) have been widely used for the
treatment of malignant melanoma. Apparently, this nononcogenic and apathogenic
paramyxovirus can alter the immunogenicity of tumor cells. To determine the
influence of NDV infection on a tumor-specific T-cell response on a functional
level, we used autologous primary melanoma cells infected with the NDV-strain
Ulster. Therefore, melanoma cells and tumor-infiltrating lymphocytes were
prepared from a freshly resected tumor, and tumor-infiltrating lymphocytes were
subjected to limited dilution cloning. Proliferation assays of the T-helper cell
clone sTS3 (CD4+) showed that the T-cell clone was rendered nonreactive against
its autologous major histocompatibility complex II+, B7-1/B7-2- melanoma SMS,
even remaining unresponsive to subsequent stimulation by interleukin-2. NDV
infection of the SMS melanoma cell line not only completely restored the
proliferative response of sTS3 to SMS, comparable with stimulation by cross
linking of anti-CD3/anti-CD28 monoclonal antibodies, but also inhibited the
induction of anergy. Electrophoretic mobility shift assays of sTS3 cell lysates
revealed the induction of the CD28-responsive complex by coincubation with NDV
infected melanoma cells. Because the induction of this complex of nuclear
proteins shows specificity for the activation of the CD28 pathway but functional
B7-1/B7-2 expression was not detectable on SMS melanoma cells at any timepoint,
we propose the induction of a costimulatory factor different from B7 by NDV viral
proteins.
PMID- 10770643
TI - Impaired tumorigenicity of human pancreatic cancer cells retrovirally transduced
with interleukin-12 or interleukin-15 gene.
AB - We examined the antitumor effect of locally secreted interleukin (IL)-12 or IL-15
on human pancreatic cancer cells (AsPC-1). We subcutaneously inoculated AsPC-1
cells retrovirally transduced with IL-12 or IL-15 cDNA into nude mice. Tumors
derived from these cells showed retarded growth compared with those from wild
type (wt) cells. Nude mice inoculated intraperitoneally with the cytokine
producers survived longer than those injected with wt cells. These cytokine
producers were also tested for their tumor growth in severe combined
immunodeficient mice. The tumor growth of IL-12 producers was similarly
suppressed as found in nude mice, but the average tumor volumes of IL-15
producers were not statistically different from those of wt tumors. In nude mice
that were administered anti-asialo GM1 antibody before the inoculation of the
tumor cells, growth retardation of tumors of IL-12 producers remained the same as
in untreated animals, but that of IL-15 producers was markedly reduced.
Immunohistochemical analysis revealed that CD11b+ cells migrated into the tumors
of cytokine producers and that the number of CD31+ endothelial cells within the
tumors was not different between IL-12 producers and wt cells. Taken together
with other data, it is possible that granulocytes are candidate cells for the IL
12-mediated antitumor effect, and that natural killer cells and gammadelta T
cells are involved in the IL-15-induced antitumor effect. We did not observe
synergistic effects of these cytokines to suppress subcutaneous tumors.
PMID- 10770644
TI - Survival efficacy of the combination of the methioninase gene and methioninase in
a lung cancer orthotopic model.
AB - We have previously demonstrated the antitumor efficacy of recombinant
methioninase (rMETase) derived from Pseudomonas putida. To enhance the efficacy
of rMETase, we have constructed the pLGFP-METSN retrovirus encoding the P. putida
methioninase (MET) gene fused with the green fluorescent protein (GFP) gene.
pLGFP-METSN or control vector pLGFPSN was introduced into the human lung cancer
cell line H460. The methionine level of H460-GFP-MET cells was reduced to 33% of
that of H460-GFP cells. rMETase (0.08 U/mL) in the medium resulted in 10%
survival of H460-GFP-MET cells compared with untreated cells in vitro. In
contrast, rMETase-treated H460-GFP cells survived at 90% of control. Tissue
fragments harvested from subcutaneous tumors of H460-GFP-MET or H460-MET were
implanted by surgical orthotopic implantation into the lungs of nude mice. A
suboptimal dose of rMETase was administered intraperitoneally daily to mice in
each group. Overall survival of rMETase-treated animals with H460-GFP-MET tumors
was significantly longer than either rMETase-treated or -untreated animals with
H460-GFP tumors (P < .05 in log-rank test). In two repeat experiments, rMETase
treated animals with H460-GFP-MET tumors had a 30-day survival of 80% and 83%,
respectively. Untreated animals with H460-GFP-MET tumors had a 30-day survival of
40% and 58%, respectively. rMETase-treated animals with H460-GFP tumors had a 30
day survival of 0% and 33%, respectively. Untreated animals with H460-GFP tumors
had a 30-day survival of 0% and 33%, respectively. The retrovirus-mediated gene
transfer of METase decreased the intracellular methionine level of tumor cells
and consequently enhanced the efficacy of treatment with the rMETase protein. We
have thus demonstrated a new strategy of combination tumor therapy with the gene
and gene product of MET.
PMID- 10770645
TI - Transfer of Ku86 RNA antisense decreases the radioresistance of human
fibroblasts.
AB - Ku86 has been shown to be involved in DNA double-strand break (DSB) repair and
radiosensitivity in rodents, but its role in human cells is still under
investigation. The purpose of this study was to evaluate the radiosensitivity and
DSB repair after transfection of a Ku86-antisense in a human fibroblast cell
line. Simian virus 40-transformed MRC5V1 human fibroblasts were transfected with
a vector (pcDNA3) containing a Ku86-antisense cDNA. The main endpoints were Ku86
protein level, Ku DNA end-binding and DNA protein kinase activity, clonogenic
survival, and DSB repair kinetics. After transfection of the Ku86-antisense,
decreased Ku86 protein expression, Ku DNA end-binding activity, and DNA protein
kinase activity were observed in the uncloned cellular population. The
fibroblasts transfected with the Ku86-antisense showed also a radiosensitive
phenotype, with a surviving fraction at 2 Gy of 0.29 compared with 0.75 for the
control and 20% of unrepaired DSB observed at 24 hours after irradiation compared
with 0% for the control. Several clones were also isolated with a decreased level
of Ku86 protein, a surviving fraction at 2 Gy between 0.05 and 0.40, and 10-20%
of unrepaired DSB at 24 hours. This study is the first to show the implication of
Ku86 in DSB repair and in the radiosensitivity of human cells. This investigation
strongly suggests that Ku86 could constitute an appealing target for combining
gene therapy and radiation therapy.
PMID- 10770646
TI - The role of cytokines as inflammatory mediators in osteoarthritis: lessons from
animal models.
AB - Studies in animal models of osteoarthritis (OA) have been used extensively to
gain insight into the pathogenesis of OA, but early studies largely ignored
inflammation except as a secondary phenomenon. Synovitis has often been noted as
a feature in experimental OA, and more recent work has established a central role
for inflammatory cytokines as biochemical signals which stimulate chondrocytes to
release cartilage-degrading proteinases. Thus, proteinase inhibitors, cytokine
antagonists and receptor blocking antibodies, and growth/differentiation factors
have been considered as potential therapeutic agents and targets for gene
therapy. Although there is some disagreement, it is generally accepted that IL-1
is the pivotal cytokine at early and late stages, while TNF-alpha is involved
primarily in the onset of arthritis. Other cytokines released during the
inflammatory process in the OA joint may be regulatory (IL-6, IL-8) or inhibitory
(IL-4, IL-10, IL-13, IFN-gamma). Furthermore, studies in animal models have
illustrated the potentially beneficial effects of anticytokine therapy with
monoclonal antibodies or receptor antagonists, although local rather than
systemic delivery would be necessary for the largely localized OA in humans.
Transgenic or knockout mice have also provided insights into general mechanisms
of cytokine-induced cartilage degradation but have not directly addressed OA
pathogenesis. Similarly, animals with spontaneous or transgenic modifications in
cartilage matrix components, growth/differentiation factors, or developmentally
regulated transcription factors have provided information about potential gene
defects that predispose to OA without addressing the role of inflammatory
mediators in cartilage destruction. Although the multiple etiologies of human OA
indicate that it is more complex than any animal model, the use of appropriate,
well-defined animal models will establish the feasibility of novel forms of
therapy.
PMID- 10770647
TI - Porcine anterior cruciate ligament fibroblasts are similar to cells derived from
the ligamentum teres, another non-healing intra-articular ligament.
AB - Porcine ligament fibroblasts were cultured from the anterior cruciate (ACL),
medial collateral (MCL), and ligamentum teres (LT). There were no apparent
differences in confluent cellular morphology among the ligament cell types as
evaluated by phase contrast microscopy. The proliferation rate of MCL cells from
24-120 h was significantly higher (p < 0.05) than that of cells from either the
LT or the ACL. MCL cells produced more collagen and less non-collagenous protein
than the LT and ACL as determined by [3H]proline incorporation. This resulted in
MCL cells producing a higher percentage (37%, p < 0.05) of collagen relative to
total protein than either the ACL (28%) or the LT (32%). The MCL cells produced a
significantly higher percentage (34.7%, p < 0.05) of type-III collagen relative
to total type-I and III collagen than either the ACL (29.2%) or the LT (29.5%).
The LT and MCL cells had similar and significantly greater coverage of in vitro
wounds than the ACL. This study provides the first in vitro study of the LT and
demonstrates that fibroblasts from the LT and ACL, two ligaments that heal
poorly, have similar in vitro characteristics, with the exception of wound
healing.
PMID- 10770648
TI - Fibroblasts and eosinophils in normal fibroplasia of ferret vulval skin, shown by
light and electron microscopy; with special reference to eosinophil
degranulation.
AB - In order to compare aspects of normal fibroplasia with reports for pathologically
fibrotic tissue, light and electron microscopic observations were made on ferret
vulval skin, which proliferates markedly with the onset of estrus and regresses
equally fast after mating. Estrous tissue, which contained hypertrophied
fibroblasts, new collagen, elastic fibers and ground substance, was invaded by
numerous eosinophils with extensive release of granules. Eosinophil degranulation
was both extra- and intracellular; some cells, completely disintegrated, had
released all contents into the extracellular matrix. Extruded granules reacted
positively for major basic protein. In regression, diminished fibroblasts
incorporated collagen fibrils. Many of the features seen in this normal
fibroplasia in ferret vulval skin are similar to those in pathologic situations.
Thus, in particular, the presence of degranulating eosinophils in pathologic
fibrosis does not necessarily indicate that they are the cause of the disease.
Our information and that from other sources implies a role for eosinophils in
connective tissue change.
PMID- 10770649
TI - Identification and immunolocalization of chondroitin sulfate proteoglycans in
tooth cementum.
AB - Proteoglycans (PGs) display a great diversity in their core proteins as well as
carbohydrate structures and are thought to be involved in many biological
functions. Recently we have identified and immunolocalized two keratan sulfate
PGs, fibromodulin and lumican, in bovine tooth cementum (Cheng et al., Connect.
Tissue Res. 34: 87-96, 1996). The objectives of this study were to identify and
characterize chondroitin sulfate (CS) PGs in cementum. In order to explore their
potential association with mineral, bovine cementum matrix molecules were
fractionated into mineral-unbound and -bound matrices by sequential extraction.
Both fractions were subjected to DEAE anion exchange column chromatography and
the eluate collected was assayed for C4S and C6S isomers by dot blot immunoassay
with specific monoclonal antibodies, 2-B-6 and 3-B-3, respectively. Two families
of CSPGs were identified mainly in the mineral-unbound fraction. One contained
only C4S glycosaminoglycan and the other both C6S and C4S. By biochemical and
immunochemical analyses, decorin and biglycan were identified in the former and
versican in the latter. The ratio of C6S to C4S isomers of cementum versican was
approximately 7:1. Furthermore, these PGs were immunolocalized in and around
tooth cementum using antibodies generated against the respective core proteins.
Intensive immunostaining for versican was found almost exclusively in the lacunae
housing cementocytes in cementum and osteocytes in alveolar bone, respectively.
Immunostaining for decorin was mainly associated with collagen fibers in the
periodontal ligament and slightly in cementum matrix, while the one for biglycan
was mainly in cementoblasts/precementum. These differential tissue distributions
of the CSPGs suggest that they may play distinct roles in cementogenesis.
PMID- 10770650
TI - Rat dentin matrix protein 3 is a compound protein of rat dentin sialoprotein and
phosphophoryn.
AB - During cloning of the rat incisor phosphophoryn gene, several clones were
identified with a PP antibody. One of the clones (2PP) was shown to encode a PP
denoted as dentin matrix protein 2, DMP2. We have now sequenced another clone,
which appears to be bifunctional, or at minimum, has two distinct domains. The 5'
region encodes for dentin sialoprotein (DSP), while the 3' region encodes a small
or "mini" PP. There is no stop codon between these domains. The whole gene has
been named Dmp3, in keeping with the current nomenclature adopted in our
laboratory. The previously reported Dmp2 gene does not encode a DSP domain but
has a 114 amino acid carboxy terminal sequence identical except for a single
residue with that of the DMP3. Thus, Dmp2, Dmp3 and their corresponding proteins,
probably represent related members of a multigene family. There is no evidence
for differential splicing. Since the DSP isolated from dentin does not carry the
mini-PP domain, it must be cleaved postranslationally from DMP3.
PMID- 10770651
TI - Effects of chronic adult periodontitis and endotoxin (LPS) on gingival fibroblast
plasma membrane Ca++-pump.
AB - Gingival fibroblasts from patients with chronic adult periodontitis are known to
produce cytokines in response to changing levels of bacterial lipopolysaccharide
(LPS). Cytokine production is one of numerous cell processes that involve calcium
dependent enzymes. It is possible that inflammation may induce changes in the
amount of the Ca++-pump protein in gingival fibroblasts which could alter Ca++
dependent activities in these cells including the production and release of
cytokines. The purpose of this study was to determine if differences exist in the
amount of Ca++-pump protein in the gingival fibroblasts of periodontitis patients
relative to control individuals without periodontal disease. Fibroblast explants
from healthy tissue and from inflamed tissue from patients with chronic adult
periodontitis, grown in culture, were analyzed for quantitative differences in
the amount of Ca++-pump protein. Fibroblasts from chronic adult periodontitis
patients exhibited significantly lower levels of Ca++-pump protein than
fibroblasts from healthy subjects (p=0.0015). However, fibroblasts from chronic
adult periodontitis patients, when activated with LPS, did not exhibit
significant differences in the amounts of Ca++-pump protein as compared to
untreated controls (p = 0.2177). Similarly, cells from healthy subjects did not
show significant reduction in Ca++-pump protein following activation with LPS (p
= 0.1732). Our results suggest that plasma membrane Ca++-pump is significantly
reduced in fibroblasts derived from patients with chronic periodontitis. However,
factors other than LPS may be involved in the down-regulation of Ca++-pump
protein.
PMID- 10770652
TI - Collagenase degradation decreases collagen fibril diameters--an in vitro study of
the rabbit medial collateral ligament.
AB - Based on the similarity of fibril diameters in healing and grafted ligaments, it
has been speculated that all small fibrils represent newly synthesized collagen.
Alternatively, small fibrils in grafts could be due to enzymatic degradation of
endogenous large fibrils. This study examined the effect of collagenase on
collagen fibril diameters in normal NZW rabbit MCLs. Midsubstance MCL slivers
were incubated in buffer for 72 or 144 h for comparison with slivers incubated in
buffer containing 4 units/ml bacterial collagenase. The samples were examined
under TEM for fibril diameter analysis. Mean fibril diameters of 3-day and 6-day
collagenase-treated MCLs were significantly reduced, resembling 40-week scar
values. These results suggest that collagenase treatment can alter collagen
fibril diameter and shape in normal rabbit MCL, thus it is possible that despite
their similarity to ligament scars, that at least some small fibrils in ligament
grafts may be enzymatically reduced endogenous fibrils.
PMID- 10770653
TI - Transient hyperphosphatasemia--where do we stand?
AB - Transient hyperphosphatasemia of infancy and early childhood (THI) is
characterized by transiently increased serum activity of alkaline phosphatase (S
ALP), predominantly its bone or liver isoform, in children under five years of
age. There are no signs of metabolic bone disease or hepatopathy corresponding
with the increased SALP, nor is there a disease common to all children with THI.
To date, THI has been reported in more than 400 children. Viral etiology of THI
has been proposed; transiently increased bone turnover and impaired clearance of
ALP from the serum were originally considered as its causes. The pathogenesis is
most probably multifactorial. THI is a benign disorder, as prospective follow-up
of children with a history of TH revealed normal growth and normal bone density.
Children with TH should be spared from excessive diagnostic procedures.
PMID- 10770654
TI - Primary intracranial germ cell tumors in children: a report of eight cases and
review of the literature.
AB - This study was conducted to evaluate the signs and symptoms on admission,
diagnosis, localization, therapy, and survival of patients with primary
intracranial germ cell tumors (PICGCT). Eight patients with surgically confirmed
PICGCTs were treated and followed up at Hacettepe University's Department of
Pediatric Oncology between 1974 and 1995. While one patient was admitted with a
second recurrence of her disease, the others were admitted or referred primarily
to our institution. In this period, 357 germ cell tumor and 684 primary
intracranial malignant tumors were diagnosed and treated at our institution.
Thus, PICGCTs comprised 1.1 percent of the primary intracranial malignant tumors
and 2.2 percent of the germ cell tumors. There were four females and four males
and the median age was eight years (13 months to 12 years). On admission, the
most common symptoms were diabetes insipidus (3/8) and vomiting (3/8). One
patient also and Down's syndrome. Locations of the tumors were suprasellar in
three, in the third ventricle in two, and in the cerebral parenchyma, and pineal
and hypothalamic regions in the remainder. There were germinomas, three malignant
teratomas, and two mixed germ cell tumors. Only two patients could be treated
with appropriate and adequate chemotherapy and radiotherapy. Three patients died:
one in the postsurgical period, one after the third surgical approach and one 11
months after the diagnosis of progressive disease; three were lost to follow-up.
The remaining two patients (with second recurrence and disseminated disease) are
alive and without disease. Our experience with these patients demonstrated that
appropriate and adequate chemotherapy is as effective a treatment as
radiotherapy, even with recurrence of the disease.
PMID- 10770655
TI - Associated brain abnormalities in patients with corpus callosum anomalies.
AB - Forty-nine patients with corpus callosum (CC) anomalies were evaluated in terms
of the clinical features and magnetic resonance imaging (MRI) findings. CC
anomalies were classified as CC agenesis: 6 (12%), CC hypogenesis: 5 (10%), and
CC hypoplasia: 38 (78%). In the CC hypoplasia group the mean value of the genu
thickness of the CC was 0.29 +/- 0.1 cm, which was less than the normal value of
the age-matched normal children (normal range: 0.6-1.2 cm). The associated brain
abnormalities were in five distinct groups: gray matter abnormalities, white
matter abnormalities, midline brain structure defects, cortical atrophy, and
encephalomalacia. There was no uniformity for the clinical spectrum of CC
anomalies. Microcephaly, developmental delay and seizures were the prominent
findings in patients. The clinical features were more severe in cases with
associated brain anomalies.
PMID- 10770656
TI - Human leukocyte antigens in Turkish pediatric celiac patients.
AB - With the aim to determine the frequency of human leukocyte antigen phenotypes of
celiac disease in Turkey, thirty celiac patients fulfilling the European Society
of Pediatric Gastroenterology and Nutrition criteria were included in the study.
The mean age of the study population was 5.8 +/- 4.3 years and of the control
subjects was 32.6 +/- 6.7 years. The human leukocyte antigens -A, -B, -DR and -DQ
were studied serologically by micro lymphocytotoxic reaction. It was found that
human leukocyte antigens A-25(10), -B8, -DR18(3) and -DQ2 were more significantly
frequent in the celiac population than in the control group. Children with
antigen -B8 showed a five times higher risk for celiac disease and those with
antigen -DQ2 showed a nine times higher risk. It was determined that human
leukocyte antigen -B4 had a protective role in celiac disease. The study suggests
that the human leukocyte antigen -A25(10) is a phenotype particularly encountered
in Turkish pediatric celiac patients.
PMID- 10770657
TI - Cryptosporidium parvum prevalence in a group of Turkish children.
AB - Stool samples from two hundred children with diarrhea and from 50 healthy
children were examined, by modified Kinyoun's acid-fast staining (MAF), Giemsa
staining and direct (DFA) and indirect immunofluorescence antibody (IFA) methods,
in order to determine cryptosporidiosis prevalence under the age of 12 and to
detect the most efficient identifying method for use in our country.
Cryptosporidium oocysts were detected in seven (3.5%) of the cases. None of the
samples from the control subjects was found to be positive for Cryptosporidium.
Our results indicate that Cryptosporidial oocysts should be detected in children
with diarrhea. Modified Kinyoun staining method is practical and reliable for
this purpose. Immunofluorescence staining methods can be applied for conformation
of the results, if available.
PMID- 10770658
TI - Methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Turkish patients
with thrombosis.
AB - Recently, the homozygote state for the thermolabile variant of the MTHFR gene
(C677T) has been identified as a determinant of elevated homocysteine levels
which are known to be a risk factor for arterial and thrombotic vascular disease.
To determine whether this variant increases the risk of thrombosis, we analyzed
the prevalence of the C677T substitution in the MTHFR gene in 94 patients with
thrombosis and in 95 unmatched controls. Although homozygosity for the mutation
was found in 12 (12.8%) of the patients with thrombosis and in only six (6.3%) of
the control subjects, the difference in the prevalence of the homozygous mutant
genotype between patients and healthy subjects was not statistically significant.
PMID- 10770659
TI - Rheumatic heart disease prevalence among schoolchildren in Ankara, Turkey.
AB - Rheumatic heart disease (RHD) continues to be a common health problem in the
developing world. Although little longitudinal data are available, evidence
suggests that there has been little if any decline in the occurrence of RHD over
the past few decades. There are only a few population surveys available in Turkey
for prevalence of RHD. This survey was undertaken to estimate its prevalence
among schoolchildren and changes over the last 20 years in the capital, Ankara.
In Ankara, 4,086 schoolchildren aged between six and 17 years were screened over
a period four months (March 1995-June 1995) by the same pediatrician. Forty-eight
percent (n = 1,945) were female and 52 percent (n = 2,141) were male. Three
children out of 4,086 (0.73 per 1,000) were noted to have findings consistent
with RHD. Fifteen children had an episode of rheumatic fever (RF). Cumulative
prevalence rate (prevalence rate for RF history) was 3.7 per 1,000. We concluded
that RHD prevalence has decreased in Ankara over the last decades.
PMID- 10770660
TI - Tropisetron in the prevention of chemotherapy-induced acute emesis in pediatric
patients.
AB - We evaluated the antiemetic efficacy of tropisetron for control of acute emesis
during grade 3 or 4 emetogenic chemotherapy in children. Tropisetron was
administered as a single intravenous dose of 0.2 mg/kg on the first day and
intravenously or orally with the same dose on subsequent days. A total of 125
courses of highly emetogenic chemotherapy was administered to 22 children with a
median age of 14 years (range: 3-18 years). All 22 patients received tropisetron
for at least two courses. Overall complete response on day 1 was observed in 80
out of 125 courses (64%). The response rates were consistent over multiple
courses; a complete and major response rate on the first day of Course I (n: 22
courses) and Course II (n: 22 courses) was observed in 73 and 77 percent of
cases, respectively. When the results were analyzed according to the daily
schedules, overall complete response for grade 4, grade 3 and grade 1-2
emetogenic treatment days was 59, 85 and 75 percent, respectively. In this study,
cost effectiveness for tropisetron was also determined; the cost per successfully
controlled course was 162 USD. No side effects of tropisetron other than mild
diarrhea and dry-mouth were documented in this study. In conclusion, the results
of this study confirmed that tropisetron is a safe, well tolerated and effective
antiemetic drug for the prevention of acute emesis in children and adolescents
during highly emetogenic chemotherapy.
PMID- 10770661
TI - Biphenotypic characteristics, cell size and prognosis in childhood acute
myeloblastic leukemia.
AB - In order to determine the prognostic significance of cell size together with
expression of biphenotypic markers in childhood acute myeloblastic leukemia
(AML), we evaluated the cell size of children with AML, 12 with and 21 without
biphenotypic markers. The patients were followed up for at least 12 months. The
cells which were stained with FITC conjugated surface marker antibodies were
divided into small, middle or large cell groups according to their mean channel
number of forward scatter by flow cytometry. Nine of 12 biphenotypic and 15 of 21
non-biphenotypic children either died or relapsed within the first 12 months. The
percentages of the small, middle and large cells were similar in children and in
deceased patients, regardless of whether or not they expressed biphenotypic
markers. We believe that biphenotypic marker expression is a poor prognostic
factor regardless of cell size.
PMID- 10770662
TI - Cyclosporin A plus prednisone treatment of steroid-sensitive frequently relapsing
nephrotic syndrome in children.
AB - Recently, there have been numerous reports on the use of cyclosporin A (CyA) in
children with nephrotic syndrome (NS). In this prospective study, we wanted to
evaluate the efficacy of CyA together with prednisone therapy in children with
steroid-sensitive frequently relapsing NS. A total of 11 children (7 boys, 4
girls) with steroid-sensitive NS were included in this study. The patients ranged
in age from 3.5 to 15 years (average 8.45 +/- 4.26 years). Renal biopsy showed
minimal change disease in five, mesangial proliferation in four, focal
glomerulosclerosis in one and membranous glomerulonephritis in one. The NS had
lasted from 13 to 113 months (average 50.27 +/- 38.60 months). The number of
relapses varied from three to 10 episodes with an average of 5.9 +/- 3.3
episodes. Patients received 5 mg/kg CyA daily in two divided doses for five
months and prednisone for a total of eight weeks (30 mg/m2 daily for 4 weeks
followed by 30 mg/m2 on alternate days for 4 weeks). After the completion of the
treatment protocol, no therapy was given unless a relapse was observed. Mean
follow-up period was 14.9 +/- 5.99 months with a range from six to 26 months.
Before this combined treatment, there was a mean relapse rate of 0.144 +/- 0.05
relapses month with a range from 0.088 to 0.238. After discontinuation of
therapy, the relapse rate dropped to a mean of 0.0179 +/- 0.031 with a range of 0
to 0.083. In conclusion, it would appear that a combination of CyA and prednisone
is effective, sustaining the remission in steroid-sensitive NS. Corticosteroids
in combination with CyA may be a better approach than conventional steroid
treatment in such patients.
PMID- 10770663
TI - Guanosine triphosphate cyclohydrolase I deficiency: a rare cause of
hyperphenylalaninemia.
AB - Tetrahydrobiopterin (BH4) deficiencies are a heterogeneous group of disorders
caused by a defect in two of the three enzymes involved in its biosynthesis or in
the two recycling enzymes. Except for the deficiency of dehydratase, an enzyme
catalyzing a reaction in the recycling pathway, all other variants of BH4
deficiency are characterized by developmental delay, progressive neurological
deterioration, hypokinesis, drooling, swallowing difficulty, truncal hypotonia,
increased limb tone, myoclonus and brisk deep tendon reflexes. A deficiency of
guanosine triphosphate cyclohydrolase I (GTPCH), the first enzyme in the
biosynthetic pathway of BH4, is described in a 14-month-old male infant with
hyperphenylalaninemia, developmental delay, hypertonia of the extremities,
seizures, feeding difficulties, and vomiting. Urinary pteridine screening
revealed very low levels of neopterin and biopterin which was highly suggestive
of GTPCH deficiency. Low cerebrospinal fluid concentrations of 5
hydroxyindoleacetic acid (5HIAA) and homovanillic acid concentrations, together
with no detectable neopterin and decreased concentrations of biopterin and
folate, agreed with the diagnosis of GTPCH deficiency. Subsequently measured
neopterin and biopterin synthesis in cytokine-stimulated skin fibroblasts
confirmed GTPCH deficiency, albeit indirectly. The patient showed marked
improvement on a low-protein low-phenylalanine diet with neurotransmitter
precursor administration. The favorable outcome in this patient clearly shows
that not only newborns with elevated phenylalanine levels but also older children
with neurological signs and symptoms should be screened for a BH4 deficiency in
order to have maximum benefit of the treatment.
PMID- 10770664
TI - A warm antibody mediated acute hemolytic anemia with reticulocytopenia in a four
month-old girl requiring immunosuppressive therapy.
AB - We present a four-month-old girl with severe hemolytic anemia and
reticulocytopenia. This case is the youngest with hemolytic anemia encountered in
our hospital. Findings of autoimmune hemolytic anemia were preceded by diphtheria
pertussis-tetanus (DPT) and oral polio vaccines which were given one month
before. At admission, she had heart failure, her hemoglobin (Hb) was 27 gm/L,
hematocrit (Hct) 8.5 percent, reticulocyte count 0.2 percent, and gamma and non
gamma Coombs tests were positive. Plasma Hb was 23 percent (N < 3%) and
haptoglobin 0 mg/dl. Bone marrow aspiration smear revealed erythroid hyperplasia.
No infection, immunodeficiency or malignancy could be established. She received
multiple transfusions and did not respond to methyl prednisolone therapy of seven
days' duration, but was successfully treated with a combination of
immunosuppressive therapy (cyclophosphamide, 6-mercaptopurine, intravenous
immunoglobulin and prednisolone, which was added later). This case is interesting
in that the disease was preceded by DPT vaccination, was associated with
reticulocytopenia and was resistant to steroids.
PMID- 10770665
TI - Rabdomyosarcoma of the biliary tree.
AB - Rabdomyosarcoma of the biliary tree is one of the rare causes of biliary tract
obstruction in childhood. Nevertheless it is the most common cause of obstructive
jaundice due to neoplastic biliary obstruction. We present a two-year-old child
with obstructive jaundice secondary to an embryonal rhabdomyosarcoma of the
biliary tree. She underwent surgery and, after total excision of the mass, a
hepaticojejunostomy and Roux-en-Y anastomosis were performed. She was referred to
the Pediatric Oncology Group for follow-up. Rhabdomyosarcoma of the bilary tree,
although rare, must be considered in the etiology of obstructive jaundice in
children.
PMID- 10770666
TI - Cerebrospinal fluid pleocytosis in acute lymphoblastic leukemia without central
nervous system relapse: a report of three cases.
AB - Three patients with acute lymphoblastic leukemia (ALL) developed mononuclear
cells in the cerebrospinal fluid (CSF) after a flu-like history during
maintenance treatment. None of the patients showed evidence of central nervous
system (CNS) involvement by either clinical or laboratory follow-up. Although the
presence of > 5 mononuclear cells/microl in the CSF is important, it may not
necessarily indicate CNS disease. Clinical findings, history and cell morphology
must be evaluated before deciding on further treatment.
PMID- 10770667
TI - Congenital primary hypoparathyroidism presented with extensive cutaneous and
subcutaneous calcifications.
AB - Congenital primary hypoparathyroidism is very rare in infancy. It may be isolated
or associated with other developmental defects, arising from the third and fourth
pharyngeal pouches such as DiGeorge syndrome. Initial symptom of isolated primary
hypoparathyroidism in an infant is usually generalized convulsion due to
hypocalcemia. However, the clinical spectrum of DiGeorge's anomaly is highly
variable. We report a two-hour-old neonate with congenital hypoparathyroidism
presenting with extensive cutaneous and subcutaneous calcifications. To our
knowledge, extensive calcification of the skin and subcutaneous tissue as a
presenting feature of congenital primary hypoparathyroidism in an infant is
reported for the first time.
PMID- 10770668
TI - A Turkish family with Greig cephalopolysyndactyly syndrome.
AB - Greig cephalopolysyndactyly syndrome is a very rare autosomal dominant disease
characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of
feet and peculiar facial features, and has been shown to be due to mutations in
the GLI3 gene. We present clinical findings of a 39-year-old man and his nine-day
old daughter with Greig cephalopolysyndactyly who showed variable expression with
regard to syndactyly of fingers and toes. The role of obstetric ultrasonography
in the prenatal diagnosis of the syndrome is also discussed.
PMID- 10770669
TI - Gastric perforation presenting as bilateral scrotal pneumatoceles.
AB - Although processus vaginalis is patent in the majority of newborn infants, the
expression of an intraabdominal pathology such as gastrointestinal perforation or
bleeding in the scrotum is very rare. In a large percentage of neonates with the
gastrointestinal perforation, pneumoperitoneum is absent. In any case, it may not
be detected in early radiographs. We report a newborn baby who presented with
bilateral scrotal pneumatoceles as a first sign of pneumoperitoneum due to
gastric perforation. Plain x-ray of the abdomen was normal except for
pneumoscrotum, but contrast study revealed gastric perforation.
PMID- 10770670
TI - Tracheal rupture: a rare complication related to foreign body aspiration.
AB - A one-year-old patient admitted following foreign body aspiration and referred
following cardiopulmonary resuscitation in a local hospital was diagnosed to have
tracheobronchial rupture. We first assumed puncture of the mucous membrane of the
left main bronchus by the tip of the tube. Later, we thought that the rupture
might have been caused by rigid bronchoscopy. Etiology and treatment are
discussed and recent literature reviewed.
PMID- 10770671
TI - Leukocytoclastic vasculitis in a child with epidermolysis bullosa simplex.
AB - A 10-year-old boy with epidermolysis bullosa simplex (Weber-Cockayne variant)
together with leukocytoclastic vasculitis is presented. He was admitted to the
hospital with the provisional diagnoses of infected epidermolysis bullosa simplex
or drug eruption. On the sixth day of hospitalization he developed palpable
purpura, abdominal pain and bloody diarrhea, together with hematuria and
proteinuria. A generalized tonic-clonic convulsion, changes in mental status,
fluctuations in arterial blood pressure and intractable pain in his extremities
occurred during the course of hospitalization. Systemic pulse steroid therapy,
antibiotics, and antihypertensive and anticonvulsive drugs were given. On the
30th day of hospitalization, a skin graft was performed to replace a large tissue
defect on his left hand. Despite high dose steroid therapy, his hematuria,
proteinuria and hypertension continued after his discharge, suggesting a steroid
resistant renal pathology, such as focal glomerulosclerosis, that occurred
secondary to leukocytoclastic vasculitis.
PMID- 10770672
TI - Stenotrophomonas maltophilia pneumonia in a premature infant.
AB - Stenotrophomonas (Xanthomonas) maltophilia is an aerobic, non-fermentative, gram
negative bacillus that is generally considered an opportunistic pathogen.
Infections due to S. maltophilia have become increasingly important in the
hospital environment. Patients compromised by debilitating illnesses, surgical
procedures or indwelling vascular catheters are most prone to S. maltophilia
infections. To our knowledge, we report the first case of S. maltophilia
pneumonia in a premature infant of 31 weeks gestational age. Although the therapy
of choice for severe infections caused by S. maltophilia remains to be decided,
this patient was successfully treated by amikacin.
PMID- 10770673
TI - Clinical and laboratory approach to a neonate suspected of an inborn error of
metabolism.
PMID- 10770674
TI - Epidemiology and antibiotic resistance of gram-negative urinary pathogens in
pediatric patients.
AB - In order to determine the etiological agents and the rate of resistance to
various antibiotics, 209 consecutive gram-negative bacteria isolated from
children admitted to Hacettepe University Children's Hospital with urinary tract
infections were investigated over a three-month period. Of these, 46 (22%) were
nosocomial isolates. The most frequently isolated organism was E.coli (n: 141)
followed by Klebsiella spp. (39), Proteus spp. (19), Pseudomonas spp. (8) and
Enterobacter spp. (2). In vitro susceptibilities were evaluated by microbroth
dilution method, following NCCLS guidelines. Overall, 75 percent of the isolates
were resistant to ampicillin, 52 percent were resistant to TMP/SMX and 25 percent
to cefuroxime. Amikacin was the most active aminoglycoside; 93 percent of the
isolates were susceptible to this agent, while resistance to gentamicin was 21
percent. Resistance to ceftazidime and ceftriaxone was 12 percent and 19 percent,
respectively. Overall, resistance to imipenem was one percent and to
ciprofloxacin three percent. These in vitro results should be taken into account
before initiating empirical therapy; broad spectrum antibiotics should not be
used if the isolate is susceptible to the older drugs in order to prevent the
increase in resistance.
PMID- 10770675
TI - The evaluation of ocular trauma in children between ages 0-12.
AB - Ocular trauma is the leading cause of noncongenital unilateral blindness in
children under 20 years old. In this study, 138 patients (36 female, 102 male)
with ocular trauma between November 1983 and October 1996 were reviewed
retrospectively at the Department of Ophthalmology, Ondokuz Mayis University
Faculty of Medicine. Twenty-four of these patients were blunt trauma and 114 were
perforating eye injury. The mean age of the patients was 6.96+/-3.01 years. Mean
post-treatment follow-up was 10.7 months (range 1 to 121 months). Forty-five
patients were admitted to the eye clinic within the first 24 hours after trauma.
The most frequent finding was hyphema in blunt injury, and corneal laceration in
perforating injury. The most frequent cause of injury was wood and stone in blunt
trauma and glass and knife in perforating trauma. While the ratio of visual
acuities equal to or better than finger counting was 37.5 percent (9 eyes) in
blunt trauma cases and 20.2 percent (23 eyes) in perforating trauma cases prior
to treatment, it was 79.2 percent (19 eyes) and 55.3 percent (63 eyes),
respectively, at last visit examination post-treatment. The most frequent
complication was traumatic cataract in blunt trauma and corneal leukoma and
anterior synechia in perforating trauma. The results obtained suggested that
socioeconomic and sociocultural status and family negligence are important
factors in eye injuries in children that occur during games.
PMID- 10770676
TI - Intermittent chemotherapy for miliary tuberculosis in children.
AB - Miliary tuberculosis is a severe manifestation of tuberculosis. Six children aged
between two months and 10 years with the diagnosis of miliary tuberculosis were
treated with intermittent antituberculous therapy for six, nine or 12 months. All
the patients showed clearance of both clinical and radiological symptoms; there
was no drug toxicity or resistance and no relapses were seen in the follow-up
period ranging from nine months to nine years. Intermittent therapy is safe and
effective in miliary tuberculosis and it may be an alternative therapy because of
its minimal toxicity and lower cost.
PMID- 10770677
TI - Rh disease: intrauterine intravascular fetal blood transfusion by cordocentesis.
AB - A total of 49 cordocenteses, including 40 intrauterine intravascular fetal blood
tranasfusions, were performed in 30 pregnancies complicated by red cell
isoimmunization. Transfusions were started at 19-33 weeks' gestation and repeated
up to five times, at one-to-four week intervals. The volumes of transfused blood
were 20-110 ml, hematocrits were 58-82 percent and the rate of transfusions was 1
15 ml/min. The pretransfusion fetal hemoglobins were 3.5-11.6 g/dl and the
posttransfusion fetal hemoglobins were 7.5-15.6 g/dl. There were three
intrauterine deaths and two neonatal deaths. The overall survival rate was 83.3
percent including all cordocenteses. The survival rate for the intrauterine
transfusions was 81 percent.
PMID- 10770678
TI - Frequency of antinuclear antibodies and rheumatoid factor in healthy Turkish
children.
AB - The frequency of antinuclear antibodies (ANA) and rheumatoid factor (RF) was
investigated in 118 apparently healthy children (56 male, 62 female). The mean
age was 9.8+/-2.3 years. Antinuclear antibodies (ANA) were detected by indirect
immunofluorescence, using a Hep-2 cell substrate. Nephelometry was used to
quantify RF in 116 children. Five serum samples (4%, 3M, 2F) were ANA-positive in
low titers and all had a speckled pattern. None of the ANA-positive children had
other extractable antinuclear antibodies. Rheumatoid factor (RF) was over 25
IU/ml in four children (3%, 3F, 1M). None of these was positive for both
antibodies. Our results suggest a similar frequency of ANA in healthy Turkish
children even with a Hep-2 cell substrate, when compared to results of other
reports. On the other hand, RF was more frequent than in other reported series.
PMID- 10770679
TI - Identity confusion and depression in groups of adolescents having psychiatric and
physical symptoms.
AB - The aim of this study was to investigate the identity status of adolescents
having psychiatric and physical symptoms and the relation of depression with
identity problems in adolescence. Three groups of university students were given
a sociodemographic questionnaire, Beck Depression Inventory (BDI) and Sense of
Identity Assessment Form (SIAF). The first group consisted of 31 students who
were seen by the consultant psychiatrist at the Student Health Center of a
university in Ankara. The second group included 37 students who applied to the
same center with various physical complaints but did not need to be consulted by
the psychiatrist. The third group was a group of 50 healthy students at the same
university. The analysis revealed that only those with psychiatric complaints had
identity confusion and that for the males in this group depressive symptoms are
significant predictors of identity confusion.
PMID- 10770680
TI - Prevalence of GB virus C/hepatitis G virus infection in pediatric patients
receiving multiple transfusions in Southern Turkey.
AB - The aim of this study was to determine the prevalence of GB virus C (GBV-C)
infection in pediatric patients receiving multiple blood transfusions in Turkey
where HBV and HCV infections are common. Sera of a total of 148 children, of whom
85 had cancer and 63 hemoglobinopathies, were tested for GBV-C RNA and HCV RNA by
RT-PCR and for antibodies to HBV and HCV. Demographic and clinical information as
well as laboratory results were recorded for the patients (81 boys, 67 girls,
aged 1-19 years). HBsAg positivity was found in 23 (15.5%) patients, HBV DNA
positivity in 12 (8.1%), HCV RNA positivity in 9 (6.7%), and GBV-C RNA positivity
in 4 (2.7%). There was no significant difference in the GBV-C RNA positivity
between patients with cancer (3.2%) and patients with hemoglobinopathies (2.4%)
(p > 0.05). GBV-C RNA was found in 4 (3.1%) out of 127 patients who had received
transfusions, but it was not found in any of 21 patients who had not received
transfusions. However, there was no relationship between GBV-C RNA positivity and
the number of transfusions. Two of the patients with GBV-C RNA had high levels of
ALT (ALT > 40 IU). In these two patients, neither HBV DNA nor HCV RNA were
detected by PCR, and serological tests were also negative for these agents. We
concluded that pediatric patients who had multiple transfusions in Turkey are at
risk of being infected with GBV-C, in addition to HBV and HCV. Investigation of
GBV-C RNA in patients with high ALT levels in the absence of other viral markers
may be useful.
PMID- 10770681
TI - Ursodeoxycholic acid therapy in children with cholestatic liver disease.
AB - The beneficial effect of ursodeoxycholic add have been documented in adults but
experience with this agent is limited in the pediatric population. The objective
of this study was to evaluate ursodeoxycholic acid treatment in children with
cholestatic liver disease. Twenty-four patients with intrahepatic cholestasis
(neonatal hepatitis 7, Byler disease 7, idiopathic intrahepatic cholestasis 10)
whose ages ranged from 1.5 months to 15 years were treated with ursodeoxycholic
acid (15-20 mg/kg/day) for 12 months. Liver biopsy was performed initially on all
patients and on 17 at the end of the twelve months. The outcome was evaluated by
monitoring clinical and biochemical markers of cholestasis, including alanine
aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma
glutamyl transpeptidase, cholesterol, total serum tasting bile acids and total
and conjugated bilirubin at entry and every three months of treatment. Pruritus
was ameliorated in all patients; there was complete disappearance of itching in
16.7 percent. There were significant decreases in mean serum levels of alanine
aminotransferase, aspartate aminotransferase, alkaline phosphatase, total
bilirubin and gamma-glutamyl transpeptidase. Liver biopsy specimens showed a
significant improvement in the cholestasis but not in fibrosis. No adverse
effects of therapy were noted. The improvements in the clinical and biochemical
parameters and tolerability of the drug suggest that ursodeoxycholic acid is a
safe and effective treatment in children with intrahepatic cholestasis.
PMID- 10770682
TI - Wilson's disease patients with normal ceruloplasmin levels.
AB - Wilson's disease, an inborn defect of copper metabolism, is a fatal disease
unless specific treatment is given. Hepatic presentation mimics almost all kinds
of liver disease and the diagnosis is sometimes problematic. The diagnosis is
based on clinical findings, family history, presence of Kayser-Fleischer rings,
and results of key laboratory tests such as low serum ceruloplasmin level,
increased urinary copper excretion and hepatic copper content. We report four
patients with Wilson's disease with hepatic manifestations with unknown there
were difficulties in making the diagnosis because of normal serum ceruloplasmin
levels. Inspite of normal ceruloplasmin levels and absence of Kayser-Fleischer
rings, strong family history suggested Wilson's disease and the diagnosis was
confirmed by increased urinary and hepatic copper amounts.
PMID- 10770683
TI - Congenital malaria: a case report.
AB - Congenital malaria is an uncommon disease even in endemic areas. A 19-day-old
female infant with congenital malaria is presented. The mother of the patient was
diagnosed to have malaria at the seventh month of gestation and was treated with
chloroquine orally for three days. No malarial prophylaxis was given. The infant
developed fever, hyperbilirubinemia, anemia and hepatosplenomegaly postnatally.
Thin blood smears revealed many Plasmodium vivax parasites. She was treated with
oral chloroquine for three days. We emphasize the importance of adequate
antenatal medical therapy and prophylaxis during pregnancy.
PMID- 10770684
TI - Two siblings with Bloom's syndrome exhibit different clinical features: possible
effect of sex.
AB - Bloom's syndrome is a rare autosomal recessive disease. All patients with Bloom's
syndrome have prenatally onset growth retardation and an increased tendency to
develop various types of cancer. Features other than these are not constant and
may not be present in some of the patients. Reason for the phenotypic
heterogeneity is not clear. Different mutations in the same locus may explain the
heterogeneous phenotypes in different ethnic groups. Here we present a seven-year
old boy and his four-year-old sister, both with Bloom's syndrome, who exhibit
different clinical features with respect to sun-sensitive skin lesions. The
sister has severe facial sun-sensitive skin lesions whereas her brother has none.
It is expected that two siblings who are supposed to have the same mutation
should also have similar clinical features. Possible role of environmental
effects and sex are discussed.
PMID- 10770685
TI - Neonatal sublingual traumatic ulceration (Riga-Fede disease): a case report.
AB - Early eruption of primary teeth rarely occurs and is referred to as "natal or
neonatal teeth". These teeth may cause some complications, including ulceration
of the sublingual area, pain during suckling and future nutritional problems. A
two-month-old infant suffering from sublingual area ulceration due to two
neonatal teeth was examined. His teeth were extracted and healing of the
ulcerated area was observed within the first week.
PMID- 10770686
TI - Failure of granulocyte colony-stimulating factor and granulocyte-macrophage
colony-stimulating factor in a patient with Kostmann syndrome.
AB - We present a seven-month-old boy referred to our hospital with a history of
recurrent suppurative infections starting in his neonatal period. Anemia,
absolute neutropenia absolute neutrophil count (ANC: 500 cells/microl),
pneumonia, purulent otitis media and maturational arrest of granulocytes at
promyelocyte-myelocyte level in bone marrow were detected on his admission. He
was diagnosed as Kostmann syndrome and recombinant human granulocyte colony
stimulating factor (rhG-CSF) therapy was started at a dose of 10 microg/kg/d,
gradually increasing up to 120 microg/kg/d in sequential seven-day courses. As
there was no response, rhG-CSF was stopped and recombinant human granulocyte
macrophage colony-stimulating factor (rhGM-CSF) was started subcutaneously with
2.5 microg/kg/d and was escalated by doubling the dose every seven days to 20
mg/kg/d. By this therapy absolute neutrophil count (ANC) transiently reached
above 500 cells/microl, but eosinophilia developed with a total white cell count
of 88.200 cells/microl, and a differential count showing 86 percent eosinophils.
Since eosinophilia of this magnitude has deleterious effects, and neutrophil
production did not significantly increase, we tried combined therapy with rhG-CSF
and rhGM-CSF at doses of 10-20 microg/kg/d and 5-10 microg/kg/d, respectively,
without any effect on absolute neutrophil count. The patient succumbed from
sepsis eight months after the diagnosis.
PMID- 10770687
TI - Late infantile acid maltase deficiency: a case report.
AB - A five-year-old boy with late-infantile (juvenile) form of acid maltase
deficiency is presented. His symptoms were restricted to skeletal muscle. There
is commonly a correlation between the amount of residual acid maltase activity
and the severity of the clinical picture. Although the residual enzyme level was
very low in our patient, no progression of his neurological findings have been
observed during the follow-up period of two years.
PMID- 10770688
TI - Echocardiographic diagnosis of sinus Valsalva aneurysm rupture in two pediatric
patients.
AB - Sinus Valsalva aneurysm rupture (SVAR) is a rare cardiac abnormality that
requires surgical correction when diagnosed. Previously, cardiac catheterization
and angiography were thought to be necessary for its diagnosis. We present two
pediatric cases of SVAR with subarterial ventricular septal defect (VSD)
diagnosed noninvasively by echocardiography; surgical findings confirmed the
diagnosis. In both of our cases the origin of SVAR was the right coronary sinus.
The first case was ruptured into the right ventricular cavity; the second was
ruptured into the right ventricular outflow tract. Continuous murmurs heard
during follow-up of children with VSD must alert the physician to this pathology.
Combined two-dimensional, Doppler and color-Doppler echocardiography is an
accurate, noninvasive method for diagnosis of SVAR.
PMID- 10770689
TI - Vascular hamartoma of the mediastinum: a case report.
AB - Vascular hamartoma of the mediastinum is a rare benign vascular tumor. A 13-year
old girl presented with back pain, persistent coughing, palpitation, and angina
pectoris. Preoperative investigations demonstrated an enlarging mass involving
the superior mediastinum extending posteriorly (T6-T8). An encapsulated, 6x5x3 cm
dark purplish mass adherent to the aortic wall was found. The main mediastinal
mass was totally excised but limited resection was carried out in the
paravertebral region. Microscopic examination revealed a vascular hamartoma.
PMID- 10770690
TI - Cartilaginous hamartoma of the chest wall with secondary aneurysmal cyst-like
areas in an infant: a case report.
AB - A case of a four-month-old infant diagnosed as cartilaginous hamartoma of the rib
is presented. This rare tumor usually presents at birth. The patient had
respiratory distress syndrome. Swelling of the ribs was palpable on physical
examination and the infant underwent surgery for excision of the ribs.
Histopathologically, the tumor showed benign focal overgrowth of normal skeletal
elements with cartilaginous, vascular and primitive-appearing mesenchymal
elements. Additionally, secondary aneurysmal cyst formation coexisted with the
tumor. The diagnosis was infantile cartilaginous hamartoma of the rib. In this
entity, primitive-appearing mesenchymal stroma may be mistaken for a malignant
condition. Usually a benign clinical course is expected and treatment is by block
excision.
PMID- 10770691
TI - An uncommon association of H-type tracheoesophageal fistula with infantile
hypertrophic pyloric stenosis.
AB - Although infantile hypertrophic pyloric stenosis following esophageal atresia
repair is known, infantile hypertrophic pyloric stenosis following H-type
tracheoesophageal fistula has not been encountered previously. A case of H-type
tracheoesophageal fistula and infantile hypertrophic pyloric stenosis is
presented. The patient, operated on for H-type fistula, a rare congenital anomaly
of the esophagus, on the tenth day of life was readmitted 19 days later because
of continuous vomiting after every feeding. The clinical findings and physical
and radiological examinations revealed infantile hypertrophic pyloric stenosis
which required surgical treatment. It is suggested that the association of H-type
tracheoesophageal fistula with infantile hypertrophic pyloric stenosis is
coincidental, given the estimated incidence of one in every 84,375,000 males and
337,500,000 females.
PMID- 10770693
TI - Large-Scale Motions in Superclusters: Their Imprint in the Cosmic Microwave
Background.
AB - We identify high-density regions of supercluster size in high-resolution n-body
simulations of a representative volume of three cold dark matter universes. By
assuming that (1) the density and peculiar velocities of baryons trace those of
the dark matter and that (2) the temperature of plasma is proportional to the
velocity dispersion of the dark matter particles in regions where the crossing
times are smaller than the supercluster free-fall time, we investigate how the
thermal motions of electrons in the intracluster medium and the peculiar velocity
of clusters can affect the secondary anisotropies in the cosmic microwave
background (CMB). We show that the thermal effect dominates the kinematic effect
and that the largest thermal decrements are associated with the most massive
clusters in superclusters. Thus, searching for the presence of two or more nearby
large CMB decrements represents a viable strategy for identifying superclusters
at cosmological distances. Moreover, maps of the kinematic effect in
superclusters are characterized by neighboring large peaks of opposite signs.
These peaks can be as high as approximately 10 uK at the arcminute angular
resolution. The simultaneous pointed observations of superclusters in the
millimeter and submillimeter bands combined with the upcoming sensitive CMB
experiments can separate the thermal effect contributions from the kinematic
effect contributions and can constrain the evolution of the velocity field in
large overdense regions.
PMID- 10770692
TI - The split notochord syndrome with dorsal enteric fistula, meningomyelocele and
imperforate anus.
AB - A male infant was referred to our department because of lumbosacral
meningomyelocele, dorsal enteric fistula and imperforate anus. The mother had
received a parenteral drug containing estradiol benzoate and progesterone for
inducing abortion in the first trimester. She also used an anal pomade containing
triamcinolone and lidocaine-HCl during the pregnancy for hemorrhoids. Sigmoid end
colostomy was performed after meningomyelocele repair. On abdominal exploration a
wandering spleen was detected but no other anomalies. Two months later, an
abdominoperineal pullthrough was performed, and the patient was discharged well
after three weeks. Our case is the sixth that had split notochord syndrome
associated with dorsal enteric fistula and imperforate anus. Additionally,
penoscrotal transposition and wandering spleen were present in this case. To our
knowledge, these associated anomalies have been extremely rare.
PMID- 10770694
TI - Discovery of a Color-selected Quasar at z = 5.50.
AB - We present observations of RD J030117+002025, a quasar at z=5.50 discovered from
deep, multicolor, ground-based observations covering 74 arcmin2. This is the most
distant quasar or active galaxy currently known. The object was targeted as an R
band dropout, with RAB>26.3 (3 sigma limit in a 3&arcsec; diameter region),
IAB=23.8, and zAB=23.4. The Keck/Low-Resolution Imaging Spectrometer spectrum
shows broad Lyalpha/N v lambda1240 emission and sharp absorption decrements from
the highly redshifted hydrogen forests. The fractional continuum depression due
to the Lyalpha forest is DA=0.90. RD J030117+002025 is the least luminous high
redshift quasar known (MB approximately -22.7).
PMID- 10770696
TI - Gravitational Lensing Effect on the Two-Point Correlation of Hot Spots in the
Cosmic Microwave Background.
AB - We investigate the weak gravitational lensing effect that is due to the large
scale structure of the universe on two-point correlations of local maxima (hot
spots) in the two-dimensional sky map of the cosmic microwave background (CMB)
anisotropy. According to the Gaussian random statistics, as most inflationary
scenarios predict, the hot spots are discretely distributed, with some
characteristic angular separations on the last scattering surface that are due to
oscillations of the CMB angular power spectrum. The weak lensing then causes
pairs of hot spots, which are separated with the characteristic scale, to be
observed with various separations. We found that the lensing fairly smooths out
the oscillatory features of the two-point correlation function of hot spots. This
indicates that the hot spot correlations can be a new statistical tool for
measuring the shape and normalization of the power spectrum of matter
fluctuations from the lensing signatures.
PMID- 10770695
TI - Thomson Thick X-Ray Absorption in a Broad Absorption Line Quasar, PG 0946+301.
AB - We present a deep ASCA observation of a broad absorption line quasar (BALQSO) PG
0946+301. The source was clearly detected in one of the gas imaging
spectrometers, but not in any other detector. If BALQSOs have intrinsic X-ray
spectra similar to normal radio-quiet quasars, our observations imply that there
is Thomson thick X-ray absorption (NH greater, similar1024 cm-2) toward PG
0946+301. This is the largest column density estimated so far toward a BALQSO.
The absorber must be at least partially ionized and may be responsible for
attenuation in the optical and UV. If the Thomson optical depth toward BALQSOs is
close to 1, as inferred here, then spectroscopy in hard X-rays with large
telescopes like XMM would be feasible.
PMID- 10770697
TI - Adaptive Optics Imaging of the CLASS Gravitational Lens System B1359+154 with the
Canada-France-Hawaii Telescope.
AB - We present adaptive optics imaging of the CLASS gravitational lens system
B1359+154 obtained with the Canada-France-Hawaii Telescope (CFHT) in the infrared
K band. The observations show at least three brightness peaks within the ring of
lensed images, which we identify as emission from multiple lensing galaxies. The
results confirm the suspected compound nature of the lens, as deduced from
preliminary mass modeling. The detection of several additional nearby galaxies
suggests that B1359+154 is lensed by the compact core of a small galaxy group. We
attempted to produce an updated lens model based on the CFHT observations and new
5 GHz radio data obtained with the MERLIN array, but there are too few
constraints to construct a realistic model at this time. The uncertainties
inherent with modeling compound lenses make B1359+154 a challenging target for
Hubble constant determination through the measurement of differential time
delays. However, time delays will offer additional constraints to help pin down
the mass model. This lens system therefore presents a unique opportunity to
directly measure the mass distribution of a galaxy group at intermediate
redshift.
PMID- 10770698
TI - Detecting the Gravitational Redshift of Cluster Gas.
AB - We examine the gravitational redshift of radiation emitted from within the
potential of a cluster. Spectral lines from the intracluster medium (ICM) are
redshifted in proportion to the emission-weighted mean potential along the line
of sight, amounting to approximately 50 km s-1 at a radius of 100 kpc h-1, for a
cluster dispersion of 1200 km s-1. We show that the relative redshifts of
different ionization states of metals in the ICM provide a unique probe of the
three-dimensional matter distribution. An examination of the reported peculiar
velocities of cD galaxies in well-studied Abell clusters reveals that they are
typically redshifted by an average of approximately 200 km s-1. This can be
achieved by gravity with the addition of a steep central potential associated
with the cD galaxy. Note that, in general, gravitational redshifts cause a small
overestimate of the recessional velocities of clusters by an average of
approximately 20 km s-1.
PMID- 10770699
TI - The Baryonic Tully-Fisher Relation.
AB - We explore the Tully-Fisher relation over five decades in stellar mass in
galaxies with circular velocities ranging over 30 less, similarVc less,
similar300 km s-1. We find a clear break in the optical Tully-Fisher relation:
field galaxies with Vc less, similar90 km s-1 fall below the relation defined by
brighter galaxies. These faint galaxies, however, are very rich in gas; adding in
the gas mass and plotting the baryonic disk mass Md=M*+Mgas in place of
luminosity restores the single linear relation. The Tully-Fisher relation thus
appears fundamentally to be a relation between rotation velocity and total
baryonic mass of the form Md~V4c.
PMID- 10770700
TI - Optical Gravitational Lensing Experiment Cepheids Have Lower Amplitudes in the
Small Magellanic Cloud than in the Large Magellanic Cloud.
AB - We selected Cepheids from the Optical Gravitational Lensing Experiment database
for the Magellanic Clouds in the period range of 101.10.36 for a thin Keplerian disk,
then energy and angular momentum are extracted from the black hole and
transferred to the disk (MH is the mass and aMH is the angular momentum of the
black hole). This way, the energy originating in the black hole may be radiated
away by the disk. The total amount of energy that can be extracted from the black
hole spun down from ca&solm0;GMH=0.998 to ca&solm0;GMH=0.36 by a thin Keplerian
disk is approximately 0.15MHc2. This is larger than approximately 0.09MHc2, which
can be extracted by the Blandford-Znajek mechanism.
PMID- 10770704
TI - Evidence for TeV Emission from GRB 970417a.
AB - Milagrito, a detector sensitive to very high energy gamma rays, monitored the
northern sky from 1997 February through 1998 May. With a large field of view and
a high duty cycle, this instrument was well suited to perform a search for TeV
gamma-ray bursts (GRBs). We report on a search made for TeV counterparts to GRBs
observed by BATSE. BATSE detected 54 GRBs within the field of view of Milagrito
during this period. An excess of events coincident in time and space with one of
these bursts, GRB 970417a, was observed by Milagrito. The excess has a chance
probability of 2.8x10-5 of being a fluctuation of the background. The probability
for observing an excess at least this large from any of the 54 bursts is 1.5x10
3. No significant correlations were detected from the other bursts.
PMID- 10770705
TI - Ultra-High-Energy Cosmic Rays from Young Neutron Star Winds.
AB - The long-held notion that the highest energy cosmic rays are of distant
extragalactic origin is challenged by observations that events above
approximately 1020 eV do not exhibit the expected high-energy cutoff from
photopion production off the cosmic microwave background. We suggest that these
unexpected ultra-high-energy events are due to iron nuclei accelerated from young
strongly magnetized neutron stars through relativistic MHD winds. We find that
neutron stars whose initial spin periods are shorter than approximately 10 ms and
whose surface magnetic fields are in the 1012-1014 G range can accelerate iron
cosmic rays to greater than approximately 1020 eV. These ions can pass through
the remnant of the supernova explosion that produced the neutron star without
suffering significant spallation reactions or energy loss. For plausible models
of the Galactic magnetic field, the trajectories of the iron ions curve
sufficiently to be consistent with the observed, largely isotropic arrival
directions of the highest energy events.
PMID- 10770706
TI - Rearrangement of the Fermi Surface of Dense Neutron Matter and the Direct Urca
Cooling of Neutron Stars.
AB - It is proposed that a rearrangement of single-particle degrees of freedom may
occur in a portion of the quantum-fluid interior of a neutron star. Such a
rearrangement is associated with the pronounced softening of the spin-isospin
collective mode which, under increasing density, leads to pion condensation.
Arguments and estimates based on fundamental relations of many-body theory show
that one realization of this phenomenon could produce very rapid cooling of the
star via a direct nucleon Urca process displaying a T5 dependence on temperature.
PMID- 10770707
TI - Detection of a 5 Hz Quasi-periodic Oscillation from X-Ray Nova GRS 1739-278.
AB - The X-ray nova GRS 1739-278 flared up near the Galactic center in the spring of
1996. Here we report on the discovery of an approximately 5 Hz quasi-periodic
oscillation (QPO) in Rossi X-Ray Timing Explorer/PCA observations of GRS 1739
278. The QPO was only present when the source was in its very high state and
disappeared later, when it made a transition down into the high state. We present
the energy spectra of this black hole candidate measured in both high and very
high states and discuss the similarities between this system and other X-ray
transients.
PMID- 10770708
TI - High-Resolution Spectroscopy of the X-Ray-photoionized Wind in Cygnus X-3 with
the Chandra High-Energy Transmission Grating Spectrometer.
AB - We present a preliminary analysis of the 1-10 keV spectrum of the massive X-ray
binary Cygnus X-3, obtained with the high-energy transmission grating
spectrometer on the Chandra X-Ray Observatory. The source reveals a richly
detailed discrete emission spectrum, with clear signatures of photoionization
driven excitation. Among the spectroscopic novelties in the data are the first
astrophysical detections of a number of He-like "triplets" (Si, S, Ar) with
emission-line ratios characteristic of photoionization equilibrium, fully
resolved narrow radiative recombination continua of Mg, Si, and S, the presence
of the H-like Fe Balmer series, and a clear detection of an approximately 800 km
s-1 large-scale velocity field as well as an approximately 1500 km s-1 FWHM
Doppler broadening in the source. We briefly touch on the implications of these
findings for the structure of the Wolf-Rayet wind.
PMID- 10770709
TI - Evidence of Multiple r-Process Sites in the Early Galaxy: New Observations of CS
22892-052.
AB - First results are reported of a new abundance study of neutron-capture elements
in the ultra-metal-poor (&sqbl0;Fe&solm0;H&sqbr0;=-3.1) halo field giant star CS
22892-052. Using new high-resolution, high signal-to-noise ratio spectra,
abundances of more than 30 neutron-capture elements (Z>30) have been determined.
Six elements in the 40/=56) stable neutron-capture elements
in CS 22892-052 match well the scaled solar system r-process abundance
distribution. From the observed Th abundance, an average age of approximately
16+/-4 Gyr is derived for CS 22892-052, consistent with the lower age limit of
approximately 11 Gyr derived from the upper limit on the U abundance. The
concordance of scaled solar r-process and CS 22892-052 abundances breaks down for
the lighter neutron-capture elements, supporting previous suggestions that
different r-process production sites are responsible for lighter and heavier
neutron-capture elements.
PMID- 10770710
TI - L1551NE-Discovery of a Binary Companion.
AB - L1551NE is a very young (class 0 or I) low-mass protostar located close to the
well-studied L1551 IRS 5. Here we present evidence, from 1.3 mm continuum
interferometric observations at approximately 1&arcsec; resolution, for a binary
companion to L1551NE. The companion, whose 1.3 mm flux density is approximately
13 that of the primary component, is located 1&farcs;43 ( approximately 230 AU at
160 pc) to the southeast. The millimeter-wave emission from the primary component
may have been just barely resolved, with a deconvolved size of approximately
0&farcm;82x0&farcm;70 ( approximately 131x112 AU). The companion emission was
unresolved (<100 AU). The pair is embedded within a flattened circumbinary
envelope of size approximately 5&farcm;4x2&farcm;3 ( approximately 860x370 AU).
The masses of the three components (i.e., from the circumstellar material of the
primary star and its companion and the envelope) are approximately 0.044, 0.014,
and 0.023 M middle dot in circle, respectively.
PMID- 10770711
TI - A High-Eccentricity Low-Mass Companion to HD 89744.
AB - HD 89744 is an F7 V star with a mass of 1.4 M middle dot in circle, an effective
temperature of 6166 K, an age of 2.0 Gyr, and metallicity
&sqbl0;Fe&solm0;H&sqbr0;=0.18. The radial velocity of the star has been monitored
with the Advanced Fiber-Optic Echelle spectrograph at the Whipple Observatory
since 1996, and evidence has been found for a low-mass companion. The data were
complemented by additional data from the Hamilton spectrograph at Lick
Observatory during the companion's periastron passage in the fall of 1999. As a
result, we have determined the star's orbital wobble to have a period P=256 days,
an orbital amplitude K=257 m s-1, and an eccentricity e=0.7. From the stellar
mass, we infer that the companion has a minimum mass m2sini=7.2 MJ in an orbit
with a semimajor axis a2=0.88 AU. The eccentricity of the orbit, among the
highest known for extrasolar planets, continues the trend that extrasolar planets
with semimajor axes greater than about 0.15 AU tend to have much higher
eccentricities than are found in our solar system. The high metallicity of the
parent star reinforces the trend that parent stars of extrasolar planets tend to
have high metallicity.
PMID- 10770712
TI - On Stellar Activity Enhancement Due to Interactions with Extrasolar Giant
Planets.
AB - We present a first attempt to identify and quantify possible interactions between
recently discovered extrasolar giant planets (and brown dwarfs) and their host
stars, resulting in activity enhancement in the stellar outer atmospheres. Many
extrasolar planets have masses comparable to or larger than Jupiter and are
within a distance of 0.5 AU, suggesting the possibility of their significant
influence on stellar winds, coronae, and even chromospheres. Beyond the well
known rotational synchronization, the interactions include tidal effects (in
which enhanced flows and turbulence in the tidal bulge lead to increased
magnetoacoustic heating and dynamo action) and direct magnetic interaction
between the stellar and planetary magnetic fields. We discuss relevant parameters
for selected systems and give preliminary estimates of the relative interaction
strengths.
PMID- 10770713
TI - An Improved Red Spectrum of the Methane or T Dwarf SDSS 1624+0029: The Role of
the Alkali Metals.
AB - A Keck II low-resolution spectrum shortward of 1 um is presented for SDSS
1624+0029, the first field methane or T dwarf discovered in the Sloan Digital Sky
Survey. Significant flux is detected down to the spectrum's short-wavelength
limit of 6200 A. The spectrum exhibits a broad absorption feature centered at
7700 A, which we interpret as the K i lambdalambda7665, 7699 resonance doublet.
The observed flux declines shortward of 7000 A, most likely owing to the red wing
of the Na i doublet. Both Cs i doublet lines are detected more strongly than in
an earlier red spectrum. Neither Li i absorption nor Halpha emission are
detected. An exploratory model fit to the spectrum suggests that the shape of the
red spectrum can be primarily accounted for by the broad wings of the K i and Na
i doublets. This behavior is consistent with the argument proffered by Burrows,
Marley, & Sharp that strong alkali absorption is principally responsible for
depressing T dwarf spectra shortward of 1 um. In particular, there seems no
compelling reason at this time to introduce dust or an additional opacity source
in the atmosphere of the Sloan object. The width of the K i and strengths of the
Cs i lines also indicate that the Sloan object is warmer than Gl 229B.
PMID- 10770714
TI - Developing a Radiative Shock Experiment Relevant to Astrophysics.
AB - We report on the initial results of experiments being developed on the Falcon
laser to simulate radiative astrophysical shocks. Cylindrically diverging blast
waves were produced in low-density ( approximately 1018 cm-3), high-Z gas by
laser-irradiating Xe gas jets containing atomic clusters. The blast-wave
trajectory was measured by Michelson interferometry. The velocity for the blast
wave is slightly less than the adiabatic Sedov-Taylor prediction, and an
ionization precursor is observed ahead of the shock front. This suggests energy
loss through radiative cooling and reduced compression due to preheat deposited
ahead of the shock, both consistent with one-dimensional radiation hydrodynamics
simulations.
PMID- 10770715
TI - Deeply Penetrating Banded Zonal Flows in the Solar Convection Zone.
AB - Helioseismic observations have detected small temporal variations of the rotation
rate below the solar surface that correspond to the so-called "torsional
oscillations" known from Doppler measurements of the surface. These appear as
bands of slower- and faster-than-average rotation moving equatorward. Here we
establish, using complementary helioseismic observations over 4 yr from the GONG
network and from the MDI instrument on board SOHO, that the banded flows are not
merely a near-surface phenomenon: rather, they extend downward at least 60 Mm
(some 8% of the total solar radius) and thus are evident over a significant
fraction of the nearly 200 Mm depth of the solar convection zone.
PMID- 10770716
TI - Radio Detection of a Rapid Disturbance Launched by a Solar Flare.
AB - We report the direct observation of motion associated with a solar flare at a
speed of 26,000 km s-1. The motion is seen from a radio source at 0.33 GHz, which
suddenly starts moving during the flare. At its peak, the radio source covers a
quiet region of dimension 500&arcsec;. Emission from any given location is
sporadic. The disturbance itself does not seem to radiate, but it excites coronal
features that continue to radiate after it passes. The inferred velocity is
larger than any previously inferred velocity of a disturbance in the solar
atmosphere apart from freely streaming beams of accelerated electrons. The
observed motion of the source at a fixed frequency, low polarization, and
moderate bandwidth are more consistent with the typical properties of moving type
IV radio bursts than with classical coronal shock-associated type II bursts, but
any disturbance at such a high velocity must be highly supersonic and should
drive a shock. We speculate that the disturbance is associated with the
realignment of magnetic fields connecting different portions of an active region.
PMID- 10770717
TI - Critical Self-Organization of Astrophysical Shocks.
AB - There are two distinct regimes of the first-order Fermi acceleration of shocks.
The first is a linear (test-particle) regime in which most of the shock energy
goes into thermal and bulk motions of the plasma. The second is an efficient
regime in which the shock energy goes into accelerated particles. Although the
transition region between them is narrow, we identify the factors that drive the
system toward a self-organized critical state between those two regimes. Using an
analytic solution, we determine this critical state and calculate the spectra and
maximum energy of accelerated particles.
PMID- 10770718
TI - Measurement of Charge Exchange and X-Ray Emission Cross Sections for Solar Wind
Comet Interactions.
AB - X-ray emission from a comet was observed for the first time in 1996. One of the
mechanisms believed to be contributing to this surprisingly strong emission is
the interaction of highly charged solar wind ions with cometary gases. Reported
herein are total absolute charge-exchange and normalized line-emission (X-ray)
cross sections for collisions of high-charge state (+3 to +10) C, N, O, and Ne
ions with the cometary species H2O and CO2. It is found that in several cases the
double charge-exchange cross sections can be large, and in the case of C3+ they
are equal to those for single charge exchange. Present results are compared to
cross section values used in recent comet models. The importance of applying
accurate cross sections, including double charge exchange, to obtain absolute
line-emission intensities is emphasized.
PMID- 10770719
TI - Transition Probabilities for the 1815 and 3344 A Forbidden Lines of Ne iii.
AB - We have measured the radiative lifetime of the 2s22p4 1S0 metastable level of
Ne2+ (Ne iii) to be 223+/-11 ms at the 90% confidence level by observing the
photons emitted at 1815 A by a decaying population of 1S0 Ne2+ ions produced and
stored in a radio-frequency ion trap. This is the first lifetime measurement for
an excited term of a ground configuration ion in the second row of the periodic
table. The transition probabilities (A-values) for the forbidden transitions in
the ground configurations of these ions are required for astrophysical line-ratio
diagnostics. Using calculated branching ratios, we estimate that
A&parl0;lambda1815&parr0;=1.94+/-0.17 and A&parl0;lambda3344&parr0;=2.55+/-0.19 s
1. Because these numbers have a sum with an experimentally determined uncertainty
of 5%, they will provide more accurate results than the calculated A-values for
determining electron temperature and density from astrophysical Ne iii line
ratios.
PMID- 10770720
TI - Eigenvector Sky Subtraction.
AB - We develop a new method for estimating and removing the spectrum of the sky from
deep spectroscopic observations. Our method does not rely on simultaneous
measurement of the sky spectrum with the object spectrum. The technique is based
on the iterative subtraction of continuum estimates and eigenvector sky models
derived from singular value decompositions of sky spectra and sky spectra
residuals. Using simulated data derived from small-telescope observations, we
demonstrate that the method is effective for faint objects on large telescopes.
We discuss simple methods to combine our new technique with the simultaneous
measurement of sky to obtain sky subtraction very near the Poisson limit.
PMID- 10770721
TI - Proposed modifications to the Duke criteria for the diagnosis of infective
endocarditis.
AB - Although the sensitivity and specificity of the Duke criteria for the diagnosis
of infective endocarditis (IE) have been validated by investigators from Europe
and the United States, several shortcomings of this schema remain. The Duke IE
database contains records collected prospectively on >800 cases of definite and
possible IE since 1984. Databases on echocardiograms and on patients with
Staphylococcus aureus bacteremia at Duke University Medical Center are also
maintained. Analyses of these databases, our experience with the Duke criteria in
clinical practice, and analysis of the work of others have led us to propose the
following modifications of the Duke schema. The category "possible IE" should be
defined as having at least 1 major criterion and 1 minor criterion or 3 minor
criteria. The minor criterion "echocardiogram consistent with IE but not meeting
major criterion" should be eliminated, given the widespread use of
transesophageal echocardiography (TEE). Bacteremia due to S. aureus should be
considered a major criterion, regardless of whether the infection is nosocomially
acquired or whether a removable source of infection is present. Positive Q-fever
serology should be changed to a major criterion.
PMID- 10770722
TI - Financial impact of a home intravenous antibiotic program on a medicare managed
care program.
AB - This study quantitates cost savings achieved by a home intravenous antibiotic
(HIVA) program in a Medicare managed health care program. In 1998, 66 treatment
courses of HIVA therapy were administered for a total of 1542 patient-days of
therapy. The calculated cost of HIVA therapy included the actual costs of drugs,
supplies, nursing and therapists' salaries, and laboratory studies. Savings were
calculated based on the average daily direct variable cost (DDVC) for hospital
acute unit or skilled nursing facility (SNF) care associated with the patient's
discharge diagnosis-related-group. The number of days on HIVA therapy was assumed
to equal the number of days in the hospital acute unit or hospital-based SNF. The
average cost per day of HIVA therapy was $122, whereas average DDVC of hospital
acute unit care was $798, and the average DDVC of SNF care was $541. In 1 year,
the HIVA program saved our health care system $646,000-$834,000, which
demonstrates that HIVA programs are powerful tools to reduce costs in Medicare
managed health care programs.
PMID- 10770723
TI - Fulminant meningococcal septicemia: dissociation between plasma thrombopoietin
levels and platelet counts.
AB - Thrombopoietin (TPO), interleukin (IL)-6, and platelets were measured serially in
9 patients with fulminant meningococcal septicemia and consumption coagulopathy.
The results were compared with those of patients with meningococcal meningitis
and mild meningococcemia (n=10) and with those of healthy control subjects
(n=19). TPO levels in control subjects were below the detection limit (<63
pg/mL). In patients with fulminant meningococcal septicemia, the median TPO level
on admission was 193 pg/mL (range, 133-401 pg/mL), and the level peaked within 3
7 days (median, 488 pg/mL; range, 239-1334 pg/mL). Platelet counts remained low,
despite the elevated TPO levels. In patients with meningitis or meningococcemia,
the median TPO level on admission was 112 pg/mL (range, <63-695 pg/mL), and the
TPO level was not detectable within 48 h. Platelet counts for these patients
remained within normal limits. Maximum IL-6 levels in patients with septicemia
were observed on admission (median, 5317 pg/mL; range, 188-651,000 pg/mL) and
increased earlier than TPO levels. In patients with fulminant septicemia, TPO
level increases significantly whereas the level of circulating platelets does
not.
PMID- 10770724
TI - Preventing meningococcal infection in college students.
AB - The incidence of invasive meningococcal disease in adolescents and young adults
of high school and college age has recently increased in the United States.
Recent studies indicate that certain groups of college students are at increased
risk. This has led to the recent Advisory Committee Immunization Practices
recommendation that college freshman dormitory residents be provided information
about meningococcal infection and the benefits of vaccination. Future studies
will need to focus on the potential vaccine prevention of the increased risk of
meningococcal infection in persons of high school age, particularly as new
conjugate meningococcal vaccines become available.
PMID- 10770725
TI - Practice guidelines for the treatment of fungal infections. For the Mycoses Study
Group. Infectious Diseases Society of America.
PMID- 10770726
TI - Introduction to antifungal drugs.
PMID- 10770727
TI - Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases
Society of America.
AB - Management of patients diagnosed with coccidioidomycosis involves defining the
extent of infection and assessing host factors that predispose to disease
severity. Patients with relatively localized acute pulmonary infections and no
risk factors for complications often require only periodic reassessment to
demonstrate resolution of their self-limited process. On the other hand, patients
with extensive spread of infection or at high risk of complications because of
immunosuppression or other preexisting factors require a variety of treatment
strategies that may include antifungal therapy, surgical debridement, or both.
Amphotericin B is often selected for treatment of patients with respiratory
failure due to Coccidioides immitis or rapidly progressive coccidioidal
infections. With other more chronic manifestations of coccidioidomycosis,
treatment with fluconazole, itraconazole, or ketoconazole is common. Duration of
therapy often ranges from many months to years, and, for some patients, chronic
suppressive therapy is needed to prevent relapses.
PMID- 10770728
TI - Practice guidelines for the treatment of candidiasis. Infectious Diseases Society
of America.
AB - Infections due to Candida species are the most common of the fungal infections.
Candida species produce a broad range of infections, ranging from nonlife
threatening mucocutaneous illnesses to invasive process that may involve
virtually any organ. Such a broad range of infections requires an equally broad
range of diagnostic and therapeutic strategies. This document summarizes current
knowledge about treatment of multiple forms of candidiasis and is the guideline
of the Infectious Diseases Society of America (IDSA) for the treatment of
candidiasis. Throughout this document, treatment recommendations are scored
according to the standard scoring scheme used in other IDSA guidelines to
illustrate the strength of the underlying data. The document covers 4 major
topical areas. The role of the microbiology laboratory. To a greater extent than
for other fungi, treatment of candidiasis can now be guided by in vitro
susceptibility testing. The guidelines review the available information
supporting current testing procedures and interpretive breakpoints and place
these data into clinical context. Susceptibility testing is most helpful in
dealing with infection due to non-albicans species of Candida. In this setting,
especially if the patient has been treated previously with an azole antifungal
agent, the possibility of microbiological resistance must be considered.
Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis,
the guidelines review strategies for treatment of 15 other forms of invasive
candidiasis. Extensive data from randomized trials are really available only for
therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of
therapy for other forms of candidiasis is based on case series and anecdotal
reports. In general, both amphotericin B and the azoles have a role to play in
treatment. Choice of therapy is guided by weighing the greater activity of
amphotericin B for some non-albicans species (e.g., Candida krusei) against the
lesser toxicity and ease of administration of the azole antifungal agents.
Flucytosine has activity against many isolates of Candida but is not often used.
Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is
dominated by the azole antifungal agents. These drugs may be used topically or
systemically and have been proven safe and efficacious. A significant problem
with mucosal disease is the propensity for a small proportion of patients to
suffer repeated relapses. In some situations, the explanation for such a relapse
is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with
advanced and uncontrolled HIV infection), but in other patients the cause is
cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for
these situations are discussed in the guidelines and must consider the
possibility of induction of resistance over time. Prevention of invasive
candidiasis. Prophylactic strategies are useful if the risk of a target disease
is sharply elevated in a readily identified group of patients. Selected patient
groups undergoing therapy that produces prolonged neutropenia (e.g., some bone
marrow transplant recipients) or who receive a solid-organ transplant (e.g., some
liver transplant recipients) have a sufficient risk of invasive candidiasis to
warrant prophylaxis.
PMID- 10770729
TI - Practice guidelines for the management of patients with blastomycosis. Infectious
Diseases Society of America.
AB - Guidelines for the treatment of blastomycosis are presented; these guidelines are
the consensus opinion of an expert panel representing the National Institute of
Allergy and Infectious Diseases Mycoses Study Group and the Infectious Diseases
Society of America. The clinical spectrum of blastomycosis is varied, including
asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease.
Most patients with blastomycosis will require therapy. Spontaneous cures may
occur in some immunocompetent individuals with acute pulmonary blastomycosis.
Thus, in a case of disease limited to the lungs, cure may have occurred before
the diagnosis is made and without treatment; such a patient should be followed up
closely for evidence of disease progression or dissemination. In contrast, all
patients who are immunocompromised, have progressive pulmonary disease, or have
extrapulmonary disease must be treated. Treatment options include amphotericin B,
ketoconazole, itraconazole, and fluconazole. Amphotericin B is the treatment of
choice for patients who are immunocompromised, have life-threatening or central
nervous system (CNS) disease, or for whom azole treatment has failed. In
addition, amphotericin B is the only drug approved for treating blastomycosis in
pregnant women. The azoles are an equally effective and less toxic alternative to
amphotericin B for treating immunocompetent patients with mild to moderate
pulmonary or extrapulmonary disease, excluding CNS disease. Although there are no
comparative trials, itraconazole appears more efficacious than either
ketoconazole or fluconazole. Thus, itraconazole is the initial treatment of
choice for nonlife-threatening non-CNS blastomycosis.
PMID- 10770730
TI - Practice guidelines for the management of patients with sporotrichosis. For the
Mycoses Study Group. Infectious Diseases Society of America.
AB - The recommendations for the treatment of sporotrichosis were derived primarily
from multicenter, nonrandomized treatment trials, small retrospective series, and
case reports; no randomized, comparative treatment trials have been reported.
Most cases of sporotrichosis are non life-threatening localized infections of the
skin and subcutaneous tissues that can be treated with oral antifungal agents.
The treatment of choice for fixed cutaneous or lymphocutaneous sporotrichosis is
itraconazole for 36 months. The preferred treatment for osteoarticular
sporotrichosis also is itraconazole, but therapy must be continued for at least
12 months. Pulmonary sporotrichosis responds poorly to treatment. Severe
infection requires treatment with amphotericin B; mild to moderate infection can
be treated with itraconazole. Meningeal and disseminated forms of sporotrichosis
are rare and usually require treatment with amphotericin B. AIDS patients most
often have disseminated infection and require life-long suppressive therapy with
itraconazole after initial use of amphotericin B. OVERVIEW: Sporotrichosis is
caused by the dimorphic fungus Sporothrix schenckii, which is found throughout
the world in decaying vegetation, sphagnum moss, and soil. The usual mode of
infection is by cutaneous inoculation of the organism. Pulmonary and disseminated
forms of infection, although uncommon, can occur when S. schenckii conidia are
inhaled. Infections are most often sporadic and usually associated with trauma
during the course of outdoor work. Infection can also be related to zoonotic
spread from infected cats or scratches from digging animals, such as armadillos.
Outbreaks have been well-described and often are traced back to activities that
involved contaminated sphagnum moss, hay, or wood. Most cases of sporotrichosis
are localized to the skin and subcutaneous tissues. Dissemination to
osteoarticular structures and viscera is uncommon and appears to occur more often
in patients who have a history of alcohol abuse or immunosuppression, especially
AIDS. Spontaneous resolution of sporotrichosis is rare, and treatment is required
for most patients. Although sporotrichosis localized to skin and subcutaneous
tissues is readily treated, management of osteoarticular, other localized
visceral, and disseminated forms of sporotrichosis is difficult. OBJECTIVE: The
objective of these guidelines is to provide recommendations for the treatment of
various forms of sporotrichosis. OUTCOMES: The desired outcomes of treatment
include eradication of S. schenckii from tissues, resolution of symptoms and
signs of active infection, and return of function of involved organs. In persons
with AIDS, eradication of the organism may not be possible, but clinical
resolution should be attained and subsequently maintained with suppressive
antifungal therapy. EVIDENCE: The English-language literature on the treatment of
sporotrichosis was reviewed. Although randomized, blinded, controlled treatment
trials were sought, none were found to have been performed for the treatment of
sporotrichosis. Therefore, most weight was placed on those reports that were
derived from multicenter trials of specific treatment modalities for
sporotrichosis. Small series from a single institution and individual case
reports were accorded less importance. VALUES: The highest value was placed on
clinical efficacy and the ability of the antifungal regimen to eradicate the
organism, but safety, tolerability, and cost of therapy were also valued.
BENEFITS AND COSTS: The benefits of successfully treating sporotrichosis accrue
primarily for the patient. Because this infection is not spread from person-to
person, public health aspects of treatment are of minor importance. Most forms of
sporotrichosis are not life-threatening; thus, therapy is aimed at decreasing
morbidity, improving quality of life, and allowing the patient to return to
occupational and familial pursuits. (ABSTRACT TRUNCATED)
PMID- 10770731
TI - Practice guidelines for the management of patients with histoplasmosis.
Infectious Diseases Society of America.
AB - OBJECTIVE: The objective of this guideline is to provide recommendations for
treating patients with the more common forms of histoplasmosis. PARTICIPANTS AND
CONSENSUS PROCESS: A working group of 8 experts in this field was convened to
develop this guideline. The working group developed and refined the guideline
through a series of conference calls. OUTCOMES: The goal of treatment is to
eradicate the infection when possible, although chronic suppression may be
adequate for patients with AIDS and other serious immunosuppressive disorders.
Other important outcomes are resolution of clinical abnormalities and prevention
of relapse. EVIDENCE: The published literature on the management of
histoplasmosis was reviewed. Controlled trials have been conducted that address
the treatment of chronic pulmonary and disseminated histoplasmosis, but clinical
experience and descriptive studies provide the basis for recommendations for
other forms of histoplasmosis. VALUE: Value was assigned on the basis of the
strength of the evidence supporting treatment recommendations, with the highest
value assigned to controlled trials, according to conventions established for
developing practice guidelines. BENEFITS AND COSTS: Certain forms of
histoplasmosis cause life-threatening illnesses and result in considerable
morbidity, whereas other manifestations cause no symptoms or minor self-limited
illnesses. The nonprogressive forms of histoplasmosis, however, may reduce
functional capacity, affecting work capacity and quality of life for several
months. Treatment is clearly beneficial and cost-effective for patients with
progressive forms of histoplasmosis, such as chronic pulmonary or disseminated
infection. It remains unknown whether treatment improves the outcome for patients
with the self-limited manifestations, since this patient population has not been
studied. Other chronic progressive forms of histoplasmosis are not responsive to
pharmacologic treatment. TREATMENT OPTIONS: Options for therapy for
histoplasmosis include ketoconazole, itraconazole, fluconazole, amphotericin B
(Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomal amphotericin B
(AmBisome; Fujisawa, Deerfield, IL), amphotericin B colloidal suspension (ABCD,
or Amphotec; Seques, Menlo Park, CA), and amphotericin B lipid complex (ABLC, or
Abelcet; Liposome, Princeton, NJ).
PMID- 10770732
TI - Practice guidelines for diseases caused by Aspergillus. Infectious Diseases
Society of America.
AB - Aspergillosis comprises a variety of manifestations of infection. These
guidelines are directed to 3 principal entities: invasive aspergillosis,
involving several organ systems (particularly pulmonary disease); pulmonary
aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations
are distilled in this summary, but the reader is encouraged to review the more
extensive discussions in subsequent sections, which show the strength of the
recommendations and the quality of the evidence, and the original publications
cited in detail. Invasive aspergillosis. Because it is highly lethal in the
immunocompromised host, even in the face of therapy, work-up must be prompt and
aggressive, and therapy may need to be initiated upon suspicion of the diagnosis,
without definitive proof (BIII). Intravenous therapy should be used initially in
rapidly progressing disease (BIII). The largest therapeutic experience is with
amphotericin B deoxycholate, which should be given at maximum tolerated doses
(e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum
creatinine levels (BIII). Lipid formulations of amphotericin are indicated for
the patient who has impaired renal function or who develops nephrotoxicity while
receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative
for patients who can take oral medication, are likely to be adherent, can be
demonstrated (by serum level monitoring) to absorb the drug, and lack the
potential for interaction with other drugs (BII). Oral itraconazole is attractive
for continuing therapy in the patient who responds to initial iv therapy (CIII).
Therapy should be prolonged beyond resolution of disease and reversible
underlying predispositions (BIII). Adjunctive therapy (particularly surgery and
combination chemotherapy, also immunotherapy), may be useful in certain
situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma
is unknown. Therapy is predominantly directed at preventing life-threatening
hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because
of significant morbidity and mortality it should be reserved for high-risk
patients such as those with episodes of life-threatening hemoptysis, and
considered for patients with underlying sarcoidosis, immunocompromised patients,
and those with increasing Aspergillus-specific IgG titers (CIII). Surgical
candidates would need to have adequate pulmonary function to undergo the
operation. Bronchial artery embolization rarely produces a permanent success, but
may be useful as a temporizing procedure in patients with life-threatening
hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral
itraconazole may be useful for this condition. Since the majority of
aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of
treatment must be weighed against the clinical benefit. Allergic bronchopulmonary
aspergillosis (APBA). Although no well-designed studies have been carried out,
the available data support the use of corticosteroids for acute exacerbations of
ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy
has been standardized, but limited data suggest the starting dose should be
approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids
should be made on an individual basis, depending on the clinical course (BIII).
The available data suggest that clinical symptoms alone are inadequate to make
such decisions, since significant lung damage may occur in asymptomatic patients.
Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and
worsening spirometry suggest that corticosteroids should be used (BII). Multiple
asthmatic exacerbations in a patient with ABPA suggest that chronic
corticosteroid therapy should be used (BIII). Itraconazole appears useful as a
corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)
PMID- 10770733
TI - Practice guidelines for the management of cryptococcal disease. Infectious
Diseases Society of America.
AB - An 8-person subcommittee of the National Institute of Allergy and Infectious
Diseases (NIAID) Mycoses Study Group evaluated available data on the treatment of
cryptococcal disease. Opinion regarding optimal treatment was based on personal
experience and information in the literature. The relative strength of each
recommendation was graded according to the type and degree of evidence available
to support the recommendation, in keeping with previously published guidelines by
the Infectious Diseases Society of America (IDSA). The panel conferred in person
(on 2 occasions), by conference call, and through written reviews of each draft
of the manuscript. The choice of treatment for disease caused by Cryptococcus
neoformans depends on both the anatomic sites of involvement and the host's
immune status. For immunocompetent hosts with isolated pulmonary disease, careful
observation may be warranted; in the case of symptomatic infection, indicated
treatment is fluconazole, 200-400 mg/day for 36 months. For those individuals
with non-CNS-isolated cryptococcemia, a positive serum cryptococcal antigen titer
>1:8, or urinary tract or cutaneous disease, recommended treatment is oral azole
therapy (fluconazole) for 36 months. In each case, careful assessment of the CNS
is required to rule out occult meningitis. For those individuals who are unable
to tolerate fluconazole, itraconazole (200-400 mg/day for 6-12 months) is an
acceptable alternative. For patients with more severe disease, treatment with
amphotericin B (0.5-1 mg/kg/d) may be necessary for 6-10 weeks. For otherwise
healthy hosts with CNS disease, standard therapy consists of amphotericin B, 0.7
1 mg/kg/d, plus flucytosine, 100 mg/kg/d, for 6-10 weeks. An alternative to this
regimen is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 2
weeks, followed by fluconazole (400 mg/day) for a minimum of 10 weeks.
Fluconazole "consolidation" therapy may be continued for as along as 6-12 months,
depending on the clinical status of the patient. HIV-negative, immunocompromised
hosts should be treated in the same fashion as those with CNS disease, regardless
of the site of involvement. Cryptococcal disease that develops in patients with
HIV infection always warrants therapy. For those patients with HIV who present
with isolated pulmonary or urinary tract disease, fluconazole at 200-400 mg/d is
indicated. Although the ultimate impact from highly active antiretroviral therapy
(HAART) is currently unclear, it is recommended that all HIV-infected individuals
continue maintenance therapy for life. Among those individuals who are unable to
tolerate fluconazole, itraconazole (200-400 mg/d) is an acceptable alternative.
For patients with more severe disease, a combination of fluconazole (400 mg/d)
plus flucytosine (100-150 mg/d) may be used for 10 weeks, followed by fluconazole
maintenance therapy. Among patients with HIV infection and cryptococcal
meningitis, induction therapy with amphotericin B (0.7-1 mg/kg/d) plus
flucytosine (100 mg/kg/d for 2 weeks) followed by fluconazole (400 mg/d) for a
minimum of 10 weeks is the treatment of choice. After 10 weeks of therapy, the
fluconazole dosage may be reduced to 200 mg/d, depending on the patient's
clinical status. Fluconazole should be continued for life. An alternative regimen
for AIDS-associated cryptococcal meningitis is amphotericin B (0.7-1 mg/kg/d)
plus 5-flucytosine (100 mg/kg/d) for 6-10 weeks, followed by fluconazole
maintenance therapy. Induction therapy beginning with an azole alone is generally
discouraged. Lipid formulations of amphotericin B can be substituted for
amphotericin B for patients whose renal function is impaired. Fluconazole (400
800 mg/d) plus flucytosine (100-150 mg/kg/d) for 6 weeks is an alternative to the
use of amphotericin B, although toxicity with this regimen is high. In all cases
of cryptococcal meningitis, careful attention to the management of intracranial
pressure is imperative to assure optimal c
PMID- 10770734
TI - The challenge of sexually transmitted diseases for the military: what has
changed?
PMID- 10770735
TI - Correlates of human immunodeficiency virus infection risk behavior in male
attendees of a clinic for sexually transmitted disease.
AB - Human immunodeficiency virus (HIV) infection risk behavior was evaluated in a
cross-sectional survey of 400 male active-duty US Army personnel who presented at
a sexually transmitted disease (STD) clinic with symptoms of acute urethritis.
High-risk partners were common, and nearly one-quarter of the sample had
previously had STDs. Logistic regression models examined correlates of HIV
exposure risk, of inconsistent condom use, and of having partners with increased
risk of HIV infection. Frequent partner turnover, sex "binging," negative
attitudes toward condom use, and engaging in sex during military leaves were
important correlates of risk. Individuals with HIV infection risk behavior
generally were cognizant of their risk for HIV infection. Implications for
intervention are discussed.
PMID- 10770736
TI - Reducing risk of sexually transmitted disease (STD) and human immunodeficiency
virus infection in a military STD clinic: evaluation of a randomized preventive
intervention trial.
AB - Three single-session preventive interventions for reducing sexually transmitted
disease (STD) and human immunodeficiency virus infection risk behaviors were
evaluated with a sample of 400 men who attended a large military STD clinic. A
quasi-experimental, pre-evaluation/postevaluation design was used, comparing
standard clinic care alone versus standard care combined with 1 of 3 experimental
interventions: health-risk appraisal, interactive video, and targeted situational
behaviors. Questionnaire data were collected at baseline and during follow-up
visits at 2 weeks and 2 months. Findings indicated that the health-risk appraisal
and interactive video increased adherence with clinic recommendations to abstain
from sex (chi(2)3199=19.67; P<.001) and increased readiness to change "risky"
partner-selection behavior (chi(2)2194=6.42; P<.04). Follow-up data suggested
that STD-related risk behavior was particularly resistant to change but that the
single-session intervention had some impact, which could be viewed as a "priming"
effect that enhances multisession interventions.
PMID- 10770737
TI - Features of urethritis in a cohort of male soldiers.
AB - Of 400 cases of urethritis in male soldiers enrolled in a behavioral intervention
project, the etiology of 69% was defined at study enrollment, as well as the
etiology of 72% of 25 repeated episodes involving 21 men during the first 78 days
of active follow-up (5% of the cohort). Chlamydia trachomatis (36%), Neisseria
gonorrhoeae (34%), and Ureaplasma urealyticum (19%) were the most common causes
of infection identified at enrollment and during subsequent visits (44%, 28%, and
12%, respectively). By univariate analysis, patients with repeated infection
("repeaters") were significantly more likely to report a history of sexually
transmitted disease (STD; relative risk [RR], 3) and sex with sex workers (RR, 4)
than were nonrepeaters. By multivariate analysis, only STD history was
significant (RR, 2.8). Characteristics of repeaters in this cohort suggest that
specific patterns may be used to establish screening "profiles" of potential
repeaters, by which such individuals might be targeted for aggressive
intervention at the time of the initial diagnosis.
PMID- 10770738
TI - Trends of gonorrhea and chlamydial infection during 1985-1996 among active-duty
soldiers at a United States Army installation.
AB - High rates of sexually transmitted diseases (STDs) have been reported in military
populations. However, it remains uncertain whether the incidence of STDs is
higher among military personnel than in the civilian population. The annual
incidence of gonorrhea and chlamydia from 1985 through 1996 at Fort Bragg, North
Carolina, was determined by use of a clinic database and demographic information
for the entire installation. A direct standardization for age, sex, and
race/ethnicity was performed, and the adjusted annual rates among active duty
soldiers were compared with rates among men and women in North Carolina and the
United States. Results showed that the adjusted incidence of gonorrhea and
chlamydia among Fort Bragg soldiers remained higher overall than comparable state
and national rates during the period of analyses. The 1996 adjusted chlamydia
rates for male and female active duty soldiers were 3-fold to 6-fold higher than
rates for males and females in North Carolina and in the United States as a
whole. STDs continue to lead to significant morbidity in this representative
military population.
PMID- 10770739
TI - Evernimicin binds exclusively to the 50S ribosomal subunit and inhibits
translation in cell-free systems derived from both gram-positive and gram
negative bacteria.
AB - Evernimicin (SCH 27899) is a new antibiotic with activity against a wide spectrum
of gram-positive bacteria and activity against some gram-negative bacteria.
Previous metabolic labeling studies indicated that evernimicin specifically
inhibited protein synthesis in Staphylococcus aureus. Using a susceptible
Escherichia coli strain, we demonstrated that evernimicin also inhibited protein
synthesis in E. coli. In cell-free translation assays with extracts from either
E. coli or S. aureus, evernimicin had a 50% inhibitory concentration of
approximately 125 nM. In contrast, cell-free systems derived from wheat germ and
rabbit reticulocytes were inhibited only by very high levels of evernimicin.
Evernimicin did not promote transcript misreading. [(14)C]evernimicin
specifically bound to the 50S subunit from E. coli. Nonlinear regression analysis
of binding data generated with 70S ribosomes from E. coli and S. aureus and 50S
subunits from E. coli returned dissociation constants of 84, 86, and 160 nM,
respectively. In binding experiments, performed in the presence of excess
quantities of a selection of antibiotics known to bind to the 50S subunit, only
the structurally similar drug avilamycin blocked binding of [(14)C]evernimicin to
ribosomes.
PMID- 10770740
TI - Selection and characterization of human immunodeficiency virus type 1 variants
resistant to the (+) and (-) enantiomers of 2'-deoxy-3'-oxa-4'-thio-5
fluorocytidine.
AB - Human immunodeficiency virus (HIV) type 1 (HIV-1) variants were selected for
resistance to the (+) and (-) enantiomers of a novel nucleoside analogue, 2'
deoxy-3'-oxa-4'-thio-5-fluorocytidine (dOTFC), by use of the infectious molecular
clone HIV HXB2D and the human T-cell line MT-4. The dOTFC-resistant variants that
were selected were 10-fold less sensitive than wild-type virus, and cloning and
sequencing of the complete reverse transcriptase (RT)-coding region identified
the mutation M184V. Studies with mutated recombinant HXB2D virus confirmed the
importance of the M184V mutation in conferring resistance to (-)dOTFC in MT-4
cells, although no difference in sensitivity was observed in primary cells. The
M184V substitution also displayed decreased susceptibility to (+)dOTFC. Selection
with (+)dOTFC also produced variants which were 10-fold more resistant than the
wild type, and a novel mutation, D67G, was identified following cloning and
sequencing of the RT genes. The D67G mutation was introduced into HXB2D by site
directed mutagenesis, and the data obtained confirmed the importance of this
mutation in conferring resistance to both (+)dOTFC and (-)dOTFC. Mutated
recombinant molecular clone HXB2D-D67G was further selected with (+)dOTFC, and
three of six clones sequenced contained both the D67G and M184V mutations, while
the other three of the six clones contained only the D67G mutation. Clinical
isolates of HIV-1 which are (-) 2'-deoxy-3'-thiacytidine-resistant also displayed
resistance to both (+)dOTFC and (-)dOTFC.
PMID- 10770741
TI - A bacteriophage lambda-based genetic screen for characterization of the activity
and phenotype of the human immunodeficiency virus type 1 protease.
AB - Human immunodeficiency virus type 1 (HIV-1) resistance to antiretroviral drugs is
the main cause of patient treatment failure. Despite the problems associated with
interpretation of HIV-1 resistance testing, resistance monitoring should help in
the rational design of initial or rescue antiretroviral therapies. It has
previously been shown that the activity of the HIV-1 protease can be monitored by
using a bacteriophage lambda-based genetic assay. This genetic screening system
is based on the bacteriophage lambda regulatory circuit in which the viral
repressor cI is specifically cleaved to initiate the lysogenic to lytic switch.
We have adapted this simple lambda-based genetic assay for the analysis of the
activities and phenotypes of different HIV-1 proteases. Lambda phages that encode
HIV-1 proteases either from laboratory strains (strain HXB2) or from clinical
samples are inhibited in a dose-dependent manner by the HIV-1 protease inhibitors
indinavir, ritonavir, saquinavir, and nelfinavir. Distinct susceptibilities to
different drugs were also detected among phages that encode HIV-1 proteases
carrying different resistance mutations, further demonstrating the specificity of
this assay. Differences in proteolytic processing activity can also be directly
monitored with this genetic screen system since two phage populations compete in
culture with each other until one phage outgrows the other. In summary, we
present here a simple, safe, and rapid genetic screening system that may be used
to predict the activities and phenotypes of HIV-1 proteases in the course of
viral infection and antiretroviral therapy. This assay responds appropriately to
well-known HIV-1 protease inhibitors and can be used to search for new protease
inhibitors.
PMID- 10770742
TI - Antibiotic resistance trends in enteropathogenic bacteria isolated in 1985-1987
and 1995-1998 in Barcelona.
AB - Trends in resistance to antimicrobial agents used for therapy have been evaluated
with 3,797 enteropathogenic bacteria, Campylobacter, Salmonella, Shigella, and
Yersinia, between 1985-1987 and 1995-1998. The greater increase in the rate of
resistance was observed in Campylobacter jejuni for quinolones (from 1 to 82%)
and tetracycline (from 23 to 72%) and in gastroenteric salmonellae for ampicillin
(from 8 to 44%), chloramphenicol (from 1.7 to 26%), and trimethoprim
sulfamethoxazole and nalidixic acid (from less than 0.5 to 11%). Multidrug
resistance was detected in several Salmonella serotypes. In the 1995-1998 period,
76% of Shigella strains were resistant to trimethoprim-sulfamethoxazole, 43% were
resistant to ampicillin, and 39% were resistant to chloramphenicol. Seventy-two
percent of Yersinia enterocolitica O3 strains were resistant to streptomycin, 45%
were resistant to sulfonamides, 28% were resistant to trimethoprim
sulfamethoxazole, and 20% were resistant to chloramphenicol.
PMID- 10770743
TI - Use of cotton rats to evaluate the efficacy of antivirals in treatment of measles
virus infections.
AB - No practical animal models for the testing of chemotherapeutic or biologic agents
identified in cell culture assays as being active against measles virus (MV) are
currently available. Cotton rats may serve this purpose. To evaluate this
possibility, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and
poly(acrylamidomethyl propanesulfonate) (PAMPS), two compounds that have been
reported to inhibit MV in vitro, and ribavirin, an established antiviral drug
with MV-inhibitory activity, were evaluated for their antiviral activities
against MV and respiratory syncytial virus (RSV) in tissue culture and in hispid
cotton rats. A single administration of PAMPS markedly inhibited pulmonary RSV or
MV replication (>3 log(10) reduction in pulmonary titer compared to that for
controls), but only if this compound was administered intranasally at about the
time of virus inoculation. Both EICAR and ribavirin exhibited therapeutic
activity against RSV and MV in cotton rats when they were administered
parenterally. However, both of these compounds were less effective against MV. On
the basis of the pulmonary virus titers on day 4 after virus inoculation, the
minimal efficacious dose of EICAR against MV (120 mg/kg of body weight/day when
delivered intraperitoneally twice daily) appeared to be three times lower against
this virus than that of ribavirin delivered at a similar dose (i.e., 360
mg/kg/day). These findings correlated with those obtained in vitro. The data
obtained suggest that cotton rats may indeed be useful for the initial evaluation
of the activities of antiviral agents against MV.
PMID- 10770744
TI - Activities of trovafloxacin and ampicillin-sulbactam alone or in combination
versus three strains of vancomycin- intermediate Staphylococcus aureus in an in
vitro pharmacodynamic infection model.
AB - The recent isolation of clinical strains of methicillin-resistant Staphylococcus
aureus (MRSA) with intermediate susceptibility (MICs, 8 microg/ml) to vancomycin
(vancomycin-intermediate S. aureus [VISA]) emphasizes the importance of
developing novel antimicrobial regimens and/or agents for future treatment. We
studied the activities of ampicillin-sulbactam and trovafloxacin alone or in
combination against three unique strains of VISA in an in vitro infection model.
Two VISA strains were trovafloxacin susceptible (MICs, < or =2 microg/ml); one
VISA strain was trovafloxacin resistant (MIC, 4 microg/ml). Trovafloxacin was
administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam
was administered to simulate a dose of 3 g every 6 h. Samples were removed from
the infection models over 48 h, and reductions in colony counts were compared
between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA
strain over the 48-h experiment but produced only slight killing of all three
VISA strains. The higher dose of trovafloxacin improved killing but did not
produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid
bactericidal activity against all four strains tested, and colony counts at 8 h
were at the limits of detection. However, regrowth occurred by 48 h for each
strain. The combination of ampicillin-sulbactam and trovafloxacin provided
additive activity against two of the three VISA strains. In conclusion,
trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity
against the VISA strains for the 48-h evaluation period, but the combination
could help improve activity against some strains of VISA.
PMID- 10770745
TI - SCH 56592, amphotericin B, or itraconazole therapy of experimental murine
cerebral phaeohyphomycosis due to Ramichloridium obovoideum ("Ramichloridium
mackenziei").
AB - Ramichloridium obovoideum ("Ramichloridium makenziei") is a rare cause of lethal
cerebral phaeohyphomycosis. It has been, so far, geographically restricted to the
Middle East. BALB/c mice were inoculated with two strains of R. obovoideum
intracranially. Therapy with amphotericin B, itraconazole, or the investigational
triazole SCH 56592 was conducted for 10 days. Half the mice were monitored for
survival and half were killed for determination of the fungal load in brain
tissue. Recipients of SCH 56592 had significantly prolonged survival and lower
brain fungal burden, and this result was found for mice infected with both of the
fungal strains tested. Itraconazole reduced the brain fungal load in mice
infected with one strain but not the other, while amphotericin B had no effect on
brain fungal concentrations. This study indicates a possible role of SCH 56592 in
the treatment of the serious cerebral phaeohyphomycosis due to R. obovoideum.
PMID- 10770746
TI - Comparison of immunogenicity and safety of a virosome influenza vaccine with
those of a subunit influenza vaccine in pediatric patients with cystic fibrosis.
AB - The objective of this study was to compare the immunogenicity and safety of a
single-dose regimen and a two-dose regimen of a trivalent virosome influenza
vaccine (Inflexal Berna V) with those of a trivalent subunit influenza vaccine
(Influvac) in children and adolescents with cystic fibrosis (CF). In an open,
randomized, multicenter study with parallel groups, 11 young children with CF (1
to 6 years old) and 53 older children and adolescents with CF (>6 years old) were
randomly assigned to one of the following immunization regimens: virosome vaccine
at 0.5 ml on study day 0 or 0.25 ml on days 0 and 28 or a standard regimen of
subunit vaccine, i. e., 0.5 ml on day 0 for older children and 0.25 ml on days 0
and 28 for younger children. Safety assessments, i.e., recording of systemic and
local adverse events (AEs) and vital signs, were made for a 5-day observation
period after each immunization. Hemagglutination inhibition (HI) titers were
determined at baseline and 4 weeks after the single-dose and the two-dose
immunizations, respectively. Immunogenicity was assessed according to the
criteria of the European Agency for the Evaluation of Medicinal Products (EMEA).
Both vaccines induced comparable HI antibody titers. Seroconversion (> or =4-fold
rise in HI antibody titers, reaching a titer of > or =1:40) was achieved in 41 to
100% of the participants. Seroprotection (HI titer, > or =1:40) and a >2.5-fold
increase in geometric mean titers were achieved in 100% of the participants.
Thus, all three EMEA requirements for influenza vaccine efficacy were met by all
treatment groups and for both vaccines. The virosome vaccine, when administered
as a single dose, seemed to induce superior immunogenicity compared with the
standard pediatric two-dose regimen. Totals of 42 and 57% of vaccinees receiving
virosome and subunit vaccines, respectively, reported at least one local AE
(predominantly pain). Totals of 84 and 71% of subjects receiving virosome and
subunit vaccines, respectively, complained in response to questions of at least
one systemic AE (mainly cough, fatigue, coryza, or headache). The majority of
events were mild or moderate and lasted 1 or 2 days only. No obvious relationship
was found between AE reporting rate and vaccine formulation, age group, or dose
regimen. The relatively high AE reporting rate seemed to be partly related to the
symptomatology of the underlying CF disease. In summary, the virosome and subunit
vaccines induced in both age groups and against all three influenza strains an
efficient immune response and were well tolerated by the children and adolescents
with CF.
PMID- 10770747
TI - Influence of resistance to streptogramin A type antibiotics on the activity of
quinupristin-dalfopristin in vitro and in experimental endocarditis due to
Staphylococcus aureus.
AB - We evaluated the activity of quinupristin-dalfopristin (Q-D) against three
clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and
Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to
D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced
activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml,
respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC)
produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation
for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at
8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8)
to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant
bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated
for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times
a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin
were similarly active and bactericidal against the three tested strains compared
to the results for control animals (P < 0.01). Among animals infected with RP 13
and treated with Q-D, one rabbit retained Q-D-resistant mutants that were
resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D,
and Q-D, respectively). We conclude that the bactericidal activity of Q-D against
strains with reduced susceptibility to D and susceptible to Q-D is retained and
is comparable to that of vancomycin. Acquisition of resistance to both Q and D is
necessary to select resistance to Q-D.
PMID- 10770748
TI - Syringomycin E inhibition of Saccharomyces cerevisiae: requirement for
biosynthesis of sphingolipids with very-long-chain fatty acids and mannose- and
phosphoinositol-containing head groups.
AB - Syringomycin E is an antifungal cyclic lipodepsinonapeptide that inhibits the
growth of Saccharomyces cerevisiae by interaction with the plasma membrane. A
screen conducted to find the yeast genes necessary for its fungicidal action
identified two novel syringomycin E response genes, SYR3 and SYR4. A syr3 mutant
allele was complemented by ELO2 and ELO3. These genes encode enzymes that
catalyze the elongation of sphingolipid very long chain fatty acids. Tetrad
analysis showed that SYR3 was ELO2. Strains with deletions of SYR3/ELO2 and ELO3
were resistant to syringomycin E, and lipid analyses of both mutants revealed
shortened fatty acid chains and lower levels of sphingolipids. SYR4 was
identified by Tn5 inactivation of genomic library plasmids that complemented a
syr4 mutant allele. SYR4 was found to be identical to IPT1, which encodes the
terminal sphingolipid biosynthetic enzyme, mannosyl-diinositolphosphoryl-ceramide
synthase. Deletion Deltasyr4/ipt1 strains were viable, were resistant to
syringomycin E, did not produce mannosyl-diinositolphosphoryl-ceramide, and
accumulated mannosyl-inositolphosphoryl-ceramide. Accumulation of mannosyl
inositolphosphoryl-ceramide was not responsible for resistance since a
temperature-sensitive secretory pathway mutant (sec14-3(ts)) accumulated this
sphingolipid and was sensitive to syringomycin E. Finally, Deltacsg1/sur1 and
Deltacsg2 strains defective in the transfer of mannose to inositolphosphoryl
ceramide were resistant to syringomycin E. These findings show that syringomycin
E growth inhibition of yeast is promoted by the production of sphingolipids with
fully elongated fatty acid chains and the mannosyl and terminal
phosphorylinositol moieties of the polar head group.
PMID- 10770749
TI - A simple screen for murein transglycosylase inhibitors.
AB - A simple assay for detection of compounds that bind to the active site in the
transglycosylation domain of the essential bifunctional transglycosylase and
transpeptidase penicillin-binding proteins (PBPs) is reported. The method is
based on a competition with the specific transglycosylase inhibitor moenomycin.
With moenomycin coupled to Affi-Gel beads, a simple filtration procedure allows
the amount of labeled PBPs that bind to moenomycin beads in the presence of test
substances to be determined. The PBPs can easily be labeled by the covalent
binding of penicillin derivatives. Crude membrane extracts can be used as a
source for the PBPs, and different kinds of labels for the penicillin-PBP
complexes can be used. The assay can be adapted to high-throughput screens.
PMID- 10770750
TI - Selective interaction of the human immunodeficiency virus type 1 reverse
transcriptase nonnucleoside inhibitor efavirenz and its thio-substituted analog
with different enzyme-substrate complexes.
AB - Accumulating data have brought the nonnucleoside reverse transcriptase (RT)
inhibitors (NNRTIs) into the forefront of antiretroviral therapy. Among the
emerging compounds in this class, a particularly attractive one is efavirenz
(Sustiva), recently approved for clinical use by the U.S. Food and Drug
Administration. In the present study, the equilibrium dissociation constants for
efavirenz binding to the different catalytic forms of human immunodeficiency
virus type 1 RT as well as the association and dissociation rates have been
determined using a steady-state kinetic approach. In addition, the same
enzymological analysis has been extended to the thio-substituted analog,
sefavirenz, which showed comparable activity in vitro against RT. Both compounds
have been found to act as purely uncompetitive inhibitors at low drug
concentrations (5 to 50 nM) and as mixed noncompetitive inhibitors at higher
doses (50 to 500 nM). This behavior can be interpreted in terms of the relative
affinities for the different catalytic forms of the enzyme. Both efavirenz and
sefavirenz showed increasing affinities for the different forms of RT in the
following order: free enzyme < (i.e., bound with lower affinity) binary RT
template-primer (TP) complex < ternary RT-TP-deoxynucleoside triphosphate (dNTP)
complex. The rate of binding of the two inhibitors to the different enzyme
substrate complexes was well below the diffusion limit (on the order of 10(4) M(
1) s(-1)); however, both inhibitors, when bound to the ternary RT-TP-dNTP
complex, showed very low dissociation rates, on the order of 10(-4) s(-1) for
both compounds, typical of tightly binding inhibitors. Thus, efavirenz and its
thio-substituted derivative sefavirenz appear to be peculiar in their mechanism
of action, being selective tightly binding inhibitors of the ternary RT-TP-dNTP
complex. Efavirenz is the first clinically approved NNRTI to show this property.
PMID- 10770751
TI - Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants
and children following administration of a single intravenous dose of
alatrofloxacin.
AB - The pharmacokinetics of trovafloxacin following administration of a single
intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of
body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children
(ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to
trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin
concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The
primary pharmacokinetic parameters (average +/- SD) analyzed were volume of
distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82
ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all
children. There were no age-related differences in any of the pharmacokinetic
parameters studied. Less than 5% of the administered dose was excreted in the
urine over 24 h. On the basis of the mean area under the concentration-time curve
of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of
common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once
or twice daily should be appropriate.
PMID- 10770752
TI - Enhanced extracellular production of aspartyl proteinase, a virulence factor, by
Candida albicans isolates following growth in subinhibitory concentrations of
fluconazole.
AB - We examined the production of secreted aspartyl proteinase (Sap), a putative
virulence factor of Candida albicans, by a series of 17 isolates representing a
single strain obtained from the oral cavity of an AIDS patient before and after
the development of clinical and in vitro resistance to fluconazole. Isolates were
grown in Sap-inducing yeast carbon base-bovine serum albumin medium containing 0,
0.25, 0.5, or 1 MIC of fluconazole, and cultures were sampled daily for 14 days
to determine extracellular Sap activity by enzymatic degradation of bovine serum
albumin. Extracellular Sap activity was significantly decreased in a dose
dependent manner for the most fluconazole-susceptible isolate (MIC, 1.0
microg/ml) and significantly increased in a dose-dependent manner for the most
fluconazole-resistant isolate (MIC, >64 microg/ml). Enhanced extracellular Sap
production could not be attributed to cell death or nonspecific release of Sap,
because there was no reduction in the number of CFU and no significant release of
enolase, a constitutive enzyme of the glycolytic pathway. Conversely,
intracellular Sap concentrations were significantly increased in a dose-dependent
manner in the most fluconazole-susceptible isolate and decreased in the most
fluconazole-resistant isolate. Enhanced Sap production correlated with the
overexpression of a gene encoding a multidrug resistance (MDR1) efflux pump
occurring in these isolates. These data indicate that exposure to subinhibitory
concentrations of fluconazole can result in enhanced extracellular production of
Sap by isolates with the capacity to overexpress MDR1 and imply that patients
infected with these isolates and subsequently treated with suboptimal doses of
fluconazole may experience enhanced C. albicans virulence in vivo.
PMID- 10770753
TI - Comparison of high-performance liquid chromatographic and microbiological methods
for determination of voriconazole levels in plasma.
AB - A new selective high-performance liquid chromatography (HPLC) method with UV
detection for the determination of the investigational triazole voriconazole in
human plasma by using acetonitrile precipitation followed by reverse-phase HPLC
on a C(18) column was compared with a simple agar well diffusion bioassay method
with Candida kefyr ATCC 46764 as the assay organism. Pooled plasma was used to
prepare standard and control samples for both methods. The results of analyses
with spiked serum samples (run as unknowns) were concordant by the bioassay and
HPLC methods, with expected values being obtained. HPLC demonstrated an improved
precision (3.47 versus 12.12%) and accuracy (0.81 versus 1.28%) compared to those
of the bioassay method. The range of linearity obtained by both methods (from 0.2
to 10 microg/ml for HPLC and from 0.25 to 20 microg/ml for the bioassay) includes
the range of concentrations of voriconazole (from 1.2 to 4.7 microg/ml) which are
considered clinically relevant. Although either methodology could be used for the
monitoring of patient therapy, the smaller variability observed with HPLC
compared to that observed with the bioassay favors the use of HPLC for
pharmacokinetic studies.
PMID- 10770754
TI - Identification of the novobiocin biosynthetic gene cluster of Streptomyces
spheroides NCIB 11891.
AB - The novobiocin biosynthetic gene cluster from Streptomyces spheroides NCIB 11891
was cloned by using homologous deoxynucleoside diphosphate (dNDP)-glucose 4,6
dehydratase gene fragments as probes. Double-stranded sequencing of 25.6 kb
revealed the presence of 23 putative open reading frames (ORFs), including the
gene for novobiocin resistance, gyrB(r), and at least 11 further ORFs to which a
possible role in novobiocin biosynthesis could be assigned. An insertional
inactivation experiment with a dNDP-glucose 4, 6-dehydratase fragment resulted in
abolishment of novobiocin production, since biosynthesis of the deoxysugar moiety
of novobiocin was blocked. Heterologous expression of a key enzyme of novobiocin
biosynthesis, i.e., novobiocic acid synthetase, in Streptomyces lividans TK24
further confirmed the involvement of the analyzed genes in the biosynthesis of
the antibiotic.
PMID- 10770755
TI - Evidence for active efflux as the primary mechanism of resistance to
ciprofloxacin in Salmonella enterica serovar typhimurium.
AB - The occurrence of active efflux and cell wall modifications were studied in
Salmonella enterica serovar Typhimurium mutants that were selected with
enrofloxacin and whose phenotypes of resistance to fluoroquinolones could not be
explained only by mutations in the genes coding for gyrase or topoisomerase IV.
Mutant BN18/21 exhibited a decreased susceptibility to ciprofloxacin (MIC = 0.125
microg/ml) but did not have a mutation in the gyrA gene. Mutants BN18/41 and
BN18/71 had the same substitution, Gly81Cys in GyrA, but exhibited different
levels of resistance to ciprofloxacin (MICs = 2 and 8 microg/ml, respectively).
None of the mutants had mutations in the parC gene. Evidence for active efflux
was provided by a classical fluorimetric method, which revealed a three- to
fourfold decrease in ciprofloxacin accumulation in the three mutants compared to
that in the parent strain, which was annulled by addition of the efflux pump
inhibitor carbonyl cyanide m-chlorophenylhydrazone. In mutant BN18/71, a second
fluorimetric method also showed a 50% reduction in the level of accumulation of
ethidium bromide, a known efflux pump substrate. Immunoblotting and enzyme-linked
immunosorbent assay experiments with an anti-AcrA antibody revealed that the
resistance phenotype was strongly correlated with the expression level of the
AcrAB efflux pump and suggested that decreased susceptibility to ciprofloxacin
due to active efflux probably related to overproduction of this pump could occur
before that due to gyrA mutations. Alterations were also found in the outer
membrane protein and lipopolysaccharide profiles of the mutants, and these
alterations were possibly responsible for the decrease in the permeability of the
outer membrane that was observed in the mutants and that could act
synergistically with active efflux to decrease the level of ciprofloxacin
accumulation.
PMID- 10770756
TI - Characterization of the metallo-beta-lactamase determinant of Acinetobacter
baumannii AC-54/97 reveals the existence of bla(IMP) allelic variants carried by
gene cassettes of different phylogeny.
AB - The metallo-beta-lactamase determinant of Acinetobacter baumannii AC-54/97, a
clinical isolate from Italy that was previously shown to produce an enzyme
related to IMP-1, was isolated by means of a PCR methodology which targets
amplification of gene cassette arrays inserted into class 1 integrons. Sequencing
revealed that this determinant was an allelic variant (named bla(IMP-2)) of
bla(IMP) found in Japanese isolates and that it was divergent from the latter by
12% of its nucleotide sequence, which evidently had been acquired independently.
Similar to bla(IMP), bla(IMP-2) was also carried by an integron-borne gene
cassette. However, the 59-base element of the bla(IMP-2) cassette was unrelated
to those of the bla(IMP) cassettes found in Japanese isolates, indicating a
different phylogeny for the gene cassettes carrying the two allelic variants.
Expression of the integron-borne bla(IMP-2) gene in Escherichia coli resulted in
a significant decrease in susceptibility to a broad array of beta-lactams
(ampicillin, carbenicillin, cephalothin, cefoxitin, ceftazidime, cefepime, and
carbapenems). The IMP-2 enzyme was purified from an Escherichia coli strain
carrying the cloned determinant, and kinetic parameters were determined with
several beta-lactam substrates. Compared to IMP-1, the kinetic parameters of IMP
2 were similar overall with some beta-lactam substrates (cefoxitin, ceftazidime,
cefepime, and imipenem) but remarkably different with others (ampicillin,
carbenicillin, cephaloridine, and meropenem), revealing a functional significance
of at least some of the mutations that differentiate the two IMP variants.
Present findings suggest that the environmental reservoir of bla(IMP) alleles
could be widespread and raise a question about the global risk of their transfer
to clinically relevant species.
PMID- 10770757
TI - Inhibition of human rhinovirus-induced cytokine production by AG7088, a human
rhinovirus 3C protease inhibitor.
AB - Symptom severity in patients with human rhinovirus (HRV)-induced respiratory
illness is associated with elevated levels of the inflammatory cytokines
interleukin-6 (IL-6) and IL-8. AG7088 is a novel, irreversible inhibitor of the
HRV 3C protease. In this study, AG7088 was tested for its antiviral activity and
ability to inhibit the production of IL-6 and IL-8 in a human bronchial
epithelial cell line, BEAS-2B. Infection of BEAS-2B cells with HRV 14 resulted in
the production of both infectious virus and the cytokines IL-6 and IL-8.
Treatment of HRV 14-infected cells with AG7088 resulted in a statistically
significant (P, <0.05) dose-dependent reduction in the levels of infectious virus
as well as IL-6 and IL-8 released into the cell supernatant compared to the
results obtained for compound-free infected cells. AG7088 was also able to
inhibit the replication of HRV 2 and 16 in BEAS-2B cells. In time-of-addition
studies, AG7088 could be added as late as 14 to 26 h after HRV 14 infection of
BEAS-2B cells and still result in a statistically significant (P, <0.05)
reduction in the levels of infectious virus, IL-6, and IL-8 compared to the
results obtained for compound-free infected cells. These findings have
implications for the development of an antirhinovirus agent that may not only
block virus replication but also diminish symptoms.
PMID- 10770758
TI - In vitro activity of A-192411.29, a novel antifungal lipopeptide.
AB - A-192411.29 is a novel antifungal agent derived from the structural template of
the natural product echinocandin. The in vitro activity of A-192411.29 against
common pathogenic yeasts was assessed by National Committee for Clinical
Laboratory Standards method M27-A. It demonstrated broad-spectrum, fungicidal
activity and was active against the most clinically relevant yeasts, such as
Candida albicans, Candida tropicalis, and Candida glabrata, as well as less
commonly encountered Candida species; in general, its potency on a weight basis
was comparable to that of amphotericin B. It maintained potent in vitro activity
against Candida strains with reduced susceptibilities to fluconazole and
amphotericin B. The in vitro activity of A-192411.29 against Cryptococcus
neoformans was comparable to its activity against Candida spp. However, A
192411.29 did not demonstrate complete growth inhibition of Aspergillus fumigatus
by the broth microdilution method used. A-192411.29 possesses an antifungal
profile comparable to or better than those of fluconazole and amphotericin B
against pathogenic yeasts, including strains resistant to fluconazole or
amphotericin B, suggesting that it may be a therapeutically useful new antifungal
drug.
PMID- 10770759
TI - Pharmacodynamics of glycopeptides in the mouse peritonitis model of Streptococcus
pneumoniae or Staphylococcus aureus infection.
AB - The emergence of resistance to various antibiotics in pneumococci leaves the
glycopeptides as the only antibiotics against which pneumococci have no
resistance mechanism. This situation has led to a renewed interest in the use of
glycopeptides. It has not yet been possible to conclude which one or more of the
pharmacokinetic or pharmacodynamic (PK/PD) parameters are the most important and
best predictors for the effects of treatment with glycopeptides in animal models
or in humans. We used the mouse peritonitis model with immunocompetent mice and
with Staphylococcus aureus and Streptococcus pneumoniae as infective organisms. A
wide spectrum of different treatment regimens with vancomycin and teicoplanin was
tested to study the pharmacodynamics of these drugs. In studies in which the
single dose that protected 50% of lethally infected mice (ED(50)) was given as
one dose or was divided into two doses, survival was significantly decreased when
the dose was divided. The only statistically significant correlations between the
percentage of survival of the mice after 6 days and each of the PK/PD parameters
were for peak concentration (C(max))/MIC and S. aureus and for the free fraction
of C(max) (C(max-free))/MIC and S. pneumoniae. For S. pneumoniae, the ED(50) for
different dosing regimens increased with the number of doses given; e.g., the
single-dose ED(50)s for vancomycin and teicoplanin were 0.65 and 0. 45 mg/kg,
respectively, but the ED(50)s for dosing regimens with 2-h doses given for 48 h
were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 different
vancomycin dosing regimens and 40 different teicoplanin dosing regimens against
S. pneumoniae, the different PK/PD parameters were analyzed using logistic
regression. The C(max-free)/MIC was one of two parameters that best explained the
effect for both drugs; for vancomycin, the other important parameter was the
AUC/MIC, and for teicoplanin, the other parameter was the time the free fraction
of the drug is above the MIC. The effect analyzed as a function of C(max
free)/MIC disclosed thresholds with shifts from almost no effect to full effect
at ratios of five to six for vancomycin and two to three for teicoplanin.
PMID- 10770760
TI - Genome-wide expression patterns in Saccharomyces cerevisiae: comparison of drug
treatments and genetic alterations affecting biosynthesis of ergosterol.
AB - Enzymes in the ergosterol-biosynthetic pathway are the targets of a number of
antifungal agents including azoles, allylamines, and morpholines. In order to
understand the response of Saccharomyces cerevisiae to perturbations in the
ergosterol pathway, genome-wide transcript profiles following exposure to a
number of antifungal agents targeting ergosterol biosynthesis (clotrimazole,
fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine, and
amorolfine) were obtained. These profiles were compared to the transcript
profiles of strains containing deletions of one of the late-stage ergosterol
genes: ERG2, ERG5, or ERG6. A total of 234 genes were identified as responsive,
including the majority of genes from the ergosterol pathway. Expression of
several responsive genes, including ERG25, YER067W, and YNL300W, was also
monitored by PCR over time following exposure to ketoconazole. The kinetics of
transcriptional response support the conditions selected for the microarray
experiment. In addition to ergosterol-biosynthetic genes, 36 mitochondrial genes
and a number of other genes with roles related to ergosterol function were
responsive, as were a number of genes responsive to oxidative stress.
Transcriptional changes related to heme biosynthesis were observed in cells
treated with chemical agents, suggesting an additional effect of exposure to
these compounds. The expression profile in response to a novel imidazole, PNU
144248E, was also determined. The concordance of responsive genes suggests that
this compound has the same mode of action as other azoles. Thus, genome-wide
transcript profiles can be used to predict the mode of action of a chemical agent
as well as to characterize expression changes in response to perturbation of a
metabolic pathway.
PMID- 10770761
TI - Identification and expression of genes involved in biosynthesis of L-oleandrose
and its intermediate L-olivose in the oleandomycin producer Streptomyces
antibioticus.
AB - A 9.8-kb DNA region from the oleandomycin gene cluster in Streptomyces
antibioticus was cloned. Sequence analysis revealed the presence of 8 open
reading frames encoding different enzyme activities involved in the biosynthesis
of one of the two 2, 6-deoxysugars attached to the oleandomycin aglycone: L
oleandrose (the oleW, oleV, oleL, and oleU genes) and D-desosamine (the oleNI and
oleT genes), or of both (the oleS and oleE genes). A Streptomyces albus strain
harboring the oleG2 glycosyltransferase gene integrated into the chromosome was
constructed. This strain was transformed with two different plasmid constructs
(pOLV and pOLE) containing a set of genes proposed to be required for the
biosynthesis of dTDP-L-olivose and dTDP-L-oleandrose, respectively. Incubation of
these recombinant strains with the erythromycin aglycon (erythronolide B) gave
rise to two new glycosylated compounds, identified as L-3-O-olivosyl- and L-3-O
oleandrosyl-erythronolide B, indicating that pOLV and pOLE encode all enzyme
activities required for the biosynthesis of these two 2,6-dideoxysugars. A
pathway is proposed for the biosynthesis of these two deoxysugars in S.
antibioticus.
PMID- 10770762
TI - The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral
effects with retention of both immunomodulatory activity and reduction of
hepatitis-induced serum alanine aminotransferase levels.
AB - The demonstrated utility of the nucleoside analog ribavirin in the treatment of
certain viral diseases can be ascribed to its multiple distinct properties. These
properties may vary in relative importance in differing viral disease conditions
and include the direct inhibition of viral replication, the promotion of T-cell
mediated immune responses via an enhanced type 1 cytokine response, and a
reduction of circulating alanine aminotransferase (ALT) levels associated with
hepatic injury. Ribavirin also has certain known toxicities, including the
induction of anemia upon chronic administration. To determine if all these
properties are linked, we compared the D-nucleoside ribavirin to its L-enantiomer
(ICN 17261) with regard to these properties. Strong similarities were seen for
these two compounds with respect to induction of type 1 cytokine bias in vitro,
enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT
levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro
antiviral activity against a panel of RNA and DNA viruses, while ribavirin
exhibited its characteristic activity profile. Importantly, the preliminary in
vivo toxicology profile of ICN 17261 is significantly more favorable than that of
ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by
oral gavage for 4 weeks generated substantial serum levels of drug but no
observable clinical pathology, whereas equivalent doses of ribavirin induced a
significant anemia and leukopenia. Thus, structural modification of ribavirin can
dissociate its immunomodulatory properties from its antiviral and toxicologic
properties, resulting in a compound (ICN 17261) with interesting therapeutic
potential.
PMID- 10770763
TI - In vitro pharmacodynamic parameters of sordarin derivatives in comparison with
those of marketed compounds against Pneumocystis carinii isolated from rats.
AB - Pneumocystis carinii pneumonia remains one of the most serious complications of
immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters
of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771)
have been evaluated by a new quantitative approach and compared with the
commercially available drugs pentamidine, atovaquone, and trimethoprim
sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therapeutic
efficacies of sordarin derivatives against P. carinii were also evaluated. In
vitro activity was determined by the broth microdilution technique, comparing the
total number of microorganisms in treated and drug-free cultures by using Giemsa
staining. The in vitro maximum effect (E(max)), the drug concentrations to reach
50% of E(max) (EC(50)), and the slope of the dose-response curve were then
estimated by the Hill equation (E(max) sigmoid model). Sordarin derivatives were
the most potent agents against P. carinii, with EC(50)s of 0.00025, 0.0007,
0.0043, and 0. 025 microg/ml for GM 191519, GM 237354, GM 193663, and GM 219771,
respectively. The EC(50)s of pentamidine, atovaquone, and TMP-SMX were 0.025,
0.16, and 26.7/133.5 microg/ml, respectively. The results obtained with this
approach showed GM 237354 and GM 191519 to be approximately 35- and 100-fold more
active in vitro than pentamidine, the most active marketed compound. All sordarin
derivatives tested were at least 5,000-fold more active in vitro than TMP-SMX.
The three sordarin derivatives tested in vivo-GM 191519, GM 237354, and GM 219771
showed a marked therapeutic efficacy, defined as reduction of cyst forms per gram
of lung. GM 191519 was the most potent (daily dose reducing 50% of the P. carinii
burden in the lungs [ED(50)], 0.05 mg/kg/day) followed by GM 237354 and GM 219771
(ED(50)s, 0.30 and 0.49 mg/kg/day, respectively). Good agreement between in vitro
parameters and in vivo outcome was obtained when P. carinii pneumonia in rats was
treated with sordarin derivatives.
PMID- 10770764
TI - Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae:
implications for breakpoint determinations.
AB - Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the
treatment of respiratory-tract infections in children. While this agent has
provided acceptable clinical success over a number of years, this study was
undertaken to better define its pharmacodynamic profile against Streptococcus
pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the
neutropenic murine thigh infection model. To simulate the pharmacokinetic profile
of cefprozil in children, the renal function of mice was impaired with uranyl
nitrate, and a commercially available cefprozil suspension (6 mg/kg of body
weight) was administered orally every 12 h. Mice were infected with 10(6) to
10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h
postinfection, thighs were harvested to determine bacterial density. Survival was
assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5
to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication
was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was
observed with MICs of < or =3 microg/ml, while either minimal killing or growth
was detected with MICs of > or =4 microg/ml. Mortality in untreated control
animals was 100%. Animals infected with strains for which the MICs were < or =2
microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in
substantial mortality. These studies demonstrate the effectiveness of cefprozil
against isolates of the pneumococcus for which the MICs are < or =2 microg/ml
using a drug exposure typically observed in children. These data support a
susceptibility breakpoint of < or =2 microg/ml for cefprozil.
PMID- 10770765
TI - Evaluation of the invader assay, a linear signal amplification method, for
identification of mutations associated with resistance to rifampin and isoniazid
in Mycobacterium tuberculosis.
AB - We evaluated a recently described linear signal amplification method for
sensitivity and specificity in detecting mutations associated with resistance to
rifampin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis. The assay
utilizes the thermostable flap endonuclease Cleavase VIII, derived from
Archaeoglobus fulgidus, which cleaves a structure formed by the hybridization of
two overlapping oligonucleotide probes to a target nucleic acid strand. This
method, termed the Invader assay, can discriminate single-base differences. Nine
pairs of probes, encompassing five mutations in rpoB and katG that are associated
with resistance to either RIF or INH, as well as the corresponding wild-type
(drug-susceptible) alleles, were tested using amplified DNA. Fluorescent-labeled
cleavage products, ranging from 4 to 13 nucleotides in length, depending on the
genotype of the test sample, were separated by denaturing polyacrylamide (20 to
24%) gel electrophoresis and then detected by scanning. All nine alleles could be
identified and differentiated on the basis of product size. Multiple mutations at
a specific rpoB nucleotide in target PCR products could be identified, as could
mutants that were present at > or =0.5% of the total population of target
sequences. The Invader assay is a sensitive screen for some mutations associated
with antituberculosis drug resistance in amplified gene regions.
PMID- 10770766
TI - Combinations of artemisinin and quinine for uncomplicated falciparum malaria:
efficacy and pharmacodynamics.
AB - Combinations of artemisinin and quinine for uncomplicated falciparum malaria were
studied. A total of 268 patients were randomized to 7 days of quinine at 10 mg/kg
of body weight three times a day (Q) or to artemisinin at 20 mg/kg of body weight
followed by 3 (AQ3) or 5 (AQ5) days of quinine. Recrudescence rates were 16, 38,
and 15% for the Q, AQ3, and AQ5 groups, respectively (P < 0.001). Recrudescence
was associated with shorter parasite clearance time (PCT) and longer treatment
after the blood smear had become negative (eradication time). However,
classification of patients to outcome-recrudescence or radical cure-was correct
in only 77% of patients. The population kinetics of the parasitemia was estimated
with nonlinear mixed-effect models. Several models were tested, but the best
model was a monoexponential decline of the parasitemia in which the mean parasite
elimination half-life was shorter after artemisinin (5.1 h; 95% confidence
interval [CI], 4.9 to 5.2 h) than after quinine (8.0 h [95% CI, 7.5 to 8.3 h]).
Attempts to simulate the initial increase of the parasitemia did not result in
better models with a biologically plausible interpretation. Recrudescence was
associated with slower parasite clearance and a higher simulated terminal
parasitemia (P(term)). The classification of patients to outcome groups based on
P(term) was correct in 78% of patients. The data suggest that parasite strains
with reduced sensitivity to quinine are prevalent in Vietnam, with slower
parasite clearance and consequent recrudescence. A single dose of artemisinin
induces rapid parasite reduction and lowers the value of P(term), but to prevent
recrudescence, this should be followed by quinine for at least 3 days after
parasite clearance, or 5 days in total.
PMID- 10770767
TI - Novel beta-lactamase genes from two environmental isolates of Vibrio harveyi.
AB - Two ampicillin-resistant (Amp(r)) isolates of Vibrio harveyi, W3B and HB3, were
obtained from the coastal waters of the Indonesian island of Java. Strain W3B was
isolated from marine water near a shrimp farm in North Java while HB3 was from
pristine seawater in South Java. In this study, novel beta-lactamase genes from
W3B (bla(VHW-1)) and HB3 (bla(VHH-1)) were cloned and their nucleotide sequences
were determined. An open reading frame (ORF) of 870 bp encoding a deduced protein
of 290 amino acids (VHW-1) was revealed for the bla gene of strain W3B while an
ORF of 849 bp encoding a 283-amino-acid protein (VHH-1) was deduced for bla(VHH
1). At the DNA level, genes for VHW-1 and VHH-1 have a 97% homology, while at the
protein level they have a 91% homology of amino acid sequences. Neither gene
sequence showed homology to any other beta-lactamases in the databases. The
deduced proteins were found to be class A beta-lactamases bearing low levels of
homology (<50%) to other beta-lactamases of the same class. The highest level of
identity was obtained with beta-lactamases from Pseudomonas aeruginosa, i.e., PSE
1, PSE-4, and CARB-3, and Vibrio cholerae CARB-6. Our study showed that both
strains W3B and HB3 possess an endogenous plasmid of approximately 60 kb in size.
However, Southern hybridization analysis employing bla(VHW-1) as a gene probe
demonstrated that the bla gene was not located in the plasmid. A total of nine
ampicillin-resistant V. harveyi strains, including W3B and HB3, were examined by
pulsed-field gel electrophoresis of NotI-digested genomic DNA. Despite a high
level of intrastrain genetic diversity, the bla(VHW-1) probe hybridized only to
an 80- or 160-kb NotI genomic fragment in different isolates.
PMID- 10770768
TI - Distribution and content of class 1 integrons in different Vibrio cholerae O
serotype strains isolated in Thailand.
AB - In this study, 176 clinical and environmental Vibrio cholerae strains of
different O serotypes isolated in Thailand from 1982 to 1995 were selected and
studied for the presence of class 1 integrons, a new group of genetic elements
which carry antibiotic resistance genes. Using PCR and DNA sequencing, we found
that 44 isolates contained class 1 integrons harboring the aadB, aadA2, blaP1,
dfrA1, and dfrA15 gene cassettes, which encode resistance to gentamicin,
kanamycin, and tobramycin; streptomycin and spectinomycin; beta-lactams; and
trimethoprim, respectively. Each cassette array contained only a single
antibiotic resistance gene. Although resistance genes in class 1 integrons were
found in strains from the same epidemic, as well as in unrelated non-O1, non-O139
strains isolated from children with diarrhea, they were found to encode only some
of the antibiotic resistance expressed by the strains. Serotype O139 strains did
not contain class 1 integrons. However, the appearance and disappearance of the
O139 serotype in the coastal city Samutsakorn in 1992 and 1993 were associated
with the emergence of a distinct V. cholerae O1 strain which contained the aadA2
resistance gene cassette. A 150-kb self-transmissible plasmid found in three O1
strains isolated in 1982 contained the aadB gene cassette. Surprisingly, several
strains harbored two integrons containing different cassettes. Thus, class 1
integrons containing various resistance gene cassettes are distributed among
different V. cholerae O serotypes of mainly clinical origin in Thailand.
PMID- 10770769
TI - Actinomycin production persists in a strain of Streptomyces antibioticus lacking
phenoxazinone synthase.
AB - Truncated fragments of the phenoxazinone synthase gene, phsA, were prepared by
the PCR. The resulting fragments were cloned into conjugative plasmid pKC1132 and
transferred to Streptomyces antibioticus by conjugation from Escherichia coli.
Two of the resulting constructs were integrated into the S. antibioticus
chromosome by homologous recombination, and each of the resulting strains,
designated 3720/pJSE173 and 3720/pJSE174, contained a disrupted phsA gene. Strain
3720/pJSE173 grew poorly, and Southern blotting suggested that genetic changes
other than the disruption of the phsA gene might have occurred during the
construction of that strain. Strain 3720/pJSE174 sporulated well and grew
normally on the medium used to prepare inocula for antibiotic production. Strain
3720/pJSE174 also grew as well as the wild-type strain on antibiotic production
medium containing either 1 or 5.7 mM phosphate. Strain 3720/pJSE174 was shown to
be devoid of phenoxazinone synthase (PHS) activity, and PHS protein was
undetectable in this strain by Western blotting. Despite the absence of
detectable PHS activity, strain 3720/pJSE174 produced slightly more actinomycin
than did the wild-type parent strain in medium containing 1 or 5.7 mM phosphate.
The observation that strain 3720/pJSE174, lacking detectable PHS protein or
enzyme activity, retained the ability to produce actinomycin supports the
conclusion that PHS is not required for actinomycin biosynthesis in S.
antibioticus.
PMID- 10770770
TI - Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1
isolates derived from patients with multidrug resistance to other protease
inhibitors.
AB - In our study we examined the anti-human immunodeficiency virus type 1 (anti-HIV
1) activity of a novel HIV-1 protease inhibitor, PNU-140690 (tipranavir), against
patient-derived isolates resistant to multiple other protease inhibitors (PIs).
The aim of our experiments was to investigate the genotypes and the in vitro
phenotypes of drug resistance of PNU-140690. We carried out drug susceptibility
tests with peripheral blood mononuclear cells and a fixed amount of infectious
virus (1,000 50% tissue culture infective doses) to determine the 50% inhibitory
concentration (IC(50)) and IC(90), PCR assays for the detection of drug
resistance mutations in RNA in plasma, and direct sequencing of PCR products.
Phenotypic resistance to PIs was invariably related to genotypic mutations. The
substitutions among the amino acid residues of the protease included L10I, K20R,
L24I, M36I, N37D, G48V, I54V, L63P, I64V, A71V, V77I, V82A, I84V, and L90M.
Isolates from all of the patients had developed a maximal degree of resistance to
indinavir, ritonavir, and nelfinavir (IC(50)s, >0.1 microM). We also compared
these mutations with the amino acid changes previously described in association
with in vivo tipranavir administration. The mutations included the following:
I15V, E35D, N37D, R41K, D60E, and A71T. Infections with IIIB, 14aPre, and N70
were inhibited by an average drug IC(90) of 0.18 +/- 0.02 microM in multiple
experiments. The average mean +/- standard error of mean IC(90) for the entire
group of multidrug-resistant isolates derived from the mean values for two
culture wells with p24 antigen supernatant appeared to be 0.619 +/- 0.055 microM
(range, 0.31 to 0.86 microM). Tipranavir retained a sustained antiviral activity
against PI-MDR clinical isolates and might be useful in combination regimens with
other antiretroviral agents for patients who have already failed other PI
containing therapies.
PMID- 10770771
TI - Efficacy of SCH27899 in an animal model of Legionnaires' disease using
immunocompromised A/J mice.
AB - The efficacy of SCH27899, a new everninomicin antibiotic, against replicative
Legionella pneumophila lung infections in an immunocompromised host was evaluated
using a murine model of Legionnaires' disease. A/J mice were immunocompromised
with cortisone acetate and inoculated intratracheally with L. pneumophila
serogroup 1 (10(5) CFU per mouse). At 24 h postinoculation, mice were
administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo
once daily for 5 days, and mortality and intrapulmonary growth of L. pneumophila
were assessed. In the absence of SCH27899, there was 100% mortality in L.
pneumophila-infected mice, with exponential intrapulmonary growth of the
bacteria. In contrast, administration of SCH27899 at a dose of > or =30 MPK
resulted in > or =90% survival of infected mice, which was associated with
inhibition of intrapulmonary growth of L. pneumophila. In subsequent studies, the
efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI).
Administration of SCH27899, OFX, or AZI at a dose of > or =30 MPK once daily for
5 days resulted in > or =85% survival of infected mice and inhibition of
intrapulmonary growth of the bacteria. However, L. pneumophila CFU were recovered
in lung homogenates following cessation of therapy with all three antibiotics.
These studies demonstrate that SCH27899 effectively prevents fatal replicative L.
pneumophila lung infection in immunocompromised A/J mice by inhibition of
intrapulmonary growth of the bacteria. However, in this murine model of pulmonary
legionellosis, SCH27899, like OFX and AZI, was bacteriostatic.
PMID- 10770773
TI - Multicenter surveillance of antimicrobial resistance of Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis in Taiwan during the 1998-1999
respiratory season.
AB - A susceptibility surveillance study of 276 isolates of Streptococcus pneumoniae,
301 of Haemophilus influenzae, and 110 of Moraxella catarrhalis was carried out
from November 1998 to May 1999 in Taiwan. High rates of nonsusceptibility to
penicillin (76%), extended-spectrum cephalosporins (56%), azithromycin (94%),
clarithromycin (95%), and trimethoprim-sulfamethoxazole (TMP-SMX) (65%) for S.
pneumoniae isolates and high rates of nonsusceptibility to amoxicillin (58%) and
TMP-SMX (52%) for H. influenzae isolates were found. Higher percentages of S.
pneumoniae isolates nonsusceptible to aminopenicillins, extended-spectrum
cephalosporins, macrolides, and TMP-SMX were observed among penicillin
intermediate and -resistant isolates. All quinolones tested were active in vitro
against these three organisms.
PMID- 10770772
TI - Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide
concentrations.
AB - Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40
adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10
healthy women). Blood was obtained for drug assay prior to administration of the
first dose, 2 h after the last dose, and at the completion of standardized
bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last
dose. Ethionamide was measured in epithelial lining fluid (ELF) and alveolar
cells (AC) using a new mass spectrometric method. The presence of AIDS or gender
was without significant effect on the concentrations of ethionamide in plasma,
AC, or ELF. Plasma concentrations (mean +/- standard deviation [SD]) were 0.97 +/
0.65 and 0.65 +/- 0.35 microg/ml at 2 and 4 h after the last dose, respectively,
and both values were significantly greater than the concentration of ethionamide
in AC (0.38 +/- 0.47 microg/ml) (P < 0. 05). The concentration of ethionamide was
significantly greater in ELF (5.63 +/- 3.8 microg/ml) than in AC or plasma at 2
and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide
susceptible strains of Mycobacterium tuberculosis. For all 40 subjects, the
ELF/plasma concentration ratios (mean +/- SD) at 2 and 4 h were 8.7 +/- 11.7 and
9.7 +/- 5.6, respectively. We conclude that the absorption of orally administered
ethionamide, as measured in this study, was not affected by gender or the
presence of AIDS. Ethionamide concentrations were significantly greater in ELF
than in plasma or AC, suggesting that substantial antimycobacterial activity
resides in this compartment.
PMID- 10770774
TI - Glycopeptide-resistant Enterococcus faecium BM4416 is a VanD-type strain with an
impaired D-Alanine:D-Alanine ligase.
AB - VanD-type Enterococcus faecium BM4416 was constitutively resistant to vancomycin
and to teicoplanin by synthesis of peptidoglycan precursors ending in D-alanyl-D
lactate. Like E. faecium BM4339, the only VanD-type strain described so far,
BM4416 produced an impaired D-alanine:D-alanine ligase. Unlike for BM4339, which
had a 5-bp insertion in ddl, inactivation of the gene in BM4416 was due to
insertion of IS19.
PMID- 10770775
TI - Geographic distribution of a large mobile element that transfers ampicillin and
vancomycin resistance between Enterococcus faecium strains.
AB - In several clonally unrelated VanB-type vancomycin-resistant Enterococcus faecium
strains, we demonstrated a common physical relationship between pbp5 and Tn5382
as well as common mutations within pbp5. The majority of these strains
transferred vancomycin and ampicillin resistance to E. faecium in vitro,
suggesting the dissemination of similar transferable pbp5-vanB-containing mobile
elements throughout the United States.
PMID- 10770776
TI - Pharmacokinetics and pharmacodynamics of levofloxacin against Streptococcus
pneumoniae and Staphylococcus aureus in human skin blister fluid.
AB - The pharmacokinetics of levofloxacin in serum and in skin blister fluid (SBF) was
determined for 20 volunteers after a single 500-mg oral dose of levofloxacin. In
addition, ex vivo bactericidal activity of SBF against Streptococcus pneumoniae
and Staphylococcus aureus was studied. SBF containing levofloxacin and
granulocytes killed 5.2 log of Streptococcus pneumoniae bacteria and 2.0 log of
Staphylococcus aureus bacteria during a 6-h incubation.
PMID- 10770777
TI - Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered
by continuous infusion to mechanically ventilated patients in an intensive care
unit.
AB - Cerebrospinal fluid (CSF) penetration and the pharmacokinetics of vancomycin were
studied after continuous infusion (50 to 60 mg/kg of body weight/day after a
loading dose of 15 mg/kg) in 13 mechanically ventilated patients hospitalized in
an intensive care unit. Seven patients were treated for a sensitive bacterial
meningitis and the other six patients, who had a severe concomitant neurologic
disease with intracranial hypertension, were treated for various infections.
Vancomycin CSF penetration was significantly higher (P < 0.05) in the meningitis
group (serum/CSF ratio, 48%) than in the other group (serum/CSF ratio, 18%).
Vancomycin pharmacokinetic parameters did not differ from those obtained with
conventional dosing. No adverse effect was observed, in particular with regard to
renal function.
PMID- 10770778
TI - Occurrence of a Salmonella enterica serovar typhimurium DT104-like antibiotic
resistance gene cluster including the floR gene in S. enterica serovar agona.
AB - Recently a chromosomal locus possibly specific for Salmonella enterica serovar
Typhimurium DT104 has been reported that contains a multiple antibiotic
resistance gene cluster. Evidence is provided that Salmonella enterica serovar
Agona strains isolated from poultry harbor a similar gene cluster including the
newly described floR gene, conferring cross-resistance to chloramphenicol and
florfenicol.
PMID- 10770779
TI - Effects of the movement of insertion sequences on the structure of VanA
glycopeptide resistance elements in Enterococcus faecium.
AB - A Tn1546-related element with IS1216V at position 8839 underwent a structural
change after storage of the host strain of Enterococcus faecium at 4 degrees C.
The element acquired IS1542 at position 3932, nucleotides 8732 to 8831 were
deleted, and the first 3417 nucleotides were lost and replaced by an inverted
copy of the IS1216V-vanY-vanZ-inverted-repeat block from the 3' end. Insertion
sequence movement is likely to play a key role in the evolution of VanA
resistance elements.
PMID- 10770780
TI - Spectinomycin resistance in Neisseria spp. due to mutations in 16S rRNA.
AB - Spectinomycin resistance in clinical isolates of Neisseria meningitidis and
Neisseria gonorrhoeae was found to be due to mutations G1064C and C1192U
(Escherichia coli numbering) in 16S rRNA genes, respectively.
PMID- 10770781
TI - MICs of oxazolidinones for Rhodococcus equi strains isolated from humans and
animals.
AB - Eperezolid and linezolid are representatives of a new class of orally active,
synthetic antimicrobial agents. The in vitro activity values (MICs) of linezolid,
eperezolid, and comparator antibiotics against 102 strains of Rhodococcus equi
isolated from humans and animals were determined. Linezolid was more active than
eperezolid against the strains tested; premafloxacin was the most active
comparator antibiotic.
PMID- 10770782
TI - In vitro activities of LY333328 and comparative agents against nosocomial gram
positive pathogens collected in a 1997 global surveillance study.
AB - The in vitro activity of LY333328 was evaluated for 1,479 nosocomial gram
positive pathogens isolated in 12 countries during 1997. LY333328 MICs at which
90% of the isolates tested were inhibited for Enterococcus faecalis (n = 351),
Enterococcus faecium (n = 100), Staphylococcus aureus (n = 593), coagulase
negative Staphylococcus species (n = 325), and Streptococcus pneumoniae (n = 110)
were 1, 1, 2, 2, and 0.015 microg/ml, respectively. LY333328 demonstrated potent
activity against isolates of vancomycin-resistant enterococci, oxacillin
resistant staphylococci, and penicillin-resistant pneumococci.
PMID- 10770783
TI - Bioavailability of once- and twice-daily regimens of didanosine in human
immunodeficiency virus-infected children.
AB - The bioavailability of didanosine at 180 mg/m(2) once daily was compared to that
at 90 mg/m(2) twice daily in 24 children with advanced human immunodeficiency
virus infection. Children were studied at steady state using optimal sampling and
prior pharmacokinetic parameter estimates. Relative bioavailability was 0. 95 +/-
0.49, supporting the potential clinical adequacy of once-daily dosing.
PMID- 10770784
TI - Comparative killing rates of fluoroquinolones and cell wall-active agents.
AB - Killing rates of fluoroquinolones, beta-lactams, and vancomycin were compared
against Enterobacteriaceae, Staphylococcus aureus, pneumococci, streptococci, and
Enterococcus faecalis. The times required for fluoroquinolones to decrease
viability by 3 log(10) were 1.5 h for Enterobacteriaceae, 4 to 6 h for
staphylococci, and >/=6 h for streptococci and enterococci. Thus, the rate of
killing by fluoroquinolones is organism group dependent; overall, they killed
more rapidly than beta-lactams and vancomycin.
PMID- 10770785
TI - In vitro activity of telithromycin (HMR3647), a new ketolide, against clinical
isolates of Mycoplasma pneumoniae in Japan.
AB - The in vitro activity of telithromycin (HMR3647), a new ketolide, against
Mycoplasma pneumoniae was determined by the broth microdilution test using 41
clinical isolates obtained in Japan, as compared with those of five macrolides
(erythromycin, clarithromycin, roxithromycin, azithromycin, and josamycin),
minocycline, and levofloxacin. Telithromycin was less potent than azithromycin,
but it was more active than four other macrolides, minocycline, and levofloxacin;
its MICs at which 50 and 90% of the isolates tested were inhibited were both
0.00097 microg/ml, justifying clinical studies to determine its efficacy for
treatment of M. pneumoniae.
PMID- 10770786
TI - Antibacterial agents and release of periplasmic pertussis toxin from Bordetella
pertussis.
AB - Pertussis toxin accumulates in the periplasm of Bordetella pertussis prior to
secretion, and we examined its fate following treatment with antimicrobial
agents. Both antibiotics that inhibit protein synthesis (erythromycin and
chloramphenicol), transcription (rifampin), or cell wall biosynthesis
(cefoperazone and piperacillin) and magnesium sulfate (which inhibits
transcription of pertussis toxin, but not bacterial growth) did not prevent
release of preformed toxin. In contrast, agents that affect bacterial membranes,
such as polymyxin B, lidocaine, procaine, and ethanol, inhibited release of
preformed pertussis toxin. These results suggest new protein synthesis is not
required for pertussis toxin secretion, but a functional membrane complex is
required.
PMID- 10770787
TI - Contributions of the AmpC beta-lactamase and the AcrAB multidrug efflux system in
intrinsic resistance of Escherichia coli K-12 to beta-lactams.
AB - The roles of the AmpC chromosomal beta-lactamase and the AcrAB efflux system in
levels of intrinsic resistance and susceptibility of Escherichia coli to beta
lactams were studied with a set of isogenic strains. MICs of ureidopenicillins,
carbenicillin, oxacillin, and cloxacillin were drastically reduced by the
inactivation of AcrAB, whereas those of the earlier cephalosporins were affected
mostly by the loss of AmpC beta-lactamase.
PMID- 10770788
TI - In vitro activities of telithromycin (HMR 3647) against Rickettsia rickettsii,
Rickettsia conorii, Rickettsia africae, Rickettsia typhi, Rickettsia prowazekii,
Coxiella burnetii, Bartonella henselae, Bartonella quintana, Bartonella
bacilliformis, and Ehrlichia chaffeensis.
AB - In vitro activities of telithromycin compared to those of erythromycin against
Rickettsia spp., Bartonella spp., Coxiella burnetii, and Ehrlichia chaffeensis
were determined. Telithromycin was more active than erythromycin against
Rickettsia, Bartonella, and Coxiella burnetii, with MICs of 0.5 microg/ml, 0.003
to 0.015 microg/ml, and 1 microg/ml, respectively, but was inactive against
Ehrlichia chaffeensis.
PMID- 10770789
TI - Vancomycin and oxacillin synergy for methicillin-resistant staphylococci.
AB - An increase in oxacillin activity was observed against methicillin-resistant
coagulase-negative staphylococci (MRCNS) and methicillin-resistant Staphylococcus
aureus (MRSA) in the presence of a sub-MIC of vancomycin. Vancomycin and
oxacillin were synergistic against 14 of 21 strains of MRCNS and MRSA. A pattern
of enhanced killing was also supported by time-kill studies. These results
suggest that combinations of sub-MICs of vancomycin and oxacillin may have
therapeutic benefits against methicillin-resistant staphylococci.
PMID- 10770790
TI - Comparison of human immunodeficiency virus type 1 Pr55(Gag) and Pr160(Gag-pol)
processing intermediates that accumulate in primary and transformed cells treated
with peptidic and nonpeptidic protease inhibitors.
AB - Human immunodeficiency virus type 1 (HIV-1) produces two polyproteins, Pr55(Gag)
and Pr160(Gag-Pol), that are cleaved into mature functional subunits by the
virally encoded protease. Drugs that inhibit this protease are an important part
of anti-HIV therapy. We studied the ordered accumulation of Gag and Gag-Pol
processing intermediates by variably blocking the protease with HIV-1 protease
inhibitors (PIs). Variable protease inhibition caused accumulation of a complex
pattern of processing intermediates, which was the same after incubating HIV-1
infected cells with increasing concentrations of either one of the peptidomimetic
inhibitors indinavir, saquinavir (SQV), ritonavir (RTV), nelfinavir, and SC-52151
or one of the nonpeptidomimetic inhibitors DMP450, DMP323, PNU-140135, and PNU
109112 for 3 days. The patterns of Gag and Gag-Pol processing intermediate
accumulation were nearly identical when the following were compared: cell- versus
virion-associated proteins, HIV-1-infected transformed cell lines versus primary
human peripheral blood mononuclear cells (PBMCs) and HIV-1(MN) versus HIV-1(IIIB)
virus strains. RTV was a more potent inhibitor of p24 production in PBMCs than
SQV by approximately 7-fold, whereas SQV was a more potent inhibitor in
transformed cells than RTV by approximately 30-fold. Although the antiretroviral
potency of HIV-1 PIs may change as a function of cell type, the polyprotein
intermediates that accumulate with increasing drug concentrations are the same.
These results support sequential processing of Gag and Gag-Pol polyproteins by
the HIV-1 protease and may have important implications for understanding common
cross-resistance pathways.
PMID- 10770791
TI - Evidence for the existence of a multidrug efflux transporter distinct from NorA
in Staphylococcus aureus.
AB - A Staphylococcus aureus norA disruption mutant was created by allelic
replacement. Exposure of this mutant to norfloxacin produced SA K1748, a
derivative with raised fluoroquinolone MICs, found to be the result of a grlA
mutation, and raised organic cation MICs. Ethidium and enoxacin uptake was
identical in SA K1748 and its parent, but pre-exposure of SA K1748 to organic
cations caused a reduction in ethidium uptake as a result of increased efflux.
Altered ethidium uptake and efflux, as well as increased MICs of other organic
cations, suggest that SA K1748 possesses a non-NorA multidrug efflux transporter
that is inducible by its substrates.
PMID- 10770792
TI - In vitro comparison of terbinafine and itraconazole against Penicillium
marneffei.
AB - We evaluated terbinafine and itraconazole against 30 isolates of Penicillium
marneffei using a modification of the National Committee for Clinical Laboratory
Standards broth macrodilution MIC testing protocol for yeasts. The minimal
fungicidal concentration (MFC) was determined by plating 100 microl from each MIC
drug dilution having no growth onto Sabouraud glucose agar incubated at 30
degrees C. The MFC was the dilution at which growth was absent at 72 h of
incubation. The MICs, in micrograms per milliliter, were as follows: terbinafine,
0.03 to 1.0 (geometric mean titer, 0.09); itraconazole, 0.03 to 0.5 (geometric
mean titer, 0.04). The MFCs, in micrograms per milliliter, were as follows:
terbinafine, 0.03 to 8 (geometric mean titer, 2.60); itraconazole, 0.03 to 8
(geometric mean titer, 2. 45). Primary fungicidal activity (MFC within 2
dilutions of MIC) was observed with terbinafine in eight isolates and with
itraconazole in four isolates. The data indicate that terbinafine is active
against P. marneffei in vitro and may have a previously unrealized role in the
management of infections caused by this fungus.
PMID- 10770793
TI - Turning on natural killer cells.
PMID- 10770794
TI - Intrahepatic T cells in hepatitis B: viral control versus liver cell injury.
PMID- 10770795
TI - The role of virus-specific CD8(+) cells in liver damage and viral control during
persistent hepatitis B virus infection.
AB - Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected
hepatocytes by HBV-specific CD8 cells has been assumed to be the central
mechanism causing both liver damage and virus control. To understand the role of
cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays
that require T cell expansion in vitro and human histocompatibility leukocyte
antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of
circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients
with persistent HBV infection were studied: one without liver inflammation and
HBV replication, the other with liver inflammation and a high level of HBV
replication. Contrary to expectation, a high frequency of intrahepatic HBV
specific CD8 cells was found in the absence of hepatic immunopathology. In
contrast, virus-specific T cells were more diluted among liver infiltrates in
viremic patients, but their absolute number was similar because of the massive
cellular infiltration. Furthermore, inhibition of HBV replication was associated
with the presence of a circulating reservoir of CD8(+) cells able to expand after
specific virus recognition that was not detectable in highly viremic patients
with liver inflammation. These results show that in the presence of an effective
HBV-specific CD8 response, inhibition of virus replication can be independent of
liver damage. When the HBV-specific CD8 response is unable to control virus
replication, it may contribute to liver pathology not only directly but by
causing the recruitment of nonvirus-specific T cells.
PMID- 10770796
TI - Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes:
modulation of interferon-regulated gene expression by rel/nuclear factor kappaB.
AB - In lymphocytes, the Rel transcription factor is essential in establishing a
pattern of gene expression that promotes cell proliferation, survival, and
differentiation. Here we show that mitogen-induced expression of interferon (IFN)
regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of
transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a
repressor of IFN-induced gene expression, the absence of IRF-4 expression in c
rel(-/-) B cells coincided with a greater sensitivity of these cells to the
antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4
transgene restored IFN modulated c-rel(-/-) B cell proliferation to that of wild
type cells. This cross-regulation between two different signaling pathways
represents a novel mechanism that Rel/nuclear factor kappaB can repress the
transcription of IFN-regulated genes in a cell type-specific manner.
PMID- 10770797
TI - Markedly different pathogenicity of four immunoglobulin G isotype-switch variants
of an antierythrocyte autoantibody is based on their capacity to interact in vivo
with the low-affinity Fcgamma receptor III.
AB - Using three different Fcgamma receptor (FcgammaR)-deficient mouse strains, we
examined the induction of autoimmune hemolytic anemia by each of the four
immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythrocyte
autoantibody and its relation to the contributions of the two FcgammaR,
FcgammaRI, and FcgammaRIII, operative in the phagocytosis of opsonized particles.
We found that the four IgG isotypes of this antibody displayed striking
differences in pathogenicity, which were related to their respective capacity to
interact in vivo with the two phagocytic FcgammaRs, defined as follows: IgG2a >
IgG2b > IgG3/IgG1 for FcgammaRI, and IgG2a > IgG1 > IgG2b > IgG3 for FcgammaRIII.
Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity,
approximately 20-100-fold more potent than its IgG1 and IgG2b variants,
respectively, while the IgG3 variant, which displays little interaction with
these FcgammaRs, was not pathogenic at all. An unexpected critical role of the
low-affinity FcgammaRIII was revealed by the use of two different IgG2a anti-red
blood cell autoantibodies, which displayed a striking preferential utilization of
FcgammaRIII, compared with the high-affinity FcgammaRI. This demonstration of the
respective roles in vivo of four different IgG isotypes, and of two phagocytic
FcgammaRs, in autoimmune hemolytic anemia highlights the major importance of the
regulation of IgG isotype responses in autoantibody-mediated pathology and
humoral immunity.
PMID- 10770798
TI - Developmental switches in chemokine response profiles during B cell
differentiation and maturation.
AB - Developing B cells undergo dramatic changes in their responses to chemoattractant
cytokines (chemokines) and in expression of chemokine receptors. Bone marrow pre
pro-B cells (AA4.1(+)/natural killer 1.1(-) Fraction A cells) and cells capable
of generating pro-B colonies in the presence of interleukin 7 and flt3 ligand
migrate to thymus-expressed chemokine (TECK), a response lost in later stages of
B cell development. B cell-attracting chemokine 1 (BCA-1) responses correlate
with CXC chemokine receptor (CXCR)5 expression, are first displayed by a pro-B
cell subset, are lost in pre-B cells, and then are regained just before and after
egress from the marrow. All peripheral B cell subsets, including follicular and
germinal center as well as marginal zone and peritoneal B1 B cells, respond to
BCA-1, implying that responsiveness to this follicular chemokine is not
sufficient to predict follicle localization. Responses to the CC chemokine
receptor (CCR)7 ligands secondary lymphoid tissue chemoattractant (SLC) and
macrophage inflammatory protein (MIP)-3beta, implicated in homing to lymphoid
tissues, are upregulated before B cell exit from the marrow, but increase further
in the periphery and are shared by all peripheral B cells. In contrast,
responsiveness to MIP-3alpha and expression of CCR6 are acquired only after
emigration to the periphery and during maturation into the recirculating B cell
pool. Chemotaxis to stromal cell-derived factor 1alpha is observed at all stages
of B cell differentiation. Thus, unique patterns of chemokine responses may help
define developing B cell populations and direct their maturation in the marrow
and migration to the periphery.
PMID- 10770800
TI - Immunoglobulin beta signaling regulates locus accessibility for ordered
immunoglobulin gene rearrangements.
AB - The antigen receptor gene rearrangement at a given locus is tightly regulated
with respect to cell lineage and developmental stage by an ill-defined mechanism.
To study the possible role of precursor B cell antigen receptor (pre-BCR)
signaling in the regulation of the ordered immunoglobulin (Ig) gene rearrangement
during B cell differentiation, a newly developed system using mu heavy (H) chain
membrane exon (microm)-deficient mice was employed. In this system, the antibody
mediated cross-linking of Igbeta on developmentally arrested progenitor B (pro-B)
cells mimicked pre-BCR signaling to induce early B cell differentiation in vivo.
Analyses with ligation-mediated polymerase chain reaction revealed that the
Igbeta cross-linking induced the redirection of Ig gene rearrangements, namely,
the suppression of ongoing rearrangements at the H chain locus and the activation
of rearrangements at the light (L) chain locus. Upon the cross-linking, the
kappaL chain germline transcription was found to be upregulated whereas the V(H)
germline transcription was promptly downregulated. Notably, this alteration of
the accessibility at the H and L chain loci was detected even before the
induction of cellular differentiation became detectable by the change of surface
phenotype. Thus, the pre-BCR signaling through Igbeta appears to regulate the
ordered Ig gene rearrangement by altering the Ig locus accessibility.
PMID- 10770799
TI - A novel B lymphocyte-associated adaptor protein, Bam32, regulates antigen
receptor signaling downstream of phosphatidylinositol 3-kinase.
AB - We have identified and characterized a novel src homology 2 (SH2) and pleckstrin
homology (PH) domain-containing adaptor protein, designated Bam32 (for B cell
adaptor molecule of 32 kD). cDNAs encoding the human and mouse Bam32 coding
sequences were isolated and the human bam32 gene was mapped to chromosome 4q25
q27. Bam32 is expressed by B lymphocytes, but not T lymphocytes or
nonhematopoietic cells. Human germinal center B cells show increased Bam32
expression, and resting B cells rapidly upregulate expression of Bam32 after
ligation of CD40, but not immunoglobulin M. Bam32 is tyrosine-phosphorylated upon
B cell antigen receptor (BCR) ligation or pervanadate stimulation and associates
with phospholipase Cgamma2. After BCR ligation, Bam32 is recruited to the plasma
membrane through its PH domain. Membrane recruitment requires
phosphatidylinositol 3-kinase (PI3K) activity and an intact PI(3,4, 5)P(3)
binding motif, suggesting that membrane association occurs through binding to 3
phosphoinositides. Expression of Bam32 in B cells leads to a dose-dependent
inhibition of BCR-induced activation of nuclear factor of activated T cells (NF
AT), which is blocked by deletion of the PH domain or mutation of the
PI(3,4,5)P(3)-binding motif. Thus, Bam32 represents a novel B cell-associated
adaptor that regulates BCR signaling downstream of PI3K.
PMID- 10770801
TI - Nonstochastic coexpression of activation receptors on murine natural killer
cells.
AB - Murine natural killer cells (NK) express lectin-like activation and inhibitory
receptors, including the CD94/NKG2 family of receptors that bind Qa-1, and the Ly
49 family that recognizes major histocompatibility complex class I molecules.
Here, we demonstrate that cross-linking of NK cells with a new specific anti-Ly
49H mAb induced NK cell cytotoxicity and cytokine production. Ly-49H is expressed
on a subset of NK cells and can be coexpressed with Ly-49 inhibitory receptors.
However, unlike Ly-49 inhibitory receptors, Ly-49H is not detectable on naive
splenic CD3(+) T cells, indicating that Ly-49H may be an NK cell-specific
activation receptor. In further contrast to the stochastically expressed Ly-49
inhibitory receptors, Ly-49H is preferentially expressed with the Ly-49D
activation receptor, and expression of both Ly-49H and Ly-49D is augmented on NK
cells that lack receptors for Qa-1 tetramers. On developing splenic NK1.1(+)
cells, Ly-49D and Ly-49H are expressed later than the inhibitory receptors. These
results directly demonstrate that Ly-49H activates primary NK cells, and suggest
that expression of Ly-49 activation receptors by NK cells may be specifically
regulated on NK cell subsets. The simultaneous expression of multiple activation
receptors by individual NK cells contrasts with that of T cell antigen receptors
and is relevant to the role of NK cells in innate immunity.
PMID- 10770802
TI - Role of 2CT cell receptor residues in the binding of self- and allo-major
histocompatibility complexes.
AB - T cell clone 2C recognizes the alloantigen L(d) and the positive selecting major
histocompatibility complex (MHC), K(b). To explore the molecular basis of T cell
antigen receptor (TCR) binding to different peptide/MHC (pMHC) complexes, we
performed alanine scanning mutagenesis of the 2C TCR. The TCR energy maps for
QL9/L(d) and SIYR/K(b) were remarkably similar, in that 16 of 41 Valpha and Vbeta
alanine mutants showed reduced binding to both ligands. Several TCR residues
varied in the magnitude of energy contributed to binding the two ligands,
indicating that there are also unique interactions. Residues in complementarity
determining region 3alpha showed the most notable differences in binding
energetics among the ligands QL9/L(d), SIYR/K(b), and the clonotypic antibody
1B2. Various lines of evidence suggest that these differences relate to the
mobility of this loop and point to the key role of conformational dynamics in
pMHC recognition.
PMID- 10770803
TI - Evidence for class-specific factors in immunoglobulin isotype switching.
AB - Immunoglobulin class switch recombination (SR) occurs by a B cell-specific,
intrachromosomal deletional process between switch regions. We have developed a
plasmid-based transient transfection assay for SR to test for the presence of
transacting switch activities. The plasmids are novel in that they lack a
eukaryotic origin of DNA replication. The recombination activity of these switch
substrates is restricted to a subset of B cell lines that support isotype
switching on their endogenous loci and to mitogen-activated normal splenic B
cells. The factors required for extrachromosomal plasmid recombination are
constitutively expressed in proliferating splenic B cells and in B cell lines
capable of inducibly undergoing immunoglobulin SR on their chromosomal genes.
These studies suggest that mitogens that induce switching on the chromosome
induce accessibility rather than switch recombinase activity. Finally, we provide
evidence for two distinct switching activities which independently mediate mu-
>alpha and mu-->gamma3 SR.
PMID- 10770804
TI - Localization of distinct Peyer's patch dendritic cell subsets and their
recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP
3beta, and secondary lymphoid organ chemokine.
AB - We describe the anatomical localization of three distinct dendritic cell (DC)
subsets in the murine Peyer's patch (PP) and explore the role of chemokines in
their recruitment. By two-color in situ immunofluorescence, CD11b(+) myeloid DCs
were determined to be present in the subepithelial dome (SED) region, whereas
CD8alpha(+) lymphoid DCs are present in the T cell-rich interfollicular region
(IFR). DCs that lack expression of CD8alpha or CD11b (double negative) are
present in both the SED and IFR. By in situ hybridization, macrophage
inflammatory protein (MIP)-3alpha mRNA was dramatically expressed only by the
follicle-associated epithelium overlying the SED, while its receptor, CCR6, was
concentrated in the SED. In contrast, CCR7 was expressed predominantly in the
IFR. Consistent with these findings, reverse transcriptase polymerase chain
reaction analysis and in vitro chemotaxis assays using freshly isolated DCs
revealed that CCR6 was functionally expressed only by DC subsets present in the
SED, while all subsets expressed functional CCR7. Moreover, none of the splenic
DC subsets migrated toward MIP-3alpha. These data support a distinct role for MIP
3alpha/CCR6 in recruitment of CD11b(+) DCs toward the mucosal surfaces and for
MIP-3beta/CCR7 in attraction of CD8alpha(+) DCs to the T cell regions. Finally,
we demonstrated that all DC subsets expressed an immature phenotype when freshly
isolated and maintained expression of subset markers upon maturation in vitro. In
contrast, CCR7 expression by myeloid PP DCs was enhanced with maturation in
vitro. In addition, this subset disappeared from the SED and appeared in the IFR
after microbial stimulation in vivo, suggesting that immature myeloid SED DCs
capture antigens and migrate to IFR to initiate T cell responses after mucosal
microbial infections.
PMID- 10770805
TI - Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis
lesions using a monoclonal antibody specific for the human histocompatibility
leukocyte antigen (HLA)-DR2-MBP 85-99 complex.
AB - Susceptibility to multiple sclerosis (MS) is associated with the human
histocompatibility leukocyte antigen (HLA)-DR2 haplotype, suggesting that major
histocompatibility complex class II-restricted presentation of central nervous
system-derived antigens is important in the disease process. Antibodies specific
for defined HLA-DR2-peptide complexes may therefore be valuable tools for
studying antigen presentation in MS. We have used phage display technology to
select HLA-DR2-peptide-specific antibodies from HLA-DR2-transgenic mice immunized
with HLA-DR2 molecules complexed with an immunodominant myelin basic protein
(MBP) peptide (residues 85-99). Detailed characterization of one clone (MK16)
demonstrated that both DR2 and the MBP peptide were required for recognition.
Furthermore, MK16 labeled intra- and extracellular HLA-DR2-MBP peptide complexes
when antigen-presenting cells (APCs) were pulsed with recombinant MBP. In
addition, MK16 inhibited interleukin 2 secretion by two transfectants that
expressed human MBP-specific T cell receptors. Analysis of the structural
requirement for MK16 binding demonstrated that the two major HLA-DR2 anchor
residues of MBP 85-99 and the COOH-terminal part of the peptide, in particular
residues Val-96, Pro-98, and Arg-99, were important for binding. Based on these
results, the antibody was used to determine if the HLA-DR2-MBP peptide complex is
presented in MS lesions. The antibody stained APCs in MS lesions, in particular
microglia/macrophages but also in some cases hypertrophic astrocytes. Staining of
APCs was only observed in MS cases with the HLA-DR2 haplotype but not in cases
that carried other haplotypes. These results demonstrate that HLA-DR2 molecules
in MS lesions present a myelin-derived self-peptide and suggest that
microglia/macrophages rather than astrocytes are the predominant APCs in these
lesions.
PMID- 10770806
TI - P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can
mediate platelet-endothelial interactions in vivo.
AB - The platelet plays a pivotal role in maintaining vascular integrity. In a manner
similar to leukocytes, platelets interact with selectins expressed on activated
endothelium. P-selectin glycoprotein ligand 1 (PSGL-1) is the main P-selectin
ligand expressed on leukocytes. Searching for platelet ligand(s), we used a P
selectin-immunoglobulin G (IgG) chimera to affinity purify surface-biotinylated
proteins from platelet lysates. P-selectin-bound ligands were eluted with
ethylenediaminetetraacetic acid. An approximately 210-kD biotinylated protein was
isolated from both human neutrophil and platelet preparations. A band of the same
size was also immunopurified from human platelets using a monoclonal anti-human
PSGL-1 antibody and could be blotted with P-selectin-IgG. Under reducing
conditions, both the predicted PSGL-1 approximately 210-kD dimer and the
approximately 120-kD monomer were isolated from platelets. Comparative
immunoelectron microscopy and Western blotting experiments suggested that
platelet PSGL-1 expression is 25-100-fold lower than that of leukocytes. However,
patients with chronic idiopathic thrombocytopenic purpura who harbor
predominantly young platelets displayed greater expression, indicating that PSGL
1 expression may be decreased during platelet aging. By flow cytometry, thrombin
activated platelets from normal individuals exhibited greater expression than
those unstimulated. An inhibitory anti-PSGL-1 antibody significantly reduced
platelet rolling in mesenteric venules, as observed by intravital microscopy. Our
results indicate that functional PSGL-1 is expressed on platelets, and suggest an
additional mechanism by which selectins and their ligands participate in
inflammatory and/or hemostatic responses.
PMID- 10770807
TI - Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95
expression.
AB - Depending on the duration and severity, psychological tension and physical stress
can enhance or suppress the immune system in both humans and animals. Although it
is well established that stress alters the release of various hormones and
neurotransmitters, the mechanisms by which stress affects immune responses remain
elusive. We report here that mice subjected to chronic 12-hour daily physical
restraint for two days exhibited a significant reduction in splenocytes, a
process likely mediated by apoptosis as demonstrated by the terminal
deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling
assay. CD95 (Fas/APO-1) expression in splenic lymphocytes of stressed mice was
substantially increased. Interestingly, Fas-immunoglobulin fusion protein and
blocking antibodies against CD95 ligand inhibit stress-induced reduction in
lymphocytes. The stress-induced changes in CD95 expression and lymphocyte number
could be blocked by naltrexone or naloxone, specific opioid receptor antagonists,
indicating a pivotal role of endogenous opioids in this process. In addition, the
reduction of splenocytes in this model system seems to be independent of the
hypothalamo-pituitary-adrenal axis, as both adrenalectomized and sham-operated
mice exhibited similar responses to chronic stress. Moreover, chronic physical
restraint failed to induce a decrease in lymphocyte numbers in CD95-deficient
(Fas(lpr/lpr)) mice. Therefore, stress modulates the immune system through CD95
mediated apoptosis dependent on endogenous opioids.
PMID- 10770808
TI - Inflammatory responses induced by the filarial nematode Brugia malayi are
mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia
bacteria.
AB - The pathogenesis of filarial disease is characterized by acute and chronic
inflammation. Inflammatory responses are thought to be generated by either the
parasite, the immune response, or opportunistic infection. We show that soluble
extracts of the human filarial parasite Brugia malayi can induce potent
inflammatory responses, including tumor necrosis factor (TNF)-alpha, interleukin
(IL)-1beta, and nitric oxide (NO) from macrophages. The active component is heat
stable, reacts positively in the Limulus amebocyte lysate assay, and can be
inhibited by polymyxin B. TNF-alpha, IL-1beta, and NO responses were not induced
in macrophages from lipopolysaccharide (LPS)-nonresponsive C3H/HeJ mice. The
production of TNF-alpha after chemotherapy of microfilariae was also only
detected in LPS-responsive C3H/HeN mice, suggesting that signaling through the
Toll-like receptor 4 (TLR4) is necessary for these responses. We also show that
CD14 is required for optimal TNF-alpha responses at low concentrations. Together,
these results suggest that extracts of B. malayi contain bacterial LPS. Extracts
from the rodent filaria, Acanthocheilonema viteae, which is not infected with the
endosymbiotic Wolbachia bacteria found in the majority of filarial parasites,
failed to induce any inflammatory responses from macrophages, suggesting that the
source of bacterial LPS in extracts of B. malayi is the Wolbachia endosymbiont.
Wolbachia extracts derived from a mosquito cell line induced similar LPS
dependent TNF-alpha and NO responses from C3H/HeN macrophages, which were
eliminated after tetracycline treatment of the bacteria. Thus, Wolbachia LPS may
be one of the major mediators of inflammatory pathogenesis in filarial nematode
disease.
PMID- 10770809
TI - Infectious agents are not necessary for murine atherogenesis.
AB - Recent work has revealed correlations between bacterial or viral infections and
atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been
observed at high frequency in human atherosclerotic lesions, prompting the
hypothesis that infectious agents may be necessary for the initiation or
progression of atherosclerosis. To determine if responses to gram-negative
bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone
apolipoprotein (apo) E(-/)- (deficient) mice with animals incapable of responding
to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient
animals. We further tested the role of infectious agents by creating a colony of
germ-free apo E(-/)- mice. These animals are free of all microbial agents
(bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not
measurably different from that in animals raised with ambient levels of microbial
challenge. These studies show that infection is not necessary for murine
atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be
fulfilled for any infectious agent in atherosclerosis.
PMID- 10770811
TI - Maintenance treatment of chronic pseudomonas aeruginosa infection in cystic
fibrosis.
PMID- 10770810
TI - Entry of B cell receptor into signaling domains is inhibited in tolerant B cells.
AB - Signal transduction through the B cell antigen receptor (BCR) is altered in B
cells that express a receptor that recognizes self-antigen. To understand the
molecular basis for the change in signaling in autoreactive B cells, a transgenic
model was used to isolate a homogeneous population of tolerant B lymphocytes.
These cells were compared with a similar population of naive B lymphocytes. We
show that the BCR from naive B cells enters a detergent-insoluble domain of the
cell within 6 s after antigen binding, before a detectable increase in BCR
phosphorylation. This fraction appears to be important for signaling because it
is enriched for lyn kinase but lacks CD45 tyrosine phosphatase and because the
BCR that moves into this domain becomes more highly phosphorylated. Partitioning
of the BCR into this fraction is unaffected by src family kinase inhibition.
Tolerant B cells do not efficiently partition the BCR into the detergent
insoluble domain, providing an explanation for their reduced tyrosine kinase
activation and calcium flux in response to antigen. These results identify an
early, regulated step in antigen receptor signaling and self-tolerance.
PMID- 10770812
TI - Diagnosis of lung cancer: FOB before CT or CT before FOB?
PMID- 10770813
TI - Role of bronchial responsiveness testing in asthma prevalence surveys.
PMID- 10770814
TI - Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with
chronic Pseudomonas infection of the lungs.
AB - BACKGROUND: A previous retrospective study suggested that a policy of regular
anti-pseudomonal antibiotic treatment improved pulmonary function and increased
survival in patients with cystic fibrosis chronically infected with Pseudomonas
species. The results of a prospective multicentre study to compare the effects on
pulmonary function and mortality of three monthly elective anti-pseudomonal
antibiotic treatment with conventional symptomatic treatment are reported.
METHODS: Sixty patients with cystic fibrosis, chronically infected with P
aeruginosa, were randomised to the two treatment arms (elective or symptomatic)
and followed clinically at yearly reviews. The major end points were changes in
forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC).
Survival was a secondary end point. RESULTS: Patients in the symptomatic group
received a mean of three antibiotic treatments each year and those in the
elective group received four antibiotic treatments during each year of the study.
No significant differences in FEV(1) and FVC were found between the two groups
after three years. There was a statistically non-significant higher rate of
deaths in the elective group (n = 4), three of which were associated with B
cepacia infection, compared with the symptomatic group (n = 0). CONCLUSIONS: This
study did not demonstrate an advantage of a policy of elective antibiotic
treatment over symptomatic treatment in patients with cystic fibrosis chronically
infected with Pseudomonas species.
PMID- 10770815
TI - Role of computed tomographic scanning of the thorax prior to bronchoscopy in the
investigation of suspected lung cancer.
AB - BACKGROUND: Fibreoptic bronchoscopy (FOB) is the usual initial investigation of
choice in patients with suspected endobronchial carcinoma, but it is often non
diagnostic. Once a positive diagnosis has been made, many patients undergo
staging by computed tomographic (CT) scanning to assess the extent of the disease
and its suitability for radical treatment. To determine whether initial CT
scanning before FOB is a cost effective way of reducing subsequent unnecessary or
unhelpful invasive diagnostic procedures, a study was undertaken in 171 patients
with suspected endobronchial carcinoma. METHODS: A randomised two group study was
performed with all patients undergoing an initial CT staging scan. In group A the
CT scans were reviewed before FOB, allowing cancellation or a change to an
alternative invasive procedure if considered appropriate. In group B all patients
proceeded to FOB with the bronchoscopist blinded to the result of the CT scan
until after the procedure. RESULTS: In group A six of 90 patients (7%) required
no further investigations as the CT scan was either normal, consistent with
benign disease, or consistent with widespread metastatic disease. Of the
remainder, bronchoscopy was diagnostic in 50 of 68 (73%) in group A compared with
44 of 81 (54%) in group B (p = 0.015). Overall, a positive diagnosis was made
after a single invasive investigation in 64 of 84 patients (76%) in group A
compared with only 45 of 81 patients (55%) in group B (p = 0.005). Only seven of
90 patients (8%) in group A required more than one invasive investigation
compared with 15 of 81 patients (18.5%) in group B. In patients with malignancy,
bronchoscopy was more likely to be diagnostic in group A (50 of 56 patients
(89%)) than in group B (44 of 62 (71%); p = 0. 012), and the diagnosis was more
frequently made on the initial invasive investigation (group A, 63 of 70 (90%);
group B, 44 of 62 (71%); p = 0.004). Because of the lower number of invasive
procedures performed in group A than in group B, the cost of performing CT scans
before FOB in all patients in group A would have equated to a projected cost of
performing CT scans in 60% of patients after FOB in group B. CONCLUSIONS:
Performing initial CT thoracic scans before bronchoscopy in patients with
suspected endobronchial malignancy is a cost effective way of improving
diagnostic yield from invasive diagnostic procedures and occasionally may obviate
the need for any further investigation.
PMID- 10770816
TI - Generation of complement C3 and expression of cell membrane complement inhibitory
proteins by human bronchial epithelium cell line.
AB - BACKGROUND: The interrelationship between human airway epithelium and complement
proteins may affect airway defence, airway function, and airway epithelial
integrity. A study was undertaken to determine (1) whether unstimulated human
bronchial epithelium generates complement proteins and expresses cell membrane
complement inhibitory proteins (CIP) and (2) whether stimulation by
proinflammatory cytokines affects the generation of complement and expression of
cell membrane CIP by these cells. METHODS: Human bronchial epithelium cell line
BEAS-2B was cultured in a serum-free medium. Cells were incubated with and
without proinflammatory cytokines to assess unstimulated and stimulated
generation of complement C3, C1q and C5 (by ELISA), and to examine the expression
of cell membrane CIP decay accelerating factor (DAF; CD55), membrane cofactor
protein (MCP; CD46), and CD59 (protectin) by flow cytometry analysis. RESULTS:
Unstimulated human bronchial epithelial cell line BEAS-2B in serum-free medium
generates complement C3 (mean 32 ng/10(6) cells/72 h, range 18-52) but not C1q
and C5, and expresses cell membrane DAF, MCP, and CD59. Interleukin (IL)-1alpha
(100 U/ml/72 h) and tumour necrosis factor (TNF-alpha; 1000 U/ml/72 h) increased
generation of C3 up to a mean of 78% and 138%, respectively, above C3 generation
by unstimulated cells. DAF was the only cell membrane CIP affected by cytokine
stimulation. Interferon (IFN)-gamma (10 U/ml/72 h) and TNF-alpha (1000 U/ml/72 h)
increased DAF expression up to a mean of 116% and 45%, respectively, above that
in unstimulated cells. MCP and CD59 expression was not consistently affected by
IL-1alpha, TNF-alpha, or IFN-gamma. CONCLUSIONS: Local generation of complement
C3 and expression of cell membrane CIP by human bronchial epithelium and its
modulation by proinflammatory cytokines might be an additional regulatory
mechanism of local airway defence and may affect airway function and epithelial
integrity in health and disease.
PMID- 10770817
TI - Bcl-2 expression in sputum eosinophils in patients with acute asthma.
AB - BACKGROUND: Eosinophils play a pivotal role in asthmatic airway inflammation.
Apoptosis is thought to be critically relevant in promoting the clearance of
inflammatory cells and the resolution of inflammation. Bcl-2 inhibits apoptosis
in cellular systems. A study was undertaken to determine whether bcl-2 expression
in sputum reflects the clinical severity of patients with asthma. The
relationship between bcl-2 expression in sputum eosinophils and eosinophil
activation markers such as interleukin (IL)-5 and eosinophil cationic protein
(ECP) levels in sputum supernatant was evaluated. METHODS: Sputum was obtained
from 18 patients with asthma. Fresh expectorated sputum separated from saliva was
treated with an equal volume of dithiothreitol 0.1%, cytospun for cell
differentials and bcl-2 stain, and the supernatant was collected for biochemical
assay. Bcl-2+ eosinophils were stained using immunocytochemistry, ECP was
measured by fluoroimmunoassay, and IL-5 was detected by sandwich enzyme linked
immunosorbant assay. RESULTS: Twelve patients with severe or life threatening
asthma had more bcl-2+ eosinophils (mean difference 46.8% (95% CI 27.0 to 66.6),
p<0.01) and a higher ECP level (p<0.01) in the sputum than those with mild to
moderate asthma (n = 6). IL-5 was frequently detected in patients with severe or
life threatening asthma (11/12 versus 1/6, p<0.01). There was a significant
positive correlation between bcl-2+ eosinophils and ECP levels (r = 0.61, p<0.01)
and between bcl-2+ eosinophils and IL-5 levels (r = 0.83, p<0.01). There was a
significant negative correlation between bcl-2+ eosinophils and FEV(1)/FVC (r =
0.54, p<0.05). CONCLUSION: The increased expression of bcl-2 in eosinophils from
sputum of subjects with severe asthma suggests that bcl-2 may prolong survival
and decrease apoptosis of airway eosinophils in asthma.
PMID- 10770818
TI - Effect of one year treatment with inhaled fluticasone propionate or
beclomethasone dipropionate on bone density and bone metabolism: a randomised
parallel group study in adult asthmatic subjects.
AB - BACKGROUND: There is some concern that prolonged treatment with high doses of
inhaled corticosteroids may have a detrimental effect on bone mass. The aim of
this one year study was to investigate the effects of low and high doses of
fluticasone propionate (FP) (400 microg/day and 750 microg/day) and
beclomethasone dipropionate (BDP) (800 microg/day and 1500 microg/day) on bone
mass and metabolism. METHODS: This was a multicentre, double blind, parallel
group study involving 69 mild to moderate asthmatic subjects who were randomised
to treatment as follows: 22 to FP400, 21 to BDP800, 13 to FP750, and 13 to
BDP1500. Their mean age was 39 years, 67% were men, and all the women were
premenopausal. RESULTS: The results of peripheral quantitative computed
tomographic (pQCT) measurements (primary variable) showed that, compared with
baseline values, there was no loss of trabecular or integral (cortical and
trabecular) bone in the distal radius or tibia in any of the patients over the 12
month study period. No consistent pattern emerged from the analysis of changes
from baseline in markers of bone formation and resorption after six and 12 months
of treatment. CONCLUSION: The results of this study provide reassuring
prospective one year data showing that inhaled corticosteroids, in the range of
doses used, had no adverse effects on bone mass and metabolism in this group of
asthmatic patients.
PMID- 10770819
TI - Childhood exposure to infection and risk of adult onset wheeze and atopy.
AB - BACKGROUND: The prevalence of asthma and allergic diseases in children and young
adults is inversely associated with family size. It has been suggested that more
frequent exposure to infections in a large family group, particularly those
spread by the faecal-oral route, may protect against atopic diseases, although
not all published data support this hypothesis. Whether similar considerations
apply to adult onset wheeze is unknown. The relationship between adult onset
wheezing and atopy measured in adulthood and childhood exposure to a range of
infections was investigated. METHODS: A nested case control study of participants
in a 30 year follow up survey was conducted. Questionnaire data on childhood
infections had been obtained in a 1964 survey. In 1995 a further questionnaire on
respiratory symptoms and other risk factors for wheezing illness was
administered, total IgE, skin and RAST tests were performed, and serum was
stored. In 1999 serological tests for hepatitis A, Helicobacter pylori, and
Toxoplasma gondii were performed on the stored samples. Information from the 1964
questionnaires was available for 97 cases and 208 controls and serological tests
were obtained for 85 cases and 190 controls. The potential risk factors were
examined for all cases, those who reported doctor diagnosed asthma, those who
described persistent cough and phlegm with wheeze, and subjects stratified by
atopic status. RESULTS: The sibship structure was similar in cases and controls.
In univariate analysis of all cases, childhood infections reported by parents as
acquired either before or after the age of three years did not influence
case:control or atopic status. Seropositivity was also similar for all cases and
controls, but cases in the subgroup with chronic cough and phlegm were more
likely to be seropositive for hepatitis A and H pylori. Seropositivity was
unrelated to atopic status. In multivariate analyses both the effect of having
two or more younger siblings (OR 0.1, 95% CI 0.03 to 0.8) and of acquiring
measles up to the age of three (OR 0.2, CI 0.03 to 0.8) were significantly
related to a lower risk of doctor diagnosed asthma. CONCLUSIONS: In these well
characterised subjects, exposure to infections as measured by parental reports
obtained at age 10-14 years and by serological tests obtained in adulthood did
not influence the development of wheezing symptoms or atopic status in adulthood.
However, early exposure to measles and family size may be associated with a lower
risk of adult onset doctor diagnosed asthma.
PMID- 10770820
TI - Clinical investigation of pulmonary Mycobacterium avium complex infection in
human T lymphotrophic virus type I carriers.
AB - BACKGROUND: Little is known about pulmonary Mycobacterium avium complex (MAC)
infection in human T lymphotrophic virus type I (HTLV-I) carriers. A study was
undertaken to investigate and clarify the characteristics of pulmonary MAC
infection in these subjects. METHODS: Twenty nine patients with pulmonary MAC
infection without any underlying pulmonary disorder were investigated. The
clinical features and radiographic appearance of HTLV-I carriers and non-carriers
were compared and the bronchoalveolar lavage (BAL) fluid of these 29 patients and
eight normal female control subjects was analysed. RESULTS: The prevalence of the
HTLV-I carrier state in patients with pulmonary MAC infection was 34.5% (10/29)
compared with 16.7% (529/3169) among all patients admitted to our department
between 1994 and 1998 (odds ratio (OR) 2.63, 95% confidence interval (CI) 1.21 to
5.68). The HTLV-I carriers were all women and all had clinical symptoms, but they
did not show systemic dissemination. Peripheral multifocal bronchiectasis with
nodular shadowing was seen frequently on the chest computed tomographic (CT)
scans of HTLV-I carriers. The area of the pulmonary lesions was more extensive
than in non-carriers (p<0.05). White blood cell (WBC) counts and C reactive
protein (CRP) levels on admission were significantly lower in HTLV-I carriers
than in non-carriers (WBC: difference (D) = 1565/microl, 95% CI -68.9 to
3198.4/microl; CRP: D = 1.8 mg/dl, 95% CI -0.35 to 3.89 mg/dl). The
concentrations of neutrophil elastase (NE) and interleukin (IL)-8 in BAL fluid
were significantly higher in HTLV-I carriers than in non-carriers (NE: D = 1342
microg/l, 95% CI 704 to 1980.3 microg/l; IL-8: D = 304.5 pg/ml, 95% CI 89.7 to
519. 4 pg/ml). CONCLUSIONS: Pulmonary MAC infection causes more diffuse and
widespread lesions in HTLV-I carriers than in non-carriers.
PMID- 10770821
TI - Which aspects of breathing during sleep influence the overnight fall of blood
pressure in a community population?
AB - BACKGROUND: Obstructive sleep apnoea (OSA) causes recurrent rises in blood
pressure during sleep, and recent community surveys have suggested a link between
mild OSA and diurnal hypertension. The fact that OSA and hypertension share some
risk factors, as well as problems accurately quantifying OSA severity, have
diluted the power of such studies. This study tries to circumvent some of these
problems by measuring the overnight change in blood pressure and relating it to
relevant measures of the severity of upper airway obstruction on the same night.
METHODS: Men born between 1930 and 1960 and their wives living in a market town
north of Oxford were identified from a GP practice register. Enough couples were
recruited to provide approximately 10 (20 individuals) per year of birth.
Subjects were visited at home where a questionnaire was administered,
anthropometric measurements made, blood pressures taken (including by the
subject), and sensors applied for a subsequent overnight sleep study. The sleep
study measured indices of hypoxia, snoring, autonomic arousal, degree of
respiratory effort; the last two of these derived from measurements of pulse
transit time (indirect beat to beat blood pressure). After waking the following
morning, the subjects took their own blood pressures again. RESULTS: Data were
available from 224 couples (448 subjects). On average, systolic BP fell 8 mm Hg
from evening to morning. Only hypoxic dips (>4% SaO(2) dips/h) and the measure of
degree of respiratory effort were significant independent predictors of this
overnight change in systolic BP, together accounting for 7-10% of the variation
(p<0.0001). Dividing the subjects into quartiles according to the respiratory
effort overnight showed a progressive reduction in the fall of systolic BP
overnight: 13.6, 10.8, 7.3, and 5.6 mm Hg, lowest to highest quartiles.
CONCLUSIONS: This study suggests that increased respiratory effort during sleep
(seen in OSA and related syndromes of increased upper airway resistance during
sleep) offsets the normal fall in BP that occurs overnight, even within this
community population. This may be one of the mechanisms by which hypertension is
carried over into the waking hours in patients with OSA.
PMID- 10770822
TI - Unpredictable results of laser assisted uvulopalatoplasty in the treatment of
obstructive sleep apnoea.
AB - BACKGROUND: Laser assisted uvulopalatoplasty (LAUP) is increasingly offered for
the treatment of obstructive sleep apnoea (OSA), although there is a lack of
objective data to support its indications and efficacy. A study was undertaken to
determine the treatment response to LAUP. METHODS: Overnight polysomnography was
performed before and at least three months after surgery in 44 consecutive
patients with symptomatic mild to moderate OSA (apnoea + hypopnoea index (AHI)
>10/h). Pharyngeal dimensions were measured by videoendoscopy (n = 11) and
disease-specific quality of life, sleepiness and snoring frequency (n = 16)
before and after surgery were determined in subgroups of patients. LAUP was
performed under local anaesthesia as a one stage resection of the uvula and soft
palate by one of two experienced otolaryngologists. RESULTS: Twelve patients
(27%) had a good response (AHI 50%
of pre-LAUP value); and 13 (30%) patients were worse (AHI >100% of pre-LAUP
value). The velopharyngeal cross sectional area and anteroposterior diameter
increased following LAUP (p<0.05). Quality of life indices improved significantly
in all domains and sleepiness decreased. The snoring index did not decrease
significantly. No preoperative anthropometric or videoendoscopic measures were
predictive of a good response to LAUP. Patients who were worse after LAUP had
milder baseline apnoea severity than those in the other response groups.
CONCLUSIONS: The treatment response to LAUP is variable and unpredictable, and
only a few patients achieve a satisfactory response. There appears to be no
relationship between subjective and objective measures of treatment efficacy.
PMID- 10770823
TI - Adult pulmonary Langerhans' cell histiocytosis.
PMID- 10770826
TI - British thoracic society winter meeting 1999
PMID- 10770824
TI - Rationale for the use of non-invasive ventilation in chronic ventilatory failure.
PMID- 10770827
TI - Management of respiratory failure with ventilation via intranasal stents in
cystic fibrosis.
AB - The case history is presented of a patient with acute respiratory failure
complicated by nasal obstruction resulting in intolerance of nasal ventilation.
Urgent insertion of nasal stents permitted restoration of ventilation with
resolution of breathlessness and stabilisation of arterial blood gases.
PMID- 10770825
TI - Is allergen exposure the major primary cause of asthma?
AB - In recent decades a number of authors have argued that allergen exposure is the
major primary cause of asthma, and that the global increases in asthma prevalence
are due to increases in exposure to aeroallergens. We have assessed the
epidemiological evidence in support of this hypothesis. No longitudinal studies
were identified in which allergen exposure during infancy in a random population
sample has been related to asthma risk after the age of six years. Two studies
have been conducted in selected populations chosen on the basis of a family
history of asthma or allergy; one study found a non-statistically significant
association whereas the other study found no association. Many of the identified
prevalence studies in children showed negative associations between allergen
exposure and current asthma, and the weighted averages of the population
attributable risks in children were 4% for Der p 1, 11% for Fel d 1, -4% for Bla
g 2, and 6% for Can f 1. There was little change in these estimates in studies in
which children whose parents had adopted allergen avoidance measures were
excluded. Furthermore, evidence from population studies is equivocal and provides
little consistent evidence that allergen exposure is associated with the
prevalence of asthma at the population level. Population-based cohort studies are
clearly required, but currently available evidence does not indicate that
allergen exposure is a major risk factor for the primary causation of asthma in
children.
PMID- 10770828
TI - Recurrent laryngeal nerve palsy associated with mediastinal amyloidosis.
AB - Amyloidosis affecting peripheral nerves causing isolated nerve palsies is
uncommon. Localised amyloidosis occurs less frequently than the reactive or
immune related systemic forms, and mediastinal localisation is virtually unknown.
We present a case of recurrent laryngeal nerve palsy associated with mediastinal
AL amyloidosis in a middle aged man.
PMID- 10770829
TI - Conservative management of a transdiaphragmatic fistula.
AB - Case reports of transdiaphragmatic fistulas connecting subphrenic collections and
empyemas are uncommon. We report the rare complication of a fistulous connection
between a subphrenic collection and the bronchial tree.
PMID- 10770830
TI - Minimizing binding errors using learned conjunctive features.
AB - We have studied some of the design trade-offs governing visual representations
based on spatially invariant conjunctive feature detectors, with an emphasis on
the susceptibility of such systems to false-positive recognition errors
Malsburg's classical binding problem. We begin by deriving an analytical model
that makes explicit how recognition performance is affected by the number of
objects that must be distinguished, the number of features included in the
representation, the complexity of individual objects, and the clutter load, that
is, the amount of visual material in the field of view in which multiple objects
must be simultaneously recognized, independent of pose, and without explicit
segmentation. Using the domain of text to model object recognition in cluttered
scenes, we show that with corrections for the nonuniform probability and
nonindependence of text features, the analytical model achieves good fits to
measured recognition rates in simulations involving a wide range of clutter
loads, word size, and feature counts. We then introduce a greedy algorithm for
feature learning, derived from the analytical model, which grows a representation
by choosing those conjunctive features that are most likely to distinguish
objects from the cluttered backgrounds in which they are embedded. We show that
the representations produced by this algorithm are compact, decorrelated, and
heavily weighted toward features of low conjunctive order. Our results provide a
more quantitative basis for understanding when spatially invariant conjunctive
features can support unambiguous perception in multiobject scenes, and lead to
several insights regarding the properties of visual representations optimized for
specific recognition tasks.
PMID- 10770831
TI - The multifractal structure of contrast changes In natural images: from sharp
edges To textures
AB - We present a formalism that leads naturally to a hierarchical description of the
different contrast structures in images, providing precise definitions of sharp
edges and other texture components. Within this formalism, we achieve a
decomposition of pixels of the image in sets, the fractal components of the
image, such that each set contains only points characterized by a fixed strength
of the singularity of the contrast gradient in its neighborhood. A crucial role
in this description of images is played by the behavior of contrast differences
under changes in scale. Contrary to naive scaling ideas where the image is
thought to have uniform transformation properties (Field, 1987), each of these
fractal components has its own transformation law and scaling exponents. A
conjecture on their biological relevance is also given.
PMID- 10770832
TI - Exponential or polynomial learning Curves? - case-based studies
AB - Learning curves exhibit a diversity of behaviors such as phase transition.
However, the understanding of learning curves is still extremely limited, and
existing theories can give the impression that without empirical studies (e.g.,
cross validation), one can probably do nothing more than qualitative
interpretations. In this note, we propose a theory of learning curves based on
the idea of reducing learning problems to hypothesis-testing ones. This theory
provides a simple approach that is potentially useful for predicting and
interpreting (a diversity of) learning curve behaviors qualitatively and
quantitatively, and it applies to finite training sample size and finite learning
machine and for learning situations not necessarily within the Bayesian
framework. We illustrate the results by examining some exponential learning curve
behaviors observed in Cohn and Tesauro (1992)'s experiment.
PMID- 10770833
TI - Training feed-forward neural networks with gain constraints
AB - Inaccurate input-output gains (partial derivatives of outputs with respect to
inputs) are common in neural network models when input variables are correlated
or when data are incomplete or inaccurate. Accurate gains are essential for
optimization, control, and other purposes. We develop and explore a method for
training feedforward neural networks subject to inequality or equality-bound
constraints on the gains of the learned mapping. Gain constraints are implemented
as penalty terms added to the objective function, and training is done using
gradient descent. Adaptive and robust procedures are devised for balancing the
relative strengths of the various terms in the objective function, which is
essential when the constraints are inconsistent with the data. The approach has
the virtue that the model domain of validity can be extended via extrapolation
training, which can dramatically improve generalization. The algorithm is
demonstrated here on artificial and real-world problems with very good results
and has been advantageously applied to dozens of models currently in commercial
use.
PMID- 10770834
TI - Variational learning for switching state-space models.
AB - We introduce a new statistical model for time series that iteratively segments
data into regimes with approximately linear dynamics and learnsthe parameters of
each of these linear regimes. This model combines and generalizes two of the most
widely used stochastic time-series models -- hidden Markov models and linear
dynamical systems -- and is closely related to models that are widely used in the
control and econometrics literatures. It can also be derived by extending the
mixture of experts neural network (Jacobs, Jordan, Nowlan, & Hinton, 1991) to its
fully dynamical version, in which both expert and gating networks are recurrent.
Inferring the posterior probabilities of the hidden states of this model is
computationally intractable, and therefore the exact expectation maximization
(EM) algorithm cannot be applied. However, we present a variational approximation
that maximizes a lower bound on the log-likelihood and makes use of both the
forward and backward recursions for hidden Markov models and the Kalman filter
recursions for linear dynamical systems. We tested the algorithm on artificial
data sets and a natural data set of respiration force from a patient with sleep
apnea. The results suggest that variational approximations are a viable method
for inference and learning in switching state-space models.
PMID- 10770835
TI - Retrieval properties of a Hopfield model with random asymmetric interactions.
AB - The process of pattern retrieval in a Hopfield model in which a random
antisymmetric component is added to the otherwise symmetric synaptic matrix is
studied by computer simulations. The introduction of the anti-symmetric component
is found to increase the fraction of random inputs that converge to the memory
states. However, the size of the basin of attraction of a memory state does not
show any significant change when asymmetry is introduced in the synaptic matrix.
We show that this is due to the fact that the spurious fixed points, which are
destabilized by the introduction of asymmetry, have very small basins of
attraction. The convergence time to spurious fixed-point attractors increases
faster than that for the memory states as the asymmetry parameter is increased.
The possibility of convergence to spurious fixed points is greatly reduced if a
suitable upper limit is set for the convergence time. This prescription works
better if the synaptic matrix has an antisymmetric component.
PMID- 10770836
TI - On 'natural' learning and pruning in multi-layered perceptrons.
AB - Several studies have shown that natural gradient descent for on-line learning is
much more efficient than standard gradient descent. In this article, we derive
natural gradients in a slightly different manner and discuss implications for
batch-mode learning and pruning, linking them to existing algorithms such as
Levenberg-Marquardt optimization and optimal brain surgeon. The Fisher matrix
plays an important role in all these algorithms. The second half of the article
discusses a layered approximation of the Fisher matrix specific to multilayered
perceptrons. Using this approximation rather than the exact Fisher matrix, we
arrive at much faster "natural" learning algorithms and more robust pruning
procedures.
PMID- 10770838
TI - Hierarchical bayesian models for regularisation in sequential learning
AB - We show that a hierarchical Bayesian modeling approach allows us to perform
regularization in sequential learning. We identify three inference levels within
this hierarchy: model selection, parameter estimation, and noise estimation. In
environments where data arrive sequentially, techniques such as cross validation
to achieve regularization or model selection are not possible. The Bayesian
approach, with extended Kalman filtering at the parameter estimation level,
allows for regularization within a minimum variance framework. A multilayer
perceptron is used to generate the extended Kalman filter nonlinear measurements
mapping. We describe several algorithms at the noise estimation level that allow
us to implement on-line regularization. We also show the theoretical links
between adaptive noise estimation in extended Kalman filtering, multiple adaptive
learning rates, and multiple smoothing regularization coefficients.
PMID- 10770837
TI - Synthesis of generalized algorithms for the fast computation of synaptic
conductances with Markov kinetic models in large network simulations.
AB - Markovkinetic models constitute a powerful framework to analyze patch-clamp data
from single-channel recordings and model the dynamics of ion conductances and
synaptic transmission between neurons. In particular, the accurate simulation of
a large number of synaptic inputs in wide-scale network models may result in a
computationally highly demanding process. We present a generalized consolidating
algorithm to simulate efficiently a large number of synaptic inputs of the same
kind (excitatory or inhibitory), converging on an isopotential compartment,
independently modeling each synaptic current by a generic n-state Markov model
characterized by piece-wise constant transition probabilities. We extend our
findings to a class of simplified phenomenological descriptions of synaptic
transmission that incorporate higher-order dynamics, such as short-term
facilitation, depression, and synaptic plasticity.
PMID- 10770839
TI - Sequential monte carlo methods To train neural network models
AB - We discuss a novel strategy for training neural networks using sequential Monte
Carlo algorithms and propose a new hybrid gradient descent sampling importance
resampling algorithm (HySIR). In terms of computational time and accuracy, the
hybrid SIR is a clear improvement over conventional sequential Monte Carlo
techniques. The new algorithm may be viewed as a global optimization strategy
that allows us to learn the probability distributions of the network weights and
outputs in a sequential framework. It is well suited to applications involving on
line, nonlinear, and nongaussian signal processing. We show how the new algorithm
outperforms extended Kalman filter training on several problems. In particular,
we address the problem of pricing option contracts, traded in financial markets.
In this context, we are able to estimate the one-step-ahead probability density
functions of the options prices.
PMID- 10770840
TI - The fight and flight responses of crickets depleted of biogenic amines.
AB - Aggressive and escape behaviors were analysed in crickets (Orthoptera) treated
with either reserpine, a nonspecific depleter of biogenic amines, or the
synthesis inhibitors alpha-methyltryptophan (AMTP) and alpha-methyl-p-tyrosine
(AMT) to specifically deplete serotonin, respectively dopamine and octopamine.
Standard immunocytochemical techniques were used to verify depletion from central
nervous tissue, and determine the effective dosages. Reserpinized crickets became
exceedingly lethargic and had severely depressed escape responses. However, they
were still able to express all the major elements of the escalating sequences of
stereotype motor performances that typifies normal aggressive behavior in the
cricket. AMT and AMTP treatment had opposing influences on escape behavior, being
enhanced by serotonin depletion, but depressed by dopamine/octopamine depletion.
AMTP-induced serotonin depletion had no influence on aggressive or submissive
behaviors. AMT-treated crickets could normally only be brought to fight by
coaxing. Though capable of expressing aggressive behavior per se, agonistic
encounters between AMT-treated crickets were shorter, and rarely involved actual
physical interactions. Hence, although amines seem to have similar actions on
escape behavior in insects and crustaceans, the aminergic control of aggression
seems to be fundamentally different in these arthropods groups. We conclude that
amines are not in principle required for the initiation and operation of the
motor circuits underlying aggression in the cricket. However, octopamine and/or
dopamine seem necessary for establishing a level of excitability sufficient for
aggressive behavior to become overt in response to appropriate natural releasing
stimuli.
PMID- 10770841
TI - Synapse formation proceeds independently of dendritic elongation in cultured
hippocampal neurons.
AB - In central neurons, dendritic differentiation begins well after axonal elongation
and is accompanied by the compartmentation of the microtubule-associated protein
2 (MAP2) in the somatodendritic domain. Whether MAP2 plays a role in the
morphological and functional maturation of dendrites remains an open question and
is the focus of this study. Cultured hippocampal neurons depleted of MAP2 by
means of antisense oligonucleotides failed to elongate their dendrites. On the
other hand, MAP2-depleted neurons were capable of receiving synapses within the
same time course as their control counterparts. However, both the number of
synapses per cell and the synaptic density were markedly reduced in neurons in
which dendritic elongation has been impaired. Taken collectively, these results
suggest that the expression of MAP2 is required for the morphological
differentiation of dendrites. Dendritic elongation, however, is not a
prerequisite for synapse formation in cultured hippocampal neurons.
PMID- 10770842
TI - Colocalization of doublecortin with the microtubules: an ex vivo colocalization
study of mutant doublecortin.
AB - Doublecortin (DCX) plays an important role in neuronal migration and development,
and the participation of DCX in neuronal migration has been demonstrated by
intensive mutational analysis for patients with X-linked or sporadic
lissencephaly, and/or subcortical laminar heterotopia. Although a previous search
for protein similarity showed that DCX has a region homologous to the putative
Ca(2+)/calmodulin-dependent protein kinase, the function of the DCX gene (DCX)
has remained unknown. We show here that mouse DCX colocalizes with the
microtubules and provide evidence that its conformational structure is important
for its subcellular localization by means of mutant doublecortin expression
study. The results of our study may suggest that the cytoskeleton involving DCX
mediates the neuronal migration during brain development.
PMID- 10770843
TI - Matrix metalloproteinase-3 removes agrin from synaptic basal lamina.
AB - Agrin, a heparin sulfate proteoglycan, is an integral member of the synaptic
basal lamina and plays a critical role in the formation and maintenance of the
neuromuscular junction. The N-terminal region of agrin binds tightly to basal
lamina, while the C-terminal region interacts with a muscle-specific tyrosine
kinase (MuSK) to induce the formation of the postsynaptic apparatus. Although the
binding of agrin to basal lamina is tight, the binding of agrin to MuSK has yet
to be shown; therefore, basal lamina binding is critical for maintaining the
presentation of agrin to MuSK. Here we report evidence that supports our
hypothesis that matrix metalloproteinase-3 (MMP-3) is responsible for the removal
of agrin from synaptic basal lamina. Antibodies to the hinge region of human MMP
3 recognize molecules concentrated at the frog neuromuscular junction in both
cross sections and whole mounts. Electron microscopy of neuromuscular junctions
stained with antibodies to MMP-3 reveals that staining is found in the
extracellular matrix surrounding the Schwann cell. Treatment of sections from
frog anterior tibialis muscle with MMP-3 results in a clear and reproducible
removal of agrin immunoreactivity from synaptic basal lamina. The same MMP-3
treatment does not alter anti-laminin staining. These results support our
hypothesis that synaptic activity results in the activation of MMP-3 at the
neuromuscular junction and that MMP-3 specifically removes agrin from synaptic
basal lamina.
PMID- 10770844
TI - Cloning and neuronal expression of a type III newt neuregulin and rescue of
denervated, nerve-dependent newt limb blastemas by rhGGF2.
AB - Urodele amphibians are the only vertebrates that can regenerate their limbs
throughout their life. The critical feature of limb regeneration is the formation
of a blastema, a process that requires an intact nerve supply. Nerves appear to
provide an unidentified factor, known as the neurotrophic factor (NTF), which
stimulates cycling of blastema cells. One candidate NTF is glial growth factor
(GGF), a member of the neuregulin (NRG) growth factor family. NRGs are both
survival factors and mitogens to glial cells, including Schwann cells. All forms
of NRGs contain an EGF-like domain that is sufficient to activate NRG receptors
erbB2, erbB3, and erbB4. To investigate the involvement of neuregulin in newt
limb regeneration, we cloned and characterized one neuregulin isoform, a
neuregulin with a cysteine-rich domain (CRD-NRG), from newt (Notophthalmus
viridescens) spinal cord. Results of in situ hybridization showed that the newt
CRD-NRG is highly expressed in dorsal root ganglia and spinal cord neurons that
innervate the limbs. We also demonstrated the biological activity of recombinant
human GGF2 (rhGGF2) in urodele limb regeneration. When rhGGF2 was injected into
denervated, nerve-dependent axolotl blastemas, the labeling index (LI) of
blastema cells was maintained at a level near to that of control, innervated
blastemas, whereas without rhGGF2 the LI decreased significantly. In another
experiment, rhGGF2 was delivered into denervated, nerve-dependent blastemas
either by direct infusion into blastemas or by injection into the intraperitoneal
cavity. The denervated blastemas were rescued into a regeneration response.
PMID- 10770845
TI - Glutamate-induced changes in the pattern of hippocampal dendrite outgrowth: a
role for calcium-dependent pathways and the microtubule cytoskeleton.
AB - Glutamate regulation of a variety of aspects of dendrite development may be
involved in neuronal plasticity and neuropathology. In this study, we examine the
calcium-dependent pathways and alterations in the microtubule (MT) cytoskeleton
that may mediate glutamate-induced changes in the pattern of dendrite outgrowth.
We used Fura-2 AM and inhibitors of the calcium-dependent proteins, calmodulin
and calpain, to identify the role of specific calcium-dependent pathways in
glutamate-regulated dendrite outgrowth. Additionally, we used a quantitative
fluorescence technique to correlate changes in MT levels with glutamate-induced
changes in dendrite outgrowth. We show that the intracellular calcium
concentration ([Ca(2+)](i)) changes in a biphasic manner over a 12-h period in
the presence of glutamate. A transient increase in [Ca(2+)](i) over the first
hour of glutamate exposure correlated with a calmodulin-associated increase in
the rate of dendrite outgrowth, whereas a sustained increase in [Ca(2+)](i) was
correlated with calpain-associated dendrite retraction. Quantitative fluorescence
measurements showed no net change in the level of MTs during calmodulin
associated increases in dendrite outgrowth, but showed a significant decline in
the level of MTs during calpain-associated dendrite retraction. These findings
provide insights into the intracellular mechanisms involved in activity-dependent
regulation of dendrite morphology during development and after pathology.
PMID- 10770846
TI - Gal-NCAM is a differentially expressed marker for mature sensory neurons in the
rat olfactory system.
AB - A new monoclonal antibody, 2E11, was produced by immunizing mice with the
microsomal fraction of rat accessory olfactory bulb cells. This IgM recognizes a
previously described complex alpha-galactosyl containing glycolipid, as well as N
linked glycoproteins at 170 and 210 kD. These proteins correspond to a new nerve
cell adhesion molecule (NCAM) glycoform, Gal-NCAM, which contains a blood group B
like oligosaccharide. During embryonic development, the 2E11 epitope is expressed
by a subset of mature olfactory sensory neurons randomly dispersed throughout the
olfactory epithelium, whereas in the olfactory bulb, immunostaining is restricted
to medial areas of the nerve layer. When compared to PSA-NCAM, another NCAM
glycoform, Gal-NCAM has a mutually exclusive distribution pattern both in the
olfactory epithelium and in the olfactory bulb. We propose a model for the
hierarchy of neuronal maturation in the olfactory epithelium, including a switch
from PSA-NCAM expression by immature neurons to the expression of Gal-NCAM by
mature neurons.
PMID- 10770847
TI - Identified motor terminals in Drosophila larvae show distinct differences in
morphology and physiology.
AB - In Drosophila, the type I motor terminals innervating the larval ventral
longitudinal muscle fibers 6 and 7 have been the most popular preparation for
combining synaptic studies with genetics. We have further characterized the
normal morphological and physiological properties of these motor terminals and
the influence of muscle size on terminal morphology. Using dye-injection and
physiological techniques, we show that the two axons supplying these terminals
have different innervation patterns: axon 1 innervates only muscle fibers 6 and
7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This
difference in innervation pattern allows the two axons to be reliably identified.
The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same
number of branches; however, axon 2 terminals are approximately 30% longer than
axon 1 terminals, resulting in a corresponding greater number of boutons for axon
2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The
excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller
than that produced by axon 2, although the size distributions show considerable
overlap. Consistent with vertebrate studies, there is a correlation between
muscle fiber size and terminal size. For a single axon, terminal area and length,
the number of terminal branches, and the number of boutons are all correlated
with muscle fiber size, but bouton size is not. During prolonged repetitive
stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1
EPSPs facilitate. The response to repetitive stimulation appears to be similar at
all motor terminals of an axon.
PMID- 10770849
TI - Disturbances of speech and language in subcortical lesions.
PMID- 10770850
TI - Study of the correlation of brainstem auditory evoked potentials and magnetic
resonance imaging in children with spastic cerebral palsy.
PMID- 10770848
TI - Neurturin is a neurotrophic factor for penile parasympathetic neurons in adult
rat.
AB - Neurturin (NRTN), a member of the GDNF family of neurotrophic factors, promotes
the survival and function of several neuronal populations in the peripheral and
central nervous system. Recent gene ablation studies have shown that NRTN is a
neurotrophic factor for many cranial parasympathetic and enteric neurons, whereas
its significance for the sacral parasympathetic neurons has not been studied.
NRTN signals via a receptor complex composed of the high-affinity binding
receptor component GFRalpha2 and the transmembrane tyrosine kinase Ret. The aim
of this study was to determine whether NRTN could be an endogenous trophic factor
for penis-projecting parasympathetic neurons. NRTN mRNA was expressed in smooth
muscle of penile blood vessels and corpus cavernosum in adult rat as well as in
several intrapelvic organs, whereas GFRalpha2 and Ret mRNAs were expressed in
virtually all cell bodies of the penile neurons, originating in the major pelvic
ganglia. (125)I-NRTN injected into the shaft of the penis was retrogradely
transported into the major pelvic and dorsal root ganglia. Mice lacking the
GFRalpha2 receptor component had significantly less nitric oxide synthase
containing nerve fibers in the dorsal penile and cavernous nerves. In conclusion,
these data suggest that NRTN acts as a target-derived survival and/or
neuritogenic factor for penile erection-inducing postganglionic neurons.
PMID- 10770851
TI - Mesoscopy and scanning electron microscopy of the trabelular projections in the
superior sagittal sinus.
PMID- 10770853
TI - Study of normal standard of adult population through quantitative
electroencephalography.
PMID- 10770852
TI - Morphological changes in the lateral ventricles choroid plexus of rats (Rattus
norvegicus) submitted to the experimental chronic alcoholism.
PMID- 10770854
TI - Sleep apnea and gastroesophageal reflux: a study with esophageal pH monitoring
and polysomnography.
PMID- 10770855
TI - The influence of the ethanol in alcoholic beverages in the atherosclerosis of the
extracranial carotid arteries.
PMID- 10770856
TI - Neurocysticercosis: a study of 177 cases from Sao Jose do Rio Preto, Sao Paulo,
Brazil.
PMID- 10770858
TI - ?
PMID- 10770857
TI - Diagnostic profile of schistosomotic myeloradiculopathy in three hospitals of
Belo Horizonte, Minas Gerais.
PMID- 10770859
TI - Arteriosclerosis and the promise of GPIIb/IIIa inhibitors in stroke.
AB - Ischemic mechanisms in pa2000Mar;58(1)1-10 studied for more than 150 years.
Antiplatelet agents did show benefit in secondary prevention. Aspirin is the most
common antiaggregant in clinical use today. However, the benefit produced by the
"best" antiplatelet regimen in stroke prevention is lower than 40%. The adherence
of circulating platelets to the subendothelium is mediated by glycoprotein (GP)
residing on the cell's surface. GPIIb/IIIa is the most important platelet
membrane receptor that mediates the process of platelet aggregation, and thrombus
formation. Thus, new drugs that block the GPIIb/IIIa receptor have recently
emerged. Clinical trials using these agents have shown effectiveness in acute
coronary syndromes. However, the absence of studies in cerebrovascular disease
and the potential hemorrhagic complications questioned their use in stroke
prevention. We review the clinical trials using the new GPIIb/IIIa agents in
myocardial ischemia, and consider the potential implications for cerebrovascular
disease.
PMID- 10770860
TI - Molecular diagnosis of Huntington disease in Brazilian patients.
AB - Huntington disease (HD) is a progressive neurodegenerative disorder with
autosomal dominant inheritance, characterized by choreiform movements and
cognitive impairment. Onset of symptoms is around 40 years of age and progression
to death occurs in approximately 10 to 15 years from the time of disease onset.
HD is associated with an unstable CAG repeat expansion at the 5' and of the IT15
gene. We have genotyped the CAG repeat in the IT15 gene in 44 Brazilian
individuals (42 patients and 2 unaffected family members) belonging to 34
unrelated families thought to segregate HD. We found one expanded CAG allele in
32 individuals (76%) belonging to 25 unrelated families. In these HD patients,
expanded alleles varied from 43 to 73 CAG units and normal alleles varied from 18
to 26 CAGs. A significant negative correlation between age at onset of symptoms
and size of the expanded CAG allele was found (r=0.6; p=0.0001); however, the
size of the expanded CAG repeat could explain only about 40% of the variability
in age at onset (r2=0.4). In addition, we genotyped 25 unrelated control
individuals (total of 50 alleles) and found normal CAG repeats varying from 16 to
33 units. The percentage of heterozigocity of the normal allele in the control
population was 88%. In conclusion, our results showed that not all patients with
the "HD" phenotype carried the expansion at the IT15 gene. Furthermore, molecular
diagnosis was possible in all individuals, since no alleles of intermediate size
were found. Therefore, molecular confirmation of the clinical diagnosis in HD
should be sought in all suspected patients, making it possible for adequate
genetic counseling.
PMID- 10770861
TI - Neurocysticercosis: detection of IgG, IgA and IgE antibodies in cerebrospinal
fluid, serum and saliva samples by ELISA with Taenia solium and Taenia crassiceps
antigens.
AB - We assayed samples of cerebrospinal fluid (CSF), serum and saliva from patients
with neurocysticercoses, control group and individuals with other parasitoses, by
ELISA with Taenia crassiceps vesicular fluid antigen (Tcra) and Taenia solium
total antigen (Tso) for the detection of antibodies. The sensitivity for IgG-Tcra
was 100% for CSF and serum, and 32.0% for saliva; and for IgG-Tso 100% for CSF,
80.0% for serum and 24.% for saliva. Specificity was 100% for CSF and 80.0% for
serum with both antigens, and 100% for saliva with Tcra and 87.5% with Tso. The
sensitivity and specificity for IgA-Tcra was, respectively, 40.0% and 100% for
CSF, 36.0% and 97.1% for serum, and 4.0% and 90.0% for saliva. IgE detection
showed 24.0% sensitivity and 97.1% specificity for serum, with no detection in
CSF samples. The search for antibodies revealed the presence of IgG > IgA > IgE
in CSF, serum and saliva samples, with IgG being present in all phases of the
disease, while IgA/IgE were more frequent in the inactive form.
PMID- 10770862
TI - Ultrastructural alterations of choroid plexuses of lateral ventricles of rats
(Rattus norvegicus) submitted to experimental chronic alcoholism.
AB - Adult male rats (Wistar lineage) were alcoholized with sugar cane liquor diluted
at 30(0) GL during 300 days and sacrificed every 60 days in 5 stages. Samples of
choroid plexuses of lateral ventricles were collected and examined at
transmission electronic microscope to detect possible ultrastructural alterations
and to raise possible pathological correlations. Gradual changes were observed in
these animals during all the experiment: dilatation and enlargement of cisternae
of Golgi complex, dilatation of RER, presence of digestive vacuoles and a large
amount of pinocytic vesicles as well as vesicles with electronlucent content
throughout cytoplasm, as well as an enlargement of intercellular space between
basolateral interdigitation of the cells and of the connective tissue. The
changes observed in the epithelium and connective tissue of choroid plexuses
specially in 240 and 300 days of treatment are presumably due to a disturbance in
hydroelectrolitic homeostasis, contributing to several morpho-functional disturbs
of central nervous system. No changes were observed in the control group animals.
PMID- 10770863
TI - Chronic insomnia in workers poisoned by inorganic mercury: psychological and
adaptive aspects.
AB - Insomnia is one of the symptoms of inorganic mercury poisoning (IMP). The
objective of this study is to analyze the chief psychological aspects in the
adjustment of workers with chronic insomnia associated with IMP. For this purpose
the Preventive Clinical Interview and the Ryad Simon Operational Adaptive
Diagnostic Scale (Escala Diagnostica Adaptativa Operacionalizada-EDAO) were
utilized. Fifteen subjects with mean age of 40 years (10 males and 5 females)
were studied. Nine were diagnosed with High Adaptive Inefficacy, five with
Moderate Inefficient Adaptation and only one with Mild Inefficient Adaptation.
Impairment occurred in four adaptive sectors: affective relationship, social
cultural, productivity and organic. Adaptive efficiency indicated that in all the
15 subjects studied the adaptive solutions were frustrating and led to psychic
suffering and/or environmental conflict confirming the severity of the
involvement in chronic IMP.
PMID- 10770864
TI - Siestas among Brazilian Native Terena adults : a study of daytime napping.
AB - Regular daytime napping behavior, also known as siesta culture, is influenced by
circadian, cultural and environmental factors. This research analyzes
characteristics of regular daytime napping in Brazilian Native Terenas. We
evaluated 65 adults ( 32 M; 33 F ) from 18 to 75 years, with a mean age of 37.2,
from the Indian Reservation village Corrego do Meio, in the central region of
Mato Grosso do Sul. Daytime napping characteristics were evaluated by means of a
standard questionnaire applied to each individual. It was observed that weekly
daytime napping (at least once a week) was present in 72. 3% of the population.
There was a tendency to occur in males. The effects of weekends was mild. Mean
onset time of daytime sleep was 12.2 h, remarkably earlier than usually described
in urban populations. This data stresses the need to consider ethnic influences
in order to understand sleep habits.
PMID- 10770866
TI - Compound osteosynthesis in the thoracic spine for treatment of vertebral
metastases. Technical report.
AB - Metastases to vertebrae often cause bone destruction leading to instability and
neural compression. Anterior surgical approaches allow tumor resection and direct
neural decompression. For patients with a short life expectancy, vertebral body
replacement with methyl-methacrylate polymerized in situ can be used for load
sharing in the axial plane. Screws hung from the rod into the corpectomy site are
incorporated into the acrylic cement. The technique described in this article
allows for immediate spinal stabilization and provides a protective environment
for the neural elements. All the patients tolerated the procedure well and were
able to ambulation without an orthoses.
PMID- 10770865
TI - Magnetic resonance imaging in the evaluation of patients with aseptic
meningoencephalitis and connective tissue disorders.
AB - OBJECTIVE: To describe the role of magnetic resonance imaging (MRI) in the
evaluation of patients with chronic and recurrent aseptic meningitis. METHOD: A
retrospective study of five patients with aseptic meningoencefalitis diagnosed by
clinical and CSF findings. CT scans showed without no relevant findings. RESULTS:
MRI showed small multifocal lesions hyperintense on T2 weighted images and FLAIR,
with mild or no gadolinium enhancement, mainly in periventricular and subcortical
regions. Meningoencephalitis preceded the diagnosis of the underlying disease in
four patients (Behcet's disease or systemic lupus erythematosus). After the
introduction of adequate treatment for the rheumatic disease, they did not
present further symptoms of aseptic meningoencephalitis. CONCLUSION: Aseptic
meningoencephalitis can be an early presentation of an autoimmune disease. It is
important to emphasize the role of MRI in the diagnosis and follow-up of these
patients.
PMID- 10770867
TI - [Diagnosis of cerebellum-pontine angle tumors using artificial intelligence
techniques].
AB - We are concerned in this paper with learning classification procedures from known
cases. More precisely, we provide a diagnostic model that discriminate between
cerebellum-pontine angle (CPA) tumors and otorhinolaryngological (ENT) disorders.
Usually, in order to distinguish between CPA tumors and ENT disorders one must
perform clinical-neurological examination together with expensive radiological
imagery (CT and MRI). The proposed model was obtained through artificial
intelligence methods and presented a good accuracy level (88.4%) when tested
against new cases, considering only clinical examination without radiological
imagery results.
PMID- 10770868
TI - [Subfrontal approach in sellar and suprasellar lesions].
AB - A variety of mass lesions are placed in and around of the sella turcica. Although
their common location these lesions have distinguishing features and different
approaches can be selected. There are conventional transcranial and sophisticated
skull base approaches. We report our experience with a subfrontal route to the
sellar region. Between February 1997 and March 1998, 19 tumors placed around the
sella have been treated surgically by this method. Eleven of them were pituitary
tumors, 3 were craniopharyngeomas, 2 were meningiomas, and 1 was germinoma. Total
removal was achieved in 17 cases. There was not operative mortality.
Postoperative complications included twelve cases of unilateral anosmia and four
cases of transitory diabetes insipidus. Progressive stroke occurred in one
patient. These results stress the importance of the subfrontal approach to reach
such lesions in sellar region.
PMID- 10770869
TI - [Stereotactic-guided surgery for cavernous angiomas].
AB - Intracerebral cavernous angiomas may cause hemorrhage, epileptic seizures and
neurological deficits. The diagnosis of these lesions became easier with the
advent of the magnetic resonance image (MRI). Radical resection is the treatment
of choice. Due to frequent subcortical or deep location, image-guided techniques,
such as stereotactic-guided surgery, offer many advantages as smaller skin
incision and craniotomy, less brain manipulation with consequently lower
morbidity. We present a series of nine cavernous angiomas treated by stereotactic
guided radical surgical resection. The diagnosis was done by MRI and confirmed by
pathologic studies in all cases. Mean age of patients was 30 years old (range 20
54 years). Postoperative morbidity occurred in two cases: one patient had a
convulsion on the third postoperative day and the other presented dysphasia and
hemiparesis on the second postoperative day, both with total recovery. Total
resection of the lesion was possible in all cases with no neurological deficit.
PMID- 10770870
TI - [Medulloblastomas: clinical, epidemiological and pathological findings in 28
cases].
AB - We report the clinical, epidemiological and pathological findings of 28 patients
with medulloblastoma: 22 were male; age ranged from 1 to 50 years, with a mean of
15 years. The most frequent symptoms and signs were headache (64%) and vomiting
(64%). Only one patient showed a desmoplastic medulloblastoma variant, the others
showed classical medulloblastomas. Regarding treatment, most patients were
submitted to total resection (n=10) or partial tumorectomy (n=7). A low rate of
tumoral recurrence was observed, occurring in 21% of the patients (n=6) after 4
years of follow-up. Chemotherapy seemed to contribute to a lower recurrence rate
amongst our patients. Our findings are similar to those reported in literature,
thus helping to understand the biological behavior of this type of tumor.
PMID- 10770871
TI - [Morbidity and mortality due to traumatic brain injury in Sao Paulo City, Brazil,
1997].
AB - There are few epidemiological studies on traumatic brain injury (TBI), and those
that allow broad comparative analyses of this problem are even more scarce, due
to methodological obstacles. Usually, the studies address head injury (they
include the cranial envelopments and content) but are reported as TBI, given the
difficulty of mutual exclusion. It is also common for them to be centered at
specific severity levels, only for hospitalized victims or according to the
external cause, such as traffic accidents. With full respect to these limits,
this study had as its objective the estimation of the TBI incidence in patients
resident and in-hospital, in the hospital network in the city of Sao Paulo,
Brazil, in 1997, as well as the estimation of TBI-caused mortality amongst
external causes, at this same time and locale. Data for the study consisted of
Ministerio da Saude data on hospital discharges, analyzed based on Autorizacoes
de Internacao Hospitalar (AIH) and obituary data on external causes, contained in
the Programa de Aprimoramento das Informacoes de Mortalidade (PROAIM) data base.
It was found that 29 717 patients were hospitalized due to lesions and poisoning;
of these 3 635 (12%) had TBI; the hospitalization rate was 0.36/1000 pop.; and
hospital mortality was 10%. The mortality coefficient due to external causes was
87.3/100 000 pop. Minimum TBI mortality rate is estimated at a minimum of 26.2
and a maximum of 39.3/100000 pop.
PMID- 10770872
TI - [Clinical evaluation of the efficacy of the paracetamol and caffeine combination
in the treatment of tension headache].
AB - Tension type headache in both its forms, episodic and chronic, is the most common
type of headache experienced by the population. The headache attack or the
prevention of new crises may be treated with pharmacological as well as non
pharmacological measures. This study included 5,490 patients from out-patient
clinics and medical offices covering various regions of Brazil. Approximately 95%
of the subjects had episodic tension type headache, while 5% had chronic tension
type headache. The majority of the patients presented with crisis of moderate
intensity (62.19%). In 5,419 patients a tension type headache crisis was treated
with acetaminophen 1000 mg and caffeine 130 mg. In 93.98%, onset of relief
occurred within 2 hours of taking the medication. In 77.61%, complete reversion
of the crisis occurred within 2 hours. Good/excellent efficacy ratings were
achieved in 61.93%/37.80% of the cases according to the physician's assessment
and in 48.51%/40.29% according to the patients' assessment. Adverse events,
commonly gastrointestinal manifestations, were reported by 5.57% of the patients.
This is a Brazilian study of the efficacy and safety of the combined use of
acetaminophen-caffeine for the treatment of tension type headache.
PMID- 10770873
TI - [Characteristics of care to patients with stroke in a secondary hospital].
AB - OBJECTIVE: To describe the assistance profile of stroke patients accomplished in
Hospital Universitario of University of Sao Paulo (HU-USP), by the Internal
Medicine team of the Emergency Room, as being a standard of non-tertiary
hospital. METHOD: Retrospective analysis of 228 patients with cerebrovascular
disease, assisted from 1989 to 1993. RESULTS: We found the following subgroup
distribution: 53% of patients had ischemic strokes, 26%, had hemorrhagic strokes,
2% had association from both and 19% were not classified. Among risk factors, we
found an incidence of 67,5% for arterial hypertension; 24.6% for cardiac disease
(chronic atrial fibrillation being the most frequent); diabetes occurred in 20.2%
of cases. Among complications, coma was present in 22.4% of cases; respiratory
insufficiency occurred in 15%; infection, in 29%. Death rate was 14. 5%. Average
permanence in hospital was 4.11 days. CONCLUSIONS: The epidemiological aspects
and complications reproduced the data described in the literature. Some negative
aspects were inadequacy of accommodations and the great incidence of pulmonary
infections. However, the mortality rate was comparable to the lowest found in
literature.
PMID- 10770874
TI - [Migration in different sorts of work, unemployment and retirement of 81
epileptic patients. 3 years of ambulatory follow-up].
AB - This study aims to assess epileptic patients migration in different sorts of
paid/non paid and formal/informal work, unemployment and retirement. Eighty one
epileptic patients were evolutively analyzed (cohort) at the Epilepsy Department
of Hospital de Base, Medical School, Sao Jose do Rio Preto, Brazil. The epileptic
percentages in different sorts of work, in March 1996 was compared with the one
after three-year follow-up period in March 1999. There were no statistical
significant changes among the same sorts of work in this period. However, there
were intense migrations in relation to different sorts of work. Paid work showed
migration to unemployment and retirement. This research shows the significant
migration of epileptic patient either to some kind of a less qualified work or to
some social security dependence as well as to early retirement.
PMID- 10770875
TI - [Neurologic semiology of a group of first grade students in an elementary
school].
AB - We evaluated children in the first grade of a elementary school using
neurological examination. With no previous knowledge of their educational
performance, were invited all children attending five classes of the first grade
of an elementary public school chosen randomly, in Itatiba / Sao Paulo / Brazil,
whose parents assigned a Commitment Term for participation in this research.
Children who missed three evaluations in different days or whose parents did not
assigned the Commitment Term were excluded. The Traditional Neurological
Examination (ENT) (Lefevre, 1972) was applied. It was considered for normal the
measurement of the skull circumference, proposed by Diament & Rodrigues (1976),
and the application of all ENT items. The data were stored in a database of the
Epi6 Program (Epidemiologic Information), and analyzed by percentage calculation
and by the chi2 test. The significance level was 0.05. Children evaluated were
124. The ENT results were normal in 87 (70.16%) and altered in 37 (29.83%). Among
the alterations, there were observed: light tremor, light muscular hypotonia,
speech acquisition delay, macrocephaly, microcephaly, hyperactivity, cranial
nerve syndrome, central facial paralysis. One child presented corticospinal tract
impairment syndrome of the distal lower extremities.
PMID- 10770876
TI - [Quality of life evaluation scale (AUQEI--Autoquestionnaire Qualite de Vie Enfant
Image). Validity and reliability of a quality of life scale for children 4 to 12
years-old].
AB - It should take into account the pediatric context and the child's development
moment to evaluate the quality of life in childhood from a standardized
instrument. We present the questionnaire AUQEI validation by its application in
353 children, between 4 and 12 years-old, obtaining a cut off point of 48,
internal consistency with a Crombach's alpha of 0.71 and construct validity (r =
0.497). With these psychometrical qualities, the scale shows its importance as a
diagnostic tool.
PMID- 10770878
TI - [Meningoencephalitis in the acute phase of measles. Report of 6 cases].
AB - We present the clinical and laboratory manifestations of encephalitis following
measles in six patients which were diagnosed during the epidemics that occurred
in the city of Sao Paulo, Brazil, in 1997. We performed retrospective case
analysis of the six patients diagnosed as having encephalitis due to measles.
Encephalitis was diagnosed based on clinical grounds and on the cerebrospinal
fluid (CSF) alterations. All the cases were serologically confirmed. Of 467
patients with measles who presented themselves for medical care at the Instituto
de Infectologia Emilio Ribas six were diagnosed with encephalitis. Patient's age
was 2 months to 28 years old. The most frequent symptoms were drowsiness and
nuchal rigidity. CSF showed an increased of white cell count in all cases. Four
patients were admitted to the intensive care unit. Two of them required
mechanical ventilation. In only two patients did the computerized tomography show
abnormalities. All showed good recovery without sequelae.
PMID- 10770877
TI - [The most frequent neurologic disturbances. A contribution to the definition of
topics for the programmatic content to the program of neurology in medical
graduation].
AB - INTRODUCTION: Knowledge accumulation is overfilling the thematic content of
medical graduation. Medical Schools must be alert to define a minimal content
related with the most frequent disturbs. We intent to suggest topics for the
minimal content, to the program of Neurology in medical graduation. METHOD: 1. To
identify the places where young doctors are working outside the School Hospital
(SH): we analysed the answers of the letters sent to 6415 resident - doctors (RD)
in Sao Paulo's State and we made personal interview with 201 RD. 2. To verify the
most frequent neuropsychiatric disturbs (ND) in the population: we made the
analysis of the patient's diagnostic records in emergency room of three
institutions: Municipal of Taubate-SP, Municipal of Sao Jose dos Campos-SP and
Faculty of Medicine of Sao Paulo Santa Casa de Misericordia. RESULTS: 1. The RD
are young and, outside the SH, they work in other emergency services. 2. The most
frequent diagnosis in institutions were listed: alcoholism, cerebrovascular
disease, coma, cranial trauma, dementia, dizziness, epilepsy, facial paralysis,
faint, headache, hemiplegia or paraplegia, meningitis, others paralysis,
periferical neuropathy and psychiatric disorders. CONCLUSIONS: Those diagnostics
most frequent are relevant topics of the programmatic content to the program of
Neurology in medical graduation.
PMID- 10770879
TI - IgG2 immunodeficiency: association to pediatric patients with bacterial
meningoencephalitis.
AB - An IgG subclass deficiency is often associated with bacterial infections. We
studied four pediatric patients suffering from meningoencephalitis, two of them
due to Streptococcus pneumoniae and two due to Haemophilus influenzae type b.
Simultaneous diagnostic serum and cerebrospinal fluid samples were taken during
income. The four subclasses of IgG and albumin were quantified in both biologic
fluids by radial immunodiffusion. Very low levels of seric IgG2 with non
detectable cerebrospinal fluid IgG2 were found in the patients. No intrathecal
IgG subclass synthesis was found in two patients. One patient with S. pneumoniae
had IgG3 intrathecal synthesis. Intrathecal IgG1, IgG3 and IgG4 synthesis was
found in one patient suffering from H. influenzae according with reibergrams.
Substitutive therapy with intravenous gammaglobulin was given to the patients as
part of the treatment.
PMID- 10770880
TI - [Primary orthostatic tremor: report of 4 cases].
AB - We report on four cases of primary orthostatic tremor. The purpose of this study
is the rarity of this type of tremor and the differential diagnosis with other
tremors. The electrophysiological study showed a 15-20 Hz tremor frequency in our
cases. There are clinical, electrophysiological and therapeutic differences of
primary orthostatic tremor in report to other tremors of legs, according to the
literature and characteristics of our cases.
PMID- 10770881
TI - [Multiple gliomas. Illustrative cases of 4 different presentations].
AB - Multiple gliomas are uncommon and may be classified according to: a) the time of
presentation in early (at diagnosis) or late (during treatment); b) the
characteristics of computed tomography or magnetic resonance imaging (CT/MRI) in
multifocal (with evidence of spread) and multicentric (without evidence of
spread). From 212 patients with histopathologic diagnosis of glioma evaluated
from March/90 to September/99, 15 (7%) had multiple lesions. We describe 4
patients: early multicentric, late multicentric, early multifocal and late
multifocal, with emphasis on characteristics of CT/MRI and possible differential
diagnosis. The differential diagnosis of multiple lesions in the central nervous
system includes mainly infectious/inflammatory diseases and metastasis, however
multiple gliomas should always be considered, even in patients with known
systemic cancer, as described by others. Considering that CT/MRI features are not
definite, the diagnosis should always be confirmed by histopathologic
examination.
PMID- 10770882
TI - [Van Der Knaap syndrome. Megalencephaly with leukodystrophy. Report of 2 cases in
the same family].
AB - We report on two brothers, aged four and six years-old, evidencing the Van Der
Knaap syndrome. Clinical and radiological aspects are discussed as well their
peculiarities. Data are compared with related literature, as etiopathogenic
mechanisms possibly involved.
PMID- 10770883
TI - Saphenous vein graft bypass in the treatment of giant cavernous sinus aneurysms:
report of two cases.
AB - Two cases of giant intracavernous aneurysms treated by high flow bypass with
saphenous vein graft between the external carotid artery (ECA) and branches of
the middle cerebral artery (MCA) are presented. Very often these aneurysms are
unclippable because they are fusiform or have a large neck. Occlusion of the
internal carotid artery (ICA) is the treatment of choice in many cases. This
procedure has however a high risk of brain infarction. Revascularization of the
brain by extra-intracranial anastomosis between the superficial temporal artery
(STA) and branches of the MCA is frequently performed. This procedure provides
however a low flow bypass and brain infarction may occur. We report two cases of
giant cavernous sinus aneurysms treated by high flow bypass and endovascular
balloon occlusion of the ICA. Immediate high flow revascularization of MCA
branches was achieved and the patients showed no ischemic events. Follow-up of 8
and 14 months after operation shows patency of the venous graft and no
neurological deficits. Angiographic control examination showed complete aneurysm
occlusion in both cases.
PMID- 10770884
TI - Posterior fossa craniotomy. Technical report.
AB - The use of craniotomy to approach supratentorial lesions is quite well
established in the literature. The use of craniotomy for posterior fossa
approaches, however, is not well described. The aim of this article is to
describe the technical aspects of this approach and to delineate the important
landmarks. In our cases, posterior fossa craniotomies have been utilized for
treat different pathologies. Additionally, the technique has not added any
additional risk, and the cosmetic results have been excellent.
PMID- 10770885
TI - Orbital myositis and rheumatoid arthritis: case report.
AB - Orbital myositis implies orbital inflammation confined to one or more of the
extraocular muscles. The acute form responds well to high doses of oral
corticosteroids tapered gradually, but it may recur or become chronic. We
describe a 38 years old female who has been suffering from rheumatoid arthritis
for six years. She developed diplopia as a result of a paralysis of the right and
left rectus medialis muscle. MRI showed inflammatory process and thickness of the
referred muscles. The patient had a total recovery with oral use of 80 mg
methylprednisolone daily. Two months after the first episode she developed a
bilateral ophthalmoplegy. The patient improved with oral use of steroids the
second time, but a paresis of the left rectus lateralis muscle remained. From the
156 cases we reviewed only three have been related to rheumatic diseases and none
has been previously related to rheumatoid arthritis.
PMID- 10770886
TI - [Temporal lobe epilepsy with aura of pleasure. Case report].
AB - We report on a woman with temporal lobe epilepsy and "orgasm sensation" like an
epileptic aura. Literature is controversial about pleasure and ecstasy as an
epileptic aura. Aura of pleasure in this case is confirmed, by clinical
investigation, electroencephalogram and seizures remission with treatment
(phenytoin).
PMID- 10770887
TI - [Vasopressin and brain death].
AB - Brain death results in the breakdown of effective central regulatory mechanisms
of cardiocirculatory stability, even in patients with artificial mechanical
ventilation, correction of electrolytic and acid-basic disorders and maximal
conventional pharmacological support of the circulation. Recent evidences have
shown that the fall of vasopressin levels in the blood circulation significantly
influences the cardiocirculatory stability of patients with brain death, and its
exogenous administration is defended by many authors for the management of
multiorgan donor patients. In this brief review we analyse and discuss some
experimental and clinical relevant studies about the role of vasopressin in the
control of cardiocirculatory stability in brain death, and its potential
usefulness in the management of multiorgan donor. We conclude that the role of
vasopressin in the pathophysiology of brain death and its usefulness as a
pharmacological agent in the management of multiorgan donor are not well
elucidated, deserving further investigations.
PMID- 10770889
TI - Prevalence study of neurologic manifestations in HTLV-I positive blood donors
PMID- 10770888
TI - [The phylogenesis of language. New approaches of old questions].
AB - The philogenesis and the anthropogenesis of language are the primary elements for
the anatomic and physiologic understanding about the mechanisms of human
communication, as well as their clinical applicability. During the process of
primates'evolution, significant changes in the animal's body, specially on the
heads, has occurred since the arboricole life that influences the genesis of
language. The adaptation of a semi-vertical body posture, the exploratory use of
the hands and the improvement of vision at the expenses of olfaction have caused
the enlargement of the cranium and the encephalon. Furthermore, as the primates
went back to the floor, and from the development of the biped march in the
Australopithecus, a progressive "fan-like" increase of the frontal, parietal and
temporal regions took place allowing the simultaneous development of the
neuroanatomical centers of language, facial expression and manual motor activity.
PMID- 10770890
TI - Computed tomography and electroencephalography in evaluation of children with
motor and language disorders
PMID- 10770891
TI - Clinical and electroencephalographical characterization of typical absence
seizures
PMID- 10770892
TI - Symptoms of depression and anxiety, and screening for mental disorder in
migrainous patients
PMID- 10770893
TI - The cognitive potentials in kidney failure before and after hemodialysis
PMID- 10770894
TI - [ [In Process Citation]
PMID- 10770895
TI - [ [In Process Citation]
PMID- 10770896
TI - [Clinical profile of cytomegalovirus (CMV) enterocolitis in acquired
immunodeficiency syndrome].
AB - OBJECTIVE: To determine the clinical profile of CMV colitis in AIDS patients,
comparing clinical, endoscopic parameters and survival time between 2 groups of
AIDS patients having chronic diarrhea. Group A being CMV colitis and group B
without CMV colitis. METHODS: 48 patients with diarrhea that lasted more than 30
days, being 27 in Group A and 21 in Group B, were studied. Age, risk factors,
interval time between the diagnosis of HIV infection and the beginning of
diarrhea, hematochesia, the endoscopic findings and life table in both groups,
were analysed. All of them were diagnosed by stool culture and stools for ovum
and parasites, along colonoscopy with biopsies. The unpaired t test was used to
assess statistical significance of differences observed in the means of
continuous and the chi-square with Yates correction for non-parametric variables.
The survival curves were assessed by the Kaplan-Meier and the Mantel-Haenszel's
tests. A P value of less than 0,05 was considered to indicate statistical
significance. RESULTS: The mucosal lesions associated with the CMV infection are
typically ulcerative on a background of hemorrhagic erythema 14 (51,8%) p < 0,01.
The life table analysis disclosed shorter survival time in the CMV colitis group
0,005> P>0,001. The others studied data did not achieve statistical significance.
CONCLUSIONS: AIDS patients with CMV colitis have a poorer long-term survival.
Among the colonoscopic findings, ulcerations with hemorrhagic background were the
most common lesions.
PMID- 10770897
TI - [Influence of socioeconomic conditions in the nutritional changes and at rest
metabolic rate in school children living in shantytowns of the city of Sao Paulo,
Brazil].
AB - PURPOSE: A cross-sectional study was carried out to characterize the alterations
in the resting metabolic rate (RMR), and socioeconomic conditions of 15 stunted
(DP= height/age < 95% and 110% (3) weight/height >90%) and 15 nonstunted (EU=
height/age > 95% and 110% (3) weight/height >90%) school girls living in
shantytowns of Sao Paulo. METHODS: Resting metabolic rate was measured using
indirect calorimetry. Socioeconomic data was collected during home visits by
administration of a questionnaire. RESULTS: The mildly stunted group had a higher
RMR when expressed as Kcal/kg body weight (EU= 40,5 Kcal/kg/day; DP=44,4
Kcal/kg/day; p<0.05) and lean body mass (EU= 49, 2 Kcal/kg/day; DP=52,5
Kcal/kg/day; p<0.05). Stunting was associated with maternal illiteracy (EU=
13,3%; DP=57,1%; p<0.05), income per capita (EU=US$107,14; DP=US$54,40; p< 0.05),
number of parasites per child (EU=0; DP=1; p<0.05), birth order (EU=2; DP=4; p<
0.05), and number of siblings (EU=4; DP=6; p<0.01). Stunting was best predicted
by income per capita and maternal illiteracy by using multiple logistic
regression. CONCLUSIONS: Although the two groups had normal weight/height, the
group with mild stunting showed socioeconomic and metabolic alterations, typical
of a malnourished condition.
PMID- 10770898
TI - [Respiratory morbidity in patients with and without pulmonary obstructive
syndrome after upper abdominal surgery].
AB - BACKGROUND: We wanted to determine the postoperative pulmonary complication after
upper abdominal surgery in patients with pulmonary obstrutive syndrome. METHODS:
We have studied 196 patients prospectively analyzed in preoperative period with
spirometry and followed for observation of PPC. The patients were divided in four
groups: COPD - those with chronic bronchitis or emphysema and VEF1/CVF< 70% (27
patients). ASMA - patients with obstruction of the airway in response to
provoking stimuli (44 patients). CHRONIC BRONCHITIS-EMPHYSEMA - those with the
clinical diagnoses of the respective diseases but VEF1/CVF > 70% (23 patients).
NORMAL - patients without pulmonary disease and normal spirometry (102 patients).
RESULTS: Postoperative pulmonary complication was recognized when the patient
presented atelectasis with clinical or gasometric alterations; bronchospasm that
needed bronchodilator therapy; respiratory failure; mechanical ventilation or
orotracheal intubation more than 48 hours in postsurgery period;
tracheobronchitis characterized by the presence of purulent sputum with normal x
ray; pneumonia. Patients with pulmonary obstruction had experienced higher rates
of pulmonary complications (32% vs 6%, p<0.05). The presence of obstructive lung
disease was associated with an increased number of ventilator days, but was not
associated with longer intensive care unit or hospital stay. CONCLUSIONS: The
incidence of postoperative pulmonary complications was strongly associated with
the presence of pulmonary obstructive syndrome.
PMID- 10770899
TI - [Hypoinsulinemia in alcoholics with minimal liver disease].
AB - The chronic pancreatitis (CP) may evolve with low insulin levels and develop
clinical picture of diabetes mellitus. Low seric levels of insulin and C peptide
after stimulus has also been described in asymptomatic alcoholics even with
normal glycemic curves. It is known that the chronic alcoholism is the main
etiological factor of CP and hepatic diseases, and that the insulin produced by
the pancreas is metabolized mainly by the liver. High levels of periferic insulin
are described in hepatic cirrhosis due to decrease of hepatic metabolization
alone or associated to increase of periferic resistance. AIM: In alcoholics with
minimal hepatic lesions to evaluate the seric insulin and glucose levels after
stimulus with intravenous glucose. METHODS: In 8 alcoholic patients with minimal
hepatic lesions characterized by hepatic biopsy, and 26 non-alcoholics, healthy
controls, it was studied the serum glucose and insulin levels in basal time, 1,
3, 5, and 10 minutes after stimulus with intravenous glucose (0.5 g/kg). RESULTS:
The insulin means in time 1, 3 minutes and total integrated response after
stimulus were lower (p < 0.05) in alcoholic group than in control, even with
normal glucose curves. CONCLUSION: Alcoholics with minimal hepatic lesions showed
low seric insulin levels after glucose stimulus, similar to former observations
in asymptomatic alcoholics, indicating hypofunction of pancreatic B cells.
PMID- 10770900
TI - [Development of a strategy to optimize the indications for the upper
gastrointestinal endoscopy in patients with dyspepsia at the primary care level].
AB - BACKGROUND: Although dyspepsia is a highly prevalent complaint, only a small
percentage of patients are found to have serious disease and to need full
investigation. The selection of dyspeptic patients who really need upper
gastrointestinal endoscopy (UGE) is crucial in order to avoid unnecessary costs
and overload services. MATERIAL AND METHODS: 200 primary care patients (age range
16-76 years) with dyspepsia and without any evidence of organic disease were
interviewed with a structured questionnaire, and afterwards they underwent UGE.
Multiple logistic regression analysis identified variables that could
discriminate individuals with abnormal UGE from individuals with normal UGE, as
well as individuals with peptic ulcer from individuals with normal UGE. RESULTS:
The variables to discriminate individuals with abnormal UGE from individuals with
normal UGE were age 45 years or above, and male sex, whereas to discriminate
individuals with peptic ulcer in UGE from individuals with normal UGE were age 45
years or above, male sex, smoking, fullness, and absenteeism. A practical model
based on these variables was developed, showing sensitivity of 78,9%, specificity
of 51,7%, positive predictive value (PPV) of 39,4 % and negative predictive value
(NPV) of 86% for the detection of individuals with UGE abnormal; and sensitivity
of 84%, specificity of 70%, PPV of 38% and NPV of 95% for the identification of
individuals with UGE identifying peptic ulcer. CONCLUSIONS: A strategy based on a
model containing clinical and social characteristics of dyspeptic patients could
potentially decrease the number of unnecessary UGEs.
PMID- 10770901
TI - [Complications of arterial catheterization in children].
AB - The radial artery catheterization with the purpose of children's monitoring has
been more and more used in Pediatric Intensive Care Units, and many times, is use
is indispensable, like in cardiac surgery post-operative cases. However, there
are only a few articles on the subject among us. PURPOSE: To analyse the
complications of radial artery catheterization in the post-operative of cardiac
surgery in children. METHODS: We studied the complications of this procedure in
120 children in cardiac surgery post-operative range from 1 month to 2 years. The
children were catheterized by percutaneous technique (n = 67) and by cutdown
technique (n = 53). The following complications were analysed in relation to the
placement time of the catheter and the used technique: local infection,
hemorrhagic complication, ischemia, catheter occlusion and accidental catheter
displacement. RESULTS: Infection, ischemia and hemorrhage were more frequent and
statistically significant in patients submitted to cutdown technique, while the
catheter occlusion and accidental displacement were similar in both groups. The
placement time of the catheter was an important variable in our study. All of the
other infection cases occurred after 72 hours of the catheterization and the
frequency of hemorrhage and ischemia was higher in the first 72 hours.
CONCLUSION: The main complications of this proceeding are related to the technic
utilized, time of utilization of the catheter and to the characteristics of the
patients.
PMID- 10770902
TI - [Education via the Internet: preliminary experience of the hematology-oncology
discipline of the ABC Foundation School of Medicine].
AB - BACKGROUND: In order to foster the use of the Internet by our medical students,
we devised a virtual test to be taken by the whole class during the Hematology
Oncology course given in the third year. MATERIAL AND METHODS: Through a
specially designed home page in the Internet students were asked questions
regarding their personal characteristics, knowledge of basic Internet skills and
were also given a short virtual course on line on the use of the Internet.
RESULTS: We noted that only 53% of our students had used the Internet before. The
use of the Internet was correlated with having more members of the household
accessing the net (p < 0.001) but not with the student's sex, age or family
income. CONCLUSION: Most of the students reacted favourably to this educational
experience through which about half of them got acquainted with the use of the
Internet for the first time.
PMID- 10770903
TI - [Mortality from sleep obstructive apnea].
PMID- 10770904
TI - [Importance of immunophenotyping of leukemia myelocytic acute].
PMID- 10770906
TI - [Process management and health quality certification].
PMID- 10770905
TI - [Pros and cons of the bone ultrasonography of calcaneus].
PMID- 10770907
TI - [Cervical perforating foreign body: case report].
AB - BACKGROUND: Neck perforations by foreign bodies are uncommon. The surgical
approach depends on the extension of visceral wounds and the development of
cervical or mediastinal infection. PURPOSE: The objective of this paper is to
report a neck perforation trauma by a piece of wire, with associated laryngeal
and hypopharyngeal wounds and extensive cervico-mediastinal emphysema. Anatomic
and clinical correlations are discussed, as well as the management of the case.
MATERIAL AND METHODS: A 28-year-old male patient suffered a perforating trauma in
his neck by a piece of wire. This foreign body was laid in the retropharyngeal
space, at the level of the sixth cervical vertebra, after perforating the larynx
and hypopharynx. There are no similar cases previously reported. The imaging
tests are presented. Despite the potential severity of the lesions, the patient
had a favorable outcome, and no surgical approach was necessary. CONCLUSIONS:
This case illustrates, by the imaging tests, the complex anatomy of the cervical
fasciae and deep neck spaces, and confirms the possibility of conservative
management in a great number of laryngeal and hypopharyngeal traumatic lesions.
PMID- 10770908
TI - [Accidental exposure to X-ray from a diffractometer].
AB - The patients's clinical pictures, characterized by an erythema preceding the skin
manifestations, their aspect and the occupational histories, made the diagnosis
of a radiation accident possible before its dosimetric identification. Doses
evaluations using thermoluminescence dosimeters and ionizing chambers correlated
well with the clinical estimations. The immediate cause of the accident was poor
maintenance of the device that caused its back window to be permanently open, but
lack of adequate information on the biological effects of ionizing radiation and
on the correct operational procedures were contributory facts. The description of
this accident is relevant in virtue of the misconception that such equipment have
"virtually no occupational risk". The patients's medical evolutions have had a
favorable course, specially because the low energy of the X-ray and its low
penetrating capacity. This accident highlights the need for the adequate training
of workers on the handling of radiation devices.
PMID- 10770909
TI - [Young's syndrome: recurrent respiratory tract infections and azoospermia].
AB - INTRODUCTION: Young's syndrome is part of primary ciliary dyskinesia,
characterized by repeated airway infections and congenital epididymis
obstruction. CASE REPORT: The authors present the case of a 28-year old male with
recurrent rhinosinusitis and pneumonia. Sweat and immunologic tests fell within
the normal range. Sperm analyses revealed absence of spermatozoa although
spermatogenesis was normal according to the findings in testis biopsy.
DISCUSSION: The final diagnosis was Young's syndrome the first case of the
disease reported in Brazilian literature. CONCLUSIONS: The authors emphasize the
need for appropriate diagnosis and genetic counselling as well as differential
diagnosis with cystic fibrosis in these cases.
PMID- 10770910
TI - Introduction to the 1999 USPHS/IDSA guidelines for the prevention of
opportunistic infections in persons infected with human immunodeficiency virus.
AB - Opportunistic infections (OIs) are well recognized to produce substantial
morbidity and mortality among patients with HIV infection. Since measures are
available for reducing the incidence and the impact of these processes for
patients, the United States Public Health Service and the Infectious Diseases
Society of America, with endorsing professional societies, have developed
guidelines for implementing a comprehensive strategy to prevent these OIs. These
guidelines have been developed by a diverse working group of expert health care
providers and patient representatives in order to synthesize available data and
to provide practical advice for health care practitioners and patients.
PMID- 10770911
TI - Epidemiology of human immunodeficiency virus-associated opportunistic infections
in the United States in the era of highly active antiretroviral therapy.
AB - The incidence of nearly all AIDS-defining opportunistic infections (OIs)
decreased significantly in the United States during 1992-1998; decreases in the
most common OIs (Pneumocystis carinii pneumonia ?PCP, esophageal candidiasis, and
disseminated Mycobacterium avium complex ?MAC disease) were more pronounced in
1996-1998, during which time highly active antiretroviral therapy (HAART) was
introduced into medical care. Those OIs that continue to occur do so at low CD4+
T lymphocyte counts, and persons whose CD4+ counts have increased in response to
HAART are at low risk for OIs, a circumstance that suggests a high degree of
immune reconstitution associated with HAART. PCP, the most common serious OI,
continues to occur primarily in persons not previously receiving medical care.
The most profound effect on survival of patients with AIDS is conferred by HAART,
but specific OI prevention measures (prophylaxis against PCP and MAC and
vaccination against Streptococcus pneumoniae) are associated with a survival
benefit, even when they coincide with the administration of HAART. Continued
monitoring of incidence trends and detection of new syndromes associated with
HAART are important priorities in the HAART era.
PMID- 10770912
TI - An overview of the 1999 US Public Health Service/Infectious Diseases Society of
America guidelines for preventing opportunistic infections in human
immunodeficiency virus-infected persons.
PMID- 10770913
TI - 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in
persons infected with human immunodeficiency virus.
PMID- 10770914
TI - Discontinuing prophylaxis for opportunistic infection: guiding principles.
AB - Several large observational studies have documented the reduced risk of
opportunistic infections among recipients of potent combination antiretroviral
therapy. These data raise the question of whether subjects who respond to
antiretroviral therapy need to continue prophylaxis for opportunistic infection.
Factors to consider when deciding whether it is safe to discontinue prophylaxis
include the following: (1) the risk of developing the specific opportunistic
infection; (2) the consequences of the infection (morbidity and availability of
effective therapy); (3) both the short-term and long-term toxicity of the agent
used for prophylaxis; (4) the potential for drug interactions between the agent
used for prophylaxis and other therapies for human immunodeficiency virus
infection; (5) the psychological benefit of discontinuing a treatment during the
course of a chronic disease; (6) the risk of development of drug resistance
during prophylaxis; and (7) costs. This article reviews current data on
predicting risk of opportunistic infection, the most critical of these factors.
PMID- 10770915
TI - Human herpesvirus 8 and Kaposi's sarcoma in persons infected with human
immunodeficiency virus.
AB - Human herpesvirus 8 (HHV-8) was detected in 1994 in biopsies of Kaposi's sarcoma
(KS) tissues from a patient with AIDS. The evidence that HHV-8 infection is
etiologically related to the development of KS is compelling. Essentially all
patients with KS of any epidemiological type have serological evidence of HHV-8
infection. About 30%-40% of homosexual men infected with human immunodeficiency
virus (HIV) are seropositive for HHV-8; rates are lower (<10%) among HIV-infected
women, hemophiliacs, and injection drug users. Among homosexual men, the
probability of HHV-8-seropositivity is directly proportional to the numbers of
previous male sex partners, which suggets that HHV-8 is a sexually transmitted
infection. Although HHV-8 is detectable in saliva and semen, the exact mechanism
of transmission is not known. A reduction in KS incidence among patients with
AIDS in the 1980s has been attributed to lower rates of HHV-8 transmission that
resulted from alterations in sexual behaviors. A further decline in KS incidence
has been associated with the use of antiretroviral therapy. Antiretroviral
therapy to control HIV replication and to limit the associated immunodeficiency
is currently the best approach for preventing KS in persons infected with HHV-8
and HIV.
PMID- 10770916
TI - Hepatitis C virus infection as an opportunistic disease in persons infected with
human immunodeficiency virus.
AB - Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major
cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to
shared routes of transmission, HCV and human immunodeficiency virus (HIV)
coinfection are common, affecting approximately one-third of all HIV-infected
persons in the United States. In addition, HIV coinfection is associated with
higher HCV RNA level and a more rapid progression of HCV-related liver disease,
which leads to an increased risk of cirrhosis. HCV infection may also impact the
course and management of HIV disease, particularly by increasing the risk of
antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as
an opportunistic disease in HIV-infected persons, because the incidence of
infection is increased and the natural history of HCV infection is accelerated in
coinfected persons. Strategies to prevent primary HCV infection and to modify the
progression of HCV-related liver disease are urgently needed for HIV-HCV
coinfected individuals.
PMID- 10770917
TI - Performance measures for guidelines on preventing opportunistic infections in
patients infected with human immunodeficiency virus.
AB - This article serves as a complement to the 1999 US Public Health
Service/Infectious Diseases Society of America guidelines on the prevention of
opportunistic infections in persons infected with HIV, published in this issue of
Clinical Infectious Diseases [1]. A number of performance measures to assess
compliance with the guidelines and to aid in their implementation are proposed.
PMID- 10770918
TI - Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species.
AB - The ubiquitously expressed c-Abl protein tyrosine kinase localizes to both the
nucleus and cytoplasm. The nuclear form of c-Abl is activated in the cellular
response to genotoxic stress. Here we show that cytoplasmic c-Abl is activated by
oxidative stress. The results also demonstrate that mitochondrial cytochrome c is
released in the cellular response to H(2)O(2) and that this effect is mediated by
a c-Abl-dependent mechanism. In concert with these results, we show that H(2)O(2)
induced apoptosis is attenuated in c-Abl-deficient cells. These findings
demonstrate that cytoplasmic c-Abl is involved in the apoptotic response of cells
to oxidative stress.
PMID- 10770919
TI - Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation
and suppress human tumor growth in nude mice.
AB - Whereas the GTPase RhoA has been shown to promote proliferation and malignant
transformation, the involvement of RhoB in these processes is not well
understood. In this manuscript RhoB is shown to be a potent suppressor of
transformation and human tumor growth in nude mice. In several human cancer cell
lines, RhoA promotes focus formation whereas RhoB is as potent as the tumor
suppressor p53 at inhibiting transformation in this assay. RhoB is both
farnesylated (F) and geranylgeranylated (GG), and RhoB-F has been suggested as a
target for the antitumor activity of farnesyltransferase inhibitors. Here we
demonstrate that both RhoB-F and RhoB-GG inhibit anchorage-dependent and
independent growth, induce apoptosis, inhibit constitutive activation of Erk and
insulin-like growth factor-1 stimulation of Akt, and suppress tumor growth in
nude mice. The data demonstrate that RhoB is a potent suppressor of human tumor
growth and that RhoB-F is not a target for farnesyltransferase inhibitors.
PMID- 10770920
TI - Evidence that collapsin response mediator protein-2 is involved in the dynamics
of microtubules.
AB - Collapsin response mediator protein-2 (CRMP-2) is a member of the
CRMP/TOAD/Ulip/DRP family of cytosolic phosphoproteins involved in neuronal
differentiation and axonal guidance. CRMP-2 mediates the intracellular response
to collapsin 1/semaphorin 3A, a repulsive extracellular guidance cue for axonal
outgrowth. The mutation of UNC-33, a Caenorhabditis elegans homolog of CRMP-2,
results in abnormality of microtubules in neurites, but the mechanism of CRMP-2
action remains to be clarified. Here, we report that overexpression of human CRMP
2 in Neuro2a cells, a mouse neuroblastoma cell line, results in blebbing of the
cytoplasm. Furthermore, some cells exhibited intranuclear inclusions, which were
labeled with antibodies to CRMP-2 and tubulin. CRMP-2 was found to be associated
with microtubule bundles in the spindles at the metaphase and in the midbodies at
the late telophase in mitotic cells. Thus, it is most likely that failure of
complete disassembly of the spindle microtubules during mitosis is responsible
for the formation of these intranuclear inclusions. We suggest that CRMP-2
functions by regulating the dynamics of microtubules.
PMID- 10770921
TI - Chitin-binding proteins in invertebrates and plants comprise a common chitin
binding structural motif.
AB - Tachycitin, a 73-residue polypeptide having antimicrobial activity is present in
the hemocyte of horseshoe crab (Tachypleus tridentatus). The first three
dimensional structure of invertebrate chitin-binding protein was determined for
tachycitin using two-dimensional nuclear magnetic resonance spectroscopy. The
measurements indicate that the structure of tachycitin is largely divided into N-
and C-terminal domains; the former comprises a three-stranded beta-sheet and the
latter a two-stranded beta-sheet following a short helical turn. The latter
structural motif shares a significant tertiary structural similarity with the
chitin-binding domain of plant chitin-binding protein. This result is thought to
provide faithful experimental evidence to the recent hypothesis that chitin
binding proteins of invertebrates and plants are correlated by a convergent
evolution process.
PMID- 10770922
TI - The gene encoding the T-box factor Tbx2 is a target for the microphthalmia
associated transcription factor in melanocytes.
AB - Commitment to the melanocyte lineage is characterized by the onset of
microphthalmia-associated transcription factor (Mitf) expression. Mitf plays a
fundamental role in melanocyte development, with mice lacking Mitf being entirely
devoid of pigment cells. In the absence of functional Mitf protein, melanoblasts
expressing Mitf mRNA disappear around 2 days after their first appearance either
by apoptosis or by losing their identity and adopting an alternative cell fate.
The role of Mitf must therefore be to regulate genes required for melanoblast
survival, proliferation, or the maintenance of melanoblast identity. Yet to date,
Mitf has been shown to regulate genes such as Tyrosinase, Tyrp-1, and Dct, which
are required for pigmentation, a differentiation-specific process. Because
expression of these genes cannot account for the complete absence of pigment
cells in Mitf-negative mice, Mitf must regulate the expression of other as yet
uncharacterized genes. Here we provide several lines of evidence to suggest that
Mitf may regulate the expression of the Tbx2 transcription factor, a member of
the T-box family of proteins implicated in the maintenance of cell identity.
First, isolation and sequencing of the entire murine Tbx2 gene revealed that the
Tbx2 promoter contains a full consensus Mitf recognition element; second, Mitf
could bind the promoter in vitro and activate Tbx2 expression in vivo in an E box
dependent fashion; and third, Tbx2 is expressed in melanoma cell lines expressing
Mitf, but not in a line in which Mitf expression was not detectable. Taken
together, with the fact that Tbx2 is expressed in Mitf-positive melanoblasts and
melanocytes, but not in Mitf-negative melanoblast precursor cells, the evidence
suggests that the Tbx2 gene may represent one of the first known targets for Mitf
that is not a gene involved directly in the manufacture of pigment.
PMID- 10770923
TI - Protein splicing in the absence of an intein penultimate histidine.
AB - Protein splicing is a self-catalytic process in which an intervening sequence,
termed an intein, is excised from a protein precursor, and the flanking
polypeptides are religated. The conserved intein penultimate His facilitates this
reaction by assisting in Asn cyclization, which results in C-terminal splice
junction cleavage. However, many inteins do not have a penultimate His. Previous
splicing studies with 2 such inteins yielded contradictory results. To resolve
this issue, the splicing capacity of 2 more inteins without penultimate His
residues was examined. Both the Methanococcus jannaschii phosphoenolpyruvate
synthase and RNA polymerase subunit A' inteins spliced. Splicing of the
phosphoenolpyruvate synthase intein improved when its penultimate Phe was changed
to His, but splicing of the RNA polymerase subunit A' intein was inhibited when
its penultimate Gly was changed to His. We propose that inteins lacking a
penultimate His (i) arose by mutation from ancestors in which a penultimate His
facilitated splicing, (ii) that loss of this His inhibited, but may not have
blocked, splicing, and (iii) that selective pressure for efficient expression of
the RNA polymerase yielded an intein that utilizes another residue to assist Asn
cyclization, changing the intein active site so that a penultimate His now
inhibits splicing.
PMID- 10770924
TI - Signaling states of rhodopsin. Retinal provides a scaffold for activating proton
transfer switches.
AB - The G-protein-coupled receptor rhodopsin is activated by photoconversion of its
covalently bound ligand 11-cis-retinal to the agonist all-trans-retinal. After
light-induced isomerization and early photointermediates, the receptor reaches a
G-protein-dependent equilibrium between active and inactive conformations
distinguished by the protonation of key opsin residues. In this report, we study
the role of the 9-methyl group of retinal, one of the crucial steric determinants
of light activation. We find that when this group is removed, the protonation
equilibrium is strongly shifted to the inactive conformation. The residually
formed active species is very similar to the active form of normal rhodopsin,
metarhodopsin II. It has a deprotonated Schiff base, binds to the retinal G
protein transducin, and is favored at acidic pH. Our data show that the normal
proton transfer reactions are inhibited in 9-demethyl rhodopsin but are still
mandatory for receptor activation. We propose that retinal and its 9-methyl group
act as a scaffold for opsin to adjust key proton donor and acceptor side chains
for the proton transfer reactions that stabilize the active conformation. The
mechanism may also be applicable to related receptors and may thus explain the
partial agonism of certain ligands.
PMID- 10770925
TI - Identification of the binding site for a novel class of CCR2b chemokine receptor
antagonists: binding to a common chemokine receptor motif within the helical
bundle.
AB - Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory
sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the
MCP-1 receptor, CCR2, a member of the G-protein-coupled seven-transmembrane
receptor superfamily. These studies identified a family of antagonists,
spiropiperidines. One of the more potent compounds blocks MCP-1 binding to CCR2
with a K(d) of 60 nm, but it is unable to block binding to CXCR1, CCR1, or CCR3.
These compounds were effective inhibitors of chemotaxis toward MCP-1 but were
very poor inhibitors of CCR1-mediated chemotaxis. The compounds are effective
blockers of MCP-1-driven inhibition of adenylate cyclase and MCP-1- and MCP-3
driven cytosolic calcium influx; the compounds are not agonists for these
pathways. We showed that glutamate 291 (Glu(291)) of CCR2 is a critical residue
for high affinity binding and that this residue contributes little to MCP-1
binding to CCR2. The basic nitrogen present in the spiropiperidine compounds may
be the interaction partner for Glu(291), because the basicity of this nitrogen
was essential for affinity; furthermore, a different class of antagonists, a
class that does not have a basic nitrogen (2-carboxypyrroles), were not affected
by mutations of Glu(291). In addition to the CCR2 receptor, spiropiperidine
compounds have affinity for several biogenic amine receptors. Receptor models
indicate that the acidic residue, Glu(291), from transmembrane-7 of CCR2 is in a
position similar to the acidic residue contributed from transmembrane-3 of
biogenic amine receptors, which may account for the shared affinity of
spiropiperidines for these two receptor classes. The models suggest that the acid
base pair, Glu(291) to piperidine nitrogen, anchors the spiropiperidine compound
within the transmembrane ovoid bundle. This binding site may overlap with the
space required by MCP-1 during binding and signaling; thus the small molecule
ligands act as antagonists. An acidic residue in transmembrane region 7 is found
in most chemokine receptors and is rare in other serpentine receptors. The model
of the binding site may suggest ways to make new small molecule chemokine
receptor antagonists, and it may rationalize the design of more potent and
selective antagonists.
PMID- 10770926
TI - Isolation and characterization of various complexes of the minichromosome
maintenance proteins of Schizosaccharomyces pombe.
AB - Minichromosome maintenance (Mcm) proteins 2-7 are highly conserved in eukaryotes
and play an essential role in DNA replication. Here, we describe the
reconstitution of the various complexes of the Mcm proteins of
Schizosaccharomyces pombe using the baculovirus expression system. The
simultaneous expression of all six of the Mcm proteins, as well as different
combinations of these proteins, yielded several stable complexes that included
the heterohexamer of Mcm2/3/4/5/6/7, the Mcm2/4/6/7 heterotetramer, the dimer of
the Mcm4/6/7 heterotrimer, and the Mcm3/5 heterodimer. The purification and
characterization of the biochemical properties of these complexes showed that
only the dimeric complex of the Mcm4/6/7 heterotrimer possessed single stranded
DNA-dependent ATPase, ATP-dependent single stranded DNA binding, and 3' to 5' DNA
helicase activities. Consistent with these results, the interaction of either
Mcm2 or Mcm3/5 with the Mcm4/6/7 complex resulted in the disassembly of the
dimeric complex of Mcm4/6/7 and the loss of DNA helicase activity. These results
suggest that the Mcm4/6/7 complex is a catalytic core of the Mcm complex and that
Mcm2 and Mcm3/5 may be involved in the regulation of the activity of this
complex.
PMID- 10770927
TI - Thermodynamic and functional characterization of protein W from bacteriophage
lambda. The three C-terminal residues are critical for activity.
AB - Gene product W (gpW), the head-tail joining protein from bacteriophage lambda,
provides a fascinating model for studying protein interactions. Composed of only
68 residues, it must interact with at least two other proteins in the phage, and
probably with DNA. To study the structural and functional properties of gpW,
plasmids were constructed expressing gpW with hexahistidine tag sequences at
either the N or C terminus. The purified wild type fusion proteins were found to
be stably folded and biologically active. The protein is monomeric as judged by
equilibrium ultracentrifugation, and appears to unfold by a cooperative two-state
mechanism. Circular dichroism studies indicate that the protein is 47% helical,
with a T(m) of 71.3 degrees C, and a DeltaG(u) of 3.01 kcal/mol at 25 degrees C.
Mutagenesis of the three hydrophobic C-terminal residues of gpW showed that they
are critical for activity, even though they do not contribute to the
thermodynamic stability of the protein. Using secondary structure prediction as a
guide, we also designed destabilized gpW mutants. The hydrophobic nature of the
gpW C terminus caused these mutants to be degraded by the ClpP-containing
proteases in Escherichia coli.
PMID- 10770928
TI - Ethanol and arachidonic acid increase alpha 2(I) collagen expression in rat
hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and
cyclooxygenase-2.
AB - The ability of ethanol and arachidonic acid (AA), as inducers of oxidative stress
and key factors in alcoholic liver disease, to up-regulate alpha 2 collagen type
I (COL1A2) gene expression was studied in a hepatic stellate cell line
overexpressing the ethanol-inducible cytochrome P450 2E1 (CYP2E1) (E5 cells). A
time- and dose-dependent induction in COL1A2 mRNA by ethanol or AA was observed
that was prevented by diallylsulfide, a CYP2E1 inhibitor. Nuclear run-on
experiments showed transcriptional activation of the COL1A2 gene by ethanol and
AA. Catalase abrogated the increase in COL1A2 mRNA suggesting an H(2)O(2)
dependent mechanism. Cyclooxygenase-2 (COX-2) levels and production of
prostaglandin E(2) upon addition of AA were elevated in the E5 cells. Incubation
with NS-398, a COX-2 inhibitor, blocked the effect of AA, but not of ethanol, on
COL1A2 expression suggesting that CYP2E1 activates COX-2 expression, and the
oxidation of AA by COX-2 is responsible for the increase in COL1A2. Activity of a
reporter construct driven by -378 base pairs of the proximal promoter region of
the COL1A2 gene increased in E5 but not control cells and was further increased
by ethanol or AA. These experiments link CYP2E1-dependent oxidative stress to
induction of COX-2 and the actions of ethanol and AA on activation of collagen
gene expression in hepatic stellate cells.
PMID- 10770929
TI - Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate
formation in neuronal and nonneuronal cells.
AB - Huntington's disease is a neurodegenerative disorder caused by CAG expansion that
results in expansion of a polyglutamine tract at the extreme N terminus of
huntingtin (htt). htt with polyglutamine expansion is proapoptotic in different
cell types. Here, we show that caspase inhibitors diminish the toxicity of htt.
Additionally, we define htt itself as an important caspase substrate by
generating a site-directed htt mutant that is resistant to caspase-3 cleavage at
positions 513 and 530 and to caspase-6 cleavage at position 586. In contrast to
cleavable htt, caspase-resistant htt with an expanded polyglutamine tract has
reduced toxicity in apoptotically stressed neuronal and nonneuronal cells and
forms aggregates at a much reduced frequency. These results suggest that
inhibiting caspase cleavage of htt may therefore be of potential therapeutic
benefit in Huntington's disease.
PMID- 10770930
TI - Maize cap1 encodes a novel SERCA-type calcium-ATPase with a calmodulin-binding
domain.
AB - A cDNA (CAP1) isolated from maize roots shares sequence identity with genes
encoding P-type Ca(2+)-ATPases and restores the growth phenotype of yeast mutants
defective in Ca(2+)-pumps. CAP1 was transcribed and translated in the yeast
mutant. Furthermore, the membrane-integrated product formed a Ca(2+)-dependent
phosphorylated intermediate and supported Ca(2+) transport. Although CAP1 shares
greater sequence identity with mammalian "endoplasmic reticulum-type" Ca(2+)
pumps, it differs from these genes by having features of calmodulin (CaM)
regulated Ca(2+)-pumps. CAP1 from yeast microsomes bound CaM, and the CAP1
dependent Ca(2+) transport in yeast was stimulated by CaM. Peptides from the C
terminus of CAP1 bound CaM. Anti-CAP1 antibodies specifically recognized a maize
microsomal polypeptide that also bound CaM. A similar polypeptide also formed a
Ca(2+)-dependent phosphoenzyme. Our results suggest that cap1 encodes a novel
form of CaM-regulated Ca(2+)-ATPase in maize. CAP1 appears to be encoded by one
or two genes in maize. CAP1 RNA is induced only during early anoxia, indicating
that the Ca(2+)-pump may play an important role in O(2)-deprived maize cells.
PMID- 10770931
TI - Pregnancy-associated changes in the glycosylation of tamm-horsfall glycoprotein.
Expression of sialyl Lewis(x) sequences on core 2 type O-glycans derived from
uromodulin.
AB - Tamm-Horsfall glycoprotein (THP) is a major glycoprotein associated with human
urine that binds pro-inflammatory cytokines and also inhibits in vitro T cell
proliferation induced by specific antigens. THP derived from human pregnancy
urine (designated uromodulin) has previously been shown to be 13-fold more
effective as an inhibitor of antigen-induced T cell proliferation than THP
obtained from other sources. Structural analysis of human THP and uromodulin has
for the first time revealed that these glycoproteins are O-glycosylated. THP from
nonpregnant females and males expresses primarily core 1 type O-glycans
terminated with either sialic acid or fucose but not the sialyl Lewis(x) epitope.
By contrast, the O-glycans linked to uromodulin include unusual core 2 type
glycans terminated with one, two, or three sialyl Lewis(x) sequences. The
specific association of these unusual carbohydrate sequences with uromodulin
could explain its enhanced immunomodulatory effects compared with THP obtained
from males and nonpregnant females. Analysis of THP from one of the pregnant
females 2 months postpartum showed a reversion of the O-glycan profile to that
found for a non-pregnant female. These data suggest that the glycosylation state
of uromodulin could be under the regulation of steroidal hormones produced during
pregnancy. The significant physiological implications of these observations are
discussed.
PMID- 10770932
TI - Negative growth regulation of SK-N-MC cells by bFGF defines a growth factor
sensitive point in G2.
AB - Basic fibroblast growth factor (bFGF) has been shown to induce growth inhibition
of the neuroepithelioma cell line SK-N-MC. Here we show that this growth
inhibition occurs in G(2). We show that bFGF is active on these cells during S
and early G(2) phase. Therefore, this constitutes a rather unusual mechanism of
growth inhibition, because it is generally believed that cells become refractory
to extracellular signals after passage through the restriction point. We show
that bFGF treatment inhibits Tyr-15 dephosphorylation of cdc2 and prevents
activation of Cdc25C, similar to what is seen upon activation of the G(2) DNA
damage checkpoint. Interestingly, both DNA damage- and bFGF-induced effects on
cdc2 phosphorylation are reverted by caffeine. To confirm the involvement of
similar pathways induced by bFGF and DNA damage, we generated tetracycline
regulatable SK-N-MC clones expressing Cdc25C-S216A. Expression of this Cdc25C
mutant can revert the bFGF-induced effects on cdc2 phosphorylation and can rescue
cells from the block in G(2) imposed by bFGF. Taken together, these data define a
growth factor-sensitive point in G(2) that most likely involves regulation of
Cdc25C phosphorylation.
PMID- 10770933
TI - Embryonic striatal neurons from niemann-pick type C mice exhibit defects in
cholesterol metabolism and neurotrophin responsiveness.
AB - Niemann-Pick type C (NP-C) disease is a progressive and fatal neuropathological
disorder previously characterized by abnormal cholesterol metabolism in
peripheral tissues. Although a defective gene has been identified in both humans
and the npc(nih) mouse model of NP-C disease, how this leads to abnormal neuronal
function is unclear. Here we show that whereas embryonic striatal neurons from
npc(nih) mice can take up low density lipoprotein-derived cholesterol, its
subsequent hydrolysis and esterification are significantly reduced. Given the
importance of cholesterol to a variety of signal transduction mechanisms, we
assessed the effect of this abnormality on the ability of these neurons to
respond to brain-derived neurotrophic factor (BDNF). In contrast to its effects
on wild type neurons, BDNF failed to induce autophosphorylation of the TrkB
receptor and to increase neurite outgrowth in npc(nih) neurons, despite
expression of TrkB on the cell surface. The results suggest that abnormal
cholesterol metabolism occurs in neurons in the brain during NP-C disease, even
at embryonic stages of development prior to the onset of phenotypic symptoms.
Moreover, this defect is associated with a lack of TrkB function and BDNF
responsiveness, which may contribute to the loss of neuronal function observed in
NP-C disease.
PMID- 10770934
TI - Characterization of a new electrophoretically silent hemoglobin variant. Hb saale
OR alpha 2beta 2 84(EF8)Thr --> Ala.
AB - A new abnormal hemoglobin was detected in a young German anemic patient by cation
exchange high performance liquid chromatography (HPLC). Using a combination of
electrospray mass spectrometry, HPLC, direct sequencing, and family screening
with polymerase chain reaction/restriction digestion approach, we have
characterized this hemoglobin variant as resulting from a Thr --> Ala replacement
at beta84(EF8). It could be separated neither by electrophoresis nor by
isoelectric focusing. Hb Saale is slightly unstable, exhibiting a moderate
tendency to auto-oxidize. Functional properties and the heterotropic interactions
are similar to those of Hb A.
PMID- 10770935
TI - Functional interactions between the estrogen receptor and DRIP205, a subunit of
the heteromeric DRIP coactivator complex.
AB - Nuclear receptors regulate transcription in direct response to their cognate
hormonal ligands. Ligand binding leads to the dissociation of corepressors and
the recruitment of coactivators. Many of these factors, acting in large
complexes, have emerged as potential chromatin remodelers through intrinsic
histone modifying activities. In addition, other ligand-recruited complexes
appear to act more directly on the transcriptional apparatus. The DRIP complex is
a 15-subunit complex required for nuclear receptor transcriptional activation in
vitro. It is recruited to the receptor in response to ligand through specific
interactions of one subunit, DRIP205. We present evidence that DRIP205 interacts
with another member of the steroid receptor subfamily, estrogen receptor (ER).
This interaction occurs in an agonist-stimulated fashion which in turn is
inhibited by several ER antagonists. In vivo, a fragment of DRIP205 containing
only its receptor interacting region acts to selectively inhibit ER's ability to
activate transcription in response to estradiol. These observations suggest a key
role for the DRIP coactivator complex in estrogen-ER signaling.
PMID- 10770936
TI - The crystal structure of phosphoglucose isomerase/autocrine motility
factor/neuroleukin complexed with its carbohydrate phosphate inhibitors suggests
its substrate/receptor recognition.
AB - Phosphoglucose isomerase catalyzes the reversible isomerization of glucose 6
phosphate to fructose 6-phosphate. In addition, phosphoglucose isomerase has been
shown to have functions equivalent to neuroleukin, autocrine motility factor, and
maturation factor. Here we present the crystal structures of phosphoglucose
isomerase complexed with 5-phospho-D-arabinonate and N-bromoacetylethanolamine
phosphate at 2.5- and 2.3-A resolution, respectively. The inhibitors bind to a
region within the domains' interface and interact with a histidine residue
(His(306)) from the other subunit. We also demonstrated that the inhibitors not
only affect the enzymatic activity of phosphoglucose isomerase, but can also
inhibit the autocrine motility factor-induced cell motility of CT-26 mouse colon
tumor cells. These results indicate that the substrate and the receptor binding
sites of phosphoglucose isomerase and autocrine motility factor are located
within close proximity to each other. Based on these two complex structures,
together with biological and biochemical results, we propose a possible
isomerization mechanism for phosphoglucose isomerase.
PMID- 10770937
TI - Direct transactivation of the anti-apoptotic gene apolipoprotein J (clusterin) by
B-MYB.
AB - B-MYB is a ubiquitously expressed transcription factor involved in the regulation
of cell survival, proliferation, and differentiation. In an attempt to isolate B
MYB-regulated genes that may explain the role of B-MYB in cellular processes,
representational difference analysis was performed in neuroblastoma cell lines
with different levels of B-MYB expression. One of the genes, the mRNA levels of
which were enhanced in B-MYB expressing cells, was ApoJ/Clusterin(SGP-2/TRMP-2)
(ApoJ/Clusterin), previously implicated in regulation of apoptosis and tumor
progression. Here we show that the human ApoJ/Clusterin gene contains a Myb
binding site in its 5' flanking region, which interacts with bacterially
synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the
ApoJ/Clusterin promoter in transient transfection assays. Endogenous
ApoJ/Clusterin expression is induced in mammalian cell lines following transient
transfection of a B-MYB cDNA. Blockage of secreted clusterin by a monoclonal
antibody results in increased apoptosis of neuroblastoma cells exposed to the
chemotherapeutic drug doxorubicin. Thus, activation of ApoJ/Clusterin by B-MYB
may be an important step in the regulation of apoptosis in normal and diseased
cells.
PMID- 10770938
TI - In mouse alpha -methylacyl-CoA racemase, the same gene product is simultaneously
located in mitochondria and peroxisomes.
AB - alpha-Methylacyl-CoA racemase, an enzyme of the bile acid biosynthesis and
branched chain fatty acid degradation pathway, was studied at the protein, cDNA,
and genomic levels in mouse liver. Immunoelectron microscopy and subcellular
fractionation located racemase to mitochondria and peroxisomes. The enzymes were
purified from both organelles with immunoaffinity chromatography. The isolated
proteins were of the same size, with identical N-terminal amino acid sequences,
and the existence of additional proteins with alpha-methylacyl-CoA racemase
activity was excluded. A racemase gene of about 15 kilobases was isolated.
Southern blot analysis and chromosomal localization showed that only one racemase
gene is present, on chromosome 15, region 15B1. The putative initial ATG in the
racemase gene was preceded by a functional promotor as shown with the luciferase
reporter gene assay. The corresponding cDNAs were isolated from rat and mouse
liver. The recombinant rat protein was overexpressed in active form in Pichia
pastoris. The presented data suggest that the polypeptide encoded by the racemase
gene can alternatively be targeted to peroxisomes or mitochondria without
modifications. It is concluded that the noncleavable N-terminal sequence of the
polypeptide acts as a weak mitochondrial and that the C-terminal sequence acts as
a peroxisomal targeting signal.
PMID- 10770939
TI - Alkaline proteinase inhibitor of Pseudomonas aeruginosa. Interaction of native
and N-terminally truncated inhibitor proteins with Pseudomonas
metalloproteinases.
AB - The apr locus of Pseudomonas aeruginosa encodes alkaline proteinase (APR), a
member of the metzincin metalloendopeptidase superfamily, and an 11.4-kDa
alkaline proteinase inhibitor (APRin). We describe here the expression in
Escherichia coli and characterization of full-length and N-terminally truncated
APRin proteins. Fluorescence and circular dichroism spectra indicated that the
recombinant proteins were folded into native-like structures. Analytical
ultracentrifugation showed that APRin was monomeric and formed a 1:1 complex with
APR. Binding of wild-type APRin to APR occurred with association (k(on)) and
dissociation (k(off)) rate constants of 0.29 +/- 0.06 x 10(6) m(-1) s(-1) and
1.15 +/- 0.08 x 10(-6) s(-1) to give an equilibrium dissociation constant (K(D))
of approximately 4 x 10(-12) m (25 degrees C, pH 7.0, ionic strength 2.4 m). The
association rate decreased by approximately 2-fold in 20% glycerol and increased
by approximately 3-fold in 0.1 m NaCl. The glycerol effect suggests a diffusion
limited reaction, and the small salt effect indicates that electrostatic
interactions contribute little to binding. Deletion of residues 1-10, 1-6, or 6
10 abolished inhibition, and deletion of residues 1-2, 1-3, 1-4, and 1-5 resulted
in a progressively decreased affinity of APRin for APR (K(D) = 0.12 micrometer
the Delta(1-5) mutant). Substitution of APRin residues 6-10 with a (Gly)(5) or
(Pro)(5) linker restored inhibitory activity of the Delta(6-10) mutant but with a
100- and 50-fold reduction in K(D). Log k(on) for the full-length and truncated
inhibitors correlated with the solvent-accessible surface area of their N
terminal regions, suggesting that increased interactions and/or desolvation of
these residues in the transition state for binding contribute to the enhanced
association rate. Treatment of APRin with pseudolysin, also secreted by P.
aeruginosa, resulted in removal of residues 1-5. APRin was neither an inhibitor
nor a substrate of other metzincins, including collagenase or gelatinases A or B.
PMID- 10770940
TI - Two distinct binding affinities of poliovirus for its cellular receptor.
AB - To study the kinetics and equilibrium of poliovirus binding to the poliovirus
receptor, we used surface plasmon resonance to examine the interaction of a
soluble form of the receptor with poliovirus. Soluble receptor purified from
mammalian cells is able to bind poliovirus, neutralize viral infectivity, and
induce structural changes in the virus particle. Binding studies revealed that
there are two binding sites for the receptor on the poliovirus type 1 capsid,
with affinity constants at 20 degrees C of K(D)(1) = 0.67 microm and K(D)(2) =
0.11 microm. The relative abundance of the two binding sites varies with
temperature. At 20 degrees C, the K(D)(2) site constitutes approximately 46% of
the total binding sites on the sensor chip, and its relative abundance decreased
with decreasing temperature such that at 5 degrees C, the relative abundance of
the K(D)(2) site is only 12% of the total binding sites. Absolute levels of the
K(D)(1) site remained relatively constant at all temperatures tested. The two
binding sites may correspond to docking sites for domain 1 of the receptor on the
viral capsid, as predicted by a model of the poliovirus-receptor complex.
Alternatively, the binding sites may be a consequence of structural breathing, or
could result from receptor-induced conformational changes in the virus.
PMID- 10770941
TI - Regulatory mechanism of Ca2+/calmodulin-dependent protein kinase kinase.
AB - Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of
the CaM kinase family, which specifically phosphorylates and activates CaM kinase
I and IV. In this study, we characterized the CaM-binding peptide of alphaCaM-KK
(residues 438-463), which suppressed the activity of constitutively active CaM-KK
(84-434) in the absence of Ca(2+)/CaM but competitively with ATP. Truncation and
site-directed mutagenesis of the CaM-binding region in CaM-KK reveal that
Ile(441) is essential for autoinhibition of CaM-KK. Furthermore, CaM-KK chimera
mutants containing the CaM-binding sequence of either myosin light chain kinases
or CaM kinase II located C-terminal of Leu(440), exhibited enhanced Ca(2+)/CaM
independent activity (60% of total activity). Although the CaM-binding domains of
myosin light chain kinases and CaM kinase II bind to the N- and C-terminal
domains of CaM in the opposite orientation to CaM-KK (Osawa, M., Tokumitsu, H.,
Swindells, M. B., Kurihara, H., Orita, M., Shibanuma, T., Furuya, T., and Ikura,
M. (1999) Nat. Struct. Biol. 6, 819-824), the chimeric CaM-KKs containing
Ile(441) remained Ca(2+)/CaM-dependent. This result demonstrates that the
orientation of the CaM binding is not critical for relief of CaM-KK
autoinhibition. However, the requirement of Ile(441) for autoinhibition, which is
located at the -3 position from the N-terminal anchoring residue (Trp(444)) to
CaM, accounts for the opposite orientation of CaM binding of CaM-KK compared with
other CaM kinases.
PMID- 10770942
TI - Chimeric melatonin mt1 and melatonin-related receptors. Identification of domains
and residues participating in ligand binding and receptor activation of the
melatonin mt1 receptor.
AB - Melatonin receptors bind and become activated by melatonin. The melatonin-related
receptor, despite sharing considerable amino acid sequence identity with
melatonin receptors, does not bind melatonin and is currently an orphan G protein
coupled receptor. To investigate the structure and function of both receptors, we
engineered a series of 14 chimeric receptor constructs, allowing us to determine
the relative contribution of each transmembrane domain to ligand binding and
receptor function. Results identified that when sequences encoding transmembrane
domains 1, 2, 3, 5, or 7 of the melatonin mt(1) receptor were replaced by the
corresponding domains of the melatonin-related receptor, the resultant chimeric
receptors all displayed specific 2-[(125)I]iodomelatonin binding. Replacement of
sequences incorporating transmembrane domains 4 or 6, however, resulted in
chimeric receptors that displayed no detectable 2-[(125)I]iodomelatonin binding.
The subsequent testing of a "reverse" chimeric receptor in which sequences
encoding transmembrane domains 4 and 6 of the melatonin-related receptor were
replaced by the corresponding melatonin mt(1) receptor sequences identified
specific 2-[(125)I]iodomelatonin binding and melatonin-mediated modulation of
cyclic AMP levels. To further investigate these findings, site-directed
mutagenesis was performed on residues within transmembrane domain 6 of the
melatonin mt(1) receptor. This identified Gly(258) (Gly(6.55)) as a critical
residue required for high affinity ligand binding and receptor function.
PMID- 10770943
TI - Syntenin-syndecan binding requires syndecan-synteny and the co-operation of both
PDZ domains of syntenin.
AB - Syntenin is an adaptor-like molecule that binds to the cytoplasmic domains of all
four vertebrate syndecans. Syntenin-syndecan binding involves the C-terminal part
of syntenin that contains a tandem of PDZ domains. Here we provide evidence that
each PDZ domain of syntenin can interact with a syndecan. Isolated or combined
mutations of the carboxylate binding lysines in the inter-betaAbetaB loops and of
the alphaB1 residues in either one or both the PDZ domains of syntenin all reduce
syntenin-syndecan binding in yeast two-hybrid, blot-overlay, and surface plasmon
resonance assays. PDZ2 mutations have more pronounced effects on binding than
PDZ1 mutations, but complete abrogation of syntenin-syndecan binding requires the
combination of both the lysine and the alphaB1 mutations in both the PDZ domains
of syntenin. Isothermal calorimetric titration of syntenin with syndecan peptide
reveals the presence of two binding sites in syntenin. Yet, unlike a tandem of
two PDZ2 domains and a reconstituted PDZ1+PDZ2 tandem, a tandem of two PDZ1
domains and isolated PDZ1 or PDZ2 domains do not interact with syndecan bait. We
conclude to a co-operative binding mode whereby neither of these two PDZ domains
is sufficient by itself but where PDZ2 functions as a "major" or "high affinity"
syndecan binding domain, and PDZ1 functions as an "accessory" or "low affinity"
syndecan binding domain. The paired, but not the isolated PDZ domains of syntenin
bind also strongly to the immobilized cytoplasmic domains of neurexin and B-class
ephrins. By inference, these data suggest a model whereby recruitment of syntenin
to membrane surfaces requires two compatible types of bait that are in "synteny"
(occurring together in location) and engages both PDZ domains of syntenin. The
synteny of compatible bait may result from the assemblies and co-assemblies of
syndecans and other similarly suited partners in larger supramolecular complexes.
In general, an intramolecular combination of PDZ domains that are weak, taken
individually, would appear to be designed to detect rather than drive the
formation of specific molecular assemblies.
PMID- 10770944
TI - The interaction of beta-arrestin with the AP-2 adaptor is required for the
clustering of beta 2-adrenergic receptor into clathrin-coated pits.
AB - Beta-arrestins are cytosolic proteins that regulate the signaling and the
internalization of G protein-coupled receptors (GPCRs). Although termination of
receptor coupling requires beta-arrestin binding to agonist-activated receptors,
GPCR endocytosis involves the coordinate interactions between receptor-beta
arrestin complexes and other endocytic proteins such as adaptor protein 2 (AP-2)
and clathrin. Clathrin interacts with a conserved motif in the beta-arrestin C
terminal tail; however, the specific molecular determinants in beta-arrestin that
bind AP-2 have not been identified. Moreover, the respective contributions of the
interactions of beta-arrestin with AP-2 and clathrin toward the targeting of
GPCRs to clathrin-coated vesicles have not been established. Here, we identify
specific arginine residues (Arg(394) and Arg(396)) in the beta-arrestin 2 C
terminus that mediate beta-arrestin binding to AP-2 and show, in vitro, that
these domains in beta-arrestin 1 and 2 interact equally well with AP-2
independently of clathrin binding. We demonstrate in HEK 293 cells by
fluorescence microscopy that beta(2)-adrenergic receptor-beta-arrestin complexes
lacking the beta-arrestin-clathrin binding motif are still targeted to clathrin
coated pits. In marked contrast, receptor-beta-arrestin complexes lacking the
beta-arrestin/AP-2 interactions are not effectively compartmentalized in
punctated areas of the plasma membrane. These results reveal that the binding of
a receptor-beta-arrestin complex to AP-2, not to clathrin, is necessary for the
initial targeting of beta(2)-adrenergic receptor to clathrin-coated pits.
PMID- 10770945
TI - The crystal structure of the chemokine domain of fractalkine shows a novel
quaternary arrangement.
AB - Fractalkine, or neurotactin, is a chemokine that is present in endothelial cells
from several tissues, including brain, liver, and kidney. It is the only member
of the CX(3)C class of chemokines. Fractalkine contains a chemokine domain (CDF)
attached to a membrane-spanning domain via a mucin-like stalk. However,
fractalkine can also be proteolytically cleaved from its membrane-spanning domain
to release a freely diffusible form. Fractalkine attracts and immobilizes
leukocytes by binding to its receptor, CX(3)CR1. The x-ray crystal structure of
CDF has been solved and refined to 2.0 A resolution. The CDF monomers form a
dimer through an intermolecular beta-sheet. This interaction is somewhat similar
to that seen in other dimeric CC chemokine crystal structures. However, the
displacement of the first disulfide in CDF causes the dimer to assume a more
compact quaternary structure relative to CC chemokines, which is unique to CX(3)C
chemokines. Although fractalkine can bind to heparin in vitro, as shown by
comparison of electrostatic surface plots with other chemokines and by heparin
chromatography, the role of this property in vivo is not well understood.
PMID- 10770946
TI - The interaction of TOGp with microtubules and tubulin.
AB - TOGp is the human homolog of XMAP215, a Xenopus microtubule-associated protein
that promotes rapid microtubule assembly at plus ends. These proteins are thought
to be critical for microtubule assembly and/or mitotic spindle formation. To
understand how TOGp interacts with the microtubule lattice, we cloned full-length
TOGp and various truncations for expression in a reticulocyte lysate system.
Based on microtubule co-pelleting assays, the microtubule binding domain is
contained within a basic 600-amino acid region near the N terminus, with critical
domains flanking a region homologous to the microtubule binding domain found in
the related proteins Stu2p (S. cerevisiae) and Dis1 (S. pombe). Both full-length
TOGp and the N-terminal fragment show enhanced binding to microtubule ends. Full
length TOGp also binds altered polymer lattice structures including parallel
protofilament sheets, antiparallel protofilament sheets induced with zinc ions,
and protofilament rings, suggesting that TOGp binds along the length of
individual protofilaments. The C-terminal region of TOGp has a low affinity for
microtubule polymer but binds tubulin dimer. We propose a model to explain the
microtubule-stabilizing and/or assembly-promoting functions of the XMAP215/TOGp
family of microtubule-associated proteins based on the binding properties we have
identified.
PMID- 10770947
TI - Channel formation by the glycosylphosphatidylinositol-anchored protein binding
toxin aerolysin is not promoted by lipid rafts.
AB - Glycosylphosphatidylinositol-anchored proteins may be concentrated in membrane
microdomains (lipid rafts) that are also enriched in cholesterol and
sphingolipids. The glycosyl anchor of these proteins is a specific, high affinity
receptor for the channel-forming protein aerolysin. We wished to determine if the
presence of rafts promotes the activity of aerolysin. Treatment of T lymphocytes
with methyl-beta-cyclodextrin, which destroys lipid rafts by sequestering
cholesterol, had no measurable effect on the sensitivity of the cells to
aerolysin; nor did similar treatment of erythrocytes decrease the rate at which
they were lysed by the toxin. We also studied the rate of aerolysin-induced
channel formation in liposomes containing glycosylphosphatidylinositol-anchored
placental alkaline phosphatase, which we show is a receptor for aerolysin. In
liposomes containing sphingolipids as well as glycerophospholipids and
cholesterol, most of the enzyme was Triton X-100-insoluble, indicating that it
was localized in rafts, whereas in liposomes prepared without sphingolipids, all
of the enzyme was soluble. Aerolysin was no more active against liposomes
containing rafts than against those that did not. We conclude that lipid rafts do
not promote channel formation by aerolysin.
PMID- 10770948
TI - Overexpression of murine Pax3 increases NCAM polysialylation in a human
medulloblastoma cell line.
AB - Polysialic acid (PSA) is a developmentally regulated carbohydrate found primarily
on neural cell adhesion molecules (NCAM) in embryonic tissues. The majority of
NCAM in adult tissues lacks this unique carbohydrate, but polysialylated NCAM
(PSA-NCAM) is present in adult brain regions where neural regeneration persists
and in some pediatric brain tumors such as medulloblastoma, which show greater
propensity for leptomeningeal spread. Pax3, a developmentally regulated paired
homeodomain transcription factor, is thought to be involved in the regulation of
neural cell adhesion molecules. Overexpression of murine Pax3 into a human
medulloblastoma cell line (DAOY) resulted in an increase in NCAM polysialylation
and a 2-4-fold increase in alpha2, 8-polysialyltransferase type II mRNA levels.
No difference was observed in alpha2,8-polysialyltransferase type IV message. The
addition of PSA to NCAM changed the adhesive behavior of these Pax3
transfectants. Transfectants expressing high PSA-NCAM show much less NCAM
dependent aggregation than those with less PSA-NCAM. In addition, Pax3
transfectants having high PSA-NCAM show heterophilic adhesion involving
polysialic acid to heparan sulfate proteoglycan and agrin. These observations
suggest that a developmentally regulated transcription factor, Pax3, could affect
NCAM polysialylation and subsequently cell-cell and cell-substratum interaction.
PMID- 10770949
TI - Mucins and molluscan calcification. Molecular characterization of mucoperlin, a
novel mucin-like protein from the nacreous shell layer of the fan mussel Pinna
nobilis (Bivalvia, pteriomorphia).
AB - A cDNA expression library constructed from mantle tissue mRNA of the
Mediterranean fan mussel Pinna nobilis was screened with antibodies raised
against the acetic acid-soluble shell matrix of the same species. This resulted
in the isolation of a 2138-base pair cDNA, containing 13 tandem repeats of 93
base pairs. The deduced protein has a molecular mass of 66.7 kDa and a
isoelectric point of 4.8. This protein, which is enriched in serine and proline
residues, was overexpressed, purified, and used for producing polyclonal
antibodies. Immunological in situ and in vitro tests showed that the protein is
localized in the nacreous aragonitic layer of P. nobilis, but not in the calcitic
prisms. Because this protein of the nacre of P. nobilis exhibits some mucin-like
characteristics, we propose the name mucoperlin. This is the first paper
reporting the cloning of a molluscan mucin and the first molecular evidence for
the involvement of a mucin in molluscan calcification. This finding corroborates
our previous hypothesis that some of the proteinaceous constituents of the
molluscan shell matrix would derive from mucins, common to many metazoan lineages
of the late Precambrian (Marin, F., Smith, M., Isa, Y., Muyzer, G. and Westbroek,
P. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1554-1559). The adaptation of an
ancestral mucin to a new function, the regulation of the mineralization process,
may be one of the molecular events, among others, that would explain the
simultaneous emergence of organized calcification in many metazoan lineages
during the Cambrian explosion.
PMID- 10770950
TI - Regulation of phospholipid scramblase activity during apoptosis and cell
activation by protein kinase Cdelta.
AB - Phospholipid scramblase induces nonspecific bidirectional movement of
phospholipids across the membrane during cell activation and has been proposed to
mediate the appearance of phosphatidylserine (PS) in the plasma membrane outer
leaflet during apoptosis, a cell surface change that is critical for apoptotic
cell removal. We report here that protein kinase C (PKC) delta plays an important
role in activated transbilayer movement of phospholipids and surface PS exposure
by directly enhancing the activity of phospholipid scramblase. Specific
inhibition of PKCdelta by rottlerin prevented both apoptosis- and activation
induced scramblase activity. PKCdelta was either selectively cleaved and
activated in a caspase 3-dependent manner (during apoptosis) or translocated to
the plasma membrane (in stimulated cells) and could directly phosphorylate
scramblase immunoprecipitated from Jurkat cells. Furthermore, reconstitution of
PKCdelta and scramblase, but not scramblase or PKCdelta alone in Chinese hamster
ovary cells demonstrated enhanced scramblase activity.
PMID- 10770951
TI - Beta 3- and alpha1-adrenergic Erk1/2 activation is Src- but not Gi-mediated in
Brown adipocytes.
AB - A novel signaling pathway for mediation of beta(3)-adrenergic activation of the
mitogen-activated protein kinases Erk1/2 (associated with proliferation,
differentiation, and apoptosis) has recently been proposed, which implies
mediation via constitutively coupled G(i)-proteins and Gbetagamma-subunits,
distinct from the classical cAMP pathway of beta-adrenergic stimulation. To
verify the significance of this pathway in cells in primary cultures that
entopically express beta(3)-adrenoreceptors, we examined the functionality of
this pathway in cultured brown adipocytes. Norepinephrine activated Erk1/2 via
both beta(3) receptors and alpha(1) receptors but not via alpha(2) receptors.
Forskolin induced Erk1/2 activation similarly to beta(3) activation, indicating
cAMP-mediation; this induction could be inhibited with H89, implying protein
kinase A mediation. The G(i)-pathway was functional in these cells, as pertussis
toxin increased agonist-induced cAMP accumulation. However, pertussis toxin was
unable to affect adrenergically induced Erk1/2 activation. Also, wortmannin was
without effect, implying that Gbetagamma activation of the phosphatidylinositol 3
kinase pathway was not involved. PP1/2, which inhibits Src, abolished both
beta(3)- and alpha(1)-induced Erk1/2 activation. Thus, the proposed novel G(i)
pathway for beta(3) mediation is not universal, because it is not functional in
the untransformed primary cell culture system with entopically expressed beta(3)
receptors examined here. Here, the beta(3) signal is mediated classically via
cAMP/protein kinase A. beta(3) and alpha(1) signals converge at Src, which thus
mediates Erk1/2 activation in both pathways.
PMID- 10770952
TI - Cytochrome c nitration by peroxynitrite.
AB - Peroxynitrite (ONOO(-)), the product of superoxide (O(2)) and nitric oxide (.NO)
reaction, inhibits mitochondrial respiration and can stimulate apoptosis.
Cytochrome c, a mediator of these two aspects of mitochondrial function, thus
represents an important potential target of ONOO(-) during conditions involving
accelerated rates of oxygen radical and.NO generation. Horse heart cytochrome
c(3+) was nitrated by ONOO(-), as indicated by spectral changes, Western blot
analysis, and mass spectrometry. A dose-dependent loss of cytochrome c(3+) 695 nm
absorption occurred, inferring that nitration of a critical heme-vicinal tyrosine
(Tyr-67) promoted a conformational change, displacing the Met-80 heme ligand.
Nitration was confirmed by cross-reactivity with a specific antibody against 3
nitrotyrosine and by increased molecular mass compatible with the addition of a
nitro-(-NO(2)) group. Mass analysis of tryptic digests indicated the preferential
nitration of Tyr-67 among the four conserved tyrosine residues in cytochrome c.
Cytochrome c(3+) was more extensively nitrated than cytochrome c(2+) because of
the preferential oxidation of the reduced heme by ONOO(-). Similar protein
nitration patterns were obtained by ONOO(-) reaction in the presence of carbon
dioxide, whereupon secondary nitrating species arise from the decomposition of
the nitroso-peroxocarboxylate (ONOOCO(2)(-)) intermediate. Peroxynitrite-nitrated
cytochrome c displayed significant changes in redox properties, including (a)
increased peroxidatic activity, (b) resistance to reduction by ascorbate, and (c)
impaired support of state 4-dependent respiration in intact rat heart
mitochondria. These results indicate that cytochrome c nitration may represent
both oxidative and signaling events occurring during .NO- and ONOO(-)-mediated
cell injury.
PMID- 10770953
TI - The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase
dependent survival signaling cascade.
AB - Liver injury during cholestasis reflects a balance between the effects of toxic
and nontoxic bile acids. However, the critical distinction between a toxic and
nontoxic bile acid remains subtle and unclear. For example, the glycine conjugate
of chenodeoxycholate (GCDC) induces hepatocyte apoptosis, whereas the taurine
conjugate (TCDC) does not. We hypothesized that the dissimilar cellular responses
may reflect differential activation of a phosphatidylinositol 3-kinase (PI3K)
dependent signaling pathway. In the bile acid-transporting McNtcp.24 rat hepatoma
cell line, TCDC, but not GCDC, stimulated PI3K activity. Consistent with this
observation, inhibition of PI3K rendered TCDC cytotoxic, and constitutive
activation of PI3K rendered GCDC nontoxic. Both Akt and the atypical protein
kinase C isoform zeta (PKCzeta) have been implicated in PI3K-dependent survival
signaling. However, TCDC activated PKCzeta, but not Akt. Moreover, inhibition of
PKCzeta converted TCDC into a cytotoxic agent, whereas overexpression of wild
type PKCzeta blocked GCDC-induced apoptosis. We also demonstrate that TCDC
activated nuclear factor kappaB (NF-kappaB) in a PI3K- and PKCzeta-dependent
manner. Moreover, inhibition of NF-kappaB by an IkappaB super-repressor rendered
TCDC cytotoxic, suggesting that NF-kappaB is also necessary to prevent the
cytotoxic effects of TCDC. Collectively, these data suggest that some hydrophobic
bile acids such as TCDC activate PI3K-dependent survival pathways, which prevent
their otherwise inherent toxicity.
PMID- 10770954
TI - Development of the pteridine pathway in the zebrafish, Danio rerio.
AB - In the zebrafish, the peripheral neurons and the pigment cells are derived from
the neural crest and share the pteridine pathway, which leads either to the
cofactor tetrahydrobiopterin or to xanthophore pigments. The components of the
pteridine pattern were identified as tetrahydrobiopterin, sepiapterin, 7
oxobiopterin, isoxanthopterin, and 2,4,7-trioxopteridine. The expression of GTP
cyclohydrolase I activity during the first 24-h postfertilization, followed by 6
pyruvoyl-5,6,7,8-tetrahydropterin synthase and sepiapterin reductase, suggest an
early supply of tetrahydrobiopterin for neurotransmitter synthesis in the neurons
and for tyrosine supply in the melanophores. At 48-h postfertilization,
sepiapterin formation branches off the de novo pathway of tetrahydrobiopterin
synthesis. Sepiapterin, via 7,8-dihydrobiopterin and biopterin, serves as a
precursor for the formation of 7-oxobiopterin, which may be further catabolized
to isoxanthopterin and 2,4,7-trioxopteridine. Neither 7, 8-dihydrobiopterin nor
biopterin is a substrate for xanthine oxidoreductase. In contrast, both of these
compounds are oxidized at C-7 by a xanthine oxidase variant form, which is
inactivated by KCN, but is insensitive to allopurinol. The oxidase and the
dehydrogenase form of xanthine oxidoreductase as well as the xanthine oxidase
variant have specific developmental patterns. It follows that GTP cyclohydrolase
I, the formation of sepiapterin, and the xanthine oxidoreductase family control
the pteridine pathway in the zebrafish.
PMID- 10770955
TI - Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is
the highest affinity receptor.
AB - TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines which
induces apoptotic cell death in a variety of tumor cell lines. It mediates its
apoptotic effects through one of two receptors, DR4 and DR5, which are members of
of the TNF receptor family, and whose cytoplasmic regions contain death domains.
In addition, TRAIL also binds to 3 "decoy" receptors, DcR2, a receptor with a
truncated death domain, DcR1, a glycosylphosphatidylinositol-anchored receptor,
and OPG a secreted protein which is also known to bind to another member of the
TNF family, RANKL. However, although apoptosis depends on the expression of one
or both of the death domain containing receptors DR4 and/or DR5, resistance to
TRAIL-induced apoptosis does not correlate with the expression of the "decoy"
receptors. Previously, TRAIL has been described to bind to all its receptors with
equivalent high affinities. In the present work, we show, by isothermal titration
calorimetry and competitive enzyme-linked immunosorbent assay, that the rank
order of affinities of TRAIL for the recombinant soluble forms of its receptors
is strongly temperature dependent. Although DR4, DR5, DcR1, and OPG show similar
affinities for TRAIL at 4 degrees C, their rank-ordered affinities are
substantially different at 37 degrees C, with DR5 having the highest affinity
(K(D) 130 micromol/L received inotropic drugs to test for reversibility of renal
dysfunction. The end point was graft failure. The average preoperative GFR of 66
+/- 17 ml/min per 1.73 m(2) declined to 52 +/- 19, 44 +/- 16, and 37 +/- 17 at 1,
5, and 9 yr after heart transplantation, respectively. Altogether, the average
GFR declined by 44%. There was no significant correlation between the
preoperative GFR and postoperative renal function or survival. Recipient age was
a predictor of renal function during the entire follow-up. Severe renal
dysfunction (GFR <20 ml/min per 1.73 m(2)) developed in 20% of the patients,
which was predicted by the recipient age at transplantation together with the GFR
1 yr after transplantation. A nomogram that shows the risk of developing severe
renal dysfunction after heart transplantation is presented. Cyclosporin A
concentrations and treatment with statins, calcium channel blockers, or
angiotensin-converting enzyme inhibitors did not correlate with the evolution of
renal function. Patients with a preoperative depressed renal function who
improved on inotropic treatment seemed to have a poorer outcome compared with the
other study patients.
PMID- 10770976
TI - Impact of gender on access to the renal transplant waiting list for pediatric and
adult patients.
AB - While the public and policy-makers place a priority on equity in the organ
allocation process, several studies suggest that women may be less likely than
men to receive a renal transplant. However, the cause of this disparity and
whether it exists among children with end-stage renal disease (ESRD) are unknown.
To address these issues, two nationally representative cohorts of incident
patients were examined: (1) 7594 adults with ESRD onset between 1986 and 1993 for
whom detailed data were available from the medical record on health status; and
(2) 3217 patients <20 yr old who developed ESRD between 1988 and 1993. Patients
were followed from initiation of dialysis for up to 10 yr until first activation
on the United Network of Organ Sharing renal transplant waiting list. Access to
the list for female and male patients with ESRD was compared using Cox
proportional hazards models with adjustment for demographic, socioeconomic, and
clinical factors. Crude rates of wait-listing per 100 person-years of ESRD were
lower for female patients than male patients in both the pediatric (28.89 versus
34.18) and adult (3.94 versus 6.54) populations. Despite adjustment for numerous
confounding factors, this gender-based disparity persisted in multivariate
analysis. Among children with ESRD, female patients were 14% less likely to be
listed than male patients (relative hazard [RH] 0.86; 95% confidence interval
[CI], 0.78 to 0.93), and in the adult group, women were 18% less likely to be
activated for transplant than men (RH 0.82; 95% CI, 0.72 to 0.93). These findings
suggest that female patients of all ages with ESRD face barriers in being
activated for cadaveric renal transplantation. Greater attention to this issue is
necessary to improve equity in the organ allocation system and potentially
improve the outcomes of female patients with ESRD.
PMID- 10770977
TI - Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and
expression.
AB - Heme oxygenase-1 (HO-1) is a microsomal enzyme involved in the degradation of
heme, resulting in the generation of biliverdin, iron, and carbon monoxide.
Recent attention has focused on the biologic effects of product(s) of this
enzymatic reaction that have important antioxidant, anti-inflammatory, and
cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial
response to a wide variety of oxidant stimuli, including heme, hydrogen peroxide,
cytokines, growth factors, heavy metals, nitric oxide, and oxidized LDL. HO-1 has
been implicated in several clinically relevant disease states, including
transplant rejection, hypertension, acute renal injury, atherosclerosis, and
others. Previous studies indicate a protective role for HO-1 in heme and non-heme
mediated models of acute renal injury using chemical inducers and inhibitors of
HO-1. Studies in HO-1 knockout mice further corroborate these observations,
highlighting the important role of HO-1 in the pathophysiology of acute renal
injury. Expression of HO-1 has been linked to prolonged xenograft survival and is
important in transplant rejection as well. More recently, the first known case of
human HO-1 deficiency was reported with several phenotypical similarities to the
mouse HO-1 knockout. The role of HO-1 has extended far beyond its initial
description as an enzyme involved in heme degradation to being an important
mediator in modulating adaptive and protective responses not only in renal
injury, but in other organ systems as well.
PMID- 10770978
TI - Renal transplant-associated hyperuricemia and gout.
PMID- 10770979
TI - Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal
adenomas. Polyp Prevention Trial Study Group.
AB - BACKGROUND: We tested the hypothesis that dietary intervention can inhibit the
development of recurrent colorectal adenomas, which are precursors of most large
bowel cancers. METHODS: We randomly assigned 2079 men and women who were 35 years
of age or older and who had had one or more histologically confirmed colorectal
adenomas removed within six months before randomization to one of two groups: an
intervention group given intensive counseling and assigned to follow a diet that
was low in fat (20 percent of total calories) and high in fiber (18 g of dietary
fiber per 1000 kcal) and fruits and vegetables (3.5 servings per 1000 kcal), and
a control group given a standard brochure on healthy eating and assigned to
follow their usual diet. Subjects entered the study after undergoing complete
colonoscopy and removal of adenomatous polyps; they remained in the study for
approximately four years, undergoing colonoscopy one and four years after
randomization. RESULTS: A total of 1905 of the randomized subjects (91.6 percent)
completed the study. Of the 958 subjects in the intervention group and the 947 in
the control group who completed the study, 39.7 percent and 39.5 percent,
respectively, had at least one recurrent adenoma; the unadjusted risk ratio was
1.00 (95 percent confidence interval, 0.90 to 1.12). Among subjects with
recurrent adenomas, the mean (+/-SE) number of such lesions was 1.85+/-0.08 in
the intervention group and 1.84+/-0.07 in the control group. The rate of
recurrence of large adenomas (with a maximal diameter of at least 1 cm) and
advanced adenomas (defined as lesions that had a maximal diameter of at least 1
cm or at least 25 percent villous elements or evidence of high-grade dysplasia,
including carcinoma) did not differ significantly between the two groups.
CONCLUSIONS: Adopting a diet that is low in fat and high in fiber, fruits, and
vegetables does not influence the risk of recurrence of colorectal adenomas.
PMID- 10770980
TI - Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal
adenomas. Phoenix Colon Cancer Prevention Physicians' Network.
AB - BACKGROUND: The risks of colorectal cancer and adenoma, the precursor lesion, are
believed to be influenced by dietary factors. Epidemiologic evidence that cereal
fiber protects against colorectal cancer is equivocal. We conducted a randomized
trial to determine whether dietary supplementation with wheat-bran fiber reduces
the rate of recurrence of colorectal adenomas. METHODS: We randomly assigned 1429
men and women who were 40 to 80 years of age and who had had one or more
histologically confirmed colorectal adenomas removed within three months before
recruitment began to a supervised program of dietary supplementation with either
high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber.
The primary end point was the presence or absence of new adenomas at the time of
follow-up colonoscopy. Subjects and physicians, including colonoscopists, were
unaware of the group assignments. RESULTS: Of the 1303 subjects who completed the
study, 719 had been randomly assigned to the high-fiber group and 584 to the low
fiber group. The median times from randomization to the last follow-up
colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber
group. By the time of the last follow-up colonoscopy, at least one adenoma had
been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299
subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds
ratio for recurrent adenoma in tile high-fiber group, as compared with the low
fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and
the relative risk of recurrence according to the number of adenomas, in the high
fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence
interval, 0.71 to 1.36; P=0.93). CONCLUSIONS: As used in this study, a dietary
supplement of wheat-bran fiber does not protect against recurrent colorectal
adenomas.
PMID- 10770981
TI - Missed diagnoses of acute cardiac ischemia in the emergency department.
AB - BACKGROUND: Discharging patients with acute myocardial infarction or unstable
angina from the emergency department because of missed diagnoses can have dire
consequences. We studied the incidence of, factors related to, and clinical
outcomes of failure to hospitalize patients with acute cardiac ischemia. METHODS:
We analyzed clinical data from a multicenter, prospective clinical trial of all
patients with chest pain or other symptoms suggesting acute cardiac ischemia who
presented to the emergency departments of 10 U.S. hospitals. RESULTS: Of 10,689
patients, 17 percent ultimately met the criteria for acute cardiac ischemia (8
percent had acute myocardial infarction and 9 percent had unstable angina), 6
percent had stable angina, 21 percent had other cardiac problems, and 55 percent
had noncardiac problems. Among the 889 patients with acute myocardial infarction,
19 (2.1 percent) were mistakenly discharged from the emergency department (95
percent confidence interval, 1.1 to 3.1 percent); among the 966 patients with
unstable angina, 22 (2.3 percent) were mistakenly discharged (95 percent
confidence interval, 1.3 to 3.2 percent). Multivariable analysis showed that
patients who presented to the emergency department with acute cardiac ischemia
were more likely not to be hospitalized if they were women less than 55 years old
(odds ratio for discharge, 6.7; 95 percent confidence interval, 1.4 to 32.5),
were nonwhite (odds ratio, 2.2; 1.1 to 4.3), reported shortness of breath as
their chief symptom (odds ratio, 2.7; 1.1 to 6.5), or had a normal or
nondiagnostic electrocardiogram (odds ratio, 3.3; 1.7 to 6.3). Patients with
acute infarction were more likely not to be hospitalized if they were nonwhite
(odds ratio for discharge, 4.5; 95 percent confidence interval, 1.8 to 11.8) or
had a normal or nondiagnostic electrocardiogram (odds ratio, 7.7; 95 percent
confidence interval, 2.9 to 20.2). For the patients with acute infarction, the
risk-adjusted mortality ratio for those who were not hospitalized, as compared
with those who were, was 1.9 (95 percent confidence interval, 0.7 to 5.2), and
for the patients with unstable angina, it was 1.7 (95 percent confidence
interval, 0.2 to 17.0). CONCLUSIONS: The percentage of patients who present to
the emergency department with acute myocardial infarction or unstable angina who
are not hospitalized is low, but the discharge of such patients is associated
with increased mortality. Failure to hospitalize is related to race, sex, and the
absence of typical features of cardiac ischemia. Continued efforts to reduce the
number of missed diagnoses are warranted.
PMID- 10770982
TI - Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.
AB - BACKGROUND: Patients with acromegaly are currently treated with surgery,
radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the
treatments may be ineffective and have adverse effects. Pegvisomant is a
genetically engineered growth hormone-receptor antagonist that blocks the action
of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind
study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo,
given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD)
serum concentration of insulin-like growth factor I (IGF-I) decreased from base
line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group
that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that
received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that
received 20 mg of pegvisomant per day (P<0.001 for the comparison of each
pegvisomant group with placebo), and the concentrations became normal in 10
percent, 54 percent, 81 percent, and 89 percent of patients, respectively
(P<0.001 for each comparison with placebo). Among patients treated with 15 mg or
20 mg of pegvisomant per day, there were significant decreases in ring size, soft
tissue swelling, the degree of excessive perspiration, and fatigue. The score
fortotal symptoms and signs of acromegaly decreased significantly in all groups
receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar
in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment
of patients who have acromegaly with a growth hormone-receptor antagonist results
in a reduction in serum IGF-I concentrations and in clinical improvement.
PMID- 10770983
TI - Images in clinical medicine. Staphylococcal scalded skin syndrome.
PMID- 10770984
TI - Effect of eliminating compensation for pain and suffering on the outcome of
insurance claims for whiplash injury.
AB - BACKGROUND AND METHODS: The incidence and prognosis of whiplash injury from motor
vehicle collisions may be related to eligibility for compensation for pain and
suffering. On January 1, 1995, the tort-compensation system for traffic injuries,
which included payments for pain and suffering, in Saskatchewan, Canada, was
changed to a no-fault system, which did not include such payments. To determine
whether this change was associated with a decrease in claims and improved
recovery after whiplash injury, we studied a population-based cohort of persons
who filed insurance claims for traffic injuries between July 1, 1994, and
December 31, 1995. RESULTS: Of 9006 potentially eligible claimants, 7462 (83
percent) met our criteria for whiplash injury. The six-month cumulative incidence
of claims was 417 per 100,000 persons in the last six months of the tort system,
as compared with 302 and 296 per 100,000, respectively, in the first and second
six-month periods of the no-fault system. The incidence of claims was higher for
women than for men in each period; the incidence decreased by 43 percent for men
and by 15 percent for women between the tort period and the two no-fault periods
combined. The median time from the date of injury to the closure of a claim
decreased from 433 days (95 percent confidence interval, 409 to 457) to 194 days
(95 percent confidence interval, 182 to 206) and 203 days (95 percent confidence
interval, 193 to 213), respectively. The intensity of neck pain, the level of
physical functioning, and the presence or absence of depressive symptoms were
strongly associated with the time to claim closure in both systems. CONCLUSIONS:
The elimination of compensation for pain and suffering is associated with a
decreased incidence and improved prognosis of whiplash injury.
PMID- 10770985
TI - Evaluation of the patient with acute chest pain.
PMID- 10770986
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 12-2000. A 60-year-old man with persistent gynecomastia after
excision of a pituitary adenoma.
PMID- 10770987
TI - Diet, colorectal adenomas, and colorectal cancer.
PMID- 10770988
TI - Missed diagnoses of acute coronary syndromes in the emergency room--continuing
challenges.
PMID- 10770989
TI - Treatment of acromegaly.
PMID- 10770990
TI - Pain and public policy.
PMID- 10770991
TI - Special issue "nicotinic neuronal receptors"
PMID- 10770992
TI - Neuronal nicotinic receptors, important new players in brain function.
AB - Acetylcholine receptors are cationic channels whose opening is controlled by
acetylcholine. They are key molecules in the cholinergic nicotinic transmission
in a number of areas of the central and peripheral nervous system. Because of the
structural complexity, given by the numerous subunits that forms these receptors,
they have different pharmacological and biophysical properties. Here we give a
brief account of the known and consolidated data regarding neuronal nicotinic
receptors, as as an introduction to the articles reported in this issue, in order
to allow readers who are not familiar with the field to place the detailed
information in the right context.
PMID- 10770993
TI - Acetylcholine receptor extracellular domain determines sensitivity to nicotine
induced inactivation.
AB - We have shown previously that chronic exposure to submicromolar concentrations of
nicotine permanently inactivates alpha4beta2 and alpha7 neuronal nicotinic
acetylcholine receptors while alpha3beta2 acetylcholine receptors are resistant
to inactivation. Phosphorylation of the large cytoplasmic domain has been
proposed to mediate functional inactivation. Chimeric subunits consisting of
human alpha4 sequence from their N-terminus to either the beginning of the first
transmembrane domain or the large cytoplasmic domain and alpha3 sequences
thereafter formed acetylcholine receptors with beta2 subunits which were as
susceptible to nicotine-induced inactivation as wild-type alpha4 acetylcholine
receptors. The converse chimeras, containing the N-terminal parts of the alpha3
subunit and the C-terminal parts of the alpha4 subunit, formed acetylcholine
receptors with beta2 subunits which were as resistant to nicotine-induced
inactivation as wild-type alpha3beta2 acetylcholine receptors. Thus, inactivation
of acetylcholine receptors produced by chronic exposure to nicotine results
primarily from effects of the agonist on the extracellular and transmembrane
domains of the alpha subunit.
PMID- 10770994
TI - beta3 subunit is present in different nicotinic receptor subtypes in chick
retina.
AB - Although the neuronal nicotinic beta3 subunit was cloned several years ago, it
has only recently been shown to form heteromeric channels when associated with
other nicotinic subunits, and very little information is available concerning its
assembly in the native nicotinic receptors of the nervous system. Using subunit
specific antibodies and immunoprecipitation experiments, we have identified the
retina as being the chick central nervous system (CNS) area that expresses the
highest level of the beta3 subunit. Sequential immunopurification experiments
showed that there are at least two populations of beta3-containing receptors in
chick retina: in one, the beta3 subunit is associated with the alpha6 and beta4
subunits; in the other more heterogeneous population, the beta3 subunit is
associated with the alpha2, alpha3, alpha4, beta2 and beta4 subunits. Both of
these receptor populations bind [3H]epibatidine and a number of nicotinic
receptor agonists with high affinity (nM) and nicotinic receptor antagonists with
a lower affinity (microM). The greatest pharmacological difference between the
two populations is the affinity for the alpha-conotoxin MII, which inhibits
binding to alpha6-containing receptors and not that to beta3-containing
receptors. We also searched for the presence of the beta3 subunit associated with
the alpha-bungarotoxin binding subunits alpha7 and/or alpha8 in retina and chick
brain. Immunoprecipitation studies using anti-beta3 antibodies did not detect any
specific alpha-bungarotoxin labeled receptors, thus, indicating that the beta3
subunit is not present in the alpha-bungarotoxin receptors of these areas.
PMID- 10770995
TI - Variations in desensitization of nicotinic acetylcholine receptors from
hippocampus and midbrain dopamine areas.
AB - This study addresses two issues arising from the desensitization of nicotinic
acetylcholine receptors from the hippocampus, ventral tegmental area, and
substantia nigra. First, biophysical studies can find potent and complete
desensitization of nicotinic receptors; but in vivo studies often find that
desensitization affecting a behavior is less than complete, or that
desensitization is important over a different nicotine concentration range. Our
results show that there can be significant differences in desensitization when
comparing nearby neurons from the same area of the brain. Thus, nicotinic
receptors on a minority of neurons may remain active and maintain a behavior
under conditions that can produce significant desensitization. Second, agonist
applications that are intended to active nicotinic receptors also cause
desensitization. The prevailing conditions and the rate of agonist application
and removal will control the degree of activation vs. desensitization. These and
other factors regulate the efficacy of nicotinic agonists experimentally and
physiologically.
PMID- 10770996
TI - Nicotinic receptors modulating somatodendritic and terminal dopamine release
differ pharmacologically.
AB - Ascending dopaminergic and noradrenergic neurons possess somatodendritic and
terminal nicotinic cholinoceptors in the rat. Each neuronal population expresses
mRNA for several types of nicotinic cholinoceptor subunit, including alpha6 and
beta3. In superfused rat striatal synaptosomes, epibatidine evoked release of
[3H]dopamine with similar efficacy to ACh, whereas nicotine and cytisine were
weaker (70+/-6% and 58+/-6%, respectively). The four agonists were equi
efficacious in evoking [3H]noradrenaline release from hippocampal synaptosomes.
Nicotine-evoked synaptosomal release was tetrodotoxin-insensitive.
Somatodendritic nicotinic cholinoceptors on dopaminergic neurons were studied
using a dendrosomal [3H]dopamine release assay and also in locomotor activity
tests. In both assays, nicotine appeared more efficacious than epibatidine.
Furthermore, with repeated nicotine exposure, the acute locomotor stimulant
response to nicotine increased, whereas the epibatidine response became
undetectable. In conclusion, somatodendritic nicotinic cholinoceptors located on
dopaminergic neurons appear to differ pharmacologically from those on striatal
dopaminergic terminals and hippocampal noradrenergic terminals.
PMID- 10770997
TI - Presynaptic nicotinic receptors modulating dopamine release in the rat striatum.
AB - The modulation of striatal dopamine release by presynaptic nicotinic
acetylcholine receptors is well documented for both synaptosomes and slices.
Because the latter retain local anatomical integrity, we have compared
[3H]dopamine release evoked by the nicotinic receptor agonists (-)-nicotine and
(+/-)-anatoxin-a from striatal synaptosome and slice preparations in parallel. At
higher agonist concentrations, mecamylamine-sensitive [3H]dopamine release was
greater from slices, indicative of an additional component, and this increase was
abolished by glutamate receptor antagonists. To begin to examine the localisation
of specific nicotinic acetylcholine receptor subtypes in the striatum, immunogold
electron microscopy was undertaken with the beta2-specific monoclonal antibody
270. In striatal sections, gold particles were associated with symmetric synapses
(dopaminergic) but were absent from asymmetric synapses (glutamatergic). Surface
labelling of striatal synaptosomes with gold particles was also demonstrated.
Taken together, these results are consistent with dopamine release mediated by
beta2-containing nicotinic acetylcholine receptors on dopamine terminals, while
non-beta2-containing nicotinic acetylcholine receptors may enhance dopamine
release indirectly by releasing glutamate from neighbouring terminals.
PMID- 10770998
TI - alpha7 nicotinic acetylcholine receptors and modulation of gabaergic synaptic
transmission in the hippocampus.
AB - The present report provides new findings regarding modulation of gamma
aminobutyric acid (GABA) transmission by alpha7 nicotinic receptor activity in
CA1 interneurons of rat hippocampal slices. Recordings were obtained from tight
seal cell-attached patches of the CA1 interneurons, and agonists were delivered
to the neurons via a modified U-tube. Application for 6 s of the alpha7 nicotinic
receptor-selective agonist choline (> or =1 mM) to all CA1 interneurons tested
triggered action potentials that were detected as fast current transients. The
activity triggered by choline terminated well before the end of the agonist
pulse, was blocked by the alpha7 nicotinic receptor antagonist methyllycaconitine
(50 nM) and was concentration dependent; the higher the concentration of choline
the higher the frequency of events and the shorter the delay for detection of the
first event. In 40% of the neurons tested, choline-triggered action potentials
decreased in amplitude progressively until no more events could be detected
despite the presence of the agonist. Primarily, this finding could be explained
by Na(+)-channel inactivation associated with membrane depolarization induced by
alpha7 nicotinic receptor activation. In 60% of the neurons, the amplitude of
choline-induced action potentials was sustained at the intial level, but again
the activity did not last as long as the agonist pulse, in this case apparently
because of agonist-induced receptor desensitization. These results altogether
demonstrate that agonists interacting with alpha7 nicotinic receptors, including
the natural transmitter acetylcholine and its metabolite choline, influence
GABAergic transmission, not only by activating these receptors, but also by
controlling the rate of Na(+)-channel inactivation and/or by inducing receptor
desensitization.
PMID- 10770999
TI - Transcriptional control of the neuronal nicotinic acetylcholine receptor gene
cluster by the beta43' enhancer, Sp1, SCIP and ETS transcription factors.
AB - Receptors assembled from the products of a neuronal beta4alpha3alpha5 NAChR gene
cluster depend on these genes being coordinately regulated in particular
populations of neurons. Little is known, however, about the transcriptional
mechanisms that are likely to underlie their co-expression in correct neuronal
cell types. We have identified several regulatory elements and transcription
factors that influence transcription of the alpha3 and beta4 genes. The promoters
of these genes appear to contain a common cis element that binds Sp1
transcription factors. They can be activated by the POU-domain factor SCIP and
activation does not require SCIP binding sites. Between these two promoters is a
cell type specific enhancer called beta43'. This enhancer has little activity in
non-neuronal cells and is preferentially active in particular populations of
central neurons. The clustered genes are potential targets of ETS factors as the
ETS domain factor, Pet-1 can activate beta43'-dependent transcription. The neuron
selective properties of beta43' and its location suggest that it is a component
of the cis regulatory information required to control expression of the beta4 and
alpha3 genes in specific populations of neurons.
PMID- 10771000
TI - Interactions between regulatory proteins that bind to the nicotinic receptor
beta4 subunit gene promoter.
AB - The genes encoding the alpha3, alpha5 and beta4 subunits of nicotinic
acetylcholine receptors are tightly clustered within the genome. As these three
subunits constitute the predominant acetylcholine receptor subtype expressed in
the peripheral nervous system, their genomic proximity suggests a regulatory
mechanism ensuring their coordinate expression. We previously identified two
transcriptional regulatory elements within the beta4 promoter. One of these
elements, a CT box, interacts with the regulatory factors heterogeneous nuclear
ribonucleoprotein K and Puralpha. Another element, a CA box, interacts with Sp1
and Sp3. The binding site for a fifth factor, Sox10, overlaps the CT and CA
boxes. As the CT and CA boxes are adjacent, we postulated that the proteins that
bind to the elements interact. Here we report that the CT box-binding factors
interact with each other as do the CA box-binding factors. However, there are no
direct associations between the two pairs of proteins. Interestingly though,
Sox10 directly interacts with all four proteins, suggesting a central role in
beta4 gene expression for this member of the Sox family of regulatory factors.
PMID- 10771001
TI - Transcriptional regulation of the human alpha5 nicotinic receptor subunit gene in
neuronal and non-neuronal tissues.
AB - The human alpha5 nicotinic receptor subunit gene appears to be expressed in
several structures of the nervous system, but also in a number of non-neuronal
tissues, with maximal expressions occurring in the entire gastrointestinal tract,
thymus and testis. To understand whether specific transcriptional mechanisms are
involved in the tissue-specific expression of the alpha5 subunit in neuronal and
non-neuronal cells, we isolated the 5'-regulatory region of the human gene and
characterized its functional properties. We demonstrate that specific DNA
elements, with positive or negative activities depending on the cell type, are
responsible for the diversified expression of the alpha5 subunit in different
tissues. We therefore conclude that the expression of the alpha5 subunit relies
on a highly complex promoter that uses distinct regulatory elements to comply
with the different functional and developmental requirements of the various
tissues and organs.
PMID- 10771002
TI - Nicotinic acetylcholine receptor gene expression in developing chick autonomic
ganglia.
AB - The developmental expression patterns of ten genes encoding nicotinic
acetylcholine receptor subunits were analyzed using Northern blots and in situ
hybridization in chick peripheral ganglia of neural crest, placodal and dual
embryonic origin. The superior cervical and ciliary ganglia were investigated in
detail because they accumulated relatively abundant transcripts of the alpha3,
beta4, alpha5 and alpha7 genes. In the superior cervical ganglion, these four
mRNA species had similar developmental time-courses. They appeared at embryonic
day 8 (E8), increased steadily until E16 and maintained a rather high plateau
level until E18. In the ciliary ganglion, alpha7 transcripts were already
abundant at E6, increased until E10, and considerably decreased thereafter. High
resolution in situ hybridization showed that alpha7 transcripts were present in
all cell types of the E6 ciliary ganglion, whereas they were restricted to large
neuronal somas at E16. Transfections with a reporter gene under the control of
the alpha7 promoter demonstrated that a sharp developmental divide occurred at
E11-12, after which stage the promoter was activatable in neurons exclusively.
PMID- 10771003
TI - Targeting alpha7-containing nicotinic receptors on neurons to distal locations.
AB - Nicotinic receptors containing the alpha7 gene product are widely expressed in
the nervous system and have a high relative permeability to Ca(2+). This permits
them to influence a variety of Ca(2+)-dependent events in neurons. On chick
ciliary ganglion neurons, the receptors are concentrated on somatic spines and
contribute directly to postsynaptic signaling. Receptors containing the alpha7
gene product can also be found in the chick sciatic nerve being transported to
distal locations. Both motoneurons and dorsal root ganglion neurons are candidate
sources of the receptors since both extend processes into the nerve and
synthesize alpha7 protein. Immunoprecipitation assays with subunit-specific
monoclonal antibodies and pharmacological comparisons fail to detect differences
between sciatic nerve and ciliary ganglion alpha7-containing receptors. Cell
specific machinery and receptor posttranslational modifications may determine
which sites the receptors populate.
PMID- 10771004
TI - Nicotinic acetylcholine receptor knockout mice as animal models for studying
receptor function.
AB - Nicotinic acetylcholine receptors are pentameric ligand-gated ion channels, which
are involved in a wide range of neuronal functions. During the past decade, a
large number of nicotinic acetylcholine receptor subunits have been cloned and
showed a discreet yet overlapping distribution pattern. Recently, several groups
have produced mutant mice lacking specific nicotinic acetylcholine receptor
subunits. In this review, we focus on how the study of these knockout mouse
models has advanced our understanding of the role individual nicotinic
acetylcholine receptor subunits play in the function and composition of
endogenous receptors and the diverse pharmacological actions of nicotine in the
mammalian nervous system.
PMID- 10771005
TI - Pharmacological and null mutation approaches reveal nicotinic receptor diversity.
AB - We have developed an array of assays for nicotinic acetylcholine receptor binding
and function. [125I]alpha-Bungarotoxin-, (-)-[3H]nicotine-, and [3H]epibatidine
binding nicotinic acetylcholine receptors were assayed in mouse brain membranes
and sections. Nicotinic acetylcholine receptor function was quantified using
synaptosomal [3H]dopamine, [3H]gamma-aminobutyric acid ([3H]GABA), and 86Rb(+)
efflux techniques. Additionally, the effects of beta2 subunit deletion on each of
the measures were assessed. Detailed pharmacological comparison revealed
minimally six nicotinic binding subtypes: [125I]alpha-bungarotoxin-binding
nicotinic acetylcholine receptors; beta2-subunit-dependent and -independent high
affinity (-)-[3H]nicotine-binding sites; beta2-dependent and -independent
cytisine-resistant [3H]epibatidine-binding sites; and a beta2-dependent low
affinity [3H]epibatidine binding site. Comparative pharmacology suggested that
[3H]GABA and dihydro-beta-erythroidine (DHbetaE)-sensitive 86Rb(+) efflux are
mediated by the same (probably alpha4beta2) nicotinic acetylcholine receptor
subtype, while other nicotinic acetylcholine receptor subtypes evoke [3H]dopamine
and DHbetaE-resistant 86Rb(+) efflux. In whole-brain preparations, each measure
of nicotinic acetylcholine receptor function was beta2 dependent. The majority of
beta2-independent [3H]epibatidine binding was located in small, scattered brain
nuclei, suggesting that individual nuclei may prove suitable for identification
of novel, native nicotinic acetylcholine receptors.
PMID- 10771006
TI - Nicotinic acetylcholine receptors in the autonomic control of bladder function.
AB - Micturition is achieved through complex neurological mechanisms involving
somatic, autonomic and central components. This article briefly reviews recent
findings on the autonomic control of urinary bladder function. Neuronal nicotinic
acetylcholine receptors mediate fast synaptic transmission in autonomic ganglia,
and activation of nicotinic receptors in parasympathetic bladder neurons produces
contraction of the detrusor muscle. Autonomic ganglia contain transcripts for the
alpha(3), alpha(4), alpha(5), alpha(7), beta(2) and beta(4) nicotinic subunits,
which can assemble to form multiple nicotinic receptor subtypes, but the exact
nicotinic receptor subunit composition in bladder ganglia is unknown. Mutant mice
lacking the alpha(3) or the beta(2) and the beta(4) nicotinic subunits have
enlarged bladders with dribbling urination and develop urinary infection and
bladder stones. Bladder strips from alpha(3) null mice do not respond to nicotine
but contract when stimulated with a muscarinic agonist or electric field
stimulation. Mice lacking the beta(2) subunit have no overt bladder phenotype,
and their bladders contract in response to nicotine. Surprisingly, bladder strips
from beta(4) mutant mice do not respond to nicotine despite the absence of major
bladder dysfunction in vivo. These findings suggest that nicotinic receptors
containing the alpha(3) and the beta(4) subunits are necessary for normal bladder
function.
PMID- 10771007
TI - Development of nicotinic drug therapy for cognitive disorders.
AB - Nicotine, as well as other nicotinic drugs, may provide useful therapeutic
treatment for a variety of cognitive impairments including those found in
Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder
(ADHD). We have found that nicotine skin patches significantly improve
attentional performance in people with these disease states as well as normal
nonsmoking adults. Animal models are critical for determining the neurobehavioral
bases for nicotinic effects on cognitive function. We have found in lesion and
local infusion studies with rats that the hippocampus is an important substrate
for nicotinic effects on working memory function. Both alpha7 and alpha4beta2
nicotinic receptors in the hippocampus are involved. Further work has
investigated the relationship of nicotinic systems with dopaminergic and
glutaminergic systems in the basis of cognitive function. Nicotine has proven to
be a useful prototypic compound for the family of nicotinic compounds. It
produces cognitive improvements in both animal models and clinical populations.
Recent work with more selective nicotinic receptor agonists and antagonists in
animal models is providing important information concerning the neural mechanisms
for nicotinic involvement in cognitive function and opening avenues for
development of safe and effective nicotinic treatments for clinical use.
PMID- 10771008
TI - Nicotine in an animal model of attention.
AB - Studies in smokers have suggested that at least part of the improved psychomotor
performance produced by nicotine is the result of an effect on attention. Many
animal experiments have assessed the effects of nicotine and its antagonists on
diverse types of learning and memory but relatively few have looked at it in
tasks designed to assess attention. In a five-choice serial reaction time task (5
CSRTT), rats with restricted access to food were presented with an array of five
holes; illumination of a randomly selected hole signalled that a nose-poke into
it would be reinforced by food presentation. Initially, signal length and the
inter-trial interval (ITI) were varied and the procedure was demonstrated to
satisfy some criteria for a vigilance task. The effects of nicotine on deficits
in performance induced by varying signal length and ITI were assessed. Under
appropriate conditions, small doses of nicotine increased the percentage of
correct responses (accuracy), decreased omission errors and reaction time, and
increased anticipatory responses. Subsequently, the effects of varying the ITI
were examined more extensively in a slightly modified task. Here, nicotine
produced small but robust, highly significant dose-related increases in accuracy,
as well as decreases in omission errors and reaction times. Nicotine also
increased accuracy when light stimuli were presented in an unpredictable manner.
The nicotine antagonist mecamylamine produced a modest deficit in reaction time
only. It is concluded that appropriate doses of nicotine can produce robust
improvements in performance of normal rats in an attentional task. The effect
cannot be attributed easily to changes in sensory or motor capability, learning
or memory and may provide the measures needed to investigate the
neuropharmacological and neuroanatomical bases of the elusive attentional effect
of nicotine.
PMID- 10771009
TI - A new look at the neuronal nicotinic acetylcholine receptor pharmacophore.
AB - Interest in the field of nicotinic receptors has been recently stimulated both by
the discovery of the potential therapeutic effects of new agonists, and by the
discovery of an association between nicotinic receptor mutations and human
neurological diseases. Expression of human receptors in an exogenous system
allows their study in isolation. Receptors reconstituted by pairwise injection of
either alpha4 or alpha3 with beta2 or beta4 subunits displayed important
differences between the resulting receptor subtypes. These results were further
compared with those obtained with alpha3:alpha4 fusion proteins. The
modifications of either the ligand-binding site in the N-terminal domain or in
the ionic pore domain were found to affect the pharmacological properties of the
receptors. Finally, the analysis of non-natural derivatives of epibatidine
demonstrates how an agonist can be modified to be selective at one receptor
subtype or to become an antagonist. These data are well explained on the basis of
a three-state allosteric model.
PMID- 10771010
TI - Allosteric modulation of nicotinic acetylcholine receptors as a treatment
strategy for Alzheimer's disease.
AB - The basic symptoms of Alzheimer's dementia, i.e., a loss in cognitive function,
are due to impaired nicotinic cholinergic neurotransmission. To compensate for
this impairment by drug treatment, blockers of the acetylcholine-degrading enzyme
acetylcholinesterase are applied, even though this approach obviously is prone to
many side-effects, including those of muscarinic nature. We have recently
described a novel class of nicotinic acetylcholine receptor ligands which,
similar to the action of benzodiazepines on GABA(A) receptors, allosterically
potentiate submaximal nicotinic responses. The sensitizing effect is a
consequence of facilitated channel opening in the presence of allosterically
potentiating ligand (APL). Representative members of this class of ligands are
the plant alkaloids physostigmine, galanthamine, and codeine. Because APLs could
enhance nicotinic neurotransmission under conditions of reduced secretion and/or
increased degradation of acetylcholine or reduced acetylcholine-sensitivity of
nicotinic acetylcholine receptors, they could have a preventive and corrective
action on impaired but still functioning nicotinic neurotransmission.
PMID- 10771011
TI - The identification of novel structural compound classes exhibiting high affinity
for neuronal nicotinic acetylcholine receptors and analgesic efficacy in
preclinical models of pain.
AB - Neuronal nicotinic acetylcholine receptors represent a new and potentially useful
target for the development of novel non-opioid, non-NSAID (nonsteroidal
antiinflammatory drug) analgesic agents. A variety of nicotinic acetylcholine
receptor agonists such as nicotine, epibatidine and the azetidinyl ether, (R)-5
(2-azetidinylmethoxy-2-chloropyridine (ABT-594) possesses significant efficacy in
preclinical models of pain. A preponderance of evidence suggests that nicotinic
acetylcholine receptor agonists produce their analgesic effects predominantly via
activation of descending inhibitory pain pathways originating in the key
brainstem regions of the nucleus raphe magnus, dorsal raphe, and locus coeruleus,
and that alpha4-containing nicotinic acetylcholine receptor subunits mediate
these effects. Although these studies may provide a pharmacological target for
the development of nicotinic acetylcholine receptor analgesics, the rational
design of selective ligands based on the protein structure of the binding site is
hampered by insufficient structural information. Using an approach based upon
homology to known high-affinity ligands for the alpha4beta2 binding site, a four
point model is proposed which defines distance and directionality parameters
common to this set of nicotinic acetylcholine receptor ligands.
PMID- 10771012
TI - alpha7 receptor-selective agonists and modes of alpha7 receptor activation.
AB - The alpha7-selective agonists 3-(2, 4-dimethoxybenzylidene)-anabaseine (GTS-21),
also known as DMXB, and 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21)
produce a variety of behavioral and cytoprotective effects that may be related to
the activation of either large transient currents at high concentrations or small
sustained currents at lower agonist concentrations. We are using acutely
dissociated hypothalamic neurons, which express a central nervous system (CNS)
alpha7-type receptor, to test a model for the concentration-dependent
desensitization of alpha7-mediated responses. Our results confirm that 4OH-GTS-21
is a potent activator of neuronal alpha7 nicotinic-acetylcholine receptor. The
rapid application of agonist leads to a brief period of maximal receptor
activation followed by desensitization. Rise rates, decay rates, and the degree
to which current was desensitized were all concentration-dependent. Following the
initial peak response to a 300-microM 4OH-GTS-21 application, current is reduced
to baseline values within about 100 ms. Application of 30 microM 4OH-GTS-21
produced both a transient peak current and a sustained current that decayed only
slowly after the removal of agonist. In the case of a 300-microM 4OH-GTS-21
application, after agonist was removed, we saw a rebound response up to the level
of the 30-microM sustained current. The data, therefore, suggest that a
sufficient level of agonist occupation can be retained on the receptor to promote
activation for up to several hundred milliseconds.
PMID- 10771013
TI - Molecular characterization of the specificity of interactions of various
neurotoxins on two distinct nicotinic acetylcholine receptors.
AB - Snake curaremimetic toxins are currently classified as short-chain and long-chain
toxins according to their size and their number of disulfide bonds. All these
toxins bind with high affinity to muscular-type nicotinic acetylcholine receptor,
whereas only long toxins recognize the alpha7 receptor with high affinity. On the
basis of binding experiments with Torpedo or neuronal alpha7 receptors using wild
type and mutated neurotoxins, we characterized the molecular determinants
involved in these different recognition processes. The functional sites by which
long and short toxins interact with the muscular-type receptor include a common
core of highly conserved residues and residues that are specific to each of toxin
families. Furthermore, the functional sites through which alpha-cobratoxin, a
long-chain toxin, interacts with muscular and alpha7 receptors share similarities
but also marked differences. Our results reveal that the three-finger fold toxins
have evolved toward various specificities by displaying distinct functional
sites.
PMID- 10771014
TI - Conus peptides: novel probes for nicotinic acetylcholine receptor structure and
function.
AB - Conus is a genus of predatory marine snails that uses venom to capture prey.
Among the neurotoxins widely utilized by the cone snails are the alpha-conotoxins
which are disulfide-rich peptides that target muscle or neuronal subtypes of
nicotinic acetylcholine receptors. The small size and receptor subtype
specificity of these peptides make them particularly useful for characterizing
both native and heterologously expressed nicotinic receptors. In this report, we
demonstrate that alpha-conotoxin MII potently blocks beta3-containing neuronal
nicotinic receptors. Furthermore, initial evidence suggests that subpopulations
of alpha3beta2beta3-containing receptors are differentially sensitive to alpha
conotoxin MII. Thus, alpha-conotoxin MII promises to be a useful tool for
studying neuronal nicotinic receptors containing the beta3 subunit.
PMID- 10771015
TI - Potentiation and inhibition of neuronal alpha4beta4 nicotinic acetylcholine
receptors by choline.
AB - The effects of choline on alpha4beta4 nicotinic acetylcholine receptors,
expressed in Xenopus oocytes, were investigated using in the two-microelectrode
voltage clamp technique. Particular attention was paid to the interaction between
the effects of acetylcholine and choline. Choline was a low-affinity agonist of
alpha4beta4 receptors with an efficacy of 10% as compared to acetylcholine.
Responses evoked by 1 microM acetylcholine were potentiated by low concentrations
of choline and inhibited by > 10mM choline, resulting in a bell-shaped
concentration-effect relationship. Conversely, the effects of choline on
responses evoked by 300 microM acetylcholine resulted in a monophasic inhibition
curve with an IC(50) of 0.87 mM. The data were fitted by a two-site receptor
occupation model, which accounts for similar effects of various cholinergic
ligands on heteromeric nicotinic receptors. The results indicate that the
potentiation was a competitive effect, whereas the inhibition was due to a
mixture of competitive and non-competitive effects. It is concluded that choline
acts as a potent, endogenous co-agonist at heteromeric alpha4beta4 nicotinic
receptors.
PMID- 10771017
TI - Nicotinic receptors and Parkinson's disease.
AB - Accumulating evidence indicates that nicotinic receptors play a role in basal
ganglia function. Furthermore, nicotine administration may be neuroprotective in
animal models of nigrostriatal degeneration, while cigarette smoking is inversely
correlated with Parkinson's disease. Because nicotinic receptors are decreased in
Parkinson's disease, these observations may suggest that nicotinic agonists are
beneficial in this disorder. We used two model systems to investigate this
possibility. One involved non-human primates, which represent a good model
because their neuroanatomical organization resembles that of man and
nigrostriatal degeneration leads to biochemical and behavioral deficits similar
to Parkinson's disease. To identify the subunits that comprise basal ganglia
nicotinic receptors, we investigated alpha4, alpha6, alpha7, beta2, beta3 and
beta4 transcript distribution in monkey substantia nigra. All mRNAs were
expressed with a selective alteration in some transcripts after 1-methyl-4-phenyl
1,2,3,6-tetrahydropteridine (MPTP) induced nigrostriatal degeneration. As an
approach to evaluate neuroprotective effects of nicotine against nigral neuron
damage, we used mesencephalic neurons in culture, treated with a selective
dopaminergic neurotoxin. The results show that nicotine pretreatment protected
against dopaminergic nigral neural degeneration. These data suggest that
nicotinic receptor ligands may be useful in Parkinson's disease therapy.
PMID- 10771016
TI - Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body
diseases.
AB - Human brain ageing is associated with reductions in a variety of nicotinic
receptors subtypes, whereas changes in age-related disorders including
Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's
disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or
7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha
bungarotoxin binding. Epibatidine binding is inversely correlated with clinical
dementia ratings and with the level of Abeta1-42, but not related to plaque or
tangle densities. In contrast, alpha-bungarotoxin binding is positively
correlated with plaque densities in the entorhinal cortex. In human temporal
cortex loss of acetylcholinesterase catalytic activity is positively correlated
with decreased epibatidine binding and in a transgenic mouse model over
expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's
disease, loss of striatal nicotine binding appears to occur early but is not
associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal
elderly individuals is associated with increased alpha4 immunoreactivity in the
cortex and lower densities of amyloid-beta plaques, and with greater numbers of
dopaminergic neurons in the substantia nigra pars compacta. These findings
indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not
in nigro-striatal dopaminergic degeneration.
PMID- 10771018
TI - Neurobiological mechanisms by which nicotine mediates different types of anxiety.
AB - The effects of nicotine administration into the dorsal hippocampus and lateral
septum provide further evidence that different neurochemical and neuroanatomical
substrates control behaviour in different animal tests. Thus, in the social
interaction test (a model of generalised anxiety disorder), bilateral
administration of nicotine (1-4 microg) into both regions has anxiogenic effects
in test conditions that generate moderate anxiety. The anxiogenic effects are
mediated by a nicotine-evoked increase in 5-hydroxytryptamine (5-HT) release and
are reversed by co-administration of the 5-HT(1A) receptor antagonist, N-(2-(6-(2
methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohex -ane carboxamide
trichloride (WAY 100,635). On trial 1 in the elevated plus-maze (which models the
escape components of panic disorder), nicotine is without effect when
administered to the dorsal hippocampus, but has anxiogenic effects after lateral
septal administration. On trial 2 in the elevated plus-maze (a model of specific
phobia), nicotine (1 microg) has anxiolytic effects when administered to the
dorsal hippocampus, but is ineffective (4 and 8 microg) in the lateral septum.
PMID- 10771019
TI - Smoking and schizophrenia: abnormal nicotinic receptor expression.
AB - Biological and genetic evidence suggests a role for the neuronal nicotinic
receptors in the neuropathophysiology of schizophrenia. Nicotine normalizes an
auditory evoked potential deficit seen in subjects who suffer from the disease.
Nicotinic receptors with both high and low affinity for nicotine are decreased in
postmortem brain of schizophrenics compared to control subjects. The chromosomal
locus of the human alpha-7 gene (15q14) is linked to the gating deficit with a
lod of 5.3, and antagonists of the alpha-7 receptor (alpha-bungarotoxin and
methyllycaconitine) induce a loss of gating in rodents. We have cloned the human
alpha-7 gene and found it to be partially duplicated proximal to the full-length
gene. The duplication is expressed in both the brain and in peripheral blood
cells of normal subjects, but is missing in some schizophrenic subjects. The
results of these studies suggest the presence of abnormal expression and function
of the neuronal nicotinic receptor gene family in schizophrenia.
PMID- 10771020
TI - Neuronal nicotinic receptors in human epilepsy.
AB - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare monogenic
idiopathic partial epilepsy characterized by clusters of frontal lobe motor
seizures during sleep. Recently, it has been shown that mutations of the
chromosome-20q-located neuronal nicotinic acetylcholine receptor alpha4-subunit
(CHRNA4) are associated with ADNFLE in some families, but that other families are
not linked to this locus. Both CHRNA4 mutations (Ser248Phe and 776ins3)
identified so far are found in the pore-forming second transmembrane region of
the gene. Electrophysiological studies showed that mutations in this functional
important part of the receptor subunit have a profound effect on the permeability
for calcium ions. Interestingly, the Ser248Phe mutation was found again in a
second ADNFLE family. Haplotype analysis excluded a founder effect and showed
that Ser248Phe occurred independently twice. This provides the possibility to
study the effect of the same mutation on different genetic backgrounds. Several
attempts have been made to identify additional genes responsible for ADNFLE. But
despite some positive linkage results including the CHRNA3-CHRNA5-CHRNB2 cluster
on chromosome 15q24, no further mutations have been found so far. The mutation
screening of functionally important parts of CHRNA5 in 12 ADNFLE patients did not
support a causative role of this nicotinic acetylcholine receptor subunit.
PMID- 10771021
TI - Chronic nicotine treatment decreases neurofilament immunoreactivity in the rat
ventral tegmental area.
AB - Region-specific decreases of neurofilament proteins have been described in the
ventral tegmental area of rats chronically treated with either morphine or
cocaine. The aim of the present study was to assess if the levels of
neurofilament proteins are changed in the ventral tegmental area by chronic
treatment with nicotine. Immunoreactivity for NF-68, NF-160 and NF-200 was
determined using NR4, BF10 and RT97 antibodies, respectively. Measurements were
performed using computer-assisted microdensitometry of brain sections from rats
exposed to chronic nicotine treatment (0.4 mg/kg/dayx6 days) or to saline.
Chronic nicotine treatment reduced NF-160 and NF-200 immunoreactivity by 44.5%
(P<0.01) and 22.5% (P<0. 05), respectively, in the ventral tegmental area but not
in the substantia nigra. A trend towards reduction was observed for NF-68
immunoreactivity in the ventral tegmental area. These preliminary results suggest
that nicotine shares the same properties with cocaine and morphine to reduce
neurofilament proteins in the ventral tegmental area, a key brain structure of
the reward system.
PMID- 10771022
TI - Modulation of beta-amyloid precursor protein processing and tau phosphorylation
by acetylcholine receptors.
AB - Neurofibrillary lesions and senile plaques that are composed mainly of
hyperphosphorylated tau protein and the amyloid-beta peptide derived from the
amyloid precursor protein, respectively, are classical hallmarks of Alzheimer's
disease. A number of studies strongly suggests that amyloid-beta formation and
amyloid depositions are linked to the pathogenesis of Alzheimer's disease. Recent
findings suggest that very low concentrations of the amyloid-beta can inhibit
various cholinergic neurotransmitter functions independently of apparent
neurotoxicity. Many factors have been shown to influence the processing of
amyloid precursor protein, including activation of muscarinic and nicotinic
receptors. This review focus on some recent studies concerning the regulation of
amyloid precursor protein processing and modulation of tau phosphorylation by
acetylcholine receptor stimulation and how cholinergic deficits and amyloid-beta
might be related to one another.
PMID- 10771023
TI - Interaction of tobacco-specific toxicants with the neuronal alpha(7) nicotinic
acetylcholine receptor and its associated mitogenic signal transduction pathway:
potential role in lung carcinogenesis and pediatric lung disorders.
AB - Pulmonary neuroendocrine cells function as hypoxia-sensitive chemoreceptors, and
they release peptides and biogenic amines that are important mediators of
pulmonary neonatal adaptation. Some of these products additionally act as
autocrine growth factors. Increased numbers of pulmonary neuroendocrine cells
have been observed in several smoking-associated pediatric lung disorders such as
bronchopulmonary dysplasia, cystic fibrosis, sudden infant death syndrome, and
asthma. Disturbed pulmonary neuroendocrine function has been implicated in the
etiology of this disease complex. One of the most common smoking-associated lung
cancer types, small cell lung carcinoma, expresses phenotypic and functional
features of pulmonary neuroendocrine cells. We, as well as others, have shown
that the release of the autocrine growth factors 5-hydroxytryptamine (5-HT,
serotonin) and mammalian bombesin/gastrin releasing peptide (MB/GRP) by cell
lines derived from human small cell lung carcinoma or fetal hamster pulmonary
neuroendocrine cells are regulated by a neuronal nicotinic acetylcholine receptor
comprised of alpha(7) subunits. In radio-receptor assays, nicotine and the
nicotine-derived carcinogenic nitrosamines NNNN. Binding of nicotine or NNK to
the alpha(7) receptor resulted in calcium influx and overexpression and
activation of the serine-threonine protein kinase Raf-1. In turn, this event lead
to overexpression and activation of the mitogen activated (MAP) kinases
extracellular signal regulated kinase 1 (ERK1) and extracellular signal regulated
kinase 2 (ERK2) and stimulation of DNA synthesis accompanied by an increase in
cell numbers in fetal pulmonary neuroendocrine cells and small cell carcinoma
cells. Exposure of fetal pulmonary neuroendocrine cells for 6 days to NNK caused
a prominant up-regulation of Raf-1. Our findings suggest that chronic exposure to
nicotine and NNK in pregnant women who smoke may up-regulate the alpha(7)
nicotinic receptor as well as components of its associated mitogenic signal
transduction pathway, thus increasing the susceptibilities of the infants for the
development of pediatric lung disorders. Similarly, up-regulation of one or
several components of this nicotinic receptor pathway in smokers may be an
important factor for the development of small cell lung carcinoma.
PMID- 10771024
TI - Neuronal nicotinic receptors in non-neuronal cells: new mediators of tobacco
toxicity?
AB - The nicotinic acetylcholine receptors are prototypic ionotropic receptors that
mediate fast synaptic transmission. However, also non-excitable cells, and
particularly the tegumental cells that line external and internal body surfaces,
express acetylcholine receptors of neuronal type sensitive to nicotine. Bronchial
epithelial cells, endothelial cells of blood vessels and skin keratinocytes
express neuronal nicotinic receptors composed of alpha(3), alpha(5), beta(2) and
beta(4) subunits, similar to those expressed in sympathetic ganglia, and neuronal
nicotinic receptors composed of alpha(7) subunits. Neuronal nicotinic receptors
in tegumental cells are involved in modulating cell shape and motility, and
therefore in maintaining the integrity of the surfaces lined by those cells.
Neuronal nicotinic receptors in non-neuronal tissues may modulate other
functions, including cell proliferation and differentiation. Acetylcholine is
synthesized, secreted and degraded by a variety of cells, including the
tegumental cells that express neuronal nicotinic receptors. Thus, acetylcholine
may function as a local "hormone" that is able to modulate cell functions that
require fast adaptation to new conditions. The presence of neuronal nicotinic
receptors sensitive to nicotine in tissues known to be involved in tobacco
toxicity, like bronchi and blood vessels, raises the possibility that they
mediate some of the toxic effects of smoking.
PMID- 10771025
TI - Role of dopamine in the behavioural actions of nicotine related to addiction.
AB - Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by
dopamine receptor antagonists shows that dopamine is involved in nicotine's
discriminative stimulus properties, nicotine-induced facilitation of intracranial
self-stimulation, intravenous nicotine self-administration, nicotine conditioned
place-preference and nicotine-induced disruption of latent inhibition. Therefore,
nicotine depends on dopamine for those behavioural effects that are most relevant
for its reinforcing properties and are likely to be the basis of the abuse
liability of tobacco smoke. On the other hand, in vivo monitoring studies show
that nicotine stimulates dopamine transmission in specific brain areas and in
particular, in the shell of the nucleus accumbens and in areas of the extended
amygdala. These effects of nicotine resemble those of a reward like food except
that nicotine-induced release of dopamine does not undergo single-trial, long
lasting habituation. It is speculated that repeated non-habituating stimulation
of dopamine release by nicotine in the nucleus accumbens shell abnormally
facilitates associative stimulus-reward learning. Acute effects of nicotine on
dopamine transmission undergo acute and chronic tolerance; with repeated,
discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine
release in the nucleus accumbens core takes place while the response in the shell
is reduced. It is speculated that these adaptive changes are the substrate of a
switch from abnormal incentive responding controlled by consequences (action
outcome responding) into abnormal habit responding, triggered by conditional
stimuli and automatically driven by action schemata relatively independent from
nicotine reward. These two modalities might coexist, being utilized alternatively
in relation to the availability of tobacco. Unavailability of tobacco disrupts
the automatic, implicit modality of abnormal habit responding switching
responding into the explicit, conscious modality of incentive drug-seeking and
craving.
PMID- 10771026
TI - Round table on nicotinic receptors in addiction: summary report.
PMID- 10771027
TI - Pyrantel resistance alters nematode nicotinic acetylcholine receptor single
channel properties.
AB - Resistance to the anthelmintics pyrantel ((E)-1,4,5, 6-tetrahydro-1-methyl-2-[2
(2thienyl)ethenyl]pyrimidine) and levamisole ((S)-2,3,5,6-tetrahydro-6
phenylimidazo[2,1-b]thiazole) is an increasingly widespread problem in gastro
intestinal nematode infestations. Both compounds act on the nicotinic
acetylcholine receptors on the surface of nematode somatic muscle. The patch
clamp technique was used to measure nematode nicotinic acetylcholine receptor
properties at 75, 50, -50 and -75 mV in a pyrantel-resistant isolate of
Oesophagostomum dentatum. Patch pipettes contained 30 microM levamisole as
agonist. We found that 28. 1% of membrane patches contained active receptors. At
50 mV, the single-channel conductance was 36.2+/-1.4 pS, the mean open-time (tau)
was 1.45+/-0.14 ms and the mean probability of opening (P(o)) was 0.004+/-0.002.
We compared these results with previous work on an anthelmintic sensitive isolate
and a levamisole-resistant isolate [Robertson, A.P., Bjorn, H.E., Martin, R.J.,
1999. Levamisole resistance resolved at the single-channel level. FASEB J. 13,
749-760.]. We found that pyrantel-resistant parasites had a reduced percentage of
active patches and a reduced P(o) value when compared to anthelmintic sensitive
worms. We concluded that pyrantel resistance is associated with a modification of
the target nicotinic receptor properties.
PMID- 10771028
TI - Effect of rabeprazole on histamine synthesis in enterochromaffin-like cells of
mast cell-deficient (Ws/Ws) rats.
AB - The effect of rabeprazole, the latest proton pump inhibitor, on the serum gastrin
concentration, histidine decarboxylase activity and histamine content of the
oxyntic mucosa in Wistar rats, mast cell-deficient (Ws/Ws) rats, and their normal
type, +/+, rats was investigated. In Wistar rats, 2 weeks of treatment with
rabeprazole (30 mg/kg/day, s.c.) induced a 1.8-fold increase in serum gastrin
concentration and a 3.9-fold increase in histidine decarboxylase activity of the
oxyntic mucosa over the control levels, whereas neither 2- nor 4-week treatment
affected the histamine content of the oxyntic mucosa. In Ws/Ws and +/+ rats, the
serum gastrin concentration, histidine decarboxylase activity and even histamine
content of the oxyntic mucosa were increased significantly as compared with
control levels after the 4-week treatment with rabeprazole. Immunohistochemistry
using a histamine antibody confirmed the increase in the histamine content of the
oxyntic mucosa after the 4-week treatment with rabeprazole. The finding that
there were no differences in serum gastrin concentration and histidine
decarboxylase activity between Ws/Ws and +/+ rats, both with and without the 4
week treatment, indicates that mast cells do not respond to endogenous
hypergastrinemia elicited by acid-inhibitory treatment. Moreover, the present
study clarified for the first time that enterochromaffin-like (ECL) cells in
Ws/Ws rats synthesize and store histamine in response to gastrin.
PMID- 10771029
TI - Pharmacological characterization of the rat metabotropic glutamate receptor type
8a revealed strong similarities and slight differences with the type 4a receptor.
AB - In the brain, group-III metabotropic glutamate (mGlu) receptors mGlu(4), mGlu(7)
and mGlu(8) receptors play a critical role in controlling the release process at
many glutamatergic synapses. The pharmacological profile of mGlu(4) receptor has
been studied extensively, allowing us to propose a pharmacophore model for this
receptor subtype. Surprisingly, the activity of only a few compounds have been
reported on mGlu(7) and mGlu(8) receptors. In order to identify new possibilities
for the design of selective compounds able to discriminate between the members of
the group-III mGlu receptors, we have undertaken a complete pharmacological
characterization of mGlu(8) receptor and compared it with that of mGlu(4)
receptor, using the same expression system, and the same read out. The activities
of 32 different molecules revealed that these two mGlu receptors subtypes share a
similar pharmacological profile. Only small differences were noticed in addition
to that previously reported with S-carboxyglutamate (S-Gla) being a partial
agonist at mGlu(4) receptor and a full antagonist at mGlu(8) receptor. These
include: a slightly higher relative potency of the agonists 1S,3R and 1S,3S
aminocyclopentane-1,3-dicarboxylic acid (ACPD), S-4-carboxyphenylglycine (S-4CPG)
and S-4-carboxy-3-hydroxyphenylglycine (S-4C3HPG), and a slightly higher potency
of the antagonists 2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY354740)
and RS-alpha-methyl-4-phosphonophenylglycine (MPPG) on mGlu(8) receptor. When
superimposed on the mGlu(4) receptor pharmacophore model, these molecules
revealed three regions that may be different between the ligand binding sites of
mGlu(8) and mGlu(4) receptors.
PMID- 10771030
TI - Control of c-fos expression in STC-1 cells by peptidomimetic stimuli.
AB - Enteroendocrine cells respond to nutrient and non-nutrient stimuli in the gut
lumen. The intestinal hormone cholecystokinin (CCK) is secreted in response to
luminal fatty acids, amino acids, peptides and proteins. The peptidomimetic
cephalosporins have been reported to provide model, stable, compounds with
similar secretagogue activity to peptide. Putative luminal stimuli also influence
transcriptional activity in enteroendocrine cells, but the mechanisms are
uncertain. In the present study we have investigated the control of c-fos
expression in STC-1 cells (an enteroendocrine cell line). Peptidomimetics
stimulated calcium-dependent release of CCK, and increased intracellular calcium,
phosphorylation of p42/44 mitogen-activated protein kinase (MAP kinase) and c-fos
mRNA abundance. Hypotonic stress also increased p42/44 MAP kinase phosphorylation
and c-fos mRNA, but not CCK release. The increase in c-fos mRNA was strikingly
potentiated by peptidomimetics in hypotonic medium. Increased c-fos expression,
but not CCK release, was suppressed by the MAP kinase (MEK) inhibitor PD98059,
and by the tyrosine kinase inhibitor genistein. We conclude that in STC-1 cells,
peptidomimetics act through the p42/44 MAP kinase pathway to increase c-fos
expression but not exocytosis. Moreover, a putative non-nutritive stimulus,
hypotonic stress, may interact with this pathway to enhance c-fos expression,
independently of hormone release.
PMID- 10771031
TI - Modulation of Ca(2+)-dependent K(+) currents in mesenteric arterial smooth muscle
cells by adenosine.
AB - The effect of adenosine on Ca(2+)-dependent K(+) currents was studied in freshly
isolated smooth muscle cells from rat mesenteric artery. Perforated-patch
recordings showed that adenosine induced transient outward currents and an
overall increase in the averaged currents at higher depolarizing potentials. The
changes in current activity induced by adenosine could be blocked by iberiotoxin.
The transient outward currents were not dependent directly on external Ca(2+) and
could be induced after brief exposure to Ca(2+)-free solutions. In conventional
whole-cell recordings, transient outward currents were also induced by adenosine
when a low EGTA concentration of 0.1 mM was included in the pipette solution.
Adenosine was not effective in inducing increases in outward currents when a
higher concentration of 5.0 mM EGTA was used. Ryanodine and thapsigargin were
also effective in blocking the effect of adenosine. These observations suggest
that adenosine may activate Ca(2+)-dependent K(+) currents by inducing Ca(2+)
release from ryanodine-sensitive channels in the sarcoplasmic reticulum of rat
mesenteric arterial cells.
PMID- 10771032
TI - Inhibition by chloral hydrate and trichloroethanol of AMPA-induced Ca(2+) influx
in rat cultured cortical neurones.
AB - The effects of chloral hydrate and its main metabolite 2,2, 2-trichloroethanol
were investigated on the (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
(AMPA)-induced rise of intracellular Ca(2+) concentration ([Ca(2+)](i)) in
cultured non-pyramidal cortical neurones of rats by using single-cell fura-2
microfluorimetry. AMPA elicited a concentration-dependent effect that peaked at
300 microM (EC(50), 7. 5 microM). Responses to AMPA (30 microM) were markedly
inhibited by superfusion with chloral hydrate (IC(50), 4.5 mM) or
trichloroethanol (IC(50), 0.9 mM). By contrast, ethanol (100 mM) caused only
slight inhibition. In conclusion, the results demonstrate that chloral hydrate
and especially its metabolite trichloroethanol, inhibit the AMPA-induced rise of
[Ca(2+)](i) by depressing the entry of Ca(2) into cortical neurones via the AMPA
receptor-channel.
PMID- 10771033
TI - The novel antagonist, S33084, and GR218,231 interact selectively with cloned and
native, rat dopamine D(3) receptors as compared with native, rat dopamine D(2)
receptors.
AB - The novel benzopyranopyrrole, S33084 ((3aR,9bS)-N[4-(8-cyano-1,3a,4, 9b
tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)), and
the aminotetralin derivative, GR218,231 (2(R,S)-(di-n-propylamino)-6-(4
methoxyphenylsulfonylmethyl)-1,2,3 , 4-tetrahydro naphthalene), displayed high
affinity at cloned, rat dopamine D(3) receptors (pK(i)s of 8.72 and 8.67,
respectively), as well as dopamine D(3) receptors in rat olfactory tubercle (8.62
and 8.94, respectively). In contrast, they showed low affinities at striatal
dopamine D(2) receptors (6.82 and 6.64, respectively). Unlike S33084 and
GR218,231, the arylpiperazine, L741,626 (4-(4-chlorophenyl)-1-(1H-indol-3
ylmethyl)piperidin-4-ol), showed lower affinity for cloned (6.46) and native
(6.92) dopamine D(3) receptors than for striatal dopamine D(2) receptors (7.52).
S33084, GR218,231 and L741,626 should prove useful tools for exploration of the
functional roles of dopamine D(3) vs. dopamine D(2) receptors.
PMID- 10771034
TI - Mechanism of histamine release induced by levofloxacin, a fluoroquinolone
antibacterial agent.
AB - The present study was designed to clarify the mechanism of histamine release
caused by levofloxacin, a fluoroquinolone antibacterial agent, using rat
peritoneal mast cells. Levofloxacin induced a concentration-dependent histamine
secretion from 300 microg/ml without lactate dehydrogenase leakage, and the
release was rapidly completed within 30 s. This action was dependent on
temperature, energy, pH and intracellular Ca(2+), similarly to the effect of
compound 48/80, a basic compound. Unlike that with the calcium ionophore A23187,
histamine secretion due to levofloxacin or compound 48/80 was prevented by
pretreatment with either pertussis toxin or benzalkonium chloride, a selective
inhibitor of G proteins of G(i) subtypes. Moreover, the histamine release
elicited by levofloxacin or compound 48/80 was suppressed by hydrolysis of sialic
acid residues on the cell surface brought about by neuraminidase. These results
demonstrate that the mechanism by which levofloxacin exerts histamine release may
be closely linked to activation of pertussis toxin-sensitive G proteins.
PMID- 10771035
TI - omega-agatoxin IVA-sensitive Ca(2+) channel blocker, alpha-eudesmol, protects
against brain injury after focal ischemia in rats.
AB - omega-Agatoxin IVA-sensitive Ca(2+) channels have been thought to be involved in
physiological excitatory amino acid glutamate release and these channels may also
contribute to the development of ischemic brain injury. Recently, we demonstrated
that alpha-eudesmol from Juniperus virginiana Linn. (Cupressaceae) inhibits
potently the presynaptic omega-agatoxin IVA-sensitive Ca(2+) channels. In the
present study, we investigated the effects of alpha-eudesmol on brain edema
formation and infarct size determined after 24 h of reperfusion following 1 h of
middle cerebral artery occlusion in rats. We first found that alpha-eudesmol
concentration-dependently inhibited glutamate release from rat brain synaptosomes
and that its inhibitory effect was Ca(2+)-dependent. In the middle cerebral
artery occlusion study, intracerebroventricular (i.c.v.) treatment with alpha
eudesmol significantly attenuated the post-ischemic increase in brain water
content. alpha-Eudesmol also significantly reduced the size of the infarct area
determined by triphenyltetrazolium chloride staining after 24 h of reperfusion.
Using a microdialysis technique, we further demonstrated that alpha-eudesmol
inhibits the elevation of the extracellular concentration of glutamate during
ischemia. From these results, we suggest that alpha-eudesmol displays an ability
to inhibit exocytotic glutamate release and to attenuate post-ischemic brain
injury.
PMID- 10771037
TI - Temporal summation and a C-fibre reflex in the rat: effects of morphine on
facilitatory and inhibitory mechanisms.
AB - In intact rats, an inhibitory mechanism counteracts the increase in excitability
of a flexor reflex, which is seen in spinal animals following temporal summation
of C-fibre inputs; the Rostral Ventromedial Medulla is involved in this
inhibitory mechanism. Electromyographic responses elicited by electrical
stimulation of the sural nerve were recorded from the biceps femoris in four
types of preparations, namely intact, sham-operated, Rostral Ventromedial Medulla
lesioned and decerebrate-spinal rats. The excitability of the C-fibre reflex was
tested during and following high intensity homotopic electrical conditioning
stimuli. Morphine (2 mg/kg) did not significantly change the basal test response
but increased the excitability of the spinal cord during conditioning. This
effect was triggered by the strength of inputs, involved the Rostral Ventromedial
Medulla and was probably related to some forms of motor stimulation through
dopaminergic transmission. While wind-up was not reduced, the inhibition related
to Diffuse Noxious Inhibitory Controls, which occurred following the conditioning
period, did. In spinal animals where inhibitory mechanisms disappear, the
depressive effects of morphine were unmasked for both wind-up and post
conditioning facilitations. All effects of morphine were completely reversed by
naloxone.
PMID- 10771036
TI - Effects of chronic risperidone on central noradrenergic transmission.
AB - In the present work, we investigated the effects of chronic risperidone
administration on the activity of locus coeruleus noradrenergic neurons. In
addition, the effect of chronic risperidone administration on the basal level of
norepinephrine in the prefrontal cortex was evaluated. Results of this research
showed that chronic risperidone administration increased the activity of locus
coeruleus noradrenergic neurons. The sensitivity of alpha(2)-adrenoceptors in the
somatodendritic region of the locus coeruleus was assessed by using the ID(50) of
clonidine. Results indicated that the firing rate of locus coeruleus
noradrenergic neurons was the same in risperidone-treated rats and controls.
Similarly, the ID(50) for (+/-)-2,5-dimetoxy-4-iodoamphetamine (DOI), an agonist
of 5-HT(2) receptors which inhibits the activity of locus coeruleus neurons by
acting on these receptors, did not show any differences between the firing rate
of these neurons in risperidone treated rats and controls. Unlike controls,
chronically treated rats showed a significant decrease in norepinephrine levels
in the prefrontal cortex. The decreased release of norepinephrine following
continuous risperidone administration could be explained by the sustained
increase in locus coeruleus neuronal activity after chronic risperidone
administration. This low norepinephrine level in the prefrontal cortex may
contribute to the relief of certain negative schizophrenic symptoms and to the
improvement of cognitive function.
PMID- 10771038
TI - Effect of AMPA receptor modulators on hippocampal and cortical function.
AB - Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl
4-isoxazole proprionic acid) receptors because of their potential for enhancing
memory and treating certain pathologies that involve glutamatergic
neurotransmission. The aim of this study was to compare and contrast the
functionality of positive allosteric modulators of AMPA receptors in the
hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs
(excitatory postsynaptic potential) in the hippocampus were augmented by CX516
[(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3
benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap
electrophysiology, it was found that the mode of application dramatically altered
the effect of the modulators of AMPA-induced depolarization. When added
simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in
the frontal cortex. However, in the hippocampus, only aniracetam and
cyclothiazide augmented the response when simultaneously added to AMPA.
Therefore, in addition to regional variations, there appears to be differences in
modulator response dependent upon whether a response is generated endogenously or
exogenously by AMPA.
PMID- 10771039
TI - The novel kappa-opioid receptor agonist TRK-820 has no affect on the development
of antinociceptive tolerance to morphine in mice.
AB - The effects of the novel kappa-opioid receptor agonist 17-cyclopropylmethyl
3,14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl)acrylamido+
++]morphinan hydrochloride (TRK-820) on the development of antinociceptive
tolerance to morphine were investigated in mice and compared with those of trans
3,4-dichloro-N-(2-(1-pyrrolidinyl)-cyclohexyl) benzenacetamide methane sulfonate
hydrochloride (U-50,488H), a well-defined exogenous kappa-opioid receptor
agonist. Morphine (1. 25-20 mg/kg, s.c.) produced a dose-related antinociceptive
effect in the 51 degrees C warm-plate test. Daily treatment with morphine (10
mg/kg, s.c.) resulted in the development of antinociceptive tolerance. The
development of antinociceptive tolerance to morphine was dose-dependently
suppressed by the co-administration of U-50, 488H (1-10 mg/kg, s.c.) with
morphine, but not TRK-820 (0.003-0.03 mg/kg, s.c.). These results suggest that
TRK-820-sensitive kappa-opioid receptor subtypes may not be involved in
modulating the development of antinociceptive tolerance to morphine.
PMID- 10771040
TI - Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5
HT(3) receptor antagonist.
AB - Intermittent cocaine administration induces sensitization (reverse tolerance) to
its behavioral effects. The mechanism(s) mediating sensitization is not clear,
however, previous research has implicated 5-HT(3) receptors in the expression of
sensitization. The present experiment evaluated the ability of the 5-HT(3)
receptor antagonist, ondansetron, administered during withdrawal from chronic
intermittent cocaine administration, to block the expression of sensitization.
Rats were pretreated for 14 days by daily subcutaneous injections of either 40
mg/kg cocaine or 0.9% saline. During the first 5 days of withdrawal from this
pretreatment regimen, all rats received a daily subcutaneous injection of 0-1.0
mg/kg ondansetron. On days 7, 14 or 28 of withdrawal from the cocaine
pretreatment, the rats received a 15.0-mg/kg cocaine challenge. Ambulatory
behavior was automatically recorded for 60 min. Ondansetron had no significant
effect on the subsequent behavioral response to cocaine in the saline control
subjects. In contrast, daily injections of ondansetron blocked the expression of
sensitization at all withdrawal times. We thus report that it is possible to
permanently block the expression of sensitization once it has developed by
administering a 5-HT(3) receptor antagonist.
PMID- 10771041
TI - Angiotensin AT(2) receptors mediate vasodepressor response to footshock in rats.
Role of kinins, nitric oxide and prostaglandins.
AB - Footshocks increased mean arterial pressure and heart rate. Systemic
administration of losartan, a specific angiotensin AT(1) receptor antagonist, not
only inhibited the pressor response to footshocks, but also resulted in
vasodepression. Administration of 1-[[4-(dimethylamino)3-methylphenyl]methyl]-5
(diphenylacetyl)-4,5,6, 7-tetrahydro-1H imidazol (4,5-c] pyridine-6-carboxilic
acid, ditrifluoro acetatemonohydrate (PD 123319), a specific angiotensin AT(2)
receptor antagonist, did not alter the hemodynamic response to footshocks.
Simultaneous blockade of angiotensin AT(1) and AT(2) receptors by combined
administration of losartan and PD 123319, eliminated the vasodepressor response
to footshocks unmasked in losartan-pretreated rats. Saralasin, a non-specific
angiotensin receptor antagonist, abolished the cardiovascular response to
footshocks similarly like the losartan+PD 123319 treatment. Our data suggest that
the vasodepressor response to footshocks in the presence of an angiotensin AT(1)
receptor antagonist is triggered by activation of angiotensin AT(2) receptors. We
studied the role of kinins, nitric oxide and prostaglandins in the vasodepressor
response observed after footshocks. The decrease in mean arterial pressure
observed after footshocks in losartan-treated rats was blunted by icatibant (HOE
140), N(G)-nitro-L-arginine-methyl ester (L-NAME) or indomethacin, indicating
that kinins, nitric oxide and prostaglandins appear to be involved in the
pressure response to footshocks during angiotensin AT(1) receptor blockade.
PMID- 10771042
TI - On the mechanisms of the antispasmodic action of some hindered phenols in rat
aorta rings.
AB - The antispasmodic effects of 3-t-butyl-4-hydroxyanisole (BHA) and some
structurally related compounds were investigated in endothelium-intact rat aorta
rings. Nordihydroguaieretic acid (NDGA), BHA, 3,5-di-t-butyl-4-hydroxyanisole
(DTBHA), 2,6-di-isopropyl phenol (propofol) and 2,2'-dihydroxy-3,3'-di-t-butyl-5,
5'-dimethoxydiphenyl (DIBHA) did not cause relaxation when added at the plateau
of phenylephrine-evoked contraction, nor did they affect the concentration
relaxation curve for acetylcholine in precontracted rings. In rings depolarised
with physiological salt solution (PSS) containing 40 mM K(+), NDGA, BHA, DTBHA,
2, 5-di-t-butyl-1,4-benzohydroquinone (BHQ), propofol and nifedipine, but not
DIBHA, inhibited the contraction induced by cumulative addition of Ca(2+) (0.05
10 mM) in a concentration-dependent manner; this inhibition was inversely related
to the Ca(2+) concentration. In 40 mM K(+) PSS, 25 nM nifedipine blocked the 1 mM
Ca(2+)-induced contraction, whereas 50 microM DTBHA, NDGA, BHA, BHQ and propofol
significantly antagonised it by 84.4%, 73.0%, 52.8%, 45.6% and 35.7%,
respectively. In the presence of 1 microM methyl-1,4-dihydro-2, 6-dimethyl-3
nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay K 8644), the
response to Ca(2+) did not differ from control values with nifedipine and BHQ,
was partially restored with DTBHA and NDGA, and was not affected with BHA and
propofol. Nifedipine markedly inhibited (85.2%) the Ba(2+)-induced contraction
and this effect was totally reversed by Bay K 8644. BHA and DTBHA showed
antispasmodic activity (45.3% and 43.1%, respectively) which was partly reversed
by Bay K 8644. In contrast, Bay K 8644 did not affect the inhibition exerted by
BHQ, NDGA and propofol (69.5%, 53. 3% and 46.1%, respectively). Nifedipine, BHA,
DTBHA, propofol and NDGA inhibited the contractile response to 1 mM Ca(2+) of
aorta rings depolarised with 40 or 80 mM K(+) PSS to a similar extent. Cromakalim
inhibited the Ca(2+)-evoked contraction only in 30 mM K(+) PSS and BHQ only in 80
mM K(+) PSS. DIBHA had no effect on this model. Cromakalim, but not BHA,
stimulated 86Rb(+) efflux from ring preparations. In 80 mM K(+) PSS containing 1
microM nifedipine, only papaverine affected the phenylephrine-induced
contraction. Moreover, when the rings were preincubated with 1 mM Ni(2+), the
response to phenylephrine in the presence of BHQ was significantly reduced. In
conclusion, we propose that BHA may non-specifically inhibit Ca(2+) influx at the
plasmalemma level rather than affect the function of K(+) channels, Ca(2+)
release from intracellular stores or endothelium-dependent relaxation.
PMID- 10771043
TI - Comparative effects of niflumic acid and nifedipine on 5-hydroxytryptamine- and
acetylcholine-induced contraction of the rat trachea.
AB - The effects of niflumic acid, an inhibitor of Ca(2+)-activated Cl(-) (Cl((Ca)))
channels, were compared with those of the voltage-dependent Ca(2+) channel (VDCC)
blocker nifedipine on 5-hydroxytryptamine (5-HT)- and acetylcholine-induced
contractions of the rat isolated trachea. Niflumic acid (3-100 microM) induced a
concentration-dependent inhibition of 5-HT (10 microM)-induced contractions, with
a reduction to 37.0+/-9.5% of the control at the highest concentration. One
micromolar nifedipine, which completely blocked 60 mM KCl-induced contractions,
reduced the response to 5-HT similarly to 39.2+/-11.5% of the control. The
inhibition of the 5-HT response was not significantly different from that
produced by the combined presence of nifedipine (1 microM) and niflumic acid (100
microM), suggesting that their effects were not additive. In contrast, neither
niflumic acid (3-100 microM) nor nifedipine (1 microM) inhibited acetylcholine
induced contractions. The contraction to 5-HT (10 microM) in Cl(-)-free solution
was decreased by more than approximately 85% of the control, whilst that of
acetylcholine was reduced only by approximately 36%. Our data show that niflumic
acid exerts selective inhibitory effects on 5-HT-induced contraction, and suggest
that activation of Cl((Ca)) channels may be a mechanism whereby 5-HT (but not
acetylcholine) induces Ca(2+) entry via VDCCs to elicit contraction.
PMID- 10771044
TI - Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function
in dogs.
AB - We examined the effect of JTH-601 (3-?N-[2-(4-hydroxy-2-isopropyl-5
methylphenoxy)ethyl]-N-methylaminom ethyl?-4-methoxy-2,5,6-trimethylphenol
hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in
isolated canine prostate and in anesthetized dogs. In the contraction study,
phenylephrine and noradrenaline produced concentration-dependent contractions in
canine prostate and carotid artery, respectively. In these tissues, JTH-601,
prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an
alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a
concentration-dependent manner. The pA(2) (pK(B)) values with prostate were
8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin.
The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was
10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In
anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral
pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1
mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but
with a significant effect on blood pressure and heart rate. JTH-601 showed higher
selectivity for canine prostate both in vitro and in vivo. In prostate, an
important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle
contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an
effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet
obstruction by benign prostatic hypertrophy with a minimum effect on the
cardiovascular system.
PMID- 10771045
TI - Aquaretic and hormonal effects of a vasopressin V(2) receptor antagonist after
acute and long-term treatment in rats.
AB - A single oral administration of 1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzene
sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethoxy)cyclohexane]indo l-2 -one
SR121463 (0.3-3 mg/kg), a vasopressin non-peptide V(2) receptor antagonist, to
rats induced dose-dependent aquaresis which was accompanied by Na(+), K(+),
aldosterone and arginine vasopressin excretion over 6 h after dosing. However, no
solute excretion was observed over 24 h. As a result of aquaresis,
hemoconcentration and increases in plasma angiotensin II and adenocorticotrophin
hormone were seen with 3 mg/kg at 2 h after dosing. Chronic treatment with
SR121463 (3 mg/kg/dayx28 days) induced a marked aquaresis associated with
aldosterone and vasopressin excretion. After a week of treatment, urine volume
and aldosterone excretion were reduced ( approximately 40%) and then stabilised,
while urine vasopressin excretion remained almost constant throughout the study.
There were no changes in arterial pressure, plasma osmolality, plasma sodium
concentration, or in number and affinity of liver vasopressin V(1A) and kidney
V(2) receptors 24 h after the last treatment. These results indicate that
SR121463 is a potent aquaretic agent and might be useful for the chronic
management of water-retaining diseases in humans.
PMID- 10771046
TI - Acute neurogenic airway plasma exudation and edema induced by inhaled wood smoke
in guinea pigs: role of tachykinins and hydroxyl radical.
AB - We studied the mechanisms underlying the wood smoke-induced acute airway injury
in 120 anaesthetized guinea pigs. Five minutes after airway exposure, various
doses of wood smoke produced a dose-dependent increase in Evans blue dye contents
at all airway levels measured. Additionally, inhaled wood smoke produced
submucosal edema of the trachea and bronchus, and peribronchial edema. These
acute airway responses were nearly abolished by pretreatment with CP-96,345 alone
[a tachykinin NK(1) receptor antagonist; (2S, 3S)-cis-2-(diphenylmethyl)-N-((2
methoxyphenyl)-methyl)-1-azabicyc lo( 2.2.2.)-octan-3-amine] or with a
combination of CP-96,345 and dimethylthiourea (a hydroxyl radical scavenger), and
were attenuated by pretreatment with dimethylthiourea alone, yet were not
affected by pretreatment with SR-48,968 [a tachykinin NK(2) receptor antagonist;
(S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)
butyl)benzamide], with a combination of CP-96,344 and SR-48,965 (inactive
enantiomers), with MK-886 [a leukotriene biosynthesis inhibitor; L-663, 536(3-(1
(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl)-2, 2-dimethylpropanoic
acid], with indomethacin (a cyclooxygenase inhibitor), or with N(G)-nitro-L
arginine methyl ester (a nitric oxide (NO) synthase inhibitor). The activity of
airway neutral endopeptidase (an enzyme for tachykinin degradation) was not
influenced by wood smoke at 5-min post-exposure. We conclude that both endogenous
tachykinins and hydroxyl radical play an important role in producing smoke
induced acute airway plasma exudation and airway edema in guinea pigs. The
contribution of tachykinins to these neurogenic responses is mediated via the
activation of tachykinin NK(1) receptors and partly via a hydroxyl radical
mechanism, and is not associated with inactivation of neutral endopeptidase.
PMID- 10771047
TI - Inhibition by nitric oxide-releasing compounds of E-selectin expression in and
neutrophil adhesion to human endothelial cells.
AB - The effects of two chemically unrelated nitric oxide (NO)-releasing compounds
were studied on adhesion molecule expression in and neutrophil adhesion to human
umbilical vein endothelial cells. Incubation of confluent monolayers of
endothelial cells with increasing concentrations of lipopolysaccharide stimulated
the adhesion of polymorphonuclear leukocytes to endothelial cells. Flow
cytometric analysis showed that lipopolysaccharide treatment upregulated the
expression of adhesion molecules E-selectin and intercellular adhesion molecule-1
(ICAM-1) in human umbilical vein endothelial cells. A novel NO-releasing compound
GEA 3175 (1,2,3, 4-oxatriazolium, -3-(3-chloro-2-methylphenyl)-5-[[(4
methylphenyl)sulfonyl]amino]-, hydroxide inner salt) inhibited lipopolysaccharide
induced adhesion being more potent than the earlier known NO donor S-nitroso-N
acetylpenicillamine. The increased E-selectin expression induced by
lipopolysaccharide was significantly attenuated by the two NO donors tested
whereas ICAM-1 expression remained unaltered. The present data show that NO
donors inhibit E-selectin expression in and neutrophil adhesion to
lipopolysaccharide-stimulated vascular endothelial cells. Thus, by inhibiting
leukocyte adhesion NO donors may reduce leukocyte infiltration and leukocyte
mediated tissue injury in inflammation and ischemia-reperfusion injury.
PMID- 10771048
TI - Suppression of cytochrome P450 gene expression in the livers of mice with
concanavalin A-induced hepatitis.
AB - Cytochrome P450 (CYP) gene expression in the livers of mice with concanavalin A
induced hepatitis was examined. Treatment of mice with concanavalin A (10 mg/kg,
i.v.) elevated plasma alanine aminotransaminase activity. In normal liver,
CYP1A2, 3A and 2E1 mRNAs were expressed, and concanavalin A treatment
differentially suppressed the expression of these CYP genes. Gadolinium chloride
(40 mg/kg, i.p.) treatment, which inhibited the concanavalin A-induced elevation
of plasma alanine aminotransferase activity without affecting concanavalin A
induced cytokine expression, counteracted the concanavalin A-induced suppression
of CYP gene expression in the liver. Kupffer cell function or hepatic injury
might contribute to the concanavalin A-induced suppression of CYP gene
expression.
PMID- 10771050
TI - Phenol-oxidase (laccase) activity in strains of the hyphomycete Chalara paradoxa
isolated from olive mill wastewater disposal ponds.
AB - Production of laccase activity by nine strains of Chalara paradoxa isolated from
olive mill wastewater disposal ponds were studied. Enzyme extracts obtained from
cultured broths by adsorption on hydroxyapatite showed a single band of laccase
activity on ABTS after polyacrylamide gel electrophoresis (PAGE). They showed
small mobility differences, with molecular masses of 67 to 68 kDa. Enzymes from
the different strains oxidized a variety of phenolic and non-phenolic substances,
and they could be divided into two groups according to their relative activities
on substrates. All laccases showed a dual pH dependence of activity, with a
maximum in the range of pH 3.0 to 4.5 for ABTS, o-dianisidine and 2,6
dimethoxyphenol, and pH 6.0 (Group 1) or pH 6.5 (Group 2) for syringaldazine and
other substrates. Optimal temperatures were in the range of 10 to 28 degrees C
for two strains (maximum at 10 degrees C) and 10 to 37 degrees C for the rest.
The different enzymes were partially inactivated by heating at 60 degrees C and
totally inactivated at 70 degrees C. Laccases were stable in a pH range of 3.0 to
9.0 (except for strain 36A, which was partially inactivated at pH 3.0), but
became inactivated at pH 2.0. Altogether these data suggest that Ch. paradoxa
strains produce different laccase isoenzymes.
PMID- 10771051
TI - Increasing the thermal stability of the water-soluble pyrroloquinoline quinone
glucose dehydrogenase by single amino acid replacement.
AB - Based on the characterization of a PCR mutation of water-soluble glucose
dehydrogenase possessing pyrroloquinoline quinone (PQQ), PQQGDH-B, Ser231Cys, we
have constructed a series of Ser231 variants. The replacement of Ser231 to Cys,
Met, Leu, Asp, Asn, His, or Lys resulted in an increase in thermal stability.
Among these variants, Ser231Lys showed the highest level of thermal stability and
also showed high catalytic activity. Considering that Ser231Lys showed more than
an 8-fold increase in its half-life during the thermal inactivation at 55 degrees
C compared with the wild-type enzyme, and also retained catalytic activity
similar to a wild-type enzyme, the application of this mutant enzyme as a glucose
sensor constituent may develop into a stable glucose sensor construction.
PMID- 10771049
TI - Chitinolytic enzymes: an exploration.
AB - Chitin and chitinolytic enzymes are gaining importance for their biotechnological
applications. Particularly, chitinases are used in agriculture to control plant
pathogens. Chitinases and chitooligomers produced by enzymatic hydrolysis of
chitin can also be used in human health care. The success in employing chitinases
for different aspects depends on the supply of highly active preparations at
reasonable cost. Therefore, the understanding of biochemistry and genetics of
chitinolytic enzymes, their phylogenetic relationships and methods of estimation
will make them more useful in a variety of processes in near future.
PMID- 10771052
TI - Immobilization of catalase on chitosan film.
AB - Catalase was immobilized on the chitosan film that is a natural polymer. Studies
were done on free catalase and immobilized catalase on chitosan film concerning
the determination of optimum temperature, optimum pH, thermal stability, storage
stability, operational stability, and kinetic parameters. It was determined that
optimum temperature for free catalase and immobilized catalase on chitosan film
is 25 degrees C, and optimum pH is 7.0. It was found as K(m) = 25.16 mM, V(max) =
24042 umole/min mg protein for free catalase, K(m) = 27.67 mM, V(max) = 1022
umole/min mg protein for immobilized catalase on chitosan. It was observed that
there was a big difference between V(max) value of the free catalase and V(max)
value of immobilized catalase on chitosan film whereas there were minor changes
in the value of K(m) for free catalase and immobilized catalase. It was found
that storage stability at 5 degrees C for immobilized catalase stored wet is
greater than free catalase and immobilized catalase stored dry, and immobilized
catalase showed a operational stability.
PMID- 10771053
TI - Thermal stability of beta-xylanases produced by different Thermomyces lanuginosus
strains.
AB - The thermostability of beta-xylanases produced by nine thermophilic Thermomyces
lanuginosus strains in a coarse corn cob medium was assessed. The xylanase
produced by T. lanuginosus strain SSBP retained 100% of its activity after 6 h at
temperatures up to 65 degrees C. In comparison seven ATCC strains and the DSM
5826 strain of T. lanuginosus only retained 100% xylanase activity at
temperatures up to 60 degrees C. Culture filtrates of T. lanuginosus strain SSBP
grown on coarse corn cobs, oatspelts xylan, birchwood xylan, wheatbran, locust
beangum, and sugar cane bagasse, retained 100% xylanase activity at temperatures
up to 60 degrees C. The xylanase produced on corn cobs was the most thermostable
and showed an increase of approximately 6% from 70 degrees C to 80 degrees C. The
T(1/2) of all strains at 70 degrees C at pH 6.5 varied greatly from 63 min for
strain ATCC 28083 to 340 min for strain SSBP. The xylanase of strain SSBP was
much less thermostable at pH 5.0 and pH 12.0 with T(1/2) values of 11.5 min and
15 min, respectively at 70 degrees C. At 50 degrees C, the enzyme of T.
lanuginosus strain SSBP produced on coarse corn cobs was stable within the pH
range of 5.5-10.0. Furthermore, the enzyme retained total activity at 60 degrees
C for over 14 days and at 65 degrees C for over 48 h. The xylanase of T.
lanuginosus strain SSBP possesses thermo- and pH stability properties that may be
attractive to industrial application.
PMID- 10771054
TI - Increase in conformational stability of enzymes immobilized on epoxy-activated
supports by favoring additional multipoint covalent attachment*
AB - Epoxy supports (Eupergit C) may be very suitable to achieve the multipoint
covalent attachment of proteins and enzymes, therefore, to stabilize their three
dimensional structure. To achieve a significant multipoint covalent attachment,
the control of the experimental conditions was found to be critical. A three-step
immobilization/stabilization procedure is here proposed: 1) the enzyme is firstly
covalently immobilized under very mild experimental conditions (e.g. pH 7.0 and
20 degrees C); 2) the already immobilized enzyme is further incubated under more
drastic conditions (higher pH values, longer incubation periods, etc.) to
"facilitate" the formation of new covalent linkages between the immobilized
enzyme molecule and the support; 3) the remaining groups of the support are
blocked to stop any additional interaction between the enzyme and the support.
Progressive establishment of new enzyme-support attachments was showed by the
progressive irreversible covalent immobilization of several subunits of multi
subunits proteins (all non-covalent structures contained in crude extracts of
different microorganism, penicillin G acylase and chymotrypsin). This multipoint
covalent attachment enabled the significant thermostabilization of two relevant
enzymes, (compared with the just immobilized derivatives): chymotrypsin (5-fold
factor) and penicillin G acylase (18-fold factor). Bearing in mind that this
stabilization was additive to that achieved by conventional immobilization, the
final stabilization factor become 100-fold comparing soluble penicillin G acylase
and optimal derivative. These stabilizations were observed also when the
inactivations were promoted by the enzyme exposure to drastic pH values or the
presence of cosolvents.
PMID- 10771055
TI - A process for high yield and scaleable recovery of high purity eicosapentaenoic
acid esters from microalgae and fish oil.
AB - A low expense process is developed for recovering esterified eicosapentaenoic
acid (EPA) from microalgae and fish oil. Over 70% of the EPA content in the
esterified crude extract of microalgae were recovered at purities exceeding 90%.
The recovery scheme utilizes either wet or freeze-dried algal biomass. The
process consists of only three main steps: 1) simultaneous extraction and
transesterification of the algal biomass; 2) argentated silica gel column
chromatography of the crude extract; and 3) removal of pigments by a second
column chromatographic step. Argentated silica gel chromatography recovered about
70% of the EPA ester present in the crude fatty ester mixture of fish oil, but at
a reduced purity ( approximately 83% pure) compared to the microalgal derived
EPA. The optimal loading of the fatty ester mixture on the chromatographic
support was about 3% (w/w) but loadings up to 4% did not affect the resolution
significantly. The process was scaled up by a factor of nearly 320 by increasing
the diameter of the chromatography columns. The elution velocity remained
constant. Compared to the green alga Monodus subterraneus, the diatom
Phaeodactylum tricornutum had important advantages as a potential commercial
producer of EPA. For a microalgal EPA process to be competitive with fish oil
derived EPA, P. tricornutum biomass (2.5% w/w EPA) needs to be obtained at less
than $4/kg. If the EPA content in the alga are increased to 3.5%, the biomass may
command a somewhat higher price. The quality of microalgal EPA compares favorably
with that of the fish oil product. Compared to free fatty acid, EPA ester is more
stable in storage. Shelf-life is extended by storing in hexane. The silver
contamination in the final purified EPA was negligibly small (<210 ppb).
PMID- 10771056
TI - Design of a control system for biotransformation of toxic substrates: toluene
hydroxylation by Pseudomonas putida UV4.
AB - Using the hydroxylation of toluene to toluene cis-glycol by Pseudomonas putida
UV4 as an example, the design of a feed-back control system for the addition of a
toxic, poorly water-soluble substrate to a fed-batch biotransformation is
described. In kinetic studies the reaction followed Michaelis-Menten behavior
until toxic toluene concentrations were reached (2.4 mM), above which
irreversible denaturation of the biocatalyst was observed. An algorithm, based on
a system mass balance, was used to maintain the aqueous phase toluene
concentration in the desired range for zero order kinetics. The mass balance
required accurate and rapid analysis of the product and reactant in both the
liquid and the vapor phase. Various analytical methods were considered and the
effect of the sampling and analysis time on the response of the control system
was examined.
PMID- 10771057
TI - Screen-printed enzyme sensors for l-lysine determination.
AB - Sensors for the determination of L-lysine in samples of fermentation broth have
been developed. Low-cost screen-printed sensors comprising a platinum working
electrode, an Ag/AgCl pseudo reference and a carbon counter electrode were used
as transducers for the enzyme sensors. L-lysine-(alpha)-oxidase from Trichoderma
viride has been immobilized by entrapment into a polyurethane hydrogel. Sensors
were characterized for L-lysine with respect to pH value, linear range,
reproducibility, repeatability, storage and working stability. The sensitivities
to other amino acids were also determined. A batch system with two working
electrodes, one with immobilized enzyme and one without was adapted for the
determination of L-lysine by differential measurements. Good agreement was found
between L-lysine concentrations measured by the enzyme sensors and by a
conventional amino acid analyzer.
PMID- 10771058
TI - Comparison of antioxidant enzyme biosynthesis by free and immobilized Aspergillus
niger cells*
AB - Effect of immobilization on antioxidant enzyme synthesis by growing and non
growing cell culture of Aspergillus niger 26 was studied. Entrapped cells showed
a greater than 1.5-fold increase in the superoxide dismutase (SOD) activity and a
moderate elevation in catalase activity. The immobilization did not cause changes
in the spectrum of SOD isoenzymes. The observed increase in SOD activity required
de novo synthesis of this enzyme, because it was suppressed by inhibitors of the
transcription and translation. The addition of various viscous substances (agar,
Na-alginate and pectin) stimulated the SOD synthesis. Despite these results, it
was found that the changes in SOD activity are induced in response to growth in
the state of immobilization rather than to presence of alginate. Immobilized A.
niger cells exhibited about a 4- to 5-fold higher level of cyanide-resistant
respiration. This latter phenomenon might use as an indicator of intracellular
oxy-intermediate generation in cell culture growing under stress conditions. The
results are discussed relative to association between physiological stress caused
by immobilization and oxidative stress.
PMID- 10771059
TI - Cross-linked glucose isomerase crystals as a liquid chromatographic separation
material.
AB - Cross-linked crystals of glucose isomerase (CLGI) were characterized as a liquid
chromatographic separation material. The experiments were done with crystals
having an average diameter of 83 um. Porosity (epsilon(p)) and pore size
distribution of the CLGI crystals were measured with size exclusion
chromatography using D(2)O and polyethylene glycols as probes. CLGI material was
capable of separating <1000 g/mol polyethylene glycols. Fifty two percent
(epsilon(p) = 0.47) of the total crystal volume was in pores. Pore size
measurement showed that CLGI crystals were microporous material, having an
average apparent pore diameter of 29 +/- 0.08 A. CLGI material separated n
alcohols C(1) to C(8) based on the hydrophobic interaction between the protein
material and the carbon chain of the alcohols. Height equivalent to a theoretical
plate (HETP, in millimeters) ranged from 1.6 to 0.89 for the C(1) to C(7) n
alcohol series. Despite the large crystal size, CLGI as a chirally active phase
effectively separated D- and L-arabitol (R(s) = 0.58) and showed potential for
chiral separation of amino acids.
PMID- 10771060
TI - Anomalous colloidal stability of protein coated polystyrene latex beads studied
by small angle light scattering.
AB - Results of small angle laser light scattering experiments carried out on
polystyrene latex beads coated with lysate of Plasmodium falciparum (Pf) antigen
(Ag) and human seropositive sera (10:1 ratio) are reported for various NaCl
concentrations (0-300 mM). The protein coated beads showed time-dependent
coagulation. The normalised intensity of scattered light I(s)(t)/I(0) showed
I(s)(t)/I(0)=1+(Gammat)(delta) behaviour with the coagulation rate, Gamma and
exponent, delta showing anomalous dependence on NaCl concentration. The
coagulation rate exhibited strong increase up to NaCl concentration of 50 mM,
above this and up to 300 mM the coagulation rate was found to remain independent
of NaCl concentration yielding non-DLVO behaviour. The same was true for delta
which increased from 1.04+/-0.06 to 6.94+/-0.07 as NaCl concentration was raised
from 0 to 50 mM. Above 50 mM it remained constant with delta=6.94+/-0.07. Results
are discussed through Smoluchowski aggregation kinetics and theoretical
construction of interparticle interaction potentials relevant to our problem.
PMID- 10771061
TI - Ionic and acid gel formation of epimerised alginates; the effect of AlgE4.
AB - AlgE4 is a mannuronan C5 epimerase converting homopolymeric sequences of
mannuronate residues in alginates into mannuronate/guluronate alternating
sequences. Treating alginates of different biological origin with AlgE4 resulted
in different amounts of alternating sequences. Both ionically cross-linked
alginate gels as well as alginic acid gels were prepared from the epimerised
alginates. Gelling kinetics and gel equilibrium properties were recorded and
compared to results obtained with the original non-epimerised alginates. An
observed reduced elasticity of the alginic acid gels following epimerisation by
AlgE4 seems to be explained by the generally increased acid solubility of the
alternating sequences. Ionically (Ca(2+)) cross-linked gels made from epimerised
alginates expressed a higher degree of syneresis compared to the native samples.
An increase in the modulus of elasticity was observed in calcium saturated
(diffusion set) gels whereas calcium limited, internally set alginate gels showed
no change in elasticity. An increase in the sol-gel transitional rate of gels
made from epimerised alginates was also observed. These results suggest an
increased possibility of creating new junction zones in the epimerised alginate
gel due to the increased mobility in the alginate chain segments caused by the
less extended alternating sequences.
PMID- 10771062
TI - A critical review of the structural mechanics of wool and hair fibres.
AB - The potential of genetic engineering gives current importance to the need to
clarify the relations between structure, properties and performance of wool.
There are at present three different models to explain the tensile stress-strain
properties of alpha-keratin fibres: a development by Wortmann and Zahn (W/Z) of
Feughelman's series-zone model based on the structure of intermediate filaments
and a gel-->sol matrix; a new model by Feughelman (F94) based on a matrix of
protein globules surrounded by water; and Chapman's model based on the composite
mechanics of microfibrils, characterised by critical and equilibrium stresses for
the alpha<-->beta transition, in an elastomeric matrix. This paper examines the
arguments related to these theories, with additional attention to the
Chapman/Hearle (C/H) treatment. The main area of uncertainty, on which more
information is much needed, concerns the chemical and physical structure and
properties of the matrix, which is composed of keratin-associated proteins. The
conclusion is that the C/H model, which is based on reasonable values of input
parameters and gives good agreement with a wide range of experimental results, is
most likely to be valid, though it needs some additional refinement and
incorporation in a total model, which includes larger-scale structural features.
PMID- 10771063
TI - New perspectives on the endo-beta-glucanases of glycosyl hydrolase Family 17.
AB - Isozymes of glycosyl hydrolase Family 17 hydrolyze 1,3-beta-glucan
polysaccharides found in the cell wall matrix of plants and fungi, enabling these
plant enzymes to serve diverse roles in plant defense and plant development.
Fourteen genes from Family 17 have been characterized in the genome of rice. A
sequence dendrogram analysis divided these genes into four subfamilies. The
recombinant GNS1 enzyme from subfamily B had 1,3;1,4-beta-glucanase activity,
suggesting a role for this isozyme in plant development.
PMID- 10771064
TI - Endo-1,3;1,4-beta-glucanase from coleoptiles of rice and maize: role in the
regulation of plant growth.
AB - The Matrix Polymer Hydrolysis Model for regulation of growth in plants is based
on the simultaneous hydrolysis and incorporation of new glucans into the cell
wall observed in growing plant tissues. The inhibition of growth in rice
coleoptile tissues treated with glucanase antibodies confirms similar results
observed previously in maize coleoptiles and provides direct evidence for a role
of glucanase in control of plant growth. Analysis of two-maize coleoptile endo
glucanase ESTs shows that these sequences are not related to any other previously
known family of glycosyl hydrolase. Thus, the coleoptile endo-glucanase enzyme
should be classified as a new enzyme group (E.C. 3.2.1.xx). These discoveries
enable new initiatives for further investigation of the glucanase role in control
of plant growth.
PMID- 10771065
TI - Cell wall autolytic activities and distribution of cell wall glucanases in Zea
mays L. seedlings.
AB - Exo- and endo-glucanases mediate specific degradation of cell wall (1,3)(1,4)
beta-D-glucans and these enzymes have been related to auxin-mediated growth and
development of cereal coleoptiles. However, their distribution and functions have
not been well established in other tissues. In this study the glucanase
activities and cell wall autolytic activities of different maize organs were
determined. Autolysis assays serve to evaluate the hydrolysis of cell wall
polymers in situ by measuring the sugars released from the insoluble cell wall
matrix resulting from the action of bound enzymes. Autolytic activities were
observed in the cell walls of elongating young leaves, mesocotyl and roots of
maize. Wall proteins extracted from all of these structures are enriched in
several types of glucanases and other wall polysaccharide hydrolases. These
enzymes therefore appear to have a widespread and fundamental role in wall
metabolism in growing tissues.
PMID- 10771066
TI - Exo- and endoglucanases of maize coleoptile cell walls: their interaction and
possible regulation.
AB - Glucanase-mediated degradation of beta-(1,3)(1,4)-glucans has been attributed to
auxin-induced cell wall loosening and thus tissue growth in cereal plants, but
the regulatory mechanisms for the auxin-enhancement of glucanase activities in
situ are not fully understood. Here, we report evidence for possible mechanisms
which might account for auxin-induced changes in glucanase activities. A likely
cause for acceleration of wall glucan degradation is the change in the ratio of
exo- and endoglucanases. The combined enzymes synergistically promote beta
(1,3)(1,4)-glucan hydrolysis. In addition, these enzyme activities are enhanced
by other enzymic and non-enzymic proteins and are also partially stimulated by
divalent cations such as Ca(2+) and Mg(2+) at certain pH values. The acceleration
of glucan degradation mediated by auxin may be mediated by changes and/or
interactions of any of these factors in situ.
PMID- 10771067
TI - On the occurrence of ternary complexes in agarose gels as studied by the contrast
variation method.
AB - The contrast variation method by isotopic labelling as used in small-angle
neutron scattering experiments is applied to the case of agarose systems (sol and
gels) in order to cast some light on the occurrence of complexes
(crystallosolvates). This approach proves to be helpful for giving further
support to the existence of ternary complexes in agarose/water/DMSO gels and in
agarose/DMSO sols. The results are discussed in the light of temperature
composition phase diagrams established previously.
PMID- 10771068
TI - Heparin reduces the alpha-helical content of cobra basic phospholipase A(2) and
promotes its complex formation.
AB - The interaction of phospholipase A(2) (PLA(2)) with glycosaminoglycans (GAGs) has
recently attracted attention in view of its implication on inflammation and cell
proliferation. By using Fourier Transformed Infrared (FTIR) spectroscopic
measurements, we demonstrate here that binding of cobra basic phospholipase A(2)
from Naja nigricollis (N-PLA(2)) to heparin may induce a significant
conformational change observed in the amide I region of the enzyme's alpha
helical and beta-sheet structure. It is observed that notable conformational
change of N-PLA(2) due to heparin binding occurs only when heparin's chain length
is at least an octasaccharide as evidenced by circular dichroism and optical
density measurements. This correlation may be an important factor in the
aggregation of N-PLA(2) and N-PLA(2)-heparin complexes. Heparin induced change in
conformation of PLA(2) is suggested to be a notable link in understanding the
diversity in PLA(2) activity when rendered to the extracellular matrix of cell
membranes that is full of GAG molecules.
PMID- 10771069
TI - In vitro biocytin injection into perinatal mouse brain: a method for tract
tracing in developing tissue.
AB - Injection of biocytin provides an effective method for labeling axonal
projections. Several difficulties arise when this technique is employed in fetal
or early postnatal animals in vivo, including limited access to injection sites
and extended post-injection survival periods. To circumvent these problems, we
adapted the technique of extracellular biocytin injection for use in explanted
brain hemispheres of developing mice. Briefly, entire brain hemispheres from
perinatal mice (E16-P9) were removed and placed in oxygenated aCSF in a brain
slice recording chamber. Following visually guided injection of biocytin (2%)
into the prelimbic cortex, the brains were then incubated in oxygenated
artificial cerebrospinal fluid (aCSF) for varying periods of time and then
immersion-fixed in 4% paraformaldehyde and 0.5% glutaraldehyde. The next day, the
brains were sectioned and processed for biocytin histochemistry using the avidin
biotin-complex method. We examined the method of injection, electrode type, time
of injection, and post-injection incubation period. We found that in E16-P9
animals iontophoresis of biocytin using 8- to 12-megaohm patch clamp electrodes
for a duration of 10 min provides optimal axonal labeling. Post-injection
incubation times of four or more hours are sufficient for labeling fine caliber
collaterals as well as axon bundles that reach distances over 3 mm. In vitro
injection of biocytin into explanted brain hemispheres provides a quick and easy
method for tract tracing in developing brains.
PMID- 10771070
TI - Quantitative analysis of cell columns in the cerebral cortex.
AB - We present a quantified imaging method that describes the cell column in
mammalian cortex. The minicolumn is an ideal template with which to examine
cortical organization because it is a basic unit of function, complete in itself,
which interacts with adjacent and distance columns to form more complex levels of
organization. The subtle details of columnar anatomy should reflect physiological
changes that have occurred in evolution as well as those that might be caused by
pathologies in the brain. In this semiautomatic method, images of Nissl-stained
tissue are digitized or scanned into a computer imaging system. The software
detects the presence of cell columns and describes details of their morphology
and of the surrounding space. Columns are detected automatically on the basis of
cell-poor and cell-rich areas using a Gaussian distribution. A line is fit to the
cell centers by least squares analysis. The line becomes the center of the column
from which the precise location of every cell can be measured. On this basis
several algorithms describe the distribution of cells from the center line and in
relation to the available surrounding space. Other algorithms use cluster
analyses to determine the spatial orientation of every column.
PMID- 10771071
TI - An operant assay of thermal pain in conscious, unrestrained rats.
AB - Methods are described which provide quantification of learned operant and innate
reflex responses to a thermal stimulus (heat or cold) and provide matched motor
controls. The apparati and procedures consist of (1) an 'Escapetest' which
measures latencies and durations of escape from a compartment where the floor is
heated or cooled to a platform at neutral temperature in an adjacent compartment;
(2) a motor and motivational control for the Escapetest, the 'Darkboxtest', which
measures escape latency from bright light in a shuttle box; and (3) assessment of
latencies and durations of licking or guarding responses to thermal stimulation
in the absence of the escape option. Avoidance responses in the Escapetest
(retreating to the escape platform in the absence of an experience of pain) are
discouraged by bright illumination of the compartment containing the escape
platform (brightly lit areas are aversive to rodents). Stimulus-response
functions for escape from heat and cold are compared to stimulus response
functions for innate lick/guard responses to the same temperatures. Substantial
differences in the relationships between learned or innate responses and
temperature attest to a need for methods which evaluate operant responses to
nociceptive stimulation.
PMID- 10771072
TI - Secure cranial-mount intrathecal cannulation - a spinal administration technique
in the rat.
AB - In order to identify an acute spinally mediated pharmacological effect of a
bioactive substance, without incurring untoward supraspinal effects, it is
necessary to administer the agent locally onto the spinal cord. The procedure
delineated herein presents a modern technique to install a stable, permanent
indwelling thecal cannulae with a cranially mounted aperture, and details a
simple, repeatable administration system. These methods facilitate a quick,
noninvasive spinal drug microadministration that is most useful for
differentiation of the locus of pharmacological action without the behavioral
disruption associated with other administration methodologies.
PMID- 10771073
TI - Effect of a neuroactive steroid infused into the cerebral ventricles of fetal
sheep in utero using small infusion volumes.
AB - Placental progesterone metabolites may influence fetal behaviour during late
gestation. We have investigated the effect of the neuroactive metabolite,
pregnanolone, on the sleep/awake behaviour of fetal sheep. These studies can only
be effectively performed in unanesthetized animals with chronically implanted
leads and catheters. The relatively large internal volumes of these catheters
raises problems for cerebroventriclear infusions. Therefore, we developed a
device with negligible deadspace ( approximately 10 microl) consisting of a
ventricular cannula attached to a small cap which allowed the instillation of
microl volumes of neuroactive steroids into a cerebral ventricle of fetal sheep
in utero. Two catheters attached to the cap allow it to be filled in a push-pull
configuration. The smaller internal diameter of the ventricular cannular prevents
the solution entering the ventricle until the outflow catheter is occluded and
solution is forced through the probe. Using this device, the infusion of 5beta
pregnane-3alpha-ol-20-one (pregnanolone, 1 mg), in 35% hydroxypropyl-beta
cyclodextrin, resulted in a marked suppression of fetal behaviour parameters
indicative of arousal, while vehicle alone did not affect these parameters. We
conclude that neuroactive steroids can be infused into the cerebroventricular
system of chronically catheterised fetal sheep in small volumes and that
pregnanolone may act directly to influence fetal behaviour.
PMID- 10771074
TI - Chronaxie calculated from current-duration and voltage-duration data.
AB - To determine the rheobase and the chronaxie of excitable cells from strength
duration curves both constant-current pulses and constant-voltage pulses are
applied. Since the complex impedance of the electrode-tissue interface varies
with both the pulsewidth and the stimulation voltage, chronaxie values estimated
from voltage-duration measurements will differ from the proper values as
determined from current-duration measurements. To allow a comparison of chronaxie
values obtained by the two stimulation methods, voltage-duration curves were
measured in human subjects with a deep brain stimulation electrode implanted,
while the current and the load impedance of the stimulation circuit were
determined in vitro as a function of both stimulation voltage and pulsewidth.
Chronaxie values calculated from voltage-duration data were shown to be 30-40%
below those estimated from current-duration data. It was also shown that in the
normal range of stimulation amplitudes (up to 7 V) the load impedance increases
almost linearly with the pulsewidth. This result led us to present a simple
method to convert voltage-duration data into current-duration data, thereby
reducing the error in the calculated chronaxie values to approximately 6%. For
this purpose voltage-duration data have to be measured for pulses up to 10-20
times the expected chronaxie.
PMID- 10771075
TI - Epicranial sensory evoked potential recordings for repeated assessment of
cortical functions in mice.
AB - In the present study, we describe a simple and minimally invasive method to
record sensory evoked potentials (SEP) in the anesthetized mouse. The hardware
includes a 16-channel acquisition system with a high signal/noise ratio and high
temporal resolution. Under general anesthesia the skull is exposed and stainless
steel electrodes are placed directly over the bone. A computer controlled
electromechanical stimulation is applied to a single whisker or a group of
whiskers unilaterally and cortical responses are recorded bilaterally. Primary
SEP are detected over the contralateral barrel cortex, but delayed signals appear
over the motor cortex, secondary somatosensory cortex and the ipsilateral
hemisphere. The size of evoked SEP correlates with the number of stimulated
whiskers and responses are reproducible and consistent over time when recorded
repeatedly for up to 6 weeks. We conclude that epicranial multichannel recording
of SEP represents an interesting, minimally invasive approach to monitor
repeatedly cortical activity and study certain aspects of long-term plasticity of
evoked responses in mice.
PMID- 10771076
TI - Behavioral assessments of auditory sensitivity in transgenic mice.
AB - This report summarizes positive reinforcement conditioning procedures for
assessing sensory function in transgenic mice. To illustrate these behavioral
methods auditory sensitivity was measured in mice lacking alpha9 acetylcholine
receptor subunits (alpha9 knock-out mice). These receptors are known to play an
important role in the efferent pathways that modify cochlear responses to sound
stimuli. The strategies of parameter manipulation that led these subjects through
their preliminary training stages to stable threshold performances are described
in detail. Techniques for estimating and interpreting sensory thresholds are
discussed from the perspective of signal detection analyses. This study found no
significant differences between alpha9 knock-out mice and control subjects when
hearing thresholds were measured under quiet conditions, as predicted by previous
behavioral and electrophysiological evidence.
PMID- 10771077
TI - Surface EMG-recordings using a miniaturised matrix electrode: a new technique for
small animals.
AB - A new method for multichannel surface-EMG measurements in small animals is
presented. The underlying scientific aim is the characterisation of the spreading
and the co-ordination of skeletal muscle activation between different muscles or
muscle parts, depending on various motor tasks. The myoelectrical signals were
recorded monopolarly by a 16-channel matrix electrode on the muscle surface
directly under the skin on the fascia of the investigated muscle, without
damaging the muscle. Surface-EMG's were recorded for at least 5 days after
surgery without electrical interferences. During defined motor tasks, the
projection of the myoelectrical activation of the different parts of the M.
triceps brachii of rats (Rattus norvegicus), pikas (Ochotona rufescens) and cuis
(Galea musteloides) or the M. anconeus of toads (Bufo marinus) on the muscle
surface was mapped. The locomotion of the investigated animals was monitored by a
three-dimensional kinematic analysis (video and/or high-speed cineradiography).
There was no perceptible influence from application of EMG matrix electrode. The
miniaturised matrix electrode seemed practicable in gaining insight into changes
in myoelectrical activation patterns (EMG mapping). This allows a
characterisation of the intramuscular co-ordination processes corresponding to
the actual morphofunctional state of the investigated animals.
PMID- 10771078
TI - Imaging the rat brain on a 1.5 T clinical MR-scanner.
AB - Magnetic resonance imaging (MRI) offers a noninvasive technique for studying
neurodegenerative events in the rat brain, however, most of the studies are
performed on small bore purpose dedicated MR scanners of limited availability and
at high cost. The present study explored the feasibility of using a clinical
whole body MR-scanner to perform imaging in rat brain and specifically in models
of Parkinson's (PD) and Huntington's disease (HD). For that purpose rats were
placed into a specially designed PVC device equipped with a flexible surface coil
and T2-weighted spin echo sequences were acquired on a Siemens Magnetom Vision at
1.5 T. In the experimental protocols of PD and HD, animals underwent 6
hydroxydopamine (6-OHDA) and quinolinic acid (QA) injections, respectively and
were subsequently grafted with fetal tissue. T2-weighted images showed a small
hyperintense area at the 6-OHDA lesion site and a diffuse hyperintensity in the
striata with QA lesions. Transplants were seen as a hypointense area surrounded
by a hyperintense rim on T1-weighted images. Moreover, disturbances of the blood
brain-barrier and its time of restoration could be monitored. In conclusion, high
resolution in vivo imaging of small animals is feasible with clinical MR-scanners
and hence allows the study of various experimental protocols.
PMID- 10771079
TI - A new intraretinal recording system with multiple-barreled electrodes for
pharmacological studies on cat retinal ganglion cells.
AB - To overcome technical difficulties associated with in vivo intraretinal
recordings of cat retinal ganglion cells (RGCs) with multiple-barreled
electrodes, we developed a new guide-trocar system that consisted of a small
diameter and large-diameter pipes. We also improved the method to construct
tungsten-in-glass multiple-barreled electrodes suitable for intraretinal
recording from RGCs. Only the small-diameter pipe was inserted into the eye ball
through the sclera, through which only the taper part of a multiple-barreled
electrode pass. The large-diameter pipe stably held the electrode at its trunk
and remained outside the eye ball. Insertion of only the small-diameter pipe
minimized damages in the eye ball and prevented the eye ball movements while
positioning the electrode. The system allowed us to keep the recordings stable
for more than 1 h. Iontophoretically applied L-glutamate successfully activated
RGCs of both X and Y types in the cat retina.
PMID- 10771080
TI - Antiviral activity of ganciclovir elaidic acid ester against herpesviruses.
AB - A fatty acid derivative of ganciclovir (GCV), elaidic acid ganciclovir (E-GCV),
has been evaluated for its inhibitory activity against laboratory and clinical
strains of herpes simplex type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster
virus (VZV) and human cytomegalovirus (HCMV) in human embryonic lung fibroblasts.
GCV, cidofovir, acyclovir (ACV), brivudin (BVDU) and foscarnet (PFA) were
included as reference compounds. The viruses studied were wild-type, thymidine
kinase-deficient (TK(-)) and PFA-resistant (PFA(r)) HSV strains. The IC(50)
values obtained for E-GCV were 5- to 30-fold lower than those observed for GCV,
the IC(50) value of E-GCV for HSV-1 strain KOS being 0.07 nM. A similarly
increased activity of E-GCV (as compared to GCV) was noted for TK(-) and PFA(r)
HSV-1 or HSV-2 strains. However, E-GCV did not exhibit superior activity over GCV
to VZV or HCMV in vitro. The antiviral efficacy of E-GCV was also evaluated in
vivo against intracerebral HSV-2 infection in NMRI mice. Animals were treated
intraperitoneally or perorally with E-GCV, GCV or placebo once daily for 10 days,
starting the day of infection. E-GCV compared to GCV at equimolar doses, proved
markedly more efficacious than GCV in terms of reduction of mortality rate and
delay of mean time of death. The elaidic acid ester of GCV should therefore be
considered as a novel approach towards the treatment of HSV infections.
PMID- 10771081
TI - Synthesis and antiviral evaluation of some beta-L-2', 3'-dideoxy-5
chloropyrimidine nucleosides and pronucleotides.
AB - The synthesis and in vitro anti human immunodeficiency virus (HIV) and anti
hepatitis B virus (HBV) activities of some unnatural beta-L-nucleoside
enantiomers related to the anti-HIV compound 2', 3'-dideoxy-3'-fluoro-5
chlorouridine (beta-D-3'Fdd5ClU) are reported. In contrast to beta-D-3'Fdd5ClU,
beta-L-3'Fdd5ClU and the other L-congeners were devoid of significant anti-HIV
effects, but beta-L-2',3'-dideoxy-5-chlorocytidine (beta-L-dd5ClC) and beta-L-2',
3'-dideoxy-3'-fluoro-cytidine (beta-L-3'FddC) showed a distinct anti-HBV
activity. Three mononucleoside phosphotriester derivatives with S-pivaloyl-2
thioethyl (t-BuSATE) groups as biolabile phosphate protective groups were also
synthesized. The bis(t-BuSATE) derivative of beta-D-3'Fdd5ClU retained anti-HIV
activity in thymidine kinase deficient (TK(-)) CEM cells.
PMID- 10771082
TI - An in vitro system for the enzymological analysis of avian hepatitis B virus
replication and inhibition in core particles.
AB - A detailed analysis of the hepatitis B virus (HBV) replication reaction is
important both in understanding viral biology and in developing effective
antiviral drugs. This can best be achieved by studying the viral reverse
transcriptase (RT) in its natural context, encapsidated within viral core
particles in a multiprotein complex, rather than as an isolated enzyme. In order
to facilitate a precise enzymological analysis of the avian HBV-RT reaction and
its inhibition within replicating cores, a scheme for the purification and
analysis of intracellular core particles derived from infected liver tissue has
been devised, optimized and evaluated. The purification scheme itself is simple
and rapid, and results in preparations with a 25-fold increase in endogenous
polymerase activity that persists for over 5 h under assay conditions. In order
to assess the suitability of these preparations for mechanistic studies, a
thorough evaluation of purity was undertaken, revealing predominantly pure viral
protein and nucleic acid, free of contaminating cellular polymerases and
phosphatase activities that potently degrade nucleotides and antiviral drugs.
Parameters governing optimal polymerase activity have been determined, and an
assay for DHBV-RT activity has been developed which offers the highest purity and
specific polymerase activity currently available to study hepadnaviral
replication and inhibition.
PMID- 10771083
TI - Anti-rhinovirus activity of 3-methylthio-5-aryl-4-isothiazolecarbonitrile
derivatives.
AB - A series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles has been evaluated as
anti rhinovirus agents against a panel of 17 representative human rhinovirus
(HRV) serotypes, belonging to both A and B groups. No anti rhinovirus activity
was detected for 3-methylthio-5-phenyl-4-isothiazolecarbonitrile (IS-2).
Isothiazole derivatives with bulky substituents (O-Bn or O-But groups) on the
para position of the phenyl ring were the most effective compounds of this
series. In fact, a reduction in virus-induced cytopathogenicity was demonstrated
for the O-Bn substituted IS-50 compound against the majority (88%) of the
rhinoviruses tested, whereas the compound with an O-Ts group (IS-44) was found to
be a specific inhibitor of group B serotypes, exhibiting the lowest IC(50)
against HRVs type 2, 85 and 89. Our studies on the mechanism of action of IS-44
demonstrated that it prevents the thermal inactivation of HRV 2 infectivity,
probably due to a conformational shift in the viral capsid and a decrease in
affinity for the cellular receptor, resulting in an inhibition of attachment of
the virions.
PMID- 10771084
TI - Selective virus-mediated intracellular delivery of membrane-impermeant compounds
by means of plasma membrane vesicles.
AB - The impermeability of the cell plasma membrane is a major obstacle to
intracellular delivery of large hydrophilic molecules, such as many kinds of
drugs. This contribution describes a general-purpose delivery system that employs
the membrane fusion capacity of enveloped viruses to circumvent cell
impermeability. Vesicles were generated from the plasma membrane of HEp-2 cells,
a human cell line host for the Newcastle disease virus (NDV). They could be
loaded with a fluorescent, high molecular weight dye (FITC/dextran, MW 70 KDa) or
with the enzyme ribonuclease A (MW 14 KDa). These vesicles were found to fuse and
deliver their lumen contents to cultured HEp-2 cells in the presence of NDV
virions. When ribonuclease was employed as the encapsulated solute, viral
replication was inhibited and death of the infected cells was accelerated.
Implications and possible applications of this technique in antiviral therapy are
discussed.
PMID- 10771085
TI - The sevenless signaling pathway: variations of a common theme.
AB - Many developmental processes are regulated by intercellular signaling mechanisms
that employ the activation of receptor tyrosine kinases. One model system that
has been particular useful in determining the role of receptor tyrosine kinase
mediated signaling processes in cell fate determination is the developing
Drosophila eye. The specification of the R7 photoreceptor cell in each ommatidium
of the developing Drosophila eye is dependent on activation of the Sevenless
receptor tyrosine kinase. This review will focus on the genetic and biochemical
approaches that have identified signaling molecules acting downstream of the
Sevenless receptor tyrosine kinase which ultimately trigger differentiation of
the R7 photoreceptor cell.
PMID- 10771086
TI - Investigation of the role of the carboxyl-terminal tails of the alpha and beta
isoforms of the human thromboxane A(2) receptor (TP) in mediating
receptor:effector coupling.
AB - We have investigated the functional coupling of alpha and beta isoforms of the
human thromboxane A(2) receptor (TP) to Galpha(16) and Galpha(12) members of the
G(q) and G(12) families of heterotrimeric G proteins in human embryonic kidney
(HEK) 293 cell lines HEK.alpha10 or HEK.beta3, stably over-expressing TPalpha and
TPbeta, respectively. Moreover, using HEK.TP(Delta328) cells which over-express a
variant of TP truncated at the point of divergence of TPalpha and TPbeta, we
investigated the requirement of the C-tail per se in mediating G protein coupling
and effector activation. Both TPalpha and TPbeta couple similarly to Galpha(16)
to affect increases in inositol 1,4,5-trisphosphate (IP(3)) and mobilisation of
intracellular calcium ([Ca(2+)](i)) in response to the TP agonist U46619. Whilst
both TP isoforms mediated [Ca(2+)](i) mobilisation in cells co-transfected with
Galpha(12), neither receptor generated corresponding increases in IP(3),
indicating that the Galpha(12)-mediated increases in [Ca(2+)](i) do not involve
PLC activation. Verapamil, an inhibitor of voltage dependent Ca(2+) channels,
reduced [Ca(2+)](i) mobilisation in TPalpha and TPbeta cells co-transfected with
Galpha(12) to approximately 40% of that mobilised in its absence, whereas [8-(N,N
diethylamino)-octyl-3,4, 5-trimethoxybenzoate, hydrochloride] (TMB-8), an
antagonist of intracellular Ca(2+) release, had no effect on [Ca(2+)](i)
mobilisation by either receptor isoform co-transfected with Galpha(12). Despite
the lack of differential coupling specificity by TPalpha and TPbeta, TP(Delta328)
signalled more efficiently in the absence of a co-transfected G protein compared
to the wild type receptors but, on the other hand, displayed an impaired ability
to couple to co-transfected Galpha(11), Galpha(12) or Galpha(16) subunits. In
studies investigating the role of the C-tail in influencing coupling to the
effector adenylyl cyclase, similar to TPalpha but not TPbeta, TP(Delta328)
coupled to Galpha(s), leading to increased adenosine 3',5'-cyclic monophosphate
(cAMP), rather than to Galpha(i). Whereas TP(Delta328) signalled more efficiently
in the absence of co-transfected G protein compared to the wild type TPalpha, co
transfection of Galpha(s) did not augment cAMP generation by TP(Delta328). Hence,
from these studies involving the wild type TPalpha, TPbeta and TP(Delta328), we
conclude that the C-tail sequences of TP are not a major determinant of G protein
coupling specificity to Galpha(11) and Galpha(16) members of the G(q) family or
to Galpha(12); it may play a role in determining G(s) versus G(i) coupling and
may act as a determinant of coupling efficiency.
PMID- 10771087
TI - Effect of N-acetylcysteine and deferoxamine on endogenous antioxidant defense
system gene expression in a rat hepatocyte model of cocaine cytotoxicity.
AB - In the present study we investigated on cultures of hepatocytes from
phenobarbital-pretreated rats, the effect of the antioxidants, 0.5 mM N
acetylcysteine (NAC) or 1.5 mM deferoxamine (DFO), previously incubated for 24 h
and coincubated with cocaine (0-1000 microM) for another 24 h. Cocaine
cytotoxicity was monitored by either the lysis of the cell membranes or
apoptosis. Lysis of the cell membranes was evidenced by lactate dehydrogenase
leakage, apoptosis was observed by detecting a hypodiploid peak (<2C) in DNA
histograms obtained by flow cytometry, peroxide production was quantified with
2', 7'-dichlorodihydrofluorescein diacetate and gene expression of the
antioxidant enzymes: Mn- and Cu,Zn-superoxide dismutases, catalase and
glutathione peroxidase were measured by Northern blot analysis. NAC and DFO
significantly decreased the extent of lysis of cell membranes and apoptosis, and
the antiapoptotic effect was parallel to peroxide generation. By the effect of
NAC and DFO, significant increases were detected in the levels of mRNA of
catalase, manganese superoxide dismutase and glutathione peroxidase. From these
results we conclude that NAC or DFO, when incubated in the presence of cocaine,
exerted a protective effect against cocaine toxicity at the level of both lysis
of the membranes and apoptosis. This protective effect, in the case of NAC, was
directed towards an increase in antioxidant enzyme expression, and in the case of
DFO against reactive oxygen species generation.
PMID- 10771088
TI - The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin
reductase.
AB - Interferons (IFNs) suppress cell growth by inducing cellular genes. The anti
estrogen tamoxifen (Tam), binds to estrogen receptor and inhibits transcription
of estrogen stimulated genes. In cells resistant to IFN-induced growth
suppression, IFN/Tam combination causes cell death. We previously reported that
the combination of IFN-beta and Tam was a more potent growth suppressor of human
tumor xenografts than either agent alone. The IFN/Tam combination acts in a
manner similar to the IFN/retinoic acid combination. Using a genetic technique,
we have recently identified several genes associated with retinoid-IFN-induced
mortality (GRIM). One such gene, GRIM-12, was identical to human thioredoxin
reductase (TR). In the present study we have examined whether the IFN/Tam
combination also requires GRIM-12 for inducing cell death. We report here that
GRIM-12 is necessary for mediating the cell death effects of IFN/Tam, and its
expression is induced by IFN/Tam at a post-transcriptional stage. Repression of
GRIM-12 levels either by antisense expression or by dominant negative inhibitors
caused resistance to IFN/Tam induced death and promoted cell growth.
Overexpression of GRIM-12 increased IFN/Tam induced apoptosis. Thus, these
studies have identified a critical role for GRIM-12 (TR) in apoptosis.
PMID- 10771089
TI - Phosphatidylinositol 3-kinase inhibitors, Wortmannin or LY294002, inhibited
accumulation of p21 protein after gamma-irradiation by stabilization of the
protein.
AB - Expression of the cyclin kinase inhibitor, p21, is regulated both
transcriptionally and posttranscriptionally by the ubiquitin-proteasome
degradation pathway. Recently, we reported that DNA damage is required for
efficient p21 expression by demonstrating that enhanced p21 mRNA expression
induced by DNA damage results in increased p21 protein, but enhanced p21 mRNA
without DNA damage does not. In addition, we demonstrated that DNA damage
suppressed the ubiquitination of p21. In this study, we analyze the link between
p21 stabilization and DNA damage. Enhanced p21 protein expression in ML-1 cells
resulting from 15 Gy gamma-irradiation was diminished by Wortmannin or LY294002
pretreatment of cells. However, the levels of p21 mRNA were not affected by
inhibitor pretreatment. Wortmannin or LY294002 pretreatment reduces p53
expression after gamma-irradiation to a lesser degree than that of p21. In
addition, we examined the involvement of DNA-PK, whose activity is inhibited by
Wortmannin or LY294002, in p21 stabilization using the SCID fibroblast cell line
and a DNA-PK targeting ML-1 cell line. Accumulation of p21 protein by gamma
irradiation was similar to that of DNA-PK intact cells and was reduced by
Wortmannin or LY294002 pretreatment. Involvement of another DNA damage detecting
enzyme, the ATM gene product, whose activity is also inhibited by Wortmannin or
LY294002, was evaluated. ATM deficient cells induced p21 after gamma-irradiation,
gamma-irradiation-induced p21 protein was diminished by pretreatment of cells
with Wortmannin or LY294002. We conclude that the p21 stabilization mechanism
functions after gamma-irradiation, was sensitive to Wortmannin or LY294002, and
required neither DNA-PK nor ATM gene product for activity.
PMID- 10771090
TI - Overexpression of hemochromatosis protein, HFE, alters transferrin recycling
process in human hepatoma cells.
AB - HFE is a MHC class 1-like protein that is mutated in hereditary hemochromatosis.
In order to elucidate the role of HFE protein on cellular iron metabolism,
functional studies were carried out in human hepatoma cells (HLF) overexpressing
a fusion gene of HFE and green fluorescent protein (GFP). The expression of HFE
GFP was found to be localized on cell membrane and perinuclear compartment by
fluorescent microscopy. By co-immunoprecipitation and Western blotting, HFE-GFP
protein formed a complex with endogenous transferrin receptor and beta(2)
microglobulin, suggesting that this fusion protein has the function of HFE
reported previously. We then examined the (59)Fe uptake and release, and
internalization and recycling of (125)I-labeled transferrin in order to elucidate
the functional roles of HFE in the cell system. In the transfectants, HFE protein
decreased the rate of transferrin receptor-dependent iron ((59)Fe) uptake by the
cells, but did not change the rate of iron release, indicating that HFE protein
decreased the rate of iron influx. Scatchard analysis of transferrin binding to
HFE-transfected cells showed an elevation of the dissociation constant from 1.9
to 4. 3 nM transferrin, indicating that HFE protein decreased the affinity of
transferrin receptor for transferrin, while the number of transferrin receptors
decreased from 1.5x10(5)/cell to 1. 2x10(5)/cell. In addition, the rate of
transferrin recycling, especially return from endosome to surface, was decreased
in the HFE-transfected cells by pulse-chase study with (125)I-labeled
transferrin. Our results strongly suggest an additional role of HFE on
transferrin receptor recycling in addition to the decrease of receptor affinity,
resulting in the reduced cellular iron.
PMID- 10771091
TI - Rapid isolation and characterization of CHO mutants deficient in peroxisome
biogenesis using the peroxisomal forms of fluorescent proteins.
AB - We isolated and characterized CHO mutants deficient in peroxisome assembly using
green fluorescent protein (GFP) and blue fluorescent protein (BFP) as the
fluorescent probes to study the molecular mechanism of peroxisome biogenesis. We
used stable transformants of CHO cells expressing GFP appending peroxisome
targeting signal-1 (PTS1) and/or peroxisome targeting signal-2 (PTS2) as the
parent strains for rapid isolation of the mutants. We have obtained six
peroxisome-deficient mutants by visual screening of the mislocalizations of the
peroxisomal GFPs. Mutual cell fusion experiments indicated that the six mutants
isolated were divided into four complementation groups. Several of the mutants
obtained possessed defective genes: the PEX2 gene was defective in SK24 and PT54;
the PEX5 gene in SK32 and the PEX7 gene in PT13 and PT32. BE41, which belonged to
the fourth complementation group, was not determined. When peroxisomal forms of
BFP were transiently expressed in mutant cells, the peroxisomal BFPs appending
both PTS1 and PTS2 appeared to bypass either the PTS1 or PTS2 pathway for
localization in SK32. This observation suggested that other important machinery,
in addition to the PTS1 or PTS2 pathway, could be involved in peroxisome
biogenesis. Thus, our approach using peroxisomal fluorescent proteins could
facilitate the isolation and analysis of peroxisome-deficient CHO mutants and
benefit studies on the identification and role of the genes responsible for
peroxisome biogenesis.
PMID- 10771092
TI - W-7 primes or inhibits the fMLP-stimulated respiratory burst in human neutrophil
by concentration-dependent dual expression of the formyl peptide receptors on
cell surface.
AB - It was investigated why the fMLP-stimulated respiratory burst in human
neutrophils was enhanced by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W
7), a considered calmodulin antagonist, at lower concentration but inhibited at
higher concentration. Flow cytometric analysis on binding of the receptor to the
fluorescence-labeled formyl peptide and the polymerization of actin in cells
showed that the drug inhibited actin polymerization and promoted expression of
the fMLP receptors on cell membrane at lower concentration, while promoted the
actin polymerization and depressed the receptor expression at higher
concentration. As intracellular Ca(2+) ([Ca(2+)](i)) is elevated, polymerization
of actin decreases and the receptor expression increases. At normal physiological
and two moderately high intracellular calcium levels, the dual effect of W-7
became less significant as [Ca(2+)](i) was elevated indicating that the dual
effect is calcium-dependent. Under two extreme conditions that the intracellular
calcium was either depleted or highly elevated, the dual effect disappeared but
only an inhibitory effect on actin polymerization was observed. Colchicine and
taxol study showed that disruption or stabilization of microtubules had no effect
on formyl peptide receptor expression. The results suggest that W-7 primes the
fMLP stimulation by direct action on actin leading to breakdown of microfilaments
and more expression of formyl peptide receptors, and inhibits the stimulation by
indirect action on actin through inactivation of some Ca(2+)-dependent proteins
resulting in assembly of actin into microfilaments. Which action is favorable
depends on the drug concentration.
PMID- 10771093
TI - Volume sensitive efflux of taurine in HEK293 cells overexpressing phospholemman.
AB - The role of the phospholemman (PLM) on the efflux of taurine and chloride induced
by swelling was studied in HEK293 cells overexpressing stable transfected PLM.
PLM, a substrate for protein kinases C and A, is a protein that induces an anion
current in Xenopus oocytes and forms taurine-selective channels in lipid
bilayers. Taurine contributes as an osmolyte to regulatory volume decrease (RVD)
and is highly permeable through PLM channels in bilayers. In PLM-overexpressing
cells the process of RVD was more rapid and efficient (75%) than in control cells
(44%). Also, [(3)H]taurine and (125)I efflux induced by hyposmolarity were
markedly increased (30-100%) in two subclones of cells overexpressing PLM. This
increased efflux was sensitive to the Cl channel blockers DDF, NPPB and DIDS.
Acute treatment of control cells with isoproterenol and norepinephrine induced a
significant potentiation (50-60%) of [(3)H]taurine release induced by
hyposmolarity. In PLM-overexpressing cells the potentiation by these drugs was
higher (100%). Insulin induced also an increase in [(3)H]taurine release, but
only in PLM-overexpressing cells (50%). These results indicate that PLM may play
a role in the RVD and that its phosphorylation may have a physiological
significance during this process. The mechanisms involved in this process could
include the activation of PLM itself as channel or the modulation of other
preexisting channels.
PMID- 10771094
TI - Widespread expression of Agouti-related protein (AGRP) in the chicken: a possible
involvement of AGRP in regulating peripheral melanocortin systems in the chicken.
AB - Agouti-related protein (AGRP) is a naturally occurring antagonist of melanocortin
action. It is expressed mainly in the arcuate nucleus where it plays an important
role in the hypothalamic control of feeding and energy homeostasis by antagonism
of central melanocortin 4 receptors in mammals. Besides in the brain, the
melanocortin 4 receptor is expressed in numerous peripheral tissues in the
chicken. To examine whether or not the peripheral melanocortin 4 receptor
signaling could be regulated by AGRP, we cloned and localized the expression of
the AGRP gene in the chicken. The chicken AGRP gene was found to encode a 154 or
165 amino acid protein, depending on the usage of two alternative translation
initiation sites. The coding sequence consisted of three exons, like that of
mammalian species. The C-terminal cysteine-rich region of the predicted AGRP
displayed high levels of identity to mammalian counterparts (78-84%) and all 10
cysteine residues conferring functional conformation of AGRP were conserved;
however, other regions showed apparently no homology, suggesting that biological
activities of AGRP are located in its C-terminal region. RT-PCR analysis detected
the AGRP mRNA in all tissues examined: the brain, adrenal gland, heart, liver,
spleen, gonads, kidney, uropygial gland, skeletal muscle and adipose tissues.
Interestingly, the skin also expressed the AGRP mRNA, where Agouti, another
melanocortin receptor antagonist regulating hair pigmentation, is expressed in
rodents. Most of those AGRP-expressing tissues have been demonstrated to express
melanocortin 4 receptors and/or other subtypes of melanocortin receptor whose
mammalian counterparts can bind AGRP. These results imply the possibility that
some peripheral melanocortin systems could be regulated by the functional
interaction between melanocortins and AGRP at melanocortin receptors in the
chicken.
PMID- 10771095
TI - Novel effects of gossypol, a chemical contraceptive in man: mobilization of
internal Ca(2+) and activation of external Ca(2+) entry in intact cells.
AB - The effect of gossypol on Ca(2+) signaling in Madin Darby canine kidney (MDCK)
cells was investigated by using fura-2 as a Ca(2+) probe. Gossypol evoked a rise
in cytosolic free Ca(2+) levels ([Ca(2+)](i)) concentration-dependently between 2
and 20 microM. The response was decreased by external Ca(2+) removal. In Ca(2+)
free medium pretreatment with gossypol nearly abolished the [Ca(2+)](i) increase
induced by carbonylcyanide m-chlorophenylhydrazone (CCCP), a mitochondrial
uncoupler, and thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)
pump; but pretreatment with CCCP and thapsigargin only partly inhibited gossypol
induced Ca(2+) release. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) increase
after pretreatment with 5 microM gossypol in Ca(2+)-free medium. This Ca(2+)
entry was decreased by 25 microM econazole, 50 microM SKF96365 and 40 microM
aristolochic acid (a phospholipase A(2) inhibitor). Pretreatment with
aristolochic acid inhibited 5 microM gossypol-induced internal Ca(2+) release by
55%, but suppression of phospholipase C with 2 microM 1-(6-((17beta-3
methoxyestra-1,3, 5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) had no
effect. Gossypol (5 microM) also increased [Ca(2+)](i) in human bladder cancer
cells and neutrophils. Collectively, we have found that gossypol increased
[Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple Ca(2+) stores in a
manner independent of the production of inositol-1,4,5-trisphosphate, followed by
Ca(2+) influx from external space.
PMID- 10771096
TI - Cyclic GMP-dependent and -independent regulation of MAP kinases by sodium
nitroprusside in isolated cardiomyocytes.
AB - Sodium nitroprusside (SNP) elicits various physiological effects, in part through
generation of the membrane permeable mediator nitric oxide (NO). In the heart,
besides its role in regulating contractility, NO is involved in both protection
from and induction of cellular damage. The present study investigated the role of
SNP in the regulation of the mitogen-activated protein kinases (MAPKs) in
isolated adult rat cardiomyocytes. SNP maximally activated Erk1, Erk2, p38 MAPK
and MAPKAPK2 in 5-10 min. The activation of MAPKAPK2 by SNP was blocked by the
soluble guanylyl cyclase inhibitor, 1H-[1, 2,4]oxadiazolol[4,3-a]quinoxalin-1-one
(ODQ) and the p38 MAPK inhibitor, SB203580. The activation of Erk1 was
insensitive to ODQ but completely blocked by the Mek1 inhibitor PD98059. The
membrane-permeable homologue of cGMP, 8-Br-cGMP, also activated p38 MAPK (A(0.5)
approximately 50 microM) but not Erk1 and Erk2. These results indicate that p38
MAPK and MAPKAPK2 are activated by SNP in cGMP-dependent pathways, while the Erk1
activation by SNP is independent of cGMP levels.
PMID- 10771097
TI - Treatment of v-Ki-ras-transformed SVC1 cells with low retinoic acid induces
malignancy reversion associated with ras p21 down-regulation.
AB - The effect of nontoxic, low concentrations (10(-8) M) of retinoic acid (RA) for a
relatively long time (28 days) on a Kirsten ras-virus transformed cell line (Ki
SVC1), derived from the rat seminal vesicle epithelium, was investigated. In
these experimental conditions, the cell treatment with RA induced a decrease of
the proliferation rate, apoptosis and a marked reduction of both anchorage
independent growth and tumorigenicity. These biological responses were either
preceded or associated with important changes in adenylate cyclase/protein kinase
C signaling pathways, the activation of important apoptosis-linked genes and a
marked decrease of the v-Ki-ras p21 protein. The significance of these findings
is discussed.
PMID- 10771098
TI - GRP94 hyperglycosylation and phosphorylation in Sf21 cells.
AB - GRP94 is an inducible resident endoplasmic reticulum/sarcoplasmic reticulum
(ER/SR) glycoprotein that functions as a protein chaperone and Ca(2+) regulator.
GRP94 has been reported to be a substrate for protein kinase CK2 in vitro,
although its phosphorylation in intact cells remains unreported. In Sf21 insect
cells, overexpression of canine GRP94 led to the appearance of a multiplet of
three or more molecular-mass isoforms which was reduced to a single mobility form
following treatment of cells with tunicamycin, suggesting stable accumulations of
consecutively modified protein. Metabolic labeling of Sf21 cells with (32)P(i)
led to a constitutive phosphorylation of GRP94 which, based upon phosphopeptide
mapping, occurred specifically on CK2-sensitive sites. Among the GRP94 multiplet,
however, only the lowest mobility form of GRP94 was phosphorylated, even though
in vitro phosphorylation of GRP94 by CK2 led to phosphorylation of all
glycosylated forms. The (32)P(i) incorporation into GRP94 indicated a slow
turnover of phosphate incorporation that was unaffected by inhibition of
biosynthesis, resulting in a steady-state level of phospho-GRP94 on CK2 sites.
These data support a role for protein kinase CK2 in the cell biology for GRP94
and other resident ER/SR proteins that may occur in ER compartments.
PMID- 10771099
TI - Transforming growth factor-beta1 regulation of resting zone chondrocytes is
mediated by two separate but interacting pathways.
AB - Previous studies have shown that transforming growth factor-beta1 (TGF-beta1)
stimulates protein kinase C (PKC) via a mechanism that is independent of
phospholipase C or tyrosine kinase, but involves a pertussis toxin-sensitive G
protein. Maximal activation occurs at 12 h and requires new gene expression. To
understand the signaling pathways involved, resting zone chondrocytes were
incubated with TGF-beta1 and PKC activity was inhibited with chelerythrine,
staurosporine or H-7. [(35)S]Sulfate incorporation was inhibited, indicating that
PKC mediates the effects of TGF-beta1 on matrix production. However, there was
little, if any, effect on TGF-beta1-dependent increases in [(3)H]thymidine
incorporation, and TGF-beta1-stimulated alkaline phosphatase was unaffected,
indicating that these responses to the growth factor are not regulated via PKC.
TGF-beta1 caused a dose-dependent increase in prostaglandin E(2) (PGE(2))
production which was further increased by PKC inhibition. The increase was
regulated by TGF-beta1-dependent effects on phospholipase A(2) (PLA(2)).
Activation of PLA(2) inhibited TGF-beta1 effects on PKC, and inhibition of PLA(2)
activated TGF-beta1-dependent PKC. Exogenous arachidonic acid also inhibited TGF
beta1-dependent increases in PKC. The effects of TGF-beta1 on PKC involve genomic
mechanisms, but not regulation of existing membrane-associated enzyme, since no
direct effect of the growth factor on plasma membrane or matrix vesicle PKC was
observed. These results support the hypothesis that TGF-beta1 modulates its
effects on matrix production through PKC, but its effects on alkaline phosphatase
are mediated by production of PGE(2) and protein kinase A (PKA). Inhibition of
PKA also decreases TGF-beta1-dependent proliferation. We have previously shown
that PGE(2) stimulates alkaline phosphatase through its EP2 receptor, whereas EP1
signaling causes a decrease in PKC. Thus, there is cross-talk between the two
pathways.
PMID- 10771100
TI - Short term regulation of cell-cell communication in TM3 Leydig cells. A
perforated patch study.
AB - Determination of the junctional conductance (g(j)) in TM3 Leydig cells by the
dual whole cell patch clamp technique (DWCPC) shows that coupling undergoes a
rapid and irreversible run down. Addition of ATP or cAMP derivatives to the
pipette solution has been shown to prevent this phenomenon in several tissues,
but this same treatment is unable to inhibit run down in Leydig cells. Because
the run down in junctional conductance may pose serious problems to the
interpretation of results, we also measured g(j) by using the double perforated
patch clamp technique (DPPT). Access to the cell interior was achieved by adding
200 microgram/ml of nystatin to the pipette solution. With this method, run down
in g(j) was greatly reduced, amounting to no more than 5% of the initial value.
Exposure of the cells, under DWCPC or DPPT, to dibutyryl cAMP or to tumor
promoting agent (TPA) led to a decrease in cell to cell communication.
Staurosporine, a PKC inhibitor, increased g(j) and was able to prevent and
reverse the uncoupling action of cAMP or TPA. Our results indicate that cell-cell
communication in Leydig cells is down regulated by both protein kinases A and C,
interacting in a complex manner.
PMID- 10771102
TI - Mitochondrial DNA-depleted neuroblastoma (Rho degrees) cells exhibit altered
calcium signaling.
AB - To investigate the role of chronic mitochondrial dysfunction on intracellular
calcium signaling, we studied basal and stimulated cytosolic calcium levels in SH
SY5Y cells and a derived cell line devoid of mitochondrial DNA (Rho degrees ).
Basal cytosolic calcium levels were slightly but significantly reduced in Rho
degrees cells. The impact of chronic depletion of mitochondrial DNA was more
evident following exposure of cells to carbachol, a calcium mobilizing agent.
Calcium transients generated in Rho degrees cells following application of
carbachol were more rapid than those in SH-SY5Y cells. A plateau phase of calcium
recovery during calcium transients was present in SH-SY5Y cells but absent in Rho
degrees cells. The rapid calcium transients in Rho degrees cells were due, in
part, to increased reliance on Na(+)/Ca(2+) exchange activity at the plasma
membrane and the plateau phase in calcium recovery in SH-SY5Y cells was dependent
on the presence of extracellular calcium. We also examined whether mitochondrial
DNA depletion influenced calcium responses to release of intracellular calcium
stores. Rho degrees cells showed reduced responses to the uncoupler, FCCP, and
the sarcoplasmic reticulum calcium ATPase inhibitor, thapsigargin. Acute exposure
of SH-SY5Y cells to mitochondrial inhibitors did not mimic the results seen in
Rho degrees cells. These results suggest that cytosolic calcium homeostasis in
this neuron-like cell line is significantly altered as a consequence of chronic
depletion of mitochondrial DNA.
PMID- 10771101
TI - Gene expression of flap endonuclease-1 during cell proliferation and
differentiation.
AB - It has been shown that flap endonuclease-1 (FEN-1), a structure-specific
nuclease, acts on the removal of RNA primers during Okazaki fragment maturation
in DNA synthesis. To study whether the gene expression of FEN-1 is inducible
during cell proliferation, we analyzed the FEN-1 mRNA levels in actively growing
cells and non-growing cells. The gene expression of FEN-1 was higher in mitotic
cells than in resting cells, and was markedly decreased, especially, when
terminal differentiation was induced in promyelocytic leukemia cells (HL-60
cells). The decline correlated substantially with the ceasing of DNA synthesis.
In the examination of tissue-specific gene expression, the human testis, spleen,
thymus and mucosal lining of colon tissues expressed this gene actively, whereas
the prostate, ovary, small intestine and peripheral blood leukocyte hardly
expressed it. In addition, FEN-1 was co-localized with the proliferating cell
nuclear antigen (PCNA) in young rat kidney according to immunohistochemistry.
These findings suggest that FEN-1 gene expression is inducible during cell
proliferation for DNA synthesis, and is down-regulated during cell
differentiation.
PMID- 10771103
TI - Characterization and hetereologous expression of cDNAs encoding two novel closely
related Ca(2+)-binding proteins in Dictyostelium discoideum.
AB - During a yeast two hybrid screen of a Dictyostelium cDNA library using the Ca(2+)
binding protein CBP1 as bait, we isolated a full-length cDNA encoding a novel
Ca(2+)-binding protein (termed CBP4a). The protein is composed of 162 amino acids
and contains four consensus EF-hands. PCR amplification of Dictyostelium genomic
DNA using primers specific for the cDNA sequence resulted in the isolation of a
gene encoding a different Ca(2+)-binding protein of 162 amino acids (designated
CBP4b) with 90% amino acid sequence identity to CBP4a. Southern blot analysis
confirmed the presence of two closely related genes in the Dictyostelium genome.
CBP4a and CBP4b mRNAs are expressed at the same stages of development as CBP1
mRNA. In addition, both novel proteins bind (45)Ca(2+) and interact with CBP1 in
vitro in a Ca(2+)-dependent manner.
PMID- 10771104
TI - Novel brain function: biosynthesis and actions of neurosteroids in neurons.
AB - Peripheral steroid hormones act on brain tissues through intracellular receptor
mediated mechanisms to regulate several important brain neuronal functions.
Therefore, the brain is considered to be a target site of steroid hormones.
However, it is now established that the brain itself also synthesizes steroids de
novo from cholesterol. The pioneering discovery of Baulieu and his colleagues,
using mammals, and our studies with non-mammals have opened the door of a new
research field. Such steroids synthesized in the brain are called neurosteroids.
Because certain structures in vertebrate brains have the capacity to produce
neurosteroids, identification of neurosteroidogenic cells in the brain is
essential to understand the physiological role of neurosteroids in brain
functions. Glial cells are generally accepted to be the major site for
neurosteroid formation, but the concept of neurosteroidogenesis in brain neurons
has up to now been uncertain. We recently demonstrated neuronal
neurosteroidogenesis in the brain and indicated that the Purkinje cell, a typical
cerebellar neuron, actively synthesizes several neurosteroids de novo from
cholesterol in both mammals and non-mammals. Pregnenolone sulfate, one of
neurosteroids synthesized in the Purkinje neuron, may contribute to some
important events in the cerebellum by modulating neurotransmission. Progesterone,
produced as a neurosteroid in this neuron only during neonatal life, may be
involved in the promotion of neuronal and glial growth and neuronal synaptic
contact in the cerebellum. More recently, biosynthesis and actions of
neurosteroids in pyramidal neurons of the hippocampus were also demonstrated.
These serve an excellent model for the study of physiological roles of
neurosteroids in the brain, because both cerebellar Purkinje neurons and
hippocampal neurons play an important role in memory and learning. This paper
summarizes the advances made in our understanding of neurosteroids, produced in
neurons, and their actions.
PMID- 10771105
TI - Effects of localized lesions in the lateral suprasylvian cortex on convergence
eye movement in cats.
AB - We evaluated the effects of electrolytic lesions in the extrastriate cortical
area on the amplitudes and velocities of vergence eye movements in six alert cats
that were trained to track a target moving in depth. Bilateral or unilateral
lesions in the lateral suprasylvian (LS) cortex reduced the amplitudes and
velocities of vergence eye movements, but the positive correlation between them
was maintained. Furthermore, unilateral lesions changed the symmetry of eye
movements. Movements of the left eye were decreased by lesions in the right LS
cortex, resulting in asymmetric vergence eye movement with right eye
predominance, and vice versa. These results support the hypothesis that the LS
cortex plays an essential role in controlling vergence eye movement.
PMID- 10771106
TI - Evidence of [Ca(2+)]i elevation by anti-calreticulin immunoreactive protein in
neurons.
AB - Calreticulin is a multifunctional Ca(2+)-binding protein. The effect of anti
calreticulin antibody on intracellular free calcium concentration [Ca(2+)]i was
studied in cultured neurons using fura-2 based microfluorometry. Anti
calreticulin increased [Ca(2+)]i in a dose dependent manner. The anti
calreticulin antibody produced a rapid transient [Ca(2+)]i peak followed by a
long slowly decaying plateau. Anti-calreticulin induced extracellular Ca(2+)
influx in cultured neuron cells was blocked partially by N-methyl-D-aspartate
receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (AP5) and spider
polyamine toxin JSTX-3, which is recognized as a blocker of glutamatergic nervous
system. Furthermore, anti-calreticulin induced intracellular Ca(2+) desensitized
NMDAR. Dual immunofluorescent staining studies revealed that NMDAR co-localized
with calreticulin in the cultured neurons. Thus, the signal transduction system
of NMDA might be closely concerned with the extracellular calreticulin like
protein.
PMID- 10771107
TI - Regional differences in the expression of DNA topoisomerase IIbeta in the
pyramidal neurons of the rat hippocampus.
AB - A detailed analysis of the differential expression of a nuclear enzyme, DNA
topoisomerase (topo) IIbeta, was performed in the rat hippocampal pyramidal
layer. Three-dimensional (3-D) reconstruction from serial sections immunostained
with anti-topo IIbeta antibody showed that the immunoreactivity was apparently
weak in the entire CA3 region. Almost all CA1 pyramidal cells showed similar
immunoreactivity to that seen in the dentate granular cells, the subicular
neurons, and the cerebral neocortical neurons. In addition, immunoblotting
analysis in the adult dorsal hippocampus showed that the expression level of topo
IIbeta in the CA3 was significantly lower than that in the CA1 region. The
dissociation in the expression level between CA1 and CA3 occurred in postnatal
days 4 (P4) through P6. The present finding suggests that the enzyme is possibly
involved in activities of the hippocampal pyramidal neurons.
PMID- 10771108
TI - An anterograde and retrograde tract-tracing study on the projections from the
thalamic gustatory area in the rat: distribution of neurons projecting to the
insular cortex and amygdaloid complex.
AB - Projections from the thalamic gustatory nucleus, i.e. the parvicellular part of
the posteromedial ventral thalamic nucleus (VPMpc) to the forebrain regions were
studied in the rat by the tract-tracing methods with anterograde tracer
(biotinylated dextran amine, BDA) and anterograde/retrograde tracer (wheat-germ
agglutinin-horseradish peroxidase, WGA-HRP). After BDA injection into the VPMpc,
terminal labeling was observed in the insular cortex, amygdaloid complex, and
fundus striati. The terminal labeling in the amygdaloid complex was distributed
in dorsolateral area of the rostral part of the lateral amygdaloid nucleus and
the rostral part of the lateral subdivision of the central amygdaloid nucleus.
The terminal labeling in the central amygdaloid nucleus extended to the fundus
striati. The retrograde tracing study with WGA-HRP revealed that the projection
fibers from the VPMpc to the amygdaloid complex originated from the medial part
of the VPMpc and also from the thalamic area medial to the VPMpc. In the rats
injected with Fluoro-Gold and WGA-HRP, respectively into the insular cortex and
amygdaloid complex, no double-labeled neuronal cell bodies were found in the
VPMpc, although neurons labeled singly with Fluoro-Gold were intermingled with
those singly labeled with WGA-HRP in the medial part of the VPMpc. The results
indicated that VPMpc neurons projecting to the amygdaloid complex constituted a
population different from VPMpc neurons projecting to the insular cortex.
PMID- 10771109
TI - Identification of gelsolin as an actin regulatory component in a triton insoluble
low density fraction (raft) of newborn bovine brain.
AB - A membrane microdomain enriched in cholesterol and glycosphingolipids, or so
called 'raft' region, was found to contain many signal transducing proteins such
as GPI-anchored cell adhesion molecules, trimeric G proteins, and protein
tyrosine kinases. In previous studies, we showed that the raft region obtained
from rat brain contains two cytoskeletal proteins, tubulin and actin, as the
major components in addition to these signal transducing proteins. In this study,
to know the biochemical mechanisms regulating the cytoskeletal organization in
this region, actin regulatory activities in raft were surveyed. We found the
presence of a Ca(2+)-dependent actin nucleation promoting activity in raft. The
solubilization and column fractionation of this activity combined with western
blotting and immunoprecipitation showed that gelsolin is one of the actin
regulatory proteins in raft.
PMID- 10771110
TI - The effect of intrastriatal single injection of GDNF on the nigrostriatal
dopaminergic system in hemiparkinsonian rats: behavioral and histological studies
using two different dosages.
AB - Glial cell line-derived neurotrophic factor (GDNF) is a member of the
transforming growth factor-beta superfamily and acts as a neurotrophic factor for
the nigrostriatal dopamine (DA) system. Although previous studies have shown that
pretreatment with GDNF could prevent degenerative changes of nigrostriatal DA
system by DA neurotoxin 6-hydroxydopamine (6-OHDA), it is not really known
whether GDNF can induce recovery of nigrostriatal DA system after partial
lesioning by 6-OHDA. Substantia nigra has been commonly chosen as injection site
for GDNF but a limited number of studies have used striatum as injection site
where neural transplantation is commonly performed. Unilateral intrastriatal
administration of 6-OHDA was performed in Sprague-Dawley rats to create partial
lesion of the nigrostriatal DA system. These hemiparkinsonian model rats received
a 10- or 100-microg single injection of human recombinant GDNF into the same
portion of the striatum 4 weeks after 6-OHDA treatment. Both animals that
received a 10- or 100-microg single injection of GDNF showed decreased
apomorphine-induced rotation at 2 weeks after injection. More potent and
prolonged functional recovery was observed in animals receiving 100 microg of
GDNF than in those receiving 10 microg of GDNF. Tyrosine hydroxylase (TH)
immunocytochemistry revealed that TH positive DA fiber density in the striatum
and the number of DA cell bodies in the substantia nigra were greater in animals
receiving 10 or 100 microg of GDNF than those receiving saline. These
immunocytochemical results have also shown that 100 microg of GDNF was more
potent than 10 microg of GDNF. These morphological and functional results
indicate that GDNF treatment 4 weeks after 6-OHDA lesioning could induce recovery
of nigrostriatal DA system. Striatum was a good site for GDNF administration for
hemiparkinsonian rats and a single injection of 100 microg of GDNF was more
potent than 10 microg of GDNF.
PMID- 10771111
TI - The relationship between neurokinin-1 receptor and substance P in the medullary
dorsal horn: a light and electron microscopic immunohistochemical study in the
rat.
AB - The synaptic relationship between substance P (SP) and its receptor, i.e.
neurokinin-1 receptor (NK1R), was examined in the superficial laminae of the
caudal subnucleus of the spinal trigeminal nucleus (medullary dorsal horn; MDH)
of the rat. For confocal laser-scanning microscopy, double-immunofluorescence
histochemistry for NK1 and SP was performed. In electron microscopic double
immunolabeling study, immunoreactivity for NK1R was detected with the silver
intensified gold method, while immunoreactivity for SP was detected with
peroxidase immunohistochemistry. SP-immunoreactive axon terminals were observed
to be in synaptic (mostly asymmetric) contact with NK1R-immunoreactive neuronal
profiles in lamina I and lamina IIo. Although some SP-immunoreactive axon
terminals were in synaptic contact with NK1R-immunoreactive sites of plasma
membranes, NK1R-immunoreactivity was observed at both synaptic and non-synaptic
sites of plasma membrane. Thus, SP released from axon terminals might not only
act on NK1Rs facing the SP-containing axon terminals, but also diffuse in the
extracellular fluid for distances larger than the synaptic cleft to act on NK1Rs
at some distances from the synaptic sites.
PMID- 10771113
TI - Quantitative imaging of substance P in the human brain using a brain mapping
analyzer.
PMID- 10771112
TI - B-mode and color Doppler ultrasound imaging for localization of microelectrode in
monkey brain.
AB - Using alert monkeys, we attempted ultrasound imaging after partial craniotomy to
localize a metal microelectrode in the brain. B-mode ultrasonography provided
images of sulcus and gyrus patterns of the cerebral cortex, and locations of the
ventricles and subarachnoid cisterns. As the microelectrode proceeded in the
brain, the position of the microelectrode was clearly identified. Electrolytic
microlesions generated by delivering direct currents via the microelectrode could
also be detected. Color Doppler imaging of blood vessels of the brain was helpful
to demarcate deep brain structures and to avoid accidental injury of the blood
vessels by the microelectrode. The ultrasonography will make it possible to place
recording microelectrodes or injection needles accurately in target regions of
the brain in physiological, anatomical or behavioral experiments.
PMID- 10771114
TI - Tonic adenosine neuromodulation is preserved in motor nerve endings of aged rats.
AB - Neuromuscular transmission is decreased in aged subject. Since endogenous
adenosine is a potent neuromodulator at motor nerve endings, either inhibiting
via A(1) receptors or facilitating via A(2A) receptors acetylcholine release, we
now investigated if the tonic effect of endogenous adenosine was modified at
phrenic nerve endings of aged rats. The A(2A) receptor antagonist (ZM241385, 50
nM) inhibited (77 +/- 9%) and the A(1) receptor antagonist (DPCPX, 50 nM)
facilitated (74 +/- 13%) acetylcholine release from young adult (6 weeks old) rat
preparations, indicating a simultaneous tonic activation of A(2A) and A(1)
receptors. Tonic modulation by adenosine was unaltered in aged (24 months old)
rats, since ZM241385 (50 nM) inhibited (73 +/- 8%) and DPCPX (50 nM) facilitated
(91 +/- 20%) acetylcholine release in aged animals similarly to young rats. This
indicates that, in contrast to the central nervous system where adenosine
neuromodulation is modified in aged animals, the control by adenosine of phrenic
nerve function is preserved in aged animals.
PMID- 10771115
TI - Involvement of the actin cytoskeleton in the regulation of serotonin transporter
(SET) activity: possible mechanism underlying SET regulation by protein kinase C.
AB - Our previous report has revealed that PKC activation by 12-O-tetradecanoylphorbol
13-acetate (TPA) inhibited the uptake activity of serotonin transporter (SET),
via an indirect mechanism unknown, but not likely via direct phosphorylation of
SET by PKC (Sakai et al., 1997. J. Neurochem. 68, 2618-2624). To elucidate
whether PKC can directly phosphorylate SET in vivo, FLAG-tagged SET (FLAG-SET)
was expressed in COS-7 cells and the TPA-induced incorporation of (32)P into
immunoprecipitated FLAG-SET was examined. PKC activation with TPA caused no
phosphorylation of FLAG-SET expressed in COS-7 cells. On the other hand,
morphological change associated with the disruption of filamentous actin (F
actin) was seen in TPA-treated COS-7 cells. Therefore, we studied the effects of
cytochalasin D, an inhibitor of actin polymerization, on the uptake activity of
the serotonin transporter (SET) to elucidate whether the actin cytoskeleton
modulates the SET uptake activity. The treatment with cytochalasin D inhibited
the uptake activity of both native and recombinant SET in a concentration
dependent manner. Eadie-Hofstee analysis revealed that cytochalasin D down
regulated the recombinant SET uptake activity by reducing the V(max), but not the
K(m), mimicking the result observed in TPA-induced inhibition of SET activity
(Sakai et al., 1997. J. Neurochem. 68, 2618-2624). The cytochalasin D-induced
inhibition of SET activity was partially, but significantly, reversed by
jasplakinolide, a cell permeable stabilizer of F-actin, whereas TPA-induced
inhibition of SET activity was not reversed by jasplakinolide. To elucidate
whether the subcellular localization of SET was changed in response to
cytochalasin D or TPA, we expressed the SET fused with the green fluorescent
protein (SET-GFP) in COS-7 cells and observed the subcellular distribution of SET
GFP under a confocal laser scanning fluorescent microscope. Neither cytochalasin
D nor TPA markedly changed the SET-GFP cellular localization, although these
drugs caused morphological change in the GFP-transfected COS-7 cells. In
addition, SET activity was not altered by the treatment with either colchicine,
an inhibitor of microtubule polymerization, or taxol, a stabilizer of microtubule
polymerization. These results suggest that the SET uptake activity was regulated
by the state of the actin cytoskeleton and that TPA exerts its inhibitory action
on SET activity, in part, via disruption of F-actin and subsequent morphological
change in cells.
PMID- 10771116
TI - Modulation of calcium-evoked [3H]noradrenaline release from permeabilized
cerebrocortical synaptosomes by the MARCKS protein, calmodulin and the actin
cytoskeleton.
AB - In order to examine intracellular modulation of CNS catecholamine release,
cerebrocortical synaptosomes were prelabeled with [3H]noradrenaline and
permeabilized with streptolysin-O in the absence or presence of Ca(2+). Plasma
membrane permeabilization allowed efflux of cytosol and left a compartmentalized
pool of [3H]noradrenaline intact, approximately 10% of which was released by
addition of 10(-5) M Ca(2+). Addition of activators or inhibitors of protein
kinase C, as well as inhibitors of Ca(2+)-calmodulin kinase II or calcineurin,
failed to change Ca(2+)-induced noradrenaline release. Evoked release from
permeabilized synaptosomes deficient in the vesicle-associated phosphoprotein
synapsin I was also unchanged. In contrast, addition of a synthetic 'active
domain' peptide from the myristoylated, alanine-rich C-kinase substrate (MARCKS)
protein increased, while addition of calmodulin decreased Ca(2+)-induced release
from the permeabilized synaptosomes, the latter effect being reversed by a
peptide inhibitor of calcineurin. Moreover, addition of the actin-destabilizing
agent DNase I, as well as antibodies to MARCKS, appeared to increase spontaneous,
Ca(2+)-independent release from noradrenergic vesicles. These results indicate
that the MARCKS protein may modulate release from permeabilized noradrenergic
synaptosomes, possibly by modulating calmodulin levels and/or the actin
cytoskeleton.
PMID- 10771117
TI - Localization of agonist and competitive antagonist binding sites on nicotinic
acetylcholine receptors.
AB - Identification of all residues involved in the recognition and binding of
cholinergic ligands (e.g. agonists, competitive antagonists, and noncompetitive
agonists) is a primary objective to understand which structural components are
related to the physiological function of the nicotinic acetylcholine receptor
(AChR). The picture for the localization of the agonist/competitive antagonist
binding sites is now clearer in the light of newer and better experimental
evidence. These sites are located mainly on both alpha subunits in a pocket
approximately 30-35 A above the surface membrane. Since both alpha subunits are
identical, the observed high and low affinity for different ligands on the
receptor is conditioned by the interaction of the alpha subunit with other non
alpha subunits. This molecular interaction takes place at the interface formed by
the different subunits. For example, the high-affinity acetylcholine (ACh)
binding site of the muscle-type AChR is located on the alphadelta subunit
interface, whereas the low-affinity ACh binding site is located on the alphagamma
subunit interface. Regarding homomeric AChRs (e.g. alpha7, alpha8, and alpha9),
up to five binding sites may be located on the alphaalpha subunit interfaces.
From the point of view of subunit arrangement, the gamma subunit is in between
both alpha subunits and the delta subunit follows the alpha aligned in a
clockwise manner from the gamma. Although some competitive antagonists such as
lophotoxin and alpha-bungarotoxin bind to the same high- and low-affinity sites
as ACh, other cholinergic drugs may bind with opposite specificity. For instance,
the location of the high- and the low-affinity binding site for curare-related
drugs as well as for agonists such as the alkaloid nicotine and the potent
analgesic epibatidine (only when the AChR is in the desensitized state) is
determined by the alphagamma and the alphadelta subunit interface, respectively.
The case of alpha-conotoxins (alpha-CoTxs) is unique since each alpha-CoTx from
different species is recognized by a specific AChR type. In addition, the
specificity of alpha-CoTxs for each subunit interface is species-dependent. In
general terms we may state that both alpha subunits carry the principal component
for the agonist/competitive antagonist binding sites, whereas the non-alpha
subunits bear the complementary component. Concerning homomeric AChRs, both the
principal and the complementary component exist on the alpha subunit. The
principal component on the muscle-type AChR involves three loops-forming binding
domains (loops A-C). Loop A (from mouse sequence) is mainly formed by residue
Y(93), loop B is molded by amino acids W(149), Y(152), and probably G(153), while
loop C is shaped by residues Y(190), C(192), C(193), and Y(198). The
complementary component corresponding to each non-alpha subunit probably
contributes with at least four loops. More specifically, the loops at the gamma
subunit are: loop D which is formed by residue K(34), loop E that is designed by
W(55) and E(57), loop F which is built by a stretch of amino acids comprising
L(109), S(111), C(115), I(116), and Y(117), and finally loop G that is shaped by
F(172) and by the negatively-charged amino acids D(174) and E(183). The
complementary component on the delta subunit, which corresponds to the high
affinity ACh binding site, is formed by homologous loops. Regarding alpha
neurotoxins, several snake and alpha-CoTxs bear specific residues that are
energetically coupled with their corresponding pairs on the AChR binding site.
The principal component for snake alpha-neurotoxins is located on the residue
sequence alpha1W(184)-D(200), which includes loop C. In addition, amino acid
sequence 55-74 from the alpha1 subunit (which includes loop E), and residues
gammaL(119) (close to loop F) and gammaE(176) (close to loop G) at the low
affinity binding site, or deltaL(121) (close to the homologous region of loop G)
at the high-affinity binding site, are i
PMID- 10771118
TI - The relationship between psychosocial work characteristics and low back pain:
underlying methodological issues.
AB - OBJECTIVE: To evaluate the current epidemiological evidence linking psychosocial
work characteristics with low back pain. BACKGROUND: Psychosocial work
characteristics have been widely evaluated as potential risk factors for low back
injury. However, studies with different study populations and using various types
of measures have had conflicting results. METHODS: This review is the most
extensive to date, reviewing 66 articles that have provided empirical evidence
about the relationship between psychosocial work characteristics and initial
reporting of lower back pain. The studies are reviewed with an emphasis on
certain methodological issues: controlling for potential confounding; timing of
the data collection; and measurement of the exposures and outcomes. RESULTS: The
results of this review suggest that controlling for potential confounding from
occupational biomechanical demands had a large influence on the associations
found between psychosocial work characteristics and lower back pain. In addition,
the use of accurate and reliable measures for the occupational exposures
(biomechanical and psychosocial) and the lower back pain outcomes appears to
influence the strength of the associations found between psychosocial work
characteristics and lower back pain. CONCLUSION: Given the methodological
concerns discussed in this review, it is difficult to draw strong causal
inferences from this literature. However, it does appear that psychosocial
characteristics are related to some lower back pain outcomes, and that employees'
reactions to psychosocial work characteristics (e.g., job dissatisfaction and job
stress) are more consistently related to lower back pain than are the
psychosocial work characteristics themselves (e.g., work overload, lack of
influence over work, quality of relationships with coworkers). RELEVANCE: This
review attempts to identify and address methodological issues in the literature
evaluating the relationship between psychosocial work characteristics and lower
back pain. Implications for future research are presented.
PMID- 10771119
TI - The effect of load on the coordination of the trunk for subjects with and without
chronic low back pain during flexion-extension and lateral bending tasks.
AB - OBJECTIVE: To evaluate if patients move their trunk sections differently than
normal subjects and to determine if these differences increase when lifting a
load. DESIGN: Comparative study using a repeated measures design. BACKGROUND:
Many studies demonstrate a modification of the lumbar-pelvic rhythm for chronic
low back pain patients but the large variability of the results impair the
discrimination power. It was hypothesized that the lifting of a load would
magnify the manifestation of lumbar impairments. METHODS: Fifteen chronic low
back pain patients and 18 normal subjects performed maximal flexion-extension and
lateral bending of the trunk with and without a 12 kg load. The pelvic, lumbar
and thoracic motions were measured with a motion analysis system. RESULTS: During
flexion-extension tasks, a significant decrease in lumbar flexion and increase in
thoracic flexion were observed for the patients. The load effect was significant
for all trunk sections but did not allow a better discrimination between groups.
CONCLUSIONS: Lifting a 12 kg load during flexion-extension of the trunk did
confirm alteration in trunk section coordination but did not help to better
discriminate patients from normal subjects. However, it was demonstrated for the
first time that chronic low back pain patients compensate for a loss of lumbar
flexion by increasing their thoracic flexion. RELEVANCE: The lumbar-pelvic rhythm
is routinely used to evaluate low back impairments. The use of kinematic measures
enhance the objectivity of the examination but the large variability of the
results impair the discrimination power. Lifting a load during such an evaluation
might magnify the low back impairments and increase the discrimination power of
this measure.
PMID- 10771120
TI - Magnetic resonance-based vertebral morphometry of the thoracic spine: age, gender
and level-specific influences.
AB - OBJECTIVE: The aim of this study was to examine age, gender, and segmental trends
in thoracic vertebral body shape, utilising thoracic spine magnetic resonance
images involving an age range spanning the life span. DESIGN: A quantitative,
cross-sectional, retrospective study design involving a sample of convenience.
BACKGROUND: Thoracic vertebral shape data are commonly derived from radiographic
resources. The non-ionising properties of magnetic resonance imaging and
availability of digital data for image analysis suggest potential for MR-based
morphometric studies. For the thoracic spine, there is limited vertebral shape
data on males, while few studies have examined the pattern of age-related changes
across the life span. METHODS: Morphometry was performed on 220 mid sagittal T1
weighted MR images using image analysis software. Three indices of vertebral
shape were utilised: the antero-posterior height ratio or anterior wedge index,
mid-posterior height ratio or biconcavity index, and ratio of posterior vertebral
height to mid antero-posterior diameter or compression index. RESULTS: Different
segmental patterns were noted for the vertebral shape indices. Significantly
lower mean values were noted in males for the compression index. Age trends were
significant, with a linear age-related decline demonstrated for the anterior
wedge and biconcavity indices, and a quadratic trend noted for the compression
index. CONCLUSIONS: Thoracic vertebral body shape may be uniquely described using
specific shape indices, for examining various segmental, gender and age
associated changes. RELEVANCE: These results suggest the importance of defining
specific reference criteria for thoracic vertebral body shape indices,
particularly age-related data encompassing a wide age range. Magnetic resonance
studies enable interpretation of vertebral shape data in relation to the wide
spectrum of pathologies afflicting the thoracic spine, without the concerns of
ionising radiation.
PMID- 10771121
TI - Cervical muscle response during whiplash: evidence of a lengthening muscle
contraction.
AB - OBJECTIVE: To assess the potential for cervical muscle injury from a rear-end
automobile collision. DESIGN: Experimental design in which human subjects were
exposed to low-speed rear-end collisions. The influence of independent variable
(gender, speed change, muscle group, and motion phase) on dependent variables
(kinematic response, muscle onset and muscle activation level) was examined using
repeated-measures analysis of variance. BACKGROUND: Injuries to various tissues
of the cervical spine have been proposed, yet little attention has been focused
on the cervical muscles as a site of injury. METHODS: 42 subjects (21 males, 20
40 yr) were exposed to collisions of 4 and 8 km/h speed change while measuring
kinematic response of the head and torso and electromyography of the
sternocleidomastoid and cervical paraspinal muscles. RESULTS: Muscle activation
occurred earlier in females and in the 8 km/h speed change. Sternocleidomastoid
onset preceded paraspinal onset. Muscle activation level varied significantly
with speed change, motion phase and muscle group. Initial rearward retraction of
the head relative to the torso resulted in lengthening of the activated
sternocleidomastoid, consistent with a contraction-induced muscle injury.
CONCLUSIONS: The cervical muscles contract rapidly in response to impact and the
potential exists for muscle injury due to lengthening contractions. RELEVANCE:
The clinician should recognize the role of cervical retraction in the mechanism
of whiplash injury and avoid aggressive motion in that plane during diagnosis and
treatment. An understanding of whiplash injury mechanisms should improve patient
education and preventative measures.
PMID- 10771122
TI - Cervical coupling during lateral head translations creates an S-configuration.
AB - OBJECTIVE: To determine cervical coupling during the posture of lateral head
translation relative to a fixed thoracic cage. DESIGN: Digitized measurements
from anteroposterior cervical radiographs of 20 volunteers were obtained in
neutral, left, and right lateral translation posture of the head compared to a
fixed thorax. BACKGROUND DATA: Clinically, lateral translation of the head is a
common posture. Ranges of motion and spinal coupling have not been reported for
this movement. METHODS: Vertebral body corners, mid-lateral articular pillars and
the superior spinous-lamina junction of C3-T4 were digitized on 60 radiographs.
Using the orthogonal axis of positive x-direction to the left, vertical as
positive y and anterior as positive z, digitized points were used to measure
projected segmental z-axis rotation, y-axis rotation, and segmental lateral
translations of each vertebra. RESULTS: Subjects translated their heads laterally
a mean of 51 mm. The major coupled motion was lateral bending (z-axis rotation),
which changed direction at the C4-C5 disc space creating an S-shape. Upper
cervical (C3-C4) lateral bending was contralateral to the main motion of head
translation direction. Lower cervical and upper thoracic lateral bending were
ipsilateral. Other segmental motions averaged less than 1 mm and 1 degrees.
CONCLUSIONS: Lateral head translations (x-axis) compared to a fixed thoracic cage
can be large with a mean of 51 mm to one side. The major spinal coupling was
lateral bending which changed direction at C4-C5 resulting in an S-configuration.
This might have application in side impacts. All other segmental movements were
small, less than 1 mm and 1 degrees. RELEVANCE: The clinically common posture of
lateral head translation results in an S-shaped cervical spine and may occur in
side impact trauma. This posture has not been studied for cervical coupling
patterns or range of motion (ROM).
PMID- 10771123
TI - Arm motion and load analysis of sit-to-stand, stand-to-sit, cane walking and
lifting.
AB - OBJECTIVE: To conduct a pilot study to characterize the hand loads, arm joint
angles and external moments corresponding to five activities of daily living
demanding of the shoulder, for healthy subjects over 50 years of age. DESIGN: The
tasks were sit-to-stand, stand-to-sit, cane walking, lifting a 5 kg box with both
hands, and lifting a 10 kg suitcase. BACKGROUND: Arm motion and loading have not
been previously studied for functional daily-living tasks involving substantial
external loads.Methods. Motion was tracked using an optoelectronic system. Loads
were measured using an instrumented chair arm, a force plate, and gravitational
and acceleration loads. Six healthy volunteers (3 male, 3 female), mean age 55,
with no history of shoulder problems participated in the study. RESULTS: Average
peak external moments ranged from 12.3 N m for sitting down into a chair to 27.9
N m for lifting a suitcase. Except for lifting the box, which had much lower
loads, average peak hand loads varied from 16% to 19% of body weight (114-134 N).
The arcs of motion were larger than for seated activities of daily-living studied
previously. CONCLUSIONS: The five tasks studied are commonly performed, yet
involve large external moments. Lifting represents the greatest potential loading
at the shoulder as it resulted in the highest external moments; furthermore,
loads larger than those used in this study might be commonly lifted. RELEVANCE:
External moments at the shoulder should not be underestimated, even for
activities of daily living.
PMID- 10771124
TI - The effects of the lower extremity joint motions on the total body motion in sit
to-stand movement.
AB - OBJECTIVE: The purpose of this study is to investigate the effects of lower
extremity joint angular motions on the whole body linear motions in a sit-to
stand movement using a biomechanical model that describes the whole body linear
velocity vector as functions of lower extremity joint angular velocities. DESIGN:
Two-dimensional video analysis of whole body and joint kinematics. BACKGROUND: A
biomechanical model that describes the whole body linear motions as functions of
lower extremity joint angular motions is needed to provide clinically relevant
information in clinical services and scientific research. METHODS: The linear
velocity vector of the whole body motion during the sit-to-stand movement was
partitioned into horizontal and vertical components and expressed as functions of
lower extremity joint angular velocities for 10 healthy subjects. The coefficient
of joint contribution to the whole body linear velocity vector was determined for
each joint in each direction. RESULTS: The ankle and hip angular motions are
critical to the development of the forward horizontal velocity of the whole body
during the sit-to-stand movement. The knee and hip angular motions are critical
to the development of the upward vertical velocity of the whole body during the
sit-to-stand movement. CONCLUSIONS: The hip, knee, and ankle joint angular
motions have various roles in whole body motions in different directions of the
sit-to-stand movement. RELEVANCE: The model and the results of this study can be
applied to study the control strategies, falls, and assessments of functional
impairments in the sit-to-stand movement.
PMID- 10771125
TI - Mechanical properties of the posterior rotator cuff.
AB - BACKGROUND: The infraspinatus is an important active and passive stabilizer of
the glenohumeral joint. It functions as external rotator and participates in
elevation of the arm. As its main posterior component, it is frequently involved
in rotator cuff tears. OBJECTIVE: The purpose of this study was to determine the
structural and mechanical properties of the infraspinatus tendon structure,
including the midsubstance and insertion regions, in the superior, mid-superior,
mid-inferior, and inferior portions, in two joint positions. METHODS: The
infraspinatus tendons from 22 fresh frozen cadaver shoulders were divided into
four strips. The tendons were held in a cryo-jaw and tested with a material
testing machine in 0 degrees or 60 degrees of glenohumeral abduction
corresponding to 90 degrees arm abduction. Ultimate load, displacement and
failure mode were recorded. Stiffness, ultimate stress and elastic modulus were
calculated. RESULTS: Significant differences between glenohumeral abduction
positions were detected only for the elastic modulus. The mid-superior (676.5 N,
S.D. 231.0 N) and the inferior portion (549.9 N, S.D. 284.6 N) had the highest
failure loads while the superior (462.8 N, S.D. 237.2 N) and the mid-inferior
portions (315.3 N, S.D. 181.5 N) were weaker. Similar trends across the tendon
strips were shown for stiffness, ultimate stress and elastic modulus. RELEVANCE:
Position dependent changes in mechanical properties of the infraspinatus tendon
probably do not play a role in the pathomechanism of posterior shoulder
dislocation. Peaks in stiffness in mid-superior and inferior tendon sections
explain the low incidence of posterior dislocations. The low ultimate failure
loads in the superior portions might explain the frequent extension of rotator
cuff ruptures into the infraspinatus tendon.
PMID- 10771126
TI - The acetabular labrum seal: a poroelastic finite element model.
AB - OBJECTIVE: The aim of the study is to investigate the labrum's ability to seal a
pressurised layer of synovial fluid within the joint, and to study the influence
of this sealing mechanism on cartilage deformation, interstitial fluid pressure
and collagen solid matrix stresses. BACKGROUND: Cartilage degeneration has been
observed in conjunction with labrum pathology. However, little is known about the
function of the labrum. Experimental observations have been reported which are
consistent with a sealing function of the labrum. METHODS: The model was an
axisymmetric geometric approximation of the acetabular and femoral cartilage
layers and the surrounding labrum. A poroelastic formulation was used to account
for the solid and fluid components of these hydrated tissues. A sensitivity
analysis of the labrum material properties was carried out. RESULTS: With a
compressive load of 1200 N applied across the joint model, the labrum could seal
a layer of pressurised fluid between the femur and acetabulum, thus preventing
contact of the articulating surfaces. With this sealing effect, loads were
transferred across the joint predominantly by uniform pressurisation of the
interstitial fluid of the cartilage layers. In the absence of this sealing,
strains within the solid matrix of the cartilage layers were higher (e.g. 20% vs.
3%). CONCLUSIONS: The labrum can seal against fluid expression from the joint
space. This sealing function protects the cartilage layers of the hip. RELEVANCE:
Current treatments for labrum damage and early arthrosis may compromise the
sealing function of the labrum. With continued study of the function and
importance of the labrum, new surgical repair strategies can be developed to
maintain the overall function of the hip joint.
PMID- 10771127
TI - Carbon monoxide poisoning--a public health perspective.
AB - Carbon monoxide (CO) may be the cause of more than one-half of the fatal
poisonings reported in many countries; fatal cases also are grossly under
reported or misdiagnosed by medical professionals. Therefore, the precise number
of individuals who have suffered from CO intoxication is not known. The health
effects associated with exposure to CO range from the more subtle cardiovascular
and neurobehavioral effects at low concentrations to unconsciousness and death
after acute or chronic exposure to higher concentrations of CO. The morbidity and
mortality resulting from the latter exposures are described briefly to complete
the picture of CO exposure in present-day society. The symptoms, signs, and
prognosis of acute CO poisoning correlate poorly with the level of
carboxyhemoglobin (COHb) measured at the time of hospital admission; however,
because CO poisoning is a diagnosis frequently overlooked, the importance of
measuring COHb in suspicious settings cannot be overstated. The early symptoms
(headache, dizziness, weakness, nausea, confusion, disorientation, and visual
disturbances) also have to be emphasized, especially if they recur with a regular
periodicity or in the same environment. Complications occur frequently in CO
poisoning. Immediate death is most likely cardiac in origin because myocardial
tissues are most sensitive to the hypoxic effects of CO. Severe poisoning results
in marked hypotension, lethal arrhythmias, and electrocardiographic changes.
Pulmonary edema may occur. Neurological manifestation of acute CO poisoning
includes disorientation, confusion, and coma. Perhaps the most insidious effect
of CO poisoning is the development of delayed neuropsychiatric impairment within
2-28 days after poisoning and the slow resolution of neurobehavioral
consequences. Carbon monoxide poisoning during pregnancy results in high risk for
the mother by increasing the short-term complication rate and for the fetus by
causing fetal death, developmental disorders, and chronic cerebral lesions. In
conclusion, CO poisoning occurs frequently; has severe consequences, including
immediate death; involves complications and late sequelae; and often is
overlooked. Efforts in prevention and in public and medical education should be
encouraged.
PMID- 10771128
TI - Effects of nickel sulfate on pulmonary natural immunity in Wistar rats.
AB - This study was designed to investigate the in vivo effect of nickel sulfate on
the pulmonary non-specific immune defences. Groups of four male Wistar rats were
treated with a single intratracheal instillation of NiSO(4) at different doses:
1, 2, 4 and 8 micromol of NiSO(4) per rat. Control rats received a corresponding
instillation of the saline vehicle. The effect of NiSO(4) on the cytotoxic
activity of the pulmonary natural killer (NK) cells and alveolar macrophages
(AM), as well as the pulmonary production of cytokines such as alpha-tumor
necrosis factor (TNF-alpha) and gamma-interferon (IFN-gamma), were examined 1, 2
and 7 days later. Spontaneous NK-cytotoxicity towards mouse-derived tumor cell
line, Yac-1 was suppressed 1 day after treatment at doses of 2 micromol/rat and
above with only one result significant (P<0.05); 2 days after treatment the
suppression was increased with all results significant at the same doses; 1 week
after treatment NK activity restoration was observed except for the highest dose,
8 micromol/rat. AM-mediated cytotoxicity towards mouse-derived tumor cell line,
3T12, did not show any significant difference in treated and untreated animals.
In contrast, whereas moderate levels of TNF-alpha were detected in the broncho
alveolar lavage (BAL) fluid supernatants of controls, the NiSO(4) treatment
highly suppressed TNF-alpha production with a maximum observed after 2 days. TNF
alpha suppression was found to be transient, at least with the lowest NiSO(4)
dose, with levels returning to normal after 7 days. A non-significant increase in
IFN-gamma was observed in the BAL fluids of treated animals at each time of
examination. Taken together, these results indicate that NK cell activity and TNF
alpha secretion are sensitive targets for instilled NiSO(4) in Wistar rats.
PMID- 10771129
TI - Cadmium induces caspase-mediated cell death: suppression by Bcl-2.
AB - Apoptosis is a process of active cell death and is characterized by activation of
caspases, DNA fragmentation, and biochemical and morphological changes. To better
understand apoptosis, we have characterized the dose- and time-dependent toxic
effects of cadmium in Rat-1 fibroblasts. Staining of cells with
phosphatidylserine (PS)-annexin V, Hoechst 33258 or Rhodamine 123 and Tunel
assays showed that incubating cells with 10 microM cadmium induced a form of cell
death exhibiting typical characteristics of apoptosis, including cell shrinkage,
externalization of PS, loss of mitochondria membrane potential, nuclear
condensation and DNA fragmentation. Expression of Bcl-2 or CrmA each suppressed
cadmium-induced cell death although Bcl-2 was somewhat more effective than CrmA.
In vitro assay of caspase activity carried out using poly(ADP-ribose) polymerase
(PARP) as a substrate as well as intracellular caspase assays using a fluorigenic
caspase-3 substrate confirmed that caspase-3 is activated in Rat-1 cells
undergoing cadmium-induced apoptosis. Both Asp-Glu-Val-Asp-aldehyde (DEVD-cho)
and Tyr-Val-Ala-Asp-chloromethylketone (YVAD-cmk), selective inhibitors of
caspase-3 and caspase-1, respectively, suppressed significantly cadmium-induced
cell death. However, the nonselective caspase inhibitor, z-Val-Ala-Asp
floromethylketone (zVAD-fmk), was the most efficacious agent, almost completely
blocking cadmium-induced cell death. Taken together, these results demonstrate
that as in other forms of apoptosis, caspases play a central role in cadmium
induced cell death.
PMID- 10771130
TI - A rat nasal epithelial model for predicting upper respiratory tract toxicity: in
vivo-in vitro correlations.
AB - An in vitro model of the rat nasal cavity has been used to compare the responses
of nasal tissues in vitro, using loss of intracellular ATP and potassium as
indices of toxicity, with the pathological changes occurring following in vivo
exposure to four test compounds. Turbinates were incubated in vitro with the test
compounds for 4 h, for 24 h or for 4 h followed by 20 h in fresh medium. Titanium
dioxide caused little or no loss of ATP in either olfactory epithelium (OE) or
respiratory epithelium (RE). Sodium carbonate decreased olfactory, but not
respiratory ATP, while acetic acid and 3-methylindole markedly decreased ATP in
both tissues. Intracellular potassium concentrations were generally affected to a
lesser degree. In vivo, no morphological changes were observed in the nasal
cavity following inhalation exposure to either titanium dioxide or sodium
carbonate. Inhalation of acetic acid resulted in a very focal lesion in the RE of
the dorsal meatus of level 1, while administration of 3-methylindole by
intraperitoneal injection caused severe degeneration of OE. In further
experiments olfactory turbinates were exposed to a range of concentrations (0-100
mM) of sodium carbonate, acetic acid and 3-methylindole for 4 h and ATP
concentrations determined. Concentration-dependent decreases in ATP were observed
for sodium carbonate and 3-methylindole, with EC(50) values estimated as 2.57 and
0.91 mM, respectively. Acetic acid only decreased ATP significantly at the 100-mM
concentration. In summary, this in vitro model has predicted the nasal toxicity
of several compounds, including both direct-acting agents (sodium carbonate,
acetic acid) and one requiring metabolic activation (3-methylindole). However,
the lack of airflow-dependent dosimetry, results in some lack of discrimination
between the different regions of the nasal cavity and may make this model overly
sensitive.
PMID- 10771131
TI - Astrocyte cultures from transgenic mice to study the role of metallothionein in
cytotoxicity of tert-butyl hydroperoxide.
AB - The cell viability, lipid peroxidation (LPO) and hydrogen peroxide (H(2)O(2))
generation were measured in cultured primary astrocytes, from metallothionein
(MT)-I isoform overexpressing transgenic (MT-I*), MT-I/MT-II null and control
mice after exposure to tert-butylhydroperoxide (tBH). Astrocytes from MT-I* mice
have high basal levels of both MT-I mRNA and MT protein, whereas there is only MT
III isoform in astrocytes from MT-I/MT-II null mice. The results showed that (1)
cultured astrocytes from MT-I* mice were most resistant to the cytotoxicity of
tBH and those from MT-I/MT-II null mice were most sensitive to the cytotoxicity
of tBH; (2) LPO after exposure to tBH were increased in all cells, but the levels
were the highest in astrocytes from MT-I/MT-II null mice, while those in MT-I*
mice were the lowest; (3) the levels of H(2)O(2) in cultured astrocytes from MT
I* mice were the lowest, while those in astrocytes from MT-I/MT-II null mice were
the highest. These results support the hypothesis that MT can scavenge free
radicals and protect astrocytes from oxidative stress.
PMID- 10771132
TI - Induction of apoptosis in caco-2 cells by wheat gliadin peptides.
AB - Recent experimental evidence suggests that enterocyte apoptosis is greater than
hitherto assumed and may be responsible for villous atrophy in coeliac disease.
We have previously demonstrated that a small peptide (M.W. 1157.5 Da), identified
as the sequence H(2)N-gln-gln-pro-gln-asp-ala-val-gln-pro-phe-COOH from durum
wheat gliadin, is able to prevent K 562 (S) cell agglutination induced by the
peptic-tryptic digests (PT) of prolamin fractions from the cereals which are not
tolerated in coeliac disease (i.e. bread wheat, rye, barley and possibly oats),
and toxic A-gliadin peptides in coeliac disease. In the present study we have
investigated the effects of the bread wheat gliadin digest (PT) on apoptosis of
Caco-2 cells and whether the '1157.5' Da peptide may in any way interfere with
them. We evaluated both earlier biochemical and later morphological nuclear
apoptotic events in the human colon adenocarcinoma cell line Caco-2. After 48 h
exposure to the PT gliadin digest and the '1157.5' Da peptide, apoptosis was
detected both for the early-stage apoptotic cells (adherent cells) and the late
stage apoptotic ones (detached cells which were floating in the culture medium).
Exposure to the PT gliadin digest resulted in a high percentage of adherent cells
that underwent cell death by apoptosis (about 30%), independent of the
concentration range used; while the presence in the culture medium of peptide
'1157.5' Da determined complete inhibition of cell death. On the other hand,
morphological nuclear modifications observed in the floating cells showed a
difference in the rate of the apoptosis dependent on the PT concentration, with
partial protection in the presence of the peptide. These findings show an action
of bread wheat gliadin peptides leading to cell death by apoptosis in the Caco-2
cell line and that the '1157.5' Da peptide is capable of preventing such an
effect.
PMID- 10771133
TI - In vitro evaluation of the sensitization potential of weak contact allergens
using langerhans-like dendritic cells and autologous T cells.
AB - Contact hypersensitivity is a major public health concern in most industrial
countries, which is why predictive tests which could identify potential allergens
are needed. We have established an in vitro approach for the detection of primary
immune response. This model uses Langerhans-like dendritic cells (LLDC) derived
from cord blood progenitors and autologous T lymphocytes, isolated from the same
blood sample. Treatment of day 12-14 LLDC, with strong haptens trinitrobenzene
sulfonic acid (TNP), fluorescein isothiocyanate (FITC) or Bandrowski's base (BB),
results in the proliferation of T lymphocytes, whereas weak allergens and
irritants, such as sodium dodecyl sulfate (SDS) are ineffective. The use of
immature (day 8) LLDC and the addition of a 48 h stage of incubation after hapten
contact, result in phenotypic maturation of LLDC in addition to lymphocyte
activation in all the cultures with strong haptens. The 48 h stage of incubation,
results in sensitization and in some cases the induction of T cell proliferation
to citronellal (1/8), coumarine (1/8) and to a prohapten p-phenylenediamine
(pPDA; 2/8). The phenotype of DC after 48 h of contact with a strong hapten,
becomes that of mature DC (CD83(+), CD86(+) and HLA-DR(++)). With fragrance
molecules, weak haptens and prohaptens, a comparable phenotype is observed only
when T lymphocytes are activated. These data suggest that the unresponsiveness
observed with weak haptens, may be the consequence on an incomplete maturation of
LLDC.
PMID- 10771134
TI - The probable involvement of soluble and deposited melanins, their intermediates
and the reactive oxygen side-products in human diseases and aging.
AB - The plasma soluble melanins (PSM) form spontaneously in vitro and in vivo and
their formation involves oxidative polymerization and copolymerization of dopa,
catecholamines, homogentisic acid, 3-hydroxyanthranilic acid, p-aminophenol, p
phenylenediamine, and other end(ex)ogenous ortho and para polyhydroxy-,
(poly)hydroxy(poly)amino- and polyamino-phenyl compounds. The build up of PSM is
visible within 2-3 h after the start of incubation at 37 degrees C with 1 mg/ml
of plasma. PSM also form similarly in blood and these processes cause hemolysis.
The mean quantity of PSM in normal human plasma is 1.61+/-0.1 (S.D.) mg/ml (n =
20) and in normal human urine is 1.1+/-1.2 g/24 h collection (n = 8). They
contribute to the yellow color of plasma and urine. Antioxidants delay the
formation of PSM. The deposited melanins also form from these precursors.
Reactive oxygen side products (ROSP) are generated during and after
melanogenesis. Melanins in vivo are generally associated with proteins or with
proteins and lipids. The PSM-protein-lipid complexes are called plasma soluble
lipofuscins (PSL), because they have histochemical and fluorescence properties
similar to those of solid lipofuscins. The soluble and deposited melanins (SDM)
and their intermediates have similar toxic chemical reactivities. The oxidizing
quinoid (they can produce partially and completely substituted conjugates) and
the semiquinoid free radical intermediates are also moieties in most human
melanin structures. Soluble melanins formed from dopa, or dopamine, or
norepinephrine in weak alkaline solution have been shown to be toxic to human
CD4+ lymphoblastic cells (MT-2) at higher than 10 microg/ml concentrations.
Alkaptonuria with high levels of homogentisic acid in the plasma is a potentially
fatal disease, exhibiting the toxic effects of the homogentisic acid melanin
(soluble and deposited), its intermediates and the ROSP. Patients with
alkaptonuria develop arthritis and often suffer from other diseases too,
including cardiovascular disease (frequent cause of death) and kidney disease.
Pheochromocytoma, with high levels of catecholamines in the plasma is another
potentially fatal disease. The catecholamine PSM of pheochromocytoma have very
light yellow or practically no colors, due to the concentrations and chemical
structures. Pheochromocytomas can cause hypertension, cardiovascular disease
(frequent cause of death), kidney disease, stroke, cancer, amyloid formation and
can mimic many other diseases, including acute pancreatitis, carcinoid,
neuroblastoma, psychiatric illness, hypercalcemia, retinal vascular lesions, and
diabetes mellitus. Pheochromocytoma is potentially fatal even in patients without
hypertension. Following trauma and surgery, heavily pigmented eyes are apt to
experience greater inflammation than lightly pigmented eyes. In Parkinson's
disease those neurons are lost first in the substantia nigra and locus ceruleus
which contain the greatest amounts of neuromelanins. The antihypertensive
alphamethyldopa causes Parkinson's syndrome. It forms PSM in a short time in
vitro. The side effects of L-dopa (immobility episodes alternate with normal or
involuntary movements; psychotic abnormalities) suggest that the SDM, their
intermediates and the ROSP present naturally in vivo are involved in the cause of
Parkinson's disease and Alzheimer's disease. There is a large overlap between
these two diseases. (ABSTRACT TRUNCATED)
PMID- 10771135
TI - The relative abilities of TCDD and its congeners to induce oxidative stress in
the hepatic and brain tissues of rats after subchronic exposure.
AB - The abilities of single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to
induce oxidative stress in hepatic and some extra-hepatic tissues of animals, are
well documented. In this study we have investigated the induction of oxidative
stress in hepatic and brain tissues of rats after subchronic (13 weeks) exposure
to TCDD and two of its congeners, namely 2,3,4,7,8-pentachlorodibenzofuran
(PeCDF) and 3,3',4,4',5-pentachlorobiphenyl (PCB126). TCDD, PeCDF and PCB126 were
administered daily to groups of rats at various doses, for 13 weeks, and
biomarkers of oxidative stress, including the production of superoxide anion,
lipid peroxidation and DNA-single strand breaks (SSBs), were determined in the
hepatic and brain tissues at the end of the exposure period. The three congeners
caused dose-dependent increases in the production of superoxide anion, lipid
proxidation and DNA-SSBs, with maximal effects achieved at doses ranging between
10-100, 20-92, and 300-550 ng/kg per day for TCDD, PeCDF and PCB126,
respectively. The doses that produce 50% of maximal responses by each of the
xenobiotics in the hepatic and brain tissues were found to be within the ranges
of 7-34, 13-32, and 137-400 ng/kg per day for TCDD, PeCDF and PCB126,
respectively. The results of the study suggest that subchronic exposures to TCDD,
PeCDF and PCB126 induce significant oxidative damage in the hepatic and brain
tissues of rats, with more damage observed in the brain as compared to the
hepatic tissues. Also, as inducers of oxidative stress in the hepatic and brain
tissues, TCDD is the most potent among the three congeners and PCB126 being the
least potent.
PMID- 10771136
TI - In vivo MRI measurements of tumor growth induced by dichloroacetate: implications
for mode of action.
AB - Dichloroacetate (DCA) is an important by-product of the chlorination of drinking
water that produces liver cancer in rodents. Assessment of the risk that results
from concentrations that occur in drinking water will be dependent upon the mode
of action held responsible for these tumors. A study by Stauber and Bull
[Stauber, A.J. and Bull, R. J (1997) Differences in phenotype and cell
replicative behavior of hepatic tumors inducted by dichloroacetate (DCA) and
trichloroacetate (TCA). Toxicol. Appl. Pharmacol. 144, 235-246] in mice treated
with DCA demonstrated a lesion distribution that was skewed towards many small,
altered foci of cells that are assumed to be precursor lesions [EPA, (1996). U.S.
Environmental Protection Agency: Proposed Guidelines for carcinogen risk
assessment; notice. Fed. Reg. 61, pp. 17960-10811]. The present study was
designed to determine the extent to which the tumorigenic effects of DCA could be
explained by its effect on tumor growth rates (i.e. tumor promoting activity). In
vivo magnetic resonance imaging (MRI) allowed accurate determination of growth
rates of individual lesions in mice that had been treated with DCA in drinking
water at 2 g/l. Out of thirty treated mice, ten were found to have hepatic tumors
detectable by MRI at 48 weeks of treatment. These tumor-bearing animals were
assigned to two groups matched on the size of lesions observed by in vivo MR1.
Treatment with DCA continued in one group of five mice and was stopped in the
other. For both groups, tumor growth rates were determined by measuring changes
in size of all lesions greater than 1 mm(3) in volume during a 14-day period.
Removal of DCA treatment resulted in growth rates that could not be distinguished
from zero across all lesion sizes represented in the sample. These data are in
agreement with previous observations of DCAs effects on replication rates within
tumors (Stauber and Bull, (1997)). Tumor growth rates observed in animals
maintained on treatment decreased with lesion volume in a manner that is
consistent with a stochastic Gompertz birth-death process proposed by Tan [Tan,
W.Y. (1986) A stochastic Gompertz birth-death process. Stat. Prob. Lett. 4, 25
28]. Parameters of this model obtained by fitting measured growth rates were used
to predict the lesion-size distribution expected after one year of DCA treatment.
The shape of the predicted lesion-size distribution was similar to that observed
by Stauber and Bull (Stauber and Bull, (1997)) in mice sacrificed after 40 weeks
of DCA treatment. We conclude that the effects of DCA on the division and/or
death rates of spontaneously initiated cells can account for the predominance of
small lesions in DCA-treated animals.
PMID- 10771137
TI - PCB 118 induces ultrastructural alterations in the rat liver.
AB - Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that
bioaccumulate in the food chain and thus pose a health risk to humans and other
animals. In this study, PCB 118 was added to the diets of Sprague Dawley rats for
13 weeks in concentrations of 2, 20, 200, 2000 p.p.b. to the females and 10, 100,
1000 and 10000 p.p.b. to the males. The chemical was dissolved in corn oil;
animals that served as the control received corn oil in the diets devoid of PCB.
Use of transmission electron microscopy and stereology revealed significant
(P<0.05) elevation in the mean volume fraction of smooth reticulum profiles (20
p.p.b.), peroxisomes (200, 2000 p.p.b.) and lipid droplets (2000 p.p.b.) in the
females. Hepatocytes from the males exhibited a significant increase in the mean
volume fraction of lipid droplets at 10000 p.p. b. (P<0.05). Interactions between
large quantity of estrogen and the PCB probably would account for more profound
alterations in the liver of female Sprague-Dawley rats than in the males.
PMID- 10771138
TI - The influence of cadmium and zinc ions on the interferon and tumor necrosis
factor production in bovine aorta endothelial cells.
AB - The influence of CdCl(2), used at 1, 10 and 100 microM concentration, and ZnCl(2)
at 1, 10 and 100 microM concentration on the production of interferon (IFN) and
tumor necrosis factor (TNF) in bovine aorta endothelial cells (BAECs) was
examined. BAECs were treated with cadmium ions or zinc ions alone or together
with cytokine inducers: Newcastle disease virus (NDV) and lipopolysaccharide
(LPS). Cadmium ions at 1 and 10 microM concentration, used alone induced a low,
but detectable TNF activity in BAECs, and zinc ions at 1, 10 and 100 microM
concentration induced both IFN and TNF activity. In contrast to that, cadmium
added to BAECs together with the virus or LPS as cytokine inducers significantly
inhibited the production of IFN and TNF. Cadmium effect depended on the
concentration used, and 1 and 10 microM CdCl(2) partially, but 100 microM cadmium
completely inhibited the production of both cytokines. Zinc ions at 1 and 10
microM concentration, which only slightly inhibited the production of both
cytokines, did not reconstitute cadmium-depressed IFN and TNF production. These
data indicate that cadmium-induced depression of cytokine production in bovine
endothelial cells, in response to viral and bacterial stimuli, cannot be reversed
by zinc supplementation.
PMID- 10771139
TI - Activation of the hsp70 promoter by environmental inorganic and organic
chemicals: relationships with cytotoxicity and lipophilicity.
AB - Stress proteins (heat shock proteins, HSPs) have been proposed as general markers
of cellular aggression and their use for environmental monitoring is often
suggested. The aim of this work was to study the potency of various
environmentally relevant organic and inorganic chemicals to induce the expression
of the HSP70 marker. For this purpose, we used an established HeLa cell line
containing the chloramphenicol acetyl transferase (CAT) gene under the control of
the hsp70 promoter. The screening of three metallic and 15 organic chemicals
revealed differences in their capacities to induce the hsp70 promoter. The three
metals tested (cadmium, zinc and mercury) were able to induce a stress response.
Some organochlorine compounds (chlorophenol derivatives, tetrachlorohydroquinone,
3, 4-dichloroaniline, ethyl parathion and 1-chloro-2,4-dinitrobenzene) induced a
response, whereas other common halogenated pesticides or aromatic hydrocarbons
(e.g. benzo(a)pyrene, 2, 4-dichlorophenoxyacetic acid, endosulfan, diuron, 4
nonylphenol) did not. The potency to induce hsp70 was significantly correlated to
the octanol-water partition coefficient (log K(ow)) of the inducing chemicals,
except for 1-chloro-2,4-dinitrobenzene and ethyl parathion. Cytotoxicity assays
run in parallel to the induction measurements revealed that the three metals were
effective at non cytotoxic doses whereas all organic compounds, except
tetrachlorohydroquinone and 1-chloro-2,4-dinitrobenzene, induced the promoter at
cytotoxic doses. These results suggest that hsp70 is induced by different
mechanisms of toxicity. We propose that this model can be used in mechanistic
studies for the detection of toxic effects of certain pollutants.
PMID- 10771140
TI - Environmental polycyclic aromatic hydrocarbons affect androgen receptor
activation in vitro.
AB - Nine structurally different polycyclic aromatic hydrocarbons (PAHs) were tested
for their ability to either agonize or antagonize the human androgen receptor
(hAR) in a sensitive reporter gene assay based on CHO cells transiently
cotransfected with a hAR vector and an MMTV-LUC vector. Benz[a]anthracene
(B[a]A), benzo[a]pyrene (B[a]P), fluoranthene, chrysene and 7,12
dimethylbenz[a]anthracene (DMBA) were acting as antiandrogens in vitro, resulting
in IC(50) values of 3.2, 3.9, 4.6, 10.3 and 10.4 microM, respectively. Only at
the highest concentration tested (10 microM), a slight inhibitory effect by
pyrene, phenanthrene, and anthracene was observed. In contrast,
dibenzo[a,h]anthracene (DB[a,h]A) gave rise to an agonistic effect, which was
added upon the effect of the androgen receptor agonist R1881 (0.1 nM). The
antiandrogenic responses by PAHs (10 microM) were found to be fully reversible,
determined in the presence of increasing concentrations of R1881. No cytotoxic
effects of the tested compounds were observed as determined either by metabolic
reduction using AlamarBlue (up to 20 microM) or determined in cells transfected
with a constitutively active hAR (up to 10 microM). The well-known ability of
certain PAHs to activate the Ah receptor was assessed in H4IIE liver cancer
cells, stably transfected with a luciferase reporter gene system. The positive
control 2,3,7,8-tetrachlorodibenzodioxin (TCDD) caused a 13-14-fold induction of
luciferase activity reaching maximum activity at 0.1 nM. DB[a,h]A, B[a]P,
Chrysene, B[a]A and DMBA gave rise to a 4.5-fold induction of luciferase activity
at 0.03, 0.4, 0.89, 3.06, and 9.27 microM, respectively, whereas fluoranthene,
pyrene, phenanthrene and anthracene were without effect. In conclusion, no clear
correlation between the antiandrogenic effects and the Ah receptor activation in
vitro was seen. However, the Ah receptor agonists containing four or five
aromatic rings (i.e. B [a] A, B [a] P, chrysene, DMBA) appeared to be the most
potent antiandrogens (with the exception of DB [a, h] A), whereas those not able
to activate the Ah receptor containing three or four aromatic rings (i.e. pyrene,
phenanthrene, anthracene) displayed either very weak or no antiandrogenic effect
at concentrations up to 10 microM (with the exception of fluoranthene which
blocked the hAR at lower concentrations, but did not activate the Ah receptor).
PMID- 10771141
TI - The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive
oxygen species (ROS) production in cell cultures.
AB - The prevention of apoptosis by Zn(2+) is a well-known phenomenon. Both in in
vitro and in vivo Zn(2+) supplementation prevents apoptosis induced by a variety
of agents, among them by cadmium ions. The target for protective action of Zn
ions on cell apoptosis is still unknown. In this paper we have evaluated the
effect of in vitro ZnCl(2) supplementation at a concentration corresponding to
the physiological level (10 microM) and higher (50 microM), on apoptosis induced
with different Cd concentrations in two cell types: HeLa human tumor cell line
and bovine aorta endothelial cells (BAECs). We demonstrated that Zn
supplementation, especially at 10 microM concentration, significantly inhibited
apoptosis in both types of cells. To assess the mechanism involved in the Zn
effect we examined the influence of Zn supplementation on Cd accumulation in
cells, Cd-induced superoxide anion (O(2)(-)) and hydrogen peroxide (H(2)O(2))
production. Zn caused 1.2-2.0-fold inhibition of Cd accumulation, 1.2-2.0-fold
inhibition of Cd-induced apoptotic cell death, 1.1-2.0-fold decrease in reactive
oxygen species (ROS) production in HeLa cells and in BAECs. These results
indicate that inhibition of Cd-induced apoptosis in cells by Zn might be due, not
only by inhibition of Cd accumulation in cells but, at least in part, to
inhibition of Cd-induced production of ROS, which in turn are known as strong
inducers of apoptosis.
PMID- 10771142
TI - Theophylline-induced changes in the activity of carnitine palmitoyltransferase in
rat cardiac tissues.
AB - This study is conducted to investigate the influence of oral theophylline
administration (100 mg/kg bw per day) on the activity of carnitine
palmitoyltransferase (CPT) in cardiac tissues of rats for 5-week interval
treatments. Results showed significant increase in the activity of CPT was
observed in cardiac tissues of theophylline-treated groups as compared to either
control or placebo groups. Moreover, the results showed positive correlations
between the cardiac concentrations of long-chain acylcarnitine (LC) and the
activity of CPT and between plasma concentrations of LC and the cardiac
concentrations of LC (P<0.01), respectively. The observed changes in activity of
cardiac CPT might be due to the result from theophylline- enhanced decrease the
sensitivity of CPT to inhibition by malonyl-CoA and/or from theophylline-enhanced
mobilization of lipid from adipose tissues which consequently stimulated an
increased carnitine transport into the tissues to form palmitoylcarnitine groups
for subsequent beta-oxidation inside the mitochondria. Thus, these accumulations
of acylcarnitine groups in mitochondria may increase the catalytic action of CPT.
PMID- 10771143
TI - Genotoxic effect of lead nitrate on mice using SCGE (comet assay).
AB - Single stranded DNA breakage induced by lead nitrate in mice has been studied in
vivo using alkaline single cell gel electrophoresis (comet assay). Mice were
administered orally 0.7, 1.4, 2.8, 5.6, 11. 2, 22.4, 44.8 and 89.6 mg/kg body
weight of lead nitrate and the assay was performed on whole blood at 24, 48, 72
h, 1st and 2nd week. Significant increase in mean tail-length of DNA was observed
at all time intervals after treatment with lead nitrate when compared to
controls. The mean tail-length did not show a dose-related increase and the
elevation in the mean tail-length was of a fluctuating type. Increase in mean
tail-lengths clearly gives evidence that lead nitrate causes DNA damage
effectively. The study indicates that the alkaline comet assay is a sensitive and
rapid method to detect DNA damage caused by heavy metals.
PMID- 10771144
TI - Lindane differently modulates intracellular calcium levels in two populations of
rainbow trout (Oncorhynchus mykiss) immune cells: head kidney phagocytes and
peripheral blood leucocytes.
AB - We studied the in vitro effects of high concentrations of the insecticide lindane
(from 2.5 to 100 microM) on intracellular calcium levels ([Ca(2+)](i)) in rainbow
trout head kidney phagocytes and peripheral blood leucocytes (PBLs). [Ca(2+)](i)
was measured during 6 min by spectrofluorimetry using Indo-1/AM as fluorescent
probe. Lindane, from 5 to 100 microM, increased [Ca(2+)](i) in PBLs and from 25
microM in phagocytes. In Ca(2+)-free medium, only 50 and 100 microM lindane
increased significantly [Ca(2+)](i) in PBLs and only 100 microM lindane in
phagocytes. However, lindane at 5 and 10 microM, induced a decrease in
[Ca(2+)](i) in phagocytes suspended in Ca(2+)-free medium. Lindane needed
extracellular calcium to rise [Ca(2+)](i) in phagocytes but not in PBLs. Lindane
effects on endoplasmic reticulum (ER) calcium store was examined. In spite of
mobilisation by lindane of ER calcium store in phagocytes, it had an opposite
effect in PBLs. The composition of the two cell population can explain the
differences in calcium modulation observed. [Ca(2+)](i) is an extremely important
signal transduction element in physiology and modulation of [Ca(2+)](i) by
lindane can be responsible for modulations of immune cell functions. Moreover,
sustained rises in [Ca(2+)](i) as observed in our study may be associated with
cell death and explained partially the cytotoxicity of this organochlorine
insecticide on fish immune cells.
PMID- 10771145
TI - Immunotoxicity of ethyl-4-isothiocyanatobutanoate in male Wistar rats.
AB - The immunotoxicity of ethyl-4-isothiocyanatobutanoate (E-4IB) using different
immuno-pathological parameters and immune function assays in male Wistar rats was
evaluated. The rats were administered intraperitoneally 12 times with E-4IB in
three varying doses of 21, 28 and 35 mg/kg of body weight, over a period of 36
days. The doses of E-4IB were set according to the results of previous
experiments by its anti-proliferative activity in vivo. High and medium doses of
E-4IB exceeded the maximum tolerated dose after the 36-day treatment period.
Symptoms of toxicity were displayed by a drop in body weight, spleen and thymus
weight and in organ and bone marrow cellularity. Haematological changes displayed
a dose-dependent decrease in the percentage of lymphocytes and dose-dependent
increase in the percentage of polymorphonuclear leukocytes in peripheral blood.
The white blood cell count in rats exposed to a high dose of E-4IB was
suppressed. The immune system of rats administered 21 mg/kg of E-4IB (low dose)
was unaffected. No changes in primary antibody response to sheep erythrocytes, in
vitro proliferative response of spleen lymphocytes to mitogens and phagocytic
activity of leukocytes were found in those rats. Our findings indicate that this
newly developed anti-cancer drug is not immunotoxic.
PMID- 10771146
TI - Alterations of thymocyte development, thymic emigrants and peripheral T cell
population in rats exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts diverse biological effects by
activating the cytosolic transcription factor, arylhydrocarbon receptor (AhR),
which translocates to nuclei by TCDD binding and induces gene expressions. Among
the well known-adverse effects of TCDD is thymus atrophy. In thymus atrophy, TCDD
alters the proliferation as well as the differentiation of immature thymocytes.
Previous studies on the effects of TCDD on thymocyte development were primarily
carried out with high doses of TCDD. The present study investigates the effects
of lower doses of TCDD (1 or 2 microg TCDD/kg by gavage) on thymocyte
development, and furthermore, their sequential consequences on the peripheral T
cell repertoire. Seven days after treatment with 1 or 2 microg TCDD/kg, the
expression of CYP1A1 mRNA, one of the sensitive responses caused by the binding
of TCDD to AhR, was detected in the thymus of rats. Thymus weights and thymus
cell numbers decreased in TCDD-treated rats in a dose-dependent manner. The
ratios of CD4 single-positive (SP) cells/CD8 SP cells were significantly reduced
by TCDD exposure, indicating that the maturation of CD4(+)CD8(+) double-positive
(DP) cells was skewed toward CD8 SP cells. These changes in the thymus were
parallel to those previously observed with high doses of TCDD exposure. However,
the specific reduction of DP cells reported in previous studies with high doses
of TCDD was not detected in the present study. On the other hand, the skewing of
mature CD4/CD8 T cell ratio in thymocytes by TCDD was not reflected in mesenteric
lymph node (LN) lymphocytes, where the proportion of CD8 T cells was rather
lowered by TCDD with a significant difference at 1 microg TCDD/kg. In LN
lymphocytes, the percentage of recent thymic emigrants (RTEs), defined by the
surface markers of Thy1(+)CD45RC(-), was shown to be significantly reduced by
exposure to 1 and 2 microg TCDD/kg. T cell supply from the thymus has a crucial
role in keeping the diversity of the T cell repertoire. The results of the
present study indicated that lower doses of TCDD affect thymocyte development,
especially differentiation, and reduce the proportion of RTE in LN, which may
cause immunosuppression by reducing the variety of the T cell receptor
repertoire.
PMID- 10771147
TI - Mating modifies c-fos expression in the brain of male and female rabbits.
AB - Copulation in rabbits provokes behavioral and neuroendocrine changes in both
sexes. To investigate if the activity of particular brain regions is modified
accordingly we quantified, by the reverse transcription-polymerase chain reaction
method, c-fos expression in the preoptic area, hypothalamus, hippocampus, and
frontal cortex of male and female rabbits before mating, immediately afterwards,
and 1 h later. Mating immediately increased c-fos expression in the hypothalamus
of both sexes, the frontal cortex of females, and the preoptic area of males. c
fos expression did not change in the hippocampus after mating in either sex but
decreased in the preoptic area of females following mating. Results show that
mating provokes changes in brain activity, in a gender- and region-specific
manner, which may underlie the behavioral and endocrine consequences of
copulation in rabbits.
PMID- 10771148
TI - High-pass filtering of carotid-vagal influences on expiration in rat: role of N
methyl-D-aspartate receptors.
AB - Repetitive electrical stimulation of the carotid sinus nerve or vagus nerve in
rats elicited abrupt reflex shortening or prolongation, respectively, of the
inter-burst interval of phrenic nerve activity followed by exponential decay from
the initial response. Removal of the stimuli resulted in transient post-stimulus
rebound excitation or inhibition that mirrored the corresponding stimulus-evoked
responses. The biphasic responses to these complementary inputs approximate the
on- and off-transients of full-wave differentiators or high-pass filters.
Blockade of N-methyl-D-aspartate (NMDA) receptors abolished the post-stimulus
rebounds and transformed both signal pathways into integrators or low-pass
filters, thus switching off part or all of the high-pass filters. We suggest that
such NMDA receptor-dependent high-pass filtering effects may serve to increase
the dynamic range and response speed of sensory neurotransmission to the brain,
thereby enhancing closed-loop stability of sensorimotor reflex.
PMID- 10771149
TI - Expression analysis of the 5'-upstream region of mouse P/Q-type Ca(2+) channel
alpha( lA) subunit gene fused to Escherichia coli lacZ reporter gene in the
spinal cord using transgenic mice.
AB - The P/Q-type Ca(2+) channel alpha(1A) subunit is expressed in spinal cord
including ventral motor neurons and interneurons and dorsal horn. To identify the
transcriptional mechanisms of the mouse alpha(IA) subunit gene in spinal cord,
transgenic mice carrying a 0.5, 1.5, 3.0 or 6.3-kb 5'-upstream region fused to
the Escherichia coli lacZ reporter gene were examined. Transgenic mice carrying
the 3.0-kb region expressed the reporter gene in dorsal horn and interneurons of
ventral horn, although those with the 0.5-kb, 1.5-kb or 6.3-kb region did not. No
transgenic mice expressed the reporter gene in motor neurons of ventral horn.
These results suggest that in spinal cord, the expression mechanisms of the
alpha(1A) subunit gene are complex, involving both positive and negative cis
regulatory elements, and the 6.3-kb 5'-upstream region alone is not sufficient
for the expression.
PMID- 10771150
TI - Time evolution of acoustic 'information' processing in the mesencephalon of
Wistar rats.
AB - A traditional analysis of intra-encephalic auditory evoked potentials does not
highlight the dynamical evolution of the auditory 'information' processing in
neither time nor space. This work presents a method for tracing such signal
evolution throughout the primary auditory pathway in the mesencephalon of adult
anesthetized Wistar rats, using a unilateral 3 kHz tone burst stimulus. The
results of the acoustic evoked potentials mapping are presented as conventional
20 ms recordings and re-analyzed in intervals of 1 ms-time windows. The parameter
used, as an 'activity' correlate, was the maximum/minimum voltage difference
obtained from each time window. The methodology used clearly indicates sequential
signal propagation from the dorsal and ventral nuclei of the lateral lemniscus up
to the inferior colliculus.
PMID- 10771151
TI - Inhibition of transmitter release and long-term depression in the avian
hippocampus.
AB - Long-term depression has recently been shown to occur at glutamatergic synapses
in the avian hippocampus and requires activation of calcium/calmodulin-dependent
protein kinase II in the nerve terminal. Here using whole cell and intracellular
recordings from brain slices, we show that the N-type calcium channel contributes
significantly to glutamate release in the avian hippocampus. Activation of the
metabotrobic gamma-aminobutyric acid (GABA)(B) receptor by the specific agonist
baclofen blocks synaptic transmission. The action of baclofen was associated with
a change in paired pulse facilitation indicating that it resulted from a
reduction in the probability of transmitter release. In contrast, no change in
paired pulse facilitation was observed following the induction of long-term
depression. These results show that activation of GABA(B) receptors and long-term
depression reduce transmitter release by distinct mechanisms.
PMID- 10771152
TI - Developing chicken oligodendrocytes express the type IV oligodendrocyte marker T4
O in situ, but not in vitro.
AB - Accumulating data suggest that the oligodendrocyte population includes
morphological and biochemical subtypes. We recently reported that a polyclonal
antiserum against an unknown antigen, the T4-O molecule, labels a subpopulation
of chicken oligodendrocytes, obviously representing the type IV variety of Del
Rio Hortega. The present study examines the developmental expression of the T4-O
molecule in situ and in vitro. The results show that T4-O immunoreactive cells
first appear at E15 in the ventral funiculus. But, oligodendrocytes cultured in
vitro with or without neurones do not develop a T4-O immunoreactivity. We
conclude that oligodendrocytes in the spinal cord of chicken embryos first
express the T4-O molecule some time after onset of myelination, and that the T4-O
immunoreactive phenotype does not develop in vitro.
PMID- 10771153
TI - Chronic n-3 polyunsaturated fatty acid deficiency alters dopamine vesicle density
in the rat frontal cortex.
AB - We studied the effects of a chronic deficiency in n-3 polyunsaturated fatty acids
(n-3 PUFA) on the vesicle dopaminergic compartment in the frontal cortex of rats.
Electronic micrographic analysis showed that the synaptic density and the clear
vesicle density were similar in deficient and control rats. However, dopaminergic
immunolabeling revealed a significantly decreased number of gold-labeled vesicles
in the dopaminergic presynaptic terminals of the deficient rats. These findings
demonstrate that dopamine cortical vesicles are specifically decreased in n-3
PUFA deficiency. The mechanism leading to this modification could involve several
abnormalities (vesicle turn-over, membrane fluidity, vesicular monoamine
transporter). This reduction in the dopaminergic vesicle pool constitutes the
first structural support for the previously described modifications of dopamine
metabolism in the frontal cortex. Such changes in dopamine neurotransmission
could be involved in behavioral abnormalities occurring in n-3 PUFA deficient
rats.
PMID- 10771154
TI - Deltamethrin induces altered expression of P53, Bax and Bcl-2 in rat brain.
AB - In this study we investigated the effects of deltamethrin on the expression of
P53, Bax and Bcl-2 in rat brain. Immunohistochemical analysis demonstrated that
the immunoreactivity for P53 was markedly increased in the cerebral cortex and
hippocampus at 5 h after deltamethrin treatment, and maintained at an increased
level at 24 and 48 h, whereas little immunoreactivity for P53 was seen in the
same brain regions of control rats. The immunostaining for Bax was also elevated
in the same brain regions, showing the same time course of P53 expression after
deltamethrin treatment. However, the immunolabeling for Bcl-2 was markedly
decreased at 24 h after a transient increase at 5 h following deltamethrin
treatment. These results indicate that deltamethrin leads to the persistent
increase of P53 and Bax expression and transient elevation of Bcl-2 expression,
resulting in an increased ratio of Bax to Bcl-2, which may contribute to
apoptotic cell death in rat brain following deltamethrin treatment.
PMID- 10771155
TI - Expression of frequenin at the frog (Rana) neuromuscular junction, muscle spindle
and nerve.
AB - Frequenin is a calcium binding protein previously implicated in the regulation of
neurotransmission in Drosophila and Xenopus. We have used the frog (Rana pipiens)
to study the localization and regulation of expression of frequenin-like
molecules in the vertebrate peripheral nervous system. Affinity purified
antibodies to frequenin recognize molecules in the neuromuscular junction, axons
in the peripheral nerve, and neuronal processes in muscle spindles. Western blots
of endplate regions, peripheral nerve, and brain, resulted in the labelling of a
single 24 kDa band, which is the expected size for frequenin. These results
suggest that frequenin expression is high in the frog peripheral nervous system,
and may reflect a function for frequenin in synaptic transmission in vertebrates.
PMID- 10771156
TI - The effects of acute nicotine on the body temperature and striatal dopamine
metabolism of mice during chronic nicotine infusion.
AB - The effects of acute nicotine administration on body temperature and striatal
dopamine metabolism of mice during chronic subcutaneous nicotine infusion were
investigated. On the 7th day of nicotine infusion the hypothermic effect of 1
mg/kg nicotine s.c. but not that of 2 mg/kg was weakened suggesting that
tolerance developing to nicotine's hypothermic effect during chronic nicotine can
be overcome by increasing the dose of nicotine. In saline-infused control mice 1
mg/kg nicotine increased striatal 3, 4-dihydroxyphenylacetic acid (DOPAC) but not
homovanillic acid (HVA) concentration whereas 2 mg/kg increased both DOPAC and
HVA. On the 7th day of nicotine infusion DOPAC and HVA concentrations were
similar to control; and acute nicotine did not increase them suggesting that
nicotinic acetylcholine receptors (nAChRs) regulating striatal dopamine
metabolism were desensitized. The results suggest that the nAChRs mediating
nicotine's effects on thermoregulation and brain dopamine metabolism differ.
PMID- 10771157
TI - The electroencephalographic beta synchronization following extension and flexion
finger movements in humans.
AB - The cortical post-movement beta synchronization (PMBS) following brisk extension
flexion and flexion-extension movements of the right index finger was analyzed in
twelve right-handed subjects using electroencephalographic recordings. The
amplitude of PMBS over the contralateral sensorimotor area was enhanced and the
focus of PMBS was widespread when finger flexion was the last movement. The
results suggest that finger extension and flexion movements induce unequal beta
synchronization over the contralateral M1 area possibly due to different
complexity of the neuronal networks controlling these movements.
PMID- 10771158
TI - Contralateral heat hyperalgesia induced by unilaterally intraplantar bee venom
injection is produced by central changes: a behavioral study in the conscious
rat.
AB - In a previous study, we found that subcutaneous (s.c.) intraplantar injection of
bee venom unilaterally could produce bilateral heat hyperalgesia. However, the
bee venom-induced heat hyperalgesia identified in the injection site was presumed
to be different from that identified in the contralateral hindpaw, since the
former co-existed with the mechanical hyperalgesia while the latter did not. The
aim of the present study was to testify whether the contralateral heat
hyperalgesia identified in the bee venom model was a consequence of central
changes. The radiant heat and von Frey-type filaments were applied to both the
injection site and the contralateral pawpad of conscious rats prior to and 4 h
after s.c. bee venom injection. After confirmation of the development of primary
heat and mechanical hyperalgesia and contralateral heat hyperalgesia following
s.c. bee venom, the sciatic nerve of the injection side was transected. After
axotomy, the bee venom-induced heat hyperalgesia in the non-injected hindpaw was
not altered at all compared with that prior to axotomy. Moreover, intrathecal pre
treatment with either N-methyl-D-aspartate (NMDA) or non-NMDA receptor antagonist
could prevent the development of the contralateral heat hyperalgesia. The present
results suggest that central sensitization contributes to development of the bee
venom-induced contralateral heat hyperalgesia and activation of both NMDA and non
NMDA receptors in the spinal cord is involved in the processing.
PMID- 10771159
TI - Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced
limbic seizures.
AB - In a temporal lobe epilepsy (TLE) model induced by kainic acid (KA), we examined
the effect of limbic seizures on A1 adenosine receptor distribution in
hippocampus and cortex. By using quantitative autoradiography, we determined a
progressive decrease in A1 receptor density in CA1 and CA3 regions of
hippocampus, which coincided in time with the degenerating process of hippocampal
pyramidal cells. This result indicates that a great amount of A1 receptors are
located postsynaptically on pyramidal cell dendrites. No difference in A1
receptor density was observed in the inner compared to the outer molecular layer
of dentate gyrus, or in the infrapyramidal band compared to the outer layer of
stratum oriens of CA3. This could indicate that the newly sprouted mossy fiber
glutamatergic terminals do not contain A1 receptors, thus lacking a restrain in
the release of glutamate.
PMID- 10771160
TI - The influence of semantic priming on event-related potentials to painful laser
heat stimuli in humans.
AB - In this study we investigated the effects of different semantic primes on the
processing of painful stimuli. For prime stimuli, descriptors of three categories
were used: somatosensory pain-related, affective pain-related, and neutral
adjectives. While subjects (n=10) processed these primes, a painful laser-heat
stimulus was applied. Laser-evoked potentials (LEPs) were recorded and pain
intensity ratings were obtained after each single laser stimulus. Painful stimuli
applied while subjects processed pain-related primes (affective and somatosensory
adjectives) resulted in larger LEP amplitudes at 370 ms post laser stimulus
compared to amplitudes of laser-evoked activities while subjects processed
neutral primes (F((2,18))=3.90, P=0.05). It is suggested that pain-related
semantic primes might preactivate neural networks subserving pain memory and pain
processing. The processing of pain-related primes seems to preactivate cortical
cell-assemblies involved in the processing of the succeeding painful laser
stimuli.
PMID- 10771161
TI - Locomotor and learning deficits in adult rats exposed to monosodium-L-glutamate
during early life.
AB - Neonatal administration of neurotoxic doses of monosodium-L-glutamate (MSG) to
rats causes neuronal necrosis of the hypothalamus along with behavioral
abnormalities. In the present study the behavioral effects in rats treated with
subneurotoxic doses of MSG (2 mg/g, p.o., for 10 days) at the weaned stage were
investigated at day 90 post-dosing. The MSG-treated rats did not show significant
changes in any of the components of spontaneous locomotor activity but, after
apomorphine challenge, marked decreases in the distance travelled, ambulatory and
stereotypic times, and the number of stereotypic movements with an increase in
the resting time were observed. Significant decrease in the active avoidance
learning performance was observed in the MSG-treated rats in the learning
(acquisition) phase without any changes in the extinction and relearning phases.
The results indicate that exposure to MSG in early life in rats could lead to
subtle behavioral aberrations in late adulthood.
PMID- 10771162
TI - Chick muscle-derived protein 62: a novel neurite outgrowth promoting protein.
AB - A 3.2 kb chick cDNA clone that coded for a novel muscle-derived protein, MDP62,
was isolated from a cDNA library of the denervated crus muscles using an antibody
which inhibited the neurite (dendritic and axonal processes) outgrowth activity.
MDP62 consisted of 539 aa with a calculated molecular mass of 62 k. The predicted
protein sequence was hydrophilic and exhibited an extended coiled-coil domain and
a leucine zipper motif. A recombinant protein promoted the neurite outgrowth from
the cultured chick neurons of the telencephalon in a dose dependent manner.
Northern blotting revealed that MDP77 was ubiquitously expressed. In the
transfected COS-7 cells with the cDNA of the epitope-tagged MDP62, the expressed
protein was detected in the culture medium, suggesting that the MDP62 might be
secreted.
PMID- 10771163
TI - Increased neurosteroids synthesis after brain and spinal cord injury in rats.
AB - We studied the effect of brain and spinal cord injury induced by fluid-percussion
on the local synthesis of neurosteroids as measured by a gas-chromatographic/mass
spectrometric method. In the nervous system of sham operated rats i.v. infusion
of pregnenolone (PREGN)-sulfate results in a 2-4 fold increase in PREGN,
progesterone (PROG), 5alpha-dehydroprogesterone (5alpha-DHP) and 3alpha-hydroxy
5alpha-pregnan-20-one (3alpha5alpha-THP, allopregnanolone) concentrations, as
compared to vehicle treated rats. When PREGN-sulfate was infused 1, 3 or 7 days
after brain or spinal cord injury it was observed a large time-dependent increase
of PROG, 5alpha-DHP and 3alpha5alpha-THP levels in the peri-focal but not in the
focal site. This increase in neurosteroids content may be due essentially to the
glial cells hyperplasia in the peri-focal area and to an activation of the
pathways involved in the metabolism of PREGN-sulfate to PROG, 5alpha-DHP and
3alpha5alpha-THP.
PMID- 10771164
TI - An examination of glutamate decarboxylase(65) immunoreactive puncta with respect
to rat ventral pallidum neurons after repeated cocaine administration.
AB - The ventral pallidum is known to have topographically organized reciprocal gamma
aminobutyric acid-ergic projections with the nucleus accumbens, and changes in
these connections may play a role in mediating the behavioral sensitizing effect
of repeated exposure to cocaine. The present study investigated glutamate
decarboxylase-65 (GAD(65)) immunoreactivity in the rat ventral pallidum after
repeated cocaine administration. Male Sprague-Dawley rats were administered bi
daily injections of 15 mg/kg cocaine or saline vehicle for 5 consecutive days.
After 2 or 14 days of withdrawal, ventral pallidal sections were
immunocytochemically processed for GAD(65) immunoreactive puncta and counts were
made. In both groups, there were no statistically significant differences in the
number or density of GAD(65) puncta in medial or lateral portions either in
contact with neuronal cell bodies or in the neuropil after 2 or 14 days of
withdrawal. The results suggest that there is no alteration in the number of
GABAergic boutons expressing GAD(65) immunoreactivity in the ventral pallidum
after repeated exposure to cocaine.
PMID- 10771165
TI - Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic
Parkinson's disease.
AB - We studied genetic polymorphisms in the promoter region (position -511) and exon
5 (position +3953) of the interleukin (IL)-1beta gene in 122 Japanese patients
with Parkinson's disease (PD) and 112 controls. We also examined polymorphisms in
the IL-1alpha and the IL-1 receptor antagonist genes. No significant difference
was found in these genetic markers between PD patients and controls. However, PD
patients with homozygotes for allele 1 at position -511 of the IL-1beta gene (IL
1B-511*1), a low producer of IL-1beta, were significantly earlier in the disease
onset than those with the IL-1B-511*2 homozygotes, a high producer of IL-1beta.
This suggests that IL-1beta might play a role, possibly a protective effect for
dopaminergic neurons, in PD. Further population and functional studies are
necessary to clarify the role of IL-1beta in PD patients.
PMID- 10771167
TI - Immunohistochemical distribution of the endothelin-converting enzyme-1 in the rat
hypothalamo-pituitary axis.
AB - We prepared a rabbit polyclonal antibody against an endothelin converting enzyme
1 (ECE-1) to examine the distribution of ECE-1 in the hypothalamus and the
pituitary of the rat. By the Western blot analysis, the antibody specifically
recognized ECE-1 proteins in membrane fractions of the rat hypothalamus.
Immunohistochemical staining revealed ECE-1 immunoreactivity in both cell bodies
and axons in some hypothalamic neurons. The immunopositive cell bodies were
located in the paraventricullar and supraoptic nuclei; immunopositive axons were
distributed in the suprachiasmatic, paraventricullar (PVN), and supraoptic (SON)
nuclei. However no immunoreactivity was detected in the posterior pituitary
gland. The present results indicate that ECE-1 converts the endothelin-1 (ET-1)
from precursor big ET-1 to mature ET-1 in the PVN/SON. The big ET-1 existing in
the posterior pituitary gland is thought to be escaped from the converting by ECE
1 in the hypothalamus.
PMID- 10771166
TI - Tau polymorphisms are not associated with Alzheimer's disease.
AB - Alzheimer's disease (AD) is one of a number of neurodegenerative conditions
including frontotemporal dementia and progressive supranuclear palsy that are
associated with abnormal tau protein aggregates in neurons. Mutations in the tau
gene cause familial forms of frontotemporal dementia and alleles of the tau gene
have been associated with risk for progressive supranuclear palsy. However,
studies evaluating whether polymorphic variation in tau is associated with AD
have produced conflicting results. We investigated the role of the tau exon 2
polymorphism in a large sample of AD cases and controls and found no evidence
that polymorphic variation in tau is associated AD.
PMID- 10771168
TI - Cerebrospinal beta-amyloid ((1-42)) in early Alzheimer's disease: association
with apolipoprotein E genotype and cognitive decline.
AB - The concentration of beta-Amyloid ((1-42)) protein (Abeta42) in cerebrospinal
fluid (CSF) was determined in 75 Alzheimer's disease (AD) patients, 35 patients
with other causes of dementia and 30 cognitively healthy age-matched controls. A
significant decrease of Abeta42 concentration was found in AD patients, even in
25 subjects with very mild dementia as compared to patients with other causes of
dementia and controls. Within AD patients we observed a significant decline of
Abeta42 from very mild to mild and moderate dementia. In addition, Abeta42 levels
were negatively correlated with the severity of cognitive impairment and with the
number of varepsilon4 alleles inherited. We conclude that measurement of Abeta42
in CSF might be helpful for identifying AD at an early stage and also for
tracking the clinical course.
PMID- 10771169
TI - NK-3 receptors are expressed on mouse striatal gamma-aminobutyric acid-ergic
interneurones and evoke [(3)H] gamma-aminobutyric acid release.
AB - In the present study the ability of tachykinin agonists and antagonists to
modulate gamma-aminobutyric acid (GABA) release has been correlated with
tachykinin receptor expression in the mouse striatum. Significant GABA release
was observed when striatal slices were challenged with the NK-3 receptor agonist
senktide, the selectivity of which was confirmed using the NK-3 receptor
antagonist SR142801. In situ hybridisation revealed co-expression of NK-3
receptors with nitric oxide synthase (NOS)/preprosomatostatin containing
GABAergic interneurones. These findings suggest that tachykinins modulate GABA
release within the striatum via interaction with NK-3 receptors on
somatostatin/NOS interneurones.
PMID- 10771170
TI - Effects of irradiation on the sensitivity of melatonin release to norepinephrine
in cultured pineal bodies of rats.
AB - We measured levels of basal and norepinephrine (NE) -induced melatonin release in
cultured pineal bodies of rats just after and 2 days after irradiation (20 or 200
Gy) or sham-irradiation. On the day of irradiation, basal and NE-induced
melatonin release were not affected by irradiation. Two days after irradiation,
basal melatonin levels in both irradiated groups were significantly lower than
those in control group, whereas NE-induced melatonin levels in the irradiated
groups were higher than those in the control group. These results suggested that
irradiation decreases basal melatonin synthesis in pineal glands but that
melatonin response to NE is increased after irradiation.
PMID- 10771171
TI - Simultaneous desynchronization and synchronization of different alpha responses
in the human electroencephalograph: a neglected paradox?
AB - This study aims to resolve a paradox. Experiments measuring alpha band power
report an event related decrease (desynchronization) in alpha activity, whereas
those measuring evoked alpha report synchronization. During a recognition memory
task with human subjects, we measured the evoked (phase locked) and induced (not
phase locked) alpha response. The findings reveal that evoked alpha is due to a
transient phase locking (at about 100-200 ms poststimulus) of three alpha sub
bands which can be observed only at parieto-occipital sites. In contrast, induced
alpha shows a widespread pattern of desynchronization at most recording sites.
Thus, opposite alpha responses occur within similar time windows. Evoked alpha
synchronization may reflect cortical inhibition which serves to increase the
signal to noise ratio for activation processes following immediately later.
PMID- 10771172
TI - Effect of halothane administration on acetylcholinesterase activity in guinea-pig
muscle and brain.
AB - The effect of halothane administration on the activity of acetylcholinesterase
molecular forms was studied in diaphragm, extensor digitorum longus (EDL), and
soleus muscles, and six regions of the brain (striatum, cerebellum, cortex,
hippocampus, medulla-pons, midbrain) of guinea-pigs. Six days after the
anaesthetic, the activity of the G4 form was significantly increased in all three
muscles and the A12 form was significantly increased in EDL. The G1 precursor
form was significantly decreased in soleus. The G4 form was significantly
increased in medulla-pons, and the G1 form was significantly decreased in
hippocampus and midbrain. These findings show that halothane can have prolonged
effects on acetylcholinesterase activity in both muscle and brain, and may have
important implications for the use of halothane and other volatile anaesthetics
in studies of the cholinergic system.
PMID- 10771173
TI - Modes of regulation of laminin-5 production by rat astrocytes.
AB - Astrocytes have a prominent role in central nervous system-specific microvascular
growth and function. Extracellular matrix molecules (ECMs) bind to specific
adhesion molecules - integrins. These adhesion complexes are responsible for
tissue integrity and cellular signalling. We have examined astrocyte-endothelial
cell interactions in relation to expression of the ECM laminin-5. Astrocytes
produce laminin-5 in cell culture. The production is enhanced by endothelial
cells. Direct cellular contact possibly involving a beta1 integrin or an
insoluble matrix compound detected by the astrocytes is responsible for the
induction of astrocytic laminin production by endothelial cells. Hypoxia also
influences ECM production. The described regulation goes in concert with the
known effects of astrocyte-endothelial cell interaction and stresses its
importance for microvascular integrity.
PMID- 10771174
TI - The neuroprotective effect of cerebral poly(ADP-ribose)polymerase inhibition in a
rat model of global ischemia.
AB - In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition
on rat cortical energy state was investigated at 24 h after global cerebral
ischemia induced by permanent bilateral common carotid artery ligation plus
transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected
10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg
intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme
activity increased from 0.425+/-0.144 to 0.794+/-0.193 units/mg protein. Cerebral
ischemia was associated by a decrease in adenosine triphosphate (ATP) and
phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In
addition, an 1.9- and 2. 2-fold increase in adenosine monophosphate and adenosine
was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected
the rat energy state by preserving cortical phosphocreatine and NAD(+). Cortical
ATP was not changed significantly after PARP inhibition. In conclusion,
activation of the nuclear enzyme PARP plays an important role in cerebral energy
metabolism during rat global ischemia. Therefore, specific PARP inhibition may
offer new strategies in the therapy of vascular diseases such as stroke.
PMID- 10771175
TI - Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients.
AB - Several studies have attempted to confirm an association between a
deletion/insertion polymorphism within the promoter region of the serotonin
transporter gene (5-HTT) and Alzheimer's disease independent from the
apolipoprotein E (APOE) varepsilon4 status. We examined this deletion/insertion
polymorphism of the serotonin transporter gene in a sample of 222 consecutively
recruited gerontopsychiatric patients which was divided into four different
diagnostic groups: Alzheimer's disease (N=84), mild cognitive impairment (N=29),
subjective cognitive complaints (N=49), depression/other psychiatric disorders
(N=56) and 118 healthy, non-demented controls. The aim of this approach was to
test whether the investigated polymorphism has a high enough selectivity and
specificity to distinguish between the different gerontopsychiatric disorders or
to differentiate genetically AD from other forms of dementia, respectively. We
could not detect any significant differences in the allelic distribution of the
deletion/insertion polymorphism of the 5-HTT gene between the four patient
subgroups and the control group. This finding indicates that the serotonin
transporter does not appear to be a major susceptibility factor in the
pathophysiology of Alzheimer's disease and other psychogeriatric disorders.
PMID- 10771176
TI - Cloning, heterologous expression and co-assembly of Mpbeta1, a nicotinic
acetylcholine receptor subunit from the aphid Myzus persicae.
AB - Nicotinic acetylcholine receptors (nAChRs) play a major role in excitatory
synaptic transmission in insects and are also the target site for chloronicotinyl
insecticides such as imidacloprid. Here we report the cloning and
characterization of a novel nAChR beta subunit, Mpbeta1, from the aphid Myzus
persicae, an economically important pest species. Sequence analysis has
identified an open reading frame of 509 amino acids with features typical of
nAChR subunits. The Mpbeta1 gene is expressed as a single major transcript of 4.6
kb, considerably larger than the predicted length of the Mpbeta1 open reading
frame (1527 bp). By heterologous expression in Drosophila S2 cells, the Mpbeta1
subunit has been shown to co-assemble with the previously cloned nAChR subunits
Mpalpha1 and Mpalpha2. In contrast, no co-assembly of Mpbeta1 could be detected
with either Mpalpha3 or Mpalpha4. With the aim of gaining a clearer insight into
the influence of subunit composition upon assembly, the ability of M. persicae
nAChR subunits to co-assemble with vertebrate nAChR subunits has also been
examined.
PMID- 10771177
TI - Deficient intracortical inhibition in drug-naive children with attention-deficit
hyperactivity disorder is enhanced by methylphenidate.
AB - In children with attention-deficit hyperactivity disorder (ADHD), motoric
hyperactivity is one of the striking abnormalities. Because this symptom might be
due to an insufficient motor control, motor system excitability in 18 drug-naive
ADHD-children aged 8-12 years was compared to 18 age-matched healthy children
using the technique of transcranial magnetic stimulation (TMS). Whereas motor
thresholds, cortical silent period, and intracortical facilitation did not differ
between the two groups, ADHD-children had significantly reduced intracortical
inhibition compared to healthy controls. In all ADHD-children, a second TMS could
be started after their first intake of 10 mg methylphenidate. Under this
medication, a significant enhancement in intracortical inhibition could be
stated. This study provides the first evidence for inhibitory deficits within the
motor cortex in ADHD-children and for an enhancement of inhibitory mechanisms in
this brain region by methylphenidate.
PMID- 10771178
TI - The scintillating grid illusion during smooth pursuit, stimulus motion, and brief
exposure in humans.
AB - The Scintillating Grid Illusion occurs when small white disks are superimposed
onto the intersections of a grey-on-black Hermann grid. As a result illusory dark
spots are seen at numerous crossings, flashing with each flick of the eye and
changing their location and distribution with each saccade. The illusion is
absent with steady fixation. The present study shows that saccadic eye movements
are not necessary to produce the illusion. Rather, the illusion was also found to
occur (i) during smooth pursuit movements when the grid was stationary, (ii)
during smooth displacement of the grid with the gaze kept steady, and (iii)
during brief exposures of the stationary grid. It is concluded that, while
transient stimulation is essential for generating the illusion, reduction in
effective luminance contrast resulting from brief exposure and high stimulus
speed are responsible for reductions in its strength.
PMID- 10771179
TI - Structure and function in the saccule of the goldfish (Carassius auratus): a
model of diversity in the non-amniote ear.
AB - The vertebrate inner ear is comprised of a remarkable diversity of cell types,
including several types of sensory hair cells. In amniotes (reptiles, birds, and
mammals), the morphological and physiological characteristics that distinguish
these cell types have been well documented, while cellular variation in the ears
of non-amniotes (all other vertebrate groups) has remained underrecognized. Since
non-amniotes have become increasingly popular models for developmental and
genetic research, a more comprehensive understanding of structure and function in
the inner ears of these species is warranted. This paper first reviews the large
body of data describing the morphology and physiology of hair cells and afferent
neurons in the inner ear of the goldfish (Carassius auratus). In particular, we
examine the structure of the goldfish saccule, an endorgan that has been the
subject of numerous investigations on audition. New data on the structural
variation of synaptic bodies in saccular hair cells are also presented, and the
functional implications of these data are discussed. Finally, we conclude that
hair cell structure varies along the length of the goldfish saccule in a manner
consistent with known physiological characteristics of the endorgan. The saccule
provides an excellent model for investigating structure-function relationships in
the vertebrate inner ear, as well as the development of auditory and vestibular
sensory epithelia.
PMID- 10771180
TI - Cochlear microphonics and otoacoustic emissions in chronically de-efferented
chinchilla.
AB - The effects of eliminating the olivocochlear bundle (OCB) on cochlear
electromechanical properties were examined by measuring cochlear microphonics
(CM) and distortion product otoacoustic emissions (DPOAEs) in chronically de
efferented chinchillas. The OCB fibers to the right ears were successfully
sectioned in six out of 15 adult chinchillas via a posterior paraflocular fossa
approach. At the end of the experiment, these ears were histologically verified
as being deprived of both lateral and medial OCB fibers. The opposite (left) ears
from the animals served as controls. Following de-efferentation, changes of the
inter-modulation distortion components (2f(1)-f(2), f(2)-f(1), 3f(1)-2f(2), 3f(2)
2f(1)) varied, depending on the frequencies and levels of the stimuli. DPOAE
amplitudes to low-level stimuli were within the 95% confidence intervals around
mean DPOAE amplitudes of the control ears at all the frequencies (1-8 kHz). At
high stimulus levels, DPOAE amplitudes increased by 5-20 dB at 1 and 2 kHz while
remaining in the normal range at 4 and 8 kHz. In contrast, the CM input/output
functions to stimuli from 1 to 8 kHz were significantly reduced by approximately
40-50% at all input levels. The results suggest that the OCB may play a role in
modulating electrical properties of the outer hair cells and in reducing the
magnitude of cochlear distortion to high-level stimuli.
PMID- 10771181
TI - Expression of inducible nitric oxide synthase (iNOS/NOS II) in the hydropic
cochlea of guinea pigs.
AB - Immunohistochemical investigations of the guinea pig cochlea, using a specific
antibody to the inducible isoform of NO synthase (iNOS/NOS II), have been
performed 3 weeks after closure of the right endolymphatic duct (n=7).
Endolymphatic hydrops, the morphological substrate of Meniere's disease, became
evident by distension of the Reissner's membrane. iNOS expression could be noted
in endothelium, spiral ganglion cells, in nerve fibers, in supporting cells of
the organ of Corti and cells of the spiral ligament. Temporal bones of non
operated controls (n=6) as well as of sham-operated animals (n=3) did not show
structures positive to iNOS. These findings imply that iNOS-generated NO could be
involved in the pathophysiology of cochlear dysfunction in Meniere's disease.
PMID- 10771183
TI - Neuronal sensitivity to interaural time differences in the sound envelope in the
auditory cortex of the pallid bat.
AB - Interaural time differences in the envelope of a sound (envelope ITDs) can
potentially provide spatial information at high frequencies where interaural
phase differences (IPDs) are not available. Interaural intensity differences
(IIDs) also provide important spatial information at high frequencies. Both IIDs
and envelope ITDs can influence spatial perception at high frequencies, but
behavioral and physiological studies suggest that IIDs dominate perception. This
study examines envelope ITD sensitivity in the auditory cortex of the pallid bat,
a species that uses passive sound localization at the low end of its audible
range to find prey. Its auditory system is entirely 'high-frequency' in that
phase-locking does not occur at the low end of its audible range. If the bat uses
ITDs, they must be derived from the envelope of the signal. A previous study of
envelope ITD sensitivity in its inferior colliculus (IC) reported that neurons
are sensitive to the small +/-70 micros range of available ITDs. This study
extends these findings to the cortical level to assess the transformation of ITD
sensitivity and the binaural response properties that underlie this sensitivity.
Two measures of sensitivity were used. The dynamic ITD range measures the range
of ITDs over which the maximum response of a neuron decreases by 80%. When
presented with square-wave amplitude-modulated tones statically delayed in
arrival time, the average dynamic ITD range in the IC is 304 micros, but dropped
to 175 micros in auditory cortex. IC neurons average a 38% change in maximum
response over the relevant ITD range, while cortical neurons average a 67%
change. Also measured were time-intensity trading ratios, which index the extent
to which a change in IID can cause a shift the dynamic ITD range. Average trading
ratios are approximately the same in the IC and auditory cortex (17.9 micros/dB
vs. 16.7 micros/dB, respectively). Binaural interactions changed from the IC to
auditory cortex. In IC, ITD sensitivity is an inhibitory, subtractive process in
which ITDs reduce the response evoked by contralateral monaural stimulation. In
the auditory cortex, both binaural inhibition and facilitation occur. In the
majority of cortical neurons, IID and ITD functions were remarkably similar in
shape, having stepped, step-peaked or peaked functions. The binaural interactions
(inhibition and/or facilitation) evoked by ITDs and IIDs were also typically
similar. These results suggest that IIDs and envelope ITDs are having similar
effects on output of the same binaural comparator system.
PMID- 10771182
TI - Sound lateralization and interaural discrimination. Effects of brainstem infarcts
and multiple sclerosis lesions.
AB - Subjects with brainstem lesions due to either an infarct or multiple sclerosis
(MS) underwent two types of binaural testing (lateralization testing and
interaural discrimination) for three types of sounds (clicks and high and low
frequency narrow-band noise) with two kinds of interaural differences (level and
time). Two major types of abnormalities were revealed in the lateralization
performances: perception of all stimuli, regardless of interaural differences
(time and/or level) in the center of the head (center-oriented), or
lateralization of all stimuli to one side or the other of the head (side
oriented). Similar patterns of abnormal lateralization (center-oriented and side
oriented) occurred for MS and stroke patients. A subject's pattern of abnormal
lateralization testing was the same regardless of the type of stimulus or type of
interaural disparity. Lateralization testing was a more sensitive test than
interaural discrimination testing for both types of subjects. Magnetic resonance
image (MRI) scanning in three orthogonal planes of the brainstem was used to
detect lesions. A semi-automated algorithm superimposed the auditory pathway onto
each MRI section. Whenever a lesion overlapped the auditory pathway, some
binaural performance was abnormal and vice versa. Given a lateralization test
abnormality, whether the pattern was center-oriented or side-oriented was mainly
determined by lesion site. Center-oriented performance was principally associated
with caudal pontine lesions and side-oriented performance with lesions rostral to
the superior olivary complex. For lesions restricted to the lateral lemniscus
and/or inferior colliculus, whether unilateral or bilateral, just noticeable
differences (JNDs) were nearly always abnormal, but for caudal pontine lesions
JNDs could be normal or abnormal. MS subjects were more sensitive to interaural
time delays than interaural level differences particularly for caudal pontine
lesions, while stroke patients showed no differential sensitivity to the two
kinds of interaural differences. These results suggest that neural processing of
binaural stimuli is multilevel and begins with independent interaural time and
level analyzers in the caudal pons.
PMID- 10771184
TI - Fine structure and multicomponents of the electrically evoked otoacoustic
emission in gerbil.
AB - Like the acoustically evoked distortion product otoacoustic emissions (DPOAE),
the amplitude spectrum of the extracochlear electrically evoked otoacoustic
emission (EEOAE) also shows peaks and valleys, which are termed the fine
structure (FS) of the EEOAE. The hypothesis that the FS of the EEOAE is generated
by multiple wave interactions in the cochlea is investigated by examining the
relationship between the FS and the multiple-delay components of the EEOAE. The
bulla of the gerbil was exposed using a ventral surgical approach. One pole of a
bipolar electrode was placed in the round window niche, and the other pole on the
surface of the first cochlear turn. A microphone was used to measure electrically
evoked sound pressure change in the ear canal. A recently developed
multicomponent analysis method was used to detect the EEOAE multiple delays. It
was found that the FS is the spectral representation of the multiple-delay
components. The relative power of a prominent long delay component (LDC) shows a
negative relationship to the electrical stimulus level. Both the FS and the LDC
were abolished by intravenous furosemide. Reconstructed signals showed that
mathematical removal of the EEOAE LDC also completely eliminated the FS. These
data demonstrate that the FS and the EEOAE multicomponents are properties of
normal cochlear mechanics in a healthy ear and that the FS is a manifestation of
the multicomponents. The findings in this study strongly indicate that the FS of
the EEOAE evoked by extracochlear electrical stimulation is generated by wave
interaction in the cochlea. The similarity between the EEOAE FS and the DPOAE FS
suggests that they may share the same mechanism.
PMID- 10771186
TI - Otolith regularities.
AB - The masses and the area sizes of the otoliths for the utriculus, sacculus and
lagena of 15 species of the Black Sea fish are analyzed. Morphometrical otolith
regularities are derived and their functional and ecomorphological explanations
are suggested. The otolith regularities are summarized in four otolith rules: (1)
the masses of the otoliths gradually increase with the fish growth. (2) The mass
ratio of the sacculus and utriculus or the sacculus and lagena otoliths does not
change with the fish growth. (3) The ratio between the otolith area s and the
otolith mass m is described by the exponential equation s=alpham(2/3). (4) The
ratio between the otolith and macula sizes does not change with fish growth.
Mathematical modeling of the otolith displacement responses to the acoustic and
the instant force stimuli is performed. Based on the modeling the functional and
ecomorphological explanations of the otolith regularities are suggested: (1) the
greater the otolith mass, the higher the acoustic sensitivity at low frequencies
and the sharper the frequency-response curve at its maximum. (2) The separation
between maxima of the frequency-response curves for the saccular and lagenar
otoliths remains virtually constant with the fish growth. (3) The bottom and
littoral fish have better auditory capabilities than the pelagic fish. (4) The
sensitivity to vestibular stimuli for greater otoliths is higher but the response
is slower. The corresponding acceleration resolution for greater otoliths is
higher and the range of accelerations in which the otolith organ can operate is
narrower. (5) The relative vestibular sensitivities of the utriculus, sacculus
and lagena otolith organs remain constant with fish growth. (6) The otolith
organs of the bottom and littoral fish are tuned to different accelerations and
possess different functional properties. The otolith organs of pelagic fish are
adapted to a limited range of accelerations and are less sensitive to low
accelerations as compared to the bottom and littoral fish.
PMID- 10771185
TI - Canalicular reticulum in vestibular hair cells.
AB - A membrane limited system referred to as canalicular reticulum (CR) has been
demonstrated in the apical cytosol of the cochlea's inner and outer hair cells.
Similarities between cochlear and vestibular hair cells prompted investigation of
the presence of CR in hair cells of the gerbil vestibular labyrinth. A method of
fixation with glutaraldehyde followed by an osmium-ferrocyanide mixture
demonstrated abundant CR in the apex of both type I and type II hair cells. The
CR was closely associated with numerous Golgi zones in the apex of the vestibular
hair cells, indicating its genesis from Golgi cisternae. Also preserved in upper
cytosol were discrete complexes of mitochondria with granular reticulum. These
complexes offered a possible site for generating the membrane in Golgi zones and
CR. Single and parallel cisternae of granular reticulum were observed in the
basal half of the hair cells together with numerous synaptic-like vesicles. These
cisternae with their terminal blebbing and accompanying canaliculi were
interpreted as novel structures mediating synaptic vesicle genesis in vestibular
hair cells in a manner comparable to that postulated for cochlear inner hair
cells.
PMID- 10771187
TI - The effects of interrupted noise exposures on the noise-damaged cochlea.
AB - A variety of interrupted noise exposure paradigms will produce a toughening
effect in the mammalian auditory system. That is, the threshold shift will
gradually become smaller with each successive daily exposure. The ability of the
system to be toughened has not been explored in subjects with a pre-existing
noise-induced hearing loss. Using the chinchilla as the experimental animal,
evoked potential audiometry to obtain thresholds, and surface preparation
histology to quantify the sensory cell population, the issue of toughening was
examined in the noise-damaged auditory system. Toughening was produced by a 1.0
kHz, narrow-band impact at 115 dB peak SPL for 10 days, 6 h/day, and trauma was
produced by a 1.0 kHz, narrow-band impact at 121 dB peak SPL for 5 days, 24
h/day. Four groups of animals were used. Group 1: traumatic exposure followed 30
days later by the toughening exposure. Group 2: toughening exposure followed 30
days later by the traumatic exposure. Group 3: a trauma-only control. Group 4: a
toughening-only control. Group 2 that received the toughening exposure 30 days
prior to the traumatic exposure showed a 10 to more than 20 dB toughening effect
between the 0.5 and 4.0 kHz test frequencies, while Group 1 that received the
traumatic exposure followed 30 days later by the toughening exposure showed no
toughening. The permanent changes in the evoked response audiograms and sensory
cell populations were the same in Groups 1, 2 and 3 that were exposed to the
traumatic noise, regardless of whether or not the animals were ever subjected to
the toughening noise or whether the toughening noise preceded or followed the
traumatic noise.
PMID- 10771188
TI - Hydroxyl radical formation in the perilymph of asphyxic guinea pig.
AB - To elucidate the role of hydroxyl radical (.OH) species in the generation
mechanism of the cochlear pathology induced by transient asphyxia and subsequent
re-ventilation, the concentrations of 2,3-hydroxybenzoic acid (DHBA) and 2,5
DHBA, major products arising from the attack of .OH upon salicylate, were
measured in the perilymph of the guinea pig by the high performance liquid
chromatography-electrochemical/UV method. The mean value of 2, 3-DHBA
concentration in the perilymph significantly increased from the pre-asphyxic
level (6.4 microM) to 7.6 microM and 8.8 microM during asphyxia of 3 min duration
and at 5 min after the onset of re-ventilation, respectively. The 2,5-DHBA
concentration was 7.9 microM before asphyxia, and also significantly increased to
11.5 microM and 16.2 microM during and after asphyxia, respectively. These
results strongly indicated that .OH was generated in the perilymph of the
asphyxic and re-ventilated guinea pig cochlea, and the significance of this
increased .OH in generating anoxia and re-perfusion injury is discussed with
respect to iron and oxygen-derived free radicals.
PMID- 10771189
TI - Metabolism of the dorsal cochlear nucleus in rat brain slices.
AB - In vitro brain slices of the cochlear nucleus have been used for
electrophysiological and pharmacological studies. More information is needed
about the extent to which the slice resembles in vivo tissue, since this affects
the interpretation of results obtained from slices. In this study, some chemical
parameters of the dorsal cochlear nucleus (DCN) in rat brain slices were measured
and compared to the in vivo state. The activities of malate dehydrogenase and
lactate dehydrogenase were reduced in some DCN layers of incubated slices
compared to in vivo brain tissue. The activities of choline acetyltransferase and
acetylcholinesterase were increased or unchanged in DCN layers of slices.
Adenosine triphosphate (ATP) concentrations for in vivo rat DCN were similar to
those of cerebellar cortex. Compared with in vivo values, ATP concentrations were
decreased in the DCN of brain slices, especially in the deep layer. Vibratome-cut
slices had lower ATP levels than chopper-cut slices. Compared with the in vivo
data, there were large losses of aspartate, glutamate, glutamine, gamma
aminobutyrate and taurine from incubated slices. These amino acid changes within
the slices correlated with the patterns of release from the slices.
PMID- 10771190
TI - Computer simulation of the mechanical stimulation of the saccular membrane of
bullfrog.
AB - A three-dimensional computer simulation of the experiment (Benser M. E., Issa
N.P., Hudspeth A.J., 1993. Hear. Res. 68, 243-252), devoted to the mechanical
stimulation of the surface of saccular membrane of bullfrog with the otoconial
mass removed was carried out by finite-element method. Comparison of the
calculated distribution of the membrane displacements with the experimental data
indicates that the gel layer of the saccular membrane is inhomogeneous. Its
lower, thin (6-10 microm) sublayer bordering the macular surface has the smaller
Young's modulus which is 20 times less than the modulus of the upper part of the
gel membrane (2.5x10(2) N/m(2) and 6.6x10(3) N/m(2), respectively). Possible
consequences of this result and modification of the experiment are being
discussed. The estimates based on the results of simulation support the
conclusion that hair bundle stiffness may dominate the elastic reactance to
otolithic membrane shear (Benser et al., 1993).
PMID- 10771191
TI - Increased cortical activation during hearing of speech in cochlear implant users.
AB - To investigate the cortical activities while listening to noise and speech in
cochlear implant (CI) users, we compared cerebral blood flow in postlingually
deafened CI users with that in normal hearing subjects using positron emission
tomography. While noise activation in CI users did not significantly differ from
that in normal subjects, hearing speech activated more cortical areas in CI users
than in normal subjects. A comparison of speech activation in these two groups
revealed higher activation in CI users not only in the temporal cortices but also
in Broca's area and its right hemisphere homologue, the supplementary motor area
and the anterior cingulate gyrus. In postlingually deafened subjects, the hearing
of speech coded by CI may be accompanied by increased activation of both the
temporal and frontal cortices.
PMID- 10771192
TI - Structural evidence for ion transport and tectorial membrane maintenance in the
gerbil limbus.
AB - Cells medial to the tunnel of Corti were examined to assess fine structural
features relevant to their proposed role in cochlear K(+) homeostasis. A dense
network of canaliculi referred to as canalicular reticulum (CR) resided in the
foot body of inner pillar cells, where it bordered and could resorb ions released
from inner radial and spiral nerves. Lateral interdental cells (IDCs) formed
columns which connected the inner sulcus epithelium with the base of the
tectorial membrane's (TM) middle zone. A spout-like neck in cells at the top of
lateral IDC columns housed a dense concentration of CR which resembled that
characteristic of ion transporting epithelia and appeared to be located here for
transporting ions and fluid toward the TM. Clustered IDCs in the center of the
limbus connected underlying limbal stroma with the TM's limbal zone and appeared
capable of transporting ions from stroma to TM. Abundant CR in limbal stellate
fibrocytes evidenced their capacity to transport ions and fluid, presumably from
inner sulcus epithelium toward central IDCs. The most medial IDCs possibly
function as the terminus of an ion cycling path from scala vestibuli to
endolymph. Light fibrocytes situated between supralimbal fibrocytes and medial
IDCs appeared to serve as a link in this pathway. The limbal zone of the TM
overlying central IDCs consisted of three distinct regions which offered a
structural basis for transformation of an amorphous matrix supplied by central
IDCs into the protofibrils of the membrane's middle zone.
PMID- 10771193
TI - In vitro effects of hydrogen peroxide on the cochlear neurosensory epithelium of
the guinea pig.
AB - Reactive oxygen species (ROS) have been postulated to be involved in drug
ototoxicity and noise-induced hearing loss. Hydrogen peroxide (H(2)O(2))-induced
cell damage in the inner ear was investigated using the neurosensory epithelium
of a guinea pig cochlea. Hair cells and supporting cells of the epithelium
incubated in Hanks' balanced salt solution were viable up to 6 h. After 2 h of
treatment with 0.2 mM H(2)O(2) about 85% of the outer hair cells lost their
viability. In contrast inner hair cells slowly began to die after 2 h of H(2)O(2)
treatment. The Deiters cells and Hensen cells did not show any signs of damage in
the presence of H(2)O(2). Nifedipine, a calcium channel blocker, Quin-2 AM, an
intracellular calcium chelator, and 2,2'-dipyridyl, a membrane-permeable iron
chelator, all provided partial protection against H(2)O(2)-induced outer hair
cell death. The combination of both chelators showed an additional protective
effect. The antioxidants N-acetylcysteine and glutathione-monoethyl ester
completely protected against H(2)O(2) damage. These results suggest that calcium,
iron, and thiol homeostasis play a crucial role in hair cell death caused by
H(2)O(2).
PMID- 10771194
TI - Cell turnover in neuromasts of zebrafish larvae.
AB - The numbers and positions of cells undergoing cell death and proliferation in the
neuromasts of 10 day old zebrafish larvae were assessed to investigate the
ability of supporting cells to differentiate into hair cells. Evaluations of cell
death and proliferation showed that a subpopulation of cells located in the
centre of the neuromast undergo cell death, and a different subpopulation located
at the periphery proliferate. This suggests that cell death of hair cells and
proliferation of mantle supporting cells occurs as part of normal development,
creating constant turnover of hair cells. We show that the caspase inhibitor
zVADfmk reduces cell death while the aminoglycoside neomycin specifically induces
an increased amount of cell death in the central population of cells. Both of
these treatments affect the rate of proliferation of the peripheral subpopulation
of cells in the neuromast suggesting that a feedback mechanism occurs regulating
cell death and proliferation. We propose that the dying population of cells are
hair cells and the proliferating cells are 'mantle' supporting cells, which is in
agreement with previous observations suggesting that supporting cells can give
rise to hair cells following hair cell death.
PMID- 10771195
TI - Characterization of hearing in an X,0 'Turner mouse'.
AB - Turner's syndrome is due to total (45,X) or partial (mosaicism) loss of one X
chromosome. The main features are short stature, ovarian dysgenesis with no
estrogen production and infertility. In addition to ear and hearing disorders,
middle ear problems including acute/serous otitis media and chronic middle ear
disease are frequent. Sensorineural hearing loss is often seen with a dip in the
mid-frequencies and also an early high frequency loss. In this study, middle-and
inner-ear pathology was characterized using physiological and morphological
techniques in a 'Turner mouse' that has been generated with the chromosomal
aberration X,0. Otitis media was found in some of these X,0 animals, a symptom
that is seldom found in control animals. The auditory brainstem responses (ABR)
of the Turner mouse showed a progressive hearing loss in the high frequency
region that exceeded the normal age-related hearing loss of control mice and
increased latencies of the first ABR wave. Outer hair cell loss was apparent in
the cochlear basal turn of Turner mice. Decreases in the amplitude of distortion
product otoacoustic emissions were correlated with the loss of ABR threshold
sensitivity. These results indicate that hearing problems in the Turner mouse
seems to be of cochlear origin with an eighth nerve component. This Turner mouse
model appears to have ear and hearing problems quite similar to humans and can
therefore be used as a model to determine the auditory pathology underlying this
syndrome.
PMID- 10771196
TI - The rat cochlea in the absence of circulating adrenal hormones: an
electrophysiological and morphological study.
AB - Circulating adrenal hormones affect strial function. Removal of endogenous levels
of adrenal steroids by bilateral adrenalectomy (ADX) in rats causes a decrease of
Na(+)/K(+)-ATPase activity in the cochlear lateral wall [Rarey et al., 1989.
Arch. Otolaryngol. Head Neck Surg. 115, 817-821] and a decrease of the volume of
the marginal cells in the stria vascularis [Lohuis et al., 1990. Acta
Otolaryngol. (Stockh.) 110, 348-356]. To study further the effect of absence of
circulating adrenocorticosteroids on cochlear function, 18 male Long Evans rats
underwent either an ADX or a SHAM operation. Electrocochleography was performed 1
week after surgery for tone bursts in a frequency range of 1-16 kHz. Thereafter,
the cochleas were harvested and examined histologically. No significant changes
in the amplitude growth curves of the summating potential (SP), the compound
action potential (CAP) and the cochlear microphonics (CM) were detected after
ADX. However, visually, there appeared to be a decrease of endolymphatic volume
(tentatively called imdrops). Reissner's membrane (RM) extended less into scala
vestibuli in ADX animals than in SHAM-operated animals. The ratio between the
length of RM and the straight distance between the medial and lateral attachment
points of RM were used as an objective measure to quantify this effect in each
sub-apical half turn of the cochlea. The decrease in length of RM was
statistically significant. Thus, circulating adrenal hormones appear to be
necessary for normal cochlear fluid homeostasis. Absence of one or more of these
hormones leads to shrinkage of the scala media (imdrops). However, the absence of
adrenal hormones does not affect the gross cochlear potentials. Apparently, the
cochlea is capable of compensating for the absence of circulating adrenal
hormones to sustain the conditions necessary for proper cochlear transduction.
PMID- 10771197
TI - Noise suppression of transient-evoked otoacoustic emissions. I. A comparison with
the non-linear method.
AB - A new method to record transient-evoked otoacoustic emissions (TEOAEs) is
introduced. Click stimuli were presented both with and without a simultaneously
presented wide-band noise burst. Subtraction of the recorded signal evoked by the
noise burst plus click from the signal evoked by the click alone, cancelled the
eardrum reflection components of the response and resulted in a measure of the
emission. This was used to obtain the TEOAEs from 21 subjects for peak click
stimulus levels of 48-66 dB SPL. The root-mean-square (RMS) level of the noise
burst was set 10 dB higher than the peak click level, and resulted in suppression
of the TEOAE by up to 20 dB. The TEOAE waveforms obtained by the new method were
compared to those obtained with Kemp's non-linear method, and were
indistinguishable in 20 of the 21 subjects. On basis of the emission spectra,
they were indistinguishable in 18 out of 21 subjects. The latencies of narrow
band filtered components from the TEOAEs obtained with the two methods were also
similar. This suggests that this noise-suppression method produces similar
results as Kemp's non-linear method with the advantage that emission components
with very short latencies can be obtained.
PMID- 10771198
TI - Noise suppression of transient-evoked otoacoustic emissions. II. Derived narrow
band contributions.
AB - Transient-evoked otoacoustic emissions (TEOAEs) were decomposed into cochlear
place specific components using high-pass noise suppression. This was performed
using high-pass filtered noise with cut-off frequencies between 0.7 and 5.6 kHz
in 0.5-octave steps. Subtraction of the TEOAEs obtained in the presence of two
high-pass noise suppressors with 0.5-octave difference in their cut-off
frequencies, f(A) and f(B), should theoretically result in TEOAE components with
frequencies between f(A) and f(B). The reconstructed wide-band emission power
spectrum obtained by summing the narrow-band emission power spectra, was nearly
identical to the power spectrum of the original wide-band emission. This suggests
that no phase-cancellation occurs and that the individual narrow-band TEOAEs are
uncorrelated, and thus that their generators are potentially independent. About
66% of the derived narrow-band emissions had spectral components that extended
below the cut-off frequency of the lower high-pass noise filter. These tail
components were interpreted as resulting from high-frequency side suppression of
the high-pass noise on the click emission and potentially distortion product
components from the TEOAE.
PMID- 10771199
TI - Medicinal plants uses of the Tacana, an Amazonian Bolivian ethnic group.
AB - We present the results of an ethnopharmacological investigation of a Bolivian
lowland ethnic group, the Tacana. The Tacana have a long tradition of exchange
with highland communities. Though facing rapid acculturation, highlighted by the
loss of the Tacana language among the younger generations, the knowledge and uses
of medicinal plants are still alive. Of the approximately 450 different plant
species collected during this survey, 33% had medicinal uses. We present an
overview of the traditional Tacana ethnomedicine and pharmacopoeia.
PMID- 10771200
TI - Antifertility studies of the root extract of the Barleria prionitis Linn in male
albino rats with special reference to testicular cell population dynamics.
AB - Oral administration of root extract of Barleria prionitis L. to male rats (100
mg/rat per day) for the period of 60 days did not cause body weight loss. The
root extract brought about an interference with spermatogenesis. The round
spermatids were decreased by 73.6% (P< or =0.001). No significant change was
found in the population of secondary spermatocytes. However, the population of
preleptotene spermatocytes were decreased by 41.9%. The extract reduced the
fertility of male rats by 100%. Cross sectional surface area of Sertoli cells and
mature Leydig cell numbers were significantly reduced (36.9%). The total protein,
sialic acid contents of the testes, epididymides, seminal vesicle and prostate
were reduced. Testicular glycogen contents were low. Antifertility effects of
Barleria seemed to be mediated by disturbances in testicular somatic cells
functions (Leydig and Sertoli cells) resulting in the physio-morphological events
of spermatogenesis.
PMID- 10771201
TI - Molluscicidal activity of some Saudi Arabian euphorbiales against the snail
Biomphalaria pfeifferi.
AB - The comparative susceptibility of the snail vector of intestinal schistosomiasis,
Biomphalaria pfeifferi to the action of extracts from Saudi Arabian Euphorbiales
has been determined. Methanol and chloroform extracts of the plants tested
(Jatropha glauca, Euphorbia helioscopia and Euphorbia schimperiana) were the most
promising from the molluscicidal point of view with LD(50) values in the range 10
100 ppm.
PMID- 10771202
TI - Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide
stimulated RAW264.7 cells from Amorpha fruticosa.
AB - Certain flavonoids were reported to show an immunoregulatory activity against
lymphocyte proliferation and cytokine production. In the course of a search for
tumor necrosis factor (TNF)-alpha inhibitory compounds from natural plants, we
also isolated a prenylfavanone type of flavonoid, amoradicin, from the extract of
Amorpha fruticosa by activity-guided fractionation. This compound significantly
inhibited TNF-alpha production in lipopolysaccharide (LPS)-stimulated RAW264.7
cells with an IC(50) value of 28.5 microM. The activity was comparable or higher
than those of standard flavonoid compounds, genistein and silybin with IC(50) of
24.9 and 140.3 microM, respectively.
PMID- 10771203
TI - The stem of sinomenium acutum inhibits mast cell-mediated anaphylactic reactions
and tumor necrosis factor-alpha production from rat peritoneal mast cells.
AB - The aqueous extract of Sinomenium acutum stem (SSAE) (0.1-1000 mg/kg) dose
dependently inhibited systemic anaphylactic reaction induced by compound 48/80 in
mice. In particular, SSAE reduced compound 48/80-induced anaphylactic reaction
with 50% at the dose of 1000 mg/kg. SSAE (100-1000 mg/kg) also significantly
inhibited local anaphylactic reaction activated by anti-dinitrophenyl (DNP) IgE.
When mice were pretreated with SSAE at a concentration ranging from 0.1 to 1000
mg/kg, the plasma histamine levels were reduced in a dose-dependent manner. SSAE
(1-1000 microg/ml) dose-dependently inhibited histamine release from the rat
peritoneal mast cells (RPMCs) activated by compound 48/80 or anti-DNP IgE. In
addition, SSAE (0.1 microg/ml) had a significant inhibitory effect on anti-DNP
IgE-induced tumor necrosis factor-alpha (TNF-alpha) production. These results
indicate that SSAE inhibits mast cell-mediated anaphylactic reactions and TNF
alpha production from mast cells.
PMID- 10771204
TI - Cytotoxicity of some medicinal plant extracts used in Tanzanian traditional
medicine.
AB - Using the ethnomedical data approach, some Tanzanian plants that are used in
Tanzanian traditional medicine for cancer or non-cancer diseases were collected
and evaluated for cytotoxic activity. The antiproliferative effect of the
methanolic extracts (10 and 100 microg/ml) of 47 plants was evaluated in vitro on
three human cell lines (HeLa, cervical carcinoma; HT29, colon adenocarcinoma; and
A431, skin carcinoma). From the nine plants that are used to treat cancer, two
plants (22%) exhibited pronounced cytotoxic effect (<25% cell proliferation) at
least in one of the tested cell lines. For the 38 plants that are used to treat
non-cancer diseases, 14 plants (37%) exhibited pronounced cytotoxic effect (<25%
cell proliferation). Cell type cytotoxic specificity was observed in some
extracts. Overall, the A431 cells were much more sensitive to most of the
extracts than the other cell lines. For the plants that are used as anticancer
herbal drugs, our results indicate that there is no correlation between the
reported use of these plants and their cytotoxic activity obtained in this study.
However, plants that have shown pronounced cytotoxic activity will be evaluated
further for the possible isolation of active antitumor compounds.
PMID- 10771205
TI - Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian
medicinal plants containing coumarin: a comparative study.
AB - This work studied the antinociceptive, antiinflammatory and bronchodilator
activities of hydroalcoholic extracts (HAEs) from Torresea cearensis, Justicia
pectoralis, Eclipta alba, Pterodon polygaliflorus and Hybanthus ipecacuanha.
These plants are largely used in north-eastern Brazil for respiratory tract
diseases, and have in common coumarin, one of their active principles. The
antinociceptive effects of all HAEs in mice were similar, and the inhibition of
the acetic acid-induced writhing was 35-55% with 200 mg/kg, p.o. At this dose,
the effect ranged from 41-77% with the formalin test in mice, and all the HAEs
inhibited preferentially the 2nd phase of the response. In one case (P.
polygaliflorus), the effect was partially reversed by naloxone. Except for the
HAE from T. cearensis (200 mg/kg, p.o.) which inhibited carrageenan-induced edema
by 47%, the others presented no effect orally but showed a significant activity
intraperitoneally. On the other hand, T. cearensis was not active in the dextran
model, while inhibitions with the other ones were lower than 30%. The
bronchodilator activities of J. pectoralis and P. polygaliflorus HAEs as
determined in isolated guinea-pig trachea were the most active.
PMID- 10771206
TI - Modulatory effect of ginseng total saponin on dopamine release and tyrosine
hydroxylase gene expression induced by nicotine in the rat.
AB - Several studies have demonstrated that behavioral activation induced by
psychostimulants is prevented by ginseng total saponin (GTS), which has been
known to act on the central dopaminergic system. In an attempt to investigate
whether the effect of GTS is through its inhibitory action on the elevated
dopaminergic transmission, we examined the effect of GTS on nicotine-induced
dopamine (DA) release in the nucleus accumbens (NA) of freely moving rats using
in vivo microdialysis. Systemic injection of nicotine (3 mg/kg; i.p.) produced a
mild increase in extracellular DA of dialysates samples in the NA (132+/-13% over
basal levels at the peak). GTS (100 mg/kg; i.p.) had no effect on resting levels
of extracelluar DA. However, an increase in accumbens DA release produced by
systemic nicotine was completely blocked by systemic pre-treatment with GTS (100
mg/kg; i.p.). In addition, the effect of GTS on nicotine-induced tyrosine
hydroxylase (TH) and immediate early gene expression in ventral tegmental area
(VTA) or NA regions was examined. A single injection of nicotine increased TH
mRNA level at VTA region. GTS, which did not affect the basal TH mRNA expression,
attenuated nicotine-induced TH mRNA expression. Nicotine slightly increased both
c-fos and c-jun mRNA level and GTS, which did not affect the basal c-fos and c
jun mRNA expression, further enhanced nicotine-induced c-fos and c-jun mRNA level
at both VTA and NA regions. Our results suggest that GTS may have an inhibitory
action against nicotine-induced DA release in NA region and TH mRNA expression in
VTA region. GTS may exert an potentiative effect on both c-fos and c-jun mRNA
expression at NA region through inhibiting the release of DA in NA.
PMID- 10771207
TI - The role of antioxidant activity of Phyllanthus emblica fruits on prevention from
indomethacin induced gastric ulcer.
AB - Pretreatment with the butanol extract of the water fraction of Phyllanthus
emblica fruits at the dose of 100 mg/kg body-weight, orally administered to rats
for 10 consecutive days, was found to enhance secretion of gastric mucus and
hexosamine (P<0.001) in the indomethacin induced ulceration of rats. The
morphological observations also supported a protective effect of the stomach wall
from lesion. The indomethacin treatment of the premedicated animals with the drug
hardly affected either the malondialdehyde (MDA) or superoxide dismutase (SOD)
level in gastric tissue while the ulcerative agent itself significantly enhanced
both the levels. An antioxidant property appears to be predominantly responsible
for this cytoprotective action of the drug.
PMID- 10771208
TI - Antiproliferative effects of alkaloids from Sedum sarmentosum on murine and human
hepatoma cell lines.
AB - The whole plant of Sedum sarmentosum (SS) has been traditionally used for the
treatment of chronic viral hepatitis in China and South Korea. Certain hepatitis
virus causes acute and chronic hepatitis and induces hepatocellular carcinoma
(HC). In the present study, we examined whether the crude alkaloid fraction (CAF)
of SS had any anticancer effects on hepatoma cell lines. Murine hepatoma (BNL CL.
2) and human hepatoma (HepG2) cell lines were cultured in the presence of CAF of
SS at various doses (50-150 microg/ml) for 24 or 48 h. CAF caused a dose
dependent inhibition of cell proliferation without necrosis or apoptosis.
Antiproliferative effects of CAF of SS were associated with an increase in the
number of cells in the G1 phase of cell cycle. This study suggests that SS may
improve survival of hepatoma patients via the inhibition of excessive growth of
tumor cells.
PMID- 10771209
TI - Studies on antidiarrhoeal activity of Jatropha curcus root extract in albino
mice.
AB - Use of Jatropha curcus L. roots in the treatment of diarrhoea is a common
ethnobotanical practice in Konkan, a part of the Western coastal area of India.
Roots of this species were undertaken for pharmacognostic studies and evaluation
of antidiarrhoeal activity in albino mice. Successive solvent extraction was
carried out using petroleum ether (60-80 degrees C) and methanol. The methanol
extract showed activity against castor oil induced diarrhoea and intraluminal
accumulation of fluid. It also reduced gastrointestinal motility after charcoal
meal administration in albino mice. The results indicate that action of J. curcus
root methanol extract could be through a combination of inhibition of elevated
prostaglandin biosynthesis and reduced propulsive movement of the small
intestine.
PMID- 10771212
TI - Refractive surgical problem
PMID- 10771210
TI - Outcomes of initial PRK and LASIK procedures.
PMID- 10771213
TI - Consultation section: reply
PMID- 10771214
TI - Consultation section: Refractive surgical problem.
PMID- 10771215
TI - Consultation section: reply
PMID- 10771216
TI - Consultation section: reply
PMID- 10771217
TI - Consultation section: reply
PMID- 10771218
TI - Consultation section: reply
PMID- 10771219
TI - Consultation section: reply
PMID- 10771220
TI - Pars plana lensectomy with double-capsule-supported intraocular lens implantation
in children.
AB - An alternative technique to manage pediatric cataracts comprises a pars plana
lensectomy and anterior vitrectomy with anterior and posterior capsulotomies and
posterior chamber heparin-surface-modified intraocular lens (IOL) implantation in
the ciliary sulcus through a scleral tunnel. The surgical results in 7 eyes of 6
consecutive patients between 3.5 and 12.0 years old with developmental or
traumatic cataract who had surgery using this technique were evaluated
prospectively. Follow-up ranged from 12 to 19 months. All 7 eyes maintained a
clear pupillary axis and a well-centered IOL from immediately after surgery to
the last follow-up. Final best corrected visual acuity was 20/40 or better in 71%
of cases.
PMID- 10771221
TI - Manual sutureless cataract surgery using a claw vectis.
AB - Two-handed sandwich methods of extracapsular cataract extraction using a self
sealing incision have proved difficult for many inexperienced surgeons. We
developed a simpler 1-handed technique using a claw vectis-a vectis with a claw
placed on its tip. When the nucleus is pulled through the scleral tunnel, it is
fixed by the claw and is smoothly removed from a wound of a size comparable to
that in the sandwich method. During nucleus removal, viscoelastic material is
constantly injected through the irrigation vectis to maintain the anterior
chamber depth, resulting in a low incidence of complications. We have performed
620 cases using the technique and found it safe and easy for both novice and
experienced surgeons.
PMID- 10771222
TI - Functional, psychological, and satisfaction outcomes of laser in situ
keratomileusis for high myopia.
AB - PURPOSE: To identify factors that motivate patients to seek laser in situ
keratomileusis (LASIK) treatment for myopia and establish subjective levels of
functional improvement and satisfaction across a range of indices after LASIK
surgery. SETTING: The Corneal Diseases and Excimer Laser Research Unit,
University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland.
METHODS: In this questionnaire-based, cross-sectional study, an anonymous 34-item
questionnaire was forwarded to 50 consecutive patients in a prospective study who
had had LASIK for high myopia by a single surgeon at a single center. The
questionnaire used visual analog scales, anchored at each end by an adjectival
descriptor. The mean preoperative myopia was -10.7 diopters +/- 4.4 (SD). Seventy
six percent of eyes (83% of patients) achieved post-LASIK uncorrected visual
acuity (UCVA) of 6/12 or better; 1 eye lost 2 lines of corrected Snellen visual
acuity. RESULTS: A 98% reply rate was achieved. The most common motivating factor
for pursuing LASIK was to improve UCVA (88%); only 21% rated improved cosmesis as
an important motive. Most patients (81% to 100%) reported functional improvement
across the spectrum of visual tasks assessed, although 8.8% reported difficulty
with nighttime driving. Ninety-six percent felt their UCVA was as good as
anticipated, 97.9% were satisfied with the speed of visual improvement, 93.8%
achieved the goals for which they had surgery, 97.9% reported an improved quality
of life, and 97.9% were satisfied with the overall outcome of LASIK. CONCLUSIONS:
Using an anonymous, wide-ranging questionnaire, high levels of functional
improvement and satisfaction with the speed of visual recovery and outcome were
reported by patients after LASIK for high myopia. Nighttime driving symptoms of
variable severity were, however, noted by 8.8% of patients, despite high levels
of satisfaction with other aspects of visual function.
PMID- 10771224
TI - Diurnal stability of refraction after implantation with intracorneal ring
segments.
AB - PURPOSE: To investigate diurnal changes in visual acuity and refraction in myopic
eyes implanted with intracorneal ring segments (ICRS). SETTING: University of
California San Diego Shiley Eye Center, La Jolla, California, and Emory
University Vision Correction Center, Atlanta, Georgia, USA. METHODS: This
prospective study involved 2 groups of patients who had ICRS (Intacs)
implantation and a follow-up of at least 6 months. The first group included 102
eyes of 51 bilaterally treated patients; the second group, 32 eyes of 16
unilaterally treated patients. Examinations including visual acuity, manifest
refraction, and videokeratography were done in the morning and evening at least 9
hours apart on a single day. Refractive changes were analyzed by power vectors;
multivariate statistics were used to determine the significance of change in any
component of the spectacle prescription. RESULTS: In the bilateral treatment
group, 97 eyes (95%) were within 1 line of spectacle-corrected visual acuity from
morning to evening. The mean change in manifest refraction was -0.14 +0.08 x 4
and in spherical equivalent, -0.10 diopters (D) (sigma = 0.3; range -0.750 to
+0.875 D). Ninety-six eyes (94%) had a change in refraction within 0.50 D of
spherical equivalent. There was no significant change in corneal power (P =.20).
In the unilateral treatment group, there was no significant difference between
treated and untreated eyes in changes in spectacle-corrected visual acuity,
manifest refraction, or corneal power and toricity (P.05). CONCLUSION: No
clinically significant diurnal variation in visual acuity or manifest refraction
was observed after ICRS implantation or in untreated paired eyes. Moreover, the
data suggest less diurnal change in visual acuity and refraction after ICRS
implantation.
PMID- 10771223
TI - Surgical outcomes of photorefractive keratectomy and laser in situ keratomileusis
by inexperienced surgeons.
AB - PURPOSE: To investigate the results of photorefractive keratectomy (PRK) and
laser in situ keratomileusis (LASIK) procedures performed by novice
ophthalmologists and compare the results with those of experienced refractive
surgeons. SETTING: Doheny Eye Institute, University of Southern California, Los
Angeles, and Department of Ophthalmology, University of California, Irvine,
California, USA. METHODS: In this retrospective case series, data were examined
from the first PRK procedures by 33 consecutive ophthalmologists and the first
LASIK procedures by 19 consecutive ophthalmologists. Preoperative and
postoperative uncorrected visual acuity (UCVA) and best spectacle-corrected
visual acuity (BSCVA), as well as intraoperative and early postoperative
complications, were recorded. RESULTS: In the PRK group, 33.3% of eyes achieved a
UCVA of 20/20 and 87.8%, 20/40 or better; 54.5% were within +/-0.5 diopter (D) of
emmetropia and 87.8%, within +/-1.0 D. Two eyes with a preoperative spherical
equivalent of greater than -11.0 D lost 2 lines of BSCVA. If eyes with low myopia
(.05). CONCLUSION: Despite use of the anti-central-island
pretreatment program, the occurrence of central islands after LASIK was
significant, as in photorefractive keratectomy. Further studies of the effect of
central islands on surgical results and clinical progress and measures to prevent
the occurrence are needed.
PMID- 10771227
TI - Effect of age on the refractive outcome of myopic photorefractive keratectomy.
AB - PURPOSE: To evaluate the effect of age on the outcome of myopic photorefractive
keratectomy (PRK). SETTING: University-based refractive surgery practice.
METHODS: A retrospective analysis of 197 eyes that had PRK for myopia was
performed. Four groups of patients were compared: Group 1, patients < 30 years
(n=35); Group 2, patients 31 to 40 years (n=56); Group 3, patients 41 to 50 year
s (n=47); Group 4, patients > 50 years (n=59). The percentage of eyes with an
uncorrected visual acuity of 20/20 or better and 20/40 or better and the
percentage of eyes with spherical correction within +/-0.5 and +/-1.0 diopter (D)
of the attempted correction were derived for each age group. The percentage of
patients overcorrected and undercorrected by 1.0 D or more in each age group was
also calculated. The difference between the percentage of patients who achieved a
visual acuity of 20/20 or better in Group 4 and in the younger groups was
statistically significant at 3 months (P =.02) but not at 6 months (P =.70) and
12 months (P =.55). The difference between the percentage of patients who
achieved an acuity of 20/40 or better was not significant at any time. The
difference between the percentage of patients who were within +/-0.5 D of
intended correction in Group 4 and in the younger groups was statistically
significant at 3 months (P =.001), 6 months (P =.006), and 12 months (P =.008);
the difference between the percentage of patients who were within +/-1.0 D of
intended correction was not significant at any time. The difference between the
percentage of patients overcorrected and undercorrected by 1.0 D or more in Group
4 and in the younger groups was not significant at any time. In the 3 younger
groups, age did not significantly affect visual outcome or predictability.
However, there was a significant difference between Group 4 and the 3 younger
groups in predictability of the refractive outcome at 3, 6, and 12 months. Age
may play a role in the outcome of refractive surgery.
PMID- 10771228
TI - Paracentral photoablations to correct higher grades of naturally occurring
astigmatism.
AB - PURPOSE: To evaluate the efficacy of paracentral ablations in treating higher
degrees of naturally occurring myopic and hyperopic astigmatism. SETTING:
Augenklinik, Kreiskrankenhaus Bad Hersfeld, Germany. METHODS: Twenty-five eyes (7
with hyperopia, 18 with myopia) with naturally occurring corneal astigmatism
greater than 1.75 diopters (D) were treated by excimer laser. The mean refractive
cylinder was -4.05 D +/- 1.46 (SD) (range -1.75 to -7.00 D). The intention was to
reduce the astigmatism without consideration of the spherical refractive error.
Two paracentral ablations were performed by photorefractive keratectomy with
treatment zones of 3.5 mm in the flatter meridian of the cornea. Objective
refraction, best corrected visual acuity (BCVA), changes in corneal radius,
development of haze, and regression were recorded. RESULTS: The paracentral
ablations induced a steepening of the corneal radius in the flatter meridian from
8.12 mm (mean preoperative value) to 7. 84 mm (mean postoperative value) and thus
reduced the mean refractive cylinder to -1.12 +/- 0.82 D (range 0.00 to - 3.00
D), corresponding to a mean reduction of 78%. No eye experienced a loss of
Snellen lines. The preoperative BCVA (mean 20/25; range 20/50 to 20/20) was
unchanged postoperatively CONCLUSIONS: Paracentral ablations resulted in a stable
corneal curvature immediately after epithelial healing, with a moderate
regression over time. Paracentral ablations with the excimer laser appear to be a
safe and effective method to correct higher grades of corneal astigmatism.
PMID- 10771229
TI - Effect of a standard paired arcuate incision and augmentation sutures on
postkeratoplasty astigmatism.
AB - To analyze the efficacy of a standardized paired arcuate incision and
augmentation suture technique in the treatment of various levels of post
penetrating keratoplasty (PKP) astigmatism. Lions Eye Institute, Royal Perth
Hospital, Perth, Australia, and University of Dundee Department of Ophthalmology,
Dundee, United Kingdom.A standardized paired arcuate incision and paired
augmentation suture technique was used to treat 34 eyes with post-PKP astigmatism
ranging from -3.50 to -20.00 diopters (D) at the spectacle plane. The technique
consisted of paired arcuate incisions of 3 clock hours, 480 microm deep in the
graft-host junction, and 2 pairs of augmentation 10-0 nylon sutures. The mean
preoperative cylinder was -9.14 D +/- 4.38 (SD) and the mean postoperative
cylinder, -3.59 +/- 1.92 D at the corneal plane after a mean follow-up of 50 +/-
43 weeks. This represents an empirical reduction in mean cylinder of 5. 55 D
(60.7%). The Alpins correction index (surgically induced astigmatism [SIA]
divided by target induced astigmatism) was calculated for each case, and the mean
was 1.01 +/- 0.34, with a median of 0.91. Approximately 53.1% of cases achieved a
correction index between 0.80 and 1.20, and the correction index correlated
poorly with the initial magnitude of cylinder. A direct numerical relationship
between SIA and the initial magnitude of cylinder was observed, although a
standard surgical procedure was used in all cases.A simple standardized technique
using paired arcuate incisions in the graft-host junction with paired
augmentation sutures reduces the amount of cylinder in proportion to the
magnitude of the preoperative cylinder and effectively reduces post-PKP
astigmatism.
PMID- 10771230
TI - Intraocular lens movement and accommodation in eyes of young patients.
AB - PURPOSE: To evaluate the position of posterior chamber intraocular lenses (PC
IOLs) at distance and near and the amplitude of pseudoaccommodation in young
eyes. SETTING: Department of Ophthalmology, University School of Medical
Sciences, Bydgoszcz, Poland. METHODS: This study comprised 45 eyes of 38 patients
aged 12 to 19 years who had removal of congenital cataract with implantation of a
PC IOL. During the follow-up, the refractive error ranged between -1.00 and +1.00
diopter (D), and near visual acuity was 0.75 or 0.50 (Snellen) without additional
correction. The position of the PC IOL was measured by A-mode ultrasound at
distance and near. Pseudoaccommodation amplitude was calculated using
Gullstrand's near-point rule. RESULTS: Mean anterior movement of the IOL was 0.42
mm at near. Mean pseudoaccommodation amplitude was 4.50 D. The correlation
between these values was significant (P <.01). CONCLUSION: The movement of PC
IOLs in young patients may be one reason they attain good near vision without
additional correction.
PMID- 10771231
TI - Two year results: sharp versus rounded optic edges on silicone lenses.
AB - To evaluate the role of optic edge design of 2 silicone intraocular lenses (IOLs)
in 2 year clinical results. Department of Ophthalmology, University of Vienna,
Medical School, Allgemeines Krankenhaus, Austria. In this comparative clinical
study, 50 eyes had phacoemulsification and implantation of a high-refractive 3
piece silicone IOL with sharp optic edges (CeeOn model 911F) (n = 25) or a 3
piece silicone lens with rounded optic edges (CeeOn model 920) (n = 25).
Biomicroscopic findings, including those of specular microscopic examination of
the anterior lens surface, were documented and the results analyzed. After 2
years, a significant between-group difference in posterior capsule opacification
(PCO) but not in anterior capsule alterations was observed. Behind all CeeOn 911F
sharp-edge IOLs, the capsule remained clear; in 2 of 23 capsules behind the CeeOn
920 rounded-edge, a neodymium: YAG laser capsulotomy had to be performed for
dense central fibrotic PCO. Seven of 21 of the remaining eyes had first-degree
central fibrotic PCO, 14 of 23 had peripheral mixed fibrotic and slender Elschnig
pearl PCO, and 8 of 23 had second-degree peripheral PCO. Specular microscopic
findings did not differ between the 2 groups. No severe IOL decentration occurred
in any eye; 25% in the sharp-edge group and 40% in the rounded-edge group had
minimal decentration. The silicone IOL with the sharp optic edge design was
associated with significantly reduced PCO 2 years postoperatively.
PMID- 10771232
TI - Optical and atomic force microscopy of an explanted AcrySof intraocular lens with
glistenings.
AB - PURPOSE: To assess the surface morphology and cause of glistenings in an
explanted AcrySof intraocular lens (IOL). SETTING: Shakai Hoken Kobe Central
Hospital, Kobe, Japan. METHODS: A 63-year-old Japanese man had implantation of an
AcrySof IOL in the capsular bag. One month postoperatively, he had a
neodymium:YAG laser capsulotomy for posterior capsule opacification, which
changed the IOL's position in the capsular bag. A few months later, the patient
developed disabling night glare from intralenticular glistenings and progressive
hyperopic refractive error. The IOL was explanted and then analyzed by optical
microscopy and atomic force microscopy (AFM). Laboratory analysis of control
AcrySof IOLs kept in a balanced salt solution at steady room and body temperature
for 2 months was also performed to evaluate the cause of the glistenings observed
clinically. RESULTS: Optical microscopy showed that the explanted AcrySof IOL had
several microvacuoles; no abnormalities were observed in the control AcrySof IOLs
before or after folding at the room and body temperatures. The AFM analysis
showed a significant change in the surface morphology of the explanted IOL,
including vacuolar formations in the posterior surface as well as numerous
anterior surface irregularities. No microvacuoles or surface morphology
alterations were observed in the control AcrySof IOLs by AFM analysis.
CONCLUSIONS: The glistenings in the explanted AcrySof IOL were likely caused by
temperature changes and not mechanical stress from folding.
PMID- 10771233
TI - Visual outcome with the array multifocal intraocular lens in patients with
concurrent eye disease.
AB - PURPOSE: To evaluate whether the distance visual outcome with the Array(R)
multifocal intraocular lens (IOL) is comparable to that of a monofocal IOL in
eyes with concurrent disease and to assess whether these eyes benefit from the
IOL's multifocality. SETTING: Department of Ophthalmology, Arrowe Park Hospital,
Wirral, United Kingdom. METHODS: This prospective study comprised 133 eyes of 111
patients with cataract and concurrent disease such as macular degeneration,
glaucoma, and diabetic retinopathy. Eighty-one eyes (70 patients) received an
Array multifocal IOL after phacoemulsification. A control group of 52 eyes (41
patients) received a monofocal IOL of similar design (AMO SI-40NB). Visual
outcomes in terms of uncorrected and best corrected distance and near acuities
were evaluated. RESULTS: In both the multifocal and the monofocal IOL groups, the
number of eyes achieving a best corrected visual acuity of 6/12 and N8 or better
(55 and 37 eyes, respectively) was comparable (P > or =.999; 95% confidence
interval [CI] -0.152 to 0.172). There was a borderline statistically significant
difference in the number of eyes achieving an uncorrected visual acuity of 6/12
or better and N8 or better in the multifocal IOL (11 eyes) and monofocal (2 eyes)
groups (P =.047, 95% CI -0.001 to 0.196). A significantly higher number of eyes
in the multifocal group (40 eyes) than in the monofocal IOL group (4 eyes)
achieved a distance-corrected acuity of 6/12 and N8 or better (P =.0001; 95% CI
0.274 to 0.539). CONCLUSIONS: The Array multifocal IOL produced distance visual
outcomes comparable to those of the AMO SI-40NB monofocal IOL in patients with
concurrent eye disease. A significant proportion of these patients benefited from
the IOL's multifocality. Management of associated eye disease was not compromised
by the nature of the IOL.
PMID- 10771234
TI - Decentration and tilt: silicone multifocal versus acrylic soft intraocular
lenses.
AB - PURPOSE: To compare differences in decentration and tilt between a silicone
multifocal and an acrylic intraocular lens (IOL) by evaluating postoperative
changes. SETTING: Department of Ophthalmology, College of Medicine, The Catholic
University of Korea, Seoul, Korea. METHODS: Forty eyes of 20 patients with IOL
implantation were randomized into 2 groups according to IOL type: 3-piece
silicone multifocal IOL or 3-piece acrylic IOL. All lenses were implanted in the
capsular bag through a clear corneal incision after continuous curvilinear
capsulorhexis and phacoemulsification. The amount of the decentration and the
degree of the tilt of each IOL were measured using the EAS-1000 anterior eye
segment analysis system 1 day and 1 and 2 months after surgery. RESULTS: No
significant difference in decentration and tilt was found among the 3 follow-ups
or between lens types. CONCLUSION: Neither IOL decentration nor tilt showed
significant progression up to 2 months in eyes with a silicone multifocal or
acrylic IOL when the IOLs were placed properly in the capsular bag. The amount of
decentration and tilt was similar between lens types.
PMID- 10771235
TI - Decentration, tilt, and near vision of the array multifocal intraocular lens.
AB - PURPOSE: To study the periodic changes in decentration, tilt, and near vision in
eyes with the Array(R) multifocal intraocular lens (IOL). SETTING: Department of
Ophthalmology, St. Mary's Hospital, College of Medicine, The Catholic University
of Korea, Seoul, Korea. METHOD: This study comprised 20 eyes of 10 patients older
than 60 years who had binocular cataract and bilateral implantation of the Array
multifocal IOL. Mean patient age was 66.0 years (range 60 to 75 years). After a
clear corneal incision and continuous curvilinear capsulorhexis were made, each
eye had phacoemulsification and in-the-bag IOL implantation. The amount of IOL
decentration and degree of tilt were evaluated using the EAS-1000 anterior eye
segment analysis system 1 day and 1 and 2 months postoperatively. Near and far
visual acuities were measured at the same examinations. RESULTS: No statistically
significant differences were observed in decentration (P =.13) or tilt (P =.32)
throughout the follow-up. Mean uncorrected distance visual acuity was 0.68 +/-
0.27 (SD), and mean uncorrected near acuity was 0.49 +/- 0.15 2 months
postoperatively. Uncorrected distance acuity better than 0.5 was achieved in 14
eyes (77.8%), in which the mean uncorrected distance acuity was 0.80 +/- 0.18 and
the mean uncorrected near acuity was 0. 53 +/- 0.14 2 months postoperatively.
CONCLUSIONS: Tilt and decentration of the Array multifocal IOL showed no
significant progression up to 2 months after implantation. For near acuity, the
Array IOL may be an effective aid.
PMID- 10771236
TI - Long-term follow-up of leiske closed-loop anterior chamber intraocular lenses.
AB - PURPOSE: To provide long-term follow-up on the rates of endothelial cell loss in
eyes with retained closed-loop anterior chamber intraocular lenses (IOLs).
SETTING: Private practices, Chicago, Illinois, USA. METHODS: In 1980 to 1982, 3
surgeons performed 587 intracapsular cataract extractions with implantation of
Leiske closed-loop anterior chamber IOLs. During the prospective part of the
study from 1991 to 1996, 59 patients with 83 eligible eyes were followed using
specular microscopy and pachymetry. The mean follow-up of the prospective study
was 41.9 months, or 12.9 years from the original cataract surgery. RESULTS: No
specific preoperative or postoperative factor except the behavior of the fellow
eye (P =.022) predicted the rate of endothelial cell loss. During the prospective
study, 6 patients required IOL exchange and corneal transplantation. The rate of
corneal decompensation was heavily dependent on the initial measurement of
endothelial cell density. Corneas with initial endothelial cell counts greater
than 1000 cells/mm(2) had a decompensation rate of 1.5%, and corneas with counts
of 500 cells/mm(2) or less had a decompensation rate of 57.1% (P <.01).
CONCLUSIONS: Clinical examination and serial measurements of endothelial cell
density provide the most reliable methods for monitoring patients with closed
loop anterior chamber IOLs. Endothelial cell counts can predict the rate of
corneal decompensation. Patients with endothelial cell counts greater than 1000
cells/mm(2) usually do not require an IOL exchange.
PMID- 10771237
TI - Neodymium:YAG laser posterior capsulotomies performed by residents at a Veterans
Administration Hospital.
AB - PURPOSE: To assess the initial efficacy of neodymium:YAG (Nd:YAG) laser posterior
capsulotomies performed by residents at a teaching institution and to evaluate
the associated complications over an extended follow-up. SETTING: Department of
Ophthalmology, Edward Hines, Jr. Veterans Administration Hospital, Hines,
Illinois, USA. METHODS: This retrospective noncomparative case review comprised
212 pseudophakic eyes having Nd:YAG laser posterior capsulotomies from April 1992
through March 1995. Evaluated were postoperative changes in best corrected visual
acuity (BCVA), intraocular pressure (IOP) elevations, and complications related
to the procedure. RESULTS: In all 212 eyes, Snellen visual acuity was obtained at
least 1 week after the capsulotomy. The BCVA in 96 eyes (45.3%) improved by 3 or
more lines, in 43 (20.3%) by 2 lines, and in 51 (24.1%) by 1 line. Nineteen eyes
(9.0%) did not improve by 1 or more lines, and 3 eyes (1.4%) had decreased
Snellen acuity. All but 4 eyes with less than 1 line of improvement had
underlying ocular pathology or a previous incomplete capsulotomy. For evaluation
of postoperative complications, long-term follow-up was available for 133 of 212
eyes (62.7%). The mean follow-up for this group was 3.18 years. Postoperative
complications were found in 14 of these eyes (10.5%). Nine (6.8%) had a rise in
IOP greater than 10 mm Hg after the capsulotomy. One eye (0.8%) developed a
persistent iritis, 2 (1.5%) had vitreous prolapse into the anterior chamber, and
2 (1.5%) developed rhegmatogenous retinal detachments. CONCLUSION: Postoperative
Snellen acuity results and complication rates compare favorably with those in
previous studies. The results indicate that Nd:YAG laser posterior capsulotomies
performed by residents with attending supervision are safe, effective, and carry
a low associated complication rate over a long follow-up.
PMID- 10771238
TI - Hearing loss and phacoemulsification.
AB - PURPOSE: To determine the acoustic spectra of currently used phacoemulsification
units and to contrast phacoemulsification-generated acoustic spectra with
representative audiograms of common types of sensorineural hearing loss. SETTING:
Mayo Clinic, Rochester, Minnesota, USA. METHODS: The acoustic spectra of 3
phacoemulsification systems (Alcon Series 20,000 Legacy, Storz Millennium, and
AMO Diplomax) were recorded in an acoustically soundproofed room using a Roland
VS-880 Digital Studio Workstation and analyzed with a Hewlett-Packard 35660A
Dynamic Signal Analyzer. RESULTS: Phacoemulsification handpiece-generated
harmonic overtones produced during ultrasound mode (6.0, 12.0, and 18.8 kHz for
the 20,000 Legacy and Diplomax; 7.0 and 14.2 kHz for the Millennium) were outside
the range of minimal decibel loss in individuals with hearing loss. Supplemental,
low-frequency, console-generated tones produced during ultrasound mode (0.4 to
2.0 kHz for the Diplomax; 0. 1 to 1.5 kHz for the Millennium) were within the
range of minimal decibel loss in individuals with hearing loss. CONCLUSION:
Phacoemulsification systems with console-generated, low-frequency tones were
audible to ophthalmologists with common types of sensorineural hearing loss.
PMID- 10771239
TI - Scleral fixation of a capsular tension ring for severe ectopia lentis.
AB - A 4-year-old boy with bilateral idiopathic and progressive ectopia lentis had
phacoaspiration of the lens and capsular tension ring (CTR) insertion in his left
eye. Postoperatively, lens capsule centration remained poor. Single-point scleral
fixation of the CTR was performed and centration of the lens capsule achieved. In
the-capsule intraocular lens (IOL) implantation was tried, but excessive IOL
manipulation sliced open the capsule at the equator. Anterior vitrectomy and
scleral IOL fixation were required. A similar approach was adopted in the right
eye with meticulous attention given to gentle maneuvers. The operation was
uneventful, with good IOL centration. Three and 11 months after surgery in the
right and left eye, respectively, best corrected visual acuity was 20/50 in both
eyes. Scleral fixation of the CTR, accompanied by gentle IOL manipulation, is an
option to improve IOL centration in patients with severe zonular deficiency.
PMID- 10771240
TI - Fungal keratitis after laser in situ keratomileusis.
AB - A 22-year-old woman presented with pain, redness, watering, and decrease in
vision in her left eye 15 days after laser in situ keratomileusis for myopia.
Slitlamp examination showed a central full-thickness infiltrate with hyphate
edges. Microscopic examination of corneal scrapings from the edge and underneath
the flap showed fungal filaments, and the growth on culture media was identified
as Scedosporium apiospermum.
PMID- 10771241
TI - Phototherapeutic keratectomy for superficial corneal fibrosis after radial
keratotomy.
AB - We report on 4 patients who developed superficial corneal fibrosis after radial
keratotomy. All 4 were treated successfully with manual debridement of the
epithelium and manual excision of the fibrous scar, followed by phototherapeutic
keratectomy.
PMID- 10771242
TI - Acute angle-closure glaucoma after hyperopic laser in situ keratomileusis.
AB - We report a case of acute angle-closure glaucoma 1 year after hyperopic laser in
situ keratomileusis (LASIK). The glaucoma was resolved with laser iridotomy, and
a prophylactic iridotomy was performed in the fellow eye. Corneal topography was
performed 2, 5, and 18 weeks after the acute episode. A myopic shift occurred
after the episode and resolved within 3 months. Hyperopic patients with narrow
angles are at risk for angle closure and should be carefully monitored.
PMID- 10771243
TI - An evaluation of the management of epilepsy by primary health care nurses in
Chitungwiza, Zimbabwe.
AB - In order to design an effective training program for nurses on the management of
epilepsy in Zimbabwe, the drug management of epilepsy by community health nurses
without prior training in epilepsy management was evaluated. Epilepsy patients in
Chitungwiza, a high-density suburb of Harare, were routinely managed at four
health clinics run by nurses. The patients also attended a monthly epilepsy
support group (ESG) program, which provided them with vocational and social
rehabilitative support. Neurologists evaluated the drug therapy of all patients
attending this support group program over a 2-year period. The specialist
interventions required to drug therapy in patients with inadequate seizure
control or drug side effects were noted. A total of 114 epilepsy patients (age
range 8-56 years, M:F=1:1.2) were seen, of these 84.2% had generalized seizures,
40.3% of patients had been seizure-free for at least 6 months, 71.9% of patients
were on phenobarbitone, while 59.6% were on monotherapy. No drug intervention was
required to on-going drug therapy in 43% of patient consultations. The most
important intervention in patients with inadequate seizure control was an
increase in drug dose, required in 29% of consultations. Of serum drug level
estimations in clinically indicated cases, 58% were below the therapeutic ranges.
This tendency to sub-therapeutic dosing with AED amongst nurses implied that a
written AED drug therapy protocol specifying optimal maintenance doses and dose
increment schedules may be beneficial to the community-based nursing management
of epilepsy.
PMID- 10771244
TI - Proconvulsant effect of aminophylline on cortical epileptic afterdischarges
varies during ontogeny.
AB - Effect of aminophylline on epileptic afterdischarges (ADs) induced repeatedly by
rhythmic electrical stimulation of sensorimotor cortical area was studied in rat
pups 12, 18 and 25 days old. The proconvulsant effect of aminophylline (50 and/or
100 mg/kg i.p.) was more expressed in 12- and 18-day-old rats than in the oldest
group. In 12-day-old rat pups there was an enormous increase of transition of the
spike-and-wave type of ADs into the second, limbic type, a situation observed
only exceptionally under control conditions. A prolongation of ADs was related to
this transition (limbic ADs are always longer than spike-and-wave ones). Eighteen
day-old rats exhibit this transition less frequently but a marked prolongation of
spike-and-wave ADs was recorded in a part of these animals forming a pattern of
status lasting some tens of minutes. Aminophylline led only to a transient
prolongation of spike-and-wave ADs in the oldest group. The transition into the
limbic type of ADs was seen in this age group only exceptionally what is in
contrast to age-matched controls in which this transition is common. The effect
of aminophylline on cortical ADs which is most marked in the youngest group
changes qualitatively during postnatal development.
PMID- 10771245
TI - Dorsal hippocampal kindling produces long-lasting changes in the origin of
spontaneous discharges in the piriform versus perirhinal cortex in vitro.
AB - In an in vitro slice preparation of the amygdala-piriform-perirhinal cortex (A-P
area), it was shown previously (McIntyre, D.C., Plant, J. R., 1993. Long-lasting
changes in the origin of spontaneous discharges from amygdala-kindled rats:
piriform vs. perirhinal cortex in vitro, Brain Res. 624, 268-276) that the
infrequent spontaneous field potentials that initially originated in or near the
perirhinal (PRh) cortex of slices from control rats began instead in the piriform
(Pir) cortex of amygdala-kindled rats. This change in onset was only observed in
the A-P area ipsilateral to the kindled amygdala. In the present experiment, we
determined whether similar changes in activity were evident following kindling
from a different limbic site, the dorsal hippocampus (DH). Kindling of the DH
resulted in changes in the origin of the spontaneous discharges in the A-P area
similar to amygdala kindling but, importantly, the changes involved both
hemispheres. In addition, the origin of spontaneous discharges in slices from
partial kindled rats (those that received as many hippocampal afterdischarges as
the fully kindled rats but had not developed generalized convulsive responses)
initially were similar to control tissue, but, during 0 Mg(2+) perfusion, changed
more quickly than control tissue to mimic the profile of generalized kindled
rats. The enduring changes in A-P area excitability caused by previous
generalized kindling highlights the importance of the A-P area in convulsive
generalization of limbic-kindled seizures.
PMID- 10771246
TI - Sequential changes in glutamate transporter protein levels during Fe(3+)-induced
epileptogenesis.
AB - Severe head injury in humans causes recurrent seizures; this form of epilepsy
appears to correlate with occurrence of parenchymal hemorrhage. Injection of
ferric cations, one component of hemoglobin, into rat amygdala, causes lipid
peroxidation, and recurrent spontaneous seizures. We wondered whether regulation
of extracellular glutamate might be perturbed as a mechanism of chronic
epileptogenesis, therefore levels of glutamate transporter proteins GLT-1, GLAST
and EAAC-1 were measured in ipsilateral and contralateral hippocampi removed from
rats having spontaneous iron-induced limbic seizures. The neuronal transporter
EAAC-1 was elevated bilaterally up to 30 days following the microinjection that
initiated seizures. The neuronal transporter EAAC-1 was elevated bilaterally up
to 30 days following the microinjection that initiated seizures. The glial
transporter GLT-1 increased 5 and 15 days after iron injection on the side
contralateral to the injection then returned to basal levels 30 days after the
lesion. GLAST also showed an initial increase but at 15 and 30 days after
injection, when experimental animals were experiencing spontaneous limbic
behavioral seizures, this protein was down-regulated. The results suggest that
iron-induced epileptogenesis involves alteration in glial glutamate transport
that may lead to enhanced excitation within the hippocampus.
PMID- 10771247
TI - Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats.
AB - We have previously shown that subgroups can be selected from large groups of
amygdala kindled Wistar rats which either respond consistently or do not respond
to the anticonvulsant effect of phenytoin. Phenytoin nonresponders were proposed
as a model for pharmaco-resistant temporal lobe epilepsy. In the present study we
examined whether the differences of individual rats in response to phenytoin are
already present before kindling or are a consequence of kindling. For this
purpose, 52 rats were once tested with phenytoin, then kindled, and then
repeatedly tested with phenytoin for selection of subgroups. For subgroup
selection after kindling, the phenytoin prodrug fosphenytoin was used because of
its water solubility and its improved tolerability and absorption after i.p.
administration in rats. Before kindling, phenytoin significantly increased the
afterdischarge threshold (ADT), i.e. a sensitive measure of focal seizure
activity, but there was large individual variation with only 32 of the 52 rats
reacting with an ADT increase, while the remaining rats showed either no effect
or ADT decreases. After kindling, the selection resulted in 16 rats with
consistent ADT increases in response to phenytoin and ten nonresponders (the
remaining 26 rats showed variable responses). Unexpectedly, in rats which were
responders after kindling, phenytoin exerted no significant anticonvulsant effect
before kindling, while kindled nonresponders were very sensitive to phenytoin
before kindling, indicating that the kindling process was responsible for the
loss of anticonvulsant efficacy in kindled nonresponders and the development of
phenytoin's efficacy in kindled responders. The present results substantiate that
kindled subgroups of Wistar rats with different response to phenytoin are a
valuable source for studying the mechanisms underlying the development of
pharmaco-resistant limbic seizures.
PMID- 10771248
TI - Antiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in
rats.
AB - Nefiracetam is being studied as a novel cognition-enhancing agent; however, it
has been suggested from studying its chemical structure that it has a potential
anticonvulsive effect. We examined the antiepileptic effect of nefiracetam on
kainic acid (KA)-induced seizures. KA was infused into the left basolateral
amygdaloid nucleus and focal limbic seizures were induced in 43 male Wistar rats.
During status epilepticus, 10, 50, 100 or 200 mg/kg of nefiracetam was
intravenously injected. Nefiracetam inhibited KA-induced limbic seizures at doses
over 100 mg/kg while it had a sedative effect on the animals. In (14C)
deoxyglucose autoradiographic studies, the propagation of seizure-induced
hypermetabolic areas was also suppressed dose-dependently. From the results, it
was indicated that nefiracetam has an antiepileptic effect and that its
application may suppress seizure propagation. Further study is required, whether
this agent is available as a novel anticonvulsant.
PMID- 10771249
TI - Changes in synaptosomal ectonucleotidase activities in two rat models of temporal
lobe epilepsy.
AB - Adenosine has been proposed as an endogenous anticonvulsant which can play an
important role in seizure initiation, propagation and arrest. Besides the release
of adenosine per se, the ectonucleotidase pathway is an important metabolic
source of extracellular adenosine. Here we evaluated ATP diphosphohydrolase and
5'-nucleotidase activities in synaptosomes from hippocampus and cerebral cortex
at different periods after induction of status epilepticus (SE) by
intraperitoneal administration of pilocarpine or kainate. Ectonucleotidase
activities from synaptosomes of hippocampus and cerebral cortex of rats were
significantly increased at 48-52 h, 7-9 days and 45-50 days after induction of SE
by pilocarpine. In relation to kainate model, both hippocampal enzymes were
enhanced at 7-9 days and 45-50 days, but only 5'-nucleotidase remained elevated
at 100-110 days after the treatment. In cerebral cortex, an increase in ATP
diphosphohydrolase was observed at 48-52 h, 7-9 days and 45-50 days after
induction of SE by kainate. However, 5'-nucleotidase activity only presented
significant changes at 45-50 and 100-110 days. Our results suggest that SE can
induce late and prolonged changes in ectonucleotidases activities. The regulation
of the ectonucleotidase pathway may play a modulatory role during the evolution
of behavioral and pathophysiological changes related to temporal lobe epilepsy.
PMID- 10771250
TI - The wada test: prediction of focus lateralization by asymmetric and symmetric
recall.
AB - PURPOSE: The intracarotid amytal test is commonly used as a predictor of memory
dysfunctioning after anterior temporal lobe resection (ATL) for intractable
epilepsy. Asymmetry in memory scores can provide focus lateralizing information.
In this study the predictive value of a set of Wada test parameters was analyzed,
including patients with symmetrical memory scores. METHODS: The Wada test was
carried out in 226 patients undergoing ATL (94 L, 132 R). Data were collected on
item recognition (five items), story recall, amytal dose, presentation time, EEG
and arterial filling of amytal. A logistic regression analysis was performed on
these data in order to find a set of variables which could best predict the side
of seizure onset. RESULTS: The analysis yielded four variables, i.e. both memory
scores, story recall after right-sided injection and presentation time of stimuli
after left-sided injection which could correctly predict seizure lateralization
in 85% of the cases. Misclassification was lower for right foci than for left
foci. Seizure outcome was four times more favourable in the correctly classified
patients. CONCLUSIONS: The results suggest that prediction of focus
lateralization in temporal lobe epilepsy can be fairly exact even if left/right
memory scores are equal. Performing the Wada test with only five memory items
keeps the time window of active amytal short enough and gives accurate
information about contralateral temporal lobe functioning. The classification
scheme can be useful in predicting a lowered chance of seizure freedom.
PMID- 10771251
TI - Audiogenic kindling in the Wistar rat: a potential model for recruitment of
limbic structures.
AB - Repetitive high intensity (110 dB) sound stimulation induces a forebrain-kindling
phenomenon in animals predisposed to sound induced seizures. Wistar audiogenic
rats (WARs) have been reported to develop a mixed brainstem-limbic seizure
pattern, after more than five to ten stimuli. Besides the original brainstem wild
running and tonic-clonic seizures, new behavioral patterns appear resembling
those of electrical amygdala kindling. Although audiogenic kindling is a well
known phenomenon, electrographic limbic recruitment during the kindling has never
been reported. Our objective was to use electrophysiology to test the hypothesis
of gradual and sequential involvement of the amygdala and then cortex during
audiogenic kindling. We used video-EEG recordings with cortical and deep
electrode implants (inferior colliculus and basolateral amygdaloid nuclei) during
audiogenic kindling on eight WARs, and their respective controls, submitted to a
protocol of three acoustic stimuli per day. A new design for 'on site' source
follower circuits was used in order to minimize noise during the recording of EEG
data from the wild running episode and the subsequent tonic-clonic or motor
limbic seizures. The video-EEG equipment assembled allowed synchronous recordings
of both behavior and EEG. WARs first recordings showed electrodecremental
responses after seizure onset and a probable epileptiform activity, particularly
in the inferior colliculus, during the tonic phase of seizure. All animals showed
very similar polyspike-wave activity in the amygdala, after behavioral seizure
patterns (Racine's scale) occurred. The morphology of such epileptiform EEG
activity is very similar to that reported for electrical amygdala kindling. Also,
when audiogenic kindling continued, both inferior colliculus and cortical
electrodes presented high amplitude and synchronized epileptiform polyspike
activity.
PMID- 10771252
TI - Interhemispheric threshold differences in idiopathic generalized epilepsies with
versive or circling seizures determined with focal magnetic transcranial
stimulation.
AB - The interhemispheric difference of the motor-cortical threshold (IDMT) was
studied with focal magnetic transcranial stimulation (TCS) in ten patients with
idiopathic generalized epilepsy (IGE) who also displayed versive or circling
seizures (IGEvc). The data were compared with those obtained from two control
groups; 13 patients with IGE without asymmetrical motor seizures, and 25 normal
volunteer subjects. The IDMT, referred to as the percentage of maximum stimulator
output, was assessed by focal TCS applied to the hand areas. Seven patients with
IGEvc and only one patient with IGE had an interhemispheric motor threshold
beyond the normal range. The IDMT in IGEvc patients was significantly higher
compared to that of IGE patients and normal individuals. An interhemispheric
imbalance of cortical excitability may explain lateralized ictal motor
manifestations in patients with IGEvc.
PMID- 10771253
TI - Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving
antiepileptic drug monotherapy.
AB - We hypothesized that elevated plasma homocysteine concentrations
(hyperhomocysteinemia) exist in patients receiving antiepileptic drugs (AED), and
a long-term administration of AED may result in an increased risk of occlusive
vascular disease in these patients. A total of 62 patients who received AED
monotherapy (phenytoin, lamotrigine, carbamazepine or valproate) participated in
this study. Blood concentrations of homocysteine, folate, vitamin B-12 and
pyridoxal-5'-phosphate (PLP, a coenzyme form of vitamin B-6) were measured, and
thermolabile genotypes of 5, 10-methylenetetrahydrofolate reductase (MTHFR) were
also determined. Of 62 patients, only seven (11.4%) had hyperhomocysteinemia. Of
20 patients who received phenytoin, three (15.0%) had hyperhomocysteinemia,
whereas 85% of these had plasma folate concentrations below the normal range.
However, erythrocyte folate concentrations were abnormally low in only 25% of the
patients who received phenytoin. Valproate administration increased serum vitamin
B-12 concentrations. Over 55% of the entire patients had PLP concentrations below
the normal range, although the reason is unknown. Only three patients had the
homozygous thermolabile genotype of MTHFR; therefore, meaningful statistical
analysis was not possible in this study. However, one patient with homozygous
genotype who received phenytoin therapy had hyperhomocysteinemia with poor folate
nutritional status, and the other two had normal homocysteine concentrations with
normal folate status. Our data suggest that hyperhomocysteinemia is not a serious
clinical concern in epileptic patients when folate nutriture is adequate.
PMID- 10771254
TI - Does cardiac conduction pathology contribute to sudden unexpected death in
epilepsy?
AB - Heart weights have been reported to be increased in those dying suddenly and
unexpectedly from epilepsy (SUDEP) and it has been suggested that cardiac
pathology including cardiac conduction pathology and coronary artery atheroma may
contribute to SUDEP. The purpose of this study was to perform a detailed
controlled study of the microscopic pathology of the cardiac conduction system in
SUDEP cases, in addition to assessing coronary artery atheroma and other cardiac
pathology. The hearts of ten SUDEPs and ten control subjects (no history of
epilepsy and a cause of death not primarily cardiac) were examined
macroscopically and microscopically by two pathologists blinded to the patient
group. Morphological abnormalities of the cardiac conduction system that could
have possibly contributed to death were not increased in the SUDEP group (four
cases showed such changes in the SUDEP group vs. six in the control). There was
no significant difference between the maximal percentage coronary artery stenoses
between the two groups and no increased prevalence of other cardiac pathology in
the SUDEP group. However, since subtle abnormalities of the conduction system
were identified in some of the epileptic deaths, it is still feasible that these
may contribute to death by causing cardiac arrhythmia, when associated with
apnoea, bradycardia or other cardiac arrhythmia related to an epileptic seizure.
PMID- 10771255
TI - Subcutaneous microdialysis in rats correlates with carbamazepine concentrations
in plasma and brain.
AB - Microdialysis simplifies the measurement of pharmacokinetics in
pharmacodynamically relevant tissues. Microdialysis permits serial measurements
of unbound drug concentration. The objective of the present work was to study
rats to correlate plasma carbamazepine pharmacokinetics with subcutaneous and
brain tissues. Microdialysis probes were inserted into the jugular vein, the
brain, and subcutaneous tissue in Sprague-Dawley rats. After receiving single
doses of carbamazepine, 12 mg/kg i.p., pharmacokinetic sampling occurred
simultaneously from three microdialysis sites. Microdialysis sampled unbound
carbamazepine and carbamazepine-10, 11-epoxide concentrations. Concentrations
measured in brain, subcutaneous, and plasma correlated with each other. Except
where differences were anticipated, pharmacokinetic parameters, including half
life and time to maximum concentration, were the same regardless of measurement
site. The present study suggests microdialysis may allow pharmacokinetic
measurements in peripheral physiological spaces that are surrogates for the
pharmacologically relevant tissue.
PMID- 10771256
TI - Superoxide dismutase and glutathione peroxidase function in progressive myoclonus
epilepsies.
AB - Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to
most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous
neurological deterioration. Oxidative stress is thought to be an important factor
in this process. We therefore analyzed a series of antioxidant enzymes in the
blood of patients and compared with healthy age matched controls. In addition
patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor
to determine if symptoms of EPM would improve. Five patients, four with EPM 1
(Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease)
were treated with 6 g/day of NAC. Before treatment, plasma samples were analyzed
for glutathione peroxidase activity, catalase activity, extracellular superoxide
dismutase (SOD) and CuZn-SOD and compared with the controls. Erythrocyte CuZn-SOD
was significantly lower in the EPM patients compared to controls. NAC improved
markedly and stabilized the neurological symptoms in patients with EPM 1 but had
a doubtful effect in the patient with EPM 2.
PMID- 10771257
TI - Pharmacokinetic-pharmacodynamic correlation of lamotrigine, flunarizine,
loreclezole, CGP40116 and CGP39551 in the cortical stimulation model.
AB - The purpose of this study was to assess the concentration-anti-convulsant effect
relationships of a number of anti-convulsant drugs in the direct cortical
stimulation model, to obtain more insight in the properties and predictive value
of this model. The time course of the effect of lamotrigine, loreclezole,
flunarizine, CGP40116 and CGP39551 was determined after iv. administration in
conjunction with their pharmacokinetics. Convulsive activity was induced by
stimulation of the motor cortex with a ramp-shaped pulse train. This technique
allows consecutive measurements of the treshold for localized (TLS) and for
generalized (TGS) seizure activity. Increase in threshold was used as measure of
the anti-convulsant effect. After administration of lamotrigine, pronounced
elevation of the TGS, with little change in the TLS, was observed. Flunarizine
caused a similar effect, but much less intense. Loreclezole strongly elevated the
TGS and to a lesser extent the TLS, also. The concentration-anti-convulsant
effect relationship of the three compounds could be fitted by an exponential
model. The NMDA antagonists, CGP40116 and CGP39551, induced minor changes in the
TLS and a slight increase in the TGS. The onset of this effect was marked by a
delay relative to blood concentrations. The biophase equilibration kinetics was
estimated and a linear model was applied to describe the concentration-effect
relationship of both NMDA antagonists. The present results show that the cortical
stimulation model is a suitable technique for integrated pharmacokinetic
pharmacodynamic modelling and for assessing anti-convulsant efficacy. The results
show that the model is rather insensitive to calcium channel blockers and NMDA
antagonists.
PMID- 10771258
TI - Decreased cerebral blood flow during seizures with ictal SPECT injections.
AB - Increased regional cerebral blood flow (rCBF) at the epileptogenic site has been
consistently reported for single photon emission computed tomography (SPECT)
injections made during seizure activity, and the increased rCBF has been shown to
remain elevated at the epileptogenic site in some cases, even when SPECT
injections are made after seizure termination (postictal). A sustained increase
in rCBF after seizure cessation was recently confirmed, but for no more than 100
s from seizure onset [Avery, R.A., Spencer, S.S., Spanaki, M.V., Corsi, M.,
Seibyl, J.P., Zubal, I.G., 1999. Effect of injection time on postictal SPET
perfusion changes in medically refractory epilepsy. Eur. J. Nucl. Med. 26, 830
836]. In the current study, it is examined whether ictal SPECT injections
demonstrate a similar change in rCBF around 100 s from seizure onset. Twenty-one
patients with medically refractory epilepsy and a known area of seizure onset
receiving ictal and interictal 99mTc-Hexamethyl-propyleneamineoxime (HMPAO) SPECT
scans were studied. The results of SPECT subtraction analysis which visualize
increased and decreased rCBF were compared to seizure duration and HMPAO
injection time. Five patients received ictal SPECT injections (during ongoing
seizure activity) more than 90 s after seizure onset and demonstrated decreased
rCBF. Two of these patients also demonstrated areas of increased rCBF. Decreased
rCBF was localized to the epileptogenic lobe in four of the five patients. By
examining ictal SPECT injections made 90 s after seizure onset, evidence was
found that reduced rCBF may exist during ictus. The change in rCBF around 90 s is
also observed in postictal injections, suggesting a common metabolic mechanism
may be responsible.
PMID- 10771259
TI - Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant
kindled rats.
AB - We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AEDs)
gabapentin and levetiracetam in amygdala kindled rats that had been preselected
with respect to their response to phenytoin. Anticonvulsant response was tested
by determining the afterdischarge threshold (ADT), i.e. a sensitive measure for
drug effects on focal seizure activity. By repeated testing with the phenytoin
prodrug fosphenytoin, three groups of kindled rats were separated: rats in which
consistent anticonvulsant effects were obtained (phenytoin responders), rats
which showed no anticonvulsant response (phenytoin nonresponders), and rats with
variable responses (variable phenytoin responders). The latter, largest group was
used to evaluate at which doses gabapentin and levetiracetam exerted significant
anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses
were then used for drug testing in phenytoin responders and nonresponders. Both
gabapentin and levetiracetam proved to be effective anticonvulsant drugs in the
kindling model by significantly increasing the ADT. In addition, both drugs
markedly decreased seizure severity recorded at ADT currents, indicating that
these drugs affect seizure threshold in the epileptic focus and seizure spread
from the focus in the kindling model. When the threshold for secondary
generalized seizures (GST) was determined in addition to ADT, gabapentin and
levetiracetam strikingly increased this threshold compared to predrug control. In
phenytoin nonresponders, gabapentin and levetiracetam significantly increased ADT
and GST, which is in line with their proven efficacy in patients with refractory
partial epilepsy in whom older AEDs have failed. In phenytoin responders,
gabapentin tended to be more efficacious in increasing ADT and GST than in
nonresponders, substantiating that the difference between these groups of kindled
rats extends to other AEDs. In contrast to gabapentin, levetiracetam was more
efficacious in increasing ADT in nonresponders than in responders. The data of
this study substantiate that phenytoin nonresponders are a unique model for the
search of new AEDs with improved efficacy in refractory partial epilepsy.
PMID- 10771260
TI - Correlation between cerebral perfusion and hyperventilation enhanced focal
spiking activity.
AB - Single photon emission computed tomography (SPECT) has frequently been used to
investigate cerebral brain perfusion (CBP) occurring ictally and inter-ictally in
epileptic patients. Several studies have addressed the multimodal analysis of the
modifications occurring in cerebral areas involved in seizure activity, by
correlating SPECT with electroencephalografic (EEG) recordings during ictal and
inter-ictal epileptiform lateralized discharges (IELDs). Although these studies
have yielded interesting results, variations in regional CBP (rCBP) observed
during ictal events are difficult to interpret since the areas of altered rCBP
might reflect not only events restricted to the epileptogenic focus, but also
large fluctuations determined by seizure spread. Inter-ictal rCBP correlates with
the area generating the local EEG epileptogenic activity in a limited percentage
of studies. Hyperventilation (HPV) represents a well established EEG activation
procedure aimed at enhancing epileptiform discharges. Since HPV-enhanced IELDs
may help analyze the CBP pathophysiology in inter-ictal epilepsy, in the present
study we investigate this specific aspect co-registering EEG with SPECT in
subjects affected by partial epilepsy responding to HPV with IELD enhancement
without seizure precipitation. This study suggests a correlation between
localized increase in rCBP and HPV-induced IELDs and provides a tool to discuss
uncommon aspects of the physiology of rCBP during the inter-ictal state in the
epileptogenic areas.
PMID- 10771266
TI - Cytogenetic evaluation of aquatic genotoxicity in human cultured lymphocytes.
AB - This paper presents the results of a cytogenetic study to evaluate the quality of
Cai river water at the area under the influence of the Petrochemical Complex of
the State of Rio Grande do Sul. Cytokinesis-block micronucleus assay (CBMN) was
performed on cultured human lymphocytes exposed to stream water samples. The Cai
River is an important tributary to the Guaiba basin that includes Porto Alegre,
the capital of Rio Grande do Sul. The Cai river water is the source of drinking
water after conventional treatment, and is also used for irrigation and primary
contact recreation according to Federal regulations. Water samples were collected
in the Cai River and some tributaries at four sites for 20 months with a
bimonthly frequency, in a total of 11 samplings, from November 1993 to July 1995.
It was possible to detect the presence of substances with clastogenic and/or
aneugenic potential in vitro human lymphocytes at the different sites analyzed.
As to the four sites studied, site B presents nearly half of the total positive
results (44%), followed by sites A (28%), D (17%) and C (11%). The CBMN assay in
human lymphocytes was a sensitive cytogenetic approach for aquatic environmental
studies, and should be better exploited to monitor industrial areas.
PMID- 10771267
TI - Statistical modeling and analyses of a base-specific Salmonella mutagenicity
assay.
AB - Statistical features of a base-specific Salmonella mutagenicity assay are
considered in detail, following up on a previous report comparing responses of
base-specific Salmonella (Ames II) strains with those of traditional tester
strains. In addition to using different Salmonella strains, the new procedure
also differs in that it is performed as a microwell fluctuation test, as opposed
to the standard plate or preincubation test. This report describes the
statistical modeling of data obtained from the use of these new strains in the
microwell test procedure. We emphasize how to assess any significant interactions
between replicate cultures and exposure doses, and how to identify a significant
increase in the mutagenic response to a series of concentrations of a test
substance.
PMID- 10771268
TI - Comparing the genotoxic sensitivities of human peripheral blood lymphocytes and
mucosa cells of the upper aerodigestive tract using the Comet assay.
AB - Carcinogenesis in the upper aerodigestive tract is influenced by multiple
factors. Besides tobacco and alcohol consumption, specific pollutants such as
phthalates, nitrosamines, and polycyclic aromatic carbohydrates may be important
in tumor initiation. Genetic factors related to mutagen sensitivity and DNA
repair capacity also play a role. The aim of this study was to investigate
whether human peripheral blood lymphocytes and mucosal epithelium of the upper
aerodigestive tract, the target for volatile and liquid xenobiotics, are equally
sensitive to genotoxic agents. The Comet assay was used to detect for DNA damage
induced by genotoxic agents in mucosal epithelial cells and peripheral blood
lymphocytes of 60 volunteers. Mucosa was harvested from larynx, oropharynx, and
inferior nasal turbinates. Xenobiotics investigated were dibutylphthalate (DBP),
diisobutylphthalate (DiBP), N'-nitrosodiethylamine (NDELA), benzo[a]pyrene
(B[a]P), and N'-methyl-N'-nitro-N-nitrosoguanidine (MNNG). DBP, DiBP, B[a]P,
NDELA and MNNG induced a significant increase in DNA migration in both cell
populations. Peripheral blood lymphocytes were more sensitive than mucosal cells
to DBP and DiBP, but not to NDELA and B[a]P. The correlation, in terms of DNA
migration, between lymphocytes and mucosal cells among volunteers was relatively
poor. Based on the poor correlation in response between the two cell types, the
sensitivity of peripheral blood lymphocytes to genotoxic agents appears to be a
poor predictor of sensitivity in the target cells of the upper aerodigestive
tract. Further attention should be focused on intra-individual mutagen
sensitivities and inter-individual genetic differences as regards susceptibility
to upper aerodigestive tract cancer.
PMID- 10771269
TI - Evaluation of micronucleated lymphocytes, constitutional karyotypes and anti-p53
antibodies in 21 children with various malignancies.
AB - The implication of environmental carcinogens in childhood cancer is still
unknown. To assess a possible link between DNA damage and alterations of the
tumor suppressor gene p53, blood samples of 21 children with malignancies were
examined for the presence of micronuclei in lymphocytes using the cytokinesis
blocked micronucleus assay (CBMA). The constitutional karyotypes were analyzed
for chromosome abnormalities and the presence of anti-p53 antibodies in blood
sera was evaluated by an enzyme-linked immuno sorbent assay (ELISA). A control
group of 20 children was also included. The rates of micronucleated cells were
5.1 per thousand+/-3.9 and 2.4 per thousand+/-2.3 for the cancer and control
groups, respectively. The difference between the groups were statistically
significant (P<0.05 by the Mann-Withney rank sum test). Two children in the
cancer group showed extensive chromosome breakage in lymphocytes. The sera of two
other children from the cancer group and of one child from the control group
contained anti-p53 antibodies. Chromosome breakage and anti-p53 antibodies from
the five children were associated with increased micronucleated cell rates. The
results of the present study suggest that genotoxic events can occur in the
lymphocytes of children with a cancerous state.
PMID- 10771270
TI - Mutagenicity of 80 chemicals in Escherichia coli tester strains IC203, deficient
in OxyR, and its oxyR(+) parent WP2 uvrA/pKM101: detection of 31 oxidative
mutagens.
AB - Strain IC203, deficient in OxyR, and its oxyR(+) parent WP2 uvrA/pKM101 (denoted
IC188) are the basis of a new bacterial reversion assay, the WP2 Mutoxitest,
which has been used in the evaluation of 80 chemicals for oxidative mutagenicity.
The following 31 oxidative mutagens were recognized by their greater mutagenic
response in IC203 than in IC188: (1) peroxides: hydrogen peroxide (HP), t-butyl
hydroperoxide (BOOH) and cumene hydroperoxide (COOH); (2) benzoquinones (BQ): 2
methyl-1,4-BQ, 2,6-dimethyl-1,4-BQ and 2,3, 5,6-tetramethyl-1,4-BQ; (3)
naphthoquinones (NQ): 1,4-NQ, 2-methyl-1, 4-NQ and 2-hydroxy-1,4-NQ; (4) phenol
derivatives: catechol, hydroquinone, pyrogallol, 1,2,4-benzenetriol, t
butylhydroquinone, gallic acid and 4-aminophenol; (5) catecholamines: DL- and L
dopa, DL- and L-epinephrine, dopamine and L-norepinephrine; (6) thiols: L
cysteine methyl ester, L-cysteine ethyl ester, L-penicillamine and
dithiothreitol; (7) diverse: 3,4-dihydroxyphenylacetic acid, hypoxanthine and
xanthine, both in the presence of xanthine oxidase, L-ascorbic acid plus copper
(II) and phenazine methosulfate. Among these oxidative mutagens, 25 were found to
be uniquely positive in IC203. With the exception of BOOH and COOH, mutagenesis
by all oxidative mutagens was inhibited by catalase present in rat liver S9,
indicating that it is mediated by HP generation, probably in autoxidation
reactions. These catalase-sensitive oxidative mutagens were poor inducers of
mutations derived from 8-oxoguanine lesions, whereas such mutations were
efficiently induced by organic hydroperoxides. The results support the usefulness
of incorporating IC203 in the bacterial battery for testing of chemicals. The
well-characterized oxidative mutagens available with the use of the WP2
Mutoxitest may serve as a reference in studies on the genotoxicity of oxidative
stress.
PMID- 10771271
TI - From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents
on the mutagenic activity of 4-nitrobiphenyl in Salmonella typhimurium. Part I.
Substituents ortho to the nitro group and in 2'-position.
AB - Eleven alkyl substituted derivatives of 4-nitrobiphenyl (4NBp) and two
corresponding nitroso compounds were synthesised and tested for mutagenic potency
in strains TA98 and TA100 of Salmonella typhimurium. The mutagenicity of
compounds substituted ortho to the nitro group (3-methyl-, 3-ethyl-, 3-isopropyl
, 3-tertbutyl-, 3, 5-diethyl-, 3,5-diisopropyl-, and 3,5-ditertbutyl-4NBp)
decreased with growing steric demand of the alkyl substituents in both tester
strains. The most sterically hindered compounds were non-mutagenic even at
highest concentrations. This reduction of mutagenicity is correlated with
deviations from the coplanar orientation of the nitro group relative to the
aromatic plane. Since a comparable decrease of mutagenicity for the nitroso
compounds (4NOBp and 3-tertbutyl-4NOBp) was not observed, the first reduction
step of non-planar nitro groups must be inhibited. Alkyl groups in the 2'
position of 4NBp (2'-methyl-, 2'-ethyl-, 2'-isopropyl-, and 2',4', 6'-trimethyl
4NBp) also reduced mutagenic activity with increasing size and removed it
completely for the most sterically hindered species (2'-isopropyl-, 2',4',6'
trimethyl-4NBp). In this case, the co-planarity of the nitro group is not
affected but the twisting of the two aromatic rings, which is associated with a
less effective charge delocalisation of the nitrenium ion. The experimental
mutagenicities of all nitro compounds were compared to predicted values, that are
based on recently developed empirical equations. While there was reasonable
correspondence for the parent compound (4NBp), its ortho methylated derivative (3
methyl-4NBp) and two highly hydrophobic dialkylated species (3,5-diisopropyl- and
3, 5-ditertbutyl-4NBp), predictions for all other alkyl substituted compounds
were too high. Thus, steric parameters should be included to improve the general
validity of predictions by means of quantitative structure-activity relationships
(QSAR).
PMID- 10771272
TI - From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents
on the mutagenic activity of nitroaromatics in Salmonella typhimurium. Part II.
Substituents far away from the nitro group.
AB - Derivatives of 4-nitrobiphenyl, 4-nitrosobiphenyl, 2-phenyl-5-nitropyridine (2
aza-4-nitrobiphenyl) and 2-nitrofluorene, bearing various alkyl substituents far
away from the nitro group (4'-position in nitrobiphenyls, 7-position in 2
nitrofluorenes) were synthesised and tested for mutagenic potency in strains TA98
and TA100 of Salmonella typhimurium. In the absence of S9 in both strains,
mutagenicity of all4'-Ad (Ad=adamantyl). Changes of the molecular shape from
'planar' to non-planar caused by the bulk of the introduced substituents (without
influencing the twisting of the nitro substituent or the phenyl rings in the
biphenyl compounds) may be responsible for this effect by interfering with an
efficient intercalation into DNA.A comparison between experimental and
theoretical values as calculated from recently developed equations (QSAR)
confirmed our previous results (see the preceding paper) that mutagenicity of
alkyl-substituted nitroaromatics cannot be predicted by hydrophobicity and LUMO
energies alone without including steric parameters.
PMID- 10771273
TI - The alkaline single cell electrophoresis assay with eight mouse organs: results
with 22 mono-functional alkylating agents (including 9 dialkyl N-nitrosoamines)
and 10 DNA crosslinkers.
AB - The genotoxicity of 22 mono-functional alkylating agents (including 9 dialkyl N
nitrosoamines) and 10 DNA crosslinkers selected from IARC (International Agency
for Research on Cancer) groups 1, 2A, and 2B was evaluated in eight mouse organs
with the alkaline single cell gel electrophoresis (SCGE) (comet) assay. Groups of
four mice were treated once intraperitoneally at the dose at which micronucleus
tests had been conducted, and the stomach, colon, liver, kidney, bladder, lung,
brain, and bone marrow were sampled 3, 8, and/or 24 h later. All chemicals were
positive in the SCGE assay in at least one organ. Of the 22 mono-functional
alkylating agents, over 50% were positive in all organs except the brain and bone
marrow. The two subsets of mono-functional alkylating agents differed in their
bone marrow genotoxicity: only 1 of the 9 dialkyl N-nitrosoamines was positive in
bone marrow as opposed to 8 of the 13 other alkylating agents, reflecting the
fact that dialkyl N-nitrosoamines are poor micronucleus inducers in hematopoietic
cells. The two groups of mono-functional alkylating agents also differ in hepatic
carcinogenicity in spite of the fact that they are similar in hepatic
genotoxicity. While dialkyl N-nitrosoamines produce tumors primarily in mouse
liver, only one (styrene-7,8-oxide) out of 10 of the other type of mono
functional alkylating agents is a mouse hepatic carcinogen. Taking into
consideration our previous results showing high concordance between hepatic
genotoxicity and carcinogenicity for aromatic amines and azo compounds, a
possible explanation for the discrepancy might be that chemicals that require
metabolic activation show high concordance between genotoxicity and
carcinogenicity in the liver. A high percent of the 10 DNA crosslinkers were
positive in the SCGE assay in the gastrointestinal mucosa, but less than 50% were
positive in the liver and lung. In this study, we allowed 10 min alkali-unwinding
to obtain low and stable control values. Considering that DNA crosslinking
lesions can be detected as lowering of not only positive but also negative
control values, low control values by short alkali-treatment might make it
difficult to detect DNA crosslinking lesions. In conclusion, although both mono
functional alkylating agents and DNA crosslinkers are genotoxic in mouse multiple
organs, the genotoxicity of DNA crosslinkers can be detected in the
gastrointestinal organs even though they were given intraperitoneally followed by
the short alkali-treatment.
PMID- 10771274
TI - Spontaneous micronuclei in peripheral blood erythrocytes from 54 animal species
(mammals, reptiles and birds): part two.
AB - The normal numbers of micronucleated erythrocytes (MNE) observed in peripheral
blood samples differ among species. This depends on the effectiveness of the
spleen (or the rest of the reticuloendothelial system) to withdraw them from
circulation. In our previous report, we assessed the number of MNE in the
peripheral blood of 35 mammalian species. Here we show the results observed in 54
species including mammals, reptiles and birds. We obtained 212 peripheral blood
samples from different species. In 14 species, only one individual was studied.
Slides were stained with acridine orange. The total number of MNE (normo and
polychromatic) in 10,000 erythrocytes per animal are shown. The species that
display the higher MNE were: ocelote, lynx, owl, gray squirrel, hedgehog, lion,
orange fronted parakeet and common barn owl. For this reason, these species could
be tested as monitors for genotoxic events. Another interesting observation was
that in the gray squirrel, we found the highest values of MNE in the smaller
(younger) animals when compared with the larger (older) of the same species.
PMID- 10771275
TI - Syntactic structure assembly in human parsing: a computational model based on
competitive inhibition and a lexicalist grammar.
AB - We present the design, implementation and simulation results of a
psycholinguistic model of human syntactic processing that meets major empirical
criteria. The parser operates in conjunction with a lexicalist grammar and is
driven by syntactic information associated with heads of phrases. The dynamics of
the model are based on competition by lateral inhibition ('competitive
inhibition'). Input words activate lexical frames (i.e. elementary trees anchored
to input words) in the mental lexicon, and a network of candidate 'unification
links' is set up between frame nodes. These links represent tentative attachments
that are graded rather than all-or-none. Candidate links that, due to grammatical
or 'treehood' constraints, are incompatible, compete for inclusion in the final
syntactic tree by sending each other inhibitory signals that reduce the
competitor's attachment strength. The outcome of these local and simultaneous
competitions is controlled by dynamic parameters, in particular by the Entry
Activation and the Activation Decay rate of syntactic nodes, and by the Strength
and Strength Build-up rate of Unification links. In case of a successful parse, a
single syntactic tree is returned that covers the whole input string and consists
of lexical frames connected by winning Unification links. Simulations are
reported of a significant range of psycholinguistic parsing phenomena in both
normal and aphasic speakers of English: (i) various effects of linguistic
complexity (single versus double, center versus right-hand self-embeddings of
relative clauses; the difference between relative clauses with subject and object
extraction; the contrast between a complement clause embedded within a relative
clause versus a relative clause embedded within a complement clause); (ii)
effects of local and global ambiguity, and of word-class and syntactic ambiguity
(including recency and length effects); (iii) certain difficulty-of-reanalysis
effects (contrasts between local ambiguities that are easy to resolve versus ones
that lead to serious garden-path effects); (iv) effects of agrammatism on parsing
performance, in particular the performance of various groups of aphasic patients
on several sentence types.
PMID- 10771276
TI - Perceptions of proportionality in young children: matching spatial ratios.
AB - Three experiments examined the ability of young children (4- and 5-year-olds) and
adults to identify correspondences in spatial ratios. In all three experiments,
children as young as 4 and 5 years of age made accurate spatial proportionality
judgments. Moreover, their judgments were no less accurate when both response
alternatives differed in spatial configuration from the sample than when all the
configurations were alike, indicating that those judgments were based on
relational information and not on the exact form of the stimuli. The findings,
which suggest that the concept of ratio may have important foundations in the
ways young children perceive relations within and between objects, have
implications for theories of mathematical development and for methods of
mathematics instruction.
PMID- 10771277
TI - Syntactic co-ordination in dialogue.
AB - There is substantial evidence that speakers co-ordinate their contributions in
dialogue. Until now, experimental studies of co-ordination have concentrated on
the development of shared strategies for reference. We present an experiment that
employed a novel confederate-scripting technique to investigate whether speakers
also co-ordinate syntactic structure in dialogue. Pairs of speakers took it in
turns to describe pictures to each other. One speaker was a confederate of the
experimenter and produced scripted descriptions that systematically varied in
syntactic structure. The syntactic structure of the confederate's description
affected the syntactic structure of the other speaker's subsequent description.
We suggest that these effects are instances of syntactic priming (Bock, 1986),
and provide evidence for a shared level of representation in comprehension and
production. We describe how these effects might be realized in a processing model
of language production, and relate them to previous findings of linguistic co
ordination in dialogue.
PMID- 10771278
TI - Word order priming in written and spoken sentence production.
AB - An experiment is reported that showed priming of the word order of auxiliary verb
and past participle in Dutch subordinate clauses, both in speaking and in
writing. Participants completed sentence fragments to full sentences. Prime
sentence fragments were constrained so as to be completed with only one possible
word order. Target sentence fragments, presented immediately after the prime
fragments, could be completed with the same word order as that of the prime and
an alternative order with the two words exchanged. Significant priming effects
were obtained, so that the same word orders tended to be used in prime and
target. We interpret this as evidence for a distinct process of constituent
structure linearization during sentence production, which serves to ensure the
fluency of speech and writing.
PMID- 10771279
TI - Long live Proust: the odour-cued autobiographical memory bump.
AB - The autobiographical memory bump is an increase in the frequency of reported
autobiographical memories (AMs) from a particular age range, and has been
reported by numerous investigators (for reviews, see Conway, M. A. & Rubin, D. C.
(1993). The structure of autobiographical memory. In A. F. Collins, S. E.
Gathercole, M. A. Conway & P. E. Morris, Theories of memory. Hove: Lawrence
Erlbaum; Rubin, D. C., Rahhal, T. A. & Poon, L. W. (1998). Things learned in
early adulthood are remembered best. Memory and Cognition, 26, 3-19) to occur in
the second and third decades of life. Invariably, word labels have been used as
AM cues but, given that a popular interpretation of the anecdotal 'Proust
phenomenon' is that odours evoke AMs which are especially aged, we wondered if a
different pattern in the AM bump might emerge if AMs were cued by odours rather
than labels. Here we report an attempt to substantiate this aspect of the 'Proust
phenomenon' by comparing the distributions of memories across the lifespan when
cued by odour and label. Data showed that, in line with previous studies, the
bump for label cues was found to peak between ages 11 and 25 years and was
confirmed to be quadratic in form. In contrast, the odour-cued memory
distribution peaked at 6-10 years and decreased linearly thereafter. In the
earliest age interval, 6-10 years, the proportion of AMs retrieved in response to
odour cues was significantly greater than that for the label cues. These results
provide empirical support for the Proust phenomenon, and have more general
implications for the structure and age distribution of stored AMs.
PMID- 10771280
TI - The semantic interference effect in the picture-word interference paradigm: does
the response set matter?
AB - In three picture-word interference experiments we explore some properties of the
semantic interference (SI) effect in the picture-word interference paradigm. In
Experiments 1 and 2, we test whether SI may be obtained when the distractor words
are not part of the response set and when only one picture per semantic category
is included in the experiment. In Experiment 3, we explore if the magnitude of
the SI effect depends on whether or not the distractor words are part of the
response set. Reliable SI effects were obtained in all three experiments and the
magnitude of the effect did not vary as a function of whether or not distractor
words are part of the response set. These results are problematic for the
selection mechanism in the WEAVER++ lexical access model (Levelt, W. J. M.,
Roelofs, A., & Meyer, A. S. (1999). A theory of lexical access in speech
production. Behavioral and Brain Sciences. 22, 1-75; Roelofs, A. (1992). A
spreading-activation theory of lemma retrieval in speaking. Cognition, 42, 107
142).
PMID- 10771281
TI - Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the
insecticide ivermectin.
AB - In the present study, the activation of rat recombinant alpha(1)beta(2)gamma(2S)
gamma-aminobutyric acid (GABA)-ergic Cl(-) channel expressed in human embryonic
kidney (HEK) 293 cells by ivermectin was investigated. Maximal activation of the
channel occurred with GABA concentrations of 10 mM or 20 microM ivermectin both
achieving about the same current amplitudes. With those saturating
concentrations, the currents rose with GABA within 1 ms to the maximal values,
whereas the rise time for ivermectin was about 500 times longer. In contrast to
activation with GABA, no desensitisation in the presence of the agonist was
observed with ivermectin. With both agonists, two different open states were
detected. On simultaneous application of GABA and ivermectin the current
amplitudes and the kinetics were determined by the agonist applied in the
concentration eliciting the higher open probability. It is concluded that GABA
and ivermectin activated the channel independently resulting in different kinetic
properties.
PMID- 10771282
TI - Properties of Ca(2+) release-activated Ca(2+) channel block by 5-nitro-2-(3
phenylpropylamino)-benzoic acid in Jurkat cells.
AB - Ca(2+) release-activated Ca(2+) current (I(crac)) has been previously
characterized biophysically in Jurkat lymphocytes and other non-excitable cells,
but pharmacology remains poorly developed. The present objective was to delineate
with whole cell recording details of the interaction of the chloride channel
blocker, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), with I(crac) in
Jurkat cells. NPPB reversibly inhibited I(crac) in a concentration-dependent
manner (IC(50)=5 microM). Kinetics for block and unblock of I(crac) by NPPB
indicated a bimolecular interaction. Michaelis-Menten analysis indicated that
NPPB interacts competitively with extracellular Ca(2+) permeating the I(crac)
pathway. Finally, analysis of the pH dependence of I(crac) block by NPPB revealed
a reduction in the apparent affinity during extracellular alkalinization that
based on the pK(a) for NPPB, suggested that the neutral form of NPPB blocks the
Ca(2+) release-activated Ca(2+) (CRAC) channel. Taken together, our results
suggest a direct interaction between NPPB and the CRAC channel, and should help
guide insights for developing novel and more selective analogues.
PMID- 10771283
TI - Involvement of protein kinase C in taxol-induced polyploidization in a cultured
sarcoma cell line.
AB - Taxol was found to inhibit the proliferation and to induce the polyploidization
of cultured methylcholanthrene-induced sarcoma cells (Meth-A cells). To
investigate whether protein kinase C is involved in taxol-induced
polyploidization, phorbol 12-myristate 13-acetate (PMA), which regulates the
activity of protein kinase C, was used along with taxol to treat the cells. We
found that PMA did not interfere with the proliferation and did not induce
polyploidization by itself. However, at low concentration, taxol, which by itself
did not induce polyploidization, clearly induced polyploidization in the presence
of PMA. To explore the mechanism by which PMA potentiates polyploidization, the
levels of the G1 checkpoint-related proteins cyclin E and cdk2, and those of the
G2 checkpoint-related proteins cyclin B and cdc2 were determined by flow
cytometry. We found that both G1 and G2 checkpoint-related proteins increased
during the induction of polyploidization. To verify the relationship between
protein kinase C and tubulin polymerization, flow cytometry was used to determine
the total content of tubulin protein, and morphological observation was used to
examine spindle organization. PMA did not affect the taxol-induced increase in
tubulin protein, but markedly potentiated taxol-induced spindle disorganization.
These findings suggest that protein kinase C plays an important role in
regulating the induction of polyploidization in Meth-A cells.
PMID- 10771284
TI - Zn(2+) enhancement of the recombinant 5-HT(3) receptor is modulated by divalent
cations.
AB - The modulation by Zn(2+) of recombinant murine 5-hydroxytryptamine(3A) (5-HT(3A))
receptor responses and its modification by Ca(2+) or Mg(2+) were studied using
whole-cell voltage clamp and radioligand binding techniques. In the absence of
other added divalent cations Zn(2+) enhanced the response to 5-HT by increasing
maximum peak current (I(max)) to a maximum of 122.5%, decreasing the rate of
desensitization (maximum t(1/2)=210%), and decreasing the EC(50) by approximately
two fold. In the presence of Ca(2+) or Mg(2+), the effects of Zn(2+) on I(max)
and t(1/2) were still manifest, although higher Zn(2+) concentrations were
required; however, the effect on EC(50) was abolished. Zn(2+) also enhanced
[3H]agonist but not [3H]antagonist binding. We propose there is more than one
Zn(2+) binding site on the 5-HT(3) receptor molecule, and that one or more of
these sites may also bind Ca(2+) and Mg(2+).
PMID- 10771285
TI - Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes
P450 to human drug metabolism.
AB - Three inhibitory monoclonal antibodies specific to cytochrome P450 3A4/5
(CYP3A4/5), CYP2C8/9/19 and CYP2E1, respectively, were used to assess the
contribution of the P450s to the metabolism of seven substrates in liver
microsomes from 18 human donors, as measured by monoclonal antibody inhibition
phenotyping of the substrate conversion to product(s). Metabolism of seven
substrates by recombinant cytochromes P450 and human liver microsomes was
performed in the presence of monoclonal antibodies and their metabolites were
analyzed by high-performance liquid chromatography (HPLC) or gas chromatography
mass spectrophotometry (GC-MS) to measure the magnitude of inhibition. Our
results showed that CYP3A4/5 contributes to testosterone 6beta-hydroxylation,
taxol phenol formation, diazepam 3-hydroxylation, diazepam N-demethylation, and
aflatoxin B1 3-hydroxylation in human liver by 79.2%, 81.5%, 73. 2%, 34.5% and
80%, respectively. CYP2E1 contributes to chlorzoxazone 6-hydroxylation, p
nitroanisole O-demethylation, and toluene hydroxylation by 45.8%, 27.7% and 44.2%
respectively, and CYP2C8/9/19 contribute to diazepam N-demethylation by 30.6%.
The additive contribution (75.3%) of human CYP3A and CYP2C to diazepam N
demethylation was also observed in the presence of both anti-CYP3A4/5 and anti
CYP2C8/9/19 monoclonal antibodies. The contribution of individual P450s to the
specific metabolic reaction in human liver varies greatly in the individual
donors and the substrates examined. Thus, inhibitory monoclonal antibodies could
play a unique role in defining the single or subfamily of cytochrome P450 that is
responsible for the metabolism of specific drugs.
PMID- 10771286
TI - [3H]ifenprodil binding to NMDA receptors in porcine hippocampal brain membranes.
AB - (+/-)-2-(4-Benzylpiperidino)-1-(4-hydroxyphenyl)propan-1-ol ([3H]ifenprodil)
binding to a subcellular fraction of porcine hippocampus, which was obtained by
centrifugation on a discontinuous sucrose gradient, was investigated with the
objective to label selectively the ifenprodil recognition site of native NMDA
receptors. Saturation experiments revealed high-affinity sites for [3H]ifenprodil
in this membrane fraction which could be characterised by a K(d) value of 23.0+/
1.8 nM using a one-site model. Calculation of saturation isotherms on the basis
of a two-site model yielded a K(d1) value of 10.4+/-2.4 nM and a K(d2) value of
2200+/-1300 nM, respectively. Inhibition of [3H]ifenprodil binding by NR2B
subunit-selective NMDA receptor antagonists, by polyamines, by sigma receptor
ligands, by a variety of ligands acting at different NMDA receptor recognition
sites and by several cations was studied and compared with the effects of these
compounds on (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10
imine ([3H]MK-801) binding under non-equilibrium conditions. It turned out that
sigma receptor ligands such as 1, 3-di(2-tolyl)-guanidine (DTG), (+)-3-(3
hydroxyphenyl)-N-propylpiperidine (R)-3-PPP, (S)-3-PPP and (1-?2-[bis(4
fluorophenyl)methoxy]ethyl?)(-4-[3-phenylpropyl]piperazi ne) (GBR-12909) did not
affect [3H]ifenprodil binding in the nanomolar range or only slightly. In
contrast, ifenprodil, eliprodil, nylidrin and haloperidol inhibited
[3H]ifenprodil binding in the nanomolar range and in the same rank order and with
the same potency as observed for the inhibition of the high-affinity fraction of
[3H]MK-801 binding. The polyamines, which activate NMDA receptors, inhibited
[3H]ifenprodil binding in a biphasic manner. Their potency to inhibit the high
affinity fraction of [3H]ifenprodil binding was found to be in the same range as
their potency to enhance [3H]MK-801 binding. In the presence of 10 microM
spermine a significantly enhanced (P=0.0097) rate of dissociation of
[3H]ifenprodil binding was found, suggesting that inhibition of [3H]ifenprodil
binding by spermine is not, or at least not exclusively mediated by a competitive
interaction.
PMID- 10771287
TI - Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary
cultured neurons.
AB - The N-methyl-D-aspartate (NMDA) receptor has been implicated as a putative sight
of action for acamprosate, a novel drug that reduces craving for alcohol. The
purpose of this study was to assess the effect of acamprosate on the function of
native NMDA receptors expressed in primary cultured striatal and cerebellar
granule cells, as well as ethanol inhibition and spermine modulation of these
receptors, using whole-cell patch-clamp electrophysiological techniques. Under
all circumstances, acamprosate (0.1-300 microM) did not alter NMDA- or glutamate
induced currents. Acamprosate did not alter the inhibitory effects of ethanol (10
100 mM) on receptor function. In a subpopulation of striatal neurons, acamprosate
did reverse the potentiating effects of spermine. These findings indicate that
although acamprosate may modify polyamine modulation of the NMDA receptor,
acamprosate alone does not alter receptor function nor does it modify ethanol
inhibition of this receptor expressed in primary cultured striatal and cerebellar
granule neurons.
PMID- 10771288
TI - Effect of zaldaride maleate, an antidiarrheal compound, on intracellular cyclic
nucleotide-mediated intestinal ion secretion in rats.
AB - The purpose of this study is to clarify the mechanisms of action of zaldaride, a
calmodulin inhibitor. 16,16-Dimethyl prostaglandin E(2), forskolin, 8-bromo cAMP,
nitroprusside, 8-bromo cGMP and Escherichia coli heat-stable enterotoxin STa
increased the short-circuit current in rat colonic mucosa. Zaldaride at >/=10
microM significantly attenuated the 16,16-dimethyl prostaglandin E(2) and
Escherichia coli heat-stable enterotoxin STa-induced increase in short-circuit
current; whereas it did not affect other secretagogues-induced effects. These
results suggest that zaldaride inhibits the activation of Ca(2+)/calmodulin
sensitive adenylate cyclase or guanylate cyclase linked to a receptor.
PMID- 10771289
TI - Long-term abecarnil administration produces tolerance and withdrawal signs in the
rat.
AB - Abecarnil is a non-benzodiazepine that possesses anxiolytic and anticonvulsant
properties. Conflicting reports of tolerance and withdrawal signs following
chronic abecarnil administration have emerged from animal studies using different
species and different models of tolerance and dependence. This study used a
radiotelemetric method to examine any emergence of tolerance and abstinence signs
in the rat following long-term abecarnil administration. Hooded Wistar rats, n=6
per group, were administered either abecarnil (8 mg/kg/bidaily, i.p.) or vehicle
for 24 days. Locomotor activity, body temperature and electromyographic (EMG)
activity were measured daily immediately following abecarnil administration.
Tolerance to the abecarnil-induced muscle relaxant effects and decreased
locomotor activity developed within 21 days. Administration of the benzodiazepine
antagonist flumazenil (25 mg/kg), 18 h after abecarnil cessation, precipitated
abstinence signs that included decreases in body temperature, and large increases
in locomotor activity and muscle tone. Moreover, continuous recording of these
measures over the 4 days after flumazenil administration indicated a prolonged
increase in daytime locomotor activity, suggestive of spontaneous withdrawal.
These data support earlier findings that reported signs of tolerance during
administration of abecarnil and abstinence signs following abecarnil cessation.
PMID- 10771290
TI - In vivo characterization of novel full and partial 2-(4-aminophenyl)-N,N
dipropylethylamine dopamine D(2) receptor agonists.
AB - Behavioral and biochemical techniques were used to compare the in vivo intrinsic
efficacy of two new 2-(4-aminophenyl)-N, N-dipropylethylamine dopamine D(2)
receptor agonists, 2-(4-amino-3-trifluoromethylphenyl)-N-N-dipropyl-ethylamine
(NBF-203) and 2-(4-amino-3-bromo-5-trifluoromethylphenyl)-N-N-dipropylethylamine
(NBF-234). Adult male Sprague-Dawley rats were used as experimental animals. NBF
203 was characterized as a full dopamine D(2) receptor agonist, whereas NBF-234
displayed properties of a partial agonist, or antagonist, at dopamine D(2)
receptors. Thus, NBF-203 produced effects similar to those of apomorphine in
models for dopamine synthesis, release and turnover. As a strong indication of
markedly less intrinsic efficacy, the administration of NBF-234 did not result in
antagonism of reserpine-induced suppression of locomotor activity in the presence
of (+/-)-1-phenyl-2,3,4,5, -tetrahydro-(1H)-3-benzazepine-7,8-diol HCl (SKF
38393)-induced dopamine D(1) receptor activation. The present series of compounds
offer the possibility of adjusting intrinsic efficacy at dopamine D(2) receptors,
and such fine-tuning could be an important strategy in the search for optimal
antipsychotic or antiparkinson drugs within the partial dopamine D(2) receptor
agonist concept.
PMID- 10771292
TI - Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in
the basolateral amygdala.
AB - Repeated administration of the GABA(A) receptor antagonist bicuculline methiodide
into the basolateral nucleus of the amygdala at doses subthreshold to eliciting a
full response will eventually produce long-term 'priming', such that heart rate,
blood pressure as well as anxiety are increased at the lower doses. The present
study was conducted in order to determine if the long-term priming of anxiety
within the basolateral nucleus is producing a condition similar to that seen in
human panic disorder by testing the response elicited by i.v. lactate infusions,
since lactate infusions induce a panic attack in patients with panic disorder.
Male Wistar rats were fitted with femoral arterial and venous catheters and
chronic microinjection cannulae into the basolateral nucleus. Repeated daily
injections of a subthreshold dose of bicuculline methiodide into the basolateral
nucleus for 4-5 days elicited a primed response, while the same procedure with
artificial cerebrospinal fluid vehicle (a-CSF; sham-primed) had no effect.
Following priming, rats received both sodium lactate infusions (0.5 N, 10 ml/kg)
or 0.9% saline in a random order separated by 48 h. Heart rate and blood pressure
were monitored throughout the infusion and the animals were immediately placed in
the social interaction test to assess their anxiety response. Only primed and not
sham-primed rats responded to a lactate infusion with significant increases in
heart rate, blood pressure and experimental anxiety. Thus, rats which are primed
with chronic subthreshold GABA receptor blockade in the basolateral nucleus
develop a sensitivity to sodium lactate, similar to human panic disorder
patients.
PMID- 10771291
TI - Thiophene analogs of naphthoxazines and 2-aminotetralins: bioisosteres with
improved relative oral bioavailability, as compared to 5-OH-DPAT.
AB - In the present study, a series of thiophene analogs of 2-aminotetralins and
hexahydronaphthoxazines were studied in vivo for their ability to decrease
striatal dopamine release, their effects on locomotor activity, and their
behavioral characteristics in reserpinized rats, in order to investigate whether
a thiophene moiety can act as a bioisostere for the phenol moiety. In general,
the new compounds showed lower in vivo activities than 5-hydroxy-2-(N,N,-di-n
propylamino)tetralin (5-OH-DPAT). However, the introduction of the thiophene
moiety gave a significant improvement of the relative oral bioavailability,
compared to 5-OH-DPAT. Our results suggest that the thiophene moiety can act as a
bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the
thianaphthoxazines it was not possible to discriminate between bioisosterism for
a phenyl or a phenol moiety. The tetrahydrobenzo[b]thiophenes could be used as
lead compounds for the development of novel dopamine receptor ligands with
improved relative oral bioavailability.
PMID- 10771293
TI - 7-Nitroindazole potentiates the antiseizure activity of some anticonvulsants in
DBA/2 mice.
AB - 7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor (25-200 mg
kg(-1), intraperitoneally (i.p.)) antagonized audiogenic seizures in DBA/2 mice
in a dose-dependent manner. We investigated the effects of 7-nitroindazole at a
dose of 25 mg kg(-1) i.p., which per se did not show anticonvulsant activity
against audiogenic seizures in DBA/2 mice, on the antiseizure activity of some
conventional antiepileptic drugs. 7-Nitroindazole sometimes potentiated the
anticonvulsant activity of carbamazepine, diazepam, lamotrigine, phenytoin,
phenobarbital and valproate against audiogenic seizures in DBA/2 mice. The degree
of potentiation by 7-nitroindazole was greatest for phenobarbital and diazepam,
less for valproate and least for carbamazepine, lamotrigine and phenytoin. The
increase in anticonvulsant activity was associated with a comparable increase in
motor impairment. However, the therapeutic index of combined treatment with
diazepam+7-nitroindazole, phenobarbital+7-nitroindazole or valproate+7
nitroindazole was more favourable than that of the diazepam+vehicle,
phenobarbital+vehicle or valproate+vehicle treatment. The results indicate that 7
nitroindazole is able to increase the protective activity of some conventional
antiepileptics and this effect appears not to result only from the impaired
synthesis of nitric oxide. In fact, mice receiving 7-nitroindazole (25 mg kg(-1),
i.p.) and L-arginine (30 microg/mouse, intracerebroventricularly (i.c.v.) did not
show significant changes of ED(50) values in comparison to those of related
groups of animals treated with 7-nitroindazole and anticonvulsants. 7
Nitroindazole was able to increase the brain levels of dopamine and noradrenaline
and its anticonvulsant effects and changes in catecholamine content were
antagonized by pretreatment with alpha-methyl-paratyrosine, an agent inhibiting
the synthesis of catecholamines. The fact that alpha-methyl-paratyrosine reverses
concomitantly both the increase in brain levels of dopamine and noradrenaline and
the anticonvulsant properties of 7-nitroindazole strongly suggests an important
role of catecholamines in the antiseizure activity of 7-nitroindazole. Since 7
nitroindazole did not significantly influence the total and free plasma levels of
the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions,
in terms of total or free plasma levels, are not probable. 7-Nitroindazole did
not significantly affect the hypothermic effects of the anticonvulsant compounds
studied. 7-Nitroindazole showed an additive effect when administered in
combination with some classical anticonvulsants, most notably diazepam,
phenobarbital and valproate and its activity could be, in part, due to an
increase of monoamine levels.
PMID- 10771294
TI - Naloxone potentiates anxiolytic-like actions of diazepam, pentobarbital and
meprobamate but not those of Ro19-8022 in the rat.
AB - The elevated plus-maze test was used to determine if the opiate antagonist
naloxone could potentiate the anxiolytic-like effects of the benzodiazepine
diazepam, the barbiturate pentobarbital, the propanediol carbamate meprobamate
and the partial benzodiazepine receptor agonist [R]-1-[(10-chloro-4-oxo-3-phenyl
4H-benzo[a]quinolizin-1-yl) carbonyl]-2-pyrrolidine-methanol (Ro19-8022) in the
rat. A subeffective dose of each of these compounds was combined with naloxone,
10 mg/kg. Naloxone had no effect by itself, but potentiated all drugs except Ro19
8022. The proportion of entries on the open arm increased while the total number
of arms entries was not modified. These results coincide with and extend data
previously obtained in the mouse. One possible explanation for naloxone's effect
could be that it blocks opioid inhibition of GABAergic (gamma-aminobutyric acid)
neurons thereby enhancing the effects of benzodiazepines. Another possibility is
that naloxone blocks opioid effects on adenosinergic systems.
PMID- 10771295
TI - Evaluation of endothelial free radical release by vascular tension responses in
insulin-resistant rat aorta.
AB - Mechanical responses to superoxide anion scavengers and nitric oxide (NO)
synthase inhibitors in aortic endothelial cells were compared in normal chow-fed
rats and those made insulin-resistant by feeding of fructose. Cu(2+), Zn(2+)
superoxide dismutase-induced vascular relaxation and superoxide production,
measured by the lucigenin-enhanced chemiluminescence method, were greater in
aortas from fructose-fed rats than in those from normal chow-fed rats. N(G)-nitro
L-arginine-induced contractions due to suppression of NO synthase activity were
smaller in aortas from fructose-fed rats. Vascular mechanical responses may
reflect the generation of superoxide and NO by the endothelium. Thus, isometric
tension studies may be a useful tool for evaluating the production of these
radicals in blood vessels.
PMID- 10771296
TI - Angiotensin I-converting enzyme activity and vascular sensitivity to angiotensin
I in rat injured carotid artery.
AB - We used a vasoreactivity assay to examine the functional significance of
angiotensin I-converting enzyme overexpression in smooth muscle cells after
vascular injury. Rat carotid arteries isolated at days 2 to 14 after in vivo
endothelial denudation were compared with the contralateral freshly denuded
(control) vessels. Arterial rings were constricted ex vivo with angiotensin I in
the absence or presence of the angiotensin I-converting enzyme inhibitors
captopril (300 nM and 3 microM) or perindoprilate (1 nM). Angiotensin I
converting enzyme activity was determined by cleavage of the chromogenic
substrate Hip-His-Leu. Angiotensin I-converting enzyme activity in injured
arteries was increased (2-fold) at day 7 only after vascular injury. Contractions
to angiotensin I were unaffected after injury. Inhibition by captopril and
perindoprilate of angiotensin I-induced contractions was significantly less
potent in injured arteries at day 7 as compared to control vessels. Mechanical
removal of neointimal smooth muscle cells normalized the inhibition by captopril
in injured arteries at day 7. Captopril did not affect angiotensin II-induced
contractions. Thus, upregulation of angiotensin I-converting enzyme after
arterial injury confers resistance to angiotensin I-converting enzyme inhibitors.
PMID- 10771297
TI - Endogenous renin and related short-term blood pressure variability in the
conscious rat.
AB - This study was designed to investigate, by use of spectral analysis, the blood
pressure variability changes induced in the conscious rat by activation of
plasmatic renin activity. Rats were surgically prepared with a supra-renal
catheter inserted via the left carotid artery to perform the infusions, and with
a femoral artery catheter to measure blood pressure and heart rate. Secretion of
renin was induced using beta-adrenoceptor stimulation produced by isoprenaline. A
first group (n=8) was infused with isoprenaline: 0.003, 10, 100 and 300
ng/kg/min, at a rate of 20 microl/min. A second group (n=8) was given a bolus
injection of the angiotensin AT(1) receptor antagonist, valsartan (2 mg/kg,
i.a.), prior to isoprenaline infusions. The lack of effect of infusion per se was
checked in additional animals (n=8) infused with saline only (20 microl/min).
Five other groups of animals were prepared with arterial catheters as mentioned
previously. Each group received one concentration of infused isoprenaline and
samples of blood were collected for further determinations of plasma renin
activity and catecholamine concentrations. Blood pressure recordings were
analysed using the fast Fourier transform on 2048 points time series (204.8 s).
Isoprenaline increased plasma renin activity and did not modify plasma
catecholamine concentrations. The low-frequency (0.02-0.2 Hz) component of the
systolic blood pressure variability was amplified by isoprenaline (10 ng/kg/min
isoprenaline: 4.16+/-0.62 mm Hg(2) vs. 2.90+/-0.44 mm Hg(2) for control value,
P<0.05), a concentration that did not alter either blood pressure or heart rate
levels. Isoprenaline lowered blood pressure and increased heart rate, starting at
concentrations of 100 ng/kg/min. Valsartan, whose principal effect was generation
of tachycardia (+25 bpm) modified neither blood pressure levels nor blood
pressure variability. Valsartan prevented the amplification of the low-frequency
oscillations of systolic blood pressure induced by isoprenaline (10 ng/kg/min
isoprenaline: 2.53+/-0.38 mm Hg(2) vs. 2.20+/-0.25 mm Hg(2) for control value
(valsartan, ns). We conclude that a moderate increase of plasma renin activity
enhanced systolic blood pressure variability in the low-frequency range, without
affecting blood pressure and heart rate levels.
PMID- 10771298
TI - Effects of body size and resource availability on dispersal in a native and a non
native estuarine snail.
AB - I manipulated snail densities of two coexisting species of salt marsh snail,
Cerithidea californica Haldeman (native) and Batillaria attramentaria Sowerby
(non-indigenous) to investigate how resource levels set by intraspecific
competition may influence dispersal rates. I used two distinct size classes of
the snails (mature and immature) to determine if the effects of competition on
dispersal differed between developmental stages of a consumer. Dispersal attempts
were measured within enclosure pens by counting snails climbing the sides of the
enclosure. The influence of snail density per se and resource levels (which were
set by snail densities) on dispersal rates were separated by comparing responses
of snails to density before and after resources became depleted. For large snails
of both species, dispersal increased as resource levels decreased, supporting the
hypothesis that competition influences dispersal rates. Small snails of both
species, in contrast, always dispersed at relatively higher rates than larger
individuals, but were not influenced by variation in resource levels. This result
corroborates other studies that have shown reduced competition in these species
at smaller size, and suggests that another mechanism, such as genetically coded
behavior to disperse when young, influences their behavior. Previous experiments
demonstrated Batillaria's superior resource conversion efficiency; therefore, I
had hypothesized that for any given resource level, Cerithidea would disperse
more, because it was more affected by resource availability. Adult Batillaria,
however, responded more sensitively to resource levels (i.e., dispersed more at
any given resource level) than Cerithidea. This counter-intuitive result
illustrates the potential importance of genetic limitations on behavioral
responses available to a species. Constraints on behavioral responses may have
been accentuated since Batillaria is a non-indigenous species whose evolved
behavioral responses are not necessarily adapted to its present, non-native
environment.
PMID- 10771299
TI - Delayed meiosis and polar body release in eggs of triploid Pacific oysters,
Crassostrea gigas, in relation to tetraploid production.
AB - The dynamics of polar body release are important for creating polyploid
shellfish. For producing triploids, these dynamics concern meiosis in diploid
eggs and are well understood. For creating tetraploids, eggs from triploids are
employed and the dynamics, variation, and environmental influences upon polar
body release are less studied. We investigated the effects of several agents on
the timing of 50% first polar body (PB1) release in eggs of triploids. PB1
release is generally slower in triploid eggs than diploid ones at 26 degrees C.
Lowering the temperature (from 26 to 19 degrees C) had a marked effect on timing
of 50% PB1 in both diploid and triploid eggs. While lower temperature merely
slowed development in diploid eggs, it nearly halted it in triploid eggs. At any
temperature, the variability in 50% PB1 release was much higher in triploid eggs
than diploid ones; this variation occurred both within eggs from individual
females and among eggs from different females. The amount of time eggs remain in
seawater between the time they are stripped and fertilized (or time of hydration)
also affected rate of meiosis. In triploid eggs, the average time necessary for
the expulsion of 50% PB1 was 23 min post-fertilization (PF) for 75 min of
hydration versus 29 min PF for 35 min. However, increasing the time of hydration
had no effect on the variability in the timing among females. Serotonin also had
no effect on the dynamics of polar body release in triploids. Variability among
triploid females in timing of meiosis cannot be improved with any treatments we
tried. Consequently we recommend that treatments of triploid eggs to produce
tetraploids incorporate a single female at a time.
PMID- 10771300
TI - Intertidal mesograzers in field microcosms: linking laboratory feeding rates to
community dynamics.
AB - Mesograzers (herbivores <2.5 cm) are both diverse and abundant, but their
relative effects on intertidal communities have rarely been quantified. Here I
examine the effects of crustacean and polychaete mesograzers on two intertidal
resources, the red alga Odonthalia floccosa Esp. (Falkenb.) and the epiphytic
diatom Isthmia nervosa Kutz. The mesograzers were hermit crabs (Pagurus
hirsutiusculus (Dana) and P. granosimanus (Benedict)), amphipods (Hyale frequens
Stout and H. pugettensis (Dana)), isopod (Idotea wosnesenskii (Brandt)), juvenile
kelp crab (Pugettia producta (Randall)), and polychaete worm (Platynereis
bicanaliculata (Baird)). Feeding rates on Isthmia, measured in the laboratory for
different consumer species and size classes, scaled allometrically with body
mass. Consumption rates were 2-23% of body mass daily on a fresh weight basis.
However, feeding rates on Odonthalia did not scale, suggesting that size will not
always indicate per capita effect. Mesograzer densities were measured on Tatoosh
Island, Washington, USA. The mesograzer predicted to have the largest total
effect (P. hirsutiusculus), based on densityxfeeding rate, was neither the most
abundant nor the most voracious. The validity of these sorts of predictions
depends on how well feeding rates measured in the laboratory approximate per
capita effects under field conditions. Predictions were compared to observed
effects in field microcosms. Given known numbers of mesograzers, predictions were
made about the amount of Isthmia biomass that should disappear over 2 weeks from
microcosms (9x9x12 cm) anchored in tidepools. Average per capita effects in field
microcosms were correlated with laboratory feeding rates, but, for three species
with significant feeding on Isthmia, effects were lower than feeding rates
predicted. Feeding trials may overestimate community impact because they fail to
account for alternative food, search times, resource productivity and stimulation
of growth, or interference from other consumers. Nevertheless, densities of
mesograzers can reach sufficiently high levels so that even feeble per capita
effects combine to alter biomass of epiphytes and perhaps other small algae.
PMID- 10771301
TI - Surface composition and orientation interact to affect subtidal epibiota.
AB - Settlement panels were used to evaluate the effects of composition of the
substratum (sandstone, concrete, wood) and orientation (vertical, horizontal
undersides) on subtidal epibiota. It was predicted that both factors would
influence the development of epibiotic assemblages, but that differences due to
composition would be less marked on horizontal undersides compared to vertical
panels. Differences in assemblages among sandstone, concrete and wooden panels
orientated vertically were predicted to be similar to those described previously
among vertical surfaces of sandstone rocky reefs and concrete and wooden urban
structures (pilings and pontoons). Multivariate analyses indicated that
assemblages were influenced greatly by orientation, whereas the effects of
surface composition differed for the two orientations and among sites.
Assemblages on wood were always significantly different from those on sandstone
or concrete - patterns between the latter two surfaces depended on the
orientation of the panels. The taxa that dominated these surfaces were not
similar in identity nor abundance to those on urban structures of the same
composition. The covers of most taxa were influenced by orientation alone or by
surface composition for just one orientation. This study demonstrates the need
for caution in generalizing about effects of orientation and surface composition
because they may interact with each other and/or with other factors and they are
certainly quite different for different taxa and among sites.
PMID- 10771302
TI - Growth increments and biomineralization process in cephalopod statoliths.
AB - A study on morphological, structural and biochemical composition of Sepia
officinalis and Loligo vulgaris statoliths and statocyst endolymph was undertaken
with the aim of determining the major factors affecting the deposition process of
statolith formation and to clarify the cause for the poor definition of the
growth increments in S. officinalis statoliths. It is suggested that the
different biochemical composition of the statocyst endolymph found in the two
species accounts for distinct statolith crystallisation processes, which results
in a different microstructure. This explains the better definition of growth
increments in L. vulgaris statoliths comparing with those of S. officinalis. The
protein content as well as Ca(2+) and Mg(2+) concentrations in the endolymph are
more implicated in growth increments formation than Sr(2+) ion concentration.
Moreover, the daily variations of the three factors mentioned, allowed us to
formulate a working hypothesis to explain the daily deposition of growth
increments: a dark ring (rich in organic matter) is deposited during daylight
whereas a light ring (rich in CaCO(3)) during darkness. These results are
discussed in the light of alternative hypotheses explaining the deposition
mechanisms in statoliths.
PMID- 10771303
TI - Predicting amphipods' brood size variation in brackish environments: an empirical
model for Corophium multisetosum Stock, 1952 (Corophiidae) in Ria de Aveiro (NW
Portugal).
AB - Data on fecundity of Corophium multisetosum from Areao (Ria de Aveiro, Portugal)
are analysed by non linear regression to quantify the relationship between brood
size (N(e)) and head length (L(h), in mm), water temperature (T, in degrees
Celsius) and salinity (S, in psu). The aim of the analysis is to obtain a simple
line N(e)=a+bL(h), in which the slope (b) and the y intercept (a) are functions
of salinity and/or temperature on each sampling occasion. The equation N(e)=(
2.940-8.027S)+(-89.431+18.171S+12.904T-0.368T(2))L(h) explains 64% of the
variability of brood size throughout the breeding period. The model predicts an
optimal temperature around 18 degrees C and a very low fecundity at low
salinities. The graphical comparison of the lines obtained by the model and by a
usual linear regression illustrates its potential usefulness to predict fecundity
changes. The authors suggest that the observed variation in the fecundity of
other brackish-water amphipods can be described and predicted using similar
models.
PMID- 10771304
TI - Light induced larval release of a colonial ascidian.
AB - Larval release and photobehavior were studied in the colonial ascidian
Polyandrocarpa zorritensis. The test hypothesis was that if larval release is
induced by light, then larvae should be attracted to settlement areas where light
is sufficient for larval release. Light induced larval release but the time
course varied with light intensity. As the intensity of either sunlight or blue
green light decreased (1) the time until the beginning of larval release
(latency) became longer, (2) the mean time of larval release increased, and (3)
the time interval over which larvae were released increased. The threshold light
intensity to induce larval release in blue-green light (8.75x10(12) photons cm(
2) s(-1)) was lower than that in sunlight (3.6x10(13) photons cm(-2) s(-1)).
Light induced larval release was not affected by currents up to 15 cm s(-1).
Larvae aggregate in light when given a choice between light and dark. This
response did not vary with larval age. The lowest light intensity, at which
larvae could distinguish between light and dark was 5.0x10(12) photons cm(-2) s(
1) in blue-green light and 2.9x10(14) photons cm(-2) s(-1) in sunlight. Thus, the
hypothesis is supported because larvae are attracted to areas where light
intensity is sufficient for larval release.
PMID- 10771305
TI - Ingestion, faecal pellet and egg production rates of Calanus helgolandicus
feeding coccolithophorid versus non-coccolithophorid diets.
AB - Ingestion rates, faecal pellet and egg production were obtained in laboratory
experiments with females of the copepod Calanus helgolandicus collected from the
English Channel in November 1994. Five different algal monocultures were used as
food: Prorocentrum micans (30 um ESD), Thalassiosira weissflogii (13 um ESD),
Dunaliella tertiolecta (7 um ESD), Emiliania huxleyi (5 um ESD) and Coccolithus
pelagicus (14 um ESD). Results obtained suggest the low ingestion efficiency of
the copepod when feeding on coccolithophorids during late autumn-early winter.
From the five species offered, only the largest non coccolithophorid Prorocentrum
micans and Thalassiosira weissflogii supported efficient feeding and calculated
respiratory demand for C. helgolandicus. Both coccolithophorids, irrespective of
cell size, were ingested at very low rates even when offered at high
concentrations (233-468 ug C l(-1)). Besides low ingestion, no egg production was
found in the copepods fed with Emiliania huxleyi, although unusual high gross
efficiency (reaching 72%) was obtained in experiments performed with Coccolithus
pelagicus. The late seasonal timing of the experiments (November) could explain
the low ingestion and egg production rates.
PMID- 10771306
TI - CART peptides.
AB - CART peptides are among the newest putative peptide
neurotransmitter/cotransmitters. They show no significant homology to any other
peptide, and they are thought to have a role in reward and reinforcement,
feeding, development, sensory processing, stress and endocrine control.
PMID- 10771307
TI - Neurokinin A, calcitonin gene-related peptide, and dynorphin A (1-8) in spinal
dorsal horn contribute to descending inhibition evoked by nociceptive afferent
pathways: an immunocytochemical study.
AB - Immunocytochemical technique was used to compare the contents of neurokinin A
(NKA), calcitonin gene-related peptide (CGRP), and dynorphin A (1-8) (DynA) on
two sides of the lumbar dorsal horn of rats in which the unilateral thoracic
dorsalateral funiculus (DLF) was transected while formalin (0.2 ml, 0.5%) was
injected equally into two hindpaws. The results showed that all the NKA-like,
CGRP-like, and DynA (1-8)-like immunoreactivities were significantly lower in the
superficial laminae of the dorsal horn on the side ipsilateral to the lesioned
DLF than that on the side with intact DLF. This implies that peripheral noxious
inputs activate the supraspinal descending inhibitory systems which in turn
modulate the transmission of noxious message at the spinal level by changing the
release of related neuropeptides.
PMID- 10771308
TI - Diuretic and natriuretic action of adrenomedullin administered
intracerebroventricularly in conscious rats.
AB - Intracerebroventricular administration of rat adrenomedullin (AM) to conscious
hydrated or salt-loaded rats, resulted in a significant increase in urinary
volume. The diuretic effect of adrenomedullin occurred during the 6-h period of
urine collection and was most effective during the 3 and 6 h. Most remarkably, AM
given IVT induced a dose-related increase in urinary sodium excretion at all
periods of urine collection. In addition, AM induced significant kaliuresis. Our
results strongly suggest that AM may play a significant role in the central
regulation of fluid and electrolyte homeostasis, and that its diuretic and
natriuretic effect may be, at least in part, centrally mediated.
PMID- 10771309
TI - Diminished prohormone convertase 3 expression (PC1/PC3) inhibits progastrin post
translational processing.
AB - Gastrin is initially synthesized as a large precursor that requires
endoproteolytic cleavage by a prohormone convertase (PC) for bioactivation.
Gastric antral G-cells process progastrin at Arg(94)Arg(95) and Lys(74)Lys(75)
residues generating gastrin heptadecapeptide (G17-NH(2)). Conversely, duodenal G
cells process progastrin to gastrin tetratriacontapeptide (G34-NH(2)) with little
processing at Lys(74)Lys(75). Both tissues express PC1/PC3 and PC2. Previously,
we demonstrated that heterologous expression of progastrin in an endocrine cell
line that expresses PC1/PC3 and little PC2 (AtT-20) resulted in the formation of
G34-NH(2). To confirm that PC1/PC3 was responsible for progastrin processing in
AtT-20 cells and capable of processing progastrin in vivo we coexpressed either
human wild-type (Lys(74)Lys(75)) or mutant (Arg(74)Arg(75), Lys(74)Arg(75), and
Arg(74)Lys(75)) progastrins in AtT-20 cells with two different antisense PC1/PC3
constructs. Coexpression of either antisense construct resulted in a consistent
decrease in G34-NH(2) formation. Gastrin mRNA expression and progastrin synthesis
were equivalent in each cell line. Although mutation of the Lys(74)Lys(75) site
within G34-NH(2) to Lys(74)Arg(75) resulted in the production of primarily G17
NH(2) rather than G34-NH(2), inhibition of PC1/PC3 did not significantly inhibit
processing at the Lys(74)Arg(75) site. We conclude that PC1/PC3 is a progastrin
processing enzyme, suggesting a role for PC1/PC3 progastrin processing in G
cells.
PMID- 10771310
TI - The role of sensorial neuropeptides in the edematogenic responses mediated by
B(1) agonist des-Arg(9)-BK in rats pre-treated with LPS.
AB - In the present study we have investigated some of the mechanisms underlying B(1)
kinin receptor-induced paw edema formation in rats that had been treated with
LPS, paying special attention to the involvement of neurogenic inflammation.
Intradermal (i.d.) injection of the B(1) receptor agonist des-Arg(9)-BK (100
nmol/paw) resulted in a marked increase in paw volume in animals pre-treated with
LPS (0.40+/-0.06 ml). The co-injection of the selective NK(1) FK888 (1 nmol/paw)
or NK(2) SR 48968 (3 nmol/paw) receptor antagonists resulted in a significant
inhibition of the edema induced by des-Arg(9)-BK (30+/-4 and 25+/-7%,
respectively). The NK(3) SR 142801 (3 nmol/paw) antagonist did not demonstrate
any significant effect on B(1) receptor-mediated paw edema. The edema induced by
des-Arg(9)-BK was also significantly inhibited (33+/-5%) by the co-injection of
the CGRP-receptor antagonist CGRP 8-37 (1 nmol/paw) or by treatment of animals
with capsaicin (50 mgkg(-1), s.c., 48 h, prior) (45+/-4%). The pre-treatment of
animals with methysergide or with mianserin, 5-HT(1) and 5HT(2) antagonists,
respectively (both 10 mgkg(-1), i.p. 30 min), resulted in a significant reduction
of the edema mediated by B(1) receptors (23+/-5 and 20+/-3%, respectively). In
addition, compound 48/80 (12 microg/paw, 24 h) significantly reduced des-Arg(9)
induced paw edema in rats pre-treated with LPS (23+/-3%), while the treatment of
animals with the H(1) receptor antagonist pyrilamine (10 mgkg(-1), i.p., 30 min)
failed to affect the edematogenic responses involving B(1) receptors. Finally,
the co-injection of NOS inhibitors L-NAME (100 nmol/paw) or 7-NINA (10 nmol/paw)
did not affect the rat paw edema caused by des-Arg(9)-BK, whereas they
significantly inhibited BK-induced paw edema. Jointly, the results of the present
study show that the edematogenic response mediated by the activation of B(1)
receptors, in animals pre-treated with LPS, involves the release of tachykinins
and CGRP, as well as serotonin, while NO and histamine seem not to be involved.
Therefore, these data further support the notion that B(1) receptors have an
important role in modulating the inflammatory processes.
PMID- 10771311
TI - Effects of aging and caloric restriction on IGF-I, IGF-I receptor, IGFBP-3 and
IGFBP-4 gene expression in the rat stomach and colon.
AB - The purpose of this study was to determine the effects of aging and caloric
restriction (CR) on insulin-like growth factor-I (IGF-I), IGF-I receptor (IGF
IR), IGF-binding protein-3 (IGFBP-3) and IGFBP-4 expression in the stomach and
colon of male Fischer 344 rats. Stomach and colonic RNA were prepared from ad
libitum (AL) fed or long-term CR rats. Stomach IGF-I, IGFBP-3 and IGFBP-4 mRNA
levels increased significantly (P 8% or fasting blood glucose > 11 mmol/l). In this paper the
obstacles in routine clinical practice for optimal type 2 diabetes care are
discussed. Long-term complications are the major cause of morbidity and mortality
in type 2 diabetes patients. Therefore, the primary aim of type 2 diabetes
management is the prevention of complications, by lowering blood glucose levels
and reducing the cardiovascular risk profile. An important component of type 2
diabetes management is an active role of the patient: diet, smoking habits,
physical exercise and self-care behavior often need to change. In addition, the
patient has to adhere to life long medical therapy. Motivating the patient for
this active role is the challenge for health care providers. A complicating
factor is that changes in lifestyle do not give immediate benefit for the
patient, as the effects are seen in the reduction of the development of long-term
complications. The cornerstones of health care to support active patient
participation are: to guarantee the continuity of care, to integrate education in
health care and to encourage the patient's attendance. It is the challenge for
physicians to give type 2 diabetes patients the tools for active participation in
the management of the disease.
PMID- 10771373
TI - In vitro analysis of platelet concentrates stored in the presence of modulators
of 3',5' adenosine monophosphate, and organic anions.
AB - The storage of conventional platelet concentrates (PCs) under standard blood bank
conditions is limited to five days, in part because longer storage periods lead
to increasing damage in platelet integrity and functionality. The growing demand
of PCs for clinical use, raises the interest to develop agents that would
potentially permit a more extended period of storage. We have evaluated and
compared the in vitro quality of PCs treated with: (1) Modulators of levels of
cAMP (PGE1, foskolin, theophylline and isobutyl-methyl-xanthine [IBMX]); and (2)
organic anions that function as alternative substrates of platelets (pyruvate and
acetate). Platelet rich plasma (PRP) from pools (n = 6) of PCs was distributed
into storage bags, and the agents to be tested were added, using saline as a
control substance. PCs were stored at 22 degrees C with continuous agitation for
up to 10 days. At 0, 5 and 10 days of storage, samples were analyzed for platelet
counts, mean platelet volume (MPV), metabolic markers, and expression of
glycoproteins (GPs). The addition of modulators of levels of cAMP, at the
concentration used in the study, did not lead to substantial improvement in the
parameters being evaluated, with respect to those in control units. The
supplementation with organic anions, while not affecting the surface levels of
GPs, favored the maintenance of metabolic values, such as pH, PCO2, and
bicarbonate concentrations, as well as the preservation of MPV (p values < 0.05
respect to control units both at 5 and 10 days of storage). Our results indicate
that while the use of modulators of levels of cAMP do not provide substantial
benefit in the prevention of platelet storage lesions, organic anions have some
advantageous effect in the storage promoted metabolic changes of PCs. These data
might be considered when designing strategies to improve PC storage.
PMID- 10771374
TI - A survey of autologous blood collection and transfusion in Japan in 1997.
AB - BACKGROUND: In spite of the fact that autologous blood is safest for a patient to
receive, it is not generally appreciated that adverse reactions during donation
and transfusion may occur. This study was conducted to assess the state and the
risk of autologous blood transfusion in Japan in 1997. STUDY DESIGN AND METHODS:
Results of a nation-wide questionnaire-based survey are presented. The
questionnaire assessed the number of autologous blood donations, donation
procedures, and the adverse reactions associated with donation, preservation,
recombination erythropoietin administration and transfusion. RESULTS: Between
November 1996 and October 1997, 10,697,000 ml (or 53,485 units, 200 ml = 1 unit)
prestorage blood donation were made by 14,200 patients (averages; 1.9
donations/patient, 753 ml/patient, 398 ml/donation). Of these, 87% were
transfused to the patients and the remainder were discarded. Using hemodilution
and blood salvage intra- or postoperatively some 2,540,000 ml of blood was
collected and > 70% of patient-donors received such blood. Adverse reactions were
observed with 1.6% (428/26,905) of donations including 6 angina and 2 asthma
attacks. There were 63 (0.2%) problems with 28,705 donations and 117 (0.5%)
errors/problems reported for 24,929 units transfused; the most frequent problems
were clotting on the units and breakage of the bags during storage. Hypotension
using hemodilution (3.7%), coagulation (0.9%) or bacterial contamination (0.4%)
using salvage were often observed. A 10-20 ml volume of autologous fresh-frozen
plasma was transfused to the wrong recipient. CONCLUSION: Autologous blood
transfusion accounts for at least 1.1% (2.8% estimated) of the red cell supply in
Japan. Errors and adverse reactions are not infrequent in autologous blood
programmes. By introducing systematic safety policies, we will be able to make
autologous blood transfusion safer.
PMID- 10771375
TI - Comparison of platelet immunity in patients with SLE and with ITP.
AB - Idiopathic thrombocytopenic purpura (ITP) is characterized by the development of
a specific anti-platelet autoantibody immune response mediating the development
of thrombocytopenia. Systemic lupus erythematosus (SLE) is an autoimmune disease
characterized by the production of a wide variety of autoantibodies. In 15-20% of
SLE cases, patients develop thrombocytopenia which appears to be autoimmune in
nature (SLE-TP). To better understand the pathogenesis of the thrombocytopenia
associated with SLE, we investigated the overlapping platelet and cellular immune
features between SLE and ITP. Thirty-one patients with SLE, eight with SLE-TP,
and 17 with ITP, were studied and compared to 60 healthy controls. We evaluated
platelet-associated IgG, platelet microparticles, reticulated platelets, platelet
HLA-DR expression, in vivo cytokine levels, lymphocyte proliferation, and the T
lymphocyte anti-platelet immune response in these patients. Patients with SLE-TP
and those with ITP had increased platelet-associated IgG, an increased percentage
of platelet microparticles, a higher percentage of reticulated platelets and
larger platelets, suggesting antibody-mediated platelet destruction and increased
platelet production. More than 50% of patients with ITP had increased HLA-DR on
their platelet surface whereas subjects with SLE-TP did not. Analysis of serum
cytokines demonstrated increased levels of IL-10, IL-15 and TNF-alpha in patients
with SLE, but in those with ITP, only increased levels of IL-15 were seen, no
increases in any of these cytokines were observed in patients with in SLE-TP. The
ability of lymphocytes to proliferate in response to phorbol myristate acetate
(PMA) stimulation was increased in SLE-TP, but was normal in both SLE and ITP.
Lymphocytes from subjects with ITP displayed an increased ability to proliferate
on exposure to platelets, in contrast, those with SLE-TP did not. While the
number of subjects evaluated with SLE-TP was small, these data reveal a number of
differences in the immunopathogenesis between SLE-TP and ITP.
PMID- 10771376
TI - Changes in the Canadian blood system: the Krever Inquiry, Canadian Blood Services
and Hema-Quebec. Krever Commission.
AB - Beginning in 1992, Canada underwent a series of investigations into the national
blood program. The Krever Commission issued an interim report in 1993 and a final
report in 1997. In all a total of 93 recommendations were made. Subsequently, in
1998, the Canadian Red Cross Society (CRC) withdrew from the blood program and
two new organizations, the Canadian Blood Services (CBS) and Hema-Quebec (HQ)
took over as operators.
PMID- 10771378
TI - The Second International Forum on variant CJD and leucodepletion: UK.
PMID- 10771377
TI - Evaluation of Cobe Trima for the collection of blood components with particular
reference to the in vitro characteristics of the red cell and platelet
concentrates and the clinical responses to transfusion.
AB - This study evaluated Cobe Trima for donor and operational acceptability, the
quality and storage stability of the blood components collected, and the clinical
responses to transfusion. The study was carried out in 2 phases; phase 1 assessed
the efficiency of red cells and platelet collection, and the characteristics of
the components collected before and after storage. Phase 2 was an evaluation of
operational issues and the in vitro characteristics of the red cells and platelet
concentrates at the time of transfusion in respect to their cellular content, and
leucocyte (interleukin IL-6 and IL-8) and platelet-derived (Rantes) cytokine
levels. Cytokine levels were also measured in the donors before and after the
collection procedure and in patients both before and after transfusion. The
clinical responses to a small number of transfusions were assessed. The Cobe
Trima was found to be straightforward to use by the operators, although
additional operator training was required to manage occasional uncertainty with
alarm messages. It was acceptable to the donors except for the occurrence of
citrate reactions in 3/6 donors in phase 1; this problem persisted in phase 2
(6/15 donors), and needs to be addressed in the future. All blood components met
UK product specifications apart from 2 platelet concentrates, 2 red cell
concentrates, and one unit of FFP; the red cell and platelet concentrates had
good storage characteristics. The 2 procedures, which resulted in low platelet
yields, were due to occlusion of the plasma line; the method for installation of
the harness has been subsequently modified to prevent this. 2 red cell
concentrates showed haemolysis; the reason for this was not established. The
Factor VIII level was satisfactory in plasma and the cellular content was low.
The responses to 12 platelet transfusions were expected as in a group of
haematology patients, and no immediate adverse effects were reported with any of
the transfusions. Leucocyte-associated (IL-8 and IL-6) and platelet-associated
(Rantes) cytokine levels were not elevated in donor samples taken before or after
the collection procedure, or in the red cell and platelet concentrates at the
time of issue. Pre- and post-transfusion IL-8 levels were raised in one patient
with non-immune platelet refractoriness, and normal in 2 patients with excellent
or almost satisfactory responses to platelet transfusions raising the question as
whether IL-8 could be used as a laboratory marker for non-immune platelet
refractoriness due to infection.
PMID- 10771379
TI - nvCJD and leucodepletion: an overview.
PMID- 10771380
TI - Prions and blood transfusion.
PMID- 10771381
TI - Distribution of normal prion protein in blood.
PMID- 10771382
TI - Removal of abnormal prion protein by plasma fractionation.
PMID- 10771383
TI - Systematic RBC leucodepletion in France: where are we after six months?
PMID- 10771384
TI - Evaluating leucodepletion systems suitable for routine use.
PMID- 10771385
TI - Leucodepletion monitoring by flow cytometry (Becton-Dickinson): from universal to
statistical process monitoring.
PMID- 10771386
TI - Selective or universal leucodepletion: the Italian experience.
PMID- 10771387
TI - Leucodepletion and regulatory aspects in Germany.
PMID- 10771388
TI - Leucofiltration of sickle cell trait blood "the blocker": NBS London & S.E.
experience.
PMID- 10771389
TI - Leucofiltration, retention/generation of soluble prion and annexin V and storage
of blood components.
PMID- 10771390
TI - National evaluation of IMAGN 2000 for quality monitoring of leucodepleted red
cell and platelet concentrates: comparison with flow and Nageotte.
PMID- 10771391
TI - Leucocyte fragments in 'prestorage-leucodepleted' blood products: a qualitative
analysis.
PMID- 10771392
TI - Laboratory and clinical aspects of platelet concentrates.
PMID- 10771393
TI - Current position on preparation and quality of leucodepleted platelet
concentrates for clinical use.
AB - Double dose leucodepleted PC without filtration is considered to be the most cost
effective way of preparing leucodepleted PC in a reasonable time. The procedure
lends itself to a multicomponent system and production of hyperconcentrate and
dry platelets, with < 10-15 ml plasma in final product and viral inactivation
without considerable loss of in vitro platelet functions. Platelet concentrates
obtained by various procedures are highly heterogeneous, even if a standard
protocol is used for the preparation. Therefore, standard/standardisation in both
production and testing procedures remain a challenging area in order to obtain
comparative results. Attention needs to be focused on growing and complex
technical features of preparation and on the use of new filter material in terms
of biocompatibility and the related effects of activated factors on function of
platelets and leucocytes. Both the production process and storage containers
appear to contribute to various cellular lesion and generation of some biological
response modifiers such as complements, cytokines and microparticles. In this
respect it is relevant to adopt a multiparameter analysis for the validation of
platelet quality as some markers of platelet storage lesion have different
affinity to various surfaces, leading to false under estimation. Further
development work is still needed in preparation and usage of dry platelet,
platelet alternative and bacterially safe products. The underlying conditions of
the transfused patients is also an important issue in this respect, it is
interesting to note that patients with high IL8 levels have a substantially lower
platelet recovery.
PMID- 10771394
TI - Platelet storage--1999 as good as it gets?
PMID- 10771395
TI - Platelet products, where to?
PMID- 10771396
TI - Lyophilized platelets: continued development.
AB - In our initial investigation of functionality of platelets freeze-dried after
stabilization with 1.8% paraformaldehyde, we found that the rehydrated cells were
morphologically intact and retained adhesive and procoagulant properties. Further
testing of fixed, washed freeze-dried platelets has demonstrated the physiologic
nature of their adhesion in vitro and their hemostatic efficacy in vivo in
correcting the bleeding time in thrombocytopenic animal models. Binding studies
with monoclonal antibodies and radiolabelled ligands indicate an intact GpIb
vonWillebrands factor receptor as on fresh platelets, but a somewhat attenuated
GpIIbIIIa fibrinogen receptor. Repeated infusion of canine lyophilized platelet
preparations in a single recipient over several months has shown no incipient
cytopenia upon infusion of new doses nor accelerated clearance of platelets.
These findings suggest minimal risk of systemic thrombosis or severe immunogenic
reaction and support the notion of approaching clinical trials as soon as
possible.
PMID- 10771397
TI - Ex vivo expansion of megakaryocytes.
PMID- 10771398
TI - Editorial.
PMID- 10771399
TI - Molecular characterization of cold agglutinins.
AB - An unusual bias involving the exclusive usage of the V4-34 gene segment by
pathogenic antibodies with I/i antigen specificity has been documented in the
literature. In addition, all unmutated and several mutated V4-34 encoded
antibodies have been shown to be reactive with the anti-idiotypic monoclonal
antibody 9G4. The 9G4 Id, therefore, is a marker for V4-34 gene segment
expression. Based on these two correlations, it became vital to localize and
characterize the nature of the 9G4 Id and to determine the relationship between
the Id and I binding. Mutational analysis indicated that the 9G4 Id is located in
framework region 1 (FR1) of V4-34 encoded antibodies. Two distinct sections of
FR1, encompassing amino acid residues 6-12 and 23-25, form the 9G4 Id. Mutational
analysis demonstrated that both FR1 and CDRH3 were required for I binding. When
either one was disrupted, the mutant antibody could not bind I. This indicates
that I binds through a framework region, and not exclusively through CDRH3. This
renders the I interaction with the V4-34 encoded portion of immunoglobulins
unconventional, with characteristics similar to superantigen binding to
immunoglobulin through FR. When the FR1 DNA sequence of V4-34 was exchanged for
FR1 sequences from other VH families I binding was lost, providing a structural
explanation for this restricted VH usage. An understanding of the localization
and structure of the 9G4 Id and the requirements of V4-34 encoded antibodies for
I binding provide insights into the structure of pathogenic antibodies and their
requirements for binding antigen. This information should be useful in analyzing
new interactions such as the lytic activity of some V4-34 encoded antibodies for
B cells.
PMID- 10771400
TI - Management of cold agglutination syndrome.
AB - Cold haemagglutination syndrome is difficult to treat. Fortunately it seldom
needs treating. In most cases cold agglutinins are an incidental finding
representing either normality or a benign chronic monoclonal gammopathy that does
not cause ill health. Two sorts of symptoms are likely in the more severe cases.
Acrocyanosis is usually treated by keeping the patient warm and if necessary
removing him or her to Florida or the Canary Islands. In the rare cases of
haemolytic anaemia, an underlying lymphoid tumour should be sought and treated.
If none exists, then it is unlikely that the treatments that are useful in warm
antibody haemolytic anaemia will be helpful. Plasma exchange ought to work but in
practice there are frequently problems of red cell agglutination within the cell
separator or the plastic tubes. For this reason plasma exchange within a heated
room is advocated. When cardiac surgery is contemplated pre-operative plasma
exchange is sometimes helpful, or the heart may be stopped by potassium solutions
and the operation is carried out in the warm.
PMID- 10771401
TI - Clinical syndromes associated with cold agglutinins.
AB - Auto-immune haemolysis (AIHA) occurs when an individual's own red blood cells are
destroyed by an autoantibody. Anaemia ensues if bone marrow production of red
cells cannot compensate for the increased loss of red blood cells.
PMID- 10771402
TI - Factors influencing the outcome of leucodepletion system.
PMID- 10771403
TI - Does bacterial contamination of platelet concentrates influence the leucocyte
content and the rate of platelet storage lesion?
AB - An observational study was carried out to assess the effect of bacterial growth
on changes in platelet cellular indices and leucocyte content. Platelet derived
from pooled buffy coats, with and without an additional leucocyte removal step by
filtration and platelet derived from Cobe LRS system were used. These were spiked
with two doses of several types of bacteria (1 and 50 CFU) in a paired control
and test experiment. The changes in cellular parameters were monitored by an
automated cell counter (Sysmex SE-9000) and the concentration of the residual
leucocyte were evaluated by two automated techniques, based on DNA staining
principles (flow cytometry-EPICS-XL Coutter and Imagn 2000). Our results indicate
that initially bacterial growth is associated with a decrease in leucocyte count,
followed by a concomitant increase in platelet large cell ratio, possibly due to
aggregate formation. During the prolonged storage a dramatic increase in
pseudoleucocytes was observed by both Imagn 2000 and flow cytometry techniques
with an abnormal dot plot around FL3 regions in the latter counting method,
making the true identification of native leucocytes rather difficult. It is
concluded that bacterial growth is associated with both changes in platelet
cellular indices and development of cellular aggregates and/or partially
fragmented cells with DNA binding properties appearing as pseudoleucocytes.
Further work on the true nature of so called 'pseudoleucocyte' is in progress.
PMID- 10771407
TI - Color vision and the four-color-map problem.
AB - Four different colors are needed to make maps that avoid adjacent countries of
the same color. Because the retinal image is two dimensional, like a map, four
dimensions of chromatic experience would also be needed to optimally distinguish
regions returning spectrally different light to the eye. We therefore suggest
that the organization of human color vision according to four-color classes
(reds, greens, blues, and yellows) has arisen as a solution to this logical
requirement in topology.
PMID- 10771408
TI - Incomplete gustatory lateralization as shown by analysis of taste discrimination
after callosotomy.
AB - The lateral organization of the gustatory pathway in man is incompletely
understood. Majority of the studies support an uncrossed projection from each
side of the tongue to the cortex, but reports of an opposite crossed organization
continue to appear in the neurological literature. We studied the lateral
organization of the gustatory pathway in normal controls, a man with a complete
callosal agenesis, and a man with a complete section of the corpus callosum, a
right anterior-frontal lesion, and language in the left hemisphere. Sapid
solutions were applied to one or the other side of the tongue, and subjects
reported the taste of the stimulus either verbally or by manually pointing to the
name of the taste. There were no differences in accuracy and reaction time
between the right and left hemitongues of the controls and the genetically
acallosal observer. By contrast, the callosotomy subject showed a constant marked
advantage of the left hemitongue over the right for both accuracy and speed of
response, though performance with right stimuli was clearly above chance. The
left advantage can be attributed to the left hemisphere being favored by the
essentially verbal nature of the task, or to the presence of a lesion in cortical
gustatory areas in the right hemisphere, or to both factors. Whichever of these
hypotheses turns out to be correct, the results unequivocally reject the notion
of an exclusively crossed organization of the gustatory pathway from the tongue
to the cortex, and favor the notion of a bilaterally distributed organization of
this pathway with a marked predominance of the uncrossed over the crossed
component.
PMID- 10771409
TI - Visual discrimination task improvement: A multi-step process occurring during
sleep.
AB - Performance on a visual discrimination task shows long-term improvement after a
single training session. When tested within 24 hr of training, improvement was
not observed unless subjects obtained at least 6 hr of posttraining sleep prior
to retesting, in which case improvement was proportional to the amount of sleep
in excess of 6 hr. For subjects averaging 8 hr of sleep, overnight improvement
was proportional to the amount of slow wave sleep (SWS) in the first quarter of
the night, as well as the amount of rapid eye movement sleep (REM) in the last
quarter. REM during the intervening 4 hr did not appear to contribute to
improvement. A two-step process, modeling throughput as the product of the amount
of early SWS and late REM, accounts for 80 percent of intersubject variance.
These results suggest that, in the case of this visual discrimination task, both
SWS and REM are required to consolidate experience-dependent neuronal changes
into a form that supports improved task performance.
PMID- 10771410
TI - Novel vs. well-learned memory for faces: a positron emission tomography study.
AB - Previous work has suggested that familiarity/novelty of learned materials affects
the circuitry involved in memory, primarily in the size of activations rather
than the pattern of activation. Although this work has examined both recall and
recognition, it has been limited to verbal material. In this study, we set out to
determine if the same result applies to nonverbal memory. We used the same
experimental design, but used faces as the memory task. Healthy volunteers
thoroughly learned a set of 18 faces a week prior to the Positron Emission
Tomography (PET) experiment (well-learned memory) and were asked to remember
another set of 18 faces, to which they were exposed 1 min before the PET
experiment (novel memory). During the PET session, their task was to recognize
the faces learned a week before and the faces seen a minute before; the
"remembered faces" were interspersed among entirely new (distractor) faces. We
found that, unlike for verbal material, the retention interval and the
familiarity level of the faces affected both the pattern and the size of
activations. Comparing the novel and well-learned recognition tasks revealed that
novel memory for faces is primarily a frontal-lobe task, while well-learned
recognition memory for faces utilizes a more distributed neural circuit,
including visual areas, which appear to serve as memory-storage sites.
PMID- 10771411
TI - The effect of divided attention on encoding and retrieval in episodic memory
revealed by positron emission tomography.
AB - The effects of divided attention (DA) on episodic memory encoding and retrieval
were investigated in 12 normal young subjects by positron emission tomography
(PET). Cerebral blood flow was measured while subjects were concurrently
performing a memory task (encoding and retrieval of visually presented word
pairs) and an auditory tone-discrimination task. The PET data were analyzed using
multivariate Partial Least Squares (PLS), and the results revealed three sets of
neural correlates related to specific task contrasts. Brain activity, relatively
greater under conditions of full attention (FA) than DA, was identified in the
occipital-temporal, medial, and ventral-frontal areas, whereas areas showing
relatively more activity under DA than FA were found in the cerebellum, temporo
parietal, left anterior-cingulate gyrus, and bilateral dorsolateral-prefrontal
areas. Regions more active during encoding than during retrieval were located in
the hippocampus, temporal and the prefrontal cortex of the left hemisphere, and
regions more active during retrieval than during encoding included areas in the
medial and right-prefrontal cortex, basal ganglia, thalamus, and cuneus. DA at
encoding was associated with specific decreases in rCBF in the left-prefrontal
areas, whereas DA at retrieval was associated with decreased rCBF in a relatively
small region in the right-prefrontal cortex. These different patterns of activity
are related to the behavioral results, which showed a substantial decrease in
memory performance when the DA task was performed at encoding, but no change in
memory levels when the DA task was performed at retrieval.
PMID- 10771412
TI - A parametric approach to orthographic processing in the brain: an fMRI study.
AB - Brain activation studies of orthographic stimuli typically start with the premise
that different types of orthographic strings (e.g., words, pseudowords) differ
from each other in discrete ways, which should be reflected in separate and
distinct areas of brain activation. The present study starts from a different
premise: Words, pseudowords, letterstrings, and false fonts vary systematically
across a continuous dimension of familiarity to English readers. Using a one-back
matching task to force encoding of the stimuli, the four types of stimuli were
visually presented to healthy adult subjects while fMRI activations were
obtained. Data analysis focused on parametric comparisons of fMRI activation
sites. We did not find any region that was exclusively activated for real words.
Rather, differences among these string types were mainly expressed as graded
changes in the balance of activations among the regions. Our results suggest that
there is a widespread network of brain regions that form a common network for the
processing of all orthographic string types.
PMID- 10771413
TI - Anterior cingulate and the monitoriing of response conflict: evidence from an
fMRI study of overt verb generation.
AB - Studies of a range of higher cognitive functions consistently activate a region
of anterior cingulate cortex (ACC), typically posterior to the genu and superior
to the corpus collosum. In particular, this ACC region appears to be active in
task situations where there is a need to override a prepotent response tendency,
when responding is underdetermined, and when errors are made. We have
hypothesized that the function of this ACC region is to monitor for the presence
of "crosstalk" or competition between incompatible responses. In prior work, we
provided initial support for this hypothesis, demonstrating ACC activity in the
same region both during error trials and during correct trials in task conditions
designed to elicit greater response competition. In the present study, we extend
our testing of this hypothesis to task situations involving underdetermined
responding. Specifically, 14 healthy control subjects performed a verb-generation
task during event-related functional magnetic resonance imaging (fMRI), with the
on-line acquisition of overt verbal responses. The results demonstrated that the
ACC, and only the ACC, was more active in a series of task conditions that
elicited competition among alternative responses. These conditions included a
greater ACC response to: (1) Nouns categorized as low vs. high constraint (i.e.,
during a norming study, multiple verbs were produced with equal frequency vs. a
single verb that produced much more frequently than any other); (2) the
production of verbs that were weak associates, rather than, strong associates of
particular nouns; and (3) the production of verbs that were weak associates for
nouns categorized as high constraint. We discuss the implication of these results
for understanding the role that the ACC plays in human cognition.
PMID- 10771414
TI - Motor area activity during mental rotation studied by time-resolved single-trial
fMRI.
AB - The functional equivalence of overt movements and dynamic imagery is of
fundamental importance in neuroscience. Here, we investigated the participation
of the neocortical motor areas in a classic task of dynamic imagery, Shepard and
Metzler's mental rotation task, by time-resolved single-trial functional Magnetic
Resonance Imaging (fMRI). The subjects performed the mental-rotation task 16
times, each time with different object pairs. Functional images were acquired for
each pair separately, and the onset times and widths of the activation peaks in
each area of interest were compared to the response times. We found a bilateral
involvement of the superior parietal lobule, lateral premotor area, and
supplementary motor area in all subjects; we found, furthermore, that those areas
likely participate in the very act of mental rotation. We also found an
activation in the left primary motor cortex, which seemed to be associated with
the right-hand button press at the end of the task period.
PMID- 10771415
TI - Common and distinct neural substrates for pragmatic, semantic, and syntactic
processing of spoken sentences: an fMRI study.
AB - Extracting meaning from speech requires the use of pragmatic, semantic, and
syntactic information. A central question is: Does the processing of these
different types of linguistic information have common or distinct neuroanatomical
substrates? We addressed this issue using functional magnetic resonance imaging
(fMRI) to measure neural activity when subjects listened to spoken normal
sentences contrasted with sentences that had either (A) pragmatical, (B) semantic
(selection restriction), or (C) syntactic (subcategorical) violations sentences.
All three contrasts revealed robust activation of the left-inferior
temporal/fusiform gyrus. Activity in this area was also observed in a combined
analysis of all three experiments, suggesting that it was modulated by all three
types of linguistic violation. Planned statistical comparisons between the three
experiments revealed (1) a greater difference between conditions in activation of
the left-superior-temporal gyrus for the pragmatic experiment than the
semantic/syntactic experiments; (2) a greater difference between conditions in
activation of the right-superior and middle-temporal gyrus in the semantic
experiment than in the syntactic experiment; and (3) no regions activated to a
greater degree in the syntactic experiment than in the semantic experiment. These
data show that, while left- and right-superior-temporal regions may be
differentially involved in processing pragmatic and lexico-semantic information
within sentences, the left-inferior-temporal/fusiform gyrus is involved in
processing all three types of linguistic information. We suggest that this region
may play a key role in using pragmatic, semantic (selection restriction), and
subcategorical information to construct a higher representation of meaning of
sentences.
PMID- 10771416
TI - Global spectral and location effects in auditory perceptual grouping.
AB - An important problem in cognitive and systems neuroscience concerns the extent to
which perceptual organization can be explained by "local," peripheral
physiological mechanisms, or rather by more "global," central, and higher-level
processes. Though central in vision research, this issue has received little
attention in the field of audition. One claim is that auditory-perceptual
grouping mechanisms, possibly related to visual figure-from-ground segregation or
"pop-out," are low level, resulting from local processing in the frequency
domain. However, no experiments have been performed specifically to test this
question. We examined the effects of perceptual grouping on detection for
reversal of two repeated target tones, one constant in frequency (1030 Hz), the
other free to vary between trials (1045-8580 Hz). Detection was examined in the
presence of a 1000-Hz background tone that repeated between target presentations.
By varying the frequency of the high-target tone, this task was designed to
modulate grouping between the background and low-target tones, thereby affecting
reversal detection. We predicted that at large target frequency differences
(deltaf), the high-target tone would segregate from the background and low-target
tones, and so render the background and low-target tones less distinct. We found
that reversal detection declined from optimal levels with increasing deltaf, and
that performance was improved by spatially separating the location of the target
and background sounds by at least 32 degrees. These results demonstrate that
global frequency integration over at least three octaves occurs through grouping,
and that grouping is affected by source location. This implies that auditory
perceptual grouping involves global neural processing, i.e., the participation of
neurons with very broad frequency input that are also sensitive to spatial
location.
PMID- 10771417
TI - Neuronal activity in early visual areas during global and local processing: a
comment on Heinze, Hinrichs, Scholz, Burchert and Mangun.
PMID- 10771419
TI - Interview with Martha Farah.
PMID- 10771420
TI - X-ray structure of azide-bound fully oxidized cytochrome c oxidase from bovine
heart at 2.9 A resolution.
AB - Two azide ions were identified, one between the Fe and Cu atoms in the O(2)
reduction site and the other at the transmembrane surface of the enzyme, in the
crystal structure of the azide-bound form of bovine heart cytochrome c oxidase at
2.9 A resolution. Two geometries, a mu-1,3 type geometry between the Fe and Cu
atoms and a terminal geometry on the Fe atom, are equally possible for an azide
ion in the O(2)--reduction site. The other azide molecule was hydrogen bonded to
an amide group of an asparagine and a hydroxyl group of tyrosine in a mu-1,1 type
geometry. The antisymmetric infrared bands arising from these azide ions, which
show essentially identical intensity [Yoshikawa & Caughey (1992), J. Biol. Chem.
267, 9757-9766], strongly suggest terminal binding of the azide to Fe. The
electron density of all three imidazole ligands to Cu(B) was clearly seen in the
electron-density map of the azide-bound form of bovine heart enzyme, in contrast
to the crystal structure of the azide-bound form of the bacterial enzyme [Iwata
et al. (1995), Nature (London), 376, 660-669], which lacks one of the three
imidazole ligands to Cu(B).
PMID- 10771421
TI - The structure of human aldose reductase bound to the inhibitor IDD384.
AB - The crystallographic structure of the complex between human aldose reductase
(AR2) and one of its inhibitors, IDD384, has been solved at 1.7 A resolution from
crystals obtained at pH 5.0. This structure shows that the binding of the
inhibitor's hydrophilic head to the catalytic residues Tyr48 and His110 differs
from that found previously with porcine AR2. The difference is attributed to a
change in the protonation state of the inhibitor (pK(a) = 4.52) when soaked with
crystals of human (at pH 5.0) or pig lens AR2 (at pH 6.2). This work demonstrates
how strongly the detailed binding of the inhibitor's polar head depends on its
protonation state.
PMID- 10771422
TI - Direct determination of the positions of the deuterium atoms of the bound water
in -concanavalin A by neutron Laue crystallography.
AB - The correct positions of the deuterium (D) atoms of many of the bound waters in
the protein concanavalin A are revealed by neutron Laue diffraction. The approach
includes cases where these water D atoms show enough mobility to render them
invisible even to ultra-high resolution synchrotron-radiation X-ray
crystallography. The positions of the bound water H atoms calculated on the basis
of chemical and energetic considerations are often incorrect. The D-atom
positions for the water molecules in the Mn-, Ca- and sugar-binding sites of
concanavalin A are described in detail.
PMID- 10771423
TI - Interactions of Streptomyces griseus aminopeptidase with a methionine product
analogue: a structural study at 1.53 A resolution.
AB - SGAP is an aminopeptidase present in the extracellular fluid of Streptomyces
griseus cultures. It is a double-zinc enzyme with a strong preference for large
hydrophobic amino-terminus residues. It is a monomeric (30 kDa) heat-stable
enzyme, with a high and efficient catalytic activity modulated by calcium ions.
The small size, high activity and heat stability make SGAP a very attractive
enzyme for various biotechnological applications. Only one other related
aminopeptidase (Aeromonas proteolytica AP; AAP) has been structurally analyzed to
date and its structure was shown to be considerably similar to SGAP, despite the
low sequence homology between the two enzymes. The motivation for the detailed
structural analysis of SGAP originated from a strong mechanistic interest in the
family of double-zinc aminopeptidases, combined with the high potential
applicability of these enzymes. The 1.75 A crystallographic structure of native
SGAP has been previously reported, but did not allow critical mechanistic
interpretations owing to inconclusive structural regions around the active site.
A more accurate structure of SGAP at 1.58 A resolution is reported in this paper,
along with the 1.53 A resolution structure of the SGAP complex with inhibitory
methionine, which is also a product of the SGAP catalytic process. These two high
resolution structures enable a better understanding of the SGAP binding mode of
both substrates and products. These studies allowed the tracing of the previously
disordered region of the enzyme (Glu196-Arg202) and the identification of some of
the functional groups of the enzyme that are involved in enzyme-substrate
interactions (Asp160, Met161, Gly201, Arg202 and Phe219). These studies also
suggest that Glu131 is directly involved in the catalytic mechanism of SGAP,
probably as the hydrolytic nucleophile. The structural results are compared with
a recent structure of AAP with an hydroxamate inhibitor in order to draw general
functional conclusions which are relevant for this family of low molecular-weight
aminopeptidases.
PMID- 10771424
TI - The structure of human MRP8, a member of the S100 calcium-binding protein family,
by MAD phasing at 1.9 A resolution.
AB - The structure of human MRP8 in the calcium-bound form was determined at 1.9 A
resolution by X-ray crystallography. The structure was initially solved by MAD
phasing of an ytterbium-substituted crystal and was refined against data obtained
from a Ca(2+)-bound crystal. The dimeric form of MRP8 was stabilized by
hydrophobic interactions between mutually wrapped helices. There were two EF-hand
motifs per monomer and each EF-hand bound one Ca(2+) with a different affinity
[the affinity of the C-terminal EF-hand (EF-2) for Ca(2+) was stronger than that
of the N-terminal EF-hand (EF-1)]. Furthermore, replacement with Yb(3+) occurred
in the C-terminal EF-hand only, suggesting a more flexible nature for EF-2 than
for EF-1. This, combined with previous observations that the helix in EF-2 (helix
III) undergoes a large conformational change upon calcium binding, suggests that
the C-terminal EF-hand (EF-2) plays a role as a trigger for Ca(2+)-induced
conformational change.
PMID- 10771425
TI - Atomic structure of the Serratia marcescens endonuclease at 1.1 A resolution and
the enzyme reaction mechanism.
AB - The three-dimensional crystal structure of Serratia marcescens endonuclease has
been refined at 1.1 A resolution to an R factor of 12.9% and an R(free) of 15.6%
with the use of anisotropic temperature factors. The model contains 3694 non-H
atoms, 715 water molecules, four sulfate ions and two Mg(2+)-binding sites at the
active sites of the homodimeric protein. It is shown that the magnesium ion
linked to the active-site Asn119 of each monomer is surrounded by five water
molecules and shows an octahedral coordination geometry. The temperature factors
for the bound Mg(2+) ions in the A and B subunits are 7.08 and 4.60 A(2),
respectively, and the average temperature factors for the surrounding water
molecules are 12.13 and 10.3 A(2), respectively. In comparison with earlier
structures, alternative side-chain conformations are defined for 51 residues of
the dimer, including the essential active-site residue Arg57. A plausible
mechanism of enzyme function is proposed based on the high-resolution S.
marcescens nuclease structure, the functional characteristics of the natural and
mutational forms of the enzyme and consideration of its structural analogy with
homing endo-nuclease I-PpoI.
PMID- 10771426
TI - Structure of Fab hGR-2 F6, a competitive antagonist of the glucagon receptor.
AB - The monoclonal antibody hGR-2 F6 has been raised against the human glucagon
receptor and shown to act as a competitive antagonist. As a first step in the
structural characterization of the receptor, the crystal structure of the Fab
fragment from this antibody is reported at 2.1 A resolution. The hGR-2 F6 Fab
crystallizes in the orthorhombic space group P2(1)2(1)2, with unit-cell
parameters a = 76.14, b = 133.74, c = 37.46 A. A model generated by homology
modelling was used as an aid in the chain-tracing and the Fab fragment structure
was subsequently refined (final R factor = 21.7%). The structure obtained
exhibits the typical immunoglobulin fold. Complementarity-determining regions
(CDRs) L1, L2, L3, H1 and H2 could be superposed onto standard canonical CDR
loops. The H3 loop could be classified according to recently published rules
regarding loop length, sequence and conformation. This loop is 14 residues long,
with an approximate beta-hairpin geometry, which is distorted somewhat by the
presence of two trans proline residues at the beginning of the loop. It is
expected that this H3 loop will facilitate the design of synthetic probes for the
glucagon receptor that may be used to investigate receptor activity.
PMID- 10771428
TI - beta-sheet propensity and its correlation with parameters based on conformation.
AB - The dispersion of the main-chain and side-chain conformations in the phi, psi,
chi(1) space for all residues have been estimated in terms of three parameters
corresponding to the entropy (S) of the distribution, the volume (D(V)) and the
area (D(A)) the points are enclosed in. These parameters are inversely correlated
with Chou and Fasman beta-sheet propensities, P(beta) (Gly and Pro excluded),
suggesting that residues with greater dispersion in the conformational space are
weak beta-sheet formers. It was also found that different residues have different
relative populations in the bridging region (intervening between the helical and
beta-sheet regions) which may lie on the pathway for interconversion between
alpha and beta conformations. The energy barrier for this transformation, as
obtained from the population of residues in the bridging region relative to the
beta region, is directly correlated to P(beta). Residues with high P(beta) have
branched side chains, which have greater steric interactions with the main-chain
atoms resulting in a shrinking of the available conformational space (first
correlation) and a steeper energy gradient beyond the allowed space (second
correlation) compared with linear residues. It is proposed that if residues exist
in an extended conformation when the polypeptide chain is synthesized, a stretch
of residues with high P(beta), because of the high energy barrier for their
conversion into the alpha conformation, will continue to remain in the extended
conformation and will ultimately constitute a beta-strand in the folded
structure.
PMID- 10771427
TI - L-Isoaspartate 115 of porcine beta-trypsin promotes crystallization of its
complex with bdellastasin.
AB - Bdellastasin is a 59-amino-acid, cysteine-rich, antistasin-type inhibitor of
sperm acrosin, plasmin and trypsin, isolated from the medicinal leech Hirudo
medicinalis. The complex formed between bdellastasin and porcine beta-trypsin has
previously been crystallized in the presence of PEG in a tetragonal crystal form
of space group P4(3)2(1)2 and has now been found to crystallize under high-salt
conditions in the enantiomorphic space group P4(1)2(1)2. These structures have
been solved and refined to 2.8 and 2.7 A resolution, respectively. Bdellastasin
turns out to have an antistasin-like fold exhibiting a bis-domainal structure. In
the second new crystal form, the flexible N-terminal subdomain is rotated with
respect to the C--terminal subdomain by about 90 degrees, fitting into a cavity
formed by symmetry-related trypsin molecules. The canonical inhibitor-proteinase
interaction is restricted to the primary binding loop comprising residues Leu31
Lys36 of bdellastasin. During the refinement, a bound sodium ion occupying the
calcium-binding site of the porcine beta-trypsin component was discovered. This
sodium ion is coordinated in a tetragonal-pyramidal manner, with the geometry of
the enclosing loop slightly changed compared with the loop in the presence of
calcium. In the crystal form of space group P4(3)2(1)2, the electron density for
residue 115 of porcine beta-trypsin clearly indicates the presence of a beta
isomerized L-aspartic acid, which is placed in spatial proximity to segment
Thr144--Gly148 of a symmetry-related trypsin molecule. This is the first
structurally observed example of an L-isoaspartate in beta--trypsin originating
from Asn. A comparison with other known crystal structures of porcine beta
trypsin-macromolecular inhibitor complexes suggests that the deamidation,
isomerization and racemization of Asn115 is the key step in crystallization.
PMID- 10771429
TI - Improving the X-ray resolution by reversible flash-cooling combined with
concentration screening, as exemplified with PPase.
AB - A significant improvement in the X-ray resolution of crystals of Escherichia coli
inorganic pyrophosphatase at cryotemperature was obtained as a result of studying
the relationship between the crystal order and cryosolution component
concentrations. To perform the experiments, the ability to reverse the flash
cooling process and to return a crystal to ambient temperature was used. In each
cycle, the crystal was transferred from a cold nitrogen-gas stream to a
cryosolution with modified concentrations of the components. The crystal was then
flash-cooled again and the diffraction quality checked. Such a technique allows
the screening of a wide concentration range rather quickly without using a large
number of crystals and allows the determination of optimal cryosolution component
concentrations. The resolution limit for crystals of pyrophosphatase increased by
almost 0.7 A, from 1.8 to 1.15 A.
PMID- 10771431
TI - Wavelet analysis of electron-density maps.
AB - The wavelet transform is a powerful technique in signal processing and image
analysis and it is shown here that wavelet analysis of low-resolution electron
density maps has the potential to increase their resolution. Like Fourier
analysis, wavelet analysis expresses the image (electron density) in terms of a
set of orthogonal functions. In the case of the Fourier transform, these
functions are sines and cosines and each one contributes to the whole of the
image. In contrast, the wavelet functions (simply called wavelets) can be quite
localized and may only contribute to a small part of the image. This gives
control over the amount of detail added to the map as the resolution increases.
The mathematical details are outlined and an algorithm which achieves a
resolution increase from 10 to 7 A using a knowledge of the wavelet-coefficient
histograms, electron-density histogram and the observed structure amplitudes is
described. These histograms are calculated from the electron density of known
structures, but it seems likely that the histograms can be predicted, just as
electron-density histograms are at high resolution. The results show that the
wavelet coefficients contain the information necessary to increase the resolution
of electron-density maps.
PMID- 10771430
TI - Optimizing DREAR and SnB parameters for determining Se-atom substructures.
AB - The determination of the anomalous scattering substructure is the first essential
step in any successful macromolecular structure determination using the
multiwavelength anomalous diffraction (MAD) technique. The diffE method of
calculating difference Es in conjunction with SnB has had considerable success in
determining large Se-atom substructures. An investigation of the parameters used
in both the data-reduction and error-analysis routines (DREAR) as well as the SnB
phasing process itself was undertaken to optimize these parameters for more
efficient use of the procedure. Two sets of selenomethionyl S
adenosylhomocysteine hydrolase MAD data were used as test data. The elimination
of all erroneously large differences prior to phasing was found to be critical
and the best results were obtained from accurate highly redundant intensity
measurements. The high-resolution data collected in the typical MAD experiment
are sufficient, but the inclusion of low-resolution data below 20 A improved the
success rate considerably. Although the best results have been obtained from
single-wavelength peak anomalous diffraction data alone, independent SnB analysis
of data measured at other wavelengths can provide confirmation for questionable
sites.
PMID- 10771432
TI - The use of wavelet transforms in low-resolution phase extension.
AB - A method to extend low-resolution phases has been developed using histogram
matching not only of the electron density itself but also of histograms obtained
from the different levels of detail provided by the wavelet transform of the
electron density. It is shown that the method can extend phases from 10 A to
around 6-7 A on a wide range of trial structures differing in size, space group
and solvent content. This level of phase extension can improve the electron
density map from little more than a molecular envelope to one in which secondary
structure can often be identified.
PMID- 10771433
TI - Crystallization and preliminary X-ray diffraction data of mouse L-chain
apoferritin crystals.
AB - Crystals of recombinant mouse L-chain apoferritin were obtained by the hanging
drop technique using ammonium sulfate as precipitant. Two crystal forms were
observed in the same drop. The crystals belong to either the P2 monoclinic or to
the P42(1)2 tetragonal space group. The monoclinic crystals diffracted to beyond
2.4 A resolution but were systematically twinned, while the tetragonal crystals
diffracted to beyond 2.9 A. These crystallization conditions in the absence of
metal salts should facilitate the study of the interaction between L-chain
ferritins and heavy metals, particularly the iron core.
PMID- 10771434
TI - Crystallization and molecular-replacement solution of a truncated form of human
recombinant tetranectin.
AB - The two C-terminal domains, TN23 (residues 17-181), of human recombinant
tetranectin, a plasminogen kringle 4 binding C-type lectin, have been
crystallized in two different space groups. Using PEG 8000 as precipitant and at
a pH of 8.5, crystals belonging to the monoclinic space group C2 are obtained,
with unit-cell parameters a = 160.4, b = 44.7, c = 107.5 A, beta = 127.6 degrees.
Using sodium formate as precipitant and at a pH of 5.0, TN23 crystallizes in a
rhombohedral space group, with unit-cell parameters a = b = c = 107.4 A, alpha =
beta = gamma = 78.3 degrees. A full data set to 4.5 A has been collected from the
monoclinic crystals. Using the structure of full-length tetranectin, a molecular
replacement solution has been obtained. The crystal packing shows that TN23
crystallizes as a trimer, with one trimer in the asymmetric unit.
PMID- 10771435
TI - Expression, purification and crystallization of enterococcus faecium
streptogramin A acetyltransferase.
AB - The streptogramin A acetyltransferase from Enterococcus faecium (SWISS-PROT
P50870) has been overexpressed in Escherichia coli, purified and crystallized.
Crystallization conditions were screened using the hanging-drop vapor-diffusion
method and resulted in two distinct crystal forms. Form I crystals diffract to
2.5 A and belong to space group P2(1)2(1)2(1), with unit-cell parameters a =
68.6, b = 102.6, c = 107.5 A. Form II crystals diffract to 2.7 A and belong to
space group F222, with unit-cell parameters a = 185.8, b = 185.8, c = 186.5 A.
Rotation-function and packing analyses for both crystal forms indicate that the
asymmetric unit may contain one and two copies of the trimeric enzyme for crystal
forms I and II, respectively.
PMID- 10771436
TI - Crystallization and preliminary crystallographic analysis of Rieske iron-sulfur
protein II (soxF) from sulfolobus acidocaldarius.
AB - An archaeal Rieske iron-sulfur protein has been crystallized for the first time.
The genetically constructed soluble form of the soxF protein was expressed in E.
coli. It contains a correctly inserted [2Fe--2S] cluster. The authentic soxF
protein is part of a terminal oxidase complex in the respiratory chain of the
hyperthermoacidophilic crenarchaeon Sulfolobus acidocaldarius (DSM 639). The
enzyme crystallizes in the space group P6(1) or P6(5), with unit-cell parameters
a = b = 80.19, c = 75.69 A. A complete data set has been collected to 1.64 A
resolution at 100 K.
PMID- 10771437
TI - Expression, purification, crystallization and preliminary X-ray diffraction
studies of bacterial and archaeal L4 ribosomal proteins.
AB - Ribosomal protein L4 is implicated in the peptidyltransferase activity of the
ribosome and in certain bacteria it regulates the transcription and translation
of the 11-gene S10 operon. The genes for the L4 ribosomal proteins from the
hyperthermophilic bacterium Thermotoga maritima and the halophilic archaeon
Haloarcula marismortui have been PCR amplified from genomic DNA and cloned under
the control of a T7 promoter to generate overexpressing Escherichia coli strains.
For both proteins, efficient purification procedures were developed to yield
material suitable for crystallization trials. Crystals of T. maritima L4 were
obtained in the orthorhombic space group P2(1)2(1)2(1), with one molecule per
asymmetric unit, diffracting to 1.7 A resolution with synchrotron radiation.
Crystals of H. marismortui L4 belonged to the trigonal space group P3(1)21 or
P3(2)21 and diffracted to 3.2 A resolution with a rotating-anode source,
presumably containing three molecules per asymmetric unit. The results
demonstrate that for certain halophilic proteins the same purification and
crystallization procedures can be employed as for conventional proteins.
PMID- 10771438
TI - Crystallization and preliminary X-ray study of Pk--REC from a hyperthermophilic
archaeon, Pyrococcus kodakaraensis KOD1.
AB - Pk-REC is a protein which binds to DNA and catalyzes the central step of
recombination and repair. The protein was crystallized using the hanging-drop
vapour-diffusion method with PEG as a precipitant. Two orthorhombic crystal forms
I and II with the same space group P2(1)2(1)2(1) were obtained at pH 8.0 using
PEG 3000 and PEG 550 monomethylether, respectively. The unit-cell parameters were
a = 151, b = 174, c = 241 A for form I and a = 151, b = 176, c = 300 A for form
II, indicating that the asymmetric unit contains more than 20 molecules.
PMID- 10771439
TI - Crystallization and preliminary crystallographic analysis of a new crystal form
of arylsulfatase A isolated from human placenta.
AB - Depending on pH, arylsulfatase A exists in solution as a dimer or as an octamer.
The enzyme isolated from human placenta was crystallized at pH 5.4 in a new
crystal form with space group C2, unit-cell parameters a = 154.0, b = 190.3, c =
112.5 A, beta = 122.4 degrees and four subunits in the asymmetric unit. At pH 6.5
6.7, tetragonal crystals are obtained that are isomorphous to the known crystals
of recombinant arylsulfatase A obtained at pH 5.0-5.4. The crystal structure of
both forms was determined by the molecular-replacement method. The monoclinic
crystals contain octamers of the same type as found in the tetragonal form.
PMID- 10771440
TI - Crystallization and preliminary X-ray analysis of nitrous oxide reductase from
Paracoccus pantotrophus.
AB - Nitrous oxide reductase is a periplasmic respiratory protein with a novel copper
catalytic centre; it catalyses the terminal step, reduction of nitrous oxide to
nitrogen, of the bacterial denitrification process. Nitrous oxide reductase from
Paracoccus pantotrophus has been crystallized by the hanging-drop method. A
prerequisite for crystallization was the oxidation of the enzyme with potassium
ferricyanide in order to obtain homogenous oxidation states of the copper
centres. The crystals belong to space group P2(1)2(1)2(1), with unit-cell
parameters a = 116.4, b = 118.3, c = 267.0 A. Two homodimers, of approximate
molecular weight 67 kDa per subunit, probably constitute the asymmetric unit and
give a Matthews coefficient, V(m), of 3.4 A(3) Da(-1) and a solvent content of
59% by volume. The crystals diffract X-rays to 3.0 A resolution on an in-house
source and are suitable for structure determination.
PMID- 10771441
TI - Crystallization and preliminary crystallographic analysis of the high-potential
iron-sulfur protein from Thermochromatium tepidum.
AB - The high-potential iron-sulfur protein (HiPIP) is an electron carrier between the
photosynthetic reaction centre and the cytochrome bc(1) complex in the electron
transfer chain of photosynthesis. The purified HiPIP from Thermochromatium
tepidum (formerly Chromatium tepidum) was crystallized in a solution of 1.4 M
ammonium sulfate and 0.1 M sodium citrate pH 3.5. The crystals diffract X-rays
beyond 1.4 A resolution and belong to the orthorhombic space group P2(1)2(1)2(1),
with unit-cell parameters a = 47.12 (6), b = 59.59 (10), c = 23.62 (3) A. The
structure was preliminarily solved by the molecular-replacement method. The
crystal structure of HiPIP from T. tepidum showed that the proteins exist as
monomers, although HiPIPs from several other species can form dimers.
PMID- 10771442
TI - Crystallization and preliminary X-ray studies of membrane-associated Escherichia
coli dihydroorotate dehydrogenase.
AB - Dihydroorotate dehydrogenases (DHODs) are flavin-containing enzymes which
catalyse the conversion of (S)-dihydroorotate to orotate, the fourth step in the
de novo biosynthesis of pyrimidine nucleotides. Two major families of DHODs have
now been identified based on their amino-acid sequence similarities. The two
families differ in their reaction mechanisms, but structures are only known of
enzymes belonging to family 1. DHOD from Escherichia coli is a typical member of
family 2, which contains the membrane-associated enzymes from Gram-negative
bacteria and eukaryotes. Yellow crystals grown of this enzyme belong to the space
group P4(1)2(1)2 or P4(3)2(1)2. The unit-cell parameters are a = b = 119.2, c =
294.3 A. Owing to the rather large c axis, the currently available resolution of
data is 2.2 A.
PMID- 10771444
TI - Crystallization and preliminary crystallographic study of cucurmosin, a ribosome
inactivating protein from the sarcocarp of Cucurbita moschata.
AB - Cucurmosin, a ribosome-inactivating protein purified from pumpkin, the sarcocarp
of Cucurbita moschata, has been crystallized using polyethylene glycol as a
precipitant. The crystals belong to space group P2(1)2(1)2(1) and have unit-cell
parameters a = 41.91, b = 59. 48, c = 98.78 A. There is one molecule in the
asymmetric unit. The diffraction data to 3.0 A resolution were collected on a MAR
Research image-plate detector.
PMID- 10771443
TI - Cloning, expression, purification and crystallization of saccharopine reductase
from Magnaporthe grisea.
AB - The gene coding for saccharopine reductase (E.C. 1.5.1.10), an enzyme of the
alpha-aminoadipic pathway of lysine biosynthesis in the pathogenic fungus
Magnaporthe grisea, was cloned and expressed in Escherichia coli. The purified
enzyme was crystallized in space groups C2 and C222(1) using ammonium sulfate pH
4.8 or PEG 6000 pH 4. 1 as precipitants. The unit-cell parameters are a = 115.0,
b = 56.6, c = 74.3 A, beta = 111.1 degrees for space group C2, and a = 89.3, b =
119.0, c = 195.9 A for space group C222(1). The crystals diffract to resolutions
of 2.0 A (C2) and 2.4 A (C222(1)) at synchrotron sources.
PMID- 10771445
TI - Crystallization and preliminary crystallographic analysis of Thermus thermophilus
leucyl-tRNA synthetase and its complexes with leucine and a non-hydrolysable
leucyl-adenylate analogue.
AB - Leucyl-tRNA synthetase from Thermus thermophilus (LeuRSTT) is the first LeuRS to
be crystallized. Two crystal forms of the native enzyme have been obtained using
the hanging-drop vapour-diffusion method with ammonium sulfate as a precipitant.
Crystals of the first form belong to space group I422 and have unit-cell
parameters a = b = 312.4, c = 100.4 A. They diffract anisotropically to 3.5 A
resolution in the c-axis direction and to only 6 A resolution in the
perpendicular direction. Crystals of the second form, which can be obtained
native or with leucine or a leucyl-adenylate analogue bound, belong to space
group C222(1) and have unit-cell parameters a = 102. 4, b = 154.1, c = 174.3 A.
They diffract to 1.9 A resolution and contain one monomer in the asymmetric unit.
Selenomethionated LeuRSTT has been produced and crystals of the second form
suitable for MAD analysis have been grown.
PMID- 10771446
TI - Crystallization and preliminary crystallographic analysis of N-acetylglucosamine
6-phosphate deacetylase from Escherichia coli.
AB - N-Acetylglucosamine 6-phosphate deacetylase (E.C. 3.5.1.25), an enzyme from
Escherichia coli involved in aminosugar catabolism, has been crystallized by the
vapour-diffusion technique using phosphate as precipitant. X-ray diffraction
experiments show the crystals to belong to the orthorhombic crystal system, with
space group P2(1)2(1)2. The unit-cell parameters are a = 82.09 (2), b = 114.50
(1), c = 80.17 (1) A. The crystals diffract to a maximum resolution of 1.8 A and
an initial data set was collected to 2.0 A.
PMID- 10771447
TI - Introduction. Ziprasidone appears to offer important therapeutic and tolerability
advantages over conventional, and some novel, antipsychotics.
PMID- 10771448
TI - Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting
conditions in healthy male volunteers.
AB - AIMS: To evaluate the pharmacokinetics and tolerability of single and multiple
oral doses of ziprasidone in healthy male volunteers, and to determine the
influence of ziprasidone on serum prolactin levels. METHODS: Single and multiple
doses of ziprasidone were given orally (as two divided daily doses), at fixed
dosages of 10 and 40 mg day(-1), and using titrated regimens of 40-80 and 40-120
mg day(-1), for 14 days. All dosages were taken immediately after food. The study
adopted a randomized, double-blind, placebo-controlled design. Prolactin
response, sedative properties, tolerability, and extrapyramidal symptoms were
also investigated. RESULTS: Steady-state exposure to ziprasidone was attained
after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose,
with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough
to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the
fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels,
respectively. Ziprasidone was associated with transient prolactin elevation but
levels of prolactin returned to baseline within the dosing interval at steady
state. There was a marginal, transient increase in serum prolactin levels which
was not dose-related at the 80 and 120 mg day(-1) doses, and which was noted to
attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most
frequent side-effect was mild or moderate headache. A minority of patients
suffered first-dose postural hypotension. Ziprasidone was also associated with a
mild sedative effect that became less pronounced as treatment continued. There
were no drug-related changes in electrocardiogram or clinical laboratory
variables that were of clinical importance. CONCLUSIONS: Ziprasidone is
characterized by a predictable pharmacokinetic profile resulting in symptoms that
reflect its pharmacological action.
PMID- 10771449
TI - Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and
elderly volunteers.
AB - AIMS: To compare the pharmacokinetics of ziprasidone in healthy young (18-45
years) men and women, and healthy elderly (> or = 65 years) men and women.
METHODS: Eight young men, 11 young women, 8 elderly men and 8 elderly women were
given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7
days, followed by a single 20 mg dose on day 8. Serum samples were collected
immediately before the morning dose on days 1-8, for up to 12 h after dosing on
day 1 and for up to 96 h after dosing on day 8. The resulting data were used to
derive pharmacokinetic parameters of ziprasidone in each age and gender group.
RESULTS: Steady-state serum concentrations of ziprasidone were achieved within 2
3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after
the initiation of treatment, were similar in the young men, elderly men and young
women. Assessment of gender effects by analysis of variance revealed
statistically significant differences in Cmax (85 vs. 69 ng ml(-1) and tmax (3.19
vs. 4.81 h) but no differences in AUC(0,12 h) or lambda(z). Assessment of age
effects by analysis of variance revealed statistically significant differences in
AUC(0,12 h) (560 vs. 465 ng ml(-1) h), Cmax (85 vs. 69 ng ml(-1) and lambda(z)
(0.126 vs. 0.197 l h(-1) but no difference in tmax. Assessment of age and gender
effects by analysis of covariance, with body weight as the covariate, did not
reveal any significant differences. The mean t(1/2), z in the young men, young
women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively.
Standard deviations of the means for the pharmacokinetic parameters for the
elderly women tended to be large. CONCLUSIONS: The influence of age and gender on
the pharmacokinetics of ziprasidone is not clinically significant.
PMID- 10771450
TI - The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic
function.
AB - AIMS: To assess whether hepatic impairment influences the pharmacokinetics of
ziprasidone. METHODS: Thirty subjects with normal hepatic function or a primary
diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled
into an open-label, multicentre, multiple-dose study. The subjects with chronic,
stable hepatic impairment and the matched control subjects received ziprasidone
40 mg day(-1), given orally with food, as two divided daily doses for 4 days and
a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were
determined from multiple venous blood samples collected on days 1 and 5. Liver
function was evaluated quantitatively using antipyrine. RESULTS: On day 1 there
were no statistically significant differences in the pharmacokinetics (AUC(0,12
h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no
statistically significant differences in the Cmax or tmax for ziprasidone between
the two groups. The mean AUC(0,12 h) for ziprasidone was statistically
significantly greater in the hepatically impaired subjects compared with the
normal subjects (590 ng ml(-1) h vs. 467 ng ml(-1) h, P = 0. 042). However, the
AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the
matched control group. The ziprasidone lambda(z) in the subjects with normal
hepatic function was statistically significantly greater than that in the
hepatically impaired subjects (P<0.001). There was no correlation between
antipyrine lambda(z) and ziprasidone lambda(z) in the subjects with normal
hepatic function or in those with hepatic impairment. CONCLUSIONS: The findings
of this study indicate that mild to moderate hepatic impairment does not result
in clinically significant alteration of ziprasidone pharmacokinetics.
PMID- 10771451
TI - The pharmacokinetics of ziprasidone in subjects with normal and impaired renal
function.
AB - AIMS: To assess whether renal impairment influences the pharmacokinetics of
ziprasidone, and to determine whether ziprasidone is cleared via haemodialysis.
METHODS: Thirty-nine subjects with varying degrees of renal impairment were
enrolled into an open-label, multicentre, multiple-dose study and assigned to
four groups according to their renal function: normal (group 1, creatinine
clearance > 70 ml min(-1); mildly impaired (group 2, creatinine clearance 30-60
ml min(-1); moderately impaired (group 3, creatinine clearance 10-29 ml min(-1),
and severely impaired (group 4, requiring haemodialysis three times-a-week).
Subjects received ziprasidone 40 mg day(-1), given orally with food, as two
divided daily doses for 7 days and a single 20 mg dose on the morning of day 8.
Pharmacokinetic variables were determined from multiple venous blood samples
collected on days 1 and 8 (haemodialysis day for subjects with severe renal
impairment). Additional samples were collected from subjects with severe renal
impairment on day 7 (nonhaemodialysis day). RESULTS: On day 1 there were no
statistically significant differences in the pharmacokinetics (AUC(0, 12 h),
Cmax, tmax) of ziprasidone among subjects with normal renal function and those
with mild, moderate and severe renal impairment. The AUC(0,12 h) and Cmax in
subjects with mildly impaired renal function were statistically significantly
greater than in those with moderately impaired renal function (P = 0.0163
0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml(-1) h in groups 1,
2, 3 and 4, respectively. Corresponding mean Cmax values were 47, 61, 41 and 50
ng ml(-1) and corresponding mean tmax values were 5, 6, 5 and 5 h. On day 8 there
were no statistically significant differences in the pharmacokinetics (AUC(0,12
h), Cmax, tmax, lambda(z), Fb) of ziprasidone among subjects with normal renal
function and those with moderate or severe renal impairment. The AUC(0,12 h) in
subjects with mild renal impairment was statistically significantly greater than
those in the other three groups (P = 0.0025-0.0221), but this was not considered
clinically significant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml(-1)
h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 68,
93, 54 and 70 ng ml(-1), corresponding mean tmax values were 4, 5, 4 and 5 h and
corresponding mean lambda(z) were 0.14, 0.11, 0.14 and 0.17 h(-1). The mean
percentage Fb was 99.84-99.88% across all groups and the mean t(1/2),z ranged
from 4.2 to 6.4 h. Comparison of the mean AUC(0,12 h) and Cmax values in subjects
with severe renal impairment on day 7 with those on day 8 suggested that
haemodialysis does not have a clinically significant effect on the
pharmacokinetics of ziprasidone. CONCLUSIONS: The findings of this study indicate
that mild-to-moderate impairment of renal function does not result in clinically
significant alteration of ziprasidone pharmacokinetics and therefore does not
necessitate dose adjustment.
PMID- 10771452
TI - Identification of the major human liver cytochrome P450 isoform(s) responsible
for the formation of the primary metabolites of ziprasidone and prediction of
possible drug interactions.
AB - AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the
formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to
determine the kinetics of its formation and to predict possible drug interactions
by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro
metabolism of [14C]-ziprasidone was studied using human liver microsomes. The
metabolites were identified using mass spectrometry. The kinetics of metabolite
formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and
Km and Vmax were estimated from Lineweaver-Burk plots. IC50 values for the
inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and
CYP3A4, by ziprasidone, risperidone and 9-hydroxyrisperidone were also determined
using human liver microsomes from three subjects. Mean Ki values were calculated.
RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone
sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax
values for the formation of the major metabolite, ziprasidone sulphoxide
(measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol
mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and
recombinant enzymes indicated that CYP3A4 is responsible for the formation of
ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms
studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki
64-80 microM) was obtained with ziprasidone, risperidone and 9
hydroxyrisperidone. The in vivo free drug concentrations associated with
clinically effective doses of ziprasidone are at least 1500-fold lower than the
mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS:
Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and
is not expected to mediate drug interactions with coadministered CYP substrates,
at clinically effective doses.
PMID- 10771453
TI - Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive
metabolizers.
AB - AIMS: To determine whether ziprasidone alters the metabolizing activity of the
2D6 isoenzyme of cytochrome P450 (CYP2D6). METHODS: Twenty-four healthy young
subjects aged 18-45 years were screened for CYP2D6 metabolizing activity and
shown to be extensive metabolizers of dextromethorphan. These subjects were then
randomized to receive a single dose of ziprasidone 80 mg, paroxetine 20 mg or
placebo, 2 h before receiving a dose of dextromethorphan. Urine samples for the
determination of dextromethorphan concentrations were collected over the 8 h
period following dextromethorphan dosing, and used for the determination of
dextromethorphan/dextrorphan ratios. Blood samples were collected immediately
before and up to 10 h after the administration of ziprasidone or paroxetine, and
used to derive pharmacokinetic parameters of ziprasidone and paroxetine. RESULTS:
There were no statistically significant changes in the urinary
dextromethorphan/dextrorphan ratio in the ziprasidone group or the placebo group.
By contrast, there was a 10-fold increase in the urinary
dextromethorphan/dextrorphan ratio in the paroxetine group and this differed
significantly from those in the ziprasidone and placebo groups (P = 0.0001).
CONCLUSIONS: The findings of this study suggest that ziprasidone does not inhibit
the clearance of drugs metabolized by CYP2D6.
PMID- 10771454
TI - Ziprasidone and the pharmacokinetics of a combined oral contraceptive.
AB - AIMS: To determine whether multiple doses of ziprasidone alter the steady-state
pharmacokinetics of the component steroids, ethinyloestradiol and levonorgestrel,
of an oral contraceptive; to evaluate the tolerability of a co-administered
combined oral contraceptive and ziprasidone; and to compare plasma concentrations
of prolactin in subjects taking a combined oral contraceptive with placebo or
ziprasidone. METHODS: Nineteen women taking a combined oral contraceptive
(ethinyloestradiol 30 microg day(-1) and levonorgestrel 150 microg day(-1)) were
enrolled into a double-blind, placebo-controlled, two-way crossover study. They
received ziprasidone 40 mg day- 1 in two divided daily doses or placebo for 8
days (days 8-15) in one of two 21 day treatment periods separated by a 7 day
washout period. Venous blood samples were collected immediately before and up to
24 h after the morning dose of oral contraceptive and ziprasidone or placebo on
day 15 of each 21 day treatment period. These were assayed for ethinyloestradiol
and levonorgestrel and the resulting data used to derive pharmacokinetic data for
these steroids. Additional samples were collected immediately before and 4 h
after the morning dose of oral contraceptive and ziprasidone or placebo on day 15
of each 21 day treatment period for prolactin assay. All observed and volunteered
adverse events were recorded throughout the study. RESULTS: The mean AUC(0,24 h),
Cmax and tmax for ethinyloestradiol and the mean AUC(0, 24 h) and Cmax for
levonorgestrel during ziprasidone co-administration were not statistically
significantly different from corresponding values occurring during placebo co
administration. The tmax for levonorgestrel was approximately 0.5 h longer.
Concomitant therapy with a combined oral contraceptive and ziprasidone did not
result in adverse events not previously seen with either preparation alone.
CONCLUSIONS: The findings of this study suggest that, based on pharmacokinetic
and tolerability data, ziprasidone may be co-administered with ethinyloestradiol
and levonorgestrel without loss of contraceptive efficacy or increased risk of
adverse events.
PMID- 10771455
TI - The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine
or antacid.
AB - AIMS: To evaluate the effects of cimetidine and Maalox(R) (aluminium hydroxide
1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone.
METHODS: Eleven healthy young subjects aged 18-45 years were given single oral
doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one
occasion ziprasidone was administered alone, on another occasion ziprasidone was
co-administered with oral cimetidine 800 mg and on a third occasion ziprasidone
was co-administered with oral Maalox(R). RESULTS: The administration of
cimetidine increased the ziprasidone AUC(0,infinity) by 6% but there were no
statistically significant differences in Cmax, tmax or lambda(z) between the
ziprasidone+cimetidine group and the ziprasidone group. The administration of
Maalox did not produce any statistically significant differences in
AUC(0,infinity), Cmax, tmax or lambda(z) between the ziprasidone+Maalox group and
the ziprasidone group. CONCLUSIONS: The pharmacokinetics of ziprasidone are not
affected by concurrent administration of cimetidine or Maalox. This suggests that
other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to
alter the pharmacokinetics of ziprasidone.
PMID- 10771456
TI - The effects of ziprasidone on steady-state lithium levels and renal clearance of
lithium.
AB - AIMS: To assess the potential of ziprasidone to alter the renal clearance and
steady-state serum levels of lithium. METHODS: Healthy subjects who had stable
serum lithium levels during the first 7 days of treatment with lithium 900 mg
day(-1), given as two divided daily doses, were randomized to receive concomitant
treatment with either ziprasidone, 40 mg day(-1), given as two divided daily
doses, on days 9-11 followed by 80 mg day(-1), given as two divided daily doses
on days 12-15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo
was administered 2 h before each dose of lithium. RESULTS: Ziprasidone
administration was associated with a 0.07 mmol l(-1) (13%) mean increase in
steady-state serum lithium levels compared with a mean increase of 0.06 mmol l(
1) (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h(-1)
(5%) in the ziprasidone group and by 0.14 l h(-1) (9%) in the placebo group. None
of these differences between the two groups was statistically or clinically
significant. CONCLUSIONS: Ziprasidone does not alter steady-state serum lithium
concentrations or renal clearance of lithium.
PMID- 10771457
TI - The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone
in healthy volunteers.
AB - AIMS: To evaluate the effect of steady-state carbamazepine administration on the
steady-state pharmacokinetics of ziprasidone in healthy young adults, in an open,
randomised, parallel-group study. METHODS: Twenty-five subjects were randomized
to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on
days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine
was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by
200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20
mg was also administered twice daily on days 26 and 27 and in the morning only on
day 28. Group 2 received the same treatment regimen with carbamazepine replaced
by placebo. Pharmacokinetic data were obtained on days 3 and 28. RESULTS: Nine
subjects in group 1 and 10 in group 2 completed all three treatment periods
(ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or
placebo). Carbamazepine administration to group 1 was associated with modest
reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12
h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3
(P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h)
and Cmax values were also statistically significantly greater in the
carbamazepine group than in the placebo group. The mean half-life of ziprasidone
decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine,
compared with virtually no change in the placebo group. All adverse events were
mild or moderate in severity and there were no serious adverse events, or
clinically significant changes in ECGs and vital signs throughout the study.
CONCLUSIONS: Induction of CYP3A4 with carbamazepine led to a modest reduction
(<36%) in steady-state exposure to ziprasidone that is believed to be clinically
insignificant.
PMID- 10771458
TI - The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled
crossover study in healthy volunteers.
AB - AIMS: To assess the effects of multiple oral doses of ketoconazole on the single
dose pharmacokinetics of oral ziprasidone HCl. METHODS: This was a 14-day, open
label, randomized, crossover study in 14 healthy subjects aged 18-31 years. Group
1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day
wash-out period and 6 days of placebo administration. Group 2 received placebo
followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were
administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic
parameters were compared between placebo and ketoconazole administration periods.
RESULTS: Co-administration of ziprasidone with ketoconazole was associated with a
modest increase in ziprasidone exposure; mean ziprasidone AUC(0,infinity)
increased by 33%, from 899 ng ml(-1) h with placebo to 1199 ng ml(-1) h with
ketoconazole. Mean Cmax increased by 34%, from 89 ng ml(-1) to 119 ng ml(-1),
respectively. The treatment effect on both of these parameters was statistically
significant (P<0.02). Most adverse events were of mild intensity. There were no
serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically
significant alterations in vital signs throughout the study. CONCLUSIONS: The
concurrent administration of ketoconazole and ziprasidone led to modest,
statistically significant increases in ziprasidone exposure, although the changes
seen were not considered clinically relevant. This suggests that other inhibitors
of CYP3A4 are unlikely to significantly affect the pharmacokinetics of
ziprasidone.
PMID- 10771459
TI - Therapeutic strategies for psoriasis.
AB - Psoriasis is a chronic, inflammatory, hyperproliferative skin disease that
affects approximately 1-2% of the general population in the U.K. and U.S.A. It is
rarely life-threatening, but causes considerable patient morbidity. The disease
waxes and wanes, with substantial variability both between and within individual
patients. There is no cure for psoriasis; therefore, the aim of treatment is to
minimize the extent and severity of the disease to the point at which it no
longer disrupts substantially the patient's quality of life. We review the
current treatment options, which include topical therapies, phototherapy and
systemic agents. Lack of efficacy, adverse effects and aesthetic problems limit
the use of many topical therapies. Likewise, the risk of toxicity is a major
problem with currently available phototherapies and systemic treatments. Advances
in understanding the aetiology and pathogenesis of psoriasis allude to the
possibility of innovative, targeted therapies in the future.
PMID- 10771460
TI - Could a common biochemical mechanism underlie addictions?
AB - The subject of 'drug addiction' is multifaceted and many aspects of it (even some
of the definitions) are controversial. Collateral medical problems include the
spread of HIV and hepatitis C virus secondary to i.v. drug abuse and effects on
prenatal brain development (1). Progress in the understanding of the causes of
addictions and its treatment has been impeded by the lack of a unifying
biochemical theory. However, recent evidence suggests that some common mechanism
might underlie addictions to otherwise apparently unrelated drugs. A major
hypothesis has emerged suggesting that the neurotransmitter dopamine (DA) might
play a central role in the molecular mechanisms of at least some addictions. If
so, it would represent an important target for discovery of effective
pharmacotherapy and revolutionize the pharmacist's role in treating addictions.
This short overview outlines the status of the theory of a common biochemical
mechanism of drug addiction.
PMID- 10771461
TI - Controlled and targeted drug delivery strategies towards intraperiodontal pocket
diseases.
AB - Advances in the understanding of the aetiology, epidemiology, pathogenesis and
microbiology of periodontal pocket flora have revolutionized the strategies for
the management of intraperiodontal pocket diseases. Intra-pocket, sustained
release, drug delivery devices have been shown to be clinically effective in the
treatment of periodontal infections. Several degradable and non-degradable
devices are under investigation for the delivery of antimicrobial agents into the
periodontal pocket including non-biodegradable fibres, films (biodegradable and
non-biodegradable), bio-absorbable dental materials, biodegradable
gels/ointments, injectables and microcapsules. With the realization that pocket
bacteria accumulate as biofilms, studies are now being directed towards
eliminating/killing biofilm concentrations rather than their planktonic (fluid
phase) counterparts. Intraperiodontal pocket drug delivery has emerged as a novel
paradigm for the future research. Similarly, bioadhesive delivery systems are
explored that could significantly improve oral therapeutics for periodontal
disease and mucosal lesions. A strategy is to target a wide range of molecular
mediators of tissue destruction and hence arrest periodontal disease progression.
Research into regenerating periodontal structures lost as a result of disease has
also shown substantial progress in the last 25 years.
PMID- 10771462
TI - Evaluation of drug activity against intracellular forms of Trypanosoma cruzi
employing enzyme immunoassay.
AB - OBJECTIVE: To describe application of a new method for the evaluation of anti
Trypanosoma cruzi activity against intracellular forms. METHOD: Vero fibroblasts
in 96-well tissue culture plates were infected with trypomastigote forms of T.
cruzi. Amastigotes growth was estimated after 24 and 96 h both by microscopic
counts of Giemsa-stained monolayers and enzyme-linked immunoIsorbent assay
(ELISA). ELISA was performed directly on the fixed cultures using a rabbit anti
T. cruzi immunoIglobulin as the first antibody and a peroxidase-labelled
antirabbit immunoglobulin as the second antibody. Three chemical series of
structural analogous of gentian violet, thiadiazines and derivatives of 5
nitrothiophene-2-carbaldehyde as well as three reference compounds (nifurtimox,
benznidazole and gentian violet) were then assayed. The anti-T. cruzi activity of
all of them had been determined previously by microscopic counting of Giemsa
stained infected cultures. RESULTS: None of the assayed compounds showed better
activity than the reference ones, but the application of the enzyme immunoassay
to quantify the inhibition of growth amastigotes is of great interest, as it
yielded results comparable with microscopic counts. CONCLUSION: ELISA can be
applied to pharmacological screening, with some advantages over the microscopic
examination, including possible automation, rapidity and objectivity in
assessment.
PMID- 10771463
TI - Comparative effectiveness of general practitioner versus pharmacist dosing of
patients requiring anticoagulation in the community.
AB - OBJECTIVE: To compare pharmacist- with general practitioner-managed
anticoagulation in the community. DESIGN: Included in the study were all patients
who had been managed by general practitioners (GPs) and subsequently referred to
the pharmacist-led outreach service within Gateshead & South Tyneside Health
Authority. A retrospective analysis was carried out recording individual
international normalized ratio (INR) estimations, the time interval between
successive tests and whether the result resided within the prescribed therapeutic
range. These values were derived for both the GP- and pharmacist-managed elements
of care. SUBJECTS: Fifty-one patients who met the inclusion criteria identified
from eight practices had been successively treated by GPs and then by
pharmacists. Eighteen patients (35.3%) had a diagnosis of non-rheumatic atrial
fibrillation, 10 (19.6%) had thromboembolic disease and 13 (25.5%) had valvular
disease. RESULTS: In total, 1782 INR results were analysed. GPs were responsible
for 1075 (60.3%) of these estimations and pharmacists for the remaining 707
(39.7%). Of the GP-monitored results the patient-mean proportion of estimates
that resided within the prescribed therapeutic range was 0.6 (SD = 0. 21, n = 51)
compared with pharmacist management where patients showed a mean in range
proportion of 0.7 (SD = 0.18, n = 51, P = 0. 03). The mean inter-test interval
was 28.6 days (SD = 8.65, n = 51) for GPs compared with 34.1 days (SD = 12.3, n =
51, P = 0.01) for pharmacists. The weighted INR index for GPs was 17.2 (SD =
7.93, n = 51) compared with 24.7 (SD = 13.15, n = 51, P < 0.001) for pharmacists.
CONCLUSION: There is no apparent detriment to INR control when pharmacist
management is compared with that of GPs. The overall proportion of INR
estimations within the prescribed range is greater for pharmacists than for GPs
and the interval between tests is longer for pharmacists compared with GPs.
PMID- 10771464
TI - A linear regression model to predict the pH of neonatal parenteral nutrition
solution.
AB - INTRODUCTION: Providing the high calcium intake necessary for normal bone
mineralization in rapidly growing very low birth weight infants is difficult
because calcium and phosphorus solubility is limited in the range of parenteral
nutrition pH. A major determinant of calcium and phosphorus solubility in vitro
is solution pH. The objective of this study was to develop and assess the
accuracy of a method to predict the final parenteral solution pH as a linear
function of the individual parenteral component concentrations. METHODS: pH
values were measured for 205 neonatal parenteral nutrition solutions prepared
during a 5-week period. Concentrations of the 13 components used to synthesize
parenteral nutrition were determined for each solution. Data from 135 samples
were used to develop a linear regression coefficient model with pH as the
dependent variable. From the regression model the pH was predicted for the
remaining 70 samples using the seven significant solution component
concentrations, and the predicted and measured solution pH values were compared.
RESULTS: The mean measured parenteral nutrition pH for all solutions was 5.364 +/
0.110 (mean +/- SD, range 5.03-5.73). The absolute mean pH difference between
the predicted and measured value for the 70 test samples was 0.04 +/- 0.04. pH
estimated with the model correlated highly with measured pH (r2 = 0.77). The
seven components in the regression model accounted for 81% of the pH variance.
CONCLUSION: The pH of neonatal parenteral nutrition solutions can be predicted
accurately as a linear function of the solution concentrations of the following
seven components: sodium acetate, sodium phosphate, potassium phosphate,
potassium acetate, magnesium sulphate, amino acid solution and dextrose. The
absolute mean difference between measured pH and predicted pH was 0.04. Applying
this method to estimate pH with the interactive properties of computer-based
ordering systems could enhance calcium and phosphorus administration to very low
birth weight infants.
PMID- 10771465
TI - Treatment of depression related to recurrence: 10-year follow-up in general
practice.
AB - OBJECTIVES: To study outcomes related to long-term treatment of depression and
differences in treatments for first episodes of depression in patients with and
without recurrences. METHODS: A historic cohort design study with 222 general
practice patients who had been followed up for 10 years after being diagnosed of
depression. Prescriptions for antidepressants, psychotropics and referrals over
the period of 10 years following the first diagnosis of depression were studied.
RESULTS: Over the 10-year period, the length of treatment with antidepressants
and the doses prescribed were low compared to what is known to be efficacious in
depression. This was also true for treatment during the first episode. Patients
with a recurrent type of illness were more often treated with antidepressants and
other psychotropics during their first episode than patients with only one
episode of depression, but they were not referred any more often. CONCLUSION:
Even though treatment was not as recommended for depression, the majority of the
patients did not have recurrences. Future prospective research is needed to study
causal relationships between treatment of depression and long-term outcome.
PMID- 10771467
TI - Alfuzosin-induced hepatotoxicity.
AB - Drug-induced hepatic injury is a potential complication of virtually all drugs
because the liver is central to the metabolic disposition of almost all drugs,
although precise mechanisms often are unknown. We report a case of severe acute
mixed hepatitis (cholestatic and hepatocellular), probably induced by alfuzosin.
This event has not been reported previously (MEDLINE 1990, March 1999). Viral
causes, autoimmune hepatitis and biliary tree obstruction were excluded. After
discontinuation of the drug, liver function test results returned to normal.
PMID- 10771466
TI - Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5
fluorouracil on plasma insulin-like growth factor-I and chosen hormones in breast
cancer pre-menopausal patients.
AB - OBJECTIVE: : To investigate the effect of chemotherapy on levels of IGF-I in
patients with breast cancer. BACKGROUND: The latest reports on the role of the
insulin-like growth factor (IGF)-I in breast cancer pathogenesis emphasize the
importance of the effect of therapy on plasma IGF-I concentration and more
generally on the hormonal state of the patient. METHOD: Twenty-four breast cancer
patients on adjuvant chemotherapy with cyclophosphamide, methotrexate and 5
fluorouracil (CMF) were studied along with 16 healthy pre-menopausal women.
RESULTS: Plasma IGF-I concentration (determined by RIA method) in breast cancer
patients prior to treatment did not differ significantly from that of healthy
women, but it was significantly decreased after the first cycle of CMF, and
significantly lowered as compared to a group of healthy women. CONCLUSION:
Further research into the significance of these findings is necessary. No
interaction was found between mean IGF-I and growth hormone, prolactin,
estradiol, progesterone, cortisol, met-enkephalin or melatonin concentrations.
PMID- 10771468
TI - In this issue
PMID- 10771469
TI - Regular articles: conditional disruption of hedgehog signaling pathway defines
its critical role in hair development and regeneration.
AB - Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been
shown to be essential for the development of various organ systems, including
neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog
and its cognate receptor Patched are expressed in the epithelial and/or
mesenchymal cell components of the hair follicle. Recent studies have
demonstrated an essential role for this pathway in hair development in the skin
of Sonic hedgehog null embryos. We have further explored the role of the hedgehog
pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice
at different stages of gestation and have generated viable offspring that lack
body coat hair. Histologic analysis revealed the presence of ectodermal placode
and primodium of dermal papilla in these mice, yet the subsequent hair shaft
formation was inhibited. In contrast, the vibrissae (whisker) development appears
to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment.
Strikingly, inhibition of body coat hair morphogenesis also was observed in mice
treated postnatally with anti-hedgehog monoclonal antibody during the growing
(anagen) phase of the hair cycle. The hairless phenotype was reversible upon
suspension of monoclonal antibody treatment. Taken together, our results
underscore a direct role of the Sonic hedgehog signaling pathway in embryonic
hair follicle development as well as in subsequent hair cycles in young and adult
mice. Our system of generating an inducible and reversible hairless phenotype by
anti-hedgehog monoclonal antibody treatment will be valuable for studying the
regulation and mechanism of hair regeneration.
PMID- 10771470
TI - Active hair growth (anagen) is associated with angiogenesis.
AB - After the completion of skin development, angiogenesis, i.e., the growth of new
capillaries from pre-existing blood vessels, is held to occur in the skin only
under pathologic conditions. It has long been noted, however, that hair follicle
cycling is associated with prominent changes in skin perfusion, that the
epithelial hair bulbs of anagen follicles display angiogenic properties, and that
the follicular dermal papilla can produce angiogenic factors. Despite these
suggestive observations, no formal proof is as yet available for the concept that
angiogenesis is a physiologic event that occurs all over the mature mammalian
integument whenever hair follicles switch from resting (telogen) to active growth
(anagen). This study uses quantitative histomorphometry and double
immunohistologic detection techniques for the demarcation of proliferating
endothelial cells, to show that synchronized hair follicle cycling in adolescent
C57BL/6 mice is associated with substantial angiogenesis, and that inhibiting
angiogenesis in vivo by the intraperitoneal application of a fumagillin
derivative retards experimentally induced anagen development in these mice. Thus,
angiogenesis is a physiologic event in normal postnatal murine skin, apparently
is dictated by the hair follicle, and appears to be required for normal anagen
development. Anagen-associated angiogenesis offers an attractive model for
identifying the physiologic controls of cutaneous angiogenesis, and an
interesting system for screening the effects of potential antiangiogenic drugs in
vivo.
PMID- 10771471
TI - Serpins in the human hair follicle.
AB - Proteinases and their inhibitors are very likely to function as mediators or
regulators of the hair growth cycle. Very little information is currently
available, however, regarding the specific inhibitors present in human hair
follicles at defined stages of their growth cycle. In this study we have analyzed
two proteinase inhibitors, plasminogen activator inhibitor type 2 and protease
nexin 1, in human hair follicles using in situ hybridization and/or
immunohistochemistry. Protease nexin 1 mRNA was found only in the mesenchymal
population of the hair follicle, i.e., the follicular papilla cells, during the
anagen but not the catagen phase. In contrast, plasminogen activator inhibitor
type 2 was localized to several epithelial populations in the follicle: the more
differentiated cells of the infundibulum; the companion layer in anagen
follicles; and the single layer of outer root sheath cells directly abutting the
club hair in telogen follicles. At least some of the plasminogen activator
inhibitor type 2 in human follicles appears to be in the relaxed form, as
evidenced by strong staining with an antibody that is specific for this form of
the inhibitor. This suggests that plasminogen activator inhibitor type 2
interacts with and is cleaved by an endogenous follicular proteinase and supports
a constitutive role for this inhibitor in human follicular epithelia.
PMID- 10771472
TI - Topical retinoic acid enhances, and a dark tan protects, from subedemal solar
simulated photocarcinogenesis.
AB - Studies into the effects of topical retinoic acid on photocarcinogenesis have
yielded ambiguous findings. This may be due to different Experimental protocols
and ultraviolet spectra. Retinoic acid is commonly used for a range of
dermatologic conditions, and therefore it is important to resolve whether it
affects skin tumor formation. To address this issue we used a protocol to mimic
as closely as possible human use of retinoic acid. Two mouse strains were used:
Skh:HR-1 (albino) and Skh:HR-2 (lightly pigmented). The pigmented mice more
closely resemble Caucasian skin as they develop a light tan in response to
ultraviolet radiation. This tan is greatly augmented by retinoic acid. As these
are congenic mice, any differences can be attributed to the development of a tan.
Mice were exposed to solar-simulated ultraviolet radiation, followed by treatment
with 0.05% retinoic acid. This modeled exposure to sunlight during the day
followed by retinoic acid treatment and a night-time period in the absence of
sunlight. As it is recommended that ultraviolet exposure is minimized when using
topical retinoic acid, the mice were only exposed to one-third of minimal edemal
dose of ultraviolet radiation per day. This retinoic acid protocol augmented
photocarcinogenesis. Retinoic acid decreased the latency period, reduced the
probability that a mouse would survive without a tumor, and increased the number
of tumors per mouse. All tumors induced were squamous cell carcinomas, and the
skin between the tumors on mice treated with retinoic acid was found to contain
carcinoma in situ upon histologic diagnosis. The light tan of the solvent-treated
pigmented mice did not provide any protection, whereas the dark tan, which
developed in Skh:HR-2 mice in response to retinoic acid, reduced
photocarcinogenesis but did not overcome the augmenting effect of retinoic acid.
Thus, using this experimental design, topical retinoic acid augmented
photocarcinogenesis, and the ability to develop a dark but not light tan provided
some, but limited, protection.
PMID- 10771473
TI - Interleukin-18 and the costimulatory molecule B7-1 have a synergistic anti-tumor
effect on murine melanoma; implication of combined immunotherapy for poorly
immunogenic malignancy.
AB - Interleukin-18 has been described recently as a cytokine secreted primarily by
Kupffer cells. Furthermore, it has been shown that it has significant anti-tumor
effects, which are mediated by T cells and natural killer cells, in a manner
similar to interleukin-12. Here, we report the evaluation of the effects of the
systemic administration of interleukin-18 in combination with B7-1 (CD80)
expressed on tumor cells [interleukin-18 + B7-1] on the growth of murine B16
melanoma in vivo. After the subcutaneous inoculation of B16 melanoma, B16 tumors
grew progressively in immunocompetent syngeneic C57BL/6 mice. Mice treated with
either interleukin-18 or immunized with B7-1-transduced B16 did not demonstrate
significant anti-tumor effect. The combination of the two treatments, however,
resulted in dramatic suppression of melanoma formation, tumor growth, and a
significant improvement in survival. Inhibitory effects of [interleukin-18 + B7
1] on lung metastasis in mice were also detected. Additionally, mice treated with
[interleukin-18 + B7-1] showed an increase of natural killer cytotoxicity and
interferon-gamma production in vivo. Unlike [interleukin-18 + B7-1], [interleukin
12 + B7-1] did not have a strong anti-tumor effect against B16 melanoma.
Histologic characterization after the [interleukin-18 + B7-1] treatment confirmed
the infiltration of natural killer cells into the tumor, suggesting that natural
killer cells may be involved in the [interleukin-18 + B7-1]-induced anti-tumor
effect. This finding was confirmed by showing that depletion of NK1.1+ cells
before immunization inhibits the [interleukin-18 + B7-1]-induced anti-tumor
effect. Depletion of CD3+ cells in vivo also decreased the anti-tumor effect of
[interleukin-18 + B7-1], suggesting the importance of CD3+ T cells. Collectively,
combination with interleukin-18 and B7-1 expression has synergistic anti-tumor
effects against B16 murine melanoma.
PMID- 10771474
TI - Effects of betulinic acid alone and in combination with irradiation in human
melanoma cells.
AB - Recently, betulinic acid was identified as a highly selective inhibitor of human
melanoma growth and was reported to induce apoptosis in these cells. We have
investigated the growth-inhibitory properties of this compound alone and in
combination with ionizing radiation in a panel of established human melanoma cell
lines as well as in normal human melanocytes. Betulinic acid strongly and
consistently suppressed the growth and colony-forming ability of all human
melanoma cell lines investigated. In combination with ionizing radiation the
effect of betulinic acid on growth inhibition was additive in colony-forming
assays. Betulinic acid also induced apoptosis in human melanoma cells as
demonstrated by Annexin V binding and by the emergence of cells with apoptotic
morphology. The growth-inhibitory action of betulinic acid was more pronounced in
human melanoma cell lines than in normal human melanocytes. Notably, despite the
induction of apoptosis, analysis of the expression of Bcl-2 family members in
betulinic-acid-treated cells revealed that expression of the anti-apoptotic
protein Mcl-1 was induced. Furthermore, the antiproliferative action of betulinic
acid seemed to be independent of the p53 status. The properties of betulinic acid
make it an interesting candidate, not only as a single agent but also in
combination with radiotherapy. We conclude that the strictly additive mode of
growth inhibition in combination with irradiation suggests that the two treatment
modalities may function by inducing different cell death pathways or by affecting
different target cell populations.
PMID- 10771475
TI - Expression of CD94/NKG2 subtypes on tumor-infiltrating lymphocytes in primary and
metastatic melanoma.
AB - Natural killer receptors are expressed both on natural killer populations and
subpopulations of T cells, mainly alpha/beta TCR+CD8+ T cells. We have
characterized the expression of the C-type lectin natural killer receptor
CD94/NKG2 on tumor-infiltrating lymphocytes in primary and metastatic melanoma
lesions. By immunohistochemistry, 5-10% of the tumor-infiltrating lymphocytes,
both in primary and metastatic lesions, expressed CD94. More than 95% of these
CD94+ cells coexpressed CD8 and the percentage of CD94 expression within the CD8+
cell population ranged from 5 to 20% with a higher expression in metastatic
lesions. CD94/NKG2 exists both in an inhibitory and an activating form; thus, it
was necessary to determine whether the inhibitory CD94/NKG2-A/B, the activating
CD94/NKG2-C/E, or both were expressed on tumor-infiltrating lymphocytes. Reverse
transcription-polymerase chain reaction using specific primers for NKG2-A/B and
C/E mRNA revealed the presence of NKG2-C/E in all primary and metastatic lesions.
In contrast, the inhibitory NKG2-A/B was only present in 50% of primary tumors
whereas 80% of tumor-infiltrating lymphocytes in metastatic lesions expressed
these transcripts. In healthy humans, the mean number of inhibitory natural
killer receptors is higher than that of activating receptors, but the opposite
was true for tumor-infiltrating lymphocytes in melanoma. The reversal of the
ratio of inhibitory to activating natural killer receptors among tumor
infiltrating lymphocytes suggests a regulated event due to either specific
factors within the tumor microenvironment, preferential homing of T cell subsets,
or certain stages of T cell activation.
PMID- 10771476
TI - Postnatal lethality of P-cadherin/desmoglein 3 double knockout mice:
demonstration of a cooperative effect of these cell adhesion molecules in tissue
homeostasis of stratified squamous epithelia.
AB - To investigate the cooperativity of different cell adhesion molecules in
maintaining the structural integrity of the epidermis, we have generated mice
deficient for both a classical cadherin, P-cadherin, and a desmosomal cadherin,
desmoglein 3. In epithelial cells, P-cadherin is localized to the adherens
junction, whereas desmoglein 3 is found in desmosomes. Previous studies have
shown that these two junctional complexes are important for keratinocyte cell
cell adhesion. Both P-cadherin and desmoglein 3 expression are restricted to the
basal and most immediate suprabasal cells of the epidermis, whereas both proteins
are found throughout the oral mucosal epithelium. Although P-cadherin mutant mice
have no apparent defect in epithelial cell adhesion, the desmoglein 3 mutant
phenotype resembles that of patients with the autoimmune disease pemphigus
vulgaris, in that the mice develop spontaneous mucous membrane blisters and
trauma-induced skin blisters. The oral lesions in DSG3-/- mice reduce their food
intake, resulting in a runted phenotype; however, most animals recover and live
past weaning age. In contrast, animals mutant for both P-cadherin and desmoglein
3 die before weaning. The majority of the double mutant animals die around 1 wk
after birth, apparently due to malnutrition. These studies suggest that loss of P
cadherin leads to a more severe desmoglein 3 mutant phenotype in the double
knockout mice. This is the first in vivo evidence of possible synergism between a
classical and desmosomal cadherin.
PMID- 10771477
TI - Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts.
AB - Extracellular matrix hyaluronan is prominent during wound healing, appearing at
elevated levels early in the repair process. It is prevalent throughout the
course of fetal wound healing, which is scar-free, but decreases late in adult
wound repair, that is often marked by scarring. To determine whether aberrant
hyaluronan metabolism is associated with the excessive scarring that
characterizes keloids, cultured fibroblasts derived from keloids and from the
dermis of normal human skin and scar were compared. Levels of hyaluronan in 48 h
conditioned media of keloid-derived cultures were significantly lower than in
cultures of normal skin and scar fibroblasts. Profiles of hyaluronan polymer size
were comparable in these two cell types, suggesting that excessive hyaluronan
degradation was not involved. Hydrocortisone decreased hyaluronan levels
approximately 70% in the conditioned media of both keloid and normal fibroblasts.
Diminished hyaluronan accumulation in keloid-derived cells compared with normal
fibroblasts was also observed in an in vitro wound healing model.
Histolocalization of hyaluronan in keloids, normal skin, and scar samples
confirmed the biochemical observations that the dermis of keloids, which
comprises most of the scar tissue, contained markedly diminished levels of
hyaluronan. Alterations in hyaluronan in the epidermis overlying keloids,
however, were also observed. A modest increase in hyaluronan staining intensity
was observed in the epidermis of keloids, as well as changes in the patterns of
distribution within the epidermis, compared with that in normal skin and scar.
Increased hyaluronan was present in the granular and spinous layers of the keloid
epidermis Abnormalities are present apparently in both the overlying epidermis as
well as in the dermis of keloids. Aberrations in signaling between keloid stroma
and keloid epidermis may underlie abnormalities that contribute to the excessive
fibrosis characteristic of these lesions.
PMID- 10771478
TI - Identification of two secreted phospholipases A2 in human epidermis.
AB - Phospholipases A2 are enzymes that catalyze the release of fatty acids from the
sn-2 position of phospholipids. Fatty acids have been suggested to play a key
role in the barrier function of the epidermis. The aim of this study was to
identify and characterize the type of secretory phospholipase A2 expressed in
human epidermis. We report the molecular cloning of two secretory phospholipase
A2 in the human epidermis. The first enzyme is identical to human pancreatic type
IB phospholipase A2. Western blots revealed a 14 kDa protein localized in the
soluble fraction. The second phospholipase A2 is identical to human synovial type
IIA enzyme and is localized in the membrane fraction. By semiquantitative reverse
transcription-polymerase chain reaction performed on horizontal sections of the
epidermis, we found that the mRNAs of both phospholipases A2 were expressed
mainly in the basal layers of the epidermis. Our data thus provide evidence for
the expression of two secretory phospholipases A2 in human epidermis. The
different localization of these two secretory proteins strongly suggests that
each enzyme might have a specific role in skin physiology and probably in the
barrier function. Taken together, these data validate the reverse transcription
polymerase chain reaction technique performed on thin sections as a first
approach to detect gene expression in different layers of the epidermis.
PMID- 10771479
TI - SPRR1 gene induction and barrier formation occur as coordinated moving fronts in
terminally differentiating epithelia.
AB - Stratified, terminally differentiated epithelia, such as epidermis and oral
epithelia, provide protective barriers against the environment. We recently
developed wholemount assays that demonstrate epidermal barrier function during
late gestation and showed that epidermal barrier forms at specific sites
(epidermal initiation sites), and then spreads around the body as apparent moving
fronts. We now ask if this is a fundamental and widespread mode of epithelial
developmental change. If so, then the pattern should be apparent when assaying
for developmental change other than barrier institution (e.g., gene induction)
and similar types of patterned change should be apparent in other types of
epithelia. In this study we demonstrate patterned barrier function in a range of
additional stratified epithelia from the oral cavity and show that the gene
induction pattern of a stratum corneum precursor small proline-rich region
protein 1 (SPRR1) precedes barrier function and occurs in the barrier pattern,
i.e., gene induction occurs first at initiation sites and propagates across
epithelia as apparent moving fronts. These results demonstrate that late
gestational developmental change in multiple terminally differentiating epithelia
occurs via initiation sites and moving fronts. The pattern precedes barrier
formation and results in a developmental gradient that influences gene induction.
PMID- 10771480
TI - Critical role of neutrophils for the generation of psoriasiform skin lesions in
flaky skin mice.
AB - Although T cell dysregulation is thought to underlie the pathogenesis of
psoriasis, prominent infiltration and microabscess formation by neutrophils is a
distinctive hallmark feature of this common disorder. The exact role of
neutrophils in the pathogenesis of psoriasiform alterations in vivo, however, is
unknown. Similar to human psoriasis, flaky skin mice (fsn/fsn) revealed a
prominent infiltrate of neutrophils, and microabscesses within the
hyperproliferative epidermis were associated with de novo expression of
intercellular adhesion molecule-1. Intraperitoneal injection with the neutrophil
depleting RB6-8C5 monoclonal antibody (anti-Ly-6G) resulted in a dramatic
reduction of the epidermal thickness by 58% compared with isotype-treated animals
(p < 0.001). In addition, epidermal microabscesses were conspicuously absent (p <
0.001), and cutaneous neutrophils and T cells, but not mast cells or dendritic
cells, were markedly reduced in anti-Ly-6G-treated mice. Proinflammatory
cytokines, including tumor necrosis factor alpha and interleukin-1, were also
downregulated. Therapeutic effects occurred as early as 4 d after beginning of
treatment. Wildtype skin was not affected. When the integrin alphaMbeta2
(CD11b/CD18), which mediates neutrophil localization through binding to
intercellular adhesion molecule-1, was blocked in vivo with the M1/70 monoclonal
antibody, the epidermal thickness was reduced by 31% (p < 0.002), and neutrophil
and T cell accumulation was diminished compared with control animals. Likewise,
treatment of fsn/fsn mice with the MP1-22E9 monoclonal antibody neutralizing
granulocyte macrophage-colony stimulating factor, a cytokine stimulating
neutrophils by upregulating alphaMbeta2, resulted in significant reduction of
inflammation and acanthosis by 30% (p < 0.003). These results demonstrate a
critical pathogenic role of neutrophils for hyperproliferative inflammatory
lesions in fsn/fsn mice, suggesting that blocking neutrophil function may have
therapeutic benefit in some human skin disorders.
PMID- 10771481
TI - Increased oxidative damage to fibroblasts in skin with and without lesions in
psoriasis.
AB - Differences in oxidative damage, as measured by an increase in the carbonylation
of macromolecules, were determined in situ with skin biopsies from psoriatic
patients and controls. High levels of carbonyl residues were consistently
detected in the dermis and never in the epidermis of sections of these skin
biopsy samples. The dermis of psoriatic skin without lesions had a higher level
of carbonylation than the dermis of normal skin. In this study, we found that
there was more oxidative damage in cultured fibroblasts prepared from skin with
and without lesions from psoriasis patients than in normal fibroblasts from the
skin of age-matched controls. The extent of protein carbonylation in cell
extracts was determined by immunoblotting, using an antidinitrophenylhydrazone
antibody, and in intact cells was determined by immunocytochemical analysis with
the same antibody. The higher level of carbonylation detected was used here as a
measure of oxidative stress, and showed that some oxidative damage occurred
before the appearance of typical psoriatic plaques. These results suggest that
fibroblasts are affected before the onset of psoriasis and that this damage is
independent of any inflammatory infiltrate.
PMID- 10771482
TI - Role of cytoplasmic dynein in melanosome transport in human melanocytes.
AB - Cytoplasmic dynein is a microtubule-associated retrograde-directed motor molecule
for transport of membrane-bound organelles. To determine whether cytoplasmic
dynein is expressed in melanocytes, we performed reverse transcriptase polymerase
chain reaction using melanocyte cDNA and primers complementary to human brain
cytoplasmic dynein heavy chain. A polymerase chain reaction product of the
expected molecular size was generated and the identity was confirmed by sequence
analysis. Western blotting of total melanocyte proteins reacted with an anti
intermediate chain cytoplasmic dynein antibody identified the appropriate 74 kDa
band. To determine whether cytoplasmic dynein plays a role in melanosome
transport, duplicate cultures were treated with cytoplasmic dynein antisense or
sense (control) oligodeoxynucleotides and the cells were observed by high
resolution time-lapse microscopy, which allows visualization of melanosomal
aggregates and individual melanosomes. Antisense-treated melanocytes demonstrated
a strong anterograde transport of melanosomes from the cell body into the
dendrites, whereas melanosome distribution was not affected in sense-treated
melanocytes. To determine whether ultraviolet irradiation modifies cytoplasmic
dynein expression, melanocyte cultures were exposed to increasing doses of solar
simulated irradiation, equivalent to a mild to moderate sunburn exposure for
intact skin. Within 24 h, doses of 5 and 10 mJ per cm2 induced cytoplasmic dynein
protein, whereas doses of 30 mJ per cm2 or more were associated with decreased
levels of cytoplasmic dynein compared with sham-irradiated controls. Our data
show that cytoplasmic dynein participates in retrograde melanosomal transport in
human melanocytes and suggest that the altered melanosomal distribution in skin
after sun exposure is due, at least in part, to decreased cytoplasmic dynein
levels resulting in augmented anterograde transport.
PMID- 10771483
TI - IgG autoantibodies from bullous pemphigoid patients recognize multiple antigenic
reactive sites located predominantly within the B and C subdomains of the COOH
terminus of BP230.
AB - Bullous pemphigoid is a subepidermal bullous disorder characterized by an
autoantibody response against the bullous pemphigoid antigen 230 (BP230) and the
bullous pemphigoid antigen 180 (BP180), a cytoplasmic component and a
transmembrane component, respectively, of hemidesmosomes. Although immunodominant
sequences within the extracellular domain of BP180 have been identified,
characterization of the antigenic sites on BP230 is still incomplete. To identify
autoantibody-reactive sites on BP230 and to examine whether the targeted regions
are contained within functionally important domains, recombinant fragments
encompassing almost the entire BP230 were used to assess the reactivity of 25
bullous pemphigoid sera by immunoblotting. Our results demonstrate that (i) the
region bearing the B and C subdomains of the COOH-terminus of BP230 contains
immunodominant sequences recognized by the majority of bullous pemphigoid sera;
(ii) additional autoantibody- reactive sites are present over extended regions of
the NH2-terminal half of BP230 without evidence for antigenic cross-reactivity
between the NH2- and COOH-termini of BP230; and, finally, (iii) autoantibodies
reacting with the BP230 tail predominantly belong to the IgG4 and IgG1
subclasses, suggesting that both autoreactive TH2 and autoreactive TH1 cells
regulate the autoantibody response to immunodominant sequences of BP230. As the
COOH- terminus of BP230 mediates the attachment of keratin intermediate filaments
to the hemidesmosomal plaque, whereas its NH2-terminus contains sequences
important for its interaction with other constituents of hemidesmosomes,
autoantibodies to BP230 might precipitate subepidermal blister formation and
perpetuate the disease not only by eliciting an inflammatory reaction but also by
interfering with the function of BP230 and thus the stability of hemidesmosomes.
PMID- 10771484
TI - FRAP DNA-dependent protein kinase mediates a late signal transduced from
ultraviolet-induced DNA damage.
AB - Ultraviolet radiation induces signal transduction at both early (<6 h) and late
(>6 h) times after exposure. The inflammatory and immunosuppressive cytokine
tumor necrosis factor alpha is induced at late times, and is induced by
ultraviolet-induced DNA damage, as defects in DNA repair increase, and enhanced
photoproduct repair reduces, tumor necrosis factor alpha expression. Here we show
that late tumor necrosis factor alpha gene expression is sensitive to rapamycin,
implicating FKBP12-rapamycin-associated protein, a member of the DNA protein
kinase family, as a signal transducer of ultraviolet-induced DNA damage. FKBP12
rapamycin-associated protein was localized in the nucleus of keratinocytes and
its level was increased following ultraviolet irradiation. Immuno- precipitated
FKBP12-rapamycin-associated protein was stimulated by ultraviolet-irradiated DNA
to phosphorylate p53 in vitro, and in vivo rapamycin reduced ultraviolet
induction of p53 by 20%. Rapamycin further inhibited the ultraviolet-induced
phosphorylation of the FKBP12-rapamycin-associated protein downstream target
kinase p70S6K. In mice, topical application of rapamycin before ultraviolet
exposure protected against suppression of the contact hypersensitivity that is a
hallmark of ultraviolet-induced cytokine gene expression. These results
demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces
the signal of ultraviolet-induced DNA damage into production of immunosuppressive
cytokines at late times after ultraviolet irradiation.
PMID- 10771485
TI - Competition analysis of the human alpha2(I) collagen promoter using synthetic
oligonucleotides.
AB - Previous studies have identified four cis-response elements which mediate the
basal transcriptional activity of the human alpha2(I) collagen gene. One of these
elements, a pyrimidine-rich region (TCCCCC motif), was shown to be a repressor
site, and the other three elements were shown to be activator sites. Furthermore,
the repressor site and two of the activator sites were found to constitute
binding sites for the transcription factors Sp1 and Sp3. In this study, we
further determined the affinity and specificity of the binding of Sp1 and Sp3 to
the human alpha2(I) collagen promoter and investigated the function of the
pyrimidine-rich region which contains the TCCCCC motif. Functional analyses of
Sp1 and Sp3 in Drosophila cells confirmed that Sp1 and Sp3 activate the human
alpha2(I) collagen promoter via the GC boxes and the TCCTCC motif, but that
binding of Sp1 or Sp3 to the repressor site does not activate or repress the
collagen promoter activity. Com- petitive analyses using DNA mobility shift
assays showed that the TCCCCC motif which constitutes the repressor site
abolished the binding of Sp1 or Sp3 to the GC boxes or the TCCTCC motif, but not
the binding of CCAAT-binding factor to the fourth cis-response element (CCAAT
binding factor site). Furthermore, the affinity of Sp1 or Sp3 for the TCCTCC
motif was shown to be greater than that of the Sp1 consensus oligonucleotide. In
vitro transcription analysis revealed that the addition of each activator site
oligonucleotide or repressor site oligonucleotide had an inhibitory effect on the
transcription of the collagen gene. These results suggest that the repressor site
regulates the transcription of the collagen gene by taking away Sp1 or Sp3 from
the activator sites.
PMID- 10771486
TI - Mutations and allelic loss of the NF2 gene in neurofibromatosis 2-associated skin
tumors.
AB - Schwannomas in the skin are frequently observed in neurofibromatosis 2 patients.
In about one-quarter of the cases, skin tumors are the first clinical symptoms of
this disease. Recognizing neurofibromatosis-2-related skin tumors is therefore
important for early diagnosis of neurofibromatosis 2, especially in pediatric
patients. In this study, we examined 40 skin tumors (36 schwannomas and four
neurofibromas) from 20 neurofibromatosis 2 patients for NF2 mutations and allelic
loss. NF2 mutations have been identified in blood from 15 (75%) of the 20
patients. We found NF2 mutations in five (13%) and NF2 allelic loss in 18 (45%)
of the 40 analyzed tumors. Genetic alterations (allelic loss or mutation) were
thus found in 50 (63%) out of the total of 80 examined alleles. In 17 (43%)
tumors, alterations were found on both NF2 alleles. These results suggest that,
as in the case of vestibular schwannomas and meningiomas, loss of functional NF2
gene product is also the critical event in the development of skin schwannomas.
Identification of genetic alterations of the NF2 gene in skin tumors may help to
identify neurofibromatosis-2-associated skin tumors, thus assisting in the
diagnosis of neurofibromatosis 2 in ambiguous cases, and excluding
neurofibromatosis 1 in unclear cases. We also report that the detection rate of
constitutional mutations was higher in patients with skin tumors (65%) than in
patients without skin tumors (40%).
PMID- 10771487
TI - Reinvestigation of the classification of five cell strains of xeroderma
pigmentosum group E with reclassification of three of them.
AB - Xeroderma pigmentosum is a photosensitive syndrome caused by a defect in
nucleotide excision repair or postreplication repair. Individuals of xeroderma
pigmentosum group E (xeroderma pigmentosum E) have a mild clinical form of the
disease and their cells exhibit a high level of nucleotide excision repair as
measured by unscheduled DNA synthesis, as well as biochemical heterogeneity. Cell
strains from one group of xeroderma pigmentosum E patients have normal damage
specific DNA binding activity (Ddb+), whereas others do not (Ddb-). Using a
refinement of a previously reported cell fusion complementation assay, the
previously assigned Ddb+ xeroderma pigmentosum E strains, XP89TO, XP43TO, and
XP24KO, with various phenotypes in DNA repair markers, were reassigned to
xeroderma pigmentosum group F, xeroderma pigmentosum variant, and ultraviolet
sensitive syndrome, respectively. The Ddb- xeroderma pigmentosum E strains,
XP82TO, and GM02415B, which showed almost normal cellular phenotypes in DNA
repair markers, however, remained assigned to xeroderma pigmentosum group E. With
the exception of the Ddb+ strain XP89TO, which demonstrated defective nucleotide
excision repair, both Ddb- and Ddb+ xeroderma pigmentosum E cells exhibited the
same levels of variation in unscheduled DNA synthesis that were seen in normal
control cells. By genome DNA sequencing, the two Ddb- xeroderma pigmentosum E
strains were shown to have mutations in the DDB2 gene, confirming previous
reports for XP82TO and GM02415B, and validating the classification of both cells.
As only the Ddb- strains investigated remain classified in the xeroderma
pigmentosum E complementation group, it is feasible that only Ddb- cells are
xeroderma pigmentosum E and that mutations in the DDB2 gene are solely
responsible for the xeroderma pigmentosum E group.
PMID- 10771488
TI - High-pressure freezing provides new information on human epidermis: simultaneous
protein antigen and lamellar lipid structure preservation. Study on human
epidermis by cryoimmobilization.
AB - Current transmission electron microscopy techniques do not permit simultaneous
visualization of skin ultrastructure and stratum corneum extracellular lipids. We
developed a new procedure, which entails application of high-pressure freezing
followed by freeze-substitution with acetone containing uranyl acetate, followed
by low temperature embedding in HM20. Electrospray ionization mass spectrometry
showed that the amount of lipids lost during preparation was minimal. The
ultrastructure of cryoprocessed skin was compared with that of conventionally
prepared skin samples. Cryoprocessing, but not conventional processing, enabled
visualization of lipid stacks within epidermal lamellar bodies, as well as the
extracellular lipid domains of the stratum corneum and the ultrastructure within
keratinocytes. Anti-filaggrin immunocytochemistry also showed, e.g., excellent
preservation of filaggrin on cryoprocessed samples. Additionally, the cytosol of
keratinocytes appeared to be organized in "microdomain"-like areas. Finally, the
stratum corneum appeared more compact with smaller intercellular spaces and hence
tighter cell-cell interactions, after cryoprocessing, than after conventional
tissue preparation for transmission electron microscopy. We conclude here that
only cryoprocessing preserves skin in a close to native state.
PMID- 10771489
TI - Mutual boosting effects of sensitization with timothy grass pollen and latex
glove extract on IgE antibody responses in a mouse model.
AB - Type I allergy to natural rubber latex can be an important health problem for
latex-exposed individuals (e.g., health care workers, spina bifida children).
Also beyond these risk groups, a high sensitization rate of varying and partly
unknown clinical relevance has been reported. Atopy represents a risk factor for
latex allergy and recent studies indicate that patients suffering from pollen
allergies may have pollen allergen-specific IgE antibodies which cross-react with
latex allergens. In order to investigate whether sensitization to pollen
allergens can have priming effects on the production of IgE antibodies against
latex in vivo, a mouse model was established. Groups of 10 BALB/C mice were
immunized with Al(OH)3-adsorbed pollen extracts from timothy grass, ragweed,
mugwort, or birch. For control purposes, one additional group received adjuvant
only and another group was not immunized. Half of the mice of each group were
subsequently immunized with Al(OH)3-adsorbed latex glove extract, the other half
with adjuvant only. Pollen and latex-specific IgE- and IgG1-antibody responses
were analyzed by enzyme-linked immunosorbent assay and statistically evaluated by
analysis of variance. Antibody responses to cross-reactive antigens were
investigated by immunoblotting. We found significantly increased IgE reactivities
to latex after pollen sensitization and vice versa. Moreover, mice immunized with
timothy grass pollen extract alone - without subsequent latex immunization -
displayed IgE reactivity to latex. Cross-reactive antibodies were directed
against pollen antigens of approximately 60 kDa molecular weight. Our results
thus demonstrate a mutual boosting effect of pollen and latex sensitization in
vivo which may be also operative in polysensitized plant allergic patients.
PMID- 10771490
TI - C-Terminus of desmoyokin/AHNAK protein is responsible for its translocation
between the nucleus and cytoplasm.
AB - We previously demonstrated that desmoyokin gene is identical to AHNAK gene, which
is downregulated in neuroblastomas. Whereas desmoyokin/AHNAK protein is
distributed in the nucleus and cytoplasm in nonepithelial tissues, it is
distributed in the cell membrane in epithelial tissues. It is present diffusely
in the cytoplasm and nucleus of epithelial cell lines cultured in low calcium
condition. Low to normal calcium shift translocates it to the cell boundary. In
this study, we investigated which domain(s) of desmoyokin/AHNAK protein are
responsible for its different distribution. We constructed three different
eukaryotic expression plasmids, pN-DY, pM-DY, and pC-DY, which expressed N
terminus, central domain, and C-terminus of this molecule, respectively, when
transfected into COS-7 cells, normal human keratinocytes, and HeLa cells. In
normal calcium medium, whereas N-terminus and central domain of desmoyokin/AHNAK
protein were present mainly in the cytoplasm, C-terminus was present in the
nucleus, cytoplasm, and weakly in the cell membrane. In low calcium medium, C
terminus was present exclusively in the nucleus, and a part of the molecules
translocated from the nucleus to the cytoplasm, 3 h after the shift to normal
calcium medium or 3 h after addition of protein kinase C activator, 12-O
tetradecanoylphorbol-13-acetate in low calcium medium. Calcium shift showed no
effects on the distribution of N-terminus and central domain. These results
suggested that C-terminus, but neither N-terminus nor central domain, is
responsible for the translocation of this protein into the nucleus. This study
may also suggest that C-terminus play a role in the translocation to the cell
membrane, although further evidence is necessary.
PMID- 10771491
TI - A novel mouse gene, Sh3yl1, is expressed in the anagen hair follicle.
AB - In an attempt to investigate the genes expressed in the anagen hair follicle, we
differentially screened a mouse anagen skin cDNA library, and identified a cDNA
encoding a novel protein containing one Src homology 3 domain at the carboxyl
terminus. The predicted amino acid sequence revealed a significant homology with
YHRO 16c/Ysc 84, the yeast Src homology 3 domain-containing protein, for which
transcripts are expressed at high levels during meiosis. The sequence identity
was remarkable at the amino terminus as well as the carboxyl-terminal Src
homology 3 domain, suggesting that the novel protein is a mouse homolog of the
yeast protein, and we have termed this protein Sh3yl1. In northern blot study,
the transcripts were detected not only in the skin but also in other tissues,
especially the kidney, stomach, small intestine, and colon. Furthermore, in mouse
skin, the expression of these transcripts basically followed the hair-growth
cycle, increasing significantly during mid and late anagen phases, and decreasing
during catagen, telogen, and early anagen phases. An in situ hybridization
experiment showed that the Sh3yl1 transcripts are expressed predominantly in the
hair bulb, the hair shaft, inner root sheath, and outer root sheath in the lower
half of the follicle during mid and late anagen phases. These transcripts were
not detected in catagen, telogen, and early anagen hair follicles, or in other
skin components. Thus, these data suggest the possible involvement of Sh3yl1 in
the development of hair follicles during the anagen phase.
PMID- 10771492
TI - A tale of two brains, one little and one big.
PMID- 10771493
TI - Motions and emotions: the treatment of depression causes constipation.
PMID- 10771494
TI - Synaptic transmission induces transient Ca2+ concentration changes in cultured
myenteric neurones.
AB - The enteric nervous system controls most of the gastrointestinal functions. We
applied confocal microscopy and the Ca2+ indicator Fluo-3 as an optical approach
to study synaptic activation in cultures of myenteric neurones. The optical
recording of [Ca2+]i (the intracellular Ca2+ concentration) was used to monitor
activation, since [Ca2+]i is crucial in the coupling between neuronal excitation
and the activation of several intracellular events. Extracellular fibre tract
stimulation (2 s, 30 Hz) caused a transient [Ca2+]i rise in a subset of neurones
(50%). These transients lasted for 5.2 s (n=36), with an average amplitude of 3.4
+/- 1.3 times the basal concentration. The removal of extracellular Ca2+ (n=15)
or the application of 10-6 M tetrodotoxin (n=16) blocked this response. The N
type Ca2+-channel blocker omega-conotoxin (5 x 10 -7M) abolished the [Ca2+]i
increase, while blockade of L-type and P/Q type Ca2+ channels had no effect.
Single stimuli evoked a [Ca2+]i rise in the processes. omega-conotoxin-sensitive
postsynaptic events required repetitive stimulation. Cholinergic blockade did not
inhibit the [Ca2+]i rise in all neurones, suggesting that, besides acetylcholine,
other neurotransmitters are involved. Optical imaging of [Ca2+]i can be used to
study synaptic spread of activation in enteric neuronal circuits expressed in
culture.
PMID- 10771495
TI - Fedotozine, a kappa-opioid agonist, prevents spinal and supra-spinal Fos
expression induced by a noxious visceral stimulus in the rat.
AB - Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic
acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in
conscious rats, central pathways activated by AA using Fos as a marker of
neuronal activation; to characterize primary afferent fibres involved in this
activation; and to investigate the effect of fedotozine on AA-induced Fos
expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either
untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously
with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist
nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after
injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain
was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar
spinal cord (laminae I, V, VII and X) and numerous brain structures such as the
nucleus tractus solitarius, and paraventricular nucleus (PVN) of the
hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin
pretreatment blocked AA-induced Fos in all structures tested. Fedotozine
significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in
the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA
induces Fos in the spinal cord and numerous brain nucuei, some of which are
involved in the control of digestive motility in rats. This effect is mediated
through capsaicin-sensitive afferent fibres and prevented by fedotozine most
likely through a peripheral action on visceral afferents.
PMID- 10771496
TI - Prolonged stationary colonic motility recording in seven patients with severe
constipation secondary to antidepressants.
AB - The aim of this study was to determine whether the colonic motor profile of seven
patients with constipation secondary to antidepressants differed from the
motility of seven patients with idiopathic constipation and seven healthy
volunteers. All constipated patients had very severe constipation. Colonic
manometric recordings were performed for 24 h. The number of high amplitude
propagating contractions (HAPC) was lower in the two groups of constipated
patients than in controls. No HAPC were observed in 5/7 patients with
constipation secondary to antidepressants and in 1/7 patients with idiopathic
constipation. The overall area under the curve (AUC) in the left colon was lower
in the two constipated patient groups than in controls. AUC increased after a
1000-kcal standard meal given at noon in controls but not in the two groups of
constipated patients. In conclusion, in patients with constipation secondary to
antidepressants, the overall AUC was as poor as in patients with idiopathic
constipation, and no colonic response to eating was observed. Moreover, the
number of HAPC was more markedly decreased in patients with constipation
secondary to antidepressants than in patients with idiopathic constipation.
PMID- 10771497
TI - Identification of the optimal parameters for recording cortical potentials evoked
by mechanical stimulation of the human oesophagus.
AB - Cortical evoked potentials (CEP) have been recorded in response to both
electrical stimulation (ES) and mechanical stimulation (MS) of the oesophagus.
While the optimal parameters for recording reproducible oesophageal CEP to ES
have recently been established, they have not yet been determined for MS, and
reported CEP to MS show considerable variability. This study aimed to identify
the optimal parameters required to record reproducible MS induced CEP. CEP were
recorded from the vertex (Cz) in six subjects (one female; age range 23-47
years). MS was performed 5 cm above the lower oesophageal sphincter by rapidly
inflating a 2-cm long silicone balloon at a frequency of 0.2 Hz. The rise time to
maximum inflation was 165 ms. In order to determine the minimum number of stimuli
required to produce optimal signal-to-noise quality, we acquired data in runs of
25, 50, 100 and 300 stimuli and to determine the stimulation intensity that
produced the shortest latency and the largest amplitude CEP, we averaged four
runs of 50 stimuli at five different intensities ranging from sensory threshold
to pain. CEP reproducibility was then assessed in three subjects on three
separate occasions using parameters determined from these measurements. We found
that optimal signal-to-noise quality was achieved by averaging four runs of 50
stimuli; that P1 latency was shortest and P1-N1 amplitude largest at intensities
of 75% and pain threshold and that highly reproducible CEP were obtained in all
individuals. We conclude that it is possible to obtain highly reproducible
oesophageal CEP to MS which can now be compared to those obtained by ES in order
to identify which is most suitable for clinical studies.
PMID- 10771498
TI - Prevalence of low-back pain in Lesotho mothers.
AB - OBJECTIVES: To identify factors that strongly affect the presence of severe low
back pain in mothers living in the Maseru District of Lesotho, to find out
whether there is any truth to the widespread belief that rural mothers are more
vulnerable to severe low-back pain than their urban counteTparts, and to identify
influential factors that are strongly associated with each other. METHODS: A
random sample of 4001 mothers was collected from the Maseru District of Lesotho
in September 1994 by using sampling techniques of stratification and proportional
allocation with respect to size. The following 10 explanatory variables of study
were used: intensive farm work, gravidity (number of births plus abortions),
residential area, heavy weight lifting, the literacy status of the mother,
strenuous manual labor, the availability of basic health services, the income
status of the mother, cooking method at home, and breast-feeding. The dependent
variable of study was the presence or absence of severe low-back pain.
Discriminant and log-linear analyses were done to analyze the data collected.
Discriminant analysis was done by using the presence or absence of severe low
back pain as a classifying variable and the 10 explanatory variables that affect
the classifying variable. Log-linear analysis was also done by using the same
data with 9 of the 11 variables of study. RESULTS: A total of 405 (10.12%) of the
4001 mothers in the study had severe low-back pain at the time of data
collection, 513 (12.82%) had moderate low-back pain, and 1422 (35.54%) had mild
low-back pain. A total of 319 (78.77%) of the 405 mothers with severe low-back
pain were poor, illiterate, and from rural communities. Results from discriminant
analysis revealed that the presence of severe low-back pain was strongly affected
by intensive farm work, the residential area of the mother, and gravidity of the
mother in a decreasing order of strength and led to results similar to those
obtained from discriminant analysis. The study also showed that rural mothers and
their children were more disadvantaged than their urban counterparts with regard
to basic health services. CONCLUSION: Recommendations were made to the Ministry
of Health and Social Welfare of Lesotho to improve the provision of basic health
services, including health education on the importance of chiropractors to the
community.
PMID- 10771499
TI - Reflex responses associated with activator treatment.
AB - BACKGROUND: Previous studies have demonstrated the existence era reflex response,
measurable by surface electromyography (sEMG), after manually delivered spinal
manipulative therapy (SMT). This reflex response has been characterized as
consistent, reproducible within individual subjects, and nonlocal because it
extends beyond the site of manipulation. However, the nature and magnitude of
possible reflex responses in the paraspinal and proximal limb muscles elicited by
nonmanual SMT, such as with an adjusting instrument, remain unknown. OBJECTIVE:
To characterize the reflex responses associated with SMT by using sEMG to record
the responses of 16 muscles before, during, and after treatment. STUDY DESIGN:
The eleetromyographic responses of 16 para-spinal and proximal limb muscles in 9
healthy, asymptomatic male volunteers were measured simultaneously by sEMG
before, during, and after chiropractic SMT. METHODS: SMT thrusts were delivered
to 9 asymptomatic volunteers at 6 bilateral sites (C3/4, T2/3, T6/8, T11/12, L2
4, and s1). Reflex responses were measured from 16 muscles with bipolar sEMG
electrodes and collected at 2000 Hz per channel with data acquisition software.
RESULTS: Approximately 68% of the SMT thrusts resulted in a detectable reflex
response. The cervical spine resulted in a detectable response of 50%, thoracic
spine 59%, lumbar spine 83%, and sacroiliac joints 94%. Treatments delivered to
the thoracic spine elicited the largest peak-to-peak amplitude sEMG responses,
whereas the lumbar spine demonstrated the most heterogeneous responses. When a
reflex response was observed, it always occurred close to the treatment site
ipsilaterally and was detected in muscles that had either their origin or
insertion at the vertebral level that was adjusted. CONCLUSIONS: Based on the
local nature, magnitude, and characteristic shape of all reflex responses
observed, we hypothesized that they were likely generated by a single
proprioceptor. Furthermore, the temporal properties of this reflex response
suggest that they originated from the muscle spindles. In contrast to previous
observations on reflex responses after manual SMT, these treatments elicited
reflex responses that varied between subjects but were consistent within an
individual and were local in nature. We conclude that SMT delivered in this
manner results in a reflex response that is both quantitatively and qualitatively
different from a manual SMT.
PMID- 10771500
TI - Is it possible to differentiate people with or without low-back pain on the basis
of test of lumbopelvic dysfunction?
AB - OBJECTIVE: To determine the prevalence of positive chiropractic test results in
relation to low back pain status and to determine the sensitivity, specificity,
and predictive (positive and negative) values of these tests. DESIGN: Study
subjects were examined by a chiropractor who was unaware of their low back pain
status. Information on low back pain was then collected in a self-report
questionnaire. SETTING: Research laboratory at the Odense University Hospital
(Denmark). SUBJECTS: A subset of 166 healthy twins taken from a panel of
population-generated twins born between 1953-1982. EXAMINER: Chiropractor with
approximately 10 years of clinical experience. MAIN OUTCOME MEASURES: The
prevalence of a number of lumbopelvic dysfunctional tests (4 observational, 6
pain-on-movement, and 2 pain provocation tests), and a diagnostic conclusion
based on these test results were studied in relation to low back pain status.
RESULTS: There was no single test that was clinically acceptable in relation to
all 5 aspects of the study. At least one pain-on-movement test was the only
variable that had a totally acceptable pattern. CONCLUSION: Although no
individual test was accurate, the diagnostic discrimination on the basis of these
tests was satisfactory.
PMID- 10771501
TI - Effects of orthotic intervention and nine holes of simulated golf on club-head
velocity in experienced golfers.
AB - OBJECTIVE: This study was an initial investigation evaluating the effects of
orthotic intervention on club-head velocity (CHV) among a group of experienced
golfers before and after 9 holes of simulated golf. SETTING: Northwestern College
of Chiropractic, Bloomington, Minnesota. PARTICIPANTS: Twelve experienced golfers
were included in the study. METHOD: CHV was measured with a device used by many
Professional Golf Association and Ladies Professional Golf Association teaching
professionals before and after wearing orthotics and before and after completing
9 holes of simulated golf. Subjects wore custom-made, flexible orthotics daily
for 6 weeks and then were retested with the same objective measurement
parameters. OUTCOME MEASURE: CHV (swing speed in miles per hour) was measured in
all subjects before and after wearing custom-fit, flexible orthotics for 6 weeks
and before and after completing 9 holes of simulated golf. RESULTS: There was an
approximate increase in CHV of between 3 and 5 mph, or a relative increase in CHV
by up to 7%, after subjects had worn custom-made, weight-bearing, flexible
orthotics daily for 6 weeks. A 5-mph increase in CHV is equivalent to an
approximate increase in golf ball travel distance of 15 yards, a significant
increase for the tour player for whom small increases in performance can reflect
large position changes on the roster board. In addition, the use of these custom
of those eliminated the effects of fatigue associated with playing 9 holes of
golf (relative to CHV) and therefore may improve the likelihood for more
consistent golf performance. CONCLUSION: The use of the custom-fit, flexible
orthotics in this study had a positive influence on CHV in experienced golfers.
PMID- 10771502
TI - Is there a role for premanipulative testing before cervical manipulation?
AB - BACKGROUND: Spinal manipulative therapy is used millions of times every year to
relieve symptoms from biomechanic dysfunction of the cervical spine. Concern
about cerebrovascular accidents after cervical manipulative therapy is common but
rarely reported. Premanipulative tests of the vertebral artery are presumed to
identify patients at risk but controversy exists about their usefulness.
OBJECTIVE: The aim of this study was to examine vertebral artery blood flow in
patients with a positive premanipulative test for contraindication to spinal
manipulative therapy and to investigate if chiropractors would reconsider
treating such patients if dynamic vascular Doppler examination was normal. DESIGN
AND SETTING: A prospective study at a university hospital vascular laboratory.
METHODS: Chiropractors in private practice from 3 Danish counties referred
patients with a positive premanipulative test for an examination of vertebral
artery blood flow. Premanipulative testing was performed by an experienced
chiropractor. Flow velocities were measured in both vertebral arteries by color
duplex sonography. In addition, chiropractors were asked if they would treat
their patient despite a positive premanipulative test if the vascular ultrasound
examination was normal. RESULTS: A total of 20 consecutive patients with a
positive premanipulative test were referred. Five were excluded because symptoms
could not be reproduced during the vascular examination. In the remaining
patients, no significant difference in peak flow velocity or time-averaged mean
flow velocity with different head positions was found. Nineteen of 21
chiropractors would treat a patient with a positive premanipulative test if the
vascular examination was normal. Eight of the patients with a positive
manipulative test were treated without complications. Six are now symptom-free,
and 2 have improved symptoms. The remaining 8 patients refused manipulation and
continue to have the same symptoms. CONCLUSION: It appears that a positive
premanipulative test is not an absolute contraindication to manipulation of the
cervical spine. If the test is able to identify patients at risk for
cerebrovascular accidents, we suggest patients with a reproducible positive test
should be referred for a duplex examination of the vertebral artery flow. If
duplex flow is normal, the patient should be eligible for cervical manipulation
despite the positive premanipulative test.
PMID- 10771503
TI - Assessment of published reliability studies for cervical spine range-of-motion
measurement tools.
AB - OBJECTIVE: To assess the reliability of tools to measure cervical spine range of
motion in clinical settings and discuss the necessary components for reliability
studies. DATA SOURCES: Database searches included Bandolier, Bath Information and
Data Services including Index of Scientific and Technical Proceedings, British
Nursing Index, Cumulative Index to Nursing and Allied Health Literature, English
National Health Care Database, MEDLINE, Occupational Therapy Index, Physiotherapy
Index, and Rehabilitation index for English language articles from 1966. In
addition, citations were searched. STUDY SELECTION: Studies were selected that
assessed the tool for intraobserver or interobserver reliability, evaluated it on
movements of flexion/extension, lateral flexion, or rotation, and measured range
of motion of the whole cervical spine. DATA EXTRACTION: All papers were read by
one nonclinical researcher with a data extraction sheet. A consultant
rheumatologist and a physiotherapist were each asked to read a sample of the
papers to give a clinical viewpoint. DATA SYNTHESIS: Evidence for the reliability
of measurement tools was assessed qualitatively based on the quality of the study
designs, appropriateness of analysis, and strength of the reliability based on
reported intraclass correlation coefficients (the most appropriate analysis
technique for reliability studies of this nature). Measurement tools were found
to have not been fully tested for reliability, particularly in terms of adequate
sample size and appropriate analysis techniques. There were also wide variations
in the research design, including the protocol for movement, the characteristics
of observers and study population, whether warm-ups were allowed, whether the
movement was active or passive, and time intervals between repeated measurements.
CONCLUSION: Although a range-of-motion device has shown promise in reliability
and has many advocates, its practicality for clinical use is questionable.
Further work must be performed on all measurement tools. Researchers need to
produce more rigorous studies and consider the issues discussed here.
PMID- 10771504
TI - Nephrolithiasis with unusual initial symptoms.
AB - OBJECTIVE: To describe a less common initial symptom of nephrolithiasis, its
diagnostic pitfalls, risk factors, and mimicry of other conditions. Intervention
and long-term management of nephrolithiasis is also discussed. CLINICAL FEATURES:
A Caucasian man aged 25 years had sudden bilateral inguinal and occasional
periumbilical pain. The initial symptom suggested an abdominal pathologic
condition; however, costovertebral angle pain followed 1 hour later with no
radiation between the 2 anatomic sites. The initial urine dipstick result was
negative for hematuria, but a kidney, ureter, and bladder radiograph revealed a
smooth 2-mm x 3-mm stone lodged at the left: vesico-ureteral junction.
INTERVENTION AND OUTCOME: The patient was referred to a regional university
medical center to receive extracorporeal shockwave lithotripsy several days after
his initial visit. He was given pain medicine for the waiting period and received
daily lumbar spine adjustments with a mild reduction in pain. He eventually
received ureteroscopic laser lithotripsy because the shock-wave unit had
malfunctioned before his appointment. The fragment analysis showed a calcium
oxalate composition, and the patient was advised to lower his intake of oxalates.
The patient had become a vegetarian approximately 3 months before this first
stone episode. CONCLUSION: Nephrolithiasis is a condition commonly seen in
chiropractic practice. Although it is usually easy to recognize, the diagnosis
can be elusive if the typical historic factors and diagnostic results are absent
or altered. The short-term management of nephrolithiasis is pain management,
stone elimination, and the collection of a specimen to identify the composition
and underlying metabolic abnormality. Long-term management is to prevent the
recurrence of stones. Conservative comanagement by the chiropractic physician can
be implemented through nutritional means.
PMID- 10771505
TI - Manual healing diversity and other challenges to chiropractic integration.
PMID- 10771506
TI - Infants with colic may have had a faster delivery: a short, preliminary report.
PMID- 10771507
TI - A review of biomechanics of the central nervous system. Part 1: spinal canal
deformations caused by changes in posture.
PMID- 10771508
TI - A review of biomechanics of the central nervous system. Part 1: Spinal canal
deformations caused by changes in posture.
PMID- 10771509
TI - Modulation of alpha5beta1 integrin functions by the phospholipid and cholesterol
contents of cell membranes.
AB - Several modifications of the alpha5beta1 integrin, which alter its intracellular
and extracellular interaction with fibronectin and other proteins, have been
reported. However, the significance of the lateral mobility of integrin molecules
in the plasma membrane, as a regulator of their distribution and function, is
poorly understood. We examined this problem by increasing the cholesterol content
of plasma membranes, and consequently modifying the fluidity of membrane
phospholipids, in rat fibroblasts. Under these conditions, the clustering of
alpha5beta1 integrin molecules in focal adhesions, their adhesion to the cell
binding domain of fibronectin, and their association with the cytoskeletal
protein talin were significantly enhanced as compared to control cells. However,
the activation of MAP-kinase pathways by the association of fibronectin with
alpha5beta1 integrin, and its association with integrin-linked kinase (ilk), were
suppressed. The treated cells also showed distinct changes in shape, and their
actin stress fiber network was more dense and thick as compared to control cells.
The changes in fluidity of phospholipids occurred differentially and fluidity of
phosphatidyl-ethanolamine increased, while that of phosphatidyl-choline was
reduced. Our results suggest that proteins in focal adhesions could be
partitioned in specific lipid domains, which regulate specific aspects of
alpha5beta1 integrin functions.
PMID- 10771510
TI - Characterization of caveolae from rat heart: localization of postreceptor signal
transduction molecules and their rearrangement after norepinephrine stimulation.
AB - Caveolae are plasma membrane subcompartments that have been implicated in signal
transduction. In many cellular systems, caveolae are rich in signal transduction
molecules such as G proteins and receptor-associated tyrosine kinases. An
important structural component of the caveolae is caveolin. Recent evidence show
that among the caveolin gene family, caveolin-3 is expressed in skeletal and
cardiac muscle and caveolae are present in cardiac myocyte cells. Both the ANP
receptor as well as the muscarinic receptor have been localized to the caveolae
of cardiac myocytes in culture. These findings prompted us to conduct a further
analysis of cardiac caveolae. In order to improve our understanding of the
mechanisms of signal transduction regulation in cardiac myocytes, we isolated
cardiac caveolae by discontinuous sucrose density gradient centrifugation from
rat ventricles and rat neonatal cardiocytes. Our analysis of caveolar content
demonstrates that heterotrimeric G proteins, p21ras and receptor-associated
tyrosine kinases are concentrated within these structures. We also show that
adrenergic stimulation induces an increase in the amount of diverse alpha- and
beta-subunits of G proteins, as well as p21ras, in both in vivo and in vitro
experimental settings. Our data show that cardiac caveolae are an important site
of signal transduction regulation. This finding suggests a potential role for
these structures in physiological and pathological states.
PMID- 10771512
TI - Effects of estradiol on corticosterone secretion in ovariectomized rats.
AB - The effects of estradiol benzoate (EB) on steroidogenesis in rat zona fasciculata
reticularis (ZFR) cells were studied. Female rats were ovariectomized (Ovx) for 2
weeks and then injected subcutaneously with oil or EB for 3 days before
decapitation. ZFR cells were isolated and incubated with adrenocorticotropin
(ACTH) or prolactin (PRL) for 1 h. Corticosterone concentrations in plasma and
cell media, and adenosine 3',5'-cyclic monophosphate (cAMP) production in ZFR
cells were determined by radioimmunoassay. The effects of EB replacement in vivo
on the activities of steroidogenic enzymes in ZFR cells were measured by the
amounts of intermediate steroidal products separated by thin-layer
chromatography. Replacement of EB in vivo resulted in a dose-dependent increase
of plasma PRL and corticosterone in Ovx rats. The basal, ACTH-, and PRL
stimulated release of corticosterone by ZFR cells was greater in EB- than in oil
treated animals. Forskolin-induced production of cAMP was greater in the EB
replaced rats than in oil-treated animals, which correlated with the increase of
corticosterone production. The 3-isobutyl-l-methylxanthine (IBMX) plus ACTH-,
IBMX plus PRL-, and forskolin plus PRL-stimulated productions of cAMP were higher
in EB- than in oil-treated rats. The enzyme activities of postpregnenolone were
not affected by EB replacement in Ovx rats. These results suggest that the EB
related increase of corticosterone production in Ovx rats is associated with an
increase of cAMP generation and the stimulatory effect of PRL on ZFR cells.
PMID- 10771511
TI - Monoclonal antibodies specific for human tumor-associated antigen 90K/Mac-2
binding protein: tools to examine protein conformation and function.
AB - As part of our effort to identify glycoproteins that contribute to colon cancer
progression, we have previously described a family of structurally related
glycoproteins expressing beta1-6 branched asparagine(Asn)-linked oligosaccharides
defined by monoclonal antibody (MAb 1H9), which are differentially expressed,
processed, and glycosylated by human colon carcinoma cell lines (Laferte and Loh
[1992]; Biochem J; 283:193-201). MAb 1H9 immunoprecipitates three glycoproteins
having apparent sizes of 92-100, 66-70, and 25 kDa, the size heterogeneity
attributable to cell-type specific glycosylation differences. We report on the
basis of partial protein and cDNA sequence information, that the 100-kDa
glycoprotein detected by MAb 1H9 is identical to the 90-kDa glycoprotein variably
known as tumor-associated antigen 90K (TAA90K), Mac-2 binding protein, and
cyclophilin C-associated protein. Using a PCR-based cloning strategy, the
complete cDNA encoding TAA90K was cloned into the eukaryotic expression vector
pCDNA-3 (pCD-TAA90K(wt)) and the protein expressed in COS-1 cells. A
[(35)S]methionine-labeled 60-kDa polypeptide, processed to an endoglycosidase H
sensitive 74-kDa glycoprotein in the presence of dog pancreas microsomes, was
detected in a coupled transcription/translation in vitro reaction. The in vitro
translated 60-kDa polypeptide and N-glycanase-treated TAA90K (60-kDa species)
immunoprecipitated from HT29 cells were shown to be structurally identical by
limited proteolytic peptide mapping. Using a new panel of 11 TAA90K-specific
monoclonal antibodies, including five specific for human TAA90K and six cross
reactive with a 90-kDa species expressed by COS-1 cells, we have detected
conformational differences between recombinant wild-type TAA90K, in vitro
synthesized TAA90K, and mutant forms of TAA90K containing point mutations at
residues 189, 223, and 259. Furthermore, we have shown that these mutant forms of
TAA90K, as well as a truncated form of TAA90K containing amino acid residues 1
383, are defective in secretion. These studies demonstrate the potential
usefulness of TAA90K-specific monoclonal antibodies for examining the structure
and function of TAA90K, and highlight the contribution of specific amino acid
residues to its normal processing and secretion.
PMID- 10771513
TI - Epidermal growth factor induces cell cycle arrest and apoptosis of squamous
carcinoma cells through reduction of cell adhesion.
AB - Most squamous epithelial cells are strictly anchorage-dependent cell types. We
observed that epidermal growth factor (EGF) promoted the growth of A431 squamous
carcinoma cells in suspension cultures but suppressed cell growth and induced
apoptosis in monolayer cultures, suggesting that loss of adhesion is responsible
for the effects observed in monolayer culture, before cell death. Consistent with
this finding, we demonstrated that EGF reduced cell attachment, cell-cell
interaction, and cell spreading. Treatment with EGF increased cell adhesion
regulated expression of p21 but suppressed expressions of cyclin A, D1, cdk2, and
retinoblastoma protein (pRb), leading to cell cycle arrest and adhesion-regulated
programmed cell death. To test directly whether promoting cell adhesion could
reduce the effects of EGF, we grew cultures on plates coated with type II
collagen. On these plates, cell adhesion was enhanced and EGF treatment had
little effect on cell adhesion and apoptosis when cells were attached to the
collagen. The collagen effects were dose dependent, and cell cycle and cell cycle
associated proteins were altered accordingly. Finally, when cultures were plated
on bacterial Petri dishes, which completely disrupted cell attachment to
substratum, the level of apoptosis was greatly higher and cell cycle was arrested
as compared with monolayer cultures. Taken together, our results strongly suggest
that the EGF-induced cell cycle arrest and apoptosis in monolayer cultures was
the result of a decline in cell adhesion.
PMID- 10771514
TI - Functional association between nicotinic acetylcholine receptor and sarcomeric
proteins via actin and desmin filaments.
AB - By affinity chromatography utilizing alpha-cobrotoxin from digitonin-solubilized
fractions of rabbit skeletal muscle, we found that many proteins are associated
with the nicotinic acetylcholine receptor (AChR). In addition to the proteins we
previously reported to bind to AChR (including dystrophin-dystrophin-associated
protein (DAP) complex, utrophin, rapsyn, and actin; Mitsui et al. [1996] Biochem.
Biophys. Res. Commun.224:802-807), alpha-actinin, desmin, myosin, tropomyosin,
troponin T, and titin are also identified to be associated with AChR. Alkaline
treatment or Triton X-100 solubilization released dystrophin-DAP complex,
utrophin, and rapsyn from the AChR fraction, while actin and desmin remained
associated. These findings demonstrate that AChR is supported primarily by a
submembranous organization of actin and desmin filaments, and is linked to
sarcomeric proteins via these filaments. To further investigate whether the
association has any functional role, we studied the effect of acetylcoline on
ATPase activity of the AChR fraction. Acetylcholine (0.5-4 microM) significantly
activated Mg(2+)-ATPase activity of digitonin-solubilized AChR fraction (P <
0.05). Furthermore, we found that desmin as well as actin activated myosin Mg(2+)
ATPase activity. From these findings, it is suggested that desmin and actin form
a submembranous organization in the postsynaptic region, and function as
mediators of excitation of AChR to the sarcomeric contraction system.
PMID- 10771515
TI - Characterization of a murine gene encoding an acidic-basic dipeptide repeat that
interacts with GADD34.
AB - GADD34 is one of a subset of proteins induced after DNA damage or cell growth
arrest. To examine the function of GADD34, we used the yeast two-hybrid system to
clone the protein that interacts with murine GADD34. We utilized as bait the
partial product of GADD34 cDNA including the PEST region and the gamma(1)34.5.
One cDNA clone was almost the same as MuRED, which encodes an acidic-basic
dipeptide repeat; we named it G34BP. The interaction between GADD34 and G34BP was
also confirmed in the NIH3T3 cells by in vivo two-hybrid analysis. For the
binding of two proteins, the PEST region was important, and the C-terminal of
G34BP was necessary. G34BP was detected in all the mouse tissues examined.
Although GADD34 was significantly elevated with methyl methanesulfonate
treatment, G34BP expression was not induced. Overexpression of G34BP in the
NIH3T3 cells inhibited the cell growth analyzed by WST1 assay.
PMID- 10771516
TI - Murine RARbeta4 displays reduced transactivation activity, lower affinity for
retinoic acid, and no anti-AP1 activity.
AB - The biological actions of retinoic acid (RA) are mediated by retinoic acid
receptors (RARalpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta,
and gamma). Each of the RARs is expressed as four to seven different isoforms.
Four isoforms of RAR beta (beta1, beta2, beta3, and beta4), which differ only in
their N-terminal sequence (A domain) have been described. These RARbeta isoforms
display a specific pattern of expression in developing and adult animals and are
highly evolutionarily conserved suggesting that they mediate distinct cellular
effects of vitamin A. Experiments were performed to examine directly the RA
binding activity, transactivation activity, and anti-AP1 activity of each of
these four RARbeta isoforms. The results demonstrate that RARbeta1, beta2, and
beta3 bind RA with a similar K(d) value, have a similar EC(50) value in RA
dependent transactivation assays and inhibit AP1 activity to a similar level. By
contrast, RARbeta4 has an elevated K(d) for RA, an increased EC(50) value in RA
dependent transactivation assays and does not display the ability to inhibit AP1
activity. This provides additional evidence that at least one RAR isoform,
RARbeta4, may mediate distinct activities within a cell. Furthermore, these data
suggest that the presence of an A domain in RARbeta is important for modulating
these activities of RARs.
PMID- 10771517
TI - Stable expression of functional CBP70 lectin during heat shock.
AB - CBP70 is a glycoslylated lectin that interacts through either glycan-lectin or
protein-protein interactions. In addition, depending on its cellular
localization, this lectin has different partners, for example, galectin-3, an 82
kDa ligand in the nucleus, or Bcl-2 in the cytoplasm. In this study, we observed
the persistence of plurilocalized lectin CBP70 after two heat-shock treatments
conducted either under mild conditions, i.e., incubating the cells for 1 h at 42
degrees C then for 1, 3, 5, 7, or 9 h at 37 degrees C, or harsh conditions, i.e.,
incubation at 42 degrees C for 1, 2, 4, 6, 8, or 10 h. By combining the
information collected from biochemical, fluorocytometric, confocal, and affinity
chromatography analyses, we concluded that CBP70 persisted in HL60 cells and its
N-acetylglucosamine-binding sites remained active after all the heat-shock
treatments tested. These data and the previously published findings reviewed in
this report concur in supporting the hypothesis that CBP70 could function as an
organizer of multimeric assembly, leading to the formation of various complexes
in different cellular compartments, according to the needs of the cell.
PMID- 10771518
TI - L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells.
AB - Prolactin (PRL) inhibits apoptosis and stimulates proliferation of the PRL
dependent rat Nb2 lymphoma cell line by divergent signaling pathways. Nitric
oxide (NO) was recently identified as a downstream regulator of PRL action, and
as an inhibitor of apoptosis in immune cells. In the present study, the role of
NO in PRL-regulated Nb2 cell function was investigated. Nb2 cells expressed the
endothelial nitric oxide synthase (eNOS) isoform, whereas neuronal NOS (nNOS) and
inducible NOS (iNOS) mRNAs were undetectable. The eNOS mRNA was abundantly
expressed in PRL-deprived, growth-arrested cells but decreased by at least 3-fold
at 3-24 h following PRL treatment. Downregulation of eNOS was not accompanied by
a corresponding decrease in the eNOS protein, the level of which remained
constant for at least 24 h after PRL treatment. PRL had no effect on the
phosphorylation state or subcellular redistribution of the eNOS enzyme, or on
production of NO by Nb2 cells. However, increasing concentrations of L-arginine
(NOS substrate) alone increased NO production in these cells and significantly
enhanced PRL-stimulated cell proliferation. NO releasers (SNAP, DEA/NO, SIN-1)
also significantly enhanced Nb2 cell proliferation in the presence of a
submaximal dose of PRL (0.125 ng/ml). In the absence of PRL, the NO releasers
alone promoted cell survival and maintained a viable cell density significantly
higher than that of untreated PRL-deprived cells. L-arginine or the NO releaser
DEA/NO alone significantly inhibited apoptosis in Nb2 cells deprived of PRL for 5
days. Expression of the anti-apoptotic gene bcl-2, which was stimulated within 1
h by PRL, was upregulated by L-arginine or DEA/NO alone at 2 h and 8 h,
respectively. These findings suggest that NO produced by eNOS inhibits apoptosis
and promotes the survival of growth-arrested Nb2 lymphoma cells via a prolactin
independent, Bcl-2-mediated pathway.
PMID- 10771519
TI - Role of desmin filaments in chicken cardiac myofibrillogenesis.
AB - Desmin filaments are muscle-specific intermediate filaments located at the
periphery of the Z-discs, and they have been postulated to play a critical role
in the lateral registration of myofibrils. Previous studies suggest that
intermediate filaments may be involved in titin assembly during the early stages
of myofibrillogenesis. In order to investigate the putative function of desmin
filaments in myofibrillogenesis, rabbit anti-desmin antibodies were introduced
into cultured cardiomyocytes by electroporation to perturb the normal function of
desmin filaments. Changes in the assembly of several sarcomeric proteins were
examined by immunofluorescence. In cardiomyocytes incorporated with normal rabbit
serum, staining for alpha-actinin and muscle actin displayed the typical Z-line
and I-band patterns, respectively, while staining for titin with monoclonal anti
titin A12 antibody, which labels a titin epitope at the A-I junction, showed the
periodic doublet staining pattern. Staining for C-protein gave an amorphous
pattern in early cultures and identified A-band doublets in older cultures. In
contrast, in cardiomyocytes incorporated with anti-desmin antibodies, alpha
actinin was found in disoriented Z-discs and the myofibrils became fragmented,
forming mini-sarcomeres. In addition, titin was not organized into the typical A
band doublet, but appeared to be aggregated. Muscle actin staining was especially
weak and appeared in tiny clusters. Moreover, in all ages of cardiomyocytes
tested, C-protein remained in the disassembled form. The present data suggest the
essential role of desmin in myofibril assembly.
PMID- 10771520
TI - Modulation of GST P1-1 activity by polymerization during apoptosis.
AB - Glutathione S-transferases (GSTs, EC 2.5.1.18) belong to a large family of
functionally different enzymes that catalyze the S-conjugation of glutathione
with a wide variety of electrophilic compounds including carcinogens and
anticancer drugs. Drug resistance may result from reduction in apoptosis of
neoplastic cells when exposed to antineoplastic drugs. The c-Jun N-terminal
Kinase (JNK) belongs to the family of stress kinases and has been shown to be
required for the maximal induction of apoptosis by DNA-damaging agents. Recently,
an inhibition of JNK activity by GST P1-1, which was reversed by polymerization
induced by oxidative stress, has been reported in 3T3-4A mouse fibroblast cell
lines. The finding that GST P1-1 might inhibit JNK activity and that it is
frequently highly expressed in tumor tissues suggests its possible implication in
"apoptosis resistance" during antineoplastic therapy. We investigated the
modulation of GST P1-1 during apoptosis in a neoplastic T-cell line (Jurkat)
induced by hydrogen peroxide and etoposide. Apoptosis was paralleled by the
appearance of a dimeric form of GST P1-1 on western blotting, associated with an
increase in the Km(GSH) and a reduction in GST P1-1 specific activity toward 1
chloro-2,4-dinitrobenzene, which reached statistical significance only in
H(2)O(2)-treated cells. Our data seem to suggest that H(2)O(2) and etoposide may
partly act through a process of partial inactivation of the GST P1-1, possibly
involving the "G" site in the process of dimerization, and thus favoring
programmed cell death.
PMID- 10771521
TI - Nuclear distribution of RNA polymerase II in human oocytes from antral follicles:
dynamics relative to the transcriptional state and association with splicing
factors.
AB - The intranuclear distribution of two (unphosphorylated and hyperphosphorylated)
forms of RNA polymerase II (Pol II) was studied in human oocytes from antral
follicles using immunogold labeling/electron microscopy. The distribution of Pol
II was analyzed relative to the transcriptional state of the oocyte as well as to
the distribution of two splicing factors (snRNPs and SC-35) in the intranuclear
entities, namely, interchromatin granule clusters (IGCs), nucleolus-like bodies
(NLBs), and perichromatin fibrils (PFs). The results showed that (1) antibodies
directed against two forms of Pol II have similar pattern of intranuclear
distribution, (2) both Pol II and splicing factors progressively accumulate in
IGCs with decrease in the transcriptional activity of the oocyte nucleus, (3)
both Pol II and splicing factors localize to PFs, and (4) Pol II is present in
the NLBs at all transcriptional states of the oocyte nucleus. These studies
confirm earlier proposals that PFs represent a nuclear domain in which RNA
transcription/processing are spatially coupled. The accumulation of Pol II and
splicing factors in IGCs concomitant with a decrease in the transcriptional
activity suggests a coordinated mechanism for the movement of both Pol II and
splicing factors from the sites of action to the sites of storage.
PMID- 10771522
TI - Nuclear localization of the human mutY homologue hMYH.
AB - The cDNA of the human mutY homologue (hMYH) was cloned from the total RNA of the
tumor cell line SU-DHL-1 by reverse transcription-polymerase chain reaction (RT
PCR). Expression of hMYH in a plasmid can partially revert the mutator phenotype
of the Escherichia coli mutY mutant MK609(DE3). The majority of the recombinant
hMYH protein in E. coli was precipitated in the inclusion bodies. A minor
fraction of the soluble recombinant protein was concentrated as the source of the
protein in the activity assay. Recombinant hMYH displayed both glycosylase and AP
lyase activity. Three independent rabbit antisera against an N-terminal peptide,
HY90, a recombinant C-terminal fragment, and the full-length hMYH recombinant
protein were prepared and affinity-purified, and these antisera recognized the 59
kDa endogenous hMYH protein in HeLa cells. Immunofluorescent staining experiments
with these three antisera showed a consistent nuclear distribution of hMYH,
excluding the nucleoli. This nuclear staining pattern was abolished if the
antisera were incubated with specific peptide/protein competitors, whereas the
staining pattern was unaffected if the antisera were incubated with nonspecific
peptide competitors. Consistent with the immunofluorescent staining results, a
flag-tagged transfected hMYH also showed a nuclear staining pattern excluding the
nucleoli. These results suggest that hMYH is indeed a functional homologue of E.
coli MutY and is localized in the nuclei of mammalian cells.
PMID- 10771523
TI - MMP-13 is induced during chondrocyte hypertrophy.
AB - During development, mRNA for matrix metalloproteinase-13 (MMP-13) is found
associated with cartilage undergoing hypertrophy, suggesting that this
collagenase plays a role in cell enlargement and/or cartilage calcification.
Using chondrocytes from prehypertrophic cartilage of chick embryo sternae, we
have examined the relationship between MMP-13 expression and the transition to
hypertrophy. When hypertrophy was induced by serum-free culture with ascorbate
and bone morphogenetic protein-2 (BMP-2), MMP-13 mRNA levels paralleled those for
type X collagen. Chondrocytes from the caudal, nonhypertrophying portion of chick
sternae expressed neither type X collagen nor MMP-13, confirming that MMP-13 mRNA
is a marker for hypertrophy. Zymography with conditioned medium yielded a
proteinase band at 59 kDa, which was absent in nonhypertrophic chondrocytes. A
polyclonal antibody raised against chick MMP-13 reacted with the 59-kDa protein,
confirming that it is MMP-13. Although mRNA for MMP-13 peaked at days 4-5 of
culture, only low levels of MMP-13 activity were present, and the activity
increased gradually in parallel with later increases in MMP-2. These results
suggest that MMP-13 is activated by MMP-2 during chondrocyte maturation, and that
the combination of both proteinases is required to prepare cartilage matrix for
subsequent calcification, before endochondral ossification.
PMID- 10771524
TI - [Is driving under influence an issue for health care services?].
PMID- 10771525
TI - [A prognostic tool in stress research. Even heart frequency reveals a worn out
regulatory system].
PMID- 10771526
TI - [Disaster management lessons can be learned from the Gothenburg fire].
AB - On the night of October 29, 1998, a fire broke out in an old warehouse in
Gothenburg, where nearly 400 teenagers had gathered for a disco party. More than
200 patients were brought to four different hospitals in the region. Sixty-one
people died at the scene due to inhalation of toxic fumes caused by the fire.
Another two died later in the hospital due to severe burns. Disaster management
in Sweden is based on mobile medical teams consisting of hospital staff
supporting ambulance crews in the event of major incidents. Only one team
together with a GP was able to be mobilized during this incident. Thus, medical
care at the scene was limited. The principle of OEload and go pi was used,
placing the major burden of triage on the hospitals. The limited numbers of
medical personnel and available supplies caused major stress for the physicians
involved at the scene.
PMID- 10771527
TI - [Survey of driving during the influence in Sweden: even a low blood level of
alcohol can indicate alcohol problems].
PMID- 10771528
TI - [Benign transient hyperphosphatasemia. A cause of increase of alkaline
phosphatase in children].
PMID- 10771529
TI - [Problems of interpretation in connection with measurements of chorionic
gonadotropin].
PMID- 10771530
TI - [Scientific theory and medical research--reflections seen from the perspective of
the MFR].
PMID- 10771531
TI - [An attempt to a conclusion: different scientific attitudes result in
complementary descriptions].
PMID- 10771532
TI - [A motion picture mystery triggered off the debate on homosexuality].
PMID- 10771533
TI - [A moment in medicine, part 4. See the whole person--not only the patient].
PMID- 10771534
TI - [How to reduce the problem of increasing sick-listing?].
PMID- 10771535
TI - [A sick rehabilitation system--responsibility should go back to the insurance
authorities!].
PMID- 10771536
TI - [Professional responsibility of physicians employed by insurance authorities--the
HSAN should supervise].
PMID- 10771537
TI - [Patient safety can be increased by a committee scrutinizing physicians employed
by insurance authorities].
PMID- 10771538
TI - [Prolonged sick-listing can have healing effects].
PMID- 10771539
TI - [Better to refer to articles from highly ranked journals within a specialty].
PMID- 10771540
TI - [From botulism to cosmetics--a story of a drug].
PMID- 10771541
TI - [Most depressed patients can be treated in primary health care].
AB - About 15% of primary care attenders suffer from depression, yet only a minority
are identified and treated. It is of major importance to spread knowledge of the
prevalence of depression and tools for recognizing the disorder. Most patients
can be successfully treated in a primary care setting. Studies have shown that
educational efforts and close cooperation between psychiatrists and general
practitioners (GP's) lead to an increase in the proportion of depressed patients
that are identified and properly treated. The use of diagnostic self-reports can
facilitate this process for the GP. It is crucial to identify and treat the
disorder early on, in order to improve prognosis, decrease the risk of
complications and reduce costs for society and the health care system. The
article reviews recent studies concerning depression in primary care, describes
relevant diagnostic tools and discusses treatment strategies, including self-care
and St Johns' wort.
PMID- 10771542
TI - [Nursing home as a risky environment when it comes to antibiotic resistance. An
audit study of antibiotic treatment at nursing homes in Kronoberg].
PMID- 10771543
TI - [Advanced home care is as efficient and as expensive as hospital care according
to the SBU].
PMID- 10771544
TI - [Patients are more positive to medical students. Changed attitude to the training
of undergraduates since 1972].
PMID- 10771545
TI - [Cholesterol embolism--a serious systemic disease].
AB - The syndrome of cholesterol embolism is a multiorgan disorder caused by
peripheral embolization of cholesterol crystals from an ulcerated aorta plaque.
The kidney is the organ most often affected (approx 50%). Prognosis is poor, with
a mortality of about 70%. We describe two of four cases of cholesterol embolism
diagnosed during the autumn of 1997. All were elderly men with advanced
generalized atherosclerosis. Positive diagnosis upon renal biopsy required
demonstrating cholesterol crystals in renal interlobar and arcuate arteries.
Workups for progressive renal failure were performed due to suspected vasculitis
in three cases and radiologically induced renal damage subsequent to coronary
angiography in another. None of the patients showed renal vasculitis upon biopsy,
but one who was ANCA positive developed vasculitis after a few months. Three
patients died within a couple of months of onset. The patient with renal
vasculitis was treated with cyclophosphamide and steroids, and survives one and a
half years after onset. It is vital to consider the diagnosis cholesterol
embolism whenever an elderly patient with pronounced atherosclerosis develops
progressive renal failure and multi-organ failure. Angiography, aorto-iliaco
femoral surgery and thrombolytic therapy increase the risk of cholesterol
embolism in this group. There is no effective therapy. The key is prophylaxis,
which means identifying patients at risk prior to invasive vascular procedures.
PMID- 10771546
TI - [Severe male infertility. Genetic investigation and counseling prior to
intracytoplasmic sperm injections].
AB - Intracytoplasmatic sperm injection (ICSI) has improved the success rate in
treating severe male infertility. The method may now be used with sperm from the
epididymis and testis. This article summarizes our knowledge on genetic factors
affecting male gamete formation or function. Infertile men with severe impairment
of spermatogenesis showed a higher than normal incidence of chromosomal
abnormalities and 10-20% had microdeletion, in the Y-chromosome. About 75% of
males with congenital bilateral absence of vas deferens (CBAVD) have mutations in
the cystic fibrosis trans-membrane conductance regulator (CFTR) gene. In
conclusion, we recommend genetic counselling to all couples with a diagnosis of
male infertility prior to ICSI. Men with severe oligozoospermia or non
obstructive azoospermia should have karyotype analysis performed and with
establishment of diagnostic tools to reveal Y-chromosome deletions, this should
be offered to the same group of men. Men with obstructive azoospermia and
congenital albilateral absence of vas deferens as well as their wives should be
screened for cystic fibrosis mutations.
PMID- 10771547
TI - [Future disease patterns. Reduced risks for the individual, increased burden to
society].
PMID- 10771548
TI - [The "father" of cornflakes was a physician--he created a gigantic health resort
for the rich America].
PMID- 10771549
TI - [A moment in medicine, part 3. Know yourself--and be yourself].
PMID- 10771550
TI - [Clopidogrel--an expensive thrombocyte inhibitor with a small marginal benefit].
PMID- 10771551
TI - [The psychiatry debate: schizophrenia--a therapeutic model].
PMID- 10771552
TI - [The value of RSV-prophylaxis: the shortage of data must not result in hasty
decisions].
PMID- 10771553
TI - [A reply: the benefit is marginal--money can be used better].
PMID- 10771554
TI - [Do dare to make priorities! For example gastroscopy in dyspepsia].
PMID- 10771555
TI - [Forensic judgments when it comes to risks are potentially the "sterilization
issue" of our time].
PMID- 10771556
TI - [Information ad on a photosensitivity allergen in a gel preparation].
PMID- 10771557
TI - [Recommendations by the German Airway League for sports and physical exercise in
patients with obstructive lung disease].
PMID- 10771558
TI - [Results of a survey of 549 patients regarding long-term clinical outcome and
quality of life four years after PTCA].
AB - BACKGROUND: Quality control becomes increasingly important in interventional
cardiology. Since in most health care systems, clinical treatment of patients who
underwent percutaneous transluminal coronary angioplasty (PTCA) is left to
general practitioners, important information on the clinical long-term outcome is
lost for the cardiologic centers. Aim of this study was to evaluate the clinical
status of these patients 4 years after treatment with a PTCA at our institution.
PATIENTS AND METHODS: Inclusion criterion was the treatment with a PTCA within
July 1, 1989 to June 30, 1991 (549 patients). A questionnaire was sent to all
patients (45 +/- 7 months after PTCA). Four time-points were defined: before PTCA
(T1), directly after PTCA (T2), 3 months after PTCA (T3) and actual status (T4).
RESULTS: Questionnaires of 500/549 (91.1%) patients could be analyzed. One
hundred and fifteen patients (23%) had to undergo reinterventions: 69 (13.8%) had
a re-PTCA and 46 (9.2%) patients an operative revascularization. At T4, 11.2%
patients still had disturbing angina. Within the study period 35 patients (7%)
died. Two-hundred and nineteen patients attended a rehabilitation institution. At
T4, the amount of patients with little angina was not different comparing
patients with/without the attendance of a rehabilitation institution (60.7% vs
66.4% p = 0.29). The rate of new pensioners after PTCA (n = 114 [22.8%]) was
higher in the group of patients who attended a rehabilitation (68 patients
[13.6%] with vs 48 patients [9.2%] without attendance, p = 0.0036). The
attendance of a rehabilitation institution, however, had positive effects on
changes of the life style and eating habits. CONCLUSIONS: This retrospective
inquiry was found to be a useful tool (response rate 91.1%) for quality control
in interventional cardiology. Important information concerning the quality of the
interventions (low reintervention rate) and the long-term outcome of our patients
(low rate with severe angina at T4) could be acquired.
PMID- 10771559
TI - [Importance of home care personally to individuals with advanced cancer and their
families].
AB - OBJECTIVE: The objective of the study is to evaluate the importance of home care
for patients with advanced tumor diseases and for their families. METHODS: The
analysis was based on structured interviews with relatives of patients with
terminal tumor diseases. They had participated in the home care of 50
consecutively treated patients 2 years previously. The value of home care was
evaluated on the basis of the personal experience of those concerned. RESULTS:
The answers were largely consistent. The holistic concept of palliative therapy
could be implemented by a specialized home care team at a high quality level.
Under the favorable conditions of the familiar surroundings, an atmosphere of
trust developed as a result of the cooperation with the family members, people
close to the patients and with family doctors. It contributed to a relatively
high quality of life and to alleviate the emotional stress. Most of those
involved were able to accept the hand of fate. On this basis, the terminal phase
could be satisfactorily arranged and preparations made for a good quality of
death. During the home care, appreciation of the value of the family increased.
The intensified family relations were mostly sustained after the patient's death.
The results document the great personal importance of home care for patients,
their caretakers and families. CONCLUSION: The positive experience and the
awareness of having contributed substantially to coping with the life crisis made
it easier for the bereaved to grieve and to rearrange their life.
PMID- 10771560
TI - [Differential diagnosis of hypercalcemia in adults].
AB - BACKGROUND: Increases in serum calcium are often detected by chance. They warrant
a prompt diagnostic work-up to identify the underlying cause. DIAGNOSIS:
Measurement of intact parathyroid hormone (PTH) is the first step to further
evaluate confirmed hypercalcemia. With few exceptions, marked increases in PTH
confirm primary hyperparathyroidism. Mildly elevated PTH levels may also be
observed in familial hypocalciuric hypercalcemia. Low-normal or decreased PTH
levels are mostly associated with clinically evident malignancies or
granulomatous diseases. A careful history will often be sufficient to make the
diagnosis of drug-related hypercalcemia. Clinical presentation, measurements of
1,25-dihydroxyvitamin D, PTH-related peptide and efforts to localize the
underlying disease are successful in over 90% in finding the cause of
hypercalcemia with low PTH. CONCLUSION: Hypercalcemia in adults can have many
different causes. Identification of the underlying disease is important, since
the corresponding treatment is very different for the different causes of
hypercalcemia. In most cases, medical history, clinical presentation, and a few
carefully directed laboratory measurements are sufficient to differentiate
between the most important hypercalcemic disorders.
PMID- 10771561
TI - [Heart failure as a cardiac symptom of sarcoidosis. Successful treatment of heart
failure with steroids, digitalis and an angiotensin-1-receptor antagonist in
sarcoidosis].
AB - BACKGROUND: Sarcoidosis is a multisystemic disorder that may involve every organ.
A symptomatic manifestation of the myocardium is possible, in these cases
arrhythmias are the most common symptoms. CASE REPORT: This case report presents
a 26-year-old female with the recurrence of Boeck's sarcoid. Fever, chill and a
severe reduction in stress tolerance were the first symptoms. At the time of
admission she complained of Grade III dyspnea according to the NYHA
classification. The echocardiogram showed a severe impairment of the global and
left ventricular function. The left ventricular ejection fraction was reduced to
30% and the Tei index was elevated to 1.0. A specimen taken from a mediastinal
tumor confirmed the hypothesis of the recurrence of the sarcoidosis. Myocardial
perfusion scintigraphy showed typical lesions for myocardial sarcoidosis. There
were signs of an old anteroseptal infarction in the resting ECG without evidence
of myocardial ischemia during a stress test. Repeated Holter-ECGs were without
signs of severe arrhythmias whereas ventricular late potentials were positive.
After the combined therapy with steroids, digitalis and an angiotensin-1 receptor
antagonist, mediastinal mass and Tei index were reduced and the ejection fraction
moved to 56%. Dyspnoea was classified with Grade II according to the NYHA
classification. CONCLUSION: Treatment of asymptomatic sarcoidosis is still
controversial, whereas the treatment of life-threatening sarcoidosis, eye
involvement or severe hypercalcemia is accepted. This case report presents the
successful treatment of severe heart failure with prednisone, glycosides and an
angiotensin-1 receptor antagonist. With this combined therapy an improvement of
subjective and objective parameters was possible.
PMID- 10771562
TI - [Sneddon syndrome: vasculitis or thrombotic disorder?].
AB - BACKGROUND: Livedo reticularis generalisata (LR) in combination with affection of
CNS is referred to as Sneddon's syndrome (SNS). Latest data suggest chronic
progressive systemic disorder with occlusion of small and medium sized vessels
(e.g., cutis, brain, kidneys, heart, eyes). No conclusive etiology is known,
though there are correlations to the antiphospholipid syndrome, systemic
secondary vasculitis and coagulopathies. Hereditary and toxic factors seem to
play a role in pathogenesis in some cases. CASE REPORT: Diagnostic procedure and
clinical course of a 56-year-old woman with dementia and hemiparesis proceeded by
LR is reported. MRI-, SPECT- and TCD-findings were congruent with diffuse
ischemic lesions of the brain due to affection of small- and medium-sized
vessels. Histopathological specimens of the brain, meninges and cutis were non
diagnostic. Some laboratory findings suggested vasculitis as an underlying cause.
LR improved under immunosuppressive therapy with prednisolone and azathioprin.
CONCLUSION: SNS does not seem to be a nosological entity. A differentiation
between primary (idiopathic) and secondary SNS is useful for different
therapeutical approaches.
PMID- 10771564
TI - [Plaque-like skin changes of the lower leg in diabetes mellitus].
PMID- 10771563
TI - [Hypereosinophilia with myocardial involvement due to toxocariasis. Diagnosis of
regional myocardial perfusion abnormalities by pulsed tissue Doppler
echocardiography].
AB - CASE REPORT: The case of a 57-year-old woman is reported who was admitted for
peripheral hypereosinophilia. DIAGNOSIS: Detailed investigations revealed first
of all a hypereosinophilic syndrome with infiltration of bone marrow and lung.
The patient suffered more and more from angina pectoris with signs of heart
failure. Coronary angiography was therefore carried out which showed normal
coronary arteries. With suspicion of myocardial involvement endomyocardial
biopsies were performed which revealed the presence of Lofflers endocarditis
parietalis fibroplastica. Finally, serological studies for parasites disclosed a
positive ELISA test for Toxocara, confirmed later to be rising. CONCLUSION:
Myocardial involvement of hypereosinophilia, caused by Toxocara is not described
until now. Further diagnostic by means of pulsed wave tissue Doppler
echocardiography provided regional differentiation of a restrictive filling
pattern which documented the importance of this new diagnostic tool in myocardial
illness.
PMID- 10771565
TI - [Therapy of community-acquired pneumonia].
PMID- 10771566
TI - [CONSORT--What is to be expected from a reputable scientific publication].
AB - The publication of the CONSORT Statement was aimed at the improvement of the
quality of research reports of randomized controlled clinical trials. It contains
the most important standards of high quality research. Although originally meant
for randomized studies only most aspects of this statement can be applied to
other kinds of clinical studies. The following--and last--article of this series
on medical biostatistics presents and comments the most important criteria.
PMID- 10771567
TI - [Meningitis in a view of cytokines].
PMID- 10771568
TI - [Differential influences of bFGF and VEGF on the expression of vascular cell
adhesion molecule-1 on human umbilical vein endothelial cells].
AB - A fundamental feature of inflammation includes angiogenesis, adhesion of
leukocytes to vascular endothelium, and entry of leukocytes into inflamed
tissues. Recent studies have suggested that angiogenesis and cellular adhesion
may be mutually linked processes. Both basic fibroblast growth factor (bFGF) and
vascular endothelial growth factor (VEGF) have been shown to facilitate
angiogenesis. However, their roles in the expression of adhesion molecules on the
endothelial cells have not been clarified. The current studies therefore examined
the effect of bFGF and VEGF on the expression of vascular cell adhesion molecule
1 (VCAM-1) on human umbilical vein endothelial cells (HUVEC) stimulated with
tumor necrosis factor alpha (TNF-alpha). HUVEC (1 x 10(4)/well) were incubated in
a 96 well microtiter plate with culture medium containing endothelial cell growth
supplement (ECGS) for 24 h. After the incubation, culture medium was replaced by
ECGS free culture medium with or without TNF-alpha (10 ng/ml), bFGF (10 ng/ml)
and VEGF (10 ng/ml), and the culture was further carried out for additional 24 h.
The expression of VCAM-1, E-selectin, and intercellular adhesion molecule-1 (ICAM
1) was measured by cell ELISA and the proliferation of HUVEC was measured by MTT
colorimetric assay. Soluble VCAM-1 (sVCAM-1) in the supernatants were assessed by
ELISA. Although, both bFGF and VEGF supported the proliferation of HUVEC, bFGF,
but not VEGF, selectively suppressed the expression of VCAM-1 on HUVEC stimulated
with TNF-alpha. The expression of ICAM-1 and E-selectin induced by TNF-alpha was
not inhibited by either bFGF or VEGF. In addition, bFGF also decreased the levels
of sVCAM-1 in the supernatants of TNF-alpha stimulated HUVEC. The data indicate
that bFGF, but not VEGF, suppresses the production of VCAM-1 by HUVEC under
stimulation with TNF-alpha. These results therefore suggest that angiogenic
cytokines bFGF and VEGF play different roles in the regulation of the expression
of adhesion molecules on endothelial cells under inflammation.
PMID- 10771569
TI - [A male case of Sjogren's syndrome presenting with generalized lymphadenopathy
and swelling of both lacrimal and salivary glands which responded remarkably well
to an administration of corticosteroids].
AB - A 68-year-old man noticed severe oral dryness and a submandibular swelling.
Sjogren's syndrome (SS) was diagnosed based on microscopic findings of a labial
salivary gland biopsy although both anti-SS-A and anti-SS-B antibodies were
negative. In addition, hypergammaglobulinemia (IgG 7940 mg/dl) and
hypocomplementemia were pointed out and he was admitted to our department. On
admission cervical, mediastinal, and abdominal lymph nodes swelling were detected
together with enlargement of lacrimal and salivary glands. Lymphoproliferative
disorders associated with SS were highly suspected. Biopsied specimens of his
lacrimal gland and cervical lymph node disclosed neither malignant cells nor
monoclonal proliferation of lymphocytes. An administration of corticosteroids
caused rapid diminution in size of lacrimal glands, salivary glands, and lymph
nodes. Both lacrimation and salivation recovered, and hypergammaglobulinemia and
hypocomplementemia returned to normal after treatment. The characteristics of
this case were an atypical onset in an elderly man, the negativity of anti-SS-A
and anti-SS-B antibodies, and reversibility of dryness by corticosteroid
treatment. These findings suggest that the pathogenesis of this case may be
different from typical SS.
PMID- 10771570
TI - [Hypersensitivity peumonitis in a patient with rheumatoid arthritis].
AB - We report a case with rheumatoid arthritis and hypersensitivity pneumonitis. A 66
year-old female was admitted to our hospital because of fever, cough, and
progressive dyspnea on October 10, 1997. She had a history of rheumatoid
arthritis from 1987 and was treated with cyclophosphamide when she developed
pulmonary symptoms in September 1997. On admission arthritis was subsided. Fine
crackles on ausculation of lung, hypoxia, ground-glass appearance on chest X-ray
were detected. The computed tomography of the chest disclosed diffuse
interstitial shadow with patchy destruction of alveolar structures.
Bronchoalveolar lavage demonstrated an increase in lymphocytes with predominance
of suppressor-cytotoxic T cell subset (CD 8+). The histopathological examination
of transbronchial lung biopsy showed interstitial inflammation with marked
predominance of lymphocyte with intraalveolar exudate. Her condition got better
and she discharged without definitive diagnosis and treatment for her respiratory
symptoms. Eight hours after she went back home, she suddenly presented high fever
and cough and gradually developed dyspnea. She was readmitted 5 days after the
previous discharge. Although no specific precipitin antibody against various
microorganisms was detected in her sera, the diagnosis of hypersensitivity
pneumonitis was made. Thirty mg per day of prednisolone was resolved her symptoms
promptly. There was no reported case with hypersensitivity pneumonitis and
rheumatoid arthritis of other collagen diseases. The clinical course that
arthritis and pulmonary symptoms appeared alternatively is of considerable
interest to investigate for the pathogenesis of these two immune disorders.
PMID- 10771571
TI - [A case of hypopituitarism and primary hypothyroidism associated with
antiphospholipid syndrome].
AB - Recent reports have indicated that antiphospholipid antibodies (aPL) are related
to other clinical manifestations such as cardiac valve lesions and hemolytic
anemia besides the major clinical features of antiphospholipid syndrome (APS),
including thrombocytopenia, and recurrent fetal demise. We recently encountered a
case of multiple hormonal deficiencies in the pituitary gland and hypothyroidism
associated with an APS. Hypopituitarism of the patient had occurred after her
delivery and a magnetic resonance imaging (MRI) examination disclosed "empty
sella" of the hypophysis, so she was thought to have Sheehan's syndrome. There
has been a few reports describing the relationship between aPL and endocrine
disorders. aPL-related onset of these diseases may be more frequent than is
generally appreciated.
PMID- 10771572
TI - [A patient with life-threatening giant hematoma caused by acquired inhibitor to
factor VIII].
AB - A 66-year-old non-hemophiliac man developed widely spreaded hematoma in soft
tissues around neck. On the day of admission, he was nearly choked by the giant
hematoma which markedly compressed trachea. Initially, to keep air way, an
intratracheal intubation using a fiber scope was carried out. Coagulation studies
revealed a marked prolongation of activated partial thromboplastin time (129
seconds, control: 24.9-33.2), a diminished activity of factor VIII (less than 1%)
and a significant increase of factor VIII inhibitor titer (60 Bethesda unit/ml).
We thereby diagnosed coagulopathy related to acquired inhibitor against factor
VIII. The general combination therapy of intravenous infusion of both prothrombin
complex concentrates and activated prothrombin complex concentrates, prednisolone
and plasma exchange successfully stopped expansion of the giant hematoma.
However, because the titer of factor VIII inhibitor remained increased and the
activity of factor VIII was continued to reduced, cyclosporin was additionally
administrated. As a result, the titer of factor VIII inhibitor was markedly
improved, but the reduced activity of factor VIII was continued and re-bleeding
around neck was observed. We thereby administered steroid pulse therapy, which
resulted in complete remission of the disease activity and recovery of factor
VIII activity.
PMID- 10771573
TI - [Sjogren's syndrome with MALT (mucosa-associated lymphoid tissue) lymphoma in a
13-year-old girl: a case report].
AB - We report A case of Sjogren's syndrome complicated with MALT (mucosa-associated
lymphoid tissue lymphoma) in childhood. Additionally, Helicobacter pylori
infection into the gastric mucosa was highly suspected in this case. A 13-year
old girl suffering from multiple joint pain had received treatment as Juvenile
Rheumatic Arthritis with no clinical improvement until introduction to our
hospital. On admission to our hospital, high levels of serum anti-SSA and anti
SSB (80.2 and 16.1 holds, respectively) were detected. Minor salivary gland
biopsy showed a typical histological finding for Sjogren's syndrome as
infiltrating lymphocytes around the excretory ducts. Computed tomography and
67Gallium scintigraphy showed a gastric tumor, and it was diagnosed as primary
gastric B-cell MALT lymphoma by the histopathological findings. Additionally,
Helicobacter pylori infection into the gastric mucosa was highly suspected.
Recently it is emphasized that infection of Helicobacter pylori is related with
gastric MALT lymphoma. There has been no reports of children who have Sjogren's
syndrome associated with malignant lymphoma. Taken together, Helicobacter pylori
infection superimposed with Sjogren's syndrome might accelerate clinical course
in our particular case.
PMID- 10771574
TI - [Three patients with systemic sclerosis complicated by microangiopathic hemolytic
anemia and thrombocytopenia].
AB - Clinical profiles and the treatment process of three female patients with
systemic sclerosis (cases 1, 2, and 3) complicated by thrombotic microangiopathic
hemolytic anemia (TMHA) were described. Thrombocytopenia preceded renal damage
and hypertension in cases 1 and 2, although the chronological relationship
between these parameters were unknown in case 3. Plasma exchange therapy using
fresh frozen plasma was beneficial in cases 1 and 2. Cases land 3 presented with
delirium and fluctuating psychosis, respectively. Early detection of
thrombocytopenia and insidious hemolysis might be essential for starting
effective plasmapheresis treatment in a part of patients with scleroderma kidney
who present with thrombotic thrombocytopenic purpura (TTP) like disorder.
PMID- 10771575
TI - [A case of collapsing variant of FSGS].
AB - We report a case of collapsing variant of FSGS. An 82-year-old man without HIV-1
infection or a history of intravenous drug abuse was admitted to our hospital
with the chief complaints of acute onset of generalized edema and loss of
appetite. Laboratory findings were consistent with nephrotic syndrome. He
developed acute renal insufficiency. Initially, we suspected minimal change
nephrotic syndrome and started steroid pulse therapy but the nephrotic syndrome
was refractory and a renal biopsy was performed. The pathologic findings were
judged to be consistent with a collapsing variant of focal segmental
glomerulosclerosis (FSGS). This form was described by Weiss et al. in 1986 as a
clinically and pathologically distinct variant of FSGS. Valeri et al. further
reported that the incidence of this idiopathic collapsing type of FSGS which is
devoid of evidence of HIV-1 infection or intravenous drug abuse has progressively
increased over the past two decades. They reported that cyclosporin is effective
for the treatment of this type of FSGS with a remission rate of about 30%. The
present case also had a nearly complete remission after 2 month-cyclosporin
treatment. In Japan, no adult case of this type of FSGS has been reported
according to our review of the literature.
PMID- 10771576
TI - [Treatment by corticosteroid and plasma exchange in 5 cases of renal cholesterol
embolic disease].
AB - Cholesterol arterial embolization is a systemic disease resulting from
cholesterol crystal embolization to multiple organs, including the kidney, skin,
brain, eye, gastrointestinal tract and extremities. In general, it is associated
with high morbidity and mortality, but no optimal treatment has yet been
developed. In this paper, we report five patients with cholesterol atheroembolic
renal failure. In three of the five patients, combined therapy with
corticosteroids and plasma exchange was performed. The three patients survived.
On the other hand, the two remaining patients died of multifactorial causes. In
this report, the literature on steroid therapy for cholesterol atheroembolic
renal disease is reviewed and the efficacy of combined therapy by use of
corticosteroids and plasma exchange is evaluated.
PMID- 10771577
TI - [Successful use of angiotensin II receptor antagonist (losartan) in a patient
with scleroderma renal crisis].
AB - A 67-year-old man with a one-and-a half-year history of Raynaud's phenomenon was
admitted to our hospital for progressive dyspnea occurring over the previous two
weeks. Physical examination revealed a blood pressure of 200/124 mmHg, and
slightly tight and smooth skin of the fingers, hands and forearms. Laboratory
evaluation included serum creatinine of 5.42 mg/dl, plasma renin activity > 20
ng/ml/hr, and antinuclear antibody with a titer of 1 : 1,280. Renal biopsy was
performed and the histopathological findings showed that some glomeruli exhibited
ischemic retraction with wrinkling of the basement membranes, and that one
arteriole exhibited significant intimal hyperplasia with luminal stenosis. These
findings were compatible with scleroderma renal crisis (SRC). On the 5th day,
serum creatinine had risen to 9.16 mg/dl, and he required temporary hemodialysis
therapy. After the administration of captopril was started, his blood pressure
fell to 160/86 mmHg and serum creatinine was reduced to 5.12 mg/dl. On the 9th
day, he exhibited skin eruptions, and captopril was discontinued accordingly and
temocapril started. Because of continued eruptions, temocapril was replaced by
losartan. His blood pressure was controlled easily and his serum creatinine level
reduced steadily. One year after the start of losartan, serum creatinine was 2.25
mg/dl and blood pressure was 130/82 mmHg. SRC is a life-threatening manifestation
of systemic sclerosis. In the late 1970s, angiotensin converting enzyme (ACE)
inhibitor was introduced and has dramatically improved the outcome in SRC
patients. As ACE inhibitors act mainly on hyperreninemic renal vasoconstrictive
hypertension in SRC, we would expect losartan, a selective antagonist of
angiotensin receptor subtype 1, to be interchangeable with ACE inhibitors in SRC.
In 1997, Caskey and colleagues reported the failure of losartan to control
hypertension in a patient of SRC, and the reason has remained unclear. We report
here, a case of SRC whose blood pressure was controlled successfully and his
renal failure reversed by the administration of losartan.
PMID- 10771578
TI - [A case of Chinese herbs nephropathy in which the progression of renal
dysfunction was slowed by steroid therapy].
AB - The patients was a 43-year-old woman whose chief complaints were nausea and
heaviness of the heads. There was a history of toxemia of pregnancy. The patient
had previously taken Tenshin Tokishigyaku-ka-goshuyu-shokyo-to for two years
because of cold sensitivity. Fever, thirst, and loss of appetite developed from
approximately 18 months after she started treatment with the Chinese herbal
preparation, and she presented at our outpatient clinic 2.5 years later. On
initial examination, deterioration of renal function was evident and the serum
creatinine level was 3.4 mg/dl. A renal biopsy specimen showed marked
interstitial fibrosis without inflammatory cell infiltration, leading to the
diagnosis of Chinese herbs nephropathy (CHN). Steroid therapy was started on the
36th hospital day after a sharp rise in the serum creatinine level to 5.1 mg/dl.
This resulted in the rapid improvement of renal function and reduction of the
serum creatinine to 2.6 mg/dl by 8 weeks after the initiation of treatment. In a
study on the use of steroids for patients with progressive moderate renal
dysfunction caused by Chinese herbs, Vanherweghem et al. reported that the
progression of renal failure was appreciably slowed in patients given steroids
when compared with the control group. We were also able to slow the progression
of renal dysfunction in our patient by steroid therapy, although the prognosis of
CHN is generally considered to be very poor.
PMID- 10771579
TI - [Interpersonal relation pattern in families with a bulimic member- interaction
analysis].
AB - Basic hypotheses concerning the interaction in families of bulimic patients are
tested. Family therapy sessions of 20 female patients of an outpatient therapy
unit for eating-disorders were coded with a micro-analytic instrument (Gottinger
Familieninteraktions-Skalen) and analysed. The siblings relationships were
systematically included in the study. The parental dyad turned out to be
significantly more conflictual than the other dyads were. In the relationship
between the patient and the parents a relatively stable pattern of interactional
behaviour was found. The relationship between mother and bulimic daughter was
more conflictual than that between father and daughter. The father-sibling-dyad
was not significantly more conflictual than the father-patient-dyad. Especially
the impact of sibling relationships on the family interaction of bulimic patients
needs further elucidation.
PMID- 10771580
TI - [Resource diagnosis with children].
AB - Traditionally the task of diagnosis in psychotherapy with children is the
description of the disturbed behavior and the analysis of its causes. But the
deficit-oriented perspective leads as a rule to a neglection of the clients',
positive potentials, whose inquiry and therapeutic use for the success of therapy
is however, following new findings of therapeutic effect research, of eminent
significance. By this article a concept of resource diagnosis is introduced that
demonstrates by several examples from the practice different methods of resource
analysis with children based on a resource taxonomy. Finally a detailed case
presentation illustrates the enlarged possibilities which are offered by the
combined application of deficit and resource analytic results for therapy
planning and intervention.
PMID- 10771581
TI - [Mental disorders in hospitalized children of migrant families from the
Mediterranean].
AB - From 1.1.1988 to 31.12.1992 928 inpatients at the child- and adolescent
psychiatric clinic "Rheinhohe" were recorded and studied. At that time the
service area for this clinic for psychiatric care contained mixed rural/urban
localities of four Southhessian sectors including a part of Frankfurt/M. The
number of inpatients of Mediterranean origin in relation to German inpatients
were significantly lower than expected but higher compared with earlier studies.
The pattern of psychiatric disorders differed also in these two populations. The
distribution according to sexes showed an moderate higher male rate for both
groups (1.2:1). To study the differences in detail, 163 Mediterranean and German
patients were matched according to age, gender, school education and SES and
subsequently the Mediterranean patients were divided into those with a short- vs.
a long-term-assimilation experience. As a result the significant higher rate of
psychotic disorders among the Mediterranean treated inpatients counted for the
different patterns, especially among the short-term assimilated patients. On the
other hand, externalizing disorders were found to be significantly higher among
the long-term assimilated Mediterranean inpatients but also among the German
inpatients in contrast to the short-term assimilated migrant inpatients from the
Mediterranean regions. Suicidal attempts were significantly more frequent among
the Mediterranean girls than among their German counterparts. Thus key
differences for utilising inpatient services remained; the reasons accounting for
these dissimilarities are questionable and noteworthy for psychiatric care.
PMID- 10771582
TI - [Spreading hope: therapeutic teams with war-traumatized children and adolescents
in Bosnia].
AB - During a year (from August 1997 until July 1998) I worked as a psychotherapist,
supervisor and trainer in Bosnia. Even though it was sometimes really difficult,
looking back it seems to me that it has been a very meaningful and helpful work
in the service of children and adults in order to provide new hope and to help
them to cope with their war trauma. Because we really had good results, I would
like to encourage other psychotherapists and psychiatrists to dare to contribute
their skills in similar work. The main topics are: general conditions and
building up, with local partners, a therapeutic and training project in a poor,
neglected and remote area; setting and therapeutic procedure; methods and
techniques (without the standard therapeutic material!); build up trust; work on
trauma; training for local professionals; results, evaluation and continuation of
the project.
PMID- 10771583
TI - Application of chitosan for treatment of wastewaters.
AB - Research has clearly demonstrated that the biopolymer chitosan (deacetylated
chitin) can be used as an effective coagulating agent for organic compounds, as a
chelating polymer for binding toxic heavy metals, as well as an adsorption medium
for dyes and small concentrations of phenols and PCBs present in various
industrial wastewaters. In these specific applications, chitosan appears more
effective than other polymers such as synthetic resins, activated charcoal, and
even chitin itself. In addition, the amino group in chitosan is an effective
functional group that can be altered chemically for production of other chitinous
derivatives with specific useful characteristics as effective absorptive agents.
Chitosans exhibiting different physicochemical characteristics, i.e., molecular
weight, crystallinity, deacetylation, particle size, and hydrophilicity, differ
in their effectiveness as waste treatment agents. The specific relationship
between methods and the particular crustacean species used in preparation of
chitosan for wastewater treatment needs further examination. Use of
bioremediation approaches, combined with immobilization of specific
microorganisms on immobilized chitinous columns, is an extremely promising area
of current research and actual plant operation.
PMID- 10771584
TI - Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure.
AB - The organophosphorus pesticides of this review were discovered in 1936 during the
search for a replacement for nicotine for cockroach control. The basic
biochemical characteristics of RBC AChE and BChE were determined in the 1940s.
The mechanism of inhibition of both enzymes and other serine esterases was known
in the 1940s and, in general, defined in the 1950s. In 1949, the death of a
parathion mixer-loader dictated blood enzyme monitoring to prevent acute illness
from organophosphorus pesticide intoxication. However, many of the chemical and
biochemical steps for serine enzyme inhibition by OP compounds remain unknown
today. The possible mechanisms of this inhibition are presented kinetically
beginning with simple (by comparison) Michaelis-Menten substrate enzyme
interaction kinetics. As complicated as the inhibition kinetics appear here, PBPK
model kinetics will be more complex. The determination of inter- and
intraindividual variation in RBC ChE and BChE was recognized early as critical
knowledge for a blood esterase monitoring program. Because of the relatively
constant production of RBCs, variation in RBC AChE was determined by about 1970.
The source of plasma (or serum) BChE was shown to be the liver in the 1960s with
the change in BChE phenotype to the donor in liver transplant patients. BChE
activity was more variable than RBC AChE, and only in the 1990s have BChE
individual variation questions been answered. We have reviewed the chemistry,
metabolism, and toxicity of organophosphorus insecticides along with their
inhibitory action toward tissue acetyl- and butyrylcholinesterases. On the basis
of the review, a monitoring program for individuals mixing-loading and applying
OP pesticides for commercial applicators was recommended. Approximately 41 OPs
are currently registered for use by USEPA in the United States. Under
agricultural working conditions, OPs primarily are absorbed through the skin.
Liver P-450 isozymes catalyze the desulfurization of phosphorothioates and
phosphorodithioates (e.g., parathion and azinphosmethyl, respectively) to the
more toxic oxons (P = O(S to O)). In some cases, P-450 isozymes catalyze the
oxidative cleavage of P-O-aryl bonds (e.g., parathion, methyl parathion,
fenitrothion, and diazinon) to form inactive water-soluble alkyl phosphates and
aryl leaving groups that are readily conjugated with glucuronic or sulfuric acids
and excreted. In addition to the P-450 isozymes, mammalian tissues contain ('A'
and 'B') esterases capable of reacting with OPs to produce hydrolysis products or
phosphorylated enzymes. 'A'-esterases hydrolyze OPs (i.e., oxons), while 'B'
esterases with serine at the active center are inhibited by OPs. OPs possessing
carboxylesters, such as malathion and isofenphos, are hydrolyzed by the direct
action of 'B'-esterases (i.e., carboxylesterase, CaE). Metabolic pathways shown
for isofenphos, parathion, and malathion define the order in which these
reactions occur, while Michaelis-Menten kinetics define reaction parameters
(Vmax, K(m)) for the enzymes and substrates involved, and rates of inhibition of
'B'-esterases (kis, bimolecular rate constants) by OPs and their oxons. OPs exert
their insecticidal action by their ability to inhibit AChE at the cholinergic
synapse, resulting in the accumulation of acetylcholine. The extent to which AChE
or other 'B'-esterases are inhibited in workers is dependent upon the rate the OP
pesticide is activated (i.e., oxon formation), metabolized to nontoxic products
by tissue enzymes, its affinity for AChE and other 'B'-esterases, and esterase
concentrations in tissues. Rapid recovery of OP BChE inhibition may be related to
reactivation of inhibited forms. AChE, BChE, and CaE appear to function in vivo
as scavengers, protecting workers against the inhibition of AChE at synapses.
Species sensitivity to OPs varies widely and results in part from binding
affinities (Ka) and rates of phosphorylation (kp) rather than rates of activation
and detoxif
PMID- 10771585
TI - Toxicology and risk assessment of freshwater cyanobacterial (blue-green algal)
toxins in water.
AB - The occurrence of cyanobacterial toxins affects aquatic organisms, terrestrial
animals (both wild and domestic), and humans. Detrimental effects have been
documented in the scientific literature during the past 50 years. Possible
guideline values of some cyanobacterial toxins (microcystins, cylindrospermopsin,
and anatoxin-a) are estimated, and they show that children and infants are more
susceptible to cyanobacterial toxins than adults. Therefore, particular attention
should be paid when cyanobacterial blooms occur, even at relatively low cell
counts, to protect children and infants from possible risks. Based on these
guideline values and the occurrence of the toxins, it can be concluded that
chronic and subchronic exposure to cyanobacterial toxins does occur in some
populations, particularly in developing countries where high proportions of the
population consume untreated surface water directly, such as pond, ditch, river,
or reservoir water. Because wildlife and domestic animals consume a large amount
of untreated water daily, they are at higher risk than humans from cyanobacterial
toxins. Calculated guideline values in Section X show that a relatively high risk
posed by the toxins to these animals is likely to occur, even at low cell
densities.
PMID- 10771586
TI - [Autoimmune diseases].
AB - In most autoimmune diseases no specific cause can be identified. Autoimmune
disorders are induced by a loss of tolerance where self cannot be differentiated
from foreign. Infections can provoke autoimmune processes, e.g. rheumatic fever.
The degree of severity and the extent of disease are influenced by environmental
factors and genetic characteristics. The identification of antibodies can be
helpful for diagnosis. Certain antibodies are associated with specific
manifestations (e.g. Ro-antibodies). Often, however, antibodies are nonspecific.
Despite considerable progress in treatment, cure is rare. Treatment of autoimmune
diseases requires continuous consideration of clinical activity and necessity of
medication.
PMID- 10771587
TI - [Changes in health politics].
AB - In the last 25 years we observed in health politics an impressive transition,
always more important became money. The big majority of physicians is not
interested in politics, neither in health politics, they permit, that there is
made politics with them. Often the "health war" (Clausewitz) is more important
for them than "the art of the possible" (Bismark). There are many groups and many
competences, but until now everybody forgot to allot the competences clearly to
the different groups. Decisions are made with few competence, with "an empty
brain". Additional services are demanded for the same money, as Mrs. Dreifuss of
the Swiss Federal Council does. She wishes the neutrality of cost, but more
services.
PMID- 10771588
TI - [Critical view of the health care of tomorrow].
AB - There are two issues in question concerning future developments in medicine:
progress and reform. In so much as the "Scientific Paradigm" will be shifted from
causality to the idea of a feed-back control system progress in medical sciences
might lead treatment to enhancing the patient's biological individuality but it
will not lead to better knowledge of the patient's person. Therefore the
physicians functions will have to include communicational skills on a higher
level. The health care system's reform primarily in Germany has to face the
inevitability of rationing medical services. For alteration two examples will
have to be considered: health care systems in the UK and in the US. Is health
care a public or a private task? Answering this question leads to a new
assignment to the medical profession.
PMID- 10771589
TI - Cost-effectiveness analysis in oncology.
AB - Economic evaluations in cancer have become increasingly important because of the
rising incidence of the disease and the proliferation of effective therapies. The
aging of the population and the increasing costs of care make it even more
important to identify those treatments of greatest value from both an
effectiveness and cost perspective. Economic research can be conducted at the
"macro" level where estimates of cost are made at the population level or at the
"micro" level where the costs of specific strategies are evaluated. This paper
reviews the types of economic evaluations and the classification of costs in
these evaluations. In all economic evaluations, several key elements need to be
considered. These are discussed in the manuscript and include the alternatives
being compared, the perspective of the analysis and the outcomes being measured.
Because of the many variables included in an economic analysis, there is real
potential for bias to be introduced. The importance of transparency in the
presentation of data and the need for sensitivity analyses to determine the
robustness of the conclusions are aspects of economic analyses that readers must
understand in order to interpret the reported results. The application of the
information in an economic evaluation to a specific clinical situation must be
interpreted in the light of the health care costs and system of care delivery
from which the study results were derived. Similarly, the cost-effectiveness of a
particular treatment intervention may be considered in relation to the cost
effectiveness of other interventions in a league table, but such comparisons are
often flawed. The reasons for this are discussed. Economic evaluations in
oncology will be increasingly important in making choices between expensive new
treatments, but great care must be exercised in the interpretation of individual
reports.
PMID- 10771590
TI - [HIV-associated myelopathy].
PMID- 10771591
TI - [Innate defense lectin: overview] [In Process Citation]
PMID- 10771592
TI - [Collecting family as host-defense lectins].
PMID- 10771593
TI - [Structure and function of the Ficolin family].
PMID- 10771594
TI - [Complement activation through the lectin pathway].
PMID- 10771595
TI - [Nonself-recognizing lectins in invertebrate innate immunity].
PMID- 10771596
TI - [Peroxisome biogenesis and human disorders].
PMID- 10771597
TI - [Metal chelatases involved in chlorophyll and heme biosynthetic pathways in
photosynthetic organisms].
PMID- 10771598
TI - [On the DNA sequence determination of human chromosome 22].
PMID- 10771599
TI - [The 25th anniversary of nucleosome discovery].
PMID- 10771600
TI - [Biomaterial to communicate with cells: adhesion and gene expression of cells].
PMID- 10771601
TI - [Mass spectrometry of a protein (1): Magnetic sector mass spectrometer and its
application].
PMID- 10771602
TI - [High-frequency active oscillation of the head in testing vestibuloocular reflex
in healthy subjects].
AB - An original device has been designed in the ENT clinic of the Russian Medical
University in cooperation with GUTA-clinic laboratory. The device registers high
frequency active oscillation of the head. This oscillation test was tried in 20
healthy individuals aged 20 to 60 years and was found easy to perform and highly
informative. This technique can be used as an additional vestibular test in
assessing function of the vestibular analyser.
PMID- 10771603
TI - [Preventive care and treatment of hearing problems in persons exposed to
radiation].
AB - Neurosensory hypoacusis (NSHA) was treated in 193 patients exposed to radiation
consequently to the Chernobyl accident. The article describes changes observed in
the examinees on audiograms, ECG, rheoencephalograms (REG) and acoustic evoked
potentials. Treatment of patients with radiation-induced NSHA was aimed at
normalization of tonicity of the cerebral vessels, venous outflow, pulse blood
filling, arterial pressure, bioelectric activity of the brain, cardiac activity
with account to hearing defects in different portions of the acoustic system. The
treatment has improved parameters of tonal and speech audiometry, cortical
acoustic evoked potentials, REG and EEG in 63.4% of the patients. The rest of the
patients achieved stabilization of the process, arrest of progressive hearing
loss. Also, positive effects were seen on the general condition of the patients,
their working ability. The patients experienced relief of the headache, stuffy
ears, noise in the ears, etc.
PMID- 10771605
TI - [Clinical classification of chronic odontogenic maxillary sinusitis].
AB - Examination of 248 patients with odontogenic maxillary sinusitis (OMS) has shown
that most of OMS forms run a chronic course. Their clinical classification is
outlined with a special emphasis on the latent form which occurs in 16.5% of the
examinees. An open form of OMS was diagnosed in 51.6% of the patients. Treatment
of chronic OMS is surgical in many cases: maxillary sinusotomy with upper jaw
teeth examination and treatment.
PMID- 10771604
TI - [Vertical vestibuloocular reflexes in unilateral labyrinthine lesions
(communication I)].
AB - Vertical vestibuloocular reflexes (VVOR) were studied in 25 patients with
unilateral labyrinthine lesions and in 22 healthy subjects. The technique of VVOR
is based on stimulation of the internal semicircular canals of the labyrinth by
active sagittal head subduction. Dysfunction of the vertical semicircular canals
manifested with: VVOR asymmetry with stronger reflexes on the side of the
labyrinth affection; predominance of upward VVOR; vertical components of the
horizontal vestibuloocular reflexes were not so intensive as VVOR but had the
same specific features.
PMID- 10771606
TI - [Pre- and postseptal orbital rhinosinusogenic complications].
AB - The authors present examination and surgical data on 78 patients with different
forms of orbital rhinosinusogenic complication. One of the major factors for the
course and therapeutic policy in such complications is pre- or postseptal
location of the process in the orbit. Such local signs as exophthalmos, chemosis,
dislocation, reduced motility of the eye ball and, later on, sight disorders
indicate the lesion focus location behind the orbital septum. Clinical
comparisons of the pre- and postseptal orbital complications evidence for more
severe and prognostically unfavorable course of the inflammation in the posterior
part of the orbit. This urges early active combined therapy and cleansing of the
affected paranasal sinuses in such patients.
PMID- 10771607
TI - [Laser surgical unit "Glasser" (lambda = 1,54 microm) in otorhinolaryngology].
AB - The paper describes experimental and clinical results obtained with application
of laser radiation (wave length 1.54 microm). The source of the radiation was a
new surgical laser unit Glasser. The techniques and advantages of the above
radiation treatment are characterized.
PMID- 10771608
TI - [Correction of microcirculatory disorders with low-energy laser radiation in
children with vasomotor rhinitis].
AB - Turbinated bone's mucosa of 46 children aged 6 to 15 years was exposed to
radiation of low-energy laser for neurovegetative vasomotor rhinitis. Repeated
biomicroscopy stated that abnormal microcirculation recovered after 10 sessions
of the radiation even in severe alterations of the microcirculatory bed and long
history of the disease. The conclusion is made that low-energy laser radiation is
effective in correction of microcirculatory disorders and tissue mechanisms of
homeostasis in children with neurovegetative vasomotor rhinitis.
PMID- 10771609
TI - [Role of macrolides in antibacterial therapy of otitis media in children].
AB - A new macrolide vilprafen (jozamicine) was used as monotherapy or in combination
with rhinopront and mucopront in 50 children with inflammation in the middle ear.
Otorrhea ceased in 41 patients. Vilprafen is recommended after failure of
penicilline or cephalosporine treatment, in allergic reaction to these
antibiotics, in simultaneous adenoiditis and exacerbation of chronic tonsillitis.
PMID- 10771610
TI - [Effects of human papilloma virus types on course of juvenile respiratory
papillomatosis and effectiveness of interferon therapy in children].
AB - Identification of the type of human papilloma virus (HPV) was done by means of
polymerase chain reaction in 40 children with juvenile respiratory papillomatosis
(JRP). Adjuvant to surgery interferon treatment was carried out in 18 patients
(study group) with severe JRP. The rest 22 patients (control group) with less
severe papillomatosis received only surgical treatment. The majority of the
patients from both the groups had the virus type 6/11 (72.2 and 77.3% for the
study and control groups, respectively). The assessment of a relationship between
HPV type and effectiveness of interferon treatment in the study group has shown
that the share of patients with effective and uneffective interferon therapy in
each category (by HPV type) was about the same, i.e. no correlation exists
between HPV type and interferon therapy effectiveness.
PMID- 10771611
TI - [Tonsillectomy effects on physical development of young men].
AB - 5 days of lowering of body mass followed by body mass gain up to its presurgery
value 3 weeks after tonsillectomy was observed in 76 young men aged 15-17. These
changes are explained by post-tonsillectomy diet. 247 adolescents with chronic
tonsillitis had height and body mass greater than those in control group of 364
healthy subjects. Still higher mass and height were registered in 109 youths 2
years after tonsillectomy. Many of the latter had obesity.
PMID- 10771612
TI - [Some aspects of pure tone audiometry].
AB - Masking procedure during hearing threshold measurement in air conduction mode,
order of investigation of bone conduction perception are proposed. Range of
application of broad band and narrow band masking noises is considered.
PMID- 10771613
TI - [Electrostimulation of tubal muscles with synchronous blowing through the middle
ear].
PMID- 10771614
TI - [Hydromassage of wound surface of surgically reconstructed laryngeal lumen and
upper trachea].
AB - In surgical reconstruction of laryngostenosis and stenosis of the upper trachea
after dissection of the scars we place laryngotracheal prosthesis (LTP) in the
created lumen for a year and longer. The LTP dilator prevents regrowing the scars
into the larynx and trachea until termination of the wound epithelization. The
author has designed a device which provides a pulsed change in the pressure of
water-filled latex balloon-dilator of the LTP. This pulsed work is realized by 7
8-s sucking out water and filling again of 1/3 of water volume in the dilator.
Such procedures lasting for 20-30 min conducted 2 times a day are called
hydromassage of the larynx and trachea. In 7 patients subjected to hydromassage
for a full time of wearing the LTP, epithelization of the wound surface of the
reconstructed part of the airways occurred within 2-2.5 months. If hydromassage
was performed for half the time of LTP wearing (12 patients) epithelization
occurred within 3-3.5 months.
PMID- 10771615
TI - [Method of non-cannula tracheostoma creation after laryngeal extirpation].
PMID- 10771616
TI - [Percussional auscultation of frontal sinuses].
AB - Percussional auscultation of the frontal sinuses is used for diagnosis of frontal
sinusitides. Phonendoscope placed by the sinus walls auscultates sounds forming
as a result of comparative percussion of the anterior sinus walls. Three main
percussional tones are singled out. This method was employed for diagnosis in 48
patients with frontal sinusitis. The technique is easy to perform, safe and
precise (90%). The trend in frontal sinusitides development can be followed up.
PMID- 10771617
TI - [Epitympanitis with cholesteatoma after craniocerebral trauma with fracture of
skull base].
PMID- 10771618
TI - [A rare complication in 1,5-year-old child in upper tracheobronchoscopy].
PMID- 10771619
TI - [Isolated tuberculosis of pharyngeal and palatine tonsils in child].
PMID- 10771620
TI - [Foreign bodies in the lower respiratory tracts as a results of medical
manipulations].
PMID- 10771621
TI - Antituberculosis drug resistance worldwide.
PMID- 10771622
TI - Statistics on medical errors misleading.
PMID- 10771623
TI - Back to the future???
PMID- 10771624
TI - Vote on helmet law should be unanimous.
PMID- 10771625
TI - Latex cases emerging.
PMID- 10771626
TI - The value of acute care simulation.
AB - Simulation of crises has long been a component of training in the aviation and
nuclear industries. This technology has been successfully transferred and adapted
to acute care medicine and allied health care. In this article, we describe the
capabilities and uses of human acute care simulation at West Virginia University
Hospital.
PMID- 10771627
TI - Blunt traumatic subclavian artery injury.
AB - Subclavian artery injury secondary to blunt trauma is uncommon, accounting for
only 3% of traumatic injuries of the upper extremity. Associated injuries of
nerve, bone and joint are common. Early recognition and appropriate surgical
intervention are essential to reduce disability. Long-term limb dysfunction
usually results from concomitant nerve injury. This article describes our
experiences treating four patients at two Level II trauma centers in Huntington,
W.Va., and reviews the literature on the subject of subclavian artery injury
secondary to blunt trauma.
PMID- 10771628
TI - Serotonin discontinuation syndrome: does it really exist?
AB - Treatment guidelines for depression have typically focused on diagnosis, how to
initiate antidepressants, and duration of therapy, while very little is discussed
about discontinuing treatment. With the advent of the serotonin-specific reuptake
inhibitors (SSRIs), there is now growing evidence to support a "discontinuation
syndrome" associated with withdrawal of therapy. This article describes two cases
and presents a review of the literature.
PMID- 10771629
TI - Cervical pathology in West Virginia adolescents.
AB - Cytologic screening is an important diagnostic tool used to detect precancerous
and cancerous lesions of the cervix. We studied the prevalence of cervical
abnormalities, based on Pap smear results, in patients at the Outpatient
Adolescent Clinic at West Virginia University. We found a high incidence of
overall intraepithelial cell pathology (24%) in this group with 2.4% high grade
and 9.9% low-grade lesions. These findings show that major cervical pathology is
present in this age group. Furthermore, repeat smears at intervals of < one year
were performed on 317 patients. Of these repeat smears, 7% changed from normal to
abnormal in this period. Sexually active adolescent females should have Pap
smears at least annually to detect abnormalities that may otherwise not be
detected until they are more advanced and difficult to manage. Higher risk
adolescents may need semiannual screening.
PMID- 10771630
TI - PEIA, Medicaid agree to properly implement RBRVS.
PMID- 10771631
TI - Officials work together to mobilize threat of hepatis A.
PMID- 10771632
TI - [Actual situation and perspective of novel drug discovery].
PMID- 10771633
TI - [Paradigm shift of drug discovery through genomics].
PMID- 10771634
TI - [The mechanism of adenoma-carcinoma sequence].
PMID- 10771636
TI - [Pharmacogenomics].
PMID- 10771635
TI - [Approaches from genetical analyses on human diseases: neurodegenerative
diseases].
PMID- 10771637
TI - [Genomic drug discovery and pharmainformatics].
PMID- 10771638
TI - [Implementation of genomics based drug discovery].
PMID- 10771639
TI - [Orphan receptors: a fruitful resource for drug discovery].
PMID- 10771640
TI - [Signal transduction and therapeutic strategies].
PMID- 10771641
TI - [Drug design based on the mechanism of transcriptional regulation].
PMID- 10771642
TI - [Drug development from protein kinase inhibitors].
PMID- 10771643
TI - [Protein-tyrosine phosphatase inhibitors].
PMID- 10771644
TI - [Ca2+ sensitizers].
PMID- 10771645
TI - [Functional genomics and pharmacogenomics using a model organism.
Schzosaccharomyces pombe].
PMID- 10771646
TI - [Microchip technologies in ultra high throughput screening (UHTS)].
PMID- 10771647
TI - [Structure-based drug design].
PMID- 10771648
TI - [Combinatorial chemistry for drug discovery].
PMID- 10771649
TI - [Novel approach for drug design by using NMR].
PMID- 10771650
TI - [Pharmacogenomics and animal models for human individuals].
PMID- 10771651
TI - [Analysis of the mice lacking the prostanoid receptor].
PMID- 10771652
TI - [Patentology for drug discovery scientists].
PMID- 10771653
TI - [The comparative analysis of alternatives for university industry relations].
PMID- 10771654
TI - [Beta 3-adrenergic receptor].
PMID- 10771655
TI - Serotonin as a research platform for new drug discovery.
PMID- 10771656
TI - [Transcriptional control by nuclear receptors and its application to drug
development].
PMID- 10771657
TI - [Angiotensin II receptor antagonists].
PMID- 10771658
TI - [Endothelin receptors].
PMID- 10771659
TI - [Leukotriene D4 antagonists].
PMID- 10771660
TI - [Thromboxane A2].
PMID- 10771661
TI - [Chemokines and chemokine receptors: approach to anti-chemokine therapy].
PMID- 10771662
TI - [Opioid receptors].
PMID- 10771663
TI - [Function of adenosine receptors in the central nervous system].
PMID- 10771664
TI - [Discovery of highly potent and orally active non-peptide bradykinin B2 receptor
antagonists].
PMID- 10771665
TI - [Selective agonists and antagonists for prostaglandin E2 receptor subtypes].
PMID- 10771666
TI - [Multiplicity of dopamine receptors].
PMID- 10771667
TI - [Voltage-dependent Ca2+ channels as targets for novel therapeutic drugs].
PMID- 10771668
TI - [K+ channel modulators].
PMID- 10771669
TI - [Cl- channels and Cl- transport].
PMID- 10771670
TI - [TRP-related proteins as new target molecules: their correspondence to native
receptor-operated cation channels].
PMID- 10771671
TI - [Development of donepezil hydrochloride (Aricept) for the treatment of
Alzheimer's disease].
PMID- 10771672
TI - [Sildenafil (Viagra)].
PMID- 10771673
TI - [Development of new specific inhibitors for cathepsins and its application for
medical field].
PMID- 10771674
TI - [Phospholipase A2 inhibitor].
PMID- 10771675
TI - [PGD synthase inhibitors, possible therapeutic use for allergic asthma].
PMID- 10771676
TI - [Telomerase antagonists].
PMID- 10771677
TI - [Matrix metalloproteinase inhibitors].
PMID- 10771678
TI - [Histone deacetylase inhibitors--new anticancer agents?].
PMID- 10771679
TI - [PPAR gamma and thiozolidinedione derivatives as an antidiabetic drug for
treating insuline resistance].
PMID- 10771680
TI - [Raloxifene mimics the effect of estrogen on bone].
PMID- 10771682
TI - [Research and development of leuplin, a highly potent LH-RH analogue].
PMID- 10771681
TI - [COX-2].
PMID- 10771683
TI - [Nitic oxide and natriuretic peptides].
PMID- 10771684
TI - [The role of leptin in human obesity and related diseases--recent progress and
future directions].
PMID- 10771685
TI - [Glutamate transporter].
PMID- 10771686
TI - [Na+/H+ exchange inhibitors].
PMID- 10771687
TI - [Research and development of FGF-2 as a promising agent for wound healing].
PMID- 10771688
TI - [Hepatocyte growth factor (HGF)].
PMID- 10771689
TI - [Adhesion molecules].
PMID- 10771690
TI - [Activated protein C].
PMID- 10771691
TI - [FXa inhibitor].
PMID- 10771692
TI - [GPIIb/IIIa inhibitor].
PMID- 10771693
TI - [Anti-angiogenic reagents].
PMID- 10771694
TI - [Immunosuppressive agent FTY720].
PMID- 10771695
TI - [Anti-tumor activity of KRN7000, an alpha-galactosylceramide and its action
mechanism].
PMID- 10771697
TI - The dependency ratio.
PMID- 10771696
TI - [Anti-inflammatory substances].
PMID- 10771698
TI - Geriatrics photo quiz. Hodgkin's disease.
PMID- 10771699
TI - Pruritic lesions on the legs.
PMID- 10771700
TI - The aging kidney. Defending a delicate balance of fluid and electrolytes.
AB - The aging kidney is characterized by reduced glomerular filtration rate, loss of
tubular volume, and narrowed homeostatic control of water and electrolyte
balance. It is unclear whether these physiologic changes represent normal aging
or subclinical disease. With aging, there is an increased risk of hyper- or
hypovolemia. Sluggish control of potassium concentration also makes hyperkalemia
more common, particularly when the patient is using certain drugs. Water
metabolism is particularly vulnerable in older patients, resulting in a frequent
tendency toward dehydration and hyperosmolality. Understanding these limitations
on fluid and electrolyte homeostasis can help the clinician recognize and prevent
complications when caring for older patients.
PMID- 10771701
TI - Restless legs syndrome. How to provide symptom relief with drug and nondrug
therapies.
AB - Restless legs syndrome (RLS) is a perplexing, debilitating, and fairly common
condition that can be challenging to manage. Hallmark symptoms include an
increase in the severity of sensations during rest and an irresistible urge to
move the affected limbs. RLS often occurs concomitantly with periodic limb
movement disorder. There are no known causes of RLS, but likely triggers include
heredity, iron and vitamin deficiencies, caffeine, and alcohol. Chronic
conditions such as diabetes, peripheral neuropathy, and Parkinson's disease can
worsen and prolong RLS symptoms. Symptom management begins by establishing proper
nutrition intake and improved sleep hygiene. If these fail, conservative
pharmacologic treatment is appropriate, with regimens chosen from dopaminergic
agents, benzodiazepines, opioids, and anticonvulsants.
PMID- 10771702
TI - Hip fracture. Surgical decisions that affect medical management.
AB - Primary care physicians can provide optimal care for their older patients with
hip fracture when they are familiar with the repair techniques used by the
orthopedic surgeon. For medically stable patients, surgical repair is now
recommended 24 to 72 hours after the fracture. The type of surgery depends on the
type of fracture and the degree of the patient's prefracture mobility; options
range from simple percutaneous pinning to total hip replacement. Surgery is not
advisable for bed-ridden or moribund patients, nor for those with very
osteoporotic bones and extensively comminuted fractures. Complications of a hip
fracture and its surgical repair that require medical management include anemia,
phlebitis, pulmonary embolism, decubitus ulcer, fluid or electrolyte imbalance,
and pneumonia.
PMID- 10771703
TI - Diabetes management. Analysis of the American Diabetes Association's clinical
practice recommendations.
AB - Type 2 diabetes generally develops in persons older than age 45 and comprises
more than 90% of the estimated 15 million diabetes cases identified in the United
States. Due to the burgeoning population of older Americans and the increased
prevalence of obesity and sedentariness, type 2 diabetes is nearing epidemic
proportions. Tight glycemic control combined with good diet and regular exercise
can reduce the incidence of complications associated with unchecked disease. To
help physicians and patients achieve such objectives, the American Diabetes
Association publishes clinical practice recommendations that propose the most
effective methods for screening, diagnosis, and disease management. The position
statements presenting the standard of care for treatment of diabetes are reviewed
and critiqued from an evidence-based medicine perspective.
PMID- 10771704
TI - Gouty arthritis of the spine: clinical presentation and effective treatments.
PMID- 10771705
TI - Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999.
AB - Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by
deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10
patients referred to the Amyloid Program at Boston University over the past 15
years. Fewer than 100 cases of TBA have been described; only 1 series encompassed
more than 3 patients. We analyzed our experience with biopsy-proven TBA to define
better its natural history. Follow-up averaged approximately 8 years and was
obtained in all cases, making this outcome reporting the largest and most
complete to date. Three of these patients were prospectively studied for up to 24
months to examine the utility of bronchoscopy, computerized tomography (CT)
imaging, and pulmonary function tests (PFTs) in monitoring disease progression.
No patient with TBA developed signs or symptoms of systemic amyloidosis during
the period reviewed. Conversely, tracheobronchial disease was not diagnosed in
685 patients with primary systemic (AL) amyloidosis during the 15-year study
period at Boston University. Bronchoscopy proved most useful in establishing the
diagnosis by biopsy. Narrowing of major airways limited its inspection of the
tracheobronchial tree, however. In contrast, CT imaging provided quantitative
assessment of airway narrowing and mural thickening--2 major consequences of
amyloid infiltration. These CT features, in the presence of mural calcifications
sparing the posterior tracheal membrane, have been reported in few disorders
other than TBA. The ability of CT to map airway involvement and identify
extraluminal manifestations of TBA made it the study of choice for establishing
disease extent. Three patterns of disease were evident by CT imaging and
bronchoscopic examination: proximal, mid, and distal airways involvement. Those
with severe proximal disease had significantly decreased air flows, air trapping,
and fixed upper airway obstruction on PFTs. Patients with distal disease had
normal airflows. PFTs could not clearly distinguish proximal from severe mid
airways disease. Thirty percent of patients died within 7-12 years after
diagnosis, all having proximal or severe mid airways disease. Repeated rigid
bronchoscopic debridement and laser treatments did not prevent progressive
airways narrowing in patients dying from TBA. Most patients with mid airways
involvement, and all distal airway cases, had either stagnant disease or slowly
increasing amyloid deposits when followed for up to 14 years. In a small subset
of patients followed prospectively, serial PFTs were most sensitive to disease
progression. CT-derived measures of airway lumen diameter and wall thickness did
not change significantly despite marked improvements in airflow after rigid
bronchoscopy. Our experience suggests that serial PFTs and CT imaging together
offer the best assessment of airway involvement and disease progression in
patients with TBA. In the future, radiation therapy may provide more definitive
treatment of TBA than debulking procedure have to date.
PMID- 10771706
TI - Biologic effects of and clinical disorders caused by nonprotein amino acids.
AB - Despite the fact that nonprotein amino acids are present in many commonly eaten
foods, the biologic and clinical significance of this class of molecules has been
largely overlooked. This is owing in part to their relatively low concentrations
and their negligible nutritive value. Many of these compounds have the ability to
interfere with a wide range of fundamental biochemical processes and cause
disease. It is likely that the clinical effects of the ingestion of some
nonprotein amino acids are yet to be described. Serious disorders in humans have
followed the ingestion of these compounds as the result of food faddism, prodded
by the commercial promotion of inadequately tested products. In view of the
current popularity of herbal remedies and alternative medicine, these facts serve
as another reminder to health care providers and the public at large about the
need for critical analysis of the alleged benefits and the risks of exotic
remedies and nutritional supplements. Beyond the public health issues they raise,
non-protein amino acids take on significance because their misincorporation into
proteins can trigger vigorous autoimmune attacks. To what extent this mechanism
is responsible for highly prevalent diseases of autoimmunity remains to be
determined.
PMID- 10771707
TI - Hemolytic uremic syndrome. Recurrence after renal transplantation. Groupe
Cooperatif de l'Ile-de-France (GCIF).
AB - Hemolytic uremic syndrome (HUS) is an uncommon cause of end-stage renal failure
in adults, and few data are available concerning the outcome of renal
transplantation in these patients. We conducted this retrospective multicentric
study to appreciate the outcome of adult renal transplant recipients whose
primary disease was HUS. Sixteen patients, transplanted between 1975 and 1995,
were included in the study. In each case, initial diagnosis of HUS was documented
by a kidney biopsy. These 16 patients received a total of 25 allografts: 1 graft
for 9 patients, 2 grafts for 5 patients, and 3 grafts for 2 patients. Nine
patients (56%) developed definite clinical and pathologic evidence of recurrence
on at least 1 graft. Four additional patients (25%) demonstrated only some
clinical or pathologic evidence of recurrence which could not be distinguished
from acute vascular rejection. Three patients had no sign of recurrence of the
initial disease. The 1-year graft survival rate was 63% and the 5-year graft
survival rate was 18.5%. In the group of patients with proven or possible
recurrence (n = 13), the 1-year and 5-year graft survival rates were 49% and less
than 10%, respectively. The recurrence was an early event, occurring before the
end of the first month after transplantation in half the cases. The recurrence
rate was 92% in non-nephrectomized patients and 50% in patients with bilateral
nephrectomy. In the literature, 71 adult patients with primary HUS had received a
total of 90 kidney grafts. Among them, 54% had a recurrence on their graft, which
was diagnosed in 52% of the kidney transplants. It is note-worthy that when data
from the literature are pooled with our results, the rate of recurrence appears
to be significantly lower in binephrectomized patients than in patients with
their native kidneys at the time of transplantation (5 of 14 versus 27 of 35
patients, respectively, p = 0.0155). By univariate analysis, no other risk factor
for recurrence could be identified. Treatment with cyclosporine A did not
influence the recurrence rate. We conclude that recurrence of HUS after renal
transplantation is a frequent, early, and severe complication, leading rapidly to
graft loss. Prospective studies are needed to confirm that bilateral nephrectomy
prior to transplantation decreases the rate of recurrence.
PMID- 10771708
TI - Thyroid disease in primary Sjogren syndrome. Study in a series of 160 patients.
AB - We studied 160 consecutive patients (147 female and 13 male) with primary Sjogren
syndrome (SS) to determine the prevalence and clinical significance of thyroid
disease in a large series of patients with primary SS from our unit and to
compare the prevalence and significance with those in 75 individuals without SS
from a primary care center. Serum levels of thyroid hormones (free thyroxine,
triiodothyronine, and thyroid-stimulating hormone) and autoantibodies against
thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) were measured in all SS
patients and in 75 control patients. Fifty-eight (36%) of the 160 patients with
primary SS had evidence of thyroid disease. Autoimmune thyroid disease (ATD) was
diagnosed in 32 (20%) patients and nonautoimmune thyroid disease (NATD) in 26
(16%). No significant differences were found when these prevalences were compared
with those in control patients. On the other hand, comparing those patients with
altered hormonal profiles, patients with NATD showed mainly hyperthyroidism
(10/17, 59% versus 2/20, 10% in patients with ATD, p = 0.001). Finally, when
clinical and immunologic manifestations of SS were analyzed in patients with and
without thyroid disease, respectively, we found that patients with thyroid
disease had a higher prevalence of female gender (98% versus 88%, p = 0.03),
antiparietal cell autoantibodies (33% versus 12%, p = 0.002), TgAb (30% versus
5%, p < 0.001), and TPOAb (40% versus 5%, p < 0.001). In conclusion, thyroid
disease occurred in more than one-third of patients with primary SS; the main
cause was ATD, which was present in 20% of the patients studied. We note that no
significant differences were observed when the prevalence of thyroid disease
(either ATD or NATD) was compared with that in a control group of similar age and
gender. Our results indicate that middle-aged women (with or without SS) should
be screened periodically for thyroid function.
PMID- 10771709
TI - Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections.
AB - In order to describe the clinical features and the epidemiologic findings of
1,383 patients hospitalized in France for acute or chronic Q fever, we conducted
a retrospective analysis based on 74,702 sera tested in our diagnostic center,
National Reference Center and World Health Organization Collaborative Center for
Rickettsial Diseases. The physicians in charge of all patients with evidence of
acute Q fever (seroconversion and/or presence of IgM) or chronic Q fever
(prolonged disease and/or IgG antibody titer to phase I of Coxiella burnetii > or
= 800) were asked to complete a questionnaire, which was computerized. A total of
1,070 cases of acute Q fever was recorded. Males were more frequently diagnosed,
and most cases were identified in the spring. Cases were observed more frequently
in patients between the ages of 30 and 69 years. We classified patients according
to the different clinical forms of acute Q fever, hepatitis (40%), pneumonia and
hepatitis (20%), pneumonia (17%), isolated fever (17%), meningoencephalitis (1%),
myocarditis (1%), pericarditis (1%), and meningitis (0.7%). We showed for the
first time, to our knowledge, that different clinical forms of acute Q fever are
associated with significantly different patient status. Hepatitis occurred in
younger patients, pneumonia in older and more immunocompromised patients, and
isolated fever was more common in female patients. Risk factors were not
specifically associated with a clinical form except meningoencephalitis and
contact with animals. The prognosis was usually good except for those with
myocarditis or meningoencephalitis as 13 patients died who were significantly
older than others. For chronic Q fever, antibody titers to C. burnetii phase I
above 800 and IgA above 50 were predictive in 94% of cases. Among 313 patients
with chronic Q fever, 259 had endocarditis, mainly patients with previous
valvulopathy; 25 had an infection of vascular aneurysm or prosthesis. Patients
with endocarditis or vascular infection were more frequently immunocompromised
and older than those with acute Q fever. Fifteen women were infected during
pregnancy; they were significantly more exposed to animals and gave birth to only
5 babies, only 2 with a normal birth weight. More rare manifestations observed
were chronic hepatitis (8 cases), osteoarticular infection (7 cases), and chronic
pericarditis (3 cases). Nineteen patients were observed who experienced first a
documented acute infection, then, due to underlying conditions, a chronic
infection. To our knowledge, we report the largest series of Q fever to date. Our
results indicate that Q fever is a protean disease, grossly underestimated, with
some of the clinical manifestations being only recently reported, such as Q fever
during pregnancy, chronic vascular infection, osteomyelitis, pericarditis, and
myocarditis. Our data confirm that chronic Q fever is mainly determined by host
factors and demonstrate for the first time that host factors may also play a role
in the clinical expression of acute Q fever.
PMID- 10771710
TI - Questions about Q fever.
PMID- 10771711
TI - [Education for future agricultural workers: role of schools and other public and
private agencies].
AB - The authors report their health education experience in the high schools of
Pavia, emphasizing the responsibility of the public school in promoting a
rational behaviour of the youth aimed at health maintenance, and illustrating the
role recently played in this regard by a private institution (linked to the
University of Pavia and several other Universities): the Salvatori Maugeri
Foundation. Since the authors' experience also encompasses the prevention of work
related injuries and diseases, the article presents a didactic plan specifically
aimed at the education of future agriculture workers. The program starts from the
fundamental principle that considers risk not as something fatally ineluctable
but as probabilty of damage, and then dwells on the consequent predictive meaning
of a series of notions which allow interventions useful to minimize the various
occupational risk factors (or "causes of damage"). The teaching program is
composed by educational steps which gradually becomes more complete and specific
according to the advancement of learning.
PMID- 10771712
TI - [Treatment plants: viruses in aerosols].
AB - A survey was carried out on the animal virus occurrence in wastewater and
aerosols, in 2 treatment plants. Forty-five samples of sewage (10 litres) and 118
aerosol (2.3 m3) were examined. Forty out of forty-five (88.9%) of sewage and
four out of one hundred and eighteen of aerosol (3.4%) samples were positive for
viruses. Thirty-three reovirus and nine enterovirus strains were recovered from
the sewage, two reovirus and two enterovirus strains from aerosol. Among
enterovirus strains 6 resulted coxsackievirus B5, 3 coxsackievirus B4, 1
poliovirus, 1 strains remained unidentified.
PMID- 10771713
TI - [Sleep disorders and day sleepiness in a population of shift workers of the State
Police].
AB - Policemen are workers exposed to risk from both shiftwork and delicate tasks.
This study aims to investigate sleep habits, prevalence of sleep disturbance,
sleepiness and hypnotic drug intake in the whole population of Italian State
Policemen working in the Genoa district. Italian literature is completely lacking
of such data. The study has been carried out by means self administered and
assisted questionnaires. Eighty-five percent of the population accepted and
answered the questionnaire. Here we focus on the differences between 540 not
shiftworkers, NS, (413 males, 127 females), and 575 shiftworkers, S, (483 males,
92 females). A higher prevalence of difficulties in falling asleep, sleep-latency
longer than 20 min. and early awakenings was found in S. No significative
differences in daytime sleepiness and drug intake were found between the two
groups. Concerning the self-evaluation of the numbers of hours slept during the
night and during the 24 hours a higher quantity of sleep was reported by S.
CONCLUSIONS: Data seem to indicate a low quality of sleep in S without any
evidence of increased daytime sleepiness or increased hypnotic drugs assumption.
Shiftworkers seem to compensate their poor quality of sleep with a greater amount
of time spent sleeping in the 24 hour period. Such a condition could be the
expression of a prolonged recovery from the shift effects.
PMID- 10771714
TI - [Reliability and validity of the analysis of hand grip and pinch force in
isometric and isokinetic conditions].
AB - Strength measurement of the hand grip is at the core of most protocols of
functional assessment of the upper limb and in rehabilitation plays a major role
in the analysis of treatment efficacy and patients' occupational ability. The
aims of this study were to: a) verify the repeatability of strength measurements
made during performance of the hand grip and three types of pinch, carried out
under isometric and isokinetic conditions; b) compare maximal isometric strength
with the corresponding isokinetic value for each of the manoeuvres studied; c)
investigate the correlations between the strength expressed in the different
manoeuvres, under both isometric and isokinetic conditions. We studied 14
voluntary subjects over three sessions conducted at 48-hr intervals, employing a
computerized isokinetic dynamometer Lido WorkSet equipped with device N(o) 21 for
the study of pinch (lateral pinch, pulp pinch, chuck pinch) and device N(o) 52
for the grip study. Isometric contractions resulted stronger than isokinetic
ones, and the hand grip was found to be the manoeuvre able to produce most
strength. The repeatability of each strength measurement test over the three days
was high (Intraclass Correlation Coefficients: 0.89-0.93). Correlations between
the isometric and isokinetic performance for each of the manoeuvres examined were
always high (Pearson's r coefficients: 0.89-0.95) as were those between the
different manoeuvres, whether performed in isometric or isokinetic modality (r:
0.60-0.94).
PMID- 10771715
TI - [Reference values in occupational and environmental medicine].
AB - Origin, significance, production and use of reference values (RV) in
environmental and occupational medicine are discussed. The concept of RV was
established in last sixties to correctly interpret data from modern clinical
chemistry, but its acceptance in occupational medicine was neither immediate nor
easy. These difficulties were mainly due to the nature and biological fate of
analytes for which RV were requested, quite different from those of clinical
chemistry. For this reason specific procedures to select the subjects, to control
the pre analytical factors and to set up analytical methods are necessary. The
Italian Society of Reference Values (SIVR) attempted to achieve concepts and
practice for RVs and proposed RVs produced by specific investigations for some
metals and organic compounds. Furthermore in this paper two provisional lists of
RVs for metals and organic substances are proposed. Finally the relationship
between RVs and other more familiar guide line values such as action levels and
limit values is discussed.
PMID- 10771716
TI - [Epicutaneous sensitization to metals and contact allergic dermatitis: analysis
of an ambulatory caseload].
AB - We have retrospectively analyzed the clinical and anamnestic features of 233 out
patients (197 females and 36 males; mean age: 33 years; SD: +/- 13.3) with
epicutaneous sensitization to metals, who had been examined at the department of
allergology of our institution during one year. Among females, nickel sulphate
was the metallic salt which most frequently resulted positive at patch testing
(87.8% of cases), followed by cobalt chloride (23.6%) and potassium bichromate
(10.2%). Nickel was the most common sensitizing metal also in males (58.3%),
among whom sensitization to chromate resulted second in order of frequency
(30.6%), and sensitization to cobalt was relatively rare (11.1%). In selected
cases, the utilization of additional, specific series allowed to document rare
cases of sensitization to metallic salts not included in the standard patch test
series (copper sulphate, cadmium chloride, zinc stearate, phenylmercuric
nitrate). 78 patients were sensitized to more than one metal. Skin sensitivity to
metals was often linked to allergic disease familiarity and/or to sensitization
toward type I allergens. Allergic contact dermatitis was diagnosed in 80
patients: cutaneous manifestations had been present on average for over four
years, sometimes in generalized or persistent form. An occupational contact with
the causative metals was identified in 15 cases. However, the occupational origin
of the disease could never be documented with certainty, due to concomitance of
frequent non-occupational exposures and to lack of information on pre-employment
skin sensitivity status. Thus, the value of patch testing, during both pre
employment screening and health surveillance, is emphasized.
PMID- 10771717
TI - Work-related posttraumatic upper limb disorder. A case report.
AB - In this paper we describe a patient with mor-sensory loss in the right forearm
and hand, which persisted more than 2 years after work-related crush trauma of
the left hand. Radiographic and electromyographic investigations, somatosensory
evoked potentials, CT scans of the encephalus as well as the Minnesota
Multiphasic Personality Inventory and the Roarschach test have been performed. On
the basis of these investigations, we think this represents a case of conversion
disorder with somatic features. Included is a brief overview of other
psychological illness with physical findings involving the upper limb.
PMID- 10771718
TI - [The Kern paradigm: professional independence and information demands of the
scientific community].
AB - Legislative decrees 277/91 and 626/94 defined in detail role and duties of the
occupational physician. There is no normative regulation about ethical principles
for occupational professionals although some international organizations, such as
the International Commission on Occupational Health (ICOH), are making proposals
in this field. In the last decades, these principles have been assuming an
increasing importance because of occupational medicine operators' major
responsibility and the need of a multidisciplinary approach in work related risk
prevention. The aim of this contribution is to present a case about professional
independence and commercial secret that involved an occupational physician (David
G. Kern), Brown University (that employees him) Memorial Hospital and a textile
firm that consulted dr. Kern to investigate a pulmonary disease that affected
some employees. The fact has been described by e-mail of OEM (Occupational
Environmental Medicine) list. This event underlines the distance between the
professional reality and ethical principles formulated in the ICOH code; these
principles must be the base for a correct professional activity aiming only at
promoting workers' health.
PMID- 10771719
TI - [Work and alcohol: considerations on a caseload of patients undergoing
treatment].
AB - An enquiry into alcohol dependent subjects admitted to the clinical wards of the
first section of Occupational Medicine belonging to Medicina Preventiva
Occupazionale e di Comunita of University of Pavia for an alcohol disaddiction
treatment has been performed through a phone interview. 289 patients have been
contacted and time elapsed from admission to interview was one to three years.
The questions focused alcohol abstinence, occupational position before and after
admission, any improvement in the work sphere (relationship with the collegues),
any feeling of empowerment of the work abilities and any increase in the
responsibilities load. From our results we can conclude that alcohol disaddiction
carried on during admission has positively contributed to the reinstatement of
alcoholics patients.
PMID- 10771720
TI - [Costs of rehabilitation in the health systems].
PMID- 10771721
TI - [Risk assessment in health care facilities].
AB - Risk assessment in health care facilities. The risk assessment is an important
procedure in occupational medicine, also due to the international and domestic
regulations and recommendations. In hospitals and other health care facilities
too, the risk assessment could enable the identification of hazards, the
characterization of risk and thus the programme of adequate preventive measures.
In this paper some theoretical and methodological aspects of risk assessment
practice and related documentation in health care facilities are focussed and the
strict relation between preventive activities, quality system and accreditation
standards for hospitals and other health services is finally discussed.
PMID- 10771722
TI - [Subjects of the risk assessment].
AB - The Dlgs 626/94 describes a safety management system based on organizational and
procedural actions, and leaves technical actions to a discretionary/secondary
moment. This article debates how safety in the workplace takes place through
planning and engineering of prevention measures. The most important mechanism is
the "Risk Evaluation Proceeding", a process which encompasses three main steps:
risks identification prevention measures identification planning of
health/medical examinations and information/formation activities Due to the
complexity of the risk evaluation, law obliges the employer to perform the
process together with the Safety Manager, the Health Manager (Competent Persons),
and after discussing with the Safety Representative. The writing specifically
analyses the roles of the aforementioned actors in the risk evaluation
proceeding, their civil as well as penal responsibilities.
PMID- 10771723
TI - [Risk assessment concerning hospital personnel participating in the preparation
and administration of antineoplastic drugs].
AB - 24 workers (10 involved in the preparation and 14 in administration) exposed to
cyclophosphamide (CP) and ifosfamide (IF) in two Italian hospitals were
monitored. The extent of exposure was assessed by the analysis of air samples,
wipe samples, pads and gloves. Urinary excretion at the beginning and at the end
of the work shift was also measured by liquid-liquid extraction and analysis by
HPLC-MS/MS. 3 out of 24 air samples resulted to be positive for CP or IF. In wipe
samples, CP concentrations ranging from < 0.001 to 82.4 micrograms/dm2 in
Hospital A (32 samples) and from 0.2 to 383.3 micrograms/dm2 in Hospital B (17
samples), were found. IF concentrations varied from < 0.001 to 90.9
micrograms/dm2 in Hospital A and from 0.01 to 141.5 micrograms/dm2 in Hospital B.
Pads (from 11 to 13 for each operator) were contaminated with CP and IF
especially on arms, legs and chest. The use of a plastic-backed liner on the
working tray in the laminar flow hoods was demonstrated to compromise the
containment properties of the hood. Urine samples were positive for CP in 50% of
the workers (range: 0.1-2.1 micrograms/L), whereas IF was detected in 2 subjects
only (range: 0.1-0.8 microgram/L). The results from this investigation
demonstrated that vertical laminar airflow hoods, when incorrectly used, might
represent a source of contamination and that higher risk may depend on lack of
educational programmes and observance of preventive guidelines.
PMID- 10771724
TI - [Health surveillance: scope, tools, efficacy, prospects].
AB - According to experts of the European Commission, NIOSH and OSHA, health
surveillance's goal is the both health protection and occupational diseases
prevention (including injury and uneasiness). This goal is pursued by assigning
workers according to his or her working capacity without any health prejudice.
Currently available instruments to protect workers' health include: (i) medical
surveillance before employment, (ii) medical surveillance before placement in a
job involving exposure to toxics, (iii) medical surveillance at periodic
intervals during employment, (iv) medical surveillance at termination of
employment. Studies carried out on the efficacy of medical surveillance show the
capacity both of identifying health problem and of being perceived as a benefit
for workers. An appropriate application of medical surveillance should take into
account points as efficacy, guidelines, costs and benefits, and effectiveness.
This entails the need to carry out research aiming (i) to make the importance of
currently used preventive instruments explicit and (ii) to study new approaches
to be applied in occupational health care.
PMID- 10771725
TI - [Analysis of a preventive health service].
AB - This paper reports the experience and organization of an Occupational Health
Service for health-care workers, in order to improve the effectiveness of the
unit. The Authors describe the activities of the unit, its organization, and
evaluate the amount of working time spent in the different activities.
PMID- 10771726
TI - [Organization of the activities of health services according to UNI EN ISO 9000
standards].
AB - Implementation of a Quality System in accordance with the ISO 9000 standard with
an Occupational Health Service. Following the lead of the industrial sector,
Quality Systems (QS), in accordance with the principles of the ISO 9000
standards, have been implemented in many health care organizations. The purpose
is to improve the health care delivered to the patient in a systematic way
improving the system efficacy and effectiveness. Our aim is to describe a
practical approach for the implementation of a QS in accordance with the ISO 9000
standard within an Occupational Health Service (OHS) in a middle-sized hospital.
The purpose of the system is to ensure that everyone at the OHS is aware of the
common quality objectives and knows how to act in order to achieve them. The
implementation of the QS has entailed 2 phases: (i) a conformity assessment to
verify that the organization and services delivered measure up to ISO standards;
(ii) the development of a deployment plan to support the activities and action
implementation for achieving the QS requirement of ISO 9000. An early conformity
assessment highlighted the need for management and control in order to assure
quality. The Service did not have a documented QS, a documented management review
and a documented procedure for corrective and preventive actions for ensuring QS
implementation and its effectiveness. A strategic quality plan, focused upon the
major areas for improvement, was developed. This practical approach shows
encouraging results because it allows to build up the basic quality and to
motivate the OHS personnel.
PMID- 10771727
TI - [Health surveillance program for the prevention of Mycobacterium tuberculosis
infection risk among health personnel of the Polyclinic and the University of
Modena].
AB - Surveillance programme for the prevention of Mycobacterium tuberculosis risk
infection among health care workers at Azienda Policlinico and Universita di
Modena. Increase in tuberculosis (TB) morbidity and mortality in the last decade
even in highly industrialized countries represents a major public health problem.
Health care workers (HCWs) are one of the high-risk group for TB infection in the
population. Several international guidelines for the prevention and control of TB
infection among HCWs have been proposed, also including expensive and not easily
applicable interventions. A surveillance programme has been set up at the
Servizio di Sorveglianza Sanitaria in the Azienda Policlinico di Modena aimed to
the early identification of hospital workers with recently-acquired latent TB
infection, B.C.G. vaccination of PPD skin negative subjects working in
intermediate-high TB risk workplaces, periodic evaluation of PPD skin conversion
rates among personnel of each working area. This programme, whose feasibility
depends on the availability of adequate resources, is considered as a tool
suitable for the individual risk assessment and should be performed together with
technical and structural interventions to carry out an effective primary
prevention of TB infection among HCWs.
PMID- 10771728
TI - [Risk during manual movement of loads].
AB - The estimation of risk from manual movement of loads in health care workers was
carried out in 8 hospitals of Veneto Region, North-eastern Italy. 49 medical
wards, 53 surgical wards, 23 surgery departments and 21 emergency and diagnostic
services were examined. Operationally, a check-list was used to analyze the
organization of the work (staff, duties, typology of patients to mobilize) and
the work environment. Results show that 61% of the medical wards and 75% of the
surgical wards have a higher risk. In particular, the medical wards of geriatrics
and neurology, the wards of neurosurgery, heart surgery, orthopedics, the big
burns center and geriatric surgery resulted in greater risk. Similarly, 70% of
the emergency and diagnostic services and all surgical areas were estimated to be
at risk. Given this reality, it has been determined that there are inadequacies
in both organizational and structural aspects. In all the examined situations,
the risk related to the relationship non self-sufficient patients/nurse was
greater when mechanical help was lacking. In 70% of the cases the nursing staff
transported patients with the bed. Concerning structural inadequacies,
insufficient space was verified in over 50% of the examined wards. Preventive
measures should be taken on the two aspects considered, variation of the work
organization and the reclamation of work environment. But above all, the need for
mechanical help should be emphasized, in order to reduce to a minimum the manual
load thus preventing the onset of low-back pain in the nursing staff.
PMID- 10771729
TI - [Multifactorial ergonomic evaluation of the hospital nursing activity in
assisting not self-sufficient patients].
AB - 8 Institutes of Health Care and Research of Northern-Central Italy participated
in the study, which consisted of on-site investigations, interviews with the
chief-nurse, and monitoring of physiological and subjective variables. We studied
the most critical phases in the laboratory, by means of video-graphical systems
for biomechanical and postural analysis. The outlined profile shows a demanding
activity, yielding important risk factors relative to musculoskeletal lesions.
The preventive attitude (education, training) must be implemented by ergonomic
interventions, aimed to minimize the risk related to manual handling.
PMID- 10771730
TI - [Evaluation of stress and human potential in the organization of nursing work].
AB - Recent specialized literature about nursing highlighted the causal link among
stress, burnout and coping processes. The aim of this study was to evaluate the
validity of specific instruments designed to select and manage professional
nurses. The instruments studied were: Nurse Stress Index (NSI, Harris, 1989),
Maslach Burnout Inventory (MBI, Maslach & Jackson, 1986); Coping Inventory for
Stressful Situations (CISS, Endler & Parker, 1990); Job Content Questionnaire
(JCQ, Karasek, 1986); and Frequency of Self Reinforcement Questionnaire (FSRQ,
Heiby, 1982). 100 professional nurses working in an Institute of Care and
Research completed the test battery. Data analysis showed a positive correlation
among stress, burnout, emotion-oriented coping, psychophysiological overload and
self-undervalue. Classification criteria such as age, sex and professional
division moreover highlighted significant differences among nurses. The battery
resulted reliable and sensitive in discriminating the different problems linked
to nursing and in identifying subjects' personal resources.
PMID- 10771731
TI - [Heat exchange between human body and environment (theoretical bases of
physiological measurement and evaluation)].
AB - In the first part of this report the theory of the heat exchange between human
body and external environment is developed. In particular, the problems
concerning energy expenditure and heat production [metabolic heat] during
physical activity, the heat exchange between internal organs and body surface,
and its elimination are considered. Proposal of heat exchange equations (in case
of conduction, convection, evaporation, radiation transport) are made, and the
involved parameters and constants are indicated. Some pages are devoted to heat
exchange through the lung and to "perspiratio insensibilis". In the second part
the problems concerning the wellbeing and the thermal discomfort are discussed. A
description of some widely employed indices of thermal stress, strain and comfort
concludes the report [P4SR index, HSI index, ITS index, TTL index, HR index, WBGT
index, TE indices]. In the end, the Fanger equations of thermal comfort are
presented and discussed.
PMID- 10771732
TI - [Apolipoprotein(a) phenotypes as markers of genetic susceptibility for
cardiovascular risk in occupational medicine].
AB - Several agents (e.g. chemical or physical) present in the work environment may be
harmful for the cardiovascular system. Recent studies on the cardiovascular
diseases linked to hyperlipidemia have demonstrated a strong correlation between
high lipoprotein(a) [Lp(a)] levels and Coronary Heart Disease (CHD). In
particular, the severity of this pathological condition correlates well with the
molecular weight (MW) of the apolipoprotein(a) [apo(a)] isoforms supporting Lp(a)
(low MW = high risk; high MW = low risk), which are characterized by a high
degree of individual variability. Since apo(a) isoforms are genetically
determined, a genetic predisposition for CHD has been identified, i.e. the apo(a)
phenotype is considered a marker of genetic susceptibility for cardiovascular
risk. After a brief presentation of the main occupational cardiovascular risk
factors (e.g. carbon disulfide, carbon monoxide, noise, psycho-physical stress)
and of the most updated theories on atherogenesis, the present review proposes to
utilize the measurement of the plasmatic Lp(a) level to screen for occupational
cardiovascular risk susceptibility. Apo(a) phenotype characterization of workers
with medium-high Lp(a) levels is then suggested. Our proposal may be realized by
means of simple and relatively unexpensive laboratory methods.
PMID- 10771733
TI - [Microtrauma radial thrombosis].
AB - The articles describes a case of radial artery thrombosis by repeated
microtrauma. It describes, by one side, the occupational history, the personal
habits and the typical movement and condition of the hands while working, on the
other, the clinical and diagnostic picture of radial artery thrombosis. Then it
shows the correlation between occupational factors and radial artery thrombosis
and so the occupational genesis (repetitive microtrauma) of the disease.
PMID- 10771734
TI - [Effects of shift work on the quality of sleep and psychological health based on
a sample of professional nurses].
AB - Impact of shiftwork on sleep and psychological health. OBJECTIVE: The purpose of
the present study was to evaluate the impact of a rapid shiftwork system on sleep
parameters and on psychopathological status among a sample of nurses. We
hypothesize that in this type of shiftwork system, the rapid and continuous
rotation of shifts doesn't lead to a lasting alteration of circadian rhythm but
to a transitory increase of psychological disturbances after the night shift.
METHODS: The population studied was the permanently employed staff of a public
hospital in Modena. We recruited fifty-five workers. Participation was entirely
voluntary. Every subject was given a self-administered questionnaire divided into
three sections. Section I consisting in a base-line evaluation (sociodemographic
data, use of psychotropic substances, General Health Questionnaire and Maslash
Burnout Inventory). Sections II and III providing an evaluation of sleep and
psychopathological parameters (Sleep Diary and Symptom Questionnaire) in two
different moments during the shiftwork: respectively after the night following
the night shift (corresponding to the end of the shift cycle), and after the
night following the last day off (corresponding to the beginning of a new shift
cycle). RESULTS: There were no significative differences in sleep parameters
between the two moments of assessment. Regarding psychopathological features we
found a reduction of SQ-Somatization (P = 0.002), SQ-Anxiety (p = 0.006) and SQ
Hostility (p = 0.075) subscale score at the end of the shift cycle. CONCLUSIONS:
We confirm this type of shiftwork as not causing alterations of sleep parameters.
We explain the improvement in psychopathological symptoms noted at the end of the
shift cycle with the favourable psychological attitude of workers in the
perspective of time off. The present data suggest that the psychological attitude
of workers may play an important role in the clinical expression of
psychopathological features.
PMID- 10771735
TI - [Residual postural changes after cranial trauma].
AB - A group of 29 clinically stable post-traumatic brain injury patients were studied
for postural disturbances utilizing both a balance force platform and the Tinetti
equilibrium test. The stabilometric exam included 6 different aspects of balance,
with the goal of evaluating the importance of the sensory afferents on postural
control. Posturographic data revealed a global reduction of postural control. TBI
patients tended to rely more on visual feedback in postural control than did age
matched controls, and exhibited problems with sensory integration as the
complexity of the balance tasks was increased. The site of lesion correlated
positively with postural control problems, with brainstem and subcortical gray
matter lesions most frequently being involved.
PMID- 10771736
TI - [PROCID: a project of the European Community for the study and prevention of
muscular disorders in computer terminal operators].
AB - This paper presents an EC funded concerted action aimed at studying the
prevention of muscle disorders in the operation of computer input devices. About
40% the today's working population use computers in their daily work. This
percentage is expected to increase dramatically in the coming years. At the same
time health statistics indicate an increased incidence of work related
musculoskeletal disorders among computer users. A deeper knowledge in this field
may improve the health risk assessment approach, the design of computer input
devices and the revision process of existing standards, norms and guidelines
concerning computer work. Specific research objectives include: the development
of intramuscular techniques suitable for mapping motor unit recruitment under
operation of computer input devices; the evaluation of muscle fatigue and motor
unit recruitment in dynamic tasks in normal subjects and in patients with pain
syndromes; the experimental evaluation of stress induced muscular tension at the
motor unit level, in operation of computer input devices; the formulation of
recommendations for work with computer input devices.
PMID- 10771737
TI - [Data on railroad technology].
AB - This article shows a concise description of working specific cycles of each
section of railway transport. In order are described: Stations and railway lines;
Engine-drivers; Ticket collectors; Ticket offices; Maintenance shops.
PMID- 10771738
TI - [Urinary excretion of arsenic and its metabolites in a population of adult males
not occupationally exposed in the province of Bari].
AB - Urinary excretion of total arsenic (AsT) and other relevant arsenic species, i.e.
inorganic arsenic (AsI), monomethylarsonic acid (MMA) and dimethylarsinic acid
(DMA), was assessed in 5 groups of subjects with different both seafood
consumption and smoking habits. All 137 subjects were young (mean age +/- S.D =
21.7 +/- 2.1), without occupationally exposure to arsenic, males living in the
province of Bari, South Italy. The separation of arsenic species was achieved by
ion exchange chromatography and the eluted fractions were then analysed by means
of Hydride generation-AAS. A quality control of the analytical data was performed
jointly to a Belgian laboratory. Statistical analysis of collected data showed
that the excretion of AsT is increased in the group with regular consumption of
fish and shellfish.
PMID- 10771739
TI - [Acute silicosis in jewelry casting].
AB - An accelerated silicosis case made our Occupational Health Unit focus on a
pathology thought dropping so far to die out. Furthermore this event occurred in
a manufacturing (lost-wax process in jewelry casting) regarded as a low-risk
exposure. Besides unsuitable procedures, the user had underestimated the specific
risk of that raw material (talcum-like powder at 60-80% silica crystalline
level), commonly called "gypsum", inappropriately labelled since not yet
adequately classified by the hazardous substances list. The widespreading of this
manufacture in our area (Vicenza district) and the recent inclusion of Silica
Crystalline in the Class 1 made by IARC (Jan 1997) have urged this Unit to take
action in industrial hygiene investigations, instructions to the workers,
mandatory directions to dealers concerning the proper hazard labelling for
products containing silica crystalline and circulation of information among other
Occupational Health Units involved.
PMID- 10771740
TI - [High resolution computerized tomography in the diagnosis of asbestosis].
AB - The clinical observation, the work history, the analysis of pulmonary function
tests and, mainly, the conventional x-ray chest radiograms have represented, til
now, the diagnostic basis for pneumoconiosis (silicosis, mixed dust
pneumoconiosis, asbestosis). Recently, the high resolution chest tomography
(HRCT) has been introduced into the diagnostic procedures: such method seems to
have its main application in the assessment of incipient clinical pictures of
pneumoconiosis, particularly when characterized by normal pulmonary function
tests. Asbestos fibers exposed workers were submitted to both radiologic methods.
The great majority of them had already been recognized to be affected by
asbestosis. A considerable statistical agreement (Cohen K) was observed between
radiographic and tomographic I.L.O. classes. In conclusion, high resolution chest
tomography doesn't appear to be an indispensable test for the diagnosis in
admitted subjects, but we underline its importance in the evaluation of pleural
thickenings.
PMID- 10771741
TI - [High resolution computerized tomography in the diagnosis of silicosis and mixed
dust pneumoconiosis].
AB - The clinical observation, the work history, the analysis of pulmonary function
tests and, mainly, the conventional x-ray chest radiograms have represented, til
now, the diagnostic basis for pneumoconiosis (silicosis, mixed dust
pneumoconiosis, asbestosis). Recently, the high resolution chest tomography
(HRCT) has been introduced into the diagnostic procedures: such method seems to
have its main application in the assessment of incipient clinical pictures of
pneumoconiosis, particularly when characterized by normal pulmonary function
tests. 75 silica- and mixed dust exposed workers were submitted to both
radiologic methods. The great majority of them had already been recognized to be
affected by asbestosis. The statistical analysis (Cohen K) showed a satisfactory
agreement between radiographic and tomographic I.L.O. classes. However, high
resolution tomography appeared to be more accurate in the assessment of less
severe clinical pictures. In conclusion, we underline the importance of high
resolution chest tomography in the evaluation of individual clinical cases,
particularly when forensic problems are involved.
PMID- 10771742
TI - [Measurement of radon concentrations in schools at 2 communities of Puglia and
oncologic risk].
AB - Measurements of radon's concentration have been effected in the schools of two
communes of Puglia: Polignano and Valenzano. The average concentration of radon,
based on the prospecting effected in the research period (spring/summer 1997),
appeared, for both communes, lower than national average (75 Bq/m3). However,
these average concentrations is below estimated caused of the limitation of the
research period, owing to organization only at the period spring/summer. In fact,
by the extrapolation applying a right factor of conversion, of the "winter"
average concentrations from that average calculated during the research period
(considering the evident limits of such procedure) we obtain, respectively, for
both schools of Polignano and Valenzano, an average concentrations about of 75
Bq/m3 e 103 Bq/m3. The research shows the existence of a correlation among the
obtained results and two important factors: the buildings materials utilized and
the geological conformation of the subsoil; in particular, the buildings having
main wall (tufa) or built by mixed materials (cement, bricks and tufa) measured
the highest radon concentrations. Nevertheless, the absolute risk to develop a
pulmonary tumour due to the radon exposition, limitedly for the population of the
common of Valenzano, appears lightly superior in respect of the national risk (6
cases on 100,000 fellows) resulted about 8.5 case on 100,000 fellows.
PMID- 10771743
TI - [Walking recovery in stroke patients with femoral fracture].
AB - The aims of this study were: 1) to evaluated the degree of walking of hemiplegic
patients after femur fracture, 2) to evaluate if the neurological damage
interferes with the recovery of walking. We studied 51 hemiplegic patients with
femur fracture. All patients could walk without any help before the fracture. At
the end of the rehabilitation period we had the following results: 5.8% of
patients regained full walking independence; 37.2% walked with a cane; 43.1% with
a quadripod; 9.8% walked with assistance; 3.9% remained unable to walk. 50.9% of
them regained their prefracture functions. 96.1% returned directly to their own
home, the remaining 3.9% were admitted to Geriatric hospitals. To address the
second aim, we divided the same patients into two groups of 20 patients each (A =
mild impairment; B = severe impairment) according to Mathew's scale. At the end
of treatment, 95% of group A and 75% of group B regained full walking
independence. IN CONCLUSION: 1) the femur fracture did not influence the recovery
of walking in stroke patients, 2) patients with mild neurological impairment had
enhanced recovery of walking.
PMID- 10771744
TI - [Xenobiotics and glutathione].
AB - Mercapturic acids (MA) are the final step in the biotransformation of compounds
deriving from conjugation of electrophiles to glutathione (GSH). GSH is an
important endogenous tripeptide (g glutamyl-cysteinil-glycine) present in
mammalians essentially in erythrocytes, liver and kidney. It is involved in
several intracellular detoxification routes. Among these routes, the conjugation
with electrophiles, usually epoxides of aromatic and aliphatic organic compounds,
avoids the formation of covalent bounds between alkylating compounds and cellular
macromolecules (DNA, RNA, proteins) and prevents their mutagenic and cancerogenic
effects. The conjugation of electrophiles to GSH can proceed spontaneously or
catalysed by GSH-S-transferase (GST). Cytosolic isoenzymes GST-T1 and GST-M1 show
a genetic polymorphism in rats and humans, which determines the individual
hypersusceptibility to the toxic effects of xenobiotics and the variability in
the formation of MA. GSH-S-conjugates are biotransformed to their corresponding
MA through several steps, involving the removal of the glutamic acid and then of
the glycine. Finally, the residual cystein-S-conjugate is acetylated by a
genetically polymorphic acetyltransferase to form a N-acetyl-cystein-S-conjugate
or mercapturic acid. The MA metabolic pathway is a process that involves several
organs, particularly the liver, the kidney and the small intestine. The intensity
of the metabolic processes of these routes in the various organs is strongly
dependent of the activities of the involved enzymes and it is different in the
various species. As shown by several studies in the last fifteen years, the
formation of MA takes place in humans too. Therefore the importance of their use
in biological monitoring as internal dose indicators of occupational and
environmental exposure to electrophiles appears undoubted.
PMID- 10771745
TI - [Traditional analytic method for determining urinary mercapturic acids].
AB - Until now, high-performance liquid chromatography (HPLC) and gas chromatography
(GC) have been shown the most useful techniques for the determination of urinary
mercapturic acids in humans. Preliminary sample treatment is often necessary,
including liquid-liquid, solid phase (SPE) or on-line extraction, in order to
obtain highly purified samples. The use of derivatizing reagents coupled with
specific and sensitive detectors allowed to develop methods suitable for the
measurement of mercapturic acids specific for a large number of xenobiotics. At
present, however, the use of urinary mercapturic acid tests for biomonitoring
purposes is limited because of the high costs and complexity of analyses. Further
improvements, in terms of cost reduction, could come from the introduction of
fully automated systems.
PMID- 10771746
TI - [Mercapturates and biologic monitoring: benzene].
AB - S-Phenylmercapturic acid (PMA), a urinary metabolite which derives from the
conjugation of benzene epoxide with glutathione, has been recently included in
the list of the biological markers of benzene exposure. We have evaluated the
urinary PMA levels in 145 workers exposed to benzene and in 87 subjects not
occupationally exposed to the solvent (45 smokers and 42 non-smokers). In non
exposed persons, the background PMA excretion was nearly constant during one day
(urine samples were collected in the morning, afternoon, and evening) and in
smokers the mean PMA levels were higher than in non-smokers (9.6 vs 1.3
micrograms/g creatinine). This difference was presumably due to the extra
exposure to benzene (from cigarette smoke) in smokers compared with non-smokers,
in fact a close relationship was found between PMA excretion and urinary benzene
concentration (r = 0.86). Urine samples from workers exposed to benzene (airborne
mean concentration = 0.52 ppm) showed higher mean levels of PMA (37.6
micrograms/g creatinine) than samples taken from not occupationally exposed
subjects, both smokers and non-smokers. The mean biotransformation rate of
benzene to PMA was 0.073%, with a large inter-individual variability (range =
0.002-0.21%). Also, statistical analysis of data revealed a clear bimodal
distribution pattern of the conversion rate frequencies in the population
examined: this is consistent with the hypothesis of the presence of "slow" and
"fast" converters, due to the polymorphism of glutathione-S-transferase isozymes.
PMID- 10771747
TI - [Significance of urinary concentrations of S-benzyl-N-acetylcysteine (S-BMA) in
subjects exposed to toluene].
AB - Toluene is a widely diffuse solvent for oils, resins, rubber and paints, either
alone or as a major component in a mixture; in the industrial environment it is
currently present at concentrations of ppm. Toluene can be absorbed via the lungs
or via the skin. The absorption of toluene via inhalation is related to the
exposure level as well as the activities level of workers. Once absorbed into the
body, toluene is metabolized in man to benzoic acid, followed by hepatic
cytochrome P450 catalyzed glycine conjugation to form hippuric acid. Relatively
small amounts appear in urine as o-cresol and p-cresol where they occur as
glucoronide and sulfate derivate. Only a minor fraction of inhaled solvent is
conjugated with glutathione with the production of S-benzyl-N-acetylcysteine (S
BMA). Several biological indicators have been proposed for evaluating toluene
exposure in the workplace. These include urinary hippuric acid, toluene in blood,
toluene in breath, o-cresol in urine and toluene in urine. We examined a group of
18 workers occupationally exposed to toluene, determining the concentrations of
toluene in ambient air and S-BMA in urine. All urine samples were collected at
the end of work shift. The renal excretion of S-BMA showed highly significant
correlations with environmental data and with the other established parameters of
biological monitoring of toluene. The median ambient air concentration was 15.7
ppm ranging from 2.9 to 70.3 ppm, the median concentration of S-BMA was 16.0
micrograms/g creatinine. S-BMA was detectable in urine samples of a control group
of 87 subjects non occupationally exposed to toluene. Most of unexposed subjects
showed S-BMA values lower than 10 micrograms/g creatinine both in smokers and in
nonsmokers and no significant difference was found in samples (20) collected at
three intervals during one day. Our finding further indicates that the metabolite
S-BMA could be a marker of occupational toluene exposure.
PMID- 10771748
TI - [Mercapturates and biologic monitoring: styrene].
AB - The biological monitoring of styrene exposure is currently performed by the
measurement of the urinary excretion of mandelic acid (MA) and phenylglyoxylic
acid (PGA), which originate from the conversion of styrene 7,8-epoxide (SO), an
electrophilic compound considered responsible for most toxic effects of styrene.
In rats, an alternative pathway in the detoxification processes of SO has been
shown, which involves its conjugation with glutathione (GSH), leading to the
excretion of N-acetyl-S-(1-phenyl-2-hydroxyethyl)-cysteine (M1) and N-acetyl-S-(2
phenyl-2-hydroxyethyl)-cysteine (M2). Giving the chiral nature of SO, which is
present in two enantiomeric forms (R and S), both M1 and M2 consist of two
diastereoisomers: thus, four specific mercapturic acids are excreted in styrene
exposed rats, namely M1-R, M1-S, M2-R and M2-S. Until now, the excretion of these
compounds in man has not been confirmed directly, giving the analytical
difficulties in measuring the low levels of urinary mercapturic acids which are
expected following styrene exposure in the working environment. In the present
study we applied an analytical method, based on HPLC with fluorometric detection,
to measure the excretion of M1-R, M1-S, and M2 in post-shift urines from 22
workers exposed to styrene and in 10 unexposed subjects. The results clearly
demonstrated that the GSH pathway is involved in the detoxification processes of
styrene, even if to a low extent (the biotransformation rates of styrene to
mercapturic acids varied from 0.021 to 0.325%) and that M1 and M2 are specific
for styrene exposure, in fact unexposed subjects showed no detectable amounts of
these metabolites. In spite of the marked interindividual variability,
significative correlations were found between mercapturic acids excretion and
environmental styrene concentration or urinary levels of MA and PGA. The urinary
levels of M1-S and M1-R were significantly different, thus indicating a
stereoselectivity of the enzymes involved in the biotransformation of styrene to
mercapturic acids.
PMID- 10771749
TI - [Biologic monitoring of carbon disulfide: role of glutathione].
AB - Work goal is a critical analysis of the possibility of using TTCA as a future
marker for next environmental limit values which will be probably fixed to much
lower levels. Four metabolites have been identified in the urines of CS2 exposed
subjects, exactly: thiocarbamide, 2-mercaptothiazolinone, 2-thiothiazolidine-4
carboxylic acid (TTCA), 2-oxothiazolidine-4-carboxylic acid. TTCA represents
about the 6% of absorbed CS2 during occupational exposure. TTCA discovery in the
urines of CS2 exposed workers (an heterocyclic compound which develops in vivo
through direct reaction between CS2 and Glutatione) allowed a more specific
approach to exposure assessment. The end-shift urine TTCA concentration seems to
be in strict relationship with CS2 absorbed amount. In 1998 ACGIH maintained the
1997 limit value (TLV-TWA 10 ppm). In the 1997 DFG cut down the limit value in
half (MAK 5 ppm), while, until 1996, it accepted the ACGIH value.
PMID- 10771750
TI - [Mercapturates and biologic monitoring of N,N-dimethylformamide].
AB - N,N-dimethyformamide (DMF) is widely used in industrial processes to prepare
synthetic fibres, films and leathers. The metabolic pathway of DMF in humans
gives raise to several products. N-hydrowymethyl-N-methylformamide (HMMF) is the
major metabolite of DMF, but appears to be N-methylformamide (NMF) on GLC
analysis, because the first product decomposes to NMF when injected at 250
degrees C. In humans, an other important metabolite of DMF is the N-acetyl-S-(N-
methylcarbamoyl)cysteine (AMCC) which is the mercapturic acid coming from DMF.
AMCC is excreted in urine with a half-time of about 23 hours. This means that it
accumulates in the body when exposures to DMF are repeated as in industrial
settings. The data of the literature on the analysis of AMCC in urine both in
experimental or field conditions are reported and compared with the results
obtained by a physiologically "based toxicokinetic model". The findings are
discussed in order to use AMCC in the biological monitoring of occupational
exposures to DMF.
PMID- 10771751
TI - [Use of diverse diagnostic techniques in the study of silicosis].
AB - This study would examine the efficiency of different diagnostic tools, imaging
and functional, in the study of pulmonary system of workers exposed to
silicotigen dusts. 24 male miners were examined with chest H.R.T.C., spirometry
with study of DLCO and of total lung capacity. 13 of 24 miners were submitted to
pulmonary ventilatory scintigraphy (99mTcDTPA). All 24 miners were previously yet
submitted to two follow-up by means of chest radiography in conformity with ILO
guidelines. The chest radiography, even evaluated in conformity with ILO
guidelines, is subject to remarkable differences when performed and reported by
different operator. Useful data are provided by functional studies. H.R.T.C. is
necessary to evaluate the degree of parenchymal involvement and for medicolegal
porpoises. Scintigraphy with 99mTc DTPA need of further studies in the evaluation
of exposure to silicotigen dusts.
PMID- 10771752
TI - [Evaluation and quantification of biologic risk in the hospital setting with ATP
determination on work surfaces].
AB - The purpose of this study was to establish whether a method of determining ATP
levels using the HY-Lite system could be reliably applied in the various hospital
workplaces. We estimated the correlation between ATP levels and the number of
C.F.U. (Colony Forming Units), observed correlation r = 0.96. We established
hygienically acceptable values for each environment, and drew up reference
tables. The study reveals that conditions of high bacterial and fungine
contamination can occur, albeit the agents are not normally pathogenic is so far
as they consist of common environmental pollutants. Consequently, these results
emphasize the need to apply strict sanitization and hygienic measures, that
health workers must be suitably trained to deal with follow. The results of the
sampling appear to suggest that condition of potential biological risk for
workers are largely due to incorrect work procedure in workplaces where
pathologic agents are present.
PMID- 10771753
TI - [Ophthalmologic evaluation of VDT/PC operators: approach to the diagnosis with
neural networks].
AB - The present study was performed to build a neural network as a diagnostic tool to
aid ophthalmologic examination of VDT/PC operators. The network was built on
anamnesic and ophthalmologic data (visual acuity and mesopic vision, contrast
sensitivity) from 278 VDT/pC operators and is able to predict 88% of total cases
who need specialist attention, when ocular pathologies are also present, and 91%
when only refraction defects are present. The tests chosen for this study are not
useful to build a very sensitive discriminant model. This study confirm the
absence for useful ophthalmologic tests in screening of VDT/PC operators,
particularly when ocular pathologies are present without refractive errors. For
their capacity to translate on a clinical-pratic plane knowledge obtained through
studies conducted on large populations, the neural networks seem to be a good
diagnostic tool.
PMID- 10771754
TI - [Vibration exposure of the hand-arm system in people working with break-rock
machines].
AB - Occupational exposure of subjects working on break-rock engins for production of
porfido cube, in hand-harm system, has been here evaluated. The breaking
mechanism of the rock and its biophysic effects has been studied. The results
show a significant exposure of hands, mainly due to the break-rock engine called
"by control falling".
PMID- 10771755
TI - [A project for the occupational reintegration of impaired subjects].
AB - In this paper we have explained the criteria for an integrated socio-medical
intervention (Local Health Care Institution, Cooperation, Scientific Institute of
Care and Research) within the frame of a Communitary Initiative titled "Local
network for return to work of persons with social disadvantage". The goal of the
Initiative is to "create and experiment new facilities to support intervention
strategies for return-to-work, and to start a virtuous circle matching the
demands of both the disadvantaged persons and the local labour market". In the
paper we describe the functional evaluations, performed in the Medical Center of
Pavia by specialists in the field of Rehabilitation, Psychology and Ergonomy, and
the following return-to-work phase, performed by operators of the Cooperation.
PMID- 10771756
TI - [Work and psychopathology: general guidelines].
AB - After pointing out that the treatises of psychiatry usually lack chapters devoted
to work psychopathology, the author discusses the relationship between occupation
and mental disease, underlining the importance of a careful occupational
anamnesis, and focussing on three fundamental aspects. The first aspect regards
mental diseases which may negatively affect work. Endogenous psychosis always
imply enormous adaptive difficulties, and a precocious incapability to carry on
the habitual occupations. Such incapability precedes the moment when every
practical activity becomes impossible. The second aspect deals with the possible
pathogenicity of work for the mind. Several occupational toxicants may damage the
central nervous system, resulting in psychiatric manifestations. The author
dwells on the psychopatogenicity of certain forms of erroneous work organization,
with special emphasis on the sanitary environment. The third aspect regards the
therapeutic and rehabilitative value of work. For this purpose the work should be
"true", i.e. objectively recognized in its productive and rewarded value.
PMID- 10771757
TI - [Risk management from the psychological point of view].
AB - Main directions of psychological research in risk factors and risk reducing
interventions in work settings are discussed. Cognitive and social communication
components that enhance or reduce risk behaviours are stressed. The author states
that knowing and valuing risks are only a portion of the cognitive factors
implied in the process, not sufficient to explain phenomena. With reference to
current literature data, the central role of representations, of direct
reinforcement procedures and of self-efficacy is affirmed.
PMID- 10771758
TI - [Burn-out risk in health workers at Alzheimer's units].
AB - On the basis of their personal experience, the Authors try to identify the
salient aspects of the occupational stress and of the consequent burn-out
syndrome in the health personnel of the Alzheimer Units of Lombardy. In these
structures, the initial motivations, the emotional involvement, and the effort
required by the job make the staff at high risk. The syndrome generally evolves
through four stages (idealistic enthusiasm, stagnation, frustration, apathy) and
may easily become a collective problem, with worsening of the quality of care and
dispersion of economical resources. The occupational physician, possibly with the
collaboration of the psychologist, should adopt adequate preventive, therapeutic,
and rehabilitative measures, regarding both the work organization (stress
reduction, creation of a group consciousness) and the single (professional
training, psychological support, health surveillance).
PMID- 10771759
TI - [Alcoholism at the work setting].
AB - Alcoholism is a nation-wide problem because of the variability and severity of
its associated phenomena. In Western European countries, according to the WHO,
the use of alcohol is the direct or indirect cause of approximately 20% of
hospital admissions of male adults of working age. In Italy, the number of lost
working days due to sickness is four times greater in drinkers, as is the risk of
serious accidents. In addition, alcohol accounts for 5% of disability payments.
In the authors' experience, alcohol abuse is a widespread problem in the work
setting, however its social and medical impact is still underestimated.
PMID- 10771760
TI - [Occupational poisoning with psychiatric manifestations].
AB - Numerous occupational intoxications (acute, chronic and their sequelae) may
affect the central nervous system and result in a wide variety of
neuropsychiatric effects, ranging from subtle behavioural disturbances to overt
psychosis. Chemicals causing such manifestations include many metals and
organometals (Hg, Mn, Pb, Al, Sn), pesticides (organophosphates), compounds
utilised in the industrial setting as solvents or intermediates (carbon
disulfide, hydrocarbons and their halogenated derivatives), and combustion
products (carbon monoxide). Some types of toxic insults may not be reflected in
any clinical manifestation. However, this type of damage may render the brain
more vulnerable to additional insult or accelerate physiological loss of neurones
with ageing. Thus, occupational exposures to chemicals (Al, Pb, organic solvents)
might be involved in the causation of neurodegenerative diseases--such as
Alzheimer's disease--which are usually labelled as "idiopathic". A careful
occupational anamnesis is crucial to diagnose work-related psychiatric
manifestations and--consequently--to interrupt the toxic exposure, to start
therapy, and to promote insurance compensation.
PMID- 10771761
TI - Understanding the psychiatric complications of pain disorders.
AB - This paper is helpful in evaluating pain disorder from a clinical and psychiatric
perspective. Pain is one of the most recurrent symptom in the daily work of any
physician. Epidemiology, diagnosis and two case reports are included in this
article. Differential diagnoses and psychiatric complications of pain disorder
are discussed in order to facilitate the physician to recognize fundamental
sequalae of pain disorder.
PMID- 10771762
TI - [Work psychopathology and migration].
AB - The author analyses the correlation between work psychopathology, migration and
the role of the occupational physician. Migration was studied and analysed by
many clinical psychiatrists, occupational psychiatrists and sociologists, who
tried to investigate the possible consequences produced by this event on the
psychological equilibrium, on social life and on working activities. It is
unquestionable, according to the actual knowledge, that a strict correlation
exists between work and psyche, or among the uneasiness of the work, cultural
belonging and a psychopathology of the work. Work psycophatology appears to be
the measurement of the repercussion of a dangerous work on human mental health
and, consequently, could have a role in better adapting the man to his work.
Therefore, in every work situation, the risk of a somatic or psycological, or
even toxicological, pathology, must not be underevaluated. In a perspective of
transcultural evaluation of the "migrant" worker who has to be introduced in a
work environment, the knowledge of the "unspecific" health risks of the migrant,
and of the cultural differences specifying the cultural value of work, becomes
fundamental. Among the symptoms that require particular attention in the
evaluation of a worker, the concept of fatigue is certainly fundamental and
crucial. Consequently, it is necessary to safeguard the health of "the whole
worker", not only acting on the physical and chemical occupational hazards, but
also considering the relational and cultural risk factors.
PMID- 10771763
TI - [Medico-legal problems in the relationship between psychopathology and work].
AB - The Author treats the relationship between work and mental health from a legal
medical viewpoint and referring to two different opposite situations: work as a
pathogenic factor and work as a therapeutic factor. In the first case, the
problem concerns the acknowledgment of the connection between work and mental
disorders. It includes the need of a careful estimate of the causation and the
meaning that it could assume during the damage evaluation process, the peculiar
psycopathological question of the relationship between disturb and damage, and
the difficulties in the estimation of this latter. Finally, it concerns the
setting peculiarity, essential to a correct methodological approach during the
evaluation. In the second case, the focus is the safeguard of both the subject
with a psychiatric disorder and his environment, with the need to insert the
occupational physician in a "net" of supportive interventions aimed at avoiding
that the work became an aggravating agent or an additional risk factor. The
Author emphasizes the implicit ethical component of the choice to introduce the
psychiatric patient in the "working life"; this choice belongs both to the single
practitioner and to the collectivity, and it is supported by the Constitution.
PMID- 10771765
TI - [The distribution characteristics of the taiga tick (Ixodidae) in the city of
Tomsk].
AB - The study conducted in 1996-1997 has shown that in large town lads there is a
steady population of the taiga tick with the maximum number 3 specimens per 1 km
of account route. In these lads there are well developed wood and shrub layer,
grass cover and thick ground litter layer. Tick larvae often occur on rodents
from these territories. In lads and gardens, where the ground litter is ruined
and herbal cover is oppressed, the taiga ticks do not occur. In outskirts the
number of ticks is higher. Abundance of ticks in these areas has an inverted
dependence upon recreational load degree.
PMID- 10771764
TI - [Fertility changes in Leptopsylla segnis (Siphonoptera: Leptopsyllidae) fleas
depending on the duration of their preliminary contact with the food source].
AB - In experiments the fecundity of Leptosylla segnis was depended upon duration of
the preliminary contact of the host (white mouse) with fleas of the same species.
As the duration of the contact was promoted the daily mean number of eggs per
female at first (at time of contact from 1 to 6 days) increased, then (at time of
contact 7-12 days) declined and decreased below original level at 13-30 days of
contact. It is supposed that observed changes in fleas fecundity were connected
with the immune reactions of the host to the bites of insects.
PMID- 10771766
TI - [The role of the water factor in the dissemination of Toxocara eggs and the
spread of toxocariasis in a megalopolis].
AB - The water factor in transfer of the activators toxocariasis was not taken into
account by parasitologists earlier. Yet in the urbanized ecosystems (first of all
-in the megalopolis) it can have rather appreciable importance in distribution of
toxocariasis in animals and man. Our researches which have been carried out in
reservoirs of Moscow with the "wild" and the "organized" beaches, have revealed
various, but as a whole their significant, of contaminations by invasion eggs
Toxocara (Toxocara canis, T. mistax, and Toxascaris leonina). It specifies an
opportunity of their hit in organism of the man and, as a consequence-
toxocariasis. The examination of the patients toxocariasis of the people (first
of all of children at the age of 3-10 years) have confirmed the fact of their
bathing and involuntary swallow of water in urban unflowing reservoirs. In
ecosystems of the megalopolis at a high level of parasite of pollution increased
superinvasion of dogs and cats and free access of animals to internal reservoirs-
the risk of infection of the people toxocariasis gradually grows.
PMID- 10771767
TI - [Natural foci of diseases: the development of the concept at the close of the
century].
AB - E. N. Pavlovskii's concept of natural focality of diseases and the development of
general knowledge about natural foci and their structural (components),
functional (mechanisms of pathogen maintenance), and ecosystem-related
organization (assortment and interrelations of ecosystems) are reviewed from
principal (in authors' opinion) aspects. The 60-year history of this theory
includes three stages at which its scope and contents differed. At the first
stage, it concerned transmissible zoonoses. It had been assumed that
structurally, natural foci necessarily include the pathogen-vector-host triad,
and the functioning of the focus is provided for by only pathogen circulation in
terrestrial ecosystems. At the second stage, it became clear that vector is not a
necessary structural component of any focus (an example of nontransmissible
diseases), although the functioning of foci remained to be unequivocally
attributed to the continuous pathogen circulation among animals of terrestrial
ecosystems. The third stage is characterized by an understanding that, in
general, the presence of a warm-blooded host in the focus is also unnecessary for
pathogen survival, and natural foci can be represented by soil and aquatic
ecosystems. The only necessary and specific component of any natural focus is the
pathogen population. In this context, modern views on natural focality of
diseases are reviewed, and the essence of the terms "natural focus" and
"epizootic process" is defined. It is proposed to distinguish the phases of
pathogen reservation and epizootic spread (circulation) in ecosystems of any
type. The current state of this concept provides evidence that, in general
biological terms, studies on natural focality of diseases belong to one of the
fields of symbiotology.
PMID- 10771768
TI - [Methodological aspects in the study of the natural foci of zoonoses].
AB - Conceptions of different authors on the natural focus of zoonosis infections are
analysed and an improved definition of this phenomenon is proposed. The natural
focus of disease is the antropoecosystem of certain hierarchic level (biosocial
system), where the existence and appearance of the infection agent is supported
and the disease is realized in people at certain infection rate.
PMID- 10771769
TI - [The role of fleas (Siphonaptera) in the epizootiology of plague].
AB - This review concerns the role of the fleas in survival and spread of the plague,
their influence on the seasonal dynamics of the epizootics, and infection rates
of these insects in different natural foci. The critical evaluation is given to
the data which are used to calculate the flea transmission probability for
mathematical simulation of plague epizootics.
PMID- 10771770
TI - [The role of blood-sucking ticks and insects in natural foci of infections].
AB - During 60 years passed after the creation of the conception on natural focus of
human infections by the academician E. N. Pavlovskii our knowledge on a role of
blood-sucking insects and ticks in this phenomenon have been significantly
enlarged. It has been recovered, that these arthropods serve not only as vectors
of infection agents, but also as natural reservoirs and amplificators of these
agents. In the process of the infection agent circulation in the natural focus
there are several additional pathways of circulations without a participation of
vertebrates. These pathways are as follows: the dispersion of infection agent in
cases of simultaneous feeding of infected and "clean" ticks, and also the sexual,
transovarial and transphase transmissions of pathogens. These mechanism of
circulation are most often occur in the ixodid ticks, which can play the main
role in supporting the infection agent in the focus.
PMID- 10771771
TI - [The sympatry of closely related species of ixodid ticks and its possible role in
the parasitic systems of natural foci of transmissible diseases].
AB - Sympatry of the following pairs (or groups) of closely related species in the
territory of the former Soviet Union amd some neighbouring countries has been
revealed as a result of a revision of the fam. Ixodidae: I. persulcatus-I.
ricinus, I. persulcatus-I. pavlovskyi, I. crenulatus-I. kaiseri, Dermacentor
marginatus-D. silvarum-D. ushakovae, D. ushakovae-D. niveus, D. pavlovskyi-D.
montanus, Rhipicephalus turanicus-R. sanguineus, R. turanicus-R. rossicus, R.
turanicus-R. pumilio, R. rossicus-R. pumilio. Biotope and host relationships of
sympatric species, as well as seasons of parasitizing have been described on the
basis of the field researches conducted by the author, the collections of the
Zoological Institute, Russian Academy of Sciences, and the publications
substantiated by collection materials studied by the author. Hypothetic ways of
the paleogenesis of each sympatric area and geological age have been considered.
The recent sympatric area for I. persulcatus-I. ricinus (fig. 1) is of Holocene
age (max. 8.000-10.000 years). During that period approximately 1600-2000
sympatric generations could have been realized. Some recent sympatric areas (I.
persulcatus-I. pavlovskyi, and some species of other genera) are of Pleistocene
and even Pliocene age (2-10 million years). In these areas the number of realized
sympatric generations must have been much higher. Several variants of joint
simultaneous and successive feeding on one and the same host individual have been
established for stages of life cycles of sympatric species of ticks. Contacts of
this kind could have created canals for multiple oscillatory exchange of
pathogenic taxa (species, genospecies, strains) in a few or many thousands of
sympatric generations of closely related vectors. Thus, the same taxon of a
pathogen may be subject to different influence of ixodid vectors in sympatric
area and in the area of separate habitat of close species of vectors.
PMID- 10771772
TI - [The epizootiological role of the population organization of the stock of fleas
on the long-tailed suslik in a natural focus of plague in Tuva].
AB - Spatial location of epizootic events in the Tuva plague focus is determined at a
considerable degree by the population structure of the flea Citellophilus
tesquorum--the main plague microbe vector. Within the enzootic territory occupied
by five populations of the long-tailed ground squirrel (Citellus undulatus) there
are six populations of C. tesquorum. Each population of fleas has a corresponding
autonomic plague focus. Various conditions for the microbe life activity in these
populations are recovered. The circulation of the microbe is closely connected
with certain intrapopulation groupings of fleas--the nuclei of populations.
PMID- 10771773
TI - [The exploratory activity of the Borrelia-infected taiga tick Ixodes
persulcatus].
AB - The infection with Borrelia burgdorferi s. l. increases the questing activity of
adults and nymphs of the taiga tick Ixodes persulcatus. High temperature inhibits
the moving and questing activities of the infected ticks in a greater extent than
that in the non-infected ones. Than more borreliae per a specimen of tick are
present, the more tick's activity is affected.
PMID- 10771774
TI - [The chronological structure of the population count of the taiga tick in the
Maritime Territory].
AB - A time series analysis of 23-years observations of the Ixodes persulcatus imago
dynamics was carried out. The tick were counted in forests of the western Sikhote
Alin' foothills near Ussuriysk. The fluctuations of the ticks number are
quasiperiodical. They are formed by near 3-years oscillations, long-term non
linear trend and accidental component. The observed process was described by
means of a statistic model. This model combines the harmonic regression analysis
with linear regression analysis. The determination coefficients are 90.8% and
92.7% for the descriptive and prognostic models respectively. The difference
between two groups of environmental factors, which influence on the tick number,
is discussed. These factors are: 1) the directly influencing factors (functional
factors), 2) the factors influencing by dint of natural rhythms being general for
a biocoenosis (synchronizing factors).
PMID- 10771775
TI - [The use of a silver staining method in the diagnosis of the late skin lesions in
ixodid tick-borne borreliosis in man].
AB - The borreliosis etiology was verified in 60% cases of the morphea, 100% cases of
the atrophoderma of Pasini-Pierini and 100% cases of anetoderma by means of IFA
with Ip-21 antigen (B. afzelii) and silver staining after Levadity. Borreliae
were located near the capillaries, muscular and areolar tissue fibers of the derm
and near the granulated cells of epidermis.
PMID- 10771776
TI - [The interrelations of the causative agents of transmissible diseases in ixodid
ticks (Ixodidae) with a mixed infection].
AB - The data on interactions between pathogens of human diseases with natural
focality in ixodid ticks (Ixodidae) with mixed infection are reviewed. Different
variants of mixed infection revealed in nature and accompanied by predominantly
extracellular, or both extra- and intracellular location of the agents in tick
organism are considered. Natural mixed infection of ticks by different pathogens
is a normal and commonly occurring phenomenon; moreover, there is no experimental
evidence for the existence of any antagonistic relationships between spirochetes,
rickettsiae, and piroplasms in such ticks. The absence of antagonism between
different agents in vectors largely provides a relative autonomy of corresponding
parasitic systems and creates conditions for coexistence of different parasitic
systems in mixed natural foci.
PMID- 10771777
TI - [An analysis of geographical differences in the appearance of tick-borne
encephalitis].
AB - Reasons of differences in clinical forms of tick-borne encephalitis within
certain regions and throughout all area are analysed. It is supposed that the
epidemic potential of natural focus depends upon temperature conditions during
the winter period.
PMID- 10771779
TI - [The mosquito fauna (Diptera: Culicidae) of the environs of the Sayan-Shushenskoe
hydroelectric power station].
AB - Among females and larvae of mosquitoes collected in 1969, 1981-1984 in the area
of the Sayan-Shushenskoe hydroelectric power station (140 km up the Yenisei River
from the Abakan city) 5 genera and 30 species were recorded. Based on recent
collections and reference data (Gornostaeva e. a., 1969; Gornostaeva, Danilov,
1986) the fauna of the region in question includes 31 species of mosquitoes
(Anopheles--1, Culiseta--2, Coquillettidia--1, Aedes--22, Culex--5).
PMID- 10771778
TI - [A revision of chiggers in the vulgaris group (Trombiculidae: Neotrombicula)].
AB - A revision of chigger mites species, being closely related to Neotrombicula
vulgaris (Schluger, 1955), is given. 2 new species are described: N. aideriensis
sp. n. from Western Kopetdagh and N. macrovulgaris sp. n. from Western Caucasus.
N. aideriensis sp. n. differs from all other species of the vulgaris group by
presence of single barb on the lateral seta of palpal tibia in most specimens.
This species differs also from N. vulgaris by lesser width of scutum, shorter
setae of scutum and idiosoma and by longer legs. N. macrovulgaris sp. n. differs
from all other species of the vulgaris group by longer legs, more numerous
idiosomal setae and by larger scutum. N. vulgaris is recorded for the first time
in Bulgaria, Turkmenistan (western Kopet-Dag) and Krasnodar Territory, N.
baschkirica Kudryashova, 1998--in Chuvashia, Kirov Province, Komi Republic and
Tyumen' Province, N. kharadovi Kudryashova, 1998--in Russia (Altai Territory) and
in Karaganda Province (Kazakhstan). The latter species is reported from several
new hosts. Variation of morphometric parameters in the vulgaris group are
investigated by the methods of multivariate analysis, the pattern of correlations
between them is shown. A complex of diagnostic features in the group is revised.
Discriminant functions produced by the computer program DIADIS (A. L. Lobanov, ZI
RAS) allows to determine confidently representatives of the vulgaris group.
Ecogeographical component of intraspecific variability and character variance at
the specific level is revealed in vulgaris group. N. macrovulgaris characterized
by the largest scutum, numerous setae and long legs was found in the most
rigorous, cold and damp climate (alpine zone of western Caucasus). On the other
hand, N. kharadovi, which have the most fine scutum and shortest setae, inhabits
rather dry and warm Middle Asia and neighbouring territories. The sample of N.
vulgaris collected in the steppe part of Stavropol' Territory differed from the
material collected in mountain forests of Western Caucasus by low values of the
most part of measurements. N. kharadovi samples from plains of Middle Asia
differed from samples of this species collected in western Pamirs, central
Kazakhstan and Altay Territory by more fine scutum and shorter setae.
PMID- 10771780
TI - Historical highlights of long-term oxygen therapy.
AB - The story of the development of oxygen and its role in mitigating the ravages of
chronic stable hypoxemia have been fascinating. Today, over one million Americans
receive home oxygen each day, usually for COPD, from one of the three available
systems. The future requires less expensive, highly portable, and practical
devices for use during all activities of daily living.
PMID- 10771781
TI - Pathophysiology and clinical effects of chronic hypoxia.
AB - Hypoxia exists when there is a reduced amount of oxygen in the tissues of the
body. Hypoxemia refers to a reduction in PO2 below the normal range, regardless
of whether gas exchange is impaired in the lung, CaO2 is adequate, or tissue
hypoxia exists. There are several potential physiologic mechanisms for hypoxemia,
but in patients with COPD the predominant one is V/Q mismatching, with or without
alveolar hypoventilation, as indicated by PaCO2. Hypoxemia caused by V/Q
mismatching as seen in COPD is relatively easy to correct, so that only
comparatively small amounts of supplemental oxygen (less than 3 L/min for the
majority of patients) are required for LTOT. Although hypoxemia normally
stimulates ventilation and produces dyspnea, these phenomena and the other
symptoms and signs of hypoxia are sufficiently variable in patients with COPD as
to be of limited value in patient assessment. Chronic alveolar hypoxia is the
main factor leading to development of cor pulmonale--right ventricular
hypertrophy with or without overt right ventricular failure--in patients with
COPD. Pulmonary hypertension adversely affects survival in COPD, to an extent
that parallels the degree to which resting mean pulmonary artery pressure is
elevated. Although the severity of airflow obstruction as measured by FEV1 is the
best correlate with overall prognosis in patients with COPD, chronic hypoxemia
increases mortality and morbidity for any severity of disease. Large-scale
studies of LTOT in patients with COPD have demonstrated a dose-response
relationship between daily hours of oxygen use and survival. There is reason to
believe that continuous, 24-hours-per-day oxygen use in appropriately selected
patients would produce a survival benefit even greater than that shown in the
NOTT and MRC studies.
PMID- 10771782
TI - Adverse effects of low-flow oxygen therapy.
AB - Exposure to oxygen at a high FIO2 can result in substantial damage to several
organ systems. In contrast, low-flow oxygen is generally quite safe. Although
there have been reports of lung tissue injury with low-flow oxygen, the benefits
of this therapy in appropriately selected individuals clearly outweighs the small
risks. Elevations in PaCO2 occur in some COPD patients receiving low-flow oxygen
and appear to be related to changes in ventilation-perfusion matching in the lung
and carbon dioxide transport in the blood stream rather than to reductions in
respiratory drive as previously thought. The effect is generally small in
magnitude and is not progressive in response to oxygen therapy alone. Nonmedical
hazards such as frostbite and fire related to oxygen equipment have been
described but are unusual. Minor problems such as skin rash or nasal irritation
in those using low-flow oxygen are usually easily handled with topical
treatments. Social and psychological problems, resulting from a perceived stigma
of wearing oxygen may lead to social isolation of the patient and should be
addressed with appropriate counseling and education.
PMID- 10771783
TI - Detection and monitoring of hypoxemia and oxygen therapy.
AB - Many techniques are available to evaluate oxygenation. These include arterial
blood gases, capillary blood gases, point-of-care testing, blood gas monitors,
pulse oximetery, transcutaneous blood gases, mixed venous blood gases, venous
oximetry, and gastric tonometry. Clinicians should understand not only the
benefits, but also the limitations of these techniques. Monitoring of oxygenation
should not be done just because it is technically feasible. The decision to
monitor, like any other clinical decision, should be based on therapeutic
objectives.
PMID- 10771784
TI - Delivery systems for long-term oxygen therapy.
AB - Table 5 summarizes my current perspective on home oxygen delivery systems in the
United States. As I already indicated, scoring for cost and labor may be very
different in other countries. As noted, all things considered, today the most
reasonable system for home oxygen therapy is the concentrator. Problems with
FIO2, liter flow, and portability are clearly overshadowed by cost, labor, ease
of use, and lack of potential hazard, as well as potential for future innovation.
I would expect with future development that the concentrator will score higher on
FIO2, liter flow, and portability. As a result of the anticipated large number of
patients worldwide expected to require home oxygen therapy, ongoing improvement
in this technology will be evident in the next few years.
PMID- 10771785
TI - Oxygen-conserving techniques and devices.
AB - OCDs are available and their use is growing in the home care market because of
economic factors associated with LTOT, but this trend has evolved with little
clinical research. There is great variability among the oxygen control systems,
and physicians need to test patients on each device, at each activity level the
patient is capable of in the home, and to write a prescription for each activity
level. OCDs should be used because of the patient benefits of improved activity
and compliance with a 24-hour prescription, and the economic benefit associated
with reduced delivery of oxygen. Clinicians and patients need to be thoroughly
familiar with the oxygen system they are using and to understand its capabilities
and limitations. More research is required to evaluate the application and
effectiveness of and the differences between products and outcomes of OCDs used
in home care. Equivalency between CFO and OCDs should not be necessary because of
the differences between these delivery methods and the great variability of
products.
PMID- 10771786
TI - Effects of long-term oxygen therapy on mortality and morbidity.
AB - In general, based on the above studies of the effects of supplemental oxygen on
reducing mortality and improving sleep and exercise function in certain patient
groups, patients whose disease is stable on a full medical regimen with PaO2 < or
= 55 mm Hg (SaO2 < or = 88%) should be considered for LTOT. Patients with PaO2 of
55-59 mm Hg with signs of tissue hypoxemia (i.e., cor pulmonale, polycythemia,
impaired cognition) should also be considered for LTOT. Oxygen therapy should
also be considered for those who desaturate during sleep or exercise. These
guidelines have been adopted by Medicare as reimbursement criteria and have also
been endorsed by the American Thoracic Society. Indications for LTOT endorsed by
the American Thoracic Society and published in the "Standards for the Diagnosis
and Care of Patients with COPD" are shown in Table 6. More research is required
to investigate the use of supplemental oxygen in patients who suffer nocturnal
desaturation but do not have signs of end organ dysfunction, those who have an
improvement in dyspnea with supplemental oxygen, and in normoxemic patients with
impaired exercise performance who improve while inspiring supplemental oxygen.
PMID- 10771787
TI - Effects of long-term oxygen therapy on neuropsychiatric function and quality of
life.
PMID- 10771788
TI - Long-term oxygen therapy in conditions other than chronic obstructive pulmonary
disease.
AB - Prescriptions of LTOT in non-COPD diseases vary from 20% to 60% of the total
number of patients profiting from this form of treatment. It seems that in
countries where the percentage of non-COPD indications is still high, the
proportions will change toward higher use of LTOT in COPD patients in the near
future. There is a death of controlled studies evaluating the effects of LTOT in
non-COPD diseases. There are at least two important factors preventing
realization of such studies. First, non-COPD indications for LTOT encompass a
large number of diseases. Each of them should be separately studied because of
differences in the pathophysiological mechanisms and natural history of the
diseases. Small numbers of patients with a specific diagnosis would require
multicenter, international studies, which are difficult to perform in a rigorous
manner. A more important handicap is ethical reasons. Many years ago LTOT was
approved as a routine method of treatment for severe stable hypoxemia. It would
be difficult to obtain the approval of any ethics committee for a project
proposing a control group of hypoxemic patients to be deprived of oxygen for a
long period of time. It would also be difficult to find clinicians eager to
participate in such a study. Do we need such studies at all, even in an era of
evidence-based medicine? Probably not for diseases presenting with airway
obstruction such as CF or bronchopulmonary dysplasia. The effects of LTOT in COPD
may also be applied to those diseases. But there remains a group of diseases with
restrictive patterns of ventilatory impairment. A typical feature of these
diseases is a severe decrease in arterial oxygen tension and saturation during
exercise. Oxygen supplementation during exercise has already been found to
relieve hypoxemia and to increase exercise capacity. Life is motion. Perhaps we
should not bother too much about prolongation of the life of our patients, which
would be difficult to prove anyway. We should rather concentrate on assuring them
as much mobility and enjoyment of life as possible. In other words we should work
on adding life to years rather than adding years to life. For this, ambulatory
oxygen is the best option.
PMID- 10771789
TI - Long-term oxygen therapy vs long-term ventilatory assistance.
AB - The use of positive-pressure nasal ventilation in combination with LTOT in stable
COPD patients with hypercapnic respiratory failure controls hypoventilation and
improves daytime ABGs, sleep, and quality of life. Nasal ventilation in COPD is
unlikely to produce benefit unless used with supplemental oxygen therapy at
night. The patients who show the greatest reduction in overnight PaCO2 with
ventilation are the patients most likely to benefit from long-term ventilatory
support. Although there is now evidence for short-term benefit from NPPV in
hypercapnic COPD, large multicenter studies with survival, exacerbations, and
hospital admissions as the primary end points are required to evaluate longer
term effects of this potentially important intervention.
PMID- 10771790
TI - Hypoxemia during sleep in patients with chronic obstructive pulmonary disease:
significance, detection, and effects of therapy.
AB - NOD is a common event in patients with symptomatic COPD who are not hypoxemic
while awake. Up to 45% of these patients may have significant oxyhemoglobin
desaturation during sleep, and most have evidence of pulmonary arterial
hypertension. Although intuitively it would seem that supplemental oxygen during
sleep should be of medical benefit in COPD patients with NOD, studies to data
have not substantiated this idea. Medicare requirements for prescribing nocturnal
oxygen are relatively liberal and there is the possibility of misuse, which would
cause a substantial increase in the cost of home health care. A well designed
multicenter study is needed to provide appropriate indications and guidelines for
therapy in these patients.
PMID- 10771791
TI - Oxygen therapy and exercise response in lung disease.
AB - Lung disease affects exercise performance through a number of mechanisms,
including hypoxemia, abnormal ventilatory mechanics, abnormal ventilatory
muscles, abnormal ventilatory patterns, abnormal right heart function and
subjective dyspnea. Supplemental oxygen improves hypoxemia and thus improves
exercise impairment resulting from hypoxemia-related reductions in oxygen
delivery. Supplemental oxygen also reduces exercise ventilation. This, in turn,
reduces ventilatory muscle work, and the concomitant permissive hypercapnia may
have beneficial effects at the cellular level. Additionally, in obstructive
disease patients, an improved ventilatory pattern may reduce air trapping.
Supplemental oxygen may also improve right ventricular dysfunction in patients
with underlying right ventricular dysfunction. Finally, supplemental oxygen may
reduce dyspnea caused by oxygen-related carotid body activity. Important
questions remain. First, is long-term oxygen use of benefit in patients with only
exercise hypoxemia? Second, is exercise conditioning possible in patients with
exercise hypoxemia? Third, does supplemental oxygen enhance exercise conditioning
efforts in those patients with CLD but without exercise hypoxemia? If the answer
to this last question is yes, what selection criteria should be used to identify
those who would benefit? The answers to all of these questions will have enormous
impact on our approach to the optimal management of CLD patients.
PMID- 10771792
TI - Ambulatory oxygen therapy, exercise, and survival with advanced chronic
obstructive pulmonary disease (the Nocturnal Oxygen Therapy Trial revisited).
AB - The NOTT study showed improved survival in COT patients who received LTOT for
longer periods (mean 17.7 h/d, median 19.4 h/d) from an ambulatory oxygen system,
compared with the survival of NOT patients who received oxygen for a mean of 11.8
h/d from a stationary system. The differences in survival could have been due to
the method or the duration of oxygen therapy, or both. An increase in cardiac
output and increased oxygenation of the arterial blood (oxygen content) results
in increased tissue oxygen transport. In addition, COT was associated with better
survival and reduced hospitalizations, compared with NOT patients who were unable
to increase their walking level.
PMID- 10771793
TI - Oxygen and air travel.
AB - In summary, the environmental stresses of commercial air travel and the
possibility of altitude-induced adverse events during flight suggest the
importance of evaluating prospective air travelers with chronic pulmonary disease
for in-flight supplemental oxygen needs. Although gaps exist in current
understanding of the risks of air travel and optimal ways of predicting the need
for in-flight oxygen, respiratory clinicians can use available techniques to
assess travelers' in-flight oxygen needs in many instances. Significant current
variation among commercial air carriers in policies regarding providing oxygen,
related equipment, and the cost of in-flight oxygen poses challenges to the
prospective air traveler and warrants attention.
PMID- 10771794
TI - The demographics and economics of long-term oxygen therapy.
AB - Home oxygen therapy represents a scientifically validated and universally
accepted therapeutic regimen for the treatment of chronic hypoxemia secondary to
COPD. The clinical benefits of home oxygen, including a decrease in morbidity and
often a concomitant increase in the quality of life have been repeatedly
confirmed through rigorous worldwide trials, studies, and investigations.
However, since home oxygen is an expensive treatment modality, important
questions continue to be raised about the overall cost-benefit of the
intervention. Such scrutiny is expected to continue, especially in the United
States, as the entire issue of health care cost-containment remains atop the
domestic political agenda. Providers of home oxygen therapy have traditionally
realized quite favorable reimbursement for home oxygen equipment, especially for
those patient-customers covered under the Medicare program. However, recent
Medicare reimbursement reductions of more than 30% have raised serious questions
about the ability of home oxygen providers, especially those with annual revenues
less than $1 million, to sustain their historical high level of support services
to home oxygen patient-customers. Of particular concern is the economic hardship
of supplying portable oxygen, especially for those patient-customers with
unusually high ambulatory needs. The use of oxygen-conserving devices is viewed
by some as one strategy to better control the costs of supplying portable oxygen,
although there are those who still question whether or not oxygen-conserving
devices can effectively forestall arterial oxygen desaturation across the entire
spectrum of ambulation. Given the evidence now being reported that compliance in
using home oxygen as prescribed may well be much lower than originally believed,
the time is probably right to revisit the role played by home oxygen providers in
determining continuing need through the performance of periodic reassessments.
Such reassessments, if designed according to prescribed and validated protocols
and conducted by home respiratory therapists under orders of the prescribing
physician, would be a valuable tool to ensure continued medical need and
identifying noncompliance. This would help ensure that those needing and using
home oxygen would continue to receive the benefit. At the same time, patient
customers who, for one reason or another, stop using their oxygen equipment
despite repeated encouragement, would have the equipment removed. The net result
would be that reimbursement dollars currently wasted on home oxygen equipment
that is not being used could be reallocated for those patient-customers willing
and able to use the equipment as prescribed.
PMID- 10771795
TI - A nationwide system of long-term oxygen therapy: the Polish experience.
AB - Poland's Institute of Tuberculosis and Lung Diseases oversees 49 provincial
clinics, which provide and monitor LTOT for patients with COPD, interstitial
pulmonary fibrosis, and other pulmonary conditions. Because of limited resources,
eligibility for LTOT is fairly strictly defined, and LTOT equipment is
distributed to and retained only by nonsmoking patients who continue to
demonstrate need of the equipment (i.e., those who have ongoing hypoxemia that
can benefit from LTOT). This national LTOT system provides a large, nonselected
population suitable for LTOT research, and recent studies have produced important
data regarding survival, pulmonary hemodynamics, and the effect of withdrawing
LTOT from patients whose oxygenation has recovered to above the LTOT
qualification level of PaO2 < or = 55 mm Hg.
PMID- 10771796
TI - Long-term oxygen therapy: conference summary.
AB - With Jan's presentation, the conference concluded. In looking back on it, I think
it is obvious that the group heard a very comprehensive, state-of-the-art review
of this very important topic. Obviously, LTOT has enormous clinical and financial
impact for millions of patients around the world. Indeed, LTOT is one of the few
therapies available that has clearly been shown in randomized controlled trials
to impact mortality. There are many questions that remain, however. To me, the
most important of these questions involve the diagnosis and management of
patients who do not have resting hypoxemia but who do have NOD and/or XOD. How
aggressively should we "screen" for these conditions? If we find them, do we
treat continuously or just during the hypoxemic episodes? What is the role of
supplemental oxygen during rehabilitative exercises (including usage in patients
who don't become hypoxemic)? The answers to these questions will clearly have
substantial clinical and financial impact. Other memorable aspects of this
conference included the tireless efforts of Ray Masferrer to pull this conference
off, the special camaraderie of the participants that made the discussions so
productive, and the lovely location that gave the conference an atmosphere of
high quality. I'd like to recognize and thank two important groups. First, the
American Association for Respiratory Care did a superb job of organizing the
conference and providing the journal Respiratory Care as a forum to publish the
proceedings. Second, our 3 industry sponsors not only provided critical funding
support but also gave the group important perspectives during many of the
discussions. These kinds of industry-profession collaborations benefit everyone.
Finally, I'd like to extend my congratulations to all the speakers for jobs well
done and to thank them for making my job as summarizer an enjoyable one.
PMID- 10771797
TI - Central oxygen delivery systems: a disaster waiting to happen?
PMID- 10771798
TI - The hospital oxygen supply: an "O2K" problem.
AB - BACKGROUND: As an essential hospital facility, the central oxygen supply system
should be designed with features allowing backup and/or redundancy in the event
of system failure. As part of an organized institutional review of The Cleveland
Clinic Foundation hospital inpatient central oxygen supply system, we undertook a
survey of all hospitals in two Ohio cities to determine the characteristics of
hospital central supply systems. METHODS: The questionnaire was developed and
completed by structured telephone interview during calls placed to managers of
facilities engineering departments in 35 hospitals in the greater Cleveland and
Columbus, Ohio, metropolitan areas. To encourage candid responses to the
telephone interview, respondents were assured that institutional names would not
be presented in published reports. The questionnaire addressed the type of
primary and reserve oxygen sources in the hospital, whether a backup system
exists, and if so, in what configuration. The questionnaire also addressed
whether any unplanned interruption or other problem (such as contamination of the
piped-in oxygen supply) had ever occurred in the facility. RESULTS: Of the 35
eligible hospitals, responses were available from 32 (91.4%). The mean number of
beds in the hospitals responding was 397 +/- 251 (standard deviation), and the
original construction dates of the responding hospitals ranged from 1887 to 1982.
All 32 responding institutions reported a reserve system, described as a liquid
reservoir in 72% (23/32), manifolded cylinders in 16% (5/32), and both in 13%
(4/32). Twenty-six (81%) of those responding reported having the reserve supply
liquid or manifolded gas cylinders at the same location as the primary liquid
vessel. The supply lines of these contiguous primary and reserve containers were
reported to join proximal to entering the hospital structure, so at each of these
26 hospitals the primary and reserve systems depend on a single length of pipe.
Only 4 (13%) of the hospitals have manifolded cylinders in addition to the
primary and reserve liquid supplies. These manifolds are in different locations
from the primary and reserve, have physically separate feed lines, and represent
the only true examples of redundant piped-in oxygen supplies recorded during the
survey. Of the 32 hospitals surveyed, 5 (16%) reported having experienced mishaps
with the bulk liquid supply. CONCLUSIONS: (1) Not surprisingly, most of the
hospitals in these two urban areas use bulk liquid oxygen systems (with primary
and reserve liquid reservoirs) as the main central supply source, with some
providing manifolded cylinders as backup. (2) Mishaps regarding the main supply
line from the bulk oxygen reservoir were reported by 16% (5/32) of responding
institutions. (3) In this context, the fact that most main and reserve tanks were
contiguous and fed through a single line to the hospital facility suggests
ongoing risk for interruption of an oxygen supply by line mishaps (e.g., street
repair). (4) Contingency planning to lessen the risk of an interrupted supply
should involve back-up systems with physically separated feed lines, as well as
tanks of manifolded cylinders along the course of the main hospital oxygen
circuit line.
PMID- 10771799
TI - The effects of passive humidifier dead space on respiratory variables in
paralyzed and spontaneously breathing patients.
AB - BACKGROUND: Passive humidifiers have gained acceptance in the intensive care unit
because of their low cost, simple operation, and elimination of condensate from
the breathing circuit. However, the additional dead space of these devices may
adversely affect respiratory function in certain patients. This study evaluates
the effects of passive humidifier dead space on respiratory function. METHODS:
Two groups of patients were studied. The first group consisted of patients
recovering from acute lung injury and breathing spontaneously on pressure support
ventilation. The second group consisted of patients who were receiving controlled
mechanical ventilation and were chemically paralyzed following operative
procedures. All patients used 3 humidification devices in random order for one
hour each. The devices were a heated humidifier (HH), a hygroscopic heat and
moisture exchanger (HHME) with a dead space of 28 mL, and a heat and moisture
exchanger (HME) with a dead space of 90 mL. During each measurement period the
following were recorded: tidal volume, minute volume, respiratory frequency,
oxygen consumption, carbon dioxide production, ratio of dead space volume to
tidal volume (VD/VT), and blood gases. In the second group, intrinsic positive
end-expiratory pressure was also measured. RESULTS: Addition of either of the
passive humidifiers was associated with increased VD/VT. In spontaneously
breathing patients, VD/VT increased from 59 +/- 13 (HH) to 62 +/- 13 (HHME) to 68
+/- 11% (HME) (p < 0.05). In these patients, constant alveolar ventilation was
maintained as a result of increased respiratory frequency, from 22.1 +/- 6.6
breaths/min (HH) to 24.5 +/- 6.9 breaths/min (HHME) to 27.7 +/- 7.4 breaths/min
(HME) (p < 0.05), and increased minute volume, from 9.1 +/- 3.5 L/min (HH) to 9.9
+/- 3.6 L/min (HHME) to 11.7 +/- 4.2 L/min (HME) (p < 0.05). There were no
changes in blood gases or carbon dioxide production. In the paralyzed patient
group, VD/VT increased from 54 +/- 12% (HH) to 56 +/- 10% (HHME) to 59 +/- 11%
(HME) (p < 0.05) and arterial partial pressure of carbon dioxide (PaCO2)
increased from 43.2 +/- 8.5 mm Hg (HH) to 43.9 +/- 8.7 mm Hg (HHME) to 46.8 +/-
11 mm Hg (HME) (p < 0.05). There were no changes in respiratory frequency, tidal
volume, minute volume, carbon dioxide production, or intrinsic positive end
expiratory pressure. DISCUSSION: These findings suggest that use of passive
humidifiers with increased dead space is associated with increased VD/VT. In
spontaneously breathing patients this is associated with an increase in
respiratory rate and minute volume to maintain constant alveolar ventilation. In
paralyzed patients this is associated with a small but statistically significant
increase in PaCO2. CONCLUSION: Clinicians should be aware that each type of
passive humidifier has inherent dead space characteristics. Passive humidifiers
with high dead space may negatively impact the respiratory function of
spontaneously breathing patients or carbon dioxide retention in paralyzed
patients. When choosing a passive humidifier, the device with the smallest dead
space, but which meets the desired moisture output requirements, should be
selected.
PMID- 10771800
TI - In vitro comparison of the circulaire and AeroTee to a traditional nebulizer T
piece with corrugated tubing.
AB - BACKGROUND: Nebulizers are a popular means of delivering aerosolized medication,
primarily albuterol, to the bronchial airways of patients, and there has been
extensive research done on numerous nebulizers used with nebulizer T-pieces and
corrugated tubing. Very little research has been performed on other types of
nebulizer delivery systems and there is no substantial information on how
effective various nebulizer delivery systems are in terms of the quantity and
particle size of aerosolized medication delivered to the patient. In this study
the Circulaire and the AeroTee, two devices that rely on bags to store aerosol
during patient exhalation, are evaluated and compared to the conventional
nebulizer T-piece with corrugated tubing. METHODS: Three each of the nebulizer T
piece with corrugated tubing, the Circulaire, and the AeroTee were sampled using
3 Vixone nebulizers. Each one of the 3 nebulizer delivery systems used the same 3
Vixone nebulizers. Each nebulizer delivery system was evaluated by connecting a
constant-flow vacuum and compressed gas source cycled to simulate patient
breathing at a respiratory rate of 14 breaths/min and an inspiration-expiration
ratio of 1:2. Medication delivered was determined by sampling a portion of the
simulated patient's flow onto a membrane filter and calculating the total
medication received by the patient. Particle size was determined by sampling with
a cascade impactor under ambient conditions. RESULTS: The Circulaire delivered
significantly less medication than the nebulizer T-piece with corrugated tubing
(p < 0.001), whereas the AeroTee delivered substantially more medication than the
nebulizer T-piece with corrugated tubing (p < 0.001). The particle size delivered
by the Circulaire was significantly smaller than that of the nebulizer T-piece
with corrugated tubing (p < 0.001), whereas the AeroTee delivered particle size
equivalent to a nebulizer T-piece with corrugated tubing (p = 0.82). CONCLUSION:
There are clinically important differences between nebulizer delivery systems.
When evaluating the optimum means for delivering aerosolized medication, equal
consideration should be given to both the brand of nebulizer and the nebulizer
delivery system.
PMID- 10771801
TI - Combining a positive expiratory pressure device with a metered-dose inhaler
reservoir system using chlorofluorocarbon albuterol and hydrofluoroalkane
albuterol: effect on dose and particle size distributions.
AB - BACKGROUND: Combining a positive expiratory pressure (PEP) device with inhalation
of albuterol via metered dose inhaler (MDI) may improve drug delivery to the
lung, but may also affect dose availability. PURPOSE: Determine the effect of
interposing a PEP device on dose availability of albuterol via MDI and reservoir
with either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant.
METHODS: MDI dose availability of CFC albuterol (Proventil) and HFA albuterol
(Proventil HFA) using an Aerosol Cloud Enhancer (ACE) reservoir with and without
a PEP device (TheraPEP) attached was determined. Drug availability was assessed
using an Andersen 8-stage cascade impactor operated at 28.3 +/- 0.5 L/min. The
PEP device was inserted between the reverse-firing ACE and the United States
Pharmacopeia induction throat. Drug collected on impactor plates was analyzed
spectrophotometrically at 276 nm, and the fine particle fraction was determined
as the mass of drug < 4.7 microns. RESULTS: With CFC albuterol, total dose and
drug mass < 4.7 microns (means and standard deviations) for the MDI-ACE alone
were 44.4 +/- 7.7 micrograms and 33.4 +/- 2.2 micrograms, respectively, and for
the MDI-ACE with TheraPEP were 50.1 +/- 6.4 micrograms and 39.8 +/- 14.3
micrograms, respectively. With HFA-albuterol sulfate, total drug and drug mass <
4.7 microns for the MDI-ACE alone, expressed as base drug, were 41.7 +/- 4.2
micrograms and 35.2 +/- 6.3 micrograms, respectively, and for the MDI-ACE with
TheraPEP were 48.9 +/- 8.0 micrograms and 44.2 +/- 6.2 micrograms, respectively.
There was no significant difference in dose availability between the MDI-ACE
alone and with the PEP device attached (Wilcoxon signed-rank test, p > 0.05), for
either CFC or HFA albuterol. CONCLUSION: Interposing the TheraPEP device at the
MDI-ACE outlet does not change total dose, drug mass < 4.7 microns, or mass
median aerodynamic diameter of MDI albuterol, with either CFC or HFA propellants.
PMID- 10771802
TI - Spontaneous pneumothorax and alpha 1-antitrypsin deficiency.
AB - Spontaneous pneumothorax has been observed in patients with abnormal levels of
alpha 1-antitrypsin. We report the case of a young woman with a low level of
alpha 1-antitrypsin who presented with recurrent episodes of spontaneous
pneumothorax and who required pleuroscopy, apical lung resection, and
pleurodesis.
PMID- 10771803
TI - Smoking cessation in hospitalized patients.
AB - The components of readiness to change for smoking cessation that are found in the
general population are also applicable to hospitalized smokers. Smoking cessation
interventions must be specifically tailored to subgroups among hospitalized
patients, with emphasis on smoking-related diagnosis when applicable.
Interventions should include key components related to smoking cessation, such as
knowledge, self-efficacy, exposure to smoking, and social support. Interventions
that include relapse prevention and are conducted in the context of other risk
reduction strategies should be developed.
PMID- 10771804
TI - Should this patient use supplemental oxygen during commercial air flight?
PMID- 10771805
TI - A 72-year-old smoker with interstitial lung disease.
PMID- 10771806
TI - Endocrine disorders.
PMID- 10771807
TI - Common childhood thyroid disorders.
AB - This article presents current knowledge about common childhood thyroid gland
disorders. Included are congenital and acquired hypothyroidism, hyperthyroidism,
disorders due to iodine deficiency, tumors and miscellaneous conditions. The
significance of early diagnosis by screening and institution of treatment of
congenital hypothyroidism is emphasized. Etiology, pathogenesis, clinical signs
and symptoms, diagnosis and treatment are discussed.
PMID- 10771808
TI - Disorders of thyroid gland in India.
AB - The profile of thyroid disorders encountered in pediatric and adolescent age
groups in India is similar to that seen in most parts of the world except for the
prevalence of iodine deficiency disorders in certain endemic regions of this
country. Clinical presentation is most commonly for hypothyroidism and goiters
and infrequently for hyperthyroidism. Of nearly 800 children referred for thyroid
problems, 79% had hypothyroidism (goitrous as well as nongoitrous), 19% had
euthyroid goiters and 2% had hyperthyroidism. Hypothyroidism was due to thyroid
dysgenesis in 75% (aplasia/hypoplasia--50% and ectopic thyroid gland 25%),
thyroiditis in nearly 5% and dyshormonogenes is in 20%. The incidence of
congenital hypothyroidism in our experience of screening nearly 40,000 newborns
is about 1 in 2,640, which is much higher than the worldwide average of 1 in
3,800. Diagnostic delay in hypothyroidism is common and is related to lack of
awareness amongst primary healthy care practitioners and family physicians as
well as the cost and availability of laboratory investigations. This delay,
compounded with inadequate therapeutic surveillance is responsible for the poor
outcome in affected children. High incidence of dyshormonogenesis, inherited as
autosomal recessive trait also calls for genetic counselling and routine sibling
examination. Our results of family studies on first degree relatives of children
with thyroiditis revealed presence of antimicrosomal antibodies in 43% and
thyroid disease in 26%. Many etiologic factors cause goiters which may be
functionally euthyroid or hypothyroid with almost equal frequency in our series.
In nearly 200 schools children surveyed for goiter prevalence, 8% in high
socioeconomic groups and about 21% in the low income group, had goiters. Female
predominance was marked. However, iodine deficiency was not the sole cause as
revealed by dietary survey and urinary iodine estimations. Hyperthyroidism is
infrequent, less severe and in our experience responded well to long-term
administration of antithyroid drugs. A high index of clinical awareness and
education of primary health workers will help a great deal in improving the
ultimate outcome in children with thyroid disorders/hypothyroidism.
PMID- 10771809
TI - Thyroid function tests and their interpretation.
AB - For general screening of children who are in fairly good health and in whom CNS
or pituitary disease is not strongly suspected, the newer THS assays are very
useful in assessing the action of both endogenous and exogenous thyroid hormone.
Those children in whom primary hypothyroidism is strongly suspected or who are
already on thyroid hormone supplementation, the free T4 assay provides a useful
adjunct to the TSH. If Grave's disease or factious hyperthyroidism is suspected,
the total T3 assay is a useful adjunct to the TSH and the free T4. The screening
of possible hypothyroidism as a result of hypothalamic or pituitary disease, the
free T4 is relied on heavily, along with the response of TSH to TRH stimulation.
Measurement of the nocturnal TSH surge may also be useful in this situation.
PMID- 10771810
TI - Recent advances in management of diabetic ketoacidosis.
AB - Diabetic ketoacidosis is the most common endocrine emergency in children and
frequently it is the initial presentation of insulin dependent diabetes mellitus.
Despite sophisticated technology and our improved understanding of the
pathophysiology of this disease, the mortality from intracranial complications
remains constant over the past two decades. Several management protocols are used
all over the world but the recent trend in opinion seems to be one of the slower
rates of initial hydration aimed at matching the osmolarity of the infusion
solutions with the patient's serum osmolarity. It remains to be seen if
widespread use of this rehydration strategy will improve morbidity in the future.
A protocol for managing diabetic ketoacidosis is suggested.
PMID- 10771811
TI - Recent advances in the management of diabetes mellitus.
AB - The Diabetes Control and Complications Trial (DCCT) demonstrated that the
improved control of blood glucose levels could delay or prevent long-term
complications in patients with insulin dependent diabetes mellitus (IDDM).
However, there are questions as to whether this degree of tight control is
realistic in community settings. This review will cover new strategies for the
management and prevention of IDDM.
PMID- 10771813
TI - Pulse polio immunization in Delhi--1995-96: a survey.
AB - A coverage evaluation survey of the campaign for mass Pulse Polio Immunization
(PPI) on 9th December, 1995 and 20th January, 1996 in Delhi was carried out using
the modified cluster sampling technique and a pre-structured proforma. Six
hundred-and-nine children of under-3 age group were covered in the survey.
Overall coverage for both the doses was found to be 77%. While coverage for 9th
December dose was found to be 80%, it rose to 90.2% on 20th January, 1996.
Coverage levels for male and female children were similar. Parental literacy was
seen as a definite factor, positively affecting the coverage levels. Proportion
of not covered under PPI was significantly higher in the 0-6 months age group.
Television and health workers were found to be the main sources of awareness
about PPI.
PMID- 10771812
TI - Hypoglycemia in infancy and childhood.
AB - Hypoglycemia is a medical emergency in the newborn nursery. The requirements for
glucose homeostasis, definition of hypoglycemia, classification of hypoglycemia
(increased glucose utilization versus decreased glucose production), diagnostic
evaluation and management will be presented. Clinical cases will be used to
illustrate important disorders.
PMID- 10771814
TI - Evaluation of pulse polio and routine immunisation coverage: Alwar District,
Rajasthan.
AB - During the last decade, India achieved 88% reduction in reported poliomyelitis
incidence. However, absolute number of reported cases still remains high. As an
added effort to eradicate the disease, the country observed its first National
Immunisation Days (NIDs) on 9.12.95 and 20.1.96. The present study evaluates the
performance of Alwar district, Rajasthan. Modified 30 cluster technique was used
to collect information. Overall coverage in rural and urban areas was 89% and 91%
respectively. Main source of information was television in urban and health staff
in rural areas. Most of the respondents knew about the usefulness of such special
activity and had favourable opinion about the facilities provided. Urban Alwar
had 80% OPV3 coverage but, in rural area it was almost half. The reported
coverage of NIDs and UIP was found to be conflicting with the study results. The
existing "dose enumeration method" of calculating reported coverage was
attributed to be the cause. The study emphasises the need to incorporate an in
built community-based evaluation of future NIDs and utilisation of such results
for planning.
PMID- 10771815
TI - Clinical profile of sickle cell disease in Orissa.
AB - Children comprised 52% of patients with Sickle Cell Disease (SCD). Types of
Sickle Cell Disease encountered were SS (92.7%). SB thalassaemia (6.7%) and SD
disease (0.7%). The disease was widespread in almost all castes and communities
in the society; largest number of patients (20%) belonging to scheduled castes
and only 1.4% were from scheduled tribes. Maximum number of cases were in the age
group 2-4 and 4-6 years, many of whom died around this age. Besides attacks of
pain, jaundice and anemia, frequent attacks of fever with anemia or only anemia
in childhood were a predominant presenting feature. Splenic sequestration was
frequent (10.1%). The patients usually had a steady state hemoglobin level of 6
10 g/dl, with which they thrived well. Fetal hemoglobin was 5-30%. Blood
transfusion was not a frequent requirement, but prophylactic long acting
penicillin was helpful in preventing frequency of crisis.
PMID- 10771816
TI - Fetal outcome and childhood mortality in offspring of mothers with sickle cell
trait and disease.
AB - The sickle cell hemoglobinopathy is a major public health problem which causes
high morbidity and mortality in India. Although the hematological and clinical
profile of the patients is extensively studies. The reproductive outcome of
mothers afflicted with sickle cell trait and disease is still unknown in India.
In a retrospective study, we have examined the reproductive profile of 190
mothers afflicted with sickle cell, attending Medical Out-Patient Department at
V.S.S. Medical College Hospital, Burla in Western Orissa, India during the year
1991-1992. Seventy-three mothers who were found normal after medical examination
and were free from hemoglobinopathic disorders, anemia, jaundice, iron
deficiency, etc. constituted the control group and 66 mothers with sickle cell
trait and 51 with sickle cell disease formed the study group. The reproductive
history was recorded for number of conceptions, fate of offspring, live birth,
surviving children and childhood mortality. Hematological investigations and
hemoglobin electrophoresis were done as per the standard procedure. There was no
difference in mean number of livebirths per mother between controls and sickle
cell trait mothers. But between the controls and sickle cell homozygotes (p <
0.01), and sickle cell trait and disease (p < 0.01) mothers, this mean number was
significant. For abortions/miscarriages, the difference between controls and
sickle cell homozygotes (p < 0.001), and sickle cell trait and disease (p < 0.01)
mothers was highly significant. The number of stillbirths per mother in
homozygous sickle cell mothers was higher (p < 0.01) as compared to controls.
There were significantly higher childhood deaths in sickle cell trait (p < 0.05)
and disease (p < 0.05) mothers than in the controls. It seems that the sickle
cell heterozygote and hemoglobin E heterozygote mothers are genetically better
fit than the sickle cell homozygotes. Further, the sickle cell disease is
clinically severer than the hemoglobin E disease in India probably due to
molecular diversity.
PMID- 10771817
TI - Lung function values in healthy children (10-15 years).
AB - The present study was designed to establish norms for pulmonary functions in
urban healthy children of Delhi under the age group of 10-15 years. Pulmonary
functions were assessed using an electronic lung function spirometer in 222 boys
and 188 girls belonging to middle income group families of East Delhi. The
pulmonary functions were separated by age and sex. All pulmonary functions showed
an increase with advancing age. FEV1 and FVC were more in boys as compared to
girls. Values of PEFR, FRC and TLC were similar in both sexes till the age of 13
years after which boys attained higher values. Prediction equations were obtained
using height, age and weight as independent variables. Forward selection method
was used to choose the best equation for each pulmonary function. Maximum
variance in the lung functions was explained with the height. It is felt that
norms established in the present study will act as reference standards for
various lung functions in well nourished urban Delhi children under the age group
of 10-15 years.
PMID- 10771818
TI - Bilirubin crystals in neutrophils in neonatal hyperbilirubinaemia.
AB - Serum unconjugated bilirubin (UCB) levels > 205.2 mumol/L were present in 120 of
143 cases of neonatal hyperbilirubinaemia. Sixty-five per cent (78/120) cases
showed bilirubin crystals in the neutrophils of Leishman's stained smears from
EDTA blood. The proportion of crystal positive (CP) neutrophils was higher in
septicaemia than in Haemolytic Disease of Newborn (HDN). Mortality rate was
significantly higher (P < 0.001) in CP septicaemic cases when compared with those
which were crystal negative (CN).
PMID- 10771819
TI - Clinical utility of serodiagnosis of tuberculosis.
AB - The use of TB-ELISA tests as a diagnostic tool offer a lot of scope in early
diagnosis of serious forms of childhood tuberculosis. The characteristics of
these tests have improved with the availability of purified and recombinant
antigens and competition assays using monoclonal antibodies. Lower antibody
titres to M. tuberculosis specific antigens in children and the presence of
'natural exposure' antibodies make the interpretation of these tests difficult at
times. Caution must be exercised in interpreting their results due to problems
inherent on currently available methods of TB-immunodiagnosis. The selection of
best combination of antigens for serology, prospective clinical trials comparing
success rate of serology with the standard different diagnostic procedures are
required.
PMID- 10771820
TI - Radionuclide scintigraphy in Caroli's disease.
AB - Congenital cystic dilatation of the intrahepatic bile ducts involving the major
intrahepatic radicles was first described by Caroli and hence named as Caroli's
disease. We present here a case in which the only symptom was intermittent pain
in the abdomen for last one-and-a-half-year and a radionuclide scan done
effectively, not only diagnosed the disease but also the associated cholangitis.
PMID- 10771821
TI - Schwannoma of infratemporal fossa in a young child.
AB - Schwannomas in children are rare. A nine-year-old boy presented with swelling
right side of face and proptosis for 4 months. CT scan showed a heterogenous mass
in the right infratemporal fossa and extending to the posterior ethmoid. There
was erosion of the bony walls of the infratemporal fossa. A biopsy through the
sublabial approach was reported as schwannoma. The tumour was approached by Weber
Ferguson approach and excised in toto with complete relief of symptoms.
PMID- 10771822
TI - A report of a rare chromosome 9 variant with an unusual G-banding pattern in the
9qh region.
AB - We present a case of a Caucasian multigravida with advanced maternal age who
showed evidence of an unusual heterochromatin banding pattern on chromosome 9 and
a similar fetal karyotype on amniocentesis. Although unusual banding patterns of
this region have been described earlier, we report a new, clinically
insignificant pattern. This case illustrates the care needed in analysing the
heterochromatin region for accurate clinical interpretation of chromosome 9
polymorphisms.
PMID- 10771823
TI - Multiple pterygium syndrome.
AB - Severely involved female child with Multiple Pterygium Syndrome (Escobar) is
described. She had the typical findings of the syndrome such as multiple
pterygiums, characteristic facial appearance, genital anomalies. She also had
bilateral optic atrophy. This is the first case described so far with optic
atrophy in Multiple Pterygium Syndrome (Escobar).
PMID- 10771824
TI - Perianal necrotizing fasciitis in a neonate.
AB - A two-week-old term male infant, weighing 1,600 grams was transferred to the
neonatology unit of Dokuz Eylul University hospital with sharply demarcated
cutaneous gangrene surrounding the perianal region. He did well at birth. In his
history, on the 10th postnatal day, a red, painful, warm cutaneous lesion was
observed which was thought to be secondary to repeated and inappropriate rectal
temperature measurements. Besides an ill-appearing child, a nontender frank
cutaneous gangrene developed within several days. Klebsiella pneumoniae was
cultured from the involved area. Blood cultures were negative. A frozen section
of soft tissue biopsy could not be performed because of the localization of the
lesion. The patient was successfully treated by surgical debridement and high
doses of parenteral antibiotics.
PMID- 10771825
TI - Mumps hemiplegia.
AB - Neurological involvement of mumps is commonly restricted to aseptic meningitis.
However, rarely mumps is associated with more severe encephalitic illness; other
known associations described with mumps are cases of transverse myelitis and
Gullain Barre like illness. We report a case of hemiplegia due to mumps parotitis
probably caused by involvement of carotid artery.
PMID- 10771826
TI - Advanced intussusception--a diagnostic error.
PMID- 10771827
TI - Objective Structured Clinical Examination for the house officers.
PMID- 10771828
TI - The causes of cancer: implications for prevention and treatment.
AB - The final clinical manifestation of cancer is a result of complex series of
changes in a single cell. This review summarizes some of the new concepts and
hypotheses that explain the evolution of cancers. The emphasis is on cancer as a
disease of the stem cells within a tissue that undergo initiation as a result of
mutational insult to one or more genes that are critical for cell growth. During
the second stage (promotion stage) the initiated cells acquire proliferative
capacity due to epigenetic changes, i.e., altered expression of genes whose
products play a central role in signal transduction. This requires continued
exposure to agents and events causing such changes. This stage is, therefore,
reversible and the various components of this stage are central targets for the
development of mechanism based anti-cancer drugs. During the stage of
progression, the neoplastic lesions acquire additional genetic alterations and
become clinically manifestable malignant neoplasms. At the biochemical and
molecular level, neoplastic transformation involves aberrations in the expression
and regulation of oncogenes, tumor suppression genes, transcription factors and
components of the cell signal transduction cascades. The understanding of the
various cellular biochemical and molecular events that metamorphose a normal cell
into a cancer cell is central to the development of rational new drugs that are
targeted against the various components. Such drugs in combination with the
conventional chemotherapeutic agents that are currently used, provide a more
effective control of cancer without the risk of toxic side effects.
PMID- 10771829
TI - Pediatric endocrinology in India.
PMID- 10771830
TI - A rational approach to short stature: focus on use and abuse of growth hormone.
AB - The abundant supply of recombinant growth hormone has raised interesting
possibilities of several new applications. While supplementation of the missing
hormone in patients with growth hormone deficiency is still the undisputed
primary indication for its use, there is now convincing evidence of its
usefulness in the therapy of short stature due to Turner syndrome and pre
transplant chronic renal failure in childhood. Numerous studies on patients with
other causes of short stature have failed to show any significant benefit in
final adult height. Social pressures notwithstanding, it is still premature to
advocate the use of this expensive therapy for indications other than the three
stated above especially since our understanding of potential long-term
complications from such treatment is far from complete.
PMID- 10771831
TI - Nutritional and metabolic rickets.
AB - Nutritional rickets is caused by vitamin D deficiency due to lack of exposure to
sunlight. Neonatal rickets occurs only in infants born to mothers with very
severe osteomalacia. Calcium deficiency alone does not cause mineralisation
defects. It only causes osteoporosis and secondary hyperparathyroidism with
raised plasma, 1,25 (OH)2D and osteocalcin. Low 25-OHD, increased IPTH, increased
alkaline phosphatase in plasma and decreased calcium and increased hydroxyproline
in urine are diagnostic of rickets. Low or undetectable plasma levels of 25-OHD,
in presence of high plasma 1,25(OH)2D and IPTH are often observed during
treatment with vitamin D. Even the marginal intakes of fluoride (> 2.5 mg/day)
cause rickets in calcium deficient children. Indian children often need high dose
of vitamin D due to severely depleted D stores, high IPTH and severe bone disease
(radiologic and histomorphometric) for treatment.
PMID- 10771832
TI - Delayed puberty.
AB - Delayed puberty is a frequently encountered problem causing much anxiety to
patient and parents alike. Proper understanding of the normal pubertal events and
its variation sets off the background to understand disorders leading to delayed
puberty. An orderly clinical approach combined with continued observation helps
to arrive at a final diagnosis in most of the patients. The treatment modalities
available, even if not curative, can achieve the goals of management set off at
the end of evaluation of the patient.
PMID- 10771833
TI - Precocious puberty.
AB - Puberty occurring before the age of 8 years in girls and 9 years in boys in
considered precocious. The numerous causes of precocity can be classified as
central or peripheral. Central or true precocious puberty (CPP) is due to
premature activation of the hypothalamopituitary-gonadal axis and is isosexual.
Peripheral or pseudoprecocious puberty (PPP) results from the production of sex
steroids independent of the H-P-G axis and may be isosexual or heterosexual. CPP
is the most common form of precocity involving more than 50% of children and is
much more common in girls than boys. CPP is more common between 4 and 8 years. A
peak serum LH levels > 10 iu/l following GnRH stimulation is the absolute
evidence of CPP. Serum IGF-I levels are predictive of the outcome. Availability
of CT and MRI has helped to determine the cause of CPP in most cases.
Hypothalamic hamartoma is the most common tumour causing CPP especially in boys.
Adrenal causes, particularly CAH, are the commonest cause of PPP in boys whereas
ovarian causes are more likely in girls. Long acting GnRH analogues provide a
safe and effective form of treatment of CPP.
PMID- 10771834
TI - Cushing's syndrome.
AB - Endogenous Cushing's Syndrome (CS) is a relatively uncommon disease in children.
The etiology is more often a primary adrenal cause in infants and younger
children, and corticotroph adenoma in older ones. Diagnostic evaluation must be
stepwise and methodical, aimed at first confirming the presence of the disease,
and then looking for the etiology. The management should preferably be carried
out at a centre which is experienced in the management of CS. Recent advances,
including MRI, sensitive ACTH assays, inferior petrosal sinus sampling (IPSS) and
transsphenoidal surgery (TSS) have dramatically improved the care of children
with CS. However, the issue of high recurrence rates after TSS in children
remains to be tackled. The prognosis of adrenal carcinoma still remains, dismal.
PMID- 10771835
TI - Ambiguous genitalia--an Indian perspective.
AB - Ambiguity of genitalia in the newborns and children still remains a poorly
understood subject and even during the postgraduate teaching programmes, very
little attention has been paid to make this subject popular. There is also no
chapter "without tears" on the subject for the proper management and to prevent
the agony of the parents resulting from the ignorance and the social stigma. The
purpose of this brief communication is to project the practical management of
Children with intersex disorders, based on our clinical experience from the
pediatric intersex clinic at AIIMS.
PMID- 10771836
TI - Diagnosis and management of ambiguous genitalia.
AB - The diagnosis and management of a newborn with ambiguous genitalia is a
diagnostic challenge. Rapid medical evaluation is necessary to uncover and treat
potentially life-threatening illnesses, and to allay the psychological stress
placed on new parents awaiting announcement of their baby's sex of rearing.
Understanding the mechanisms of sexual differentiation can facilitate this task
for the physician faced with this dilemma. This article reviews these mechanisms
and suggests a logical approach to handling the work-up and treatment plan.
PMID- 10771837
TI - Transient hyperglycemia in acute childhood illnesses: to attend or ignore?
AB - Transient hyperglycemia occurs as a part of stress response in acute illnesses
and is brought about by elevated levels of counter regulatory hormones. It is
frequently encountered but the exact prevalence and implications, especially in
childhood have not been studied in detail, 758 children (1 month to 6 years) with
acute illness were screened for hyperglycemia; of these 36 children were found to
have a glucose level of > or = 150 mg/dl at admission and were designated
hyperglycemics. The overall prevalence of hyperglycemia was 4.7 per cent. The
disease-wise prevalence in neurological disorders, septicemia, respiratory
illnesses and diarrhoea was 7.9, 7.6, 4.2 and 3.0 per cent respectively. Family
history of diabetes did not predispose towards developing transient
hyperglycemia. The demographic profile (age, sex, nutrition status and disease
pattern) and severity of illness (as assessed by temperature, heart rate,
respiratory rate, duration of illness and hospitalization, treatment modalities
required, hypoxia and acidosis) did not affect the prevalence, extent and the
rate of normalization of hyperglycemia. The mortality in hyperglycemics was
double (13.9%) as compared to 6.9% in non-hyperglycemics, although the difference
was insignificant, statistically (O.R = 2.17, CI = 0.81-5.82, p > 0.05). It was,
therefore, concluded that transient hyperglycemia occurs in 4-5% of patients with
acute pediatric illnesses. However, it does not significantly correlate with the
clinical profile and severity of the illness, and has no immediate prognostic
significance.
PMID- 10771838
TI - Epilepsy and teachers: a survey.
AB - Teachers in five primary schools were surveyed for their knowledge and attitudes
about epilepsy. An analysis of 113 teacher responses revealed knowledge deficits,
especially regarding the prevalence of epilepsy, the future of children with the
disorder and E.E.G. as an aid to diagnosis. Misconceptions regarding first aid
were also common. More than two-thirds of the teachers believed that children
with epilepsy have academic problems more often, although about half of the
respondents were in favour of normal schools for such children. Most respondents
recommended a teacher's career for these children in future but considered that
of a bus driver, as unsuitable. Few teachers had attended any educational
programme on epilepsy. Only about one-fifth of the teachers were confident in
dealing with an epiletic child. Communication about epilepsy among the teachers,
parents and doctors was virtually non-existent.
PMID- 10771839
TI - Serum immunoglobulins, IgG subclasses, isohemagglutinins and complement-3 levels
in patients with thalassemia major.
AB - Serum IgG, IgM, IgA, IgG subclasses (IgG1, G2, G3, G4), isohemagglutinins and
complement-3 concentrations were measured in 23 beta-thalassemic patients
suffering from recurrent infections. No significant abnormalities were found in
these humoral immunity investigations, both in splenectomized and non
splenectomized patients. On the other hand, iron overload or repeated blood
transfusions were not found to down-regulate the humoral immune system of
thalassemic patients.
PMID- 10771840
TI - Small for gestational age babies: Indian scene.
AB - Intrauterine growth retardation (IUGR) is an important determinant of neonatal
mortality, morbidity and poor neurologic outcome. The study was aimed to evaluate
the magnitude of perinatal risk factors in causation and the neonatal outcome of
small for gestational age (SGA) babies. One hundred and three SGA babies born
over a period of one year were retrospectively analysed during their hospital
stay. 3.53 per cent of the babies were SGA with mean birth weight of 1657 +/- SD
354 gm (range 600-2200 gm). 68.9 per cent were term babies and 51.5 per cent were
females. Toxemia of pregnancy (30.09%), hypertensive diseases of pregnancy (HDP)
excluding toxemia (5.8%), diabetes mellitus (1.94%), medical disorders including
renal and cardiac (3.88%), anemia (Hb < 8 gm%) and IU infection (0.97%) were the
main conditions responsible for SGA. In 56.3% pregnancies, no cause could be
ascertained. The common perinatal problems were infections in 27 (26.2%), birth
asphyxia in 22 (21.36%), polycythemia in 25 (24.3%), jaundice in 22 (21.36%) and
hypoglycemia in 7 (6.8%). Congenital malformations in 2 (1.94%) and Hyaline
membrane disease in 1 (0.97%) were uncommon problems. 5.8 per cent babies died
due to various perinatal problems. Based on these findings it was concluded that
idiopathic (? Constitutional) intrauterine growth retardation was the commonest
cause of SGA in Indian babies. 58.3 per cent babies had neonatal problems and
they had a better survival compared to their western counterparts.
PMID- 10771841
TI - Prevalence of goitre in school children in Baramulla (Kashmir valley).
AB - 1,876 school children were surveyed in Baramulla district of Kashmir for the
presence of goitre. There were 964 boys and 912 girls in the age group of 5-15
years. An overall goitre prevalence of 52.08 per cent was found (54.77% in boys
and 49.23% in girls). Iodine content was assayed in urine samples of 44 randomly
selected subjects. The mean +/- SEM urinary iodine was 41.85 +/- 2.52
micrograms/g of creatinine (Range 6.25-69.41).
PMID- 10771842
TI - Prevalence of rubella virus in suspected cases of congenital infections.
AB - This study includes a total of 342 infants suspected of having congenital
infections from January 1991-December 1993. Serum samples of these infants were
tested for rubella specific IgM antibodies by mu ELISA. Of the total 342 infants,
52 (15.2%) were found to be positive for IgM antibodies to rubella virus. The
commonest clinical presentation in infants with IgM antibodies to rubella virus
was bilateral congenital cataract and hepatosplenomegaly.
PMID- 10771843
TI - Recognition and management of ARI--a KAP study on private medical practitioners.
AB - We interviewed 113 private medical practitioners (PMPs) of all system of medicine
in Ambedkar Nagar area of South Delhi to determine as to how they recognise and
treat Acute Respiratory tract Infections (ARI) in children, in particular,
pneumonia. Allopathic PMPs reported viruses and bacteria as causes of ARI as
compared to PMPs of other system of medicine who often reported exposure to cold,
change in weather and dietary habits as a cause of ARI. Sixty-eight PMPs out of
113 did not count the respiratory rate (RR) in children with ARI and among those
who counted, only 19.5% PMPs could correctly tell the normal RR in children aged
less than two months. In children aged 2-12 months, the percentage of PMPs
responding correctly was 15.0%. Relatively greater proportion of PMPs (31.8%)
could correctly tell the normal respiratory rate in children aged 1-5 years. X
ray to diagnose pneumonia was suggested by 102 (90.3%) PMPs. Majority of PMPs
prescribed some form of medication including antibiotics for the treatment of
cough and cold. Eighty-seven (77%) PMPs prescribed antibiotics, 53 (46.9%)
antihistaminics and 49 (43.4%) prescribed allopathic cough syrups to treat cough
and cold. For pneumonia, 108 (96.4%) PMPs prescribed antibiotics and 31 (27.7%)
PMPs prescribed steroids among other things.
PMID- 10771844
TI - Japanese encephalitis in India.
AB - Japanese encephalitis (JE), caused by a mosquito-borne virus was first recognised
in India in 1955 and since then many major out-breaks from different parts of the
country have been reported, predominantly in rural areas. Children are mainly
affected, with morbidity rate estimated at 0.30 to 1.5 per 100,000 population.
Case fatality rate has ranged from 10% to 60%, and up to 50% of those who recover
may be left with neurological deficits. Reported incidence has generally been
higher in males than in females, but subclinical infections have occurred equally
in both sexes. A large number of subclinical infections occur each year during
the transmission season. Diagnosis at the primary health centre (PHC) level is
based on clinical symptoms only. Therefore, there is a need to develop simple
tests for use at the peripheral level both for diagnosis and for epidemiological
surveys. JE is a vaccine preventable disease, but there are many logistic
problems for effective implementation of vaccination.
PMID- 10771845
TI - Melioidosis--rare or overlooked?
AB - The word melioidosis conjures images of a rare, exotic disease meant only for
large textbooks of pediatrics, to be read only to be forgotten or even to be
ignored completely. The following two cases of melioidosis from India will surely
serve as an eye opener.
PMID- 10771846
TI - Pseudohypophosphatasia.
AB - Two rare cases of pseudohypophosphatasia in two siblings which so far, to best of
our knowledge have not been reported.
PMID- 10771847
TI - Infantile Cronkhite-Canada syndrome.
AB - Since 1955, numerous cases of Cronkhite-Canada syndrome have been reported in
adults. We present here the first Asian report of the infantile Cronkhite-Canada
syndrome. While the prognosis in adults is variable, in children, it is less
optimistic.
PMID- 10771848
TI - Arginase deficiency.
AB - Hyperargininemia due to arginase deficiency is a rare, inherited, urea cycle
disorder. We report a case of arginase deficiency in a 5-year old boy presenting
with mild hyperammonemia, hyperargininemia, and dibasic aminoaciduria.
PMID- 10771849
TI - DeSanctis-Cacchione syndrome.
AB - We report a case of DeSanctis-Cacchione Syndrome presenting with unusual features
like early onset of cutaneous lesions and optic atrophy.
PMID- 10771850
TI - Medical bioethics and cultural diversity.
AB - Medical bioethics has developed as a new field of study in the US in the past
quarter decade, focusing upon the moral principles of autonomy, beneficence,
nonmaleficence, and justice. These principles may, however, reflect biases in
American culture, rather than a truly universal approach to ethical problems in
medicine and health care. Alternative models for bioethics may take the cultural
beliefs and practices of different countries more seriously. These different
models of bioethics may have important implications for the study of ethical
issues in pediatrics. Effective dialogue between America and other countries such
as India, especially when focused on particular clinical cases, should expand the
understanding of bioethics in those other countries, as well as bringing new
light upon American bioethical principles.
PMID- 10771851
TI - An overview of extracorporeal membrane oxygenation therapy.
AB - A brief overview of extracorporeal membrane oxygenation and its use in infants
and children is presented. The history, selection, operative procedure, daily
management and complications are discussed. The international results are shown.
PMID- 10771852
TI - Postnatal management of hydronephrosis diagnosed in utero.
AB - In this review we identify the causes of antenatal hydronephrosis and detail
management options. A large majority of these patients can be treated safely and
effectively after birth.
PMID- 10771853
TI - Neurogenic bladder.
AB - Management of neurogenic bladder in children is challenging for the practising
clinician. This involves consideration of multiple and diverse factors which must
be balanced in an ever changing environment. Also the dynamics of a child's
growth must always be considered because it contributes to the ongoing
instability of the neurologic lesion. Prevention and proactive approaches have
become the mainstay of the therapy. It is not appropriate to wait for problems to
occur before treating these children, because changes that take place may not be
reversible, even if they are detected early. The clinician should be aware of the
various clinical presentations of neurogenic bladder dysfunction in children and
familiarize themselves with the modes of treatment available. Long term follow-up
is mandatory. Finally, the value of streamlining these children into society at
an early age must always be considered.
PMID- 10771854
TI - Exstrophic anomalies: recent advances and long-term outlook.
AB - Exstrophy-epispadias complex has been a difficult disease to treat. As in the
minds of the public and most physicians alike, these children are crippled with
life-long ailments and multiple operations. Much of the morbidity of this
condition relates to failure to preserve urogenital tract function in these
children. In recent years, through better understanding of the exstrophic anatomy
and improved surgical techniques, complete repair of the exstrophic anomaly has
become possible as soon as the child is born. Results of such closure indicate
that such repair is not only feasible but mandatory for a successful outcome.
Continence rate and cosmetic appearance are superior to the conventional 3-stage
technique. Such repair is also socially acceptable as the parents will bring home
a normal-looking baby with much fewer operations expected in the future. It is
anticipated that complete one-stage exstrophy closure in the newborn period will
revolutionize the outcome of all exstrophy patients.
PMID- 10771855
TI - Chest wall deformities.
AB - Children present with chest wall deformities to their pediatrician because of
physiologic and psychologic causes. We have a 22-year experience in the operative
management of more than 300 of these children. Initial evaluation should
accurately categorize the deformity, determine the severity, assess for
associated problems and refer the child at an appropriate time for further
management. Pectus carinatum is the most common deformity that can cause physical
pain from an intercostal neuropathy and psychologic pain from the unsightly
protuberance. Poland syndrome is managed by early correction of the hand
deformity and later correction of the chest wall deformity if necessary for
psychologic or functional reasons. Jeune syndrome and failure of sternal fusion
may have severe associated cardiopulmonary compromise. Each should be corrected
in infancy for the best results.
PMID- 10771857
TI - Education for primary pediatric care.
PMID- 10771856
TI - Post-operative pain management.
AB - For many years pediatric procedural and postoperative pain has been undertreated
or not treated. In some areas this practice still exists and is a likely
reflection of persistence of myths related to the infant's ability to perceive
pain. Such myths include the lack of ability to perceive pain or remember painful
experiences. New literature exists showing that these former beliefs do not hold
true. The appropriate management of postoperative pain is contingent on a
cooperative effort from pediatric surgeons, pediatric anesthesiologists,
pediatricians, and parents. There are many ways to treat postoperative pain. The
method of postoperative analgesia depends on the patient, underlying medical
conditions, the type of surgery, the patient's disposition following surgery
(inpatient vs. outpatient), and the physician's comfort level with a particular
analgesic regimen. Many pediatric anesthesiologists and surgeons have excellent
success with the utilization of regional anesthetic techniques as treatment for
postoperative pain. Caudal epidural blocks, ilioinguinal/iliohypogastric nerve
blocks, and penile nerve blocks are some of the commonly used blocks. These
blocks not only provide excellent postoperative analgesia, but are great adjuncts
to general anesthesia, thus, reducing the amount of general anesthesia required.
Additionally, the use of epidural opioids is extremely useful in patients
following major abdominal, thoracic, and orthopedic surgery. Traditional
medications such as oral and parenteral narcotics, non-steroidal anti
inflammatory drugs, and acetaminophen (paracetamol), are much more commonly used
to treat postoperative pain. Regardless of the analgesic regimen chosen, we must
assure our pediatric patients the least painful perioperative experience
possible.
PMID- 10771858
TI - Maternal biosocial factors affecting low birth weight.
AB - The causes of low birth weight (LBW) are multifactoral with genetic, placental,
fetal and maternal factors interplaying with each other. To assess the influence
of some of the maternal bio-social factors on the variance of birth weight, this
study was undertaken. A total of 984 consecutive live births delivered at an
urban hospital were analysed. The rate of LBW was 28.3% and preterms accounted
for 3.2%. A strong correlation existed between birth weight and maternal height,
weight, age, ANC visits and risk status at pregnancy. A short, malnourished,
young, unregistered or primiparous mother was associated with a higher rate of
LBW. On multiple regression analysis it was noted that maternal weight, parity
and ANC visits independently affected the birthweight of the new born. Therefore
emphasis needs to be given to maternal biosocial factors which are amenable to
improvement to reduce the incidence of LBW. This can be done by selectively
targeting interventions to improve nutrition, and curtailing parity and promoting
contraception.
PMID- 10771859
TI - Macronutrient and energy content of breast milk of mothers delivering
prematurely.
AB - The protein, lactose, fat and energy contents of the fore-milk of mother with
term (n = 23) and preterm (n = 29) infants were estimated on postpartum days 3,
7, 14 and 21. During the first 4 weeks of lactation, the mean (+/- SD) energy
(Kcal/dl), protein (g/dl), fat (g/dl) and lactose (g/dl) levels of the preterm
milk were: 56.39 (+/- 7.99), 2.17 (+/- 0.66), 2.30 (+/- 0.48) and 5.78 (+/-
0.99), respectively. The same for term milk were: 59.39 (+/- 8.30), 1.99 (+/-
0.70), 2.48 (+/- 0.53) and 6.24 (+/- 1.08), respectively. The differences in
composition between the term and preterm milk were not significant. The
composition of breast milk showed changes over the first 3 weeks of lactation.
With increasing post-partum days, there was a decline in protein content while
fat, lactose and energy contents increased. These trends were more pronounced for
preterm milk than term milk. The macronutrient composition and energy estimates
of preterm breast milk of Indian mothers in this study may be useful for
calculation of nutritional intake by premature neonates fed on expressed breast
milk.
PMID- 10771860
TI - Postnatal weight velocity patterns in very low birthweight infants.
AB - The care of very-low-birth-weight infants has improved over the years with
continuing changes in medical and nutritional management. In view of these
changes, there is a need to study the pattern of postnatal weight gain. Postnatal
weight gain patterns of 32 very-low-birth-weight infants were examined during the
first two months of life. Their mean gestational age was 29.5 +/- 2.3 weeks and
mean birth weight was 1255 +/- 258 grams. The babies were weighed daily and
weight changes were expressed in gram/day. All data were accurately recorded.
When mean weight gain profiles were obtained by computing increments at 1, 3, 7
and 14 day intervals, the babies weight gain showed a non-linear pulsatile
pattern which did not change even after full enteral nutrition had been
established. This study demonstrates that weight velocity profile in very-low
birth-weight infants is not linear as expected from available standard curves and
these data might therefore be considered while monitoring the adequacy of the
increments of the weight gain of the individual subjects.
PMID- 10771861
TI - End tidal carbon dioxide monitoring--its reliability in neonates.
AB - End tidal Carbon dioxide monitoring was undertaken prospectively in all
Ventilated neonates in our NICU admitted from March 1995 to August 1995
irrespective of the birth weight, gestational age and indication of ventilation.
The aim was to determine the correlation between ETCO2 and PaCO2 in various
clinical situations. The arterial blood gases were obtained in all ventilated
babies with simultaneous and continuous ETCO2 monitoring and were analysed by AVL
995 Hb blood gas analyser. ETCO2 was analysed by side stream technique by Datex
Cardiocap II monitor. A total of 152 samples from in-dwelling radial artery
catheters were analysed from babies with birth weight from 900 g to 3400 g,
gestation age from 28 to 42 wks and were ventilated for various indications like
Severe Birth Asphyxia (SBA), Meconium Aspiration Syndrome (MAS), Recurrent Apnoea
and Hyaline Membrane Disease (HMD). Statistical analysis was done in 10 groups to
see if the ETCO2 correlated with its corresponding PaCO2 value. The study groups
comprised three groups based on birth weight being < 1.5-2.5 kg and > 2.5 kg
three groups as per the gestational age being 28-31+6 wks, 32-36+6 wks and 37
41+6 wks and four groups as per the need for ventilation being Severe Birth
Asphyxia, Meconium Aspiration Syndrome, Apnoea of Prematurity and Hyaline
Membrane Disease. Results of the correlation analysis revealed that the
correlation coefficient in the study group ranged from 0.55 to 0.96 and was
statistically significant in babies > 2.5 kg and 1.5-2.5 kg, in term and preterms
32-36 wks, and in babies with MAS, SBA and Recurrent Apnoea. The correlation
coefficient was lowest in babies with HMD, being 0.55. The study showed that
ETCO2 correlates closely with PaCO2 in most clinical situations in neonates and
we recommend its use in all level III NICUs in ventilated babies.
PMID- 10771862
TI - Hematological responses to hydroxyurea therapy in multitransfused thalassemic
children.
AB - Fifteen multi-transfused thalassemic children between 3-6 years of age (seven
boys and eight girls) were administered hydroxyurea for 5 days and three such
cycles were repeated at 15 days interval. Rise in hemoglobin levels was observed
in 13, 8 and 7 cases, while rise in mean hemoglobin F was seen in 8, 11 and 10
cases following 1st, 2nd and 3rd course of hydroxyurea therapy respectively. Rise
in hemoglobin level was associated with transient rise in fetal hemoglobin level.
Though the changes in mean hemoglobin levels and hemoglobin F levels were
statistically insignificant, a definite trend of rise in hemoglobin and
hemoglobin F was observed.
PMID- 10771863
TI - Brainstem auditory evoked response in tuberculous meningitis.
AB - Brainstem auditory evoked response (BAER) abnormalities in tuberculous meningitis
(TBM) were determined in 50 cases of tuberculous meningitis (36 male and 14
female) and 50 normal healthy children. Fifty six per cent cases had abnormal
BAER findings. The commonest BAER abnormality observed in 32% was a combination
of prolonged latency and prolonged interval while unilateral and bilateral absent
response was observed in 4% cases. Prolonged latency was observed in 16%
patients. Seizure activities, modified glasgow coma scale (GCS), raised
intracranial pressure (ICP) and TBM stage III were significantly correlated with
abnormal BAER, while age, sex, duration of illness, depressed sensorium,
neurological deficit and CSF findings did not have a significant correlation with
abnormal BAER. Follow up could be done in ten patients only. All the three
patients with only prolonged latency had a normal BAER on follow up, two out of
four patients with prolonged latency and prolonged interval had normalization of
BAER while in three patients, initial as well as follow up BAER was normal. The
present study shows that BAER abnormalities are observed in more than fifty per
cent of the patients of tuberculous meningitis.
PMID- 10771864
TI - Infant and child mortality in Bhil tribe of Jhabua district.
AB - Nearly 25 million children are born in India every year of which almost 2.7
million die before attaining the age of five years. Forty seven per cent of
births take place in the four states, namely Uttar Pradesh, Madhya Pradesh, Bihar
and Orissa, while fifty per cent of all deaths below five years also take place
in these states. The present study was carried out in Jhabua district in which
five per cent villages of each tehsil were selected by random sampling.
Information was obtained on 430 households of 67 villages on infant and child
mortality, birth order, age, sex and cause of death. 38.2% households reported
the death of at least one child below the age of five years. Out of these 59.3%,
27.2% and 13.2% reported the death of one, two or three and more children
respectively. 46% of infant deaths or 29.3% of all deaths occurred in the
neonatal period. The major causes of death were preventable such as tetanus,
diarrhoea, measles, ARI and fever. 51.3% deaths were of children who were third
or more in birth order. 54.8% deaths were males and 47.59% were females. The
study shows the need for an effective Dai (Midwife) Training Programme to upgrade
the skills and an urgent necessity to improve the outreach services in remote
tribal areas to bring down the infant mortality.
PMID- 10771865
TI - Human immunodeficiency virus infection transmitted through breast milk.
AB - Perinatal acquisition of human immunodeficiency virus is responsible for most
cases of pediatric AIDS. Breast feeding has been found to carry a higher risk of
transmission of HIV and is not recommended to HIV infected mothers in the western
world. In our country we have to be aware of the increasing incidence of
pediatric AIDS and the varied constellation of symptoms it can present with.
Also, we have to ensure that safe blood is available to avoid transfusion
acquired diseases.
PMID- 10771866
TI - Familial male pseudohermaphroditism.
AB - Familial male pseudohermaphroditism (MPH) due to 17,20-desmolase deficiency is
rare. Here we present two siblings with MPH possibly due to 17,20-desmolase
deficiency. The first patient presented with unambiguous female external
genitalia and hypergonadotrophic hypogonadism. Chromosomal analysis revealed 46
XY. Ultrasound evaluation of pelvis revealed gonads in the inguinal canal, and no
uterus. These findings were confirmed on laparotomy. Histology revealed the
gonads to be testes. The second patient had ambiguous genitalia (perineoscrotal
hypospadias, bifid scrotum with palpable gonads) with a 46 XY chromosomal
pattern. Both patients had high plasma 17-hydroxy progestrone (17 OHP), low
normal dehydro epiandrosterone sulphate (DHEAS) and low plasma testosterone.
Plasma testosterone and DHEAS showed no response to ACTH or HCG. These features
are compatible with the diagnosis of 17,20-desmolase deficiency.
PMID- 10771867
TI - Oral clonazepam sensitive focal status epilepticus (FSE).
AB - Focal status epilepticus (FSE) and Epilepsia partialis continua (EPC) are
relatively uncommon disorders. Antiepileptic drugs do not usually alter the FSE
EPC. An 11 year old female patient with progressive neurologic deficits and FSE
showed a remarkable response to clonazepam, both clinically and
electrophysiologically.
PMID- 10771868
TI - Intramedullary spinal cord abscess.
AB - Intramedullary spinal cord abscess is a treatable cause of paraparesis. Magnetic
resonance imaging is an important diagnostic modality. Combination of
antimicrobial therapy and surgical intervention can provide good results in
patients with subacute presentation.
PMID- 10771869
TI - A case of aminolevulenic acid dehydratase deficiency porphyria (ALADP)
PMID- 10771870
TI - Molecular diagnosis of infectious diseases.
AB - The Polymerase Chain Reaction (PCR) is a revolutionary new means of amplifying,
i.e., replicating, selected DNA sequences in vitro. This procedure is highly
sensitive and rapid, requiring few hours for detection of amplified target DNA
whereas it often takes several weeks for the identification of many fastidious
organisms by culture. Studies have shown that as few as one microorganism can be
detected by PCR. Therefore, it is revolutionizing our ability in the diagnosis of
infectious diseases. Currently, this technique is very expensive and complex
which will probably restrict its immediate role for diagnosing infections where
the causative organism is impossible to culture or untypeable by conventional
means. As further progress occurs, however, this powerful technique will be
applied as a major new tool to diagnose infections and to the study of individual
genome variations.
PMID- 10771871
TI - Poisoning--old wine in new bottle.
PMID- 10771872
TI - Role and functions of Poisons Information Centre.
AB - The Poisons Information Centre (PIC) is a specialized unit providing information
on prevention, early diagnosis and treatment of poisoning and hazard management.
Most of the developed and many developing countries have well established poison
control centres with poisons information service, patient management facility and
analytical laboratory. In India, the National Poisons Information Centre (NPIC)
was established in February, 1995 in the Department of Pharmacology at the All
India Institute of Medical Sciences, New Delhi. The centre provides toxicological
information and advice on the management of poisoned patients adopted to the
level of the enquirer. The basis of this service are the databases on poisoning,
drug reactions and also the continuous and systematic collection of data from the
library. This information service is available round the clock. The PIC has the
training responsibility extending to medical and other health professionals and
community. The NPIC organized two successive training courses for medical
professionals and para professionals at all health levels. Further, NPIC is a
participant of INTOX project of IPCS/WHO, receiving regular yearly training on
the use of INTOX database. Laboratory service is an essential component of a
poisons control programme, providing analytical services on emergency basis to
help in diagnosis and management. The NPIC is developing facilities for quick
diagnosis of poisoning cases. Toxicovigilance and prevention of poisoning is
another major function of PIC. The Centre has prepared manuals and leaflets on
prevention and management cards on treatment of various poisonings. Thus the
Centre provides a service with considerable health benefits, reducing morbidity
and mortality from poisoning and gives significant financial savings to the
community.
PMID- 10771873
TI - Gastrointestinal decontamination in the emergency department.
AB - Pediatric poisoning is a problem commonly encountered in the emergency
department. After stabilization of airway, breathing, and circulation, one of the
goals of treatment is decontamination in order to limit poison absorption and the
resulting systemic toxicity. Decontamination modalities include gastric emptying
(ipecac and gastric lavage), inhibiting absorption (activated charcoal), and
catharsis (sorbital, magnesium citrate, and whole bowel irrigation). Each
modality is discussed. Choice of modality by the practitioner must be
individualized to each patient's situation.
PMID- 10771874
TI - Childhood poisoning in Sri Lanka.
AB - Poisoning in children is a common accident and poison information services should
be aware of the toxic agents responsible for poisoning in the community. A
retrospective hospital based study was performed, before the establishment of the
National Poisons Information Centre in Sri Lanka. There were 4,556 admissions of
poisoning to the selected hospitals in the Western Province in 1986 and of this,
540 (11.4%) were below 15 years. Males accounted for 66%. Kerosene oil was
responsible for 47% of the poisoning cases in less than 5 years age group, while
kerosene oil, pesticides and plants/mushrooms were the commonest toxic agents in
the 5 to 14 years age group. The case fatality rate was 3.2%.
PMID- 10771875
TI - Poisoning in children in Japan.
AB - The Japan Poison Information Centre (JPIC) received 31,510 inquiries about
poisoning in children under 6 years old being exposed to poison in the fiscal
year 1995. The most frequently implicated products were tobacco (20%) and the
peak age for ingestion of household products was 1 year and younger (83.3%).
Especially, the inquiries related to children less than 1 year old were 35.7% of
the cases. In contrast, the American Association of Poison Control Centers
(AAPCC) data showed that the most common poisonings were due to pharmaceutical
products and the inquiries related to children less than 1 year old were only
12.1%. The objective of this report was to find out the poison exposure in
children in Japan and to compare the data with that of AAPCC.
PMID- 10771876
TI - Children poisoning in Taiwan.
AB - Poisoning is a well known cause of morbidity and mortality in children. In
Taiwan, little information has been published regarding the status of pediatric
poisoning exposures. To provide more information on pediatric poisoning exposures
for the purpose of poison prevention, a retrospective study was designed and
conducted to analyse the data of National Poison Centre (NPC), Taiwan. All
telephone inquiries concerning poisoning exposures in those under 19 years of
age, received by NPC-Taiwan from July 1985 through December 1993, were included
in this study. The age, sex, reason for exposure, route of exposure, substances
involved and clinical outcome of those telephone calls were then analyzed. A
total of 5,812 inquiries concerning poisoning exposures in children were
recorded. Male exposures were more prevalent than females (59%) Vs. 41%)
Accidental exposures accounted for 77.7% of the cases and most were exposed by
the oral route. Substances most frequently ingested were household products,
benzodiazepines and pesticides. The data revealed a mortality rate of 1.4%.
Accidental poisoning exposures from household products and drugs remain a
significant problem for those younger than 6 years of age. Further education of
parents and care takers and the employment of child-resistant containers are
needed to prevent cases of pediatric poisoning. Reduction of amphetamine abuse in
adolescents is also of major concern and deserves more attention.
PMID- 10771878
TI - Plant poisoning: a hospital-based study in Sri Lanka.
AB - This is a prospective hospital based study of 148 cases of plant poisoning seen
by the author during a 12 year period. All cases were accidental. There were 2
deaths. Some measures to reduce the incidence of plant poisoning in Sri Lanka are
listed.
PMID- 10771877
TI - Acute iron poisoning.
AB - Accidental iron ingestion is not uncommon in children and has become a leading
cause of unintentional pharmaceutical ingestion fatality. Difficulty in obtaining
urgent serum iron levels in majority of hospitals in India, lack of objective
indices for starting and stopping the chelation therapy and the cost of chelation
therapy, all pose a significant challenge for a clinician in managing an acutely
intoxicated patient. This review emphasizes the need for early recognition and
correct intervention of a child with acute iron overdose to avoid undue morbidity
and mortality.
PMID- 10771879
TI - Enhancement in seroconversion to measles vaccine with simultaneous administration
of vitamin A in 9-months-old Indian infants.
AB - The mutual interactions of measles vaccine and vitamin A dose when administered
simultaneously to 9 month old infants are explored in this study. One hundred
healthy infants of 9 months of age received EZ strain of measles vaccine in the
routine immunization clinic along with either 100,000 IU of vitamin A or a
placebo orally. Blood samples were collected before and 4 weeks after
intervention. They were coded and analysed for serum retinol and Hemagglutination
Inhibition (HI) antibodies to measles. Ninety five per cent of the infants were
seronegative to measles prior to vaccination with a seroconversion rate of 63% in
the control group and a significantly higher percent of 83.7% in the experimental
group (P < 0.01). Seroconversion was not related to initial serum retinol levels
in either of the groups. 42% of infants had serum retinol levels less than 20
ug/dl before administration of the vaccine and both the groups showed improvement
in vitamin A status following intervention, the increase being significant in the
experimental group (from 22.4 +/- 1.32 to 26.0 +/- 1.07; P < 0.05). The results
indicate that majority of the infants at 9 months of age were seronegative to
measles. Seroconversion to measles vaccine in the routine immunization clinics
was low. Simultaneous administration of vitamin A and measles vaccine had
beneficial effects on vitamin A status as well as seroconversion rates to the
vaccine in 9 months old infants.
PMID- 10771880
TI - Seroconversion following killed polio vaccine in neonates.
AB - The study was carried out to evaluate the efficacy of IPV in neonates and to
study the additive effect of IPV or OPV at birth on seroconversion with three
subsequent doses of OPV. Addition of IPV or OPV at birth to the conventional OPV
schedule resulted in significantly higher seroconversion rates than in the
controls, who received three doses of OPV. Three doses of IPV beginning from
birth resulted in significantly better seroconversion rates than in the control
group. Children receiving 3 doses of IPV showed significantly greater
seroconversion rates against type III polio virus than those receiving IPV/OPV at
birth followed by 3 doses of OPV. The difference in the seroconversion rates
against the other virus types was not significant. A significantly greater number
of children who received some vaccine at birth (IPV or OPV) were protected
against poliomyelitis by 6 weeks age as compared to those who received no
immunization at birth. The study recommends that seroconversion rates following
three doses of IPV are satisfactory. Addition of IPV or OPV at birth to the
conventional schedule markedly increases the seroconversion rates. Immunization
can be started at birth to ensure early protection against poliomyelitis.
PMID- 10771882
TI - Early neonatal morbidity and mortality in 'at-risk' and 'normal' term
pregnancies.
AB - It is a universally known fact that maternal well-being is related to neonatal
health. This case-control study aims to assess the pattern and strength of
association of neonatal morbidity and mortality (in first 7 days of life) in
relation to the presence of obstetric & medical risk factors in the mother
(indicating maternal ill-health). In 250 cases (at-risk pregnancies), 75 (30%)
developed neonatal illnesses while 17 (6.8%) perinatal deaths occurred in first
seven days. In the same number of controls (uncomplicated pregnancies) there were
only two perinatal deaths and lesser number of newborns (45/250, 16.4%) developed
neonatal diseases in the first 7 days. Perinatal deaths, (still births and early
neonatal deaths), (OR = 9.05; AR = 88.2%) and neonatal illnesses (OR = 2.2 and AR
= 45) were strongly associated with presence of maternal risk factors. This study
supports the fact that 'at risk' pregnancies have highly significant chances of
developing early (first 7 days) neonatal morbidity (p < 0.001) and mortality (p <
0.001). Still births also occurred significantly more (p < 0.005) in number among
'at risk' (cases) than normal term pregnancies (controls).
PMID- 10771881
TI - Dexamethasone as an adjunctive treatment of bacterial meningitis.
AB - This study was conducted on 77 Libyan infants and children aged month to 10 years
with acute bacterial meningitis. Upon admission, the patients were divided
randomly in two groups. Group I (38 patients) received ceftriaxone plus
dexamethasone i.v. Group II (39 patients) received ceftriaxone alone. Both groups
were compared for mean changes in CSF sugar, CSF protein and CSF polymorph count
at 4th day of treatment. There was a significant difference between the two
groups in CSF sugar and protein changes (P < 0.05) but not in CSF polymorph (P >
0.05). Both groups showed prompt clinical response and similar occurrence of
acute complications, fatality rate and permanent neurological sequelae. However,
group I manifested shorter duration of fever (P < 0.05). Dexamethasone improved
the inflammatory reaction in acute bacterial meningitis and shortened the
duration of fever but it did not have any significant effect on the fatality and
the occurrence of neurological sequelae of this disease.
PMID- 10771883
TI - Nosocomial sepsis in neonates with single lumen vascular catheters.
AB - Catheter-related sepsis is commonly encountered in the neonatal intensive care
unit. We retrospectively studied infants with vascular catheters at 2 NICUs. Data
were obtained from the computerised admission records available at both the
hospitals. Our aims were to describe the clinical and microbial profile of
nosocomial sepsis in infants with vascular catheters [umbilical artery (UA),
umbilical venous (UV), central venous Broviac (CV), percutaneously placed central
venous (PC), peripheral artery (PA)], and to determine the association between
catheter type, duration and sepsis in a subset of the population. Nosocomial
sepsis (positive blood culture after the 3rd postnatal day) occurred in 217 of
2091 (10.4%) infants. Infected infants, in contrast to non-infected, had a
significantly (P < 0.001) greater number of multiple catheters (2.3 vs 1.4) had
lower birth weights (1.2 vs 2.1 kg), were younger (28 vs 33 weeks) and had lower
1 and 5 minute Apgar scores (4.3 and 6.7 vs 5.5 and 7.4). The most common
organism was coagulase negative Staphylococcus. In a subset population as
analyses revealed, longer duration of UA use was associated with higher infection
rates [13.6% with UA use for > or = 8 days vs 1.3% for < or = 7 days (P <
0.0001)]. PC use had a lower rate of sepsis than CV use (5.1% vs 15.2%; P <
0.05). Use of intravascular catheters should be balanced between the need for
vascular access and the risk of sepsis.
PMID- 10771884
TI - Neonatal bacteremia due to high level aminoglycoside resistant (HLAR)
enterococci.
AB - A study was conducted to determine the drug resistance pattern of enterococci
isolated from cases of neonatal bacteremia. A total of 41 strains of enterococci
were isolated of which 35 (85.4%) were Enterococcus faecalis and 6 (14.6%) were
Enterococcus faecium. A total of 3 (8.6%) strains of E. faecalis and 2 (33.3%) E.
faecium strains showed high level aminoglycoside resistance (HLAR). None of the
enterococci tested were vancomycin resistant. Drug resistance was more common
among E. faecium strains. All clinically significant isolates of enterococci
should be tested for their antibiotic sensitivity pattern including HLAR, and for
treatment, antibiotics are selected based on in vitro antibiotic sensitivity test
results.
PMID- 10771885
TI - Neonatal polycythemia.
AB - 461 consecutive inborn babies, delivered during the period September 1993-March
1994 were subjected to a microhematocrit assessment at 6 hours of age to
determine the incidence of polycythemia. 47 babies (inborn and out born),
admitted to the neonatal unit with confirmed polycythemia were studied for
clinical and laboratory abnormalities. These 47 babies were then randomly
assigned to receive partial exchange transfusion with either normal saline or
fresh plasma. The incidence of polycythemia was 27 of 461 (5.8%). 23 of 27
(85.1%) were term babies and 15 of 27 (55.5%) were small for gestational age. 14
of 27 (51.1%) babies had mothers who had pregnancy induced hypertension. Feeding
problems (16/47) and lethargy (25/47) were the commonest symptoms (34% and 51%
respectively). 25 of 47 (51%) babies had hypoglycemia and 5 of 47 (10.6%) had
hypocalcemia. Thrombocytopenia was seen in 13/47 (27.65%) of cases. 24 babies
received normal saline and 23 received fresh plasma for partial exchange
transfusion. The immediate post-exchange fall in hematocrit was significant in
both groups and this was well sustained over the following 48 hours. However,
improvement in clinical and laboratory parameters was more remarkable with fresh
plasma. Polycythemia appears to be a real clinical entity in neonates in India
and babies with known risk factors should be actively screened for this
condition. Once diagnosis is established special attempts should be made to rule
out hypoglycemia. For treatment of polycythemia fresh plasma is preferable for
partial exchange transfusion but normal saline appears to be an adequate
substitute.
PMID- 10771886
TI - Breast-feeding and human immunodeficiency virus.
AB - Breast-feeding provides nutritional, immunological, and psychological benefits.
It protects children from mortality and morbidity associated with diarrheal
diseases, pneumonia and other infections. Breast feeding has also been shown to
prolong the interval between births and thereby improve child survival and
maternal health. However, studies suggest that in certain populations, breast
feeding may account for nearly 14% of perinatal human immunodeficiency virus type
1 (HIV-1) transmission. It is therefore important that the risk of HIV-1
infection through breast feeding be weighed against the morbidity and mortality
associated with bottle feeding. This paper discusses the literature dealing with
breast feeding in women with HIV-1 infection. Specifically, the review addresses
the issues surrounding infant mortality in areas of different HIV-1 prevalence
where breast-feeding or bottle-feeding may be employed. Analysis suggests that
the benefits of breast-feeding or bottle-feeding may be employed. Analysis
suggests that the benefits of breast-feeding can substantially outweigh the
putative risk of HIV-1 transmission unless the prevalence of HIV-1 infection is
high or the difference in mortality between breast-fed and bottle-fed infants is
very low.
PMID- 10771887
TI - Neonatal ovarian cyst associated with intestinal obstruction.
AB - Cystic and solid tumors of the ovary are rare during the newborn period and
infancy. We present the case of a term female infant born to a mother with 24
years of age and found to have a cystic abdominal mass through prenatal
sonographic evaluation in the third trimester. The cyst was also demonstrated by
postnatal abdominal ultrasonography. Because of the clinical and radiological
findings of intestinal obstruction, laparatomy was performed at the age of three
days and a cyst of 10' 8' 8 cm was found in the right ovary. Pathological
examination of cyst revealed a teach-lutein cyst.
PMID- 10771888
TI - Type Ib glycogenosis.
AB - Type Ib glycogenosis is a rare glycogen storage disorder resulting from a defect
in the enzyme, glucose-6-phosphatase microsomal translocase. We report a case of
Type Ib glycogenosis in an 18 month-old male child who presented with a history
of hypoglycemic seizures and recurrent infections and had a massive hepatomegaly,
recurrent hypoglycemia, hyperuricemia, hypertriglyceridemia, neutropenia and
fasting lactacidemia which decreased sharply on glucose administration.
PMID- 10771889
TI - Wolman's disease.
PMID- 10771890
TI - Acute myeloid leukemia in TAR syndrome.
AB - TAR syndrome is a rare inherited autosomal recessive disorder with a mortality
rate of 30-40% mainly as a result of haemorrhage, in the first year of life. Most
of the infants recover from the effects of thrombocytopenia and associated
haematological complications with the modern medical care. Very rarely, the
outcome is fatal, with the occurrence of acute leukemias.
PMID- 10771891
TI - Serum free carnitine levels during valproic acid therapy.
PMID- 10771892
TI - Brain imaging during seizure: ictal brain SPECT.
AB - The role of single photon computed tomography (SPECT) in presurgical localization
of medically intractable complex partial epilepsy (CPE) in children is reviewed.
99mTechnetium Neurolite, a newer lipophylic agent with a high first pass brain
extraction and little or no redistribution is injected during a seizure, while
the child is monitored with a video recording and continuous EEG and SPECT
imaging is performed in the next 1-3 hours with the images representing regional
cerebral profusion at the time of injection. On SPECT studies performed with
radiopharmaceutical injected during a seizure, ictal focus is generally
hypervascular. Other findings on ictal brain SPECT include hypoperfusion of
adjacent cerebral cortex and white matter, hyperperfusion of contralateral motor
cortex, hyperperfusion of ipsilateral basal ganglia and thalamus, brain stem and
contralateral cerebellum. Ictal brain SPECT is non-invasive, cost effective and
highly sensitive for localization of epileptic focus in patients with intractable
CPE.
PMID- 10771894
TI - Epileptic encephalopathies in early infancy.
AB - Of the epileptic syndromes beginning in early infancy, we described the clinical
and electrical characteristics of early myoclonic encephalopathy (EME) and
Ohtahara syndrome (OS), and the differential diagnosis between the two syndromes,
reviewing previous articles and our own study of 6 cases with EME and 15 cases
with OS. With regard to the clinical seizure types, the main seizure type was
tonic spasms in OS while myoclonias, especially erratic myoclonias, and frequent
partial seizures were predominant in EME. The suppression-burst (S-B) pattern was
a common feature of both syndromes, although their form, time of appearance, and
duration of appearance differed considerably. The S-B pattern in OS was
characterized by periodic and consistent appearances during both waking and
sleeping states, whereas in EME, the S-B pattern was enhanced by sleep and often
not manifested in the awake states. OS showed a specific pattern of evolution as
age-dependent epileptic encephalopathy with concomitant EEG change while EME had
no specific evolution with age. In OS, obvious brain lesions such as brain
malformations were often seen. In contrast, frequent occurrence of familial cases
suggested some kind of congenital metabolic disorder as the etiological factor in
EME.
PMID- 10771893
TI - Myoclonus and epilepsies.
AB - The possible associations of myoclonic phenomenae, progressive or non-progressive
encephalopathies and epileptic features are reviewed, with special emphasis on
pediatric age. This leads to recognize the following five groups of conditions:
(1) Myoclonus without encephalopathy and without epilepsy; (2) Encephalopathies
with non-epileptic myoclonus; (3) Progressive encephalopathies presenting
myoclonus seizures of epileptic syndromes (Progressive myoclonus epilepsies); (4)
Epileptic encephalopathies with myoclonic seizures; (5) Myoclonic epilepsies.
Within the first group, which also includes physiologic myoclonus, a more
thorough description of "Benign sleep myoclonus of newborn" and "Benign myoclonus
of early infancy" is given. Characteristics of group 2 are "Kinsbourne Syndrome"
and certain types of "Hyperekplexia" which pose interesting differential
diagnosis with stimulus-sensitive epilepsies. In group 3, the concept of
progressive encephalopathies is stressed. The fourth group refers to severe
epilepsies, mainly on infancy and childhood, which lead to mental retardation
irrespective of their aetiology. Group 5 comprises the true myoclonic epilepsies,
differentiating syndromes recognized as idiopathic--such as "Benign myoclonic
epilepsy of infancy" and "Juvenile myoclonic epilepsy"--from those which are
cryptogenic and carry a more cautious prognosis--as "Cryptogenic myoclonic and
myoclonoastatic epilepsies" and "Severe myoclonic epilepsy of infancy". Other
epileptic syndromes not usually considered as myoclonic epilepsies, but
presenting sometimes as myoclonic seizures, are finally referred.
PMID- 10771895
TI - Ischemic strokes in children.
AB - Ischemic stroke is an uncommon, but significant cause of disability in childhood.
Children with strokes present with predictable deficits as adults do; however,
fever and seizures at stroke onset are more common in children than in adults.
Strokes in children have diverse etiologies and require extensive evaluation.
Etiology remains obscure in up to half of the patients. Prognosis in childhood
stroke is not benign and up to 50% of pediatric stroke patients have chronic
sequelae. Emerging therapies may alter prognosis in certain populations of
children at risk for stroke, but more research is necessary.
PMID- 10771896
TI - Sleep disorders in school-age children.
AB - This article on school age children reviews relevant issues in sleep physiology,
the classification of sleep disorders, their clinical and laboratory assessment,
some common sleep disorders, the sleep-epilepsy relationship, as well as the
impact of daytime sleepiness on higher cortical functions.
PMID- 10771897
TI - Brain stem evoked potentials in childhood neurological diseases.
AB - This review article tries to highlight the most important information available
at present on the use of brainstem acoustic evoked potentials (BAEPs) in child
neurology. It lists the main original papers with considerable materials and
discusses the main territories of use in child neurology according to the
diagnosis. Particular emphasis has been placed on the neurodegenerative and
neurometabolic disorders, asphyxia, head trauma, brain tumours, autoimmune NS
diseases and evaluation of dizziness. It summarizes the importance of BAEPs in
child neurology relying, on the data from the literature and the experience and
opinion of the author.
PMID- 10771898
TI - Rett syndrome.
AB - Rett syndrome (RS) is a neurological disorder that mainly, and possibly
exclusively, affects girls. After its description in 1966 by Andreas Rett in the
Wiener Klinische Wochenschrift, awareness and interest in RS were enhanced by the
1983 report of Hagberg et al. in the Annals of Neurology. Diagnosis, and indeed
the hypothesis that it exists, continue to be based upon a consistent
constellation of clinical features observed in thousands of female patients world
wide. A diagnostic marker has not been identified. Notwithstanding this serious
limitation, it is generally agreed that RS is a distinct entity and that it is
genetically determined. Although it is associated with devastating loss of
function between infancy and the fifth year of life, its course becomes
relatively static thereafter, setting it apart from most of the genetic
neurodegenerative disorders of childhood. Neuropathological and neurochemical
studies call attention to RS as a neurodevelopmental disorder. Clarification of
its pathogenesis may provide new insight into normal brain development. This
report summarizes existing information and concepts about RS, and presents recent
advances.
PMID- 10771899
TI - Molecular diagnosis of neurological disorders in India.
AB - The last decade has seen remarkable advances in sequencing the human genes. There
are more genes expressed in the brain than any other organ. The knowledge
regarding the genome has led to tremendous progress in molecular characterization
of the genes responsible for neurological disorders. The present review covers
the molecular diagnosis of Duchenne muscular dystrophy, spinal muscular atrophy,
and fragile X syndrome. These are three neurologic disorders common in India for
which facilities of molecular diagnosis are currently available in the country.
As a result of funding by the Department of Biotechnology of the Government of
India, a number of molecular diagnostic centers are being established. It is
hoped that molecular diagnosis of many more neurological disorders will soon
become available in India.
PMID- 10771900
TI - Clinical profile and management of PDA in neonates.
AB - Patent ductus arteriosus (PDA) is recognised more often with increasing survival
of preterm babies. The pharmacological closure of ductus by indomethacin has
changed the management of PDA. Twenty neonates admitted over a period of 21
months to Neonatal Intensive Care Unit (NICU) of M.S. Ramaiah Medical College
hospital, Bangalore, who were diagnosed to have PDA, were analyzed. The
objectives of this retrospective analysis were to study the clinical profile, the
efficacy of oral indomethacin and the outcome of PDA. 2-D and Doppler
echocardiaography were used to confirm the clinically suspected PDA. These
neonates were treated with 3 doses of oral indomethacin (0.2-0.25 mg/kg/dose 12
hourly) along with fluid restriction and oxygen. Echocardiography was repeated to
demonstrate the closure of PDA. The incidence of PDA was 2.3% of total NICU
admissions. Seventy percent of this cohort were < 32 weeks of gestation, 55% had
birth weight of < 1500 gms. Seventy percent (14) neonates had onset of PDA after
48 hrs of life. 81.25% of neonates responded to indomethacin and overall survival
rate in treated group was 67%. Drug related complications were noted in 2
newborns. This study illustrates the utility of echocardiography in diagnosing
and monitoring PDA in preterm and low birth weight babies with high index of
suspicion of this common congenital heart disease. Pharmacological intervention
with indomethacin is rewarding with acceptable results.
PMID- 10771901
TI - The pediatric non-epileptic seizure.
AB - In order to observe the pattern of behaviour, the underlying stressors and
possible association with psychosocial factors in Pediatric Non-Epileptic Seizure
(NES); 22 children with unusual feature of poor control of their symptoms were
studied. Detailed historical account, examination including psychiatric
evaluation, EEG and CT Scan in all and video recording with provocative
procedures were done wherever feasible. Ten males (45.5%) and 12 females (55.5%)
were in the age range from 5 through 18 years. Ten children (45.5%) had
uncontrolled symptoms while 12 (55.5%) had unusual symptoms. History and eye
witness account was accurate in 15 (68.1%). Separate video recording could be
done in 6 (27.3%) while induction with provocative procedures was possible in 7
(31.8%) older children. Pointers to NES were: stress induced events 13 (59.4%),
persistence of symptom despite adequate treatment 10 (45%), lack of physical
injury 20 (90.0%), symptoms when some one was around 12 (54.5%), lack of
postictal phenomenon 12 (54.5%), lack of incontinence 22 (100%), positive gains 6
(27.0%) and gradual onset and offset 12 (54.5%). Nine children (40.0%) had
coexisting epilepsy and NES. The present study addresses the need of awareness,
provocative procedure, video recording of the event and individualised management
of NES in our circumstances where video EEG facility is not available.
PMID- 10771902
TI - Risk factors for cerebral palsy.
AB - Cerebral palsy is a major cause of crippling in children, but it's etiology is
poorly understood. This case control study was done to assess some of the
identified risk factors for cerebral palsy, 125 cerebral palsy cases selected
from hospital clinic and 125 age and sex matched neighbourhood controls, all aged
less than 5 years and residing in Delhi (India) were studied. Information
regarding antenatal, natal and postnatal period was collected by mother's
interview, and wherever available, from hospital records with the study subjects.
Most common type of cerebral palsy was spastic (88%). Quadriplegia was the
commonest topographical subtype (86.4%). Birth asphyxia was found to be present
in only 25.6% of cases. The commonest risk factor amongst cases was low birth
weight (28.8%). The multivariate odds ratios (confidence limits) for the risk
factors found to be significantly associated with cerebral palsy were 36.1 (7.76
160) for birth asphyxia, 13.8 (4.95-38.3) for low birth weight, 37.4 (4.47-313)
for neonatal convulsion, 23 (4.7-112) for neonatal jaundice, 14.4 (3.69-56.4) for
neonatal infection, 24.9 (2.78-223) for instrument assisted delivery and 15.4
(1.57-152) for antepartum hemorrhage. Precipitate labour, caesarean section,
twins, toxemia, breech delivery and head injury were not found to be
significantly associated with cerebral palsy. Thus birth asphyxia, low birth
weight, neonatal convulsions, neonatal jaundice, neonatal infection, instrument
assisted delivery and antepartum hemorrhage are significant risk factors for
cerebral palsy.
PMID- 10771903
TI - Spinal muscular atrophy--a clinicopathologic analysis.
AB - In this retrospective study the clinical features in 16 children with spinal
muscular atrophy (SMA) were reviewed and classified into three stages. The muscle
biopsy specimen were routinely processed with liquid-nitrogen-isopentane and 8
micron thick frozen-sections were studied for histochemical changes. The clinical
features in Type III SMA resembled with limb-girdle muscular dystrophy and the
muscle biopsy was useful in distinguishing these two entities. It is being
evaluated that prenatal diagnosis of SMA is possible with DNA technology
developed recently in our country.
PMID- 10771904
TI - Medulloblastoma--a retrospective analysis.
AB - A retrospective review of 45 patients was undertaken at the All India Institute
of Medical Sciences to assess the outcome and prognostic factors for these
patients who received post operative radiotherapy with or without chemotherapy
for medulloblastoma. The median age at diagnosis was 11 years, with 34 males and
11 female patients. Thirty four tumours were confined to midline structures, and
11 were localised to one cerebellar hemisphere or involved midline and lateral
structures. Complete macroscopic removal was achieved in 24 patients and subtotal
removal in 21 patients. Forty one patients underwent craniospinal irradiation and
27 patients received adjuvant chemotherapy. Median overall and disease free
survival was 57 and 31 months respectively and 3 year overall survival was 76%.
The addition of adjuvant chemotherapy was a significant factor for disease free
survival (p = 0.01) whereas extent of surgery (total vs subtotal, p = 0.01) was a
significant factor for overall survival only. Eleven patients developed recurrent
disease, with ten relapsing first in the posterior fossa.
PMID- 10771905
TI - Anterior encephaloceles.
AB - Sixty five children with anterior encephaloceles were retrospectively studied for
clinical presentation, radiological findings, surgery and outcome. They were
sampled over a 22 years period (Jan 1973-Dec 1994). Only 6 children were above 10
years of age. Naso-ethmoid type was the most frequent type, encountered in 45
patients. Surprisingly, nasopharyngeal type was observed in 6 children. Swelling
over the nose and hypertelorism were usual findings, recorded in 53 and 50
patients respectively. Ten patients, each, had CSF rhinorrhoea and proptosis. In
fifty four patients CT scans were performed and bony defect could be demonstrated
in 45 of them. Three each had agenesis of corpus callosum and porencphalic cysts.
Six patients with hydrocephalus underwent ventricul operitoneal shunt, prior to
surgical repair of the encephaloceles. In fifty nine patients, one stage repair
of encephalocele and hpertelorism was carried out. There was one postoperative
mortality. Ten patients developed postoperative CSF rhinorrhoea, among them 6
required percutaneous lumbo-peritoneal shunt. This study brings out the rare
cases of nasopharyngeal encephaloceles and highlights the need for one stage
repair in these patients.
PMID- 10771906
TI - Pelizaeus-Merzbacher disease.
PMID- 10771907
TI - Guillain Barre syndrome associated with hepatitis B vaccination.
PMID- 10771908
TI - Two-dimensional ultrasonographic findings of atelectatic lung segments.
AB - Thirteen cases with pulmonary atelectasis were examined by two-dimensional
sonography in our clinics between October 1990 and April 1993. Patients' ages
ranged from 2 to 16 years. Five patients revealed atelectasis with pleural
effusion and eight patients had only atelectasis. Two-dimensional sonography
showed a solid mass indistinguishable from lung parenchyma in patients with
atelectatic lung segment without pleural effusion while atelectatic segment was
readily identified in those with pleural effusion. We conclude that sonography is
a useful and non-invasive technique in differentiating cardiac from extracardiac
masses, because atelectatic lung segment with moderate to large pleural effusion
may mimic intrapericardial masses.
PMID- 10771909
TI - Congenital megalourethra.
AB - Congenital non-obstructive dilatation of penile urethra (megalourethra) can
result from absence of corpus spongiosum alone (scaphoid) or along with the
absence of corpora cavernosa (fusiform). Associated urogenital or other systemic
anomalies are usually present and require detection and appropriate management.
Urethroplasty (Nesbitt) gives desirable results. Condition has been reviewed with
report of a case.
PMID- 10771910
TI - Abdomino-scrotal lymphangioma.
AB - Retroperitoneum, pelvis and scrotum are unusual sites of lymphangiomas.
Retroperitoneal lymphangiomas presenting as inguino-scrotal masses are extremely
rare. An unusual case of retroperitoneal lymphangioma extending into scrotum,
presenting as acute scrotum is reported due to its unusual location. Complete
surgical excision with careful attention to avoid damaging contiguous structures
is the treatment of choice.
PMID- 10771911
TI - Central pontine myelinolysis.
AB - A 9 year old boy presented with fever, drowsiness, quadriparesis and facial
myokymia. MRI showed demyelination in the pontine region. A diagnosis of central
pontine myelinolysis was made. Literature review revealed the rarity of
uneventful recovery as has been seen in our case.
PMID- 10771912
TI - Seizures in neonates and young infants due to hypomagnesemia.
PMID- 10771913
TI - Tracheo-oesophageal fistula with hydrocephalus.
PMID- 10771914
TI - Reproductive health/family planning and the health of infants, girls and women.
AB - The 1994 International Conference on Population and Development developed
international consensus amongst health providers, policy makers, and group
representing the whole of civil society regarding the concept of reproductive
health and its definition. In line with this definition, reproductive health care
is defined as the constellation of methods, techniques and services that
contribute to reproductive health and well-being by preventing and solving
reproductive health problems. Reproductive health care saves lives and prevents
significant levels of morbidity through family planning programmes, antenatal,
delivery and post-natal services, prevention and management programmes for
reproductive tract infections (including sexually transmitted diseases and
HIV/AIDS), prevention of abortion and management of its complications, cancers of
the reproductive system, and harmful practices that impact on reproductive
function. Reproductive health care needs are evident at all stages of the life
cycle and account for a greater proportion of disability adjusted life years
(DALYS) in girls and women than in boys and men. Reproductive health protects
infant health by enabling birth spacing and birth limitation to be practiced
through family planning. The prevention and early detection of reproductive tract
infections, including sexually transmitted diseases and HIV, through the
integration of preventive measures in family planning service delivery not only
improves the quality of care provided but is also directly responsible for
improvement in survival and health of infants. Addressing harmful practices such
as son preference, sex selection, sexual violence and female genital mutilation
complements the positive impact of planned and spaced children through family
planning services on infant mortality and the reproductive health of young girls
and women. They are also in addition to prenatal, delivery and postnatal
services, positive determinants of low maternal mortality and morbidity and are
integral to the promotion of reproductive health in women of child bearing age.
Reproductive tract infections, including sexually transmitted diseases and HIV
contribute to significant level of ill-health in women of reproductive age and
continue to pose a threat through the menopause which in turn brings with it
increasing risk of cancers of the reproductive system.
PMID- 10771915
TI - Families regarded the general practitioner as their primary care giver.
PMID- 10771916
TI - Inflammatory diseases of the ear.
AB - The inflammatory diseases of external and middle ear are one of the commonest
conditions encountered by the pediatric physician. Inner ear inflammations are
less common and need special and urgent attention. Special management in each
case requires detailed history, examination, necessary investigations and
appropriate referral to otolaryngologist when necessary. The article is aimed to
help formulate a plan in managing the inflammatory conditions of ear. Otalgia
constitutes the most prominent of the symptoms in external and middle ear
inflammations whereas vertigo, tinnitus and sensory hearing loss form the symptom
complex for inner ear infections. It is necessary to understand the basic
pathophysiology of the inflammatory condition to be able to institute a targetted
treatment. The audiometry impedance studies, microbiology of discharge and
occasionally ABR and CT scan from the mainstay of investigative workup. The
treatment is specific and based on the precise diagnosis. It often requires the
help of an otolaryngologist. Decisions may have to be made with regards to the
need for any surgical intervention particularly in acute otitis media, an
external canal abscess or an acute mastoiditis. A case of chronic otitis media
with facial palsy or vertigo (labyrinthitis being a possibility) needs urgent
intervention.
PMID- 10771917
TI - Middle ear effusion in children.
AB - Acute otitis media (AOM) and otitis media with effusion (OME) in children can
present with a variety of middle ear effusions (MEE). Even though the character
of the effusion may vary, the underlying pathogenesis is often similar. In the
last decade, there has been an abundance of new information in the fields of
immunobiology and immunochemistry to explain the chronicity of MEE. There are
also studies examining the efficacy of vaccination and immunoprophylaxis for
recurrent AOM. Diagnosis of otitis media (OM) in a child can be difficult but
good visualization by pneumatic otoscopy improves the accuracy of diagnosis of
OME. The development of increasing bacterial resistance to antimicrobial therapy
reinforces the need to be more rational in treating AOM and OME. The variability
of the natural history and the long term sequelae of OME makes medical management
more difficult. All children with chronic MEE should have audiologic evaluation.
Surgery is recommended should the condition be refractory to medical therapy or
if the complications of MEE develop.
PMID- 10771918
TI - Foreign bodies of the upper aerodigestive tract.
AB - Foreign bodies of the upper aerodigestive tract in the pediatric population are a
common occurrence. However, despite significant advances in prevention, first aid
and endoscopic technology, they remain a diagnostic and therapeutic challenge.
Early diagnosis is the key to successful and uncomplicated management of these
accidents. An orderly and systematic approach to these patients including a
careful history, physical exam and radiographic studies is detailed in this
review.
PMID- 10771919
TI - Evaluation of head and neck masses.
AB - There is always concern for a malignancy or other serious disease when a child
presents with a chief complaint of a neck mass. However, a neck mass in child is
commonly inflammatory or congenital rather than neoplastic. A complete history
and physical exam will often provide enough information to guide management and
reassure the concerned parents. In some cases, laboratory tests, radiologic
studies or a surgical procedure may be necessary to determine a specific
diagnosis and treatment plan. An organized and systematic approach is recommended
and detailed in this review.
PMID- 10771920
TI - Auditory brainstem responses in high risk and normal newborns.
AB - We studied the auditory brainstem responses of 50 high risk neonates from NICU
and compared with those of 25 normal neonates in order to determine the
percentage of significant auditory impairment in NICU and correlated it to
various risk factors. Infants with the risk factors of low birth weight,
hyperbilirubinemia, asphyxia, septicemia and meningitis were included in the
study group. All the 150 ears were tested at 4 intensities 30 dB, 46 dB, 60 dB
and 75 dB. The study recorded prolongation of latency of wave V and I-V Interwave
interval in the study group with a statistically significant difference denoting
an impaired condition. Incidence of significant auditory impairment was 18%. On
follow up at 6 months incidence of persistent auditory abnormality was 4%. On the
basis of this study it is suggested that all high risk neonates should undergo
screening for hearing impairment.
PMID- 10771921
TI - The identification and management of deaf children.
AB - Deafness is defined as the inability to use hearing as a primary channel for
receiving speech, even with amplification. Hearing loss, on the other hand, is
hearing impairment of various degrees that could be unilateral or bilateral. In
the United States, approximately one out of every 1,000 children is born deaf
with 3-5 being born with less severe degrees of hearing impairment. Deafness
present at birth could be due to genetic abnormalities or due to injury to the
developing auditory system or due to developmental anomalies of this system.
Deafness can also develop after birth and, in broad terms, the cause can be
toxic, infectious, neoplastic, traumatic or degenerative. The purpose of this
paper is to: (1) review the effects of deafness on the child, (2) discuss the
causes of deafness, (3) describe the clinical characteristics which allow early
diagnosis and the algorithm otolaryngologists use to investigate a child
suspected to be deaf, (4) describe the management of the deaf child and finally,
(5) review the results of rehabilitation.
PMID- 10771922
TI - Long-term otologic status of older cleft palate patients.
AB - The purpose of this study was to evaluate the effectiveness of regular otologic
care on the long-term outcome in patients with cleft palates. We report the
otoscopic and audiologic findings of 50 patients who were followed regularly at
our center for an average of 15.4 years. All these patients had their cleft
palates repaired by the same surgical team and all ears were examined by one of
the authors under the microscope and a chart review completed. Thirty eight
patients had at least one tube placement. The physical abnormalities noted were
tympanosclerosis (36%), retraction of tympanic membrane (TM) (20%), atrophy of TM
(15%), perforation (11%), PE tube in situ (11%), thick TM (6%) and PE tube in
middle ear (1%). The examination was normal in 36%. A conductive loss was noted
in 18% and sensorineural loss in 3%. The results of this study support the
concept of regular otologic care for cleft palate patients even when they are
overtly asymptomatic.
PMID- 10771923
TI - Deafness and its prevention--Indian scenario.
AB - Auditory sense is crucial for the mental development of a child and for the human
abilities and social adaptation subsequently in life. Unfortunately, for various
reasons the deafness has not drawn enough attention. There have been many studies
in India on etiology and prevalence on regional basis. Rural population has been
shown to be affected more often than the urban population. Poor economic
background has also been held partially responsible. The lack of health awareness
and education has played a significant role in high incidence of hearing
impairment. Primary and secondary prevention have not been paid due attention.
There are very few multicentric studies available. However, there are some
studies which have been able to clearly assess the magnitude of the problem,
etiology and areas which need thrust. The studies have also shown that it is
feasible to focus attention to primary and secondary prevention through the
existing health infrastructure with some modifications. Main emphasis has been on
health education with special attention to hearing impairment and its prevention,
proper attention to pre- and postnatal causes in early age and care of upper
respiratory infections. Emphasis is on a nationwide programme to pay focussed
attention to the primary and secondary prevention of hearing impairment in
addition to dealing with those already affected.
PMID- 10771924
TI - Atrial natriuretic factor and neonatal body fluid homeostasis.
PMID- 10771926
TI - Child and adolescent psychiatry in-patient facility.
AB - The short-term in-patent facility of the Child and Adolescent Psychiatry Unit in
the National Institute of Mental Health and Neurosciences, Bangalore is
described. Its clientele over one year is reviewed. Totally 152 admissions were
made. Hysterical neurosis (30.8%), Psychoses (25.2%), Conduct disorder (10.5%)
and Hyperkinetic syndrome (9.8%) were the most common diagnoses observed in this
population who needed short-term intervention. Average duration of stay was 4-12
weeks. All children were admitted with a parent. In 95.8% of the cases the
treatment expenses were borne partially/fully by the hospital. The policy and
functioning of the facility is discussed.
PMID- 10771927
TI - Does digoxin still have a role in congestive heart failure?
AB - The role of digoxin in the treatment of congestive heart failure is (CHF) being
questioned. Digoxin continues to be the drug of choice for patients with atrial
fibrillation in CHF. Large randomised trials have shown that digoxin (in addition
to ACE inhibitors and diuretic) is beneficial in CHF due to systolic dysfunction,
although it does not reduce mortality. Limited data suggest that digoxin benefit
some, but not all patients with CHF due to left to right shunts. Digoxin does not
benefit CHF due to diastolic dysfunction and it is not routinely recommended for
prematures with patent ductus and CHF. The treatment with digoxin should be
individualised.
PMID- 10771925
TI - Diagnosis of Helicobacter pylori.
AB - In view of its potential risk for the development of gastrointestinal disease or
even gastric cancer at a later age, the study of Helicobacter pylori infection in
childhood is gaining increasing importance and H. pylori infection is being
considered a major issue of public health. H. pylori infection can be detected by
a variety of methods. Because of its easy use, affordability, and overall
availability, serology is the preferred diagnostic test, especially for large
epidemiological studies. Based on our results, one might consider treating a
child with recurrent abdominal pain and positive serology for H. pylori without
further work-up, and only perform additional investigations when an anti-H.
pylori therapy fails to resolve the complaints. According to this proposition,
endoscopy of the upper gastrointestinal tract remains indicated in children if
the noninvasive tests for Helicobacter pylori are negative in the absence of a
diagnosis, or if symptomatology persists despite treatment.
PMID- 10771928
TI - Immunogenicity and tolerance of H. influenzae type b, tetanus toxoid conjugate
vaccine given concurrently or in combination.
AB - The present prospective, open, controlled, randomised comparative trial was
undertaken to evaluate the sero response and side effects of PRP-T Conjugate
Vaccine (ACT-HIB) in infants and children aged 2 months and 16-24 months. Fifty
four babies aged 2 months formed group A, 56 children aged 16-24 months formed
group B. Groups A and B were further subdivided into two sub groups each destined
to receive either PRP-T vaccine in association with DPT vaccine at different
sites (I) or PRP-T and DPT both vaccines at the same site mixed in the same
syringe (II). Group A received 3 doses at 2, 3 and 4 months of age and group B
received one dose between 16-24 months. The Geometric mean titres of Anti PRP
antibodies observed in primary immunisation schedule (A) and single dose
vaccination schedule (B) were comparable and significantly higher to
prevaccination titres. A serum anti PRP level of > 1.0 mcg/ml after immunisation
is believed to correlate with long term protection. Ninety-six percent of infants
in Group A and 98% in Group B achieved titres > 1.0 mcg/ml. The side effects were
minimal, local and were comparable between the study and control groups,
suggesting that PRP-T vaccine is highly immunogenic and well tolerated in Indian
infants and children.
PMID- 10771929
TI - In vitro antibiotic sensitivity pattern of common bacterial isolates from cases
of acute bacterial meningitis with special reference to ceftriaxone.
AB - Ceftriaxone (RO 13-9904) has only recently been introduced in Benghazi and many
parts of the word. We determined its in-vitro antibacterial activity against the
primary aetiological agents of childhood meningitis in Benghazi, that included
eighteen (23.3%) strains of H. influenzae, 17 (22.1%) of Str. pneumoniae and 1
(1.3%) of N. meningitidis isolated from 77 cases of acute purulent meningitis
above the age of neonatal period. All strains of H. influenzae. Str. pneumoniae
and N. meningitidis were sensitive to ceftriaxone and showed wide zones of
inhibition by the disc diffusion technique of Kirby-Bauer. Ampicillin and
chloramphenicol resistance was observed for H. influenzae (23% and 11%
respectively), and Str. pneumoniae (12% and 0% respectively), in addition, 18% of
strains of Str. pneumoniae showed resistance to penicillin. The broad spectrum
activity of ceftriaxone has been confirmed for our locality and this finding,
together with its exceptionally long half-life, excellent penetration into the
C.S.F. and ease of administration (single daily dose) warrants it as the drug of
choice in empherical treatment of cases of acute bacterial meningitis in children
in Benghazi and in cases where resistance to ampicillin and chloramphenicol are
found on subsequent testing.
PMID- 10771930
TI - Development of secondary sex characteristics in multitransfused thalassemic
children.
AB - Secondary sex characteristics were evaluated in thalassemic children (41, boys
and 30 girls), who were on regular transfusion therapy and were above 11 years of
age. The results of this study indicate that the development of secondary sex
characteristics in thalassemic children is markedly delayed as compared to their
non-thalassemic siblings and to the expected development criteria. Delay in
development of secondary sex characteristics appears to be secondary to chronic
hypoxia and iron overload.
PMID- 10771931
TI - Physical growth parameters in thalassemic children.
AB - Various growth parameters of 233 (140 boys, 93 girls) thalassemic children were
compared with 74 (45 boys and 29 girls) non-thalassemic siblings, ICMR and NCHS
norms. Weight and height were retarded in thalassemic children. The difference
between thalassemic and non-thalassemic siblings, was evident from 9+ years in
both boys and girls. Growth parameters seemed to be adversely affected with the
advancing age. Among head, chest and mid arm circumferences, the mid arm
circumference was more affected than head and chest circumferences. Height and
weight were more severely retarded in children with hemoglobin levels of less
than 8 gm/dl. The findings seemed to suggest that press of retardation was
probably secondary to chronic hypoxia and iron overload.
PMID- 10771932
TI - Malignancies in Down syndrome.
AB - Down Syndrome (DS) is associated with an increased incidence of malignancies,
especially leukaemias. We came across 8 DS children presenting with malignancies
and having trisomy 21 as the sole cytogenetic abnormality. Of these 8 DS cases, 4
presented with acute lymphocytic leukaemia, 2 with acute myeloid leukaemia and
one case each with Hodgkin's disease and Wilms' tumour. There are contradictory
reports regarding the distribution of myeloid versus lymphoid malignancies in DS
children and their response to therapy. The exact mechanism by which patients
with DS are predisposed to develop malignancies is unclear. However, presence of
the extra chromosome no. 21 is presumed to disrupt the genetic balance which
increases generalized susceptibility to genetic and environmental trauma.
Furthermore, an increased methotrexate toxicity observed in these patients should
also be taken into consideration in designing treatment for DS children with
malignancies.
PMID- 10771933
TI - Toxoplasmosis in women of child bearing age and infant follow up after in-utero
treatment.
AB - A total of 540 women (including 70 pregnant cases) of child bearing age with bad
obstetrical history were tested serologically for anti-toxoplasma antibody using
microlatex agglutination test. Forty two women including 5 cases of pregnancy
were found to be seropositive in a titre of 1:32 or more. Maximum prevalence
(10.2%) and highest titer of anti-toxoplasma antibodies were observed in women of
35-42 years age group. The overall prevalence of toxoplasmosis in these women was
7.7%, whereas it was 7.1% in pregnant women. Further studies are needed to
estimate the exact rate of prevalence of infection. Of the 70 pregnant women, 5
were seropositive and two of them acquired infection during pregnancy which was
detected by IgM immunosorbent assay. Seropositive pregnant women were treated
using combined regimen of sulfadiazine and pyrimethamine. Four infected women
with pregnancy were followed up and one did not turn up subsequently. There was
spontaneous abortion in one case and in 3 other cases full term normal babies
were delivered. Incidence of toxoplasmosis in women is low because of infrequent
and uncommon practices of ingesting undercooked or uncooked food stuff specially
meat by a substantial number of the population surveyed.
PMID- 10771935
TI - Liver biopsies in patients with lysosomal storage disease: experience with
effective sedation.
AB - We prospectively applied a protocol used to sedate children who required a liver
biopsy. Sixty liver biopsies were performed on thirty pediatric patients to
assess the effects of treatment. Sixteen patients had Type 1 Gaucher's disease of
which seven had a platelet count between 50-100,000/mm3. All seven had bleeding
time performed and when indicated, intravenous DDAVP (1-deamino-8-D-arginine
vasopressin) was used to improve hemostasis. Fourteen patients had Niemann-Pick
disease type C of which eight were significantly demented and uncooperative.
Before liver biopsy, all patients were sedated with the following regimen: oral
chlorpromazine (1 mg/kg) followed one hour later by intravenous meperidine (1
mg/kg) and pentobarbital (maximum dosage 6 mg/kg) administered by slow
intravenous injection. Liver biopsies were obtained safely on all patients. Only
1 patient (2%) developed a potentially serious complication: an obstructed airway
which was readily corrected by simple repositioning. Transient less serious
complications occurred in another 7 patients (12%). There was no long term
sequalae of the biopsy procedures. Our study indicates that with appropriate
patient selection, this sedation protocol may be useful in pediatric patients
requiring a liver biopsy.
PMID- 10771934
TI - Iodine loss from iodised salt on heating.
AB - Iodine deficiency disorders constitute a major public health problem in India.
The national IDD control programme (NIDDCP) relies solely on iodine
supplementation through fortification of common salt with potassium iodate.
However, data regarding iodine loss due to high temperatures of cooking procedure
is scarce. Using iodometric titration methods, we calculated iodine content of
iodised salt samples subjected to incremental heat up to 350 degree Celsius. The
results of the study indicate a gradual but minimal loss of iodine content from
the iodised salt samples when subjected to high temperature with a maximum loss
noticed being 18.5% at 350 degree Celsius. We conclude that there is minimal loss
of iodine from the salt fortified with potassium iodate when subjected to heating
(temperature normally attained during cooling process).
PMID- 10771936
TI - Isoimmune hemolysis in an infant due to maternal Evans' syndrome.
PMID- 10771937
TI - Immature gastric teratoma.
AB - Gastric teratoma, a very rare tumor of infancy is essentially benign. Immature
(embryonic) elements have been described in only three of the sixty-six cases
described previously. This report concerns with one "immature" gastric teratoma
seen in infancy.
PMID- 10771938
TI - Tubercular retropharyngeal abscess in early childhood.
AB - We present two cases of Pott's lower cervical spine with retro-pharyngeal abscess
presenting at an unusually young age. These children presented with a life
threatening respiratory distress; one of them had neurological deficit in the
form of paraparesis. External drainage of abscess without anterior cervical
fusion was adequate as a surgical measure for their prompt recovery while these
cases were on conventional anti-tubercular therapy.
PMID- 10771939
TI - Comments on "Small for gestational age babies: Indian scene" published in IJP
March-April, 1997; vol. 64; no. 2; pp 221-224. IUGR is it commonly idiopathic.
PMID- 10771940
TI - Macrolide antibiotics.
AB - This article is an extensive review of current information available on the
macrolide antibiotics. This includes antimicrobial spectrum, pharmacology,
complications and side effects, and pediatric use of these drugs. These are
important antibiotics, but careful selection of patients must be made and the
physician must be alert for evidence of drug-drug interactions, which are not
uncommon with several members of this class.
PMID- 10771941
TI - Advances in the diagnostic methods and therapeutic techniques for congenital and
acquired heart defects in children.
PMID- 10771942
TI - Recent advances in the treatment of congestive heart failure.
AB - Treatment of heart failure should include correction of the underlying cause.
These causes include large left to right shunts, obstructive lesions,
arrhythmias, primary myocardial disease etc. The main pharmacological therapy
includes inotropic agents, vasodilators and diuretics. Inotropic agents increase
myocardial contractility and include digoxin, intravenous dopamine, dobutamine
and isoproterenol. Vasodilators improve cardiac pump performance by decreasing
the vascular resistance and/or increasing the venous capacitance. Commonly used
vasodilator agents include angiotensin converting enzyme inhibitors (captopril,
enalapril etc.), hydralazine, prazosin hydrochloride etc. Diuretics inhibit salt
and water reabsorption promoting their excretion. Furosemide, thiazide diuretics,
aldactone, are commonly used diuretics. Electrolyte and acid-base imbalance can
occur on chronic diuretic therapy. Cardiac transplantation is considered for
patients where all medical management has failed.
PMID- 10771943
TI - Chest pain in children.
AB - Chronic chest pain is a complaint that frequently prompts referral to pediatric
cardiology clinics although very few pediatric patients with this symptom will be
found to have cardiac disease. This review will discuss the common non-cardiac
and cardiac causes of chest pain. Guidelines on the office management of this
group of patients will be presented as well as the indications for referring
patients for evaluation and treatment by the subspecialist.
PMID- 10771944
TI - Optimal timing of surgery in common left to right shunts.
AB - Left to right shunts like atrial septal defect, ventricular septal defect and
patent ducts arteriosus are commonly encountered congenital malformations of the
heart. With advances in diagnostic and therapeutic technology over the last three
decades the recognition and management of these lesions has markedly improved.
Currently, the surgical procedures are being performed in infants and neonates
with the hope that long term results would be better. Children with atrial septal
defects are usually asymptomatic or mildly symptomatic and closure of the defect
is best performed at 3-4 years of age. Large ventricular septal defects, on the
other hand, may produce symptoms like congestive heart failure in early infancy
and early closure is recommended for these babies. These defects are also known
to close spontaneously and therefore in mildly symptomatic cases without
pulmonary arterial hypertension, one may wait for a natural reduction in size.
Surgical ligation of a patent ductus arteriosus is a safe and simple procedure
and all these cases must undergo closure of the duct.
PMID- 10771945
TI - Obstructive total anomalous pulmonary venous drainage.
AB - Obstructive total anomalous pulmonary venous drainage (TAPVD) has a florid
presentation in the neonatal period from the resulting pulmonary edema. A
complete anatomical and functional diagnosis is usually possible by transthoracic
color Doppler echocardiography, and cardiac catheterization with its attendant
risks can usually be avoided in the sick neonate. Currently balloon atrial
septostomy has a limited role in palliation of these neonates. Corrective surgery
on urgent basis has gratifying results and prevents progression of pulmonary
vascular occlusive disease. Pulmonary hypertensive crisis in the early post
operative course needs to be avoided and treated vigorously if it were to
develop. Late post-operative course can be complicated by anastomotic obstruction
or progressive narrowing of the individual pulmonary veins. Although the former
can be dealt successfully by re-operation, surgical treatment of the latter is
not satisfactory. Balloon dilatation of the obstructed pulmonary venous pathways,
native and post-operative, has been reported with equivocal results. Infant heart
lung transplant is a viable option in patients with diffusely narrow pulmonary
veins or complex TAPVDs.
PMID- 10771946
TI - Care of mothers and infants.
PMID- 10771947
TI - Newer concepts and approaches to neonatal brain asphyxia.
AB - The asphyxial injury to neonate brain seems to be mediated through a cascade of
biochemical events during ischaemia--reperfusion which includes excitatory amino
acids, free radicals and accelerated programmed cell death (Apoptosis). The
diagnosis of asphyxia requires rigorous approach based on background clinical
information, certain diagnostic tests and exclusion of alternative diagnosis
which may have similar clinical presentation. The treatment currently employed
for the management of birth asphyxia controversial and requires critical
appraisal. The future strategies for management include a number of approaches
based on putative mechanism for asphyxial brain injury but they are still being
evaluated as research and should not be used for clinical purposes in human
newborns as yet.
PMID- 10771949
TI - Endotracheal aspirate cultures in predicting sepsis in ventilated neonates.
AB - Nosocomial infections are the most common complications encountered in the
neonatal intensive care unit (NICU). They are associated with high mortality and
prolonged duration of hospitalization in the survivors, contributing to an
increased cost of health care. In this article, we review the literature on the
value of routine endotracheal aspirate cultures for the prediction of neonatal
sepsis and provide guidelines to prevent nosocomial infections. Upon reviewing
the literature it appears that the practice of routine cultures of endotracheal
aspirate and cultures obtained from multiple body sites is an expensive
proposition with low yield. The sensitivity of this test is at best 50% and all
studies report a very low positive predictive value. The specificity of this test
is 80%, hence its role is mainly limited to identifying infants who are at low
risk for sepsis. As we do not have any reliable test for early diagnosis of
neonatal sepsis and also to identify infants at high risk for sepsis, our main
emphasis should be towards preventing nosocomial infections. Guidelines for
reducing nosocomial infections are described.
PMID- 10771950
TI - Role of pediatrician in dental caries.
PMID- 10771951
TI - Cefoperazone: an analysis of results in the pediatric population from a post
marketing surveillance study in hospitalized patients. The Cefoperazone
Collaborative Post-marketing Surveillance Study Group.
AB - The injectable third-generation cephalosporin, cefoperazone, was introduced in
India in early 1994. A post-marketing surveillance study was conducted in 1994-95
to collect local data on efficacy and safety, evaluate the native pattern of
bacterial susceptibility, and assess the relationship of in vitro susceptibility
tests to clinical efficacy. Hospitalized patients with features suggestive of
infections that are approved indications for cefoperazone were eligible for the
study. This report presents an analysis of the results among patients in the
pediatric age group. The recommended dose range for children was 50-200
mg/kg/day. At analysis, 95 patients aged 6 days to 14 years were evaluable for
efficacy. About a third of these (31%) were judged to have hospital acquired
infections, and 22 (23%) had failed prophylaxis or previous treatment. A
successful clinical outcome was observed in 91% of 75 non-neutropenic patients.
Eighteen (95%) of 19 patients with pneumonia and 8 (89%) of 9 patients with
pyogenic meningitis responded to cefoperazone. Five of 6 patients with
complicated or hospital-acquired upper urinary tract infections, 2 of 3 patients
with peritonitis, and all patients with skin or soft tissue infections, intra
abdominal abscess, osteomyelitis, and brain abscess also responded. Four of 5 non
neutropenic patients with septicemia recovered with cefoperazone monotherapy. The
response rate was 70% among 20 neutropenic patients, 16 of whom were deemed
septicemic. Antibiotic disc susceptibility data among pediatric patients was
available for 63 isolates and 13% were reported resistant to cefoperazone.
Microbiologic eradication was reported with 94% of initial isolates. Mild to
moderate adverse events of study, drug-related or uncertain causation occurred in
4 (3.7%) of patients.
PMID- 10771948
TI - Early diagnosis and treatment of neonatal sepsis.
AB - Perinatally acquired bacterial neonatal sepsis is a low incidence, high risk
disease with a relatively benign treatment. Accurate diagnosis is difficult
because there is no definitive diagnostic test; even blood cultures have an
unacceptably low sensitivity. Therefore, the clinician must accept that a number
of neonates who do not have the disease will have treatment initiated for sepsis.
In order to treat rapidly all infants with sepsis and to minimize therapy for
those without infection, historical, clinical, and laboratory data can be used
together in a management approach to achieve optimal results. A systemized
approach using history, examination, sepsis screen laboratory tests, and cultures
is presented to guide clinical management.
PMID- 10771952
TI - Study of gene probes in childhood leprosy.
AB - The objective was to detect nucleic acids of M. leprae in skin lesions of leprosy
patients and study the effect of treatment on these nucleic acids, using r-RNA
gene probes, using a cross sectional study. The study was carried out at
Department of Paediatrics, S.N. Medical College, Agra and Department of
Microbiology, Central JALMA Institute for leprosy, Agra. The study included 32
cases of leprosy less than 16 years of age, divided into 3 groups viz. without
treatment (12 cases), in middle of treatment (11 cases) and at the end of
treatment (9 cases). All cases were subjected to a detailed history and thorough
clinical examination. All of them had smear examination and lepromin test done
and their skin biopsies were subjected to gene detection. Nucleic acids were
isolated from skin biopsies of all cases by standard procedure. After dot
blotting of these nucleic acids, they were hybridised with radioactive (p32) r
RNA probes. The results were interpreted after getting the X-ray films processed
with background signals from controls. Majority of cases were between 13-16 years
of age. As age advanced, the disease moved from tuberculoid end of spectrum
towards lepromatous end (p < 0.05). Majority of paucibacillary (PB) cases were
lepromin positive while majority of multibacillary (MB) cases were lepromin
negative (p < 0.05). In specimens of untreated cases, 50% of PB specimens and
87.5% of MB specimens were positive for r-RNA probes. In multibacillary type 100%
smear positive specimens and 67% smear negative specimens were positive for r-RNA
probes. In patients during the middle of treatment positivity for r-RNA decreased
and 20% of PB specimens and 16.6% MB specimens were positive. At the end of
treatment (1 year for PB cases and 2 years for MB cases), the results of r-RNA
were negative, which indicated that the treatment regimens used in the study were
effective. This study supports the usefulness of r-RNA probes as a diagnostic and
therapeutic tool in childhood leprosy.
PMID- 10771953
TI - Pituitary tumours.
AB - This report describes the presentation, pre-operative findings, surgical
management and follow-up results of 20 pediatric patients with pituitary
adenomas. The most common presenting complaints encountered were, headache and
decrease in visual acuity. Among the patients with endocrine problems, majority
had frank Cushing's disease (30%). Nine patients (45%) were endocrinally normal.
The most common, histological type of pituitary tumour encountered in this series
was the Chromophobe adenoma. One patient died following surgery. Radiation
therapy was given in all post operative cases. Response to radiation therapy has
been satisfactory on follow up. The generally encouraging results we have
observed following the multi-disciplinary treatment, confirms the findings
reported by other workers.
PMID- 10771954
TI - Knowledge beliefs and practices regarding iodine deficiency disorders among the
tribals in Car Nicobar.
AB - It is estimated that 1,570 million people are at risk of iodine deficiency.
Because of the wide spectrum of disorders that IDD includes, and lack of any
obvious association between iodine deficiency and its health effects, IDD is not
perceived as a major public health problem. For any disease to be effectively
controlled, awareness at all levels from community to policy makers is necessary.
This study was conducted to assess knowledge, beliefs and practices regarding
iodine deficiency Disorders in Car Nicobar districts of Andaman and Nicobar
Islands. The population is predominantly tribals involved in coconut plantations.
All the village heads of the sixteen villages and parents of 10% of the school
children examined for goiter were interviewed. Initial focus group discussions
were conducted as no prior knowledge about local names for goitre or other
related IDD information was available. The interview schedule was designed in
English which was then translated into Hindi and Nicobarese and back translated
into Hindi and English. A total of 114 persons were interviewed 60 males, 54
females. The local name for goiter was "Rulo" and 44% felt that it only affected
females. No one had correct knowledge of the cause of goiter. About half of the
respondents believed that these swellings caused problems. Sixty three (55.3%) of
respondents believed that there was treatment, of which 33 said there was medical
treatment, 18 respondents said traditional treatment by "LAM-EEN" and 12 felt
that both therapies are required. Majority (85%) brought salt samples from the
Government canteen. They did not now whether this salt was iodised. Salt was not
washed before use and storage practice was satisfactory. The awareness about IDD
needs reinforcement. At present the community is a passive participant in the
I.D.D. Control Programme.
PMID- 10771955
TI - Neonatal Klebsiella pneumonia sepsis and imipenem/cilastatin.
AB - Efficacy and safety of imipenem/cilastatin in neonatal Klebsiella pneumonia
sepsis was investigated in 45 infants compared to 39 control infants on
conventional antibiotic regimen. Sensitivity to imipenem was 94% followed by
cephoxitin (88%), quinolons (80%), and amikacin (52%) according to susceptibility
results in the study group. Treatment duration of surviving infants was 16.5 +/-
4.6 and 20.3 +/- 6.4 days in the study and control groups respectively (p <
0.05). Five infants (11%) vs 27 (69%) were unresponsive (septic deaths) to
treatment in the study and control groups respectively (p < 0.001). The cure
rates were 73% and 28% respectively (p < 0.001). Sequelae free discharge rates
were 67% and 23% respectively (p < 0.001). The most frequent adverse effects of
imipenem/cilastatin were Candida albicans superinfection (20%); Candida albicans
colonisation (10%); impairment of liver and renal functions (19% and 10%
respectively); seizures (5%); thrombocytosis (3%); thrombophlebitis (3%); urine
discoloration (3%); and Staphylococcus epidermidis colonisation (2%). Imipenem is
considered a good alternative for neonatal Klebsiella pneumonia sepsis with these
results, however, one must be aware of the increased risk of Candida albicans
superinfection.
PMID- 10771956
TI - Early prediction of neonatal hyperbilirubinemia.
AB - The study aim was to predict, using serum bilirubin level measured 18 to 24 hours
(SB, 18-24) after birth, the occurrence of peak serum bilirubin level > 15 mg/dL
(hyperbilirubinemia) or the requirement of phototherapy, any time from the second
to fifth postnatal day. The study was conducted on a prospective cohort of 274
neonates born in north India. The main outcome measures were (a)
hyperbilirubinemia and (b) phototherapy. Serum bilirubin level was estimated at
18-24 hours of age and then daily from second to fifth postnatal day. Exclusion
criteria were Rh incompatibility, asphyxia and life threatening congenital
malformations; and neonates of women with gestational diabetes or history intake
of drugs affecting the fetal liver. Hyperbilirubinemia was found in 12.8%; and
19.3% neonates received phototherapy. Dichotomous SB 18-24, using a cut-off of >
3.99 mg/dL, as the "prediction test" had the following sensitivity and
specificity for predicting (a) hyperbilirubinemia: 67% and 67%, respectively, and
(b) the treatment with phototherapy: 64% and 68%, respectively. We concluded that
by using SB 18-24 as the "prediction test", approximately two-thirds of neonates
were test negative and had about one in ten chances of re-admission for treatment
of hyperbilirubinemia, if discharged. After further validation, our results will
be of benefit to neonates delivered in developing countries.
PMID- 10771957
TI - Incidence of hearing impairment among rural and urban school going children: a
survey.
AB - A total of 1,670 school going children (urban 1030 and rural 640) in the age
range of 12-14 years were screened for hearing loss during a survey conducted by
the Department of Otolaryngology of the Postgraduate Institute of Medical
Education & Research, Chandigarh. 6.31% of cases in the urban group were found to
be having hearing loss as compared to 32.81% of cases in the rural group.
Secretory otitis media was found to be the commonest cause of hearing impairment
in both the urban and rural group accounting for 5.33% and 33.59% respectively.
PMID- 10771958
TI - Abnormal migration of ascaris into the middle ear.
AB - Ascaris in the middle ear is very rare with very few cases having been reported.
We report here two such cases with different presentations.
PMID- 10771959
TI - Pentalogy of Cantrell.
AB - Omphalocele is often associated with various abnormalities. In two patients
admitted with omphalocele, we additionally found defects both in the pars
stenalis of diaphragm and in the diaphragmatic surface of the pericardium,
sternal defect and tetralogy of Fallot. These entities form the components of a
syndrome, named pentalogy of Cantrell. It is extremely in the spectrum of midline
closure defects that display wide variations and its incidence is very low.
Existing cardiac defect is the most important factor influencing morbidity and
mortality. Herein we report two cases of pentalogy of Cantrell with the review of
the syndrome in the light of literature.
PMID- 10771960
TI - Cholestatic jaundice due to congenital Toxoplasma gondii infection.
AB - A case of congenital toxoplasmosis manifesting as hepatosplenomegaly and
cholestatic jaundice in a 4 month old child is reported. To the best of our
knowledge this is the first report of cholestatic jaundice due to congenital
toxoplasmosis from India. The child was successfully treated with sulphadiazine
and pyremethamine combination.
PMID- 10771961
TI - Cord blood transplant: current and future issues.
AB - Cord blood as the source of hematopoietic stem cells has several advantages over
bone marrow cells for transplant purpose. It is readily available, and causes no
physical harm or inconveniences to the donor in the processing of harvesting
cells. Waiting time between initiating the search and the time to transplant from
an unrelated donor is much shorter with cord blood than with unrelated donor bone
marrow. The incidence of graft-versus-host diseases is much less. Because of
these advantages, cord blood has been increasingly used as the source of stem
cells. As of this writing, more than 200 cord blood transplants have been done in
patients with hematological malignancies, solid tumors, hematological diseases,
immunodeficiency syndromes, and metabolic diseases. One of the limitations
inherent in the cord blood is its limited number of hematopoietic stem cells.
Thus it has been primarily used for pediatric patients, though more recently,
adult patients also have been transplanted with cord blood as people have become
more experienced in harvesting cord blood thus yielding a larger number of stem
cells in a given specimen. Efforts have been made to amplify stem cells in vitro
following harvesting cord blood stem cells, so that adult recipients also would
routinely benefit from this resource. Cord blood lymphocytes are functionally
"naive", do not generate vigorous mixed lymphocyte culture reactivities. The low
incidence of graft-versus-host disease in the recipients of cord blood is due to
this particular property. It is highly desirable that the world wide cord blood
registry, similar to the international bone marrow registry would be instituted,
but there are logistic, ethical and financial problems that need to be resolved.
Cord blood is one of the best stem cell sources, and its application is quite
wide.
PMID- 10771962
TI - Cerebral infarction in infants and children: clinical features, CT and EEG
findings.
AB - In a retrospective study, medical records of twenty one infants and children who
were diagnosed for cerebrovascular disease, were analysed. Patients with history
of head injury, brain tumor and intracranial infections were excluded from the
study. Age ranged between six weeks and 12 years. Fourteen were boys and 7 girls.
Ten patients (47%) had known underlying risk factor. Hemiparesis and seizures
were commonest presenting features as well as long term neurological sequelae in
survivors. CT scan was abnormal in all patients whereas, EEG was abnormal in 90%
with 76% lateralizing effect.
PMID- 10771963
TI - Fragile X syndrome.
AB - Fragile X syndrome is the most common form of inherited mental retardation. It is
seen in people of all nationalities and in all areas of the world. Fragile X
syndrome can be a devastating condition, as many boys are severely retarded and
require multiple services. Treatment involves behaviour management techniques,
appropriate school placement, community support for the family, and careful
medical follow-up often including psychopharmacology. The genetics of fragile X
syndrome is now understood, prenatal testing is available, and the disorder is
preventable through appropriate genetic counselling. This review focuses on the
neurobiology of fragile X syndrome, its clinical features and treatment.
PMID- 10771964
TI - Pediatric cardiology is a subspeciality of cardiology.
PMID- 10771965
TI - Non surgical treatment in congenital heart disease.
AB - Dilation of blood vessels transluminally was demonstrated by Dr Andreas Gruntzig
in 1978. In 1982, Kan demonstrated that congenitally stenosed valve can be
dilated with the use of cylindrical balloon and opened up new vistas in the non
surgical treatment of congenital heart lesions. Rapid progress has been now made
in (1) Understanding of mechanism of success or failure of balloon dilation (2)
Development of newer hardwares like low profile balloon, high pressure balloons,
extra support wires which have contributed to increase in success rate of the
procedures (3) Understanding the unnatural history of various congenital heart
lesions from the vast data bank of Registries of balloon dilation. As a
consequence balloon dilation has become the first procedure of choice in the
treatment of valvar pulmonary stenosis and post surgical recurrent coarctation.
Although an essentially palliative procedure for the treatment of valvar aortic
stenosis and native coarctation beyond the neonatal period, non-randomised
studies have shown results similar to that of surgical correction. Balloon
dilation of pulmonary artery, pulmonary vein, venous baffles stenosis have shown
poor overall results. Balloon dilation for sub-pulmonary stenosis like tetralogy
of Fallot is controversial. The development of stents to keep dilated vessel open
has also found a place in treatment of congenital heart lesions. Thus pulmonary
artery stenosis, recurrent coarctation in adults, venous baffle obstruction,
conduit stenosis which respond poorly to balloon dilation alone have shown
promising early and mid term results with stents. The use of stents to keep the
ductus open, recurrent coarctation in children, in right ventricular outflow
tract obstruction is controversial. Development of devices to achieve closure of
cardiac defects is relatively new. Patent arterial duct was the first defect to
be closed with the help of devices and has shown good results on long term follow
up. Recently stainless steel coils have been used to close dose small ducti (up
to 3 mm) with very promising medium term results. Its use has also been extended
to larger ducti (up to 7 mm). Devices used for closing atrial septal defects,
ventricular septal defects are undergoing rapid development. In atrial septal
defects its use is restricted to small defects in the fossa ovalis area and in
ventricular defects, to only those which are in the muscular septum. Most of the
devices in use today for atrial septal closure are relatively new and await long
term results. The results achieved by non surgical treatment for many congenital
heart lesions are essentially palliative and may require repeat interventions at
some point in the unnatural history which increases the cost of treatment
substantially. The reuse of balloons, guide wires in developing countries helps
reduce the overall cost of the procedure.
PMID- 10771966
TI - Prostaglandin E1: first stage palliation in neonates with congenital cardiac
defects.
AB - E-type prostaglandins (PGE1) can effectively maintain the patency of the ductus
arteriosus in neonates. Its use, therefore can be life saving in infants born
with ductus dependent congenital heart disease. Although PGE1 is available for
over two decades in western world, it has been introduced in India only since
April, 1995. Various cardiac defects where PGE1 is useful include (a) lesions
with ductus dependent pulmonary blood flow e.g. pulmonary atresia with or without
ventricular septal defect, critical valvular pulmonic stenosis etc, (b) lesions
with ductus dependent systemic blood flow e.g. critical aortic stenosis,
coarctation of aorta, interruption of aortic arch etc, and (c) admixture lesions
like transposition of great arteries. The drug is given as a continuous
intravenous infusion. The initial dose is 0.05 to 0.4 ug/kg/min, infusion rate
must be decreased to 0.01 ug/kg/min as soon as the desired effect is achieved as
incidence of side effects is more at higher doses. Serious side effects include
apnoea, hypotension, hyperthermia, seizures etc. We have used this drug in 43
infants ranging in age from one to forty five days. Beneficial response was seen
in 41 of 43 infants and the major side effect was apnoea (seen in 5 of 32
spontaneously breathing infants). Unfortunately the high cost of the drug
prohibits its wide spread and long term use. PGE1 is a life saving drug for
infants born with ductus dependent congenital cardiac malformations. It helps in
stabilizing these patients prior to further surgical palliation or correction.
PMID- 10771968
TI - Kawasaki disease: an update.
AB - Kawasaki disease is the leading cause of acquired heart disease in children in
many parts of the world. It is an acute systemic vasculitis of unknown etiology
predominantly affecting children under 5 years of age. It is diagnosed clinically
by the presence of a constellation of manifestations and exclusion of other
diseases with similar findings. Children develop a spectrum of cardiovascular
manifestations including coronary artery involvement in 30-35% of untreated cases
with myocardial infarction and death in < or = 2% of them. Acute stage treatment
is by administration of intravenous immunoglobulin and aspirin. Those with
coronary artery involvement need long-term cardiac risk stratification and
management because many of them will become the part of a growing pool of adults
with ischemic heart disease.
PMID- 10771969
TI - Neonatal care perspectives in India.
PMID- 10771967
TI - Congenital coronary artery abnormalities.
AB - Congenital coronary artery abnormalities are rare and account for approximately
0.1 to 2% of congenital heart defects. They may pose significant risk of
mortality or morbidity to the patient. The pediatrician and the pediatric
cardiologist should be aware of their subtle but very serious presentations and
diagnostic steps to be undertaken to pinpoint the diagnosis. Prevention of
serious complications from these abnormalities can be achieved by making the
appropriate diagnosis and performing timely surgical intervention. This review
will discuss the most common congenital coronary artery abnormalities and their
management.
PMID- 10771970
TI - Cost of neonatal intensive care.
AB - Neonates are among those patients generating the highest hospital costs in recent
years. There are no published data on the costs of neonatal intensive care in our
country. The aim of our study was to analyse the cost of neonatal intensive care
in a tertiary care unit. The average hospital charges per day were higher among
non-survivors (Rs. 1857) compared to survivors (Rs. 727). Care of more than 1250
gms infant is cost beneficial in our set up.
PMID- 10771971
TI - Care mapping: a common sense approach.
AB - Because of trends in the health care environment, hospitals are searching for
ways to continuously improve the quality of care and to decrease the costs of
care. One approach that is gaining widespread recognition throughout the United
States is the use of case management and practice guidelines such as critical
paths, CareMaps, and in the neonatal field, NeoMaps. The NeoMap is a clinical
tool which delineates practice guidelines for each discipline that provide care
to a specific infant population. It reduces variation in clinical process and
thereby has been shown to improve the quality of infant care. When practice
guidelines are linked to both health and economic outcomes, they have significant
impact on health care costs. In this paper, case management and the development
of the NeoMap will be described in relation to the Intensive Care Nursery (ICN)
at Pennsylvania Hospital.
PMID- 10771972
TI - Continuous positive airway pressure (CPAP).
AB - Progress in neonatal intensive care is closely linked to improvements in the
management of respiratory failure in small infants. This applies to the care of
the preterm infants with immature lungs, and also to treatment of the preterm or
full term infants with specific diseases that are associated with respiratory
failure. Respiratory distress of the newborn continues to account for significant
morbidity in the intensive care unit. The spectrum of disease ranges from mild
distress to severe respiratory failure requiring varying degrees of support. The
current modalities of ventilatory assistance range from the more benign
continuous positive airway pressure (CPAP) to conventional mechanical
ventilation, and on to high frequency ventilation. It is a reasonable supposition
that the type of ventilatory assistance provided to these infants should be
graded according to the severity of the disease. However, the principal objective
in selecting the mode of respiratory support should be to use a modality which
results in minimal volo- or barotrauma to the infant. The following detailed
description on CPAP explains its physiological effects, delivery system,
indications for use, application, maintenance, and associated complications. The
equipment described is simple to use, has a greater cost benefit, and has a more
universal application, which is of help to smaller units including those in the
developing parts of the world. We have also included our institutional clinical
experience of CPAP usage in very low birth weight infants from the periods before
and after commercial availability of surfactant in the United States.
PMID- 10771973
TI - Respiratory and systemic effects of inhaled dexamethasone on ventilator dependant
preterm infants at risk for bronchopulmonary dysplasia.
AB - Short-term inhaled dexamethasone therapy was evaluated in a double blind placebo
controlled trial in 36 ventilator dependent preterm neonates (BW < 1500 gm,
postnatal age > 7 days) who were at risk for bronchopulmonary dysplasia.
Pulmonary and systemic effects were compared at early (day 3), late (7-10 days)
and post (14 days after initiation) phases of therapy. Airflow mechanics improved
as demonstrated by a net 101% improvement in pulmonary resistance (a decrease
from 139 to 101 cm H2O/L/s in the dexamethasone treated infants as compared to an
increase from 153 to 267 cmH2O/L/s in the placebo treated infants during the
early phase of therapy); this was associated with a 45% increase in inspiratory
airflow (1.29 +/- 0.43 to 1.87 +/- 0.978 L/min; p < 0.01), and 37% increase in
expiratory airflow. These changes resulted in a significant reduction in the work
of breathing such that the mean tidal driving pressure significantly decreased
from 13.6 cmH2O to 9.4 cm H2O with inhaled steroid administration. Though the
brief duration of therapy did not result in cessation of ventilatory support, the
level of support was significantly reduced (decreased values of oxygen
supplementation, mean airway pressure and oxygenation index and increased
ventilatory efficiency index). The inhaled dexamethasone therapy was also
associated with systemic absorption of the drug as evidenced by transient but
apparently reversible reduction in serum cortisol levels. No systemic side
effects of hypertension, hyperglycemia or nosocomial sepsis were observed. These
data demonstrate beneficial effects of short-term inhaled dexamethasone on the
resistive airflow properties of preterm infants at risk for BPD and may provide
adjunctive means to facilitate weaning in the ventilator dependent neonates.
PMID- 10771974
TI - Maternal substance abuse.
AB - The epidemic of substance abuse, which has swept through much of the world, has
left behind a trail of devastated lives and families. Alcohol and substance abuse
by women during pregnancy has also been reported to be widespread and can affect
the unborn fetus with the potential for life-long disabilities. While the
magnitude of the perinatal substance abuse has been the focus of much discussion
in the West, the problem is greatly underestimated in other parts of the world.
In this article, the author has focused on five highly-abused substances and
explored the effects of the drugs on the fetus and the newborn. There is a
constant need for evaluating the epidemiology and the consequences of perinatal
substance abuse so that health programs can target measures to eliminate the
preventable morbidity that results from this practice.
PMID- 10771975
TI - Neonatal mechanical ventilation--experience at a level II care centre.
AB - One hundred and fifty nine neonates were ventilated over a period of one year of
whom 74 (46.54%) survived. This study aims to analyse the indications,
complications and outcome of babies requiring mechanical ventilation. The early
outcome measures were (i) survival rate with respect to birth weight, gestation
and indication of ventilation, and (ii) Complications of assisted ventilation.
One hundred and forty seven babies received IPPV and 34 received CPAP. Twenty two
out of these 34 required IPPV later. Survival was cent percent on exclusive CPAP
mode. HMD was the commonest indication for ventilation followed by Birth
asphyxia, Apnea of prematurity, Meconium Aspiration Syndrome and Persistent
Pulmonary Hypertension of the New born. Survival rates increased with increasing
birth weight and gestational age, changing from 25% for < 1000 gm and 20% for <
28 wks to 53% for > 2500 gms and 50.2% for > 37 wks. Prolonged ventilatory
support was needed for HMD (mean 114 hrs) and PPHN (mean 156 hrs). Commonest
complication was Sepsis (26%) followed by Pulmonary hemorrhage, Pneumothorax and
IVH. Lower success rates in ventilation is due to the poor survival of babies
weighing < 1000 gms and those with a gestation of < 28 wks with nosocomial
infections as a major complication of assisted ventilation being an additional
factor.
PMID- 10771976
TI - The effect of asphyxia on gut blood flow in term neonates.
AB - Transcutaneous Doppler ultrasound measurements were made of the superior
mesenteric artery of 25 term infants to correlate the intestinal blood flow with
neonatal acid-base status as measured in umbilical artery blood and newborn
condition as reflected by Apgar score. Compared with the babies whose umbilical
artery pH was higher than 7.20 (peak systolic velocity: 84.1 cn/sn, mean velocity
48.6 cm/sn), the blood flow of superior mesenteric artery was significantly
decreased in the newborn babies whose umbilical artery pH was less than 7.20
(peak systolic velocity 48.8 cm/sn, mean velocity = 32.6 cm/sn). Although no such
relationship existed between Apgar scores and superior mesenteric artery blood
flow indices, a significant linear correlation between superior mesenteric artery
blood flow and umbilical artery pH was noted. A reduction of intestinal
circulation was observed during umbilical cord blood acidemia and hypoxemia.
PMID- 10771977
TI - Epidemiology of endemic cretinism in Sikkim, India.
AB - A survey was conducted in Sikkim to determine the prevalence of endemic cretinism
in the state. A household was the basic sampling unit. Villages were selected
randomly in the state and from these households were selected randomly using the
electoral lists. All members of the households were studied. Total of 17,837
individuals from 3,197 households from 249 villages were studied. There were
8,953 males and 8,884 females. A total of 617 endemic cretins were identified:
316 males and 301 females. The overall prevalence of endemic cretinism was 3.46%:
(males 3.53% and females 3.39%). Endemic cretinism was observed in 194 (77.9%)
villages studied. Neurological cretinism was the predominant form (98.7%). Deaf
mutism was the most salient neurological feature seen in 472 (76.5%) subjects.
Motor system examination revealed proximal spasticity and brisk reflexes, both
more marked in the lower limbs. Recording of daily life activities revealed 14.1%
of the cretins to be totally dependent and another 23% to be requiring
considerable assistance for their daily routine activities. The overall
prevalence of goitre found in this survey was 54%. Urinary iodine concentration
was estimated from a representative sample of the population; mean 4
micrograms/dl (SD 2.68). This survey shows the existence of severe iodine
deficiency in Sikkim.
PMID- 10771979
TI - Nut-bolt in the nasopharynx.
PMID- 10771978
TI - Renal dysplasia: an autopsy study of associated congenital malformations.
AB - A retrospective analysis of infant autopsies in the last 14 years was done with
the aim of determining the frequency of associated malformations. Renal dysplasia
comprised 36 of 594 autopsies done and was the commonest congenital urologic
malformation (6.06% of all infant autopsies). Histologically all cases were
characterised by hallmarks of disordered metanephric differentiation and
organisation. Extrarenal malformations were seen in all (100%) of the cases of
which other urologic anomalies were the commonest (28) followed by those of
musculoskeletal (18), gastrointestinal (13), cardiovascular (10) and central
nervous system (6). Syndromic association was seen in 5 (14%) cases. There were
twenty two percent still births and 47% infants died perinatally. A thorough
search for systemic malformations is mandatory in all cases of renal dysplasia as
these may influence the survival significantly. Cystic renal dysplasia should be
differentiated from other causes of cystic renal diseases.
PMID- 10771980
TI - Etretinate in the management of harlequin siblings.
AB - Harlequin fetus is the severe form of congenital ichthyosis. There are very few
reports of babies with this condition surviving the first few weeks of life. We
treated two siblings who lived for 22 months and six weeks respectively. We
started treatment with oral etretinate every early in their lives and achieved
good improvement in the skin condition of these babies.
PMID- 10771981
TI - Measles practices and surveillances in Karachi, Pakistan.
PMID- 10771982
TI - Nitric oxide: biological role and clinical uses.
AB - Nitric oxide is a product of the conversion of L-arginine by the enzyme nitric
oxide synthase. Nitric oxide is involved in a variety of physiological situations
and is produced by many different cell types. It is involved in
neurotransmission, maintenance of vascular smooth muscle tone, and cytotoxicity.
Nitric oxide has been suggested to play an anti-inflammatory role by inhibiting
the expression of the genes for inflammatory cytokines. The pathophysiological
role of nitric oxide is also evident in a variety of diseases, including septic
shock, asthma, reperfusion injury, etc. Nitric oxide, by stimulating the
production of cyclic GMP, relaxes smooth muscles of the cardiovascular,
respiratory, gastrointestinal, and genito-urinary systems. Recent studies have
provided important information on the use of inhaled nitric oxide for the
management of several diseases characterized by the presence of abnormal
pulmonary vascular tone, such as persistent pulmonary hypertension of the
newborn. This review addresses the biology and clinical uses of inhaled nitric
oxide.
PMID- 10771983
TI - Emerging issues in pediatric pulmonology in India.
AB - With the advent of ventilatory care for newborn in India, the practicing
pediatrician is likely to see the "intensive care nursery survivors" who are
likely to manifest an abnormal pulmonary outcome during infancy. These include:
sudden death, bronchopulmonary dysplasia (with chronic lung disease and even core
pulmonale), reactive airway disease, an increased propensity for respiratory
infections and anatomical complications as subglottic stenosis,
tracheobronchomalacia or palatal grooves. These not only have effects on
respiratory compromise but also impact on feeding, growth and development.
PMID- 10771984
TI - Upper airway disease.
AB - More than 40% of children admitted to hospitals have respiratory disorders. Acute
respiratory emergencies are either upper or lower airway obstructive diseases due
to various etiological factors. A comprehensive knowledge and understanding of
the anatomical variation of the upper airway in children is essential in the
management of the critically ill.
PMID- 10771986
TI - Accidental pediatric poisoning--a preventable medical emergency.
PMID- 10771985
TI - Lower airway disease caused by respiratory syncytial virus.
AB - Respiratory syncytial virus (RSV) is the most common cause of lower respiratory
tract disease in infants and young children. Most infections due to RSV are mild
and do not require hospitalization. RSV causes both upper respiratory tract
infections as well as lower respiratory tract infections. Infants with underlying
disease states like bronchopulmonary dyslasia, congenital heart disease and
prematurity appear more prone to develop severe infection and have a higher
incidence of hospitalization. The exact pathogenesis of RSV is not well
understood. The mortality associated with primary RSV infection in healthy
children is estimated to be between .005% to .02%. In hospitalized children the
mortality rate is estimated to be from 1% to 3%. Several treatment modalities in
the form of bronchodilators, corticosteroids, ribavirin, intravenous immune
gammaglobulin and antibiotics are available. Studies have failed to show the true
beneficial effect of any of the above treatment modalities. Supportive care is
only needed. The best treatment is the supportive care in the form of oxygen and
fluids and close monitoring of the vital signs including oxygen saturation.
PMID- 10771987
TI - Poisoning in children: Indian scenario.
AB - The retrospective data on childhood poisoning from eight regional hospitals in
India has been reviewed. The demographic features and types of poisonings
encountered have been compared. The analysis of the data indicated that pediatric
poisonings constituted 0.23-3.3% of the total poisoning. The mortality ranged
from 0.64-11.6% with highest being from Shimla. Accidental poisoning was common
involving 50-90% of children below 5 years of age and males outnumbered the
females. Suicidal poisoning was seen after 13 years of age and was due to drugs
and household chemicals. One of the hospitals in Delhi recorded a very high
incidence (66.6%) of drug poisoning in children. The drugs consumed belonged to
phenothiazines, antiepileptics and antipyretics. Iron poisoning was seen in
younger children. Kerosene was one of the causes of accidental poisoning at all
hospitals except Shimla and rural Maharashtra were probably wood charcoal is
widely used. Pesticide poisoning was more prevalent in Punjab and West Bengal
whereas plant poisoning was very common in Shimla. Significant number of snake
envenomation has been recorded from rural Maharashtra. Other less common
accidental poisonings in children included alcohol, corrosives, heavy metals,
rodenticides, detergents and disinfectants. Thus various regions in the country
showed some variation in types and frequency of childhood poisoning which could
be attributed to different geographical and socio-economic background.
PMID- 10771988
TI - Endemic chronic fluoride toxicity and dietary calcium deficiency interaction
syndromes of metabolic bone disease and deformities in India: year 2000.
AB - Epidemiological studies during 1963-1997 were conducted in 45,725 children
exposed to high intake of endemic fluoride in the drinking water since their
birth. Children with adequate (dietary calcium > 800 mg/d) and inadequate
(dietary calcium < 300 mg/d) calcium nutrition and with comparable intakes of
fluoride (mean 9.5 +/- 1.9 mg/d) were compared. The toxic-effects of fluoride
were severe and more complex and the incidence of metabolic bone disease
(rickets, osteoporosis. PTH bone disease) and bony leg deformities (genu valgum,
genu varum, bowing, rotational and wind-swept) was greater (> 90%) in children
with calcium deficiency as compared to < 25% in children with adequate calcium
who largely had osteosclerotic form of skeletal fluorosis with minimal secondary
hyperparathyroidism. The syndrome of skeletal fluorosis and associated metabolic
bone disease and deformity is a unique clinical entity classified as a variant of
osteosclerotic form of skeletal fluorosis. This syndrome chiefly results from the
biological impact of excess fluoride, low calcium, high PTH and 1,25 (OH)2D3
separately and through their interactions on bone structure and metabolism as
studied by radiology, bone scanning, bone histomorphometry and relevant metabolic
and endocrine laboratory investigations. Metabolically active and vascular bones
of children accumulate fluoride at faster and greater rate than adults (at the
sites of active growth). In calcium deficient children the toxic effects of
fluoride manifest even at marginally high (> 2.5 mg/d) exposures to fluoride.
Fluoride toxicity also exaggerates the metabolic effects of calcium deficiency on
bone. The findings strongly suggest that children with calcium deficiency rickets
reported in the literature should be re-investigated for possible fluoride
interactions. Deep bore drinking water supply with fluoride < 0.5 ppm and
improvement of calcium nutrition provide 100% protection against the toxic
effects of fluoride and are recommended as the cost effective and practical
public health measures for the prevention and control of endemic fluorosis.
PMID- 10771989
TI - Indian red scorpion envenoming.
AB - The clinical course and treatment outcome of scorpion envenoming in 293 children
was studied in a hospital at Mahad in Raigad district of Maharastra. 111 (38%)
children who reported 1-10 hours (mean 3.5 hours) after sting had hypertension,
87 (29.6%) with tachycardia reported within 1-24 hours (mean 6.7 hours) of being
envenomed and 72 (24.5%) children developed acute pulmonary edema after 6-24
hours (mean 8 hours) of sting. Six victims were brought dead, while 17 (6%) died
later owing to multiorgan failure with loss of consciousness and convulsions (who
reported after 24 hours of sting). Early administration of prazosin (125-250 ug
orally) improved the clinical symptoms. Morbidity and mortality due to scorpion
envenoming depends upon time lapse between sting and administration of post
synaptic alpha-1 blocker, prazosin hydrochloride.
PMID- 10771990
TI - Paracetamol poisoning in children.
AB - Paracetamol (acetaminophen) has become an antipyretic drug of choice. Due to its
widespread use, toxicity secondary to overdose has increased in recent years.
Children are especially vulnerable to accidental exposure due to non availability
of child proof containers in India. The main clinical features of acute toxicity
include anorexia, vomiting, abdominal pain, jaundice, hematuria and metabolic
acidoses. Diagnosis is based on history and laboratory findings of acidosis and
abnormal liver function tests. N-acetylcysteine is the specific antidote. This
article reviews in detail the toxicokinetics, pathophysiology, clinical features
and management of paracetamol poisoning in children.
PMID- 10771991
TI - Management of idiopathic thrombocytopenic purpura.
AB - Idiopathic thrombocytopenic purpura is not an uncommon bleeding disorder with a
prevalence of 40-80 per million children per year. Over the last six decades, the
subject of ITP has attracted the attention of pediatricians and hematologists. It
is one of the subjects which has many controversies because of its unpredictable
course heralded by remission relapses, and chronicity with mortality in less than
1% of cases. In the present review only the controversies in the management of
acute and chronic ITP have been reviewed as it interests most pediatricians.
Management of intracranial hemorrhage (ICH), severe gastrointestinal hemorrhage
and menorrhagia continues to still remain a challenge in spite of newer
therapies.
PMID- 10771992
TI - Respiratory function monitoring during mechanical ventilation in pediatric
intensive care unit.
AB - Noninvasive monitoring of lung function during mechanical ventilation has been
used to study disease processes causing respiratory failure. Pediatric pulmonary
function monitoring during mechanical ventilation in the pediatric intensive care
unit in patient with respiratory failure is becoming more common in western
countries. The article describes a review of principles and methods of
respiratory function monitoring in the pediatric age group. It attempts to
incorporate experience from original articles previously published as well as the
experience in monitoring pulmonary mechanics at our institution. Routine
monitoring of pulmonary mechanics in patients being mechanically ventilated may
have significant impact on morbidity and/or mortality of pediatric patients with
respiratory failure. Key articles pertaining to lung function testing in
pediatric age group from past 15 years were used as well as clinical experience
encountered by attending pediatric intensivists at Henrico Doctors' Hospital was
incorporated. Over the past ten years the use of monitoring of gas exchange and
bedside pulmonary mechanics monitoring as a part of respiratory function
monitoring has become more common. With better clinical information to precisely
document the status of lung function, it may lead to improved methods of
ventilator management which may prevent complications and may significantly
impact on morbidity and/or mortality of mechanically ventilated pediatric
patients.
PMID- 10771993
TI - Free oxygen radicals--predictors of neonatal outcome following perinatal
asphyxia.
AB - The study was undertaken to evaluate the role of free oxygen radicals in
asphyxiated neonates. Thirty term neonates appropriate for gestational age and
with severe birth asphyxia (Apgar score of 3 or less at 1 minute of life) formed
the study subjects. The levels of superoxide dismutase (SOD), glutathione
peroxidase (GPx), creatine phosphokinase (CPK) and lipid peroxidase (LPO) in the
CSF of these neonates were estimated between 12 and 48 hrs of life. Enzyme
estimation was performed by standard methods and the results were analysed
statistically using Multivariate Logistic Regression analysis and non parametric
tests namely Kruskal Wallis test and Wilcoxon's rank sum test. Out of the thirty
babies, 14 were observed to be neurologically normal, 9 had significant morbidity
and 7 died. The SOD levels ranged from 12.4 to 140 units/ml, GPx from 128 to 1933
nmol/min/dl, CPK from 2 to 2098 IU/dl and LPO from 5.4 to 30.8 umol/hr/dl. The
SOD and GPx levels had an inverse relationship whereas rise in LPO and CPK levels
were directly proportional to the extent of neurological damage and ultimate
clinical outcome. CPK levels higher than 140 IU/ml were lethal and associated
with 100% mortality whereas all normal neonates had CPK below 37 IU/ml. The
levels of antioxidant enzymes can reliably and significantly predict mortality
and morbidity whereas level of an enzyme cannot confidently confer normalcy.
Hence antioxidant enzyme levels with a cut off value can be a useful marker and
serve as a prognostic indicator in times to come.
PMID- 10771994
TI - Neonatal mortality rate: relationship to birth weight and gestational age.
AB - A total of 2063 live births were studied during one year period from July 1994 to
June 1995. Neonatal mortality rate (NMR) was 35.4 per thousand live births. The
case fatality rate among low birth weight and preterms was 10.1% and 18.1%
respectively. Though, low birth weight babies accounted for 27.8% of the live
births but contributed for 79.5% of neonatal deaths [p < 0.001]. Similarly,
preterm babies accounted for 13.2% of the live births but contributed for 69.9%
of neonatal deaths [p < 0.001]. The causes of neonatal deaths found were birth
asphyxia (31.1%), infections (23.3%), immaturity (17.8%), hypothermia (9.6%),
hyaline membrane disease (2.7%) and cogenital malformation (1.4%). There is need
to identify strategies to reduce the incidence of prematurity and low birth
weight babies. Comprehensive antenatal coverage and adequate care followed by
optimal management of newborns at birth is likely to reduce NMR and improve
quality of life among survivors.
PMID- 10771995
TI - Evaluation of pulse polio immunisation (1996) in Chandigarh, India.
AB - An evaluation survey on pulse polio immunization (PPI) was conducted in Union
Territory of Chandigarh with a population of 88,100 children under the age of
five years. Information was collected by interviewing the companions of 438
children in 18 polio centres, selected by stratified random sampling.
Participation of children in the age-group of 4 and 5 years was found to be low.
Awareness regarding various components of pulse polio immunization was found to
be good in urban areas whereas it was unsatisfactory in slums. Two-dose-coverage
of polio drops in 1996 campaign was recorded to be 81.5%. High risk pockets like
slums need more attention for the success of polio eradication.
PMID- 10771996
TI - Neonatal morbidity and mortality in Nigeria.
AB - A retrospective analysis of neonatal morbidity and mortality was conducted over a
ten-year period (1981-1990) at a tertiary hospital in Ilesa, Nigeria, to
determine the trends in neonatal morbidity and mortality in relation to places of
delivery. 7,225 babies were admitted into the neonatal unit during the period
wherein 3,232 (44.7%) were inborns and 3,993 (55.3%) outborns. Places of delivery
of outborn babies were government hospitals/maternity centres (44.1%), home
(28.5%), private hospitals/clinics (18.8%), and mission houses (8.7%). Major
indications for admission among inborns were neonatal jaundice (45.6%), low
birthweight (18.6%), birth asphyxia (14.2%), and neonatal infections (9.3%),
while those for outborns were neonatal jaundice (39.5%), low birthweight (23.2%),
neonatal infections (18.0%), neonatal tetanus (5.7%), birth asphyxia (4.8%).
Overall mortality rate was 13.0%. It was higher in outborns than inborns (p <
0.001). Mortality was lowest in 1983 and peaked in 1987 and 1988. It was higher
in outborns than inborns during the period (p < 0.001). Major causes of death
were low birth weight (42.8%), neonatal jaundice (14.1%), neonatal tetanus
(12.8%), infections (12.4%), and birth asphyxia (11.6%). In almost all cases,
case fatality rates were higher among the outborns (p < 0.001). Similarly,
mortality was higher in outborns than inborns in almost all the weight range.
Among the outborns, mortality was highest in babies delivered at home and private
hospitals. Improved access to neonatal medical and antenatal care will
significantly reduce neonatal morbidity and mortality in Nigeria.
PMID- 10771997
TI - Iodine deficiency in district Kinnaur, Himachal Pradesh.
AB - The state of Himachal Pradesh is a known iodine deficiency endemic region since
the last 40 years. The state government is supplying iodised salt to the district
since 1970. No recent survey has been conducted on the prevalence of iodine
deficiency from the district Kinnaur which is located at an average altitude of
10,000 feet above sea level. A total of 1094 children in the age group of 6-10
years were included in the study and clinically examined. The total goitre
prevalence of 6.1% was found in the subjects studied. Urine samples were
collected from 226 children and were analysed using standard laboratory
procedures. It was found that the percentage of children with < 2 mcg/dl, 2-4.9
mcg/dl, 5-9.9 mcg/dl and 10 and above mcg/dl of urinary iodine excretion (UIE)
level was 1.3, 5.8, 10.6 and 82.3 respectively. A total of 242 salt samples were
collected and analysed using the standard iodometric titration method. Results
showed that almost 90% of the families were consuming salt with an iodine content
of 15 ppm and more which is the stipulated level of iodisation of salt. The
findings of the study indicate that iodine nutrition is in the transition phase
from iodine deficient to iodine sufficient. Findings revealed a need for further
strengthening the monitoring of the quality of salt being distributed in Kinnaur
to achieve elimination of iodine deficiency.
PMID- 10771998
TI - Interleukin-1-beta, tumor necrosis factor-alpha, insulin secretion and oral
glucose tolerance in non-diabetic siblings of children with IDDM.
AB - Recent reports suggest that the pancreas participates in tumor necrosis factor
alpha (TNF-A) production during stress, and that the islets are predominantly
responsible for such synthesis. In vitro TNF-A and interleukin 1-beta (IL-1-beta)
inhibit insulin release from islet beta-cells. We measured the circulating levels
of IL-1-beta, TNF-A and islet cell antibody (ICA) in 30 children with IDDM (10 of
them at their first presentation), 30 of their non-diabetic siblings, and 30
normal age-matched children. In the non-diabetic children we investigated the
early phase of insulin release after intravenous bolus of glucose and evaluated
tolerance to oral glucose (OGTT). IL-1-beta and TNF-A concentrations were
significantly higher in IDDM-siblings (31.8 +/- 7.7 pg/ml and 650 +/- 155 pg/ml
respectively) versus normal children (21.2 +/- 6.4 pg/ml and 383 +/- 122 pg/ml
respectively). IL-1-beta and TNF-A concentrations did not differ significantly
between the diabetic children and healthy age-matched controls. ICA were detected
in 60% of the recently diagnosed diabetic children vs. 30% of those with longer
duration of diabetes (3.1 +/- 1.2 years). Despite the significantly high
prevalence of ICA in the recently diagnosed children with IDDM, their IL-1-beta
and TNF-A concentrations were lower than those for the normal children. In
experimental animals these cytokines can induce round cell infiltration
(insulinitis) and inhibit insulin secretion by beta-cell. The presence of
significantly higher concentrations of these cytokines in IDDM siblings, with
high prevalence of ICA (16%), was associated with normal oral glucose tolerance
and normal peak insulin response (60 +/- 10.4 mlU/ml) after i.v. glucose bolus
compared to normal children (52.3 +/- 9.5 mlU/ml). However, after 2 years of
follow up, one of them developed IDDM and another developed IGT but none of the
normal controls developed abnormal glucose tolerance. It appears that the process
of autoimmune aggression against beta-cells, and its effect on insulin release
and glucose homeostasis, is a slow and chronic process. However, the production
of these cytokines and consequently the degree of beta-cell destruction, in a
genetically susceptible subject, might be enhanced by several factors including
viral infections. In summary, IL-1-beta and TNF-A levels can be used as
indicators of continuing autoimmune aggression against beta-cells before the
development of extensive beta-cell destruction.
PMID- 10771999
TI - Bone and joint infection in neonates.
AB - A retrospective study was done to review the clinical experience of septic
arthritis and osteomyelitis in the newborns in our centre. Case records of all
the neonates born from January 1989 to August 1994 and those admitted to outborn
nursery from 1985 to 1993 were reviewed. Diagnosis of septic
arthritis/osteomyelitis was made in the presence of relevant clinical signs and
supported by positive culture from blood or joint fluid and abnormal X-ray or
ultrasound findings. The incidence of septic arthritis and osteomyelitis among
inborn babies was 1 in 1500. There were 25 neonates with mean gestational age
34.5 (range 27-40) weeks and mean birth weight 2269 (range 990-4750) gms.
Limitation of movement (64%) and local swelling (60%) were commonest
presentations. A total of 33 joints were involved in 25 babies. Eight babies
(32%) had multiple joint involvement. Hip and knee were the most commonly
involved joints (48% each). In 19 babies (76%) joint involvement occurred in
association with a generalized septicemic illness while 6 babies (24%) had
localised signs and symptoms. Joint aspirate was positive for gram stain or
culture in 12 (48%) and 10 babies (40%) had positive blood culture. Klebsiella
pneumoniae and Staphylococcus aureus were commonest isolates. Radiological
changes were seen in 13 (52%) babies. All were treated with appropriate
antibiotics and open surgical drainage was done in 5 (20%) cases. Bone and joint
infections are important complications in sick septicemic neonates and need early
diagnosis, appropriate management with antibiotics, surgical drainage in selected
cases to prevent long term morbidity.
PMID- 10772000
TI - Rheumatic fever.
PMID- 10772001
TI - Churg-Strauss syndrome.
PMID- 10772002
TI - Anaerobic septicaemia by Fusobacterium necrophorum: Lemierre's syndrome.
AB - Lemierre's syndrome is characterized by acute pharyngotonsillitis with secondary
thrombophlebitis of the internal jugular vein which is complicated by multiple
metastatic foci of infections. This syndrome is caused by Fusobacterium
necrophorum in healthy young persons and is extremely rare in occurrence. A pre
school child with Lemierre's syndrome is reported. The diagnostic and therapeutic
aspects are emphasized in order to sensitize physicians to this uncommon
condition.
PMID- 10772003
TI - Dermoid (hairy polyp) of the nasopharynx.
AB - Dermoids or hairy polyps, the most primitive forms of teratoma are rare lesions
affecting the nasopharynx. They arise during early embryogenesis, being derived
from only two germinal layers, ectoderm and mesoderm and are invariably benign.
They usually present at or soon after birth with signs of upper aerodigestive
tract obstruction. A case of hairy polyp of nasopharynx in a neonate is reported
for its rarity. The etiology of teratomas, their classification in head and neck
region, clinical features, and management in neonates are discussed.
PMID- 10772004
TI - Pseudohypoparathyroidism-Albright hereditary osteodystrophy.
AB - A 13 year old girl with short stature, and retarded mental growth with coarse
facies and deranged thyroid function test was initially suspected as a case of
hypothyroidism and was started on thyroxine. Lack of response to treatment and on
further investigations it was diagnosed as a case of pseudohypoparathyroidism.
High index of suspicion and careful evaluation is important to diagnose such an
entity.
PMID- 10772005
TI - Small cell carcinoma of lung.
PMID- 10772006
TI - Cervical screening: how often should women be screened?
PMID- 10772007
TI - The cervical (Pap) smear--personal experience on both sides of the Atlantic.
PMID- 10772008
TI - Nuclear grooves in intermediate cells in cervical smears.
AB - One thousand cervical smears from women who took part in a hospital-based
screening programme for early detection of cervical cancer were studied for the
presence of nuclear grooves. Grooved nuclei were frequently detected in
intermediate cells in all phases of the menstrual cycle, although their frequency
of occurrence was slightly lower in the luteal and premenstrual phases. The mean
number of nuclear grooves varied from 3.6 to 4.2 in different phases of the
menstrual cycle. The differences, however, were not statistically significant.
The presence of nuclear grooves in cervical cells appears to be a nonspecific
finding at present.
PMID- 10772009
TI - DNA ploidy and p53 protein expression in superficial transitional cell carcinoma
of the bladder.
AB - Superficial transitional cell carcinoma of the bladder (STCCB) is a heterogeneous
group of neoplasias with an unpredictable clinical course. In recent years many
techniques have been used in order to predict the behaviour of these tumours at
individual patient level. The aim of this study was to investigate in imprints
from tumour biopsies the DNA ploidy and p53 protein expression in a group of 80
STCCB (pTa-pT1) patients in relation to histological grade and recurrence status.
The DNA content was studied in Feulgen-stained imprints by the image analysis
technique using a SAMBA 2005 analyser. In order to investigate p53 protein
expression an avidin-extravidin immunocytochemical technique was used. According
to our measurements a strong correlation was observed between recurrence status
and DNA ploidy status (P < 0.001). No statistical difference was found in DNA
ploidy status and grade of malignancy (P = 0.68). A statistically significant
difference was found in p53 protein expression between recurrent and nonrecurrent
tumours (P < 0.001). No statistically significant difference was found among
tumours of grade I, grade II and grade III (P = 0.42). These results could
provide useful information on the potential behaviour of STCCB.
PMID- 10772010
TI - Thin layer compared to direct smear in thyroid fine needle aspiration.
AB - The efficacy of preparing thyroid fine needle aspirations (FNAs) by the thin
layer as opposed to the direct smear method has not been evaluated sufficiently
in a regional laboratory setting. At the Foothills Hospital (Calgary, Canada),
the method of processing thyroid FNAs was changed from direct smear to thin layer
in January 1996. The results of 327 patients who had direct smear from 1994 to
1995 were compared to 401 who had thin layer between 1996 and 1997. While there
were no significant differences across a broad range of quality indicators, thin
layer showed a trend towards a higher proportion of true benign diagnoses (31% vs
24%), a lower proportion of inadequate specimens (41% vs 50%) and, most
importantly, a lower false negative rate (3% vs 9%). In conclusion, the
changeover to thin layer did not compromise the interpretation of thyroid FNAs.
PMID- 10772011
TI - Comparison of transformation zone sampling rates--a potentially useful indicator
of smear taker performance.
AB - Retrospective analysis of 18555 routinely collected smears from women in the age
range 20-50 years reveals that there is a statistically significant relationship
between the overall transformation zone sampling rate achieved in general
practice and the detection rates for cervical abnormality. Similar analysis
comparing unsatisfactory smear rates with rates for the detection of abnormality
demonstrates a negative correlation which fails to achieve statistical
significance. Comparison of transformation zone sampling rates achieved by smear
takers sending samples to the same laboratory is proposed as a potentially useful
performance indicator for smear takers.
PMID- 10772012
TI - A morphometric analysis of cytological features of tall cell variant and
classical papillary carcinoma of the thyroid.
AB - In order to assess whether morphometric parameters could be of value in
distinguishing between tall cell variant and classical pattern of thyroid
papillary carcinoma, the fine needle aspiration cytology (FNAC) samples of 14
cases were analysed using Arcimage 5 software on an Acorn computer. Histological
examination of the specimens allowe classification of nine of them as classical
pattern and the remaining five as tall cell variants. The nuclear diameter (NDD)
and standard deviation distribution (NDSDD), th nuclear area (NAD) and standard
deviation distribution (NASDD), and the nuclear/cytoplasmic ratio (NCR) were
assessed on May-Grunwald-Giemsa stained smears. Statistical analysis was
performed by use of one-way analysis of variance (ANOVA) of the two groups as
identified by histology. Whilst NDD (P = 0.007), NAD (P = 0.015) and NADSD (P =
0.026) all appeared statistically significant, NDSD (P = 0.06) and NCR (P = 0.71)
were not. The cytological diagnosis of papillary carcinoma is established and
reproducible, but morphometric data on the thyroid have so far focused on the
differential diagnosis between benign and malignant nodules. The choice of simple
morphometric parameters appears to be helpful in the preoperative distinction
between the classical pattern and tall cell variant of papillary carcinoma.
PMID- 10772013
TI - Carcinoma arising in a tailgut cyst diagnosed on fine needle aspiration (FNA)
cytology.
PMID- 10772014
TI - Pelvic ganglioneuroma: cytological findings by fine needle aspiration.
PMID- 10772015
TI - Who should be reporting gynaecological cytopathology?
PMID- 10772016
TI - Follicular dendritic cell sarcoma of lymph node.
PMID- 10772017
TI - Uranium.
PMID- 10772018
TI - Liquid destruction.
PMID- 10772019
TI - VIP-Man: an image-based whole-body adult male model constructed from color
photographs of the Visible Human Project for multi-particle Monte Carlo
calculations.
AB - Human anatomical models have been indispensable to radiation protection dosimetry
using Monte Carlo calculations. Existing MIRD-based mathematical models are easy
to compute and standardize, but they are simplified and crude compared to human
anatomy. This article describes the development of an image-based whole-body
model, called VIP-Man, using transversal color photographic images obtained from
the National Library of Medicine's Visible Human Project for Monte Carlo organ
dose calculations involving photons, electron, neutrons, and protons. As the
first of a series of papers on dose calculations based on VIP-Man, this article
provides detailed information about how to construct an image-based model, as
well as how to adopt it into well-tested Monte Carlo codes, EGS4, MCNP4B, and
MCNPX.
PMID- 10772020
TI - Foodstuff survey around a major nuclear facility with test of satellite images
application.
AB - A foodstuff survey was performed around the Savannah River Site, Aiken, South
Carolina. It included a census of buildings and fields within 5 km of the
boundary and determination of the locations and amounts of crops grown within 80
km of the Savannah River Site center. Recent information for this region was
collected on the amounts of meat, poultry, milk, and eggs produced, of deer
hunted, and of sports fish caught. The locations and areas devoted to growing
each crop were determined by the usual process of applying county agricultural
statistics reported by state agencies. This process was compared to crop analysis
of two LANDSAT Thematic Mapper images. For use with environmental radionuclide
transfer and radiation dose calculation codes, locations within 80 km were
defined for 64 sections by 16 sectors centered on the Site and by 16-km distance
intervals from 16 km to 80 km. The median areas per section devoted to each of
four food crops based on county agricultural statistics were about two-thirds of
those based on satellite image analysis. Most locally-raised foodstuff was
distributed regionally and not retained locally for consumption.
PMID- 10772021
TI - Radiation-epidemiological analysis of incidence of non-cancer diseases among the
Chernobyl liquidators.
AB - The work is concerned with assessment of radiation risks for non-cancer disease
among the Chernobyl liquidators from 1986 to 1996. As of 1 January 1999, the
Russian National Medical and Dosimetric Registry contains medical and dosimetric
data for 174,000 liquidators. The cohort of 68,309 liquidators for whom best
verified medical data are available is discussed. The dose dependency of
incidence of non-cancer diseases was estimated by the cohort method and using the
software package Epicure. For some classes of non-cancer diseases among
liquidators, statistically significant estimates of radiation risk were derived
for the first time. The highest excess relative risk per 1 Gy was found for
cerebrovascular diseases; ERR Gy(-1)=1.17 at the 95% confidence interval (0.45;
1.88).
PMID- 10772022
TI - Increased 137Cs metabolism during pregnancy.
AB - A woman temporarily visiting the Brjansk area in southern Russia ingested,
without her knowledge, 35.5 kBq of 137Cs in a single mushroom meal. Seven months
later the woman became pregnant. Her total body content of 137Cs and 40K was
measured regularly in a whole-body counter for three years following this intake.
Data were thus available for the whole-body content for the periods before,
during, and after pregnancy. Urine samples were collected regularly, and on two
occasions breast milk was sampled. The 137Cs concentration in urine and breast
milk was analyzed with a gamma-ray spectrometer. The body content of 137Cs
decreased with a biological half-time of 107 d [95% confidence interval (CI):
106,109] before pregnancy, 58 d (95% CI: 53,64) during pregnancy, and 96 d (95%
CI: 43,346) after the child was born. The ratio between the concentration of
137Cs in the urine (Bq/L urine) and in the body (Bq/kg body weight) increased
during pregnancy from 18 +/- 6% to 35 +/- 6% (+/- 1 SD). The results show that
there was a rapid decrease in the biological half-time of 137Cs at the beginning
of the pregnancy and an increase after the child was born. The biological half
time during pregnancy was 54% of the half-time before pregnancy, which was
reflected in the increased excretion of 137Cs in the urine. The ratio of the
137Cs concentration in breast milk to the whole body was 15% in the first month
of breast-feeding. The effective dose, E, to the mother as a result from this
intake was estimated to be 0.5 mSv, and the absorbed dose to the fetus was 0.06
mGy. These results are consistent with those reported elsewhere.
PMID- 10772023
TI - Study of stabilizing CaF2:Dy ultraviolet sensitivity by double annealing
treatment.
AB - The intrinsic thermoluminescent response to ultraviolet radiation of CaF2:Dy
phosphor is enhanced by pre-irradiation high-temperature annealing treatment. The
thermoluminescent response is stabilized by adding a medium temperature annealing
treatment after the previous annealing. The experimental results show that the
annealing treatment of 1 h 850 degrees C high-temperature annealing followed by 1
h 350 degrees C medium-temperature annealing is the optimum treatment to have
high thermoluminescent response and good stability. The results also show that
(1) the thermoluminescent response to 253.7 nm ultraviolet radiation is increased
and stabilized, (2) the thermoluminescent sensitivity and glow curve distribution
to 235.7 nm ultraviolet radiation are retained, and (3) the thermoluminescent
response to 253.7 nm ultraviolet is linear from 3 to 1 x 10(3) Jm(-2), but there
is no linear response with respect to 365 nm ultraviolet.
PMID- 10772024
TI - Chelating agents for uranium(VI): 2. Efficacy and toxicity of tetradentate
catecholate and hydroxypyridinonate ligands in mice.
AB - Uranium(VI) (UO2(2+), uranyl) is nephrotoxic. Depending on isotopic composition
and dosage, U(VI) is also chemically toxic and carcinogenic in bone. Several
ligands containing two, three, or four bidentate catecholate or
hydroxypyridinonate metal binding groups, developed for in vivo chelation of
other actinides, were found, on evaluation in mice, to be effective for in vivo
chelation of U(VI). The most promising ligands contained two bidentate groups per
chelator molecule (tetradentate) attached to linear 4- or 5-carbon backbones (4
LI, butylene; 5-LI, pentylene; 5-LIO, diethyl ether). New ligands were then
prepared to optimize ligand affinity for U(VI) in vivo and low acute toxicity.
Five bidentate binding groups--sulfocatechol [CAM(S)], carboxycatechol [CAM(C)],
methylterephthalamide (MeTAM), 1,2-hydroxypyridinone (1,2-HOPO), or 3,2
hydroxypyridinone (Me-3,2-HOPO)--were each attached to two linear backbones (4-LI
and 5-LI or 5-LIO). Those ten tetradentate ligands and octadentate 3,4,3-LI(1,2
HOPO), an effective actinide chelator, were evaluated in mice for in vivo
chelation of 233U(VI) (injection at 3 min, 1 h, or 24 h or oral administration at
3 min after intravenous injection of 233UO2Cl2) and for acute toxicity (100
micromol kg(-1) injected daily for 10 d). The combined efficacy and toxicity
screening identified 5-LIO(Me-3,2-HOPO) and 5-LICAM(S) as the most effective low
toxicity agents. They chelate circulating U(VI) efficiently at ligand:uranium
molar ratios > or = 20, remove useful amounts of newly deposited U(VI) from
kidney and bone at molar ratios > or = 100, and reduce kidney U(VI) levels
significantly when given orally at molar ratios > or = 100. 5-LIO(Me-3,2-HOPO)
has greater affinity for kidney U(VI) while 5-LICAM(S) has greater affinity for
bone U(VI), and a 1:1 mixture (total molar ratio = 91) reduced kidney and bone
U(VI) to 15 and 58% of control, respectively--more than an equimolar amount of
either ligand alone.
PMID- 10772025
TI - Testing a BEIR-VI suggestion for explaining the lung cancer vs. radon
relationship for U.S. counties.
AB - The BEIR-VI Report suggests that the large discrepancy between the observed lung
cancer rate vs. radon exposure relationship for U.S. counties, and the
predictions of linear no-threshold theory, may be explained by a strong negative
correlation between smoking intensity and radon exposure. It proposes a model for
testing that suggestion. We apply that model to the detailed data for U.S.
counties; analysis shows that even a perfect negative correlation explains little
more than half of the discrepancy, and the largest not-implausible correlation
can explain less than a quarter of the discrepancy. We then extend the BEIR-VI
suggestion to include a strong negative correlation between both the prevalence
of smoking and the intensity of smoking. The largest not-implausible correlations
can explain no more than 30% of the discrepancy. It is concluded that the
previous interpretation of these data, that linear no-threshold theory fails this
test, is sustained.
PMID- 10772026
TI - An improved model for the reconstruction of past radon exposure.
AB - If the behavior of long-lived radon progeny was well understood, measurements of
these could be used in epidemiological studies to estimate past radon exposure.
Field measurements were done in a radon-prone area in the Ardennes (Belgium). The
surface activity of several glass sheets was measured using detectors that were
fixed on indoor glass surfaces. Simultaneously the indoor radon concentration was
measured using diffusion chambers. By using Monte Carlo techniques, it could be
proven that there is a discrepancy between this data set and the room model
calculations, which are normally used to correlate surface activity and past
radon exposure. To solve this, a modification of the model is proposed.
PMID- 10772027
TI - Modeled concentrations in rice and ingestion doses from chronic atmospheric
releases of tritium.
AB - The expansion of nuclear power programs in Asia has stimulated interest in the
improved modeling of concentrations of tritium in rice, a staple crop grown
throughout the far east. Normally, the specific activity model is used to
calculate concentrations of tritium in the tissue water of edible plants to
assess ingestion dose from chronic releases. However, because rice, like other
grains, has much lower water content than most crops, the calculation must also
account for organically bound tritium. This paper reviews ways to calculate
steady-state concentrations of tritium in rice, including the methods of Canadian
and United States regulatory models, and the assumptions behind them.
Concentrations in rice and resulting ingestion doses are compared for the various
methods, and equations for calculating concentrations are recommended. The
regulatory models underestimate doses received from ingestion of rice
contaminated with tritium since they do not account explicitly for organically
bound tritium. The importance of including organically bound tritium is
illustrated in a comparison of doses from rice, leafy vegetables and milk for an
Asian diet. Dose factors from tritium for these foods are estimated to be 135,
47, and 20 nSv y(-1)/(Bq m(-3)), respectively. Assuming known air concentrations,
tritium concentrations in rice, calculated with the recommended equations, are
uncertain by less than a factor 2 when tritium concentrations in the rice paddy
water are known, and by less than a factor of 2.3 when concentrations in paddy
water are unknown.
PMID- 10772029
TI - Population dose due to natural radiation in Hong Kong.
AB - In densely populated cities such as Hong Kong where people live and work in high
rise buildings that are all built with concrete, the indoor gamma dose rate and
indoor radon concentration are not wide ranging. Indoor gamma dose rates
(including cosmic rays) follow a normal distribution with an arithmetic mean of
0.22 +/- 0.04 microGy h(-1), whereas indoor radon concentrations follow a log
normal distribution with geometric means of 48 +/- 2 Bq m(-3) and 90 +/- 2 Bq m(
3) for the two main categories of buildings: residential and non-residential.
Since different occupations result in different occupancy in different categories
of buildings, the annual total dose [indoor and outdoor radon effective dose +
indoor and outdoor gamma absorbed dose (including cosmic ray)] to the population
in Hong Kong was estimated based on the number of people for each occupation; the
occupancy of each occupation; indoor radon concentration distribution and indoor
gamma dose rate distribution for each category of buildings; outdoor radon
concentration and gamma dose rate; and indoor and outdoor cosmic ray dose rates.
The result shows that the annual doses for every occupation follow a log-normal
distribution. This is expected since the total dose is dominated by radon
effective dose, which has a log-normal distribution. The annual dose to the
population of Hong Kong is characterized by a log-normal distribution with a
geometric mean of 2.4 mSv and a geometric standard deviation of 1.3 mSv.
PMID- 10772028
TI - Dose reconstruction system for the exposed population living along the Techa
River.
AB - The Mayak Production Association, which began operation in 1948, was the first
facility in the former Soviet Union for the production of plutonium. Significant
worker and population exposure occurred as a result of failures in the
technological processes in the late 1940's and early 1950's. Members of the
public were exposed via discharge of about 1017 Bq of liquid wastes into the
Techa River during 1949-1956, an explosion in the radioactive waste-storage
facility in 1957, and gaseous aerosol releases within the first decades of the
facility's operation. Residents of many villages downstream on the Techa River
were exposed via a variety of pathways; the more significant included drinking of
water from the river and external gamma exposure due to proximity to sediments
and shoreline. The specific aim of this project is to enhance the reconstruction
of external and internal radiation doses for individuals in the Extended Techa
River Cohort. The purpose of this paper is to present the details of the methods
that are being used in this enhanced dose-reconstruction effort and to provide
example and representative results of the calculations. The methods of dose
assessment currently being developed for the exposed population [termed the Techa
River Dosimetry System-2000 (TRDS-2000)], which are a significant improvement on
past methods (TRDS-1996), are presented. The new TRDS-2000 doses from the
ingestion of radionuclides are substantially higher for the gastrointestinal
tract, due to consideration of short-lived radionuclides. The TRDS-2000 doses
from external exposure are substantially lower due to improvements in several
factors. Assessment of uncertainty and validation of the "new" doses are
significant issues currently under investigation.
PMID- 10772030
TI - Systematic indoor radon and gamma-ray measurements in Slovenian schools.
AB - During the winter months of 1992/93 and 1993/94, instantaneous indoor radon
concentrations and gamma dose rates were measured in 890 schools in Slovenia
attended in total by about 280,000 pupils. Under "closed conditions," the room to
be surveyed was closed for more than 12 h prior to sampling, the air was sampled
into alpha scintillation cells with a volume of 700 cm3, and alpha activity was
measured. An arithmetic mean of 168 Bq m(-3) and a geometric mean of 82 Bq m(-3)
were obtained. In 67% of schools, indoor radon concentrations were below 100 Bq
m(-3), and in 8.7% (77 schools with about 16,000 pupils) they exceeded 400 Bq m(
3), which is the proposed Slovene action level. In the majority of cases, radon
concentrations were high due to the geological characteristics of the ground.
Approximately 70% of schools with high radon levels were found in the Karst
region. Gamma dose rates were measured using a portable scintillation counter. An
arithmetic mean of 102 nGy h(-1) and a geometric mean of 95 nGy h(-1) were
obtained. No extraordinarily high values were recorded.
PMID- 10772031
TI - Decorporation: officially a word.
AB - This note is the brief history of a word. Decorporation is a scientific term
known to health physicists who have an interest in the removal of internally
deposited radionuclides from the body after an accidental or inadvertent intake.
Although the word decorporation appears many times in the radiation protection
literature, it was only recently accepted by the editors of the Oxford English
Dictionary as an entry for their latest edition.
PMID- 10772033
TI - The pulmonary autograft: the Ross principle (or Ross procedural confusion)
PMID- 10772032
TI - The Silzone dilemma--what did we learn?
PMID- 10772034
TI - Pulmonary autograft versus aortic homograft for aortic valve replacement: interim
results from a prospective randomized trial.
AB - BACKGROUND AND AIM OF THE STUDY: Although pulmonary autografts offer advantages
over aortic homografts, they may also carry additional risks. We reviewed the
interim results of a prospective randomized trial of autograft versus homograft
aortic valve replacement (AVR) to determine if the greater complexity of the
autograft insertion is justified, particularly with regard to time-related
hemodynamic function. METHODS: A total of 182 patients (82% male, 18% female;
mean age 37.2 +/- 14.3 years; range: 2-64 years) with isolated aortic valve
disease were randomized to pulmonary autograft (group A, n = 97) or aortic
homograft (group H, n = 85); 42% had previous aortic valve surgery and 19% had
native or prosthetic valve endocarditis. Follow up included annual outpatient
visits and echocardiography. RESULTS: Autograft AVR required longer cross-clamp
(41%) and bypass (43%) times, but did not result in significantly more bleeding,
longer recovery or more complications. One 30-day death occurred in group A (1%),
and three deaths in group H (4%). Median follow up was 33.9 months (range: 1-61
months). There was one late death in each group, three reoperations in group A
(all for pulmonary homografts), and three in group H (including two aortic
homograft reoperations, both in children). There were no autograft reoperations.
There were no other valve-related events. At 48 months, actuarial survival and
reoperation-free survival rates were 97.8% and 94.2% in group A, and 95.3% and
87.7% in group H (p = NS). Echocardiography showed near-perfect function in all
autografts, but early signs of subclinical dysfunction in many homografts.
CONCLUSION: Both autograft and homograft AVR are safe and produce good
intermediate-term results. Early homograft degeneration appears to favor
autografts in children. The echocardiographic findings may translate into
superior long-term autograft durability and hemodynamics.
PMID- 10772035
TI - Does the Ross operation fulfil the objective performance criteria established for
new prosthetic heart valves?
AB - BACKGROUND AND AIM OF THE STUDY: Objective Performance Criteria (OPC) were
established to compare a new heart valve prosthesis with fixed standards of
linearized complication rates for morbid events: thromboembolism, thrombosis,
hemorrhage, leakage and endocarditis. Although the pulmonary autograft operation
provides optimal hemodynamic performances, the morbidity of both the autograft
and homograft remain topics of controversy. METHODS: Valve-related morbid events
and echocardiography in 109 patients who have undergone the Ross operation since
1991 were evaluated at annual follow up examination (mean 2.8 years; range: 1
month to 8 years). Linearized rates (number of events per 100 years patient
exposure) were calculated to establish the safety and efficacy of this operation
(288.7 years cumulative patient-years). RESULTS: Three patients died
perioperatively (2.8%); two patients were reoperated due to autograft
incompetence (1.8%, both valve repairs). No patient is currently on
anticoagulation therapy, and no events of thromboembolism, valve thrombosis or
bleeding were observed during follow up. Two patients had homograft endocarditis
but were asymptomatic with moderate incompetence at the last follow up
examination. There was no significant increase in aortic incompetence (AI) or
pulmonary incompetence (PI) between discharge and follow up (AI, 0.4 +/- 0.5
versus 0.6 +/- 0.6; PI, 0.2 +/- 0.4 versus 0.4 +/- 0.6). In comparing the OPC
(events per patient-year) for the Ross operation with those for tissue and
mechanical valves, the results were: thromboembolism 0% (tissue 2.5%, mechanical
3%), valve thrombosis 0% (0.2% and 0.8%), all bleeding 0% (1.4% and 3.5%), major
bleeding 0% (0.9% and 1.5%), all leakage 0.7% (1.2% and 1.2%), major leakage 0.7%
(1.2% and 1.2%) and endocarditis 0.7% (1.2% and 1.2%). CONCLUSION: The pulmonary
autograft procedure provides optimal hemodynamics and echocardiographic
performance, and low valve-related complication rates; thus, the OPC for tissue
and mechanical heart valve prostheses can be fulfilled by this technically
demanding operation. These results confirm that the autograft is an ideal aortic
valve replacement device.
PMID- 10772036
TI - Annuloplasty and aortoplasty as modifications of the Ross procedure for the
correction of geometric mismatch.
AB - BACKGROUND AND AIM OF THE STUDY: Pulmonary autograft replacement of the aortic
valve (the Ross procedure) is reliable and durable; however, geometric mismatch
of the autograft and systemic outflow tract may lead to poor results.
Manipulation of the aortic annulus and sinotubular diameters to match the
autograft can prevent geometric mismatch, and improve results. METHODS:
Annuloplasty and/or aortoplasty were combined with the Ross procedure in 26 of 44
patients (median age 42.5 years; range: 3 days to 62 years) undergoing surgery
between April 1994 and July 1998. Plication of the aortic annulus at either two
or three of the commissures was done in five cases, aortic annulus fixation with
an external pericardial pledget incorporated in the proximal suture line in 12
cases, and tailoring aortoplasty in nine patients. RESULTS: There was one
operative death. Two patients required reoperation; one for progressive autograft
dysfunction and one for homograft dysfunction. Annular fixation was performed on
the patient requiring reoperation for autograft dysfunction. Doppler
echocardiography during the follow up (median 9 months; range: 1-50 months)
revealed 10 patients with trace 1+ and one patient with 2+ aortic insufficiency.
Trace 1+ and 2+ aortic stenosis were present in one patient each. None of the
patients undergoing commissural plication had significant regurgitation or
stenosis. Both patients with stenosis underwent annular fixation. Aortoplasty was
associated with 1+ insufficiency in two patients. CONCLUSION: Prevention of
geometric mismatch between the autograft and systemic outflow tract at the
annulus and sinotubular junction by plication techniques allows better
performance of the autograft, and extends the Ross procedure to patients who
otherwise may be unable to undergo such surgery. Fixation may provide similar
benefit, but appears to be more susceptible to insufficiency and stenosis.
PMID- 10772037
TI - Interstitial ice formation in cryopreserved homografts: a possible cause of
tissue deterioration and calcification in vivo.
AB - BACKGROUND AND AIM OF THE STUDY: Cryopreserved valve homografts often fail in
infants. Controversies are ongoing concerning the relative contributions of
cryopreservation variables, immune responses, cellular viability, and durability
of the extracellular matrix to the mode of tissue failure. METHODS: Tissues to be
examined for patterns of ice crystal distribution were cryopreserved. Tissue
water was substituted with methanol and the tissues cryopreserved conventionally
using dimethylsulfoxide, after which they were warmed and processed for light or
electron microscopy. Selected specimens were vitrified to prevent ice crystal
formation, cryopreserved, and subsequently warmed and processed for light and
electron microscopy. RESULTS: Cryosubstitution of conventionally cryopreserved
heart valves, while still frozen, demonstrated extensive extracellular ice
formation, with smaller crystals in the ventricularis than in either the
spongiosa or fibrosa. Extracellular ice formation was prevented by vitrification,
a process in which the biological system is stabilized as an amorphous solid in
the absence of crystalline ice. CONCLUSION: It is proposed that the extensive ice
formation observed in conventionally cryopreserved heart valves may cause
extracellular matrix damage that predisposes the valves to calcification. Future
studies will assess the above hypothesis by comparison of conventional and ice
free (vitrification) cryopreservation methods in animal models of calcification.
PMID- 10772038
TI - Banking of cryopreserved heart valves in Europe: assessment of a 10-year
operation in the European Homograft Bank (EHB).
AB - BACKGROUND AND AIM OF THE STUDY: The preparation, banking and distribution of
cryopreserved heart valves has been carried out at the European Homograft Bank
(EHB) in Brussels without interruption since January 1989. We present an
assessment of the Bank's activities during this 10-year period. METHODS: Heart
valve donors aged <62 years form three categories: multiorgan donors with non
transplantable hearts; recipients of cardiac transplantation; and non-beating
heart cadavers with a warm ischemia time of less than 6 h. Past history and
biology are checked for transmissible diseases. Dissection, incubation in
antibiotics and cryopreservation in 10% dimethylsulfoxide with storage in liquid
nitrogen vapors (about -150 degrees C), and quality control are according to the
standards of the Belgian Ministry of Health. Cryopreserved valves are shipped to
the implantation centers in a dry shipper at about -150 degrees C. RESULTS:
Between January 30th 1989 and December 31st 1998, 1,817 non-transplantable hearts
and 12 excised semilunar valves were obtained. In total, 2,077 valves (1,032
pulmonary, 931 aortic and 13 mitral) were decontaminated, cryopreserved and
stored in liquid nitrogen vapor (six more valves were refrigerated). In total,
1,515 valves were discarded at different stages of the protocol, the main causes
of rejection being significant macroscopic lesions (68.2% aortic and 26.67%
pulmonary). Inadequate excision at procurement (10.37% pulmonary), persistent
contamination after antibiotics (5.6%) and positive serology for hepatitis B and
C and Q fever (5.4%) were other frequent causes for rejection. Among the 2,117
accepted valves, 1,398 were graded first and 719 second choice, mainly on the
basis of morphology. In total, 2,090 cryopreserved valves and one refrigerated
valve were implanted in 39 institutions between May 1989 and December 1998. Of
requests, 10.02% could not be satisfied. In total, 967 pulmonary valves were
implanted in the right ventricular outflow tract (RVOT); 424 during a Ross
procedure, and 76 in the left ventricular outflow tract (LVOT). Of the aortic
valves, 732 were implanted in the LVOT and 266 in the RVOT. Mitral homografts
were used for tricuspid valve replacement in two cases, and in the mitral
position in seven. Complications at distribution and thawing included 10 bag
ruptures and 16 transversal conduit wall fractures. Of the valves shipped, 317
(13.16%) were not used and were returned safely in the dry shipper. Comparison of
distribution rates in the first 5.5 and last 4.5 years of EHB activity shows: (i)
a significant increase in pulmonary valve implantations in the RVOT (from 71.95%
to 81.95%); and (ii) a marked increase (265%) in pulmonary homograft
implantations as part of a Ross operation, and a significant decrease (28%) in
aortic homograft implantation in the LVOT. CONCLUSION: While macroscopic lesions
of procured aortic valves remain the most frequent and unavoidable cause of
homograft rejection during quality control, the high percentage of inadequate
surgical heart valve excision should be corrected. The rates of bacterial
contamination and positive serology seem acceptable. Storage and shipping of
cryopreserved homografts in liquid nitrogen vapor permits them to be spared very
efficiently. The increasing use of pulmonary valves for RVOT reconstruction
either in congenital heart disease or as part of the Ross procedure compensates
for the limited availability of good quality aortic valves.
PMID- 10772039
TI - Results of aortic valve replacement with pulmonary and aortic homografts.
AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement with cryopreserved
human pulmonary or aortic valves (homografts) is an attractive alternative to the
implantation of mechanical valves or bioprostheses, as anticoagulation can be
avoided and a near-normal anatomy restored. However, few reports exist on the
long-term follow up of patients with this type of valve. METHODS: Between 1990
and 1997, a total of 64 homografts were implanted in 62 adults (mean age 42 +/-
12 years) with non-endocarditic valve lesions (insufficiency, n = 16; stenosis, n
= 20; combined lesions, n = 12; redo, n = 16). In total, 23 pulmonary grafts (PG)
and 41 aortic grafts (AG) were used. Valves were obtained from the European
Homograft Bank in Brussels. Two patients with aortic homografts were lost to
follow up; the others were examined clinically and echocardiographically at
yearly intervals (mean 3.6 +/- 2.0 years). Children aged less than 16 years (n =
21), and patients receiving a homograft due to endocarditis (n = 28) or during a
Ross procedure (n = 16) were excluded from the study. RESULTS: Three patients
(5%) died due to early postoperative complications (two with AG, one with PG).
Three PG had to be explanted due to primary malfunction, and five (total 35%)
during further follow up due to severe aortic insufficiency (at a mean of 3.3 +/-
1.8 years). In contrast, all AG were functioning at the end of the observation
period (log rank test, p = 0.0001, chi-square test 13.9). The mean
echocardiographic degree of regurgitation for PG was significantly higher than
for AG (2.2 +/- 1 vs. 0.75 +/- 0.7, p <0.0001). The peak transvalvular gradient
did not differ between groups (PG 12.3 +/- 9 mmHg vs. AG 16.7 +/- 10 mmHg, p =
NS). In respect of perioperative parameters, patients with PG showed a
significantly higher body temperature during the first seven postoperative days
(37.3 +/- 0.6 degrees C vs. 36.8 +/- 0.3 degrees C, p = 0.003). All three
patients with acute graft malfunction in long-term follow up had a perioperative
febrile response without overt bacterial infection. CONCLUSION: In contrast to
grafts of aortic origin, pulmonary homograft valves should not be used for aortic
valve replacement because of their high rate of malfunction, both acutely and
chronically. Higher postoperative body temperatures should lead to further
investigations of possible enhanced immunoreactions against pulmonary homografts.
PMID- 10772040
TI - Mitral valve surgery utilizing homografts: early results.
AB - BACKGROUND AND AIM OF THE STUDY: Mitral valve repair is superior to prosthetic
valve replacement due to preservation of the subvalvular apparatus. We used
cryopreserved homografts for mitral valve replacement in selected cases, in whom
valve repair would not have been successful. METHODS: Cryopreserved homografts
were used in 10 patients (four males, six females; mean age 47 +/- 8 years;
range: 27-65 years), for either complete (n = 7) or partial (n = 3) mitral valve
replacement. Surgery was indicated due to acute endocarditis (n = 3), stenosis (n
= 4) or combined mitral valve disease (n = 3). Transesophageal echocardiography
(TEE) was performed to determine correct homograft size; these values were
compared with intraoperative measurements of valvular dimensions. The function of
the implanted grafts was examined intraoperatively by TEE. Follow up included
clinical examination, electrocardiography and echocardiography. RESULTS: All
patients survived surgery. Intraoperative TEE revealed mild insufficiency (grade
I) in six cases and no insufficiency in four. The papillary muscle-mitral annulus
distance was the most reliable preoperative echocardiographic parameter to
determine the required homograft. Mean pressure gradients were 3.2 +/- 0.7 mmHg
for complete and 2.4 +/- 0.5 mmHg for partial homograft replacement. Sinus rhythm
was present in all cases at discharge. Mean follow up was 24 months (range: 6-36
months). At six-month and one-year follow up, the pressure gradients had risen
slightly to 3.4 +/- 0.6 mmHg (complete) and 2.8 +/- 0.6 mmHg (partial). To date,
four patients had competent grafts, and six presented with an insufficiency
(grade I). All patients had normal left ventricular function (EF 65 +/- 6%) at
their last follow up; there were no signs of endocarditis during the follow up
period. CONCLUSION: Mitral homografts for valve replacement or repair are
recommended in selected cases in whom conservative reconstruction techniques are
not possible. The avoidance of long-term anticoagulation therapy and preservation
of left ventricular geometry are clear advantages to other mitral valve
prostheses.
PMID- 10772041
TI - Glutaraldehyde detoxification in addition to enhanced amine cross-linking
dramatically reduces bioprosthetic tissue calcification in the rat model.
AB - BACKGROUND AND AIM OF THE STUDY: Enhanced fixation of bioprosthetic tissue by
both increased concentrations of glutaraldehyde (GA) and the introduction of
additional cross-links with L-lysine significantly reduces calcification. We have
previously reported that prolonged exposure to high-volume amino-compounds under
warm, acidic conditions leads to thorough, non-rebounding GA detoxification. The
aim of the present study was to prove that removal of excess GA can amplify the
benefits of enhanced GA cross-linking with regard to bioprosthetic tissue
calcification. METHODS: Porcine ascending aortas and leaflet tissue, and bovine
pericardium were immediately fixed using three GA concentrations (0.2%, 1.0%,
3.0% (v/v)) for seven days at 4 degrees C. Samples were allocated to nine groups.
Groups I to III received no further treatment (one at each GA concentration);
groups IV to IX underwent an additional L-lysine interim step (48 h/37 degrees
C/0.1 M) two days before completion of standard seven-day GA fixation; and groups
VII to IX were additionally treated with a GA extraction process using high
volume urazole solution (acetic acid buffer, pH 4.5, 37 degrees C, one week)
followed by NaBH4 reduction (2 days, 37 degrees C). Samples were implanted
subcutaneously in rats (six per group) for six weeks. Tissue calcium was measured
by atomic absorption spectrophotometry and examined histologically after von
Kossa staining. RESULTS: Calcification was reduced in all three tissue types by
enhanced cross-linking and by extraction of excess GA. Increasing the GA
concentration from 0.2% to 3.0% led to a reduction in calcification of 11.5% (p =
0.074; Student's t-test) in leaflets; 63.6% (p <0.0001) in pericardium; and 17.5%
(p = 0.034) in aortic wall tissue. The introduction of additional cross-links
with L-lysine resulted in a significant reduction of calcium in all tissues
(maximally 42.5%, p = 0.0003 in leaflets; 79.3%, p = 0.005 in pericardium; and
49.6%, p <0.0001 in aortic wall; Student's t-test). Optimal reduction in
calcification could be achieved with the combined effect of 3.0% GA fixation, L
lysine enhancement and urazole detoxification. When compared with 0.2% GA-fixed
tissue, calcification could be reduced by 99.1% in leaflets, 95.9% in
pericardium, and 90.8% in aortic wall tissue (p <0.0001 for all tissue types;
Student's t-test). CONCLUSION: Removal of excess GA from fixed bioprosthetic
tissue was capable of markedly improving the anti-calcific effect of enhanced GA
cross-linking.
PMID- 10772042
TI - Glutaraldehyde-induced cross-links: a study of model compounds and commercial
bioprosthetic valves.
AB - BACKGROUND AND AIM OF THE STUDY: The treatment of bioprosthetic tissue routinely
involves the use of glutaraldehyde, although the specific chemistry of
glutaraldehyde fixation is not fully understood. Descriptions of definitive work
on this reaction using model compounds are limited. The aim of the present study
was to increase our understanding of the chemistry involved in the treatment of
collagen-rich tissue with glutaraldehyde. Initially, 6-aminohexanoic acid (6-AHA)
was used to model the lysine/hydroxylysine molecules in collagen before studying
the more complex chemistry of the tissue. METHODS: The reaction between 0.6%
glutaraldehyde and 6-AHA was studied by positive ion electrospray-mass
spectroscopy. Untreated, locally treated and commercially produced explanted and
non-implanted tissue were hydrolyzed under various conditions and analyzed both
directly and after derivatization with 4-chlorophenylhydrazine, 4-bromophenacyl
bromide and dansyl chloride by reverse-phase-high performance liquid
chromatography-mass spectrometry. RESULTS: The mass spectral data obtained from
the reaction of glutaraldehyde with 6-AHA showed the presence of alpha,beta
unsaturated aldehydes and their further condensation products involving Michael
reactions of glutaraldehyde, Schiff base cross-links and various cyclization
products incorporating pyridinium and dihydropyridine ring structures. The only
stable cross-link detected was an 'anabilysine'-like compound. Similar structures
were present in the tissue, and anabilysine was identified by tandem mass
spectrometry. CONCLUSION: The results from the reaction of glutaraldehyde with 6
AHA agree with those published previously. The only detectable stable cross-link
definitively identified in treated bioprosthetic tissue was anabilysine. No long
chain polymers of glutaraldehyde were detected.
PMID- 10772043
TI - Receptor-mediated contraction of aortic valve leaflets.
AB - BACKGROUND AND AIM OF THE STUDY: The mechanisms that regulate the function of the
aortic valve are not fully understood. Cusp tissue has been shown to have
contractile properties, but little is known as to which receptors mediate these
effects. METHODS: We have examined, using isolated organ baths, the response of
porcine aortic valve leaflets to a range of vasoactive agents including
endothelin-1, noradrenaline, adrenaline, the thromboxane (TX) A2 mimetic U46619,
5-hydroxytryptamine (5-HT), histamine and angiotensin II. The viability of each
individual leaflet was tested by the addition of 90 mM KCl. RESULTS: All agents
tested, with the exception of angiotensin II, were capable of inducing
concentration-dependent contractions of the valve leaflets. The responses to
endothelin-1 and U46619 were significantly greater than those of all the other
agents tested. Responses to endothelin-1 could be inhibited by 10(-5) M of the
mixed ET(A/B) receptor antagonist bosantan. The response to both catecholamines
was blocked by 10(-6) M yohimbine, but not by 3 x 10(-7) M prazosin, indicating
the presence of alpha2-adrenoceptors. The response to histamine was mediated
exclusively by H1-receptors, as judged by the antagonistic effect of 10(-6) M of
the H1-receptor antagonist mepyramine. The response to 5-HT could be blocked by
10(-6) M of the 5-HT2A-receptor antagonist ketanserin, and that of U46619 by 10(
6) M of the TXA2-receptor antagonist SQ30741. CONCLUSION: These results
demonstrate the range of receptor systems that can mediate contraction of aortic
valve leaflets. Further studies are required to elucidate the role of these
receptors in the physiology and pathophysiology of the aortic valve.
PMID- 10772044
TI - Expression of 5-hydroxytryptamine receptor subtype messenger RNA in interstitial
cells from human heart valves.
AB - BACKGROUND AND AIM OF THE STUDY: Severe heart valve disorder has been reported in
patients receiving a combination of the anorectic drugs fenfluramine and
phentermine. The exact molecular mechanisms involved remain unknown. Fenfluramine
alters the serotonin level in the brain, while phentermine interferes with the
pulmonary clearance of serotonin; these data suggest that serotonin levels affect
regulation of valve function. The aim of the present study was to characterize
the serotonin receptor (5-hydroxytryptamine) subtypes expressed in the
interstitial cells of human heart valves. METHODS: Interstitial cells were
isolated and cultured from the aortic, pulmonary, mitral and tricuspid valves of
recipient hearts obtained during transplantation. Total RNA was extracted from
cultured cells in order to determine gene expression by reverse transcription
polymerase chain reaction (RT-PCR) using 5-hydroxytryptamine (5-HT) subtype
specific primer pairs. RESULTS: The results show that: (i) 5-HT 1B and 1D
receptor subtypes are expressed in all four heart valves. This is significant as
the 1B and 1D receptor subfamilies are the target of the anti-migraine drug
sumatriptan, and these receptors regulate cardiac function and movement; (ii) 5
HT 1A, 5-HT 1E and 5-HT 1F are not expressed in interstitial cells isolated from
the valves. CONCLUSION: We conclude that preliminary evidence exists for the
presence of distinct subsets of 5-HT receptors in human heart valves, indicating
that interstitial cells of the valves potentially respond to serotonin levels.
PMID- 10772045
TI - Mitral regurgitation following percutaneous transvenous mitral commissurotomy: a
single-center experience.
AB - BACKGROUND AND AIM OF THE STUDY: Percutaneous transvenous mitral commissurotomy
(PTMC) has revolutionized the treatment of patients with symptomatic mitral
stenosis and is now established as the procedure of choice. Despite high
technical expertise in PTMC using the Inoue balloon, mitral regurgitation (MR)
remains a major procedure-related complication. We retrospectively analyzed our
data of PTMC using the Inoue balloon with regard to the incidence of MR, its
likely causative mechanism, and follow up of these patients. METHODS: During the
past ten years, PTMC was performed in 3,650 patients (median age 26 years; range:
8-76 years), of whom 910 (24.9%) were juveniles. Preprocedure mitral valve area
(MVA) was 0.9 +/- 0.4 cm2 (range: 0.3-1.3 cm2); MR was mild in 1,396 cases
(38.2%), moderate in 394 (10.8%) and severe in 22 (0.6%). None of the patients
was rejected on the basis of echocardiographic score. RESULTS: The procedure was
successful in 3,276 (89.8%), with post-procedure MVA of 1.7 +/- 0.6 cm2 (range:
1.4-2.6 cm2), and without development of any major complication. Severe MR was
seen in 120 patients (3.3%), of whom 66 (1.8%) required urgent mitral valve
replacement (MVR). Echocardiography in these latter patients showed leaflet
rupture in 48 (72.7%), chordal rupture in 12 (18.2%) and excessive commissural
tear in six (9.1%). Fifty-four patients (1.5%) with severe MR post PTMC were
followed with medical treatment; echocardiography in these patients revealed
chordal rupture in 40 (74.1%) and excessive commissural tear in 14 (25.9%).
Follow up data were available in 49 patients (1.3%); 30 (0.8%) required MVR and
19 (0.5%) were in NYHA class II at a median follow up of 24 months. Moderate MR
was seen in 188 cases (5.1%), with predominant causative mechanisms of excessive
commissural tear in 120 (63.8%) and chordal rupture in 68 (36.2%). Severity of MR
worsened in 30 cases (0.8%), of which 20 (0.6%) required elective MVR on follow
up. MR decreased in 58 patients (1.6%), in whom excessive commissural tear was
the causative mechanism. CONCLUSION: Significant MR (moderate or severe) after
PTMC was seen in 308 patients (8.4%), of whom 116 (3.2%) required MVR urgently or
on follow up. All patients with leaflet rupture during PTMC developed severe MR
and required urgent MVR. There was a tendency for the severity of MR to decrease
with time in cases where excessive commissural tear was the causative mechanism.
PMID- 10772046
TI - Transient mitral regurgitation following vagal stimulation-induced ventricular
arrhythmia in rabbits: a color Doppler echocardiographic study.
AB - BACKGROUND AND AIM OF THE STUDY: Cervical vagal stimulation in rabbits frequently
causes systolic murmur with bigeminy due to premature ventricular contractions.
The bigeminy disappears in a few minutes, but the systolic murmur persists for a
few days. Peculiar lesions of the mitral valves, mitral annulus and papillary
muscles, and an increase in left atrial weight, frequently develop in a week. In
this study, color Doppler echocardiography was used to examine whether the
systolic murmur was due to mitral regurgitation. METHODS: Echocardiographic
monitoring was carried out in anesthetized rabbits restrained in the supine
position. RESULTS: Doppler echocardiography and phonocardiography showed systolic
murmur at 6 h, three days, and at one, two, three and four weeks after vagal
stimulation. At 6 h after stimulation, phonocardiography showed systolic click
and late systolic murmur; Doppler echocardiography showed marked mitral
regurgitation. The systolic murmur and mitral regurgitation were attenuated and
the papillary muscle was swollen three days after vagal stimulation. Following
stimulation, mitral regurgitation disappeared within one week, and papillary
muscle swelling improved after three weeks. CONCLUSION: Doppler echocardiography
confirmed that systolic murmur caused by vagal stimulation in rabbits was due to
mitral regurgitation.
PMID- 10772047
TI - Worsening of mitral regurgitation secondary to ventricular pacing.
AB - A 68-year-old woman was admitted to hospital for possible mitral valve surgery
for severe mitral regurgitation (MR). Six months before admission, a DDD
pacemaker was implanted for symptomatic bradycardia. She developed atrial
fibrillation and the pacer was changed to a VVI mode. At cardiac catheterization,
the pulmonary artery and wedge pressures were elevated; coronary angiography
showed non-obstructive coronary artery disease. 2-D echocardiography confirmed
preserved left ventricular function, severe MR and moderate tricuspid
regurgitation. The change in pacing had a dramatic effect on MR severity;
ventricular pacing was associated with a MR jet that occupied a larger area of
the left atrium than with the unpaced rhythm, the continuous-wave mitral
regurgitant Doppler profile was 'dagger'-shaped, and the signal intensity
stronger compared with the unpaced rhythm. These findings are consistent with
severe MR. The pacer was reprogrammed to reduce the pacing rate from 70 to 45
beats/min, allowing an unpaced rhythm for the most part. The patient improved and
was discharged two days later. Six months later she was asymptomatic; repeat
echocardiography confirmed mild to moderate MR.
PMID- 10772048
TI - Tricuspid valve repair: a rational alternative.
AB - BACKGROUND AND AIMS OF THE STUDY: The prosthetic ring annuloplasty and
incompletely encircling suture techniques are effective methods of tricuspid
valve repair when the problem is only annular dilatation, but not when organic
tricuspid valve disease is present. A surgical technique of valve repair has been
developed that is equally effective in correcting purely functional as well as
organic valvular incompetence. METHODS: The Manipal method of repairing the
incompetent tricuspid valve consists of three steps: (i) anteroseptal
commissurotomy and asymmetric 'U-on-side' suture annuloplasty, to push the plane
of coaptation of the anterior and septal leaflets into the right ventricle; (ii)
a semicircular De Vega-type of plicating suture through the annulus, starting and
ending just cephalad to the posteroseptal commissure and extending anticlockwise
to a point just caudal to the meridian, to exclude the posterior leaflet; and
(iii) tying the plicating suture after positioning a 3M Starr-Edward valve sizer
across the tricuspid valve (in an adult), to ensure that the valve orifice is not
excessively narrowed. RESULTS: Between July 1986 and January 1997, the Manipal
method was used to repair 52 tricuspid valves, always combined with surgery for
the mitral and/or aortic valve. Tricuspid stenosis of varying degree was present
in 61% of cases. One of two hospital deaths was related to the repaired valve.
Although the proportion of patients followed up fell progressively to 33% at 10
years, none of the patients either seen personally or who had replied to a postal
questionnaire (78% of total patients) required reoperation for valve
regurgitation or obstruction. No patient had more than mild tricuspid
regurgitation clinically, even seven and 10 years after tricuspid valve repair
surgery. CONCLUSION: This alternative method of tricuspid valve repair is simple
to execute, is equally effective in correcting both pure tricuspid regurgitation
and organic tricuspid valve disease, and appears to be extremely stable.
PMID- 10772049
TI - Idiopathic annular dilation: a rare cause of isolated severe tricuspid
regurgitation.
AB - The management of patients with severe tricuspid regurgitation (TR) requires the
clinician to clarify the mechanism of regurgitation. Primary disorders of the
tricuspid valve, either congenital or acquired, may be readily identified by
echocardiography. Severe TR most often results from left-sided heart disease and
secondary pulmonary hypertension. Cardiomyopathic processes may also cause right
ventricular failure and functional TR. We report three patients with severe TR
due to idiopathic annular dilation. The tricuspid valves were otherwise normal on
surgical inspection, and the pulmonary pressures were not significantly elevated.
Each patient was aged over 65 years and had chronic atrial fibrillation with
preserved left ventricular systolic function. Surgical treatment was associated
with marked clinical improvement. Clinicians should recognize this unusual but
treatable cause of right-sided congestive heart failure.
PMID- 10772050
TI - Myxoma of the tricuspid valve.
AB - Tricuspid valve myxomas are extremely rare, with only 21 case reports having been
identified in the literature. A case of tricuspid valve myxoma in a 5-year-old
child is presented. The tumor was a solid type myxoma attached to the septal
leaflet of the tricuspid valve, and manifested as right-sided heart failure. The
patient successfully underwent surgical excision of the tumor without any
recurrence during a follow up of 30 months.
PMID- 10772051
TI - Simultaneous Doppler/catheter measurements of pressure gradients in aortic valve
disease: a correction to the Bernoulli equation based on velocity decay in the
stenotic jet.
AB - BACKGROUND AND AIM OF THE STUDY: Characterization of the severity of a stenotic
aortic valve relies on accurate measurement of the pressure drop across the
valve. A simplified form of the Bernoulli equation has been used to estimate
pressure drops using Doppler ultrasound, but these measurements often
overestimate gold standard measurements performed during cardiac catheterization.
Sources of discrepancy between the Doppler and catheter measurements have been
identified, but no method has been developed to fully reconcile the two
techniques. METHODS: In this study we developed a correction to the clinical form
of the Bernoulli equation based on receiving chamber geometry and turbulent jet
profiles. The theoretical treatment of the mechanical energy balance, assuming a
shape to the stenotic jet profile is described, and the assumptions in our model
are discussed. The use of the model was then demonstrated in an in vivo clinical
study in which simultaneous Doppler and catheter data were obtained. RESULTS:
Discrepancies between Doppler and catheter are shown to be a function of the
predicted pressure recovery location based on our assumed profile. There exists a
distance of about 8.67 valve radii downstream where agreement in peak pressure
gradients is theoretically achieved. CONCLUSION: The results demonstrate the
ability to characterize pressure recovery distal to the valve. Our approach, to
substitute a more appropriate velocity profile into the mechanical energy
balance, unifies geometric parameters and the physics of turbulent jet flow in an
equation involving quantities already routinely measured in an echocardiographic
examination of aortic stenosis. This allows for both the maximal and recovered
pressure gradient to be obtained from the Doppler data. These results have
implications for optimal pressure sensor placement for the assessment of aortic
stenosis and also for the evaluation of prosthetic heart valves in vitro.
PMID- 10772052
TI - A comparison of the classical and modified forms of the continuity equation in
the On-X prosthetic heart valve in the aortic position.
AB - BACKGROUND AND AIM OF THE STUDY: The use of echocardiography to determine
prosthetic valve hemodynamics has become generally accepted; however, there are
still many differing methodologies in use. The continuity equation, which uses
the ratio of the subaortic and transaortic velocity-time integrals for
determining aortic effective orifice area (EOA), has been established as an
accurate method. Another method using the more easily measured peak velocities in
ratio has also been employed. These methods were compared to determine if the
simpler method gave equivalent results. METHODS: Early postoperative
echocardiographic data on prosthetic valves from the MCRI Multicenter Trial were
used to compare the two methods of calculating EOA (A2). Results using the two
methods were compared by paired t-tests, the Wilcoxon signed rank test,
regression and Bland-Altman analysis. RESULTS: Despite a good correlation between
the two methods (r = 0.91), results were different when compared by a paired t
test. On average, results by the modified method were 0.2 cm2 lower, but in 28%
of cases they were in fact higher than the classical method. CONCLUSION: The
modified continuity equation based on the peak velocity ratio does not give the
same result as the classical formula based on the velocity-time ratio. The
modified method cannot reliably be substituted for the classical method in
normally functioning On-X valves.
PMID- 10772053
TI - CarboMedics and Monostrut valves: clinical and hemodynamic outcomes in a
randomized study.
AB - BACKGROUND AND AIM OF THE STUDY: Our aim was to compare the CarboMedics (CM) and
Monostrut (M) mechanical heart valve prostheses in the aortic position. These
prostheses have been studied extensively in the past, both have well-defined
characteristics, and have not been modified for many years. METHODS: This
randomized, prospective study included 200 consecutive patients; 100 received the
CM prosthesis and 100 the M prosthesis. Both groups were statistically similar in
terms of age, aortic valve lesion, and preoperative clinical and surgical
characteristics. Mean follow up was 5.58 years (range: 2 months to 11 years);
total follow up was 1095 patient-years (pt-yr) (CM 5.33 years, 528 pt-yr; M 5.85
years, 567 pt-yr). RESULTS: Early mortality rates were 1% in the CM group and 3%
in the M group. Late mortality rates were 7% and 9%, respectively. Mean (+/- SD)
survival rates at 11 years were 80.51 +/- 7.36% for the CM group and 79.62 +/-
5.59% for the M group. There were no cases of mechanical valve failure in either
group. The linearized rates of major thromboembolism were 1.03% and 0.20% per pt
yr for the CM and M groups, respectively; the rates of major bleeding-events were
0.71% and 0.61% per pt-yr, respectively. The rate of paravalvular leak was 0.35%
and 0% per pt-yr in the CM and M groups, respectively. Postoperative NYHA class
was I-II in 95.83% of CM patients, and in 94.37% of M patients. CONCLUSION:
Clinical results with CarboMedics and Monostrut prostheses are highly
satisfactory, but no superiority of one valve over the other can be identified.
PMID- 10772054
TI - Tilting disc versus bileaflet aortic valve substitutes: intraoperative and
postoperative hemodynamic performance in humans.
AB - BACKGROUND AND AIM OF THE STUDY: Due to an asymmetrical/eccentric flow profile at
the level of the aortic valve, there is an optimal orientation for each aortic
valve design. This study evaluates intraoperative flow dynamics (turbulence and
pressure gradient) and follow up results (pressure gradient and left ventricular
mass regression) for Medtronic Hall tilting disc (MH) and St. Jude Medical
bileaflet (SJM) valves, with both valves in their optimum orientation as defined
in previous animal experiments. METHODS: In a randomized prospective study, MH
and SJM valves (size > or = 23 mm) were implanted in their optimum orientation in
24 patients with aortic stenosis. Turbulence measurements were performed
intraoperatively via a perivascular ultrasound transducer; Reynold's normal
stress (RNS) values were calculated as key markers for turbulent stresses.
Transvalvular pressure gradients, interventricular septum and posterior wall
thickness were measured by transesophageal echocardiography intraoperatively and
six months postoperatively. RESULTS: Mean valve size was 23.8 mm in both groups.
Intraoperative RNS values (MH 7.5 +/- 2.2 N/m2 versus SJM 9.8 +/- 2.3 N/m2) and
pressure gradients (MH 10.0 +/- 2.6 mmHg versus SJM 20.0 +/- 3.4 mmHg) were
significantly lower for the tilting disc valve. At six months follow up, pressure
gradients were reduced by half for both valves (MH 5.3 +/- 1.7 mmHg; SJM 10.4 +/-
2.3 mmHg), with the difference between the valves being maintained. Left
ventricular mass regression was accelerated for MH patients with regard to
interventricular septum thickness. CONCLUSION: Our results indicate that the
tilting disc mechanism shows superior hemodynamic performance with respect to
turbulence and transvalvular pressure gradients compared with the bileaflet
mechanism when both valves are implanted in their optimum orientation. This led
to significant acceleration of interventricular septum mass regression. The
superiority of the tilting disc mechanism is more pronounced in the smaller-sized
valves.
PMID- 10772055
TI - Cardiovascular alpha1-adrenoceptor subtypes: functions and signaling.
AB - alpha-Adrenoceptors (alpha1AR) are G protein-coupled receptors and include
alpha1A, alpha1B, and alpha1D subtypes corresponding to cloned alpha1a, alpha1b,
and alpha1d, respectively. alpha1AR mediate several cardiovascular actions of
sympathomimetic amines such as vasoconstriction and cardiac inotropy,
hypertrophy, metabolism, and remodeling. alpha1AR subtypes are products of
separate genes and differ in structure, G protein-coupling, tissue distribution,
signaling, regulation, and functions. Both alpha(1A)AR and alpha(1B)AR mediate
positive inotropic responses. On the other hand, cardiac hypertrophy is primarily
mediated by alpha(1A)AR. The only demonstrated major function of alpha(1D)AR is
vasoconstriction. alpha1AR are coupled to phospholipase C, phospholipase D, and
phospholipase A2; they increase intracellular Ca2+ and myofibrillar sensitivity
to Ca2+ and cause translocation of specific phosphokinase C isoforms to the
particulate fraction. Cardiac hypertrophic responses to alpha1AR agonists might
involve activation of phosphokinase C and mitogen-activated protein kinase via Gq
x alpha1AR subtypes might interact with each other and with other receptors and
signaling mechanisms.
PMID- 10772056
TI - Ion channel modifying agents influence the electrical activity generated by
canine intrinsic cardiac neurons in situ.
AB - This study was designed to establish whether agents known to modify neuronal ion
channels influence the behavior of mammalian intrinsic cardiac neurons in situ
and, if so, in a manner consistent with that found previously in vitro. The
activity generated by right atrial neurons was recorded extracellularly in
varying numbers of anesthetized dogs before and during continuous local arterial
infusion of several neuronal ion channel modifying agents. Veratridine (7.5
microM), the specific modifier of Na+-selective channels, increased neuronal
activity (95% above control) in 80% of dogs tested (n = 25). The membrane
depolarizing agent potassium chloride (40 mM) reduced neuronal activity (43%
below control) in 84% of dogs tested (n = 19). The inhibitor of voltage-sensitive
K+ channels, tetraethylammonium (10 mM), decreased neuronal activity (42% below
control) in 73% of dogs tested (n = 11). The nonspecific potassium channel
inhibitor barium chloride (5 mM) excited neurons (47% above control) in 13 of 19
animals tested. Cadmium chloride (200 microM), which inhibits Ca2+-selective
channels and Ca2+-dependent K+ channels, increased neuronal activity (65% above
control) in 79% of dogs tested (n = 14). The specific L-type Ca2+ channel
blocking agent nifedipine (5 microM) reduced neuronal activity (52% blow control
in 72% of 11 dogs tested), as did the nonspecific inhibitor of L-type Ca2+
channels, nickel chloride (5 mM) (36% below control in 69% of 13 dogs tested).
Each agent induced either excitatory or inhibitory responses, depending on the
agent tested. It is concluded that specific ion channels (I(Na), I(CaL), I(Kv),
and I(KCa)) that have been associated with intrinsic cardiac neurons in vitro are
involved in their capacity to generate action potentials in situ.
PMID- 10772057
TI - Acute cord occlusion increases blood ionized magnesium concentration in preterm
fetal sheep during maternal magnesium sulfate exposure.
AB - This study tested the hypothesis that a pathophysiologic insult to the fetus that
decreases pH (umbilical cord occlusion) produces an increase in physiologically
active (i.e., ionized) magnesium concentration. Preterm pregnant sheep (n = 7)
were instrumented with maternal and fetal catheters and an inflatable vascular
occluder was placed around the umbilical cord. After a 2-day recovery period,
each ewe received a 4-g loading dose, followed by continuous intravenous infusion
of 1 g magnesium sulfate/h. After 48 h, an episode of acute fetal distress was
produced by inflation of the umbilical occluder for 10 min. Maternal and fetal
arterial blood samples were collected at regular intervals to quantitate ionized
magnesium concentration and monitor physiologic status. Magnesium sulfate
infusion increased maternal and fetal blood ionized magnesium concentration. In
vitro blood analysis demonstrated that there was a linear inverse correlation (r2
= 0.99) between fetal sheep blood pH and ionized magnesium concentration. In
vivo, 10 min of umbilical cord occlusion produced an increase in fetal blood
ionized magnesium concentration in all animals (P = 0.02) that was temporally
related to the decrease in fetal blood pH. Whether this increase in
physiologically active magnesium concentration is beneficial (via
neuroprotection) or deleterious (via suppression of stress response) to the
distressed fetus remains to be determined.
PMID- 10772058
TI - Tissue distribution and antithrombotic activity of unlabeled or 14C-labeled
porcine intestinal mucosal heparin following administration to rats by the oral
route.
AB - Distribution and antithrombotic activity of orally administered unfractionated
porcine heparin were studied. [14C]Heparin was prepared by de-N-acetylation of
porcine mucosal heparin followed by re-N-acetylation, using [14C]acetic
anhydride. [14C]Heparin and (or) cold heparin (60 mg/kg) were administered by
stomach tube to male Wistar rats. Blood, all levels of gut and gut contents,
liver, lung, spleen, kidney, and aortic and vena caval endothelium were collected
under deep anesthesia at 3, 6, 15, 30, and 60 min and 4 and 24 h (6 rats/group)
after administration. Urine and feces were collected at 24 h, using metabolic
cages. In three additional rats, drugs were administered in gelatin capsules.
Tissues listed above and tongue, esophagus, trachea, brain, heart, thymus, bile
ducts, vena caval and aortic walls, ureters, bladder, samples of muscle, skin,
hair, and bone marrow were collected at 24 h. Radioactivity and chemical heparin,
measured by agarose gel electrophoresis, were observed in all tissues examined as
well as gut washes, plasma, urine, and feces. Radiolabel recovered was confirmed
to be heparin by autoradiograms of gradient polyacrylamide electrophoretic gels.
[14C]Heparin and chemical heparin in gut tissue suggest a transit time of 4 h.
Porcine or bovine heparin (7.5 mg/kg), administered by stomach tube, decreased
the incidence of thrombosis induced by applying 10% formalin in 65% methanol to
the exposed jugular vein of rats. Heparin isolation from non-gut tissue,
endothelium, urine, and plasma and the observed antithrombotic effect are
consistent with oral bioavailability.
PMID- 10772059
TI - Age-dependent metabolic effects of repeated hypoxemia in piglets.
AB - The aim of this study was to determine whether repeated exposure to hypoxemia
would modify the response to hypoxemia during maturation. We exposed piglets to
three 1-h cycles of hypoxemia (PaO2 = 30 to 35 mmHg; 1 mmHg = 133.3 Pa) at 1 week
(n = 9), 2-3 weeks (n = 10), and 4-5 weeks of age (n = 10). O2 consumption
(V(O2)) and CO2 production (V(CO2)) were measured, and alveolar ventilation
(V(A)) was derived from V(CO2) and PaCO2. Levels of lactic acid (lactate) and
serum catecholamines were also measured. With hypoxemia, time had a significant
effect on V(O2) and body temperature in an age-dependent fashion: that is,
whereas the 1 week group and the 4-5 week group showed both variables decreasing
over time, the 2-3 week group showed no drop in V(O2) and a small increase in
body temperature over time. Lactate levels increased with hypoxemia in all
animals during the first exposure. However, with repeated exposures to hypoxemia,
only the 2-3 week group continued to increase its lactate levels. Furthermore,
the changes in lactate levels paralleled the changes in epinephrine levels with
hypoxemia. We found, too, that although V(A) increased significantly with
hypoxemia in all animals, this change was not modified by age or repeated
exposures. No significant effects of age or repeated exposures were found in the
cardiovascular response to hypoxemia. We concluded that, from a metabolic
viewpoint, after repeated exposures to hypoxemia the 2-3 week animals responded
differently.
PMID- 10772061
TI - Relationship between vanadate induced relaxation and vanadium content in guinea
pig taenia coli.
AB - Abstract: Vanadate has been known to induce a transient increase in high K+
induced contraction, and also gradually relax the high K+ contraction itself in
guinea pig taenia coli. The relationship between the rate of relaxation and ion
content of Na+, K+, and V ion at the cellular level was investigated when
vanadate was applied to contracted muscle. Tissue Na+ and V ion content increased
linearly, depending on the time after vanadate treatment, reaching maximum levels
of approximately 50 mM x kg(-1) and 0.25 mM x kg(-1) wet weight, respectively.
There was a positive correlation between the V ion and Na+ contents, while there
was a negative correlation between both ions and the relaxed rate of the high K+
induced contraction. The uptake of V ion was affected by the external K+
concentration, and the maximum rate of V ion uptake decreased to 40% in the
presence of 90 mM external K+. These results suggest that a small amount of V ion
was enough to inhibit the Na+ pump activity and muscle contraction in the high K+
solution.
PMID- 10772060
TI - Doxorubicin-induced late cardiotoxicity: delayed impairment of Ca2+-handling
mechanisms in the sarcoplasmic reticulum in the rat.
AB - Doxorubicin treatment causes delayed development of cardiotoxicity. Whether the
doxorubicin-induced impairment of cardiac functions reverses or progresses with
time after the cessation of the treatment was examined. The rats were injected
with doxorubicin (2.5 mg/kg, i.v., once a week for 3 weeks) and sacrificed at 1
(1W), 13 (13W), or 18 (18W) weeks after the final doxorubicin administration. The
time to peak of twitch contraction observed at 2-Hz stimulation was not altered
in left atrial or ventricular muscle preparations isolated from 1W rats, but it
was prolonged in those from 13W and 18W rats. The reduction of the magnitude of
postrest contraction and the alteration of force-frequency relationships in left
atrial muscle preparations in 1W rats were not significant, but were intensified
in the 13W and 18W groups. Alterations in the postrest contraction and the force
frequency relationships in ventricular muscle preparations isolated from
doxorubicin-treated rat hearts were weaker, but the pattern of alteration was
similar to that observed in left atrial muscle preparations. Caffeine-induced
contraction observed in skinned fibers that were isolated from the 1W rats was
not altered, but it was reduced in the 18W rats. The Ca2+ sensitivity of
contractile proteins was not altered in doxorubicin-treated rat hearts in any of
the groups. The K(d) values estimated from a [3H]ryanodine binding study were not
altered, but the B(max) values were significantly lower in the 13W and 18W groups
than those observed in control rats. These results suggest that the dysfunction
of the sarcoplasmic reticulum progresses after the completion of doxorubicin
treatment and contributes to the doxorubicin-induced late cardiotoxicity.
PMID- 10772062
TI - Potentiation of carbon monoxide-induced relaxation of rat aorta by YC-1 [3-(5'
hydroxymethyl-2'-furyl)-1-benzylindazole].
AB - The hypothesis that endogenous carbon monoxide (CO), produced during the
oxidation of heme catalyzed by heme oxygenase (HO), plays a role similar to that
of nitric oxide (NO) in the regulation of cardiovascular tone has been criticized
because of the low potency of CO compared with NO in relaxing blood vessels and
stimulating soluble guanylyl cyclase (sGC). This criticism has been muted by the
demonstration that, in the presence of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1
benzylindazole], CO has similar potency to NO in stimulating sGC activity. In
this study, we determined that YC-1 potentiated CO-induced relaxation of rat
aortic strips (RtAS) by approximately ten-fold. Furthermore, CO-induced
relaxation of RtAS was shown to be mediated through stimulation of sGC because
vasorelaxation was inhibited by ODQ (1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1
one), a selective sGC inhibitor, in the absence and presence of YC-1. A gas
chromatographic-headspace method was used to measure CO concentration in Krebs'
solution following the addition of CO-saturated saline solution to the tissue
bath, in order to provide an accurate determination of RtAS exposure to CO. The
tissue bath concentration of CO was shown to be approximately one-half of that
calculated to be present. We conclude that should an endogenous compound exist
with properties similar to that of YC-1, then the potency of CO as a vasorelaxant
in the presence of this factor would be increased. As a consequence, CO could
play a role in the regulation of cardiovascular tone, comparable to that of NO.
PMID- 10772064
TI - Ascorbic acid and copper in linoleate oxidation--Dunkley revisited.
PMID- 10772063
TI - Length dependence of staircase potentiation: interactions with caffeine and
dantrolene sodium.
AB - In skeletal muscle, there is a length dependence of staircase potentiation for
which the mechanism is unclear. In this study we tested the hypothesis that
abolition of this length dependence by caffeine is effected by a mechanism
independent of enhanced Ca2+ release. To test this hypothesis we have used
caffeine, which abolishes length dependence of potentiation, and dantrolene
sodium, which inhibits Ca2+ release. In situ isometric twitch contractions of rat
gastrocnemius muscle before and after 20 s of repetitive stimulation at 5 Hz were
analyzed at optimal length (Lo), Lo - 10%, and Lo + 10%. Potentiation was
observed to be length dependent, with an increase in developed tension (DT) of 78
+/- 12, 51 +/- 5, and 34 +/- 9% (mean +/- SEM), at Lo - 10%, Lo, and Lo + 10%,
respectively. Caffeine diminished the length dependence of activation and
suppressed the length dependence of staircase potentiation, giving increases in
DT of 65+/-13, 53 +/- 11, and 45 +/- 12% for Lo - 10%, Lo, and Lo + 10%,
respectively. Dantrolene administered after caffeine did not reverse this effect.
Dantrolene alone depressed the potentiation response, but did not affect the
length dependence of staircase potentiation, with increases in DT of 58 +/- 17,
26 +/- 8, and 18 +/- 7%, respectively. This study confirms that there is a length
dependence of staircase potentiation in mammalian skeletal muscle which is
suppressed by caffeine. Since dantrolene did not alter this suppression of the
length dependence of potentiation by caffeine, it is apparently not directly
modulated by Ca2+ availability in the myoplasm.
PMID- 10772066
TI - The involvement of singlet oxygen in copper-phenanthroline/H2O2-induced DNA base
damage: a chemiluminescent study.
AB - Copper in the presence of excess 1,10-phenanthroline, a reducing agent, and H2O2
causes DNA base damage as well as strand breakage. We have reported in previous
work that a strong chemiluminescence was followed by DNA base damage in this
system, which is characteristic of guanine. In the present work, the mechanism of
the chemiluminescence was studied. Results show that the luminescence was
inhibited by all three classes of reactive oxygen species (*OH, O2-, (1)O2)
scavengers to different degrees. Singlet oxygen scavengers showed the most
powerful inhibition while the other two classes of scavengers were relatively
weaker. The emission intensity in D2O was 3-fold that in H2O. Comparing the
effect of scavengers on the luminescence of DNA with that of dGMP, the ratio of
inhibition was similar. On the other hand, DNA breakage analysis showed that
inhibition by the singlet oxygen scavenger NaN3 of strand breakage was strong and
comparable to that of the scavengers of the two oxygen radicals. The results
suggest that singlet oxygen may be a major factor for the chemiluminescence of
guanine, while DNA strand breakage may be caused by many active species.
PMID- 10772065
TI - Glyceryl trinitrate, a nitric oxide donor, suppresses renal oxidant damage caused
by potassium bromate.
AB - Nitric oxide (NO) is a short-lived, readily diffusible intracellular messenger
molecule associated with multiple organ-specific regulatory functions. Endogenous
stimulation or exogenous administration of NO have been shown to inhibit
production of reactive oxygen species (ROS) and expression of oxidant-mediated
molecular or tissue injury. Potassium bromate (KBrO3) is one such potent renal
oxidant that acts through generation of ROS-mediated lipid peroxidation, and
causes increased ornithine decarboxylase activity, enhanced rate of DNA synthesis
and depletion of the antioxidant armoury of the tissue. In this study, we
elucidate the effect of exogenous NO administration, using the NO donor glyceryl
trinitrate (GTN), on KBrO3-induced nephrotoxicity, oxidative stress and cell
proliferation. KBrO3 administration at a dose of 125 mg/kg body weight results in
significant (P < 0.001) depletion in renal glutathione (GSH) content, and
glutathione reductase (GR) activity with a concomitant increase in microsomal
lipid peroxidation, and blood urea nitrogen (BUN) and creatinine levels. Parallel
to these changes, we found significant enhancement in ornithine decarboxylase
(ODC) activity and rate of renal DNA synthesis. Subsequent administration of GTN
resulted in dose-dependent amelioration of GSH content and GR activity with
concomitant inhibition of lipid peroxidation, and BUN and creatinine levels. In
addition, GTN administration to KBrO3-intoxicated rats resulted in significant
dose-dependent down regulation of enhanced ODC activity and rate of [3H]
thymidine incorporation in renal DNA, providing support for the protective role
of NO in attenuation of KBrO3-induced oxidative stress and cell proliferation.
Enhancement of oxidative tissue injury and cell proliferation on administration
of the NO inhibitor, L-NAME, further demonstrates the protective efficacy of
endogenous NO. These data suggest that NO inhibits KBrO3-induced tissue injury,
oxidative stress and proliferative response in the rat kidney.
PMID- 10772067
TI - Antioxidants suitable for use with chemiluminescence to identify oxyradical
species.
AB - From a panel of 24 alleged antioxidants the most suitable antioxidants (AO) for
use with chemiluminescence (CL) experiments were determined. Superoxide dismutase
(SOD), using luminol as the chemiluminescence probe (Lum-CL), was inhibitory only
towards O2*- and not HO* or (1)O2. SOD was thus a suitable antioxidant for O2*-,
as was tiron. Tiron had advantages, however, since SOD acted as a pro-oxidant in
the presence of H2O2 or H2O2/HO* generators. The two most suitable antioxidants
for (1)O2 were diphenylisobenzofuran (DBF) and tryptophan, for both Lum and
Lucigenin-CL (Luc-CL). Desferrioxamine, with both Lum and Luc-CL, was a very
effective scavenger for HO*, but appeared to be an even more effective scavenger
for (1)O2. Cysteamine showed the best discrimination between IC50s when the two
(1)O2 generators NaOCl/H2O2 and NDPO2 were compared. Cysteamine was, therefore,
the only scavenger that was appropriate for studies with hypochlorite. Melatonin,
with Lum-CL, was found to be the most suitable scavenger for HO*. Mannitol, the
classical AO for HO*, was not suitable when used with CL since it acted as a pro
oxidant. Some of the AOs revealed either calyx- or bell-shaped CL inhibition
profiles and presumably, therefore, may act as both pro- or antioxidants at
different concentrations. Antioxidants showing these kinds of dual activities
should be used with caution in CL studies.
PMID- 10772068
TI - Effect of antioxidant supplementation on the adaptive response of human skin
fibroblasts to UV-induced oxidative stress.
AB - The effect of supplementation with substances having antioxidant properties on
the adaptive responses of human skin fibroblasts to UV-induced oxidative stress
was studied in vitro. UVR was found to induce a substantial oxidative stress in
fibroblasts, resulting in an increased release of superoxide anions and an
increase in lipid peroxidation (shown by an elevated malonaldehyde content). Sub
lethal doses of UVR were also found to induce adaptive responses in the
fibroblast antioxidant defences, with a transient rise in catalase and superoxide
dismutase activities followed by a slower, large increase in cellular glutathione
content. Supplementation of the fibroblasts with the antioxidants, Trolox (a
water soluble analogue of alpha-tocopherol), ascorbic acid or beta-carotene, had
differential effects on these responses. Trolox supplementation reduced the UVR
induced cellular oxidative stress and adaptive response in a predictable
concentration-dependent manner. This was in contrast to ascorbic acid which
increased superoxide release from fibroblasts. At low doses, ascorbate
supplements also reduced the magnitude of the adaptive increases in catalase and
superoxide dismutase activities and increase in glutathione content. Beta
carotene had a similar effect to ascorbic acid, reducing the extent of the
adaptations to UVR at lower doses while simultaneously increasing superoxide
release and malonaldehyde content. These in vitro data indicate that only the
vitamin E analogue suppressed UVR-induced oxidative stress in a predictable
manner and suggest that common dietary antioxidants may not be equally effective
in reducing the potential deleterious effects of UVR-induced oxidative stress in
skin.
PMID- 10772069
TI - Sunscreens, oxidative stress and antioxidant functions in marine organisms of the
Great Barrier Reef.
AB - An overview of the biochemical photophysiology of tropical, reef-building corals
is presented with a discussion on the biosynthetic relationship between natural
UV-absorbing sunscreens and certain antioxidant functions in marine organisms.
Our studies reveal that marine organisms, including 'UV-extremophilic' bacteria,
are a rich source of novel antioxidants having potential for the development of
commercial and biomedical applications. Novel sunscreening agents derived from
tropical marine organisms of the Great Barrier Reef are in development. New
marine-derived antioxidants are being isolated for testing as chemopreventatives
in a variety of oxidatively degenerative diseases.
PMID- 10772070
TI - Transcriptional responses of human melanocytes to solar UV.
PMID- 10772071
TI - Does sunscreen protection from immunosuppression by solar UV radiation predict
protection from photocarcinogenesis?
PMID- 10772072
TI - Effect of iron chelators with potent anti-proliferative activity on the
expression of molecules involved in cell cycle progression and growth.
PMID- 10772073
TI - Redox availability of lens iron and copper: implications for HO* generation in
cataract.
PMID- 10772074
TI - Effect of inhibitors of oxygen radical and nitric oxide formation on UV radiation
induced erythema, immunosuppression and carcinogenesis.
AB - We investigated whether supplementation of a sunscreen containing the UVB
absorber 2-ethyl-hexyl-methoxycinnamate (cinnamate) with oxygen radical
inhibitors (ORI) would improve protection from sunburn, immunosuppression and
carcinogenesis. Mice were exposed to solar-simulated UV radiation (ssUV)
containing a mixture of UVB and UVA. In initial studies, the ORI 2,2'-dipyridyl
and N(G)-monomethyl-L-arginine acetate (L-NMMA) were shown to prevent UVA-induced
suppression of contact sensitivity (CS) in mice. Addition of these inhibitors to
the sunscreen did not affect the sun protection factor (SPF), but lowered the
level of edema when mice were exposed to ssUV. Combination of both inhibitors
with the sunscreen, however, increased the SPF from 5 to 5.5. The immune
protection factor (IPF) of the sunscreen was only 1.18, but addition of neither
dipyridyl nor L-NMMA singly or in combination measurably improved immune
protection. However, the ORI improved the ability of the sunscreen to prevent
carcinogenesis. The results indicate that reactive oxygen or nitrogen species
produced in response to UV radiation are important for erythema,
immunosuppression and carcinogenesis, and addition of inhibitors improves the
protective capacity of sunscreens.
PMID- 10772075
TI - Chlorination of nucleobases, RNA and DNA by myeloperoxidase: a pathway for
cytotoxicity and mutagenesis by activated phagocytes.
PMID- 10772076
TI - Role of immune mediators in the pathology of experimental murine cerebral
malaria.
PMID- 10772077
TI - A general mechanism of polypeptide cross-linking by 3-hydroxykynurenine.
PMID- 10772078
TI - Determination of hydroperoxides by the ferric-xylenol orange method.
PMID- 10772079
TI - The effect of antioxidants on global and cytokine gene expression in T
lymphocytes.
PMID- 10772080
TI - Fas and perforin contribute to the pathogenesis of murine cerebral malaria.
PMID- 10772081
TI - Oxidative modification of a specific apolipoprotein B lysine residue confers
altered receptor specificity on LDL.
PMID- 10772082
TI - Skrljevo disease--two centuries of history.
AB - Skrljevo disease, also called Rijeka (Fiume) or Grobnik disease, by some
physicians was first identified in the village of Skrljevo in Croatia in 1790.
From texts dating back to the beginning of the 19th century it is clear that it
was a non-venereal (endemic) form of syphilis and represented a great calamity
for the local people and a problem for the physicians. The disease was considered
by some to be lepra, scurvy, scabies or others. The occurrence of the disease in
the region around Rijeka was closely associated with the poor socioeconomic
conditions present at that time in the region. It is interesting to note that
many of the greatest physicians of the time such as Alibert, Frank, Hebra,
Sigmund were acquainted with the disease and dealt with it in their writings.
This paper gives a brief chronology of the major political events in the region
since that time, underlying the measures used in fighting the disease.
PMID- 10772083
TI - Symptomatic and health status outcomes in the Canadian randomized MAC treatment
trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.
AB - Our objective was to compare the effect of 2 regimens for treatment of
Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on
symptoms and health status outcomes using a substudy of an open-label randomized
controlled trial. The study was conducted in 24 hospital-based human
immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV
infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol
15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4
drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial),
ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm).
The primary health status outcome was the change on the 8-item symptom subscale
of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on
other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients
on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks
(P=0.06), with statistically significant differences restricted to night sweats
and fever and chills (P < 0.001). The proportion of patients improving on the
symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4
drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks
(P < 0.001) and better outcomes on the social function, mental health,
energy/fatigue, health distress and cognitive function subscales of the MOS-HIV.
The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated
symptoms, functional status and other aspects of health status.
PMID- 10772084
TI - The efficacy and tolerability of combination antiretroviral therapy in pregnancy:
infant and maternal outcome.
AB - Antiretroviral therapy (ART) and Caesarean section (CS) delivery significantly
reduce the risk of vertically transmitted HIV infection. Attention must focus on
determining the optimal management strategy for HIV-positive pregnancies.
Guidelines must reflect not only the activity and tolerability of combination ART
in pregnancy for mother and infant and the potential short and long-term infant
toxicity, but also whether surgical delivery can confer an added benefit if
combination ART had reduced plasma viraemia to undetectable levels. To aid the
development of management strategies for the Republic of Ireland, a retrospective
detailed review of all HIV-positive pregnancies since the introduction of
combination ART was undertaken. Since 1997 there have been 25 deliveries to 24
women. Combination ART reduced plasma viraemia to undetectable levels in 76%
mothers at delivery. The CS rate was 28% and no unanticipated infant toxicity was
encountered. To date no infant has proven infected. Three infants have
seroreverted and 24 of 26 infants have had at least 2 negative HIV ribonucleic
acid (RNA) and polymerase chain reaction (PCR) tests. Two infants are less than
one month old. In this study, the CS rate of 28% is below that reported from many
centres yet no vertical transmission was found. Given the efficacy of ART in
reducing plasma viraemia, the additional benefit of CS for these women is
questionable.
PMID- 10772085
TI - Significance of laboratory findings for the diagnosis of neurosyphilis.
AB - Our objective is to assess the specificity and sensitivity, and thus elaborate
the relevance, of different laboratory findings for the diagnosis of
neurosyphilis. One hundred and fourteen HIV-negative pairs of serum and
cerebrospinal fluid (CSF) samples were examined by the Venereal Disease Research
Laboratory (VDRL) test, a fluorescent treponemal antibody-absorption (FTA-ABS)
test, microhaemagglutination assay with Treponema pallidum antigen (MHA-TP) test
(serum) and Treponema pallidum haemagglutination assay (TPHA) test (CSF);
further, albumin, total protein, and total IgG were determined and, in the CSF,
cell count was performed. The donors were 60 patients with active neurosyphilis
and 54 healthy persons with a former history of syphilis and with persisting
positive results in the T. pallidum haemagglutination tests (serum: MHA-TP, CSF:
TPHA), who supplied specimens for control. Albumin quotient, IgG index, TPHA
index, modified TPHA index, Intrathecally produced T. pallidum Antigen (ITpA)
index, its 2 modifications and, in 12 samples, the adenovirus group antibody
(AVGA)/TPHA index were ascertained. The specificity and sensitivity of the TPHA
index were 100% and 98.3%, of the modified TPHA index 50.0% and 96.7%, of the
ITpA index 42.6% and 90.0%, of the modified ITpA indices 51.8% and 68.3% (first
modification) and 53.7% and 63.3% (second modification). The AVGA/TPHA index
yielded a specificity of 91.7% (11/12). The CSF VDRL test was positive in 55/60
(91.7%) of samples from patients with neurosyphilis and in none of the controls
(0/54). A CSF-TPHA titre greater than 1:320 was observed in 59/60 (98.3%) of the
neurosyphilis specimens and in none of the controls (0/54). A TPHA index above an
outcome of 70, a positive CSF-TPHA test at a titre greater than 1:320 and, with
lower sensitivity, the criteria of the Centers for Disease Control (CDC)
guidelines yield the most reliable results for laboratory support to a diagnosis
of neurosyphilis. The modified TPHA index, the ITpA index, and its 2
modifications produce results of minor sensitivity and poor specificity.
Observations on the AVGA/THPA index are too limited yet for judgement. The
diagnostic significance of a CSF-TPHA titre above 320 needs further confirmation
on a greater number of observations made by different laboratories.
PMID- 10772086
TI - Can a two-glass urine test or leucocyte esterase test of first-void urine improve
syndromic management of male urethritis in southern Thailand?
AB - The goal of this study was to determine whether a urine two-glass test or a
leucocyte esterase (LE) test of first-void urine (FVU) improve the sensitivity or
specificity of the World Health Organization (WHO) algorithm for the syndromic
management of men with urethritis in southern Thailand. A secondary aim was to
determine whether infection with Trichomonas vaginalis was sufficiently common to
include treatment for it in a syndromic management protocol. One hundred and
twenty-nine men with symptoms of urethritis seen at 2 STD clinics in Songkla
Province, Thailand were enrolled. Symptoms and signs of each man were recorded
and a urethral swab collected for microscopy and culture for Neisseria
gonorrhoeae. A two-glass urine test and an LE test of an FVU specimen were
performed. The FVU was tested by polymerase chain reaction (PCR) for N.
gonorrhoeae, Chlamydia trachomatis and T. vaginalis. Dysuria was a symptom in 78%
of men. A urethral discharge was a symptom in 68% but was evident on examination
in 95% of the men. The prevalences of infection were 32.6% for N. gonorrhoeae,
23.3% for C. trachomatis, 1.6% for T. vaginalis and 51.9% for any infection. The
sensitivities and specificities of urethral discharge on examination, two-glass
test and LE test of FVU as indicators of infection with either or both of N.
gonorrhoeae or C. trachomatis were 97% and 8%; 57% and 83%; and 59% and 78%
respectively. Combinations of urethral discharge on examination and one of the
other indicators were more specific but much less sensitive than the presence of
discharge alone. Culture for N. gonorrhoeae was found to be only 43% sensitive
compared with an expanded gold standard involving a PCR test. Our analysis
demonstrates that neither the two-glass test nor the LE test of FVU were useful
in improving on the WHO algorithm for management of men with urethritis. T.
vaginalis was not common enough to include in a first-line syndromic management
protocol for male urethritis. We recommend that, in southern Thailand, men with
symptoms of urethritis in whom a urethral discharge is present on examination be
offered immediate treatment for both N. gonorrhoeae and C. trachomatis as per the
WHO algorithm.
PMID- 10772087
TI - Prevalence of HIV infection and risk behaviours among Montreal street youth.
AB - We aim to estimate HIV prevalence and associated risk factors among street youth
in Montreal, Canada. We conducted a one-year cross-sectional anonymous study in
1995. We recruited youth aged 13-25 years meeting specific criteria for
itinerancy through the 20 major Montreal street youth agencies. Participation
included a structured interview and provision of an oral specimen for HIV
testing. Among the 909 subjects studied, 99.3% had been sexually active, 25.9%
had exchanged sex for money, gifts, drugs, a place to sleep, or other things;
31.8% reported anal sex; and 36.4% reported having ever injected drugs. Overall,
HIV prevalence was 1.9% (1.1% in girls and 2.2% in boys). Multivariate logistic
regression showed that being over 20 years of age (adjusted odds ratio (AOR)
7.09), having injected drugs (AOR 4.48), having engaged in prostitution (AOR
3.32), and being born outside Canada (AOR 4.41) were all independently associated
with HIV infection.
PMID- 10772088
TI - Community control of Chlamydia trachomatis.
AB - In order to determine the amount of Chlamydia trachomatis that is diagnosed
outside genitourinary medicine (GUM) clinics in a large university city, a review
of all positive chlamydial infections diagnosed on specimens received from
hospitals (non-GUM) and community sources in 1996 was performed. It was also
ascertained whether these patients subsequently attended at GUM. Eight hundred
and nine cases of C. trachomatis were diagnosed during the study period. Three
hundred and ninety-seven (49%) were initially diagnosed outside GUM of which 264
(66.5%) were referred, giving an overall involvement of GUM in 667 (83.6%) of all
cases. The proportion of cases referred varied according to service: Family
Planning Clinics 94.5%, Obstetrics and Gynaecology 73%, General Practice 52.5%.
Referral rates also showed within service variation, with University Health
Services referring 19% vs 73% (P < 0.001). High levels of referral to GUM of
patients diagnosed with C. trachomatis are achievable, but referrals show inter-
and intra-service variations. Efforts should be made to improve referral rates
from those services with the lowest rates. IN CONCLUSION: (1) The proportion of
cases of C. trachomatis diagnosed in the community who are referred to a GUM
clinic, varies according to service type. (2) Referral rates vary within services
and (3) Distance of services from a GUM clinic does not appear to influence
referral rates.
PMID- 10772089
TI - Marriage, monogamy and HIV: a profile of HIV-infected women in south India.
AB - A retrospective study was conducted on 134 HIV-infected females evaluated at an
HIV/AIDS centre in south India to characterize their sociodemographics, HIV risk
factors and initial clinical presentations. The mean age was 29 years; 81% were
housewives; 95% were currently or previously married; 89% reported heterosexual
sex as their only HIV risk factor; and 88% reported a history of monogamy. The
majority were of reproductive age, thus the potential for vertical transmission
of HIV and devastating impacts on families is alarming. Nearly half of these
women initially presented asymptomatically implying that partner recruitment can
enable early HIV detection. Single partner heterosexual sex with their husband
was the only HIV risk factor for the majority of women. HIV prevention and
intervention strategies need to focus on married, monogamous Indian women whose
self-perception of HIV risk may be low, but whose risk is inextricably linked to
the behaviour of their husbands.
PMID- 10772090
TI - Herpes zoster and HIV infection in Tanzania.
AB - Two hundred consecutive patients with herpes zoster attending the skin clinic at
the Kilimanjaro Christian Medical Centre (KCMC) were examined and checked for HIV
infection. They ranged in age from 10 months to 86 years with the majority in
their 20s and 30s. The dermatomes involved were thoracic (97), trigeminal (50),
cervical (37), lumbar (19) and sacral (3). Six (3%) had more than one dermatome
involved and 2 (1%) had disseminated disease. Only 2 (1%) had severe ulceration
of the skin and all healed in less than 4 weeks. In children under the age of 10
years and in adults between the ages of 20 and 49 years virtually 100% were HIV
positive; even in the age group 50-59 more than three-quarters were HIV positive.
We conclude that the presence of herpes zoster at any site is a good indication
that the patient is HIV positive except in the teens and the very elderly.
PMID- 10772091
TI - Partner notification of pregnant women infected with syphilis in Nairobi, Kenya.
AB - We examined partner notification among syphilitic pregnant women in Nairobi. At
delivery, 377 women were found to be rapid plasma reagin (RPR) reactive. Data
were available for 94% of the partners of women who were tested during pregnancy;
over 67% of the partners had received syphilis treatment while 23% had not sought
treatment mainly because they felt healthy. Six per cent of the women had not
informed their partners as they feared blame and/or violence. Adverse pregnancy
outcome was related to lack of partner treatment during pregnancy (7% versus 19%,
odds ratio (OR) 3.0, 95% confidence interval (CI) 0.9-10.0). Our data suggest
that messages focusing on the health of the unborn child have a positive effect
on partner notification and innovative and locally adapted strategies for partner
notification need more attention.
PMID- 10772092
TI - Determinants of condom use in female sex workers in Surabaya, Indonesia.
AB - In the developing world condom use among sex workers and their clients plays a
dominant role in the transmission of HIV/STD. In Surabaya, Indonesia, data from
the 1993 STD prevalence survey in female sex workers (brothels, street, massage
parlours, barber shops, call-girl houses, and nightclubs) reveal that only 5%
(33/692) of the brothel workers and 14% (25/177) of the street walkers had
condoms in their possession at the time of the interview. During the last paid
sexual intercourse, sex workers from the brothels, streets, and nightclubs used
condoms infrequently (14%, 20%, and 25%, respectively). Sex workers from massage
parlours, barber shops, and call girls were about 5 to 3 times more likely to use
condoms than sex workers from nightclubs (adjusted odds ratio of 3.5, 4.9, and
4.2, respectively); thus condom promotion programmes should be targeted at sex
workers at brothels, streets, and nightclubs. Programmes should include: (1) free
distribution of condoms to sex establishments at the initial stage, and condom
social marketing at later stages; (2) penalties, including legal sanctions,
against any sex establishments that do not consistently use condoms; (3)
participation of brothel owners and madams in encouraging sex workers to
consistently have clients use condoms during sexual intercourse; and (4)
establishment of sentinel surveillance to monitor STD/HIV and condom-use
compliance.
PMID- 10772093
TI - The frequency of mutation in CCR5 gene among Koreans.
AB - To better understand a role of the delta32 allele of the CCR5 gene in HIV-1
transmission and disease progression, we determined the CCR5 genotypes within
several groups of Koreans. Amplification of DNA from each subject was achieved
with polymerase chain reaction, using the CCR5 specific primer pair, which flanks
the 32 bp deletion. The 1.2 kb coding sequences of CCR5 were examined to see the
possible effects of CCR5 polymorphism. All of the 339 healthy, HIV-uninfected
individuals had no mutation in the CCR5 gene. All of the 115 HIV-1-infected
patients including 11 long-term non-progressors (LTNPs) and 18 discordant spouses
were also wild homozygotes. No variation in the 1.2kb CCR5 coding sequence was
found in 5 LTNPs and 5 discordant spouses. In conclusion, the 32 bp deletion
mutant is rarely present in Koreans. Our data suggest that factors other than the
CCR5 coding sequences may also play a role in the resistance to HIV infection.
PMID- 10772094
TI - An audit of patients who have received imiquimod cream 5% for the treatment of
anogenital warts.
AB - With the licensing of the new drug Imiquimod cream 5% (Aldara 3M Health Care) for
the treatment of anogenital warts and its inclusion into clinic guidelines, a
case note review audit was performed of its use. The treatment of 52 patients was
audited. Results showed that clinic guidelines were being followed and that
patient outcomes in terms of clearance were at least as good as the quoted rates
in the literature. Significant issues included firstly patient education
especially for those who had previously received ablative therapy. Secondly the
length of time that therapy would be continued before a patient was deemed to be
a non-responder to Imiquimod cream 5%, and if this was the case should the
frequency of application be amended from the manufacturer's recommended regime of
3 times a week.
PMID- 10772095
TI - Genitourinary chlamydial infections.
PMID- 10772096
TI - Knowledge, attitudes, beliefs and practices regarding sexually transmitted
infections in rural Philippines.
PMID- 10772097
TI - Gastrointestinal volatile fatty acid concentrations and pH in cats.
AB - OBJECTIVE: To measure volatile fatty acid (VFA) concentrations and pH in the
gastrointestinal tracts of healthy adult cats fed a commercial dry cat food.
ANIMALS: 14 cats. PROCEDURE: The gastrointestinal tracts were excised immediately
after euthanasia and divided into 6 sections (stomach, duodenum, jejunum, ileum,
proximal portion of the colon, and distal portion of the colon). Luminal contents
were collected from each segment, pH was measured, and contents were centrifuged.
The supernatant was analyzed for acetate, proprionate, butyrate, isobutyrate,
valerate, and isovalerate concentrations by use of gas chromatography. RESULTS:
Mean total VFA concentrations were lowest in the stomach (20 mmol/L); increased
through the duodenum, jejunum, and ileum (30, 29, and 41 mmol/L, respectively);
and were greatest in the proximal and distal portions of the colon (109 and 131
mmol/L, respectively). Estimated mean total VFA amounts were low (<600 micromol)
throughout all segments of the gastrointestinal tract; pH values increased from
the stomach through the ileum and subsequently decreased in the colon.
CONCLUSIONS AND CLINICAL RELEVANCE: Total VFA concentrations in the colon were
comparable to values reported for the forestomach of ruminants and large
intestines of monogastric animals, whereas values in the small intestine were
higher than reported for other species. Total VFA amounts were low, consistent
with the short, nonvoluminous gastrointestinal tract of carnivores. Luminal pH
varied throughout the gastrointestinal tract in a pattern similar to other
monogastric animals. Volatile fatty acids probably contribute minimal metabolic
energy in cats but may be important in the maintenance of local mucosal health.
PMID- 10772098
TI - Intracellular microelectrode recording to characterize inhibitory neuromuscular
transmission in jejunum of horses.
AB - OBJECTIVE: To evaluate electrical activity of jejunal circular muscle in horses
and characterize electrical responses to stimulation by intrinsic inhibitory
neurons. SAMPLE POPULATION: Portions of jejunum obtained from horses euthanatized
for reasons other than gastrointestinal tract disease. PROCEDURE: Isolated
circular muscle preparations were perfused with oxygenated modified Krebs
solution. Glass microelectrodes were used for intracellular recording of membrane
potentials from single smooth muscle cells. Electrical activity and responses to
electrical field stimulation (EFS) of intrinsic neurons in the presence of
guanethidine and atropine were recorded. Mediators of responses to nerve
stimulation were also evaluated, using N-nitro-L-arginine methyl ester (L-NAME)
and apamin. RESULTS: Mean resting membrane potential (RMP) was 41.5+/-1.8 mV.
Small membrane potential oscillations were observed in muscle cells. Single or
multiple action potentials were often superimposed on the peaks of these
oscillations. Spontaneous oscillations and action potentials were blocked by
nifedipine. Transient hyperpolarizations of smooth muscle cell membrane
potentials (inhibitory junction potentials [IJP]) were observed in response to
electrical field stimulation. The IJP evoked by stimulus trains consisted of an
initial fast component followed by a slow component. The L-NAME did not have a
significant effect on RMP and did not significantly affect the fast component of
IJP at any stimulus frequency tested. In contrast, L-NAME abolished the slow
component of IJP observed after trains of pulses. In the continued presence of L
NAME, apamin had no significant effect on RMP but effectively reduced the fast
component of IJP. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggest that
inhibitory neurotransmitters supplying equine jejunum act through different ionic
mechanisms. Understanding these mechanisms may suggest new therapeutic targets
for treatment of motility disorders.
PMID- 10772099
TI - Effect of carboxymethylcellulose and a hyaluronate-carboxymethylcellulose
membrane on healing of intestinal anastomoses in horses.
AB - OBJECTIVE: To evaluate the effect of sodium carboxymethylcellulose (SCMC) or a
hyaluronate-carboxymethylcellulose membrane (HA membrane) on healing of the small
intestine in horses. ANIMALS: 18 healthy adult horses. PROCEDURE: Midline
celiotomy and 2 jejunal resection-and-anastomosis surgeries were performed. In
treated horses, SCMC (n = 6) or a HA membrane (6) was applied to the jejunum to
cover the anastomosis. There were 6 untreated control horses. Horses were
euthanatized 10 days after surgery. For each horse, 1 anastomosis was used for
histologic examination, and the second was used to determine intestinal bursting
strength. Intestinal bursting tension, serosal granulation tissue, serosal fibrin
deposition, and width of the fibrous seal at the anastomosis were compared among
groups. RESULTS: 3 control horses had adhesions associated with the anastomosis,
but none of the treated horses had adhesions associated with the anastomosis.
Mean thickness of fibrin deposited on the serosal surfaces for the SCMC and HA
membrane groups was significantly less than that for control horses. Mean
thickness of serosal granulation tissue, width of fibrous seal between inverted
musculature, inflammatory cell infiltrate scores, and bursting tension did not
differ significantly among groups. CONCLUSIONS AND CLINICAL RELEVANCE: Use of
SCMC or application of a HA membrane to small intestinal anastomoses in horses
resulted in fewer adhesions and decreased fibrin deposition, and it did not
adversely affect anastomotic healing. In horses at increased risk for intra
abdominal adhesions, SCMC or application of HA membranes may decrease the
frequency of adhesions without adversely affecting healing of small intestinal
anastomoses.
PMID- 10772100
TI - Clinical disease in kittens inoculated with a pathogenic strain of Bartonella
henselae.
AB - OBJECTIVE: To evaluate disease in kittens inoculated with Bartonella henselae
strain LSU16. ANIMALS: Eighteen 12-week-old specific-pathogen-free kittens.
PROCEDURE: Kittens were inoculated with B henselae strain LSU16 or saline (0.9%
NaCl) solution. Blood samples were collected from kittens on alternate weeks, and
bacteremia, clinical signs, and antibody concentrations were monitored for 6
months after inoculation. RESULTS: Kittens developed raised, erythematous areas
at the site of inoculation within 72 hours. Swelling peaked at 14 days and
resolved by 28 days after inoculation. Fever had a biphasic pattern, with an
episode of 1- to 3-days' duration beginning 6 to 7 days after inoculation
followed by an episode of 3- to 8-days' duration beginning 11 to 13 days after
inoculation. Kittens were bacteremic by day 14 with peak bacteremia at days 14 to
28. Strong antibody responses to B henselae were detected. Clinical disease
resolved before bacteremia became undetectable, but signs of disease correlated
with the highest degree of bacteremia. Regional lymphadenopathy also was evident.
CONCLUSION AND CLINICAL RELEVANCE: Clinical disease in kittens was similar to
that in adult cats infected with B henselae strain LSU16, except that lethargy
and anorexia were less severe in kittens, and a biphasic pattern of fever was
detected in kittens. Clinical disease after inoculation with B henselae may be
strain-dependent. To limit transmission of Bartonella organisms, appropriate flea
prevention should be instituted. IMPACT FOR HUMAN MEDICINE: Kittens that are
febrile, anorectic, lethargic, and that have lymphadenopathy should be tested for
Bartonella organisms, and contact with immunocompromised owners should be
discouraged.
PMID- 10772101
TI - Association among filamentous actin content, CD11b expression, and membrane
deformability in stimulated and unstimulated bovine neutrophils.
AB - OBJECTIVE: To investigate rheologic properties of bovine neutrophils that may
result in adhesion molecule-independent sequestration of neutrophils in inflamed
lungs of cattle. ANIMALS: Healthy 2- to 4-week-old male Holstein calves.
PROCEDURES: Neutrophil deformability, filamentous actin (F-actin) content, and
CD11b expression was determined for unstimulated bovine neutrophils and bovine
neutrophils incubated with the inflammatory mediators tumor necrosis factor-alpha
(TNF), platelet-activating factor (PAF), interleukin-8 (IL-8), zymosan-activated
plasma (ZAP), Pasteurella haemolytica-derived lipopolysaccharide (LPS), and P
haemolytica leukotoxin. Neutrophils were separated into 3 subpopulations on the
basis of size. The Factin content and CD11 b expression were evaluated by use of
flow cytometry. Leukocyte deformability was evaluated by filtration of dilute
whole blood. RESULTS: The subpopulation of the smallest-sized neutrophils (>90%
of neutrophils) contained little F-actin. A subpopulation of slightly larger
neutrophils had a profound increase in F-actin content and CD11 b expression. The
subpopulation of the largest neutrophils had increased F-actin content and CD11b
expression, compared with those for both subpopulations of smaller neutrophils.
Incubation of neutrophils with PAF and ZAP but not TNF, IL-8, LPS, or leukotoxin,
resulted in decreased neutrophil deformability and increased F-actin content.
Incubation with PAF and TNF induced an increase in size of neutrophils.
CONCLUSIONS AND CLINICAL RELEVANCE: Size can be used to identify subpopulations
of large and rigid neutrophils in blood samples from healthy calves. Platelet
activating factor and activated complement fragments are potent inducers of F
actin formation and neutrophil rigidity. Physical changes in neutrophils may
impede their transit through lung microvasculature and result in leukocyte
trapping independent of adhesion molecule interactions with endothelial cells.
PMID- 10772102
TI - Isolation and measurement of carbonic anhydrase isoenzymes in erythrocytes of
dogs.
AB - OBJECTIVE: To purify canine carbonic anhydrase (CA) isoenzymes CA-I and CA-II and
to determine concentrations of CA-I and CA-II in erythrocytes of Beagles and dogs
native to Japan. SAMPLE POPULATION: Blood samples from 116 Beagles, including 24
pregnant Beagles, and blood samples from 29 dogs native to Japan. PROCEDURE:
Canine CA-I and CA-II were purified by use of column chromatography.
Concentrations of CA-I and CA-II in erythrocytes of dogs were determined, using
an ELISA. RESULTS: Mean (+/- SD) concentrations of CA-I and CA-II in erythrocytes
of Beagles were 3.21+/-0.86 and 1.63+/-0.39 mg/g of Hb, respectively. Mean
concentration of CA-I was greater in male Beagles than female Beagles. In
contrast, mean concentration of CA-II was greater in female Beagles than male
Beagles. Furthermore, concentration of CA-II was greater in pregnant female
Beagles than male or nonpregnant female Beagles. Mean concentrations of CA-I and
CA-II in erythrocytes of dogs native to Japan were 11.03+/-4.39 and 3.29+/-0.91
mg/g of Hb, respectively. Mean concentration of CA-I was greater in male dogs
from Japan than female dogs from Japan. CONCLUSIONS AND CLINICAL RELEVANCE: The
ELISA used in this study proved to be precise and sensitive for determining CA-I
and CA-II concentrations in dogs. The ELISA may enable study of changes in
isoenzymes associated with hereditary or metabolic disorders of blood or other
body fluids, using only a small sample. Measurement of the concentrations of CA
isoenzymes in dogs may be of diagnostic value.
PMID- 10772103
TI - D-dimer concentrations in healthy dogs and dogs with disseminated intravascular
coagulation.
AB - OBJECTIVE: To determine sensitivity and specificity of assays of D-dimer
concentrations in dogs with disseminated intravascular coagulation (DIC) and
healthy dogs and to compare these results with those of serum and plasma fibrin
fibrinogen degradation product (FDP) assays. ANIMALS: 20 dogs with DIC and 30
healthy dogs. PROCEDURE: Semi-quantitative and quantitative D-dimer
concentrations were determined by use of latex-agglutination and
immunoturbidometry, respectively. Fibrin-fibrinogen degradation products were
measured by use of latex-agglutination. A reference range for the
immunoturbidometric D-dimer concentration assay was established; sensitivity and
specificity of the assay were determined at 2 cutoff concentrations (0.30
microg/ml and 0.39 microg/ml). RESULTS: Reference range for the
immunoturbidometric D-dimer concentration assay was 0.08 to 0.39 microg/ml;
median concentrations were significantly higher in dogs with DIC than in healthy
dogs. Latex-agglutination D-dimer and serum and plasma FDP assays had similar
sensitivity (85 to 100%) and specificity (90 to 100%); the immunoturbidometric
assay had lower specificity (77%) at the 0.30 microg/ml cutoff and lower
sensitivity (65%) at the 0.39 microg/ml cutoff. Sensitivity or specificity of the
latex-agglutination D-dimer assay was not significantly improved when interpreted
in series or parallel with FDP assays. CONCLUSIONS AND CLINICAL RELEVANCE:
Measurement of D-dimer concentrations by latex-agglutination appears to be a
sensitive and specific ancillary test for DIC in dogs. Specificity of D-dimer
concentrations in dogs with systemic disease other than DIC has not been
determined, therefore FDP and D-dimer assays should be performed concurrently as
supportive tests for the diagnosis of DIC in dogs.
PMID- 10772104
TI - Basic three-dimensional kinematics of the vertebral column of horses walking on a
treadmill.
AB - OBJECTIVE: To determine kinematic movements of the vertebral column of horses
during normal locomotion. ANIMALS: 5 Dutch Warmblood horses without apparent
lameness or problems associated with the vertebral column. PROCEDURE: Kinematics
of 8 vertebrae (T6, T10, T13, T17, L1, L3, L5, and S3) and both tuber coxae were
determined, using bone-fixated markers. Horses were recorded while walking on a
treadmill at a constant speed of 1.6 m/s. RESULTS: Flexion-extension was
characterized by 2 periods of extension and flexion during 1 stride cycle,
whereas lateral bending and axial rotation were characterized by 1 peak and 1
trough. The range of motion for flexion-extension was fairly constant for
vertebrae caudal to T10 (approximately 7 degrees). For lateral bending, the
cranial thoracic vertebrae and segments in the pelvic region had the maximal
amount of motion, with values of up to 5.6 degrees. For vertebrae between T17 and
L5, the amount of lateral bending decreased to <4 degrees The amount of axial
rotation increased gradually from 4 degrees for T6 to 13 degrees for the tuber
coxae. CONCLUSIONS: This direct measurement method provides 3-dimensional
kinematic data for flexion-extension, lateral bending, and axial rotation of the
thoracolumbar portion of the vertebral column of horses walking on a treadmill.
Regional differences were observed in the magnitude and pattern of the rotations.
Understanding of the normal kinematics of the vertebral column in healthy horses
is a prerequisite for a better understanding of abnormal function.
PMID- 10772105
TI - Continuous infusion of gentamicin into the tarsocrural joint of horses.
AB - OBJECTIVE: To develop a method for continuous infusion of gentamicin into the
tarsocrural joint of horses, to determine pharmacokinetics of gentamicin in
synovial fluid of the tarsocrural joint during continuous infusion, and to
evaluate effects of continuous infusion of gentamicin on characteristics of the
synovial fluid. ANIMALS: 12 healthy adult horses. PROCEDURE: An infusion catheter
consisting of flow control tubing connected to a balloon infuser was used.
Gentamicin solution (100 mg/ml) was infused in the right tarsocrural joint and
balanced electrolyte solution was infused in the left tarsocrural joint for 5
days. Synovial fluid and serum gentamicin concentrations were measured by use of
a fluorescence polarization immunoassay. RESULTS: 17 of the 24 (71%) infusion
catheters initially placed functioned without complications for the entire 5-day
infusion period. Median gentamicin concentration in synovial fluid from treated
joints during the 5-day infusion period ranged from 2875 to 982 microg/ml. Median
serum gentamicin concentration during this period ranged from 2.31 to 2.59
microg/ml. Mean (+/- SD) elimination half-life and total clearance of gentamicin
from the synovial fluid were 6.25+/-1.01 hours and 1.52+/-0.96 ml/min,
respectively. CONCLUSIONS AND CLINICAL RELEVANCE: An infusion catheter can be
used for continuous infusion of gentamicin into the tarsocrural joints of horses
for up to 5 days. At a gentamicin dosage of 0.17+/-0.02 mg/kg/h, continuous intra
articular infusion results in synovial fluid gentamicin concentrations greater
than 100 times the minimal inhibitory concentration reported for common equine
pathogens.
PMID- 10772106
TI - In vitro effects of erythromycin, lidocaine, and metoclopramide on smooth muscle
from the pyloric antrum, proximal portion of the duodenum, and middle portion of
the jejunum of horses.
AB - OBJECTIVE: To evaluate effects of erythromycin, lidocaine, and metoclopramide on
smooth muscle of the pyloric antrum (PA), proximal portion of the duodenum (PD),
and middle portion of the jejunum (MJ) of horses. Sample Population-Strips of
smooth muscle from 7 horses. PROCEDURE: Isolated muscle strips were suspended in
a bath and attached to isometric force transducers. Once stable spontaneous
contractions were observed, agents were added. Isometric stress responses were
compared with the amplitude of spontaneous contractions. RESULTS: A single dose
of erythromycin to the PA increased contractile amplitude (CA) for the
longitudinal smooth muscle (mean +/- SEM, 76+/-16 g/cm2) but decreased CA for
circular smooth muscle (-79+/-23 g/cm2). The inhibitory effect was decreased by
tetrodotoxin, N(G)-nitro-L-arginine methyl ester, and a vasoactive intestinal
peptide antagonist. Erythromycin increased CA for the MJ, which was maximal at
10(-4)M (171+/-36 g/cm2). Lidocaine increased CA for the PD, which was maximal at
10(-4) M (60+/-5 g/cm2). Metoclopramide increased the CA, which was maximal at
10(-4) M for the PA (75+/-26 g/cm2), PD (279+/-33 g/cm2), and MJ (456+/-59
g/cm2). CONCLUSIONS: Regional differences in responses to erythromycin,
lidocaine, and metoclopramide were evident in the gastrointestinal tract of
horses. Metoclopramide increased CA in all tissues used, whereas erythromycin
inhibited CA in circular smooth muscle but stimulated CA in longitudinal smooth
muscle from the PA. Inhibition is caused by stimulation of inhibitory nerves and
is mediated, in part, by nitric oxide and vasoactive intestinal peptide.
PMID- 10772107
TI - Prokinetic effects of erythromycin on the ileum, cecum, and pelvic flexure of
horses during the postoperative period.
AB - OBJECTIVE: To evaluate the effect of erythromycin on motility of the ileum,
cecum, and pelvic flexure of horses during the postoperative and post-recovery
periods. ANIMALS: 8 healthy adult horses. PROCEDURE: Horses were anesthetized and
bipolar electrodes were implanted in smooth muscle of the ileum, cecum, and
pelvic flexure. Approximately 4, 16, and 24 hours (postoperative recording
sessions) and at least 8 days (post-recovery recording session) after surgery,
myoelectric activity was recorded before and after administration of erythromycin
(0.5 mg/kg). RESULTS: Following erythromycin administration, myoelectric activity
was increased in the ileum during all postoperative recording sessions but not
during the post-recovery recording session. Myoelectric activity was increased in
the cecum following erythromycin administration only during the post-recovery
recording session. Myoelectric activity was increased in the pelvic flexure
following erythromycin administration during all recording sessions. During
several recording sessions, there were short periods during which myoelectric
activity was significantly decreased following erythromycin administration.
CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that erythromycin has an
effect on myoelectric activity of the ileum, cecum, and pelvic flexure in horses;
however, prokinetic effects of erythromycin administered during the postoperative
period were not always the same as effects obtained when the drug was
administered after horses had recovered from the effects of surgical implantation
of recording devices. Therefore, caution must be exercised when extrapolating
results of prokinetic studies in healthy animals to animals with abnormal
gastrointestinal tract motility.
PMID- 10772108
TI - Acute, subchronic, and chronic toxicity of ecadotril in dogs.
AB - OBJECTIVE: To determine the toxicity of ecadotril in dogs. ANIMALS: 74 healthy 4-
to 11-month-old Beagles. PROCEDURE: To determine acute toxicity, ecadotril (2,000
mg/kg of body weight, PO) in a gelatin capsule was administered once to 2 dogs,
and dogs were observed for 2 weeks. To determine subchronic and chronic toxicity,
ecadotril was administered every day for 3 months (50 mg/kg [n = 8], 100 mg/kg
[8], 300 mg/kg [12]) and 12 months (25 mg/kg [n = 8], 50 mg/kg [8], 100 mg/kg
[8]), respectively. Dogs in control groups (n = 12 or 8) received an empty
gelatin capsule. Physical examinations, CBC, plasma biochemical analyses, and
urinalyses were performed before and at various times during each experiment.
Dogs were euthanatized at the end of each experiment, and necropsies were
performed. RESULTS: Dogs that received 1 dose of 2,000 mg of ecadotril/kg
developed nonspecific clinical signs of toxicosis. Dogs that received 300 mg of
ecadotril/kg/d for 3 months developed pronounced anemia, bone marrow suppression,
and some evidence of liver impairment. There was no evidence of an effect
accumulated over time, and reversibility of toxic effects was evident. Dogs that
received < or =100 mg of ecadotril/kg/d for 3 or 12 months tolerated treatment
without apparent effect. CONCLUSIONS AND CLINICAL RELEVANCE: Degree of acute
toxicity of a single high dose of ecadotril in dogs was low. The no-observable
adverse effect level of ecadotril following daily oral administration was 100
mg/kg/d; repeated administration of 300 mg/kg/d revealed the hematopoietic system
as the primary toxicologic target.
PMID- 10772109
TI - Effects of dietary potassium citrate supplementation on urine pH and urinary
relative supersaturation of calcium oxalate and struvite in healthy dogs.
AB - OBJECTIVE: To assess the effect of dietary potassium citrate supplementation on
the urinary pH, relative supersaturation of calcium oxalate and struvite (defined
as the activity product/solubility product of the substance), and concentrations
of magnesium, ammonium, phosphate, citrate, calcium, and oxalate in dogs.
ANIMALS: 12 healthy adult dogs. PROCEDURE: Canned dog food was fed to dogs for 37
days. Dogs were randomly allocated to 3 groups and fed test diets for a period of
8 days. Study periods were separated by 6-day intervals. During each study period
the dogs were fed either standard diet solus (control) or standard diet plus 1 of
2 types of potassium citrate supplements (150 mg potassium citrate/kg of body
weight/d) twice daily. Urinary pH, volume and specific gravity, relative
supersaturation of calcium oxalate and struvite, and concentrations of magnesium,
ammonium, phosphate, calcium, oxalate, and citrate were assessed for each
treatment. RESULTS: Mean urine pH was not significantly affected by dietary
potassium citrate supplementation, although urine pH did increase by 0.2 pH units
with supplementation. Diets containing potassium citrate maintained a higher
urine pH for a longer part of the day than control diet. Three Miniature
Schnauzers had a significantly lower urinary relative calcium oxalate
supersaturation when fed a diet supplemented with potassium citrate, compared
with control diet. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary potassium citrate
supplementation has limited effects on urinary variables in most healthy dogs,
although supplementation results in maintenance of a higher urine pH later in the
day. Consequently, if supplementation is introduced, dogs should be fed twice
daily and potassium citrate should be given with both meals or with the evening
meal only.
PMID- 10772110
TI - Metabolic and mitogenic activities of insulin-like growth factor-1 in interleukin
1-conditioned equine cartilage.
AB - OBJECTIVE: To determine response of interleukin-1alpha (IL-1alpha)-conditioned
equine articular cartilage explants to insulin-like growth factor-1 (IGF-1).
Sample Population-Cartilage from the trochlea and condyles of the femur of a
clinically normal 4-year-old horse. PROCEDURE: Effects of IGF-1 (0 to 500 ng/ml)
after addition of IL-1alpha were evaluated by assessing matrix responses, using a
sulfated glycosaminoglycan (GAG) assay, matrix 35SO4 GAG incorporation, and
release of GAG. Mitogenic response was assessed by 3H-thymidine incorporation
into DNA and fluorometric assay of total DNA concentration. RESULTS: Human
recombinant IL-1alpha (40 ng/ml) increased the amount of labeled GAG released and
decreased labeled and total GAG remaining in explants, and IL-1alpha decreased
mitogenic response. Addition of IGF-1 counteracted effects seen with IL-1alpha
alone. In general, IGF-1 decreased total and labeled GAG released into the
medium, compared with IL-1alpha-treated explants (positive-control sample).
Values for these variables did not differ significantly from those for negative
control explants. A significant increase in total and newly synthesized GAG in
the explants at termination of the experiment was observed with 500 ng of IGF
1/ml. Labeled GAG remaining in explants was greater with treatment at 50 ng of
IGF-1/ml, compared with treatment with IL-1alpha alone. Concentrations of 200 ng
of IGF-1/ml abolished actions of IL-1alpha and restored DNA synthesis to values
similar to those of negative-control explants. CONCLUSIONS AND CLINICAL
RELEVANCE: IGF-1 at 500 ng/ml was best at overcoming detrimental effects
associated with IL-1alpha in in vitro explants. These beneficial effects may be
useful in horses with osteoarthritis.
PMID- 10772111
TI - Impedance audiometric measurements in clinically normal dogs.
AB - OBJECTIVE: To measure impedance audiometric values in clinically normal dogs that
were sedated or anesthetized, evaluate effects of ear flushing on tympanometric
measurements, and determine effects of performing acoustic reflex testing in a
sound-attenuated room. ANIMALS: 35 mixed-breed and purebred client-owned dogs and
21 laboratory-bred Beagles. PROCEDURES: Tympanometry and acoustic reflex testing
were performed on 27 mixed-breed and purebred dogs under isoflurane anesthesia in
a non-sound-attenuated room and 21 Beagles under sedation in a sound-attenuated
room. Tympanometry was performed on 8 mixed-breed dogs under halothane anesthesia
before and after ear canal flushing. RESULTS: Among impedance audiometric values,
ear canal volume and compliance peak were smaller in Beagles than in mixed-breed
dogs; differences among other values were not detected. Ear canal volume was
dependent on body weight. Differences were not found for tympanometric values
measured before and after ear canal flushing. CONCLUSIONS AND CLINICAL RELEVANCE:
Results of this study established reference range values for impedance
audiometric measurements in clinically normal dogs under isoflurane anesthesia or
sedation. Acoustic reflex testing does not need to be performed in a sound
attenuated room. The ear canals of clinically normal dogs can be flushed prior to
performing tympanometry without altering the results. Impedance audiometry may be
a useful noninvasive procedure for the diagnosis of otitis media in dogs.
PMID- 10772112
TI - Use of specific sugars to inhibit bacterial adherence to equine endometrium in
vitro.
AB - OBJECTIVE: To determine whether specific sugars inhibit adhesion of Streptococcus
zooepidemicus, Pseudomonas aeruginosa, and Escherichia coli to equine endometrial
epithelial cells in vitro. SAMPLE POPULATION: Endometrial biopsy specimens
collected during estrus from 7 healthy mares. PROCEDURE: Endometrial specimens on
glass slides were incubated for 30 minutes at 4 C with suspensions of S.
zooepidemicus, P. aeruginosa, or E. coli in phosphate-buffered saline solution
(PBSS) alone or with various concentrations of D-(+)-mannose, N-acetyl-D
glucosamine, N-acetyl-D-galactosamine, D-(+)-glucose, galactose, or N-acetyl
neuraminic acid. Inhibition of bacterial adherence was determined by comparing
adhesion of bacteria (i.e., percentage of glandular epithelial cells with
adherent bacteria) suspended in each sugar solution with that of bacteria
suspended in PBSS. RESULTS: Mannose and N-acetyl-D-galactosamine inhibited
adhesion of E. coli and P. aeruginosa to epithelial cells, whereas only mannose
inhibited adhesion of S. zooepidemicus. The other sugars did not affect bacterial
adherence. CONCLUSIONS AND CLINICAL RELEVANCE: Mannose and N-acetyl-D
galactosamine appear to play a role in adhesion of S. zooepidemicus, P.
aeruginosa, and E. coli to equine endometrium. In horses with uterine infections,
use of sugars to competitively displace bacteria from attachment sites on cells
may provide an adjunct to antibiotic treatment.
PMID- 10772113
TI - Inhibition of canine and feline alcohol dehydrogenase activity by fomepizole.
AB - OBJECTIVE: To determine and compare substrate specificity and kinetic rate
constants of feline and canine alcohol dehydrogenase (ADH) with ethanol (EtOH)
and ethylene glycol (EG) as substrates in vitro, with and without fomepizole.
SAMPLE POPULATION: Livers from 3 dogs and 3 cats. PROCEDURE: Canine and feline
ADH activity, in cytosolic fractions of homogenized liver, was determined by use
of various concentrations of nicotinamide adenine dinucleotide (NAD), EtOH, or EG
as substrates. Initial reaction velocities were calculated, and kinetic
inhibition rate constants (Ki) for fomepizole were determined. RESULTS: Substrate
specificity of canine and feline ADH for EtOH or EG was not significantly
different. A 2-fold difference was detected in the maximal velocity of canine,
compared with feline, ADH, using either substrate. Fomepizole Ki in feline
hepatic homogenates was significantly greater than Ki in canine hepatic
homogenates when either EtOH or EG was used as substrate (10- and 30-fold,
respectively). A 6-fold increase in the concentration of fomepizole was required
to achieve ADH inhibition, with feline homogenates equivalent to those of canine
homogenates. CONCLUSIONS AND CLINICAL RELEVANCE: Feline ADH has lower enzymatic
capacity for turnover or is less concentrated in liver than canine ADH with
regard to EtOH and EG catalysis. Canine ADH was more effectively inhibited by
fomepizole than feline ADH. Results suggest that higher dosages of fomepizole may
be more effective to treat cats with EG intoxication than dosages reported to
treat dogs.
PMID- 10772114
TI - Experimental infection of Mouflon-domestic sheep hybrids with caprine arthritis
encephalitis virus.
AB - OBJECTIVE: To determine whether monocyte-derived macrophages from Mouflon
domestic sheep hybrids (Ovis musimon X Ovis spp) were susceptible to productive
infection with caprine arthritis-encephalitis virus (CAEV) in vitro and whether
experimental inoculation of Mouflon-domestic sheep hybrids with a molecularly
cloned CAEV would result in persistent infection. ANIMALS: 5 Mouflon hybrids.
PROCEDURE: Macrophage monolayers were inoculated with virus in vitro. Three
animals were inoculated with virus intratracheally. RESULTS: Productive
replication of CAEV was demonstrated in monocyte-derived macrophages following in
vitro and in vivo inoculation. Titer of infectious cytopathic CAEV produced by
macrophages from the Mouflon hybrids was similar to titers produced by
macrophages from an infected goat or by synovial membrane cells. Isolation of
virus from monocyte-derived macrophages and use of a semiquantitative polymerase
chain reaction assay to amplify a portion of the viral genome demonstrated
persistent virus replication in all 3 inoculated animals. Two weeks after
inoculation of sheep, approximately 1 of 5,000 monocytes was harboring the virus.
CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that Mouflon-domestic sheep
hybrids are susceptible to infection with isolates of CAEV that cause infection
in domestic small ruminants.
PMID- 10772115
TI - Inheritance of gluten-sensitive enteropathy in Irish Setters.
AB - OBJECTIVE: To establish a model for inheritance of gluten-sensitive enteropathy
(GSE) in Irish Setters. ANIMALS: 44 dogs of a 6-generation family of Irish
Setters with GSE and 7 healthy Irish Setters. PROCEDURE: Phenotype of each dog
was determined after oral administration of gluten in the weaning diet, using
morphometric evaluation of jejunal biopsies (all generations) and measurement of
small intestinal permeability by use of a lactulose-rhamnose permeation test
(generations 1, 2, and 3). Overall probability for each of 4 genetic models of
inheritance (autosomal recessive, autosomal dominant, sex-linked recessive, and
sex-linked dominant) accounting for segregation of partial villus atrophy within
the entire family was calculated. RESULTS: The autosomal recessive model was most
tenable and was 56,250 times more likely to account for segregation of partial
villus atrophy than the autosomal dominant model, assuming disease prevalence of
0.8%. Both sex-linked models were untenable. These conclusions were robust to the
error attached to estimation of disease prevalence. High intestinal permeability
without morphometric jejunal abnormalities in 4 of 20 dogs in the 3 youngest
generations suggested heterogeneity of lesions associated with GSE. CONCLUSIONS:
Genetic transmission of GSE is under the control of a single major autosomal
recessive locus.
PMID- 10772117
TI - Medical treatment of pulmonary aspergilloma.
PMID- 10772116
TI - Electrodiagnostic evaluation of peripheral nerve function in rheas and barred
owls.
AB - OBJECTIVE: To establish reference values for electrodiagnostic evaluation of
peripheral nerve function in birds. ANIMALS: 6 rheas and 6 barred owls.
PROCEDURE: Birds were anesthetized with propofol or isoflurane in oxygen. Using a
computer-based electromyograph system and needle electrodes for stimulation and
recording, electromyography (EMG) was performed on the pectoral, biceps
brachialis, and gastrocnemius muscles, and evoked EMG was performed on the tibial
and ulnar nerves. Motor nerve conduction velocity (MNCV) was calculated.
Repetitive stimulation was performed on these 2 nerves. Late F waves were
recorded for each nerve, when possible. RESULTS: Activity was evident during
insertion of the electrodes, but muscles tested were electrically quiescent after
spontaneous EMG. Motor nerve conduction velocity was faster in the tibial nerve
than ulnar nerve but did not differ significantly between species. Mean +/- SEM
MNCV was 132.3+/-7.8 m/s for the tibial nerve and 59.7+/-7.8 m/s for the ulnar
nerve. A significant difference was not observed in responses at the fourth or
ninth stimulation during repetitive stimulation. Subsequent to the initial
stimulation, amplitudes were +/-22.7% of the initial motor potential amplitude.
Recorded F waves were inconsistent, which may have been associated with
technique. CONCLUSIONS AND CLINICAL RELEVANCE: Reference range (mean +/-2 SEM)
for MNCV was 34.1 to 75.3 m/s for the ulnar nerve and 116.7 to 147.9 m/s for the
tibial nerve in barred owls and rheas. After repetitive stimulation, motor
potential amplitudes may be +/-22.7% of the initial amplitude response.
PMID- 10772118
TI - Sjogren's syndrome associated with liver and neurological disorders, and
malignant lymphoma.
PMID- 10772119
TI - Streptococcal toxic shock-like syndrome.
PMID- 10772120
TI - A new approach to non-Hodgkin's lymphoma.
AB - The incidence of non-Hodgkin's lymphomas continues to rise and the number of
deaths attributable to these malignancies currently rank in the top five causes
of cancer-related deaths in the United States. Recent insights into the
pathogenesis and molecular characterization of these disorders have led to
improvements in a clinicopathologically relevant classification system, as well
as in the ability to accurately diagnose specific entities. Several new treatment
modalities have been developed which may improve the outcome for selected
patients. A better understanding of the biology of non-Hodgkin's lymphomas will
hopefully translate into different therapies with improved outcomes. This article
describes a new system for classifying the non-Hodgkin's lymphomas, highlights
key aspects of the pathogenesis of non-Hodgkin's lymphomas and briefly reviews
clinical and therapeutic approaches to the most common of these lymphomas.
PMID- 10772121
TI - Clinical evaluation of 61 patients with pulmonary aspergilloma.
AB - OBJECTIVE AND METHODS: We retrospectively evaluated 61 cases with pulmonary
aspergilloma representing patients admitted to Nagasaki University Hospital
between January 1991 to June 1998. RESULTS: Fifty-two (85%) were males and 9
(15%) were females, aged between 14 to 80 years (average, 65 years). Forty-four
(72%) patients had history of old pulmonary tuberculosis. Chest radiographs
showed "fungus ball" in the cavities in 42 (67%) cases while 16 (26%) cases
showed thickening of the cavity wall. Aspergillus fumigatus was isolated in 24
(39%) patients. Aspergillus antigen or antibody was positive in 8 (13%) and 43
(70%) patients, respectively. Oral itraconazole was used in 16 (26%) of patients,
and surgical excision was performed in 15 (25%) patients. During hospitalization
or after discharge, 19 (31 %) patients died. SUMMARY AND CONCLUSION: Pulmonary
aspergilloma usually occurs in elderly patients with old tuberculosis and
respiratory failure. Many cases did not respond to antifungal therapy with
itraconazole or amphotericin B. Our analysis indicates that more effective and
appropriate therapeutic regimens are needed for the treatment of patients with
pulmonary aspergilloma.
PMID- 10772122
TI - Clinical evaluation of idiopathic interstitial pneumonia and interstitial
pneumonia associated with collagen vascular disease using logistic regression
analysis.
AB - OBJECTIVE: To clarify the differences in the clinical features between idiopathic
interstitial pneumonia (IIP) and interstitial pneumonia associated with collagen
vascular diseases (CVD-IP). METHODS: Symptoms, radiographic findings, pulmonary
function, blood chemistry data including autoantibody, and bronchoalveolar lavage
fluid (BALF) findings were compared using multiple logistic regression analysis.
PATIENTS: The subjects were 44 patients clinically diagnosed with IIP and 33
patients with CVD-IP. RESULTS: The clinical features related to IIP were as
follows: male sex, advanced age, past history of hypertension, presence of cough,
exertional dyspnea, digital clubbing, an increased level of gamma-globulin,
decreased lung volume on chest X-ray, and typical type according to the criteria
for IIP on chest X-ray. Increased levels of rheumatoid factor and total cell
number in BALF were related to CVD-IP. CONCLUSION: These findings are considered
to be useful to differentiate IIP and CVD-IP.
PMID- 10772123
TI - Analyses of serum concentrations of apolipoproteins in the demented elderly.
AB - OBJECTIVE: The aim was to analyze serum concentrations of apolipoproteins in the
demented elderly to elucidate some biological markers related to dementia.
PATIENTS AND METHODS: Serum concentrations of apolipoproteins (AI, AII, B, CII,
CIII, E) of patients with Alzheimer type dementia (AD), vascular dementia (VD)
and controls (C) without dementia were compared among the three groups (AD, VD,
C) and 15 correlation coefficients among the 6 measured items of apolipoproteins
were analyzed. RESULTS: Serum levels of apo CII were significantly lower in AD
group compared with VD or C groups. Serum levels of apo B, CIII and E were
significantly lower in AD group compared with VD group, but not with C group.
Analyses of correlations among the items of apolipoproteins revealed high
significant correlations between apo E and/or apo CII and other items in AD
group. CONCLUSION: These results suggest that apolipoproteins such as apo CII, as
well as apo E, might be involved in the pathogenesis of AD.
PMID- 10772124
TI - Meningitis carcinomatosa originating from an alpha fetoprotein-producing gastric
cancer.
AB - Alpha fetoprotein (AFP)-producing gastric cancer is relatively rare and
meningitis carcinomatosa is similarly a rare manifestation among the neoplastic
diseases. There have been no previous reports of meningitis carcinomatosa
originating from AFP-producing gastric cancer. A 68-year-old man with AFP
producing gastric cancer was treated with cisplatin and doxifluridine because of
multiple liver metastases. Although the liver lesion was reduced to 30% of
pretreatment size after 6 courses of chemotherapy, meningitis carcinomatosa
subsequently occurred. Immunostaining of AFP and magnetic resonance imaging (MRI)
were useful in the diagnosis of meningitis caused by AFP producing cancer cells.
PMID- 10772125
TI - Multilocular pyogenic hepatic abscess complicating ascaris lumbricoides
infestation.
AB - A 74-year-old man was admitted to our hospital with frequent right flank pain.
The multiple multilocular hepatic abscesses were revealed by computed tomography.
Radiographs following a barium meal showed a linear filling defect in the ileum
consistent with ascariasis. One day after treatment with pyrantel pamoate, an
Ascaris was passed in the stool. The pyogenic hepatic abscesses gradually healed
with both antibiotics and continuous drainage. After 2 months, he was discharged.
In this case, the pyogenic hepatic abscesses were thus considered to have been
caused by an inflammation which spread through the portal vein.
PMID- 10772126
TI - A giant intramural gastric hematoma successfully treated by transcatheter
arterial embolization.
AB - We describe a case of intramural gastric hematoma with hemorrhagic shock caused
by the formation of a large hematoma. Computed tomographic and angiographic
examinations confirmed the presence of active bleeding into the hematoma.
Transcatheter arterial embolization (TAE) was performed for hemostasis. To our
knowledge, although 21 cases of intramural gastric hematoma have been reported in
the literature, this is apparently the first case treated by TAE. We conclude
that TAE is a safe and effective treatment option for intramural gastric hematoma
confirmed to be associated with active bleeding into the hematoma.
PMID- 10772127
TI - Rheumatoid arthritis accompanied by colonic lesions.
AB - A 69-year-old woman with a 6-year history of rheumatoid arthritis treated solely
with an orally administered NSAID had slowly progressing persistent mild
abdominal pain and diarrhea, accompanied with marked sing of inflammation as well
as hypoproteinemia due to protein-losing gastroenteropathy. Examinations of the
large intestine revealed variously shaped ulcerative lesions, centered around the
left hemicolon, as well as luminal narrowing. The course of the disease and the
shape of the lesions strongly suggested involvement of rheumatoid vasculitis;
oral administration of prednisolone was effective.
PMID- 10772128
TI - Scirrhous cancer of the stomach which survived for more than five years after
neoadjuvant chemotherapy with UFT (uracil and tegafur) and cisplatin.
AB - A 68-year-old man was diagnosed as having a scirrhous cancer of the stomach.
Carcinomatous peritonitis was suspected on abdominal CT examination. Three
courses of uracil and tegafur (UFT)/cisplatin (CDDP) chemotherapy were
administered. The primary foci were reduced in size, then total gastrectomy was
performed. Histological findings revealed a poorly differentiated adenocarcinoma
with scirrhous invasion into the subserosa. Histological efficacy of the
chemotherapy was judged to be grade 2. The patient has been alive without disease
for more than five years after total gastrectomy. Neoadjuvant chemotherapy with
UFT and CDDP may have contributed to the favorable clinical outcome in this
patient.
PMID- 10772129
TI - Successfully treated complete atrioventricular block with corticosteroid in a
patient with cardiac sarcoidosis: usefulness of gallium-67 and thallium-201
scintigraphy.
AB - A 71-year-old male with sarcoidosis was followed for 6 years without steroid
therapy. He was admitted because of complete atrioventricular block. Chest X-ray
showed hilar lymphadenopathy. Echocardiogram showed mild left ventricular
hypertrophy without local wall thinning. Cardiac sarcoidosis was diagnosed by a
defect of Thallium-201 (Tl-201) imaging and abnormal uptake of Gallium-67 (Ga
67). After the start of corticosteroid therapy, complete atrioventricular block
was recovered. Abnormal uptake of Ga-67 was improved. Tl-201 and Ga-67 are useful
to diagnose cardiac sarcoidosis, to evaluate the lesion of cardiac involvement
and to estimate the efficacy of corticosteroid therapy.
PMID- 10772130
TI - Diabetes mellitus, deafness, muscle weakness and hypocalcemia in a patient with
an A3243G mutation of the mitochondrial DNA.
AB - In a 54-year-old woman with diabetes mellitus, hearing loss, muscle weakness and
hypocalcemia, caused by idiopathic hypoparathyroidism, an A to G transition at
the nucleotide position of 3243 (A3243G mutation) was found in the mitochondrial
DNA from her leukocytes. Clinical features of diabetes mellitus and hearing loss
in association with the A3243G mutation are compatible with a diagnosis of
maternally inherited diabetes and deafness (MIDD). Although hypoparathyroidism is
rarely seen in MIDD, we consider that hypoparathyroidism in this patient is a
possible phenotype caused by the A3243G mutation of mitochondrial DNA.
PMID- 10772131
TI - Cupric sulfate intoxication with rhabdomyolysis, treated with chelating agents
and blood purification.
AB - We report a case of cupric sulfate intoxication complicated by hemolytic anemia,
hepato-renal damage and acute rhabdomyolysis. The patient was successfully
treated with dimercaprol, penicillamine, direct hemoperfusion and
hemodiafiltration. We discuss the pathophysiology of cupric intoxication, and
propose a treatment combined with chelating agents and blood purification.
PMID- 10772132
TI - Successful treatment of a patient with nephrotic syndrome associated with chronic
lymphocytic leukemia.
AB - We report the case of a 62-year-old man with nephrotic syndrome associated with
stage B chronic lymphocytic leukemia (CLL). Kappa Bence Jones proteinuria and the
glomerular deposition of kappa-light chain were observed. Although treatment with
cyclophosphamide and prednisolone tended to reduce the level of proteinuria, the
administration of angiotensin-converting enzyme inhibitor, enalapril, resulted in
complete remission of nephrotic syndrome.
PMID- 10772134
TI - Toxic shock-like syndrome caused by T serotype B3264 streptococcus.
AB - A 45-year-old woman was transferred from a local hospital to our hospital because
of shock-like manifestations in addition to septic polyarthritis and necrotizing
cellulitis of the left leg. Since Streptococcus pyogenes was isolated from the
blood culture examined one day before admission, the diagnosis of streptococcal
toxic shock-like syndrome (TSLS) was made. Antibiotic treatment together with
supportive care started at the time of admission, resulting in clinical
improvement, although poststreptococcal acute glomerulonephritis occurred during
the period. TSLS is a life-threatening disease, but early recognition of the
disease and prompt initiation of appropriate treatment may lead to successful
outcome.
PMID- 10772133
TI - Sjogren's syndrome with primary biliary cirrhosis, complicated by transverse
myelitis and malignant lymphoma.
AB - A 53-year-old woman with Sjogren's syndrome (SS) and primary biliary cirrhosis
(PBC) complicated by transverse myelitis (TM) and malignant lymphoma (ML) is
reported. TM has been described only in seven cases of primary SS, including
three with PBC and four without PBC. The features of SS associated with PBC and
complicated by TM were less typical compared with those seen in SS without PBC
complicated by TM. This case is the first report of a case with SS, PBC, TM and
ML. SS in association with PBC is, in general, overlooked, but such cases must be
investigated with great caution for extraglandular complications.
PMID- 10772135
TI - Imaging and radiological-pathological correlation in histologically proven cases
of focal cortical dysplasia and other glial and neuronoglial malformative lesions
in adults.
AB - Focal cortical dysplasia (FCD) is a pathological entity first described in 1971.
Other more subtle cortical malformations found in patients with epilepsy include
microdysgenesis (MD), and glioneuronal hamartias. Although these glial and
neuronoglial malformations have distinct histological features, there is
terminological confusion in the radiological literature. Few cases have been
reported in adults with both imaging and histology. We address these issues,
giving a radiological-pathological correlation of histologically proven cortical
malformations in adults. We describe clinical, radiological and histological
features of 12 cases (five FCD, five MD with glioneuronal hamartias, and two
hamartomas), unassociated with other conditions, and discuss them in the light of
the literature. FCD is usually seen on MRI as cortical thickening, with or
without signal change, which may extend into the adjacent white matter. On
histology, abnormal neurons and/or glial cells, blurring of the grey-white matter
interface, myelin pallor, demyelination, and gliosis may be found. Glioneuronal
hamartias and hamartomas usually appear as complex masses on MRI. FCD and
hamartias may be associated, and a combination of imaging findings may be seen on
MRI. Atrophy of the ipsilateral hippocampus may be present on MRI in patients
with hamartias, and minor cell loss on histology, but not definitive hippocampal
sclerosis. Although the imaging findings of cortical malformations are protean,
some characteristic MRI features, with histological correlates, may be found. The
relevance of most of these observations remains unclear.
PMID- 10772136
TI - Xenon CT cerebral blood flow in patients with head injury: influence of pulmonary
trauma on the input function.
AB - The noninvasive xenon-enhanced CT (Xe CT) cerebral blood flow (CBF) method has
been used in patients with severe traumatic brain injury (TBI) to identify the
blood-flow thresholds for the development of irreversible ischaemia or infarction
following severe TBI. Quantitative regional CBF (rCBF) estimates are based on the
assumption of identity between the end-tidal xenon concentration curve, used as
the input function, and the arterial xenon concentration curve, being the true
input function to the brain. Accordingly, rCBF data addressing the issue of
ischaemia should be viewed in relation to possible deviations between the end
tidal and arterial xenon concentration curves. To evaluate this possible source
of error, we studied five patients with severe TBI (Glasgow coma score < or =7)
who also had pulmonary trauma. CBF was studied with the Xe CT CBF method and flow
rates were determined by fitting the Kety equation to each CT voxel using either
the end-tidal or the arterial xenon curve as input function. In all patients rCBF
estimates were lower using the end-tidal xenon curve than with the arterial xenon
curve; the mean underestimation was 20.3% in gray metter and 17.3 % in white
matter. The deviation between the end-tidal and arterial xenon concentration
curves should be considered as a source of error when defining critical flow
values according to the flow thresholds of tissue viability.
PMID- 10772137
TI - Magnetisation transfer ratio is low in normal-appearing cerebral white matter in
patients with normal pressure hydrocephalus.
AB - We measured the magnetisation transfer ratios (MTR) of normal-appearing rostral
(PR) and caudal (PC) periventricular white matter, the genu (CG) and the splenium
(CS) of the corpus callosum and the thalamus (TH) in 12 patients with normal
pressure hydrocephalus (NPH) and compared them with 16 healthy control subjects.
We found a significantly lower MTR in the NPH group than in the normal group for
PR, PC, CG, and CS but not for TH. MT measurements give additional information
which cannot be gained by conventional MRI, suggesting that NPH is associated
with diffuse white matter damage, even in normal-appearing cerebral white matter.
PMID- 10772138
TI - MRI of the intraorbital optic nerve in patients with autosomal dominant optic
atrophy.
AB - Measurements of the intraorbital optic nerve were made using high-resolution
coronal MRI in 10 adults with autosomal dominant optic atrophy. Comparisons were
made with previous studies of 10 normal adult subjects. The cross-sectional
diameters of the optic nerve and the perineural subarachnoid space were measured
and a ratio of there diameters at anterior, mid and posterior positions along the
optic nerve was determined. We found a statistically significant difference in
the mean optic nerve: sheath ratio between the control group and patients with
autosomal dominant optic atrophy. At anterior, mid and posterior locations along
the optic nerve it is significantly smaller in patients with optic atrophy. We
have demonstrated that the loss of ganglion cells, previously documented in
dominant optic atrophy, is associated with a significant loss of optic nerve
tissue and thinning of the nerve along its length.
PMID- 10772139
TI - Diffusion-weighted imaging in ischaemic stroke: a follow-up study.
AB - Diffusion-weighted (DWI) echo-planar (EPI) MRI has been used for imaging acute
ischaemic stroke. We used DWI and conventional spin-echo (SE) MRI to study the
dynamics of ischaemic human stroke. We examined 30 patients (mean age 57.5 years,
range 27-82 years, median 57 years) with a diagnosis of stroke. They were
examined in the acute (120 min to 47 h, mean 15.3 h), subacute (8 days) and
chronic (2-3 months) stages of ischaemia using clinical scores and MRI. Imaging
was performed on an 1.5-T imager. Anisotropic DWI with diffusion gradients in all
three axes, an isotropic tensor trace pulse DWI sequence and SE MRI were used. In
all patients both DWI sequences showed a decrease in the apparent diffusion
coefficient (ADC) in the acute stage, even when SE images did not reveal signal
abnormalities. Clinical features correlated with lesion site but not size. The
ADC was initially 19.6-43% less than that of nonischaemic tissue and increased to
normal after 7 days in conventionally treated patients and after 2-5 days in
patients who underwent intra-arterial fibrinolysis. In the chronic stage the ADC
rose by up to 254.4 %. In patients who did not undergo fibrinolysis DWI changes
correlated with the final infarct size (P<0.05). It was possible to differentiate
acute from chronic ischaemic lesions. We conclude that DWI is a sensitive and
practicable tool for detecting early cerebral ischaemia. It is possible to
predict in the acute stage the final size of an infarct. DWI may be helpful for
clinical decisions and for monitoring therapy.
PMID- 10772140
TI - Normal diffusion-weighted imaging in cerebral air embolism complicating
angiography.
AB - We report a case of cerebral air embolism resulting from accidental air infection
during cerebral angiography. A 60-year-old man was accidentally injected with air
via the left subclavian artery. Angiography demonstrated air within the basilar
artery. The patient showed signs of posterior circulation ischaemia (confusion,
blindness, gaze palsy and hemiparesis). However, MRI, including diffusion
weighted imaging, showed no abnormality 4 h later. The patient was treated with
hyperbaric oxygen within 5 h of the embolism. All symptoms and signs resolved
completely within a week.
PMID- 10772141
TI - A vascular sarcoid mass mimicking a convexity meningioma.
AB - We report a 48-year-old woman with a left posterior temporal extra-axial mass
that had the imaging characteristics of a meningioma on preoperative CT, MRI and
angiography. However, a biopsy diagnosis of sarcoidosis was made. This case
illustrates that dural-based sarcoid masses can be very vascular and
radiographically indistinguishable from meningiomas. Characteristic imaging
features of extra- and intra-axial sarcoid lesions are discussed.
PMID- 10772142
TI - MRI appearances mimicking the dural tail sign: a report of two cases.
AB - We report two cases in which the MRI appearances mimicked the dural tail sign; a
glioma extending into the subarachnoid space, and a meningioma extending to the
subdural space. They indicate that tumour invasion into the subarachnoid or
subdural space, should be considered when prominent linear enhancement is
observed along the dura mater adjacent to tumours.
PMID- 10772143
TI - The double lumen: a pathognomonic angiographic sign of arterial dissection?
AB - A case is reported which questions the absolute significance of the "double-lumen
sign" in the diagnosis of arterial dissection. I suggest that when demonstrated
in isolation, this sign should be interpreted with caution, giving consideration
to the possibility of arterial fenestration, and appropriate diagnostic measures
implemented.
PMID- 10772144
TI - Parasitic lesion of the insula suggesting cerebral sparganosis: case report.
AB - Cerebral sparganosis, a parasitic disease, rarely produces a chronic active
inflammatory response in the brain. Clinically and radiographically the process
may mimic a neoplasm. We report a 30-year-old man who underwent surgical
exploration for a mass in the insular cortex. Histology revealed a densely
fibrotic mass heavily infiltrated with plasma cells and lymphocytes, in which
were embedded parasitic forms consistent with sparganosis. We describe the MRI
appearances and pathologic features. Intracranial mass lesions secondary to
sparganosis must be considered in patients with a history of travel to endemic
areas, especially Asia.
PMID- 10772145
TI - Brain damage in hanging: a new CT finding.
AB - We report a 23-year-old man who attempted suicide by hanging. There have been few
reports of involvement of the brain parenchyma shown on CT, all showing ischaemic
lesions. This is the first report of multifocal intracerebral haematomas due to
hanging seen on CT.
PMID- 10772146
TI - Intracranial haemorrhage following lumbar myelography: case report and review of
the literature.
AB - We describe a subacute intracranial subdural haematoma following lumbar
myelography. This rare but potentially life-threatening complication has been
reported both after lumbar myelography and following lumbar puncture for spinal
anaesthesia. We review 16 previously reported cases of intracranial haemorrhage
following lumbar myelography, and discuss the pathogenesis. In all reported cases
post-puncture headache was the leading symptom and should therefore be regarded
as a warning sign.
PMID- 10772147
TI - MRI and CT of a haemangioma of the mandible in Kasabach-Merritt syndrome.
AB - Since the description in 1940 of Kasabach-Merritt syndrome (KMS) in patients with
capillary haemangiomas, several other vascular tumours have been recognised as
possible causes of this coagulopathy. The literature suggests a specific
histological pattern of vascular tumours responsible for KMS, excluding capillary
haemangioma [1]. There is an extensive literature on, haemangiomas accompanied by
thrombocytopenia, and imaging of thrombosis in the lesion, especially cavernous
haemangioma of the liver. However, no report has described a haemangioma of the
mandible in the acute stage of the coagulopathy, or serial examinations of such a
lesion. We report the features of a mandible lesion with KMS and discusses the
interpretations of the changes observed.
PMID- 10772148
TI - Cerebral angioplasty practice at major medical centers in the United States.
AB - Concern has been expressed recently regarding the proliferation of angioplasty
and/or stenting of cerebral vessels. However, little is known about the volume of
angioplasties being performed or the number of experienced interventionalists. A
questionnaire was mailed to directors of accredited radiology residency programs
in the United States, to define the level of expertise available at teaching
hospitals in terms of angioplasty and/or stenting. Of 200 programs surveyed, 111
responded (56 %). Of 111 program directors 47 (42%) indicated that cerebral
angioplasty was being performed at their center. The greatest experience is
currently for angioplasty of post-subarachnoid hemorrhage vasospasm (mean 16
procedures performed) and the least experience for dilation of basilar artery
atherosclerosis (mean five procedures performed). The reported stroke and/or
death rate in centers performing angioplasty of the extracranial carotid system
is 1.5 %. Comparisons with other medical specialties (e.g., cardiologists,
neurologists, neurosurgeons) are necessary to determine the full scope of
extracranial neurovascular procedures being performed and the corresponding
complication rates.
PMID- 10772149
TI - Characterization of a novel organophosphorus hydrolase from Nocardiodes simplex
NRRL B-24074.
AB - We characterized a novel organophosphorus hydrolase (OPH) activity expressed by
Nocardiodes simplex NRRL B-24074, a member of a coumaphos-degrading microbial
consortium from cattle dip waste. Like the previously characterized OPH from
Nocardia sp. strain B- (NRRL B- 16944), OPH activity in N. simplex is located in
the cytoplasm and is expressed constitutively. The purified enzyme is monomeric,
has a native molecular size of 45,000 Da and has a specific activity toward ethyl
parathion of 33 micromole/min x mg protein. Km constants for the enzyme with the
structurally related organophosphate pesticides ethyl parathion and EPN were 100
microM and 345 microM, respectively. Although OPH activity in extracts did not
require the addition of divalent cations, the purified enzyme lost activity
during dialysis against phosphate buffer and this activity could be restored
after incubation in buffer containing either CoSO4 or CuSO4. Our results suggest
that OPH activity in N. simplex is distinct from other known OPHs and that the
responsible gene is unrelated to known genes.
PMID- 10772150
TI - Formaldehyde and methanol biodegradation with the methylotrophic yeast Hansenula
polymorpha in a model wastewater system.
AB - In search of the optimal way to reduce the hazards of environmental contamination
by formaldehyde (FD) and methanol the use of unconventional yeasts is proposed as
exemplified by the methylotrophic yeast Hansenula polymorpha. In a very
simplified environment of a model wastewater solution, H. polymorpha cells were
able to grow on, and metabolize formaldehyde and methanol, applied as sole carbon
sources, at concentrations typical for wastewaters of the chemical industry.
Several experimental conditions were tested for cell growth and biodegradation
kinetics. It was found that the yeast culture inoculated at low cell density was
able to grow on initial FD levels up to 400mg/l and the biomass yield was
dependent on both, the amount of total carbon added and the physiological state
of the cells. When high density of pre-adapted cell culture was used, the
methylotrophs were fully viable and able to degrade formaldehyde present at
initial concentrations up to 700 mg/l. The maximum limiting FD consumption rate
was determined as approx. 400 mg/1 per hour. Methanol, at concentrations up to
2%, was easily utilized and did not have a negative effect on cell growth and
respiration. It is suggested that in real wastewaters the eukaryotic
microorganisms--in contrast to bacteria--might reveal greater adaptation
potential to toxic levels of formaldehyde as well as to other wastewater
constituents.
PMID- 10772151
TI - Effects of hydrostatic pressure and temperature on physiological traits of
Thermococcus guaymasensis and Thermococcus aggregans growing on starch.
AB - The effects of temperature and hydrostatic pressure on growth of two novel
Thermococcus species, T. guaymasensis and T. aggregans, were investigated. These
archaea, isolated from the Guaymas Basin hydrothermal vent site at 2000 meters
depth, are able to grow on starch in sulfur-depleted medium producing significant
amounts of amylases and pullulanases. At 85 degrees C, T. guaymasensis exhibited
a barophilic response at 20 and 35 MPa but inhibition of growth occurred at 50
MPa; at 50 MPa, cell replication was repressed, the mean cell size increased, and
production of starch-hydrolysing enzymes was significantly stimulated. Barophily
was also expressed by T. guaymasensis under 20 MPa at sub-optimal temperature (70
C) but morphological alterations of cells were observed earlier (35 MPa). No
barophily was exhibited by T. aggregans at 85 degrees C. In this case, cell
replication was repressed at 20 MPa and remarkable inhibition of growth occurred
at 50 MPa. Only when T. aggregans was cultivated at 75 degrees C, a significant
barophilic response was exhibited at 20 MPa, as shown by the rate of replication
and metabolism. These results show that Thermococcus species, although isolated
from the same ecosystem, differ with regard to the effects of pressure and
temperature on cell physiology. The metabolic responses and their significance
for potential biotechnological applications are also discussed.
PMID- 10772152
TI - Effects of micronutrients on growth and starch hydrolysis of Thermococcus
guaymasensis and Thermococcus aggregans.
AB - The effects of micronutrients on growth of Thermococcus guaymasensis and
Thenrmococcus aggregans in a starch-containing medium were investigated. A trace
minerals solution, a vitamins solution and calcium chloride were omitted from the
medium or added in different amounts. The growth rates of both species were not
affected over a significant range of concentrations of these compounds, but
appreciable inhibition of growth was observed after the addition of elemental
sulfur to the medium. T. guaymasensis exhibited a significant tolerance to high
amounts of trace element and vitamin solutions but growth was inhibited by the
omission of these compounds from the medium. Moreover, both amylolytic and
pullulytic activities increased in the presence of 6-fold higher amounts of trace
element and vitamin solutions, compared to the concentrations used in the usual
medium. In T. aggregans, both enzymatic activities were enhanced in the presence
of either increased (4-fold) amounts of trace element and vitamin solutions, or
after the addition of elemental sulfur to the medium. Furthermore, larger
activities of starch-hydrolysing enzymes were detected with a 10-fold higher
concentration of calcium chloride, compared to the usual medium, in the absence
of trace element and vitamin solutions. When both Thermococcus species were
tested for the tolerance to specific cations and oxyanions, T. guaymasensis
exhibited higher tolerance compared to T. aggregans, the former strain being
capable to grow in the presence of 6 mM Ni2+, 4mM Cu2+, 1.5 mM SeO4(2-), and 1.5
mM MoO4(2-). The content of total cell proteins followed the pattern of starch
hydrolysing enzymes and an over-expression of proteins in the range of 35, 50 and
70 kDa was observed.
PMID- 10772153
TI - Citrate utilization by homo- and heterofermentative lactobacilli.
AB - Citrate utilization by several homo- and heterofermentative lactobacilli was
determined in Kempler and McKay and in calcium citrate media. The last medium
with glucose permitted best to distinguish citrate-fermenting lactobacilli.
Lactobacillus rhamnosus ATCC 11443, Lactobacillus zeae ATCC 15820 and
Lactobacillus plantarum ATCC 8014 used citrate as sole energy source, whereas in
the other strains, glucose and citrate were cometabolized. Some lactobacilli
strains produced aroma compounds from citrate. Citrate transport experiments
suggested that all strains studied presented a citrate transport system inducible
by citrate. The levels of induction were variable between several strains. Dot
blot experiment showed that lactobacilli do not present an equivalent plasmid
coding for citrate permease.
PMID- 10772154
TI - Isolation, screening and characterization of bacteriocin-producing lactic acid
bacteria isolated from traditional fermented food.
AB - 100 lactic acid bacterial strains isolated from traditional fermented foods
(yoghurt, milk cream, sour dough and milk) were screened for bacteriocin
production. Twenty six strains producing a nisin-like bacteriocin were selected.
Most of these isolates gave only a narrow inhibitory spectrum, although one
showed a broad inhibitory spectrum against the indicator strains tested, this
strain was determined as Lactococcus lactis. The influence of several parameters
on the fermentative production of nisin by Lactococcus lactis was studied.
Production of nisin was optimal at 30 degrees C and in the pH range 5.5-6.3. The
effect of different sulphur and nitrogen sources on Lactococcus lactis growth and
nisin production was studied. Magnesium sulfate and manganese sulfate were found
to be the best sulphur sources while triammonium citrate was the best inorganic
nitrogen source and meat extract, peptone and yeast extract were the best organic
nitrogen source for nisin production.
PMID- 10772155
TI - Solid formulations of binucleate Rhizoctonia isolates suppress Rhizoctonia solani
and Pythium ultimum in potting medium.
AB - Two isolates of binucleate Rhizoctonia spp., previously selected for efficacy in
suppression of Rhizoctonia solani and Pythium spp., as well as plant growth
promotion, were incorporated into various solid substrate formulations. These
formulated products were assayed at three doses in three glass-house experiments
for biocontrol of damping-off diseases in Capsicum annuum. R. solani anastomosis
group 4 or Pythium ultimum var. sporangiiferum were incorporated into pasteurized
potting medium with each formulated binucleate Rhizoctonia product. All
formulations were effective against both pathogens in at least two experiments,
but some formulations of one isolate of binucleate Rhizoctonia did not give
consistent control of R. solani in one experiment. The most consistent
formulation, which provided control of both pathogens at all doses of binucleate
Rhizoctonia, was the simple substrate of rice hulls. The implications for
commercialization of a biocontrol product are discussed.
PMID- 10772156
TI - Physiological aspects of fungi isolated from root nodules of faba bean (Vicia
faba L.).
AB - The present study was made to isolate and assess some physiological
characteristics of root nodule-colonizing fungi. During this study, 17 fungal
species were isolated from root nodule samples taken from faba bean plants (Vicia
faba L.) collected from different sites at Assiut area (Egypt). The growth of
faba bean plants in pots was significantly promoted by soil inoculation with most
fungi. Growth was checked in pots with inocula of Cladosporium cladosporioides,
Fusarium moniliforme, F: oxysporium, F solani, Macrophominia phaseolina and
Rhizoctonia solani which were added separately. All growth-promoting fungi were
capable of producing cellulase, pectin lyase, polygalacturonase, protease,
urease, amidase, acid phosphatase, alkaline phosphatase and arylsulfatase in
growth medium supplemented with the corresponding substrates. Four fungal
species, Aspergillus awamori, A. flavus, Penicillium chrysogenum and Trichoderma
koningii showed the highest rates of enzyme formation. The effect of the addition
of six trace elements to the growth media at 30 micromol/ml on enzyme production
revealed some dependency on species, enzyme and metal ion. Cd2+, Hg2+ and Zn2+
generally inhibited enzyme activity. Cu(1+), Fe3+ and Al3+ showed a stimulatory
effect. Fungicides (afugan and tilt) and herbicides (brominal and fusilade) at 50
ppm generally promoted enzyme activity, but insecticides (kelthane and
fenvalerate) caused some inhibition to enzyme activities. Salinization of the
growth media with NaCl strongly inhibited the enzymatic activity of all fungi at
concentrations between 0.5 and 1.5%.
PMID- 10772157
TI - Response of Eucalyptus tereticornis to inoculation with indigenous AM fungi in a
semiarid alfisol achieved with different concentrations of available soil P.
AB - Eucalyptus tereticornis was grown in a green house in a low phosphorus (0.67 ppm
Olsen's P) soil (Typic Haplustalf) inoculated with mixed indigenous arbuscular
mycorrhizal (AM) fungi. Soil was amended to achieve P levels of 10, 20, 25, 30
and 40 ppm to evaluate the growth response and dependence of E. tereticornis to
inoculation with AM fungi. A positive response to mycorrhizal inoculation was
evident at the first two levels of soil P, i.e., at 0.67 and 10 ppm but not at
the higher levels of soil P. Dry matter yield of inoculated plants beyond 20 ppm
soil P was similar or even less compared to their uninoculated counterparts.
Inoculated plants produced maximum dry matter (root and shoot) at 10 ppm soil P,
whereas uninoculated plants did not produce until the level reached 20 ppm. The
percentage root length colonized by AM fungi decreased from 31% to 3% as the
concentration of P increased beyond 10 ppm soil P. Higher levels of soil P
depressed the AM colonization significantly. Inoculated plants had higher shoot P
and N contents compared to their uninoculated counterparts at all levels of soil
P. However, at the first two lower levels of soil P, inoculated plants showed
significantly higher shoot P and N contents over their respective uninoculated
counterparts. The increasing shoot P accumulation beyond 10 ppm did not enhance
dry matter yields. Inoculated plants had lower values of phosphorus utilization
efficiency (PUE) and nitrogen utilization efficiency (NUE) at all levels of soil
P except at the unamended level (0.67 ppm) where the inoculated plants showed
higher values of NUE compared to uninoculated control plants. Taking dry matter
yield into consideration, Eucalyptus plants were found to be highly dependent on
10 ppm of soil P for maximum dry matter production. Any further amendment of P to
soil was not beneficial neither for AM symbiosis nor plant growth.
PMID- 10772158
TI - Screening and characterization of Bacillus thuringiensis isolates from Brazil for
the presence of coleoptera-specific cry genes.
AB - Forty-three Bacillus thuringiensis isolates from Brazil and 3 from Argentina were
screened, using the polymerase chain reaction (PCR), for various coleoptera
specific cry genes. Seven isolates produced specific and/or nonspecific DNA
fragments in a PCR reaction with primers specific for two coleopteran cry genes
and 4 of these produced DNA fragments with primers specific for 7 known
coleopteran cry genes. These isolates showed, by electron microscopy, the
presence of spherical crystals. They also showed proteins of around 70 kDa which
were immunologically similar to the Cry3Aa protein from B. thuringiensis subsp.
tenebrionis. The 3 isolates from Argentina were toxic to T. molitor, and although
no isolate from Brazil showed toxicity, they might show toxicity to another
insect species.
PMID- 10772159
TI - Changes in protein composition and hydrolytic enzyme activity of Escherichia coli
and Hafnia alvei grown in human fluids.
AB - Growing of Escherichia coli and Hafnia alvei cells in several cell-free human
fluids, such as normal serum, serum from diabetic patients, pleural, ascitic and
spinal fluid, revealed that various biochemical changes occurred. Protein profile
on SDS-PAGE as well as acid and alkaline phosphohydrolytic enzymes on native gels
of cell extracts were affected after culturing of bacteria in the above fluids.
Gelatinolytic and hyaluronolytic activity was of interest because both of them
are histolytic enzymes. Although there was a potential appearance of
gelatinolytic bands on gelatin-SDS-PAGE in cells starved in seawater, none of
these activities were expressed in cells grown in human fluids. A hyaluronolytic
activity of approximately 45 KDa was present in cells cultured in Mueller Hinton
broth. This enzyme was decreased either in cells starved in seawater or in cells
grown in human fluids to an almost invisible band on hyaluronan-SDS-PAGE.
PMID- 10772160
TI - Antibiotic use in food animals: controlling the human health impact.
AB - Resistance to antimicrobial drugs has compromised control of many bacterial
pathogens. For foodborne pathogens, the most likely source of resistance is use
of antimicrobials in food-producing animals. To control the human health impact
from use of antimicrobials in animals, the U.S. Food and Drug Administration
(FDA) recently announced plans to assess the microbial safety of all
antimicrobials intended for use in food-producing animals. This paper describes
the history of antimicrobial use and regulation in animals, the public health
concern, the current animal drug approval process in the United States, the
international perspective, and FDA's proposed procedures to evaluate the human
health impact of the antimicrobial effects associated with animal drugs intended
for use in food-producing animals. The primary public health goal of the improved
regulatory paradigm is to ensure that significant human antimicrobial therapies
are not lost due to use of antimicrobials in food animals.
PMID- 10772161
TI - Determination of sulfamethazine in swine and cattle feed by reversed-phase liquid
chromatography with post-column derivatization: pre-collaborative study.
AB - In-house validation of a liquid chromatographic method for determination of
sulfamethazine in swine and cattle feed was performed to verify that the method
was ready for collaborative study under AOAC INTERNATIONAL guidelines. In this
method, sulfamerazine is added during the extraction procedure and is used as an
internal standard to correct for variable recovery of sulfamethazine from a
variety of swine and cattle feed matrixes. The determinative step involves the
use of post-column derivatization with dimethylaminobenzaldehyde which reacts
with the primary amine group on the sulfonamides. Detection is at 450 nm, a
wavelength at which most co-extracted matrix materials and other feed additives
do not absorb light. The results indicate that the method recovery, precision,
and ruggedness meet normal criteria to be ready for a collaborative study.
Fortification experiments over a range of sulfamethazine concentrations from
0.006 to 0.26% showed an overall recovery relative to the internal standard of
100 +/- 2%. These studies include both swine and cattle feed matrixes. The mean
recovery in the analysis of 3 beef cattle experimental feeds was 98.9%. The
method results agreed with the AOAC INTERNATIONAL Official Method for
colorimetric analysis of swine feed. Method precision was excellent during in
house validation studies, with coefficients of variation (CVs) ranging from about
0.5 to 3%. The method ruggedness was verified with an overall CV of 3.5%.
PMID- 10772162
TI - Determination of sulfamethazine in swine and cattle feed by reversed-phase liquid
chromatography with post-column derivatization: collaborative study.
AB - A liquid chromatographic (LC) method for the analysis of sulfamethazine (SMT) in
complete swine and cattle feed was collaboratively studied. The method uses post
column derivatization with dimethylaminobenzaldehyde and detection at 450 nm. To
5g finely ground feed, extractant (0.2N HCl + 1.5% diethylamine in 25% methanol),
and internal standard solutions are added, and the SMT is extracted by shaking
for 1 h. Clarified extract (high-level sample extract diluted to a target
concentration of ca 5.5 microg/mL) is chromatographed on a Cla reversed-phase LC
column with acetonitrile-2% acetic acid (17 + 83) mobile phase. Sulfamerazine is
used as an internal, or surrogate standard to correct for variable recovery of
sulfamethazine from a variety of feed matrixes. Six Youden matched-pair samples
were sent to 10 collaborators in Korea, Canada, and the United States. Label
claims on the commercial feeds ranged from 0.0077 to 0.22% SMT. The SMT mean
recovery as determined from the 5 samples with known analyte content was 99.8%.
The within-laboratory relative standard deviation (repeatability) ranged from
0.28 to 4.72%. Among-laboratory (including within-laboratory) relative standard
deviation (reproducibility) ranged from 1.26 to 4.87%. The authors recommend the
method for AOAC INTERNATIONAL Official First Action status.
PMID- 10772163
TI - Use of Dacron as an alternative carrier for evaluating oxidizing sterilants in
the AOAC sporicidal test.
AB - The AOAC sporicidal method (966.04) recommends the use of porcelain penicylinders
and black waxed silk sutures as carriers for demonstrating the sporicidal
activity of sterilants. However, the silk carriers are not suitable for
evaluating the sporicidal efficacy of oxidizing agents, and an inert polyester
material (Dacron) is recommended as an alternative. Dacron provides an equivalent
microbial and physical challenge to silk. Microbiologically, both materials
demonstrated similar HCI resistance, which is required by the AOAC test, as well
as equivalent spore loading and spore wash-off. Electron microscopy showed that
both materials present the same braided microstructure, providing an equivalent
physical challenge to the test sterilant. Dacron was more consistent than silk,
and did not require extraction prior to spore loading. The extraction method for
black waxed silk was variable and incomplete, which may compromise the activity
of oxidizing sterilants and add to method variability. Silk was also structurally
altered in the presence of oxidizing sterilants and increased sterilant
degradation. Dacron did not affect the sterilant and was inert in the presence of
oxidizing agents. Dacron sutures are proposed as inert alternatives to silk for
evaluating the sporicidal efficacy of oxidizing agents.
PMID- 10772164
TI - Determination of carbon dioxide evolution rates using a novel noninstrumental
microrespirometer.
AB - A novel noninstrumental microrespirometer was developed to determine carbon
dioxide evolution rates of solid or liquid samples at microL/h levels accurately
and rapidly. The respirometer is based on the simple principle of acid-base
titration at a steady-state of carbon dioxide absorption/evolution. The structure
and operation of the microrespirometer are simple and the cost is modest in
comparison to instrumental methods. The microrespirometer is suitable for
laboratory studies and field routine examinations of food, agricultural, and
environmental samples.
PMID- 10772165
TI - pH-metric determination of acid numbers of petroleum oils without titration.
AB - A pH-metric method was developed for determination of the acid numbers of oils
containing organic and inorganic acids at levels <0.1 mg KOH/g oil. The method is
based on rapid and complete extraction of acids from a test portion of oil into a
special reagent, and measurement of the conditional pH of the mixture "oil
reagent" by a glass electrode. The method uses nontoxic reagents, is not time and
labor consuming, and is cheap and simple enough for automation.
PMID- 10772166
TI - Determination of bisphenol A in sewage effluent and sludge by solid-phase and
supercritical fluid extraction and gas chromatography/mass spectrometry.
AB - Methods have been developed for the determination of bisphenol A (BPA) residues
in municipal sewage and sludge samples. BPA in wastewater samples was enriched
with a C18 solid-phase extraction cartridge, eluted with acetone, and converted
to the pentafluoropropionyl derivative. For sludge samples, BPA was acetylated
and extracted with supercritical carbon dioxide. In both cases, BPA-d16 was used
as a surrogate to monitor extraction efficiency. Final analyses of derivatized
sample extracts were performed by gas chromatography/mass spectrometry operating
in the electron impact mode. For water samples, mean recoveries and standard
deviations were 89 +/- 6, 94 +/- 4, and 85 +/- 7% at fortification levels of 1,
0.1, and 0.025 microg/L, respectively, with a method detection limit of 0.006
microg/L. For solid waste samples, mean recoveries and standard deviations were
93 +/- 5 and 92 +/- 6% at fortification levels of 2.5 and 0.25 microg/g,
respectively, and the method detection limit was 0.05 microg/g. For the Canadian
samples under investigation, concentrations of BPA ranged from 49.9 to 0.031
microg/L in sewage influent and effluent, and from 36.7 to 0.104 microg/g in
sludge.
PMID- 10772167
TI - Rapid enzyme-linked immunoassay for detection of Salmonella in food and feed
products: performance testing program.
AB - The BIOLINE Salmonella ELISA Test for Salmonella spp., which is a rapid, easy,
and convenient assay was evaluated for use in detecting Salmonella in foods and
feeds. Each food matrix or feed was artificially contaminated with low levels of
Salmonella. Twenty different matrixes were studied and 20 different Salmonella
strains from a broad variety of serogroups (B, C, D, E, F, G, H, I, M, O, P, and
U) were used. The EUSA Test kit detected levels as low as 1 cfu/25 g sample with
at least 4 of the 20 matrixes tested. The test kit is applicable to all sample
types tested. The BIOLINE Salmonella ELISA Test kit has been granted AOAC-RI
performance tested status.
PMID- 10772168
TI - Proficiency testing of eight French laboratories in using the AOAC mouse bioassay
for paralytic shellfish poisoning: interlaboratory collaborative study.
AB - In an interlaboratory study, 8 French laboratories were tested for their
proficiency in using the AOAC mouse bioassay for paralytic shellfish poisoning
(PSP). Each laboratory received 1 saxitoxin (STX) standard solution, 1 STX
acidified water solution for determination of the titer, 1 noncontaminated
shellfish sample, 1 naturally contaminated shellfish sample, and 2 shellfish
samples spiked, respectively, at low (152.8 microg STX/100 g meat) and moderate
(334.7 microg STX/100 g meat) levels. All samples were analyzed in duplicate.
Mean recoveries were 35.1% for the low level and 46.6% for the moderate level.
Relative standard deviations (RSD) for within-laboratory variations
(repeatability) ranged from 5.4 to 9.8%; RSD for between-laboratory variations
(reproducibility) varied from 7.8 to 39.6%, depending on STX level. On the basis
of overall performance, all 8 participating laboratories were proficient in their
use of the AOAC mouse bioassay.
PMID- 10772169
TI - Determination of paraffins in food simulants and packaging materials by liquid
chromatography with evaporative mass detection and identification of paraffin
type by liquid chromatography/gas chromatography and fourier transform infrared
spectroscopy.
AB - A liquid chromatographic method with evaporative mass detection (EMD) is
described for the determination of paraffins in food contact materials that do
not contain polyolefin oligomers, or paraffins migrating from these materials
into fatty food simulants or certain simple foods. A normal-phase column
operating at maximum column efficiency separates nonparaffinic and paraffinic
materials without resolving the latter into individual components, and EMD is
used to quantitate the paraffins. An on-line qualitative method that uses liquid
chromatography/gas chromatography with flame ionization detection discriminates
between paraffin waxes and oils in food contact materials, food simulants, and
certain simple foods; a Fourier transform infrared spectrophotometric qualitative
method also discriminates between waxes and oils, but is usually restricted to
food contact materials that do not contain polyolefins and to migration
experiments with organic solvents as fatty food simulants (with some other fatty
food simulants, paraffin type must then be identified in the food contact
material).
PMID- 10772170
TI - Immunoaffinity column cleanup with liquid chromatography using post-column
bromination for determination of aflatoxins in peanut butter, pistachio paste,
fig paste, and paprika powder: collaborative study.
AB - A collaborative study was conducted to evaluate the effectiveness of an
immunoaffinity column cleanup liquid chromatography (LC) method for the
determination of aflatoxin B1 and total aflatoxins at European regulatory limits.
The test portion is extracted with methanol-water (8 + 2) for dried figs and
paprika, and with methanol-water (8 + 2) plus hexane (or cyclohexane) for peanut
butter and pistachios. The sample extract is filtered, diluted with phosphate
buffer saline, and applied to an immunoaffinity column. The column is washed with
water and the aflatoxins are eluted with methanol. Aflatoxins are quantitated by
reversed-phase LC with post-column derivatization (PCD) involving bromination.
PCD is achieved with either an electrochemical cell (Kobra cell) and addition of
bromide to the mobile phase or pyridinium hydrobromide perbromide. Determination
is by fluorescence. Peanut butter, pistachio paste, dried fig paste, and paprika
powder samples, both naturally contaminated with aflatoxins and containing added
aflatoxins, were sent to 16 collaborators in 16 European countries. Test portions
of samples were spiked at levels of 2.4 and 9.6 ng/g for total aflatoxins which
included 1.0 and 4.0 ng/g aflatoxin B1, respectively. Recoveries for total
aflatoxins ranged from 71 to 92% with corresponding recoveries for aflatoxin B1
of 82 to 109%. Based on results for spiked samples (blind duplicates at 2 levels)
as well as naturally contaminated samples (blind duplicates at 4 levels,
including blank), the relative standard deviation for repeatability ranged from
4.6 to 23.3% for total aflatoxins and from 3.1 to 20.0% for aflatoxin B1. The
relative standard deviation for reproducibility ranged from 14.1 to 34.2% for
total aflatoxins, and from 9.1 to 32.2% for aflatoxin B1. The method showed
acceptable within-laboratory and between-laboratory precision for all 4 matrixes,
as evidenced by HORRAT values <1, at the low levels of determination for both
total aflatoxins and aflatoxin B1.
PMID- 10772171
TI - Identification of smoked Atlantic salmon (Salmo salar) and rainbow trout
(Oncorhynchus mykiss) using PCR-restriction fragment length polymorphism of the
p53 gene.
AB - Raw and smoked samples of Atlantic salmon (Salmo salar) and rainbow trout
(Oncorhynchus mykiss) were identified using polymerase chain reaction-restriction
fragment length polymorphism (PCR-RFLP) of the p53 gene. DNA from S. salar and 0.
mykiss was amplified by using primers flanking exons 5 to 6 of the p53 nuclear
gene. PCR products of different length were obtained for each species (532 and
518 base pairs, respectively). Sequences of PCR products obtained from S. salar
and O. mykiss were compared in the search for polymorphic restriction sites. The
restriction fragments obtained with Eco RV, Hinf I, and Taq I endonucleases
showed interspecific polymorphism, making it a useful method for identification
of Atlantic salmon and rainbow trout.
PMID- 10772172
TI - Measurement of bromate in bread by liquid chromatography with post-column flow
reactor detection.
AB - This method is suitable for the determination of bromate residues in a variety of
baked goods. The peer-verified method trial was performed on white bread,
multigrain bread, and coffee cake spiked with known levels of potassium bromate.
The analytical portion is extracted with deionized water to remove bromate from
the bulk of the baked product. The aqueous extract is carried through a series of
steps to remove co-extractives that would interfere with the liquid
chromatography (LC) in the determinative step or hasten the deterioration of the
LC column. The extract is filtered before passing it through a reversed-phase
solid-phase extraction (SPE) column and a cation-exchange column in the silver
form to remove lipids and chloride, respectively. Ultrafiltration is then used to
remove proteins with molecular weights of >30,000 daltons. Finally, a cation
exchange column in the sodium form is used to remove silver ions from the
extract. The determinative step uses LC with a reversed-phase column and an ion
pairing agent in the mobile phase. Detection is based on the post-column reaction
of bromate with o-dianisidine to form an oxidation product that is quantitated
spectrophotometrically at 450 nm. Overall agreement between the submitting and
peer laboratories was quite good. For bromate levels of 10-52 ppb, overall mean
recoveries were 76.9 and 78.8% for the submitting and peer laboratories,
respectively. The standard deviations were higher for the results of the peer
laboratory, probably because of the generally higher level of baseline noise
present in the chromatograms. The results demonstrate that the method provides
adequate accuracy with low-fat as well as high-fat foods. Bromate at levels as
low as 5 ppb (ng/g) can be detected with the method.
PMID- 10772173
TI - Measurement of total fructan in foods by enzymatic/spectrophotometric method:
collaborative study.
AB - An AOAC collaborative study was conducted to evaluate the accuracy and
reliability of an enzyme assay kit procedure for measuring oligofructans and
fructan polysaccharide (inulins) in mixed materials and food products. The sample
is extracted with hot water, and an aliquot is treated with a mixture of sucrase
(a specific sucrose-degrading enzyme), alpha-amylase, pullulanase, and maltase to
hydrolyze sucrose to glucose and fructose, and starch to glucose. These reducing
sugars are then reduced to sugar alcohols by treatment with alkaline borohydride
solution. The solution is neutralized, and excess borohydride is removed with
dilute acetic acid. The fructan is hydrolyzed to fructose and glucose using a
mixture of purified exo- and endo-inulinanases (fructanase mixture). The reducing
sugars produced (fructose and glucose) are measured with a spectrophotometer
after reaction with para-hydroxybenzoic acid hydrazide. The samples analyzed
included pure fructan, chocolate, low-fat spread, milk powder, vitamin tablets,
onion powder, Jerusalem artichoke flour, wheat stalks, and a sucrose/cellulose
control flour. Repeatability relative standard deviations ranged from 2.3 to
7.3%; reproducibility relative standard deviations ranged from 5.0 to 10.8%.
PMID- 10772174
TI - Liquid chromatographic determination of residual nitrite/nitrate in foods: NMKL
collaborative study.
AB - Nitrite and nitrate are used as additives in the food industry to provide color
and taste and to control undesirable gas and flavor production by anaerobic
bacteria by virtue of their antimicrobial properties. The analytical method that
has been widely used to determine nitrite and nitrate involves the use of toxic
cadmium. In response to a request from the Nordic Committee on Food Analysis, a
study was performed to obtain an alternative chromatographic method to determine
residual nitrite and nitrate in meat products. The study was done in 3 stages:
(1) comparative evaluation of the performance of 3 liquid chromatographic
methods, (2) internal validation of the selected ion chromatographic method, and
(3) a collaborative study in which 17 laboratories from European countries
participated. Furthermore, the applicability of the method to matrixes other than
meat and meat products was demonstrated. The results of the collaborative study
show that the European Prestandard prENV 12014-4 is well suited for the
determination of nitrite and nitrate in different foods (e.g., meat products,
vegetables, baby food, and cheese). The limits of detection for nitrite and
nitrate ions are 1 and 10 mg/kg, respectively. Recoveries of residual
nitrite/nitrate ranged from 96 to 108%. Repeatability and reproducibility were
satisfactory.
PMID- 10772175
TI - Determination of lithium in human serum by electrothermal atomic absorption
spectrometry.
AB - An efficient method was developed for the determination of nanogram levels of
lithium in biological samples. Serum samples from human subjects from
southeastern Spain, treated or not treated with lithium carbonate, were analyzed
by electrothermal atomic absorption spectrometry. The samples were previously
treated with a matrix modifier consisting of 0.1% Triton X-100 and injected
through a graphite tube with L'vov platform. The Li concentrations measured by
the procedure described for the 3 certified reference samples used were not
significantly different (p > 0.05) than certified levels. Sample recoveries and
variability during several days, with coefficients of variation from 4.00 to
14.8%, demonstrated the reliability and accuracy of this technique. Mean Li
concentration determined in the serum of individuals with psychiatric disorders
treated with Li (n = 117, 5.077 +/- 1.795 microg Li/mL) was significantly higher
(p < 0.001) than that in individuals not treated with Li (n = 24, 1.902 +/- 2.054
ng Li/mL).
PMID- 10772176
TI - Determination of lead in botanicals/Chinese prepared medicines by using microwave
digestion with flow injection-inductively coupled plasma-mass spectrometry.
AB - A simple, sensitive, and rapid method was developed for the determination of lead
in botanicals and Chinese prepared medicines (CPM) by using closed-vessel
microwave digestion with flow injection-inductively coupled plasma-mass
spectrometry. The limits of detection and quantitation for the method, based on
0.5 g digested sample, were calculated to be 0.10 and 0.61 mg/kg, respectively. A
simple approach was proposed for calibration by multiple linear regression (MLR)
with 207Pb, 206Pb, and 204Pb for the determination of lead in botanical and CPM
samples. The results from calibration by MLR were compared with those obtained by
conventional modes using 207Pb and the sum of 207Pb and 206Pb. The results
obtained by the different modes of calibration were in good agreement for
botanical and CPM samples. The method was found to have good accuracy for the
analysis of botanical reference materials. Method precision based on analyses of
different types of CPM samples by different analysts on different days for
different levels of lead was between 3.0 and 8.0% (relative standard deviation, n
= 6). The effect of possible matrix interference caused by nitric acid and the
extent of digestion was investigated with the method of standard additions.
Significant matrix interference was not observed for the CPM samples analyzed.
MLR was used to examine the effect of variation in isotopic abundance, which was
found to present no significant problem in the determination of lead in the
botanical and CPM samples.
PMID- 10772177
TI - Application of partial least-squares calibration to phosphorimetric data for
determination of polycyclic aromatic hydrocarbons in spiked environmental
samples.
AB - A partial least-squares calibration method is proposed, for the first time, for
phosphorescence signals. The proposed method is based on the determination of
phenanthrene, fluoranthene, and benz[a]anthracene by room temperature
phosphorimetry, using microemulsion solutions. The emission and first-derivative
emission spectra of the ternary mixtures were tested to perform the calibration
matrix. Improved recoveries were found for the prior differentiation step in the
analysis of ternary mixtures of these polycyclic aromatic hydrocarbons in road
dust samples. The proposed method yielded recoveries ranging from 93.2 to 115.3%,
with relative standard deviations of < 6.8%.
PMID- 10772178
TI - Relationship of (known) control values to (unknown) test values in proficiency
studies of pesticide residues.
AB - Proficiency studies have been suggested as an alternative source of information
for evaluating method performance characteristics when results from
interlaboratory method performance studies conforming to internationally
recognized protocols are not available. To explore this possibility, results were
examined from ongoing proficiency studies of pesticide residue analyses in
celery, carrot, and grape purees, and in wine. Statistical performance parameters
were calculated from 18 data sets analyzed as unknowns by about 60 analysts for
12 analytes in the 25-1,000 microg/kg range, and from presumably parallel control
(spike) analyses conducted by about half of the participants. A surprising
finding was that recovery of known, independent control additions by the
participant did not correlate with the recoveries determined as unknowns in the
exercise. The data suggest that censoring or truncating of control data has
occurred. The question of substitution of proficiency data for method performance
data cannot be answered until the problem of unbiased reporting of control data
is resolved.
PMID- 10772179
TI - Accelerated solvent extraction of vitamin K1 in medical foods in conjunction with
matrix solid-phase dispersion.
AB - An extraction technique is described for vitamin K1 in medical foods, using
accelerated solvent extraction (ASE) in conjunction with matrix solid-phase
dispersion (MSPD). The medical food sample is treated as it would be with MSPD
extraction, followed by ASE for a hands-free automated extraction. The vitamin K1
in the ASE extract is then quantitated by reversed-phase liquid chromatography
with fluorescence detection. The chromatography specifications are identical to
those in previous work that used MSPD only, with a limit of detection of 6.6 pg
and a limit of quantitation of 22 pg on column. Recoveries, which were determined
for an analyte-fortified zero control reference material for medical foods,
averaged 97.6% (n = 25) for vitamin K1. The method provides a rapid, automatic,
specific, and easily controlled assay for vitamin K1 in fortified medical foods
with minimal solvent usage.
PMID- 10772180
TI - Stability of domoic acid in saline dosing solutions.
AB - Studies designed to assess the effects of repeated low doses of domoic acid
require an assessment of its stability in solution under the conditions used for
in vivo studies. The stability of 1 mg/mL solutions of domoic acid in saline,
with or without ascorbic acid, was determined for 15 weeks. Solutions were
refrigerated, but warmed to room temperature for several hours each working day
to simulate conditions of actual use. The solutions of domoic acid showed no
evidence of decomposition as evidenced by stability of UV absorbance spectrum,
concentration of domoic acid as determined by a liquid chromatographic method,
and the chromatographic elution pattern. The addition of ascorbate to the domoic
acid/saline solution did not alter the stability, but was deemed unnecessary
because of the firm stability of the domoic acid/saline solution.
PMID- 10772181
TI - Value assignment of nutrient concentrations in five standard reference materials
and six reference materials.
AB - A number of food-matrix reference materials (RMs) are available from the National
Institute of Standards and Technology (NIST) and from Agriculture Canada through
NIST. Most of these materials were originally value-assigned for their elemental
composition (major, minor, and trace elements), but no additional nutritional
information was provided. Two of the materials were certified for selected
organic constituents. Ten of these materials (Standard Reference Material [SRM]
1,563 Cholesterol and Fat-Soluble Vitamins in Coconut Oil [Natural and
Fortified], SRM 1,566b Oyster Tissue, SRM 1,570a Spinach Leaves, SRM 1,974a
Organics in Mussel Tissue (Mytilus edulis), RM 8,415 Whole Egg Powder, RM 8,418
Wheat Gluten, RM 8,432 Corn Starch, RM 8,433 Corn Bran, RM 8,435 Whole Milk
Powder, and RM 8,436 Durum Wheat Flour) were recently distributed by NIST to 4
laboratories with expertise in food analysis for the measurement of proximates
(solids, fat, protein, etc.), calories, and total dietary fiber, as appropriate.
SRM 1846 Infant Formula was distributed as a quality control sample for the
proximates and for analysis for individual fatty acids. Two of the materials
(Whole Egg Powder and Whole Milk Powder) were distributed in an earlier
interlaboratory comparison exercise in which they were analyzed for several
vitamins. Value assignment of analyte concentrations in these 11 SRMs and RMs,
based on analyses by the collaborating laboratories, is described in this paper.
These materials are intended primarily for validation of analytical methods for
the measurement of nutrients in foods of similar composition (based on AOAC
INTERNATIONAL's fat-protein-carbohydrate triangle). They may also be used as
"primary control materials" in the value assignment of in-house control materials
of similar composition. The addition of proximate information for 10 existing
reference materials means that RMs are now available from NIST with assigned
values for proximates in 6 of the 9 sectors of the AOAC triangle. Five of these
materials have values assigned for total dietary fiber-the first such information
provided for materials available from NIST.
PMID- 10772182
TI - Time-dependent variation in weight and body composition in healthy adults.
AB - OBJECTIVES: To define the limits of change in body weight and body composition
after different time intervals in healthy, normal adults. METHODS: Prospective
and retrospective analyses of paired body composition studies in a total of 326
healthy adults, ages 18 to 97. Measurements included body weight, fat and fat
free mass (FFM) by dual x-ray absorptiometry (DXA) and bioimpedance analysis
(BIA), plus body cell mass (BCM) by whole-body counting of 40K and BIA. RESULTS:
Time interval between studies was a significant predictor of the differences in
paired studies. The 95% confidence intervals for percent difference were lowest
for body weight, intermediate for BCM and FFM, and highest for fat, in part
because of the differences in sizes of these body compartments. There were
significant associations among the changes in body composition by BIA and by
criterion methods, suggesting that the observed changes are real. CONCLUSIONS:
The normal variation in body weight and body composition increases over time.
Time-dependent criteria may increase the sensitivity in diagnosing malnutrition.
Interpreting changes in body compartments requires consideration of the size of
each compartment.
PMID- 10772183
TI - Effect of oral genistein and isoflavone-free diet on cecal flora and bacterial
translocation in antibiotic-treated mice.
AB - BACKGROUND: There are several reports indicating that the isoflavone genistein
may augment the integrity of the intestinal epithelial barrier as well inhibit
bacterial internalization by cultured enterocytes. We speculated that oral
genistein might enhance the integrity of the intestinal epithelial barrier as
monitored by the extraintestinal dissemination of intestinal bacteria. METHODS:
Mice were treated with oral antibiotics to induce cecal bacterial overgrowth
accompanied by bacterial translocation of antibiotic-resistant enterobacteria,
especially Escherichia coli. These mice were divided into separate groups that
included chow-fed mice orally inoculated either with saline, vehicle, or
genistein, and mice fed isoflavone-free diet and orally inoculated with either
saline, vehicle, or genistein. Intestinal bacterial overgrowth was monitored by
quantitative culture of excised ceca and bacterial translocation was monitored by
quantitative culture of draining mesenteric lymph nodes. RESULTS: Mice fed the
isoflavone-free diet had decreased populations of cecal bacteria compared with
chow-fed mice, and bacterial translocation was reduced in chow-fed mice compared
with mice fed isoflavone-free diet. However, bacterial translocation was similar
in mice given oral genistein compared with appropriate control mice. CONCLUSIONS:
Oral genistein had no noticeable effect on bacterial translocation in this model.
However, the isoflavone-free diet had an antibacterial effect on cecal flora, and
the isoflavone-free diet was associated with decreased numbers of cecal bacteria
and decreased incidence of bacterial translocation.
PMID- 10772184
TI - Effect of oral glutamine supplementation during bone marrow transplantation.
AB - BACKGROUND: Because all patients receiving bone marrow transplant (BMT) and
peripheral blood progenitor cell transplant (PBPCT) experience gastrointestinal
(GI) toxicity from the preparative regimen of chemotherapy, with or without
radiation, oral glutamine was administered during the preparatory regimen and
after transplant to maintain GI structure and function. METHODS: To evaluate
effects of oral glutamine on nutritional status and overall outcome, a
prospective, randomized, double-blinded study was performed on 58 autologous and
allogeneic BMT patients. Patients received 30 g of oral glutamine or placebo
daily. RESULTS: The trends of decreased median length of stay and the median
number of days of total parenteral nutrition (TPN) were seen in the group
supplemented with the >0.285-g/kg (the recommended dosage) dose of glutamine;
however, there was no statistically significant difference in the nutritional
status and overall patient outcome as assessed by days receiving TPN, number of
days required until oral intake resumed, length of hospitalization, number of
days and highest grade of mucositis, and quantity and number of days of diarrhea.
CONCLUSIONS: This study does not support the hypothesis that oral glutamine may
offer benefit. Further investigation is required regarding clinical tools for
determining effectiveness, administration for tolerance and compliance, dosage,
and potential of oral glutamine usage.
PMID- 10772185
TI - Enteral nutrition and keratinocyte growth factor regulate expression of
glutathione-related enzyme messenger RNAs in rat intestine.
AB - BACKGROUND: Malnutrition is associated with increased reactive oxygen species
(ROS) formation and depletion of the critical antioxidant glutathione (GSH) in
the intestine. The malnutrition-induced decrease in gut GSH levels is prevented
by recombinant keratinocyte growth factor (KGF) administration. We investigated
whether enzymes that are induced by oxidants and modulate tissue GSH supply are
regulated by enteral nutrients or KGF at the messenger RNA (mRNA) level. METHODS:
Adult rats were fasted for 3 days alone or fasted for 3 days then refed ad
libitum. In a second model, rats were fasted for 3 days and then refed ad libitum
or 25% of ad libitum intake with daily intraperitoneal saline or recombinant KGF
(5 mg/kg/d) for 3 subsequent days. mRNA levels for gamma-glutamylcysteine
synthetase (gamma-GCS), gamma-glutamyl transpeptidase (gamma-GT), glutathione-S
transferase Ya-subunit, gastrointestinal glutathione peroxidase (GI-GPx), and non
selenium-dependent glutathione peroxidase (ns-GPx) were determined in ileum and
colon by ribonuclease protection assay. RESULTS: Fasting increased ileal gamma
GCS, ns-GPx, and glutathione-S-transferase mRNAs (by 36%, 165%, and 130% of
controls) and decreased GI-GPx mRNA (to 55% of controls). In the colon, mRNAs for
GSH-related enzymes were unchanged by fasting or refeeding. Prolonged enteral
nutrient restriction (25% refeeding after a 3-day fast) increased gamma-GCS and
glutathione-S-transferase mRNAs (by >270% of controls), decreased GI-GPx mRNA (to
<50% of controls) in ileum and colon and increased ns-GPx mRNA (by 180%) in
colon. KGF treatment increased ns-GPx mRNA in the ileum and colon and glutathione
S-transferase mRNA in the colon (by >200% of controls). CONCLUSIONS: Enteral
nutrient intake regulates GSH-related enzyme mRNA levels in the intestine, which
may contribute to the decrease in mucosal GSH during malnutrition. Increased ns
GPx and glutathione-S-transferase mRNA levels during malnutrition and with KGF
administration may increase detoxifying functions in the gut under these
conditions.
PMID- 10772186
TI - Malnutrition impairs postresection intestinal adaptation.
AB - BACKGROUND: Postresection intestinal adaptation is influenced by several factors,
including luminal nutrients. Adaptation is impaired in the absence of luminal
nutrients, even if the nutrition is maintained via total parenteral nutrition
(TPN). Reduced enteral intake also inhibits adaptation if malnutrition is
present, but the mechanism has not been completely defined. Our aim was to study
the effect of reduced enteral nutrition on adaptation and enterocyte production
and death after 50% proximal resection in rats. METHODS: Eighteen Lewis rats
underwent either transection (n =6) or 50% proximal resection (n =12). The
resected animals either ate ad libitum (n = 6) or were offered 75% of ad libitum
intake (n =6). Nutritional status and intestinal adaptation were determined 14
days after surgery. RESULTS: Resected animals receiving 75% normal intake had
decreased body weight (89% +/- 4% vs 112% +/- 2% and 112% +/- 1%, p < .05) and
serum albumin (2.7 +/- 0.1 vs 3.2 +/- 0.0 g/dL and 3.0 +/- 0.1 g/dL, p < .05)
compared with resection with normal intake and transection, respectively.
Intestinal weight (0.32 +/- 03 vs 0.22 +/- 0.02 g/cm and 0.19 +/- 0.03 g/cm, p <
.05) and diameter (10.5 +/- 0.5 vs 8.5 +/- 1.0 mm and 7.8 +/- 0.8 mm, p < .05)
increased after resection alone compared with transection and malnourished
resection groups. Gut weight and diameter and villus height were lower in
malnourished resected animals than with transection. Crypt cell production rate
was significantly lower in the reduced intake animals. Apoptosis was increased in
both crypt and villus enterocytes in normally nourished but not malnourished
resected animals. Villus apoptosis correlated with villus height. CONCLUSIONS:
Intestinal adaptation is impaired by a 25% reduction in enteral nutrients,
confirming that both the route and quantity of nutrient intake are important in
this process. Both enterocyte production and loss via apoptosis are decreased by
reduced enteral intake and malnutrition after resection. The correlation between
villus height and apoptosis suggests that the reduced apoptosis reflects the
smaller enterocyte number in malnourished animals rather than an adaptive
response to maintain intestinal structure.
PMID- 10772187
TI - Vitamin A status modulates intestinal adaptation after partial small bowel
resection.
AB - BACKGROUND: Intestinal adaptation after loss of functional small bowel surface
area is characterized by cellular hyperplasia and increased absorptive function.
Interventions to enhance the adaptive response are needed to decrease the
morbidity and mortality associated with short bowel syndrome. Retinoic acid was
shown to stimulate crypt cell proliferation in the adapting remnant rat ileum by
6 hours after resection. Thus, vitamin A, which is required for normal epithelial
cell proliferation and differentiation and which can modulate programmed cell
death, may play an important role in the adapting intestine. On the basis of
these observations, the effects of vitamin A deficiency on intestinal morphology,
epithelial cell proliferation, and apoptosis in the adapting intestine after
resection were investigated. METHODS: Weanling male Sprague-Dawley rats fed
either a vitamin A-deficient or -sufficient diet for 58 days underwent 70%
proximal small bowel resection. The deficient rats were divided into cohorts that
were either maintained on the experimental diet after surgery or replenished with
vitamin A 20 hours before surgery and switched to the control diet after surgery.
RESULTS: Ten days after resection, vitamin A-deficient rats exhibited a markedly
blunted adaptive response. The adaptive increase in villus height and crypt depth
was absent in the deficient rats. However, adaptive increases in crypt cell
proliferation were not attenuated by vitamin A deficiency, and there were no
differences in apoptotic indices. CONCLUSIONS: Vitamin A deficiency inhibits the
adaptive response to partial small bowel resection, supporting a role for vitamin
A in the adaptive process. Changes in cellular proliferation or programmed cell
death are not sufficient to account for this inhibition. This model system will
be useful for examining the role of other mechanisms, such as changes in cell
cell and cell-extracellular matrix interactions, and rates of epithelial cell
migration and cell extrusion.
PMID- 10772188
TI - Arginine-supplemented diet decreases expression of inflammatory cytokines and
improves survival in burned rats.
AB - BACKGROUND: We examined whether the expression of inflammatory cytokines in
organs was influenced by the enteral diet supplemented with arginine in burned
rats. METHODS: Male Wistar rats weighing about 200 g underwent catheter
jejunostomy and received scald burns covering 30% of the whole-body surface area.
Animals were divided into two groups: a control group (no supplemental arginine,
n = 12) and an arginine group (supplemental arginine: 7.7 g/L, n = 10), which
continuously received total enteral nutrition for 7 days (250 kcal/kg/d, 1.72
gN/kg/d). The following were measured after the experiment: (1) messenger RNA
(mRNA) expression of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma
(IFN-gamma), interleukin-1beta (IL-1beta), and IL-6 in the spleen, thymus, lung,
and liver by a semiquantitative reverse transcription-polymerase chain reaction
method, (2) inflammatory cytokines in the plasma and supernatant of cultured
splenic lymphocytes by enzyme-linked immunosorbant assay, (3) nitric oxide (NO)
product, NO2-/NO3-, in the plasma and supernatant of cultured splenic lymphocytes
by the Griess method, and (4) survival rate by the Kaplan-Meier method. RESULTS:
The mRNA expression of TNF-alpha was significantly decreased in the spleen and
lung (p < .01, p < .05), IFN-gamma in the lung (p < .05), IL-1beta in the spleen
(p < .05), and IL-6 in the thymus and liver (p < .05, p < .05) in the arginine
group when compared with the control group. The production of TNF-alpha by
splenic lymphocytes was suppressed in the arginine group in both concanavalin A
(Con A)-treated and -untreated cultures (p < .01, p < .05). The production of IFN
gamma by splenic lymphocytes treated with Con A was suppressed in the arginine
group (p < .05). The NO product in the supernatant without Con A was increased in
the arginine group (p < .05). The mortality rate of the arginine group (0%) was
lower than that in the control group (33.3%) on day 7 after the burn injury (p <
.05). CONCLUSIONS: The data suggest that dietary arginine supplementation
decreases the mRNA expression of inflammatory cytokines in organs and improves
the survival rate after thermal injury.
PMID- 10772189
TI - Effectiveness of feeding tubes in nursing home residents with swallowing
disorders.
AB - BACKGROUND: Among nursing home residents who stop eating, a common decision for
residents, caregivers, and families is the decision to begin tube feeding. This
study examines the effectiveness of feeding tubes at reducing mortality among
nursing home residents with swallowing disorders and feeding disabilities.
METHODS: Data from a version of the Minimum Data Set+ (MDS +) encompassing three
different states from calendar years 1993 and 1994 were analyzed. Residents were
included in the study if they were not totally dependent on staff for eating upon
their first assessment but became totally dependent on staff for eating and had a
swallowing disorder at some point during their nursing home stay. We used a
proportional hazard regression to examine the relationship of feeding tubes with
mortality after total eating dependence occurred. RESULTS: Unadjusted Kaplan
Meier curves found that those with feeding tubes were less likely to die than
comparable residents without feeding tubes (p < .001). Estimated survival at 1
year was 39% for those without feeding tubes and 50% for those with feeding
tubes. The multivariate results indicated that feeding tubes were associated with
a reduced risk of death (risk ratio, 0.71; 95% confidence interval, 0.59, 0.86).
CONCLUSIONS: This study provides evidence that tube feeding can be life
prolonging, even if the gain in life is not substantial. Such information can be
useful to nursing home staff, residents, and families when trying to decide
whether to place a feeding tube in a resident with swallowing disorders and
eating disabilities.
PMID- 10772190
TI - Incidence of gastroesophageal reflux and aspiration in mechanically ventilated
patients using small-bore nasogastric tubes.
AB - BACKGROUND: Use of a large-bore nasogastric tube (NGT) and patient position are
considered key factors in promoting gastroesophageal reflux (GER) and pulmonary
aspiration in critically ill patients. The objective of this study was to
determine the incidence of GER and pulmonary aspiration of gastric contents in
mechanically ventilated (MV) patients using small-bore NGTs. METHODS: We studied
30 patients on mechanical ventilation for acute respiratory failure who tolerated
enteral nutrition through a small-bore NGT. Patients were randomly assigned to a
group with (n = 16) or without (n = 14) a small-bore NGT and were maintained in a
semirecumbent position during the study. GER and aspiration of gastric contents
were assessed by a radioisotopic technique. Scans were done 24 hours after
technetium-99m administration (n = 30). In 9 patients a dynamic scintigraphy was
performed immediately after colloid administration, and samples of blood and
tracheal and oropharyngeal secretions were obtained basally, 30 minutes, and 24
hours after technetium administration and analyzed for radioactivity using a
gamma counter. RESULTS: Both groups were similar in age, underlying diagnosis,
number of days of mechanical ventilation at the day of study, and mortality.
There were no GER reaching the oropharynx and aspiration of gastric contents in
both groups. CONCLUSIONS: GER and aspiration of gastric contents were not
detected in MV patients using small-bore NGTs and may be a simple measure to
prevent ventilator-associated pneumonia.
PMID- 10772191
TI - With medium-chain triglycerides, higher and faster oxygen radical production by
stimulated polymorphonuclear leukocytes occurs.
AB - BACKGROUND: Parenteral lipid emulsions are suspected of suppressing the immune
function. However, study results are contradictory and mainly concern the
conventional long-chain triglyceride emulsions. METHODS: Polymorphonuclear
leukocytes were preincubated with parenteral lipid emulsions. The influence of
the lipid emulsions on the production of oxygen radicals by these stimulated
leukocytes was studied by measuring chemiluminescence. Three different parenteral
lipid emulsions were tested: long-chain triglycerides, a physical mixture of
medium- and long-chain triglycerides, and structured triglycerides. Structured
triglycerides consist of triglycerides where the medium- and long-chain fatty
acids are attached to the same glycerol molecule. RESULTS: Stimulated
polymorphonuclear leukocytes preincubated with the physical mixture of medium-
and long-chain triglycerides showed higher levels of oxygen radicals (p < .005)
and faster production of oxygen radicals (p < .005) compared with
polymorphonuclear leukocytes preincubated with long-chain triglycerides or
structured triglycerides. Additional studies indicated that differences in
results of various lipid emulsions were not caused by differences in emulsifier.
The overall production of oxygen radicals was significantly lower after
preincubation with the three lipid emulsions compared with controls without lipid
emulsion. CONCLUSIONS: A physical mixture of medium- and long-chain triglycerides
induced faster production of oxygen radicals, resulting in higher levels of
oxygen radicals, compared with long-chain triglycerides or structured
triglycerides. This can be detrimental in cases where oxygen radicals play either
a pathogenic role or a beneficial one, such as when rapid phagocytosis and
killing of bacteria is needed. The observed lower production of oxygen radicals
by polymorphonuclear leukocytes in the presence of parenteral lipid emulsions may
result in immunosuppression by these lipids.
PMID- 10772192
TI - Effects of parenteral lipid emulsions with different fatty acid composition on
immune cell functions in vitro.
AB - BACKGROUND: Numerous studies suggest that immune function may be compromised by
lipid emulsions rich in polyunsaturated fatty acids (PUFAs). In our study, we
compared the effect of a new olive oil-based lipid emulsion (ClinOleic)
containing a moderate level of PUFAs, with emulsions based on soybean oil
(Intralipid or Ivelip), on immune functions of human cell in vitro. METHODS:
Peripheral white blood cells were collected from healthy volunteers. Lymphocyte
proliferation was evaluated by [3H]-thymidine incorporation after stimulation
with either phytohemagglutinin (PHA) or antibodies against T-cell specific
antigens. Lymphocytes subsets and T-cell activation markers (CD25 and HLA-DR)
were measured by flow cytometry. The release of cytokines (interleukin [IL]-2, IL
1beta, and tumor necrosis factor-alpha [TNF-alpha]) was measured by enzyme-linked
immunosorbent assay (ELISA), after lymphocytes or monocytes/macrophages
stimulation with PHA or lipopolysaccharide (LPS). RESULTS: A significant dose
dependent inhibition of thymidine incorporation was observed with Intralipid and
Ivelip (incorporation down to 39.9% of control, p < .001) whereas ClinOleic
showed no inhibitory effect. Activation antigen expression on both CD4+ and CD8+
T-cells tended to decrease with Intralipid (CD25: -53.4% on CD4+ and -57.4% on
CD8+; HLA-DR: -61.5% on CD4+ and -58.5% on CD8+) but not with ClinOleic (from
2.9% for CD25 on CD4+ to 16.7% for HLA-DR on CD4+). Intralipid decreased
significantly IL-2 production (-39.0%, p < .05) whereas ClinOleic had little
effect (-13.0%, NS). Intralipid and ClinOleic tended to inhibit to a similar
extent the release of pro-inflammatory cytokines (TNF-alpha: -21.5% and -34.8%,
IL-1beta: -45.1% and -40.3%; respectively). CONCLUSIONS: Our results suggest that
an olive oil-based lipid emulsion could modulate immune response selectively,
maintaining protective immunity and reducing inflammatory response. Olive oil may
offer an immunologically neutral alternative to soybean oil for use in parenteral
lipid emulsions.
PMID- 10772193
TI - Success rates and cost-effectiveness of antibiotic combinations for initial
treatment of central-venous-line infections during total parenteral nutrition.
AB - BACKGROUND: Central-venous-line infections can be successfully treated with
appropriate antibiotics, thus avoiding the need for catheter removal. Based on
our experience, vancomycin, gentamicin, piperacillin, ceftazidime, and
amphotericin, alone or in combination, are usually administered, pending
sensitivity results. This empirical list, however, has never been verified
against actual sensitivity results nor has it been tested for cost or efficacy.
METHODS: Medical records of inpatients on hyperalimentation over 1 year were
reviewed. Success rate, therapy duration, and drug acquisition cost and charge
were assessed for central-venous-line infections. Antibiotics then were paired
and evaluated in terms of charge and efficacy against all microorganisms as
determined by sensitivity results. RESULTS: In 500 inpatients receiving
hyperalimentation for 9,698 patient-days, 8.4 central-venous-line
infections/1,000 patient-days occurred. Staphylococcus non-aureus, Candida
species, Enterococcus faecium, and Staphylococcus aureus predominantly were
isolated. Of the infections, 51 (67%) were sensitive to one or more of the
initial antibiotics. A 2-week course of antibiotics successfully treated 50 (66%)
catheter infections without line removal. Appropriate initial therapy on average
reduced treatment duration by 8 to 10 days and drug charges by $400 to $700.
CONCLUSIONS: Amikacin-vancomycin appears to be the most cost-effective selection
for presumed central-venous-line infections, pending sensitivity results,
followed by valid alternatives. Lower failure rates are well worth the extra cost
in pharmaceutical charges.
PMID- 10772194
TI - Managing the obese patient after bariatric surgery: a case report of severe
malnutrition and review of the literature.
AB - Surgery is now considered to be the most effective treatment for reducing weight
and maintaining weight loss in patients with clinically severe obesity. Although
the jejuno-ileal bypass has been abandoned, the vertical banded gastroplasty
(VBG) and Roux-en-Y gastric bypass (RYGB) operations are now commonly performed.
A third operation, the bilio-pancreatic diversion (BPD), is performed less
frequently. The RYGB and BPD procedures cause predictable selective micronutrient
deficiencies that can be avoided by early supplementation. Surgical complications
from all of these procedures may result in more severe forms of malnutrition.
This article is intended to familiarize the nutrition support specialist with the
anatomic and physiologic changes produced by these procedures, the resulting
nutritional deficiencies and recommended supplementation, and the manifestations
of severe malnutrition caused by complications. A case of severe malnutrition
after RYGB surgery is reported for illustration.
PMID- 10772195
TI - Indomethacin and corticosteroids: an additive constrictive effect on the fetal
ductus arteriosus.
AB - The objective of this paper is to study the possible additive effect of
corticosteroids to the known effect of indomethacin on potency of the human
ductus arteriosus. Systolic and diastolic blood flow of the fetal ductus
arteriosus was measured by echo Doppler at 26-32 weeks of gestation. Four groups
of patients were studied according to the treatment they have received: group A
(exposure to indomethacin and betamethasone); group B (indomethacin alone); group
C (betamethasone); and group D (controls). Children in whom ductal constriction
was noted in utero were followed by repeat cardiac echo Doppler examinations at
the age of 1 to 2 years. In group A (indomethacin and betamethasone) fetal ductal
constriction was significantly higher (p = 0.02) and occurred in 11 out of 15
fetuses (73.3%), compared with 5 out of 14 (37.2%) of the fetuses in group B
(indomethacin alone). In group C (betamethasone) and D fetuses (no treatment), no
significant ductal constriction was observed. Pathological tricuspid
regurgitation and right ventricular dilation were found more frequently in
fetuses from group A. No long-term sequella was noted in the infants in whom
ductal constriction had been noted in utero. Corticosteroids and indomethacin
have a synergistic effect on the frequency and severity of fetal ductus
arteriosus constriction. In short-term treatment this effect is transient, and
has no deleterious effects on fetal and neonatal cardiac function.
PMID- 10772197
TI - ABO hemolytic disease of the newborn: a unique constellation of findings in
siblings and review of protective mechanisms in the fetal-maternal system.
AB - Two siblings born 6 years apart presented with similar findings of
hepatosplenomegaly, dermal hematopoiesis, hemoglobinuria, and increased platelet
consumption, but only moderate anemia and normal serum bilirubin. ABO
incompatibility was identified, and other causes were excluded. A review of the
current understanding of mechanisms that promote and prevent antibody-mediated
hemolysis in the fetus is reviewed. Due to the low ratio of observed to expected
significant clinical events among ABO incompatible mother-infant pairs, and the
multiplicity of mechanisms that diminish hemolysis, we speculate that severe ABO
hemolytic disease of the newborn occurs when there is a specific failure in one
of these preventive mechanisms.
PMID- 10772196
TI - Hypertension-hyponatremia syndrome in neonates: case report and review of
literature.
AB - Hypertension hyponatremia syndrome occurred in a 32-week male neonate following
septicemic shock on Day 9. The systolic blood pressure rose from 60 to 85 mmHg as
the serum sodium dropped from 136 to 121 mmol/L associated with natriuresis,
polyuria, and dehydration. Convulsions occurred at a systolic blood pressure of
102 mmHg. Investigations for hypertension revealed hyper-reninemia without
cardio/renovascular or neuroendocrine abnormalities. Salt supplementation and
antihypertensive therapy with captopril led to resolution of natriuresis and
hyponatremia. Review of literature revealed associated renovascular pathology in
all neonatal cases of the syndrome reported so far. Renal ischemia from possible
renal microthrombi may have been the triggering event in our case. Decline in
renin levels during follow-up favors this hypothesis.
PMID- 10772198
TI - Characteristics of normal lochia.
AB - The objective of this paper is to determine the characteristics of each phase of
lochia and how these may be influenced by a number of obstetric variables. Thirty
nine healthy women who had spontaneous vaginal delivery following uncomplicated
pregnancy volunteered to complete a diary sheet immediately postpartum. The women
were instructed to assess the color of their lochia by a color slide with
differential gradation from dark red to white. The color was labeled as rubra
(red, red-brown), serosa (brown-pink, brown), or alba (yellow, white). The
overall duration of lochia was 36.0 +/- 7.5 days (range 17 to 51 days, median 37
days). Three types of lochia color patterns were identified: type 1--rubra-
>serosa-->alba sequence (n = 20); type 2-rubra-->serosa-->alba sequence with
prolonged rubra phase and short serosa and alba phases (n = 11); and type 3-with
two rubra phases (rubra-->serosa/alba-->rubra-->serosa/alba sequence with near
equal duration of each phase) (n = 8). The rubra phase lasts 12.1 +/- 6.7 days in
type 1, 24.8 +/- 5.0 days in type 2, and 5.5 +/- 2.5 days (the first rubra) in
type 3 pattern (p < 0.05). There was a higher proportion of lactating women among
women with type 1 pattern as compared with type 2 (11/20 and 2/11, p < 0.05,
respectively). Women with type 2 pattern were of higher parity (2.8 +/- 1.3) as
compared with those with type 1 (1.8 +/- 0.8) (p < 0.05). There were no
significant differences in infants' birth weight between the various color types
(3,276.0 +/- 379.8 g, 3,564.4 +/- 737.9 g, and 3,080.0 +/- 180.0 g for type 1,
type 2, and type 3, respectively. There were no significant differences in
overall duration of lochia or gestational age at delivery between the various
color types. The results confirm the clinical impression that lochia persists
longer than classically reported and is of diverse patterns. Three unique types
of color patterns were identified. Type 1 is the most prevalent and is associated
with prolonged breast feeding and thus can be considered as the classic type.
Type 2 is associated with short or no breast feeding and higher parity. Type 3
may be a variant of type 2. We suggest that traditional teaching on lochia
characteristics needs reappraisal.
PMID- 10772199
TI - Successful outcome after antibiotic treatment of postamniocentesis membrane
rupture and chorioamnionitis in multiple pregnancy.
AB - Postamniocentesis chorioamnionitis is usually managed with induction of labor to
prevent maternal sepsis and related morbidity and mortality. We report a case of
chorioamnionitis in a triplet pregnancy after midtrimester genetic amniocentesis,
in which multiple antibiotic treatment (ampicillin 2 g i.v. loading dose followed
by 1 g i.v. every 6 hr; clindamycin 900 mg i.v. every 8 hr; gentamicin 120 mg
i.v. loading dose followed by 100 mg i.v. every 8 hrs; and erythromycin 500 mg
i.v. every 6 hr) for 7 days and delivery of the presumably infected triplet A
successfully reversed the clinical symptomatology, allowing prolongation of
pregnancy until 26 weeks and survival of the remaining fetuses. At age 2 years,
both infants are doing well and are meeting their developmental milestones. The
viable outcome of this management strategy suggests that antibiotic treatment and
expectancy may be an option in selected cases of postamniocentesis
chorioamnionitis in multiple pregnancies.
PMID- 10772200
TI - Prenatal MRI evaluation of congenital diaphragmatic hernia.
AB - The objective of this paper is to evaluate the efficacy of various magnetic
resonance imaging (MRI) sequences and the general usefulness of prenatal MRI in
determining the position of the fetal liver and visualizing lung tissue in
fetuses who have congenital diaphragmatic hernia (CDH). This was a retrospective
review of prenatal MRI of fetuses with a confirmed diagnosis by surgery or
autopsy of CDH. MRI was performed in a 1.5-Tesla magnet using fast gradient echo,
half-Fourier single-shot turbo spin-echo (HASTE) and echo planar images. The
presence of a chest mass, position of the stomach and liver and visualization of
the lungs by MRI was noted in all fetuses. This was compared to ultrasound
studies performed the same day and correlated with postnatal or autopsy studies.
The fetuses were 18-36 weeks gestational age (mean 24.5 weeks). MRI diagnosed
left CDH (33), right CDH (4), and bilateral CDH (1) and agreed with the postnatal
diagnosis in all patients. Ultrasound (US) diagnosed left CDH (33), right CDH
(2), and congenital cystic adenomatoid malformation (3). MRI changed the
diagnosis in four patients. The fetal liver was easily demonstrated with MRI in
all fetuses and was herniated into the chest in 25 of the 38. US diagnosed liver
up in 21. Correlation with postnatal studies found MRI correctly diagnosed liver
position in 37 out of 38 cases. US correctly diagnosed liver position in 32 out
of 38. Both lungs could be visualized in all fetuses with MRI. MRI accurately and
easily diagnoses CDH and can differentiate it from other chest masses. MRI was
superior to US in demonstrating the position of the fetal liver above or below
the diaphragm. MRI reliably visualized fetal lung tissue. These findings are
important for counseling parents, selecting fetal surgical candidates, and
estimating prognosis.
PMID- 10772201
TI - Management of spontaneous congenital chylothorax: oral medium-chain triglycerides
versus total parenteral nutrition.
AB - The aim of this article is to compare total parenteral nutrition (TPN) with oral
medium-chain triglycerides-diets (MCT) in the management of spontaneous
congenital chylothorax. We analyzed retrospectively the charts of 6 patients seen
in our tertiary care center and of 11 comparable patients from the literature.
All neonates were symptomatic at birth; 15 had bilateral chylothorax. In the
neonates who received mainly TPN (n = 9), the chylothorax resolved significantly
(p < 0.05) earlier (mean 10 days, SE 1) than in the others, who received mainly
MCT (n = 8) (mean 23 days, SE 4). The mean chyle loss was not significantly
different between the 2 groups. Our results suggest that TPN is more effective
than oral MCT in the treatment of spontaneous congenital chylothorax. These
results support the data of Peitersen et al, who reported that most of the
positive results with MCT were achieved in postoperative chylothorax of the
newborn.
PMID- 10772202
TI - Changes in erythrocytic deformability and plasma viscosity in neonatal ictericia.
AB - We studied 45 full-term newborns divided into 3 groups. Group 1: 17 newborns with
bilirubin <10 mg/dL; Group 2: 18 newborns with hemolytic ictericia (bilirubin 11
20 mg/dL) and Group 3: 10 newborns with moderate hemolytic ictericia needing
exchange transfusion. The following were studied: erythrocytic deformability,
plasma viscosity, plasmatic osmolarity, seric bilirubin, bilirubin/albumin ratio,
free fatty acids and corpuscular volume of the erythrocytes. In full-term
newborns, the following are risk factors for increased erythrocytic rigidity:
neonatal hemolytic illness (p = 0.004, odds ratio: 7.02), increases in total
bilirubin (p = 0.02, odds ratio: 4.3) and increases in the bilirubin/albumin
ratio (p = 0.025, odds ratio: 4.25). Furthermore, the most important risk factor
for high plasma viscosity is also neonatal hemolytic illness (p = 0.01, odds
ratio: 2.30). The role of total bilirubin is also important (p = 0.09, odds
ratio: 2.10), while that of the bilirubin/albumin ratio (p = 0.012, NS) is less
so. The greater the hemolysis, the greater the erythrocytic rigidity and plasma
viscosity (p < 0.01). In full-term newborns with moderate ictericia, hemolytic
illness and increases in the bilirubin/albumin ratio are accompanied by
rheological alterations that could affect cerebral microcirculation and cause a
neurological deficit not exclusively related to the levels of bilirubin in
plasma.
PMID- 10772203
TI - Value of inferior vena cava Doppler waveform analysis for prediction of neonatal
outcome.
AB - The objective of this article is to determine the value of the inferior vena cava
preload index (IVC) to predict neonatal outcome and compare it to other
biophysical methods of antenatal surveillance. A clinical outcome study of
patients referred to the author's institution for Doppler velocity blood flow
studies was undertaken by comparing the ability of three antenatal surveillance
tests: the nonstress test (NST); umbilical artery S/D ratio (UA); and the ratio
of the middle cerebral artery to umbilical artery S/D ratios (MCUA) to predict
poor neonatal outcome to the ability of the IVC to predict poor outcome. Patients
were followed serially and neonatal outcome data was tabulated. Those patients
that delivered within 10 days of their last study were included in the analysis.
Seventy patients met the inclusion criterion. Neonatal outcome based on the
results of the IVC as compared with outcome based on the results of the NST, UA,
and MCUA tests. Odds ratios (with 95% confidence limits) for significant neonatal
morbidity predicted by each test were: NST: 2.6 (0.14-14.6); UA: 5.7 (1.7-18.8);
MCUA: 3.6 (1.1-13.1); and IVC: 4.1 (1.3-13.2). Logistic regression analysis
indicated that the combination of MCUA and IVC was the best method of predicting
poor neonatal outcome. This study of the utility of fetal IVC suggests that this
noninvasive method of antenatal surveillance may provide an additional sensitive
method of evaluating the status of the high-risk fetus.
PMID- 10772204
TI - Management of a case of chloroquine-resistant falciparum malaria in a pregnant
woman with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
AB - The available antimalarial drugs for the treatment of Plasmodium falciparum
malaria during pregnancy are potentially toxic, especially in the presence of red
blood cells (RBC) defects. We describe a case of chloroquine-resistant malaria by
P. falciparum in a pregnant woman with glucose-6-phosphate dehydrogenase (G6PD)
deficiency successfully treated with pyrimethamine followed by mefloquine
administration. The susceptibility of P. falciparum to chloroquine and mefloquine
was assessed by an in vitro test before treatment. Pyrimethamine and mefloquine
were administered at the 18th and 22nd week of pregnancy, respectively.
Mefloquine concentrations were monitored in the mother's blood at 2, 4, 8, 12, 24
and 48 hr after the administration to define effective blood-drug concentrations.
Blood smear examination was negative after 48 hr post mefloquine treatment. No
histologic lesions of the placenta were observed. The newborn presented normal
clinical parameters. The administration of pyrimethamine prevented massive
placental infection, thus permitting the fetus to achieve suitable gestational
age for further treatment with mefloquine to eradicate P. falciparum malaria
without deleterious effects to the newborn. Subsequent studies could contribute
to define safe administration of mefloquine in G6PD-deficient pregnant woman.
PMID- 10772205
TI - A microscopic method to visualize Escherichia coli interaction with beef muscle.
AB - The genetic determinant for enhanced green fluorescent protein (EGFP) was
introduced into Escherichia coli JM109 (ATCC 53323) and E. coli O157:H7 (ATCC
43895) on plasmid EGFP. The expression of EGFP did not change the growth kinetics
or surface properties tested (hydrophobicity and electrophoretic mobility).
Microscope slides were modified to allow for optimal viewing of thick meat
samples with an inverted microscope. Two fluorescent dyes, nile red and Cy3 were
used to stain for lipid and protein portions of beef muscle, respectively. Laser
scanning confocal microscopy was used to observe interaction of the EGFP
expressing E. coli strains and the fluorescently stained muscle components
without changing the spatial and temporal environment of the organisms.
PMID- 10772206
TI - Penetration of Escherichia coli O157:H7 into lettuce tissues as affected by
inoculum size and temperature and the effect of chlorine treatment on cell
viability.
AB - Penetration of Escherichia coli O157:H7 into iceberg lettuce tissues and the
effect of chlorine treatment on cell viability were evaluated. Attachment of
different inoculum levels (10(9), 10(8), and 10(7) CFU/ml) was examined by
determining the number of cells at the surface and the cut edge of lettuce leaves
(2 by 2 cm). E. coli O157:H7 attached preferentially to cut edges at all inoculum
levels, with greater attachment per cm2 of lettuce at higher inoculum levels. A
longer attachment time allowed more cells to attach at both sites. Immunostaining
with a fluorescein isothiocyanate-labeled antibody revealed that cells penetrated
into lettuce leaves from cut edges. Cells showed greater penetration when lettuce
was held at 4 degrees C compared with 7, 25, or 37 degrees C and were detected at
an average of 73.5 +/- 16.0 microm below the surfaces of cut tissues. Penetrating
cells were mostly found at the junction of lettuce cells. The viability of
attached cells after treatment with 200 mg/liter (200 ppm) of free chlorine for 5
min was examined by plating on tryptic soy agar and by a nalidixic acid
elongation method. Although chlorine treatment caused significant reduction in
attachment (0.7- and 1.0-log reduction at surfaces and cut edges, respectively),
cells remained attached at high numbers (7.9 and 8.1 log CFU/cm2 at surfaces and
cut edges, respectively). Elongated cells were observed in stomata and within the
tissues of the lettuce, indicating they were protected from contact with
chlorine.
PMID- 10772207
TI - Survival of Escherichia coli O157:H7 in buttermilk as affected by contamination
point and storage temperature.
AB - The effects of contamination point (during fermentation versus postfermentation)
and storage temperature (5 and 12 degrees C) were determined for survival of
Escherichia coli O157:H7 in fermented buttermilk. E. coli O157:H7 was recovered
from buttermilk inoculated during fermentation for 22 days and in buttermilk
inoculated postfermentation for 32 days. For storage temperatures of 5 and 12
degrees C, D-values were lower for E. coli O157:H7 inoculated during fermentation
(2.5, 2.2 days) than postfermentation (5.6, 4.8 days) (P < 0.05). Developed
acidity in inoculated buttermilks was not different from controls (P > 0.05). The
extended recovery of viable enterohemorrhagic E. coli O157:H7 from both
processing scenarios indicates that the presence of E. coli O157:H7 in buttermilk
is not limited to postprocessing contamination.
PMID- 10772208
TI - Survival of Vibrio cholerae O1 in ceviche and its reduction by heat pretreatment
of raw ingredients.
AB - The survival of Vibrio cholerae O1 serotypes Inaba and Ogawa was determined in
ceviche prepared from inoculated ground fish. Ground mackerel purchased from a
seafood distribution center was inoculated with V. cholerae and stored at 8 or 20
degrees C. Counts of V. cholerae decreased in 2.6 to 2.7 log10 CFU/g during 96 h
of storage at 8 degrees C or 2.5 to 2.6 log10 CFU/g during 24 h at 20 degrees C.
Survival studies indicated that serotype Inaba decreased its number following a
linear or retarded trend, whereas serotype Ogawa followed an accelerated death
trend. No effect of the initial level of inoculum was observed. Odor scores of
ceviche indicated that this food became marginally acceptable within as little as
48 h of storage at 8 degrees C or 3 h at 20 degrees C and were related to total
volatile nitrogen values but not to aerobic plate counts, pH, or coliform counts.
A heat pretreatment that consisted of stirring 100 g of inoculated ground fish
into 40 ml of boiling water produced an 8-log reduction of V. cholerae within 3
min without affecting the color, odor, or flavor of ceviche prepared with such
pretreated fish. According to this study, V. cholerae present in contaminated
ceviche will likely survive longer than the shelf life of this food. Preheating
the ground raw fish used for preparing ceviche for 3 min should effectively
eliminate V. cholerae O1, providing science-based conditions for implementing a
critical control point if a hazard analysis critical control point plan were to
be developed for preparation of ceviche.
PMID- 10772209
TI - Inactivation of Salmonella Enteritidis, Salmonella Typhimurium, and Salmonella
Senftenberg by ultrasonic waves under pressure.
AB - The resistance of Salmonella Enteritidis (ATCC 13076), Salmonella Typhimurium
(ATCC 13311), and Salmonella Senftenberg 775W (ATCC 43845) to ultrasonic waves
under pressure treatments, at sublethal (manosonication) and lethal temperatures
(manothermosonication) in citrate-phosphate buffer and in liquid whole egg was
investigated. The influence of treatment parameters on the inactivation rate of
manosonication was also studied. Decimal reduction times (Dt) of Salmonella
Enteritidis, Salmonella Typhimurium, and Salmonella Senftenberg 775W
corresponding to a heat treatment at 60 degrees C in pH 7 buffer and in liquid
whole egg were 0.068, 0.12, and 1.0 min for buffer, and 0.12, 0.20, and 5.5 min
for liquid whole egg. Those corresponding to a manosonication treatment (117
microns, 200 kPa, 40 degrees C) in both media were 0.73, 0.78, and 0.84 min, and
0.76, 0.84, and 1.4 min, respectively. When the amplitude of ultrasonic waves was
increased linearly, the inactivation rate of manosonication increased
exponentially. The inactivation rate also increased when pressure was raised.
However, the magnitude of this increase was progressively smaller at higher
pressures. The magnitude of the influence of the amplitude of ultrasonic waves
and static pressure on the inactivation rate of manosonication was the same in
the three serotypes investigated. Whereas a heat treatment at 60 degrees C only
attained a 1/2-log cycle reduction in the number of Salmonella Senftenberg 775W
survivors, a manothermosonication treatment (117 microns and 200 kPa) at this
temperature attained a 3-log cycle reduction.
PMID- 10772210
TI - Rapid hot dog surface pasteurization using cycles of vacuum and steam to kill
Listeria innocua.
AB - The vacuum/steam/vacuum surface pasteurization process was applied to hot dogs
inoculated on the surface with non-pathogenic Listeria innocua. Using the optimum
conditions previously found for processing chicken carcasses as a starting point,
optimum process conditions were determined for a hot dog treatment compatible
with current process line speed. Cycling the treatment significantly improved the
microbiological kill. At the optimum conditions of steam time of 0.3 s at 138
degrees C (two cycles), a bacteria kill >3 log CFU/ml was attained.
Pasteurization, frequently considered to be a kill of >5 log CFU/ml, was reached
by increasing the number of cycles to three. The surface pasteurization process
should ensure that hot dogs reaching the consumer are free of Listeria.
PMID- 10772211
TI - Development of a simple recovery-enrichment system for enhanced detection of heat
injured Listeria monocytogenes in pasteurized milk.
AB - A simple anaerobic recovery-enrichment system, semisolid Penn State University
(ssPSU) broth, that enhances recovery of heat-injured Listeria monocytogenes, was
rapidly achieved in 10-ml screw-capped tubes by adding Bacto-agar (2.5 g/liter)
and L-cysteine (0.5 g/liter) to Penn State University broth. Glucose was removed
from the formulation for ssPSU broth to prevent the growth of thermoduric
lactobacilli. Ferric ammonium citrate was added to ssPSU broth to detect esculin
hydrolysis and to indicate the presumptive presence of L. monocytogenes.
Replacement of phosphate buffer with 3-[N-morpholino]propanesulfonic acid (MOPS)
buffer and addition of magnesium sulfate (15 mM) enhanced recovery and detection
of L. monocytogenes heat treated at 62.8 degrees C for 20 min. D-Serine, at a
concentration of 150 mM, was found to inhibit germination of Bacillus spp. spores
but did not inhibit severely heat-injured L. monocytogenes. Finally, ssPSU broth
was modified (to mPSU broth) to contain the following: (i) Bacto-agar, 2.5
g/liter; (ii) ferric ammonium citrate, 0.5 g/liter; (iii) MOPS buffer, pH 7.0;
(iv) D-serine, 13.7 g/liter; (v) D-alanine, 11.6 g/liter; and (iv) magnesium
sulfate, 1.81 g/liter. Incubation temperature significantly affected the recovery
and detection of severely heat-injured L. monocytogenes. L. monocytogenes that
were heat challenged in filter-sterilized whole milk at 62.8 degrees C for 20,
25, and 30 min could not be detected at incubation temperatures > or = 30 degrees
C but were consistently detected after incubation at 25 degrees C for 174, 199,
and 330 h, respectively. Heat-injured cells of L. monocytogenes that were added
to various commercial brands of pasteurized whole milk were also detected using
mPSU broth. When clostridial spores (10(4) spores per ml) were added to filter
sterilized milk containing either heat-injured or non-heat-injured L.
monocytogenes, only the latter could be detected in mPSU broth. The mPSU broth
system requires no purging with nitrogen gas to create anaerobic conditions and
permits recovery, growth, and detection of L. monocytogenes in one vessel in the
presence of thermoduric background microflora commonly found in pasteurized milk.
PMID- 10772212
TI - Effect of low water activity on staphylococcal enterotoxin A and B biosynthesis.
AB - Staphylococcus aureus strains FDA 743 (staphylococcal enterotoxin A [SEA]
producing), FDA 778 (staphylococcal enterotoxin B [SEB]-producing), and S6 (SEA-
and SEB-producing) were used to examine the effect of low water activity (a(w))
on SEA and SEB biosynthesis. In this report, we show that SEB production is more
sensitive to low a(w) than SEA production. We also show that when proline is
available as a compatible solute for S. aureus, SEB production is significantly
stimulated at low a(w). This stimulatory effect was not observed when other
compatible solutes (i.e., glycine betaine or carnitine) were added to low a(w)
growth media. Finally, Northern blot analysis revealed that the stimulation of
SEB production at low a(w) by added proline occurs at the level of transcription.
PMID- 10772213
TI - The detection of enterotoxins and toxic shock syndrome toxin genes in
Staphylococcus aureus by polymerase chain reaction.
AB - A simple polymerase chain reaction (PCR)-based procedure was developed for the
detection of fragments of staphylococcal enterotoxins (SEs) SEA, SEB, SEC, SED,
SEE, SEG, SEH, and SEI together with the toxic shock syndrome toxin (TSST-1)
genes of Staphylococcus aureus. One hundred and twenty-nine cultures of S. aureus
were selected, 39 of which were recovered from 38 suspected staphylococcal food
poisoning incidents. The method was reproducible, and 32 different toxin
genotypes were recognized. The presence of SE genes was associated with S. aureus
strains reacting with phages in group III, and the TSST-1 gene with phages in
group I. There was a 96% agreement between the PCR results for detection of SEA-D
and TSST-1 as compared with a commercial reverse passive latex agglutination
assay for the detection of SEs from cultures grown in vitro. Enterotoxin gene
fragments were detected in S. aureus cultures recovered from 32 of the 38
suspected staphylococcal food poisoning incidents, and of these, 17 were
associated with SEE, SEG, SEH, and SEI in the absence of SEA-D. Simple PCR
procedures were also developed for the detection of SE directly in spiked food
samples, and this was most successfully achieved in mushroom soup and ham.
Detection was less successful in three types of cheese and in cream. SEA or SEB
were detected by enzyme-linked immunosorbent assay in three food samples (two of
which were associated with food poisoning incidents) naturally heavily
contaminated with S. aureus: the appropriate SEA or SEB gene fragments were
detected directly in these three foods by PCR.
PMID- 10772214
TI - Rapid and specific enzyme immunoassay on hydrophobic grid membrane filter for
detection and enumeration of thermophilic Campylobacter spp. from milk and
chicken rinses.
AB - Six commercially available anti-Campylobacter antibodies were examined for their
applicability in an enzyme immunoassay on hydrophobic grid membrane filters, both
for the detection and enumeration of Campylobacter spp. When a panel of nine
Campylobacter (seven Campylobacter jejuni and two Campylobacter coli) and eight
non-Campylobacter strains were used in a dot-blot format enzyme immunoassay to
test the specificity of these antibodies, only one polyclonal antibody
(Biodesign) detected all Campylobacter strains. Escherichia coli O157:H7 produced
weak nonspecific signals due to endogenous peroxidase activity. The specificity
of this Biodesign antibody was further tested against 30 more Campylobacter
strains and more than 600 non-Campylobacter strains on hydrophobic grid membrane
filters grown on modified Campylobacter agar with charcoal and deoxycholate, a
Campylobacter selective medium. All the Campylobacter strains were detected,
whereas only two (Acinetobacter calcoaceticus, Salmonella Minnesota) of the
approximately 130 non-Campylobacter strains, which grew on modified Campylobacter
agar with charcoal and deoxycholate, gave false-positive signals. This simple,
rapid, and specific enzyme immunoassay also detected Campylobacter spp. from
inoculated milk and chicken rinses and naturally contaminated chicken rinses.
PMID- 10772215
TI - A method of assessing the efficacy of hand sanitizers: use of real soil
encountered in the food service industry.
AB - In many outbreaks of foodborne illness, the food worker has been implicated as
the source of the infection. To decrease the likelihood of cross-contamination,
food workers must clean and disinfect their hands frequently. To ensure their
effectiveness, hand disinfectants should be tested using rigorous conditions that
mimic normal use. Currently, several different methods are used to assess the
efficacy of hand disinfectants. However, most of these methods were designed with
the health care worker in mind and do not model the specific contamination
situations encountered by the food worker. To fill this void, we developed a
model that uses soil from fresh meat and a means of quantifying bacteria that is
encountered and transferred during food preparation activities. Results of
studies using various doses of para-chloro-meta-xylenol and triclosan confirm
that the method is reproducible and predictable in measuring the efficacy of
sanitizers. Consistent, dose-dependent results were obtained with relatively few
subjects. Other studies showed that washing hands with a mild soap and water for
20 s was more effective than applying a 70% alcohol hand sanitizer.
PMID- 10772216
TI - Effect of salt and smoke on the microbiological quality of cold-smoked salmon
during storage at 5 degrees C as estimated by the factorial design method.
AB - The simultaneous effect of salt and smoke on the natural flora of cold-smoked
salmon was studied during 5 weeks of vacuum storage at 5 degrees C. The quadratic
polynomial, as a function of factors, was used to express total viable count
(TVC), total lactic acid bacteria, lactobacilli numerated on Rogosa agar, H2S
producing bacteria, and yeasts at different sampling times. TVC and total lactic
acid bacteria were mainly inhibited by the salt concentration (5% wt/wt) in the
meat and to a lesser extent by the phenol content. Inhibition was linearly
proportional to salt and smoke content (the higher the concentration, the greater
the inhibition). No synergistic effect on inhibition was observed between the two
factors. In our working conditions, the TVC French standard (<10(6) CFU g(-1))
was maintained during 4 weeks of storage at 5 degrees C, with a minimum
concentration of 2.4% (wt/wt) of salt in meat and smoking treatment corresponding
to 0.6 mg 100 g(-1) of phenol. When the salt level was higher than 3%, the TVC
standard was maintained, regardless of phenol level. A negative interaction
between the two factors was found for H2S-producing bacteria and a positive one
for yeasts.
PMID- 10772217
TI - Thermal and chemical inactivation of indigenous Streptococcus thermophilus
bacteriophages isolated from Argentinian dairy plants.
AB - Thermal and chemical resistance of five autochthonal bacteriophages of
Streptococcus thermophilus, isolated from Cuartirolo cheese wheys and yogurt, was
investigated. Times to obtain 99% inactivation of phages (T99) at 63 degrees C
and 72 degrees C in three suspension media (enriched tryptic soy broth,
reconstituted commercial nonfat skim milk, and tris magnesium gelatin buffer)
were determined. The thermal resistance was dependent on the phages studied but
not detectable counts (<10 PFU/ml) were only achieved by heating at 90 degrees C
during 5 min. The data obtained for the three assayed media did not permit
verifying significant differences among them. Sodium hypochlorite (100 ppm)
provided a fast inactivation of bacteriophage particles (<10 PFU/ml after 5 min).
Ethanol, at concentrations of 75% and 100%, was also effective for phage
destruction. Isopropanol was slightly less effective than ethanol at the same
concentrations. Peracetic acid (0.15%) was also a very effective agent for phage
inactivation. The results showed that these autochthonal bacteriophages were not
completely inactivated neither by normal pasteurization treatments nor by some
biocides commonly used in disinfection, except sodium hypochlorite and peracetic
acid. The practical implications of these findings have pointed out the necessity
of recognizing the importance of establishing adequate conditions to assure
effective thermal and chemical treatments in dairy plants and laboratory
environments.
PMID- 10772218
TI - Characterization of chocolate milk spoilage patterns.
AB - Standard plate counts (SPC) and psychrotrophic plate counts (PPC) from chocolate
milk samples were compared with those of unflavored milk samples plated within 24
h of processing and at 7, 10, and 14 days of storage at 6 degrees C using matched
samples collected over four time periods from four milk-processing plants.
Bacterial numbers within 24 h of processing were not significantly different in
unflavored and in chocolate milk samples (P > 0.001), with SPC less than 1,000
CFU/ml and PPC below 10 CFU/ml for both types of products. SPC and PPC were
higher in chocolate milk samples than in unflavored milk samples collected from
all four plants after 14 days of storage (P < 0.001). To examine the effects of
chocolate milk components on bacterial numbers, SPC for days 0, 7, 14, and 21
were monitored in samples of experimentally prepared unflavored milk, milk with
chocolate powder and sucrose (chocolate milk), milk with sucrose only, and milk
containing chocolate powder only. At days 14 and 21, SPC were higher in both
chocolate milk and in milk with chocolate powder only, than in either the
unflavored milk or milk with sucrose only (P < 0.001). These findings suggest
that the addition of chocolate powder to milk can contribute to a greater
relative increase in bacterial numbers in pasteurized chocolate milk than in
identically processed unflavored milk at 14 days postprocessing.
PMID- 10772219
TI - Heat inactivation of hepatitis A virus in dairy foods.
AB - Experiments were performed to determine the thermal resistance of hepatitis A
virus (HAV) in three types of dairy products containing increased amounts of fat
content (skim milk, homogenized milk; 3.5% MFG, and table cream; 18% MFG). HAV
inoculated dairy products were introduced into custom-made U-shaped
microcapillary tubes that in turn were simultaneously immersed in a waterbath,
using custom-made floating boats and a carrying platform. Following exposure to
the desired time and temperature combinations, the contents of each of the tubes
was retrieved and was tested by plaque assay to determine the reduction in virus
titer. Our data indicated that < 0.5 min at 85 degrees C was sufficient to cause
a 5-log reduction in HAV titer in all three dairy products, whereas at 80 degrees
C, < or = 0.68 min (for skim and homogenized milk), and 1.24 min (for cream) were
needed to cause a similar log reduction. Using a nonlinear two-phase negative
exponential model (two-compartment model) to analyze the data, it was found that
at temperatures of 65, 67, 69, 71, and 75 degrees C, significantly (P < 0.05)
higher exposure times were needed to achieve a 1-log reduction in virus titer in
cream, as compared to skim and homogenized milk. For example, at 71 degrees C, a
significantly (P < 0.05) higher exposure time of 0.52 min (for cream) was needed
as compared to < or = 0.18 min (for skim and homogenized milk) to achieve a 1-log
reduction in virus titer. A similar trend of inactivation was observed at 73 and
75 degrees C where significantly (P < 0.05) higher exposure times of 0.29 to 0.36
min for cream were needed to cause a 1-log reduction in HAV in cream, as compared
to < or = 0.17 min for skim and homogenized milk. This study has provided
information on the heat resistance of HAV in skim milk, homogenized milk, and
table cream and demonstrated that an increase in fat content appears to play a
protective role and contributes to the heat stability of HAV.
PMID- 10772220
TI - Comparison of methods for enumeration of yeasts and molds in shredded low
moisture, part-skim mozzarella cheese.
AB - Two studies were conducted to compare established and new methods for enumerating
yeasts and molds in shredded low-moisture, part-skim mozzarella cheese stored
under refrigeration and temperature-abuse conditions. Yeast and mold counts
covered a range of 6 log10 units. In study 1, the potato dextrose agar plus
chlortetracycline (PDA) pour plate, dichloran rose bengal chloramphenicol (DRBC)
spread plate, Petrifilm, and Iso-Grid hydrophobic grid-membrane filtration
methods were used to analyze samples after < or = 1 day of unopened storage at 7
degrees C and after opening, resealing, and 2 days of storage at 25 degrees C.
The results of all methods were highly correlated (r2 > or = 0.96). In study 2,
the PDA, DRBC, and Iso-Grid methods were compared with the Simplate 2-day method
in an analysis of 42 samples stored for various times at 8, 11, 15, and/or 22
degrees C. The results of all methods except the Simplate method were again
highly correlated (r2 > or = 0.94), although yeasts and molds were not always
detected by all methods. Compared with the PDA, DRBC, and Iso-Grid methods, the
Simplate method most often (10 of 42 samples, 23.8%) failed to detect yeasts and
molds when at least one other method did, and the results were less highly
correlated with those of other methods (r2 = 0.88 to 0.90). Our results suggest
that the PDA, DRBC, Petrifilm, and Iso-Grid methods are equivalent for
enumerating yeasts and molds in shredded low-moisture, part-skim mozzarella
cheese samples.
PMID- 10772221
TI - Rapid detection of enterotoxigenic Escherichia coli O6 in water by using
monoclonal antibody and a photon-counting television camera.
AB - Monoclonal antibodies (MAbs) raised against Escherichia coli O6:H16 were screened
against 15 strains of E. coli and 19 non-E. coli bacteria. A MAb-luminescence
assay using MAb-5.8, which shows no cross-reactions with non-E. coli bacteria,
and a photon-counting television camera were developed for rapid enumeration of
E. coli O6:H16 in water. The membrane filter that retained bacteria was boiled
for 5 min in a buffer and incubated with biotinylated MAb-5.8. After incubation
with streptavidin-peroxidase conjugate, it was reacted with luminol-based
reaction mixture. Luminous image and light intensity of the filter was recorded
with a Biocell Counter. Levels of E. coli O6 higher than 7 x 10(3) CFU were
detected by the MAb-luminescence assay when E. coli O6 was spotted onto the
membrane filter. The sample that contained E. coli O6:H16 was filtered through a
membrane filter, and the filter that retained bacteria was incubated on a filter
paper soaked with nutrient broth supplemented with 0.5% NaCl at 37 degrees C for
6 h. The number of light emission points on the filter correlated well with
initial E. coli O6:H16 counts within the range of 1 to 3 x 10(2) CFU. The
correlation coefficient was 0.89.
PMID- 10772222
TI - Efficacy of chromocult coliform agar for coliform and Escherichia coil detection
in foods.
AB - Chromocult coliform agar (CCA) was compared with Petrifilm Escherichia coli count
plate (PEC) for identifying coliforms and E. coli in a variety of meat products.
Products examined included 45 raw beef samples, 12 sausage emulsion samples, 11
samples of meat-based ready-to-eat appetizers, and 8 pork trimming samples.
Coliforms from CCA and PEC were confirmed by gassing in brilliant green lactose
broth plus a positive reaction on purple broth agar plus lactose after incubation
at 35 degrees C for 48 h. Lauryl sulfate tryptose plus methylumbelliferyl-beta
glucuronide and tryptophan broth were used to confirm E. coli from CCA and PEC
with 48-h incubations at 35 and 42.5 degrees C, respectively. API 20E test strips
were inoculated for final confirmation. The overall respective confirmation
percentages (CFU/g) for the PEC and the CCA methods were 93.1 and 93.7% for
coliforms and 99.8 and 98.1% for E. coli, although the CCA method yielded
significantly (P < 0.001) higher mean CFU/g values for both coliforms and E.
coli. Regression analyses of these data indicated a strong positive linear
relationship existed between the two methods over a wide CFU/g range for both
coliforms and E. coli. The respective correlation coefficients obtained for
coliforms and E. coli of 0.89 and 0.86 indicate that the CCA method provides a
reliable optional method for these determinations in meat products.
PMID- 10772223
TI - Isolation of Yersinia from raw meat (pork and chicken) and precooked meat
(porcine tongues and sausages) collected from commercial establishments in Mexico
City.
AB - A total of 160 meat product samples were collected from commercial outlets in
Mexico City to investigate the presence of different species of Yersinia by the 4
degrees C enrichment method after 1, 3, 5, and 7 days of incubation using
alkaline treatment and isolating in cefsulodin-Irgasan-novobiocin and MacConkey
agars with Tween 80. Overall, Yersinia spp. were isolated from 27% of the samples
analyzed, whereas 40% of the raw and only 13% of the precooked samples were
contaminated. Although 2,970 colonies showed Yersinia characteristics, only 706
(24%) actually corresponded to this genus: 49% were Yersinia enterocolitica, 25%
Yersinia kristensenii, 15% Yersinia intermedia, 9% Yersinia frederiksenii, and 2%
Yersinia aldovae; 10% corresponded to biotype 2, 2% to biotype 3, and 4% to
biotype 4. The presence of Yersinia in raw and cooked meat products represents a
health risk for consumers in Mexico, where further clinical studies are needed to
assess the epidemiological importance of this pathogen.
PMID- 10772224
TI - Combined effect of antibiotic and competitive exclusion treatment on Salmonella
enteritidis fecal shedding in molted laying hens.
AB - Salmonella Enteritidis is an important pathogen for the layer industry, primarily
because of its ability to infect hens and ultimately contaminate egg contents.
Studies have shown that stress situations, such as flock recycling (induced
molting), can increase Salmonella Enteritidis problems in the flock. The present
study examined the effect of antibiotic treatment and competitive exclusion (CE)
on Salmonella Enteritidis shedding in the period following molt and 14-day feed
withdrawal. In two separate trials, 48 birds after molt and feed withdrawal were
divided into one group that was treated for 10 days with enrofloxacin in water
followed by administration of CE culture and a group that was left untreated.
Salmonella Enteritidis shedding was significantly reduced in the antibiotic-CE
group. The Salmonella Enteritidis shedding rate was 33 and 25% in untreated birds
versus 4 and 0% in the enrofloxacin-CE group on the two test days. These results
indicate that treatment of Salmonella Enteritidis-positive laying hens after
molting with enrofloxacin and CE culture can substantially reduce Salmonella
Enteritidis problems due to molting and would be a possible alternative to
diverting eggs for pasteurization or slaughtering the infected flock. Possible
development of bacterial resistance in conjunction with antibiotic use is also
discussed.
PMID- 10772225
TI - Ability of Lactobacillus and Propionibacterium strains to remove aflatoxin B,
from the chicken duodenum.
AB - The ability of Lactobacillus rhamnosus strains GG and LC-705 to remove AFB1 from
the intestinal luminal liquid medium has been tested in vivo using a chicken
intestinal loop technique. In this study, the GG strain of L. rhamnosus decreased
AFB1 concentration by 54% in the soluble fraction of the luminal fluid within 1
min. This strain was more efficient in binding AFB1 compared with L. rhamnosus
strain LC-705 (P < 0.05) that removed 44% of AFBl under similar conditions.
Accumulation of AFB1 into the intestinal tissue was also determined. There was a
74% reduction in the uptake of AFB1 by the intestinal tissue, in the presence of
L. rhamnosus strain GG compared with 63% and 37% in the case of Propionibacterium
freudenreichii ssp. shermanii JS and L. rhamnosus strain LC-705, respectively.
The complexes formed in vitro between either L. rhamnosus strain GG or L.
rhamnosus strain LC-705 and AFB1 were stable under the luminal conditions for a
period of 1 h.
PMID- 10772226
TI - President's report.
PMID- 10772227
TI - Comparison between MEM and Nott dynamic retinoscopy.
PMID- 10772228
TI - Localized orbital inflammation: a case of dacryoadenitis.
AB - Nonspecific orbital inflammatory syndrome includes a variety of ocular
inflammatory disorders. These may be classified by location (anterior or
posterior) and by time of presentation (acute or chronic). The four
subclassifications of nonspecific orbital inflammatory syndrome are myositis,
perineuritis, periscleritis, and dacryoadenitis. When a proper diagnosis is
established using clinical signs, imaging studies, and laboratory results,
treatment of the condition can be initiated. Treatment of the acute form is with
oral corticosteroids. This case discusses the diagnosis and treatment of a
patient with an acute onset of inflammatory dacryoadenitis.
PMID- 10772229
TI - Interview expectations and experiences of optometry applicants and interviewers.
AB - This 1996 study examined the admission interview employed at the University of
Waterloo School of Optometry (UWSO). A questionnaire was developed, piloted, and
mailed to 157 UWSO applicants and 23 UWSO interviewers. Their expectations of an
ideal optometry admission interview were compared with their experiences of the
UWSO admission interview. The response rate was 71.7% (n = 129; 109 applicants,
20 interviewers). Statistical analysis involved principle component analysis and
t-tests (independent and paired). Participants believed the ideal optometry
admission interview should gather information, verify information, provide
information, and select candidates by appraising their 'people skills,'
'professional skills,' and 'attitude orientation.' Although the participants'
expectations of the ideal interview resembled the mission statement of the UWSO
interview, the expectations, particularly among applicants, significantly
deviated from their experiences of the UWSO interview.
PMID- 10772230
TI - Distance stereopsis as a screening device.
AB - PURPOSE: To determine the efficacy of distance stereotesting as a screening
device. METHODS: Distance stereoacuity using the global Random Dot and contour
Circle test of the Mentor BVAT II-SG computerized testing system was measured for
216 patients, ages 6 to 18 years, before the clinical examination. Patients were
classified into pass/fail groups in the areas of refractive error change (REC),
ocular deviation (DEV), visual acuity (VA), and all three together (EXAM).
Legitimate cutoff scores were obtained when patients were classified as 'pass' as
follows: REC if the change was 0.50 D or less in sphere or cylinder relative to
the habitual correction or to emmetropia if no habitual correction; DEV if there
was no heterophoria or strabismus at distance (criteria of heterophoria of < 6
prism diopters and heterophorias of any magnitude were also tested); VA if the
acuity at distance was better than or equal to 20/25 in the poorer eye and better
than or equal to 20/20 in the better eye; EXAM if they were pass in REC, DEV, and
VA. Optimal pass/fail cutoff values for the stereopsis measurements were
determined by finding the maximum chi2 value from contingency tables constructed
using pass/fail levels for the screening test at each of the observed levels.
RESULTS: The pass rates for REC, DEV, VA, and EXAM were 45%, 72%, 42%, and 24%,
respectively. Patients passed the BVAT at the analytically determined optimal
cutoff values of less than or equal to 120 sec arc for global and less than or
equal to 30 sec arc for contour stereopsis. The sensitivity and specificity for
global stereopsis were 0.90 and 0.40 for REC, 0.89 and 0.30 for DEV, 0.93 and
0.51 for VA, and 0.87 and 0.63 for EXAM. For contour stereopsis, the
corresponding values were 0.85 and 0.42, 0.89 and 0.34, 0.91 and 0.53, and 0.84
and 0.62. CONCLUSION: Distance stereotesting is highly sensitive to small
refractive error changes, heterophorias and strabismus, visual acuities < 20/25,
or any of the three. Global stereopsis is only slightly better than contour
stereopsis at classifying patients. Distance stereotesting has potential as an
effective screening test.
PMID- 10772232
TI - Accommodation causes with-the-rule astigmatism in emmetropes.
AB - PURPOSE: To measure the changes in astigmatism when bilateral emmetropes
accommodate. METHODS: Bilateral emmetropes accommodative responses were measured
with an improved photorefractometer PR-1100, which measured binocular refraction
in all meridians simultaneously as a fixation target was shown in natural space.
RESULTS: The accommodative responses in the vertical meridian are greater than
those in the horizontal meridian. In the horizontal meridian, the accommodative
responses are less than the accommodative stimulus. CONCLUSIONS: When
accommodating the majority of bilateral emmetropes show with-the-rule astigmatism
and lag of accommodation in the horizontal meridian.
PMID- 10772231
TI - Measurement of refractive error in Native American preschoolers: validity and
reproducibility of autorefraction.
AB - PURPOSE: To examine (1) reproducibility of cycloplegic retinoscopy (C-RNS),
cycloplegic autorefraction (C-Autoref), and noncycloplegic autorefraction (NC
Autoref), and (2) validity of C-Autoref and NC-Autoref compared with C-RNS in
preschoolers with astigmatism. METHODS: Subjects were 36 Native American
preschoolers. Three measurements of right eye refractive error were obtained with
each of three methods: C-RNS (by three different retinoscopists), C-Autoref, and
NC-Autoref (Nikon Retinomax K+). Vector methods (vector dioptric distance, VDD)
were used in the analyses. RESULTS: Mean reproducibility was 0.41 D (SD = 0.18)
for C-RNS, 0.25 D (SD = 0.17) for C-Autoref, and 0.37 D (SD = 0.21) for NC
Autoref. Mean agreement between C-Autoref and C-RNS ranged from 0.51 to 0.61 VDD
(SD = 0.24 to 0.35), and ranged from 1.66 to 1.74 VDD (SD = 1.11 to 1.25) for
agreement between NC-Autoref and C-RNS. Mean bias was -0.07 +0.21 x 149 and -1.33
+0.34 x 178 for C-Autoref and NC-Autoref, respectively. CONCLUSIONS: C-Autoref
provided reliable and valid measurements of refractive error in young children.
NC-Autoref measurements were reliable within subjects, but there was large
variability in validity among subjects.
PMID- 10772233
TI - Expression for aberration coefficients using nonlinear transforms--extension to
spherocylindrical surfaces.
AB - Previously we have used a matrix method to do nonlinear calculations and
presented exact expressions for the third and fifth order aberration coefficients
for a general conic surface as functions of the latus rectum and eccentricity. In
this paper we show how the method can be extended to include the case of a
general spherocylindrical surface.
PMID- 10772234
TI - The Bristol 'OA500 study': progression and impact of the disease after 8 years.
AB - OBJECTIVE: To study the natural history of peripheral joint osteoarthritis (OA)
and assess its impact over eight years in a prospective study of 500 patients.
METHODS: 500 consecutive patients with peripheral joint OA were recruited from a
hospital-based rheumatology clinic. All were invited for review 3 and 8 years
after entry. Joint sites involved, pain severity, change in index joints, global
change in the condition, use of medication, surgery and walking aids were all
recorded at each visit, and after eight years disability was assessed by the
health assessment questionnaire (HAQ) and anxiety and depression by the Hospital
anxiety and depression scale (HAD). RESULTS: At eight-year review, 349 patients
were seen: 90% of those remaining alive. Outcome was heterogeneous. Sixty
patients (17.2%) reported worsening in all three subjective parameters (pain,
index joint and global change) compared with 22 (6.3%) who improved in all three
parameters. Using this definition of worsening or improvement, strong baseline
predictors of clinical outcome did not emerge. For further description, the group
was split according to the index joint sites involved at entry to the study,
there being 111 with knee OA alone, 87 with hand and knee OA, 72 with hand
disease alone, and 29 with hip disease alone. Forty-four percent of those with
lone hand disease at entry had acquired significant knee or hip OA 8 years later.
The mean HAQ and HAD scores at 8 years were high, especially in those with knee
disease, indicating significant disability as a result of the disease. Those with
knee or knee and hand disease had the worst outcome in all parameters recorded.
The data showed a general decrease in use of NSAIDs over the eight years, but an
increase in utilization of analgesics, surgery (especially for hip disease) and
walking aids. CONCLUSIONS: Patients with peripheral joint OA of sufficient
severity to lead to hospital referral have a heterogeneous, but generally bad
outcome over 8 years, the disease resulting in high levels of physical
disability, anxiety and depression, with a high level of utilization of
healthcare resources, including joint replacement, drugs and walking aids. The
results were consistent with previous suggestions that peripheral joint OA in
older people is characterized by the slow acquisition of new joint sites.
Progression and outcome may depend on a complex set of psychosocial factors, as
well as biological ones.
PMID- 10772235
TI - Radiographically defined osteoarthritis of the hand and knee in young and middle
aged African American and Caucasian women.
AB - Osteoarthritis (OA) has been characterized as a slowly evolving degenerative
disease affecting cartilage and bone, with a multifactorial etiology that may
differ depending on the joint site. Because OA has been considered a disease of
the elderly, few population-based studies have examined its frequency and
characteristics in persons under the age of 45. OBJECTIVE: In this cross
sectional study, we examined X-rays of both knees and the dominant hand in a
population of younger black and white pre- and perimenopausal women in
southeastern Michigan (N = 1053) for evidence of osteoarthritis, and reported
these outcomes according to the risk factors of age, body size, injury, and
smoking behavior. DESIGN: Sixteen joints of the dominant hand as well as both
knee joints (weight bearing) were evaluated using the Kellgren and Lawrence Atlas
of Standard Radiographs of Arthritis. RESULTS: By age 40, radiographically
defined osteoarthritis emerges in both the hands and knees. These age
characteristics are observed in both black and white women, however prevalence of
knee OA was higher in black females (23.1%) compared with white females (8.5%),
and although prevalence of hand OA was more comparable between black (25.5%) and
white females (19.2%), the joint sites affected differed. The major risk factors
reported in studies of older populations are present in this younger population
where OA is newly emerging. CONCLUSIONS: This study provides strong evidence that
primary prevention of OA must be implemented in young adulthood to curtail the
emergence of radiographically-defined OA at the mid-life.
PMID- 10772236
TI - Occupation and knee pain: a community study.
AB - OBJECTIVE: To examine the relationship between knee pain and occupation in a
community setting. DESIGN: A postal survey was sent to 4057 men and women aged 40
80. Subjects were asked about chronic knee pain. A question concerning job title
and industry was included in addition to demographic details. Prevalence of knee
pain and odds ratios for pain were calculated for the most common occupational
groups. RESULTS: Response was 82% and overall prevalence of knee pain was 28%.
Highest prevalence of pain was seen in carpenters and miners. Increased odds for
pain (adjusted for age, gender, body mass index, social class, smoking history
and psychological distress) were apparent in carpenters (4.6, 95% confidence
intervals 1.9-11.1), miners (1.9, 95%CI 1.3-2.8) and construction workers (2.4,
95%CI 1.4-4.1). CONCLUSIONS: Increased risk of knee pain is apparent in miners,
construction workers and carpenters; occupations which are likely to involve knee
bending and possibly heavy lifting.
PMID- 10772237
TI - Role of nitric oxide in the inhibition of BMP-2-mediated stimulation of
proteoglycan synthesis in articular cartilage.
AB - OBJECTIVE: Bone morphogenetic protein-2 (BMP-2)-mediated stimulation of articular
cartilage proteoglycan (PG) synthesis is suppressed in arthritic murine knee
joints and by interleukin-1 (IL-1). The goal of this study was to investigate
whether the gaseous mediator nitric oxide (NO) plays a crucial role in the
inhibition of BMP-2 effects by IL-1. METHODS: Bone morphogenetic protein-2 alone
or in combination with IL-1 was injected into the right knee joint of wild-type
and NOS2 deficient C57BI/6x129/Sv mice. Proteoglycan synthesis was measured ex
vivo by incorporation of 35S-sulfate on day 1, 2 and 3 after injection. To study
the role of NO in the inhibition BMP-2-mediated stimulation of PG synthesis in
arthritic joints, BMP-2 was injected intra-articularly in the joints of wild-type
and NOS2 deficient mice with zymosan-induced arthritis. To check for NOS2
deficiency, NO production was measured in conditioned medium after challenge of
patellae with surrounding tissue with IL-1. RESULTS: BMP-2 potently stimulated
proteoglycan synthesis in articular cartilage of normal knees (up to 4-fold) but
not in arthritic knees. Co-injection of BMP-2 with tumor necrosis factor alpha
had no effect on BMP-2-mediated stimulation of PG synthesis but co-injection with
IL-1 alpha resulted in a nearly total inhibition of BMP-2-mediated stimulation.
In contrast, in NOS2 deficient mice IL-1 had no effect on BMP-2-mediated
stimulation of PG synthesis. However, injection of BMP-2 into arthritic knee
joints of NOS2 knock out mice did not result in significant stimulation of PG
synthesis. CONCLUSIONS: In this study we show that NO plays a role in the
inhibition of BMP-2-mediated stimulation of PG synthesis by IL-1. However, NO, or
at least NOS2, plays no dominant role in the inhibition of BMP-2 effects in
arthritic knee joints.
PMID- 10772238
TI - Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal
chondrocytes, osteoblasts and osteocytes by in-situ hybridization.
AB - OBJECTIVE: To examine the expression pattern of human cartilage glycoprotein 39
(HC gp-39) mRNA in human cartilage and bone. DESIGN: In-situ hybridization
analysis was used to examine the expression pattern of human cartilage
glycoprotein 39 (HC gp-39) mRNA in adult human osteoarthritic articular cartilage
from various stages of disease, as well as in human osteophytic tissue and in
human fetal bone. RESULTS: In cartilage from patients with mild osteoarthritic
cartilage degeneration, HC gp-39 was expressed at moderate to high levels only in
chondrocytes of the superficial zone. In advanced OA cartilage, cloning
chondrocytes of the superficial zone expressed high levels of HC gp-39 and
chondrocytes of the mid- and deep zones were also positive. HC gp-39 was
undetectable in the chondrocytes of normal articular cartilage. In osteophytic
tissue, the expression of HC gp-39 mRNA was intense in flattened, end-stage
osteoblasts and in primary osteocytes in both endochondral and intramembranous
bone formation. Proliferating osteoblasts expressed low to moderate levels.
Notably, mature osteocytes were negative for HC gp-39 expression. Chondrocytes in
the secondary ossification center of developing fetal cartilage demonstrated high
expression while growth plate and mineralized cartilage chondrocytes had lower
expression. Osteoblasts at sites of endochondral and intramembranous bone
formation were positive for expression of HC gp-39. CONCLUSIONS: The stage
specific expression of HC gp-39 in fetal development and adult remodelling bone
and cartilage provides evidence for a specific functional or structural role for
HC gp-39 in bone and cartilage tissue. HC gp-39 is expressed in diseased human
osteoarthritic cartilage and osteophyte, but not in non-diseased tissue, and its
distribution within the tissue changes as disease progresses. OA is characterized
not only by cartilage degeneration, but by increased subchondral bone formation
and osteophytosis. The results from this study indicate that the increased HC gp
39 expression in OA serum and synovial fluid may reflect not only cartilage
degeneration but increased osteogenesis.
PMID- 10772239
TI - Integrin expression by primary and immortalized human chondrocytes: evidence of a
differential role for alpha1beta1 and alpha2beta1 integrins in mediating
chondrocyte adhesion to types II and VI collagen.
AB - OBJECTIVE: Chondrocytes have been shown to express beta1-containing integrins
both in vitro and in situ, but their role in regulating chondrocyte function is
poorly understood. The objective of this study was to determine how the relative
expression of different integrins may be modulated in relation to the
differentiated state and proliferative capacity of the chondrocyte. DESIGN:
Integrin expression by four different cell lines of human chondrocytes
immortalized with Simian virus 40 large T-antigen (SV40-TAg) was studied and
compared to primary chondrocytes. Differences in alpha1 and alpha2 integrin
subunit expression were utilized to further study the role of these integrins in
mediating adhesion to types II and VI collagen. RESULTS: The overall cell-surface
levels of beta1-containing integrins were higher on all four immortalized cell
lines which expressed over 10-fold higher levels of alpha2 and alpha3 integrin
subunits compared to primary cells. However, primary cells expressed higher
levels of the alpha1 integrin subunit which was not expressed by T/C28a4 cells
and expressed at variable and lower levels in the other lines. Levels of the
alpha3 integrin subunit were significantly greater on the highly proliferative
juvenile costal chondrocyte lines (T/C-28a4, C-2812, and C-20a4) compared to
primary articular chondrocytes and tsT/AC-62 cells which were derived from adult
articular chondrocytes. Expression of alpha5 was similar among primary cells and
cell lines except on C-20/A4 cells which had an average of over 4-fold higher
levels. None of the primary or immortalized chondrocytes tested expressed
significant levels of alpha4. Cell adhesion assays revealed that both alpha1beta1
and alpha2beta1 could serve as chondrocyte adhesion receptors for types II and VI
collagen. In cell lines expressing both integrins, alpha1beta1 was the
preferential receptor for type VI collagen while alpha2beta1 was the preferential
receptor for type II collagen. Rather than inhibiting adhesion, incubation with
the alpha3 blocking antibody P1B5 increased adhesion of C-28/12 cells to both
fibronectin and type II collagen by 67% and 100% respectively. CONCLUSIONS:
Immortalization with SV40-TAg results in altered integrin expression by
chondrocytes. Changes in the relative levels of alpha1, alpha2, and alpha3
subunits may significantly alter the manner in which chondrocytes interact with
types II and VI collagen in the extracellular matrix.
PMID- 10772240
TI - Validation of high-resolution water-excitation magnetic resonance imaging for
quantitative assessment of thin cartilage layers.
AB - OBJECTIVE: To employ a magnetic resonance (MR) imaging technique for quantitative
assessment of thin cartilage layers, and to validate the cartilage volume and
thickness measurements. METHODS: We investigated 10 normal elbow joints (age 20
to 69 years) with a 3D gradient echo sequence with selective water excitation (TR
18 ms; TE 9 ms; FA 25 degrees, resolution 1x0.25x0.25 mm2, imaging time 19 min).
After interpolating the image data to a 0.125x0.125 mm2 in-plane resolution, the
cartilage plates were segmented, reconstructed in 3D, and the cartilage volume
and thickness determined with a 3D Euclidean distance transformation algorithm,
independent of the original section plane. The cartilage volume and thickness
values were compared with CT arthrography and A-mode ultrasound. RESULTS: The
mean systematic difference between the elbow cartilage volume obtained from MR
imaging and CT arthrography was -0.11% (-6.0 mm3) and the mean random difference
5.7% (314 mm3). Except for the fovea capitis radii, the deviations were not
statistically significant (range -7.6 to +11.7%). In the humerus, the mean
cartilage thickness (average = 1.35 mm) was overestimated relative to CT
arthrography (+20.7%/+0.23 mm), and slightly underestimated relative to A-mode
ultrasound (-6.0%/-0.05 mm). With few exceptions, there were no significant
differences between MRI, CT arthrography and ultrasound in the other joint
surfaces of the elbow (random deviations between 0.08 and 0.39 mm). CONCLUSIONS:
The technique presented can be applied for determining the cartilage volume and
3D thickness in joints with thin cartilage layers with a reasonable degree of
accuracy.
PMID- 10772241
TI - Mechanical stress induces the expression of high molecular mass heat shock
protein in human chondrocytic cell line CS-OKB.
AB - OBJECTIVE: Mechanical stress is an important regulator of chondrocyte function,
but it is unknown how chondrocytes respond to mechanical stress. This study was
performed to clarify the underlying mechanisms in human chondrocytes. DESIGN:
Using a Flexercell strain unit (25% maximal elongation, 0.05 Hz-cyclic manner,
and 48 h), mechanical stimulation was applied to confluent CS-OKB cells, human
chondrocytic cells. To analyze transcriptional changes in response to mechanical
stress, differential display reverse transcription-polymerase chain reaction
(DDRT-PCR) and Northern blot analysis were performed. RESULTS: Among several
differentially displayed fragments, one fragment (927 bp) tentatively named as
SIC (Stress-Induced Chondrocytic) 1 was isolated from the human chondrocytic cell
line and identified as one of the high molecular mass heat shock proteins.
CONCLUSION: Mechanical stress induces the expression of a high molecular mass
heat shock protein corresponding to SIC 1 in human chondrocytic cells. SIC 1 may
play an important role in the mechanical stress-responded metabolism of human
chondrocytes.
PMID- 10772242
TI - Expression of hyaluronan synthases in articular cartilage.
AB - OBJECTIVE: To investigate the mRNA expression profiles of three mammalian
hyaluronan synthases (HAS1, HAS2 and HAS3) in chondrocytes from normal
(undiseased) animal cartilage and osteoarthritic human cartilage maintained in
experimental culture systems and exposed to catabolic or anabolic stimuli
provided by cytokines, growth factors and retinoic acid. DESIGN: Chondrocytes
isolated from normal bovine, porcine or from osteoarthritic human cartilage were
cultured as monolayers or embedded in agarose. Cultures were maintained for 3-5
days in the presence or absence of catabolic stimuli (IL-1, TNF-alpha or retinoic
acid) or anabolic stimuli (TGF-beta or IGF-1) followed by extraction of RNA and
analysis of HAS mRNA expression by RT-PCR. RESULTS: Whereas mRNA for HAS1 was not
detected in any sample, the mRNAs for HAS2 and HAS3 were expressed in human,
bovine and porcine chondrocytes. HAS2 mRNA was present in chondrocytes from all
cartilages and under all culture conditions, whereas HAS3 did not show such
constitutive expression. In agarose cultures of bovine and porcine chondrocytes
HAS2 mRNA was present in control, IL-1 and retinoic acid treated cultures,
whereas HAS3 mRNA was only detected in IL-1 stimulated cultures. Mature bovine
chondrocytes cultured in monolayers expressed mRNAs for both HAS2 and HAS3 in the
presence of IL-1, TNF-alpha, TGF-beta and IGF-1, however immature bovine
chondrocytes in monolayer cultures displayed virtually no HAS3 mRNA expression in
the presence of these cytokines and growth factors. HAS2 and HAS3 mRNAs were also
expressed by bovine chondrocytes isolated from either the superficial or deep
zone of articular cartilage, and by human chondrocytes cultured either in the
absence or presence of IL-1 and retinoic acid. CONCLUSIONS: Our data indicate
that HAS2 and HAS3 (but not HAS1) mRNAs are expressed in several mammalian
cartilages. Chondrocyte HAS2 mRNA appears to be constitutively expressed while
chondrocyte HAS3 mRNA expression can be differentially regulated in an age
dependent fashion, and may be affected by local and/or systemic catabolic or
anabolic stimuli provided by cytokines or growth factors.
PMID- 10772243
TI - Osteogenic protein-1 promotes the synthesis and retention of extracellular matrix
within bovine articular cartilage and chondrocyte cultures.
AB - OBJECTIVE: We have used recombinant osteogenic protein-1 to investigate our
hypothesis that proper repair and maintenance of cartilage requires not only
enhanced biosynthesis and replenishment of the extracellular matrix but also the
enhancement of components necessary for matrix retention. DESIGN: The effects of
osteogenic protein-1 were examined on bovine articular cartilage slices as well
as isolated chondrocytes grown in alginate beads. Cartilage slices were examined
for accumulation of proteoglycan by incorporation of 35S-sulfate and staining
using Safranin O or, a biotinylated probe specific for hyaluronan. Bovine
chondrocytes were characterized by use of a particle exclusion assay, in-situ
hybridization, quantitative-competitive RT-PCR and a hyaluronan-binding assay.
RESULTS: Osteogenic protein-1 treatment substantially enhanced the accumulation
of hyaluronan and proteoglycan within cartilage tissue slices. As with the
tissue, osteogenic protein-1 enhanced the size of cell-associated matrices
assembled and retained by chondrocytes in vitro. This enhanced matrix assembly
was paralleled by an increased expression of mRNA for aggrecan, hyaluronan
synthase-2 and CD44. Of the two hyaluronan synthase genes expressed by
chondrocytes, only hyaluronan synthase-2 was upregulated by osteogenic protein-1.
Coupled with the increase in the CD44 mRNA was an increase in functional
hyaluronan binding activity present at the chondrocyte cell surface. CONCLUSIONS:
These results demonstrate that osteogenic protein-1 stimulates not only the
synthesis of the major cartilage extracellular matrix component aggrecan, but
also two associated molecules necessary for the retention of aggrecan, namely
hyaluronan and CD44.
PMID- 10772244
TI - Effect of melatonin agonists and antagonists on horizontal cell spinule formation
and dopamine release in a fish retina.
AB - The crucian carp retina was used to study the effects of the melatonin antagonist
p697 (N-pentanoyl 2-benzyltryptamine) and the melatonin agonists [+]- and [-]
AMMTC (N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazol e)
on horizontal cell spinule formation, an indicator of the state of retinal
adaptation. DH97 was capable of both counteracting dark-adaptive spinule
degradation and inducing light-adaptive spinule formation at the beginning of the
dark phase. Addition of dopamine receptor blockers opposed the action of DH97 on
spinules, with SCH 23930, a D1 dopamine receptor antagonist, being more effective
than the D2 receptor antagonist sulpiride. DH97 induced a twofold increase in
dopamine release. We conclude that melatonin acts as a dark signal within the
teleost retina by inhibiting the dopaminergic system. In accordance with this,
both enantiomers of AMMTC prevented light-induced spinule formation, and reduced
dopamine release to below dark-adaptive baseline levels. We suggest that the
suppression of spinule formation by AMMTC may be due to either a direct
inhibitory interaction between the melatonin agonist and horizontal cell dopamine
D1 receptors, or an inhibitory effect on the activity of the dopamine-releasing
interplexiform cells.
PMID- 10772245
TI - Capillary-contacting horizontal cells in the retina of the tree shrew Tupaia
belangeri belong to the mammalian type A.
AB - Previously, ultrastructural evidence has been presented that, in the retina of
adult Tupaia belangeri, the perikarya and processes of horizontal cells
extensively ensheath the basal lamina of capillary cross sections located between
the inner nuclear layer and the outer plexiform layer. The present study tests
whether these horizontal cells can be further characterized by applying a
polyclonal antibody against glial fibrillary acidic protein (GFAP). GFAP
immunoreactivity was noted in the astrocytic plexus ensheathing retinofugal axons
in the nerve fiber layer. The vitreal endfeet and parts of the trunks of M*uller
cells were also labelled. Moreover, a large subpopulation of vessel-contacting
horizontal cells was strongly GFAP-immunoreactive. Immunoreactivity was found in
the perinuclear cytoplasm and in the sturdy primary dendrites of these cells. The
somata of GFAP-immunoreactive horizontal cells were unevenly distributed. These
cells had three to seven primary dendrites that showed considerable overlap with
the dendrites of neighbouring horizontal cells. For these reasons, GFAP
immunoreactive horizontal cells were classified as belonging to the mammalian
type A. Whether the simultaneous occurrence of two glial features, viz. extensive
ensheathment of retinal capillaries and immunoreactivity for a polyclonal
antibody towards GFAP, supports the view that retinal horizontal cells represent
a cell type intermediate between neurons and glial cells is discussed.
PMID- 10772246
TI - Olfactory epithelium consisting of supporting cells and horizontal basal cells in
the posterior nasal cavity of mice.
AB - The olfactory epithelium of mice generally consists of olfactory cells,
progenitors of olfactory cells (globose basal cells), supporting cells, and
horizontal basal cells. However, in the dorsal fossa (the roof) of the posterior
nasal cavity of mice, we found seven epithelial patches consisting of only non
neuronal cell types, i.e., supporting cells and horizontal basal cells, among the
normal olfactory epithelium. The supporting cells occupied three or four layers
in the apical to middle regions; in the basal region, horizontal basal cells were
localized in a single row adjacent to the basement membrane. Bowman's gland ducts
were also present in the epithelium. Neuronal cells (olfactory cells and globose
basal cells) were totally absent. The ultrastructure of the supporting cells,
horizontal basal cells, and Bowman's glands was essentially similar to that in
the normal olfactory epithelium. In the early postnatal period (P1-P7), cell
types in the epithelium were the same as those in the normal olfactory
epithelium. From P10 to P21, olfactory cells and globose basal cells had
disappeared from the olfactory epithelium. At this period, the number of TUNEL
positive cells was significantly higher than that in the surrounding olfactory
epithelium; ultrastructurally, many apoptotic figures were observed. This
suggests that the epithelium consisting of supporting cells and horizontal basal
cells is generated by the apoptotic death of olfactory cells and globose basal
cells during postnatal development.
PMID- 10772247
TI - Epithelial Na+ channels and stomatin are expressed in rat trigeminal
mechanosensory neurons.
AB - Caenorhabditis elegans MEC-4 and MEC-10 are subunits of the degenerin/epithelial
Na+ channel (DEG/ENaC) ion channel superfamily thought to be associated with MEC
2 (a stomatin-like protein) in a mechanotransducing molecular complex in
specialized touch sensory neurons. A key question is whether analogous molecular
complexes in higher organisms transduce mechanical signals. To address this
question, we selected mechanoreceptors of the rat vibrissal follicle-sinus
complex in the mystacial pad and the trigeminal ganglia for an immunocytochemical
and molecular biological study. RT-PCR of poly(A+) mRNA of rat trigeminal ganglia
indicated that alpha-, beta-, and gamma-ENaC and stomatin mRNA are expressed in
rat trigeminal ganglia. Using immunocytochemistry, we found that alpha-, beta-,
and gamma-ENaC subunits and stomatin are localized in the perikarya of the
trigeminal neurons and in a minor fraction of their termination site in the
vibrissal follicle-sinus complex, where longitudinal lanceolate endings are
immunopositive. We conclude that alpha-, beta-, and gamma-ENaC subunits as well
as the candidate interacting protein stomatin are coexpressed in a mammalian
mechanoreceptor, a location consistent with a possible role in
mechanotransduction.
PMID- 10772248
TI - Acute-phase cytokines IL-1beta and TNF-alpha in brain development.
AB - The nervous and the immune systems share several molecules that control their
development and function. We studied the temporal and spatial distribution of the
immunoreactivity of two acute-phase cytokines, TNF-alpha and IL-1beta, in the
developing sheep neocortex and compared it with the well-described distribution
of fetuin, a fetal glycoprotein also known to modulate the production of
cytokines by lipopolysaccharide (LPS)-stimulated monocytes and macrophages. TNF
alpha was present first at embryonic day 30 (E30) (term is 150 days in sheep) as
a faint band of immunoreactivity between the ventricular zone and the primordial
plexiform layer (preplate). IL-1beta was detected at the first appearance of the
cortical plate (E35-E40). Both cytokines were present on both sides of the
cortical plate, which contained fetuin-positive cells, but was free from cytokine
staining. By E60, TNF-alpha immunoreactivity was less prominent than that of IL
1beta and was confined to the marginal zone and outer developing white matter; IL
1beta was present in the marginal zone and in two bands of immunoreactive cells,
one at the border of the cortical plate/developing layer VI (cells of neuronal
morphology) and the other at the border of layer V and the developing white
matter (identified as microglia). By E80, TNF-alpha staining had disappeared and
IL-1beta-immunopositive microglia were no longer detectable. By E100-E140 only a
few immunoreactive cells were identified in layers V-VI; these did not co
localize with fetuin-positive cells. The differences in distribution between
fetuin and the two cytokines suggest that the opsonizing role of fetuin, proposed
for monocyte production of cytokines, is probably not present in the developing
brain. However, early in neocortical development TNF-alpha and IL-1beta were
present in the subplate zone at a time of intense synaptogenesis.
PMID- 10772249
TI - Visualization of gap junction mobility in living cells.
AB - In order to study the dynamics of gap junctions in living cells, a cDNA was
expressed in hepatocellular carcinoma-derived PLC cells coding for chimerical
polypeptide Cx.EGFP-1, which consists of rat connexin32 and enhanced green
fluorescent protein (EGFP). Cx.EGFP-1 was integrated into gap junctions, and the
emitted epifluorescence reliably reported the distribution of the chimera.
Therefore, stably transfected PLC clone PCx-9 was used to examine the dynamic
behavior of gap junctions by time-lapse fluorescence microscopy. The pleomorphic
fluorescent junctional plaques were highly motile within the plasma membrane.
They often fused with each other or segregated into smaller patches, and
fluctuation of fluorescence was detected within individual gap junctions.
Furthermore, the uptake of junctional fragments into the cytoplasm of live cells
was documented as originating from dynamic invaginations that form long
tubulovesicular structures that pinch off. Endocytosis and subsequent lysosomal
degradation, however, appeared to contribute only a little to the rapid gap
junction turnover (determined half-life of 3.3 h for Cx.EGFP-1), since most
cytoplasmic Cx.EGFP-1 fluorescence did not colocalize with the endocytosed fluid
phase marker horseradish peroxidase or the receptor-specific endocytotic ligand
transferrin and since it was distinct from lysosomes. Disassembly of gap
junctions was monitored in the presence of the translation-inhibitor
cycloheximide and showed increased endocytosis and continuous reduction of
junctional plaques. Highly motile cytoplasmic microvesicles, which were
detectable as multiple, weakly fluorescent puncta in all movies, are proposed to
contribute significantly to gap junction morphogenesis by the transport of small
subunits between biosynthetic, degradative, and recycling compartments.
PMID- 10772250
TI - Dietary restriction reduces hepatocyte proliferation and enhances p53 expression
but does not increase apoptosis in normal rats during development.
AB - Dietary restriction (DR) retards physical growth, resulting in small body size,
reduced liver weight and reduced number of hepatocytes in rats. We examined the
effects of DR on proliferation and apoptosis of hepatocytes during development
and explained these changes subcellularly using immunohistochemistry for
bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA)
and p53, terminal dUTP nick end labeling (TUNEL) and quantitative reverse
transcription-polymerase chain reaction (RT-PCR) for TGFalpha, TGFbeta1, p53, Fas
and TNF receptor (TNFr). Tissue samples included the livers of 3-month-old male
Fischer 344 rats fed ad libitum (AL) or on 70% DR. DR significantly reduced the
proportions of BrdU-positive and PCNA-strongly-positive hepatocytes compared with
AL rats but not the proportions of PCNA-positive hepatocytes and TUNEL-positive
hepatocytes. On the other hand, DR enhanced the expression of p53 and Fas mRNAs
but failed to influence the expression of TGFalpha, TGFbeta1 and TNFr mRNAs.
Moreover, DR significantly increased the proportion of p53-positive hepatocytes.
Our findings suggest that DR suppresses the proliferation of hepatocytes,
resulting in a reduced number of hepatocytes during development. This process may
be mediated by overexpression of p53 suppressor gene. While DR accelerates the
expression of Fas antigen, this result does not influence the rate of apoptosis
of hepatocytes under physiological conditions.
PMID- 10772251
TI - Identification of growth-hormone- and prolactin-containing neurons within the
avian brain.
AB - Prolactin (PRL)- and growth-hormone (GH)-containing perikarya and fibers
independent of the anterior pituitary gland have been reported to exist in the
central nervous system of several mammalian species. The specific distributions
of PRL- or GH-like neurons in the avian forebrain and midbrain, however, have not
been reported. The objective of the study was to identify GH- and PRL-containing
neurons in the hypothalamus and a few extrahypothalamic areas of two avian
species. Brain and peripheral blood samples were collected from laying and broody
turkey hens and ring doves. Broody turkey hens and doves had significantly higher
plasma PRL concentrations compared with laying hens. Coronal brain sections were
prepared and immunostained using anti-turkey GH and anti-chicken synthetic PRL
antibodies. In turkey hens, the most dense GH-immunoreactive (ir) perikarya and
fibers were found in hippocampus (Hp), periventricular hypothalamic nucleus,
paraventricular nucleus, inferior hypothalamic nucleus, infundibular hypothalamic
nucleus, medial and lateral septal area, and external zone of the median eminence
(ME). In the ring dove, a similar pattern of distribution of GH-ir neurons was
noticed at the brain sites listed above except that GH-ir fibers and granules
were found only in the internal zone of ME and not in the external zone. In both
turkeys and doves, the most immunoreactive PRL-ir perikarya and fibers were found
in the medial and lateral septal area, Hp (turkey only), and bed nucleus of the
stria terminalis pars magnocellularis. There were no apparent differences in the
staining pattern of GH- or PRL-ir neurons between the laying and broody states in
either species. However, the presence of GH-ir- and PRL-ir perikarya and fibers
in several hypothalamic nuclei indicates that GH and PRL may influence parental
behavior, food intake, autonomic nervous system function, and/or reproduction.
PMID- 10772252
TI - Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone.
AB - There is strong evidence that matrix metalloproteinases (MMPs) play a crucial
role during osteogenesis and bone remodelling. Their synthesis by osteoblasts has
been demonstrated during osteoid degradation prior to resorption of mineralised
matrix by osteoclasts and their activities are regulated by tissue inhibitors of
metalloproteinases (TIMPs). For this study we developed and utilised specific
polyclonal antibodies to assess the presence of collagenase (MMP13), stromelysin
1 (MMP3), gelatinase A (MMP2), gelatinase B (MMP9) and TIMP-2 in both freshly
isolated neonatal mouse calvariae and tissues cultured with and without bone
resorbing agents. Monensin was added towards the end of the culture period in
order to promote intracellular accumulation of proteins and facilitate antigen
detection. In addition, bone sections were stained for the osteoclast marker,
tartrate-resistant acid phosphatase (TRAP). In uncultured tissues the bone
surfaces had isolated foci of collagenase staining, and cartilage matrix stained
for gelatinase B (MMP9) and TIMP-2. Calvariae cultured for as little as 3 h with
monensin revealed intracellular staining for MMPs and TIMP-2 in mesenchymal
tissues, as well as in cells lining the bone plates. The addition of cytokines to
stimulate bone resorption resulted in pronounced TRAP activity along bone
surfaces, indicating active resorption. There was a marked upregulation of enzyme
synthesis, with matrix staining for collagenase and gelatinase B observed in
regions of eroded bone. Increased staining for TIMP-2 was also observed in
association with increased synthesis of MMPs. The new antibodies to murine MMPs
should prove valuable in future studies of matrix degradation.
PMID- 10772253
TI - Follicular dendritic cells in vitro modulate the expression of Fas and Bcl-2 on
germinal center B cells.
AB - Germinal center (GC) B cells are highly susceptible to apoptosis. The cellular
mechanism regulating this sensitivity, however, has not yet been fully
delineated. To investigate whether follicular dendritic cells (FDC) are capable
of regulating the susceptibility to apoptosis of GC B cells, we constructed a GC
model in vitro: emperipolesis of tonsillar B cells by FDC. We then analyzed the
expressions of apoptosis-related proteins (Bcl-2 and Fas) on the cells by three
color flow cytometry. B cells nonentrapped by FDC decreased rapidly in number
owing to early apoptosis in vitro, whereas entrapped B cells were rescued for at
least 18 h and showed peculiar regulation of Fas and Bcl-2. GC founder cells
(CD38+, IgD+; GCFC) and GC B cells (CD38+, IgD-) showed approximately a twofold
increased expression of Fas; in contrast, mantle zone B cells (CD38-, IgD+) and
memory B cells (CD38-, IgD-) showed no changes. Bcl-2 expression in mantle zone
and memory B cells was reduced by approximately one-half; however, GCFC and GC B
cells continued to express little Bcl-2 and this did not change. Our findings
strongly suggest that FDC play a part in the modulation of the susceptibility to
apoptosis on B cells within GC.
PMID- 10772254
TI - Ultrastructural localization of arginine vasopressin in coronary vessels of
newborn rat.
AB - We report on the ultrastructural distribution of arginine-vasopressin (AVP) in
the heart of newborn rats using pre-embedding peroxidase-antiperoxidase
immunocytochemistry with a polyclonal AVP antibody for electron microscopy.
Positive labelling for AVP was localized in endothelial cells of main coronary
arteries and cardiac vessels of smaller diameter (microvessels). Examination of
the right coronary artery showed that approximately 58% of the endothelial cells
were positive for AVP. Immunoreactivity to AVP in the cytoplasm of arterial
endothelium predominated in association with the membranes of granular
endoplasmic reticulum and in subplasmalemmal areas. The endothelium of small
vessels exhibits less endoplasmic reticulum, but still shows AVP
immunoprecipitate in the cytoplasm. It is suggested that endothelial AVP may
contribute to vasomotor control of the coronary circulation in the early stages
of postnatal development. AVP antibody also labelled some fibroblast/fibroblast
like cells associated with the coronary arteries and microvessels; thus, these
cells as well as the endothelium appear to be a source of AVP in the newborn rat
heart. The functional significance of these findings is discussed.
PMID- 10772255
TI - Neurturin, RET, GFRalpha-1 and GFRalpha-2, but not GFRalpha-3, mRNA are expressed
in mice gonads.
AB - The gonads are known to produce numerous hormones and also neurotrophins and
their receptors. Here we demonstrate expression of glial-cell-line-derived
neurotrophic factor (GDNF) family ligands and related receptors in adult mice
gonads by in situ hybridization. GDNF mRNA was expressed in the ovary, but was
not detectable in testis. Neurturin (NTN), another ligand in this family, gave
rise to strong mRNA hybridization signals in a mosaic pattern in the seminiferous
tubules of the testis at stages IX-XII and I-II of the cycle. NTN mRNA signals
were also found in uterus and the oviduct. In testis, the transducing receptor
RET as well as GDNF receptor alpha-1 (GFR)alpha-1 and GFRalpha-2 were distributed
in complementary and overlapping patterns, the former at stages XI-XII-I and the
latter at stages VII and VIII. GFRalpha-3 could not be detected. Expression of
these trophic molecules suggests involvement of GDNF family ligands and related
receptor components in reproduction.
PMID- 10772256
TI - Immunocytochemical localization and secretion process of the toxin CSTX-1 in the
venom gland of the wandering spider Cupiennius salei (Araneae: Ctenidae).
AB - Fluorescein and horseradish peroxidase-labeled monoclonal antibodies were used to
localize the predominant toxic peptide CSTX-1 in the venom gland of the spider
Cupiennius salei. There was no polarity of CSTX-1 expression in repleted glands,
whereas the glands of previously milked spiders showed a decreasing
immunofluorescent response from the distal to the proximal portion. Detailed
investigation revealed a new structure in the venom-secreting epithelium, which
is postulated to be an evolutionary adaptation to increasing gland volume. CSTX-1
was found to be synthesized and stored as a fully active toxin within complex
units, composed of long interdigitating cells running perpendicular to the
muscular sheath and extending into the central lumen of the gland. These venom
producing units were found in all sectors of the gland, including the
transitional region between the main gland and the venom duct. The venom is
liberated from the venom-producing units into the glandular lumen following the
contraction of the surrounding muscle layer. Free nuclei or other cellular
fragments, which would have provided evidence for a holocrine secretion process,
were not found in the glandular lumen or in the crude venom obtained by
electrical stimulation. The fine regulation of the spider's venom injection
process is postulated to be the function of the bulbous ampulla, situated in the
anterior third of the venom duct.
PMID- 10772257
TI - Neurons projecting to the retrocerebral complex of the adult blow fly,
Protophormia terraenovae.
AB - Anatomical study of neurons projecting to the retrocerebral complex of the adult
blow fly, Protophormia terraenovae, was done by NiCl2 filling and
immunocytochemistry. Retrograde filling through the cardiac-recurrent nerve
labeled three groups of neurons in the brain/subesophageal ganglion: (1)
paramedial clusters of the pars intercerebralis, (2) neurons in each pars
lateralis, and (3) neurons in the subesophageal ganglion. The pars
intercerebralis neurons send prominent axons into the median bundle and exit from
the brain via the contralateral nervus corporis cardiaci. Based on the projection
pattern, two types of the pars lateralis neurons can be distinguished: the most
lateral pairs of neurons contralaterally extend through the posterior lateral
tract and the remainder ipsilaterally extend through the posterior lateral tract.
The neurons in the subesophageal ganglion run through the contralateral nervus
corporis cardiaci. The dendritic arborization of the pars intercerebralis and
pars lateralis neurons is restricted to the superior protocerebral neuropil and
to the anterior neuropil of the subesophageal ganglion where the neurons in the
subesophageal ganglion also project. Retrograde filling from the corpus allatum
indicated that the pars lateralis neurons and a few pars intercerebralis neurons
project to the corpus allatum, but that the neurons in the subesophageal ganglion
do not. Orthograde filling from the pars intercerebralis and staining by
paraldehyde-thionin/paraldehyde-fuchsin indicated that the pars intercerebralis
neurons project primarily to the corpus cardiacum/hypocerebral ganglion complex.
Immunostaining with a polyclonal antiserum against diapause hormone, a member of
the FXPRLamide family, suggests that some of the subesophageal ganglion neurons
contain FXPRLamide-like peptides.
PMID- 10772258
TI - 1H NMR study of N(CH3)4H(ClF2CCOO)2.
AB - The proton spin-lattice relaxation times and 1H NMR second moments were measured
over a wide range of temperature. The results were compared with those of the 19F
NMR relaxation that we obtained earlier. For both nuclear species, the evolution
of the longitudinal magnetizations with time is observed to be strongly bi
exponential and were in good quantitative agreement with the cross-relaxation
theory.
PMID- 10772259
TI - Methods for correlating T1rho and FID components in wideline 1H NMR studies of
motionally heterogeneous polymer systems.
AB - We address the problem of correlating the observed FID and T1rho components in
wideline 1H relaxation measurements of motionally heterogeneous polymers, and
show that different methods of data treatment can highlight different aspects of
the correlations present. For a sample of polypropylene we find that the T1rho
relaxation behaviour is driven by relaxation associated with the intermediate FID
component, which strongly suggests a motionally inhomogeneous amorphous region in
the sample.
PMID- 10772260
TI - H2O/OH ratio determination in hydrous aluminosilicate glasses by static proton
NMR and the effect of chemical shift anisotropy.
AB - Static 1H NMR spectra of hydrous NaAlSi3O8 glasses have been acquired at low
temperature (140 K) in order to quantitatively determine OH and H2O
concentrations. Since both components overlap in the spectra, an unambiguous
determination of the line shapes is required. The structurally bonded hydroxyl
groups are well described by a Gaussian line and the water molecules exhibit a
Pake doublet-like line shape due to the strong proton-proton dipolar interaction.
However, at proton resonance frequencies used in this study (360 MHz), the Pake
doublet has an asymmetric line shape due to chemical shift anisotropy (CSA),
which is significant and must be included in any simulation in order to reproduce
the experimental line shape successfully. The simulations for rigid water
molecules dissolved in our hydrous aluminosilicate glasses result in a CSA of
30+/-5 ppm and a dipolar interaction constant of 63.8+/-2.5 kHz (i.e., dipolar
coupling constant (DCC) of 42.6+/-1.7 kHz), corresponding to a proton-proton
distance of r(ij) = 154+/-2 pm. In contrast to earlier work, water speciation
obtained from the simulations of our 1H NMR spectra are in excellent agreement
with those obtained from infrared (IR) spectroscopy.
PMID- 10772261
TI - Spin-locking mechanism of spin I = 3/2 quadrupolar nuclei undergo magic angle
spinning.
AB - The spin-locking mechanism of the spin I = 3/2 quadrupolar nuclei under magic
angle spinning (MAS) has been theoretically and experimentally investigated, and
the criterion of adiabatic passage around zero-crossings of the quadrupole
splitting was inferred from the time-dependent Shrodinger equation in this
article. The theory, numerical simulations, and experiments conducted in this
work all indicated that second-order quadrupole interaction and off-resonance
play important roles in the spin-locking of the quadrupolar nuclei, and they were
responsible for the great loss of the spin-locking signals. The spin-locking for
a spin I = 3/2 nucleus might be achieved by minimizing the effect of the second
order quadrupole interaction by using a radio frequency (RF) offset. This offset
was realized by setting the RF to the opposite position of the isotropic second
order quadrupolar shift of single quantum coherences.
PMID- 10772262
TI - Synchronized double rotation 2D NMR.
AB - Analytical expressions for multi-quantum signal generation of quadrupole nuclei
have been derived. Combined with numerical simulation of the double rotor motion,
a strategy is suggested for partial sideband suppression in multi-quantum NMR
spectra. Synchronization of multi-quantum excitation and selective flip pulses
with outer rotor motion increase outer rotor speed effectively two times. This is
also demonstrated experimentally by triple-single quantum correlation spectra of
23Na and 67Rb.
PMID- 10772263
TI - Molecular dynamics in solid pregnenolone studied by 1H spin-lattice relaxation.
AB - Spin-lattice relaxation times T1 in solid pregnenolone have been studied over a
wide range of temperatures, from 77 up to 417 K. The dynamic processes arising
from C3 motion of the three methyl substituents are separated, and their
activation parameters are determined.
PMID- 10772264
TI - Determination of titanium NMR parameters of ATiO3 compounds: correlations with
structural distortion.
AB - Solid state 47,49Ti NMR spectra have been obtained for a number of perovskite and
ilmenite ATiO3 compounds. The 49Ti quadrupole coupling constant varies from 2.75
MHz (CaTiO3) to 15.5 MHz (MgTiO3) and the electric field gradient at the titanium
site was found to correlate well with the shear strain, independent of structure.
The chemical shift in the perovskite structures varies by approximately 160 ppm
and correlates well with the mean Ti-O distance. The 25Mg and 113Cd NMR
parameters are also reported for the relevant compounds.
PMID- 10772265
TI - Kinetics of NMR cross-polarization from protons to phosphorus-31 in natural
brushite.
AB - Cross-polarization in natural brushite proceeds according to an isolated spin
pair kinetics.
PMID- 10772266
TI - 13C CPMAS studies of plant cell wall materials and model systems using proton
relaxation-induced spectral editing techniques.
AB - The solid state 13C CPMAS NMR spectra of plant cell walls are often complex owing
to superposition of resonances from different polysaccharides and the
heterogeneity of the cell wall assembly. In this paper, we describe the
application of a set of proton relaxation-induced spectral editing (PRISE)
experiments which combine 1H relaxation properties (T1, T1rho, T2) with 13C high
resolution spectroscopy (CPMAS) to relate the dynamics of the plant cell walls
and model systems to their domain structural details. With PRISE it has been
found that in plant cell wall materials, cellulose is always associated with the
long components of spin-lattice relaxation in both the laboratory and rotating
frames whereas non-cellulose polysaccharides (pectin and hemicellulose) are
associated with the short ones. For the proton T2 relaxation, cellulose is only
associated with the short component (below 20 micros), pectin contributes to both
the short component and the long one.
PMID- 10772267
TI - The mother-offspring dyad and the immune system.
AB - A. The mother and the fetus. The mother's immune system reacts against the fetus
and there is therefore a risk of destruction of or damage to the fetus. We are
now beginning to understand some of the mechanisms that protect the fetus, but,
when these are defective, intrauterine growth retardation or abortions may ensue.
However, the cytokines of this maternal immune response to the fetus also monitor
different phases of pregnancy, starting with effects on the ovarium and involving
preparation of the decidua for the implantation of the fertilized egg, the growth
of the trophoblasts, the production of hormones important for the pregnancy and
finally of the prostaglandins that induce delivery. B. The mother and the child.
Human milk contains anti-idiotypic antibodies which after transfer to the
offspring are capable of enhancing antibody responses. Human milk contains
numerous leucocytes especially during early lactation. There is increasing
evidence that milk lymphocytes are taken up by the breastfed infant, which seems
to have become tolerant to maternal HLA. Breastfeeding mothers are therefore good
donors of renal transplants to their breastfed offspring in adult age, too.
CONCLUSION: It is suggested that the milk lymphocytes may be taken up by the
offspring and that immunological information is thereby carried over from the
mother. This mechanism may explain why breastfeeding seems to confer enhanced
protection against infections also some years after the termination of
breastfeeding.
PMID- 10772268
TI - A future for neonatal alpha1-antitrypsin screening?
AB - A WHO expert group recommends neonatal screening for alpha1-antitrypsin
deficiency (alpha1ATD). Homozygous alpha1ATD PiZZ occurs in 1 in 5000 of the U.S.
Caucasian population and up to 1 in 500 individuals of the European population,
with a large regional variation. It is a risk factor that predisposes mainly to
liver disease in early infancy and emphysema in early adulthood. Most
importantly, smoking decreases the duration of the asymptomatic phase and life
expectancy by 10-20 y. The Swedish alpha1AT screening programme and subsequent
information and advice prevented the majority of adolescents from starting to
smoke. The involved parents and alpha1ATD adolescents retrospectively recommended
neonatal screening. Potential advantages of neonatal alpha1AT screening are:
early diagnosis and treatment of neonatal liver disease, optimal treatment of
fever and bacterial infections theoretically preventing liver cell damage,
genetic advice and information about the consequences of passive and active
smoking. Potential advantages of postponing screening until age 11-12y are:
identification of alpha1ATD close to the age when smoking may start, and
possibility for the child to take part in the screening decision. Disadvantages
of alpha1AT screening are: psychosocial reactions--the mother probably being most
vulnerable in the neonatal period--and discrimination by insurance companies and
employers. Important uncertainties are: lack of knowledge concerning
participation in a voluntary alpha1AT screening, psychosocial reactions and the
efficacy of anti-smoking advice if the information is given to school-age
children and families. Thus the question whether and when to screen for alpha1ATD
is still the topic of lively debate.
PMID- 10772269
TI - Predicting the outcome of term neonates with intrapartum asphyxia.
PMID- 10772270
TI - Magnetic resonance imaging in newborn infants.
PMID- 10772271
TI - DAMP and MBD versus AD/HD and hyperkinetic disorders.
PMID- 10772272
TI - Sexual abuse of children: continuing challenges for the new millennium.
PMID- 10772273
TI - Nutrient intake among two-year-old children on cows' milk-restricted diets.
AB - Approximately 2-3% of young children develop allergy or intolerance to cows'
milk. The only available treatment is elimination of milk from the diet. However,
as milk is an important source of nutrients in childhood, a milk-free diet may
not adequately meet the child's nutritional needs. A dietary survey was conducted
to assess the nutrient intake of children on cows' milk-restricted diets. A
population-based sample of families with young children (31-37 mo) with adverse
reaction to cows' milk and/or eggs was contacted, of which 75% agreed to complete
a dietary intake assessment. Dietary intake was assessed using a 4-d weighed
recording. The nutrient intake in a group of children on cows' milk protein-free
(n = 16) and cows' milk reduced (n = 8) diets were compared to a group of cows'
milk consumers (n = 10). There were significant differences in nutrient intake of
children on milk-free diets and children consuming milk. Children on milk-free
diets had significantly lower intake of energy, fat, protein, calcium, riboflavin
and niacin. Use of milk substitutes improved the nutritional content of the cows'
milk-free diets; however, the recommendations for riboflavin and calcium were
still not met. CONCLUSION: The results reveal a risk for malnutrition in children
on cows' milk-free diets, unless precautions are taken to replace the valuable
nutrients from milk in the diet. Parents of children on milk-free diets need
advice about food choices in order to reduce the risk of low intake of energy,
fat and protein. Supplements with calcium, vitamin D and riboflavin are
indicated.
PMID- 10772274
TI - Abnormal fatty acid composition in umbilical cord blood of infants at high risk
of atopic disease.
AB - It is well known that patients with atopic disease have anomalies of fatty acid
composition in their blood. The aim of the present study was to evaluate whether
infants from atopic families also have abnormal cord blood levels of long-chain
polyunsaturated fatty acids (LC-PUFA) in plasma and red blood cells. The levels
of LC-PUFA in umbilical cord blood of 50 healthy, full-term infants with a
hereditary risk of atopic disease were analysed and compared with a control group
of 50 infants from families without a history of atopic disease. The atopy group
was comprised of children from families suffering from atopic dermatitis,
allergic rhinitis, asthma bronchiale and food allergy. Within this group, a group
(n = 11) was formed in which the risk was determined only by paternal atopy.
Fatty acids of plasma and red blood cell phospholipids, triglycerides and sterol
esters were separated by high-resolution gas-liquid chromatography. In
particular, the levels of arachidonic acid (C20:4n-6) and docosatetraenoic acid
(C22:4n-6) were significantly lower in infants at risk of atopic disease than in
infants not at risk. Interestingly, there were more significant differences shown
between the control group and the paternal atopy group than between the control
group and the entire atopy group. CONCLUSION: The results of this study could be
due to a genetic influence of fatty acid metabolism or could reflect the
different dietary behaviours of the mothers during pregnancy.
PMID- 10772275
TI - Intraepithelial lymphocytes and coeliac disease: permanent changes in CD3-/CD7+
and T cell receptor gammadelta subsets studied by flow cytometry.
AB - Permanent changes in intestinal intraepithelial lymphocytes have been observed in
coeliac patients. The aim of this investigation was to study small intestinal
intraepithelial lymphocytes by using flow cytometry and to evaluate its
diagnostic value in coeliac disease. Three-colour flow cytometry analyses were
performed on isolated epithelial cells of 117 intestinal biopsies obtained from
113 children (54 coeliac disease, 4 other enteropathies, 18 Helicobacter pylori
associated gastritis and 37 normal controls). A multiple logistic regression
model was developed to select the best intraepithelial lymphocytes subset
predictor of coeliac disease. Coeliac patients had significant higher levels of T
cell receptor gammadelta intraepithelial lymphocytes than control patients (p <
0.01), H. pylori patients (p < 0.01) and other enteropathies (p < 0.05). The
density of CD3-/CD7+ intraepithelial lymphocytes, a intraepithelial lymphocyte
subset poorly characterized by immunohistochemical methods, was significantly
lower in coeliac patients than in the control group (p < 0.01). H. pylori group
(p < 0.01) and other enteropathies (p < 0.01). Both changes remained altered
independent of the coeliac patient's diet. The data were used on a logistic
regression analysis in order to calculate sensitivity [94.4%; 95% confidence
interval (CI) 83.7-98.6%], specificity (94.9%; 95% CI 84.9-98.7%) and likelihood
ratio for a positive test 18.5 (95% CI 6.1-55.8) in the diagnosis of coeliac
disease. CONCLUSION: Changes in T cell receptor gammadelta and CD3-/CD7+
intraepithelial lymphocytes subsets are permanently observed in paediatric
coeliac disease. Their assessment, by three-colour flow cytometry on routine
diagnostic biopsies, permits a better characterization of coeliac enteropathy and
represents a valuable procedure to identify coeliac patients with different
clinical presentations.
PMID- 10772276
TI - Neurologic development of the newborn and young child in relation to maternal
thyroid function.
AB - A prospective observational study was performed in pregnant women with known
thyroid disease. We studied the effect of maternal thyroid function in the first
half of pregnancy on the neurologic development of the infant in the first 2 y of
life. Clinical and thyroid function data were collected from 20 pregnant women
with known thyroid disease and their newborn children. Infants were divided into
three groups according to their maternal thyroid function within the first half
of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n =
6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or
subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction
velocity and somatosensory evoked potentials and neurologic and developmental
(Bayley scales) assessments were done. One infant, born to a mother with Graves'
disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean
mental developmental index (MDI) score was 16 points lower for infants in Group A
than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo,
the mean MDI score was 6 points lower, which was not statistically significant.
Neurophysiologic and neurologic assessments and the mean Psychomotor
Developmental scores did not differ among the three groups. In conclusion,
maternal subclinical hypothyroidism in the first half of pregnancy was associated
with a lower mean MDI score in their infants during the first year of life.
PMID- 10772277
TI - Consequences of infections for three-month length increment in young children in
rural Zambia.
AB - It was the aim of this study to describe the relationship of infections with
subsequent 3-mo length increment in children below 2 y of age in rural Zambia.
Children aged 6-9 mo ('infants'; n = 84) and 14-20 mo ('toddlers'; n = 81)
attending Mother-and-Child Health clinics, were included and followed up after
3.0 mo (min-max; 2.1-3.7 mo). Anthropometric measurements were taken at each
visit. At baseline, C-reactive protein (CRP), alpha1-acid glycoprotein (AGP),
retinol and malaria parasitaemia were assessed. Length increment during the 3.0+/
0.5 mo was 1.0+/-0.5 cm/mo for infants and 0.6+/-0.4 cm/mo for toddlers; 50-71%
of the children showed increased acute phase proteins, 79-83% had malaria
parasitaemia and 55-64% had low serum retinol concentrations. In the total group
of children, serum AGP concentrations (r = -0.18; p = 0.03) and serum CRP
concentrations (r = -0.15; p = 0.05) showed a negative relation with length
increment. After correcting for micronutrient status, dietary intake and maternal
height, results of multiple regression analyses showed that the relation between
serum AGP concentration and subsequent length increment remained significant. We
conclude that, within the multifactorial model, presence of infections in these
Zambian children contributes to the short-term retardation of linear growth.
PMID- 10772278
TI - Deficits in attention, motor control and perception (DAMP): a simplified school
entry examination.
AB - OBJECTIVE: To suggest an empirically based school entry screening examination for
the detection of deficits in attention, motor control and perception (DAMP) in 6
y-old children. MATERIAL AND METHODS: A population-based cohort of 113 children,
6-7 y of age (62 with and 51 without DAMP), compared on measures of attention,
motor functions, language and cognition. RESULTS: Attention deficits were
convincingly identified by both parents and paediatrician. The motor function
tests clearly distinguished between the two groups. Linguistic and meta
linguistic tests demonstrated greater phonological processing difficulties in the
DAMP group. The cognitive test revealed an overall lower IQ but no consistent
characteristic pattern in the DAMP group. CONCLUSIONS: A simplified paediatric
school entry examination test is suggested. Four motor tests (standing on one
foot, Fog test, design copying and diadochokinesis) administered by the
paediatrician, combined with a brief structured clinical observation and a
structured parent interview, identified 80% of children with DAMP-and all those
with severe DAMP-as well as a small number of false positives.
PMID- 10772279
TI - Prevalence and characteristics of sexual abuse in a national sample of Swedish
seventeen-year-old boys and girls.
AB - The aims of this study, which was part of a survey on adolescent sexual
behaviour, were to investigate adolescents' experience of child sexual abuse and
to present possible abuse-related problems. Representative samples of 2% of
Sweden's 17-y-old male and female students and school non-attenders were selected
in a two-step procedure. In all, 1943 students and 210 school non-attenders
answered a self-administered anonymous questionnaire, distributed by school
nurses. Six out of 170 questions dealt with personal experiences of child sexual
abuse, i.e. age at onset, frequency of abuse and relationship to the offender.
Peer abuse was excluded by the definitions used. The overall response rate was
92.2% for students and 44.2% for school dropouts. Among male and female students,
3.1% and 11.2%, respectively, acknowledged sexual abuse, 2.3% and 7.1%,
respectively, when exhibitionism was excluded. Mean age at onset was 9.1 y (SD
4.3) for boys and 9.0 y (SD 3.9) for girls; 1.2% of the boys and 3.1% of the
girls reported abusive oral, vaginal and/or anal intercourse. Suicide attempts or
other acts of self-harm were reported by 33.3% of the male students reporting
abuse and by 5.1% (p < 0.001) of those who had not been abused, and by 30.4% of
the abused student girls compared to 9.1% of the non-abused (p < 0.001). Sleep
and eating disorders, use of alcohol at an early age and/or experimentation with
illicit drugs and consensual coitarche before age 15 y was reported significantly
more often by abused than non-abused girls (p < 0.001, differences not found
among the student boys). Of school non-attenders, 4% of the boys and 28% of the
girls reported sexual abuse. Of the abused girls, 49% reported abusive vaginal
intercourse and 64% reported self-destructive behaviour or suicide attempts. No
abused boys and few abused girls had confided in a teacher, health professional
or social worker. Results from the student sample should be interpreted as
markers of "minimum prevalence", as female school non-attenders report
significantly higher prevalence of sexual abuse. Potential high-risk groups are
better included in prevalence investigations of child sexual abuse. The fact that
so few adolescents confided in "professionals" about the abuse, despite having
severe symptoms and signs of distress, underlines the need to address sexual
abuse when recording the social, medical and psychiatric histories of
adolescents.
PMID- 10772280
TI - Clinical value of a single postnatal lactate measurement after intrapartum
asphyxia.
AB - Our aim was to compare the respective values of base deficit and lactate in birth
asphyxia. METHODS: Base deficit and lactate levels were measured from radial
artery blood samples taken at 30 min of life in 115 term newborns suspected as
having been asphyxiated during labour. Both base deficit and lactate levels were
compared between patients who further developed moderate or severe encephalopathy
and those who experienced no or only mild encephalopathy. Receiver operating
characteristics curves and clinical values of both indicators were computed.
RESULTS: The correlation between base deficit and lactate was significant (r2 =
0.51, p < 0.0001). Both indicators were significantly associated with neonatal
outcome. Lactacidaemia lower than 5 mmol/l and/or base deficit level lower than
10 mEq/l were not followed by neurological complications. Plasma lactate
concentration greater than 9 mmol/l was associated with moderate or severe
encephalopathy with a sensitivity of 84% and a specificity of 67%. Base deficit
and lactate had similar clinical values. CONCLUSIONS: Base deficit and lactate
measurements in arterial blood at 30 min of life are equally valuable in
assessing the severity of birth asphyxia.
PMID- 10772281
TI - Postnatal intestinal disturbances in small-for-gestational-age premature infants
after prenatal haemodynamic disturbances.
AB - Uteroplacental insufficiency leads to fetal growth retardation, which is a major
cause of perinatal and postnatal morbidity. In the present study we investigated
the relationship between prenatal haemodynamic disturbances and postnatal
intestinal perfusion and gastrointestinal function in small-for-gestational-age
neonates. Prospectively, 114 preterm neonates with a birthweight below 1500 g
were assigned to one of two groups according to their prenatal Doppler
sonographic measurements: neonates with or without prenatal haemodynamic
disturbances. We defined a pathological fetal perfusion by a pulsatility index of
uterine arteries, umbilical artery and fetal thoracic aorta above the 90th
percentile and by a pulsatility index of middle cerebral artery below the 10th
percentile of a normal group. We compared the postnatal respiratory and
intestinal adaptation in both groups as well as the blood flow velocity waveforms
of the superior mesenteric artery in all neonates. Postnatally, all 36 neonates
with prenatal haemodynamic disturbances were classified to be small for
gestational age. Thirty-one of these neonates developed abdominal problems with
delayed meconium passage, abdominal distension, bilious vomiting and a delay in
tolerating in enteral feeding within the first days of life. Six of them needed
surgical intervention, but none of these infants revealed typical signs of
necrotizing enterocolitis. In contrast, all neonates after normal prenatal
perfusion were classified to be appropriate for gestational age. Only 19 of 78
neonates of this group showed signs of intestinal disturbances postnatally. By
Doppler sonographic investigations we found significant lower systolic, mean and
end-diastolic flow velocities and higher pulsatility indices of the superior
mesenteric artery in neonates with prenatal haemodynamic disturbances. This may
occur as a result of postnatal persistent redistribution of regional blood flow
and results in gastrointestinal problems and may adversely affect gut motility.
PMID- 10772282
TI - Effect of indomethacin on IL-1beta, IL-6 and TNFalpha production by mononuclear
cells of preterm newborns and adults.
AB - The in vitro effect of indomethacin (IM) on the production of interleukin (IL)
1beta, IL-6 and tumor necrosis factor (TNF)alpha by cord blood mononuclear cells
(CBMC) from preterm newborns was compared to that of peripheral blood MC of
adults (PBMC). MC isolated from peripheral blood of adults (PBMC) and cord blood
of preterm newborns (CBMC) were incubated without or with lipopolysaccharide
(LPS) in the absence or presence of various concentrations of IM. The levels of
IL-1beta, IL-6 and TNFalpha in the supernatants were tested by ELISA. MC isolated
from preterm newborns were less sensitive to the in vitro effect of IM on IL
1beta and TNFalpha secretion than adult cells. While the spontaneous secretion of
IL-1beta and TNFalpha and the production of TNFalpha induced by LPS were
significantly increased following incubation of adult PBMC with IM, only the
spontaneous synthesis of TNFalpha by CBMC of preterm newborns was affected by
this drug. The in vitro production of IL-6 by MC in the two groups was not
affected by the addition of IM. It is suggested that IM may affect the preterm's
immune response. However, the role of the drug in the frequency and severity of
infections in the neonatal intensive care unit needs further investigation.
PMID- 10772283
TI - High total antioxidant activity and uric acid in tracheobronchial aspirate fluid
of preterm infants during oxidative stress: an adaptive response to hyperoxia?
AB - The effect of O2 exposure, expressed by mean daily fractional inspired oxygen
concentration (FiO2), was evaluated during the first 6 d of life in the
tracheobronchial aspirate fluid of 16 mechanically ventilated preterm infants in
terms of both antioxidant response and oxidative damage, by measuring total
antioxidant activity, uric acid concentrations and protein carbonyl content. Each
day linear regression analysis was performed and a positive correlation was found
between total antioxidant activity and FiO2 during the study period, especially
on day 2 of life (r = 0.91, p < 0.0001), but uric acid correlated only in the
first 3 d, especially on the 2nd day (r = 0.83, p < 0.0001). No correlation was
found between carbonyl content and FiO2. The highest values of total antioxidant
activity (416 and 790 micromol l(-1)) were found in 2 babies ventilated with
highest FiO2: 1 and 0.80, respectively. Total antioxidant activity was not
detectable or was very low in the babies not requiring O2 therapy. The highest
value of uric acid (270 micromol l(-1)) was found in the baby ventilated with
100% oxygen. Uric acid concentrations obtained in these babies were much higher
then those reported in the bronchoalveolar lavage fluid of adults. Preterm babies
seem to have an antioxidant response in the tracheobronchial aspirate fluid
following an oxidative stress and uric acid may be physiologically important as
an antioxidant of the respiratory tract, especially during the first days of
life.
PMID- 10772284
TI - Early predictors of adverse outcome in term infants with post-asphyxial hypoxic
ischaemic encephalopathy.
AB - A retrospective study of 35 term infants with post-asphyxial hypoxic-ischaemic
encephalopathy (HIE) was conducted to identify early clinical predictors of
either death or major motor disability at 18 mo of age. Twenty-three had severe
adverse outcome:13 died and 10 had major neurological sequelae. The significant
risk factors were a low 5 min Apgar score, use of adrenaline, low first arterial
pH and high base deficit. A base deficit > or =20 mEq/L is a useful predictor of
death or disability with a high positive predictive value (PPV) of 93.8%,
followed by 93.3% and 84.2% for pH <7.1 and 5 min Apgar score <4, respectively.
The PPV of death or disability is enhanced in the model combining base deficit of
> or =20 mEq/L and 5 min Apgar score of <4. This model has a sensitivity of 66.7%
and specificity of 100%. Severe metabolic acidosis of base deficit > or =25 mEq/L
was associated with a high risk of dying: PPV 77.8% and specificity 88.9%.
PMID- 10772285
TI - Magnetic resonance imaging at term and neuromotor outcome in preterm infants.
AB - In order to evaluate the value of neonatal brain magnetic resonance imaging (MRI)
for predicting neuromotor outcome in very low birthweight (VLBW) preterm infants,
51 such infants with gestational age <34 wk underwent brain MRI at term age.
Myelination, parenchymal lesions (haemorrhage, leukomalacia, infarction,
reduction of white matter), parenchymal lesions without subependymal haemorrhage,
ventricular/brain ratios and widths of the extracerebral spaces were assessed.
The MRI findings were compared with cranial ultrasound (US) performed at term.
Infants' neuromotor development was followed up until 18 mo corrected age.
Parenchymal lesions seen in MRI at term predicted cerebral palsy (CP) with 100%
sensitivity and 79% specificity, the corresponding figures for US being 67% and
85%, respectively. Parenchymal lesions in MRI, excluding subependymal
haemorrhages, predicted CP with a sensitivity of 82% and a specificity of 97%,
the corresponding figures for US being 58% and 100%, respectively. Delayed
myelination, ventricular/brain ratios and widths of the extracerebral spaces
failed to predict CP. Term age is a good time for neuroradiological examinations
in prematurely born high-risk infants. Parenchymal lesions seen in MRI are
reliable predictors for CP.
PMID- 10772286
TI - Upper airway obstruction as a presenting sign of achalasia in childhood.
PMID- 10772287
TI - Hormonal changes before and after dietary intervention in a patient with dumping
syndrome.
PMID- 10772288
TI - Acute hydrocephalus in carbon monoxide poisoning.
PMID- 10772289
TI - Breastfeeding and allergy counselling: theory and practice.
PMID- 10772290
TI - Breastfeeding rates among hyperphenylalaninemic infants.
PMID- 10772291
TI - Influence of fever on total cholesterol and triglyceride levels in childhood.
PMID- 10772292
TI - Haemophagocytic syndrome in Plasmodium falciparum malaria.
PMID- 10772293
TI - Severe injuries in children related to improvised sledging.
PMID- 10772294
TI - Mumps seroprevalence in an unvaccinated population in Izmir, Turkey.
PMID- 10772295
TI - High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic
jaundice.
PMID- 10772296
TI - Ambulatory management of acute pyelonephritis in children.
PMID- 10772297
TI - Immunological and virological effects of highly active antiretroviral therapy in
two HIV-1 infected children.
PMID- 10772298
TI - Assessing quality of life in patients with head and neck cancer: cross-validation
of the European Organization for Research and Treatment of Cancer (EORTC) Quality
of Life Head and Neck module (QLQ-H&N35).
AB - OBJECTIVE: To evaluate the reliability and validity of a new, disease-specific
quality-of-life measure for patients with head and neck cancer: the European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire--QLQ-H&N35. DESIGN: Cross-sectional study using questionnaire data
and medical chart review. SETTING: Academic tertiary care otolaryngology clinic.
PARTICIPANTS: One hundred twenty ambulatory patients, including 30 patients with
advanced head and neck cancer in each of the following stages of treatment: (1)
prior to treatment, (2) during active treatment, (3) within 6 months of
completing treatment, and (4) more than 6 months after completing treatment. In
addition, (5) a comparison group of 40 patients without malignant disease was
included (total sample, N = 160). MAIN OUTCOME MEASURES: Scores on EORTC Quality
of Life Core Questionnaire (QLQ-C30) and head and neck module (QLQ-H&N35),
Profile of Mood States, and Impact of Events Scale. RESULTS: The QLQ-H&N35
demonstrated acceptable reliability (internal consistency). It successfully
discriminated between cancer patients and the comparison group, and among
subgroups of cancer patients at different phases of treatment (construct
validity). The instrument was sensitive to the effects of radiation treatment and
to site of disease. Its low-to-moderate correlations with the EORTC core
questionnaire indicated that the QLQ-H&N35 provided unique information
(discriminant validity). Scores were significantly associated with a number of
demographic variables. CONCLUSION: Results support the use of this disease
specific measure to assess quality of life among patients with advanced head and
neck cancer.
PMID- 10772299
TI - Pediatric rhabdomyosarcoma of the head and neck: is there a place for surgical
management?
AB - OBJECTIVE: To review and evaluate the place of surgical treatment in the
management of rhabdomyosarcoma of the head and neck in children. DESIGN:
Retrospective analysis of patient charts from January 1, 1972, to December 31,
1998. SETTING: Tertiary pediatric referral center. PATIENTS: Twenty-nine
consecutive children with nonorbital head and neck rhabdomyosarcoma.
INTERVENTIONS: Surgery, chemotherapy, and radiotherapy. MAIN OUTCOME MEASURES:
Disease-free survival and long-term morbidity from treatment. RESULTS: Twenty
patients had parameningeal and 9 had nonparameningeal head and neck tumors. All
were treated with chemotherapy. For 18 patients, diagnostic biopsies were
performed and they received radiotherapy. Eleven patients underwent surgery as
definitive therapy. Using the Intergroup Rhabdomyosarcoma Study (IRS) staging
system, 5 of these 11 patients had complete resection of tumor (IRS group I) and
avoided radiotherapy. The other 6 patients required radiation because of
compromised, regional, or incomplete resection of tumor. One had undergone
regional resection with nodal involvement, and 2 had compromised resections with
microscopic residual disease (IRS group II). Three had incomplete resections with
gross residual tumor (IRS group III). Only 1 patient who underwent surgery
ultimately died from recurrence at 2.7 years after an incomplete resection. The
other 10 patients were relapse free at a median follow-up of 3.7 years (range 0.8
21.0 years). Long-term surgical morbidity was seen in 36% (4/11) of the patients
and included facial nerve paralysis, trismus, and cosmetic deformity.
CONCLUSIONS: Children with localized disease of the head and neck are able to
undergo complete surgical resection, with low long-term surgical morbidity. By
undergoing complete surgical resection, these children are able to avoid
radiotherapy and its long-term complications, with no compromise in survival.
PMID- 10772300
TI - Anti-CD3/anti-CD28 bead stimulation overcomes CD3 unresponsiveness in patients
with head and neck squamous cell carcinoma.
AB - OBJECTIVES: To test whether T-cell CD3 responses are altered in patients with
advanced-stage head and neck squamous cell carcinoma (HNSCC) and whether anti
CD3/anti-CD28 (alphaCD3/alphaCD28) bead stimulation could reverse CD3
unresponsiveness. DESIGN: Anti-CD3 (alphaCD3) monoclonal antibody immobilized on
tissue culture plastic was used to stimulate lymph node mononuclear cells (LNMCs)
and peripheral blood mononuclear cells (PBMCs) from patients with advanced-stage
HNSCC. Proliferation, T-cell phenotype, and cytokines were measured during 8-day
in vitro stimulation. Immune-enhancing properties of alphaCD3/ alphaCD28 beads
were also tested on LNMCs and PBMCs. Cytotoxicity of bead-activated T cells
(ATCs) was measured against autologous and allogeneic HNSCC. RESULTS: Six
patients were nonresponders to alphaCD3 stimulation defined by tritium (3H)
incorporation of less than 3500 cpm, whereas 11 patients were responders with 3H
incorporation of 3500 cpm or more. Responders produced higher levels of
interleukin (IL)-12 and interferon gamma (IFN-gamma) after alphaCD3 stimulation
than nonresponders. No phenotypic or clinical differences were identified between
groups. Stimulation with alphaCD3/alphaCD28 beads enhanced IFN-gamma and IL-2
produced by both groups. Bead ATCs were generated from PBMCs of patient 11 in the
responder group and lysed (+/- SD) 100% +/-1% of autologous tumor and 49% +/-1%
of allogeneic tumor. Bead ATCs from LNMCs of this patient lysed 58%+/-1% of
autologous tumor and 63%+/-1% of allogeneic tumor. CONCLUSIONS: A subpopulation
of patients with HNSCC who are nonresponders to alphaCD3 stimulation has been
identified, showing reduced proliferation and IL-12 and IFN-gamma secretion.
Nonresponders stimulated with alphaCD3/alphaCD28 beads reversed immune
unresponsiveness and induced a type 1 cytokine response. Bead-generated ATCs from
patient 11 in the responder group lysed autologous and allogeneic HNSCC in vitro,
suggesting a possible effective immunotherapeutic modality in the treatment of
HNSCC.
PMID- 10772301
TI - Snoring and obstructive sleep apnea in children: a 6-month follow-up study.
AB - BACKGROUND: Snoring children may present symptoms suggestive of obstructive sleep
apnea syndrome (OSAS). Different and controversial methods to establish the
diagnosis and to choose the treatment modalities have been proposed. OBJECTIVES:
To study children with symptoms raising the suspicion of OSAS with overnight
polysomnography (PSG). To evaluate the efficacy of adenotonsillectomy as
treatment of pediatric OSAS and to elucidate the natural history of OSAS and
primary snoring. DESIGN: A controlled, prospective, nonrandomized clinical trial.
SETTING: Academic medical center. SUBJECTS: Fifty-eight snoring but otherwise
healthy children aged 3 to 10 years with symptoms suggestive of OSAS underwent
PSG twice, 6 months apart. Thirty healthy children served as controls. RESULTS:
Twenty-seven children had OSAS with an obstructive apnea/hypopnea index greater
than 1, while 31 had primary snoring. There were statistical differences in the
symptoms and signs among the 3 study groups. Adenotonsillectomy was curative in
the 21 children with OSAS who were operated on. Obstructive apneas and hypopneas
in the healthy, nonsnoring children were almost nonexistent in this study.
CONCLUSIONS: Half of the children or fewer with symptoms suggestive of OSAS
actually had the condition. Clinical symptoms may raise the suspicion, but it is
not possible to establish the diagnosis without PSG. Because snoring and
obstructive symptoms may resolve over time, a normal PSG finding may help the
clinician decide on an observation period. Adenotonsillectomy is curative in most
cases of pediatric OSAS. Obstructive symptoms may continue after adenoidectomy
alone.
PMID- 10772302
TI - Efficacy of acupuncture as a treatment for tinnitus: a systematic review.
AB - BACKGROUND: Tinnitus is a prevalent condition for which patients may seek
treatment with acupuncture since no conventional treatment has been shown to be
effective. OBJECTIVE: To summarize and critically review all randomized
controlled trials on the efficacy of acupuncture as a treatment for tinnitus.
DATA SOURCES: Four independent computerized literature searches (MEDLINE,
Cochrane Controlled Trials Register, Embase, and CISCOM) were conducted in
December 1998 using the key words acupuncture and tinnitus. STUDY SELECTION: All
randomized controlled trials that compared any form of acupuncture with any
control intervention in the treatment of tinnitus were included. DATA EXTRACTION:
Data were extracted by 2 authors independently. The methodological quality of the
included randomized controlled trials was assessed using the Jadad score. DATA
SYNTHESIS: Six randomized controlled trials were included in the review, 4 of
which used crossover design. Four studies used manual acupuncture and 2 used
electroacupuncture. Five of 6 studies used inconsistent acupoints. Three studies
scored 3 points or more on the Jadad scale. MAIN OUTCOME MEASURES: Outcome
measurements were visual analog scale scores for loudness, annoyance, and
awareness of tinnitus; subjective severity scale scores for tinnitus; or
Nottingham Health Profile scores. RESULTS: Two unblinded studies showed a
positive result, whereas 4 blinded studies showed no significant effect of
acupuncture. CONCLUSION: Acupuncture has not been demonstrated to be efficacious
as a treatment for tinnitus on the evidence of rigorous randomized controlled
trials.
PMID- 10772303
TI - Impact of tonsillectomy and adenoidectomy on child behavior.
AB - OBJECTIVE: To measure the impact of tonsillectomy and adenoidectomy (T&A) on
children's behavioral and emotional problems using a standardized assessment.
DESIGN: Prospective study. SETTING: Tertiary care children's hospital. PATIENTS:
Thirty-six children, aged 2 through 18 years, with symptoms of nighttime snoring,
observed apneas, and daytime mouth breathing and physical examination results
demonstrating 3+ or 4+ tonsils scheduled for T&A. INTERVENTION: Parents completed
a standard survey of their children's symptoms of sleep apnea and a standardized
measure of children's competencies and problems, the Child Behavior Checklist for
ages 2 through 3 years or 4 through 18 years, before T&A and 3 months
postoperatively. MAIN OUTCOME MEASURE: The Child Behavior Checklist total problem
score. RESULTS: The preoperative Child Behavior Checklist total problem score was
consistent with abnormal behavior for 10 children (28%). After T&A (n = 15), only
2 scores were abnormal, but the change was not statistically significant. In
contrast, the mean total problem score was 7.5 points lower after surgery (95%
confidence interval, 5.1-9.7), indicating a significant decrease (P<.001, matched
t test). CONCLUSIONS: This pilot study demonstrates a high prevalence (28%) of
abnormal behavior in children undergoing T&A for chronic upper airway
obstruction. Scores on a standardized measure of behavior improve following T&A,
but larger studies with increased statistical power are needed to clarify the
degree of improvement and its clinical importance.
PMID- 10772304
TI - Delayed repair of transected nerves: effect of brain-derived neurotrophic factor.
AB - OBJECTIVE: To determine if administration of brain-derived neurotrophic factor
(BDNF) after peripheral nerve transection can improve the functional outcome in
situations where epineurial repair must be delayed. DESIGN: Randomized, blinded,
controlled trial. SUBJECTS: Thirty-four Sprague-Dawley rats. INTERVENTION:
Sciatic nerves were transected and, after a 2-week delay, repaired with
epineurial sutures. Animals were assigned to receive daily administration of
lactated Ringer solution (LR [control] group); BDNF delivered at the time of
nerve transection through 2 weeks after nerve repair, for a total of 4 weeks
(BDNF-early group); or BDNF delivered at the time of nerve repair through 2 weeks
after repair (BDNF-late group). Outcome was assessed using sciatic functional
indices (SFIs) and histomorphometric analysis. RESULTS: The SFI maximal recovery
was superior in the BDNF groups, but this difference did not reach statistical
significance (SFI, -90.1+/-9.6 [LR group], -85.7+/-7.6 [BDNF-early group], and
84.6+/-4.8 [BDNF-late group], where normal function is 0 and complete loss of
function is -100; P = .27). The mean axon diameter tended to be greater in the
BDNF groups compared with the LR group, i.e., 2.43+/-0.23 microm (LR group),
2.80+/-0.44 microm (BDNF-early group), and 2.83+/-0.38 microm (BDNF-late group)
(P = .05). CONCLUSIONS: The local administration of BDNF to nerves that underwent
transection and then repair after a delay resulted in an increase in axonal
diameters and maximal SFIs, a difference that did not reach statistical
significance. The timing of BDNF administration after nerve transection did not
affect neuronal regeneration.
PMID- 10772306
TI - First branchial cleft cyst excision with electrophysiological facial nerve
localization.
AB - OBJECTIVE: To assess the safety and efficacy of surgical excision of selected
first branchial cleft cysts using electrophysiological rather than anatomical
location of the facial nerve. DESIGN: Retrospective review of consecutive
surgical procedures by a single surgeon, using a consistent technique during a 9
year period. SETTING: Tertiary pediatric medical center. PATIENTS: Eleven
children with first branchial cleft cysts. INTERVENTIONS: Selected first
branchial cleft cysts were removed using a smaller surgical approach than that
generally advocated. The facial nerve was localized using electrophysiological
means rather than superficial parotidectomy and identification of the nerve trunk
and branches. MAIN OUTCOME MEASURES: Successful removal of the lesion, avoidance
of facial nerve injury, incidence of Fry syndrome, and cosmesis. RESULTS: Eleven
patients underwent surgical excision of first branchial cleft cysts during a 9
year period. Ten lesions were removed without the need for anatomical
localization of the facial nerve trunk. There was no facial weakness, recurrence
of the lesions, or Fry syndrome during a follow-up of 6 months to 7 years.
Cosmesis was superior. CONCLUSION: Electrophysiological location of the facial
nerve may, in the appropriate setting, replace anatomical localization for first
branchial cleft cysts that are (1) superior to the stylomastoid foramen and (2)
not previously infected or surgically violated.
PMID- 10772305
TI - Limitations of magnetic resonance imaging in the evaluation of perineural tumor
spread causing facial nerve paralysis.
AB - OBJECTIVE: To present and discuss the clinical presentation and treatment in
patients with long-duration unilateral facial paralysis and normal magnetic
resonance imaging (MRI) findings. DESIGN: Case series. SETTING: Ear, nose, and
throat department of the University of Cologne, Cologne, Germany. PATIENTS: A
total of 486 patients with unilateral facial paralysis who were treated from 1986
to 1998. Besides the usual diagnostic workup, a complete electrophysiological
evaluation, including investigations such as needle electromyography and
neuromyography (also known as electroneurography), of the facial nerve was
performed at repeated intervals. In 19 patients, a malignant tumor was delineated
with ultrasonography or MRI. In 8 of these patients, the initially performed MRI
did not detect any parotid gland lesion causing the paralysis, whereas long
duration of the paralysis and electroneurography indicated malignancy. RESULTS:
Exploration surgery was performed as total parotidectomy in these 8 patients and
malignant parotid gland tumors were proved in all 8 patients. CONCLUSIONS:
Individuals with facial nerve paralysis without any signs of regeneration 6
months after the onset of paralysis and/or persistent electrophysiological
evidence of ongoing neuronal degeneration should undergo surgical exploration of
the parotid gland and facial nerve, even if MRI studies show no tumoral lesion.
PMID- 10772307
TI - Carotid stenosis after radiotherapy for nasopharyngeal carcinoma.
AB - OBJECTIVE: To determine the prevalence and risk factors for radiation-induced
carotid stenosis in patients with malignant neoplasms of the head and neck.
DESIGN: Prospective cross-sectional screening of extracranial carotid stenosis by
color-flow duplex ultrasonography with an analysis of demographic and comorbid
risk factors. SETTING: Tertiary oncology and vascular referral center. PATIENTS:
The study included 96 consecutive patients (75 men and 21 women; mean age, 53.6
years) who had undergone cervical radiotherapy (RT) for nasopharyngeal carcinoma
more than 12 months ago. The mean post-RT interval was 79.9 months. Fourteen
patients had cerebrovascular symptoms. A group of 96 healthy individuals were
used as controls. MAIN OUTCOME MEASURES: Internal carotid stenosis and common
carotid artery stenosis were classified by duplex ultrasonography into moderate
(30%-69%), severe (70%-99%), and totally occlusive. RESULTS: Internal carotid
artery stenosis of 70% or more was detected in 14 arteries in 12 patients (6
occlusions). Common carotid artery stenosis of 70% or more was found in 11
arteries in 9 patients (4 occlusions). Overall, 15 patients (16%) had critical
stenosis in their common or internal carotid arteries, and another 20 (21%) had
stenosis in the moderate range. Critical carotid stenosis was not present in any
of the control subjects. Severe post-RT carotid stenosis was associated with age
(P = .003), smoking (P = .004), heart disease (P<.001), no prior oncological
surgery (P<.001), cerebrovascular symptoms (P<.001), and interval from RT
(P<.001). Smoking, interval from RT, cerebrovascular symptoms, and no head and
neck surgery were significant independent predictors for severe carotid stenosis
on multivariate logistic regression analysis. CONCLUSIONS: Patients who undergo
irradiation of the head and neck for more than 5 years have a higher risk of
developing significant carotid stenosis (relative risk, 15), and routine duplex
ultrasound screening is recommended.
PMID- 10772308
TI - Cytokine production by sinus lavage, bronchial lavage, and blood mononuclear
cells in chronic rhinosinusitis with or without atopy.
AB - BACKGROUND: Chronic sinus inflammation may be determined partly by a balance of
proinflammatory and counterregulatory cytokines and other mediators in the sinus.
However, their mechanistic roles in chronic rhinosinusitis (CRS) are not well
understood. OBJECTIVE: To evaluate production of proinflammatory (interferon
gamma [IFN-gamma] and interleukin [IL] 12) and counterregulatory cytokines (IL-10
and IL-4) by sinus lavage (SL), bronchial lavage (BL), and peripheral blood
mononuclear (PBMN) cells in patients with CRS. METHODS: We analyzed SL, BL, and
PB samples obtained at surgery from 26 patients with CRS. Cytokine production was
determined by culturing cells with or without stimuli. The results were evaluated
in comparison with other inflammatory variables (cytologic findings, total
protein, IgG, and lactose dehydrogenase), bacterial cultures, and clinical
features. RESULTS: Production of IFN-gamma by SL cells was variable and did not
correlate with other inflammatory variables, microbes grown, IL-10/IL-12p40
production by SL cells, or IFN-gamma production by BL or PBMN cells. Production
of IL-4 by lavage cells was undetectable. None of 10 patients with elevated IFN
gamma production (>800 pg/10(6) SL cells with mitogen stimuli) had allergic
rhinitis, whereas 12 of 16 patients with low IFN-gamma production (<500 pg/10(6)
SL cells) had allergic rhinitis with positive reactivity to common
aeoroallergens. There was no significant difference in other variables measured
between low and high IFN-gamma production groups. CONCLUSIONS: Elevated IFN-gamma
production by SL cells may indicate much less possibility of allergic rhinitis in
patients with CRS, but other variables measured did not differ in patients with
high or low IFN-gamma production by SL cells.
PMID- 10772310
TI - Resistance to botulinum toxin injections for spasmodic dysphonia.
AB - A known complication of botulinum toxin injections in the treatment of dystonia
has been the occasional development of resistance. This has been seen primarily
with patients who receive injections for torticollis. We report on 2 patients
who, after several years of receiving injections for spasmodic dysphonia,
developed clinical resistance by failing to have expected voice improvement after
receiving laryngeal reinjection. One of the 2 patients demonstrated antibodies to
botulinum toxin by mouse neutralization bioassay. The second patient had negative
bioassay results but had no clinical response to the test toxin injection of
facial muscles. These cases demonstrate that, although uncommon, resistance to
botulinum toxin injections can occur in the treatment of spasmodic dysphonia. We
offer suggestions to limit this complication.
PMID- 10772309
TI - Interferon gamma levels in the sinus, ear, and airway in a rabbit sinusitis model
induced by Bacteroides inoculation.
AB - BACKGROUND: Previously, we found minimal bacterial dissemination and no evidence
of systemic inflammation in a rabbit sinusitis model in which the left maxillary
sinus was inflamed by Bacteroides inoculation with the ostium closed. However, we
observed an increase in anti-Bacteroides IgG antibodies in the contralateral
sinus, lower airway, and middle ear, with an apparent increase in interferon
gamma (IFN-gamma) messenger RNA expression in the ear and sinus mucosa.
OBJECTIVE: To evaluate how IFN-gamma production in the upper and lower airway is
associated with localized bacterial sinusitis. DESIGN: Interferon gamma levels
were measured in lavage solutions from the sinus, airway, and middle ear and in
serum at 1, 2, 3, and 4 weeks following bacterial inoculation. SUBJECTS: The
subjects were 6 rabbits at each time point. The controls were untreated (n = 5)
and sham-operated (n = 4-5) rabbits at 2 and 4 weeks. INTERVENTION: Bacteroides
fragilis (10(8) plaque-forming units) was inoculated into the left maxillary
sinus. RESULTS: Interferon gamma levels in the ear and sinus were less than 0.2
microg/g protein in controls. Following bacterial inoculation into the left
sinus, IFN-gamma levels increased up to 10-fold in both sinuses and even more in
the middle ear at 3 weeks, independent of bacterial dissemination. Mean +/- SD
IFN-gamma levels in the airway (0.3+/-0.28 microg/g protein in controls) were not
altered by bacterial inoculation into the sinus. Serum IFN-gamma levels were very
low (<0.05 microg/g protein) in most rabbits and were unchanged by bacterial
inoculation. CONCLUSIONS: Interferon gamma levels increase in the ear and
contralateral sinus in response to localized sinus inflammation, indicating
concerted mucosal proinflammatory immune responses in the upper airway. Such
responses may lead to the aseptic middle ear inflammation often observed in
patients with chronic sinusitis.
PMID- 10772311
TI - Sarcoidosis of the pediatric larynx.
AB - Sarcoidosis is a chronic granulomatous disease of unknown pathogenesis. Reports
of sarcoidosis are much less common in the pediatric literature than in the adult
literature. The disease is usually systemic; rarely, however, single organs are
affected. Isolated laryngeal involvement is an unusual presentation. We report a
well-documented case of isolated laryngeal sarcoidosis in a 14-year-old white boy
who presented to our institution with a 6-month history of dysphonia, dyspnea on
exertion, and extremely sonorous snoring at night owing to his supraglottic
airway disease. To our knowledge, this is only the second case of isolated
laryngeal sarcoidosis reported in the pediatric literature. We review the
literature and discuss the differential diagnosis, diagnostic evaluation, and
treatment with carbon dioxide laser epiglottectomy and intralesional
glucocorticoid deposition, which resulted in marked resolution of our patient's
symptoms.
PMID- 10772312
TI - Cerebrospinal fluid otorrhea through a congenitally patent fallopian canal.
AB - Cerebrospinal fluid (CSF) otorrhea is a relatively rare entity that may occur
either as a spontaneous occurrence or as a result of trauma or surgery.
Spontaneous CSF leaks may be found during tympanocentesis, myringotomy, or tube
insertion for chronic middle ear effusion. Rapid identification of the problem
and timely treatment are required to avoid life-threatening complications such as
meningitis. The site of leakage must also be identified so that the disorder can
be treated effectively. Computed tomography, magnetic resonance imaging, and
radionucleotide localization scanning all play a role in the early identification
of the leakage site. A detailed knowledge of possible CSF leakage pathways aids
in evaluating imaging studies. We report 2 rare cases of CSF otorrhea through a
congenitally patent facial canal and their management.
PMID- 10772313
TI - Histopathologic study of the human eustachian tube and its surrounding structures
following irradiation for carcinoma of the oropharynx.
AB - OBJECTIVE: To describe a histopathologic analysis of a human temporal bone
demonstrating patulous changes of the eustachian tube (ET) and its surrounding
structures following radiation therapy. DESIGN: Retrospective histopathologic
case review and comparison with an age-matched control. SETTING: Elizabeth
McCullough Knowles Otopathology Laboratory, University of Pittsburgh School of
Medicine, Pittsburgh, Pa. RESULTS: A widened patulous ET was verified by
demonstrating fibrous tissue replacement of the surrounding supporting structures
related to the ET. The ET lumen was patulous and wider than the control case.
Ostmann fatty tissue, the levator veli palatini muscle, and submucosal glands
around the ET cartilage were replaced by dense connective tissue. CONCLUSION:
This is the first histopathologic report, to our knowledge, demonstrating the
effects on the ET lumen and supporting structures following acute weight loss,
possible tumor infiltration, and radiation changes for carcinoma of the
oropharynx.
PMID- 10772314
TI - Intracanalicular schwannoma of the facial nerve: a manifestation of
neurofibromatosis type 2.
AB - Primary facial nerve tumors, which are relatively uncommon, can present a
diagnostic dilemma based on their location and variable pattern of symptoms. Of
primary cranial nerve tumors, schwannomas of the facial nerve rank third in
frequency after those of the eighth and fifth cranial nerves. We report an
illustrative case of an intracanalicular schwannoma associated with several
central nervous system tumors, consistent with neurofibromatosis type 2.
Initially assumed to be an eighth cranial nerve tumor, the schwannoma was found
intraoperatively to arise from the facial nerve. Early diagnosis and treatment
enabled excision of the tumor without sacrifice of the facial nerve. Facial nerve
schwannomas can resemble acoustic schwannomas in their clinical presentation.
Only a heightened level of clinical vigilance will point to the correct diagnosis
and result in an optimal therapeutic outcome for patients with these rare tumors.
PMID- 10772315
TI - Quiz case 1. Periosteal osteosarcoma (PO) of the mandible.
PMID- 10772316
TI - Quiz case 2. Bilateral laryngocele.
PMID- 10772317
TI - The fallacy of preventing Frey syndrome during parotidectomy.
PMID- 10772318
TI - Unlocking the basic transduction and genetic aspects of olfaction.
PMID- 10772319
TI - Grafts in rhinoplasty: alloplastic vs. autogenous.
PMID- 10772320
TI - Grafts in rhinoplasty: autogenous grafts are superior to alloplastic.
PMID- 10772321
TI - Autogenous grafts are worth the extra time.
PMID- 10772322
TI - Helicoverpa armigera granulovirus interference with progression of H. zea
nucleopolyhedrovirus disease in H. zea larvae.
AB - Capsular proteins from Helicoverpa armigera granulovirus (HaGV) have previously
been shown to enhance H. armigera nucleopolyhedrovirus (HaSNPV) infection in H.
armigera larvae. Yet, HaGV and HaS-NPV, as viable viruses, interfered with one
another. In our study, we have examined the effects of co-infection of the slow
killing virus HaGV with the fast-killing virus Helicoverpa zea NPV (HzSNPV) on H.
zea larvae. The mortality parameter measured was survival time. Virus stocks had
50% lethal concentrations of 3.2x10(-9) g HaGV-infected cadavers (GVC) (HaGV) and
32 occlusion bodies (HzSNPV) per cup. Average survival times were 16.8 and 5.5
days for larvae treated with HaGV and HzSNPV, respectively; death of HzSNPV
treated larvae was as early as 72 h posttreatment. In co-infection experiments in
which larvae were treated concurrently with both viruses, the viruses competed in
typical fashion for host resources. However, interference with disease
progression in HzSNPV-fed larvae occurred even when HaGV was fed to larvae up to
36 h after the NPV, a time at which NPV infection should have been well
established in host larvae. At death, co-infected larvae were observed
microscopically to be filled with HaGV granules rather than HzSNPV polyhedra. The
time study results imply that HaGV might be outcompeting HzSNPV by inhibiting its
replication. We also observed that H. zea larvae treated with high dosages of
HaGV (> or =3x10(-5) g GVC) were initially stunted but had survival times similar
to those of larvae treated with lower dosages.
PMID- 10772323
TI - Comparative analysis of the binding of antibodies prepared against the insect
Spodoptera exigua and against the mycopathogen Nomuraea rileyi.
AB - Polyclonal antibodies were produced in mice against Spodoptera exigua (beet
armyworm) larval hemolymph and hemocytes and against cell wall surfaces of hyphal
bodies and hyphae of the entomopathogenic hyphomycete Nomuraea rileyi. In
addition to exhibiting strong activity against their original antigenic
substrates, all of the antibodies cross-react extensively with other substrates.
The hemolymph antibody binds to hemocytes and vice versa, and both antibodies
cross-react to the insect fat body basement membrane (extracellular matrix (ECM)
and to N. rileyi and Beauveria bassiana (another entomopathogenic fungus) cell
wall surfaces (ECM). Likewise, the anti-fungal antibodies cross-react with S.
exigua hemolymph and hemocytes, especially the granules that may contain ECM
components, and with fat body basement membrane. These cross-reactivities are
specific as indicated by negative controls in the microscopy and Western blotting
assays. Parallel labeling experiments using Con A suggest that the reactive
epitopes contain mannose; however, none of the antibodies bind to mannose
residues of nonentomopathogenic Candida albicans or Saccharomyces cerevisiae
yeast cells. Thus, these cross-reactivities suggest that the host mimicry
expressed by surface components of entomopathogenic fungi represents an important
pathogenic determinant.
PMID- 10772324
TI - Cytology of Leidyana canadensis (apicomplexa: eugregarinida) in Lambdina
fiscellaria fiscellaria larvae (lepidoptera: geometridae).
AB - The eugregarine Leidyana canadensis infects the larval gut of the eastern hemlock
looper, Lambdina fiscellaria fiscellaria. Guts of infected larvae were chemically
fixed, embedded in epoxy resin, and sectioned for light and electron microscopy
to describe the cytology of L. canadensis and its pathology in the larval host.
Oocysts of L. canadensis are ingested by larval hemlock looper. Trophozoites
emerge from the oocysts, pass through the peritrophic membrane into the
ectoperitrophic space, and attach to the epithelium of the midgut by means of an
apical epimerite. The epimerite does not actually penetrate the affected
epithelial cell; instead, it causes an invagination of the plasma membrane of the
cell. The center of the epimerite contains membrane cisternae, and mitochondria
line its periphery. Microtubules and mitochondria in the host cell cytoplasm
surround the epimerite. At the light microscopic level, there appeared to be
septa between the epimerite and the protomerite and between the protomerite and
the deutomerite; however, in the electron microscope, no septa were evident. Only
differences in the concentrations and nature of the inclusions in the cytoplasms
of these three regions were apparent. The deutomerite contains a single nucleus
in the central-posterior area. After an undetermined period, the epimerite
detaches from the host gut epithelium and is withdrawn into the protomerite, and
the trophozoites float freely in the ectoperitrophic space before differentiating
into gamonts. Division of the single, large nucleus into numerous small nuclei
appears to occur prior to syzygy. Gamonts pair and a cyst wall is laid down
around them, forming a gametocyst. Oocysts are extruded from mature gametocysts,
in chains, through sporoducts.
PMID- 10772325
TI - Expression of the insect parvovirus GmDNV in vivo: the structural and
nonstructural proteins are encoded by opposite DNA strands.
AB - The nucleotide sequence of GmDNV, an insect parvovirus, reveals large open
reading frames (ORFs) on both strands of the viral replicative form DNA.
Previously, we identified two viral transcripts within the polyadenylated RNA
fraction of infected host larvae (Gross et al., 1990, J. Invertebr. Pathol. 56,
175-180). In this work we used hybridization of single-stranded, unidirectional
probes to RNA blots to show that the two transcripts, synthesized in vivo in
GmDNV-infected Galleria mellonella larvae, are of antiparallel orientation. To
determine their coding specificities, polyadenylated RNAs were isolated from
hybrids with DNA from the left and right halves of the viral genome and
translated in a rabbit reticulocyte system. The "right," 2.4-kb hybrid-selected
RNA was shown to direct the synthesis of four polypeptides that comigrated with
the four viral capsid proteins and were immunoprecipitated with anti-GmDNV serum.
Translation of the "left," 1.8-kb RNA yielded three polypeptides, none of which
was detected among the viral capsid proteins. This type of expression strategy is
unique among vertebrate and most invertebrate parvoviruses, which use only one
DNA strand to encode all their proteins. On the other hand, the basic
organization of parvoviruses, in which the regulatory and structural proteins are
encoded, respectively, by two clusters of ORFs located at the left and right
halves of the genome, is conserved.
PMID- 10772326
TI - Molecular characterization and taxonomy of a new species of Caudosporidae
(Microsporidia) from black flies (diptera: simuliidae) with host-derived
relationships of the North American caudosporids.
AB - A new species of microsporidium, Caudospora palustris (Microsporidia:
Caudosporidae), is described from 3 species of black flies (Cnephia ornithophilia
and diploid and triploid cytospecies of Stegopterna mutata), bringing to 7 the
total species of caudosporids recorded from North America. This new species of
caudosporid is recorded from swamp streams of the Coastal Plain from New Jersey
to Georgia, with single records from the New Jersey mountains and the Upper
Peninsula of Michigan. Densities of patently infected larvae (up to 10,600/m2)
and spore production (nearly 8x10(11)/m2) are the greatest recorded for any
microsporidium of black flies. The ultrastructure of this new species is
presented, along with the first molecular characterization for a microsporidium
of black flies. The phylogenetic position of black fly microsporidia within the
phylum Microsporidia is presented; however, the analysis does not support the
inclusion of C. palustris in any clade. Key features of all North American
caudosporids are provided, and possible evolutionary trajectories are proposed
based on optimization of caudosporid species on the phylogeny of their 22 known
host species, including 16 that represent new host species records.
PMID- 10772327
TI - Virulence variability of the Drosophila C virus and effects of the microparasite
on demographic parameters of the host (Drosophila melanogaster).
AB - We carried out experiments with the Drosophila C virus (DCV), a nonhereditary
virus acting on demographic parameters of infected Drosophila host populations.
It is well known that DCV increases mortality rate, decreases developmental time,
and increases daily fecundity. As usual for Drosophila viruses, the DCV was
multiplied in vivo. In this study we tested the hypothesis of virulence
variability in DCV strains by isolating different stocks of the virus. The flies
were tested for susceptibility to injection of such isolates and for virulence
variability. Possible interactions between demographic parameters in three
Drosophila host populations and injected isolates were studied under two egg
densities (low and high). The hypothesis of virulence variability of DCV was
supported by significant differences in mortality rates, depending on whether
virus isolates were ingested or injected. When DCV was ingested, differences
between host mortality rates were independent of the Drosophila host populations.
Nevertheless, the developmental time was equally decreased by each virus isolate,
independent of the host population. Moreover, the two viral stocks strongly
increased the egg production of the flies. This experimental approach clearly
showed that DCV could be considered a polymorphic virus. The phenotypic
interactions between DCV and host flies varied according to parasite genotype.
PMID- 10772328
TI - Influence of insect larvae and seedling roots on the host-finding ability of
Steinernema feltiae (Nematoda: Steinernematidae).
AB - The ability of nematode foragers to locate appropriate insect hosts is essential
to their performance as successful biological control agents. We investigated the
host-finding ability and chemotaxis of Steinernema feltiae in the presence of
cues from Galleria mellonella larvae and tomato and radish seedling roots, given
individually and in combination, over 120 min. In agar arena tests, infective
juveniles of S. feltiae responded positively to unsterilized and sterilized
larvae and tomato seedling roots and negatively to unsterilized radish seedling
roots. This negative response changed following surface sterilization of these
seeds. The response of the infective juveniles to a combination of larva and
seedling roots depended on the nature of the individual cues and their proximity
to each other. For example, the response of the nematodes to a combination of
cues from a sterilized larva and an unsterilized tomato seedling root placed
adjacent to each other was intermediate to the separate responses to cues from a
sterilized larva and an unsterilized tomato seedling root given individually.
However, the response of the nematodes to a combination of adjacent cues from a
sterilized larva and an unsterilized radish seedling root was not significantly
different from that to cues from an unsterilized radish seedling root given
individually. When the cues from the larva and seedling roots were separated by a
distance, the response of the nematodes favored the larva. However, this positive
effect was lessened when the larva was surface sterilized as compared with the
response to the unsterilized larva. The altered responses of the infective
juveniles to target cues following surface sterilization suggest that cues from
the larval cuticle and seedling roots, such as those associated with their
surface microflora, may significantly influence their host-finding ability. The
use of entomopathogenic nematodes as biological control agents under field
applications can be improved by careful consideration of the application
protocols and by the recognition that chemical alterations of the soil
rhizosphere may influence their host-finding ability.
PMID- 10772329
TI - Changes in the electrophoretic profiles of gill mucus proteases of the eastern
oyster Crassostrea virginica in response to infection by the turbellarian
Urastoma cyprinae.
AB - Urastoma cyprinae occurs on the gills of various bivalves species, including the
eastern oyster Crassostrea virginica. While the worm is known to cause severe
gill disruption in mussels, no evidence of this nature has been described for
oysters. Nonetheless, high levels of U. cyprinae have been reported in oysters,
which may, in turn, reduce the oyster's overall condition. U. cyprinae is
strongly attracted to oyster gill mucus, which is suggested to play an active
role in the worm's feeding activities. Furthermore, host mucus contains many
active components, including proteases, which have been suggested to play a
defensive role against invading organisms. It follows, therefore, that some of
the interactions between U. cyprinae and oysters take place in host gill mucus.
Studies were undertaken to determine whether the presence of U. cyprinae altered
the electrophoretic profiles of oyster gill mucus, using proteases as indicators.
Findings reveal that oyster gill mucus contains three proteases, a putative acid
protease at 96 kDa, a zinc metalloprotease at 64 kDa, and a serine protease at 33
kDa. Results based on experiments using mucus preparations extracted from
infected and noninfected oysters, along with those using lyophilized mucus
incubated with live U. cyprinae, confirm that the presence of U. cyprinae alters
the protease composition of gill mucus. The present data demonstrate that both U.
cyprinae and host gill mucus actively secrete proteases. While the precise roles
of these enzymes still need to be defined, one of their functions may be
associated with digestion-related activities induced by the worm.
PMID- 10772330
TI - Prevalence and transovum transmission of Bacillus thuringiensis berliner in a
navel orangeworm colony.
PMID- 10772331
TI - Morphological and molecular characterization of the Thelohania solenopsae complex
(microsporidia: thelohaniidae).
PMID- 10772332
TI - Occurrence of Contracaecum sp. larvae (nematoda, anisakidae) in Gundlachia
radiata (Guilding, 1828) (mollusca, gastropoda, ancylidae) in Brazil.
PMID- 10772333
TI - Detection of Rickettsiales-like prokaryotes by in situ hybridization in black
abalone, Haliotis cracherodii, with withering syndrome.
PMID- 10772334
TI - The two faces of mutation: extinction and adaptation in RNA viruses.
AB - From a population standpoint, two main features characterize the replication of
RNA viruses and viruses that use RNA as a replicative intermediate: high genetic
variability, and enormous fluctuations in population size. Their genetic
variability mainly reflects a lack of the proof-reading and post-replicative
error correction mechanisms that operate during cellular DNA replication, but
recombination and segment exchange can also play an important role. Viral
population size can change tremendously as a consequence of transmission between
hosts or between different tissues within an infected host. A new infection can
be initiated with very few particles that subsequently expand many trillion-fold.
Repeated bottleneck events can lead to drastic fitness losses or even to viral
extinction, whereas continuously large population sizes result in fitness gains
and adaptation. Here we review experimental evidence for the effects of mutation,
selection, and genetic drift on the adaptation and extinction of RNA viruses.
PMID- 10772335
TI - Reactions of heme peroxidases with peroxynitrite.
AB - The interaction of peroxynitrite, produced by ozonation of azide, with two heme
peroxidases (horseradish peroxidase and lactoperoxidase) was studied. Enzymes
retained full activity after incubation with peroxynitrite at neutral pH.
Lactoperoxidase alone was found to catalyze peroxynitrite decomposition, whereas
horseradish peroxidase accelerated peroxynitrite decomposition only in the
presence of certain substrates. For example, in the presence of guaiacol the
catalyzing effect was clear, but in the presence of trolox was only noticeable.
PMID- 10772336
TI - Specific domain of cGMP-dependent protein kinase Ibeta but not Ialpha functions
as a transcriptional activator in yeast.
AB - Recently, cyclic GMP-dependent protein kinase (cGK) was shown to translocate to
the nucleus and regulate gene transcription. To determine whether cGK I proteins
function as transcriptional activators, we produced the constructs of cGK Ialpha
or Ibeta fused with the DNA binding domain of the yeast transcriptional activator
GAL4. Here, we demonstrate that the amino-terminal region of cGK Ibeta (amino
acids 1-107) exhibits transcriptional activation in yeast. However, full-length
cGK Ialpha and Ibeta and the amino-terminal region of cGK Ialpha had no
transcriptional activation function. Amino acid replacement in the leucine zipper
motif of the amino-terminal region of cGK Ibeta substantially reduced
transcriptional activation. These results suggest that the Ibeta-specific region
in cGK I proteins may interact with other proteins by way of the leucine zipper
motif and has a transcriptional activation function.
PMID- 10772337
TI - Study on the growth inhibition of human multiple myeloma cells by an IL-6Ralpha
mutant.
AB - DM650, a soluble human IL-6Ralpha mutant with mutation of C277D/H280I, was
previously shown to exhibit an antagonism to IL-6, which resulted in growth
inhibition of human multiple myeloma cell line AF-10 autocrining as the growth
stimulating factor. We investigated here the nature of the growth inhibition by
examining cell apoptosis. Flow-cytometric analysis of the DNA fragmentation
demonstrated that 7.2% of the AF-10 cells were apoptotic after 24 h of treatment
with DM650. The constitutive gene expression of bcl-2 in AF-10 cells indicated
that apoptosis suppressed by IL-6 was independent of bcl-2 regulation. The
altered gene expression of c-myc and p53 suggested that a novel apoptosis
pathway, other than that suppressed by IL-6, might be triggered by a complex of
DM650 and IL-6.
PMID- 10772338
TI - Regulation of human eIF4E by 4E-BP1: binding analysis using surface plasmon
resonance.
AB - The interaction between recombinant human eukaryotic initiation factor (eIF)4E
and recombinant glutathione S-transferase (GST)-fused human 4E-binding protein
(BP)1 was analyzed by using the surface plasmon resonance method. The association
rate of 4E-BP1 with eIF4E increased by about two orders of magnitude in the
presence of m7GTP (a model compound of mRNA cap structure), but the dissociation
rate was scarcely affected, indicating the cap-dependent binding of 4E-BP1 to
eIF4E. On the other hand, phosphorylation of 4E-BP1 weakened its interaction with
eIF4E whether m7GTP was present or not. However, phosphorylation of 4E-BP1
already associated with eIF4E or its m7GTP complex did not cause any change of
the association, probably because of incomplete phosphorylation. This suggests
that the regulation of eIF4E by 4E-BP phosphorylation is performed at its free
state, not when it is in the associated state with eIF4E. Given these results, we
discuss how 4E-BP regulates eIF4E at the first step of translation initiation.
PMID- 10772339
TI - Activity of pp60c-src and association of pp60c-src, pp54/58lyn, pp60fyn, and
pp72syk with the cytoskeleton in platelets activated by collagen.
AB - Collagen stimulation of platelets induced an increase in the specific activity of
pp60c-src immunoprecipitated from the Triton-soluble fraction. The earliest time
after collagen stimulation that an increase in pp60c-src activity was observed
was 30 s. However, the maximum activity of pp60c-src in the Triton-soluble
fraction was observed 60 s after collagen stimulation. At this time an
approximately twofold increase of pp60c-src activity towards phosphorylation of
KVEKIGEGTYGVVKK specific peptide and enolase and a 4.5-fold increase towards
phosphorylation of pp60c-src itself was measured. Furthermore, the majority of
pp60c-src as well as pp54/58lyn, pp60fyn, and pp72syk were found in the Triton
soluble fraction in resting platelets. Collagen induced, to different extents and
velocities, translocation of all of these proteins from the Triton-soluble
fraction to the Triton-insoluble, cytoskeleton-rich, platelets fraction. These
results provide direct evidence that collagen stimulation of platelets increases
the tyrosine kinase activity of pp60c-src and suggest that the platelet
cytoskeleton plays an important role in collagen-induced signal transduction by
localizing signaling molecules.
PMID- 10772340
TI - Tyrosine phosphorylation of a 34-kDa protein induced by cross-linking a novel
glycosylphosphatidylinositol-anchored glycoprotein (GPI-80) on human neutrophils
that may regulate their adherence and migration.
AB - We previously found a novel glycosylphosphatidylinositol (GPI)-anchored
glycoprotein designated GPI-80 that modulates complement receptor 3 integrin
dependent adhesion and in vitro transendothelial migration of neutrophils. In
this study, we show that antibody-mediated cross-linking of GPI-80 led to rapid
tyrosine phosphorylation mainly of a 34-kDa protein (pp34). Chemical inhibitors,
such as genistein, sodium orthovanadate, wortmannin, cytochalasin B, Ro 31-8220,
and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid inhibited this
response, whereas pertussis toxin had no effect. These findings demonstrate that
the tyrosine phosphorylation of pp34 by cross-linking GPI-80 in human neutrophils
involves tyrosine kinases, tyrosine phosphatases, phosphatidylinositol 3-kinase,
cytoskeleton reorganization, protein kinase C, and cytoplasmic calcium, but not
heterotrimeric G proteins.
PMID- 10772341
TI - Specific processing of poly(ADP-ribose) polymerase, accompanied by activation of
caspase-3 and elevation/reduction of ceramide/hydrogen peroxide levels, during
induction of apoptosis in host HL-60 cells infected by the human granulocytic
ehrlichiosis (HGE) agent.
AB - We studied the mechanism by which the human granulocytic ehrlichiosis (HGE) agent
induces programmed cell death (apoptosis) in human promyelocytic HL-60 leukemia
cells. Using several New York HGE isolates, we show that the HGE agent-elicited
apoptosis is accompanied by increased processing of nuclear enzyme poly(ADP
ribose) polymerase (PARP), concurrent with a noticeable increase in caspase 3
activities. A marked increase in the amounts of the signaling molecule ceramide
but not of diacylglycerol was also observed in HGE agent-infected HL-60 cells,
compared with the amounts in uninfected controls. Simultaneous or prior treatment
of infected HL-60 cells with the ceramide synthase inhibitor fumonisin B1 did not
affect the magnitude of infection by the intracellular pathogen, as determined by
both the presence of morulae and the expression of its outer surface membrane
protein, p44. These results suggest that the observed changes in ceramide are
generated through the sphingomyelinase pathway and not by way of de novo
synthesis of ceramide. We also assayed for changes in intracellular hydrogen
peroxide and show that the HGE agent causes a decrease in its concentrations in
infected cells.
PMID- 10772342
TI - Expression of murine poly(A) binding protein II gene in testis.
AB - The poly(A) binding protein II gene (PAB II) has been highly conserved among
mouse, bovine, and human. The promoter region of the murine PAB II gene (mPAB II)
was investigated in this study. Primer extension analysis demonstrated that there
are multiple sites for starting transcription. The promoter region of mPAB II
gene contains a CpG island but lacks a TATA box, suggesting that the mPAB II mRNA
is transcribed by a TATA-less promoter. Two transcription factor binding sites
flanking the major transcription start site were confirmed by gel shift assay.
The transcription level of the mPAB II gene in testis increases during
spermatogenesis, and mPAB II protein accumulates densely in the nuclei of
spermatocytes and round spermatids.
PMID- 10772343
TI - Specific sequence of motifs of mitochondrial uncoupling proteins.
AB - We have searched for the exclusivity of common sequence motifs of the
mitochondrial uncoupling proteins (UCP1, UCP2, UCP3, UCP4, BMCP1, and plant UCP
[PUMP]) within the gene family of mitochondrial anion carrier proteins. The UCP
specific sequences, "UCP signatures", were found in the first, second, and fourth
alpha-helices. First: Ala/Ser-Cys/Thr/n-n/Phe-Ala/Gly-[negatively charged
residue]-n/Phe-n/Cys-Thr-Phe/n; second: Gly/Ala-Ile/Leu-Gln/X-[positively charged
residue]-NH-n/Cys-Ser/nphi/X-n/Ser-OH/Gly-n-[positively charged residue]-Ile/Met
Gly/Val-n/Thr; fourth: Pro-Asn/ Thr-n-X-[positively charged residue]-Asn/Ser/Ala
n-n-Ile/Leu-n-Asn/Val-Cys/n-n/Thr-[negatively charged residue]-n-n/Thr/Pro-OH/Val
(n, nonpolar; phi, aromatic; (positively charged residue/negatively charged
residue, charged residue). The second and part of the third signature are also
present in the yeast dicarboxylate transporter. The UCP signature excluding BMCP1
was also found in the second matrix segment: [positively charged residue]-(Pro/
del-Leu/del)-[positively charged residue]-phi-X-Gly/Ser-Thr/n-X-NH/[negatively
charged residue]-Ala-phi. These UCP signatures are thought to be involved in
fatty acid anion binding and translocation.
PMID- 10772344
TI - Cloning and characterization of two cDNAs encoding sulfatases in the Roman snail,
Helix pomatia.
AB - The sulfatase from the snail Heli pomatia is widely used for analytical
applications. We have investigated the content of sulfatases in H. pomatia, using
a biochemical and a molecular approach. A 112-kDa protein from the intestinal
juice of H. pomatia comigrated with sulfatase activity when chromatographed on
Sephacryl S300 and concanavalin A-Sepharose. The N-terminal amino acid sequence
of the protein was similar to one of three sulfatase motifs defined by sequence
alignment of known sulfatases. Degenerate primers designed from the motifs and
the N-terminal amino acid sequence obtained were used to generate PCR fragments
and to isolate both a full-length and a 3'-truncated cDNA encoding H. pomatia
sulfatases, designated SULF1 and SULF2. SULF1 consists of 503 amino acids and
shows 53-55% identity to the mammalian arylsulfatase B. The amino acid sequence
deduced from the 878-bp SULF2 cDNA fragment is 55% identical with SULF1. Both
SULF1 and SULF2 contain the cysteine residue conserved in the active site of many
sulfatases, which is known to be posttranslationally modified into formylglycine
in eukaryotic sulfatases. However, the SULF1 and SULF2 cDNAs do not code for the
protein purified. This indicates the presence of at least three sulfatase genes
in H. pomatia.
PMID- 10772345
TI - Polymerization of actin induced by a molar excess of ATP in a low salt buffer.
AB - The polymerization of actin induced by dilution has previously been reported,
where a 1000-fold molar excess of ATP over actin resulted when actin was diluted
to 4.0 microg/ml in low salt buffer A (0.1 mM ATP, 0.1 mM CaCl2, 2 mM Tris-HCl,
pH 8.0, 5 mM 2-mercaptoethanol, 1 mM NaN3). Filaments formed by the addition of
ATP to a 1000-fold molar excess over actin in buffer B (0.1 mM CaCl2, 2 mM Tris
HCl, pH 8.0, 1 mM NaN3) were then separated by gel-filtration. When ATP was
removed from these filaments using Dowex-1, depolymerization occurred. Thus, the
reversible polymerization induced by the dilution of actin or by addition of ATP
can be ascribed to the binding of ATP at the low affinity site of actin.
PMID- 10772347
TI - Dimensions of early childhood behavior problems: stability and predictors of
change from 18 to 30 months.
AB - The prevalence, structure, stability, and predictors of change in early behavior
problems were examined in a population-based sample of Norwegian children at 18
and 30 months of age (N = 750). A clear factor structure involving four
dimensions emerged at both assessment times: Two factors were characterized by
externalizing behaviors and were labeled Social Adjustment and Overactive
Inattentive; one factor tapped internalizing problems and was labeled Emotional
Adjustment; and the fourth, related to general immaturity, was labeled
Regulation. Specific patterns of child and family risk factors were associated
with stability and change over the two time points for each factor. Children with
stable problems had the most problematic characteristics on all significant
predictors, followed by children with problems at one, but not both, time points.
The data suggest that it is possible to identify risk factors for stable problems
at 18 months, allowing some prediction of those children whose problems will
persist over early childhood. Since specific risk factors emerged for specific
types of behavior problems, the results may provide some much-needed guidance to
early intervention efforts.
PMID- 10772346
TI - Genetic studies of autism: from the 1970s into the millennium.
AB - Reviewers in the 1960s and early 1970s were skeptical about any substantial role
for genetic factors in the etiology of autism. A realization that the 2% rate of
autism in siblings (as estimated at that time) was far above the general
population base rate, and that this suggested a possible high genetic liability,
led to the first small-scale twin study of autism. The replicated evidence from
both twin and family studies undertaken in the 1970s and 1980s indicated both
strong genetic influences and the likelihood that they applied to a phenotype
that was much broader than the traditional diagnostic category of autism. Medical
and chromosomal findings also indicated genetic heterogeneity. Advances in
molecular genetics led to genome-wide scans of affected relative pair samples
with a positive log of the odds to base 10 score for a location on chromosome 7.
The major remaining research challenges and the likely clinical benefits that
should derive from genetic research are considered in relation to both current
knowledge and that anticipated to emerge from research over the next decade.
PMID- 10772348
TI - More than the terrible twos: the nature and severity of behavior problems in
clinic-referred preschool children.
AB - The primary goals of this study are to describe the nature and severity of
disruptive behavior problems in clinic-referred preschoolers from low-income
environments and to explore the validity of DSM-IV disruptive disorders for young
children. We examine the relation between DSM-IV symptoms, standardized behavior
checklists, and observational ratings as a means of exploring measurement
validity in this age group. Seventy-nine clinic-referred preschoolers (ages 2
through 5 years) from low-income environments were assessed. To examine whether
clinic-referred preschool children have symptoms that are consistent with DSM-IV
disruptive behavior disorders, parents were administered a semistructured
diagnostic interview, modified for developmentally appropriate usage. In
addition, parents completed the Child Behavior Checklist (CBCL) and children's
behavior problems were assessed with observational ratings during parent-child
interaction. Nearly half of the sample met criteria for conduct disorder, and
three quarters met criteria for oppositional defiant disorder. Preliminary
evidence for the validity of DSM-IV disruptive disorders in preschool children
was demonstrated through association with CBCL scores, behavior ratings, and
significant levels of impairment. Future efforts aimed at validating these
diagnoses in preschoolers and implications for prevention are discussed.
PMID- 10772349
TI - Correlates of mental disorders in the Quebec general population of 6 to 14-year
olds.
AB - Previous epidemiological studies of correlates of child and adolescent mental
disorders in the general population have focused more on child/adolescent and
socioeconomic/sociodemographic characteristics than on family characteristics.
Moreover, there are no generally accepted methods to analyze and interpret
correlates. The purpose of the Quebec Child Mental Health Survey in this regard
was twofold: (1) to identify correlates of DSM-III-R internalizing and
externalizing disorders according to informant (youth, parent, teacher), for
three age groups (6-8, 9-11, and 12-14 years), including relevant family
characteristics not considered in previous studies; and (2) to interpret the
relative importance of risk indicators by ranking correlates according to
strength and consistency of association across age groups. Logistic regression
models suggest the inconsistency of correlates across informants. The ranking of
correlates reveals that individual and family characteristics make a more
important contribution than do socioeconomic characteristics, thereby supporting
the relevance of proximal variables in the development of psychopathology.
PMID- 10772350
TI - What do youth referred for anxiety problems worry about? Worry and its relation
to anxiety and anxiety disorders in children and adolescents.
AB - This study examined worry and the parameters of worry that may be associated with
clinical anxiety in a sample of 119 children and adolescents referred to a
childhood anxiety disorders specialty clinic. Using an interviewing procedure,
results indicated that the types of worries reported by the children were similar
to those reported in previous studies of nonreferred community children. Also
similar to previous community studies were findings showing moderate but
significant correlations between different indices of worry (i.e., number,
intensity, and frequency of the worries) and children's scores on self-rating
scales of anxiety. Results further indicated that worry contributed additional
variance beyond that of anxiety in predicting fear. In addition, intensity
differentiated clinic children's worries from nonreferred children's. Intensity
and number of worries differentiated subsamples of children within the clinic
referred sample (i.e., children with overanxious disorder or generalized anxiety
disorder and children with simple phobia). The importance of examining children's
worries to further understand anxiety and its disorders in youth is discussed.
PMID- 10772351
TI - Emotion regulation and parenting in AD/HD and comparison boys: linkages with
social behaviors and peer preference.
AB - Children's emotion regulation strategies and parenting responses in a family task
that elicited frustration are investigated by comparing core attention
deficit/hyperactivity disorder (AD/HD) symptomatology, emotional reactivity, and
emotional regulation in the prediction of social behaviors and peer social
preference. Participants were boys, ages 6-12 years, either with AD/HD (n = 45)
or without problem behaviors (comparison; n = 34). A high-aggressive subgroup of
AD/HD boys showed a significantly less constructive pattern of emotional coping
than did both a low-aggressive AD/HD subgroup of boys and nondiagnosed comparison
boys, who did not differ. With statistical control of core AD/HD symptomatology,
noncompliance in a naturalistic summer camp was predicted by boys' overall
emotion regulation and three specific strategies (emotional accommodation,
problem solving, negative responses) during the parent-child interaction.
Emotional accommodation and negative responses to the frustration task also
marginally predicted social preference at the camp. These emotion regulation
variables outperformed emotional reactivity in predicting such outcomes. Some
emotion-related parenting behaviors were associated with child coping in the
task. We discuss the relationship of emotion regulation to core AD/HD
symptomatology and emotional reactivity, and the role of parents' behaviors in
influencing children's emotional responses.
PMID- 10772352
TI - Maternal acceptance and consistency of discipline as buffers of divorce stressors
on children's psychological adjustment problems.
AB - This study examines whether two aspects of mothering--acceptance and consistency
of discipline--buffer the effect of divorce stressors on adjustment problems in
678 children, ages 8 to 15, whose families had divorced within the past 2 years.
Children reported on divorce stressors; both mothers and children reported on
mothering and internalizing and externalizing problems. Multiple regressions
indicate that for maternal report of mothering, acceptance interacted with
divorce stressors in predicting both dimensions of adjustment problems, with the
pattern of findings supporting a stress-buffering effect. For child report of
mothering, acceptance, consistency of discipline, and divorce stressors
interacted in predicting adjustment problems. The relation between divorce
stressors and internalizing and externalizing problems is stronger for children
who report low acceptance and low consistency of discipline than for children who
report either low acceptance and high consistency of discipline or high
acceptance and low consistency of discipline. Children reporting high acceptance
and high consistency of discipline have the lowest levels of adjustment problems.
Implications of these results for understanding variability in children's
postdivorce adjustment and interventions for divorced families are discussed.
PMID- 10772353
TI - Design and pilot evaluation of a system to develop computer-based site-specific
practice guidelines from decision models.
AB - BACKGROUND: Local tailoring of clinical practice guidelines (CPGs) requires
experts in medicine and evidence synthesis unavailable in many practice settings.
The authors' computer-based system enables developers and users to create,
disseminate, and tailor CPGs, using normative decision models (DMs). METHODS:
ALCHEMIST, a web-based system, analyzes a DM, creates a CPG in the form of an
annotated algorithm, and displays for the guideline user the optimal strategy.
ALCHEMIST'S interface enables remote users to tailor the guideline by changing
underlying input variables and observing the new annotated algorithm that is
developed automatically. In a pilot evaluation of the system, a DM was used to
evaluate strategies for staging non-small-cell lung cancer. Subjects (n = 15)
compared the automatically created CPG with published guidelines for this staging
and critiqued both using a previously developed instrument to rate the CPGs'
usability, accountability, and accuracy on a scale of 0 (worst) to 2 (best), with
higher scores reflecting higher quality. RESULTS: The mean overall score for the
ALCHEMIST CPG was 1.502, compared with the published-CPG score of 0.987 (p =
0.002). The ALCHEMIST CPG scores for usability, accountability, and accuracy were
1.683, 1.393, and 1.430, respectively; the published CPG scores were 1.192,
0.941, and 0.830 (each comparison p < 0.05). On a scale of 1 (worst) to 5 (best),
users' mean ratings of ALCHEMIST'S ease of use, usefulness of content, and
presentation format were 4.76, 3.98, and 4.64, respectively. CONCLUSIONS: The
results demonstrate the feasibility of a web-based system that automatically
analyzes a DM and creates a CPG as an annotated algorithm, enabling remote users
to develop site-specific CPGs. In the pilot evaluation, the ALCHEMIST guidelines
met established criteria for quality and compared favorably with national CPGs.
The high usability and usefulness ratings suggest that such systems can be a good
tool for guideline development.
PMID- 10772354
TI - A comparison of human and machine-based predictions of successful weaning from
mechanical ventilation.
AB - PURPOSE: To evaluate the ability of an appropriately trained neural network to
correctly interpret a set of weaning parameters to predict the liberation of a
patient from mechanical ventilation, and to contrast these predictions with those
of human experts restricted to the same limited set of physiologic data. METHODS:
For each set of weaning parameters, a prediction was made by multiple
realizations of a neural network and six expert volunteers. RESULTS: The
percentage of correct predictions made by the neural network when the decision
threshold was set to 0.5 (range 0-1) was 83.3 +/- 4.2 (mean +/- SD) and that for
the experts was 83.3 +/- 4.7. Predictions by the network when the threshold was
0.5 had a sensitivity of 0.83 and a specificity of 0.84, compared with 0.90 and
0.77, respectively, for the experts. However, sensitivity and specificity
comparable to those of the human experts could be obtained by adjusting the
decision threshold of the network predictor so that only the most clearly
ventilator-dependent patients would not be given a trial of extubation.
CONCLUSION: When both are restricted to the same limited set of patient data,
appropriately trained neural networks can be as effective as human experts in
predicting whether weaning from mechanical ventilation will be successful.
PMID- 10772355
TI - Using localization data from image interpretations to improve estimates of
performance accuracy.
AB - A recently developed model uses the localization of abnormalities on images to
improve statistical precision in measuring detection accuracy Az, the area below
an observer's receiver operating characteristic (ROC) curve for ratings of
sampled normal and abnormal cases. This study evaluated that improvement by
investigating how much the standard error of estimated Az decreased when the
statistical analysis included localization data. Comparisons of analyses with vs
without localizations were made for: 1) the estimates of Az from observers'
rating ROC curves for nodular lesions on clinical chest films and liver CT scans;
2) the probability of correct choices between paired samples of normal and
abnormal cases (equivalent to Az); and 3) the sampling distributions of Az
measured in Monte Carlo simulations of 2,000 independent rating experiments.
Localization information considerably improved the precision of Az estimates,
particularly when detection accuracy was low (Az approximately 0.60). These data
provided roughly the same benefits in estimation precision as would two-to
fourfold increases in the sizes of both 1) the samples of positive and negative
cases and 2) the observer samples used to estimate Az means.
PMID- 10772356
TI - Response shift and adaptation in chronically ill patients.
AB - The purpose was to explore the impact of response shift on quality-of-life
measurement and consequently on cost-effectiveness analysis. This was done by
using data from an earlier study. Adaptation to illness provides a probable
explanation for the occurrence of response shift. In the case of proxy
respondents, it is likely that the adaptation effect is absent. Therefore, two
hypotheses were tested: 1) retrospective quality-of-life measurement does not
differ from ratings given by proxies; and 2) proxy ratings differ from
prospectively assessed pretreatment quality-of-life scores. Quality of life was
assessed using a visual analog scale (VAS), time tradeoff (TTO), and the standard
gamble (SG). Analyses revealed that neither hypothesis could be rejected,
indicating that prospectively assessed pretreatment quality of life is enhanced
by adaptation to the imperfect health state during the pretreatment period.
Consequently, the cost-effectiveness ratio is different when using proxy measures
or retrospective assessments of pretreatment quality of life, compared with using
assessments of the quality of life in currently ill patients.
PMID- 10772357
TI - The discrete-choice willingness-to-pay question format in health economics:
should we adopt environmental guidelines?
AB - The use of willingness to pay (WTP) in valuing the benefits of health care
programs is increasing. Although such values have been derived using open-ended,
bidding, or payment-card techniques, recently discrete-choice questionnaires have
been advocated, particularly following the report of the National Oceanographic
and Atmospheric Administration concerning the validity of using WTP to estimate
environmental benefits. It is argued that discrete-choice questions offer a more
realistic market, and will therefore lead to more valid responses and yield
higher response rates through reduced mental demands. The author reviews these
issues in a critical assessment of discrete-choice questions.
PMID- 10772358
TI - Income effects of reduced health and health effects of reduced income:
implications for health-state valuation.
AB - There is increasing use of multiattribute health-state utility systems, such as
the Health Utilities Index and the EuroQol (now EQ-5D), to estimate quality
adjusted life years (QALYs) for cost-utility analysis. Whereas the preferences
elicited from individuals using willingness-to-pay techniques for cost-benefit
analysis would be expected to reflect those individuals' income levels, it is
often suggested that cost-utility analysis can avoid this income effect by not
valuing health in monetary terms. Contrary to this view, the authors argue that
income can influence the measurement of utilities used to estimate QALYs. In the
context of multiattribute utility instruments, two income effects can take place:
1) when individuals are asked to value health states to generate the set of
utilities to apply in subsequent evaluation studies; 2) when those multiattribute
systems are used to categorize individuals' (usually patients') health status in
the field in applied evaluation studies. The authors review the most popular
utility systems regarding how these income effects are handled and assess the
implications for the measurement of utilities using these systems.
PMID- 10772359
TI - Withholding information from cancer patients as a physician's decision under
risk.
AB - When cancer is diagnosed, the physician may face a dilemma regarding disclosure
of information to the patient. While he or she may feel a responsibility to
maintain the patient's hope, even through the withholding of information, there
is a risk involved: if treatment fails, the patient will eventually know the
truth. Patients who would rather live their final days in peace rather than
undergo unpleasant treatment of an uncertain nature may be furious and frustrated
that they have been deprived of this liberty, ending their lives feeling worse
than they would have had they been told the truth at the outset. The author
applies three theories of decision making under uncertainty (expected utility
theory, prospect theory, and regret theory) to the physician's problem of whether
and to what extent to withhold information from a cancer patient, deriving
comparative predictions with regard to the relationships between the physician's
behavior and illness, patient, and physician characteristics. The results help
explain why physicians whose norm of behavior is full disclosure sometimes opt to
withhold information and why junior physicians are more likely to disclose the
truth than their senior colleagues, as well as the empirical findings that
physicians tend to disclose more truthful information to patients the greater the
severity of illness and the more inquisitive the patient.
PMID- 10772360
TI - Perception of quantitative information for treatment decisions.
AB - The study was designed to determine which formats for displaying quantities, such
as probabilities of treatment risks and benefits, are perceived most accurately
and easily by patients. Accuracy and speed of processing were compared for six
different presentation formats: pie charts, vertical bars, horizontal bars,
numbers, systematic ovals, and random ovals. Quantities were used in two tasks: a
choice task that required larger/smaller judgments and an estimate task that
required more precise evaluation. The impacts of blue-yellow color and of a
treatment-decision context on performance in the two tasks were also
investigated. The study included four experiments. Taken together the results
suggest that the formats best for making a choice differ from those best for
estimating the size of an amount. For making a choice, vertical bars, horizontal
bars, numbers, and systematic ovals were equally well perceived; pie charts and
random ovals caused slower and less accurate performances. For estimating,
numbers led to the most accurate estimates, followed by systematic ovals. The
other four formats led to the least accurate estimates. Color and context did not
alter which formats were best.
PMID- 10772361
TI - Five minutes with the Governor.
AB - This paper aims to initiate a dialog among readers regarding the positioning and
promotion of health-related decision analysis in the public sector. It is
motivated by the author's personal observations that quantitative and economic
evaluation methods continue to be viewed with skepticism by some public officials
and that no consensus exists within our community as to what an appropriate
message to such decision makers might be. A personal view of some key themes to
be stressed in defining a vision for the field is presented.
PMID- 10772362
TI - Artificial neural networks: are they ready for use as clinical decision aids?
PMID- 10772363
TI - Law and ethics.
PMID- 10772364
TI - Judgmental psychology.
PMID- 10772365
TI - Tissue plasminogen activator inhibits reactive oxygen species production by
macrophages.
AB - STUDY OBJECTIVE: To determine whether tissue plasminogen activator (tPA) alters
macrophage reactive oxygen species (ROS) production. INTERVENTION: Cultured
macrophages were exposed to either phorbol myristate acetate (PMA) or zymosan
(ZMA) after a 1-hour incubation with either tPA 100 microg/ml or L-arginine 3.5
mg/ml, an excipient used in the formulation of tPA. MEASUREMENTS AND MAIN
RESULTS: Production of ROS was measured using chemiluminescence (CL). Tissue
plasminogen activator reduced the mean peak CL of macrophages exposed to PMA or
ZMA by 20% and 36%, respectively (p=0.0008 and p=0.028, analysis of variance). L
arginine had no effect on either PMA- or ZMA-induced macrophage CL. CONCLUSION:
Our results suggest that tPA has broad inhibitory effects on inflammatory cell
ROS production. In diseases such as atherosclerosis and acute respiratory
distress syndrome, these data suggest the possible utility of exogenous tPA as an
antiinflammatory agent and a physiologic role for endogenous tPA that goes beyond
maintenance of homeostasis.
PMID- 10772366
TI - Assessment of the drug interaction between alteplase and nitroglycerin: an in
vitro study.
AB - Alteplase is the most commonly administered thrombolytic agent in the United
States. However, concurrent therapy with nitroglycerin reduces plasma alteplase
concentrations and its clinical efficacy. We sought to determine if this
interaction is concentration and pH dependent. Seventy plasma samples were
prepared and divided into three groups: alteplase 500 IU/ml alone (group 1),
alteplase 500 IU/ml plus nitroglycerin 5 ng/ml (group 2), and alteplase 500 IU/ml
plus nitroglycerin 200 ng/ml (group 3). The samples were analyzed at time zero
and 3 hours (incubated at 37 degrees C). Group 1 had significantly higher plasma
alteplase concentrations than group 3 (p<0.001). When alteplase and nitroglycerin
are combined, the degradation of alteplase in plasma is enhanced.
PMID- 10772367
TI - Relationship between benign prostatic hyperplasia and history of coronary artery
disease in elderly men.
AB - STUDY OBJECTIVE: To assess the relationship between the occurrence of benign
prostatic hyperplasia (BPH), an androgen-dependent disease, and coronary artery
disease (defined as history of coronary artery bypass grafting, coronary
angioplasty, myocardial infarction) in elderly men. DESIGN: Retrospective chart
review. SETTING: Urology practice. PATIENTS: Seven hundred two elderly men aged
65-80 years. INTERVENTION: The men's charts were reviewed for data pertaining to
coronary artery disease, risk factors for coronary artery disease, and serum
prostate-specific antigen (PSA) levels. Men who had medical conditions,
pharmacologic interventions, or surgical procedures that could alter PSA, and
those taking lipid-lowering agents were not included. MEASUREMENTS AND MAIN
RESULTS: PSA levels correlate positively with prostatic volume of BPH. In men
with levels under 1.0 pg/L (no BPH) and over 1.0 microg/L (BPH present), the
frequency of coronary artery disease was 9% and 29%, respectively (p<0.03). No
significant differences were noted between groups in other accepted risk factors
for coronary artery disease including age, smoking, diabetes mellitus, or
hypertension. CONCLUSION: Smooth muscle proliferation is an important and
possibly androgen-dependent step in the development of atherosclerosis and BPH.
Prospective studies are required to assess the effect of antiandrogens on
atherosclerosis.
PMID- 10772368
TI - Underuse of inhaled corticosteroids in adults with asthma.
AB - Despite strong evidence that inhaled corticosteroids are beneficial in treating
asthma, a number of small studies suggest a use rate of only 34-56%. The primary
objective of this study was to determine patterns of prescribing inhaled
corticosteroids for high-risk patients with asthma. Secondary objectives were to
assess patterns of practice with respect to other agents prescribed before and at
hospital discharge, and to determine if an emergency room asthma care map at one
of the study hospitals was being followed. We retrospectively reviewed charts of
1022 patients with an acute attack of asthma treated in the emergency rooms of
the Royal Alexandra Hospital and University of Alberta Hospital from January 1,
1996, to March 31, 1997. A forward stepwise logistic regression analysis was
performed with the dependent variable defined as whether or not the patient was
using an inhaled or oral corticosteroid during the index visit, and the
independent variable being all major demographic variables. Inhaled
corticosteroids were prescribed for 460 patients (52.0%) at the index visit.
Overall, antiinflammatory drugs were prescribed for 548 patients (62.1%). An
asthma care map was followed for 107 (16.8%) patients treated at the Royal
Alexandra Hospital at the index visit. Logistic regression analysis showed that
women and patients with more than one emergency room visit most likely were to be
using inhaled or inhaled plus oral corticosteroids at the index visit.
Documentation of drug therapy at discharge was poor for 42% of patients;
therefore, analysis of practice patterns in this group was not attempted. This
study shows that inhaled corticosteroids were prescribed for only about one-half
of patients with an acute asthma attack. Given this low use by high-risk
patients, the need for programs designed to improve asthma therapy is evident.
PMID- 10772369
TI - Antibiotic-heparin lock: in vitro antibiotic stability combined with heparin in a
central venous catheter.
AB - Long-term hemodialysis frequently requires vascular access through central venous
catheters (CVCs). Infection related to these catheters is a significant
complication. The use of an antibiotic-heparin lock could decrease the risks
associated with infected permanent catheters. As an initial step in developing an
antibiotic-heparin lock, we investigated the in vitro stability of antibiotic
heparin combinations in CVCs. Initially, cefazolin, vancomycin, ceftazidime,
ciprofloxacin 10 mg/ml each, and gentamicin 5 mg/ml were incubated separately in
glass test tubes in the dark at 37 degrees C for 72 hours. Samples were analyzed
spectrophotometrically for stability at 24-hour intervals. The procedure was
repeated with the addition of heparin (final concentration 5000 U/ml in glass
test tubes), and the combination was also examined in CVCs. High-performance
liquid chromatography analysis was conducted on the antibiotic-heparin
combinations at 72 hours to confirm the spectrophotometric results. Ciprofloxacin
produced an immediate precipitate with the addition of heparin and was not
analyzed further. Absorbance values decreased for all antibiotics, with the
greatest decreases at 72 hours for cefazolin (27.4%), vancomycin (29.7%),
ceftazidime (40.2%), and gentamicin (8%) when combined with heparin. These
decreases were postulated to be secondary to adsorption of the antibiotics to the
luminal surface of the catheters because submitting the catheters to ultrasound
with 1% sodium bicarbonate and analyzing the resulting solution for absorbance
revealed that some of the drug was recovered. Although free antibiotic in CVC
solution was reduced, the concentration should be sufficient (approximately 5
mg/ml) to decrease the frequency of infections associated with CVCs. We conclude
that the concentrations of vancomycin, ceftazidime, cefazolin, or gentamicin used
in our study should be sufficient for an antibiotic-heparin lock.
PMID- 10772370
TI - Pharmacokinetics of intravenous trovafloxacin in critically ill adults.
AB - The pharmacokinetic disposition of numerous antimicrobial agents is altered in
critically ill patients. Pharmacokinetics of trovafloxacin, a fluoroquinolone
indicated specifically for severe, life-threatening infections in the intensive
care unit, have not been well studied in this population. We characterized the
pharmacokinetic disposition of trovafloxacin after administration of
alatrofloxacin, the intravenous prodrug, in critically ill adults. Seven patients
(3 men, 4 women; mean +/- SD age 59.4 +/- 20.6 yrs; baseline aspartate
aminotransferase [AST]/alanine aminotransferase [ALT] 66.0 +/- 40.6/51.5 +/-37.5
IU/L; median Acute Physiology and Chronic Health Evaluation [APACHE II] score 27,
range 15-32) were studied at estimated steady state. Calculated (mean +/- SD)
half-life, clearance at steady state, and volume of distribution in all patients
were 10.9 +/- 1.8 hours, 161.3 +/- 41.1 ml/minute, and 1.4 +/- 0.4 L/kg. In
patients receiving 300 mg, maximum concentration, minimum concentration, and area
under the curve from 0-24 hours were 3.6 +/- 0.5 mg/L, 0.6 +/- 0.3 mg/L, and 34.2
+/- 10.6 mg x hr/L, respectively. These results are consistent with published
values in other patient populations, indicating that trovafloxacin
pharmacokinetics are not substantially altered in critically ill patients with
normal or mildly impaired hepatic function.
PMID- 10772371
TI - Prevalence of osteoporosis risk factors and treatment among women aged 50 years
and older.
AB - We conducted a cross-sectional, retrospective review to evaluate screening,
diagnosis, and treatment of 389 women aged 50 years or older at risk for
osteoporosis in a large primary care practice. Records randomly selected from a
computerized database were reviewed for drug history, age, height, weight, and
osteoporosis-related diagnoses, symptoms, and risk factors. Among the 389 women,
255 (65.5%) were receiving bone-preserving treatment (247 estrogen replacement
exclusively). Most (70.4%) were white, with an average age of 61 years, and an
average of 3.3 risk factors for osteoporosis. Risk factors were postmenopausal
status 94%, age 65 years or older 53%, hysterectomy 39%, cigarette smoking 33%,
and physical inactivity 30%. By logistic regression, the only positive predictor
of antiresorptive therapy was hysterectomy (adjusted odds ratio [AOR] 2.52, 95%
confidence interval [CI] 1.54-4.14). Negative predictors were physical inactivity
(AOR 0.44, 95% CI 0.25-0.71), rheumatoid arthritis (AOR 0.31, 95% CI 0.12-0.79),
and age 65 years and older (AOR 0.54, 95% CI 0.34-0.86). Controlling for age,
women with four or more risk factors were 62% less likely to be receiving
antiresorptive treatment (AOR 0.38, 95% CI 0.23-0.64) than those with fewer risk
factors.
PMID- 10772372
TI - Impact of pharmacy counseling on compliance and effectiveness of combination
lipid-lowering therapy in patients undergoing coronary artery revascularization:
a randomized, controlled trial.
AB - This randomized, controlled trial evaluated the impact of personalized follow-up
on compliance rates in high-risk patients receiving combination lipid-lowering
therapy over 2 years. A random sample of 30 patients 7-30 days after cardiac
surgery had baseline fasting low-density lipoprotein levels higher than 130
mg/dl. All patients received lovastatin 20 mg/day and colestipol 5 g twice/day.
Weekly telephone contact was made with each patient for 12 weeks. Short- and long
term compliance was assessed by pill and packet counts and refill records.
Compliance and lipid profile results were significantly better in the
intervention group (p<0.05) up to 2 years after the start of therapy than in the
control group for all parameters except high-density lipoprotein. However, this
effect was not apparent during the first 12 weeks of therapy. Short-term
telephone follow-up favorably affected compliance and lipid profile results up to
2 years after start of therapy.
PMID- 10772373
TI - Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic
parameters.
AB - Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory
concentrations (MICs) alone is insufficient to predict in vivo potency.
Achievable serum and tissue concentrations as well as pharmacokinetic
characteristics must be considered. When pharmacokinetic and pharmacodynamic
values are combined, the area under the inhibitory curve (AUIC) and peak
concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data
and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125
and above are predictive of a clinical cure for this class of antimicrobials
against gram-negative organisms. The values may be used to compare and contrast
fluoroquinolones to determine which would be best for treating a specific
microorganism. Pharmacodynamic data also can be used to design regimens that
minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone
dosage based on pharmacodynamic principles would diminish the emergence of
resistant organisms and prevent treatment failures.
PMID- 10772374
TI - Types of interventions made by clinical pharmacists in the IMPROVE study. Impact
of Managed Pharmaceutical Care on Resource Utilization and Outcomes in Veterans
Affairs Medical Centers.
AB - The purpose of this study was to describe and evaluate the activities and
interventions provided by ambulatory care clinical pharmacists during the IMPROVE
(Impact of Managed Pharmaceutical Care on Resource Utilization and Outcomes in
Veterans Affairs Medical Centers) study. A total of 523 patients were randomized
into the intervention arm at nine Veterans Affairs medical centers if they were
considered to be at high risk for drug-related problems. Patients randomized to
the control group had no interventions and they are not reported. Using a
standard form, pharmacists were asked to document the length of visit, method of
contact, medical conditions addressed, and drug-related problems addressed and
resolved during each contact. Seventy-eight ambulatory care clinical pharmacists
documented 1855 contacts over 12 months, an average of 3.54 +/- 2.31/patient. The
length of visits was 15 minutes or more for 73% of contacts. In-person contacts
accounted for 1421 visits (76.6%), with the remainder being telephone contacts.
During each contact the average number of drug-related problems addressed and
resolved were 1.64 +/- 1.16 and 1.14 +/- 0.98, respectively. More drug-related
problems were addressed and resolved when visits were 15 minutes or longer
(p=0.001) and when the contact was in person (p=0.001). These data may provide
information to clinical pharmacists developing pharmacy-managed clinics for
patients at high risk for drug-related problems. The information may be a
benchmark for types of interventions that can be made, as well as the time
commitments required to make them.
PMID- 10772375
TI - 1998 national clinical pharmacy services study.
AB - This study determined the extent of hospital-based clinical pharmacy services in
950 United States acute care, general, medical-surgical, and pediatric hospitals
with 50 or more licensed beds in 1998 and compared results with data from similar
national surveys in 1989, 1992, and 1995. Fifteen clinical pharmacy services were
assessed to determine pharmacists' specific patient care responsibilities. Two
services increased substantially over both the 9-year period and between 1995 and
1998: drug therapy protocol management and clinical pharmacokinetics
consultations, which were offered in 70% and 80% of hospitals in 1998,
respectively. Pharmacists' provision of in-service programs decreased 6% between
1995 and 1998, whereas other services remained constant. Pharmacists conducted
clinical research in 14% of hospitals in 1998, averaging 7.2 +/- 19.7
protocols/department annually; total budget was $224,572 +/- 753,321; and mean
clinical research funding increased 2.3-fold between 1995 and 1998. Clinical
pharmacy services continue to expand, with pharmacists providing higher-level
direct patient care related to drug therapy management and pharmacokinetics
consultations.
PMID- 10772376
TI - Cost-effectiveness of sparfloxacin compared with other oral antimicrobials in
outpatient treatment of community-acquired pneumonia.
AB - We examined the cost-effectiveness of sparfloxacin compared with other selected
oral antimicrobials in outpatient treatment of community-acquired pneumonia (CAP)
using clinical pathway-based decision analysis. Cost estimates were obtained from
medical claims databases and Medicare reimbursement schedules. Probability
estimates were derived from published clinical trials, the medical literature,
and clinical expert opinion. Overall adjusted efficacy rates were 89% for
sparfloxacin, 79.4% for azithromycin, 77.8% for clarithromycin, 73% for cefaclor,
70.8% for amoxicillin-clavulanic acid, and 69% for erythromycin. The expected
total cost/CAP episode of treatment with sparfloxacin was $216.07 compared with
$258.97, $297.08, $345.75, $389.80, and $395.93 for azithromycin, clarithromycin,
erythromycin, amoxicillin-clavulanic acid, and cefaclor, respectively. Therapy
with sparfloxacin for managing CAP is cost effective-relative to other commonly
prescribed antibiotics, resulting in net cost savings.
PMID- 10772377
TI - Immediate-release oxybutynin versus tolterodine in detrusor overactivity: a
population analysis.
AB - We evaluated adherence to treatment with immediate-release (IR) oxybutynin (515
patients) and tolterodine (505 patients) for detrusor overactivity through
retrospective analysis of a pharmacy claims database. Outcomes included
percentage of patients continuing therapy for 6 months, medication possession
ratios, and time to discontinuation of therapy. The proportion of patients
continuing therapy for 6 months was statistically superior for tolterodine (32%)
compared with IR oxybutynin (22%, p<0.001). Medication possession ratios were
also superior for patients in the tolterodine group (medians 0.83 and 0.64,
ranges 0.11-1.15 and 0.07-1.13, respectively, p<0.001). Oxybutynin was
discontinued significantly earlier (mean 45 days) than tolterodine (mean 59 days,
p<0.001) and was switched to another therapy more commonly than tolterodine (19%
and 14%, respectively). Tolterodine was favored over oxybutynin for several
measurements of patient adherence. However, less than one-third of patients
continued therapy with either agent for 6 months. The clinical relevance of these
differences is unknown.
PMID- 10772378
TI - Hypertensive urgency induced by an interaction of mirtazapine and clonidine.
AB - Mirtazapine is a new antidepressant with a tetracyclic chemical structure that is
not related to selective serotonin reuptake inhibitors, tricyclic
antidepressants, or monoamine oxidase inhibitors. The antidepressant effect
results from stimulation of the noradrenergic system through antagonism at
central (alpha2-inhibitory receptors. Clonidine exerts its antihypertensive
effect by stimulating these receptors to cause a reduction in endogenous release
of norepinephrine. Therefore, the two agents have mechanisms of action that
potentially oppose one another. We report a case of hypertensive urgency that
ensued after a patient stabilized on clonidine began taking mirtazapine.
PMID- 10772379
TI - Psychotic symptoms and confusion associated with intravenous ganciclovir in a
heart transplant recipient.
AB - A 65-year-old man underwent orthotopic cardiac transplantation and was
prophylactically treated for cytomegalovirus infection with intravenous
ganciclovir. He received standard dosages and had normal renal function. After 6
days of therapy he experienced psychotic symptoms with hallucinations, confusion,
and disorientation. His altered mental status resolved after the drug had been
discontinued for 5 days. Ganciclovir was suspected as a cause of the symptoms.
Alternative etiologies of were explored and excluded.
PMID- 10772381
TI - Practice guidelines for pharmacotherapy specialists. The ACCP Clinical Practice
Affairs Committee, Subcommittee B, 1998-1999. American College of Clinical
Pharmacy.
PMID- 10772380
TI - Fluconazole-induced agranulocytosis with eosinophilia.
AB - Fluconazole is a commonly prescribed antifungal agent with a favorable safety
profile. A patient experienced agranulocytosis and eosinophilia associated with
the drug. Similar bone marrow-suppressive effect due to the azoles is rarely
described in the English-language literature.
PMID- 10772382
TI - Connexins: a connection with the skin.
AB - The intercellular signaling system mediated by connexin channels is crucial for
maintaining tissue homeostasis, growth control, development, and synchronized
response of cells to stimuli. This review summarizes the structure, assembly, and
properties of the components of the complex and diverse connexin system, and
their biological functions in skin. The importance of gap junctional
intercellular communication for normal development and differentiation of human
epidermis as well as the hearing function of the inner ear is illustrated by the
examples of erythrokeratodermia variabilis and palmoplantar keratoderma
associated with hearing loss. These autosomal dominant inherited disorders are
caused by germline mutations in the connexin genes GJB3 (encoding connexin-31)
and GJB2 (encoding connexin-26), respectively. Recent functional studies of
individual connexin mutations suggest that they may exert a dominant inhibitory
effect on normal connexin channel function and perturb gap junctional
intercellular communication, resulting in phenotypic manifestation in patients
with these disorders.
PMID- 10772383
TI - Conversion of vitamin D3 to 1alpha,25-dihydroxyvitamin D3 in human skin
equivalents.
AB - These results demonstrate for the first time that human keratinocytes under in
vivo-like conditions have the capacity of the enzymatic hydroxylation of vitamin
D3 to hormonally active calcitriol (1alpha,25(OH)2D3). Supplementation of the
culture medium with bovine serum albumin (BSA) up to 1.5%) (w/v) amplifies the
conversion of vitamin D3 to 1alpha,25(OH)2D3. The maximum turnover rate of this
reaction at 780 nM vitamin D3 in presence of 1.0% (w/v) BSA amounts to
approximately 3 pmol 1alpha,25(OH)2D3 per 10(6) cells after 6 h of incubation.
The hydroxylation of vitamin D3 to 1alpha,25(OH)2D3 is inhibited by the P-450
oxidase inhibitor ketoconazole. The generation of 1alpha,25(OH)2D3 from vitamin
D3 has an apparent Michaelis constant (Km) of 2.3x10(-6) M. The intrinsic
conversion of vitamin D3 to biologically active 1alpha,25(OH)2D3 may be of
importance for the regulation of proliferation and differentiation of
keratinocytes.
PMID- 10772384
TI - Spontaneous keratinocyte cell lines representing early and advanced stages of
malignant transformation of the epidermis.
AB - A unique series of epidermal cell lines representing different stages of
malignant transformation were spontaneously derived from a single adult
immunosuppressed individual. Four keratinocyte lines (PM1-4) established from
forehead skin are here compared with 4 squamous cell carcinoma (SCC) lines (MET1
4) derived respectively from a primary cutaneous tumour, two local recurrences
and a distant metastasis of invasive SCC. Despite altered growth properties, the
PM lines retained many features of normal keratinocytes including keratin
phenotype, differentiation capacity and non-tumorigenicity in athymic mice. In
contrast, from early passage, the MET lines displayed markedly reduced growth
requirements, abnormal differentiation, aberrant K18 expression and
tumorigenicity in athymic mice. The abnormal keratin profile of individual MET
lines closely reflected the keratin phenotype of the tumour of origin. Although
unusual HPV types were identified in the original tissue, there was no evidence
of persistent virus within any cell line and it appears that HPV is not critical
for maintenance of the immortal phenotype. The PM lines were distinctly different
from invasive SCC lines and are likely to be useful for studies of mutations
important early in neoplastic progression. The SCC series represent primary,
recurrent and metastatic carcinoma. Availability of such a series from the same
individual will facilitate genetic analysis of the malignant process.
PMID- 10772385
TI - Inhibition of cytokine secretion from human leukemic mast cells and basophils by
H1- and H2-receptor antagonists.
AB - H1-type antihistamines have recently been reported to inhibit cytokine secretion
from human and murine mast cells and basophils. In order to confirm and expand
these studies, we have compared several H1-blockers and the H2-blocker ranitidine
for their effect on TNF-alpha, IL-3, 6, 8 and GM-CSF release from human leukemic
mast (HMC-1) and basophilic (KU812) cells, compared to dexamethasone. Cells were
stimulated for 24 h with phorbol myristate acetate (25 ng/ml) and calcium
ionophore A 23187 (2.5x10(-7) M) alone or with the drugs added at 10(-4) to 10(
15) M, and production of cytokines was measured by ELISA. All antihistamines
caused a dose-dependent inhibition of TNF-alpha release from HMC-1 cells, with
maximal effects at 10(-12) M for azelastine, 10(-9) M for loratadine and
cetirizine, and 10(-8) M for ranitidine. The inhibitory potency of H1-blockers on
cytokines from HMC-1 cells was TNF-alpha >IL-8> or =IL-6> or =IL-3, with no
significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-alpha
and GM-CSF, the sequence was IL-6 >IL-8 after preincubation. Dexamethasone
inhibited all cytokines, but ranitidine only TNF-alpha and IL-3. Antihistamines
had no effect on calcium flux in resting or stimulated cells. At the mRNA level,
inhibition was only seen with KU812 cells and IL-8 in the presence of azelastine
at 10-(10) M. These data show thus distinct inhibitory patterns for different
antihistamines during cytokine production from human mast cells and basophils
which may contribute to the anti-inflammatory effects of these drugs during
treatment of allergic diseases.
PMID- 10772386
TI - Alopecia mice derived from albino ddY mice: breeding, histological and
ultrastructural studies.
AB - Sparse-haired (SH) mice arose spontaneously in a stock of sib-mated albino ddY
mice. Hair loss in the skin of SH mice begins at 3 weeks of age and progresses
with age. On the basis of breeding studies between SH mice and albino ddY mice,
the phenotype of SH mice is identified as autosomal recessive inheritance.
Histological examination shows that numerous pilary canals begin to widen and the
outer root sheath becomes thin at 1 week of age. The inner root sheath and the
hair were separated. Ultrastructural examination reveals that electron dense
materials which formed coalesced and irregularly coiled chains are seen at the
level of firm attachment of the hair to its inner root sheath. At the level of
hair and inner root sheath separation, linear materials with high electron
density are observed in the exocuticle of the hair cuticle. These results suggest
that the appearance of electron dense materials is closely related to the
mechanism of hair loss in SH mice and SH mice may be useful as an animal model in
human hypotrichosis.
PMID- 10772387
TI - Increased tryptase and myeloperoxidase levels in blister fluids of patients with
bullous pemphigoid: correlations with cytokines, adhesion molecules and anti
basement membrane zone antibodies.
AB - Tryptase and myeloperoxidase respectively represent 2 specific markers of
activated mast cells or neutrophils. Therefore, establishing the levels of these
enzymes may be useful to quantify the cell involvement in the tissues or fluids
of different origins and in different pathologies. The aim of this study was to
analyse the levels of these 2 markers in both the sera and blister fluids of
patients affected with bullous pemphigoid. These levels were then correlated to
the concentrations of 19 cytokines and 2 soluble adhesion molecules determined in
the same samples and also with the log (anti-basement membrane zone antibody)
titres, evaluated in the patients' sera. For these purposes, 15 patients with
bullous pemphigoid (10 males and 5 females; median age: 84 years, range 66-87;
median disease duration: 0 years, range 0-3: median number of skin lesions: 17,
range 14-30; median anti-basement membrane zone antibody titre: 1:320, range 0.0
1:2560) and 15 normal subjects (11 males and 4 females, median age: 81 years,
range 59-86) were analysed by means of commercially available kits. Results
showed that blister fluid myeloperoxidase and tryptase levels were increased as
compared with the respective sera (P<0.01) and several correlations were observed
with cytokines and adhesion molecules. In fact, significant correlations of
blister fluid tryptase levels were observed with IL-3, IL-4, IL-5, IL-6, IL-7, IL
8, VEGF, RANTES and sICAM-1, while myeloperoxidase was correlated with IL-1beta,
IL-13 and IL-15. The blister fluid tryptase levels were also significantly
correlated with the anti-basement membrane zone antibody titres (R=0.53, P=0.05).
In conclusion, these findings are in accord with an involvement of both mast
cells and neutrophils in bullous pemphigoid and their recruitment may be mediated
by different biological modulators. Our findings seem to indicate that the
cytokine (IL-3, IFN-gamma and OSM) or adhesion molecule (sICAM-1) concentrations
in blister fluid are logarithmically related to the anti-basement membrane zone
antibody titers.
PMID- 10772388
TI - Regulation of cholesterol synthesis by oleic and palmitic acid in keratinocytes.
AB - Cholesterol synthesis is essential for homeostasis of the epidermis, being
required for both cell division and differentiation, as well as maintenance of
the epidermal permeability barrier. Cholesterol synthesis in keratinocytes has
been demonstrated to be regulated by sterol levels and the barrier function of
the stratum corneum. Cholesterol synthesis in the epidermis is correlated with
changes in mRNA levels for key enzymes, such as HMG-CoA synthase and HMG-CoA
reductase, which have been previously demonstrated to be coordinately regulated
by the sterol regulatory element binding proteins (SREBPs). In this study we
demonstrate that a functional sterol regulatory element is required for sterol
regulation of HMG-CoA synthase in keratinocytes. We also investigate the
regulation of cholesterol synthesis by fatty acids, which are another important
constituent of the stratum corneum lipids. Palmitic and oleic acid inhibit 14C
labelled acetate incorporation into sterols in a similar manner to sterols.
However, unlike sterols, 50 microM oleic acid increase the steady state mRNA
levels of HMG-CoA synthase and the activity of the HMG-CoA synthase promoter. The
addition of 50 microM oleic acid to 25-hydroxycholesterol results in an
enhancement of the inhibitory effect of the sterol on promoter activity. The
inhibition of acetate incorporation into sterols in human keratinocytes by 50
microM palmitic and 50 microM oleic acid is not due to regulation of HMG-CoA
synthase at the level of transcription.
PMID- 10772389
TI - Ornithine decarboxylase transgenic mice as a model for human atrichia with
papular lesions.
AB - The hair follicle is characterized by cyclic transformations from active growth
and hair fiber production through regression into a resting phase. The growth
phase, known as anagen, is associated with rapid rates of cell turnover, and
variations in the rate of DNA synthesis in mouse skin throughout the hair cycle
are accompanied by changes in the activity of ornithine decarboxylase (ODC), a
key enzyme in the synthesis of polyamines, which are actively involved in
regulation of normal cell division, differentiation, and growth. Previously, a
transgenic mouse was created that overexpressed ODC in the skin using a K6
promoter. The first hair cycle in neonatal transgenic mice appeared to be normal,
but by the third week of postnatal life transgenic pups begin to progressively
lose hair. The lower portion of the hair follicle was progressively replaced with
enlarging cystic structures located in the deep dermis, and the transgenic mice
exhibited excessive growth of skin mass resulting in pronounced wrinkling and
folding. Interestingly, these findings bore striking resemblance to the rhino
mouse phenotype and to human patients with papular atrichia, a rare congenital
ectodermal disorder characterized by progressive and irreversible hair loss in
early childhood. The similarities in phenotype between transgenic mice and human
atrichia with papular lesions suggest that ODC transgenics may represent a useful
model for studying this disorder. It appears that ODC plays a functionally
important, yet still obscure role in a complex metabolic pathway that is critical
in hair follicle function not only in mice, but in humans as well.
PMID- 10772390
TI - Germline PTEN mutations in three families with Cowden syndrome.
AB - Cowden syndrome (CS) is an autosomal dominant inherited disorder characterized by
hamartomas in a variety of tissues including the skin, thyroid, breast,
endometrium, and the brain. Individuals with CS are predisposed to development of
malignancy in these organs, especially the breast and the thyroid. We describe 3
unrelated individuals with CS associated with germline PTEN mutations. While the
frameshift (375insTTTA) and the missense (Gly69Arg) mutations reported herein are
novel in CS, the nonsense (Arg130stop) mutation has been described in 2 families
with CS and in a single family exhibiting both CS and Bannayan Zonana phenotype.
PMID- 10772391
TI - A novel missense mutation (C622G) in the zinc-finger domain of the human hairless
gene associated with congenital atrichia with papular lesions.
AB - Congenital atrichia with papular lesions is a rare, recessively inherited form of
hair loss characterized by a complete absence of all body hair shortly after
birth. Mutations in the human ortholog of the mouse hairless (hr) gene have been
implicated in the pathogenesis of this disorder. In this study, we screened, by
direct sequence analysis, the hairless gene in a family of Polish descent and
identified a novel missense mutation (C622G). The mutation alters the third of
four invariant cysteins in the zinc-finger domain, which has high homology to the
C-X-X-C-(X)17-C-X-X-C structure of the zinc-fingers of the GATA family of
transcription factors. The human hairless gene encodes a putative transcription
factor with restricted expression in the brain and skin, which is involved in the
regulation of apoptosis during catagen remodeling in the hair cycle.
PMID- 10772392
TI - Stalked by the past: the influence of ethnicity on health.
AB - Ethnicity impacts the course of illness and medical treatment. There are enormous
ethnic differences in care delivered to patients who are treated for pain.
However, in addition to these social forces, there are enormous ethnic
differences in physiological response to stimuli as diverse as diet, exposure to
agonist infusions, or habitual patterns of response to stressors. The author's
clinical research studies on this topic for the last 20 years are reviewed in
this article.
PMID- 10772393
TI - Multiaxial diagnosis and the psychosomatic model of disease.
AB - Current medical diagnosis reflects the prevailing biomedical model of disease. A
need exists for a new system of diagnosis that, instead, is based on the
psychosomatic model. This article presents an analysis of the underlying
framework of the multiaxial system developed in recent years for diagnosis in
Psychiatry that indicates its relevance to the psychosomatic model. It goes on to
describe a new multiaxial system of diagnosis derived from that analysis that
allows diagnosis to be stated as a process of adaptation in the environment,
which includes biological, psychological, and social factors. The practical
application of this system to the broad range of medical illnesses is explained
and illustrated. This multiaxial approach represents a first step toward, and a
stimulus for, the development of a better diagnostic system that can provide one
basis for the crucial transformation of medical care to reflect the psychosomatic
model of disease.
PMID- 10772394
TI - The very model of a modern etiology: a biopsychosocial view of peptic ulcer.
AB - OBJECTIVE: Research on ulcer psychosomatics has plummeted since the early 1970s,
to the applause of many who argue that ulcer is simply an infectious disease. The
purpose of this article is to discuss the relevance of ulcer psychogenesis in the
age of Helicobacter pylori. METHODS: A critical literature review was conducted.
RESULTS: There is a substantial and methodologically sound body of prospective
studies linking stress with the onset and course of peptic ulcer. Psychosocial
factors can be estimated to contribute to 30% to 65% of ulcers, whether related
to nonsteroidal antiinflammatory drugs, H. pylori, or neither. The observed
association between stress and ulcer is accounted for, in part, by recall bias,
misreported diagnoses, and confounding by low socioeconomic status (a source of
stress and of ulcer risk factors, such as H. pylori and on-the-job exertion) and
by distressing medical conditions (which lead to use of nonsteroidal
antiinflammatory drugs). Of the residual, true association, a substantial
proportion is accounted for by mediation by health risk behaviors, such as
smoking, sleeplessness, irregular meals, heavy drinking, and, again, nonsteroidal
antiinflammatory drugs. The remainder results from psychophysiologic mechanisms
that probably include increased duodenal acid load, the effects of hypothalamic
pituitary-adrenal axis activation on healing, altered blood flow, and impairment
of gastroduodenal mucosal defenses. CONCLUSIONS: Peptic ulcer is a valuable model
for understanding the interactions among psychosocial, socioeconomic, behavioral,
and infectious factors in causing disease. The discovery of H. pylori may serve,
paradoxically, as a stimulus to researchers for whom the concepts of psychology
and infection are not necessarily a contradiction in terms.
PMID- 10772395
TI - Peptic ulcer is not a disease, only a sign!--Stress is a factor in more than a
few dyspeptics.
PMID- 10772396
TI - Negative affect as a prospective risk factor for hypertension.
AB - OBJECTIVE: The objective of this study was to test the hypothesis that negative
affect is a prospective risk factor for hypertension among white and black
persons. METHODS: A population-based cohort of 3310 initially normotensive and
chronic disease-free persons in the NHANES I Epidemiologic Follow-up Study was
tracked through four follow-up waves (maximum, 22 years). The association between
hypertension and baseline negative affect was analyzed using Cox proportional
hazards regression, adjusting for baseline age, sex, race, education, smoking,
alcohol use, diastolic and systolic blood pressure, body mass index, and change
in body mass index as a time-dependent covariate. Negative affect was based on
combined symptoms of depression and anxiety. Hypertension end points included 1)
self-reported, 2) treated (prescription of antihypertensive medications), and 3)
incident (blood pressure > or =160/95 mm Hg or treated) hypertension. Blood
pressure measurements were obtained only at baseline and the first follow-up
examination (maximum, 13 years). RESULTS: Increased negative affect was
associated with elevated risk for self-reported, treated, and incident
hypertension at first follow-up. Through four waves of follow-up, high negative
affect was associated with treated hypertension in baseline risk-adjusted models
for white women (relative risk [RR] = 1.73, 95% confidence interval [95% CI] =
1.30-2.30), black women (RR = 3.12, 95% CI = 1.24-7.88), and all men (RR = 1.56,
95% CI = 1.08-2.25). Time-dependent covariate models produced similar RRs.
CONCLUSIONS: Negative affect is predictive of development of hypertension. For
treated hypertension, white women and all men with increased negative affect had
similarly elevated RRs, whereas black women with increased negative affect had
substantially higher RRs.
PMID- 10772397
TI - Familial resemblance for hostility: the National Heart, Lung, and Blood Institute
Family Heart Study.
AB - OBJECTIVE: The purpose of this study was to examine whether several aspects of
hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive
responding, hostile affect, cynicism, and overall hostility score) were
determined in part by family factors (ie, genes and/or familial environments).
METHODS: Analyses were based on 680 European-American families (2525 individuals)
from the NHLBI Family Heart Study (FHS), a population-based study of genetic and
nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors.
The influence of family relationships, age, and education on the variation in
each of the four hostility scores were estimated. RESULTS: Significant familial
resemblance in all hostility scores was found, accounting for 42% of the variance
in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in
hostile affect. Very little of this resemblance could be explained by
similarities in education. Familial resemblance for cynicism was solely due to
significant parent-offspring and sibling correlations (ie, no spouse
resemblance), suggesting the possibility of genetic influences. Gender and
generation differences were also evident in the familial correlations.
CONCLUSIONS: Hostility aggregates in families. Both family environmental and
genetic sources of resemblance are suggested for hostility.
PMID- 10772398
TI - Higher prevalence of depressive symptoms in middle-aged men with low serum
cholesterol levels.
AB - OBJECTIVE: Investigators from several studies have reported a positive
relationship between low cholesterol levels and death due to violent causes (eg,
suicide and accidents), possibly mediated by depressive symptoms, aggression or
hostility, or impulsivity. We set out to establish whether middle-aged men with
chronically low cholesterol levels (< or =4.5 mmol/liter) have a higher risk of
having depressive symptoms, according to scores on the Beck Depression Inventory,
compared with a reference group of men with cholesterol levels between 6 and 7
mmol/liter. A similar comparison was also made for measures of anger, hostility,
and impulsivity. METHODS: Cholesterol measurements were obtained as part of a
population-based cholesterol screening study in 1990-1991. These levels were
remeasured in 1993-1994. Only those whose cholesterol level remained in the same
range were included in the study. Depressive symptoms were assessed by using the
Beck Depression Inventory; anger, by questionnaires based on the Spielberger
Anger Expression Scale and State-Trait Anger Scale; hostility, by the Buss-Durkee
Hostility Inventory; and impulsivity, by the Eysenck and Eysenck Impulsivity
Questionnaire. RESULTS: Men with chronically low cholesterol levels showed a
consistently higher risk of having depressive symptoms (Beck Depression Inventory
score > or =15 or > or =17) than the reference group, even after adjusting for
age, energy intake, alcohol use, and presence of chronic diseases. No differences
in anger, hostility, and impulsivity were observed between the two groups.
CONCLUSIONS: Men with a lower cholesterol level (< or =4.5 mmol/liter) have a
higher prevalence of depressive symptoms than those with a cholesterol level
between 6 and 7 mmol/liter. These data may be important in the ongoing debate on
the putative association between low cholesterol levels and violent death.
PMID- 10772399
TI - Depression and anxiety as predictors of outcome after myocardial infarction.
AB - OBJECTIVE: The objective of this study was to investigate the significance of
emotional distress immediately after a myocardial infarction as a predictor of
physical, psychological, and social outcomes and resource use. METHODS: In an
epidemiological survey, demographic and cardiological data were obtained for all
patients from a defined geographical area who had had a myocardial infarction
(according to diagnostic criteria of the Monitoring Trends and Determinants in
Cardiovascular Disease [MONICA] trial). Hospital survivors were interviewed and
were asked to complete self-report assessments on mental state and quality of
life. Full replies were available at baseline for 347 subjects. Self-report
follow-up questionnaire information was collected 3 months and 1 year later.
RESULTS: Fifteen percent of patients scored as probable cases of anxiety or
depression. They were more likely than noncases to report preinfarct distress and
poor adjustment (as indicated on the 36-item Medical Outcome Study short form).
There was an improvement at 3 months, but there was little overall or individual
change after that time. Anxiety and depression did not predict subsequent
mortality but did significantly predict poor outcome at 1 year on all dimensions
of the 36-item short form quality-of-life measure and on specific measures of
everyday activity and reports of chest pain, use of primary care resources, and
secondary prevention lifestyle changes. CONCLUSIONS: Subjects who are distressed
in the hospital are at high risk of adverse psychological and quality-of-life
outcomes during the ensuing year. Our findings strengthen the argument for in
hospital identification and treatment of patients with depression and anxiety
after myocardial infarction.
PMID- 10772400
TI - How JFK killed my father
PMID- 10772401
TI - Differences in nocturnal and daytime sleep between primary and psychiatric
hypersomnia: diagnostic and treatment implications.
AB - OBJECTIVE: The differential diagnosis of primary (idiopathic) vs. psychiatric
hypersomnia is challenging because of the lack of specific clinical or laboratory
criteria differentiating these two disorders and the frequent comorbidity of
mental disorders in patients with primary hypersomnia. The aim of this study was
to assess whether polysomnography aids in the differential diagnosis of these two
disorders. METHODS: After excluding patients taking medication and those with an
additional diagnosis of sleep-disordered breathing, we compared the nocturnal and
daytime sleep of 82 consecutive patients with a diagnosis of either primary
hypersomnia (N = 59) or psychiatric hypersomnia (N = 23) and normal control
subjects (N = 50). RESULTS: During nocturnal sleep, patients with psychiatric
hypersomnia showed significantly higher sleep latency, wake time after sleep
onset, and total wake time and a significantly lower percentage of sleep time
than patients with primary hypersomnia and control subjects (p < .05). In
addition, the daytime sleep of patients with psychiatric hypersomnia was
significantly higher in terms of sleep latency, total wake time, and percentage
of light (stage 1) sleep and lower in terms of percentage of sleep time and stage
2 sleep than in patients with primary hypersomnia and control subjects (p < .05).
The daytime sleep of patients with primary hypersomnia as compared with that of
control subjects was characterized by lower sleep latency and total wake time and
a higher percentage of sleep time (p < .05). Finally, a sleep latency of less
than 10 minutes or a sleep time percentage greater than 70% in either of the two
daytime naps was associated with a sensitivity of 78.0% and a specificity of
95.7%. CONCLUSIONS: Our findings indicate that psychiatric hypersomnia is a
disorder of hyperarousal, whereas primary hypersomnia is a disorder of
hypoarousal. Polysomnographic measures may provide useful information in the
differential diagnosis and treatment of these two disorders.
PMID- 10772402
TI - Symptoms of stress and depression as correlates of sleep in primary insomnia.
AB - OBJECTIVE: Previous studies have not evaluated the clinical correlates of the
electroencephalographic spectral profile in patients with insomnia. In the
preliminary study described here, we evaluated the extent to which symptoms of
stress and depression are associated with subjective sleep complaints and
quantitative measures of sleep in individuals with chronic insomnia. METHODS:
Subjects were 14 healthy adults who met criteria for primary insomnia as
specified in the fourth edition of the Diagnostic and Statistical Manual of
Mental Disorders. Measures of stress, depression, and subjective sleep quality
were collected before subjects participated in a two-night laboratory sleep
series. We hypothesized that elevated symptoms of stress and depression would be
associated with subjective sleep complaints and electroencephalographic evidence
of hyperarousal during sleep. Hyperarousal during sleep was defined as decreases
in delta power and elevations in alpha and beta power throughout non-rapid eye
movement sleep, and symptoms of stress were defined as the tendency to experience
stress-related intrusive thoughts and the interaction between intrusion tendency
and the number of recent stressful events (subjective stress burden). RESULTS: A
stronger tendency to experience stress-related intrusive thoughts was associated
with greater sleep complaints and a trend toward higher beta power, whereas
increases in subjective stress burden were associated with decreases in delta
power. In addition, elevations in subclinical symptoms of depression were
associated with greater sleep complaints and elevations in alpha power.
CONCLUSIONS: Observed relationships among symptoms of stress, depression,
subjective sleep complaints, and electroencephalographic power may be relevant to
the discrepancy between subjective and objective measures of sleep in patients
with insomnia and may be more broadly applicable to sleep complaints in
association with stressful life events and major depression.
PMID- 10772403
TI - Does socioeconomic status relate to central serotonergic responsivity in healthy
adults?
AB - OBJECTIVE: We tested whether low SES was associated with reduced central
serotonergic responsivity in a community sample of adult men and women and the
extent to which standardized measures of aggression and impulsivity mediate the
association. METHODS: A total of 270 adults who were enrolled in a clinical trial
on the neurobehavioral effects of lipid lowering were given a neuropharmacologic
challenge (plasma prolactin response to orally administered fenfluramine) to
measure serotonergic responsivity. Measures of family income and educational
attainment were standardized and summed to derive an overall index of SES. Scores
from the Brown-Goodwin Life History of Aggression interview, the Barratt
Impulsiveness Scale, and the Angry Hostility subscale from the NEO Personality
Inventory were also standardized and summed to form an aggression/impulsivity
score. RESULTS: Low SES was correlated with low prolactin responses to the
fenfluramine challenge in the full sample (r = .15) as well as in whites, men,
and women evaluated separately. Although the standardized SES score was
correlated inversely with aggression/impulsivity measure (r = -.19, p < .01), the
association between SES and prolactin responses remained significant when
statistical adjustments were made for age, gender, body mass index, and
aggression/impulsivity scores. CONCLUSIONS: Blunted serotonergic responsivity is
associated with low social class as measured by annual family income and
educational attainment.
PMID- 10772404
TI - When children tell their friends they have AIDS: possible consequences for
psychological well-being and disease progression.
AB - OBJECTIVE: Past research has demonstrated that self-disclosure of traumatic or
secretive information produces observable health benefits. Self-disclosure has
also been linked, albeit less consistently, to improved psychological health. The
present study examined the physiological and psychological consequences of
children's self-disclosure of their HIV/AIDS status to friends. METHODS: Data
were collected twice, one year apart, from 64 caregiver-child dyads in which all
of the children were infected with HIV. Dependent variables included the child's
CD4%, self-concept, and level of behavioral problems. RESULTS: Children who had
disclosed their HIV+ diagnosis to friends during the 1-year course of the study
had a significantly larger increase in CD4% than children who had told their
friends before the study or those children who had not yet disclosed their HIV+
diagnosis to friends. This effect remained significant when the child's age and
level of medication (protease inhibitors) were statistically controlled. Self
disclosure to friends did not impact the child's behavior or self-concept.
CONCLUSIONS: This is the first study to investigate the effect of self-disclosure
in children. The results were consistent with previous studies showing the
positive health consequences of self-disclosure in adults, and suggest
potentially important implications for professional and familial care givers of
HIV/AIDS individuals.
PMID- 10772405
TI - Antagonistic behavior, dominance, hostility, and coronary heart disease.
AB - PURPOSE: This study investigated the relationship between antagonistic behavior,
dominance, attitudinal hostility, and coronary heart disease (CHD). METHODS: One
hundred one men and 95 women referred for thallium stress testing were
administered the Structured Interview and the Cook-Medley Hostility Scale. The
Hostile Behavior Index, derived from the Structured Interview and developed by
Haney et al., served as an index of antagonism, and the frequency with which
interviewees interrupted their interviewer served as a measure of dominance. On
the basis of their medical history and thallium stress test results, patients
were classified as having (N = 44) or not having (N = 99) CHD. RESULTS AND
CONCLUSIONS: Multivariate logistic regressions (with age, gender, disease, and
lifestyle risk factors in the model) revealed that both the Hostile Behavior
Index and dominance were significant independent risk factors for CHD (relative
risk [RR] = 1.22 and 1.47, p < .03). Of the two Hostile Behavior Index component
scores, indirect challenge and irritability, only the latter correlated
significantly with CHD (RR = 1.27, p < .03). Separate logistic regressions for
men and women suggest that subtle, indirect manifestations of antagonism confer
CHD risk in women and that more overt expressions of anger confer risk in men. A
significant univariate correlation between hostility scale scores and CHD became
not significant when we adjusted for socioeconomic status.
PMID- 10772406
TI - Screening for postnatal depression using the double-test strategy.
AB - OBJECTIVE: Postnatal depression affects 10% to 15% of women after childbirth.
Self-report rating instruments, such as the Edinburgh Postnatal Depression Scale
(EPDS), have been developed and administered to postpartum women to facilitate
early detection. Most postnatal depression screening scales, however, focus
solely on depressive symptomatology. We hypothesized that applying two
complementary rating scales of symptoms and functioning as a double test would
significantly enhance the positive predictive value of screening. METHODS: A
prospective cohort study was conducted at the postnatal clinic of a university
teaching hospital. One hundred forty-five Chinese women completed the EPDS and 12
item General Health Questionnaire (GHQ) 6 weeks after delivery. They were then
interviewed by a psychiatrist, who used the Structured Clinical Interview for
third revised edition of the Diagnostic and Statistical Manual of Mental
Disorders, nonpatient version (SCID-NP), to validate the diagnoses. RESULTS: The
positive predictive value of the EPDS and GHQ, when administered independently,
was 44% and 52%, respectively, at their respective optimal cutoff scores. When
the EPDS-GHQ double test was administered, the positive predictive value was
significantly increased to 78%. CONCLUSIONS: Simultaneous administration of the
EPDS and GHQ can substantially improve identification of women with postnatal
depression. This can potentially reduce unnecessary referrals to general
practitioners and psychiatrists and may enhance the overall cost-effectiveness of
population-wide screening.
PMID- 10772407
TI - Body mass index, eating attitudes, and symptoms of depression and anxiety in
pregnancy and the postpartum period.
AB - OBJECTIVE: This report describes associations between body mass index (BMI;
kg/m2), eating attitudes, and affective symptoms across pregnancy and the
postpartum period in a sample of 64 women. METHODS: As part of a larger study,
women were recruited during pregnancy and followed prospectively to 14 months
postpartum. Measures included self-reported prepregnancy and 4-month postpartum
BMI as well as pregnancy, 4-month, and 14-month postpartum eating attitudes
(EAT), depressive symptoms (CES-D), and anxiety symptoms (STAI). RESULTS: During
pregnancy, symptoms of depression or anxiety were not significantly correlated
with concurrent eating attitudes or measures of BMI. However, at 14 months
postpartum, measures of eating attitudes and both depression and anxiety symptoms
were associated. Measures of BMI were associated with depressive and anxiety
symptoms at both 4 and 14 months postpartum. Four-month eating attitudes and BMI
predicted 14-month postpartum depressive symptoms, beyond pregnancy, and 4-month
postpartum measures of affective symptoms. Results suggested that overweight
women were at risk for elevated anxiety at 4 months and depressive symptoms at
both 4 and 14 months postpartum. CONCLUSIONS: These results provide evidence for
a significant, albeit moderate, relationship between BMI, eating attitudes, and
symptoms of depression and anxiety in the postpartum period that are not present
during pregnancy.
PMID- 10772408
TI - Resilience and distress among amyotrophic lateral sclerosis patients and
caregivers.
AB - OBJECTIVES: The objectives of this study were to assess the prevalence of
depressive disorders and symptoms and their correlates in patients with
amyotrophic lateral sclerosis (ALS) and caregiver spouses and to identify
dimensions of resilience as well as distress. METHODS: Fifty-six patients with
ALS and 31 caregivers were interviewed on one occasion, and 20 patients were
subsequently reinterviewed during a scheduled medical visit at an ALS center.
Major measures included the Structured Clinical Interview for DSM-IV, the Beck
Depression Inventory, the Schedule of Attitudes Toward Hastened Death, quality of
life, spirituality, and degree of hopelessness. The ALS Functional Rating Scale,
spirometry measures of forced vital capacity, and the Karnofsky Performance Index
were used to assess physical status. RESULTS: Neither patients nor caregivers
displayed significant psychopathology with respect to either current depressive
disorders or scores on symptom scales. Depressive symptoms and psychological
distress were not related to time since diagnosis, degree of disability, or
illness progression during the period of observation. More interest in hastened
death was associated with greater distress, but willingness to consider assisted
suicide was not. Among caregivers, perceived caregiver burden was significantly
associated with finding positive meaning in caregiving. Concordance between
patient and caregiver distress was high, suggesting that attention to the mental
health needs of caregivers may alleviate the patient's distress as well.
CONCLUSIONS: Clinical depression or significant depressive symptomatology is not
an inevitable or common outcome of life-threatening illness, even in the presence
of major disability.
PMID- 10772409
TI - Irritability during the month of Ramadan.
AB - OBJECTIVES: We hypothesized that people in Morocco are more irritable during the
month of Ramadan than during the rest of the year. Our objectives were to measure
irritability in fasting Muslims during the month of Ramadan, to describe its
various modes of expression, and to examine risk factors for this irritability.
METHODS AND SUBJECTS: We studied 100 healthy volunteers during the month of
Ramadan for two successive years (1994 and 1995). All subjects were male (mean
age, 32+/-5.8 years), and 51% of them were smokers. Irritability was assessed
over a 6-week period (before, four times during, and after the end of Ramadan).
We assessed both subjective (visual analog scale) and objective irritability. We
also recorded the consumption of psychostimulants, duration of sleep, and anxiety
level as measured by the Hamilton Anxiety Scale. RESULTS: Irritability was
significantly higher in smokers than in nonsmokers before the beginning of
Ramadan. It was higher in both groups during the Ramadan month. Irritability
increased continuously during Ramadan and reached its peak at the end of the
month. Consumption of psychostimulants (coffee and tea) and anxiety level
followed the same pattern. Smokers and nonsmokers had a similar pattern of
irritability over time, but irritability increased more in smokers than in
nonsmokers.
PMID- 10772410
TI - Job strain and anger expression predict early morning elevations in salivary
cortisol.
AB - OBJECTIVE: The objectives of this study were to test the hypothesis that high job
demands and low job control (job strain) are associated with elevated free
cortisol levels early in the working day and with reduced variability across the
day and to evaluate the contribution of anger expression to this pattern.
METHODS: One hundred five school teachers (41 men and 64 women) classified 12
months earlier as high (N = 48) or low (N = 57) in job strain according to the
demand/control model sampled saliva at 2-hour intervals from 8:00 to 8:30 hours
to 22:00 to 22:30 hours on a working day. Anger expression was assessed with the
Speilberger State-Trait Anger Expression Inventory, and negative affect was also
measured. RESULTS: Free cortisol was significantly elevated at 8:00 to 8:30 hours
in the high job strain group but not at later times of the day or evening. After
adjustment for age and negative affect, cortisol was an average of 21.7% higher
early in the working day in the high job strain group. This effect was
significantly greater in high job strain teachers, who also reported high anger
out. The cortisol decline from morning to evening was greater in the high than
low job strain individuals. Independently of job strain, women had a higher
cortisol concentration at 8:00 to 8:30 hours than men, whereas cortisol
concentration was greater in men than women in the middle of the working day
between 12:00 and 16:30 hours. CONCLUSIONS: Job strain is associated with
elevated free cortisol concentrations early in the working day but not with
reduced cortisol variability. The interaction with outward anger expression
suggests that individual characteristics modulate the impact of chronic work
stress on the hypothalamic-pituitary-adrenocortical system.
PMID- 10772411
TI - New Perspectives in Colorectal Cancer Research. Proceedings of a workshop. Dijon,
France, 27-28 November 1998.
PMID- 10772412
TI - Are there several colorectal cancers? Epidemiological data.
AB - The knowledge of descriptive epidemiology of colorectal cancer is a prerequisite
essential to a better understanding of the aetiology of the disease and the
development of prevention strategies. This work provides an update of descriptive
epidemiological data on colorectal cancer incidence in the world. In 1988-1992,
incidence rates of colorectal cancer varied from 15- to 25-fold according to the
geographical area. The highest rates were observed in Western countries,
especially in North America, Australasia and, to a lesser extent, in northern and
western Europe. The geographical distribution of colorectal cancer was similar in
men and women. An examination of incidence data by subsites showed that the
magnitude of geographical variations was more important for colon cancer than for
rectal cancer. Contrasting with the male predominance for rectal cancer and, to a
lesser degree, for left colon cancer, cancers of the right colon were found to be
as frequent in women as in men. Examination of time trends during the last
decades reveals a sharp increase in incidence of colorectal cancer in Japan and
in eastern and southern Europe. On the other hand, incidence rates show some
stagnation in North America and western Europe in recent years. In fact, there
are some suggestions for differential time trends according to the anatomical
subsite, with a recent proximal shift in the distribution of cancers of the large
bowel in Western countries. In conclusion, descriptive epidemiological data
support the notion that distinct pathogenic mechanisms may be involved in the
carcinogenesis of the proximal and distal bowel.
PMID- 10772413
TI - Are there several types of colorectal carcinomas? Correlations with genetic data.
AB - Molecular studies have shown that different genetic pathways are involved in the
history of colorectal carcinomas. This suggests that a correlation exists between
the molecular, clinical and pathological features of tumours. Two large groups
can be individualized: the first group is characterized by allelic losses and
hyperdiploidy. These LOH (for loss of heterozygosity)-positive tumours represent
80% of colorectal carcinomas. Among them more than two-thirds are located in the
distal colon. They have the worst prognosis. The second group has a normal
diploid pattern and a phenotypic microsatellite instability without allelic
losses. These tumours represent 10-15% of all colorectal carcinomas and about 30%
of the right-sided tumours. They are associated with a better prognosis. In the
future, it would perhaps be better to classify colorectal carcinomas according to
their molecular features rather than to their topographical localizations.
PMID- 10772414
TI - Nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of colorectal
cancer.
AB - Shortly after the discovery of prostaglandins being involved in vertebrate
carcinogenesis (during the 1970s), trials in patients with familial adenomatous
polyposis (FAP) had shown that nonsteroidal anti-inflammatory drugs (NSAIDs)
could reduce the number and size of these precancerous lesions. In the late 1980s
epidemiological evidence was provided that long term use of aminosalicylic acid
(ASA) for various indications seemed to be protective against colonic cancer and
malignancies of other sites. Controlled intervention studies with nonselective
cyclo-oxygenase (COX) inhibitors (i.e. traditional NSAIDs) were hampered by the
risks of gastrointestinal and renal side effects. Recently, selective COX-2
receptor antagonists have been developed, improving pain and inflammation without
the above mentioned adverse effects. In animal models it has been shown that COX
2 inhibitors are able to reduce colonic neoplasia and/or its proxy markers. This
is the rationale for the presently ongoing testing of those drugs in hereditary
and sporadic colonic adenomas.
PMID- 10772415
TI - Genetic risk factors in colorectal cancer.
AB - Familial risk factors are known to play an important role in colorectal cancer
(CRC) risk, particularly when the relatives are affected by early-onset cancer.
Part of this familial aggregation can be accounted for by inherited forms of
colorectal cancer, i.e. familial adenomatous polyposis (less than 1% of all CRC)
and hereditary nonpolyposis colorectal cancer (about 3%). Other genetic factors
may be involved in the development of adenoma or in the transformation of adenoma
into carcinoma. That the existence of polymorphisms of the adenomatous polyposis
coli gene increase susceptibility to both adenomas and cancer favours this
hypothesis. Interactions between environmental factors, and most of all dietary
factors, and polymorphisms of carcinogen-metabolizing enzymes may also be
involved. Better knowledge of these mechanisms will substantially widen the scope
of colorectal cancer prevention.
PMID- 10772416
TI - Germline mutation and genome instability.
AB - Colorectal tumorigenesis has been associated with the progressive acquisition of
a variety of genomic alterations in neoplastic cells. In 5-10% of cases, a strong
family history of cancer suggests a major predisposition, either familial
adenomatous polyposis (FAP) or HNPCC syndrome. In 1987, the gene responsible for
FAP was localized on chromosome 5q. In 1991, the International Collaborative
Group on HNPCC set stringent criteria for the diagnosis of HNPCC, to homogenize
families that should be entered in large linkage analyses. In the past five
years, five MMR genes could be identified as the site of germline mutations
associated with a HNPCC syndrome (MSH2, MLH1, PMS1, PMS2, and MSH6). The TGFbeta
RII gene has been found mutated at the germline level in a small number of HNPCC
patients. The DNA mismatch repair pathway is essential for the correct
maintenance of genetic information. The slippage occurs usually at microsatellite
loci and the defect of one MMR gene leads to the accumulation of replication
errors in such deficient cells. The tumours that exhibit the highest frequency of
RER at microsatellite loci, thus termed RER+, account for 10-15% of all
colorectal cancers, and for 92% of those developed in a context of a HNPCC
syndrome.
PMID- 10772417
TI - Sequence of molecular genetic events in colorectal tumorigenesis.
AB - Intensive screening for genetic alteration in colorectal cancer led to the
identification of two types of colorectal tumours that are distinct by their
carcinogenesis processes. The first group, named LOH (for loss of heterozygosity)
positive, is characterized by hyperploidy and allelic losses involving
preferentially chromosome 18q and chromosome 17p. More than two-thirds of
colorectal cancers belong to this group. The second group, called multiple
microsatellite loci (MSI)-positive cancers, is characterized by genetic
instability at microsatellite loci. Although colorectal cancer cells are
characterized by specific microsatellite alterations, the same four different
signalling pathways, WNT/Wingless pathway, K-ras pathway, transforming growth
factor (TGF)beta pathway and p53 pathway, could be implicated in tumour
progression. The WNT/Wingless pathway could be altered in two different ways
according to whether the cancer cells belong to the group of LOH-positive or MSI
positive tumours. LOH-positive tumours activate the WNT/Wingless signalling
pathway through an adenomatous polyposis coli (APC) mutation, whereas the MSI
positive tumours activate this pathway through a beta-catenin stabilizing
mutation. Beta-catenin and APC mutations were observed as early as the
adenomatous stage of colorectal neoplasia. In TGFbeta pathways LOH-positive
tumours inactivated SMAD2 (similar to mother against decapentaplegic drosophilia)
or SMAD4, whereas in MSI-positive tumours the TGFbeta type II receptor is
frequently deleted. Alteration of these genes correlated closely with the
progression of the adenoma to cancer. In the p53 pathway LOH-positive tumours
showed frequent p53 mutation, whereas MSI-positive tumours demonstrated BAX (BCL
2-associated X protein)-inactivating mutation. These alterations contribute to
the adenoma-carcinoma transition.
PMID- 10772418
TI - Nutrients and food groups and large bowel cancer in Europe.
AB - Several uncertainties remain with respect to the role of intake of fat and/or
total energy in the aetiology of cancer of the colon-rectum. Between 1992 and
1996, 1953 subjects with cancer of the colon-rectum (median age = 62 years) and
4154 hospital controls were interviewed in six Italian areas. The validated food
frequency questionnaire included questions on 78 foods and recipes, and specific
questions on individual fat intake pattern. Significant trends of increasing
colorectal cancer risk with increasing intake emerged for bread and pasta, cakes
and desserts, and refined sugar. Most vegetables, including pulses, were
inversely associated with cancer of the colon and rectum. High fruit intake was
associated only with a reduction of rectal cancer. Total energy intake was
directly associated with colorectal cancer risk. Among macronutrients, a high
intake of starch and saturated fat seemed to lead to an increased risk of cancer.
High intakes of polyunsaturated fatty acids (chiefly derived from olive oil and
seed oils) showed a marginal inverse association with colorectal cancer risk.
Among micronutrients, beta-carotene, vitamin E and calcium showed the most
consistent inverse associations. An excess of energy intake, particularly from
refined bread and pasta, can be an unfavourable feature of the Mediterranean diet
with respect to colorectal cancer risk, especially in the presence of sedentary
life.
PMID- 10772419
TI - Energy intake, overweight, physical exercise and colorectal cancer risk.
AB - Epidemiological studies on risk factors for CRC have focused mainly on diet. In
any case, the results of these studies show several inconsistencies, except for
the beneficial role of high intake of vegetables and, to some lesser extent, of
fruit. Weight and height have also been studied, partly because they reflect the
balance between energy intake and expenditure in different age periods. Energy
intake, body size and physical activity will be reviewed in this paper focusing
mostly on recent data coming from Italian, English and Scandinavian studies.
Overweight has long been recognized as a risk factor for hormone related and
other cancers and this is confirmed not simply from case-control studies but from
large cohort studies as well. The major findings of recent Italian studies are
that excessive weight at various ages predicts colorectal cancer risk in men
while in women, abdominal obesity, as indicated by a high WHR, represents a more
reliable risk indicator. If all men could reduce their BMI below 25, about 9% of
male colorectal cancer might be avoided in Italy. A decrease of WHR below 0.82
might reduce colorectal cancer in women by 19%. In addition, the epidemiological
evidence consistently shows that physical activity reduces the risk of colon
cancer. On the contrary, evidence on rectal cancer is less impressive. Some
uncertainty still exists in relation to the intensity and duration of physical
activity. In conclusion, body size control along all life and physical activity
represent important factors to prevent colon cancer and a wide range of chronic
conditions. Therefore, strategies to favour these goals through counselling from
health-care providers, regulatory changes and programs aimed at individuals and
communities should be implemented.
PMID- 10772420
TI - Family history, metabolic gene polymorphism, diet and risk of colorectal cancer.
AB - Colorectal cancer is thought to be largely due to dietary factors. There is
evidence of familial aggregation of colorectal cancer suggesting that genetic
susceptibility may be important in the aetiology of the disease. Only limited
data are available comparing risk factors for colorectal cancer with and without
a family history. There are arguments suggesting that individuals with a first
degree relative with colorectal cancer are at a greater risk from a diet high in
energy than individuals without such a family history. Failure to take into
account both genetic and environmental factors can lead to bias in the estimation
of disease risk. Genetic polymorphisms interact with dietary intake. A number of
associations have been observed between specific genetic polymorphisms and
colorectal cancer. But there are inconsistencies between studies, because of
methodological limitations in initial studies. Different effects of dietary
factors on colorectal cancer risk among individuals with different genotypes or
of different effects of a genotype on colorectal cancer risk among individuals
with different exposures need to be addressed in future works.
PMID- 10772421
TI - Clinical evidence for the adenoma-carcinoma sequence.
AB - A review is given on evidence supporting or rejecting the hypothesis of a
colorectal adenoma-carcinoma sequence. The majority of studies discuss adenomas
from a clinical point of view, but pathology has also been considered in detail,
and molecular biology has been touched on. It is concluded the adenoma stage is,
most probably, a phase on the way to carcinoma. But it remains to be shown what
effect the removal of adenomas will have in the long run on the incidence of
colorectal carcinoma.
PMID- 10772422
TI - Carcinogenesis in the colon: interaction between luminal factors and genetic
factors.
AB - At last, inroads are beginning to be made into the hitherto unknown and complex
area of gene-environment interactions in the colon. Interestingly, many of the
studies to date would suggest: that the Apc gene is a target for such
interactions; that luminal factors can regulate the level of cellular proteins of
central importance in the control of cell growth/arrest; and that some of the
newly discovered members of the nuclear hormone receptor superfamily may be
mediating gene-environment interactions in the colon. This is a very exciting
area and will presumably be the subject of intense research in the near future.
By characterizing the dietary/luminal factors that interact with the genes
implicated in tumour development in the colon, we will reach another level of
certainty regarding the dietary components responsible for tumour formation and
their underlying mechanisms. It is gratifying to see at last the fields of
epidemiology and molecular biology begin to overlap, and without doubt results
from this new area of research will give a new and better status to the field of
making dietary recommendations to decrease the risk of developing colorectal
cancer.
PMID- 10772423
TI - Mechanisms of diet and colon carcinogenesis.
AB - There is consistent and strong evidence that a high risk of colorectal cancer is
associated with obesity and with a low intake of vegetables, of whole grain
cereals and of fish. Many other food groups or nutrients have been associated
with this cancer, but the evidence for them is inconsistent and therefore
untenable. Vegetables contain a wide range of protective agents that protect
against cancer at many other sites as well as the large bowel. The same is true
of whole grain cereals; these can also protect against colorectal cancer by
mechanisms specific to the large bowel. Fish are rich in n-3 polyunsaturated
fatty acids that are thought to protect the colon against malignancy via the
prostaglandin pathway. Overweight is the result of an excess of energy intake
over energy output, and there is good evidence to suggest that overweight might
be a surrogate measure of lack of exercise.
PMID- 10772425
TI - Effect of aging on the incidence of digoxin toxicity.
AB - OBJECTIVE: To evaluate the relationship of the therapeutic serum digoxin
concentration (SDC) range (0.5-2 ng/mL, as recommended in previous clinical
studies) with the incidence of digoxin toxicity during digoxin maintenance
therapy. METHODS: Subjects included all inpatients (n = 462) and outpatients (n =
437) receiving digoxin oral maintenance therapy for heart failure and/or atrial
fibrillation with tachycardia at Kosei Hospital, Anjo, Japan. SDC and blood
chemistry analysis were determined, and a 24-hour Holter electrocardiographic
recording was performed when the SDC was at the presumed steady-state
concentration. RESULTS: Analysis of clinical data showed that there was an
overlapping (toxic and nontoxic) range of SDCs in which the incidence of digoxin
toxicity was patient-dependent (1.4-2.9 ng/mL). No patient exhibited signs or
symptoms of digoxin toxicity when the SDC was <1.4 ng/mL; all patients had
evidence of toxicity when the SDC was >3 ng/mL. Additionally, it was shown that
the concentration range of this overlapping range tended to broaden and shift to
lower concentrations with increasing age. Patients with signs of toxicity when
their SDCs were in the overlapping range had normal serum creatinine, blood urea
nitrogen, digoxin clearance, creatinine clearance, and potassium concentrations,
except for a significantly higher mean age than patients without toxicity. The
incidence of digoxin toxicity was dependent on increasing age in patients whose
SDCs were within the recommended therapeutic range. Moreover, clinical evidence
of digoxin toxicity in patients >71 years old was 26.5%, despite their SDCs
falling between 1.4 and 2 ng/mL. CONCLUSIONS: Increased age is most likely
associated with enhanced susceptibility to digoxin toxicity, possibly due to
unknown pharmacodynamic changes. This raises the possibility that patients >71
years show clinical evidence of digoxin toxicity despite having SDCs within the
recommended therapeutic range.
PMID- 10772426
TI - Factors associated with successful epoetin alfa therapy in premature infants.
AB - OBJECTIVE: To determine the impact of two different recombinant human
erythropoietin (epoetin alfa) dosing strategies on the number of red blood cell
(RBC) transfusions, and explore relationships between specific patient and drug
regimen variables with epoetin alfa therapy outcomes. DESIGN: Retrospective
cohort study. SETTING: Level III university neonatal intensive care unit.
METHODS: Infants who received epoetin alfa therapy three times weekly for more
than one week were categorized into two epoetin alfa dosing strategy groups:
group A (300-749 units/kg/wk) and group B (750-1200 units/kg/wk). The following
patient variables were collected and their relationship to therapy outcomes
(corrected reticulocyte count [%], hematocrit [%], and number of RBC transfusions
after therapy was started) were evaluated using independent Student's t-test,
correlation analysis, and stepwise linear regression: birth weight (kg),
gestational age (weeks), postnatal age at therapy onset (days), duration of
mechanical ventilation (days), number of RBC transfusions before epoetin alfa
therapy, phlebotomy loss (mL/kg), epoetin alfa dosage (units/kg/dose), iron
dosage (mg/kg/d), duration of therapy (days), and postconceptional age at therapy
discontinuation (weeks). RESULTS: The charts of 44 patients were reviewed. No
significant impact on outcome was attributed to overall dosing strategy (group A
vs. group B). Linear regression identified postnatal age at therapy onset as a
significant contributor to mean hematocrit (R2 = 2 0.116; p = 0.023) and
postconceptional age at therapy discontinuation as a significant contributor to
number of transfusions during and after epoetin alfa use (R2 = 0.118; p = 0.022).
A significant positive correlation was found between weekly mean epoetin alfa
dosage and mean reticulocyte count (r = 0.326; p = 0.046), mean iron dosage and
mean reticulocyte count (r = 0.439; p = 0.006), and ventilator days and total
number of transfusions (r = 0.606; p < 0.001). A significant negative correlation
was found between number of transfusions and reticulocyte count (r = -0.367; p =
0.023). CONCLUSIONS: Epoetin alfa dosing strategy, as defined in our study, did
not significantly affect the number of transfusions. However, postnatal age at
therapy initiation, postconceptional age at therapy discontinuation, mean epoetin
alfa dosage, and iron dosage correlate with specific outcomes of epoetin alfa
therapy in premature infants.
PMID- 10772427
TI - Contribution of multivitamins, air, and light in the generation of peroxides in
adult and neonatal parenteral nutrition solutions.
AB - OBJECTIVE: To compare the concentrations of peroxides between adult and neonatal
total parenteral nutrition (TPN) solutions in response to protection against
inducers of peroxidation such as multivitamins and exposure to light or air.
METHODS: Peroxide concentrations were measured in freshly prepared adult and
neonatal solutions of fat-free TPN in four settings: with or without an air
inlet, and protected or unprotected from ambient light. An oxygen washout was
performed by exposing a fat-free neonatal TPN solution to a continuous flow of
nitrogen. RESULTS: Globally, light was the main inducer of peroxides in adult and
neonatal solutions. However, in adult solutions the concentration of peroxides
remained <15 micromol/L, while in neonatal solutions the peroxide concentration
was as high as 300 micromol/L in ambient light. Although the oxygen washout did
prevent the generation of peroxides, avoiding air inlet was not as effective as
was photoprotection in decreasing the important peroxide load in the neonatal TPN
solution. CONCLUSIONS: The higher concentration of peroxides found in neonatal
solutions compared with adult solutions is explained by the differences in
nutrient composition between the two solutions. Contamination of parenteral
solutions by air during compounding accounts for the photoinduced generation of
peroxides in TPN solutions. It is more convenient to protect TPN solutions from
light exposure after the admixture of the multivitamin solution than to avoid
contact with oxygen.
PMID- 10772429
TI - Photoreaction potential of orally administered levofloxacin in healthy subjects.
AB - OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to
solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined
as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a
single-center, double-blind, randomized study, 30 adults (20 men, 10 women)
received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline
photoexposure prior to drug administration, each subject was exposed to UVB light
at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25
J/cm2). Photoexposure was repeated on day 5, two hours following final drug
administration, and response was determined using both a photoreaction rating
scale and investigator assessment. RESULTS: Using the photoreaction rating scale,
following UVB exposure on day 5, no abnormal photoreactions were observed among
levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of
24 levofloxacin-treated and three of six placebo-treated subjects, with no
associated symptoms. By investigator assessment, all subjects had a negative
reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six
placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal
reactions were mild and similar for both treatment groups. No subject experienced
an immediate wheal-and-flare reaction. There were no statistically significant
differences between treatment groups for any of the comparisons. CONCLUSIONS:
Levofloxacin has a low photosensitizing potential when administered to healthy
subjects.
PMID- 10772428
TI - Antimicrobial selection for hospitalized patients with presumed community
acquired pneumonia: a survey of nonteaching US community hospitals.
AB - OBJECTIVE: To describe and evaluate empiric antimicrobial regimens chosen for
hospitalized patients with presumed community-acquired pneumonia (CAP) in US
hospitals, including compliance with the American Thoracic Society (ATS)
guidelines. Secondary outcomes included length of stay (LOS) and mortality
associated with the choice of therapy. METHODS: A nonrandomized, prospective,
observational study was performed in 72 nonteaching hospitals affiliated with a
national group purchasing organization. Patients with an admission diagnosis of
physician-presumed CAP and an X-ray taken within 72 hours of admission were
eligible for the study. Demographic, antibiotic selection, and outcomes data were
collected prospectively from patient charts. RESULTS: 3035 patients were
enrolled; 2963 were eligible for analysis. Compliance with the ATS guidelines was
81% in patients with nonsevere CAP. The most common antibiotic regimen used for
empiric treatment was ceftriaxone alone or in combination with a macrolide (42%).
The overall mortality rate was 5.5%. The addition of a macrolide to either a
second- or third-generation cephalosporin or a beta-lactam/beta-lactamase
inhibitor was associated with decreased mortality and reduced LOS. CONCLUSIONS:
Most hospitalized patients with CAP receive antimicrobial therapy consistent with
the ATS guidelines. The addition of a macrolide may be associated with improved
patient outcomes.
PMID- 10772430
TI - Antibiotic use in a Canadian Province, 1995-1998.
AB - OBJECTIVE: Antibiotics are among the most commonly used classes of agents in
community practice; yet, studies of antibiotic use in this setting are scarce.
Data from developed countries suggest increasing use of newer broad-spectrum
agents, which has implications for the development of antibiotic resistance as
well as cost of therapy. In this study, we quantified changing patterns of
antibiotic use in community practice in Manitoba, Canada, from 1995 to 1998.
DESIGN: A descriptive, population-based study of antibiotic use in Manitoba was
facilitated by the Drug Programs Information Network (DPIN) of Manitoba Health; a
data management system responsible for recording details of prescriptions
dispensed for all Manitoba residents. Antibiotic use data, defined as numbers of
prescriptions dispensed, were extracted from the DPIN from January 1, 1995, to
March 31, 1998. Antibiotic use is reported as prescriptions per 1000 persons per
year (Rx/1000/Yr) based on quarterly use. RESULTS: Penicillins (48.3%),
macrolides (16.0%), and sulfonamides (12.5%) accounted for 75% of total
antibiotic use; total use decreased 19.1% between 1995 and 1998. Use of the four
most commonly prescribed agents decreased over the study period (amoxicillin,
17.4%; erythromycin, -29.0%; trimethoprim/sulfamethoxazole, -18.7%; penicillins G
and V, -19.2%). In contrast, use of newer and/or broad-spectrum agents increased
(ciprofloxacin, 21.9%; cefuroxime, 30.7%; and azithromycin/clarithromycin,
29.5%). Use of second-line agents as a percentage of total antibiotic use
increased from 14.4% to 19.3% between January 1995 and March 1998 (p < 0.001).
CONCLUSIONS: Penicillins, macrolides, and sulfonamides accounted for 75% of
antibiotic use. Total antibiotic use declined over the study period; however, use
of newer, broad-spectrum agents increased while use of older, narrow-spectrum
agents decreased.
PMID- 10772431
TI - Carbamazepine--indinavir interaction causes antiretroviral therapy failure.
AB - OBJECTIVE: To report a case of antiretroviral therapy failure caused by an
interaction between carbamazepine and indinavir. CASE SUMMARY: A 48-year-old HIV
positive white man was treated with antiretroviral triple therapy, consisting of
indinavir, zidovudine, and lamivudine. His HIV-RNA (viral load) became
undetectable (<400 copies/mL) less than two months after this therapy was
started; this was confirmed one month later. Shortly after the start of
antiretroviral therapy, the patient developed herpes zoster, which was treated
with famciclovir. Tramadol was initially prescribed for postherpetic neuralgia;
however, this was substituted with carbamazepine due to insufficient analgesic
effect. Indinavir plasma concentrations decreased substantially during
carbamazepine therapy. Carbamazepine was stopped after 2.5 months and, two weeks
later, the HIV-RNA was detectable (6 x 103 copies/mL). Resistance for lamivudine
was observed in that blood sample; resistance for zidovudine might have been
present, and resistance to indinavir was not detected. A few months later, a
further increase of the HIV-RNA occurred (300 x 103 copies/mL), after which the
therapy was switched to a new antiretroviral regimen containing nevirapine,
didanosine, and stavudine. DISCUSSION: Physicians may prescribe carbamazepine for
HIV-infected patients to treat seizures or postherpetic neuralgia, which are
complications of opportunistic infections such as herpes zoster or toxoplasmosis.
Carbamazepine is a potent enzyme inducer, predominantly of the CYP3A enzyme
system, while HIV-protease inhibitors such as indinavir are substrates for and
inhibitors of CYP3A. Therefore, an interaction between these drugs could be
expected. A low dose of carbamazepine (200 mg/d) and the usual dose of indinavir
(800 mg q8h) in our patient resulted in carbamazepine concentrations within the
therapeutic range for epilepsy treatment; indinavir concentrations dropped
substantially. The virologic, resistance, and plasma drug concentration data, as
well as the chronology of events, are highly indicative of antiretroviral
treatment failure due to the interaction between carbamazepine and indinavir.
CONCLUSIONS: Concomitant use of carbamazepine and indinavir may cause failure of
antiretroviral therapy due to insufficient indinavir plasma concentrations. Drugs
other than carbamazepine should be considered to prevent this interaction.
Amitriptyline or gabapentin are alternatives for postherpetic neuralgia; valproic
acid or lamotrigine are alternatives for seizures. When alternate drug therapy is
not possible, dosage adjustments, therapeutic drug monitoring, and careful
clinical observation may help reduce adverse clinical consequences.
PMID- 10772432
TI - Bupropion-induced serum sickness-like reaction.
AB - OBJECTIVE: To report three cases of serum sickness-like reaction (SSLR)
associated with bupropion ingestion. CASE SUMMARY: A 27-year-old woman, a 46-year
old man, and a 43-year-old woman presented to our emergency department within a
three-week period with symptoms consistent with SSLR. Symptoms consisted of
pruritic skin rash, tongue swelling, and arthralgias. All three patients had
initiated bupropion therapy within two to three weeks prior to arrival.
DISCUSSION: This is the second published case describing SSLRs associated with
bupropion. Reports of urticaria and rash with bupropion use are numerous and the
incidence has been estimated at between 1% and 4%. Arthralgia and arthropathy
with bupropion use are reported much less commonly. The onset of symptoms of
SSLRs typically begins six to 21 days after administration of the causative
agent. SSLRs are usually self-limiting, lasting four to 14 days. CONCLUSIONS:
SSLRs following bupropion ingestion appear to be rare. However, the fact that
this cluster of patients presented to our emergency department within a three
week period suggests that this reaction may be underreported.
PMID- 10772433
TI - Anaphylactic reactions to proton-pump inhibitors.
AB - OBJECTIVE: To report two cases of anaphylactic reactions to proton-pump
inhibitors (PPIs). CASE SUMMARIES: A 54-year-old woman who had taken omeprazole
in the past was treated with omeprazole 40 mg and developed periorbital edema,
edema of the skin, pruritus, nausea, and vomiting about 45 minutes after taking
one capsule. Five months later, she was treated with lansoprazole 30-mg capsules.
Again, within 45 minutes she developed an even more serious reaction, with
pruritus and urticaria on her whole body, increased sweating, facial edema, and
loss of consciousness. A 61 -year-old man took one tablet of pantoprazole 40 mg
one year after first being treated with the drug. Within hours after ingestion,
he developed malaise, generalized pruritus and urticaria, a swollen tongue and
eyes, and diffuse sweating; his blood pressure decreased to 75/50 mm Hg.
DISCUSSION: Because of the acute onset of symptoms and close temporal association
with exposure to the drug, as well as previous exposure to it, the reactions can
be classified as anaphylactic shock to PPIs. These benzimidazole derivatives are
chemically related; observations in a few patients, such as the first case above,
suggest that cross-sensitivity may occur. The Uppsala Monitoring Centre (UMC) has
received a total of 42 reports of anaphylactic reactions or anaphylactic shock in
association with PPIs. These reports account for 0.2% of the total of reported
suspected adverse drug reactions to PPIs, compared with 0.8% anaphylactic
reactions in the UMC database as a whole. CONCLUSIONS: These findings suggest
that the chemically related PPIs can, as a group, cause anaphylactic reactions;
however, the rate is comparatively low. Since anaphylaxis is a potentially
serious reaction, more precise information is needed regarding its frequency, and
healthcare professionals need to be aware of this possibility when prescribing
these agents.
PMID- 10772434
TI - Outpatient carboplatin desensitization in a pediatric patient with bilateral
optic glioma.
AB - OBJECTIVE: To report a case of successful outpatient carboplatin desensitization
in a pediatric patient with bilateral optic glioma. CASE SUMMARY: A 10-year-old
white girl with bilateral optic glioma developed a hypersensitivity reaction to
carboplatin after nine courses. She had received 18 courses six years earlier
without incident. A desensitization regimen was administered, and she has
tolerated all subsequent courses of carboplatin therapy. DISCUSSION: Carboplatin
is an important chemotherapeutic agent in the treatment of a variety of pediatric
brain tumors. It is usually given in an outpatient setting. Hypersensitivity to
this agent appears to develop after frequent exposure such as with the once
weekly regimens often used to treat brain tumors in pediatric patients.
CONCLUSIONS: Carboplatin desensitization can be successfully performed on an
outpatient basis with close observation and cardiorespiratory monitoring. This
regimen could prove useful for other patients who develop hypersensitivity
reactions to carboplatin and allow therapy to continue.
PMID- 10772435
TI - Epididymo-orchitis following intravesical bacillus Calmette-Guerin therapy.
AB - OBJECTIVE: To describe a case of epididymo-orchitis that developed four years
after treatment with intravesical bacillus Calmette-Guerin (BCG) and to review
the incidence of this adverse effect. DATA SOURCES: Information about the patient
was obtained from the medical chart. A MEDLINE search of English-language
literature (from January 1976 to April 1999) was conducted. STUDY SELECTION: All
case reports of BCG-related epididymo-orchitis were evaluated. Review articles
describing complications of BCG therapy for bladder cancer and the prevention and
treatment of these complications were reviewed. DATA EXTRACTION: Studies were
evaluated for reports of BCG-related epididymo-orchitis and its treatment. DATA
SYNTHESIS: Our case report is compared with others reported in the literature.
The incidence of BCG-associated epididymoorchitis is rare. CONCLUSIONS: Epididymo
orchitis should be considered as a late complication of BCG therapy for bladder
cancer. Proper patient selection may help decrease the risk of complications from
BCG therapy.
PMID- 10772436
TI - Possible hypothyroidism associated with quetiapine.
AB - OBJECTIVE: To report a case of hypothyroidism occurring after the addition of
quetiapine to an existing drug regimen. CASE SUMMARY: A 46-year-old African
American woman diagnosed with schizoaffective disorder, bipolar type, and a four
year history of successfully treated hyperthyroidism, was suboptimally responsive
to olanzapine treatment. Transition from olanzapine to quetiapine was initiated
and, approximately two months after adding quetiapine to a standing
pharmacotherapeutic regimen, the patient developed an elevated thyroid
stimulating hormone (TSH) concentration of 8.45 microU/L. A diagnosis of
hypothyroidism was subsequently made, treatment with levothyroxine was initiated,
and the patient's thyroid function became stable. DISCUSSION: Drug induced
hypothyroidism is known to occur with several medications. Quetiapine is an
atypical antipsychotic with the potential to decrease thyroid hormone
concentrations in some patients; this effect may be dose related. Despite this
known adverse effect, the manufacturer of quetiapine reports that elevated TSH
concentrations and subsequent treatment with thyroid hormone supplementation have
occurred only rarely. We report the development of hypothyroidism in a patient
who had previously received successful radioactive iodine treatment for
hyperthyroidism in 1994, but who had no detected thyroid abnormalities until
treatment with quetiapine was started four years later. CONCLUSIONS: Patients
with compromised thyroid function who receive treatment with quetiapine may
develop hypothyroidism. Appropriate care for these patients may include an
increased awareness of possible hypothyroidism and consideration of thyroid
function monitoring.
PMID- 10772437
TI - Combination therapy with interferon and ribavirin in the treatment of chronic
hepatitis C infection.
AB - OBJECTIVE: To review and critique the medical literature regarding the
combination of interferon and ribavirin in the initial treatment of chronic
hepatitis C virus (HCV) infection. DATA SOURCES: A MEDLINE search (January 1966
June 1999) was conducted to identify human clinical trials regarding the
combination of interferon and ribavirin therapy for the initial treatment of
chronic HCV. Bibliographies were reviewed for relevant literature. STUDY
SELECTION: Clinical trials of combination interferon and ribavirin for the
treatment of chronic HCV in interferon-naive adults were reviewed. DATA
SYNTHESIS: The combination of ribavirin and interferon in the treatment of
chronic HCV has been beneficial in patients who are interferon-naive. Patients
with predictors of poor response, such as baseline cirrhosis, male gender, age
>40 years, high baseline viral loads (>2 x 10(6) copies/mL), and genotype 1
respond better to combination treatment when compared with those who receive
interferon monotherapy. Patients with genotype 1 and/or high viral loads may
benefit most from 48 weeks of combination therapy; however, adverse effects are
of greater concern in these patients. Monitoring can limit these complications.
CONCLUSIONS: Combination therapy is effective in the treatment of interferon
naive patients with chronic HCV infection. Patients should be evaluated for
duration of treatment with combination therapy by determination of predictors of
response. Further trials are needed to more closely evaluate the duration of
treatment and to determine the best patient population to receive combination
therapy.
PMID- 10772438
TI - Macrolide drug interactions: an update.
AB - OBJECTIVE: To describe the current drug interaction profiles for the commonly
used macrolides in the US and Europe, and to comment on the clinical impact of
these interactions. DATA SOURCES: A MEDLINE search (1975-1998) was performed to
identify all pertinent studies, review articles, and case reports. When
appropriate information was not available in the literature, data were obtained
from the product manufacturers. STUDY SELECTION: All available data were reviewed
to provide an unbiased account of possible drug interactions. DATA EXTRACTION:
Data for some of the interactions were not available from the literature, but
were available from abstracts or company-supplied materials. Although the data
were not always explicit, the best attempt was made to deliver pertinent
information that clinical practitioners would need to formulate practice
opinions. When more in-depth information was supplied in the form of a review or
study report, a thorough explanation of pertinent methodology was supplied. DATA
SYNTHESIS: Several clinically significant drug interactions have been identified
since the approval of erythromycin. These interactions usually were related to
the inhibition of the cytochrome P450 enzyme systems, which are responsible for
the metabolism of many drugs. The decreased metabolism by the macrolides has in
some instances resulted in potentially severe adverse events. The development and
marketing of newer macrolides are hoped to improve the drug interaction profile
associated with this class. However, this has produced variable success. Some of
the newer macrolides demonstrated an interaction profile similar to that of
erythromycin; others have improved profiles. The most success in avoiding drug
interactions related to the inhibition of cytochrome P450 has been through the
development of the azalide subclass, of which azithromycin is the first and only
to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome
P450 system in studies using a human liver microsome model, and to date has
produced none of the classic drug interactions characteristic of the macrolides.
CONCLUSIONS: Most of the available data regarding macrolide drug interactions are
from studies in healthy volunteers and case reports. These data suggest that
clarithromycin appears to have an interaction profile similar to that of
erythromycin. Given this similarity, it is important to consider the interaction
profile of clarithromycin when using erythromycin. This is especially necessary
as funds for further studies of a medication available in generic form (e.g.,
erythromycin) are limited. Azithromycin has produced few clinically significant
interactions with any agent cleared through the cytochrome P450 enzyme system.
Although the available data are promising, the final test should come from
studies conducted in patients who are taking potentially interacting compounds on
a chronic basis.
PMID- 10772439
TI - Enteral nutrition support in acute pancreatitis.
AB - OBJECTIVE: To review the controversies surrounding the use of nutritional
interventions, particularly enteral support, in patients with acute pancreatitis.
DATA SOURCES: Articles were obtained through a MEDLINE search (1966-June 1999).
Additionally, several textbooks containing information on the diagnosis and
management of acute pancreatitis were reviewed. The bibliographies of retrieved
publications and textbooks were reviewed for additional references. STUDY
SELECTION: All original investigations in humans pertaining to the use of enteral
nutritional support in acute pancreatitis were reviewed for inclusion. Studies
that investigated parenteral nutrition in acute pancreatitis were also reviewed,
with preference given to controlled comparisons with enteral regimens or no
nutritional support. DATA EXTRACTION: The primary outcomes extracted from the
literature were time to oral feeding tolerance, complications (e.g., infection)
associated with nutritional support, and length of stay. DATA SYNTHESIS: The
duration of pancreatitis and time to oral feedings is similar whether patients
receive enteral (i.e., jejunal tube feedings) or parenteral nutrition.
Additionally, complications, length of stay, and costs are either similar or
decreased with enteral versus parenteral nutrition. CONCLUSIONS: Current evidence
suggests that the enteral rather than parenteral route should be used to provide
nutrition to patients with acute pancreatitis. Parenteral nutrition should be
reserved for patients in whom nasojejunal feeding is not possible.
PMID- 10772440
TI - Bismuth subgallate-epinephrine paste in adenotonsillectomies.
AB - OBJECTIVE: To evaluate the role of bismuth subgallate-epinephrine (BSE) paste as
a hemostatic in adenotonsillectomies. DATA SOURCES: MEDLINE (January 1966-October
1999) and Current Contents (January 1997-October 1999) were searched, using
bismuth subgallate, adenoidectomy, tonsillectomy, and adenotonsillectomy as
search terms. A citation search was performed using Science Citation Index
(January 1977-October 1999). DATA SYNTHESIS: Adenotonsillectomies are common
procedures; although there are few complications, hemorrhage is a concern.
Bismuth subgallate has historically been used as an astringent and hemostatic. An
evaluation of studies of bismuth subgallate and BSE paste was conducted.
CONCLUSIONS: There is minimal evidence to support this practice, but data suggest
that epinephrine may be the active ingredient in BSE paste. BSE paste is
inexpensive, poses little risk, and may decrease postoperative bleeding;
therefore, it may be a reasonable hemostatic agent.
PMID- 10772441
TI - Angiotensin II receptor blockers in patients with ACE inhibitor-induced
angioedema.
AB - OBJECTIVE: To determine the safety of using angiotensin II receptor blockers in
patients who have experienced angioedema following treatment with angiotensin
converting enzyme (ACE) inhibitors. DATA SOURCES: Clinical literature identified
through MEDLINE (January 1966-August 1999). Key search terms included
angioneurotic edema, angiotensin-converting enzyme inhibitors, receptors
angiotensin, and losartan. DATA SYNTHESIS: ACE inhibitor-induced angioedema
occurs with an incidence of 0.1-0.5%. Alternative therapy is necessary for
patients who experience this potentially life-threatening adverse effect. Since
angiotensin II receptor blockers do not increase concentrations of bradykinin,
the proposed mechanism of ACE inhibitor-induced angioedema, they were presumed to
be safe alternatives. Recent case reports, however, document angioedema following
therapy with angiotensin II receptor blockers; 32% of the reported patients
experienced a prior episode of angioedema attributed to ACE inhibitor therapy.
CONCLUSIONS: Until the exact cause of both ACE inhibitor- and angiotensin II
receptor blocker-induced angioedema is determined, angiotensin II receptor
blockers should be used with extreme caution in patients with a prior history of
angioedema.
PMID- 10772442
TI - Management of complications of bacillus Calmette-Guerin immunotherapy in the
treatment of bladder cancer.
AB - OBJECTIVE: To evaluate the management strategies available for the complications
associated with bacillus Calmette-Guerin (BCG) immunotherapy in the treatment of
bladder cancer. DATA SOURCES: Clinical literature accessed through MEDLINE
(January 1983-January 1999). Key search terms included bacillus Calmette-Guerin,
BCG, and bladder cancer. DATA SYNTHESIS: BCG vaccine is a live-attenuated strain
of Mycobacterium bovis; therefore, the risk for complications exists. An
evaluation of treatment regimens was conducted, and the management strategies are
presented. CONCLUSIONS: The complications associated with BCG immunotherapy range
from local reactions to potentially fatal systemic reactions requiring long-term
therapy. Therefore, healthcare practitioners need to be aware of the current
treatment regimens available.
PMID- 10772443
TI - Efficacy of cryopreserved recombinant alteplase for declotting thrombosed central
catheters.
PMID- 10772444
TI - Recurrent NNRTI-induced hepatotoxicity in an HIV-HCV-coinfected patient.
PMID- 10772445
TI - Tacrolimus-itraconazole interaction in a kidney transplant patient.
PMID- 10772446
TI - Change of valproic acid concentrations during cerebrospinal fluid perfusion
chemotherapy.
PMID- 10772448
TI - Correction: switching antipsychotic therapies
PMID- 10772447
TI - Comment: possible interaction between nefazodone and pravastatin.
PMID- 10772449
TI - Correction: montelukast in asthma management
PMID- 10772450
TI - USPHS-CDC News. Abortion surveillance: preliminary analysis--US, 1997.
PMID- 10772451
TI - Upgrading the twin variables algorithm for large structures.
AB - Phase extension from lower to higher resolution by using an upgraded TWIN
variables algorithm [Hountas & Tsoucaris (1995). Acta Cryst. A51, 754-763] in
protein molecules with close to 1,000 non-H atoms is presented. Three points of
this procedure are of particular interest. (i) The use of a set of auxiliary
variables providing a satisfactory fit for many kinds of constraints: the new
algorithm works efficiently despite the extreme 'dilution' of very limited
initial phase information into a much larger set of auxiliary variables. (ii) The
extension of this auxiliary variables set beyond the resolution of the observed
data, which enhances the phase extension in a so-called 'super-resolution'
sphere. (iii) The use of the crystallographic symmetry as a new figure of merit
and as a reliable test for the correctness of the phase-extension process allows
an efficient screening.
PMID- 10772452
TI - Ill-conditioned Shake-and-Bake: the trap of the false minimum.
AB - The alternation of phase refinement with the imposition of real-space constraints
is the essence of the Shake-and-Bake procedure. Typically, these constraints
prevent trial structures from falling into local minima. Nevertheless, P1
structures appear to migrate to false minima with significant frequency. These
false minima are characterized by the presence of a large 'uranium' peak on the
corresponding Fourier map. Fortunately, they can be recognized and avoided by
considering the values of the minimal function both before and after the
application of constraints. However, it appears that finding solutions for large
P1 structures is likely also to require parameter-shift conditions different from
those that have been found to work well in other space groups. In fact, these
conditions often yield an unusually high percentage of solutions.
PMID- 10772453
TI - Inversion of dynamical electron diffraction data including absorption
AB - A method to invert the dynamical diffraction of high-energy electrons inside a
crystal, which takes into account absorption, is discussed. It is shown that,
working at fixed energy, the projected potentials associated with both the
elastic and the absorptive scattering can be uniquely obtained from the
scattering matrix. Inversion is possible for any principal orientation of the
incident beam. Model examples are given.
PMID- 10772454
TI - Solving the Sayre equation by simulated annealing
AB - Simulated annealing is used to solve the Sayre equation formulated as a
minimization problem. Trial calculations for structures containing up to 126 non
H equal atoms have been carried out. The residual as a function of the fictitious
temperature always exhibits a sudden drop before the emergence of the correct
structure at low temperature. This behavior casts doubt on the suitability of
solving the Sayre equation by steepest-descent methods.
PMID- 10772455
TI - Twins and allotwins of basic mica polytypes: theoretical derivation and
identification in the reciprocal space
AB - The geometry of the diffraction pattern from twins and allotwins of the four
basic mica polytypes (1M, 2M1, 3T, 2M2) is analysed in terms of the 'minimal
rhombus', a geometrical asymmetric unit in reciprocal space defined by nine
translationally independent reciprocal-lattice rows. The minimal rhombus contains
the necessary information to decompose the reciprocal lattice of twins or
allotwins into the reciprocal lattices of the individuals. The nine
translationally independent reciprocal-lattice rows are divided into three types
(S, D and X): rows of different type are not overlapped by the n x 60 degrees
rotations about c*, which correspond to the relative rotations between pairs of
twinned or allotwinned individuals. A symbolic representation of the absolute
orientation of the individuals, similar to that used for layers in polytypes, is
introduced. The polytypes 1M and 2M1 undergo twinning by reticular pseudo
merohedry with five pairs of twin laws: they produce twelve independent twins, of
which nine can be distinguished by the minimal rhombus analysis. The 2M2 polytype
has two pairs of twin laws by pseudo-merohedry, which give a single diffraction
pattern geometrically indistinguishable from that of the single crystal, and
three pairs of twin laws by reticular pseudo-merohedry, which give a single
diffraction pattern different from that of the single crystal. The 3T polytype
has three twin laws: one corresponds to complete merohedry and the other two to
selective merohedry. Selective merohedry produces only partial restoration of the
weighted reciprocal lattice built on the family rows and the presence of twinning
can be recognized from the geometry of the diffraction pattern.
PMID- 10772456
TI - New aspects in the crystal chemistry of (M2CU2O3)m(CuO2)n-type (M = Ca, Sr, Y,
Bi) cuprates
AB - The structural regularities of (M2Cu2O3)m(CuO2)n-type (M = Ca, Sr, Y, Bi)
cuprates with ladder-type planes have been considered. On the basis of the
structural studies of the samples grown by floating-zone and flux methods, it was
concluded that the phase (M2Cu2O3)(CU1+deltaO2+gamma), described as the m/n = 1/1
member, with Cu-deficient Cu-O ribbons in the series (M2Cu2O3)m(CuO2)n can be
treated as an individual structural type intermediate between SrCu2O3 and
incommensurate-type phases (M2Cu2O3)m(CuO2)n with m not equal n. The deficiency
of the Cu sites in CuO ribbons is a particular crystal-chemistry feature of this
structural type, in addition to the geometrical feature (m = n). The structural
type of the 'Cu-deficient ladder' can transform into the incommensurate-type
phases (M2Cu2O3)m(CUO2)n (m/n = 5/7, 7/10, 9/13 etc.) in the presence of free
[CuO4]6- radicals in the melt. A realization of the (M2Cu2O3)m(CuO2)n phase with
a particular m/n value is caused by the type of M cation. On the basis of recent
data, the role of trivalent ions in the chemical composition of the
(M2Cu2O3)m(CuO2)n-type compounds was also analyzed. The occurrence of the
superconductivity in (Sr,Ca)CuO2 samples is discussed by analogy with cuprates of
the infinite-layer structure.
PMID- 10772457
TI - Expansion of scalar validation criteria to three dimensions: the R tensor
AB - Assessment of quality in crystal structure determination entails analysis of
global statistics. In data reduction, quality is assessed using R(merge) and mean
I/sigma(I). Progress in structure solution and refinement is checked by the
goodness of fit, variants of the R index, R(cryst), and its cross-validation
counterpart, R(free). These statistics are useful and provide a convenient means
of comparison but their scalar nature renders them unable to capture the essence
of three-dimensional entities such as diffraction patterns and molecular models.
A simple general method to quantify spatial variations in scalar statistics has
been developed. In it, a symmetric matrix, the R tensor, is used to represent the
local average residual as a function of diffraction geometry. An effective value
of the statistic in question can then be found for any direction in reciprocal
space. Differences between these effective R indices for individual reflections
or groups of reflections can help to steer refinement strategy and assess the
final structure.
PMID- 10772458
TI - X-ray diffraction from an atomic plane
AB - Reflection and transmission coefficients of X-rays by a single atomic plane are
obtained in the general case where the plane consists of any two-dimensional
Bravais lattice and the incident and exit X-ray beams take any direction with
respect to the plane. A formula obtained for the coefficients is written in a
simple form, different from that obtained by Durbin [Acta Cryst. (1995), A51, 258
268]. This makes it possible to extend Darwin's dynamical theory of X-ray
diffraction to general geometries which include the cases of asymmetric skew
reflection and noncoplanar multibeam diffraction.
PMID- 10772459
TI - The likelihood function in fiber diffraction
AB - The likelihood function is an appropriate target function for refinement of
molecular structures using fiber diffraction data. However, its practical
application to fiber diffraction faces two significant obstacles: (i) the
intensities of layer lines in a fiber diffraction pattern usually arise from the
superposition of several terms, each equivalent to a crystallographic structure
factor, thereby making the calculation significantly more complex than for the
crystallographic case; (ii) to describe a molecular structure at the atomic level
based on fiber diffraction data, the radial and phase parts of the atomic
coordinates must be treated separately owing to the uniaxial symmetry of the
structure. These issues are addressed here in order to derive equations of
likelihood functions for fiber diffraction. The special case of a single term on
a layer line is treated first followed by extension of the method to the
multiterm case. A practical difficulty in implementation of likelihood for the
multiterm case is that each term has a different variance. An analytical
technique is described that allows the conversion of the unequal-variance case to
an equal-variance case. This makes it possible to express the likelihood by an
explicit formula, allowing a direct implementation of the likelihood calculation.
A cylindrically symmetric model is proposed for error distribution of the atomic
coordinates in a helical structure. Variances and offset coefficients of the
contributing terms in the likelihood functions are expressed in terms of the
variance of the atomic coordinates in the cylindrical reference system.
PMID- 10772460
TI - Search for isotypism in crystal structures by means of the graph theory
AB - A method for the classification of crystal structures of chemical compounds is
proposed, which is based on the representation of the system of interatomic bonds
in a crystal as a finite 'reduced' graph. The program IsoTest is described,
allowing one to find automatically the topological similarity (isotypism) for
large groups of stoichiometrically and structurally different compounds. The
analysis of crystal structures of simple and double sulfates and binary inorganic
compounds was carried out and numerous examples of topological isotypism of the
representatives of these groups of substances were found. It is shown that in
many cases the ionic sublattices, constructed according to one of the close
packings, can be selected in the sulfate crystal structures.
PMID- 10772461
TI - Measurement of Debye-Waller factors in Co3Ti by quantitative CBED
AB - The Debye-Waller factors (DWFs) of Co and Ti atoms in Co3Ti have been obtained by
quantitative convergent-beam electron diffraction (QCBED). They are B(Co) = 0.20
0.24 and BTi = 0.41-0.43 A2 in Co3Ti at room temperature. A modified simulated
annealing algorithm and its parallel algorithm were employed to obtain reliable
results efficiently.
PMID- 10772462
TI - Large-scale production of CMP-NeuAc and sialylated oligosaccharides through
bacterial coupling.
AB - A large-scale production system of cytidine 5'monophospho-N-acetylneuraminic acid
(CMP-NeuAc) and sialyloligosaccharides was established by a whole-cell reaction
through the combination of recombinant Escherichia coli strains and
Corynebacterium ammonia-genes. For the production of CMP-NeuAc, two recombinant
E. coli strains were generated that overexpressed the genes of CMP-NeuAc
synthetase and CTP synthetase, respectively. C. ammoniagenes contributed to the
formation of UTP from orotic acid. CMP-NeuAc was accumulated at 27 mM (17 g/l)
after a 27-h reaction starting with orotic acid and N-acetylneuraminic acid. When
E. coli cells that overexpressed the alpha-(2-->3)-sialyltransferase gene of
Neisseria gonorrhoeae were put into the CMP-NeuAc production system, 3'
sialyllactose was accumulated at 52 mM (33 g/l) after an 11-h reaction starting
with orotic acid, N-acetylneuraminic acid, and lactose. Almost no oligosaccharide
byproducts other than 3'-sialyllactose were observed after the reaction. The
production of 3'-sialyllactose at a 5-l jar fermenter scale was almost the same
as that at a beaker scale, which indicated the high potential of the 3'
sialyllactose production on an industrial scale.
PMID- 10772463
TI - Effects of buffered media upon growth and alkaloid production of Catharanthus
roseus hairy roots.
AB - The influence of buffered media upon the growth and alkaloid productivity of
Catharanthus roseus hairy root culture was examined. As expected, the buffers
minimized shifts in the pH of the media and had slightly negative effects upon
growth. The growth of the hairy roots remained optimal in unbuffered media. The
specific yield of lochnericine was significantly lower in response to the
addition of buffers, while tabersonine was significantly higher. In contrast, the
specific yields of ajmalicine, serpentine, and horhammericine remained unchanged.
PMID- 10772464
TI - Optimization of the hydroxylation of 2-cyclopentylbenzoxazole with Cunninghamella
blakesleeana DSMZ 1906.
AB - Biohydroxylation of 2-cyclopentyl-1,3-benzoxazole with the filamentous fungus
Cunninghamella blakesleeana DSMZ 1906 was studied in a 15-l stirred tank reactor.
The aim of the work was to avoid substrate limitation through sub-optimal mixing
by formation of pellets with a uniform pellet size distribution of 250-500
microm, obtained at an inoculum concentration of 10(7) spores ml(-1) and an
agitation rate of 390 rpm. Due to the high toxicity of the educt, 2-cyclopentyl
1,3-benzoxazole, on the fungus, the medium composition, the time of educt
addition, and the educt starting concentration were optimized to reach high educt
tolerance and hydroxylation activity. A good maintenance of biotransformation
capacity was obtained without excessive loss of activity of the biocatalyst by
addition of 30 mg 2-cyclopentyl-1,3-benzoxazole/g biomass (cell dry mass) during
the stationary phase in a medium which was optimized in batch fermentations with
experimental designs. An increase in product yield and quality (enantiomeric
excess) was achieved by developing feeding strategies combining the educt and
medium components. The resulting fermentation broth contained 450 mg l(-1) of the
product (1S,3S)-3-(benz-1,3-oxazol-2-yl)cyclopentan-1-ol with an enantiomeric
excess of 95%, which represents a 48% increase over former reported results.
PMID- 10772465
TI - Glucoamylase production in batch, chemostat and fed-batch cultivations by an
industrial strain of Aspergillus niger.
AB - The Aspergillus niger strain BO-1 was grown in batch, continuous (chemostat) and
fed-batch cultivations in order to study the production of the extracellular
enzyme glucoamylase under different growth conditions. In the pH range 2.5-6.0,
the specific glucoamylase productivity and the specific growth rate of the fungus
were independent of pH when grown in batch cultivations. The specific
glucoamylase productivity increased linearly with the specific growth rate in the
range 0-0.1 h(-1) and was constant in the range 0.1-0.2 h(-1). Maltose and
maltodextrin were non-inducing carbon sources compared to glucose, and the
maximum specific growth rate was 0.19 +/- 0.02 h(-1) irrespective of whether
glucose or maltose was the carbon source. In fed-batch cultivations, glucoamylase
titres of up to 6.5 g l(-1) were obtained even though the strain contained only
one copy of the glaA gene.
PMID- 10772466
TI - The influence of nitrogen sources on the alpha-amylase productivity of
Aspergillus oryzae in continuous cultures.
AB - The influence of the nitrogen source on the alpha-amylase productivity of
Aspergillus oryzae was quantified in continuous cultivations. Both inorganic and
complex nitrogen sources were investigated and glucose was used as the carbon and
energy sources. For production of alpha-amylase, nitrate was shown to be inferior
to ammonia as a nitrogen source. A mixture of ammonia and complex nitrogen
sources, such as yeast extract or casein hydrolysate, was better than with
ammonia as the sole nitrogen source. Even a low concentration of casein
hydrolysate (0.05 g l(-1)) resulted in a 35% increase in the alpha-amylase
productivity. The higher alpha-amylase productivity during growth on casein
hydrolysate was not caused by increased transcription of the alpha-amylase genes
but was caused by a faster secretion of alpha-amylase or by a lower binding of
alpha-amylase to the biomass.
PMID- 10772467
TI - Overexpression of the lat gene in Nocardia lactamdurans from strong heterologous
promoters results in very high levels of lysine-6-aminotransferase and up to two
fold increase in cephamycin C production.
AB - The level of lysine-6-aminotransferase (encoded by the lat gene), an enzyme that
commits lysine to the cephamycin biosynthesis pathway, is very low in wild type
Nocardia lactamdurans. Two lat overexpression systems (pAMEXlat and pSAFlat) were
constructed to express the promoterless lat gene of N. lactamdurans from the
strong promoters amyP (of the alpha-amylase gene) and safP (of the secretion
activating factor gene) of Streptomyces griseus. Both constructions led to very
high levels of lysine-6-aminotransferase (between 8- and 15-fold) in the cells.
Expression of lat from the amy promoter was optimal in glycerol-containing medium
and was negatively regulated by glucose. The high levels of lysine-6
aminotransferase resulted in a 50-200% increase in cephamycin C production in the
standard fermentation conditions. Onset of cephamycin C biosynthesis occurred at
the same time in control and in lat-overexpressing strains, but the cephamycin
production rate was clearly higher in transformants overexpressing the lat gene.
Furthermore, HPLC analysis of cephamycin C in the culture broths revealed an
early depletion of biosynthetic intermediates and an accumulation of cephamycin C
when the lat gene was overexpressed. These results indicate that lysine-6
aminotransferase activity is limiting for cephamycin C biosynthesis under some
culture conditions.
PMID- 10772468
TI - Molecular identification of Acetobacter isolates from submerged vinegar
production, sequence analysis of plasmid pJK2-1 and application in the
development of a cloning vector.
AB - Three new Acetobacter strains were isolated from vinegar. By plasmid profiling
they were recognized as genotypically different from each other. Sequencing of
the genes for 16S and 23S rRNA and DNA-DNA hybridization of total DNA against DNA
of all type strains of Acetobacter identified Acetobacter strains JK2 and V3 as
A. europaeus, and Acetobacter strain JK3 as A. intermedius. In contrast to the
type strain of A. europaeus (DSM 6160), A. europaeus JK2 and V3 do not require
acetic acid for growth and can be successfully transferred between media with and
without acetic acid. This phenotypic characteristic enables convenient handling
of both strains in genetic studies. Plasmid pJK2-1 from A. europaeus JK2 was used
as the basis for shuttle plasmid construction with the aim of developing an
efficient vector system for these strains. The entire nucleotide sequence of pJK2
1 was determined. High amino acid identities were found for three open reading
frames: Rep (replication protein); Dinjl (DNA damage inducible enzyme); and Dinj2
proteins. A recombinant plasmid pUCJK2-1 (5.6 kb) consisting of the entire
plasmid pJK2-1 and the entire plasmid pUC18 was successfully used in
transformation experiments. Plasmid pJT2 (5.8 kb) was constructed from pUCJK2-1
with the aim of reactivating the lacZ' gene.
PMID- 10772469
TI - Molecular analysis of the Aureobasidium pullulans ura3 gene encoding orotidine-5'
phosphate decarboxylase and isolation of mutants defective in this gene.
AB - Orotidine-5'-phosphate decarboxylase (OMP decarboxylase) catalyses the final step
in the pyrimidine biosynthesis, the conversion of orotidine-5'-phosphate (OMP) to
uridine-5'-phosphate. The ura3 gene of Aureobasidium pullulans. encoding OMP
decarboxylase, was isolated from an Aureobasidium genomic library constructed in
the plasmid pBlueskriptSK-. The ura3 gene of A. pullulans has an open reading
frame of 271 amino acid residues. Analysis of the sequence revealed the presence
of two introns. In the predicted amino acid sequence there are regions of strong
homology to the equivalent genes of Aspergillus niger, Neurospora crassa,
Phycomyces blakesleeanus and Homo sapiens. The ura3 gene is the third
Aureobasidium gene that has been cloned and analysed. We have also isolated ura3
mutants by selection of ethyl methanesulphonate mutagenised cells on 5
fluoroorotic acid. Transformation of these A. pullulans mutant strains to
prototrophy showed the functionality of the cloned gene.
PMID- 10772470
TI - Simultaneous bioconversion of glucose and xylose to ethanol by Saccharomyces
cerevisiae in the presence of xylose isomerase.
AB - Simultaneous isomerisation and fermentation (SIF) of xylose and simultaneous
isomerisation and cofermentation (SICF) of a glucose/xylose mixture was carried
out by Saccharomyces cerevisiae in the presence of xylose isomerase. The SIF of
50 g I(-1) xylose gave an ethanol concentration and metabolic yield of 7.5 g l(
1) and 0.36 g (g xylose consumed)(-1). These parameters improved to 13.4 g l(-1)
and 0.40 respectively, when borate was added to the medium. The SICF of a mixture
of 50 g l(-1) glucose and 50 g l(-1) xylose gave an ethanol concentration and
metabolic yield of 29.8 g l(-1) and 0.42 respectively, in the presence of borate.
Temperature modulation from 30 degrees C to 35 degrees C during fermentation
further enhanced the above parameters to 39 g l(-1) and 0.45 respectively. The
approach was extended to the bioconversion of sugars present in a real
lignocellulose hydrolysate (peanut-shell hydrolysate) to ethanol, with a fairly
good yield.
PMID- 10772471
TI - Metabolism of the ethanolamine-type antihistamine diphenhydramine (Benadryl) by
the fungus Cunninghamella elegans.
AB - Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC
36112) were grown in Sabouraud dextrose broth and screened for the ability to
metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the
amount of parent drug recovered after 7 days incubation, both C. elegans strains
metabolized approximately 74% of the diphenhydramine, 58% of this being
identified as organic extractable metabolites. The organic extractable
metabolites were isolated by reversed-phase high-performance liquid
chromatography and identified by analyzing their mass and nuclear magnetic
resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with
deuterated ammonia was used to differentiate possible isobaric diphenhydramine
metabolites and to probe the mechanisms of ion formation under ammonia DCIMS
conditions. C. elegans transformed diphenhydramine by demethylation, oxidation,
and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide
(3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%),
and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known
mammalian metabolites of diphenhydramine and may be useful for further
toxicological studies.
PMID- 10772472
TI - The effect of culture conditions on the morphology of the dimorphic yeast
Kluyveromyces marxianus var. marxianus NRRLy2415: a study incorporating image
analysis.
AB - The effect of changing environmental conditions on the morphology of the yeast
Kluyveromyces marxianus var. marxianus NRRLy2415 was investigated in batch and
continuous culture, using a previously developed computer-aided image analysis
protocol [O'Shea and Walsh (1996) Biotechnol Bioeng 51: 679 690]. The morphology
of the organism is primarily controlled by the specific growth rate, mu. This
finding was contrary to a previous investigation [Walker and O'Neill (1990) J
Chem Tech Biotechnol 49: 75-89]. When the organism is cultured in batch with
excess oxygen, mu can approach the maximum specific growth rate, microm, and the
primary morphology of the culture is yeast-like. However, if the organism is
cultured in a chemostat, thereby controlling the growth rate, the morphology
reverts to a pseudohyphal form. This response is thought to be an adaptation by
the organism to its environment, whereby it assumes a foraging form under adverse
environmental conditions. The use of computer-aided image analysis made possible
the discrimination of subtle morphological differences between samples and the
determination of the relationship between morphology and growth rate.
PMID- 10772473
TI - Characterization of an extracellular poly(3-hydroxy-5-phenylvalerate)
depolymerase from Xanthomonas sp. JS02.
AB - A bacterium, JS02, capable of degrading an aromatic medium-chain-length
polyhydroxyalkanoate (PHA(MCL)), poly(3-hydroxy-5-phenylvalerate) (PHPV), was
isolated from wastewater-treatment sludge (Ju et al. 1998), and was identified as
a Xanthomonas species. An extracellular PHPV depolymerase was purified from the
concentrated culture broth of Xanthomonas sp. JS02 by using a chromatography
series on Sephadex G-75, QAE-Sephadex A-50 and hydroxyapatite. The molecular mass
of the purified enzyme was estimated to be 41.7 kDa. The purified enzyme could
hydrolyse PHPV and p-nitrophenyl (PNP)-esters of fatty acids, but did not
hydrolyse short-chain-length PHAs, though the culture supernatant could hydrolyse
them. The optimum pH range was 8.0-9.0 and the optimum temperature was 60 degrees
C for PNP-octanoate hydrolysis. The Km values for PNP-hexanoate and PNP-octanoate
were 10.9 and 0.88 microM, respectively.
PMID- 10772474
TI - Degradation of the metal-cyano complex tetracyanonickelate (II) by Fusarium
oxysporum N-10.
AB - A fungus with the ability to utilize a metalcyano compound, tetracyanonickelate
(II) ?K2[Ni (CN)4]; TCN?, as its sole source of nitrogen was isolated from soil
and identified as Fusarium oxysporum N-10. Both intact mycelia and cell-free
extract of the strain catalyzed hydrolysis of TCN to formate and ammonia and
produced formamide as an intermediate, thereby indicating that a hydratase and an
amidase sequentially participated in the degradation of TCN. The enzyme
catalyzing the hydration of TCN was purified approximately ten-fold from the cell
free extract of strain N-10 with a yield of 29%. The molecular mass of the active
enzyme was estimated to be 160 kDa. The enzyme appears to exist as a
homotetramer, each subunit having a molecular mass of 40 kDa. The enzyme also
catalyzed the hydration of KCN, with a cyanide-hydrating activity 2 x 10(4) times
greater than for TCN. The kinetic parameters for TCN and KCN indicated that
hydratase isolated from F. oxysporum was a cyanide hydratase able to utilize a
broad range of cyano compounds and nitriles as substrates.
PMID- 10772475
TI - Bioconversion of alpha pinene to verbenone by resting cells of Aspergillus niger.
AB - Resting cells of a locally isolated strain of Aspergillus niger caused the
bioconversion of alpha pinene to verbenone. The formation of verbenone was raised
from trace amounts (under screening conditions) to 3.28 mg/100 ml (equivalent to
a molar yield of 16.5% conversion of the substrate) by amending the cultivation
medium for the fungus. The optimal conditions were: 6 g/100 ml for the glucose
concentration, a pH of 7.0, an alpha pinene concentration of 20 mg/100 ml, and a
6-h incubation period for the reaction.
PMID- 10772476
TI - Lead, copper and zinc biosorption from biocomponent systems modelled by empirical
Freundlich isotherm.
AB - The biosorption of lead, copper and zinc ions on Rhizopus arrhizus has been
studied for three single-component and two binary systems. The equilibrium data
have been analysed using the Freundlich adsorption model. The characteristic
parameters for the Freundlich adsorption model have been determined and the
competition coefficients for the competitive biosorption of Pb(II)-Cu(II) at pH
4.0 and 5.0, and Pb(II)-Zn(II) at pH 5.0 have been calculated. For the individual
single-component isotherms, lead has the highest biosorption capacity followed by
copper, then zinc. The capacity of lead in the two binary systems is always
significantly greater than those of the other metal ions, in agreement with the
single-component data. Only a partial selectivity for copper ions has been
obtained at pH 4.0.
PMID- 10772477
TI - Anaerobic degradation of fluorinated aromatic compounds.
AB - Anaerobic enrichment cultures with sediment from an intertidal strait as inoculum
were established under denitrifying, sulfate-reducing, iron-reducing and
methanogenic conditions to examine the biodegradation of mono-fluorophenol and
mono-fluorobenzoate isomers. Both phenol and benzoate were utilized within 2-6
weeks under all electron-accepting conditions. However, no degradation of the
fluorophenols was observed within 1 year under any of the anaerobic conditions
tested. Under denitrifying conditions, 2-fluorobenzoate and 4-fluorobenzoate were
depleted within 84 days and 28 days, respectively. No loss of 3-fluorobenzoate
was observed. All three fluorobenzoate isomers were recalcitrant under sulfate
reducing, iron-reducing, and methanogenic conditions. The degradation of the
fluorobenzoate isomers under denitrifying conditions was examined in more detail
using soils and sediments from different geographic regions around the world.
Stable enrichment cultures were obtained on 2-fluorobenzoate or 4-fluorobenzoate
with inoculum from most sites. Fluoride was released stoichiometrically, and
nitrate reduction corresponded to the values predicted for oxidation of
fluorobenzoate to CO2 coupled to denitrification. The 2-fluorobenzoate-utilizing
and 4-fluorobenzoate-utilizing cultures were specific for fluorobenzoates and did
not utilize other halogenated (chloro-, bromo-, iodo-) benzoic acids. Two
denitrifying strains were isolated that utilized 2-fluorobenzoate and 4
fluorobenzoate as growth substrates. Preliminary characterization indicated that
the strains were closely related to Pseudomonas stutzeri.
PMID- 10772478
TI - Hexavalent chromium reduction by a dichromate-resistant gram-positive bacterium
isolated from effluents of tanneries.
AB - A gram-positive, chromium (Cr)-resistant bacterial strain (ATCC 700729) was
isolated from effluent of tanneries. It was grown in media containing potassium
dichromate concentration up to 80 mg ml(-1) of the medium. The dichromate
reducing capability of the bacterium was checked by estimating the amount of Cr
VI in the medium before and after introduction of bacterial culture. The
influence of factors like pH of the medium, concentration of Cr, and the amount
of the inoculum was studied to determine the ability of the bacterium to reduce
Cr VI in the medium under various conditions. In a medium containing dichromate
20 mg ml(-1) more than 87% reduction of dichromate ions was achieved within 72 h.
The feasibility of the use of this bacterial strain for detoxification of
dichromate in the industrial wastewater has been assessed. The isolated strain
can be exploited for specific environmental clean-up operations.
PMID- 10772479
TI - Reports of clinical studies of cancer chemotherapy are retrospective and
uncontrolled.
PMID- 10772480
TI - Towards evidence-based veterinary medicine.
PMID- 10772481
TI - Evaluation of a high-dose chemotherapy protocol with no maintenance therapy for
dogs with lymphoma.
AB - The purpose of this study was to evaluate the efficacy and toxicity of an
intensified dose protocol with no maintenance phase for the treatment of canine
lymphoma. Forty-nine dogs all weighing more than 15 kg were entered. Dogs were
staged and treated with a modified version of the University of Wisconsin (UW)
Madison protocol for lymphoma. Modifications included increased dosages of
cyclophosphamide (250 mg/m2 compared to 200 mg/m2) and doxorubicin (37.5 mg/m2
compared to 30 mg/m2), with no crossover to chlorambucil or methotrexate. After
25 weeks on protocol (17 treatments), therapy was discontinued and dogs were
monitored for relapse on a monthly basis. Disease-free interval (DFI) and overall
survival were compared to 55 historical controls treated with the UW-Madison
protocol. The 2 groups were comparable with respect to age, sex, breed, stage,
presence of hypercalcemia, and CD3 status; a trend toward more substage b dogs
was present in the high-dose group (P = .076). When comparing response rate, DFI,
death due to disease, and death due to treatment-related toxicity, more dogs were
dead due to toxicity (P < .001; odds ratio = 8.8) in the high-dose group. Overall
survival between the high-dose and control groups did not differ significantly (P
= .55) at 270 and 318 days, respectively. The intensified dose protocol is an
option for owners who are willing to risk higher toxicity for a shorter protocol
with no statistical difference in survival from the UW-Madison protocol.
PMID- 10772482
TI - Helicobacter infection in dogs and cats: facts and fiction.
AB - The discovery of the spiral bacterium Helicobacter pylori and its causative role
in gastric disease in humans has brought a dramatic change to gastroenterology.
Although spiral bacteria have been known for more than a century to infect the
stomachs of dogs and cats, recent research has been conducted mainly in the wake
of interest in H. pylori. H. pylori has not been found in dogs and only very
rarely in cats and zoonotic risk is minimal. A variety of other Helicobacter spp.
can infect the stomach of pets; however, their pathogenic role is far from clear,
and they have a small but real zoonotic potential. The prevalence of gastric
Helicobacter spp. in dogs and cats is high, irrespective of clinical signs, and
as in human medicine, mode of transmission is unclear. The relationship of
Helicobacter spp. to gastric inflammation in cats and dogs is unresolved, with
inflammation, glandular degeneration, and lymphoid follicle hyperplasia
accompanying infection in some but not all subjects. Circulating anti
Helicobacter immunoglobulin G antibodies have been detected in 80% of dogs with
naturally acquired infection and most dogs and cats with experimental infection.
The gastric secretory axis is similar in infected and uninfected cats and dogs
and no relationship of infection to gastrointestinal ulcers has been found.
Differences in the pathogenicity of Helicobacter spp. are apparent, because
infection with H pylori is associated with a more severe gastritis than infection
with other Helicobacter spp. in both cats and dogs. Rapid urease test,
histopathology, and touch cytology are all highly accurate invasive diagnostic
tests for gastric Helicobacter-like organisms in dogs and cats, whereas culture
and polymerase chain reaction are the only means to identify them to the species
level. Urea breath and blood tests or serology can be used to diagnose
Helicobacter spp. noninvasively in dogs and cats. Most therapeutic studies in
pets have not shown long-term eradication of Helicobacter spp. Whether this is
due to reinfection or recrudescence has not been established.
PMID- 10772483
TI - Prospective comparative study of 3 treatment protocols using doxycycline or
imidocarb dipropionate in dogs with naturally occurring ehrlichiosis.
AB - This paper reports the clinicopathologic responses of 93 dogs with spontaneously
occurring ehrlichiosis to 3 different treatment protocols. Thirty-two dogs were
treated with doxycycline (10 mg/kg/day for 28 days), 31 were treated with
imidocarb dipropionate (5 mg/kg given 15 days apart in 2 separate injections),
and 30 were treated with both drugs simultaneously, at the doses as specified.
The dogs underwent clinicopathologic evaluation before and after treatment, and
were examined periodically during the 24-month period after the treatment. No
differences were found in the clinical responses among the dogs in the 3
treatment groups. As for the clinicopathologic response, in spite of the fact
that at the end of the study the results obtained with the 3 protocols were
similar, the platelet count and serum protein electrophoresis results returned to
normal more slowly in dogs that received imidocarb dipropionate as compared to
those given the other 2 treatments.
PMID- 10772484
TI - A study of the lifetime occurrence of neoplasia and breed differences in a cohort
of German Shepherd Dogs and Belgian Malinois military working dogs that died in
1992.
AB - The population of U.S. Department of Defense military working dogs provides an
opportunity to study the lifetime occurrence of neoplasia in 2 breeds of dogs-
the German Shepherd Dog and the Belgian Malinois. Medical records were reviewed
for all dogs that died or were euthanized in 1992 (135 German Shepherd Dogs and
106 Belgian Malinois). Histologically confirmed neoplasms were recorded. More
than 30% of both breeds (41 German Shepherd Dogs and 33 Belgian Malinois)
developed at least 1 primary neoplasm during their lives, with 10% developing
more than 1 neoplasm. Nearly 57% of the neoplasms were benign, and approximately
43% were malignant. German Shepherd Dogs lived 9.7 years, on average, and Belgian
Malinois lived 7.9 years, on average. Of the dogs that developed any neoplasm,
Belgian Malinois had a mean age at 1st diagnosis that was 1.1 years younger and a
mean age at 1st diagnosis of malignancy that was 1.7 years younger than those in
German Shepherd Dogs. The risk of a malignancy being the cause of death or
euthanasia of a Belgian Malinois was 4.21 times the risk in German Shepherd Dogs
(95% CI: 1.32, 13.47). Seminoma was the malignancy that occurred most frequently.
Hemangioma was the benign neoplasm that occurred most frequently. Veterinarians
identified masses clinically at equal rates in both groups.
PMID- 10772485
TI - Telomerase enzyme activity as a diagnostic tool to distinguish effusions of
malignant and benign origin.
AB - Telomerase enzyme activity is high in populations of cells that are dividing, and
is low or undetectable in quiescent cell populations. Activation of telomerase in
tissues that normally lack the capacity for self-renewal is strongly correlated
with neoplasia. Telomerase activity can be detected in samples containing very
small numbers of cells and studies of human patients suggest that measurement of
telomerase activity may be useful for the evaluation of samples that can be
obtained in a minimally invasive manner. This study compares the presence or
absence of telomerase activity with cytologic evaluation of body cavity
effusions, to determine if neoplasia is the underlying cause for the effusion in
dogs and cats. Detection of telomerase in effusions was no more sensitive than
cytologic evaluation for the identification of underlying neoplasia, and was less
specific (telomerase assay: sensitivity = 50%, specificity = 83%; cytology:
sensitivity = 50%, specificity = 100%). We conclude that although the telomerase
assay may constitute a useful adjunctive test for the diagnosis of neoplasia in
some dogs and cats with body cavity effusions, the results of this assay are not
sufficiently reliable to be used as a sole diagnostic test.
PMID- 10772486
TI - Frequency of pulmonary mineralization and hypoxemia in 21 dogs with pituitary
dependent hyperadrenocorticism.
AB - The purpose of this study was to determine the frequency of hypoxemia and
pulmonary mineralization using 99mTc-methylene diphosphonate (99mTc-MDP) in dogs
with pituitary-dependent hyperadrenocorticism (PDH). Twenty-one dogs with PDH
were prospectively evaluated using thoracic radiography, arterial blood gas
analysis, and bone phase and pulmonary perfusion scintigraphy (using 99mTc-macro
aggregated albumin [99mTc-MAA]). The radiographs and bone and perfusion studies
were evaluated subjectively. An averaged quantitative count density ratio was
calculated between the thorax and cranial thoraco-lumbar vertebrae from lateral
thoracic 99mTc-MDP images. Thoracic:vertebral ratios were calculated using 99mTc
MDP studies from 21 control dogs. The thoracic:vertebral ratios were compared
between the 2 groups (PDH and control). The mean age (+/-SD) of the 21 PDH dogs
was 10.2 (+/-3) years, whereas the mean age of the control group was 9.8 (+/-3)
years. Seven of the 21 dogs with PDH were hypoxemic (defined as an arterial
partial pressure of oxygen [PaO2] < 80 mm Hg) with an average PaO2 (+/-SD) of 62
(+/-15) mm Hg. Of the 7 hypoxemic dogs, 2 were found to have pulmonary
mineralization based on bone scintigraphic images. Pulmonary perfusion
abnormalities were not identified using 99mTc-MAA in any of the 21 PDH dogs. Six
PDH dogs had an abnormal interstitial pulmonary pattern and 5 of these dogs were
hypoxemic. The average quantitative thoracic:vertebral ratio was not
significantly different between the PDH and control dogs (0.5 +/- 0.4 versus 0.4
+/- 0.1, P = .16). Causes of hypoxemia other than pulmonary thromboembolism
should be considered in dogs with PDH. Pulmonary mineralization may contribute to
hypoxemia in dogs with PDH.
PMID- 10772487
TI - Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and
adrenal function tests in dogs.
AB - Phenobarbital can interfere with the thyroid axis in human beings and rats by
accelerating hepatic thyroxine metabolism because of enzyme induction. In human
beings, it also can interfere with the low-dose dexamethasone suppression test
(LDDST) used to assess adrenal function by accelerating dexamethasone metabolism.
This effect can cause a lack of suppression of pituitary ACTH and subsequent
adrenal cortisol release after dexamethasone administration. The effects of
phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests
were prospectively investigated in 12 normal, adult dogs. Phenobarbital was
administered at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h
for 29 weeks, resulting in therapeutic serum concentrations (20-40 microg/mL).
Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total
triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before
and during phenobarbital treatment. LDDST, ACTH stimulation tests, and
ultrasonographic evaluation of the adrenal glands were performed before and
during treatment. TT4 and FT4 decreased significantly (P < or = .05), TT3 had
minimal fluctuation, TSH had only a delayed compensatory increase, and
cholesterol increased during phenobarbital treatment. The delayed increase in
TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic
thyroxine elimination may not be the only effect of phenobarbital on the thyroid
axis. There was no significant effect of phenobarbital on either of the adrenal
function tests. With the methods employed, we did not find any effects of the
drug on the hormonal equilibrium of the adrenal axis.
PMID- 10772488
TI - Effects of long-term phenobarbital treatment on the liver in dogs.
AB - Long-term administration of phenobarbital has been reported to cause hepatic
injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to
distinguish the effect of enzyme induction on serum liver enzyme activities from
actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of
enzyme induction on serum liver enzyme activity were investigated prospectively
in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per
kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h, resulting in therapeutic
serum phenobarbital concentrations (20-40 microg/mL). Serum alkaline phosphatase
(ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma
glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin
were determined before and during treatment. Lateral abdominal radiographs,
abdominal ultrasounds, and histopathologic examinations of liver tissue obtained
by ultrasound-guided biopsy were performed before and during treatment.
Radiographs revealed a moderate increase in liver size in most dogs.
Ultrasonographic examination revealed no change in liver echogenicity or
architecture. No evidence of morphologic liver damage was observed
histopathologically. ALP and ALT increased significantly (P < .05), GGT increased
transiently, and albumin decreased transiently during the study. There were no
significant changes in AST, bilirubin, and fBA. These results suggest that
increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than
hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and
bilirubin, and ultrasonographic evaluation of the liver are not affected by the
enzyme-inducing effect of phenobarbital and can therefore be helpful to assess
liver disease in dogs treated with the drug.
PMID- 10772489
TI - Population dynamics of inherited copper toxicosis in Dutch Bedlington terriers
(1977-1997).
AB - Inherited copper toxicosis in Bedlington terriers was 1st reported in 1975 and
the entire Dutch population was examined from 1976 until the present for presence
of the disease. To examine the effect on the prevalence of the disease of
excluding affected dogs from breeding we have compared 2 time cohorts, the 1st
consisting of dogs born from January 1, 1976, to January 1, 1986 (n = 155), and
the 2nd of dogs born from January 1, 1990, to January 1, 1997 (n = 195). The
diagnosis was made in the 1st cohort by evaluating liver biopsies, and in the 2nd
cohort with a DNA marker. The population was also resolved into clusters of
related dogs to analyze the familial distribution of the disease in the
population and to search for ancient founders of the disease among the ancestors
of sick dogs. Forty-six percent of dogs examined between 1976 and 1986 had copper
toxicosis. Eleven percent of dogs examined in the 2nd cohort had evidence of
disease. This reduction was achieved while maintaining the already limited
genetic heterogeneity of the population: the number of clusters and the mean
relatedness between the clusters were similar in both time cohorts. The disease
was evenly distributed over the clusters of related dogs in both cohorts. All
ancestors had contributed to the distribution of copper toxicosis and no specific
founders could be identified. This indicates that when the breed was established
in The Netherlands, the disease was already highly prevalent in the founding
dogs.
PMID- 10772490
TI - The role of Acinetobacter baumannii as a nosocomial pathogen for dogs and cats in
an intensive care unit.
AB - Acinetobacter baumannii is a nosocomial pathogen associated with high morbidity
and mortality in humans. Whereas infections with strains of Acinetobacter species
have been reported in various situations, the importance of A baumannii as a
nosocomial pathogen in veterinary hospitals has not been studied so far. In this
retrospective case series, we describe 17 dogs and 2 cats from which A baumannii
had been isolated during a 2 1/2-year period. In 7 dogs, A baumannii induced
systemic signs of illness, whereas 12 animals showed signs of local infection. In
all animals with systemic infection, and in 2 with localized infection, A
baumannii contributed to the death of the animal or contributed to euthanasia;
the remaining 8 dogs and both cats recovered. Molecular typing of the isolates
with restriction polymorphisms of ribosomal DNA provided evidence of nosocomial
spread of this pathogen and for the presence of several strains of A baumannii in
the hospital environment.
PMID- 10772491
TI - Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997).
AB - A retrospective study was conducted to characterize the diseases, clinical
findings, and clinicopathologic and ultrasonographic findings associated with
hypercalcemia (serum calcium concentration >11 mg/dL) in 71 cats presented to
North Carolina State University Veterinary Teaching Hospital. The 3 most common
diagnoses were neoplasia (n = 21), renal failure (n = 18), and urolithiasis (n =
11). Primary hyperparathyroidism was diagnosed in 4 cats. Lymphoma and squamous
cell carcinoma were the most frequently diagnosed tumors. Calcium oxalate
uroliths were diagnosed in 8 of 11 cats with urolithiasis. Cats with neoplasia
had a higher serum calcium concentration (13.5 +/- 2.5 mg/dL) than cats with
renal failure or urolithiasis and renal failure (11.5 +/- 0.4 mg/dL; P < .03).
Serum phosphorus concentration was higher in cats with renal failure than in cats
with neoplasia (P < .004). Despite the fact that the majority of cats with
uroliths were azotemic, their serum urea nitrogen and creatinine concentrations
and urine specific gravity differed from that of cats with renal failure.
Additional studies are warranted to determine the underlying disease mechanism in
the cats we identified with hypercalcemia and urolithiasis. We also identified a
small number of cats with diseases that are not commonly reported with
hypercalcemia. Further studies are needed to determine whether an association
exists between these diseases and hypercalcemia, as well as to characterize the
underlying pathophysiologic mechanism for each disease process.
PMID- 10772492
TI - Isotype-specific antibodies in horses and dogs with immune-mediated hemolytic
anemia.
AB - Classes of antibody bound to erythrocytes were determined using direct
immunofluorescence (DIF) flow cytometry in 3 horses and 12 dogs with immune
mediated hemolytic anemia (IMHA). Background levels of antibody binding were
determined in samples from 12 horses and 12 dogs that were free of clinical
disease. The range of nonspecific binding of a fluorescein isothiocyanate (FITC)
conjugated goat anti-equine immunoglobulin G (IgG) was 19.9-36.7%, but was
eliminated by the use of the F(ab')2 fragment of FITC-conjugated goat anti-equine
IgG. Background binding by other class-specific antibodies to equine and canine
erythrocytes was negligible. The DIF results were compared to the direct
antiglobulin (Coombs') test in 5 horses and 20 dogs with anemia. The former assay
was more sensitive in dogs with IMHA than was the Coombs' test (100% versus 58%).
In contrast, the Coombs' test had better specificity than the DIF assay (100%
versus 87.5%, respectively). Using clinical parameters or response to therapy as
the comparison, the positive and negative predictive values for the DIF test were
92% and 100% compared to the values of the Coombs' test of 100% and 62%. The DIF
assay detected low levels of cells bound with antibody (<30%) in 5 dogs that were
Coombs' test-negative. For both species, performance of the DIF test was
independent of the prozone effect. Five dogs with IMHA had IgG and IgM on
erythrocytes, 5 had IgG, and 2 had IgM. Three horses had surface-bound IgG,
including a horse with suspected penicillin-induced IMHA, a foal with neonatal
isoerythrolysis, and a foal with clostridial septicemia. The DIF method was
valuable in monitoring the response to therapy in the foal with neonatal
isoerythrolysis.
PMID- 10772493
TI - Ataxia and paresis with equine herpesvirus type 1 infection in a herd of riding
school horses.
AB - An outbreak of neurologic disease associated with serologic evidence of equine
herpesvirus type 1 (EHV-1) infection occurred in a herd of 46 riding school
horses. Ataxia and paresis were observed in 14 geldings and 5 barren mares. Eight
affected horses had distal limb edema, 1 horse had a head tilt, and 3 others had
urinary incontinence. Other clinical signs included fever, depression, and
inappetance in 30 horses. Seven horses with neurologic signs were treated with
acyclovir. Serum neutralizing antibody titers against EHV-1 increased 4-fold
between acute and convalescent samples or exceeded 1:256 in 19 of 44 horses,
confirming recent infection. A significantly greater proportion of horses that
seroconverted were mares (P = .014). Of the 19 horses exhibiting ataxia and
paresis, 17 made a complete recovery, 1 made a partial recovery, and 1 was
euthanized.
PMID- 10772494
TI - Prevalence of ocular abnormalities in cats with hyperthyroidism.
AB - The purpose of this study was to investigate the occurrence of ocular
abnormalities in hyperthyroid cats. One hundred hyperthyroid cats and 30
clinically normal, geriatric cats were studied. In both groups, ophthalmic
examination was performed by use of slit-lamp biomicroscopy and indirect
ophthalmoscopy after application of 1% tropicamide to dilate the pupil. Ocular
abnormalities were common in both the hyperthyroid and euthyroid cats.
Approximately 75% of all eyes were affected with 1 or more abnormalities, and the
range of abnormalities involved all structures of the eye. Significant
differences between the euthyroid and hyperthyroid cats were found in the
prevalence of prominent suture lines, nonpigmented deposits on the posterior lens
capsule, hyperreflective ring around the optic nerve, and hyperpigmentation of
the area centralis, but all of these abnormalities were more common in the
euthyroid cats than in the cats with hyperthyroidism. Active retinal lesions were
only observed in 3 hyperthyroid cats (3%). The results of this study indicate
that hyperthyroidism does not seem to be a frequent cause of abnormalities in the
eyes of cats.
PMID- 10772495
TI - Bronchiolitis obliterans with organizing pneumonia in a dog.
PMID- 10772496
TI - Aortic dissection and congestive heart failure associated with systemic
hypertension in a cat.
PMID- 10772497
TI - An accidental transfusion of a type A kitten with type B blood causes a transient
switch from blood type A to B.
PMID- 10772498
TI - Persistent thrombopathy causing bleeding in 2 domestic shorthaired cats.
PMID- 10772499
TI - Equine vaccination.
PMID- 10772500
TI - The relationship of Helicobacter spp. infection to gastric disease in dogs and
cats.
PMID- 10772501
TI - Feasibility of ablating normal renal parenchyma by interstitial photon radiation
energy: study in a canine model.
AB - BACKGROUND AND PURPOSE: A miniature photon radiosurgery system (PRS) has been
described as an alternative to surgical resection and external-beam radiation for
tumors and may now offer an alternative for ablation of renal lesions. We
evaluated the feasibility of ablation by PRS in a normal parenchyma canine model.
MATERIALS AND METHODS: Twelve mongrel dogs were used in this survival study. In
the left and right kidneys of each animal, a peripheral lesion and central-hilar
lesion, respectively, were induced with PRS. The probes were placed in the renal
parenchyma, and local radiation of 15 Gy at a radius of 1.3 cm was delivered over
10 minutes. Serum electrolytes were measured serially. Computed tomography scans
were obtained, and the animals were sacrificed for pathologic correlation. In a
separate study, the liver received three additional treatments of 10 to 20
minutes of radiation. RESULTS: Eleven dogs survived this 6-month study and were
sacrificed as scheduled. One animal expired after 2 weeks from radiation-induced
fulminant hepatic failure with normal renal function. No other complications were
observed. The average lesion size was 2.5 cm in diameter. Histologic analysis
confirmed coagulative necrosis with sharp demarcation from the surrounding
parenchyma. CONCLUSION: Preliminary studies demonstrate the feasibility of PRS
ablation of the renal parenchyma. Further tumor model testing will be important
to determine the ultimate efficacy of local photon radiation energy.
PMID- 10772502
TI - Protective effect of aminophylline on renal perfusion changes induced by high
energy shockwaves identified by Gd-DTPA-enhanced first-pass perfusion MRI.
AB - PURPOSE: The purpose of this study was to evaluate regional renal hemodynamics in
a noninvasive manner using gadolinium-DPTA magnetic resonance imaging (MRI)
before and after extracorporeal shockwave lithotripsy (SWL). In addition, the
renoprotective effect of intravenous aminophylline was evaluated on the perfusion
on kidneys undergoing SWL. PATIENTS AND METHODS: Ten randomly selected patients
were evaluated for regional renal blood flow in the cortex and medulla with Gd
DTPA MRI studies within 2 weeks before and 4 hours after SWL. Five of these
patients were treated with 500 mg of intravenous aminophylline 45 minutes prior
to SWL. Renal hemodynamics were assessed utilizing relative perfusion indices
(PI) calculated from signal intensity-v-time curves obtained from regions of
interest (ROI). The ROI choice was based on the contrast-enhanced MRI images.
Relative PIs of pre-SWL and post-SWL studies were compared in the first group of
patients. Relative PIs of the treated kidney were compared with those of the
contralateral kidney in the second group of patients, who received aminophylline.
RESULTS: In the group not treated with aminophylline, there was no significant
difference in cortical perfusion before SWL (average PI -7+/-3%). However, after
lithotripsy, there was a reduction of cortical flow (average PI 31+/-12%) in the
treated kidney. In the group treated with aminophylline, renal hemodynamics study
after SWL revealed no significant difference in relative perfusion (average PI
8+/-6%). Relative PIs of the medulla were small for all patients, but standard
errors were large, indicating a wide range of values. CONCLUSIONS: This study
helps to establish reduced cortical flow after SWL and demonstrates that
aminophylline attenuated this response in the kidneys subjected to lithotripsy.
It appears that aminophylline administration causes no alteration in medullary
blood flow.
PMID- 10772503
TI - Laparoscopic aortorenal bypass.
AB - BACKGROUND AND PURPOSE: Open surgical renovascular repair, although producing
excellent results, confers significant operative morbidity. As a result, less
morbid procedures such as percutaneous balloon angioplasty and stenting have
gained increasing acceptance. Laparoscopic techniques have not previously been
applied to renal revascularization. The aim of this study was to demonstrate the
technical feasibility and the long-term clinical and pathologic outcomes of
laparoscopic aorto-left renal artery bypass in a chronic porcine model. MATERIALS
AND METHODS: Eight animals were used in the study. All laparoscopic suturing and
knot-tying were performed intracorporeally using free-hand techniques. The
following operative steps were employed: (1) aortic dissection and cross
clamping; (2) transection and refashioning of the left renal artery ostium; (3)
in-situ renal hypothermia; (4) end-to-side aorto-left renal artery anastomosis;
and (5) aortic unclamping. In situ renal hypothermia was achieved
laparoscopically by infusion of ice-cold heparinized saline into the renal artery
through a balloon catheter. RESULTS: All eight pigs underwent laparoscopic
aortorenal bypass successfully. The median surgical time was 110 minutes, and the
aortic cross-clamping time was 45.5 minutes. The median anastomotic time was 40
minutes, and the renal warm ischemia time was 9 minutes. The median estimated
blood loss was 30 mL. An intraoperative complication of suture breakage leading
to anastomotic hemorrhage occurred in one animal; the problem was corrected
laparoscopically. Postoperatively, one animal died from pneumonia. The remaining
seven animals experienced no postoperative complications and were euthanized, one
each at postoperative day 0 and 1 and week 1, 2, 3, 4, and 6. The median
preoperative and postoperative (at euthanasia) serum creatinine values (1.15
mg/dL v 1.2 mg/dL; P = 0.39) were similar. However, compared with preoperative
peripheral renin activity (0.25 microg/L per hour), the postoperative peripheral
renin activity was elevated (0.9 microg/L per hour; P = 0.047). Autopsy revealed
a grossly normal left kidney, with Doppler confirmation of flow in the repaired
renal artery in all seven animals. Ex vivo angiography confirmed a patent
anastomosis. On histopathology examination, the early left renal parenchymal
specimens revealed transient, mild acute tubular necrosis that resolved over
sequential specimens without significant long-term sequelae. Histologic analysis
of the aorto-left renal artery anastomotic site revealed gradual
endothelialization with time. CONCLUSIONS: Laparoscopic aortorenal artery
revascularization is technically feasible. Our chronic animal model has
demonstrated durable success over a 6-week follow-up. This study represents the
initial report in the literature.
PMID- 10772504
TI - Effect of time delay on surgical performance during telesurgical manipulation.
AB - BACKGROUND: Telementoring allows a less experienced surgeon to benefit from an
expert surgical consultation, reducing cost, travel, and the learning curve
associated with new procedures. However, there are several technical limitations
that affect practical applications. One potentially serious problem is the time
delay that occurs any time data are transferred across long distances. To date,
the effect of time delay on surgical performance has not been studied. MATERIALS
AND METHODS: A two-phase trial was designed to examine the effect of time delay
on surgical performance. In the first phase, a series of tasks was performed, and
the numbers of robotic movements required for completion was counted. Programmed
incremental time delays were made in audiovisual acquisition and robotic
controls. The number of errors made while performing each task at various time
delay intervals was noted. In the second phase, a remote surgeon in Baltimore
performed the tasks 9000 miles away in Singapore. The number of errors made was
recorded. RESULTS: As the time delay increased, the number of operator errors
increased. The accuracy needed to perform remote robotic procedures was
diminished as the time delay increased. A learning curve did exist for each task,
but as the time delay interval increased, it took longer to complete the task.
CONCLUSIONS: Time delay does affect surgical performance. There is an acceptable
delay of <700 msec in which surgeons can compensate for this phenomenon. Clinical
studies will be needed to evaluate the true impact of time delay.
PMID- 10772505
TI - Acute histologic changes in human renal tumors after cryoablation.
AB - BACKGROUND AND PURPOSE: Cryoablation is a treatment option for some patients with
small, exophytic lesions of the kidney. Several investigators have evaluated the
effects of cryoablation in normal renal tissue of animals. The purpose of this
study was to investigate the tissue changes following cryoablation in human renal
tumors. PATIENTS AND METHODS: We prospectively evaluated patients with solid
renal lesions (1.5-1.8 cm) confirmed by CT, MRI, or both. Metastatic work-up for
all patients was negative. All lesions were biopsied prior to freezing. Two
patients with bilateral renal tumors underwent argon-gas-based CRYOcare System
(Endocare, Irvine, CA) treatment via an open approach. A 3-mm cryoprobe was
placed directly into each tumor. A single 15-minute freeze preceded an active
thaw (helium gas) for each lesion. Iceball dimensions were monitored by
intraoperative ultrasonography. After successful cryoablation, partial
nephrectomy was performed to remove the lesion, and the renal tissue underwent
histologic evaluation. RESULTS: The cryoprobes achieved a temperature of -135
degrees C. No bleeding was noted, and there were no intraoperative or
postoperative complications with a mean follow-up of 3 months. Histologically,
freezing of renal tissue resulted in coagulative necrosis and hemorrhage beyond
the boundaries of the lesions. There was a zone of demarcation between the viable
and nonviable tissue. CONCLUSIONS: In our series, cryoablation was effective in
destroying tumor tissue in vivo in human kidneys. Freezing was sufficient to
achieve a negative surgical margin. Cryoablation of renal tumor is an alternative
to the currently available nephron-sparing surgical techniques. The long-term
effect of tumor tissue destruction by cryosurgery requires further investigation.
PMID- 10772506
TI - Use of epidermal growth factor and collagen synthesis inhibition as adjuvant to
healing of ureteroureteral anastomosis.
AB - BACKGROUND AND PURPOSE: When treating a ureteral narrowing by endopyelotomy or
endoureterotomy, the urologist hopes that after the narrowed area is cut, it will
heal with a patent lumen. A ureteral stent is usually left in place to provide a
framework for healing. In cases of failure, histologic examination shows a
predominance of collagen. We evaluated the effects of epidermal growth factor
(EGF) and a collagen synthesis inhibitor, halofuginone, as adjuncts to ureteral
healing. MATERIALS AND METHODS: Ten female pigs underwent ureteroureteral
anastomosis bilaterally, with the left side being stented. They were then
randomized to receive EGF (N = 4), halofunginone (N = 3), or saline (control; N =
3). On postoperative day 30, the ureters were examined grossly and
histologically. RESULTS: The lumens of the ureters were significantly larger in
the animals that received either EGF or funginone than in the control animals.
The epithelium was significantly thicker in the animals that received
halofunginone than in the controls or animals receiving EGF. The thickness of the
smooth muscle and adventitia was similar in the three groups. Stenting improved
the results. CONCLUSION: Both EGF and halofuginone show promise as adjuncts to
endopyelotomy and endoureterotomy.
PMID- 10772507
TI - Laparoscopic adrenalectomy for large-volume (> or = 5 cm) adrenal masses.
AB - BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy has emerged as the standard of
care at many centers for small surgical adrenal masses. However, the role of
laparoscopic adrenalectomy in the treatment of large adrenal masses has not been
specifically addressed. Our aim was to evaluate the outcome of laparoscopic v
open adrenalectomy for large-volume (> or =5 cm) adrenal masses and to compare
laparoscopic adrenalectomy for large- and small-volume (<5 cm) masses. PATIENTS
AND METHODS: Data from 14 patients with large adrenal masses undergoing
laparoscopic adrenalectomy between February 1998 and March 1999 (Group I) were
retrospectively compared with 14 contemporary large-volume open adrenalectomies
between December 1992 and May 1998 (Group II) and 45 small-volume laparoscopic
adrenalectomies between July 1997 and November 1998 (Group III). RESULTS: In
Group I and Group II, the mean surgical time (205 min v 216 min) and blood loss
(400 mL v 584 mL) were similar. Although the mean adrenal size was also
comparable (8 cm v 7.8 cm), the specimen weight of the en bloc adrenal gland and
periadrenal fat was greater in Group I (168 g v 106 g). The hospital stay was
shorter in Group I (2.4 days v 7.7 days). Minor complications occurred in 21.4%
of Group I and 50% of Group II patients. On comparing Group I and Group III
(laparoscopic <5 cm), Group I had larger specimen weight (168 g v 51.4 g), longer
surgical time (205 min v 158 min), greater blood loss (400 mL v 113 mL), longer
hospital stay (2.4 days v 1.5 days), a higher complication rate (21.4% v 8.9%),
and a higher incidence of open surgical conversion (14.3% v 2.2%). Over a mean
follow-up of 9.9 months, no local or port-site recurrences have been noted in
Group I. CONCLUSIONS: Laparoscopic adrenalectomy for large-volume adrenal masses
is technically feasible and seems to replicate open surgical oncologic principles
of achieving a wide-margin, en bloc excision of the adrenal gland and periadrenal
fat. Successful laparoscopic resection is not impacted by the large size of the
adrenal mass per se but rather by the presence of local invasion and poorly
defined tissue planes that may be encountered in adrenal malignancy. As such,
laparoscopic adrenalectomy for large masses should be attempted only by
experienced laparoscopic surgeons and then with a low threshold for open
conversion.
PMID- 10772508
TI - Radiofrequency ablation of rabbit kidney using liquid electrode: acute and
chronic observations.
AB - BACKGROUND AND PURPOSE: The percentage of small renal tumors being diagnosed has
increased at least five-fold in the last 20 years. The question of how best to
treat these lesions remains unanswered. We studied the effectiveness of "wet"
radiofrequency (RF) ablation of renal tissue. MATERIALS AND METHODS: New Zealand
white rabbits (N = 48) underwent a 1- or 2-minute ablation of renal parenchyma
with a modified insulated spinal needle capable of infusing saline, measuring
temperature and impedance, and delivering RF energy. Animals were followed and
examined up to 54 days after surgery. RESULTS: All animals survived for the
planned period. Intravenous urograms showed no fistula or urinoma formation and
confirmed continued function of the remaining parenchyma. The 1-minute treatments
consistently ablated 20% to 25% (average 7 cm) of the tissue, whereas the 2
minute treatments ablated 34% to 36% (average 10 cm). Acutely, there was
coagulative necrosis and infiltration of inflammatory cells. Chronically, there
were well-demarcated lesions with complete effacement of the tubular epithelium
and destruction of the glomeruli. CONCLUSION: Wet radiofrequency ablation with a
liquid electrode can reproducibly create large lesions safely and quickly. The
technique may soon become an alternative, minimally invasive therapy for small
renal tumors.
PMID- 10772509
TI - Free electron laser lithotripsy: threshold radiant exposures.
AB - PURPOSE: To determine the threshold radiant exposures (J/cm2) needed for ablation
or fragmentation as a function of infrared wavelengths on various urinary calculi
and to determine if there is a relation between these thresholds and lithotripsy
efficiencies with respect to optical absorption coefficients. MATERIALS AND
METHODS: Human calculi composed of uric acid, calcium oxalate monohydrate (COM),
cystine, or magnesium ammonium phosphate hexahydrate (MAPH) were used. The
calculi were irradiated in air with the free electron laser (FEL) at six
wavelengths: 2.12, 2.5, 2.94, 3.13, 5, and 6.45 microm. RESULTS: Threshold
radiant exposures increased as optical absorption decreased. At the near-infrared
wave-lengths with low optical absorption, the thresholds were >1.5 J/cm2. The
thresholds decreased below 0.5 J/cm2 for regions of high absorption for all the
calculus types. Thresholds within the high-absorption regions were statistically
different from those in the low-absorption regions, with P values much less than
0.05. CONCLUSIONS: Optical absorption coefficients or threshold radiant exposures
can be used to predict lithotripsy efficiencies. For low ablation thresholds,
smaller radiant exposures were required to achieve breakdown temperatures or to
exceed the dynamic tensile strength of the material. Therefore, more energy is
available for fragmentation, resulting in higher lithotripsy efficiencies.
PMID- 10772511
TI - Comparison of transperitoneal laparoscopic access techniques: Optiview
visualizing trocar and Veress needle.
AB - PURPOSE: We retrospectively compared the safety, efficacy, and relative
indications of the Optiview visualizing trocar and the Veress needle for
obtaining transperitoneal laparoscopic access. PATIENTS AND METHODS: Of 100
consecutive transperitoneal laparoscopic procedures performed by a single
surgeon, the Veress needle was used initially in 96 patients. The Optiview was
used on 26 occasions: in 4 patients as the initial access attempt, and in 22
patients after the Veress needle had failed. Patient characteristics (age, body
mass index [BMI], American Society of Anesthesiologists [ASA] score, and history
of abdominal surgery), success rates, and complications were compared. RESULTS:
Access was obtained successfully with the Optiview in 25 of 26 cases (96%),
whereas the Veress needle was successful in 72 of 96 (75%; P = 0.02). The Hasson
cannula was used successfully after two of the Veress needle failures and the
single Optiview failure. Age, BMI, ASA score, and history of abdominal surgery
were not associated with access failure. There were no Optiview-related
complications. Use of the Hasson cannula was not associated with any
complications, but it was difficult to place, leaked gas, or both in two of the
three patients. There were four Veress-related access complications (all minor):
one colon insufflation, two retroperitoneal hematomas, and one liver laceration.
CONCLUSIONS: As an alternative to the Hasson cannula, the Optiview visualizing
trocar is a safe and highly effective method of obtaining transperitoneal
laparoscopic access, particularly in those patients in whom difficulty is
encountered with the Veress needle. However, the needle is less expensive and, in
our experience, has not been associated with significant complications. Because
we were unable to determine objective patient characteristics that increase the
risk for Veress needle failure, we continue to use it for the first attempts at
transperitoneal access in most patients.
PMID- 10772510
TI - Laser lithotripsy and cyanide.
AB - BACKGROUND AND PURPOSE: Holmium:YAG lithotripsy of uric acid calculi produces
cyanide. The laser and stone parameters required to produce cyanide are poorly
defined. In this study, we tested the hypotheses that cyanide production: (1)
varies with holmium:YAG power settings; (2) varies among holmium:YAG, pulsed-dye,
and alexandrite lasers; and (3) occurs during holmium:YAG lithotripsy of all
purine calculi. MATERIALS AND METHODS: Holmium:YAG lithotripsy of uric acid
calculi was done using various optical fiber diameters (272-940 microm) and pulse
energies (0.5-1.5 J) for constant irradiation (0.25 kJ). Fragmentation and
cyanide were quantified. Cyanide values were divided by fragmentation values, and
fragment sizes were characterized. To test the second hypothesis, uric acid
calculi were irradiated with Ho:YAG, pulsed-dye, and alexandrite lasers.
Fragmentation and cyanide were measured, and cyanide per fragmentation was
calculated. Fragment sizes were characterized. Finally, Ho:YAG lithotripsy (0.25
kJ) of purine and nonpurine calculi was done, and cyanide production was
measured. RESULTS: Fragmentation increased as pulse energy increased for the 550-
and 940-microm optical fibers (P < 0.05). Cyanide increased as pulse energy
increased for all optical fibers (P < 0.002). Cyanide per fragmentation increased
as pulse energy increased for the 272-microm optical fiber (P = 0.03). Fragment
size increased as pulse energy increased for the 272-microm, 550-microm, and 940
microm optical fibers (P < 0.001). The mean cyanide production from 0.25 kJ of
optical energy was Ho:YAG laser 106 microg, pulsed-dye 55 microm, and alexandrite
1 microg (P < 0.001). The mean cyanide normalized for fragmentation (microg/mg)
was 1.18, 0.85, and 0.02, respectively (P < 0.001). The mean fragment size was
0.6, 1.1, and 1.9 mm, respectively (P < 0.001). After 0.25 kJ, the mean amount of
cyanide produced was monosodium urate stones 85 microg, uric acid 78 microg,
xanthine 17 microg, ammonium acid urate 16 microg, calcium phosphate 8 microg,
cystine 7 microg, and struvite 4 microg (P < 0.001). CONCLUSIONS: Cyanide
production varies with Ho:YAG pulse energy. To minimize cyanide and fragment
size, Ho:YAG lasertripsy is best done at a pulse energy < or = 1.0 J. Cyanide
production from laser lithotripsy of uric acid calculi varies among Ho:YAG,
pulsed-dye, and alexandrite lasers and is related to pulse duration. Cyanide is
produced by Ho:YAG lasertripsy of all purine calculi.
PMID- 10772512
TI - Grooved ureteral stent: preliminary evaluation.
PMID- 10772513
TI - Tissue removal utilizing Steiner Morcellator within a LapSac: effects of a fluid
filled environment.
AB - BACKGROUND AND PURPOSE: Tissue removal can be a simple process of withdrawal of
the entire organ, piecemeal removal with surgical clamps, or mechanical
morcellation. Different mechanical morcellators exist that each have advantages
and disadvantages. We have investigated a particular morcellator having an
internal mechanized blade system that increases the chances of damage to tissue
isolation sacks but removes large volumes of intact organ that can more readily
be evaluated histologically. The primary premise of this investigation is that a
fluid-filled sack would be less likely to be damaged by the activated blades of
the morcellator. MATERIALS AND METHODS: Utilizing a Steiner Morcellator (Karl
Storz, Culver City, CA), two porcine kidneys were morcellated within the large
LapSac (Cook Urological, Spencer, IN). Two environmental variables were
evaluated: dry sac morcellation and fluid-filled sac morcellation. Each session
was timed, fluid leakage identified, grasping of the sacks quantified, and gross
spillage noted. The tissues were submitted for pathologic evaluation to quantify
any differences grossly or histologically. All LapSacs were inspected for gross
violation and inflated to distention with fluid to check for tiny leaks. RESULTS:
The Steiner Morcellator worked much better within the confines of the LapSac
filled with fluid. There were no perforations in our experimental setting. It was
not possible discern use of fluid-filled sacks histologically. CONCLUSIONS: The
Steiner Morcellator can be utilized safely in the LapSac if cautious observation
and fluid-filled sack conditions are maintained. The extracted tissue is easily
evaluated histologically.
PMID- 10772514
TI - Running suturing: the ideal length facilitates this task.
AB - BACKGROUND AND PURPOSE: Laparoscopic intracorporeal suturing is difficult, a
complex task involving several integrated skills such as needle handling,
suturing, and knotting. Running suturing is even more complex in the closed
environment secondary to the angles of the suture lines, the tension maintained
on the suture line, and the need to secure the ends, including tying a knot from
the tail of the suture to the loop of the preceding stitch. We have hypothesized
that the ideal suture length facilitates this process, and this study was
specifically designed to determine the ideal suture length for an intracorporeal
running suture. MATERIALS AND METHODS: Latex phantoms were incised for 1 or 2 cm,
and each was marked with black points to indicate suture entrance and exit sites.
These marks were placed 2 mm from the incision, starting 2 mm proximally and
ending 2 mm distally. Suture lengths could then be varied in direct proportion to
the length of the incision, keeping all of these points as constants. The ratios
of suture length:incision length were 9:1, 10:1, and 11:1. One surgeon performed
all of the running suturing utilizing dry 3-0 coated polyglactin with a tapered
SH needle. The times needed to create running suture lines were recorded
(seconds), the number of ideal entrance and exit points tabulated, and the number
of technical errors (missed movements resulting in prolonged suturing) recorded.
RESULTS: The lengths of both the incision and the suture affect the ability to
perform laparoscopic intracorporeal running suturing. As the incision increased,
the suture:incision ratio of 9:1 resulted in the most efficient results (quickest
suturing and fewest errors). In smaller suture lines (1 cm), the ratios 10:1 and
11:1 appeared better. CONCLUSIONS: A suture:incision ratio of 9:1 is best for
longer suture lines and 10:1 is better for short suture lines.
PMID- 10772515
TI - Clinical effectiveness of new stent design: randomized single-blind comparison of
tail and double-pigtail stents.
AB - BACKGROUND AND PURPOSE: Stent morbidity appears to be secondary to lower urinary
tract irritation. In an effort to decrease stent morbidity, a "one size fits all"
Tail stent (Microvasive [Boston Scientific] Natick, MA) was developed with a 7F
proximal pigtail and 7F shaft which tapers to a lumenless straight 3F tail.
PATIENTS AND METHODS: We randomized 60 patients in a single-blind fashion to a 7F
tail stent or 7F double-pigtail Percuflex stent. Patients were evaluated at the
time of stent removal and 2 weeks later with a standardized questionnaire
assessing: irritative lower tract symptoms individually and on a total scale of 0
(no symptoms) to 30 (worst symptoms), obstructive lower tract symptoms (on a
total scale of 0-20), and upper tract irritative symptoms (on a total scale of 0
10). RESULTS: Patient age, weight, and height were similar in the two groups.
Complications, including fever, urinary tract infections, emergency room visits,
and the need for antispasmodics and pain medication, also demonstrated no
significant difference. At the time of stent removal, patients who received a
tail stent had significantly less urinary frequency and a statistically
significant (21%) decrease in overall irritative voiding symptoms (12.2 v 15.4; p
= 0.048). Two weeks after stent removal, the total irritative voiding symptoms
was markedly decreased in both groups (7.1 in the Tail v 5.3 in the double
pigtail group; p = 0.15). Obstructive bladder and flank symptoms were not
significantly different in the two stent groups, either at the time of stent
removal or at 2 weeks after removal. CONCLUSION: In this randomized, single-blind
study, the 7F Tail stent produced significantly less irritative symptoms than did
the standard 7F double-pigtail stent. Obstructive symptoms tended to be less with
the new stent, while flank symptoms were similar.
PMID- 10772516
TI - Laparoscopic midsagittal hemicystectomy and replacement of bladder wall with
small intestinal submucosa and reimplantation of ureter into graft.
AB - BACKGROUND AND PURPOSE: A variety of biodegradable organic materials have been
used for bladder wall replacement. In some instances, partial replacement has
been done using laparoscopic reconstructive techniques. However, to date, this
activity has been limited to small patches. Herein, we present the initial
experience with laparoscopic sagittal hemicystectomy and the use of laparoscopic
reconstructive techniques to replace half of the bladder with small-intestinal
submucosa (SIS) and to reimplant the ureter into SIS. MATERIALS AND METHODS: Six
female minipigs (20-25 kg) underwent transperitoneal laparoscopic sagittal
hemicystectomy; the excised bladder wall was replaced with a 5 x 15-cm patch of
SIS (Cook Biotechnology, Spencer, IN). The ipsilateral ureter was reimplanted
through a small incision in the graft and secured with two sutures. Cystoscopy
and cystometrograms were performed under general anesthesia preoperatively and at
6 and 12 weeks postoperatively. Tissues were harvested at 12 weeks. RESULTS: The
procedure was successful in six animals (left three, right three). During
cystoscopy at 12 weeks, the area of the graft was not distinguishable from normal
mucosa. Cystometrograms revealed maintenance of volume and compliance, with
volumes of 338, 343, and 369 mL and intravesical leak-point pressures of 37, 59,
and 39 cm H2O at 0, 6, and 12 weeks, respectively. Antegrade ureterograms
demonstrated extrinsic obstruction, minimal (two), moderate (three), or complete
(one), at the ureterovesical junction. The kidney associated with the completely
obstructed ureter was grossly hydronephrotic at sacrifice. Histologically, patchy
epithelialization of the graft with a mixture of squamoid and mature transitional
cell epithelium was found. CONCLUSIONS: Laparoscopic hemicystectomy with
replacement of the bladder wall and implantation of the ureter into the SIS graft
is a feasible procedure. Clinical application awaits improvements in the method
of ureteral reimplantation and longer follow-up to assess for ingrowth of muscle
and nerve fibers.
PMID- 10772517
TI - Laparoscopic augmentation cystoplasty using the novel biomaterial Surgisis: small
intestinal submucosa.
AB - BACKGROUND AND PURPOSE: Urinary bladder augmentation is indicated for diverse
conditions, including neurogenic bladder, cancer resection, spinal cord injury,
and congenital anomalies. The ideal cystoplasty material is yet to be described.
Native gastrointestinal segments commonly used are limited by leakage and small
bowel obstruction, metabolic/nutritional abnormalities, calculi, and malignancy.
This study assessed laparoscopic bladder augmentation with porcine small
intestinal submucosa (SIS). MATERIALS AND METHODS: Five female pigs (<25 kg) were
prepared for surgery under general anesthesia. After Veress needle insufflation,
a main 10-mm trocar was placed in the midline for the laparoscope, with two
lateral 10-mm ports added for operative instruments. The bladder dome was
incised, and a patch of SIS was sewn into the bladder using running 2-0 Vicryl.
Three animals served as technical studies. Two additional sows underwent long
term survival surgery: one undiverted and one diverted via a Stamey suprapubic
catheter. RESULTS: There were no operative losses. The mean operative time was
140 minutes. The SIS graft held the sutures without tearing. Laparoscopic survey
revealed no urine leaks at bladder closure. All five animals voided
postoperatively. Urinary extravasation was evident in the three undiverted
technique animals. In the other two sows, cystoscopy at 7 days showed intact
suture lines without evidence of urinary extravasation and with normal vesicular
volumes. Tissue growth was evident, but the graft margins were still discernible.
CONCLUSIONS: Laparoscopic bladder augmentation was possible using SIS but at
minimal volumes. There were no operative complications; however, the material was
difficult to deploy and may benefit from application of an absorbable scaffold.
Postoperative urinary drainage is necessary. Further studies will optimize the
graft configuration for maximal augmentation.
PMID- 10772518
TI - Holmium laser enucleation of the prostate with tissue morcellation: initial
United States experience.
PMID- 10772519
TI - Electrical burn of urethra as cause of stricture after transurethral resection.
AB - BACKGROUND AND PURPOSE: One of the most common complications of transurethral
resection is urethral stricture. The exact etiology is still controversial.
Postulated pathophysiology ranges from mechanical trauma to the urethra during
the resection to inflammatory reaction secondary to local anesthesia. We propose
electrical burn to the urethra as a contributory factor in some cases. MATERIALS
AND METHODS: Electrical events during transurethral resection were simulated in
vitro. The distribution of current was measured at the loop/rollerball and in the
outer metal sheath. Both an intact loop/rollerball and loop/rollerball with
faulty insulation were tested. Various power outputs simulating coagulation,
cutting, and vaporization were used. Data were recorded both in settings where
the outer metal sheath was and was not smeared with nonconductive lubricating
gel. RESULTS: Approximately 20% of the total current output was shunted to the
metal sheath when an intact loop/rollerball was used. One hundred percent of the
current was short-circuited to the sheath when a loop/rollerball with faulty
insulation was retracted into the sheath. Little current was detectable in the
nonconductive lubricating gel. We then calculated the length of time required, in
various settings, to reach tissue temperature of 45 degrees C, when protein
denaturation starts. The higher the power output and the smaller the contacting
surface area, the more likely it is for urethral burns to occur. CONCLUSION: Our
in vitro experiment showed that urethral burns secondary to stray current in the
resectoscope sheath are unlikely when an intact loop is used. However, urethral
burns can occur when a loop/rollerball with faulty insulation is used, especially
in combination with nonconductive gel that is dispersed unevenly within the
urethra.
PMID- 10772520
TI - The reflections of an early innovator in the field of laparoscopic surgery.
PMID- 10772521
TI - Review of pain associated with minimal endometriosis.
AB - Endometriosis has been examined in numerous ways and, primarily, it presents in
two forms: painful, often associated with minimal findings; and non-painful,
often associated with marked disease. The focus of this review article is to
examine the pain aspect associated with minimal endometriosis.
PMID- 10772522
TI - Randomized trial comparing a radially expandable needle system with cutting
trocars.
AB - Sharp trocar insertion for laparoscopic procedures carries with it increased risk
for vascular and visceral complications and incisional hernia. In a trial, which
randomized 87 patients to treatment with either sharp trocars or a radially
expanding needle system with blunt dilator, results showed that with the latter
system there was statistically improved patient assessment of pain, a lower
complications rate, and shorter procedure time. In the group of patients
randomized to treatment with conventional trocars, there were a total of six
instrument-related adverse events (6/42): four cases (five incidences) of
abdominal wall injuries and one small bowel perforation caused by a Veress
needle. Of the 45 patients randomized to the blunt dilator/cannula treatment,
there was one adverse event (1/45) that was unrelated to the blunt
dilator/cannula system: Veress needle injury to abdominal vasculature. The
radially expanding access system demonstrates statistically improved patient
postoperative comfort and improved patient safety.
PMID- 10772523
TI - Intracorporeal knot-tying and suturing techniques in laparoscopic surgery:
technical details.
AB - BACKGROUND: Intracorporeal suturing and knot-tying in laparoscopic surgery
require great manual dexterity; these techniques must absolutely be mastered by
every surgeon who is interested in pursuing the minimally invasive approach.
METHOD: The initial and final knot of a laparoscopic continuous suture can be
accomplished in several ways and with easy technical solutions that are fully
illustrated in the present study. CONCLUSION: We think it is better to perform a
continuous suture than an interrupted one. It is advisable, moreover, to use
traditional suture materials (not specially created for laparoscopy) that cost
less than the more sophisticated ones.
PMID- 10772524
TI - Videolaparoscopic approach of the splenic cyst: a case report.
AB - The authors report a case of an asymptomatic 30-year-old female patient with an
extensive cystic lesion continuous with the splenic parenchyma. A review of the
literature and use of a videolaparoscopic approach to the treatment of these
lesions is presented.
PMID- 10772525
TI - Molecular epidemiology of HIV type 1 in a rural community in southwest Uganda.
AB - The molecular epidemiology of a population-based cohort in a cluster of 15
villages in southwestern Uganda was investigated by sequencing part of the p24
gag gene and performing heteroduplex mobility assays (HMAs) of the V3 region of
the env gene. Sequence and HMA data, obtained for 69 and 88 proviruses,
respectively, showed that the clade A and D viruses were present at a ratio of
about 0.67:1. No other clades were detected. Thirteen (22%) of 59 proviruses for
which both gag and env data were obtained appeared to be recombinants. Although
both clade A and D viruses were present in 13 of the villages, their distribution
was unequal: for example, from env data 59% of clade A viruses were found in the
eastern villages, compared with only 27% of clade D viruses. Phylogenetic
(maximum likelihood) analysis of the p24 gag sequences showed a total of five
clusters supported by bootstrap resampling values above or close to 75%. Four
clusters were sexual partners, but there was no known sexual contact between the
persons in the other cluster. The DNA sequences showed between 0.5 and 8.3%
divergence from the cohort clade A or D consensus sequences. The sequences were
not closely related to those published for other clade A or D proviruses.
PMID- 10772526
TI - Effect of highly active antiretroviral therapy and thymic transplantation on
immunoreconstitution in HIV infection.
AB - The purpose of this study was to determine whether thymic transplantation in
addition to highly active antiretroviral therapy (HAART) will restore T cell
function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+
T cell counts of 200-500/mm3 were randomized into thymic transplantation and
control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir)
for 6 weeks prior to transplantation. Thymic transplantation was done without
immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus
tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet
hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and
function and T cell receptor rearrangement excision circles (TRECs) were
assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients
completed the study. Four patients received cultured allogeneic postnatal thymic
grafts, two others were controls. CD4+ T cell counts increased and T cell
proliferative responses to Candida antigen and TT normalized in all patients.
Proliferative responses to KLH developed in three of four transplant recipients
and one of two controls. Patients responding to KLH after secondary immunization
had greater TREC increases compared with the patients who did not respond. All
thymic allografts were rejected within 2 months. In summary, four of six patients
developed T cell-proliferative responses to the neoantigen KLH over the first 2
years of HAART. The transplanted thymus tissue, however, was rejected. There was
no clear difference in restoration of T cell function in the transplant
recipients compared with the controls. Increases in TRECs after initiation of
HAART may correlate with improved immune function.
PMID- 10772527
TI - Effect of food and pharmacokinetic variability on didanosine systemic exposure in
HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study
Team.
AB - The effect of food on didanosine bioavailability and interpatient pharmacokinetic
variability was examined in children infected with human immunodeficiency virus
type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and
fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical
Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150
mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n
= 39) and high (n = 38) dosing groups were not significantly different, but
intersubject variability was substantial. The fraction absorbed was higher while
fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero
order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003);
and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p <
0.0001). The lower fraction absorbed with food was offset by the absorption rate
becoming rate limiting for elimination, resulting in similar areas under the
concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8
microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances
during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3
liters/hr/m2) were similar, but these values in children are substantially higher
than previously reported for adults. The systemic exposure (i.e., AUC) of
didanosine was highly variable in children but similar in the presence and
absence of food. Administration of didanosine with food in children may be
permissible if total systemic exposure rather than maximum plasma concentration
is sufficient for antiretroviral activity. The higher oral clearance and
substantial pharmacokinetic variability suggest the need to reexamine current
didanosine dose recommendations for HIV-infected children.
PMID- 10772528
TI - Quantitative study of beta1-integrin expression and fibronectin interaction
profile of T lymphocytes in vitro infected with HIV.
AB - Cell-extracellular matrix interactions, regulated in part by beta1-integrins,
play a key role in the recirculation of T lymphocytes and tissue infiltration in
inflammatory and immune responses. HIV infection may affect CD4+ T cell adhesion,
and the trafficking and migration of these cells, which are crucial for foreign
antigen recognition. We investigated this by studying the expression of the beta1
integrin chains CD29 and CD49c, -d, -e, and -f, on in vitro HIV-infected primary
T cells. We also assessed fibronectin binding and production by CD4+ lymphocytes.
X4 (HIV-1/LAI), R5 (HIV-1/Ba-L), and X4R5 (HIV-2/ROD) strains, and X4R5 primary
isolates (HIV-1/DAS, HIV-1/THI), with different cytopathogenicity and replication
kinetics, were used. Beta1-integrin expression on CD4+ and CD4- T cell
subpopulations was regulated by cell activation with phytohemagglutinin-P and
interleukin 2, but was unaffected by HIV infection, even at the peak of viral
replication and CD4+ cell depletion. Similarly, fibronectin binding to CD4+
lymphocytes was not affected by HIV infection. This suggests that infected
lymphocytes may be able to extravasate, migrate, and recirculate within the body
until their death.
PMID- 10772529
TI - Mycobacterium avium induces HIV upregulation through mechanisms independent of
cytokine induction.
AB - Mycobacterium avium complex (MAC) can induce upregulation of HIV. To investigate
the underlying mechanisms, the effect of MAC-induced cytokines on HIV replication
was first studied. Semiquantitative RT-PCR, followed by Northern blot analysis,
revealed that mRNA encoding IL-6 and TNF-alpha was induced by MAC. However,
production of these cytokines was undetectable and the addition of anti-cytokine
antibodies to coinfected cells could only minimally block the MAC effect on HIV.
Infection of U38 cells with MAC resulted in enhancement of HIV-1 LTR-CAT
transcription. In addition, transient transfection of U937 cells with full-length
wild-type as well as NF-kappaB-binding site-deleted mutant HIV-1 LTR-CAT
constructs revealed that MAC-induced HIV-LTR CAT is NF-kappaB dependent. These
findings, together with our previous work, indicate that MAC-induced cytokine
expression increases the formation of NF-kappaB, which in turn enhances HIV-1 LTR
CAT transcription. However, additional factor(s) yet to be elucidated may play a
more significant role in MAC-mediated HIV-upregulation.
PMID- 10772530
TI - nef/long terminal repeat quasispecies from HIV type 1-infected Mexican patients
with different progression patterns and their pathogenesis in hu-PBL-SCID mice.
AB - To examine the genetic features of the long terminal repeat (LTR) derived from
six HIV-1-infected individuals enrolled in the Mexico City Cohort, we cloned and
sequenced a 505-bp fragment of the proviral LTR from their peripheral blood
mononuclear cells (PBMCs). All patients harbored HIV-1 LTR quasispecies
corresponding to the B subtype. Three patients with high CD4+ T cell counts
(>500/mm3) presented LTR sequences with point mutations in the TAR bulge. The LTR
sequence from a patient classified as a long-term nonprogressor (LTNP) presented
the most frequent naturally occurring length polymorphism (MFNLP) and two
substitutions in the TAR region that were predicted to result in two alternative
secondary RNA structures. A novel 18-bp deletion, which eliminates part of the
putative binding site for the nuclear factor of activated T cells (NFAT-1), was
identified in the overlapping nef/LTR sequence derived from a patient progressing
to AIDS. This deletion coincides with the ability of this virus to consistently
replicate at low levels in vivo (viral load <500 RNA copies/ml) and in vitro
(unsuccessful virus isolation). On one occasion, when virus isolation was
successful, the 18-bp deletion was no longer evident and LTR sequences with
intact NFAT-1-binding sites were observed. Inoculation of hu-PBL-SCID mice with
viruses from several Mexican patients resulted in differential CD4+ T cell
depletion patterns 15 days postinfection, which agree with the in vivo CD4+ T
cell count data from each patient.
PMID- 10772531
TI - Human immunodeficiency virus type 1 can infect human retinal pigment epithelial
cells in culture and alter the ability of the cells to phagocytose rod outer
segment membranes.
AB - Human immunodeficiency virus type 1 (HIV-1) has been found in the vitreous of
persons with AIDS. Here we investigated the susceptibility of human retinal
pigment epithelial (RPE) cells to HIV-1 infection in culture and the effects of
HIV-1 on the phagocytic function of the RPE. We found that 10 of 11 populations
of RPE cells isolated from different fetal or adult eyes were susceptible to low
level replication of HIV-1/NL4-3 as determined by the detection of viral DNA and
spliced viral RNA encoding envelope. HIV-1 infection was not inhibited by
recombinant soluble CD4, suggesting that CD4 is not required for virus entry into
RPE cells. RPE cells fused with target cells constitutively expressing HIV-1
envelope glycoproteins, indicating that HIV-1 enters cells by receptor-mediated
fusion. Exposure to HIV-1 or recombinant gp120 caused a two- to four-fold
increase in the binding and uptake of isolated rod outer segments by RPE cells.
These findings introduce a new cell target of HIV-1 replication in the eye and
indicate that RPE cells function aberrantly when exposed to HIV-1 or its envelope
glycoprotein.
PMID- 10772532
TI - Construction of chimeric simian and human immunodeficiency viruses that produce
interleukin 12.
AB - Chimeric simian and human immunodeficiency viruses (SHIVs) are useful for
evaluating vaccine candidates against HIV-1 and for investigating the
pathogenesis of HIV-1 in vivo. In addition, SHIVs are candidates for a vaccine
against HIV-1 because attenuated SHIVs can induce long-lasting anti-HIV-1 Env
humoral and cell-mediated immunity in monkeys without AIDS-like diseases. In this
study, we inserted IL-12 genes in a nef-deleted SHIV to increase the ability of
the SHIV to induce cell-mediated immunity against HIV-1. The SHIV vector was
constructed by deleting the nef gene and replacing it with restriction enzyme
sites. Since IL-12 consists of two subunit genes, p35 and p40, SHIVs with one or
both of these genes were constructed. SHIVs with either one of the subunit genes
could replicate without a deletion of the inserted gene, but SHIVs with two
subunit genes replicated poorly and the inserted genes were rapidly deleted.
Production of IL-12 was detected when both of the single-subunit SHIVs were
coinfected. The production of IL-12 by the coinfection reached 800 pg/ml, and IL
12 was detected after serial passage in cell cultures, although this amount of IL
12 heterodimer was 150-1500 times less than that of the p40 subunits. These IL-12
producing SHIVs are candidates for a live-attenuated vaccine to induce effective
cellular immunity against HIV-1.
PMID- 10772533
TI - HERV-IP-T47D, a novel type C-related human endogenous retroviral sequence derived
from T47D particles.
AB - A new type C retrovirus-related endogenous pol sequence (ERV-FTD) found to be
occasionally copackaged in retrovirus-like particles released by the human
mammary carcinoma cell line T47D was used to screen a human genomic library
(Seifarth W, Skladny H, Krieg-Schneider F, Reichert A, Hehlmann R, and Leib-Mosch
C: J Virol 1995;69:6408-6416). The DNA sequence of one full-length clone now
reveals a human endogenous proviral sequence (HERV) of 4190 bp in length
comprising a 5' LTR (489 bp) and regions with 37 and 74% overall amino acid
homology to RTVL-Ia gag and pol genes, respectively. About 35 related elements
were found to be distributed on all human chromosomes except 16, 17, and Y.
Sequence comparisons with Mo-MuLV and various type C-related HERVs suggest that
despite a proline primer-binding site this novel HERV element, now named HERV-IP
T47D, can be assigned to one family together with known HERV-I elements.
Phylogenetic analyses of 5 proviral and 25 solitary LTR sequences confirmed the
existence of two distinct but closely related subgroups of the HERV-IP
superfamily in the primate genome. In contrast to most known HERV-families, the
evolutionary age of HERV-IP elements dates back prior to the divergence of New
and Old World monkeys. Despite their old age, members of the HERV-IP family are
still transcriptionally active and were found to be highly expressed in specific
human tissues such as liver and kidney.
PMID- 10772534
TI - Mice transgenic for monocyte-tropic HIV type 1 produce infectious virus and
display plasma viremia: a new in vivo system for studying the postintegration
phase of HIV replication.
AB - To generate an in vivo system for investigating the postintegration phase of HIV
1 replication, mouse lines transgenic for a full-length infectious proviral clone
of a monocyte-tropic HIV-1 isolate, HIV-1JR-CSF, were constructed. Leukocytes
from two independent JR-CSF transgenic mouse lines produced HIV-1 that infected
human PBMCs. Plasma viremia was detected in these mice at levels (mean, >60,000
HIV RNA copies/ml) comparable to those reported for HIV-1-infected individuals.
The levels of HIV RNA in these mice increased several-fold after either treatment
with the superantigen Staphylococcus enterotoxin B or infection with
Mycobacterium tuberculosis. Thus, a provirus encoding a monocyte-tropic HIV-1
strain under the control of its LTR expressed as a transgene in mice can proceed
through the postintegration replication phase and produce infectious virus. In
addition, the presence of plasma viremia that can be monitored by measuring
plasma HIV-1 RNA levels permits these mice to be used to study the impact of
different interventions on modulating in vivo HIV-1 production. Therefore, these
mice provide a novel manipulable system to investigate the in vivo regulation of
HIV-1 production by factors that activate the immune system. Furthermore, this
murine system should be useful in delineating the role of human-specific factors
in modulating HIV-1 replication and investigating the in vivo therapeutic
efficacy of agents that target the postintegration stages of HIV-1 replication.
PMID- 10772535
TI - Identification of HIV type 1 intersubtype recombinants in South Africa using env
and gag heteroduplex mobility assays.
PMID- 10772536
TI - Subtype-specific sequence variation of the HIV type 1 long terminal repeat and
primer-binding site.
AB - We studied sequence differences in regulatory elements of the long terminal
repeat (LTR) and primer-binding site (PBS) among various human immunodeficiency
virus type 1 (HIV-1) subtypes. Phylogenetic sequence analysis of a fragment of
729 base pairs (bp) covering the Gag-coding region for half of p24 and all of p17
revealed the gag subtype of all 60 viruses included in the study: A (n = 20), B
(n = 12), C (n = 7), D (n = 10), E (n = 3), F (n = 4), G (n = 3), and H (n = 1).
The subtype was also determined by analysis of a 689-bp fragment comprising the
LTR and the PBS motif. Comparison of the LTR versus gag sequences showed a mosaic
genome for seven isolates. After analysis of all sequences, we could describe
subtype-specific differences in sequences encompassing the regulatory elements of
the LTR and the PBS motif.
PMID- 10772537
TI - Recombinant human immunodeficiency viruses type 1 circulating in Spain.
AB - The protease, reverse transcriptase (RT), and envelope (env) genes of human
immunodeficiency virus type 1 (HIV-1) clinical isolates from 13 immigrants
(mainly of African origin) living in Spain were examined. Phylogenetic analyses
were performed, taking as reference a panel of 25 HIV-1 sequences representing
various subtypes. A discrepant topology was recognized in comparing the protease,
RT, and/or env phylogenetic trees in 10 isolates, in which sequences clustering
in 2 or 3 different HIV-1 subtypes were found. In eight of these strains, the
discrepant region was env with respect to concordant pol genes. Five of nine
patients harboring subtype G sequences at the protease and RT genes showed
discrepant env sequences, being subtype A (three) or B (two). In addition, one
recombinant H/A strain, one recombinant H/B isolate, and a triple recombinant,
A/D/C, variant were found. This work represents the first phylogenetic
characterization of HIV-1 recombinant clinical isolates in Spain.
PMID- 10772538
TI - A comparison of various "housekeeping" probes for northern analysis of normal and
osteoarthritic articular cartilage RNA.
AB - Several approaches are commonly used to normalize variations in RNA loading on
Northern blots, including: ethidium bromide (EthBr) fluorescence of 18S or 28S
rRNA or autoradiograms of radioactive probes hybridized with constitutively
expressed RNAs such as elongation factor-1alpha (ELF), glyceraldehyde-3-phosphate
dehydrogenase (G3PDH), actin, 18S or 28S rRNA, or others. However, in
osteoarthritis (OA) the amount of total RNA changes significantly and none of
these RNAs has been clearly demonstrated to be expressed at a constant level, so
it is unclear if any of these approaches can be used reliably for normalizing RNA
extracted from osteoarthritic cartilage. Total RNA was extracted from normal and
osteoarthritic cartilage and assessed by EthBr fluorescence. RNA was then
transferred to a nylon membrane hybridized with radioactive probes for ELF,
G3PDH, Max, actin, and an oligo-dT probe. The autoradiographic signal across the
six lanes of a gel was quantified by scanning densitometry. When compared on the
basis of total RNA, the coefficient of variation was lowest for 28S ethidium
bromide fluorescence and oligo-dT (approximately 7%), followed by 18S ethidium
bromide fluorescence and G3PDH (approximately 13%). When these values were
normalized to DNA concentration, the coefficient of variation exceeded 50% for
all signals. Total RNA and the signals for 18S, 28S rRNA, and oligo-dT all
correlated highly. These data indicate that osteoarthritic chondrocytes express
similar ratios of mRNA to rRNA and mRNA to total RNA as do normal chondrocytes.
Of all the "housekeeping" probes, G3PDH correlated best with the measurements of
RNA. All of these "housekeeping" probes are expressed at greater levels by
osteoarthritic chondrocytes when compared with normal chondrocytes. Thus, while
G3PDH is satisfactory for evaluating the amount of RNA loaded, its level of
expression is not the same in normal and osteoarthritic chondrocytes.
PMID- 10772539
TI - Characterization of the collagen phenotype of rabbit proximal tubule cells in
culture.
AB - Studies were performed to characterize the collagen phenotype of cultured rabbit
proximal tubule (RPT) epithelial cells grown on plastic and on the reconstituted
basement membrane preparation, Matrigel. When grown on a plastic substratum, RPT
cells display a cobblestone appearance characteristic of glomerular epithelial
cells. While initially forming an interlocking network of cells after subculture
on Matrigel, this pattern of culture morphology rapidly develops into one
characterized by isolated, organized groups of cells. Notwithstanding the effects
of Matrigel on culture morphology, total cellular proliferation was reduced only
25% when RPT cells were grown on this substrate. Greater than 90% of the collagen
synthesized by RPT cells grown on plastic was secreted into the culture medium.
Qualitative analysis by SDS-PAGE revealed components exhibiting electrophoretic
mobilities corresponding to the chains present in type IV and type I collagens.
Quantitative analysis by CM-Trisacryl chromatography established that
approximately 2/3 of the total collagen synthesized by RPT cells grown on plastic
was type IV and approximately 1/3 type I. Quantitative analysis of the collagens
produced by RPT cells grown on Matrigel again indicated the synthesis of only
type IV and type I molecules but in a slightly more equal ratio of both collagen
types and in the ratio of secreted to cell-associated molecules. However, the
total amount of collagen synthesized by RPT cells grown on Matrigel was reduced
to approximately 1% of the level synthesized by the cells grown on plastic. On
plastic, approximately 3/4 of the type I collagen produced was recovered as the
type I homotrimer, but on Matrigel type I homotrimers represented only
approximately 55% of the total type I collagen synthesized. On Matrigel, the
majority of the type IV collagen was recovered as heterotrimers containing
alpha1(IV) and alpha2(IV) chains. In contrast, RTP cells grown on plastic
predominantly produced type IV homotrimers containing only the alpha1(IV) chain.
These data represent the initial report describing the collagens produced by
nonimmortalized cultured proximal tubule cells. The finding that a significant
amount of the total collagen synthesized was type IV (basement membrane)
collagen, regardless of culture substrate, suggests that the RPT cells have
maintained a significant degree of differentiation in culture, and thus
establishes RPT cells as an appropriate model for investigating ECM changes in
proximal tubule cells that occur in kidney disease. Finally, the observation that
culture of RPT cells on a reconstituted basement membrane preparation results in
a significant reduction in total collagen production and alterations in the
molecular forms of type IV and type I molecules synthesized indicates that
integrity of the tubular basement membrane may represent an important component
in preventing the development of tubulointerstitial fibrosis.
PMID- 10772540
TI - Bone material elasticity in a murine model of osteogenesis imperfecta.
AB - To investigate the source of bone brittleness in the disease osteogenesis
imperfecta (OI), biomechanical properties have been measured in the femurs from a
homozygous (oim/oim) mutant mouse model of OI, its heterozygous littermates, and
wild-type animals. The novel technique of ultrasound critical-angle reflectometry
(UCR) was used to determine bone material elasticity matrix from measurements of
the pressure and shear wave velocity at different orientations about selected
points of the bone specimens. This nondestructive method is the only available
means for obtaining measurements of this nature from a single surface. The
ultrasound pressure wave velocity showed an increased isotropy in the homozygous
compared to the wild-type specimens. This was reflected in a significant decrease
in the principal elastic modulus measured along the length of the oim/oim bones
(E33) while the modulus along the width (E11) did not change significantly,
compared to wild-type specimens. The Poisson's ratio, v12, also had a
significantly increased value in oim/oim bones. Measurements of these parameters
in heterozygous animals generally fell between those from homozygous and control
mice. The differences in the elasticity components in oim/oim bones indicate an
altered stress distribution and a modified elastic response to loads, compared to
normal bone.
PMID- 10772541
TI - Articular cartilage proteoglycan metabolism in avian degenerative joint disease:
effects of strain selection and body weight.
AB - The effects of strain selection and body weight on proteoglycan metabolism and
the onset of degenerative joint disease (DJD) were investigated in avian
articular cartilage. Samples from the hock joint (proximal tarsometatarsus, PTM;
distal tibiotarsus, DTT) of rapidly growing broiler fowl, fed either ad libitum
or on a restricted-diet, were compared with those from a slow growing, light and
non-selected strain (J-line). Synthesis and degradation of proteoglycans were
investigated by radioactive pulse-chase studies, determination of total sulphated
glycosaminoglycans and electrophoretic analysis. By gross morphology,
degenerative changes in articular cartilage occurred solely in the DTT from ad
libitum-fed broiler fowl, after 13 weeks. Differences in proteoglycan metabolism
were also observed, most markedly in the DTT, where the rate of proteoglycan
synthesis in the ad libitum-fed group was less than in age-matched J-line
cartilage, and the proportions of both newly synthesised and resident
proteoglycans released into the culture medium were greater. Results with the
feed-restricted group were intermediate between ad libitum-fed and J-line.
Electrophoretic analysis of proteoglycans in the culture media showed evidence of
degradation solely in the ad libitum-fed group, with earliest onset in the DTT.
The results indicate that proteoglycan metabolism in avian articular cartilage is
similar to that in mammalian cartilage during the development of DJD, and that
the onset of cartilage degeneration is linked with excessive load bearing.
PMID- 10772542
TI - Cloning of cDNA for rat pro alpha1(V) collagen mRNA. Expression patterns of type
I, type III and type V collagen genes in experimental granulation tissue.
AB - A cDNA clone for rat pro alpha1(V) collagen mRNA was constructed using PCR
amplification, with primers based on human and hamster COL5A1 gene sequences. The
clone pRCVA1 is 560 nucleotides long and it encodes for the carboxy propeptide of
type V procollagen. Homology shared with type I collagen sequence was 64%, with
type II collagen 65% and with type III collagen 61%. To evaluate the spatial and
temporal expression of type V collagen mRNA in wound healing model,
subcutaneously implanted viscose cellulose sponges in rats were used to induce
granulation tissue formation. Analyses on granulation tissue were carried out on
days 5, 8, 14, 21, 30, 59 and 84. Specific cDNA probes to pro alpha1(I), pro
alpha1(III) and pro alpha1(V) collagen mRNA were used in slot blot, Northern and
in situ hybridization. Type I collagen gene expression was upregulated at the
initial stage of wound healing, type III collagen gene expression was constant
and from the day 14 onwards type I and III collagen gene expressions were at the
same level. Type V collagen gene expression was seen at every time point studied
but at a considerably lower level than type I and III collagens. In situ
hybridization showed that type V collagen was expressed in two different cell
types. In conclusion, type V collagen was expressed in the wound healing model
from at least day 5 onwards and it was synthesized by fibroblast-like and rounded
cells.
PMID- 10772543
TI - Inhibition of tumor cell proliferation by type IV collagen requires increased
levels of cAMP.
AB - Previous studies from our laboratories demonstrated that a peptide from the
noncollagenous domain of the alpha3 chain of basement membrane collagen (COL IV),
comprising residues 185-203, inhibits polymorphonuclear leukocyte activation and
melanoma cell proliferation; this property requires the presence of the triplet
SNS- in residues 189-191 (Monboisse et al., J. Biol. Chem., 269, 25475, 1994; Han
et al., J. Biol. Chem., 272, 20395, 1997). In the present study, we demonstrate
that whole native COL IV and -SNS- containing synthetic peptides (10 microg/ml)
added to culture medium inhibit the proliferation of not only melanoma cells, but
also breast-, pancreas- and stomach-tumor cells up to 67%, and prostate tumor
cells by 15%. ALC-COL IV at 5 microg/ml was shown to inhibit melanoma cell
proliferation maximally at 69% and the alpha3(IV)185-203 peptide inhibited
proliferation (62%) maximally at 10 microg/ml. Treatment of the alpha3(IV)185-203
peptide with either a specific mAb or a polyclonal antibody, prepared against the
sequence alpha3(IV)179-208, decreased the ability of the peptide to inhibit cell
proliferation by 97%, while treatment of ALC-COL IV with the same antibodies
inhibited proliferation by 44%. Exposure of the above tumor cells to COL IV or
the peptides resulted in an increase of intracellular cAMP that was inhibited by
prior treatment of the protein with the above antibodies. To investigate the role
of cAMP in the inhibition of cell proliferation, cAMP analogs and inhibitors were
used. cAMP analogs mimicked the inhibitory effect of the peptide. Rp-cAMPS, a
cAMP competitive inhibitor, suppressed the inhibitory effect of ALC-COL IV and of
the cAMP analogs. The protein kinase-A inhibitor H-89 blocked the ability of ALC
COL IV and of the alpha3(IV)185-203 peptide to inhibit tumor cell proliferation.
These data suggest that ALC-COL IV, through its alpha3(IV) chain, inhibits tumor
cell proliferation utilizing a signal transduction pathway which includes cAMP
and cAMP-dependent protein kinase(s).
PMID- 10772544
TI - Health, wealth and the world around us.
PMID- 10772545
TI - Application of geographical information systems to co-analysis of disease and
economic resources: dengue and malaria in Thailand.
AB - Two vector-borne communicable diseases, malaria and dengue, are among a number of
diseases of particular importance in relation to economic development in
Southeast Asia and thus need to be assessed in relation to economic parameters in
the region. Geographical Information Systems (GIS) provide one means of comparing
disease and resource data versus time and place, to facilitate rapid
visualization by planners and administrators. Given that Thailand is a global
epicenter of multidrug resistant falciparum malaria and of dengue hemorrhagic
fever, both of which are mosquito-borne, application of GIS methods to these two
diseases gives opportunity for comparison of resource needs and allocation in
relation to disease epidemiologic patterns. This study examined per capita gross
provincial product (GPPpc) and health care resources in relation to geographic
distribution of malaria and dengue in Thailand. The two diseases vary greatly in
overall seasonal patterns and in relation to provincial economic status, and
present differing demands on resource utilization: planned integration of control
of malaria and dengue could utilize such analyses in relation to resource sharing
and consideration of allocative efficiency. The concentration of malaria (and to
a lesser extent dengue) along international border areas underscores the
desirability of multi-country coordination of disease management and control
programs. Because socio-economic and disease data are collected by quite
different means and in different time frames, there are some limitations to the
dynamic interpolation of these two broad data sets, but useful inferences can be
drawn from this approach for application to overall planning, at both national
and multi-country levels.
PMID- 10772546
TI - Humoral immune responses against Plasmodium vivax MSP1 in humans living in a
malaria endemic area in Flores, Indonesia.
AB - The aim of this study was to evaluate the relationship among age, parasitemia
status, spleen size, hematocrit, and antibody levels to Plasmodium vivax
merozoite surface protein 1 (MSP1) in individuals chronically exposed to P.
vivax. Subjects were recruited from the population of three adjacent villages on
the Island of Flores in Indonesia where malaria transmission is hyperendemic and
tropical splenomegaly syndrome is highly prevalent. Subjects were evaluated for
spleen size, hematocrit, presence of parasitemia, and presence of antibodies to a
recombinant peptide consisting of 90 amino acids from the carboxy terminus of
MSP1. Fifty-seven percent of 2-4 year olds, 45% of 5-9 years old, and 7% of > or
= 15 years old were parasitemic; 99% of the > or = 15 years old had splenomegaly,
and 31% of them had Hackett 4 or 5 spleens. The frequency of antibody positivity
to MSP1 antigen in ELISA increased with age reaching a maximum of 89% in > or =
20 years old. The frequency of antibody positivity to MSPI also increased with
spleen size, and with a decline in the prevalence of parasitemia.
PMID- 10772547
TI - The in vivo sensitivity of Plasmodium falciparum to chloroquine in the Red River
basin, Yunnan, China.
AB - The sensitivity of Plasmodium falciparum to chloroquine in vivo was examined out
in a small town in the Red River basin from 1995 to 1996. forty cases were
recruited into the present study, 32 cases were completely followed-up. The
results of the in vivo study revealed that only 3 (9%) cases were sensitive to
chloroquine, 29 (90.6%) showed resistance to chloroquine, among whom 7 cases
(22%) showed resistance at RI, 12 cases (38%) at RII, and 10 cases (31%) at RIII.
It is suggested that P. falciparum endemic areas should stop using chloroquine
and other 4-aminoquinolines in the Red River basin now. Qinhaosu and pyronaridine
were recommended to use as the first line antimalarial drugs of P. falciparum
infection in the basin.
PMID- 10772548
TI - A clinical trial of combination of artesunate and mefloquine in the treatment of
acute uncomplicated falciparum malaria: a short and practical regimen.
AB - The difficulties in treating drug-resistant falciparum malaria in Thailand are
compounded by the necessity of giving antimalarials over long periods of time.
The resultant fall in patient compliance not only lowers cure rates but also
predisposes to the further spread of drug-resistance. Sequential treatment with
artesunate given over 5 days followed by mefloquine produced 100% cure rates in
previous study, but might not be a suitable regimen for field treatment. We
conducted a clinical trial of a combination of artesunate and mefloquine given
twice daily for 2 days in 150 patients with acute uncomplicated falciparum
malaria. The dose of artesunate (200 mg) and mefloquine (312.5 mg) were given
simultaneously in a separate package. All patients were admitted to a hospital in
Bangkok for 28 days to exclude re-infection and monitor the possible adverse
effects. One hundred and thirty patients completed the study with 28 days follow
up. Twenty patients (13%) left the hospital prior to completion of follow-up for
reasons unrelated to their treatment. Cure rate was 97% (126/130). There were no
RII or RIII failures and all four patients with treatment failures were of the RI
type. The mean parasite clearance time and fever clearance time were 46.4 and
42.5 hours, respectively. All patients were tolerated the combination drugs well
and there were no serious toxic adverse reactions. The results indicate that
combination of artesunate and mefloquine given twice daily for 2 days is
effective and well tolerated in patients with acute, uncomplicated falciparum
malaria and suitable as an alternative treatment for multidrug resistant
falciparum malaria.
PMID- 10772549
TI - Maternal influence on the use of impregnated bednets in the protection of
infantile malaria.
AB - A cross-sectional survey of 184 mothers or caretakers was undertaken to
investigate the effect of socio-behavioral background on decision making in
relation to the use of impregnated bednets to prevent malaria for their children
in Ratchaburi Province, Thailand. It was found that most mothers had knowledge of
the cause, transmission and prevention of malaria. They perceived susceptibility
and severity of malaria as a risk to their children, which might even cause
death. They also perceived and had positive attitudes toward impregnated bednets
as a protection for their children. Three-quaters (76.4%) of them used
impregnated bednets regularly to protect their children whereas one-quarter
(23.6%) used infrequently and few never used. Bivariate analysis showed that the
use of impregnated bednets was significantly related to the factors such as
knowledge of malaria prevention, perception of benefits of the use, the receipt
of information about the impregnated bednets from malaria workers.
PMID- 10772550
TI - Field activity cost estimates for the first 3 years of the World Bank Loan
Project for schistosomiasis control in China.
AB - The World Bank Loan Project for schistosomiasis in China commenced field
activities in 1992. In this paper, we describe disease control strategies for
levels of different endemicity, and estimate unit costs and total expenditure of
screening, treatment (cattle and humans) and snail control for 8 provinces where
Schistosoma japonicum infection is endemic. Overall, we estimate that more than
21 million US dollars were spent on field activities during the first three years
of the project. Mollusciciding (43% of the total expenditure) and screening (28%
of the total) are estimated to have the most expensive field activities. However,
despite the expense of screening, a simple model predicts that selective
chemotherapy could have been cheaper than mass chemotherapy in areas where
infection prevalence was higher than 15%, which was the threshold for mass
chemotherapy intervention. It is concluded that considerable cost savings could
be made in the future by narrowing the scope of snail control activities,
redefining the threshold infection prevalence for mass chemotherapy, defining
smaller administrative units, and developing rapid assessment tools.
PMID- 10772551
TI - Viability of metacercariae in northern Thai traditional foods.
PMID- 10772552
TI - An epidemiological survey on intestinal parasite infection in Khammouane
Province, Lao PDR, with special reference to Strongyloides infection.
AB - To estimate the current prevalence of intestinal helminth infection in Lao PDR, a
parasitological survey was conducted in three villages in Khammouane Province in
December 1996, with special reference to Strongyloides infection. A total of 669
fecal samples were collected in the villages and examined by agar-plate culture
method and Kato-Katz thick smear method. Intestinal helminths were demonstrated
in 82% of the samples as follows: Ascaris lumbricoides (30.5%), Trichuris
trichiura (23.7%), hookworm (28.8%), Strongyloides stercoralis (19.0%),
Enterobius vermicuralis (3.4%), Opisthorchis viverrini (56.7%) and Taenia sp
(3.0%). The infection rates of S. stercoralis were 27.5% and 18.4% in two rural
villages, but only 9.4% in an urban village. The highest prevalence rate of
Strongyloides infection was obtained in the age group from 20 to 29 years old,
although the infection rate already reached 10% in the age group under 10 years
old. The prevalence was consistently higher in male subject than females in
almost all age groups.
PMID- 10772553
TI - Recovery and distribution of Ascaris suum superimposed on a Schistosoma japonicum
infection in pigs.
AB - The aim of this study was to examine the effect of a primary patent Schistosoma
japonicum infection on the establishment and location of a superimposed Ascaris
suum infection in pigs. The study comprised two experiments each containing two
groups of pigs. In the first experiment, 7 pigs were injected intramuscular
(i.m.) with 800 S. japonicum cercariae and inoculated with 1,000 A. suum eggs 11
weeks post primary infection (ppi) and 8 pigs were inoculated with 1,000 A. suum
eggs at the time of challenge infection. In the second experiment, 7 pigs were
injected i.m. with 1,100 S. japonicum cercariae and inoculated with 1,000 A. suum
eggs 16 weeks ppi and 8 pigs were inoculated with 1,000 A. suum eggs at the time
of challenge infection. All pigs were slaughtered 10 days after the A. suum
challenge infection. The number of white spots caused by A. suum on the surface
of the liver was significantly lower in the groups with primary infections of S.
japonicum compared with the control groups. However, the present experiments did
not demonstrate any effect of a primary S. japonicum infection on the total
recovery and distribution of an A. suum challenge infection.
PMID- 10772555
TI - Prevalence and some risk factors of Giardia duodenalis infection in a rural
community in Malaysia.
AB - A study on prevalence and risk factors of Giardia duodenalis infection was
conducted in rural communities of Malaysia. A total of 917 individuals between 2
70 years old (431 males and 486 females), participated in this study. The overall
prevalence of G. duodenalis infection was 19.2%. The prevalence was significantly
different between different age groups, but not genders. Our study indicated that
age < or = 12 years old and the presence of family members infected with G.
duodenalis were the risk factors of infection. Person-to-person contact within
the family members was the possible mode of transmission. Health education on
personal hygiene, together with the treatment of the infected people, may help in
reducing and controlling this infection in these communities.
PMID- 10772554
TI - Ascariasis, trichuriasis, and growth of schoolchildren in Northeastern Peninsular
Malaysia.
AB - A study to determine the effect of antihelminthic treatment on growth and
nutritional status was undertaken on 103 children in the second grade of primary
school, 71 of whom were found to be infected with Ascaris lumbricoides or
Trichuris trichiura. The median Ascaris and Trichuris intensities in the infected
group were 19,600 (range; 0-488,000) and 2,800 (range; 0-84,600) eggs per gram of
feces respectively. Forty-three children harbored both types of worm. Fourteen
weeks after two 400 mg doses of albendazole were administered to infected
children, the increases in weight, height, weight for age, height for age and
weight for height were significantly higher among infected children than controls
who were uninfected at baseline. The observed gains were independent of sex and
socioeconomic status. Decrease in log transformed Trichuris intensity correlated
with increases in weight (r=0.24; p=0.02) and weight for age (r=0.20; p=0.06) but
decrease in Ascaris intensity did not correlate with increases in any of the
anthropometric parameters. The results suggest that antihelminthic treatment has
beneficial short-term effects on growth and nutritional status of a modest
magnitude among early primary schoolchildren in the area.
PMID- 10772556
TI - Toxoplasma antibody prevalence in Nepalese pregnant women and women with bad
obstetric history.
AB - Sera from randomly selected 345 pregnant Nepalese women aged 16-36 years and 13
women with bad obstetric history (BOH) were tested for the presence of Toxoplasma
antibodies using microlatex agglutination (MLA) and ELISA methods. The overall
prevalence was 55.4% (191/345). Prevalence was slightly higher (59.0%) in older
age-group (27-36 years) compared with younger age-group (16-26 years) (52.2%). No
significant difference in antibody prevalence in women belonging to two different
ethnic-groups (Tibeto-Burmans 57.8%, Indo-Aryans 52.7%) was observed (p>0.05).
MLA antibody titer ranged from 1:16 to 1:2,048. Over three-fourth of the women
showed either high (1:510 or over) or low (1:16 or 1:32) antibody titer. Three
percent (6/191) of MLA antibody positive subjects had Toxoplasma IgM antibodies
by IgM-ELISA. All six IgM antibody positive pregnant women had MLA antibody titer
of over 1:510. Of the total 13 women with BOH, 5 (38.5%) had Toxoplasma
antibodies of which 2 (40.0%) were positive for Toxoplasma-IgM antibodies.
PMID- 10772557
TI - Toxocara and Gnathostoma among stray canines in Bangkok.
AB - Stomachs and intestines of 88 adult and 112 young stray dogs were obtained from
the Rabies Control Subdivision, Bangkok, and examined especially for the presence
of Gnathostoma spinigerum and Toxocara canis. Forty-five dogs were found positive
for T. canis (overall prevalence 22.5%) but none were found infected with G.
spinigerum. The prevalence of T. canis in young dogs was 37.5% (42 of 112)
whereas in adult dogs was only 3.4% (3 of 88). The total number of T. canis
recovered from the 45 positive dogs was 272 (averaging 6.0 worms/dog). This
includes 268 worms from 42 young dogs (averaging 6.4 worms/dog) and four worms
from three adult dogs (averaging 1.3 worms/dog). The average number of worms,
according to sex and stage, per young dog were as follows: male worms 2.4 +/- 3.5
(range 0-15), female worms 2.8 +/- 3.5 (0-16), immature worms 1.2 +/- 2.5 (0-9),
and all worms 6.4 +/- 8.2 (1-34). The maximum number of worms per young dog was
34 while the minimum was one, and 35.7% (15/42) of these young dogs harbored only
one worm. The body length of the recovered T. canis were as follows: males
measuring 3.0-12.0 cm (averaging 7.1 +/- 2.1 cm), females 4.1-18.2 cm (11.0 +/-
4.1 cm), and immature worms 0.7-3.7 cm (2.1 +/- 0.8 cm).
PMID- 10772558
TI - Scanning electron microscopy of newly excysted metacercariae of Paragonimus
westermani-like, Nakhon Nayok, Thailand.
AB - Scanning electron microscope (SEM) observation of surface structure was done on
newly excysted metacercariae of Paragonimus westermani-like (Nakhon Nayok,
Thailand). The surface of the body was covered with numerous single-pointed
tegumentary spines, large dome-shaped papillae, small one with a pit, and small
one with a smooth surface were situated around the suckers. There were 27 to 30
of the small dome-shaped papillae with a pit around the oral sucker and 10 to 13
of the small ones with a smooth surface around the ventral sucker. The present
report is the new record of excysted metacercariae of P. westermani-like (Nakhon
Nayok, Thailand) by SEM.
PMID- 10772559
TI - Subgroup determination of respiratory syncytial virus by RT-PCR.
AB - PCR optimization for differentiation of RSV subgroup A (RT-PCR-1) and RSV
subgroup B (RT-PCR-2) were developed. Various conditions of RT-PCR-1 and RT-PCR-2
were summarized. These methods are highly specific and sensitive to differentiate
RSV subgroup A and RSV subgroup B from the other respiratory viruses.
PMID- 10772560
TI - A sensitive assay for anti-HIV-1 drug discovery in a biological safety level-2
laboratory.
AB - Studies involving infectious, wild type HIV-1 must be performed under strict BSL
3 practice. We have employed a defective (deltaTat/Rev)MC99 and cloned 1A2 line,
ie, mutated HIV-1 and Tat/Rev transfected cells to verify anti-HIV-1 activity in
a BSL-2 laboratory. A number of extracts from various parts of 11 species of
plants were studied. Results were correlated with those of an anti-HIV-1 reverse
transcriptase (RT) assay.
PMID- 10772561
TI - Development and assessment of ELISA for serodiagnosis of HIV-infection.
AB - A home-made ELISA for serodiagnosis of HIV-infection was developed. It made use
of the HIV viral lysate to coat on ELISA microplates. The purpose was to
establish an ELISA for serodiagnosis of HIV-infection. The newly-developed ELISA,
"H-ELISA", was applied to test 792 samples of HIV-positive serum as confirmed by
Western blot. All 792 samples were positive by H-ELISA. It was also applied to
test 540 samples of normal sera obtained from different laboratories in
Srinagarind Hospital. A number 530 normal sera was negative, 8 samples were
positive and confirmed by Western blot and 2 samples were false positive. It was
concluded that the H-ELISA possessed 100% sensitivity with a false positive rate
of 2/532(0.38%). The H-ELISA, the cost/test was less than 5 bahts, appears to be
promising for substitution of imported commercial kits.
PMID- 10772562
TI - Intestinal microsporidiosis in HIV infected patients with chronic diarrhea in
Thailand.
AB - Microsporidia have been recognized as emerging opportunistic agents affecting
multiple organs. Intestinal microsporidiosis caused by Enterocytozoon bieneusi
and Encephalitozoon intestinalis is a common disease which is associated with
gastrointestinal symptoms, particularly in AIDS patients. So far, information on
the frequency of this enteric disease in Thailand is not available. Therefore,
the present study was undertaken to investigate the prevalence of intestinal
microsporidiosis in HIV infected persons with chronic diarrhea. From 1995 to
1996, multiple diarrheal stool specimens were received and examined for the
presence of the organism using Weber's modified trichrome staining method and
transmission electron microscopy for confirmation. Twenty-two of 66 patients
(33.3%) were positive for microsporidia which appeared as pink-red spores of 0.8
1.2 x 0.7-0.9 microm with the characteristic transverse or oblique band
representing the coiled polar filament. Clinical features of these patients
included chronic diarrhea (100%), weight loss (100%), abdominal pain (77%), fever
(36%), vomiting (36%) and anorexia (18%). Transmission electron microscopic
examination of fecal specimens from the 22 patients with positive staining
results revealed E. bieneusi in 18 cases.
PMID- 10772563
TI - The new DTPw-HBV-Hib combination vaccine can be used at the who schedule with a
monovalent dose of hepatitis B vaccine at birth.
AB - An open, randomized, clinical trial was conducted in order to assess the
reactogenicity and immunogenicity of DTPw-HBV and Haemophilus influenzae type b
(Hib) vaccines when given either as a mixed administration or as separate
concomitant injections using the WHO schedule at 6, 10 and 14 weeks of age,
following a dose of HBV at birth. There were no clinically relevant differences
in the immune response to any component between the mixed and separate
administrations. In fact the anti-tetanus GMTs were significantly higher
(p=0.002) in mixed administration (3.9 IU/ml) compared with the separate
administration (1.9 IU/ml). However although all subjects achieved anti-PRP
titers > or = 0.15 microg/ml, higher anti-PRP GMTs were seen in the group
receiving the separate administration. Importantly, the addition of Hib did not
adversely alter the reactogenicity profile of DTPw-HBV. This report which
demonstrates that this novel combination can be used in WHO recommended schedule.
PMID- 10772564
TI - Immunogenicity and safety of a new inactivated hepatitis A vaccine in Thai young
adults.
AB - In view of the increasing median age of hepatitis A virus (HAV) infection
observed recently in Asia, and the resulting increased number of symptomatic
cases occurring in adults, with the concomitant risk of outbreaks, immunization
against this agent on a national scale might be considered. An open clinical
trial was conducted in Thai adolescents and young adults in order to establish
the immunogenicity and safety of a new inactivated hepatitis A vaccine. At 24
week intervals, two doses (primary dose and booster) of the hepatitis A vaccine
(160 antigenic units per dose) were administered to 80 HAV-seronegative healthy
volunteers, their ages ranging from 16 to 25 years. Local and systemic reactions
were recorded within the first 7 days after each injection. Anti-hepatitis A
virus antibody concentrations were measured by a modified radioimmunoassay before
and one month after each injection. No serious adverse reactions were reported.
Local reactions were confined to transient pain at the injection site, occurring
within 24 hours after injection in 42.5% of the subjects after the first dose and
24.1% of the patients after the booster dose. Systemic reactions (particularly
asthenia or myalgia) were observed in 35.0% and 8.9% of subjects after the first
and the booster injection, respectively. Most of these reactions were transient.
One month after the first dose, all 78 formerly seronegative subjects had
attained satisfactory seroconversion levels of anti-HAV antibody concentrations
(> or = 20 mIU/ml) which they maintained until the booster. The booster dose
elicited a 21-fold increase of HAV antibody levels, with a geometric mean titer
of 2,964 mIU/ml (95% CI, 2,467-3,560), indicative of long-term protection. This
new inactivated hepatitis A vaccine appears to be safe and highly immunogenic
upon administration of a primary dose followed by a booster dose after 24 weeks.
In countries where socio-economic improvement has postponed hepatitis A infection
from early childhood (mostly asymptomatic) towards adolescence and adulthood,
with the symptoms increasing in severity, inclusion of inactivated hepatitis A
vaccine in a preventive vaccination program might be of benefit.
PMID- 10772565
TI - Genotypes and subtypes of hepatitis B virus in Thailand.
AB - Hepatitis B virus exhibits considerable variability evident in its various
antigenic subtypes, which complicates the characterization of epidemiological
factors, particularly in areas endemic for hepatitis B. Our group investigated
the genotypes and subtypes prevalent in Thailand employing nested PCR and
sequencing of the a determinant, as well as the sub-determinants located on the S
gene. The sera examined originated from a mixed range of HBV-infected
individuals. The results were mostly consistent with those reported for Southeast
Asia in that genotype C (54.4%) dominates over genotypes A (22.1%) and B1
(23.5%). Regarding the subtypes, we have exclusively found adw2 (45.6%) and adr
(54.4%) as expected for this area, with one case of subtype adw representing the
exception. While genotype and/or subtype of HBV do not predispose to clinical
disease, they nevertheless may account for those few cases reported in which a
mutation, particularly within the a determinant of the S gene, causes evasion of
routine detection by commercial kits, particularly as long as the respective
individuals remain asymptomatic carriers solely expressing anti-HBc.
PMID- 10772566
TI - Seroprevalence of hepatitis B, hepatitis C, CMV and HIV in multiply transfused
thalassemia patients: results from a thalassemia day care center in Malaysia.
AB - Regular blood transfusions for patients with thalassemia have improved their
overall survival although these transfusions carry a definite risk of the
transmission of certain viruses. Infection with hepatitis B virus (HBV),
hepatitis C virus (HCV), cytomegalovirus (CMV) and human immunodeficiency virus
(HIV) leads to complications which contribute to the morbidity and mortality of
patients with thalassemia. We analyzed the blood samples taken from 85
transfusion dependent thalassemics receiving treatment at the day care center in
Hospital Universiti Kebangsaan Malaysia and found that the seroprevalence rates
for HBV, HCV and CMV were 2.4%, 22.4% and 91.8% respectively. None of the
patients tested positive for HIV. Those positive for HBV and HCV will require
further tests and treatment if chronic hepatitis is confirmed.
PMID- 10772567
TI - Prenatal diagnosis of thalassemia in Songklanagarind Hospital in southern
Thailand.
AB - A thalassemia screening program for pregnant women has been established in
Songklanagarind Hospital since 1992. After genetic counseling, a total of 5078
pregnant women accepted entry into a screening program for thalassemia. Couples
at risk who should receive prenatal diagnosis were 2.8%. Total cases who accepted
prenatal diagnosis were 135. Total clinical cases were 40 (29.6%) with
achievement by prenatal diagnosis of 33 cases (82.5%). Genetic amniocentesis is
the most acceptable method for prenatal diagnosis. Five cases (12.5%) were
misdiagnosed due to contamination of maternal blood cells in amniotic fluid
cases. Questionable results were reported in 2 cases (5%). Abortion occurred in
one case (0.7%). Improvement of surgical technic in prenatal diagnosis reduced
the complications and contamination of maternal cells. This program shows the
feasibility of prevention and control of thalassemia disease in southern
Thailand.
PMID- 10772568
TI - HLA class I antibodies in thalassemic patients.
AB - This study was undertaken to demonstrate the prevalence of HLA class I antibodies
among 62 polytransfused patients. The diagnosis included beta-thalassemia major,
beta-thalassemia/Hb E disease and severe Hb H disease. Their ages ranged from 1
year to 23 years with the mean age of 10.7 years. The number of packed red cell
transfusions ranged from 3 to 235 with the mean of 60 episodes per patient. The
standard microlymphocytotoxicity test was performed using 50 panels of
lymphocytes which specifically identified the majority of HLA class I antibodies.
31/62 cases (50%) were positive for HLA class I antibodies. The detection of
single or multiple antibodies depended upon the number of blood transfusions and
the patients' ages. These antibodies were induced by the leukocytes present in
the transfused packed red cells. Therefore, leukocyte-reduced packed red cells
prepared by either additional inverted centrifrugation or leukocyte filter is
suggested for the routine blood bank service.
PMID- 10772569
TI - Intention of private hospitals to become contractors in the prepaid social
security scheme in Thailand: why and why not?
AB - The objective of the study was to examine whether private hospitals wanted be
main contractors (MCs) under the social security scheme. Data were obtained from
a cross-sectional survey of 94 private hospitals in Bangkok and its vicinity area
conducted between August 1995 and May 1996 using in-person interview and hospital
survey forms. The overall response rate was 88.3%. The results showed that some
46 hospitals (55%) expressed their intention to become MCs. However, nearly 40%
of MCs in 1995 indicated that they really did not want to join the scheme while
several non-MC hospitals said that they wanted to participate. The most prevalent
justifications for the intention of the hospitals to become MCs, or not, were
operational and marketing-related in nature. While the scheme was considered a
profitable market opportunity by many, it affected hospital positioning.
Participation in the scheme might also complicate health services delivery.
Whether private hospitals wanted, or did not want, to become MCs was associated
with ownership status (p = 0.001) and leading competitive strategies of the
hospitals (p = 0.041).
PMID- 10772570
TI - A survey into process and worker's characteristics in the wood furniture industry
in Songkhla Province, southern region of Thailand.
AB - A cross-sectional survey of the wood furniture industry was conducted in southern
Thailand in February 1993. The aim was to examine the manufacturing process,
occupational hazards at the workplace, workers' demographic characteristics,
period of employment, incidence rate of work related injury and some reproductive
history of workers. Altogether 69 managers and 1,000 workers participated in the
study. There are 2 main types of wood industry, rubberwood and hardwood. The
rubberwood industry is semi-automated with advanced technology, has a female
dominated workforce of 200-300 workers per factory and overseas-market
orientation. The hardwood industry is based in small-scale workplaces ranging
from 20 to 60 workers, domestic-market orientation and has a male-dominated
workforce. Most of the workers were young, single, of low education and were high
turnover rate laborforce, with arduous work and long working hours per week.
Solvent was the most frequent chemical exposure. The person-year incidence of
chemical exposure in female workers was higher than in male workers for every
group of chemicals. The incidence of accidents was twice as high as the official
rate. The standardized fertility ratio of female wood workers was only 51.6% of
that of the Thai female population. There was a high abortion rate among women
who became pregnant inside the wood industry compared to that among pregnancies
outside the wood factory. Wood industry workers were exposed to occupational
hazards and accident-prone work conditions.
PMID- 10772571
TI - A profile of hypertension among rural elderly Malaysians.
AB - The main objective of this study was to survey the prevalence of hypertension in
Malaysians aged 55 years and above who responded to a public health screening
campaign in Kuala Langat district, Selangor, Malaysia. The relationship between
the detection, treatment and control in the study population was also examined.
An epidemiological survey of the elderly was conducted in Kuala Langat, a rural
district in Malaysia for a consecutive period of six weeks. The survey was
conducted using a standardized questionnaire and interview by trained research
assistants. The medical students and nurses were trained on the correct protocol
of measuring blood pressure based on the recommendations of the British
Hypertension Society. Newly detected persons with blood pressure readings 160/95
mmHg and above, were given a green card to return to the nearest health center
for a further 2 visits to check his/her blood pressure. A total of 1,392 people
with a mean age of 65 years and comprising of 53.1% males and 46.9% females
responded to the health survey. Based on the history 335 (24.1%) of the
respondents were known hypertensives and 82.1% of this hypertensive group were on
regular treatment. However good control of hypertension was achieved only in 161
(48.1%) of them. Newly detected hypertension was found in 204 (14.6%) of the
respondents. The overall prevalence of hypertension in our sample of respondents
was 25.6%. There was no significant difference between the sexes and the races in
terms of their detection, treatment and control. However there was a significant
difference between the persons aged less than 65 years of age and those older
than 65 years. There was a large proportion of previously known hypertensives
among the survey population. Of those detected, not all were on regular
medications and the majority on medications were not well controlled. Education
of the public through intensive public health campaigns is vital to improve their
knowledge on hypertension and the need for effective control. More community
studies are needed to formulate better methods in the detection, treatment and
control of hypertension.
PMID- 10772572
TI - Tobacco consumption practices and risk of oro-pharyngeal cancer: a case-control
study in Central India.
AB - A hospital based, group matched case control study was conducted with the
objective to assess the association between tobacco consumption practices and
risk of development of oro-pharyngeal cancer in Central India. The study included
123 cases of oro-pharyngeal cancer, diagnosed on the basis of histopathology at
three tertiary care centers in Nagpur city. Each case was matched for age and sex
with two hospital controls: one selected from non-cancer patients and another
from patients having cancer of other sites. Tobacco chewing (OR=7.98, 95% CI 4.11
13.58) and tobacco smoking (OR=2.25, 95% CI 1.22-3.70) were found to be
significantly associated with oro-pharyngeal cancer on unconditional multiple
logistic regression analysis. Further analysis revealed a dose-response
relationship between increasing frequency, duration and retention time of tobacco
in mouth and risk of oro-pharyngeal cancer. Other risk factors which were also
found to contribute significantly in the outcome of oro-pharyngeal cancer in the
study population were: use of traditional/local substances (eg pan, betel nut,
lime) with or without tobacco, use of tobacco containing material for teeth
cleaning, type of smoking (eg bidi, chillum, cigarette) and outdoor occupations.
High values of estimates of attributable risk percent (ARP) and population
attributable risk percent (PARP) confirmed the positive impact of reduction or
elimination of the tobacco consumption practices on reducing the risk of oro
pharyngeal cancer in the population of Central India.
PMID- 10772573
TI - Pyomyositis--with special reference to the comparison between extra- and
intrapelvic muscle abscess.
AB - Fifteen patients, nine males and six females, diagnosed with pyomyositis from
1988 to 1994, and followed for an average of 69.8 months, were reviewed.
Excluding two children, the average age was 56.6 years. Eleven adults (73.3%) had
underlying diseases. The lesions were multiple in five patients (33.3%) and a
total of twenty-four muscle abscesses, including eleven extrapelvic and thirteen
intrapelvic, were identified. When comparing extra- and intrapelvic pyomyositis,
intrapelvic pyomyositis presents a diagnostic challenge requiring a high index of
suspicion. Distinct clinical features such as local heat and painful swelling
were all identified in extrapelvic pyomyositis, but they rarely (in only two of
the thirteen lesions) emerged in intrapelvic pyomyositis. The average time from
presentation to diagnosis was significantly longer in intrapelvic than in
extrapelvic pyomyositis (1.4 vs 9.7 days). Although aspiration showed a high
diagnostic rate in extrapelvic muscle abscesses, it was difficult to perform and
was occasionally misinterpreted in intrapelvic cases. Routine X-rays were not
helpful in making the diagnosis. CT scan was valuable because it provided
positive diagnostic findings in all twelve patients who received one. The
causative organisms in our patients were Staphylococcus aureus in eight (53.3%),
Escherichia coli in three (20%), and Klebsiella in three (20%). Treatments
consisted of parenteral antibiotics for all patients, image-guided aspiration in
four patients, and surgical drainage in eleven patients. Two intrapelvic
pyomyositis patients expired due to sepsis. At the completion of the study,
twelve patients were asymptomatic without sequel, and one patient had a
recurrence.
PMID- 10772574
TI - Isoenzyme study and hybridization of two forms of Anopheles sinensis (Diptera:
Culicidae) in northern Thailand.
AB - The screening of ten isoenzymes of two forms of Anopheles sinensis, Form A and B,
using electrophoretic gels revealed that Est-5(96) allele was the marker in both
4th larva and adult female of An. sinensis Form B, whereas it was lacking in Form
A. Hybridization tests of the two sinensis forms were done by induced copulation.
The results of crosses indicated that they were genetically compatible, providing
viable progeny and completely synaptic polytene chromosomes.
PMID- 10772575
TI - Rate of resistance development in wild Culex quinquefasciatus (Say) selected by
malathion and permethrin.
AB - Wild caught female Culex quinquefasciatus (Say) from Kuala Lumpur were blood fed
and reared in the insectarium. The late third stage of the F1 larvae which
survived the high selection pressure of malathion and permethrin were reared and
colonies were established from adults that emerged. Larvae from these colonies
were then subjected in the subsequent 9 generations to higher selection pressure.
The rate of resistance development were measured by LC50 value of larval
bioassay, LT50 value of adult bioassay and the frequency of the elevated esterase
levels. In another set of experiments using the same batch of Culex mosquitos,
the larvae were not exposed to any insecticides and the decrease in resistance
rate was monitored in each subsequent 9 generations by using similar methods. The
heterozygous standard laboratory strain was selected for susceptibility using the
single raft sib-selection method. The result showed that the field collected F1
generation was 96.0 and 6.3 fold more resistant to malathion and permethrin,
respectively. After selection for about 9 generations the resistance ratio to
malathion and permethrin was 6.2 and 767.3 fold more compared to the LC50 values
of F1 generations, respectively. Esterase in F1 larvae was 6.0 fold more than the
standard laboratory strain.
PMID- 10772576
TI - Neurological manifestations of melioidosis in children.
PMID- 10772577
TI - The value of fluorescence microscopy of auramine stained sputum smears for the
diagnosis of pulmonary tuberculosis.
AB - Laboratory diagnosis of pulmonary tuberculosis rests on the bacteriological
examination of sputum smears stained by the Ziehl-Neelsen (ZN) method for acid
fast bacilli (AFB). In the present study, we have compared light microscopy of ZN
stained smears with that of fluorescence microscopy of sputum smears stained by
auramine-phenol flurochrome dye for detection of AFB in sputum specimens. Sputum
specimens from a total of 2,600 clinically suspected and diagnosed cases of
pulmonary tuberculosis were examined by both the methods. Sputum specimens from a
total of 1,104 patients were found to be positive for AFB. These included sputa
from 975 (37.5%) patients positive for AFB by both ZN and auramine staining
methods and sputa from an additional 129 (4.96%) patients positive for AFB by
auramine staining only. Thus auramine staining of sputum smears in comparison to
that of ZN staining is a better method of sputum microscopy for demonstration of
AFB in sputum specimens. Fluorescence microscopy is relatively more sensitive and
has the added advantage of allowing a large number of sputum specimens to be
examined in a given time, in laboratories equipped with a fluorescent microscope.
PMID- 10772578
TI - Detection of IgM antibody against region IV flagellin of Salmonella paratyphi A.
AB - Salmonella paratyphi A is a pathogenic bacterium that causes paratyphoid fever.
The current laboratory diagnostic techniques are unsatisfactory. To improve
diagnosis, a plasmid (pSK-8E) encoding phase 1 flagellin gene nucleotide position
452-890 from S. paratyphi A has been constructed. The recombinant protein
expressed from the plasmid has been used to develop an indirect ELISA for IgM
antibody detection. Sera from patients with hemoculture positive for S. paratyphi
A, S. typhi, other gram-positive and gram-negative bacteria, and dengue
hemorrhagic fever as well as from healthy control subjects were tested.
Sensitivity, specificity, positive and negative predictive values of the test
were 56.9%, 98.8%, 90.6% and 92.1%, respectively. Since the sensitivity was low,
the explanation for this result was investigated. It was found that the
sensitivity of the test could be increased to 83.3% if the sera were obtained 9
12 days after onset of fever. The sera obtained earlier or later gave only 33.3%
and 66.6% sensitivity, respectively. This result suggests that the IgM antibody
detection assay which we have developed is a valuable tool for diagnosis of S.
paratyphi A infection when the serum samples are taken at the appropriate time.
PMID- 10772579
TI - Serotyping of Flavobacterium meningosepticum by co-agglutination method.
AB - The purpose of this investigation was to evaluate the usefulness of a co
agglutination procedure for the typing of Flavobacterium meningosepticum. The
sensitivity and specificity of the co-agglutination test was compared to the
slide agglutination test using reference strains of the bacterial species.
Antisera were characterized by both technics to determine their titer and working
dilution. The specificity of the sera was assessed by performing tests which
include strains of other species and serotypes. A collection of 47 strains of F.
meningosepticum isolated from clinical specimens were typed by both co
agglutination and slide agglutination methods. Co-agglutination proved to be
markedly more specific than the slide procedure although both methods were
similar in sensitivity. It was concluded that co-agglutination proved to be an
excellent method for the serotyping of F. meningosepticum.
PMID- 10772580
TI - Genetically modified food: consternation, confusion, and crack-up.
PMID- 10772581
TI - Communicating the evidence.
PMID- 10772582
TI - The health of young Australians.
PMID- 10772583
TI - Mood disturbances and coronary heart disease: progress in the past decade.
PMID- 10772584
TI - Applying the results of a systematic review in general practice.
AB - OBJECTIVE: To assess how general practitioners might interpret and apply the
results of a systematic review relevant to general practice. DESIGN: Cross
sectional postal survey of general practitioners in August 1997. PARTICIPANTS: 51
general practitioners in the Southern Division of General Practice in Adelaide
and 11 professors or heads of departments of general practice. MAIN OUTCOME
MEASURES: Extent to which comments on the implications for practice and
implications for research coincided with the evidence presented in a systematic
review of antibiotics for the treatment of acute otitis media in children; and
reported probability that respondents would prescribe antibiotics in three brief
case scenarios. RESULTS: There was considerable variation in the comments made by
general practitioners on the implications of the review for clinical practice.
After reading the review, respondents with training in critical appraisal were
more likely to state that children with acute otitis media would usually recover
spontaneously and reported a lower probability of prescribing antibiotics in two
of the three case scenarios. CONCLUSIONS: Providing systematic reviews is not
sufficient for the results of such evidence to be translated into clinical
practice. There is an association between critical appraisal skills and the
application of evidence-based practice.
PMID- 10772585
TI - Intravenous lignocaine infusions for severe chronic daily headache.
AB - OBJECTIVES: To determine the safety and efficacy of intravenous lignocaine
infusion in patients with severe chronic daily headache (CDH). DESIGN:
Retrospective survey of consecutive patients. PARTICIPANTS: 19 patients, 18 with
rebound headache and three with status migrainosus. Two patients had both
conditions at different times. SETTING: Neurology unit in a major metropolitan
teaching hospital, 1994-1998. MAIN OUTCOME MEASURES: Adverse events; headache
resolution; long term efficacy. RESULTS: The 19 patients (16 women) received 27
lignocaine infusions. Seven minor adverse events were noted during four
infusions. Twenty-two infusions were given for analgesic rebound headache in 18
patients, with headache resolution in 82% of infusions (17 of the 18 patients
responded at least once). Four patients obtained lasting relief, six returned to
their regular manageable pattern of migraine (in two of these patients CDH
recurred after six months), four were lost to follow-up, and in four there was no
long term benefit. Five infusions were given for status migrainosus in three
patients, with four of these infusions successfully relieving the headache.
CONCLUSIONS: Intravenous lignocaine appears to be useful in the management of
severe intractable CDH and status migrainosus.
PMID- 10772586
TI - Three clusters of ciguatera poisoning: clinical manifestations and public health
implications.
AB - Between July 1997 and August 1998 we investigated three clusters (26 cases) of
ciguatera poisoning in the inner Sydney area. Tropical reef fish were implicated
in each cluster. Most of those affected had musculoskeletal, neurological and
gastrointestinal symptoms. The clusters raise questions about the need for rapid
diagnosis and enhanced surveillance mechanisms, the regulation of fish supply,
and the lack of testing facilities for ciguatera toxin.
PMID- 10772587
TI - A targeted, single-dose azithromycin strategy for trachoma.
AB - OBJECTIVE: To evaluate the impact of treating children with acute trachoma and
their contacts with oral azithromycin. DESIGN: Open, uncontrolled, prospective
evaluation of a community-based treatment strategy. SETTING: Central Australian
semi-desert Aboriginal community (1995-1996). PARTICIPANTS: 216 school- and pre
schoolchildren aged 6 months and up to 15 years. INTERVENTION: All children with
acute trachoma and their contacts (co-resident siblings aged between 6 months and
15 years) received single-dose oral azithromycin suspension (20 mg/kg, to a
maximum of 1000 mg). MAIN OUTCOME MEASURE: Prevalence of acute trachoma (World
Health Organization trachoma diagnostic criteria). RESULTS: Trachoma prevalence
at baseline was 42% (71/169) and 55% (18/33) for schoolchildren and pre
schoolchildren, respectively: 103 schoolchildren and 21 pre-schoolchildren,
comprising 77 with follicular trachoma and their 47 contacts, were treated with
azithromycin over an 8-week period. Acute trachoma prevalence in schoolchildren
fell to 22% at 6-8 months (P < 0.0001) and was 31% at 12 months (P < 0.05
compared with baseline). Pre-schoolchildren were followed up for 6 months after
treatment, and their trachoma prevalence fell from 55% to 25% (P < 0.05). Further
treatment was given to children with trachoma at 12 months, and the point
prevalence of trachoma for schoolchildren at 24 months was 34%. CONCLUSIONS: In
contrast to mass-treatment strategies, significant reductions in trachoma
prevalence at 6 months were achieved by screening 35% of community members (216)
and treating 20% (124). The subsequent prevalence increases support the need for
more comprehensive treatment programs, including health promotion and efforts to
improve living conditions.
PMID- 10772588
TI - Two cases of mycetoma due to Nocardia brasiliensis in central Australia.
AB - Comparatively few cases of mycetoma ("Madura foot") have been reported in
Australia, and only one caused by Nocardia brasiliensis. We report two Aboriginal
women from remote communities in central Australia who presented with
longstanding mycetomas caused by this organism. Difficulties in diagnosis
substantially delayed commencement of effective treatment, illustrating the need
to consider this condition in chronic suppurative skin infection.
PMID- 10772589
TI - Genetically modified foods--safety and regulatory issues.
AB - Gene technology is a new form of biotechnology with much greater potential
applications.
PMID- 10772590
TI - Genetically modified foods--food for thought.
AB - We would be wise to hold off until we know more about the health, ecological and
economic effects of genetically modified food.
PMID- 10772591
TI - Ciguatera update.
AB - Ciguatera fish poisoning is probably more important than any other form of
seafood poisoning. Its epidemiology is complex and it is impossible to predict
outbreaks. Toxic fish (which look, taste and smell normal) contain ciguatoxins
derived from microalgae via the food chain. The toxins are not destroyed by
cooking and, if consumed in sufficient dose, can cause symptoms persisting for
weeks, months or years. The incidence of ciguatera is expected to increase in
association with global warming and widespread bleaching and death of coral.
PMID- 10772592
TI - Getting new evidence into medicine.
AB - The rate of transfer of the knowledge gained from health and medical research
into evidence-based practice is determined by many factors. Preconditions for the
uptake of new evidence are the availability of good evidence, ready access to the
evidence, a supportive organisational environment, and effective mechanisms for
promoting knowledge uptake. Evidence-based medicine is being promoted in
Australia by a body of enthusiastic clinicians, public health practitioners and
consumer advocates, supported by initiatives from national, State and local
healthcare services and professional bodies. The short to medium term future of
evidence-based medicine in Australia is likely to be shaped by three major
factors: a reduction in cost and technical barriers which limit access to
computerised databases; a trend towards shared decision-making between clinicians
and patients; and increased demand for information to fill the gaps in research
based evidence on specific problems.
PMID- 10772593
TI - Diuretics, ACE inhibitors and NSAIDs--the triple whammy.
PMID- 10772594
TI - Recent changes in the profile of prescription NSAID use in Australia.
PMID- 10772595
TI - Antenatal screening for HIV in Australia: time to revise policies?
PMID- 10772596
TI - Antenatal screening for HIV in Australia: time to revise policies?
PMID- 10772597
TI - Prostate cancer testing.
PMID- 10772598
TI - Sildenafil.
PMID- 10772599
TI - Brain morphological changes and early marijuana use: a magnetic resonance and
positron emission tomography study.
AB - BACKGROUND: The focus of this report is on the possible role that the age of
first use of marijuana may play on brain morphology and function. METHODS:
Magnetic resonance imaging (MRI) and positron emission tomography (PET) were
utilized to study 57 subjects. Brain volume measures (whole brain, gray matter,
white matter and lateral ventricle volumes), global cerebral blood flow (CBF) and
body size were evaluated. RESULTS: There are three primary findings related to
age of first use of marijuana. Subjects who started using marijuana before age
17, compared to those who started later, had smaller whole brain and percent
cortical gray matter and larger percent white matter volumes. Functionally, males
who started using marijuana before 17 had significantly higher CBF than other
males. Both males and females who started younger were physically smaller in
height and weight, with the effects being greater in males. CONCLUSIONS: These
findings suggest that the age at which exposure to marijuana begins is important.
Early adolescence may be a critical period for effects that are not present when
exposure begins later. These results are discussed in light of reported effects
of marijuana on gonadal and pituitary hormones.
PMID- 10772600
TI - Characteristics of substance-abusing persons with schizophrenia: the paradox of
the dually diagnosed.
AB - Previous studies have noted the paradox of the dually-diagnosed (serious mental
illness and substance abuse) in which the dually-diagnosed are judged to be both
behaviorally more disorganized and simultaneously more socially competent. This
study sought to further assess this paradox with a large sample size and a
comprehensive assessment approach. In this study, the dually-diagnosed (N = 233)
differed significantly from the non-dually-diagnosed (N = 262) in the symptom
paradox. The dually-diagnosed were judged both more behaviorally disorganized and
socially intact. The comprehensive assessment approach yielded empirical data in
support of three possible hypotheses to explain the paradox. The implications of
the findings and the three possible hypotheses are discussed.
PMID- 10772601
TI - Psychopathology in substance abusing women reporting childhood sexual abuse.
AB - This study compared MMPI-2 profiles and evaluated the ability of the MMPI-2 and
its two new post-traumatic stress scales (PK and PS) to discriminate women in
outpatient substance abuse treatment reporting positive (n = 24) and negative (n
= 69) child sexual abuse histories. T-tests revealed significantly higher mean
scores for the sexual abuse group for the following scales: F, 1, 2, 3, 4, 6, 7,
and 8. A discriminant analysis yielded a linear function of L, F, 3, 5, 8, and PK
that correctly categorized 75% with positive histories and 77% with negative
histories. The optimal cutoff PK score was 17, which correctly classified 75% and
46% of those reporting positive and negative abuse histories, respectively. These
findings support early identification of abuse survivors among substance abusing
women and suggests that the MMPI-2 may be useful in patient-treatment matching.
PMID- 10772602
TI - Emergency physician attitudes concerning intervention for alcohol
abuse/dependence delivered in the emergency department: a brief report.
AB - Emergency Medicine (EM) physicians frequently see patients with alcohol abuse or
dependence (AA/AD). Brief interventions delivered in the Emergency Department
(ED) have been advocated for these patients, however, little is known regarding
EM physician willingness to support such interventions. We conducted a study to
determine EM physicians' attitudes toward the use of interventions for AA/AD in
the ED. All members of the Michigan College of Emergency Physicians (n = 569)
were mailed a survey to assess their attitudes toward the use of intervention for
AA/AD in the ED. Of the 257 respondents (45.9%), a total of 76% agreed that AA/AD
is a treatable illness and only 15% would not agree to support of ED
interventions. Both supporters and non-supporters thought that the lack of
sufficient time was an impediment to treating AA/AD in the ED. Our study suggests
that the majority of ED physicians would support the implementation of brief
intervention for AA/AD in the ED.
PMID- 10772603
TI - Longitudinal pathways to condom use: a psychosocial study of male IDUs.
AB - This longitudinal study examined the psychosocial risk and protective factors
involved in condom use among 265 male IDUs. Subjects were individually
interviewed at two points in time using a structured questionnaire, which
included psychosocial measures and questions about drug use and condom use. Data
were analyzed using Pearson correlations and hierarchical regression analyses. T1
condom use was the most powerful predictor of T2 condom use, with or without
control on other variables. T1 family support for condom use, friends' support
for condom use, adaptive coping with AIDS or the threat of AIDS, and planning to
use condoms were significantly related to T2 condom use. Protective father
factors enhanced the effects of other protective psychosocial factors, increasing
T2 condom use. The results suggest several approaches for changing risk-taking
sexual behavior in male IDUs: enhancing coping abilities, selecting peers who
take fewer risks, and planning to use condoms.
PMID- 10772604
TI - Improving naltrexone response: an intervention for medical practitioners to
enhance medication compliance in alcohol dependent patients.
AB - The effectiveness of naltrexone, a FDA-approved medication for alcohol
dependence, can be improved if we support and help patients to consistently take
their medication. We illustrate how patient noncompliance with treatment
negatively affects outcome, and, we describe a new intervention to enhance
medication compliance. Outcome was evaluated for 196 alcohol dependent
outpatients who were treated with 50 mg/day naltrexone or placebo for 12 weeks.
For patients who adhered to the prescribed treatment, relapse rates were lower
with naltrexone than placebo (10% vs. 38.6%, p < 0.001). For noncompliant
patients, relapse rates were high and comparable between naltrexone- and placebo
treated patients (42.9% vs. 40%). In a second study of 100 alcohol dependent
outpatients, we introduced an intervention that resulted in better medication
compliance rates compared to a previous naltrexone study of patients who did not
receive the intervention (77.0% vs. 60.8%, p < 0.01). This provided some support
for the use of an intervention that targets medication compliance when
prescribing naltrexone.
PMID- 10772605
TI - Use of antiretroviral therapies by HIV-infected persons receiving methadone
maintenance.
AB - HIV-infected persons receiving methadone maintenance must often seek their
medical care at a separate site. However, little data is available on the receipt
of antiretroviral therapy (ART), beliefs about ART, and influences on the
decision to initiate ART among those referred off-site. HIV-infected injection
drug users (n = 72) were interviewed at three methadone maintenance programs; 83%
with CD4 cell counts under 500 reported that they had received ART. Of these
persons, 56% had used three drug combination therapy. Beliefs about the benefits
of ART included: increased survival, 96%; decreased viral load 87%; decreased HIV
related infections 87%; could cure HIV, 29%. For those receiving ART, physician
input, CD4 count, and possible side effects were more important than friends,
family or mass media in deciding to start ART. We conclude that the model of
referral for HIV care off-site does not appear to impede access to ART for HIV
infected IDUs in methadone maintenance.
PMID- 10772606
TI - Treatment resistant smokers: a pilot study of nicotine nasal spray and inhaler.
AB - A growing proportion of smokers are those who have failed prior treatments for
cessation. We tested the efficacy of nicotine nasal spray and nicotine inhaler in
two uncontrolled, open-label studies of 19 and 20 smokers who had previously
failed nicotine patch therapy. As in the three prior studies of treatment
failures, 6 month abstinence rates were extremely low both with the nasal spray
(0%) and the inhaler (5%). We discuss possible treatments for and methodological
issues in researching treatment-resistant smokers.
PMID- 10772607
TI - Selective guide to current reference sources on topics discussed in this issue.
PMID- 10772608
TI - Infrared radiation exposure in traditional glass factories.
AB - This article reports on a general method of evaluating exposure to infrared
radiation (IR-A, IR-B, IR-C) from high temperature (T > 1000 degrees C) black
body sources, simply by performing measurements with a luxometric and/or near IR
detector. The method, which may be applied to any black body source, uses the
universality of the Planck formula for the black body spectrum, which allows
estimation of the radiated power in any wavelength range by measuring the power
radiated in another range. This capability may be very useful when the range of
interest is one in which radiometers are expensive and difficult to calibrate, as
for the IR-B and IR-C ranges, because a more commonly available luxometer can be
used instead. The results of measurements and evaluations in two traditional
Italian glass factories are reported and compared with the threshold limit value
given by the American Conference of Governmental Industrial Hygienists. Intense
exposures in the IR-B and IR-C ranges has been found for some workers, exceeding
the limit by a large factor. This exposure must be reduced, as it has been shown
by epidemiologic studies that there is indeed a correlation between
cataractogenesis and work with fused glass and metals.
PMID- 10772609
TI - Use of comparison populations for evaluating the effectiveness of hearing loss
prevention programs.
AB - One approach for evaluating the effectiveness of Hearing loss prevention programs
(HLPPs) is to compare the rate of hearing loss in a study population with that in
a reference population. This approach was used to evaluate the HLPP of a
population of 14,900 employees of an industrial company with branches across the
United States. Three reference populations were selected from a database of 22
industrial companies compiled under the sponsorship of the National Institute for
Occupational Safety and Health. The risk of hearing loss in the study population
was estimated relative to each of the three reference populations using the Cox
proportional hazards model after adjustment for race, age at baseline, and
hearing threshold at time of enrollment in the HLPP. In comparison with the three
reference populations, hearing loss was 2.1 to 3.9 times more likely to occur in
study population males and 1.8 to 5.1 times more likely in study population
females. The 95% confidence interval around each risk estimate precluded unity,
indicating that each risk estimate was statistically significant. These results
indicate that the performance of the subject HLPP needs improvement. This study
demonstrated the use of comparison populations for evaluating the effectiveness
of HLPPs.
PMID- 10772610
TI - Monitoring effluents from an air toxic control device using continuous nonmethane
organic carbon analyzer.
AB - Nonmethane organic carbon (NMOC) is a measure of total organic carbon other than
methane in an air emission. It is a convenient way of expressing total organic
emissions in terms of carbon. Development of a continuous NMOC (referred to as
the C-NMOC) analyzer was recently reported. A microsorbent trap called the
microtrap is the key component of this instrument. The microtrap selectively
concentrates the organic compounds and then desorbs them as an injection pulse
for NMOC detection. The process of concentration and injection is quite fast, and
the analysis can be carried out every few seconds to every few minutes. The
characteristics of this instrument as applied to on-line monitoring are presented
in this article. Its applicability is demonstrated by monitoring emissions from
an air toxic control device. The instrument performed well with the oxygenated,
chlorinated, aliphatic, and aromatic hydrocarbons in this study. The instrument
also demonstrated linear response and high sensitivity.
PMID- 10772611
TI - Mist generation at a machining center.
AB - Control of occupational exposure to metalworking fluid mist generally involves
enclosing the machining center and exhausting to an air cleaner that returns
cleaned air to the workplace. To select an appropriate air cleaner, particle size
and generation rate of the mists need to be known. Mist particle size and
concentration were measured as a function of tool speed, fluid flow rate, and
cutting rate at an enclosed machining center. A vertical machining center was
totally enclosed and the air from this enclosure was exhausted into a duct where
mist concentration and size distribution were measured using a time-of-flight
aerosol spectrometer and a cascade impactor. Mist generation during the face
milling of a 30 x 31-cm piece of aluminum with a 10-cm diameter face mill was
studied. Machining parameters were varied as a 2 x 2 x 3 factorial experiment
with these variables: coolant flow rate (18 and 44 m/sec), tool rpm (1900 and
3800 rpm), and metal removal (no removal, two teeth on face mill, and six teeth
on face mill). Mist concentration increased with increasing tool speed and fluid
application velocity. Whether the tool was actually removing metal did not affect
the mist generation. Thus, mist generation is a function of fluid and tool
motion. During a second experiment, effect of tool speed and diameter on mist
generation was studied. Mist concentrations measured with the aerosol
spectrometer were proportional to the 2 and 3.5 powers of the tool speed for the
face mill and end mill, respectively. In both experiments the shape of the size
distribution was largely unaffected by the experimental variables.
PMID- 10772612
TI - Within-day variability of magnetic fields among electric utility workers:
consequences for measurement strategies.
AB - Occupational exposure to 50-Hz magnetic fields was surveyed among electric
utility workers to investigate (1) components of exposure variability, (2)
patterns of autocorrelation between short-term measurements, and (3) imprecision
and misclassification due to short-term measurements. Spot measurements every 10
seconds during 81 working days were analyzed for 42 electric utility workers from
10 occupational subgroups and during 8 working days for 4 office workers from the
same company. For the 8-hour time-weighted average (TWA) magnetic fields, the
variability was partitioned into its components: within workers, between workers,
and between groups. For spot measurements of magnetic fields, the within-day
variance component also was examined. Autocorrelation functions were determined
and numbers of short-term measurements necessary for reliable estimates of 8-hour
TWA magnetic fields were assessed. Spot measurements of magnetic fields, as well
as 8-hour TWA magnetic fields, were approximately lognormally distributed among
workers. The mean exposure to magnetic fields was 0.47 microT (n = 81 days) in
electric utility workers and 0.12 microT (n = 8 days) in office workers. A large
fraction, 76% of the spot measurements total variance, could be attributed to
variability within days. For the 8-hour TWA magnetic fields, between-group
variability was small and of the same magnitude as between-worker variability.
Significant autocorrelations between short-term averages of 7.5, 15, and 30
minutes were present, when taken within periods of 30 minutes. One-hour averages
showed no autocorrelation. Simulations showed that, due to high within-day
variability and autocorrelation, a limited number of short-term measurements of
magnetic fields in electric utility workers are likely to result in imprecise
estimates of 8-hour TWA magnetic fields. Measurement strategies relying on short
term (spot) measurements are therefore likely to result in misclassification of
exposure and consequently absent or spurious exposure-response relations.
PMID- 10772613
TI - Workplace risk factors and occupational musculoskeletal disorders, Part 1: A
review of biomechanical and psychophysical research on risk factors associated
with low-back pain.
AB - Injuries and disorders caused by overexertion and repetitive motion are the
leading causes of compensable lost-time cases in the United States.
Epidemiological and laboratory-based research methods have been used to evaluate
the significance of various risk factors associated with overuse injuries and
disorders. The National Institute for Occupational Safety and Health performed a
comprehensive review of over 600 epidemiological studies in 1997 and concluded
that there was evidence of a causal relationship between low-back injuries and
disorders and workplace exposures to forceful exertions, awkward posture, and
vibration. Although epidemiological studies provide important insights to
understanding the causes of work-related overuse disorders, they are sometimes
criticized for their inability to measure precisely how people respond to
specific risk factors found in the workplace. This article presents a review of
recent laboratory studies and biomechanical models of work factors believed to be
associated with increased risk of low-back injuries and disorders. Biomechanical
models and laboratory studies do not replace epidemiological studies. However,
these approaches provide important complementary information that is needed to
understand the complex process of how exposures to physical risk factors result
in strain that may ultimately lead to injury or disease. These studies also
provide important insights as to how people react and respond to specific
physical risk factors found in the workplace. Combined with epidemiological
research, laboratory studies are an essential element in understanding the causes
and prevention of work-related overexertion injuries.
PMID- 10772614
TI - Air movement visualization in the workplace: current methods and new approaches.
AB - Airflow visualization in the workplace to assess containment, ventilation, or
general air movements is often carried out using smoke tracers. The most
prevalent method uses a disposable smoke tube that generates a plume of
concentrated sulfuric acid fume. However, use of the smoke tube exposes
occupational hygienists to the risk of sulfuric acid exposure through inhalation
or dermal contact, as well as injury from sharps. Following concern over the
potential health hazard associated with smoke tube usage, alternative flow
visualization methods and technologies have been reviewed. Methods of generating
smoke or bubbles other than using smoke tubes suitable for visualizing air
movements include heated element smoke generators, combustion generators,
generation of metallic chlorides and ammonium chloride, generation of neutral
density bubbles, and water fog generation. Some of these methods are applicable
in specific workplace situations. However, there is no commercially available
smoke or bubble generator currently available that matches the smoke tube for
cost effectiveness, ease of use, and wide applicability, while also reducing the
potential health risks associated with smoke tube usage. Despite this, certain
technologies, in particular water/glycerol smoke generation using heated element
generators, have the potential to be developed into viable alternatives to the
smoke tube. Thus, with further development, an air movement visualization method
that poses a significantly lower health hazard than the smoke tube is feasible.
PMID- 10772616
TI - Evaluation of the cost-effectiveness of various passive monitors and active
monitors for industrial hygiene sampling.
AB - A framework for evaluating passive or active industrial hygiene air sampling
monitors on a cost-effectiveness basis is described. Five passive monitors and
one active monitor (charcoal tube with pump) were compared in several
hypothetical scenarios. Using certain assumptions regarding method validation
costs, sampling equipment costs, and labor costs, both a per sample cost and a
total annual cost were calculated for each type of sampling monitor as a function
of total samples taken per year. The results of this study indicate that even
when the additional expense of full validation of the passive sampling monitor is
required, these monitors are more cost-effective than active monitors. A specific
type of passive monitor utilizing replaceable capsules is the most cost-effective
when more than 500 samples per year are taken.
PMID- 10772615
TI - Influence of building maintenance, environmental factors, and seasons on airborne
contaminants of swine confinement buildings.
AB - Eight swine confinement buildings, selected to cover the widest possible range of
cleanliness, were visited twice during winter and once during summer to verify
the range, seasonal variations, and correlations between biological and chemical
contaminants. Physical aspects were graded for dirtiness (1 = clean, 10 = dirty),
ventilation, air temperature, number of animals, building, and room size. Air
samples were taken to measure relative humidity, CO2, ammonia, total dust, and
microbiological counts and/or identification (bacteria and molds); endotoxin
levels also were measured. During winter, average measurements and ranges were:
CO2 = 0.304% (0.254 to 0.349%); ammonia = 19.6 ppm (1.9 to 25.9 ppm); dust = 3.54
mg/m3 (2.15 to 5.60 mg/m3). There were 883 cfu/m3 (547 to 2862 cfu/m3) of molds,
4.25 x 10(5) cfu/m3 (1.67 x 10(5) to 9.30 x 10(5) cfu/m3) of total bacteria, 29
cfu/m3 (3 to 94 cfu/m3) of thermophilic actinomycetes). A significant decrease in
bacterial levels (p = 0.04), dust (p = 0.0008), ammonia (p = 0.005), and CO2 (p <
0.0001) was observed during summer sampling when compared with winter levels.
Mold counts were positively correlated (p = 0.03) with dirtiness scores, while
bacterial counts were negatively correlated with this parameter (p < 0.002),
whereas bacteria and endotoxins were correlated with the number of animals (p <
0.05). Ambient gases (CO2 and ammonia) correlated with each other (p = 0.006).
Bacteria were the most important contaminant in swine confinement buildings, and
endotoxin levels found were also very high (mean = 4.9 x 10(3) EU/m3). We
conclude that a wide range of air contamination exists in swine confinement
buildings of different maintenance. There is a decrease in some of these
contaminants during summer. Observed dirtiness of the swine confinement buildings
has a poor predictive value concerning air quality.
PMID- 10772617
TI - Multisorbent tubes for collecting volatile organic compounds in spacecraft air.
AB - The sampling capability of Tenax-TA tubes, used in the National Aeronautics and
Space Administration's solid sorbent air sampler to trap and concentrate
contaminants from air aboard spacecraft, was improved by incorporating two
sorbents within the tubes. Existing tubes containing only Tenax-TA allowed highly
volatile compounds to "break through" during collection of a 1.5 L air sample.
First the carbon molecular sieve-type sorbents Carboxen 569 and Carbosieve S-III
were tested for their ability to quantitatively trap the highly volatile
compounds. Breakthrough volumes were determined with the direct method, whereby
low ppm levels of methanol or Freon 12 in nitrogen were flowed through the
sorbent tubes at 30 mL/min, and breakthrough was detected by gas chromatography.
Breakthrough volumes for methanol were about 9 L/g on Carboxen 569 and 11 L/g on
Carbosieve S-III; breakthrough volumes for Freon 12 were about 7 L/g on Carboxen
569 and > 26 L/g on Carbosieve S-III. Next, dual-bed tubes containing either
Tenax-TA/Carbosieve S-III, Tenax-TA/Carboxen 569, or Carbotrap/Carboxen 569 to a
10-component gas mixture were exposed, in dry and in humidified air (50% relative
humidity), and percentage recoveries of each compound were determined. The Tenax
TA/Carboxen 569 combination gave the best overall recoveries (75-114% for the 10
compounds). Acetaldehyde had the lowest recovery (75%) of the 10 compounds, but
this value was still an improvement over either the other two sorbent
combinations or the original single-sorbent tubes.
PMID- 10772618
TI - An analysis of the implications of a magnetic field threshold limit value on
utility work practices.
AB - This article examines the implications of a 10 gauss (G) occupational threshold
limit value (TLV) on the work practices of a utility that must maintain and
repair 500 and 230 kV transmission lines. Three work practices are compared: bare
handed work with live lines (the current practice at the example utility), use of
hot sticks, and de-energizing lines prior to work. Bare-handed work with live
lines leads to occasional exceedances of the 10 G TLV. Use of hot sticks and de
energizing lines eliminate these exceedances, but they do so at a price. Both
practices increase the job duration and, as a result, may increase occupational
injury risks. The annual costs for the current live-line, bare-handed practice is
approximately $175,000. Use of hot sticks increases this annual cost of
maintenance and repair by 30 to 55%. De-energizing lines can increase annual
costs by $4 million to $14 million, due to the need for adding additional
electricity generation during the planned outages. De-energizing lines also
increases the risk to service reliability slightly.
PMID- 10772619
TI - Comparison of solvents for removing pesticides from skin using an in vitro
porcine model.
AB - This study compared four solvents (1-propanol, polyethylene glycol [avg. MW 400],
10% Ivory Liquid and water, and D-TAM) for their ability to remove selected
pesticides from an in vitro porcine skin model using a solvent-moistened wipe.
Wipes were performed 90 min after pesticide was applied to the skin. The four
pesticides selected (glyphosate, alachlor, methyl parathion, and trifluralin)
were chosen because of their differences in water solubility. This study also
determined whether pretreatment of skin with a solvent prior to pesticide
application would either increase or decrease recovery of the pesticide. Recovery
efficiencies for all solvents and pesticides were affected by the amount of
contaminant on the skin. Although pesticide recoveries from all four solvents
were similar (range: 45-57%), on average 1-propanol had significantly higher
recoveries, followed by soap and water. There was no significant difference
between polyethylene glycol, and D-TAM. When skin was pretreated with any of the
four solvents before pesticide application, the recoveries of the more water
soluble compounds, glyphosate and alachlor, decreased. When pretreatment with
solvent preceded application of trifluralin, the pesticide with the lowest water
solubility, recoveries increased. 1-Propanol or soap and water were more
effective in removing pesticides from skin than polyethylene glycol or D-TAM, but
the amount of pesticide recovered from skin was affected by the chemical
characteristics of the pesticide (such as water solubility) and the amount of
pesticide originally on the skin. This study provides information useful to the
interpretation of skin wipe sample results collected in field studies.
PMID- 10772620
TI - Urinary fluoride as an exposure index in aluminum smelting.
AB - Urinary fluoride was evaluated as an exposure index for a prospective study of
asthma in an aluminum smelter. Two studies were conducted to evaluate the
relationship between airborne exposure and urinary excretion over a workweek, and
to describe exposures among jobs and over time. Thirty-two subjects were
evaluated on Days 1 and 3 of a 3-day workweek. On each day, spot urine samples
were collected prior to the start of work and again at the end of the shift.
Samples were analyzed for fluoride and expressed as milligrams fluoride per gram
of creatinine. Airborne exposures to total particulate, fluoride particulate, and
hydrogen fluoride (HF; using a 37-mm filter cassette containing a filter and
treated back-up pad) were also evaluated on each subject. In the second study,
postshift urine samples were collected from asthma study volunteers in three
surveys extending over 1.5 years and analyzed for fluoride. Average airborne
exposures were 15.7, 4.1, and 0.7 mg/m3 for particulates, particulate fluorides
and HF, respectively, and were substantially higher among carbon setters than
other workers. However, average urine fluorides among the same workers were
reasonably low, 1.3 and 3.0 mg/g creatinine in pre- and postshift urine samples,
respectively. Carbon setters, who routinely wore respiratory protection during
high exposure periods, had urinary fluoride levels similar to those of other
potroom personnel. A significant variation in dose, as expressed by postshift
urinary fluoride levels, was observed between potroom and nonpotroom jobs and
over three survey periods. These results suggest that postshift urinary fluorides
provide a reasonable exposure index for surveillance of exposure levels for an
epidemiologic study, and that a substantial variation of exposure occurs between
jobs and over time. Although urinary fluorides may be used for exposure
surveillance, additional details on individual exposure agents and patterns of
exposure over time are required for complete assessment.
PMID- 10772621
TI - Airborne aldehydes from heating rosin core solder and liquid rosin flux to
soldering temperatures.
AB - Gas phase aldehydes produced from heating rosin core solder and liquid rosin flux
to temperatures commonly used in soldering were trapped on sampling tubes
containing XAD-2 resin coated with the derivatizing agent 2
hydroxymethylpiperidine. Analysis of the resulting oxazolidine derivatives was
performed using gas chromatography/mass spectrometry (GC/MS). The observed
aldehyde derivatives included formaldehyde, acetaldehyde, propionaldehyde,
acrolein, isobutyraldehyde, butyraldehyde, isovaleraldehyde, valeraldehyde,
furfural, hexanal, cyclohexane carboxaldehyde and other unidentified compounds
likely to be aldehyde isomers. Formaldehyde, acetaldehyde, and benzaldehyde were
detected in blank samples. By comparison with an internal standard, a sample
produced by drawing air with contaminants derived by heating rosin core solder
through a sampling tube contained levels of formaldehyde and acetaldehyde much
greater than seen in sampling tube blanks. Benzaldehyde was not shown to be
present at a significantly greater level in samples from heating rosin core
solder than in blanks prepared using the same analysis protocol. The use of
National Institute of Occupational Safety and Health (NIOSH) method 2539
extraction procedures produced blanks with levels of formaldehyde significantly
lower than with a modified extraction method (methylene chloride, no sonication).
The modified extraction method produced significantly lower benzaldehyde levels
in blanks compared with the NIOSH extraction method using toluene and sonication
of sampling sorbent tubes.
PMID- 10772622
TI - The effect of inhalation resistance on facepiece leakage.
AB - Air purifying respirators use filters to remove particulate air contaminants.
Resistance to airflow generally increases as the filter loads and a "filter cake"
is formed. It has been recommended by ANSI and the Occupational Safety and Health
Administration that filters should be replaced when the wearer notices they are
hard to breathe through. Repeated faceseal leak rate measurements were made
during respiratory wear over a range of simulated breathing resistances from 5.6
to 19.6 mm (0.22 to 0.77 inches) of water. The measured faceseal leak rates
increased as the breathing resistance increased and varied depending on the
initial leak rate at the 5.6 mm pressure. The increase in faceseal leak rate from
5.6 to 19.6 mm breathing resistance was as high as a factor of 4. Theoretically,
a person with an initial respirator penetration of 2.5% could have that value
increase to 10% as filter loading increased breathing resistance by 14 mm. Some
research has shown that breathing resistances between 60 and 140 mm of water
would be "noticeable but well tolerated." It is not known if workers would be
able to detect an increase in breathing resistance that would lead to a
significant increase in faceseal leakage. These data suggest a need to establish
a replacement schedule for all filters used in the workplace. How often a filter
should be replaced is difficult to determine. Breathing resistance would vary
depending on the individual filter and aerosol loading characteristics, the
concentration of the aerosol in the workplace, and breathing rates.
PMID- 10772623
TI - Hazardous peak concentrations of hydrogen sulfide gas related to the sewage
purification process.
AB - The concentration of hydrogen sulfide in the atmosphere of a sewage purification
plant in Norway was studied. Continuous measurements over several 3-week periods
showed that the concentrations generally were lower than 2 ppm, but peak
concentrations over 100 ppm were discovered. Rapid onset and decline
characterized these peak concentrations, which occurred at regular intervals.
Through evaluation of the time pattern of these peaks compared with plant
operations, a specific process was identified as the likely causative factor of
the spikes. Through simple remedial actions the hydrogen sulfide concentration
associated with this activity was reduced from above 100 ppm to less than 2 ppm.
Olfactory fatigue to hydrogen sulfide and strong offensive odors from other
compounds in the sewage makes smell ineffective for signaling high
concentrations. Peak concentrations may therefore pass unnoticed unless detected
with continuous measuring equipment. The risk for exposure may be reduced by
enclosing processes and through the use of spot extraction ventilation in areas
with compacted anaerobic waste material.
PMID- 10772624
TI - Proficiency Analytical Testing (PAT) Program. August 1999.
PMID- 10772625
TI - Environmental lead proficiency analytical testing (ELPAT) program. March and June
1999.
PMID- 10772626
TI - Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the
glucocorticoid and pregnane X receptors.
AB - The molecular mechanisms of regulation of the CYP3A4 gene have been examined in
an in vitro reporter gene system, containing -1 kb of the CYP3A4 promoter, in a
HepG2 cell line. This system allows for the separate and combined transfection of
expression plasmids encoding the human glucocorticoid receptor (hGR) and the
human pregnane X receptor (hPXR), and, therefore, the opportunity to assess the
role of these receptors in the induction process. Hydrocortisone produces a dose
dependent increase in CYP3A4 activation, a response that is increased in the
presence of either receptor. Moreover, transfection of the hPXR decreased the
EC(50) for hydrocortisone-dependent induction by a factor of 3.3, a response that
was not changed by simultaneous cotransfection of the hGR. In addition, the
hydrocortisone dose-response curve falls within the physiological blood level
concentration of this steroid, implicating a regulatory role for hydrocortisone
in the basal level of CYP3A4 expression. Although the responses to dexamethasone
and rifampicin were both increased by both receptors, dexamethasone activation of
CYP3A4 was similar for both the hGR and the hPXR, whereas rifampicin-dependent
activation favored the hPXR. We conclude that regulation of the CYP3A4 gene is
receptor-dependent and that hydrocortisone may function as a regulator of basal
expression via the hPXR and the hGR. The implications of this latter conclusion
for possible regulatory interactions between hydrocortisone and xenobiotic
inducers remain to be clarified.
PMID- 10772627
TI - 3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP
glucuronosyltransferase 2B7 (UGT2B7).
AB - 3'-Azido-3'-deoxythymidine (AZT) is frequently prescribed to patients infected
with the human immunodeficiency virus. After absorption, AZT is rapidly
metabolized into 3'-azido-3'-deoxy-5'-glucuronylthymidine by UDP
glucuronosyltransferase (UGT) enzymes. Using labeled [(14)C]UDP-glucuronic acid
and microsomal preparations from human kidney 293 cells stably expressing the
different human UGT2B isoenzymes, it was demonstrated that AZT glucuronidation is
catalyzed specifically by human UGT2B7. The identity of the metabolite formed was
confirmed as AZT-G by liquid chromatography coupled with mass spectrometry.
UGT2B7 is encoded by a polymorphic gene and kinetic analysis of AZT
glucuronidation by the two allelic variants UGT2B7(H(268)) and UGT2B7(Y(268)),
yielded apparent K(m) values of 91.0 and 80.1 microM, respectively. Normalization
to protein levels yielded glucuronidation efficiency ratios (V(max)/K(m)) of 21.3
and 11.0 microl. min(-1). mg protein(-1) for UGT2B7(H(268)) and UGT2B7(Y(268)),
respectively. It remains possible that other UGT enzymes are also involved in AZT
conjugation; however, the glucuronidation of AZT by UGT2B7, which is a UGT2B
protein expressed in the liver, is consistent with previous findings and supports
the physiological relevance of this enzyme in AZT conjugation.
PMID- 10772628
TI - Metabolism, disposition, excretion, and pharmacokinetics of levormeloxifene, a
selective estrogen receptor modulator, in the rat.
AB - The tissue distribution, pharmacokinetics, metabolism, and excretion of the
selective estrogen receptor modulator levormeloxifene have been investigated
after oral administration of [(14)C]-levormeloxifene to male and female Sprague
Dawley rats. The quantitative distribution of radiolabeled levormeloxifene and/or
metabolites was confirmed by whole body autoradiography. Levormeloxifene was
absorbed from the gastrointestinal tract and was widely distributed into tissues,
with peak radioactive concentrations generally being observed 4 h after
administration in the intestine, liver, lung, kidney, spleen, pancreas, adrenals,
and ovary (females). Fecal elimination was the major excretion route of
radioactivity. In a separate pharmacokinetic study, plasma C(max) was generally
observed 6 h after dose administration and the half-life of elimination was long
(24 h) and a doubling in dose resulted in an approximate doubling in exposure.
The majority of the drug was excreted as norlevormeloxifene; the 7-desmethyl
metabolite of levormeloxifene, via the formation of phase II metabolites
(glucuronides) and excretion into the bile. Unchanged drug was also excreted,
mainly from 0 to 24 h, and accounted for about 6 to 12% of the dose. Together
these two components accounted for approximately 50% of the radioactivity
excreted. Additional metabolites isolated and identified by liquid chromatography
tandem mass spectrometry, and accounting for 1 to 5% of the excreted
radioactivity in rat feces during the first 24 h, included two
monohydroxylevormeloxifene species, a pyrrolidinone ring-opened metabolite of
levormeloxifene, and desmethylnorlevormeloxifene.
PMID- 10772629
TI - Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in
rats.
AB - The pharmacokinetics, tissue distribution, metabolism, and excretion of
celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]
benzenesulfonamide, a cyclooxygenase-2 inhibitor, were investigated in rats.
Celecoxib was metabolized extensively after i.v. administration of
[(14)C]celecoxib, and elimination of unchanged compound was minor (less than 2%)
in male and female rats. The only metabolism of celecoxib observed in rats was
via a single oxidative pathway. The methyl group of celecoxib is first oxidized
to a hydroxymethyl metabolite, followed by additional oxidation of the
hydroxymethyl group to a carboxylic acid metabolite. Glucuronide conjugates of
both the hydroxymethyl and carboxylic acid metabolites are formed. Total mean
percent recovery of the radioactive dose was about 100% for both the male rat
(9.6% in urine; 91.7% in feces) and the female rat (10.6% in urine; 91.3% in
feces). After oral administration of [(14)C]celecoxib at doses of 20, 80, and 400
mg/kg, the majority of the radioactivity was excreted in the feces (88-94%) with
the remainder of the dose excreted in the urine (7-10%). Both unchanged drug and
the carboxylic acid metabolite of celecoxib were the major radioactive components
excreted with the amount of celecoxib excreted in the feces increasing with dose.
When administered orally, celecoxib was well distributed to the tissues examined
with the highest concentrations of radioactivity found in the gastrointestinal
tract. Maximal concentration of radioactivity was reached in most all tissues
between 1 and 3 h postdose with the half-life paralleling that of plasma, with
the exception of the gastrointestinal tract tissues.
PMID- 10772630
TI - In vitro flow cytometry method to quantitatively assess inhibitors of P
glycoprotein.
AB - P-glycoprotein (Pgp)-mediated drug efflux is a major factor contributing to the
variance of absorption and distribution of many drugs. A simple and reliable in
vitro method to identify inhibitors of Pgp helps to prevent the potential of drug
interactions. Using daunorubicin as a fluorescent marker and vanadate as a
positive control compound, a functional flow cytometry method for assessing the
ability of a drug to inhibit Pgp-mediated drug efflux from CR1R12 multidrug
resistant cells has been evaluated. Quantitation of the relative fluorescence was
used to compare potency of individual inhibitors. Known Pgp inhibitors, such as
cyclosporin A, nicardipine, verapamil, quinidine, terfenadine, tamoxifen, and
vinblastine were demonstrated to inhibit the Pgp-mediated efflux of daunorubicin.
Cyclosporin A and terfenadine were the most potent inhibitors among the compounds
tested. Tetraphenylphosphonium and alpha-tocopherol had little inhibitory effect.
Progesterone produced significant inhibition at relatively high concentrations.
This study demonstrated that this in vitro flow cytometry method is a simple,
sensitive, and quantitative tool to assess the capacity of a drug to inhibit Pgp
transporters, and is useful for screening or identifying inhibitors of Pgp as
well as evaluation of potential for drug interactions.
PMID- 10772631
TI - Rabbit pregnane X receptor is activated by rifampicin.
AB - Reverse transcriptase-polymerase chain reaction was used to amplify a partial
cDNA from rabbit lung mRNA that shared 77% protein sequence identity with the
mouse pregnane X receptor (PXR). Rapid amplification of cDNA ends from a rabbit
kidney lambdaZAP expression library resulted in the isolation of overlapping
cDNAs spanning the complete coding sequence. The deduced amino acid sequence of
411 residues exhibited 79% overall amino acid identity with human PXR and 77%
identity with mouse PXR. Based on this protein sequence relationship and a
similar degree of conservation exhibited by the mouse and human PXR orthologs,
the cDNA appears to encode the rabbit PXR ortholog. 5'-rapid amplification of
cDNA ends performed on an adaptor-ligated cDNA library from rabbit liver revealed
the presence of an alternate mRNA, which differed at the 5'-terminus. RNase
protection assays indicated that the alternate mRNA was expressed at >50-fold
lower levels in rabbit kidney and liver. Rifampicin treatment of CV-1 cells
cotransfected with a rabbit PXR expression plasmid and a luciferase reporter
construct containing two copies of the DR3 enhancer from CYP3A23 produced a 6
fold induction of luciferase activity. In contrast, rat PXR was not responsive to
this antibiotic under the same conditions. Pregnenolone 16alpha-carbonitrile was
an efficacious activator of rat PXR, but failed to significantly activate rabbit
PXR at equivalent concentrations. These results indicate that the ligand
activation profile of rabbit PXR is distinct from rat PXR and more closely
resembles that of human PXR. The rabbit PXR activation profile is consistent with
the cytochrome P450 (P450) 3A6 induction profile in rabbits.
PMID- 10772632
TI - Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in perfused rat
liver: involvement of hepatic aldehyde oxidase as a detoxification enzyme.
AB - To elucidate the toxicological relevance of hepatic aldehyde oxidase (AO) as a
detoxification enzyme of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), we
studied the metabolism and the hepatotoxicity of MPTP in intact rat livers
exhibiting different AO activities by using a recirculating perfusion method. In
the perfusate during a 90-min recirculation of 1 mM MPTP, the perfused liver from
Jcl:Wistar rat, a strain showing high AO activity, generated almost equal amounts
of 1-methyl-4-phenylpyridinium species (MPP(+)) and 1-methyl-4-phenyl-5,6-dihydro
2-pyridone (MPTP lactam) as major metabolites, together with 4-phenyl-1,2,3, 6
tetrahydropyridine, 1-methyl-4-phenyl-2-pyridone (MP 2-pyridone) and 1-methyl-4
phenyl-1,2,3,6-tetrahydropyridine N-oxide. However, a marked decrease of MPTP
lactam as well as MP 2-pyridone and a concomitant increase of MPP(+) were caused
by coinfusion of 2-hydroxypyrimidine (2-OH PM), a competitive inhibitor of AO,
into Jcl:Wistar rat liver. A quite similar metabolic profile was obtained on
perfusion of AO-deficient WKA/Sea rat liver. Rather large amounts of MPP(+) were
retained in the liver in all cases, but especially in Jcl:Wistar rat in the
presence of 2-OH PM. Lactate dehydrogenase leakage into the perfusate from rat
liver perfused with 1 mM MPTP was greater in the strain with lower AO activity,
WKA/Sea, than in that with higher AO activity, Jcl:Wistar. Furthermore,
inhibition of AO in Jcl:Wistar rat in the presence of 2-OH PM caused an
enhancement of lactate dehydrogenase leakage. These results suggest that hepatic
AO is a key detoxification enzyme for MPTP.
PMID- 10772633
TI - Affinity and potency of proinhibitory antipeptide antibodies against CYP2D6 is
enhanced using cyclic peptides as immunogens.
AB - A series of antipeptide antibodies directed against CYP2D6 were produced by
immunizing rabbits with peptides that were sterically unrestrained (linear) or
conformationally restricted by cyclization. A variety of sites within the region
comprising residues 254 to 290 of CYP2D6 were targeted. In immunoblotting
studies, each of the antibodies against the linear and cyclic peptides recognized
only a single immunoreactive band of 54 kDa in human liver microsomal fraction
and bound to recombinant CYP2D6, but not recombinant CYP1A1, CYP1A2, CYP2A6,
CYP2B6, CYP2C9, CYP2C19, CYP2E1, or CYP3A4. However, the relative intensity of
immunoreactive bands was considerably stronger for those antibodies raised
against cyclic peptides. Similarly, in an enzyme-linked immunosorbent assay,
antibodies raised against cyclic peptides bound 10 to 100 times more strongly to
recombinant CYP2D6 than antibodies raised against the corresponding linear
peptides. None of the antibodies raised against linear peptides had any effect on
debrisoquine 4-hydroxylase activity of human hepatic microsomal fraction;
however, anticyclic peptide antibodies targeted against residues 254 to 273, 261
to 272, and 257 to 268 of CYP2D6 inhibited enzyme activity by a maximum of 60,
75, and 91%, respectively. In contrast, despite binding strongly to CYP2D6, an
anticyclic peptide antibody directed against residues 278 to 290 did not inhibit
enzyme activity. The epitope of the proinhibitory anticyclic peptide antibody
directed against residues 257 to 268 of CYP2D6 included Thr-261 and Trp-262, and
indicates a role for these residues in enzyme inhibition. In conclusion,
immunization with peptides conformationally restricted by cyclization to mimic
loop regions of CYP2D6 resulted in strongly binding antibodies that when targeted
appropriately were able to inhibit CYP2D6-catalyzed activity.
PMID- 10772634
TI - Identification of the metabolites of roxithromycin in humans.
AB - The semisynthetic antibiotic roxithromycin (RXM) exists in an (E)-configuration.
Metabolites of RXM in the bile of four cholecystectomy patients with T-tube
drainage and in the urine and plasma of four healthy volunteers after single oral
doses of 150 mg of RXM were investigated. A total of 15 metabolites were found in
bile, urine, and plasma by HPLC with ion trap mass spectrometric and
electrochemical detection. These metabolites were identified as descladinose
derivative of RXM (M1), erythromycin-oxime (M2), N-, O-, and N,O-di-demethylated
derivatives of RXM (M3, M4, and M6), and N-mono- and N-di-demethylated
derivatives of erythromycin-oxime (M5 and M7), as well as the (Z)-isomers (M8
M15) of RXM and metabolites M1 to M7, respectively. Structures of six major
metabolites (M1-M4, M8, and M10) were established by chromatographic and mass
spectrometric determination and comparison with synthesized standards. The
stability of RXM and the six synthesized substances was investigated to exclude
artifact products. These results, together with previous findings, suggest that
biotransformation pathways elucidated for RXM include: 1) isomerization of RXM
derivatives, from E-isomer to Z-isomer; 2) O-demethylation; 3) N-demethylation;
4) hydrolysis of the cladinose moiety; and 5) dealkylation of the oxime ether
side chain. Secondary metabolism via these pathways was also evidenced. The O
demethylation and isomerization of RXM derivatives represent two novel
biotransformation pathways recovered for RXM.
PMID- 10772635
TI - In vitro glucuronidation using human liver microsomes and the pore-forming
peptide alamethicin.
AB - The UDP-glucuronosyltransferases (UGTs) are a superfamily of membrane-bound
enzymes whose active site is localized inside the endoplasmic reticulum.
Glucuronidation using human liver microsomes has traditionally involved
disruption of the membrane barrier, usually by detergent treatment, to attain
maximal enzyme activity. The goals of the current work were to develop a
universal method to glucuronidate xenobiotic substrates using microsomes, and to
apply this method to sequential oxidation-glucuronidation reactions. Three assays
of UGT catalytic activity estradiol-3-glucuronidation, acetaminophen-O
glucuronidation, and morphine-3-glucuronidation, which are relatively selective
probes for human UGT1A1, 1A6, and 2B7 isoforms, respectively, were developed.
Treatment of microsomes with the pore-forming peptide alamethicin (50 microg/mg
protein) resulted in conjugation rates 2 to 3 times the rates observed with
untreated microsomes. Addition of physiological concentrations of Mg(2+) to the
alamethicin-treated microsomes yielded rates that were 4 to 7 times the rates
with untreated microsomes. Optimized assay conditions were found not to
detrimentally affect cytochrome P450 activity as determined by effects on
testosterone 6beta-hydroxylation and 7-ethoxycoumarin deethylation. Formation of
estradiol-3-glucuronide displayed atypical kinetics, and data best fit the Hill
equation, yielding apparent kinetic parameters of K(m)(app) = 0.017 mM,
V(max)(app) = 0.4 nmol/mg/min, and n = 1.8. Formation of acetaminophen-O
glucuronide also best fit the Hill equation, with K(m)(app) = 4 mM, V(max)(app) =
1.5 nmol/mg/min, and n = 1.4. Alternatively, morphine-3-glucuronide formation
displayed Michaelis-Menten kinetics, with K(m)(app) = 2 mM and V(max)(app) = 2. 5
nmol/mg/min. Finally, alamethicin treatment of microsomes was found to be
effective in facilitating the sequential oxidation-glucuronidation of 7
ethoxycoumarin.
PMID- 10772637
TI - Metabolism of ifosfamide to chloroacetaldehyde contributes to antitumor activity
in vivo.
AB - Metabolic activation of ifosfamide (IFO) leads to the active 4-hydroxy-metabolite
and to a substantial liberation of chloroacetaldehyde (CAA). CAA has been
presumed responsible for side effects of IFO. We recently have shown cytotoxic
effects of CAA against human tumor cells in vitro. The aim of this study was to
demonstrate antitumor effects of CAA in vivo, and to compare its potency to 4-OH
IFO. Pharmacokinetics of IFO and metabolites were evaluated after infusion of 250
mg/kg IFO in mice. The area under the curve (AUC) for 4-hydroxyifosfamide (4-OH
IFO) and CAA were 138. 5 and 102.4 micromol. h/liter, respectively. To compare
pharmacokinetics and antitumor effects, the mice received isolated infusion of 4
OH-IFO or CAA in equimolar doses to IFO. Administration of 4-OH-IFO yielded AUC
values comparable with those obtained after administration of the parent drug. In
contrast, infusion of isolated CAA via tail vein gave a low AUC value of 51.5
micromol. h/liter due to slow flow in the tail vein and rapid degradation.
Administration of the parent drug gave highly cytotoxic intratumoral peak
concentrations of 25 and 12 micromol/kg tumor weight for 4-OH-IFO and CAA in MX1
xenotransplanted nude mice. Both IFO and isolated 4-OH-IFO led to complete
remissions. Administration of isolated CAA (75 mg/kg) delayed tumor growth
significantly. The equitoxic dose of isolated 4-OH-IFO was 40 mg/kg. On a molar
basis CAA was seven times less potent as 4-OH-IFO. However, on the basis of
achieved AUC values, CAA seems to exhibit a similar antitumor activity to 4-OH
IFO.
PMID- 10772636
TI - Substrate-dependent effect of acetonitrile on human liver microsomal cytochrome
P450 2C9 (CYP2C9) activity.
AB - Acetonitrile is an organic solvent commonly used to increase the solubility of
lipophilic substrates for in vitro studies. In this study, we examined its effect
on four reactions (diclofenac hydroxylation, tolbutamide methyl hydroxylation,
phenytoin hydroxylation, and celecoxib methyl hydroxylation) catalyzed by human
liver microsomes and by the recombinant CYP2C9. In both cases, the effect of
acetonitrile on activity was found to be substrate-dependent. Namely, it
increased diclofenac 4'-hydroxylase and tolbutamide methyl hydroxylase
activities, but decreased celecoxib methyl hydroxylase activity in a
concentration-dependent manner. By comparison, hydroxylation of phenytoin was
resistant to its effect. The presence of acetonitrile (3%, v/v) gave rise to a
lower K(m) and a higher V(max) for diclofenac hydroxylase in both liver
microsomes and recombinant CYP2C9 preparations (87 and 52% increase in
V(max)/K(m) ratio, respectively). On the other hand, the inhibitory effect of the
solvent (1%, v/v) toward celecoxib hydroxylase was characterized by a decrease in
V(max) (human liver microsomes) or a change in both K(m) and V(max) (rCYP2C9),
leading to 25 and 46% decrease in V(max)/K(m) for both systems. The results of
this study underscore the need for careful evaluation of solvent effects before
initiation of inhibition or cytochrome P450 reaction phenotyping studies.
PMID- 10772638
TI - Analysis and prediction of absorption profile including hepatic first-pass
metabolism of N-methyltyramine, a potent stimulant of gastrin release present in
beer, after oral ingestion in rats by gastrointestinal-transit-absorption model.
AB - The prediction method for the plasma concentration-time profile of N
methyltyramine (NMT), a potent stimulant of gastrin release present in beer after
oral ingestion in rats was examined using the previously developed
Gastrointestinal (GI)-Transit-Absorption Model, with the addition of a process of
hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for
estimation of the GI transit rate constant for eight segments in the GI tract.
The first order absorption rate constant for each segment was estimated by means
of a conventional in situ closed loop method. The results of in situ absorption
experiments showed that NMT is well absorbed in the small intestine, especially
in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was
demonstrated that more than 90% of orally ingested NMT is absorbed in the small
intestine, and that the substantial absorption site for NMT in vivo is the lower
jejunum and the ileum. However, the observed bioavailability was only 39.0%. The
in vitro metabolism study clarified that NMT is metabolized in the liver, but not
in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0
liters/h) calculated from the rate of metabolism in vitro, the hepatic
availability was estimated to be 0.510 on the basis of a well stirred model,
which was validated by two other methods to calculate the hepatic availability of
NMT. The plasma concentration-time curve and bioavailability of NMT after oral
ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic
first-pass metabolism process.
PMID- 10772639
TI - Dose-dependent pharmacokinetics of cyclosporin A in rats: events in tissues.
AB - Cyclosporin A (CyA) tissue distribution kinetics was extensively studied after
single 1.2-, 6-, and 30-mg/kg CyA doses (via 2-min i.v. infusion) to rats. Drug
concentrations in blood and various tissues were measured using a specific
radioimmunoassay. Based on total blood concentration data alone, CyA systemic
pharmacokinetics appeared essentially linear. However, after taking the
saturable, nonlinear blood cell binding into account, multiple nonlinear factors
were identified. Intrinsic clearance at 30 mg/kg was about half the value at the
two lower doses. Tissue distribution was also dose-dependent, with evidence of
saturable binding in many tissues. In general, blood binding saturation
(dissociation constant K(D) = 0. 18 microg/ml) occurred at a lower dose
(concentration) than saturation of tissue binding (K(D), 0.005-0.77 microg/g),
such that the volume of distribution at steady state first increased as the dose
increased from 1.2 to 6 mg/kg, and then decreased as the dose increased to 30
mg/kg. Tissue binding was further investigated by various graphical analyses.
Some organs showed a monophasic (single site) Scatchard plot of the tissue data
at steady state, with high K(D) values. In other organs, biphasic binding
characteristics were observed with the K(D) values of the high-affinity site in
the same range as the K(D) reported for the binding of CyA with cyclophilin, the
putative target. Saturable tissue binding may therefore influence not only the
pharmacokinetics but also the efficacy of CyA.
PMID- 10772640
TI - Stability and interactions of recombinant human nerve growth factor in different
biological matrices: in vitro and in vivo studies.
AB - The purpose of this investigation was to characterize the stability, activity,
and interactions of recombinant human nerve growth factor (rhNGF) in various
biological matrices in vitro and in vivo. rhNGF (10 microg/ml) remained stable in
human plasma for up to 4 days at 37 degrees C. There was a decrease in the
recovery of rhNGF after incubation at lower concentrations (20 ng/ml) and for
longer time periods (3 and 5 days at 37 degrees C). Size exclusion HPLC analysis
indicated that rhNGF forms high molecular weight (HMW) complexes after long
incubation periods. We confirmed that alpha(2)-macroglobulin (alpha(2)M) is the
major plasma component that binds to rhNGF. Furthermore, this interaction was
considerably increased by treatment of plasma with primary amines such as
CH(3)NH(2). Changes in the pH environment did not affect the interaction of rhNGF
with alpha(2)M. We also determined that the binding of rhNGF to CH(3)NH(2)
treated pure alpha(2)M or alpha(2)M present in human plasma substantially
diminished its immunoreactivity and bioactivity detection. The interaction of
rhNGF with activated alpha(2)M was reversed and inhibited by coincubation with
dimethyl sulfoxide. Released rhNGF under these conditions was fully bioactive.
(125)I-rhNGF also binds to alpha(2)M by forming similar (125)I-rhNGF/HMW
complexes in plasma after i.v. administration in rats and mice. Sixty minutes
after dosing in rats, most of the labeled material was in the form of a (125)I
rhNGF/HMW complex. These studies have provided a better understanding of the
nature of the interactions of rhNGF with plasma components as well as methods to
enhance, reverse, and inhibit these interactions.
PMID- 10772641
TI - Tissue disposition and pharmacokinetics of recombinant human nerve growth factor
after acute and chronic subcutaneous administration in monkeys.
AB - In this study, we have characterized the metabolism, tissue disposition,
excretion routes, and plasma pharmacokinetics of recombinant human nerve growth
factor after single and multiple s.c. administration in male cynomolgus monkeys.
Unlabeled nerve growth factor (NGF; 2 mg/kg) was administered three times a week
for 4 weeks and a full pharmacokinetic profile was obtained for doses 1 and 12.
For the tissue distribution studies, 0.8 microg/kg of trace (125)I-labeled
recombinant human nerve growth factor was dosed. Histological analysis of
emulsion-microautoradiography indicated that specific (125)I-NGF labeling was
confined to sections of nerves most frequently localized adjacent to large
vessels in sections of kidney, spleen, liver, and salivary gland. A small
percentage of large neurons within the sympathetic ganglia were intensely
labeled, as well as large neurons within the dorsal root ganglia. We found an
increased disposition of (125)I-NGF in parts of the peripheral nervous system
(including sympathetic ganglia) from 8 to 24 h postdose. In contrast,
radioactivity in most non-neuronal tissues declined. This suggests specific
uptake in these target tissues known to express specific receptors for NGF. We
also identified changes in pharmacokinetic parameters after single versus chronic
s. c. administration. These studies demonstrated that s.c. administration of NGF
at 0.8 microg/kg doses in monkeys is capable of accessing and localizing in the
target tissues.
PMID- 10772642
TI - Detection of chemical-induced differential expression of rat hepatic cytochrome
P450 mRNA transcripts using branched DNA signal amplification technology.
AB - The importance of the cytochrome P450 (CYP) enzyme family in xenobiotic
metabolism, as well as their differential expression and activity in response to
a wide range of environmental chemicals and pharmaceuticals, is well documented.
The objective of this study was to evaluate the specificity of the branched DNA
(bDNA) signal amplification technique for the detection of multiple rat CYPs from
hepatocellular RNA. Oligonucleotide probe sets were designed to various
chemically inducible rat CYP mRNA transcripts, including CYP1A1, CYP1A2,
CYP2B1/2, CYP2E1, CYP3A1/23, and CYP4A2/3. The robustness of the bDNA assay was
assessed with the CYP2B1/2-specific probe set, and total RNA was isolated from
control and phenobarbital (PB)-treated rats. Analysis of these RNA samples by
bDNA signal amplification resulted in a linear quantifiable range of RNA
detection that spanned three orders of magnitude (0.1-100 microg of total RNA).
The fidelity of the bDNA assay was evaluated within a single assay and between
assays where repeated measurements of a single sample were reproduced reliably.
The specificity of individual CYP probe sets was evaluated with five typical CYP
inducing chemicals on the expression of specific hepatic CYP mRNA transcripts.
Male Sprague-Dawley rats were administered 3-methylcholanthrene, PB, isoniazid,
pregnenolone-16alpha-carbonitrile, or clofibric acid to induce transcription of
CYP1A1, CYP1A2, CYP2B1/2, CYP2E1, CYP3A1/23, and CYP4A2/3 mRNA, respectively.
Analysis of chemical-induced differences in gene expression by bDNA signal
amplification indicated that 3-methylcholanthrene induced CYP1A1 and CYP1A2 mRNA
levels 670- and 11-fold, respectively; PB induced CYP2B1/2 expression 71-fold;
pregnenolone-16alpha-carbonitrile induced CYP3A1/23 expression 34-fold; and
clofibric acid induced CYP4A2/3 expression 4.7-fold. Overall, these data support
the use of bDNA signal amplification technology as a robust, reproducible, and
efficient means of monitoring the differential expression of multiple isoforms of
the CYP enzyme family.
PMID- 10772643
TI - Use of preferentially replicating bacteria for the treatment of cancer.
PMID- 10772644
TI - Poxvirus vectors: orphaned and underappreciated.
PMID- 10772645
TI - Reovirus as a novel oncolytic agent.
PMID- 10772646
TI - Scavenging new insights into atherogenesis.
PMID- 10772647
TI - Cytokines and the regulation of tolerance.
PMID- 10772648
TI - Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor
angiogenesis in mice.
PMID- 10772649
TI - Targeted disruption of the class B scavenger receptor CD36 protects against
atherosclerotic lesion development in mice.
AB - Macrophage scavenger receptors have been implicated as key players in the
pathogenesis of atherosclerosis. To assess the role of the class B scavenger
receptor CD36 in atherogenesis, we crossed a CD36-null strain with the
atherogenic apo E-null strain and quantified lesion development. There was a
76.5% decrease in aortic tree lesion area (Western diet) and a 45% decrease in
aortic sinus lesion area (normal chow) in the CD36-apo E double-null mice when
compared with controls, despite alterations in lipoprotein profiles that often
correlate with increased atherogenicity. Macrophages derived from CD36-apo E
double-null mice bound and internalized more than 60% less copper-oxidized LDL
and LDL modified by monocyte-generated reactive nitrogen species. A similar
inhibition of in vitro lipid accumulation and foam cell formation after exposure
to these ligands was seen. These results support a major role for CD36 in
atherosclerotic lesion development in vivo and suggest that blockade of CD36 can
be protective even in more extreme proatherogenic circumstances.
PMID- 10772650
TI - Loss of TGF-beta signaling contributes to autoimmune pancreatitis.
AB - Recent observations suggest that immune response is involved in the development
of pancreatitis. However, the exact pathogenesis underlying this immune-mediated
response is still under debate. TGF-beta has been known to be an important
regulating factor in maintaining immune homeostasis. To determine the role of TGF
beta in the initiation or progression of pancreatitis, TGF-beta signaling was
inactivated in mouse pancreata by overexpressing a dominant-negative mutant form
of TGF-beta type II receptor in the pancreas, under control of the pS2 mouse
trefoil peptide promoter. Transgenic mice showed marked increases in MHC class II
molecules and matrix metalloproteinase expression in pancreatic acinar cells.
These mice also showed increased susceptibility to cerulein-induced pancreatitis.
This pancreatitis was characterized by severe pancreatic edema, inflammatory cell
infiltration, T- and B-cell hyperactivation, IgG-type autoantibodies against
pancreatic acinar cells, and IgM-type autoantibodies against pancreatic ductal
epithelial cells. Therefore, TGF-beta signaling seems to be essential either in
maintaining the normal immune homeostasis and suppressing autoimmunity or in
preserving the integrity of pancreatic acinar cells.
PMID- 10772651
TI - CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine
nonalcoholic steatohepatitis.
AB - Nonalcoholic steatohepatitis (NASH) and alcoholic liver disease have similar
pathological features. Because CYP2E1 plays a key role in alcoholic liver disease
with its ability to stimulate lipid peroxidation, we tested the proposal that
CYP2E1 could also be a factor in the development of NASH. In a dietary model -
mice fed a methionine- and choline-deficient (MCD) diet - liver injury was
associated with both induction of CYP2E1 and a 100-fold increase in hepatic
content of lipid peroxides. Microsomal NADPH-dependent lipid oxidases contributed
to the formation of these lipid peroxides, and in vitro inhibition studies
demonstrated that CYP2E1 was the major catalyst. To further define the role of
CYP2E1 as an initiator of oxidative stress in NASH, Cyp2e1(-/-)mice were
administered the MCD diet. CYP2E1 deficiency neither prevented the development of
NASH nor abrogated the increased microsomal NADPH-dependent lipid peroxidation,
indicating the operation of a non-CYP2E1 peroxidase pathway. In Cyp2e1(-/-) mice
with NASH (but not in wild-type mice), CYP4A10 and CYP4A14 were upregulated.
Furthermore, hepatic microsomal lipid peroxidation was substantially inhibited by
anti-mouse CYP4A10 antibody in vitro. These results show that experimental NASH
is strongly associated with hepatic microsomal lipid peroxidation. CYP2E1, the
main enzyme associated with that process in wild-type mice, is not unique among
P450 proteins in catalyzing peroxidation of endogenous lipids. We have now
identified CYP4A enzymes as alternative initiators of oxidative stress in the
liver.
PMID- 10772652
TI - Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer.
AB - Heart failure leads to marked suppression of the Ca(2+)-independent transient
outward current (I(to1)), but it is not clear whether I(to1) downregulation
suffices to explain the concomitant action potential prolongation. To investigate
the role of I(to1) in cardiac repolarization while circumventing culture-related
action potential alterations, we injected adenovirus vectors in vivo to
overexpress or to suppress I(to1) in guinea pigs and rats, respectively. Myocytes
were isolated 72 hours after intramyocardial injection and stimulation of the
ecdysone-inducible vectors with intraperitoneal injection of an ecdysone analog.
Kv4.3-infected guinea pig myocytes exhibited robust transient outward currents.
Increasing density of I(to1) progressively depressed the plateau potential in
Kv4. 3-infected guinea pig myocytes and abbreviated action potential duration
(APD). In vivo infection with a dominant-negative Kv4. 3-W362F construct
suppressed peak I(to1) in rat ventriculocytes, elevated the plateau height,
significantly prolonged the APD, and resulted in a prolongation by about 30% of
the QT interval in surface electrocardiogram recordings. These results indicate
that I(to1) plays a crucial role in setting the plateau potential and overall
APD, supporting a causative role for suppression of this current in the
electrophysiological alterations of heart failure. The electrocardiographic
findings indicate that somatic gene transfer can be used to create gene-specific
animal models of the long QT syndrome.
PMID- 10772653
TI - Disruption of the fibroblast growth factor-2 gene results in decreased bone mass
and bone formation.
AB - Basic fibroblast growth factor (FGF-2), an important modulator of cartilage and
bone growth and differentiation, is expressed and regulated in osteoblastic
cells. To investigate the role of FGF-2 in bone, we examined mice with a
disruption of the Fgf2 gene. Measurement of trabecular bone architecture of the
femoral metaphysis of Fgf2(+/+) and Fgf2(-/-) adult mice by micro-CT revealed
that the platelike trabecular structures were markedly reduced and many of the
connecting rods of trabecular bone were lost in the Fgf2(-/-) mice. Dynamic
histomorphometry confirmed a significant decrease in trabecular bone volume,
mineral apposition, and bone formation rates. In addition, there was a profound
decreased mineralization of bone marrow stromal cultures from Fgf2(-/-) mice.
This study provides strong evidence that FGF-2 helps determine bone mass as well
as bone formation.
PMID- 10772655
TI - Role of passive T-cell death in chronic experimental autoimmune
encephalomyelitis.
AB - The mechanisms of chronic disease and recovery from relapses in experimental
autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, are
unknown. Deletion of myelin-specific lymphocytes by apoptosis may play a role in
termination of the inflammatory response. One pathway of apoptosis is the passive
cell death or "cell death by neglect" pathway, which is under the control of the
Bcl family of genes. To investigate the role of passive cell death pathway in
EAE, we used mice with transgenic expression of the long form of the bcl-x gene
(Bcl-x(L)) targeted to the T-cell lineage. We found that mice transgenic for Bcl
x(L) have an earlier onset and a more chronic form of EAE induced by myelin
oligodendrocyte glycoprotein (MOG) peptide 35-55 compared with wild-type
littermate mice. This was not due to an expanded autoreactive cell repertoire.
Primed peripheral lymphocytes from Bcl-x(L) transgenic mice showed increased
proliferation and cytokine production to MOG peptide in vitro compared with
lymphocytes from wild-type animals. Immunohistologic studies demonstrated
increased cellular infiltrates, immunoglobulin precipitation, and demyelination
in the Bcl-x(L) transgenic central nervous system (CNS) compared with controls.
There was also a decreased number of apoptotic cells in the CNS of Bcl-x(L)
transgenic mice when compared with littermates at all time points tested. This is
the first report of an autoimmune disease model in Bcl-x(L) transgenic mice. Our
data indicate that the passive cell death pathway is important in the
pathogenesis of chronic EAE. These findings have implications for understanding
the pathogenesis of multiple sclerosis and other autoimmune diseases.
PMID- 10772654
TI - Macrophage scavenger receptor CD36 is the major receptor for LDL modified by
monocyte-generated reactive nitrogen species.
AB - The oxidative conversion of LDL into an atherogenic form is considered a pivotal
event in the development of cardiovascular disease. Recent studies have
identified reactive nitrogen species generated by monocytes by way of the
myeloperoxidase-hydrogen peroxide-nitrite (MPO-H(2)O(2)-NO(2)(-)) system as a
novel mechanism for converting LDL into a high-uptake form (NO(2)-LDL) for
macrophages. We now identify the scavenger receptor CD36 as the major receptor
responsible for high-affinity and saturable cellular recognition of NO(2)-LDL by
murine and human macrophages. Using cells stably transfected with CD36, CD36
specific blocking mAbs, and CD36-null macrophages, we demonstrated CD36-dependent
binding, cholesterol loading, and macrophage foam cell formation after exposure
to NO(2)-LDL. Modification of LDL by the MPO-H(2)O(2)-NO(2)(-) system in the
presence of up to 80% lipoprotein-deficient serum (LPDS) still resulted in the
conversion of the lipoprotein into a high-uptake form for macrophages, whereas
addition of less than 5% LPDS totally blocked Cu(2+)-catalyzed LDL oxidation and
conversion into a ligand for CD36. Competition studies demonstrated that lipid
oxidation products derived from 1-palmitoyl-2-arachidonyl-sn-glycero-3
phosphocholine can serve as essential moieties on NO(2)-LDL recognized by CD36.
Collectively, these results suggest that MPO-dependent conversion of LDL into a
ligand for CD36 is a likely pathway for generating foam cells in vivo. MPO
secreted from activated phagocytes may also tag phospholipid-containing targets
for removal by CD36-positive cells.
PMID- 10772656
TI - Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice.
AB - Diabetes is associated with increased prevalence, severity, and progression of
periodontal disease. To test the hypothesis that activation of RAGE (Receptor for
Advanced Glycation End products) contributes to the pathogenesis of diabetes
associated periodontitis, we treated diabetic mice, infected with the human
periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE
is the extracellular domain of the receptor, which binds ligand and blocks
interaction with, and activation of, cell-surface RAGE. Blockade of RAGE
diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted
decreased generation of the proinflammatory cytokines TNF-alpha and IL-6 in
gingival tissue, as well as decreased levels of matrix metalloproteinases.
Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the
observed suppression in alveolar bone loss. These findings link RAGE and
exaggerated inflammatory responses to the pathogenesis of destructive periodontal
disease in diabetes.
PMID- 10772657
TI - Lethal host-versus-graft disease and hypereosinophilia in the absence of MHC I-T
cell interactions.
AB - Neonatal injection of semiallogeneic spleen cells in BALB/c mice induces a self
limited state of chimerism that promotes the differentiation of donor-specific
CD4 T cells toward the Th2 phenotype. Here we show that injection of spleen cells
from beta2-microglobulin-deficient (BALB/c x C57BL/6) F1 mice into BALB/c
newborns with a disrupted beta2-microglobulin (beta2m) gene results in a lethal
lymphoproliferative disorder associated with uncontrolled Th2 response, long-term
persistence of donor B cells, and sustained blood eosinophilia. Autoimmune
manifestations are also enhanced and characterized by a severe autoantibody
mediated glomerulonephritis. Histological examination of the spleen shows a
hyperplasia of periarteriolar lymphoid sheaths, with accumulation of eosinophils
and basophils, and variable degree of fibrosis. Perivascular lymphoid infiltrates
with eosinophils are also found in the lung and are correlated with disease
severity. Such abnormalities are almost absent using beta2m-sufficient mice.
These data demonstrate that induction of lymphoid chimerism in the absence of MHC
class I-T-cell interactions results in a lethal form of host-versus-graft disease
that represents a unique model of Th2-dependent chronic inflammatory disease
associated with an hypereosinophilic syndrome in mice.
PMID- 10772658
TI - A revised view of cardiac sodium channel "blockade" in the long-QT syndrome.
AB - Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a
form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular
arrhythmias. These autosomal dominant mutations disrupt Na channel function,
inhibiting channel inactivation, thereby causing a sustained ionic current that
delays cardiac repolarization. Sodium channel-blocking antiarrhythmics, such as
lidocaine, potently inhibit this pathologic Na current (I(Na)) and are being
evaluated in patients with LQT3. The mechanism underlying this effect is unknown,
although high-affinity "block" of the open Na channel pore has been proposed.
Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual
lidocaine sensitivity to the Na channel that is attributable to its altered
functional behavior. Studies of lidocaine on individual R1623Q single-channel
openings indicate that the open-time distribution is not changed, indicating the
drug does not block the open pore as proposed previously. Rather, the mutant
channels have a propensity to inactivate without ever opening ("closed-state
inactivation"), and lidocaine augments this gating behavior. An allosteric gating
model incorporating closed-state inactivation recapitulates the effects of
lidocaine on pathologic I(Na). These findings explain the unusual drug
sensitivity of R1623Q and provide a general and unanticipated mechanism for
understanding how Na channel-blocking agents may suppress the pathologic,
sustained Na current induced by LQT3 mutations.
PMID- 10772659
TI - Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal
convoluted tubule.
AB - The proximal convoluted tubule (PCT) reabsorbs most of the filtered bicarbonate.
Proton secretion is believed to be mediated predominantly by an apical membrane
Na(+)/H(+) exchanger (NHE). Several NHE isoforms have been cloned, but only NHE3
and NHE2 are known to be present on the apical membrane of the PCT. Here we
examined apical membrane PCT sodium-dependent proton secretion of wild-type
(NHE3(+/+)/NHE2(+/+)), NHE3(-/-), NHE2(-/-), and double-knockout NHE3(-/-)/NHE2(
/-) mice to determine their relative contribution to luminal proton secretion.
NHE2(-/-) and wild-type mice had comparable rates of sodium-dependent proton
secretion. Sodium-dependent proton secretion in NHE3(-/-) mice was approximately
50% that of wild-type mice. The residual sodium-dependent proton secretion was
inhibited by 100 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA). Luminal sodium
dependent proton secretion was the same in NHE3(-/-)/NHE2(-/-) as in NHE3(-/-)
mice. These data point to a previously unrecognized Na(+)-dependent EIPA
sensitive proton secretory mechanism in the proximal tubule that may play an
important role in acid-base homeostasis.
PMID- 10772660
TI - p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte
necrosis, IL-8 production, and enteritis.
AB - Clostridium difficile toxin A causes acute neutrophil infiltration and intestinal
mucosal injury. In cultured cells, toxin A inactivates Rho proteins by
monoglucosylation. In monocytes, toxin A induces IL-8 production and necrosis by
unknown mechanisms. We investigated the role of mitogen-activated protein (MAP)
kinases in these events. In THP-1 monocytic cells, toxin A activated the 3 main
MAP kinase cascades within 1 to 2 minutes. Activation of p38 was sustained,
whereas stimulation of extracellular signal-regulated kinases and c-Jun NH(2)
terminal kinase was transient. Rho glucosylation became evident after 15 minutes.
IL-8 gene expression was reduced by 70% by the MEK inhibitor PD98059 and
abrogated by the p38 inhibitor SB203580 or by overexpression of dominant-negative
mutants of the p38-activating kinases MKK3 and MKK6. SB203580 also blocked
monocyte necrosis and IL-1beta release caused by toxin A but not by other toxins.
Finally, in mouse ileum, SB203580 prevented toxin A-induced neutrophil
recruitment by 92% and villous destruction by 90%. Thus, in monocytes exposed to
toxin A, MAP kinase activation appears to precede Rho glucosylation and is
required for IL-8 transcription and cell necrosis. p38 MAP kinase also mediates
intestinal inflammation and mucosal damage induced by toxin A.
PMID- 10772663
TI - MEMORANDUM FOR: science writers and editors on the journal press list: new
insight into development of Paget's disease of the breast
PMID- 10772662
TI - MEMORANDUM FOR: science writers and editors on the journal press list: accuracy
of death certificates of prostate cancer patients questioned
PMID- 10772661
TI - Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces
sustained tumor regression without overt toxicity.
AB - Various conventional chemotherapeutic drugs can block angiogenesis or even kill
activated, dividing endothelial cells. Such effects may contribute to the
antitumor efficacy of chemotherapy in vivo and may delay or prevent the
acquisition of drug-resistance by cancer cells. We have implemented a treatment
regimen that augments the potential antivascular effects of chemotherapy, that is
devoid of obvious toxic side effects, and that obstructs the development of drug
resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines
were subjected to either continuous treatment with low doses of vinblastine, a
monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2)
receptor for VEGF, or both agents together. The rationale for this combination
was that any antivascular effects of the low-dose chemotherapy would be
selectively enhanced in cells of newly formed vessels when survival signals
mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment
individually resulted in significant but transient xenograft regression,
diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably,
the combination therapy resulted in full and sustained regressions of large
established tumors, without an ensuing increase in host toxicity or any signs of
acquired drug resistance during the course of treatment, which lasted for >6
months. This article may have been published online in advance of the print
edition. The date of publication is available from the JCI website,
http://www.jci.org.
PMID- 10772664
TI - When is a death from prostate cancer not a death from prostate cancer?
PMID- 10772665
TI - Larger debate underlies spiral CT screening for lung cancer
PMID- 10772666
TI - Consumer research looks at patient perspectives of spiral CT for lung cancer
PMID- 10772667
TI - Genome data announcement fuels stock plunge, misunderstanding.
PMID- 10772668
TI - Stat bite: All-cancer mortality in selected Asian countries, 1996.
PMID- 10772669
TI - NCI-Myriad agreement offers BRCA testing at reduced cost.
PMID- 10772670
TI - Correction
PMID- 10772672
TI - Correction
PMID- 10772671
TI - Nurses' health study: nurses helping science and themselves.
PMID- 10772673
TI - Additional large observational and clinical studies
PMID- 10772674
TI - Experts discuss concerns about cancer rates on staten island
PMID- 10772676
TI - Experts discuss concerns about cancer rates on staten island
PMID- 10772675
TI - Online databases bring research to the desktop.
PMID- 10772677
TI - Molecular epidemiology: on the path to prevention?
AB - Cancer prevention has been the stated goal of molecular cancer epidemiology for
the past 17 years. In this review, progress toward that goal is evaluated by
using as examples well-studied environmental exposures-i.e., tobacco smoke,
polycyclic aromatic hydrocarbons, aflatoxin B(1), benzene, and hepatitis B virus
and their roles in lung, breast, and liver cancers and leukemia. The
contributions of molecular epidemiology discussed here include providing evidence
that environmental agents pose carcinogenic risks, helping establish the causal
roles of environmental factors in cancer, identifying environment-susceptibility
interactions and populations at greatest risk, and developing new intervention
strategies. Molecular epidemiologic and other data indicate that assessment of
carcinogenic risks should address both the range of risk across the population
and the risk to subgroups who may be at high risk because of genetic or acquired
susceptibilities, including young children. However, for the most part, research
results have not yet been effectively translated into risk assessments and
preventive health policies. An infrastructure linking scientists, policy makers,
and other constituencies is needed to facilitate this process. To extend our
knowledge, the second generation of molecular epidemiologic research should
include large-scale, collaborative studies incorporating validated biomarkers and
automated technologies. An incentive to make the necessary investment is the
recognition that prevention of only 20% of cancer in the United States would
result in 200000 fewer new cases diagnosed each year and an annual savings of
$21.4 billion in direct costs alone.
PMID- 10772678
TI - Causes of death in elderly prostate cancer patients and in a comparison
nonprostate cancer cohort.
AB - BACKGROUND: Prostate cancer tends to affect older men and to progress relatively
slowly. Since the prevalence of comorbidity increases with advancing age,
competing causes of death are important contributors to death rates among
prostate cancer patients. Accurate determination of the underlying causes of
death in older men dying with prostate cancer may thus also be more difficult.
METHODS: We compared the distribution of underlying causes of death in decedents
from a population-based cohort of elderly prostate cancer patients to that from a
population-based comparison cohort of elderly men without prostate cancer. Among
decedents from the prostate cancer patient cohort, we examined associations of
patient demographics, disease stage, and initial treatment, with assignment of a
prostate cancer underlying cause of death (versus any other cause) by use of
multivariable logistic regression. In the subgroup of prostate cancer patient
decedents having underlying causes of death other than prostate cancer, the
underlying cause distribution was compared with that in nonprostate cancer cohort
decedents. RESULTS: Prostate cancer was the underlying cause for 39% (95%
confidence interval [CI] = 36.3-41.9) of the decedents in the prostate cancer
cohort. Causes of death among prostate cancer patients not dying of prostate
cancer were similar to those among the nonprostate cancer cohort decedents.
However, in those who were aggressively treated, the adjusted odds of other
cancer causes of death were 51% higher (odds ratio [OR] = 1.51; 95% CI = 1.08
2.10) than that in nonprostate cancer patient decedents, while in those treated
with watchful waiting the adjusted odds were 34% lower (OR = 0.66; 95% CI = 0.47
0.93). CONCLUSIONS: Initial treatment may influence the underlying cause of death
reported in vital statistics for prostate cancer patients.
PMID- 10772679
TI - Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and
the HER receptor family.
AB - BACKGROUND AND METHODS: In Paget's disease of the breast, the epidermis of the
nipple is infiltrated by large neoplastic cells of glandular origin. It has been
hypothesized that the spread of Paget cells through the nipple epidermis is
induced by a motility factor that acts via the HER2/NEU receptor. To test this
hypothesis, we characterized and purified a motility factor released by
keratinocytes and identified its target receptors in specimens from patients with
Paget's disease and in SK-BR-3 breast adenocarcinoma cells, which overexpress
HER2/NEU. RESULTS: We isolated the motility factor from keratinocyte-conditioned
medium and sequenced tryptic peptides. These sequences were used to identify the
motility factor as heregulin-alpha, which is released by skin keratinocytes.
Heregulin-alpha induces spreading, motility, and chemotaxis of SK-BR-3 cells, as
does motility factor. Motility factor activities of heregulin-alpha are inhibited
by monoclonal antibody AB2, directed against the extracellular domain of
HER2/NEU, which blocks the binding of heregulin-alpha. We used in situ
hybridization to show that normal epidermal cells produce heregulin-alpha
messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their
coreceptor HER2/NEU, are expressed by Paget cells. CONCLUSIONS: Heregulin-alpha
is a motility factor that is produced and released by normal epidermal
keratinocytes and thus plays a key role in the pathogenesis of Paget's disease.
Paget cells express heregulin receptors HER2/NEU, as well as HER3 and/or HER4,
both of which function as a co-receptor of HER2/NEU. Binding of heregulin-alpha
to the receptor complex on Paget cells results in the chemotaxis of these breast
cancer cells, which eventually migrate into the overlying nipple epidermis.
PMID- 10772680
TI - Stromal cell-derived factor-1 as a chemoattractant for follicular center lymphoma
B cells.
AB - BACKGROUND: Follicular center lymphoma displays widespread lymph node involvement
at diagnosis. The chemoattractants that control the locomotion of follicular
center lymphoma B cells have not been established. Stromal cell-derived factor-1
(SDF-1) is a CXC-class chemokine that enhances the migration of normal human B
cells and is expressed in peripheral lymphoid tissues. Here we have investigated
1) whether SDF-1 stimulates the in vitro locomotion of follicular center lymphoma
B cells and of their presumed normal counterparts (i. e., germinal center B
cells) and 2) whether the same cells express SDF-1 transcripts. METHODS: B cells
were purified by immunomagnetic bead manipulation. Messenger RNA was detected by
reverse transcription-polymerase chain reaction. Migration was assessed by the
filter and collagen invasion assays. All P values were two sided. RESULTS:
Follicular center lymphoma B lymphocytes showed a statistically significant
migratory response to 300 ng/mL SDF-1, both in the filter and in the collagen
assays (P =.002 for each). Such response was mediated by the SDF-1 receptor,
CXCR4. CD40 monoclonal antibody (MAb) and tonsillar germinal center B cells
treated with CD40 MAb and recombinant interleukin 4, but not freshly isolated,
migrated statistically significantly faster in the presence than in the absence
of SDF-1 (P =.002 in both filter and collagen assays). Freshly isolated
follicular center lymphoma and germinal center B cells expressed SDF-1
transcripts. CONCLUSIONS: This study shows that SDF-1 substantially enhances the
migration of follicular center lymphoma B cells but not the migration of freshly
purified germinal center B cells. This difference may be related to the extended
survival of follicular center lymphoma versus germinal center B cells. SDF-1
produced in follicular center lymphoma lymph nodes may play a role in the local
dissemination of tumor cells.
PMID- 10772681
TI - Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells.
AB - BACKGROUND: The p14(ARF) protein encoded by the INK4a/ARF locus promotes
degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of
p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma
and may result in the loss of p14(ARF) and the inactivation of p53. We designed
this study to evaluate the biologic and potential therapeutic roles of p14(ARF)
expression in mesothelioma cells. METHODS AND RESULTS: We constructed Adp14, an
adenoviral vector carrying human p14(ARF) complementary DNA, and used it to
transfect human mesothelioma cell lines H28, H513, H2052, and MSTO-211H.
Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF)
proteins and dephosphorylation of the retinoblastoma protein. The growth rate of
mesothelioma cells was inhibited markedly by infection with Adp14 compared with
mock infection or infection with a control adenovirus vector, AdCtrl.
Overexpression of p14(ARF) induced G(1)-phase cell cycle arrest and apoptotic
cell death. Cytotoxicity assays showed that Adp14 had a statistically
significantly (P =.002) greater effect on colon cancer (HCT116) cell lines
containing two copies of the wild-type p53 gene than on p53-null cells,
suggesting that functional p53 is a critical determinant of p14(ARF)-mediated
cytotoxicity. CONCLUSIONS: The transfection of p14(ARF) into mesothelioma cells
led to the overexpression of p14(ARF), which resulted in G(1)-phase arrest and
apoptotic cell death. These results suggest that this gene therapy-based approach
may be of use in the treatment of mesothelioma.
PMID- 10772682
TI - Transactivation of the metallothionein promoter in cisplatin-resistant cancer
cells: a specific gene therapy strategy.
AB - BACKGROUND: Cisplatin (cis-diamminedichloroplatinum) is one of the most active
agents against a broad range of malignancies, including ovarian cancer. Cisplatin
resistance appears to be associated with several molecular alterations, including
overexpression of metallothionein, a metal-binding protein. In the present study,
we attempted to take advantage of metallothionein overexpression to overcome
cisplatin resistance. METHODS: Using a virus-free system (liposomes), we sought
to express the suicide gene, thymidine kinase (TK), driven by the promoter of the
human metallothionein IIa (hMTIIa) gene using the pMT-TK plasmid. We used
cisplatin-resistant human ovarian carcinoma cells as a model. RESULTS: We first
analyzed metallothionein expression using a ribonuclease protection assay. In
comparison to parental cells, the cisplatin-resistant cells were found to have
increased expression of metallothionein messenger RNA (mRNA). Metallothionein
overexpression in these cells was not associated with an increased copy number of
the hMTIIa gene or with different transfection efficiencies. Furthermore, we
showed by reverse transcription-polymerase chain reaction analysis that
transfection of the pMT-TK plasmid results in a 56-fold higher expression of
thymidine kinase mRNA in cisplatin-resistant cells compared with parental cells,
consistent with increased metallothionein promoter-mediated transactivation in
the cisplatin-resistant cells. Transfection of resistant cells with pMT-TK or a
control plasmid (pCD3-TK) resulted in a marked sensitization to ganciclovir, with
a 50% cell growth-inhibitory concentration (IC(50)) of 20 microg/mL and 9
microg/mL, respectively. Transfections of the cisplatin-sensitive cells resulted
in no sensitization to ganciclovir with pMT-TK (IC(50) 200 microg/mL) and a high
sensitization with pCD3-TK (IC(50) = 6 microg/mL). CONCLUSION: These studies
suggest that pMT-TK gene therapy may provide an alternative treatment for
cisplatin-refractory ovarian tumors.
PMID- 10772683
TI - Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary
brain tumors.
PMID- 10772684
TI - Penetrance of mutations in the familial Wilms tumor gene FWT1.
PMID- 10772685
TI - Re: detection of Epstein-Barr virus in invasive breast cancers.
PMID- 10772687
TI - Re: tamoxifen prevention of breast cancer: an instance of the fingerpost.
PMID- 10772688
TI - Re: randomized trial of radiation therapy versus concomitant chemotherapy and
radiation therapy for advanced-stage oropharynx carcinoma.
PMID- 10772690
TI - RESPONSE: re: tamoxifen prevention of breast cancer: an instance of the
fingerpost
PMID- 10772689
TI - Re: tamoxifen prevention of breast cancer: an instance of the fingerpost
PMID- 10772691
TI - Re: tamoxifen prevention of breast cancer: an instance of the fingerpost.
PMID- 10772692
TI - More about: safe cigarette alternatives? Industry critics say 'not yet'.
PMID- 10772694
TI - Juvenile idiopathic inflammatory myopathies: the value of magnetic resonance
imaging in the detection of muscle involvement.
AB - CONTEXT: One of the major current challenges related to juvenile idiopathic
inflammatory myopathy is the search for highly sensitive and specific non
invasive methods for diagnosis as well as for follow-up. OBJECTIVES: The aim of
our study was to describe typical magnetic resonance imaging findings and to
investigate the usefulness of this method in detecting active muscle disease in
juvenile dermatomyositis and juvenile systemic lupus erythematosus patients.
DESIGN: Transverse study, blinded assessment. SETTING: University referral unit
(Pediatric Rheumatology section, Department of Pediatrics, Universidade Federal
de Sao Paulo / Escola Paulista de Medicina). SAMPLE: Thirteen patients (9 girls)
with dermatomyositis, as well as 13 patients (12 girls) with juvenile systemic
lupus erythematosus and 10 normal children (5 girls), were enrolled in the study.
MAIN MEASUREMENTS: Qualitative and quantitative analyses of gluteus maximus,
quadriceps, adductors and flexors were performed and evaluated by two
radiologists, blinded to all clinical information. Spin-echo in T1, DP, T2 and IR
was used in all MRI images. RESULTS: The different muscle groups presented non
uniform involvement in the patients. The patients with dermatomyositis presented
acute and chronic muscular alterations, while those with lupus presented only
chronic myopathy, especially atrophy. In the dermatomyositis group, the major
alterations were found in the gluteus and flexor regions (signal intensity and
fat replacement). The signal intensity was increased in all acute myopathies.
CONCLUSION: The qualitative and quantitative resonance analyses are useful in
detecting clinically active disease in patients with dermatomyositis.
PMID- 10772695
TI - Enzymes and membrane proteins of ADSOL-preserved red blood cells.
AB - CONTEXT: The preservative solution ADSOL (adenine, dextrose, sorbitol, sodium
chloride and mannitol) maintains red cell viability for blood trans-fusion for 6
weeks. It would be useful to know about its preservation qualities over longer
periods. OBJECTIVE: To determine some red cell biochemical parameters for peri
ods of up to 14 weeks in order to determine whether the red cell metabo-lism
integrity would justify further studies aiming at increasing red cell
preservation and viability. DESIGN: Biochemical evaluation designed to study red
cell preservation. SETTING: Sao Paulo University erythrocyte metabolism referral
center. SAMPLE: Six normal blood donors from the University Hospital of the
Universidade Federal do Parana, Curitiba, Brazil. MAIN MEASUREMENTS: Weekly assay
of erythrocyte adenosine-5;-triphosphate (ATP), 2, 3-diphosphoglycerate (2,3DPG),
hexokinase (HX), phosphofructokinase (PFK), pyruvate kinase (PK), glucose-6
phosphate dehydrogenase (G-6-PD), 6-phosphogluconic dehydrogenase (6-PGD),
glyceraldehyde-3-phosphate dehydrogenase (GAPD), glutathione reduc-tase (GR),
glutathione peroxidase (GSHPx), plasma sodium and potas-sium, blood pH, and
membrane proteins of red cells preserved in ADSOL were studied during storage for
14 weeks storage. RESULTS: During ADSOL preservation, erythrocyte ATP
concentration decreased 60% after 5 weeks, and 90% after 10 weeks; the pH fell
from 6.8 to 6. 4 by the 14th week. 2,3-DPG concentration was stable during the
first week, but fell 90% after 3 weeks and was exhausted after 5 weeks. By the
end of the 5th week, an activity decrease of 16-30% for Hx, GAPD, GR, G-6-PD and
6-PGD, 35% for PFK and GSHPx, and 45% for PK were observed. Thereafter, a uniform
10% decay was observed for all enzymes up to the 14th week. The red blood cell
membrane pro-teins did not show significant alterations in polyacrylamide gel
electro-phoresis (SDS-PAGE) during the 14 weeks. CONCLUSION: Although the blood
viability was shown to be poor from the 6th week up to the 14th week of storage
due to ATP and 2,3-DPG depletion, the other biochemical parameters remained in
fairly good condition for longer storage. As there is a gradual and uniform decay
in activity throughout these 14 weeks, it seems that ADSOL-preserved red cells
may be used as red cell enzyme standards and membrane proteins as well.
PMID- 10772696
TI - Malignant phyllodes tumor in the right breast and invasive lobular carcinoma
within fibroadenoma in the other: case report.
AB - CONTEXT: The malignant variety of the phyllodes tumor is rare. The occurrence of
invasive lobular carcinoma within fibroadenoma is rare as well. DESIGN: Case
report. CASE REPORT: A 58-year-old black female patient was referred to the
Mastology unit of the Department of Gynecology, Federal University of Sao Paulo /
Escola Paulista de Medicina, in February 1990, presenting an ulcerated tumor in
the right breast with fast growth over the preceding six months. She was a
virgin, with meno-pause at the age of 45 years and had not undergone hormone
replacement treatment. The physical examination showed, in her right breast, an
ulcerated tumor of 20 x 30 cm which was not adher-ent to the muscle level,
multilobular and with fibroelastic consistency. The axillary lymph nodes were not
palpable. The left breast showed a 2 x 3 cm painless, movable nodule, with well
defined edges, and fibroelastic consistency. We performed left-breast
mammography, which showed several nodules with well-defined edges, the largest
being 2 x 3 cm and exhibiting rough calcification and grouped microcalcifications
within it. The patient underwent a frozen biopsy that showed a malignant variant
of the phyllodes tumor in the right breast and fibroadenoma in the left one.
After that, we performed a total mastectomy in the right breast and an excision
biopsy in the left one. Paraffin study confirmed the frozen biopsy result from
the right breast, yet we observed that in the interior of the fibroadenoma that
was removed on the left, there was a focal area of invasive lobular carcinoma
measuring 0.4 cm. The patient then underwent a modi-fied radical mastectomy with
total axillary lymphadenectomy. None of the 21 dissected lymph nodes showed
evidence of metastasis. In the follow-up, the patient evolved asymptomatically
and with normal physical and laboratory examination results up to July 1997.
PMID- 10772697
TI - Analysis of the p53 gene by PCR-SSCP in ten cases of Wilms' tumor.
AB - CONTEXT: Mutations of the p53 tumor suppressor gene are the most frequent
alterations observed in human neoplasias affecting adults. In pediatric oncology,
however, they have seldom been identified. Wilms' tumor is a renal neoplasia
commonly occurring in children and is associated with mutations of the WT1 gene.
The correlation between Wilms' tumor and alterations of the p53 gene has not been
well established, with a low frequency of mutations having been reported in this
type of tumor. Mutation may be associated with advanced stage disease and
unfavorable histology. OBJECTIVE: To screen for mutations of the p53 gene by the
PCR-SSCP method and DNA sequencing in cases of Wilms' tumor sug-gestive of
mutation. DESIGN: Case Report. CASE REPORT: Evaluations of exons 5-9 of the p53
gene in DNA samples extracted by PCR-SSCP from 10 Wilms' tumors in children at
different stages, and DNA sequencing. Changes in SSCP analy-sis were observed in
exon 8 in two samples. The probable muta-tions were not confirmed by DNA
sequencing. The absence of point mutations in p53 gene observed in the 10 samples
of Wilms' tumor studied agrees with literature data, with DNA sequencing being of
fundamental importance for the confirmation of possible mutations.
PMID- 10772698
TI - Malignant melanoma with liver and spleen metastases: case report.
AB - CONTEXT: The diagnosis of primary melanoma is easily confirmed after histological
analysis of the lesion, whereas it is rarely diagnosed when the patient even has
distant metastases. DESIGN: Case report CASE REPORT: Malignant melanoma is
responsible for about 1% of all deaths caused by cancer in the USA and only 3% of
all malignant skin diseases. Malignant melanoma is a rare disease, although it
corresponds to 65% of all deaths caused by skin cancer. The liver and spleen are
rarely the first sites of melanoma metastases. This paper reports on the clinical
picture of a patient with fatal malignant melanoma and hepatic and spleen
metastases. As this was an un-usual presentation, the melanoma diagnosis could
only be made after pathological analysis of the skin and hepatic lesions.
PMID- 10772699
TI - The "beta-fluorine effect" in the non-metal hydride radical deoxygenation of
fluorine-containing nucleoside xanthates.
AB - An alternative method to conduct a Barton-McCombie deoxygenation in nucleosides
is described. The utility of the procedure is limited to structures with an
electronegative substituent, particularly fluorine, in the beta-position relative
to the radical center. The process is radical in nature and triggered by
peroxides. The abstraction of hydrogen from the solvent is favorably influenced
by the presence of a beta-fluorine.
PMID- 10772700
TI - Conformation and local environment of nucleotides bound to HIV type 1 reverse
transcriptase (HIV-1 RT) in the ground state.
AB - Nuclear Overhauser effect experiments were used to characterize the protein
environment and conformations of dTTP, dATP and AZTTP bound to HIV-RT in the
ground state. The results show the initial binding sites for the nucleotides
overlap but are not completely coincident. All of the bound nucleotides assume
the same anti C4'-exo conformation.
PMID- 10772701
TI - Synthesis of (Z)- and (E)-9-[(2-hydroxyethylidene)cyclopropyl]adenine--new
methylenecyclopropane analogues of adenosine and their substrate activity for
adenosine deaminase.
AB - Synthesis of Z- and E-methylenecyclopropane analogues of adenosine 3 and 4 by
alkylation of adenine with novel alkylating agent 5 is described. The E-isomer 4
is a substrate for adenosine deaminase. Compounds 3 and 4 were tested for
antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1.
PMID- 10772702
TI - Synthesis of 4-substituted imidazo[4,5-d][1,2,3]triazine (2
azapurine)nucleosides.
AB - Several methods for functionalization of the 4-position of imidazo[4,5
d][1,2,3]triazin-4-one were investigated. These investigations were successful
and led to the preparation of 4-amino, 4-triazol-1-yl, 4-methoxy, 4-methylthio, 4
methylamino, 4-thio, 4-nitrobenzyl, and 4-unsubstituted 9-(beta-D-ribofuranosyl)
imidazo-[4,5-d][1,2,3]triazine (2-azapurine ribosides). The 4-unsubstituted
compound (19) was slightly active against HCMV in plaque and yield reduction
experiments and was not cytotoxic at 100 microM. The methylamino (15), hydrazino
(16), and p-nitrobenzylthio (20) were inactive against HCMV but slightly
cytotoxic. The thiomethyl-substituted analog (21) was the most active with
activity comparable to ganciclovir but with greater cytotoxicity. We conclude
that even though none of the tested compounds had antiviral activity superior to
ganciclovir, the new synthetic methods will provide a route to more interesting
compounds.
PMID- 10772703
TI - Synthesis of amide-linked [(3')CH2CO-NH(5')] nucleoside analogues of small
oligonucleotides.
AB - We report syntheses of new amide-linked (di-penta)nucleoside analogues of
antisense oligonucleotide components. Solution-phase coupling of 3'
(carboxymethyl)-3'-deoxy- and 5'-amino-5'-deoxynucleoside derivatives provides
amide dimers. Activated [3'-(carboxymethyl)-3'-deoxy] units with a 5'-azido-5'
deoxy function provide "masked" 5'-amino-5'-deoxy residues for chain extension,
and a 5'-O-DMT-protected unit provides the 5'-terminus for attachment to a
phosphodiester linkage.
PMID- 10772704
TI - Synthesis and antiviral activity of amino acid carbamate derivatives of AZT.
AB - Lipophilic amino acid methyl ester and methyl amide carbamates of 3'-azido-3'
deoxythymidine (AZT) were synthesized and their anti-HIV-1 activity in PBMCs was
determined. The methyl amides were more potent (EC50s = 1.8-4.0 microM) than the
methyl esters (EC50s = 2.0-20 microM). Carbamate hydrolysis by cell lysates and
liberation of AZT was not observed for representative methyl ester or methyl
amide AZT carbamates. No evidence of direct inhibition of HIV reverse
transcriptase or integrase was observed.
PMID- 10772706
TI - Design, synthesis, and antiviral evaluation of 2-deoxy-D-ribosides of substituted
benzimidazoles as potential agents for human cytomegalovirus infections.
AB - Stereoselective glycosylation of 2,5,6-trichlorobenzimidazole (1b), 2-bromo-5,6
dichlorobenzimidazole (1c), 5,6-dichlorobenzimidazole (1d), 5,6
dichlorobenzimidazole-2-thione (1e), 5,6-dichloro-2-(methylthio)benzimidazole
(1f), 2-(benzylthio)-5,6-dichlorobenzimidazole (1g), and 2-chloro-5,6
dimethylbenzimidazole (1h) with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro
pentofuranosyl chloride was achieved to give the desired beta nucleosides 2b-h.
Subsequent deprotection afforded the corresponding free beta-D-2-deoxyribosides
3b-h. The 2-methoxy derivative 3i was synthesized by the treatment of 2b with
methanolic sodium methoxide. Displacement of the 2-chloro group of 2b with
lithium azide followed by a removal of the protective groups gave the 2-azido-5,6
dichlorobenzimidazole derivative (5). The 2-amino derivative (6) was obtained by
hydrogenolysis of 5 over Raney nickel. 5,6-Dichloro-2-isopropylamino-1-(2-deoxy
beta-D-erythro- pentofuranosyl)benzimidazole (10) was prepared using 2'
deoxyuridine (7), N-deoxyribofuranosyl transferase and 1d followed by
functionalization of the C2 position. Antiviral evaluation of target compounds
established that compounds 3b and 3c were active against human cytomegalovirus
(HCMV) at non-cytotoxic concentrations. The activity of these 2-deoxy ribosides,
however, was less than the activity of the parent riboside, 2,5,6-trichloro-1
beta-D-ribofuranosylbenzimidazole (TCRB). Compared to TCRB, 3b and 3c were
somewhat more cytotoxic and active against herpes simplex virus type 1. Compounds
3d-i with other substituents in the 2-position were inactive against both viruses
and non-cytotoxic. In contrast, compounds with amine substituents in the 2
position (5, 6, 10) were active against HCMV albeit less so than TCRB. These
results establish that 2-deoxy-D-ribosyl benzimidazoles are less active against
the DNA virus HCMV than are the corresponding D-ribosides.
PMID- 10772705
TI - Synthesis and evaluation of a series of 2'-deoxy analogues of the antiviral agent
5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole
(1263W94).
AB - A series of 2'-deoxy analogues of the antiviral agent 5,6-dichloro-2
isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole (1263W94) were
synthesized and evaluated for activity against human cytomegalovirus (HCMV) and
for cytotoxicity. The 2-substituents in the benzimidazole moiety correspond to
those that were used in the 1263W94 series. In general, as was found in the
1263W94 series, cyclic and branched alkylamino groups were needed for potent
activity against HCMV. Three analogues 3a, 3b and 3d were as potent as 1263W94.
Further evaluation of two analogues, 3a and 3b, suggested that these 2'-deoxy
analogues may act via a novel mechanism of action similar to that of 1263W94.
These 2'-deoxy analogues generally lacked cytotoxicity in vitro. Pharmacokinetic
parameters in mice and protein binding properties of 3a were quite similar to
1263W94. However, the oral bioavailability of 3a was only half of that observed
for 1263W94.
PMID- 10772707
TI - Benzimidazole 2'-isonucleosides: design, synthesis, and antiviral activity of 2
substituted-5,6-dichlorobenzimidazole 2'-isonucleosides.
AB - 2,5,6-Trihalogenated benzimidazole-beta-D-ribofuranosyl nucleosides and 2
substituted amino-5,6-dichlorobenzimidazole-beta-L-ribofuranosyl nucleosides are
potent and selective inhibitors of human cytomegalovirus (HCMV). The D
ribofuranosyl analogs are metabolized rapidly in vivo rendering them unsuitable
as drug candidates. The primary source of instability is thought to be the
anomeric bond. The synthesis of a series of chemically stable benzimidazole-2'
isonucleosides is presented. The synthetic schemes employed are based on
nucleophilic displacements of a 2'-tosylate from carbohydrate intermediates with
2-bromo-5,6-dichlorobenzidazole. 2-Bromo and 2-isopropyl amino analogs with 3'-
and 5'-oxo and deoxy substitutions were prepared. The benzimidazole-2
'isonucleosides presented here demonstrated reduced activity against HCMV when
compared to other D-ribofuranosyl benzimidazole analogs. In addition, they were
not found to be inhibitors of HIV.
PMID- 10772708
TI - Nucleosides and nucleotides. 192. Toward the total synthesis of cyclic ADP
carbocyclic-ribose. Formation of the intramolecular pyrophosphate linkage by a
conformation-restriction strategy in a syn-form using a halogen substitution at
the 8-position of the adenine ring.
AB - The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic
ADP-ribose, was investigated. Construction of the 18-membered backbone structure
was successfully achieved by condensation of the two phosphate groups of 19,
possibly due to restriction of the conformation of the substrate in a syn-form
using an 8-chloro substituent at the adenine moiety. SN2 reactions between an
optically active carbocyclic unit 8, which was constructed by a previously
developed method, and 8-bromo-N6-trichloroacetyl-2',3'-O-isopropylideneadenosine
9c gave N-1-carbocyclic derivative, which was deprotected to give 5'-5"-diol
derivatives 18. When 18 was treated with POCl3 in PO(OEt)3, the bromo group at
the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5',5"
diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired
intramolecular condensation product 20 in 10% yield. This is the first chemical
construction of the 18-membered backbone structure containing an intramolecular
pyrophosphate linkage of a cADPR-related compound with an adenine base.
PMID- 10772709
TI - Investigation of the kinetics of degradation of hexopyranosylated cytosine
nucleosides using liquid chromatography.
AB - Liquid chromatography was used to follow the degradation of hexopyranosylated
cytosine nucleosides in buffers of acid, neutral and alkaline pH and of constant
ionic strength. The compounds were found to degrade by hydrolysis to cytosine
and/or by deamination to the corresponding uracil nucleosides. Degradation in
acid is influenced by the number of sugar hydroxyl groups, presence of sugar
double bonds and the type of anomer. Stability of some of the compounds was
compared with that of related thymine nucleosides. Temperature studies support a
unimolecular mechanism of hydrolysis at pH 1.22.
PMID- 10772710
TI - Synthesis and antiviral evaluation of unnatural beta-L-enantiomers of 3'-fluoro-
and 3'-azido-2',3'-dideoxyguanosine derivatives.
AB - 3'-fluoro-2',3'-dideoxy- (3) and 3'-azido-2',3'-dideoxy- (4) beta-L
ribofuranonucleoside derivatives of guanine have been synthesized and their
antiviral properties examined. All these derivatives were regioselectively and
stereospecifically prepared by glycosylation of 2-N-acetyl-6-O
(diphenylcarbamoyl)guanine 5 with a suitable peracylated L-xylo-furanose sugar 6,
followed by appropriate chemical modifications. The prepared compounds were
tested for their activity against HIV and HBV viruses, but they did not show
significant activity.
PMID- 10772711
TI - Synthesis of L-3'-hydroxymethylribonucleosides.
AB - The target compounds were synthesized via the key intermediate carbohydrate 8,
which was synthesized by first selectively protecting the 1'- and 2'-hydroxyl
groups followed by selective tosylation of the 5'-hydroxyl group to obtain
compound 3. The tosyl moiety was then replaced by a benzyl either to obtain 4.
Compound 4 underwent Dess-Martin oxidation to afford the ketone 5. Compound 5 was
subjected to Wittig olefination to afford the alkene 6 followed by regioselective
hydroboration to obtain 7. Compound 7 was fully acetylated using acetic acid,
acetic anhydride and sulfuric acid to obtain the key intermediate 8.
PMID- 10772712
TI - Pyrrolo[2,3-d]pyrimidine nucleosides: synthesis and antitumor activity of 7
substituted 7-deaza-2'-deoxyadenosines.
AB - A one step synthesis, using the nucleoside 7-iodo-2'-deoxytubercidin (2b) in a
Pd(0)/Cu(I)-catalyzed cross coupling reaction furnished a series of 7-alkynyl-2'
deoxytubercidin derivatives. The 7-iodo-, 7-chloro- or 7-bromo 2'
deoxytubercidins 2b-d as well as certain 7-alkynyl derivatives show significant
activity against several tumor cell lines, with 7-iodo-2'-deoxytubercidin (2b) as
the most effective compound.
PMID- 10772713
TI - Synthesis and antiviral activities of enantiomeric 1-[2-(hydroxymethyl)
cyclopropyl] methyl nucleosides.
AB - Cyclopropyl carbocyclic nucleosides have been synthesized from the key
intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3.
Condensation of compound 3 with various purine and pyrimidine bases gave the
desired nucleosides. All synthesized nucleosides were evaluated for antiviral
activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives
showed moderate antiviral activity against HIV-1 and HBV. None of the other
compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1
and HSV-2 in vitro up to 100 microM.
PMID- 10772714
TI - Carbocyclic 5'-noruridine.
AB - A convenient preparation of (1'R,2'S,3'R,4'S)-1-(2',3',4'-trihydroxycyclopent-1'
yl)-1H-uracil (carbocyclic 5'-noruridine, 1) is described in 2 steps from the
palladium complex of (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (3) and the
sodium salt of uracil (2). Compound 1 was sought as a previously unknown member
of the series of carbocyclic 5'-nor nucleosides needed as moieties for new
oligomers. With 1 available, its antiviral properties and those of its enantiomer
(5) are reported with 5 showing promising activity towards Epstein-Barr virus.
PMID- 10772715
TI - Rapid and selective reduction of amide group by borane-amine complexes in acyl
protected nucleosides.
AB - Borane-amine complexes provide an unusually fast and selective reduction of a
deoxynucleoside N-acyl group to a corresponding N-alkyl group. Three different
nucleosides (dG, dA, and dC) each having one of three N-protecting groups
(benzoyl, isobutyryl, or acetyl) were used to prepare N-alkylated nucleosides in
good yields under mild conditions. Deoxyribose O-acyl protecting groups remain
intact at the conditions of N-acyl group reduction.
PMID- 10772716
TI - Synthesis of biomimetic analogs of neomycin B: potential inhibitors of the HIV
RNA Rev response element.
AB - The aminoglycosidic antibiotic, neomycin B, is an inhibitor of the binding of Rev
to RRE. This paper reports on the synthesis of analogs of neomycin B as potential
anti-HIV compounds designed to function as inhibitors of Rev/RRE binding.
PMID- 10772717
TI - An efficient, scalable synthesis of the HIV reverse transcriptase inhibitor
Ziagen (1592U89).
AB - Ziagen, (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]- 2-cyclopentene-1
methanol, was synthesized from (1S,4R)-azabicyclo[2.2.1]hept-5-en-3-one by
efficient processes which bypass problematic steps in earlier routes. 2-Amino-4,6
dichloro-5-formamidopyrimidine is a key intermediate which makes possible an
efficient construction of the purine from a chiral cyclopentenyl precursor.
PMID- 10772718
TI - Synthesis of 4'-thio-beta-D-arabinofuranosylcytosine (4'-thio-ara-C) and
comparison of its anticancer activity with that of ara-C.
AB - 4'-thio-beta-D-arabinofuranosylcytosine was synthesized by a facile route in high
yields. It was evaluated for antitumor activity against a panel of human tumors,
both in vitro and in vivo.
PMID- 10772719
TI - Phosphorylation of ganciclovir phosphonate by cellular GMP kinase determines the
stereoselectivity of anti-human cytomegalovirus activity.
AB - A racemic mixture of ganciclovir phosphonate was resolved by stereoselective
phosphorylation using GMP kinase. The R-enantiomer of ganciclovir phosphonate was
active against human cytomegalovirus but the S-enantiomer was less active. We
show that enantiomeric selectivity of antiviral for ganciclovir phosphonate was
conferred by stereoselective phosphorylations by mammalian enzymes, not by
stereoselective inhibition of DNA polymerase from human cytomegalovirus.
PMID- 10772720
TI - Rational design of selective antimetabolites of DNA-thymine biosynthesis: 5
propynylpyrimidine nucleoside derivatives.
AB - A novel series of 5-propynylpyrimidine nucleosides are proposed as potential
antimetabolites of DNA-thymine biosynthesis. This proposal is based on the
results of detailed mechanistic analyses of the molecular interactions between
dTMP synthase and its inhibitors. It is proposed that a propynyl side-chain at
the 5-position of dUMP, bearing an appropriate leaving group, would cause
irreversible inactivation of dTMP synthase, which would not require the presence
of the cofactor, CH2H4folate.
PMID- 10772721
TI - Potentiation of the anti-HIV activity of zalcitabine and lamivudine by a CTP
synthase inhibitor, 3-deazauridine.
AB - Low levels of the CTP synthase inhibitor 3-deazauridine (3-DU) strongly
potentiated the anti-HIV-1 activity of the 5'-triphosphates of the cytidine-based
analogues [-]2'-deoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxycytidine
(ddC). The potentiation was associated with a 3-DU-induced decrease in dCTP pool
size; no changes were seen in cellular pool sizes of dATP, dGTP or dTTP.
PMID- 10772722
TI - Synthesis and biological activity of a novel class of purine nucleoside
phosphorylase inhibitors.
PMID- 10772723
TI - Cellular phosphorylation of 2',3'-dideoxyadenosine-5'-monophosphate, a key
intermediate in the activation of the antiviral agent DDI, in human peripheral
blood mononuclear cells.
AB - 2',3'-dideoxyadenosine 5-monophosphate (ddAMP), is a key intermediate in the
metabolism of the antiviral agent 2',3'-dideoxyinosine (ddI) to its active
triphosphate derivative, 2',3'-dideoxyadenosine-5'-triphosphate (ddATP). The
potential role of adenylate kinase in the phosphorylation of ddAMP was studied in
human peripheral blood mononuclear cells (PBMC) and a human T cell line, CEMss.
Subcellular distribution, sulfhydryl inhibitor, and substrate specificity studies
support the hypothesis that the mitochondrial adenylate kinase (AK2) is a major
route of cellular activation of these compounds in human lymphocytes.
PMID- 10772724
TI - Differential transport of cytosine-containing nucleosides by recombinant human
concentrative nucleoside transporter protein hCNT1.
AB - The transportability of cytosine-containing nucleosides by recombinant hCNT1 was
investigated in transfected mammalian cells. Apparent K(m) values for hCNT1
mediated transport of uridine, cytidine and deoxycytidine were, respectively, 59,
140 and 150 microM. Uridine transport was inhibited 89, 32 and 11%, respectively,
by 500 microM gemcitabine, cytarabine and lamivudine, demonstrating that, unlike
gemcitabine (a high-affinity hCNT1 permeant), cytarabine and lamivudine are poor
hCNT1 permeants.
PMID- 10772725
TI - Excision of beta-L- and beta-D-nucleotide analogs from DNA by p53 protein.
AB - The tumor suppressor p53 protein plays a critical role in the cell-cycle
progression. The role of the 3'-to-5' exonuclease activity of p53 protein in the
DNA repair process remains elusive. Using an in vitro exonuclease assay and
defined oligonucleotides terminated with beta-D- and beta-L-nucleoside analogs at
the 3'-terminus, we studied the ability of p53 protein to excise beta-L- and beta
D-nucleoside analogs which have anticancer or antiviral potential. p53 protein
removes beta-D-nucleoside analogs more efficiently compared to that of beta-L
nucleoside analogs. The affinity of p53 protein for an beta-L-nucleotide
terminated primer was 5 fold lower compared to non-modified primer. The
hypothesis on an important role of the 3'-to-5' exonuclease activity of p53
protein in the action of nucleoside analogs was proposed.
PMID- 10772726
TI - Preclinical antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-
arabinofuranosyl)adenine (Cl-F-ara-A).
AB - Cl-F-ara-A, an analog of fludarabine, was evaluated against a spectrum of tumor
systems in culture and in mice. The compound exhibited significant cytotoxicity
against a variety of human tumor cell lines. More importantly, the compound
showed selectivity in vivo, with excellent activity being demonstrated against
human colon and renal tumors. Human nonsmall cell lung and prostate tumors were
also sensitive in vivo to the compound, albeit at a reduced level.
PMID- 10772727
TI - Early therapy with valaciclovir or famciclovir reduces but does not abrogate
herpes simplex virus neuronal latency.
AB - Mice were infected via the ear pinna using a recombinant strain of HSV-1
expressing the beta-gal gene under the LAT promoter. Mice were treated
continuously with valaciclovir or famciclovir, from 1 day before or 1 day after
virus inoculation for 10 days. Ipsilateral and contralateral trigeminal and
cervical ganglia were later assessed by co-cultivation or for X-Gal-positive or
LAT-positive neurons. Latency was markedly reduced by early therapy, however, a
basal level of HSV-1-positive neurons was detected in all mice.
PMID- 10772729
TI - In vitro and in vivo metabolism and pharmacokinetics of bis [(t-butyl)-S-acyl-2
thioethyl]-beta-L-2',3'-dideoxy-5-fluorocytidine monophosphate.
AB - Exposure to 10 &M L-FddCMP-bisSATE led to formation of intracellular L-FddCTP
levels of 410.1(+/-) +/- 46.2 and 242.1 +/- 13.2 pmol/10(6) cells in unstimulated
and PHAstimulated PBM cells, respectively; whereas, exposure of cells to the
parent nucleoside, L-FddC, generated 5-10-fold less L-FddCTP. In Hep-G2 cells and
EGF/HGF stimulated and unstimulated primary cultured hepatocytes, the active
metabolite reached 113 +/- 29, 23.9 +/- 15.6, and 20.6 +/- 10.5 pmol/10(6) cells.
Three other metabolites, L-FddCMP-monoSATE, L-FddCMP-SH, and M I, were detected
intracellularly and extracellularly in all cell types examined. Intravenous
administered dose of 3 mg/kg L-FddCMP-bisSATE to rhesus monkeys resulted in
plasma concentration levels of 2.06 +/- 1.00 and 0.39 +/- 0.15 &M of L-FddCMP
monoSATE and L-FddC, respectively, while the prodrug was completely cleared
metabolically within 15 min. Following oral administration of an equivalent dose,
the absolute oral bioavailability of L-FddC derived from L-FddCMP-bisSATE
administration was 65%.
PMID- 10772728
TI - Synthesis and antiviral evaluation of 1-O-hexadecylpropanediol-3-P-acyclovir:
efficacy against HSV-1 infection in mice.
AB - We synthesized, 1-O-hexadecylpropanediol-3-P-acyclovir, an orally bioavailable
lipid prodrug of acyclovir and evaluated it for in vitro and in vivo activity
against herpes simplex virus infections. Although 1-O-hexadecylpropanediol-3-P-
acyclovir was less active in vitro than acyclovir, on a molar basis it was 2.4
times more active orally in preventing mortality from acute HSV-1 infection in
mice. In vitro, 1-O-hexadecylpropanediol-3-P-acyclovir was also more active than
acyclovir in a thymidine kinase negative mutant strain of HSV-1 (DM21) and had
somewhat higher activity in cytomegalovirus infection in vitro due to it's
ability to bypass thymidine kinase.
PMID- 10772730
TI - Efficacy of topical acyclovir monophosphate, acyclovir, or penciclovir in
orofacial HSV-1 infections of mice and genital HSV-2 infections of guinea pigs.
AB - The purpose of these studies was to compare the efficacy of acyclovir
monophosphate (ACVMP), acyclovir (ACV), or penciclovir (PCV) against HSV-1 in an
orofacial infection of mice and against ACV sensitive and resistant genital HSV-2
infections of guinea pigs. Treatment was initiated 24, 48, or 72 hours post
inoculation with 5% ACVMP, 5% ACV (Zovirax) or 1% PCV (Denavir). In all
experiments, similar efficacy was obtained for ACVMP and ACV, whereas PCV was
considerably less effective.
PMID- 10772731
TI - A model of exemplary midwifery practice: results of a Delphi study.
AB - What is unique and exemplary about the midwifery model of care? Does exemplary
midwifery care result in improved outcomes for the recipient(s) of that care?
These are the questions that the profession of midwifery grapples with today
within the context of a changing health care arena. Exemplary midwives, and women
who had received their care, came to consensus about these issues in a Delphi
study. A model of exemplary midwifery care is presented based on the
identification of essential elements aligned within three dimensions:
therapeutics, caring, and the profession of midwifery. Supporting the normalcy of
pregnancy and birth, vigilance and attention to detail, and respecting the
uniqueness of the woman, were several of many processes of care identified. The
critical difference that emerged was the art of doing "nothing" well. By ensuring
that normalcy continued through vigilant and attentive care, the midwives were
content to foster the normal processes of labor and birth, intervening and using
technology only when the individual situation required. Health care, whether in
the gynecologic setting or during pregnancy, was geared to help the woman achieve
a level of control of the process and outcome. The ultimate outcomes were optimal
health in the given situation, and the experience of health care that is both
respectful and empowering. The model provides structure for future research on
the unique aspects of midwifery care to support its correlation with excellent
outcomes and value in health care economics.
PMID- 10772732
TI - Midwifery care research: what questions are being asked? What lessons have been
learned?
AB - PURPOSE: To create and critically evaluate a research database about midwifery
care that identifies topics studied, research methods, results, funding,
publication data, and implications for a future midwifery research agenda.
METHODS: Systematic literature review. Studies included were 1) data-based
research; 2) about midwifery care or practice; 3) in the United States; and 4)
published between 1984-1998. The CINAHL and MEDLINE electronic databases were
searched using a defined strategy, and relevant journals and bibliographies were
searched by hand. RESULTS: This 15-year review identified 140 studies of
midwifery care published in 161 papers. A midwife was the lead author on 60%.
Sixty percent were published in the Journal of Nurse-Midwifery. Six to 15 studies
were published each year, and both the number of publications and funding
increased over the time period. The six major areas of focus were: 1) midwifery
management, 2) structure of care, 3) midwifery practice, 4) midwife-physician
comparisons, 5) place of birth, and 6) care of vulnerable populations.
DISCUSSION: Although retrospective descriptive studies still predominate, more
prospective studies, randomized controlled trials, multi-site studies, and quasi
experimental designs are being conducted. Qualitative methods are helping to
measure nontraditional outcomes. A research agenda should be established based on
discussion and debate within the profession. Midwife investigators need to build
research teams and collaborate with other disciplines. Key areas for future
research include alternative therapies, breastfeeding, cost-effectiveness,
cultural studies, gynecology, health policy, menopause, postpartum care,
substance abuse interventions, and the woman's experience of birth and midwifery
care.
PMID- 10772733
TI - A comparison of visits and practices of nurse-midwives and obstetrician
gynecologists in ambulatory care settings.
AB - With more than 5 million patient visits annually, certified nurse-midwives (CNMs)
substantially contribute to women's health care in the United States. The
objective of this study was to describe ambulatory visits and practices of CNMs,
and compare them with those of obstetrician-gynecologists (OB/GYNs). Sources of
population-based data used to compare characteristics of provider visits were
three national surveys of CNMs and two National Ambulatory Medical Care Surveys
of physicians. When a subset of 4,305 visits to CNMs in 1991 and 1992 were
compared to 5,473 visits to OB/GYNs in similar office-based ambulatory care
settings in 1989 and 1990, it was found that a larger proportion of CNM visits
were made by women who were publicly insured and below age 25. The majority of
visits to CNMs were for maternity care; the majority of visits to OB/GYNs were
for gynecologic and/or family planning concerns. Face-to-face visit time was
longer for CNMs, and involved more client education or counseling. This
population-based comparison suggests that CNMs and OB/GYNs provide ambulatory
care for women with diverse demographic characteristics and differing clinical
service needs. Enhancing collaborative practice could improve health care access
for women, which would be especially beneficial for those who are underserved and
vulnerable.
PMID- 10772734
TI - Integrating qualified nurses and non-nurses in midwifery education: the two-year
experience of an ACNM DOA Accredited Program.
AB - In 1996, the Division of Accreditation (DOA) of the American College of Nurse
Midwives (ACNM) preaccredited the first direct entry program of midwifery
education for candidates who already possess undergraduate degrees in non-nursing
disciplines. Inaugurated through the partnership of the State University of New
York Health Science Center at Brooklyn and the North Central Bronx Hospital, this
1-year, postbaccalaureate, certificate program of studies graduated two
integrated classes of 22 registered nurse (RN) and nine direct entry (DE)
students between 1997 and 1998. This article presents the experience of the first
2 years of this innovative program, focusing on the profiles of the DE students,
their achievements, and their experiences entering the workforce. All of the data
comparing nurse and non-nurse student progress through the program of studies
strongly support the conclusion that, within an ACNM DOA preaccredited/accredited
midwifery education program, DE students can achieve standards of academic
excellence and clinical competency that are at least equivalent to those
demonstrated by their RN peers.
PMID- 10772735
TI - Health problems after childbirth.
AB - Of the entire maternity care cycle, the postpartum period occupies the lowest
priority in practice, teaching, and research. Despite this, data from research
outside the United States show that health problems after birth are very common,
may persist over time, and are often under-recognized by care providers. Women's
health would be favorably impacted by updating patterns of postpartum care, and
by obtaining baseline population data in midwifery practices on the extent of
postnatal morbidity.
PMID- 10772736
TI - Umbilical cord clamping: beliefs and practices of American nurse-midwives.
AB - The optimal time for umbilical cord clamping after birth remains a critical
unknown fact that has implications for the infant, the mother, and science. A
national survey was conducted using a randomized sample (n = 303) of the active
membership of the ACNM to determine cord clamping practices and beliefs of
American nurse-midwives. The response rate was 56%. The respondents fell into
three cord clamping categories: early (EC) or before 1 minute (26%); intermediate
(IC) or 1 to 3 minutes (35%); and late (LC) or after pulsations cease (33%). The
EC group believes that early clamping facilitates management of the newborn. The
IC group believes that a moderate delay of clamping allows for a gradual
transition to extrauterine circulation, although many think that the timing of
cord clamping is not significant. The LC group have strongly held beliefs that
late clamping supports physiologic birth processes. The majority of CNMs (87%)
place the baby on the mother's abdomen immediately after birth and 96% avoid
clamping a nuchal cord whenever possible. Although Varney's Midwifery was cited
most frequently as a reference, 78% of the respondents listed no references
reflecting, in part, the absence of evidence-based recommendations for cord
clamping practices.
PMID- 10772737
TI - The length of the second stage of labor in uncomplicated, nulliparous African
American and Puerto Rican women.
AB - The Friedman Curve of Normal Labor, based on Emanuel Friedman's studies of
Caucasian women in 1954 and 1955, remains the "gold standard" for assessing
progress in the second stage of labor. Clinical observation by the authors,
however, suggests that the second stage of labor is shorter in African American
and Puerto Rican women. This descriptive, comparative study examined the duration
of the second stage of labor in nulliparous African American and Puerto Rican
women with uncomplicated births. The labor and delivery records of 373 African
American and 157 Puerto Rican nulliparous women were randomly selected and
reviewed, and the mean durations of the second stage of labor for both groups
were compared to Friedman's labor curve. The mean length of second stage of labor
in the sample of African American women was 31.6 minutes with a standard
deviation of +/- 22.5 minutes, significantly shorter than Friedman's duration (P
< .01). The mean length of second stage of labor in the sample of Puerto Rican
women was 44.32 minutes with a standard deviation of +/- 33.03 minutes. This was
also shorter than Friedman's figure for the second stage of labor (P < .01).
These findings provide a more appropriate curve for monitoring labor progress in
women from different ethnic backgrounds.
PMID- 10772738
TI - Meeting women's health needs in Yemen: a midwifery perspective.
AB - Maternal mortality in Yemen is one of the highest in the world. Reaching the
rural majority of the population with primary health care services has been a
continual priority for the nation. Despite efforts to expand health services,
access to maternal and child health care remains low. The training of community
midwives nationwide has been undertaken recently to address the need for maternal
and child health services, particularly in rural areas. Several lessons have been
gained through this initial training that will improve future efforts.
PMID- 10772739
TI - Considering technology: living and working in a technocratic society.
AB - In this article, a framework is provided for consideration of technologies that
are frequently viewed as either a source of power or frustration. The two widely
accepted paradigms of technological and social determinism are analyzed in
relationship to women's health care. Those ascribing to the model of
technological determinism believe that a technology, once created, takes on a
life of its own. Those believing in social determinism view a technology as a
neutral tool that can be used in any way that the user desires. Finally, a third
model that addresses both of these propensities in conjunction with the
technology and social factors underlying its use is presented and recommended for
critical analysis of devices used when caring for women.
PMID- 10772740
TI - Midwives as primary care providers.
AB - Historically, primary health care services for women have been vastly inadequate.
It was not until 1990, when the National Institutes of Health established the
Office of Research on Women's Health, that the United States began to acknowledge
the importance of providing primary care services to women. Even today, women
continue to be a greatly underserved population when it comes to primary health
care services. Midwives are ideal providers of health promotion services for
women because their entire philosophy of care centers on the promotion of women's
health throughout the lifecycle.
PMID- 10772741
TI - Acupuncture.
PMID- 10772742
TI - An endoluminal method of hemorrhage control and repair of ruptured abdominal
aortic aneurysms.
AB - PURPOSE: To report our initial experience with endovascular grafting to treat
ruptured abdominal aortic aneurysms (AAAs). METHODS: Three consecutive patients
with severe comorbid illnesses and symptoms of aneurysm rupture and hemodynamic
instability were treated with aortomonoiliac grafts. The Z-stent-based devices
were implanted with the assistance of an occlusion balloon placed in the distal
descending thoracic aorta. RESULTS: All patients survived the procedure with
successfully excluded AAAs. Two patients had relatively short hospital stays (4
and 14 days), while the third required prolonged treatment for pre-existing
conditions. All patients required blood transfusions; 2 developed significant
coagulopathies. Definitive management was delayed significantly by imaging
protocols and graft construction. CONCLUSIONS: Endovascular repair of ruptured
aortic aneurysms is feasible. Proximal aortic control is readily attainable with
the use of an aortic occlusion balloon placed through the left axillary artery.
The absence of a laparotomy, extensive retroperitoneal dissection, and aortic
cross-clamping likely contributes to patient survival; however, the delay in
operative therapy to obtain adequate imaging and construct an endograft could be
a hindrance to the ultimate success of this approach. The concepts of alternative
aortic imaging techniques and endograft design, construction, and storage must be
addressed.
PMID- 10772743
TI - Endograft planning without preoperative arteriography: a clinical feasibility
study.
AB - PURPOSE: To investigate an alternative method of preprocedural planning for
aortic endografting based solely on spiral computed tomography (CT) with 3
dimensional (3D) reconstruction without preoperative arteriography. METHODS: From
August 1997 to April 1998, 25 consecutive patients with abdominal aortic
aneurysms (AAA) were evaluated for endovascular repair by spiral CT scans (2-mm
slice thickness) and computerized 3D model construction. No additional imaging
for planning was performed. The aortoiliac dimensions, thrombus load,
calcification, and vessel tortuosity were measured and evaluated from the 3D
model of the aortoiliac segment. These data were used for selecting the patients;
the configuration, diameter, and length of the endograft; and the attachment
sites for deployment. RESULTS: Primary procedural success was 92% (23/25). All
endografts were deployed as planned, and there were no conversions to open
repair. Six patients required adjunctive procedures for delivery system access or
for iliac aneurysm exclusion, as predicted by the 3D model. Mean procedural time
was 91 minutes (range 24 to 273). Two (8%) type II (side branch) endoleaks both
sealed spontaneously within 1 month. No graft-related complications or death
occurred, for a 30-day technical success rate of 100%. CONCLUSIONS: This
computerized 3D model provided accurate data for preoperative evaluation of the
aortoiliac segment for endovascular AAA repair. Satisfactory technical outcomes
for aortic endografts can be achieved without the use of preprocedural invasive
imaging.
PMID- 10772744
TI - Immediate endovascular repair for descending thoracic aortic transection
secondary to blunt trauma.
AB - PURPOSE: To report the immediate endovascular treatment of a thoracic aortic tear
secondary to blunt trauma. METHODS AND RESULTS: A 39-year-old man was injured in
a motor vehicle collision. In addition to significant trauma to the head, chest,
and abdomen, there were signs of a deceleration injury to the thoracic aorta.
After urgent celiotomy to repair a lacerated spleen, the thoracic aortic
transection was treated intraluminally using an endograft made of Gianturco Z
stents covered with polytetrafluoroethylene. The patient recovered from his
injuries, and the thoracic endograft shows no evidence of endoleak 7 months after
treatment. CONCLUSIONS: Endoluminal techniques can be used successfully in the
immediate repair of thoracic aortic injuries.
PMID- 10772745
TI - Sigmoid ischemia and the inflammatory response following endovascular abdominal
aortic aneurysm repair.
AB - PURPOSE: To assess the relationship between sigmoid colonic perfusion,
endotoxemia, and cytokine generation in patients undergoing elective open repair
(OR) or endovascular repair (EVR) of infrarenal abdominal aortic aneurysms (AAA).
METHODS: Ten patients (9 males; average age 67.6 +/- 2.5 years, mean aneurysm
diameter 6.9 +/- 0.6 cm) undergoing OR were compared to 10 patients (all males;
average age 70.3 +/- 2.6 years, mean aneurysm diameter 6.5 +/- 0.5 cm) whose
repair was performed using the EVR technique. The partial pressure of the carbon
dioxide gap (PCO2gap = tissue PCO2 - arterial PCO2) of the sigmoid colonic mucosa
was measured using a silicone tonometer to evaluate bowel perfusion. Blood
samples were collected into pyrogen-free heparinized tubes for quantification of
plasma concentrations of endotoxin, tumor necrosis factor alpha (TNF-alpha), and
interleukin 6 (IL-6) before, during, and after aortic repair. RESULTS: Patients
in the OR group had a significantly greater increase in PCO2gap, suggesting a
greater degree of bowel ischemia compared to the EVR group. This was associated
with significantly greater postoperative concentrations of endotoxin, TNF-alpha,
and IL-6 in the OR group. A significant correlation was found between PCO2gap, IL
6, and postoperative core temperature. CONCLUSIONS: The results suggest that the
degree of bowel ischemia, endotoxemia, and cytokine generation following elective
infrarenal AAA reconstruction may be reduced if the endovascular technique is
used instead of conventional surgery.
PMID- 10772746
TI - Endovascular treatment of an aortic aneurysm ruptured into the inferior vena
cava.
AB - PURPOSE: To report the endovascular repair of a rare abdominal aortic aneurysm
(AAA) rupture into the inferior vena cava. METHODS AND RESULTS: A 74-year-old man
with a 6.0-cm saccular aortic aneurysm and a previously undiagnosed aortocaval
fistula of more than 2 weeks' duration was treated successfully with a Vanguard
bifurcated stent-graft. The aneurysm was excluded and no endoleak or
communication between the aorta and inferior vena cava was seen on computed
tomographic imaging at the 6-month evaluation. CONCLUSIONS: Aortic endografting
in this life-threatening complication is an effective treatment option that
avoids the significant blood loss encountered in conventional repair.
PMID- 10772747
TI - Carotid stenting for severe radiation-induced extracranial carotid artery
occlusive disease.
AB - PURPOSE: To present our experience with carotid artery stenting as an alternative
treatment to endarterectomy in patients with radiation-induced carotid artery
occlusive disease. METHODS AND RESULTS: Fourteen patients (10 males; mean age 61
years, range 52 to 79) underwent percutaneous stenting of 15 carotid arteries for
severe radiation-induced extracranial stenoses. Technical success was achieved in
all patients, with reduction of the mean stenosis from 77% +/- 6% to 8% +/- 2%.
In 2 patients, ipsilateral vertebral artery lesions were stented concomitantly.
One patient had a minor stroke after the procedure but recovered fully in 2 days.
No other complications were encountered. Nine (64%) patients had 6-month follow
up imaging (angiography or duplex scanning) that showed no evidence of restenoses
(obstruction > or = 50%). At 18 +/- 2 months, 3 (21%) patients had died from
unrelated causes. No neurological events occurred, and no repeat carotid artery
interventions were required in the remaining patients. CONCLUSIONS: Carotid
stenting is an effective treatment option for severe radiation-induced carotid
artery occlusive disease.
PMID- 10772748
TI - Slimgraft: a percutaneous endovascular graft system.
AB - PURPOSE: To describe an in vitro feasibility trial of a new percutaneous
endograft delivery technique. METHODS AND RESULTS: A water flow model of 9-mm
(inner diameter) transparent plastic tubing was used to test the feasibility of
sequentially delivering the components of an endograft through a 7-F sheath for
assembly in situ. The tubular endovascular graft was fabricated from a 10-mm x 68
mm Wallstent and 50-microm-thick Dacron graft. The graft material was formed into
a tube, attached with a suture to a guidewire, and delivered into the plastic
tubing. The Wallstent was then delivered through the tubular graft and deployed,
affixing the graft to the plastic tube wall. In 4 trials, only 1 attempt was not
successful. CONCLUSIONS: These concepts and techniques may have implications in
the development of percutaneously deliverable endovascular grafts.
PMID- 10772749
TI - Endovascular repair of thoracic aortic aneurysm in dogs: evaluation of a nitinol
polyester self-expanding stent-graft.
AB - PURPOSE: To validate the ease of deployment and in vivo healing performance of a
nitinol-polyester self-expanding stent-graft using a canine thoracic aortic
aneurysm model. METHODS: Arterial aneurysms were surgically created in 8 dogs by
sewing a polyester patch onto the anterior side of the thoracic aorta. The
nitinol-polyester self-expandable stent-grafts (Cragg EndoPro System 1) were
implanted transluminally via the femoral route and deployed at the site of the
thoracic aneurysm. Aneurysm exclusion and endograft patency were assessed by
angiography after implantation and before animal sacrifice at scheduled periods
ranging from 1 week to 3 months. The explanted specimens were examined with
magnetic resonance imaging (MRI) to study the position of the stent-graft with
respect to the aneurysmal sac. Histological analysis using light microscopy and
scanning electron microscopy was performed to examine the inflammatory response
and healing characteristics of the device. RESULTS: Seven of 8 stent-grafts were
implanted successfully; a bend occurred within the aneurysmal sac in 1 dog, which
led to continued perfusion of side branches. This endoleak sealed spontaneously
within 1 week, and complete exclusion of the aneurysms in all 8 animals continued
throughout implantation. At the time of explantation, all devices were
structurally intact and well positioned in the aneurysmal sac. At 1 week, the
luminal surface displayed a thin layer of thrombotic matrix, which was gradually
replaced by a collagenous internal capsule with endothelial-like cell coverage
along both ends of the stent-grafts at 2 and 3 months. No exacerbated
inflammatory reaction due to either the nitinol wires or the polyester sleeve was
observed after 3 months of implantation. CONCLUSIONS: This short-term in vivo
study of a nitinol-polyester self-expanding endograft demonstrated the effective
exclusion of thoracic aneurysms with a satisfactory healing response and no
excessive tissue or inflammatory reactions.
PMID- 10772750
TI - Open subintimal angioplasty of the superficial femoral and distal arteries.
AB - PURPOSE: To describe an open approach to subintimal angioplasty. TECHNIQUE:
Through a subinguinal incision and arteriotomy over the superficial femoral
artery origin, the opening of a subintimal channel is created surgically. The
subintimal plane is advanced distally with a guidewire, and this neolumen is
expanded with sequential balloon dilations. The atherosclerotic core is dissected
proximally in the common femoral artery and tacked down to ensure inflow. A patch
graft closes the arteriotomy. CONCLUSIONS: Open subintimal angioplasty is a
simple, minimally invasive alternative treatment for complete SFA occlusion. Long
term follow-up in a large group of patients will be necessary to determine the
durability of the false arterial lumen.
PMID- 10772751
TI - The role of thrombolytic therapy in the management of acute and chronic lower
extremity ischemia.
PMID- 10772752
TI - Guest editorial
PMID- 10772753
TI - Updates on the mechanics and regulation of cytokinesis in animal cells.
PMID- 10772754
TI - Unilateral and wandering furrows during mitosis in vertebrates: implications for
the mechanism of cytokinesis.
AB - Vertebrate somatic cells sometimes form unilateral furrows during cytokinesis
that ingress from only one edge of the cell. In some cases after a cell initiates
a normal symmetrical circumferential furrow, one of its edges stops furrowing and
regresses while the furrow associated with the opposing edge continues across the
cell. In cells containing two independent spindles unilateral furrows are
sometimes formed that do not follow a linear path but instead sharply change
their direction and wander for >40 microm through the cell. These observations
reveal that the 'contractile ring' normally seen during cytokinesis is composed
of multiple independent 'furrowing units' that are normally coordinated to form a
symmetrical furrow around the cell, and that once formed this so-called
contractile band does not function as a 'purse string' as commonly envisioned.
Individual furrowing units can work independently of one another, and cytokinesis
in vertebrates can be consummated by the formation of a single functional
furrowing unit in a localized region of the cell cortex that is then propagated
across the cell. How this propagation occurs remains an important question for
the future.
PMID- 10772755
TI - Cytokinesis in cells undergoing mitosis without genome replication.
AB - Chinese hamster ovary cells can be forced to enter mitosis without prior DNA
replication by treatment with hydroxyurea and caffeine. Cells treated in this way
assemble a spindle that functions normally except that it does not accomplish
anaphase spindle elongation (anaphase B). The chromatin detaches from the
unreplicated kinetochores, which fragment, but establish microtubule attachments
and migrate to the metaphase plate. Partitioning of the kinetochore fragments
ensues on the normal schedule. Typical midbodies and cleavage furrows are
established and daughter cells of equal size are produced. These results imply
that intact chromosomes are not necessary for correct cleavage furrow placement
but that kinetochores might be. Further, it is clear that cleavage furrow
placement does not depend on anaphase spindle elongation.
PMID- 10772756
TI - Inhibition of cell division but not nuclear division by 1-O- octadecyl-2-O-methyl
Sn-glycero-3-phosphocholine.
AB - 1-O-Octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OCH(3)) selectively
inhibits the growth of cancer cells. Here we show that in some cell types ET-18
OCH(3)and liposome-associated ET-18-OCH(3)inhibit cell division without
concurrent inhibition of nuclear division, leading to multinucleate cell
formation, and cell death through apoptosis. Cell cycle analysis revealed that ET
18-OCH(3)-treated U-937 cells continued to move through the cell cycle, but many
cells were not able to divide and instead accumulated as tetraploid cells or
octaploid cells in the G0/G1 phase of the cell cycle. Inhibition of cytokinesis
has been shown to be paralleled by activation of U-937 cells, including
upregulation of some cell-surface markers, acquisition of phagocytic activity,
and secretion of tumor necrosis factor (TNF)-alpha (Pushkareva et al., 2000).
Furthermore, treatment of cells with ET-18-OCH(3)results in the accumulation of
apoptotic cells in time- and dose-dependent manner. It is possible that
inhibition of cytokinesis may be related to cytoskeletal effects.
PMID- 10772757
TI - Inhibition of cytokinesis by asbestos and synthetic fibres.
AB - Using high-resolution timelapse microscopy, we have followed individual
phagocytized fibres through the later stages of division in MeT-5A human
mesothelial cells and LLC-MK(2)monkey epithelial cells. The fibres used were
crocidolite and chrysotile asbestos, fibrous glass (MMVF), and refractory ceramic
fibres (RCF). Long fibres (15-80 microm) trapped within the cleavage furrow can
partially or completely block cytokinesis. Cells proceed in one of three ways:
(1) eventual completion of cytokinesis; (2) incomplete cytokinesis, resulting in
two cells joined by a fibre-containing intercellular channel; or (3) failure of
cytokinesis, resulting in a binucleate or trinucleate cell. Two factors
associated with fibre-induced bi/trinucleation are: (1) an initial association
between the fibre and the forming daughter nuclei, which is sometimes lost over
time, and (2) disintegration of the midbody. The studies suggest that delay of
cytokinesis by interzonal fibres can result in bi/trinucleation through the loss
of midbody/intercellular bridge proteins that are required for completion of
cytokinesis.
PMID- 10772758
TI - Rotokinesis, a novel phenomenon of cell locomotion-assisted cytokinesis in the
ciliate Tetrahymena thermophila.
AB - The mechanism responsible for final cell separation at the end of cytokinesis is
currently unknown. Knockout strains of the ciliate, Tetrahymena thermophila
lacking the kinesin-II homologous molecular motors, Kin1p and Kin2p are paralyzed
due to their complete loss of cilia and undergo frequent cytokinesis failures.
Observations of live dividing cells revealed that cleavage furrow ingression is
normal in kinesin-II double knockout cells until the final stage of cell
separation (Brown et al., 1999). During closer inspection of dividing cells using
video differential interference contrast microscopy, we found that wild-type
cells undergo an extremely complex motile behavior near the end of cytokinesis.
This process, which we have named rotokinesis, appears to facilitate the physical
separation of daughter cells. Here we present recent work on Tetrahymena
rotokinesis, and review studies in other organisms which suggest that the use of
cell locomotion in the completion of cytokinesis is a general phenomenon of
motile cell types.
PMID- 10772759
TI - Macronuclear division and cytokinesis in Tetrahymena.
AB - Tetrahymena contains a micronucleus and a macronucleus. The micronucleus divides
with typical mitosis, while the macronucleus divides amitotically. Although the
mechanism responsible for macronuclear division was previously unknown, we
clarified the organization of microtubules during macronuclear division. The
macronuclear microtubules dynamically changed their distribution in an organized
way throughout the macronuclear division. The macronuclear microtubules and the
cytoplasmic microtubules cooperatively carried out the macronuclear division.
When the micronuclear division was finished, p85 appeared at the presumptive
division plane prior to the cytokinesis. The p85 directly interacted with
calmodulin in a Ca(2+)-dependent manner, and p85 and CaM colocalized to the
division furrow during cytokinesis. Moreover, the Ca(2+)/CaM inhibitor, W7,
inhibited the direct interaction between p85 and CaM, the localization of both
proteins to the division plane, and the formation of the division furrow. Thus,
Ca(2+)/CaM and p85 have important roles in initiation and progression of
cytokinesis in Tetrahymena.
PMID- 10772760
TI - Aphidicolin inhibits DNA replication in the micronucleus and blocks cytokinesis
in Paramecium caudatum.
AB - Aphidicolin, a selective inhibitor of DNA polymerase, totally blocks DNA
replication in the micronucleus but not in the macronucleus of Paramecium
caudatum. The ciliates no longer divide and after 4 days the DNA content of the
macronucleus has increased by 64%. Concomitantly the cell volume has increased by
53%.
PMID- 10772761
TI - Abnormalities of spindle and cytokine behavior leading to the formation of
meiotic restitution nuclei in intergeneric cereal hybrids
AB - Mobile stages of meiosis have been analysed by visualizing the spindle in fertile
cereal F1 hybrids. We describe four different mechanisms of the formation of
restitution nuclei in meiotic division: (1) centripetal migration of telophase
chromosome groups from the poles of a curved spindle at early telophase; (2)
centripetal migration of the chromosome groups at late telophase when cell plate
formation has failed; (3) preferable migration of univalents to one of the poles
although spindle appearance is morphologically normal; and (4) in the absence of
chromosome segregation where kinetochore fibers have failed to form. Copyright
1999 Academic Press.
PMID- 10772763
TI - CYTOKINESIS A special issue of cell biology international focusing on a topic
which is of current interest and in which rapid progress is being made
PMID- 10772762
TI - Cytokinesis: lessons from rappaport and the Drosophila blastoderm embryo.
PMID- 10772764
TI - Arrest in metaphase and anatomy of mitotic catastrophe: mild heat shock in two
human osteosarcoma cell lines.
AB - The exits from metaphase arrest and anatomy of mitotic catastrophe were studied
in two human osteosarcoma cell lines, nontumorigenic HOS TE85 and its chemically
transformed strain MNNG-HOS, applying mild genotoxic damage by heat shock at 41.8
degrees C for 24 h. Under these conditions, both cell lines doubled or tripled
their mitotic index entering arrest in metaphase. On return to 37 degrees C, the
arrest was either released or ended in apoptosis. The transformed strain showed a
greater capacity to arrest in metaphase as well as a greater probability of
developing the third pathway: to restitute this arrest in polyploid interphase.
This, in turn, either entered an 'endocycle' or, following a delay, apoptosis.
Thus, arrest in metaphase was a cross-point of the mitotic cycle, apoptosis, and
endocycle. Mitotic catastrophe can morphologically manifest combinations of
elements of these three processes.
PMID- 10772765
TI - Iron regulation of transferrin synthesis in the human hepatoma cell line HepG2.
AB - In human beings, serum transferrin levels increase during iron deficiency and
decrease with iron overload. Yet, whether or not iron levels actually affect the
synthesis of transferrin in human liver cells is not known. In previous studies,
iron was shown to suppress the expression of chimeric human transferrin genes in
livers of transgenic mice. The goal of this study was to determine if iron
suppresses intact endogenous human transferrin synthesis by testing the effects
of changes in iron levels on synthesis of transferrin in a human hepatoma cell
line HepG2. In HepG2 cells, normalized(35)S-metabolically labeled transferrin
synthesis was consistently less following iron treatment with hemin or ferric
citrate, than following treatment with an iron-chelator deferroxamine. Thus, this
study provides new evidence that iron can regulate synthesis of intact endogenous
human transferrin.
PMID- 10772766
TI - Involvement of the protein kinase pathway in melanin synthesis by chick retinal
pigment epithelial cells.
AB - Protein kinases are involved in a variety of cellular functions and cell
proliferation in eyes. We have explored the involvement of protein kinase C (PKC)
in cell proliferation and melanin synthesis by chick retinal pigment epithelial
(RPE) cells in vitro. This was achieved by incubation of confluent RPE cells with
known inhibitors of protein kinase, H-7, W-7, H-8, and staurosporine. Chick RPE
cells were cultured in the presence or absence of the protein kinase inhibitors
for a 10-day period. Effects of the inhibitors on cell proliferation and melanin
synthesis, as an indication of cell differentiation, were assessed by counting
the number of surviving cells and by measuring the melanin content in the cells,
respectively. H-7, W-7, and staurosporine inhibited cell proliferation and
increased melanin synthesis in a concentration-dependent manner during culture;
however, H-8 did not produce these cellular effects. These findings indicate that
PKC and calcium/calmodulin-dependent kinase pathways are involved in the
proliferation and differentiation of chick RPE cells.
PMID- 10772767
TI - Neutral endopeptidase-24.11 (NEP) deactivates PDGF- and TGF-beta-induced cell
shape changes in invertebrate immunocytes.
AB - Using a cytofluorimetric assay, we found that immunocytes of the mollusc, Mytilus
galloprovincialis, express CD10, a surface antigen known to be identical to
neutral endopeptidase-24.11 (NEP). The spectrofluorimetric analysis demonstrates
that the growth factors PDGF-AB and TGF-beta1 provoke an increase in NEP-like
activity in membrane preparations from the immunocytes, but have no effect on the
soluble form in the serum. On the other hand, computer-assisted microscopic image
analysis reveals that NEP deactivates the PDGF-AB- and TGF-beta1-induced shape
changes in immunocytes. However, Western blots show that, in solution, NEP does
not cleave PDGF-AB or TGF-beta1, indicating that the inactivation is not due to
proteolysis. These results suggest a functional interplay in invertebrate
immunocytes between growth factors and NEP, as previously shown in vertebrate
cells.
PMID- 10772768
TI - Variability in E-selectin expression, mRNA levels and sE-selectin release between
endothelial cell lines and primary endothelial cells.
AB - Endothelial cell lines express markers and are assumed to exhibit other
endothelial cell responses. We investigated E-selectin expression from human
umbilical vein endothelial cells, the spontaneously transformed ECV304 line and
the hybrid line EA.hy926 by flow cytometry and immunofluorescence, mRNA and
soluble E-selectin release. In cells exposed to tumour necrosis factor alpha (TNF
alpha) and interleukin-1beta (IL-1beta), median (range) percentage of E-selectin
positive HUVECs increased from 1.6(0.9-6. 2)% to 91.4(83.0-96.1)%, (P=0.001)
using flow cytometry. In contrast, E-selectin expression by ECV304 and EA.hy926
cell lines was 100-fold lower. E-selectin mRNA was detectable after 2 h, maximal
at 6 h in HUVECs and undetectable in EA.hy926 and ECV304 cell lines after
exposure to TNF-alpha/IL-1beta. sE-selectin accumulation increased (P=0.004) in
HUVECs only. Neutrophil adherence to ECV304 and EA.hy926 cells was poor compared
to HUVECs (P=0.004). The cell lines ECV304 and EA.hy926 do not exhibit normal
endothelium expression of E-selectin, and may not be appropriate for studies of
adhesion.
PMID- 10772769
TI - CD56 directly interacts in the process of NCAM-positive target cell-killing by NK
cells.
AB - The role of CD56 in the process of target cell killing by NK cells has been
investigated. Addition of NK cells to HuH28 cells, a CD56-expressing cell line,
led to inhibition of the growth of the target cells, which exhibited
morphological features of apoptosis. These changes were prevented by the addition
of a polyclonal anti-NCAM to the cultures. Since neither Fas antigen expression
nor apoptotic changes were induced by addition to a mixed culture supernatant of
NK and target cells, both the Fas-Fas ligand system and soluble factors do not
seem to participate in apoptosis in these circumstances. Increased secretion of
interferon-gamma and tumour necrosis factor-alpha by NK cells must therefore have
been suppressed by the presence of the polyclonal antibody. These results lead us
to conclude that CD56, through homophilic binding, plays an important role in the
process of target cell killing by an apoptosis mechanism.
PMID- 10772770
TI - Interleukin-6-induced production of type II acute phase proteins and expression
of junB gene are downregulated by human recombinant growth hormone in vitro.
AB - Growth hormone (GH), given therapeutically in many human diseases, is able to
modulate the maturation and function of many cells of immune system. The present
study demonstrates the effect of human recombinant GH on the production of acute
phase proteins (APP) as well as on the gene expression of junB proto-oncogene on
human hepatoma cell line, HepG2. When applied alone GH resulted in an increase in
the transcription of junB proto-oncogene within 30 min. The production of alpha2
macroglobulin, haptoglobin and fibrinogen was also enhanced by rhGH treatment.
However, both IL-6-stimulated junB gene expression (junB mRNA) and biosynthesis
of type II APP (alpha2-macroglobulin, fibrinogen, haptoglobin) were strongly
inhibited by the GH. The results indicate that GH has a modulatory role in
regulating inflammation both in the absence and presence of IL-6. These findings
call for further in vivo studies to determine the potential anti-inflammatory
actions of GH therapy.
PMID- 10772771
TI - Resting cyst wall glycoproteins isolated from two colpodid ciliates are glycine
rich proteins.
AB - Two glycoproteins bands isolated from the cyst wall protein pattern of two
colpodid ciliates, Colpoda inflata (gp46CI) and Colpoda cucullus (gp46CC) were
analysed for their amino acid composition. Both glycoproteins are very rich in
glycine and have a relatively high hydrophobicity, containing additionally many
leucine and alanine residues. Their high degree of similarity is both
quantitative and qualitative. Compared with just two previously published
reports, their amino acid compositions are similar to those found in the
hydrolysed cyst wall total proteins from the ciliates C. steinii and Paraurostyla
spp. The amino acid composition corroborates that they are indeed glycoproteins,
because asparagine, an amino acid residue suitable for the attachment to N
acetylglucosamine by its amide group (N-glycan), is abundant in both proteins. We
discuss our data in relation to other glycine-rich proteins and a comparison with
amino acid composition protein databases is carried out.
PMID- 10772772
TI - Are cells rescued from 'low density death' by co-operation between phospholipases
C AND D?
AB - Cells of the ciliate Tetrahymena thermophila die when transferred at low density
to a lipid-free nutritionally complete medium. This death is prevented and they
will start to proliferate if protein kinase C is activated and this activation is
sustained. We propose that this takes place in two stages. Firstly, the
phospholipase C pathway beginning with and specific for phosphatidylinositol
leads to the formation of diacylglycerol and inositol tris -phosphate.
Diacylglycerol activates protein kinase C, and inositol tris -phosphate via
Ca(2+)phospholipase D (PLD). Secondly, the protein kinase C response can now be
sustained by diacylglycerol produced by phospholipase D, using
phosphatidylcholine and phosphatidylserine as substrates. Should this switching
from PI-specific phospholipase C (PLC) to phospholipase D fail, then the cell
will die in the course of milliseconds during the minutes following inoculation.
PMID- 10772773
TI - Induction of DNA synthesis or apoptosis in mammalian nuclei by Xenopus egg
extracts that fail to support the replication of sperm chromatin.
AB - Cell-free extracts of Xenopus eggs are widely used to study DNA replication in
higher eukaryotes. However, with Xenopus sperm chromatin as template, it is a
common experience that the efficiency of replication varies from extract to
extract, for reasons that are unclear. Here we show that the majority of extracts
unable to support sperm replication are nevertheless able to induce DNA synthesis
in intact mammalian nuclei. Those that do not, induce apoptosis.
PMID- 10772774
TI - Differences in the microtubule organization between normal and cml granulocytes
after stimulation with chemotactic peptide.
AB - Chemotaxis of polymorphonuclear leukocytes (PMNL) from chronic myeloid leukemia
(CML) patients followed in a gradient of a chemotactic peptide n-formyl-methionyl
leucyl-phenylalanine (fMLP) is consistently defective in all the phases of the
disease. Chemoattractant-induced polymerization of cytoskeletal proteins (actin
and tubulin) plays a major role in regulation of cell shape and cellular
motility. To study the role of microtubules in defective chemotaxis, we have
compared fMLP-induced alterations in organization of microtubules in PMNL from
CML patients with those from normal subjects by laser confocal microscopy. Our
analysis shows differences in microtubule organization between normal and CML
PMNL and suggests that both nucleation of new microtubule and elongation of pre
existing microtubules are essential for PMNL chemotaxis.
PMID- 10772775
TI - Cellular signalling after in vivo heat shock in the liver.
AB - In an experimental model of in vivo hyperthermia, we investigated the involvement
of a number of signalling events in rat liver. We report that in vivo heat shock
causes a powerful activation of c-Jun N-terminal kinase and p38 kinase but does
not trigger poly(ADP-ribose) polymerase cleavage, a signature event of apoptosis.
Among the upstream regulators of the kinases, we show that stress-activated
protein kinase/extracellular signal-regulated kinase/nitrogen-activated protein
kinase kinase 4 SEK1/MKK4 is not involved whereas MKK3 and/or MKK6 are activated.
PAK activity displays a transient rise, whereas GCK does not change. PI3-kinase
activity increases in anti-phosphotyrosine immunoprecipitates, suggesting a
tyrosine kinase-dependent induction mechanism, and the co-immunoprecipitation of
PI3-kinase with p60 Src kinase supports the involvement of this latter. GSK3,
which may act downstream to PI3-kinase through AKT, undergoes
hyperphosphorylation, thus playing a possible role in the protection from
apoptosis and in the modulation of heat-shock transcription factor activity.
PMID- 10772776
TI - Effect of the serine protease inhibitor N-tosyl-l-phenylalanine-chloromethyl
ketone (TPCK) on MCF-7 mammary tumour cells growth and differentiation.
AB - Previous studies from this and other laboratories indicated that the oestrogen
regulated heat shock protein HSP27 is involved in the control of MCF-7 cells
growth and differentiation, as it also appears to be in other cell types,
including osteoblasts and HL-60 cells. In the latter instance, induction of
differentiation is associated with the downregulation of myeloblastin, a serine
protease now identified as proteinase 3 (hence its designation as PR3/Mbn),
mirrored by an increase in the cellular content of the small heat shock protein
HSP27, a substrate to this enzyme. Besides, antisense inhibition of PR3/Mbn
production sufficed for inducing HL-60 cells monocytic differentiation. This
prompted us to examine the hypothesis that a post-translational control on HSP27
levels (and by this on differentiation) by a serine protease might also be
operating in human mammary tumour cells. As part of our attempt to evaluate this
hypothesis, the present work consisted of testing the effects of a treatment of
MCF-7 cells with the serine protease inhibitor N-tosyl-L-phenylalanine
chloromethyl ketone (TPCK). Our data show that this resulted in a four-fold
increase in HSP27 content, associated with a 2.5-fold decrease in growth rate,
the formation of cytoplasmic vesicles and increased secretion of 52 kDa peptides,
identified by Western immunoblot as the isoforms of the oestrogen-regulated
protein, cathepsin D. TPCK only affected growth in MDAMB-231 cells (in which
HSP27 levels are very low and remained below MCF-7 cells basal levels after
treatment) and failed to affect L929 cells, in which the hsp27 gene is silent.
This provides circumstantial support for the assumption that effects of TPCK on
the MCF-7 cells phenotype are linked to the associated increase in HSP27 content.
Our recent demonstration that MCF-7 cells do in fact express PR3/Mbn fits with
our concept and opens the way to test it directly, using antisense strategy.
PMID- 10772777
TI - Annexin I is stored within gelatinase granules of human neutrophil and mobilized
on the cell surface upon adhesion but not phagocytosis.
AB - Annexin I, a member of the calcium- and phospholipid-binding annexin superfamily
of proteins, is largely present in human neutrophils. To determine its exact
intracellular distribution a combination of flow cytometry, confocal microscopy
and electron microscopy analyses were performed on resting human neutrophils as
well as on cells which had been activated. In resting neutrophils, annexin I was
found to be present in small amounts in the nucleus, in the cytoplasm and
partially also associated with the plasma membrane. The cytoplasmic pool of
annexin I was predominant, and the protein was co-localized with gelatinase
(marker of gelatinase granules), but not with human serum albumin or CD35
(markers of secretory vesicles), or with lysosomes. Electron microscopy showed
the presence of annexin I inside the gelatinase granules. Neutrophil adhesion to
monolayers of endothelial cells, but not phagocytosis of particles of opsonized
zymosan, provoked an intense mobilization of annexin I, with a marked
externalization on the outer leaflet of the plasma membrane. Remaining
intracellular annexin I was also found in proximity of the plasma membrane. These
results provide a novel mechanism for annexin I secretion from human neutrophils,
which is via a degranulation event involving gelatinase granules.
PMID- 10772778
TI - Partial characterization of mosquito larvae extract inducing dna synthesis
alterations on human mononuclear cells.
AB - A crude mosquito larvae and dialysed extract alters the mitotic rate of several
epithelial cell populations in normal young and adult hepatectomized mice. A
crude extract also showed a biphasic effect on the proliferation of human
mononuclear cells (MNCs), either stimulating or inhibiting them depending on the
dose applied. In the present paper, we assayed the effect of the dialysed
mosquito larvae extract and two different protein fractions on human MNCs.
Analysis of cell viability after culture indicated that the extract did not have
toxic effects. Our results show a dual response of the MNCs to the dialysed, as
well as to the protein fraction, with the highest molecular weight inhibiting or
stimulating proliferation, depending on the dose applied. The protein fraction
with the lowest molecular weight (range between 12-80 kDa) showed only an
inhibitory effect on cell proliferation.
PMID- 10772779
TI - Mitochondrial kinetics during amphibian erythropoiesis related to haeme
synthesis.
AB - Flow cytometry, light and epifluorescence microscopies and transmission electron
microscopy were used to follow the mitochondrial kinetics during amphibian
erythropoiesis. A similar behaviour in response to the induction of anaemia was
observed in the diploid Bufo ictericus and the tetraploid Odontophrynus
americanus. A high cellular activity was observed ten days after haemolytic
anaemia induced by phenylhydrazine, based on the higher Rhodamine 123 uptake by
the erythroid cells. In addition, the more intense expression of the
mitochondrial enzyme cytochrome oxidase, isocitrate and succinic dehydrogenases
were cytochemically detected at this stage. This suggests that erythroid cell
mitochondria, at this time, could be in a more active functional state than at
other stages. In both species, mitochondrial plasticity was observed during cell
maturation. A progressive loss of oxidation-reduction enzyme expression seemed to
follow changes at the mitochondrial cristae morphology, from transverse to
longitudinal form, mainly at the 20th day of recovery from anaemia, possibly
related to a natural loss of function. The presence of these mitochondrial
enzymes in mitochondrion-like organelles also favours their participation in the
haeme synthesis, although with a reduced expression, since this suggests the
presence of a complete and active enzymatic complex in these modified organelles.
This also supports the idea that all these organelles are mitochondria in
distinct metabolic stages, and not mitochondrion-like organelles or haemosomes,
as proposed by some authors.
PMID- 10772780
TI - Coding neuroradiology reports for the Northern Manhattan Stroke Study: a
comparison of natural language processing and manual review.
AB - Automated systems using natural language processing may greatly speed chart
review tasks for clinical research, but their accuracy in this setting is
unknown. The objective of this study was to compare the accuracy of automated and
manual coding in the data acquisition tasks of an ongoing clinical research
study, the Northern Manhattan Stroke Study(NOMASS). We identified 471
neuroradiology reports of brain images used in the NOMASS study. Using both
automated and manual coding, we completed a standardized NOMASS imaging form with
the information contained in these reports. We then generated ROC curves for both
manual and automated coding by comparing our results to the original NOMASS data,
where study in investigators directly coded their interpretations of brain
images. The areas under the ROC curves for both manual and automated coding were
the main outcome measure. The overall predictive value of the automated system
(ROC area 0.85, 95% CI 0.84-0.87) was not statistically different from the
predictive value of the manual coding (ROC area 0.87, 95% CI 0.83-0.91). Measured
in terms of accuracy, the automated system performed slightly worse than manual
coding. The overall accuracy of the automated system was 84% (CI 83-85%). The
overall accuracy of manual coding was 86% (CI 84-88%). The difference in accuracy
between the two methods was small but statistically significant (P = 0.026).
Errors in manual coding appeared to be due to differences between neurologists'
and nueroradiologists' interpretation, different use of detailed anatomic terms,
and lack of clinical information. Automated systems can use natural language
processing to rapidly perform complex data acquisition tasks. Although there is a
small decrease in the accuracy of the data as compared to traditional methods,
automated systems may greatly expand the power of chart review in clinical
research design and implementation.
PMID- 10772781
TI - Augmented reality simulator for training in two-dimensional echocardiography.
AB - In two-dimensional echocardiography the sonographer must synthesize multiple
tomographic slices into a mental three-dimensional (3D) model of the heart.
Computer graphics and virtual reality environments are ideal to visualize complex
3D spatial relationships. In augmented reality (AR) applications, real and
virtual image data are linked, to increase the information content. In the
presented AR simulator a 3D surface model of the human heart is linked with
echocardiographic volume data sets. The 3D echocardiographic data sets are
registered with the heart model to establish spatial and temporal congruence. The
heart model, together with an animated ultrasound sector represents a reference
scenario, which displays the currently selected two-dimensional echocardiographic
cutting plane calculated from the volume data set. Modifications of the cutting
plane within the echocardiographic data are transferred and visualized
simultaneously and in real time within the reference scenario. The trainee can
interactively explore the 3D heart model and the registered 3D echocardiographic
data sets by an animated ultrasound probe, whose position is controlled by an
electromagnetic tracking system. The tracking system is attached to a dummy
transducer and placed on a plastic puppet to give a realistic impression of a two
dimensional echocardiographic examination.
PMID- 10772782
TI - Constructing a 3-D mesh model for electrical cardiac activity simulation.
AB - The 3-D ventricle model in this study was reconstructed from a series of MRI
torso cross-section data. We used a 3-D voxel array to represent the ventricle.
As in cardiac simulations proposed by previous studies, the activation sequence
and body surface ECG were simulated in this model. But to reduce the amount of
elements in the model, so that the amount of parameters in the model can be
handled numerically, we propose another approach to simulate cardiac activity. A
mesh model was constructed on the closed surface formed by epicardiac and
endocardiac surfaces of the ventricle. We propose a method to simulate the
activation sequence on the epicardiac and endocardiac surfaces of the mesh model.
As with the uniform double layer theorem, body surface ECG can be estimated in
terms of epicardiac and endocardiac surface current source. Consequently, we can
also generate ECG waveforms corresponding to this mesh simulation. Both the
depolarization sequence and ECG simulated by the mesh model resemble those
generated by the 3-D voxel model. However, the mesh model greatly simplified the
process of ECG simulation. Both the simulation of depolarization and ECG
estimation were expressed in terms of clear and simple mathematical
representations. Consequently, we can analytically investigate the effects of the
mesh model's parameters on the cardiac activation sequence and ECG. It could be a
useful tool to numerically study the relation of ECG waveforms and electrical
activity of the heart.
PMID- 10772783
TI - Using an artificial neural network to detect activations during ventricular
fibrillation.
AB - Ventricular fibrillation is a cardiac arrhythmia that can result in sudden death.
Understanding and treatment of this disorder would be improved if patterns of
electrical activation could be accurately identified and studied during
fibrillation. A feedforward artificial neural network using backpropagation was
trained with the Rule-Based Method and the Current Source Density Method to
identify cardiac tissue activation during fibrillation. Another feedforward
artificial neural network that used backpropagation was trained with data
preprocessed by those methods and the Transmembrane Current Method. Staged
training, a new method that uses different sets of training examples in different
stages, was used to improve the ability of the artificial neural networks to
detect activation. Both artificial neural networks were able to correctly
classify more than 92% of new test examples. The performance of both artificial
neural networks improved when staged training was used. Thus, artificial neural
networks may beuseful for identifying activation during ventricular fibrillation.
PMID- 10772784
TI - Comparison between human and artificial neural network detection of Laplacian
derived electroencephalographic activity related to unilateral voluntary
movements.
AB - A back-propagation artificial neural network (ANN) was tested to verify its
capacity to select different classes of single trials (STs) based on the spatial
information content of electroencephalographic activity related to voluntary
unilateral finger movements. The rationale was that ipsilateral and contralateral
primary sensorimotor cortex can be involved in a nonstationary way in the control
of unilateral voluntary movements. The movement-related potentials were surface
Laplacian-transformed (SL) to reduce head volume conductor effects and to model
the response of the primary sensorimotor cortex. The ANN sampled the SL from four
or two central channels overlying the primary motor area of both sides in the
period of 80 ms preceding the electromyographic response onset in the active
muscle. The performance of the ANN was evaluated statistically by calculating the
percentage value of agreement between the STs classified by the ANN and those of
two investigators (used as a reference). The results showed that both
investigator and ANN were capable of selecting STs with the SL maximum in the
central area contralateral to the movement (contralateral STs, about 25%), STs
with considerable SL values also in the ipsilateral central area (bilateral STs,
about 50%), and STs with neither the contralateral nor bilateral pattern
("spatially incoherent" single trials; about 25%). The maximum agreement (64-84%)
between the ANN and the investigator was obtained when the ANN used four spatial
inputs (P < 0.0000001). Importantly, the common means of all single trials showed
a weak or absent ipsilateral response. These results may suggest that a back
propagation ANN could select EEG single trials showing stationary and
nonstationary responses of the primary sensorimotor cortex, based on the same
spatial criteria as the experimenter.
PMID- 10772785
TI - The use of the personalized estimate of death probabilities for medical decision
making.
AB - Data coming from the French national statistics on the cause of deaths are used
to calculate the probabilities of death from pathologies. These probabilities are
calculated according to age, sex, and place of residence of the patient to
"personalize" the estimate. This individual prediction of the risk of death is
proposed for pathologies for which the feasibility and the utility of prevention
measures had been demonstrated. Relative risks of death according to the
socioprofessional category, which are coming from the scientific literature, are
used to adjust the probabilities of death as a function of the patient
socioprofessional category. The aim of this work is to guide a scientist toward a
prevention strategy according to the age and characteristics of patient. The use
of computers by the scientists will make possible the diffusion of such tool of
prediction to improve a personalized prevention.
PMID- 10772786
TI - Sexual behavior, heterosexual transmission, and the spread of HIV in sub-Saharan
Africa: a simulation study.
AB - A stochastic simulation model has been used to assess the extent to which
variation in sexual behavior and transmission characteristics can explain the
striking spatial heterogeneity in the prevalence of HIV among different
geographical locations in sub-Saharan Africa. Of the various parameters
describing sexual behavior the most important determinant of the spread of HIV is
the proportion of men engaging in sexual relationships with people other than
spouses, including contacts with sex workers and short-term partners. Considering
factors other than sexual behavior the model shows that this heterogeneity in HIV
prevalence could be the result of differences in the transmission probability of
HIV or in the prevalence of other sexuality transmitted diseases. These factors
could play a key role in determining the patterns of spread of HIV in sub-Saharan
Africa and should be considered in the design of intervention strategies.
PMID- 10772787
TI - The control of cyclin B1 mRNA translation during mouse oocyte maturation.
AB - In maturing mouse oocytes, protein synthesis is required for meiotic maturation
subsequent to germinal vesicle breakdown (GVBD). While the number of different
proteins that must be synthesized for this progression to occur is unknown, at
least one of them appears to be cyclin B1, the regulatory subunit of M-phase
promoting factor. Here, we investigate the mechanism of cyclin B1 mRNA
translational control during mouse oocyte maturation. We show that the U-rich
cytoplasmic polyadenylation element (CPE), a cis element in the 3' UTR of cyclin
B1 mRNA, mediates translational repression in GV-stage oocytes. The CPE is also
necessary for cytoplasmic polyadenylation, which stimulates translation during
oocyte maturation. The injection of oocytes with a cyclin B1 antisense RNA, which
probably precludes the binding of a factor to the CPE, delays cytoplasmic
polyadenylation as well as the transition from GVBD to metaphase II. CPEB, which
interacts with the cyclin B1 CPE and is present throughout meiotic maturation,
becomes phosphorylated at metaphase I. These data indicate that CPEB is involved
in both the repression and the stimulation of cyclin B1 mRNA and suggest that the
phosphorylation of this protein could be involved in regulating its activity.
PMID- 10772788
TI - Altered retinoid signaling in the heads of small eye mouse embryos.
AB - The vitamin A derivative retinoic acid (RA) is necessary for eye development,
though its role in signaling within eye tissues is poorly understood. We
investigated this question in two transgenic mouse strains carrying a retinoic
acid response element (RARE) fused to beta-galactosidase that identify regions of
the embryo expressing activated retinoic acid receptors. Retinoid signaling
appears in the retina and lens ectoderm of wild-type embryos prior to neural tube
closure, when lens induction is under way. To determine if there are interactions
between retinoid signaling and the transcription factor Pax-6, also essential for
lens development, we examined RARE transgene expression in Small eye (Sey) mice,
which carry a Pax-6 mutation. Retinoid signaling in the eye, nose, and forebrain
of Sey embryos is decreased, with the most severe effects in the developing lens.
In Sey mice the lens anlage cannot respond to exogenous RA after E9, though it is
responsive earlier; the retina and other neural ectoderm can respond to RA at any
stage. In Sey mice the ability of presumptive lens and retina to produce and/or
sequester RA is also decreased, as assayed with a retinoid-reporter cell line.
These results implicate retinoid signaling in lens formation and show that RA
signaling in the developing eye is dependent upon Pax-6.
PMID- 10772789
TI - The L63 gene is necessary for the ecdysone-induced 63E late puff and encodes CDK
proteins required for Drosophila development.
AB - The pulse of ecdysone that triggers Drosophila metamorphosis activates six early
genes in a primary response made visible by polytene chromosome puffs. The
secondary response is detected by the induction of over 100 late puffs, only a
few of which have been subject to molecular genetic analysis. We present a
molecular and mutational analysis of the L63 gene responsible for the late puff
at 63E. This gene contains overlapping L63A, B, and C transcription units of
which the A unit encodes two isoforms and the B unit three. The C unit, which
exhibits little activity, encodes one of the B isoforms. Evidence that L63B, but
not L63A, transcription is ecdysone responsive derives from their developmental
transcription profiles and from P-element mutagenesis showing that ecdysone
induction of the 63E puff requires sequences adjacent to the 5' end of L63B but
not those adjacent to the 5' end of L63A. L63-specific lethal mutations showed
that L63 is required not only for metamorphosis, but also maternally and for
embryonic and larval development. The L63 proteins contain a common C-terminal
294-aa sequence that is 71% identical to the CDK sequence of the murine PFTAIRE
protein. In vivo tests of L63 proteins altered by site-directed mutagenesis
showed that they exhibit CDK functions. L63 proteins are widely distributed among
late larval and prepupal tissues and are unlikely to be involved in cell cycle
functions.
PMID- 10772790
TI - Exogenous FGF-4 can suppress anterior development in the mouse embryo during
neurulation and early organogenesis.
AB - Members of the fibroblast growth factor (FGF) family of peptide growth factors
are widely expressed in the germ layer derivatives during gastrulation and early
organogenesis of the mouse. We have investigated the effect of administering
recombinant FGF-4 in the late-primitive streak stage embryo to test if the
patterning of the body plan may be influenced by this growth factor. Shortly
after FGF treatment the embryonic tissues up-regulated the expression of
Brachyury and the RTK signaling regulator Spry2, suggesting that FGF signaling
was activated as an immediate response to exogenous FGF. Concomitantly, Hesx1
expression was suppressed in the prospective anterior region of the embryo. After
24 h of in vitro development, embryos displayed a dosage-related suppression of
forebrain morphogenesis, disruption of the midbrain-hindbrain partition, and
inhibition of the differentiation of the embryonic mesoderm. Overall, development
of the anterior-posterior axis in the late gastrula is sensitive to the delivery
of exogenous FGF-4. The early response associated with the expression of Spry2
suggests that the later phenotype observed could be primarily related to an
inhibition of the FGF signaling pathway.
PMID- 10772791
TI - Kruppel-homolog, a stage-specific modulator of the prepupal ecdysone response, is
essential for Drosophila metamorphosis.
AB - We have characterised a P-element-induced prepupal mutant of Drosophila
melanogaster which after an apparently normal embryonic and larval development
fails to complete head eversion, an essential step in metamorphosis. The P
element insertion disrupts an ecdysone-regulated transcript which, although
expressed during embryonic and larval stages, appears critical for preparing the
late prepupal response to ecdysone. By a combination of molecular and genetic
studies, in which we recovered new alleles, we show that the locus is complex,
containing at least two distinct promoters. Its transcripts contain a short
region described previously by R. Schuh et al. (1986, Cell 47, 1025-1032), who
screened for homologues of the Kruppel gene. Our studies on the corresponding
gene, named Kruppel-homolog (Kr-h), add to a growing body of evidence that
specific isoforms of a number of key genes are implicated in both embryogenesis
and metamorphosis.
PMID- 10772792
TI - Evolution of vulva development in the Cephalobina (Nematoda).
AB - Ventral cord and vulva development are analyzed in a large sample of nematode
species of the suborder Cephalobina. We find a specific range of evolutionary
variations at distinct developmental steps. (1) Unlike Caenorhabditis elegans and
relatives, the vulva is formed from the four precursor cells P(5-8).p or,
exceptionally, from P(6, 7).p only. (2) The vulval competence group is restricted
to these four cells or is larger. (3) The fates of more anterior and posterior
Pn.p cells vary between closely related species (mostly cell death versus
epidermal fate). (4) The mechanism of vulval cell fate patterning varies within a
single genus, even between strains of the same species. (5) We describe the first
example of a vulval cell lineage that is asymmetric between the anterior and the
posterior sides of the vulva. For a selection of the investigated taxa,
phylogenetic trees were constructed in order to map vulval characters and infer
evolutionary polarities. We can conclude that in this group, death of the Pn.p
cells probably constitutes a derived character state compared to a syncytial
fate. Rhabditophanes sp. and Strongyloides ratti are placed as sister taxa,
probably sharing an exclusive common ancestor in which the number of precursor
cells forming the vulva was reduced from four to two.
PMID- 10772793
TI - A sequence-specific RNA binding complex expressed in murine germ cells contains
MSY2 and MSY4.
AB - The protamine mRNAs are stored for up to 8 days as translationally repressed
ribonucleoprotein particles during murine spermatogenesis. Translational
repression of the protamine 1, Prm1, mRNA is controlled by sequences in its 3'
untranslated region (UTR). In this study we used the yeast three-hybrid system to
clone Msy4, which encodes a novel member of the Y box family of nucleic acid
binding proteins. MSY4 specifically binds to a site within the 5' most 37
nucleotides in the Prm1 3' UTR. Msy4 is highly expressed in the testis, and the
protein is detected in the cytoplasm of germ cells in both the testis and the
ovary, where repressed messages are stored. Analysis of a previously described
48/50-kDa binding activity in testis extracts by electrophoretic mobility shift
assays and immunoprecipitation indicates the activity is composed of MSY4 and
MSY2, another mouse Y box protein. Polysome analysis demonstrates MSY4 is
associated with mRNPs, consistent with MSY4 having a role in storing repressed
messages.
PMID- 10772794
TI - Role of cAMP-dependent protein kinase during growth and early development of
Dictyostelium discoideum.
AB - cAMP-dependent protein kinase (PKA) is an essential regulator of gene expression
and cell differentiation during multicellular development of Dictyostelium
discoideum. Here we show that PKA activity also regulates gene expression during
the growth phase and at the transition from growth to development. Overexpression
of PKA leads to overexpression of the discoidinIgamma promoter, while expression
of the discoidinIgamma promoter is reduced when PKA activity is reduced, either
by expression of a dominant negative mutant of the regulatory subunit or by
disruption of the gene for the catalytic subunit (PKA-C). The discoidin phenotype
of PKA-C null cells is cell autonomous. In particular, normal secretion of
discoidin-inducing factors was demonstrated. In addition, PKA-C null cells are
able to respond to media conditioned by PSF and CMF. We conclude that PKA is a
major activator of discoidin expression. However, it is not required for
production or transduction of the inducing extracellular signals. Therefore, PKA
dependent and PKA-independent pathways regulate the expression of the discoidin
genes.
PMID- 10772795
TI - Neural cell adhesion molecule (NCAM) and myoblast fusion.
AB - Considerable evidence points to an involvement of neural cell adhesion molecule
(NCAM) in myoblast fusion. Changes in the level of NCAM expression, isoform
specificity, and localization in muscle cells and tissues correspond to key
morphogenetic events during muscle differentiation and repair. Furthermore, anti
NCAM antibodies have been shown by others to reduce the rate of myoblast fusion,
whereas overexpression of NCAM cDNAs increases the rate of myoblast fusion
compared to controls. In this study we have used a novel fusion assay based on
intracistronic complementation of lacZ, in combination with fluorescent X-gal
histochemistry and immunocytochemistry to assess levels of NCAM expression in
individual muscle cells. Our results indicate that a substantial proportion of
newly fused myoblasts have NCAM expression levels unchanged from the levels of
the surrounding unfused population suggesting that increased expression of NCAM
is not required for wild-type myoblasts to fuse. Moreover, pure populations of
primary myoblasts isolated from mice homozygous null for NCAM and therefore
lacking the molecule, when placed in differentiation medium, consistently fused
to form contractile myotubes with kinetics equivalent to wild-type primary
myoblasts. We conclude that the increase in expression of NCAM, although
typically observed during myogenesis, is not essential to myoblast fusion to form
myotubes.
PMID- 10772796
TI - cato encodes a basic helix-loop-helix transcription factor implicated in the
correct differentiation of Drosophila sense organs.
AB - In Drosophila neurogenesis, proneural genes encode bHLH proteins that are
required for neural precursor selection. But many vertebrate homologues are
expressed later and are postulated to have multiple roles during neurogenesis. We
have isolated a new Drosophila gene, cato, which encodes a protein with a bHLH
domain that is closely related to that of the proneural protein Atonal. cato
expression is restricted to the developing PNS, where it is expressed in between
the stages of precursor selection and terminal differentiation (and therefore
later than the proneural genes). We present evidence from loss-of-function and
misexpression experiments that cato is involved in sensory neurone morphology.
Moreover, in prospero mutants, in which axon and dendrite outgrowth is defective,
cato is strongly derepressed in the developing CNS.
PMID- 10772797
TI - Axon guidance in the mouse optic chiasm: retinal neurite inhibition by ephrin "A"
expressing hypothalamic cells in vitro.
AB - In the mammalian visual system, retinal axons undergo temporal and spatial
rearrangements as they project bilaterally to targets on the brain. Retinal axons
cross the neuraxis to form the optic chiasm on the hypothalamus in a position
defined by overlapping domains of regulatory gene expression. However, the
downstream molecules that direct these processes remain largely unknown. Here we
use a novel in vitro paradigm to study possible roles of the Eph family of
receptor tyrosine kinases in chiasm formation. In vivo, Eph receptors and their
ligands distribute in complex patterns in the retina and hypothalamus. In vitro,
retinal axons are inhibited by reaggregates of isolated hypothalamic, but not
dorsal diencephalic or cerebellar cells. Furthermore, temporal retinal neurites
are more inhibited than nasal neurites by hypothalamic cells. Addition of soluble
EphA5-Fc to block Eph "A" subclass interactions decreases both the inhibition and
the differential response of retinal neurites by hypothalamic reaggregates. These
data show that isolated hypothalamic cells elicit specific, position-dependent
inhibitory responses from retinal neurites in culture. Moreover, these responses
are mediated, in part, by Eph interactions. Together with the in vivo
distributions, these data suggest possible roles for Eph family members in
directing retinal axon growth and/or reorganization during optic chiasm
formation.
PMID- 10772798
TI - Genetic analysis of bristle loss in hybrids between Drosophila melanogaster and
D. simulans provides evidence for divergence of cis-regulatory sequences in the
achaete-scute gene complex.
AB - The two closely related species of Drosophila, D. melanogaster and D. simulans,
display an identical bristle pattern on the notum, but hybrids between the two
are lacking a variable number of bristles. We show that the loss is temperature
dependent and provide evidence for two periods of temperature sensitivity. A
first period of heat sensitivity occurs during larval development and corresponds
to the time when the prepattern of expression of genes whose products activate
achaete-scute in the proneural clusters preceding bristle precursor formation is
established. A second period of cold sensitivity corresponds to the time of
emergence of the bristle precursor cells and the maintenance of their neural
fate, a process requiring high levels of Achaete-Scute. Expression of achaete
scute at these two critical periods depends on cis-regulatory elements of the
achaete-scute complex (AS-C). The differences between males, which have only one
copy of the X-linked AS-C from D. simulans, and females, which have copies from
both parental species, are compared, together with the effects of crossing in
different rearrangements of the D. melanogaster AS-C that delete regulatory
and/or coding sequences. We provide evidence that bristle loss in the hybrids may
result from a decrease in the level of transcription at the AS-C and argue that
interaction between trans-acting factors and cis-regulatory elements within the
AS-C has diverged between the two species.
PMID- 10772799
TI - Antagonizing activity of chick Grg4 against tectum-organizing activity.
AB - Alar plate of chick mesencephalon differentiates into the optic tectum. It has
been shown that factors expressed in the mes-metencephalic boundary induce the
tectum and give positional specificity. Chick Grg4 is expressed at first in the
anterior neural fold. The expression localizes from the posterior diencephalon to
the mesencephalon by stage 10. To investigate the function of Grg4 in
mesencephalic development, Grg4 overexpression was carried out by in ovo
electroporation. After Grg4 overexpression, expression of En-2, Pax5, Fgf8, and
EphrinA2 was repressed, and Pax6 was upregulated in the mesencephalic region.
Grg4 overexpression caused the morphological change; mesencephalic swelling
became smaller and the di-mesencephalic boundary shifted posteriorly, that is,
the anterior limit of tectum shifted posteriorly. Importantly, cotransfection of
Grg4 with Pax5 canceled the tectum-inducing activity of Pax5. These results
suggest that Grg4 works as an antagonist against tectum-organizing activity. It
was also shown that transfected N-terminal domains of Grg4 induced En-2
expression. Since N-terminal domains were transported to the nucleus in the
neuroepithelium, they could act as dominant negative for endogenous Grg4. These
results indicate that Grg4 has repressing activity against the organizing
molecules and suggest that Grg4 plays important roles in formation of anterior
tectal boundary and polarity.
PMID- 10772800
TI - Functional analysis of Cdc42 in actin filament assembly, epithelial
morphogenesis, and cell signaling during Drosophila development.
AB - Cdc42, a member of the Rho family of GTP binding proteins, functions in the
formation of polarized actin structures, in elongation of cell shape, and in cell
signaling. Although genetic mutations previously have not been available in
multicellular organisms, studies have attempted to discern Cdc42 functions in
organisms, including Drosophila, using dominant active or interfering alleles.
Here, for the first time, we examine the functions of Cdc42 in developing tissues
using loss-of-function mutations in the Drosophila Cdc42 gene. We find that
Cdc42(-) epithelial cells fail to elongate into a columnar cell shape and cannot
maintain a monolayered epithelial structure. In contrast to previous studies, we
find no requirement for Cdc42 in cell division or in activation of the Jun N
terminal kinase pathway. In addition, Cdc42 function is not required for
cytoplasmic actin filament assembly in the nurse cells during oogenesis, although
it may facilitate this process. Furthermore, our results indicate that Cdc42
plays a role in intercellular interactions between the germ line and the somatic
follicle cells. These results confirm the role of Cdc42 in actin filament
assembly and provide new insights into its functions in epithelial morphogenesis
and regulating intercellular signaling events.
PMID- 10772801
TI - Snail-related transcriptional repressors are required in Xenopus for both the
induction of the neural crest and its subsequent migration.
AB - The neural crest is a transient population of precursor cells that arises at the
border between the neural plate and prospective epidermis in vertebrate embryos.
The earliest known response to neural-crest-inducing signals is the expression of
the zinc-finger transcription factors slug and snail. Although it is widely
believed that these transcription factors play an essential role in neural crest
development, relatively little is understood about their mechanism of action
during this process. We have previously shown that overexpression of XSlug leads
to expanded expression of neural crest markers and an excess of at least one
neural crest derivative, melanocytes. In order to further investigate XSlug
function, we overexpressed mutant constructs in which the DNA-binding domain was
fused to either the activation domain from Gal4 or the repressor domain from
Drosophila Engrailed. The Engrailed repressor fusion was found to mimic the
effects of wild-type XSlug, indicating that XSlug functions as a transcriptional
repressor during neural crest formation. In contrast, overexpression of either
the activation domain fusion or the DNA-binding domain alone was found to inhibit
XSlug function. Using a hormone-inducible inhibitory mutant, we show that
inhibition of XSlug function at early stages prevents the formation of neural
crest precursors, while inhibition at later stages interferes with neural crest
migration, demonstrating for the first time that this transcriptional repressor
is required during multiple stages of neural crest development.
PMID- 10772802
TI - Chondroitin sulfates affect the formation of the segmental motor nerves in
zebrafish embryos.
AB - Chondroitin sulfates have been implicated in the promotion and in the inhibition
of axon growth. In the zebrafish embryo, chondroitin sulfates are present at the
interface of the somites and the notochord where spinal motor axons extend
ventrally to establish the midsegmental ventral motor nerves. Injection of
chondroitinase ABC prior to motor axon outgrowth effectively removed all
chondroitin sulfate immunoreactivity and induced abnormal axonal outgrowth in
many (39%) of the ventral motor nerves. The most common abnormality was the
formation of side branches, approximately half of which extended posteriorly, the
others anteriorly. The effect was specific to the removal of chondroitin
sulfates, since injections of vehicle solution or of heparinase III did not
affect the ventral motor nerves. Electron microscopic examination demonstrated
that the injections caused no damage to spinal cord, somite, and notochord. This
suggests that chondroitin sulfates normally constrain the outgrowth of the
ventral motor nerves. Consistent with this hypothesis, injections of soluble
chondroitin sulfates, either as a mixture or individually, led to truncated or
missing ventral motor nerves. Truncations were most frequent after injection of
chondroitin sulfate-B (up to 23%) while chondroitin sulfate-A had a lesser, and
chondroitin sulfate-C no apparent, effect.
PMID- 10772803
TI - Expression and regulation of type I BMP receptors during early avian sympathetic
ganglion development.
AB - We have investigated the expression and regulation of the mRNAs for the type I
BMP receptors, BMPR-IA and BMPR-IB, in quail embryos in vivo and in neural crest
cultures in vitro. BMPR-IB mRNA was expressed in the primordial sympathetic
ganglia at stage 17, soon after the first expression of Cash-1 mRNA, the avian
homolog of the Drosophila transcription factor achaete-scute. BMP-4 mRNA was
detected in the dorsal aorta at stage 17, coincident with BMPR-IB mRNA expression
in the sympathetic ganglia. BMPR-IA mRNA was first expressed in the sympathetic
ganglia at stage 18. Moreover, BMP-4 ligand mRNA was detected in the sympathetic
ganglia starting at stage 18. BMPR-IA and BMPR-IB were differentially regulated
in cultured neural crest cells. BMPR-IB was expressed in primary outgrowths of
neural crest cells but was downregulated after primary outgrowths were harvested
and replated in secondary cultures. In secondary cultures of neural crest cells,
exogenous BMP-2 and BMP-4 increased the expression of BMPR-IA but decreased the
expression of BMPR-IB. The expression of both type I BMP receptors was inhibited
by exogenous TGF-beta1. Our results suggest distinct roles for BMPR-IA and BMPR
IB in the development of the sympathoadrenal phenotype from cells of the neural
crest.
PMID- 10772804
TI - Ring formation drives invagination of the vulva in Caenorhabditis elegans: Ras,
cell fusion, and cell migration determine structural fates.
AB - Directed cell rearrangements occur during gastrulation, neurulation, and organ
formation. Despite the identification of developmental processes in which
invagination is a critical component of pattern formation, little is known
regarding the underlying cellular and molecular details. Caenorhabditis elegans
vulval epithelial cells undergo morphological changes that generate an
invagination through the formation of seven stacked rings. Here, we study the
dynamics of ring formation during multivulva morphogenesis of a let-60/ras gain
of-function mutant as a model system to explore the cellular mechanisms that
drive invagination. The behavior of individual cells was analyzed in a let-60/ras
mutant by three-dimensional confocal microscopy. We showed that stereotyped cell
fusion events occur within the rings that form functional and nonfunctional
vulvae in a let-60/ras mutant. Expression of let-60/ras gain-of-function results
in abnormal cell migration, ectopic cell fusion, and structural fate
transformation. Within each developing vulva the anterior and posterior halves
develop autonomously. Contrary to prevailing hypotheses which proposed three cell
fates (1 degrees, 2 degrees, and 3 degrees), we found that each of the seven
rings is a product of a discrete structural pathway that is derived from arrays
of seven distinct cell fates (A, B, C, D, E, F, and H). We have also shown how
autonomous ring formation is the morphogenetic force that drives invagination of
the vulva.
PMID- 10772805
TI - BMP type II receptor is required for gastrulation and early development of mouse
embryos.
AB - Bone morphogenetic proteins (BMPs), members of the transforming growth factor
beta superfamily, play a variety of roles during mouse development. BMP type II
receptor (BMPR-II) is a type II serine/threonine kinase receptor, which
transduces signals for BMPs through heteromeric complexes with type I receptors,
including activin receptor-like kinase 2 (ALK2), ALK3/BMPR-IA, and ALK6/BMPR-IB.
To elucidate the function of BMPR-II in mammalian development, we generated BMPR
II mutant mice by gene targeting. Homozygous mutant embryos were arrested at the
egg cylinder stage and could not be recovered at 9.5 days postcoitum.
Histological analysis revealed that homozygous mutant embryos failed to form
organized structure and lacked mesoderm. The BMPR-II mutant embryos are
morphologically very similar to the ALK3/BMPR-IA mutant embryos, suggesting that
BMPR-II is important for transducing BMP signals during early mouse development.
Moreover, the epiblast of the BMPR-II mutant embryo exhibited an undifferentiated
character, although the expression of tissue-specific genes for the visceral
endoderm was essentially normal. Our results suggest that the function of BMPR-II
is essential for epiblast differentiation and mesoderm induction during early
mouse development.
PMID- 10772806
TI - nhr-25, the Caenorhabditis elegans ortholog of ftz-f1, is required for epidermal
and somatic gonad development.
AB - We have analyzed the expression and function of the Caenorhabditis elegans gene
nhr-25, a member of the widely conserved FTZ-F1 family of nuclear receptors. The
gene encodes two protein isoforms, only one of which has a DNA binding domain.
nhr-25 is transcribed during embryonic and larval development. A nhr-25::GFP
fusion gene is expressed in the epidermis, the developing somatic gonad, and a
subset of other epithelial cells. RNA-mediated interference indicates a
requirement for nhr-25 function during development: disruption of nhr-25 function
leads to embryonic arrest due to failure of the epidermally mediated process of
embryo elongation. Animals that survive to hatching arrest as misshapen larvae
that occasionally exhibit defects in shedding molted cuticle. In addition,
somatic gonad development is defective in these larvae. These results further
establish the importance of FTZ-F1 nuclear receptors in molting and developmental
control across evolutionarily distant phyla.
PMID- 10772807
TI - Hyperoxia induces S-phase cell-cycle arrest and p21(Cip1/Waf1)-independent Cdk2
inhibition in human carcinoma T47D-H3 cells.
AB - Little is known about cell-cycle checkpoint activation by oxidative stress in
mammalian cells. The effects of hyperoxia on cell-cycle progression were
investigated in asynchronous human T47D-H3 cells, which contain mutated p53 and
fail to arrest at G1/S in response to DNA damage. Hyperoxic exposure (95% O(2),
40-64 h) induced an S-phase arrest associated with acute inhibition of Cdk2
activity and DNA synthesis. In contrast, exit from G2/M was not inhibited in
these cells. After 40 h of hyperoxia, these effects were partially reversible
during recovery under normoxic conditions. The inhibition of Cdk2 activity was
not due to degradation of Cdk2, cyclin E or A, nor impairment of Cdk2 complex
formation with cyclin A or E and p21(Cip1). The loss of Cdk2 activity occurred in
the absence of induction and recruitment of cdk inhibitor p21(Cip1) or p27(Kip1)
in cyclin A/Cdk2 or cyclin E/Cdk2 complexes. In contrast, Cdk2 inhibition was
associated with increased Cdk2-Tyr15 phosphorylation, increased E2F-1
recruitment, and decreased PCNA contents in Cdk2 complexes. The latter results
indicate a p21(Cip1)/p27(Kip1)-independent mechanism of S-phase checkpoint
activation in the hyperoxic T47D cell model investigated.
PMID- 10772808
TI - Elevation in phosphatidylethanolamine is an early but not essential event for
cardiac cell differentiation.
AB - The biosynthesis of phosphatidylethanolamine was examined during differentiation
of P19 teratocarcinoma cells into cardiac myocytes. P19 cells were induced to
undergo differentiation into cardiac myocytes by the addition of dimethyl
sulfoxide to the medium. Immunofluorescence labeling confirmed the expression of
striated myosin 10 days postinduction of differentiation. The content of
phosphatidylethanolamine increased significantly within the first 2 days of
differentiation. [1,3-(3)H]Glycerol incorporation into phosphatidylethanolamine
was increased 7.2-fold during differentiation, indicating an elevation in de novo
synthesis from 1, 2-diacyl-sn-glycerol. The mechanism for the increase in
phosphatidylethanolamine levels during cardiac cell differentiation was a 2.8
fold increase in the activity of ethanolaminephosphotransferase, the 1,2-diacyl
sn-glycerol utilizing reaction of the cytidine 5'-diphosphate-ethanolamine
pathway of phosphatidylethanolamine biosynthesis. Incubation of P19 cells with
the phosphatidylethanolamine biosynthesis inhibitor 8-(4-chlorophenylthio)-cAMP
inhibited the differentiation-induced elevation in phosphatidylethanolamine
levels but did not affect the expression of striated myosin. The results suggest
that elevation in phosphatidylethanolamine is an early event of P19 cell
differentiation into cardiac myocytes, but is not essential for differentiation
to proceed.
PMID- 10772809
TI - The relationship between SMN, the spinal muscular atrophy protein, and nuclear
coiled bodies in differentiated tissues and cultured cells.
AB - The spinal muscular atrophy protein, SMN, is a cytoplasmic protein that is also
found in distinct nuclear structures called "gems." Gems are closely associated
with nuclear coiled bodies and both may have a direct role in snRNP maturation
and pre-RNA splicing. There has been some controversy over whether gems and
coiled bodies colocalize or form adjacent/independent structures in HeLa and
other cultured cells. Using a new panel of antibodies against SMN and antibodies
against coilin-p80, a systematic and quantitative study of adult differentiated
tissues has shown that gems always colocalize with coiled bodies. In some
tissues, a small proportion of coiled bodies (<10%) had no SMN, but independent
or adjacent gems were not found. The most striking observation, however, was that
many cell types appear to have neither gems nor coiled bodies (e.g., cardiac and
smooth muscle, blood vessels, stomach, and spleen) and this expression pattern is
conserved across human, rabbit, and pig species. This shows that assembly of
distinct nuclear bodies is not essential for RNA splicing and supports the view
that they may be storage sites for reserves of essential proteins and snRNPs.
Overexpression of SMN in COS-7 cells produced supernumerary nuclear bodies, most
of which also contained coilin-p80, confirming the close relationship between
gems and coiled bodies. However, when SMN is reduced to very low levels in type I
SMA fibroblasts, coiled bodies are still formed. Overall, the data suggest that
gem/coiled body formation is not determined by high cytoplasmic SMN
concentrations or high metabolic activity alone and that a differentiation
specific factor may control their formation.
PMID- 10772810
TI - Cleavage of Bax enhances its cell death function.
AB - Members of the Bcl-2 family of proteins are key regulators of apoptosis. Some of
these proteins undergo posttranslational modification, such as phosphorylation or
proteolysis, that serves to alter their function. Caspases are known to cleave
Bid, a proapoptotic family member, as well as Bcl-2 and Bcl-X(L), two prosurvival
family members, which activate their cytotoxic activity resulting in the release
of cytochrome c from mitochondria. Previously we showed that Bax was cleaved by
calpain rather than by caspases from full-length 21 kDa to generate a cleavage
fragment of 18 kDa. Since cleavage of Bid serves to activate its cytotoxic
activity, we wanted to determine if the p18 form of Bax exhibited increased
cytotoxicity compared to p21 Bax. Using a transient transfection system in human
embryonic kidney 293T cells we show that the p18 form of Bax displays a more
potent ability to induce cell death. The pancaspase inhibitor Z-VAD-fmk
completely blocked apoptosis induced by p21 Bax but only partially inhibited
apoptosis induced by p18 Bax. Cyclosporin A, an inhibitor of the mitochondrial
permeability transition (PT) pore, had no effect on Bax-mediated apoptosis of
293T cells suggesting that apoptosis was independent of the PT. Thus cleavage of
p21 Bax during apoptosis to the p18 form may serve to increase the intrinsic
cytotoxic properties of this proapoptotic molecule and enhance its cell death
function at the mitochondria.
PMID- 10772811
TI - Mechanoregulation of chondrocyte proliferation, maturation, and hypertrophy: ion
channel dependent transduction of matrix deformation signals.
AB - Mechanical stress-induced matrix deformation plays a fundamental role in
regulating cellular activities; however, little is known about its underlying
mechanisms. To understand the effects of matrix deformation on chondrocytes, we
characterized primary chondrocytes cultured on three-dimensional collagen
scaffoldings, which can be loaded mechanically with a computer-controlled "Bio
Stretch" device. Cyclic matrix deformation greatly stimulated proliferation of
immature chondrocytes, but not that of hypertrophic chondrocytes. This indicates
that mechanical stimulation of chondrocyte proliferation is developmental stage
specific. Synthesis of cartilage matrix protein (CMP/matrilin-1), a mature
chondrocyte marker, and type X collagen, a hypertrophic chondrocyte marker, was
up-regulated by stretch-induced matrix deformation. Therefore, genes of CMP and
type X collagen are responsive to mechanical stress. Mechanical stimulation of
the mRNA levels of CMP and type X collagen occurred exactly at the same time
points when these markers were synthesized by nonloading cells. This indicates
that cyclic matrix deformation does not alter the speed of differentiation, but
affects the extent of differentiation. The addition of the stretch-activated
channel blocker gadolinium during loading abolished mechanical stimulation of
chondrocyte proliferation, but did not affect the up-regulation of CMP mRNA by
mechanical stretch. In contrast, the calcium channel blocker nifedipine inhibited
both the stretch-induced proliferation and the increase of CMP mRNA. This
suggests that stretch-induced matrix deformation regulates chondrocyte
proliferation and differentiation via two signal transduction pathways, with
stretch-activated channels involved in transducing the proliferative signals and
calcium channels involved in transducing the signals for both proliferation and
differentiation.
PMID- 10772812
TI - Tetracycline-regulated gene expression switch in Xenopus laevis.
AB - Xenopus is a well-characterized model system for the investigation of biological
processes at the molecular, cellular, and developmental level. The successful
application of a rapid and reliable method for transgenic approaches in Xenopus
has led to renewed interest in this system. We have explored the applicability of
tetracycline-regulated gene expression, first described by Gossen and Bujard in
1992, to the Xenopus system. By optimizing conditions, tetracycline repressor
induced expression of a luciferase reporter gene was readily and reproducibly
achieved in both the Xenopus oocyte and developing embryo. This high level of
expression was effectively abrogated by addition of low levels of tetracycline.
The significance of this newly defined system for studies of chromatin dynamics
and developmental processes is discussed.
PMID- 10772813
TI - Immunolocalization of human p14(ARF) to the granular component of the interphase
nucleolus.
AB - The human p14(ARF) protein is encoded by an alternative transcript from the
INK4a/ARF locus on chromosome 9p21, a locus frequently afflicted in human tumors.
By use of two novel specific antisera against p14(ARF) we show that the protein
is localized mainly in nucleoli but also in the nucleoplasm. Transfection of full
length and deletion mutant GFP-p14(ARF) fusion proteins confirmed this
subcellular localization and assigned the nucleolar localization signal to the
exon 2-encoded C-terminal region. In order to determine p14(ARF) expression in
human tumor cells, we examined p14(ARF) in 32 tumor cell lines by
immunofluorescence staining. Nucleolar p14(ARF) was detected in 10 lines, all of
which lacked functional p53. Double immunostaining with p14(ARF) and
B23/nucleophosmin or fibrillarin antibodies using 3D microscopy revealed that
p14(ARF) is located mainly in the granular component of the nucleolus. p14(ARF)
was also found in distinct granular aggregates scattered throughout the
nucleoplasm. RNase digestion or selective inhibition of rRNA transcription by low
doses of actinomycin D caused nucleoplasmic translocation of p14(ARF). This
indicates that the nucleolar localization of p14(ARF) is dependent on ongoing
transcriptional activity in intact functional nucleoli.
PMID- 10772814
TI - Requirement of regulated activation of Ras for response of MDCK cells to
hepatocyte growth factor/scatter factor.
AB - Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering,
migration, and branching tubule formation of MDCK cells. To examine the role of
the Ras protein in the HGF/SF-induced responses, we constructed MDCK cell clones
expressing either inducible dominant-negative Ras or constitutively activated Ras
and analyzed their effects on responses of cells to HGF/SF. Induced expression of
dominant-negative Ras prevented cell dissociation required for cell scattering,
migration, and cystic formation as well as branching morphology required for
branching tubule formation. Constitutively activated Ras induced cell
dissociation, but not a scattered fibroblastic morphology even in the presence of
HGF/SF. MDCK cells expressing constitutively activated Ras migrated at a level
similar to that of wild-type MDCK cells stimulated by HGF/SF. MDCK cells
expressing constitutively activated Ras showed disorganized growth in three
dimensional culture and did not form the branching tubule structures. These
results indicate that activation of the Ras protein is essential for the cell
scattering, migration, and branching tubule formation of MDCK cells induced by
HGF/SF, and a properly regulated activation is required for some stages of the
HGF/SF-induced responses of MDCK cells.
PMID- 10772815
TI - Adenovirus-mediated transfer of caspase-3 with Fas ligand induces drastic
apoptosis in U-373MG glioma cells.
AB - Impaired function of apoptosis-related genes is deeply involved in oncogenesis
and the progression of cancers, and caspase-3 plays a critical role as an
executioner of apoptosis. We introduced the caspase-3 gene via an adenovirus
(Adv) vector into Alexander hepatoma cells, MCF-7 breast cancer cells, and U251
and U-373MG glioma cells which have different endogenous levels of caspase-3
expression. None of the cell lines underwent apoptosis by overexpression of
caspase-3, indicating that induction of caspase-3 alone is not applicable for
cancer gene therapy. Next, we investigated whether overexpression of caspase-3
could enhance Fas ligand-mediated apoptosis in these four cell lines. In U-373MG
cells, which showed the highest level of expression of surface Fas among the four
cell lines, coinfection of the Adv for caspase-3 (Adv-caspase-3) and the Adv for
Fas ligand (Adv-FL) induced a remarkably increased degree of apoptosis compared
with that induced by the single infection of either Adv-caspase-3 or Adv-FL.
Similar results were obtained by cotreatment with anti-Fas antibody in U-373MG
cells. These data suggest that when strong proapoptotic upstream stimuli are
induced, the level of caspase-3 expression determines the degree of apoptosis in
cancer cell lines. In conclusion, overexpression of caspase-3 alone did not
induce apoptosis in cancer cells. Both a strong proapoptotic signal and a high
expression of caspase-3 were required to induce drastic apoptosis in cancers.
This strategy would be highly beneficial for selected cancer patients.
PMID- 10772816
TI - Participation of syndecan 2 in the induction of stress fiber formation in
cooperation with integrin alpha5beta1: structural characteristics of heparan
sulfate chains with avidity to COOH-terminal heparin-binding domain of
fibronectin.
AB - The present study provides direct evidence that syndecan 2 participates
selectively in the induction of stress fiber formation in cooperation with
integrin alpha5beta1 through specific binding of its heparan sulfate side chains
to the fibronectin substrate. Our previous study with Lewis lung carcinoma
derived P29 cells demonstrated that the cell surface heparan sulfate
proteoglycan, which binds to fibronectin, is syndecan 2 (N. Itano et al., 1996,
Biochem. J. 315, 925-930). We here report that in vitro treatment of the cells by
antisense oligonucleotide for syndecan 2 resulted in a failure to form stress
fibers on fibronectin substrate in association with specific suppression of its
cell surface expression. Instead, localization of actin filaments in the
cytoplasmic cortex occurred. A similar response of the cells was observed when
the cells were treated to eliminate functions of cell surface heparan sulfates,
including exogenous addition of heparin and pretreatment with anti-heparan
sulfate antibody, F58-10E4, and with proteinase-free heparitinase I. Size- and
structure-defined oligosaccharides prepared from heparin and chemically modified
heparins were utilized as competitive inhibitors to examine the structural
characteristics of the cell surface heparan sulfates involved in organization of
the actin cytoskeleton. Their affinity chromatography on a column linked with a
recombinant H-271 peptide containing a C-terminal heparin-binding domain of
fibronectin demonstrated that 2-O-sulfated iduronates were essential for the
binding. Inhibition studies revealed that a heparin-derived dodecasaccharide
sample enriched with an IdoA(2OS)-GlcNS(6OS) disaccharide completely blocked
binding of the syndecan 2 ectodomain to immobilized H-271 peptide. Finally, the
dodecasaccharide sample was shown to inhibit stress fiber formation, triggered by
adhesion of P29 cells to a CH-271 polypeptide consisting of both the RGD cell
binding and the C-terminal heparin-binding domains of fibronectin in a fused
form. All these results consistently suggest that syndecan 2 proteoglycan
interacts with the C-terminal heparin-binding domain of fibronectin at the highly
sulfated cluster(s), such as [IdoA(2OS)-GlcNS(6OS)](6) present in its heparan
sulfate chains, to result in the induction of stress fiber formation in
cooperation with integrin alpha5beta1.
PMID- 10772817
TI - Adhesion of lymphoid cells to CD44-specific substrata: the consequences of
attachment depend on the ligand.
AB - Interactions between cell-surface adhesion receptors and immobilized specific
substrata can exert profound effects on cell morphology. Using phase-contrast
microscopy, we show that CD44-expressing mouse lymphoid cells display a spread
morphology when adhering to CD44-specific monoclonal antibody (mAb) immobilized
on plastic. This spread morphology is different from that of these same cells
when adhering to immobilized hyaluronan, the natural ligand of CD44. Morphometric
measurements, in combination with intracellular actin staining and fluorescence
microscopy, revealed that the adhesion of lymphoid cells to hyaluronan required
essentially no cytoskeletal reorganization and resulted in no fundamental change
in morphology. On the other hand, cells adhering to immobilized CD44-specific mAb
rearranged their actin structure and established multiple membrane contact sites
(spread). Cell spreading on antibody, but not attachment to hyaluronan, was
inhibited by cytoskeleton-disrupting agents. Transfection of CD44-negative
lymphoid cells with full-length and tailless CD44 enabled these cells to bind to
both immobilized hyaluronan and mAb. However, the transfectant lacking the
cytoplasmic tail of CD44 spread only transiently on the antibody-coated surface.
Our results suggest that CD44 may mediate lymphocyte attachment to its
carbohydrate ligand hyaluronan by mechanisms broadly similar to those used by
selectins. When immobilized CD44-specific antibody is the ligand, however, CD44
may regulate the activity of the cytoskeleton by mechanisms broadly similar to
those used by integrins. In the latter case, the cytoplasmic domain of CD44
contributes to cell spreading.
PMID- 10772818
TI - Activation and protein kinase C-dependent nuclear accumulation of ERK in
differentiating human neuroblastoma cells.
AB - The human neuroblastoma cell line SH-SY5Y is a well characterized model for
sympathetic neuronal differentiation in vitro. Several differentiation protocols
exist, one of which, the addition of the phorbol ester 12-O-tetradecanoylphorbol
13-acetate (TPA) in the presence of serum, has been thoroughly studied. Wild-type
SH-SY5Y cells are unresponsive to nerve growth factor (NGF), but cells
transfected with the high-affinity NGF receptor TrkA (SH-SY5Y/TrkA) differentiate
in response to NGF. In the present study, we have addressed the existence of a
differentiation-specific mode of activation and subcellular distribution of the
extracellular signal-regulated kinases ERK1 and ERK2 in SH-SY5Y/wt and SH
SY5Y/TrkA. Both TPA and NGF induced a sustained activation and nuclear
accumulation of ERK that was accompanied by transactivation of a serum response
element (SRE)-driven reporter and of the c-fos gene. However, activation and
nuclear accumulation of ERK were not sufficient to induce neuronal
differentiation in SH-SY5Y, as demonstrated by the response to TPA in serum-free
cultures. Nuclear accumulation but not activation of ERK was demonstrated to
require active protein kinase C (PKC). The effect of specific PKC inhibitors on
subcellular distribution of ERK and ERK-dependent transcription suggests a
functional role for PKC in the regulation of nuclear ERK activity in SH-SY5Y
neuroblastoma cells.
PMID- 10772819
TI - Selective accumulation of the endoplasmic reticulum-Golgi intermediate
compartment induced by the antitumor drug KRN5500.
AB - KRN5500 is a semisynthetic spicamycin analogue consisting of a seven-carbon amino
sugar linked to a C(14) unsaturated fatty acid through glycine and to the amino
group of adenine. The drug inhibits cell growth potently and has antitumor
activity in in vivo models. The mechanism of the antiproliferative effect of
KRN5500 remains to be elucidated. We have found that acute exposure of drug
sensitive HT-29 colon adenocarcinoma cells to the drug results initially in
swelling of the Golgi apparatus. Continuous exposure to the drug resulted in the
emergence of a resistant population of cells characterized by numerous
intracellular vacuoles. These KRN5500-resistant tumor cells exhibited increased
staining with the Golgi stain NBD C(6)-ceramide and the ER-Golgi fluorescent dye
BODIPY-brefeldin A, which, unlike the parental drug-sensitive cells, was
dispersed throughout the cytoplasm. Marker enzymes associated with the ER
(glucose 6-phosphatase) and cis-Golgi (GalNAc transferase) were elevated >2-fold
and nearly 4-fold, respectively, in drug-resistant cell lines while the trans
Golgi marker enzyme, galactosyltransferase, was not. The additional findings that
the KRN5500-resistant cells have a >2-fold elevation in ERGIC-53, a cis-Golgi
marker protein of the ER-Golgi intermediate compartment (ERGIC), as well as
increased 58K, a 58-kDa microtubule-binding protein with formiminotransferase
cyclodeaminase activity, and tubulin indicate that the cellular secretory pathway
is a primary determinant of sensitivity to KRN5500, as resistance to this agent
corresponds with accumulation of several components relatable to ER and cis-Golgi
function. Further support for this conclusion is provided by studies which
demonstrate that KRN5500 alters the distribution of newly synthesized
carcinoembryonic antigen within the secretory pathway, including arrest of this N
glycosylated protein in the Golgi of LS-174T colon carcinoma cells.
PMID- 10772820
TI - Functional expression of human DNA topoisomerase I and its subcellular
localization in HeLa cells.
AB - DNA topoisomerase (topo) I plays an important role in DNA metabolism by relieving
the torsional restraints of DNA topology through ATP-independent single-strand
DNA breakage. In the present study, we expressed human topo I in HeLa cells by
fusing it to enhanced green fluorescent protein (EGFP). The EGFP-topo I fusion
protein is functionally active in that it relaxes supercoiled plasmid DNA; forms
complexes with DNA, as revealed by band depletion assays; and increases the
sensitivity of cells to topo I inhibitors such as topotecan, as determined by
growth inhibition assays. In contrast, a mutant form of the EGFP-topo I fusion
protein, in which the active Tyr has been replaced by Phe (Y723F), has no such
activities. Furthermore, the fusion protein localizes to the nucleus at
interphase and completely associates with chromatids at every stage of mitosis.
Of importance, the mutant fusion protein (Y723F) displays a pattern of
subcellular localization identical to that of the wild-type fusion protein,
although the mutant fusion protein is catalytically inactive. These results
suggest that in addition to its role in DNA metabolism, topo I might also play a
structural role in chromosomal organization; moreover, the association of topo I
with chromosomal DNA is independent of its catalytic activity. Finally, the
fusion constructs may provide a useful tool to study drug action in tumor cells,
as demonstrated by nucleolar delocalization of the fusion proteins in response to
treatment with the topo I inhibitor topotecan.
PMID- 10772821
TI - BAG-1 promotes apoptosis induced by N-(4-hydroxyphenyl)retinamide in human
cervical carcinoma cells.
AB - N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic apoptosis-inducing retinoid
with cancer chemopreventive properties and lower toxicity than all-trans retinoic
acid. BAG-1 is an antiapoptotic gene that is overexpressed in cervical and other
cancers. In this study, we examined whether BAG-1 can inhibit 4-HPR-induced
apoptosis in the C33A cervical carcinoma cell line. Surprisingly, although it
inhibited apoptosis induced by five different apoptotic stimuli, overexpression
of BAG-1 enhanced apoptosis induced by 4-HPR, producing a 2.5-fold lower IC(50)
of 4-HPR. The effects of BAG-1 on 4-HPR-induced apoptosis were mediated by
enhancing the caspase-3 activation pathway. Deletion mutation experiments showed
that the central ubiquitin homology domain of BAG-1 protein was necessary for its
promotion of 4-HPR-induced apoptosis, whereas its C-terminal Hsp70/Hsc70
interacting domain was required for its inhibition of staurosporine-induced
apoptosis. These in vitro results suggest that the effectiveness of 4-HPR against
the development of malignancy may be due to the overexpression of BAG-1 in cancer
cells.
PMID- 10772822
TI - Laminin alpha4 and integrin alpha6 are upregulated in regenerating dy/dy skeletal
muscle: comparative expression of laminin and integrin isoforms in muscles
regenerating after crush injury.
AB - The expression of laminin isoforms and laminin-binding integrin receptors known
to occur in muscle was investigated during myogenic regeneration after crush
injury. Comparisons were made between dystrophic 129ReJ dy/dy mice, which have
reduced laminin alpha2 expression, and their normal littermates. The overall
histological pattern of regeneration after crush injury was similar in dy/dy and
control muscle, but proceeded faster in dy/dy mice. In vitro studies revealed a
greater yield of mononuclear cells extracted from dy/dy muscle and a reduced
proportion of desmin-positive cells upon in vitro cultivation, reflecting the
presence of inflammatory cells and "preactivated" myoblasts due to ongoing
regenerative processes within the endogenous dystrophic lesions. Laminin alpha1
was not detectable in skeletal muscle. Laminin alpha2 was present in basement
membranes of mature myofibers and newly formed myotubes in control and dy/dy
muscles, albeit weaker in dy/dy. Laminin alpha2-negative myogenic cells were
detected in dy/dy and control muscle, suggesting the involvement of other laminin
alpha chains in early myogenic differentiation, such as laminin alpha4 and alpha5
which were both transiently expressed in basement membranes of newly formed
myotubes of dy/dy and control mice. Integrin beta1 was expressed on endothelial
cells, muscle fibers, and peripheral nerves in uninjured muscle and broadened
after crush injury to the interstitium where it occurred on myogenic and
nonmyogenic cells. Integrin alpha3 was not expressed in uninjured or regenerating
muscle, while integrin alpha6 was expressed mainly on endothelial cells and
peripheral nerves in uninjured muscle. Upon crush injury integrin alpha6
increased in the interstitium mainly on nonmyogenic cells, including infiltrating
leukocytes, endothelial cells, and fibroblasts. In dy/dy muscle, integrin alpha6
occurred on some newly formed myotubes. Integrin alpha7 was expressed on muscle
fibers at the myotendinous junction and showed weak and irregular expression on
muscle fibers. After crush injury, integrin alpha7 expression extended to the
newly formed myotubes and some myoblasts. However, many myoblasts and newly
formed myotubes were integrin alpha7 negative. No marked difference was observed
in integrin alpha7 expression between dy/dy and control muscle, either uninjured
or after crush injury. Only laminin alpha4 and integrin alpha6 expression
patterns were notably different between dy/dy and control muscle. Expression of
both molecules was more extensive in dy/dy muscle, especially in the interstitium
of regenerating areas and on newly formed myotubes. In view of the faster
myogenic regeneration observed in dy/dy mice, the data suggest that laminin
alpha4 and integrin alpha6 support myogenic regeneration. However, whether these
accelerated myogenic effects are a direct consequence of the reduced laminin
alpha2 expression in dy/dy mice, or an accentuation of the ongoing regenerative
events in focal lesions in the muscle, requires further investigation.
PMID- 10772823
TI - B2-1, a Sec7- and pleckstrin homology domain-containing protein, localizes to the
Golgi complex.
AB - B2-1 is a human protein that contains both a Sec7 and a pleckstrin homology
domain. The yeast Sec7 protein was previously shown to be involved in vesicle
formation in the Golgi and endoplasmic reticulum. Recently, several groups have
shown that B2-1 and highly similar proteins (e.g., ARNO, ARNO3) have varied
cellular functions and subcellular locations. One of these is an association of
the B2-1 Sec7 domain with the plasma membrane, binding to the cytoplasmic portion
of the integrin beta2 chain (CD18) and is postulated to be involved in inside-out
signaling. Other groups have shown that B2-1 and these related proteins are
guanine nucleotide-exchange factors that act upon ADP ribosylation factors (ARFs)
and are localized to the Golgi or plasma membrane. Here we report the subcellular
localization of B2-1 protein. Interestingly, B2-1 does not localize to the plasma
membrane but rather associates with a distinct Golgi complex compartment. B2-1's
distribution can be disrupted by brefeldin A, a drug that rapidly disrupts the
Golgi apparatus by inhibiting ARF activity. Furthermore, transient transfection
of GFP-tagged B2-1 shows Golgi complex targeting. Excessive overexpression of
transfected B2-1 causes partial Golgi dispersion.
PMID- 10772824
TI - The RGG domain in hnRNP A2 affects subcellular localization.
AB - The heterogeneous nuclear ribonucleoproteins (hnRNP) associate with pre-mRNA in
the nucleus and play an important role in RNA processing and splice site
selection. In addition, hnRNP A proteins function in the export of mRNA to the
cytoplasm. Although the hnRNP A proteins are predominantly nuclear, hnRNP A1
shuttles rapidly between the nucleus and the cytoplasm. HnRNP A2, whose
cytoplasmic overexpression has been identified as an early biomarker of lung
cancer, has been less well studied. Cytosolic hnRNP A2 overexpression has also
been noted in brain tumors, in which it has been correlated with translational
repression of Glucose Transporter-1 expression. We now examine the role of
arginine methylation on the nucleocytoplasmic localization of hnRNP A2 in the HEK
293 and NIH-3T3 mammalian cell lines. Treatment of either cell line with the
methyltransferase inhibitor adenosine dialdehyde dramatically shifts hnRNP A2
localization from the nuclear to the cytoplasmic compartment, as shown both by
immunoblotting and by immunocytochemistry. In vitro radiolabeling with
[(3)H]AdoMet of GST-tagged hnRNP A2 RGG mutants, using recombinant protein
arginine methyltransferase (PRMT1), shows (i) that hnRNP A2 is a substrate for
PRMT1 and (ii) that methylated residues are found only in the RGG domain.
Deletion of the RGG domain (R191-G253) of hnRNP A2 results in a cytoplasmic
localization phenotype, detected both by immunoblotting and by
immunocytochemistry. These studies indicate that the RGG domain of hnRNP A2
contains sequences critical for cellular localization of the protein. The data
suggest that hnRNP A2 may contain a novel nuclear localization sequence,
regulated by arginine methylation, that lies in the R191-G253 region and may
function independently of the M9 transportin-1-binding region in hnRNP A2.
PMID- 10772825
TI - The p65/RelA subunit of NF-kappaB interacts with actin-containing structures.
AB - Nuclear factor-kappa B (NF-kappaB) is a universal transcription factor that
participates in induction of a wide variety of cellular genes. In nonstimulated
cells, NF-kappaB is sequestered in the cytoplasm. However, little is known about
where NF-kappaB is located. We have studied the effect of inducing a
reorganization of the actin filament system on NF-kappaB distribution, using
normal and E1A+cHa-ras-transformed rat fibroblasts. This paper demonstrates that
the p65/RelA subunit of NF-kappaB interacts with actin-containing structures.
Immunofluorescence reveals that p65 is concentrated in focal contacts and along
stress fibers in normal fibroblasts. Restoration of actin stress fibers in
transformants spread on fibronectin is followed by reallocation of p65 to focal
contacts and stress fibers, as in normal cells. The p65 is accumulated at the
edge of leading lamellae in transformants spread on laminin and is redistributed
to cell-to-cell contacts after a prolonged cultivation. Treatment of cells with
Cytochalasin D leads to redistribution of p65 into the actin-containing
aggregates. Affinity chromatography on matrix-bound F-actin confirms that p65 can
bind to filamentous actin. Taken together, these data indicate that distribution
of p65 in the cytoplasm depends on the state of the actin cytoskeleton and
suggest an additional, yet unknown, function of the NF-kappaB in the cytoplasm.
PMID- 10772826
TI - Retinoic acid and its receptors repress the expression and transactivation
functions of Nur77: a possible mechanism for the inhibition of apoptosis by
retinoic acid.
AB - Nur77 (NGFI-B) is an orphan nuclear receptor that has been implicated in
activation-induced T-cell apoptosis. Retinoids, potent immune modulators, were
shown to inhibit the activation-induced apoptosis of immature thymocytes and T
cell hybridomas. To illustrate the mechanism of the inhibition, we examined the
effects of retinoic acid (RA) on the expression and transactivation functions of
Nur77 in the human peripheral blood mononuclear cells and the human T-cell
leukemia, Jurkat. All-trans-RA remarkably repressed the DNA binding and
transcriptional induction of Nur77. Among the two potential trans-acting factors
that activate Nur77 gene promoter, i.e., AP-1 and related serum response factor
(RSRF), all-trans-RA repressed DNA binding and reporter gene activity of AP-1 but
not that of RSRF, suggesting that the inhibition may be mediated through AP-1. We
also demonstrated a posttranscriptional regulation of Nur77 function by retinoid
receptors by showing that transactivation activity of Nur77 was significantly
inhibited by cotransfection of RARalpha or RXRalpha. Nur77 bound RARalpha or
RXRalpha in both yeast and mammalian two-hybrid tests, suggesting that direct
protein-protein interaction between these receptors may mediate the inhibition.
Taken all together, we demonstrated that RA repressed Nur77 function through
multiple mechanisms that may provide the basis for RA inhibition on the apoptosis
of activated T-lymphocytes.
PMID- 10772827
TI - PTHrP expression in chondrocytes, regulation by TGF-beta, and interactions
between epiphyseal and growth plate chondrocytes.
AB - Although PTHrP has been identified as a key regulator of chondrocyte
differentiation in the growth plate, the factors directly regulating PTHrP
expression have not been identified. Furthermore, while cells from the epiphysis
are considered the physiologic source of PTHrP, the relative expression of PTHrP
in epiphyseal and growth plate chondrocytes has not been defined. PTHrP
expression was examined in chondrocytes isolated from 3- to 5-week-old chick long
bones. The expression of PTHrP mRNA was 10-fold higher in epiphyseal chondrocytes
compared to cells from the growth plate. Growth plate chondrocytes were isolated
into populations with distinct maturational characteristics by countercurrent
centrifugal elutriation and analyzed for PTHrP expression. The expression was
highest in the least mature cells and progressively declined with the onset of
maturation. The regulation of PTHrP expression was further examined in epiphyseal
chondrocytes. Both TGF-beta1 and cis-retinoic acid stimulation markedly increased
PTHrP mRNA levels, while BMP-2 and PTHrP stimulation decreased the expression of
this transcript. The effects of TGF-beta1 (8.9-fold stimulation) and TGF-beta3
(9.2-fold) were slightly greater than the effects of TGF-beta2 (4.9-fold). The
effect of TGF-beta was dose-dependent and increases could be detected after 68 h
of treatment. To analyze the paracrine effect of epiphyseal and growth plate
chondrocytes on each other, these cells were placed in coculture and the mRNA
from each of the populations was harvested separately after 24 h. Following
coculture the PTHrP mRNA levels increased in the epiphyseal cells while the
expression of type X collagen and Indian hedgehog transcripts decreased in growth
plate chondrocytes. The results demonstrate potentially important paracrine
interactions between these cell populations, possibly mediated by TGF-beta and
PTHrP.
PMID- 10772828
TI - Lack of cyclooxygenase-2 activity in HT-29 human colorectal carcinoma cells.
AB - Induction of cyclooxygenase-2 (COX-2) is an early event in the sequence of polyp
formation to colon carcinogenesis. COX-2 is at elevated levels in human
colorectal cancers and in tumors and polyps of mouse models of colorectal cancer.
Mutation of the adenomatous polyposis coli (APC) gene is the initial event
leading to colorectal cancer. Colorectal cells in culture which express mutant
APC are often used to examine the association of COX-2 expression and apoptosis.
The expression of full-length APC in HT-29 cells, a human colorectal carcinoma
cell line which normally expresses truncated APC and highly expresses COX-2,
inhibits cell growth through increased apoptosis and results in a down-regulation
of COX-2 protein. In this report, we examine whether down-regulation of COX-2 is
directly linked to the increase in apoptosis observed in these HT-29-APC cells.
We present evidence that COX-2 and apoptosis are not linked since COX-2, although
expressed, is catalytically inactive. Interestingly, the COX-2 cloned from HT-29
cells is catalytically active when transfected into HCT-116 cells, a colorectal
cell line which normally does not express COX-2, but is not active in the HT-29
cell line itself.
PMID- 10772829
TI - Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may
require protein phosphatase activity.
AB - PTEN, a tumor suppressor commonly targeted in human cancer, possesses phosphatase
activities toward both protein and lipid substrates. While PTEN suppresses
gliomas through cell cycle inhibition which requires its lipid phosphatase
activity, PTEN's effects on other tumor types and the role of its protein
phosphatase activity are controversial or unknown. Here we show that exogenous
wild-type PTEN arrests some, but not all human breast cancer cell lines in G1, in
a manner independent of endogenous PTEN. Unexpectedly, the G129E mutant of PTEN
selectively deficient in the lipid phosphatase activity still blocked the cell
cycle of MCF-7 cells, while the G129R and H123Y mutants lacking both phosphatase
activities were ineffective. These results suggest that PTEN's protein
phosphatase activity likely contributes to its tumor suppressor function in
subsets of tumors and that elucidation of downstream targets which dictate
cellular responses to PTEN may have important implications for future cancer
treatment strategies.
PMID- 10772830
TI - Telomere reduction in human liver tissues with age and chronic inflammation.
AB - Telomere shortening in human liver with aging and chronic inflammation was
examined by hybridization protection assay using telomere and Alu probes. The
reduction rate of telomere repeats in normal liver (23 samples from patients 17
81 years old) was 120 bp per year, which is in good agreement with the reported
reduction rate in fibroblasts of 50-150 bp at each cell division and replacement
rate of human liver cells, once a year. Mean telomere repeat length shortened to
about 10 kbp in normal livers from 80-year-old individuals. The number of
telomere repeats in chronic hepatitis (26 samples) and liver cirrhosis (11
samples) was significantly lower than that in normal liver of the same age (P <
0. 01). Telomere length in all these chronic liver disease samples, other than
two exceptions, was not reduced shorter than 5 kbp, which was assumed to give a
limit of proliferation (Hayflick's limit) to untransformed cells.
PMID- 10772831
TI - Preventing pancreatic infection in acute pancreatitis.
AB - In acute pancreatitis, pancreatic inflammation may be complicated by the
development of pancreatic infection with a high associated mortality. Pancreatic
infection is related to the extent of pancreatic inflammation and necrosis and
typically occurs in the second or third week of severe disease. It may be
associated with a wide range of Gram-positive and Gram-negative bacteria, notably
enterobacteria and also with Candida spp. Current surgical practice in the UK is
to use prophylactic antimicrobial therapy in patients with severe disease, with
the aim of preventing secondary pancreatic infection. Experimental evidence
demonstrates that prophylactic antibacterial therapy prevents pancreatic
infection and reduces mortality. Furthermore, studies of antibacterial
prophylaxis in patients with acute pancreatitis suggest that prophylactic
antibacterial therapy is associated with a reduction in mortality, particularly
in those with severe disease. In general, broad-spectrum antibiotics have been
used in animal and human studies. However, current evidence does not allow
comparisons to be made between different antimicrobial agents. Nutritional
strategies may also be important in the prevention of pancreatic infection.
Enteral, rather than parenteral, nutrition has been associated with an improved
clinical outcome in severe pancreatitis.
PMID- 10772832
TI - Use of RAPD-ALF analysis for investigating the frequency of bacterial cross
transmission in an adult intensive care unit.
AB - Bacterial cross-transmission was investigated during a 12-month period in an
adult intensive care unit (ICU) by the generation of random amplified polymorphic
DNA (RAPD) fingerprinting profiles, combined with automated laser fluorescence
(ALF) analysis. The potential episodes of cross-transmission identified, were
compared with those detected by the conventional first-line screen of antibiogram
typing. Over the year, 215 primary gram-negative bacterial isolates were obtained
from 160 patients. In total, 22 possible episodes of cross-transmission,
involving 70 (44%) of the 160 patients, were identified by RAPD-ALF analysis, and
19 of these were substantiated with epidemiological evidence. Conversely, 31
possible episodes were identified on the basis of antibiogram data, but only
three of these episodes, two involving Acinetobacter baumannii and one involving
Serratia marcescens, correlated with those identified by RAPD-ALF analysis. It
was concluded that analysis of antibiogram data alone is an unreliable method for
assessing bacterial cross-transmission, unless the organism involved has a
particularly stable or unusual resistance pattern. In contrast, the technique of
RAPD-ALF analysis may provide a rapid and simple technique for obtaining an
insight into the population dynamics of gram-negative bacteria in adult ICUs.
PMID- 10772833
TI - Hospital outbreak of Salmonella virchow possibly associated with a food handler.
AB - A foodborne outbreak of salmonella infection at a private hospital in London in
1994 was found to be associated with eating turkey sandwiches prepared by a food
handler. One patient, nine staff, and a foodhandler's baby were confirmed to have
Salmonella enterica serotype virchow, phage type 26 infection. The attack rate
was estimated to be 5% among the approximately 200 patients and staff at risk. A
food handler reportedly became ill days after, but her baby days before, the
first hospital case. Although it appeared to be a single outbreak, antibiogram
analysis, supplemented by plasmid profile typing, demonstrated that there were
two strains of S. virchow involved, one with resistance to sulphonamides and
trimethoprim and a second sensitive to these antimicrobial drugs. Mother and
child had different strains. The investigation demonstrated the importance of
full phenotypic characterization of putative outbreak strains including
antimicrobial susceptibility testing. Outbreaks of foodborne infection in
hospitals are preventable and are associated with high attack rates and
disruption of services. There is a need for good infection control policies and
training of all staff involved in patient care as well as in catering services.
Consultants in Communicable Disease (CCDCs) should include private hospitals in
their outbreak control plans. Good working relations between Infection Control
Doctors (ICDs) in the private health sector and their local CCDCs are important
if outbreaks are to be properly investigated.
PMID- 10772834
TI - Investigation of an outbreak of Ralstonia pickettii in a paediatric hospital by
RAPD.
AB - In 1995, over a 5-day period, Ralstonia pickettii was isolated from six separate
blood cultures from six paediatric patients in four different units of the
Bordeaux paediatric hospital. The patients did not present fever or any other
symptom of septicaemia. Epidemiological investigation cast suspicion on distilled
water and 0.05% aqueous solutions of chlorhexidine used for topical disinfection
as the source of R. pickettii. The organism was isolated from three of the seven
distilled water specimens and from seven of the thirty-seven chlorhexidine
specimens collected. Conventional biochemical tests showed no differences between
isolates and antimicrobial agent susceptibility testing indicated that the six
blood cultures contained the same strain of R. pickettii. This was confirmed by
RAPD (random amplified polymorphic DNA) analysis. The primers P3 (5'AGACGTCCAC3')
and P15 (5'AATGGCGCAG3') from the kit 'OPH Operon' (Bioprobe Systems, Montreuil,
France) were used. The chlorhexidine solutions and the distilled water used to
prepare the solutions were contaminated with various strains of R. pickettii
including the patient strain. The distilled water originating from the local
pharmacy had been deionized on an ion-exchange resin. Circumstantial evidence
points to this water treatment as the source of contamination. RAPD proved to be
a discriminatory and reproducible technique in this context, but antibiotyping
was also very helpful in detecting outbreak and was equally discriminatory.
PMID- 10772835
TI - Molecular typing of Aspergillus terreus isolates by random amplification of
polymorphic DNA.
AB - Forty three isolates of Aspergillus terreus of environmental or clinical origin
were typed by random amplification of polymorphic DNA (RAPD) with two different
primers NS3 and NS7 from the fungal ribosomal 18S subunit gene. For the 31
epidemiologically unrelated isolates tested, the primers NS3 and NS7 gave rise to
23 and 24 different genotypes, respectively, and combining the results obtained
with the two primers allowed the differentiation of all these isolates. No
clustering was found in relation to pathogenicity, clinical signs, or geographic
origin of the isolates. Five groups of related isolates of A. terreus were also
typed. Analysis of sequential isolates from patients with cystic fibrosis or with
invasive aspergillosis showed the clonality of the colonization or infection by
A. terreus. Likewise, this straightforward typing method demonstrated the clonal
origin of a massive contamination of the environment in a haematology unit.
Therefore this RAPD typing method may constitute a valuable tool for the
epidemiological follow-up of airway colonization in patients with cystic fibrosis
or investigations of links between nosocomial outbreaks of invasive aspergillosis
and environmental contamination.
PMID- 10772836
TI - Nosocomial cross transmission as a primary cause of vancomycin-resistant
enterococci in Austria.
AB - Stool specimens from 226 patients from intensive care units (N=69), general wards
(N=112), and outpatient-clinics (N=45) at the Innsbruck University Hospital and
from 433 healthy volunteers were inoculated on to Enterococcosel Agar
supplemented with 5 microg/mL vancomycin and 4 microg/mL cefodizime. Faecal
specimens from 105 dairy cows, 171 pigs and 47 egg-laying hens were processed the
same way. Thirteen of 226 patients (5.8%) harboured 14 vancomycin-resistant
enterococci (VRE) of the vanA genotype; 12 E. faecium (from 11 patients) and two
E. faecalis (ICU patients: 5.8%, general ward patients: 5.4%, outpatients: 6.7%).
None of the faecal specimens from healthy volunteers or animals yielded VRE. Nine
of the 13 patients harbouring VRE had received antibiotic therapy during the
previous four weeks (broad-spectrum cephalosporins: six patients; i.v.
vancomycin: five patients). Of the 14 VRE (vanA type) isolates six strains were
indistinguishable by PFGE using Sma I as restriction endonuclease, six strains
formed three pairs, and only two single isolates showed unique patterns. The
results of our study supports the view that nosocomial cross transmission is
currently the main cause of colonization and infection with VRE in Austria.
PMID- 10772837
TI - Control of an outbreak of vancomycin-resistant Enterococcus faecium in an
oncology ward in South Africa: effective use of limited resources.
AB - An outbreak of vancomycin-resistant enterococci (VRE) occurred in an adult
oncology ward of a large teaching hospital in Johannesburg, South Africa. The
outbreak strain was identified as an Enterococcus faecium carrying the vanA
resistance genotype. Macro-restriction analysis showed that the majority of
strains were clonally related. Modified infection control interventions were
implemented and control of the outbreak was achieved. Although the epidemiology
of VRE is well documented in Europe, North America and Australia, this problem
has only recently emerged in South Africa. The epidemiology of the outbreak
appears similar to that described for outbreaks elsewhere.
PMID- 10772838
TI - Rapid dissemination of Staphylococcus aureus with classic oxacillin resistance
phenotype at a new university hospital.
AB - To determine the prevalence rates of oxacillin-resistant Staphylococcus aureus
(ORSA) at a new university hospital since its opening, the results of disk
diffusion tests on all clinical isolates, recovered between 1990 and 1998 at the
National Cheng Kung University Hospital, were reviewed. In order, to investigate
the mechanisms of oxacillin resistance among strains of S. aureus in Taiwan, MICs
were determined by an agar dilution method, and polymerase chain reaction and
colony hybridization assays were performed on 288 isolates collected during
November 1998 to detect the mecA gene. The prevalence rates of ORSA increased
rapidly from 14.1% in 1990 to 61.0% in 1998. The increasing rates were most rapid
in the first four-year period, ranging from 11.6 to 106.7% per year, and became
steady after 1994, ranging from 1.8% to 11.6%. Of 288 clinical isolates collected
in November 1998, 206 (71.5%) were resistant to oxacillin (MIC >/= 16 mg/L), and
four were borderline resistant (MIC 2-8 mg/L). All 210 strains possessed the mec
A gene (classic resistance). The present study demonstrated that ORSA could
disseminate in a new hospital with great speed, and indicated that all ORSA
strains in Taiwan revealed classic resistance phenotype.
PMID- 10772839
TI - Hospital Infection Society International Activities. Argentina - British
infection control experience.
PMID- 10772840
TI - The potential risk of transmitting vCJD through surgery.
PMID- 10772841
TI - Value of surveillance specimens in predicting and classifying ICU infections.
PMID- 10772842
TI - Commodes: a health hazard.
PMID- 10772844
TI - Shape and dynamics of thermoregulating honey bee clusters.
AB - A model of simple algorithmic "agents" acting in a discrete temperature field is
used to investigate the movement of individuals in thermoregulating honey bee
(Apis mellifera) clusters. Thermoregulation in over-wintering clusters is thought
to be the result of individual bees attempting to regulate their own body
temperatures. At ambient temperatures above 0( degrees )C, a clustering bee will
move relative to its neighbours so as to put its local temperature within some
ideal range. The proposed model incorporates this behaviour into an algorithm for
bee agents moving on a two-dimensional lattice. Heat transport on the lattice is
modelled by a discrete diffusion process. Computer simulation of this model
demonstrates qualitative behaviour which agrees with that of real honey bee
clusters. In particular, we observe the formation of both disc- and ring-like
cluster shapes. The simulation also suggests that at lower ambient temperatures,
clusters do not always have a stable shape but can oscillate between insulating
rings of different sizes and densities.
PMID- 10772845
TI - On the classes of aminoacyl-tRNA synthetases and the error minimization in the
genetic code.
AB - As a consequence of the existence of two classes of aminoacyl-tRNA synthetases
(aaRSs), we defined two types of mutations: g (mutations that do not change the
class of the involved amino acids) and u (those which change the class). We have
found that the mean chemical distance resulting from g mutations is smaller than
that corresponding to u mutations, indicating that g mutations are responsible
for most of the known minimization of the genetic code. This supports models for
the origin and evolution of the code, in which new amino acids were added after
duplications or modification of existing aaRSs.
PMID- 10772846
TI - A simple nonlinear model of electrical activity in the intestine.
AB - We have simulated electrical activity of the intestine in a computer model that
describes the coupled layers of longitudinal muscle (LM) and interstitial cells
of Cajal (ICC). The model suggests that pacemaker activity is due to the ICC
layer, while the pulse propagation involves the LM layer that is in the
excitatory state. The model describes well the experimentally observed phenomena:
frequency change along the intestine, synchronization along short distances and
desynchronization for long distances, and the decrease of propagation distance
and propagation time along the intestine. We have observed the occurrence of
phase interruptions or breaks, which are responsible for the limited values of
propagation distance and time.
PMID- 10772847
TI - Special factors in biological strings.
AB - Biological macromolecules such as DNA, RNA, and proteins can be regarded as
finite sequences of symbols (or words) over a finite alphabet. In this paper, we
refer to DNA (RNA) sequences which are words on a four-letter alphabet. A
comparison is made between some "genes", or fragments of them, with random
sequences or random reshuffled sequences on the same alphabet and having the same
length. Some combinatorial techniques of analysis of finite words are developed.
A crucial role in the comparison is played by the so-called special factors of a
given word. In all the analysed DNA (RNA) fragments the distribution on the
length of the number of right (left) special factors differs, in a very typical
way, from the corresponding distribution in a string on the same alphabet and
having the same length generated by a random source or obtained by making a
random alteration (=shuffling) of the original string. This kind of change is
irrespective of the length in the range that we have considered <2650 bp and of
the phylogenetic origin of the fragment.
PMID- 10772848
TI - A simplified approach for modeling diffusion into cells.
AB - Regulation of the intracellular concentration of substrates is essential for the
maintenance of a stable cellular environment. Diffusion and reaction processes
supply and consume substrates within cells and determine their steady-state
concentrations. To realistically represent these processes by computer simulation
they must be modeled in three dimensions. Yet three-dimensional models are
inherently computing intensive. This study describes a method, which
substantially simplifies the modeling of diffusion into a polyhedral body (a
cube), that was used as a model representation of a cell. The method is applied
to a case study of oxygen diffusion into nitrogen-fixing, rhizobia-infected cells
in legume nodules. The method involved generating a one-dimensional
representation of the three-dimensional problem to provide a "surface area
profile" of three-dimensional diffusion. The one-dimensional models were
significantly easier to program, several orders of magnitude faster to solve and
in this study were validated by assessing their results against those of
comparable three-dimensional models of diffusion into the same body. The results
show the one-dimensional method to be a close approximation of a three
dimensional source-sink problem with systematic differences below 10% for
fractional oxygenation of leghemoglobin, cell respiration and nitrogenase
activity. Larger differences between models (up to 45%) in the predicted average
and innermost O(2)concentrations had no effects on the physiological conclusions
of the study, but were attributed to the poorer resolution of the three- than the
one-dimensional model, and to an inherent simplification in the derivation of the
one-dimensional surface area profiles. The one-dimensional modeling approach was
found to be a simple, yet powerful tool for the study of diffusion and reaction
in biological systems.
PMID- 10772849
TI - The two-state cross-bridge model of muscle is an asymptotic limit of multi-state
models.
AB - The relationship between the two-state model of muscle contraction and multi
state models is examined from the perspective of matched asymptotic expansions,
under the assumption that transition rates between attached states are fast
compared to those between detached and attached states. A detailed formal
analysis of a three-state model reveals that the classic Huxley (1957. Prog.
Biophys. Biophys. Chem.7, 225-318) rate equation, as modified for thermodynamic
self-consistency by Hill et al. (1975. Biophys. J.15, 335-372), governs the
"outer" solution of the three-state equations. Thus, the two-state model remains
a valid description of muscle dynamics on physiologically relevant time scales,
which are slow compared to millisecond-scale transitions between attached states.
But the asymptotic analysis reveals also that the cross-bridge force must be
considered to be a nonlinear function of the cross-bridge strain, in contrast to
the usual assumption of two-state models. This apparent, or effective, force is
determined by both the intrinsic stiffness of the cross-bridge and the
equilibrium distribution of cross-bridges among attached states. Further, the
asymptotic analysis yields an expression for the energy liberation rate that
implies a reduced rate in stretch vs. shortening. Some behaviors of multi-state
models that are suggested by the three-state analysis are discussed in
qualitative terms.
PMID- 10772850
TI - Molecular evolution near a two-locus balanced polymorphism.
AB - Balancing selection at one locus can increase the amount of selectively neutral
variation within neighboring genomic regions. Discrete phenotypic polymorphisms
studied in natural populations are frequently determined by sets of interacting
genes instead of alternative alleles at single loci. We extend coalescent theory
to investigate balancing selection on combinations of linked genes. We find that
variation at neutral sites is increased across a much larger genomic region
relative to the single-locus models: the entire region lying between the two loci
in balanced combination is affected to some degree. Epistatic selection maintains
these high levels of neutral variation because it directly opposes the
homogenizing effect of recombination. The results of the theory are discussed in
relation to published gene sequence data, primarily from Drosophila.
PMID- 10772851
TI - Theoretical analysis of the implication of PrP in neuronal death during
transmissible subacute spongiform encephalopathies: hypothesis of a PrP
oligomeric channel.
AB - Transmissible subacute spongiform encephalopathies (TSE) are animal and human
neurodegenerative diseases. The nature of the transmissible agent remains
unknown. The specific molecular marker of these diseases is the abnormal isoform
of the prion protein (PrP). This protein is encoded by a cellular gene and
accumulates in a pathological isoform (PrPres) which is partially resistant to
proteolysis. The tridimensional structure of this protein remains theoretical. F.
Cohen proposed one of the most realistic models. According to this model and from
molecular mechanics calculation, we suggest a PrP oligomeric ionic channel model
that may be involved in TSE-induced neuronal apoptosis.
PMID- 10772852
TI - Physical constraints on body size in teleost embryos.
AB - All members of the subphylum "Vertebrata" display the characteristics of the
vertebrate body plan. These characteristics become apparent during the phylotypic
period, in which all vertebrate embryos have a similar body shape and internal
organization. Phylogenetic constraints probably limit the morphological variation
during the phylotypic period. Physical laws, however, also limit growth and
morphogenesis in embryos. We investigated to what extent oxygen availability-as a
physical constraint-might limit morphological variation during embryonic
development. This paper gives an analysis of time-dependent diffusion into
spherical embryos without a circulatory system. Equilibrium appeared to settle in
about 1.5 min in running water and in about 10min in stagnant water. Hence,
steady-state conditions were assumed and expressions for maximum body size were
obtained for spherical, cylindrical and sheet-like embryos in running water and
spherical embyros in stagnant water. Predictions of the model based on literature
data suggest that in running water-both for spherical, cylindrical and sheet-like
embryos-diffusion alone suffices to cover the oxygen needs of a teleost embryo in
its phylotypic period. The size of carp (Cyprinus carpio) and African catfish
(Clarias gariepinus) embryos is very close to the predicted maximum. This
suggests that in these species the development of a functional circulatory system
is correlated with the onset of oxygen shortage. Oxygen availability is therefore
a potentially important physical constraint on embryonic morphology, though in
most species the circulatory system becomes functional well in advance of the
onset of oxygen shortage and other demands than oxygen delivery (e.g. nutrient
distribution, waste disposal, osmoregulation) might require the development of a
circulatory system.
PMID- 10772853
TI - Deterministic modeling of negative cross-resistance strategies for use in
transgenic host-plant resistance.
AB - Negative cross-resistance refers to a situation in which an insect population
that is tolerant (resistant, virulent) to one insecticide is hyper-sensitive
(avirulent) to a second insecticide and insects hyper-sensitive to the first
compound are tolerant to the second. Most research dealing with negative cross
resistance has focused on the molecular biology and chemical aspects of this
phenomenon. We explored, from a population genetics perspective, whether negative
cross-resistance is feasible in the control of an insect population. As a first
step towards this goal, we used a deterministic approach to evaluate different
control scenarios and to identify some of the potential limitations of negative
cross-resistance strategies. Specifically, we investigated how such approaches
could be used in a host-plant resistance program. Homo- and heterozygous insect
fitness influenced the effectiveness of the toxins in controlling the insect
population. The negative cross-resistance strategy was most useful when the
insects' virulence to both host-plant toxins was recessive. When virulence was
dominant, there were many periods when intervention with an outside (or third)
class of compounds, which had a different mode of action than that of the
negative cross-resistance compounds, was needed to control the insect population.
The greater the number of insect generations per plant generation, in the absence
of immigration or emigration in the insect population, the greater the
requirement for intervention with a third class of compound to maintain effective
control of the insect population. When the toxins were rotated every insect
generation, and virulence in the insect was recessive to both toxins, effective
control of the insect population was maintained without intervention of a third
class of compounds.
PMID- 10772854
TI - Color-coding reveals tandem repeats in the Escherichia coli genome.
AB - Genomic DNA contains a wide variety of repetitive sequences. In Escherichia coli,
there have been several classes of repetitive sequences reported, some of which
cluster as tandem repeats. We propose a novel method for analyzing symbolic
sequences by two-dimensional pattern formation with color-coding. We applied this
method for searching tandem repeats in the E. coli genome and found approximately
50 repeats with periods longer than 30 bases. The longest repeat has a period of
1267 bases.
PMID- 10772855
TI - Architecture of the Streptomyces lividans DnaA protein-replication origin
complexes.
AB - The Streptomyces oriC region contains two clusters of 19 DnaA boxes separated by
a spacer (134 bp). The Streptomyces DnaA protein consists, like all other DnaA
proteins, of four domains: domain III and the carboxyterminal part (domain IV)
are responsible for binding of ATP and DNA, respectively. Binding of the DnaA
protein to the entire oriC region analysed by electron microscopy showed that the
DnaA protein forms separate complexes at each of the clusters of DnaA boxes, but
not at the spacer separating them. In vivo mutational analysis revealed that the
number of DnaA boxes and the presence of the spacer linking both groups of DnaA
boxes seem to be important for a functional Streptomyces origin. We suggest that
the arrangement of DnaA boxes allows the DNA-bound DnaA protein to induce bending
and looping of the oriC region. As it was shown by electrophoretic mobility shift
assay and "one hybrid system", two domains, I and III, facilitate interactions
between DnaA molecules. We postulate that domain I and domain III could be
involved in cooperativity at distant and at closely spaced DnaA boxes,
respectively. The long domain II extends the range over which N termini (domain
I) of DNA-bound DnaA protein can form dimers. Thus, interactions between DnaA
molecules may bring two clusters of DnaA boxes separated by the spacer into
functional contact by loop formation. Removal of the spacer region or deletion of
domains I and II resulted, respectively, in nucleoprotein complexes which are not
fully developed, or huge nucleoprotein aggregates.
PMID- 10772856
TI - Evolutionary inventions and continuity of CORE-SINEs in mammals.
AB - We characterized short interspersed elements (SINEs), of the CORE-suprafamily in
egg-laying (monotremes), pouched (marsupials) and placental mammals. Five
families of these repeats distinguished by the presence of distinct LINE-related
3'-segments shared tRNA-like promoter and the central core region. The putative
active elements were reconstructed from the alignment of genomic repeats
representing molecular fossils of sequences that amplified in the past and since
then underwent multiple mutations. Their mode of proliferation by retroposition
was indicated by the presence of: (1) internal RNA PolIII promoter; (2) simple
sequence repeated tail; (3) direct repeats; and (4) subfamilies recording the
evolution of elements. The copy number of CORE-SINEs in placental genomes was
estimated at about 300,000; they were highly divergent and apparently ceased to
amplify before radiation of these lineages. On the other hand, among almost half
a million fossil elements present in marsupials and monotremes, the youngest
subfamilies could still be retropositionally active. CORE-SINEs terminate in
sequence repeats of a few nucleotides similar to their 3'-segment LINE
homologues, CR1, L2 and Bov-B. These three LINE elements fall into clades
distinct from that of L1 elements which, similar to their co-amplifying SINEs,
end in a poly(A) tail. We propose a model in which new CORE-families, with
distinct 3'-segments, are created at the RNA level due to template switching
between LINE and CORE-RNA during reverse transcription. The proposed mechanism
suggests that such an adaptation to the changing amplification machinery
facilitated the survival and prosperity of CORE-elements over long evolutionary
periods in different lineages.
PMID- 10772857
TI - Tagging ribosomal protein S7 allows rapid identification of mutants defective in
assembly and function of 30 S subunits.
AB - Ribosomal protein S7 nucleates folding of the 16 S rRNA 3' major domain, which
ultimately forms the head of the 30 S ribosomal subunit. Recent crystal
structures indicate that S7 lies on the interface side of the 30 S subunit, near
the tRNA binding sites of the ribosome. To map the functional surface of S7, we
have tagged the protein with a Protein Kinase A recognition site and engineered
alanine substitutions that target each exposed, conserved residue. We have also
deleted conserved features of S7, using its structure to guide our design. By
radiolabeling the tag sequence using Protein Kinase A, we are able to track the
partitioning of each mutant protein into 30 S, 70 S, and polyribosome fractions
in vivo. Overexpression of S7 confers a growth defect, and we observe a striking
correlation between this phenotype and proficiency in 30 S subunit assembly among
our collection of mutants. We find that the side chain of K35 is required for
efficient assembly of S7 into 30 S subunits in vivo, whereas those of at least 17
other conserved exposed residues are not required. In addition, an S7 derivative
lacking the N-terminal 17 residues causes ribosomes to accumulate on mRNA to
abnormally high levels, indicating that our approach can yield interesting mutant
ribosomes.
PMID- 10772858
TI - Protein-protein interaction among hnRNPs shuttling between nucleus and cytoplasm.
AB - Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in several RNA
related biological processes such as transcription, pre-mRNA processing, mature
mRNA transport to the cytoplasm, and translation. About 20 major hnRNPs from A1
to U are known. Among them, hnRNP A, D, E, I, and K are known to shuttle between
the nucleus and the cytoplasm. hnRNP E2 has been seen to stabilize alpha-globin
mRNA and to enhance polioviral mRNA translation. hnRNP K modulates transcription
and translation of some mRNAs. hnRNP I and its homologue hnRNP L have been
suggested to enhance translation of some IRES-dependent mRNAs. In order to better
understand the molecular mechanisms of the biological functions of hnRNPs, we
investigated protein-protein interactions of six hnRNPs (hnRNP A1, C1, E2, I, K,
and L) using the yeast two-hybrid system and in vitro co-precipitation assays.
All of the hnRNPs tested exerted homomeric interactions, and hnRNP E2, I, K, and
L interacted with each other. In the case of hnRNP E2 and hnRNP K, the N-terminal
half of the proteins containing two KH (K homologous) domains were required for
protein-protein interaction, and the second quarter of hnRNP I and hnRNP L
containing RRM2 (RNA recognition motif 2) was essential for protein-protein
interaction. hnRNP A1 and C1 did not form complexes with other hnRNPs in our
assay systems. This suggests that the hnRNPs could fall into two groups: one
group, including hnRNP A1 and C1, involved in hnRNP core complex formation and
another group, including hnRNP E2, I, K, and L, involved in a variety of RNA
related biological processes. Different combinations of the proteins of the
second group may facilitate different biological processes in conjunction with
other factors.
PMID- 10772859
TI - Modulation of RuvB function by the mobile domain III of the Holliday junction
recognition protein RuvA.
AB - In prokaryotes, RuvA-RuvB complexes play a crucial role in the migration of the
Holliday junction, which is a key intermediate of homologous recombination. RuvA
binds to the Holliday junction and enhances the ATPase activity of RuvB required
for branch migration. RuvA adopts a unique domain structure, which assembles into
a tetrameric molecule. The previous mutational and proteolytic analyses suggested
that mutations in a carboxyl-terminal domain (domain III) impair binding of RuvA
to RuvB. In order to clarify the functional role of each domain in vitro, we
established the recombinant expression systems, which allow us to analyze
structural and biochemical properties of each domain separately. A small-angle X
ray scattering solution study, combined with X-ray crystallographic analyses, was
applied to the tetrameric full-length RuvA and its tetrameric NH2 region (domains
I and II) lacking the domain III. These results demonstrated that domain III can
be completely separate from the tetrameric major core of the NH2 region and
freely mobile in solution, through a remarkably flexible loop. Biochemical
analyses indicated that domain III not only interacts with RuvB, but also
modulates its ATPase activity. This modulation may facilitate the dynamic
coupling between RuvA and RuvB during branch migration.
PMID- 10772860
TI - An algorithm for the prediction of proteasomal cleavages.
AB - Proteasomes, major proteolytic sites in eukaryotic cells, play an important part
in major histocompatibility class I (MHC I) ligand generation and thus in the
regulation of specific immune responses. Their cleavage specificity is of
outstanding interest for this process. In order to generalize previously
determined cleavage motifs of 20 S proteasomes, we developed network-based model
proteasomes trained by an evolutionary algorithm with experimental cleavage data
of yeast and human 20 S proteasomes. A window of ten flanking amino acid residues
proved sufficient for the model proteasomes to reproduce the experimental results
with 98-100 % accuracy. Actual experimental data were reproduced significantly
better than randomly selected cleavage sites, suggesting that our model
proteasomes were able to extract rules inherent to proteasomal cleavage data. The
affinity parameters of the model, which decide for or against cleavage,
correspond with the cleavage motifs determined experimentally. The predictive
power of the model was verified for unknown (to the program) test conditions: the
prediction of cleavage numbers in proteins and the generation of MHC I ligands
from short peptides. In summary, our model proteasomes reproduce and predict
proteasomal cleavages with high degree of accuracy. They present a promising
approach for predicting proteasomal cleavage products in future attempts and, in
combination with existing algorithms for MHC I ligand prediction, will be tested
to improve cytotoxic T lymphocyte epitope prediction.
PMID- 10772861
TI - Phage display mapping for peptide 11 sensitive sequences binding to laminin-1.
AB - We utilized a 9-mer random phage display library to identify sequences which bind
to laminin-1 and elute with heparan sulfate or peptide 11 (CDPGYIGSR). Laminin-1
derivatized plates were used for biopanning. Three consecutive rounds of low pH
elutions were carried out, followed by three rounds of specific elutions, each
consisting of a heparan sulfate elution followed by a peptide 11 elution. The
random sequence inserts were sequenced for phage populations eluted at low pH, by
heparan sulfate and by peptide 11. Specifically eluted phage populations
exhibited three classes of mimotopes for different regions in the cDNA derived
amino acid sequence of the 67 kDa laminin binding protein (LBP). These regions
were (1) a palindromic sequence known as peptide G, (2) a predicted helical
domain corresponding to LBP residues 205-229, and (3) TEDWS-containing C-terminal
repeats. All elution conditions also yielded phage with putative heparin binding
sequences. We modeled the LBP(205-229) domain, which is strongly predicted to
have a helical secondary structure, and determined that this region likely
possesses heparin-binding characteristics located to one side of the helix, while
the opposite side appears to contain a hydrophobic patch where peptide 11 could
bind. Using ELISA plate assays, we demonstrated that peptide 11 and heparan
sulfate individually bound to synthetic LBP(205-229) peptide. We also
demonstrated that the QPATEDWSA peptide could inhibit tumor cell adhesion to
laminin-1. These data support the proposal that the 67 kDa LBP can bind the beta
1 laminin chain at the peptide 11 region, and suggest that heparan sulfate is a
likely alternate ligand for the binding interactions. Our results also confirm
previous data suggesting that the most C-terminal region of the LBP, which
contains the TEDWS repeats, is involved in cell adhesion to laminin-1, and we
specifically implicate the repeat sequence in that activity.
PMID- 10772862
TI - Mapping the protein-DNA interface and the metal-binding site of the major human
apurinic/apyrimidinic endonuclease.
AB - Apurinic/apyrimidinic (AP) endonuclease Ape1 is a key enzyme in the mammalian
base excision repair pathway that corrects AP sites in the genome. Ape1 cleaves
the phosphodiester bond immediately 5' to AP sites through a hydrolytic reaction
involving a divalent metal co-factor. Here, site-directed mutagenesis, chemical
footprinting techniques, and molecular dynamics simulations were employed to gain
insights into how Ape1 interacts with its metal cation and AP DNA. It was found
that Ape1 binds predominantly to the minor groove of AP DNA, and that residues
R156 and Y128 contribute to protein-DNA complex stability. Furthermore, the Ape1
AP DNA footprint does not change along its reaction pathway upon active-site
coordination of Mg(2+) or in the presence of DNA polymerase beta (polbeta), an
interactive protein partner in AP site repair. The DNA region immediately 5' to
the abasic residue was determined to be in close proximity to the Ape1 metal
binding site. Experimental evidence is provided that amino acid residues E96,
D70, and D308 of Ape1 are involved in metal coordination. Molecular dynamics
simulations, starting from the active site of the Ape1 crystal structure, suggest
that D70 and E96 bind directly to the metal, while D308 coordinates the cation
through the first hydration shell. These studies define the Ape1-AP DNA
interface, determine the effect of polbeta on the Ape1-DNA interaction, and
reveal new insights into the Ape1 active site and overall protein dynamics.
PMID- 10772863
TI - Alternative geometries of DNA looping: an analysis using the SfiI endonuclease.
AB - Many processes are governed by proteins that bind to separate sites in DNA and
loop out the intervening DNA, but the geometries of the loops have seldom been
determined. The SfiI endonuclease cleaves DNA after interacting with two
recognition sites, and is a favourable system for the analysis of DNA looping. A
gel-shift assay was used here to examine the binding of SfiI to a series of
linear DNA molecules containing two SfiI sites separated by 109-170 base-pairs.
The complexes in which SfiI trapped a loop by binding to two sites in the same
DNA were separated from the complexes containing SfiI bound to separate DNA
molecules. Step-wise changes in the inter-site spacing generated two forms of the
looped complex with different electrophoretic mobilities. The yields of each
looped complex and the complexes from intermolecular synapses all varied
cyclically with the inter-site spacing, with similar periodicities (
approximately 10.5 base-pairs) but with different phases. One looped complex
predominated whenever the DNA between the sites needed to be underwound in order
to produce the correct helical orientation of the binding sites. The other looped
complex predominated whenever the intervening DNA needed to be overwound. We
conclude that the former has trapped a right-handed loop with a negative node and
the latter a left-handed loop with a positive node.
PMID- 10772864
TI - Crystal structure of cancer chemopreventive Bowman-Birk inhibitor in ternary
complex with bovine trypsin at 2.3 A resolution. Structural basis of Janus-faced
serine protease inhibitor specificity.
AB - Understanding molecular recognition on a structural basis is an objective with
broad academic and applied significance. In the complexes of serine proteases and
their proteinaceous inhibitors, recognition is governed mainly by residue P1 in
accord with primary serine protease specificity. The bifunctional soybean Bowman
Birk inhibitor (sBBI) should, therefore, interact at LysI16 (subdomain 1) with
trypsin and at LeuI43 (subdomain 2) with chymotrypsin. In contrast with this
prediction, a 2:1 assembly with trypsin was observed in solution and in the
crystal structure of sBBI in complex with trypsin, determined at 2.3 A resolution
by molecular replacement. Strikingly, P1LeuI43 of sBBI was fully embedded into
the S(1) pocket of trypsin in contrast to primary specificity. The triple
stranded beta-hairpin unique to the BBI-family and the surface loops surrounding
the active site of the enzyme formed a protein-protein-interface far extended
beyond the primary contact region. Polar residues, hydrophilic bridges and weak
hydrophobic contacts were predominant in subdomain 1, interacting specifically
with trypsin. However, close hydrophobic contacts across the interface were
characteristic of subdomain 2 reacting with both trypsin and chymotrypsin. A
Met27Ile replacement shifted the ratio with trypsin to the predicted 1:1 ratio.
Thus, the buried salt-bridge responsible for trypsin specificity was stabilised
in a polar, and destabilized in a hydrophobic, environment. This may be used for
adjusting the specificity of protease inhibitors for applications such as
insecticides and cancer chemopreventive agents.
PMID- 10772865
TI - Folding of bovine pancreatic trypsin inhibitor (BPTI) variants in which almost
half the residues are alanine.
AB - Recent studies indicate that a fraction of the information contained in an amino
acid sequence may be sufficient for specifying a native protein structure. An
earlier alanine-scanning experiment conducted on bovine pancreatic trypsin
inhibitor (BPTI; 58 residues) suggested that if cumulative mutations have
additive effects on protein stability, a native protein structure could be built
from BPTI sequences that contained many alanine residues distributed throughout
the protein. To test this hypothesis, we designed and produced six BPTI mutants
containing from 21 to 29 alanine residues. We found that the melting temperature
of mutants containing up to 27 alanine residues (48 % of the total number of
residues) could be predicted quite well by the sum of the change in melting
temperature for the single mutations. Additionally, these same mutants folded
into a native-like structure, as judged by their cooperative thermal denaturation
curves and heteronuclear multiple quantum correlation (HMQC) NMR spectra. A BPTI
mutant containing 22 alanine residues was further shown by 2D and 3D-NMR to fold
into a structure very similar to that of native BPTI, and to be a functional
trypsin inhibitor. These results provide insight into the extent to which native
protein structure and function can be achieved with a highly simplified amino
acid sequence.
PMID- 10772866
TI - Evaluation of direct and cooperative contributions towards the strength of buried
hydrogen bonds and salt bridges.
AB - An experimental approach to evaluate the net binding free energy of buried
hydrogen bonds and salt bridges is presented. The approach, which involves a
modified multiple-mutant cycle protocol, was applied to selected interactions
between TEM-1-beta-lactamase and its protein inhibitor, BLIP. The selected
interactions (two salt bridges and two hydrogen bonds) all involving BLIP-D49,
define a distinct binding unit. The penta mutant, where all side-chains
constructing the binding unit were mutated to Ala, was used as a reference state
to which combinations of side-chains were introduced. At first, pairs of
interacting residues were added allowing the determination of interaction
energies in the absence of neighbors, using double mutant cycles. Addition of
neighboring residues allowed the evaluation of their cooperative effects on the
interaction. The two isolated salt bridges were either neutral or repulsive
whereas the two hydrogen bonds contribute 0.3 kcal mol(-1 )each. Conversely, a
double mutant cycle analysis of these interactions in their native environment
showed that they all stabilize the complex by 1-1.5 kcal mol(-1). Examination of
the effects of neighboring residues on each of the interactions revealed that the
formation of a salt bridge triad, which involves two connected salt bridges, had
a strong cooperative effect on stabilizing the complex independent of the
presence or absence of additional neighbors. These results demonstrate the
importance of forming net-works of buried salt bridges. We present theoretical
electrostatic calculations which predict the observed mode of cooperativity, and
suggest that the cooperative networking effect results from the favorable
contribution of the protein to the interaction. Furthermore, a good correlation
between calculated and experimentally determined interaction energies for the two
salt bridges, and to a lesser extent for the two hydrogen bonds, is shown. The
data analysis was performed on values of DeltaDeltaG(double dagger)K(d) which
reflect the strength of short range interactions, while DeltaDeltaG(o)K(D) values
which include the effects of long range electrostatic forces that alter
specifically DeltaDeltaG(double dagger)k(a) were treated separately.
PMID- 10772867
TI - Homology-based method for identification of protein repeats using statistical
significance estimates.
AB - Short protein repeats, frequently with a length between 20 and 40 residues,
represent a significant fraction of known proteins. Many repeats appear to
possess high amino acid substitution rates and thus recognition of repeat
homologues is highly problematic. Even if the presence of a certain repeat family
is known, the exact locations and the number of repetitive units often cannot be
determined using current methods. We have devised an iterative algorithm based on
optimal and sub-optimal score distributions from profile analysis that estimates
the significance of all repeats that are detected in a single sequence. This
procedure allows the identification of homologues at alignment scores lower than
the highest optimal alignment score for non-homologous sequences. The method has
been used to investigate the occurrence of eleven families of repeats in
Saccharomyces cerevisiae, Caenorhabditis elegans and Homo sapiens accounting for
1055, 2205 and 2320 repeats, respectively. For these examples, the method is both
more sensitive and more selective than conventional homology search procedures.
The method allowed the detection in the SwissProt database of more than 2000
previously unrecognised repeats belonging to the 11 families. In addition, the
method was used to merge several repeat families that previously were supposed to
be distinct, indicating common phylogenetic origins for these families.
PMID- 10772869
TI - Message from the editor
PMID- 10772868
TI - Probing non-selective cation binding in the hairpin ribozyme with Tb(III).
AB - Catalysis by the hairpin ribozyme is stimulated by a wide range of both simple
and complex metallic and organic cations. This independence from divalent metal
ion binding unequivocally excludes inner-sphere coordination to RNA as an
obligatory role for metal ions in catalysis. Hence, the hairpin ribozyme is a
unique model to study the role of outer-sphere coordinated cations in folding of
a catalytically functional RNA structure. Here, we demonstrate that micromolar
concentrations of a deprotonated aqueous complex of the lanthanide metal ion
terbium(III), Tb(OH)(aq)(2+), reversibly inhibit the ribozyme by competing for a
crucial, yet non-selective cation binding site. Tb(OH)(aq)(2+) also reports a
likely location of this binding site through backbone hydrolysis, and permits the
analysis of metal binding through sensitized luminescence. We propose that the
critical cation-binding site is located at a position within the catalytic core
that displays an appropriately-sized pocket and a high negative charge density.
We show that cationic occupancy of this site is required for tertiary folding and
catalysis, yet the site can be productively occupied by a wide variety of
cations. It is striking that micromolar Tb(OH)(aq)(2+) concentrations are
compatible with tertiary folding, yet interfere with catalysis. The motif
implicated here in cation-binding has also been found to organize the structure
of multi-helix loops in evolutionary ancient ribosomal RNAs. Our findings,
therefore, illuminate general principles of non-selective outer-sphere cation
binding in RNA structure and function that may have prevailed in primitive
ribozymes of an early "RNA world".
PMID- 10772870
TI - Immunohistochemistry of the Hfe protein in patients with hereditary
hemochromatosis, iron deficiency anemia, and normal controls.
AB - In 1996 two mutations in Hfe, the gene affected in hereditary hemochromatosis,
were identified as C282Y (c.845G. A) and H63D (c.187C. G). Immunohistochemical
studies have localized the protein product of Hfe to the deep crypts of the
duodenum, the maximum site of iron absorption. To date, there are no published
data on the cellular location and regulation of Hfe in patients with
hemochromatosis who are homozygous for C282Y. The aim of this study was to
identify the cellular localization of Hfe in genotyped individuals and to study
possible regulation of this protein by the mutations described in the Hfe gene
locus and iron deficiency. Duodenal biopsy specimens and serum for iron,
ferritin, and transferrin saturation were taken from controls (n = 10) and
patients with hereditary hemochromatosis (n = 10) and iron deficiency anemia (n =
10). All participants were genotyped for C282Y and H63D mutations. Expression of
Hfe in the duodenum was demonstrated by immunohistochemistry. Hfe was expressed
in the deep crypts of the duodenum in all three groups in a perinuclear fashion.
Hfe staining was weaker in the hemochromatosis and iron deficiency patients (mean
transferrin saturation 69.6%, SD 23% and 15%, SD 11%, respectively) when compared
to controls (mean transferrin saturation 33.1%, SD 15%). There was no difference
in the intensity of Hfe staining within the hemochromatosis group who were iron
overloaded when compared to their iron-depleted counterparts. In summary, Hfe is
expressed strongly in the deep crypts of the small intestine of normal subjects.
Homozygosity for C282Y and conditions of iron deficiency result in a
downregulation of Hfe. Furthermore, Hfe is not regulated by therapeutic iron
depletion in patients with hemochromatosis who are homozygous for the C282Y
mutation.
PMID- 10772871
TI - Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint
Jean (Quebec, canada).
AB - We report the clinical, biochemical, and genetic characteristics of 13
hemochromatosis patients from Saguenay-Lac-Saint-Jean in whom the first symptoms
appeared before age 30. Although the mean age at onset of the first symptoms was
21. 5 years, their mean age at diagnosis was 23.8 years; the diagnosis was
particularly delayed among women. Seventy-seven percent of the patients had
hypogonadotrophic hypogonadism and 69% heart failure and/or cardiac arrhythmias.
Genetic analysis of the HFE gene revealed heterozygosity for the C282Y mutation
in 2 patients and for the S65C mutation in 2 others and homozygosity for the H63D
mutation in 1 patient. The remaining 8 patients had no identified mutation in the
HFE gene, although sequencing of all seven codons and intron-exon junctions was
performed (5 patients). All 13 patients fulfill the clinical criteria of juvenile
hemochromatosis and represent the largest cluster thus far reported.
PMID- 10772872
TI - SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT
7/Epo cells.
AB - We have investigated the interaction of the SH2-containing protein tyrosine
phosphatase-1 (SHP-1) and Jak2 in an erythropoietin (Epo)-dependent human
leukemia cell line, UT-7/Epo, using reciprocal immunoprecipitation and
immunoblotting. The Epo-induced kinetics and dose response on phosphorylated Jak2
in anti-SHP-1 precipitates of UT-7/Epo cell lysates were similar to those in
direct anti-Jak2 precipitates, suggesting that Jak2 coprecipitated with SHP-1.
Furthermore, immunoblotting with anti-Jak2 and anti-SHP-1 antibodies indicated
that SHP-1 appeared to be constitutively associated with non-tyrosine
phosphorylated Jak2 in UT-7/Epo cells in the absence of Epo and without
phosphorylation of the Epo receptor (EpoR). Competition studies with C-terminal
SHP-1 and Jak2 peptides decreased the amounts of SHP-1 and Jak2 detected in
immunoprecipitates supporting the specific coprecipitation of SHP-1 and Jak2. In
the presence of a recombinant GST-fusion protein containing both the N-terminal
and C-terminal SH2 domains of SHP-1, anti-GST precipitated the fusion protein but
not cellular Jak2. These studies suggest that SHP-1 and Jak2 are constitutively
associated in UT-7/EPO cells. The association is not dependent upon Epo and is
not mediated via SHP-1 SH2 binding. Sequential double immunoprecipitation
demonstrated that only a small portion of intracellular Jak2 and SHP-1 molecules
are constitutively associated. This partial association pattern may allow a more
flexible and diverse regulation of Jak2 and SHP-1 activities. Whether Jak2 and
SHP-1 are directly associated with each other or are part of a larger complex
needs further investigation.
PMID- 10772874
TI - Commentary: should whole-body red cell mass Be measured or calculated
PMID- 10772873
TI - Should whole-body red cell mass be measured or calculated?
AB - The whole-body volume of red blood cells must be known for correct diagnosis of
polycythemia vera. Since the venous hematocrit may not correctly reflect the
absolute amount of red blood cells, the red cell mass (RCM) is usually determined
by radioisotope labeling of red blood cells according to recommendations of the
International Committee for Standardization in Haematology. We examined whether
the radioisotope labeling procedure can be replaced by a simple calculation of
RCM from the values of venous blood hematocrit and plasma volume, using an
empirical factor (Ratio f) equal to the mean ratio between whole-body and venous
hematocrit. A retrospective study was performed of 264 cases in which the RCM was
assayed using (51)Cr or (99m)Tc for red cell labeling, and (125)I-labeled albumin
was used for estimation of plasma volume. The results showed wide scattering of
Ratio f (mean value 0.911; range from 0.76 to 1.15) that was responsible for
substantial differences between the measured and calculated values of RCM. We
also tested whether the calculated RCM may be used as an appropriate marker for
polycythemia vera according to recommendations of the International Council for
Standardization in Haematology. Our data showed that 146 patients had measured
RCM values more than 25% above the mean normal predicted value. Using the
calculated RCM, 17 of these patients would be lost from the polycythemia vera
group, whereas 29 subjects with measured RCM levels equal to or lower than 125%
of predicted values would incorrectly meet the RCM criterion for polycythemia
vera. Thus, a total of 46 patients would be misclassified by using the calculated
RCM. We conclude that the radioisotope labeling of red blood cells remains
mandatory for correct determination of the whole-body red cell volume.
PMID- 10772875
TI - Genomic structure of the human p47-phox (NCF1) gene.
AB - The cytosolic factor p47-phox, encoded by the NCF1 gene, is an essential
component of the phagocyte NADPH-oxidase system. Upon activation of this
multicomponent system, p47-phox translocates to the membrane and participates in
the electron transfer from NADPH to molecular oxygen. A deficiency or absence of
p47-phox is the most common autosomal form of chronic granulomatous disease
(CGD). We have cloned and characterized the NCF1 gene from four bacteriophage
clones, a P1 clone and genomic DNA from normal individuals. The gene is 15,236
base pairs long and includes 11 exons. It is 98.6% homologous in sequence to at
least one pseudogene that maps to the same region of chromosome 7q11.23. Slightly
more than half (50.37%) of the wild-type NCF1 gene consists of repetitive
elements. In particular, the density of Alu sequences is high (1.4 Alu/kb); there
are 21 Alu repeats interspersed through 10 introns. These findings are consistent
with the observation that recombination events between the wild-type gene and its
highly homologous pseudogenes account for the majority of potentially lethal
mutations in p47-phox-deficient chronic granulomatous disease. Analysis of 1.96
kb of sequence 5' of the start of translation revealed a high homology (99.6%)
between wild-type and pseudogene clones. Characterization of NCF1 establishes a
foundation for detailed molecular analysis of p47-phox-deficient CGD patients as
well as for the study of the regulation of the NCF1 gene and pseudogenes, both of
which are present as full-length transcripts in normal individuals.
PMID- 10772876
TI - Hematologically important mutations: red cell pyruvate kinase (Third update).
PMID- 10772877
TI - Leukemia Society of America workshop abstracts. Antisense molecular therapy.
PMID- 10772878
TI - Erythroid phosphatidyl serine exposure is not predictive of thrombotic risk in
mice with hemolytic anemia.
AB - Thrombosis is a major complication of human hemolytic anemias such as sickle cell
disease, thalassemia, and severe hereditary spherocytosis (HS). Mice with severe
HS and severe hereditary elliptocytosis (HE) also suffer from thrombosis, with
incidences ranging from 15 and 22% in beta-spectrin- and ankyrin-deficient mice,
respectively, to 85 to 100% in alpha-spectrin-deficient and band 3 knockout mice.
A contributing factor to thrombosis could be loss of phospholipid asymmetry of
the mutant red blood cells (RBCs), with concomitant exposure of the
aminophospholipid phosphatidylserine (PS). Increased PS exposure occurs in RBCs
from sickle cell and thalassemia patients and in RBCs from band 3-deficient mice.
To determine if increased PS exposure correlates with thrombotic risk in HS and
HE mice with ankyrin, beta-spectrin, and alpha-spectrin deficiencies,
measurements of FITC-labeled annexin V binding to externalized PS on RBCs were
performed. PS exposure is elevated in all mice with HS and HE, but the percentage
of RBCs with exposed PS does not correlate with thrombotic risk in these mice.
PMID- 10772879
TI - The ETS family member Tel antagonizes the Fli-1 phenotype in hematopoietic cells.
AB - The ETS family member Tel is rearranged in human leukemia of both myeloid and
lymphoid origin while the ETS member Fli-1 is insertionally activated in Friend
erythroleukemia in mice and is translocated to the EWS locus in Ewing's sarcoma.
In previous studies we demonstrated that Tel binds to Fli-1 and blocks
transactivation of megakaryocytic promoters by Fli-1. In this study we
demonstrate that expression of Fli-1 in the leukemia cell line K562 induces a
megakaryocytic phenotype and the expression of the platelet markers GPIX,
GP1balpha, and GPIIb. Introduction of Tel blocked the megakaryocytic phenotype
induced by Fli-1, suggesting a biological correlation to the biochemical
interaction of Tel and Fli-1 reported previously.
PMID- 10772881
TI - Molecular characterization of a German variant of glucose-6-phosphate
dehydrogenase deficiency (G6PD Aachen).
AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-chromosome-linked
hereditary disorder. Clinically, patients with G6PD deficiency often present with
drug- or food-induced hemolytic crises or neonatal jaundice. G6PD is involved in
the generation of NADPH and reduced glutathione. In contrast to American,
Mediterranean, and African ancestries, only few variants are known from Middle
and Northern Europe. We describe the molecular characterization of a distinct
variant from the northwestern area of Germany, G6PD Aachen. The sequence of the
G6PD gene from three afflicted males was found to be hemizygous at cDNA residue
1089 for a C-->G mutation with a predicted amino acid change of Asn363Lys. The
1089 C-->G point mutation is unique, but produces the identical amino acid change
found in a Mexican variant of G6PD deficiency, G6PD Loma Linda. This G6PD
deficient variant is caused by a 1089 C-->A mutation. The 363-amino-acid
replacement is located outside a known mutation cluster region between amino acid
residues 380 and 450, but may disrupt or weaken dimer interactions of G6PD enzyme
subunits.
PMID- 10772880
TI - Diminished blood levels of reduced glutathione and alpha-tocopherol in two
triosephosphate isomerase-deficient brothers.
AB - The glutathione redox system and alpha-tocopherol, both of which are essential
for maintaining the normal structure of biological membranes, some other lipid
soluble antioxidants (lycopene, beta-carotene, retinol), and lipid peroxidation,
were investigated in the blood from two triosephosphate isomerase (TPI)-deficient
brothers. Both of the genetically identical compound heterozygote brothers have
congenital hemolytic anemia, but only one of them has a neurological defect, the
second cardinal symptom of TPI deficiency. Whole blood reduced glutathione levels
were markedly decreased in both brothers. The glutathione reductase activities as
well as the NADPH contents of their erythrocytes were in the normal range or
slightly enhanced. Increased ratio of oxidized/reduced glutathione, elevated
glutathione S-transferase activity, and increased d-lactate level, a metabolite
of the glyoxalase pathway, were detected only in the neurologically affected
propositus. The plasma carotenoids (lycopene + beta-carotene), alpha
tocopherol/cholesterol + triglyceride ratios, and the erythrocyte alpha
tocopherol levels were significantly decreased in both patients. It seems
conceivable that membrane alterations due to the low level of these reducing
agents may contribute to the shortened life span of erythrocytes. The imbalance
of the prooxidant/antioxidant homeostasis as well as the increased rate of
methylglyoxal formation may also have been involved in the development of the
neurological manifestations in the propositus.
PMID- 10772882
TI - Oral isobutyramide therapy in patients with thalassemia intermedia: results of a
phase II open study.
AB - A pilot phase II open study on 12 patients with thalassemia intermedia (7 men, 5
women; age 31 +/- 2.0 years SE) treated with oral isobutyramide, a derivative of
butyric acid (150 mg/kg body wt/day), was performed in order to evaluate the
effect of this compound in stimulating hemoglobin F (HbF) production. No patient
underwent blood transfusion in the 1-year time frame prior to the study. Nine
patients were splenectomized. Safety was monitored by clinical and laboratory
tests. Efficacy was assessed in terms of the non-alpha/alpha globin chain
biosynthetic ratio and the percentage increase of HbF. The study design consisted
of a screening phase, a treatment phase of 28 days, and a posttreatment follow-up
of 28 days. All patients completed the study. Compliance to treatment was 100%.
No drug-related adverse event was recorded. We observed little or no increase in
the non-alpha/alpha ratio in the majority of patients. Six patients showed a
percentage increase of HbF at the end of treatment and in 5 of those 6 further
increases at the end of the follow-up period were observed. The change in
percentage of HbF over time was close to significance both in the treatment
period (P = 0. 06) and in the follow-up period (P = 0.08). These results indicate
that butyrate derivatives can stimulate fetal hemoglobin in patients with
intermediate thalassemia. Testing of the effects of different schedules of
administration of isobutyramide will be required in order to determine the
optimal use of this compound in the treatment of the beta-thalassemia syndromes.
PMID- 10772883
TI - Muscle force arises by actin filament rotation and torque in the Z-filaments.
AB - Actin filament rotation in skeletal muscle is studied by a mechanical model that
simulates structure and tension. The four anchoring Z-filaments are twisted
around and change the structure of the Z-lattice. The "small square" without
twist represents the resting stage of muscle. Torque causes contraction by
clockwise rotation (as seen from the Z-band), drilling into the A-band and
transition of the "small square" to "basket weave" by increasing the twist and
decreasing the torque. Release decreases the torque ("force-depression") by
passive clockwise rotation. Stretch causes increased torque ("stretch
activation") by passive counterclockwise rotation. Torque arises during Ca(2+)
activation by a conformational change in the highly charged coiled-coils: The
four alpha-actinin Z-filaments generate strong torque for the isometric tension.
Quick release experiments show that less than one rotation reduces this torque to
zero. The 5-12 rotations necessary for isotonic shortening result from torque
generation in the two long tropomyosin coiled-coils. Myosin controls the velocity
of active and passive rotations.
PMID- 10772884
TI - Surface and interface beta-chain residues synergistically affect hemoglobin
assembly.
AB - Homo- and heterotetramer formations of beta112 variants (beta(112Cys-->Asp),
beta(112Cys-->Ser), beta(112Cys-->Thr), and beta(112Cys-->Val)) of hemoglobin
were characterized in the presence and absence of beta(16Gly-->Asp) in vitro. In
all cases an alteration in overall surface charge (beta(16Gly-->Asp)) decreased
the beta(4) homotetramer stability (association constants as determined by gel
permeation chromatography) albeit to differing extents. In contrast, competition
experiments of hemoglobin subunits showed that heterotetramer formation was
promoted by this substitution. Order of increase in tetramer formation by the
additional negative surface charge in the beta112 variants was as follows: Hb
betaG16D, C112D > Hb betaG16D, C112S > Hb betaG16D > Hb G16D, C112T > Hb
betaG16D, C112V. Thus, the overall surface charge of the beta chain and its
contribution to electrostatic interaction in these instances appear to act in
synergy with alpha(1)beta(1) interface residues to affect the assembly of
hemoglobin molecules.
PMID- 10772885
TI - Purification of the newly found selenium-containing proteins in the arterial wall
and brain of the rat.
AB - Previously several selenium-containing proteins with different subunit molecular
masses (M(r)) were detected in the arterial wall and brain of rats. In
continuation of this work, after labeling of rats in vivo with [(75)Se]selenite,
the new selenium-containing proteins of interest were purified on a Sephadex G
200 column followed by preparative isoelectric focusing. Nuclear analytical
methods (gamma-counter and gamma-detector) were applied in the detection and
identification of the (75)Se-labeled proteins. The two (75)Se-containing proteins
from the arterial wall migrated as 15.0- and 67.0-kDa species on SDS-PAGE gels
with pI values of 4.5 and 5.1, respectively. The three (75)Se-containing proteins
from brain purified to homogeneity had M(r) values of 18.0, 30.0, and 42.9 kDa
and pI values of 6.3, 6.5, and 6.0, respectively. Of these proteins, the 67.0-,
42.9-, and 30.0-kDa species may be yet not characterized selenoproteins with
important biological functions.
PMID- 10772886
TI - The homeodomain of Nkx2.2 carries two cooperatively acting nuclear localization
signals.
AB - NK-2 family members of homeodomain proteins have been identified as important
regulators of growth and development in the ventral forebrain, heart, lung, and
thyroid. In addition, Nk2.2 expression has been detected in the pancreas, where
it is vital for the final differentiation of beta-cells. In our present paper, we
have analyzed the domains necessary for nuclear transport of Nkx2.2. With the
help of deletion mutants we identified two separate nuclear localization signals
(NLS). Interestingly, both NLSs are situated in the homeodomain. They belong to
the monopartite class of NLS; the proximal NLS has the sequence KKRKRR and lies
at the very N-terminus of the homeodomain, while the more distal NLS RYKMKRAR is
at the homeodomain C-terminus. Each NLS per se is sufficient for nuclear
transport of Nkx2.2 into the nucleus, although inefficiently. Both identified
NLSs act cooperatively in mediating complete nuclear transport of Nkx2.2.
PMID- 10772887
TI - Potent inhibition of dendritic cell differentiation and maturation by vitamin D
analogs.
AB - We show that the immunosuppressive effects of 1alpha, 25-dihydroxyvitamin D(3)
(1alpha,25(OH)(2)D(3)) are due, in part, to inhibition of the T cell stimulatory
functions of dendritic cells (DCs). Addition of 10(-12) and 10(-8) M
1alpha,25(OH)(2)D(3) to murine DC cultures resulted in a concentration-dependent
reduction in levels of class II MHC and the co-stimulatory ligands B7-1, B7-2,
and CD40 without affecting the number of DCs generated. Higher concentrations of
1alpha,25(OH)(2)D(3) reduced DC yield. The capacity of DCs to induce
proliferation of purified allogeneic T cells was reduced by 1alpha,25(OH)(2)D(3).
The vitamin D(3) analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor
D(3), exerted identical effects at 100-fold lower concentrations. Inhibition of
DC maturation and stimulatory function was absent in cultures from mice
genetically lacking vitamin D receptors (VDR). Vitamin D analogs effectively
reduce DC function via VDR-dependent pathways.
PMID- 10772888
TI - Expression of vascular endothelial growth factor mRNA in GI-101A and HL-60 cell
lines.
AB - Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has
a strong association with growth and metastasis of various cancers. We analyzed
the expression of VEGF mRNA levels in human breast-tumor derived GI-101A cells
and in human promyelocytic leukemia derived HL-60 cells using RT-PCR technique.
During our RT-PCR analysis we detected the expression of three splice variants of
VEGF mRNA at 400, 520 and, 650 bp lengths, which were amplified by a single set
of VEGF specific forward and reverse primers. The three RT-PCR products detected
by us in these cells correspond to the mRNA splice variants coding for the three
isoforms of VEGF respectively, VEGF(121), VEGF(165), and VEGF(189). Treatment of
GI-101A and HL-60 cells with phorbol 12, 13-dibutyrate (PDB) or
diethylstilbestrol (DES) resulted in a significant increase of VEGF mRNA levels
in a dose dependent manner. Both treatments increased the levels of all three
splice variants of VEGF mRNA and a maximum increase was detected with 10 microM
concentrations of PDB or DES treatments after 2 h. Interestingly, both PDB and
DES mediated stimulation of VEGF mRNA expression was completely blocked by the
PKC inhibitor chelerythrine. Quantitation of VEGF levels by ELISA technique
confirmed that changes seen in mRNA levels following different treatments altered
the release of VEGF. Our results suggest that PDB and DES mediated effects on
VEGF expression in GI-101A and HL-60 cells occur at the gene transcription level.
PMID- 10772889
TI - Improvement in circulating superoxide dismutase levels: role of nonsteroidal anti
inflammatory drugs in rheumatoid arthritis.
AB - Superoxide anion radical plays a significant role in inflammation, like
rheumatoid arthritis. Superoxide dismutase enzyme known to dismutate superoxide
anion radical does not play any significant role in this multisystem disease.
This paper reports that very low levels of circulating superoxide dismutase
levels are observed in patients with rheumatoid arthritis and these levels
significantly improve with NSAID therapy. The possible mechanism of the action is
discussed.
PMID- 10772890
TI - A missense mutation in the RING finger motif of PEX2 protein disturbs the import
of peroxisome targeting signal 1 (PTS1)-containing protein but not the PTS2
containing protein.
AB - SK24 and PT54 mutant cells, which are peroxisome-deficient Chinese hamster ovary
(CHO) cells isolated using peroxisomal forms of green fluorescent protein (GFP),
were found to be defective in the PEX2 gene. The nucleotide sequences of PEX2
cDNA from the mutant cells were determined to identify mutation sites in the
mutant cells. The mutation in SK24 cells changed cysteine to tyrosine at amino
acid position 258, which is a component of the RING finger (C(3)HC(4)) motif in
the carboxyl terminus of the protein. PT54 cells contained a nonsense mutation in
the codon for glutamine at position 101, resulting in premature termination. The
immunocytochemical analyses revealed distinct phenotypes between mutant cells
defective in the PEX2 gene. Both mutant cells exhibited cytosolic
mislocalizations on catalase and urate oxidase containing PTS1. On the other
hand, on 3-ketoacyl-CoA thiolase containing PTS2, PT54 cells exhibited cytosolic
mislocalization, but SK24 cells exhibited peroxisomal localization. When wild
type or mutant-type PEX2 cDNA was transfected into both mutant cells, the stable
transformants restored the phenotype in accordance with the transfected cDNA.
These observations indicate that an amino acid substitution, cysteine-258 to
tyrosine, in the RING finger motif of PEX2 protein, whose function is required
for peroxisomal localizations of both PTS1- and PTS2-containing proteins, results
in a complete defect in the PTS1 pathway but not in the PTS2 pathway.
PMID- 10772891
TI - Disulfide-bound proteolytic fragments of gastric mucin are 100- and 140-kDa
proteins.
AB - Pig gastric mucus was tested for its autodegradative proteolytic degradation at
pH 7.0, in the presence or absence of proteinase inhibitors and SDS. Samples of
crude mucus were incubated at room temperature for 48 and 96 h in sodium azide
stabilized buffer, pH 7. 0, and urea-extracted mucin was purified.
Electrophoretically homogenic mucin preparation was reduced and alkylated with
iodo[(14)C]acetamide, and analyzed for labeled products. On 7.5% SDS/PAGE protein
bands at 80 and 120 kDa were noted, but radioactivity was incorporated into 100-
and 140-kDa bands, with increasing intensity from T(0) to T(96), and into high
molecular mass mucin subunits. The results confirmed the autodegradative
properties of gastric mucin and demonstrated that the 100- and 140-kDa fragments
are the main proteolytical products of pig gastric mucin and are disulfide bound
with the rest of the molecule.
PMID- 10772893
TI - Plasmid-encoded degradation of p-nitrophenol and 4-nitrocatechol by Arthrobacter
protophormiae.
AB - Arthrobacter protophormiae strain RKJ100 is capable of utilizing p-nitrophenol
(PNP) as well as 4-nitrocatechol (NC) as the sole source of carbon, nitrogen and
energy. The degradation of PNP and NC by this microorganism takes place through
an oxidative route, as stoichiometry of nitrite molecules was observed when the
strain was grown on PNP or NC as sole carbon and energy sources. The degradative
pathways of PNP and NC were elucidated on the basis of enzyme assays and chemical
characterization of the intermediates by TLC, GC, (1)H NMR, GC-MS, UV
spectroscopy, and HPLC analyses. Our studies clearly indicate that the
degradation of PNP proceeds with the formation of p-benzoquinone (BQ) and
hydroquinone (HQ) and is further degraded via the beta-ketoadipate pathway.
Degradation of NC involved initial oxidation to generate 1,2,4-benzenetriol (BT)
and 2-hydroxy-1,4-benzoquinone; the latter intermediate is then reductively
dehydroxylated, forming BQ and HQ, and is further cleaved via beta-ketoadipate to
TCA intermediates. It is likely, therefore, that the same set of genes encode the
further metabolism of HQ in PNP and NC degradation. A plasmid of approximately 65
kb was found to be responsible for harboring genes for PNP and NC degradation in
this strain. This was based on the fact that PNP(-) NC(-) derivatives were devoid
of the plasmid and had simultaneously lost their capability to grow at the
expense of these nitroaromatic compounds.
PMID- 10772892
TI - Characterization of 5'-flanking region of human MRP3.
AB - We previously cloned MRP3, which is responsible for the cellular extrusion of
organic anions, as an inducible transporter in the liver under cholestatic
conditions. In the present study, we investigated the mechanism for the
expression of human MRP3. The cap site hunting method revealed that the
transcription starts at -25 and -27 nt upstream of the initiation codon.
Luciferase assay with a series of truncated 5'-flanking regions indicated that
the region from -127 to -23 nt is important for MRP3 expression. Moreover,
carrying out a gel shift assay indicated that Sp1 binds to the sequence between
92 and -58 nt. Collectively, it was demonstrated that human MRP3 is under the
control of TATA-less promoter and Sp1 binding sites may be involved in the
transcription.
PMID- 10772894
TI - Ca(2+)-modulated phosphorylation of a low-molecular-mass polypeptide in rat liver
mitochondria: evidence that it is identical with subunit c of F(0)F(1)-ATPase.
AB - A 3.5-kDa polypeptide associated with the inner membrane of rat liver was found
to be phosphorylated by [gamma-(32)P]ATP, presumably via a cAMP-dependent kinase.
The phosphorylation was modulated by [Ca(2+)] in the physiological range, with a
minimum at 1 microM and rising fourfold toward lower (10 nM) and higher (10
microM) concentrations. Further characterization of the 3.5-kDa component showed
that the polypeptide has the same electrophoretic mobility as subunit c of
F(0)F(1)-ATPase and that it selectively binds to antibodies against subunit c.
PMID- 10772895
TI - Magnetic field exposure stimulates transposition through the induction of DnaK/J
synthesis.
AB - Like some naturally occurring environmental stress factors such as heat shock and
UV irradiation, magnetic field exposure is also stimulatory to transposition
activity. This feature could be illustrated by a bacterial conjugation study
using an Escherichia coli strain that carries the transposable element Tn5 as the
donor. When the donor cultures were exposed to a low-frequency (50 Hz) magnetic
field of 1.2 mT, Tn5 located on the bacterial chromosome was stimulated to
transpose and settled on the extrachromosomal episome, and eventually transferred
to the recipient cell through conjugation. Such transposition activity
stimulation was mediated by the induced synthesis and accumulation of the heat
shock proteins DnaK/J.
PMID- 10772896
TI - Protein degradation by peroxide catalyzed by chromium (III): role of coordinated
ligand.
AB - In order to understand the role of coordinated ligands in controlling the
biotoxicity of chromium (III), interactions of three types of chromium (III)
complexes viz. trans-diaquo [1,2 bis (salicyledeneamino) ethane chromium (III)
perchlorate, [(Cr(salen)(H(2)O)(2)](ClO(4)); tris (ethylenediamine) chromium
(III) chloride, [Cr(en)(3)]Cl(3), and monosodium ethylene diamine tetraacetato
monoaquo chromiate (III), [Cr(EDTA)(H(2)O)]Na with BSA has been investigated.
Spectroscopic and equilibrium dialysis studies show that the two cationic
complexes Cr(salen)(H(2)O)(+)(2) and Cr(en)(3+)(3) bind to the protein with a
protein-metal ratio of 1:8 and 1:4. The anionic complex Cr(EDTA)(H(2)O)(-) binds
to the protein with a protein-metal ratio of 1:2. The binding constant K(b) as
estimated from the fluorescence quenching studies has been found to be 7.6 +/-
0.4 x 10(3) M(-1), 3.1 +/- 0.2 x 10(2) M(-1), and 1.8 +/- 0.2 x 10(2) M(-1) for
Cr(salen)(H(2)O)(+)(2), Cr(en)(3+)(3), and Cr(EDTA)(H(2)O)(-) respectively
indicating that the thermodynamic stability of protein-chromium complex is
Cr(salen)(H(2)O)(+)(2) > Cr(en)(3+)(3) approximately Cr(EDTA)(H(2)O)(-). The
complexes Cr(salen)(H(2)O)(+)(2) and Cr(EDTA)(H(2)O)(-) in the presence of
hydrogen peroxide have been found to bring about protein degradation, whereas
Cr(en)(3+)(3) does not bring about any protein damage. This clearly shows that
the nature of the chromium (III) complex plays a major role in the biotoxicity of
chromium (III).
PMID- 10772897
TI - Targeting of liposomes carrying recombinant fragments of platelet membrane
glycoprotein Ibalpha to immobilized von Willebrand factor under flow conditions.
AB - Liposomes with covalently bound recombinant fragments of platelet membrane
glycoprotein Ibalpha that retain the von Willebrand factor (vWf)-binding function
(rGPIbalpha-liposomes) were prepared. Their interactions with an immobilized vWf
surface under flow conditions were evaluated with a recirculating flow chamber,
mounted on an epifluorescence microscope, which allows real-time visualization of
fluorescence-labeled liposomes interacting with the surface. The interaction of
rGPIbalpha-liposomes with the vWf surface was directly related to shear rate. At
high densities of rGPIbalpha and vWf, rGPIbalpha-liposomes establishing contact
with the vWf surface exhibited continuous displacement with decreased velocity
relative to the hydrodynamic flow, depending on receptor density and matrix
concentration. At lower densities of rGPIbalpha and vWf, rGPIbalpha-liposomes
stopped only transiently, in the millisecond range, on the surface. This is the
first study to demonstrate that the targeting of rGPIbalpha-liposomes is specific
to the vWf surface under flow conditions.
PMID- 10772898
TI - PYK2/CAKbeta represents a redox-sensitive tyrosine kinase in vascular smooth
muscle cells.
AB - In vascular smooth muscle cells (VSMCs), the focal adhesion kinase-related
tyrosine kinase PYK2/CAKbeta is activated by vascular mitogens. Because reactive
oxygen species (ROS) are assumed to mediate mitogenic signals by these agonists,
we examined the possible link between ROS and PYK2 in cultured rat VSMCs. Here we
present several lines of evidence showing that PYK2 is activated by ROS in VSMCs.
The inhibitory effect of an antioxidant, N-acetyl-cysteine, on PYK2 activation by
its specific agonists further suggests the pivotal role of PYK2 in vascular
remodeling associated with enhanced ROS production.
PMID- 10772899
TI - Identification of an upstream promoter in the human gonadotropin-releasing
hormone receptor gene.
AB - Analysis of the human gonadotropin-releasing hormone receptor (hGnRHR) gene 5'
flanking region revealed the presence of multiple TATA, CCAAT, and transcription
start sites. In addition, at least three different transcripts (5.0, 2.5, and 1.5
kb) were detected by Northern blot analysis. Taken together, these data indicated
the existence of multiple promoter elements in the hGnRHR gene, and these
promoters are responsible for the multiplicity of regulation of human
reproductive functions. In this report, by progressive 5' and 3' deletion (-2197
to -1351, relative to the ATG) and NotI linker scanning mutagenesis coupled to
transient transfection into the mouse gonadotrope-derived alphaT3-1 cell, a
distal promoter element was identified at -1705/-1674. The promoter was located
immediately 5' to a previously identified CAP site at -1673 in human pituitary
and it drove a 17.6- +/- 1.0-fold increase in reporter gene activity. Within the
promoter, a pyrimidine-rich initiator element (Inr) (-1682) and a CCAAT box (
1702) were found and mutation of these elements abrogated both protein bindings
and promoter activities. By 1- and 2-D SouthWestern blot assays, multiple nuclear
factors (40 to 54 kDa) were found to interact specifically with this promoter
element. These nuclear factors were also present in other cells, including COS-7,
JEG-3, and SKOV-3 cells, and these findings were consistent with functional
studies which showed that the promoter is also active in these cells.
PMID- 10772900
TI - Analysis of Drosophila yellow-B cDNA reveals a new family of proteins related to
the royal jelly proteins in the honeybee and to an orphan protein in an unusual
bacterium Deinococcus radiodurans.
AB - The yellow locus in Drosophila is involved in both cuticle development and
behaviour. However, the function of the encoded protein is unknown. Here we have
characterised the sequence and expression pattern of a new Drosophila gene,
designated yellow-B, encoding a 453-amino-acid protein that is 57% identical to
Yellow. High levels of yellow-B mRNA are present in the larval-pupal stages, but
the gene is also expressed in the head. Bioinformatics analysis indicates that
the Drosophila genome encodes at least 7 members of the Yellow family distributed
among chromosomes 2, 3, and X. The Yellow proteins are related to the Royal Jelly
proteins and have no relatives in other non-insect metazoan species.
Interestingly, a Yellow-like protein is encoded by the genome of a radiation
tolerant bacterium, Deinococcus radiodurans.
PMID- 10772901
TI - Residue 285 in cytochrome P450 2B4 lacking the NH(2)-terminal hydrophobic
sequence has a role in the functional association of NADPH-cytochrome P450
reductase.
AB - Cytochrome P450 2B4 (CYP2B4) lacking the NH(2)-terminal signal anchor sequence (2
27) was used to study the impact of replacement of histidine with alanine at
position 285 on electron transfer from NADPH-cytochrome P450 reductase (P450R).
Absorption and circular dichroism spectra of the recombinant hemoproteins
indicated that amino acid substitution neither grossly perturbed the geometry of
the immediate heme vicinity nor the global polypeptide backbone folding. Fitting
of the initial-velocity patterns of P450R-directed reduction of the ferric CYP2B4
(2-27) forms to the Michaelis-Menten kinetics revealed an approximately 3.5-fold
increase in the apparent K(m) value for the electron donor of the H285A mutant,
while its reductive capacity (V(max)) remained unchanged; this caused a strong
drop in reductive efficiency of the engineered enzyme. Circumstantial analysis
suggested that impaired association of the redox partners accounted for this
phenomenon. Thus, deletion of the positive charge at position 285 of CYP2B4 (2
27) might have disrupted contacts with oppositely charged entities on the P450R
surface. Measurements of the stoichiometry of aerobic NADPH consumption and
H(2)O(2) production disclosed the oxyferrous H285A species to autoxidize more
readily compared with the shortened wild type. This was assumed to arise from
less efficient coupling of the system due to defective donation of the second
electron by P450R. These results are consistent with the view that His-285 in the
truncated CYP2B4 is of importance in the functional interaction with the
flavoprotein reductase.
PMID- 10772902
TI - Methylene blue photosensitized oxidation of cysteine sulfinic acid and other
sulfinates: the involvement of singlet oxygen and the azide paradox.
AB - The methylene blue photosensitized oxidation of cysteine sulfinic acid is
investigated. Enhancement of the oxygen consumption rate in deuterium oxide
suggests the involvement of singlet oxygen ((1)O(2)) in oxidation. Addition of
the (1)O(2) quencher azide produced an unusual enhancement of the oxidation rate
of all the sulfinates assayed. It is assumed that azide works as a one-electron
carrier between (1)O(2) and the sulfur compounds. Analyses of the products
indicate that the photochemical oxidation of cysteine sulfinic acid proceeds
through two simultaneous mechanisms. The Type II (singlet oxygen) mechanism is
responsible for oxidation of the sulfinic group to the sulfonic group with
production of cysteic acid, stable to the photooxidation system, whereas the Type
I (electron transfer) mechanism is involved in the degradation of cysteine
sulfinic acid to acetaldehyde. Other products detected were ammonia, sulfate, and
hydrogen peroxide which account for the degradation of cysteine sulfinic acid and
for the excess of oxygen consumption detected during the oxidative reaction.
PMID- 10772903
TI - Characterization of the human porin isoform 1 (HVDAC1) gene by amplification on
the whole human genome: A tool for porin deficiency analysis.
AB - The deficiency of porin isoform 1 (HVDAC1) in human skeletal muscle has been
associated with a pathological phenotype related to defects in the bioenergetic
metabolism. In the best studied case, porin deficiency was not apparent in
cultured fibroblasts: this observation raised the conclusion that no molecular
defect was in the cDNA sequence coding for the protein. To get more insight in
the pathogenetic mechanism that is involved in porin isoform 1 deficiency, we
have determined the whole structure of the corresponding human gene. On the basis
of the corresponding mouse gene structure and the human cDNA sequence, we
designed long extension PCR amplifications using the whole genomic DNA as a
template. Exonic/intronic regions were isolated and the exons and surrounding
introns sequenced. The 5' and 3' extremities of the gene were determined by
genome walking. The porin isoform 1 human gene is made up of 9 exons and spans
about 33 kbp. A whole panel of PCR parameters was set and is now ready to be used
for specific amplification upon patients' genomic DNA. The analysis of the
putative promoter sequence was performed. It revealed the presence of a sterol
Repressor element (SRE), an SRY, the testis-determining factor, and a nuclear
respiratory factor 2 (NRF-2) binding site. These sites, according to results from
literature, could be involved in the functional modulation of the gene
expression.
PMID- 10772904
TI - Involvement of caspase-3 in epigallocatechin-3-gallate-mediated apoptosis of
human chondrosarcoma cells.
AB - Green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG)-is a potent
chemopreventive agent in many test systems and has been shown to inhibit tumor
promotion and induce apoptosis. In this study we describe a novel observation
that EGCG displayed strong inhibitory effects on the proliferation and viability
of HTB-94 human chondrosarcoma cells in a dose-dependent manner and induced
apoptosis. Investigation of the mechanism of EGCG-induced apoptosis revealed that
treatment with EGCG resulted in DNA fragmentation, induction of caspase-3/CPP32
activity, and cleavage of the death substrate poly(ADP-ribose)polymerase (PARP).
Pretreatment of cells with a synthetic pan-caspase inhibitor (Z-VAD-FMK) and a
caspase-3-specific inhibitor (DEVD-CHO) prevented EGCG-induced PARP cleavage. The
induction of apoptosis by EGCG via activation of caspase-3/CPP32-like proteases
may provide a mechanistic explanation for its antitumor effects.
PMID- 10772905
TI - Wortmannin, a PI3-kinase inhibitor: promoting effect on insulin secretion from
pancreatic beta cells through a cAMP-dependent pathway.
AB - To determine the role of phosphatidylinositol 3-kinase (PI3-kinase) in the
regulation of insulin secretion, we examined the effect of wortmannin, a PI3
kinase inhibitor, on insulin secretion using the isolated perfused rat pancreas
and freshly isolated islets. In the perfused pancreas, 10(-8) M wortmannin
significantly enhanced the insulin secretion induced by the combination of 8.3 mM
glucose and 10(-5) M forskolin. In isolated islets, cyclic AMP (cAMP) content was
significantly increased by wortmannin in the presence of 3.3 mM, 8.3 mM, and 16.7
mM glucose with or without forskolin. In the presence of 16.7 mM glucose with or
without forskolin, wortmannin promoted insulin secretion significantly. On the
other hand, in the presence of 8.3 mM glucose with forskolin, wortmannin
augmented insulin secretion significantly; although wortmannin tended to promote
insulin secretion in the presence of glucose alone, it was not significant. To
determine if wortmannin increases cAMP content by promoting cAMP production or by
inhibiting cAMP reduction, we examined the effects of wortmannin on 10(-4) M 3
isobutyl-1-methylxantine (IBMX)-induced insulin secretion and cAMP content. In
contrast to the effect on forskolin-induced secretion, wortmannin had no effect
on IBMX-induced insulin secretion or cAMP content. Moreover, wortmannin had no
effect on nonhydrolyzable cAMP analog-induced insulin secretion in the perfusion
study. These data indicate that wortmannin induces insulin secretion by
inhibiting phosphodiesterase to increase cAMP content, and suggest that PI3
kinase inhibits insulin secretion by activating phosphodiesterase to reduce cAMP
content.
PMID- 10772906
TI - Activation of neuroendocrine L-type channels (alpha1D subunits) in retinal
pigment epithelial cells and brain neurons by pp60(c-src).
AB - The aim of this study is to characterize the subtype of tyrosine kinase-regulated
L-type Ca(2+) channels in retinal pigment epithelial (RPE) cells. Ca(2+) channel
alpha1D-subunits were enriched by immunoprecipitation from membrane proteins
isolated from rat RPE cells. Western blot analysis of the precipitates revealed
coprecipitation of pp60(c-src). In addition, in precipitates obtained with
antibodies against pp60(c-src), alpha1D-subunits were identified. The same was
observed in immunoprecipitations from rat brain neurons. Tyrosine phosphorylation
of alpha1D-subunits was confirmed using anti-phosphotyrosine antibodies. Ba(2+)
currents through L-type channels in cultured rat RPE cells were increased by
intracellular application of active pp60(c-src) (30 U/ml) (heat-inactivated
pp60(c-src) had no effect). Thus, L-type channels of the neuroendocrine subtype
can be expressed in epithelial cells and are activated by tyrosine kinase of the
src subtype. This kind of regulation is also suggested for brain-derived neurons.
PMID- 10772907
TI - Paradoxical effects of mineralocorticoids on the ion gated sodium channel in
embryologically diverse cells.
AB - PCR analysis and Western blotting revealed the expression of the
mineralocorticoid receptor (MCR) and the epithelial sodium channel (ENaC) genes
at the level of RNA, DNA, and protein in several leukemic cell lines, fibroblasts
from human cornea, and epithelial cells from ocular tissues. Following
immunofluorescence, the MCR appeared to be primarily nuclear whereas the ENaC was
almost exclusively membrane-bound. Paradoxically, the MCR-specific antagonist ZK
91587 actually stimulated the multiplication of human erythroblastic leukemia
cells, contrary to the inhibitory effect of the antagonist RU 26752 on the
multiplication of corneal fibroblasts; both effects were opposed by aldosterone.
In quantitative PCR, both basal and aldosterone-induced levels of ENaC were
diminished by ZK 91587 in the corneal fibroblast, in contrast to the stimulation
observed in the retinal pigmentary epithelium. Thus, contrary to the existing
notions, (a) antimineralocorticoids can act both as agonists and antagonists, and
(b) the receptor-mediated action of mineralocorticoids on the sodium channel is
not restricted to the epithelial cell.
PMID- 10772908
TI - Bcl-2 antibodies induce hemoglobin release by red blood cells loaded with in
vitro translated Bcl-2 and its cleaved fragment.
AB - Apoptosis induced by proteasome inhibitor in human THP-1 leukemia cells is
associated with the cleavage of Bcl-2 into a shortened fragment, Bcl-2/Delta34.
Both Bcl-2 and its cleaved fragment were located exclusively on the mitochondria
of THP-1 cells. No translocation of Bcl-2 or Bcl-2/Delta34 to the cytosolic
fraction was detected during apoptosis. Treatment of isolated mitochondria with
recombinant caspase-3 induced the same cleavage of Bcl-2 in vitro and triggered
the release of cytochrome c from the mitochondria. The ability of Bcl-2/Delta34
in regulating the opening of membrane "pores" was investigated using a sheep red
blood cell (RBC) model with in vitro translated Bcl-2/Delta34 and Bcl-2 proteins.
Bcl-2 and Bcl-2/Delta34 generated in vitro were relocated rapidly to sheep RBC
but caused no hemoglobin release in either case. Addition of anti-Bcl-2
antibodies directly to the RBC that had been loaded with either Bcl-2 or Bcl
2/Delta34 resulted in a rapid release of hemoglobin from the blood cells.
Treatment of the sheep RBC with anti-Bcl-2 or anti-sheep RBC antibodies alone did
not trigger hemoglobin release from the RBC. Based on these findings, we proposed
that, upon "enforced aggregation," both Bcl-2 and Bcl-2/Delta34 can form "pores"
in membranes, which may contribute to the release of cytochrome c in apoptosis.
PMID- 10772909
TI - Lysine residues 162 and 340 are involved in the catalysis and coenzyme binding of
NADP(+)-dependent malic enzyme from pigeon.
AB - Alanine-scanning site-directed mutagenesis was carried out on all conserved
lysine residues of pigeon cytosolic NADP(+)-dependent malic enzyme. Only two
mutant enzymes, K162A and K340A, showed significant effect on their kinetic
parameters. Both mutant enzymes have K(m) values for Mn(2+) and l-malate similar
to those of wild-type. The K(m) value for NADP(+) of K162A is identical to that
of wild-type. However, K162A demonstrated a 235-fold decrease in the k(cat) value
(0.17 +/- 0.01 vs 40.0 +/- 1.3 s(-1)). These data suggested that the side chain
of K162 is important for the enzyme catalytic reaction. We propose that the
epsilon-amino group of K162 may serve as a general acid to protonate the 3-carbon
of enolpyruvate after decarboxylation. The K340A mutant demonstrated no effect on
the k(cat) value. However, its K(m) value for NADP(+) was increased by a factor
of 65 (225.7 +/- 5.07 vs 3.49 +/- 0.05 microM). We propose that the NADP(+)
specificity is determined by the electrostatic interaction between the epsilon
amino group of K340 and 2'-phosphate of NADP(+).
PMID- 10772910
TI - Evaluation of boar sperm as a model system to study the mechanism of spermicidal
activity of vanadocenes.
AB - bis-cyclopentadienyl [Cp] complexes of vanadium(IV) or vanadocenes are rapid and
potent inhibitors of human sperm motility with potential as a new class of
contraceptive agents. We investigated the utility of boar sperm as a model system
to study the mechanisms of drug action because boar sperm lacks phosphocreatine
and creatine kinase activity, the essential components of the "phosphagen
shuttle" system for human sperm motility. Two representative vanadocenes,
vanadocene dichloride [VDC] and bis[pentamethylcyclopentadienyl] vanadium
dichloride [VPMDC], in which the bis-Cp rings were substituted with five electron
donating methyl groups were evaluated. The concentration-dependent effects of VDC
and VPMDC on spermicidal activity, axonemal dynein adenosine triphosphatase
(ATPase) activity, and tyrosine phosphorylation of global sperm proteins were
assessed by computer-assisted sperm analysis, spectrophotometry, and
immunoblotting, respectively. Both the unsubstituted and the pentamethyl
substituted vanadocene induced rapid sperm immobilization (T(1/2) < 15 s).
Substitution of the bis-Cp rings by five methyl groups augmented the SIA of VDC
threefold. The EC(50) values for VDC and VPMDC were 2.1 and 0.76 microM,
respectively. Spermicidal activity of vanadocenes was not associated with the
inhibition of dynein ATPase(s) or increase in tyrosine phosphorylation of sperm
proteins. These results suggest that the potent spermicidal activity of
vanadocenes against boar sperm is mediated by a unique mechanism that is
independent of dynein ATPase activity, phosphatase activity, and
phosphocreatine/creatine kinase system. Therefore, boar sperm is a suitable model
for further investigating the molecular mechanism of spermicidal action of
vanadocenes.
PMID- 10772911
TI - Surfactant protein A exhibits inhibitory effect on eosinophils IL-8 production.
AB - Eosinophils are believed to be one of the important sources of cytokines such as
IL-8 at the site of allergic inflammation. It has been demonstrated that
pulmonary surfactant protein A (SP-A) plays a potential role in modifying
inflammation and the immune function. To verify the regulating effect of SP-A on
eosinophil cytokine generation, we studied the effect of SP-A by determining of
IL-8 production and expression stimulated with sIgA or PMA. SP-A purified from
surfactant recovered from patients with alveolar proteinosis was added to
eosinophils isolated by the negative selection method with immunomagnetic beads,
and cultured for 24 h. The concentrations of IL-8 in the cell-free supernatants
and cell lysates were then measured by ELISA. We also used a semiquantitative
reverse transcriptase-polymerase chain reaction assay to detect the effect of SP
A on IL-8 mRNA expression. SP-A inhibited the secretion of IL-8 in a dose
dependent fashion. Suppression of IL-8 production by SP-A was significantly
inhibited by SP-A antibody (PE10). SP-A also attenuated expression of IL-8 mRNA
in eosinophils. These results indicate that SP-A might have the potential role to
modify allergic inflammation by inhibiting IL-8 expression and production from
eosinophils.
PMID- 10772912
TI - Electrogenic nature of rat sodium-dependent multivitamin transport.
AB - We report on the electrogenic nature of the transport process mediated by the rat
sodium-dependent multivitamin transporter. In Cos-7 cells, the relationship of
Na(+) concentration versus biotin and pantothenate uptake rate was sigmoidal with
a Na(+):substrate stoichiometry of 2:1. In Cos-7 cells expressing rat SMVT biotin
transport was significantly higher when the membrane was hyperpolarized and
considerably reduced when the membrane was depolarized. Similarly, biotin uptake
in X. laevis oocytes expressing rat SMVT was inhibited with depolarized oocyte
membrane by altering the K(+) permeability across the membrane. It is concluded
that the transport of biotin and pantothenate mediated by rat SMVT is
electrogenic with a Na(+):substrate coupling ratio of 2:1 and that the transport
process is associated with the transfer of one net positive charge across the
membrane per transport cycle.
PMID- 10772913
TI - Quantification of SNARE protein levels in 3T3-L1 adipocytes: implications for
insulin-stimulated glucose transport.
AB - Insulin-stimulates glucose transport in peripheral tissues by stimulating the
movement ('translocation') of a pool of intracellular vesicles containing the
glucose transporter Glut4 to the cell surface. The fusion of these vesicles with
the plasma membrane results in a large increase in the numbers of Glut4 molecules
at the cell surface and a concomitant enhancement of glucose uptake. It is well
established that proteins of the VAMP- (synaptobrevin) and syntaxin-families play
a fundamental role in the insulin-stimulated fusion of Glut4-containing vesicles
with the plasma membrane. Studies have identified key roles for vesicle
associated membrane protein-2 (VAMP2) and syntaxin-4 in this event, and more
recently have also implicated SNAP-23 and Munc18c in this process. In this study,
we have quantified the absolute levels of expression of these proteins in murine
3T3-L1 adipocytes, with the objective of determining the stoichiometry of these
proteins both relative to each other and also in comparison with previous
estimates of Glut4 levels within these cells. To achieve this, we performed
quantitative immunoblot analysis of these proteins in 3T3-L1 membranes compared
to known amounts of purified recombinant proteins. Such analyses suggest that in
3T3-L1 adipocytes there are approximately 374,000 copies of syntaxin 4, 1.15 x
10(6) copies of SNAP23, 495,000 copies of VAMP2, 4.3 x 10(6) copies of
cellubrevin and 452,000 copies of Munc18c per cell, compared to previous
estimates of 280,000 copies of Glut4. Thus, the main SNARE proteins involved in
insulin-stimulated Glut4 exocytosis (syntaxin 4 and VAMP2) are expressed in
approximately equimolar amounts in adipocytes, whereas by contrast the endosomal
v-SNARE cellubrevin is present at approximately 10-fold higher levels and the t
SNARE SNAP-23 is also present in an approximately 3-fold molar excess. The
implications of this quantification for the mechanism of insulin-stimulated Glut4
translocation are discussed.
PMID- 10772914
TI - Retinoic acid inhibits nitric oxide synthase-2 expression through the retinoic
acid receptor-alpha.
AB - Retinoids are multipotent modulators of cellular functions and suppress cytokine
induced production of nitric oxide (NO) in several cell types. We have explored
the mechanisms by which retinoic acid (RA) regulates NO production in rat aortic
smooth muscle cells (VSMC), which express NOS2 in response to proinflammatory
cytokines. RA inhibited interleukin-1beta (IL-1beta)-induced NOS2 mRNA expression
and NO production. These effects were attenuated by the retinoic acid receptor
(RAR) antagonist CD3106, indicating that they were mediated through retinoic acid
receptors (RARs). The synthetic retinoid agonists CD336 (which specifically binds
RARalpha) and CD367 (which binds all RARs) but not agonists specific for RARbeta,
RARgamma, or RXRs reduced IL-1beta-induced NOS2 expression and NO production.
When transfecting VSMC with a 1570-bp NOS2 promoter fragment fused to a
luciferase reporter gene, the NOS2 promoter activity was inhibited by RA. These
results indicate that retinoids modulate NO production in VSMC via RARalpha,
which inhibits the transcription of the NOS2 gene.
PMID- 10772915
TI - Measurement of 5-hydroxy-2-aminovaleric acid as a specific marker of iron
mediated oxidation of proline and arginine side-chain residues of low-density
lipoprotein apolipoprotein B-100.
AB - An alteration of apolipoprotein (apo) B-100 structure by direct oxidative
modification is supposed to be an important mechanism involved in atherogenesis.
There is difficulty in quantifying this type of modification owing to a lack of
specific assays. We evaluated a methodology based on the oxidation of protein
arginine and proline to gamma-glutamyl semialdehyde which by reduction forms 5
hydroxy-2-aminovaleric acid (HAVA). We determined HAVA by using derivatization to
N(O)-ethoxycarbonyl ethyl esters and gas chromatography-mass spectrometry in
different low-density lipoprotein preparations subjected to oxidative damage in
the presence of iron. Results suggest that apoB-100 proline and arginine residues
are highly reactive toward oxygen radicals ex vivo. Femtomole levels of HAVA can
be reproducible measured. HAVA determination compares well with the measurement
of carbonyl group formation used as a generally accepted but nonspecific index of
protein oxidation. Thus, HAVA could prove to be a sensitive assay for studying
specific modification of apoB-100.
PMID- 10772916
TI - Neutrophil beta2-integrin upregulation is blocked by a p38 MAP kinase inhibitor.
AB - Tumor necrosis factor-alpha is known to upregulate the expression of surface
adhesion molecules on polymorphonuclear leukocytes (PMNs). The purpose of this
investigation was to study possible intracellular signaling pathways responsible
for the upregulation of beta2 integrins on normal human PMNs induced by TNF. We
report that treatment with TNF (10 ng/ml) for 30 min resulted in a significant
increase in CD18 and MAC-1 surface expression (P < 0.001). In addition,
pretreatment with 15 microM SB203580, a p38 MAP kinase inhibitor, for 10 min
significantly inhibited TNF upregulation of CD18 and MAC-1 (P < 0.0001).
Pretreatment with either 15 microM PD 98059, a p42/44 MAP kinase inhibitor, or 5
microM GO 6850, a protein kinase C inhibitor, had no significant inhibitory
effect. These data suggest that the TNF-induced upregulation of beta2 integrins
is mediated specifically through the p38 MAP kinase pathway and not through the
p42/44 MAP kinase or protein kinase C pathways.
PMID- 10772917
TI - NifH and NifM proteins interact as demonstrated by the yeast two-hybrid system.
AB - Biological nitrogen fixation is catalyzed by nitrogenase, a two-component enzyme
consisting of the MoFe protein and the Fe protein. Two genes are involved in the
formation of active Fe protein: nifH encodes the structural polypeptide, while
nifM specifies a stabilizing and activation function by yet unknown mechanisms.
Our studies were directed to clarify whether the NifM exerts its function through
physical protein-protein interaction with NifH. To accomplish this, we used the
yeast two-hybrid system. The simultaneous expression of the GAL4 binding domain
nifH fusion and GAL4 activation domain-nifM fusion resulted in the successful
activation of GAL4-responsive HIS3, ADE2, and lacZ reporter genes in the two
hybrid system used. The system was also used to evidence the potential for in
vivo NifH and NifM self-association. The results obtained suggest that NifH and
NifM form homomers and also associate in between to form higher order complexes,
which may be needed to exert the effect of NifM on Fe protein stability and
activity.
PMID- 10772918
TI - Characterization of Bax-sigma, a cell death-inducing isoform of Bax.
AB - The Ced-9/Bcl-like family of genes codes for proteins that have antiapoptotic and
proapoptotic activity. Several Bax isoproteins have been detected by 2-D gel
electrophoresis, and a novel human member, designated as Bax-sigma, has been
identified and cloned from human cancer promyelocytic cells. Bax-sigma contains
BH-3, BH-1, and BH-2 domains, putative alpha-5 and alpha-6 helices, and the
carboxy-terminal hydrophobic transmembrane domain but lacks amino acids 159 to
171 compared to Bax-alpha. mRNA expression analysis by reverse transcription
polymerase chain reaction and RNase protection assays have revealed that Bax
sigma is expressed in a variety of human cancer cell lines and normal tissues. To
investigate the potential role of Bax-sigma in apoptosis, first its effects were
compared to those of Bax-alpha by transient expression in human B lymphoma
Namalwa cells. Both Bax-sigma and Bax-alpha promoted apoptosis, as detected by
DNA fragmentation and morphological analysis by electron microscopy. The
apoptosis induced by Bax-sigma and Bax-alpha was correlated with their
expression, cytochrome c release, and caspase activation. In a yeast two-hybrid
system, Bax-sigma interacted with several Ced-9/Bcl family members but had no
affinity for the human Egl-1 homologs Bik and Bad and the Ced-4 homolog Apaf-1.
In human cells, Bax-sigma function was counteracted by Bcl-xL overexpression, and
co-immunoprecipitation experiments indicated that Bax-sigma was associated with
Bcl-xL. Furthermore, Bax-sigma overexpression increased cell death induced by
various concentrations of genotoxic agents with the most pronounced effect
occurring at low camptothecin and vinblastine dose levels. Our results suggest
that Bax-sigma, a novel variant of Bax, encodes a protein with a proapoptotic
effect and mode of action similar to those of Bax-alpha.
PMID- 10772919
TI - Reduction of organic nitrites to nitric oxide catalyzed by xanthine oxidase:
possible role in metabolism of nitrovasodilators.
AB - Xanthine oxidase (XO) was shown to catalyze the reduction of isoamyl and isobutyl
nitrites to nitric oxide (NO) in the presence of xanthine under anaerobic
conditions. NO was produced at a stoichiometric ratio of 2:1 versus urate
generation, steady-state analysis of which showed Michaelis-Menten kinetics with
xanthine as varied substrate and substrate inhibition with varied organic
nitrite. Under the conditions of NO generation from isoamyl nitrite, XO was
progressively inactivated by a mechanism involving conversion of Mo=S to Mo=O,
yielding "desulfo" enzyme. It is proposed that XO is involved in the metabolism
of organic nitrites to NO in vivo and that the observed inactivation serves to
explain the phenomenon of tolerance.
PMID- 10772921
TI - Regulation of urokinase receptor transcription by Ras- and Rho-family GTPases.
AB - How cell adhesion is coordinated with extracellular proteolysis is a key question
in understanding cell migration. Potentially, the small GTP-binding proteins that
affect actin organisation and signal transduction may also regulate the
expression of genes associated with extracellular proteolysis. We investigated
the ability of Ras, Rac-1, Cdc42Hs, and RhoA to regulate transcription from
the1.55-kb promoter region of the human urokinase plasminogen activator receptor
(uPAR) gene. Constitutively active V12 H-Ras and Rho-A stimulated uPAR
transcription while Cdc42Hs and Rac-1 did not. The use of Ras effector-loop
mutants indicated that signalling via multiple Ras-effectors is necessary for the
maximum activation of transcription.
PMID- 10772920
TI - Anabolic function of the type II isozyme of hexokinase in hepatic lipid
synthesis.
AB - The mRNA encoding the Type II isozyme of hexokinase was markedly elevated in
livers of transgenic mice overexpressing the transcriptionally active nuclear
form of sterol regulatory element binding protein-1a (nSREBP-1a), but not in
transgenic mice overexpressing the nSREBP-1c or nSREBP-2 isoforms. Cellulose
acetate electrophoresis and immunoblotting results confirmed selective increase
of the Type II isozyme in livers of transgenic mice expressing nSREBP-1a. SREBP
1a has previously been shown to activate transcription of genes encoding enzymes
involved in biosynthesis of fatty acids and glycerolipids and to a lesser extent
the enzymes of cholesterol biosynthesis. Thus, these results are consistent with
the view that the Type II isozyme serves an anabolic function, providing
precursors and reducing equivalents required for increased rates of hepatic lipid
synthesis.
PMID- 10772922
TI - Alpha-galactosidase stimulates acetylcholine receptor aggregation in skeletal
muscle cells via PNA-binding carbohydrates.
AB - Aggregation of nicotinic acetylcholine receptors (AChRs) in skeletal muscle is an
essential step in the formation of the mammalian neuromuscular junction. While
proteins that bind to myotube receptors such as agrin and laminin can stimulate
AChR aggregation in cultured myotubes, removal of cell surface sialic acids
stimulates aggregation in a ligand-independent manner. Here, we show that removal
of cell surface alpha-galactosides also stimulates AChR aggregation in the
absence of added laminin or agrin. AChR aggregation stimulated by alpha
galactosidase was blocked by peanut agglutinin (PNA), which binds to lactosamine
containing disaccharides, but not by the GalNAc-binding lectin Vicia villosa
agglutinin (VVA-B4). AChR aggregation stimulated by alpha-galactosidase
potentiated AChR clustering induced by either neural agrin or laminin-1 and could
be inhibited by muscle agrin. These data suggest that capping of cell surface
lactosamines or N-acetyllactosamines with alpha-galactose affects AChR
aggregation much as capping with sialic acids does.
PMID- 10772923
TI - MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion
structures.
AB - The family of membrane-associated guanylate kinases (MAGUK) comprises peripheral
membrane proteins involved in the formation of specialized cell-cell junctions.
MAGUK proteins possess a conserved domain composition, containing PDZ, guanylate
kinase, and SH3 or WW domains. MAGI-1 is a recently identified member of the
MAGUK protein family. Three splice variantsof MAGI-1 have been characterized to
date, including MAGI-1a, -1b, and -1c. MAGI-1b is predominantly associated with
the crude membrane fraction. Here we show that the fifth PDZ domain of MAGI-1b is
essential for membrane localization. We have also identified beta-catenin as a
potential ligand for this PDZ domain. MAGI-1b forms complexes with beta-catenin
and E-cadherin during the formation of cell-cell junctions in MDCK cells. In
agreement with this observation, a significant portion of a GFP fusion of MAGI-1b
localizes to the basolateral membrane of polarized MDCK cells.
PMID- 10772924
TI - Evidence for tryptophan in proximity to histidine and cysteine as essential to
the active site of an alkaline protease.
AB - The presence, microenvironment, and proximity of an essential Trp with the
essential His and Cys residues in the active site of an alkaline protease have
been demonstrated for the first time using chemical modification, chemo-affinity
labeling, and fluorescence spectroscopy. Kinetic analysis of the N
bromosuccinimide- (NBS) or p-hydroxymercuribenzoate- (PHMB) modified enzyme from
Conidiobolus sp. revealed that a single Trp and Cys are essential for activity in
addition to the Asp, His, and Ser residues of the catalytic triad. Full
protection by casein against inactivation of the enzyme by NBS and quenching of
Trp fluorescence upon binding of the enzyme with NBS, substrate (sAAPF-pNA), or
inhibitor (SSI) confirmed participation of the Trp residue at the
substrate/inhibitor binding site of the alkaline protease. Comparison of the
K(sv) values for the charged quenchers CsCI (1.66) and KI (7.0) suggested that
the overall Trp microenvironment in the protease is electropositive. The
proximity of Trp with His was demonstrated by the sigmoidal shape of the pH
dependent fluorometric titration curve with a pK(F) of 6.1. The vicinity of Trp
with Cys was indicated by resonance energy transfer between the intrinsic
fluorophore (Trp) and 5-iodoacetamide-fluorescein labeled Cys (extrinsic
fluorophore). Our results on the proximity of Trp with essential His and Cys thus
confirm the presence of Trp in the active site of the alkaline protease.
PMID- 10772925
TI - Estrogen receptor-mediated effects of a xenoestrogen, bisphenol A, on
preimplantation mouse embryos.
AB - The effects of bisphenol A, a xenoestrogen widely used in industry and dentistry,
were studied in early preimplantation mouse embryos. Two-cell mouse embryos were
cultured with 100 pM to 100 microM bisphenol A with or without 100 nM tamoxifen
and evaluated at 24-h intervals for their development to eight-cell and
blastocyst stages. At 72 h, blastocysts were cultured for another 48 h without
bisphenol A, and surface areas of trophoblast spread were measured. At 24 h, more
embryos exposed to 3 nM bisphenol A than to controls had reached the eight-cell
stage. At 48 h, more embryos exposed to 1 nM and 3 nM bisphenol A than to
controls had become blastocysts. At 100 microM, bisphenol A decreased frequency
of development to blastocysts. Tamoxifen counteracted both stimulatory and
inhibitory effects of bisphenol A on blastocyst formation. Although bisphenol A
did not alter blastocyst morphology or cell number, early exposure to 100 microM
bisphenol A increased subsequent trophoblast areas. These findings suggest that
bisphenol A may not only effect early embryonic development via estrogen
receptors even at low, environmentally relevant doses, but also exert some late
effects on subsequent development of these embryos.
PMID- 10772926
TI - CYP2D6 polymorphism and the presence of anti-LKM-1 in patients with chronic
hepatitis C.
AB - Anti-LKM-1 autoantibodies are directed mostly at cytochrome P450 2D6 (CYP2D6)
autoantigen, whose activity ranges from "complete deficiency" to "extensive
metabolism" due to genetic polymorphism. We aimed to find any relevance of CYP2D6
alleles to the presence/absence of anti-LKM-1 in Japanese patients with chronic
hepatitis C. The frequency of an extensive metabolizer-type allele (CYP2D6*1) in
anti-LKM-1-positive patients was higher than that in anti-LKM-1-negative patients
(0.800 vs 0.431; P = 0.0035), while the CYP2D6*10 allele with moderately reduced
activity was less frequent in the former than the latter (0.050 vs 0.389; P =
0.0069). Moreover, the rate of homozygosity for CYP2D6*1 showed a striking
difference between the two groups (70% vs 19%; P = 0.0021). These findings
suggest that a genetic predisposition to produce the enzyme CYP2D6 of extensive
metabolizer-type is associated with the induction of anti-LKM-1 in chronic
hepatitis C patients.
PMID- 10772927
TI - Phosphorylation of the 105-kDa heat shock proteins, HSP105alpha and HSP105beta,
by casein kinase II.
AB - The 105-kDa heat shock protein alpha (HSP105alpha) and HSP105beta are mammalian
heat shock proteins that belong to the HSP105/HSP110 family. Both HSP105alpha and
HSP105beta consist of acidic and basic isoforms. Here we report that the acidic
isoforms are serine phosphorylated HSP105alpha or HSP105beta. Furthermore, using
an in-gel kinase assay with HSP105alpha or HSP105beta as the substrate, the
protein kinase that phosphorylates HSP105alpha and HSP105beta was identified as
casein kinase II. Since phosphorylated HSP105alpha is especially prominent in the
brain compared to other tissues of mice and rats, the phosphorylation of
HSP105alpha by casein kinase II may be biologically significant.
PMID- 10772928
TI - Role of the recombinant non-integrin platelet collagen receptor P65 on platelet
activation induced by convulxin.
AB - Convulxin (Cvx) isolated from Crotalus durissus terrificus venom selectively
binds with a high affinity to platelets and induces platelet aggregation by a
mechanism that resembles that induced by collagen. Taking advantage that P65 has
been recently cloned and expressed as a recombinant soluble protein (rec-P65), we
examined the role of this non-integrin collagen receptor in platelet activation
induced by Cvx. Rec-P65 blocked platelet adhesion to collagen-coated surfaces and
inhibited platelet aggregation and ATP secretion induced by type I collagen. On
the other hand, rec-P65 did not inhibit platelet aggregation and ATP secretion
induced by Cvx, and it did not affect platelet adhesion to Cvx. In addition,
ligand-blotting indicated that the Cvx binding to the collagen receptor GPVI was
preserved in the presence of rec-P65. These observations indicate that P65 does
not play a significant role in platelet activation by Cvx; in contrast, platelet
response to collagen involves multiple receptors.
PMID- 10772929
TI - LDL receptor-related protein as a component of the midkine receptor.
AB - Midkine (MK) is a heparin-binding growth factor with migration-promoting and
survival-promoting activities. To identify signaling receptor(s) of MK, membrane
glycoproteins with MK-binding activity were isolated from day 13 mouse embryos by
lectin- and MK-affinity chromatography. SDS-PAGE followed by protein sequence
analysis revealed the presence of LDL receptor-related protein (LRP) and NCAM in
the fraction. The dissociation constant of binding between LRP and MK was 3.5 nM.
Receptor-associated protein (RAP), which interfered with the binding, inhibited
MK-dependent survival of embryonic neurons. Brushin/megalin, which is also a high
molecular weight protein belonging to the LDL receptor family, bound to MK less
strongly than LRP. These findings suggest that LRP is a component of the receptor
complex for MK.
PMID- 10772930
TI - Evidence for production of hydroxyl radicals by pentachlorophenol metabolites and
hydrogen peroxide: A metal-independent organic Fenton reaction.
AB - The production of hydroxyl radicals by tetrachlorohydroquinone (TCHQ, a major
metabolite of the widely used biocide pentachlorophenol) in the presence of
H(2)O(2) was studied by salicylate hydroxylation method. HPLC with
electrochemical detection was used to measure the levels of 2,3- and 2,5
dihydroxybenzoic acid (DHBA) formed when the hydroxyl radicals react with
salicylate. We found that TCHQ and H(2)O(2) could produce both 2,3- and 2,5-DHBA
when incubated with salicylate. Their production was markedly inhibited by
hydroxyl radical scavenging agents dimethyl sulfoxide and ethanol, as well as by
tetrachlorosemiquinone radical scavengers desferrioxamine and other hydroxamic
acids. In contrast, their production was not affected by the nonhydroxamate iron
chelators diethylenetriaminepentaacetic acid (DTPA), bathophenanthroline
disulfonic acid, and phytic acid, as well as the copper-specific chelator
bathocuprione disulfonic acid. A comparison of product formation and distribution
from the reaction of ferrous iron with hydrogen peroxide (the classic Fenton
system) strongly suggests that the same hydroxyl radical adducts are formed as in
the TCHQ/H(2)O(2) experiments. Taken together, we propose that hydroxyl radicals
were produced by TCHQ in the presence of H(2)O(2), probably through a metal
independent organic Fenton reaction.
PMID- 10772931
TI - Activation of Akt during simulated ischemia/reperfusion in cardiac myocytes.
AB - In the present study we have investigated whether Akt was activated during
simulated ischemia (SI) and simulated ischemia/reperfusion (SI/R) in neonatal rat
cardiomyocytes. Akt was phosphorylated on both S473 and T308 residues after 10
min of simulated SI/R and remained elevated for 60 min before returning to basal
levels after 2 h. No phosphorylation was observed during SI alone. SI/R
stimulated Akt activation was inhibited by the phosphatidylinositol 3-kinase (PI3
K) inhibitor wortmannin, the tyrosine kinase inhibitor genistein and the Src
tyrosine kinase inhibitor PP2, indicating a requirement for tyrosine kinase
activity in Akt activation. Furthermore, SB203580, a p38 MAPK inhibitor,
partially inhibited Akt activation. SI/R also induced the phosphorylation of PHAS
I, a downstream Akt target, in a wortmannin-dependent manner. These results
demonstrate for the first time that SI/R stimulates Akt activation via PI3-K-and
Src tyrosine kinase-dependent pathways, whereas p38 MAPK appears to be involved
in maintaining Akt activation.
PMID- 10772933
TI - Air exposure promotes fibroblast growth with increased expression of mitogen
activated protein kinase cascade.
AB - Subepithelial tissue cell types in vivo are separated from air by the surface
covering epithelial layer of various organs, e.g., the skin, cornea, and
respiratory and upper alimentary tracts. The epithelial defect caused by
inflammatory, traumatic or surgical injury would be expected to expose the
subepithelial tissue-localized fibroblasts to influx air. However, it is unclear
what effects air stimulation elicits in fibroblast growth, which is critical for
wound healing. To address this question, we examined the proliferation of 3T3
fibroblasts with bromodeoxyuridine (BrdU) uptake, using fibroblast-embedded
collagen gel culture with or without air exposure. The BrdU intake of air-exposed
fibroblasts was about 6 times that of air-nonexposed cells. To further
characterize this fibroblast growth, we examined the expression of mitogen
activated protein kinase (MAPK) cascade, which plays a key role in the growth
signaling pathway of various cell types. Immunohistochemistry and Western
blotting showed that air exposure increased MAPK cascade expression of the cells
more strongly than air nonexposure. The data indicate that air exposure promotes
MAPK cascade-associated fibroblast growth, suggesting in turn that in wound
repair air stimulation itself may be involved in the basic mechanisms of
subepithelial fibroblast proliferation and that it may be related to the
pathogenesis of excessive fibroplasia through fibroblast overgrowth.
PMID- 10772932
TI - Inhibition of HIV-1 replication by a new type of circular dumbbell RNA/DNA
chimeric oligonucleotides.
AB - We have designed a new class of oligonucleotides, "dumbbell RNA/DNA chimeric
phosphodiesters," containing two alkyl loop structures with RNA/DNA base pairs
[sense (RNA) and antisense (DNA)] in the double helical stem. The reaction of
nicked (NDRDON-gag-AUG) and circular (CDRDON-gag-AUG) dumbbell RNA/DNA chimeric
oligonucleotides with RNaseH gave the corresponding antisense phosphodiester
oligonucleotide together with the sense RNA cleavage products. The liberated
antisense phosphodiester oligodeoxynucleotide was bound to the target RNA. The
circular dumbbell RNA/DNA chimeric oligoncleotide showed more nuclease resistance
and cellular uptake than the linear antisense phosphorothioate
oligodeoxynucleotide (S-ODN-gag-AUG) and nicked dumbbell RNA/DNA chimeric
oligonucleotide. The CDRDON-gag-AUG with an AUG initiation codon sequence, as the
target of the HIV-1 gag-gene (779-801), was synthesized and tested for inhibitory
effects using peripheral blood mononuclear cells. The circular dumbbell RNA/DNA
chimeric oligonucleotide (CDRDON-gag-AUG) showed highly inhibitory effects
compared to the antisense phosphorothioate oligonucleotide (S-ODN-gag-AUG),
indicating sequence-specific inhibition of HIV-1 replication without the
inhibition of reverse transcriptase and/or the viral entry process such as
antisense phosphorothioate oligonucleotides.
PMID- 10772935
TI - Localization of active form of caspase-8 in mouse L929 cells induced by TNF
treatment and polyglutamine aggregates.
AB - The relation between activation of caspase-8 and polyglutamine aggregates has
been focused. We prepared an antiserum (anti-m8D387) that recognizes the active
form but not the proform of mouse caspase-8. We used immunostaining with anti
m8D387 antiserum to compare the localizations of activated mcaspase-8 in L929
(clone 1422) cells induced by TNF and polyglutamine aggregates. Anti-m8D387 was
positive throughout cytoplasm of the TUNEL-positive cells induced by TNF
treatment, whereas the anti-m8D387 reactivity was not positive throughout
cytoplasm of the cells expressing polyglutamine but was restricted to
polyglutamine aggregates. In contrast with TNF-treated cells, cells expressing
anti-m8D387-positive cytoplasmic polyglutamine aggregates did not undergo TUNEL
positive apoptosis. Thus activated caspase-8 associated with polyglutamine
aggregates alone was not sufficient to induce TUNEL-positive apoptosis of L929
(clone 1422) cells. The distribution of activated caspase-8 associated with
polyglutamine aggregates may be essential for the polyglutamine-mediated cell
death or downstream of caspase-8 may be different in the TNF-treated cells and
cells expressing polyglutamine.
PMID- 10772936
TI - Emx1-specific expression of foreign genes using "knock-in" approach.
AB - Emx1 is a mouse homologue of the Drosophila homeobox gene empty spiracles. Its
expression is limited to the neurons in developing and adult cerebral cortex and
hippocampus. Because of the highly restricted expression pattern of the Emx1
gene, it would be quite desirable to characterize the promoter of the Emx1 for
directing foreign gene expression in the transgenic mouse. We report here that we
have achieved the Emx1-specific expression in transgenic mice by inserting the
lacZ reporter and cre genes directly into the exon 1 of the Emx1 gene using
embryonic stem (ES) cell technology. The distribution of the beta-galactosidase
activity in the transgenic mice was consistent with the published results
obtained using in situ hybridization and immunohistochemistry. Furthermore, we
have demonstrated that Cre protein was present in the cerebral cortex of the
transgenic mice and was able to mediate loxP-specific recombination in vitro. The
creation of this line of cre transgenic mice, and the demonstration that the
insertion site located in the exon 1 of the Emx1 gene could render foreign genes
a specific expression pattern restricted to the developing and adult cerebral
cortex and hippocampus, should be conducive to further studies of the effect of a
gene mutation or overexpression upon the development and plasticity of cerebral
cortex and hippocampus.
PMID- 10772934
TI - NMR observation of a novel C-tetrad in the structure of the SV40 repeat sequence
GGGCGG.
AB - We report the NMR structure of the DNA sequence d-TGGGCGGT in Na(+) solutions at
neutral pH, containing a repeat sequence from SV40 viral genome. The structure is
a novel quadruplex incorporating the C-tetrad formed by symmetrical pairing of
four Cs via NH(2)&bond;O(2) H-bonds in a plane. The C-tetrad has a wider cavity
compared to G-tetrads and stacks well over the adjacent G4-tetrad, but poorly on
the G6 tetrad. The quadruplex helix is largely underwound by 8-10 degrees
compared to B-DNA except at the C5-G6 step. To our knowledge this is the first
report of C-tetrad formation in DNA structures, and would be of significance from
the point of view of both structural diversity and specific recognition.
PMID- 10772937
TI - Arginines 97 and 108 in CYP2C9 are important determinants of the catalytic
function.
AB - Human cytochrome P450 2C9 (CYP2C9) is one of the major drug metabolising enzymes
which exhibits a broad substrate specificity. The B-C loop is located in the
active-site but has been difficult to model, owing to its diverse and flexible
structure. To elucidate the function of the B-C loop we used homology modelling
based on the Cyp102 structure in combination with functional studies of mutants
using diclofenac as a model substrate for CYP2C9. The study shows the importance
of the conserved arginine in position 97 and the arginine in position 108 for the
catalytic function. The R97A mutant had a 13-fold higher K(m) value while the
V(max) was in the same order as the wild type. The R108 mutant had a 100-fold
lower activity with diclofenac compared to the wild-type enzyme. The other six
mutants (S95A, F100A, L102A, E104A, R105A, and N107A) had kinetic parameters
similar to the CYP2C9 wild-type. Our homology model based on the CYP102 structure
as template indicates that R97, L102, and R105 are directed into the active site,
whereas R108 is not. The change in catalytic function when arginine 97 was
replaced with alanine and the orientation of this amino acid in our homology
model indicates its importance for substrate interaction.
PMID- 10772938
TI - Conformational changes in the human estrogen receptor observed by (19)F NMR.
AB - The (19)F NMR spectra of the 5F-Trp labeled glutathione-S-transferase fusion
protein with residues 282-595 of the human estrogen receptor show that there is a
distinct conformational change in the protein when estradiol is added to the
unliganded protein. Our studies show the empty receptor to have more
conformational flexibility than the liganded form. This study shows the
applicability of (19)F NMR to study conformational change in large protein
systems.
PMID- 10772939
TI - Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat.
AB - Certain chemokines inhibit HIV replication through binding to cell surface
receptors which also act as viral coreceptors. Based on our previous observations
that HIV-1 Tat can interact with alpha- and beta-chemokine receptors, we
investigated the potential effect of extracellular Tat (ecTat) on infection and
replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 strains in primary
activated peripheral blood mononuclear cells (PBMC) of uninfected donors.
Receptor desensitization and binding competition studies were used to determine
chemokine receptor binding by ecTat. Standard HIV replication assays based on
reverse transcriptase (RT) activity determination in culture supernatants of PBMC
and real time PCR for HIV-1 gag DNA were used to determine potential effects on
early (entry or RT) steps of infection. ecTat bound to CXCR4 expressing monocytes
and mitogen-activated PBMC, and competed with the natural ligand of CXCR4, SDF
1alpha (stromal cell-derived factor-1alpha) in calcium mobilization assays. EcTat
inhibited replication of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at
concentrations close to those of SDF-1alpha, whereas it only modestly interfered
with R5 HIV-1 (BaL) replication in PBMC. Both SDF-1alpha and ecTat inhibited
accumulation of X4 HIV-1 gag DNA, indicating interference with viral entry and/or
RT. Our data show the surprising and counter-intuitive observation that ecTat
selectively represses X4 HIV replication. This could favour spreading of R5
viruses, a condition observed in vivo immediately after transmission and in the
early asymptomatic phase of infection.
PMID- 10772940
TI - Increased intracellular triglyceride in C(2)C(12) muscle cells transfected with
human lipoprotein lipase.
AB - Much of the knowledge about the cell biology of lipoprotein lipase (LPL) in vitro
has been gained from adipose tissue model systems. However, the importance of
skeletal muscle lipoprotein lipase (SMLPL) to both lipoprotein and muscle
metabolism remains unclear. Although the production of LPL in cultured myocytes
has been documented, the amount of enzyme activity produced is small. To develop
a more suitable tissue culture model for SMLPL, mouse C(2)C(12) myoblasts were
stably transduced with a retroviral vector encoding the full-length human LPL
(hLPL) cDNA. Control cells were transduced with a vector encoding beta
galactosidase. LPL expression was assayed as a function of cell growth by
measuring LPL activity on days 3, 7, 9, 11, and 14 after subculture. The hLPL
transduced myoblasts increasingly overexpressed both heparin-releasable (HR) and
intracellular (IN) LPL activity compared to nontransduced myoblasts (P < 0.001 at
Day 11) and myoblasts transduced with the control vector (P < 0.001 at Day 11).
This increase occurred while LPL mRNA levels remained stable between days 3 and
14. As expected, IN LPL activity was also increased in the transduced cells. High
levels of LPL activity were also obtained after differentiating the C(2)C(12)
cells into myotubes by serum deprivation. Additionally, throughout the time
course, C(2)/LPL cells had greater amounts of intracellular triglyceride than
both the C(2)C(12) and the C(2)/beta-GEO cells (P = 0.005 and P < 0.001,
respectively) with the largest differences seen on day 14 of the time course (P =
0.001, C(2)/LPL vs C(2)C(12) (r) or C(2)/beta-GEO cells). Thus, C(2)C(12)
myoblasts stably transduced with hLPL markedly overexpressed both HR and IN LPL
activity compared to control cells which, in turn, was associated with increases
in intracellular triglyceride content. Because LPL regulation in tissues is
mostly posttranslational, this new in vitro model will permit the in-depth study
of the posttranslational regulation of SMLPL and provide new insights into the
fate of lipoprotein-derived fatty acids in muscle.
PMID- 10772941
TI - Identification of tranilast-binding protein as 36-kDa microfibril-associated
glycoprotein by drug affinity chromatography, and its localization in human skin.
AB - To elucidate the molecular mechanism involved in the suppression of keloids and
hypertrophic scars by tranilast, we investigated the target protein of tranilast
in bovine skin and aorta. A specific tranilast-binding protein was isolated from
both tissues by drug affinity chromatography and was identified as 36-kDa
microfibril-associated glycoprotein (36-kDa MAGP). Binding of 36-kDa MAGP to
tranilast seemed to be specific since 36-kDa MAGP could be eluted from the drug
affinity column by tranilast itself and also binding of 36-kDa MAGP to other anti
allergy drugs (amlexanox and cromolyn) is significantly weaker than that to
tranilast. Light and electron microscopic immunohistochemistry detected the
protein at the periphery of elastic fibers in normal human skin. In hypertrophic
scar tissue, however, 36-kDa MAGP was located on small bundles of microfibrils.
These findings provide support for the concept that elastogenesis occurs in scar
tissue and 36-kDa MAGP might be one of the targets for tranilast.
PMID- 10772942
TI - Functional characterization of Jurkat T cells rescued from CD95/Fas-induced
apoptosis through the inhibition of caspases.
AB - The caspases are known to play a pivotal role in the triggering and execution of
apoptosis in virtually all cell types. Because inappropriate apoptosis is a
prominent feature of many human diseases, the caspases are attractive targets for
therapeutic intervention. In the present study we investigated whether Jurkat T
lymphocytes rescued from Fas-induced cell death through the inhibition of
caspases are functional. Here we show that the pan-caspase, tripeptide inhibitor,
benzyloxycarbonyl-Val-Ala-Asp (Ome) fluoromethylketone (z-VAD-FMK), inhibited the
activation of caspase-2, -3, -7, and -8, and subsequently apoptosis in Jurkat T
lymphocytes induced by agonistic anti-Fas. The apoptotic signals induced by the
cross-linking of the Fas antigen have a relatively long half-life, as z-VAD-FMK
had to be continuously present in the culture medium for 72 h after Fas
stimulation in order to maintain cell survival. After 72 h, the z-VAD-FMK-rescued
cells proliferate normally and responded to activation induced cell death after
phytohaemaglutinin treatment, and readily undergo apoptosis when restimulated
with agonistic Fas antibodies. Taken together, our results demonstrate that
Jurkat T cells rescued from Fas-mediated cell death through the inhibition of
caspases are functional.
PMID- 10772944
TI - Comparative studies of two transthyretin variants with protective effects on
familial amyloidotic polyneuropathy: TTR R104H and TTR T119M.
AB - Recently, a new nonpathogenic transthyretin (TTR) variant-TTR R104H (TTR H104)
has been described in heterozygotic and compound heterozygotic individuals from a
Japanese family with familial amyloidotic polyneuropathy (FAP). The compound
heterozygotic individual, a carrier of TTR V30M (TTR M30) and TTR R104H (TTR
M30/H104) presented a very mild form of FAP with slow progression of the disease.
TTR and retinol binding protein (RBP) levels were found to be increased in serum
from TTR H104 carriers. These characteristics are very similar to those found in
compound heterozygotic carriers of TTR V30M-T119M (TTR M30/M119). To structurally
compare these variants, we performed stability and thyroxine (T(4)) binding
studies. TTR M30/H104 showed an increased resistance to dissociation into
monomers similar to TTR M30/M119. This suggests that the His104 substitution has
the same stabilizing effect on tetrameric TTR as the Met119 substitution.
Concerning T(4) binding, TTR H104 presents a T(4) binding affinity lower than
that of TTR M119, but still higher than normal TTR. However, TTR from the
compound heterozygotic carrier of TTR M30/H104 presented a T(4) binding affinity
lower than normal. The results indicate that the His 104 substitution induces
structural alterations that increase the stability of the tetramer in compound
heterozygotes for TTR M30 despite a lower affinity for T(4) binding. Thus,
stability of TTR and binding affinity for T(4) may not be related. More detailed
characterization of these variants is needed to clarify the structural
alterations responsible for their increased stability.
PMID- 10772943
TI - Characterization of P5, a novel NFAT/AP-1 site in the human IL-4 promoter.
AB - Interleukin 4 (IL-4) gene expression is controlled at the level of transcription
by the complex interactions of multiple factors that bind to a proximal promoter
region. Nuclear factor of activated T cells (NFAT) can bind up to five purine
rich sequences in the IL-4 promoter termed the P elements (P0-P4). In this paper,
we characterize a novel P element in the upstream region of the human IL-4
promoter that we term P5. P5 shares a core NFAT motif ((-353)GGAAA(-357)) and
additional sequence similarity with the other P elements and supported strong
interactions between the NFATp DNA-binding domain (DBD) and the AP-1 proteins
cFos and cJun in DNA-binding assays. Inducibility of the IL-4 promoter was
significantly impaired in a reporter construct in which the P5 element was
mutated in the context of the full-length promoter. We conclude that P5
represents a novel IL-4 promoter P element that contributes to IL-4 promoter
inducibility.
PMID- 10772945
TI - IGF-1 regulates apoptosis of cardiac myocyte induced by osmotic-stress.
AB - Insulin-like growth factor-1 (IGF-1) is a natural protectant of cardiac myocytes
that has been shown to improve cardiac function. The role of IGF-1 in attenuating
apoptosis induced by osmotic stress (sorbitol, SOR) or by other known apoptotic
stimuli (doxorubicin, angiotensin II, and serum withdrawal) was determined in
cultured cardiac myocytes. After 6 h of exposure to SOR, apoptosis was initiated,
concomitant with a decrease in cell survival and increases in poly-[ADP-ribose]
polymerase (PARP) degradation and DNA fragmentation. These effects were maximal
after 24 h. IGF-1 partially attenuated apoptosis induced by sorbitol but not that
induced by angiotensin II, doxorubicin, or serum withdrawal. In cells
preincubated with IGF-1 before the addition of SOR, we detected an increase in
the number of viable cells, a decrease in the generation of DNA fragments on
agarose gel electrophoresis and in the percentage of positive TUNEL cells, and a
reduction on PARP levels. These results suggest that IGF-1 prevents apoptosis
induced by osmotic stress in cardiac myocytes but not apoptosis induced by
doxorubicin and angiotensin II.
PMID- 10772946
TI - Stimulation of yeast 3-phosphoglycerate kinase gene promoter by paraquat.
AB - Yeast cells exposed to adverse conditions employ a number of defense mechanisms
in order to respond effectively to the stress and sustain a high proliferation
rate. It has been shown that several glycolytic enzymes are induced upon heat
treatment of yeast. In this work, we used a reporter plasmid construct to study
the effects of oxidative stress, induced by the O(*-)(2)-generating compound
paraquat (PQ), on the yeast 3-phosphoglycerate kinase gene (PGK) promoter. Our
results show that (i) moderate, as opposed to excessive, doses of PQ induce
increased stimulation of the PGK promoter, at midlogarithmic phase of growth; and
(ii) the thiol antioxidant N-acetylcysteine cancels this stimulatory effect.
These observations may represent one aspect of a more general role for glycolysis
in maintaining the energy pools of yeast cells under stress.
PMID- 10772947
TI - Characterization of rat OX40 ligand by monoclonal antibody.
AB - OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor superfamily
first identified as a rat T cell activation marker. We previously identified the
rat ligand for OX40 (OX40L) by molecular cloning. In the present study, we newly
generated an anti-rat OX40L mAb (ATM-2) that can inhibit the binding of OX40 to
rat OX40L and thus efficiently inhibits the T cell costimulatory activity of rat
OX40L. Flow cytometric analyses using ATM-2 and an anti-rat OX40 mAb (MRC OX40)
indicated that OX40 was inducible on splenic CD4(+) T cells by stimulation with
immobilized anti-CD3 mAb, while OX40L was not expressed on resting or activated T
cells. OX40L was expressed on splenic B cells after stimulation with
lipopolysaccharide (LPS), but not on peritoneal macrophages. Interestingly,
splenic dendritic cells (DC) expressed OX40L constitutively, which was further
upregulated by LPS stimulation. The potent costimulatory activities of splenic DC
for anti-CD3-stimulated rat CD4(+) T cell proliferation and cytokine (IL-2, IFN
gamma, IL-10, and IL-13) production were substantially inhibited by ATM-2. These
results indicated that OX40L is expressed on professional antigen-presenting
cells (APC), and may be involved in humoral immune responses via T-B interaction
and in cellular immune responses via T-DC interaction in the rat system.
PMID- 10772948
TI - The regulatory expression of procollagen COOH-terminal proteinase enhancer in the
proliferation of vascular smooth muscle cells.
AB - Intimal hyperplasia following arterial endothelial denudation results in large
part from the proliferation of vascular smooth muscle cells (SMCs) and matrix
accumulation. Procollagen COOH-terminal proteinase enhancer (PCPE) binds
procollagen COOH-propeptides and potentiates procollagen COOH-proteinase activity
to cleave COOH-propeptides of procollagens I-III. Here we report the enhanced
expression of PCPE in cultured SMCs and in intimal thickening induced by arterial
injury. The levels of PCPE mRNA in parallel with the level of p21(Cip1) mRNA, as
a negative regulator of cellular proliferation, increased under serum deprivation
or reduced cellular proliferation in cultured SMCs. In contrast, rapidly
proliferating cells show the decreased levels of PCPE mRNA. In vivo, the marked
induction of PCPE in injured rat arteries occurred at 14 days after endothelial
denudation. The induced expression levels of PCPE as well as p21(Cip1) were
maintained until 42 days, although cyclin E expression declined. Furthermore,
transforming growth factor beta1 (TGF-beta1), an important regulator of cellular
proliferation in atheroma, increased the levels of the PCPE mRNA in cultured
SMCs. Thus, the regulatory expression of PCPE dependent on cellular
proliferation, and particularly contact inhibition, may play a key role in the
proliferation of SMCs and matrix production during the process of atheroma
formation.
PMID- 10772949
TI - Intranuclear binding by the HIV-1 regulatory protein VPR is dependent on
cytosolic factors.
AB - The regulatory protein Vpr of the human immunodeficiency virus HIV-1 performs
multiple functions during the HIV replicative cycle. It is involved in the
transport of the viral preintegration complex into the nucleus, and has the
ability to interact with nuclear proteins such as transcription factors and
cyclin-dependent kinases. In this study we examine for the first time the
kinetics of intranuclear binding and accumulation at the nuclear envelope of
fluorescently labelled full-length Vpr in vitro. We show that intranuclear
binding is strongly dependent on the presence of cytosolic factors; in the
absence of cytosol, Vpr associates predominantly with the nuclear envelope.
Specific regulation of the interactions of Vpr with cytosolic factors, as well as
with sites at the nuclear envelope and within the nucleus, is thus implicated,
but conventional nuclear transport factors such as importin alpha/beta do not
appear to be involved.
PMID- 10772950
TI - Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth
muscle cells.
AB - A recent report has shown that in vitro the RAMP2/CRLR complex is a functional
adrenomedullin receptor in human endothelial and vascular smooth muscle cells.
However, in vivo, it is well known that CGRP receptors are expressed in human
coronary arteries and that a beneficial effect is observed in patients after CGRP
infusion of patients with congestive cardiac failure. This contrast may be
explained by the in vivo impregnation of major hormones, so we have tested if
glucocorticoids were able in vitro to enhance the expression of the RAMP1/CRLR
expression leading to functional CGRP receptors. The expression of RAMP1, RAMP2,
CRLR, and adrenomedullin was evaluated by semiquantitative reverse-transcriptase
polymerase chain reaction (RT-PCR) using (33)P in human coronary arteries
vascular smooth muscle cells (VSMC) cultured in the presence of dexamethasone.
Under basal conditions, the CRLR mRNA was expressed, but RAMP2 mRNA was clearly
more abundant than RAMP1 mRNA. Increases in CRLR and RAMP1 mRNA expressions
occurred 4 h after treatment of VSMC with 10(-7) M dexamethasone and no change
was found for RAMP2 mRNA. Adrenomedullin mRNA increased later, i.e., 8 and 16 h
after dexamethasone treatment. The RAMP1 mRNA expression was elevated with doses
of dexamethasone ranging from 10(-10) to 10(-7) M, thus a 5-fold increase in the
ratio between RAMP1 and RAMP2 was observed with the lowest dose of dexamethasone
and a 2-fold rise at 10(-7) M. CRLR mRNA levels were half-reduced with the two
lowest doses of dexamethasone (10(-10) and 10(-9) M), but increased from 10(-8)
to 10(-7) M. Thus, we suggest that, in vivo, glucocorticoids are involved in the
expression of CGRP receptors by human coronary VSMC.
PMID- 10772951
TI - Functional expression of four PDH-E(1)alpha recombinant histidine mutants in a
human fibroblast cell line with zero endogenous PDH complex activity.
AB - Conserved histidine residues have been implicated in the geometry and catalytic
mechanism of the E(1)alpha proteins of the PDH complex. We constructed and
expressed a series of PDH-E(1)alpha histidine mutants (H63, H84, H92, and H263)
in a cell line with zero PDH complex activity due to a null E(1)alpha allele.
Based on immunoblot and enzyme activity analyses, all introduced histidine
mutations, with the exception of H92, affected the specific activity of the PDH
complex. We showed that H63 and H263 are essential for the activity since
mutations introduced at those sites produced a PDH complex with near-zero
activity. Mutations introduced at H84 only partially reduced activity, implying
that H84 may play a less critical role in the PDH complex. Mutations introduced
at H92 caused the absence of immunoreactive material for both the E(1)alpha and
E(1)beta subunits and may have impaired import or assembly of precursor peptides
into the mature PDH complex.
PMID- 10772952
TI - Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic
mice.
AB - A cardiac homeobox-containing gene Csx/Nkx2-5, which is essential for cardiac
development, is abundantly expressed in the adult heart as well as in the heart
primordia. Targeted disruption of this gene results in embryonic lethality due to
abnormal heart morphogenesis. To elucidate the role of Csx/Nkx2-5 in the adult
heart, we generated transgenic mice which overexpress human Csx/Nkx2-5. The
transgene was expressed abundantly in the heart and the skeletal muscle. mRNA
levels of several cardiac genes including natriuretic peptides, CARP, MLC2v, and
endogenous Csx/Nkx2-5 were increased in the ventricle of the transgenic mice.
Electron microscopic analysis revealed that the ventricular myocardium of the
transgenic mice had many secretory granules, which disappeared after
administration of vasopressin. These results suggest that Csx/Nkx2-5 regulates
many cardiac genes and induces formation of secretory granules in the adult
ventricle.
PMID- 10772953
TI - Differential stimulation by PGE(2) and calcemic hormones of IL-6 in
stromal/osteoblastic cells.
AB - Formation of osteoclast-like cells in mouse bone marrow cultures induced by
either 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), parathyroid hormone (PTH)
or prostaglandin E(2) (PGE(2)), respectively, shows partial dependence on
interleukin-6 receptor (IL-6R) activation. This suggests that locally produced IL
6 could be relevant for osteoclast formation. Therefore, we evaluated the effects
of 1,25-(OH)(2)D(3), PTH, and PGE(2) on IL-6 production in stromal/osteoblastic
cell lines. It appeared that these bone resorptive factors differed widely in
their ability to modulate IL-6 mRNA expression and, consequently, protein
synthesis in each of the cell lines studied. While 1,25-(OH)(2)D(3) was
marginally effective only in ST2 cells, and PTH caused a 2- to 20-fold increase
in IL-6 levels MC3T3-E1 and UMR-106 cells, PGE(2) enhanced IL-6 production in the
ST2 and MC3T3-E1 cell line by two to three orders of magnitude, respectively, and
also induced IL-6 in fibroblastic L929 cells. PGE(2)-stimulated IL-6 release from
mesenchymal cells seems to be important for autocrine/paracrine control of
osteoclast formation in health and disease.
PMID- 10772954
TI - Myeloperoxidase-catalyzed phenoxyl radicals of vitamin E homologue, 2,2,5,7,8
pentamethyl- 6-hydroxychromane, do not induce oxidative stress in live HL-60
cells.
AB - We used myeloperoxidase-containing HL-60 cells to generate phenoxyl radicals from
nontoxic concentrations of a vitamin E homologue, 2,2, 5,7,8-pentamethyl-6
hydroxychromane (PMC) to test whether these radicals can induce oxidative stress
in a physiological intracellular environment. In the presence of H(2)O(2), we
were able to generate steady-state concentrations of PMC phenoxyl radicals
readily detectable by EPR in viable HL-60 cells. In HL-60 cells pretreated with
succinylacetone, an inhibitor of heme synthesis, a greater than 4-fold decrease
in myeloperoxidase activity resulted in a dramatically decreased steady-state
concentrations of PMC phenoxyl radicals hardly detectable in EPR spectra. We
further conducted sensitive measurements of GSH oxidation and protein sulfhydryl
oxidation as well as peroxidation in different classes of membrane phospholipids
in HL-60 cells. We found that conditions compatible with the generation and
detection of PMC phenoxyl radicals were not associated with either oxidation of
GSH, protein SH-groups or phospholipid peroxidation. We conclude that PMC
phenoxyl radicals do not induce oxidative stress under physiological conditions
in contrast to their ability to cause lipid peroxidation in isolated lipoproteins
in vitro.
PMID- 10772955
TI - Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of
SCF(skp2) toward p27(kip1).
AB - The periodic expression of cell cycle proteins is important for the regulation of
cell cycle progression. The amount of CDK inhibitor, p27(kip1), one such protein,
seems to be regulated by the ubiquitin-proteasome system. The ubiquitin ligase
(E3) toward p27(kip1) is thought to be SCF(skp2). The activity of SCF(skp2) was
increased by the addition of Roc1 protein to the complex. Furthermore, the
ubiquitination of p27(kip1) seemed to be dependent on the phosphorylation of T187
of p27(kip1) because the mutant T187A was not ubiquitinated at all in an in vitro
ubiquitination system. Cullin-1, a component of SCF, is modified by ubiquitin
like protein Nedd8. The modification site of cullin-1 was shown to be K696
because the K696R mutant was not modified. When the effect of the Nedd8
modification on the SCF(skp2) activity toward p27(kip1) was investigated, the
activity was markedly decreased by using the Nedd8-unmodified mutant cullin-1
(K696R), indicating that the modification may play an important role on the
SCF(skp2) activity toward p27(kip1).
PMID- 10772956
TI - Breast cancer cell line MDA-231 stimulates osteoclastogenesis and bone resorption
in human osteoclasts.
AB - Breast cancers commonly cause osteolytic metastases in bone, a process that is
dependent upon osteoclast-mediated bone resorption, but the mechanism responsible
for tumor-mediated osteoclast activation has not yet been clarified. In the
present study we utilized a well-known human breast cancer cell line (MDA-231) in
order to assess its capability to influence osteoclastogenesis in human bone
marrow cultures and bone resorption in fully differentiated osteoclasts. We
demonstrated that conditioned medium (CM) harvested from MDA-231 increased the
formation of multinucleated TRAP-positive cells in bone marrow cultures. Bone
resorption activity of fully differentiated human osteoclasts and of osteoclast
like cell lines, from giant cell tumors of bone (GCT), was highly increased by
the presence of MDA-231 CM. Moreover, while MDA-231 by themselves did not produce
IL-6 tumor cell, CM increased the secretion of IL-6 by primary human osteoclasts
and GCT cell lines compared to untreated controls. These data suggest that MDA
231 produce osteoclastic activating factor(s) that increase both osteoclast
formation in bone marrow culture and bone resorption activity by mature cells.
Moreover, breast cancer cells stimulate IL-6 secretion by osteoclasts that is one
of the factors known to supports osteoclastogenesis.
PMID- 10772957
TI - Molecular cloning and expression of human L-pipecolate oxidase.
AB - In higher eukaryotes L-lysine can be degraded via two distinct routes including
the saccharopine pathway and the L-pipecolate pathway. The saccharopine pathway
is the primary route of degradation of lysine in most tissues except the brain in
which the L-pipecolate pathway is most active. L-pipecolate is formed from L
lysine via two enzymatic reactions and then undergoes dehydrogenation to Delta(1)
piperideine-6-carboxylate. At least in humans and monkeys, this is brought about
by the enzyme L-pipecolate oxidase (PIPOX) localized in peroxisomes. In
literature, several patients have been described with hyperpipecolic acidaemia.
The underlying mechanism responsible for the impaired degradation of pipecolate
has remained unclear through the years. In order to resolve this question, we
have now cloned the human L-pipecolate oxidase cDNA which codes for a protein of
390 amino acids and contains an ADP-betaalphabeta-binding fold compatible with
its identity as a flavoprotein. Furthermore, the deduced protein ends in -KAHL at
its carboxy terminus which constitutes a typical Type I peroxisomal-targeting
signal (PTS I).
PMID- 10772958
TI - Structure of the human ubiquitin fusion gene Uba80 (RPS27a) and one of its
pseudogenes.
AB - Ubiquitin is a highly conserved 76 amino acid protein that is generated in the
cell by proteolysis of larger proteins containing either polyubiquitin chains or
ubiquitin fused to carboxyl extension proteins (CEPs). In humans, the two human
ubiquitin-CEP genes are Uba80 and Uba52, which code for ubiquitin fused to
ribosomal protein S27a and L40, respectively. Working from a recently generated
physical map of human chromosome 2p16, we determined the genetic and physical
location and the genomic structure of the Uba80 gene in its entirety. A
comparison of Uba80 to Uba52 revealed that the two genes share a conserved 5'-end
structure, but that the structure of the ubiquitin coding regions was not
conserved. Analysis of 400 bp of the promoter of Uba80 revealed strong similarity
not only to the Uba52 promoter, but also to the other known human ribosomal gene
promoters that have been identified to date. Homology searches also detected the
presence of a pseudogene for Uba80, and the structure of this sequence feature is
also reported.
PMID- 10772959
TI - TUBA8: A new tissue-specific isoform of alpha-tubulin that is highly conserved in
human and mouse.
AB - We have cloned and sequenced a cDNA from a human adult skeletal muscle cDNA
library, encoding for a novel isoform of alpha-tubulin (tuba8) that is
preferentially expressed in heart, skeletal muscle, and testis. A genomic DNA
sequence from the chromosomal region 22q11 allowed us to determine the complete
structure of the TUBA8 gene that mirrors the canonical exon/intron organization
of the vertebrate alpha-tubulin genes. We also cloned and sequenced the cDNA of
its murine homologue (MMU-TUBA8). The latter encodes for a protein that differs
from its human counterpart in only three amino acids, revealing an extreme rate
of conservation that is even extended to both the 3' and 5' UTRs of the mRNAs.
Sequence comparison of these novel isoforms with other known alpha tubulins shows
that tuba8 is the most divergent member of the mammalian alpha-tubulin family.
The sequence peculiarity of the human and murine tuba8 strongly suggests that
they might have functional significance and, according to the multi-tubulin
hypothesis, that they might play specific functional roles in the cell
cytoskeleton.
PMID- 10772960
TI - Depolarizing stimuli reduce Ca(2+)/calmodulin-dependent protein kinase II
activity in islets of Langerhans.
AB - Elevations in intracellular Ca(2+) ([Ca(2+)](i)) initiate insulin secretion from
pancreatic beta-cells, but the secretory responses become rapidly desensitised to
maintained elevations in [Ca(2+)](i). We have investigated the mechanisms
underlying the Ca(2+) desensitization of insulin secretion using electrically
permeabilized rat islets of Langerhans. Measurements of Ca(2+)/calmodulin
dependent protein kinase II (CaMK II) enzyme activity and immunoreactivity in
permeabilized islets demonstrated Ca(2+)-induced reductions in enzyme activity
which could not be attributed to reductions in CaMK II immunoreactive protein.
Measurements in intact islets demonstrated that the Ca(2+)-induced reduction of
CaMK II activity was also operative in intact cells, suggesting that this
mechanism may have pathophysiological implications for beta-cell function.
PMID- 10772961
TI - A CD36-binding peptide from thrombospondin-1 can stimulate resorption by
osteoclasts in vitro.
AB - Thrombospondin-1 (TSP-1), purified from platelets, stimulates resorption by avian
osteoclasts in an in vitro resorption assay. TSP-1 binds to a number of different
cellular receptors via different domains of the molecule and several short
receptor-binding sequences have been identified within the TSP-1 molecule. In
this study, we have used synthetic peptides representing these various sequences
in order to identify the cellular receptor and TSP domain responsible for
stimulation of resorption. We show that one peptide CSVTCG, which represents the
CD36-binding region of TSP-1, stimulates resorption in a fashion similar to the
intact molecule, while the peptides RGDS, RFYVVMWK, and RFYVVM, representing
other cell-binding domains of TSP, have no effect on resorption. Using RT-PCR and
immunoblotting, we further demonstrate expression of CD36 in human osteoclastoma
(giant cell tumour), primary human bone derived cells, and clonal osteoblastic
cells. These studies suggest that CD36 is involved in regulation of resorption by
osteoclasts and is the receptor responsible for the resorption-promoting effects
of TSP-1.
PMID- 10772962
TI - Antibody binding of deletion mutants of Asp f 2, the major Aspergillus fumigatus
allergen.
AB - Asp f 2, a 268 amino acid major allergen from Aspergillus fumigatus (Af)
demonstrated nine linear IgE binding regions. It is not known whether any of
these linear epitopes are also conformatory epitopes. Hence, we constructed
deletion mutants of Asp f 2 devoid of one or more epitopes, and the IgE binding
of these proteins with sera from patients with ABPA was compared with the full
length Asp f 2 expressed in E. coli and Pichia. The Pichia expressed protein
reacted weakly with IgE, but strongly with IgG of ABPA sera compared to E. coli
expressed Asp f 2. Weak IgE binding only was seen when the C-terminal or N
terminal was deleted, while depletion of both ends negated all reactivity. The
monoclonal antibody IL-B8 and IgE and IgG of ABPA sera bound significantly to the
Asp f 2 E-4 fragment indicating that the major B-cell epitope is located at the N
terminal end of Asp f 2.
PMID- 10772963
TI - Sense codon-dependent introduction of unnatural amino acids into multiple sites
of a protein.
AB - Cell-free protein synthesis, driven by a crude S30 extract from Escherichia coli,
has been applied to the preparation of proteins containing unnatural amino acids
at specific positions. We have developed methods for inactivating tRNA(Asp) and
tRNA(Phe) within a crude E. coli tRNA by an antisense treatment and for digesting
most of the tRNA within the S30 extract without essential damage to the ribosomal
activity. In the present study, we applied these methods to the substitution of
Asp and Phe residues of the HIV-1 protease with unnatural amino acids. With 10 mM
Mg(2+), the translation efficiency was higher than that with the other tested
concentration, and the misreading efficiency was low. The protease mRNA was
translated in the presence of an antisense DNA-treated tRNA mixture and 2
naphthylalanyl- and/or p-phenylazophenylalanyl-tRNA. The results suggest that a
good portion of the translation products are substituted at all of the seven
positions originally occupied by Asp or Phe.
PMID- 10772964
TI - Hepatic zinc response via metallothionein induction after tumor transplantation.
AB - Based on previous findings that liver zinc and metallothionein (MT) levels
increase after tumor transplantation, zinc metabolism in tumor-bearing mice was
studied to clarify the role of zinc-MT in host defense systems. Zinc in the
hepatic cytosolic MT fraction did not increase in tumor-bearing mice fed a zinc
deficient diet, suggesting that dietary zinc is necessary for apo-MT induction in
the liver after tumor transplantation and is then incorporated into the apo-MT.
When (65)ZnCl(2) was intravenously injected, liver (65)Zn levels in the tumor
bearing mice were higher than those in control mice for 72 h after the injection.
Pancreatic and blood (65)Zn levels in tumor-bearing mice were lower than those in
controls for 24 h (pancreas) and 6 h (blood) after the injection. These findings
indicate that the hepatic zinc response via MT induction influences zinc
metabolism in the body after tumor transplantation. Moreover, (65)Zn uptake in
the liver of MT-deficient tumor-bearing mice was lower than that in control tumor
bearing mice 1 h after injection. (65)Zn uptake in the tumor and blood (65)Zn
levels in the MT-deficient tumor-bearing mice were higher than those in the
control tumor-bearing mice. Tumor weight increased more in MT-deficient mice than
in control mice. The formation of zinc-MT in the liver of tumor-bearing mice
might decrease blood zinc availability for tumors and other tissues, such as the
pancreas.
PMID- 10772965
TI - The orphan receptor COUP-TFII regulates G2/M progression of breast cancer cells
by modulating the expression/activity of p21(WAF1/CIP1), cyclin D1, and cdk2.
AB - The orphan receptors COUP-TFI and COUP-TFII play an important role in development
and differentiation by activating specific genes and by modulating the activity
of nuclear receptors including estrogen receptor alpha (ERalpha) and retinoic
acid receptors (RARs). Previously, it was demonstrated that the expression and
activity of ERalpha and RARs are lost or impaired in anti-estrogen-resistant
breast cancers. Here we show that, similar to ERalpha and RARs, the expression of
COUP-TFII but not COUP-TFI is reduced in approximately 30% of breast cancer cell
lines. Introduction of COUP-TFII to MDA-MB-435 cells resulted in reduced growth
and plating efficiency. Interestingly, COUP-TFII increased the expression of
cyclin D1 and p21(WAF1/CIP1) in MDA-MB-435 cells. Although parental and COUP-TFII
transduced cells progressed through the G1-S phase at a similar rate, progression
of COUP-TFII cells through the G2/M transition phase was delayed. The activity of
cdk2 required for G2/M progression was reduced in COUP-TFII cells compared to
parental cells. This property of COUP-TFII is distinct from that of ERalpha and
RARs, which usually modulate the G1 phase of breast cancer cells. Furthermore,
these results reveal an important physiological function of COUP-TFII, which
correlates with its ability to induce gene expression rather than modulation of
nuclear receptor activity.
PMID- 10772966
TI - Adjuvant interferon-alpha in malignant melanoma: current status.
AB - High-risk surgically resected primary or loco-regional cutaneous malignant
melanoma, although uncommon, can be associated with less than 50% 5-year
survival; adjuvant therapy of proven efficacy is therefore appropriate. Since
immunological control mechanisms seem to be important in the natural history of
melanoma, biological agents have been the subject of many adjuvant studies. Most
popular has been recombinant interferon. Well over 4000 patients have been
entered into randomized studies. Results suggest that there may be a clinical
benefit, most clearly in relapse-free but also perhaps in overall survival. More
precise estimates of the magnitude of any benefits are needed. The doses,
schedules and cost-benefits have yet to be fully evaluated. Interferon cannot yet
be recommended as standard adjuvant therapy in high-risk malignant melanoma.
PMID- 10772967
TI - Tumour marker measurements in the diagnosis and monitoring of breast cancer.
AB - Elevation of established blood tumour markers correlates with the stage of breast
cancer. The major role of current blood markers is therefore in the diagnosis and
monitoring of metastatic disease. A combination of markers is better than a
single marker with the most widely adopted combination being CEA and one MUC1
mucin, commonly detected as either CA15.3 or CA27.29. Tumour marker measurement
is now used as a complementary test in the diagnosis of symptomatic metastases.
In the monitoring of therapeutic response to both endocrine and cytotoxic
therapies in advanced disease, biochemical assessment using blood markers not
only correlates with conventional UICC criteria but has a lot of advantages which
make it a potentially superior way of assessment. In this regard, CA15.3, CEA and
ESR are the best validated combination. Studies are ongoing to evaluate the use
of sequential blood tumour marker measurements in the follow-up of patients after
treatment for their primary breast cancer, in terms of both early detection and
early therapeutic intervention. Further randomized studies are also required to
ascertain that marker-directed therapy is superior to the current practice for
metastatic disease. In line with clinical studies, intensive laboratory work is
being carried out to optimize the use of blood markers in advanced disease as
well as to exploit their use in screening and diagnosis of early primary breast
cancer.
PMID- 10772968
TI - Ductal carcinoma in situ (DCIS) of the breast: evolving perspectives.
AB - Ductal carcinoma in situ (DCIS) of the breast is an early, localized stage of
carcinoma in the process of multistep breast carcinogenesis. The incidence of
DCIS is increasing, mainly due to screening mammography, which results in
diagnosing the disease in an increasing proportion of asymptomatic patients.
Consequently, clinicians are being confronted with growing numbers of women who
present with DCIS of the breast; thus, the concepts of managing such patients are
assuming greater importance. The most common presentation is calcifications on
mammography. DCIS is a biologically and morphologically heterogeneous disease. If
left untreated, a significant proportion of these tumours will evolve into
invasive cancer. However, when appropriately treated, the prognosis of DCIS is
excellent. Optimal management of DCIS remains controversial. The goal in the
treatment of patients with DCIS is to control local disease and prevent
subsequent development of invasive cancer. For several decades, total mastectomy
was the treatment of choice for DCIS and it should still be considered the
standard of care, to which more conservative forms of treatment must be compared.
Mastectomy is associated with a risk for chest wall recurrence of approximately
1%. Axillary lymph node dissection is not routinely recommended in the management
of DCIS. However, mastectomy probably represents overtreatment in a substantial
number of patients, especially those with small, mammographically detected
lesions. Local excision alone has been suggested in carefully selected patients,
whilst the rest of the patients undergoing breast-conservation surgery should be
treated with breast irradiation. There is evidence that breast-conservation
therapy is an effective option in the management of selected patients with DCIS.
The use of radiotherapy after lumpectomy significantly decreases the rate of
recurrence. Nuclear grade, presence of comedo necrosis, and margin involvement
are the most commonly used predictors of the likelihood of recurrence. There is
no role for adjuvant chemotherapy in the management of this disease. The role of
tamoxifen in the treatment of DCIS is not clearly defined; tamoxifen should be
given only in patients enrolled in clinical trials. Following breast-conservation
therapy, about 50% of the tumours recur as invasive cancer. Most patients with
recurrent disease can be treated effectively, usually by salvage mastectomy, but
also in selected cases by breast-conservation therapy.
PMID- 10772969
TI - Malignant thymoma: current status and future directions.
AB - Malignant thymomas are rare indolent tumours of the anterior superior
mediastinum. Despite a benign histologic appearance, some thymomas invade nearby
structures or metastasize. Patients are commonly asymptomatic, but some may
present with unusual paraneoplastic syndromes such as myasthenia gravis, pure red
cell aplasia, or hypogammaglobulinemia. Since tumour biopsy may potentially
disrupt the thymic capsule, it is often not performed. Patients are therefore
diagnosed and staged at the time of definitive surgery. Thymomas can generally be
categorized into two stages: non-invasive and invasive. Prognosis closely
parallels the disease stage. Surgery is the principal treatment and is curative
in early stage disease. Radiation therapy, either alone or in combination with
chemotherapy, is an option for both incompletely or completely resected disease.
Chemotherapy is offered to patients with locally advanced, recurrent, or
metastatic thymoma, with excellent responses and prolonged survival. Multicentre
co-operative group clinical trials are required to assess novel thymoma therapies
to maximize patient resources in this uncommon tumour.
PMID- 10772970
TI - Intraperitoneal chemotherapy in ovarian cancer.
AB - From a theoretical viewpoint, intraperitoneal therapy (IP) in patients with
ovarian cancer, a malignancy which remains mainly confined to the peritoneal
cavity, is logical. Over the past decades this approach has evolved into a
therapeutic strategy for a selected group of patients. Data available at present
suggest a beneficiary role (for IP therapy) as first-line treatment in patients
with small residual disease and possibly following initial reduction of tumor
load by systemic chemotherapy. The theoretical basis, the present status of IP
therapy in different settings, pharmacology, factors limiting its clinical
utility and future directions are reviewed.
PMID- 10772971
TI - Articles to appear in forthcoming issues of cancer treatment reviews
PMID- 10772972
TI - Calendar
PMID- 10772973
TI - Antibody and virus: binding and neutralization.
PMID- 10772974
TI - Consequences of cross-reactive and bystander CTL responses during viral
infections.
PMID- 10772975
TI - Fine mapping of virus-neutralizing epitopes on hepatitis B virus PreS1.
AB - We identified the epitopes on the preS1 which induce antibodies that neutralize
both ad and ay subtypes of hepatitis B virus (HBV). Previously we generated
murine monoclonal antibodies KR359 and KR127 that bind specifically to the preS1
of HBV. In this study we have performed fine mappings of the epitopes of the
antibodies by examining their reactivity with GST fusion proteins, which contain
a series of deletion mutants of the preS1. KR359 and KR127 specifically recognize
aa 19-26 and 37-45 of the preS1, respectively. The antibodies neutralized both
adr and ayw subtypes of the virus in an in vitro neutralization assay using in
vitro infection of adult human hepatocyte primary culture by HBV. The epitopes
showed little sequence divergence and the antibodies bound to the preS1 of all
the HBV subtypes and variants tested.
PMID- 10772976
TI - Fusion protein of the paramyxovirus SV5: destabilizing and stabilizing mutants of
fusion activation.
AB - The fusion (F) protein of the paramyxovirus SV5 strain W3A causes syncytium
formation without coexpression of the SV5 hemagglutinin-neuraminidase (HN)
glycoprotein, whereas the F protein of the SV5 strain WR requires coexpression of
HN for fusion activity. SV5 strains W3A and WR differ by three amino acid
residues at positions 22, 443, and 516. The W3A F protein residues P22, S443, and
V516 were changed to amino acids found in the WR F protein (L22, P443, and A516,
respectively). Three single-mutants, three double-mutants, and the triple-mutant
were constructed, expressed, and assayed for fusion using three different assays.
Mutant P22L did not cause fusion under physiological conditions, but fusion was
activated at elevated temperatures. Compared with the W3A F protein, mutant S443P
enhanced the fusion kinetics with a faster rate and greater extent, and had a
lower activation temperature. Mutant V516A had little effect on F protein
mediated fusion. The double-mutant P22L,S443P was capable of causing fusion,
suggesting that the two mutations have opposing effects on fusion activation. The
WR F protein requires coexpression of HN to cause fusion at 37 degrees C, and
does not cause fusion at 37 degrees C when coexpressed with influenza virus
hemagglutinin (HA); however, at elevated temperatures coexpression of WR F
protein with HA resulted in fusion activation. In the crystal structure of the
core trimer of the SV5 F protein (Baker, K. A., Dutch, R. E., Lamb, R.A., and
Jardetzky, T. S. (1999). Mol. Cell 3, 309-319), S443 is the last residue (with
interpretable electron density) in an extended chain region and the temperature
factor for S443 is high, suggesting conformational flexibility at this point.
Thus, the presence of prolines at residues 22 and 443 may destabilize the F
protein and thereby decrease the energy required to trigger the presumptive
conformational change to the fusion-active state.
PMID- 10772977
TI - Complementation of the movement-deficient mutations in potato virus X: potyvirus
coat protein mediates cell-to-cell trafficking of C-terminal truncation but not
deletion mutant of potexvirus coat protein.
AB - The cell-to-cell movement of the GUS-tagged potato virus X (PVX) coat protein
(CP) movement-deficient mutant was restored by potyviral CPs of potato virus A
(PVA) and potato virus Y (PVY) in Nicotiana benthamiana leaves in transient
cobombardment experiments. Viral cell-to-cell movement of PVX CP mutant was
complemented in Nicotiana tabacum cv. SR1 transgenic plants expressing PVY CP:
PVX RNA and polymerase were detected in the PVX CP mutant-inoculated leaves of
transgenic plants. These findings demonstrated the ability of the PVX CP
deficient mutant to move from cell to cell but not long distances in the
transgenic plants and suggest that CPs of potex- and potyviruses display
complementary activities in the movement process. Potyviral CP alone is not able
to carry out these activities, since the mutated PVX CP is indispensable for
restored movement. No trans-encapsidation between potyviral CP and PVX RNA was
observed. Therefore, potyviral CP facilitates the PVX CP mutant movement by the
mechanism that cannot be explained by coat protein substitution. Our data also
suggest that CP functioning in cell-to-cell movement is not restricted to a
simple passive role in forming virions.
PMID- 10772978
TI - The herpes simplex virus 1 Us11 protein cooperates with suboptimal amounts of
human immunodeficiency virus type 1 (HIV-1) Rev protein to rescue HIV-1
production.
AB - The human immunodeficiency virus type 1 (HIV-1) RNA-binding Rev protein governs
the expression of structural and enzymatic viral proteins at a
posttranscriptional level. Binding of Rev to the stem-loop IIB (SLIIB) sequence
of the Rev-response element (RRE) within unspliced and singly spliced viral mRNAs
and to the nuclear export signal-binding receptor, hCRM1 (or exportin 1), is
required for the export of these transcripts to the cytoplasm. We have previously
shown that herpes simplex virus type 1 (HSV-1) RNA-binding Us11 protein is able
to bind the RRE and substitute for Rev in inducing the expression of HIV-1
envelope glycoproteins. We show here that Us11 cannot substitute for Rev in
rescuing a rev-deleted HIV-1 provirus. However, HIV-1 production is observed when
Us11 is expressed with suboptimal amounts of Rev. An in vivo RNA-protein binding
assay indicates that Us11 is unable to directly interact with the SLIIB RNA but
can bind Rev assembled on that stem-loop structure. This association of US11 with
Rev, which was confirmed by in vivo coimmunoprecipitation and GST-pulldown
assays, therefore underlies a biological Us11-Rev cooperation. Furthermore this
cooperation was shown to remain susceptible to the effect of leptomycin B, which
blocks the binding of hCRM1 to the nuclear export signal of Rev. These
observations performed with intron-containing constructs provide evidence that
HSV-1 Us11 protein is not directly involved in the cytoplasmic accumulation of
viral mRNAs but may be rather acting as an auxiliary protein, thus allowing this
retroviral protein to fulfill the nuclear export of these transcripts and to
rescue HIV-1 production.
PMID- 10772979
TI - Maintenance of CD8(+) T-cell memory following infection with recombinant sindbis
and vaccinia viruses.
AB - CD8(+) T-cell memory is critical for protection against pathogens poorly
controlled by humoral immunity. To characterize two distinct vaccine vectors, the
acute and memory CD8(+) T-cell responses to an HIV-1 epitope (p18) expressed by
recombinant vaccinia (vp18) and Sindbis (SINp18) viruses were compared. Whereas 9
to 13% of CD8(+) splenocytes were p18 specific during the acute response to vp18,
4% were induced by SINp18 as revealed by class I tetramer staining. Increased T
cell activation by vp18 was confirmed by higher numbers of both p18-specific IFN
gamma-secreting splenocytes and activated CD8(+) and CD4(+) T cells. Although
higher frequencies of p18-specific CD8(+) T cells during primary responses
correlated with higher frequencies during memory, the overall decline was only
two- to threefold during the transition to memory, demonstrating equally
efficient maintenance of memory in SINp18- as in vp18-immune mice. Despite modest
in vivo activation, SINp18-induced CD4(+) T cells secreted substantial amounts of
IFN-gamma and IL-2, potentially contributing to sustained CD8(+) memory.
Collectively the data indicate that Sindbis virus recombinants provide effective
vaccines for inducing protective memory CD8(+) T cells in the absence of the
extensive inflammation and replication associated with vaccinia virus.
PMID- 10772980
TI - Homologous recombination between a lactococcal bacteriophage and the chromosome
of its host strain.
AB - Genetic exchanges constitute a significant means by which bacteriophages acquire
novel characteristics. Phages of Lactococcus lactis occupy a particular niche,
the dairy factory environment, where their populations are subjected to constant
changes. Little is known about the mechanisms of evolution that lead to the
genetic diversity of lactococcal phages. In this study, we described two DNA
exchanges involving the lytic phage ul36, a member of the P335 species, and its
L. lactis host. They occurred by homologous recombination with phage-related
sequences present in the host chromosome. Both mutants generated by these
recombination events are insensitive to the phage resistance mechanism AbiK and
one has a reduced burst size as well as a new origin of replication. We propose
that this type of DNA exchange with prophages or remnants of prophages occurs
frequently within the P335 species as supported by DNA-DNA comparisons between
P335-like phages.
PMID- 10772981
TI - Immune recognition of swine vesicular disease virus structural proteins: novel
antigenic regions that are not exposed in the capsid.
AB - Swine vesicular disease virus (SVDV) is an enterovirus of the Picornaviridae
family that belongs to the coxsackievirus B group. A number of antigenic sites
have been identified in SVDV by analysis of neutralizing monoclonal antibody
resistant mutants and shown to be exposed on the surface of the capsid. In this
paper we have identified seven new immunodominant antigenic regions in SVDV
capsid proteins by a peptide scanning method, using a panel of sera from infected
pigs. When these antigenic regions were located in the capsid by using a computer
generated three-dimensional model of the virion, one was readily exposed on the
surface of the virus and the remaining sites were located facing the inner side
of the capsid shell, at subunit contacts, or in the interior of the subunit
structure.
PMID- 10772982
TI - Genetic manipulation of equine arteritis virus using full-length cDNA clones:
separation of overlapping genes and expression of a foreign epitope.
AB - Equine arteritis virus (EAV) is an enveloped, positive-stranded RNA virus
belonging to the family Arteriviridae of the order Nidovirales. The unsegmented,
infectious genome of EAV is 12,704 nt in length [exclusive of the poly(A) tail]
and contains eight overlapping genes that are expressed from a 3'-coterminal
nested set of seven leader-containing mRNAs. To investigate the importance of the
overlapping gene arrangement in the viral life-cycle and to facilitate the
genetic manipulation of the viral genome, a series of mutant full-length cDNA
clones was constructed in which either EAV open reading frames (ORFs) 4 and 5 or
ORFs 5 and 6 or ORFs 4, 5, and 6 were separated by newly introduced AflII
restriction endonuclease cleavage sites. RNA transcribed from each of these
plasmids was infectious, demonstrating that the overlapping gene organization is
not essential for EAV viability. Moreover, the recombinant viruses replicated
with almost the same efficiency, i.e., reached nearly the same infectious titers
as the wildtype virus, and stably maintained the mutations that were introduced.
The AflII site engineered between ORFs 5 and 6 was subsequently used to generate
a virus in which the ectodomain of the ORF 6-encoded M protein was extended with
nine amino acids derived from the extreme N-terminus of the homologous protein of
mouse hepatitis virus (MHV; family Coronaviridae, order Nidovirales). This
nonapeptide contains a functional O-glycosylation signal as well as an epitope
recognized by an MHV-specific monoclonal antibody, both of which were expressed
by the recombinant virus. Although the hybrid virus had a clear growth
disadvantage in comparison to the parental virus, three serial passages did not
result in the loss of the foreign genetic material.
PMID- 10772983
TI - Conditional cell transformation by doxycycline-controlled expression of the ASV17
v-jun allele.
AB - To investigate the molecular basis of oncogenesis induced by the v-jun oncogene
of avian sarcoma virus 17 (ASV17), we developed a conditional cell transformation
system in which transcription of the ASV17 v-jun allele is controlled by a
doxycycline-sensitive transactivator (tTA) or a reverse (doxycycline-dependent)
transactivator (rtTA), respectively. Permanent cell lines of quail embryo
fibroblasts conditionally transformed by a doxycycline-controlled v-jun allele
revert to the normal phenotype within 3 days and lose their ability to grow in
soft agar, strictly dependent on the addition or removal of the drug,
respectively. The reverted cells are rapidly retransformed on conditional
activation of v-jun. While full-level synthesis of v-jun mRNA and v-Jun protein
in these cells is established within 2 and 14 h, respectively, after switching to
the permissive conditions, the first morphological alterations are observed after
24 h, and as early as 2 days later the morphology has changed entirely from flat
cells resembling normal fibroblasts to spindle-shaped fusiform cells showing a
typical jun-transformed phenotype. Kinetic expression analysis revealed that
transcriptional activation of the direct jun target gene BKJ precisely coincides
with the establishment of full-level v-Jun protein synthesis. Furthermore, we
have analyzed the expression of a novel candidate v-jun target gene, termed JAC,
which shows no sequence homology to known genes. Similar to BKJ, JAC is
specifically activated in jun-transformed fibroblasts, and induction of JAC is
tightly linked to the conditional expression of oncogenic v-Jun. These results
demonstrate the high stringency of the doxycycline-controlled v-jun expression
system, and they also indicate that expression of v-jun in these cells is
indispensable for enhanced proliferation, cell transformation, and the induction
of specific expression patterns of downstream target genes.
PMID- 10772984
TI - A single-site mutant and revertants arising in vivo define early steps in the
pathogenesis of Venezuelan equine encephalitis virus.
AB - The early stages of Venezuelan equine encephalitis virus (VEE) pathogenesis in
the mouse model have been examined using a genetic approach. Disease progression
of a molecularly cloned single-site mutant was compared with that of the parental
virus to determine the step in the VEE pathogenetic sequence at which the mutant
was blocked. Assuming that such a block constitutes a genetic screen, isolates
from different tissues thought to be distal to the block in the VEE pathogenetic
sequence were analyzed to determine the pathogenetic step at which revertants of
the mutant were selected. Directed mutation and analysis of reversion in vivo
provide two powerful genetic tools for the dissection of the wild-type VEE
pathogenetic sequence. Virus from the parental virulent clone, V3000, first
replicated in the draining lymph node after subcutaneous inoculation in the left
rear footpad. Movement of a cloned avirulent mutant, V3010 (E2 76 Glu to Lys), to
the draining lymph node was impaired, replication in the node was delayed, and
spread beyond the draining lymph node was sporadic. Serum, contralateral lymph
node, spleen, and brain isolates from V3010 inoculated animals were invariably
revertant with respect to sequence at E2 76 and/or virulence in mice. Revertants
isolated from serum and contralateral lymph node retained the V3010 E2 Lys 76
mutation but also contained a second-site mutation, Glu to Lys at E2 116.
Modification of the V3010 clone by addition of the second-site mutation at E2 116
produced a virus that bypassed the V3010 block at the draining lymph node but
that did not possess full wild-type capacity for replication in the central
nervous system or for induction of mortality. A control construct containing only
the E2 116 reverting mutation on the V3000 background was identical to V3000 in
terms of early pathogenetic steps and virulence. Therefore, analysis of mutant
replication and reversion in vivo suggested (1) that the earliest steps in VEE
pathogenesis are transit to the draining lymph node and replication at that site,
(2) that the mutation in V3010 impairs transit to the draining lymph node and
blocks dissemination to other tissues, and (3) that reversion can overcome the
block without restoring full virulence.
PMID- 10772985
TI - Interaction of the papillomavirus E2 protein with mitotic chromosomes.
AB - The bovine papillomavirus E2 transactivator protein is a multifunctional protein
that activates viral transcription, cooperates in initiation of viral DNA
replication, and is required for long-term episomal maintenance of viral genomes.
We have shown previously that the E2 transactivator protein and bovine
papillomavirus type 1 genomes are associated with mitotic chromosomes and have
proposed that E2 links the genomes to cellular chromosomes to ensure segregation
to daughter nuclei. In this study, we show that E2 is associated with cellular
chromosomes at all stages of mitosis. We also further map the regions of E2 that
are required for this association. The transactivation domain of E2 is necessary
and sufficient to mediate the interaction with mitotic chromosomes; the DNA
binding domain, and the flexible hinge region that separates the two domains, is
not required. Furthermore, mutation of previously identified phosphorylation
sites (serine residues 235, 298, and 301) has no effect on the ability of the E2
protein to bind mitotic chromosomes.
PMID- 10772986
TI - Characterization of a novel human immunodeficiency virus type 1 neutralizable
epitope within the immunodominant region of gp41.
AB - Previously, we generated human monoclonal antibodies using peripheral blood
mononuclear cells from an asymptomatic human immunodeficiency virus type 1 (HIV
1)-seropositive donor. One of these monoclonal antibodies (designated clone 3,
CL3) recognized 10 amino acids (GCSGKLICTT) within the immunodominant region
(cluster I) of the transmembrane envelope glycoprotein gp41 and neutralized
infection of target cells with different laboratory isolates. Because the epitope
recognized by CL3 has two cysteine residues that could potentially produce a
disulfide loop in gp41, we analyzed binding of our monoclonal antibody to the
cyclic and linear motif of the peptide sequence IWGCSGKLICTTAVP (residues 600
614). The CL3 antibody did not bind to the synthetic cyclic peptide but did
recognize the linear form. Two polyclonal rabbit sera against both the linear and
cyclic peptides were then generated. Both antisera bound to viral glycoproteins
gp41 and gp160, but neither sera neutralized HIV-1 laboratory isolates. Using a
set of alanine-substituted IWGCSGKLICTTAV peptides, we analyzed binding of
polyclonal antisera and CL3. The profile of binding of polyclonal antisera to
these peptides was different from that of CL3 to the same peptides. This suggests
that CL3 recognized a unique neutralizable core epitope, which was not
immunogenic in either the cyclic or the linear IWGCSGKLICTTAVP peptides used as
immunogens in the rabbits.
PMID- 10772987
TI - Viral recombinant vaccines to the E6 and E7 antigens of HPV-16.
AB - Most cancerous lesions of the uterine cervix are linked to persistent infections
with human papillomaviruses (HPV), most notably HPV-16 or -18. Vaccine-induced
immune responses to the HPV early antigens E6 and E7, which contribute to cell
transformation and are thus expressed in these cervical cancers, could
potentially eradicate malignant cells. We generated recombinant vaccines based on
E1-deleted adenovirus human strain 5 or on vaccinia virus strain Copenhagen
expressing either the E6 or E7 oncoproteins of HPV-16. The different vaccines
were compared in two experimental mouse tumor models employing Balb/c or C57Bl/6
mice. Data presented here demonstrate that depending on the model either CD4(+)
or CD8(+) T cells provide protection to tumor cell challenge, resulting in
striking differences in the efficacy of the four vaccines under investigation.
PMID- 10772988
TI - An ovine adenovirus vector lacks transforming ability in cells that are
transformed by AD5 E1A/B sequences.
AB - Adenoviruses of the Mastadenovirus and Aviadenovirus genera are able to transform
certain cell types and induce tumor formation in susceptible animals. For the
mastadenoviruses the E1A/B sequences are largely responsible for these properties
but E4 sequences may also be involved. The transforming sequences of the
aviadenoviruses, which lack E1A/B and E4 homologues, have not yet been fully
identified. The recent proposal for a third genus of adenoviruses, which
apparently lack an E1A homologue and have weak E1B homology, prompted an
examination of the transforming properties of ovine adenovirus OAV287 (OAV), the
prototype member of the new group. When OAV and human adenovirus type 5 (Ad5)
were used to infect primary rat embryo cells, transformed foci developed in Ad5-
but not in OAV-infected cultures. Similarly, after plasmid transfection, baby rat
kidney cells were transformed by Ad5 E1A/B but not by OAV sequences. When CSL503
cells, an ovine cell line that is permissive for OAV, were transfected with Ad5
E1A/B sequences, transformed foci again appeared. However, plasmids or fragments
containing complete or partial OAV genome sequences did not detectably transform
CSL503 cells under the same conditions. When Ad5 E1A/B sequences were
incorporated into the complete OAV genome and transfected, transformed clones
were again obtained, showing that the gene dosage and transfection conditions
were not limiting for transformation. The provision of Ad5 E1A and OAV sequences
in combination marginally increased the number of morphologically altered foci in
baby rat kidney cells but failed to induce multilayered focus formation. The data
suggest that OAV lacks transforming functions in the cell types examined.
Additional information suggesting that OAV may have a fundamentally distinct
strategy for replication compared with other Ads is discussed.
PMID- 10772989
TI - The effect of mutant peptide cofactors on adenovirus protease activity and virus
infection.
AB - Adenoviruses encode a cysteine protease, adenain, required for uncoating and
virion maturation. Adenain activity is regulated by an 11-amino-acid peptide
cofactor thiol-bonded distal to the active site. Structural and experimental data
suggest that the peptide might stabilize adenain in an optimal conformation for
enzyme activity by bridging two noncontiguous regions of the molecule. The
sequence requirements for this mechanism were examined both in vitro and ex vivo
by means of mutant peptides and databank analysis. The results of in vitro
experiments suggested that activation is not an all or nothing mechanism. With
the exception of the smallest peptide, the mutant peptides bound to adenain,
activated it, and competed with the wild-type peptide, but all of this occurred
with reduced efficiency. When added to the medium of infected cells, most of the
peptides inhibited infectious virus production to varying degrees in a dose
dependent manner and in accordance with their in vitro activity on adenain. We
interpret this inhibition to be due to unscheduled adenain activation.
Examination of the activation peptide sequences from 19 adenovirus serotypes
revealed a limited number of conserved sequence features. These features were in
agreement with the experimental data. We conclude that binding and activation of
adenain by pVIc may be reversible and this reversibility may be an integral
aspect of the in vivo regulation of enzyme activity in the course of virus
assembly. The peptide cofactor binding domain is therefore a potential target for
the development of anti-adenoviral agents.
PMID- 10772990
TI - Helix-destabilizing properties of the baculovirus single-stranded DNA-binding
protein (LEF-3).
AB - The helix-destabilizing properties of a single-stranded DNA-binding protein, LEF
3, of Bombyx mori nucleopolyhedrovirus (BmNPV) were studied. Partial duplexes of
DNA containing single-stranded (ss) tails of different sizes and orientations
were used as substrates for assay of the unwinding ability of LEF-3. Upon
noncooperative binding to ssDNA, LEF-3 was capable of unwinding the duplexes with
5' ss tails. However, it did not cause melting of the duplexes containing 3' ss
tails, even at oversaturation of ssDNA adjacent to the duplexes. Upon cooperative
binding to long ss tails, LEF-3 also produced the polar melting effect; it
unwound the duplexes with long 5' ss tails, but not those with long 3' ss tails.
These data suggest that LEF-3 has a preferential direction for entry into duplex
DNA, namely 5' to 3' with respect to the bound DNA strand. In agreement with its
polarity, LEF-3 efficiently melted the primer-template complexes which serve as
substrates for DNA polymerases. However, the formation of a complex with viral
DNA polymerase before addition of LEF-3 protected the primer-templates from the
destabilization effect of LEF-3. Although the destabilization effect of LEF-3 was
highly sensitive to monovalent and divalent salts, the protein was capable of
melting DNA duplexes in a polar manner at physiological conditions, i.e., 30
degrees C in 0.15 M NaCl. Therefore, the polar destabilization effect of LEF-3
seems to be physiologically important and may be connected, in particular, with
the polar action of viral helicase holoenzyme during baculovirus replication.
PMID- 10772991
TI - Herpes simplex virus 1 late gene expression is preferentially inhibited during
infection of the TAF250 mutant ts13 cell line.
AB - A key component of the polymerase II transcription machinery is the transcription
factor TFIID, a complex that contains the TATA-box binding protein and several
(10-12) associated factors designated as TAFs (TBP-associated factors). ts13
cells, which contain a temperature-sensitive mutant in TAF250, the largest
subunit of TFIID, exhibit promoter-specific defects in gene expression at the
nonpermissive temperature, suggesting that individual TAFs are required for
transcription of specific subsets of eukaryotic genes. Herpes simplex virus 1
(HSV-1) does not replicate in ts13 cells at the nonpermissive temperature, but
the point at which the replicative process is blocked is not known. We used the
TAF250 defect in ts13 cells to investigate the role of TAF250 in the expression
of HSV-1 genes of each temporal class. At a low m.o.i., expression of most
immediate-early mRNAs is reduced at the nonpermissive temperature, and
consequently, there is little expression of early genes and no viral DNA
replication. In contrast, at high m.o.i., expression of immediate-early genes is
unaffected by the TAF250 defect and is not dependent on de novo viral protein
synthesis. Early genes and early proteins are produced under these conditions,
and viral DNA replication ensues, albeit at somewhat reduced levels. In contrast,
late gene expression and late protein synthesis are severely restricted, even in
the presence of appreciable viral DNA replication. Thus the lack of late protein
synthesis is responsible for the inability of HSV-1 to replicate in ts13 cells at
the nonpermissive temperature. Further, it appears that late viral gene
expression may be preferentially inhibited by the TAF250 mutation in ts13 cells.
PMID- 10772992
TI - Similarity and divergence among viruses in the genus Furovirus.
AB - Nucleotide sequences of RNAs 1 and 2 of a Japanese strain of soil-borne wheat
mosaic virus (SBWMV), the type species of the genus Furovirus, and sorghum
chlorotic spot virus (SCSV) were determined from cloned cDNA. The relationship
among the Japanese and US strains of SBWMV, SCSV, oat golden stripe virus (OGSV),
and recently proposed Chinese wheat mosaic and European wheat mosaic viruses
(CWMV and EWMV) were examined at the nucleotide and amino acid levels. Pairwise
comparisons of genome-encoded proteins among the six viruses showed that the US
strains of SBWMV and CWMV were the most closely related pair in RNA 1 and the
Japanese strains of SBWMV and EWMV were most closely related in RNA 2. SCSV was
most distantly related to the other five viruses. Phylogenetic analysis indicated
that there may have been an ancient reassortment between RNAs 1 and 2 of the four
wheat-infecting viruses and OGSV, while SCSV was shown to have separated from the
rest before the other five viruses diverged. The fact that CWMV and EWMV have
almost identical biological properties as well as the sequence similarities to
the two strains of SBWMV suggests that they be regarded as strains of SBWMV,
considering that SBWMV consists of genetically diverged strains. OGSV and SCSV
are distinct in biological properties in addition to genetic divergence in the
genus Furovirus.
PMID- 10772993
TI - Crystallization of Newcastle disease virus hemagglutinin-neuraminidase
glycoprotein.
AB - The hemagglutinin-neuraminidase (HN) glycoprotein of Newcastle disease virus was
isolated by cleaving HN (cHN) from reconstituted virosome with chymotrypsin. N
terminal sequence analysis of the purified cHN showed that chymotrypsin cleavage
had occurred at amino acid 123, freeing the C-terminal 454 amino acids. The
purified cHN retained its neuraminidase and receptor binding activities and
reacted with specific monoclonal antibodies, showing that the isolated cHN was
biologically and antigenically functional. The crystals of the cHN were obtained
in acetate buffer (pH 4.6) containing polyethylene glycol 3350 and ammonium
sulfate and belong to the orthorhombic space group P2(1)2(1)2(1) with unit cell
dimension of approximately a = 72 A, b = 78 A, and c = 198 A. Crystals of cHN
grown in the presence of sialic acid (Neu5Ac) were grown in HEPES buffer (pH 6.2)
containing polyethylene glycol 3350 and belong to the hexagonal space groups
P6(1) or P6(5) with unit cell dimensions of a = b = 137.5 A and c = 116.6A. The
orthorhombic crystals produced in this study diffract X rays to at least 2.0-A
resolution, thereby setting the stage for the solution of the three-dimensional
structure of the HN glycoprotein of a paramyxovirus.
PMID- 10772994
TI - Mutational analysis of the bovine respiratory syncytial virus nucleocapsid
protein using a minigenome system: mutations that affect encapsidation, RNA
synthesis, and interaction with the phosphoprotein.
AB - The nucleocapsid (N) protein of bovine respiratory syncytial virus (BRSV) is a
multifunctional protein that plays a central role in transcription and
replication of viral genomic RNA. To investigate the domains and specific
residues involved in different N activities, we generated a total of 27 deletion
and 12 point mutants of the N protein. These mutants were characterized using an
intracellular BRSV-CAT minigenome replication system for the ability to (1)
direct minigenome RNA synthesis, (2) direct minigenome encapsidation, and (3)
form a complex with the phosphoprotein (P). The mutations tested were defective
in synthesis of RNA from the BRSV-CAT minigenome template with the exception of
the following: a deletion involving the first N-terminal amino acid and mutations
involving conservative substitution at the second amino acid and at certain
internal cysteine residues. Micrococcal nuclease enzyme protection assays showed
that mutations involving amino acids 1-364 of the 391-amino-acid N protein
prevented minigenome encapsidation. Thus the BRSV N protein has a C-terminal, 27
amino-acid tail that is not required for encapsidation. Interestingly, two of the
mutations that ablated encapsidation did not greatly affect RNA synthesis; the
mutant involving deletion of the N-terminal amino acid and the mutant involving a
substitution at position 2. This finding indicates that the formation of a
nucleocapsid sufficient to protect the RNA from nuclease is not required for
template function. Coimmunoprecipitation of N and P using N- or P-specific
antiserum revealed two regions of the N protein that are important for
association with the P protein: a central portion of 244-290 amino acids and a C
terminal portion of 338-364 amino acids.
PMID- 10772995
TI - Selective binding of hepatitis C virus core protein to synthetic oligonucleotides
corresponding to the 5' untranslated region of the viral genome.
AB - Although it is assumed that hepatitis C virus (HCV) core protein binds with viral
RNA to form a nucleocapsid, little is known about the resulting molecular
interactions. We utilized surface plasmon resonance technology to study the
structural basis of the affinity and the preference of the interaction between
HCV core protein and oligonucleotides derived from the viral genome. Among the 10
oligonucleotides corresponding to the 5' untranslated region (5'UTR) of the
tested HCV genome, the real-time analysis of sensorgrams indicated that the core
protein binds most efficiently and stably to the 31-nucleotide-long sequence of
the loop IIId domain, whose secondary structure is highly conserved not only
among different HCV genotypes but also among pestiviruses. There also could be
some interactions of the core protein with the loop I domain and the region of nt
23-41. The kinetic profiles, together with those obtained in experiments using
single- and double-stranded polymeric oligonucleotides, suggest a multimerization
of the core protein in solution. These newly characterized properties could
provide a basis for understanding the pathway of the viral nucleocapsid assembly.
PMID- 10772997
TI - New molecular targets for cholesterol-lowering therapy.
AB - The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
(statins) in randomized clinical trials has established that cholesterol-lowering
treatment reduces the risk of both cardiovascular and total mortality. This
reduction in risk occurs in patients with or without existing cardiovascular
disease and in patients with high or average plasma cholesterol concentrations.
Aggressive treatment to lower plasma cholesterol has been shown to slow
progression of atherosclerosis and in some instances may be as successful as
angioplasty in reducing ischemic events. These studies suggest that reduction of
plasma cholesterol to levels even below 100 mg/dl might be desirable. New targets
for cholesterol-lowering therapy with mechanisms of action different from the
statins have been identified. One of these targets is the Na(+)-dependent bile
acid transporter that is expressed in the terminal ileum. This protein is
responsible for recycling bile acids from the intestine to the liver. Several
compounds that demonstrate the ability to decrease transporter activity and to
lower plasma cholesterol have been investigated. Absorption of cholesterol from
the small intestine is another potential target. Compounds that inhibit
cholesterol absorption may act by interacting stoichiometrically with cholesterol
within the intestinal lumen or substoichiometrically, presumably within the
enterocyte. Finally, the transcriptional regulation of cholesterol 7alpha
hydroxylase by members of the nuclear receptor superfamily provides at least two
other molecular targets for cholesterol-lowering drugs.
PMID- 10772996
TI - Passive infusion of immune serum into simian immunodeficiency virus-infected
rhesus macaques undergoing a rapid disease course has minimal effect on plasma
viremia.
AB - Antibody responses are often considered to play only a limited role in
controlling viremia during chronic infections with human or simian
immunodeficiency virus (SIV). We investigated this by determining the effect of
passively infused antibody on plasma viremia in infected rhesus macaques. The
emphasis of the study was to understand the mechanism(s) underlying any observed
effects. We infused serum immunoglobulins (SIVIG) purified from SIV(mac)251
infected macaques into other SIV(mac)251-infected macaques. The rapid progressor
recipients had high viral loads but negligible titers of antibodies to SIV. Thus,
we could significantly increase antibody titers with exogenous SIVIG. Despite
restoring anti-SIV titers to levels typical of macaques with a normal disease
course, SIVIG had only a modest effect on plasma SIV RNA and cell-associated
viral load; the maximum, transient, reduction was threefold. The decrease in
plasma RNA commenced within 1-2 h of SIVIG infusion, the nadir was at 12 h, and
then a rebound occurred. A two- to threefold drop in cell-associated viral RNA
was simultaneous with the decrease in plasma RNA. The kinetics of the viremia
changes are inconsistent with neutralization of new cycles of infection. More
likely, perhaps unexpectedly, is that infused antibodies killed SIV-infected
cells, via an effector mechanism such as antibody-dependent cellular
cytotoxicity.
PMID- 10772998
TI - Affinities, selectivities, potencies, and intrinsic activities of natural and
synthetic prostanoids using endogenous receptors: focus on DP class prostanoids.
AB - The prostanoid receptor-subtype binding affinities, selectivities, potencies, and
intrinsic activities of four natural prostanoids and six synthetic DP class
prostanoids were determined using binding and functional assays with endogenous
receptors. SQ27986 exhibited the highest affinity for the human platelet DP
receptor and the best DP receptor selectivity profile. Prostaglandin (PG)D(2) was
the least DP receptor-selective. The rank order of compound affinities at the DP
receptor was SQ27986 (K(i) = 10 +/- 2 nM) > RS93520 = ZK110841 = BW245C (K(i) =
23-26 nM) > ZK118182 (K(i) = 50 +/- 9 nM) > PGD(2) (K(i) = 80 +/- 5 nM). DP
receptor agonists produced cAMP in embryonic bovine tracheal fibroblasts with
different potencies (EC(50) values in nM): ZK118182 (18 +/- 6), RS93520 (28 +/-
6), SQ27986 (29 +/- 7), ZK110841 (31 +/- 7), BW245C (53 +/- 16), and PGD(2) (98
+/- 10). BW245C was more efficacious and RS93520 was less efficacious than
PGD(2). ZK110841 and ZK118182 exhibited a relatively high potency at the adenylyl
cyclase-coupled EP(2) receptor in human nonpigmented ciliary epithelial cells but
were partial agonists. None of the DP class agonists showed any EP(4) receptor
functional activity in Chinese hamster ovary cells. The DP receptor antagonist
BWA868C competitively antagonized the PGD(2)-induced cAMP accumulation in
embryonic bovine tracheal fibroblast cells (pA(2) = 7.83 +/- 0.08). The
dissociation constants for BWA868C antagonizing PGD(2)-, BW245C-, and ZK118182
induced cAMP production were quite similar (apparent -log K(b) = 7.9-8.2, n = 5
9). The pharmacological properties of some natural and numerous DP class
synthetic prostanoids have been determined using endogenous receptors.
PMID- 10772999
TI - In vitro studies of striatal vesicles containing the vesicular monoamine
transporter (VMAT2): rat versus mouse differences in sequestration of 1-methyl-4
phenylpyridinium.
AB - Significant differences exist in the sensitivity of mice and rats to the
neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot
be explained by differences in exposure to or uptake of 1-methyl-4
phenylpyridinium (MPP(+)) into dopamine (DA) neurons. MPP(+) is also a substrate
for the brain vesicular monoamine transporter (VMAT2), and sequestration into
synaptic vesicles may be one mechanism of protection against MPP(+) toxicity. A
greater sequestration of MPP(+) into vesicles of DA neurons in rats versus mice
could explain the lower vulnerability of DA neurons in the rat to MPP(+)
toxicity. To test this hypothesis, the kinetics of uptake for [(3)H]MPP(+) and
[(3)H]DA as well as [(3)H]dihydrotetrabenazine binding to VMAT2 were compared in
vesicles isolated from the striata of rats and mice. The K(m) value of
[(3)H]MPP(+) transport was similar in the two species. In contrast, the maximal
transport rate (V(max)) was 2-fold greater in vesicles from rats than in those
from mice. Likewise, the K(m) value for [(3)H]DA transport was similar in both
preparations, but the V(max) value was 2-fold greater in rat than in mouse
vesicles. The B(max) value for [(3)H]dihydrotetrabenazine binding was also 2-fold
greater in striatal vesicles from rats than in those from mice. Electron
micrographs demonstrated that vesicles isolated from rats and mice were
approximately the same size. Based on these observations, we propose that
striatal vesicles from rats have more VMAT2 than vesicles from mice and that this
species difference in VMAT2 density may help explain the reduced vulnerability of
rat DA neurons to MPP(+) neurotoxicity.
PMID- 10773000
TI - Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4
phenylpyridinium neurotoxicity in vivo in rat striata.
AB - Dopamine neurons from various animal species differ in sensitivity to the
neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl
4-phenylpyridinium (MPP(+)). Compared with striatal vesicles isolated from mice,
those from rats have a higher density of the brain vesicular monoamine
transporter (VMAT2) and a greater ability to sequester MPP(+), suggesting a
larger storage capacity for MPP(+) in rat vesicles. In the present study, we
examined whether striatal VMAT2-containing vesicles might provide protection
against the neurotoxic effects of MPP(+) in vivo. Dose-response curves for
striatally infused MPP(+) were determined in animals pretreated with or without a
VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor)
produced a 5-fold leftward shift in the MPP(+) dose-response curve and a
significant lowering of the EC(50) concentration for MPP(+)-induced damage. These
findings provide evidence for a substantial accumulation of MPP(+) in VMAT2
containing vesicles in vivo in the rat striatum and support the hypothesis that
MPP(+) sequestration in vesicles can provide protection against its toxic
actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by
a striatal infusion of MPP(+) or by systemic administration of MPTP. These data
suggest that vesicular sequestration of MPP(+) may be of less importance in mice
than in rats as relates to protection from the toxin. The present results also
reveal that although VMAT2 inhibition enhanced striatal MPP(+) toxicity in the
rat, the potency of MPP(+) in the rat striatum was less than that in mouse
striatum. This implies that there are other factors that either exacerbate MPP(+)
toxicity in the mouse or attenuate MPP(+) toxicity in rats.
PMID- 10773001
TI - Microsomal binding of amitriptyline: effect on estimation of enzyme kinetic
parameters in vitro.
AB - The effect of binding of amitriptyline to human liver microsomes and to
microsomes from human B-lymphoblastoid cells on the estimation of enzyme kinetic
parameters describing N-demethylation to nortriptyline was investigated using a
combination of microsomal binding and in vitro enzyme kinetic studies.
Quantitative binding in both matrices increased with higher microsomal protein
concentrations (free fractions 0.88-0.32 at 100-500 microg protein/ml in human
liver microsomes and 0.82-0.26 at 250-1000 microg protein/ml in microsomes from B
lymphoblastoid cells) and was independent of amitriptyline concentration over a
concentration range of 0.2 to 200 microM. Addition of heat-inactivated microsomal
protein (50-450 microg/ml) to native human liver microsomes (50 microg/ml)
reduced the amitriptyline N-demethylation rate in a protein concentration
dependent manner. This effect was greater at lower substrate concentrations and
was overcome by saturating concentrations of substrate, thereby decreasing the
apparent affinities of the high- and low-affinity components of the N
demethylation process, with minimal effect on the net V(max). Addition of
metabolically inactive microsomes from untransfected human lymphoblastoid cells
(750 microg/ml) to CYP2C19 (250 microg/ml protein) increased the apparent K(m)
value for amitriptyline N-demethylation by 3.5-fold and increased the
uncompetitive substrate inhibition constant (K(s)) by 2.2-fold, making substrate
inhibition essentially undetectable. A similar effect was seen with CYP3A4, with
a 1.8-fold increase in the S(50) (substrate concentration at which half-maximal
velocity of a Hill enzyme is achieved). Microsomal binding did not alter the
V(max) of either CYP isoform to any appreciable extent. These findings emphasize
the importance of incorporating microsomal binding in the estimation of enzyme
kinetic parameters in vitro and making appropriate corrections for unbound drug
concentrations.
PMID- 10773002
TI - Long-term effects of the endothelin(A) receptor antagonist LU 135252 and the
angiotensin-converting enzyme inhibitor trandolapril on diabetic angiopathy and
nephropathy in a chronic type I diabetes mellitus rat model.
AB - Diabetic angiopathy is a serious problem in antidiabetic therapy. We wanted to
investigate whether treatment with the endothelin(A) receptor antagonist LU
135252 or with the angiotensin-converting enzyme inhibitor trandolapril might
prevent angiopathy in long-term type I diabetes mellitus. Six groups of male
Wistar rats were investigated: untreated age-matched control rats, healthy
controls treated with trandolapril (0.3 mg/kg), healthy controls treated with LU
135252 (100 mg/kg), untreated diabetic rats, and diabetic rats treated with
either trandolapril or LU 135252. Rats were rendered diabetic by injection of
streptozotozin. Duration of the disease was 6 months. Thereafter, rats were
sacrificed, and hearts, kidneys, and a mesenterial loop were removed. Hearts and
kidneys were processed histologically; the mesenterial loop was perfused with
saline at constant pressure for investigation of microvessels using
microvideoangiometry while treated with either 30 mM KCl, 1 microM acetylcholine,
or 1 microM sodium nitroprusside. All diabetic rats developed hyperglycemia
without differences among these three groups. Diabetic rats exhibited marked
anemia, which was significantly antagonized by both treatments. The heart
capillaries/muscle fibers ratio was decreased significantly in diabetic animals,
which was prevented fully by both treatments. Renal glomerular diameter was
increased in diabetic rats. This was significantly antagonized by LU 135252 but
not by trandolapril. Deposition of homogeneous eosinophilic material within the
glomeruli was nearly completely prevented by LU 135252. The acetylcholine-induced
vasodilation in mesenteric microvessels was significantly attenuated in diabetic
rats, which was significantly antagonized by both treatments. We conclude that
both angiotensin and endothelin seem to contribute to the development of diabetic
angiopathy and that, in addition to angiotensin-converting enzyme inhibition,
blockade of endothelin(A) receptors may be an interesting new approach to
antiangiopathic therapy.
PMID- 10773003
TI - Effects of volatile anesthetics on the direct and indirect protein kinase C
mediated enhancement of alpha1E-type Ca(2+) current in Xenopus oocytes.
AB - The effect of the volatile anesthetics (VAs) halothane (0.59 mM) and isoflurane
(0.70 mM) on protein kinase C (PKC)-mediated modulation of alpha1E type of high
voltage-gated Ca(2+) channels was examined in Xenopus oocytes coexpressing m1
muscarinic acetylcholine receptors. Phorbol-12-myristate-13-acetate (PMA) or 1, 2
dioctanoyl-sn-glycerol (DOG) was used to activate PKC directly, whereas indirect
activation was induced with acetyl-beta-methylcholine (MCh). The interaction
between PKC activators and VAs was examined by perfusing either VA before,
during, or after the administration of PMA, DOG, or MCh. In addition, the effect
of VAs was studied after the down-regulation of PKC. The application of VAs
inhibited Ba(2+) current (I(Ba)), whereas PMA (500 nM), DOG (100 microM), or MCh
(1 and 10 microM) markedly potentiated I(Ba). VAs inhibited PMA- or DOG-enhanced
I(Ba) to the same extent as seen in controls. The inhibition of I(Ba) induced by
VAs was not reversed by PMA or DOG. The administration of VAs in combination with
PMA, DOG, or MCh (1 microM) led to the inhibition of I(Ba). MCh (10 microM)
counteracted the inhibitory effect of VAs when administered together and reversed
the inhibition of I(Ba) produced by VAs. These differences in the responses
between PMA and MCh (10 microM) may be based on the involvement of various pools
of PKC. It is suggested that VAs act directly at the membrane, because they
blocked the membrane-based action of PMA, whereas the receptor-based action of
MCh was only partially blocked. It is possible that some PKC isoforms may not be
a direct target of VAs.
PMID- 10773004
TI - Selective inhibitor of p38 mitogen-activated protein kinase inhibits
lipopolysaccharide-induced interleukin-8 expression in human pulmonary vascular
endothelial cells.
AB - Adult respiratory distress syndrome (ARDS) characterized by permeability edema is
observed in severe insults such as bacteremia sepsis. Interleukin (IL)-8, which
chemoattracts and activates neutrophils, has been suggested to play an important
role in the production of ARDS. Therefore, the inhibition of IL-8 production is
an important strategy for the treatment of ARDS. Recent studies have revealed the
role of p38 mitogen-activated protein (MAP) kinase in cytokine expression and the
inhibition by a selective inhibitor of p38 MAP kinase activity of cytokine
expression in a variety of cell types. However, little is known about the role of
p38 MAP kinase in lipopolysaccharide (LPS)-induced IL-8 expression in pulmonary
vascular endothelial cells and the effect of a selective p38 MAP kinase inhibitor
on it. In the present study, we therefore attempted to clarify these issues. The
results showed that LPS induced p38 MAP kinase phosphorylation and activity, and
SB 203580 as a selective inhibitor of p38 MAP kinase activity inhibited p38 MAP
kinase activity and IL-8 expression in LPS-stimulated pulmonary vascular
endothelial cells. These results indicate that p38 MAP kinase regulates LPS
induced IL-8 expression in pulmonary vascular endothelial cells. Although it is
currently not known whether SB 203580 is capable of producing beneficial effects
on ARDS, a strategy of inhibiting p38 MAP kinase activity by a selective p38 MAP
kinase inhibitor may apply to the therapy for ARDS.
PMID- 10773005
TI - Characterization of the major metabolites of verapamil as substrates and
inhibitors of P-glycoprotein.
AB - Verapamil is subject to extensive oxidative metabolism mediated by cytochrome
P450 enzymes with less than 5% of an oral dose being excreted unchanged in urine.
Furthermore, verapamil is known to be a potent inhibitor of P-glycoprotein
function. There is evidence from in vivo investigations that some verapamil
metabolites might be actively transported. The aim of the present study was to
investigate P-glycoprotein-mediated transport and inhibition properties of
verapamil and its metabolites norverapamil, D-620, D-617, and D-703. Polarized
transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and
L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1-P-glycoprotein).
Inhibition of P-glycoprotein-mediated transport by these compounds was determined
using digoxin as P-glycoprotein substrate. At concentrations of 5 microM,
significant differences between basal-to-apical and apical-to-basal apparent
permeability coefficients were observed for D-617 and D-620 in all P-glycoprotein
expressing cell monolayers, indicating that both are P-glycoprotein substrates.
In contrast, no P-glycoprotein-dependent transport was found for verapamil,
norverapamil, and D-703 in Caco-2 cells and for D-703 in L-MDR1 cells. Moreover,
verapamil, norverapamil, and D-703 inhibited P-glycoprotein-mediated digoxin
transport with IC(50) values of 1.1, 0.3, and 1.6 microM, respectively, whereas D
617 and D-620 did not (at concentrations up to 100 microM). We conclude that
verapamil phase I metabolites exhibit different P-glycoprotein substrate and
inhibition characteristics, with the N-dealkylated metabolites D-617 and D-620
being P-glycoprotein substrates and norverapamil and D-703 being inhibitors of P
glycoprotein function, which may influence P-glycoprotein-dependent drug
disposition and elimination.
PMID- 10773006
TI - Cocaine potentiates ethanol-induced excitation of dopaminergic reward neurons in
the ventral tegmental area.
AB - The coabuse of cocaine and ethanol is one of the most frequently used substance
abuse combinations in the United States. The dopamine (DA) neurons in the ventral
tegmental area (VTA) are important in the rewarding mechanism of these two
substances. Cocaine is known to block the reuptake of DA and serotonin (5-HT). At
concentrations below 1 microM, cocaine preferentially blocks the reuptake of 5-HT
compared with DA. We have previously shown that ethanol increases the firing rate
of DA neurons in the VTA, and that this excitation is enhanced by 5-HT.
Extracellular single-unit recordings were made from VTA dopaminergic neurons in
coronal brain slices from young adult Fischer 344 rats. Cocaine (1-10 microM)
reduced the spontaneous firing rate in VTA dopaminergic neurons in a
concentration-related manner. A lower concentration of cocaine (500 nM), which is
a concentration that is pharmacologically relevant in addicts, produced only a
very small decrease in the firing rate of VTA neurons but potentiated ethanol
excitation of these neurons. Higher concentrations of cocaine (1 microM) did not
enhance ethanol excitation. Ethanol-induced excitation was potentiated by the
higher concentrations of cocaine (1 and 2 microM) in the presence of the D(2)
receptor antagonist sulpiride (1 microM). Furthermore, cocaine potentiation of
ethanol-induced excitation was reversed by ketanserin (2 microM), a 5-HT(2)
antagonist. The enhanced ethanol excitation of VTA dopaminergic neurons caused by
cocaine may partially explain the high incidence of the coabuse of these two
substances.
PMID- 10773007
TI - Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor
cells to 4-hydroperoxycyclophosphamide in vitro.
AB - Previous studies in this laboratory showed that the overexpression of human
aldehyde dehydrogenase class-1 (ALDH-1) with a retroviral vector resulted in
increased resistance to 4-hydroperoxycyclophosphamide (4-HC), an active
metabolite of cyclophosphamide. The present study examined the effect of ALDH-1
antisense RNA expression on ALDH-1 activity and sensitivity to 4-HC toxicity.
Three different ALDH-1 cDNAs were synthesized that are either missing the N
terminus (N), C terminus (C), or both (NC) and subcloned into the BamHI cloning
site of pLXSN retroviral vector in the antisense (AS) orientation (AS-N, AS-C,
and AS-NC, respectively). It was demonstrated that the overexpression of each of
the AS constructs in K562 leukemic cells and A549 lung cancer cells results in
suppression of ALDH-1 mRNA and enzymatic activity. Furthermore, the AS-N and AS
NC were generally more effective than AS-C in reducing the ALDH-1 activity. Both
K562 and A549 cells expressing the ALDH-1 AS became significantly more sensitive
to 4-HC toxicity as demonstrated by clonogenic and liquid culture assays. The
increase in 4-HC sensitivity was in correlation with the degree of suppression of
ALDH-1 activity. Moreover, such increase in 4-HC sensitivity, especially with AS
N and AS-NC, was to a similar degree seen with the use of
diethylaminobenzaldehyde, a specific inhibitor of ALDH-1. These results indicate
that ALDH-1 expression and activity can be specifically and effectively
suppressed by AS RNA and lead to increased sensitivity to 4-HC.
PMID- 10773008
TI - Nitric-oxide synthase-containing nerves facilitate adrenergic transmitter release
in sheep middle cerebral arteries.
AB - Cerebral blood vessels contain both sympathetic and nitric oxide (NO) synthase
(NOS)-containing nerves. NO has been proposed to modulate smooth muscle function
and adrenergic nerve activity, and the nature of this modulation is
controversial: some data show NO inhibits norepinephrine (NE) release, whereas
others suggest that NO augments release. To test the hypothesis that in cerebral
arteries NO released by NOS-containing nerves augments stimulation-evoked NE
release, we used direct measurement of NE and NO release in isolated sheep middle
cerebral arteries. The facial artery, which has not been reported to be
innervated with NOS-containing nerves, was used as an artery comparison model.
HPLC and redox electrochemical detection was used to measure NE, and NO was
measured by chemiluminescence. Stimulation-evoked NE release from the middle
cerebral artery significantly declined in the presence of the NOS inhibitor
N(omega)-nitro-L-arginine methyl ester (L-NAME). The effect of L-NAME was
reversed by the addition of the NO donor S-nitroso-N-acetyl-DL-penicillamine. In
contrast, in facial arteries, L-NAME had no effect on stimulation-evoked NE
release, whereas S-nitroso-N-acetyl-DL-penicillamine still significantly elevated
NE release. Activation of perivascular nerves significantly increased NE release
in both the middle cerebral and facial arteries. However, when NO was measured in
the same samples, stimulation-evoked release of NO was significantly increased
compared with basal release only in middle cerebral arteries. These data support
the concept that cerebral arteries in the sheep contain both adrenergic and NOS
containing nerves. Furthermore, this study provides succinct evidence that NO
released from NOS nerves augments stimulation-evoked NE release.
PMID- 10773009
TI - Designing stable blood-brain barrier-permeable prosaptide peptides for treatment
of central nervous system neurodegeneration.
AB - Prosaposin-derived peptides have been proposed as potential therapeutics for
neurodegenerative diseases. Previously, we reported that the minimal length for
bioactivity was 12 amino acids, and key amino acids were described based on
interspecies conservation. In this article, we have further investigated the
sequence requirements for bioactive Prosaptide (Myelos Corporation) peptides in
terms of length and amino acid identity. The use of Prosaptide peptides for
treatment of central nervous system (CNS) disorders requires that they are stable
in vivo. Although robust effects of our prototypical peptide Prosaptide TX14(A)
have been shown in the peripheral nervous system, minimal success has been
achieved when treating the CNS in rats and this may be due to instability of
Prosaptide TX14(A) in brain. Herein, we demonstrate that, indeed, Prosaptide
TX14(A) is rapidly degraded in the brain and we have attempted to design
prosaptides with increased CNS stability. One peptide, Prosaptide TX15-2, shows
increased stability in brain and may be of use in the treatment of CNS disorders.
With the aim of designing Prosaptide peptides that may be systemically
administered for CNS treatment, we have investigated the blood-brain barrier
permeability of Prosaptide TX14(A) and TX15-2. Both of these peptides cross the
blood-brain barrier via a nonspecific mechanism.
PMID- 10773010
TI - Role of cysteinyl leukotrienes in CD4(+) T cell-driven late allergic airway
responses.
AB - Cysteinyl leukotrienes (cys LTs) play an important role in late responses to
allergen challenge of actively sensitized rats. The aim of this study was to
determine whether T cell-dependent late airway responses (LARs) also are mediated
by cys LTs. To do this we tested the effects of the selective and potent LTD(4)
antagonist pranlukast on airway responses to ovalbumin (OVA) challenge of naive
recipients of CD4(+) T cells isolated from the cervical lymph nodes of OVA
sensitized donor rats. CD4(+) T cells (5 million) were purified by immunomagnetic
separation and administered i.p. 2 days before OVA challenge. The pulmonary
resistance was measured for 8 h after challenge and bronchoalveolar lavage (BAL)
was performed for analysis of leukocytes and major basic protein-positive cells.
The LAR, determined as the area under the curve of pulmonary resistance against
time from 3 to 8 h after challenge, was 8.9 +/- 1.79 cm H(2)O/ml/s x min after
OVA compared with 2.8 +/- 0.50 cm H(2)O/ml/s x min (P <.01) after OVA and
pranlukast treatment. The total cell count in BAL was not significantly greater
in the OVA challenged group (3.55 +/- 0.41 x 10(6) cells) compared with the OVA-
and pranlukast-treated group (2.65 +/- 0.45 x 10(6) cells). However, lymphocytes
and eosinophils were reduced in numbers by pranlukast. Interleukin-5 mRNA
positive cells were diminished by 50% in pranlukast-treated animals. In
conclusion, pranlukast inhibits LAR, BAL eosinophilia, and Interleukin-5
expression in rats with adoptively transferred LAR, indicating an important role
for cys LTs in these T cell-driven responses.
PMID- 10773011
TI - Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death
in primary cortical cell culture.
AB - Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively
expressed in brain, with neuronal expression of COX-2 being rapidly induced after
numerous insults, including cerebral ischemia. Because overactivation of N-methyl
D-aspartate (NMDA) receptors has been implicated in the cell loss associated with
ischemia, we characterized the expression of the COX isozymes in murine mixed
cortical cell cultures and used isozyme-selective inhibitors to determine their
relative contribution to NMDA receptor-stimulated prostaglandin (PG) production
and excitotoxic neuronal cell death. Immunocytochemical analysis of mixed
cortical cell cultures revealed that COX-2 expression was restricted to neurons,
whereas COX-1 was expressed in both neurons and astrocytes. Brief exposure to
NMDA (5 min; 100 microM) elicited a time-dependent accumulation of PGs in the
culture medium that preceded neuronal cell death and correlated with the
induction of COX-2 mRNA. COX-1 expression remained unchanged. Flurbiprofen, a
nonselective COX-1/COX-2 inhibitor, blocked NMDA-stimulated PG production and
attenuated neuronal death in a concentration-dependent manner. Similar results
were obtained with the specific COX-2 inhibitor NS-398 (10-30 microM) but not
with the selective COX-1 inhibitor valeryl salicylate (10-300 microM). Inhibition
of total constitutive COX activity with aspirin (100 microM, 1.5 h) before NMDA
exposure did not prevent subsequent NMDA-mediated neuronal cell death. However,
neuronal injury in aspirin-pretreated cultures was attenuated by flurbiprofen
administration after NMDA exposure. Finally, the protection afforded by COX-2
inhibition was specific for NMDA because neither flurbiprofen nor NS-398
protected neurons against kainate-mediated neurotoxicity. Together, these results
support the conclusion that newly synthesized COX-2 protein contributes to NMDA
induced neuronal injury.
PMID- 10773012
TI - Altered regulation of the D(1) dopamine receptor in mutant Chinese hamster ovary
cells deficient in cyclic AMP-dependent protein kinase activity.
AB - To investigate the role of the cAMP-dependent protein kinase (PKA) in the
desensitization and down-regulation of the D(1) dopamine receptor, we stably
expressed the rat cDNA for this receptor in mutant Chinese hamster ovary (CHO)
cell lines deficient in PKA activity. The 10260 mutant CHO cell line has been
characterized as expressing less than 10% of type I and type II PKA activities
relative to the parental 10001 CHO cell line. The 10248 mutant CHO line lacks
type II PKA activity and expresses a defective type I PKA. The transfected
parental and mutant cell lines were found to express approximately 1 pmol/mg D(1)
receptor binding activity (B(max)) as determined using [(3)H]SCH-23390 binding
assays. All three cell lines demonstrated similar levels of dopamine-stimulated
adenylyl cyclase activity. Pretreatment of all three CHO cells with dopamine
resulted in desensitization of the adenylyl cyclase response, although the
maximum desensitization was attenuated by 20 and 40% in the 10260 and 10248 cell
lines, respectively. Dopamine also promoted, in a time- and dose-dependent
fashion, a >90% down-regulation of D(1) receptors in the parental cell line but
only a 50 and 30% decrease in the 10260 and 10248 cells, respectively. Similarly,
treatment of the cells with the membrane-permeable cAMP analog 8-(4
chlorophenylthio)-cAMP induced functional desensitization and down-regulation of
the D(1) receptor, although it was not as great as that observed with agonist
pretreatment. As with the agonist pretreatments, the 8-(4-chlorophenylthio)
induced responses were attenuated in the mutant cells with the 10248 line
exhibiting the least desensitization/down-regulation. Our results suggest that
PKA significantly contributes to the desensitization and down-regulation of D(1)
receptors in CHO cells and that type II PKA may be the more relevant isoform with
respect to regulating D(1) receptor function.
PMID- 10773013
TI - Comparative kinetics and response to the benzodiazepine agonists triazolam and
zolpidem: evaluation of sex-dependent differences.
AB - Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose,
double-blind, three-way crossover pharmacokinetic and pharmacodynamic study.
Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine
ligand; 10 mg of zolpidem, an imidazopyridine having relative selectivity for the
type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance
of triazolam was higher in women than in men (8.7 versus 5. 5 ml/min/kg), but the
difference was not significant. In contrast, zolpidem clearance was lower in
women than in men (3.5 versus 6.7 ml/min/kg, P <.06). Compared to placebo, both
active medications produced significant benzodiazepine agonist-like
pharmacodynamic effects: sedation, impaired psychomotor performance, impaired
information recall, and increased electroencephalographic beta-amplitude. Effects
of triazolam and zolpidem in general were comparable and less than 8 h in
duration. There was no evidence of a substantial or consistent sex difference in
pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle
differences could not be ruled out due to low statistical power. The complete
dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP
participation in zolpidem clearance, may explain the differing sex effects on
clearance of the two compounds.
PMID- 10773014
TI - Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with
nateglinide: A comparison with sulfonylureas and repaglinide.
AB - Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in
clinical development for treatment of type 2 diabetes. The aim of this study was
to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea
receptor underlies its more rapid onset and shorter duration of action in animal
models. Binding studies were carried out with membranes prepared from RIN-m5F
cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1
(SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive
binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride >
repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results
with HEK-293/recombinant human SUR1 cells were similar with the exception that
glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide
had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent
with both compounds competitively binding to the glibenclamide-binding site on
SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that
nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with
K(ATP) channels in rat pancreatic beta-cells was investigated with the patch
clamp method. The relative potency for inhibition of the K(ATP) channel was
repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on
K(ATP) current showed that the onset of inhibition by nateglinide was comparable
to glibenclamide but more rapid than that of repaglinide. The time for reversal
of channel inhibition by nateglinide was also faster than with glibenclamide and
repaglinide. These results suggest that the unique characteristics of nateglinide
are largely the result of its interaction at the K(ATP) channel.
PMID- 10773015
TI - Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the
oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor.
AB - In vitro studies were conducted to identify the cytochromes P450 (CYP) involved
in the oxidative metabolism of celecoxib. The hydroxylation of celecoxib
conformed to monophasic Michaelis-Menten kinetics (mean +/- S.D., n = 4 livers,
K(m) = 3.8 +/- 0.95 microM, V(max) = 0.70 +/- 0.45 nmol/min/mg protein) in the
presence of human liver microsomes, although substrate inhibition was significant
at higher celecoxib concentrations. The treatment of a panel of human liver
microsomal samples (n = 16 subjects) with antibodies against CYP2C9 and CYP3A4
inhibited the formation of hydroxy celecoxib by 72 to 92% and 0 to 27%,
respectively. The presence of both antibodies in the incubation suppressed the
activity by 90 to 94%. In addition, the formation of hydroxy celecoxib
significantly correlated with CYP2C9-selective tolbutamide methyl hydroxylation
(r = 0.92, P <. 001) and CYP3A-selective testosterone 6beta-hydroxylation (r =
0.55, P <.02). In contrast, correlation with activities selective for other forms
of CYP was weak (r liver > brain > heart. Human HO-1 was detectable for up to 4 weeks in all
tissues studied. Administration of adenovirus human HO-1 resulted in maximal
increase of HO activity after 1 to 2 weeks in rats. The increase in HO activity
due to gene transfer also was associated with a parallel decrease (approximately
25%) in cytochrome P-450 (CYP) content and in CYP-dependent arachidonic acid
metabolism. In addition, we investigated the possibility that the human HO-1 gene
altered the expression of the endogenous rat enzyme after administration of
cobalt chloride s.c. Cobalt chloride administration resulted in increased HO
activity in all tissues examined in rats transduced with the human HO-1 gene to
the same degree as in nontransduced rats. The metal was a more potent inducer of
renal HO activity than was the adenoviral-mediated human HO-1 vector. The
increase in HO activity after adenoviral-mediated human HO-1 transfer was
associated with a decrease in microsomal heme-CYP and CYP activity. The increase
in HO-1 activity after adenovirus-mediated human HO-1 gene transfer may prove
useful as a means of selectively increasing enzyme activity in a specific organ
and regulating homeostasis by modulation of vasoactive molecules such as carbon
monoxide and bilirubin and, in addition, providing a means of delivering the
human HO-1 gene for experimental purposes.
PMID- 10773021
TI - Effects of mitoxantrone on excitation-contraction coupling in guinea pig
ventricular myocytes.
AB - The mechanisms of the inotropic effect of mitoxantrone (MTO), a synthetic
dihydroxyanthracenedione derivative with antineoplastic activity, was
investigated in guinea pig ventricular myocytes using whole-cell patch-clamp
methods combined with fura-2 fluorescence and cell-edge tracking techniques. In
right ventricular papillary muscles, 30 microM MTO increased isometric force of
contraction as well as action potential duration (APD) in a time-dependent
manner. The force of contraction was increased approximately 3-fold within 4 h.
This positive inotropic effect was accompanied by a prolongation of time to peak
force and relaxation time. In current-clamped single myocytes treated with 30
microM MTO for 30 min, an increase of cell shortening by 77% and a prolongation
of APD by 19% was observed. Peak amplitude of the intracellular Ca(2+) transients
was also increased by 10%. The contribution of APD prolongation to the
enhancement of cell shortening induced by MTO was assessed by clamping control
myocytes with action potentials of various duration. Prolongation of APD(90) (ADP
measured at 90% of repolarization) by 24% led to an increase of cell shortening
by 13%. When the cells were clamped by an action potential with constant APD, MTO
still caused an increase of cell shortening by 59% within 30 min. No increase of
the peak intracellular Ca(2+) transients, however, was observed under this
condition. We conclude that both the APD prolongation and a direct interaction
with the contractile proteins contributed to the positive inotropic effect of
MTO.
PMID- 10773022
TI - Inhibition of cyclooxygenase-2 decreases DNA synthesis induced by platelet
derived growth factor in Swiss 3T3 fibroblasts.
AB - NS-398 [N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide], a selective
inhibitor of cyclooxygenase-2 (COX-2), inhibited proliferation induced by
platelet-derived growth factor (PDGF) in Swiss 3T3 fibroblasts. The effect of NS
398 was found to be concentration-dependent. The half-maximal effect occurred at
approximately 0.1 microM. NS-398 decreased mitogenesis at subsaturating PDGF
concentrations and the inhibitory effect of NS-398 was overcome by increasing
PDGF concentration. SC-236, another COX-2 selective inhibitor, also inhibited
PDGF-induced proliferation. In contrast, two selective COX-1 inhibitors, valeryl
salicylate and ketorolac, had no significant inhibitory effect on PDGF-stimulated
DNA synthesis. The inhibition was obtained when NS-398 was added during the first
hour after PDGF addition. At 1 h, PDGF induced COX-2 protein and prostaglandin
(PG)E(2) synthesis, and NS-398 blocked the synthesis of PGE(2). The inhibitory
effect of NS-398 on PDGF-stimulated DNA synthesis was counteracted by 280 nM
PGE(2). The antimitogenic action of NS-398 and SC-236 suggests that selective
inhibition of COX-2 may produce antiproliferative effects with substantial safety
advantages over nonselective COX inhibitors.
PMID- 10773023
TI - Extracellular signal-regulated kinases are involved in the antiapoptotic effect
of endothelin-1.
AB - An imbalance between proliferation and apoptosis is an important causal factor
for disorders involving abnormal cell accumulation. The role and mechanism of how
G protein-coupled receptors are linked to apoptosis are poorly understood.
Endothelin-1 (ET-1), a 21-amino acid peptide that binds to G protein-coupled
receptors with mitogenic and vasoconstricting activities, suppressed apoptosis of
human prostatic smooth muscle cells induced by paclitaxel treatment or serum
withdrawal. Serum withdrawal or paclitaxel (1-10 microM) treatment for 48 h
resulted in DNA fragmentation, a characteristic of apoptosis. The addition of ET
1 attenuated DNA fragmentation. The attenuating effect of ET-1 on DNA
fragmentation was not affected by wortmannin, bisindolylmaleimide I, tyrphostin
AG490, or AG1478. However, PD98059, an inhibitor for the extracellular signal
regulated kinase (ERK) kinase, induced apoptosis, potentiated the effect of serum
withdrawal on inducing apoptosis, and blocked the antiapoptotic effect of ET-1.
The ERK1/2 activity in these cells decreased rapidly after paclitaxel treatment
or serum withdrawal, but was maintained at a 2-fold higher level in the presence
of ET-1 for at least 4 h. These results suggest that the ERK1/2 pathway is
activated by ET-1, and blocking this pathway abolishes the antiapoptotic effect
of ET-1.
PMID- 10773024
TI - Preferential inhibition by a novel Na(+)/Ca(2+) channel blocker NS-7 of severe to
mild hypoxic injury in rat cerebrocortical slices: A possible involvement of a
highly voltage-dependent blockade of Ca(2+) channel.
AB - The hypoxic injury was induced in rat cerebrocortical slices by the exposure to
hypoxia for 45 min in the absence or presence of 3 mM glucose, followed by
reoxygenation for 5 h. The injury was more pronounced in the absence of glucose
(severe hypoxic injury) than in the presence of glucose (mild hypoxic injury). A
novel Na(+)/Ca(2+) channel blocker, NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5
piperidinopentyloxy) pyrimidine hydrochloride], at 3 to 30 microM inhibited
preferentially the severe hypoxic injury, whereas MK-801, omega-conotoxin GVIA
(omega-CTX), and N(G)-nitro-L-arginine methylester suppressed preferentially the
mild hypoxic injury. The extracellular cyclic GMP formation, a marker of nitric
oxide synthesis, was enhanced during hypoxia, although the extent was greater in
the absence of glucose. As observed in the hypoxic injury, NS-7 preferentially
inhibited the cyclic GMP formation induced by severe hypoxic insults, whereas MK
801 or omega-CTX reduced it under mild hypoxic condition. When 30 to 50 mM KCl
was applied to normoxic slices, a concentration-dependent increase in the
extracellular cyclic GMP formation was observed. NS-7 blocked the cyclic GMP
formation induced by 50 mM KCl but not by 30 to 40 mM KCl, whereas omega-CTX
suppressed only the 30 mM KCl-evoked response. In primary neuronal culture, NS-7
reversed KCl-induced increase in intracellular Ca(2+) in which the inhibition was
marked when the KCl concentration was increased. These findings suggest that NS
7, unlike other neuroprotective compounds used in this study, is more effective
in severe hypoxic injury. The highly voltage-dependent Ca(2+) channel blockade
may contribute to the mode of neuroprotective action of NS-7.
PMID- 10773025
TI - Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance
protein 1 (MRP1).
AB - Multidrug resistance in tumor cells is often associated with reduced drug
accumulation resulting from increased expression of the 190-kDa multidrug
resistance protein 1 (MRP1) or the 170-kDa P-glycoprotein. However, unlike P
glycoprotein, MRP1 is a primary active transporter of many conjugated organic
anions, including the cysteinyl leukotriene LTC(4). Moreover, agents such as
verapamil that reverse P-glycoprotein-mediated resistance are often poorly, or
not at all, effective in MRP1-overexpressing cells. In the present study, we
investigated the effects of verapamil on MRP1-mediated transport processes. We
found that verapamil inhibited LTC(4) transport into inside-out membrane vesicles
prepared from MRP1-transfected cells in a competitive manner, but only in the
presence of reduced glutathione (GSH) or its nonreducing S-methyl derivative. In
the presence of 1 mM GSH, the apparent K(i) for verapamil was 1.2 microM, and in
the presence of 100 microM verapamil, the apparent K(i) for GSH was 77 microM.
Verapamil itself was not transported by MRP1 in either intact cells or membrane
vesicles. However, verapamil strongly stimulated MRP1-mediated GSH uptake by
membrane vesicles in a concentration-dependent and osmotically sensitive manner
that was inhibitable by MRP1-specific monoclonal antibodies. In the presence of
100 microM verapamil, the apparent K(m) and V(max) for GSH uptake were 83 microM
and 55 pmol mg(-1) min(-1), respectively. It is proposed that the variable
ability of verapamil to modulate MRP1-mediated resistance in different cell lines
may be more closely linked to its effect on the GSH status of the cells than on
its ability to inhibit the MRP1 transporter itself.
PMID- 10773026
TI - Role of constitutive cyclooxygenase-2 in prostaglandin-dependent secretion in
mouse colon in vitro.
AB - The relative contributions of cyclooxygenase (COX)-1 and COX-2 in mediating
prostaglandin (PG)-dependent chloride secretion were investigated in segments of
mouse colon mounted in Ussing-type diffusion chambers. COX-2 mRNA and protein
were constitutively expressed as shown by reverse transcription-polymerase chain
reaction and Western immunoblot, respectively. COX-2 immunoreactivity was
detected immunohistochemically in cells lying subjacent to the crypt epithelial
cells. In segments of colon mounted in Ussing chambers, arachidonic acid caused a
concentration-dependent increase in short-circuit current that was blocked by
piroxicam, the COX-2 inhibitor NS-398, and the COX-1 inhibitor SC-560. Exposure
to the PG-dependent secretagogue, bradykinin, also caused an increase in short
circuit current that was not blocked by piroxicam or SC-560, and only by the
highest dose of NS-398. When incubated in the presence of 10 microM arachidonic
acid, segments of mouse colon produced both PGE(2) and PGD(2). Synthesis of
PGE(2) but not PGD(2) was blocked by NS-398 and SC-560. These data demonstrate
that both COX-1 and COX-2 are constitutively expressed in the mouse colon, and
both contribute to PG-dependent electrolyte transport.
PMID- 10773027
TI - Nitric oxide redox species exert differential permeability effects on the blood
brain barrier.
AB - Excessive production of nitric oxide (NO) in the central nervous system is
suspected to contribute to neurodegenerative diseases. Previous studies showed
that excessive central nervous system NO increased the permeability of the blood
brain barrier (BBB) during experimental meningitis. The present work hypothesizes
that the various NO redox forms (NO(*), NO(+), NO(-)) differentially mediate
disruption of the BBB. Pharmacological agents that release NO redox forms (i.e.,
NO prodrugs) were selected based on the rate of NO release and the liberated NO
redox form. An in situ rodent brain perfusion preparation was used to administer
NO prodrugs into the cerebrovascular circulation, followed by brain perfusion
with [(14)C]sucrose, a marker of BBB integrity. Cerebrovasculature infusion of
certain NO prodrugs caused a significant, 2- to 5-fold BBB permeability increase
in all forebrain regions (P <.01). The NO prodrug rank order of BBB disruption
was S-nitroso-N-acetylpenicillamine-beta-cyclodextrin (releases NO(*), NO(+), and
NO(-)) > Angeli's salt (NO(*), NO(-)) > MAHMA NONOate approximately diethylamine
NONOate (NO(*)) > spermine NONOate (NO(*)) > DETA NONOate approximately Piloty's
acid (negligible NO redox release) approximately saline. When normalized to BBB
disruption caused by hyperosmotic mannitol (100%), S-nitroso-N
acetylpenicillamine-beta-cyclodextrin (NO(*), NO(+), and NO(-)) elicited
approximately 45% disruption, Angeli's salt (NO(*), NO(-)) elicited approximately
18% disruption, and the NONOates (NO(*)) ranged from approximately 0 to 8%
disruption. Cerebral blood flows and intracranial pressures were within normal
limits for each tested NO prodrug, thereby suggesting that BBB disruption was not
secondary to altered cerebral perfusion. Collectively, the results of this work
identify that NO(*) alone exerts modest BBB disruption compared with the specie
combination of NO(*) and NO(-), and the greatest disruption is exerted by the
combination of NO(*), NO(-), and NO(+).
PMID- 10773028
TI - Effects of ethanol on working memory and attention in pigeons.
AB - To determine whether the effects of ethanol on working memory are mediated by a
secondary effect on attention, dose-response curves for ethanol were determined
in eight pigeons trained under a titrating matching-to-sample (TMTS) procedure,
in eight pigeons trained under a discrete-trial measure of attention, and in
eight pigeons trained under a continuous-trial measure of attention. Ethanol
decreased accuracy under the TMTS procedure following the three highest doses (1,
1.8, and 3 g/kg). Only the highest dose (3 mg/kg) decreased rates of responding.
Attention, as measured under the discrete-trial procedure, was affected only by
the two highest doses (1.8 and 3 g/kg). The 3-g/kg dose caused significant
decreases in the probability of a hit and probability of a correct rejection, as
well as significant increases in the probability of an error of omission and
response latencies. Sensitivity to the signal decreased following 1.8 and 3 g/kg
ethanol. Under the continuous-trial procedure, ethanol caused a peak in false
alarms after the 1.8-g/kg dose, decreased the probability of a hit following the
1.8- and 3-g/kg doses, and increased probability of a miss at all doses.
Sensitivity to the signal was not affected. A comparison of the dose-response
curves for the TMTS procedure and the two measures of attention revealed that
working memory (TMTS) was decreased by a lower dose than that affecting
attention. This suggests that the effects of ethanol on working memory are not
mediated by the subject's ability to pay attention to stimulus changes in the
environment.
PMID- 10773029
TI - Neurokinin(3) receptors couple to the activation of neuronal nitric-oxide
synthase in stably transfected Chinese hamster ovary cells.
AB - Several physiological effects induced by activation of neurokinin(3) (NK(3))
receptors are mediated by the production of nitric oxide (NO). We investigated
the intracellular coupling of NK(3) receptors to NO synthase (NOS) using a
Chinese hamster ovary cell line that was stably transfected with both the NK(3)
receptor and type I (neuronal) NOS. NOS activity in the transfected cell line was
assayed directly, by measuring the formation of L-citrulline, another product of
NOS, as well as indirectly, by measuring the production of cGMP in cultured rat
fetal lung fibroblasts (RFL-6 cells). MePhe(7)-neurokinin B (NKB) stimulation of
L-[(3)H]citrulline production was concentration-dependent and yielded a two-site
model for the concentration-response relationship. The production of L-citrulline
in response to two other tachykinins, substance P or neurokinin A, revealed only
a one-site nature of the response. The production of cGMP in response to MePhe(7)
NKB had an EC(50) value that corresponded to the high-potency component of
MePhe(7)-NKB-induced production of L-[(3)H]citrulline. Agonist-induced calcium
signaling was also concentration-dependent, and the acute increase in the
production of cGMP by MePhe(7)-NKB (0.1 nM) was dependent on the release of
calcium from intracellular stores. Results of this study provide the first direct
evidence that NK(3) receptors couple to the generation of NO within the same
cell.
PMID- 10773030
TI - Effects of the flavoprotein inhibitor, diphenyleneiodonium sulfate, on ex vivo
organic nitrate tolerance in the rat.
AB - The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of
glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but
not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the
bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which
also is inhibited by DPI, has been proposed to generate superoxide that quenches
nitric oxide (NO) produced during GTN biotransformation, and increased oxidase
levels are proposed to contribute to the phenomenon of organic nitrate tolerance.
We examined the effect of DPI on isolated rat aorta using an in vivo model of
organic nitrate tolerance. The EC(50) values for GTN-, D-IIDN-, and L-IIDN
induced relaxation of aorta from GTN-tolerant rats were increased 4.5- to 7.5
fold. Treatment of blood vessels with DPI (0.3 microM) increased the EC(50)
values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a
result that would not be predicted if DPI and GTN tolerance affected common
targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo
tolerance was assessed by NADPH-dependent cytochrome c reductase activity of
aortic microsomes, immunoblotting, and Northern analysis. By all three
determinants, CPR expression was unchanged in aorta from GTN-tolerant rats.
Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity
(a measure of superoxide generation) of tolerant rat aortic microsomes was not
different from that of controls. Superoxide dismutase-inhibitable NADH-dependent
cytochrome c reductase activity was detected only in microsomes from tolerant
animals. DPI caused a modest increase in the sensitivity for relaxation by the NO
donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas
the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had
no effect on the sensitivity for relaxation by GTN. These results would not be
expected if tolerance-induced increases in superoxide were a causative factor for
the reduced relaxation response in tolerance. We conclude that neither reduced
flavoprotein-dependent metabolic activation of organic nitrates, such as that
mediated by CPR, nor increased superoxide due to increased NAD(P)H oxidase
activity can account for the development of in vivo tolerance to GTN.
PMID- 10773031
TI - Changes in catecholaminergic pathways innervating paraventricular nucleus and
pituitary-adrenal axis response during morphine dependence: implication of
alpha(1)- and alpha(2)-adrenoceptors.
AB - We have previously shown an enhanced activity of the pituitary-adrenal response
in rats dependent on morphine, which occurs concomitantly with an increase in the
activity of catecholaminergic terminals in the hypothalamic paraventricular
nucleus (PVN). The present study examined the possible role of noradrenergic
system in the regulation of opioid withdrawal-induced activation of the
hypothalamus-pituitary-adrenocortical (HPA) axis activity. Rats were given
morphine by s.c. implantation of morphine pellets for 7 days. On the seventh day,
morphine withdrawal was induced by s.c. administration of naloxone (1 mg/kg),
rats were sacrificed 30 min later, and changes in noradrenaline (NA) turnover
(estimated by the 3-methoxy-4-hydroxyphenylethylen glycol/NA ratio) and in
dopamine turnover (estimated by the 3,4-dihydroxyphenylacetic acid/dopamine
ratio) in the PVN (HPLC with electrochemical detection) and in plasma
corticosterone levels were determined. We found a parallelism between the
behavioral signs of withdrawal, an increased activity of noradrenergic and
dopaminergic terminals in the PVN, and the hypersecretion of the HPA axis.
Pretreatment with alpha(1)- or alpha(2)-adrenoceptor antagonists prazosin or
yohimbine, respectively, 15 min before naloxone administration significantly
prevented the withdrawal-induced corticosterone hypersecretion and attenuated the
behavioral signs of morphine withdrawal. In addition, biochemical analysis
indicated that both prazosin and yohimbine completely abolished the withdrawal
induced increase in NA turnover in the PVN. In contrast, neither prazosin nor
yohimbine modified the hyperactivity of dopaminergic terminals in the PVN during
withdrawal. Collectively, these data suggest that the secretory activity in the
HPA axis after morphine withdrawal results from an increase in noradrenergic
activity that is dependent on alpha(1)- and alpha(2)-adrenoceptor activation.
Activation of dopaminergic pathways might not contribute to the neuroendocrine
response during withdrawal.
PMID- 10773032
TI - Dual role of human cytochrome P450 3A4 residue Phe-304 in substrate specificity
and cooperativity.
AB - The structural basis of cooperativity of progesterone hydroxylation catalyzed by
human cytochrome P450 3A4 has been investigated. A recent study suggested that
substitution of larger side chains at positions Leu-211 and Asp-214 partially
mimics the action of effector by reducing the size of the active site. Based on
predictions from molecular modeling that Phe-304 in the highly conserved I helix
is involved in both effector and substrate binding, a tryptophan residue was
substituted at this position. The purified F304W mutant displayed hyperbolic
progesterone hydroxylase kinetics, indicating a lack of homotropic cooperativity.
However, the mutant remained responsive to stimulation by alpha-naphthoflavone,
exhibiting a 2-fold decrease in the K(m) value for progesterone 6beta
hydroxylation in the presence of 25 microM effector. Combining substitutions to
yield the triple mutant L211F/D214E/F304W maintained the V(max) and decreased the
K(m) for progesterone 6beta-hydroxylation, minimized stimulation by alpha
naphthoflavone, and decreased the rate of alpha-naphthoflavone oxidation to one
eighth of the wild type. Interestingly, the DeltaA(max) for spectral binding of
alpha-naphthoflavone was unaltered in L211F/D214E/F304W. Overall, the results
suggest that progesterone and alpha-naphthoflavone are oxidized at separate
locations within the P450 3A4 binding pocket, although both substrates appear to
have equal access to the reactive oxygen.
PMID- 10773033
TI - Enhanced responses to 17beta-estradiol in rat hearts treated with isoproterenol:
involvement of a cyclic AMP-dependent pathway.
AB - We determined the effects of 17beta-estradiol, the most effective estrogen,
acutely administered, on the heart/ventricular myocyte with or without treatment
with isoproterenol (Iso). At 0.1 to 1 nM, 17beta-estradiol, which itself had no
effect, reduced the heart rate and developed pressures in the isolated perfused
heart treated with 10(-7) M Iso. One nanomolar 17beta-estradiol also inhibited
the cyclic AMP (cAMP) production in Iso-treated ventricular myocytes. At 10 nM to
1 microM, 17beta-estradiol itself reduced the heart rate and incidence of
ischemia/reperfusion-induced arrhythmias, with the exception of diastolic
pressure. The effects of 17beta-estradiol on heart rate, systolic and mean
pressures, and arrhythmias were significantly enhanced in the heart/ventricular
myocyte treated with Iso. Tamoxifen, an estrogen receptor antagonist, did not
antagonize the effect of 17beta-estradiol on the Ca(2+) current in ventricular
myocytes treated with Iso, nor did it alter the effect of the hormone on the cAMP
production augmented by Iso and forskolin. The effects of 17beta-estradiol on
Ca(2+) current in the presence or absence of tamoxifen and/or Iso were similar in
male rats, which do not possess the estrogen receptor, and female rats, which
have the estrogen receptor. In conclusion, we have shown for the first time that
estrogen at physiological concentrations modulates negatively the stimulatory
actions of Iso on the heart rate and cardiac contractility. The effects may
result from activation of an unknown membrane receptor and the adenylate
cyclase/cAMP pathway, which enhances Ca(2+) influx across the L-type Ca(2+)
channel.
PMID- 10773034
TI - Effects of cyclopentyladenosine on isoproterenol response in adult and senescent
cardiac tissue from Fischer 344 rats.
AB - To characterize age-related changes in beta-adrenergic responsiveness and to test
the hypothesis that an increase in the effects of adenosine contribute to
impaired beta-adrenergic responsiveness, Fischer 344 rat right atria (RA), left
atria (LA), and left ventricular trabeculae carnae were exposed to the beta
receptor agonist isoproterenol (ISO), followed by four doses of the selective
adenosine A(1) receptor agonist cyclopentyladenosine (CPA). Spontaneous
contractile rates of adult RA were inhibited more than senescent RA by CPA.
Contractility (+dF/dt) of adult LA was reduced more than senescent LA by CPA.
Left trabeculae carnae tissue responded weakly to CPA, but senescent tissue was
less responsive than adult tissue. Senescent atrial A(1) receptor density was 56%
greater than in adult tissue, whereas the density in senescent ventricles was 39%
lower than in adult tissue. No significant difference in antagonist affinities
(K(d)) of A(1) receptor was observed between adult and senescent atria. In
addition, agonist competition curves indicated a significant increase in
senescent atrial and a decrease in senescent ventricular tissue in the affinity
of agonist for high-affinity A(1) receptors with no difference in dissociation
constant (K(i)). No significant age-related differences in atrial or ventricular
tissues occurred in either the antagonist affinity (K(d)) or density (B(max)) of
the beta-adrenergic receptors. CPA was found to inhibit ISO-stimulated adenylate
cyclase activity more in senescent than in adult atrial and ventricular membrane
preparations. We conclude that age-related differences in functional response to
ISO and CPA, A(1) receptor density, and ISO-stimulated adenylate cyclase activity
differ in atrial and ventricular myocardium.
PMID- 10773035
TI - Naloxone protects rat dopaminergic neurons against inflammatory damage through
inhibition of microglia activation and superoxide generation.
AB - Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is
a hallmark of Parkinson's disease and inflammation and oxidative stress are
closely associated with the pathogenesis of degenerative neurological disorders.
Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide
(LPS)-activated microglia, resident immune cells of the brain, to release
proinflammatory and neurotoxic factors tumor necrosis factor-alpha, interleukin
1beta, nitric oxide, and superoxide and subsequently caused damage to midbrain
neurons, including dopaminergic neurons. The LPS-induced degeneration of the
midbrain neurons was significantly reduced by cotreatment with naloxone, an
opioid receptor antagonist. This study focused on understanding the mechanism of
action for the protective effect of naloxone on dopaminergic neurons because of
relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive
stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency.
Naloxone inhibited LPS-induced activation of microglia and release of
proinflammatory factors, and inhibition of microglia generation of superoxide
free radical best correlated with the neuroprotective effect of naloxone isomers.
To further delineate the site of action, naloxone was found to partially inhibit
the binding of [(3)H]LPS to cell membranes, whereas it failed to prevent damage
to dopaminergic neurons by peroxynitrite, a product of nitric oxide and
superoxide. These results suggest that naloxone at least in part interferes with
the binding of LPS to cell membranes to inhibit microglia activation and protect
dopaminergic neurons as well as other neurons in the midbrain cultures from
inflammatory damage.
PMID- 10773036
TI - Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for
phase I trial.
AB - rPSGL-Ig is a recombinant, soluble, and chimeric form of P-selectin glycoprotein
ligand-1, which is developed as an antagonist to P-selectin. Allometric and
pharmacokinetic/pharmacodynamic modeling was used to select doses for human
clinical trials. Pharmacokinetic parameters of rPSGL-Ig such as clearance (CL),
volume of distribution (Vc), and t(1/2) across animal species are well described
by power functions with body weight as an independent variable. The power
functions for CL, Vc, and t(1/2) were CL = 0.37. W(0.93) ml/h (r(2) = 0.94), Vc =
45.0.W(1.064) ml (r(2) = 0.988), and t(1/2) = 190.W(0.159) h (r(2) = 0.75),
respectively. These functions provide a means to predict pharmacokinetics of
rPSGL-Ig in humans. For a 70-kg human, the values of CL, Vc, and t(1/2) are
predicted to be 19.9 ml/h, 4138 ml, and 15.5 days, respectively. The predicted
pharmacokinetics in humans is used in conjunction with pharmacological data to
estimate appropriate doses for clinical trials. The doses that may provide
potential effects in humans range from 0.13 to 4.7 mg/kg. The predicted doses
produce concentrations above those that are associated with efficacy in animal
disease models and, maintain concentrations above the EC(50) of in vitro binding
between rPSGL-Ig and stimulated human platelets. Hence, rPSGL-Ig in clinical
trials may provide therapeutic activities for P-selectin-mediated diseases.
PMID- 10773037
TI - Toward development of an in vitro model of methamphetamine-induced dopamine nerve
terminal toxicity.
AB - To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA)
neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for
different periods of time (10-80 min), washed once, then tested for DA
transporter function at 37 degrees C. METH produced time- and dose-dependent
reductions in the V(max) of DA uptake, without producing any change in K(m).
Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium
ion, 6-hydroxydopamine, and amphetamine under similar conditions produced
comparable effects. In contrast, incubation with fenfluramine, a serotonin
neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar
as striatal glutamate uptake was unaffected. Various DA transporter blockers
(cocaine, methylphenidate, and bupropion) afforded complete protection against
METH-induced decreases in DA uptake, without producing any effect themselves.
METH's effects were also temperature dependent, with greater decreases in DA
uptake occurring at higher temperatures. Tests for residual drug revealed small
amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that
decreases in DA uptake were not likely to be due to METH acting as a competitive
inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied
by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no
mechanism for removing damaged DA nerve endings from the in vitro preparation
Collectively, these results give good support to the development of a valid in
vitro model that may prove helpful for elucidating the mechanisms underlying METH
induced DA neurotoxicity.
PMID- 10773038
TI - Direct block by bisindolylmaleimide of rat Kv1.5 expressed in Chinese hamster
ovary cells.
AB - The interaction of bisindolylmaleimide (BIM), widely used as a specific protein
kinase C (PKC) inhibitor, with rat brain Kv1.5 (rKv1.5) channels stably expressed
in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp
technique. BIM (I) and its inactive analog, BIM (V), inhibited rKv1.5 currents at
+50 mV in a reversible concentration-dependent manner with an apparent K(d) value
of 0.38 and 1.70 microM, respectively. BIM (I) accelerated the decay rate of
inactivation of rKv1.5 currents but did not significantly modify the kinetics of
current activation. Other specific PKC inhibitors, chelerythrine and PKC 19-36,
had no effect on rKv1.5 and did not prevent the inhibitory effect of BIM (I). The
inhibition of rKv1.5 by BIM (I) and BIM (V) was highly voltage-dependent between
30 and 0 mV (voltage range of channel opening), suggesting that both drugs
interact preferentially with the open state of the channel. The additional
inhibition by BIM (I) displayed a voltage dependence (delta = 0.19) in the full
activation voltage range positive to 0 mV, but was not shown in BIM (V) (delta =
0). The rate constants of association and dissociation for BIM (I) were 9.63
microM(-1) s(-1) and 5.82 s(-1), respectively. BIM (I) increased the time
constant of deactivation of tail currents from 26. 35 to 45.79 ms, resulting in
tail crossover phenomenon. BIM (I) had no effect on the voltage dependence of
steady-state inactivation. BIM (I) produced use-dependent inhibition of rKv1.5,
which was consistent with the slow recovery from inactivation in the presence of
drug. These results suggest that BIM (I) directly inhibits rKv1.5 channels in a
phosphorylation-independent, and state-, voltage-, time-, and use-dependent
manner.
PMID- 10773039
TI - Acute oxygen supplementation restores markers of hepatocyte energy status and
hypoxia in cirrhotic rats.
AB - The oxygen limitation hypothesis states that hepatocyte hypoxia is the mechanism
determining metabolic restriction in the cirrhotic liver. Therefore we studied
markers of hepatocyte energy state and cellular hypoxia in livers of normal and
cirrhotic rats before and after oxygen supplementation. Rats with carbon
tetrachloride-induced cirrhosis and procedural control rats were exposed to
either room air or a hyperoxic gas mixture for 1 h immediately before freeze
clamping and perchloric acid extraction of liver tissue. Extracts were assessed
by (31)P NMR and enzymatic assays. Livers from cirrhotic rats breathing room air
showed a reduced ratio of ATP/ADP, an increased ratio of inorganic phosphate/ATP,
and a trend toward an increased ratio of lactate/pyruvate compared with
procedural control livers (ATP/ADP 1.73 +/- 0.35 versus 2.68 +/- 0.61, P <.05;
P(i)/ATP 2.74 +/- 0.48 versus 1.56 +/- 0.26, P <.05; lactate/pyruvate 29.3 +/-
6.4 versus 22.5 +/- 7.4, P =.18). After supplementation with oxygen for 1 h,
these ratios in cirrhotic livers approached control values. A variety of other
metabolic markers affected by cirrhosis showed variable trends toward normal in
response to oxygen supplementation, whereas minor trends toward an increase in
ATP levels in control animals suggest the possibility of marginal oxygen
limitation in normal livers. The data are consistent with the hypothesis that
hepatocytes in cirrhotic livers have normal metabolic capacity but are
constrained by a deficit in oxygen supply. Interventions aimed at increasing
oxygen supply to the liver may have both short- and long-term therapeutic value
in the management of cirrhosis.
PMID- 10773040
TI - Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main
active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O
desmethyltramadol, in rats.
AB - The pharmacokinetics and pharmacodynamics of the two main metabolites of
tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied in
rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured
as the change in arterial blood pCO(2), pO(2), and pH levels; and
antinociception, measured by the tail-flick technique. The administration of 10
mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered
pCO(2), pO(2), and pH values in comparison with baseline and lower-dose groups (P
<.05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to
achieve 100% antinociception without respiratory depression. Moreover, the beta
funaltrexamine pretreatment completely eliminated the antinociception of the 2
mg/kg dose, suggesting that such an effect is due to mu-opioid receptor
activation. To describe and adequately characterize the in vivo antinociceptive
effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates
of varying lengths (10-300 min). Pharmacokinetics was best described by a two
compartmental model. The time course of response was described using an effect
compartment associated with a linear pharmacodynamic model. The estimates of the
slope of the effect versus concentration relationship were significantly
decreased (P <. 05) as the length of infusion was increased, suggesting the
development of tolerance. Doses of up to 8 mg/kg (-)-O-desmethyltramadol given in
10-min i.v. infusion did not elicit either antinociception in the tail-flick test
or respiratory effects. These in vivo results are in accordance with the opiate
and nonopiate properties reported for these compounds in several in vitro
studies.
PMID- 10773041
TI - Ethanol enhances gamma-aminobutyric acid responses in a subpopulation of nucleus
accumbens neurons: role of metabotropic glutamate receptors.
AB - The nucleus accumbens (NAcc) may be a key area in the rewarding effects of abused
drugs. We previously showed that low ethanol concentrations decreased both N
methyl-D-aspartate (NMDA)-induced and kainate-induced currents in NAcc core
neurons. To explore the effects of ethanol on gamma-aminobutyric acid (GABA)
responses in NAcc, we used intracellular voltage-clamp recordings and locally
applied GABA in a slice preparation containing the NAcc. Ethanol (11-200 mM) had
no effect on resting membrane properties, but 11, 22, 44, 100, and 200 mM ethanol
increased GABA currents in 17, 33, 45, 50, and 22% of cells, respectively.
Superfusion of low glutamate concentrations that had no direct effect on membrane
properties enhanced ethanol potentiation of GABA currents in more than half the
NAcc cells. Neither alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid/kainate receptor nor NMDA receptor antagonists affected the percentage of
cells showing ethanol enhancement of GABA responses or the degree of ethanol
enhancement of GABA currents in NAcc neurons. However, in ethanol-sensitive
cells, the metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine
(MCPG) blocked the ethanol enhancement of GABA currents. In addition, the
metabotropic receptor agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid
enhanced GABA responses in 50% of cells tested, an effect blocked by MCPG. These
data suggest that NAcc core neurons possess both ethanol-sensitive and
insensitive GABA receptors and that glutamate can mimic and enhance the ethanol
potentiation of GABA currents in many of these neurons. Furthermore, the ethanol
potentiation of GABA currents may involve metabotropic glutamate receptors,
perhaps via a phosphorylation mechanism that regulates ethanol sensitivity of
GABA receptors in some NAcc neurons.
PMID- 10773043
TI - Pentoxifylline ameliorates cerulein-induced pancreatitis in rats: role of
glutathione and nitric oxide.
AB - Reactive oxygen radicals, nitric oxide, and cytokines have been implicated in the
initiation of pancreatic tissue damage and impairment of the pancreatic
microcirculation in acute pancreatitis. Pentoxifylline is a methylxanthine
derivative with rheologic and marked anti-inflammatory properties and inhibits
the production of proinflammatory cytokines. We have examined whether
pentoxifylline ameliorates interstitial edema, inflammatory infiltrate, and
glutathione depletion associated with cerulein-induced pancreatitis. Cotreatment
of animals with pentoxifylline significantly reduced cerulein-induced pancreatic
inflammation and edema and attenuated the depletion of pancreatic glutathione and
the increase in serum lipase activity, nitrate, and tumor necrosis factor-alpha
levels. Pentoxifylline also prevented both mitochondrial swelling and damage to
mitochondrial cristae caused by cerulein. Our findings provide an experimental
basis for using pentoxifylline to attenuate inflammatory responses within the
pancreas in acute pancreatitis and as an adjuvant in the treatment of acute
pancreatitis.
PMID- 10773042
TI - Protein kinase C-mediated acute tolerance to peripheral mu-opioid analgesia in
the bradykinin-nociception test in mice.
AB - We studied the acute tolerance liability of peripheral opioid analgesia in mice.
The analgesia was assessed by the inhibition of bradykinin (BK)-induced
nociceptive action by using a newly developed flexor reflex paradigm. Morphine
[intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent
reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of
morphine into the contralateral side failed to show any significant analgesic
effects. Furthermore, DAMGO ([D-Ala(2),MePhe(4), Gly-ol(5)]-enkephalin), a mu
opioid receptor (MOR) agonist, and U-69593, a kappa-opioid receptor (KOR)
agonist, but not DSLET ([D-Ser(2)]Leu-enkephalin-Thr(6)), a delta-opioid receptor
agonist, showed similar analgesia on the BK responses. The morphine- or U-69593
[(5alpha,7alpha, 8beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec
8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the
intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR,
respectively, suggesting that these peripheral analgesia are mediated through
MORs and KORs located on nociceptor endings, respectively. As BK response was
completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U
69593 (10 nmol i.pl.) administration, these compounds were challenged again to
see the inhibition of BK responses. Although morphine analgesia by the second
challenge was markedly attenuated, U-69593 analgesia was not. The attenuated
morphine analgesia was completely reversed by the pretreatment of calphostin C,
Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein
kinase A inhibitor. These results suggest that selective acute tolerance of
peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs
located on polymodal nociceptors, respectively, in the bradykinin-nociception
test in mice was mediated through protein kinase C activation.
PMID- 10773044
TI - Expression of glutathione-dependent enzymes and cytochrome P450s in freshly
isolated and primary cultures of proximal tubular cells from human kidney.
AB - The expression of glutathione (GSH)-dependent enzymes and cytochrome P450 (P450)
proteins in freshly isolated proximal tubular cells from human kidney (hPT), and
the effect of primary culture on these enzymes, were determined. Freshly isolated
hPT cells had relatively high activities of gamma-glutamyltransferase, gamma
glutamylcysteine synthetase, glutathione S-transferase (GST), glutathione
disulfide reductase, and GSH peroxidase. Cytochrome P450 4A11 was detected in
freshly isolated hPT cells, whereas CYP2E1 was not. Freshly isolated hPT cells
also expressed GSTA, GSTP, and GSTT but not GSTM. Primary cultures of hPT cells
maintained their epithelial-like nature and diploid status, based on measurements
of morphology, cytokeratin expression, and flow cytometric analysis. hPT cells
retained GSH-dependent enzyme activities during primary culture, whereas cells
that had undergone subsequent passage exhibited a loss of activities of most GSH
dependent enzymes and no longer expressed P450s or GSTs. CYP4A11 expression in
primary cultures of hPT cells was significantly increased after treatment for 48
h with either ethanol (50 mM) or dexamethasone (7 nM). GSTA, GSTP, and GSTT
contents, although still detectable, were decreased compared with those of
freshly isolated hPT cells. Our data show that hPT cells express enzymes involved
in xenobiotic disposition, and that they thus provide a model suitable for
studies of human renal drug metabolism. Furthermore, primary cultures of hPT
cells may afford the opportunity to study factors regulating P450 enzyme
expression in human kidney.
PMID- 10773045
TI - Characterization of a tropane radioligand, [(3)H]2beta-propanoyl-3beta-(4-tolyl)
tropane ([(3)H]PTT), for dopamine transport sites in rat brain.
AB - PTT (2beta-propanoyl-3beta-[4-tolyl] tropane) is a tropane analog relatively
selective for dopamine transporters in binding and uptake assays in vitro, with
long-acting psychostimulant properties in vivo. To explore its utility in binding
to dopamine transporters, [(3)H]PTT was synthesized and assayed for binding in
rat striatal membranes and by in vitro autoradiography. In membranes, binding of
[(3)H]PTT was saturable to a single class of binding sites with a K(D) value of 3
nM. The pharmacology of [(3)H]PTT binding in striatal membranes was consistent
with that of a ligand selective for dopamine transporters, with dopamine
selective compounds being significantly more potent in displacing [(3)H]PTT
binding than those for 5-HT or norepinephrine transporters. Although the ability
of various transporter inhibitors to displace both [(125)I]RTI-55 and [(3)H]PTT
binding correlated significantly with each other, there was a better correlation
of inhibitor potencies versus [(3)H]PTT binding and dopamine uptake than versus
[(125)I]RTI-55 binding and dopamine uptake. The differences in correlations were
most noticeable for compounds relatively selective at the 5-hydroxytryptamine
(serotonin) transporter. The autoradiographic distribution of [(3)H]PTT binding
in coronal sections was consistent with the known distribution of the dopamine
transporter, with high levels of binding evident in caudate nucleus, nucleus
accumbens, and olfactory tubercle. Moderate densities of [(3)H]PTT binding were
also observed in substantia nigra pars compacta, and ventral tegmental area, as
well as in the anterior cingulate cortex and portions of the hypothalamus. In
addition, nonspecific binding was less than 5% of total binding. Thus, [(3)H]PTT
provides an accurate and convenient marker for the dopamine transporter.
PMID- 10773046
TI - Outward transfer of dopamine precursor L-3,4-dihydroxyphenylalanine (L-dopa) by
native and human P-glycoprotein in LLC-PK(1) and LLC-GA5 col300 renal cells.
AB - The role of P-glycoprotein (P-gp) in the basal-to-apical uptake and flux of L-3,4
dihydroxyphenylalanine (L-dopa) was studied in LLC-PK(1) and LLC-GA5 Col300
cells, a renal cell line expressing the human P-gp in the apical membrane. In the
absence of verapamil, LLC-GA5 Col300 cells accumulate less calcein (0.5 microM)
than do LLC-PK(1) cells. In LLC-PK(1) cells, pretreatment with verapamil (25
microM) for 30 min increased the rate of accumulation of calcein by 5-fold,
whereas in LLC-GA5 Col300 cells, no significant change in the rate of
accumulation of calcein was observed. Exposure for 3 h to verapamil (25 microM)
was found to increase the rate of accumulation of calcein by 2.5-fold in LLC
PK(1) cells and by 3. 7-fold in LLC-GA5 Col300 cells. A 30-min exposure to UIC2
(3 microg/ml) or verapamil (25 microM) increased L-dopa accumulation in LLC-PK(1)
cells by 27 +/- 4 and 88 +/- 14% and reduced L-dopa apical extrusion by 29 +/- 4
and 23 +/- 1%, respectively. The exposure of LLC-GA5 Col300 cells to UIC2 (3
microg/ml) or verapamil (25 microM) for 30 min produced no significant changes in
cell accumulation and apical extrusion of L-dopa. A more prolonged exposure (3 h)
to UIC2 or verapamil resulted in a marked increase in L-dopa accumulation in the
cell (105 +/- 13 and 146 +/- 24% increase) and a pronounced decrease (91 +/- 1
and 92 +/- 1% reduction) in the apical extrusion of L-dopa. It is concluded that
LLC-PK(1) cells are endowed with P-gp and that the outward transfer of L-dopa at
the apical cell border in both LLC-PK(1) and LLC-GA5 Col300 cells is in part
promoted through this transporter.
PMID- 10773047
TI - Adoptive immunotherapy:insights from donor lymphocyte infusions.
PMID- 10773048
TI - Special interest groups at the AABB website.
PMID- 10773049
TI - Reactions and platelet increments after transfusion of platelet concentrates in
plasma or an additive solution: a prospective, randomized study.
AB - BACKGROUND: Reactions after platelet transfusions are rather common and
frequently are caused by plasma constituents. In recent developments, the
preparation and storage of platelet concentrates (PCs) in a platelet additive
solution (PAS-2) have been shown to result in acceptable storage conditions. A
major drawback of the use of these PCs is the progressive increase of P-selectin
positive platelets during storage. The clinical benefit of transfusions of PCs in
PAS-2 was studied. STUDY DESIGN AND METHODS: PCs prepared from buffy coats were
suspended in either plasma or PAS-2 and stored for up to 5 days. Clinical
responses were evaluated in a prospective study in 21 patients treated with
intensive chemotherapy for hematologic malignancies. Eligible patients were
randomly assigned to receive prophylactic transfusions of PCs prepared in either
plasma or PAS-2. Reactions and CCIs were recorded after each transfusion.
RESULTS: The incidence of reactions in 12 patients given PCs in plasma (n = 192)
was 12 percent. Transfusions to 9 patients of PCs in PAS-2 (n = 132) showed a
reduction in the incidence of reactions to 5.3 percent (p<0.05). The average 1
hour and 20-hour CCIs after transfusion of PCs in plasma were 20.7 +/- 8. 5 and
11.5 +/- 8.0, respectively. CCIs after transfusion of PCs in PAS-2 were
significantly lower: the average 1-hour CCI was 17.1 +/- 6.6 (p<0.001) and the
average 20-hour CCI was 9.5 +/- 7.0 (p<0.05). Storage conditions of PCs were
optimal: in each group, average 1-hour CCIs of both fresh and stored PCs were
similar. The 20-hour CCIs after the transfusion of fresh and stored PCs in PAS-2
also were similar. CONCLUSION: Transfusion of PCs in PAS-2 significantly reduces
the incidence of reactions. The 1-hour and 20-hour CCIs after transfusion of PCs
in PAS-2 were significantly lower than the CCIs after transfusion of PCs in
plasma. Because storage conditions of both PCs were found to be optimal, the
decrease in CCIs after transfusion of PCs prepared in PAS-2 may be caused by
rapid elimination of a subpopulation of P-selectin-positive platelets from the
circulation.
PMID- 10773050
TI - Enhanced HPC recruitment in children using LVL and a new automated apheresis
system.
AB - BACKGROUND: A new automated apheresis system has recently been reported as useful
in improving peripheral blood HPC collection in adults. The aim of this study has
been to verify the utility of this system (AutoPBSC, COBE BCT) for standard
leukapheresis and for LVL in the pediatric setting. STUDY DESIGN AND METHODS: A
prospective study was set up in 29 leukapheresis procedures carried out in 26
children with malignant diseases and body weight under 40 kg who had undergone
mobilization with G-CSF or with G-CSF and chemotherapy. Leukapheresis procedures
were performed under two protocols, depending on the total blood volume
processed: standard leukapheresis (< or=3) and LVL (>3). The need to prime the
tubing set with blood was determined, and the inlet flow rate, collection time,
recruitment of CD34+ cells, CD34+ cell collection efficiency, component volume,
leukapheresis cell composition, and preapheresis and postapheresis peripheral
blood counts were measured. Paired t test, Spearman's correlation coefficient,
and the Mann-Whitney U test were employed for statistical analysis. RESULTS:
Because of the low extracorporeal volume (167 mL) of the tubing set of the
automated blood processor, priming was necessary in only 2 of 26 patients, both
weighing under 10 kg. LVL showed better CD34+ cell yield (7.5 vs. 2.3 x 10(6)/kg;
p = 0.047), higher recruitment (2.1 vs. 0.9; p = 0.002), and greater collection
efficiency (50% vs. 33%; p = 0.005) than standard leukapheresis. No significant
differences were found between groups in collection time. In LVL procedures,
CD34+ cell collection efficiency and recruitment were not significantly
influenced by the inlet flow rate. CONCLUSION: The AutoPBSC is a reliable system
for peripheral blood HPC collection in children mainly when used in combination
with LVL. The major advantage of this software is a reduced need for priming. LVL
allows better CD34+ cell collection efficiency, enhanced recruitment, and
improved CD34+ cell yield.
PMID- 10773051
TI - Antibiotic-labeled probes and microvolume fluorimetry for the rapid detection of
bacterial contamination in platelet components: a preliminary report.
AB - BACKGROUND: Approximately 1 platelet in 2000 components is bacterially
contaminated. Most commonly, contaminating organisms are gram positive skin
saprophytes (such as Staphylococcus sp. or Bacillus sp.). A novel approach to the
rapid diagnosis of gram positive contamination by the use of a fluorescence
labeled antibiotic probe with affinity for the gram positive cell was
investigated. STUDY DESIGN AND METHODS: Two isolates of Staphylococcus
epidermidis were inoculated into bags of Day 0 platelets. Quantitative cultures
along with a semi-automated screening assay on a microvolume fluorimeter
employing a fluorescence-conjugated vancomycin probe was performed for each day
of storage. In addition, serial dilutions of the bacteria were added to sterile
platelets to achieve a range spanning 10(1) to 10(8) CFUs per mL. RESULTS: All
samples with a bacterial contamination of > or =10(5) CFU per mL were detected.
Sterile samples were nonreactive. The entire procedure requires three pipetting
steps and took less than 1 hour to perform. CONCLUSION: These preliminary results
with the use of fluorescence-labeled antibiotics as probes combined with
microvolume fluorimetry for the rapid detection of bacterial contamination of
platelet components suggest that this is a promising approach. Further studies
with additional organisms and alternative conjugates, bacteria, and antibiotics
are underway.
PMID- 10773052
TI - Functional characteristics of neutrophils collected and stored after
administration of G-CSF.
AB - BACKGROUND: Granulocyte transfusion may be used in neutropenic patients with
severe bacterial or fungal infections that are unresponsive to antibiotic
therapy. However, the inability to store granulocyte concentrates limits their
clinical usefulness. STUDY DESIGN AND METHODS: Neutrophil chemotaxis and NADPH
oxidase activity and the integrity of the neutrophil NADPH oxidase system were
examined after apheresis collection and during storage to 48 hours. Neutrophils
were mobilized in vivo by G-CSF, collected by apheresis techniques, and stored in
apheresis bags in the presence and absence of additional G-CSF. For all
experiments, cells were further purified by standard techniques of dextran
sedimentation and hypotonic RBC lysis. RESULTS: Neutrophil chemotaxis was
preserved to 24 hours of storage but was not affected by the G-CSF added to
storage units. The NADPH oxidase system was also preserved as a functioning
complex, and both cytosolic proteins and membrane-associated proteins were normal
to 48 hours. However, there were divergent responses by intact cells to
activating stimuli and reduced oxidase activity in the cell-free system. G-CSF
did not appear to significantly affect NADPH oxidase activity or NADPH oxidase
system integrity during storage. CONCLUSION: Neutrophils collected after the
administration of G-CSF retained functional and biochemical characteristics for
at least 24 hours of storage, which suggests additional effects of G-CSF
mobilization beyond enhancing PMN yields and the possibility of storage of these
components after collection.
PMID- 10773053
TI - Generation of annexin V-positive platelets and shedding of microparticles with
stimulus-dependent procoagulant activity during storage of platelets at 4 degrees
C.
AB - BACKGROUND: The ability of propyl gallate to activate platelet factor 3 has been
determined through the activated partial thromboplastin time, but its effect on
phosphatidylserine has not been established. STUDY DESIGN AND METHODS: A novel
platelet activator, propyl gallate, was introduced to a study of platelets stored
at 4 degrees C. The effects of storage on platelet coagulation activity, on
phosphatidylserine, and on the shedding of activated and activable membrane
particles (microparticles) were examined by activated plasma clotting time, and
the effect on annexin V binding was examined by gated flow cytometry. The ratios
of annexin V binding and microparticle shedding in stored platelet samples were
compared with those in fresh platelets stimulated with propyl gallate. RESULTS:
Microparticle shedding by stored platelets compensated for the diminished
procoagulant potential of intact platelets (shown as the total propyl gallate
dependent platelet factor 3 activity), which did not change during prolonged (20
day) storage, but levels of phosphatidylserine confined to microparticles
increased dramatically as platelet counts fell. Both annexin V binding and
microparticle shedding increased spontaneously with storage and artificially with
propyl gallate stimulation. However, at the same level of annexin V binding,
stored platelets shed more microparticles than did fresh platelets stimulated
with propyl gallate. CONCLUSION: Propyl gallate induces platelet procoagulant
activity and annexin V binding. Stored platelets differ from fresh platelets in a
lower reactivity to propyl gallate activation and a higher rate of microparticle
shedding.
PMID- 10773054
TI - Primary anti-D immunization by weak D type 2 RBCs.
AB - BACKGROUND: D is the most immunogenic blood group antigen. In about 0.4 percent
of whites, D is expressed on RBCs in a weak form. Recently, it was found that the
weak D phenotypes are caused by a large number of distinct RHD alleles generally
encoding altered D proteins. No particular molecular weak D type has yet been
shown to induce anti-D. The threshold of D antigen density required for anti-D
immunization is not known. CASE REPORT: A 72-year-old D- white man received
apparently D- RBCs. Nineteen days later, he developed a positive DAT, and anti-D
was found in his serum and an eluate from his RBCs. One donor was found to be D+
with a weak D type. The weak D type was determined by RHD exon 9-specific
nucleotide sequencing from genomic DNA. The transfusion recipient showed alloanti
D. Ten months later, anti-D but no other antibody was detectable; the DAT was
negative and the eluate was nonreactive. The donor of the incriminated unit was
D+ (ccDEe) with weak D due to the weak D type 2 allele, expressing about 450 D
antigens per RBC. CONCLUSION: This case provides formal proof that RBCs of weak D
type 2 phenotype may cause alloanti-D immunization. Among the more prevalent weak
D types in whites, weak D type 2 has the lowest D antigen density. Thus, units of
blood from donors of the weak D type 2 phenotype should be labeled D+; the weak D
type 2 phenotype may be useful for quality assurance.
PMID- 10773055
TI - The release of unsuitable units through misinterpretation of laboratory results
transmitted by facsimile.
AB - BACKGROUND: Preventable errors in transfusion medicine that have a significant
risk of adverse outcome include the erroneous administration of blood of the
wrong type or blood with unsuitable laboratory test results. Mandatory reports of
errors by facilities providing blood services in New York State offer the
opportunity for review and analysis of common factors. The state also collects
statistics on the collection, laboratory testing, distribution, and disposition
of blood in these facilities. CASE REPORTS: Three serious errors in transfusion
medicine occurred within 3 months as a result of the misinterpretation of
laboratory test results transmitted by facsimile. Two unsuitable units of blood
were erroneously released, and a unit mislabeled as to the ABO group was
incorporated into the hospital inventory. One of the unsuitable units was
repeatedly reactive for HIV (although negative on confirmatory testing), and the
other was confirmed positive for HCV. CONCLUSIONS: The vast majority of blood
collected in New York State is tested by reference laboratories. Results are
often transmitted by facsimile. Facsimile results may be misinterpreted because
of distortion during transmission, misreading, or failure to note a separate
report of pending results. Such misinterpretation results in an increased risk of
adverse outcome for transfusion recipients. Laboratory results to be transmitted
by facsimile could readily-and should-be clarified.
PMID- 10773056
TI - The utility of < or =3-day-old whole-blood platelets in reducing the incidence of
febrile nonhemolytic transfusion reactions.
AB - BACKGROUND: Febrile nonhemolytic transfusion reactions (FNHTRs) to platelet
transfusions have been linked to the presence of cytokines in supernatant plasma.
Cytokine concentration is directly related to WBC content and storage time. This
study evaluated the effect of limiting the storage time of random-donor platelet
concentrates on the FNHTR rate. STUDY DESIGN AND METHODS: FNHTR rates were
calculated retrospectively for single-donor apheresis platelet (SDP) and pooled
random-donor platelet (PP) transfusions given during three consecutive 5-month
study periods (November 1995 to February 1997) to patients on a single
hematology/oncology/bone marrow transplant unit. Transfusion practice policies
were: Baseline Period, SDPs preferred; Study Period A, PPs preferred; and Study
Period B, < or =3-day-old PPs preferred. FNHTR rates were calculated from
physicians' interpretations of reported reactions and the total number of SDP and
PP transfusions in each period. SDPs were collected on two cell separators. All
platelet components were filtered at issue in the laboratory by WBC-reduction
filters. RESULTS: FNHTR rates for PP transfusions were: baseline, 11.1 percent
(3/27); Study Period A, 4.6 percent (22/481); and Study Period B, 1.1 percent
(3/282). The rates for SDP transfusions were 0. 15 percent (1/650), 0.75 percent
(2/267), and 0.36 percent (1/273), respectively. The FNHTR rate for < or =3-day
old PPs was significantly less than the rate for older PPs (p = 0.0086 for Study
Period A vs. Study Period B), and was not significantly different than that for
SDPs (p = 0.33 for PPs vs. SDPs in Study Period B). CONCLUSION: Limiting
transfusion of PPs to those stored 200), shorter repeats (n = 20-80) were methylated or unmethylated, longer
repeats ( n = 100-150) were often completely methylated, but one repeat with n =
160 proved to be completely unmethylated. This type of methylation mosaicism was
observed in several FRAXA patients. In healthy females, methylated 5'-CG-3'
sequences were found in some repeats and 5'-UTRs, as expected for the sequences
from one of the X chromosomes. The natural FMR1 promoter is methylation
sensitive, as demonstrated by the loss of activity in transfection experiments
using the unmethylated or M- Sss I-premethylated FMR1 promoter fused to the
luciferase gene as an activity indicator.
PMID- 10773085
TI - Targeted elimination of zygotic messages in Xenopus laevis embryos by modified
oligonucleotides possessing terminal cationic linkages.
AB - We have designed a new class of modified antisense oligodeoxyribonucleotides
(ODN) consisting of a central contiguous stretch of 6-8 unmodified nucleotides
flanked by 3'- and 5'-regions containing several nucleotides joined by cationic
internucleoside linkages. The positive charge results from modification of the
internucleoside linkages as N, N -diethylethylene-diamine phosphoramidates. These
zwitterionic compounds show improved antisense activity in both Xenopus oocytes
and embryos compared to our previously described chimeric oligonucleotides
possessing neutral terminal internucleoside linkages. Using the localized
maternal mRNA An2 as a target, we have shown that chimeric oligonucleotides with
terminal positive charges are very effective in the sequence-specific elimination
of maternal messages present in both oocytes and embryos. In addition, using the
embryonic mRNA GS17 as a target, we have shown that these oligonucleotides can
direct RNase H-mediated cleavage of messages produced at the onset of zygotic
transcription, after the mid-blastula stage. These new compounds should be useful
in attenuating embryonic gene expression to study the role of specific proteins
in early vertebrate development.
PMID- 10773086
TI - Specific binding of Hoechst 33258 to site 1 thymidylate synthase mRNA.
AB - The translational initiator codon in thymidylate synthetase (TS) mRNA is located
in a stem-loop structure with a CC bubble. TS is an important target for
anticancer drugs. Aminoglycoside antibiotics have been shown to specifically bind
to TS mRNA site 1 constructs and, furthermore, specific binding requires the non
duplex CC bubble region. It is shown here that DNA intercalating agents and DNA
minor groove-binding drugs also bind to a TS mRNA site 1 construct. This binding
is competitive with aminoglycosides, suggesting that the binding sites overlap.
Hoechst 33258 binds with a dissociation constant of 60 nM, a value significantly
lower than the approximately 1 microM values found for aminoglycosides.
Footprinting and direct binding studies show that the CC bubble is important for
binding of the Hoechst compound. However, the exact structure of the bubble is
unimportant. Interestingly, mutations in regions adjacent to the bulge also
affect binding. These studies point to the important role of non-duplex RNA
structures in binding of the DNA minor groove binder Hoechst 33258.
PMID- 10773087
TI - Cloning of neuronal mtDNA variants in cultured cells by synaptosome fusion with
mtDNA-less cells.
AB - Synaptosome cybrids were used to confirm the presence of heteroplasmic mtDNA
sequence variants in the human brain. Synaptosomes contain one to several
mitochondria, and when fused to mtDNA-deficient (rho degrees ) mouse or human
cell lines result in viable cybrid cell lines. The brain origin of mouse
synaptosome cybrid mtDNAs was confirmed using sequence polymorphisms in the mtDNA
COIII, ND3 and tRNA(Arg)genes. The brain origin of the human synaptosome cybrids
was confirmed using a rare mtDNA Mbo I polymorphism. Fusion of synaptosomes from
the brain of a 35-year-old woman resulted in 71 synaptosome cybrids. Sequencing
the mtDNA control region of these cybrid clones revealed differences in the
number of Cs in a poly C track between nucleotide pairs (nps) 301 and 309. Three
percent of the cybrid clones had mtDNAs with 10 Cs, 76% had nine, 18% had eight
and 3% had seven Cs. Comparable results were obtained by PCR amplification,
cloning and sequencing of mtDNA control regions directly from the patient's brain
tissue, but not when the control region was amplified and cloned from a
synaptosome cybrid homoplasmic for a mtDNA with nine Cs. Thus, we have clonally
recovered mtDNA control region length variants from an adult human brain without
recourse to PCR, and established the variant mtDNAs within living cultured cells.
This confirms that some mtDNA heteroplasmy can exist in human neurons, and
provides the opportunity to study its functional significance.
PMID- 10773088
TI - Crystal structure of a DNA.RNA hybrid duplex with a polypurine RNA r(gaagaagag)
and a complementary polypyrimidine DNA d(CTCTTCTTC).
AB - DNA.RNA hybrid duplexes are substrates of RNase H and reverse transcriptase. The
crystal structure of a hybrid duplex, d(5'-CTCTTCTTC-3').r(5'-gaagaagag-3') (the
uppercase letters indicate DNA and lowercase letters RNA), with a polypurine RNA
strand and a complementary DNA strand has been determined at 1.8 A resolution.
The structure was refined first at 1.9 A by XPLOR and subsequently by CNS at 1.8
A. The hybrid is found in a standard A-form conformation with all the sugars in
the C3'-endo puckering. The 5'-terminal base dC of the DNA strand was clearly
visible in the electron density map of the present structure, in contrast to the
previously reported structure d(TTCTTBr(5)CTTC).r(gaagaagaa) where the 5'
terminal base dT was not visible, leaving the terminal rA unpaired. Thus, the
comparison of the terminal base pairs, C.g versus T.a, in the two hybrid crystal
structures provides information on the stability of these base pairs in hydrogen
bonding (three versus two) and base stacking interactions. The differences in the
terminal base pairs produce different kinks in the two structures. Minor groove
widening is observed in the present structure at a distinctive kink in the lower
half of the duplex, in contrast to the small widening of the minor groove and a
very slight bend in the upper half of the T.a structure.
PMID- 10773090
TI - Hemicatenanes form upon inhibition of DNA replication.
AB - Plasmid DNA incubated in interphase Xenopus egg extracts is normally assembled
into chromatin and then into synthetic nuclei which undergo one round of
regulated replication. During a study of restriction endonuclease cut plasmid
replication intermediates (RIs) by the Brewer-Fangman 2D gel electrophoresis
technique, we have observed the formation of a strong spike of X-shaped DNA
molecules in extracts that otherwise yield very little or no RIs. Formation of
these joint molecules is also efficiently induced in replication-competent
extracts upon inhibition of replication fork progression by aphidicolin. Although
their electrophoretic properties are quite similar to those of Holliday
junctions, 2D gels of doubly cut plasmids show that these junctions can link two
plasmid molecules at any pair of DNA sequences, with no regard for sequence
homology at the branch points. Neutral-neutral-alkaline 3D gels show that the
junctions only contain single strands of parental size and no recombinant
strands. A hemicatenane, in which one strand of a duplex is wound around one
strand of another duplex, is the most likely structure to account for these
observations. The mechanism of formation of these novel joint DNA molecules and
their biological implications are discussed.
PMID- 10773091
TI - Flanking sequences with an essential role in hydrolysis of a self-cleaving group
I-like ribozyme.
AB - DiGIR1 is a group I-like ribozyme derived from the mobile twin ribozyme group I
intron DiSSU1 in the nuclear ribosomal DNA of the myxomycete Didymium iridis.
This ribozyme is responsible for intron RNA processing in vitro and in vivo at
two internal sites close to the 5'-end of the intron endo-nuclease open reading
frame and is a unique example of a group I ribozyme with an evolved biological
function. DiGIR1 is the smallest functional group I ribozyme known from nature
and has an unusual core organization including the 6 bp P15 pseudoknot. Here we
report results of functional and structural analyses that identify RNA elements
critical for hydrolysis outside the DiGIR1 ribozyme core moiety. Results from
deletion analysis, disruption/compensation mutagenesis and RNA structure probing
analysis all support the existence of two new segments, named P2 and P2.1,
involved in the hydrolysis of DiGIR1. Significant decreases in the hydrolysis
rate, k (obs), were observed in disruption mutants involving both segments. These
effects were restored by compensatory base pairing mutants. The possible role of
P2 is to tether the ribozyme core, whereas P2.1 appears to be more directly
involved in catalysis.
PMID- 10773089
TI - The complete DNA sequence and analysis of R27, a large IncHI plasmid from
Salmonella typhi that is temperature sensitive for transfer.
AB - Salmonella typhi, the causative agent of typhoid fever, annually infects 16
million people and kills 600 000 world wide. Plasmid-encoded multiple drug
resistance in S. typhi is always encoded by plasmids of incompatibility group H
(IncH). The complete DNA sequence of the large temperature-sensitive conjugative
plasmid R27, the prototype for the IncHI1 family of plasmids, has been compiled
and analyzed. This 180 kb plasmid contains 210 open reading frames (ORFs), of
which 14 have been previously identified and 56 exhibit similarity to other
plasmid and prokaryotic ORFs. A number of insertion elements were found,
including the full Tn 10 transposon, which carries tetracycline resistance genes.
Two transfer regions, Tra1 and Tra2, are present, which are separated by a
minimum of 64 kb. Homologs of the DNA-binding proteins TlpA and H-NS that act as
temperature-regulated repressors in other systems have been located in R27.
Sequence analysis of transfer and replication regions supports a mosaic-like
structure for R27. The genes responsible for conjugation and plasmid maintenance
have been identified and mechanisms responsible for thermosensitive transfer are
discussed.
PMID- 10773092
TI - Histone deacetylase-independent transcriptional repression by methyl-CpG-binding
protein 2.
AB - Methyl-CpG-binding protein 2 (MeCP2) contains a transcriptional repression domain
(TRD), which can act by recruitment of a large transcriptional co-repressor
complex containing histone deacetylases HDAC1 and 2. We demonstrate here that
transient transcription from the SV40 enhancer/promoter or the SV40 promoter is
strongly repressed in a histone deacetylase-independent manner, since repression
is not alleviated by Trichostatin A (TSA). In a mutational analysis, repression
depends on a conserved 30 residue sequence containing two clusters of basic amino
acids. Mutation of the first of these clusters inhibits in vitro interaction
between TRD and mSin3A. Furthermore, a subdomain of the TRD containing the
conserved 30-residue sequence and 16 flanking amino acids was sufficient to
compromise VP16-activated transcription. In summary, our results indicate an
alternative, histone deacetylase-independent pathway of transcriptional
repression by MeCP2.
PMID- 10773093
TI - Antisense delivery using protamine-oligonucleotide particles.
AB - Protamine, a polycationic peptide (mol. wt 4000-4500), was evaluated as a
potential penetration enhancer for phosphodiester antisense oligonucleotides
(ODNs). Unique complexes in the form of nanoparticles were spontaneously formed,
which we call 'proticles'. The stability of the particles and the ODNs bound into
the proticles was examined in foetal calf serum and cell culture medium. FITC
labelled ODNs bound to protamine showed an increased cellular uptake into human
histiocytic lymphoma U 937 cells compared to free ODNs. Proticles significantly
decreased cellular growth in a cell proliferation assay using ODNs against the c-
myc proto-oncogene.
PMID- 10773094
TI - Alkaline fixation drastically improves the signal of in situ hybridization.
AB - In situ hybridization (ISH) is widely used to detect DNA and RNA sequences within
the cell and tissue sections. The important step in performing this technique is
tissue fixation. We investigated the influence of the pH of the fixative on the
outcome of ISH. Our studies indicate that alkaline formaldehyde dramatically
increases the ISH signal with RNA probes. The increase in signal was observed for
detection of low as well as for high abundance messages. The sensitivity of the
method was increased 5- to 6-fold.
PMID- 10773095
TI - Normalization strategies for cDNA microarrays.
AB - Multiple Arabidopsis thaliana clones from an experimental series of cDNA
microarrays are evaluated in order to identify essential sources of noise in the
spotting and hybridization process. Theoretical and experimental strategies for
an improved quantitative evaluation of cDNA microarrays are proposed and tested
on a series of differently diluted control clones. Several sources of noise are
identified from the data. Systematic and stochastic fluctuations in the spotting
process are reduced by control spots and statistical techniques. The reliability
of slide to slide comparison is critically assessed within the statistical
framework of pattern matching and classification.
PMID- 10773096
TI - In-gel DNA radiolabelling and two-dimensional pulsed field gel electrophoresis
procedures suitable for fingerprinting and mapping small eukaryotic genomes.
AB - A simple method for complete genome radiolabelling is described, involving long
wave UV exposure of agarose-embedded chromosomal DNA and [alpha-(32)P]dCTP
incorporation mediated by the Klenow fragment. Experiments on the budding yeast
genome show that the labelling procedure can be coupled with two new two
dimensional pulsed field gel electrophoresis (2D-PFGE) protocols of genome
analysis: (i) the KARD (karyotype and restriction display)-PFGE which provides a
complete view of the fragments resulting from a single restriction of the whole
genome and (ii) the DDIC (double digestion of isolated chromosome)-PFGE which is
the eukaryotic counterpart of complete/complete 2D-PFGE in bacterial genomics.
PMID- 10773098
TI - Controversies in bone mineral density diagnostic classifications.
PMID- 10773097
TI - Characterization of the mRNA ligands bound by the RNA binding protein hnRNP A2
utilizing a novel in vivo technique.
AB - Post-transcriptional regulation is an important mechanism in cellular response to
stimuli, allowing for the rapid and discrete expression of relevant proteins.
Genes regulated by this mechanism have specific cis -acting elements, frequently
in their 3' untranslated regions (UTRs), that have been shown to serve as
recognition sites for trans -acting RNA-binding proteins. Unfortunately, the
identification of specific mRNA ligands for different RNA binding proteins in
vivo has been limited by a lack of adequate methodology. We have developed a
novel technique that addresses this shortcoming, using immunoprecipitation of RNA
binding proteins from polysomes followed by RT-PCR and library screening to
identify the in vivo mRNA ligands of RNA binding proteins. Utilizing this
approach, we have identified 32 known and 16 novel mRNAs specifically bound by
the heterogeneous nuclear ribonucleoprotein (hnRNP) A2. Of the clones identified,
74% contained AU-rich elements and/or poly-uridine tracts in their 3' UTRs, cis
acting elements that have been established as impacting mRNA stability. The high
percentage of clones containing these uridine-rich sequences compares favorably
with the high affinity binding of poly-uridine RNA by hnRNP A2 in vitro. These
data thus support the representative nature of the technique.
PMID- 10773099
TI - Lifestyle determinants of bone mineral: a comparison between prepubertal Asian-
and Caucasian-Canadian boys and girls.
AB - The purpose of this study was to examine the difference in lifestyle and
morphometric factors that affect bone mineral and the attainment of peak bone
mass in 168 healthy Asian (n = 58) and Caucasian (n = 110) Canadian, prepubertal
girls and boys (mean age 8.9+/-0.7) living in close geographical proximity. DXA
(Hologic 4500) scans of the proximal femur (with regions), lumbar spine, and
total body (TB) were acquired. We report areal bone mineral densities (aBMD
g/cm(2)) at all sites and estimated volumetric density (aBMD, g/cm(3)) at the
femoral neck. Dietary calcium, physical activity, and maturity were estimated by
questionnaire. Of these prepubertal children, all of the boys and 89% of the
girls were Tanner stage 1. A 2x2 ANOVA demonstrated no difference between
ethnicities for height, weight, body fat, or bone mineral free lean mass. Asian
children consumed significantly less dietary calcium (35%) on average and were
significantly less active (15%) than their Caucasian counterparts (P<0.001).
There were significant ethnicity main effects for femoral neck bone mineral
content (BMC) and alphaBMD (both P<0.001) and significant sex by ethnicity
interactions (P<0.01). The Asian boys had significantly lower femoral neck BMC
(11%), aBMD (8%), and vBMD (4.4%). At the femoral neck, BMFL mass, sex, and
physical activity explained 37% of the total variance in aBMD (P<0.05). In
summary, this study demonstrated differences in modifiable lifestyle factors and
femoral neck bone mineral between Asian and Caucasian boys.
PMID- 10773100
TI - Bone mineral density and bone turnover in patients with knee osteoarthritis
compared with generalized osteoarthritis.
AB - The aim of this study was to investigate bone mineral density (BMD) and bone
turnover in patients with primary knee osteoarthritis (KOA) and to compare them
with generalized OA (GOA) and nonGOA patients. A total of 88 postmenopausal
primary KOA patients were studied. OA was graded by using knee radiographs. BMD
of the lumber spine, femur, and radius, and biochemical markers of bone turnover,
pyridinoline (Pyr), deoxypyridinoline (Dpyr), CTx, and osteocalcin were compared
among each grade. BMD was also compared with 88 normal controls who were age and
weight-matched. In 88 KOA patients, 56 were divided into 28 GOA and 28 non-GOA
groups by grading hand radiographs. BMD and biochemical markers were compared
between GOA and non-GOA. KOA patients had higher BMD at several skeletal sites
compared with age- and weight-matched normals. A significant difference of BMD
between each grade was observed between grades 0-1 and 3 (0.774+/-0.143 versus
0.940+/-0.185 g/cm(2), P<0.001), grades 2 and 3 (0.781+/-0.125 versus 0.940+/
0.185 g/cm(2), P<0.01) in the spine, and between grades 0-1 and 3 (0.505+/-0.100
versus 0.564+/-0.127 g/cm(2), P<0.05) in the trochanter. A significant difference
of biochemical bone markers was observed between grades 0-1 and 3 (P<0.05) and
between grades 2 and 3 (P<0.05) in Pyr and grades 0-1 and 3 (P<0.05) and between
grades 1 and 4 (P<0.05) in Dpyr, but not in osteocalcin and CTx. GOA patients had
higher BMD of the spine (0.902+/-0.175 versus 0.747+/-0.138 g/cm(2), P<0.01),
trochanter (0.535+/-0.107 versus 0.480+/-0.107 g/cm(2), P<0.05), and one-third of
the radius (0.526+/-0.068 versus 0.472+/-0. 089 g/cm(2), P<0.05) and had
significantly higher biochemical markers in Pyr and Dpyr than non-GOA patients.
It is concluded that KOA patients had higher BMD at several skeletal sites.
Biochemical bone markers were influenced by some degree of cartilage damage in OA
patients. This tendency was stronger in GOA patients than in non-GOA patients.
PMID- 10773101
TI - The immunohistochemical localization of Fas and Fas ligand in jaw bone and tooth
germ of human fetuses.
AB - The cellular localization and roles of bone morphogenetic protein (BMP)-2 and
apoptosis-associating factors in human orofacial development remain unclear. In
this study, BMP-2, osteocalcin, and TGF-beta, which are bone-differentiating
markers, apoptosis-associating factors (i.e., Bcl-2, Bax, Fas, and Fas ligand),
apoptotic cells detected by the in situ 3'-end labeling method (TUNEL), and
proliferating cell nuclear antigen (PCNA) were immunohistochemically examined in
the heads (in particular, the jaw bone and tooth germs) of human fetuses of 11
week pregnancy. BMP-2 was positive in osteoblasts and newly formed osteoid of the
incisive and palatal bone of the maxilla and the mandible, which indicated that
BMP-2 was exclusively involved in intramembranous ossification in the human fetal
head. Fas was positive in the cytoplasm of osteocytes and a few osteoblasts. In
contrast, Fas ligand was positive in the cytoplasm of osteoblasts and abundant in
the stroma of the osteoblastic layer, periosteum, and perichondrium. The Fas
ligand in the stroma was recognized as the soluble form, which was possibly
produced by osteoblasts. TUNEL-positive apoptotic cells were found in a few
osteocytes and a few osteoblastic cells in new bone, and in monocytes of
degenerate Meckel's cartilage. The induction of apoptosis observed in monocytes
seems to be caused via a Fas-Fas ligand cell death system, because some of these
monocytes were Fas-positive, and most of them were Fas ligand-positive.
Interestingly, the abundant soluble Fas ligand observed in the periosteum
probably protects the bone-formative zone from the invasion of the activated
lymphocytes by binding to Fas expressing in these lymphocytes and killing these
cells. Fas and Fas ligand were focally positive in the dental lamina and inner
enamel epithelium and cusps of the enamel organ, nevertheless, the presence of
TUNEL-positive cells was very rare. Bcl-2 was clearly and Bax was weakly positive
in the cells throughout the dental lamina and enamel organ. These findings
indicated that Fas-mediated apoptosis was inhibited by the Bcl-2 family in the
development of teeth.
PMID- 10773102
TI - Ultrasound and X-ray-based bone densitometry in patients with anorexia nervosa.
AB - In 20 patients (mean age 23+/-5 years) with anorexia nervosa (AN), bone mass was
evaluated by broadband ultrasound attenuation (BUA) of the calcaneus, peripheral
quantitative computed tomography (pQCT) of the distal radius, and dual X-ray
absorptiometry (DXA) of the lumbar spine and the hip. Compared with 20 age- and
sex- matched healthy controls, patients with AN showed marked osteopenia at all
measuring sites. Values of BUA (33.0+/-9 dB/MHz vs. 51.0+/-5.7 dB/MHz; P<0.0001)
and of BMD of all regions of the hip (e.g., femoral neck: 0.71+/-0.13 g/cm(2)
versus 0.89+/-0.07 g/cm(2); P<0.001), lumbar spine (0.82+/-0.15 g/cm(2) versus
1.24+/-0.06 g/cm(2); P<0.003) and total BMD of the peripheral radius (303.2+/-75
g/cm(3) versus 369.4+/-53.2 g/cm(3), P<0.001) were significantly reduced.
Calculating a Z-score we found the most prominent differences between AN and
controls by BUA of the calcaneus (-3.2+/-1.6), followed by DXA at the lumbar
spine (-2.9+/-2.2) and the hip (femoral neck -2.1+/-1.7) and by pQCT at the
distal radius (total BMD -1.2+/-2.0). There were highly significant correlations
between BUA of the calcaneus and BMD of the femoral neck (r = 0.78, P<0.0001) and
lumbar spine (r = 0.75, P<0.0001) as well as between BMD values of the femoral
neck and lumbar spine (r = 0.95; P<0.0001). In addition, there were significant
correlations (P<0.001) between body mass index (BMI) and the three different
measuring sites and between the duration of the disease and BUA (r = 0.5,
P<0.05). Our data suggest that BUA of the calcaneus is a valuable tool in the
management of osteoporosis. Being a fast, radiation-free investigation method of
good acceptance, it may be well suited for an assessment of the skeletal status
in patients with AN.
PMID- 10773103
TI - Serum isoforms of bone alkaline phosphatase increase during physical exercise in
women.
AB - Physical activity is an important factor for maintaining and probably increasing
bone mass in humans. However, the mechanism by which this takes place is not
completely understood. The purpose of this study was to examine the influence of
physical exercise on serum alkaline phosphatase (ALP) and in particular, the bone
isoforms of ALP. Six ALP isoforms were quantified by high-performance liquid
chromatography: three bone (B/I, B1, and B2), and three liver ALP isoforms. In
addition, serum calcium, parathyroid hormone (PTH), and other markers of bone
formation and degradation, as measured by osteocalcin and cross-linked
carboxyterminal telopeptide of type I collagen (ICTP), were analyzed. The study
groups comprised 15 women, 8 postmenopausal (range 51-62 years) and 7 near age of
peak bone mass (range 21-27 years). When the postmenopausal women exercised on an
ergometer cycle until exhaustion we found significant increases in serum of bone
ALP isoforms B1 and B2, and phosphate, even considering the hemoconcentration
that occurred during the exercise. When the young women jogged in a moderate
tempo for 40-40 minutes the levels of serum B2 and PTH increased. All changes
turned towards baseline within 20 minutes after exercise. In conclusion, exercise
increased serum ALP bone isoforms B1 and B2, and their responses were
differentiated. As B1 and B2 are known to represent specific bone compartments,
cortical and trabecular bone, the present findings may indicate different effects
on bone of weight- and nonweight-bearing exercise.
PMID- 10773104
TI - Cyclical etidronate therapy for prevention of postmenopausal bone loss: a 1-year
open-label follow-up study.
AB - The objective of this study was to evaluate whether the pharmacological activity
of cyclical etidronate therapy is sustained beyond the dosing period. A group of
121 postmenopausal women who had completed a 2-year, double-blind, placebo
controlled parallel study with etidronate or placebo (400 mg/day for 14 days
every 3 months) and calcium agreed to participate in a 1-year open-label follow
up study to evaluate the effect of discontinuing etidronate treatment. Fifty-nine
subjects in the former etidronate group and 62 in the placebo group received 500
mg/day of elemental calcium; 54/59 and 58/62 subjects, respectively, completed
the study. Outcomes of the study were bone mineral density (BMD), measured by
dual energy X-ray absorptiometry (DXA), and biochemical markers of bone turnover
(urinary deoxypyridinoline/creatinine and serum osteocalcin). To determine
whether there was a residual effect of previous therapy we compared mean
percentage changes from baseline (year 0) to year 3 for both spinal and femoral
neck BMD and markers of bone turnover in the former cyclical etidronate and
placebo groups. To evaluate the carryover effect of treatment we compared the
percent change from year 2 to year 3 for the same variables. Mean percentage
change (SEM) from year 2 to year 3 for spinal BMD in the former cyclical
etidronate group was -2.87% (0.48%) versus -0.99% (0.36%) in the placebo group (P
= 0.0022). In the femoral neck, the BMD changes were -0.86% (0.42%) versus -1.01%
(0.41%) (NS). Biochemical markers increased within 6 months toward baseline
levels. Mean percentage changes from baseline (year 0) in both spinal and femoral
neck BMD were significantly different between groups 1 year after treatment
discontinuation. No differences between groups were maintained in
deoxypyridinoline and osteocalcin. It is concluded that following withdrawal of
cyclical etidronate therapy bone loss resumes at a normal and moderately
accelerated rate in the proximal femur and lumbar spine, respectively. A positive
effect on BMD at both cortical and trabecular sites is maintained for 1 year
after treatment withdrawal.
PMID- 10773105
TI - Growth parameters in the epiphyseal cartilage of brachymorphic (bm/bm) mice.
AB - We studied kinetics in the epiphyseal cartilage of the brachymorphic (bm/bm)
mouse, combining morphometry and labeling with halogenated nucleotides. The
defective synthesis of the sulfate donor PAPS in these homozygous mutants is
evident in tissues with a large production of glycosaminoglycans; these compounds
become undersulfated. Compared with their heterozygous siblings, the longitudinal
growth of the mutant mice was reduced by two-thirds. This was mainly associated
with (1) reduced height of the proliferating zone, (2) a substantial number of G0
cells in this zone, and (3) reduced hypertrophy which, in turn, may be related to
premature mineralization and prevention of normal expansion of cells. No
significant effects on cell-cycle parameters were detected, such as S-phase time
or cell-cycle time, and the rate at which each cell increased the matrix volume
seemed normal. An effect on matrix mineralization may be related to known changes
in the structure of matrix PGs, whereas the effect on proliferation may be
related to other factors. Candidates for such other effects of undersulfation are
the cell surface PGs, which are important for binding of growth factors.
PMID- 10773106
TI - Interleukin-1beta upregulates PTHrP-mRNA expression and protein production and
decreases TGF-beta in normal human osteoblast-like cells.
AB - Osteoblasts are regulated by complex interactions among systemic hormones,
cytokines, and local growth factors. Bone resorption, at the level of the basic
multicellular unit, is initiated by stimulation of osteoblast activity. The
stimulatory effect of interleukin-1beta (IL-1beta) on bone resorption has not
been fully clarified. We have therefore studied the influence of IL-1beta on the
local production and secretion of parathyroid hormone-related protein (PTHrP) and
transforming growth factor-beta (TGF-beta) from normal human osteoblast-like
cells (hOB cells). Using a quantitative PCR-assay following reverse transcription
of RNA, in situ hybridization, and a two-site immunofluorometric assay for PTHrP,
we demonstrate that IL-1beta in a dose- and time-dependent manner increases PTHrP
mRNA expression and PTHrP-protein secretion. In addition, IL-1beta decreased the
TGF-beta protein concentration in conditioned medium. Our results suggest that
the actions of IL-1beta on bone may be mediated by novel mechanisms involving
both local increase of PTHrP, a potent stimulator of bone resorption, and a
decrease of TGF-beta, an important anabolic and coupling factor for bone
turnover.
PMID- 10773107
TI - Steroid receptor co-activator-1 mediates 1,25-dihydroxyvitamin D(3)-stimulated
alkaline phosphatase in human osteosarcoma cells.
AB - For steroid hormone function to occur, nuclear receptors interact with a series
of coactivators including steroid receptor coactivator-1 (SRC-1). The SRC-1 binds
the vitamin D receptor (VDR) in the presence of ligand in an activation function
2 (AF-2)-dependent manner. In order to understand the role of this interaction in
1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]-mediated gene expression, the level
of SRC-1 expression was altered in MG-63 cells. Previous studies had demonstrated
that MG-63 cells express the VDR and that 1,25(OH)(2)D(3) regulates expression of
alkaline phosphatase (ALP). Analysis of MG-63 cells demonstrated that SRC-1 is
expressed. A full-length cDNA coding for SRC-1 was inserted in antisense
orientation into an expression vector (anti-SRC-1). The MG-63 cells were
transfected with anti-SRC-1 or mock vector and stable transformants were
selected. Western blot analysis showed a 95% reduction in SRC-1 protein as
compared with mock cells. We determined the effect of normal and reduced SRC-1
expression in MG-63 cells on 1,25(OH)(2)D(3)-mediated stimulation of ALP. Whereas
10(-8) M 1,25(OH)(2)D(3) produced a 3.6-fold stimulation in ALP in mock cells
expressing normal levels of SRC-1, it did not alter ALP in cells expressing
reduced levels of SRC-1. Thus, SRC-1 is required for 1,25(OH)(2)D(3)-mediated
gene expression of ALP by human MG-63 cells.
PMID- 10773108
TI - Enhanced expression of extracellular calcium sensing receptor in monocyte
differentiated versus undifferentiated HL-60 cells: potential role in regulation
of a nonselective cation channel.
AB - Human promyelocytic leukemia cells (HL-60) have been used widely as a model for
studying the differentiation of hematopoietic progenitor cells in vitro. After
treatment with phorbol-12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin
D(3) [1,25(OH)(2)D(3)], HL-60 cells differentiate into cells with the phenotype
of monocytes/macrophages. We previously showed that peripheral blood monocytes
and the murine J774 monocytic cell line express the CaR, and myeloid progenitors
in the bone marrow and myeloid cells in peripheral blood other than monocytes
express lower levels of the CaR. Therefore, we investigated whether
undifferentiated HL-60 cells express a functional G protein-coupled,
extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) and if the expression of
the CaR increases as these cells differentiate along the monocytic lineage. The
use of reverse transcription-polymerase chain reaction (RT-PCR) with CaR-specific
primers, followed by sequencing of the amplified products, identified an
authentic CaR transcript in undifferentiated HL-60 cells. Both
immunocytochemistry and Western blot analysis using a CaR-specific antiserum
detected low levels of CaR protein expression in undifferentiated HL-60 cells.
The levels of CaR protein increased considerably following treatment of the cells
with PMA (50 nM) or 1,25(OH)(2)D(3) (100 nM) for 5 days. Northern analysis using
a CaR-specific riboprobe identified CaR transcripts in undifferentiated HL-60
cells, but CaR mRNA levels did not change appreciably after treatment with either
agent, suggesting that upregulation of CaR protein occurs at a translational
level. PMA-treated HL-60 cells expressed a nonselective cation channel (NCC), and
the calcimimetic CaR activator, NPS R-467, but not its less active stereoisomer,
NPS S-467, as well as the polycationic CaR agonist, neomycin, activated this NCC,
demonstrating that the CaR expressed in these cells is functionally active.
Therefore, HL-60 cells exhibit an increase in CaR protein expression, occurring
at a translational level during their differentiation into cells with a
monocyte/macrophage phenotype in response to treatment with PMA or 1,
25(OH)(2)D(3), which is functionally linked to activation of a nonselective
cation channel.
PMID- 10773109
TI - The reducing effects of a calcium-deficient diet and high sucrose diet on dentin
apposition of rat molars.
AB - A high sucrose diet reduces dentin apposition of growing rats. The mechanisms of
reduction are unclear, but disturbances in calcium balance or in mineralization
of predentin may explain them. In this experiment, 29 Sprague-Dawley rats, 21
days old, were weaned and randomized into calcium-deficient, high-sucrose or
standard-diet groups for 3 weeks. They were given food and water ad libitum.
During the experiment, animals were individually housed in metabolic cages where
urine samples were collected. At ages of 21 and 40 days mineralizing dentin was
marked using I.P. injections of oxytetracycline hydrochloride. At 42 days of age,
the animals were anesthetized and their blood was collected by cardiac puncture.
Right hemimandibles were sectioned sagittally and left hemimandibles were fixed,
decalcified, and cut into histological sections. Dentin appositions were measured
planimetrically, predentin width, from histological sections. Ca, K, and Na
levels of serum and urine were measured flame photimetrically and P levels were
measured by the UV method. Statistical analyses were done using one-way analysis
of variation (ANOVA) Tuckey's HSD t test. In the calcium-deficient group,
hypocalcemia, reduced dentin apposition, and increased predentin width were
noticed when compared with the control group (P<0.05). Also, the increase in
predentin width, caused by calcium deficiency, was significant compared with
sucrose-fed animals (P<0.05). Sucrose diet reduced dentinogenesis, increased Ca
excretion to urine, but also reduced urinary levels of P, K, and Na, and the
differences were significant for the controls (P<0.05). In conclusion, despite
the same kind of reduced dentinogenesis in calcium-deficient and high-sucrose
groups, calcium imbalance or reduced mineralization of predentin does not explain
reduced dentinogenesis in sucrose-fed animals.
PMID- 10773111
TI - European calcified tissue society
PMID- 10773112
TI - Metabolic management of patients with severe surgical illness: introduction
PMID- 10773110
TI - Bone sialoprotein (BSP) is a crucial factor for the expression of osteoblastic
phenotypes of bone marrow cells cultured on type I collagen matrix.
AB - In this study, we demonstrated that type I collagen matrix induced the expression
of osteoblastic phenotypes of bone marrow cells, and that antibone sialoprotein
(BSP) monoclonal antibody suppressed the expression of these phenotypes. On the
other hand, BSP accelerated the expression of osteoblastic phenotypes of bone
marrow cells. The adherent bone marrow cells were harvested from rat femur and
cultured on type I collagen matrix gels in medium containing 15% fetal calf
serum, neither beta-glycerophosphate nor glucocorticoid. Cells showed
osteoblastic phenotypes (high alkaline phosphatase activity, osteocalcin
synthesis, and responsiveness against parathyroid hormone) on collagen matrix
gels at week 3 after the inoculation, and simultaneously, BSP was detected in the
conditioned medium by Western blotting using an anti-BSP monoclonal antibody.
However, cells in the conventional culture dishes did not show osteoblastic
phenotypes during the experimental period. To investigate the physiological
function of BSP in osteoblastic differentiation, bone marrow cells were cultured
on collagen matrix with an anti-BSP monoclonal antibody for 3 weeks. This
treatment suppressed the expression of the osteoblastic phenotypes, and the
effect of the antibody was abolished by the addition of bovine bone BSP.
Furthermore, bovine bone BSP stimulated the expression of osteoblastic phenotypes
of bone marrow cells. Our results indicate that BSP plays a crucial role in the
expression of osteoblastic phenotypes of bone marrow cells.
PMID- 10773113
TI - Initiators and propagators of the metabolic response to injury.
AB - Injury produces tissue hypoperfusion and subsequent reperfusion, afferent neural
activity, and immune and vascular endothelial activation. These, in turn, set up
a cascade of events coordinated by the central nervous system and at the level of
individual tissues such as the liver, gut, and skeletal muscle. They are mediated
by a complex array of neutrophil and macrophage products. The changes result in
hypermetabolism, lypolysis, lysis of skeletal muscle and visceral protein, and
expanded extracellular fluid with consequent organ failure.
PMID- 10773114
TI - Sequential metabolic changes following induction of systemic inflammatory
response in patients with severe sepsis or major blunt trauma.
AB - We have recently completed studies in critically ill patients with severe sepsis
or major trauma that investigated sequential changes in the metabolic response
following admission to the intensive care unit. Protein, water, and energy
metabolism were measured using in vivo neutron activation analysis, tracer
dilution, dual-energy x-ray absorptiometry, and indirect calorimetry. Over the 3
week study period both groups of patients lost 13% of their total body protein.
The severe sepsis patients retained twice the volume of fluid of those with major
trauma, and the return to normal hydration in the sepsis group was
correspondingly prolonged, especially for those in the elderly age group. In both
groups of patients resting energy expenditure increased progressively over the
first week to around 40% above normal and was still elevated 3 weeks from onset
of illness. A twofold increase in total energy expenditure occurred in both
groups of patients between the first and second weeks of critical care admission.
The prolonged hypermetabolism throughout the study period was not reflected in
the concentrations of circulating proinflammatory cytokines, which fell rapidly
over the first week. The pattern of changes seen in plasma proinflammatory and
antiinflammatory cytokine concentrations is similar for sepsis and trauma. The
remarkably similar metabolic sequelae seen in critically ill patients following
the onset of severe sepsis or major trauma may constitute a universal response to
the induction of the systemic inflammatory response syndrome.
PMID- 10773116
TI - Wound healing associated with severe surgical illness.
AB - Severe injury or infection is associated with a hypermetabolic response that,
when excessive, results in impaired wound healing and as a consequence increased
morbidity and mortality. The objective examination of wound healing in humans is
difficult and generally requires the use of models. Evidence is accumulating that
nutritional and growth factors play important roles in improving the wound
healing response, particularly after thermal injury and uncomplicated major
surgery. The septic patient represents the biggest challenge to those seeking to
optimize wound healing capacity. Advances in molecular biology have provided
promising therapies in experimental studies of wound healing that await clinical
investigation.
PMID- 10773115
TI - Changes in intermediary metabolism in severe surgical illness.
AB - Under normal circumstances there is a reciprocal relation between the
availability of free fatty acids (FFAs) and glucose in plasma. In the fasted
state, FFAs predominate in both availability and the relative contribution to
energy production, whereas the same is true for glucose in the fed state. The
extent of glucose oxidation is directly determined by its availability, whereas
FFAs are normally available well in excess of their rate of oxidation. The rate
of FFA oxidation is determined by the rate of transfer into the mitochondria via
the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is
regulated by the metabolism of glucose. With critical illness the stress response
involves mobilization of both plasma glucose and FFAs simultaneously in both the
fed and fasted states. In the situation of excess availability of substrates, the
metabolism of glucose limits the oxidation of FFAs, thereby channeling those
fatty acids into triglyceride (TG) stores in the muscle and the liver. The high
FFA concentrations and increased tissue TG stores can limit glucose clearance
from the blood, thereby contributing to the development of hyperglycemia. Also,
the excessive metabolism of glucose can result in lacticacidemia and can
contribute to the depletion of muscle glutamine. The nutritional treatment of
such patients must account for these underlying metabolic responses to avoid
amplifying potentially detrimental responses to the excess availability of
substrates already present in the fasting state.
PMID- 10773117
TI - Overview of modern management of patients with critical injury and severe sepsis.
AB - Over the last 10 years there have been substantial changes in the issues
confronting intensivists and surgeons caring for critically ill patients. A
substantial increase in the number of elderly patients with surgical illness and
complex co-morbidity has accompanied the increase in the proportion of elderly in
populations in the developed world. This phenomenon has been seen particularly
with sepsis. Incidence rates for blunt trauma have declined overall, but the
problems of the elderly trauma patient have become more evident. Major elective
surgery remains a common indication for short-term intensive care in many
countries, but the need for cost-containment has led to increased use of high
dependency care for many such patients. Expectations of both society and
clinicians have increased, and this has been reflected in the increased demand
for complex procedures (e.g., liver transplantation, cerebral artery aneurysm
clipping, aortic aneurysm repair) in patients previously considered at too high
risk. Along with these expectations have come pressures on clinicians to reduce
costs at the same time as improving clinical outcomes. Despite many advances in
the care of critically ill patients with injury or sepsis, mortality, morbidity,
and cost remain high; and nutritional support is frequently required. The
duration and extent of the metabolic changes seen in response to critical
surgical illness and intensive care treatments have become better characterized.
Although some of the changes in body water and fat are modifiable, loss of large
amounts of (functional) protein has been resistant to various strategies so far
studied.
PMID- 10773118
TI - Metabolic management of severe acute pancreatitis.
AB - The metabolic management of severe acute pancreatitis involves early
identification of patients with severe pancreatitis, aggressive fluid
resuscitation, organ support, and careful monitoring in an intensive care
environment. Recent evidence has helped to define the roles of enteral feeding,
prophylactic antibiotics, endoscopic retrograde cholangiopancreatography,
computed tomography, and fine-needle aspiration for bacteriology. The most
difficult decision in the management of these patients is whether surgery is
required and which of the complementary approaches to necrosectomy and drainage
is appropriate. Key metabolic events in the acinar cell, pancreas, and intestines
are now being unraveled, as is the basis for the systemic manifestations and
organ dysfunction associated with pancreatitis. This gives hope for the
development of more specific metabolic interventions, which will likely target
the maintenance of intestinal integrity and function, preservation of pancreatic
microcirculation, and balanced modulation of the inflammatory response.
PMID- 10773119
TI - Metabolic management of patients with severe burns.
AB - Burn injury results in profound metabolic abnormalities perpetuated by an
exaggerated stress response to injury. Hypermetabolism and marked catabolism,
with rapid erosion of lean body mass, becomes evident shortly after injury. Much
of the morbidity and mortality of a major burn can be attributed to this process,
which increases infection risks, decreases the healing rate, and alters cell
function. Rapid removal of devitalized burn tissue combined with early aggressive
nutritional support significantly attenuates this autodestructive process. The
addition of anabolic agents decreases the degree of lean mass loss and increases
the rate of restoration. Immediate attention to the metabolic response to a
severe burn significantly decreases complications and improves outcome.
PMID- 10773120
TI - Disordered metabolic response with cancer and its management.
AB - The metabolic changes in cancer cachexia appear to be mediated by a complex
network of proinflammatory cytokines, neuroendocrine hormones, neurotransmitters,
eicosanoids, and tumor-derived factors produced by the body in response to the
tumor and by the tumor itself. The relative importance of these various mediator
pathways in relation to either the anorexia or hypermetabolism associated with
weight loss in cancer remains to be fully elucidated. Our current understanding
suggests that proinflammatory mediators may indeed be a valid target for
therapeutic intervention. Trials attempting to modify the inflammatory response
to cancer with the hope of improving appetite and reversing catabolism and
perhaps thereby improving qualityof life and survival are currently underway.
PMID- 10773121
TI - Manipulation of the metabolic response in clinical practice.
AB - Surgical injury is followed by profound changes in endocrine metabolic function
and various host defense mechanisms leading to catabolism, immunosuppression,
ileus, impaired pulmonary function, and hypoxemia. These physiologic changes are
supposed to be involved in the pathogenesis of postoperative morbidity. Effective
afferent neural blockade with continuous epidural local anesthetic techniques
inhibits a major part of the endocrine metabolic response, leading to improved
protein economy but without important effects on inflammatory or immunologic
responses. In contrast, pain treatment with other modalities such as nonsteroidal
antiinflammatory drugs (NSAIDs) and opioids has only a small inhibitory effect on
endocrine metabolic responses. Preoperative high-dose glucocorticoid therapy
provides additional pain relief and improves pulmonary function, but it reduces
the inflammatory response (acute-phase proteins, cytokines, hyperthermia) and
immune function. Minimally invasive surgery leaves the endocrine metabolic
responses largely unaltered but reduces the inflammatory response and immune
suppression. Thus several techniques are available to modify the stress responses
in elective surgery patients. The effect of these techniques to alter endocrine
metabolic and inflammatory responses during severe surgical illness has not been
established. Neural blockade and minimally invasive surgery have improved outcome
following elective surgery, especially when integrated into a multimodal
postoperative rehabilitation program. Application of this knowledge from
pathophysiologic responses to uncomplicated surgical injury should be explored in
patients with severe surgical illness.
PMID- 10773122
TI - Manipulations of the metabolic response for management of patients with severe
surgical illness: review.
AB - The metabolic response to severe surgical illness is complex and varied. Much
recent laboratory and clinical research has focused on increasing our
understanding of the metabolic response and the development of new therapies
designed to modify this response. Antiinflammatory agents can target harmful
aspects of the metabolic response; the immune system can be stimulated; and
anabolic factors can be used in an attempt to enhance recovery. The nutritional
support of the surgical patient remains crucial, but the effects of new additives
are being studied in a variety of surgical conditions. As yet, few of these
"novel" agents have found an established role in the management of surgical
patients. This review focuses on many "novel" agents or those that do not yet
have a clearly defined role in surgical illness. Clinical trials in the areas of
severe sepsis, major surgical trauma, and major elective surgery have been
emphasized.
PMID- 10773123
TI - Metabolic response to severe surgical illness: overview.
AB - Severe surgical illness results in metabolic responses that mobilize substrate
(amino acids and fatty acids) from body stores to support vital organs, enhance
resistance to infection, and ensure wound healing. Central to this process is the
redistribution of body protein, which moves from skeletal muscle to support the
central viscera. If unsupported, this protein-wasting state could result in
prolonged convalescence, diminished immunity, and poor wound healing. Present
evidence suggests that the central nervous system plays a major role in
regulating this protein catabolic response. Infusing exceedingly small quantities
of the proinflammatory cytokines into the brain can mimic injury responses, and
central cytokine blockade may be one therapeutic approach to attenuating these
responses safely in the future. Additional evidence also demonstrates that the
function of the hypothalamus and anterior pituitary is dampened during the later
stages of severe surgical illness, and the possibility of hormonal replacement
therapy needs to be explored.
PMID- 10773124
TI - Treatment of complicated hepatolithiasis with intrahepatic biliary stricture by
ductal dilatation and stenting: long-term results.
AB - A group of 190 cases of hepatolithiasis with postoperative residual stones
located proximal to the stricture sites were managed with the aim of complete
clearance of stones and relief of bile stasis to decrease the potential risk of
recurrence. All procedures were performed through a T-tube track with gradual
dilatation and stent placement through the stricture sites, creating a channel
that allows cholangioscopy and electrohydraulic lithotripsy. Complete clearance
of intrahepatic duct (IHD) stones was achieved in 88.4% of cases. Multiple
sharply angulated IHD strictures in right-sided hepatolithiasis constituted a
major cause of failure. Recurrent stone formation and repeated cholangitis,
subsequent drainage, and liver resection are associated with high mortality rates
particularly if there is late development of a cholangiocarcinoma. We concluded
that postoperative ductal dilatation and stenting through the T-tube track
combined with endoscopic electrohydraulic lithotripsy is effective and safe for
managing complicated hepatolithiasis. Persistent irreversible aneurysmal
dilatation of IHD and atrophic change of the affected hepatic lobe at follow-up
were ominous signs of recurrence and cholangiocarcinoma development. Early
drainage with stone extraction combined with surgical intervention can prevent
subsequent morbidity and mortality.
PMID- 10773125
TI - Radical surgical therapy of abdominal cystic hydatid disease: factors of
recurrence.
AB - A series of 74 consecutive patients (48 women, 26 men) were operated for
abdominal hydatid disease between June 1949 and December 1995. The patients
ranged in age from 15 to 81 years (median 49 years). In 69 cases only the liver
was affected; two patients had concomitant extrahepatic disease (one spleen, one
spleen and lung), and 3 had cysts in the spleen only. Cysts were multiple in 11
patients and calcified in 24. Conservative surgical procedures were used for 22
cysts in 20 patients [open partial (n = 3), open total (n = 6), closed total
cystectomy (n = 9), marsupialization (n = 2), drainage (n = 2)] and radical
surgical procedures for 72 cysts in 54 patients [pericystectomy (n = 41), wedge
liver resection or hemihepatectomy (n = 25), splenectomy (n = 5), radical
resection of a lung cyst (n = 1)]. Altogether 37 patients (50%) were given
perioperative antihelmintic chemotherapy with mebendazole (18 patients) or
albendazole (19 patients). Operative mortality rates were 5.0% after conservative
surgery and 1.8% after radical surgery. Morbidity rates were 25.0% following
conservative surgery and 24.1% following radical surgery. Antihelmintic therapy
was well tolerated by all but five patients. All side effects were entirely
reversible. Among the 74 patients, 60 (81.0%) were available for long-term follow
up (median 7.2 years; range 2.0-47.0 years). Recurrence of disease was seen in 9
of 60 patients at an interval of 3 months to 20 years from the first operation.
The rate of recurrence was significantly lower after radical surgical procedures
(p = 0.03) and after closed removal of the cyst (p = 0.04).
PMID- 10773126
TI - Hypomagnesemia and hypocalcemia after thyroidectomy: prospective study.
AB - Hypomagnesemia after total thyroidectomy has not been studied extensively. Our
anecdotal experience suggests that it may be important in some patients after
thyroid excision. The hypomagnesemic hypocalcemic syndrome has been described in
other disease states in which a state of functional hypoparathyroidism exists.
This study was designed to determine the incidence of hypomagnesemia after total
thyroidectomy and relate it to hypocalcemia and symptoms during the postoperative
period. A prospective study of all patients undergoing total thyroidectomy
between September 1994 and July 1996 was performed. Patient data, thyroid
function, retrosternal extension, initial versus reoperative surgery, operative
details, parathyroid resection, and pathology were recorded. Calcium, magnesium,
electrolytes, blood count, liver function tests, and albumin were measured prior
to surgery and twice daily during the postoperative period. Fifty patients
underwent total thyroidectomy: 68% were hypocalcemic, 72% were hypomagnesemic,
and 36% were symptomatic during the postoperative period. Hypomagnesemia and
gender were associated with hypocalcemia. Volume of fluid and neck dissection
were associated with low magnesium levels. Hypomagnesemia and parathyroid
resection were risk factors for symptoms after thyroidectomy. No patients
developed permanent hypoparathyroidism. Transient hypocalcemia and hypomagnesemia
occur frequently after total thyroidectomy. The etiology of this phenomenon is
probably multifactorial. Patients are more likely to be symptomatic when both
cations are low, and attempting to correct only hypocalcemia may prolong
symptoms. It is important to monitor both calcium and magnesium levels after
total thyroidectomy and to correct deficiencies to facilitate prompt resolution
of symptoms.
PMID- 10773127
TI - Limits of infrapopliteal bypass surgery for critical leg ischemia: when not to
reconstruct.
AB - The aim of this study was to identify the risk factors affecting the immediate 30
day postoperative outcome of infrapopliteal bypass grafts. A series of 511
revascularization procedures to the infrapopliteal arteries have been performed
in 439 patients with critical leg ischemia. There were 306 crural bypasses and
205 pedal bypasses. The 30-day postoperative primary and secondary patency rates
were 77.5% and 83.4%, respectively; the leg salvage rate was 89.8%; the survival
rate was 94.7%; and 85.1% of patients were alive with a salvaged leg. A history
of myocardial infarction, angina pectoris, or stroke had a great impact on the
postoperative cardiac and cerebrovascular fatal and nonfatal complications. C
reactive protein arose as an important predictor of the length of hospital stay
(p = 0.03), postoperative cardiac complications (p = 0.02), leg salvage (p =
0.009), amputation with patent graft (p = 0.009), and patients who survived with
a salvaged leg (p = 0.006). Poor results were achieved in patients on long-term
dialysis. Surgical experience had an influence on leg salvage (p = 0.02) and on
patients alive with salvaged leg rates (p = 0.009). Infrapopliteal bypass surgery
is a demanding procedure requiring high surgical skill and experience.
Revascularization may be contraindicated when severe coronary disease, previous
stroke, renal failure requiring long-term dialysis, diabetes, or high serum
concentration of C-reactive protein coexist with critical leg ischemia, as these
patients are at high risk for early postoperative leg or life loss.
PMID- 10773128
TI - Effect of laparoscopic cholecystectomy on platelet aggregation.
AB - The purpose of this study was to investigate the effect of laparoscopic
cholecystectomy on platelet function. We operated on 40 women with symptomatic
gallbladder stone, 20 of whom (study group) underwent laparoscopic
cholecystectomy and 20 of whom (control group) open cholecystectomy. Patients
with a history of bleeding, abnormal platelet count, or systemic disorders and
those who were on salicylates, heparin, or oral anticoagulants were excluded.
Blood parameters were checked at the beginning and the end of the operation,
including platelet aggregation using adenosine 5'-diphosphate (ADP), collagen,
and ristocetin in a whole-blood aggregometer. Platelet aggregation was evaluated
by percent aggregation. Platelet aggregation due to collagen and ristocetin
increased significantly at the end of the operation in the study group (p <
0.001). Aggregation due to ADP did not differ significantly from the start to the
end of the operation. Control group results did not show any differences.
Although the clinical findings of aggregated platelet are not frequently observed
in practice, we suggest that laparoscopy increases platelet aggregation.
PMID- 10773129
TI - Laparoscopic hernioplasty versus conventional hernioplasty (Shouldice): results
of a prospective randomized trial.
AB - The results of our randomized trial of 176 patients comprising primary hernias
[Shouldice versus transabdominal preperitoneal approach (TAPP)] showed only
slight advantages for the laparoscopically operated group compared to the
conventionally operated group: less subjective pain (significant only on fifth
postoperative day, p < 0.05), reduced analgesic requirement (significant only on
third postoperative day, p < 0.05), significantly shorter duration of
hospitalization (4 days vs. 6 days, p < 0.05) and faster return to work (27 days
vs. 34 days, NS). Regarding the incidence of recurrences, there was no
significant difference between the groups (two recurrences vs. one recurrence)
within a follow-up period of 2 years. Postoperative morbidity was similar and the
total cost was less for the TAPP group.
PMID- 10773130
TI - Incisional hernia after laparotomy: prospective randomized comparison between
early-absorbable and late-absorbable suture materials.
AB - Incisional hernia is a serious postoperative complication of laparotomy.
Selecting an appropriate suture material may lessen such morbidity. This study
undertook a prospective, randomized comparison of early-absorbable polyglactin
910 suture versus late-absorbable polydioxanone loop suture for fascial closure
after abdominal surgery. A series of 340 consecutive patients undergoing elective
laparotomy were randomized to have fascial closure with either polyglactin 910
suture or polydioxanone loop suture between October 1993 and August 1996. A 2
year follow-up revealed that 23 patients had died, and the overall mortality rate
was 6.8% (23/340). Ten (10/340, 2.9%) patients, including seven with polyglactin
910 suture and three with polydioxanone loop suture, developed incisional
hernias. The early postoperative evaluation revealed an incidence of wound
infection of 4.1% (14/340). The development of incisional hernia was not
secondary to postoperative wound infection in this study. Among these 340
patients, 192 had malignant diseases and 148 had nonmalignant ones. Fascial
closure with polyglactin 910 suture was associated with more incisional hernias
than that with polydioxanone loop suture, with marginal significance for patients
in the malignant group (4.7% versus 0%, p = 0.07) but not in the nonmalignant
group (2.6% versus 4.2%, p = 0.67). In conclusion, abdominal closure with a late
absorbable polydioxanone loop suture may be beneficial to patients with a
malignant disease for preventing incisional hernia.
PMID- 10773131
TI - Endoscopic surgery: ideal for endocrine surgery?
PMID- 10773132
TI - Development of monocrotaline-induced pulmonary hypertension is attenuated by a
serotonin receptor antagonist.
AB - The significance of serotonin in the pathogenesis of monocrotaline-induced
pulmonary hypertension (MCT-PH) in rats, plasma serotonin concentrations, and the
effect of a serotonin receptor antagonist administration in association with the
number of proliferative cells were investigated. The thickness of the media of
the small pulmonary arteries and the weight ratio of the RV to that of LV + S
(RV/[LV + S] weight ratio) were used as indices of the severity of PH. Plasma
serotonin concentrations were measured by high-performance liquid chromatography.
Histopathologic analysis of the lung tissue was performed by hematoxylin-eosin
and elastin van Gieson staining. Immunohistopathologic staining for proliferating
cell nuclear antigen (PCNA) was performed to identify proliferative cells. The
severity of PH as determined by the medial thickness of the small pulmonary
arteries and RV/(LV + S) weight ratio in rats with MCT-PH was significantly
reduced after treatment with MCI-9042 (p < 0.01 and p < 0.05, respectively). The
serotonin concentration was significantly greater in MCT-PH rats than in normal
control rats (p < 0.05). The scores for histopathologic changes, such as
thickening of the alveolar walls and interstitial inflammatory cell infiltration
in MCT-PH rats, were significantly reduced after treatment with MCI-9042 (p <
0.05 and p < 0.01, respectively). The number of PCNA-positive cells was
significantly greater in MCT-PH rats than in normal control rats (p < 0.0001) and
was reduced after treatment with MCI-9042 (p < 0.0001). Treatment with MCI-9042
significantly inhibited the development of MCT-PH along with a decrease in the
number of PCNA-positive cells, suggesting a pivotal role of serotonin in the
development of PH induced by MCT.
PMID- 10773133
TI - Tissue polypeptide specific antigen and squamous cell carcinoma antigen for early
prediction of recurrence in lung squamous cell carcinoma.
AB - One of the major problems in the follow-up of patients with lung cancer is the
early detection of recurrent disease. Tumor markers have been found helpful in
detecting early recurrent disease. The aims of this study were to evaluate and
compare the clinical usefulness of serial and simultaneous measurement of tissue
polypeptide antigen (TPS) and squamous cell carcinoma (SCC) antigen for the early
prediction of recurrence in patients with SCC of the lung. Sixty patients with
SCC of the lung, including 25 patients with recurrence and 35 patients without
recurrence after 1 year's follow-up after surgery, were enrolled in this study.
The serial serum levels of TPS and SCC antigen were measured before surgery and 1
week, 1 month, 3 months, 6 months, 9 months, and 12 months after the operation
for early detection of recurrence. The results revealed that (1) the mean serum
values of TPS were significantly greater at all times after surgery in the 25
patients with recurrent SCC compared with the 35 patients without recurrent SCC,
and (2) the mean serum values of SCC antigen were significantly greater only at 9
and 12 months after surgery in the 25 patients with recurrent SCC compared with
the 35 patients without recurrent SCC. We conclude that TPS is a better marker
than SCC antigen for early prediction of SCC recurrence in the lung.
PMID- 10773134
TI - Basal layer reactivity in hyperplastic and metaplastic lesions of the bronchi as
studied by lectin histochemistry.
AB - The relationship between squamous metaplasia and squamous cell carcinoma of the
bronchi has been the subject of controversy. We investigated basal cell
hyperplasia, stratification, squamous metaplasia, and squamous cell carcinoma by
means of lectin histochemistry with peanut agglutinin (PNA), Ulex europeus
agglutinin-I, soybean agglutinin, and Dolichos biflorus agglutinin for all normal
basal cells that are reactive. A basal layer stained with PNA was observed in
basal cell hyperplasia, stratification, and squamous metaplasia, but this layer
was not exhibited by squamous cell carcinoma. In hyperplasia and metaplasia, PNA
staining was biased toward the lowest (basal) layer, whereas staining for the
other lectins was more uniformly distributed across the layers. A PNA-positive
basal layer may be important for the morphologic reversibility of the bronchial
mucosa in hyperplastic and metaplastic lesions, and destruction of this layer may
be associated with a progression from metaplasia to squamous cell carcinoma.
PMID- 10773135
TI - Bactericidal activity of alveolar macrophages is suppressed by V-ATPase
inhibition.
AB - Bafilomycin A(1), a selective inhibitor of V-type H(+)-translocating ATPase (V
ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J
Exp Med 187:1583-1598). Therapeutic uses of the enzyme inhibitor need to consider
the agent's potential effects on normal (nontumor) cells. This study determined
the effects of bafilomycin A(1) on resident alveolar macrophages (mphi).
Treatment of alveolar mphi with bafilomycin A(1) (10 microM, 1 h) caused a
significant decrement in cytosolic pH. This was accompanied by marked alteration
of mphi bactericidal capabilities. The enzyme inhibitor caused a marginal
reduction in the phagocytosis of opsonized Staphylococcus aureus and
significantly suppressed intracellular killing of the phagocytosed bacteria. In
keeping with the effects on intracellular killing, bafilomycin A(1) significantly
reduced the production of reactive oxygen species (ROS). On the other hand, cell
spreading was enhanced significantly by bafilomycin A(1). Comparable changes in
ROS generation and mphi spreading were produced by altering cytosolic pH through
changes in extracellular pH (pH(o)) in the absence of bafilomycin A(1). These
findings suggest that the agent's effects on ROS production and mphi spreading
were related to the accompanying changes in cytosolic pH. The enzyme inhibitor
also altered mphi morphology, leading to the shortening of microvilli and focal
loss of surface ruffles. These morphologic effects differed from those produced
by altering cytosolic pH by changes in pH(o). The results demonstrate that V
ATPase activity is an important determinant of mphi functioning and structure.
Therapeutic use of V-ATPase inhibitors might be expected to compromise the
bactericidal activity of alveolar mphi.
PMID- 10773136
TI - Measurements of free radicals in isolated, ischemic lungs and lung mitochondria.
AB - Previous studies in isolated, ventilated lungs have demonstrated by indirect
measurements that oxidant generation occurs during pulmonary ischemia before
reperfusion. To identify and quantify the types of free radical species generated
during ischemia, we used electron paramagnetic resonance (EPR) spectroscopy in
the presence and absence of the spin trap, 5,5-dimethyl-1-pyrroline-N-oxide
(DMPO). EPR spectra obtained from the vascular effluent of isolated ferret lungs,
contained a doublet signal (g = 2.005) indicative of ascorbyl radical. This
signal doubled in magnitude after 180 min of ischemia, providing evidence of
oxidant formation during ischemia. When DMPO, which reacts with radicals
including superoxide anions and hydroxyl radicals, was added to the perfusate,
the spectra contained ascorbyl radical signals but no DMPO-adducts. To clarify
the relationship between ascorbyl radical and DMPO-adduct formation, additional
studies were conducted in the presence and absence of ascorbate with isolated
lung mitochondria as the source of free radicals. The results showed that in the
presence of ascorbate, oxygen free radicals were not detected by EPR spin
trapping with DMPO because of the formation of prominent ascorbyl radical
signals. These data suggest that DMPO may be useful for the detection of reactive
oxygen species in isolated lungs, provided the ascorbate can be sufficiently
depleted. Alternatively, as shown by our results, EPR studies that directly
monitor ascorbyl radical formation may be used as a marker of oxidative stress in
the lung.
PMID- 10773137
TI - The relation of fat-free mass to maximum exercise performance in patients with
chronic obstructive pulmonary disease.
AB - To assess the factors determining maximum exercise performance in patients with
chronic obstructive pulmonary disease (COPD), we examined nutritional status with
special reference to body composition and pulmonary function in 50 stable COPD
patients. Nutritional status was evaluated by body weight and body composition,
including fat mass (FM) and fat-free mass (FFM) assessed by bioelectrical
impedance analysis (BIA). Exercise performance was evaluated by maximum oxygen
uptake (Vo(2max)) on a cycle ergometer. A total of 50 patients (FEV(1) = 0.98 L)
was divided randomly into either a study group (group A, n = 25) or validation
group (group B, n = 25). Stepwise regression analysis was performed in group A to
determine the best predictors of Vo(2max) from measurements of pulmonary function
and nutritional status. Stepwise regression analysis revealed that Vo(2max) was
predicted best by the following equation in group A: Vo(2max) (mL/min) = 10.223 x
FFM (kg) + 4.188 x MVV (L/min) + 9.952 x DL(co) (mL/min/mmHg) - 127.9 (r = 0.84,
p < 0. 001). This equation was then cross-validated in group B: Measured Vo(2max)
(mL/min) = 1.554 x Predicted Vo(2max) (mL/min) - 324.0 (r = 0.87, p < 0.001). We
conclude that FFM is an important factor in determining maximum exercise
performance, along with pulmonary function parameters, in patients with COPD.
PMID- 10773138
TI - Lumpectomy margins, reexcision, and local recurrence of breast cancer.
AB - BACKGROUND: The diagnosis of breast cancer is often made by excisional biopsy
without margin assessment for mammographic findings or palpable masses. Many
patients treated with breast conservation undergo reexcision to obtain clear
margins although the relationship between clear margins and local recurrence
remains controversial. METHODS: Patients undergoing breast conservation and
adjuvant radiation therapy with complete follow-up over 5 years were studied.
Factors associated with obtaining clear histopathologic margins and undergoing
reexcision to obtain clear margins were studied in relation to the risk of local
recurrence. RESULTS: Clear biopsy margins were associated with diagnosis by fine
needle aspiration cytology (fine-needle aspiration 42%, spot localization 11%,
excisional biopsy 10%; P <0.001). Reexcision was significantly related to
diagnostic method (spot localization 63%, excisional biopsy 36%, fine-needle
aspiration 10%; P <0.001), first margin status (clear 0%, close 11%, positive
46%, unknown 48%; P <0.001), patient age (54 years for reexcised patients and 58
for non-reexcised patients; P <0.001), and tumor size (mean tumor size 1. 4 cm
for reexcised patients and 1.7 cm for non-reexcised patients; P = 0.003).
Patients undergoing reexcision were significantly more likely to be diagnosed by
spot localization, have nonnegative excisional biopsy margins, be younger, and
have smaller tumors than patients not undergoing reexcision. Local recurrence was
not significantly related to margin status (8% with clear margins, 7% with
positive margins, 19% with close margins, and 11% with unknown margins) or
reexcision (10% local recurrence rate for patients with negative final margins
after reexcision and 12% with positive, close or unknown first margin without
reexcision). Estrogen receptor status was the only variable related to local
recurrence in Cox proportional hazards model (P = 0.009). Estrogen receptor
negative patients with nonnegative margins experienced a 20% rate of local
recurrence compared with 10% for estrogen receptor negative patients with
negative margins and 7% for estrogen receptor positive patients regardless of
margin status (P = 0.021). CONCLUSIONS: Clear excision margins are facilitated by
preoperative diagnosis by fine-needle cytology. For patients with nonnegative
margins, reexcision was more commonly performed in young patients with small
tumors diagnosed by spot localization biopsy. The relationship of local
recurrence to margins and reexcision was not statistically significant. Estrogen
receptor negative tumors with nonnegative margins had a significantly higher rate
of local recurrence than estrogen receptor negative tumors with clear margins and
estrogen receptor positive tumors regardless of margin status.
PMID- 10773139
TI - Local control in differentiated thyroid carcinoma with extrathyroidal invasion.
AB - BACKGROUND: The clinical significance of microscopically locoresional-residual
differentiated thyroid carcinoma is still an unsolved problem. METHODS: Patients
who underwent resectional management for advanced differentiated thyroid
carcinoma were divided into complete (n = 58), microscopic (n = 37), macroscopic
(n = 14), and distant (n = 22) groups. RESULTS: Postoperative recurrence was
similar in the complete (28%) and microscopic (22%) groups and was significantly
lower than that of the macroscopic (57%) and distant (67%) groups. Age, gender,
lymph node metastasis, and the residual status (complete and microscopic versus
macroscopic and distant) were independent risk factors for recurrence.
Postoperative survival of the complete and microscopic groups groups was better
than that of the macroscopic and distant groups. Age and the residual status were
independent prognostic factors for overall and cause-specific survival.
CONCLUSIONS: Postoperative recurrence and survival of patients with microscopic
residual cancer were similar to those of patients with complete resection, and
macroscopic residual cancer either in locoregional or distant loci was an ominous
prognostic sign.
PMID- 10773141
TI - Laparoscopic lower anterior resection is equivalent to laparotomy for lower
rectal cancer at the distal line of resection.
AB - BACKGROUND: Procedures that involve resection of the distal rectum challenge the
current limitations of laparoscopic technology, because of lack of compact
articulating stapling instruments. METHOD: We improve the procedure with the aid
of a Lap disk, an abdominal wall sealing device that was developed for hand
assisted manipulation. A linear stapler capable of changing its stop angle is
inserted through the disk, and the rectum is transected by the disk during a
second pneumoperitoneum. RESULTS: The transection line becomes equivalent to that
obtained with laparotomy. CONCLUSION: This new technique made laparoscopic lower
anterior resection possible to transect the lower rectum in the same way as is
done with laparotomy.
PMID- 10773140
TI - Risk factors for anastomotic leakage after low anterior resection with total
mesorectal excision.
AB - BACKGROUND: This study aims to analyze the risk factors for anastomotic leakage
after low anterior resection with the technique of total mesorectal excision
(TME). METHODS: From September 1993 to November 1998, 196 patients with rectal
cancer from 3 to 12 cm from the anal verge were treated with low anterior
resection with TME. The data were entered in a prospective manner, and the
factors that might affect anastomotic leakage were analyzed. RESULTS: The mean
level of anastomosis was 3.6 cm from the anal verge (range 1 to 5 cm). The
leakage rate was 10.2%. Female gender (P = 0.01; 95% confidence interval [CI] 1.3
to 14.3; odds ratio 4.3) and presence of a diversion stoma (P = 0.01; 95% CI 1.4
to 14.2; odds ratio 4.5) were independent significant factors for lower
anastomotic leakage. The absence of a stoma was associated with significantly
increased leakage in male (P = 0.001) but not in female (P = 0.51) patients.
CONCLUSIONS: With low anastomosis after low anterior resection with TME,
diversion stoma construction should be performed routinely in men. In women, the
need for diversion can be more selective.
PMID- 10773142
TI - Risk factors for intra-abdominal infection after pancreas transplantation.
AB - BACKGROUND: This study was designed to determine risk factors for intra-abdominal
abscess after pancreas transplantation. METHODS: We performed a single-center
retrospective review of all pancreas transplants from 1994 to 1999. Risk factors
studied were donor age, body weight, body mass index, peak serum glucose, peak
serum amylase, need for pressor agents, cause of death, cold ischemic
preservation time, recipient age, type of dialysis, surgical technique, and peak
recipient amylase. RESULTS: The 1-year graft survival rate was 90%. Of the 34
patients studied, there were 4 cases of peripancreatic abscess formation (12%).
Elevated donor body weight (P <0.01), elevated body mass index (P <0.05), and the
peak recipient serum amylase in the first postoperative week (P <0.01) were
significant risk factors for the development of intra-abdominal infection.
CONCLUSIONS: These data suggest that pancreas grafts from obese donors may be
more susceptible to ischemia-reperfusion injury resulting in abscess formation.
PMID- 10773143
TI - Prevention of deep abdominal complications with omentoplasty on the raw surface
after hepatic resection. The French Associations for Surgical Research.
AB - BACKGROUND: Several methods have been suggested to treat the hepatic raw surface
after resection. Among these, omentoplasty (OP) has been employed occasionally
but there are no clinical studies that clearly demonstrate its usefulness.
METHODS: Of 172 randomized patients undergoing hepatic resection between January
1991 and December 1994, 5 were withdrawn for protocol violation, leaving 167 who
were randomly allotted to undergo OP (n = 87) on the hepatic raw surface or not
(NO; n = 80). This procedure was performed for malignant tumor in 125 cases,
benign tumor in 33, and for other causes in 15. Six patients had more than two
types of lesions, and 32 patients had associated cirrhosis. Sixty-five major and
102 minor hepatic resections were performed. The main outcome measures studied
were the number of patients with deep abdominal complications (DAC; deep bleeding
or hematoma, deep infection, with or without pus discharge through drains, bile
leakage), as well as repeat operations and postoperative death. Patients were
divided into two strata according to the site of the lesion with respect to the
diaphragm: (1) in contact (posterosuperior segments II, VII and VIII) or (2) not
in contact (anterior segments III, IV, V, and VI). RESULTS: Both groups were
comparable as regards patient demographics, intraoperative procedures,
intraoperative search for bile leaks and intraoperative transfusion requirements.
Fewer patients had DAC in OP (n = 11) than in NO (n = 15) (difference not
significant). Ten patients (6%) required repeat operations: 4 in OP without
immediate mortality and 6 in NO, 3 followed by death. One further patient in OP
required repeat operation after discharge and died. Four patients died in OP and
7 in NO, 1 and 4 of DAC, respectively (not significant). Deep abdominal
complications were significantly associated with major hepatic resection (P
<0.05) whereas postoperative death was significantly correlated with cirrhosis (P
<0.05). CONCLUSIONS: OP on the raw surface after hepatic resection lowers the
rate of all complications related to DAC (except biliary leaks) and their
severity (repeat operations and death) but not significantly so. OP is not
recommended as a routine measure to complete elective hepatic resections.
PMID- 10773144
TI - Pneumatosis intestinalis.
PMID- 10773145
TI - Percutaneous gallbladder drainage for delayed laparoscopic cholecystectomy in
patients with acute cholecystitis.
AB - BACKGROUND: Many studies have concluded that delayed or interval laparoscopic
cholecystectomy (LC) in patients with acute cholecystitis (AC) demonstrated
higher conversion rates and complication rates compared with early LC. However,
if the acutely inflamed gallbladder is decompressed by emergent percutaneous
gallbladder drainage (PGBD), it may decrease the technical difficulty of LC
allowing successful delayed LC when the patient is in better condition. The
purpose of this retrospective study was to assess the outcomes of delayed LC
following PGBD in patients with AC. METHODS: A total of 72 LC for AC were divided
into PGBD (n = 27) and non-PGBD groups (n = 45). The PGBD group had delayed LC
(after 72 hours of admission). Thirty-two non-PGBD patients had early LC (within
72 hours of admission) and 13 non-PGBD had delayed LC. Outcome of delayed LC for
the PGBD group was assessed by LC time, conversion rate, morbidity rate, and
hospital stay, and compared with that of the non-PGBD group. RESULTS: Compared
with early and delayed LC of the non-PGBD group, the PGBD group showed longer LC
time (median 110 minutes versus 87.5 minutes versus 85 minutes, P <0. 05), a
little lower conversion rate (15% versus 25% versus 23%), similar morbidity rate
(15% versus 9% versus 15%), and prolonged hospital stay (13 days versus 7 days
versus 10 days). CONCLUSIONS: PGBD did not significantly improve the outcome of
LC for AC as assessed by conversion and morbidity rate and hospital stay compared
with no PGBD. Thus, we can conclude that although PGBD is a safe and effective
emergency procedure for AC, it should be limited to higher risk groups such as
elderly or critically ill patients and to acalculous cholecystitis.
PMID- 10773146
TI - Preoperative evaluation to predict technical difficulties of laparoscopic
cholecystectomy on the basis of histological inflammation findings on resected
gallbladder.
AB - BACKGROUND: No papers have heretofore documented histological studies of cases
involving the inflammation of resected gallbladder or examined surgical
difficulties on the basis of pathological findings. METHODS: On the basis of the
histological inflammation findings on the resected gallbladders of 437 patients
who underwent laparoscopic cholecystectomy (LC), the factors affecting the
technical difficulty of the operation were examined through preoperative clinical
findings (13 items), diagnostic imaging (22 items), and blood test findings (6
items), using multivariate analysis. RESULTS: In accordance with the four-stage
classification of inflammation findings for the resected gallbladder, the
inflammation findings on the resected gallbladder indicated a higher correlation
with the time required for gallbladder dissection (30.2 +/- 16.3 minutes) than
with the operation time (77.6 +/- 32.7 minutes). Thus, the technical difficulty
of the operation was judged according to the time required for gallbladder
dissection. For the preoperative findings on 418 patients who underwent
successful LC, the most influential factors on the time required for gallbladder
dissection were the presence of abnormal findings on computed tomography, the
degree of fever, obesity index, nonvisualized gallbladder cholangiography, and
cystic duct length. According to the multiple regression equation of these five
factors, the gallbladder dissection for the 19 patients who underwent conversion
to open cholecystectomy (OC) due to extreme inflammation was calculated to
require 61.9 +/- 12.3 minutes, and the patients who showed a gallbladder
dissection time longer than 49.6 minutes were judged to have high technical
difficulty predicted from the preoperative evaluation. In the preoperative
evaluation, sensitivity was 79.6%, specificity was 97.6%, accuracy was 95.0%,
positive predictive value was 85.0%, and negative predictive value was 96.6%.
Next, each finding was scored on the basis of a multiple regression equation of
five factors, and the technical difficulty of the operation was quantified using
these scores. The score of the patients who underwent conversion to OC was 8.0 +/
2.0, and the patients who showed a score higher than 6 were judged to have high
technical difficulty. Almost the same results as in the aforementioned
preoperative evaluation were obtained using these scores. CONCLUSION: The
judgment using the scores was satisfactory in terms of the simplicity of
evaluating the technical difficulties associated with each patient and the ease
of obtaining information for each factor. The quantification of technical
difficulty using the scores is useful for preoperative prediction of which
patients will have difficulties in gallbladder dissection and the conversion to
OC in LC. Our results suggest that the consideration of technical difficulties is
important for conducting safe operations with avoiding intraoperative
complications.
PMID- 10773147
TI - Importance of the control of lung recurrence soon after surgery of pulmonary
metastases.
AB - PURPOSE: In this study, we investigated factors that determined prognosis in
patients who underwent surgery for metastatic lung tumors, focusing on early
relapse of metastatic lung lesions after surgery, and considered countermeasures
for improving long-term results based on this study. PATIENTS: This study was
performed in patients with metastatic lung tumors who underwent surgery during
the 22 years after November 1975 in this department. RESULTS: The 1-year, 3-year,
and 5-year survival rates in all patients were 70%, 42%, and 37%, respectively.
On comparison among the groups, there were no significant differences by gender,
age, organ with the primary lesion, disease-free interval, number of metastases,
or surgical procedure. However, prognosis was significantly poorer in patients
with recurrent metastatic lung lesions. Prognosis was especially poor in patients
with recurrence within 6 months after pneumonectomy, and this was an important
factor that worsened the surgical results. CONCLUSIONS: As the mechanism of early
recurrence of lung metastasis after surgery for metastatic lung tumor, multiple
micrometastases (dormancy) that cannot be detected during surgery for metastatic
lung tumor may be present in the lung. Establishment of a method of controlling
an increase in dormant metastasis may lead to improvement of surgical results of
metastatic lung tumors.
PMID- 10773148
TI - Treatment of vaginal vault prolapse with abdominal sacral colpopexy using prolene
mesh.
AB - BACKGROUND: We report our experience of abdominal sacral colpopexy (ASC) with a
prolene mesh in women with total vaginal vault prolapse. MATERIALS AND METHODS:
From 1994 to 1997, 15 patients (average age 57 years), underwent ASC. All the
patients suffered from a serious vaginal vault prolapse. Eight of them also had a
uterine prolapse. Seven patients had already been operated on for hysterectomy (5
vaginal, 2 abdominal), and 4 of them had already undergone an operation for
urinary incontinence (3 Raz, 1 Burch). In 6 cases ASC was associated with a
colposuspension in accordance with Burch. Average follow-up was 20 months.
RESULTS: All the patients carried a bladder catheter for 4 to 12 days (mean 5).
The 11 patients who were sexually active began having normal sexual intercourse
again. Neither relapses of the treated prolapses nor infection or rejections of
the prostheses occurred. In 1 patient frequent micturition unresponsive to
anticholinergics persisted. Four patients presented with hypogastric "sense of
heaviness," with no clinical evidence of any pathology. CONCLUSION: ASC with a
prolene net is confirmed as the most valid technique, with no complications, in
the treatment of total vaginal vault prolapse, above all when there is also the
need for other operations via the abdomen at the same time (colposuspension,
culdoplasty, and so forth), or when the vagina is too short to fix the
sacrospinal ligament transvaginally.
PMID- 10773149
TI - The significance of sinistral portal hypertension complicating chronic
pancreatitis.
AB - BACKGROUND: Sinistral portal hypertension, a localized (left-sided) form of
portal hypertension may complicate chronic pancreatitis as a result of splenic
vein thrombosis/obstruction. AIM: To determine appropriate surgical strategy for
patients with splenic vein thrombosis/obstruction secondary to chronic
pancreatitis. METHODS: We reviewed our experience with operative management of
484 consecutive patients with histologically documented chronic pancreatitis
treated between 1976 and 1997. The diagnosis of sinistral portal hypertension was
based on clinical presentation, preoperative endoscopic and radiographic imaging,
and operative findings. "Symptomatic," herein defined, denotes those patients
with sinistral hypertension and either gastrointestinal bleeding or
hypersplenism. "Asymptomatic" patients were those with sinistral hypertension
alone. RESULTS: Sinistral portal hypertension was present in 34 of the 484
patients (7%). Gastric or gastroesophageal varices were confirmed in 12 patients
(35%), of whom 6 had variceal bleeding and 4 had hypersplenism (25%). All
symptomatic patients were treated by splenectomy alone or in conjunction with
distal pancreatectomy. Splenectomy at the time of pancreatectomy for primary
pancreatic symptoms was also performed in 15 patients with (asymptomatic)
sinistral portal hypertension. None of the 23 patients who had splenectomy rebled
in mean follow-up of 4.8 years. In contrast, 1 of the 11 patients with
asymptomatic sinistral portal hypertension who underwent pancreatic surgery
without splenectomy died of later variceal bleeding 3 years after lateral
pancreatojejunostomy. CONCLUSIONS: Symptomatic sinistral portal hypertension is
best treated by splenectomy. Concomitant splenectomy should be strongly
considered in patients undergoing operative treatment of symptomatic chronic
pancreatitis if sinistral portal hypertension and gastroesophageal varices are
also present.
PMID- 10773150
TI - The cut-closed-reconnected Roux loop.
AB - BACKGROUND: Motility disturbances in the Roux loop can negatively influence the
outcome of reflux gastritis; the uncut Roux loop does not have these
disadvantages, but is less suitable for clinical application because of staple
dehiscence. The reported "cut-closed-reconnected" Roux loop has the same
physiological starting points as the uncut Roux loop, but a difference is an
extra closure at the site of the seromuscular level. METHOD: The technique of the
cut-closed-reconnected Roux loop is described. RESULTS: After 1 year, the
clinical findings in 8 patients were as follows: 1 patient free of symptoms, 4
with gastric pain, 2 patients vomited (1 bilious), and 1 felt fullness.
CONCLUSION: Dehiscence of the closure could not be demonstrated by endoscopy,
barium contrast roentgenography, and HIDA scan.
PMID- 10773151
TI - Assessment of a surgery clerkship's performance evaluation system.
AB - BACKGROUND: This study was designed to examine the validity of a surgery
clerkship's performance evaluation system. The study also assessed faculty
members' confidence in how clerks are evaluated and promotion decisions made.
METHODS: Student files from five classes (n = 339) were analyzed. A 25-item
published survey designed to study faculty perceptions of a student evaluation
system was distributed. Chi-square tests of independence and descriptive
statistics were used. RESULTS: Faculty survey results showed faculty perceptions
of strengths and weaknesses in the evaluation system. Significant relationships
were found with prior performance indicators and clerkship performance yielding
evidence of concurrent and predictive validity. CONCLUSIONS: Findings provide
guidance for enhancing how clerks are evaluated as well as specific profiles of
students who may need special attention or additional challenges during the
surgery clerkship. This study provides a model for other clerkships to assess
their student evaluations systems.
PMID- 10773152
TI - The role of the community teaching hospital in surgical undergraduate education.
AB - BACKGROUND: Significant changes in surgical practice have resulted in a
reexamination of surgical undergraduate education. The increasing emphasis toward
ambulatory procedures positions the community hospital as an excellent
alternative site for surgical education. This study compares the quality of one
medical school's surgical education at a principal teaching hospital to that of
affiliated teaching hospitals. METHODS: Surgical undergraduate education offered
through four programs was evaluated for 1993 to 1997. Students' performance was
objectively rated by the National Board Examination in surgery, an oral
examination, and a clinical appraisal. A subjective appraisal was determined via
students' clerkship evaluation. RESULTS: There was a significant difference (P
<0.01) in National Board Examination scores and clerkship evaluations that
favored some affiliated teaching hospitals over the principal teaching hospital.
CONCLUSION: The quality of surgical undergraduate education, documented by
objective testing and subjective perception, indicated that the education
obtained at the affiliated hospitals was at least equivalent to the principal
teaching hospital.
PMID- 10773154
TI - Biliary indocyanine green excretion as a predictor of hepatic adenosine
triphosphate levels in patients with obstructive jaundice.
AB - BACKGROUND: Correlation of the hepatic adenosine triphosphate (ATP) level with
indocyanine green (ICG) excretion into bile was examined in patients with
obstructive jaundice after the relief of hyperbilirubinemia by preoperative
percutaneous transhepatic biliary drainage (PTBD). METHODS: Patients with
complete bile duct obstruction, the mean serum total bilirubin concentration
being 13.6 +/- 8.5 (SD) mg/dL, underwent PTBD prior to surgery. Within a few days
before surgery when the mean serum total bilirubin level decreased to 1.2 mg/dL,
ICG (0.5 mg/kg) was intravenously injected, and the whole bile was collected at 1
hour intervals for 5 hours. The ICG concentration in bile, bile flow rate, amount
of ICG excreted in bile, and biliary ICG excretion rate as percentage of the
injected dose were determined. At the time of surgery, a small liver tissue
sample was obtained immediately after laparotomy without any ischemic procedures,
and ATP concentrations were determined. Results of hepatic ATP levels were
correlated with laboratory and clinical determinations. RESULTS: The bile flow
rate was essentially constant during the 5-hour period, the mean value being 21
mL/hour. The ICG concentrations in bile gradually increased, reached the maximal
level in 3 hour, and declined thereafter. The biliary ICG excretion rate for 5
hours was 40% +/- 18% of its injected dose. The biliary ICG excretion rate and
amount of ICG excreted in bile for 5 hours significantly (P <0.05) correlated
with the hepatic ATP level. The decline index of serum bilirubin during PTBD was
also correlated with the hepatic ATP level. The serum ICG retention rate, bile
flow rate, maximal ICG concentration in bile, and other liver function tests
including serum albumin and cholinesterase levels did not correlate with the
hepatic ATP level. CONCLUSIONS: Both the amount of and excretion rate of ICG in
bile reflect the hepatic ATP level. Determination of biliary ICG excretion
contributes to precise evaluation of hepatic energy status before surgery in
patients with obstructive jaundice.
PMID- 10773153
TI - The effects of various organ preservation solutions on hepatocyte membrane
potentials, intracellular calcium concentrations, and outcome following liver
transplantation.
AB - BACKGROUND: Hepatocyte membrane potential differences (PDs) may be altered by the
preservation solutions used in liver transplantation. Such alterations could
impact on the survival of the donor liver, extent of biochemical injury, and flux
of important ionic compounds. The purpose of the present study was to document
these outcomes in the presence of four different preservation solutions. METHODS:
Livers of adult male Sprague-Dawley rats (N = 3 to 4 per group) were impaled with
intracellular microelectrodes prior to and at various time periods for 6 hours
following complete hepatic resection. Just prior to resection, each liver was
perfused with preservation solutions associated with high (normal saline [NS]),
moderate (Euro-Collins [EC]), and low (University of Wisconsin solution [UW])
risks of reperfusion injury. RESULTS: Baseline (in situ) PDs were similar in all
groups (-37 +/- 4 mV, mean +/- SD). Ten minutes postresection, hepatic PDs were
as follows: NS, -23.8 +/- 3.5 mV; EC, -11.4 +/- 0.4 mV; and UW, -8.7 +/- 0.3 mV
(P <0.01 for all groups). Maximum depolarization occurred at 6 hours
postresection (NS, -8.1 +/- 1.1 mV; EC, -7.7 +/- 1.3 mV; and UW, -8.6 +/- 1.0
mV). To determine whether these changes are of pathophysiologic importance, the
NS solution was modified (addition of 0.1% ethanol) to achieve similar PD changes
as those observed with UW. Liver transplants were then performed where the donor
livers had been perfused and preserved for 6 hours with either NS or the modified
NS (MNS) solution. Posttransplant (10 day) survival was 1 of 6 (17%) in the NS
group and 4 of 6 (67%) in the MNS group (P <0.05). Regarding the effects of PD
changes on ionic flux, intracellular calcium levels were documented for up to 4
hours by fluorescence video microscopy using Fura-2 in isolated hepatocytes
exposed to NS, UW, and MNS solutions. Intracellular calcium levels were similar
in all solutions at each time point studied. CONCLUSIONS: The results of this
study indicate that hepatocytes undergo prompt and marked depolarization
following hepatic resection, and the extent of the depolarization correlates with
survival following transplantation.
PMID- 10773155
TI - First photosystem II crystals capable of water oxidation.
AB - Oxygen evolution and proton release of crystallised photosystem II core complexes
isolated from Synechococcus elongatus were measured. The yields show that the
crystals themselves are capable of highly active water oxidation. This opens the
possibility for the structural analysis of the outstanding water-oxidising
apparatus.
PMID- 10773156
TI - Interaction of photosynthetic pigments with various organic solvents 2.
Application of magnetic circular dichroism to bacteriochlorophyll a and light
harvesting complex 1.
AB - Magnetic circular dichroism (MCD) and absorption spectra of metal bacteriochlorin
complexes have been measured on bacteriochlorophyll (BChl) a in various solvents
and different forms of light-harvesting complexes 1 (LH1 complexes). In
hydrophilic organic solvents, the MCD intensity of the Q(y)(0-0) transition of
BChl a was sensitive to the wavelength of absorption maximum of Q(x)(0-0), and
the ratio of MCD Q(y)(0-0) intensity to the dipole strength (B/D) was inversely
proportional to the difference in energy between the Q(x)(0-0) and Q(y)(0-0). The
similar correlation has been observed in metal chlorin derivatives as previously
reported. The correlation depends on the coordination number of the Mg atom in
BChl a and the molecules ligating to it. In a hydrophobic solvent such as carbon
tetrachloride (CCl(4)), however, the correlation did not hold because of the
existence of aggregates. Hence, the correlation between the values of B/D and the
energy difference can be used to estimate the type and number of the molecules
ligated to the Mg atom and to disclose the existence of aggregated pigments. We
further apply the correlation to the LH 1 complex treated with n-octyl beta-D
glucopyranoside.
PMID- 10773157
TI - Morphological and functional changes of mitochondria from density separated trout
erythrocytes.
AB - Density separated trout erythrocytes, using a discontinuous Percoll gradient,
yielded three distinct subfractions (top, middle and bottom) since older cells
are characterized by increasing density. Cells from each subfraction were
incubated with mitochondria-specific fluorescent probe Mitotracker and JC-1 in
order to assess mitochondrial mass and membrane potential by means of
cytofluorimetric analysis, confocal microscopy and subsequent computer-aided
image analysis allowing a detailed investigation at single cell level. Both
cytofluorimetric data and image analysis revealed changes in size and
redistribution of mitochondria starting from the light fraction to the bottom. In
particular in young erythrocytes small mitochondria were detected localized
exclusively around the nucleus in a crown-like shape, the middle fraction
revealed enlarged mitochondria partially scattered throughout the cytosol,
whereas the last fraction represented again mitochondria with reduced size being
distinctly dispersed throughout the cytosol in the cells. Concerning membrane
potential considerations, our study revealed a dramatic decrease of DeltaPsi(m)
in the bottom layer cell mitochondria compared to the top and unusual membrane
potential increase of a subpopulation of enlarged mitochondria. DeltapH was also
investigated in the three fractions by pretreating the cells with nigericin,
allowing to confirm a mitochondrial energetic impairment in older cells.
PMID- 10773158
TI - Salt shock-inducible photosystem I cyclic electron transfer in Synechocystis
PCC6803 relies on binding of ferredoxin:NADP(+) reductase to the thylakoid
membranes via its CpcD phycobilisome-linker homologous N-terminal domain.
AB - Relative to ferredoxin:NADP(+) reductase (FNR) from chloroplasts, the comparable
enzyme in cyanobacteria contains an additional 9 kDa domain at its amino
terminus. The domain is homologous to the phycocyanin associated linker
polypeptide CpcD of the light harvesting phycobilisome antennae. The phenotypic
consequences of the genetic removal of this domain from the petH gene, which
encodes FNR, have been studied in Synechocystis PCC 6803. The in frame deletion
of 75 residues at the amino-terminus, rendered chloroplast length FNR enzyme with
normal functionality in linear photosynthetic electron transfer. Salt shock
correlated with increased abundance of petH mRNA in the wild-type and mutant
alike. The truncation stopped salt stress-inducible increase of Photosystem I
dependent cyclic electron flow. Both photoacoustic determination of the storage
of energy from Photosystem I specific far-red light, and the re-reduction
kinetics of P700(+), suggest lack of function of the truncated FNR in the
plastoquinone-cytochrome b(6)f complex reductase step of the PS I-dependent
cyclic electron transfer chain. Independent gold-immunodecoration studies and
analysis of FNR distribution through activity staining after native
polyacrylamide gelelectrophoresis showed that association of FNR with the
thylakoid membranes of Synechocystis PCC 6803 requires the presence of the
extended amino-terminal domain of the enzyme. The truncated DeltapetH gene was
also transformed into a NAD(P)H dehydrogenase (NDH1) deficient mutant of
Synechocystis PCC 6803 (strain M55) (T. Ogawa, Proc. Natl. Acad. Sci. USA 88
(1991) 4275-4279). Phenotypic characterisation of the double mutant supported our
conclusion that both the NAD(P)H dehydrogenase complex and FNR contribute
independently to the quinone cytochrome b(6)f reductase step in PS I-dependent
cyclic electron transfer. The distribution, binding properties and function of
FNR in the model cyanobacterium Synechocystis PCC 6803 will be discussed.
PMID- 10773159
TI - Comparative study of the g=4.1 EPR signals in the S(2) state of photosystem II.
AB - The Mn(4) complex which is involved in water oxidation in photosystem II is known
to exhibit three types of EPR signals in the S(2) state, one of the five redox
states of the enzyme cycle: a multiline signal (spin 1/2), signals at g5 (spin
5/2) and a signal at g=4.1 (or g=4.25). The g=4.1 signal could be generated under
two distinct sets of conditions: either by illumination at room temperature or at
200 K in certain experimental conditions (g4(S) signal) or by near-infrared
illumination between approximately 77 and approximately 160 K of the S(2)
multiline state (g4(IR) signal). The two g=4.1 signals arise from states which
have quite different stability in terms of temperature. In the present work we
have compared these two signals in order to test if they originate from the same
or from different chemical origins. The microwave power saturation properties of
the two signals measured at 4.2 K were found to be virtually identical. Their
temperature dependencies measured at non-saturating powers were also identical.
The presence of Curie law behavior for the g4(S) and g4(IR) signals indicates
that the states responsible for both signals are ground states. The orientation
dependence, anisotropy and resolved hyperfine structure of the two g4 signals
were also found to be virtually indistinguishable. We have been unable to confirm
the behavior reported earlier indicating that the g4(S) signal is an excited
state, nor were we able to confirm the presence of signal from a higher excited
state in samples containing the g4(S), nor a radical signal in samples containing
the g4(IR). These findings are best interpreted assuming that the two signals
have a common origin i.e. a spin 5/2 ground state arising from a magnetically
coupled Mn-cluster of 4 Mn ions.
PMID- 10773160
TI - pH-dependent characteristics of Y(Z) radical in Ca(2+)-depleted photosystem II
studied by CW-EPR and pulsed ENDOR.
AB - The Y(Z)-tyrosine radical was trapped by freezing immediately after illumination
in Ca(2+)-depleted Photosystem II (PS II) membranes and the pH-dependent
characteristics of the radical were investigated using CW-EPR and pulsed ENDOR.
The spectrum of the Y*(Z) radical trapped in the Y*(Z)S(1) state at pH 5.5 was
cation-like as reported in Mn-depleted PS II (H. Mino et al., Spectrochim. Acta A
53 (1997) 1465-1483). By illuminating the PS II-retaining S(2) state, the Y*(Z)
radical and a broad doublet signal formed in the g approximately 2 region were
trapped concomitantly. The spectrum of the trapped Y*(Z) radical in the Y*(Z)S(2)
state was cation-like at pH 5.5 but the pulsed ENDOR measurements reveals the
involvement of the neutral Y*(Z) radical in the doublet signal. At pH 7.0, the
resulting Y*(Z) signal was the mixture of the cation-like and neutral radical
spectra, and considerably different from the neutral radical found in Mn-depleted
PS II. pH-Dependent changes in the properties of the Y*(Z) radical are discussed
in relation to the redox events occurring in Ca(2+)-depleted PS II.
PMID- 10773161
TI - Mitochondrial protonophoric activity induced by a thyromimetic fatty acid
analogue.
AB - Calcium-dependent uncoupling of liver mitochondrial oxidative phosphorylation by
a non-metabolizable long chain fatty acyl analogue was compared with uncoupling
induced by in vivo thyroid hormone treatment. beta,beta'-Methyl-substituted
hexadecane alpha, omega-dioic acid (Medica 16) is reported here to induce a
saturable 20-30% decrease in liver mitochondrial DeltaPsi, DeltapH and
protonmotive force which proceeds in the presence of added Ca(2+) to cyclosporin
A-sensitive mitochondrial permeabilization. Ca(2+)-dependent uncoupling by Medica
16 was accompanied by atractylate-enhanced, bongkrekic-inhibited activation of
mitochondrial Ca(2+) efflux. The direct mitochondrial effect exerted in vitro by
Medica 16 is similar to that induced by in vivo thyroid hormone treatment. Hence,
the thyromimetic protonophoric activity of Medica 16 and the uncoupling activity
of TH converge onto components of the mitochondrial permeabilization transition
pore.
PMID- 10773162
TI - Rapid spectrophotometric method for quantitation of cytochrome c release from
isolated mitochondria or permeabilized cells revisited.
AB - This paper recalls the earlier work by Keilin, Margoliash and others at the
beginning of the 20th century and shows how their results can be used for the
rapid solution of new problems of modern science. It describes a rapid and simple
spectrophotometric method for quantitative determination of cytochrome c release
from isolated mitochondria or permeabilized cells induced by proapoptotic
proteins. For this, the Soret (gamma) peak at 414 nm in the spectrum of
cytochrome c is used. The results of spectrophotometric assay of cytochrome c
release are in accord with those of oxygraphic determination of cytochrome c
dependent respiration of isolated mitochondria and permeabilized cardiomyocytes.
PMID- 10773163
TI - Molecular cloning of rat brain mitochondrial carrier protein-1 cDNA and its up
regulation during postnatal development.
AB - Brain mitochondrial carrier protein-1 (BMCP1), a new member of the mitochondrial
uncoupling carrier, has been shown to be expressed predominantly in the brain of
the mice and humans. We cloned rat BMCP1 cDNA and investigated its mRNA level
during postnatal development and under various metabolic conditions. The
nucleotide sequence of the cDNA revealed that rat BMCP1 protein was composed of
322 amino acid residues, and was 99 and 96% identical to the mouse and human
proteins and 29, 33 and 35% identical to rat uncoupling protein (UCP) 1, UCP2 and
UCP3, respectively. The molecular weight was predicted to be 36017 Da and the
protein of this size was detectable when the cDNA was expressed in vitro. Using
Northern blot analysis, the corresponding mRNA, approximately 1.8-kb in size, was
found expressed predominantly in the cerebrum, cerebellum and hypothalamus. A
unique developmental pattern was identified in the brain, where BMCP1 expression
was low in their fetal life, but significantly elevated in the first postnatal
week. Thereafter BMCP1 mRNA was maintained to be gradually increased. In 48-h
fasted or insulin-induced hypoglycemic rats, BMCP1 mRNA expression in the
hypothalamus slightly, but significantly, decreased compared with that in their
appropriate controls. The present results indicate that BMCP1 may be involved in
pathogenesis of mitochondrial dysfunction in neurons induced by aging or
neurodegenerative disorders, and perhaps in energy balance in the brain.
PMID- 10773164
TI - Organization of the pigment molecules in the chlorophyll a/b/c containing alga
Mantoniella squamata (Prasinophyceae) studied by means of absorption, circular
and linear dichroism spectroscopy.
AB - In order to obtain information on the organization of the pigment molecules in
chlorophyll (Chl) a/b/c-containing organisms, we have carried out circular
dichroism (CD), linear dichroism (LD) and absorption spectroscopic measurements
on intact cells, isolated thylakoids and purified light-harvesting complexes
(LHCs) of the prasinophycean alga Mantoniella squamata. The CD spectra of the
intact cells and isolated thylakoids were predominated by the excitonic bands of
the Chl a/b/c LHC. However, some anomalous bands indicated the existence of
chiral macrodomains, which could be correlated with the multilayered membrane
system in the intact cells. In the red, the thylakoid membranes and the LHC
exhibited a well-discernible CD band originating from Chl c, but otherwise the CD
spectra were similar to that of non-aggregated LHC II, the main Chl a/b LHC in
higher plants. In the Soret region, however, an unusually intense (+) 441 nm band
was observed, which was accompanied by negative bands between 465 and 510 nm. It
is proposed that these bands originate from intense excitonic interactions
between Chl a and carotenoid molecules. LD measurements revealed that the Q(Y)
dipoles of Chl a in Mantoniella thylakoids are preferentially oriented in the
plane of the membrane, with orientation angles tilting out more at shorter than
at longer wavelengths (9 degrees at 677 nm, 20 degrees at 670 nm and 26 degrees
at 662 nm); the Q(Y) dipole of Chl c was found to be oriented at 29 degrees with
respect to the membrane plane. These data and the LD spectrum of the LHC, apart
from the presence of Chl c, suggest an orientation pattern of dipoles similar to
those of higher plant thylakoids and LHC II. However, the tendency of the Q(Y)
dipoles of Chl b to lie preferentially in the plane of the membrane (23 degrees
at 653 nm and 30 degrees at 646 nm) is markedly different from the orientation
pattern in higher plant membranes and LHC II. Hence, our CD and LD data show that
the molecular organization of the Chl a/b/c LHC, despite evident similarities,
differs significantly from that of LHC II.
PMID- 10773165
TI - Oxidative phosphorylation supported by an alternative respiratory pathway in
mitochondria from Euglena.
AB - The effect of antimycin, myxothiazol, 2-heptyl-4-hydroxyquinoline-N-oxide,
stigmatellin and cyanide on respiration, ATP synthesis, cytochrome c reductase,
and membrane potential in mitochondria isolated from dark-grown Euglena cells was
determined. With L-lactate as substrate, ATP synthesis was partially inhibited by
antimycin, but the other four inhibitors completely abolished the process.
Cyanide also inhibited the antimycin-resistant ATP synthesis. Membrane potential
was collapsed (<60 mV) by cyanide and stigmatellin. However, in the presence of
antimycin, a H(+)60 mV) that sufficed to drive ATP synthesis remained. Cytochrome
c reductase, with L-lactate as donor, was diminished by antimycin and
myxothiazol. Cytochrome bc(1) complex activity was fully inhibited by antimycin,
but it was resistant to myxothiazol. Stigmatellin inhibited both L-lactate
dependent cytochrome c reductase and cytochrome bc(1) complex activities.
Respiration was partially inhibited by the five inhibitors. The cyanide-resistant
respiration was strongly inhibited by diphenylamine, n-propyl-gallate,
salicylhydroxamic acid and disulfiram. Based on these results, a model of the
respiratory chain of Euglena mitochondria is proposed, in which a quinol
cytochrome c oxidoreductase resistant to antimycin, and a quinol oxidase
resistant to antimycin and cyanide are included.
PMID- 10773166
TI - Proton translocating nicotinamide nucleotide transhydrogenase from E. coli.
Mechanism of action deduced from its structural and catalytic properties.
AB - Transhydrogenase couples the stereospecific and reversible transfer of hydride
equivalents from NADH to NADP(+) to the translocation of proton across the inner
membrane in mitochondria and the cytoplasmic membrane in bacteria. Like all
transhydrogenases, the Escherichia coli enzyme is composed of three domains.
Domains I and III protrude from the membrane and contain the binding site for
NAD(H) and NADP(H), respectively. Domain II spans the membrane and constitutes at
least partly the proton translocating pathway. Three-dimensional models of the
hydrophilic domains I and III deduced from crystallographic and NMR data and a
new topology of domain II are presented. The new information obtained from the
structures and the numerous mutation studies strengthen the proposition of a
binding change mechanism, as a way to couple the reduction of NADP(+) by NADH to
proton translocation and occurring mainly at the level of the NADP(H) binding
site.
PMID- 10773167
TI - Photosystem II fluorescence quenching in the cyanobacterium Synechocystis PCC
6803: involvement of two different mechanisms.
AB - The structural changes associated to non-photochemical quenching in cyanobacteria
is still a matter of discussion. The role of phycobilisome and/or photosystem
mobility in this mechanism is a point of interest to be elucidated. Changes in
photosystem II fluorescence induced by different quality of illumination (state
transitions) or by strong light were characterized at different temperatures in
wild-type and mutant cells, that lacked polyunsaturated fatty acids, of the
cyanobacterium Synechocystis PCC 6803. The amplitude and the rate of state
transitions decreased by lowering temperature in both strains. Our results
support the hypothesis that a movement of membrane complexes and/or changes in
the oligomerization state of these complexes are involved in the mechanism of
state transitions. The quenching induced by strong blue light which was not
associated to D1 damage and photoinhibition, did not depend on temperature or on
the membrane state. Thus, the mechanism involved in the formation of this type of
quenching seems to be unrelated to the movement of membrane complexes. Our
results strongly support the idea that the mechanism involved in the fluorescence
quenching induced by light 2 is different from that involved in strong blue light
induced quenching.
PMID- 10773168
TI - Role of two forms of the D1 protein in the recovery from photoinhibition of
photosystem II in the cyanobacterium Synechococcus PCC 7942.
AB - The study of turnover of two distinct forms of the photosystem II (PSII) D1
protein in cells of the cyanobacterium Synechococcus PCC 7942 showed that the
'high-light' form D1:2 is degraded significantly faster at 500 microE m(-2) s(-1)
as compared with 50 microE m(-2) s(-1) while the degradation rates of the 'low
light' form D1:1 under low and high irradiance are not substantially different.
Consequently, the D1:1 turnover does not match photoinactivation of PSII under
increased irradiance and therefore the cells containing this D1 form exhibit a
decrease in the PSII activity. Monitoring of the content of each D1 form during a
recovery from growth-temperature photoinhibition showed a good correlation
between the synthesis of D1:2 and restoration of the PSII activity. In contrast,
when photoinhibitory treatment was conducted at low temperature, a fast recovery
was not accompanied by the D1:2 accumulation. The data suggest that
photoinactivation at growth temperature results in a modification of PSII that
inhibits insertion of D1:1 and, therefore, for restoration of the photochemical
activity in the photoinactivated PSII complexes the D1:2 synthesis is needed.
This may represent the primary reason for the requirement of psbAII/psbAIII
expression under increased irradiance.
PMID- 10773169
TI - High-field EPR studies of the structure and conformational changes of site
directed spin labeled bacteriorhodopsin.
AB - Cw and pulsed high-field EPR (95 GHz, 3.4 T) are performed on site-directed spin
labeled bacteriorhodopsin (BR) mutants. The enhanced Zeeman splitting leads to
spectra with resolved g-tensor components of the nitroxide spin label. The g(xx)
component shift determined for 10 spin labels located in the cytoplasmic loop
region and in the protein interior along the BR proton channel reveals a maximum
close to position 46 between the proton donor D96 and the retinal. A plot of
g(xx) versus A(zz) of the nitrogen discloses grouping of 12 spin labeled sites in
protic and aprotic sites. Spin labels at positions 46, 167 and 171 show the
aprotic character of the cytoplasmic moiety of the proton channel whereas
nitroxides at positions 53, 194 and 129 reveal the protic environment in the
extracellular channel. The enhanced sensitivity of high-field EPR with respect to
anisotropic reorientational motion of nitroxides allows the characterization of
different motional modes for spin labels bound to positions 167 and 170. The
motional restriction of the nitroxide at position 167 of the double mutant
V167C/D96N is decreased in the M(N) photo-intermediate. An outward shift of the
cytoplasmic moiety of helix F in the M(N) intermediate would account for the high
field EPR results and is in agreement with diffraction and recent X-band EPR
data.
PMID- 10773170
TI - Specific elevation of transcript levels of particular protein subtypes induced in
brown adipose tissue by cold exposure.
AB - To understand the difference in metabolic flow in rat brown adipose tissue (BAT)
from that in white adipose tissue (WAT) at the molecular level, we examined the
steady-state transcript levels of 39 proteins in both adipose tissues with and
without cold exposure by Northern blot analysis. In addition to the transcript
levels of uncoupling protein isoforms, those of proteins involved in the
transport and catabolism of fatty acids and glucose in BAT were elevated by cold
exposure, suggesting the stimulation of utilization of fatty acids and glucose as
fuels in BAT. As to these changes, the muscle-type subtypes were remarkable; and
therefore, they were suggested to be responsible for the cold exposure-induced
acceleration of energy expenditure in BAT. Furthermore, of the isoforms of beta
adrenergic receptor (beta-AR) and CCAAT enhancer binding protein (C/EBP),
transcript levels of beta(1)-AR and C/EBPbeta in BAT were increased by the cold
exposure. Possible roles of these proteins in energy metabolism in BAT were
discussed.
PMID- 10773172
TI - The use of placebos in randomized clinical trials of mood disorders: well
justified, but improvements in design are indicated.
PMID- 10773171
TI - The comparative content of the mitochondrial phosphoglyceroyl-ATP-containing
polymer, purinogen, in rat tissues.
AB - Here, we describe an assay for the tissue content of purinogen, a highly
phosphorylated labile polymer containing ATP and phosphoglycerate found in the
mitochondrial intermembrane space. We report the purinogen content (as adenine
nucleotide equivalents) of rat heart and, for the first time, of rat liver,
kidney, brain and mixed skeletal muscle. The findings show that purinogen
contains very significant proportions of cell adenine nucleotides ranging from
25% of the free pool in brain and skeletal muscle to 135% of it in kidney. The
evidence that purinogen may form a controlled intracellular reservoir of
inorganic phosphate is briefly discussed.
PMID- 10773173
TI - An NIMH perspective on the use of placebos. National Institute of Mental Health.
PMID- 10773174
TI - The national depressive and manic-depressive association: an introduction
PMID- 10773175
TI - Placebos, active control groups, and the unpredictability paradox.
AB - Randomized controlled trials often rely on placebo control groups to estimate
treatment differences. Recently, the high frequency of negative trials and
ethical concerns surrounding the use of placebos have brought the use of placebo
control groups under increased scrutiny. Although many psychiatric researchers
argue that placebo control groups should be replaced with active control groups,
we argue that preferential use of active control groups will not reduce the
number of negative trials. Rather, we suggest that some of the variation and
contradiction in randomized controlled trial results arises from the clinical
heterogeneity of patient characteristics, disease severity, comorbidity, and
cotherapies. Further characterization of patient heterogeneity, through improved
disease taxonomies, severity indices, and classification of comorbid diseases,
will serve to reduce clinical heterogeneity among patients and reduce the number
of negative trials produced by wide variation in treatment and control response
rates.
PMID- 10773176
TI - The use of placebo control groups in the assessment of psychiatric drugs: an
historical context.
AB - The reliable evaluation of treatments intended for the management of psychiatric
illness would not be possible without the use of placebo. Other types of control
groups can provide useful information, but none are capable of adducing a finding
as compelling and unambiguously interpretable as a statistically significant drug
placebo difference. Its epistemological advantage notwithstanding, the ethicality
of employing a placebo control group has been increasingly challenged in recent
years. Many who object to the use of placebo on ethical grounds assume,
incorrectly, that there are fungible alternatives to the use of placebo in the
assessment of psychotropic drugs. This essay attempts to explain, within an
historical context, not only why placebo is irreplaceable, but why it is often so
difficult to communicate its advantages to those unfamiliar with the
epistemological aims and methods of controlled clinical trials.
PMID- 10773177
TI - Placebo-controlled trials in psychiatric research: an ethical perspective.
AB - The placebo-controlled trial is widely regarded as the gold standard for testing
the efficacy of new treatments; however, this research design is subject to
ethical controversy, especially when standard treatments of proven efficacy
exist. After examining regulatory standards and ethical codes relevant to placebo
controlled trials, I offer a critique of arguments against the use of placebo
control groups in psychiatric research. An absolute ethical prohibition of
placebo-controlled trials in psychiatric disorders for which standard, effective
treatments exist is rejected because it is based on a flawed conception of
research ethics, ignores important contextual factors characteristic of
psychiatric research, and could lead to the approval and use of new medications
that appear equivalent in efficacy to standard treatments but may be no more
effective than placebos. Four standards governing the ethical use of placebos in
psychiatric clinical trials are explicated: 1) placebo-controlled trials should
have scientific and clinical merit; 2) risks should be minimized and justified by
the anticipated benefits of generating clinically relevant scientific knowledge
and the expected benefits, if any, to individual patient volunteers; 3) patient
volunteers should give informed consent; and 4) investigators should offer short
term treatment optimization to patient volunteers after completion of research
participation.
PMID- 10773178
TI - Placebo control groups in randomized treatment trials: a statistician's
perspective.
AB - Because a statistical tie between standard treatment and an innovation is
uninterpretable, most trials intended to demonstrate efficacy of innovations in
psychopharmacology employ a placebo control group, despite the existence of
standard medications for many disorders. In this review I consider the
statistical issues that inform the ethics of the decision to use a placebo
condition and make the following points: 1) the investigator is relying on the
assumption that the effects of delayed standard treatment are neither long
lasting nor harmful; 2) the usual practice of truncating follow-up when a patient
ceases to adhere to a study treatment makes it difficult to empirically test that
assumption; 3) placebo control trials often suffer from methodological weaknesses
(including nonrandom truncation) that reduce their inferential power; 4) these
subtleties place a substantial burden on the informed consent process; 5)
alternative designs are available but not well explored, due to the dominant role
of "regulatory" trial methodology; and 6) researchers should consider other goals
besides helping to introduce another treatment that improves on placebos but not
the standard treatment.
PMID- 10773179
TI - Efficient trial designs to reduce placebo requirements.
AB - This brief discussion summarizes possible trial design changes that could be
utilized to reduce the number of subjects exposed to ineffective treatment--in
this case placebo; however, these designs are fairly complex and have not been
implemented sufficiently to judge their utility. Clearly, such studies are
essential before embarking on these paradigms as a primary method for assessing
antidepressant efficacy.
PMID- 10773180
TI - Special issues in trial design and use of placebo in bipolar illness.
PMID- 10773181
TI - Are drug and placebo effects in depression additive?
PMID- 10773182
TI - Use of placebo control groups in evaluating efficacy of treatment of unipolar
major depression.
AB - Double-blind, random-assignment placebo-controlled trials are routinely used in
evaluating efficacy of potential antidepressant agents. In recent years concern
has risen that placebo response rates in unipolar depression are too high, and
this has eroded confidence in both old and new agents. At the same time, the use
of placebos has been questioned by patients and their advocates. We review
factors that have been commonly explored as associated with placebo response
(e.g., length of episode, severity, subtype), as well as issues in methodology
(e.g., interrater reliability, statistical artifacts). We discuss possible
methods of dealing with the problem of placebo response, emphasizing
reconceptualizing effect sizes to design more powerful single trials and a
systematic sequence of trials to achieve the right answers.
PMID- 10773183
TI - The use of placebos in unipolar major depression: the current status.
PMID- 10773184
TI - Placebo effect in randomized, controlled studies of acute bipolar mania and
depression.
AB - Randomized, double-blind, placebo-controlled, parallel group clinical trials have
been the standard methodology for establishing the efficacy of new treatments for
patients with bipolar disorder in manic, mixed, or depressive episodes. We
examine the placebo response rate in acute treatment trials of acute mania (and
mixed states) and bipolar depression. Also addressed are potential variables
associated with placebo response, strategies to minimize placebo response, the
optimum duration of placebo-controlled acute treatment trials, possible
alternatives to the use of placebo, and the ramifications of these issues with
regard to the design of studies in children, adolescents, and older adults with
bipolar disorder.
PMID- 10773185
TI - Placebo effect in randomized, controlled maintenance studies of patients with
bipolar disorder.
AB - The prevention of mood episodes is an important goal of the maintenance treatment
of patients with bipolar disorder. The rate of relapse on placebo compared with
that on active treatment is an important issue in the design of future clinical
trials of maintenance treatment. We examine the range and time course of placebo
relapse rates in studies of patients with bipolar I disorder. In addition, we
address the potential variables associated with placebo response, strategies to
minimize placebo response, the optimum duration of placebo-controlled maintenance
trials, possible alternatives to placebo control groups, and the impact of these
considerations in maintenance studies of children, adolescents, and older adults
with bipolar disorder.
PMID- 10773186
TI - Penny-wise and pound-foolish: the impact of measurement error on sample size
requirements in clinical trials.
AB - BACKGROUND: Clinical research studies must compensate for measurement error by
increasing the number of subjects that are studied, thereby increasing the
financial costs of research and exposing greater numbers of subjects to study
risks. In this article, we model the relationship between reliability and sample
size requirements and consider the potential tangible cost savings resulting from
the decreased number of subjects needed when reliability of raters is improved or
multiple ratings are used. METHODS: Standard methods are used to model
reliability based on the intraclass correlation coefficient (R) and to perform
power calculations. The impact of multiple raters on reliability for a given
baseline level of reliability is modeled according to the Spearman Brown formula.
RESULTS: Our models demonstrate that meaningful reductions in sample size
requirements are gained from improvements in reliability. For example, improving
reliability from R = .7 to R = .9 will decreases sample size requirements by 22%.
Reliability is improved by training and by the use of the mean of multiple
ratings. For example, if the reliability of a single rating is 0.7, the
reliability of the mean of two ratings will be 0.8. CONCLUSIONS: The costs to
improve reliability either through rater training efforts or use of the mean of
multiple ratings is cost effective because of the consequent reduction in number
of subjects needed. Efforts to improve reliability and thus reduce subject
requirements in a study also may lead to fewer patients bearing the burden of
research participation and to a shortening of the duration of studies.
PMID- 10773187
TI - Enhanced serotonin-mediated responses in the nucleus tractus solitarius of
spontaneously hypertensive rats.
AB - Previous studies have demonstrated that injection of serotonin into the nucleus
tractus solitarius (NTS) elicits hypotension and bradycardia in rats. The present
study sought to further characterize this response and to examine the role of
serotonergic mechanisms in the NTS in cardiovascular regulation in spontaneously
hypertensive (SHR) rats. Injections of picomole amounts of serotonin into the NTS
of chloralose-anesthetized normotensive Sprague-Dawley (S-D) or Wistar-Kyoto
(WKY) rats produced hypotension and bradycardia that were eliminated by prior
injection into the NTS of the selective 5HT(2) antagonist sarpogrelate. Bilateral
injection of sarpogrelate did not alter blood pressure or reflex changes in heart
rate in response to phenylephrine-induced increases in blood pressure or
nitroprusside-induced decreases in blood pressure. In SHR rats, the depressor
response produced by injection of serotonin into the NTS was markedly larger than
in WKY rats, and was larger than depressor responses previously reported for
other excitatory substances injected into the NTS. In SHR rats bilateral
injection of sarpogrelate produced an increase in blood pressure, although it did
not alter baroreceptor-evoked changes in heart rate. These results provide
further support for the hypothesis that stimulation of 5HT(2) receptors in the
NTS contributes to cardiovascular regulation independent of the baroreceptor
reflex. Furthermore, this serotonergic system is altered in SHR rats, apparently
acting tonically to reduce blood pressure.
PMID- 10773188
TI - Differential effects of a dihydropyridine calcium channel antagonist on the
components of ethanol tolerance.
AB - The dihydropyridine calcium channel antagonist, nimodipine, was found to decrease
the extent of tolerance that developed to the ataxic action of ethanol in
experimental designs in which the tolerance was not context-specific, when
ethanol was given by liquid diet. When ethanol was given by injection, so that
cues were present for the effects of ethanol during the chronic treatment,
tolerance to the ataxic actions of ethanol was unaffected. Nimodipine, however,
decreased the tolerance to the hypothermic actions of ethanol, when the ethanol
was given by injection. When the rats were given practice sessions on the motor
task while under the influence of the ethanol, during the chronic treatment,
nimodipine did not affect tolerance to the ataxic actions of ethanol. When
nimodipine was given before the motor task learning and ethanol after the
practice sessions, the tolerance to the ataxic effect of ethanol was increased. A
similar schedule of drug treatment with the NMDA antagonist CGP37849 given before
the practice sessions, and ethanol afterwards, resulted in decreased tolerance to
ethanol. It is suggested that these changes in ethanol tolerance may be explained
by dual actions of nimodipine in, firstly, decreasing the form of tolerance to
ethanol that is not dependent on contextual cues and, secondarily, in increasing
the learning of a motor task.
PMID- 10773189
TI - Droperidol suppresses spontaneous electrical activity in neurons cultured from
ventral midbrain. Implications for neuroleptanesthesia.
AB - Droperidol is used in anesthesia as an antiemetic and as a component in
neuroleptanalgesia. Its mechanism of action is thought to involve dopamine
receptor blockade in the brain. The electrophysiological consequences associated
with this action however, have not been elucidated. In this study we demonstrate
a dose-dependent electrophysiological response to droperidol in central nervous
system (CNS) neurons that express dopamine receptors that is absent in CNS
neurons that do not express dopamine receptors. Primary dissociated cell (PDC)
cultures were prepared from embryonal tissue dissected from ventral mesencephalon
(VM) and spinal cord (SC). VM neurons were used to investigate the
electrophysiological action of droperidol, a dopamine receptor antagonist, since
these cultures contain neurons having dopamine receptors on their surface. SC
neurons were used as a control as they do not express dopamine receptors. Some
dopamine receptors are on dopaminergic neurons and therefore are called
autoreceptors, while others are on nondopaminergic neurons, such as GABA
producing (GABAergic) neurons. All neurons in both PDC cultures were
spontaneously active. The percentage of neurons which spontaneously generated
action potentials was reduced in a dose-dependent manner by droperidol (1 nM-10
microM) only in PDC cultures of VM. Exposure to droperidol had no effect on
neurons from PDC cultures of SC which lack dopamine receptors. Our results
suggest that droperidol modulates the electrophysiological properties of VM
neurons with dopamine receptors possibly through facilitation of inhibitory
interneurons. The reduced activity of VM neurons might contribute to the
antiemetic and/or anesthetic activity of droperidol, since the concentrations of
droperidol used in this study are at clinically relevant concentrations.
PMID- 10773190
TI - Electrophysiological evidence for reciprocal insulo-insular connectivity of
baroreceptor-related neurons.
AB - The recent indications of specialized lateralization of cardiovascular regulation
within the right and left posterior insular cortex of the rat, suggest the
possibility of transcallosal connectivity between these regions. This has not
been previously demonstrated using physiological techniques. Extracellular neural
recordings in 34 urethane anesthetized male Sprague-Dawley rats demonstrated
reciprocal interinsular antidromic and orthodromic activation, elicited with
similar median onset latencies (18 ms). The corresponding conduction velocity of
these fibers (0.6 m/s) suggests that they may be unmyelinated. Many of the cells
showing interhemispheric connectivity also responded to baroreceptor activation,
further emphasizing the connectivity pattern in baroreceptor-related units. Both
1 and 25 Hz microstimulation of the contralateral insula indicated that the most
frequent orthodromic response was inhibitory, either alone or as part of a
biphasic pattern including activation. Chemical stimulation of the insula using L
glutamate was associated with both excitatory and inhibitory orthodromic
activation of the contralateral posterior insula, confirming that the orthodromic
electrical stimulation was not solely due to activation of fibers of passage.
These data suggest that the two insulae may communicate with each other to
integrate and balance cardiovascular function between hemispheres.
PMID- 10773191
TI - Involvement of chondroitin sulfates on brain-derived tenascin-R in carbohydrate
dependent interactions with fibronectin and tenascin-C.
AB - Tenascin-R (TN-R), a matrix glycoprotein of the central nervous system (CNS), has
been implicated in a variety of cell-matrix interactions involved in the control
of axon growth, myelination and cell adhesion to fibronectin during development
and regeneration. While most of the functional analyses have concentrated
exclusively on the role of the core protein, the contribution of TN-R
glycoconjugates present on many potential sites for N- and O-glycosylation is
presently unknown. Here we provide evidence that TN-R derived from adult mouse
brain expresses chondroitin sulfate (CS) glycosaminoglycans (GAGs), i.e. C-6S and
C-4S, that are recognized by the CS/dermatan sulfate-specific monoclonal
antibodies 473 HD and CS-56. Using ligand-binding, cell adhesion and neurite
outgrowth assays, we show that TN-R-linked CS GAGs (i) are involved in the
interaction with the heparin-binding sites of fibronectin and are responsible for
TN-R-mediated inhibition of cell adhesion to a 33/66-kD heparin-binding
fibronectin fragment or to FN-C/H I and FN-C/H II peptides, known to participate
in fibronectin binding to cell surface proteoglycans; and (ii) partially
contribute to the interaction between TN-R and TN-C which, however, does not lead
to an interference with TN-R- and TN-C-mediated inhibition of neurite outgrowth
when the two molecules are offered as a mixed substrate in culture. Our findings
suggest the functional implication of TN-R-linked CS GAGs in matrix interactions
with fibronectin and TN-C that are likely to contribute to a modulation of
cellular behavior and the macromolecular organization of matrix components in the
developing or injured adult CNS.
PMID- 10773192
TI - Morphine-induced suppression of saccharin intake is correlated with elevated
corticosterone levels.
AB - Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with a
drug of abuse. This phenomenon, however, is not uniform across all subjects and
is greater following exposure to stress and in animals that more readily self
administer drugs of abuse. The present study was designed to examine these
individual differences in intake suppression following seven saccharin-morphine
pairings. Plasma corticosterone also was evaluated both before and after
conditioning in order to determine whether the magnitude of CS suppression is, or
is not, related to circulating corticosterone levels. The findings indicated
that, while all rats were exposed to the same number of saccharin-morphine
pairings, only half of these animals actually suppressed intake of the saccharin
CS. Moreover, the results showed that greater suppression of CS intake was
associated with higher corticosterone levels at test (r=-0.84, P<0.0001). Taken
together, the results demonstrate that individual differences affect not only the
reduction in CS intake following taste-drug pairings, but also the associated cue
induced elevation in circulating corticosterone.
PMID- 10773193
TI - Differential effects of methamphetamine on Na(+)/Cl(-)-dependent transporters.
AB - It has been demonstrated that methamphetamine (METH) administration affects
Na(+)/Cl(-)-dependent transporters; for example, METH treatment rapidly and
reversibly decreases dopamine (DA) and serotonin (5HT) transporter function in
rat striatum in vivo, as assessed in synaptosomes prepared from METH-treated
rats. Because acute effects of METH on other transporters within this family have
been less studied, the responses of norepinephrine (NE) and gamma-aminobutyric
acid (GABA) transporters to METH administration(s) were determined. Both single
and multiple METH administrations inhibited hippocampal NE uptake 1 h after METH
treatment(s). In contrast, striatal GABA uptake was not affected by either
treatment paradigm. The effects observed after both single and multiple METH
administrations on NE transporters were attributable to increases in K(m,) with
no changes in V(max); effects that were eliminated by repeated washing of the
synaptosomes. These 'washout' data suggest that residual METH introduced by the
in vivo subcutaneous injection(s) directly reduced NE transporter activity in the
in vitro assay and that, unlike DA and 5HT transporters, METH did not indirectly
alter NE transporter function. Taken together, these data demonstrate differences
in the responses of NE, GABA, DA, and 5HT transporters to METH treatment.
PMID- 10773194
TI - Electrical responses in hippocampal slices after prolonged global ischemia:
effects of neuroprotectors.
AB - A simple and reproducible animal model of global ischemia, induced by
decapitation in 30-day-old Wistar rats, has been developed. It allows to perform
electrophysiological analysis of the postischemic reperfusion period in the brain
slices. Periods of ischemia up to 40 min increase population spikes measured in
the CA1 area of the hippocampus during 2-5 h of reperfusion. Thus after 30-min
decapitation-induced ischemia (at t(ischem)=25 degrees C), the mean amplitude of
the recorded maximum orthodromic population spikes was 159% of the control
obtained in the non-ischemic animals. Longer ischemic episodes result in the
depression of the population spikes. After 2 h of ischemia, the amplitude of
population spikes was about 89% of control. After 3 h of decapitation ischemia,
the neurons could not be reactivated. The duration of ischemic episode needed for
the irreversible depression of the electrical activity of the brain neurons
drastically depends on the temperature at which the ischemic brain is maintained.
Thus, only 2 h were needed at 30 degrees C as compared to nearly 3 h at 25
degrees C. We have found that intraperitoneal injection of neuroprotectors which
precedes decapitation enables reactivation of the post-ischemic neurons even
after very long periods of global ischemia. Thus, MK-801, a non-competitive NMDA
receptors antagonist, or NBQX, a blocker of AMPA receptors, administrated 15 min
before the long-term (90 min) decapitation ischemia (30 degrees C), induced dose
dependent recovery of population spike with ED(50) values 0.2 mg/kg and 3 mg/kg
respectively. Our results demonstrate that, in spite of the high vulnerability of
hippocampal neurons to hypoxia and ischemia, their electrical activity can be
restored after prolonged (more then 1 h) decapitation ischemia. Administration of
NMDA or AMPA antagonists enhances recovery.
PMID- 10773195
TI - Opioid site in nucleus accumbens shell mediates eating and hedonic 'liking' for
food: map based on microinjection Fos plumes.
AB - Microinjection of opioid agonists, such as morphine, into the nucleus accumbens
shell produces increases in eating behavior (i.e. 'wanting' for food). This study
(1) reports direct evidence that activation of accumbens opioid receptors in rats
also augments food 'liking', or the hedonic impact of taste, and (2) identified a
neural site that definitely contains receptors capable of increasing food intake.
Morphine microinjections (0.5 microgram) into accumbens shell, which caused rats
to increase eating, were found also to cause selective increases in positive
hedonic patterns of behavioral affective reaction elicited by oral sucrose, using
the 'taste reactivity' test of hedonic palatability. This positive shift
indicated that morphine microinjections enhanced the hedonic impact of food
palatability. The accumbens site mediating morphine-induced increases in food
'wanting' and 'liking' was identified using a novel method based on local
expression of Fos induced directly by drug microinjections. The plume-shaped
region of drug-induced increase in Fos immunoreactivity immediately surrounding a
morphine microinjection site (Fos plume) was objectively mapped. A point-sampling
procedure was used to measure the shape and size of 'positive' plumes of Fos
expression triggered by microinjections of morphine at locations that caused
increases in eating behavior. This revealed a functionally 'positive' neural
region, containing receptors directly activated by behaviorally-effective drug
microinjections. A subtraction mapping procedure was then used to eliminate all
surrounding regions containing any 'negative' Fos plumes that failed to increase
food intake. The subtraction produced a conservative map of the positive site, by
eliminating regions that gave mixed effects, and leaving only a positive region
that must contain receptors capable of mediating increases in food intake. The
resulting mapped 'opioid eating site' was contained primarily within the medial
caudal subregion of the nucleus accumbens shell, and did not substantially
penetrate either into the accumbens core or into other subregions of the shell.
Several other structures outside the nucleus accumbens (such as rostral ventral
pallidum), immediately medial and adjacent to the shell, also appeared to be
included in the functional site. Opioid receptors within this site thus are
capable of mediating morphine-induced increases in eating, in part by enhancing
the hedonic reward properties of food.
PMID- 10773196
TI - Biochemical and immunohistochemical demonstration of tissue kallikrein in the
neuronal nuclei of the developing rat brains.
AB - Kallikrein content and cellular localization in the prenatal, newborn and adult
rat brains were determined by the enzyme-linked immunosorbent assay and
immunohistochemistry. The content was the highest in the prenatal rats and highly
predominant in the neuronal nuclei during the prenatal to newborn periods,
whereas the immunoreactive kallikrein was mainly located around neuronal cell
bodies and their processes in the adult rats. The preferential nuclear
localization in the prenatal rat brains was further confirmed by the
immunoblotting technique after the SDS-polyacrylamide gel electrophoresis of the
lysate of the nuclei fractionated from the prenatal rat brains. The meaning(s) of
this kallikrein localization in the neuronal nuclei at the prenatal and newborn
stages is unknown. However, we would like to conclude that this enzyme plays an
important role in the morphogenesis of brain by acting on the substance(s) in the
neuronal nuclei at the developing stage.
PMID- 10773197
TI - Neurological impairment in rats after transient middle cerebral artery occlusion:
a comparative study under various treatment paradigms.
AB - The assessment of the functional outcome - in addition to the conventional
endpoints as histomorphometry of the ischemic brain damage - for the evaluation
of cerebroprotective therapies is increasingly recommended, although there is
little consensus on appropriate procedures. We evaluated a battery of
sensorimotor tasks in rats after transient middle cerebral artery occlusion
(MCAO) to select those with the highest potential to discriminate between various
degrees of neuronal damage. A total of 40 Sprague-Dawley rats were subjected to
90 min of MCAO and assigned to one of four treatment arms: (1) sham-operated
controls, (2) vehicle-treated controls, (3) moderately effective neuroprotection
by 2x100 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN), (4) highly effective
neuroprotection by mild hypothermia (33 degrees C). Functional deficits were
daily quantified using the beam balance task (1.5 cm, 2.5 cm diameter rectangular
and 2.5 cm diameter cylindrical beam), the prehensile traction task, the rotarod,
and a six-point neuro-score. Infarction of cerebral cortex and basal ganglia was
assessed one week after ischemia. Treatment with PBN significantly reduced
cortical infarction (-31%), while treatment with hypothermia resulted in a
significantly smaller infarct volume of cortex (-94%) and basal ganglia (-27%).
Beam balance, prehensile traction and rotarod failed to demonstrate any
difference in motor performance. The six-point neuro-score showed a significant
correlation with cortical infarction from day 2 and with total infarct volume
from day 3. The smaller the reduction of infarct volume, the later the
corresponding difference in neuro-score became apparent. Functional outcome after
MCAO in rats can be assessed by a relatively simple measurement of neurological
deficit. The slope of functional recovery is closely related with the degree of
the morphological, particularly cortical damage. If expected treatment effects
are small, an observation period of at least 3 days should be planned for the
study design. The functional impairment from focal brain ischemia and its
subsequent recovery could provide valuable information for future studies
evaluating the neuroprotective potential of novel agents and procedures.
PMID- 10773198
TI - Time-course of methamphetamine-induced neurotoxicity in rat caudate-putamen after
single-dose treatment.
AB - The time-course of monoamine and tyrosine hydroxylase depletion after single-dose
administration of D-methamphetamine (40 mg/kg s.c.) was investigated in caudate
putamen of male Sprague-Dawley rats. Times evaluated were 6, 12, 48, 72 and 240 h
following treatment. Tyrosine hydroxylase was significantly reduced by 29, 60,
66, 76 and 76% of control at each of the respective post-treatment time
intervals. Dopamine was not reduced 6 h following treatment. Dopamine was
significantly reduced by 53, 57, 68 and 74% 12, 48, 72 and 240 h post-treatment,
respectively. Reductions in caudate-putamen serotonin began earlier and were
ultimately larger than for dopamine, with significant reductions of 28, 33 55, 74
and 81% at each of the respective post-treatment intervals. Confirmation of
neurotoxicity was provided by measurement of glial fibrillary acidic protein
(GFAP) 240 h post-treatment. GFAP was increased at this time interval by 150%
above control. Methamphetamine-induced hyperthermia during the 6 h immediately
after treatment was comparable among the groups of animals used for analyses at
each time interval. The results demonstrate that methamphetamine-induced
monoamine reductions in the caudate-putamen occur rapidly, peak at 75-80% below
controls, and last for at least 10 days after a single dose. These effects are as
large or larger than those reported after the commonly used 10 mg/kgx4 dose
treatment regimen administered at 2-h intervals and provides an alternate model
for the investigation of methamphetamine-induced neurotoxicity.
PMID- 10773199
TI - Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal
subregions by haloperidol and clozapine.
AB - Disturbances of retinoid activated transcription mechanisms have recently been
implicated as risk factors for schizophrenia. In this study we have compared the
regulation of mRNAs for the nuclear orphan receptor NGFI-B, which forms a
functional heterodimer with the retinoid x receptor and the related orphan
nuclear receptor Nor1 with c-fos mRNA after acute and chronic treatments with
haloperidol and clozapine. The antipsychotic drugs haloperidol and clozapine have
different clinical profiles. Haloperidol is a typical neuroleptic giving
extrapyramidal side effects (EPS), whereas the atypical compound clozapine does
not. Acute haloperidol treatment increased NGFI-B, Nor1 and c-fos mRNAs in
nucleus accumbens shell and core as well as medial and lateral caudate putamen.
In contrast, clozapine lead to an increase of NGFI-B, Nor1 and c-fos only in the
accumbens shell. No haloperidol or clozapine effect on these mRNAs was detected
in cingulate, sensory or motor cortex. Chronic haloperidol lead to an increase of
NGFI-B mRNA in the accumbens core. Acutely, it is possible that the increased
levels of NGFI-B, Nor1 and c-fos mRNA levels in striatum and accumbens might
indicate a neural activation which possibly can be used when screening for drugs
that do not produce EPS. Also, the increased levels of NGFI-B, which is an
important component in retinoid signaling, both after acute and chronic
treatments of haloperidol suggests altered sensitivity to retinoids which could
be an important component for the beneficial antipsychotic effect.
PMID- 10773200
TI - Cannabinoid receptor activation in CA1 pyramidal cells in adult rat hippocampus.
AB - Intracellular assessments of the physiological actions of cannabinoid receptor
agonists and antagonists on adult hippocampal CA1 pyramidal cells in the in vitro
slice preparation were performed using current clamp and conventional sharp
electrode intracellular recording procedures. Several manipulations were
performed to delineate putative currents and conductance mechanisms affected by
the cannabinoid receptor agonist WIN 55,212-2 (WIN-2). This compound produced a
tonic hyperpolarization of the pyramidal cell membrane that was bicuculline
sensitive, reversed by changing the chloride gradient, and abolished by the
addition of TTX to the bathing medium. Instantaneous membrane input resistance,
computed from hyperpolarizing current pulses (peak R(in)) was also reduced
significantly in the presence of WIN-2 and was accompanied by enhancement of a
superimposed slow depolarization that reduced steady-state R(in) (SSR(in)); both
effects were resistant to barium. Intracellular perfusion of cesium acetate
(CsAc) and the sodium/potassium channel blocker, QX314, each blocked the effect
of WIN-2 on R(in) and SSR(in). WIN-2 also reduced input resistance calculated
from depolarizing current injections (R(d)). This effect was also blocked by
atropine, as well as media containing TTX or low Ca(2+). Each of the above
effects of WIN-2 was blocked by the cannabinoid receptor antagonist SR141716A,
showing a dependence on CB1 cannabinoid receptors. Several known pre- and
postsynaptic processes in adult pyramidal cells are discussed which could be
responsible for these cannabinoid-produced changes in membrane resistances.
PMID- 10773202
TI - Calpain-mediated truncation of rat brain AMPA receptors increases their Triton X
100 solubility.
AB - Previous studies have indicated that calpain activation results in the truncation
of the C-terminal domains of AMPA and NMDA receptor subunits. The present study
determined the distribution of the truncated species of the subunits between
Triton-soluble and -insoluble fractions. Western blots were performed with
various antibodies to quantify the amounts of the various species of GluR1,
GluR2, GluR3 and NR2B subunits. The results indicate that calpain activation
decreased the amount of all the intact subunits in Triton-insoluble fractions.
Calpain-generated truncated forms of GluR1 and GluR2, but not NR2B, were absent
in these fractions, and were recovered in Triton-soluble fractions. These
findings suggest that calpain-mediated truncation of AMPA but not NMDA receptor C
terminal domains results in modifications of the interactions between the
receptors and postsynaptic densities, and that this mechanism could be involved
in activity-dependent changes in the subcellular distribution of AMPA receptors.
PMID- 10773201
TI - Transporter-mediated GABA release induced by excitatory amino acid agonist is
associated with GAD-67 but not GAD-65 immunoreactive cells of the primate retina.
AB - The release of GABA from amacrine and interplexiform cells after exposure to
excitatory amino acids (EAAs) agonists was investigated by immunohistochemistry.
Cebus monkey retinas were treated in vitro with 50 microM kainate (KA) or 5 mM L
Glutamate (L-Glu), for 30 min at 37 degrees C. The effects of the EAAs were
measured by detecting immunocytochemically the GABA remaining in the tissue after
stimulation. L-Glu and KA reduced the number of GABA-immunoreactive perikarya in
the innermost part of the inner nuclear layer by approximately 60% and 80%,
respectively, as compared to controls. The cell processes in the inner plexiform
layer (IPL) were restricted to only three defined bands in the strata 1, 3 and 5,
as compared to an intense and homogeneous labeling in the IPL of the untreated
retinas. The effect of KA was inhibited by 100 microM CNQX, 100 microM NNC-711,
or when Na(+) was replaced by choline. The release of GABA was Ca(2+)
independent, suggesting the mobilization of GABA from the cytoplasmic pool of
this neurotransmitter. At least two subsets of retinal neurons including amacrine
and interplexiform cells retained GABA-immunoreactivity after stimulation with
EAAs, as revealed by glutamic acid decarboxylase (GAD) immunocytochemistry. Our
results suggest that non-NMDA receptor activation by KA and glutamate are
associated with the efflux of GABA from cells of the inner retina (amacrine and
interplexiform cells). The data also show that cells containing GAD-67 released
GABA via its transporter, while cells containing exclusively GAD-65 apparently
did not release the neurotransmitter by the reversal of the transporter.
PMID- 10773203
TI - Non-spatial water radial-arm maze learning in mice.
AB - Recently, we published a method for examining working and reference memory in
mice using a spatial version of the water radial-arm maze. Here we describe a non
spatial version of the same maze. BXSB mice were able to learn the maze as shown
by the decrease in the number of working and reference memory errors over
sessions. This maze was used to examine learning differences between males and
females and between mice with misplaced clusters of neurons in layer I of cortex
(ectopias) and those without. In a prior study using the spatial version of the
water radial-arm maze, male BXSB mice had poorer working memory than females
during the acquisition phase. Similarly, in this study male BXSB mice
demonstrated impaired working memory during the asymptotic phase of non-spatial
radial-arm maze learning. Two prior studies showed that mice with neocortical
ectopias demonstrated working memory impairments compared to non-ectopic
littermates in the spatial version of the water radial-arm maze. Contrary to
this, in the non-spatial radial-arm maze used here, ectopic mice were not
impaired in working memory and showed better memory when the working memory
'load' was the highest. Overall, both versions of the maze can be useful tools to
assess spatial and non-spatial working and reference memory in mice.
PMID- 10773204
TI - Hypoinsulinemia may mediate the lowering of self-stimulation thresholds by food
restriction and streptozotocin-induced diabetes.
AB - 7 days beyond cessation of insulin treatment) elevation of threshold in ad
libitum fed rats and, more transiently, reversed the threshold-lowering effect of
food restriction. Acute insulin treatment (3 mU, 15 min prior) also elevated
threshold in food-restricted rats. These results are consistent with the
hypothesis that insulin modulates sensitivity of a brain reward system and that
hypoinsulinemia may be the common factor in food restriction and diabetes that
accounts for the enhancement of perifornical LHSS.
PMID- 10773205
TI - Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged
astrogliosis with expression of Hsp27.
AB - We have established a focal preconditioning (PC) paradigm that produces
significant and prolonged ischemic tolerance (IT) of the brain to subsequent
permanent middle cerebral artery occlusion (MCAO). PC using 10 min of MCAO
induces brain tolerance at 1-7 days of reperfusion that requires active protein
synthesis. The protective protein(s) involved are unknown. In these studies the
increased transcription and translation of the inducible 70-kDa heat shock
protein (Hsp70) and the 27-kDa heat shock protein (Hsp27), and astrogliosis/glial
fibrillary acidic protein (GFAP) were determined by Northern analysis and
immunohistochemistry following PC. Cellular localization of proteins was
determined by double labeling. PC produced no brain injury but did increase Hsp70
mRNA transiently at 6 h and increased Hsp27 mRNA later at 24 h for at least 5
days. Protein expression induced by PC exhibited a similar profile. Hsp70 protein
was primarily expressed in neurons from 1 to 5 days post-PC throughout the PC
cortex. Hsp27 protein expression was initiated later for a much longer period of
time. A remarkable astroglyosis was verified with increased astrocytic Hsp27 from
1 to 7 days after PC. Gliosis with increased Hsp27 in the PC cortex was still
present but reduced 4 weeks after PC. Therefore, PC that results in brain
tolerance/neuroprotection increases neuronal Hsp70 in the PC cortex and activated
astrocytic Hsp27 in the PC cortex in a temporal fashion associated with
developing IT. The short duration of benign ischemia (PC) that produces IT
produces a robust, long-lived cellular and protein synthetic response that
extends throughout the entire cortex (i.e. well beyond the MCA perfusion
territory). The resulting IT is associated with changes in astrocyte-activation
that might provide increased support and protection from injury. Although both
Hsp70 and Hsp27 may participate in the neuroprotection/brain tolerance induced by
PC, the temporal expression patterns of these proteins indicate that they are not
solely responsible for the tolerance to brain injury.
PMID- 10773206
TI - Striatal interneurons expressing calretinin, parvalbumin or NADPH-diaphorase: a
comparative study in the rat, monkey and human.
AB - The present study is aimed at evaluating the relative number and comparing the
pattern of distribution of interneurons containing calretinin (CR), parvalbumin
(PV) or NADPH-d in the striatum of rats, squirrel monkeys and humans. A series of
adjacent coronal sections taken at three comparable rostrocaudal levels in the
three species were treated to reveal the three neuronal markers and the density
of each type of chemospecific interneurons was analyzed with a computerized image
analysis system. In primates, the most abundant interneurons were those
expressing CR. The ratio of CR+/PV+ neurons was approximately 2-3:1 compared to a
ratio of 3-4:1 for CR+/NADPH-d+ neurons. In contrast, the most frequently
encountered interneurons in the rat striatum were those expressing PV. In
rodents, all three interneurons were more abundant rostrally than caudally, but
CR+ neurons displayed a particularly striking rostrocaudal decreasing gradient.
In monkeys and humans, the three striatal interneurons were distributed rather
uniformly rostrocaudally, but CR+ and PV+ interneurons were significantly more
numerous in the caudate nucleus than in the putamen in humans. In monkeys, only
PV+ neurons were more abundant in the caudate nucleus than in putamen. Overall,
the density of the three striatal interneurons was much higher in monkeys than in
rats and humans. These results reveal important species differences in respect to
the relative density and pattern of distribution of striatal interneurons. These
findings should be taken into account when evaluating the effect of
neurodegenerative processes on cell densities in the human striatum or when
studying animal models of the such diseases.
PMID- 10773207
TI - Intracellular [Cl(-)] modulates synchronous electrical activity in rat
neocortical neurons in culture by way of GABAergic inputs.
AB - The influence of GABAergic neurons on spontaneous electrical activities of
neocortical neurons in culture, which was estimated to be about 9.5% of the total
neurons by immunohistochemistry, was examined using dual whole-cell recording.
Synchronized depolarization or hyperpolarization was observed in recorded neurons
with pipettes containing low [Cl(-)] solution, while synchronized bursting of
action potentials (APs) was observed with pipettes containing high [Cl(-)]
solution. Spontaneous currents (SCs) were synchronous in all pairs tested with
either pipettes containing low or high [Cl(-)] solution and spontaneous outward
currents (SOCs) observed at around -30 mV were sensitive to the GABA-A receptor
antagonist, bicuculline. Their reversal potential (V(rev)) was linearly related
to the logarithm of Cl(-) activity in the pipette (-56.9 mV/decade). The
intracellular chloride concentration was estimated from the V(rev) of SCs with
gramicidin perforated-patch recordings and was between 5.9 and 28.1 mM (mean:
13.0 mM). These results suggest that GABA depolarized some neurons and
hyperpolarized others, depending on the E(Cl). Bicuculline decreased the
frequency of periodic depolarized potentials and increased their amplitudes.
However, perfusion with low [Cl(-)] bath solution did not decrease the frequency.
Our data indicate that recurrent subthreshold electrical activities by GABAergic
inputs along with glutamatergic inputs take part in deterring synchronized
bursting and that intracellular [Cl(-)] can modulate this bursting.
PMID- 10773208
TI - Nitric oxide synthase interneurons in the monkey cerebral cortex are subsets of
the somatostatin, neuropeptide Y, and calbindin cells.
AB - 99%) immunoreactive for somatostatin and neuropeptide Y, but did not express
calbindin. The LNOS cells comprised about 30% of the somatostatin cells and about
60% of the neuropeptide Y cells. The SNOS cells were nearly always (87-98%)
calbindin-immunoreactive, and were rarely or never labeled with antibodies to
somatostatin or neuropeptide Y. The SNOS cells accounted for about 20% of all of
the calbindin cells. The findings demonstrate that the two types of nNOS cells
can be distinguished by antibodies to calbindin, somatostatin and neuropeptide Y,
but none of these markers is found exclusively in nNOS cells. Nevertheless,
neuropeptide Y-immunoreactivity provides a useful marker for LNOS cells, because
it is very dense in these cells and only light in the interneurons that lack
nNOS.
PMID- 10773209
TI - Molecular serotonergic mechanisms appear to mediate genetic sensitivity to
cocaine-induced convulsions.
AB - Cocaine-induced convulsions appear to be mediated by serotonin (5-HT)
neurotransmission, acting primarily at 5-HT(2) receptors. However, this effect of
cocaine is attenuated by cocaine binding at sigma and muscarinic M(1) and M(2)
sites. This study examined whether the aforementioned neural sites mediate the
nearly two-fold difference in sensitivity to cocaine-induced convulsions across
C57BL/6J (6J) and C57BL/6ByJ (6ByJ) mice. Experiment 1 compared 5-HT transporter
densities across several brain regions of 6J and 6ByJ mice and cocaine-induced
convulsions following pretreatment with the 5-HT reuptake inhibitor fluoxetine.
Experiment 2 compared 5-HT(2) receptor densities across these mice and cocaine
induced convulsions following pretreatment with the 5-HT(2) antagonist
cinanserin. There were no differences in 5-HT transporter densities, however,
fluoxetine produced a greater facilitation of cocaine-induced convulsions in 6ByJ
relative to 6J mice, suggesting that sensitivity to convulsions is mediated
postsynaptically. Indeed, 5-HT(2) density was higher in 6ByJ relative to 6J mice
in the amygdaloid ridge, hypothalamus, and midbrain. In addition, cinanserin
attenuated convulsions more potently in 6J relative to 6ByJ mice. There were no
differences in the densities or affinities of 5-HT(1), muscarinic, or sigma
receptors across these strains, suggesting that density of these latter sites
does not mediate genetic sensitivity to cocaine-induced convulsions. Since 6ByJ
mice are less sensitive to convulsions despite the fact that they have more 5
HT(2) receptors, we hypothesized that these mice may exhibit a weaker linkage of
5-HT(2) sites to their second-messenger system relative to 6J mice. However, in
experiment 3 we demonstrated that 5-HT(2)-receptor mediated phosphoinositide
hydrolysis was higher in 6ByJ relative to 6J mice in the same regions also
displaying higher 5-HT(2) densities. This study suggests that 5-HT(2) receptors
mediate genetic sensitivity to cocaine-induced convulsions, further supporting
the role of these sites in mediating this toxic effect of cocaine.
PMID- 10773210
TI - Immunohistochemical expression of doublecortin in the human cerebrum: comparison
of normal development and neuronal migration disorders.
AB - Immunohistochemical expression of the doublecortin (DCX) gene product was
investigated in cerebral cortices from 33 normal developing human, aged 9
gestational weeks (GW) to 29 years, and from 26 patients with various neuronal
migration disorders, aged 19 GW to 34 years. DCX immunoreactivity was detected
predominantly in the fetal cerebral cortex. The neurons in the cortical plate
(CP) exhibited positive labeling at 9 GW. Staining was the most marked intense at
12-20 GW, and gradually decreased thereafter, only relatively weak
immunoreactivity remaining in pyramidal cells. Comparison of the
immunohistochemical characteristics of DCX and those of nestin and vimentin
indicated the early expression of DCX in neuroepithelial stem cells of the
subventricular germinal layer, as well as in neurons of the CP. The most marked
intense expression in the period of neuronal migration strongly indicated its
role in neuronal migration. The abnormal distribution of DCX immunolabeling in
the cerebral cortex was associated with a neuronal disarrangement in some
migration disorders, such as Miller-Dieker syndrome and Fukuyama congenital
muscular dystrophy. Decreased DCX immunolabeling was demonstrated in fetuses and
infants with Zellweger syndrome, implicating DCX in the neuronal migration
abnormality in this syndrome.
PMID- 10773211
TI - Neonatal herpes simplex virus type 1 brain infection affects the development of
sensorimotor gating in rats.
AB - The effect of neonatal brain infection of herpes simplex virus type 1 (HSV-1) on
the development of sensorimotor function in the rat was investigated using an
acoustic startle paradigm. Intracerebral inoculation of HSV-1 at day 2 after
birth, but not at day 4, caused a significant delay in the development of
prepulse inhibition of acoustic startle. A decrease in prepulse inhibition was
shown at 37, 46 and 58 days of age in these rats compared to control rats. No
evidence was obtained for other behavioural dysfunctions such as differences in
sensorimotor reactivity, sensorimotor response habituation, spontaneous locomotor
activity, rearing activity or stereotyped behaviour. Prepulse inhibition of
acoustic startle is an accepted model of sensorimotor gating in the CNS, a
function which has been shown diminished in schizophrenic persons. The present
results suggest that early viral infections during a neurone-susceptible period
may contribute to the development of this deficit.
PMID- 10773212
TI - 65Zn localization in rat brain after intracerebroventricular injection of 65Zn
histidine.
AB - Previous studies have shown that 65Zn uptake in the brain expressed relative to
plasma 65Zn level is enhanced by histidine infusion into the blood vessel. To
study the effect of histidine on zinc uptake in the brain parenchyma via the CSF,
the brains of rats injected intracerebroventricularly with 65Zn-His were
subjected to autoradiography. Six days after injection, the radioactivity from
65Zn-His was distributed in the major part of the brain parenchyma higher than
that from 65ZnCl(2), and relatively concentrated in the hippocampal formation,
globus pallidus and hypothalamus. The radioactivity of the aqueduct was also
higher in the 65Zn-His group, indicating that CSF clearance of the 65Zn-His group
may be lower than that of the 65ZnCl(2) group. These results suggest an
enhancement by histidine on zinc uptake in the brain parenchyma via the CSF.
PMID- 10773213
TI - Inhibition of protein kinase C counteracts TNFalpha-induced intercellular
adhesion molecule 1 expression and fluid phase endocytosis on brain microvascular
endothelial cells.
AB - TNFalpha (100 U/ml, 24 h) upregulated intercellular adhesion molecule 1 (ICAM1)
expression and fluid phase endocytosis (FPE) of horseradish peroxidase on brain
microvascular endothelial cell (BMEC) culture. The protein kinase C (PKC)
inhibitor staurosporin (0. 5-10 nM) antagonized ICAM1 expression and FPE due to
TNFalpha, whereas the protein kinase A inhibitor H89 (0.5-10 nM) did not. These
findings indicate that a PKC-dependent mechanism may affect TNFalpha signalling
on different barrier properties of BMECs.
PMID- 10773214
TI - Effects of cholinergic deafferentation upon the expression of the alpha2 subunit
of the nicotinic acetylcholine receptors in the chick lateral spiriform nucleus.
AB - Lesion, immunohistochemical, and immunoblotting methods were used to evaluate the
effects of cholinergic deafferentation upon the expression of the alpha2 subunit
of the nicotinic acetylcholine receptors in the lateral spiriform nucleus (SpL)
of the chick brain. The expression of the alpha2 subunit in the SpL showed
biphasic changes after lesion of its cholinergic source (nucleus semilunaris),
with an increase after 2 days postlesion and a decrease after 3-7 days. Our
results could represent a correlate of the phenomena of nicotinic receptor up-
and down-regulation, induced by removal of the cholinergic input.
PMID- 10773215
TI - Enhanced accumbal dopamine release following 5-HT(2A) receptor stimulation in
rats pretreated with intermittent cocaine.
AB - This study was conducted to determine whether dopamine (DA) release in the
nucleus accumbens (NACC) following 5-HT(2A) receptor stimulation is potentiated
by intermittent cocaine. Rats received daily injections of either saline or
cocaine (30 mg/kg, s.c.) for 14 days. At the 7th day after withdrawal,
microdialysis was performed in the NACC. Infusion of (+/-)-1-(4-iodo-2, 5
dimethoxyphenyl)-2-aminopropane (DOI, 50 microM), a 5-HT(2) receptor agonist,
into the NACC produced greater and longer-lasting increases in extracellular DA
in the rats pretreated with cocaine than in the rats pretreated with saline. The
DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin
(50 microM), a 5-HT(2A) receptor antagonist. The results are consistent with the
concept that intermittent cocaine may cause enhanced sensitivity of 5-HT(2A)
receptors within the NACC.
PMID- 10773216
TI - Nicotine reverses GABAergic inhibition of long-term potentiation induction in the
hippocampal CA1 region.
AB - Nicotine is known to enhance cognitive function but the mechanism is unknown. The
present study examined the modulatory effect of nicotine on the induction of long
term potentiation (LTP), a synaptic model of learning and memory. A weak tetanic
stimulation consisting of 20 pulses at 100 Hz induced stable LTP in the
hippocampal CA1. The induction of LTP was completely blocked if the tetanus was
delivered in the presence of muscimol (2.5 microM), a gamma-aminobutyric acid
(GABA) receptor agonist. This inhibition was sensitive to, and reversed by, not
only nicotinic acetylcholine receptor (nAChR) agonists (nicotine and
epibatidine), but also the alpha7 nAChR-selective antagonist methyllycaconitine
(MLA). Furthermore, ACh-puff activation of alpha7 nAChRs on feedforward
interneurons induced inhibitory postsynaptic currents in pyramidal cells that
were blocked by nicotine or MLA. In addition, nicotine reduced field monosynaptic
inhibitory postsynaptic potentials in the presence of MLA. These results suggest
not only two pathways of nicotine-induced disinhibition of pyramidal cells, one
involving desensitization of alpha7 nAChRs and the other involving non-alpha7
nAChRs, but also two potential mechanisms underlying the modulatory effect of
nicotine on LTP induction, both reducing GABAergic inhibition, thereby indirectly
increasing the excitability of pyramidal cells.
PMID- 10773217
TI - In vitro effects of metrifonate on neuronal amyloid precursor protein processing
and protein kinase C level.
AB - Alteration in the processing of the amyloid precursor protein (APP) is a central
event in the formation of amyloid deposits in the brains of individuals with
Alzheimer's disease (AD). It has been suggested that acetylcholinesterase (AChE)
inhibitors, which promote the cholinergic function and consequently improve the
cognitive deficits, may also exert a neuroprotective effect by activating normal
APP processing. We now report that an irreversible AChE inhibitor (metrifonate)
increase the cell-associated APP level in a basal forebrain neuronal culture and
also elevate the amount of APP secreted into the medium. The alterations in APP
processing were accompanied by increased protein kinase C (PKC) levels. The
results suggest that AChE inhibitors modulate the metabolism of APP, possibly via
their stimulatory effects on PKC. Since changes in the activity and level of PKC
may be involved in the pathogenesis of AD, it is concluded that the beneficial
effect of metrifonate in AD therapy may be due not only to the stimulatory
cholinergic function, but also to its activating effect on PKC.
PMID- 10773218
TI - Excitability of rat dentate gyrus granule cells in vivo is controlled by tonic
and evoked GABA(B) receptor-mediated inhibition.
AB - Tonic or evoked gamma-aminobutyric acid(B) (GABA(B)) receptor-mediated modulation
of dentate gyrus excitability was evaluated in vivo in urethane-anesthetized
rats. Two stimuli at an interpulse interval (IPI) of 10-9000 ms were given to the
medial perforant path. Population excitatory postsynaptic potentials (pEPSPs) and
population spikes (PSs) were recorded in the dentate gyrus using a glass
micropipette or a multichannel silicon probe. The GABA(B) receptor antagonist
CGP35348, delivered intracerebroventricularly (i.c.v.) or locally, caused a
significant increase in the PS amplitude evoked by the first pulse (PS1) without
an increase in either the slope or current sink of the population EPSP evoked by
the first pulse (pEPSP1). The average spontaneous firing rate of putative granule
cells was also increased following i. c.v. CGP35348. The PS evoked by the second
pulse (PS2) relative to PS1 (PS2/PS1) was consistently suppressed at IPIs from 30
to 70 ms, even when PS1 was matched before and after CGP35348. CGP35348 increased
PS1 mainly by blocking tonic postsynaptic GABA(B) receptors and decreased PS2 at
30-70 ms IPI by blocking presynaptic GABA(B) autoreceptors. These data suggest
that GABA(B) receptors are tonically active in the dentate gyrus in vivo.
PMID- 10773220
TI - Insulin-like growth factor II receptors in human brain and their absence in
astrogliotic plaques in multiple sclerosis.
AB - Insulin-like growth factor (IGF) II receptors were studied in human adult brain
by using autoradiography with [125I]IGF-II. Receptors were found to be widely
distributed throughout all neuronal regions. The highest densities were found in
plexus choroideus, granular layer of the cerebellar cortex, gyrus dendatus and
pyramidal layer of the hippocampus, striatum, and cerebral cortex. White matter
was devoid of IGF-II receptors. We also examined [125I]IGF-II binding in six
plaques of multiple sclerosis, which were characterized by a dense network of
astrocytes. We were unable to detect IGF-II receptors in any of the astrogliotic
plaques, suggesting that IGF-II receptors in human brain are not involved in
astrogliosis. The regional variations in neuronal distribution of IGF-II
receptors suggest involvement of IGF-II in functions associated with specific
neuronal pathways.
PMID- 10773219
TI - Osteopontin-immunoreactive primary sensory neurons in the rat spinal and
trigeminal nervous systems.
AB - 1200 micrometer(2) and 9% of those in the range 600-1200 micrometer(2) showed the
immunoreactivity (ir). DRG neurons <600 micrometer(2)800 micrometer(2) showed the
ir and 21% of those in the range 400-800 micrometer(2) were immunoreactive for
this protein. TG neurons <400 micrometer(2) were mostly devoid of OPN-ir (2%).
Virtually all (99%) Mes5 primary sensory neurons exhibited the ir. Muscle
spindles in the soleus and masseter muscles contained OPN-ir spiral axon
terminals. In the hard palate and incisor periodontal ligament, unencapsulated
corpuscular endings exhibited the ir. The co-expression of OPN with parvalbumin
and calcitonin gene-related peptide (CGRP) was also examined in the DRG and TG.
In the DRG, virtually all (97%) OPN-ir neurons exhibited parvalbumin-ir.
Conversely, 66% of parvalbumin-ir DRG neurons co-expressed OPN-ir. In the TG, 81%
of OPN-ir neurons exhibited parvalbumin-ir and 69% of parvalbumin-ir ones showed
OPN-ir. Virtually all OPN-ir DRG and TG neurons were devoid of CGRP-ir. The
present study indicates that OPN-ir primary sensory neurons in the DRG and Mes5
are spinal and trigeminal proprioceptors. OPN-ir TG neurons appear to include low
threshold mechanoreceptors.
PMID- 10773221
TI - Differential effects of trigeminal tractotomy on Adelta- and C-fiber-mediated
nociceptive responses.
AB - In this study we have tested in the rat, whether trigeminal tractotomy, which
deprives the spinal trigeminal nucleus caudalis (Sp5C) of its trigeminal inputs,
affected differentially nociceptive responses mediated by C- vs. Adelta
nociceptors from oral and perioral regions. Tractotomy had no effect on the
threshold of the jaw opening reflex, induced by incisive pulp stimulation (Adelta
fiber-mediated), but blocked the formalin response (mainly C-fiber-mediated).
These results suggest that nociceptive responses mediated by trigeminal C-fibers
completely depend on the integrity of the Sp5C, while intraoral sensations
triggered Adelta-fibers (especially of dental origin) are primarily processed in
the rostral part of the spinal trigeminal nucleus.
PMID- 10773222
TI - The O-methylated derivative of L-DOPA, 3-O-methyl-L-DOPA, fails to inhibit
neuronal and non-neuronal aromatic L-amino acid decarboxylase.
AB - The present study examined whether the O-methylated derivative of L-DOPA, 3-O
methyl-L-DOPA (3-OM-L-DOPA), inhibits neuronal (brain) and non-neuronal (liver
and kidney) aromatic L-amino acid decarboxylase (AADC) activity. The incubation
of brain, liver and kidney homogenates with 3-OM-L-DOPA (5 mM) did not result in
the formation of 3-methoxytyramine, the compound expected to result from the
decarboxylation of 3-OM-L-DOPA. Incubation of tissue homogenates with L-DOPA
resulted in a concentration-dependent formation of dopamine, revealing K(m)
values (in mM) of similar magnitude for brain (0.8), liver (1.6) and kidney
(1.0). Both benserazide and L-5-hydroxytryptophan (L-5-HTP) were found to produce
concentration dependent decreases in AADC activity with K(i) values in the microM
range. By contrast, 3-OM-L95% reduction) in liver and kidney AADC activity
accompanied by a marked decrease (49% reduction) in brain AADC activity. By
contrast, the administration of 30 mg/kg (p.o.) 3-OM-L-DOPA, which generates
levels in brain, liver and kidney six-fold those in L-DOPA-treated rats, was
found to change neither neuronal nor non-neuronal AADC activity. In conclusion, 3
OM-L-DOPA fails to interact with neuronal and non-neuronal AADC, either as
substrate or inhibitor.
PMID- 10773223
TI - Neuronal excitability and conduction velocity changes in hippocampal slices from
streptozotocin-treated diabetic rats.
AB - The effects of streptozotocin-induced diabetes on the electrophysiological
properties of central neurones were investigated in rat hippocampal slices. No
differences in membrane potential, input resistance or action potential
parameters could be detected in pyramidal or granule cells. However, a slowing of
conduction velocity in granule cells and an increase in excitability of fibre
volleys in both the perforant pathway and granule cell mossy fibre projections
was observed. The lack of effect on evoked fEPSPs in these pathways is also
consistent with diabetes-dependent changes in the voltage-dependence of synaptic
strength.
PMID- 10773224
TI - A whisper on the wind spawns a storm.
PMID- 10773225
TI - Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases
and their regulators in cardiac matrix remodeling.
AB - Myocardial fibrosis due to maladaptive extracellular matrix remodeling
contributes to dysfunction of the failing heart. Further elucidation of the
mechanism by which myocardial fibrosis and dilatation can be prevented or even
reversed remains of great interest as a potential means to limit myocardial
remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving
force behind extracellular matrix degradation during remodeling and are increased
in the failing human heart. MMPs are regulated by a variety of growth factors,
cytokines, and matrix fragments such as matrikines. In the present report, we
discuss the regulation of MMPs, the role of MMPs in the development of cardiac
fibrosis, and the modulation of MMP activity using gene transfer and knockout
technologies. We also present recent findings from our laboratory on the
regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming
growth factor-beta(1) in the failing human heart before and after left
ventricular assist device support, as well as the possibility of preventing
ventricular fibrosis using different anti-MMP strategies. Several studies suggest
that such modulation of MMP activity can alter ventricular remodeling, myocardial
dysfunction, and the progression of heart failure. It is therefore suggested that
the interplay of MMPs and their regulators is important in the development of the
heart failure phenotype, and myocardial fibrosis in heart failure may be modified
by modulating MMP activity.
PMID- 10773226
TI - Myocardial matrix degradation and metalloproteinase activation in the failing
heart: a potential therapeutic target.
AB - A fundamental structural event in the progression of heart failure due to dilated
cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix
metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to
matrix remodeling in several disease states. The goal of this report is to
summarize recent findings regarding the myocardial MMP system and the relation to
matrix remodeling in the failing heart. In both experimental and clinical forms
of dilated cardiomyopathy (DCM), increased expression of certain species of
myocardial MMPs have been demonstrated. Specifically, increased myocardial levels
of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic
forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold
in DCM. The increased levels of MMP-3 in DCM may have particular importance since
this MMP degrades a wide range of extracellular proteins and can activate other
MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was
detected. These MT-MMPs may provide important sites for local MMP activation
within the myocardium. In a pacing model of LV failure, MMP expression and
activity increased early and were temporally associated with LV myocardial matrix
remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing
model, the degree of LV dilation was attenuated and associated with an
improvement in LV pump function. Thus, increased LV myocardial MMP expression and
activity are contributory factors in the LV remodeling process in cardiomyopathic
disease states. Regulation of myocardial MMP expression and activity may be an
important therapeutic target for controlling myocardial matrix remodeling in the
setting of developing heart failure.
PMID- 10773227
TI - Matrix gene expression and decompensated heart failure: the aged SHR model.
AB - Impaired functional performance despite hypertrophic enlargement, and an
excessive accumulation of extracellular matrix, are hallmarks of the
decompensated failing heart. Age is the leading risk factor for heart failure,
and there is evidence suggesting that a number of age-associated changes in the
cardiac phenotype predispose the heart to failure. The spontaneously hypertensive
rat (SHR) exhibits compensated cardiac hypertrophy followed by a transition to
heart failure in the last quartile of the lifespan, and thus provides a useful
model of the transition from stable compensated hypertrophy to decompensated
heart failure in the context of aging. The transition to failure in the SHR is
accompanied by marked changes in the expression of an array of genes in the
heart, including increased expression of a number of genes associated with the
extracellular matrix. Drug treatments that prevent or reverse matrix gene
expression in the SHR heart improve myocardial function and survival. The aged
SHR model of decompensated heart failure has provided insight into the role of
the extracellular matrix in the transition to failure, and can be useful to
further investigate the mechanistic bases of heart failure, as well as to
evaluate the potential efficacy of novel therapeutic approaches to the treatment
of heart failure.
PMID- 10773228
TI - Infarct scar: a dynamic tissue.
AB - Infarct scar, a requisite to the rebuilding of necrotic myocardium following
myocardial infarction (MI), has long been considered inert. Earlier morphologic
studies suggested healing at the infarct site was complete within 6-8 weeks
following MI and resultant scar tissue, albeit necessary, was acellular and
simply fibrillar collagen. Utilizing molecular and cellular biologic
technologies, recent studies indicate otherwise. Infarct scar is composed of
phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb)
because they express alpha-smooth muscle actin (alpha-SMA) and these
microfilaments confer contractile behavior in response to various peptides and
amines. These cells are nourished by a neovasculature and are persistent at the
MI site, where they are metabolically active expressing components requisite to
angiotensin (Ang) peptide generation, including converting enzyme, receptors for
AngII and transforming growth factor (TGF)-beta1. They continue to elaborate
fibrillar type I collagen. Their generation of these peptides contribute to
ongoing scar tissue collagen turnover and to fibrous tissue formation of
noninfarcted myocardium. Infarct scar contraction accounts for its thinning and
its tonus may contribute to abnormal ventricular chamber stiffness with diastolic
dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized,
metabolically active and contractile. Pharmacologic interventions with
angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven
effective in attenuating scar tissue metabolic activity and minimizing adverse
accumulation of fibrous tissue in noninfarcted myocardium.
PMID- 10773229
TI - Role of mechanical factors in modulating cardiac fibroblast function and
extracellular matrix synthesis.
AB - The cardiac fibroblast is the most abundant cell type present in the myocardium
and is mainly responsible for the deposition of extracellular matrix (ECM).
Important components of cardiac ECM include structural and adhesive proteins such
as collagen and fibronectin. Excess deposition of cardiac ECM (fibrosis) has been
associated with the pathophysiological mechanical overload of the heart.
Therefore, the role of cardiac fibroblasts in "sensing", "integrating" and
"responding" to mechanical stimuli is of great interest. The development of in
vitro strain apparatuses has allowed scientists to investigate the effects of
mechanical stimuli on cardiac fibroblast function. Cardiac fibroblasts express
ECM receptors (integrins) which couple mechanical stimuli to functional
responses. Mechanical stimulation of cardiac fibroblasts has been shown to result
in activation of various signal transduction pathways. The application of defined
mechanical stimuli to cultured cardiac fibroblasts has been associated with ECM
gene expression, growth factor production, release and/or bioactivity as well as
collagenase activity. Ultimately, for fibrosis to develop the overproduction of
ECM must overcome any associated increases in collagenase activity. Mechanically
induced upregulation of ECM production may follow direct or indirect pathways
through the autocrine or paracrine action of growth factors. Given the complex
nature of the interstitial milieu of the working heart, additional research is
needed to further our understanding of the roles that mechanical stimuli play in
excess deposition of myocardial ECM.
PMID- 10773230
TI - Angiotensin II, adhesion, and cardiac fibrosis.
AB - Angiotensin II (AII) plays a critical role in cardiac remodeling. This peptide
promotes cardiac myocyte hypertrophy and cardiac fibroblast interstitial fibrotic
changes associated with left ventricular hypertrophy, post myocardial infarction
remodeling and congestive heart failure. AII mediates cardiac myocyte hypertrophy
directly via induction of immediate early genes through a MAP kinase dependent
pathway. In addition, it mediates cardiac hypertrophy indirectly by stimulating
release of norepinephrine from cardiac nerve endings and endothelin from
endothelial cells. AII also has multiple effects on cardiac fibroblasts: it
induces cardiac fibroblast proliferation, synthesis and secretion of adhesion
molecules and extracellular matrix proteins, and expression of integrin adhesion
receptors. In addition it stimulates cardiac fibroblasts to adhere more
vigorously to defined matrixes. This review will discuss the molecular pathways
that have been implicated in these AII induced effects in the cardiac fibroblast.
PMID- 10773231
TI - Pressure-independent contribution of sodium to large artery structure and
function in hypertension.
AB - BACKGROUND: Sodium sensitivity is usually studied in terms of change of blood
pressure (BP) but the specific effects on conduit arteries have not been
addressed. EXPERIMENTAL STUDIES: In genetic models of hypertension, chronically
increased sodium diet is associated with aortic hypertrophy and development of
extracellular matrix independent of BP. These alterations, often associated with
increased stiffness and secretory properties of vascular smooth muscle, are
reversed by lowering sodium intake and/or giving diuretics, independently of BP
changes. The arterial changes are chronically modulated by hormonal
counterregulatory mechanisms since, when sodium intake is high, bradykinin
blockade produces more carotid hypertrophy, and when sodium intake is normal,
less aortic collagen accumulates because of AT(1)-receptor blockade. CLINICAL
STUDIES: In longitudinal studies on hypertensive subjects, increased sodium
intake not only increases BP but also decreases brachial artery diameter,
implying pressure-independent mechanisms acting on the arterial wall. The
antihypertensive effect of diuretics is associated with little change of arterial
geometry and stiffness, probably resulting from marked angiotensin-induced
increase of arterial stiffness. This latter effect is blocked by converting
enzyme inhibition. All these arterial changes may be genetically modulated since
in salt-sensitive hypertensives, increased sodium intake is associated with
decreased arterial distensibility, and in some hypertensive subjects, a
polymorphism of the AT(1)-receptor gene has been described in association with
increased aortic stiffness and is reversed by converting-enzyme inhibition
independent of BP. CONCLUSION: In genetic models of human and rat hypertension,
increased sodium intake is associated with specific alterations of the structure
and function of conduit arteries involving extracellular matrix, but independent
of BP and atherosclerosis.
PMID- 10773232
TI - Specialization at the Z line of cardiac myocytes.
PMID- 10773233
TI - Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in
hereditary cardiomyopathic hamsters.
AB - OBJECTIVE: As the pharmacological suppression of angiotensin has been associated
with cardioprotective effects in cardiomyopathy, our primary aim was to determine
whether the expression of Smad protein components of the cardiac TGF-beta
signaling cascade is modulated by chronic AT(1) receptor blockade. Furthermore,
we examined the relationship between cardiac Smad protein expression and altered
collagen turnover in the cardiomyopathic heart. METHODS: Male UM-X7. 1
cardiomyopathic (CMP) Syrian hamsters at early (65 days) and late (200 days)
stages of cardiomyopathy were subjected to 4 week losartan (15 mg/kg/day)
treatment. Expression of left ventricular (LV) receptor-activated (Smad 2) and
common-mediator (Smad 4) Smads from control (F1-beta strain) hamsters, non
treated cardiomyopathic (CMP), and losartan-treated CMP animals was assessed.
Collagen turnover, including fibrillar collagen synthesis/accretion and cardiac
MMP activity was assessed. RESULTS: Elevated mRNA abundance of fibrillar
collagens and ANF were present in cardiomyopathic hearts and these trends were
normalized in the early stage losartan-treated group. 4-Hydroxyproline and
zymographic assays confirmed fibrosis and elevated MMP-1 and -2 activities in CMP
hearts. Losartan treatment was associated with a modest reduction of cardiac 4
hydroxyproline concentration, and a significant reduction of both MMP-1 and MMP-2
activities. While TGF-beta(1) mRNAs were elevated in both CMP groups vs.
controls, total TGF-beta protein content was not different in CMP vs. controls.
In LV preparations containing nuclear extract, elevated Smad 2 and Smad 4 protein
expression was noted in cardiomyopathic hearts vs. controls. Losartan treatment
of late-stage CMP hamsters was associated with a significant reduction in Smad 2
and a modest reduction of Smad 4 protein expression vs. untreated CMP samples.
CONCLUSIONS: Altered cardiac Smad expression, present in both early and late
stage cardiomyopathy, is positively correlated with the occurrence of cardiac
fibrosis and elevated collagen turnover in failing CMP hearts. Four week AT(1)
blockade is associated with normalized expression of cardiac Smad 2 proteins, and
these changes occur in parallel with some aspects of collagen turnover in failing
cardiomyopathic hearts.
PMID- 10773235
TI - Evolution of matrix metalloprotease and tissue inhibitor expression during heart
failure progression in the infarcted rat.
AB - OBJECTIVE: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2,
3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP
1, -2, -3, and -4) upregulation during left ventricular (LV) remodeling following
myocardial infarction (MI) in rats. METHODS: The descending left coronary artery
of male rats (Rattus norvegicus) was ligated to produce a MI. LV function and
dilation were assessed from 1 day to 16 weeks post-MI. Protein and mRNA
extraction was done on LV samples containing scar and myocardium together.
Gelatinase activity was measured by zymography. Westerns were run on the MMPs
known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as
TIMP-1, -2, and -4. RESULTS: Average infarct size was 38.6+/-1.1%, and produced
LV dysfunction and progressive LV dilation. Thoracic ascites, a marker of
congestive heart failure (HF), was not present until 12 weeks post-MI.
Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at
different timepoints during HF progression. Increased MMP protein levels occurred
sometimes without a corresponding elevation in mRNA levels, and increased TIMP
mRNA levels without increased protein levels. MMP-13 active form was elevated
during the first 2 weeks post-MI while TIMP-1 and TIMP-2 protein levels were not
significantly elevated until 2 weeks post-MI. MMP-8 and MMP-14 protein levels
increased later during heart failure progression. CONCLUSION: MMP/TIMP
upregulation evolves over time following infarction in the rat LV. Some MMPs were
significantly elevated during the first week post-MI (MMP-13, -2, and -9) and
another was not until 16 weeks post-MI (MMP-14). The dissociation between LV
MMP/TIMP mRNA and protein levels shows that post-translation processing occurs in
the rat heart.
PMID- 10773236
TI - Altered cardiac collagen and associated changes in diastolic function of
infarcted rat hearts.
AB - OBJECTIVE: Anti-inflammatory drugs have been shown to modulate collagen
deposition during myocardial infarction (MI) induced remodeling. Chronic effects
of methylprednisolone (5 mg/kg/day) and low-dose aspirin (25 mg/kg/day) on
cardiac collagen and left ventricular diastolic function were studied in rat
hearts, 21 days after MI. METHODS: Left ventricular function was assessed at
baseline and after beta-adrenergic stimulation with isoproterenol in isolated
perfused hearts, using an intraventricular balloon. After diastolic arrest, left
ventricular pressure-volume curves were obtained. Left ventricular dilation was
defined as the corresponding left ventricular volume at 20 mmHg left ventricular
diastolic pressure. In histological sections, perivascular and interstitial
collagen content were quantified morphometrically as the Sirius Red positive area
in the non-infarcted interventricular septum. RESULTS: Impaired baseline left
ventricular function of MI-hearts was improved by methylprednisolone but not by
low-dose aspirin. Isoprotenerol significantly enhanced systolic function in all
hearts, whereas it augmented the decrease in left ventricular diastolic pressure
only in methylprednisolone-treated MI-hearts. The rightward shift of the pressure
volume curve after MI was aggravated by methylprednisolone but not with low-dose
aspirin treatment. Low-dose aspirin reduced perivascular but not interstitial
collagen whereas methylprednisolone decreased both perivascular and interstitial
collagen. CONCLUSIONS: Our findings indicate that MI-induced collagen deposition
in the spared myocardium can be affected by chronic therapy with low-dose aspirin
or methylprednisolone. The effects on interstitial collagen seemed reflected in
an altered left ventricular diastolic function.
PMID- 10773234
TI - MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect
of ACE- and MMP-inhibition.
AB - OBJECTIVE: Determine the effect of a matrix metalloproteinase inhibitor (MMPi)
and angiotensin converting enzyme inhibitor (ACEi) on collagen, MMP, tissue
inhibitors of MMPs (TIMPs) expression in the spontaneously hypertensive heart
failure (SHHF) rat. METHODS: Six groups were tested: normotensive 9- and 13-month
old Wistar-Furth (WF) rats, 9-month-old SHHFs (compensatory hypertrophy), 13
month-old SHHFs with HF, and 13-month-old SHHFs orally administered with either
an MMPi (PD166793, 5 mgkg(-1)day(-1)) or ACEi (quinapril, 10 mgkg(-1)day(-1)) for
4 months. Collagen volume fraction was assessed histomorphometrically. Left
ventricular (LV) mRNA [MMP-1,-2,-3,-7,-9,-11,-13,-14; TIMP-1,-2,-3,-4; and
collagen alpha1(I) and alpha1(III)] and protein (MMP-2 and MMP-9 zymographic
activity; Western blot analysis of MMP-13, and TIMP-1,-2,-4) levels could be
quantified. RESULTS: Collagen mRNA levels were elevated in SHHFs compared to age
matched controls, but collagen volume fraction was elevated only in 13-month-old
SHHFs (approximately 2x). Only MMP-2 mRNA levels increased significantly with HF.
However, MMP-2 and MMP-9 zymographic activity, and MMP-13 protein levels
increased. TIMP-1 and TIMP-2 mRNA and protein levels increased, and TIMP-4
protein levels decreased in SHHFs vs. controls. Both drug treatments reduced LV
dilation; preserved systolic function; and normalized MMP/TIMP expression. Both
drug treatments also reduced collagen volume fraction, but only quinapril reduced
collagen mRNA levels and LV hypertrophy. CONCLUSIONS: The divergent effect of
MMPi and ACEi on collagen mRNA levels and hypertrophy indicate that drug efficacy
is mediated by different pathways in the SHHF rat.
PMID- 10773237
TI - Regression of myocardial fibrosis in hypertensive heart disease: diverse effects
of various antihypertensive drugs.
AB - OBJECTIVE: In left ventricular hypertrophy (LVH) due to systemic hypertension,
myocardial fibrosis is an important determinant of pathologic hypertrophy.
Therefore, it is most relevant to utilize an antihypertensive regimen that
permits a regression in myocardial fibrosis along with blood pressure
normalization and regression of LVH. METHODS: To address this issue we examined
60 Sprague-Dawley rats. We treated 16-week-old rats having established LVH and
myocardial fibrosis due to 8-week renovascular hypertension (RHT) with either 6
mg/kg/day zofenopril (ZOF), 30 mg/kg/day nifedipine (NIF) or 40 mg/kg/day
labetalol (LAB) for 12 weeks. Systolic arterial pressure (SAP, mmHg), left
ventricular/body weight ratio (LV/BW, mg/g), and left and right ventricular
collagen volume fractions (LVCVF, RVCVF, %) were obtained and compared with
age/sex matched untreated rats with RHT and sham-operated controls. RESULTS: In
RHT, SAP was significantly elevated compared with controls (188+/-11 vs. 125+/-5
mmHg; P<0.001) while in each treated group SAP was normalized. LV/BW was
significantly increased in RHT (2.61+/-0.12 mg/g; P<0.00001) while in each
treated group LVH was completely regressed (P<0.002 vs. untreated RHT) with LV/BW
values comparable to controls (1.82+/-0.03 mg/g) irrespective of the utilized
antihypertensive agent. In untreated RHT, myocardial fibrosis was present in the
left (LVCVF: 12.3+/-1.9%; P<0.0005 vs. 4.5+/-0.2% of controls) and right
ventricles (RVCVF: 20.6+/-2.5%; P<0.00005 vs. 8.8+/-0.4% of controls). In rats
treated with ZOF or NIF, LVCVF was significantly reduced to 5.6+/-0.4 and 5.4+/
0.6%, respectively (P<0.005 vs. untreated RHT), and RVCVF was decreased as well
(ZOF: 11.0+/-0.9%; NIF: 10.4+/-2.4%; P<0.007 vs. untreated RHT) where no
significant difference to controls remained. In contrast, treatment with LAB did
not affect myocardial fibrosis where LVCVF was 9.3+/-1.3% and RVCVF was 19.8+/
2.8%, i.e., remained significantly elevated compared with controls (P<0.007).
CONCLUSIONS: In rats with renovascular hypertension and hypertensive heart
disease that included LVH and fibrosis, equipotent doses of ZOF, NIF, and LAB
normalized arterial pressure associated with regression of LVH while only ZOF and
NIF were found to regress myocardial fibrosis.
PMID- 10773238
TI - Birth associated changes in pulmonary arterial connective tissue gene expression
in the normal and hypertensive lung.
AB - OBJECTIVES: To determine the temporal and spatial expression of the connective
tissue precursors, procollagen and tropoelastin mRNA in normal and pulmonary
hypertensive porcine pulmonary arteries from birth onwards. METHODS: Using in
situ hybridisation, connective tissue gene expression for procollagen alpha1(I)
and alpha1(III) and tropoelastin was studied in intrapulmonary arteries from
normal piglets, 5 min-16 weeks, and from piglets made pulmonary hypertensive by
exposure to hypobaric hypoxia for 3 days, from birth, 3 or 14 days of age. In
addition, Type III pN-procollagen, tropoelastin and collagen I and III were
studied by immunohistochemistry. Quantitative or semi-quantitative techniques
were applied to both in situ and immunohistochemical studies. RESULTS:
Procollagen alpha1(I) and alpha1(III) mRNA expression increased rapidly in the
media and adventitia between birth and 3 days of age (P<0.05). The increase was
transient and the number of cells expressing procollagen mRNA decreased to the
low newborn number after 6 days of age. Type III pN-procollagen immunostaining
was greatest in newborn elastic and muscular arteries and then decreased.
Collagen I and III increased mainly after 6 days of age. In animals exposed to
chronic hypobaric hypoxia from birth, the increase in procollagens I and III mRNA
was prevented. Exposure to hypoxia from 3 or 14 days led to little change in
either gene expression or in procollagen and mature collagen from the normal.
Tropoelastin gene expression was high at birth in the endothelium and media for
the first 6 days, and then decreased. Normally, tropoelastin decreased in the
media and increased in the adventitia after 16 days of age. Hypoxia had no effect
on the mRNA but led to increased tropoelastin. CONCLUSION: We demonstrated
marked, rapid changes in temporal and cell specific connective tissue gene
expression in normal pulmonary arteries immediately after birth as the
vasculature remodels. Each gene appeared to have its own timetable of expression
and responded differently to hypoxia-induced hypertension.
PMID- 10773239
TI - Expression of laminin alpha2 chain during normal and pathological growth of
myocardium in rat and human.
AB - OBJECTIVES: Fibrosis is a classical feature of cardiac hypertrophy. To date
changes within the basal lamina during normal and pathological cardiac growth
have been poorly investigated. The goal of the present study was to determine if
the expression of the muscle specific subunit of merosin (laminin alpha2 chain)
together with that of fibronectin (FN) is modified in the diseased human heart.
Laminin alpha2 chain expression was also investigated during physiological and
pathological cardiac growth in the rat. METHODS: In ten normal human hearts and
ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-alpha2 and
FN mRNA levels were quantified by slot-blot using total RNA and the protein
distribution was analysed using an immunofluorescence approach. In Wistar rats,
laminin alpha2 and FN mRNA expression was analyzed using RNase protection assay
(RPA) and slot-blot assays. RESULTS: The amount of laminin alpha2 mRNA did not
vary in normal and pathological human hearts whereas it was significantly
decreased in renovascular hypertensive rats (-20%) P<0.05 versus normal tissue).
The amount of fibronectin mRNA increased in IDMC patients (x2, P<0.05 versus
normal tissue), but was unchanged in hypertensive rats. A negative correlation
was found between the cardiac laminin-alpha2 level and the age of the patients
whatever the cardiac status. During postnatal development in the rat, a similar
decrease in cardiac laminin-alpha2 level was observed between 3 and 30 weeks of
age. Finally, the immunofluorescent approach failed to detect any alteration in
laminin alpha2 distribution within the human myocardium. CONCLUSION: These data
indicate that an imbalance between myocyte hypertrophy and the level of laminin
alpha2 might contribute to alterations in sarcolemmal properties, which occur
during the development of cardiac hypertrophy and its transition to cardiac
failure.
PMID- 10773240
TI - Oxygen and carotid body chemotransduction: the cholinergic hypothesis - a brief
history and new evaluation.
AB - Oxygen can be said to be the most fundamentally necessary substrate for life. In
those organisms having a cardiopulmonary system for delivering it in blood to the
tissues the carotid body functions as the principal detector of decreases in
arterial oxygen. Such a decrease stimulates an increase in neural output from the
carotid body to the nucleus tractus solitarii, and this can precipitate a wide
array of systemic reflex responses. The neural mechanisms involved in the genesis
of increased signal from the carotid body remain unclear. But a current model of
carotid body chemotransduction postulates that transmitter-laden glomus cells
initiate the neural activity by being depolarized by hypoxemia and releasing an
excitatory transmitter which binds to postsynaptic receptors of the adjacent
sensory afferent fibers as well as to presynaptic glomus cell autoreceptors. This
Frontiers Review evaluates anew the data supporting the hypothesis that
acetylcholine (ACh) is an (the) essential excitatory transmitter in this process
by examining ACh's fulfillment of criteria required to establish a substance as a
synaptic transmitter. All eight criteria are fulfilled in the case of ACh.
Indeed, additional data further support the Cholinergic Hypothesis.
PMID- 10773241
TI - Respiratory response to spontaneous contractions of the urinary bladder in awake
and decerebrate rats.
AB - Spontaneous contractions of the urinary bladder (SBCs) have been shown to
decrease the frequency and depth of respiration in anesthetized or
unanesthetized, decerebrate cats. The respiratory responses to bladder voiding
reflexes in the awake state have not been previously addressed. Because a chronic
rat model for the study of bladder function has been established and breathing
measurements can be made in the awake rat, we chose the rat as an experimental
model to assess whether SBCs would alter breathing in the conscious, intact
animal. Respiratory frequency increased during bladder contractions but tidal
volume remained unaffected. To assess whether the respiratory response to bladder
reflexes in rats differed from that previously observed in cats, we also studied
decerebrate, vagotomized, paralyzed and artificially ventilated rats. Contrary to
the respiratory inhibition observed in decerebrate cats, phrenic and hypoglossal
nerve activities remained unaffected during SBCs in decerebrate rats. These
results indicate a species difference in the coupling between respiration and
bladder voiding reflexes.
PMID- 10773243
TI - Gravitational effects on volume distribution in a model of partial and total
liquid ventilation.
AB - To estimate regional lung volume during ventilation with liquids (e. g.
perfluorochemicals, PFC) we developed a multi-compartment mathematical model of a
lung and thorax. The height of the fluid column and the fluid's density determine
alveolar pressure (PA). The weight of thoracic contents above any given
gravitational plane influences pleural pressure (PPL). Transpulmonary pressure
(PTP=PA&MINUS;PPL) and compliance of the lung and chest wall permit estimation of
volumes. The results indicate the lung inflates almost uniformly during total
liquid ventilation despite a substantial vertical PA gradient. Inflation
uniformity is due to the offsetting vertical PPL gradient created by the added
weight of the PFC and sustained by the relative rigidity of the chest wall.
During partial liquid ventilation our model indicates that the combination of
uniform PA with a large vertical gradient in PPL leads to a vertical PTP gradient
and therefore relative over-inflation of the top of the lung. This effect
increases with increasing PFC dose and with lung height.
PMID- 10773242
TI - Effects of protein kinase A inhibition on rat diaphragm force generation.
AB - Although protein kinases are known to play a role in modulating a variety of
intracellular functions, the direct effect of inhibition of these enzymes on
skeletal muscle force production has not been studied. The purpose of the present
study was to examine this issue by determining the effects produced on diaphragm
force generation by two protein kinase inhibitors: (a) H7, an inhibitor of both
cAMP-dependent protein kinase (PKA) and of protein kinase C, and (b) H89, a
selective inhibitor of PKA. Experiments (n=15) were performed using isolated,
arterially perfused, electrically stimulated rat diaphragms. Perfusate
temperature was adjusted to maintain muscle temperature at 27 degrees C and
arterial pressure was kept at 150 Torr. Animals were divided into three groups:
(a) a control group perfused with Krebs-Henselheit solution equilibrated with 95%
O(2)/5% CO(2), (b) a group in which H7 (2 microM) was added to the perfusate, and
(c) a group perfused with solution containing H89 (4 microM). In all three
groups, we assessed diaphragm twitch kinetics, force-frequency relationships and
in vitro fatiguability. We found that both H7 and H89 administration slowed
twitch relaxation, augmented force generation in response to low frequency
stimulation, and increased the rate of development of fatigue. Specifically, for
control, H7 and H89 groups, respectively, we found: (a) 1/2 relaxation time
averaged 64+/-2 S.E.M., 87+/-6 and 90+/-2 ms, P<0. 003, (b) force production
during 10-Hz stimulation averaged 12.6+/-1. 1, 20.1+/-2.3, and 20.3+/-2.1
N/cm(2), P<0.035, and (c) force fell to 14.3+/-2.0, 9.5+/-0.5 and 8.7+/-0.2% of
its initial value after 20 min of fatiguing stimulation, P<0.035. These data show
that it is possible to produce large increases in low frequency skeletal muscle
force generation by directly inhibiting PKA. We speculate that it may be possible
to pharmacologically augment respiratory muscle force and pressure generation in
clinical medicine by administration of PKA inhibitors.
PMID- 10773244
TI - Functional lung unit in the pig.
AB - To study the size of the vessels supplying the functional lung unit, polystyrene
beads of uniform diameter were injected intravenously in anaesthetised pigs and
subsequent gas exchange abnormalities were studied using the multiple inert gas
elimination technique. Beads of different sizes, ranging from 63 to 262 microm,
were used, each pig receiving beads of only one size. Successive 0.25 g boli of
beads (cumulative dose 1.0-1.5 g) increased shunt (from 3% baseline to 20% of
cardiac output) and pulmonary artery mean pressure (from 26 to 45 mmHg) and
decreased arterial P(O(2)) (from 96 to 43 mmHg) and cardiac output from 2.8 to
2.2 L min(-1) with no differences according to bead sizes. The dispersion of the
ventilation dist ribution (log SDV), normal at 0.39 before beads, increased
progressively with bead size from 0.48 (63 microm to 0.91 (262 microm). The 63
microm beads were lodged in vessels associated with respiratory bronchioles and
smaller airways, whereas larger beads were positioned in vessels associated with
non-respiratory airways. A linear correlation analysis between log SDV and bead
size showed that 59 microm beads produce a log SDV that is 2 SEM above mean
baseline log SDV. These findings suggest that the functional lung unit in this
species (with no collateral ventilation) is smaller than in a species of the same
size and with collateral ventilation (dog) in whom occlusion of 124 microm or
larger diameter vessels is required to increase log SDV.
PMID- 10773245
TI - Cardiorespiratory impact of the nitric oxide synthase inhibitor L-NAME in the
exercising horse.
AB - To investigate the role of nitric oxide, NO, in facilitating cardiorespiratory
function during exercise, five horses ran on a treadmill at speeds that yielded
50, 80 and 100% of peak pulmonary oxygen uptake (V(O(2)) peak) as determined on a
maximal incremental test. Each horse underwent one control (C) and one (NO
synthase inhibitor; N(G)-L-nitro-arginine methyl ester (L-NAME), 20 mg/kg) trial
in randomized order. Pulmonary gas exchange (open flow system), arterial and
mixed-venous blood gases, cardiac output (Fick Principle), and pulmonary and
systemic conductances were determined. L-NAME reduced exercise tolerance, as well
as cardiac output (C, 291+/-34; L-NAME, 246+/-38 L/min), body O(2) delivery (C,
74.4+/-5. 5; L-NAME, 62.1+/-5.6 L/min), and both pulmonary (C, 3.07+/-0.26; L
NAME, 2.84+/-0.35 L/min per mmHg) and systemic (C, 1.55+/-0.24; L-NAME, 1.17+/
0.16 L/min per mmHg) effective vascular conductances at peak running speeds (all
P<0.05). On the 50 and 80% trials, L-NAME increased O(2) extraction, which
compensated for the reduced body O(2) delivery and prevented a fall in V(O(2)).
However, at peak running speed in the L-NAME trial, an elevated O(2) extraction
(P<0. 05) was not sufficient to prevent V(O(2)) from falling consequent to the
reduced O(2) delivery. At the 50 and 80% running speeds (as for peak), L-NAME
reduced pulmonary and systemic effective conductances. These data demonstrate
that the NO synthase inhibitor, L-NAME, induces a profound hemodynamic impairment
at submaximal and peak running speeds in the horse thereby unveiling a
potentially crucial role for NO in mediating endothelial function during
exercise.
PMID- 10773246
TI - The lung of the marmoset (Callithrix jacchus): ultrastructure and morphometric
data.
AB - Owing to its small size (body weight 300-400 g), its modest demands on animal
husbandry, and in particular its relatively long life-span (up to 12 years) the
common marmoset (cotton ear marmoset: Callithrix jacchus (Cj)) might be a useful
animal model to study the adaptive capacity to different energetic demands,
adverse environmental influences such as air pollution, and aging of the lung. In
order to describe the gas exchange apparatus of healthy marmosets as a basis for
further pulmonary research, the lungs of three young adult animals have been
analysed both qualitatively and quantitatively (by morphometry) at the light and
electronmicroscopic level. Qualitatively, there is a general similarity in the
architecture and structure of lung parenchyma between marmosets and other
mammals. Quantitatively, the alveolar surface area was found to be 7662+/-1647
cm(2). Capillary surface area and volume were 6000+/-1549 cm(2), and 1.01+/-0.34
ml, respectively. The harmonic mean thickness of the air-blood barrier was
0.517+/-0.117 microm. These morphometric parameters allowed to estimate the
diffusing capacity for oxygen at 0.0299+/-0.0134 ml O(2) (sec mmHg)(-1). In
comparison with mammals of similar body size (rats, quinea pigs) it appears that
the marmoset has a higher gas exchanging capacity of the lung, which might
reflect the 'athletic' activity of this small primate. An incidental finding
worth mentioning is the individual variability of septal structures due to
variations in capillary blood volume and hematocrit. The distinction between such
functional variations and subtle pathologic alterations of lung tissue requires a
morphometric analysis at the electron-microscopic level.
PMID- 10773247
TI - Continuous circadian measurements of ventilation in behaving adult rats.
AB - Body temperature (Tb) and oxygen consumption (V(O(2))) are important determinants
of ventilation (VE). While the circadian rhythms in Tb and V(O(2)) have been well
described, the daily pattern of VE has not due to limitations in the available
methods for measuring VE. Here we describe an adaptation of the barometric method
using a chamber in which a large flow through very small restrictions was
generated by the combined action of a positive pressure pump on the entrance and
a negative pressure pump at the outlet. In this way the chamber effectively
behaved as a closed system, despite having a high enough flow for long-term
recording in freely moving, undisturbed small animals. This system was then used
to test the hypothesis that VE oscillates with a circadian pattern similar to
that of Tb(.) Measurements of tidal volume (VT) and breathing rate (f), in
combination with Tb and activity by telemetry, were made in eight adult rats over
4-6 days under 12:12 light:dark conditions. Both VT, f, and thus VE, showed a
circadian pattern similar to that of Tb and activity; that is, values were higher
during the dark compared to the light phase. The differences in VE levels
according to the time of the day suggest that mechanisms involved in the control
of breathing may also have circadian patterns.
PMID- 10773248
TI - In this issue ellipsis
PMID- 10773249
TI - The Dutch normal-pressure hydrocephalus study. How to select patients for
shunting? An analysis of four diagnostic criteria.
AB - BACKGROUND: Comparison of the predictive value of four "diagnostic tests" for the
outcome of shunting in patients with normal-pressure hydrocephalus (NPH).
METHODS: Ninety-five NPH patients who received shunts were followed for 1 year.
Gait disturbance and dementia were quantified by an NPH scale and handicap by a
modified Rankin scale. Primary outcome measures were differences between the
preoperative and last scores on both the NPH scale and the modified Rankin scale.
Clinical and computed tomographic (CT) findings typical of NPH, absence of
cerebrovascular disease, and a resistance to outflow of cerebrospinal fluid (CSF)
>/= 18 mmHg/ml/minute were designated as a positive test outcome; clinical and CT
findings compatible with NPH, presence of cerebrovascular disease, and an outflow
resistance < 18 mmHg/ml/minute as a negative test outcome. RESULTS: For each of
the four tests the percentage of patients classified as improved was
significantly greater for those with positive than with negative test results.
Measurement of CSF outflow resistance was the only significant prognostic factor
for the improvement ratio in NPH scale and CT in the modified Rankin scale
according to multivariate logistic regression analysis. The accurate predictive
value of the combination of typical clinical and CT findings was 0.65, that of
the positive test results of outflow resistance, clinical and CT findings was
0.74. CONCLUSION: The best strategy is to shunt NPH patients if their outflow
resistance is >/= 18 mmHg/ml/minute or, when the outflow resistance is lower, if
their clinical as well as their CT findings are typical of NPH.
PMID- 10773250
TI - The optimal transarticular c1-2 screw length and the location of the hypoglossal
nerve.
AB - BACKGROUND: Injury to the hypoglossal nerve is a complication associated with
transarticular C1-2 screw placement. This complication can be caused by a
misdirected or too long screw. Little is known about the optimal screw length and
its relationship to the hypoglossal nerve. METHODS: Twenty cervical spine
specimens were used to study the optimal length of the transarticular C1-2 screw.
Using the Magerl technique, a 3.0 mm drill bit was inserted into the C2 lateral
mass, passing through the C1-2 facet joint and penetrating the upper portion of
the ventral cortex of the lateral mass of the atlas. After drilling, the hole
length was measured between the dorsal cortex of the C2 inferior articular
process and the ventral cortex of the C1 lateral mass. In addition, six sagittal
sectioned cadavers were carefully dissected to observe the location of the
hypoglossal nerve in the anterior aspect of the atlantoaxial region. RESULTS: The
results of the measurements showed that the mean optimal screw path length for
all specimens was 38.1 +/- 2.2 mm with a range of 34-43 mm. There was no
significant difference between sexes in the screw path length (p 0.05). The
hypoglossal nerve lies vertically in front of the lateral portion of the C1
lateral mass and the C1-2 facet joint. The area where the hypoglossal nerve lies
is approximately 2-3 mm lateral to the middle of the anterior aspect of the C1
lateral mass. CONCLUSIONS: This study suggests that the mean optimal
transarticular C1-2 screw length may be 38 mm; however, the determination of the
accurate optimal C1-2 screw length should be made on an individual basis. Risk to
the hypoglossal nerve can be eliminated if Magerl's technique is performed
exactly.
PMID- 10773251
TI - Pituitary adenomas: results of 684 surgically treated patients and review of the
literature.
AB - BACKGROUND: The outcome of patients with pituitary adenomas who were treated
surgically with or without postoperative radiotherapy was analyzed. The purpose
of this study was to determine the factors that strongly influence (A) tumor
control, (B) the efficacy of surgery, and (C) radiotherapy based on the hormonal
activity of adenomas and its invasion characteristics. METHODS: Between 1982
1996, 684 patients with the diagnosis of pituitary adenoma were operated on. The
mean age was 38 years and the mean follow-up time was 40.5 months. A total of 516
patients who were followed for more than 1 year were studied to analyze the
effect of treatment modalities and invasion characteristics on tumor control.
There were 297 patients with prolactinomas, 118 patients with somatotropinomas,
45 with corticotropinomas, 17 with mixed adenomas, two with thyrotropinomas, and
205 with null cell adenomas. All patients were classified according to Hardy's
modified radiological classification scheme and analyzed in invasive and
noninvasive groups individually based on this classification system. In the early
postoperative period, 230 of these patients were given conventional radiotherapy
with a mean dose of 4400 cGy. The following factors were analyzed for prognostic
significance in tumor control: the effects of surgery and radiotherapy based on
tumor types and invasion characteristics, the existence of histologically proven
invasion of the dura mater overlying the sellar floor, and the early results of
topical bromocriptine application in macroprolactinoma patients. RESULTS: Overall
surgical complications and mortality rate were similar to those of large series
reported in the literature. Except for the invasive somatotropinomas and null
cell adenomas, statistical analysis demonstrated the ineffectiveness of
radiotherapy on tumor control. We did not detect any positive correlation between
the recurrence rate and mean recurrence time or dural invasion of the sellar
floor. Topical bromocriptine application seemed to improve tumor control in 21
selected macroprolactinoma patients. CONCLUSION: Conventional radiotherapy is not
as effective as expected, considering its adverse effects. The increased side
effects of radiotherapy in cases with supra-parasellar extension, especially to
the optic pathway and hypothalamus, limit its benefits, which could be
demonstrated only in invasive somatotropinomas and null cell adenomas. In
contrast with our current beliefs, tumoral infiltration of the sellar dura mater
is not a prognostic factor for recurrence and therefore should not be a criterion
for radiotherapy after surgery. Topical application of bromocriptine into the
sellar cavity after tumor removal seems to provide superior results compared with
the conventional treatment modalities.
PMID- 10773252
TI - Tumor bed cyst formation after BCNU wafer implantation: report of two cases.
AB - BACKGROUND: Interstitial implantation of BCNU wafers is currently used to treat
glioblastoma multiforme. Known complications of BCNU wafer implantation include
abnormalities of wound healing (including CSF leak), edema formation, and
intracranial infection. The purpose of this report is to alert neurosurgeons to
an additional potential side effect: formation of a cystic mass within the
implanted tumor bed. CASE PRESENTATIONS: Two patients are described: a 54-year
old male, who presented with a large right parieto-occipital mass, and a 47-year
old woman with a large right frontal lobe tumor. Both tumors were found on
initial craniotomy to be glioblastoma multiforme; both recurred rapidly despite
radiation therapy. Patients were treated with a second craniotomy for tumor
resection and placement of BCNU wafers. After implantation, the first patient did
well for 6 weeks, then developed lethargy, headaches, and vomiting. CT scan
showed a large cyst at the craniotomy site; this required reoperation for
drainage. The second patient had a seizure, deterioration of mental status, and
progressive hemiparesis 10 days after wafer implantation. CT scan again showed
that a large cyst had formed in the area of the previous surgery; she also
required reoperation. In each case, minimal tumor and no evidence of infection
were found. Within a few more weeks, each patient succumbed to progressive
disease. CONCLUSIONS: The hypodense, roughly spherical cysts clearly demonstrated
clinically significant mass effect, and required reoperation despite treatment
with high-dose corticosteroids. Neurosurgeons should be alert to the possibility
of tumor bed cyst formation in patients treated with interstitial BCNU wafers.
PMID- 10773253
TI - Is decompressive craniectomy for acute cerebral infarction of any benefit?
AB - BACKGROUND: Acute occlusion of the major cerebral arteries results in ischaemic
changes to the brain, without time for reperfusion by the collateral circulation.
The subsequent cellular events lead to a breakdown of the blood-brain barrier,
causing malignant cerebral edema manifested clinically by a rapid neurological
deterioration. The aim of this study was to determine the value of surgical
decompression in patients who present with acute cerebral infarction. METHODS:
Retrospective review of patients with deteriorating consciousness level from
massive cerebral ischemia and secondary edema, treated by decompressive
craniectomy. RESULTSThere were 10 patients over a 2-year period from 1997-99,
consisting of seven male and three female patients (mean age 47.56 years) with a
mean preoperative Glasgow Coma Scale (GCS) score of 6/15. Three patients had
dominant middle cerebral artery (MCA) infarction, four had nondominant MCA
infarction, one had posterior cerebral artery infarction, and the remaining two
had cerebellar infarction. At a mean follow-up period of 7 months, two patients
had died (20% mortality), four patients (40%) were vegetative or severely
disabled, and the remaining four patients (40%) had mild disability or good
outcome. Favorable prognostic factors were younger age (less than 50 years) and
good initial GCS score (14 or better). CONCLUSION: Decompressive craniectomy in
the setting of acute brain swelling from cerebral infarction is a life-saving
procedure and should be considered in younger patients who have a rapidly
deteriorating neurologic status.
PMID- 10773254
TI - Considerations on surgical treatment for elderly patients with intracranial
aneurysms.
AB - BACKGROUND: The purpose of this study was to investigate why elderly patients
have poorer outcomes and to determine indications for surgery in elderly
patients. METHODS: One hundred fifty-four patients with intracranial aneurysms
admitted to the Department of Neurosurgery, Showa University School of Medicine,
from 1990 through 1996 were reviewed. The patients were classified by age into
three groups (young group, middle-aged group, elderly group). RESULTS: Forty-four
patients (28.6%) were in the elderly group (mean age, 73 years). No difference in
outcome was found between middle-aged and elderly patients if patients were
stratified according to clinical grade. In addition, the main factors related to
unfavorable outcomes in elderly patients were infection, organ failure, aneurysm
rerupture before operation, and delayed ischemic deterioration. Elderly patients
were more likely to experience rebleeding and have poor outcomes. CONCLUSIONS:
Our results suggest that elderly patients should have early surgery. Furthermore,
we found that the presence of hypertension or atherosclerosis had no significant
effect on outcome. We conclude that early surgical treatment of aneurysms is
indicated for elderly patients with good clinical grades in the absence of organ
failure.
PMID- 10773255
TI - Cerebellar hemorrhage after coil embolization for a ruptured vertebral dissecting
aneurysm.
AB - BACKGROUND: We present a case of ruptured vertebral dissecting aneurysm that
exhibited cerebellar hemorrhage after successful embolization of the vertebral
artery including the dissected site. CASE PRESENTATION: A 59-year-old man
suffered a sudden onset of severe occipital headache when he looked up. Computed
tomography demonstrated subarachnoid hemorrhage. Angiography revealed a right
vertebral dissecting aneurysm distal to the posterior inferior cerebellar artery.
Endovascular embolization of the aneurysm was performed with preservation of the
posterior inferior cerebellar artery. The next day, the patient suffered a
cerebellar hemorrhage in the vermis. The intracranial pressure was controlled by
external ventricular drainage. The patient was discharged with mild cerebellar
ataxia and bilateral abducens nerve palsy. CONCLUSION: In a case of vertebral
dissecting aneurysm distal to the posterior inferior cerebellar artery, blood
circulation in the vertebral arterial system may change after embolization of the
aneurysm. In our case, the preserved posterior inferior cerebellar artery might
have been hemodynamically stressed postoperatively, resulting in cerebellar
hemorrhage. Therefore, strict control of blood pressure is essential in the acute
stage after occlusion of the aneurysm.
PMID- 10773256
TI - Chronological changes in MRI findings of spinal dural arteriovenous fistula.
AB - BACKGROUND: Intramedullary high-intensity changes on T2-weighted magnetic
resonance images (MRI) occur in patients with spinal dural arteriovenous fistulas
(AVF). Reduction of the high-intensity area after treatment has been noted;
however, there are still questions about whether the change is related to
preoperative clinical grade, postoperative improvement, or efficacy of treatment.
This study tried to clarify the relationship between chronological changes in the
high intensity area with the treatment and clinical course. METHODS:
Chronological changes in an intramedullary high-intensity area after surgery were
retrospectively analyzed in recent 13 patients with spinal dural AVFs who were
treated and followed by MRI. RESULTS: Preoperative intramedullary high-intensity
areas were observed on T2-weighted images in all cases. The extent of the high
intensity area correlated with preoperative neurological deficits. The
intramedullary high-intensity area was reduced or diminished after successful
interruption of AVFs. The high-intensity area started to decrease within 1 to 4
months after treatment in all patients, and disappeared at 2 weeks to 23 months
in seven patients. The reduction may suggest interruption of the fistula and
improvement of venous circulation, but was not always correlated to clinical
improvement. The intramedullary high-intensity areas rapidly disappeared in two
patients, but did not clearly correspond to the clinical improvement.
CONCLUSIONS: The time course of postoperative MRI changes is helpful for
evaluating the efficacy of treatment after surgery for spinal dural AVFs.
PMID- 10773257
TI - Intraoperative direct subcortical stimulation for identification of the internal
capsule, combined with an image-guided stereotactic system during surgery for
basal ganglia lesions.
AB - BACKGROUND: The two main problems of surgery for basal ganglia lesions are:
first, the difficulty of accurately localizing the lesion in this deep location;
and second, the proximity to the internal capsule, with the risk of permanent
postoperative sequelae. The author describes the use of intraoperative direct
electrical subcortical stimulation in the identification and preservation of the
internal capsule, combined with an image-guided stereotactic system for the
selection of the best surgical approach in a case of deep cavernoma. CASE
DESCRIPTION: A 33-year-old man was admitted to our institution with a history of
three episodes of transitory left hemiparesia in the last 12 years. Neurological
examination revealed a mild left weakness. Magnetic resonance imaging (MRI)
showed typical features of a right posterior capsular-lentiform cavernoma. To
prevent another hemorrhagic event, surgery was performed via a right transdistal
sylvian approach, using a computer-assisted stereotactic method that allowed us
to reach the lesion directly and direct stimulations to detect the subcortical
pyramidal pathways. The patient had a transitory worsening with complete recovery
in 10 days. Control MRI showed total resection. CONCLUSION: As described at the
cortical level, the intraoperative direct subcortical stimulations seem also to
represent an easy, safe, accurate, and reliable method of real-time functional
identification of the internal capsule during surgery for basal ganglia lesions.
The combination with an image-guided stereotactic system to accurately localize
the lesion minimizes the risk of postoperative sequelae, and seems to warrant an
increase of the surgical indications in this location.
PMID- 10773258
TI - Familial arteriovenous malformations in siblings.
AB - BACKGROUND: Familial arteriovenous malformations (AVMs) of the brain are rare. We
present two sisters with the same parents who harbored AVMs that were
successfully treated. METHODS: The elder sister presented with a unilateral
migrainous type of headache overlying the right parietal area. The younger one
suffered from exercise-induced headaches. Both were neurologically intact.
Magnetic resonance imaging scans of the brain and cerebral angiography delineated
the lesions. Both sisters underwent endovascular embolization followed by
surgical resection. RESULTS: Postoperatively, aside from a left inferior
quadrantanopsia in the elder sister, both were neurologically intact.
CONCLUSIONS: We report the rare occurrence of familial AVMs in two siblings and
review the literature of 14 reports. No genetic predisposition was found.
PMID- 10773259
TI - Apoptosis of endothelial cells in vessels affected by cerebral vasospasm.
AB - BACKGROUND: Cerebral vasospasm after subarachnoid hemorrhage is a prolonged
contraction that leads to cerebral ischemia or infarction. Morphological studies
of cerebral arteries during vasospasm have shown extensive necrosis of smooth
muscle cells and desquamation and dystrophy of endothelial cells. The mechanism
of cellular death is unknown. METHODS: We report an observation of apoptotic
changes in the cerebral arteries of a patient who died after suffering severe
cerebral vasospasm caused by aneurysmal rupture. Subarachnoid hemorrhage and
cerebral vasospasm were confirmed by computed tomography scanning and angiogram.
Histological and immunohistological examinations for apoptosis were performed in
cerebral arteries. For control, the arteries from another patient, who died of
trauma without head injury, were used. RESULTS: Corrugation of the internal
elastic lamina and increased amounts of connective tissue was demonstrated by
light microscopy. Apoptotic changes, characterized by condensation of chromatin
of the nucleus and detachment from the basal membrane, were found on transmission
electron microscopy in endothelial cells. Terminal deoxynucleotidyl transferase
mediated deoxyuridine triphosphate-biotin nick end labeling reaction revealed
positive staining of the nuclei of the endothelial cells. CONCLUSIONS: This study
demonstrates that apoptosis occurred in the cerebral arteries in a patient who
died of cerebral vasospasm. The possible role of apoptosis in cerebral vasospasm
is discussed.
PMID- 10773260
TI - Telomerase activity and the expression of telomerase components in pituitary
adenoma with malignant transformation.
AB - BACKGROUND: Telomerase activity responsible for cellular immortality may
participate the development of human cancers. Telomerase is a multisubunit
ribonucleoprotein composed of at least three components: hTERT, hTERC, and TEP1.
This is the first report showing telomerase activity and telomerase component
expression in pituitary adenoma with histological malignant transformation.
DESCRIPTION: A 16-year-old male with a prolactin-producing pituitary adenoma with
metastasis is presented. The patient underwent three partial resections of an
intra- and suprasellar lesion over a 2-year period and received focal
irradiation. Eight years after the first admission, a metastatic lesion to the
subarachnoid space around the medulla oblongata was detected and the lesion was
resected as the fourth operation. Furthermore, the suprasellar lesion showed
regrowth and partial resection was performed as the fifth operation. The last two
specimens were diagnosed as pituitary carcinoma. Radiotherapy with gamma knife
was performed for the residual suprasellar lesion and a new lesion in the left
temporal lobe after the fifth operation. Telomerase activity was examined by
TRAP/TRAP-HPA methods, qualitatively and quantitatively. Telomere length was
examined by Southern blot analysis, and the expression of telomerase components
(hTERT, hTERC, and TEP1) was examined by reverse transcriptase-polymerase chain
reaction (RT-PCR). The MIB1 index, telomerase activity, and hTERT expression
increased according to histologic malignancy chronologically in this patient.
None of the specimens showed immunoreactivity for p53, EGFR, or bc12. No
telomerase activity was detected in pituitary adenomas without malignant
transformation, other benign brain tumors, or normal brain tissues. CONCLUSION:
We report a patient with pituitary adenoma transforming to carcinoma. The tumor
cells acquired immortality and revealed malignant transformation during the
course of the disease, that was proved by an increase of telomerase activity and
hTERT expression.
PMID- 10773261
TI - Successful closure of recurrent traumatic csf rhinorrhea using the free rectus
abdominis muscle flap.
AB - BACKGROUND: We present two patients in whom a free rectus abdominis muscle flap
was used to close recurrent traumatic CSF rhinorrhea. CASE DESCRIPTION: CT scan
of both patients showed frontal lobe atrophy and porencephaly after contusional
hematoma. In the first patient, because the site of CSF leakage was not
identified and the patient underwent three unsuccessful attempts to close the
fistula using the fascia lata, we treated the patient by unifying all paranasal
sinuses and by filling them with a free rectus abdominis muscle flap. In the
second patient, CSF rhinorrhea recurred 6 years after closure of the fistula
using the fascia lata. The patient underwent separation of a porencephalic cyst
from the paranasal sinus and a free muscle flap was placed extradurally, because
the CSF pulse pressure in the enlarged left anterior horn eroded the previously
repaired fascia lata, resulting in the recurrence of CSF leakage. CONCLUSION:
Although duraplasty is the primary procedure for repairing dural fistulas, the
vascularized free muscle flap is an alternative method when the location of the
fistula is not identified or the patient with recurrent CSF rhinorrhea has severe
frontal lobe atrophy and porencephaly.
PMID- 10773262
TI - Teflon granuloma after microvascular decompression for trigeminal neuralgia.
AB - BACKGROUND: Our purpose was to research the factors that may induce Teflon
granuloma in trigeminal neuralgia patients who have undergone microvascular
decompression (MVD) procedures, to propose methods for the early diagnosis of
Teflon granuloma, and provide suggestions for reducing this complication.
METHODS: From 1985 to 1996, 89 trigeminal neuralgia patients underwent MVD with
Teflon felt to separate the offending vessels and the trigeminal nerve. Ten
patients had secondary explorations for recurrent symptoms. Five patients
developed recurrent facial pain associated with facial numbness within a certain
period after the first operation. We reviewed the onset and site of the initial
symptoms, the duration of the symptoms, the operative findings and methods, and
the results of the operations. In the reoperative patients, we analyzed the
initial and secondary symptoms after the first operation, and the time to
relapse. We compared the operative findings and methods in these operations.
RESULTS: The operative findings in the 10 patients with recurrence were Teflon
granuloma in five patients, arterial loop compression in three patients, venous
compression in one patient, and negative exploration in one patient. The Teflon
granuloma patients all complained of facial numbness after the first MVD
operation. The incidence of Teflon granuloma after MVD was 5.6% (5/89).
CONCLUSION: The Teflon felt used in the MVD procedure can produce complications.
It is not absolutely inert when used in MVD procedures. When it contacts the
tentorium and/or dura, an inflammatory giant-cell foreign body reaction can be
induced. In the future, we should search for other implants to replace the Teflon
felt. However, until new materials are found, we suggest that the Teflon felt be
kept away from the tentorium and dura and placed completely within the CSF
cisterna. We can diagnose Teflon granuloma early with enhanced CT and/or MRI,
especially in patients with new facial numbness symptoms after Teflon MVD
procedures. The results of reexploration of Teflon granulomas are more
satisfactory than a negative exploration or venous compression. We may be able to
decrease the incidence of Teflon granuloma. We should be more aggressive in
performing reexploration in these recurrent patients.
PMID- 10773263
TI - Ethyl-2-cyanoacrylate fixation of the cranial bone flap after craniotomy.
AB - BACKGROUND: This procedure was done in order to evaluate the efficacy and safety
of ethylcyanoacrylate as an adhesive for fixation of the bone flap. METHODS: One
hundred consecutive craniotomies in patients older than 16 years in which the
bone flap was fixed with ethyl-2-cyanoacrylate were studied. The osteosynthesis
and any complications in all cases were followed clinically and radiologically
for 3 months. RESULTS: Clinical and radiographic observation demonstrated that
osteosynthesis was produced in 100% of the cases with no complications related to
this procedure. CONCLUSION: This technique proved to be safe, fast, and easy to
accomplish, with immediate stability of the bone flap and excellent cosmetic
results.
PMID- 10773264
TI - The neurosurgical travel club, part two-finis.
PMID- 10773313
TI - Characterization of avian reovirus non structural protein sigmaNS synthesized in
Escherichia coli.
AB - The coding region of avian reovirus S1133 genomic segment S4, encoding the non
structural protein sigmaNS, was inserted into expression vector pET28a and the
protein was expressed in Escherichia coli BL21(DE3) as a fusion protein
containing a C-terminal peptide with six tandem histidines (His-tag). The
expressed protein (esigmaNS) consistent with the expected molecular size of the
avian reovirus protein sigmaNS synthesized in infected cells was readily purified
by His-Bind Resin. The esigmaNS was further confirmed to be indistinguishable
from viral sigmaNS by immunoblot analysis. The esigmaNS binds 32P-labeled ssRNA
probe produced by run-off transcription of clone pGEM-3Zf(+)S4. The binding
activity is blocked by heterologous yeast rRNA, but not by homologous avian
reovirus dsRNA and heterologous infectious bursal disease virus dsRNA and salmon
sperm dsDNA. Therefore, the ssRNA-binding activity of the expressed protein
sigmaNS is non sequence-specific, similar to that previously described for viral
sigmaNS purified from avian reovirus infected cell extracts. In addition, the
recent data also show that the optimal salt (NaCl) concentration and pH for its
binding are 100-150 mM and 7.0, respectively, in terms of the UV cross-linking
and RNase A treatment of the reaction mixtures prior to the denaturing gel
analysis.
PMID- 10773314
TI - A new densovirus isolated from the mosquito Culex pipiens (Diptera: culicidae).
AB - We have isolated from a laboratory strain of Culex pipiens in which abnormal
larval mortality occurred a small icosahedral nonenveloped DNA virus sharing the
main biological and biophysical properties of densoviruses (DNVs). Unlike DNVs
isolated previously from Aedes species, i.e. the AaeDNV and the AalDNV
(Afanasiev, B.N., Galyov, E. E., Buchatsky, L.P., Kozlov, Y.V., 1991. Nucleotide
sequence and genomic organization of Aedes densonucleosis virus. Virology 185,
323-336; Boublik, Y., Jousset, F.-X., Bergoin, M., 1994. Complete nucleotide
sequence and genomic organization of the Aedes albopictus Parvovirus (AaPV)
pathogenic for Aedes aegypti larvae. Virology 200, 752-763), this mosquito DNV
named CpDNV possesses a genome of 6 kb separately encapsidated in stoichiometric
proportion as 'plus' and 'minus' strands. The lack of sequence homology between
the CpDNV and the AalDNV genome and of antigenic cross-reactivity between their
capsid polypeptides indicates that these two mosquito DNVs are phylogenetically
distant. In contrast, the CpDNV appears to be related to the Junonia coenia
densovirus (JcDNV) at both serological and genomic levels.
PMID- 10773316
TI - The amino and carboxyl domains of the infectious bronchitis virus nucleocapsid
protein interact with 3' genomic RNA.
AB - Previous studies indicated that the nucleocapsid (N) protein of infectious
bronchitis virus (IBV) interacted with specific sequences in the 3' non-coding
region of IBV RNA. In order to identify domains in the N protein that bind to
RNA, the whole protein (409 amino acids) and six overlapping fragments were
expressed as fusion polypeptides with six histidine-tags. Using gel shift assays,
the intact N protein and amino polypeptides, from residues 1 to 171 and residues
1 to 274, and carboxyl polypeptides, extending from residues 203 to 409 and
residues 268 to 407, were found to interact with positive-stranded IBV RNA
representing the 3' end of the genome. The two 32P-labeled probes that interacted
with N and the amino and carboxyl fragments of N were RNA consisting of the IBV N
gene and adjacent 3' non-coding terminus, and RNA consisting of the 155
nucleotide sequences at the 3' end of the 504-nt 3' untranslated region. In
contrast, the polypeptide fragment from the middle region, residues 101-283, did
not interact with these 3' IBV RNAs. The binding site in the amino region of N
was either not present or only partially present in the first 91 residues because
no interaction with RNA was observed with the polypeptide incorporating these
residues. Cache Valley virus N expressed with a histidine tag, bovine serum
albumin, and the basic lysozyme protein did not shift the IBV RNA. The lower
molarities of the carboxyl fragment compared with residue 1-274 fragment needed
for equivalent shifts suggested that the binding avidity for RNA at the carboxyl
domain was greater than the amino domain.
PMID- 10773315
TI - Epstein-barr virus latent membrane protein (LMP1) induces specific NFkappaB
complexes in human T-lymphoid cells.
AB - The Epstein-Barr virus (EBV) latent membrane protein (LMP1) is believed to play a
crucial role in oncogenesis mediated by this virus. We and others previously
showed that LMP1 can induce NFkappaB activity in several non-lymphoid cells and B
lymphoid cell lines. Here we show that LMP1 is also able to efficiently induce
NFkappaB in human T-lymphoid and monocytic cells. Specific NFkappaB complexes
were detected in the nuclei of transfected Jurkat cells using gel mobility shift
assays and Western blot analyses. Using antibodies, we demonstrated that these
complexes contain NFkappaB subunits NFkB1, NFkB2, RelA and c-Rel. Our results
also showed that the NFkappaB complexes induced by LMP1 are able to bind to the
NFkappaB consensus sequence in the promoter of the interleukin-2alpha receptor
gene and induce expression from a minimal promoter linked to four tandem copies
of this sequence. This suggests a possible mechanism by which LMP1 could induce T
cell activation and proliferation.
PMID- 10773317
TI - Rescue of synthetic RNAs into thogoto and influenza A virus particles using core
proteins purified from Thogoto virus.
AB - The ribonucleoprotein (RNP) complexes of Thogoto virus (THOV), a tick-borne
orthomyxovirus, have been purified from detergent-lysed virions. The purified
RNPs were then disrupted by centrifugation through a CsCl-glycerol gradient to
obtain fractions highly enriched in nucleoprotein (NP) and virtually devoid of
viral genomic RNA. When these NP-enriched fractions were incubated with a
synthetic THOV-like RNA, and the mixtures were transfected into THOV-infected
cells, the synthetic RNA was expressed and packaged into THOV particles.
Similarly, hybrid mixtures containing purified THOV NP and influenza A virus
synthetic RNAs (either a model CAT RNA or a gene encoding the viral
neuraminidase), were prepared and transfected into influenza A virus-infected
cells. The synthetic CAT RNA, was shown to be expressed and packaged into virus
particles, and the neuraminidase gene was rescued into influenza virions. These
data are discussed in terms of the similarities observed between THOV and
influenza A virus and the potential application of the THOV purified proteins for
rescuing synthetic genes into infectious viruses.
PMID- 10773318
TI - Biological characteristics of genetic variants of Urabe AM9 mumps vaccine virus.
AB - The Urabe AM9 mumps vaccine is composed of a mixture of variants distinguishable
by a difference at nucleotide (nt) 1081 of the hemagglutinin-neuraminidase (HN)
gene (Brown, E.G., Dimock, K., Wright, K.E., 1996. The Urabe AM9 mumps vaccine is
a mixture of viruses differing at amino acid (aa) 335 of the hemagglutinin
neuraminidase gene with one form associated with disease. J. Infect. Dis. 174,
619-622.). Further genetic and biological variation was detected in plaque
purified viruses from the Urabe AM9 vaccine by examining the HN gene sequence,
plaque morphology, cytopathic effects and growth in Vero cells, and temperature
sensitivity (ts). Infection of Vero cells with plaque purified viruses with a G
at nt 1081 of the HN gene produced large, clear plaques, caused significant CPE
early after infection but yielded lower titres of virus than other purified
viruses. None of these viruses were ts. In contrast, half of the plaque purified
viruses with an A at nt 1081 were sensitive to a temperature of 39.5 degrees C.
These viruses produced small plaques, caused significant CPE and grew to low
titres. Two ts viruses possessed a unique aa substitution at aa 468 of HN. The
remaining A(1081) viruses were not ts, produced large plaques but little CPE, and
grew to titres 10-fold higher than the G(1081) viruses. Isolates of Urabe AM9
associated with post-vaccination illness were similar to these non-ts A(1081)
viruses, but could be further sub-divided into two groups on the basis of a
difference at aa 464 of HN. The post-vaccination isolates may represent
insufficiently attenuated components of the vaccine, while the G(1081) and ts
subset of A(1081) viruses may be more fully attenuated.
PMID- 10773319
TI - Changes in the outer capsid proteins of bluetongue virus serotype ten that
abrogate neutralization by monoclonal antibodies.
AB - Six neutralizing monoclonal antibodies (Mabs) and nine neutralization resistant
viral variants (escape-mutant viruses (EMVs)) were used to further characterize
the neutralization determinants of bluetongue virus serotype 10 (BTV10). The EMVs
were produced by sequential passage of a highly cell culture adapted United
States prototype strain of BTV10 in the presence of individual neutralizing Mabs.
Mabs were characterized by neutralization and immune precipitation assays, and
phenotypic properties of EMVs were characterized by neutralization assay.
Sequencing of the gene segments encoding outer capsid proteins VP2 and VP5
identified mutations responsible for the altered phenotypic properties exhibited
by individual EMVs. Amino acid substitutions in VP2 were responsible for
neutralization resistance in most EMVs, whereas an amino acid substitution in
VP5, without any change in VP2, was responsible for the neutralization resistance
of one EMV. The data confirm that VP2 contains the major neutralization
determinants of BTV, and that VP5 also can influence neutralization of the virus.
The considerable plasticity of the neutralization determinants of BTV has
significant implications for future development of non-replicating vaccines.
PMID- 10773320
TI - CD4(+) T-cell responses to bovine viral diarrhoea virus in cattle.
AB - Friesian calves were infected with one of three isolates of bovine viral
diarrhoea virus (BVDV) and used to establish parameters for an in vitro model of
BVDV-reactive T-cell responses in cattle. The study assessed virus clearance,
seroconversion, maturation of lymphoproliferative responses (both during and
following disease resolution) and the antigen-specificity of CD4(+) T cells from
recovered animals. Seroconversion and virus-specific lymphoproliferation were not
detected until viraemia had resolved. Interestingly, lymphoproliferation was
detected earlier in the animals infected with cytopathic viruses than in those
infected with noncytopathic virus despite broadly similar rates of virus
clearance and seroconversion for both biotypes. CD4(+) and CD8(+) T cells were
induced to proliferate by virus-infected stimulator cells whereas only CD4(+) T
cells responded to non-infectious antigens. Lymphoproliferation was strain cross
reactive and MHC-restricted. Induction of T-cell proliferation by recombinant
proteins identified the major envelope proteins E(rns) and E2 and the
nonstructural (NS) 2-3 protein as T-cell determinants. In addition, the capsid
(C) and/or the amino-terminal proteinase, N(pro) were identified as T-cell
determinants from the responses of short-term T-cell lines. Thus, in this model,
the CD4(+) T-cell repertoire induce by acute BVDV infection includes at least the
major envelope proteins, NS2-3, and capsid and/or N(pro).
PMID- 10773321
TI - Murine polyomavirus infection of 3T6 mouse cells shows evidence of predominant
necrosis as well as limited apoptosis.
AB - The current study was developed to determine if polyomavirus infected 3T6 mouse
cells evoked an apoptotic or a necrotic mechanism during infection. Infected
cells were analyzed by flow cytometry, transmission electron microscopy (TEM),
DNA electrophoresis and by measuring caspase-3 enzymatic activity. Infected cells
that were analyzed at 72 h post-infection showed the following: flow cytometry
analysis revealed a 5% increase in apoptotic cells and a 46% increase in necrotic
cells when compared to uninfected cells; electron microscopy showed 10% cells
with characteristic apoptotic morphology and 40% with necrotic appearance;
caspase-3 activity was found to increase two fold when compared to uninfected
cells and DNA fragmentation (laddering) was clearly evident late in infection. It
was concluded that infected cells predominantly showed necrosis, although some
cells showed apoptosis in late infection. Recombinant capsid-like particles
composed of the polyomavirus structural proteins were not able to induce cell
death.
PMID- 10773322
TI - Spatial and temporal dynamics of Puumala hantavirus infection in red bank vole
(Clethrionomys glareolus) populations in Belgium.
AB - Dynamics of hantavirus infection and population densities in rodents were
investigated from 1996 to 1999 in southern Belgium. Evidence of Puumala infection
was restricted to Clethrionomys glareolus. Although the serotype was not
determined, antibodies against hantavirus were also found in eight Apodemus
sylvaticus. In fall 1996, the seroprevalence in C. glareolus was high (20.1%, 37
of 184) and the infection was widely distributed in the area studied whereas a
focal occurrence of positive rodents and lower seroprevalence rates were recorded
in spring 1997 (14.3%, six of 42), fall 1997 (6. 6%, 11 of 166), spring 1998
(6.4%, three of 47) and fall 1998 (6.7%, 11 of 165). A pullulation of rodents was
observed in spring 1999 and was associated with a markedly higher seroprevalence
in C. glareolus (47.7%, 189 of 396). In all seasons, infection rates in adults
were higher than in juveniles and subadults. No significant difference of
prevalence was recorded between males and females. In two trapping sites, the
temporary disappearance of positive animals after a crash in rodent populations
suggests that a threshold in density is necessary for the maintenance of the
enzootic cycle.
PMID- 10773323
TI - Delivery of nalbuphine and its prodrugs across skin by passive diffusion and
iontophoresis.
AB - The in vitro transport of nalbuphine (NA) and its prodrugs across various skins
was investigated in order to assess the effects of prodrug lipophilicity on
passive as well as iontophoretic permeation. The passive diffusion of NA and its
prodrugs increased with the drug lipophilicity. Iontophoresis significantly
increased the transport of NA and its prodrugs; the enhancement ratio was highest
for NA and decreased as the drug lipophilicity increased. Measurements using
intact and stratum corneum (SC)-stripped skins showed that the SC was the major
skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate
(NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped
skins indicated that the SC layer was not rate-limiting for the permeation of NA,
but remained the rate-limiting barrier for transdermal permeation of NAP.
Permeation studies using SC-stripped and delipidized skins suggested that the
intercellular pathway was the predominant route for the passive permeation of NA
and NAP as well as the iontophoretic permeation of NAP across the SC. The
relative rates of passive and iontophoretic permeation across Wistar rat skins
demonstrated that a significant amount of NA may permeate skin via the
appendageal routes, whereas NAP permeated predominantly through the lipid matrix.
PMID- 10773324
TI - Glucose-sensitivity of glucose oxidase-containing cationic copolymer hydrogels
having poly(ethylene glycol) grafts.
AB - Glucose oxidase and catalase were immobilized on poly(diethylaminoethyl
methacrylate-g-ethylene glycol) gels by copolymerization of the constituent
monomers and the functionalized enzyme solutions. The hydrogels were prepared in
the form of discs and microparticles. The amount and the activity of enzymes
immobilized in the matrix were determined. The hydrogels were tested for their
response to glucose by exposing microparticles to varying concentrations of
glucose. The generation of gluconic acid as a result of the reaction of glucose
with oxygen was investigated as a function of polymer parameters, such as
crosslinking ratio and enzyme loading. Pulsatile variation of the glucose
concentration was used to confirm the glucose-dependent swelling properties of
these hydrogels.
PMID- 10773325
TI - In vitro and in vivo evaluation of a somatostatin analogue released from PLGA
microspheres.
AB - The purpose of this study was to design poly(lactide-co-glycolide) (PLGA)
microspheres for the continuous delivery of the somatostatin analogue,
vapreotide, over 2-4 weeks. The microspheres were produced by spray-drying and
the desired characteristics, i.e. high encapsulation efficiency and controlled
release over 2-4 weeks, achieved through optimizing the type of polymer,
processing solvent, and co-encapsulated additive. The in vitro release was tested
in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore,
formulations were injected intramuscularly into rats to obtain pharmacokinetic
profiles. Encapsulation efficiency was between 34 and 91%, depending on the
particular formulation. The initial peptide release (within 6 h) was lowest, i.e.
<20%, when acetic acid was used as processing solvent and highest, i.e. 57%, with
dichloromethane. The various co-encapsulated additives generally lowered the
encapsulation efficiency by 15-30%. The best formulation in terms of low burst
and effective drug serum levels (>1 ng/ml) over 21-28 days in rats was the one
made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive
polyethyleneglycol. In conclusion, the optimization of formulation parameters
allowed us to produce vapreotide-loaded PLGA microspheres of suitable
characteristics for therapeutic use.
PMID- 10773326
TI - Utilization of poly(DL-lactide-co-glycolide) nanoparticles for preparation of
mini-depot tablets by direct compression.
AB - PURPOSE: The objectives of this study were to prepare the long-acting matrix
tablets by direct compression of the mixture of drug and poly(DL-lactide-co
glycolide) (PLGA) nanoparticles and to clarify the effects of such factors as
polymer species, mixing ratio of nanoparticles with different molecular weights,
and the tablet weight on the drug release and to discuss the mechanism of drug
release from matrix tablets. In addition, mini-matrix tablets were prepared to
investigate the possibility of application as an implantable dosage form.
METHODS: PLGA nanoparticles were prepared by the modified spontaneous emulsion
solvent diffusion method. The matrix tablets were prepared by direct compression
of mixtures of drug and nanoparticles, and then the release properties, swelling
properties and changes in molecular weight of PLGA during the release test were
evaluated. RESULTS: The drug showed the biphasic release patterns from all matrix
tablets; i.e. a portion of the drug was released rapidly (the initial release
phase), the release stopped for a long period (the lag time), and then the
residual drug was released (the second release phase). Matrix tablets with
various biphasic release patterns could be prepared by altering the molecular
weight or copolymer ratio of PLGA. The addition of nanoparticles of low molecular
weight PLGA to those of high molecular weight reduced the release rate at the
initial release phase, but that at the second release phase was almost entirely
unaffected by mixing ratio. Also, the release patterns could be changed by
altering the tablet weight and size, but the amounts released per unit of surface
area were the same. Hydration analysis suggested that the initial release rates
were correlated well with the swelling properties of tablets. CONCLUSION: This
system had advantages in terms of simplicity in design and predictability of drug
release rate and may be useful as an implantable dosage form.
PMID- 10773327
TI - Evaluation of floating and sticking extended release delivery systems: an
unconventional dissolution test.
AB - The extent to which hydrophilic matrix tablets with a propensity to stick to the
dissolution apparatus and/or float are susceptible to variations in hydrodynamic
conditions during dissolution testing was investigated. Furthermore the
usefulness of simple alternatives to the current compendial tests is examined.
Swellable hydrocolloid (guar) matrix tablets containing verapamil HCl were
evaluated using USP dissolution apparatus I and II. Two additional configurations
where an additional single ring and mesh device or a double mesh device was
located below the paddle in the dissolution vessel were also evaluated. Tablets
were placed on top of the single mesh device or in the compartment formed by the
two mesh surfaces of the double mesh device. In all cases near linear (n>/=0.82)
release profiles were observed. When using apparatus I it was observed that the
highly swellable tablets were fully constricted by the basket within 5-7 h. This
prevented further independent movement and unimpeded swelling and coincided with
a departure from linear release and increased variability (S.D.
50% at 25 degrees C, respectively. It appears that for both sparingly and highly
soluble drugs, sum of the dissolution/diffusion rates, dynamics of diffusional
pathlength and system erosion rate control the release process. The heterogeneous
nature of changes in coat thickness, stiffening dynamics and erosion rate in
relation to disk geometry is discussed. The developed technology has potential to
provide release patterns, compatible with specific chronophysiological
conditions, and overcome the absorption-limited capacity of the distal
gastrointestinal tract
PMID- 10773328
TI - The pH-dependent biphasic release of azidothymidine from a layered composite of
PVA disks and P(MMA/MAA) spheres.
AB - A composite device was developed to provide a biphasic drug release using
poly(vinyl alcohol) (PVA) and poly(methylmethacrylate-co-methacrylic acid)
(P(MMA/MAA)) spheres. Azidothymidine (AZT), an anti-HIV agent with a short
biological half-life, was used as the model drug. Dynamic and equilibrium
swelling of the polymers, and kinetics of AZT release from these polymers were
determined in pH 1.2 and 6.8 buffer solutions. The swelling of PVA and release of
AZT from PVA disks were fast and nearly pH-independent, whereas the swelling
behavior and drug release kinetics of P(MMA/MAA) spheres were strongly pH
dependent. A swelling interface number for the spheres at pH 6.8 was determined
to be Sw&z.Lt;1 and time dependent. Nevertheless, Fickian diffusion might also
contribute to the drug release in this system. The composite disks consisting of
PVA matrix and P(MMA/MAA) spheres provided prolonged (over 20 h) and more steady
release profiles, differing profoundly from individual components. Such release
profiles resulted from the second phase release at pH 6.8 and the presence of PVA
layer. The relative drug loading in the matrix could be tailored to produce
release profiles varying from a distinct bimodal release to a pseudo zero-order
release with an initial burst.
PMID- 10773330
TI - A novel approach for constant rate delivery of highly soluble bioactives from a
simple monolithic system.
AB - A novel monolithic drug delivery system for highly water-soluble bioactive agents
to follow pH-independent zero-order kinetics is described. The system utilizes a
hydrophilic gel-based swellable polymeric material (polyethylene oxide), a model
drug (metoprolol tartrate, 100% water soluble at 25 degrees C) and different
electrolytes, such as sodium carbonate and/or pentasodium tripolyphosphate. Based
on the induction of in situ intra-gel chemical reactions between different ionic
species, drug and polymer, a heterogeneous structure manifested as 'peripheral
boundary stiffening,' is accomplished. The consequence of these interactions
essentially include the development of gradient-controlled matrix swelling as
elucidated through textural profiling, which may contribute to inhibition of drug
solubility and its outward diffusion. Analysis of textural profiles and
photomicroscopy distinctly provides information on the disposition of peripheral
boundary densification for the electrolyte-containing matrices. Electrolytic
conductivity measurements performed with the simultaneous analysis of matrix
swelling showed that sodium carbonate forms a highly reactive matrix within the
first 3 h of medium penetration. On the other hand, larger molecules such as
pentasodium tripolyphosphate maintain a constant conductivity level, which may be
related to its lower solubility and diffusion in comparison to sodium carbonate.
Based on model fitting and statistical analysis, it is shown that drug release
kinetics were adequately described by M(t)/M(infinity)=k(0)t, with zero-order
release rate constant k(0) of 0.054 h(-1). This novel approach in formulation
development could potentially be used for constant rate delivery of highly
soluble bioactive agents over an extended period for specific biopharmaceutical
needs.
PMID- 10773331
TI - Leakage of enteric (Eudragit L)-coated dosage forms in simulated gastric juice in
the presence of poly(ethylene glycol).
AB - Poly(methacrylic acid) (PMAA) and related copolymers strongly interact with
poly(ethylene glycol) (PEG) in acidic fluids. Due to the in vitro experiments
presented in this paper, there is a clear indication for a drug-drug interaction
in vivo between PEG solutions, e.g., commercially available laxatives, and dosage
forms with PMAA-based enteric-coatings (Eudragit L). In these studies, enteric
coated tablets did not fulfil the pharmacopoeias' criteria of the disintegration
test if PEGs were present in the simulated gastric juice. Drug substances which
are known to be unstable in acidic media or which can cause gastric irritation
were released from their enteric-coated dosage forms in acidic PEG media (pH 1).
Various drug dosage forms, single and multiple unit systems, were tested. They
show higher and faster drug release in the presence of PEG. To get insight into
the mechanism of the interaction, experiments and theoretical calculations were
performed which reveal that PEGs with high molecular weight show stronger
interactions with PMAA coatings indicating a contribution of hydrophobic
interactions to the occurring intermolecular forces. Hydrogen bonds can be build
between each monomeric unit of PEG and the acidic sequences of the copolymer.
PMID- 10773332
TI - Poly(ethylene carbonate) microspheres: manufacturing process and internal
structure characterization.
AB - The granulocyte-macrophage colony stimulating factor (GM-CSF), a water-soluble
cytokine, was encapsulated in poly(ethylene carbonate) microspheres (MS) by a
double emulsion w(1)/o/w(2) solvent evaporation method. Poly(ethylene carbonate)
is a new polymer of high molecular weight (MW) and forms polymer matrices that
are exclusively surface bioerodible. In the frame of this study, the influence of
the polymer molecular weight and the polymer concentration in the organic phase
on the physico-chemical characteristics of the microspheres were investigated.
Ninety percent of the microspheres had a diameter ranging between 4 and 136
microm, with a mean value of 30 microm. The encapsulation ratios ranged from 2.22
to 2.51% (w/w) depending on the molecular weight of the polymer corresponding to
an encapsulation efficiency of 70 to 100%, respectively. Independent of the
polymer molecular weight used, the in vitro drug release was very low, ranging
from 5.61 to less than 1% of the total encapsulated GM-CSF amount. Scanning
electron microscopy (SEM) analysis showed microparticles with spherical shapes
and smooth surfaces containing a few small globules. The inner structure of the
microspheres appeared to consist of a polymeric matrix surrounding numerous
globules. These globules have different sizes, shape and distribution in the
polymeric matrix, depending on the concentration of the polymer solution and on
the polymer molecular weight. In addition, it was demonstrated that the GM-CSF
lowered the interfacial tension between the GM-CSF aqueous solution and the
methylene chloride organic phase. The active critical concentration was as low as
0.008 mg/ml. It was therefore suggested that this particular behavior contributed
to the stabilization of the primary emulsion during the formation of the
microspheres, leading to rather high encapsulation efficiency.
PMID- 10773333
TI - pH-independent release of a weakly basic drug from water-insoluble and -soluble
matrix tablets.
AB - Weakly basic drugs or salts thereof demonstrate pH-dependent solubility. The
resulting release from conventional matrix tablets decreases with increasing pH
milieu of the gastrointestinal tract. The aim of this study was to overcome this
problem and to achieve pH-independent drug release. Two different polymers were
used as matrix formers, the water-insoluble and almost unswellable ethylcellulose
(EC), and the water-soluble and highly swellable hydroxypropyl methylcellulose
(HPMC). Two different approaches to solve the problem of pH-dependent release of
weakly basic drugs are demonstrated in this paper. The first one is based on the
addition of hydroxypropyl methylcellulose acetate succinate (HPMCAS, an enteric
polymer), the second one on the addition of organic acids such as fumaric,
succinic or adipic acid to the drug-polymer system. The first approach failed to
achieve pH-independent drug release, whereas the addition of organic acids to
both matrix formers was found to maintain low pH values within the tablets during
drug release in phosphate buffer (pH 6.8 or 7.4). Thus, the micro-environmental
conditions for the dissolution and diffusion of the weakly basic drug were almost
kept constant. The release of verapamil hydrochloride from tablets composed of
ethylcellulose or HPMC and organic acids was found to be pH-independent.
PMID- 10773334
TI - Improved biomass productivity and water use efficiency under water deficit
conditions in transgenic wheat constitutively expressing the barley HVA1 gene.
AB - The ABA-responsive barley gene HVA1, a member of group 3 late embryogenesis
abundant (LEA) protein genes, was introduced into spring wheat (Triticum aestivum
L.) cv. Hi-Line using the biolistic bombardment method. High levels of expression
of the HVA1 gene, regulated by the maize ubi1 promoter, were observed in leaves
and roots of independent transgenic wheat plants and were inherited by offspring
generations. T(3) progenies of four selected transgenic wheat lines were tested
under greenhouse conditions for tolerance of soil water deficit. Potted plants
were grown under moderate water deficit and well-watered conditions,
respectively. Two homozygous and one heterozygous transgenic lines expressing the
HVA1 gene had significantly (P<0.01) higher water use efficiency values, 0.66
0.68 g kg(-1), as compared to 0.57 and 0.53 g kg(-1), respectively, for the non
expressing transgenic and non-transgenic controls under moderate water deficit
conditions. The two homozygous transgenic plant lines also had significantly
greater total dry mass, root fresh and dry weights, and shoot dry weight compared
to the two controls under soil water deficit conditions. Results of this study
indicate that growth characteristics were improved in transgenic wheat plants
constitutively expressing the barley HVA1 gene in response to soil water deficit.
PMID- 10773335
TI - Purification and cloning of the two domain glyoxalase I from wheat bran.
AB - Investigation of proteins extracted from wheat bran lead to the isolation of a 37
kDa polypeptide extracted from a polyacrylamide gel. Extensive internal peptide
sequence information of this protein identified it as a glyoxalase I. Glyoxalase
I activity in crude wheat bran extract was measured to 1 U/mg protein (1U=1 umol
S-lactoyl glutathione formed/min). Degenerate primers were designed and used for
PCR-RACE-based cloning of the corresponding composite cDNA sequence (AJ243528).
The wheat bran glyoxalase I amino acid sequence is very similar to the translated
sequence of a RNA transcript induced by desiccation of the resurrection grass
Sporobulus stapfianus, suggesting a role for glyoxalase in de- or rehydration of
plant tissue. The 37 kDa wheat enzyme belongs to a group of monomeric glyoxalases
and is composed of two similar halves each representing the full-length human
glyoxalase I enzyme. A survey of glyoxalase I sequences, including one (not
previously reported) from Drosophila melanogaster, is presented and alignments of
these sequences show that amino acid residues involved in co-ordinating zinc or
interaction with the substrate are conserved. The alignments indicate a non
linear evolution of glyoxalase I enzymes.
PMID- 10773336
TI - The maize streak virus coat protein transcription unit exhibits tissue-specific
expression in transgenic rice.
AB - Maize streak geminivirus (MSV) is a single-stranded DNA virus that infects
cereals and other grasses. A promoter region incorporating the MSV large
intergenic region and movement protein gene sequence was ligated to the gus (beta
glucuronidase) reporter gene which replaced the virus coat protein (CP) gene. The
CP promoter activity was analysed in transgenic rice plants (Oryza sativa L.) and
was compared with that obtained in plants transformed with the gus gene
downstream of the cauliflower mosaic virus (CaMV) 35S promoter. The MSV CP
promoter activity varied in the five plant lines tested, but was always less than
that of the CaMV promoter. Histochemistry showed that the MSV CP promoter was
active in cells of regenerating callus but in regenerated plants it provided an
expression pattern restricted to the vascular tissues of the root, stem, leaf and
floral organs. Expression was highest in phloem-associated tissues of the
vegetative organs and was absent from the tip and elongation region of seedling
roots. Thus, the MSV CP promoter shows a degree of developmental regulation and
can be used to confer tissue-specific expression in transgenic rice plants.
PMID- 10773337
TI - Characterization of a new antifungal non-specific lipid transfer protein (nsLTP)
from sugar beet leaves.
AB - A novel protein (IWF5) comprising 92 amino acids has been purified from the
intercellular washing fluid of sugar beet leaves using cation exchange
chromatography and reversed phase high performance liquid chromatography. Based
on amino acid sequence homology, including the presence of eight cysteines at
conserved positions, the protein can be classified as a member of the plant
family of non-specific lipid transfer proteins (nsLTPs). The protein is 47%
identical to IWF1, an antifungal nsLTP previously isolated from leaves of sugar
beet. A potential site for N-linked glycosylation present in IWF5 (Asn-Xxx
Ser/Thr) was found not to be glycosylated. The amino acid sequence data were used
to generate a polymerase chain reaction (PCR) clone, employed for the isolation
of a corresponding cDNA clone. According to the cDNA clone, IWF5 is expressed as
a preprotein with an N-terminal signal sequence of 26 amino acid residues. The
protein shows a strong in vitro antifungal activity against Cercospora beticola
(causal agent of leaf spot disease in sugar beet) and inhibits fungal growth at
concentrations below 10 ug ml(-1).
PMID- 10773338
TI - Genetic variability and molecular responses of root penetration in cotton.
AB - Compacted soils restrict root penetration hindering productivity. In this paper,
genetic variability of cotton (Gossipium spp.) root capacity to penetrate hard
soil layers and the patterns of gene expression during penetration event were
investigated. To mimic hard soil layers, wax-petrolatum mixtures were used.
Genetic variability among 27 cotton genotypes for the root capacity to penetrate
wax-petrolatum disks of 500-700 g wax/kg of mixture was high indicating that
breeding efforts targeted to improve this trait can be successful. In the root
tips of a cotton strain with high root penetrating ability (G. hirsutum HS 200)
which penetrated through wax-petrolatum disks (P), quantity of four polypeptides
with molecular weights 35-66 kDa increased compared to those root tips which grew
in the absence of mechanical impedance (NP). Differential display showed
significant differences in the sets of mRNA expressed in P and NP roots. Out of a
total of 917 cDNAs scored in the differential display experiment, 118 cDNAs, or
13%, were specific to P roots and hence could be associated with the root
penetration event. Further detailed study of gene expression in penetrated roots
will pinpoint molecular factors involved in root penetration ability in cotton.
PMID- 10773339
TI - Distribution of the Mo-enzymes aldehyde oxidase, xanthine dehydrogenase and
nitrate reductase in maize (Zea mays L.) nodal roots as affected by nitrogen and
salinity.
AB - The distribution of the Mo-enzymes aldehyde oxidase (AO; EC 1.2.3.1) xanthine
dehydrogenase (XDH; EC 1.2.1.37) and nitrate reductase (NAD(P)H NR; EC 1.6.6.1-2)
was studied along the longitudinal and transversal axes of maize (Zea mays L. cv.
Jubily) nodal roots as affected by nitrogen sources and salinity. Activities of
the Mo-enzymes were considerably enhanced under mild saline conditions. The
activities of AO and XDH increased following addition of ammonium to the nutrient
solution. Immunoblot analysis with antibodies raised against maize AO protein
revealed increased levels of AO proteins in root tips of ammonium fed plants.
Application of salinity to nitrate fed plants did not affect the enzyme protein
level, although it enhanced the activity of the Mo-hydroxylases. The specific
activities of the Mo-enzymes were the highest in root tips (0-1 cm segments)
while on the transversal axis maximal activity was observed in the stele or
vascular cylinder. Activity staining of AO after native PAGE of root extracts
revealed four bands of AO proteins (AO1-4) capable of oxidizing a number of
aliphatic and aromatic aldehydes. Increased AO activity in maize nodal roots
grown with ammonium, and salinity were observed mainly at the AO3 and AO4 bands.
Tips and stele contained primarily AO3 and AO4, and only traces of AO1 and AO2.
SDS-PAGE of root extracts followed by Western blots revealed, besides the major
150 kD subunit of AO, two polypeptides with molecular masses of 72 and 85 kD
located specifically in the cortex. Part of the polymorphism of AO in plant roots
may be related to the allocation of distinct isoforms to different regions of the
root, although the specific metabolic roles of the different bands have not been
established.
PMID- 10773340
TI - The evolution of photosynthetic capacity and the antioxidant enzymatic system
during acclimatization of micropropagated Calathea plants.
AB - The effects of an increased PPFD on photosynthesis, the functioning of the
photosynthetic apparatus and the response of the antioxidant enzymatic system
were studied during the ex vitro establishment of micropropagated Calathea 'Maui
Queen' plantlets. Measured chlorophyll and carotenoids contents in ex vitro
formed leaves were almost three times higher compared to the in vitro formed
ones. At the end of the acclimatization, an inverse relation between PPFD and the
chlorophyll (a+b)/carotenoids ratio was observed. During the first days after
transplantation Calathea plants are not photosynthetically active, as is
illustrated by the photosynthetic light response curves. With the appearance of
new leaves, higher photosynthetic capacities were observed and light saturation
point increased (days 17 and 25). Also the maximal photosynthetic efficiency
enlarged as shown by the increased initial slope of the curves. F(v)/F(m)
decreased directly after transplantation of the micropropagated plantlets,
afterwards a recovery was observed, but highest F(v)/F(m) values were observed in
low light (LL) plants. The photochemical quenching coefficient increased
gradually during the first two weeks of the acclimatization. In high light (HL)
plants, q(P) decreased directly after transfer, while this was not observed in LL
and medium light (ML). During the acclimatization period to increasing light
intensities significant changes in the activity of the antioxidant enzymatic
system were observed. A decrease in superoxide dismutase (SOD) activity was
measured during the first half of the acclimatization period followed by a
recovery in ML and HL plants by day 35. Dehydroascorbate reductase (DHAR)
activity decreased during acclimatization. At the end of the experimental period
the lowest levels were measured in ML plants. Catalase (CAT) activity increased
significantly during the first two weeks after transfer, a clear inverse
relationship to PPFD was detected. The relation between the adquisition of full
photosynthetic capacity and the activation of the enzymatic antioxidant system in
the leaves of calathea plants during ex vitro acclimatization is discussed.
PMID- 10773341
TI - Purification and characterization of a beta-glucosidase from rye (Secale cereale
L.) seedlings.
AB - Cyclic hydroxamic acids and a glucosidase that occur in rye seedlings were
investigated. The concentration of the glucoside of 2,4-dihydroxy-1,4-benzoxazin
3-one (DIBOA-Glc) in shoots increased soon after germination and decreased to a
lower, constant level as the plants started autotrophic growth. Cyclic hydroxamic
acid glucoside beta-glucosidase activity also occurred transiently, and the
timing of the increase and decrease was concurrent with that of cyclic hydroxamic
acid glucosides. The glucosidase was isolated from 48-h-old rye shoots and
purified to apparent homogeneity by using isoelectric precipitation, anion
exchange chromatography, and gel filtration. The isoelectric point and the
optimum reaction temperature were 4.9-5.1 and 25-30 degrees C, respectively. The
N-terminal amino acid sequence was almost identical to that of the wheat
glucosidases, but did not show any similarity to the sequences of other
glucosidases of plant origin. SDS- and native-PAGE analyses showed that rye had
several isozymes of glucosidase, and each isozyme was an oligomer of 60-kDa
monomers with a molecular mass of approximately 300 kDa. The enzyme was highly
active not only for DIMBOA-Glc but also for its 7-demethoxy analogue, DIBOA-Glc,
which was different from the specificities of maize and wheat glucosidases.
PMID- 10773342
TI - Four developmental stages identified by genetic dissection of pea (Pisum sativum
L.) root nodule morphogenesis.
AB - Root nodule structural organisation of nine pea Fix(-) mutants representing seven
symbiotic loci has been studied. This set of mutants has revealed lesions at four
developmental stages in the pea-Rhizobium symbiosis. (i) Mutant RisFixA is
affected in infection thread differentiation in nodule tissue, infection droplet
formation, bacteroid differentiation and nodule persistence. (ii) Allelic mutants
RisFixL and RisFixO (sym32) are blocked in bacteroid differentiation. (iii)
Mutants RisFixM (sym26), RisFixN, RisFixQ (sym27), RisFixT (sym26) show premature
degradation of symbiotic structures. (iv) Mutant RisFixV shows similar defects in
nodule persistence but, in addition, this mutant is characterised by an abnormal
and severe increase in the thickness of infection thread walls during the process
of infection thread 'maturation' and senescence. Combining our new data with
previously published studies of pea mutant phenotypes has allowed us to create an
integrated scheme for the sequential functioning of the late pea symbiotic genes
identified and characterised to date.
PMID- 10773343
TI - Xylem-specific expression of wound-inducible rice peroxidase genes in transgenic
plants.
AB - A peroxidase gene, poxA, was isolated from a rice (Oryza sativa L.) genomic
library. The gene consists of four exons whose combined sequences were identical
to that of the prxRPA mRNA whose levels were dramatically stimulated by wounding
as well as by treatment of rice shoots with ethephon or UV irradiation [H. Ito,
F. Kimizuka, A. Ohbayashi, H. Matsui, M. Honma, A. Shinmyo, Y. Ohashi, A.B.
Caplan, R.L. Rodriguez, Molecular cloning and characterization of two
complementary DNAs encoding putative peroxidases from rice (Oryza sativa L.)
shoots, Plant Cell Rep. 13 (1994) 361-366]. The temporal and spatial expression
properties of the poxA gene promoter as well as that from a second related
peroxidase gene, poxN, were analyzed in transgenic tobacco and rice plants using
the uidA gene as a reporter. In transgenic tobacco, UV- and wound-responsive cis
elements were located within 144 bp from the translational start codon of the
poxA gene. The poxN promoter, however, was inactive in the heterologous host as
no significant GUS activity was evident. On the other hand, chimeric uidA genes
containing 2.2 kb of the poxA promoter or 1.4 kb of poxN promoter were active in
transgenic rice plants. Both peroxidase promoters directed GUS activities in a
spatial and tissue specific manner coincident with the expression patterns
exhibited by their mRNAs. Histochemical analysis of transgenic rice plants showed
that both peroxidase genes are expressed in the vascular bundles of the shoot
apex and lamina joint, and in xylem-parenchyma cells of the leaf blade and
sheath.
PMID- 10773344
TI - Cloning and characterization of eight cytochrome P450 cDNAs from chickpea (Cicer
arietinum L.) cell suspension cultures.
AB - Eight different P450 sequences were isolated from a cDNA library derived from
cultured chickpea cells (cultivar ILC3279) elicited with a Phytophthora sojae
(formerly megasperma) elicitor (Pmg-elicitor) by screening with heterologous and
homologous probes. Screening with CYP73A1 from Helianthus tuberosus yielded
several clones with one identical sequence. A full-length clone could be isolated
and this sequence was assigned CYP73A19. Heterologous expression in yeast
confirmed that CYP73A19 is the trans-cinnamic acid 4-hydroxylase of chickpea.
Screening with a CYP81E2 polymerase chain reaction fragment from chickpea yielded
a CYP81E2 full-length sequence and two almost identical CYP81E3 sequences,
differing in only 16 out of 498 amino acids; both share more than 85% homology
with the isoflavone 2'-hydroxylase from licorice (Glycyrrhiza echinata L.). Using
CYP93A1 as a probe, it was possible to isolate a full-length member of the CYP93
family, CYP93C3, that shares more than 80% homology with isoflavone synthase from
soybean. In addition, partial sequences CYP81E3, CYP81E4 and CYP81E5 were also
found in this screening. The use of a CYP82A2 probe derived from BAC F10N7 from
Arabidopsis thaliana yielded only one sequence, CYP76F1. Rescreening with CYP81E4
and CYP81E5 did not result in the isolation of any new P450 sequences. Northern
blot experiments revealed that all but the CYP76F1 are induced rapidly and
transiently in cell cultures upon elicitor treatment.
PMID- 10773345
TI - Role of the CD1a molecule in the superantigen-induced activation of MHC class II
negative human thymocytes.
AB - Bacterial superantigens (Sag) are potent activators of T cells. This T-cell
activation has been described as an MHC class II dependent phenomenon. We have
observed that human thymocytes depleted of MHC class II positive cells are still
able to proliferate in response to the staphylococcal enterotoxin A (SEA). This
proliferation was clearly inhibited by the addition of monoclonal antibodies
directed against the CD1a molecule. In contrast, monoclonal antibodies directed
against the CD1b and CD1c molecules have no effect on the Sag-induced activation
of the CD2 (+) MHC class II (-) thymocytes. We next examined the ability of the
CD1a molecule to transmit transmembrane signals. Results obtained indicate that
CD1a ligation on these thymocytes induced tyrosine phosphorylation of the
p56(lck) tyrosine kinase. Signal transduction via CD1a is further confirmed by
the observation of a significant intracellular calcium flux (Ca(i)(++)) in
thymocytes following CD1a engagement. These data demonstrate that CD1a ligation
induces a signal transduction pathway which has a potential role in the bacterial
superantigen-induced activation of human CD2 (+) MHC class II (-) thymocytes.
PMID- 10773346
TI - Human memory CTL response specific for influenza A virus is broad and
multispecific.
AB - Class I restricted cytotoxic T-lymphocyte (CTL) responses are thought to be
focused against few immunodominant epitopes. In humans, an often quoted example
of such narrow focus is the influenza A (FLU) matrix 58-66 specific memory CTL
activity, detectable in HLA-A2 individuals as a result of natural infection.
Herein, we analyzed the repertoire of memory, FLU-specific CTLs in A2 and A11
positive individuals. Eighteen A2.1 binding peptides, derived from the FLU-Puerto
Rico/8/34 (PR8) isolate, elicited CTL activity in A2. 1/Kb transgenic mice upon
direct immunization. These peptides were also tested for their capacity to recall
memory CTL responses from peripheral blood mononuclear cells (PBMC) of human A2.1
donors. Besides the known dominant M1.58 peptide, 5 new epitopes (PA.46, PA. 225,
PB1.413, NA.75 and M1.59) were identified. Similarly, eleven, A11-binding, FLU
PR8 peptides, which were immunogenic in HLA-A11/Kb transgenic mice, were assayed
for induction of recall CTL responses using peripheral blood lymphocytes from a
cohort of A11-positive donors. Eight different peptides (NP.188, NP.342, HA.63(,)
HA.149, HA.450, M1.13, M1.178, and M2.70) induced memory CTL activity. Several of
these peptides were found to be highly conserved amongst different FLU isolates,
and also capable of binding multiple A2 and A11 supertype molecules. Finally, 37
HLA-B7 binding peptides were also identified. In conclusion, a previously
unappreciated breadth of FLU-specific, memory CTL responses in humans was
revealed. The relevance of these findings to the design of multiepitope vaccines
is discussed.
PMID- 10773347
TI - High affinity interactions of Coxsackievirus A9 with integrin alphavbeta3
(CD51/61) require the CYDMKTTC sequence of beta3, but do not require the RGD
sequence of the CAV-9 VP1 protein.
AB - Integrins are transmembrane molecules involved in numerous cell matrix, cell-cell
adhesion phenomena and also utilised as viral receptors. These interactions with
integrins are mediated by brief oligopeptide recognition sequences. The Arg-Gly
Asp sequence (RGD), is recognized by many integrins, including integrin
alphavbeta3 (CD51/61). Coxsackievirus A9 (CAV-9), a human pathogen that has an
Arg-Gly-Asp sequence in the VP1 capsid protein, has been known to be one of the
many viruses that utilise integrin alphavbeta3 as a receptor. In order to
determine important binding sites of CAV-9 on integrin alphavbeta3, we performed
binding studies of CAV-9 on CHO-alphavbeta3, CHO-alphavbeta1 and CHO-alphavbeta1
3-1 mutant cell line, in the presence of function blocking mAb specific for
integrin alphavbeta3 and natural ligand vitronectin. Our experiments show that
the CYDMKTTC sequence (187-193 residue) of integrin beta3, which has been shown
to be involved in ligand specificity, is an important binding site for CAV-9. We
also report that an RGD-less Coxsackievirus A9 mutant can bind efficiently on the
ligand binding site of integrin alphavbeta3. Thus documenting the capability of
this RNA virus to interact with integrin alphavbeta3, without the presence of an
Arg-Gly-Asp sequence.
PMID- 10773348
TI - Knowledge-based grouping of modeled HLA peptide complexes.
AB - Human leukocyte antigens are the most polymorphic of human genes and multiple
sequence alignment shows that such polymorphisms are clustered in the functional
peptide binding domains. Because of such polymorphism among the peptide binding
residues, the prediction of peptides that bind to specific HLA molecules is very
difficult. In recent years two different types of computer based prediction
methods have been developed and both the methods have their own advantages and
disadvantages. The nonavailability of allele specific binding data restricts the
use of knowledge-based prediction methods for a wide range of HLA alleles.
Alternatively, the modeling scheme appears to be a promising predictive tool for
the selection of peptides that bind to specific HLA molecules. The scoring of the
modeled HLA-peptide complexes is a major concern. The use of knowledge based
rules (van der Waals clashes and solvent exposed hydrophobic residues) to
distinguish binders from nonbinders is applied in the present study. The rules
based on (1) number of observed atomic clashes between the modeled peptide and
the HLA structure, and (2) number of solvent exposed hydrophobic residues on the
modeled peptide effectively discriminate experimentally known binders from
poor/nonbinders. Solved crystal complexes show no vdW Clash (vdWC) in 95% cases
and no solvent exposed hydrophobic peptide residues (SEHPR) were seen in 86%
cases. In our attempt to compare experimental binding data with the predicted
scores by this scoring scheme, 77% of the peptides are correctly grouped as good
binders with a sensitivity of 71%.
PMID- 10773349
TI - A novel HLA-B*39 allele (HLA-B*3916) due to a rare mutation causing cryptic
splice site activation.
AB - A novel HLA-B*39 variant, found in an African patient with sickle cell anemia
undergoing bone marrow transplantation is described. Initially suspected by
inconsistent serological typing (B-blank, Bw6), then recognized by PCR-SSP, and
finally characterized by nucleotide sequencing, this novel allele is designated
HLA-B*3916. It differs from HLA-B*3910 by a point mutation (G to C) at position
17 of exon 3 causing glutamine to histidine change at codon 96 of alpha(2)
domain, a conserved position among HLA class I alleles. cDNA sequence analysis
further revealed the presence of both normally and abnormally spliced mRNA
species in established cell lines. The abnormal species correspond to partial
truncation of exon 3 presumably due to the nucleotide change in exon 3, which
constitutes a new consensus acceptor splice site within this exon. We postulate
that the observed blank is essentially the consequence of qualitative change in a
critical region of this novel antigen as abnormal mRNA species are relatively
less abundant than normal species. Because the residue 96 of the HLA class I
heavy chain is directly involved in interaction with alpha(2)m, another
interesting possibility is that an aminoacid change in this position would
perturb such interaction and consequently could affect the serological
specificity of B*3916, or its expression or both.
PMID- 10773350
TI - Molecular cloning and characterization of cynomolgus monkey Fas.
AB - The Fas-FasL system plays a crucial role in the maintenance of homeostasis in the
immune system. To characterize the Fas/FasL system in macaque monkeys that are
commonly used as experimental primates, we cloned and sequenced Fas cDNA derived
from the cynomolgus monkey. The predicted amino acid sequence consists of 331
amino acids with a calculated molecular weight of 35,800. The extracellular
cysteine-rich motif of cynomolgus Fas is highly homologous to that of humans
(96%), whereas the intracellular death domain has a relatively low similarity to
that of humans (86%). An agonistic Fas antibody (CH11) or cynomolgus FasL induced
apoptosis in human Fas-transfected K562 cells in the presence of CHX but not in
the cynomolgus Fas transfectant. CH11 and FasL failed to trigger apoptosis in the
transfectant expressing human-cynomolgus chimera Fas consisting mostly of human
derived extracellular region and cynomolgus-derived intracellular portion. On the
other hand, the transfectant expressing cynomolgus-human chimera Fas with human
derived intracellular region underwent apoptosis upon exposure to FasL. In
addition, the virus-transformed, Fas-positive cynomolgus monkey cell line was
highly sensitive to FasL. These findings suggest that the lack of apoptotic
activity in the cynomolgus Fas transfectant in the human cell line might be
related to the species-specific structure of Fas, especially of the death domain.
PMID- 10773351
TI - Cloning and functional characterization of the 5'-regulatory region of the human
CD86 gene.
AB - The induction of CD86 expression by IFN-gamma on the surface of various antigen
presenting cells has been previously reported. In order to understand the
mechanisms by which the expression of the CD86 gene is regulated by IFN-gamma at
the transcriptional level, we have cloned and characterized the 5'-flanking
region of the human CD86 gene. To functionally analyze the upstream regulatory
region of the CD86 gene, a series of luciferase reporter gene constructs were
prepared and used for transfection of cells from the monocytic line U937 and Raji
B cell line. Under basal conditions, functional activity of these constructs was
detected in Raji cells, which show high constitutive expression of the CD86
molecule, but not in U937 cells, which show low expression of CD86 in non
activated state. Induction of CD86 expression by stimulation of U937 cells with
IFN-gamma revealed the presence of two functional GAS (gamma-interferon
activation site) elements. Gel mobility shift assays showed that these two GAS
elements specifically bind an IFN-gamma-induced transcriptional complex. The DNA
protein complex was supershifted by antibody to Stat1 alpha (signal transducer
and activator of transcription), but not by antibodies to Stat 2, Stat 3 and Sp1,
indicating that GAS elements interact with Stat1 alpha. Point mutations in the
GAS elements prevented the formation of DNA-protein complex and significantly
reduced the responsiveness of the reporter gene to IFN-gamma. These findings
suggest that two functional GAS elements within the human CD86 promoter play an
important role in the induction of CD86 gene by binding to IFN-gamma-induced
Stat1 alpha.
PMID- 10773352
TI - High frequency of altered HLA class I phenotypes in laryngeal carcinomas.
AB - The exact frequency of HLA class I losses in human tumors is unknown. We have
previously shown that primary breast and colorectal carcinomas frequently lose
HLA class I molecules (88% and 73%, respectively). Now we report that this
phenomenon is also a frequent event in laryngeal carcinomas. Of a total of 76
laryngeal carcinomas analyzed, 66% of the tumors showed an alteration in HLA
class I phenotype. These altered HLA phenotypes were classified as total HLA loss
(10.52%) (phenotype I); HLA-A locus-specific loss (13.15%) (phenotype IIIa); HLA
B locus-specific loss (10.52%) (phenotype IIIb); HLA allelic loss (27.63%)
(phenotype IV); and HLA-A and B locus loss (3.9%). Comparison of
histopathological parameters with HLA expression showed that poorly
differentiated tumors had the lowest levels of HLA class I expression (p < 0.05).
PMID- 10773353
TI - Association between type 1 diabetes age-at-onset and intercellular adhesion
molecule-1 (ICAM-1) gene polymorphism.
AB - We investigated the intercellular adhesion molecule-1 (ICAM-1) gene polymorphism
in 90 patients with young-onset type 1 diabetes, 74 with adult-onset type 1
diabetes, and 171 control subjects. The distribution of C-T genotypes and allele
frequencies in exon 6 of the ICAM-1 gene was significantly different between
adult-onset type 1 diabetes patients and controls (chi(2) = 9.76, p = 0.0076),
and between patients with adult-onset and young-onset type 1 diabetes (chi(2) =
11.28, p = 0.0036). In contrast, we failed to detect any association between
patients with young-onset type 1 diabetes and controls. Our data suggest that
ICAM-1 exon 6 gene polymorphism affects the age-at-onset of type 1 diabetes and
that different pathogenetic mechanisms may exist between young-onset and adult
onset type 1 diabetes.
PMID- 10773354
TI - Identification of four novel dinucleotide repeat polymorphisms in the TNF-alpha
and TNF-beta genes.
AB - Five polymorphic regions (a to e) have been recognized within the TNF gene
region. These polymorphisms appear to be of biological importance as individual
alleles have been associated with higher production of TNF and/or an increased
risk of rheumatoid arthritis or diabetes mellitus. We report here the detection
of four new alleles designated a14 (122 bp), b8 (131 bp), b9 (132 bp), and d0
(122 bp) in patients with rheumatoid arthritis and normal controls from the
Pacific Northwest. This increases to 39 the number of alleles now recognized at
these loci.
PMID- 10773355
TI - Celiac disease and TNF promoter polymorphisms.
AB - The possibility that genetic susceptibility to celiac disease (CD) might be
influenced by tumor necrosis factor (TNF) genes polymorphism has repeatedly been
put forward. To date, this has only been investigated in case-control studies and
results have been contradictory. In order to avoid any possible ethnic
mismatching between patients and controls, we have approached this problem
studying 71 celiac families, establishing the parental haplotypes and comparing
CD versus control haplotypes (the so-called AFBAC or affected family-based
controls). We used DNA-based methods to screen for HLA-DRB1, -DQA1, and -DQB1
alleles, TNFalpha promoter polymorphims and TNFa and b microsatellites. The
guanine-to-adenine polymorphism at position -308 of the TNFalpha gene promoter
region was found associated with CD as the TNF-308A allele appeared significantly
increased in frequency in CD haplotypes, and this was shown to be independent of
the association between CD and the DRB1*0301,DQA1*0501,DQB1*0201 alleles. Our
results indicate that at least another gene, in addition to the known association
of CD with HLA class II, has a susceptibility role in this disease. This should
be either TNFalpha or another polymorphic gene in the telomeric end of the HLA
class III region.
PMID- 10773356
TI - Antibodies eluted from acutely rejected renal allografts bind to and activate
human endothelial cells.
AB - This study was designed to investigate how antiendothelial antibodies (EAbs) are
involved in acute irreversible renal graft rejection. Eluates from 25 renal
allografts, lost by irreversible rejection (n = 22) and by renal vein thrombosis
(controls n = 3), were tested against a panel of cultured human umbilical vein
endothelial cells (HUVEC). All patients were under immunosuppression at the time
of nephrectomy. EAbs binding and membrane expression of adhesion molecules ELAM-1
and VCAM-1 were analyzed by flow cytometry (FACS) and by semiquantitative RT-PCR
for mRNAs coding for those molecules. The absence of anti-HLA antibodies against
the donor was ascertained at transplant, and before and after nephrectomy by the
negativity of specific crossmatches performed using the most sensitive
techniques. EAbs eluted from eight rejected kidneys bound to HUVEC. They did not
induce any cytotoxicity, but their incubation with HUVEC (4 h at 37 degrees C;
2.5 mg/ml) led to upregulation of mRNAs coding for VCAM-1 (35- to 60-fold
increases) and ICAM-1 (8- to 12-fold increases) as compared with control EAbs.
Membrane expression of adhesion molecules was also strikingly increased, with 80%
of the cells expressing VCAM-1 and 65% expressing ELAM-1 upon incubation. EAbs
were detected in eight out of nine (88.8%) eluates from kidneys lost from acute
vascular rejection, but in none of the 13 (0.0%) kidneys lost from other types of
rejection (p < 0.0001). We conclude that EAbs, capable of activating human
endothelial cells, can be recovered from acutely rejected kidneys and may play a
direct role in the pathogenesis of acute rejection.
PMID- 10773357
TI - Nomenclature for factors of the HLA system, update january 2000
PMID- 10773358
TI - Prolonged elevation in blood pressure in the unrestrained rat exposed to
chlorpyrifos.
AB - Organophosphate (OP) pesticides are likely to alter the regulation of blood
pressure (BP) because (i) BP control centers in the brain stem utilize
cholinergic synapses and (ii) the irreversible inhibition of acetylcholinesterase
activity by OP's causes cholinergic stimulation in the CNS. This study used
radiotelemetric techniques to monitor systolic (S), diastolic (D), mean (M) BP,
pulse pressure (systolic-diastolic), heart rate (HR), core temperature (T(c)),
and motor activity in male Long-Evans rats treated with the OP pesticide
chlorpyrifos (CHP) at doses of 0, 5, 10, and 25 mg/kg (p.o.) at 15:00 h 10 and 25
mg/kg CHP led to parallel elevations in S-BP, M-BP, and D-BP within 2 h after
dosing. BP increased 15-20 mmHg above controls and increases persisted throughout
the night and into the next day. HR decreased slightly in rats administered 25
but not 10 mg/kg CHP. T(c) was reduced by treatment with 25 mg/kg CHP and then
increased above controls the next day. Motor activity was reduced by treatment
with 25 but not 10 mg/kg CHP. Pulse pressure was elevated by 2-4 mmHg for 40 h
after exposure to 10 and 25 mg/kg CHP. The increase in BP without an increase in
HR suggests that CHP increases total peripheral resistance and may alter the
baroreflex control of BP. Cholinergic stimulation of the CNS may explain the
initial effects of CHP on BP; however, the persistent elevation suggests an
involvement of neurohumoral pressor pathways.
PMID- 10773359
TI - Inhibition of gap-junctional-intercellular communication in intact rat liver by
nongenotoxic hepatocarcinogens.
AB - Many nongenotoxic hepatocarcinogens can induce cell proliferation, and inhibit
apoptosis and gap-junctional-intercellular communication (GJIC). GJIC, the
movement of small molecules (less than 1.2 kD) through membrane channels, is
important in regulating cellular homeostasis and differentiation. The inhibition
of hepatic GJIC can increase cell proliferation and possibly, inhibit apoptosis.
In this study, the relationship between hepatic GJIC, proliferation, and
apoptosis was examined in rats treated for 7 days with tumor-promoting doses of
the nongenotoxic hepatocarcinogens phenobarbital (PB; 800 ppm), pregnenolone
16alpha-carbonitrile (PCN; 1000 ppm), and Aroclor 1254 (PCB; 100 ppm). In
addition, 3-methylcholanthrene (3MC) was included as a negative control. PB, PCN,
and PCB increased parenchymal-cell proliferation and inhibited hepatic apoptosis,
while no alteration in these growth parameters was observed in 3MC-treated rats.
GJIC, as measured by fluorescent-dye transfer through intact liver, was decreased
nearly 50% by PB, PCN, and PCB, yet no effect on GJIC was observed in liver from
3MC-treated rats. These data indicate that compounds that inhibit GJIC in liver
may be nongenotoxic hepatocarcinogens, which occurs simultaneously during
increased cell proliferation and inhibited apoptosis.
PMID- 10773360
TI - Effects of molybdate and pentachlorophenol on the sulfation of acetaminophen.
AB - Pentachlorophenol (PCP) is an inhibitor of phenol-sulfotransferases and has been
used to ascertain the role of sulfation in toxicology. Recently, molybdate has
been shown to inhibit the sulfation of various chemicals by decreasing hepatic
concentrations of the cosubstrate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS).
The purpose of this study was to compare the effectiveness of these two chemicals
in inhibiting the sulfation of various doses of acetaminophen (AA) in the rat.
PCP (40 micromol/kg) decreased the 2-h combined biliary and urinary excretion of
AA-sulfate by 78, 83, 84, and 47% of the 0.1, 0.3, 1, and 3 mmol/kg doses of AA,
respectively. Molybdate (7.5 mmol/kg) decreased the sulfation of these same doses
of AA by 50, 65, 62, and 81%, respectively. These data indicate that PCP is more
effective in decreasing the sulfation of low than high doses of AA, which may
result from less AA, at lower doses, to compete with PCP for sulfotransferases.
Conversely, molybdate is more effective in decreasing sulfation of high rather
than low doses of AA because molybdate decreases sulfate availability and
decreases PAPS synthesis. More PAPS is required for the sulfation of high than
low doses of AA. Therefore, PCP inhibits sulfation more effectively at low doses
of AA when sulfation is limited by sulfotransferases, and molybdate inhibits
sulfation more effectively at high doses of AA when sulfation is limited by PAPS.
PMID- 10773361
TI - Beta-carotene and protein oxidation: effects of ascorbic acid and alpha
tocopherol.
AB - The effect of beta-carotene on protein oxidation was examined under different
oxygen (O(2)) tensions and with other antioxidants: alpha-tocopherol, ascorbic
acid, and mixtures of antioxidants. Human serum albumin (HSA) was incubated with
2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) to induce protein oxidation
(carbonyl formation), under 15, 150, and 760 torr of O(2) tension. Antioxidant
activity was related to O(2) tension, antioxidant concentrations and interaction
between mixtures of antioxidants: (1) Under 15 torr of O(2), incubating HSA with
AAPH, 1. 6 microM beta-carotene, 80 microM alpha-tocopherol, 160 microM ascorbic
acid, and mixtures (0.1 microM beta-carotene, 5.0 microM alpha-tocopherol and 10
microM ascorbic acid) resulted in 24, 29, 39, and 44% reduction of carbonyl
formation, respectively. (2) Under 150 torr of O(2) tension, the antioxidant
effect of beta-carotene was decreased by 4% but increasing O(2) tension did not
diminish the antioxidant effects of alpha-tocopherol, ascorbic acid, or
antioxidant mixtures. (3). Under 760 torr of O(2) tension, adding 1. 6 microM
beta-carotene resulted in 26% more carbonyl formation. (4) Under 760 torr of O(2)
tension, the antioxidant effect of ascorbic acid was decreased 32% compared to
what was observed at 150 torr of O(2) tension. Changes in O(2) tension had no
effect on the antioxidant effect of alpha-tocopherol. The mixture of antioxidants
inhibited carbonyl formation by 37% and was 7% less effective than that of 15 and
150 torr of O(2) tension. High concentration of beta-carotene produces more
protein oxidation in the presence of high O(2) tension by a prooxidant mechanism.
Mixtures of beta-carotene, alpha-tocopherol, and ascorbic acid provided better
protective effects on protein oxidation than any single compound.
PMID- 10773362
TI - A quantitative method for assessing the sensitizing potency of low molecular
weight chemicals using a local lymph node assay: employment of a regression
method that includes determination of the uncertainty margins.
AB - Risk assessment of sensitizing chemicals requires, besides hazard identification,
the assessment of potency. To examine the sensitizing capacity of low molecular
weight chemicals, a murine local lymph node assay (LLNA) was used. The
sensitizing capacity of known allergens was quantified by dose-response modeling.
At a stimulatory index (SI) of 3, the corresponding estimated concentration was
calculated (EC(3)), together with a confidence interval to take account of the
quality of the particular data set. We tested ten allergens (ethyl-p
aminobenzoate (benzocaine), diethylamine (DEA), 2,4-dinitrochlorobenzene (DNCB),
2-mercaptobenzothiazole (MBT), 4-ethoxymethylene 2-phenyl oxazol-5-one
(oxazolone), phthalic anhydride (PA), toluene diisocyanate (TDI), trimellitic
anhydride (TMA), tetramethylthiuramdisulfide (TMTD) and
zincdimethyldithiocarbamate (ZDMC)). Oxazolone showed the strongest sensitizing
potency followed in this order by DNCB, TDI, TMA, PA, TMTD, ZDMC, MBT, benzocaine
and DEA. The approach performed in this study is a way to accurately assess the
potency of sensitizing chemicals and thus a possibility for classification.
PMID- 10773363
TI - Varied protocols of cadmium exposure produce different effects on nitric oxide
production in macrophages.
AB - Different protocols of cadmium (Cd) exposure in non-cytotoxic conditions (i.e. 10
microM Cd for 18 h), and their effect on nitric oxide (NO) generation induced by
NO inductor agents (NOIA) in peritoneal macrophages (pM) were studied. In all
cases, NOIA (i.e. bacterial lipopolysaccharide [LPS], phorbol ester [PMA],
okadaic acid [OA] or their combinations [LPS/OA] and [LPS/PMA]) were added at the
beginning of the first incubation, only. Simultaneously exposure with 10 microM
Cd enhanced NO generation and inducible NO synthase (iNOS) expression evoked by
LPS, OA, PMA; those induced by LPS/PMA were not modified; and those caused by
LPS/OA in relation to culture without Cd (medium) decreased. Double incubation,
either with or without Cd (Cd+Cd or medium+medium), or Cd added at the start of
the first or second incubation only (Cd+medium or medium+Cd), were tested. After
the second incubation, medium+Cd protocol produced the highest NO generation in
relation to other exposure protocols. When NO production was measured at the end
of the second incubation, Cd+medium protocol enhanced NO production induced by
OA, and LPS/OA, while medium+Cd protocol enhanced the response to LPS, PMA, and
LPS/OA, in both cases in relation to the first incubation. Cd+Cd incubation
protocol decreases the response to all NOIA in relation to another protocols. Cd
effect on NO generation in macrophages is dependent on protocol and timing of
exposure.
PMID- 10773364
TI - The popliteal lymph node response to streptozotocin is under type 1, MHC class-I
restricted, CD8(+) T-cell control.
AB - The popliteal lymph node (PLN) assay has been proposed to predict the
'autoimmunogenic' potential of xenobiotics. A better understanding of the
processes involved in PLN responses is needed to establish the value of this
assay for preclinical safety evaluation. In order to determine whether PLN
responses involve CD4(+) or CD8(+) T-cells, the effects of streptozotocin (STZ),
a prototypic immunotoxic compound, were analyzed after injection into the hind
footpad of C57 BL/6 mice and major histocompatibility complex (MHC) class I or II
deficient mice. The involvement of type 1 or type 2 cell control on the
production of cytokine mRNAs was analyzed in lymph node cells by quantitative RT
PCR, together with the analysis of a wide range of cytokine mRNAs after STZ
injection (IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, IL-2, IL-2 receptor, IL-4,
IL-5, IL-6, IL-10 and IL-12). We have found that mice depleted in CD8(+) T-cells
did not respond to STZ, whereas mice depleted in CD4(+) T-cells exhibited the
expected positive PLN responses, with increased weight and cellularity indices.
STZ induced a low production of interleukin (IL)-2 mRNAs, a mild increase in IL
1alpha and IL-6 mRNAs production, and a dramatic increase in IFN-gamma, IL-1beta,
TNF-alpha, IL-12 and IL-2 receptor mRNAs, which correlated with positive PLN
responses. No effects on IL-4, IL-5 and IL-10 mRNAs synthesis were noted. In
CD8(+) T-cell deficient mice, there was no production of IFN-gamma or IL-6 mRNAs.
These results suggest that PLN responses to STZ are under the control of type 1,
MHC class-I-restricted, CD8(+) T-cells. This is in accordance to the known
physiopathology of STZ-induced diabetes. Additional studies are necessary to
establish the mechanism of CD8+ T-cell activation.
PMID- 10773365
TI - International recommendations and guidelines for the safe use of diagnostic
ultrasound in medicine.
AB - Modern sophisticated ultrasonographic equipment is capable of delivering
substantial levels of acoustic energy into the body when used at maximum outputs.
The risk of producing bioeffects has been studied by international expert groups
during symposia supported by the World Federation for Ultrasound in Medicine and
Biology (WFUMB). These have resulted in the publication of internationally
accepted conclusions and recommendations. National ultrasound safety committees
have published guidelines as well. These recommendations and safety guidelines
offer valuable information to help users apply diagnostic ultrasound in a safe
and effective manner. Acoustic output from ultrasound medical devices is directly
regulated only in the USA and this is done by the Food and Drug Administration
(FDA). However, there is also a modern trend towards self-regulation which has
implications for the worldwide use of diagnostic ultrasound. It has resulted in a
move away from the relatively simple scheme of FDA-enforced, application-specific
limits on acoustic output to a scheme whereby risk of adverse effects of
ultrasound exposure is assessed from information provided by the equipment in the
form of a real-time display of safety indices. Under this option, the FDA allows
a relaxation of some intensity limits, specifically approving the use of medical
ultrasound devices that can expose the fetus or embryo to nearly eight times the
intensity that was previously allowed. The shift of responsibility for risk
assessment from a regulatory authority to the user creates an urgent need for
awareness of risk and the development of knowledgeable and responsible attitudes
to safety issues. To encourage this approach, it is incumbent on authorities,
ultrasound societies and expert groups to provide relevant information on
biological effects that might result from ultrasonographic procedures. It is
obvious from the continued stream of enquiries received by ultrasound societies
that effective dissemination of such knowledge requires sustained strenuous
effort on the part of ultrasound safety committees. There is a strong need for
continuing education to ensure that appropriate risk/benefit assessments are made
by users based on an appropriate knowledge of the probability of biological
effects occurring with each type of ultrasound procedure. The primary purpose of
this paper is to draw attention to current safety guidelines and show the
similarities and areas of general agreement with those issued by the parent
ultrasound organisation, the WFUMB. It is equally important to identify gaps in
our knowledge, where applicable.
PMID- 10773366
TI - Reproducibility of volumetric quantification in intravascular ultrasound images.
AB - The reproducibility of volume measurements in intravascular ultrasound (IVUS)
images derived from separate pull-back manoeuvres remains to be elucidated.
Patients (n = 23) were imaged with IVUS prior to (first series) and following
percutaneous transluminal angioplasty (PTA) (second series). In 15 patients, one
matched vascular segment (3-4 cm in length), not subjected to PTA, was used for
analysis of lumen, vessel and plaque volume using an automated contour analysis
system. Volume measurements assessed by two independent observers and in the two
separate series were compared. Interobserver differences in volume measurements
were small (< or =0.4%), with low coefficients of variation (< or =1.7%) and high
correlation coefficients (r = 1.00). Differences in volume measurements obtained
in the two separate series were small (< or =2.6%), with low coefficients of
variation (< or = 8.6%) and high correlation coefficients (r = 0.97-0.99). In
conclusion, volume measurements derived from IVUS images are highly reproducible.
Therefore, IVUS may be used to monitor the progression/regression of
atherosclerotic plaque volume in a longitudinal study.
PMID- 10773367
TI - High-frequency ultrasound for quantitative characterization of myocardial edema.
AB - Myocardial edema has been associated with impaired ventricular compliance and
diastolic filling. To determine the sensitivity of high-frequency (40 MHz)
ultrasound to myocardial edema, we employed a model in which myocardial edema was
induced by immersion of tissue in isotonic saline. The effect of freezing tissue
on edema formation was also evaluated. Rat hearts were arrested at end-diastole
and insonified fresh within 15 min of excision (n = 5) or following being frozen
for 24 h and thawed (n = 4). Measurements of attenuation, backscatter, tissue
thickness and speed of sound were performed at baseline and hourly for 4 h, and
compared with direct measurements of myocardial edema. Fresh tissue demonstrated
a greater propensity for the development of edema than frozen tissue. Integrated
backscatter increased in both tissues, whereas the magnitude and slope of
attenuation decreased as edema evolved. We conclude that high-frequency
ultrasound sensitively detects myocardial edema, and we propose that the
extension of these methods to clinical frequencies may prove useful for
monitoring and treatment of cardiac edematous disease states.
PMID- 10773368
TI - Intraluminal ultrasonic palpation: assessment of local and cross-sectional tissue
stiffness.
AB - Many intravascular therapeutic techniques for the treatment of significant
atherosclerotic lesions are mechanical in nature: examples are angioplasty,
stenting and atherectomy. The selection of the most adequate treatment would be
advantageously aided by knowledge of the mechanical properties of the lesion and
surrounding tissues. Based on the success of intravascular ultrasound (IVUS) in
accurately depicting the morphology of atheromatous lesions, ultrasonic tissue
characterisation has been proposed as a tool to determine the composition of
atheroma. We describe the addition of local compliance information to the IVUS
image in the form of a colour-coded line congruent with the lumen perimeter. The
technique involves analysis of echo signals obtained at two or more states of
incremental intravascular pressure. Using vessel phantoms and specimens, we
demonstrate the utility of intravascular compliance imaging. The palpograms are
able to identify lesions of different elasticity independently of the
echogenicity contrast, because the information provided by the elastograms is
generally independent of that obtained from the IVUS image. Thus, the palpogram
can complement the characterisation of lesion from the IVUS image. We also
describe cross-sectional measures of elasticity that are based on the elastogram.
Finally, natural extensions of intravascular palpation to other endoluminal
ultrasound applications are proposed.
PMID- 10773369
TI - Acoustic shear-wave imaging using echo ultrasound compared to magnetic resonance
elastography.
AB - We compare a previously developed phase contrast-based magnetic resonance imaging
technique (MRE) to a phase-based ultrasound (US) method for measuring small
cyclic displacements (submicrometer level) caused by propagating acoustic shear
waves in tissue-like media. Our preliminary experiments with gelatin phantoms
show that acoustic shear-wave propagation can be measured with US, and we
speculate that this technique could find applications in medical imaging.
PMID- 10773370
TI - Breast cancer diagnosis using self-organizing map for sonography.
AB - The purpose of this study was to evaluate the performance of neural network model
self-organizing maps (SOM) in the classification of benign and malignant
sonographic breast lesions. A total of 243 breast tumors (82 malignant and 161
benign) were retrospectively evaluated. When a sonogram was performed, the analog
video signal was captured to obtain a digitized sonographic image. The physician
selected the region of interest in the sonography. An SOM model using 24
autocorrelation texture features classified the tumor as benign or malignant. In
the experiment, cases were sampled with k-fold cross-validation (k = 10) to
evaluate the performance using receiver operating characteristic (ROC) curves.
The ROC area index for the proposed SOM system is 0.9357 +/- 0.0152, the accuracy
is 85. 6%, the sensitivity is 97.6%, the specificity is 79.5%, the positive
predictive value is 70.8%, and the negative predictive value is 98. 5%. This
computer-aided diagnosis system can provide a useful tool and its high negative
predictive value could potentially help avert benign biopsies.
PMID- 10773371
TI - A new algorithm for off-line automated emboli detection based on the pseudo
wigner power distribution and the dual gate TCD technique.
AB - Research on microembolic signals (MES) using the dual-gate technique has shown
promising results, when the time difference (Deltat) of a MES in two sample
volumes (SVs) placed serially has been measured manually. On the other hand, the
computerized discrimination of MES and artefacts has been reported not to be
superior to algorithms based on a single SV. Therefore, a dataset containing MES
as well as four types of artefacts was made to test a preliminary version of a
new algorithm for automated emboli detection. We monitored 20 patients during
carotid endarterectomy (n = 17) and heart surgery (n = 3). Two transcranial
Doppler (TCD) signals with a partial overlap of the SVs were recorded online and
analysed off-line with an algorithm based on three consecutive steps: 1. Is there
an intensity increase in both channels (64-point FFT; 50% overlap)? 2. What is
the expected time difference (Deltat), with the velocity measured in channel 1 as
the calculation basis? 3. What is the 'exact' Deltat (pseudo-Wigner power
function)? Two human experts decided whether a signal was a MES or belonged to
one of the four artefact groups. Of a total of 97 MES, 28% (n = 27) could not be
detected in the distal channel. Thus, 72% (n = 70) of the MES were present in
both channels and could be analysed based on the abovementioned criteria. Of
these 70 MES, 87% (n = 61) were correctly identified off-line. We assessed
artefact rejection for four different types of artefacts: changes of TCD
settings, probe movement, low flow artefacts and electrocautery. The reliability
of artefact rejection was 98% for setting changes (n = 382), 96% for probe
movement (n = 477) and 98% for low flow artefacts (n = 91), but only 68% for
electrocautery (n = 264). These preliminary results are promising, but need
careful interpretation: 28% of the MES were not detectable in the distal SV,
probably due to a poor signal-to-noise ratio (SNR) and anatomical restrictions.
Electrocautery signals were insufficiently rejected. However, even an artefact
rejection of 96% can be insufficient if the number of MES is very small compared
to the number of artefacts.
PMID- 10773372
TI - Comparison of time-frequency estimators for peripheral embolus detection.
AB - Recently, a time-frequency processing of peripheral arterial Doppler signals,
based on the spectrogram, was proposed to detect automatically high-intensity
transient signal. Three time-frequency representations, the smooth-pseudo-Wigner
Ville, the Choi-Williams and the cone-kernel distributions were compared with the
spectrogram, following the detection scheme previously reported. The results
showed that the spectrogram provided the best compromises between false-detection
and no-detection compared with the other time-frequency representations.
PMID- 10773373
TI - Accuracy of in-vitro volume estimation of small structures using three
dimensional ultrasound.
AB - We describe an ultrasound probe for three-dimensional transvaginal imaging. The
transducer was an annular array with a center frequency of 7.5 MHz which was
rotated with an internal stepper motor. The probe had no external moving parts,
and the total volume covered by a full rotation defined a half sphere. The raw
digital data from the scanner were transferred to an external PC for three
dimensional reconstruction. We evaluated the three-dimensional imaging system by
measuring the volumes of phantoms (range 24.8-3362.5 mm(3)) in a water tank, and
found good correlation with true volumes (two observers' measurements gave a
linear regression with a slope of 1. 010 and R(2) = 0.993, and a slope of 0.956
and R(2) = 0.993, respectively). The size of the point-spread function was used
in the calculations to eliminate the effect of under- or overestimation due to
the limited ultrasound beam resolution. An example of data acquisition, volume
estimation and imaging of an embryo less than 8 weeks old in vivo with the brain
cavities and body is given. We conclude that the three-dimensional reconstruction
and volume estimation were accurate and repeatable.
PMID- 10773374
TI - A theoretical investigation of the effect of nonlinear propagation on
measurements of mechanical index.
AB - Safety parameters for diagnostic ultrasound scanners are calculated from
measurements made in water, which are derated to account for the attenuation of
tissues. Sound is attenuated less by water than by tissue, and so the effects of
nonlinear propagation are greater in water. This study compares mechanical index
(MI) and derated intensity with the analogous quantities in idealised soft
tissue, for simplified models of scanners with source amplitudes up to 2.5 MPa.
As expected, MI is much smaller than implied by linear extrapolation from low
amplitude measurements but, in a system with moderate gain, the reduction in
tissue is commensurate with that in water, MI and derated intensity
underestimating the values in tissue by at most 20%. Determining MI at the
location of peak negative pressure halves the error. In high gain systems,
however, MI can be less than 60% of the value in tissue.
PMID- 10773375
TI - The intensity dependence of lesion position shift during focused ultrasound
surgery.
AB - Knowledge of the spatial distribution of intensity loss from an ultrasonic beam
is critical for predicting lesion formation in focused ultrasound (US) surgery
(FUS). To date, most models have used linear propagation models to predict
intensity profiles required to compute the temporally varying temperature
distributions used to compute thermal dose contours. These are used to predict
the extent of thermal damage. However, these simulations fail to describe
adequately the abnormal lesion formation behaviour observed during ex vivo
experiments in cases for which the transducer drive levels are varied over a wide
range. In such experiments, the extent of thermal damage has been observed to
move significantly closer to the transducer with increased transducer drive
levels than would be predicted using linear-propagation models. The first set of
simulations described herein use the KZK (Khokhlov-Zabolotskaya-Kuznetsov)
nonlinear propagation model with the parabolic approximation for highly focused
US waves to demonstrate that both the peak intensity and the lesion positions do,
indeed, move closer to the transducer. This illustrates that, for accurate
modelling of heating during FUS, nonlinear effects should be considered.
Additionally, a first order approximation has been employed that attempts to
account for the abnormal heat deposition distributions that accompany high
transducer drive level FUS exposures where cavitation and boiling may be present.
The results of these simulations are presented. It is suggested that this type of
approach may be a useful tool in understanding thermal damage mechanisms.
PMID- 10773376
TI - Biomechanical assessment of plantar foot tissue in diabetic patients using an
ultrasound indentation system.
AB - The biomechanical properties of plantar tissues were investigated for four older
neuropathic diabetic patients and four healthy younger subjects. Indentation
tests were performed at four high-pressure areas with three postures in each
subject. The tissue thickness and effective Young's modulus were measured by an
ultrasound (US) indentation system. The system comprised a pen-size probe having
a US transducer at the tip and a load cell connected in series with it. Results
showed that the plantar soft tissues of the elderly diabetic patients were
significantly stiffer and thinner when compared with the healthy young subjects.
For the diabetic subjects tested, the Young's modulus at the 1st metatarsal head
was significantly larger than those at the other three sites. This site
dependence was not observed in the healthy young subjects. The plantar tissue
became significantly stiffer in the healthy young subjects as a result of posture
changes. This posture-dependence of the Young's modulus was not established for
the elderly diabetic group.
PMID- 10773377
TI - Improvement of stone fragmentation during shock-wave lithotripsy using a combined
EH/PEAA shock-wave generator-in vitro experiments.
AB - To control the collapse of cavitation bubbles induced during shock-wave
lithotripsy (SWL), a piezoelectric annular array (PEAA) shock-wave generator was
fabricated and combined with an experimental electrohydraulic (EH) shock-wave
lithotripter with a truncated HM-3 reflector. The PEAA generator consists of
eight individual transducers of 200-kHz resonant frequency. At a discharge
voltage of 15 kV, the PEAA generator produces a shock wave with a peak positive
pressure of 8.2 MPa, a positive half cycle duration of 2.9 micros, and a -6-dB
beam width of 5 mm. The trigger of the PEAA generator was controlled via
fiberoptic link with reference to the spark discharge of the EH generator. Hence,
the PEAA-generated shock wave could be used to interact with cavitation bubbles
induced by the EH source at various stages of their oscillation. The duration of
bubble oscillation during SWL was monitored by a 2.25-MHz focused hydrophone, and
this information was used to control the release timing of the PEAA generator.
Stone fragmentation tests in vitro were carried out, and demonstrated that stone
comminution could be significantly enhanced when the shock wave-bubble
interaction occurred during the collapsing phase of the bubbles. A maximum
increment of 60% to 80% in stone fragmentation was achieved when the PEAA
generated shock wave arrives near the collapse of the bubbles. Under these
conditions, much intensified collapse of the bubbles near the surface of the
stone, with strong secondary shock-wave emission and increased stress
concentration at the impact site of the solid boundary, was observed using high
speed shadowgraph and photoelastic imaging.
PMID- 10773378
TI - Temperature dependence of ultrasonic attenuation in human calcaneus.
AB - Ultrasonic attenuation in calcaneus has been shown to be a useful measurement for
the diagnosis of osteoporosis. Several studies indicate that this measurement is
affected by temperature fluctuations, although the fundamental causes for this
are currently not well understood. To investigate this phenomenon, six defatted
human calcanei were interrogated in vitro at six temperatures ranging from 10
degrees C to 40 degrees C. The temperature-related variation was -0.18 dB/cm MHz
degrees C (95% confidence interval: -0.27 dB/cm MHz degrees C, -0.10 dB/cm MHz
degrees C). This study reinforces the notion, advanced by other investigators,
that temperature-related effects need to be taken into account when performing
diagnostic measurements that require high precision (such as monitoring responses
to drug intervention), will aid in the interpretation of in vivo experiments
designed to investigate temperature-dependent precision limitations, will
facilitate comparisons between in vitro studies normally carried out at room
temperature with in vivo studies carried out at body temperature, and fills a gap
in the compendium of measurements of temperature-dependences of acoustic
properties of biologic tissues.
PMID- 10773379
TI - Ultrasound-induced intercellular space widening in fish epidermis.
AB - Transmission electron microscopy was employed to determine the effects of
therapeutic ultrasound (US) (I(sata) < or =2.2 W cm(-2), 3 MHz), sonicated at
different angles and durations, on the external epithelia of fish skin.
Sonication at 1.7 W cm(-2) (90 s), where the ultrasonic beam was perpendicular to
the skin surface, produced minor intercellular space widening (ICSW), as well as
the disruption of desmosomes connecting between the cells. Increasing the
intensity to 2.2 W cm(-2) increased ICSW, the extent of which was positively
correlated to the duration of exposure (30 to 90 s). Perpendicular sonication
produced ICSW, almost exclusively between cells of the two outermost cell layers,
parallel to the skin surface. Sonicating at 45 degrees (2.2 W cm(-2), 90 s)
produced ICSW in deeper cell layers in the tissues, in which the spaces were at
seemingly random orientations. Mucous cells and macrophages were also found to be
damaged, as were apoptotic epidermal cells. The suggested mechanism for ICSW is
the formation of transverse (shear) waves at the interface between the aquatic
medium and the skin surface. The waves, which are damped out within a few cell
layers, give rise to shear stresses that, in turn, cause strains that act to
separate between cells and damage some of the relatively weaker cells.
PMID- 10773380
TI - A new anechoic material for medical ultrasonic applications.
AB - This paper describes a newly developed material with acoustic properties that
make it ideal for applications as radiation force balance-absorbing targets. The
material is now commercially available from National Physical Laboratory (NPL)
and is based on a polyurethane rubber. It exhibits an echo reduction of 45 dB,
and single-pass transmission loss of 30 dB, both determined at an acoustic
frequency of 1 MHz. The composition and structure of the new NPL absorber are
presented, along with values for the frequency and temperature variation of the
echo reduction and transmission loss. Over the frequency range 1 to 10 MHz, its
acoustic properties comply with the requirements for force balance-absorbing
targets specified in IEC 61161.
PMID- 10773381
TI - Optical imaging of contrast agent microbubbles in an ultrasound field with a 100
MHz camera.
AB - Ultrasound (US) contrast agents, used in the field of medical diagnosis, contain
small microbubbles of a mean diameter of about 3 microm. The acoustic behavior of
these bubbles in US field has been subject to many investigations. In this study,
we propose a method to visualize the behavior of the bubbles in a 0.5-MHz US
field under a microscope with a frame rate of 4 MHz. For low acoustic pressures
(peak negative pressure of 0.12 MPa), the radius-time curve as measured from the
optical images is in agreement with the theory. For higher acoustic pressures
(peak negative pressure of 0.6 MPa), the recorded radius is significantly larger
than predicted by theory and sudden change in the bubbles shapes has been
noticed. The proposed method enables the study and characterization of individual
bubbles and their encapsulation. It is expected that this will open new areas for
quality control, US contrast imaging and US-guided drug delivery.
PMID- 10773382
TI - Differentiation between true microembolic signals and artefacts using an
arbitrary sample volume.
AB - We evaluated a new discrimination technique between microemboli (MES) and
artefact signals. Monitoring was performed over the middle cerebral artery (55
mm) and the brain parenchyma (29 mm). Intensity changes were expressed as percent
of change compared to the value measured in the proximal depth. The cut-off value
providing the highest sensitivity and specificity in the differentiation was
evaluated using 250 MES and 250 artefact signals, and subsequently analysed in
the first part of the study. Intensity values derived from the distal depth were
subsequently evaluated in 10 patients undergoing cardiac surgery and 45 patients
with potential arterial or cardioembolic source. Intensity changes of 87% (84%
90%) and -58% (-71%-(-48%)) were measured in the initial 500 signals for MES and
artefact signals, respectively. The best intensity cut-off value was calculated
at 27%. This value was subsequently applied to a total of 1858 MES and 1958
artefacts, resulting to sensitivity and specificity of 96% and 98%, respectively.
The proposed technique provided adequate results, warranting further evaluation.
PMID- 10773383
TI - Proceedings of the International Symposium on Gonadal Failure: New Perspectives.
Cortina d'Ampezzo, Italy. 10-11 September 1999.
PMID- 10773384
TI - Fine structure of human oogonia in the foetal ovary.
AB - Foetal ovarian tissue is now being cultured or frozen, to generate oocytes for
assisted reproduction, an emerging technology. This study examines the
ultrastructure of oogonia at 13-15 weeks of gestation, which could be used as a
control for culture and freezing of foetal ovaries. Oogonia are largely located
in the ovarian cortex, whilst primordial germ cells (PGC) and somatic follicle
cells compose the surface epithelium. Oogonia and PGC have large vesicular nuclei
with clear cytoplasm, compared to dense follicle cells, which have polymorphic
nuclei. Follicle cells intermingle with oogonia and establish close contacts -
beginning of folliculogenesis. Nuclei of oogonia contain one to three highly
reticulated nucleoli, reflecting high levels of RNA synthesis at the onset of
growth. Rough endoplasmic reticulum (RER) form stacks of cisternae associated
with numerous ribosomes. Prominent organelles in the ooplasm are elongated
mitochondria with dense matrices and tubular cristate presenting a multilocular
appearance. Typical Golgi complexes, dense bodies and clear vacuoles are present
and microfilaments are located beneath the plasma membrane. The most remarkable
feature of oogonia is that they have typical juxtanuclear centrioles (diplosomes)
with dense pericentriolar material, which nucleate microtubules, characteristic
of functional centrosomes organizing the cytoskeleton. The mature oocyte has no
centrioles, since the maternal centrosome is inactivated or reduced, while the
paternal is dominant. Centrioles are most likely involved in mitosis of oogonia.
PMID- 10773385
TI - Mutations of follicle stimulating hormone-beta and its receptor in human and
mouse: genotype/phenotype.
AB - The pituitary gonadotropin follicle stimulating hormone (FSH) interacts with its
membrane-bound receptor, to produce biologic effects. Traditional functions of
FSH include, follicular development and estradiol production in females and the
regulation of Sertoli cell action and spermatogenesis in males. FSHbeta knock-out
mice and transgenic mice, serve as models for FSH deficiency and excess,
respectively. In addition, mutations of both FSHbeta and FSHR genes have been
characterized in humans, although phenotypic effects of the ligand appear to be
more profound than those of its receptor. FSH is essential for normal puberty and
fertility in females, particularly ovarian follicular development beyond the
antral stage. In males, FSH is necessary for normal spermatogenesis and when FSH
function is completely absent, infertility occurs. With partial FSH deficiency in
males, spermatogenesis is affected, but fertility may still be possible. FSH may
also be necessary for normal androgen synthesis in males and females.
PMID- 10773386
TI - Signal transduction mechanism for LH in the cumulus-oocyte complex.
AB - The paper reviews recently described signalling mechanisms by which cumulus cells
exposed to peak levels of gonadotropins, activate oocyte maturation. Cumulus
cells react to LH with a prompt Ca raise which diffuses through gap junctions in
a few minutes also into the oocyte where a local amplification system spreads the
signal all over the cell. Few h later, still as a consequence of LH stimulation,
cumulus cells undergo aprogressive depolarisation of their plasma membrane
potential. Due to the electric coupling with these cells the oocyte depolarises
too and this open specific voltage gated Ca channels responsible for a second
wider and more sustained intracellular Ca rise. As a result of changes throughout
maturation with a consequent modification of the size and charge of the molecules
that can diffuse from one cell compartment to the other. This cell to cell
interaction is further modified with cumulus expansion that leads to a
progressive uncoupling of outer cumulus cells while the inner cell layer, corona
radiata, remains in oocyte maturation by addressing to the oocyte nutrients and
instructions in a well-orchestrated sequence. The identification of these
mechanisms are a fundamental prerequisite for the development of in vitro systems
suitable to produce oocytes matured in vitro with normal developmental
competence.
PMID- 10773387
TI - Role of LH and FSH in ovarian function.
AB - Human gonadotrophin preparations have been used in the treatment of infertility
for almost four decades. The earliest preparations were derived from urine from
postmenopausal women and contained approximately equal amounts of follicle
stimulating hormone (FSH) and luteinizing hormone (LH) activities. However, with
the recognition that FSH is the principal regulator of follicular growth and
maturation, these have been largely superseded by highly purified urinary FSH
preparations and, more recently, recombinant human FSH (r-hFSH). Because of its
complexity, r-hFSH is expressed in mammalian cells grown in culture and, from a
manufacturing stand point, offers superior purity and batch-to-batch consistency,
compared with urinary preparations. A number of clinical trials have compared the
efficacy of r-hFSH and urinary FSH in women undergoing assisted reproductive
technologies (ART). In general, these have shown that fewer FSH ampoules are
required to achieve ovarian stimulation with r-hFSH, while the number of oocytes
retrieved and embryos produced are higher than with urinary FSH. Additionally,
the results of a recent meta-analysis have also shown that the clinical pregnancy
rate per cycle started is significantly higher with r-hFSH, compared with urinary
FSH. Furthermore, in poor responder patients, higher implantation rates were seen
in patients treated with r-hFSH than in those treated with urinary FSH,
suggesting that embryo viability is increased following use of the recombinant
preparations. The finding that FSH preparations produce effective ovarian
stimulation compared to human menopausal gonadotrophins in women undergoing ART
raises the question of whether LH is required for ovarian stimulation. This has
been investigated in a number of recent studies. For example, results have
suggested that implantation rates may actually be lower in women who received
exogenous LH. Such studies suggest, therefore, that in normogonadotrophic women,
the addition of LH to an r-hFSH regimen does not add any further clinical benefit
and may actually be detrimental. Hence, it appears that LH administration is
necessary only in women with hypogonadotrophic hypogonadism. In conclusion, r
hFSH is a consistently pure and high quality gonadotrophin preparation and
contributes to increasing the successful outcome of an ART cycle. Together with
careful auditing of routine clinical practice, and the application of evidence
based medicine to facilitate clinical decision making, this means that a total
quality management approach can be applied to optimize the outcome of assisted
reproduction.
PMID- 10773388
TI - A novel functional estrogen receptor on human sperm membrane interferes with
progesterone effects.
AB - We have identified an estrogen receptor of approximately 29 kDa apparent
molecular weight in human sperm membranes by ligand and Western blot analysis,
respectively, using peroxidase-conjugated E(2) and an antibody directed against
the ligand binding region of the genomic receptor (alphaH222). Such receptor is
functional since 17betaE(2) induces a rapid and sustained increase of
intracellular calcium concentrations ([Ca(2+)](i)) which is completely eliminated
by preincubation with alphaH222. 17betaE(2) effects on calcium are clearly
mediated by a membrane receptor, as they are reproduced by the membrane
impermeable conjugate of the hormone BSA-E(2). Dose-response curve for this
effect is biphasic with EC(50)s in the nanomolar and micromolar range. In
addition to calcium increase, 17betaE(2) stimulates tyrosine phosphorylation of
several sperm proteins including the 29-kDa protein band. Preincubation of human
sperm with 17betaE(2) inhibits calcium and acrosome reaction increases in
response to progesterone. We conclude that estrogens may play a role in the
modulation of non-genomic action of progesterone (P) in human sperm during the
process of fertilization.
PMID- 10773389
TI - Influence of non-gonadotrophic hormones on gonadal function.
AB - Inhibins and activins are dimeric glycoproteins, member of the transforming
growth factor beta (TGF beta) superfamily. The main source and targets of
inhibins during the fertile age, in non pregnant women, are the ovaries, while
during pregnancy placental production becomes predominant. Activin is produced
from several organs: brain, ovary, uterus, placenta and spleen. During the
menstrual cycles, inhibin B concentrations rise in the follicular phase with a
peak after the ovulation peak of LH, inhibin A becomes predominant in the luteal
phase. During reproductive life no significant change of activin A serum
concentrations have been demonstrated. Inhibins and activins play an important
biological role in the regulation of the HPO axis. The evaluation of inhibins and
activins change is useful in understanding the pathophysiology of gynecological
diseases and in the diagnosis of obstetric and gynecological pathologies.
PMID- 10773390
TI - The roles of inhibin and related peptides in gonadal function.
AB - Inhibin A and B are dimeric proteins capable of suppressing FSH both in vitro and
in vivo. The principal form in the male is inhibin B which is produced in the
testis and circulates to inhibit pituitary FSH secretion. Activin A, B and AB are
dimeric proteins that share the same beta subunits with the inhibins but, in
contrast, stimulate FSH secretion. Although activin A circulates, castration does
not lead to a decrease in serum concentrations, indicating that the testis is not
the major source of activin A. In the circulation, the activins are bound to a
structurally unrelated binding protein, follistatin, that neutralizes the
biological actions of these proteins. The subunits of the inhibins/activins as
well as follistatin are also produced locally within the pituitary and their
levels can be modulated by testosterone and gonadotrophin releasing hormone as
well as by autocrine mechanisms. Consequently, the output of FSH is dependent of
the balance between local processes and the circulating feedback exerted by
testosterone and inhibin. There is increasing data to support the local gonadal
production of not only inhibin but also activin and follistatin by both germ
cells and somatic cells such as the Sertoli cells. Evidence is accumulating to
support the concept that these proteins exert local regulatory mechanisms in the
testis.
PMID- 10773391
TI - Effects of hormonal replacement treatment on bone mineral density and metabolism
in hypogonadal patients.
AB - We investigated 22 male patients affected by prepubertal hypogonadism with a mean
age of 34.3+/-5.2. A significant reduction of bone mineral density (BMD) at both
the lumbar spine (L2-L4, -14%, 1.039+/-0.11 vs. 1.217+/-0.16 g/cm(2), P=0.005)
and femoral neck (-11%; 0.927+/-0.09 vs. 1.034+/-0.16 g/cm(2), P=0.01) was found
in patients compared to age-matched controls. The mean Z score was -1. 55 for
vertebrae and -1.33 for femur. Eleven and nine patients, respectively, had a
lumbar and femoral BMD at least 1 S.D. below the normal mean; 8 and 4,
respectively, 2 S.D. below. There was a strong positive correlation between BMD
and duration of hormone replacement treatment (HRT) for both sites: respectively,
r=0.71, P<0.005 for the vertebrae, and r=0.60, P<0.01 for the femur. A weak
correlation was also present between onset of HRT and BMD: r=0.6, P<0.01 at the
lumbar level, and r=0.47, P<0.05 at the femoral neck.
PMID- 10773392
TI - Premature ovarian failure.
AB - Secondary amenorrhoea with elevated gonadotrophins occurring under the age of 40
(premature ovarian failure (POF)), and at the age between 41 and 44 years (early
menopause (EM)), respectively, affects 1-2% and 5% of women in the general
population. Objective of this study was to evaluate the prevalence of familial
cases of POF and EM and to assess the clinical and genetic characteristics of
these patients. One hundred and sixty women with idiopathic secondary amenorrhoea
before the age of 45 and serum follicle-stimulating hormone (FSH) levels greater
than or equal to 40 IU/l were included in the study. Tests performed on patients
included complete medical history, pedigree's analysis, clinical pelvic
examination, gonadotrophins and thyroid assessment, chromosomal analysis. The 160
patients included in the study showed idiopathic POF (n=130) or EM (n=30).
Following pedigree assessment, we were able to identify an incidence of familial
cases of 28.5% in the POF group (n=37) and of 50% in the EM group (n=15). POF and
EM condition were often present in the same family. There were no differences
between POF and EM patients and between familial and sporadic cases regarding age
at menarche, personal history, gynaecological history, weight, height and diet
habits. There was a statistically significant difference between sporadic and
familial cases in age at POF onset: 32.0+/-7.3 years (12-40) compared to 35. 0+/
5.8 (18-40), respectively (P<0.05). The POF and EM families identified showed two
or more affected females and transmission through either maternal or paternal
relatives; in four families both maternal and paternal transmission was observed.
This study suggests that idiopathic POF and EM conditions, differing only in age
of menopause onset, may represent a variable expression of the same genetic
disease. The different age of menopause onset in these patients may be explained
by genetic heterogeneity and/or by different environmental factors. Our results
indicate a high rate of familial transmission of the condition. Pedigree's
analysis suggests an autosomal or an X-linked dominant sex-limited pattern of
inheritance for POF and EM.
PMID- 10773393
TI - Female poor responders.
AB - Female poor responders are represented by normovulatory women showing a 'gonadal
failure' in term of inadequate number of recruited follicles under conventional
controlled ovarian hyperstimulation (COH) for assisted reproductive technologies
(ART). ARTs offers today a high chance of pregnancy to infertile couples when a
normal ovarian response provides a large choice of embryos for transfer. On the
contrary, failure of the ovary to produce enough oocyte for treatment, reduces
significantly the likelihood of conceiving in ART, not only in the treatment
cycle, but also predicting a poor prognosis in subsequent cycles. Up to date,
poor response remains one of the most frequent problems in the field of assisted
reproduction. First described in 1981, poor response has been investigated by
several authors, but many aspects are still controversial. In this paper
definition, pathophysiology and management of poor response are revised and
discussed.
PMID- 10773394
TI - Y chromosome microdeletions in infertile men with varicocele.
AB - The pathogenic mechanisms by which varicocele disrupt spermatogenesis are not
clearly understood and it is possible that when varicocele is associated with a
severe bilateral testiculopathy, other causes may represent the actual
aetiological factor. Since microdeletions in the Y chromosome long arm (Yq) have
become in last years a major cause of male infertility, we perform a Yq
microdeletion screening in infertile men with varicocele. We selected 40 patients
with severe oligozoospermia (sperm count<5x10(6)/ml, group 1) and 80 with
varicocele and mild oligozoospermia (sperm count 10-20x10(6)/ml, group 2).
Deletions of Yq was observed in seven out of 40 patients (17.5%) of group 1,
while no deletions were found in patients of group 2, suggesting that the
bilateral testicular damage observed in patients of group 1 is due to the
underlying genetic anomaly, and not to varicocele itself. The finding of a
genetic aetiology in infertile men with varicocele suggests that in such patients
a Yq microdeletion screening should be performed, both for a proper diagnosis and
to avoid unnecessary treatments that will probably not improve the sperm count.
PMID- 10773395
TI - Hormone substitution in male hypogonadism.
AB - Male hypogonadism is characterised by androgen deficiency and infertility.
Hypogonadism can be caused by disorders at the hypothalamic or pituitary level
(hypogonadotropic forms) or by testicular dysfunction (hypergonadotropic forms).
Testosterone substitution is necessary in all hypogonadal patients, because
androgen deficiency causes slight anemia, changes in coagulation parameters,
decreased bone density, muscle atrophy, regression of sexual function and
alterations in mood and cognitive abilities. Androgen replacement comprises
injectable forms of testosterone as well as implants, transdermal systems,
sublingual, buccal and oral preparations. Transdermal systems provide the
pharmacokinetic modality closest to natural diurnal variations in testosterone
levels. New injectable forms of testosterone are currently under clinical
evaluation (testosterone undecanoate, testosterone buciclate), allowing extended
injection intervals. If patients with hypogonadotropic hypogonadism wish to
father a child, spermatogenesis can be initiated and maintained by gonadotropin
therapy (conventionally in the form of human chorionic gonadotropin (hCG) and
human menopausal gonadotropin (hMG) or, more recently, purified or recombinant
follicle stimulating hormone (FSH)). Apart from this option, patients with
disorders at the hypothalamic level can be stimulated with pulsatile gonadotropin
releasing hormone (GnRH). Both treatment modalities have to be administered on
average for 7-10 months until pregnancy is achieved. In individual cases,
treatment may be necessary for up to 46 months. Testosterone treatment is
interrupted for the time of GnRH of gonadotropin therapy, but resumed after
cessation of this therapy.
PMID- 10773396
TI - FSH in the treatment of oligozoospermia.
AB - The aim of this study was to individuate parameters able to distinguish
oligozoospermic subjects who will respond to follicle-stimulating hormone (FSH)
therapy. A group of 135 oligozoospermic subjects was divided in three groups
considering basal FSH and inhibin B concentrations: group A (normal FSH and
inhibin B) characterized by moderate hypospermatogenesis sometimes associated to
partial spermatidic arrest; group B (high FSH and normal inhibin B) characterized
by hypospermatogenesis associated or not to spermatogonial/spermatocytic arrest;
group C (high FSH and low inhibin B) characterized by severe hypospermatogenesis.
Seventy-eight patients were treated with FSH at the dose of 75 IU on alternate
days while 57 were treated with the same dose every day for 3 months. After FSH
treatment a significant increase in ejaculated sperm concentration was observed
only in oligozoospermic subjects with normal basal FSH and inhibin B plasma
levels (group A) showing a testicular cytological picture of moderate
hypospermatogenesis. In these subjects no differences in sperm production were
observed between the two protocols of therapy. In the remaining patients of group
A, characterized by hypospermatogenesis associated with maturation arrest at
spermatidic level and in group B and C, no increase in sperm concentration was
observed after therapy. These data suggest that FSH treatment may have a role in
oligozoospermic subjects only when the spermatogenetic alterations consist in
germ cell depopulation without maturative disturbances and with normal FSH
concentrations.
PMID- 10773397
TI - Oocyte donation: clinical and practical aspects.
AB - Oocyte donation is an effective treatment modality for women lacking functioning
ovaries, but also for women in whom repetitive in-vitro fertilization (IVF)
cycles did not result in the development of adequate number of oocytes as well as
for those at risk of transmitting genetic diseases. In women with ovarian
failure, artificial menstrual cycles are required in order to produce endometrial
growth and differentiation similar to that in women with normal ovarian function.
Synchronization of donor's and recipient's cycles is mandatory, since the window
of implantation is rather limited. The excellent results of oocyte donation
treatment confirm that this assisted reproduction technique can provide a novel
approach for the treatment of infertility in these groups of patients.
Nevertheless, pregnancies in women of advanced reproductive age are associated
with significantly more obstetrical complications and higher perinatal morbidity
and mortality rates. Furthermore, aging parents have considerably higher chances
to develop serious or life-threatening diseases. Thus, careful medical screening
and extensive counselling is mandatory, taking into account the psychosocial
ramifications of the procedure and, especially, the best interest of the child-to
be.
PMID- 10773398
TI - Evaluation of the long-term function of cryopreserved ovarian grafts in the
mouse, implications for human applications.
AB - Ovarian tissue storage has several potentially very valuable clinical
applications, including the management of young female patients that are at risk
of premature menopause. Ovarian tissue collection, used alone or in combination
with oocyte and embryo cryopreservation, may help these patients safeguard their
own future fertility. All available evidence from animal studies indicates that
grafting of frozen ovarian tissue should be feasible in the human. This study on
the mouse shows that frozen thawed ovarian tissue grafts can restore long term
fertility to previously ovariectomised recipients. This, and other available
evidence, indicates that ovarian tissue collection and storage, used alone or in
combination with oocyte or embryo collection, may help safeguard the fertility of
patients at risk of premature menopause.
PMID- 10773399
TI - Gonadal activity and chromosomal constitution of in vitro generated embryos.
AB - Chromosomal analysis of pre-implantation embryos was carried out in patients with
a poor prognosis of full term pregnancy, which underwent induction of multiple
follicular growth. In all, 1034 embryos generated from 191 stimulated cycles were
screened for nine chromosome aneuploidy by using the multicolour fluorescence in
situ hybridisation technique. Thirty-five percent of the diagnosed embryos were
chromosomally normal, whereas the remaining presented with numerical
abnormalities, which made them not suitable for transfer. The results obtained
confirmed that the incidence of abnormalities is mostly dependent on age;
however, monosomy and trisomy are more frequent in poor responders. Accordingly,
the pregnancy rate per started cycle was significantly higher in women with a
normal response to gonadotropic stimulation (33% vs. 8%, P<0. 001). These
findings indicate that poor responder patients are physiologically exposed not
only to reduced chances of implantation, but also to an increased risk of
spontaneous abortion and trisomic pregnancies.
PMID- 10773400
TI - Spermatogonial transplantation - an update for the millennium.
AB - Spermatogonial transplantation as developed in the laboratory of Ralph Brinster
has been a technological breakthrough in the study of Sertoli-germ cell
interactions. For the first time, germ cells can be transferred from one animal
to another and from one species to another. The transfer technology combined with
developments in freezing germ cells, long-term culture of germ cells, and
enrichment of stem cell populations portend even more significant breakthroughs
in the new millennium. The ultimate application of germ cell transfer would allow
the in vitro genetic manipulation of cultured stem cells that could then be
transplanted into recipient syngeneic or xenogeneic recipients and give rise to
functional male gametes. Clearly, this achievement would have applications in
basic science, human medicine, and domestic and wild animal reproduction. While
progress in this direction has been significant and swift, significant barriers
such as immunological response and mechanisms for introducing genetic material
into the stem cells remain to be examined. This report is a chronological review
of the technological advances made and conceptual insights gained since the first
report of successful transplantation in 1994.
PMID- 10773402
TI - Bleomycin-induced chromosome aberrations in head and neck cancer patients
analyzed by classical cytogenetics and FISH.
AB - Individual sensitivity to mutagens has been considered to play an important role
in head-and-neck squamous cells carcinoma (HNSCC) development. The bleomycin test
was introduced for establishing constitutional susceptibility to mutagens (T.C.
Hsu, D.A. Johnston, L.M. Cherry, D. Ramkisson, S.P. Schantz, J.M. Jessup, R.J.
Winn, L. Shirley, C. Furlong, Sensitivity to genotoxic effects of bleomycin in
humans: possible relationship to environmental carcinogenesis, Int. J. Cancer 43
(1989) 403-409). Its criteria are based on scoring of chromosome aberrations
(CAs, mainly breaks) in Giemsa-stained chromosomes. Fluorescence in situ
hybridization (FISH) offers an easy method for analysis of translocations,
acentric fragments and dicentrics. In the present study FISH was applied in the
analysis of bleomycin-induced CAs of the HNSCC patients and controls. The results
proved that FISH is a complementary method to the classical staining in
monitoring of bleomycin-induced CAs.
PMID- 10773401
TI - Folk medicine Terminalia catappa and its major tannin component, punicalagin, are
effective against bleomycin-induced genotoxicity in Chinese hamster ovary cells.
AB - Terminalia catappa L. is a popular folk medicine for preventing hepatoma and
treating hepatitis in Taiwan. In this paper, we examined the protective effects
of T. catappa leaf water extract (TCE) and its major tannin component,
punicalagin, on bleomycin-induced genotoxicity in cultured Chinese hamster ovary
cells. Pre-treatment with TCE or punicalagin prevented bleomycin-induced hgprt
gene mutations and DNA strand breaks. TCE and punicalagin suppressed the
generation of bleomycin-induced intracellular free radicals, identified as
superoxides and hydrogen peroxides. The effectiveness of TCE and punicalagin
against bleomycin-induced genotoxicity could be, at least in part, due to their
antioxidative potentials.
PMID- 10773403
TI - Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1, 3-butadiene
induced mouse lymphomas.
AB - The pRb pathway plays a key role in controlling the G1/S transition in cell cycle
progression. Aberrations of various components of the pRb pathway, such as
retinoblastoma protein and its upstream actors including cyclin D1, cyclin
dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been
reported in a variety of human tumors. Furthermore, the alterations of
retinoblastoma protein and its upstream components often occur in a reciprocal
manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b
loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'
dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A.
Schippert, A. Haugen-Strano, R.W. Wiseman, P. Soderkvist, Inactivation of
p16(INK4a)-alpha, p16(INK4a)-beta and p15(INK4b) genes in 2', 3'-dideoxycytidine-
and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the
involvement of pRb pathway in lymphomagenesis. To investigate whether alteration
of other components in pRb pathway is an alternative mechanism underlying the
development of these chemically induced lymphomas, we have examined the genetic
status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1
and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1,
Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors
examined. In addition, single-strand conformation analysis failed to reveal point
mutations in the Cdk4 amino terminal domain that is important for its association
with Cdkn2a gene products. These results indicate that the mechanisms underlying
the development of 2', 3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas
involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not
genomic alterations of the Rb1, Ccnd1 and Cdk4 genes.
PMID- 10773404
TI - Limited synergistic effect of antisense oligonucleotides against bcr-abl and
transferrin receptor mRNA in leukemic cells in culture.
AB - The synergistic use of antisense oligonucleotides (ASOs) towards the bcr-abl and
the transferrin receptor (TfR) mRNA was studied in a chronic myeloid leukemia
(CML) cell line, aiming to improve the efficiency of individual ASO treatment. At
20 microM concentration, bcr-abl ASOs reduced cell growth by 40% and was specific
for cells that have the translocation: there was a 34% reduction of BCR-ABL
protein. The TfR ASO reduced cell growth by 20% and decreased TfR protein by 24%.
The ASOs were more potent at reducing cell growth when used in combination
(respectively, -20 and -17% than bcr-abl ASO and TfR ASO when used individually
at the 10 microM concentration), thus we postulate that there is synergism of
action. Cell cycle analysis also revealed that the sub-G1 peak was bigger in the
synergistic treatment.
PMID- 10773405
TI - Helicobacter pylori induces DNA damage in vitro.
AB - A close association between Helicobacter pylori infection and the development of
gastric adenocarcinoma in humans has been demonstrated. Therefore, the direct
induction of DNA damage by H. pylori was investigated here using the in vitro
micronucleus assay. After 5 days of incubation with bacterial lysate a dose
dependent formation of micronuclei was found, which was not limited to cytotoxic
protein concentrations and was not observed after treatment with Escherichia coli
lysate (control). This induction of DNA damage may be a link between chronic H.
pylori infection and development of adenocarcinoma of the stomach.
PMID- 10773406
TI - Quantitative assessment of spontaneous lung metastases of human HT29 colon cancer
cells transplanted into SCID mice.
AB - The number of spontaneous lung metastases of the human colon cancer cell line
HT29 transplanted into SCID mice was quantified. The lungs were sliced, randomly
distributed in agar blocks and the number of lung metastases was counted for each
of 39 animals. A nearly exponential increase of metastases with weight of the
tumor at the implantation site was observed. This suggests that a critical tumor
weight for the initiation of metastatic spread exists. Calculating the data, a
simplified quantitative assessment of the metastatic load by counting ten
histological sections only for the estimation of the total number of lung
metastases is proposed.
PMID- 10773407
TI - Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by
inducing apoptosis in a p53-independent manner.
AB - The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines
with a different p53 status were investigated. A reduction of radiation-induced
G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines.
The reduction of survival was observed in a combination of radiation and 2 mM
caffeine only in a lower radiation dose range, but not in a higher dose range in
NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in
a higher dose range for cells with a mutant-type p53. Apoptosis, which was not
prominent after irradiation alone or caffeine treatment alone, was induced by
irradiation in combination with caffeine in cells with a mutant-type p53 through
a p53-independent pathway.
PMID- 10773408
TI - Inhibition by methionine of pancreatic carcinogenesis in hamsters after
initiation with N-nitrosobis(2-oxopropyl) amine.
AB - The modifying effects of dietary L-methionine in the post-initiation phase of
pancreatic carcinogenesis were investigated in hamsters treated with N
nitrosobis(2-oxopropyl)amine (BOP). Groups consisting of 20 and 30 animals,
respectively, were given BOP subcutaneously, once a week five times at a dose of
10 mg/kg body wt. and then continuously fed diet supplemented with 2% (group 1)
or 0% (group 2) methionine (weeks 5-32). After five subcutaneous injections of
saline, group 3 animals were similarly fed diet supplemented with 2% methionine
for the same period. The incidence of pancreatic ductal adenocarcinomas was
significantly lower in group 1 (36.8%, P<0.05) than in group 2 (71.4%).
Multiplicity of adenocarcinomas was also significantly lowered (0.52 and
1.28/hamster, P<0.05). Similarly, total numbers of combined adenocarcinomas and
dysplastic lesions were significantly decreased in group 1 (2.05, P<0.05) as
compared with group 2 (3.67). Methionine enhanced atrophic change of pancreatic
acinar cells in hamsters given BOP, indicating that the inhibitory effects on the
post-initiation stage of BOP-induced pancreatic carcinogenesis in hamsters could
be generally linked to suppression of growth.
PMID- 10773409
TI - Lipid peroxidation status, somatic mutations and micronuclei in peripheral
lymphocytes: a case observation on a possible interrelationship.
AB - A controlled dietary study was conducted in healthy female volunteers and
reported elsewhere [1]. In a subset of samples four different biomarkers were
analyzed: plasma malondialdehyde (MDA) levels and urinary 8-isoprostaglandin
F(2alpha) were measured as markers for lipid peroxidation. The frequency of hprt
(hypoxanthine guanine phosphoribosyl transferase) mutants and micronuclei in
peripheral blood lymphocytes were analyzed as indicators of genotoxic effects.
One of the ten individuals showed extremely high background levels in all of the
four endpoints measured. This case observation raises the possibility that life
style factors and dietary habits affect the level of DNA reactive lipid
peroxidation products, which in turn increase mutagenic and cytogenetic effects.
A possible association between these biomarkers, particularly in relation to
dietary fat intake and antioxidant status, should now be studied in a larger
trial.
PMID- 10773410
TI - Therapeutic efficiency of IL-2 gene transduced tumor vaccine for head and neck
carcinoma.
AB - Transduction of the human interleukin-2 (IL-2) gene into tumor cells was carried
out in order to develop a new immunotherapy for advanced head and neck carcinomas
with a poor outcome. We transduced the IL-2 gene into KB cells, a head and neck
squamous cell carcinoma cell line, using a defective herpes simplex viral (HSV)
amplicon vector as a gene transfer vehicle. A high level of IL-2 was secreted by
IL-2 gene-transduced KB cells (KB/IL-2). The IL-2 producibility of irradiated
KB/IL-2 cells was almost the same as that of non-irradiated cells. In the tumor
establishment model in nude mice, IL-2 and interferon-gamma (IFN-gamma) at high
concentrations were detected in the sera of mice transplanted with KB/IL-2 cells.
The spleen cells of nude mice transplanted with KB/IL-2 cells exhibited high
cytotoxic activity compared to those from mice transplanted with KB cells and
from untreated mice. Three of five mice transplanted with KB/IL-2 cells rejected
tumors. In the treatment of established tumors, therapeutic effects due to
irradiated KB/IL-2 were dose-dependent. The suppressive effects on tumor growth
were blocked by anti-asialo GM1, anti-human IL-2 and anti-IFN-gamma antibodies.
Immunohistochemical observation revealed the presence of asialo GM1(+) cells
among the KB/IL-2 cells in tumors transplanted into nude mice.
PMID- 10773411
TI - Anti-tumor-promoting effects of isoflavonoids on Epstein-Barr virus activation
and two-stage mouse skin carcinogenesis.
AB - As a part of screening studies for anti-tumor promoters, fifteen isoflavonoids
isolated from plants of the genus Millettia (Leguminosae) were evaluated by
examining their possible inhibitory effects on Epstein-Barr virus early antigen
(EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji
cells. All of the compounds tested in this study showed inhibitory activity
against EBV, without showing any cytotoxicity. Auriculasin (11) and millepurone
(13), which is an oxidized isoflavone analogue, both having one or more prenyl
side-chains and a 3',4'-dihydroxyphenyl group in the molecule, showed more potent
activity than any of the other compounds tested. Furthermore, millepurone (13)
exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo
two-stage carcinogenesis test. The results of the present investigation indicate
that some of these isoflavonoids might be valuable anti-tumor promoters.
PMID- 10773412
TI - Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast
cancer cell lines.
AB - Genetic instability is a hallmark feature of breast, colorectal and other types
of cancers. One type characterized by chromosomal instability is thought to be
important in the pathogenesis of many solid tumors displaying aneuploidy. Two
related protein kinases and homologues of the yeast checkpoint genes, hBUB1 and
hBUB1B, have been implicated in the pathogenesis of colorectal cancers. Mutations
in hBUB1 have demonstrated a dominant negative effect by disrupting the mitotic
checkpoint when transfected into euploid colon cancer cell lines. In Brca2
deficient murine cells, Bub1 mutants potentiate growth and cellular
transformation. This would suggest that aneuploidy in solid tumors including
breast, could be the result of defects in mitotic checkpoint genes and may be
responsible for a chromosomal instability phenotype contributing to tumor
progression. We conducted mutational analysis of 19 aneuploid breast cancer cell
lines. No mutations were found but we identified nine sequence variations
including five previously unreported sequence variants in hBUB1B, two of which
affect restrictions sites. None of these nucleotide changes predict significant
changes in the predicted protein structure. Expression analysis by Northern blot
of breast cell lines showed variable expression of hBUB1 and hBUB1B genes. This
suggest that while regulation of expression of these genes may be important in
cancer, the lack of putative deleterious mutations in the coding sequence does
not support a frequent role for mutant hBUB1 and hBUB1B alleles in the
pathogenesis of breast cancer.
PMID- 10773413
TI - The expression of fragile sites in lymphocytes of patients with rectum cancer and
their first-degree relatives.
AB - Fragile sites are non-staining gaps and breaks in specific points of chromosomes.
These sites also include acentric fragments, triradial figures and several
rearrangements. Although this issue has been controversial recently, they may be
related to structural chromosomal rearrangement in some neoplasms. In this study,
the expression of fragile sites induced by aphidicolin (Apc), 5-bromodeoxyuridine
(BrdU) and caffeine was investigated on prometaphase chromosomes obtained from
the peripheral blood lymphocytes of 36 patients with rectum cancer, 30 first
degree relatives and 30 normal healthy controls. The results of the structural
chromosome aberrations determined in patients and their first-degree relatives
were significantly higher than those in control subjects (P<0.001). We determined
aphidicolin type common fragile sites (1p36, 1p31, 1p21, 1q21, 1q25, 1q44, 2p24,
2q21, 2q33, 2q37, 3p14, 5q21, 5q33, 13q13, 14q24, 16q23 and 18q21). When the
rates of sites such as 1p21, 1q25, 2q33, 3p14, 5q21 and 14q24 in patients and in
their first-degree relatives were compared with the control group, the difference
was statistically significant. Our results indicated an increased genetic
instability in patients with rectum cancer and their first-degree relatives.
Therefore, the increase of fragile site expression may be an important marker
showing genetic predisposition to rectum cancer.
PMID- 10773414
TI - Lack of susceptibility of transgenic mice carrying the human c-Ha-ras proto
oncogene (rasH2 mice) to phenolphthalein in a 6-month carcinogenicity study.
AB - Phenolphthalein has carcinogenic activity, causing malignant lymphomas in B6C3F1
mice at a dietary dose of 3000 ppm in a 2-year carcinogenicity study and in
heterozygous p53-deficient female mice at the same dose in a 6-month study. To
examine whether phenolphthalein carcinogenic potential can be detected in male
and female transgenic (Tg) mice carrying the human c-Ha-ras gene (rasH2 mice) and
their wild-type littermates (non-Tg mice), a diet containing 3000, 6000 or 12000
ppm was given for 6 months. Unequivocal induction of neoplastic lesions was not
apparent, suggesting that rasH2 mice are resistant to the induction of malignant
lymphomas by the treatment of phenolphthalein.
PMID- 10773415
TI - Effect of prostaglandin E(2) on the proliferation, Ca(2+) mobilization and cAMP
in HT-29 human colon adenocarcinoma cells.
AB - Several lines of evidence suggest that non-steroidal antiinflammatory drugs
(NSAIDs) have anticarcinogenic effects. The causal relationship linking the
preventive effect of NSAIDs on colon cancer and the inhibition of prostaglandin
synthesis is questioned by the contrasting results obtained by many laboratories.
The experiments reported in this paper demonstrate that prostaglandin E(2)
(PGE(2)) did not stimulate the proliferation in HT-29 human colon adenocarcinoma
cells under several experimental conditions. Moreover, PGE(2) and 17-phenyl
trinor prostaglandin E(2) (a specific agonist of EP1 receptors) did not increase
intracellular Ca(2+) concentration. Finally, PGE(2) did not affect the
intracellular cAMP and did not reduce the isoproterenol dependent increase in
cAMP. These results indicate that in HT-29 cells: (1) proliferation is not
directly sensitive to PGE(2); and (2) PGE(2) does not stimulate a signal
transduction pathway leading to intracellular increase in cAMP or Ca(2+)
mobilization. Therefore, other cell lines should be used to assess the direct
role played by prostanoids in promoting cell proliferation in colon cancer.
PMID- 10773416
TI - Altered gene expressions during hypoxia and reoxygenation in cortical neurons
isolated from stroke-prone spontaneously hypertensive rats.
AB - The expressions of Bcl-2, thioredoxin (TRX) and cytochrome c oxidase III (CO III)
mRNAs after hypoxia and reoxygenation (H/R) were examined by quantitative reverse
transcription-polymerase chain reaction using cultured cortical neurons isolated
from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats
(WKY). The differences in gene expressions of Bcl-2, TRX and CO III mRNA between
SHRSP and WKY were most remarkable at 30 min of oxygen stimulation, and the
expressions of these genes were significantly lower in SHRSP compared with those
in WKY. These findings pointed out that redox regulatory function and energy
metabolism in SHRSP neurons were markedly reduced by oxygen stimulation after
hypoxia, and such changes may be involved in neuronal vulnerability.
PMID- 10773417
TI - Temporal profile of release of interleukin-1beta in neurotrauma.
AB - Timing and extent of trauma-induced release of interleukin-1beta (IL-1beta) in
extracellular fluid of the CNS were analyzed. In brain tissue perfusates obtained
by in vivo microdialysis a marked release of IL-1beta was unexpectedly detected
within less than 60 min. At such an early stage of neurotrauma, mRNA expression
of IL-1beta was detected whereas immunoreactivity for the IL-1beta protein was
negative. Concentrations of extracellularly secreted IL-1beta protein gradually
increased, peaked at day 2 and decreased thereafter. Drugs acting on mononuclear
phagocytes significantly modulated IL-1beta secretion. This so far unrecognized
acuity of IL-1beta release demonstrated here, may represent a precondition for
the orchestrating role of this mediator in the cascade of inflammatory host
response.
PMID- 10773418
TI - Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice.
AB - Breathing patterns are influenced by body temperature. However, the central
mechanism for changes of breathing patterns is unknown. We previously showed that
central histamine contributed to temperature-induced polypnea in mice (Izumizaki,
M., Iwase, M., Homma, I., Yanai, K., Watanabe, T. and Watanabe, T., Central
histamine contributed to the temperature-induced polypnea in mice, Neurosci.
Res., 23 (1999) S282). In this study we examined the role of central histamine H1
receptors in temperature-induced polypnea using wild and mutant mice lacking
histamine H1 receptors. Breathing patterns were characterized at two different
body temperatures during hypercapnia under conscious conditions. In wild mice a
raised body temperature increased respiratory frequency mainly due to a reduction
in expiratory time, whereas in mutant mice respiratory frequency did not increase
even though the body temperature was elevated. These results indicate that
central histamine contributes to an increase in respiratory frequency due to a
reduction in expiratory time through histamine H1 receptors when body temperature
is raised.
PMID- 10773419
TI - Activin promotes astrocytic differentiation of a multipotent neural stem cell
line and an astrocyte progenitor cell line from murine central nervous system.
AB - The effects of activin A were investigated on the development of a multipotent
neural stem cell line (MEB5) and an astrocyte progenitor cell line (AP-16) that
were established from murine central nervous system (CNS). Reverse transcriptase
polymerase chain reaction (RT-PCR) analysis demonstrated that each cell line
expresses both type I and type II activin receptors and signaling molecules for
activin, Smad2, Smad3, and Smad4. Activin A did not affect the proliferation of
MEB5 and AP-16 cells. When each cell line was treated alone with activin A, glial
fibrillary acidic protein (GFAP), a marker for astrocytes, was induced in AP-16
cells, but not in MEB5 cells. However, activin A accelerated the leukemia
inhibitory factor (LIF)-induced astroglial differentiation of MEB5 cells. These
results suggest that activin promotes astrocyte differentiation of CNS neural
progenitors, and the competence to activin is different between multipotent stem
cells and unipotent astrocyte progenitor cells.
PMID- 10773420
TI - Repetitive transcranial magnetic stimulation causes a short-term increase in the
duration of the cortical silent period in patients with Parkinson's disease.
AB - In ten patients with Parkinson's disease (PD) and ten age-matched healthy
controls, we applied 15 30-s trains of subthreshold 5-Hz repetitive transcranial
magnetic stimulation (rTMS) over the primary motor hand area. Ten minutes after
rTMS, PD patients showed a significant prolongation of the transcranially evoked
silent period (SP) in the contralateral first dorsal interosseus muscle, whereas
the SP remained unchanged in healthy subjects. Since the duration of the
transcranially evoked SP is a well-established measure of intracortical
inhibition, this finding demonstrates that rTMS is capable of inducing a short
term increase in intracortical inhibition in PD. The lack of a prolongation of
the SP in healthy controls suggests that PD patients may be particularly
susceptible to modulatory effects of rTMS on motocortical inhibition.
PMID- 10773421
TI - Hypoxia influences somatostatin release in rats.
AB - The impact of hypoxia on somatostatin (SS) secretion from the median eminence
(ME) of the hypothalamus and the possible glucocorticosteroid involvement in
modulating secretion, were investigated in adult male rats exposed to hypoxia. SS
levels were measured by specific radioimmunoassay during acute and prolonged
hypoxia as well as after bilateral adrenalectomy (ADX) with or without a
replacement with dexamethasone (DEX). The results were as follows: (a) acute
hypoxia (5 km altitude, 10.8% O(2)) for 2 and 24 h markedly increased SS content
in ME, but acute severe hypoxia (7 km, 8.2% O(2) for 24 h) markedly decreased SS
level in ME. (b) Chronic hypoxia (10.8% O(2)) from 5 to 25 days exposure did not
significantly affect SS content of ME. (c) ADX alone increased SS content of ME
and this increase was further enhanced after 2 h exposure to hypoxia. (d) The
increased SS in ME of ADX rats was blocked by replacement with DEX (500
microg/rat i.p.). The data presented suggest that acute hypoxia stress may
increase or decrease SS content of ME in rats, depending on the severity and
duration of the hypoxia and that the stimulatory action of hypoxia on SS content
of ME be may in part mediated by the increased corticosterone levels during
hypoxia.
PMID- 10773422
TI - Inhibitory effect of intrathecally administered nociceptin on the expression of
Fos-like immunoreactivity in the rat formalin test.
AB - Nociceptin, an opioid receptor-like 1 receptor agonist, has been reported to
produce an analgesic effect in the rat formalin test. The authors examined the
effect of 17 nmol of nociceptin on the expression of Fos-like immunoreactivity
(Fos-LI) in the spinal dorsal horn induced by paw formalin injection and compared
the effect of 17 nmol of nociceptin with that of equiantinociceptive dose (3
nmol) of morphine. Nociceptin and morphine were administered intrathecally 10 min
before the formalin injection and the expression of Fos-LI was examined 2.5 h
after the formalin injection. Both 17 nmol of nociceptin and 3 nmol of morphine
suppressed the expression of Fos-LI in laminae I-II, but not in laminae III-V, to
the same extent. These data suggest that intratheally administered nociceptin and
morphine suppress the nociceptive input into the laminae I-II and produce
antinociceptive effect.
PMID- 10773423
TI - Effects of bacterial lipopolysaccharide on central monoamines and fever in the
rat: involvement of the vagus.
AB - Lipopolysaccharide (LPS) is known to produce a number of central and
neuroendocrine effects but the mechanisms involved are still unclear. This study
was done to investigate the possibility that LPS-induced fever and activation of
central monoamines are mediated through the vagus. Adult male rats were subjected
to sub-diaphragmatic vagotomy (SDV), or sham operation and treated with saline or
LPS in saline (10 microg/kg bw) 2 h later. Rectal temperature was monitored at
half-hourly intervals for 5 h after which the animals were sacrificed and
monoamine concentrations in hypothalamic nuclei were measured using HPLC-EC. SDV
delayed the rise in rectal temperature induced by LPS by 1 h when compared to
Sham animals. It also increased the concentrations of monoamines in the
paraventricular nucleus of both Sham and SDV rats. This indicates that routes
other than the vagus probably mediate LPS' actions on the central nervous system.
PMID- 10773424
TI - Enhancement of cerebral cortical acetylcholine release by intraperitoneal acetic
acid and its suppression by analgesics in freely moving rats.
AB - Several lines of evidence suggest that central cholinergic neurons play a key
role in the perception and control of pain. We investigated the effects of
analgesics on the increase in central cholinergic activity and writhing responses
elicited by i.p. injection of acetic acid. ACh efflux from the rat cerebral
cortex and hippocampus was measured in the absence of a cholinesterase inhibitor
using an in vivo microdialysis technique and a highly sensitive and specific
radioimmunoassay. ACh efflux from the cerebral cortex was significantly increased
during the first 30 min after acetic acid injection and then returned to the
control levels. In contrast, acetic acid-induced writhing responses, indicative
of the perception of pain, persisted for almost the entire 120 min observation
period. No changes in ACh efflux were observed in the hippocampus. The centrally
acting analgesic morphine and the peripherally-acting analgesic indomethacin each
completely abolished the enhanced cerebral cortical ACh efflux and the writhing,
whereas diazepam, a muscle relaxant, selectively suppressed only the writhing.
These results demonstrate that peripheral nociceptive stimulation transiently
increases cholinergic activity in the cerebral cortex, but not in the
hippocampus, and that analgesics suppress both the enhanced ACh efflux and the
writhing induced by acetic acid.
PMID- 10773425
TI - Propofol potentiates ATP-activated currents of recombinant P2X(4) receptor
channels expressed in human embryonic kidney 293 cells.
AB - We examined the effects of a general anesthetic 2, 6-diisopropylphenol (propofol)
on ATP- and alpha,beta-methylene ATP (alphabetameATP)-activated currents in the
human embryonic kidney 293 (HEK 293) cells expressing recombinant P2X receptor
channels, using the whole-cell patch-clamp method. Propofol at clinical relevant
concentrations ( approximately 56 microM) potentiated the current responses
through the P2X(4) receptor in a dose-dependent manner, whereas propofol did not
affect the responses through the P2X(2) receptor or through the heterologous
complex of the P2X(2) and P2X(3) (P2X(2+3)) receptor. These results suggest that
activation of P2X(4) subtype in the brain and the motor neurons of the spinal
anterior horn might be involved in the excitatory effect by propofol such as
convulsion and unexpected movements.
PMID- 10773426
TI - mRNA encoding 'ClC-K1, a kidney Cl(-)- channel' is expressed in marginal cells of
the stria vascularis of rat cochlea: its possible contribution to Cl(-) currents.
AB - The cochlear stria vascularis is essential for the normal function of hair cells.
mRNA encoding the ClC-K1 Cl(-) channel, previously thought to be found only in
the kidney, was detected in epithelial marginal cells of the rat stria vascularis
by single cell RT-PCR. When Cl(-) currents were recorded from rat marginal cells
by the whole-cell patch clamp method, the steady-state currents showed weak
outward rectification and an ion selectivity sequence of SCN(-)Br(-)=Cl(-)F(
)NO(3)(-)I(-)gluconate(-). The Cl(-) currents were regulated by extracellular
Ca(2+) and pH. These characteristics resemble those reported for the currents
recorded from Xenopus oocytes expressing ClC-K1 Cl(-) channels. These data
together suggest that ClC-K1 Cl(-) channels may contribute to the whole-cell
currents of marginal cells.
PMID- 10773427
TI - Comparison of French natural scrapie isolates with bovine spongiform
encephalopathy and experimental scrapie infected sheep.
AB - We compared the glycoform pattern of the abnormal prion protein (PrP(Sc))
detected by immunoblotting in 21 sheep with natural scrapie, from 21 different
outbreaks identified in France since 1996, with a bovine spongiform
encephalopathy (BSE)-infected sheep. All the natural scrapie isolates had a
higher molecular mass of the unglycosylated PrP(Sc) than in BSE-infected sheep.
In the latter case, this molecular mass appeared identical to that found in the
CH 1641 experimental scrapie strain (type C pattern), whereas in natural scrapie
cases it was similar to that found in the SSBP/1 experimental scrapie strains.
These results suggest that all French natural scrapie isolates studied so far
would belong, as SSBP/1, to the group of scrapie cases with type A
electrophoretic pattern.
PMID- 10773428
TI - Adenosine triphosphate is full antagonist at human P2Y(1) purinoceptors.
AB - Both agonistic and antagonistic effects have been reported for ATP at P2Y(1)
purinoceptors at micromolar ligand concentrations. These conflicting data hamper
specification of the true pharmacological profile as well as structural
requirements for antagonistic ligands of this receptor. In this report the type
of ATP activity at human P2Y(1) receptors in hP2Y(1)-1321N1 cells was revisited.
In parallel, kinetics of degradation of ATP in the assay mixture was analysed. It
was found that transformation of this ligand to ADP was responsible for
initiation of synthesis of inositol phosphates, observed in the presence of ATP
in hP2Y(1)-1321N1 cells. This agonistic effect was abolished in the presence of
the triphosphate regeneration system (CP/CPK). On the other hand, if the
agonistic effect caused by degradation product of ATP was taken into
consideration, this ligand behaved as a full antagonist at P2Y(1) receptors and
was characterized by the apparent inhibitory constant 5 microM.
PMID- 10773429
TI - Localization of M(2) muscarinic acetylcholine receptor protein in cholinergic and
non-cholinergic terminals in rat hippocampus.
AB - The muscarinic receptor family (M(1)-M(4)) mediates cholinergic modulation of
hippocampal transmission. Pharmacological and physiological studies have
indicated that a presynaptic receptor on cholinergic terminals plays a key role
in regulating ACh release, although the molecular identity of this subtype is
uncertain. In this study, the localization of the M(2) receptor is described in
detail for the pyramidal cell layer in the CAl region of the hippocampus.
Electron microscopic analysis of M(2) immunoreactivity in this area revealed
mainly presynaptic expression of this subtype. Double-labeling experiments using
antibodies to M(2) and to the vesicular acetylcholine transporter, a novel,
specific marker of cholinergic terminals, were used to investigate the nature of
these presynaptic receptors. These studies have revealed that M(2) is located in
cholinergic and non-cholinergic terminals. This is the first direct anatomical
evidence that suggests that M(2) may indeed function as a cholinergic
autoreceptor in the hippocampus. The distribution of the M(2) receptor in non
cholinergic terminals also suggests functional roles for M(2) as a presynaptic
heteroreceptor.
PMID- 10773430
TI - Neurons containing Alz-50-immunoreactive granules around the cerebral infarction:
evidence for the lysosomal degradation of altered tau in human brain?
AB - Little is known about the metabolic process of tau and tau-derived substances.
Alz-50- and tau 2-immunoreactivities in intracellular granules of neurons were
observed in regions surrounding infarcted foci in the human cerebral cortex.
Ultrastructurally, these granules in the fresh infarcted region exhibited primary
lysosome-like structures, while those in old infarctions were lipofuscin. These
findings indicate that tau is metabolized within lysosomes in neurons damaged by
ischemic injury in human cortical penumbra. Alz-50-positive granules were more
prominent in fresh infarction than in old infarction. After undergoing
degradation and modification, altered tau might remain, at least partially, in
secondary lysosomes.
PMID- 10773431
TI - Effects of the androgenic anabolic steroid, nandrolone decanoate, on
adrenocorticotropin hormone, corticosterone and proopiomelanocortin,
corticotropin releasing factor (CRF) and CRF receptor1 mRNA levels in the
hypothalamus, pituitary and amygdala of the rat.
AB - There is increasing abuse of androgenic anabolic steroids (AAS) by non-athletes.
AAS abuse has been associated with psychiatric symptoms such as mania, major
depression and aggression and the development of dependence. Little is known
about the effects of AAS on hypothalamic-pituitary-adrenal axis function or
corticotropin releasing factor, which may be involved in mediating some of the
psychiatric symptoms associated with AAS abuse. Male Sprague-Dawley rats received
one daily intra-muscular injection of the AAS nandrolone decanoate (ND, 15 mg/kg)
or vehicle for 3 days. Animals were sacrificed either 1 h or 24 h after the last
injection, brain regions dissected and trunk blood collected. Corticotropin
releasing factor (CRF), CRF receptor1 (CRF-R1) and proopiomelanocortin (POMC)
mRNAs were measured with solution hybridization/RNase protection. Circulating
levels of corticosterone and adrenocorticotropin hormone (ACTH) were determined
using radioimmunoassays. One hour following the last injection, ND significantly
increased circulating levels of both corticosterone and ACTH levels. In the
amygdala, CRF mRNA levels were unchanged 1 h after the last injection of ND but
were significantly reduced at 24 h. The same was found for hypothalamic POMC. No
significant AAS effects were observed on: hypothalamic CRF mRNA; POMC mRNA in the
amygdala or CRF R1 mRNA in the anterior pituitary.
PMID- 10773432
TI - c-Jun N-terminal kinase (JNK) and JNK interacting protein response in rat brain
after transient middle cerebral artery occlusion.
AB - c-Jun response is involved in the development of ischemic brain injury, which is
activated by c-Jun N-terminal kinase-1 (JNK-1). The activity of JNK-1 is strictly
regulated, and only the phosphorylated form of JNK (phospho-JNK) which is
translocated to the nucleus has an ability to activate c-Jun response. There is a
protein which inhibits JNK-1 activation, and known as JNK interacting protein-1
(JIP-1). In this study, we investigated change in JNK-1, phospho-JNK, and JIP-1
immunoreactivity in rat brain after transient middle cerebral artery (MCA)
occlusion. Immunoreactive JNK-1 was scant in the sham-control brain, but it was
induced at 1 h after reperfusion, which was slightly increased at 3 h of
reperfusion. By contrast, phospho-JNK remained negative till 3 h. At 8 h, JNK-1
and phospho-JNK became distinctly positive, and nuclei as well as cytoplasm were
stained. Thereafter, immunoreactivity for JNK-1 and phospho-JNK became
furthermore dense, and most neurons revealed positively stained nuclei.
Immunoreactivity for JIP-1 remained negative till 8 h of reperfusion, but at 24
and 72 h, cytoplasm of cortical neurons at the MCA boundary area was positively
stained. This JIP-1 induction got behind the JNK-1 activation, and therefore, may
be a vain effort for neurons to survive. Inhibition of JNK-1 activation might
become an innovative means of therapy for stroke treatment in the future.
PMID- 10773433
TI - Introduction to tobacco, nicotine, and youth: the tobacco etiology research
network.
PMID- 10773434
TI - Investing in substance abuse research: The Robert Wood Johnson Foundation story.
PMID- 10773435
TI - Current models of nicotine dependence: what is known and what is needed to
advance understanding of tobacco etiology among youth.
AB - Youth smoking has risen dramatically during the last 5 years, leading one to the
conclusion that prevention interventions have not been particularly effective.
This paper provides an examination of features that define adult nicotine
dependence and argues that these features need to be considered in any studied
examination of youth etiology and development to nicotine dependence. We review
the historical context for the concept of nicotine dependence, features that
define the concept and current models of substance dependence more generally.
Recommendations for future research are provided.
PMID- 10773436
TI - Measuring nicotine dependence among youth: a review of available approaches and
instruments.
AB - This paper reviews issues and concepts related to the measurement of nicotine
dependence among youth. The primary objectives of this review are to: (1) review
the measures of nicotine dependence currently being used; and (2) delineate a
future research agenda in an attempt to advance the quality of measurement and
instrumentation for this important research endeavor. Existing measures of
nicotine dependence, including formal diagnostic interviews, related withdrawal
assessments, brief self-report measures, and single-item indicators, are
described. While formal diagnostic systems have been considered the 'gold
standard' for evaluating dependence clinically, their specific limitations
related to use for research purposes are outlined. Each broad class of measure is
evaluated in terms of its rationale for use, strengths and limitations, and the
extent to which it has successfully been applied to adolescent populations. A
research agenda follows in the second section of the paper. In this section, the
need for identification and inclusion of a standard set of optimal dependence
measures, for enhancement of current measures, and for the onset of a new and
comprehensive measures development program is outlined.
PMID- 10773437
TI - Initial tobacco use episodes in children and adolescents: current knowledge,
future directions.
AB - Approximately three-quarters of adult tobacco users report that their first
tobacco use occurred between ages 11 and 17, while many adults who do not
regularly use tobacco report that they experimented with it as adolescents.
Surprisingly little is known about the effects of these initial tobacco use
episodes and their influence on adult tobacco use patterns. In particular,
understanding the role that nicotine plays in these early tobacco use experiences
may be important in understanding the development of regular tobacco use and
concomitant nicotine dependence. One goal of this review is to summarize current
knowledge regarding the effects of initial tobacco use episodes in adolescents
and to discuss nicotine exposure in initial tobacco use episodes. Another goal is
to outline a research agenda designed to learn more about initial tobacco use
episodes and the effects of nicotine in children. An ethical rationale and some
potential methods for this research agenda are presented.
PMID- 10773438
TI - Stages in the development of adolescent smoking.
AB - Many researchers have conceptualized smoking uptake behavior in adolescence as
progressing through a sequence of developmental stages. Multiple social,
psychological, and biological factors influence this process, and may play
different functions at different points in the progression, and play different
roles for different people. The major objective of this paper is to review
empirical studies of predictors of transitions in stages of smoking progression,
and identify similarities and differences related to predictors of stages and
transitions across studies. While a number of factors related to stage of
progression replicated across studies, few variables uniquely predicted a
particular stage or transition in smoking behavior. Subsequently, theoretical
considerations related to stage conceptualization and measurement, inter
individual differences in intra-individual change, and the staged or continuous
nature of smoking progression are discussed.
PMID- 10773439
TI - Are adolescent smokers dependent on nicotine? A review of the evidence.
AB - This paper reviews the empirical literature on adolescent nicotine dependence,
withdrawal, and their associated features. Data documenting nicotine dependence
scores, diagnoses, and individual features among adolescents are reviewed in
detail and compared to observations based on adult smokers. These data are
derived from a broad variety of sources, including national surveys, school-based
surveys, and smoking cessation studies. Overall, results indicate that one to
three out of five adolescent smokers is dependent on nicotine, with some
adolescent groups clearly at higher risk for dependence (those who are
incarcerated, in vocational schools, daily smokers, and/or heavy smokers). Across
studies, data consistently indicate that a large majority (two-thirds or more) of
adolescent smokers report experiencing withdrawal symptoms during attempts to
quit or reduce their smoking. Craving or strong desire to smoke was the most
commonly reported withdrawal symptom in every study reviewed. Although analyses
of concurrent validity generally support the dependence and withdrawal findings
among adolescents, data on the predictive validity of measures used are needed.
Moreover, studies of adolescent tobacco withdrawal rely almost exclusively on
retrospective self-report data. Recommendations for enhancing methodology and
advancing our understanding of adolescent nicotine dependence and withdrawal are
offered.
PMID- 10773440
TI - Cell-cycle inhibitors: three families united by a common cause.
AB - In the cellular program leading to DNA synthesis, signals that drive cells into S
phase converge at the level of CDK activity. The products of at least three
different gene families, Ink4, Cip/Kip and the pRb pocket-protein family,
suppress S-phase entry. Ink4 proteins act by antagonizing the formation and
activation of cyclin D-CDK4 complexes, of which the ultimate downstream target as
related to S-phase entry appears to be pRb. Cip/Kip inhibitors impinge upon that
pathway by inhibiting CDK2 kinases that participate in the inactivation of pRb
and, like cyclin E, may also have roles independent of pRb. How the activities of
these three classes of proteins are coordinated remains obscure. In recent years,
development of mouse models has accelerated the elucidation of this complex
network, showing roles that are sometimes cooperative and sometimes overlapping.
We will discuss the interrelationships between Cip/Kip inhibitors and the
components of the pRb pathway, and how their activities ultimately regulate cell
proliferation.
PMID- 10773441
TI - Roles for Msx and Dlx homeoproteins in vertebrate development.
AB - This review provides a comparative analysis of the expression patterns,
functions, and biochemical properties of Msx and Dlx homeobox genes. These
comprise multi-gene families that are closely related with respect to sequence
features as well as expression patterns during vertebrate development. Thus,
members of the Msx and Dlx families are expressed in overlapping, but distinct,
patterns and display complementary or antagonistic functions, depending upon the
context. A common theme shared among Msx and Dlx genes is that they are required
during early, middle, and late phases of development where their differential
expression mediates patterning, morphogenesis, and histogenesis of tissues in
which they are expressed. With respect to their biochemical properties, Msx
proteins function as transcriptional repressors, while Dlx proteins are
transcriptional activators. Moreover, their ability to oppose each other's
transcriptional actions implies a mechanism underlying their complementary or
antagonistic functions during development.
PMID- 10773442
TI - In vivo footprinting studies suggest a role for chromatin in transcription of the
human 7SK gene.
AB - Mutation and deletion analyses of mammalian class III small nuclear RNA genes
transcribed by RNA polymerase (pol) III have defined three functional promoter
elements: a distal sequence element (DSE) at around -220, a proximal sequence
element (PSE) at around -60 and a TATA box at around -30. Although binding
studies have identified factors that bind to these sites in vitro, it is not
known exactly how proteins interact with the promoters of these genes in vivo. In
this study, we have used dimethyl sulphate and DNase I treatment of HeLa cells
and nuclei, respectively, followed by linker-mediated polymerase chain reaction,
to obtain in vivo footprints of proteins binding to the promoter of the Pol III
transcribed 7SK gene. Our results show that most of the characterised promoter
elements of this gene are protected in vivo in these cells, and the pattern of
DNase I protection suggests that a nucleosome lies between the DSE and the PSE.
Methylation protection was also seen upstream of the DSE over a sequence
corresponding to the binding site of a POZ domain-containing protein, ZID, which
interacts with components of histone deacetylase complexes. These findings
suggest that chromatin structure plays a role in the cascade of protein-DNA
interactions that regulate expression of this pol III-transcribed gene.
PMID- 10773443
TI - Mass-murder deletion of 19 ORFs from Saccharomyces cerevisiae chromosome XI.
AB - Nineteen open reading frames (ORFs) in the left arm of chromosome XI of the yeast
Saccharomyces cerevisiae were inactivated. This was done by producing single-gene
or contiguous-gene deletions in haploid and diploid strains. Four deletions are
lethal to the corresponding haploid strains, and two result in a failure to grow
on a rich glycerol medium. Complementation experiments showed that five of the
six identified phenotypes were due to deletion of a single gene (ORFs YKL173w,
YKL172w, YKL165c, YKL154w are essential, and YKL160w is required for growth on
glycerol medium). One of the phenotypes observed on glycerol medium was not
suppressed by the corresponding deleted genes. None of the other deletions,
covering 13 ORFs in all, gave rise to any obvious phenotype when the cells were
grown at three different temperatures on rich glycerol or glucose medium or on
minimal synthetic medium.
PMID- 10773444
TI - Zero background yeast reporter plasmids.
AB - UAS-less reporter plasmids are widespread and powerful tools for the
identification and analysis of binding sites for transcriptional activators. The
common reporter plasmids for the yeast Saccharomyces cerevisiae are multicopy
(2mu) vectors with the CYC1 core promoter upstream of the lacZ gene. Insertion of
putative or known activator binding sites upstream of the core promoter puts lacZ
(beta-galactosidase) expression under the control of the corresponding activator.
Although these constructs have proved to work well for most purposes, they have
certain limitations: (1) they give significant and carbon-source-dependent lacZ
background expression; (2) unlike most other yeast promoters, the CYC1 upstream
region has a partially open chromatin structure with an accessible TATA box; (3)
they use only a single, moderately sensitive reporter; and (4) the use of
multicopy vectors can result in activator titration. Here, we introduce novel
reporter plasmids based on the yeast MEL1 (alpha-galactosidase) gene that can
overcome all of these limitations. It is also shown that background expression is
due to fortuitous activator binding sites within the plasmid backbones that are
insufficiently shielded from the core promoters in the common CYC1 reporter
plasmids.
PMID- 10773445
TI - Human COX6A1 gene: promoter analysis, cDNA isolation and expression in the monkey
brain.
AB - The human COX6A1 gene encodes the ubiquitous isoform of cytochrome c oxidase
(COX) subunit VIa (VIa-L), and is located in a CpG island on chromosome 12q24.2.
We compared the COX6A1 gene with the published cDNA and several ESTs and
concluded that subunit COX VIa-L is synthesized as a preprotein, as are other COX
subunits. The same transcription start sites were identified by primer extension
analysis of human brain and lymphoblastoid RNA. Analysis of the COX6A1 promoter
revealed several conserved sequence elements found in other COX genes, namely
binding sites for nuclear respiratory factor 1 (NRF-1), nuclear respiratory
factor 2/GA binding protein (NRF-2/GABP), and ying-yang protein 1 (YY1). These
conserved elements were shown to bind nuclear proteins from HeLa nuclear
extracts. COX6A1 cDNA was isolated from a human brain cDNA library, and the
sequence was identical to that of human liver. The expression of this gene was
demonstrated by in-situ hybridization in monkey brain sections with our human
brain cDNA. Monocular impulse blockade in adult monkeys induced a downregulation
of COX6A1 expression in deprived visual neurons, suggesting that this subunit
gene is regulated by neuronal activity.
PMID- 10773446
TI - U4 small nuclear RNA genes of trypanosomes: cloning of the Leptomonas seymouri
gene and mutational analysis of core snRNP assembly.
AB - Trans mRNA splicing in trypanosomatids requires as cofactors small nuclear RNAs
(snRNAs) U2, U4, U5, and U6, in addition to the spliced leader (SL) RNA. To allow
a phylogenetic comparison and functional analysis of trypanosomatid U4 snRNAs, we
have cloned the single-copy gene for the Leptomonas seymouri U4 snRNA. In
addition, a putative U4 snRNA gene from Leishmania tarentolae was identified by
database searching. Using an episomal expression system, we introduced mutations
into the conserved Sm region of the L. seymouri U4, which is the putative binding
site for the common proteins that are present in each of the trans-spliceosomal
snRNPs. As demonstrated by CsCl density gradient centrifugation, Sm mutant U4
snRNAs are non-functional in core RNP assembly. Furthermore, we present evidence
by cell fractionation that U4 snRNAs with Sm mutations are partially defective in
nuclear-cytoplasmic translocation. Taken together this indicates that the Sm site
of U4 snRNA is responsible for stable core RNP assembly and nuclear localization.
PMID- 10773447
TI - The complete Tirant transposable element in Drosophila melanogaster shows a
structural relationship with retrovirus-like retrotransposons.
AB - We have determined the structure and organization of Tirant, a retrotransposon of
Drosophila melanogaster reported in literature to be responsible for four
independent mutations. Tirant is a long terminal repeat (LTR) retrotransposon
8527bp long. It possesses three open reading frames (ORF) encoding Gag, Pol and
Env proteins with a strong similarity with ZAM, a recently identified member of
the gypsy class of retrovirus-like mobile elements. Molecular analysis of the
Tirant genomic copies present in four D. melanogaster strains revealed that most
of them are defective, non-autonomous elements that differ in the position and
extension of the conserved internal portion. Defective elements lacking the Gag
ORF but retaining the Env ORF are abundant in heterochromatin. Four discrete
Tirant transcripts are observed during embryogenesis in the strain Oregon-R, the
smaller of which, 1.8kb in size, originates from the splicing of a primary
transcript and leads to a subgenomic RNA coding for the Env product.
PMID- 10773448
TI - An approach for obtaining perfect hybridization probes for unknown polyketide
synthase genes: a search for the epothilone gene cluster.
AB - An approach is described for obtaining 'perfect probes' for type I modular
polyketide synthase (PKS) gene clusters that in turn enables the identification
of all such gene clusters in a genome. The approach involves sequencing small
fragments of a random genomic DNA library containing one or more modular PKS gene
clusters, and identifying which fragments emanate from PKS genes. Knowing the
approximate sizes of the genome and the target gene cluster, one can predict the
the frequency that a PKS gene fragment will be present in the library sequenced.
Computer simulations of the approach were applied to the known PKS and non
ribosomal peptide synthetase (NRPS) gene clusters in the Bacillus subtilus
genome. The approach was then used to identify PKS gene fragments in a strain of
Sorangium cellulosum that produces epothilone. In addition to identifying
fragments of the epothilone gene cluster, we obtained 11 unique fragments from
other PKS gene clusters; the results suggest that there may be six to eight PKS
gene clusters in this organism. In addition, we identified four unique fragments
of NRPS genes, demonstrating that the approach is also applicable for
identification of these modular gene clusters.
PMID- 10773449
TI - The p65 domain from NF-kappaB is an efficient human activator in the tetracycline
regulatable gene expression system.
AB - The tc-responsive TetR protein allows the investigation of various
transcriptional activators in respective fusion proteins. We have fused eight
well-known human activator domains to the C-terminus of TetR and determined the
properties of the resulting transactivators using a tetracycline-responsive
promoter in three human cell lines (HeLa, BJAB, and Jurkat). Several-hundred-fold
activation was exclusively obtained with the acidic p65 domain from NF-kappaB and
with VP16, which served as a positive control. In contrast, at least 10-fold
lower factors of activation were achieved with ITF-1, ITF-2, and MTF-1. The
induction properties of the p65 domain are identical to those of VP16 in all
three human cell lines and when fused to the reverse TetR. The combination of the
novel reverse p65 fusion with the TetR(B/E)-KRAB construct resulted in active
silencing and full activation. This is the first report of an expression system
with minimal basal activity and high induction levels without viral protein
domains.
PMID- 10773450
TI - Cryptic splice site activation during RNA processing of MLL/AF4 chimeric
transcripts in infants with t(4;11) positive ALL.
AB - Co-expression of multiple variants of the MLL/AF4 fusion transcript is a common
phenomenon in patients with acute lymphoblastic leukemia (ALL) with
t(4;11)(q21;q23). Different transcriptional and post-transcriptional mechanisms
were found to contribute to the heterogeneity of the chimeric transcripts.
Multiple splice variants are generated by utilizing alternative splice sites that
result in the joining of different MLL-exons within the breakpoint cluster region
to one of three exons in the AF4 fusion partner. To address the question of how
splice site selection occurs during RNA processing, we investigated der(11)
transcripts in 10 infants with t(4;11) positive ALL. Specific RT-PCR products
were analyzed by Southern blot hybridization, SSCP, endonuclease digestion,
cloning and sequencing. In patients co-expressing as many as six different
chimeric mRNA species, activation of cryptic splice sites has been detected in
MLL-exons 8 and 10. This led to the formation of four novel transcript variants,
three of which maintained open reading frames (ORFs). Patients with cryptic donor
site activation in MLL-exon 8 did not have any MLL-exon 8/AF4 transcripts using
the authentic 5' splice site, although this site is 100% homologous to the
consensus sequence. However, since MLL-exon 8 does not end in-phase, the use of
the authentic splice site would result in loss of the ORF of the fusion message.
The activated cryptic splicing sites are located in the vicinity of the
polypurine stretches present in MLL-exons 8 and 10, which are known to function
as splicing enhancers recognized by SR proteins. We postulate that both the
nonsense-mediated decay eliminating correctly spliced MLL-exon 8/AF4 mRNAs and
activation of suboptimal splicing sites contribute to the diversity of MLL/AF4
RNA species.
PMID- 10773451
TI - Identification and analysis of two snail genes in the pufferfish (Fugu rubripes)
and mapping of human SNA to 20q.
AB - All members of the snail gene family are zinc-finger transcription factors
expressed early in embryonic development and are involved in the formation of
tissues such as mesoderm and presumptive neural crest. Here, we report the
identification and structural organisation of two snail genes in the compact
genome of the pufferfish Fugu rubripes, and examine the phylogenetic
relationships between these and other members of the snail gene family. Both
genes have a three exon, two intron structure similar to that previously reported
for human SLUG. While human SLUG has been mapped to 8q (Cohen, M.E., Yin, M.,
Paznekas, W.A., Schertzer, M., Wood, S., Jabs, E.W., 1998. Human SLUG
organisation, expression and chromosome map location on 8q. Genomics 51, 468
471), the human sna gene SNA, was previously unmapped. We have used sequence
similarity to the Fugu genes to identify a human SNA EST and mapped this by
radiation hybrid and physical mapping to the distal end of human 20q. This is
likely to be the mapping location of the human sna gene (SNA).
PMID- 10773452
TI - Inactivation of the SNF5 transcription factor gene abolishes the lethal phenotype
induced by the expression of HIV-1 integrase in yeast.
AB - The ubiquitous human transcription factor Ini1 has been shown to interact with
HIV-1 integrase (IN) and to stimulate in vitro the reactions catalyzed by this
enzyme. We have previously used a yeast model to study the effect of HIV-1 IN
expression (Caumont, A.B., Jamieson, G.A., Pichuantes, S., Nguyen, A.T., Litvak,
S., Dupont, C. -H., 1996. Expression of functional HIV-1 integrase in the yeast
Saccharomyces cerevisiae leads to the emergence of a lethal phenotype: potential
use for inhibitor screening. Curr. Genet. 29, 503-510). Here, we describe the
effect of the inactivation of the gene encoding for SNF5, a yeast transcription
factor homologous to Ini1, on the lethality induced by the expression of HIV-1 IN
in yeast. We observed that the retroviral IN was unable to perform its lethal
activity in cells where the SNF5 gene has been disrupted, suggesting that SNF5
may play a role in the lethal effect induced by IN in yeast. SNF5 inactivation
affects neither yeast viability nor expression of HIV-1 IN. Given the homology
between SNF5 and its human counterpart Ini1, our results suggest that this factor
may be important for IN activity in infected cells. Moreover, given the important
role proposed for this transcription factor in the integration step and the fact
that it is dispensable for cell viability, the interaction between Ini1/ySNF5 and
HIV-1 IN should become a potential target in the search for new antiretroviral
agents.
PMID- 10773453
TI - Cloning, sequencing, and characterization of the bifunctional xylosidase
arabinosidase from the anaerobic thermophile thermoanaerobacter ethanolicus.
AB - The gene for the bifunctional xylosidase-arabinosidase (xarB) from the
thermophilic anaerobe Thermoanaerobacter ethanolicus JW200 was cloned, sequenced,
and expressed in Escherichia coli (Genebank Accession No. AF135015). Analysis of
the recombinant enzyme revealed activity against multiple substrates with the
highest affinity towards p-nitrophenyl beta-D-xylopyranoside (pNPX) and highest
activity against p-nitrophenyl alpha-L-arabinopyranoside (pNPAP), respectively.
Thus, we classify this enzyme as a bifunctional xylosidase-arabinosidase. Even
though both sequences are 96% identical on the amino acid level, excluding the
amino-terminal end, a frame-shift mutation in the 5' region of the gene in T.
brockii ATCC 33075 and a deletion in a downstream open reading frame in T.
ethanolicus seem to have occurred through evolutionary divergence of these two
species. This represents an interesting phenomenon of molecular evolution of
bacterial species, as PCR analysis of the region around the deletion indicates
that the deletion is not present in T. brockii ssp. finnii and T. brockii ssp.
brockii type strain HTD4.
PMID- 10773454
TI - Structure, mapping and expression of the human gene encoding the homeodomain
protein, SIX2.
AB - Vertebrate genes with sequence similarity to the Drosophila homeobox gene, sine
oculis (so), constitute the SIX family. There is notable expression of members of
this family in anterior neural structures, and several SIX genes have been shown
to play roles in vertebrate and insect development, or have been implicated in
maintenance of the differentiated state of tissues. Mutations in three of these
genes in man (SIX5, SIX6 and SIX3) are associated with severe phenotypes, and
therefore, the cloning of other human genes from this family is of interest. We
have cloned and characterised the gene that encodes human SIX2, elucidated its
gene structure and conducted expression studies in a range of tissues. SIX2 is
widely expressed in the late first-trimester fetus, but has a limited range of
expression sites in the adult. The expression pattern of SIX2 and its
localisation to chromosome 2p15-p16 will be of use in assessing its candidacy in
human developmental disorders.
PMID- 10773455
TI - Transcriptional regulation of the murine erythroid-specific 5-aminolevulinate
synthase gene.
AB - 5-Aminolevulinate synthase (ALAS) catalyzes the first step of the heme
biosynthetic pathway in mammalian cells. Separate genes encode the two isoforms:
ubiquitously expressed ALAS (ALAS1) and erythroid-specific ALAS (ALAS2).
Transcription of the ALAS2 gene is only activated during erythroid cell
differentiation. This stimulation allows for the formation of hemoglobin-specific
heme. The 5'-flanking region of the mouse ALAS2 gene was studied in order to
define its erythroid-specific function in transcriptional activation. Putative
binding sites for the erythroid-specific nuclear factors GATA-1, NF-E2, and EKLF
were identified within the first 300bp region of the mouse ALAS2 5'-flanking
region. However, this 300bp region alone did not efficiently activate transient
expression in erythroid MEL and K562 cell lines. Additional DNA regulatory
sequences found within 300-718bp upstream of the transcription start site were
required for maximal transcriptional activation, even though these regions
stimulated similar expression in the non-erythroid HeLa and NIH/3T3 cells. This
suggests that cis-acting elements present in the 5'-flanking region are not
responsible for maintenance of transcriptional silencing in non-erythroid cell
lines and that tissue-specific regulation of ALAS2 depends on other regions of
the gene or on chromatin remodeling. A putative hypoxia inducible factor 1 (HIF
1) response element was identified within the 300-718bp upstream region.
Significantly, two proximal GATA-1-binding sites (-118/-113 and -98/-93) and a
region located within -518 to -315bp of the mouse ALAS2 promoter were essential
for transcriptional activation during chemically induced differentiation of MEL
cells, implying their importance in conferring erythroid specificity to the ALAS2
transcriptional activation. This is the first study to delimit the cis-acting
region responsible for activation of the ALAS2 promoter upon dimethyl-sulfoxide
induction in MEL cells.
PMID- 10773457
TI - A satellite DNA containing CENP-B box-like motifs is present in the antarctic
scallop Adamussium colbecki.
AB - The DNA of the Antarctic scallop Adamussium colbecki was found to contain a
highly repeated sequence identifiable upon restriction with endonuclease BglII.
The monomeric unit - denominated pACS (about 170bp long) - was cloned. Southern
blot hybridization yielded a ladder-like banding pattern, indicating that the
repeated elements are tandemly arranged in the genome and therefore represent a
sequence of satellite DNA. Sequence analysis of five different clones revealed
the presence of various subfamilies, some of which showed a high degree of
divergence. In each clone, regions homologous to the mammalian CENP-B box were
observed. A region homologous to the CDEIII centromeric sequence of yeast was
also found in one of the clones. These observations suggest a relationship of the
pACS family to the centromeric area in A. colbecki.
PMID- 10773456
TI - Cloning and characterization of a new theta-class glutathione-S-transferase (GST)
gene, gst-3, from Drosophila melanogaster.
AB - We report here on the cloning and characterization of a new theta-class
glutathione-S-transferase (GST) gene, gst-3, from Drosophila melanogaster. Its
sequence is distinct from previously characterized Drosophila GST genes, and
Southern blotting shows no other closely related genes in the genome. In-situ
hybridization localizes the gene to chromosome 2 (55D), near gst-2 (53F), and
clearly separate from the gst-D cluster at 87B. The gene is intronless and
appears to possess conventional 5' TATA, Cap and 3' polyadenylation signals. A
single transcript, approximately 1kb in size, appears to be expressed at high
levels in all developmental stages examined. When this gene is overexpressed
using various upstream GAL4 driver systems, no striking phenotypes are observed;
however, we detect bristle morphology defects in some progeny. The gst-3 gene
does not appear to be essential, based upon our observation that mutant flies
homozygous for an EP element insertion 5' to the TATA box produce little or no
detectable gst-3 mRNA; these flies are viable and fertile at 25 and 29 degrees C.
Nevertheless, the gst-3 gene appears to be evolutionarily conserved in other
Drosophila species, suggesting that it may be functionally important.
PMID- 10773458
TI - Structure and chromosomal localization of the mouse SNAP-23 gene.
AB - SNAP-23 plays an important role in the regulation of vesicle trafficking in
mammalian cells. In this report, we have determined the exon/intron organization
of the mouse SNAP-23 gene. The SNAP-23 gene spans 31kb of the mouse genome and
consists of eight exons interrupted by seven introns. The exon organization of
the mouse SNAP-23 gene is identical to that of the related SNAP-25 gene in both
chicken and Drosophila, suggesting that SNAP-23 arose by duplication of the SNAP
25 gene. Primer extension analysis revealed a major transcription start site
approximately 112bp upstream of the translation start site. Like many
ubiquitously expressed housekeeping genes, the proximal promoter region for the
mouse SNAP-23 gene lacks consensus TATA and CAAT boxes. The SNAP-23 gene was
localized to mouse chromosome 2 at band 2E5 using both fluorescence in-situ
hybridization and radiation hybrid panel mapping studies. The identification of
the structure of the mouse SNAP-23 gene reveals that the overall exon
organization of SNAP-25 family members is conserved throughout evolution.
PMID- 10773459
TI - Determination of beta-glucosidase enzymatic function of the histoplasma
capsulatum H antigen using a native expression system.
AB - The Histoplasma capsulatum H antigen is a major secreted glycoprotein of this
pathogenic fungus that is a target of humoral and cell-mediated host responses.
Its predicted protein sequence displays homology to beta-glucosidases of other
organisms, but a recombinant antigen expressed in a prokaryotic system showed no
enzymatic activity. We expressed a recombinant form of the protein carrying a
carboxyl-terminus oligohistidine tag in the native fungal background to
facilitate proper glycosylation and folding of a product that could then be
purified from culture supernatants using nickel affinity chromatography. The
recombinant protein was expressed and secreted by a transformant carrying the
modified gene under the control of its native promoter. The purified protein from
the native expression system showed beta-glucosidase enzymatic activity in
substrate gels and quantitative microplate assays. This activity was blocked by
glucosidase-specific inhibitors. These results are the first direct demonstration
of the function of this protein, and show the utility of expression in a native
system to achieve post-translational modification necessary for structural and
functional integrity.
PMID- 10773460
TI - Characterization and expression of the pseudomonas putida bacterioferritin alpha
subunit gene.
AB - The root-colonizing pseudomonad Pseudomonas putida (Pp) appears to produce two
subunits, alpha and beta, of the iron-binding protein, bacterioferritin. A gene
encoding the alpha-bacterioferritin subunit was located adjacent to the major
catalase in Pp. The deduced protein sequence of the Pp bfralpha gene had a very
high identity with other alpha-subunits, possessing conserved amino acids
responsible for ferroxidase activity. The gene also lacked a deduced methionine
at residue 52, associated with heme binding in beta-subunits. An antibody
generated toward the Escherichia coli (E. coli) multifunctional single subunit
bacterioferritin recognized two proteins in the Pp extract, a 22 kDa protein
likely to be a beta-subunit and, to a lesser extent, a 23 kDa band. The 23 kDa
band was absent in a Pp mutant in which the bfralpha gene was disrupted. Loss of
alpha-bacterioferritin stimulated production of fluorescent siderophore. Growth
on media and on root surfaces was not impaired by deletion of the alpha
bacterioferritin. Transcription of bfralpha was independent of the catalase gene
and was dependent on iron. The transcript levels from bfralpha decreased in iron
deficiency experienced during stationary-phase or upon treatment during growth
with an iron chelator.
PMID- 10773461
TI - Expression of the transcripts of the sigma factors and putative sigma factor
regulators of Chlamydia trachomatis L2.
AB - The steady state levels of the transcripts of the beta' subunit of RNA polymerase
gene (rpoC), three sigma factor genes (rpoD, rpoN, and rpsD), and four putative
sigma factor regulatory genes (rsbW, rsbV1, rsbV2, and rsbU) of Chlamydia
trachomatis L2 were examined during the chlamydial developmental cycle by reverse
transcription-polymerase chain reaction (RT-PCR) analysis. rpoC and the major
sigma factor rpoD transcripts were detected at all times post-infection,
consistent with their expected function in the expression of housekeeping genes.
Transcripts of the alternative sigma factors and the putative regulatory genes
(with the exception of those of rsbV2, which were present at near constant levels
at all times) were present at low or undetectable levels at the time of
elementary body (EB) to reticulate body conversion early in the cycle, but were
easily detected during the logarithmic growth phase of RBs, indicating that these
genes are not expressed in a cascade fashion and that it is unlikely that their
major role is to recognize the promoters of stage-specific genes.
PMID- 10773462
TI - Criteria for gene identification and features of genome organization: analysis of
6.5 Mb of DNA sequence from human chromosome 21.
AB - To establish criteria for and the limitations of novel gene identification, to
identify novel genes of potential relevance to Down Syndrome and to investigate
features of genome organization, 6. 550kb. In total, 41 novel gene models were
predicted, and for a subset of these, RT-PCR experiments helped to verify and
refine the models, and were used to assess expression in early development and in
adult brain regions of potential relevance to Down syndrome. Results suggest
generally low and/or restricted patterns of expression, and also reveal examples
of complex alternative processing, especially in brain, that may have important
implications for regulation of protein function. Analysis of complete gene
structures of the known genes identified a number of very large introns, a number
of very short intergenic distances, and at least one potentially bi-directional
promoter. At least 3/4 of known genes and 1/2 of predicted genes are associated
with CpG islands. For novel genes, three cases of overlapping genes are
predicted. Results of these analyses illustrate some of the complexities inherent
in mammalian genome organization and some of the limitations of current sequence
analysis technologies. They also doubled the number of potential genes within the
region.
PMID- 10773463
TI - Molecular characterization and population study of an X chromosome homolog of the
Y-linked microsatellite DYS391.
AB - A novel microsatellite homologous to DYS391, a (GATA)(n) short tandem repeat on
the human Y chromosome, was identified and characterized in the present work.
Employing somatic cell hybrid and deletion panels in a PCR-based approach, we
found out that the new microsatellite is located in Xp21.2-22.3, while its Y
counterpart mapped to Yq11.21. This X-linked locus (provisionally called DXYS391)
and its Y homolog constitute one more example of similarity outside the
pseudoautosomal regions between the two human sex chromosomes. Sequencing data
showed high levels of homology in the flanking regions of DXYS391 and DYS391 that
differ primarily by the presence of a (GACA)(3) motif in the Y locus. Both loci
were detected in chimpanzee DNA, suggesting that a putative transposition from
the X to the Y occurred before the human/chimpanzee split. The allele frequencies
of DYS391 and DXYS391 were investigated, respectively, in 271 Y and 337 X
chromosomes from distinct human populations worldwide. DYS391 consistently
displayed greater among-population component of the variance of the allele
frequencies than DXYS391, as expected due to the three-times lower effective
population size of Y chromosomes relative to the X. The intra-population
diversity of DYS391, measured by Nei's locus diversity as well as by allele size
variance, was lowest in Amerindians, while very low diversity of DXYS391 was seen
in Africans. Since our African data are based on a small sample, further studies
will be necessary to evaluate better this observation.
PMID- 10773464
TI - Structure and chromosomal localization of the human and mouse muscle fructose-1,6
bisphosphatase genes.
AB - Mammalian skeletal muscle contains fructose-1,6-bisphosphatase (Fru-1,6-P(2)ase),
a key enzyme of glyconeogenesis. We have shown previously that muscle Fru-1,6
P(2)ase is encoded by a gene different from that coding for the liver isoenzyme.
Starting with genomic YAC libraries and based on the cDNA sequences of human and
mouse muscle Fru-1,6-P(2)ases together with the known gene structures of two
mammalian liver fructose-1,6-bisphosphatases, we have PCR-amplified and sequenced
all functional parts of the human and mouse muscle fructose-1,6-bisphosphatase
genes and determined their chromosomal localization. The human gene (FBP2),
localized at chromosome 1p36.1-2, spans about 30 kb, while the mouse gene (Fbp2)
at chromosome 13B3-C1 is more compact (about 21 kb). Intron lengths are only
poorly conserved between the two genes, while intron number and positions are
identical in all hitherto analyzed mammalian fructose-1,6-bisphosphatase
isoenzyme genes. Transcriptional start sites were found to be located 97 and 95bp
before the start codon in the human gene and 35 bp before the start codon in the
mouse homolog. A comparison of the 5'-flanking sequences of the two genes
revealed a 56% homology up to human bp -607 before the first transcriptional
start point, while upstream of this region we found no similarity. The data
presented in this paper provide a basis for further studies of the mechanism of
expression regulation and the elucidation of the physiological role of the
enzyme.
PMID- 10773465
TI - A family of removable cassettes designed to obtain antibiotic-resistance-free
genomic modifications of Escherichia coli and other bacteria.
AB - Modifications of microbial genomes often require the use of the antibiotic
resistance (Anb(R))-encoding genes and other easily selectable markers. We have
developed a set of such selectable markers (Cm(R), Km(R) and Gm(R)), which could
easily be inserted into the genome and subsequently removed by using the Cre/loxP
site-specific recombination system of bacteriophage P1. In this manner the same
marker could be used more than once in the same background, while the resulting
strain could or would remain Anb(R) marker-free. Three plasmids were constructed,
each containing a cassette consisting of the Cm(R), Km(R), or Gm(R) gene flanked
by two parallel loxP sites and two polylinkers (MCS). To test insertion and
excision, cassettes were inserted into the lacZ or galE genes carried on an
origamma/pir-dependent suicide plasmid, which contained a dominant Sm(R) gene.
The cassettes were crossed into the E. coli genome by homologous recombination
(allelic exchange), in a manner analogous to that described by Posfai et al.
[Nucl. Acids Res. 22 (1994) 2392-2398], selecting for the Cm(R), Km(R), or Gm(R),
for the LacZ(-) or GalE(-) and for the Sm(S) phenotypes (the latter to assure
allelic exchange rather than insertion of the entire plasmid). When required,
after selecting the strain with the desired modification, the Cm(R), Km(R), or
Gm(R) marker was excised by supplying the Cre function. Cre was provided by the
thermosensitive plasmid pJW168, which was transformed into the Anb(R) host at 30
degrees C, and was subsequently eliminated at 42 degrees C. Thus the Anb(R)
marker was removed, whereas the lacZ or galE gene remained interrupted by the
retained loxP site.
PMID- 10773466
TI - Differences in HERV-K LTR insertions in orthologous loci of humans and great
apes.
AB - The classification of the long terminal repeats (LTRs) of the human endogenous
retrovirus HERV-K (HML-2) family was refined according to diagnostic differences
between the LTR sequences. The mutation rate was estimated to be approximately
equal for LTRs belonging to different families and branches of human endogenous
retroviruses (HERVs). An average mutation rate value was calculated based on
differences between LTRs of the same HERV and was found to be 0.13% per million
years (Myr). Using this value, the ages of different LTR groups belonging to the
LTR HML-2 subfamily were found to vary from 3 to 50Myr. Orthologous potential LTR
containing loci from different primate species were PCR amplified using primers
corresponding to the genomic sequences flanking LTR integration sites. This
allowed us to calculate the phylogenetic times of LTR integrations in primate
lineages in the course of the evolution and to demonstrate that they are in good
agreement with the LTR ages calculated from the mutation rates. Human-specific
integrations for some very young LTRs were demonstrated. The possibility of LTRs
and HERVs involvement in the evolution of primates is discussed.
PMID- 10773467
TI - Cloning and characterization of the gene encoding mouse IkappaBbeta.
AB - IkappaBbeta is a member of the IkappaB family of structurally related proteins
that are important regulators of the inducible transcription factor NF-kappaB. In
the present study, the mouse IkappaBbeta gene was cloned and sequenced, and its
structure determined. The mouse IkappaBbeta gene contains six exons and five
introns that span 7435 nucleotides. A single major transcription initiation site
is located 59 nucleotides upstream of the initiating methionine. A translation
termination codon and a single polyadenylation signal are found within exon 6.
The exon/intron structure of IkappaBbeta and IkappaBalpha genes were compared and
found to be very similar, with individual ankyrin repeats being maintained on
corresponding exons. This suggests a close evolutionary relationship between
these two IkappaB isoforms. The significance of this evolutionary relationship is
discussed.
PMID- 10773468
TI - The distribution of genes in the Drosophila genome.
AB - In the present work we show that in the Drosophila genome (which covers a 37-51%
GC range at a DNA size of approx.50kb) a linear correlation holds between GC (or
GC(3)50kb) genomic sequences embedding them. This correlation allows us to
position the two compositional distributions of (a) coding sequences, and (b) of
long DNA segments relative to each other and to calculate gene concentration
across the compositional range of the Drosophila genome. Using this approach, we
show that gene concentration increases with increasing GC of the regions
embedding the genes, reaching a 7-fold higher level in the GC-richest regions
compared with the GC-poorest regions. The gene distribution of the Drosophila
genome is, therefore, similar to (although less striking than) that of the human
genome, whereas it is very different from those of the Arabidopsis genome, which
has about the same size as the Drosophila genome.
PMID- 10773482
TI - Guest editorial
PMID- 10773483
TI - Introduction. Selective toxicity, side effects and resistance.
PMID- 10773484
TI - Phenothiazines: an alternative to conventional therapy for the initial management
of suspected multidrug resistant tuberculosis. A call for studies.
AB - Increased frequency of multidrug resistant strains of Mycobacterium tuberculosis
results from inappropriate treatment and lack of patient compliance. The Center
for Disease Control/American Thoracic Society (CDC/ATS) guidelines issued for the
management of newly diagnosed cases of tuberculosis (TB) will not be totally
effective regardless of adherence to the guidelines and patient cooperation. The
long interim period between the diagnosis of TB and confirmation of antibiotic
susceptibility contributes to the infection rate. Consequently, the use of an
adjuvant that is known to inhibit all encountered multidrug resistant strains of
M. tuberculosis may be helpful until antibiotic susceptibility is known.
Phenothiazines such as chlorpromazine, methdilazine and thioridazine are
effective against strains of M. tuberculosis in vitro and in vivo. It is
recommended that studies be designed and conducted for the purpose of managing
new cases of TB that emanate from areas known to harbour multidrug resistant
strains of M. tuberculosis, with phenothiazines as adjuvants to the regimen
recommended by the CDC/ATS guidelines until antibiotic susceptibility is defined.
Because the normal maximum period for obtaining conventional antibiotic
susceptibility results is less than 7 or 8 weeks, the probability of serious side
effects from the use of a phenothiazine is remote.
PMID- 10773485
TI - Antimicrobial activity of psychotropic drugs: selective serotonin reuptake
inhibitors.
AB - Psychotropic drugs have been shown to have antimicrobial activity against several
groups of microorganisms. Some of these drugs, such as the new antidepressant
agents sertraline, fluoxetine and paroxetine are known to act as efflux pump
inhibitors in human cells. Their activity has been studied, alone and combined
with antibiotics, against bacterial species, mainly in multiply resistant
strains. These agents have surprising activity, mainly against Gram positive
microorganisms. They also show synergistic activity when combined with some
antibiotics against several bacteria, shown by a decrease in MICs, that converts
strains previously resistant to the category of sensitive, and modify
physiological aspects related with pathogenicity.
PMID- 10773486
TI - Immunomodulatory agents for prophylaxis and therapy of infections.
AB - The advent of the antibiotic era ushered in a shift towards non-pathogen-specific
therapy of infectious diseases. This led to an overt emphasis on targeting
microbial pathogens while strategies directed towards enhancing host immunity
were neglected. In an effort to decrease sole reliance on antimicrobials, the
time has come for a critical reappraisal of nonantibiotic, albeit immune response
enhancing substances. The diverse array of natural, synthetic, and recombinant
immunomodulators discussed in this review succinctly demonstrate the potential of
these agents to stimulate host defense mechanisms for prophylaxis and treatment
of various microbial infections.
PMID- 10773487
TI - Chemistry and biological activity of new 3-benzazepines.
AB - This review summarizes our experiments investigating structure-activity
relationships of 3-benzazepines. Three 7, 8-dihydroxy-3-benzazepines [7-9] were
cytotoxic to human promyelotic leukaemia HL-60 cells. Compound [9] showed the
highest cytotoxicity and the activity was twice as high as that of dopamine (DA,
[11]). Three active compounds [7-9] produced radicals, whereas other less potent
benzazepines [1-6, 10] did not produce radicals. Furthermore, cytotoxic 3
benzazepines [7-9] also enhanced the decay of ascorbic acid in rat brain
homogenate. Two 7,8-dimethoxy-3-benzazepines [5, 10] were able to form a complex
with the replicative form of plasmid DNA. The multidrug resistance (MDR) P
glycoprotein (Pgp) efflux pump of mouse lymphoma cells was inhibited by three
compounds [5, 8, 10]. Compound [8] has the highest activity in MDR reversal and
is two times more potent than verapamil. Three cytotoxic 3-benzazepines [7-9]
showed inhibitory effects against reverse transcriptase (RT) of Moloney leukemia.
PMID- 10773488
TI - Synthesis and biological activity of N-acylphenothiazines.
AB - Previous studies have demonstrated the relationship between radical intensity and
cytotoxic activity in water-soluble compounds. This relationship was investigated
in lipophilic compounds. Several N-acylphenothiazines showed higher cytotoxic
activity against human leukemic and squamous carcinoma cell lines than
phenothiazine, the parent compound. Electron spin resonance (ESR) spectroscopy
showed that these active compounds produced much lower amounts of radicals than
phenothiazine. Several compounds failed to inhibit the cytopathic effects of
human immunodeficiency virus (HIV) infection in MT-4 cells. It suggested that the
radical-mediated-mechanisms has not involved in the induction of cytotoxic
activity by lipophilic compounds, such as N-acylphenothiazines.
PMID- 10773489
TI - Inhibition of HIV replication by neuroleptic agents and their potential use in
HIV infected patients with AIDS related dementia.
AB - A series of neuroleptic agents and their structural isomers have been tested as
inhibitors of HIV-replication. At non-toxic concentrations, cis (Z)- and trans
(E)-flupentixol and several derivatives of the 5HT-uptake-inhibitors paroxetine
and femoxetine, inhibit HIV-1 replication. The findings indicated that these
compounds could be used in combination with other anti-retroviral therapy in HIV
1 infected patients with AIDS-related dementia.
PMID- 10773490
TI - Screening for anti-HIV drugs that can combine virucidal and virustatic activities
synergistically.
AB - Chlorcyclizine HCl and ciprofloxacin HCl were shown to have anti-HIV activity.
They possess virustatic and virucidal activities against HIV, a murine retrovirus
(RV) and several other RNA and DNA viruses. These drugs were screened from a
large number of compounds on the basis of in vitro mutagenicity and
antimetabolite detection tests. Subsequent studies were based on different exo
vivo cell cultures. These two compounds were then tested on an animal model,
following standard test protocols, using another retrovirus, maintained as
Ehrlich's ascites cell tumour virus (EACTV). The animal mortality and protection
tests corroborated the findings obtained in vitro, suggesting that these drugs
acted synergistically against HIV, exhibiting both virucidal and virustatic
properties.
PMID- 10773491
TI - Immunomodulating effect of 2,3,4,5-tetrahydro-1H-3-benzazepines (a new class of
non-nucleoside inhibitors of reverse transcriptase).
AB - The effects of newly synthesized, reverse transcriptase inhibitors, 3
benzazepines, for their effects on natural killer (NK) cell and blast
transformation in human peripheral blood mononuclear cells were investigated. The
most effective reverse transcriptase inhibitors were KF1, KF2 and KF3, which
primarily suppressed immunological functions. Besides the inhibition of T cell
proliferation, the benzazepines also show inhibitory effect on NK cell functions,
in particularly, against large granular lymphocytes and monocytes. The B
lymphocytes and Fc mediated killer functions were less inhibited.
PMID- 10773492
TI - The effects of chlorpromazine on the outer cell wall of Salmonella typhimurium in
ensuring resistance to the drug.
AB - Chlorpromazine (CPZ), a compound employed for the management of psychosis, has a
wide ranging antibacterial activity. The growth of Salmonella typhimurium100
mg/l), was initially inhibited during the first 8-16 h of exposure to
concentrations of CPZ below the MIC. During this period of transient
susceptibility, the distribution of ribosomes was markedly altered in a
concentration dependent manner; the rough cell wall was transformed into a smooth
form. The protein composition of the outer cell wall of 55 kDa was markedly
decreased, whilst there was an increased number of high molecular weight
proteins. After 16 h of exposure to sub-MIC levels of CPZ, the inhibitory effect
of the drug was no longer apparent whereas the effects noted on the cell wall
were retained. These Salmonella were, as the control, agglutinated by O antigen
specific antibody. Whereas agglutination of the control Salmonella was blocked by
the presence of CPZ at concentrations that induced the cell-wall effects,
agglutination of CPZ exposed-Salmonella for periods in excess of 16 h was not
blocked by any concentration of CPZ. These results suggested that eventual
resistance to CPZ was dependent upon changes induced by CPZ at the cell wall
level. The results also suggested that the CPZ binds to the 55 kDa protein and
that such binding interfered with the recognition of the O antigen by antibody.
PMID- 10773493
TI - Potentiation of the action of metronidazole on Helicobacter pylori by omeprazole
and bismuth subcitrate.
AB - Treatment failures using triple therapy that include metronidazole, are common in
patients infected with metronidazole-resistant Helicobacter pylori in the gastric
mucosa. Higher eradication rates in such patients have been described when
treatment regimens include bismuth salts compared to regimens that include proton
pump inhibitors. In the present study, the synergistic effect of subinhibitory
concentrations (0.25-0.5 MIC) of either bismuth subcitrate or omeprazole with
metronidazole on the susceptibility of 42 H. pylori strains was investigated by
agar dilution method and the Epsilometer test (Etest). With 0.5 MIC of either of
the two drugs, the susceptibility of all H. pylori4 mg/l) reverted to being
metronidazole sensitive. These results suggested that either bismuth salts or
proton pump inhibitors may be effective in the treatment of some infections with
metronidazole-resistant H. pylori strains when used in sufficiently high doses.
PMID- 10773494
TI - Effect of some psychotropic drugs and a barbiturate on mycoplasmas.
AB - The inhibitory effect of selected membrane stabilisers on Mycoplasma pneumoniae,
M. hominis and Ureaplasma urealyticum was investigated in vitro. The
phenothiazine chlorpromazine (CPZ) and the barbiturate thiopental (Leopental(R))
as well as the stereo-isomeric thioxanthene derivatives; cis(Z)-clopenthixol (Zu
clopenthixol(R))/ trans (E)-clopenthixol and cis (Z)-chlorprothixen
(Truxal(R))/trans(E)-chlorprothixen, all have antimycoplasmal effect in the range
3.9-312 mg/l, measured as growth inhibition. It was also demonstrated that the
enzymatic functions of the different mycoplasma strains, such as breakdown of
glucose, arginine and urea, were abolished by concentrations of CPZ that were
sufficiently low to allow multiplication of the organisms. A similar effect was
obtained with Leopental(R) although the mycoplasmas were generally only half as
sensitive to this drug. Also M. gallisepticum and Acholeplasma laidlawii were
inhibited by CPZ and Thiopental. The four thioxanthenes were all inhibitory to
mycoplasmal growth and the effect was independent of their stereo-isomeric
configuration. The clopenthixol stereoisomers, but not the chlorprothixene
isomers, inhibited colour change at concentrations lower than those which
inhibited growth. While enzyme activity may continue for some time in vitro when
classic antibiotics have inhibited mycoplasmal growth, the reverse effect was
observed with phenothiazines and thioxanthenes. The membrane stabilisers may be
useful tools in the investigation of microbiological activity on the mycoplasma
membrane. From these drugs, new 'antibiotics' might be developed with another
action than that of the known antimycoplasmal drugs.
PMID- 10773496
TI - Guanine-cytosine rich regions of plasmid DNA can be the target in anti-plasmid
effect of phenothiazines.
AB - The antiplasmid effects of promethazine on E. coli is the consequence of special
complex formed with a covalently closed circular (ccc) form of plasmid DNA. The
exact target in this macromolecule, however, was not clarified until recently.
Caffeine and the chemically similar guanosine-5'- monophosphate (GMP) could
compete with the antiplasmid effect of promethazine, showing that promethazine or
other phenothiazines preferentially bind to xanthine type molecules. Among the
xanthines, GMP was more effective at complex-forming than adenosine-5'
monophosphate (AMP). In addition, the Z-DNA was more susceptible than B-DNA.
Therefore, one could suppose that guanine-cytosine (G-C) rich regions have higher
affinity than adenine-thymine (A-T) rich region on phenothiazines. Because the G
C rich regions have a special role in the DNA stability via three hydrogen bonds,
we suppose that these regions could have a key role in some biological effects
such as antiplasmid and anticancer activity.
PMID- 10773495
TI - Interaction between antibiotics and non-conventional antibiotics on bacteria.
AB - The individual activity of antibiotics such as ampicillin, tetracycline,
erythromycin and gentamicin in combination with compounds known to modify
bacterial resistance to given antibiotics was studied using the checkerboard
method. The combination of promethazine with either ampicillin, tetracycline or
erythromycin or the combination of methylene blue and erythromycin produced
significant synergistic activity against Escherichia coli. Verapamil, however, in
combination with ampicillin reduced the activity of ampicillin against E. coli.
Combinations of clomipramine with either tetracycline or erythromycin,
promethazine and erythromycin or verapamil and ampicillin were synergistic
against Staphylococcus epidermidis that was resistant to these antibiotics. The
only synergy against Pseudomonas aeruginosa was shown by the combination of
methylene blue and gentamicin.
PMID- 10773497
TI - The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis.
AB - Most strains of Gram-positive and Gram-negative bacteria were inhibited by 50-100
mg/l of the anti-inflammatory agent, diclofenac sodium (Dc). In vivo test using
30 or 50 microg Dc per 20 g mouse (Swiss Albino variety) significantly (P <0.001)
protected the animals when challenged with 50 MLD of a virulent Salmonella
typhimurium. The anti-bacterial action of Dc was found to be due to inhibition of
DNA synthesis which was demonstrated using 2 micro Ci (3H) deoxythymidine uptake.
PMID- 10773498
TI - Alternating current aspects of antimicrobial molecular complexes.
AB - A novel method was designed involving the titration of alternating current
titration in a cell where one electrode was shielded by a capillary enclosure
restricting access to it by charge carriers. With this cell, charge transfer
complex titration of several thiazines all with some antimicrobial properties was
effected in acetonitrile, against the electron accepting molecule iodine. The
maxima of the Job plots generated by these titrations exhibited displacement of
their positions for the forward and reverse titrations with respect to electron
donor-acceptor complexation conductivity and apparent stoichiometry. A plot of
inverse conductivity maxima differences against literature-cited dipole moments
squared yielded a straight line passing through the origin. The titration plot
profiles are discussed in terms of the type, number, and mobility of charge
carriers produced in the complexation interaction. This novel method may be used
to determine dipole moments of bioactive homologues empirically. There was
correlation between thiazine drug dipole moments and minimal inhibitory
concentrations of these drugs for some bacterial and yeast species. Several new
avenues of investigation of possible relevance to microbiology are suggested.
PMID- 10773499
TI - Charge transfer complexes of K vitamins with several classes of antimicrobials.
AB - The charge transfer donor (D)-acceptor (A) complexes formed between three classes
of vitamin K (all electron acceptors in this study) with several thiazine
psychotropes, used also as antimicrobials, antimalarials, antibiotics, and
anticoagulants, were studied by means of alternating current titrations. The
monochloride thiazines formed 2:1 (D:A) complexes, interacting from 26 to 47.5%;
the dihydrochloride formed a 3:1 (D:A) complex. The antimalarials quinine and its
isomer quinidine yielded 2:1 (D:A) complexes, interacting 51 and 60%,
respectively. Quinacrine did not complex with vitamin K. The antibiotics
sulfisoxasole and sulfamethisole gave 1:1 complexes, respectively interacting 6.2
and 11.7%. The anticoagulants warfarin, coumarin and dicumarol, rather than
forming complexes proceeded rapidly to chemical reaction. When the above thiazine
antimicrobials, antimalarials and antibiotics are present in patients receiving
vitamin K post-operatively the dosage of administered vitamin K should be
increased to counteract the donor-acceptor interaction effect.
PMID- 10773500
TI - Pooled analysis of three large clinical trials to determine the optimal dose of
dolasetron mesylate needed to prevent postoperative nausea and vomiting. The
Dolasetron Prophylaxis Study Group.
AB - STUDY OBJECTIVE: To identify the maximally effective dolasetron dose (i.e.,
maximum efficacy with minimum adverse events) for prevention of postoperative
nausea and vomiting (PONV) using the statistical power generated in a pooled
patient sample from three large, nearly identical clinical trials. DESIGN: Three
randomized, multicenter, placebo-controlled, double-blinded trials. SETTING:
Trials 1, 2, and 3 enrolled patients at 10, 25, and 17 hospitals and/or surgical
centers, respectively. PATIENTS: A total of 1,946 ASA physical status, I, II, and
III patients. Trials 1 and 2 enrolled only female patients (n = 916) undergoing
gynecologic surgery. Trial three enrolled 722 females (approximately 70%
gynecologic surgeries) and 308 males (approximately 46% orthopedic surgeries)
undergoing a variety of surgical procedures. INTERVENTIONS: All surgical
procedures used balanced general anesthesia. Patients received 12.5, 25, 50, or
100 mg of the antiemetic, dolasetron, near the end of anesthesia. MEASUREMENTS
AND MAIN RESULTS: Efficacy endpoints were identical and measured for 24 hours:
complete response (no vomiting or rescue medication) and maximum nausea, reported
using a 100-mm visual analog scale (VAS). Safety was assessed using adverse event
reports, laboratory and electrocardiographic data, and vital signs. All four
dolasetron doses produced significant increases in complete response and
decreases in maximum VAS nausea compared with placebo (p < 0.01). No increased
efficacy was observed with dolasetron doses higher than 12.5 mg. Safety was
similar between each dolasetron dose and placebo. CONCLUSION: Dolasetron 12.5 mg,
given near the end of anesthesia, is the maximally effective dose studied for
preventing postoperative nausea and vomiting.
PMID- 10773501
TI - Additional droperidol, not butorphanol, augments epidural fentanyl analgesia
following anorectal surgery.
AB - STUDY OBJECTIVE: To examine the effects of additional droperidol or butorphanol
to epidural fentanyl infusion on postsurgical analgesia. DESIGN: Prospective,
randomized, single blinded clinical study. SETTING: University-affiliated medical
center. PATIENTS: 60 ASA physical status I and II patients undergoing anorectal
surgery by one surgeon. INTERVENTIONS: Patients were randomly allocated to the
following groups according to the medication that was continuously administered
into the epidural space: 1) Group C (n = 20) received 0.4 mg fentanyl in 40 ml of
0.125% bupivacaine; 2) Group D (n = 20) received 2.5 mg droperidol and 0.4 mg
fentanyl in 40 ml of 0.125% bupivacaine; and 3) Group B (n = 20) received 2 mg
butorphanol and 0.4 mg fentanyl in 40 ml of 0.125% bupivacaine over 24 hours
postoperatively. MEASUREMENTS AND MAIN RESULT: Postsurgical analgesia and the
incidence of fentanyl-related complications, such as nausea/vomiting, somnolence,
pruritus, and respiratory depression, were assessed for 24 hours postoperatively.
At 16 and 24 hours after surgery, 75% of patients in Group D reported no pain
versus 35% in Group C (p < 0.05). In addition, the overall visual analogue scale
examined at 24 hours was significantly lower in Group D than that in Group C (22
+/- 17 mm vs. 44 +/- 22 mm, respectively; p < 0.05). Simultaneously, the
incidence of postoperative nausea/vomiting was lower in Group D compared with
Group C (20% vs. 60%; p < 0.05). On the other hand, butorphanol did not modify
the analgesic effects or complications of epidural fentanyl infusion. CONCLUSION:
In this study population, additional droperidol, not butorphanol, improved
postsurgical analgesia accompanied by less incidence of nausea/vomiting during
epidural fentanyl administration.
PMID- 10773502
TI - Effects of epidural anesthesia on the cardiovascular response to a rapid increase
in isoflurane concentration.
AB - STUDY OBJECTIVE: To compare circulatory variables to an abrupt increase in
isoflurance concentration via mask in patients who received either upper thoracic
or lumbar epidural anesthesia, or neither. DESIGN: Prospective study. SETTING:
Operating room at a university hospital. PATIENTS: 45 ASA physical status I
female patients scheduled for elective surgeries with general anesthesia.
INTERVENTIONS: Patients received thoracic (TEA group) or lumbar (LEA group)
epidural anesthesia, or neither (control group) (n = 15 per group). An epidural
catheter was inserted through the T1-T2 intervertebral space in the TEA group or
L2-L3 in the LEA group, and 10 mL of 2% lidocaine without epinephrine was
injected. Two minutes after induction of anesthesia with thiamylal, the inspired
isoflurane concentration was rapidly increased from 0.5% to 5% and maintained for
5 minutes. MEASUREMENTS AND MAIN RESULTS: Heart rate and mean arterial pressure
(MAP) were measured every minute. Mean analgesic levels obtained by epidural
block were C4-T6 and T10-S1 in the TEA and LEA groups, respectively. Heart rate
increased after the increase in isoflurane concentration in all groups, but
increased significantly less in the TEA group than in the control or LEA groups
(p < 0.05). Isoflurane also increased MAP in the control group throughout the 5
minute period, but only at the first minute of inhalation in the TEA and LEA
groups. The increases in MAP in the TEA and LEA groups were significantly less
than that in the control group (p < 0.05). CONCLUSION: Epidural anesthesia can
blunt circulatory responses to a sudden increase in isoflurane concentration.
PMID- 10773503
TI - Effects of oral clonidine premedication on side effects of intravenous ketamine
anesthesia: a randomized, double-blind, placebo-controlled study.
AB - STUDY OBJECTIVE: To determine the effects of oral clonidine premedication on
hemodynamic changes during the entire course of ketamine anesthesia and incidence
of postoperative adverse reactions. DESIGN: Randomized, prospective, double
blind, placebo-controlled study. SETTING: Department of Anesthesiology,
University of Tsukuba Hospital, Ibaraki, Japan. PATIENTS: 39 ASA physical status
I and II patients undergoing superficial surgeries. INTERVENTIONS: Placebo,
clonidine 2.5 micrograms/kg, and clonidine 5 micrograms/kg groups received
respective doses of oral clonidine 90 minutes prior to surgery. Anesthesia was
induced with ketamine 2 mg/kg intravenously (i.v.), trachea was intubated, and
anesthesia was maintained with 67% nitrous oxide, oxygen, and supplemental
ketamine (1 mg/kg) when systolic blood pressure and heart rate (HR) exceeded 180
mmHg and 100 bpm, respectively. MEASUREMENTS AND MAIN RESULTS: In the clonidine
2.5 micrograms/kg group, HR response to tracheal intubation was significantly
less, while in the clonidine 5 micrograms/kg group both mean arterial pressure
and HR responses were significantly suppressed, compared with the placebo group.
Intraoperative coefficients of variations of HR were significantly less in both
clonidine groups than the placebo group. Incidence of nightmare and degree of
salivation were significantly less in the clonidine 5 micrograms/kg group than in
the placebo group. CONCLUSION: Oral clonidine 2.5 micrograms/kg and clonidine 5
micrograms/kg attenuates cardiostimulatory effects, while clonidine 5
micrograms/kg was associated with reduced incidence and severity of nightmare and
salivation attributable to i.v. ketamine.
PMID- 10773505
TI - Comparison of acute normovolemic hemodilution and preoperative autologous blood
donation in clinical practice.
AB - STUDY OBJECTIVE: To compare, by model simulation, acute normovolemic hemodilution
(ANH) and preoperative autologous blood donation (PABD) to predict their efficacy
in current clinical practice. To discuss their similarities and offer guidelines
based on expected operative blood loss. DESIGN: Model simulation using data
obtained from total hip arthroplasty procedures. SETTING: University medical
center. PATIENTS: 91 patients who participated in PABD undergoing single,
primary, total hip replacement surgeries from January to December 1997.
INTERVENTIONS: A nonanemic (Hb baseline 14 g/dL), average-sized patient
(estimated blood volume 5,000 mL) who donated two units by either PABD or ANH was
assumed for model simulation. The Hb-final, as a function of 250-mL blood loss
increments after retransfusion of two autologous units, was calculated for each
technique and compared to a control (nondonor) to predict the effectiveness of
PABD and ANH in conserving red cell mass. Data from hip arthroplasties over a 12
month period were used to determine the parameters for the model. Results were
subjected to regression analysis and tested for parallelism of slopes, with p <
0.05 accepted to indicate a statistical difference. MAIN RESULTS: The difference
in Hb-final between PABD and ANH was not statistically different over a wide
range of blood loss. When compared to control, there was no difference in Hb
final measurements in the estimated blood loss (EBL) range of less than 1,000 mL.
ANH and PABD provide some benefit when EBL is greater than 1,500 mL in nonanemic,
average-sized patients. As blood loss increases, the benefit of autologous
collection becomes more clinically evident. CONCLUSION: PABD exemplifies a
"chronic" form of ANH in current clinical practice and offers little advantage
over ANH as a blood conservation technique for high-blood-loss operations. When
surgical blood loss is predictably mild to moderate (range 250 to 1,000 mL),
neither blood conservation technique is necessary.
PMID- 10773504
TI - Transfer of methohexital across the perfused human placenta.
AB - STUDY OBJECTIVES: To evaluate the transfer properties of methohexital and the
influence of protein binding using the in vitro human placental perfusion model.
DESIGN: Fresh term human placentae from healthy parturients were perfused
bidirectionally via a cannulated fetal chorionic artery and vein and needles
placed into the maternal intervillous space. Maternal-to-fetal (M-->F) and fetal
to-maternal (F-->M) transfer and ultimate distribution of methohexital was
investigated using a closed (recirculating) placental perfusion model. SETTING:
Obstetric anesthesia laboratories of two university medical centers. PATIENTS: No
patient participation occurred as placentae were obtained after delivery.
INTERVENTION: M-->F and F-->M transfer of methohexital was compared in vitro in
perfusates with equal protein concentrations (2 g/100 mL in both perfusates) or
albumin-simulated physiologic protein binding concentrations (maternal 8 g/100
mL; fetal 4 g/100 mL). MEASUREMENTS AND MAIN RESULTS: Data obtained consisted of
measurements of methohexital and antipyrine concentrations by high-performance
liquid chromatography. Glucose and lactate concentrations and perfusate loss were
measured to assess placental viability. Methohexital protein binding was assessed
at 2, 4, and 8 g/100 mL of albumin by equilibrium dialysis. The transfer index of
0.83 +/- 0.11 for the M-->F perfusions was significantly greater (p < or = 0.05)
than in the F-->M direction (0.61 +/- 0.04) when albumin concentration was equal
in both perfusates. This transfer asymmetry disappeared when albumin
concentrations simulating maternal (8 g/100 mL) versus fetal (4 g/100 mL) protein
concentrations in the perfusate were used (M-->F 0.87 +/- 0.12 and F-->M 0.95 +/-
0.11). CONCLUSION: Methohexital readily crosses the placenta in both directions.
Protein binding has significant effects on the degree of transfer of methohexital
at any time when compared with antipyrine and its ultimate fetal/maternal
distribution.
PMID- 10773506
TI - Pharmacokinetics of ropivacaine during extradural anesthesia for total hip
replacement.
AB - STUDY OBJECTIVE: To determine plasma concentrations of ropivacaine during
epidural anesthesia with ropivacaine 10 mg/mL in patients undergoing elective
total hip replacement. DESIGN: Phase III prospective study. SETTING: Orthopedic
surgical unit of the University Hospital in Kiel, Germany PATIENTS: 11 ASA
physical status I, II, and III patients undergoing elective total hip replacement
after premedication with a benzodiazepine. INTERVENTIONS: Peripheral venous
plasma samples were collected prior to and 10, 15, 20, 30, 45, 60, 90, and 120
minutes following the epidural dose. MEASUREMENTS AND MAIN RESULTS: After solid
phase extraction, plasma concentrations of ropivacaine were measured by high
performance liquid chromatography (HPLC). Free unbound concentrations were
determined after ultracentrifugation. In 9 of 11 patients excellent epidural
anesthesia was achieved with an initial dose of 144 +/- 13 mg (120 to 150 mg) of
ropivacaine corresponding to a dose of 1.9 +/- 0.4 mg/kg body weight. We
suspected inadvertent intravascular catheter malposition in one case. Peak plasma
concentrations occurred after 20 minutes (10 to 30 min) with a mean of 1.38 +/-
0.42 micrograms/mL (range 0.95 to 2.26 micrograms/mL). Maximum unbound free
plasma concentrations of ropivacaine were 0.05 +/- 0.03 microgram/mL (range 0.02
to 0.13 microgram/mL). CONCLUSION: Ropivacaine 10 mg/mL proved to be suitable for
epidural anesthesia for total hip replacement. The plasma concentrations after
120 to 200 mg of its epidural application were not associated with signs of local
anesthetic toxicity in patients pretreated with benzodiazepines, even in one case
of suspected inadvertent intravascular application.
PMID- 10773507
TI - Improved flow and pressure capabilities of the Datex-Ohmeda SmartVent anesthesia
ventilator.
AB - STUDY OBJECTIVE: To compare the flow and pressure capabilities of the Datex
Ohmeda SmartVent (Ohmeda 7900, Datex-Ohmeda, Madison, WI) to previous Ohmeda
(7810 and 7000, Datex-Ohmeda, Madison, WI) anesthesia ventilators. To determine
airway pressure and minute ventilation thresholds for intraoperative use of a
critical care ventilator. DESIGN: Three anesthesia ventilators and one critical
care ventilator (Siemens Servo 900C, Siemens, Solna, Sweden) were studied in a
lung model. Retrospective medical record review. SETTING: Research Laboratory and
Critical Care Unit of a Level I Trauma Center. PATIENTS: 145 mechanically
ventilated patients treated for acute respiratory failure who underwent 200
surgical procedures. INTERVENTIONS: The effect of increasing pressure on mean
inspiratory flow was determined by cycling each ventilator through increasing
restrictors. Maximum minute ventilation was measured at low compliance (10-30
mL/cm H2O), positive end-expiratory pressure (PEEP) (0-20 cm H2O), and increased
airway resistance (approximately 19 and approximately 36 cm H2O/L/sec) in a
mechanical lung model. MEASUREMENTS AND MAIN RESULTS: Flow, volume, and pressure
were measured with a pulmonary mechanics monitor (BICORE CP-100, Thermo
Respiratory Group, Yorba Linda, CA). Preoperative peak airway pressure and minute
ventilation (VE) were extracted from the medical record. Mean inspiratory flow
declined with increasing pressure in all anesthesia ventilators. The SmartVent
and the 7810 produced greater mean inspiratory flow than did the 7000 ventilator.
As compliance progressively decreased, the Siemens, the SmartVent, and the 7810
ventilators maintained VE compared to the 7000 ventilator. The Siemens and the
SmartVent maintained VE with PEEP, compared to the 7810 and 7000 ventilators.
During increased airway resistance, maximal VE was lower for all ventilators. The
SmartVent met the ventilation requirements in 90% of the patients compared to 67%
of patients with the 7000 ventilator. CONCLUSION: The improved pressure and flow
capabilities of the SmartVent increase the threshold for using a critical care
ventilator intraoperatively to a peak airway pressure > 65 cm H2O and/or VE > 18
L/min.
PMID- 10773508
TI - The effect of a new NPO policy on operating room utilization.
AB - STUDY OBJECTIVES: To prospectively assess the impact of a liberalized
preoperative fasting policy on operating room (OR) utilization. STUDY DESIGN:
Prospective cohort study involving data collection before and after a change in
nil per os (NPO) policy. SETTING: Academic teaching hospital. PATIENTS: 5,420
consecutive outpatients and AM admissions. INTERVENTIONS: Data collection was
done on all adult patients who presented to our OR suite over two 15-week
periods. During the first 15-week period, patients were instructed to drink no
liquids after midnight (control group, n = 2,646). In the second 15-week period,
patients were allowed to consume unlimited clear fluids until 2 to 3 hours prior
to surgery (study group, n = 2,774). MEASUREMENTS AND MAIN RESULTS: We found no
difference between the control and study groups in the number of cases cancelled
(0 in each group) or delayed (8 vs. 9; relative risk [RR] = 1.07, 95% confidence
interval [CI] = 1.000 to 1.148) due to noncompliance with fasting guidelines.
There was no difference between the groups in the number of cases of aspiration
(0 in each group). In the control group, significantly more episodes of
regurgitation were noted (12 vs. 9; RR = 0.715, 95% CI = 0.535 to 0.955) and more
rapid-sequence/awake intubations were performed (119 vs. 51; RR = 0.409, 95% CI =
0.306 to 0.546) than in the study group. CONCLUSIONS: Liberalizing a preoperative
fasting policy and allowing patients to consume unrestricted clear fluids up
until 3 hours before their scheduled time of surgery did not affect their
compliance with fasting requirements. No increase in cancellations or delays of
surgical procedures due to inappropriate oral intake was observed.
PMID- 10773509
TI - Influence of intravenous clonidine pretreatment on anesthetic requirements during
bispectral EEG-guided sevoflurane anesthesia.
AB - STUDY OBJECTIVE: To assess the anesthetic effects of clonidine during sevoflurane
anesthesia guided by the bispectral index (BIS), which is a processed EEG
variable correlated with anesthetic-hypnotic depth. DESIGN: Placebo-controlled,
double-blind clinical trial. SETTINGS: Elective laparoscopic surgery. PATIENTS:
60 ASA physical status I patients scheduled for laparoscopic surgery.
INTERVENTIONS: Patients received either clonidine (3 micrograms/kg, 15 min before
induction) or placebo premedication for a sevoflurane-induced and sevoflurane
maintained anesthesia. Sevoflurane was titrated against a BIS held between 40 and
50. Analgesia was provided by local infiltration with bupivacaine. Need for
postoperative analgesia was recorded. RESULTS AND CONCLUSION: Mean sevoflurane
requirements were not lower with clonidine pretreatment. There was statistically
better perioperative hemodynamic stability (i.e., fewer episodes of hypertension
and tachycardia) without clinical relevance. A decreased need for postoperative
analgesia was observed.
PMID- 10773511
TI - Perioperative stroke associated with postoperative epidural analgesia.
AB - A patient with an epidural catheter for postoperative analgesia developed a
stroke in association with a hypotensive episode resulting from a bolus of local
anesthetic. After undergoing resection for femoral chondrosarcoma under epidural
anesthesia, the patient received a continuous infusion of epidural morphine for
postoperative analgesia. Lidocaine 1% (10 mL in divided doses) was administered
through the catheter for breakthrough pain. The patient experienced a hypotensive
episode and was noted to have a motor and cortical sensory deficit of the left
arm and leg 8 hours after the hypotensive episode. Clinical presentation and
subsequent workup were consistent with a watershed infarction. The patient
recovered full neurologic function before discharge. Postoperative hypotension
from epidural analgesia may be associated with stroke; however, a cause-and
effect relationship usually cannot be established with certainty.
PMID- 10773510
TI - Topical anesthesia versus retrobulbar block for cataract surgery: the patients'
perspective.
AB - STUDY OBJECTIVES: To compare patients' perception of topical anesthesia (TA) with
combined peribulbar and retrobulbar block (PRBB) for cataract surgery. DESIGN:
Prospective, randomized, controlled, cross-over observational study. SETTING:
Private clinic. PATIENTS: 98 ASA physical status I and II patients presenting for
bilateral cataract surgery 1 week apart. INTERVENTIONS: Patients were
prospectively randomized to receive either TA for surgery to one eye, followed by
PRBB for surgery to the other eye 1 week later, or to receive PRBB first,
followed by TA for the second operation the following week. Surgery, PRBB, and TA
were standard for all cases. Interviews were conducted the day following surgery
by an unbiased observer unaware of the technique used. Surgical pain was
estimated on a visual analog scale of 0 to 10, and the surgeon judged the
difficulty of surgery based on patient compliance and cooperation on a scale of 0
to 5. Means and variance of results were compared with analysis of variance.
MEASUREMENTS AND MAIN RESULTS: Mean age was 71.45 +/- 9.76 years (mean +/- SD).
Seventy patients (71.43%) preferred PRBB while 10 patients (10.20%) preferred TA
(p = 0.0001). Eighteen patients (18.37%) reported no difference between the two
techniques. Ninety-six patients (97.96%) were not aware of the PRBB being
injected. Duration of surgery was similar for TA (11.92 +/- 3.43 min) and PRBB
(10.78 +/- 3.00 min; p = 0.06). Surgery was more difficult during TA (p =
0.0004). Pain was worse during TA (p = 0.0001). Surgical and anaesthetic
complications were unremarkable for both techniques. CONCLUSIONS: Patients who
experienced both TA and PRBB preferred PRBB.
PMID- 10773512
TI - Delayed diagnosis of vascular injuries during lumbar discectomy.
AB - We report an accidental perforation of the left iliac artery and vein during
lumbar discectomy in the kneeling position. During the surgical procedure, a
brief and transient hypotension occurred, although the surgeon did not observe
any abnormal bleeding in the operating field. In the recovery room, arterial
blood pressure decreased, and tachycardia, pallor, and abdominal pain occurred.
Retroperitoneal bleeding was suspected. Immediate fluid resuscitation was
initiated, anesthesia was continued, and red blood cells were ordered. The use of
medical antishock trousers enabled temporization until vascular surgeons were
ready. An emergent laparotomy was performed to repair vascular injuries. The
delayed symptoms, use of medical antishock trousers, and implications for
anesthetists are discussed.
PMID- 10773513
TI - Complex regional pain syndrome (CRPS) with resistance to local anesthetic block:
a case report.
AB - We present a case of complex regional pain syndrome (CRPS) Type 1 in a 12-year
old girl. The patient did not respond to the usual therapeutic modalities used to
treat CRPS, including physical therapy, lumbar sympathetic block, epidural local
anesthetic block, intravenous lidocaine infusion, or other oral medications. Of
note is the fact that, during epidural block, the patient demonstrated a
resistance to local anesthetic neural blockade in the area of the body involved
with the pain problem. The mechanism of this resistance could be related to the
changes in the dorsal horn cells of the spinal cord, secondary to activation of N
methyl-D-aspartate receptors, which may play a role in the pathophysiology of
this pain syndrome.
PMID- 10773514
TI - Postoperative fatal intestinal necrosis after enalapril treatment in a patient
with rheumatoid arthritis.
AB - The inappropriate use of antihypertensive medications may cause hypotensive
responses associated with organ failure. We describe a patient who developed
nonocclusive splanchnic ischemia leading to death following the administration of
enalapril to treat postoperative hypertension. The mechanisms and consequences of
refractory hypotension induced by angiotensin-converting enzyme inhibitors are
discussed.
PMID- 10773515
TI - Thoracic epidural anesthesia for modified radical mastectomy in a patient with
cryptogenic fibrosing alveolitis: a case report.
AB - A case of advanced cryptogenic fibrosing alveolitis (CFA) with multiple bullae
and extensive pulmonary fibrosis, scheduled for modified radical mastectomy for
carcinoma of breast, is presented. This patient had ischemic heart disease,
corticosteroid-induced hypertension, diabetes mellitus, and a difficult airway.
Thoracic epidural segmental anesthesia was successfully given to this patient.
Preoperative problems, perioperative management, and alternative anesthetic
techniques are discussed.
PMID- 10773516
TI - Cardiac arrest due to succinylcholine-induced hyperkalemia in a patient with
wound botulism.
AB - Cardiac arrest due to hyperkalemia is a known complication of succinylcholine
administration in patients with neuromuscular disease, extensive burns, and
prolonged immobility. We report a case of hyperkalemic cardiac arrest following
the administration of succinylcholine in a patient suffering from wound botulism.
PMID- 10773517
TI - An anteromedial internal jugular vein successfully cannulated using the
assistance of ultrasonography.
AB - The internal jugular vein usually is found either lateral or anterolateral to the
carotid artery when it is cannulated for central vein access using external
anatomical landmarks. We report a case in which the carotid artery was
inadvertently punctured, but the right internal jugular vein could not be found.
We used ultrasonic guidance to determine that the right internal jugular vein was
anteromedial to the carotid artery. A figure showing the ultrasound of this rare
anatomical variation is provided. The advantages and utility of ultrasound when
used for the placement of internal jugular central vein catheters are reviewed.
PMID- 10773538
TI - 18F-labeled radiopharmaceuticals for PET in oncology, excluding FDG.
AB - This article reviews possible use of (18)F-labelled radiopharmaceuticals in
oncology with positron emission tomography. The characteristics of various (18)F
labelled compounds are proteins and peptides, those that bind to. receptors,
agents to assess hypoxia, and agents to evaluate gene therapy are highlighted.
Furthermore, different (18)F-labelled tissue specific agents are indicated for
the detection and monitoring of various malignancies: melanoma, brain tumours,
breast cancer, prostate cancer and colorectal cancer. (18)F-fluorodeoxyglucose
has been excluded from this summary.
PMID- 10773539
TI - [(11)C]FMAU and [(18)F]FHPG as PET tracers for herpes simplex virus thymidine
kinase enzyme activity and human cytomegalovirus infections.
AB - [(11)C]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([(11)C]FMAU) and
[(18)F]-9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG),
radiolabeled representatives of two classes of antiviral agents, were evaluated
as tracers for measuring herpes simplex virus thymidine kinase (HSV-tk) enzyme
activity after gene transfer and as tracers for localization of active human
cytomegalovirus (HCMV) infections. In vitro accumulation experiments revealed
that both [(11)C]FMAU and [(18)F]FHPG accumulated significantly more in HSV-tk
expressing cells than they did in control cells. [(18)F]FHPG uptake in HSV-tk
expressing cells, however, was found to depend strongly on the cell line used,
which might be due to cell type dependent membrane transport or cell type
dependent substrate specific susceptibility of the enzyme. In vitro, both tracers
exhibited a good selectivity for accumulation in HCMV-infected human umbilical
vein endothelial cells over uninfected cells. In contrast to [(18)F]FHPG,
[(11)C]FMAU uptake in control cells was relatively high due to phosphorylation of
the tracer by host kinases. Therefore, [(18)F]FHPG appears to be the more
selective tracer not only to predict HSV-tk gene therapy outcome, but also to
localize active HCMV infections with PET.
PMID- 10773540
TI - A PET-MRI registration technique for PET studies of the rat brain.
PMID- 10773541
TI - Assessment of resistance to paclitaxel of murine tumors by (99m)Tc-MIBI/(201)Tl
dual-radionuclide imaging.
AB - This study investigated P-glycoprotein (Pgp) expression by murine tumors with and
without resistance to paclitaxel and the role of (99m)Tc-2
methoxyisobutylisonitrile (MIBI)/(201)Tl imaging in predicting the effect of
paclitaxel. Antitumor effect of paclitaxel and biodistribution of the
radiopharmaceuticals were evaluated in mice bearing four tumor types. Pgp
expression did not correlate with the antitumor efficacy of paclitaxel. Although
the absolute uptake of (99m)Tc-MIBI did not correlate with Pgp expression,
(99m)Tc-MIBI could predict paclitaxel sensitivity by its higher uptake.
PMID- 10773543
TI - Radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine: [(18)F]FLT for imaging of
cellular proliferation in vivo.
AB - A reliable radiosynthesis of 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has
been developed based on [(18)10 mCi (370 MBq) of radiochemically pure [(18)1
Ci/micromol (37 GBq/micromol) at EOS within 100 min and in 13% radiochemical
yield (end of bombardment (EOB); 7% end of synthesis (EOS)). [(18)F]FLT has been
designed as a new positron emission tomography imaging agent for visualizing
cellular proliferation in vivo based on the metabolism of thymidine.
PMID- 10773542
TI - Assessment of the in vitro and in vivo properties of a (99m)Tc-labeled inhibitor
of the multidrug resistant gene product P-glycoprotein.
AB - Overexpression of P-glycoprotein (Pgp), which is present in the plasma membrane
of various tumor cells and in several normal cell types, contributes to the
multidrug resistance (MDR) phenotype of many human cancers. As a prerequisite for
therapy, the expression of Pgp must be studied. The available clinical
radiopharmaceuticals for studying the expression of Pgp include the lipophilic
(99m)Tc cations (sestamibi, tetrofosmin) as well as [(99m)Tc]Q57, [(99m)Tc]Q58,
and [(99m)Tc]Q63. Here we describe the in vitro and in vivo properties of the
structurally different complex (3-thiapentane-1, 5-dithiolato)[[N-(3
phenylpropyl)-N-2(3-quinazoline-2, 4-dionyl)-ethyl]amino-ethylthiolato?
oxotechnetium(V) ((99/99m)Tc1) as a potential inhibitor of Pgp. (99)Tc1 enhances
the net cell accumulation of Pgp substrates [(3)H]vinblastine, [(3)H]vincristine,
[(3)H]colchicine, [(99m)Tc]sestamibi, and [(99m)Tc]tetrofosmin in rat brain
endothelial cells (RBE4), an immortalized endothelial cell line that expresses
Pgp. In addition, the cell accumulation of (99m)Tc1 could be increased by
verapamil and reserpine, which are known Pgp inhibitors. A multitracer approach
was used to study the side effects of (99)Tc1 on cell metabolism. The cells were
simultaneously incubated with [(99m)Tc]sestamibi, 2-[(18)F]fluoro-2-deoxyglucose
([(18)F]FDG), and various (3)H-labeled tracers. Two-dimensional scatter plots of
[(99m)Tc]sestamibi uptake/[(18)F]FDG uptake show typical changes of known Pgp
inhibitors including (99)Tc1. The effects of (99)Tc1 on the in vivo distribution
of [(99m)Tc]sestamibi and [(18)F]FDG in rats also are comparable with the effects
of verapamil, an established Pgp inhibitor and calcium channel blocker. We
conclude that (99/99m)Tc1 is a transport substrate and a potential inhibitor of
Pgp. Our approach may be useful in the design of further radiotracers with
specificity to Pgp.
PMID- 10773544
TI - Synthesis of 8-[(18)F]fluoroguanine derivatives: in vivo probes for imaging gene
expression with positron emission tomography.
AB - A new method for the preparation of 8-[(18)F]fluoroguanine derivatives based on a
direct radiofluorination reaction has been developed. The radiofluorination of
ganciclovir (1a) with [(18)F]F(2) was carried out in absolute ethanol in the
presence of tetraethylammonium hydroxide at room temperature to give 8
[(18)F]fluoroganciclovir (3a) in an approximately 1% radiochemical yield.
Similarly, 8-[(18)F]fluoropenciclovir (3b), 8-[(18)F]fluoroacyclovir (3c), and 8
[(18)F]fluoroguanosine (3d) were synthesized from penciclovir (1b), acyclovir
(1c), and guanosine (1d), respectively, using [(18)F]F(2). The structural
analyses of the final products (3a, 3b, 3c, and 3d) were carried out after (18)F
decay by (1)H, (13)C, and (19)F nuclear magnetic resonance and high resolution
mass spectroscopy.
PMID- 10773545
TI - Biologically stable [(18)F]-labeled benzylfluoride derivatives.
AB - Use of the [(18)F]-fluoromethyl phenyl group is an attractive alternative to
direct fluorination of phenyl groups because the fluorination of the methyl group
takes place under milder reaction conditions. However, we have found that 4
FMeBWAY showed femur uptake equal to that of fluoride up to 30 min in rat whereas
4-FMeQNB had a significantly lower percent injected dose per gram in femur up to
120 min. For these and other benzylfluoride derivatives, there was no clear in
vivo structure-defluorination relationship. Because benzylchlorides (BzCls) are
known alkylating agents, benzylfluorides may be alkylating agents as well, which
may be the mechanism of defluorination. On this basis, the effects of
substitution on chemical stability were evaluated by the 4-(4-nitro-benzyl)
pyridine (NBP) test, which is used to estimate alkylating activity with NBP. The
effect of substitution on the alkylating activity was evaluated for nine BzCl
derivatives: BzCl; 3- or 4-methoxy (electron donation) substituted BzCl; 2-, 3-,
or 4-nitro (electron withdrawing) substituted BzCl; and 2-, 3-, or 4-chloro
(electron withdrawing) substituted BzCl. Taken together, the alkylating
reactivity of 3-chloro-BzCl was the weakest. This result was then applied to
[(18)F]-benzylfluoride derivatives and in vivo and in vitro stability were
evaluated. Consequently, 3-chloro-[(18)F]-benzylfluoride showed a 70-80% decrease
of defluorination in both experiments in comparison with [(18)F]-benzylfluoride,
as expected. Moreover, a good linear relationship between in vivo femur uptake
and in vitro hepatocyte metabolism was observed with seven (18)F-labeled
radiopharmaceuticals, which were benzylfluorides, alkylfluorides, and
arylfluorides. Apparently, the [(18)F]-fluoride ion is released by metabolism in
the liver in vivo. In conclusion, 3-chloro substituted BzCls are the most stable,
which suggests that 3-chloro benzylfluorides will be the most chemically stable
compound. This result should be important in future design of radioligands
labeled with a benzylfluoride moiety.
PMID- 10773546
TI - A novel serotonin transporter ligand: (5-iodo-2-(2-dimethylaminomethylphenoxy)
benzyl alcohol.
AB - The serotonin transporters (SERT) are the primary binding sites for selective
serotonin reuptake inhibitors, commonly used antidepressants such as fluoxetine,
sertraline, and paroxetine. Imaging of SERT with positron emission tomography and
single photon emission computed tomography in humans would provide a useful tool
for understanding how alterations of this system are related to depressive
illnesses and other psychiatric disorders. In this article the synthesis and
characterization of [(125)I]ODAM [(5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl
alcohol, 9)] as an imaging agent in the evaluation of central nervous system SERT
are reported. A new reaction scheme was developed for the preparation of compound
9, ODAM, and the corresponding tri-n-butyltin derivative 10. Upon reacting 10
with hydrogen peroxide and sodium[(125)I]iodide, the radiolabeled [(125)95%). In
an initial binding study using cortical membrane homogenates of rat brain, ODAM
displayed a good binding affinity with a value of K(i) = 2.8 +/- 0.88 nM. Using
LLC-PK(1) cells specifically expressing the individual transporter (i.e. dopamine
[DAT], norepinephrine [NET], and SERT, respectively), ODAM showed a strong
inhibition on SERT (K(i) = 0.12 +/- 0.02 nM). Inhibition constants for the other
two transporters were lower (K(i) = 3.9 +/- 0.7 microM and 20.0 +/- 1.9 nM for
DAT and NET, respectively). Initial biodistribution study in rats after an
intravenous (IV) injection of [(125)I]ODAM showed a rapid brain uptake and
washout (2.03, 1.49, 0.79, 0.27, and 0.07% dose/organ at 2, 30, 60, 120, and 240
min, respectively). The hypothalamus region where the serotonin neurons are
located exhibited a high specific uptake. Ratios of hypothalamus
cerebellum/cerebellum based on percent dose per gram of these two regions showed
values of 0.35, 0. 86, 0.86, 0.63, and 0.34 at 2, 30, 60, 120, and 240 min, post
IV injection, respectively. The specific uptake in hypothalamus can be
effectively blocked by pretreatment of known SERT ligands. The results suggest
that this novel ligand displays desirable in vitro and in vivo properties as a
potential SERT imaging agent.
PMID- 10773547
TI - Evaluation of [O-methyl-(11)C]fluvoxamine as a tracer for serotonin re-uptake
sites.
AB - We evaluated [(11)C]fluvoxamine as a tracer for the serotonin re-uptake site.
Studies of the distribution of the tracer in rat and primate brain showed
adequate uptake of [(11)C]fluvoxamine, but failed to reveal regions with known
high density of serotoninergic re-uptake sites. Pretreatment with unlabeled
fluvoxamine did not substantially change the distribution. In rat brain tissue,
nearly all radioactivity represented intact [(11)C]fluvoxamine.
[(11)C]Fluvoxamine does not function as a tracer for serotonin re-uptake sites,
owing to high nonspecific binding in the brain.
PMID- 10773548
TI - 114mIn, a candidate for radionuclide therapy: low-energy cyclotron production and
labeling of DTPA-D-phe-octreotide.
AB - A method for production of carrier-free (114m)In (half-life 49.5 days), which is
a potential radionuclide for radionuclide therapy of slowly growing tumors, is
presented. A target consisting of five enriched cadmium ((114)Cd) foils, each 50
microm thick, was irradiated by protons (from 12.6-6.5 MeV) giving a target yield
of 0. 8 MBq/microAh. A simple and cost-efficient thermal diffusion method was
used for the separation. The irradiated target foils were heated for 2 h at 306
degrees C and then etched in 0.05 M HCl. The obtained cadmium/indium solution was
purified using a cation ion-exchange resin (AG 1 x 8, Bio-Rad Laboratories,
Hercules, CA USA). An overall yield of approximately 60% was obtained, whereas
the loss of the target material was <1% per separation cycle. The (114m)In
production gave (114m)In with high specific radioactivity and was successfully
used to label diethylenetriamine pentaacetic acid (DTPA)-D-Phe-octreotide.
Furthermore, no difference in biodistribution between [(114m)In]- and [(111)In]
DTPA-D-Phe(1)-octreotide in tumor-bearing nude mice was seen. The high
radionuclide uptake in the tumors indicates a good receptor binding of the
labeled octreotide.
PMID- 10773550
TI - Humanized versus murine anti-human epidermal growth factor receptor monoclonal
antibodies for immunoscintigraphic studies.
AB - The anti-human epidermal growth factor receptor (EGF-R) humanized antibody h-R3
(IgG(1)), which binds to an extracellular domain of EGF-R, was used to evaluate
the biodistribution on nude mice xenografted with A431 epidermoid carcinoma cell
line. Results are compared with its murine version ior egf/r3 monoclonal antibody
(mAb). Twenty-one athymic female 4NMRI nu/nu mice were injected intravenously
with 10 microg/100 microCi of (99m)Tc-labeled mAbs. The mAb ior C5 that
recognizes an antigen expressed preferentially on the surface of malignant and
cytoplasm of normal colorectal cells was used as negative control.
Immunoreactivity of (99m)Tc-labeled mAbs was measured by enzyme linked
immunosorbent assay on A431 cell line and the immunoreactive fractions determined
by Lindmo method. Among all organs significative accumulation was found in tumor
(6.14 +/- 2.50 %ID/g, 5.06 +/- 2.61 %ID/g for murine and humanized mAbs,
respectively) 4 h after injection. The immunoreactive fractions were found to be
0.88 and 0.81 for murine and humanized mAb, respectively. Thus, we expect better
results using the humanized mAb h-R3 for diagnostic immunoscintigraphy.
PMID- 10773549
TI - [(186/188)Re] rhenium-ethylene dicysteine (Re-Ec): preparation and evaluation for
possible use in endovascular brachytherapy.
AB - 188ReO(4)(-), (188)Re-MAG(3), and (188)Re-DTPA are currently under investigation
as radiation sources in liquid-filled balloons for prevention of restenosis
following coronary angioplasty. Because (99m)Tc-labeled ethylene dicysteine (EC)
is a well-established agent for renal tubular function imaging, the use of
[(188)Re] rhenium-labeled EC as a potential agent for prevention of restenosis
after angioplasty is worth evaluation. In this article, the preparation and
pharmacological behavior of [(188/186)Re]Re complex of EC are reported. The yield
of the Re complex was optimized by varying the parameters of complexation. The
complex prepared under the optimized conditions was found to be stable over a
period of 7 days when stored at pH 2 and at 4 degrees C. The pharmacological
behavior of [(188/186)Re]Re-EC confirms its similarity to (188)Re-MAG(3) and its
superiority over (188)ReO(4)(-) for use in endovascular brachytherapy.
PMID- 10773551
TI - Synthesis and biological evaluation of the four isomers of technetium-99m labeled
ethylenecysteamine cysteine ((99m)Tc-ECC), the mono-acid derivative of (99m)tc
L,L-ethylenedicysteine.
AB - A few years ago (99m)Tc-ethylenedicysteine ((99m)Tc-L,L-EC) had been proposed as
an interesting substitute for technetium-99m labeled mercaptoacetyltriglycine
(MAG3) as renal function tracer agent. It possesses in its structure two
carboxylate functions and is in this respect different from other renal tracers
such as (99m)Tc-N, N'-bis-(mercaptoacetyl)-2,3-diaminopropionate ((99m)Tc
CO(2)DADS), (99m)Tc-MAG3, and Hippuran, which have only one carboxylic group. To
study whether both carboxylic acid groups of (99m)Tc-L,L-EC contribute to the
efficient renal handling of this compound we synthesized and biologically
evaluated the technetium-99m labeled isomers of L- and D-ethylenecysteamine
cysteine (ECC), the mono-acid derivative of (99m)Tc-L,L-EC. Labeling of L-ECC or
D-ECC with (99m)Tc using a direct or exchange labeling method yields for each of
them two diastereomeric (99m)Tc complexes (A and B, in the order of elution
during reversed phase high performance liquid chromatography) in relative amounts
depending on the pH during labeling. In mice, all four isomers of (99m)Tc-ECC
(LA, LB, DA, and DB) are cleared rapidly from the blood, mainly by the renal
system. The isomers LB and DB show the most efficient renal handling, but none of
the mono-acid derivatives has a urinary excretion rate as high as that of (99m)Tc
L,L-EC. The renal handling of the isomers of (99m)Tc-ECC is partly due to tubular
secretion because the urinary excretion of these compounds is significantly lower
in mice pretreated with probenecid. In the baboon, isomers DA and DB show a
plasma clearance comparable to that of (99m)Tc-L,L-EC. The plasma clearance of
isomers LA and LB is lower but still comparable to or higher than that of (99m)Tc
MAG3. In a human volunteer, isomer DB shows a plasma clearance rate only slightly
lower than that of (99m)Tc-L,L-EC. Thus, it appears that the presence of one
carboxylate in (99m)Tc-EC-like compounds can be sufficient for efficient renal
handling. However, it is also evident that the configuration at the chiral carbon
atom and the orientation of the oxotechnetium core determine in a significant way
the biological characteristics.
PMID- 10773552
TI - 99mTc-ENS ventilation scintigraphy: preliminary study in human volunteers.
AB - Exogenous natural surfactant (ENS) labeled with (99m)Tc ((99m)Tc-ENS, 900-1110
MBq), a new radiopharmaceutical for ventilation scintigraphy, was nebulized
during 3 min to five volunteers. For comparative purposes, (99m)Tc
diethylenetriamine pentaacetic acid (DTPA) was studied in the same way. (99m)Tc
ENS images were of at least the same quality as (99m)Tc-DTPA images. However, in
smoking volunteers, the (99m)Tc-DTPA images show some areas that seemed to be not
well-ventilated, although these areas appeared well-ventilated when the study was
performed with (99m)Tc-ENS. These results suggest that (99m)Tc-ENS can be used
for ventilation scintigraphy to allow the observation of some areas that cannot
been visualized using (99m)Tc-DTPA as ventilation agent.
PMID- 10773553
TI - Tricuspid valve dysfunction and surgery after orthotopic cardiac transplantation.
AB - OBJECTIVE: The study examines the prevalence of tricuspid regurgitation and
biopsy-induced flail tricuspid leaflets after orthotopic heart transplantation
and evaluates the results of the tricuspid valve surgery. METHODS: By a
computerized search of the databases 647 of 889 patients who survived heart
transplantation for more than 30 days were identified for this study. The primary
tool for rejection monitoring in our institution is the daily observation of
intramyocardial ECG (IMEG) based on day-by-day changes of the maximal QRS complex
amplitude. Endomyocardial biopsy with 45-cm-long sheath bioptome was performed
only in doubtful IMEG and echocardiographic data and at times of annual routine
heart catheterization. Tricuspid regurgitation was diagnosed clinically and by
echocardiography as mild, moderate and severe. Eleven patients received
prosthetic valve replacements (four bioprostheses and seven mechanical valves)
and six patients underwent valve reconstruction. The choice of xenograft valve
was dictated by the condition of renal function. Patient survival and incidence
of tricuspid regurgitation and freedom from operation for severe tricuspid
regurgitation were analyzed with Kaplan-Meier method. RESULTS: The prevalence of
tricuspid regurgitation was 20.1%. Mild and moderate tricuspid regurgitation was
seen in 14.5 and 3.1% of the patients, respectively, who were responsive to
medical therapy and remained clinically stable in NYHA class I-II. Severe
tricuspid regurgitation was seen in 16 (2.5%) patients who presented signs of an
acute right heart dysfunction. Tricuspid valve pathology at operation revealed
biopsy-induced rupture of the Chordae tendineae at various valve segments mostly
the anterior and posterior leaflets. There was one hospital death (<30 day) and
five late deaths due to infection, arrhythmia and trauma and no procedural
related or directly cardiac related death. Ten patients (62.5%) are alive at a
mean follow-up time of 29.9 months (range 4-81 months) and nine survivors are in
NYHA class I-II and one in class III. CONCLUSIONS: Severe tricuspid regurgitation
in transplanted hearts is associated mainly with biopsy-induced injury or
endocarditis. Other regimes of rejection monitoring may help to eliminate this
complication. Apart from our preference of valve repair, the choice of valve
substitute may be influenced by the presence or the prospect of chronic renal
failure. Heart transplant patients can safely undergo valve surgery with
acceptable mortality, low morbidity and excellent intermediate-term clinical
results. Mild to moderate functional tricuspid regurgitation is responsive to
medical therapy and non-progressive and occur in 17.6% of orthotopic transplanted
hearts without having a detrimental effect on the right ventricular performance.
PMID- 10773554
TI - Early and long-term results of heart transplantation after previous cardiac
surgery.
AB - OBJECTIVES: The aim of this study was to evaluate the preoperative management and
long-term survival of patients undergoing heart transplantation as a redo
operation and compare the results with those obtained in patients undergoing
transplantation as their first cardiac surgical procedure. METHODS: Between 1990
and 1997, 49 heart transplantation procedures were performed in patients who had
undergone previous cardiac surgery (group A). This subgroup of patients was
compared to 109 control patients who underwent cardiac transplantation as the
primary cardiac procedure (group B). Patient groups were analysed regarding their
preoperative, intra-operative, and postoperative variables in addition to
survival. RESULTS: Pre-operative events were comparable in both groups but the
duration of the operation was longer for group A (311+/-68 min) compared to group
B (202+/-34 min); P=0.02. Post-operative exploration for bleeding was 6/49
patients in group A compared to 2/107 patients in group B (P=0.02). Post
operative blood loss and intensive care stay were greater for group A (1302+/-360
ml and 6.1+/-3.1 days, respectively) compared to group B (763+/-126 ml and 4.1+/
1.9 days, respectively); P=0.02. There was no difference in hospital mortality
(group A 12.5%, group B 13 % P=0.9) and the 5-year survival rates were 68 and 71%
for group A and B, respectively (P=0.9). CONCLUSIONS: Heart transplantation after
previous open cardiac surgery is entirely justified in terms of outcome and graft
function even in time of profound organ scarcity. Long-term events in these
recipients are similar to patients in whom transplantation is the primary
procedure.
PMID- 10773555
TI - Mechanisms of pulmonary transfer factor decline following heart transplantation.
AB - OBJECTIVE: Although the decline in the pulmonary transfer factor (TL(CO))
following heart transplantation is well documented, the causes and mechanisms of
this decline remain unknown. The aim of this study was to determine the relative
contribution of each of TL(CO) components (the diffusing capacity of the alveolar
capillary membrane (D(M)), the pulmonary capillary blood volume (V(C)) and
haemoglobin concentration) to TL(CO) reduction in heart transplant recipients.
METHODS: TL(CO) and its components were measured in 75 heart transplant
recipients (mean age 48 years, range 19-61) between 6 weeks and 36 months after
transplantation using the Roughton and Forster method and the single-breath
technique. Results were compared with data from 38 heart transplant candidates
(mean age 51 years, range 34-61) and 26 normal subjects (mean age 47 years, range
27-62). RESULTS: The mean percentage predicted TL(CO) was reduced in recipients
compared to candidates (56.9 and 69.9%, respectively, P<0. 001) and both were
lower than normal controls (97.7%, P<0.001). The mean percent predicted V(C) was
also reduced in recipients compared to candidates (52.8% vs. 80.2 (4.2)%,
P<0.001) which was also lower than normal subjects (102%, P<0.001). D(M) was
equally reduced in recipients and candidates (77.7 and 81.4%, respectively,
P=0.48) compared to normal subjects (100.0%, P<0.001). Correction for haemoglobin
concentration increased TL(CO) in recipients to 63.5% (P<0.001), but it remained
lower than haemoglobin-corrected TL(CO) in candidates (71.1%, P<0.001). In
recipients, the intra-capillary resistance (1/thetaV(C)) formed 60% of the total
resistance to CO transfer (1/TL(CO)) compared to 50% in candidates and normal
subjects. CONCLUSIONS: TL(CO) decline following heart transplantation is due to
an increase in the intra-capillary resistance, and this appears to be due to a
combination of anaemia and reduced pulmonary capillary blood volume, with the
diffusing capacity of the alveolar-capillary membrane remaining unchanged.
PMID- 10773556
TI - The clinical significance of flow cytometry crossmatching in heart
transplantation.
AB - OBJECTIVE: Flow cytometry crossmatching (FCXM) is more sensitive than the
cytotoxic crossmatch in identifying preformed antibodies to donor alloantigens,
but its clinical importance is controversial. The objective of this study was to
determine the association of a FCXM with survival and incidence of vascular
rejection in cardiac transplant recipients with a negative cytotoxic crossmatch.
METHODS: Between 1993 and 1998, 357 heart transplant recipients with a negative T
cell cytotoxic crossmatch were studied by three-color FCXM to quantitate anti
donor IgG reactions against B and T lymphocytes. Reactions positive against both
were consistent with human leukocyte antigen (HLA) Class I reactivity, and those
against B cells only were considered to be against HLA Class II antigens.
Endpoints were episodes of vascular rejection, death from acute and chronic
rejection and overall survival. RESULTS: Fifty patients were FCXM for Class I
positive, 144 for Class II-positive, and 163 were negative. At 1 month, freedom
from vascular rejection was 64% in Class I patients, but 90% and 96% in Class II
or negative crossmatch patients (P<0.0001). Survival of the negative crossmatch
group was higher than either Class I or II groups (94%, 74% and 76%,
respectively, at 3 years; P<0.0001). Death from acute rejection was 3% and 2% at
3 years in negative or Class II-positive patients, but 19% in Class I patients
(P<0.0001). Death from chronic rejection occurred only in Class II patients
(P=0.002). CONCLUSIONS: Despite a negative T-cell cytotoxic crossmatch, a
positive flow cytometry crossmatch correlates with important clinical events
after heart transplantation.
PMID- 10773557
TI - Bronchoplasty for malignant and benign conditions: a retrospective study of 44
cases.
AB - OBJECTIVE: To study the different operative techniques employed, the problems
encountered and the outcome in bronchoplastic procedures both during and after
surgery. PATIENTS AND METHODS: Forty-four patients with a mean age of 51.6 years
(range 15-80 years) underwent bronchoplastic procedures in the period from 1976
to 1998. There were 27 males and 17 females. Forty-two of these had planned
surgery. Two trauma patients had emergency surgery. Out of 42 planned operations,
27 suffered from cancer and 15 had benign lesions. Amongst the non-small cell
lung cancer (NSCLC) group, the nodal status was N0 in nine patients, N1 in 12 and
N2 in six. Bronchial sleeve resection with lobectomy was performed in 24
patients. Six patients had sleeve pneumonectomies. Fourteen others had bronchial
sleeve resections without lobectomies, and bronchoplasties for trauma and
stricture. Reconstruction was performed in the earlier years with stainless steel
wire of 38/40 SS gauge (n=22), vicryl (n=4) and prolene (n=1). More recently,
ethibond (n=18) was routinely used for this purpose. Anaesthesia was maintained
via oro-tracheal intubation, interrupted when necessary with a short period of
intubation of one or the other bronchus through the thoracotomy incision.
RESULTS: The mean operating theatre time, including the anaesthesia, was 207 min
(range 120-375 min). The duration of stay in the high dependency unit (HDU) was
no longer than 3 days. Post-operative problems included excessive bronchial
secretions and partial atelectasis (one patient requiring therapeutic
bronchoscopy), prolonged mechanical ventilation (n=1) and prolonged air leak
(n=1). There was no per-operative, hospital, or 30 day mortality. Four out of 27
cancer patients lived more than 5 years, 12 died between 2 and 5 years, and 11
lived less than 2 years. CONCLUSIONS: Whilst bronchoplasties require special
anaesthetic techniques and stringent high dependency post-operative care, there
is minimal operative morbidity and mortality. Acceptable duration of survival can
be expected even in the cancer patients.
PMID- 10773558
TI - 18-FDG positron emission tomography in the evaluation of malignant pleural
diseases - a pilot study.
AB - OBJECTIVE: The diagnostic approach to pleural diseases may be difficult. The CT
scan, which is the current diagnostic technique, has limited accuracy both in the
differentiation between benign and malignant pleural diseases and in the
diagnosis of primary and metastatic pleural neoplasms. Invasive procedures, such
as thoracoscopy, are therefore frequently required to complete the diagnostic
approach. The increasing incidence of malignant pleural mesothelioma has led to
the development of new treatment strategies, which still need to be fully
validated. There is, therefore, a need for new diagnostic techniques that can
lead to a definite diagnosis and a satisfactory evaluation of the response to
treatment. Encouraging results have been reported with the F-18-labeled analogue
of 2-deoxyglucose (18-FDG) positron emission tomography (PET) in the evaluation
of chest tumors such as lung cancer. The aim of this study was to evaluate the
role of 18-FDG PET in the diagnostic assessment of pleural diseases. METHODS:
Patients with CT scan evidence of pleural thickening, or fluid, entered a study
to evaluate the accuracy of 18-FDG PET in diagnosing pleural diseases. Image
analysis was performed both with visual interpretation and using a
semiquantitative method, standardized uptake values (SUV), on coronal, sagittal
and axial reconstructions. The results of PET imaging were compared to
histological data. PET was also performed before and after treatment in patients
who underwent chemotherapy to evaluate the accuracy of this technique in the
assessment of the response. RESULTS: Fourteen patients entered the study.
Histology demonstrated a malignant pleural disease in 13 patients; malignant
pleural mesothelioma in ten patients, adenocarcinoma in two and liposarcoma in
one. Benign pleural disease was diagnosed in the remaining patient. PET
assessment demonstrated significant 18-FDG uptake in 12 of the 13 patients with a
malignant disease, also revealing distant metastases in two of them. A false
negative result was observed in a patient with an epithelial mesothelioma. The
overall accuracy was 92%. A benign pleural disease without significant uptake was
correctly diagnosed in another patient. An aspecific uptake was observed in two
patients who had undergone pleurectomy and intrapleural chemotherapy. A decreased
tracer uptake was observed after chemotherapy in four patients. CONCLUSIONS:
These preliminary results demonstrate that 18-FDG PET may have a great potential,
both in the differential diagnosis of pleural diseases and in the evaluation of
the response to treatment. At present, however, histological thoracoscopic
diagnosis remains mandatory before planning treatment. Further studies in larger
groups of patients are needed to draw definite conclusions on the role of PET in
the assessment of pleural diseases.
PMID- 10773559
TI - Superior vena cava syndrome of malignant origin. Which surgical procedure for
which diagnosis?
AB - OBJECTIVE: Since some malignancies causing superior vena cava syndrome (SVCS) are
only sensitive to a specific treatment regimen, it is crucial to diagnose the
underlying pathology in such cases. The aim of the present study was to review
the surgical procedures used to establish the aetiology of SVCS of a malignant
origin. METHODS: This retrospective study was based on a series of 88 patients
referred to surgeons for SVCS, for whom biological and/or endoscopic procedures
had failed to establish the diagnosis. On the basis of the results of clinical
examination, biological tests and CT-scan presentation, we performed 99 sampling
procedures to obtain a diagnosis for all 88 patients. These procedures were the
following: biopsy of peripheral adenopathy (n=11), CT-guided biopsy (CTGB; n=23),
axial mediastinoscopy (MDS; n=23), anterior mediastinotomy (n=26), anterior
mediastinoscopy (n=6), biopsy of the suprascapular mass (n=3), pericardioscopy
(n=3), thoracoscopy (n=1), thoracotomy (n=2) and sternotomy (n=1). RESULTS: Per
operative morbidity consisted of one case of massive venous bleeding during MDS
requiring a salvage sternotomy to achieve hemostasis. The diagnoses finally
established for the 88 patients were non-Hodgkin's lymphoma (NHL) for 36, small
cell lung cancer for 25, non-small cell lung cancer for 17, Hodgkin's disease for
five, thymoma for three, germ cell tumour for one and sarcoma for one. For the
diagnosis of lung cancer, the sensitivities of CTGB and MDS were 85 and 100%,
respectively. For the diagnosis of NHL, the sensitivity of anterior
mediastinotomy was 95%. CONCLUSION: The surgical diagnostic procedure, chosen on
the basis of the clinical presentation and CT-scan, can be performed safely in
the case of SVCS, with the same accuracy as in the absence of this syndrome.
Among the patients referred to surgeons, NHL is the most frequent aetiology of
SVCS, together with small cell lung cancer.
PMID- 10773560
TI - A tailored surgical approach for gastro-oesophageal reflux disease: the
Nottingham experience.
AB - OBJECTIVE: The objective was to assess the results which can be achieved by
tailoring the anti-reflux procedure to the anatomical and functional situation of
the patient with gastro-oesophageal reflux disease (GORD). PATIENTS AND METHODS:
Two hundred and seventy six patients undergoing a primary tailored anti-reflux
procedure between 1986 and 1996 were evaluated. An anti-reflux procedure was
selected on the basis of the anatomical and functional findings assessed by means
of barium video, endoscopy, manometry and prolonged pH monitoring. The operations
performed were Nissen fundoplication (77), total fundoplication gastroplasty
(TFG; 140) and Belsey Mark IV (BMIV; 59). The unit policy is for life-long follow
up. The symptoms at review were assessed and graded according to previously
published criteria (Orringer MB, Skinner DB, Besley HR. Long-term results of the
mark IV operation for hiatal hernia and analyses of recurrences and their
treatment. J Thorac Cardiovasc Surg 1972;63:25-31). Patients with recurrent
symptoms were fully re-investigated. RESULTS: Mean hospital stay was 8.2 days (5
32 days). There was one hospital death (0.36%). Mean follow-up was 6.7 years
(range, 2.2-13.1 years). Overall excellent or good results were achieved in 247
(89.5%) patients (92.2% in Nissen, 90.7% in TFG and 83.1% in BMIV group, P=0.1).
In patients without oesophagitis (n=72), the success rate was 93.1%, while for
patients with grade IV oesophagitis (n=89) this was 87.6% (P=0.2). Kaplan-Meier
freedom from recurrent or new, operation-induced, symptoms at 10 years was 88.1%
(89.5% in Nissen, 87.4% in TFG and 73.8% in BMIV groups, P=0.08). CONCLUSIONS:
These data suggest that where the appropriate anti-reflux procedure is selected,
surgery can achieve satisfactory mid- and long-term success rates across the
spectrum of GORD. When oesophageal shortening is evident, or merely suspected, we
favour a TFG. In the presence of impaired motility and no evidence of oesophageal
shortening, a BMIV is the preferred approach. The Nissen procedure is used for
uncomplicated cases.
PMID- 10773561
TI - Coronary surgery in Europe: comparison of the national subsets of the European
system for cardiac operative risk evaluation database.
AB - OBJECTIVE: To compare the national samples of patients who underwent isolated
coronary artery bypass grafting (CABG) during the European System for Cardiac
Operative Risk Evaluation (EuroSCORE) trial in order to evaluate national
differences in epidemiology, patient risk profile and surgical methods. METHODS:
From September to November 1995, 11731 patients had CABG in the six largest
contributing nations to the EuroSCORE project: Germany, UK, Spain, Finland,
France and Italy. The Chi-square and Kruskal-Wallis tests were applied to obtain
an international comparison of patient general status, including pre-operative
risk factors, cardiac status, critical pre-operative states, rare conditions,
urgency of surgery, angina status, coronary lesions, procedures and EuroSCORE
risk assessment. RESULTS: Large national samples (from 984 patients in Finland to
3138 in Germany) identified significant differences in epidemiology, risk profile
and surgical practice. Regarding epidemiology, CABG accounted for 62.8% of adult
cardiac surgery, with a range of 46.2 in Spain to 77.7% in Finland (P<0.001). The
mean age was 62.9 years (61.4 in Britain to 64.4 in France, P<0.001). The mean
body mass index was 26.8 (26 in France to 27.5 in Finland, P<0.001). With regard
to risk profile, diabetes was present in 20.3% of patients (11.8% in Britain to
27.7% in Spain, P<0.001). Chronic renal failure was present in 8.3% (6.8% in
Germany to 10.6% in Spain, P<0.001). Chronic airway disease affected 3.8% (1.9%
in Italy to 5. 1% in Germany, P<0.001). The mean ejection fraction was 0.56 (0.48
in Britain to 0.58 in Finland, P<0.001). The mean predicted mortality (according
to EuroSCORE) was 3.3% (2.8% in Finland to 3.6% in France, P<0.001). The
prevalence of chronic congestive heart failure, unstable angina and recent
myocardial infarction also showed statistically significant differences. No
differences were found for some critical preoperative states (such as immediate
preoperative cardiac massage and pre-operative intubation), or for surgery for
catheter laboratory complication. Regarding surgical practice, major differences
were noted in preoperative intra-aortic balloon use (mean 1%, Finland 0%, Spain
2.3%, P<0.001), the number of mammary artery conduits used (mean 0.9, Spain 0.7,
France 1.1, P=0.0001) and the number of distal anastomoses (mean 3, France 2.7,
Finland 3.8, P=0.001). CONCLUSION: There are important epidemiological
differences in the national cohorts of CABG patients in the EuroSCORE database.
Any international comparison of European surgical results must therefore take
into account the risk profile of patients by using a compatible risk
stratification system.
PMID- 10773562
TI - Risk stratification in heart surgery: comparison of six score systems.
AB - OBJECTIVE: Risk scores have become an important tool in patient assessment, as
age, severity of heart disease, and comorbidity in patients undergoing heart
surgery have considerably increased. Various risk scores have been developed to
predict mortality after heart surgery. However, there are significant differences
between scores with regard to score design and the initial patient population on
which score development was based. It was the purpose of our study to compare six
commonly used risk scores with regard to their validity in our patient
population. METHODS: Between September 1, 1998 and February 28, 1999, all adult
patients undergoing heart surgery with cardiopulmonary bypass in our institution
were preoperatively scored using the initial Parsonnet, Cleveland Clinic, French,
Euro, Pons, and Ontario Province Risk (OPR) scores. Postoperatively, we
registered 30-day mortality, use of mechanical assist devices, renal failure
requiring hemodialysis or hemofiltration, stroke, myocardial infarction, and
duration of ventilation and intensive care stay. Score validity was assessed by
calculating the area under the ROC curve. Odds ratios were calculated to
investigate the predictive relevance of risk factors. RESULTS: Follow-up was able
to be completed in 504 prospectively scored patients. Receiver operating
characteristics (ROC) curve analysis for mortality showed the best predictive
value for the Euro score. Predictive values for morbidity were considerably lower
than predictive values for mortality in all of the investigated score systems.
For most risk factors, odds ratios for mortality were substantially different
from ratios for morbidity. CONCLUSIONS: Among the investigated scores, the Euro
score yielded the highest predictive value in our patient population. For most
risk factors, predictive values for morbidity were substantially different from
predictive values for mortality. Therefore, development of specific morbidity
risk scores may improve prediction of outcome and hospital cost. Due to the
heterogeneity of morbidity events, future score systems may have to generate
separate predictions for mortality and major morbidity events.
PMID- 10773563
TI - Long-term clinical and angiographic follow-up of sequential internal thoracic
artery grafting.
AB - OBJECTIVE: Sequential internal thoracic artery (ITA) grafting allows a more
complete arterial revascularization of the myocardium. We wanted to verify
whether the excellent clinical and angiographic short term results reported by us
before where maintained over 10 years and more. METHODS: the first consecutive
500 patients having received at least one sequential ITA graft between October
1985 and August 1991 were reviewed. Age averaged 61 years. Fifty-three patients
had a left ventricular ejection fraction less than 40%, 117 were not elective, 35
(7%) were reoperations, 56 (11%) had diabetes. In total 2156 anastomoses were
constructed (4.3/patient), among them 1367 arterial anastomoses (2.7/patient) and
1150 sequential ITA anastomoses (2.3/patient). The clinical follow-up was 97.4%
complete and averaged 9.6 (range 8.6-13.6) years. One hundred and sixty-one
patients consented to a late angiographic restudy after a mean interval of 7.4
(range 1-12.2) years. RESULTS: At 5 and 10 years, 89 and 72% of the patients were
still alive. At 10 years 82% are still asymptomatic and 71% free of any type of
ischaemia. Only four patients (0.8%) needed a repeat surgical revascularization,
and 11 (2.3%) a percutaneous coronary angioplasty. At 5 and 10 years, 92.8 and
69% of the patients remained free of any cardiac event. Overall, 95.5% of the
arterial anastomoses were patent and 96.1% of the sequential ITA were patent.
There was a significant difference between the patency rate of pedicled ITA and
free ITA anastomoses: 96.3 vs. 86.5% (P=0.02). There was no difference in patency
between left ITA and right ITA anastomoses for the LAD and Cx areas. Sequential
ITA anastomoses showed excellent patency rates to all coronary vessels but the
very distal circumflex and the distal branches of right coronary artery (85%).
There was no significant difference between the patency of the proximal and the
distal sequential ITA anastomoses. The sequential anastomoses constructed in the
length tend to remain more patent than the diamond-shaped ones: 97.2 vs. 91.5%
(P=0.004). CONCLUSIONS: Sequential ITA grafting optimizes arterial
revascularization. The long-term patency is excellent, is identical to that of
single ITA grafting, and appears not much different from postoperative patency.
The need for repeat surgical and interventional revascularization has been
extremely low: 3.1% over the whole follow-up.
PMID- 10773564
TI - Results of surgery for aortic root aneurysm in patients with the Marfan syndrome.
AB - OBJECTIVE: To evaluate the results of two operations, aortic valve-sparing and
aortic root replacement, in patients with aortic root aneurysm and the Marfan
syndrome. METHODS: A retrospective review of 78 consecutive patients with aortic
root aneurysm and the Marfan syndrome according to the Gent criteria indicated
that 42 patients with normal aortic cusps had an aortic valve-sparing operation,
and 36 patients had aortic root replacement (mechanical valve in 25 patients and
biological valve in 11). The mean age was similar in both groups, but patients
who had aortic root replacement had larger aneurysms, higher grade aortic
insufficiency, worse left ventricular function and more cardiac co-morbidity than
patients who had aortic valve-sparing operations. The mean follow-up was 41+/-35
months for patients who had aortic valve-sparing, and 65+/-50 months for those
who had aortic root replacement. RESULTS: Kaplan-Meyer estimates of survival at 5
years was 100% for patients who had aortic valve-sparing, and 88+/-6% for those
who had aortic root replacement (P=0.04). Five patients who had aortic root
replacement required seven aortic root re-replacements: three for endocarditis
and four for valve failure (biological valves). There have been no reoperations
in patients who had aortic valve-sparing operations and annual Doppler
echocardiography revealed mild or no aortic insufficiency in 39 patients and
moderate aortic insufficiency in three. CONCLUSIONS: These data suggest that
aortic valve-sparing operations are safe in patients with the Marfan syndrome and
may provide better clinical outcomes than aortic root replacement. Since the size
of the aneurysm often determines the feasibility of a valve-sparing procedure, we
now recommend surgery when the diameter of the aortic root reaches 50 mm in
patients with the Marfan syndrome who have echocardiographically normal aortic
valve cusps.
PMID- 10773565
TI - Successful valve-sparing in aortic root reconstruction under endoscopic guidance.
AB - OBJECTIVE: Aortic insufficiency (AI) associated with ascending aneurysm can be
corrected by valve-sparing aortic root reconstruction ('David' reimplantation,
'Yacoub' remodeling). Intraoperative endoscopic evaluation in the aortic root may
help to clarify the procedure and to access competence of the preserved valve.
METHODS: Following cross-clamping of the ascending aorta, an endoscopy was
inserted into the proximal aortic root. Perfusion of crystalloid cardioplegia
enabled the visualization of the pressure-loaded valve in the closed position.
Conventional macroscopic evaluation would have overlooked valve prolapse because
of a release from perfusion pressure. Valve coaptation was imaged directly before
and after the valve-sparing procedure. A total of 17 patients underwent aortic
root reconstruction under endoscopic guidance. Indications of the valve-sparing
were determined with endoscopic findings. The degree of AI before and after the
surgery was evaluated by aortography and scored (0, none; 1 trivial; 2, mild; 3,
moderate; 4, severe). RESULTS: Remodeling was employed to eight patients and
reimplantation to four. The other five patients were replaced with prosthetic
valved-conduit. There was no early and late mortality. Before and after the valve
sparing surgery, grades of AI were significantly reduced. Three patients who
underwent reimplantation procedure required late valve replacement for late
progression of AI, however, none of the patients with remodeling required
reoperation. CONCLUSION: Introduction of an endoscopy successfully reduced
postoperative AI and clarified indications and limitations of valve-sparing
aortic root operations.
PMID- 10773566
TI - Mitral-valve replacement in children under 6 years of age.
AB - OBJECTIVE: In patients with congenital mitral-valve disease, reconstructive
surgery is the primary goal. However, in cases with severely dysplastic valves or
failed repair, mitral-valve replacement (MVR) is the only option. We analyzed,
retrospectively, data of 35 patients younger than 6 years of age, who underwent
MVR at our institution. METHODS: Between 1974 and 1997, 35 children underwent
MVR. The ages ranged from 2.7 months to 5.5 years (mean=1. 9+/-1.7 years) and
body weight varied between 3.2 and 16.7 kg (mean=8.2+/-4 kg). The main indication
(57%) for valve replacement was severe mitral-valve insufficiency. Eighteen
patients (51%) had undergone at least one previous reconstructive operation
(mean=1. 46+/-1.86 years) before the MVR. In 29 cases (83%), mechanical
prostheses were implanted. Six patients received a bioprosthesis. The size of the
prostheses ranged between 14 and 27 mm. RESULTS: The overall hospital mortality
was 17.1% (6/35), and decreased from 33 (1974-1985) to 11.5% (1986-1997). Seven
children died late. The actuarial survival after 20 years was 51.2+/-13.3%. Eight
patients (23%) required 10 reoperations (8.2%/100 patient-years). Freedom from
reoperation at 10 years was 50+/-22%. Valve-related complications were thrombo
embolism (n=2; 1.6%/100 patient-years), hemorrhage (n=1; 0.8%/100 patient-years),
structural deterioration (n=3; 2.5%/100 patient-years) and non-structural
dysfunction (n=3; 2. 5%/100 patient-years). Follow-up is 96% complete, with a
total of 122 patient-years (mean=4.2+/-4.7 years). Eighty six percent of the
patients are in New York Heart Association (NYHA) class I, 95% have sinus rhythm
and 59% do not need medication. All survivors, except for those who received a
bioprosthesis, were placed on a regimen of Phenprocoumon (Marcumar((R))), aiming
to maintain the International Normalized Ratio (INR) between 2.5 and 3.5. In one
third of these children, self-management of oral anticoagulation was performed
either by the patients or their parents. CONCLUSIONS: MVR in small children still
carries a high risk. In our experience, the long-term results are satisfying.
After failed reconstructive surgery, or as a primary procedure, we prefer
mechanical prostheses. They are well tolerated and the incidence of
anticoagulation-related complications is low.
PMID- 10773567
TI - Biological versus prosthetic ring in mitral-valve repair: enhancement of mitral
annulus dynamics and left-ventricular function with pericardial annuloplasty at
long term.
AB - OBJECTIVE: The effects of different annuloplasty rings on mitral annulus dynamics
and left-ventricular (LV) function after mitral-valve repair (MVR) are still
controversial. This study sought to compare biological versus prosthetic rigid
rings for annular remodelling in MVR at long term. METHODS: Forty-four
consecutive patients were retrospectively enrolled. All patients had isolated
posterior-leaflet prolapse and underwent identical surgical mitral-valve
reconstruction (quadrangular resection of the posterior leaflet associated with
annuloplasty). Twenty-three patients underwent mitral annuloplasty with an
autologous pericardial ring (group I), whereas 21 patients had MVR with a
Carpentier-Edwards rigid ring (group II). No differences existed between the
groups in terms of pre-operative patient profile. Post-operative LV systolic
indices have been assessed by two-dimensional echocardiography at rest and during
supine bicycle exercise. Mitral annular motion has been examined by means of the
extent of mitral annulus systolic excursion (MASE), as measured in four
longitudinal LV segments (anterior, inferior, septal and lateral). Mean and peak
trans-mitral flow velocities (TMFV) have been also evaluated by continuous-wave
Doppler. RESULTS: The mean follow-up did not differ between the groups, those
being 41+/-12 months in group I (range17-65 months) and 46+/-15 months in group
II (range 23-83 months), respectively. Post-operative echocardiographic study did
not show significant mitral regurgitation at rest or at peak exercise in any
patient. ANOVA analysis for repeated measures showed a significant interaction in
peak TMFV (F((1,42))=5.23; P=0.03), and in left-ventricular ejection fraction
(LVEF; F((1,42))=7.61, P=0.01). The analysis of contrasts showed a significant
increase in TMFV in both groups (group I from 1.22+/-0.22 to 1.79+/-0.32 m/s, t=
8.8, P<0.0001; and group II from 1.19+/-0.17 to 1.96+/-0.33 m/s, t=-12.8,
P<0.0001). Recruitment of LVEF reserve during exercise was observed only in group
I (from 59.5+/-6 to 65.8+/-6%, t=-3.95, P<0.005), whereas no substantial change
occurred in LV performance in group II. A trend towards better MASE at all the
studied longitudinal segments at rest and during exercise was observed in group
I. No minor or major calcifications have been observed on pericardial rings.
CONCLUSIONS: The autologous pericardium seems to be superior to rigid prosthetic
rings for annuloplasty in MVR since it provides more favourable mitral annulus
dynamics and preserves LV function during stress conditions. Effective and
durable annular remodelling with the autologous pericardium is achieved up to 6
years from surgery, with no echocardiographic sign of degeneration in the long
term. Further studies are required to compare biological versus flexible
prosthetic rings in MVR.
PMID- 10773568
TI - Polyurethane: material for the next generation of heart valve prostheses?
AB - OBJECTIVES: The prospects for a durable, athrombogenic, synthetic, flexible
leaflet heart valve are enhanced by the recent availability of novel, biostable
polyurethanes. As a forerunner to evaluation of such biostable valves, a
prototype trileaflet polyurethane valve (utilising conventional material of known
in vitro behaviour) was compared with mechanical and bioprosthetic valves for
assessment of in vivo function, durability, thromboembolic potential and
calcification. METHODS: Polyurethane (PU), ATS bileaflet mechanical, and
Carpentier-Edwards porcine (CE) valves were implanted in the mitral position of
growing sheep. Counting of high-intensity transient signals (HITS) in the carotid
arteries, echocardiographic assessment of valve function, and examination of
blood smears for platelet aggregates were undertaken during the 6-month
anticoagulant-free survival period. Valve structure and hydrodynamic performance
were assessed following elective sacrifice. RESULTS: Twenty-eight animals
survived surgery (ten ATS; ten CE; eight PU). At 6 months the mechanical valve
group (n=9) showed highest numbers of HITS (mean 40/h, P=0.01 cf. porcine
valves), and platelet aggregates (mean 62.22/standard field), but no
thromboembolism, and no structural or functional change. The bioprosthetic group
(n=6) showed low HITS (1/h) and fewer aggregates (41.67, P=1.00, not
significant), calcification and severe pannus overgrowth with progressive
stenosis. The PU valves (n=8) showed a small degree of fibrin attachment to
leaflet surfaces, no pannus overgrowth, little change in haemodynamic
performance, low levels of HITS (5/h) and platelet aggregates (17.50, P<0.01 cf.
mechanical valves, P=0.23 cf. porcine valves), and no evidence of
thromboembolism. CONCLUSIONS: In the absence of valve-related death and
morbidity, and retention of good haemodynamic function, the PU valve was superior
to the bioprosthesis; lower HITS and aggregate counts in the PU valve imply lower
thrombogenicity compared with the mechanical valve. A biostable polyurethane
valve could offer clinical advantage with the promise of improved durability (cf.
bioprostheses) and low thrombogenicity (cf. mechanical valves).
PMID- 10773569
TI - Tissue engineering in cardiovascular surgery: new approach to develop completely
human autologous tissue.
AB - OBJECTIVE: In cardiovascular tissue engineering, three-dimensional scaffolds
serve as physical supports and templates for cell attachment and tissue
development. Currently used scaffolds are still far from ideal, they are
potentially immunogenic and they show toxic degradation and inflammatory
reactions. The aim of this study is to develop a new method for a three
dimensional completely autologous human tissue without using any scaffold
materials. METHODS: Human aortic tissue is harvested from the ascending aorta in
the operation room and worked up to pure human myofibroblasts cultures. These
human aortic myofibroblasts cultures (1.5x10(6) cells, passage 3) were seeded
into 15-cm culture dishes. Cells were cultured with Dulbecco' s modified Eagle's
medium supplemented with 1 mM L-ascorbic acid 2-phosphate for 4 weeks to form
myofibroblast sheets. The harvested cell sheets were folded to form four-layer
sheets. The folded sheets were then framed up and cultured for another 4 weeks.
Tissue development was evaluated by biochemical assay and light and electron
microscopy. RESULTS: After 4 weeks of culture in ascorbic acid supplemented
medium, myofibroblasts formed thin cell sheets in culture dishes. The cell sheets
presented in a multi-layered pattern surrounded by extracellular matrices.
Cultured for additional 4 weeks on the frames, the folded sheets further
developed into more solid and flexible tissues. Light microscopy documented a
structure resembling to a native tissue with confluent extracellular matrix.
Under transmission electron microscope, viable cells and confluent bundles of
striated mature collagen fibers were observed. Hydroxyproline assays showed
significant increase of collagen content after culturing on the frames and were
80.5% of that of natural human pericardium. CONCLUSIONS: Improved cell culture
technique may render human aortic myofibroblasts to a native tissue-like
structure. A three-dimensional completely autologous human tissue may be further
developed on the base of this structure with no show toxic degradation or
inflammatory reactions.
PMID- 10773570
TI - Twenty years experience with pediatric pacing: epicardial and transvenous
stimulation.
AB - OBJECTIVE: Permanent cardiac pacing in children and adolescents is rare and often
occurs by means of epicardial pacing. Based on two decades of experience,
operative and postoperative data of patients with epicardial and transvenous
pacing were analyzed retrospectively. METHODS: Between October 1979 and December
1998, 71 patients (mean age, 5.3+/-4.2, range, 1 day-16.2 years; mean body
weight, 18+/-12; range, 8-56 kg) underwent permanent pacemaker implantation.
Indications were sinus node dysfunction and atrio-ventricular block following
surgery for congenital heart disease (69%), or congenital atrioventricular block
(31%). Pacing was purely atrial (1.4%), purely ventricular (73%), ventricular
with atrial synchronization (5. 6%), or atrioventricular synchronized (20%).
Epicardial pacing was established in 49 (69%), transvenous in 22 (31%) patients.
Follow-up was 3.4+/-3.8 years (epicardial) and 3.0+/-4.0 years (transvenous).
RESULTS: Epicardial leads were implanted in younger patients (mean age: 4.5 vs.
7.0 years, P<0.05) and preferably after surgery induced atrioventricular block
(78 vs. 46%, P<0.05). The youngest patient with transvenous pacing was 1.3 years
old (weight, 8.5 kg). At implantation epicardial ventricular stimulation
threshold at 1.0 ms was 1.07+/-0.46 vs. 0.53+/-0.31 V (transvenous) (P<0.05). The
age-adjusted rate of lead-related reoperations was significantly higher in
patients with epicardial leads (P<0.05), mainly due to increasing chronic
stimulation thresholds resulting in early battery depletion. In three patients
who received steroid-eluting epicardial leads initial low thresholds persisted
after five month to one years. In two patients with recurrent epicardial
threshold increase, steroid-eluting epicardial leads led to good acute and
chronic thresholds after nine to 15 month. Two post-operative death (2.8%) were
probably due to a dysfunction of the (epicardial) pacing system. CONCLUSIONS:
Transvenous pacing in the pediatric population is associated with a lower acute
stimulation threshold and a lower rate of lead-related complications. If
epicardial pacing is necessary (e. g. small body weight, special intracardiac
anatomy (e.g. Fontan), impossible access to superior caval vein), steroid-eluting
leads may be considered.
PMID- 10773571
TI - Bilateral antegrade selective cerebral perfusion during surgery on the proximal
thoracic aorta.
AB - OBJECTIVE: To assess risk factors for hospital death and neurologic outcome after
surgery on the proximal thoracic aorta using moderate hypothermic circulatory
arrest and bilateral antegrade selective cerebral perfusion. METHODS: From
October 1995 through June 1999, 163 patients with a mean age of 63+/-11 years
underwent surgery using bilateral antegrade selective cerebral perfusion.
Degenerative aneurysms (55%) and acute type A dissection (28%) were the
predominant indications for operation. Forty-six (28%) operations were considered
as emergency procedure. Twenty-four (15%) procedures were reoperations. RESULTS:
Mean ASCP time was 48+/-20 min. Hospital mortality was 8.6% (n=14; 70% confidence
limit (CL): 6.4-10.8%). Univariate risk factors for hospital mortality were acute
type A dissection (P=0.003), central neurologic damage <24 h before the operation
(P=0.000), preoperative hemodynamic instability (P=0.034), and rethoracotomy for
any cause (P=0.036). Logistic regression analysis identified central neurologic
damage <24 h (P=0.006, odds ratio 14) as an independent risk factor. Temporary
neurologic damage occurred in 3.8% (n=6; 70% CL: 2.3-5.3%) of patients. Logistic
regression analysis indicated preoperative hemodynamic instability (P=0.003, odds
ratio 13) as an independent risk factor. Perioperative permanent central
neurologic damage was reported in another 3.8% (n=6; 70% CL: 2.3-5.3%) patients.
Acute type A dissection (P=0.018, odds ratio 8) and the non-use of a midline
sternotomy (P=0.049, odds ratio 8) were retained as independent risk factors.
CONCLUSION: Hospital mortality and perioperative neurologic complications are not
significantly influenced by the duration of antegrade selective cerebral
perfusion. Overall complication rate is low.
PMID- 10773572
TI - Effect of impaired vasa vasorum flow on the structure and mechanics of the
thoracic aorta: implications for the pathogenesis of aortic dissection.
AB - OBJECTIVE: To investigate the alterations of structure and mechanical properties
of the aortic wall, resulting from impairment of vasa vasorum flow. METHODS:
Eight healthy Landrace pigs were subjected to interruption of vasa vasorum flow
to the upper segment of their descending thoracic aorta. Under sterile
conditions, the periaortic tissue was excised and the contiguous intercostal
arteries were ligated. Ten sham-operated pigs were used as controls. Fifteen days
postoperatively, the animals were sacrificed and their upper descending thoracic
aortas were removed. Histology, and collagen and elastin content determination by
image analysis technique were performed. Mechanical analysis of aortic strips was
carried out with a uniaxial tension device and stress-strain curves were
obtained. RESULTS: In contrast to normal aortic walls of the control group,
histology of the avascular aortas revealed severe ischemic necrosis of the outer
media along with abnormal straightening of the elastin and collagen fibers,
without significant collagen and elastin content changes. The borderline between
the outer ischemic and inner non-ischemic media was sharp, and an outset of
dissection was observed at this point. Mechanical analysis showed that at the
same level of strain, the ischemic aorta was significantly stiffer at both low
(P=0.03) and high strains (P=0. 003). CONCLUSIONS: Impairment of blood supply to
the thoracic aorta leads to abnormal morphology of elastin and collagen fibers of
the outer media, resulting in increased aortic stiffness under a wide range of
stresses. In the clinical setting, decreased vasa vasorum flow, reportedly
occurring in arterial hypertension, may increase the stiffness of the outer media
of the thoracic aorta and produce interlaminar shear stresses, contributing to
the development of aortic dissection.
PMID- 10773573
TI - Heterotopic heart transplantation: experimental development and clinical
experience.
AB - Heterotopic heart transplantation was initially developed in the laboratory for
experimental transplantation. While it was more widely utilized in the pre
cyclosporine era to provide adjunct circulatory support in combination with the
native heart, associated complications as well as improved long-term graft
survival have now established orthotopic transplantation as the procedure of
choice. Heterotopic heart transplantation is currently reserved for highly
selected patients. The technique is only performed at selected transplantation
centers, and indications include significant donor recipient size mismatch or
irreversible recipient pulmonary hypertension. The foreseeable introduction of
clinical porcine xenotransplantation may lead to renewed interest in the
technique of heterotopic heart transplantation as a bridge to potential native
heart recovery or allotransplantation in selected patients.
PMID- 10773574
TI - Novel application of vacuum assisted closure technique to the treatment of
sternotomy wound infection.
AB - Infection of the sternotomy wound is a potentially devastating and sometimes
lethal complication following cardiac surgery. Established treatment may involve
a combination of debridement, packing, delayed closure, plastic reconstruction,
re-wiring and irrigation dependent on the severity of infection. Vacuum assisted
closure, originally adopted for the treatment of non-healing wounds, has recently
gained popularity among various surgical specialities in managing complex wound
infection. Here we describe this novel technique of managing postoperative
sternal wound infection.
PMID- 10773575
TI - Transabdominal mimially invasive direct coronary artery bypass grafting (MIDCAB).
AB - The major limitations of current minimally invasive direct coronary artery bypass
(MIDCAB) techniques are multivessel and distal vessel disease frequently seen in
patients with extensive stent restenosis ('full metal jacket syndrome') and
reoperative surgery. Two separate minimal access incisions (minithoracotomy,
lower partial sternotomy) have been used to bypass two separate arteries (left
internal mammary artery (LIMA) to left anterior descending (LAD), right
gastroepiploic artery (RGEA) to posterior descending artery (PDA)). To bypass
multiple coronary arteries using multiple arterial conduits without violation of
bony parts, we use a new minimal access incision by 'transabdominal approach'.
PMID- 10773576
TI - Surgical management of idiopathic subglottic tracheal stenosis.
AB - A case of idiopathic subglottic tracheal stenosis in a 50-year-old female is
presented. A procedure of single-stage resection of the lesion and end-to-end
anastomosis was performed with excellent results 1 year after the operation. The
clinical, paraclinical, diagnostic, therapeutic and histopathological aspects of
this rare pathologic condition are discussed and the literature on this topic is
reviewed.
PMID- 10773577
TI - Acute ischemic hepatic failure resulting from intraaortic balloon pump
malposition.
AB - We describe a rare intraaortic balloon pump (IABP) vascular complication as a
result of malpositioning of the IABP. A 61-year-old man with unstable angina
underwent emergency coronary artery bypass grafting soon after the insertion of
an IABP. Postoperative hemodynamics were stable, but acute hepatic dysfunction
occurred on the second postoperative day. Doppler echography revealed the absence
of hepatic arterial flow. The IABP was removed, and arterial flow was immediately
restored. Thereafter, the hepatic function recovered rapidly. This is a rare case
that demonstrates how IABP can cause mechanical abdominal arterial branch
obstruction. Evaluations using Doppler echography are useful in detecting such
IABP complications.
PMID- 10773578
TI - Combined repair of pectus excavatum and coronary artery bypass grafting.
AB - Coronary artery bypass grafting (CABG) in patients with severe pectus excavatum
is a surgical challenge. A two-stage correction of sternal deformities and
cardiac lesions has been described and myocardial revascularization through a
left lateral thoracotomy is a valid alternative in urgent situations. We report a
one-stage repair of severe pectus excavatum and CABG with the use of bilateral
internal thoracic arteries in a young patient requiring urgent myocardial
revascularization. The technical aspects and operative consideration are
discussed.
PMID- 10773579
TI - Gap junctions and biophysical regulation of bone cell differentiation.
AB - Physical signals, in particular mechanical loading, are clearly important
regulators of bone turnover. Indeed, the structural success of the skeleton is
due in large part to the bone's capacity to recognize some aspect of its
functional environment as a stimulus for achievement and retention of a
structurally adequate morphology. However, while the skeleton's ability to
respond to its mechanical environment is widely accepted, identification of a
reasonable mechanism through which a mechanical "load" could be transformed to a
signal relevant to the bone cell population has been elusive. In addition, the
downstream response of bone cells to load-induced signals is unclear. In this
work, we review evidence suggesting that gap junctional intercellular
communication (GJIC) contributes to mechanotransduction in bone and, in so doing,
contributes to the regulation of bone cell differentiation by biophysical
signals. In this context, mechanotransduction is defined as transduction of a
load-induced biophysical signal, such as fluid flow, substrate deformation, or
electrokinetic effects, to a cell and ultimately throughout a cellular network.
Thus, mechanotransduction would include interactions of extracellular signals
with cellular membranes, generation of intracellular second messengers, and the
propagation of these messengers, or signals they induce, through a cellular
network. We propose that gap junctions contribute largely to the propagation of
intracellular signals.
PMID- 10773580
TI - Preliminary evidence for impaired estrogen receptor-alpha protein expression in
osteoblasts and osteocytes from men with idiopathic osteoporosis.
AB - Although osteoporosis is usually associated with women, 1 in 12 men in the UK
have the disease, and a third of these cases are idiopathic. Estrogen is now
known to be associated with bone loss in older men, but we found, previously,
that levels of this hormone were normal in younger cases of male idiopathic
osteoporosis (MIO) in the age range 33-61 years. We therefore hypothesized that
their estrogen responses in bone might be defective, through impaired estrogen
receptor-alpha (ER)-alpha expression. Consequently, in the present study, we
compared expression of ER-alpha by indirect immunofluorescence, semiquantitative
image analysis, and in situ reverse transcription-polymerase chain reaction in
bone sections from MIO patients (33-56 years) (N = 7); age-matched control men (N
= 7); and, for reference, ovarian steroid (OS)-replete (N = 7) and OS-deficient
women (N = 6). In the control men, 23 +/- 6% (mean +/- SEM) of osteoblasts and 14
+/- 2% of osteocytes expressed ER-alpha protein, similar to OS-replete women.
Although receptor expression decreased in OS-deficient women, the loss of ER
alpha protein in MIO patients was more severe (1 +/- 0.5% osteocytes, 2 +/- 1%
osteoblasts expressed receptor); however, ER-alpha messenger RNA (mRNA) was still
expressed in controls and MIO patients. Bone loss in these patients may be due to
deficient ER-alpha protein expression.
PMID- 10773581
TI - Endogenous parathyroid hormone-related peptide enhances proliferation and
inhibits differentiation in the osteoblast-like cell line ROS 17/2.8.
AB - To investigate potential effects of endogenous parathyroid hormone-related
peptide (PTHrP) on osteoblast function, ROS 17/2.8 cells were transfected with
full-length PTHrP cDNA in a sense or antisense orientation to alter PTHrP
production. Compared with vector-transfected control cells, PTHrP-overproducing
(sense-transfected) cells showed increased DNA synthesis ([(3)H]-thymidine
incorporation) and increased growth (cell number). The extent of apoptosis was
compared for the different clones using the terminal deoxynucleotide-mediated
dUTP nick-end-labeling assay (TUNEL) and Hoechst staining. No differences in
percentages of apoptotic cells were found under basal culture conditions or after
3 days of serum deprivation, which, itself, markedly increased numbers of
apoptotic cells. The effect of PTHrP on osteoblast differentiation was assessed
by examining two protein markers of differentiation, alkaline phosphatase, and
bone morphogenetic protein (BMP)-2. Alkaline phosphatase activity was decreased
in sense-transfected cells and increased in antisense-transfected cells, compared
with cells transfected with empty vector. PTHrP-overproducing cells also showed
decreased numbers of BMP-2-positive cells, whereas antisense-transfected cells
showed no difference compared with vector control. The results indicate that: (a)
endogenously produced PTHrP can increase growth of these osteoblastic cells by
stimulating proliferation while not affecting apoptosis; and (b) the increased
cell proliferation produced by PTHrP was accompanied by a reduction in activity
or amount of two proteins normally expressed by differentiated osteoblasts.
PMID- 10773582
TI - Parathyroid hormone-related protein analog RS-66271 is an effective therapy for
impaired bone healing in rabbits on corticosteroid therapy.
AB - A new class of parathyroid hormone-related protein (PTHrP) analogs has been
developed that causes a rapid gain in both trabecular and cortical bone in models
of osteopenia. This study investigates the efficacy of the PTHrP analog, RS-66271
([MAP(1-10)]22-31 hPTHrP(1-34)-NH(2)), as systemic therapy for impaired bone
healing in corticosteroid-treated rabbits. A 1 mm defect was created bilaterally
in the ulnae of 30 rabbits. Delayed healing was induced by daily injections of
prednisone (0.15 mg/kg) beginning 2 months prior to surgery and continuing until
killing. Rabbits in the experimental group received daily subcutaneous injections
of PTHrP analog RS-66271 (0.01 mg/kg) starting 1 day after surgery. Control
animals received subcutaneous normal saline. At the 6 week timepoint, nine of ten
ulnae from PTHrP-treated rabbits achieved radiographic union, whereas only two of
ten limbs achieved union in control rabbits (p < 0.01). In a separate part of the
study, 20 animals (10 control, 10 RS-66271-treated) were killed when radiographic
union was achieved bilaterally. In this portion of the study, all limbs in
animals treated with PTHrP achieved union by 6 weeks. In the control animals that
were allowed to heal for 10 weeks, only 20% of the limbs achieved radiographic
union. In addition, ulnae in the PTHrP-analog-treated rabbits showed greater
radiographic intensity (20%-40%), larger callus area (209% anteroposterior view,
417% lateral view) (mean area on AP radiographs: control, = 387 +/- 276 mm(2);
PTHrP analog, 1195 +/- 408 mm(2)), and greater stiffness (64%) and torque (87%)
when compared with controls. RS-66271 was shown to be an effective therapy for
preventing impaired bone healing caused by prednisone in a rabbit model.
PMID- 10773583
TI - Osteoprotegerin mitigates tail suspension-induced osteopenia.
AB - Osteoprotegerin (OPG) is a recently discovered protein related to the tumor
necrosis factor receptor family. It has been shown to inhibit ovariectomy (ovx)
induced resorption in rats and increase bone mineral density in young mice. Tail
suspension is a procedure that inhibits bone formation in maturing rodents. This
study was designed to quantify OPG's effect on cortical bone formation. Fifty
four mice were assigned to one of five groups (n = 10-11/group). A baseline
control group was killed on day 0 of the 10 day study. The remaining groups were:
vivarium housed (nonsuspended) control mice receiving 0.3 mg/kg per day OPG;
vivarium control mice receiving daily placebo injections; tail-suspended mice
receiving 0. 3 mg/kg per day OPG; and tail-suspended mice receiving placebo
injections. Tetracycline was administered on days 0 and 8. OPG treatment of tail
suspended mice produced mechanical properties similar to those of placebo
treated, vivarium-housed mice: structural stiffness (8.5%, 20.7%) and elastic
(13.9%, 10.1%) and maximum (4.7%, 8.1%) force were increased compared with
placebo controls (vivarium, suspended groups). Percent mineral composition was
highly significantly greater (p < 0.001 for all comparisons) for OPG-treated mice
in the femur, tibia, and humerus, relative to placebo treatment. Matrix mass was
also significantly increased in the femur, although not to the same degree as
mineral mass. OPG decreased the amount of femoral endocortical resorption
compared with the placebo-treated groups for both vivarium (27%) and suspended
(24%) mice. Administration of OPG significantly decreased endocortical formation
of the tibia. Periosteal bone formation rates were not altered by OPG. OPG
mitigated tail suspension induced osteopenia not by returning bone formation to
normal levels, but by inhibiting resorption and increasing percent mineral
composition.
PMID- 10773584
TI - A peptidyl derivative structurally based on the inhibitory center of cystatin C
inhibits bone resorption in vitro.
AB - Human cystatin C is a cysteine proteinase inhibitor belonging to the cystatin
superfamily, which previously has been shown to inhibit bone resorption in bone
organ culture. The aminoterminal segment, Arg(8)-Leu(9)-Val(10)-Gly(11) (RLVG),
of the single polypeptide chain of cystatin C constitutes an essential part of
its inhibitory center. In the present study, the effect of benzyloxycarbonyl
Arg(8)-Leu(9)-Val(10)-Gly(11)-diazomethane (Z-RLVG-CHN(2)) on bone resorption in
vitro was compared with the effects of cystatin C and calcitonin. Bone resorption
was assessed by the release of (45)Ca and (3)H from mouse calvarial bones
prelabeled with [(45)Ca]CaCl(2) and [(3)H]-proline, respectively. Z-RLVG-CHN(2)
concentration-dependently inhibited the release of (45)Ca and (3)H in bones
stimulated by parathyroid hormone (PTH), with half-maximal inhibition obtained at
1 micromol/L. The inhibitory actions of Z-RLVG-CHN(2) and cystatin C were
persistent, whereas action induced initially by calcitonin was lost with time.
The inhibition caused by Z-RLVG-CHN(2) and cystatin C on PTH-stimulated (45)Ca
release was observed after 6 h, whereas inhibition by calcitonin was seen already
after 2 h. In contrast, the inhibitory effects of Z-RLVG-CHN(2) and cystatin C,
as well as that of calcitonin, on (3)H release was seen already after 2 h. Z-RLVG
CHN(2), in which the reactive carboxyterminal diazomethane was substituted by
nonreactive groups [-OH, -NH(2), or -N(CH(3))(2)], resulted in peptidyl
derivatives, which, in contrast to Z-RLVG-CHN(2) and cystatin C, inhibited
neither cysteine proteinases nor bone resorption. In contrast to wild-type
cystatin C, recombinant human cystatin C with Gly substitutions for residues
Arg(8), Leu(9), Val(10), and Trp(106), and with low or nonexistent affinity for
cysteine proteinases, did not display any inhibitory effect on bone resorption.
These data strongly indicate that Z-RLVG-CHN(2) inhibits bone resorption in vitro
by a mechanism that seems primarily to be due to an inhibition of bone matrix
degradation via cysteine proteinases. The data also corroborate the hypothesis
that cystatin C inhibits bone resorption by virtue of its cysteine proteinase
inhibitory capacity.
PMID- 10773585
TI - Unbiased determination of cytokine localization in bone: colocalization of
interleukin-6 with osteoblasts in serial sections from monkey vertebrae.
AB - Few data are available describing the in vivo localization of cytokines in bone.
The objective of this study was to describe the histological localization of
interleukin-6 (IL-6) relative to osteoblasts (alkaline phosphate [ALP]-positive
cells) and osteoclasts (tartrate-resistant acid phosphate [TRAP]-positive cells)
in midsagittal, paraffin-embedded serial sections of thoracic 13 (T-13) vertebrae
from 49 female cynomolgus monkeys. Serial sections 1 and 4 were immunostained for
IL-6, section 2 was histochemically stained for TRAP, and section 3 was
immunostained for ALP. Sixteen centrally located fields were measured in the
cancellous compartment and grid alignment among sections was verified using image
analysis. Using a Merz grid, IL-6 localized to 6% of the bone surface on sections
1 and 4, whereas TRAP localized to 8.5% and ALP to 12% of the bone surface.
Colocalization was defined as positive staining within an 80 x 80 microm block in
the first serial section that "overlapped" staining in either the corresponding
block or its eight surrounding blocks within the second serial section. For each
section, 1600 blocks were analyzed. Using Monte Carlo simulations, random
colocalization was calculated to determine the statistical significance of
experimental colocalizations. Colocalization of approximately 90% between the two
IL-6 sections verified staining reproducibility and proper grid alignment among
sections. Colocalization of TRAP and ALP was not statistically different from
random (p 0.3). As identified using ALP- or TRAP-positive surfaces, there was
significant IL-6 colocalization with osteoblasts (p < 0.003), but not with
osteoclasts (p 0.3). These in vivo colocalization data support the hypothesis
that osteoblasts produce and respond to IL-6.
PMID- 10773586
TI - Interleukin-6 modulates trabecular and endochondral bone turnover in the nude
mouse by stimulating osteoclast differentiation.
AB - A great deal of evidence has been accumulating that implicates the immune system
in normal and pathological bone turnover. The objective of the present study was
to examine the possible involvement of cytokines produced by T lymphocytes in
bone metabolism. We have chosen the immunologically compromised athymic mouse,
which demonstrate sclerotic features in its trabecular bone, as the animal model
for assessment of possible modulation effects of interleukin-1alpha (IL-1alpha)
and interleukin-6 (IL-6) on bone and cartilage metabolism. The cytokines were
applied by daily subcutaneous injections for 3 consecutive days.
Histomorphometry, measuring epiphyseal trabecular bone volume (ETBV), metaphyseal
trabecular bone volume (MTBV), and the width of the growth plate, and tartrate
resistant acid phosphatase (TRAP) histochemistry were used to assess parameters
of bone turnover in the proximal tibia. IL-6, but not IL-1alpha, reduced ETBV and
MTBV. Both IL-6 and IL-1alpha reduced the width of the growth plate. IL-6, but
not IL-1alpha, increased the number of chondroclasts and osteoclasts in the
primary spongiosa of the proximal tibia, as well as the number of nuclei. The
resultant bone resembled that of the wild-type mouse. The results point to IL-6
as a possible regulator of bone turnover in vivo. It is suggested that the
athymic mouse has a deficiency somewhere in the cascade of events leading to the
production of IL-6 or, alternatively, that IL-6 replaces other factors that are
supplied by T lymphocytes directly or indirectly. As T lymphocytes interact with
B lymphocytes it is suggested that the athymic mouse might be appropriate for
studying the in vivo effects of the immune system on normal bone metabolism.
PMID- 10773587
TI - Association between histomorphometry and biochemical markers of bone turnover in
a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated
tumor osteolysis.
AB - Advanced tumor osteopathy is characterized by abnormal bone turnover. Using a rat
model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis,
the aim of the present study was to define the sequential changes in, and the
association between, biochemical and histomorphometric indices of bone metabolism
during the early stages of developing tumor osteopathy. Eight-month-old Wistar
rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the
Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or
the bisphosphonate ibandronate until killing on day 8. Serum calcium (sCa),
alkaline phosphatase (sTAP), and osteocalcin (sOC) and urinary calcium (uCa),
deoxypyridinoline (uDPD), and pyridinoline (uPYD) were measured daily. In a
second semilongitudinal experiment (n = 70), the number of osteoclasts and
osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume
(O.Ar) were assessed by histomorphometry. In untreated tumor-bearing animals,
osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2),
p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8
+/- 1.2%, p < 0.05). Both time course and magnitude of these changes were closely
reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0. 31 +/- 0.15 nmol/12 h, p <
0.05) and uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h, p < 0.05), sCa
(3.8 +/- 0.52 vs. 3.0 +/- 0. 13 mmol/L, p < 0.01), and uCa (0.13 +/- 0.08 vs.
0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/-
40 U/L, p < 0.001) on day 7 (mean +/- SD), whereas sOC remained unchanged until
day 8. When combining the results of the two experiments, a high correlation was
found between the number of osteoclasts and the urinary excretion of PYD (r =
0.91) and DPD (r = 0.89). Treatment with ibandronate delayed hypercalcemia,
abolished hypercalciuria, and accelerated bone resorption. We conclude that
osteoclast activation is an early event in PTHrP-mediated osteolysis, which is
closely reflected by the renal excretion of pyridinium cross-links of type I
collagen. Therefore, specific biochemical markers of collagen breakdown may be
useful as early indicators of developing tumor osteopathy.
PMID- 10773588
TI - Influence of mature adipocytes on osteoblast proliferation in human primary
cocultures.
AB - It has been shown that the bone loss occurring with aging in spongy bone is
associated with a reduced osteoblastic bone formation and an increased volume of
marrow adipose tissue. This observation suggests a relationship between cells
from the osteoblastic and adipogenic lineages. The purpose of the present study
was to evaluate the influence of mature adipocytes on osteoblastic proliferation
and activity in a model of coculture. Human primary osteoblastic (hBOB) cells
were derived from femoral bone explants collected in patients undergoing
orthopedic surgery. Human stromal osteoblastic (hMSOB) cells were obtained from
bone marrow samples collected by aspiration during orthopedic surgery.
Extramedullary and medullary mature adipocytes (hAd) showing similar functions,
except for their response to insulin, hAd were isolated from mammary adipose
tissue collected in women undergoing tumorectomy. Cells were cocultured, with hAd
being separated from osteoblastic cells (hBOB or hMSOB) by a porous membrane (0.4
microm). When hBOB cells were seeded on the upper side of the insert and hAd were
floating on the lower side, cell contacts between the two cell types were
possible through the pores of the membrane. At the end of the experiment,
proliferation of the osteoblastic cells was evaluated by [(3)H]-thymidine
incorporation and alkaline phosphatase (AP) activity was measured. After 20 h of
coculture, proliferation of the hBOB cells was significantly decreased when
compared with control hBOB (-40 +/- 6%, p < 0.05). To establish whether or not
the influence of hAd on hBOB proliferation required intercellular communications,
hAd and hBOB cells were cocultured far from the porous membrane. Six other
independent experiments confirmed an inhibition of hBOB proliferation under both
experimental conditions (p < 0.05): -35 +/- 7% with possible intercellular
contacts, and -30 +/- 7% without any contact. In contrast, the proliferation of
hMSOB cells was not significantly modified after coculture with hAd. In addition,
the presence of hAd did not significantly modify the AP activity of hBOB (0.163
+/- 0.143 and 0.181 +/- 0.114 nmol/min per microgram of protein in controls and
after coculture, respectively). No reproducible effect of hAd-conditioned medium
was noted on hBOB- and hMSOB-cell proliferation or hBOB-cell activity. In
conclusion, mature adipocytes induced an inhibition of hBOB-cells proliferation,
probably mediated by a factor secreted by hAd. This effect may contribute to the
age-related reduction of bone formation and bone loss.
PMID- 10773589
TI - In vivo bone metabolism and ex vivo bone marrow osteoprogenitors in vitamin D
deprived pigs.
AB - Vitamin D insufficiency is still a concern in countries where there is no routine
food supplementation, such as France. A low vitamin D status is clearly
associated with an increased risk of fracture in the elderly, but the long-term
consequences of latent vitamin D insufficiency in young people and adults are not
known. We fed 26 growing pigs a high calcium diet (1.1%) with a 1000 IU
cholecalciferol/kg diet (controls), or without vitamin D (0D) for 4 months. We
then analyzed the overall impact of low vitamin D status on osteotropic hormones
(calcitriol and immunoreactive parathyroid hormone), plasma markers of bone
remodeling (alkaline phosphatase [ALP] activity, carboxyterminal propeptide of
type I procollagen [PICP], osteocalcin, hydroxyproline), whole bone parameters
(ash content, bending moment), histomorphometry, and the populations of marrow
osteoblastic and osteoclastic precursors by ex vivo cultures. The fall in plasma
25-dihydroxyvitamin [25(OH)D] in the 0D pigs indicated severe depletion of their
vitamin D stores. However, they remained normocalcemic, were mildly
hyperparathyroid after 2 months of vitamin D deprivation, and showed only a
slight decrease in plasma calcitriol. The bone mineral content and bending moment
of metatarsals decreased and they had increased osteoblastic (+59%, p < 0.05 0D
vs. controls) and osteoclastic (+31%, p < 0.1 0D vs. controls) surfaces. This was
not paralleled by increased bone turnover, because plasma hydroxyproline and ALP
were unchanged and PICP and osteocalcin were decreased. The adherent fraction of
bone marrow cells showed a great increase in the number of total stromal colony
forming units (CFU-F; +93%, p < 0.05 0D vs. controls) and in the percent of
ALP(+) CFU-F (+58%, p < 0.01 0D vs. controls) in cultures from 0D pigs. More
tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated cells were
generated in cultures of nonadherent marrow cells from 0D pigs, and the area of
resorption was 345% greater than in controls. Thus, vitamin D deprivation caused
only moderate hormonal changes in growing pigs fed a high-calcium diet, but
affected their bone characteristics and greatly enhanced the pool of osteoblasts
and osteoclasts by stimulating the commitment of their precursors in bone marrow.
PMID- 10773590
TI - Fracture toughness of human femoral neck: effect of microstructure, composition,
and age.
AB - The effects of porosity and pore size; osteonal area, size, and density; mineral
content; water content; wet and dry apparent densities; and age on mode I
(tensile) and mode II (shear) strain energy release rate were investigated for
femoral neck cortical bone from human cadavers aged >/=50 years. The results
suggest that porosity- and density-based parameters that are related to bone
quantity are more consistently determinant for femoral neck fracture toughness
than morphology-based parameters that are related to microstructural
organization. Bone features examined here were more explanatory for shear than
tension fracture toughness. Tension and shear fracture toughness did not change
with age, unlike in previous reports investigating the femoral and tibial shaft.
It was concluded that the femoral neck is different from the femoral and tibial
shaft in terms of its microstructure and composition and in its relationship of
fracture toughness to its constituents and age.
PMID- 10773591
TI - Serum CrossLaps for monitoring the response in individuals undergoing
antiresorptive therapy.
AB - The Serum CrossLaps (CTx) enzyme-linked immunosorbent assay (ELISA) is specific
for a cross-linked, beta-aspartate-isomerized form of the epitope EKAHDGGR
derived from the carboxyterminal telopeptide region of type I collagen alpha(1)
chain. Collagen type I fragments reactive in the CTx assay are released during
osteoclastic bone resorption and can be used as a measure of bone resorption
activity. Our objectives were to assess the intraindividual variation of serum
CTx concentration as well as the clinical value of the serum CTx assay for
monitoring antiresorptive therapy in individual patients. The influence of the
sampling time and fasting on the serum CTx measurements was studied with the aim
of determining an optimal sampling protocol. Studies of circadian variation in
serum CTx concentration in 15 postmenopausal women showed that fasting
significantly reduced the average circadian variation of the marker from 36% to
8.7%. This was further supported by assessing short-term (2 weeks)
intraindividual variation in ten postmenopausal women who were sampled in the
morning, either fasting or nonfasting. The average short-term intraindividual
coefficient of variation (CV) was 7.9% in the samples obtained from fasting
women, and 14.3% in the samples obtained from nonfasting women. The long-term
intraindividual biological variation was 13.4% in 44 postmenopausal women sampled
every 6 months (fasting morning samples) over a 1 year period. The ability of the
serum CTx assay to monitor individual responses to antiresorptive therapy was
assessed in studies of the effects of hormone replacement therapy (HRT) and
bisphosphonate (alendronate). Serum samples (morning fasting) were obtained from
postmenopausal women treated with either bisphosphonate or HRT at baseline and
then after various timepoints of therapy. Spine bone mineral density (BMD)
measurements were carried out and the annual percentage change in spine BMD
(alphaBMD) was calculated. Sixteen of 17 (94%) of the HRT-treated and 12 of 13
(92%) of the bisphosphonate-treated women showed a decrease in serum CTx after 6
months that was greater than the calculated least significant change (LSC) of the
marker (LSC(CTx)). In contrast, only 59% of the HRT-treated and 64% of the
bisphosphonate-treated women showed a response in spine BMD greater than the
LSC(BMD) 0%) from women with a loss in spine BMD (alphaBMD < 0%). In conclusion,
the serum CTx showed high specificity and sensitivity for monitoring individual
responses to antiresorptive therapy. More than 92% of the treated women showed
significant responses in serum CTx measurements after 6 months.
PMID- 10773593
TI - Speed of sound reflects Young's modulus as assessed by microstructural finite
element analysis.
AB - We analyzed the ability of the quantitative ultrasound (QUS) parameter, speed of
sound (SOS), and bone mineral density (BMD), as measured by dual-energy X-ray
absorptiometry (DXA), to predict Young's modulus, as assessed by microstructural
finite element analysis (muFEA) from microcomputed tomography (muCT)
reconstructions. With muFEA simulation, all bone elements in the model can be
assigned the same isotropic Young's modulus; therefore, in contrast to mechanical
tests, only the trabecular structure plays a role in the determination of the
elastic properties of the specimen. SOS, BMD, and microCT measurements were
performed in 15 cubes of pure trabecular bovine bone in three orthogonal
directions: anteroposterior (AP); mediolateral (ML); and craniocaudal (CC). The
anisotropy of the architecture was determined using mean intercept length (MIL)
measurements. SOS, MIL, and Young's modulus (E) values were significantly
different in all three directions (p < 0.001), with the highest values in the CC
direction. There was a strong linear relationship between E and SOS in each of
the three orthogonal directions, with r(2) being 0.88, 0.92, and 0.84 (all p <
0.0001) for the CC, ML, and AP directions, respectively. The relationship between
E and BMD was less strong, with r(2) being between 0.66 and 0.85 (all p < 0.0001)
in the different directions. There was also a significant, positive correlation
between SOS and BMD in each of the three axes (r(2) being 0.81, 0.42, and 0.92 in
the CC, ML, and AP directions, respectively; p < 0.0001). After correction for
BMD, the correlations between SOS and E in each of the three directions remained
highly significant (r(2) = 0.77, p < 0. 0001 for the AP direction; r(2) = 0.48, p
< 0.001 for the CC direction; r(2) = 0.52, p < 0.005 for the ML direction). After
correction for SOS, BMD remained significantly correlated with Young's modulus in
the AP and CC directions (r(2) = 0.52, p < 0.005; r(2) = 0.30, p < 0.05,
respectively), but the correlation in the ML direction was no longer
statistically significant. In a stepwise regression model, E was best predicted
by SOS in each of the orthogonal directions. These observations illustrate the
ability of the SOS technique to assess the architectural mechanical quality of
trabecular bone.
PMID- 10773592
TI - Bone mineral density and serum levels of aminoterminal propeptides and cross
linked N-telopeptides of type I collagen in elderly men.
AB - Serum levels of aminoterminal extension propeptides (PINP), the carboxyterminal
telopeptide (ICTP), and the cross-linked N-telopeptides (NTx) of type I collagen
were determined in 78 healthy, elderly men aged 76 +/- 5 years in 1993 and 1996
and compared with bone mineral density (BMD) measurements of their lumbar spine,
femoral neck, and total body regions made using dual X-ray absorptiometry.
Compared with 11 men who had normal lumbar spine (SBMD) and femoral neck BMD
(NBMD), 13 of the subjects with SBMD and NBMD classified as osteopenic by t-score
criterion had higher mean serum levels of PINP and alkaline phosphatase activity,
but these increases were not statistically significant at the 95% confidence
interval. In osteopenic men, a correlation between SBMD and NTx was detected (r =
-0.66, p = 0.01). Within the entire population, the serum NTx level correlated
with NBMD (r = -0.26, p < 0.05) and PINP (r = +0.63, p < 0.0001), and the change
in the circulating concentration of PINP over the 3 year interval correlated with
the magnitude of change in total body BMD (r = -0.28, p = 0.02), NBMD (r = -0.24,
p = 0.05), and SBMD (r = -0.36, p = 0. 03) as well as with the change in serum
NTx levels (r = 0.43, p < 0. 001). The change in the circulating ICTP level was
also related to the change in NBMD (r = -0.24, p = 0.01). Together, weight and
the serum PINP level accounted for 25% of total body BMD variance in elderly men.
These results indicate that larger populations of men and women should be
screened over longer time intervals to explore the value of serial measurement of
serum collagen metabolites in predicting bone loss in the spine and hip.
PMID- 10773594
TI - Ultrasound velocity and dual-energy X-ray absorptiometry in normal and pagetic
bone.
AB - Bone affected by Paget's disease is known to be dense but more prone to
fractures. It is proposed that dual-energy X-ray absorptiometry (DXA) and
quantitative ultrasound (QUS) assess different aspects of the skeletal status. In
this study, we used Paget's disease of the tibia as a model to explore this. Ten
patients with Paget's disease affecting a single tibia were investigated with the
normal side acting as the control within each individual. Tibial speed of sound
(SOS) was measured at the midpoint of the affected and control tibiae using a
Soundscan 2000 (Myriad Ultrasound System, Rehovot, Israel) device. Bone mineral
density (BMD) of the tibia was measured at a level corresponding to the site of
the tibial ultrasound using a QDR-2000+ (Hologic, Inc., Waltham, MA). The mean
bone area and estimated volume in the pagetic tibia was greater than that in the
normal tibia (bone area: 25.10 +/- 8.00 vs. 20.23 +/- 5.43 cm(2), p = 0.017;
estimated bone volume: 68.79 +/- 41.99 vs. 43.62 +/- 22.56 cm(3), p = 0.02),
reflecting the bone expansion characteristic of Paget's disease. The bone mineral
content (BMC) was more markedly increased in the pagetic tibia (27.38 +/- 12.98
vs. 14.39 +/- 6.14 g, p = 0.003) and, consequently, areal bone mineral density
(BMD) was also markedly increased in the pagetic bone (1.09 +/- 0.38 vs. 0.77 +/-
0.44 g/cm(2), p = 0.018). There was no significant difference in the estimated
volumetric BMD between the pagetic and the normal tibia (0.48 +/- 0.24 vs. 0.47
+/- 0.51 g/cm(3), p = 0.96). In contrast, the mean tibial SOS in the leg affected
by Paget's disease was significantly lower than in the unaffected leg (3228 +/-
234 vs. 3840 +/- 164 m/sec, p < 0.001). When expressed as a z score using the
normal limb as reference, areal BMD was 0.72 SD higher in the affected limb,
whereas tibial SOS was 3.72 SD lower. We conclude that tibial SOS detects
important changes in bone quality in Paget's disease of bone, which are unrelated
to calcium content.
PMID- 10773595
TI - Prediction of bone strength of distal forearm using radius bone mineral density
and phalangeal speed of sound.
AB - This investigation compares quantitative ultrasound (QUS) measurement of the
phalanges with peripheral quantitative computed tomography (pQCT) and dual X-ray
absorptiometry (DXA) measurement of the forearm, to estimate the strength of the
distal radius in 13 cadaveric forearms. The cadavers were scanned at the distal
radius by pQCT and DXA for bone mineral density (BMD) and at the approximate
phalanges by QUS for speed of sound (SOS). The distal radii were subjected to a
simulated Colles fracture produced with a materials testing machine. The load at
which the distal radius was fractured was considered as a representation of bone
strength. The bone strength correlated significantly with SOS at different
phalanges (r = 0.63-0.72), BMD at different regions of interest by DXA (r = 0.67
0.75), and cortical BMD at different sites by pQCT (r = 0.61-0.67). Standard
stepwise regression analysis showed that adding phalangeal SOS into forearm
densitometric variables significantly enhanced the statistical power for
prediction of the strength of the distal radius. Our results suggest that, for
assessment of site-specific distal forearm strength, QUS measurement of the
phalanges is comparable to forearm densitometry. Phalangeal QUS may add clinical
value if distal forearm strength has a high priority.
PMID- 10773596
TI - Primary hyperparathyroidism: bone structure, balance, and remodeling before and 3
years after surgical treatment.
AB - In 19 patients with primary hyperparathyroidism (PHPT) (14 women and 5 men; age
53 +/- 11 years, range 29-69 years), bone densitometry, biochemical markers of
bone turnover, and iliac crest bone biopsies were obtained before and 3 years
after successful surgical treatment. A significant increase in bone mineral
content (BMC) was observed in both the lumbar spine (p < 0.001) and the proximal
part of the distal forearm (p < 0.001), whereas the increase in BMC in the
femoral neck was insignificant. Biochemical markers of bone formation (serum
alkaline phosphatase, serum bone alkaline phosphatase and serum osteocalcin) and
resorption (serum pyridinoline cross-linked telopeptide of type I collagen and
urine N-telopeptide of type I collagen) all decreased following treatment. In
cortical bone, relative cortical width increased following surgery (p < 0.05) and
cortical porosity decreased (p < 0.01). No changes were observed in core width or
cortical width. In cancellous bone, no significant changes were observed in any
of the measured structural parameters. However, significant reductions in the
extent of osteoid- (p < 0.01) and tetracycline-labeled surfaces (p < 0.001), and
in bone formation rate (p < 0.001) and activation frequency (p < 0.001), were
found. The numerical decrease in the extent of eroded surfaces did not reach
significance (p = 0.057). No changes were observed in mineral appositional rate
and adjusted appositional rate. The amount of bone resorbed (expressed as the
resorption depth) and the amount of bone reformed (expressed as wall thickness)
per remodeling cycle seemed unaffected by the treatment. Consequently, no effect
on bone balance per remodeling cycle could be detected. The present study of PHPT
patients showed that, within 3 years after surgery, BMC of both cancellous and
cortical bone areas had increased. At the same time, bone turnover decreased
markedly, as judged from biochemical as well as histomorphometric data, but no
changes were seen in trabecular bone structure. In cortical bone, the relative
cortical width increased and the cortical porosity decreased.
PMID- 10773597
TI - Emergency contraception with levonorgestrel: one hormone better than two.
PMID- 10773598
TI - Women's knowledge of, and attitudes to, contraceptive effectiveness and adverse
health effects.
AB - Our objectives were to determine women's knowledge of the effectiveness of
different contraceptive methods and the risks of thrombosis with use of hormonal
contraceptives, and their attitudes regarding the acceptability of bleeding
irregularities and weight change. An additional aim was to determine what
information women want to be given about contraceptives. In order to satisfy the
study objectives, a series of semi-structured focus groups was conducted with
women of differing life-stage and background from Oxford. Quantitative data were
collected using a structured questionnaire. Qualitative data were collected
through discussion with group members. Forty-five women attended four focus
groups. Women were segregated into the following groups: professional working
mothers; non-professional mothers; young, unmarried professional women; and
undergraduate students. Women tended to overestimate the risks and underestimate
the effectiveness of hormonal contraceptives. They were resistant to interference
with their bleeding patterns and weight.
PMID- 10773599
TI - A survey of GP views in intra-uterine contraception.
AB - AIMS: To investigate knowledge and attitudes towards intra-uterine contraception.
DESIGN: Anonymous postal survey of 441 GPs (153 female and 288 male GPs) from the
FHSA register in Stockport and Manchester. SETTING: General practices in
Stockport and Manchester. Main outcome measure. Response to a series of questions
concerning attitudes and knowledge of intra-uterine contraception. RESULTS: One
hundred and forty-two responses were received, giving a 35% response rate. Thirty
four percent of responding GPs did not fit intra-uterine devices (IUDs), with
only 10% fitting more than 30 a year. There was a significant trend against IUD
fitting by male GPs and GPs aged <40 years. Younger GPs with <10 years experience
were significantly more aware of the reliability of intra-uterine contraception,
but perceived IUD fitting as inconvenient for both the patient and the doctor.
Female GPs had better knowledge and more positive attitudes to IUDs than male
GPs. CONCLUSION: GPs may have difficulties in maintaining expertise. Primary care
groups may opt to concentrate fittings in a few expert practices, or refer women
to centrally based family planning clinics for IUD fitting.
PMID- 10773600
TI - Immediate post-abortal insertion of the frameless GyneFix IUD: initial experience
in China.
AB - The promising results obtained with the frameless GyneFix IUD for interval
insertion led to the belief that the technology could be useful for immediate
post-abortal application to reduce the number of induced and repeat abortions.
IUDs have many advantages and the method is acceptable and safe. However, side
effects and expulsion of conventional IUDs remain a problem. In an attempt to
minimise these problems, the frameless GyneFix IUD was developed. Clinical
studies conducted over the past 14 years have shown that the principles on which
the device is based are valid. An increasing bulk of clinical evidence shows that
the design characteristics of the device (fixed, frameless and flexible) are
responsible for the low expulsion, high effectiveness, and high tolerance and
continuation rates.1 Experience with the frameless IUD in China since 1989
confirms the international experience with the device. The present communication
is a second report from China with the GyneFix IUD. In the present study the
GyneFix IUD is inserted immediately following termination of pregnancy of less
than 10 weeks amenorrhea. It is concluded that immediate post-abortal insertion
of the frameless IUD is easy and safe, and appears to be as reliable and as
effective as when it is inserted at interval. The GyneFix IUD could, therefore,
constitute an important new option in the prevention of abortion.
PMID- 10773601
TI - Sexual health and the practice nurse: a survey of reported practice and
attitudes.
AB - BACKGROUND: Practice nurses have an important role in the provision of sexual
health services in general practice. AIM: This study set out to determine
practice nurses' reported practice and training in sexual health, attitudes
towards sexual health, barriers to discussing sexual health with patients, and
training needs. METHOD: A confidential self-administered postal questionnaire
survey was sent to all 298 practice nurses in one English health district
(Leicestershire). RESULTS: Completed questionnaires were returned by 234 practice
nurses (response rate 79%). Most nurses routinely offered well-person checks
(90%), cervical smears (89%), travel clinics (83%), saw women with genito-urinary
symptoms (77%) and offered family planning advice (54%). Only a minority of
nurses (13%) offered specific teenage health clinics. Sexual health issues were
always discussed in a majority of consultations when giving family planning
advice (65%) and in women with genito-urinary symptoms (58%). Most practice
nurses (62%) had undertaken at least one course dealing with sexual health issues
in the last 5 years. Uptake of training was, however, significantly lower in
certain groups of nurses. An analysis of the attitude statements suggested that
nurses were more comfortable discussing sexual health issues with female patients
and teenagers than with male patients and those of different sexual orientations.
Nurses who had received training reported more positive attitudes towards
discussing sexual health issues with patients. CONCLUSION: Practice nurses offer
a wide range of services in which the need to be able to take a sexual history
and offer appropriate advice is important. There is scope to improve the
provision of sexual health services by nurses in general practice, particularly
in relation to services for teenagers.
PMID- 10773602
TI - The demand and supply of nutritional advice and guidance in Scottish family
planning services.
AB - Recent changes to the health services have led to an increased provision of
clinical care in family planning clinics. While some women may only require
contraceptive services, others may demand advice on a breadth of lifestyle
issues, including diet and nutrition. Obesity affects 17% of women of
childbearing age in Scotland and being overweight during pregnancy has
significant health risks. A postal survey of 227 nurses identified as working in
family planning clinics in Scotland was conducted in 1998. After a mail shot and
one reminder, a net response rate of 64% (n = 145) was achieved. Overall, it was
found that obesity was perceived as the most extensive problem in women of
childbearing age. Seventy nurses (48%) reported that, in addition to offering
family planning services, they gave dietary advice 'frequently' or 'always' to
their clients without being asked. There were differences in nutrition-related
activities in consultations between nurses offering family planning services only
and those who routinely offered nutritional advice. Over half (61%) of the nurses
reported that they would give advice regarding weight management even if the
patients were not seeking help, although there was no significant difference
between the two comparison groups. In some cases, the nutritional advice offered
to clients highlighted a deficit in training. Most nutrition education came from
diploma and/or training courses and scientific literature, followed by
'experience'. Those nurses already embracing a nutritional advice and guidance
role were more interested in further nutrition training (p = 0.018) than the
other nurses. However, overall, 67% of the nurses wished to train further in
nutrition and weight management. The findings suggest that family planning nurses
should be supported to develop nutritional advice and guidance skills, and that
there is a pressing need for training in public health nutrition and weight
management for nurses working in family planning services.
PMID- 10773603
TI - Are computers of any use in a family planning clinic?
PMID- 10773604
TI - Medroxyprogesterone acetate [Depo Provera] injections. Development of striae.
AB - A young girl developed extensive striae while on Depo Provera injections. She had
gained some weight during the treatment. Endocrinal investigations were negative.
The development of striae was attributed to her weight gain.
PMID- 10773605
TI - Amenorrhoea despite displaced levonorgestrel intra-uterine system.
PMID- 10773606
TI - Multidisciplinary learning in family planning clinics.
PMID- 10773607
TI - Hyperparathyroidism and anemia in renal failure.
AB - Patients with severe secondary hyperparathyroidism, usually associated with
osteitis fibrosa on bone histology, show considerable resistance to Epoetin,
partly because of replacement of the cellular components of the bone marrow by
fibrous tissue. In case of unexplained resistance to Epoetin, investigation of
secondary hyperparathyroidism is strongly recommended, with measurement of serum
parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels and,
where needed, skeletal radiology and bone biopsy. Treatment of severe secondary
hyperparathyroidism consists of active vitamin D metabolites or
parathyroidectomy, although the marrow fibrosis, if present, may be irreversible.
The finding of a progressive inability of the bone marrow to respond to Epoetin
treatment with higher levels of parathyroid hormone suggests the importance to
prevent metabolic bone disease and in particular secondary hyperparathyroidism.
Moreover, there are several reports of a beneficial action on hemoglobin levels
of an effective treatment of hyperparathyroidism. Larger, controlled studies are
necessary to confirm these preliminary and exciting findings, and to elucidate
the mechanisms underlying the improvement in anemia after medical or surgical
treatment of hyperparathyroidism.
PMID- 10773608
TI - Cystatin C: efficacy as screening test for reduced glomerular filtration rate.
AB - Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker
of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and
creatinine clearance were measured in 226 patients with various nephropathies,
covering the entire range of renal function, to evaluate the efficacy of cystatin
C as a screening test to detect reduced creatinine clearance in comparison to
creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular
impairment were compared to assess whether cystatin C performed differently in
either glomerular or tubular impairment. Cystatin C detected reduced creatinine
clearance with higher sensitivity (97 vs. 83%), and higher negative predictive
value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of
cystatin C as derived from receiver-operating characteristic plot was
significantly higher (p < 0.05). In the subgroups with glomerular or tubular
impairment, cystatin C and creatinine did not significantly differ with regard to
efficacy. Serum cystatin C is as efficacious as serum creatinine to detect
reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a
screening test may even be superior compared to creatinine. In addition, the
efficacy of cystatin C is independent of either glomerular or tubular impairment.
PMID- 10773609
TI - Hand contamination with hepatitis C virus in staff looking after hepatitis C
positive hemodialysis patients.
AB - BACKGROUND: Hepatitis C virus (HCV) is a major cause of hepatitis in hemodialysis
(HD) patients. Routes other than blood transfusion play a role in the spread of
HCV in HD patients. Molecular studies of HCV implicate nosocomial transmission of
the virus in HD units. We conducted a clinicovirological study in our HD unit to
investigate if the hands of dialysis personnel could represent a mode of
transmission of HCV among HD patients. METHODS: One liter of sterile water was
used for each handwashing of dialysis personnel. The washing was collected in a
sterile container and tested for HCV-RNA by polymerase chain reaction (PCR)
within 3 h of collection. Eighty handwashings from nurses dialyzing HCV-positive
patients (groupe A) and 100 handwashing from nurses dialyzing HCV-negative
patients (group B) were tested for HCV-RNA. As a control, 60 handwashings were
collected from the dialysis personnel before entering the dialysis unit (group C)
and tested for HCV-RNA. RESULTS: HCV-RNA was positive in 19 (23.75%) of samples
of group A, in 8 (8%) of samples of group B (p < 0.003) and in 2 (3.3%) of
samples of group C (p < 0. 35). These two positive samples of group C were from
nurses who had dialyzed HCV-negative patients. CONCLUSION: These results indicate
the presence of HCV-RNA on the hands of some dialysis personnel in our HD unit,
in spite fo adherence to the standard precautions. The hands of dialysis
personnel are therefore a potential mode for facilitating transmission of HCV
between HD patients.
PMID- 10773610
TI - The significance of atherogenic indices in patients on hemodialysis.
AB - Atherosclerotic diseases (ASD) are the major cause of mortality and morbidity in
patients on hemodialysis (HD). To evaluate the significance and usefulness of
atherogenic indices, we examined lipoprotein(a) (Lp(a)), remnant-like particles
cholesterol (RLP.C), homocysteine (Hcy), cardiac troponin T (TnT), and ankle-arm
blood pressure index (AABI) in 114 patients on HD (male 79, female 35; age 62.1
+/- 1.3 years). As a result, serum cardiac TnT and AABI levels in patients with
diabetes mellitus (DM) (n = 33) were significantly higher than those in patients
without DM (n = 81). In patients with cerebrovascular diseases (CVD), serum
levels of both RLP.C and Hcy, and AABI levels were significantly higher than
those in patients without CVD. In patients with coronary artery diseases (CAD),
serum cardiac TnT and AABI levels were significantly higher than those in
patients without CAD. In patients with peripheral vascular diseases (PVD), serum
levels of both Hcy and cardiac TnT were significantly higher than those in
patients without PVD. Multiple regression analysis did show that the presence of
DM, serum Hcy levels and age were independent factors as- sociated with ASD: ASD
= -0.348 + 0.426 x DM (scored: 0, absence; 1, presence) + 0.005 x Hcy (nmol/ml) +
0. 010 x Age (years) (p < 0.001). In conclusion, the presence of DM and advanced
age are major determinants for atherosclerosis. In addition, serum Hcy levels are
independent risk factors for atherosclerosis irrespective of the absence of DM.
PMID- 10773611
TI - Efficiency of different hollow-fiber hemofilters in continuous arteriovenous
hemodiafiltration.
AB - Low dialysate to blood flow rate ratios are a unique characteristic of continuous
arteriovenous hemodiafiltration (CAVHDF) that should allow complete saturation of
dialysis fluid with small-molecular-weight blood solutes. The aim of the
investigation was to evaluate the performance of different hemofilters in CAVHDF.
In 10 critically ill patients with acute renal failure, the efficiency of four
hollow-fiber hemofilters, polyamide 0.6 m(2), polyacrylonitrile (PAN) 0.3 and 0.6
m(2), acrylonitrile sodium methallylsulfonate (AN69HF) 0.6 m(2), has been
evaluated. For comparison, dialysate flow rates (Q(di)) were standardized to 16.6
and 25 ml/min. Samples for urea nitrogen were obtained from the arterial blood
line (C(bi)) and from the dialysate exit port (C(do)) within 24-hour running
time. Outflowing dialysate (Q(do)) was also measured at the same time. Blood flow
(Q(b)) was calculated by the bubble transit time technique. Diffusive and total
urea clearances were determined. AN69HF and PAN hemofilters provided higher
clearances than the polyamide hemofilter. Despite the smaller surface area, PAN
0.3 m(2) had a total urea clearance comparable to that of PAN 0.6 m(2) and AN69HF
at Q(di) = 16.6 ml/min. While at Q(di) = 16.6 ml/min equilibrium between blood
and dialysate (C(do)/C(bi) congruent with 1) occurred with the AN69HF and PAN
hemofilters, at Q(di) = 25 ml/min the equilibrium was obtained only with the
AN69HF hemofilter. In conclusion, almost complete urea saturation of dialysis
fluid has not been obtained with all hemofilters tested here. In our experience,
membrane characteristics play an important role in determining diffusive
efficiency in CAVHDF.
PMID- 10773612
TI - Significance of glomerular deposition of C3c and C3d in IgA nephropathy.
AB - BACKGROUND: Complement activation plays an important role in the pathogenesis of
IgA nephropathy. The clinico-pathological significance of the glomerular
deposition of complement breakdown products, C3c and C3d in IgA nephropathy
remains to be clarified. METHODS: We examined the relationship between glomerular
staining patterns of C3c and C3d and clinico-pathological findings with 163
patients with IgA nephropathy. Renal biopsy specimens were stained with C3c and
C3d by immunofluorescence, and patients were divided into the following two
groups: the intensity of C3c deposition stronger than C3d deposition, or equal to
it (group A); the intensity of C3d deposition stronger than C3c deposition (group
B). RESULTS: In group A, the incidence of severe hematuria (over 20 urinary red
blood cells in high-power field microscope (x400)) or of higher urinary
fibrinogen degenerated products (over 0.1 microg/ml) was significantly higher
than that in group B. In addition, group A showed a significant decrease in the
glomerular filtration rate. Group A also showed a significantly higher incidence
of glomerular endocapillary proliferation than in group B. CONCLUSION: These
findings suggest that the glomerular deposition of C3c is associated with the
inflammatory active phase of glomeruli in IgA nephropathy.
PMID- 10773613
TI - Calcitriol therapy modulates the cellular immune responses in hemodialysis
patients.
AB - We studied the in vitro and in vivo effects of calcitriol (1,25D) on the cellular
immune responses in 19 hemodialysis (HD) patients. In vitro 5-day treatment with
1,25D markedly reduced the HLA-DR expression by peripheral blood CD14(+)
monocytes from both HD patients and normal subjects in a similar fashion. The HLA
DR expression by monocytes and the phorbol myristate acetate (PMA)-induced
superoxide production (SOP) by neutrophils were significantly higher in the HD
patients than in the normal subjects (p < 0.01 and p < 0.05, respectively). The
phagocytic activity in the HD patients was significantly lower than that in the
normal subjects (p < 0.05). Moreover, the mitogen response of HD peripheral blood
lymphocytes against pokeweed mitogen (PWM) was significantly lower than that of
the controls (p < 0.01) but was only slightly and insignificantly lower against
Con A. Oral 1,25D pulse therapy resulted in a marked decrease in the HLA-DR
expression by peripheral blood monocytes 2 and 4 days after the first 1,25D
administration (p < 0.01) in HD patients. Moreover, the treatment significantly
enhanced the PMA-induced SOP 2 days after the treatment (p < 0.01). However, the
phagocytic activity by neutrophils and the mitogen responses to Con A and PWM by
lymphocytes were not significantly affected by this treatment. These results
suggest that 1,25D plays a significant role in the regulation of both the
monocyte and neutrophil functions in HD patients.
PMID- 10773614
TI - Subcutaneous nodules attributed to nocardiosis in a renal transplant recipient on
tacrolimus therapy.
AB - We report a renal transplant patient who suffered from disseminated nocardiosis
after empirical tacrolimus rescue therapy for chronic allograft rejection. The
nocardiosis presented initially as only mildly tender subcutaneous calf nodules
without any other signs of inflammation nor constitutional upset, which later
spread to the lung and brain causing bronchopneumonia and brain abscesses. The
risk factors for nocardial infection in our patient include the use of potent
immunosuppressive agents such as tacrolimus, poorly controlled diabetes mellitus
and kidney dysfunction. She responded well to combination antibiotic therapy
comprising parenteral meropenem, cefotaxime and oral minocycline. We conclude
that in transplant recipients, especially those receiving newer and more potent
immunosuppressive agents like tacrolimus, nocardial infection can present as
apparently 'cold' subcutaneous nodules without any systemic upset. An associated
brain lesion should be excluded even in patients without neurological symptoms.
PMID- 10773616
TI - Low doses of liquorice can induce hypertension encephalopathy.
AB - Prolonged ingestion of liquorice is a well-known cause of hypertension due to
hypermineralocorticoidism. We describe 2 cases of hypertension encephalopathy (in
addition to the classical symptoms of hypertension, hypokalemia and suppression
of the renin-aldosterone system) which resulted in pseudohyperaldosteronism
syndrome due to the regular daily intake of low doses of liquorice. Glycyrrhizic
acid, a component of liquorice, produces both hypermineralocorticism and the
onset of encephalopathy through the inhibition of 11beta-hydroxysteroid
dehydrogenase. Hypertension encephalopathy due to the daily intake of low doses
of liquorice, however, has not been previously documented. It is proposed that
some people could be susceptible to low doses of glycyrrhizic acid because of a
11beta-hydroxysteroid dehydrogenase deficiency.
PMID- 10773615
TI - Early posttransplant lymphoproliferative disorder presenting with ureteric
obstruction in en bloc kidneys.
AB - We describe a female patient who received double pediatric (en bloc) kidney
transplants. She presented initially with fever of unknown origin 3 months after
transplantation; 5 months after surgery, she presented with obstruction of one
ureter followed by obstruction of the other. After 9 months she developed
posttransplant lymphoproliferative disorder in both kidneys. To our knowledge,
this is the first case report of this disorder occurring in en bloc kidneys and
presenting with bilateral ureteric obstruction.
PMID- 10773617
TI - Acute tubular necrosis due to captopril.
AB - Angiotensin-converting enzyme (ACE) inhibitors are standard therapy for
congestive cardiac failure. ACE inhibitors have been used worldwide and are
usually safe and have relatively few side effects. Hypotension can develop with
the first dose of captopril and can lead to symptomatic renal hypoperfusion with
subsequent acute renal failure (ARF). The case of a 65-year-old patient with
congestive heart failure who developed acute renal failure following the first
dose of captopril is described. He required hemodialysis for 8 weeks for the
improvement of his renal function and urinary output. The renal biopsy confirmed
the presence of acute tubular necrosis. The reversibility of captopril-induced
ARF is confirmed and the patient made an uneventful recovery. An immunoallergic
mechanism is not thought to have been responsible for this adverse effect. It is
advised that caution should be exerted in giving ACE inhibitors to elderly
patients with congestive heart failure, particularly if they are on diuretics.
Routine biochemical monitoring is suggested before and during captopril therapy.
PMID- 10773618
TI - Protein tyrosine kinase inhibitors block the stimulatory actions of
phosphotyrosine phosphatase inhibitors to increase cell proliferation, alkaline
phosphatase activity, and collagen synthesis in normal human bone cells.
AB - The present study sought to test whether inhibition of phosphotyrosine
phosphatases (PTPs) would stimulate proliferation and differentiation of normal
bone cells, and whether the PTP inhibitor-mediated effects would be blocked by
protein tyrosine kinase (PTK) inhibitors. Three inhibitors [phenylarsine oxide
(PAO), orthovanadate (VO(4)), and molybdate (MoO(4))] and two normal human bone
cells with different basal differentiation status (i.e., mandible- and vertebra
derived bone cells) were used. Cell proliferation was determined with
[(3)H]thymidine incorporation, and confirmed by cell counting. Bone cell
differentiation was assessed by increases in alkaline phosphatase (ALP) specific
activity and collagen synthesis. The three test PTP inhibitors each stimulated
[(3)H]thymidine incorporation in both human bone cell types in a biphasic, dose
dependent manner with optimal doses of 20 nM PAO, 1 microM VO(4) and 2 microM
MoO(4), respectively. These PTP inhibitors at mitogenic doses each significantly
and reproducibly increased ALP specific activity and collagen synthesis. To
determine whether the stimulatory effects of PTP inhibitors could be blocked by
PTK inhibitors, the effects of tyrphostin A51 and erbstatin, two potent PTK
inhibitors, on the actions of PTK inhibitors on [(3)H]thymidine incorporation and
ALP specific activity were evaluated. Both tyrphostin A51 and erbstatin, which by
themselves alone significantly inhibited human bone cell proliferation and
increased ALP specific activity, completely abolished the stimulatory effects of
each of the three test PTP inhibitors on bone cell proliferation and ALP specific
activity. In conclusion, these findings confirm the premise that inhibition of
PTP activities in normal human bone cells could lead to increases in cell
proliferation and differentiation, effects that are independent of basal
differentiation status of the cells. More importantly, this study demonstrates
for the first time that the stimulatory actions of the PTP inhibitor on bone cell
proliferation and ALP could be blocked by a PTK inhibitor, suggesting that the
osteogenic effects of PTP inhibitors may depend on PTK activities, presumably to
increase basal tyrosyl phosphorylation level. Accordingly, one should interpret
results of studies using PTK inhibitors with caution in that an inhibition by a
PTK inhibitor does not necessarily indicate the requirement of PTK activities, as
it could also suggest involvement of an inhibition of PTPs.
PMID- 10773619
TI - Nephrology, a newly rich speciality, is looking for an illustrious ancestry: what
about a famous grandfather?
AB - Nephrology is a newborn speciality compared to the other medical specialities.
However, the study of the urinary tract's physiology and pathology had begun
simultaneously with the birth of medicine. The scientific revolution of the
renaissance and enlightenment eras caused an intense contestation of earlier
theories and methods as if all knowledge had evolved suddenly from
parthenogenesis after the dark (?) medieval years and human intellect suddenly
exploded to huge intelligence quotients after the 15th century while before that
humans were mentally deprived. Indeed most of the scientific knowledge did evolve
impressively during renaissance and enlightenment years but not through
parthenogenesis. Some observations, discoveries and inventions of this era were
actually reobservations, rediscoveries and reinventions. Such an example is that
of the experiments of Sanctorius Santorii of the 16th century AD and of
Erasistratus of the 3rd century BC. Sanctorius and Erasistratus carried out an
experiment with the same basic principles, similar methodology and proportional
results with an almost 2000 years lag phase. With our paper we wish to give
credit to earlier researchers of physiological and medical knowledge who, despite
the lack of technological support, often concluded in extremely accurate
observations.
PMID- 10773620
TI - Relevance of investigating the presence of hepatitis C virus RNA in HCV antibody
negative hemodialysis patients.
PMID- 10773621
TI - Fiber connections of the corpus mamillare in a percomorph teleost, tilapia
Oreochromis niloticus.
AB - The hypothalamus and perhaps its function appear to be similar among vertebrates.
Thus, studying the teleostean hypothalamus could be a good model for
understanding common neural circuits and mechanisms retained through the
vertebrates. However, connections of the inferior lobe, which is considered the
hypothalamus in teleosts, is poorly known. The corpus mamillare (CM) is a nucleus
of the inferior lobe named after the mammalian mamillary body based on
similarities in external morphology. Afferent connections of the CM have been
reported only in cypriniform teleosts. These include projections from the nucleus
pretectalis superficialis pars magnocellularis, a nucleus lacking in percomorph
teleosts, and projections from the secondary gustatory nucleus. Efferent
connections of the CM have not been reported in teleosts. In the present study,
the CM and its subdivisions and the connections of these subnuclei were
identified in isolated and maintained brains of tilapia Oreochromis niloticus by
local DiI and biocytin injection. Afferent connections confirmed by reciprocal
injections were from the nucleus diffusus lobi inferioris (NDLI) and the nucleus
diffusus tori lateralis (NDTL). Efferent connections of each CM subnuclei were
also reciprocally confirmed. These connections were to the area dorsalis pars
medialis of the telencephalon, the nucleus ventromedialis (NVM) of the thalamus,
the tectum opticum (TO), and the nucleus posterioris periventricularis. Because
the NDLI is known to receive gustatory information in tilapia, the CM could relay
gustatory inputs to multisensory areas, the TO and NVM, for which there are no
current reports regarding gustatory inputs.
PMID- 10773622
TI - Immunocytochemical localization of gonadotropin-releasing hormones in the brain
of a viviparous caecilian amphibian, Typhlonectes natans (Amphibia: Gymnophiona).
AB - The molecular forms and brain distribution of gonadotropin-releasing hormone
(GnRH) have been well studied in the amphibian orders Urodela (salamanders and
newts) and Anura (frogs and toads). In the order Gymnophiona (caecilians),
however, few species have been investigated. Antibodies against different
molecular forms of GnRH were used to immunohistochemically localize the GnRH
containing neurons in the brain of the caecilian, Typhlonectes natans which
differs from most other amphibians in that it is viviparous. An antibody
selective for mammalian GnRH recognized cell bodies predominantly in the septo
preoptic area but only with occasional cell bodies in the lateral hypothalamus
and ventral thalamic eminence. Thick, prominent fibers in the septal region and
fibers within the terminal nerve were also labeled. An antibody selective for
chicken-II GnRH labeled a population of cell bodies in the dorsal hypothalamus,
ventral thalamus and midbrain tegmentum. Thin fibers projected laterally from
these cells. An antibody specific for salmon GnRH did not label cell bodies but
did show intense terminal field immunoreactivity. The brain of this caecilian,
therefore, contains three antigenically distinct forms of GnRH. The mammalian and
chicken-II GnRH peptides have been shown in other amphibians but the distribution
of cells and fibers was unique in this caecilian.
PMID- 10773623
TI - Succinic dehydrogenase histochemistry reveals the location of the putative
primary visual and auditory areas within the dorsal ventricular ridge of
Sphenodon punctatus.
AB - In turtles, crocodilians, lizards and snakes, the dorsal ventricular ridge (DVR)
is a nuclear cell mass that contains distinct visual and auditory
thalamorecipient cell groups. In the tuatara (Sphenodon punctatus), the DVR is
not organized into diverse cell groups but instead possesses a trilaminar
cytoarchitecture resembling that characteristic of the telencephalic cortex in
reptiles. To determine if visual and auditory fields might also be present in the
DVR of Sphenodon punctatus, we used succinic dehydrogenase (SDH) histochemistry,
which has been shown to delineate the visual and auditory fields of the DVR in
turtles, crocodilians and lizards. We also used acetylcholinesterase (AChE)
histochemistry to determine the boundary between the DVR and the basal ganglia in
Sphenodon. We found an SDH-rich region in the neuropil ventral to the cell plate
of the rostrolateral DVR and a slightly less intense SDH-rich zone in the
neuropil deep to the cell plate of the ventromedial DVR. These SDH-rich zones
appear to be located at the apical dendrites of the neurons of the adjacent cell
plate. These SDH-rich zones were clearly located within the DVR and were distinct
from the AChE-rich striatal part of the basal ganglia, which occupied the
ventrolateral wall of the telencephalon. Based on findings in other reptiles, it
seems likely that the SDH-rich zone in rostrolateral DVR represents the zone of
termination of nucleus rotundus visual input to the DVR, whereas the zone in
ventromedial DVR represents the zone of termination of nucleus reuniens auditory
input. Because a trilaminar DVR such as that in Sphenodon might be the primitive
DVR condition for reptiles, our results suggest that the cytoarchitecture of the
DVR and the synaptic organization of its thalamic sensory input in the common
ancestor of living reptiles might have been much like of the dorsal cortex.
PMID- 10773624
TI - Cross-species and intraspecies morphometric analysis of the corpus callosum.
AB - A cross-species morphometric study of the corpus callosum was performed in the
rat, rabbit, cat, dog, horse, cow and human. Across species, the results indicate
a strong, although less than linear, dependency of callosal size on brain weight.
This relation tends to lose significance within species. This is consistent with
other morphometric studies indicating a tendency to decrease the correlations
between morphometric variables in within-species analyses as compared to between
species analyses. There are species differences in the relative size of some
callosal segments particularly in the posterior third, which is larger in
frontally-looking species than in laterally-looking species. No sex differences
in callosal size were detected in any of the species examined. These findings are
discussed in the light of possible developmental and functional correlates of the
variability observed.
PMID- 10773625
TI - Comparative tests of primate cognition: different scaling methods produce
different results.
AB - Although early comparative studies supported hypotheses that ecological demands
selected for primate cognition, later work indicated that social demands were
more important. One difference between earlier and later studies is that earlier
studies scaled brain structures by (A) taking residuals from an interspecific
regression of the brain structure in question on body mass, whereas later studies
scaled them by (B) taking residuals from an interspecific regression of the brain
structure in question on another brain structure or by (C) taking ratios of the
brain structure in question to another brain structure. We conducted a series of
comparative tests to explore the possibility that the different methods are
responsible for the discrepancy between earlier and later studies. Specifically,
we tested the ability of a social variable - group size - and an ecological
variable - home range size - to explain variation in the non-V1 isocortex
(isocortex minus primary visual cortex) when this structure was scaled with the
three different methods. In multiple regression analysis, group size was a better
predictor of the non-V1 isocortex with method (B). With methods (A) and (C),
however, results were ambiguous: either home range size or group size explained
more of the variation, depending on the inclusion of outliers, the use of
independent contrasts, and whether home range size was scaled relative to body
mass. We examine the three scaling methods and find no reasonable basis for
preferring any of them. Hence, our results do not allow a distinction between
social and ecological hypotheses. The general implications of our study are that
(1) previous comparative studies are inconclusive and (2) further research is
needed to develop a scaling method where relative measures of brain structure
size are demonstrated to correspond with behavioral performance.
PMID- 10773626
TI - A caries susceptibility classification of tooth surfaces by survival time.
AB - Individual tooth surfaces have vastly different susceptibilities to caries and
this susceptibility also varies over time. The aim of this study was to develop a
method of grouping tooth surfaces into a caries susceptibility classification
based on their survival experience. The data used in the study were from a 3-year
caries clinical trial. The definition of survival time was taken to be the time
from the start of the trial to when a surface is recorded as decayed or filled.
Cluster analysis was used to divide the tooth surfaces into groups in such a way
that surfaces in the same group have similar survival time distributions. The 13
groups identified were ordered from 1 to 13 starting with the group with the
shortest survival time, i.e. the occlusal surfaces of the four first molars.
Approximately 80% of symmetrical pairs of tooth surfaces were in the same group.
The groups obtained using cluster analysis were compared to groups defined using
dental/anatomical criteria. It is concluded that the cluster analysis method
developed for grouping the tooth surfaces cn provide a useful descriptive measure
of caries susceptibility which can be applied to data from any longitudinal study
of caries.
PMID- 10773627
TI - Some factors associated with the caries decline among Norwegian children and
adolescents: age-specific and cohort analyses.
AB - The purpose of this study was to evaluate factors related to the caries decline
in children between 1966 and 1983. The decline started in the late sixties for
the 8- to 11- and the 17-year-olds, and after 1971 for the remaining age groups.
Regression analyses confirmed a significantly different start of the decline.
Fluorides in school-based programmes, lozenges, and toothpaste, as well as
education and sale of antibiotics were significantly (p< or =0.01) related to the
caries decline in partial correlation analyses. Fluoride toothpaste was only
significantly related to the decline in the last part of the period of
observation. Supervised fluoride rinsing and brushing programmes at school may
explain most of the decline before 1971. The later decline may be related to all
fluoride agents and to education. Use of fluorides and other preventive efforts
aimed at pre-school children may have contributed to the continual decline in the
number of fillings in the permanent teeth of the youngest cohorts.
PMID- 10773628
TI - Parental smoking practices and caries experience in pre-school children.
AB - Voluntary and involuntary smoking influence general health. Links between
voluntary smoking and oral health are confirmed for periodontal diseases and oral
cancer/precancer. Since recent reports have suggested an association between
parental smoking and caries experience in young children, this study aimed to
explore varying patterns of parental smoking, adjusted for social class, with
caries prevalence, using data derived from the UK National Diet and Nutrition
Survey (1995). Data analysis was confined to 749 children aged 3.0-4.5 years, to
avoid confounding effects of unerupted teeth. Bivariate analysis indicated that
the prevalence of maternal rather than paternal smoking was significantly related
to caries and substantially attenuated social class differences. The reported
number of cigarettes smoked was not important. To compensate for the association
between social class and maternal smoking, data were dichotomised by social class
(manual/non-manual). With caries prevalence as the dependent variable, logistic
regression analysis recorded maternal smoking as a significant independent
variable in each case, with odds ratios of 1.55/1.96, respectively. The process
was repeated for the combined dataset, using the more extensive (six) social
class categories. This further analysis yielded an odds ratio for maternal
smoking of 1.54 compared with 1.46 for social class. Nutrition status (as growth
parameters) and dietary intake (as household spending on confectionery) were not
significant independent variables in these equations. The rationale for these
findings is discussed. Further research is required to determine mechanisms
underlying these observations. It is concluded that maternal smoking is a
significant factor to be considered as an additional risk indicator beyond social
class when predicting caries risk in young children.
PMID- 10773629
TI - The fidelity of mutans streptococci transmission and caries status correlate with
breast-feeding experience among Chinese families.
AB - Our previous study reported that the fidelity of mutans streptococci (MS)
transmission from mother to infant was gender- and race-specific within a
Birmingham, Ala., population. We hypothesized that fidelity might be a function
of postnatal nurturing practices. The purpose of the present study was to
investigate those factors that could be correlated with MS transmission among
Chinese children whose nurturing histories were known. Forty-eight families with
2- to 3-year-old children were selected from two kindergartens of Beijing, China.
A questionnaire concerning the childhood nursing practice was obtained from the
parents. Dental caries status was examined, and bacterial samples were collected
for all participants twice at 6-month intervals. An average of six isolates of MS
was picked at random from selective medium from each individual at each visit.
Chromosomal DNA fingerprints were performed for all MS isolates to determine the
genomic similarity within each family and among individuals. The results showed
that 66% of the children at 2-3 years of age harbored MS, and 46% were caries
active. Of those children, 70% were breast-fed. Among the children whose
chromosomal DNA fingerprint genotypes of MS matched that of their mothers, 88%
were breast-fed compared with only 12% who were not breast-fed (p = 0.03). We
also found that children who were breast-fed for more than 9 months were likely
to harbor strains of MS common to their mothers (p = 0.04) and experience more
dental caries (dmft = 4.4) at 3 years of age compared with children who were
breast-fed less than 9 months (dmft = 1.4, p = 0.04). The data suggest that
breast-feeding, especially prolonged breast-feeding, may correlate with the
fidelity of transmission and that prolonged breast-feeding may contribute to a
higher caries rate.
PMID- 10773630
TI - Genotypes of mutans streptococci tend to persist in their host for several years.
AB - The aim of this study was to evaluate the consistency of the prevalence of mutans
streptococci in a group of Swedish families. Eleven families, which had
previously been examined for genotypes of mutans streptococci, were re-examined
after 2-5 years. The families consisted of mother, father and a child (mean age
7.2 years at the follow-up examination). One father did not participate. Pooled
plaque samples were obtained from buccal and occlusal surfaces. Isolates of
mutans streptococci were genotyped using chromosomal DNA digested with
restriction endonuclease HaeIII, separated by gel electrophoresis and visualised
through UV illumination after ethidium bromide staining. Comparing the DNA
fingerprints of mutans streptococci found at baseline and follow-up, 9 children
harboured one or two genotypes which were similar on the two sampling occasions.
Two of these children had also gained a genotype. The remaining 2 children had
lost a genotype each and 1 of them had gained two new genotypes. All 21 adults
showed one or two genotypes identical to those found at baseline. Nine of these
21 adults had also lost one genotype. Four of these 9 and additionally 4 of the
remaining adults showed one or two new genotypes. Six mother-child pairs shared a
genotype at baseline and this pattern remained for five pairs at the end of the
study. The results suggest that genotypes of mutans streptococci have a fairly
high degree of consistency in children between 3 and 8 years of age as well as in
adults, indicating persistence of the strains. However, the results also indicate
that some subjects may gain and/or lose genotypes.
PMID- 10773631
TI - Effect of quarterly treatments with a chlorhexidine and a fluoride varnish on
approximal caries in caries-susceptible teenagers: a 3-year clinical study.
AB - The aim of this study was to compare the effect of two different dental varnishes
on approximal caries incidence in teenagers with proven caries susceptibility
during a 3-year period. Two hundred 13- to 14-year-old subjects exhibiting at
least two approximal enamel caries lesions were selected to take part in the
study. One hundred and eighty subjects participated after informed consent and
were randomly assigned to two equally sized groups. One group was treated with a
fluoride varnish (FV, Fluor Protector) containing 0.1% F every 3rd month and the
participants of the other group were treated in the same mode with a
chlorhexidine varnish (CV, Cervitec((R))) containing 1% chlorhexidine and 1%
thymol. In total, each subject was treated 12 times during the experimental
period. Approximal caries including enamel lesions (DMFS(appr)) were recorded
from four bitewing radiographs exposed at the start and end of the study. The
mean (+/-SD) caries prevalence at baseline was 2.2+/-3.4 in the FV group and
2.5+/-4.0 in the CV group. After 3 years, the average approximal caries incidence
was 2.7+/-3.1 and 3.1+/-3.5 in the FV and CV groups, respectively. The
differences at baseline and after 3 years were not statistically significant. In
conclusion, treatments every 3rd month with either a fluoride- or a
chlorhexidine/thymol-containing varnish showed a promising effect with low
approximal caries incidence and progression in teenagers with proven caries
susceptibility.
PMID- 10773632
TI - In vitro evaluation of five alternative methods of carious dentine excavation.
AB - This in-vitro, split-tooth study aimed to evaluate the efficiency (time taken)
and effectiveness (quantity of dentine removed) of four techniques of carious
dentine excavation (bur, air-abrasion, sono-abrasion and Carisolv gel) compared
to conventional hand excavation. Eighty freshly extracted human molars were
assigned to four experimental groups (n = 20), sectioned longitudinally through
occlusal lesions and pre-excavation colour photomicrographs obtained. Using the
natural autofluorescence of carious dentine (detected using confocal laser
scanning microscopy) as an objective and reproducible guide, carious dentine
removal was assessed in each half of the split tooth sample, comparing hand
excavation to the test method. The time taken to reach a cavity floor that was
hard to a dental probe was noted and final colour photomicrographs were taken.
From the results, it was concluded that bur excavation was quickest but
overprepared cavities relative to the autofluorescent signature, whereas Carisolv
excavation was slowest but removed adequate quantities of tissue. Sono-abrasion
tended to underprepare whereas air-abrasion was more comparable to hand
excavation in both the time and amounts of dentine removed. Conventional hand
excavation appeared to offer the best combination of efficiency and effectiveness
for carious dentine excavation within the parameters used in this study.
PMID- 10773633
TI - Occlusal caries detection with KaVo DIAGNOdent and radiography: an in vitro
comparison.
AB - A new laser fluorescence method, KaVo DIAGNOdent, was tested with respect to
reproducibility and validity and compared with radiography regarding accuracy in
the detection of occlusal caries. Seventy-six extracted premolar and molar teeth
were measured twice with DIAGNOdent under both wet and dry conditions, at an
interval of 2 weeks. Conventional film radiographs were exposed.
Microradiographic analysis of sections of the teeth served as the gold standard.
Intra-class correlation coefficient and Pearson's correlation coefficient were
used to assess the reproducibility and the validity of the method, respectively.
The influence of time and varying humidities on DIAGNOdent readings were analysed
by two-way repeated measure ANOVA. ROC curves were plotted for DIAGNOdent
readings and radiographic registration of caries by 6 observers, and the areas
under the curves were compared using Student's t test. Under both wet and dry
conditions, the reproducibility of the DIAGNOdent method was excellent: R = 0.97
and 0.96, respectively. The diagnostic accuracy of DIAGNOdent was significantly
better than that of radiography (p< or =0.001). In this in vitro study of
detection of occlusal caries, the diagnostic performance of the DIAGNOdent method
was superior to that of radiography.
PMID- 10773634
TI - Value of bite-wing radiographs in a clinical epidemiological study and their
effect on the DMFS index.
AB - The aim of this study was to determine, for different age groups, the additional
value of bite-wing radiographs compared to the clinical information, and to
calculate the subsequent effect on the DMFS index. Subjects were 14, 17, 20, 23
years old, or in the age groups 25-34 and 35-54, who participated in a clinical
epidemiological survey. After obtaining consent, bite-wings were taken of
approximately 25% of the participants (n = 663). The extra diagnostic yield of
the bite-wings varied between 163 and 700% for approximal dentine caries
diagnosis of untreated surfaces, and between 233 and 593% for inadequate
restoration judgement for filled surfaces. The DS score went up by about 20-98%,
whereas the DMFS index increased between 1 and 12%, resulting in a radiographic
correction factor of 1.01-1.12. In conclusion, the considerable increase in the
prevalence of approximal dentinal lesions and inadequate restorations for all age
groups results in higher numbers of surfaces in need of treatment, but is not
accompanied by a significant increase in DMFS scores.
PMID- 10773635
TI - Optical profilometric study of changes in surface roughness of enamel during in
vitro demineralization.
AB - The application of non-contact optical profilometry for non-destructive study of
changes in the surface roughness of natural enamel surfaces during in vitro
demineralization was investigated. Repeated measurement of profiles of the same
enamel surfaces after successive demineralization episodes was achieved by a
kinematic specimen mount that could be removed, then accurately repositioned.
Surface roughness parameters and reflectivity of natural enamel surfaces exposed
to either a demineralizing solution (test) or deionized water (control) for up to
6 days were measured at 6- to 24-hour intervals. The results prior to
demineralization showed that surface roughness varies with position on the enamel
surface. During demineralization there was an approximately linear increase in
surface roughness for the first 70 h followed by somewhat erratic behaviour, and
a saturating exponential with time increase in reflectivity for the first 70 h
which subsequently remained constant. Changes in enamel surface during in vitro
demineralization were also observed using scanning electron microscopy.
PMID- 10773636
TI - Reproducibility of quantitative measurement of white enamel demineralisation by
image analysis.
AB - The reproducibility of measuring artificial enamel white spot lesions from
captured photographic images using computerised image analysis was assessed.
Enamel lesions were induced on the buccal surface of 22 human teeth over periods
of 3, 7 and 14 days. Standardised photographs were taken from above and below the
occlusal plane. These were repeated after 2 weeks. The photographs were converted
into TIFF images and mean grey scale levels of the areas of etched enamel were
measured using computerised image analysis. Assessment of repeat readings of the
same slide showed good reproducibility for photographs taken below the occlusal
plane. The limits of agreement showed reasonable agreement between readings
carried out on two slides of the same tooth. Capturing TIFF images via 35-mm film
and measuring grey scale levels by computerised image analysis is a useful method
of quantitative study of early enamel demineralisation. This may be developed for
application in the clinical setting.
PMID- 10773637
TI - Progression of and risk factors for dental erosion and wedge-shaped defects over
a 6-year period.
AB - It has been shown that dental erosion is not a very rare condition. Careful
observation and clinical experience led us to hypothesize a progression of these
lesions with time despite dietary counselling and oral hygiene instruction. The
purpose of this study was to determine the progression rate and risk factors of
dental erosion and wedge-shaped defects over a 6-year period. In the year 1987,
204 randomly selected persons living in Bern from two age groups (26-30 and 46-50
years) were examined for frequency and severity of dental erosion and wedge
shaped defects. In the year 1993, 55 persons could be re-examined by the same
dentist using the same indices. Further, detailed case histories of the patients
were recorded and the flow rate and buffering capacity of the saliva were
determined. The results indicated a distinct progression of erosion on facial and
occlusal surfaces and wedge-shaped defects over the 6-year period. The increase
in the defects was more marked in the older age group. Surprisingly, nutritional
habits did not change despite thorough informative discussion about erosive
foodstuff with every patient during the first session. Multiple linear regression
analysis revealed consumption of nutritional acids and age as significant risk
factors explaining 28% of the variability of the progression of erosions. The
significant factors for the progression of wedge-shaped defects were identified
to be frequency of tooth brushing and age, explaining 21% of the variability of
the progression of wedge-shaped defects. In summary, there was a definite
statistically significant progression of non-carious dental hard tissue defects
in our sample. This progression was correlated with age (erosion and wedge-shaped
defects), consumption of dietary acids (erosion) and frequency of toothbrushing
(wedge-shaped defects).
PMID- 10773639
TI - The effect of chronic clonidine administration on salivary glands and caries in
the rat.
AB - Clonidine is a widely prescribed, centrally acting antihypertensive with proposed
pharmacologic mechanisms of stimulation of central postsynaptic alpha(2)
adrenergic receptors and agonist activity at presynaptic alpha(2)-adrenergic
receptors, interfering with peripheral regulation of norepinephrine and
acetylcholine release. Both of these mechanisms are capable of adversely
influencing salivary output and composition, potentially leaving an individual
with increased caries risk. The purpose of the present study was to determine the
effect of chronic administration of clonidine on saliva, salivary glands, and
caries in rats. Sprague-Dawley rat pups were infected with Streptococcus
sobrinus, given Diet 2000 and 10% sucrose water ad libitum, and either
desalivated, or treated with clonidine HCl (125 or 250 microg/kg administered
daily for 28 days by means of osmotic minipumps), or assigned as controls. There
were no statistical differences in stimulated parotid or submandibular gland
salivary output or sublingual gland weights among the groups. The weight of the
submandibular glands as a percent of total body weight was significantly
decreased in animals that received clonidine when compared with controls. Sulcal
caries scores in both clonidine groups and smooth surface caries scores in the
high clonidine group were increased when compared with control animals. Positive
control animals (desalivated) had significantly higher caries scores than all
other groups. These data show that chronic administration of clonidine
significantly decreases submandibular gland weight and increases susceptibility
to dental caries.
PMID- 10773638
TI - Distribution of exogenous proteins in caries lesions in relation to the pattern
of demineralisation.
AB - While it is believed that proteins may protect enamel from demineralisation,
recent work has indicated that such material may also hinder remineralisation.
For example, albumin will inhibit apatite crystal growth in vitro and is present
in carious enamel in vivo. However, it is not clear whether (1) the distribution
of proteins within lesions is restricted to specific lesion zones or (2) the
origin of such proteins is endogenous (i.e. as a remnant of the developmental
process) or exogenous, originating in the saliva or gingival crevicular fluid.
The present study used a combination of immunohistochemistry and microradiography
to determine the distribution of two proteins, serum albumin and salivary
amylase, within natural white-spot carious lesions in relation to specific levels
of demineralisation. The results indicated that albumin is found primarily in a
region of between 10 and 20% demineralisation (an area of transition between the
'dark' zone and lesion 'body'), with smaller quantities occurring in the region
between 0 and 10% demineralisation and trace amounts in the zone
indistinguishable from sound enamel by microradiography. A similar distribution
was found for amylase in that the heaviest labelling was within the 10-20%
demineralisation zone, although little if any was present in the 0-10% zone. The
presence of these molecules in a region of the lesion where some potential for
reprecipitation may exist will have important implications with respect to lesion
progression.
PMID- 10773640
TI - Predicting occlusal caries using the Electronic Caries Monitor.
PMID- 10773641
TI - Apoptosis and cerebral ischemia.
PMID- 10773642
TI - Posterior cerebral artery territory infarcts: clinical features, infarct
topography, causes and outcome. Multicenter results and a review of the
literature.
AB - Only a few large series of posterior cerebral artery (PCA) stroke exist, and
clinical features and causes have not been studied as extensively as in other
vascular territories. The PCA syndrome includes more clinical signs than the well
known visual field deficits. Concomitant findings are frequently sensory, slight
motor and neuropsychological deficits. Unilateral headaches are the common
presenting symptom making complicated migraine an important differential
diagnosis. Combined deep and superficial PCA territory infarcts involving the
lateral thalamus are more frequent than commonly assumed and are mostly
associated with sensory and reversible slight motor deficits. Occlusion of the
precommunal PCA segment with associated paramedian midbrain infarction causes
severe motor deficits, oculomotor signs, and decreased consciousness and has a
poorer outcome than other PCA territory infarcts. Embolism from a cardiac or
undetermined source is the leading mechanism accounting for up to half of the
cases, whereas arterial embolism from significant proximal vertebrobasilar
disease is less frequent. Local atherothrombotic stenosis or occlusion of the PCA
is uncommon. In spite of thorough diagnostic evaluation, the etiology of PCA
territory infarction cannot be determined in at least one quarter of patients.
Among the rare causes of PCA territory infarction carotid artery disease is
important while the significance of migraine remains controversial.
PMID- 10773643
TI - Long-term outcome after local intra-arterial fibrinolysis of basilar artery
thrombosis.
AB - Thrombolytic therapy of acute basilar artery (BA) thrombosis has been shown to
reduce mortality and avoid a fatal outcome. Objective of this study was to
investigate the long-term clinical outcome following intra-arterial fibrinolysis
of occlusions of the BA. We retrospectively analyzed the clinical records and
neuroradiologic results of 20 consecutive patients who had intra-arterial
fibrinolysis of acute occlusions of the BA between 1982 and 1990. All patients
were followed neurologically for a period of up to 12 years, including assessment
of the Barthel index (BI) and brain CT or MRI studies. At the time of treatment,
6 patients were somnolent and 14 comatose, and tetraparesis was present in 15.
The time between the onset of symptoms and treatment ranged from 1 to 48 h. The
mortality rate was 35% (7/20 patients). Functional outcome was excellent in 9,
78%, of 13 survivors (BI <85). During the cumulative follow-up period (125
patient years) there was 1 death from myocardial infarction and 1 death from
pneumonia. Vascular events during follow-up were myocardial infarction (n = 3)
and a single cerebral transient ischemic attack. Despite the fact that our series
was biased towards patients with severe symptoms, 65% (13/20) survived, and 78%
of the survivors reached independence in daily life. These results provide
evidence that local fibrinolysis of BA occlusion reduces mortality, and the long
term prognosis of the survivors is better than previously thought. None of our
patients had a further stroke during the follow-up period, which indicates that
acute BA occlusion is not a strong indicator for advanced arteriosclerotic
disease.
PMID- 10773644
TI - Effect of nimodipine on final infarct volume after acute ischemic stroke.
AB - Placebo-controlled clinical trials with nimodipine in acute ischemic stroke have
not fulfilled the early optimistic expectations. Nimodipine has in some
experimental studies, when administered either before or up to 90 min after
induction of cerebral ischemia, resulted in a reduction of infarct size. No
studies on the effects of nimodipine on infarct size in man have been published.
We measured the infarct volumes in the admission and control CT examinations 3
weeks to 3 months later in 153 patients who had participated in a multicenter,
randomized and placebo-controlled study. No statistically significant differences
overall were found within or between the treatment groups. Subgroup analyses
revealed in the placebo, but not in the nimodipine arm, an increase in the median
infarct volumes if the treatment was started within 24 h of onset, and if the
volume in the admission CT was less than median. A beneficial effect of
nimodipine in prevention of infarct size increase in these circumstances cannot
be excluded.
PMID- 10773645
TI - The carotid compression test for therapeutic occlusion of the internal carotid
artery. Comparison of angiography with transcranial Doppler sonography.
AB - BACKGROUND: The anterior communicating artery is a key collateral pathway in
patients with internal carotid artery (ICA) occlusions. Diagnostic balloon or
manual occlusion of the ICA is a qualified test for the collateral function of
the circle of Willis. The aim of our study was to test whether transcranial
Doppler sonography (TCD) with manual carotid compression is able to predict the
degree of cross-over flow and tolerance of ICA occlusion. METHODS: A prospective
study was performed on 88 patients suffering from neck tumors or inoperable ICA
aneurysms with planned ligation or permanent balloon occlusion of the ICA.
Preceding a balloon occlusion lasting 20 min we performed TCD with manual carotid
compression test. Insufficient cross-over flow during transient carotid occlusion
was defined angiographically as missing opacification of the middle cerebral
artery (MCA) after selective injection of contrast media in the contralateral
ICA, and sonographically as a decrease greater than 60% in flow velocity of the
MCA ipsilateral to the carotid occlusion. RESULTS: TCD and angiography could be
compared in 70 of 88 patients. Angiography showed no or insufficient collateral
flow in 26%. All patients (n = 10) with a decrease in MCA velocity greater than
60% on angiography showed missing or poor cross-over flow. A greater than 50%
increase in the anterior cerebral artery (ACA) predicted moderate or good cross
over flow in 98%. Clinical observation revealed 11 transient neurological
deficits. Eight of them showed insufficient cross-over flow angiographically and
sonographically. In 2 of 11 only TCD revealed such low collateral supply. Neither
technique predicted hemodynamic ischemia in only 1 of the 11. CONCLUSION: TCD
with carotid compression test is a valid method for predicting interhemispheric
flow and clinically relevant hemodynamic compromise in cases of occlusion of the
ICA.
PMID- 10773646
TI - Intrathecal release of nitric oxide and its relation to final brain damage in
patients with stroke.
AB - The potential role of inflammatory mechanisms in the pathophysiology of ischemic
brain damage has intensely been discussed. We have recently demonstrated that
stroke patients display an intrathecal production of proinflammatory cytokines
early after onset of symptoms. IL-1beta, one of these cytokines, stimulates the
production of nitric oxide (NO), a potent inflammatory mediator. The aim of the
present study was to investigate the intrathecal levels of nitrate, one of the
main metabolites of NO in acute stroke and to relate its levels to brain damage.
Stroke patients were prospectively studied with clinical evaluation, radiological
assessment and analysis of intrathecal levels of nitrate by gas
chromatography/mass spectrometry. In addition, simultaneous analyses of cytokines
and of soluble Fas/APO-1 and bcl-2, two proteins regulating apoptosis, were
performed. The intrathecal levels of nitrate were not significantly different in
stroke patients compared to controls throughout the observation period. However,
the intrathecal levels of nitrate increased significantly 3 months after stroke
onset compared with the first 3 days. Interestingly, the levels of nitrate
measured at stroke onset were negatively correlated to the final size of infarct
volume (r = -0.69, p < 0.05) measured by MRI. In addition, patients with large
infarcts displayed significantly (p = 0.008) lower levels of nitrate in
cerebrospinal fluid compared to patients with small infarcts during the first 3
days after stroke onset. In contrast, the intrathecal levels of nitrate were
significantly positively correlated (r = 0.79, p < 0. 001) to the neurological
deficit and negatively correlated (r = -0. 76, p < 0.05) to bcl-2, a protein
downregulating neuronal apoptosis, in the late stage of the stroke. Early NO
production is associated with a smaller infarct volume, suggesting a protective
effect, whereas late NO production is associated with severer neurological
deficits, suggesting a neurotoxic effect. Treatment trials pertaining to modulate
NO production in stroke should take into consideration the dual effect of NO on
ischemic brain damage.
PMID- 10773647
TI - Intersonographer reproducibility and intermethod variability of ultrasound
measurements of carotid artery stenosis: The Tromso Study.
AB - BACKGROUND AND PURPOSE: Knowledge of the reproducibility of a diagnostic method
is important in order to evaluate its usefulness. Few studies have examined
interobserver and intermethod agreement on ultrasound measurements of carotid
stenosis. METHODS: Intersonographer agreement on ultrasound measurements of
carotid plaque morphology and the estimated degree of stenosis by three
ultrasound methods were assessed in a random sample of 51 participants with
stenotic carotid arteries selected from a population health survey. The degree of
stenosis was assessed by measurements of velocity, lumen diameter reduction and
cross-sectional lumen area. Intermethod agreement on the degree of carotid
stenosis was also assessed. RESULTS: Agreement on plaque echogenicity and
heterogeneity was moderate (kappa = 0.56 and kappa = 0.60, respectively). The
mean degree of stenosis and median absolute difference between observers of the
estimated degree of stenosis by the velocity method were 46.3 and 10.8%,
respectively. The corresponding values were 51.0 and 5.8% for the diameter
method, and 57.1 and 7.2%, for the cross-sectional lumen method. The limits of
agreement for intersonographer reproducibility varied between +/-19.7 and 26.5%.
For all methods, reproducibility increased with increasing degree of stenosis.
Differences between the methods were large in low-grade stenosis but were
acceptable in high-grade stenosis. CONCLUSIONS: Considerable differences in
ultrasound measurement of stenosis, which could lead to different clinical
conclusions, were regularly encountered no matter what ultrasound method was
used.
PMID- 10773648
TI - Correlates of informant-rated cognitive decline after stroke.
AB - Cognitive impairment is common after stroke, but measurement is problematic. Six
tests of mental ability, unaffected by loss of limb function, were administered
to 49 subjects of mean age 74.2 years at a median of 4.3 years (range 0.1-16.8)
after stroke together with a depression score and the IQCODE, an informant-rated
scale of estimated cognitive decline. Over 90% of stroke patients were able to
complete most tests. IQCODE correlated significantly with the HADS depression
score (r = 0.35, p = 0.040), the 2-year Barthel score (r = -0.60, p = 0.001) and
with a general cognitive factor extracted from the mental ability test scores (r
= -0.42, p = 0.016). We conclude that informant-rated methods offer a promising
approach to measuring cognitive decline after stroke.
PMID- 10773649
TI - Remote effects of acute ischemic stroke: A xenon CT cerebral blood flow study.
AB - OBJECTIVE: The purpose of this study was to verify transhemispheric diaschisis in
the early hours after an ischemic event. METHODS: XeCT cerebral blood flow (CBF)
studies within 8 h of stroke were studied in 23 patients. Mean CBF was evaluated
in the ischemic area, contralateral hemisphere and ipsilateral cerebellum.
RESULTS: A severe CBF reduction was found in the ischemic area (mean 9 +/- 3
ml/100 g/min). The mean CBF in the unaffected hemisphere (33 +/- 10 ml/100 g/min)
was 35% less compared to the normal mean value. CBF was decreased in the
cerebellum ipsilateral to the stroke (mean 31 +/- 12 ml/100 g/min) suggesting a
blood flow depression of the whole brain. CONCLUSIONS: During the initial hours
of cerebral ischemia, the asymptomatic hemisphere demonstrated CBF depression
that was part of the global flow reduction.
PMID- 10773650
TI - Hemorrhagic lacunar stroke.
AB - A total of 17 patients with lacunar syndromes due to intracerebral hemorrhage or
hemorrhagic lacunar stroke (pure motor hemiparesis 9, sensorimotor stroke 5, pure
sensory stroke 3) are reported. Data from these patients were obtained from
consecutive stroke patients included in the prospective Hospital Sagrat Cor
Alianca Stroke Registry. Hemorrhagic lacunar stroke accounted for 3.8% of all
cases of lacunar syndrome (n = 439) and 7.4% of all cases of intracerebral
hemorrhage (n = 229) entered in the database. Demographic, anamnestic, clinical
and neuroimaging variables in patients with hemorrhagic lacunar stroke, non
lacunar intracerebral hemorrhage and non-hemorrhagic lacunar stroke were
compared. Predictors of hemorrhagic lacunar stroke were assessed by logistic
regression analysis. Hypertension, cigarette smoking and involvement of the
internal capsule were significantly more frequent in patients with hemorrhagic
lacunar stroke than in those with non-lacunar intracerebral hemorrhage, whereas
nausea and vomiting, altered consciousness, speech disturbances, hemianopia, and
ventricular hemorrhage were significantly less frequent. As compared with non
hemorrhagic lacunar stroke, patients with hemorrhagic lacunar stroke were more
likely to have hypertension, sudden stroke onset (minutes), head injury,
headache, and basal ganglia involvement and less likely to have diabetes, gradual
stroke onset (hours), and dysarthria. After multivariate analysis, only headache
(OR 10.14), sudden onset (OR 9.89), and dysarthria (OR 0.10) were independent
predictors of hemorrhagic lacunar stroke. Accordingly, the presence of headache
and sudden onset of symptoms and absence of dysarthria may be useful signs for
distinguishing hemorrhagic lacunar stroke from other causes of lacunar stroke.
PMID- 10773651
TI - Cerebral venous infarction following thrombosis of the draining vein of a venous
angioma (developmental abnormality).
AB - We report two cases of cerebral venous angioma presenting as venous infarction,
one in the left parietal lobe, the other in the left frontal lobe. Cerebral
imaging demonstrated thrombotic occlusion of the draining vein of the venous
angioma associated in the latter case with thrombosis of the anterior part of the
superior longitudinal sinus. Both patients were free of coagulopathy. They were
treated with anticoagulant therapy. One completely recovered, while the other was
left with slight residual disability. Thrombosis of the draining vein has been
reported in only 6 previous cases, of whom only 2 received anticoagulant therapy.
Discovery of a venous angioma in the diagnostic workup of a patient with recent
neurological disorders should raise the question of a possible occlusion of the
draining vein and lead to an appropriate therapy.
PMID- 10773652
TI - Acute bilateral arm paresis.
AB - OBJECTIVE: To study pure motor bilateral arm paresis of acute onset. This
syndrome is as yet a barely described clinical feature attributed to ischemia in
the territory of the anterior spinal artery (ASA). CASES: We present 2 patients
with acute onset of pure motor deficit in both upper extremities. RESULTS:
Magnetic resonance imaging of the cervical spinal cord revealed infarcts in the
territory of the ASA. In 1 case, electrophysiology further suggested discrete
gray matter involvement. CONCLUSION: In patients with acute weakness of both arms
without further neurological deficits, an incomplete ASA syndrome should be
considered with the anterior horns predominantly being affected. Magnetic
resonance imaging and electrophysiology are valuable tools to further confirm
both location and extension of the spinal lesion.
PMID- 10773653
TI - Physician opinion on the secondary prevention of stroke: results of a survey in
New Zealand.
PMID- 10773654
TI - Systemic thrombolysis in cerebral venous thrombosis extended from the jugular
vein.
PMID- 10773655
TI - Report of the ninth international workshop on the identification of transcribed
sequences.
PMID- 10773656
TI - Replication banding patterns of the diploid-tetraploid treefrogs Hyla
chrysoscelis and H. versicolor.
AB - Populations of the diploid-tetraploid treefrogs Hyla chrysoscelis and H.
versicolor can be defined by the polymorphic positions of the nucleolar
organizing regions (NORs) on their chromosomes. Evidence from NOR positions and
interstitial telomere sequence data shows that gene flow between H. chrysoscelis
populations appears to be restricted, with contact occurring only in narrow
"hybrid" zones. Hyla versicolor appears to have had multiple origins from H.
chrysoscelis populations, and this, too, is reflected in the NOR positions. We
used replication banding to determine if genetic isolation of H. chrysoscelis
populations was accompanied by karyotype evolution in the populations or in
contact zones. We also sought to detect karyotype alteration or replication
differences associated with polyploidy in H. versicolor. Homologous chromosome
pairs of all H. chrysoscelis studied displayed no differences in replication
banding patterns, nor did they differ from those of H. versicolor. Although NOR
positions differed between the populations studied, no disturbance of the
replication banding patterns was found, indicating that structural rearrangements
were not involved in creating the multiple NOR positions seen in populations of
H. versicolor and H. chrysoscelis.
PMID- 10773657
TI - Cooperation of selection and meiotic mechanisms in the production of imbalances
in reciprocal translocations.
AB - We have used data from chromosomally unbalanced offspring observed at birth, as
well as data from sperm chromosome analysis, to study the meiotic segregation of
reciprocal translocations. Using data from a total of 1,597 unbalanced children,
we have observed an excess in maternal origin for all modes of imbalance. This
excess is particularly marked for the 3:1 unbalanced mode, for which we have also
observed a maternal age effect, indicating a close relationship with autosomal
trisomies. In addition, a statistical analysis of data from 34 different
published studies using sperm chromosome analysis has demonstrated that factors
which, for reasons of viability, produce a predisposition for a particular mode
of imbalance at birth also appear to favor meiotic production of this type of
imbalance. Thus the production of unbalanced gametes of a particular type is
influenced by the size of the imbalance.
PMID- 10773658
TI - Physical linkage of the lysyl oxidase-like (LOXL1) gene to the PML gene on human
chromosome 15q22.
AB - A contig was constructed centered on the PML (promyelocytic leukemia) gene. Using
an exon-trapping approach to identify potential genes from a pool of cosmids
located 5' of the PML gene, four exons were identified that showed 100% sequence
homology with the previously cloned lysyl oxidase-like (LOXL1) gene. An exon
probe identified a single transcript of 2.4 kb on a multitissue Northern blot
with a pattern identical to the one reported for the LOXL1 gene. Pulsed-field gel
electrophoresis showed comigrating bands for both the PML cDNA and LOXL1 probes,
demonstrating a physical linkage between these two genes. These data provide
physical mapping information to complement the previous cytogenetic localization
of LOXL1.
PMID- 10773659
TI - Jumping translocations in spontaneous abortions.
AB - Chromosome translocations involving one donor chromosome and multiple recipient
chromosomes have been referred to as jumping translocations (JTs). Acquired JTs
are commonly observed in cancer patients, mainly involving chromosome 1.
Constitutional forms of JTs mostly involve the acrocentric chromosomes and their
satellites and have been reported in patients with clinical abnormalities.
Recognizable phenotypes resulting from these events have included Down, Prader
Willi, and DiGeorge syndromes. The presence of JTs in spontaneous abortions has
not been previously described. The breakpoints of all JTs occur in areas rich in
repetitive DNA (telomeric, centromeric, and nucleolus organizing regions). We
report two different unstable chromosome rearrangements in samples derived from
spontaneous abortions. The first case involved a chromosome 15 donor. The
recipient chromosomes were 1, 9, 15, and 21, and the respective breakpoints were
in either the heterochromatic regions or the centromeres. FISH studies confirmed
that the breakpoints of the jumping 15 rearrangement did not involve the Prader
Willi region but originated at the centromere or in the proximal short arm. A
second case of instability was observed with a rearrangement resulting from a
presumed de novo 8;21 translocation. Three JT cell lines were observed. They
consisted of a deleted 8p chromosome, a dicentric 8;21 translocation, and an 8q
isochromosome. The instability regions appeared to be at the pericentromeric
region of chromosome 8 and the satellite region of chromosome 21. Both cases
proved to be de novo events. The unstable nature of the JT resulting in
chromosomal imbalance most likely contributed to the fetal loss. It appears that
JT events may predispose to chromosomal imbalance via nondisjunction and
chromosomal rearrangement and, therefore, may be an unrecognized cause of fetal
loss.
PMID- 10773660
TI - The SRY gene HMG-box in micro- and megabats.
AB - Sex determination in mammals is controlled by the Y-linked SRY gene, which
encodes a transcription factor with a DNA-binding motif of the HMG type. The only
conserved region in this gene is the HMG-box, whose nucleotide sequence is
currently available in a number of mammalian taxa. However, nothing is known
about this gene in bats. Here, we report partial sequences of the SRY HMG-box
from four microbat and four megabat species. We used the SRY HMG- box sequences
from micro- and megabats to test the phylogenetic relationships between
microbats, megabats, and primates. In maximum parsimony and maximum-likelihood
trees, mega- and microbat branches start in the same internal node, which is
consistent with a monophyletic origin of this mammalian group.
PMID- 10773661
TI - Cloning and mapping of murine superoxide dismutase copper chaperone (Ccsd) and
mapping of the human ortholog.
AB - Copper does not exist in a free state within cells but is found consistently
bound to metalloproteins. Specific metallochaperones escort copper to numerous
targets within the cell, providing protection from the toxic effects of
intracellular free copper. Many metallochaperones have been characterized in
yeast, mouse, and human. To further characterize mouse metallochaperones, we
cloned murine Ccsd from an adult mouse cDNA brain library, including both the
coding region and the 5' and 3' UTRs. We obtained a 1,174-bp cDNA with an 825-bp
open reading frame, translating a 274 amino acid protein that is 86.9% identical
to human CCS. Using a mouse x hamster radiation hybrid panel, we mapped Ccsd to a
proximal position on mouse chromosome 19. We mapped human CCS to 11q13
(homologous with mouse chromosome 19), utilizing a human x hamster radiation
hybrid panel. The human and mouse metallochaperones are ubiquitously expressed in
the major tissues of the body but seem to have different transcription products.
PMID- 10773662
TI - Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human
and rodent chromosomes by fluorescence in situ hybridization.
AB - Previously, a rodent cDNA encoding the third member of the Akt/PKB family of
serine/threonine kinases was cloned. We have now cloned the human homolog of this
cDNA, and we have used this clone to map the AKT3 gene to human chromosome 1q44
by fluorescence in situ hybridization (FISH). We have also mapped the rodent
homologs of AKT3 to rat chromosome 13q24-->q26 and mouse chromosome 1H4-6 by
FISH.
PMID- 10773663
TI - Assignment of the kinesin family member 4 genes (KIF4A and KIF4B) to human
chromosome bands Xq13.1 and 5q33.1 by in situ hybridization.
PMID- 10773664
TI - Cloning and characterization of human FTCD on 21q22.3, a candidate gene for
glutamate formiminotransferase deficiency.
AB - We have identified a new human gene, FTCD, which maps to chromosome 21q22.3 and
encodes the enzyme formiminotransferase cyclodeaminase, an intermediate
metabolism enzyme that links histidine catabolism to folate metabolism. The major
cDNA encodes a protein containing 541 amino acid residues and shows 84% identity
with porcine FTCD. Several other cDNAs have been isolated, which may result from
alternative splicing events and have the potential to code for three different
protein isoforms. The gene is highly expressed in human fetal and adult liver.
The two FTCD protein domains show high sequence similarity to two distinct open
reading frames from eubacterial genomes, suggesting that eukaryotic FTCD appeared
through a gene fusion event. Defects in the glutamate formiminotransferase
pathway have been documented, and the deficiency is presumed to be inherited as
an autosomal recessive trait. The sequence reported here may be helpful in
identifying the primary defect in glutamate formiminotransferase deficiency and
establishing a molecular diagnosis.
PMID- 10773665
TI - Karyotype and chromosome location of characteristic tandem repeats in the
pufferfish Tetraodon nigroviridis.
AB - Karyotype analysis of Tetraodon nigroviridis, a pufferfish of the family
Tetraodontidae with a small compact genome (385 Mb) which is currently being
investigated in our laboratory, indicates that this species has 2n = 42
chromosomes. The small chromosome size (the largest pair measuring less than 3
microm) has complicated accurate chromosome pairing based on morphology alone.
DAPI staining, however, provides a banding-like pattern. Because of quantitative
variations of some heterochromatin classes, the chromosome formula can not be
established precisely, but is estimated to include approximately 20 meta- or
submetacentric chromosomes and 22 subtelocentric chromosomes. A centromeric
satellite, telomeric repeats, and the major and minor rRNA clusters have been
localized unequivocally by FISH. As a result, the 28S and 5S rDNA sequences can
be used as chromosome-specific probes.
PMID- 10773666
TI - RET rearrangements in papillary thyroid carcinomas and adenomas detected by
interphase FISH.
AB - Activation of the RET protooncogene through somatic rearrangements represents the
most common genetic alteration in papillary thyroid carcinoma (PTC). Three main
rearranged forms of RET have been described: RET/PTC1 and RET/PTC3, which arise
from a paracentric inversion of the long arm of chromosome 10, and RET/PTC2,
which originates from a 10;17 translocation. We have developed a dual-color FISH
approach to detect RET/PTC rearrangements in interphase nuclei of thyroid
lesions. By using a pool of three cosmids encompassing the RET chromosome region
and a chromosome 10 centromeric probe, we could discriminate between the presence
of an inversion (RET/PTC1 and RET/PTC3) or a translocation (RET/PTC2). We have
investigated a series of thyroid tissue samples from Italian and French patients
corresponding to a total of 69 PTCs and 22 benign lesions. Among PTCs, 13 (18.8%)
showed a RET rearrangement, and 11 (15.9%) of these carried an inversion
(RET/PTC1 or RET/PTC3) in more than 10% of the nuclei examined. Activated forms
of RET were also observed in three adenomas. RT-PCR analysis on the same samples
confirmed the presence and the type of rearrangement predicted using FISH
analysis. An interesting difference in the frequency and type of RET
rearrangements was detected between the Italian and the French patients.
Furthermore, we identified a putative novel type of rearrangement in at least one
PTC sample. Several PTCs carried a significant number of cells characterized by a
trisomy or a tetrasomy of chromosome 10. Overall, the FISH approach in interphase
nuclei represents a powerful tool for detecting, at the single cell level,
RET/PTC rearrangements and other anomalies involving the RET chromosome region.
PMID- 10773667
TI - HMG20A and HMG20B map to human chromosomes 15q24 and 19p13.3 and constitute a
distinct class of HMG-box genes with ubiquitous expression.
AB - The HMG box encodes a conserved DNA binding domain found in many proteins and is
involved in the regulation of transcription and chromatin conformation. We
describe HMG20A and HMG20B, two novel human HMG box-containing genes, discovered
within the EURO-IMAGE Consortium full-length cDNA sequencing initiative. The
predicted proteins encoded by these two genes are 48.4% identical (73.9% within
the HMG domain). The HMG domain of both HMG20 proteins is most similar to that of
yeast NHP6A (38% to 42%). Outside of this domain, HMG20 proteins lack any
significant homology to other known proteins. We determined the genomic structure
and expression pattern of HMG20A and HMG20B. Both genes have several alternative
transcripts, expressed almost ubiquitously. HMG20A maps to chromosome 15q24 (near
D15S1227) and HMG20B to 19p13.3 (between D19S209 and D19S216). The HMG20 genes
define a distinct class of mammalian HMG box genes.
PMID- 10773668
TI - Chromosome localization and characterization of the mouse and human zinc finger
protein 265 gene.
AB - The chromosome location and pattern of expression of the gene encoding the zinc
finger protein 265 (alias "Zis") in human (ZNF265) and mouse (Zfp265) was
determined. By interspecific backcross analysis, we mapped Zfp265 to mouse
chromosome 3q. ZNF265 was localized to human chromosome 1p31 by fluorescence in
situ hybridization. Since discovery of Zfp265 (in rat) came from studies of
changes in renin expression in kidney cell lines, we examined the cell
specificity of expression in kidney and also determined hybridization of cDNA
with RNA in other tissues. We found that expression was not confined to renin
mRNA-containing cells but was ubiquitous. Moreover, the fact that highly
conserved homologs of ZNF265p exist in lower organisms (e.g., C4SR in Xenopus),
suggests that this protein may have a generalized role in posttranscriptional
mechanisms in various cell types and species.
PMID- 10773669
TI - Assignment of rat estrogen sulfotransferase gene (Ste) to rat chromosome band
14p21.3-->p21.2.
PMID- 10773670
TI - Assignment of liver-specific organic anion transporter (SLC22A7) to human
chromosome 6 bands p21.2-->p21.1 using radiation hybrids.
PMID- 10773671
TI - Cloning and expression of CIS6, chromosome assignment to 3p22 and 2p21 by in situ
hybridization.
AB - A family of negative regulators of JAK signaling pathway referred to as
suppressor of cytokines signaling (SOCS) or cytokine-inducible SH2 protein (CIS)
has been recently identified. In order to find additional members of this family,
we have used a consensus amino acid sequence contained in the well-conserved
central SH2 domain to search DNA databases. We isolated cDNA coding for the human
homologue of SOCS-5, referred to as CIS6. Northern blot analysis revealed CIS6
mRNA expression in various tissues such as heart, muscle, spleen, and thymus and
in all myeloma cell lines examined. The gene was assigned to human chromosome
bands 2p21 and 3p22 by in situ hybridization. CIS6 is structurally related to
other members of the CIS family and therefore could act as a negative regulator
of signal transduction.
PMID- 10773672
TI - Eukaryotic translation termination factor gene (ETF1/eRF1) maps at D5S500 in a
commonly deleted region of chromosome 5q31 in malignant myeloid diseases.
AB - The human genome contains four ETF1 (eukaryotic translation termination factor 1)
homologous sequences, localized on chromosomes 5, 6, 7 and X, and corresponding
to a functional gene on chromosome 5 and three processed pseudogenes on the other
chromosomes. ETF1 genomic or cDNA probes were mapped by fluorescence in situ
hybridization to 5q31, 6p21, 7q11 and Xp11.4-->p11.1. A microsatellite marker
(D5S500) was identified in intron 7 of the functional ETF1 gene providing its
exact position in the 5q31 band. Thus, the ETF1 gene is located in a 5q region
which contains unidentified genes responsible for genetic or malignant disorders,
and it might be considered as a candidate gene involved in the pathogenesis of
these diseases.
PMID- 10773673
TI - Assignment of OSTF1 to human chromosome bands 12q24.1-->q24.2 by in situ
hybridization.
PMID- 10773674
TI - Assignment of SYNJ1 to human chromosome 21q22.2 and Synj12 to the murine
homologous region on chromosome 16C3-4 by in situ hybridization.
PMID- 10773676
TI - Assignment of desert hedgehog (DHH) to human chromosome bands 12q12-->q13.1 by in
situ hybridization.
PMID- 10773675
TI - Assignment of the human mitochondrial translational release factor 1 (MTRF1) to
chromosome 13q14.1-->q14.3 and of the human mitochondrial ribosome recycling
factor (MRRF) to chromosome 9q32-->q34.1 with radiation hybrid mapping.
PMID- 10773677
TI - Assignment of human GADD45G to chromosome 9q22.1-->q22.3 by radiation hybrid
mapping.
PMID- 10773678
TI - Assignment of the neuropsin gene (Prss19) to mouse chromosome band 7B4 by in situ
hybridization.
PMID- 10773679
TI - Assignment of the dipeptidyl peptidase III gene (DPP3) to human chromosome 11
band q12-->q13.1 by in situ hybridization.
PMID- 10773680
TI - Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by
radiation hybrid mapping.
PMID- 10773681
TI - Suppressor genes for malignant and anchorage-independent phenotypes located on
human chromosome 9 have no dosage effects.
AB - We have previously shown that microcell-mediated transfer of a der(9)t(X;9) human
chromosome (HSA), derived from human fibroblast strain GM0705, into the Syrian
hamster cell line BHK-191-5C produced only near-tetraploid hybrids, although the
recipient cell line contained a 1:1 ratio of near-diploid and near-tetraploid
cells. However, the tumorigenicity and the anchorage independence could be
suppressed in the near-tetraploid hybrids with one copy of the der(9)t(X;9)
chromosome. The introduction of an HSA X chromosome did not suppress either of
these phenotypes. We concluded that in addition to two suppressor genes, one for
tumorigenicity and another for anchorage independence, HSA 9 might carry a third
gene capable of inhibiting cellular growth in vitro, which had dosage effects. In
the present study, keeping one copy of the der(9)t(X;9) chromosome, we have
increased the hamster background chromosome number beyond hexaploid level by
fusing two microcell-generated hybrid cell lines, where both malignant and
anchorage-independent phenotypes were suppressed, with the parental malignant BHK
191-5C cell line. Tests with nude mice showed that hybrids containing one copy of
the der(9)t(X;9) chromosome against the increased background of chromosomes of
malignant parental origin were still suppressed for both phenotypes. These
results suggest that the suppressor genes for malignancy and for anchorage
independence have no dosage effects, in contrast to the suppressor gene(s) for
cellular growth.
PMID- 10773682
TI - Evidence for suppression of cellular growth in vitro and selection against the
indigenous mouse X chromosome in A9 cell hybrids after microcell-mediated
transfer of an X from other mammalian species.
AB - Introduction of a human or Syrian hamster X chromosome (derived from BHK-191-5C
cell hybrids) into tumorigenic mouse A9 cells via microcell fusion induced
changes in cellular morphology and a retardation of cellular growth. The
suppression of growth of the hybrids could be abolished, however, by daily
changes of medium containing 20% serum. G-banding analysis showed the absence of
a single, cytogenetically identifiable, indigenous X chromosome (marker Z) in two
of four hybrid clones after an X chromosome was transferred from either hamster
or human cells. All hybrids were tumorigenic when tested in nude mice. Together,
these data suggest that the loss of the mouse X chromosome took place probably
because of growth inhibitory effects imposed on hybrid cells due to the increase
in X chromosome dosage. In addition, our results show a lack of association
between the phenotype of cellular growth suppression in vitro and the phenotype
of suppression of tumorigenicity in vivo.
PMID- 10773683
TI - FISH-microdissection (FISH-MD) analysis of complex chromosome rearrangements.
AB - We combined the techniques of fluorescence in situ hybridization (FISH) and
chromosomal microdissection in one experiment (FISH-MD). This novel method
permits rapid identification of the composition, origin, and breakpoints of
rearranged chromosomes. Rearranged chromosomes are first identified by multicolor
FISH, then the fluorophore-labeled derivative chromosomes are directly isolated
by microdissection and reverse painted to identify the breakpoints.
PMID- 10773684
TI - Localization of new, microdissection- generated, anonymous markers and of the
genes Pcsk1, Dhfr, Ndub13, and Ccnb1 to rat chromosome region 2q1.
AB - The centromeric region of rat chromosome 2 (2q1) harbors unidentified
quantitative trait loci of genes that control tumor growth or development. To
improve the mapping of this chromosome region, we microdissected it and generated
10 new microsatellite markers, which we included in the linkage map and/or
radiation hybrid map of 2q1, together with other known markers, including four
genes: Pcsk1 (protein convertase 1), Dhfr (dihydrofolate reductase), Ndub13 (NADH
ubiquinone oxidoreductase subunit b13), and Ccnb1 (cyclin B1). To generate anchor
points between the different maps, the gene Ndub13 and the microsatellite markers
D2Ulb25 and D2Mit1 were also localized cytogenetically. The radiation map
generated in region 2q1 extends its centromeric end of about 150 cR.
PMID- 10773685
TI - X;Y translocation revealed by chromosome microdissection and FISH in fertile XY
females in the Brazilian rodent Akodon montensis.
AB - In a Brazilian population of the neotropical rodent Akodon montensis we found
five sex-reversed XY females. These animals were cytogenetically analyzed by
chromosome painting using species-specific DNA probes from the Y chromosome,
generated by chromosomal microdissection and subsequent use of the degenerate
oligonucleotide-primed polymerase chain reaction (DOP-PCR). The results showed a
chromosome complement with an apparently normal Y chromosome and an X chromosome
carrying a translocation that encompasses a large portion of the Y chromosome
(seemingly the entire Y). Ovarian histology suggested that these females are
fertile. Amplification of the SRY HMG box sequence by PCR shows that at least one
copy of the Sry gene is present in the A. montensis XY females. Based on our
findings, we suggest that the breakpoint of the X;Y translocation probably
altered an X-linked sex-determining locus (or loci), blocking testicular
organogenesis in the XY females. Further studies are necessary to determine the
precise location and role of this putative sex-determining chromosomal region.
Genetic mechanisms of XY sex reversal in A. montensis populations are discussed.
PMID- 10773686
TI - Structure of the human glutamate-L-cysteine ligase catalytic (GLCLC) subunit
gene.
AB - Glutamate-L-cysteine ligase (GLCL [EC 6.3.2.2], also referred to as gamma
glutamylcysteine synthetase) catalyzes the rate-limiting reaction in the
synthesis of the important cellular antioxidant glutathione. GLCL is a
heterodimer consisting of a catalytic (GLCLC) and a regulatory (GLCLR) subunit.
The structure of the human GLCLC subunit gene, GLCLC, which has been mapped to
chromosome 6p12, spans 51.4 kb and consists of 16 exons separated by 15 introns.
PMID- 10773687
TI - Analysis of genetic heterogeneity among five gynogenetic clones of silver crucian
carp, Carassius auratus gibelio Bloch, based on detection of RAPD molecular
markers.
AB - The gynogenetic silver crucian carp, Carassius auratus gibelio, is a unique model
system for studying evolutionary genetics and selective breeding, owing to its
specific genetic background and reproductive modes. Five gynogenetic clones were
analyzed by the random amplified polymorphic DNA (RAPD) technique, using 30 10
nucleotide-long primers. Twenty-six primers produced well-amplified DNA fragments
with reproducible banding patterns, and 24 primers were polymorphic. Nearly
identical banding patterns were observed among individuals within each clone,
suggesting that each clone might possess a specific pattern owing to its
gynogenesis. In contrast, the RAPD patterns of the five clones differed from each
other. A phylogenetic tree was constructed using UPGMA cluster analysis based on
a total of 3,744 distinguishable fragments (156 per individual). Average genetic
distances within and among the five clones clearly indicated their intraclonal
homogeneity, interclonal heterogeneity, and phylogenetic relationships. Clones A
and P were the most closely related, whereas the most divergence was seen between
clone D and clone E or F. A total of 88 polymorphic fragments were scored from 24
primers after excluding bands that were monomorphic for the five clones. Most
primers corresponding to the polymorphic fragments amplified reproducible markers
specific for one clone or that were shared by two, three, or four clones. Several
primers (e.g., Opj-1, Opj-7, and Opp-10) produced abundant banding patterns that
could be used to discriminate between the five clones. Markers specific for one
or two clones were also identified. The RAPD markers identified in this study
will likely benefit evolutionary genetics and selective breeding studies.
PMID- 10773688
TI - Cloning, characterization, and physical mapping of the canine Prop-1 gene
(PROP1): exclusion as a candidate for combined pituitary hormone deficiency in
German shepherd dogs.
AB - Abnormalities in the genes encoding Pit-1 and Prop-1 have been reported to cause
combined pituitary hormone deficiency (CPHD) in mice and humans. In dogs, a
similar phenotype has been described in the German shepherd breed. We have
previously reported that the Pit-1 gene (POU1F1) is not mutated in affected
German shepherd dogs. In this study, we report the isolation and mapping of the
canine Prop-1 gene (PROP1), and we assessed the involvement of PROP1 in German
shepherd dog dwarfism. The canine PROP1 gene was found to contain three exons,
encoding a 226 amino acid protein. The deduced amino acid sequence was 79% and
84% homologous with the mouse and human Prop-1 protein, respectively. Using
fluorescence in situ hybridization, PROP1 was mapped to canine chromosome 11.
Further mapping with a canine radiation hybrid panel showed co-localization with
the polymorphic DNA marker AHT137. Sequence analysis of genomic DNA from dwarf
German shepherd dogs revealed no alterations in the PROP1 gene. Moreover, linkage
analysis of AHT137 revealed no co-segregation between the PROP1 locus and the
CPHD phenotype, excluding this gene as candidate for canine CPHD and providing a
new spontaneous model of hypopituitarism.
PMID- 10773689
TI - Spectral karyotyping of the human colon cancer cell lines SW480 and SW620.
AB - The cell lines SW480 and SW620, derived from different stages of colon carcinoma
in the same patient, have been used for a number of biochemical, immunological,
and genetic studies on colon cancer. A comparative analysis of their karyotypes
may identify chromosomal aberrations that might represent markers for metastatic
spread. In the present study spectral karyotyping (SKY) was applied to these two
colon cancer cell lines. Compared to previously reported G-banded karyotypes, 9
(SW480) and 7 (SW620) markers were identical, 3 (SW480) and 3 (SW620) markers
could be redefined, 5 (SW480) and 8 (SW620) markers were newly identified, and 4
(SW480) and 5 (SW620) of the previous described markers could not be confirmed.
The redefined aberrations include very complex rearrangements, such as a der(16)
t(3;16;1;16;8;16; 1;16;10) and a der(18)t(18;15;17)(q12; p11p13;??) in SW620 and
a der(19)t(19;8;19;5) in SW480, that have not been identified by conventional
banding techniques. The resulting chromosome gains (5q11-->5q15, 7pter-->q22, 11,
13q14-->qter, 20pter-->p12, X) and losses (8pter-->p2, 18q12-->qter, Y) found in
both SW480 and SW620 were in good agreement with those frequently described in
colorectal tumors as primary changes in the stem cell. Abnormalities found
exclusively in SW620 cells only (gains of 5pter-->5q11, 12q12-->q23, 15p13-->p11,
and 16q21-->q24 and losses of 2pter-->2p24, 4q28-->qter, and 6q25-->qter) can be
viewed as changes that occurred in a putative metastatic founder cell.
PMID- 10773690
TI - Murine chromosome 16 telomeric region, homologous with human chromosome 21q22,
contains the osmoregulatory Na(+)/myo-inositol cotransporter (SLC5A3) gene.
AB - The murine Na(+)/myo-inositol cotransporter (SLC5A3) gene (Slc5a3) was cloned,
the restriction sites mapped, and the coding region sequenced. Similar to other
mammalian counterparts, including human, the gene has a single coding exon, with
an open reading frame of 2.2 kb. The predicted protein of 718 amino acids is also
highly conserved, compared to other mammalian homologs. Using fluorescence in
situ hybridization, Slc5a3 was localized to the telomeric region of mouse
chromosome 16, which is syntenic to human chromosome 21q22. An increased Slc5a3
copy number may explain the increased levels of myo-inositol in the brains of
trisomy 16 mice and the increased rate of transport of myo-inositol into cultured
neurons derived from trisomy 16 mice.
PMID- 10773691
TI - Characterization of a new TSPY gene family member in Yq (TSPYq1).
AB - We investigated subinterval 6E on the human Y chromosome, a region frequently
deleted in infertile males. YAC yOX17, mapped within subinterval 6E by STS-PCR,
was analyzed for the presence of new genes. TSPYq1, a member of the TSPY multi
copy gene family, was isolated and characterized from a yOX17 cosmid subclone.
PCR and FISH analysis performed on normal subjects and on patients with
microdeletions of Yq suggested the presence of multiple copies of TSPY in Yq.
PMID- 10773692
TI - Mouse linkage cytogenetics (L-C) probes.
AB - We have identified 149 hybridization probes at 10-cM intervals in the mouse and
have confirmed their order and linkage by fluorescence in situ hybridization.
These probes represent a new resource for mapping in the mouse and can be used to
correlate linkage and cytogenetic maps, to map novel sequences to within a few
centimorgans, to relate cytogenetic abnormalities to the genetic map, and to make
cross-species comparisons.
PMID- 10773693
TI - From axioms to new insights into dandruff.
AB - This review addresses the current concepts about dandruff. The nature, origin and
treatments of such skin conditions are scrutinized. The role of Malassezia spp.
and other triggering factors is highlighted.
PMID- 10773694
TI - A peculiar sequence motif in the alpha-1-domain of the HLA-C molecule in
psoriasis.
AB - BACKGROUND: Most immunogenetic studies restrict the location of the
susceptibility gene for psoriasis to the HLA-C locus. OBJECTIVE: The present
study evaluates the amino acid sequences of the HLA-C binding groove associated
with the disease in a restricted population of Italian descent: Pavia, Northern
Italy. METHOD: Forty patients, affected by psoriasis, underwent genomic analysis
of exons 2 and 3 of the HLA-C gene by means of the PCR-SSP technique. RESULTS:
The HLA-C*0602 gene frequency was significantly higher in patients with respect
to 122 sex-, age- and ethnically matched controls (25 vs. 8.6%, chi(2) = 14.65, p
= 0.000129). This frequency rose to 39.5% in patients with a family history
positive for psoriasis. In particular, 4 amino acid substitutions were shown to
be crucial for the predisposition to the disease, namely Ala 73 and Asn 77
(located in the C pocket of the antigen binding groove), Lys 80 in the F pocket
and Asp 90 in the outer loop of the molecule. This peculiar motif, entirely
located in the alpha(1)-domain of the HLA-C molecule, was characteristic of
psoriatic patients being present in 77.5% of the cases against the 50.82% of
controls (chi(2) = 8.77; p = 0.0031). Homozygosity for the amino acids considered
at these residues was found in 15% of patients and in 0% of controls (chi(2) =
20.74, p = 0.0000053). CONCLUSION: The most important results emerging from this
study indicate that Ala 73, Asn 77, Lys 80 and Asp 90 together form a motif
restricted to few pathogenic peptides to be studied in the near future.
PMID- 10773695
TI - Detection of Herpes simplex virus DNA in non-herpetic areas of patients with
eczema herpeticum.
AB - BACKGROUND: Patients with atopic dermatitis may develop a widespread cutaneous
herpes simplex virus (HSV) infection called eczema herpeticum. OBJECTIVE: We
examined the possible routes of indirect HSV dissemination in 10 patients with
eczema herpeticum, although direct spread of HSV is the most likely route of
infection. METHODS: Specimens were collected from hands and 'non-herpetic' areas
(i.e. without eczema herpeticum), with or without eczematous and/or erythematous
lesions of atopic dermatitis, of 10 patients with eczema herpeticum. We tried to
detect HSV DNA in the samples by polymerase chain reaction. RESULTS: HSV DNA was
frequently detected on both hands and on cutaneous surfaces clinically free of
eczema herpeticum. These patients had scratched such lesions because of itching.
Moreover, they had taken baths the day before the examination. CONCLUSION: These
results suggest that there may be two routes of indirect transmission of this
virus, namely via manual scratching of herpetic lesions or via a contaminated
bath towel or item of underwear.
PMID- 10773696
TI - Alopecia areata and coeliac disease: no effect of a gluten-free diet on hair
growth.
AB - BACKGROUND: An association between alopecia areata (AA) and coeliac disease has
recently been reported. AIM: The aim of this paper was to evaluate the possible
effect of a gluten-free diet (GFD) on the new growth of hair in 5 alopecic
patients with CD. METHODS: CD was diagnosed in 5 patients with AA (universalis in
3 cases and patchy in 2 cases). The diagnosis of CD was based on serological and
histological standard criteria. RESULTS: In all patients the GFD resolved CD
clinically, serologically and histologically but had no effect on the course of
alopecia. CONCLUSION: AA and CD, when associated, present different responses to
a GFD and have an independent course.
PMID- 10773697
TI - Penicillin G does not alter collagen type I metabolism of dermal fibroblasts in
culture.
AB - BACKGROUND: Penicillin G (PenG) has successfully been used for therapy of dermal
fibrosis in patients suffering from systemic sclerosis (SSc). However, there is
little knowledge on the mechanism of the antifibrotic action of PenG. OBJECTIVE:
We studied the effects of PenG on dermal fibroblasts by analysing the influence
of various amounts of PenG on the proliferation, synthesis and degradation of
collagen by human dermal fibroblasts from healthy donors and 1 SSc patient
(collagen high producer). METHODS: Collagen metabolism of cultured dermal
fibroblasts was studied by Northern hybridisation for mRNA of collagen I, proline
4-hydroxylase, lysyl hydroxylase, matrix metalloproteinase I and determination of
collagen content in culture supernatants. RESULTS: PenG did not alter the
expression of the investigated mRNA, independently of the dosage and the
incubation times used. The amount of collagen I protein was not influenced.
CONCLUSION: There is no evidence of a direct antifibrotic effect of PenG on
dermal fibroblasts; therefore, other mechanisms might be responsible for its
effect in the treatment of SSc patients.
PMID- 10773698
TI - Blisters on psoriatic lesions treated with TL-01 lamps.
AB - BACKGROUND: Asymptomatic blisters on psoriatic plaques are an uncommon adverse
effect of TL-01 (UVB narrow-band 312 nm) phototherapy. OBJECTIVE: We report 7 new
cases aiming to clarify the pathogenesis. METHODS: Blisters were biopsied at
different times after onset. Blood porphyrins and antibodies to nuclear antigens
and the cell surface of keratinocytes were investigated. RESULTS: We observed 7
asymptomatic blistering eruptions strictly limited to recovering psoriatic
plaques. Biopsies taken within 24 h showed junctional detachment and apoptotic
necrosis of basal keratinocytes. After 48 and 72 h, the blisters were
intraepithelial, due to basal cell regeneration, and were no longer evident at 96
and 120 h. Dermal inflammation was always mild. Direct immunofluorescence tests
as well as stainings for p53 protein did not show substantial changes. Blood
investigations were negative. CONCLUSIONS: TL-01 blisters are caused by the quick
reduction of acanthosis and desquamation before defensive mechanisms, i.e. the
increase in the thickness of the stratum corneum and pigmentation, develop.
However, the pathogenetic mechanisms of apoptosis of keratinocytes remain
unknown.
PMID- 10773699
TI - Treatment of Old World cutaneous leishmaniasis by pentamidine isethionate. An
open study of 11 patients.
AB - BACKGROUND: Pentavalent antimonial derivatives (PAD), especially meglumine
antimoniate (Glucantime((R))), are usually considered as the first-line drugs for
Old World leishmaniasis, but their potential toxicity and the number of required
injection, either intralesional or intramuscular, prompt to search for
alternative treatments. OBJECTIVE: To evaluate the efficiency and tolerance of
pentamidine isethionate in Old World leishmaniasis. METHODS: An open pilot study
included 11 patients from two regional academic centers, with varied
parasitological forms of Old World leishmaniasis, treated with three strictly
intramuscular injections of 4 mg/kg of base-pentamidine every other day. RESULTS:
Tolerance was good overall, and 8/11 (73%) of patients responded well with a
quick healing of their lesions, little scarring and no relapse. CONCLUSION:
Pentamidine isethionate is a safe and effective first-line treatment for Old
World leishmaniasis. Larger-scale prospective studies comparing several dosage
regimens of pentamidine and pentamidine isethionate to PAD are warranted.
PMID- 10773700
TI - Exposure at home to airborne concentrations of nitrogen mustard during topical
application for the treatment of mycosis fungoides: a case study.
AB - BACKGROUND: Although effective at treating mycosis fungoides (MF), nitrogen
mustard (HN(2)) creates potential exposure risks to those who administer it,
including health care workers and family members. OBJECTIVE: The main objective
was to examine the potential for nontarget individuals to be exposed to HN(2)
vapors during and shortly after treatment with HN(2) in a home environment.
METHODS: Air concentrations of HN(2) were measured during the topical treatment
of MF in a patients home. RESULTS: The results demonstrate that eye and mucous
membrane irritation may occur at HN(2) levels commonly encountered during the
treatment of MF in the home, hospital or health clinic. Because no exposure
thresholds have been developed for HN(2), the exposure thresholds of a surrogate
chemical (sulfur mustard) were used. CONCLUSIONS: The study findings show that
eye and mucous membrane irritation may occur at HN(2) levels below the exposure
thresholds of the surrogate chemical. Recommendations for controlling exposures
to HN(2) in the home are given.
PMID- 10773701
TI - Long-term cefuroxime axetil in subacute cutaneous lupus erythematosus. A report
of three cases.
AB - BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) is a subset of lupus
erythematosus characterized mainly by prominent photoaggravated cutaneous
manifestations. Standard therapies for SCLE include topical or systemic steroids
and antimalarial drugs. Both methods show limited efficacy in clearing cutaneous
lesions and occasionally produce serious side effects. AIM: To assess the
efficacy of cefuroxime axetil, an oral cephalosporin with antibacterial and
immunosuppressive activity, in patients with SCLE. METHODS: Three patients with
SCLE were treated with cefuroxime axetil at a daily dose of 500 mg for 30-60
days. RESULTS: In all patients complete clearing of skin lesions was achieved and
no side effects were observed. CONCLUSION: We suggest that long-term cefuroxime
axetil administration might be an alternative treatment for patients with SCLE
skin lesions.
PMID- 10773702
TI - Downward trend of sensitization to glyceryl monothioglycolate in German
hairdressers. IVDK study group. Information Network of Departments of
Dermatology.
AB - BACKGROUND: Due to a high incidence of cases of (occupational) sensitization to
glyceryl monothioglycolate (GMT), products containing this compound were
withdrawn from the German market some 8 years ago. METHODS: We analyzed the data
of the Information Network of Departments of Dermatology in Germany which
included 1, 336 hairdressers who had been tested with GMT (1% in petrolatum)
between 1992 and 1998. RESULTS: The proportion of hairdressers reacting
positively to GMT fell from initially 45% in 1992 to less than 20% in 1997 and
1998. CONCLUSION: This most likely reflects the above-mentioned preventive
action.
PMID- 10773703
TI - Coincidence of multiple, disseminated, tardive-eruptive blue nevi with cutis
marmorata teleangiectatica congenita.
AB - A 71-year-old woman reported a slow progression of multiple bluish dark
asymptomatic macules and papules on the pretibial region of both lower legs for
over 30 years. At birth a left-sided hypoplasia of the leg including the buttock
accompanied by a connatal vascular nevus had been diagnosed. The ipsilateral deep
veins of the pelvis and leg had a normal anlage. Histopathological examination
revealed multiple blue nevi of the common type. The association of multiple blue
nevi and cutis marmorata teleangiectatica congenita with limb hypoplasia has not
previously been reported and is discussed in this paper. One could speculate
whether these symptoms represent a new syndrome, because by thorough examination
the NAME syndrome could be ruled out.
PMID- 10773704
TI - Takayasu arteritis and cutaneous necrotizing vasculitis.
AB - Takayasu arteritis (TA) is an inflammatory arteriopathy involving predominantly
the aorta and its main branches. The disease evolves in two phases: a first,
nonspecific inflammatory stage and a late 'pulseless' stage, in which
complications related to arterial stenosis and aneurysm formation predominate. In
both phases, skin manifestations, such as inflammatory nodules, erythema-nodosum-
and pyoderma-gangrenosum-like ulcers, have been described. We report 2 patients
with TA, who had cutaneous necrotizing vasculitis as presenting manifestation of
the disease. A review of the literature revealed 8 similar cases. TA does not
only involve large arteries, but also small blood vessels. The observation that
in TA the inflammatory process of the large arteries affects regions of the walls
supplied by the vasa vasorum, the anatomy of which bears resemblance to the
cutaneous vessel system, suggests that primary involvement of small vessels
contributes to the development of the clinicopathological features of TA.
Knowledge of the skin manifestations associated with TA remains important for its
diagnosis and prompt instauration of life-saving treatment.
PMID- 10773705
TI - Late cutaneous schistosomiasis representing an isolated skin manifestation of
schistosoma mansoni infection.
AB - Ectopic late cutaneous schistosomiasis is usually preceded or accompanied by
visceral schistosomiasis infection. Our patient presented the very rare case of
late cutaneous schistosomiasis as an isolated skin manifestation. Perigenital
lesions occurred 1 year after contact with infested water. Identification of the
few eggs remaining in the late lesion among the dense cellular infiltrate was
difficult. Electron-microscopic studies clearly demonstrated the characteristic
eggshell ultrastructure.
PMID- 10773706
TI - Diffuse calcinosis cutis in a patient with congenital leukemia and leukemia
cutis.
AB - We report an unusual case of congenital leukemia with leukemia cutis (LC) and
diffuse calcinosis cutis. A newborn girl presented with widespread dusky red and
yellowish cutaneous nodules and papules. Bone marrow morphology was consistent
with the diagnosis of acute monocytic leukemia of the FAB M5 type. Skin biopsy
specimens confirmed the presence of a leukemic infiltrate and revealed calcium
salt deposition in the papillary and reticular dermis. Calcinosis was diffuse in
the whole skin but spared other organs. Vascular calcification was not present.
Serum calcium levels oscillated between 2.5 and 2.86 mmol/l, and phosphorus,
parathyroid hormone and 25-hydroxyvitamin D(3) levels were normal. There were
diffuse osteoporosis and spontaneous fractures of small tubular bones. The
patient responded to chemotherapy but, following consolidation treatment,
developed sepsis and died at 120 days of age. Congenital leukemia is rare and LC
is uncommon. Hypercalcemia may be a complication of leukemia, which leads to
multiorgan metastatic calcification. Despite the absence of frank hypercalcemia,
the presence of bone lesions suggests that the patient's calcinosis cutis was of
the metastatic type. However, the cutaneous leukemic infiltrate may also
represent a triggering factor for calcium deposition in the skin.
PMID- 10773707
TI - Transverse nasal line associated with congenital persistent milia.
PMID- 10773708
TI - Verrucous carcinoma of the penis completely cured with shaving and intralesional
interferon.
PMID- 10773709
TI - Conjugal HHV-8 infection with cutaneous Kaposi's sarcomas and Castleman's
disease: fortuitous association or not?
PMID- 10773710
TI - Role of iron in dermatology.
AB - Iron is involved in several biological reactions and is essential to almost all
forms of life. In contrast, iron is potentially toxic. It may participate in many
dermatological disorders, including pigmentation changes, inflammation,
porphyrias, infections and cancers. The involvement of iron in these disorders
entails a variety of mechanisms, including among others simple deposition
processes, activation or inactivation of enzymatic systems, impairment of
phagocyte functions and interference with apoptosis. A better understanding of
the role of iron might provide novel therapeutic strategies based on iron
chelating and/or anti-oxidant agents.
PMID- 10773711
TI - Current guidelines in melanoma treatment. Melanoma Working Group of Gent and
Bordet.
AB - This article focuses on the actual management of cutaneous melanoma, dealing both
with established, internationally well-accepted standard procedures and
interventions which are still being investigated. It wants to offer a global
picture to the dermatologist of what is currently available in the therapeutic
arsenal against melanoma.
PMID- 10773712
TI - An appraisal of 18-fluorodeoxyglucose positron emission tomography for melanoma
staging.
AB - BACKGROUND: Positron emission tomography (PET scan) using fluorodeoxyglucose
(FDG) is increasingly recognized as a reliable diagnostic method to detect
metastases of malignant melanoma (MM). OBJECTIVE: To compare the diagnostic
performance of 18-FDG PET scan to that of conventional imaging. METHODS: A total
of 28 assessments were conducted in 24 patients at risk of metastatic MM.
RESULTS: The diagnostic accuracy was over 80% and similar for PET scan and
conventional imaging. CONCLUSION: Both the specificity and sensitivity of PET
scan are high although not perfect. Confrontation of data with anatomical
location and clinicopathological findings remains mandatory.
PMID- 10773713
TI - Medullary CD30+ T cell lymphoma with eosinophilia and hyper-IgE supervening
during the relentless course of pityriasis lichenoides.
AB - We report a case of extensive pityriasis lichenoides exhibiting a relentless
course. PUVA therapy and oral retinoids cleared temporarily the lesions but did
not really halt the course of the disease. Eosinophilia and hyper-IgE occurred
after 50 years of evolution. An aggressive medullary CD30+ T cell lymphoma
without skin involvement was then diagnosed when pityriasis lichenoides became
more extensive and necrotic. The disease was rapidly fatal.
PMID- 10773714
TI - Varicella-zoster virus vasculitis: a case of recurrent varicella without
epidermal involvement.
AB - New types of diseases due to the varicella-zoster virus (VZV) are increasingly
recognized. A case of cutaneous VZV vasculitis without epidermal involvement is
presented. The patient received chemotherapy for a large B cell lymphoma. He
presented a few painless papules on one hand and in the axilla. A lymphocytic
vasculitis was evidenced. Immunohistochemistry revealed the presence of VZV in
endothelial cells and dermal dendrocytes. Nerves and keratinocytes were free of
the virus infection. Such a presentation probably represents a mild form of
recurrent varicella with prominent but limited vascular involvement.
PMID- 10773715
TI - Pyoderma gangrenosum as an early revelator of acute leukemia.
AB - Bullous pyoderma gangrenosum is an atypical, more superficial variety of the
classical pyoderma and is often associated with myeloproliferative disorders. We
present the case of a patient who presented initially with subcutaneous nodules
and who developed bullous lesions afterwards. Histological evaluation showed the
presence of neutrophilic infiltrates in both lesions. A few months after the
diagnosis of bullous pyoderma gangrenosum, an underlying leukemia was revealed.
Our case illustrates the importance of regular blood and bone marrow examinations
in patients with atypical bullous pyoderma gangrenosum, resulting in a rapid
diagnosis of the underlying disease.
PMID- 10773716
TI - Epithelioid sarcoma: a puzzling soft tissue neoplasm in a child.
AB - Epithelioid sarcoma (ES) is a rare soft tissue neoplasm that usually occurs on
the upper extremity of adolescents and young adults. It rarely occurs during
childhood. ES is a slowly growing tumor with a high propensity for recurrences
and metastases. This neoplasm is likely to be confused with a variety of benign
and malignant conditions. Recognition of ES is important. The treatment consists
of wide excision. Misdiagnosis can lead to inappropriate treatment and local
recurrences or metastases. We report the case of a 5-year-old girl with an ES on
the right forefinger.
PMID- 10773718
TI - The boosted oral antifungal treatment for onychomycosis beyond the regular
itraconazole pulse dosing regimen.
AB - BACKGROUND: Modern treatments for onychomycosis do not yield an ideal cure rate.
OBJECTIVE: The boosted oral antifungal treatment (BOAT) is introduced as a novel
approach improving the efficacy of oral treatment with the itraconazole pulse
dosing regimen. METHOD: The BOAT design targets resting fungal cells in order to
produce sensitive hyphae which are less refractory to antifungals. This is
performed by securing a piece of a Sabouraud's agar slide onto the affected nail
in alternance with oral intake of itraconazole. RESULTS: The present comparative
intraindividual trial suggests that BOAT improves the mycological cure rate
compared to the regular treatment. CONCLUSION: BOAT is a promising simple and
cheap combined therapy for onychomycosis. However, the present pilot study calls
for further clinical investigations.
PMID- 10773717
TI - Comparative anti-dandruff efficacy between a tar and a non-tar shampoo.
AB - A randomized double-blind clinical study was conducted on two groups of 30
volunteers using either a non-tar shampoo (2% salicylic acid, 0.75% piroctone
olamine and 0.5% elubiol) or a 0.5% coal tar shampoo. Subjects were diagnosed as
having moderate to marked dandruff. The study consisted of a 3-week washout,
followed by a 4-week treatment and a 4-week posttreatment regression phase. The
clinical evaluations and subject self-assessments showed that the non-tar shampoo
was as effective as the tar shampoo. Both received high approval ratings (> or
=70%). Biometrological methods proved to be more sensitive than clinical
evaluations to assess the efficacy of the shampoos. The non-tar shampoo yielded a
significantly better reduction of Malassezia spp. counts (p<0.02) during the
treatment phase and reduced the spontaneous increase in squamometry values (p<
0.01) during the posttreatment phase. It is concluded that a formulation
associating salicylic acid, piroctone olamine and elubiol exhibited increased
beneficial effects compared to the coal tar shampoo.
PMID- 10773719
TI - Two-month glucocorticoid treatment increases proliferation in the stomach and
large intestine of rats.
AB - BACKGROUND/AIMS: It has been shown that acute or short-term treatments with
glucocorticoids lead to a marked decrease in proliferation in the stomach and
large intestine. The effects of more prolonged glucocorticoid treatment on cell
renewal in these organs are not known. The present work was therefore undertaken
to examine the proliferative activity in the stomach and colon during 2 months of
glucocorticoid treatment in comparison with shorter treatments. METHODS: Rats
were treated with either the glucocorticoid triamcinolone acetonide or vehicle
for 63, 33 or 3 days. Proliferation was assessed in the glandular epithelium of
the fundal part of the stomach and in the epithelium of the colonic crypts using
three criteria: the mitotic index; the bromodeoxyuridine labelling index, and the
proliferating cell nuclear antigen-labelling index (percentage of mitotic or
labelled cells). RESULTS: Treatment with glucocorticoid for 63 days resulted in a
very significant increase in all proliferative parameters tested in the gastric
mucosa and the colonic crypts. On the contrary, treatments with glucocorticoid
for 3 or 33 days had a marked inhibitory influence on proliferation in these
tissues. CONCLUSION: As opposed to treatments for 3 or 33 days, glucocorticoid
treatment for 2 months leads to an increase in the number of cycling cells in the
gastric and colonic mucosae.
PMID- 10773720
TI - Pentoxifylline accelerates gastric ulcer healing in rats: roles of tumor necrosis
factor alpha and neutrophils during the early phase of ulcer healing.
AB - BACKGROUND/AIMS: Pentoxifylline has many anti-inflammatory properties including
inhibition of production of tumor necrosis factor alpha (TNF-alpha). Although
pentoxifylline prevents several types of gastric mucosal injury, the effect of
this drug on ulcer healing is unknown. In this study, we examined the effect of
pentoxifylline on healing of acetic acid induced gastric ulcers in rats. METHODS:
Rats with gastric ulcer received an intraperitoneal injection of 10 mg/kg
pentoxifylline once daily for 14 days or for only the first 7 days or the last 7
days of the 14-day treatment period. Some rats were given antirat neutrophil
antiserum intraperitoneally every other day. Ulcer size, myeloperoxidase
activity, and concentration and location of TNF-alpha in ulcer tissue were
assessed. RESULTS: Administration of pentoxifylline for 14 days or for the first
7 days, but not for the last 7 days, of the 14-day treatment period accelerated
ulcer healing. TNF-alpha was detected mainly in monocytes/macrophages and in some
neutrophils at ulcer bases and margins. Pentoxifylline markedly decreased the
concentration of TNF-alpha as well as the myeloperoxidase activity in ulcer
tissue on days 2 and 4. Antirat neutrophil antiserum inhibited neutrophil
infiltration into ulcer tissue and accelerated ulcer healing. CONCLUSION:
Pentoxifylline accelerates healing of acetic acid induced gastric ulcer in rats.
This effect may be due in part to reduction of neutrophil infiltration and
inhibition of production of TNF-alpha by inflammatory cells. Early-phase
inhibition of inflammatory response may accelerate ulcer healing.
PMID- 10773721
TI - Comparison of the 1-gram (14)C-D-xylose breath test and the 50-gram hydrogen
glucose breath test for diagnosis of small intestinal bacterial overgrowth.
AB - BACKGROUND/AIMS: Culture of small bowel aspirate is the most direct method and
the gold standard for diagnosing small intestinal bacterial overgrowth. However,
cultures are cumbersome and fluoroscopy is required for obtaining aspirate.
Therefore, different breath tests such as the xylose breath test and the hydrogen
breath test have been developed. There is no general agreement as to which test
is to be preferred. In the only previous direct comparison between these two
tests an advantage for the 1-gram-(14)C-D-xylose breath test was found. The aim
of the study was to compare the 50-gram glucose hydrogen breath test and the 1
gram (14)C-D-xylose breath test in relation to results of cultures of small bowel
aspirate. METHODS: Forty-six consecutive patients, mean age 57 (range 27-87)
years, 12 men and 34 women, were included because of suspicion of small
intestinal bacterial overgrowth. After small bowel aspiration, all patients
received a solution of 1 g xylose, labelled with 50 microg (14)C-D-xylose, and 50
g glucose dissolved in 250 ml water. The concentration of breath hydrogen was
analyzed every 15 min for 2 h and (14)CO(2) was analyzed every 30 min for 4 h. A
positive hydrogen breath test was defined as a rise in hydrogen concentration of
15 ppm. A positive xylose test was defined as an accumulated dose 4.5% after 4 h.
Two definitions for a positive culture were used, either growth of 10(5 )colonic
type bacteria/ml or growth of 10(5) bacteria/ml of any type. RESULTS: Twenty-four
patients had growth of 10(5) bacteria, of whom 10 had growth of 10(5) colonic
type bacteria in small bowel aspirate. Twenty-two patients had no significant
growth. The hydrogen breath test and the xylose breath test had a sensitivity for
growth of 10(5) bacteria of 58 and 42%, respectively. For growth of 10(5 )colonic
type bacteria the sensitivity was 90% for the hydrogen breath test and 70% for
the xylose breath test. The specificity was similar for the two tests.
CONCLUSION: Although no significant difference between the two tests was found,
there was a tendency in favor of the 50-gram glucose hydrogen breath test. The
simplicity in combination with high sensitivity makes the hydrogen breath test
suitable as a screening method to select patients for further investigation.
PMID- 10773722
TI - Impact of gastrin-releasing peptide on intestinal microcirculation after ischemia
reperfusion in rats.
AB - We investigated the effect of gastrin-releasing peptide (GRP) and its antagonist
RC-3095 on intestinal microcirculation after ischemia-reperfusion. Intestinal
ischemia was induced in female Wistar rats by occlusion of the superior
mesenteric artery for 40 min. Ten minutes prior to reperfusion, infusion of GRP
or RC-3095 was started. A jejunal segment was exteriorized and the
microhemodynamics of the mucosa and submucosa were examined by intravital
microscopy and compared both with normal and ischemic controls (without
application of the regulatory peptide). Ischemia-reperfusion significantly
decreased functional capillary density from 891.2 +/- 14.1 to 398.3 +/- 11.4 cm(
1). Capillary red blood cell velocity was reduced from 0.46 +/- 0.01 to 0.37 +/-
0.01 mm/s (p < 0.05). Furthermore, both sticking and rolling of leukocytes were
enhanced. 3.4 +/- 1.1% of the villi were not perfused at all. GRP infusion
reversed the microcirculatory ischemia-reperfusion injury by increasing
functional capillary density to 669.8 +/- 8.3 cm(-1) and red blood cell velocity
to 0.62 +/- 0.01 mm/s (p < 0.05). In addition, application of GRP resulted in a
complete absence of stasis (0%) in the villi. Leukocyte-endothelium adherence
remained unchanged when compared to the ischemic controls. In contrast,
application of RC-3095 caused an aggravation of microcirculatory disturbances
demonstrated by a markedly increased number of non-perfused villi (42.5 +/- 4.2%;
p < 0.05 vs. ischemic controls) and a significantly reduced functional capillary
density (346.2 +/- 8.4 cm(-1), p < 0.05 vs. ischemic controls). In addition, RC
3095 led to an increased permanent leukocyte adherence in postcapillary venules
whereas rolling was significantly reduced when compared to normal controls. We
conclude that GRP in pharmacological doses has a protective effect on intestinal
microcirculation during reperfusion. Furthermore, these data suggest that
endogenous GRP may play a decisive role in the maintenance of microvascular
integrity during reperfusion.
PMID- 10773723
TI - Structure and composition of common bile duct stones in relation to duodenal
diverticula, gastric resection, cholecystectomy and infection.
AB - BACKGROUND: Common bile duct stones represent a clinical problem often involving
severe infection, cholangitis and cholestasis. Stasis and infection are thought
to play a part in the pathogenesis of choledocholithiasis. Investigations on the
etiology of common bile duct stones are, however, scarce because of the difficult
access to common bile duct stones and bile. In a clinical series of common bile
duct stones, we studied the gross appearance of stones extracted endoscopically
from the common bile duct and measured the cholesterol and bilirubinate content
in order to elucidate factors of importance to etiology. METHODS: In 135 patients
treated endoscopically for bile duct stones, the stones or parts of the stones
were collected. Appearances of the cut surface of the stones were studied and
described. Cholesterol and bilirubinate content were analyzed enzymatically and
with infrared spectroscopy. The growth in bile of gas-producing bacteria
previously shown to be correlated with enterobacteriacea was investigated.
RESULTS: Seventy-five percent of the stones were pigment stones, the majority
with concentric pigmented layering. There was good agreement between cholesterol
measurements. With a cutoff at 50% for the infrared measurements and 25% for the
enzymatic assay only 3 stones were discordant between cholesterol measurements
and visual inspection. Twenty-one of 23 patients with a previous Billroth-II
gastric resection had pigment stones (p < 0.05). Gas-producing bacteria were
significantly more prevalent in the bile from patients with layered pigment
stones. CONCLUSION: Pigment stones with concentric layering highly suggestive of
a cyclic process of crystallization were recovered from the common bile duct in
70% of the patients in our series.
PMID- 10773724
TI - Analysis of urgent colonoscopy for lower gastrointestinal tract bleeding.
AB - BACKGROUND: Three hundred and forty-five patients who underwent urgent
colonoscopy for acute hematochezia during the past 20 years (from 1976 to 1995)
were retrospectively analyzed. METHODS: Urgent colonoscopy was defined as
endoscopy performed within 24 h after a bleeding episode. Preparation was
initially minimal with a water or glycerine enema. Recently, however,
polyethylene glycol is used. RESULTS: The overall diagnostic accuracy for
bleeding site detection was 89.1% (307 cases). Successful insertion was made to
the ileocecal region in 193 cases (55.9%). The disease most frequently discoverd
by urgent colonoscopy was transient ischemic colitis (62 cases). Negative urgent
colonoscopy specimens (18 cases) were later diagnosed by other methods as being
small intestinal bleeding foci. In 10 cases, initial colonoscopy failed to detect
the bleeding foci. Endoscopic hemostasis was performed in 48 cases. Permanent
hemostasis succeeded in 32 cases (66.7%). Complications of urgent colonoscopy
were fever after the examination (22 cases) and hypotension during endoscopy (7
cases). CONCLUSION: Urgent colonoscopy is considered to be a safe and useful
examination for acute lower gastrointestinal bleeding and hemostasis.
PMID- 10773725
TI - Application of the colon-simulation technique for studying the effects of
Saccharomyces boulardii on basic parameters of porcine cecal microbial metabolism
disturbed by clindamycin.
AB - AIMS: The present study analyzed the effects of Saccharomyces boulardii on the
biochemical parameters of microbial hindgut metabolism disturbed by clindamycin.
METHODS: The experiments were carried out under in vitro conditions using the
semicontinuous colon-simulation technique. This technique is standardized for
quantitatively measuring parameters of microbial hindgut metabolism. The fluid
and particle phase of pig hindgut contents were used for the in vitro
incubations. The 5-day control period was followed by clindamycin exposure alone
(312.5 mg/day for 5 days) or by a combined treatment of clindamycin and S.
boulardii (400 mg/day for 5 days). RESULTS: Clindamycin resulted in significant
decreases in production rates of short-chain fatty acids (SCFAs) which were
associated with substantial changes in molar SCFA proportions at the expense of
butyrate. These effects could at least partly be compensated for by S. boulardii,
in particular by enhancements of acetate and propionate fermentation to control
levels. In contrast, butyrate fermentation could not be reconstituted. In a
second experiment the potential use of S. boulardii as a substrate for hindgut
microbial metabolism was studied by comparing living and autoclaved yeast.
Propionate and butyrate fermentation rates were unaffected whereas acetate
fermentation tended to be higher in the presence of living yeast. CONCLUSIONS: S.
boulardii can be effective to compensate for changes in microbial fermentation in
response to antibiotic treatment. Despite the lack of statistical significance it
might be concluded that the increase in fermentation end products can only partly
be explained by the utilization of the yeast as a substrate for microbial
metabolism.
PMID- 10773726
TI - Significant increase in prostaglandin E-main urinary metabolite by laxative
administration: comparison with ulcerative colitis.
AB - OBJECTIVE: To assess the production of prostaglandin E(2), an important chemical
mediator in diarrhea induced by laxative administration, a prostaglandin E-main
urinary metabolite (7alpha-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid,
PGE-MUM) was measured in healthy volunteers and compared with the values of
patients with ulcerative colitis. METHODS: PGE-MUM was determined by a simplified
immunoassay of bicyclic PGE-MUM and analyzed for the influence of laxative
administration and active/remission phases of ulcerative colitis. RESULTS:
Administration of laxatives induced a significant increase in PGE-MUM in healthy
volunteers. A significant elevation was also found in the active as compared with
the remission phase of ulcerative colitis. The PGE-MUM levels were significantly
correlated with our modified Talstad scores, clinical disease activity indices in
ulcerative colitis. It was confirmed by time course studies of individual
patients that changes in PGE-MUM correlated well with colitis activity.
CONCLUSION: Laxative administration induces production of prostaglandin E(2) as
one of the chemical mediators, although its production grade is relatively low as
compared with ulcerative colitis in the active phase.
PMID- 10773727
TI - Prospective assessment of the clinical value of anorectal investigations.
AB - BACKGROUND/AIM: Anorectal physiological testing and imaging have become part of
routine colorectal and gastro-enterological practice, but their clinical value is
controversial. We prospectively evaluated the new diagnostic information, impact
on management and prognostic information provided by anorectal testing. METHODS:
One hundred consecutive patients referred for testing were studied. The referring
doctor's diagnosis, reason for referral, planned management and expectation of
the value of investigations were recorded. Incontinent patients underwent
anorectal physiological testing and endo-anal ultrasound. Patients with
constipation underwent anorectal physiological testing and a study of whole-gut
transit time to distinguish between slow and normal transit. Constipated patients
over age 45, or those younger patients who digitated to assist defaecation, also
underwent evacuation proctography to identify large rectoceles. RESULTS: Fifty
one patients had faecal incontinence. Of 12 patients with suspected anterior
external anal sphincter obstetric damage, all of whom were planned for surgical
repair, 3 were unsuitable for repair, 3 had a normal sphincter, 2 had a weak but
structurally intact sphincter, and 1 had internal anal sphincter damage only. Of
6 patients with failed anterior repair, 3 had a defect suitable for repeat
repair, 2 had intact repairs and good function, and 1 had extensive damage
requiring reconstructive surgery. The tests also influenced management for
incontinent patients after haemorrhoidectomy surgery (n = 5), after fistula
surgery (n = 5), with congenital abnormalities (n = 3), after cerebrovascular
accident (n = 1) and those with no presumptive diagnosis (n = 15). Of the 20
patients referred with constipation, demonstration of a recto-anal reflex in 1
patient with a megarectum excluded the need for full-thickness biopsy. A further
patient with altered electrosensation went on to have a neurological lesion
defined. Definition of slow transit in some patients did not immediately affect
management. New information or a change in management was provided in patients
referred for pre-operative assessment (n = 13). Information was gained in only 1
of 7 patients with solitary rectal ulcer and in none of the 8 patients with anal
pain. CONCLUSION: Anorectal assessment provides important diagnostic and
prognostic information and directly alters management in patients with benign
anorectal disorders.
PMID- 10773728
TI - Pneumatosis cystoides intestinalis: an unexpected finding in intestinal bleeding
under therapy with phenprocoumon.
AB - Pneumatosis cystoides intestinalis is a rarely observed disorder on plain
abdominal X-ray or colonoscopy examination. Although causing few complaints in
adults, it can nevertheless lead to gastrointestinal bleeding. In the reported
case, gastrointestinal bleeding was observed with coinciding pneumatosis and
phenprocoumon therapy. After stopping anticoagulant therapy, pneumatosis vanished
completely, thus suggesting that phenprocoumon is probably a further cause of the
cystic disease. In the known list of drugs able to provoke pneumatosis, this case
adds a new mechanism of affliction different to either immunosuppression or gas
production.
PMID- 10773729
TI - Uncommon metastasis of a glioblastoma multiforme in liver and spleen.
AB - A case of a glioblastoma multiforme is presented. Craniotomy was performed with
total resection of the right temporal tumor. Postoperatively, the patient
received adjuvant radiotherapy, but 6 months after therapy he developed severe
nausea and weight loss. Recurrence of an intracranial tumor in the right temporal
region with nodules in the liver and spleen were detected by CT scan. Fine-needle
biopsies of the liver confirmed the diagnosis of a glioblastoma metastasis with
characteristic immunohistochemical staining for glial fibrillary acidic protein.
This rare case of an intracerebral glioblastoma metastasizing to liver and spleen
was managed by systemic chemotherapy.
PMID- 10773730
TI - Effects of varying concentrations of bleach on in vitro HIV-1 replication and the
relevance to injection drug use.
AB - The use of bleach (hypochlorite) as a disinfectant for drug injection equipment
in the intravenous-drug-using population was recommended early in the HIV-1/AIDS
epidemic. Epidemiological studies have challenged the use of bleach as an
effective measure to prevent HIV-1 transmission. However, in vitro HIV-1
coculture studies have shown that a high concentration of bleach is an effective
cytotoxic and potentially virucidal agent. In this study, we demonstrate that HIV
1 peripheral blood mononuclear cell cocultures containing low concentrations of
hypochlorite in the media showed earlier conversion to HIV-1 positivity, as
measured by the presence of p24 antigen. HIV-1 cocultures with high
concentrations of hypochlorite in the culture media, which appeared to be highly
cytotoxic, and HIV-1 cocultures without bleach in the media did not exhibit this
early p24 antigen positivity. Hypochlorite chemically disinfects by releasing
free chlorine that is a potent oxidant. In injection drug equipment, a low
residual concentration of bleach is likely to remain in cleaned equipment despite
rinsing with water. Low concentrations of oxidants have been shown to enhance
tissue inflammation, in vivo, as well as HIV-1 replication in vitro. Previous
studies have shown that despite vigorous cleaning of blood-contaminated injection
syringes with bleach followed by water, microaggregates of residual blood
remained in bleach-cleaned blood-contaminated syringes. Hypothetically, oxidant
effects of the residual bleach in the bleach-cleaned syringes could enhance the
possibility of infection by remaining HIV-1 contained in a contaminated syringe.
We suggest that the likelihood of an injection drug user contracting HIV-1
through the sharing of a bleach-cleaned blood-contaminated syringe may be
increased by the cotransmission of residual bleach and its localized tissue
inflammatory effects; however, this has not been statistically proven in
epidemiological studies.
PMID- 10773732
TI - TTV positivity and transfusion history in non-B, non-C hepatocellular carcinoma
compared with HBV- and HCV-positive cases.
AB - The prevalence of TT virus (TTV) and its rate of transmission through transfusion
were investigated to determine its possible hepatocarcinogenic role in non-B, non
C hepatocellular carcinoma (HCC) as compared with that in hepatitis B virus (HBV)
and hepatitis C virus (HCV)-positive HCC. Its transfection route in TTV-positive
cases was also studied. Serum was positive for TTV in 77.8% (7/9) of HBV
positive, 36.4% (12/33) of HCV-positive, and 63. 6% (7/11) of non-B, non-C cases
of HCC. The rate of transmission through transfusion was 52.4% (11/21) in HBV
positive, 40.1% (61/152) in HCV-positive, 33.3% (2/6) in HBV+HCV-positive, and
40% (8/20) in non-B, non-C HCCs, while it was 48.3% (14/29) in TTV-positive and
39.3% (11/28) in TTV-negative cases. The association between TTV and HCC was
limited, and the main route of infection of TTV was not through transfusion.
PMID- 10773731
TI - Sequence analysis of porcine adenovirus type 3 E1 region, pIX and pIVa2 genes,
and two novel open reading frames.
AB - The porcine adenovirus type 3 (PAd3) genome between map units 0 and 13.7 was
sequenced and compared with similar regions of other adenoviruses. This region
consists of the left inverted terminal repeat sequences involved in DNA
packaging, the entire early region 1 (E1) and the protein IX (pIX) transcription
unit. The lower strand contains the C-terminal end of IVa2 of the E2A
transcriptional unit and two novel open reading frames (ORFs). The E1
transcription unit consists of ORFs for proteins homologous to the E1A, E1B-17k
and E1B-55k of both human adenovirus type 5 (HAd5) and bovine adenovirus type 3
(BAd3). The predicted PAd3 pIX demonstrated homology with the N-terminal portion
of the pIXs of HAd5 and BAd3. On the lower strand, immediately after the putative
IVa2 ORF, there are two unique ORFs of 208 and 203 amino acid residues that
showed homology with Epstein-Barr virus nuclear antigens and other cellular
transcription factors.
PMID- 10773733
TI - Existence of TT virus DNA in extracellular body fluids from normal healthy
Japanese subjects.
AB - Although recent studies indicate a high prevalence (12-92%) of TT virus (TTV) DNA
in sera of healthy Japanese individuals, there is a paucity of information
regarding the route of transmission of this virus. Analyzing the nucleotide
sequences of the existing polymerase chain reaction (PCR) primers of TTV DNA, we
developed a set of noble primers (HM-1) and looked for the prevalence of TTV DNA
in sera from 39 normal healthy Japanese individuals using PCR. The existence of
TTV DNA was also checked in saliva, urine, sweat, stool, and tears from 11 and in
semen from 10 serum TTV-positive normal subjects. TTV DNA was detected in sera
from 23 of 39 (59.0%) normal subjects. TTV DNA was also detected in saliva,
stool, semen and tears from all cases with TTV-DNA-positive serum, but not in
body fluids from subjects with TTV-DNA-negative serum. TTV DNA remained
undetected in urine and sweat from all cases. Data from these experiments showing
the existence of TTV DNA in different body fluids suggest that the high rates of
prevalence of TTV among normal healthy subjects might be due to a possible fecal
oral, droplet, or sexual route of transmission of TTV.
PMID- 10773735
TI - Efficacy of an inactivated vaccine for equine herpesvirus type 1 in a novel
hamster model.
AB - A vaccine designated F.EHV1(S(-))BHK, which was prepared by formaldehyde
treatment of equine herpesvirus type 1 (EHV1)-infected baby hamster kidney cells,
stimulated neutralising antibodies in hamsters and rabbits and protected new-born
hamsters against a lethal challenge with EHV1 by vaccination of their pregnant
mothers. The preparative method was then modified to eliminate virus particles
and intraparticulate DNA, producing a vaccine designated Bg.F.EHV1(S(-))BHK. this
modification stimulated neutralising antibodies with evidence of in vivo
inactivation of the virus above non-specific levels in a mouse model. There were
no adverse effects from these vaccines in rodent or rabbit species.
PMID- 10773734
TI - Close association between high serum ALT and more rapid recurrence of
hepatocellular carcinoma in hepatectomized patients with HCV-associated liver
cirrhosis and hepatocellular carcinoma.
AB - We investigated whether or not a high serum alanine aminotransferase (ALT) level
is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in
hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis
(LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC
of a single nodule who had no histologic evidence of portal or hepatic vein
invasion and who had been followed up for more than 3 years were included in the
study. They were subdivided into two groups according to their serum ALT levels,
ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen
patients whose serum ALT levels showed several peaks or plateaus above 80
international units (IU) were designated as the high ALT group, and 16 patients
whose serum ALT levels showed a sustained low level below 80 IU until the first
recurrence were designated as the low ALT group, and the interval between
hepatectomy and the first recurrence was observed. In the high ALT group, HCC
recurred within 3 years in 70.6% of the patients. In contrast, it recurred in
only 18.8% of the low ALT group within the same period (p < 0.05). There was a
significant difference (p = 0.0201) between the two groups in the cumulative
nonrecurrence rate. The mean interval in recurrent patients between hepatectomy
and the first recurrence in the high ALT group (23.6 +/- 2.8 months; mean +/- SE)
was significantly (p < 0.02) shorter than that in the low ALT group (49.3 +/- 9.7
months). The expected interval between hepatectomy and recurrence was as short as
2.8 +/- 0.5 years (mean +/- SE) in the high ALT group, compared with 5.8 +/- 0.7
years in the low ALT group (p < 0.05). These results showed that the recurrence
of HCC was accelerated in the high ALT group, suggesting that suppression of the
rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may
prolong the interval until recurrence by about 2 years in hepatectomized patients
with HCC and HCV-LC.
PMID- 10773736
TI - Hepatitis A virus replication: an intermediate in the uncoating process.
AB - Dense, RNase-sensitive, VP2-containing, non-infectious hepatitis A virus (HAV)
particles were found to be formed at early times after the infection of cultured
cells. These particles formed with kinetics mirroring those reported for HAV
uncoating. The kinetics of the formation of dense HAV particles corresponded to a
decrease in detectable, mature input virions, as detected by RNA dot blot
hybridization of CsCl density gradient fractions. The dense HAV particles did not
appear to have altered sedimentation coefficients, and as the fate of small
capsid protein VP4 is not yet known, these particles cannot yet be termed 'A
particles' or 'infectosomes', as have the uncoating intermediates in some
picornavirus-cell systems.
PMID- 10773737
TI - Phylogenetic comparison of the DEN-2 Mexican isolate with other flaviviruses.
AB - Recent attention has focused on the geographic variation of dengue viruses, since
major epidemies may follow introduction of a new virus strain into susceptible
populations. We cloned and sequenced a very interesting Mexican isolate
(200787/1983) which is antigenically unique by signature analysis with respect to
all other dengue-2 topotype viruses. This strain is also unique in biological
behavior (neurotropism) and is of epidemiological significance in Mexico. The
dengue-2 Mexican isolate sequence information was compared with that of other
flaviviruses, analyzing the branching structure of the phylogenetic tree
reconstructed from the E gene amino acid sequences. The E glycoprotein, is target
for neutralizing antibodies and T-cell responses, and defines the tropism and
virulence of flaviviruses. In the phylogram, our strain was located in the
position of greatest dissimilarity within serotype-2. Also, frequency analysis of
amino acids revealed a very different signature pattern from that found in viral
serotype-2.
PMID- 10773738
TI - An arthrogenic alphavirus induces monocyte chemoattractant protein-1 and
interleukin-8.
AB - Cytokines and chemokines play important roles in both autoimmune and infectious
arthritides. Here we describe the cytokines and chemokines induced by Ross River
(RR) virus infection of synovial fibroblasts and macrophages in vitro. RR virus
is the aetiological agent of epidemic polyarthritis (EPA), a principally acute
and chronic rheumatic disease affecting up to 7,000 Australians annually.
Infected fibroblasts increased expression of mRNA coding for monocyte
chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and granulocyte
macrophage colony-stimulating factor. MCP-1, IL-8, macrophage inflammatory
protein-2, and to a lesser extent interferon gamma-induced protein-10 mRNA were
upregulated in infected macrophages. Expression of MCP-1 is consistent with the
predominantly monocytic effusion found in EPA synovia.
PMID- 10773740
TI - Temperature-dependent phosphorylation state of the H5R protein synthesised at the
early stage of infection in cells infected with vaccinia virus ts mutants of the
B1R and F10L protein kinases.
AB - The phosphorylation state of H5R protein was investigated by two-dimensional gel
electrophoresis of proteins of BSC-40 cells infected at 32 degrees or 39.5
degrees with vaccinia virus ts mutants of the viral B1R or F10L protein kinase
genes. A temperature-dependent increase of underphosphorylated H5R protein (pI
6.8) was demonstrated in the case of the B1R, but not of the F10L gene. The
temperature-dependent cytoplasmic location of underphosphorylated H5R protein
after infection with the ts mutants of the B1R gene was the consequence of the
associated viral DNA replication block. These results show that the B1R protein
kinase controls the phosphorylation state of the H5R protein synthesised at the
early stage in vaccinia-virus-infected cells.
PMID- 10773739
TI - Influence of viral load and alanine aminotransferase on viral genetic
heterogeneity in patients with chronic hepatitis C virus infection.
AB - BACKGROUND/AIM: Hepatitis C virus (HCV) populations in vivo consist of
genetically different heterogeneous mixtures defined as 'quasispecies', which
vary in the hypervariable region 1 (HVR1) mostly. To further address the role of
quasispecies diversity in hepatitis C infection, this study aimed to evaluate the
influence of ALT, viral load and genotypes on quasispecies heterogeneity in
patients with HCV infection. METHODS: Thirty-six chronic hepatitis C patients
with high levels of alanine aminotransferase (ALT) were studied. None of them
received any antiviral therapy. HCV RNA serum levels, genotype and genetic
heterogeneity were determined by branched-chain DNA assay, restriction fragment
length patterns and RT-PCR single-strand conformational polymorphism analysis of
HVR1, respectively. RESULTS: Twenty-eight patients had genotype 1b (28/36; 78%),
6 patients had genotype 1a (6/36; 17%), 1 patient was 2a (1/36; 3%) and genotype
could not be determined in 1 patient. The patients were categorized into two
groups according to the number of bands representing the dominant strains in the
circulation: group A with 2 bands having 1 strain (14/36 patients; 39%) and group
B with more than 2 bands indicating more than 1 strain (22/36 patients; 61%). The
serum viremia and ALT levels for these groups were 11 +/- 8.8 and 5.3 +/- 4.6
mEq/ml (p < 0.05), and 79 +/- 20, and 127 +/- 80 IU/l (p < 0.05), respectively.
CONCLUSION: The results of this study suggest that hepatitis C patients having 1
dominant strain in the circulation may show a relatively weaker immune response
resulting in lower ALT and higher viremia levels, whereas patients with high
degrees of virus quasispecies diversity have higher ALT levels and a more active
immune response causing the selection of new genome variants and depressing viral
replication partly.
PMID- 10773741
TI - Estradiol attenuates the forskolin-induced increase in hypothalamic tyrosine
hydroxylase activity.
AB - The purpose of this study was to evaluate interactions between estradiol and the
3',5' cyclic adenosine monophosphate (cAMP) signaling pathway to regulate
tyrosine hydroxylase (TH) activity in hypothalamic dopaminergic neurons. The
first experiment examined the ability of forskolin to activate TH in the
tuberoinfundibular dopaminergic neurons of adult ovariectomized rats with or
without estradiol treatment. Estradiol treatment reduced both basal and forskolin
stimulated TH activity in the median eminence. The second group of experiments
examined the effect of estradiol on the forskolin-induced activation of TH in
fetal hypothalamic cells cultures. Estradiol decreased basal TH activity in the
hypothalamic cell cultures to 80% of control levels. Forskolin treatment for 1 h
increased TH activity in a concentration-dependent manner in control and
estradiol-treated cells, but estradiol attenuated the stimulatory response to
0.01-10 microM forskolin. The suppressive effect of estradiol on cAMP-dependent
activation of TH was evident with 1-12 h of forskolin treatment. The responses to
other activators of the cAMP- protein kinase A pathway, including dibutyryl cAMP
and 8-bromo-cAMP, and to a depolarizing stimulus were blunted in estradiol
treated cultures. Forskolin treatment for 1 h increased radiolabeled phosphate
incorporation into TH protein in control but not estradiol-treated cells,
suggesting that estradiol interferes with the ability of the cAMP pathway to
phosphorylate TH. Forskolin caused a time-dependent increase in TH mRNA signal
levels in control cultures. The magnitude of the forskolin-induced increase in TH
mRNA levels was less in the estradiol-treated cells after 6 h of forskolin
treatment, indicating that estradiol hinders cAMP-regulated TH gene expression.
These data indicate that estradiol attenuates the ability of hypothalamic
dopaminergic neurons to respond to cAMP-dependent stimulation by interfering with
phosphorylation mechanisms in the short term and control of TH mRNA levels in the
long term.
PMID- 10773742
TI - Variations in plasma levels of substance P and effects of a specific substance P
antagonist of the NK(1) receptor on preovulatory LH and FSH surges and
progesterone secretion in the cycling cynomolgus monkey.
AB - These studies investigated the role of substance P (SP) in the regulation of the
hypothalamic-pituitary-ovarian axis in cynomolgus monkeys with normal menstrual
cycles. Plasma concentrations of SP were determined in blood samples taken every
morning in normally menstruating cynomolgus monkeys throughout the menstrual
cycle. There was a significant decreasing linear trend of SP during the
follicular phase (cycle day -13 to day 0) and a significant inverse relationship
between SP plasma values and plasma 17beta-estradiol (E(2)) values from day -13
to day 0 of the adjusted cycle. Correspondingly, SP area under the curve was
significantly greater during the follicular phase than the luteal phase. In a
second experiment, plasma concentrations of E(2), luteinizing hormone (LH),
follicle-stimulating hormone (FSH) and progesterone and length of cycles were
measured after five daily intragastric administrations (10 mg/kg) of an NK(1)
receptor (SP receptor) antagonist (RPR 100893; 10 mg/kg) initiated after serum
E(2) concentrations had exceeded 125 pg/ml. There was a statistically significant
reduction in the amplitude (41% of control) and the area under the curve (37% of
control) of the preovulatory LH surge. In addition, there was a reduction of the
duration of the LH surge (3 +/- 0.1 days in controls vs. 2.1 +/- 0.2 days in
treated animals). The present results show for the first time that there are
significant variations in plasma levels of SP, with a strong negative correlation
with serum levels of E(2) during the follicular phase of the cynomolgus monkey,
and that endogenous SP has a potentiating role in the interactive hypothalamo
anterior-pituitary mechanisms which lead to the preovulatory LH and FSH surges
during the menstrual cycle in the monkey.
PMID- 10773744
TI - Sex- and age-related P75 neurotrophin receptor expression in the human supraoptic
nucleus.
AB - The human supraoptic nucleus (SON) is the main production site of plasma
vasopressin. Previously, using the Golgi apparatus and cell size as measures for
neuronal metabolic activity, an activation of vasopressinergic neurons was found
during ageing in the human SON in women but not in men. We hypothesized that the
low-affinity neurotrophin receptor p75 (p75(NTR)) might be involved in the
mechanism of activation of vasopressin neurons in postmenopausal women, since
this receptor was found to be expressed in the SON neurons of aged individuals,
and because p75(NTR) expression was shown to be suppressed by estrogens.
Therefore, we investigated whether p75(NTR) immunoreactivity in the SON neurons
was age- and sex-dependent. For this purpose, we studied paraffin sections of the
SON in 32 postmortem brains of control patients ranging in age from 29 to 94
years with an anti-p75(NTR) antibody and determined the area of p75(NTR)
immunoreactivity per neuron using an image analysis system. To study whether the
p75(NTR) might also participate in the activation of SON neurons, we related
Golgi apparatus size to the area of p75(NTR) immunoreactivity per cell in the
same patients. We found that the area of p75(NTR) immunoreactivity per cell
correlated indeed significantly with age and with Golgi apparatus size only in
women but not in men. Therefore, our results suggest that p75(NTR) is involved in
postmenopausal activation of vasopressinergic neurons in the human SON.
PMID- 10773743
TI - Ovine fetal estrogen sulfotransferase in brain regions important for hypothalamus
pituitary-adrenal axis control.
AB - Ovine parturition is initiated by increases in fetal hypothalamus-pituitary
adrenal (HPA) axis activity which, in turn, increase placental estrogen
biosynthesis and ultimately increase uterine contractility. In addition to their
action in the uterus, estrogens in fetal plasma augment fetal corticotropin
(ACTH) secretion. In late gestation, estrone sulfate is more abundant in fetal
plasma than unconjugated estrone and it is possible that there is interconversion
of sulfoconjugated and unconjugated steroids within the fetal brain. We studied
hypothalamus and brainstem tissue from fetal, neonatal, and adult sheep to test
the hypothesis that the ovine brain contains estrogen sulfotransferase. Although
no significant ontogenic pattern was revealed, the presence of estrogen
sulfotransferase within the hypothalamus and brainstem was detectable.
Immunohistochemistry revealed the presence of estrogen sulfotransferase in the
paraventricular nucleus of the hypothalamus, the nucleus of the tractus
solatarius, and the rostral ventral lateral medulla. We conclude that ovine fetal
hypothalamus and brainstem contain estrogen sulfotransferase in brain regions
important for HPA axis control.
PMID- 10773745
TI - Organization and activation of sexual and agonistic behavior in the leopard
gecko, Eublepharis macularius.
AB - Gonadal sex is determined by the temperature experienced during incubation in the
leopard gecko (Eublepharis macularius). Furthermore, both factors, incubation
temperature and gonadal sex, influence adult sexual and agonistic behavior in
this species. Yet it is unclear whether such differences in behavior are
irreversibly organized during development or are mediated by differences in
hormone levels in adulthood. To address this question, we gonadectomized adult
females and males generated from a female-biased (30 degrees C) and a male-biased
(32.5 degrees C) incubation temperature and treated them with equivalent levels
of various sex steroids. We found that 17beta-estradiol (E(2)) activated sexual
receptivity in females but not males, suggesting an organized sex difference in
behavioral sensitivity to E(2). There were also organized and activated sex
differences in attractivity to stimulus males. Although females were more
attractive than males when treated with E(2), both sexes were equally
unattractive when treated with dihydrotestosterone (DHT) or testosterone (T).
Likewise, sex differences in aggressive and submissive behavior were organized
and activated. Attacks on stimulus males were activated by T in males but not in
females. In contrast, hormones did not influence flight behavior in males but did
affect female submissiveness. Overall, males also evoked more attacks by stimulus
males than did females. Nevertheless, females and males treated with androgens
evoked more attacks than animals of the same sex that were treated with
cholesterol or E(2). Incubation temperature had some weak effects on certain
behaviors and no effect on others. This suggests that temperature effects in
gonadally intact geckos may be due primarily to differences in circulating levels
of hormones in adulthood. We conclude that gonadal sex has both organizational
and activational effects on various behaviors in the leopard gecko.
PMID- 10773746
TI - Prolactin-releasing peptides do not stimulate prolactin release in vivo.
AB - The prolactin (PRL)-releasing activity of the novel prolactin-releasing peptides
(PrRPs) was studied in vivo using male and lactating female rats. Whereas
thyrotropin-releasing hormone effectively stimulated PRL and thyrotropin release
as expected, PrRP in both animal models neither stimulated PRL secretion nor
affected the release of other pituitary hormones. At the anterior pituitary
level, in situ hybridization (ISH) histochemistry and Northern blot analysis
revealed significantly higher expression levels of PrRP receptor (UHR-1)
transcripts in female compared to male rats but not between lactating and
nonlactating animals. By ISH, expression of UHR-1 mRNA was also detected in the
intermediate lobe but not in the posterior pituitary. UHR-1 transcripts were also
readily detectable in various hypothalamic brain areas whereas expression of PrRP
mRNA was restricted to the ventral part of the dorsomedial hypothalamic nucleus
but was not detected in neuroendocrine hypothalamic nuclei (e.g. PVN, SON). We
thus assume that in the central nervous system, PrRP may likely have functions as
a neuromodulator. However, together with the detailed cytochemical studies of
various investigators that failed to detect PrRP-immunopositive nerve endings in
the median eminence, our results strongly suggest that the hypothalamic PrRPs
cannot be classified as hypophysiotrophic factors.
PMID- 10773747
TI - Immunoneutralization of endogenous opioid peptides prevents the suckling-induced
prolactin increase and the inhibition of tuberoinfundibular dopaminergic neurons.
AB - Previous studies have shown that the endogenous opioid peptides, acting at
specific opiate receptor subtypes, are involved in the suckling-induced prolactin
secretory response. The prolactin increase elicited by suckling is due, at least
in part, to an inhibition of tuberoinfundibular dopaminergic (TIDA) neurons in
the hypothalamus. We investigated the effects of immunoneutralization of
dynorphin, leu-enkephalin and met-enkephalin on the suckling-induced prolactin
increase and on the activity of the TIDA neurons in lactating female rats between
days 7 and 12 postpartum. Rats were injected into the right lateral ventricle
with antiserum specific for one of these three peptides. Control rats were
administered equal amounts of immunoglobulin proteins. Suckling produced a
profound and significant increase in prolactin levels, as well as a decrease in
DOPA accumulation in the median eminence of lactating rats. Administration of
immunoglobulin concentrations of up to 3.6 microg did not inhibit the prolactin
secretory response to the suckling stimulus and did not prevent the suckling
induced inhibition of TIDA neurons. Antisera to all three endogenous opioid
peptides abolished the suckling-induced prolactin increase and prevented the
inhibition in DOPA accumulation in the median eminence. Thus, the endogenous
opioid peptides, dynorphin, leu-enkephalin and met-enkephalin, are essential for
the prolactin secretory response to suckling and inhibition of TIDA neuronal
activity is at least one of the mechanisms of action utilized by these peptides.
PMID- 10773748
TI - Non-compliance in patients receiving haemodialysis: an in-depth review.
PMID- 10773749
TI - Nephrotic syndrome: molecular and genetic basis.
AB - Nephrotic syndrome results from varying injuries to the capillary wall of the
glomerulus. The components of the capillary wall, including the endothelial cell,
glomerular basement membrane and glomerular visceral epithelial cell all may be
targets of injury and contribute to proteinuria. These mechanisms of injury
include immune complexes, cytotoxins, abnormal protein deposition, metabolic
abnormalities, reactive oxygen species, growth factors, hemodynamic stress, and
genetic abnormalities. We review mechanisms of glomerular permselectivity, with
focus on emerging new understanding of the functions of the glomerular visceral
epithelial cell. The significance and consequences of proteinuria and possible
pathogenic mechanisms and the effect of interventions in clinical renal disease
on these factors are considered.
PMID- 10773750
TI - Kidney disease and silicosis.
AB - AIM: To determine the prevalence of kidney disease in a cohort of individuals
with silicosis. METHODS: Review of medical records and questionnaires from
patients reported to a state surveillance system for silicosis. Reporting of
individuals with silicosis is required by state law. All individuals with
silicosis reported as required by law to the State of Michigan. Individuals
included in this article were reported from 1987 to 1995. Cases were reported by
hospitals, physicians, the state workers' compensation bureau, or from death
certificates. Only individuals who met the criteria for silicosis developed by
the National Institute for Occupational Safety and Health (NIOSH) were included.
RESULTS: Medical records were reviewed of 583 individuals with confirmed
silicosis. This was mainly a population of elderly men. Ten percent of the 583
silicotics were found to have some mention of chronic kidney disease, and 33% of
the 283 silicotics who we had laboratory tests on had a serum creatinine level
>1.5 mg/dl. An association between kidney disease and age and between kidney
disease and race was found among this cohort of 583 silicotics. Individuals with
silicosis were more likely to have a serum creatinine level >1.5 mg/dl than age-
and race-matched controls. However, no relationship between duration of exposure
to silica or profusion of scarring on chest X-ray and prevalence of kidney
disease or elevated creatinine levels was found. CONCLUSIONS: This study confirms
previous case reports and epidemiologic studies of end-stage renal disease that
found an association between kidney disease and exposure to silica. The
epidemiologic data are conflicting on the mechanism by which silica causes kidney
disease and are compatible with silica being able to cause kidney disease by both
an autoimmune and direct nephrotoxic effect. Chronic kidney disease should be
considered as a complication of silicosis.
PMID- 10773751
TI - Water immersion increases urinary excretion of aquaporin-2 in healthy humans.
AB - Many previous studies have shown that aquaporin-2 (AQP2), the vasopressin
regulated water channel, is excreted in the urine and that the excretion
increases in response to vasopressin. Moreover, recently a close correlation
between AQP2 excretion in urine and kidney AQP2 expression has been demonstrated,
showing that urinary excretion of AQP2 is a reliable indicator for AQP-2
function. As head-out water immersion causes an expansion in the central vascular
volume equal to that induced by 2 liters of saline, without modifying plasma
composition, we used immersion in water to evaluate if the response to acute
expansion of the central vascular volume could involve vasporessin (AVP) and
AQP2. In healthy subjects, concentrations of plasma atrial natriuretic factor
(ANF) and AVP, and urinary AQP2 were measured during a 2-hour immersion period.
In all subjects, immersion caused a prompt and marked increase in immunoreactive
ANF (23.0 +/- 2.12 pg/ml at second hour vs. 2.17 +/- 0.42 pg/ml at baseline) and
in urinary excretion of AQP2 (23.9 +/- 2. 69 pmol/mg creatinine at second hour
vs. 4.42 +/- 0.14 pmol/mg creatinine at baseline), while a significant decrease
was found in plasma AVP. Recovery was associated with a prompt return to pre
study levels. These findings demonstrate that heat-out water immersion stimulates
urinary excretion of AQP2 in absence of an increase in plasma AVP.
PMID- 10773752
TI - Relationship of lipoprotein(a) and its phenotypes with the albumin excretion rate
in diabetic patients: a multivariate analysis.
AB - BACKGROUND/AIM: The possible association between lipoprotein(a) [Lp(a)] and
albumin excretion rate (AER) is a topic that has generated conflicting views. The
aim of this study was to determine the relationship between serum Lp(a)
concentrations and AER in diabetic patients, taking into account Lp(a) phenotypes
in a multivariate analysis. METHODS: For this purpose 191 consecutive diabetic
patients (69 type 1 and 122 type 2) were included in the study. Lp(a) was
determined by ELISA and its phenotypes by SDS-PAGE followed by immunoblotting.
Lp(a) phenotypes were grouped by size in small (F, B, S1, S2), big (S3, S4) and
null. RESULTS: Diabetic patients with an AER >20 microg/min presented higher
Lp(a) concentrations than patients with an AER <20 microg/min: median 19 mg/dl
versus 5 mg/dl (p < 0.0001). The differences remained at a significant level when
the type of diabetes was considered. A linear correlation was observed between
Lp(a) concentration and AER (type 1: r = 0.32, p = 0.01; type 2: r = 0.25, p <
0.05). The AER was independently correlated with Lp(a) concentrations in a
multiple regression analysis (p < 0.01), and Lp(a) was independently associated
with the presence of diabetic nephropathy in the logistic regression analysis.
The overall frequency distribution of Lp(a) phenotypes differed significantly
between patients with or without microalbuminuria (p < 0.05). In addition, the
AER (microg/min) was different among the Lp(a) phenotypes: small 55 +/- 122
(median 4.9), big 58 +/- 123 (median 5.7) and null 3 +/- 2 (median 2.3); p =
0.01. The significant difference mainly resulted from low AER (<10 microg/min)
detected in all patients with the null phenotype. CONCLUSIONS: In diabetic
patients the serum Lp(a) concentration is associated with AER. Thus, the elevated
cardiovascular risk observed in diabetic patients with a high AER could be
related to the Lp(a) concentration. Finally, patients with the null Lp(a)
phenotype can be considered as a group at low risk of the development of diabetic
nephropathy.
PMID- 10773753
TI - Structural analysis of human beta-defensin-1 and its significance in urinary
tract infection.
AB - Human beta-defensin-1 (hBD-1) is a 36-amino-acid antimicrobial peptide that
functions in the host innate defense. We developed a highly sensitive
radioimmunoassay for hBD-1 and identified several hBD-1 peptides in human kidney,
urine, and plasma by amino acid sequencing and mass spectrometry. Large
quantities of hBD-1 peptides are produced in the kidney, are released into the
tubular lumen as 47-amino-acid pro-hBD1, and then undergo proteolytic processing
and generate multiple truncated forms. The respective urine and plasma
concentrations of hBD-1 in patients with pyelonephritis are 48.1 +/- (SEM) 15.7
pmol/mg creatinine and 2.66 +/- 0.41 pmol/ml, 3.1-fold and 1.8-fold those of
normal individuals. hBD-1 is thought to contribute to mucosal defense in the
urinary tract. Our findings provide a better understanding of the biosynthesis of
this peptide and its pathophysiological significance in infectious diseases.
PMID- 10773754
TI - An increased serum level of free Apo(a) in renal patients is more striking than
that of Lp(a) and is influenced by homocysteine.
AB - Lipoprotein(a) [Lp(a)] excess combined with hyperhomocysteinaemia and
hyperfibrinogenaemia may contribute to the high incidence of vascular diseases in
dialysis patients. This study is aimed at investigating the role of free
apolipoprotein(a) [fapo(a)] in renal patients. We have been able to show that, as
compared with controls (0.53 mg/l), the median serum concentrations of fapo(a) in
patients with nephrotic syndrome (2.58 mg/l) and with peritoneal dialysis (3. 40
mg/l) were strongly elevated (5- to 7-fold), while the fapo(a) levels in patients
undergoing haemodialyis (1.02 mg/l) and after renal transplantation (0.90 mg/l)
were about doubled. The observed differences in fapo(a) levels indicate that
several mechanisms may increase the level of fapo(a), i.e., reduced renal
clearance, enhanced hepatic synthesis, or homocysteine releasing
apolipoprotein(a) from Lp(a). In the study collective, the median total
homocysteine levels were significantly elevated in all patient groups, stronger
in patients on haemodialysis (31.4 micromol/l) and peritoneal dialysis (31.2
micromol/l) than in patients with nephrotic syndrome (19.7 micromol/l) and after
renal transplantation (19.5 micromol/l). In transplant patients with adequate
renal function and without other apolipoprotein(a)-increasing factors, fapo(a)
was significantly increased when total homocysteine exceeded 22 micromol/l. In
conclusion, our findings let us presume that an increased fapo(a) level in renal
patients possibly could be one of the reasons contributing to the high incidence
of vascular diseases in these patients, because fapo(a) not covalently linked
with Lp(a) is even more easily able to inhibit the fibrinolytic system than the
complete Lp(a). These preliminary results have to be confirmed by further
investigations.
PMID- 10773755
TI - Dimensions of arteriovenous fistulas in patients with autosomal dominant
polycystic kidney disease.
AB - BACKGROUND/AIM: Aneurysms are known manifestations of autosomal dominant
polycystic kidney disease (ADPKD). We investigated whether the dimensions of
arteriovenous fistulas created for performance of haemodialysis were affected by
the original disease. METHODS: The lumen diameter of the fistula was studied by
ultrasound in 19 patients with ADPKD and in 19 control patients. The patients'
sex, age, the duration of their fistulas, haemoglobin values and blood pressure
levels were similar in both groups. The monitoring was performed along the
forearm part of the vein, and the maximal diameter was measured. The diameters at
the two needle insertion sites were also measured. RESULTS: The ADPKD patients
had a significantly higher fistula diameter than the control patients: 12 (range
8-19) mm versus 8 (range 6-24) mm at the widest level (p = 0. 003). There were no
significant differences in the diameters at the needle insertion sites.
CONCLUSION: The receiving veins of arteriovenous fistulas in patients with ADPKD
have an abnormality that causes a greater than normal dilatation in response to
the arterialization. We postulate that this phenomenon is linked with the
increased prevalence of aneurysms in ADPKD.
PMID- 10773756
TI - Polymorphism of the angiotensin-converting enzyme gene in end-stage renal failure
patients.
AB - The plasma levels of angiotensin-converting enzyme (ACE) are modulated by the
insertion (I)/deletion (D) polymorphism within the ACE gene locus. An association
between progressive renal disease, raised cardiovascular risk, and ACE plasma
levels has been shown. To evaluate the genotype frequencies of the I/D
polymorphism in terminal renal failure, we have enrolled 341 dialysis patients
(321 on hemodialysis and 20 on peritoneal dialysis) in a district of southern
Italy (Foggia). As controls, 1,307 subjects from the same area have been
enrolled. Genomic DNA was obtained from leukocytes, and the ACE I/D polymorphism
was determined by polymerase chain reaction. Among uremics, 151 subjects (44.3%)
carried the DD genotype, 149 (43.7%) the ID, and 41 (12.0%) the II genotype. In
controls, 560 subjects (42.8%) had the DD genotype, 577 (44.1%) the ID, and 170
(13.1%) the II genotype (p = n.s.). Among patients, the frequency of DD subjects
was higher in men (48.3%) than in women (39. 7%, p < 0.01). A slight different
frequency of the DD genotype was found according to the duration of dialysis
treatment: 47.5% in patients on dialysis up to 60 months and 41.7 and 40.6% in
those with a dialytic age of 60-120 and >120 months, respectively (p for trend:
0.53). Patients with or without cardiovascular diseases, such as hypertension,
left ventricular hypertrophy, coronary artery disease, and chronic cardiac
failure, did not exhibit any difference in ACE I/D allele and genotype
frequencies (p always >0.05). In conclusion, frequencies of the ACE DD genotype
were similar in uremics and in controls and did not differ between patients with
and without cardiovascular diseases. A nonsignificant inverse relationship with
the time spent on dialysis was observed, suggesting that ACE I/D polymorphism may
influence the cardiovascular death rate.
PMID- 10773757
TI - Decreased bilirubin-binding capacity in uremic serum caused by an accumulation of
furan dicarboxylic acid.
AB - In chronic renal failure, substances that are effectively excreted in healthy
subjects accumulate in serum. These substances, uremic toxins, include a variety
of organic acids. It has been reported that a decrease in the bilirubin (BR)
binding capacity occurs in the serum of renal failure patients. 3-Carboxy-4
methyl-5-propyl-2-furanpropanoic acid (CMPF) has a high affinity for human serum
albumin (HSA) and is a potent inhibitor of the serum protein binding of many
drugs. We recently reported that CMPF and BR share the binding site for
dicarboxylate molecules on the HSA molecule [Pharm Res 1999;16:916-923]. In this
study, in order to confirm whether CMPF is involved in the decrease of BR serum
binding capacity in chronic renal failure patients, the total concentrations of
uremic toxins, CMPF, and indoxyl sulfate (IS) and the free BR concentration in
serum from healthy volunteers and renal failure patients were determined. Both
total CMPF and IS concentrations correlate with the free BR concentration.
However, results from the peroxidase method reveal that IS cannot displace BR
under the physiological condition [IS]/[HSA] <1. We, therefore, conclude that
CMPF is one of the substances which contribute to the decreased binding capacity
of BR in uremic serum.
PMID- 10773758
TI - Hyperlipidemic nephropathy induced by adriamycin in ovariectomized rats: role of
free radicals and effect of 17-beta-estradiol administration.
AB - The present study in rats evaluates the effects of the ovariectomy (OVX) with and
without the simultaneous administration of 17beta-estradiol (17betaE(2)) on
oxidative stress and hyperlipidemic nephropathy induced by a single high dose of
adriamycin (AD). OVX enhances oxidative stress and worsens nephropathy induced by
AD. These changes are prevented by simultaneous administration of 17betaE(2). OVX
alone induced oxidative stress and hyperlipidemia without biochemical evidence of
renal dysfunction. Our results revealed that ovarian hormones, especially
estrogens, have a protective effect against oxidative stress and nephropathy
induced by AD. Since the reactive oxygen species plays a role in the pathogenesis
of renal lesion, it is important to emphasize that estrogens and their
hydroxylated compounds function as biological antioxidants.
PMID- 10773759
TI - Calcium channel blockers inhibit proliferation and matrix production in rat
mesangial cells: possible mechanism of suppression of AP-1 and CREB activities.
AB - BACKGROUND: Calcium channel blockers (CCBs) are reported to attenuate the loss of
renal function in various glomerulonephritides. METHODS: To determine the
mechanism of action of these drugs, we investigated the effects of CCBs on cell
proliferation and extracellular matrix (ECM) production in cultured rat mesangial
cells. RESULTS: While stimulation with 5% fetal calf serum (FCS) increased
[(3)H]thymidine and [(3)H]proline incorporation into quiescent mesangial cells,
incubation with nifedipine and cilnidipine inhibited the increase in a dose
dependent manner. Northern blot analysis demonstrated that 5% FCS increased the
expression of transforming growth factor beta (TGF-beta) and fibronectin (FN)
mRNA and that CCBs significantly reduced this induction, indicating that CCBs may
reduce ECM production through inhibiting TGF-beta and FN. Since activator protein
1 (AP-1) regulates cell proliferation and TGF-beta expression, we evaluated the
AP-1 activity by gel mobility shift analysis. Nuclear extracts of FCS-treated
cells showed a strong binding to AP-1-specific oligonucleotides which was
suppressed by CCBs, suggesting that these agents may inhibit cell proliferation
by suppressing AP-1. CCBs also inhibited the binding activity of cyclic adenosine
monophosphate responsive element binding protein which regulates FN gene
expression. However, neither CCBs nor FCS affected the NFkappaB activity.
CONCLUSION: These results suggest that CCBs may, in part, inhibit the progression
of glomerulonephritis through non-hemodynamic actions that include the
suppression of mesangial cell proliferation and the production of ECM.
PMID- 10773760
TI - Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with
diabetic nephropathy.
AB - BACKGROUND/AIM: Interleukin-6 (IL-6) promotes the growth of renal mesangial
cells. IL-6 may play a major role in such mesangial proliferation, but there has
been little research on IL-6 in relation to diabetic nephropathy because of the
difficulty in measuring urinary and serum IL-6 levels. Using a newly developed,
highly sensitive IL-6 assay, we studied the relationship between serum and
urinary IL-6 and diabetic nephropathy. METHODS: We investigated 72 patients with
type 2 diabetes. Urinary and serum IL-6 concentrations were measured using a
chemiluminescent enzyme immunoassay with a detection limit of 0.11 pg/ml.
RESULTS: There was a significant increase of the serum IL-6 level as diabetic
nephropathy progressed, with the level being 1.4 +/- 0.3 pg/ml in patients with
normal albuminuria, rising to 2.4 +/- 0.6 pg/ml in patients with microalbuminuria
and then to 4.4 +/- 0.8 pg/ml in those having proteinuria. The serum IL-6 level
was also significantly correlated with fibrinogen and aortic pulse wave velocity.
The urinary IL-6 level was also significantly increased in diabetic patients as
nephropathy progressed. Both serum and urinary IL-6 levels were high in the group
with nephropathy, but there was no correlation between the two. CONCLUSION: The
urinary IL-6 level seems to be a good indicator of diabetic nephropathy, and
atherosclerotic changes were related to the serum IL-6 level. The serum IL-6 may,
therefore, be useful in the evaluation of atherosclerosis including nephropathy.
PMID- 10773762
TI - Recurrent calcium oxalate nephrolithiasis induced by naftidrofuryl oxalate.
PMID- 10773761
TI - Vitamin-D receptor genotype and renal disorder in Japanese patients with systemic
lupus erythematosus.
AB - BACKGROUND/AIMS: It is known that allelic variants of the gene encoding the
vitamin-D receptor (VDR) detected by BsmI increase the risk of some advanced
malignant tumors, suggesting that such variants may cause functional differences
in 1,25(OH)(2) vitamin D(3). We examined the VDR genes of Japanese systemic lupus
erythematosus (SLE) patients, to determine whether different genotypes are
correlated with SLE or its criteria. METHODS: VDR genotyping of 58 unrelated
Japanese SLE patients was performed based on polymerase chain reaction
restriction fragment length polymorphism (RFLP). Following amplification,
products were digested with BsmI. The RFLPs were coded as Bb, where the uppercase
letter signifies the absence of the digested site and the lowercase letter
signifies the presence of the site. RESULTS: The frequency of the VDR BB genotype
was significantly higher in SLE patients (15.5%, n = 9/58, p < 0.0001) than in
controls (5.7%, n = 5/87). Furthermore, a larger proportion of bb individuals was
observed among patients with nephrotic syndrome (61.5%, n = 8/13) than among SLE
patients without renal dysfunction (35.7%, n = 10/28). There was a significant
tendency for the population of patients with the bb genotype to be correlated
with that of patients with renal dysfunction (p = 0.0304). CONCLUSION: These
findings suggest that the BB genotype might trigger the development of SLE, and
that the bb genotype is associated with lupus nephritis.
PMID- 10773763
TI - Cadaveric-related renal transplantation.
PMID- 10773764
TI - Hypercalcemia and insomnia in hemodialysis patients.
PMID- 10773765
TI - Injection of diclofenac precipitating oliguric acute renal failure in a patient
with kidney myeloma.
PMID- 10773766
TI - Depression and the severity of substance abuse.
AB - BACKGROUND: Psychosocial factors have been considered important in the initiation
of drug abuse and seem to affect its clinical course and outcome. Several studies
have reported psychopathology, namely depression, to be consistently high in
addiction. The aim of this investigation was to evaluate the prevalence of
depression and its relationship to the severity of drug abuse in a Portuguese
sample of drug addicts. METHODS: Two hundred and eighty-five drug addicts (23
women and 262 men, aged between 16 and 41 years old), diagnosed according to the
DSM-IV criteria, were contacted during their first visit for treatment at public
health centres. Social, demographic and behavioural characteristics of the study
sample were obtained by interview using a structured questionnaire. The severity
of drug abuse was evaluated using a Portuguese version of the Drug Abuse
Screening Test, and depression was assessed by the Zung self-rating depression
scale. RESULTS: The prevalence of depression was 51.2% and was higher in females
than males (77.8 vs. 48.7%, p = 0.034). A significant correlation was also found
between the severity of drug abuse and depression scores, which was also stronger
in females (r = 0.53 vs. r = 0.24). CONCLUSIONS: This study showed a high
prevalence of depression in drug addicts, regardless of the type and duration of
drug abuse, and a significant association between depression and severity of drug
addiction.
PMID- 10773767
TI - Relationships between subjective experiences of deficit and other
psychopathological features in schizophrenia.
AB - The study of subjective symptomatology among schizophrenic patients has been
neglected. Even if the patient complaints have always been at the root of the
psychiatrist's work, it has not been conceivable to integrate them in objective
studies. Since 1950, Huber has been interested in the basic symptoms and has
developed his concept of 'a pure defect state', a syndrome which is present as
soon as the beginning of the disease and on which episodes of decompensation
would crop up. In the 1980s, a majority of the scales for the assessment of
subjective complaints appeared. Our study used the French version of the Scale of
Subjective Experiences of Deficit, a scale which has a good internal consistency
and interrater and test-retest reliability. In this study of 50 longterm
schizophrenic patients, we compare subjective symptoms and objective symptoms
using the Positive and Negative Syndrome Scale. We point out - in agreement with
previous work - a statistically significant correlation between subjective
symptoms and positive symptoms.
PMID- 10773768
TI - Screening for DSM-IV somatoform disorders in chronic pain patients.
AB - BACKGROUND: The Screening Instrument for Somatoform Symptoms (SOMS) has been
developed for selecting subjects with various somatoform disorders. To date, this
instrument has not been used for pain patients. The purpose of this study was,
therefore, to apply the SOMS to chronic pain patients, and to compare different
SOMS cutoff item scores with regard to their sensitivity, specificity and
(positive and negative) predictive value for selecting subjects with DSM-IV
somatoform disorders among pain patients. METHODS: In a consecutive sample of 105
chronic pain outpatients, the SOMS was administered in addition to an
operationalized psychiatric assessment according to DSM-IV. RESULTS: Patients
with a somatoform disorder reported significantly more SOMS symptoms than
patients without somatoform disorders (p < 0.02). As shown, a cutoff score of
>/=4 somatoform items appeared useful for determining a somatoform disorder.
However, only a limited number of cases could be correctly classified by the SOMS
(range 53-66%). CONCLUSION: Therefore, the applicability of the SOMS as a
screening instrument for somatoform disorders in chronic pain patients awaits
further clarification.
PMID- 10773770
TI - Objective and subjective extrapyramidal side effects in schizophrenia: their
relationships with negative and depressive symptoms.
AB - The aim of this study was to show that objective extrapyramidal symptoms (O-EPS)
were strongly correlated to negative and depressive symptoms while subjective
extrapyramidal symptoms (S-EPS) were not. Ninety-one schizophrenic patients were
evaluated by the Extrapyramidal Symptoms Rating Scale (ESRS), Montgomery and
Asberg Depression Rating Scale (MADRS) and Scale for the Assessment of Negative
Symptoms (SANS). While significant correlations were found between O-EPS and SANS
(r = 0.51; p < 0.001) and between O-EPS and MADRS (r = 0.26; p < 0.01), no
significant relationship existed between S-EPS and SANS (r = 0.19) or MADRS (r =
0.19). Similar results regarding the relationships between EPS and SANS were
found in stabilized and acute subgroups and in deficit and nondeficit subgroups.
A stepwise multiple regression showed that 41% of the variance of the SANS scores
was due to facial mask and bradykinesia, and that 17% of the variance of the
MADRS scores was due to facial mask and akathisia. This study shows the interest
of evaluating subjective parkinsonism symptoms over objective ones since they are
less interrelated to other symptoms, in particular to negatives ones.
PMID- 10773771
TI - Segmentation of behavior and time structure of movements in depressed patients.
AB - Psychomotor alterations are fundamental psychopathological features of major
depression and observable components of behavior. Human behavior is segmented
into action units with a duration of a few seconds. Cognitive and emotional
dysfunctions in depression may affect the time structure of movements. Therefore,
upper limb movements (total n = 707) of depressed patients and matched healtyh
controls were studied using videotaped interviews and frame-by-frame analysis
with an accuracy of 40 ms. Both groups displayed a similar temporal distribution,
but nonrepetitive action units were significantly shorter (median = 1.16 s) and
repetitive units longer (median = 4.92 s) in depressed patients compared to
controls (median = 1.93 and 3.01, respectively). Movement alterations were
related to anhedonia and subjective severity of depression. Altered time
structure of movements represents an observable psychopathological sign and may
be relevant for pathophysiological and behavioral aspects in depression.
PMID- 10773769
TI - Polythetic diagnostic approach to the borderline personality disorder. the
valency of the single criterion in the concept of professional therapists.
AB - The present study addresses the question whether the polythetic approach of ICD
10 and DSM-IV is useful in clinical practice for the diagnosis 'Borderline'
personality disorder (BPD). A questionnaire containing all individual criteria
for the 9 personality disorders and the schizotypal disorder used by the ICD-10,
completed by the DSM-IV criteria for the BPD not covered by the ICD-10, was
developed. Eight hundred therapists were asked to mark the importance of every
single criterion for forming the diagnosis or for ruling out BPD. Our data
analysis of the received questionnaires performed a rankscore based on an altered
calculation of the mean value. The criteria which described the patients'
instability in relationship and mood, and identity disturbances were seen as the
most important features for the diagnosis of BPD. The criterion of cognitive
disturbances, newly introduced in DSM-IV, was not felt to be a major clinical
feature. In conclusion, our study reflects the results of other authors in the
sense that a single criterion cannot be considered pathognomonic for BPD, but has
greater importance and a higher priority in establishing the diagnosis BPD. This
should be taken into account to reconsider the polythetic concept in favor of a
hierarchical approach with core criteria.
PMID- 10773772
TI - Age- and gender-related psychological characteristics of adolescent ballet
dancers.
AB - Ballet school students (n = 90) aged 11-17 years, and nondancing adolescents (n =
156) aged 13-17 completed the Eating Disorder Inventory (EDI). Significant
differences between female dancers and controls were seen in five subscales, with
higher scores for the dancers ('Drive for thinness', 'Bulimia', 'Interpersonal
distrust', 'Ineffectiveness' and 'Perfectionism'). Their highest scores on most
subscales were for the 16-year-olds. The only difference between male dancers and
controls was seen for Ineffectiveness. Our data suggest important psychological
inconsistency in the course of the adolescence of female ballet dancers, whilst
the psychological profile of male ballet dancers appeared quite similar to that
of nondancing adolescents.
PMID- 10773773
TI - The role of psychopathology and suicidal intention in predicting suicide risk: a
longitudinal study.
AB - OBJECTIVE: In this study, we describe psychological symptoms, any relationship
with suicidal intention in a sample of subjects recently attempting suicide and
the predictive value of this association in later completed suicide. METHODS: An
assessment was made of 467 suicidological consultations carried out by the
Suicidology Unit of the Department of Neurology and Psychiatry, University of
Padua, on 421 patients admitted to hospital following attempted suicide in the 5
year period 1990-1994. Suicidal intention was appraised by the Intent Score Scale
(ISS). Suicide mortality was assessed after a mean follow-up period of 3.5 years.
RESULTS: Psychiatric evaluation was completely negative in only 8% of cases. The
most commonly identified symptom was depressed mood (79% of cases, 22% severe
depression), followed by anxiety (43% of cases, 32% severe anxiety). From the
study, it emerged that psychopathology seemed to influence suicidal intent, where
this was characterized by severe depression. Anxiety and other symptoms appeared
to have a secondary role. Assessments of suicidal intent showed that intention
heightened as the number of symptoms increased. The symptom 'anxiety' did not
prove to have a significant bearing on assessment of the seriousness of suicidal
intention, whereas severely depressed mood did. The total number of subsequent
suicide victims was 5.5%. During consultation relating to the index parasuicide,
these subjects did not manifest a discriminate psychopathological profile (the
only distinguishing characteristic was anxiety, which was less frequently
identified in suicide victims), but did present a more positive personal and
family psychiatric history. CONCLUSIONS: In subjects who had recently attempted
suicide, the psychopathological profile appeared to be related to suicidal
intent, where this was characterized by severe depression. Anxiety and other
symptoms seemed to have a secondary role. Nonetheless, both total scores and
subscores should be taken into consideration when assessing suicidal intention
through the ISS. The psychopathological profile and ISS score following attempted
suicide do not appear to permit prediction, in the medium to long term, of
subsequent completed suicide.
PMID- 10773774
TI - Exploring the benefits of group psychotherapy in reducing alexithymia in coronary
heart disease patients: a preliminary study.
AB - BACKGROUND: Although there is preliminary evidence that alexithymia may influence
the course of coronary heart disease (CHD), there are no studies exploring
attempts to modify alexithymic characteristics in cardiac patients. METHOD:
Twenty post-myocardial infarction (MI) patients (19 men and 1 woman) were placed
in a treatment group, which received weekly group psychotherapy for 4 months.
Seventeen post-MI patients (16 men and 1 woman) were placed in a comparison group
which received two educational sessions over a period of 1 month. All subjects
completed the Toronto Alexithymia Scale (TAS) before the start of group therapy,
at the end of the 4-month period, and in follow-up assessment after 6-month, 1
year, and 2-year intervals. RESULTS: In the psychotherapy treatment group, there
was a significant reduction in the mean TAS score following group therapy, which
was maintained over the 2-year follow-up period. In the educational group, there
were no significant changes in mean TAS scores between the initial testing and
any of the follow-up intervals. On an individual basis, a decrease to a lower
level of TAS scores occurred in a higher percentage of patients in the treatment
group than in the educational group. Over the 2-year follow-up period, patients
with decreased alexithymia following group therapy experienced fewer cardiac
events (reinfarction, sudden cardiac death, or rehospitalization for rhythm
disorder or severe angina) than patients whose alexithymia remained unchanged.
CONCLUSIONS: The results indicate that group psychotherapy is able to decrease
alexithymia and that for many patients this change can be maintained for at least
2 years. A reduction in the degree of alexithymia seems to influence favorably
the clinical course of CHD.
PMID- 10773775
TI - Relationship between alexithymia, dissociation and personality in psychiatric
outpatients.
AB - BACKGROUND: The relationship between alexithymia and dissociation is not known.
Both mechanisms ward off overwhelming affective states; hence, this report
examines the relationship between dissociation, alexithymia, depressed mood and
the five-factor model of personality in a sample of psychiatric outpatients.
METHODS: One hundred and sixteen outpatients were evaluated using the Toronto
Alexithymia Scale (TAS), the Dissociative Experiences Scale (DES), NEO Five
Factor Inventory and visual analog scales assessing depression and anxiety. Data
was analyzed using multivariate analysis of variance, logistic regression and
linear regression techniques. RESULTS: Depressed mood accounted for the group
differences between the global TAS and DES scores. Using DES both dimensionally
and categorically with regression models, there was minimal contribution of DES
or its subfactors to predict TAS. CONCLUSIONS: These data reaffirm previous
findings that dissociation fundamentally differs from alexithymia. Dissociation
involves a change of one's sense, of self, whereas alexithymia reflects a
cognitive state of externally oriented thinking with an inability to identify and
report discrete emotions.
PMID- 10773776
TI - The relationship between dimensions of alexithymia and dissociation.
AB - BACKGROUND: The study investigated the following hypotheses: (1) Alexithymia is
significantly associated with dissociation. (2) Pathological versus
nonpathological dissociation is associated with alexithymic traits. METHODS:
Psychiatric in- and outpatients (n = 173) and nonclinical subjects (n = 38) were
investigated with the Toronto Alexithymia Scale (TAS-20), the FDS (German version
of Dissociation Experience Scale) and the Symptom Check List (SCL-90-R; GSI).
Correlation analyses followed by MANOVA and logistic regression were performed.
RESULTS: Significant correlations and partial correlations, controlling for GSI,
were observed between dissociation and alexithymia. The MANOVA demonstrated
significantly higher scores for the two TAS-20 dimensions 'difficulty identifying
feelings' and 'difficulty expressing feelings' in the group with pathological
dissociation. On the basis of the TAS-20 subscores, logistic regression analysis
correctly classified 72.5% of the cases into the pathological and the
nonpathological dissociation group. CONCLUSIONS: These results support our
hypothesis that pathological traits of dissociation are highly associated with
alexithymia. A model is discussed in which alexithymic characteristics may
contribute to the development of pathological dissociation and stress-related
disorders such as posttraumatic stress disorder.
PMID- 10773777
TI - Polysymptomatic conversion disorder in childhood and adolescence in Japan. Early
manifestation or incomplete form of somatization disorder?
AB - BACKGROUND: In conversion disorder in childhood and adolescence, polysymptomatic
(PS) presentations are reportedly commoner than monosymptomatic (MS) ones.
Somatization disorder is also associated with pseudoneurological symptoms, but is
extremely rare in childhood. This occurs despite the age of onset peaking in the
teens among adult somatization disorder patients. METHOD: We reviewed the records
of 44 children and adolescents with pseudoneurological symptoms. They were
categorized as MS cases (19) or PS cases (25), and their psychological
backgrounds and clinical courses were compared. RESULTS: PS patients had a poorer
prognosis and more past psychiatric and family problems. While none met the DSM
IV criteria for somatization disorder, 2 PS patients met all but the sexual
symptoms criteria. CONCLUSION: PS conversion disorder in childhood and
adolescence may constitute a different entity from MS conversion disorder and may
be an early manifestation or incomplete form of somatization disorder.
PMID- 10773778
TI - Cognitive behavior therapy versus supportive therapy in social phobia: a
randomized controlled trial.
AB - BACKGROUND: The efficacy of cognitive behaviour therapy (CBT) in social phobia
has been demonstrated in several controlled trials and meta-analyses, but no
comparison of CBT with supportive therapy (ST) can be found in the literature.
METHOD: The aim of the trial was to study the effectiveness of CBT versus ST
carried out 'as usual'. Sixty-seven DSM-4 social phobic patients (89% generalized
subtype, most with avoidant personality) were randomly allocated into two groups.
Group 1 (CBT) received 8 1-hour sessions of individual cognitive therapy (CT) for
6 weeks, followed by 6 2-hour sessions of social skills training (SST) in group
weekly. Group 2 received ST for 12 weeks (6 half-hour sessions), then the
patients were switched to CBT. All patients agreed not to take any medication
during the whole trial. In group 1, 29 patients reached week 6, 27 reached week
12, and 24 weeks 36 and 60 (endpoint). In group 2, 29 patients reached week 6, 28
reached weeks 12 and 18, 26 week 24, and 23 reached weeks 48 and 72 (endpoint).
RESULTS: At week 6, after CT, group 1 was better than group 2 on the main social
phobia measure. At week 12, after SST, group 1 was better than group 2 on most of
the measures and demonstrated a significantly higher rate of responders. This
finding was replicated after switching group 2 to CBT. Sustained improvement was
observed in both groups at follow-up. Compliance with abstinence from medication
increased over time. CONCLUSIONS: CBT was more effective than ST and demonstrated
long-lasting effects. This may suggest that social phobia management requires
more than a simple and inexpensive psychological intervention.
PMID- 10773779
TI - Depression but not anxiety is a significant predictor of physicians' assessments
of medical status in physically ill patients.
AB - BACKGROUND: In a cross-sectional study we investigated associations between self
ratings of anxiety and depression, physical factors and physicians' assessments
of patients' medical status. METHODS: Hospital inpatients (n = 574) consecutively
admitted to internal medical wards were evaluated for the presence of anxiety and
depressive symptoms using the Hospital Anxiety and Depression Scale (HADS).
Physicians were asked for their perception of psychiatric problems in their
patients and for their assessments of patients' severity of illness, functional
impairment and 1-year prognosis on 3-point ranking scales. Detailed somatic data
including comorbidity and accepted risk factors were taken from the patients'
records. RESULTS: Almost two thirds of all patients with abnormal HADS scores
(65.2%) were not identified by their attending physicians as suffering from
psychiatric problems. Using multiple-regression models, HADS scores for
depression, but not for anxiety, proved to be an independent predictor for the
clinicians' judgements of disease severity [exp(beta) = 1.08; 95% confidence
interval (CI) 1. 03-1.13; p < 0.01] and functional impairment [exp(beta) = 1.11;
95% CI 1.05-1.17; p < 0.01]. The estimation of prognosis, however, was only
related to physical predictors and showed no association with depressive symptoms
or other psychosocial factors. CONCLUSIONS: Our data demonstrate that internists'
ratings of severity of illness and functional impairment, but not prognosis, are
associated with HADS depression scores, whereas there is no such association with
self-rated anxiety.
PMID- 10773780
TI - Attachment representation and cortisol response to the adult attachment interview
in idiopathic spasmodic torticollis.
AB - OBJECTIVE: The study investigates individual differences in the mental
representation of attachment and their impact on the cortisol response to
psychosocial stress in idiopathic spasmodic torticollis (IST). It was
hypothesized (a) that in IST insecure attachment is more prevalent than in a non
clinical control group and (b) that subjects with dismissing attachment respond
with higher physiological arousal to a specific stimulus activating the
attachment behavioural system than subjects with secure attachment. METHOD: 20
patients with IST and 20 healthy controls matched for age and sex underwent the
Adult Attachment Interview, an hour-long, semiclinical interview on attachment
experiences. During the interview salivary cortisol levels were monitored. The
subjects' mental state with regard to attachment was classified using the
attachment Q-sort method. Anxiety and depression were measured as potential
covariates of the adrenocortical stress response. RESULTS: Compared to the non
clinical group, dismissing attachment was strongly overrepresented in IST. In
IST, but not in the healthy control group, dismissing attachment correlated with
an elevated cortisol response to the interview. CONCLUSION: In clinical, but not
in non-clinical samples dismissing attachment may be associated with increased
vulnerability to psychosocial stress. The factors contributing to this
interaction are not yet fully elucidated.
PMID- 10773781
TI - Hungarian psychotherapists about psychotherapy: the results of a survey.
PMID- 10773782
TI - Paroxetine in a case of psychogenic pruritus and neurotic excoriations.
PMID- 10773783
TI - Genotype and phenotype in cystic fibrosis.
AB - Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance
regulator (CFTR) gene which encodes a protein expressed in the apical membrane of
exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride
channel and appears capable of regulating other ion channels. Besides the most
common mutation, DeltaF508, accounting for about 70% of CF chromosomes worldwide,
more than 850 mutant alleles have been reported to the CF Genetic Analysis
Consortium. These mutations affect CFTR through a variety of molecular mechanisms
which can produce little or no functional CFTR at the apical membrane. This
genotypic variation provides a rationale for phenotypic effects of the specific
mutations. The extent to which various CFTR alleles contribute to clinical
variation in CF is evaluated by genotype-phenotype studies. These demonstrated
that the degree of correlation between CFTR genotype and CF phenotype varies
between its clinical components and is highest for the pancreatic status and
lowest for pulmonary disease. The poor correlation between CFTR genotype and
severity of lung disease strongly suggests an influence of environmental and
secondary genetic factors (CF modifiers). Several candidate genes related to
innate and adaptive immune response have been implicated as pulmonary CF
modifiers. In addition, the presence of a genetic CF modifier for meconium ileus
has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum
associated with mutations in the CFTR gene extends beyond the classically defined
CF. Besides patients with atypical CF, there are large numbers of so-called
monosymptomatic diseases such as various forms of obstructive azoospermia,
idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR
mutations uncharacteristic for CF. The composition, frequency and type of CFTR
mutations/variants parallel the spectrum of CFTR-associated phenotypes, from
classic CF to mild monosymptomatic presentations. Expansion of the spectrum of
disease associated with the CFTR mutant genes creates a need for revision of the
diagnostic criteria for CF and a dilemma for setting nosologic boundaries between
CF and other diseases with CFTR etiology.
PMID- 10773784
TI - High-resolution computed tomography in cases with environmental exposure to
asbestos in Turkey.
AB - BACKGROUND AND OBJECTIVES: Although all parts of the lung can be affected as a
consequence of asbestos exposure, most CT protocols tend to scan only the middle
and lower parts of the thorax. The aim of this study was to investigate
parenchymal and pleural lesions of persons exposed to environmental asbestos,
using a high-resolution computed tomography (HRCT) protocol scanning the whole
thorax. METHODS: We analyzed the chest radiographs and HRCT scans of 26 patients
who presented bilaterally with multiple pleural plaques related to environmental
asbestos exposure. RESULTS: Twenty-four cases (92%) had an abnormal HRCT
suggestive of asbestosis. Apart from common HRCT changes related to asbestosis,
we detected apical pleural thickening (APT) in 9 cases as well as a coarse
honeycomb pattern adjacent to APT in 7 of these cases. Cavitary lesions due to
pulmonary tuberculosis were observed on HRCT scans from 4 patients in total.
Neither apical pulmonary fibrosis nor cavitary lesions were visible on chest
radiographs. CONCLUSIONS: We suggest that the HRCT protocol for examining
asbestos-exposed individuals with pleural plaques on chest X-rays should include
the whole thorax, since the asbestos-related pathologies may involve all parts of
the lung.
PMID- 10773785
TI - Role of carbohydrate antigens sialyl Lewis (a) (CA19-9) in bronchoalveolar lavage
in patients with pulmonary fibrosis.
AB - BACKGROUND: It has been reported that carbohydrate antigen sialyl Lewis (a) (CA19
9) levels are elevated in serum as well as in bronchoalveolar lavage fluid (BALF)
of patients with pulmonary fibrosis. However, the biological significance of CA19
9 is unclear. OBJECTIVE: The purpose of the present study was to evaluate
correlations between CA19-9 levels in BALF and several biochemical as well as
clinical parameters in patients with pulmonary fibrosis. In addition, biological
functions of CA19-9 were also examined. METHODS: We studied 24 patients with a
diagnosis of pulmonary fibrosis: 16 with idiopathic pulmonary fibrosis (IPF) and
8 with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD).
In BALF, carbohydrate antigens sialyl Lewis (a) (CA19-9), elastase: alpha(1)
proteinase inhibitor complex (E-PI), hepatocyte growth factor (HGF), LDH, IgG,
IgA, albumin, and cell differentiation were measured. We also evaluated the
effects of CA19-9 on neutrophil functions. RESULTS: CA19-9/albumin levels in BALF
significantly correlated with HGF/albumin, elastase/albumin, LDH/albumin, total
number of alveolar macrophages, and total number of neutrophils. Purified CA19-9
had a chemotactic activity for neutrophils. In addition, neutrophil chemotactic
activity to C5a, fMLP, and interleukin 8 was significantly stimulated after
incubation with purified CA19-9. Furthermore, CA19-9 increased the expression of
CD15s on neutrophils. CONCLUSIONS: Our data demonstrated (i) CA19-9 in BALF
correlated with other markers of inflammation in pulmonary fibrosis, and (ii)
CA19-9 can modify neutrophil functions. These results suggest that CA19-9 may
play a role in the process of lung injury in patients with pulmonary fibrosis.
PMID- 10773786
TI - Laparoscopic and laparotomic cholecystectomy: a randomized trial comparing
postoperative respiratory function.
AB - BACKGROUND: The fact that pulmonary complications occur in 20-60% of the patients
subjected to abdominal operations clearly indicates that the lungs are the most
endangered organ during the postoperative period. OBJECTIVE: The aim of this
study was to demonstrate the impact of cholecystectomy on postoperative
respiratory disturbances by comparing the laparotomic cholecystectomy with
laparoscopic gallbladder removal. PATIENTS AND METHODS: A hundred
cholecystectomized patients were included in the prospective randomized clinical
trial. Half of the patients were operated on by the laparotomic procedure,
whereas the other half underwent laparoscopic cholecystectomy. Spirometric
parameters, arterial blood gases, and acid-base balance were determined before
the operation, and at 6, 24, 72 and 144 h postoperatively. Abdominal distension
was assessed by auscultating intestinal peristaltics, abdominal circumference
measurement, and time interval to restitution of defecation. RESULTS: Six hours
postoperatively, the values of ventilation parameters decreased on average by 40
50% from the baseline preoperative values in both groups of patients. The group
of patients submitted to laparotomic cholecystectomy had significantly lower
spirometric values and slower recovery of the ventilation parameters than the
laparoscopic cholecystectomy group. Abdominal circumference was significantly
greater and the time needed for restitution of peristaltics and defecation was
significantly longer in the laparotomic cholecystectomy group compared to the
group of laparoscopic cholecystectomy. CONCLUSIONS: Statistically significant
impairments including hypoxia, hypocapnia and hyperventilation were observed in
the patients submitted to laparotomic cholecystectomy, indicating the presence of
objective respiratory risk, especially in elderly patients and patients with
obstructive pulmonary diseases or cardiac insufficiency.
PMID- 10773787
TI - Health-related quality of life in lung transplant candidates and recipients.
AB - BACKGROUND: Studies on the health-related quality of life in lung transplantation
have used general questionnaires, although lung-specific instruments might be
more sensitive to small differences. OBJECTIVES: To compare the health-related
quality of life of lung transplant recipients with lung transplant candidates,
using lung-specific and general instruments, and to assess the reliability and
validity of these questionnaires. METHODS: The study is a cross-sectional postal
survey of 31 lung transplant recipients and 15 candidates, using the following
outcome measures: St. George's Respiratory Questionnaire (SGRQ), a lung-specific
health status instrument; the Short Form 36 (SF-36), a general measure, and the
Hospital Anxiety and Depression scale (HAD). RESULTS: The SGRQ showed a
significantly better score (p < 0.05) for transplant recipients in the impacts
and activity dimensions and the total score than for candidates. SF-36 scores
showed a similar improvement in all subscales of the SF-36 except bodily pain.
Cronbach's alpha for all dimensions of the SGRQ, SF-36, and HAD were 0.77-0.95.
CONCLUSIONS: Patients surviving lung transplantations can expect a considerable
improvement in most dimensions of health-related quality of life. This finding
was consistent using both lung-specific and general measures. The reliability of
the questionnaires was acceptable. The associations between scales support the
validity of the questionnaires in this setting.
PMID- 10773788
TI - Detection of CMV pneumonitis after lung transplantation using PCR of DNA from
bronchoalveolar lavage cells.
AB - BACKGROUND: Cytomegalovirus (CMV) is known as a common pathogen causing
infections after lung transplantation. Rapid diagnosis of CMV infection is
important for the initiation of a specific treatment. OBJECTIVE: Evaluation of
methods for the rapid diagnosis of CMV pneumonitis. METHODS: The detection rates
of CMV DNA in bronchoalveolar lavage (BAL) and bronchial brushes by polymerase
chain reaction (PCR), of viral antigens (p52 and IE1) in BAL and of pp65 antigen
in peripheral blood leukocytes were compared to the clinical status after lung
transplantation. In 28 patients, 105 BAL, 96 blood samples and 14 brushes were
analyzed. RESULTS: In 6 patients, a total of eight episodes of CMV pneumonitis
occurred. Five of the 6 with positive CMV antigens in BAL (p52 or IE1) showed
signs of CMV pneumonitis. All episodes of CMV pneumonitis were detected by the
PCR of BAL cells. Fourteen samples positive for CMV pp65 antigen in blood were
negative in BAL PCR. In these cases, no clinical signs of pulmonary CMV infection
occurred. Overall sensitivity, specificity, and positive and negative predictive
values for the detection of CMV pneumonitis by PCR of BAL cells were 100, 98.9,
88.9 and 100%, respectively. In brush samples, PCR did not provide additional
information to the results of the PCR of BAL cells. CONCLUSIONS: PCR of DNA from
BAL cells is suitable for reliable and rapid detection of CMV pneumonitis.
PMID- 10773789
TI - A comparison of induced and expectorated sputum for the microbiological diagnosis
of community acquired pneumonia.
AB - BACKGROUND: Sputum induction has proved useful in the diagnosis of Pneumocystis
carinii pneumonia and mycobacterial infections but there are scant data on its
use in the diagnosis of community-acquired pneumonia (CAP). OBJECTIVE: To better
define the usage of sputum induction by hypertonic saline in the setting of CAP.
METHODS: A retrospective review of records of patients admitted to a community
teaching hospital in the year 1995 with a diagnosis of CAP. RESULTS: Of 492
patients admitted with CAP, 71 (14%) had attempted sputum induction. A group of
66 patients with CAP and attempted sputum collection by spontaneous expectoration
was compared with this group. Sputum induction failed to yield a sample in 22
patients (31%). Forty-five of 49 patients (92%) with induced sputum had received
prior antibiotics as compared to 23 of 34 patients (68%) with expectorated
samples (p < 0.05), due to sputum induction often being attempted later in the
hospital course. The diagnostic yield of sputum induction was 14 of 71 (20%)
compared to 16 out of 66 (24%) for attempted spontaneously expectorated samples.
Antibiotic therapy was changed for 5 of 34 patients (15%) who spontaneously
expectorated samples and for 9 of 49 patients (18%) with successful induction.
CONCLUSIONS: Sputum induction is effective in obtaining sputum in some patients
with CAP who fail to expectorate a sample. Attempting induction early, preferably
before starting antibiotics, may increase its diagnostic yield.
PMID- 10773790
TI - Effect of intravenous fructose 1,6-diphosphate administration in malnourished
chronic obstructive pulmonary disease patients with chronic respiratory failure.
AB - BACKGROUND: Weight loss and skeletal muscle wasting are common in patients with
chronic obstructive pulmonary disease (COPD) and can influence the course and the
prognosis of COPD. Hypophosphatemia is a pathologic status often characterized by
muscle weakness and is a frequent laboratory finding in these patients.
OBJECTIVE: The aim of the present study was to evaluate the effect of an organic
phosphate (fructose 1,6-diphosphate, FDP) administration on respiratory
performance in 45 malnourished COPD patients in stable clinical conditions.
METHODS: Physiologic evaluation including spirometry, maximal voluntary
ventilation (MMV), elevated arm test, maximal mouth pressures (PImax and PEmax),
respiratory response to CO(2), oxygen (PaO(2)) and carbon dioxide (PaCO(2))
arterial tension, a visual analogic scale (VAS) to measure dyspnea, and complete
blood tests were done at the beginning and again at the end of the study.
RESULTS: After FDP administration, there was a significant increase in PImax
(43.0 +/- 18.3 cm H(2)O before treatment vs. 49.8 +/- 14.9 cm H(2)O after
treatment; p < 0.005). This did not occur in the placebo group (40.3 +/- 17.4 cm
H(2)O before treatment vs. 42.6 +/- 20.1 cm H(2)O after treatment,
nonsignificant). There was also a trend of VAS to decrease and of MVV to
increase. CONCLUSIONS: These results show that FDP administration may be useful
in the management of malnourished COPD patients, especially in increasing their
respiratory muscle strength.
PMID- 10773791
TI - Immunohistochemically stained activated eosinophils in sputum in patients with
asthma.
AB - BACKGROUND: Eosinophils play an important role in asthmatic airway inflammation.
Monoclonal antibody EG2 has been considered to identify activated eosinophils.
OBJECTIVE: The present study was aimed to investigate whether
immunohistochemically stained EG2+ eosinophils in sputum reflect the severity of
asthma. METHODS: Sputum was obtained in 23 asthmatic patients, of whom 13
patients were examined before and after antiasthma treatment including steroid
preparations. We used immunohistochemical staining to detect EG2+ (activation
marker) eosinophils and fluoroimmunoassay to detect eosinophil cationic protein
(ECP). RESULTS: Moderate to severe asthmatics had a significantly higher
proportion of eosinophils and EG2+ eosinophils and higher levels of ECP compared
to mild asthmatics (40.9 +/- 5.8 vs. 6.4 +/- 1.2%, 35.5 +/- 5.6 vs. 2.7 +/- 1.0%,
1.470.2 +/- 251.5 vs. 210.6 +/- 52.0 microgram/l, respectively; p < 0.01).
Significant increases in proportions of eosinophils, EG2+ eosinophils and ECP in
the sputum from patients with exacerbated asthma were evident. The proportions of
eosinophils, EG2+ eosinophils, and the levels of ECP were reduced following
treatment with antiasthmatic drugs. FEV(1) and FEV(1)/FVC were significantly
correlated with EG2+ eosinophils. CONCLUSION: These findings demonstrate that
EG2+ eosinophils in sputum are closely related to the clinical status in patients
with asthma.
PMID- 10773792
TI - Difference in the effects of low temperatures on the tension of human pulmonary
artery and vein ring segments.
AB - BACKGROUND: Although limited data suggest that pulmonary flushing with organ
preservation solutions should not be performed at too low temperatures, the
influence of temperature on pulmonary vascular tone is unclear. OBJECTIVE: The
purpose of this study was to examine the effect of low temperatures of the
tension of human pulmonary artery and vein ring segments and the vascular
resistance of perfused rat lungs. METHODS: 5 sets of human pulmonary artery and
vein ring segments were suspended from a force displacement transducer at 37, 24
and 8 degrees C, and the effect of 30 mM K(+) on the tension was monitored. The
effect of 30 mM K(+) on vascular resistance was also examined at low temperatures
in 5 perfused rat lungs. RESULTS: Pulmonary artery segments dilated at 24 degrees
C, and more significant vasodilatation was observed at 8 degrees C. In contrast,
there was a significant constriction of pulmonary veins at 8 degrees C.
Vasoconstriction induced by 30 mM K(+) at 37 degrees C was significantly
inhibited at low temperatures in both pulmonary arteries and veins. In rat lungs,
perfusion at 8 degrees C caused a significant increase in pulmonary vascular
resistance, even though no further increase was observed in the presence of 30 mM
K(+). CONCLUSIONS: Our data indicate that pulmonary arteries dilate and the veins
constrict at 8 degrees C and may increase pulmonary vascular resistance. We
conclude that the different effect of low temperatures between pulmonary arteries
and veins may explain why pulmonary vascular flushing with organ preservation
solutions at room temperature is more satisfactory.
PMID- 10773793
TI - Equivalence of two steroid-containing inhalers: easyhaler multidose powder
inhaler compared with conventional aerosol with large-volume spacer.
AB - BACKGROUND AND OBJECTIVES: An equivalence study was conducted in which the
efficacy and safety of a daily dose of 800 microgram of beclomethasone
diproprionate administered via a multidose powder inhaler, Easyhaler, and via a
metered-dose inhaler (MDI) with a large-volume spacer were compared in adult,
newly diagnosed, steroid-naive asthmatic patients. Acceptability of the
medications was also compared. METHODS: One hundred and forty-four patients were
recruited into the double-blind, double-dummy, randomised, parallel-group
multicentre study. The study treatment period was 8 weeks. It was preceded by a 2
week run-in period. Morning and evening peak expiratory flow (PEF), numbers of
inhalations of a sympathomimetic and asthma symptoms were recorded daily.
Spirometry and histamine challenge were performed, and health-related quality of
life and morning serum cortisol levels measured during control visits. RESULTS:
Criteria indicating treatment equivalence were met. The mean of the primary
outcome variable, morning PEF, increased significantly, from 426 to 461
litres/min in the Easyhaler group and from 436 to 467 litres/min in the
MDI+spacer group. Similar improvements between groups were also seen in relation
to all secondary variables. Changes in serum cortisol levels were minor. In 6 out
of 10 questions about device acceptability, the majority of patients rated
Easyhaler as better than the MDI+spacer combination. CONCLUSION: It was concluded
that the devices tested were equivalent in terms of efficacy and safety.
PMID- 10773794
TI - Cheyne-stokes respiration or obstructive sleep apnoea: patterns of desaturation.
PMID- 10773795
TI - Sarcoidosis and common variable immunodeficiency. A case of a malignant course of
sarcoidosis in conjunction with severe impairment of the cellular and humoral
immune system.
AB - The occurrence of sarcoidosis in combination with common variable
immunodeficiency (CVID) has been described in a small number of patients. In
these patients, sarcoidosis consisted of lymphadenopathy, mild to moderate
pulmonary involvement and hepatosplenomegaly. However, severe and rapidly
progressive pulmonary fibrosis in combination with a severe defect of the
cellular and humoral immune system has not been described yet. In our patient,
defects of the T and B cell system resulted in severe immunodeficiency. The
defect of the humoral immune system was characterized by the impairment of
specific antibody production in vivo. In addition, hypogammaglobulinemia with
missing IgA and IgE along with a marked defect in IgM and IgG production was
noted. There was a progressively reduced lymphocyte proliferation in response to
T cell mitogens, while proliferation after specific IL-2 stimulation was normal.
A Th1 lymphocyte-subset-like profile might thus play a role in the pathogenesis
and might form the connecting link between sarcoidosis and CVID. This is the
report of a so far new and unique combination of severe immunodeficiency and
sarcoidosis also associated with a congenital dysmorphia consisting of a palatal
cleft. The findings of the 40 patients with CVID and sarcoidosis reported so far
are discussed in order to point out the typical features of patients with this
uncommon syndrome.
PMID- 10773796
TI - Hard metal alveolitis accompanied by rheumatoid arthritis.
AB - Hard metal lung diseases (HML) are rare, and complex to diagnose. We describe the
case of a patient with allergic alveolitis accompanied by rheumatoid arthritis. A
sharpener of hard metal by trade, our patient was a 45-year-old, nonsmoking
Caucasian female who experienced symptoms of cough and phlegm, and dyspnea on
exertion. Preliminary lung findings were inspiratory rales in both basal areas,
decreased diffusion capacity and a radiological picture resembling sarcoidosis. A
high-resolution computed tomography scan indicated patchy alveolitis as well. An
open lung biopsy revealed non-necrotizing granulomas consisting of epitheloid
cells and surrounded by lymphocytes, plasma cells and a few eosinophils. These
cells also occupied the thickened alveolar interstitium. Macrophages in the
alveolar spaces, some of them multinuclear, contained dust particles. Hard metal
alveolitis is clinically well known and, in this patient, has been described
histologically. After the patient had quit working with hard metal and following
corticosteroid therapy, pulmonary symptoms and signs were relieved. During this
recovery period, however, she contracted rheumatoid arthritis.
PMID- 10773797
TI - Takayasu disease with predominant pulmonary involvement.
AB - We report a case of Takayasu's arteritis with predominant pulmonary involvement,
which led eventually to complete obliteration of the right pulmonary artery.
Subsequently, cavitation and chronic inflammation developed in the nonperfused
right lung. A right pneumonectomy was performed to control the infectious
process, leading to functional improvement and better control of the underlying
immunologic disorder.
PMID- 10773798
TI - Transient mediastinal enlargement: an unusual computed tomographic manifestation
of pulmonary venous hypertension and congestive heart failure.
AB - We describe a case of diffuse superior and middle mediastinal enlargement of soft
tissue attenuation noted on helical computed tomography (CT) of a patient with
clinical and radiographic findings of congestive heart failure (CHF). Upon
treatment and improvement of his pulmonary venous hypertension, a repeat CT scan
revealed resolution of the mediastinal abnormalities. We, therefore, advocate a
search for primary CT signs of CHF in patients with findings of widespread
mediastinal distension. If present, repeat CT scanning after resolution of the
cardiac condition should be performed before further intervention for the
mediastinal abnormality is attempted.
PMID- 10773799
TI - Miliary sarcoidosis following miliary tuberculosis.
AB - A patient who presented with a miliary radiographic pattern due to tuberculosis
and later with a similar miliary pattern due to sarcoidosis is described. The
patient, a 47-year-old man, was admitted to the hospital due to coughing,
weakness, weight loss and an abnormal chest radiograph with a miliary pattern. A
gastric fluid culture was positive for Mycobacterium tuberculosis and he was
treated appropriately. He showed complete clinical and radiological remission.
One year later he presented with a dry cough and a similar miliary pattern on the
chest roentgenogram. Lung biopsy taken by thoracoscopy revealed sarcoidosis. The
patient had a complete remission with corticosteroids. To our knowledge, this is
the first report describing a miliary pattern as presenting radiological sign in
a patient with tuberculosis who subsequently developed a new miliary pattern due
to sarcoidosis.
PMID- 10773800
TI - Malignant mesothelioma in subjects with Marfan's syndrome and Ehlers-Danlos
syndrome: only an apparent association?
AB - Malignant mesothelioma is a rare neoplasm which could be favored by an hereditary
predisposing factor. So far, malignant mesothelioma have never been described in
patients with hereditary diseases of the connective tissue. Here, we report some
cases of mesothelioma affecting subjects who were not exposed to inhalation of
asbestos. One of these subjects was affected by Ehlers-Danlos syndrome, whereas
in two brothers, mesothelioma was associated with Marfan's syndrome. The
observation of the same histologic subtype of mesothelioma in two brothers and
the coexistence of two pathologic conditions of mesodermal origin indicate the
presence of hereditary factors predisposing to the cancerogenic action of even
small amounts of asbestos. Structural alterations of collagen and primary
immunodeficiency may represent the host factor inducing development of the
neoplasm. We conclude that the association between these rare disorders of the
connective tissue and mesothelioma may not be coincidental, but could be the
result of the exposition to small amounts of asbestos in predisposed individuals.
PMID- 10773801
TI - Isolated azygos continuation of the inferior vena cava in the elderly.
AB - A 70-year-old woman with the isolated anomaly of azygos continuation of the
inferior vena cava is presented. The interest in this anomaly lies in its
presentation as a mediastinal mass on the chest roentgenogram. This article
reviews the embryogenesis and the diagnostic testing of this venous anomaly.
PMID- 10773802
TI - Posterior mediastinal mass in patients with von Recklinghausen's disease.
PMID- 10773803
TI - On "supplemental therapeutic oxygen for prethreshold retinopathy of prematurity
(STOP-ROP), a randomized, controlled trial. I: Primary outcomes".
PMID- 10773804
TI - Clinical rationale for manifest congenital nystagmus surgery.
AB - Although electronystagmography is most useful, especially in furthering our
knowledge of nystagmus, simple clinical study is the first step to any
understanding of nystagmus. Ophthalmologists should be aware that they may
understand a good deal about nystagmus merely by studying visual acuity in their
surgery. Testing visual acuity at distance with both eyes open will lead to the
qualitative and quantitative diagnosis of compensatory abnormal head postures.
Testing at distance with 1 eye covered will help to distinguish between the
concordant head turn, one eye fixing in abduction and the other fixing in
adduction (ABD + ADD) as manifest congenital nystagmus, and the discordant head
turn in which each eye fixes in adduction (ADD + ADD), as is seen in manifest
latent nystagmus, for which surgery is totally different. Pseudolatent nystagmus
found in congenital nystagmus with exophoria can be differentiated from latent
nystagmus. This illustrates de visu (with the naked eye) the "beauty" of the
movement of blocking fusional convergence and the nature of the involved
mechanisms with artificial divergence surgery. Testing at near will bring out the
existence of blocking convergence. Depending on the results, the clinical
rationale for surgery is thus made clear: horizontal, vertical, rotatory
Kestenbaum-like surgery should be used in cases of abnormal head posture, whereas
artificial divergence surgery is our most satisfactory armamentarium in cases of
blocking convergence.
PMID- 10773805
TI - Combined superior oblique muscle recession and inferior oblique muscle
advancement and transposition for cyclotorsion associated with macular
translocation surgery.
AB - PURPOSE: The purpose of this study was to evaluate the effects of oblique muscle
surgery on the large-angle incyclotorsion resulting from macular translocation
surgery for severe age-related macular degeneration. METHODS: Patients undergoing
macular translocation (superiorly) at our institution from May 1996 until
November 1998 were included. In the Staged Group, strabismus surgery for
symptomatic incyclotorsion was performed after the macular translocation, and in
the Combined Group, it was performed simultaneous with the macular translocation.
Cyclotorsion was quantified using Maddox rod testing. Surgery for incyclotorsion
included superior oblique muscle recession combined with inferior oblique muscle
advancement and transposition in the affected eyes. The minimum follow-up time
was 6 weeks. RESULTS: Fifteen patients (15 eyes) were included (ages 66-89
years). Nine eyes (Baseline Group) had macular translocation surgery before any
strabismus surgery; the mean postoperative incylotorsional angle was 33.4 +/-
18.3 degrees (range, 20-80 degrees) after a mean follow-up of 6.6 months. Four of
these eyes (Staged Group) underwent oblique muscle surgery for symptomatic
incyclotorsion, which reduced the mean incyclotorsion from 26.9 +/- 6.9 degrees
(range, 20-35 degrees) to 9. 9 +/- 7.9 degrees (range, 2.5-20 degrees)-a mean
reduction of 16.9 +/- 1.3 degrees (P =.00012), after a mean follow-up of 4.6
months. Six additional eyes (Combined Group) had simultaneous macular
translocation and oblique muscle surgery, with a mean postoperative
cyclotorsional angle of 14.0 +/- 6.7 degrees (range, 4-22.5 degrees), after a
mean follow-up of 3.75 months. CONCLUSION: Oblique muscle surgery is effective at
reducing the large degree of incyclotorsion resulting from macular translocation
surgery and may be used either following or simultaneous with retinal surgery.
PMID- 10773806
TI - Magnetic resonance imaging of the arc of contact of extraocular muscles:
implications regarding the incidence of slipped muscles.
AB - BACKGROUND: Slipped muscles are complications of strabismus surgery that are
encountered more frequently after recessions of the inferior and medial rectus
muscles. METHODS: We obtained multipositional high-resolution magnetic resonance
imaging of 10 orbits of 6 normal subjects, 9 orbits of 5 patients with thyroid
associated eye disease, and 4 orbits of 2 patients with thyroid-associated eye
disease on the day after rectus muscle recessions using a suspension technique.
The arc of contact and the distance between the insertion and the point of
tangency of each of the extraocular muscles to the globe were measured in primary
position as well as in the cardinal fields. RESULTS: The data confirm that the
inferior and medial rectus muscles have a significantly smaller wraparound effect
on the globe than the superior and lateral rectus muscles, respectively (P =.022
for the vertical rectus muscles; P =.05 for the horizontal rectus muscles, paired
t test), and that their insertions may be found several millimeters posterior to
their points of tangency in extreme rotation of the globe in their respective
field of action. The appearance of the suspended recessed inferior rectus muscle
on the first postoperative day and its decreased apposition to the globe raise
concerns about the muscle losing contact with the globe in extreme downgaze.
CONCLUSIONS: The small wraparound effect of the inferior and medial rectus
muscles may explain one of the mechanisms accounting for the increased incidence
of slipped muscles encountered after recessions of these muscles.
PMID- 10773807
TI - Outcomes from surgical treatment for dissociated horizontal deviation.
AB - BACKGROUND AND PURPOSE: Long-term treatment results and recommendations for
dissociated horizontal deviation (DHD) are sparse in the literature. We report
the results of surgery for DHD with a mean of 48 months postsurgical follow-up.
PATIENTS AND METHODS: Records were reviewed for 33 consecutive patients who
underwent surgery to correct DHD between 1991 and 1997. Patient data were
recorded, including age at time of DHD operation, initial diagnosis, history of
prior surgery, number of operations related to DHD, amount of preoperative DHD
for each operation, presence of concomitant esotropia or exotropia (XT), presence
of amblyopia, type of operation performed, time interval between operations, and
final alignment. RESULTS: Twenty-five patients (78%) underwent a single operation
for DHD. Seven patients (22%) underwent 2 operations, and 2 of those 7 patients
(6% of the total) underwent 3 operations to control DHD and/or horizontal
strabismus accompanying the DHD. Most patients (75%) had a prior history of
congenital esotropia, which had been previously corrected with bilateral medial
rectus muscle recession. Patients with an XT and DHD required bilateral surgery
more frequently to control their deviation. CONCLUSION: When DHD is prominent and
manifests frequently, a surgical plan specific to the horizontal drift of the
eyes is needed. Unilateral lateral rectus muscle recession appears to be adequate
to control manifest DHD over time in most patients. Bilateral surgery will be
needed occasionally for bilateral DHD when alternate fixation is present and
frequently when XT and DHD coexist.
PMID- 10773808
TI - Effect of prior orbital decompression on outcome of strabismus surgery in
patients with thyroid ophthalmopathy.
AB - PURPOSE: To compare strabismus surgery outcomes of patients who have had prior
orbital decompression for thyroid ophthalmopathy with those of patients who have
not had decompression. METHODS: The records of all patients operated on by the
author for strabismus related to thyroid ophthalmopathy were retrospectively
reviewed. RESULTS: Fifty patients were included in this study. Seventeen patients
had previously undergone orbital decompression, and 33 patients had not. Seventy
six percent of patients who had had orbital decompression had a good or excellent
outcome compared with 91% of those who had not had orbital decompression.
Patients in the orbital decompression group had an average of 1.4 operations
compared with 1.2 in the no-decompression group. The average numbers of muscles
operated on were 3.1 in the decompression group and 1.9 in the no-decompression
group. Patients who had been decompressed were more than 4 times as likely to
require surgery for both a horizontal and vertical deviation than patients who
had not been decompressed. CONCLUSIONS: Patients with thyroid ophthalmopathy who
have had orbital decompression have a lower success rate of surgery for
strabismus, more frequently need correction for both horizontal and vertical
deviations, and have more muscles operated on than patients who have not had
orbital decompression. The need for orbital decompression in patients with
Graves' disease is reflective of a worse degree of orbitopathy. In addition,
ocular changes from decompression surgery may interfere with a successful result
from strabismus surgery.
PMID- 10773809
TI - Congenital anomalies in patients with Duane retraction syndrome and their
relatives.
AB - PURPOSE: Although the high incidence of skeletal, neural, and other ocular
problems has been identified in previous reports of large cohorts of patients
with Duane syndrome, there has not been any documentation of anomalies in close
relatives. Patients with Duane syndrome have a greater than 50% incidence of
associated abnormalities that include deafness, other ocular anomalies, cranial
nerve palsies, and skeletal abnormalities. This study was undertaken to review
the experience of our strabismus service with patients who have Duane retraction
syndrome (DRS) and to delineate the associated anomalies in them and their first
degree relatives. METHODS: A prospective study of all patients with Duane
syndrome who were seen at the strabismus service at Moorfields Eye Hospital has
been ongoing for the last 4 years. All patients were assessed for the presence of
ophthalmologic features of DRS and then referred to the pediatric service for a
physical and neurologic examination. First-degree relatives were also examined,
and a family pedigree was generated. RESULTS: We have evaluated 68 patients with
DRS, of which 60.2% were female patients. The left eye was involved at a ratio of
4:1 in unilateral cases. The number of bilateral cases was 57.3%. Among the
patients with DRS, 46% had first-degree relatives with associated abnormalities.
CONCLUSIONS: The high incidence of associated anomalies in patients and first
degree relatives may suggest that a common genetic defect is responsible. This
has to be confirmed with molecular genetic studies, which were not performed on
these families because of a lack of available resources. However, our findings
may indicate that the inheritance of Duane syndrome is much higher than the 10%
previously reported, if any congenital abnormality is accepted as DRS associated.
Children with Duane syndrome may benefit from a full medical assessment, in view
of the frequency of other abnormalities, and so may their siblings.
PMID- 10773810
TI - Ophthalmologic findings in children with congenital cytomegalovirus infection.
AB - BACKGROUND: Cytomegalovirus (CMV) infection is the most common congenital viral
infection in the United States, affecting 0.5% to 2% of live births.
Approximately 90% of infected infants are asymptomatic at birth. We undertook
this study to determine the incidence and etiology of visual impairment and other
ophthalmologic abnormalities in children with congenital CMV infection. METHODS:
We prospectively evaluated 42 symptomatic and 83 asymptomatic children with
congenital CMV infection, along with 21 control patients. One or more
comprehensive ophthalmologic examinations were performed on each patient. The
frequency and etiology of visual impairment and other ophthalmologic problems
were tabulated for each patient. RESULTS: Nine of 42 (22%) patients in the
symptomatic group had moderate to severe visual impairment in 16 eyes. Visual
impairment was primarily due to optic atrophy in 6 of 16 (37%) eyes, macular
scars in 2 of 16 (13%) eyes, and cortical visual impairment in 8 of 16 (50%)
eyes. In comparison, none of 83 asymptomatic patients had severe visual
impairment (P <.001). One asymptomatic patient had mild unilateral visual
impairment caused by a macular scar. Strabismus developed in 12 of 42 (29%)
symptomatic patients compared with 1 of 83 (1.2%) asymptomatic patients (P
<.001). CONCLUSIONS: Visual impairment and strabismus are common in patients with
symptomatic congenital CMV infection and rare in patients with asymptomatic
congenital CMV infection. Visual impairment may be caused by cortical, optic
nerve, and/or retinal abnormalities. Infants with symptomatic congenital CMV
infection should undergo careful ophthalmologic screening and follow-up
examinations.
PMID- 10773811
TI - Strabismus surgery complicated by "pulled in two syndrome" in a case of breast
carcinoma metastatic to the medial rectus muscle.
AB - Metastatic carcinoma to the extraocular muscles is extremely rare; it is reported
to occur from breast, lung, and gastric carcinoma as well as skin melanoma. (1-3)
Overall, intraocular metastases occur much more frequently than orbital
metastases.(4) The most common primary tumors causing orbital metastases are
breast and lung carcinomas.(5) Strabismus due to orbital metastases from breast
carcinoma usually results from fibrosis of the muscle, which often causes painful
ophthalmoplegia and enophthalmos. (6,7) We report a case of presumed metastatic
carcinoma to the medial rectus muscle causing restrictive strabismus in which
surgery was complicated by the "pulled in two syndrome," or PITS.
PMID- 10773812
TI - Transient exotropia after posterior spinal fusion in a child: a new case.
AB - Ocular complications after spinal surgery are rare, although ischemic optic
neuropathy, occipital lobe infarcts, and central retinal vein thrombosis have
been reported. Our purpose is to report a case of an acute, comitant,
postoperative exotropia that rapidly and spontaneously resolved. This case is
particularly interesting in that it may indirectly shed some light on mechanisms
of vergence control.
PMID- 10773813
TI - Orbital extension of a frontal sinus osteoma in a thirteen-year-old girl.
AB - Osteomas are uncommon, slow-growing, benign osteogenic neoplasms that arise most
frequently in the craniofacial skeleton. (1,2) Osteoma is the most common benign
tumor of the nose and paranasal sinuses and the most common neoplasm of the
frontal sinus. (3-5) Paranasal sinus osteomas originate in the sinus wall, fill
the lumen with well-defined mature osseous tissue, and occasionally extend into
the orbit where they give rise to orbital signs and symptoms. Osteomas most
commonly become symptomatic in the second to fifth decade in life, but orbital
involvement has rarely been reported in patients aged 18 years and younger. (2,6
10) We report a case of a frontal sinus osteoma with orbital extension in a 13
year-old girl.
PMID- 10773814
TI - A novel mutation in the Norrie disease gene.
AB - Norrie disease is an X-linked recessive disorder characterized by congenital
blindness and in some cases mental retardation and deafness.(1) The variability
of signs among patients often complicates diagnosis. Signs such as an ocular
pseudoglioma, progressive deafness, and mental disturbance are considered classic
features.(2) Only one third of patients with Norrie disease have sensorineural
deafness, and approximately one half of the affected individuals exhibit mental
retardation, often with psychotic features.(3) Histologic analysis has suggested
that retinal dysgenesis occurs early in eye development and involves cells in the
inner wall of the optic cup.(4) The gene associated with Norrie disease was
identified in 1992. (5,6) We report a novel mutation identified in a patient in
whom Norrie disease was diagnosed.
PMID- 10773815
TI - Normal visual development after unilateral complete ptosis at birth.
PMID- 10773816
TI - Reply.
PMID- 10773817
TI - Ultrastructural localization of cytochrome c in apoptosis demonstrates
mitochondrial heterogeneity.
AB - Release of apoptogenic factors into the cytosol including cytochrome c is
triggering the execution phase of apoptosis through activation of cytoplasmic
effector caspases. How loss of function of the electron transport chain can be
reconciled with an adequate energy supply necessary for executing the apoptotic
program was studied in granulosa cell (GC) sheets cultured up to 72 h without
gonadotrophic support. Cytochrome c was localized ultrastructurally by oxidation
of diaminobenzidine tetrahydrochloride both in living and fixed cells. In
uncultured GC sheets all cells show staining over their entire mitochondrial
population. In 72 h cultured sheets in the absence of FSH pre-apoptotic GC's
display two subsets of mitochondria: normal sized stained mitochondria and small
orthodox mitochondria without demonstrable cytochrome function. Apoptotic cells
contain several mitochondria with preservation of respiratory function besides
unstained orthodox mitochondria. The cytochrome c containing mitochondria
typically display dilated intracristal spaces, a mitochondrial conformation
related to increased ATP production. Cytochrome c release was confirmed by
Western blotting. In 72 h cultures supplemented with FSH, GC's displayed staining
over their entire mitochondrial population. In cultures lacking FSH, but
partially protected from apoptosis through caspase inhibition, the cytochrome c
release was not inhibited. Thus in the present studied model dysfunction of only
a subset of mitochondria is instrumental to initiate the apoptotic program while
a functional electron transport chain is maintained until the degradation phase
in a subset of respiring mitochondria.
PMID- 10773818
TI - The BH3 domain is required for caspase-independent cell death induced by Bax and
oligomycin.
AB - Bax causes apoptosis by associating with mitochondria and triggering cytochrome c
release, which activates the caspase cascade. Bax can also kill some cells
independently of caspases, but the requirements for such killing are poorly
understood. Here we describe an inducible fibroblast line that expresses Bax when
tetracycline is withdrawn; the resulting apoptosis can be blocked by the caspase
inhibitor zVAD-fmk. Even when caspases are inhibited, however, treating the Bax
expressing cells with the mitochondrial toxin oligomycin efficiently triggers
death with features resembling apoptosis. Bax mutants lacking the BH3 domain
remain able to cause cytochrome c release and caspase-mediated death, but cannot
support this caspase-independent killing. Mutating specific BH3 residues needed
for binding Bcl2 does not prevent synergy with oligomycin, implying that no such
binding is required. These findings illuminate a caspase-independent pathway of
death that depends on the Bax BH3 domain and on effectors emanating from
mitochondria.
PMID- 10773819
TI - Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines
resistance.
AB - Metastasis is a highly complex process involving the survival of tumor cells,
both in the blood stream and within specific organs. Cell-death and survival are
determined by a number of gene products from an expanding family of the Bcl-2
gene, either promoting or preventing apoptosis. Furthermore, the survival of
tumor cells may favor the accumulation of additional genetic alterations causing
further growth and invasive opportunities which may lead to metastasis. To
examine whether the prevention of cell-death influences the metastatic behavior,
we transfected a human breast cancer cell line MDA-MB-435 with the Bcl-xL cDNA
and then studied metastatic ability of the selected clones in vivo. Our results
show that Bcl-xL-clones had a decreased tumor growth latency and an increased
metastatic ability. Apoptosis-resistance to cytokines was induced in 435 cells by
Bcl-xL-expression with minor modifications in their proliferation rates. These
cells also showed diminished adhesion to extracellular matrix proteins and a
survival advantage in suspension over 435/Neo cells. Moreover, to determine
survival in blood stream and in cells lodged in the lungs, we injected 435/Bcl-xL
and 435/Neo cells at 1:3 proportion i.v., and animals were killed at intervals of
15' to 16 h after injection. Tumor cells were recovered from the lungs and
Southern-blot analysis revealed the presence of exogenous Bcl-xL cDNA. These
results showed that 435/Bcl-xL cells had a survival advantage in circulation over
435/Neo cells. This advantage in vivo was attributable to Bcl-xL expression. We
conclude that Bcl-xL expression in breast cancer cells can increase metastatic
activity. This advantage could be created by inducing resistance to apoptosis
against cytokines, increasing cell survival in circulation, and enhancing
anchorage-independent growth.
PMID- 10773820
TI - Laminin-rich extracellular matrix association with mammary epithelial cells
suppresses Brca1 expression.
AB - Brca1 mRNA was detectable in female mouse mammary gland tissue from adult
virgins, during pregnancy and early lactation. It was associated with phases of
mammary epithelial cell proliferation and differentiation but the pattern of
Brca1 expression was dissociable from that of a true differentiation marker, beta
casein, by virtue of its significant expression in the virgin gland and
termination of its expression in early lactation. In a primary cell culture
model, association of a laminin-rich extracellular matrix (ECM) with mammary
epithelial cells was required for cell survival and cell differentiation and
suppressed Brca1 expression in these cells. ECM-association may significantly
contribute to the final restriction in Brca1 expression in the lactating gland in
vivo. Interestingly, our results suggest that mammary epithelial cells undergo
apoptosis both when expressing and when not expressing Brca1, depending on
whether the dying cell populations had been terminally differentiated or not.
PMID- 10773822
TI - Regions essential for the interaction between Bcl-2 and SMN, the spinal muscular
atrophy disease gene product.
AB - The SMN gene is implicated in spinal muscular atrophy (SMA), and its product has
been shown to interact with Bcl-2 protein to enhance its anti-apoptotic activity.
In this study, we determined the regions that were essential for the interaction
of Bcl-2 and SMN by co-immunoprecipitation of deletion mutants. Bcl-2 lacking its
amino-terminal 20 amino acid residues or its carboxyl-terminal membrane-anchoring
domain showed no or greatly reduced binding with SMN, respectively. However, Bcl
2 lacking other regions could still bind to SMN. Because Bcl-2 lacking the
membrane-anchoring domain could bind to SMN in a yeast two-hybrid system, the
amino-terminal region of Bcl-2 seems to be the most important domain for binding
with SMN. A fragment of SMN encoded by exon 6 could bind to Bcl-2, but SMN
lacking this region could not. From these results, we concluded that Bcl-2 and
SMN proteins bound with each other at the amino-terminal region near the BH4
domain of Bcl-2 and the region encoded by exon 6 of SMN, both regions known to be
important for their function.
PMID- 10773821
TI - Proteasome activation as a critical event of thymocyte apoptosis.
AB - Caspase activation may occur in a direct fashion as a result of CD95 death
receptor crosslinking (exogenous pathway) or may be triggered indirectly, via a
Bcl-2 inhibitable mitochondrial permeabilization event (endogenous pathway).
Thymocyte apoptosis is generally accompanied by proteasome activation. If death
is induced by DNA damage, inactivation of p53, overexpression of a Bcl-2
transgene, inhibition of protein synthesis, and antioxidants (N-acetylcyteine,
catalase) prevent proteasome activation. Glucocorticoid-induced proteasome
activation follows a similar pattern of inhibition except for p53. Caspase
inhibition fails to affect proteasome activation induced by topoisomerase
inhibition or glucocorticoid receptor ligation. In contrast, caspase activation
(but not p53 knockout or Bcl-2 overexpression) does interfere with proteasome
activation induced by CD95. Specific inhibition of proteasomes with lactacystin
or MG123 blocks caspase activation at a pre-mitochondrial level if thymocyte
apoptosis is induced by DNA damage or glucocorticoids. In strict contrast,
proteasome inhibition has no inhibitory effect on the mitochondrial and nuclear
phases of apoptosis induced via CD95. Thus, proteasome activation is a critical
event of thymocyte apoptosis stimulated via the endogenous pathway yet
dispensable for CD95-triggered death.
PMID- 10773823
TI - Bcl-2 and Bax proteins are present in interphase nuclei of mammalian cells.
AB - The Bcl-2 family of proteins comprises both cell death inhibiting and cell death
promoting members, generally believed to be cytoplasmic and predominantly
membrane-associated. Like Bcl-2, many Bcl-2-related proteins contain a C-terminal
membrane insertion domain and much research is aimed at evaluating the functional
role of their localization to the outer membranes of mitochondria, the
endoplasmic reticulum, and perinuclear membranes. However, confocal fluorescence
microscopy of human breast cancer cells and rat colon cancer cells immunostained
with commercial antibodies raised against different epitopes of the anti
apoptotic Bcl-2 and the pro-apoptotic Bax protein revealed that these proteins
are not only present in the cellular cytoplasm, but also within interphase
nuclei. This was confirmed by Western blot analysis of isolated nuclei. In human
cells, certain epitopes of Bcl-2, but not of Bax, were also found to be
associated with mitotic chromatin. Anti-estrogen treatment of human breast cancer
cells or transfection with antisense bcl-2 led to a reduction in both cytoplasmic
and nuclear Bcl-2. Transfection of human bcl-2 and bax into rat cells resulted in
cytoplasmic and nuclear Bcl-2 and Bax. This data seems in line with increasing
evidence that the role of the Bcl-2 family of proteins should be extended to
activities inside the nuclear compartment.
PMID- 10773824
TI - DNA repair is activated in early stages of p53-induced apoptosis.
AB - p53 is a complex molecule involved in apoptosis, cell cycle arrest, and DNA
repair. Since apoptosis may play an important role in deletion of neoplastic
cells, an understanding of the mechanism of p53-induced apoptosis may be critical
for possible future therapeutic interventions. Recent evidence suggests that p53
induced apoptosis may involve members of the nucleotide excision repair (NER)
family, linking these two cellular events. Our work using a temperature-sensitive
p53 construct further analyzes p53-induced apoptosis in cultured murine mammary
epithelial cells and also suggests that DNA repair plays a role in that process.
Although p21 is induced in our system, apoptosis occurs without a detectable
preceding G1 cell cycle arrest and independent of cellular alterations brought on
by the temperature shift. In addition, clonogenic assays suggest that early
stages of p53-induced apoptosis may be reversible upon removal of the apoptosis
stimulus. As a possible explanation for this reversibility, our results show that
general DNA repair activity increases early in p53-induced apoptosis. We also
show that caspase-3 is activated at a timepoint when colony formation begins to
drop, suggesting a possible mechanism for the point of no return in p53-induced
apoptosis.
PMID- 10773825
TI - Bcl-xL does not inhibit the function of Apaf-1.
AB - Bcl-2 and its relative, Bcl-xL, inhibit apoptotic cell death primarily by
controlling the activation of caspase proteases. Previous reports have suggested
at least two distinct mechanisms: Bcl-2 and Bcl-xL may inhibit either the
formation of the cytochrome c/Apaf-1/caspase-9 apoptosome complex (by preventing
cytochrome c release from mitochondria) or the function of this apoptosome
(through a direct interaction of Bcl-2 or Bcl-xL with Apaf-1). To evaluate this
latter possibility, we added recombinant Bcl-xL protein to cell-free apoptotic
systems derived from Jurkat cells and Xenopus eggs. At low concentrations (50
nM), Bcl-xL was able to block the release of cytochrome c from mitochondria.
However, although Bcl-xL did associate with Apaf-1, it was unable to inhibit
caspase activation induced by the addition of cytochrome c, even at much higher
concentrations (1-5 microM). These observations, together with previous results
obtained with Bcl-2, argue that Bcl-xL and Bcl-2 cannot block the apoptosome
mediated activation of caspase-9.
PMID- 10773839
TI - The in vitro percutaneous penetration of chlorpyrifos.
AB - Chlorpyrifos is a widely used organophosphate pesticide. In order to study the
pharmacokinetics of the penetration of chlorpyrifos through human skin we
measured the percutaneous penetration of chlorpyrifos through human skin using an
in vitro flow through apparatus. The chlorpyrifos was applied to the skin as a
commercial concentrate or as a reference standard dissolved in ethanol. There was
a significant difference (P=0.03) between the rate of penetration from the
commercial concentrate (9.0 nmoles cm(-2) h(-1)) and that from the reference
standard (4.9 nmoles cm(-2) h(-1)). Each experiment was run for 24 h. The
recoveries from experiments where chlorpyrifos was applied to the skin as a
commercial concentrate and as a reference standard dissolved in ethanol were,
respectively, in total 91 and 87% of the applied dose of which 15 and 10% was
recovered from the skin, 56 and 66% was recovered from the surface of the skin
and 20 and 11% was recovered from the receptor fluid. There was a significant
difference in the recoveries from the skin but there was no significant
difference in the recoveries from the surface of the skin. We concluded that the
majority of a dermal dose of chlorpyrifos was still present at or in the surface
of the skin 24 h after application of a dermal dose. Because chlorpyrifos was
recovered from the skin after 24 h, it is possible that the skin could act as a
reservoir and release chlorpyrifos over a longer period. We also conclude that
the solvent vehicle for chlorpyrifos can affect the rate of penetration of the
pesticide.
PMID- 10773838
TI - A long-term follow-up of lung function in survivors of paraquat poisoning.
AB - 1. Respiratory failure is a frequent cause of death in moderate to severe
paraquat poisoning, and a transient fall in the gas transfer factor may be seen
in mild poisoning. 2. The objectives of this study were to detect long-term
changes in lung function in survivors of paraquat poisoning. 3. We analyzed 12
survivors retrospectively for age, sex, signs and symptoms, laboratory findings,
chest X-ray findings, serum paraquat level, and lung function test. The first and
the follow-up lung tests were performed at 3.7+/-1.4 weeks and 3.4+/-1.4 years,
respectively. 4. Serum paraquat levels were assayed in all patients and 3/12 were
above the Proudfoot's predictive line. Liver dysfunction (GOT > 50) and renal
dysfunction (BUN > 30) were noted in 5/12 and 8/12, respectively. D(L)/V(A) was
lower than the normal limit in the first study (3.9+/-0.6 L), but increased
significantly and returned to the normal range in the follow-up study (4.5+/-0.6
L). %VC was within the normal range in either examination, but significantly
decreased in the follow-up. %TLC was within the normal range in the first study
(87+/-13%), but significantly decreased below the normal limit in the follow-up
(81+/-13%). 5. These results indicate that survivors of paraquat poisoning may be
left with a restrictive type of pulmonary dysfunction and suggest that a long
term follow-up of lung function may be necessary for survivors of paraquat
poisoning.
PMID- 10773840
TI - An assessment of the in vitro toxicology of Clostridium perfringens type D
epsilon-toxin in human and animal cells.
AB - The epithelial Madin Darby canine kidney (MDCK) cell line and 17 human cell lines
were examined for sensitivity to Clostridium perfringens type D epsilon-toxin.
MDCK cells were confirmed as being sensitive to the toxin. In addition, the
Caucasian renal leiomyoblastoma (G-402) human cell line was identified as being
epsilon-toxin sensitive. Using the MTS/PMS assay system the concentration of
toxin reducing cell culture viability by 50% (LC50) was found to be 2 microg/ml
in MDCK cells. The LC50 for G-402 cells was 280 microg/ml. Epsilon-Toxin was
found to be rapid acting in MDCK cells exposed to a maximum lethal dose of the
toxin (40% loss of viability after a 0.5 h exposure), but slower acting in G-402
cells (40% loss of viability after 1.7 h exposure). Photomicrography of toxin
exposed cultures indicated necrotic cell death on exposure to epsilon-toxin.
Investigations using an antibody probe indicated that epsilon-toxin could bind to
many cell surface proteins in both MDCK, G-402 and a toxin insensitive human cell
line (CAKI-2). It has previously been found that the toxin may bind to the cell
surface via glycosylated moieties. However, exposing MDCK and G-402 cells to
epsilon-toxin in the presence of sialic acid and several different sugars did not
reduce the lethal effects of the toxin.
PMID- 10773841
TI - Steroidogenic alterations in testes and sera of rats exposed to trichloroethylene
(TCE) by inhalation.
AB - 1. Trichloroethylene (TCE) is an organic unsaturated solvent used in dry
cleaning, metal degreasing, thinner for paints/varnishes, anaesthetic agents etc.
Human beings are considerably exposed to TCE vapours by inhalation route. 2. TCE
has been reported to induce spontaneous abortions and congenital cardiac
malformation in occupationally exposed women. However, scanty on-line information
is available regarding toxic effects of TCE on male reproductive efficiency in
experimental animals. 3. Our earlier observations with TCE inhalation in male
rats (376 p.p.m., 4 h/day, 5 days a week) for 12 and 24 weeks using whole body
dynamic inhalation chamber consistently showed significant decrease (P<0.05) in
total epididymal sperm count and sperm motility. The mating experiments of above
TCE inhaled rats with virgin unexposed females showed significantly decreased
fertility. 4. These observations prompted us to investigate whether or not
primary testicular steroidal precursors (cholesterol and ascorbic acid) and
testosterone have any role in TCE induced significantly decreased epididymal
sperm count, sperm motility and overall male reproductive inefficiency resulting
therefrom. 5. The results indicate significant decrease (P<0.05) in total
epididymal sperm count, sperm motility, specific activities of enzymes Glucose 6
p dehydrogenase (G6PDH) and 17 beta hydroxy steroid dehydrogenase (17betaHSD)
with concomitant decrease in serum testosterone concentrations in TCE inhaled
rats showing reduced male reproductive efficiency. There was net accumulation in
total cholesterol contents in testes of TCE exposed rats. 6. The findings in the
present study indicate possible impairment of testosterone biosynthesis in TCE
inhaled rats after 12 and 24 weeks. These findings also serve in parts to
elucidate the mechanism of reproductive inefficiency in TCE exposed rats. The
role of testosterone in this phenomenon is being reported for the first time.
PMID- 10773842
TI - Differences in chlorzoxazone metabolism in full mature male and female Sprague
Dawley rat, Beagle dog and Cynomolgus monkey liver.
PMID- 10773843
TI - Glucocorticoid-dependent maintenance of CYP2C11-dependent oxidation in male rat
liver in vivo.
AB - 1. Hormonal factors participate in the regulation of xenobiotic metabolising
enzymes in liver. Hepatic xenobiotic oxidation capacity is decreased in
adrenalectomised rats, which directly implicates adrenal hormones in the control
of cytochrome P450 (CYP) expression. In addition, recent studies in cultured
hepatocytes have demonstrated that low concentrations of glucocorticoid
upregulate the male-specific CYP2C11, which is a major enzyme that catalyses
xenobiotic and steroid hydroxylations in rat liver. The present study evaluated
whether glucocorticoid or mineralocorticoid may be the adrenal factor that
contributes to the in vivo expression of CYP2C11 in liver. 2. Adrenalectomy of
male rats selectively decreased CYP2C11-dependent 2alpha-/16alpha-hydroxylation
of testosterone and other steroid substrates to 60-70% of control, whereas
activities mediated by other constitutive CYPs were unaffected. The decrease in
CYP2C11 activity was due to impaired protein expression in liver after
adrenalectomy. Administration of dexamethasone (DEX; 0.2 mg/kg i.p. daily for 6
days) restored CYP2C11 activity and protein, whereas the mineralocorticoid
deoxycorticosterone (DOC) and adrenocorticotropic hormone (ACTH) were
ineffective. 3. These findings establish that glucocorticoids have a partial role
in the maintenance of CYP2C11 expression and associated microsomal oxidation in
liver and provide a physiological correlate for similar observations made in
vitro in hepatocyte culture.
PMID- 10773845
TI - Sodium monochloroacetate causes cytotoxic effects, an increased lactate and
pyruvate level and induces ultra structural and cytoskeletal alterations in
cultured kidney and liver epithelial cells.
AB - 1. Monochloroacetic acid (MCAA) and its sodium salt, sodium monochloroacetate
(SMCA) are widely used in chemical industries as intermediates in the synthesis
of carboxymethylcellulose, phenoxyacetic acid, thioglycolic acid, glycine,
indigoid dyes and others. Moreover, MCAA has been found as a by-product of the
chlorination disinfection of drinking water and as an environmental contaminant
of the atmosphere from the photodechlorination reactions of chlorinated
hydrocarbons. Little is known about the mode of action of both compounds on the
cellular level. From cases of accidental poisoning of man it is known that MCAA
accumulates in liver and kidney. 2. In this study, the cytotoxicity of SMCA on
cultured liver (Chang liver cells) and kidney epithelial cells of the proximal
tubule (Opossum kidney cells) was investigated and its effect on metabolism,
ultrastructure and organization of cytoskeleton was examined. 3. Independent from
the growth state of the cells (proliferating or quiescent), the results clearly
show that SMCA causes a dose-dependent decrease in cell viability after an
exposure period of 24 h. In all experiments, proliferating cells were more
sensitive than quiescent and confluent cells. Liver cells were less sensitive
against SMCA treatment than kidney epithelial cells. In contrast to liver cells,
kidney cells exhibited a dose-dependent decrease in cell volume. The decrease in
cell viability was accompanied by an increase of lactate and pyruvate
concentrations released into the culture medium. In the case of Opossum kidney
cells, lactate and pyruvate levels increased 5 - 6-fold, whereas in the case of
Chang liver cells the increase was approximately twofold. While the
ultrastructure of liver cells remained unaltered after drug treatment, kidney
cells exhibited cytoplasmic vacuolization, membraneous disruption and especially
mitochondrial alterations. In accordance with the changes in the ultrastructure
of Opossum cells, was the reorganization of cytoskeletal elements with an
increased stress fiber network at the basolateral surface as well as a partial
depolymerization of microtubules and vimentin filaments. A cytoskeletal
reorganization was not observed for Chang liver cells after SMCA treatment. 4.
The results demonstrate that SMCA causes a dose-dependent cytotoxicity which is
accompanied by metabolic, mitochondrial and cytoskeletal alterations in the
cells.
PMID- 10773844
TI - Antidotal effects of 2,3-dimercaptopropane-1-sulfonic acid (DMPS) and meso-2,3
dimercaptosuccinic acid (DMSA) on the organotoxicity of dibutyltin dichloride
(DBTC) in rats.
AB - 1. Dialkyltin compounds have been widely used in industry and agriculture, mainly
as biocides, catalysts and plast stabilizer. In dependence on the length of the
alkyl chains these organotins exert toxic effects on the immune system, the bile
duct, liver and pancreas. It has been supposed that similar to organoarsenic the
toxicity of the dialkyltin compounds is related to reactions with biological
dithiol groups. Therefore, in the present study, the antidotal effects of 2,3
dimercapto-propane-1-sulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid
(DMSA) on the organotoxic effects of dibutyltin dichloride (DBTC, single
administration of 27 micromol kg(-1) b.w. i.v.) in rats were studied using
different doses (100 and 500 micromol kg(-1) b.w.) and routes of administration
(i.p. and p.o.) of both chelators. Several parameters of organotoxicity (thymus
weight and cellularity, bile duct diameter, histological lesions of pancreas and
liver, activities of amylase, lipase and alkaline phosphatase, bilirubin and
hyaluronic acid in serum) were measured from 6 h to 8 weeks. 2. DMPS and DMSA
diminished the DBTC induced bile duct, pancreas and liver lesions stronger than
the thymus atrophy. Moreover, the development of a fibrosis of the pancreas and a
cirrhosis of liver several weeks after single administration of DBTC to rats was
inhibited by DMPS and DMSA. The antidotal effects on serum parameter were
observed after both administration routes of the chelators. DMPS was more
effective than DMSA in most measured parameters. The decrease in the biliary
excretion of organotin by DMPS and DMSA seems to be the reason for the pronounced
protective effects of DMPS and DMSA on bile duct, pancreas and liver. 3. For the
treatment of poisonings with dibutyltin compounds, the administration of DMPS or
DMSA can be recommended.
PMID- 10773846
TI - Acute delirium induced by intravenous trimethoprim-sulfamethoxazole therapy in a
patient with the acquired immunodeficiency syndrome.
AB - The development of a rash in response to trimethoprim-sulfamethoxazole (TMP-SMX)
administration is a frequent adverse reaction in people with the acquired
immunodeficiency syndrome (AIDS). In contrast, there are no published reports in
the English language literature describing TMP-SMX induced delirium in an AIDS
patient. This report describes the development of frank delirium in a person with
AIDS receiving TMP-SMX. The episode resolved completely within 72 h of withdrawal
of the drug.
PMID- 10773847
TI - Non-fatal ethylene dibromide ingestion.
AB - Ethylene dibromide (1,2-dibromoethane) is widely used to fumigate grain and fruit
in India. However, acute poisoning due to it has rarely been reported in the
literature and most of these patients had an fatal outcome. We describe the
suicide attempt of a young male who ingested an ampoule (3 ml) of it, developed
acute hepatic and renal failure, metabolic acidosis and coagulopathy but survived
following supportive measures.
PMID- 10773848
TI - Systemic upregulation of CD40 and CD40 ligand mRNA expression in multiple
sclerosis.
AB - It is increasingly clear that the CD40 and CD40 ligand (CD40L) receptor-ligand
pair mediates a crucial activation signal in both cell-mediated and humoral
immune responses. Here, we detected mRNA levels of CD40 and CD40L in non
stimulated peripheral blood mononuclear cells in 46 patients with multiple
sclerosis (MS) and 46 healthy controls by a competitive RT - PCR procedure
allowing quantification without previous culture or antigenic stimulation. The
levels of CD40 and CD40L mRNA were markedly increased in MS patients (P<0.0001)
compared with healthy controls. There was no difference between clinical MS
subgroups or stage of disease. Our findings indicate that, although MS is an
organ specific disorder, an increased signaling via the CD40 and CD40L pathway
may be present at the systemic level. The nature of this upregulation, whether
primary or secondary to the organ-specific autoimmune response, is yet to be
determined. Since interference with CD40/CD40L is an effective way to interfere
with autoimmune model diseases such as experimental autoimmune encephalomyelitis,
it may be relevant to investigate further the role of these molecules in the
pathogenesis of MS.
PMID- 10773849
TI - Leukotropic herpesviruses in multiple sclerosis.
AB - Detection frequency of human herpesvirus 6 (HHV-6) and Epstein Barr virus (EBV)
DNA in multiple sclerosis (MS) patients and controls was investigated. DNA of
peripheral blood mononuclear leukocytes (PBL) was isolated and amplified by
polymerase chain reaction techniques. EBV DNA was detected in all patients and
controls. HHV-6 DNA was detected in 7% of MS patients and in 14% of controls.
Results are compared with other investigations of HHV-6 DNA in PBL, serum, CSF
and brain of patients with MS. Results of the present study and other
investigations do not show an association between HHV-6 in PBL and MS. Multiple
Sclerosis (2000) 6, 66 - 68
PMID- 10773850
TI - Cytokine secretion profile of myelin basic protein-specific T cells in multiple
sclerosis.
AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system
with a presumed autoimmune pathogenesis involving autoantigen-specific CD4+ T
cells and cytokines. A similar frequency of T cells responding to myelin basic
protein (MBP), a putative target in MS, has been observed in MS patients and
controls. To dissect the differences between MBP-specific T cells in patients and
controls, we have analyzed the cytokine secretion profile of such autoreactive T
cells. MBP-specific T cell clones (TCC) were isolated from the peripheral blood
of MS patients and controls by limiting dilution. Expression of mRNA for
interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-10, tumor necrosis factor
alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) was assessed by
polymerase chain reaction whereas secretion of cytokine protein was measured by
ELISA. MBP-specific TCC exhibited a heterogeneous cytokine secretion profile with
clones displaying Th1, Th2 and Th0 phenotypes. A significant difference in the
distribution of the cytokine profile was noted between MS patients and controls.
Although the frequency of Th1 secreting MBP-reactive TCC was similar between MS
patients and controls, stable MS patients had a significant association with the
Th0 phenotype whereas healthy individuals were associated with the Th2 phenotype.
In comparison to control TCC, MBP-specific TCC from MS patients secreted
increased amounts of IFN-gamma, IL-4 and IL-10 and decreased quantities of TGF
beta. Thus, these studies suggest that there is a dysregulation in the balance
between pro-inflammatory Th1 and anti-inflammatory Th2 cytokines in MS. It
appears that the presence of Th1 secreting autoreactive T cells in healthy
individuals may be counterbalanced by the presence of cells secreting Th2
cytokines and by the augmented production of the immunosuppressive cytokine TGF
beta, whereas in MS there is a decrease in these anti-inflammatory agents.
PMID- 10773851
TI - TNF-alpha polymorphisms in multiple sclerosis: no association with -238 and -308
promoter alleles, but the microsatellite allele a11 is associated with the
disease in French patients.
AB - Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is believed
to play an important role in multiple sclerosis (MS) pathogenesis. The objective
of this study was to determine whether sequence variation in the TNF-alpha gene
is associated with MS. Bi-allelic polymorphisms in the TNF-alpha promoter region
(TNF-alpha -238 and -308) and microsatellite TNF-alpha were previously reported.
We investigated these polymorphisms in 74 French patients with MS, compared with
75 controls. No significant differences regarding the TNF-alpha -238 and -308
polymorphisms were observed between MS patients and controls. Allele frequency
for the a11 allele is in very significant association (P<0.0001) with MS, due in
part to the association of the a11 allele with the HLA-DRB1*15 allele in
patients.
PMID- 10773852
TI - Diagnostic brain MRI findings in primary progressive multiple sclerosis.
AB - The clinical course of multiple sclerosis can be classified as relapsing from
onset (relapsing-remitting), or progressive from onset (primary progressive -
PPMS). These clinical phenotypes have been based on historical and clinical
observations. It has been reported that PPMS patients tend to have quantitatively
less MRI activity and disease burden. We evaluated the sensitivity and diagnostic
value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were
blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic
criteria. Patients were divided into those with typical, atypical or normal
scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131
typical, four atypical, and eight normal scans. All 12 non-typical scans'
subjects had spinal onset; spinal MRI scans were positive in four of seven cases.
Sex, age of onset, site and number of symptoms involved at onset among those
groups were not significantly different but accumulation of disability had a
tendency to be slower in these few individuals with normal or atypical head
MRI's. Although there may be quantitative differences in lesion activity/burden,
MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that
seen in RRMS. A normal brain MRI is unusual in PPMS patients.
PMID- 10773853
TI - MRI and clinical activity in MS patients after terminating treatment with
interferon beta-1b.
AB - Monthly MRI activity and clinical disability were evaluated in two relapsing
remitting multiple sclerosis (RRMS) patients for 4 years during a cross-over
treatment trial with IFNbeta-1b, and for a mean of 21 months after terminating
treatment with IFNbeta-1b. Post-treatment MRI activity was compared to baseline
activity in these patients. Although contrast enhancing lesions (CEL) and the
bulk white matter lesion load (BWMLL) on T2-weighted images eventually returned
to baseline values, there was a refractory period of 6 - 10 months after
terminating treatment, before baseline MRI activity was restored. Although the
mechanism for a sustained effect of IFNbeta-1b is unclear at this time, these
results have important implications for enrollment of such patients into new
treatment protocols that rely on contrast enhancing lesion frequency as an
outcome measure.
PMID- 10773854
TI - Cost and health related quality of life consequences of multiple sclerosis.
AB - OBJECTIVES: To (i) quantify the cost of multiple sclerosis (MS) to the Canadian
health care system and society; (ii) measure health utility in MS patients, and
(iii) examine the influence of disability on patient utility and health care
costs. MATERIALS AND METHODS: A comprehensive patient survey and chart review of
relapsing MS patients in remission, relapse and recalling a relapse. RESULTS:
Annual remission costs increased with EDSS level ($7596 at EDSS 1, $33 206 at
EDSS 6). At all EDSS levels the largest costs were due to inability to work,
which increased with EDSS. The average relapse cost for all EDSS levels was
$1367. An inverse correlation was found between EDSS level and patient utility
for patients in remission and relapse. The decrease in remission health utility
from EDSS 1 to 6 was 0.24, which is 25% greater than the difference in health
status between an average 25 and 85 year-old. CONCLUSIONS: This study
demonstrates that MS produces substantial health care costs and reductions in
patient quality of life and ability to work, losses that can be avoided or
delayed if disease progression is slowed. These data provide health-care decision
makers with the opportunity to consider the full impact of MS when faced with
budget allocation decisions.
PMID- 10773855
TI - Linomide in the treatment of multiple sclerosis: MRI results from prematurely
terminated phase-III trials.
AB - Due to an unexpected increase in serious cardiovascular events in MS patients
treated with Linomide, a synthetic immunomodulator, two phase-III multinational
relapsing remitting (RR) and secondary progressive (SP) MS trials had to be
discontinued. MRI results of 413 patients who participated for at least 3 months
were analysed. Patients received placebo, 2.5 or 5 mg Linomide. Scans were
performed at pre-enrolment, month 3 and termination. The number and volume of
enhancing lesions (ELV), and the number of active scans were evaluated. At month
3, the decrease in the number of enhancing lesions in the placebo group was 11%,
compared with 15% in the 2.5 mg group (P=0.027) and 23% in the 5 mg group
(P=0.057). Using the percentage of active scans as outcome parameter, the odds
ratio for improvement between placebo and 2.5 mg group was 1.62 (P=0.14); between
placebo and 5 mg Linomide group 3.58 (P=0.003). At termination, a rebound effect
was noted in the 2.5 mg group (P=0.01). Analysis of the ELV showed no significant
difference between placebo and treatment groups. Although Linomide has
unacceptable side effects, it seems to have a modest effect on MS disease
activity, as measured by MRI. Multiple Sclerosis (2000) 6, 99 - 104
PMID- 10773856
TI - Baclofen increases the soleus stretch reflex threshold in the early swing phase
during walking in spastic multiple sclerosis patients.
AB - The effect of baclofen on walking performance was examined in nine spastic
multiple sclerosis patients. In addition, nine healthy subjects were tested as
controls. The modulation of the short latency soleus stretch reflex was closer to
normal with baclofen compared to the recordings without baclofen, the modulation
index being 74% (range: 60 - 100) with baclofen and 62% (range: 20 - 100) without
baclofen, P=0.03. In healthy subjects the modulation index was 100% (range: 52 -
100). In the early swing phase the threshold of the soleus stretch reflex was
significantly higher during baclofen medication being 139 deg/s (range: 63 - 302)
compared with 93 deg/s (range: 37 - 187) without baclofen, P=0.004. The relation
between the stretch velocity (input) and the amplitude of the stretch reflex
(output) in early swing phase was unchanged being 0. 27 microVs/deg (range: 0.1 -
1.51) in patients with baclofen and 0. 24 microVs/deg (range: 0.08 - 0.79)
without baclofen, P=0.25. Baclofen induced no change in input - output properties
of the stretch reflex during walking compared with findings in a sitting position
at matched EMG activity. There was a significant correlation between clinical
spasticity score and stretch reflex threshold in the early swing phase (rho=
0.61, P=0.04) and between clinical spasticity score and the slope of the best
linear fit in the early swing phase (rho=0.72, P=0.009).
PMID- 10773857
TI - Biopsychosocial correlates of lifetime major depression in a multiple sclerosis
population.
AB - The objective of this paper was to evaluate the lifetime and point prevalence of
major depression in a population-based Multiple Sclerosis (MS) clinic sample, and
to describe associations between selected biopsychosocial variables and the
prevalence of lifetime major depression in this sample. Subjects who had
participated in an earlier study were re-contacted for additional data
collection. Eighty-three per cent (n=136) of those eligible consented to
participate. Each subject completed the Composite International Diagnostic
Interview (CIDI) and an interviewer-administered questionnaire evaluating a
series of biopsychosocial variables. The lifetime prevalence of major depression
in this sample was 22.8%, somewhat lower than previous estimates in MS clinic
populations. Women, those under 35, and those with a family history of major
depression had a higher prevalence. Also, subjects reporting high levels of
stress and heavy ingestion of caffeine (>400 mg) had a higher prevalence of major
depression. As this was a cross-sectional analysis, the direction of causal
effect for the observed associations could not be determined. By identifying
variables that are associated with lifetime major depression, these data generate
hypotheses for future prospective studies. Such studies will be needed to further
understand the etiology of depressive disorders in MS.
PMID- 10773858
TI - Multiple sclerosis and tonsillectomy: no evidence for an influence on the
development of disease or clinical phenotype.
AB - The notion that cervical lymphatic surgery may influence the development of
multiple sclerosis has been suggested before. Recent work in experimental
allergic encephalomyelitis lends further support to this idea. We, therefore
conducted a case:control study of tonsillectomy in multiple sclerosis. We found
no evidence to suggest that tonsillectomy affects susceptibility to multiple
sclerosis. This result supports previous studies, which have largely failed to
show any link between prior tonsillectomy and the subsequent development of
multiple sclerosis. In addition, we failed to show any effect of tonsillectomy on
the extent of cerebral demyelination as assessed clinically or with magnetic
resonance imaging.
PMID- 10773859
TI - Modalities of fatigue in multiple sclerosis: correlation with clinical and
biological factors.
AB - Although different factors are probably involved in the etiology of fatigue in
multiple sclerosis patients, no definite mechanism has been proposed. We have
proposed that fatigue is a complex symptom that includes three clinical different
entities (asthenia, fatigability and worsening of symptoms with effort). The goal
of this study is to demonstrate if there is a peculiar mechanism for each of the
different varieties of fatigue. A control sample of 155 patients (105 women, 50
men) with clinically definite MS was studied. Fatigue was measured using the
Fatigue Descriptive Scale (FDS) and the Fatigue Severity Scale (FSS). Treatment,
depression, anxiety, sleep and cellular immune status were studied too. Fatigue
was a symptom in 118 patients (76.13%); 26 patients (22.03%) described it as
asthenia (fatigue at rest); 85 patients (72.03%) as fatigability (fatigue with
exercise), and seven patients (5.9%) as worsening of symptoms. The severity of
pyramidal involvement was significantly more severe in patients suffering from
fatigue; some immunological parameters were associated with fatigue as well. The
discriminant analysis of the data shows that some of the immunoactivation
parameters are associated with asthenia (F=21.5, P<0.001), and pyramidal tract
involvement is associated with fatigability (F=10.5, P<0.001). Sleep disorders,
anxiety and depression were linked with fatigue in a few patients. No
relationship with treatment was proven. In conclusion, fatigue in MS seems to be
a heterogeneous entity. Asthenia and fatigability may be different clinical
entities. Certain immunoactivation parameters correlate with the presence of
asthenia while pyramidal involvement is associated with fatigability.
PMID- 10773860
TI - Fatigue in multiple sclerosis: relationship to depression, disability, and
disease pattern.
AB - In order to investigate the associations between fatigue and depression,
disability, and disease subtype, 207 individuals with clinically definite
Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung
Self-rating Depression Scale during a regular clinic appointment. Their current
level of disability was established using the Expanded Disability Status Scale.
Fatigue and depression were highly correlated (r=0.58), even when the depression
measure was corrected for items overlapping with fatigue and other symptoms or
consequences of MS (r=0.44). Fatigue and disability were also correlated
(r=0.33). Multiple regression revealed that both depressed mood and disability
were significant predictors of fatigue, together accounting for approximately 23%
of the variance in patients' self-reported fatigue. The combined groups of
primary progressive (n=45) and secondary progressive patients (n=25) appeared to
have higher fatigue scores than relapsing-remitting patients (n=137). However, an
analysis of covariance revealed that this apparent difference was in fact
attributable almost exclusively to differences in disability among the three
subtypes of MS. Other reports of differences in fatigue between subtypes of MS
should be re-examined in light of this finding.
PMID- 10773875
TI - Restoration of retinoblastoma mediated signaling to Cdk2 results in cell cycle
arrest.
AB - Phosphorylation/inactivation of RB is typically required for cell cycle
progression. However, we have identified a tumor cell line, C33A, which
progresses through the cell cycle in the presence of an active allele of RB (PSM
RB). To determine how C33A cells evade RB-mediated arrest, we compared RB
signaling to downstream effectors in this resistant cell line to that of the RB
sensitive SAOS-2 cell line. Although introduction of PSM-RB repressed E2F
mediated transcription in both C33A and SAOS-2 cells, PSM-RB failed to repress
Cyclin A promoter activity in C33A. Ectopic expression of PSM-RB in SAOS-2 cells
resulted in a decrease in both Cyclin A and Cdk2 protein levels without affecting
Cyclin E or Cdk4. In contrast, over-expression of PSM-RB in C33A cells did not
alter endogenous Cyclin A, Cyclin E, or Cdk2 protein levels or impact Cdk2 kinase
activity, indicating that signaling from RB to down-stream targets is abrogated
in this cell line. The importance of Cdk2 activity was demonstrated by p27Kip1,
which attenuated Cdk2 activity and inhibited cell cycle progression in C33A
cells. Since RB signaling to Cdk2 is disrupted in these tumor cells, we co
expressed two proteins that cooperate with RB in transcriptional repression, AHR
and BRG-1, in an attempt to correct this signaling dysfunction. Co-expression of
AHR/BRG-1 with PSM-RB attenuated Cyclin A and Cdk2 expression as well as Cdk2
associated kinase activity, resulting in cell cycle inhibition of C33A cells.
Importantly, ectopic expression of Cyclin A was able to reverse the arrest
mediated by co-expression of AHR/BRG-1 with PSM-RB. These results indicate that
down-regulation of Cdk2 activity is requisite for RB-mediated cell cycle arrest.
Thus, this study reveals a new mechanism through which tumor cells evade anti
proliferative signals, and provides insight into how RB-signaling is mediated.
PMID- 10773876
TI - Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and
cancer in mice.
AB - The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is
a central mediator of TGF-beta signaling. It was previously shown that mice
homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation
displaying impaired extraembryonic membrane formation and endoderm
differentiation. Here we show that Smad4+/- mice began to develop polyposis in
the fundus and antrum when they were over 6 - 12 months old, and in the duodenum
and cecum in older animals at a lower frequency. With increasing age, polyps in
the antrum show sequential changes from hyperplasia, to dysplasia, in-situ
carcinoma, and finally invasion. These alterations are initiated by a dramatic
expansion of the gastric epithelium where Smad4 is expressed. However, loss of
the remaining Smad4 wild-type allele was detected only in later stages of tumor
progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor
initiation. Our data also showed that overexpression of TGF-beta1 and Cyclin D1
was associated with increased proliferation of gastric polyps and tumors. These
studies demonstrate that Smad4 functions as a tumor suppressor in the
gastrointestinal tract and also provide a valuable model for screening factors
that promote or prevent gastric tumorigenesis.
PMID- 10773877
TI - p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone
(GHRH)-induced somatotrope proliferation and adenoma formation.
AB - p27Kip1 (p27) controls cell cycle progression by binding to and inhibiting the
activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p27-/-)
results in increased body growth with a disproportionate enlargement of the
spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is
due to selective hyperplasia of the intermediate lobe (IL) while the anterior
lobe (AL) is not overtly affected. p27 heterozygous mice (p27+/-), as well as p27
/- mice, are hypersensitive to radiation- and chemical-induced tumors compared to
wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors,
only a reduction in p27 levels is necessary to predispose tissues to secondary
tumor promoters. Consistent with these studies is the fact that the p27 gene
sequence and mRNA levels appear normal in human pituitary adenomas while p27
protein levels are decreased. Therefore, a reduction in p27 levels could be
sufficient to sensitize pituitary cells to tumorigenic factors. To test this
hypothesis, metallothionein promoter-driven, human growth hormone-releasing
hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9
months of age and subsequent adenoma formation with 30 - 40% penetrance, were
crossbred with p27+/- mice for two successive generations to produce p27+/+,
p27+/- and p27-/- mice that expressed the hGHRH transgene. At 10 - 12 weeks of
age, p27-/- and p27+/+, hGHRH mice were larger than their p27+/+ littermates and
displayed characteristic hyperplasia of the IL and AL, respectively. Expression
of the hGHRH transgene in both p27+/- and p27-/- mice selectively expanded the
population of somatotropes within the AL, where pituitaries of p27+/-, hGHRH and
p27-/-, hGHRH mice were two- and fivefold larger than p27+/+, hGHRH pituitaries,
respectively. There was also a synergistic effect of hGHRH transgene expression
and p27-deficiency on liver, spleen and ovarian growth. At 6 - 8 months of age,
83% of p27+/-, hGHRH mice displayed macroscopic AL adenomas (>100 mg), while all
pituitaries from p27+/+, hGHRH mice remained hyperplastic (<20 mg). In contrast
to the dramatic effects of p27-deficiency on hGHRH-induced organ growth,
elimination of p53, by crossbreeding MT-hGHRH mice to p53-deficient mice, did not
augment the hyperplastic/tumorigenic effects of hGHRH transgene expression. Taken
together these results demonstrate that a reduction in p27 expression is
sufficient to sensitize somatotropes to the proliferative actions of excess GHRH,
resulting in the earlier appearance and increased penetrance of hGHRH-induced
pituitary tumors.
PMID- 10773878
TI - Analysis of p73 in human borderline and invasive ovarian tumor.
AB - p73 is a novel gene that has high sequence homology and similar gene structure to
the tumor suppressor gene p53. We analysed p73 in seven ovarian carcinoma cell
lines and a total of 63 human borderline and invasive ovarian tumor samples. Loss
of heterozygosity at this locus was observed in 50% of invasive tumors but in
none of the borderline tumors. Biallelic expression of the gene was observed in
the heterozygous tumor tissues. Direct sequencing and single-strand conformation
polymorphism analyses of the p73 cDNA sequence homologous to the highly mutatable
region of p53 did not reveal any mutations. When compared to the primary cultures
of normal human ovarian surface epithelial cells and immortalized cell lines,
four of the seven ovarian carcinoma cell lines, 71% of the invasive tumors, and
92% of the borderline tumor tissues express elevated levels of p73 transcript.
Except for the OVCA3 cell line, Western blot analysis of the nuclear extracts
prepared from the cell lines showed concordant levels of p73 protein. Our
analysis also demonstrated the expression of a spliced variant of p73 transcript
with the omission of exon 2 solely in the cancer cell lines and invasive tumor
tissues. This exon 2-spliced transcript would give rise to a truncated p73
protein without the N-terminal transactivation domain. In reminiscence of the
dominant negative phenotype of the N-terminal truncated variants of another p53
related gene, p63, the expression of the truncated p73 variant form in ovarian
tumors may play an important role in the pathogenesis of ovarian cancer.
PMID- 10773879
TI - Reversible activation of c-Myc in thymocytes enhances positive selection and
induces proliferation and apoptosis in vitro.
AB - In order to study the effect of c-Myc activation in T lymphocytes in vivo, we
generated transgenic mice that express a 4-hydroxytamoxifen (4-OHT)-dependent
switchable c-myc oncoprotein under the control of the proximal lck promoter.
Activation of c-MycER causes no obvious alteration in T cell ontogeny. However,
using MHC class I restricted H-Y-TCR transgenic mice, we found that c-Myc
activation in vivo enhances the efficiency of positive selection. Moreover,
splenic T cells derived from lck-c-mycER transgenic mice in which c-Myc had been
activated exhibited increased proliferation in vitro in response to activation
with anti-CD3/CD28 antibody. Activation of c-MycER also promotes apoptosis in
thymocytes in vitro.
PMID- 10773880
TI - Defective cleavage of membrane bound TGFalpha leads to enhanced activation of the
EGF receptor in malignant cells.
AB - Transforming growth factor alpha (TGFalpha) is widely expressed in malignant as
well as normal cells and is involved in regulating cell growth and
differentiation. Although processing of TGFalpha has been extensively studied in
normal cells, there is little information regarding TGFalpha cleavage in
malignant cells. Therefore, we compared the processing of TGFalpha in two human
colon carcinoma cell lines. We found that there was a defective cleavage pattern
for the TGFalpha precursor resulting in retention of partially processed TGFalpha
on the cell surface of both the HCT116a2alphaS3 and CBS4alphaS2 cell lines. This
raised the possibility that signaling from the resulting defective cleavage
species could differ from that of soluble TGFalpha. The membrane-associated
TGFalpha induced higher phosphorylation of EGFR on the cell surface of adjacent
cells than equivalent levels of mature TGFalpha. The interaction of membrane
bound TGFalpha precursor with the EGFR caused a slower internalization of
activated EGFR relative to the internalization of the soluble TGFalpha/EGFR
complexes. In addition, the tethered TGFalpha was resistant to the ability of
protein-tyrosine phosphatases (PTPs) to reduce EGFR tyrosine phosphorylation,
also contributing to higher activation of EGFR. The enhanced activation of EGFR
by the tethered form of TGFalpha was reflected by higher activation of Grb2, SHC
and Erk downstream mediators of EGF receptor signaling. The higher activation of
EGFR by membrane tethered TGFalpha indicates that defective TGFalpha processing
provides a mechanism whereby malignant cells can obtain a growth advantage over
normal cells.
PMID- 10773881
TI - Cell growth and matrix invasion of EBV-immortalized human B lymphocytes is
regulated by expression of alpha(v) integrins.
AB - alpha(v) integrins have been shown to play an important role in epithelial
derived cell migration, cell growth and tumor invasion/metastasis, however their
role on cells of hematopoietic origin is less clear. Epstein-Barr virus (EBV), a
human herpesvirus associated with several lymphoproliferative disorders in man,
induces expression of alpha(v) integrins on transformed B lymphocytes. In the
studies reported here, we show that EBV infection increases alpha(v), beta3 and
beta5 integrin subunit mRNAs as well as upregulates the expression of the
alphavbeta3 integrin protein on human B cells. Among the nine different EBV
proteins expressed in latently infected B cells (nuclear and plasma membrane
associated), only LMP1, LMP2A and EBNA2 were shown to selectively transactivate
the alpha(v) integrin promoter. Treatment of EBV-transformed B cells with
alpha(v) antisense oligonucleotides specifically reduced cell surface expression
of alpha(v) integrins, inhibited cell growth in low serum, reduced cell invasion
in matrigels and decreased expression of metalloprotease, MMP9. These studies
indicate that alpha(v) integrins play a significant role in EBV-induced B
lymphocyte proliferation and invasion. Strategies to interfere with alphav
integrin expression and/or function may therefore be of potential value in the
treatment of EBV-associated lymphoproliferative disorders.
PMID- 10773882
TI - Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP
prostate cancer cells.
AB - Androgens via their cognate receptor may be involved in the development and
progression of prostate cancer. The aim of this study was to determine whether
tea polyphenols have inhibitory effects on androgen action in an androgen
responsive, prostate cancer cell line, LNCaP. The tea polyphenol, EGCG, inhibited
LNCaP cell growth and the expression of androgen regulated PSA and hK2 genes.
Moreover, EGCG had a significant inhibitory effect on the androgenic inducibility
of the PSA promoter. Immunoblotting detected a decrease in androgen receptor
protein with treatments of the tea polyphenols EGCG, GCG and theaflavins.
Northern blot analysis showed decreased levels of androgen receptor mRNA by EGCG.
Transient transfections demonstrated that EGCG and theaflavins could repress the
transcriptional activities of the androgen receptor promoter region. An Sp1
binding site in the androgen receptor gene promoter is an important regulatory
component for its expression. This study suggests Sp1 is the target for the tea
polyphenols because treatments of EGCG decreased the expression, DNA binding
activity and transactivation activity of Sp1 protein. In conclusion, we have
described a new property of tea polyphenols that inhibits androgen action by
repressing the transcription of the androgen receptor gene.
PMID- 10773883
TI - GA-binding protein alpha/beta is a critical regulator of the BRCA1 promoter.
AB - Decreased expression of BRCA1 may play a role in the etiology of sporadic breast
cancer. Deletion and point mutant analysis of proximal promoter elements in the
BRCA1 1a promoter revealed a 22 bp region which was critical for the expression
of the promoter in MCF-7 cells, but had a much reduced effect in T47D cells. The
main transcription factor interacting with this site was identified as
GABPalpha/beta, and a discrete DNA binding complex was only observed in nuclear
extracts from MCF-7 cells. Cotransfection experiments with GABPalpha and beta1
expression vectors produced transactivation of this element in both lines. These
results suggest that GABPalpha/beta is a critical activator of BRCA1 expression,
and that its activity may differ in human breast cell lines.
PMID- 10773884
TI - Dual function of the epithelial specific ets transcription factor, ELF3, in
modulating differentiation.
AB - The ets family of transcription factors comprises many members which contribute
to diverse cellular functions that vary depending upon the cell- and tissue-type
context. Recently, different groups have identified a novel member of the ets
family that is epithelial-specific. Variably called ESE-1, ERT, jen, ESX, this
gene is designated currently as ELF3. In order to understand transcriptional
regulatory mechanisms mediated by ELF3, we investigated its effect on the human
keratin 4 gene promoter based upon the role of keratin 4 in early differentiation
of the esophageal squamous epithelium. Interestingly, ELF3 suppressed basal
keratin 4 promoter activity in both esophageal and cervical epithelial cancer
cell lines, a novel result, while simultaneously activating the late
differentiation linked SPRR2A promoter. Furthermore, serial deletion constructs
of the keratin 4 promoter continued to be suppressed by ELF3, a phenomenon that
was only partially rescued by ELF3 ets domain mutants, but completely abrogated
by deletion of the ELF3 pointed domain. These results suggest that ELF3 may have
dual functions in the transcriptional regulation of genes involved in squamous
epithelial differentiation. One of these functions may not be exclusively
mediated through DNA binding in the context of transcriptional suppression of the
keratin 4 promoter.
PMID- 10773885
TI - Regulation and function of the interaction between the APC tumour suppressor
protein and EB1.
AB - The interaction between the adenomatous polyposis coli (APC) tumour suppressor
and the microtubule-associated protein EB1 was examined. Immunoprecipitation
suggested that APC and EB1 were not associated in cultures of HCT116 cells
arrested in mitosis. The C-terminal 170 amino acids of APC, purified as a
bacterial fusion protein, precipitated EB1 from cell extracts, significantly
refining the location of the EB1 interaction domain in APC. In vitro
phosphorylation of this fusion protein by either protein kinase A or p34cdc2
reduced its ability to bind to EB1. Expression of GFP fusions to C-terminal APC
sequences lacking or including the APC basic domain but encompassing the EB1
binding region in SW480 cells revealed a microtubule tip association which co
localized with that of EB1. Expression of the basic domain alone revealed a non
specific microtubule localization. In vitro interaction studies confirmed that
the APC basic domain did not contribute to EB1 binding. These findings strongly
suggest that the interaction between APC and EB1 targets APC to microtubule tips,
and that the interaction between the two proteins is down-regulated during
mitosis by the previously described mitotic phosphorylation of APC.
PMID- 10773886
TI - p53 is involved in tumor necrosis factor-alpha-induced apoptosis in the human
prostatic carcinoma cell line LNCaP.
AB - The human prostatic carcinoma cell line LNCaP is sensitive to TNF-alpha treatment
and expresses wild-type p53. To analyse the possible role of p53 in TNF-alpha
mediated apoptosis, we generated a derivative of LNCaP, LN-56, expressing a
dominant-negative element of p53, GSE56. P53 inactivation in LN-56 was associated
with an increased resistance to apoptosis induced by TNF-alpha. Surface
expression of TNF-alpha receptors was unchanged in LN-56 compared to LNCaP. TNF
alpha treatment resulted in accumulation of p53 in LNCaP and upregulation of
p21/WAF1. Activation of caspase-7 and PARP proteolysis were delayed in LN-56
under TNF-alpha treatment. TNF-alpha-induced apoptosis in LNCaP cells was
accompanied by caspase-dependent proteolysis of p21/WAF1 and Rb, which was
significantly attenuated in LN-56. Cytochrome c release was induced by TNF-alpha
treatment in both cell lines, but caspase-9 was not activated. LNCaP and LN-56
were injected s.c. in nude mice and tumors were identified in all LN-56, but not
LNCaP, bearing mice indicating that p53 plays an important role in growth control
of prostatic neoplasms. Interestingly, accumulation of p53 in TNF-alpha-treated
LNCaP cells was decreased in the presence of the caspase inhibitor Z-VAD-FMK,
suggesting a new role of activated caspases in acceleration of p53 response. In
summary, these results indicate that p53 is involved in TNF-alpha-mediated
apoptosis in LNCaP.
PMID- 10773887
TI - The Ets1 proto-oncogene is upregulated by retinoic acid: characterization of a
functional retinoic acid response element in the Ets1 promoter.
AB - The v-ets oncoprotein and its progenitor Ets1 belong to a family of transcription
factors that are related by an 85 amino acid conserved DNA binding domain, the
ets domain. Ets1 plays important role(s) in control of cell proliferation,
differentiation and apoptosis. Abnormal expression of Ets1 could lead to
disruption of these processes and contribute to development of malignancy.
Retinoic acid (RA) inhibits proliferation, induces differentiation and regulates
apoptosis in many different cell types. Here, we demonstrate that RA treatment
increases the expression of Ets1 mRNA, but not that of Ets2, Elk1 or Fli1 in
MC3T3-E1 cells. Ets1 induction is detectable after 4 h, can be maintained for at
least 14 days, and is inhibited by Actinomycin D, which suggests that RA
regulation of Ets1 occurs at the transcriptional level. The promoter region of
Ets1 contains four retinoic acid response element (RARE) half sites located at
94, -152, -1765 and -2252 from the translation start site. We show that RARbeta
is expressed by MC3T3-E1 cells in the presence of RA and demonstrate that it
binds to the -94 RARE half site. Furthermore, RA induces transcription of Ets1
promoter-reporter constructs containing this RARE half site.
PMID- 10773888
TI - Maintenance operations: workstation adjustment, working posture, and workers'
perceptions.
AB - In the study maintenance workers were involved in pneumatic wrenching, oxy-gas
cutting, and grinding at 5 different heights. Working posture and workers'
perceptions were measured. Guidelines on working height were formulated in order
to minimize the load on the musculoskeletal system. Data from the present
experiment as well as from literature were studied in depth in order to disclose
generic mechanisms behind the adoption of working postures during visual-manual
operations in relation to workstation adjustment. It was found, for instance,
that the working posture was constrained by a strictly followed relationship
between gaze inclination and head inclination for-/backwards. Also, the study
provided insight into the role of visual interference, viewing distance,
manipulation distance, hand grip of the tool, and body support for stability.
Concerning evaluation criteria for working postures, it was concluded that neck
flexion/extension (i.e., head inclination for-/backwards versus trunk inclination
for-/backwards) seems to be the dominant determinant of neck load, as compared to
head inclination for-/backwards. Furthermore, the position of the upper arm with
respect to the trunk, that is, shoulder flexion/retroflexion in particular,
seemed to be a dominant determinant of shoulder and shoulder girdle load, as
compared to upper arm elevation.
PMID- 10773889
TI - Isometric pull and push strengths of paraplegics in the workspace: 1. Strength
measurement profiles.
AB - The isometric strength profiles of male and female paraplegics were determined
for pull and push strengths in the normal, maximum, and extreme working reach
envelopes. A computerized isometric strength measurement system was designed and
constructed for the purpose. The strongest pull location was at extreme reach
vertically above the shoulder and the strength values for males and females were
473 and 318 newtons (N), respectively. The strongest push location was at maximum
reach, at vertical (phi) angle of 45 degrees and at horizontal (theta) angle of
45 degrees for males and at 0 degrees for women and the strength values were 235
and 172 N, respectively. The nature of the strength profiles was found to be
similar for both the sexes. The pull and push strengths of the female were 77 and
68% that of the male, respectively.
PMID- 10773890
TI - Isometric pull and push strengths of paraplegics in the workspace: 2. Statistical
analysis of spatial factors.
AB - The effect of reach levels, horizontal angles, and vertical angles on isometric
pull and push strengths of male and female was determined. Highly significant
increases in men's push strength were found between extreme to maximum reaches,
and from extreme to normal reaches. However, for women's push strength, a
significant increase was found only between extreme to maximum reach. Significant
or highly significant increases were found in men's and women's pull strength
between the horizontal angle (theta) sagittal through the active shoulder (90
degrees ) and other angles (0, 45, and 135 degrees ). However, for men's push
strength, highly significant increases were found between the horizontal angle 45
degrees from the frontal plane, and other angles. For women's push strength,
significant or highly significant increases were found between the horizontal
angles 0 degrees and angles of 90 and 135 degrees. For men's and women's pull
strength, significant or highly significant increases were found between the
vertical angle (phi), 90 degrees, and other angles (-20, 0, and 45 degrees ).
Similar increases were found for women's push strength between the 45 degrees
angle and other angles. In the design of a workstation for paraplegics that
requires pull and push forces, consideration must be given to the spatial
factors.
PMID- 10773891
TI - Method of testing the penetration of acid solutions through safety gloves.
AB - Because they cause burns that are difficult to heal, acids are dangerous, and
steps should be taken to ensure that the human skin does not come into contact
with them. For this purpose safety gloves are generally used by workers who have
to handle acids. Such gloves need to be tested to ensure that they are acid
resistant. Standard EN 374 (European Committee for Standardization [CEN], 1993c)
specifies a method of testing the permeation of liquid chemicals, on a molecular
level, through glove material, but it may be difficult to ensure the fitness of
the joints of a two-compartment cell, when gloves are lined with jersey. To deal
with this a simple pH-meter method to test the permeation of acid and alkali
solutions through safety gloves has been developed. The permeation of
H&inf2;SO&inf4;, HCl, HNO&inf3;, and CH&inf3;COOH through gloves made from
neoprene, nitrile, and PVC was tested. This method seems to be simple and
economical.
PMID- 10773892
TI - The indigenous fisherman divers of Thailand: diving practices.
AB - Diving practices of a group of indigenous people living on Thailand's west coast
were investigated. Village chiefs were first interviewed using a questionnaire.
Three hundred and forty-two active divers were then interviewed by health care
workers using a second questionnaire. Field observation was used to further
develop information and confirm diving practices. Divers in 6 villages, whose
basic means of making a living is from diving for marine products such as fish
and shellfish, have diving patterns that put them at substantial risk of
decompression illness. Breathing air from a primitive compressor through
approximately 100 m of air hose, these divers have long bottom times coupled with
short surface intervals. Forty-six point two percent of the divers indicated that
they would not make a stop during ascent from a long deep dive (40 m for 30 min).
When comparing their previous day of diving to the U.S. Navy Standard Air
Decompression Table (U.S. Navy, 1993), 72.1% exceeded the no-decompression limits
set by the tables. Diving patterns point to a need for more in-depth research
into the diving patterns of this indigenous group. Future research should include
the use of dive logging devices to record depths and times. There is also a need
to provide divers with information and training to reinforce positive practices
and strengthen knowledge of the risks associated with their current diving
practices.
PMID- 10773894
TI - Working conditions in small private enterprises in Poland.
AB - The study deals with working conditions in small private enterprises in Poland.
Data come from 50 small enterprises from the Warsaw area. Information about the
evaluation of working conditions and the existence of programmes for their
improvement was gathered with the help of questionnaires addressed to employees
and employers. The results constitute a "photograph" of the Polish reality at the
beginning of its transition from planned to market economy. The study revealed a
lack of programmes for the improvement of working conditions in a significant
number of the enterprises studied as well as little interest in occupational
safety on the part of employers (owners). The study also revealed that all
decisions--including those about the improvement of working conditions--were made
by employers. Hence, the need for the widest possible dissemination of knowledge
on occupational safety and the protection of human in the working environment
with particular stress put on employers. Employers who are knowledgeable in this
field and who are aware of its importance can significantly influence the
improvement of working conditions in small enterprises.
PMID- 10773893
TI - Low back muscle activity in an automobile seat with a lumbar massage system.
AB - This investigation was conducted to determine the effects of a massaging lumbar
support system on low back muscle activity. The apparatus included a luxury-level
automobile seat, six 10-mm diameter bipolar surface electrodes, an amplifier, an
analog-to-digital conversion board, data acquisition software, and a personal
computer. Six experimental conditions, each involving a variation of massage
time, were considered. The dependent variable was the change in the root mean
square variation of the EMG signal. One minute of lumbar massage every 5 min was
found to have a beneficial effect on low back muscle activity (as compared to no
massage). This may prove to be an extremely important result in the quest to
combat low back pain attributable to automobile seating.
PMID- 10773895
TI - Eating disorders.
AB - Anorexia nervosa and bulimia nervosa are primarily psychiatric disorders
characterized by severe disturbances of eating behaviour. Anorexia nervosa has
been well documented in pre-pubertal children. Eating disorders are most
prevalent in the Western cultures where food is in abundance and for females
attractiveness is equated with thinness. Eating disorders are rare in countries
like India. As Western sociocultural ideals become more widespread one may expect
to see an increase in number of cases of eating disorders in non-Western
societies. Etiological theories suggest a complex interaction among
psychological, sociocultural, and biological factors. Patients with anorexia
nervosa manifest weight loss, fear of becoming fat, and disturbances in how they
experience their body weight and shape. Patients with bulimia nervosa present
with recurrent episodes of binge eating and inappropriate methods of weight
control such as self-induced vomiting, and abuse of diuretics and laxatives.
Major complications of eating disorders include severe fluid and electrolyte
disturbances and cardiac arrhythmias. The most common cause of death in anorexia
nervosa is suicide. Management requires a team approach in which different
professionals work together. Individual and family psychotherapy are effective in
patients with anorexia nervosa and cognitive-behavioral therapy is effective in
bulimia nervosa. Pharmacotherapy is not universally effective by itself. Patients
with eating disorders suffer a chronic course of illness. The pediatrician plays
important role in early diagnosis, management of medical complications, and
psychological support to the patient and the family.
PMID- 10773896
TI - Management of traumatic shock.
AB - Trauma is the leading cause of death in the pediatric age group. About 25,000
children die each year and one million children are injured each year in the USA.
Aggressive resuscitation determines the outcome of these injured children. The
initial hour following the traumatic injury is referred to as the "golden hour"
during which we have an opportunity to intervene and improve the outcome. It is
not only the first hour which is important but every minute in trauma
resuscitation is important. The outcome of traumatic children has a direct
correlation to resuscitation. In order to manage traumatic shock there are four
basic principles: (a) control of active hemorrhage, (b) assessment of circulatory
status, (c) rapid intravascular access, and (d) aggressive fluid resuscitation.
Following the four principles of management of traumatic shock and aggressive
resuscitation improves the outcome.
PMID- 10773897
TI - Pediatric head injury.
AB - Pediatric head injury is a public health problem that exacts a high price from
patients, their families and society alike. While much of the brain damage in
head-injured patients occurs at the moment of impact, secondary injuries can be
prevented by aggressive medical and surgical intervention. Modern imaging devices
have simplified the task of diagnosing intracranial injuries. Recent advances in
monitoring technology have made it easier to assess the effectiveness of medical
therapy. These include intracranial pressure monitoring devices that are accurate
and safe, and jugular bulb monitoring which provides a continuous, qualitative
measure of cerebral blood flow. The cornerstones of treatment remain
hyperventilation and osmotherapy. Despite maximal treatment, however, the
mortality and morbidity associated with pediatric head injury remains high.
Reduction of this mortality and morbidity will likely depend upon prevention
rather than treatment.
PMID- 10773898
TI - Fragile X syndrome.
AB - Fragile X syndrome is the most common familial form of mental retardation. This X
linked disorder affects one in every 1000 males and one in every 2000 females.
The female carrier rate in the general population is estimated to be 1/600. A
fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark
cytogenetic feature of the syndrome. Clinical features include physical as well
as cognitive and neuropsychological deficits. Although fragile X syndrome follows
an X-linked pattern of inheritance (which explains the predominance of affected
males), females can also be affected. Many inconsistencies exist between the
genetic inheritance pattern of fragile X and traditional Mendelian inheritance
tenets of most X-linked diseases. Due to recent molecular advances, our
understanding of the perplexing genetic issues surrounding fragile X syndrome has
grown and diagnostic techniques have become both reliable and readily available.
PMID- 10773899
TI - Perioperative management of the pediatric transplant patient.
AB - With advances in surgical techniques, an increasing number of children are
becoming transplant candidates. Pediatric critical care physicians may need to
manage both transplant donors and recipients in the pediatric intensive care
unit. Care of such patients needs to be performed aggressively with complete
attention to details in order to obtain successful transplant outcomes. The
postoperative management of the transplant recipient includes the basic intensive
care monitoring and management of postoperative patients who are critically ill.
Besides this, there are some unique features among these patients which may
complicate the postoperative stay in the pediatric intensive care unit and these
are discussed here. It is important to remember that the successful management of
a transplant patient includes the pediatric critical care physician's abilities
of not only taking care of acute issues but also of coordinating care between
subspecialists. The pediatric critical care physician must always continue to
provide support to families of these transplant patients during their intensive
care unit stay.
PMID- 10773900
TI - Brain death.
AB - Death is a natural process, but the definition of death varies depending on the
cultural and religious background, all over the world. The historical development
of the concept and the current criteria in the determination of brain death must
be well understood. Termination of life support measures in a brain dead child
should be undertaken after due consideration of moral, ethical, psychosocial and
legal issues.
PMID- 10773901
TI - The interface of nutrition and dentition.
PMID- 10773902
TI - Modified food starches in baby foods.
AB - Modified food starches were developed as a stabilizer, providing desirable
consistency, texture, and storage ability. They are used primarily in strained
and junior foods and, to a minor extent, in infant formulas. However, despite the
fact that there is an increasing tendency to introduce solid foods to infants at
a very early age, there is few long-term studies to delineate the effect of
starch feeding on the growth of young infants. Modified food starches used by the
food industry for infants and young children are of concern and there is an
urgent need for additional data regarding their bioavailability, effect on
nutrient absorption, intestinal changes, and toxic, mutagenic, and carcinogenic
effects. Therefore, the inclusion of modified food starches should be used
prudently and sparingly.
PMID- 10773903
TI - Nutrition education and mega-dose vitamin A supplementation in Nepal.
AB - Two approaches to improve vitamin A nutriture are compared: nutrition education
and mega-dose capsule distribution. The impact of these programmes on vitamin A
deficiency (VAD), wasting malnutrition, and excessive childhood mortality are
compared for approximately 40,000 children who were assigned to either
intervention cohorts or a control group from 75 sites within seven districts in
two ecological settings (Terai, or lowland, and hills) of Nepal. Twenty-four
months after the implementation of the project, the reduction of risk of
xerophthalmia was greater among children of mothers who were able to identify
vitamin A-rich foods [relative risk (RR) = 0.25; 95% CI = 0.10-0.62] than among
children who received mega-dose capsules (RR = 0.59; 95% CI = 0.41-0.84). The
risk of mortality at two years was reduced for both the nutrition education
cohort (RR = 0.64; 95% CI = 0.48-0.86) and capsule distribution cohort (RR =
0.57; 95% CI = 0.42-0.77). The nutrition education program, however, was more
expensive to deliver than the capsule distribution programme. High rates of
participation in the supplementation programme were achieved within a short
period. The nutrition education message spread rapidly throughout the study
population, although practice was slower to change. Where maternal literacy was
low and channels of communication were limited, the capsule programme appeared to
be more cost-effective. However, economies of scale for nationwide programmes
exist for nutrition education programmes that do not exist for capsule
distribution programmes. A comprehensive national programme requires both dietary
supplementation and nutrition education.
PMID- 10773904
TI - Pulse corticosteroid therapy with methylprednisolone or dexamethasone.
AB - Intravenous pulse steroid therapy consists of administration of
supraphysiological doses of glucocorticoids. It is useful in conditions where
rapid immunosuppression and antiinflammatory effect is desired, as in systemic
lupus erythematosus, pemphigus, renal transplantation, steroid resistant
nephrotic syndrome and crescentic glomerulonephritis. This therapy may be
associated with significant adverse reactions including hypertension,
arrhythmias, hypokalemia, psychosis and infections. High dose steroid therapy
should therefore be used in selected cases and under careful supervision. The
drug most widely used for this treatment is methylprednisolone. However, in view
of its easy availability and cost, dexamethasone has been often used in India for
the above conditions. While there are no controlled studies comparing the two
drugs, it appears that the two drugs may be similar in efficacy. Patients
requiring high dose intravenous steroid therapy may be treated effectively with
either methylprednisolone or dexamethasone.
PMID- 10773905
TI - Rapid diagnosis of typhoid fever.
AB - A Reverse Passive Haemagglutination Test (RPHA) was designed for the detection of
Salmonella typhi antigen and rapid diagnosis of typhoid fever. Two per cent fresh
sheep RBC's were coated with 32 micrograms/ml of immunoglobulin. The minimal
detectable level of the antigen was 1250 micrograms/ml. Cross reactions were
observed with the samples of patients suffering from Salmonella paratyphi A and
pseudomonas infections. The RPHA established was used for the detection of S.
typhi antigen in culture broths from 100 patients with clinically suspected
typhoid fever with culture and/or widal positive, 50 patients with septicemia
caused by bacteria other than S. typhi and 50 normal, afebrile healthy controls.
It was found that the sensitivity and specificity of this assay was 70% and 92%
respectively.
PMID- 10773907
TI - Augmenting cognitive learning of community nutrition by tutorials.
AB - Community health interventions are increasingly being considered a priority area
in medical curriculum. In the topic of nutrition, a situation analysis of final
MBBS students in our institution revealed significantly lower levels of knowledge
in community applications as compared to basics and clinical aspects, indicating
the need for some educational intervention. An improvised tutorial was conducted
to address this deficiency at cognitive level. The intervention was a special
scheme of flow of discussion with a positive bias in favour of nutritional
applications at community level. Half of the learners were given routine
tutorial, as part of existing teaching schedule in nutrition and the remaining
were subjected to educational intervention, to provide control and study groups
respectively. Before and after assessment of the recall of learners on community
applications demonstrated a positive impact of improvised tutorial. The learners'
level of knowledge in two groups was comparable before the tutorial but it was
significantly higher ('P' < 0.001) in study group as compared to control, after
the tutorial (mean scores: 134.38/150 and 91.20/150 respectively). No extra
resources, tutor time or student's learning hours were needed for the improvised
tutorial. Tutor's positive bias in favour of applied aspects can bring about a
desired change even in conventional teaching-learning process, without asking for
extra resources. It can be a supplement to community-based learning.
PMID- 10773906
TI - Tamil Nadu nutritional survey comparing children aged 0-3 years with the NCHS/CDC
reference population.
AB - A cross-sectional nutritional survey of children belonging to Tamil Nadu State of
India, aged 0-3 years was conducted on a representative sample of 2039 children.
The collected data was analysed using the recommended indices of height-for-age
and weight-for-height based on standard deviation (SD scores) and cross
classified using the SD scores. The nutritional status of these children was
compared with the NCHS standard. Prevalence of stunting (27.6%), wasting (9.9%)
and simultaneous wasting and stunting (10.7%) was high among the children
studied.
PMID- 10773908
TI - Validation of the verbal autopsy method to ascertain acute respiratory infection
as cause of death.
AB - The validity of the Verbal Autopsy (VA) in death due to acute respiratory
infection (ARI), was tested in 36 children who died by any acute infectious
disease as stated by the necropsy diagnosis, at two public hospitals in Mexico
City; the illness started at home. Clinical data obtained through VA were
compared with diagnoses of necropsies, which were considered as "gold standard".
The presence of dyspnoea for more than one day showed sensitivity of 0.69 and
specificity of 0.74, while history of coughing showed a sensitivity of 0.61 and a
specificity of 0.73. Combination of both clinical data improved specificity
(0.83), but decreased sensitivity (0.54). Additional sources of diagnosis (a
panel of assessors, the clinical record and the death certificate), also showed
good sensitivity (0.69-0.77) and specificity (0.74-7.8). Focus on history of
dyspnea and/or cough in children with an infectious syndrome should be
emphasized, as a useful epidemiologic tool to determine children's mortality due
to ARI in areas where diagnosis resources are constrained.
PMID- 10773909
TI - Portal hypertension in north Indian children.
AB - Etiological factors associated with portal hypertension in children influence the
decision about therapy and the prognosis. This cross-sectional observational
study was performed at a tertiary care centre in northern India from January,
1990 to December, 1994. Children below the age of 14 years with suspected portal
hypertension were prospectively assembled into a cohort to determine the etiology
and clinical profile of portal hypertension. Of the 115 patients with portal
hypertension, 76.5% had extrahepatic portal hypertension (EHPH). Remaining 23.5%
of the cases had intrahepatic and post-hepatic causes of portal hypertension.
Children with EHPH had a significantly earlier onset of symptoms as compared to
those with intrahepatic portal hypertension (p = 0.002) and bled significantly
more frequently (p = 0.00). Forty per cent of patients with chronic liver disease
(CLD) never had jaundice. History suggestive of potential etiological factors
could be elicited in only 7% of EHPH patients. The commonest site of block in
splenoportal axis was at the formation of the portal vein. An inverse relation of
bleeding rates with duration of illness was seen in EHPH. Of the 10 CLD patients
in whom liver biopsy could be done, cirrhosis was present in 6 patients.
Understanding the natural history of EHPH and portal hypertension due to other
etiologies may have significant implications in choosing the appropriate
intervention and predicting the outcome.
PMID- 10773910
TI - Process evaluation of pulse polio immunisation in Delhi.
AB - The aim of the study was to assess the functional aspects and the staffing at
Pulse Polio immunisations posts. Interns and medical students conducted the
survey in eighty seven pulse polio immunisation posts scattered all over National
Capital Territory of Delhi on 18th January 1997. A pre-tested structured format
containing information pertaining to dose utilisation and staffing was filled.
Number of children given pulse polio was on an average 459.2 per immunisation
post (474.7 rural, 516.35 slums and 435.0 urban). Average number of neonates
(below one month) per immunisation post given polio drops was 5.1 (1.1%). The
break-up for rural area, slums and urban area was 3.0 (0.63%), 6.7 (1.30%) and
4.9 (1.13%) respectively. By 12 pm, 67.8% and by 2 pm 88.7% of the doses had been
administered. Staffing at most of the immunisation posts was adequate for all
categories of staff except doctors (0.48 per booth).
PMID- 10773911
TI - Discontinuous electrophoresis of glycosaminoglycans: a screening method for
mucopolysaccharidoses.
AB - A modified discontinuous electrophoretic method for the separation of standard
and urinary glycosaminoglycans has been reported. The merits of the method are
the simple and easy to handle apparatus, non-requirement of elaborate cooling
system, sensitivity and high reproducibility of the results and applicability of
the method for the preliminary grouping of the MPS patients to reduce the number
of enzyme assays to be done.
PMID- 10773912
TI - Effect of phototherapy on behaviour of jaundiced neonates.
AB - Thirty full term newborns appropriate for gestational age with icterus neonatorum
were divided into two groups of 15 each. Group I (study group) newborns had serum
bilirubin in the range of 12.1 to 15.0 mg/dl. Group II (control group) included
neonates with serum bilirubin in the range of 8 to 12.0 mg/dl. Only the study
group was given phototherapy. The comparative study of neonatal behaviour in both
these groups was done using BNBAS (Brazelton's neonatal behaviour assessment
scale), 24 to 48 hrs, both after initiation and cessation of phototherapy in the
study group and at corresponding postnatal ages in control group. Many newborns
in the study group were on top feeds and had more crying episodes. The study
group scores were significantly poorer in orientation response to visual
inanimate, visual animate and visual and auditory animates in the cluster
interactive processes. Followup assessment showed similar results in the same
items. Other items in the same cluster and all items in the other clusters showed
no significant difference in the two groups in the initial as well as followup
assessments. As maternal separation during phototherapy also possibly affects
neonatal behaviour, the effect of this factor can be minimized by keeping the
phototherapy unit with the mother of the jaundiced baby. The mother should be
encouraged to breast feed her baby regularly and have more mother-baby
interaction.
PMID- 10773914
TI - Childhood autism in tuberous sclerosis.
AB - The article reports two cases of childhood autism in tuberous sclerosis (TS).
Certain atypical features are highlighted. The probands did not show the common
seizure types associated with either TS or autism. No ventricular dilatation,
cerebral atrophy or temporal lobe involvement was evident. The high prevalence of
childhood autism in TS probands with moderate to severe mental retardation has
been emphasized.
PMID- 10773913
TI - Changes in anti-oxidant enzymes and lipid peroxidation in hyaline membrane
disease.
AB - This study was conducted to elucidate the changes in key antioxidant enzymes e.g.
Superoxide dismutase (SOD), Catalase and Glutathione peroxidase (GPx) along with
lipid peroxidation (LPO) in preterm newborns having hyaline membrane disease
(HMD) and thus to find out role of free radicals mediated injury in this disease.
Twenty one preterm appropriate for gestational age newborns were included in the
study. Eleven of them had hyaline membrane disease and ten were controls without
any disease. Status of superoxide dismutase, glutathione peroxidase and catalase,
the three main antioxidant enzymes and lipid peroxidation was monitored at 12-24
hours of age. SOD and catalase were found significantly elevated in cases having
hyaline membrane disease along with significantly more lipid peroxidation. It is
evident that free radicals result in the induction of the antioxidant enzymes;
however, the elevated enzymes are unable to counteract the high concentration of
the free radicals which are being produced in the diseased cases and leads to
increase in lipid peroxidation in hyaline membrane disease. It is concluded that
free radicals play a significant role in hyaline membrane disease and the preterm
newborns have ability to induce antioxidant enzymes in response to oxidative
stress.
PMID- 10773915
TI - Systemic lupus erythematosus and sickle cell disease.
AB - A case of 10-year-old girl with an unusual association of sickle cell disease
(SCD) with systemic lupus erythematosus (SLE) is presented. The report discusses
the clues to the diagnosis of this rare combination with review of relevant
literature and highlights the diagnostic dilemma that may arise because of the
similarity of symptoms.
PMID- 10773916
TI - Twin fetus in fetu.
AB - Fetus in fetu is a rare cause of intra-abdominal mass. The presence of vertebral
and skeletal axis differentiates it from a teratoma. We report an unusual case of
two well developed fetuses in the retroperitoneal area of a neonate delivered at
term.
PMID- 10773918
TI - Hemato-oncology--the Indian scene.
PMID- 10773919
TI - Prenatal diagnosis of haemophilia.
AB - Haemophilia A is a severe bleeding disorder caused by a deficiency in clotting
factor VIII (FVIII). It is an X-linked recessive bleeding disorder affecting one
in 10,000 males. Prevalence of the haemophilia gene in the general population has
increased recently due to advances in treatment, which has resulted in
reproductive fitness among heamophiliacs. Patients suffering from this disease
and their families are faced with problems relating to morbidity and mortality
from the disease. These include a continual risk of uncontrolled bleeding,
haemarthroses and subsequent arthropathy and above all, the genetic risk to
progeny. Factor VIII gene is very large with 26 exons. Defects in this gene
result in the deficiency of FVIII molecule. With the advent of recent advances in
the molecular biology, it is possible to identify the multiple molecular defects
such as point mutations, premature stop codons, deletions, and inversions etc in
the FVIII gene in patients with haemophilia. Nowadays the use of polymerase chain
reaction (PCR)-based linkage analysis and direct mutation detection in the
chorionic villus sample obtained at 10-12 weeks of gestation has significantly
improved the prenatal diagnosis of haemophilia.
PMID- 10773920
TI - Anemia in newborn.
AB - Various blood indices vary in a newborn as compared to older child or adult. It
depends on the gestational age, day of life, maternal factors, mode of delivery
and site of blood collection. Hemoglobin, HCT & MCV tend to be higher in
newborns. They further increase in first 2 days of life. Reticulocytosis and
presence of nucleated red cells are normally seen in first week of life. Neonatal
anemia is a common problem in NICU. It is usually caused by either hemorrhage or
hemolysis and rarely due to decreased production. Hemorrhage can be ante or intra
or post natal and it could be external or internal. It could be acute or chronic.
Management of acute severe hemorrhage includes packed cell transfusion. Hemolysis
is usually due to isoimmune hemolysis, G6PD deficiency or rarely due to the
hemoglobinopathy like alpha-thalassemia or due to spherocytosis. Usually patients
will have indirect hyperbilirubinemia which needs phototherapy or exchange
transfusion. Rarely congenital pure red cell aplasia can present at birth with
physical anomalies and anemia. Treatment of neonatal anemia depends on the
arteriology.
PMID- 10773917
TI - Surfactant protein-A: new insights into an old protein--Part I.
AB - Pulmonary surfactant is a lipoprotein substance that lines the lungs and helps
reduce surface tension. Surfactant associated protein-A (SP-A) is the most
abundant non-serum protein in pulmonary surfactant. This complex glycoprotein
aids in the synthesis, secretion and recycling of surfactant phospholipids, and
facilitates the reduction of surface tension by surfactant phospholipids. Recent
evidence has highlighted the role of SP-A in the innate immune system present in
the lung. SP-A may play a major role in defense against pathogens by interacting
with both infectious agents and the immune system. Factors that affect fetal lung
maturation, e.g., gestational age and hormones, regulate SP-A gene expression.
Mediators of immune function also regulate SP-A levels. A number of lung
disorders, including infectious diseases and respiratory distress syndrome are
associated with abnormal alveolar SP-A levels. SP-A can no longer be called a
lung-specific protein, since it has recently been detected in other tissues. In
most species, SP-A is encoded by a single gene, however in humans it is encoded
by two, very similar genes. Models for the structure of the human SP-A protein
molecule have been proposed, suggesting that the mature alveolar SP-A molecule is
composed of both gene products. The study of SP-A may provide information helpful
in understanding disease processes and formulating new treatment modalities.
PMID- 10773921
TI - Autoimmune hemolytic anemia.
AB - Immune hemolytic anemia can be either isoimmune or autoimmune. Autoimmune
hemolytic anemias (AIHA) consist of group of disorders whose common
characteristics are the presence of an antibody which in turn causes short red
blood cell (RBC) life. The rate and site of hemolysis and hence the clinical
manifestations depends on the type of antibody attached and its propensity to fix
complement. Antibodies of the IgG class are most commonly responsible for AIHA in
children. Rh erythrocyte antigen is involved in more than 70% of cases. Since the
antibody has its maximal activity at 37 degrees C, the resultant hemolysis is
called warm antibody induced hemolytic anemia. This is a severe life threatening
condition, the clinical features are: sudden onset of pallor, jaundice and dark
urine. The cornerstone of diagnosis is a positive Coomb's antiglobulin test in
the presence of hemolysis. Coomb's test has false negative and false positive
rates in about 2-4% and 8% of all cases respectively. The modalities for
treatment of warm AIHA include blood transfusion, steroid therapy, intravenous
gammaglobulin, plasma-pheresis and splenectomy. The choice depends on the
severity of the disease and child's response to therapy.
PMID- 10773922
TI - Childhood lymphoma.
AB - Lymphoma accounts for some 10% of childhood malignancy. Hodgkins disease is
slightly less common than Non Hodgkins lymphoma, of which lymphoblastic, Burkitts
and large cell anaplastic are the common subtypes. Accurate subtyping and staging
are critical to ensure correct therapy is initiated. With current therapeutic
strategies, almost all cases of Hodgkins and in excess of 70% of Non Hodgkins
lymphomas can be cured.
PMID- 10773925
TI - Pediatric critical care in the 21st century.
PMID- 10773923
TI - Immunoglobulin therapy in immunohematological disorders.
AB - Over the last few decades many biological factors have been discovered. Among
these immunoglobulins are currently being used for large number of indications.
Initially it was used for primary and secondary immunodeficiency states.
Subsequently, intravenous immunoglobulins are being used for variety of
immunohematological, autoimmune, and immunopathological disorders. In the present
communication besides it basic structure, pharmacology and immunoregulation, its
use in various hematological disorders is being reviewed. Currently, it is the
preferred treatment for conditions such as immune mediated thrombocytopenic
purpura, neutropenia, and autoimmune hemolytic anemia.
PMID- 10773926
TI - Perinatal mortality in a rural district of south India.
AB - Perinatal mortality is one of the most sensitive indices of maternal and child
health. The perinatal mortality rate is an indicator of the extent of pregnancy
wastage as well as of the quality and quantity of health care available to the
mother and the newborn. A community based prospective study carried out on 13,214
births in South Kanara district between Oct. 1991-Sept. 1992 revealed a perinatal
mortality rate (PNMR) of 44.65/1000 births. Among the various factors influencing
perinatal mortality, breech deliveries and babies of multiple pregnancies had a
very high perinatal mortality rate of 180.81/1000 births (adjusted odd's ratio:
4.90) and 128/1000 births (adjusted odd's ratio: 2.64). The previous bad
obstetric history of the mother, parity and sex of the newborn were among the
other important factors influencing the PNMR.
PMID- 10773924
TI - Neuroblastoma.
AB - The neuroblastic tumours originate from primordial neural crest cells that
normally develop into sympathetic nervous system, including the adrenal medulla.
Neuroblastoma is the most intriguing pediatric neoplasm displaying diverse
clinical and biologic characteristics and natural history. It has the highest
rate of spontaneous regression of all human cancers, yet exhibits extremely
malignant behaviour in older children with regional and disseminated disease. In
the last 30 years, only a nominal improvement has occurred in the outlook of
older children with metastatic disease at diagnosis. Tremendous gains in
understanding of the biology of neuroblastoma in recent years have led to
development of risk-related therapy based on age, stage and biological
characteristics of neuroblastoma.
PMID- 10773927
TI - Prevalence of Mycoplasma pneumoniae and Chlamydia pneumoniae in children with
community acquired pneumonia.
AB - A prospective one year study was performed on 62 children admitted at the All
India Institute of Medical Sciences with community acquired pneumonia (CAP) for
the prevalence of Mycoplasma pneumoniae and Chlamydia pneumoniae. Diagnosis of
infection with M. pneumoniae was based on serological tests viz microparticle
agglutination test for detection of IgM antibodies and indirect
immunofluorescence test for antigen detection from throat swabs (sensitivity
85.7%, specificity 93.3%). The indirect solid-phase enzyme immunoassay for
detection of IgG antibodies was used to determine the prevalence of C. pneumoniae
(sensitivity 88.8%, specificity 75.8%). Seventeen patients (27.4%) were found to
have serological evidence of M. pneumoniae infection whereas only 4 (6.4%)
patients were seropositive for C. pneumoniae. Results of this study indicate that
M. Pneumoniae plays a significant role in CAP in infants and young children. Thus
specialized laboratory testing for these agents should be more widely used
thereby affecting empiric antibiotic regimens.
PMID- 10773928
TI - Viral infections in newborns through exchange transfusion.
AB - Preprocedure sera of thirty one neonates requiring exchange transfusion were
tested for serological markers of HBV, HCV, CMV, HIV and LFT. All the babies were
investigated for these parameters one week and two months after transfusion to
evaluate the risk of transmission of viral infection. Serological markers for
these viral infections were also studied in the mothers and donors' blood to
establish the route of infection. Donors' blood used for transfusion was
pretested for HBsAg, VDRL and anti-HIV. HBsAg was detected one week post exchange
in one baby and two months post exchange in two babies. Exchange transfusion was
implicated in two of them, where one donor had HBsAg and the other anti-HBc.
Vertical transmission accounted for the remaining one. Out of these HbsAg
positive cases, one showed evidence of recently acquired CMV infection. Vertical
transmission of anti-HCV was observed in one case. None of the neonates, mothers
and donors were positive for anti-HIV. In view of probable serious consequences
of HBV and HCV infections, blood used for exchange transfusion ought to be
screened for anti-HBc and anti-HCV, besides routine HBsAg, VDRL and anti-HIV
screening.
PMID- 10773930
TI - Dengue virus infection among children with undifferentiated fever in Karachi.
AB - Sera were collected from a total of 122 children, comprising 117 cases with
undifferentiated fever and 5 cases with dengue hemorrhagic fever (DHF), during
June to September 1994 in Karachi, Pakistan. Sera were tested by the IgM-capture
ELISA using dengue type 1 (D1), dengue type 2 (D2), West Nile (WN), and Japanese
encephalitis (JE) viral antigens. Among 92 single sera from undifferentiated
fever cases, IgM antibodies were detected in 5 cases by D1, 8 cases by D2, and 5
cases by WN antigens, respectively. Corresponding number of positives among 25
paired sera from undifferentiated fever cases were 3 by D1, 6 by D2, and 1 by WN
antigen. Four out of 5 DHF cases possessed anti-D1 as well as anti-D2 IgM
antibodies. Only a single DHF case was positive for anti-WN IgM antibodies. Anti
JE IgM antibodies were not detected in any of the tested serum specimens.
Clinical manifestations of undifferentiated fever patients were generally non
specific, but the percentage of children with anemia, hepatomegaly and
splenomegaly was higher in patients possessing anti-dengue IgM antibodies than
those without. Among the groups with anti-dengue IgM antibodies, those possessing
only anti-D2 but not anti-D1 IgM antibodies showed higher percentages with cough,
edema, and splenomegaly. The results indicated that up to 26% of the
undifferentiated fever cases were caused by dengue virus infection in Karachi,
Pakistan.
PMID- 10773929
TI - Efficacy of leucocyte filters during transfusions in preventing the development
of anti-HLA antibodies.
AB - The study was planned to investigate the effectiveness of using leucocyte filters
in neonates during exchange and erythrocyte transfusion in preventing the
development of anti-HLA antibodies. Twenty-four newborn infants who were admitted
to the Neonatology Unit and received either exchange or at least two erythrocyte
transfusions were recruited. The study group comprised of 12 infants on whom
leucocyte filters were used during transfusions. Control group included the
remaining 12 infants who were transfused without using a leucocyte filter. Anti
HLA antibodies in the serum samples were studied using modified Amos technique.
Presence of anti-HLA antibodies in post-transfusion sera was detected in 3 (25%)
of 12 infants in the study (filter) group, while in 10 (83.33%) of 12 infants in
the control (no-filter) group. The difference between two groups was
statistically significant (p < 0.05). The study demonstrated that term and
preterm neonates were capable of developing anti-HLA antibodies following
exchange and erythrocyte transfusions, and use of leucocyte filters could
efficiently prevent the formation of anti-HLA antibodies.
PMID- 10773932
TI - Childhood leprosy in a rural hospital.
AB - Sixty six cases of childhood leprosy were studied in detail. They comprised of
7.2% of the Hansen's disease cases and 0.1/1000 of the total hospital out
patients. Male: female ratio was 2:1. Four cases (6%) only belonged to the
multibacillary group. All the multibacillary patients had a family contact of
leprosy. Twelve cases (18.2%) showed nerve involvement and 2 cases (3%) had
deformities also. One patient had pure neuritic type of leprosy. Leprosy
reactions were not observed in any case. Out of 42 patients adequately followed
up after completion of treatment, 3 patients (7.1%) had relapse of the disease.
PMID- 10773931
TI - Defective growth hormone (GH) secretion and short-term treatment in Noonan
syndrome.
AB - Auxological and endocrine data from 12 prepubertal children (3 males, 9 females)
with Noonan syndrome (NS) were compared with those of 15 children with
constitutional short stature (CSS), 20 children with partial GH deficiency (GHD),
and 6 children with Turner syndrome (TS). Four children with NS were treated with
human growth hormone (hGH) (n = 4) (25 units/m2 week, divided on daily s.c.
doses). In children with NS, the peak serum GH response to clonidine (5.4 +/- 2.7
ug/L) and glucagon (7.4 +/- 3.4 ug/L) were significantly lower than those for
children with CSS (14.8 +/- 3.4 and 12.8 +/- 2.8 ug/L respectively). Nine out of
the 12 (75%) children with NS did not mount normal GH peak (10 ug/L or more)
after provocation. The 12-h integrated GH secretion in the 3 children with NS who
had normal GH response to provocation (2.7 +/- 0.7 ug/L) was markedly lower
compared to that for children with CSS (6.7 +/- 1.2 ug/L). The serum insulin-like
growth factor-1 (IGF-I) concentrations were lower in children with NS (67 +/- 32
ng/ml) vs CSS (165 +/- 35 ng/ml), but not different from those for GHD children
(59 +/- 33 ng/ml). In 4 children with NS, hGH therapy for a year increased height
growth velocity from 4.1 +/- 0.3 cm/yr to 7.4 +/- 0.6 cm/yr and height standard
deviation score (Ht SDS) from -2.2 +/- 0.6 to -1.45 +/- 0.3. This growth
acceleration was accompanied by an increase in IGF-I concentration (from 52 +/-
21 ng/ml to 89 +/- 25 ng/ml). In summary, these results prove a defect of the GH
secretion in children with NS and suggest that GH therapy has an important role
in the management of their short stature.
PMID- 10773933
TI - Congenital indifference to pain.
AB - Congenital analgesia can vary from simple analgesia without any systemic
dysfunction to more serious conditions associated with peripheral neuropathy,
self-mutilation, and mental retardation. Prevention of injury is important for
normal growth of the child.
PMID- 10773934
TI - Primary antiphospholipid syndrome in stroke in the young.
AB - Antiphospholipid syndrome is an uncommon cause of stroke. A 12 year old girl with
this syndrome is reported who presented with thrombotic stroke and high titres of
anticardiolipin (aCL) and lupus anticoagulant (LAC). The patient improved
subsequently and was put on aspirin. The present report highlights the importance
of screening for aCL and LAC in cases of stroke in young patients.
PMID- 10773935
TI - Trichobezoar with small bowel obstruction.
AB - Trichobezoar is a rare clinical entity. Stomach is the common site of occurrence.
Intestinal obstruction due to trichobezoar is extremely rare. We report a case of
subacute bowel obstruction in a 7-year-old girl which required resection of the
involved ileal segment and release of small bowel adhesions.
PMID- 10773936
TI - Esophageal atresia with blocked distal tracheo-esophageal fistula.
AB - A new born male child diagnosed for pure esophageal atresia was subsequently
found to have blocked tracheo-esophageal fistula. The case is reported in view of
its rarity and difficulty in management.
PMID- 10773938
TI - Coagulopathy in Gaucher disease.
PMID- 10773937
TI - Proximal femoral focal deficiency (PFFD).
AB - A 1-year-old child with proximal femoral focal deficiency (PFFD) is presented.
The clinical spectrum and associated abnormalities is described and the diagnosis
and management of this entity is discussed.
PMID- 10773939
TI - Duration of antiepileptic drug (AED) therapy.
PMID- 10773940
TI - Peripheral venous access in children.
PMID- 10773941
TI - Rejoinder to article: "Iodine loss from iodised salt on heating".
PMID- 10773943
TI - Childhood cancer: improved prospects for survival but is prevention possible?
AB - With optimum treatment 65-70% of children diagnosed with cancer should be long
term survivors and probably cured. Prevention is better than cure. Recent studies
into the causes of childhood malignancy are reviewed. The incidence of childhood
acute lymphoblastic leukaemia (ALL) is steadily increasing. The cause for this
may be increasing social and economic development. Exposure to electromagnetic
fields has been a cause of concern for almost 20 years. A recent large case
control study has shown no increased risk of cancer or leukaemia in those who
have measurably increased exposure to electromagnetic fields. Leukaemia which has
the cytogenetic abnormality 11q23 or MLL gene rearrangement characteristically
occurs as a second malignancy after exposure to epipodophyllotoxins which act by
inhibiting topoisomerase. Infant leukaemia has the same cytogenetic profile.
Mothers of babies who develop infant leukaemia have high exposure to potential
dietary inhibitors of topoisomerase during pregnancy. Clusters of leukaemia can
probably best be accounted for by population mixing. There may be an increased
risk of ALL following vitamin K given to newborns.
PMID- 10773942
TI - Surfactant protein-A: new insights into an old protein--II.
AB - Pulmonary surfactant is a lipoprotein substance that lines the lungs and helps
reduce surface tension. Surfactant associated protein-A (SP-A) is the most
abundant non-serum protein in pulmonary surfactant. This complex glycoprotein
aids in the synthesis, secretion and recycling of surfactant phospholipids, and
facilitates the reduction of surface tension by surfactant phospholipids. Recent
evidence has highlighted the role of SP-A in the innate immune system present in
the lung. SP-A may play a major role in defense against pathogens by interacting
with both infectious agents and the immune system. Factors that affect fetal lung
maturation, e.g. gestational age and hormones regulate SP-A gene expression.
Mediators of immune function also regulate SP-A levels. A number of lung
disorders, including infectious diseases and respiratory distress syndrome are
associated with abnormal alveolar SP-A levels. SP-A can no longer be called a
lung-specific protein, since it has recently been detected in other tissues. In
most species, SP-A is encoded by a single gene, however in humans it is encoded
by two, very similar genes. Models for the structure of the human SP-A protein
molecule have been proposed, suggesting that the mature alveolar SP-A molecule is
composed of both gene products. The study of SP-A may provide information helpful
in understanding disease processes and formulating new treatment modalities.
PMID- 10773944
TI - Cell cycle control and cancer.
AB - This review consists of two parts. In the first part normal mechanisms regulating
the progression of cells through the cell cycle are briefly reviewed. Besides
mitogenic stimulation, cyclin kinase inhibition, the G1 restriction point and the
prb pathway, accuracy of DNA replication and DNA repair, the G2 to M transition,
apoptosis and the p 53 pathway, proteolytic, in particular ubiquitin-dependent
mechanisms involved in the initiation of DNA synthesis in the separation of
sister chromatids and in the telophase to GO/G1 transition, are discussed. In the
second part oncogene and tumor suppressor gene products are briefly
characterized. Aberrations of cell cycle control mechanisms associated with
cancer are grouped as follows: deregulation of protooncogenes by translocations
juxtaposing protooncogenes to immunoglobulin--or T cell receptor genes;
translocations producing chimeric proteins unique to cancer cells; inversions and
amplifications resulting in over expression of regulator genes; and deletions and
mutations of tumor suppressor genes. It is emphasized that cancer is the result
of a multistep process and that uncontrolled cell production and other
alterations are, as a rule, late phenomena.
PMID- 10773945
TI - Beta-thalassemias: expression, molecular mechanisms and mutations in Indians.
AB - The beta-thalassemias are a heterogenous group of inherited disorders of
hemoglobin (Hb) synthesis characterized by a reduction (beta+) or absence (beta
zero) of synthesis of the beta globin chains of Hb, resulting in an imbalanced
chain synthesis. To understand their expression and molecular basis in Indians,
it is essential to review briefly the genetic control of normal Hb production and
the structure, organization and regulation of different globin genes. The Indian
beta-thalassemia mutations and strategies for prevention are described.
PMID- 10773946
TI - Oral deferiprone--controversies on its efficacy and safety.
PMID- 10773947
TI - Follow-up care of the low birth weight infant.
AB - Care of the preterm infant after discharge is a challenge for the pediatric
follow-up team. All premature infants should be followed through infancy and into
preschool and school years because of the common ongoing medical concerns and the
high risk of developmental disabilities. Although impossible to predict with
great accuracy in the neonatal period, it is appropriate to select those preterm
infants who have the highest risk for disabilities and provide to them a closer
degree of surveillance.
PMID- 10773948
TI - Perinatal bacterial infection: an update.
AB - This article reviews the current trends in the evaluation and management of
bacterial infection involving the uterus, placenta, membranes, amniotic fluid,
and fetus occurring near the time of birth. The discussion includes information
regarding risk, incidence, pathophysiology, bedside diagnosis, interventional
options including antibiotics, corticosteroids, fetal monitoring, and delivery,
and possible preventive measures which affect the outcome. The adequate
evaluation and management of perinatal infection requires a team approach with
obstetricians and pediatricians. Clinical screening is useful in developing the
diagnosis, but amniotic fluid evaluation remains the proposed gold standard. The
role of cytokines is becoming increasingly important, as is seen in the
association of IL-6 with positive amniotic fluid cultures and periventricular
leukomalacia. Prompt recognition and management of the pregnancy affected by
infection can improve perinatal outcomes. A management protocol is presented to
help structure the approach to suspected infection. Premature delivery due to
perinatal infection may be preventable.
PMID- 10773949
TI - Cost of vitamin A and iron supplementation to "at risk" population.
AB - This is a cost descriptive study which estimates the cost of providing iron and
vitamin A supplementation through the primary health care system in India. The
norms for the primary health care workers were taken as per national norms. The
costs included the proportionate cost of the building, workers' salary and the
cost of the supplements. The total cost of providing iron supplementation through
the PHC was estimated at Rs. 43,800. The cost per beneficiary for adult folifer
was Rs. 3.60, for paediatric folifer was Rs. 2.90 and for syrup folifer, it was
Rs. 15.50. The overall cost of providing iron and folic acid supplements to the
"at risk" population was estimated as Rs 4.40 per beneficiary per year. The cost
of vitamin A supplementation to under three through the PHC system was estimated
at Rs. 3.20 per beneficiary per year. Both iron as well as vitamin A
supplementation through the PHC system appear to be low cost interventions.
PMID- 10773951
TI - Detection of high risk pregnancies with relation to ABO haemolytic disease of
newborn.
AB - IgM and IgG anti A and anti B antibody status of 100 antenatal O group mothers
(who had non O group husbands) were studied. Of these, 3 mothers had an IgM anti
A antibody levels ranging from 1:512 to 1:2048 and IgG ranging from 1:1204 to
1:2048, IgM anti B ranging from 1:128 to 1:512 and IgG anti B ranging from 1:256
to 1:512. All these mothers had A + ve children and all these children suffered
from ABO haemolytic disease of newborn (HDN). A 4th mother had an IgM anti A
titre of 1:64 and IgG anti A titre of 1:16. The titre of IgM anti B in this
mother was 1:512 and that of IgG 1:1024. The child was A + ve and did not suffer
from ABO haemolytic disease of newborn.
PMID- 10773950
TI - Neurodevelopmental outcome of 'at risk' nursery graduates.
AB - A cohort study at a tertiary care neonatal service was undertaken to determine
the neurodevelopmental outcome of neonates who required intensive care. One
hundred and nineteen nursery graduates were enrolled for follow up if they
fulfilled any of the following risk factors: birth weight less than 1500 g, Apgar
score less than 4 at 5 minutes, seizure(s), and required assisted ventilation for
more than 24 hours. They were subjected to periodic clinical evaluation and
administered the Bayley Scales of Infant Development in early childhood. Of the
total infants enrolled, 101 completed the required follow up. They included 55
infants with birth weight < 1500 g, 45 with low Apgar scores, 12 with seizure(s)
and 28 who received assisted ventilation. An overwhelming majority of subjects
(85%) had normal neurodevelopmental outcome. The adverse outcome in the remaining
15 included mental retardation in all, subnormal motor development in 14,
microcephaly in 1, hearing loss in 2 and visual impairment in 4. Among the
neonatal risk factors, seizures, sepsis and hypoxic ischemic encephalopathy had a
significant association with adverse outcome. Despite serious neonatal morbidity,
the early neurodevelopmental outcome of nursery graduates was reasonably good.
The association of neonatal sepsis with neurodevelopmental sequelae merits a
prospective evaluation.
PMID- 10773952
TI - Breast feeding patterns in an urban resettlement colony of Delhi.
AB - Studies on duration and patterns of breast feeding based on recall may lead to a
bias about the exact feeding status. The present study was designed to overcome
this bias using the 'current status analysis method'. Mothers of 650 infants from
0 to 12 months of age attending a Health Centre were interviewed about the
current feeding patterns of the infants and other socioeconomic variables. Month
wise prevalence of feeding patterns was determined. It was observed that breast
feeding was maintained at a high level (more than 90%) throughout infancy while
exclusive breast feeding showed a rapid decline. At 1 month, 74% and at 4 months,
46% of infants were exclusively breast-fed. The median duration of exclusive
breast feeding was 3.83 months. Mothers with lesser education and lower family
income were more likely to exclusively breast feed (p < 0.05). The time interval
between birth and first breast feed was 24-48 hours in most (48.9%) of the
infants. Majority (76.9%) of the infants received pre-lacteal feeds. Hospital
born infants received their first feed earlier and were less likely to receive
pre-lacteal feeds as compared to those born at home (p < 0.001). Thus, the
practice of exclusive breast feeding has to be promoted amongst pregnant and
lactating mothers by health personnel. Also knowledge regarding infant feeding
has to be imparted in schools and colleges.
PMID- 10773953
TI - Congenital malformations at birth--a prospective study from south India.
AB - Congenital malformations were studied prospectively from September 1989 to
December 1992 covering 12,797 consecutive deliveries. The overall incidence of
malformations was 3.7% and it was 3.2% among live births and 15.7% among still
births. Three hundred and ninety seven birth defects were observed among 308 live
births and 72 among 45 still births. The incidence of malformation was
significantly higher among male babies (p < 0.001), still births (p < 0.001), low
birth weights (p < 0.001) and preterm babies (p < 0.001). Consanguinity among
parents of malformed babies was more common (p < 0.001). Musculo-skeletal
malformations were the commonest (9.69 per 1000) followed by cutaneous (6.33 per
1000), genitourinary (5.47 per 1000), gastrointestinal (5.47 per 1000), central
nervous system (3.99 per 1000) and cardiac anomalies (2.03 per 1000).
Musculoskeletal, cutaneous and genitourinary malformations were common among live
born babies while central nervous system and gastrointestinal defects were common
among still born babies. Antenatal infections and ingestion of drugs were not
found to be significant factors in the causation of birth defects.
PMID- 10773954
TI - Epidemiological study of dental caries.
AB - A total of 2000 children (1-14 year age group) attending pediatric OPD, school
clinic & well body clinic of Dr. R.N. Cooper Municipal Hospital & K.E.M Hospital,
Mumbai were examined for caries prevalence and 35.6% had dental caries. Parental
income was not shown to have any bearing on caries prevalence. Parental literacy,
particularly maternal literacy was shown to influence caries prevalence in
children. The prevalence was low in well-nourished children and in those taking
vegetarian type of diet. Frequency of sweet consumption was shown to be
associated with prevalence of dental caries. In 1-4 year age group it was noted
that bottle fed children were more affected by dental caries. Tooth brush with
paste was the commonest method used for cleaning their teeth in all age groups in
our study. Caries prevalence was low in those children using tooth brush than in
those using tooth powder. Those children who were using neem datun were found to
be less affected with dental caries. Dental caries was also found to be low in
those who rinsed their mouth with water after food.
PMID- 10773955
TI - Status of toxoplasma antibodies in recurrent fetal loss in U.A.E. women.
AB - A retrospective analysis to determine the status of toxoplasma (IgG & IgM)
antibodies in UAE women with recurrent fetal loss was done using
immunofluorescence assay. Two thousand three hundred and fourty three patients
with one or more fetal loss were studied over a period of five years. In patients
with fetal loss, the range of toxoplasma IgG seropositivity varied from 24.2
30.6%. There were 3 patients with IgM positive. Only in a single patient one of
her two abortions could be attributed to acute toxoplasmosis. Habitual fetal loss
cannot be attributed to chronic toxoplasmosis. Also, 67.2% of the women of child
bearing age group in U.A.E were found to be seronegative, highlighting the need
for routine antenatal screening to detect primary acute toxoplasmosis.
PMID- 10773956
TI - Serum copper in newborns and their mothers.
AB - Serum copper levels in the cord blood of 100 newborns and the respective maternal
serum copper at the time of delivery was estimated by atomic absorption
spectrophotometer. The cases were classified into term AGA, term SGA, term LGA,
preterm AGA and preterm SGA. The mean maternal serum copper level 152.42 +/- 2.06
micrograms/dl) was significantly higher than the mean cord serum copper level
(39.84 +/- 1.19 micrograms/dl). There was positive correlation between the
maternal serum copper level and cord serum copper level. The mean serum copper
level of term neonates was (44.42 +/- 1.26 micrograms/dl) significantly higher (p
< 0.001) than that of preterm neonates (30.30 +/- 1.14 micrograms/dl). There was
a positive correlation between cord serum cooper level and gestational age. The
mean cord serum copper levels of term AGA, term SGA, preterm AGA and preterm SGA
neonates was 45.42 +/- 1.44 ug/dl, 39.22 +/- 2.45 ug/dl, 31.00 +/- 2.11 ud/dl and
29.47 +/- 2.08 ug/dl respectively. There was no statistically significant
difference in the mean serum copper level of AGA and SGA group of both term and
preterm neonates. The difference amongst mean maternal serum copper level of
various neonatal groups was not significant.
PMID- 10773958
TI - Urinoma--an unusual complication following kidney biopsy.
AB - Development of urinoma is an unusual complication following kidney biopsy. We
describe one such case who was managed successfully by ultrasound guided
percutaneous catheter drainage.
PMID- 10773957
TI - Segregation distortions for the ABO system in pairs of sibs.
AB - The influence of maternal phenotype was observed in 471 consecutive sib pairs to
explore the segregation distortions for the ABO system. The ABO typing was done
using the standard technique of haemagglutination reaction and the sib pairs were
named according to their phenotypes. Thus A-B is the pair where first sib was A
and the consecutive one was B. The statistical computations involved calculations
of ABO gene frequencies, and application of chi-square and Z test for proportions
to study the segregation distortions in sibs. A significant excess of B gene in
the first sib and reduction of O in the second sib was observed when the Z test
was applied to study the covariance, whereas no significant distortions were
observed with simple Chi-square test. Heterozygote AO mothers segregated
insignificantly in favour of A allele whereas BO mothers segregated significantly
in favour of B allele in the first as well as in the second sib indicating that
selection is favouring the B gene in our population.
PMID- 10773959
TI - Colorectal carcinoma.
AB - Two rare cases of colorectal adenocarcinoma seen during the last 3 years in
children under 10 years of age are reported. To improve survival, emphasis is
given on its early diagnosis by a thorough examination and investigation of the
child in every case of prolonged bleeding per rectum, diarrhoea and other non
specific abdominal symptoms.
PMID- 10773960
TI - Leiomyoblastoma of small intestine.
AB - Gastrointestinal tumours are rare in children and leiomyoblastoma of small
intestine is still rarer. We report a case of leiomyoblastoma of small intestine
in a child who presented with acute intestinal obstruction.
PMID- 10773961
TI - Pregnancy-exaggerated galactosemia and congenital cataracts.
AB - One child in a family and two children in another family had galactosemia and
congenital cataract. Two of them had total soft cataracts while in one, cataract
was less soft. In addition, they had mild lactosuria. The mothers of the affected
children had significant lactosuria and mild galactosuria without cataracts.
Fathers did not have galactosuria or lactosuria. Clinically unaffected siblings
in one family had mild galactosuria and lactosuria. Pregnancy-exaggerated
galactosemia was suspected in these two mothers who gave birth to children with
congenital cataract. As an extension of this work, 5001 pregnant women were
screened for galactose in urine just before the delivery of babies. Mild
galactosuria was present in 54 (1.08%). Three children had congenital cataract
and one had changes in posterior pole and cornea. Restriction of lactose by
reducing intake of milk and milk products during pregnancy by mothers with
galactosuria is recommended to avoid the birth of children with congenital
cataract.
PMID- 10773962
TI - The "bone and joint decade" will turn the spotlight on rheumatic diseases
worldwide from 2000 to 2010.
PMID- 10773963
TI - Multidrug resistances genes in rheumatology. Is their role immunological or
pharmacological?
PMID- 10773964
TI - Pyogenic arthritis in adults.
AB - Septic arthritis has shown no change in incidence, and despite advances in
antimicrobial therapy is often responsible for residual functional impairment and
for a high mortality rate among debilitated patients. Risk factors include older
age, diabetes mellitus, rheumatoid arthritis, immunodeficiency, and a preexisting
joint disease (e.g., rheumatoid arthritis) to which the symptoms of septic
arthritis are sometimes ascribed. Staphylococcus aureus contributes over two
thirds of identified organisms; a range of streptococci and gram-negative bacilli
are next in frequency. The most common site is the knee, followed by the hip and
shoulder. Over 10% of patients have polyarticular involvement reflecting
bacteremia and diminished resistance to infection; (over 50% of polyarticular
forms occur in rheumatoid arthritis patients). Prosthetic joint infection is
becoming increasingly common; chronic forms due to intraoperative contamination
and resulting in septic loosening should be distinguished from acute hematogenous
infection in which emergency treatment can allow to salvage the prosthesis.
Demonstration of the organism in the joint is the key to the diagnosis. Joint
aspiration should be performed on an emergency basis, if needed after
identification of radiographic landmarks or under ultrasonographic guidance.
Seeding the fluid on blood culture flasks immediately after aspiration increases
the yield. Antibiotics should be started as soon as the microbiological specimens
have been collected. When aspiration is difficult (hip) or inadequate,
arthroscopic drainage usually makes arthrotomy unnecessary. Early
antiinflammatory therapy (nonsteroidal antiinflammatory drugs, systemic or local
glucocorticoids, anticytokines, and antiinflammatory cytokines) are being
considered as tools for limiting joint damage; their efficacy and safety will
first have to be established in animal studies.
PMID- 10773965
TI - Mechanisms of action of bisphosphonates on tumor cells and prospects for use in
the treatment of malignant osteolysis.
AB - Malignant osteolysis is a common complication of many cancers, most notably
breast cancer, prostate cancer, and multiple myeloma. Hypercalcemia, pain, and
fractures are the main manifestations. Malignant osteolysis can be fatal or cause
a rapid deterioration in quality of life. The underlying mechanism in tumor cem
mediated activation of osteoclasts, whose function is normally to resorb bone. It
follows that pharmacological agents capable of inhibiting osteoclast activity,
including bisphosphonates, are likely to be useful in the treatment of malignant
osteolysis. Also, experimental evidence suggest that bisphosphonates act on the
tumor cells themselves, either by inhibiting mechanisms involved in the
development of bone metastasis (tumor invasion, adhesion of tumor cells to the
bone matrix) or by inducing apoptosis of tumor cells. Many clinical trials have
found bisphophonates to be effective in the treatment of complications due to
malignant osteolysis. Based on these studies, bisphosphonates are now indicated
to treat hypercalcemia and to prevent skeletal complications of metastatic breast
cancer and myeloma, in a dosage of 1600 mg.d orally for clodronate or 90 mg every
four weeks intravenously for pamidronate. Osteoclast inhibition is clearly the
mechanism underlying the efficacy of bisphosphonates in these clinical trials.
Recent clinical trials found that prophylactic bisphosphonates therapy in
patients with nonmetastasic breast cancer decreased the incidence of bone
metastases, thus supporting a direct effect of biphosphonates on tumor cells.
However, conflicting experimental and clinical data have been reported, so that
it remains uncertain whether bisphosphonates have anti-tumor effects in vivo in
humans. Nevertheless, biphosphonates now have an undisputed place in the
therapeutic armamentarium for cancer.
PMID- 10773966
TI - Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I:
Increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis
patients might influence disease outcome.
AB - BACKGROUND: Multidrug resistance (MDR) is characterized by overexpression of P
glycoprotein, a pump molecule that decreases intracellular drug concentrations by
increasing drug efflux from cells. OBJECTIVE: To look for correlations between
clinical status and P-glycoprotein activity and/or TNF-alpha mRNA levels in
patients with rheumatoid arthritis. METHODS: Sixteen patients were studied. Based
on response to therapy, eight were refractory and eight nonrefractory to
treatment. Findings were compared to those in 24 healthy controls. Flow cytometry
was used to evaluate P-glycoprotein activity in peripheral blood mononuclear
cells isolated by gradient centrifugation and incubated with the P-glycoprotein
substrate daunorubicin. TNF-alpha mRNA levels were determined using quantitative
PCR. RESULTS: Patients with rheumatoid arthritis showed an increased number of
lymphocytes with high P-glycoprotein activity (p = 0.0001) as compared to the
normal controls. P-glycoprotein activity was higher in the refractory than in the
non-refractory patient subgroup (p = 0.006). Also, TNF-alpha mRNA levels were
markedly higher in the refractory subgroup than in the nonrefractory subgroup,
and were undetectable in the normal controls. CONCLUSIONS: Enhanced P
glycoprotein activity may be closely related to an unfavorable clinical course
and a poor response to treatment. Increased TNF-alpha expression and chronic
exposure to various drugs, including glucocorticoids, may contribute to increase
P-glycoprotein activity. Both high P-glycoprotein activity and excessive amounts
of TNF-alpha seem associated with poor outcome in rheumatoid arthritis.
PMID- 10773967
TI - Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part II:
Increased P-glycoprotein activity in lymphocytes from systemic lupus
erythematosus patients might affect steroid requirements for disease control.
AB - BACKGROUND: Over-expression of the membrane glycoprotein called P-glycoprotein
has been widely observed in a variety of both normal and neoplastic cells. P
glycoprotein is a pump molecule that transports hydrophobic drugs (including
steroids) and toxins outside the cells, thus inhibiting their therapeutic or
toxic effects. The gene encoding P-glycoprotein is named multidrug resistance-1
(MDR-1). OBJECTIVE: To evaluate the functional activity of P-glycoprotein in
lymphocytes and monocytes from patients with systemic lupus erythematosus.
METHODS: 30 systemic lupus erythematosus patients and 20 healthy controls were
studied. Peripheral blood mononuclear cells isolated by gradient centrifugation
were incubated in the presence of daunorubicin (a fluorescent drug extruded by P
glycoprotein) at 37 degrees C or 4 degrees C for 30 min. P-glycoprotein activity
was then analyzed using flow cytometry. Results were expressed as the percentage
of lymphocytes or monocytes with high P-glycoprotein activity (i.e., low
fluorescence). RESULTS: Mean fluorescence values for lymphocytes and monocytes
were comparable between patients and healthy controls. However, because our
method allowed to measure P-glycoprotein function at the single-cell level, we
were able to show that the mean percentage of lymphocytes with high P
glycoprotein activity was increased in the patients (11.51% +/- 14.3%) as
compared to the healthy controls (0.71% +/- 0.57%) (P < 0.05). Moreover, P
glycoprotein activity was lower in the patients in clinical remission than in
those with active disease. CONCLUSIONS: Our results suggest that P-glycoprotein
function might affect glucocorticoid requirements in systemic lupus
erythematosus.
PMID- 10773968
TI - Outcomes in patients with incipient undifferentiated arthritis.
AB - OBJECTIVE: To determine outcomes in patients with onset within the last year of
peripheral inflammatory arthritis that does not meet classification criteria for
any specific disease. METHODS: Symptoms and laboratory tests were evaluated at
baseline and 14 to 60 months later in 43 patients, 32 women and 11 men, with a
mean age of 50 years. RESULTS: At baseline, a presumptive clinical diagnosis was
made in 16 of the 43 patients. Diagnoses at last follow-up were undifferentiated
inflammatory arthritis in seven cases, mild rheumatoid arthritis in 18, psoriatic
arthritis in two, Sjogren's syndrome in two, lupus in one, and paraneoplastic
syndrome in one. The remaining 12 patients were free of inflammatory joint
symptoms; three had symptoms of osteoarthritis and nine were asymptomatic.
Factors present at baseline and predictive of progression to definite rheumatoid
arthritis were a positive test for rheumatoid factor, presence of an HLA DRB1*04
allele, and a presumptive clinical diagnosis of rheumatoid arthritis. CONCLUSION:
55% of our patients developed a specific inflammatory joint disease, and 42%
developed rheumatoid arthritis, which was consistently mild. Resolution of all
inflammatory joint symptoms occurred in 28% of cases. A number of clinical
laboratory, and genetic findings of use for predicting the outcome of
undifferentiated arthritis were identified.
PMID- 10773969
TI - Intraarticular glucocorticosteroid injection into the lateral atlantoaxial joint
under fluoroscopic control. A retrospective comparative study in patients with
mechanical and inflammatory disorders.
AB - OBJECTIVES: To evaluate the overall efficacy in various disorders of
glucocorticoid injection into the lateral atlantoaxial joints, performed via the
posterior route under fluoroscopic control. METHODS: Retrospective study of 26
patients including 16 (19 injections) with mechanical disorders and ten (16
injections) with inflammatory disorders. RESULTS: The response rate was 69.3%,
the mean pain scale score decrease was 52.3 +/- 40.1%, and the mean duration of
pain relief was 8.1 +/- 11.8 months. All three parameters were significantly (P <
0.005) better in the subgroup with inflammatory disorders than in the subgroup
with mechanical disorders (response rate, 100% vs 50%; pain scale score decrease,
80 +/- 27% vs 34.2 +/- 40%, and pain relief duration, 16.9 +/- 14.9 months vs
24.5 months). A single patient developed a side effect (moderately severe
hypertension). CONCLUSION: Glucocorticoid injection into the lateral atlantoaxial
joints is a valid treatment alternative in patients who fail to respond to
conventional noninvasive therapy.
PMID- 10773970
TI - Adolescent idiopathic scoliosis. Is low melatonin a cause?
AB - BACKGROUND: Although the cause of adolescent idiopathic scoliosis remains
unclear, pinealectomy is followed by the development of scoliosis in chickens.
Melatonin is the only hormone secreted by pineal gland. OBJECTIVE: To assess
serum melatonin levels in adolescents with idiopathic scoliosis. METHODS: Serum
melatonin was assayed once, at 12:00 hours, in each of 20 adolescents with
idiopathic scoliosis and 10 age-matched siblings. In the patient group, mean age
was 14.3 years and the mean Cobb angle was 54.5 degrees (range, 20 degrees-110
degrees). Mean age in the control group was 14 years. RESULTS: Serum melatonin
was significantly lower in the patients (mean, 7.7 pg/mL; range, 4 to 13 pg/mL)
than in the controls (mean, 29.9 pg/mL; range, 19.3 to 46 pg/mL) (P < 0.00001).
The 12 surgically treated patients had a mean melatonin level of 8.1 pg/mL,
versus 7.2 pg/mL in the eight other patients (nonsignificant P and regression
coefficient values). Serum melatonin was not significantly correlated with the
Cobb's angle (regression coefficient, 0.18; P < 0.44). CONCLUSION: Our data
suggest that serum melatonin levels may contribute to the pathogenesis of
idiopathic scoliosis.
PMID- 10773971
TI - Monostotic fibrous dysplasia of the lumbar spine.
AB - Monostotic fibrous dysplasia is exceedingly rare. We report a case in a 61-year
old woman with a history of recurrent low back pain and sciatica since 35 years
of age. While walking, she suddenly experienced pain in her right thigh. The pain
spread gradually to the buttock and calf on the same side, becoming increasingly
severe. The time pattern was mechanical, with exacerbation during straining.
Paresthesia developed over the dorsal aspect of the right foot. Nonsteroidal
antiinflammatory drugs were ineffective. Radiographs of the spine showed an
expansile and heterogeneous lesion in the body of L2. Hyperactivity of L3 and L4
was seen on the bone scan. Computed tomography demonstrated heterogeneity of L2,
L3, and L4, as well as hypertrophy of the neural arch of L3 and of the right
posterior lamina and spinous process of L4. Alterations in L2, L3, and L4 were
noted on the magnetic resonance imaging study, which showed no evidence of
epidural involvement. Laboratory tests were normal. A surgical biopsy of L3
established the diagnosis of fibrous dysplasia. Since the seminal description of
fibrous dysplasia in 1891, only 21 cases of monostotic spinal involvement have
been published. The spinal lesions can remain clinically silent or cause spinal
pain with or without neurological symptoms. Radiographic findings are variable
(heterogeneity, osteolysis, expansion without cortical violation or soft tissue
involvement). Calcium and phosphate levels are normal. The diagnosis depends on
examination of a vertebral biopsy specimen.
PMID- 10773972
TI - Intraosseous xanthoma without lipid disorders. Case-report and literature review.
AB - A case of intraosseous xanthoma in a patient with a normal lipid profile is
reported. Hyperlipidemia is present in most patients with xanthomas. Intraosseous
xanthomas are rare, particularly in normolipidemic patients, in whom the
presenting symptom is pain without skin lesions. A lytic lesion with a rim of
sclerosis is seen on radiographs. Histology shows foam cells, giant cells, and
fibrosis. Intraosseous xanthoma is a benign tumor, and other diagnoses must be
ruled out (histiocytosis X, Erdheim Chester disease, clear cell carcinoma
metastasis). Surgical excision of the lesion is the elective treatment.
PMID- 10773974
TI - [Combined position of DOG and BVA on photodynamic therapy].
PMID- 10773973
TI - Frozen shoulder in identical twins.
PMID- 10773975
TI - [Photoreceptor renewal and the pigment epithelium of the retina--congratulations
to a pioneer in retinal research: Richard W. Young].
AB - In 1999, a pioneer in retinal cell biology celebrates his seventieth birthday:
Richard W. Young, Professor of Anatomy at the Dept. of Anatomy and Jules Stein
Eye Institute, University of Southern California, Los Angeles, California, USA.
Against the current dogma of visual cells as static structures he demonstrated
that they undergo continual renewal of their light-sensitive outer segments.
Entire membranes and/or single molecules are being replaced, and the tips of
outer segments are shed (disk-shedding), and phagocytized and degrade by pigment
epithelial (PE) cells. About 100 disks are made per rod within 24 hours, and
about 30,000 disk membranes from overlying rods are degraded by one PE cell thus
rendering the PE one of the most active phagocytic systems of the body. It is not
surprising, therefore, that the age pigment lipofuscin accumulates within PE
cells, which is mainly composed of undigestible outer segment material. It is
generally concluded that lipofuscin can contribute to the pathogenesis of age
related macular degeneration (AMD). Early on Young has postulated that light
exposure may accelerate AMD and some forms of retinitis pigmentosa (RP). Today we
know that indeed in several animal models of RP light exposure can significantly
enhance the disease progression. With a similar insight and intuition he
described apoptosis of the retina thus preceding the "apoptotic wave" in eye
research. Apoptosis now is considered the final common death pathway of many
retinal diseases including degenerations and dystrophies. With his work young has
created may scientific children, who directly or indirectly were inspired by his
pioneering work.
PMID- 10773976
TI - [Intrastromal corneal ring segments (ICRS, KeraVision Ring, Intacs): clinical
outcome after 2 years].
AB - BACKGROUND: Since 1996 Intrastromal Corneal Ring Segments (Intacs, KeraVision,
Inc., Fremont, CA, USA) have been used for the correction of mild to moderate
myopia at the Salzburg Eye Clinic. Aim of this study was to evaluate the
stability, reversibility and adjustability of this new method. PATIENTS AND
METHODS: Our experiences and final results of 54 surgeries--30 eyes with a
minimum follow-up of 2 years--, as well as the potential reversibility (3
explanations, 2 of them followed by PRK) and adjustability (3 exchanges) are
reported in detail. RESULTS: None of the eyes lost more than one line in BSCVA
(in 14 of 30 eyes the BSCVA improved, "Safety-Index": 1.13). 73% (22/30) reached
an UCVA of 1.0 or better, 47% (14/30) of 1.25 or better ("Efficacy-Index": 0.79).
After two years 47% (14/30) were within +/- 0.5 D of the attempted correction. We
observed no significant intra- or postoperative complications. After ICRS removal
the refractive data returned to within +/- 0.75 D (MRSE) and +/- 0.5 D (mean
keratometry) of preoperative values, respectively. Patients with an ICRS exchange
obtained an improved UCVA between 0.8 and 1.0, gaining between 2 to 4 lines.
CONCLUSIONS: Within the follow-up period of 2 years the ICRS seem to provide a
very stable correction of low to moderate myopia. The procedure is reversible to
a large extent, potentially adjustable (within certain limits) and carries a
minimal risk only. After explantation PRK can be performed with good visual
results.
PMID- 10773977
TI - [Clinical experiences with the "Swedish interactive threshold algorithm" (SITA)].
AB - BACKGROUND: The "Swedish Interactive Threshold Algorithm" (SITA) is a new
technique minimizing test time without reduction of data quality. In this
retrospective study we compared visual fields assessed with the conventional full
threshold technique with those by SITA and analyzed qualitative and quantitative
differences and the test time reduction of SITA. PATIENTS AND METHODS: 113 eyes
with different glaucomatous field damage of 66 patients aged from 22 to 89 years
were included. The patients underwent perimetry with each strategy within four
months. Exclusion criteria were eyes with progressing glaucomatous damage and
high rate of false-positive results or artifacts by corrective glasses. RESULTS:
The qualitative differences of the analysis were small: full threshold
demonstrated more relative scotomas in eyes with normal SITA readings, whereas
scotomas assessed with SITA were often pronounced to absolute scotomas. Average
time reduction by SITA was 40% and depended on the severity of glaucomatous
stage. No reduction was found for advanced glaucoma, whereas normal fields using
SITA were performed in half of the time of full threshold strategy. CONCLUSION:
Differences of SITA to conventional full threshold testing may be related to
fatigue effects of full threshold strategy due to longer test time. The reduction
of test time enables more motivation for more frequent visual field examinations
and thus a better detection of early glaucoma or progressing visual field damage.
PMID- 10773978
TI - [Operation of the floppy eyelid. Symptomatic cases require surgical eyelid
stabilization].
AB - BACKGROUND: Floppy Eyelid is a rare condition causing chronic papillary
conjunctivitis and chronic corneal disorders (superficial punctate keratitis,
epithelial and stromal ulcers). It is characterized by an extremely enlarged and
"floppy" upper eyelid which can be easily everted by slight elevation. Usually
obese men are affected who use to sleep face down either on the right or on the
left side. Pushing the eyelid against the pillow, the lid is intermittently
everted at sleep. This lagophthalmus with rubbing of the exposed eye and lid
structures causes all pathologic disorders. Shielding the eye at night may help
temporarily. PATIENTS: We performed surgery on 7 men with symptomatic floppy
eyelid in the age of 42 to 61 years. The patients had been symptomatic between 1
month and 4 years prior to the definite diagnosis. Follow-up time has been 7
months to 4.5 years. RESULTS: In all cases surgery achieved improvement.
CONCLUSIONS: Cases of unclear conjunctival or corneal damage and inflammation
should led consider Floppy Eyelid as a possible cause. The typical clinical
findings make diagnosis easy. As complete stopping of eyelid-rubbing by changing
the patient's sleeping habits is mostly not easily possible, for acute therapy of
threatening damages to cornea and conjunctiva a surgical shortening of the lid is
necessary which stabilizes the lid in order to avoid nightly spontaneous eversion
for a long time.
PMID- 10773979
TI - [An automated and spectral differentiating dark adaptometer--initial results of a
clinical study].
AB - BACKGROUND: Routine measurement of dark adaptation is a lengthy process and the
presence of a qualified operator is required. MATERIALS AND METHODS: Our dark
adaptometer uses either a red or a green light-emitting diode to produce the
threshold stimulus. Through an electronic circuit arrangement the dark adaptation
curve is automatically measured. A computer stores the resulting data and renders
the statistical analysis possible. To obtain the normal adaptation curve, 33
healthy volunteers were tested. We subsequently examined 32 patients in the
clinical assay. RESULTS: The adaptation for the green test light results in an
overlapping photopic/scotopic graph and is used as an analogy for the curve
resulting from a white test light. The red LED produces the scotopic graph later
on with a more elevated threshold. Of the patients examined, 14 with night
blindness show the expected pathological results. Correlating to the type of
disease, the other 18 patients without night blindness show normal dark
adaptation. CONCLUSIONS: In 150 examinations the dark adaptometer proved to be
easy to handle, yielding valid and reliable results. The automatic recording
allows operator-independent measurements. The dark adaptation rate for red and
green and the final cone and rod threshold can be evaluated. The computer control
provides statistical analysis and the possibility to delegate the examination.
PMID- 10773980
TI - [Micro-perimetric documentation of retinal function in photodynamic therapy of
choroid neovascularizations].
AB - PURPOSE: Photodynamic therapy provides occlusion of choroidal neovascularization
by intravascular endothelial damage. The photodynamic approach offers the
potential to occlude choroidal neovascularization selectively without altering
adjacent sensory retina and therefore to preserve visual acuity. To determine the
selectivity of photodynamic therapy photoreceptor function was measured by
microperimetry allowing topic mapping of retinal function. METHODS: A Rodenstock
scanning laser ophthalmoscope was used to document preservation of central visual
fields before and after photodynamic therapy. Single photodynamic therapy without
known efficient parameters was performed in 13 patients and repeated photodynamic
therapy using optimised light doses was performed in 10 patients with subfoveal
choroidal neovascularization using benzoporphyrin derivate (verteporfin).
Intensity and dimension of central scotomas were measured, using a grading system
of stimuli ranging from 0-32 dB. Areas of absolute and relative defect were
defined and fixation localisation was monitored. Perimetric testing was done pre
photodynamic therapy, one week, one month and three months post photodynamic
therapy. RESULTS: Postoperative scotomas after single photodynamic therapy were
smaller in 8%, identical in 61% and larger in 31% compared with preoperative
findings. After repeated photodynamic therapy postoperative scotomas were smaller
in 70%, identical in 30% and larger in no case. The observed increase was less
than 25% of the original size. Postoperative defects were always significantly
smaller than the entire size of the irradiated area. No new scotomas were found
after photodynamic therapy. Angiographically visible occlusion post photodynamic
therapy was in general larger than scotoma size. CONCLUSION: Documentation of the
retinal function by microperimetry after photodynamic therapy of subfoveal
choroidal neovascularization shows no new scotoma in the treated area. This can
also be documented in the hypofluorescent area around the lesion one week after
the treatment. After repeated treatment a reduced scotoma size due to choroidal
neovascularization could be seen in 2/3 of the patients after 3 months. No
initial vision loss as seen in conventional photocoagulation could be documented
after photodynamic therapy.
PMID- 10773981
TI - [Immunological effect of systemically administered allopurinol in experimental
autoimmune uveitis].
AB - PURPOSE: Allopurinol shows beneficial effects in the systemic treatment of lens
induced uveitis. This is believed to be due to the reduction of oxidative tissue
damage via a dose-dependent free radical scavenging ability and an
immunomodulating effect. The purpose of this study was to investigate the
immunological effects in experimental autoimmune uveitis after systemic treatment
with allopurinol (AL) and steroids (STER). METHODS: 31 male Lewis rats were
immunized with crude retinal extract, Freund's Adjuvans and pertussis toxin. The
rats were divided into four groups: healthy rats (BASIS, n = 3), experimental
autoimmune-uveitis without therapy (EAU, n = 9), 50 mg/kg bw. allopurinol i.v.
(ALSYS, n = 9), and 7.5 mg/kg bw. methylprednisolone i.v. (STSYS, n = 10). ALSYS
and STSYS received five intravenous injections during the 2 weeks immunization
period. The rats' sera were tested against Western Blots (WB) of electrophoretic
separations of retinal proteins. Based on digital image analysis, an analysis of
discriminance was performed. RESULTS: The multivariate analysis of discriminance
revealed a significance difference between the WBs of ALSYS and STSYS (p < 0.01)
compared to EAU without therapy. The number and intensity of peaks in WBs were
strongly reduced in the ALSYS group compared to EAU. CONCLUSION: AL revealed a
strong immunomodulating effect in the treatment of experimental autoimmune
uveitis that is markedly stronger than that of steroids. Together with the
antioxidative effect of allopurinol known from previous studies, this drug could
be a new promising therapeutic approach in the treatment of uveitis.
PMID- 10773982
TI - [Hallermann-Streiff syndrome: should spontaneous resorption of the lens opacity
be awaited?].
AB - BACKGROUND: As the lens may become absorbed spontaneously extraction of the
congenital cataract in the Hallermann-Streiff syndrome is controversial. PATIENT:
A male newborn with Hallermann-Streiff syndrome was referred to the eye clinic
because of a bilateral mature cataract. The risks of an operation seemed too
serious because the eyes were extremely microphthalmic (a-p diameter approx. 10.5
mm). Instead, it was decided to await spontaneous lens absorption which then
occurred slowly and completely between the beginning of the 2nd and the end of
the 3rd year of life without considerable inflammatory responses. In the
meantime, the child has a good orientation and is able to paint and to
discriminate colours without optic correction. CONCLUSIONS: The critical
investigation of the literature reveals that the frequency of spontaneous lens
absorption in the Hallermann-Streiff syndrome is probably (widely)
underestimated. It can be estimated with up to 50% (or even more) if patients
which were operated on are excluded and if untreated patients are followed up
till the end of the 5th year of life. Functional results seem to be quite similar
for treated and untreated eyes. Therefore we would recommend to await the
spontaneous lens absorption in the Hallermann-Steiff syndrome especially when the
cataract is combined with considerable microphthalmia.
PMID- 10773983
TI - [Sequestrating senile scleral plaque simulating "necrotizing scleritis". Surgical
management].
AB - BACKGROUND: Presentation and surgical treatment of a sequestrating senile scleral
plaque, a rare clinical disorder. PATIENT: A 76 year-old-female patient presented
with foreign body sensation and epiphora. Half a year before, she had first
noticed a "black spot" in her eye which had now progressed to a painless yellow
greyish plaque. CASE HISTORY: The patient had previously undergone a steroid
treatment elsewhere with a diagnosis "necrotizing scleritis" without any
improvement. We found a yellow-greyish degenerative plaque sequestrating from the
surrounding scleral tissue. In order to prevent superinfection and to secure the
tissue defect we surgically removed the plaque and covered the remaining thin
inner scleral tissue layers with autologous sclera and conjunctiva. The clinical
diagnosis of a calcified senile scleral plaque was histologically confirmed. The
patient has been free from any symptoms since the operation. To our knowledge
this is the first description of surgical removal of a deeply sequestrating
senile sceral plaque. CONCLUSION: Calcified sequesters represent a very rare
complication of the otherwise frequent senile scleral plaques. Surgical
intervention may be required to prevent superinfection and to cover the deep
sceral defect. The clinical picture can be distinguished from necrotizing
scleritis or scleromalacia perforans. Sequestrating senile scleraplaques do not
tend to perforate. They are, however, a risk for infection and chronic
inflammation.
PMID- 10773984
TI - [Intraocular involvement as initial symptoms of non-Hodgkin lymphoma].
AB - BACKGROUND: The diagnosis of a intraocular lymphoma is often delayed because of a
symptomatic pseudouveitis. CASE REPORT: We report on a 68-year-old female
patient, who was referred because of a tumor of the optic disk in her right eye
and bilateral uveitis with secondary glaucoma. The painful blind right eye was
enucleated. The assumed diagnosis of a pseudouveitis as an initial manifestation
of a B-cell lymphoma was confirmed histologically. She developed systemic
extension and recurrence in the second eye despite polychemotherapy. The patient
died from complications of her systemic tumor disease 15 months after initial
symptoms. CONCLUSIONS: An initially unilateral and later bilateral uveitis in
elderly patients which does not respond to steroid therapy could also be
suspicious for an intraocular lymphoma. If the conjunctiva is not involved, the
confirmation of the diagnosis requires a diagnostic viteous biopsy.
PMID- 10773985
TI - [Future of surgery].
AB - Most current surgical techniques were developed in the 20th century, especially
during the past 50 years. Open heart surgery, vascular surgery, neonatal surgery,
organ transplantation and artificial organs, microsurgery, intravenous
hyperalimentation, and, more recently, endoscopic surgery emerged during the past
five decades. Many of the dreams of surgeons in the past have now been realized.
These advances in surgery were made possible by the development of new
technologies and instrumentation, but most importantly were initiated by the
pioneering spirit of surgeons. This will continue on in the next century, since
history shows that classical or conventional treatment modalities are constantly
changing and being replaced by new ones based on new ideas and technologies. In
this age of molecular biology, gene therapy, computer science, and the Internet,
the pace of change in medicine and surgery will accelerate. Systems for training
and communications, and even medical ethics, will inevitably change. We may not
be able to predict precisely the future changes in surgery and surgeons, but we
must be prepared for them and steer the future of surgery for the benefit of
patients.
PMID- 10773986
TI - The quincunx of surgery.
AB - From the earliest days of surgery the central and unifying theme of the
discipline has been the mastery of technical proficiency with the view to not
only management of the diseased or damaged part but the preservation of general
health and well being. This central tenet of the discipline has been supported by
four critical columns of knowledge, each of which has amplified over the passage
of time. Initially anatomy was the cornerstone of surgical intervention and
mastery of surgery to a large part depended upon a secure grasp of the
intricacies and relationships of corporeal macro structure. The second column
comprised functional anatomy or physiology and the appreciation of organ activity
enabled the subsequent delineation of malfunction during disease. Regardless of
the level of sophistication that could be brought to bear upon the disease a
requisite for most successful technical intervention was the management of pain
and the prevention of sepsis. As the quincunx of surgery embraces a new century
it must continue to evolve to maintain the balance of growth in the four
supporting columns. Thus anatomy has been expanded into subcellular structure and
the elucidation of function has amplified into the role of individual organelles.
Similarly pathology has moved beyond the organ and cell into the genome and
deletion may be conceived of in terms of codons and sequences rather than colons
and spleens. Indeed it is feasible that antisense strategies may become more
sensible than antibiotics. Manual and digital techniques will be supplanted by
robotic intervention and visualization will move beyond the visible into the non
visible world of spectroscopy. Millimetric dexterity will need to become
nanometric and the mantra must become molecular and intervention directed not
only at adults or neonates but the fetus. In order to achieve such goals teaching
and training strategies need dramatic revision to produce individuals capable of
transforming from tactile to telemetric skills and from gentle technique to
genomic intervention.
PMID- 10773987
TI - [Development of surgery in the 20th century].
AB - The 100-year history of the Japan Surgical Society (JSS) spanned the 20th
century. The first congress of the JSS was held in 1899 in Tokyo. In Japan, many
specialist surgery societies and several closely related to surgery were
established in the latter half of the 20th century although both the Japanese
Association for Thoracic Surgery and the Japan Neurosurgical Society were founded
before that in 1948. Significant advances in the field of surgery were witnessed
in the second half of the 20th century in Japan as well as in other countries.
The progress in biotechnology and medical engineering in the latter half of the
20th century and the beginning of the 21st will result in remarkable change in
the field of surgery in the future. Significant changes in postgraduate and
continuing education and training of surgeons will also be necessary to ensure
that surgeons and surgical researchers adhere strictly to bioethical standards.
PMID- 10773988
TI - Reflections on tissue engineering and trauma therapy.
AB - Although all of Trauma Care has remarkably improved during the latter half of the
last century the treatment of burn injury has substantially out paced other areas
and serves as an excellent example illustrating the improvements taking place in
the treatment of injured patients. Although Trauma treatment lagged behind the
rest of medicine in mid-century today it rests solidly on the cutting edge of
advancing therapeutic knowledge and practice in areas of metabolism, immunology,
infection control, critical care, tissue engineering and the delivery of clinical
care. It is important to understand what has happened to allow the treatment of
injury to be so effective. The bench mark therapeutic moves that have had major
effects allowing the present highly effective treatment are: immediate tailored
fluid resuscitation, preventive (prophylactic) and topical antibiotics,
metabolically designed nutritional therapy and most important early definitive
repair of the injury. All must be delivered early after trauma if they are to be
optimally effective in preventing the complications of injury that are
devastating if encountered. Unfortunately, all problems are not solved by todays
treatment of injury, improved as it is. These problems are largely related to an
inexact understanding: of the physiologic changes of aging, of the exact
pathophysiologic events in inhalation injury and multisystem organ failure and of
the technology required to replace those body parts damaged by the injury itself
that lead to death or to healing with loss of function. There will be major
improvements in the understanding and ability to effectively deal with the
problems of aging and inhalation injury through basic and clinical research but
perhaps the major improvement in injury treatment will come through the ability
to replace worn out, defective or damaged body parts through technologies that
resemble regeneration. Here the concepts of Tissue Engineering have much to
contribute and it is worth exploring the donation of Tissue Engineering to dermal
replacement following burn injury to serve as an example of what types of
additions to treatment Tissue Engineering can make.
PMID- 10773989
TI - The historical impact of minimally invasive surgery.
AB - At first there is an idea which asks for more comfort for the patient and equal
results compared to conventional procedures. This means less pain and fatigue,
quicker convalescence and shorter hospital stay. The new procedures requests an
entirely new operative skill and a new technique with new instruments. Those were
early developed in Germany. The roads on which this was performed will be
described. In another chapter the history of this development is shown,
especially the German, French and US inventors with a special view on their
personal experiences and disappointments like in the German surgeon M_he and the
gynecologist Semm from Kiel, Germany. But they all remained enthusiastic as a
common personal quality. The new technique (MIC) was translated "Mickey-Mouse
Surgery" and medicolegal consequences like in M_he were usual events. Another
example of misunderstanding of the impact of the new technique: the first
publication of Semm about the laoaroscopically removed appendix has been withheld
so long in Germany until it was published in the USA in the Journal "Obstetrics
and Gynecology". Besides this it is reported about the life cycle of this
innovation pointing out to the final promising report, the professional adoption
and public acceptance and the randomized controlled trials. The last stage is
characterized by "jumping on another train". Pictures are shown of those pioneers
who had the idea, who understood what they were doing and who took the
responsibility. The final chapter will deal with the consequences for the future
generation of surgeons and their training and the unanswered questions as to
further fields. Doubtlessly, the pioneer period did not come to an end yet. A
glance into the future may be allowed.
PMID- 10773990
TI - Transplantation in the 21st century.
AB - Remarkable results have been achieved in the field of organ transplantation over
the past 40 years, perhaps inconceivable in the pioneering days of the 1950's.
Factors which have contributed to these results include better immuno
suppression, matching for HLA, better preservation, and resolution of most of the
technical problems associated with organ transplantation. Nevertheless, major
problems still remain to be resolved. Chronic rejection leads to a steady
attrition of all solid organ grafts. In addition, the penalty of our more potent
immunosuppression is becoming evident with the ever-increasing incidence of
cardiovascular disease and malignancy in long-surviving patients. These problems
would be solved by the achievement of tolerance to an organ graft. However, there
will never be sufficient human organs or tissues to meet the demand, which has
led to a revival of interest in xenotransplantation, but enormous immunological
and infectious problems have still to be resolved. New immunosuppressive agents,
both drugs and biological agents, are being evaluated continually in the
laboratory and some are going on to clinical trials. The explosion in molecular
biology is allowing new approaches, such as genetic engineering, to be taken in
the achievement of tolerance as well as solving some of the problems of
xenotransplantation. Cloning of tissues and perhaps even organs may become
possible in the future. Undoubtedly transplantation will look very different in
twenty years' time as we enter the "Dawn of the New Millennium".
PMID- 10773991
TI - The importance of molecular biology to cancer surgery.
AB - Over the last two decades there have been striking advances in molecular biology,
which now have, and will continue to have, great impact on the diagnosis and
treatment of patients with either benign or malignant diseases. The translation
of these new findings from the laboratory to the clinic has just begun and
promises to revolutionize the care of patients with certain neoplastic diseases.
The most significant advances relate to molecular genetics, particularly the
identification of inherited germline mutations that can be identified in kindred
members by direct DNA testing. The surgical oncologist is in a pivotal position
to define prophylactic interventional strategies for patients who are destined to
develop certain solid tumor malignancies. The most immediate opportunities will
be in the patients with hereditary disorders, such as breast cancer, large bowel
cancer, and the endocrine neoplasia syndromes.
PMID- 10773992
TI - Therapy which enhances surgical recovery: the potential for multimodality, fast
track surgery in the 21st century.
AB - Hospital stay will be greatly reduced following major operations in the years to
come. Already, minimally invasive procedures, selected anesthetic techniques and
the use of appropriate pharmaceutical agents have reduced postoperative
hospitalization. However, surgeons and their anesthesiology colleagues have
combined many of these therapies in a multimodality approach, which has greatly
shortened surgical convalescence following major surgery. The literature reports
that patients can be discharged following recovery in 48 hours following a
partial colectomy, in 1-2 days following pneumonectomy and in 4-5 days following
knee or hip replacement operations. This multimodality approach appears to
greatly reduce postoperative stress. Postoperative hospitalization will continue
to be reduced throughout the coming century.
PMID- 10773993
TI - [Development of endoscopic surgery in the 21st century].
AB - After its introduction by Dr. K. Semm in the 1970s and subsequent refinement of
laparoscopic cholecystectomy by Dr. Erich Muhe 1985, endoscopic surgery is now
commonly performed in clinical practice. Although some institutions have still
not embraced these techniques, surgery has been transformed, not only technically
but also conceptually, by endoscopic procedures. Less invasive surgery results in
a better quality of life for patients. The theme of this centennial anniversary
meeting of the Japanese Surgical Society comes from the words of Keio University
founder Yukichi Fukuzawa: "Act now for the future." At this meeting, robotic
surgery and telesurgery techniques will be presented, and attendees will be
updated on the latest developments in the field, including three-dimensional
monitoring, telecommunications, robotics, and other new forms of instrumentation
and technology.
PMID- 10773994
TI - [Multimedia (visual collaboration) brings true nature of human life].
AB - Videoconferencing system, high-quality visual collaboration, is bringing
Multimedia into a society. Multimedia, high quality media such as TV broadcast,
looks expensive because it requires broadband network with 100-200 Mpbs bandwidth
or 3,700 analog telephone lines. However, thanks to the existing digital-line
called N-ISDN (Narrow Integrated Service Digital Network) and PictureTel's
audio/video compression technologies, it becomes far less expensive. N-ISDN
provides 128 Kbps bandwidth, over twice wider than analog line. PictureTel's
technology instantly compress audio/video signal into 1/1,000 in size. This
means, with ISDN and PictureTel technology. Multimedia is materialized over even
single ISDN line. This will allow doctor to remotely meet face-to-face with a
medical specialist or patients to interview, conduct physical examinations,
review records, and prescribe treatments. Bonding multiple ISDN lines will
further improve video quality that enables remote surgery. Surgeon can perform an
operation on internal organ by projecting motion video from Endoscope's CCD
camera to large display monitor. Also, PictureTel provides advanced technologies
of eliminating background noise generated by surgical knives or scalpels during
surgery. This will allow sound of the breath or heartbeat be clearly transmitted
to the remote site. Thus, Multimedia eliminates the barrier of distance, enabling
people to be just at home, to be anywhere in the world, to undergo up-to-date
medical treatment by expertise. This will reduce medical cost and allow people to
live in the suburbs, in less pollution, closer to the nature. People will foster
more open and collaborative environment by participating in local activities.
Such community-oriented life-style will atone for mass consumption, materialistic
economy in the past, then bring true happiness and welfare into our life after
all.
PMID- 10773995
TI - [Surgery using master-slave manipulators and telementoring].
AB - Master-slave manipulators enhance surgeons' dexterity and improve the precision
of surgical techniques by filtering out surgeons' tremors and scaling the
movements of surgical instruments. Among clinically available master-slave
manipulators, the epoch-making system called "da Vinci" developed by Intuitive
Surgical Inc. (Mountain View, CA, USA), equipped with 2 articulated joints at the
tip of the surgical instruments allowing 7 degrees of freedom, mimics the
movements of surgeons' wrists and fingers in the abdominal or thoracic cavity.
Today advanced telecommunications technology provides us excellent motion images
using only 3-ISDN telephone lines. Experienced surgeons at primary surgical sites
have been able to perform complex procedures successfully by consulting
specialists at remote sites. Because telecommunications costs have become lower
each year, telementoring will be come a routine surgical practice in the near
future. The usefulness of surgical telementoring has been greatly enhanced by the
development of a technique to illustrate on video images from two directions.
Moreover, remote advisory surgeons will be able to provide the optimal operative
field to operating surgeons using robotic camera holders with voice-recognition
systems. In the near future, when master-slave manipulators will also be coupled
with telementoring systems, remote experts could actually perform complex
surgical procedures.
PMID- 10773996
TI - [A note form chair person: International Symposium on transplantation].
AB - Orthotopic liver transplantation is now a widely accepted surgical modality for
end-stage liver disease, although the shortage of grafts has remained a serious
medical and social problem. This has led to the development of new approaches
such as split liver transplantation and living related-donor liver
transplantation, which have not completely resolved the problem. It is expected
that future techniques will rely on better and less toxic agents for preventing
rejection, xenotransplantation, and "organ engineering" methods based on tissue
engineering techniques. More research is required before xenotransplantation is
established clinically due to the current lack of knowledge of physiology,
immunology, and infection risks. The mechanism of hyperacute rejection has been
the subject of intensive investigation and is gradually being clarified. However,
the detailed mechanisms of delayed xengraft rejection and cell-mediated immune
response are still poorly understood. Improvement of cell culture conditions in
tissue engineering may permit the generation of human organs as substitutes for
grafts in the transplantation setting.
PMID- 10773997
TI - Prope tolerance with induction using Campath 1H and low-dose cyclosporin
monotherapy in 31 cadaveric renal allograft recipients.
AB - The last 40 years has been a period of remarkable evolution of organ
transplantation from nothing to a well-established form of treatment with good
short-term and tolerable long-term results. Nevertheless by ten years
approximately 50% of grafts will have been lost due, mainly, to chronic rejection
or the side-effects of immunosuppressive therapy. We now have a number of
extremely powerful immunosuppressive drugs and antibodies with different
mechanisms of action and the stage is set for a move from current continuous high
dose immunosuppressive maintenance therapy to low dose or no maintenance
immunosuppression. True tolerance can occur in man, examples being successful
bone marrow transplantation and patients with liver grafts who have stopped
immunosuppression after years of good function. The antibody Campath 1H with a
unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate
lymphocytes from the blood for a month in patients with renal allografts who have
then been maintained on half dose Cyclosporin without any other maintenance drug.
The results with a mean two year follow-up have been encouraging, 29 patients
having good function without receiving maintenance steroids. It is likely that
this protocol could be improved since dosage timing and various minimal
maintenance immunosuppressive protocols have not been fully investigated. This
almost or "Prope" tolerance could be a major step forward providing a better
quality of life for patients and inexpensive maintenance immunosuppression.
PMID- 10773998
TI - [Sentinel node concept and its application for cancer surgery].
AB - The sentinel node is the first lymph node that drains a primary tumor. A negative
sentinel lymph node accurately predicts the absence of metastasis to any other
regional lymph nodes. A higher rate of feasibility, sensitivity, specificity, and
diagnostic accuracy in sentinel lymph node mapping has been demonstrated of
cancer of the breast, penis, and vulva and in malignant melanoma. Intraoperative
endoscopic lymphatic mapping, which we developed for gastric cancer in 1994, was
also useful in accurately predicting nodal status in 163 early-stage gastric
cancer patients: the rate of sensitivity, specificity, and accuracy was 91%,
100%, and 98%, respectively. Therefore if the sentinel lymph node biopsy is free
of metastasis, limited surgery such as wedge resection, segmental resection,
pylorus-preserving gastrectomy, or proximal gastrectomy is indicated. The tumor
free sentinel lymph node allows dissection of regional lymph nodes to be avoided
and results in an improved quality of life in postoperative patients. In
addition, sentinel lymph node biopsy has the advantages of enhancing staging
accuracy, detecting micrometastases, and identifying variations in the regional
lymphatic basin. Further progress may change the mode of nodal dissection and the
indications for adjuvant chemotherapy for cancer.
PMID- 10773999
TI - [Sentinel node navigation surgery in breast cancer].
AB - Sentinel node navigation surgery (SNNS) is a promising surgical technique to
avoid unnecessary axillary lymph node dissection (ALND) in breast cancer. There
are various choices regarding the site of injection of the vital blue dye or
radiopharmaceuticals, the dose of radioactivity used, the interval between dye
injection or lymphoscintiscan and SNNS, and various surgical procedures for SNNS
in breast cancer. However, many investigators have reported that SNNS is feasible
and reliable in histologically sentinel node-negative breast cancer. In our
hospital, SNNS with indigocarmine began in January 1998. After a feasibility
study of SNNS in 200 cases of early breast cancer, practical SNNS is being
performed using indigocarmine and double-tracer technetium-99m-human serum
albumin and technetium-99m-tin colloid. As of January 2000, the identification
rate of sentinel lymph nodes was 97% and ALND was omitted in 57 (63%) of 90 cases
examined. Clinical outcome, arm morbidity, and cost benefits should be evaluated
in a randomized trial comparing SNNS to ALND. Nevertheless, SNNS in breast cancer
will be necessary for surgical oncologists in the near future.
PMID- 10774000
TI - [The validity of the sentinel node concept in gastrointestinal cancers].
AB - Although the sentinel node concept has been validated and clinically applied to
breast cancer and malignant melanoma, its clinical significance in other solid
tumors has not been thoroughly investigated. With regard to gastrointestinal (GI)
cancers in particular, our surgeons have been cautious because of the high
frequency of skip metastasis and the complicated lymphatic system in the GI
tract. We would like to emphasize that so-called skip metastasis has been defined
according to anatomic classification of regional lymph nodes and that the
lymphatic drainage route must be patient or lesion specific. To test the validity
and feasibility of this concept in GI cancers, we have established a radio-guided
intraoperative sentinel node navigation system using preoperative endoscopic
submucosal injection of radioactive tracer followed by intra-operative gamma
probing. In 131 patients with GI cancers (esophagus: 22, stomach: 71, colorectum:
38), the detection rate of sentinel nades was 91% and overall diagnostic accuracy
of lymph node metastasis by sentinel node status was 97%. Initial results suggest
further investigation of this procedure as an accurate staging and a minimally
invasive approach to early GI cancers.
PMID- 10774001
TI - Exaggerated pulmonary hypertension is not sufficient to trigger high-altitude
pulmonary oedema in humans.
AB - High altitude pulmonary oedema (HAPE) is a paradigm of pulmonary oedema that
occurs in otherwise healthy subjects and thereby allows us to study underlying
mechanisms in the absence of damning factors. Exaggerated pulmonary hypertension,
which is related at least in part to endothelial dysfunction, is a hallmark of
high-altitude pulmonary oedema. It is thought to play an important part in the
pathogenesis of HAPE, but the predisposing factors are not clear. In rats,
transient exposure to hypoxia during the first few days of life predisposes to
exaggerated hypoxic pulmonary vasoconstriction in adulthood. We hypothesised that
a similar mechanism may operate in humans, and if so may predispose to high
altitude pulmonary oedema. To test this hypothesis we studied the effects of high
altitude exposure (4559 m) on pulmonary-artery pressure and incidence of
pulmonary oedema in 10 healthy young adults who had suffered from transient
hypoxic pulmonary hypertension during perinatal period, and compared these
effects with those observed in 10 controls of similar age and sex distribution,
and in 14 HAPE-prone mountaineers. We found that at high altitude, the subjects
who had suffered from transient perinatal hypoxic pulmonary hypertension had
exaggerated pulmonary hypertension compared to controls (62 +/- 7 vs 50 +/- 11 mm
Hg, p < 0.01). Despite exaggerated pulmonary vasoconstriction of similar
magnitude to that observed in HAPE-prone subjects (59 +/- 10 mm Hg), none of the
young adults developed HAPE. In contrast, 8 of the 14 HAPE-prone subjects had
radiographic evidence of lung oedema (p < 0.001 for the comparison with the other
2 groups). These data challenge previous concepts and indicate that exaggerated
hypoxic pulmonary vasoconstriction, while consistently associated with HAPE, is
not sufficient to trigger pulmonary oedema. This suggests that additional
mechanisms play a role.
PMID- 10774002
TI - Predictive characteristics of users of alternative medicine.
AB - BACKGROUND: The use of alternative medicine has become an important factor in
health care delivery. OBJECTIVES: To evaluate patient characteristics, morbidity,
functional status, quality of life, satisfaction with care, practice
characteristics and health care utilisation in general practice patients using
alternative medicine. DESIGN: Cross-sectional survey of GP patients completing a
self-administered questionnaire. SETTING: A stratified sample of 36 GP offices in
Slovenia. MAIN OUTPUT DATA: Patient's age, sex, educational status, residence,
presence of chronic condition, incidence of anxiety or depressive symptoms,
incidence of patient-expressed need for emergency care in one year, data on self
care, data on functional status, quality of life, satisfaction with care,
incidence of use of out-of-hours services and specialist or hospital services in
users versus non-users. RESULTS: 115/1753 patients (6.6%) reported visits to
alternative practitioners in 1997. Users of alternative medicine were from
midlife age groups, were more likely to have a chronic condition, had a lower
perception of life quality and a higher incidence of anxiety and depressive
symptoms, and had had more need for emergency treatment. They are heavier users
of primary as well as secondary care services; they have changed their GP
recently but are not significantly dissatisfied with their current regular GP.
CONCLUSIONS: Use of alternative medicine appears to be characteristic of patients
with a more active approach to managing their problems. GPs should enquire about
the use of alternative medicine by their patients, especially those more likely
to seek such help. Raising the question of alternative medicine will improve
doctor-patient communication and help to resolve underlying health problems.
PMID- 10774003
TI - Unusual association: Streptococcus bovis tricuspid endocarditis with atrial
septal aneurysm and patent foramen ovale.
AB - Streptococcus bovis endocarditis is a frequent cause of streptococcal
endocarditis and is associated with colonic tumours. The tricuspid valve is very
rarely affected and its involvement is a complication which can lead to a less
favourable outcome. We report the seventh case of tricuspid valve endocarditis
due to S. bovis, and the first, to our knowledge, to be associated with an atrial
septal aneurysm and a patent foramen ovale. The underlying medical conditions and
predisposing factors for development of tricuspid valve endocarditis are
described and interesting new echocardiographic data are presented. The current
guidelines on antibiotic therapy for S. bovis tricuspid valve endocarditis are
reviewed.
PMID- 10774004
TI - [Kidney function and kidney diseases in the elderly].
AB - The significance of age-induced alterations in renal function is described in
order to explain clinically important entities in older people, such as hypo- and
hypervolaemia, hyper- and hyponatraemia, hyperkalaemia and metabolic acidosis. A
sound knowledge of the age-dependent changes in renal function enables the
physician to effectively prevent many of these metabolic disturbances.
Renovascular disease, nephrotic syndrome, renal cysts and acute renal failure are
renal diseases which typically have a higher incidence in older people and
require special consideration when evaluating renal disease in the elderly.
PMID- 10774005
TI - [Varicella pneumonia].
PMID- 10774006
TI - [Reference: Egger M. Under the metascope: possibilities and limits of met
analyses. Schweiz Med Wochenschr 1998;128:1893-901].
PMID- 10774007
TI - Three- to six-carbon ring-enlargement reaction of cyclic ortho esters bearing a
diazocarbonyl side chain. Use of the intramolecular formation of tricyclooxonium
ylides
AB - Two types of bicyclic ortho esters 14 and 18, which are tethered to a
diazocarbonyl group by polymethylene linkages--(CH2)n--of different lengths (n =
1-3 for 14 and 1-4 for 18), were prepared and catalytically decomposed by
treatment with Rh2(OAc)4 either in the presence or absence of a protic
nucleophile (MeOH, PhOH, AcOH) to give ring-enlargement product lactones 25 and
30 of different sizes. With 14, the enlargement took place when n = 1 or 2, but
not when n = 3. With 18, in which the diazo carbon is substituted with a
methoxycarbonyl group, the length of the chain can be extended further to n = 4
to obtain ring-enlargement products or their derivatives. All of these reactions
could be explained in terms of the intermediacy of tricyclooxonium ylides 22 and
28. The ylides form an equilibrium with the corresponding ring-opened zwitterions
22' and 28', respectively, which, after protonation by a protic nucleophile,
undergo mainly ring-enlargement to form medium-sized or large oxalactones rather
than 1,2-rearrangement.
PMID- 10774009
TI - Chemoselective C-H oxidation of alcohols to carbonyl compounds with iodosobenzene
catalyzed by (salen)chromium complex
AB - Primary and secondary alcohols with benzylically and allylically activated C-H
bonds are chemoselectively oxidized to the corresponding carbonyl compounds by
the (salen)Cr(III) complex I as the catalyst and iodosobenzene as the oxygen
source; the oxidizing species is the Cr(V) oxo complex. Allylic alcohols with
fully substituted double bonds give appreciable amounts of epoxides besides the C
H oxidation products enones, while saturated alcohols are less readily oxidized.
PMID- 10774008
TI - Troger's base molecular scaffolds in dicarboxylic acid recognition.
AB - Artificial receptors (1-5) have been designed and synthesized from simple
precursors. The chain length selectivity studies of dicarboxylic acids within the
cavities of new fluorescent Troger's base molecular frameworks (1-3) have been
carried out with a critical examination of their role of rigidity as well as
flexibility in selective binding in comparison to receptor 5. The chiral
resolution of the racemic Troger's base receptors (1 and 2) by chiral recognition
with (+)- camphoric acid using hydrogen-bonding interactions has been studied.
PMID- 10774010
TI - Further studies on the synthesis of 24(S),25-epoxycholesterol. A new, efficient
preparation of desmosterol.
AB - Efforts to improve the synthesis of 24(S),25-epoxycholesterol (1) from
stigmasterol (3) have included identification of 6 alpha-hydroxy-i-steroid 11 as
a byproduct from the ozonolysis of 9 and an attempt to effect conversion of
sulfone 14 to diol 18 via Payne rearrangement and nucleophilic trapping of
epoxide 25, which led instead to 27 and 28 (97% yield). A more efficient
synthesis of 1 was achieved via coupling of cuprate 21 with allylic acetate 31 to
give 73% of 16, in the most efficient conversion yet of a C22 intermediate to
desmosterol (5) or its acetate 6.
PMID- 10774011
TI - Switching of pseudorotaxanes and catenanes incorporating a tetrathiafulvalene
unit by redox and chemical inputs
AB - An acyclic polyether 1a, incorporating a central tetrathiafulvalene (TTF)
electron donor unit and two 4-tert-butylphenoxy groups at its termini, has been
synthesized. Two macrocyclic polyethers containing two different electron donors,
namely a TTF unit with, in one case, a 1,4-dioxybenzene ring (2a), and, in the
other case (2b), a 1,5-dioxynaphthalene ring system, have also been synthesized.
These two macrocyclic polyethers have been mechanically interlocked in
kinetically controlled template-directed syntheses with cyclobis(paraquat-p
phenylene) cyclophane (3(4+)) to afford the [2]catenanes 2a/3(4+) and 2b/3(4+),
respectively. X-ray crystallography reveals that the [2]-catenane 2b/3(4+) has
the TTF unit of 2b located inside the cavity of 3(4+). The spectroscopic (UV/vis
and 1H NMR) and electrochemical properties of compounds 1a, 2a, 2b, 2a/3(4+), and
2b/3(4+) and of the [2]pseudorotaxane 1a.3(4+) were investigated. The absorption
and emission properties of the mono- and dioxidized forms of the TTF unit in
these various species have also been studied. The results obtained in
acetonitrile solution can be summarized as follows. (a) While TTF2+ exhibits a
strong fluorescence, no emission can be observed for the TTF2+ units contained in
the polyethers and in their pseudorotaxanes and catenanes. (b) A donor-acceptor
absorption band is observed upon two-electron oxidation of the TTF unit in the
macrocyclic polyethers 2a and 2b. (c) The spontaneous self-assembly of 1a and
3(4+) to give the [2]pseudorotaxane 1a.3(4+) is strongly favored (Kass. = 5 x
10(5) L mol-1) but slow (at 296 K, k = 11.3 L mol-1 s-1 and delta G++ = 15.9 kcal
mol-1) because of the steric hindrance associated with the bulky end groups of
1a. (d) In the pseudorotaxane 1a.3(4+), the reversible displacement of the
cyclophane from the TTF unit in the threadlike substrate occurs on
oxidation/reduction of its electroactive components. (e) Switching between the
two translational isomers of the catenanes 2a/3(4+) and 2b/3(4+) occurs by cyclic
oxidation and reduction of the TTF unit contained in 2a and in 2b, respectively.
(f) Addition of o-chloroanil to the pseudorotaxane 1a.3(4+) and to the catenanes
2a/3(4+) and 2b/3(4+) causes the displacement of the TTF unit from the cavity of
the cyclophane 3(4+) because of the formation of an adduct between the TTF unit
and o-chloroanil.
PMID- 10774012
TI - Molecular shuttles by the protecting group approach
AB - Two new [2]rotaxane-based molecular shuttles, in which a mechanically bound
dibenzo[24]crown-8 (DB24C8) macroring shunts back and forth between two
dialkylammonium recognition sites situated on a chemical dumbbell, have been
constructed by a novel synthetic strategy that relies upon the use of the tert
butoxycarbonyl (Boc) protecting group. During the syntheses of both molecular
shuttles, this protecting group masks a dialkylammonium recognition center which
is liberated only after the [2]rotaxane constitution is established. In both
cases, the molecular shuttles' other dialkylammonium center is essential for the
rotaxane-forming reactions and it ensures that DB24C8 is interpenetrated by
threadlike precursors, as a result of noncovalent bonding interactions, to
produce [2]pseudorotaxanes which are stoppered subsequently through 1,3-dipolar
cycloadditions between azides and bulky acetylenedicarboxylates. The new
molecular shuttles have been examined by means of dynamic 1H NMR spectroscopy,
which reveals that the movements of the DB24C8 macroring are very highly
dependent both on solvent properties and on the nature of the spacer unit linking
the two dialkylammonium centers. Thus, DB24C8 shunts facilely between the
dialkylammonium centers when the shuttles are dissolved in solvents that readily
donate their nonbonding electrons into noncovalent bonds, e.g., DMF, and when
spacer units that do not offer much steric resistance to shuttling, e.g.,
hexamethylene, are used. On the other hand, shuttling is difficult in solvents
that are less inclined to donate their electrons into noncovalent bonds, e.g.,
(CDCl2)2, and when relatively bulky benzenoid spacer units, e.g., p-xylylene,
link the two dialkylammonium centers. It has been proposed that the DB24C8 might
act as a "ferry" which carries a proton between dialkylammonium and dialkylamine
moieties in a singly protonated [2]rotaxane by means of ion-dipole interactions.
PMID- 10774013
TI - The electrochemically-driven decomplexation/recomplexation of inclusion adducts
of ferrocene derivatives with an electron-accepting receptor
AB - The tetracationic cyclophane, cyclobis(paraquat-4,4'-biphenylene), binds 1,1'
disubstituted ferrocene-based polyethers as a result of (i) [pi...pi] stacking
between the pi-electron-deficient bipyridinium units and the pi-electron-rich
cyclopentadienyl rings and (ii) [C-H...O] hydrogen bonds between the alpha
bipyridinium hydrogen atoms and the polyether oxygen atoms. However, even the
presence of a bulky tetraarylmethane group--which is too large to thread through
the cavity of the cyclophane host--at the end of each of the two polyether
substituents of the ferrocene-containing guest does not discourage adduct
formation of the inclusion type. Thus, in these adducts, the ferrocene unit of
the guest is located inside the cavity of the host with its two polyether chains
protruding outward from the same side of the host. The alternative pseudorotaxane
geometry is not observed in solutions of these 1:1 adducts. The host-guest
adducts display absorption bands in the visible spectral region, characteristic
of charge-transfer interactions. In the case of one of these adducts, reversible
decomplexation/recomplexation takes place upon electrochemical
oxidation/reduction of the ferrocene-based unit or upon reduction/oxidation of
the tetracationic cyclophane.
PMID- 10774014
TI - Utility of the tandem Pauson-Khand reaction in the construction of tetracycles
AB - The scope of the tandem Pauson-Khand reaction has been explored for the
regiospecific construction of [5.5.5.5]- and [5.6.6.5]tetracyclic systems via the
photolytic method of Livinghouse. The rapid regiospecific entry into the two
dicyclopentapentanoid systems 17 and 29 was accomplished from the key diene
diynes 11 and 19b. A photochemically mediated catalytic tandem Pauson-Khand
cyclization was employed to prepare the parent ring systems of
dicyclopenta[a,e]pentalene (from 19b) and dicyclopenta[a,f]pentalene (from 11) in
regiospecific fashion in a one-pot process. Under these conditions, conversion of
acyclic diene-diyne 16 into tetracyclic system 17 was achieved in 74% yield,
while a similar process was employed to convert 28 into tetracycle 29 in 90%
yield. This is much improved over the previous conditions that employed NMO. Six
carbon-carbon bonds were generated in this process constituting up to 98% yield
for each carbon-carbon bond so formed. Furthermore, tetracyclic [5.6.6.5] systems
such as dicyclopenta[b,g]decalins 37, 38, and 40 were prepared from similar diene
diyne precursors via the tandem Pauson-Khand cyclization. Importantly, acetal 36
provided the desired cis-fused [5.6.6.5] system 38a (via 40a/b) in stereospecific
fashion. This reaction is unique in that it provides a cis-decalin ring system;
moreover, the yield of each of the six carbon-carbon bonds formed in this process
was at least 89%. The structure of cis diol 38a was confirmed by X-ray
crystallography.
PMID- 10774015
TI - Photoreactivity of 2-pyridones with furan, benzene, and naphthalene. Inter- and
intramolecular photocycloadditions.
AB - Pyridones, well-known for their ability to photodimerize, have been found to
undergo [4 + 4] photocycloaddition with furan and naphthalene but not with
benzene. In some cases these reactions can be highly regio- and stereospecific.
Intramolecular reaction with furan produces both cis and trans [4 + 4] products.
The cycloaddition with naphthalene can occur both inter- and intramolecularly.
The intermolecular reaction yields primarily the cis isomer, whereas the trans
isomer is the major product from the intramolecular reaction. A mixture of 4
methoxy-2-pyridone and 2-methoxynaphthalene that could form up to eight regio-
and stereoisomers forms largely one [4 + 4] product.
PMID- 10774016
TI - Efficient charge separation in C60-based dyads: triazolino
AB - Triazoline[4,5][60]fullerenes are strong electron acceptors that form with
tetrathiafulvalene (TTF), a novel type of donor-acceptor dyad exhibiting
efficient improved electron-transfer dynamics. In particular, a rapid
photoinduced intramolecular electron transfer, forming a charge-separated state,
is followed by a slow charge recombination to generate the fullerene triplet
excited state in moderate quantum yields.
PMID- 10774018
TI - Regioselective chlorocarbonylation of polybenzyl cores and functionalization
using dendritic and organometallic nucleophiles
AB - Regiospecific chlorocarbonylation of the polybenzyl cores PhCH2CH2Ph,
C6(CH2CH2Ph)6, 7, and CH(CH2Ph)24-1,2,4,5-C6H2, 8, in the para position of the
benzyl groups gives the chlorocarbonyl derivatives 2, 9, and 10, respectively, in
good yields. The octachlorocarbonyl derivative 10 reacts with Newkome's
aminotripod NH2C(CH2OCH2CH2CN)3 to give the 24-nitrile dendrimer 13 which is
characterized by its molecular peak in the MALDI TOF mass spectrum and with (5
aminopentyl)-1-ferrocene to give the octaferrocene complex 14. Reactions of 2, 9,
and 10 with sodium methanolate in methanol gives the methyl esters 3, 15, and 16
which are reduced by LiAlH4 to the primary alcohols 4, 17, and 18; reactions of
these alcohols with NaI and BF3.Et2O yield the iodomethyl derivatives 5, 19, and
20. The organoiron nucleophile [FeIICp(eta 5-C6Me5CH2)], 1, reacts with 5, 19,
and 20 leading to C-C bond formation and recovery of the aromatic structure of
the ligand. This reaction with 5 yields a soluble complex, [FeIICp(eta 6
C6Me5CH2CH2C6H4CH2-)]2, 6, in which the two redox groups, separated by 14 carbon
atoms, are independent, being reversibly reduced at approximately the same
potential in an overall two-electron wave recorded by cyclic voltammetry. The
analogous reaction with 19 and 20, however, gave almost insoluble hexa- and octa
iron complexes 21 and 22 with mediocre purities.
PMID- 10774017
TI - Conjugate additions of 1-propenylphosphonates to metalated Schollkopf's bis
lactim ether: stereocontrolled access to 2-amino-3-methyl-4-phosphonobutanoic
acids.
AB - Diastereoselectivity in the conjugate addition of metalated Schollkopf's bis
lactim ethers 5a-e to (E)- and (Z)-1-propenylphosphonates 4a,b was studied
experimentally and theoretically and utilized to achieve a direct and
stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl-4
phosphonobutanoic acid, 6a,b and their enantiomers. The relative stereochemistry
was assigned from an NMR study of cyclic derivatives 13a,b. According to
semiempirical calculations, both in vacuo (PM3) or a dielectric continuum
(PM3/COSMO), initial lithium-phosphoryl coordination, without an energy barrier,
to form a solvated chelate complex is followed by the rate-determining
reorganization to the 1,4-addition product through an eight-membered transition
state. The translation of the Z,E geometry into a syn, anti configuration at the
adducts originates from an orientational preference in the transition state for a
compact disposition of the reaction partners.
PMID- 10774019
TI - Synthesis of 3-trifluoroethylfurans by palladium-catalyzed cyclization
isomerization of (Z)-2-alkynyl-3-trifluoromethyl allylic alcohols
AB - Hydroiodonation of trifluoromethyl propargylic alcohols 1 regio- and
stereoselectively produce (Z)-2-iodo-3-trifluoromethyl allylic alcohols 2. (Z)-2
Alkynyl-3-trifluoromethyl allylic alcohols 5, available through Pd(PPh3)4
mediated coupling of 2 and terminal alkynes 4, cyclize and subsequently isomerize
to 3-trifluoroethylfurans 6 upon catalysis under PdCl2(CH3CN)2 in THF at 5-10
degrees C.
PMID- 10774021
TI - Solvation and structural effects on the stability of 10-X-2 ate-complexes: a
computational study.
AB - The structures and energies of a variety of 10-X-2 ate-complexes derived from
reaction of alkyllithiums and aryllithiums with the corresponding organohalides
have been studied at the B3LYP/6-31+2G** theoretical level. The results of the
calculations, which are in good agreement with the available experimental data,
indicate that diaryl ate-complexes are more stable than their dialkyl
counterparts. Fluorine substitution was found to confer substantial stability to
both diaryl and dialkyl ate-complexes, and the calculations suggest that
perfluoro dialkyl 10-X-2 ate-complexes should be experimentally observable
species. One of the most important factors contributing to stability of a 10-X-2
ate-complex is removal of the formally cationic lithium from the vicinity of the
ate-anion via coordination with a Lewis basic solvent.
PMID- 10774022
TI - Trapping phosphodiester-quinone methide adducts through in situ lactonization.
AB - The goal of in situ modification of DNA via phosphodiester alkylation has led to
our design of quinone methide derivatives capable of alkylating dialkyl
phosphates. A series of catechol derivatives were investigated to trap the
phosphodiester-quinone methide alkylation adduct through in situ lactonization.
The catechol derivatives were uniquely capable of characterizable p-quinone
methide formation for mechanistic clarity. These investigations revealed that
with a highly reactive lactonization group (phenyl ester), lactonization competed
with quinone methide formation. Lactone-forming groups of lower reactivity
(methyl ester, n-propyl ester, and dimethyl amide) allowed quinone methide
formation followed by phosphodiester alkylation; however, they were ineffective
at in situ lactonization to drain the phosphodiester alkylation equilibrium to
the desired phosphotriester product. The derivatives tethered with lactone
forming functionality of intermediate reactivity (chloro-, trichloro-, and
trifluoroethyl esters), allowed quinone methide formation, phosphodiester
alkylation, and in situ lactonization to efficiently afford the trapped
phosphotriester adduct.
PMID- 10774023
TI - Epoxidation of acyclic chiral allylic alcohols with peroxy acids: spiro or planar
butterfly transition structures? A computational DFT answer
AB - The mechanism of the epoxidation of two chiral allylic alcohols, i.e., 3-methyl-3
buten-2-ol and (Z)-3-penten-2-ol, with peroxyformic acid has been investigated by
locating 20 transition structures with the B3LYP/6-31G* method and by evaluating
their electronic energy also at the B3LYP/6-311+G**@B3LYP/6-31G* theory level.
Relative stability of TSs, as far as electronic energy is concerned, is basis set
dependent; moreover, it also depends on entropy and solvent effects. Free
enthalpies, calculated by using electronic energy at the higher theory level and
with inclusion of solvent effects, indicates that syn, exo TSs, where the
olefinic OH group hydrogen bonds the peroxy oxygens of the peroxy acid, outweigh
syn, endo TSs, where the peroxy acid carbonyl oxygen is involved in hydrogen
bonding. In the former TSs the peroxy acid moiety maintains its planar geometry
while in the latter ones a strong out-of-plane distortion of peroxy acid is
observed. This distortion makes it viable an unprecedented 1,2-H shift, as a
possible alternative to the 1,4-H shift, for the peroxy acid hydrogen. In fact,
for one syn, endo TS IRC analysis demonstrated that the 1,2-H shift mechanism is
actually operative. The geometry of all TSs substantially conforms to a spiro
(i.e., with the peroxy acid plane almost perpendicular to the C=C bond axis)
butterfly orientation of the reactants while no TS resembles, even loosely, the
planar butterfly structure. Theoretical threo/erythro epoxide ratios are in fair
accord with experimental data. Calculations indicate that threo epoxides derive
mostly from TSs in which the olefinic OH assumes an outside conformation while
erythro epoxides originate from TSs with the OH group in an inside position.
Computational findings do not support the qualitative TS models recently proposed
for these reactions.
PMID- 10774024
TI - 2,2',5,5'-tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene: a new, very
efficient, easily accessible, chiral biheteroaromatic ligand for homogeneous
stereoselective catalysis
AB - The four-step straightforward synthesis of enantiopure (+)- and (-)-2,2',5,5'
tetramethyl-4,4'-bis-(diphenylphoshino)-3,3'-bithiophene (tetraMe-BITIOP), a new
C2-symmetry chelating ligand for transition metals, is described, starting from
2,5-dimethylthiophene. The complexes of this electron-rich diphosphine with
Ru(II) and Rh(I) were used as catalysts in some homogeneous hydrogenation
reactions of prostereogenic carbonyl functions of alpha- and beta-ketoesters, of
prostereogenic carbon-carbon double bonds of substituted acrylic acids, and of N
acetylenamino acids. The enantiomeric excesses were found to be excellent in all
the experiments and comparable with the best results reported in the literature
for the same reactions, carried out under similar experimental conditions, with
the metal complexes of the most popular chiral diphosphine ligands as catalysts.
PMID- 10774025
TI - The utility of furan-, pyrrole-, and thiophene-based 2-silyloxy dienes as
demonstrated by modular synthesis of annonaceous acetogenin core units and their
pyrrolidine and thiolane analogues.
AB - We report a modular strategy for obtaining the core units of annonaceous
acetogenins and their nitrogen and sulfur analogues, which generates great
structural diversity. This synthesis is based on the application of a reiterative
vinylogous addition protocol involving a unique triad of silyloxy diene modules,
2-[(tert-butyldimethylsilyl)oxy]furan (TBSOF), N-(tert-butoxycarbonyl)-2-[(tert
butyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert
butyldimethylsilyl)oxy]thiophene (TBSOT) and suitable heteroatom-stabilized
carbenium ions. By combining TBSOF, TBSOP, and TBSOT nucleophilic synthons with
certain tetrahydrofuran, pyrrolidine, and thiolane acceptors, the construction of
varied, adjacently linked oligo-heterocyclic motifs related to the core segments
of the annonaceous acetogenins is assured. At first, the reliability of the
pivotal coupling maneuver was certified, by assembling a collection of 18 model
constructs, covering all oxygen, nitrogen, and sulfur heteroatom combinations
(i.e., compounds 7-9, 13-15, and 19-21). This uniformed protocol was then suited
to forge advanced bis-tetrahydrofuran, bis-pyrrolidine, and bis-thiolane
scaffolds encompassing the heterocyclic core portion of various binuclear
annonaceous acetogenins and relatives. The utility of this synthesis was
demonstrated by the preparation of a repertoire of eight isomeric bis
tetrahydrofuran units, 41-48, two bis-pyrrolidine units, 62 and 63, and four bis
thiolane units, 78-81.
PMID- 10774026
TI - P(MeNCH2CH2)3N: an efficient catalyst for the desilylation of tert
butyldimethylsilyl ethers
AB - tert-Butyldimethylsilyl (TBDMS) ethers of primary, secondary, and tertiary
alcohols and phenolic TBDMS ethers are desilylated to their corresponding
alcohols and phenols, respectively, in DMSO, at 80 degrees C, in 68-94% yield in
the presence of 0.2-0.4 equiv of P(MeNCH2CH2)3N. Using P(i-PrNCH2-CH2)3N as the
catalyst, 85-97% yields of desilylated alcohols were obtained from TBDMS ethers
of 1-octanol, 2-phenoxyethanol, and racemic alpha-phenyl ethanol. These are the
first examples of desilylations of silyl ethers catalyzed by nonionic bases. Both
catalysts were much less effective for the desilylation of tert
butyldiphenylsilyl (TBDPS) ethers (22-45% yield) under the same conditions as
used for TBDMS ethers. Possible pathways involving nucleophilic attack of the
anion of the solvent molecule (generated by the catalyst) at the Si-O bond of
silyl ether or a prior activation of the silyl ether by the catalyst via a P-Si
interaction followed by nucleophilic attack of the solvent anion are proposed on
the basis of 1H and 31P NMR experimental data.
PMID- 10774027
TI - First atropo-divergent total synthesis of the antimalarial korupensamines A and B
by the "lactone method".
AB - The stereoselective total synthesis of the antimalarial korupensamines A (1a) and
B (1b) by application of the "lactone method" is described. Key steps of this
first atropo-selective access to 5,8'-coupled naphthylisoquinoline alkaloids were
the regioselective intramolecular coupling of ester 8 to give the
configurationally labile lactone-bridged biaryl 9 and its atropisomer-selective
cleavage with a variety of chiral and achiral H-nucleophiles, yielding the
configurationally stable P-diol 10a or, optionally, the M-product 10b. From the
axially chiral phenylisoquinolines thus obtained atropo-diastereodivergently, the
authentic natural naphthylisoquinolines with the respective axial configurations,
korupensamines A (1a) and B (1b), were obtained by completion of the second
naphthalene ring, starting from the previous "bridgehead" C1 unit.
PMID- 10774028
TI - Hydrogen-bonding effects on the fluorescence versus electron-transfer-initiated
chemiluminescence spectra of the m-oxybenzoate ion derived from a bicyclic
dioxetane
AB - A comparative spectral study of the fluorescence of the m-oxybenzoate anion
versus the electron-transfer-initiated chemiluminescence (CIEEL) of the same
anion derived from the bicyclic dioxetanes in various solvents is reported. The
present study reveals that the fluorescence of this oxyanion is blue-shifted in
protic versus aprotic solvents, while the CIEEL-spectral maximum is independent
of the medium. The same phenomenon has been recently observed for the m
oxybenzoate ion derived from CIEEL-active spiroadamantyl dioxetanes. The reported
spectral differences between the fluorescence and chemiluminescence emissions
cannot be attributed to exciplex formation in the CIEEL process, but result from
the differences in hydrogen-bonding effects on the photo- and chemiexcited
oxyanion species. The observed solvatochromism is qualitatively rationalized in
terms of the semiempirical AM1 calculations.
PMID- 10774029
TI - Computational studies of inclusion phenomena and synthesis of a novel and
selective molecular receptor for 1,4-disubstituted benzenes and 4,4'
disubstituted biphenyls
AB - A new tetracationic molecular receptor has been synthesized and studied by
semiempirical molecular orbital theory. This novel macrocycle, 1(4+), derived
from pentacyclo[5.0.0.0.(2,6)0.(3,10)0(5,9)]undecane-8,11-dione (PCU-8,11-dione),
structurally resembles cyclobis(paraquat-p-phenylene), 2(4+), in which a xylyl
group has been replaced by a PCU unit. This derivatization effectively increases
the size and flexibility of 1(4+) and changes its electronic, dynamical, and
binding properties. A conformational search using Osawa's corner flapping
technique and the PM3 semiempirical method identifies eight unique and low-energy
1(4+) conformers. The principal regions of structural variation occur in the
bipyridinium torsion and in the ethylene bridges between PCU and the
tetracationic unit. The inclusion complexes of 1(4+) with 1,4-disubstituted
benzenes and 4,4'-disubstituted biphenyls have been studied by PM3. The first
shell of solvation is approximated by the explicit inclusion of 12 acetonitriles
in the computed supramolecular complexes. Binding of 1,4-disubstituted benzenes
and 4,4'-biphenol is shifted from the 1(4+) geometric center. From the
computations, host 1(4+) is predicted to have an enhanced binding preference for
benzidine over 4,4'-biphenol, as compared to 2(4+). For all guests computed,
1(4+) binds more strongly than 2(4+). These properties can be exploited in the
future design of supramolecular systems with potential applications as nanoscale
devices.
PMID- 10774030
TI - Reaction of selenobenzophenones with olefins. Formation of 1H-2
benzoselenopyrans. Reaction of 1H-2-benzoselenopyrans with diazoalkanes
AB - Selenobenzophenone reacts as a diene with dimethyl acetylenedicarboxylate (DMAD)
to lead to dimethyl 1H-1-diphenylmethyl-1-phenyl-2-benzoselenopyran-3,4
dicarboxylate (5c) in moderate yield; the initial [4 + 2] cycloaddition is
followed by the addition of another 1 mol equiv of selenobenzophenone. The
reaction might proceed through carbene insertion of the primary cycloadduct. On
the other hand, 4,4'-dimethoxyselenobenzophenone combines as a diene with DMAD
furnishing dimethyl 1H-1-p-methoxyphenyl-6-methoxy-2-benzoselenopyran-3,4
dicarboxylate (4a). The reaction of benzoselenopyran derivative (4) with
diaryldiazomethanes afforded another type of carbene insertion product.
PMID- 10774031
TI - Synthesis of aminocyclopentitols from chromium carbene complex derived
aminocyclobutanones.
AB - Functionalized cyclopentenones were synthesized by the diazomethane ring
expansion of cyclobutanones, produced by the photochemical reaction of vinyl
oxazolidinones with chromium carbene complexes.
PMID- 10774032
TI - Short stereoselective route to gamma-CF3 allylic alcohols: rearrangements with
creation of quaternary CF3-substituted carbons
AB - A concise preparation of tetrasubstituted hindered functionalized CF3-olefins 2-7
from corresponding enol ether 3 is described. Geometrically pure gamma-CF3, gamma
alkyl allylic alcohols thus prepared could undergo Claisen-type rearrangements
and provide, in good yields, carboxylic esters and amides containing a beta-
quaternary CF3-substituted carbon.
PMID- 10774033
TI - Enantioselective addition of diethylzinc to aldehydes catalyzed by N-(9
phenylfluoren-9-yl) beta-amino alcohols
AB - A set of secondary N-phenylfluorenyl beta-amino alcohols have been prepared and
evaluated as catalysts for the enantioselective addition of diethylzinc to
benzaldehyde. The influence of the substituents on the stereogenic centers of the
ligand has been studied, and enantioselectivities up to 97% have been obtained.
Those ligands with bulky groups in the carbinol stereocenter and small groups
alpha to the nitrogen atom displayed the best catalytic activity and
enantioselectivity. The most enantioselective ligand (4e) was found to possess
general applicability for the enantioselective addition of diethylzinc to a
variety of aromatic and aliphatic aldehydes.
PMID- 10774036
TI - Isolation of stable enantiomerically pure telluroxides and their stereochemistry
AB - Optical resolution of kinetically and thermodynamically stabilized diaryl
telluroxides possessing bulky substituents (rac-1a-d) and amino group (rac-2a-c),
respectively, by liquid chromatography using optically active columns yielded
stable enantiomerically pure telluroxides. The absolute configurations of the
optically active telluroxides were determined by comparing their specific
rotations and CD spectra with those of sulfur or selenium analogues. The kinetics
for the racemization of optically active telluroxides in solution was studied,
and it was found that kinetic and thermodynamic stabilization were very effective
preventing the racemization of telluroxides. The stabilization energy of
telluroxides by intramolecular coordination of the amino group to the tellurium
atom was estimated to be ca. 5 kcal mol-1 by variable temperature 1H NMR
measurement. The mechanism for the racemization of optically active telluroxides
was studied by an isotope experiment using H2(18)O, and the results indicated
that optically active telluroxides underwent racemization via an achiral
tetracoordinated hydrate.
PMID- 10774035
TI - An enantioselective route to paeonilactone A via palladium- and copper-catalyzed
reactions.
AB - We herein report on a formal total synthesis of paeonilactone A involving
palladium-, copper-, and enzyme-catalyzed reactions starting from 1,3
cyclohexadiene. The key step in the synthesis, a palladium(II)-catalyzed 1,4
oxylactonization of a conjugated diene, simultaneously introduces two of the
oxygen substituents required for the target molecule. The synthesis also includes
our recently developed copper(I)-catalyzed cross-coupling reaction between
dienyltriflates with Grignard reagents, introducing one of the methyl groups
present in the target molecule. This new approach toward paeonilactone A allows
complete control of all four stereogenic centers and is the first
enantioselective route toward paeonilactone A starting from an achiral substrate.
PMID- 10774037
TI - Synthesis of trifluoromethylated amines using 1,1-bis(dimethylamino)-2,2,2
trifluoroethane
AB - Lewis acid-catalyzed deamination of aminal, 1,1-bis(dimethylamino)-2,2,2
trifluoroethane, using ZnI2 in ether, generates the 2,2,2-trifluoro-1,1
dimethylaminoethyl carbocation, which undergoes synthetically useful
electrophilic reactions with alkynes, a variety of electron-rich alkenes, and TMS
cyanide to form trifluoromethylated alkynylamines, homoallylic amines, alpha,beta
unsaturated ketones, and cyanoamines in fair to good yields.
PMID- 10774038
TI - Stereoselective synthesis of 4 alpha-hydroxy-8,12-guaianolides from santonin
AB - Hydroxyester 2, easily obtained from santonin (1), has been transformed into 10
alpha-hydroxyguai-3-en-8,12-olide 6, a good intermediate for the synthesis of
natural 8,12-guaianolides. Compound 6 was obtained from 2 by photochemical
rearrangement of its acetyl derivative 7, stereoselective hydrogenation on Pd/C,
reduction, regioselective elimination, hydrolysis, and lactonization. The
synthesis of the natural guaianolides 3-5 was carried out in two sequences in
which the regioselective elimination of a hydroxyl group at C10 with triflic
anhydride or SOCl2 to afford, respectively, the endo or exo double bond on C10
and the regioselective opening of the C3-C4 alpha-epoxide were the key steps.
PMID- 10774039
TI - Photochemistry of substituted benzyldiphenylphosphine oxides
AB - Photochemical reactions (lambda irr = 254 nm) of substituted
benzyldiphenylphosphine oxides 1a-e have been investigated in benzene and
acetonitrile. alpha-Cleavage from the singlet excited state is proposed as the
primary process, and products formed both before and after escape of the primary
intermediates from the solvent cage result. Radicals 2 and 3 are observed by
nanosecond flash photolysis following excitation of 1a at 266 nm in acetonitrile.
Acetone sensitization of 1a,b fails to improve the efficiency of product
formation. The quantum yields of disappearance of 1a,b are unaffected by O2, and
mechanisms for product formation from 1a in the presence of oxygen are proposed.
PMID- 10774040
TI - Novel preparation of alpha,beta-unsaturated aldehydes. Benzeneselenolate promotes
elimination of HBr from alpha-bromoacetals
AB - Acetalization, alpha-bromination, nucleophilic phenylselenenylation, oxidative
elimination/hydrolysis was investigated as a novel protocol for the alpha,beta
dehydrogenation of aldehydes. Treatment of acetals with bromine in methylene
chloride afforded the corresponding alpha-bromoacetals in 80-90% yields.
Nucleophilic phenylselenenylation was then conveniently effected by treatment
with benzeneselenolate generated in situ in dimethyl sulfoxide from diphenyl
diselenide, hydrazine and potassium carbonate. Unbranched alpha-bromoacetals
cleanly afforded substitution products whereas beta- and gamma-branched ones gave
substantial amounts of alpha,beta-unsaturated acetals via formal loss of hydrogen
bromide. Oxidative elimination/hydrolysis of these mixtures afforded alpha,beta
unsaturated aldehydes in 50-80% overall yields. In the case of tertiary alpha
bromoacetals, treatment with benzeneselenolate afforded only dehydrobromination
products as mixtures of isomers. The presence of at least a catalytic amount of
the organoselenium reagent was found to be crucial for olefin formation. A SET
mechanism, involving benzeneselenolate-induced electron transfer to the halide,
loss of bromide ion, and hydrogen atom or proton/electron was proposed for the
benzenselenolate-promoted elimination reaction. Experiments designed to trap
carbon-centered radicals in intramolecular cyclization or ring-opening reactions
failed to provide any evidence for free-radical intermediates.
PMID- 10774042
TI - Construction of the bicyclo[3.1.0]hexane template of a conformationally locked
carbocyclic adenosine via an olefin keto-carbene cycloaddition.
AB - An intramolecular olefin keto-carbene cycloaddition reaction created the
bicyclo[3.1.0]hexane template 10 that was necessary for the synthesis of
carbocyclic amine 15. This amine is a direct precursor to a family of rigid
nucleosides that are conformationally locked in the Southern hemisphere of the
pseudorotational cycle. The synthesis of the conformationally locked adenosine
analogue is reported herein as an illustrative example of the methodology. The
racemic (South)-methanocarba adenosine analogue (+/-)-4 is the first example of a
conformationally locked ribonucleoside version in the Southern hemisphere.
PMID- 10774043
TI - Solid-phase synthesis and structural characterization of highly substituted
hydroxyproline-based 2,5-diketopiperazines
AB - Two general solid-phase methods for the synthesis of a new class of 2,5
diketopiperazines (DKPs) containing the trans-4-hydroxy-L-proline amino acid
residue (Hyp) have been developed. An N-protected hydroxyproline methyl ester was
linked through the hydroxyl function to the Ellman resin. The synthesis
procedures were conceived to enable a sequence of Hyp alkylation, Hyp N
acylation, cyclization, and amide bond alkylation. Up to three different centers
of molecular diversity were introduced around the DKP scaffold. Highly
functionalized bicyclic compounds were obtained in good yield and purity. The
alkylation of hydroxyproline alpha CH was performed without control of the
diastereoselectivity. During the final alkylation of the backbone, amide bond
epimerization at the alpha-carbon atoms of the two amino acid residues was
observed. The structures of representative DKPs were elucidated with
multidimensional NMR experiments. The described reaction pathways can be applied
to the identification of heterocyclic molecule inhibitors to diverse enzyme
targets.
PMID- 10774041
TI - Rigid dipeptide surrogates: syntheses of enantiopure quinolizidinone and
pyrroloazepinone amino acids from a common diaminodicarboxylate precursor.
AB - A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino
acids of different ring sizes from a common diaminodicarboxylate precursor has
been developed as a means for mimicking different peptide conformations. (2S,9S)
1-tert-Butyl 10-benzyl 5-oxo-2-[N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate
(18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination
of N-(PhF)aspartate beta-aldehyde 8 with pyroglutamate-derived beta-keto
phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach
for making azabicyclo[X.Y.0]alkane amino acids was then illustrated by the first
synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40%
overall yield from L-pyroglutamic acid. Hydrogenation of delta-keto alpha,omega
diaminosebacate 18, followed by lactam cyclization and protection, gave
quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this
approach was next demonstrated by the synthesis of both ring-fusion isomers of
pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from
pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate
displacement, gave 5-alkylproline 22. Protective group manipulations, lactam
cyclization, and removal of the ester group afforded readily separable
pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By
introducing two new azabicycloalkane amino acids using our olefination approach,
we have expanded the diversity of these important heterocycles for studying the
conformational requirements for peptide biological activity.
PMID- 10774044
TI - Kinetics and mechanism of the addition of benzylamines to
benzylidenemalononitriles in acetonitrile
AB - Nucleophilic addition reactions of benzylamines (BA) to benzylidenemalononitrile
(BMN) have been studied in acetonitrile at 15.0 degrees C. The rate is first
order with respect to both BA and BMN and no base catalysis is observed. The rate
decreases as the electron-withdrawing power of the substituent (Y) in the
substrate increases (rho Y < 0). This is in contrast to the similar reactions of
beta-nitrostyrenes (NS) with BAs in acetonitrile and the addition reactions of NS
and BMN in aqueous solution (rho Y > 0). This sign change of rho Y is considered
to result from the strong electron-withdrawing power of the (CN)2 group in BMN,
which leads to polarization of C alpha delta+C delta- (CN)2 in the transition
state. The mechanism of amine addition to BMN in acetonitrile is radically
different from that in water. The reaction is predicted to proceed concertedly in
a single step with a hydrogen-bonded, four-center cyclic transition state.
PMID- 10774045
TI - Polar bromination of cyclopropane: a DFT study
AB - Hitherto the polar addition of bromine to cyclopropane has been considered as a
two-step process. Current calculations have established the energetics for the
proposed cation-anion pairs required by these mechanisms. An energetically lower
pathway is proposed here in the form of a syn-cycloaddition process. Compared to
the two-step process, a significantly lower activation enthalpy for this process
has been found. The stereochemical consequences of the cyclic mechanism are
retention-retention for the two adding moieties. This result is consistent with
published experimental data on the bromination of a deuterated cyclpropane.
PMID- 10774046
TI - Theoretical calculation of ionization potentials for disubstituted benzenes:
additivity vs non-additivity of substituent effects
AB - The ionization potentials of 55 para- and 55 meta-disubstituted benzenes,
consisting of all binary combinations of electron-withdrawing groups (-NO2, -CF3,
-CHO, -COOH) and electron-donating groups (-Cl, -CH3, -OH, -OCH3, -NH2, and
N(CH3)2) have been calculated using density functional theory with the B3LYP
functional and a 6-31G(d) basis set. Relative ionization potentials (delta IP),
referred to benzene, are compared with experimental values and shown to be in
good agreement. The disubstituted data were correlated with monosubstituted delta
IP data and shown to require quadratic terms in order to achieve a good fit; the
validity of this conclusion was possible due to the low scatter in the calculated
data. A simple MO analysis gives a semiquantitative interpretation of the
observed trends in substitutent effects, including a discussion of combinations
of substituents for which nonadditivity should be expected.
PMID- 10774047
TI - Ruthenium carbene complexes with N,N'-bis(mesityl)imidazol-2-ylidene ligands: RCM
catalysts of extended scope
AB - The ruthenium carbene complexes 3a,b bearing imidazol-2-ylidene ligands
constitute excellent precatalysts for ring-closing metathesis (RCM) reactions
allowing the formation of tri- and tetrasubstituted cycloalkenes. They also apply
to annulations that are beyond the scope of the standard Grubbs carbene 1 as well
as to ring-closing reactions of acrylic acid derivatives even if the resulting
alpha,beta-unsaturated lactones (or lactams) are tri- or tetrasubstituted. The
reactivity of 3a was found to be highly dependent on the reaction medium:
particularly high reaction rates are observed in toluene, although this solvent
also leads to an increased tendency of the catalyst to isomerize the double bonds
of the substrates.
PMID- 10774048
TI - Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)
triptophenolide, and (+)-triptoquinonide.
AB - The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide
(2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key
step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)
8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with
good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)
Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess
(> 99% ee), and readily converted to natural products 1-4. In addition,
transition state models were proposed to explain the opposite chiral induction
observed in the oxidative radical cyclization reactions of chiral beta-keto
esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro
substituent).
PMID- 10774049
TI - Oxidative cleavage of N,N-Dimethylhydrazones to ketones with hydrogen peroxide,
catalyzed by methyltrioxorhenium (VII)
PMID- 10774050
TI - Synthesis of substituted 1-methyl-2-cyanopyrroles via unprecedented addition of
N,N-dimethylformamide to electron-deficient alkenes in the presence of copper(I)
cyanide
PMID- 10774051
TI - Linear tetraheterocycles composed of both bidentate diisoxazole and bidentate
isoxazole--furyl/thienyl/pyridyl motifs
PMID- 10774053
TI - Reactions of Grignard reagents with an azacrown ether; formation of RMg(14N4)+
and XMg(14N4)+ cations and RnMgX3-n- and X- anions
PMID- 10774052
TI - Synthesis of (+/-)-homohistidine.
PMID- 10774054
TI - Soluble, infrared-absorbing croconate dyes from 2,6-di-tert-butyl-4
methylchalcogenopyrylium salts
PMID- 10774056
TI - []
PMID- 10774055
TI - Novel base-induced [1,2]-acyl shift of allylic esters of cyclopropanecarboxylic
acids.
PMID- 10774057
TI - Direct and efficient synthesis of dimethylformamidrazones using bentriazole
Vilsmeier reagent
PMID- 10774058
TI - Rational synthesis of meso-substituted porphyrins bearing one nitrogen
heterocyclic group.
PMID- 10774059
TI - Double isomerization of oxetane amides to azetidine esters with ring expansion
and contraction
PMID- 10774060
TI - Novel synthesis of liquid crystalline phthalocyanines
PMID- 10774061
TI - Acid mediated phosphine-borane decomplexation: a model for characterizing short
lived intermediates with experimental and ab initio NMR data
PMID- 10774062
TI - Neurosteroid analogues. 7. A synthetic route for the conversion of 5 beta-methyl
3-ketosteroids into 7(S)-methyl-substituted analogues of neuroactive
benz[e]indenes.
PMID- 10774063
TI - [The question of killing in animal protection ethics].
AB - About twenty years ago the traditional question whether humans are allowed to
kill animals was replaced by two new questions: the question of killing and the
question of suffering. The question of killing ist the abstract question if--in
isolation from the question of suffering--finishing an animal's life is moral. So
the question of killing can be raised for every single case of an animal killed
by man. The moral evaluation of a killing without suffering (of all directly and
indirectly involved beings) concerns just the question of killing; for example,
an experiment in which the animal is made unconscious by an anesthetic prior to
the experiment being performed and is then killed before it regains
consciousness.--The comparative analysis of the popular arguments demonstrates
fallacies in some of them and shows a new view of the problem. Because not the
killing itself (without fear or pain) but the innate fear of death is the real
motive to reject ones own killing, it is necessary to demand that every killing
of an animal by man is done without any fear (or pain) for the animal. To claim
an animal's right to life however is not yet justified.
PMID- 10774064
TI - [Practical problems in criminal laws of prevention of cruelty to animals].
AB - 1. To ascertain serious pains and sufferings in the meaning of section 17 no. 2 b
law of prevention of cruelty to animals you cannot do without the help of an
expert witness for taking possession of evidence--apart from simple cases. Except
the clarifying of fundamental questions concerning prevention of cruelty to
animals a professional statement of the administrative veterinary surgeon will be
as a rule sufficient. 2. For the actual seizure of animals for the purpose of
confiscation and compulsory disposal the criminal justice is extremely dependent
on the support of the authorities of administration. Therefore a trouble-free
cooperation of criminal justice, veterinary authorities, animal homes and-
concerning the protection of species--authorities for protection of endangered
nature is imperative. 3. The main problems with the application of the regulation
concerning the interdiction of keeping animals according to sections 20 and 20 a
law of prevention of cruelty to animals are justified in the legal prerequisites.
It is unsatisfactory that an interdiction of keeping animals cannot be imposed by
summary punishment order and that a confiscation of animals is not possible by
criminal proceedings in case of offence against sections 20 subsection 3, 20 a
subsection 3 law of prevention of cruelty to animals. Therefore an admission of
the sections as mentioned above to section 19 law of prevention of cruelty to
animals seems to be convenient.
PMID- 10774065
TI - [Combat dogs--dangerous dogs].
AB - The claim that the so-called "Kampfhunde" are becoming increasingly dangerous to
humans has been the subject of much discussion in Germany. A critical analyses of
canine breeds that have been classified as "Kampfhunde" convinces that breed is
not an useful possibility for avoiding accidents with dogs: 1. Zoologically no
particular breed of dog can be classified as being more dangerous than others and
2. so-called "Kampfhunde" are statistically unimportend as a vector in dog
accidents. It would be more productive in the future to substitute the term
"Kampfhund" with "dangerous dog" without reference to the breed and to emphasize
the role of the owner in the human danger posed by a dog.
PMID- 10774066
TI - [Dangerous dogs: application of federal regulations].
AB - During the last years nearly in all provinces in Germany new, hotly debated rules
were published in order to meet the threat dangerous dogs or so-called fighting
dogs mean to animals and men. Comparing current regulations of different
provinces two categories of rules can be identified: one considering particular
breeds as extremely dangerous and the other defining and characterising the
dangerous dog. The application of these regulations differs enormously in
expenditure and procedure. Recent statistics of all registered dog-bites allow
other conclusions than those which seemed to have been relevant for the
elaboration of the existing legislation. This is particularly true for the breeds
which are considered extremely dangerous. It seems to be more useful to use the
expression dangerous dog in general. Routine application of the new regulations
have, except from some cases, increased administrative input but have not
improved the situation itself. Animals homes are complaining of more "fighting"
dogs. The fact that it is extremely difficult to find a new owner for these dogs
leads to additional animal health problems. Judgement and treatment of dogs
presented to public authorities because of dog-biting has not become any easier
and dogs causing severe injury are not even presented. The new regulations are
not sufficiently preventive and do not really tackle the cause of the problem of
dangerous dogs. The existing regulations were developed under a strong political
pressure. Authorities are now calling into question the usefulness and purpose of
the new legislation. In the past the problem of dangerous dogs was dealt with
using general safety legislation and police regulations offering flexibility.
Obviously there is an urgent need to identify countermeasures on a larger scale.
PMID- 10774067
TI - [Diseases with relevance to protection of animals with an example of the
musculoskeletal system of dogs].
AB - Protection of animals needs major concern in breeding programmes especially if
inherited diseases occur which cause pain, suffering and/or damages for the
animals. Dogs breeders and people keeping dogs as well as veterinarians should be
informed about the etiology on sequels of diseases which cause pain to the
animals and from which the animals have to be protected in order to make them
more conscious on these problems and to achieve changes in dog breeding
programmes. The information system "Inherited Diseases of the Musculoskeletal
System of Dogs" should display the already published knowledge about etiology,
pathogenesis, appearance, therapy and genetics of these diseases. This
information system was built up in such a way that it can be used by students as
a learning programme to understand the basic relationships among animal
protection, diseases, and dog breeding. The user is also supplied with support
for breeding decisions as well as for interpretation of breeding values and
genotype probabilities. Additionally, information can be obtained on all in the
German Association for Dog Breeding (VDH) represented breeds and breeding clubs.
Actions to reduce genetically caused diseases required for members of dog
breeding clubs are also available. The information system ist programmed by using
HTML (Hyper Text Markup Language). Publication is possible on CD-ROM and on
Internet. The supplied hyperlinks allow to make use of other publications on the
world wide web related to dog and diseases of dogs.
PMID- 10774068
TI - [Health aspects and the duty of care in the rearing of young horses].
AB - Future competition horses may suffer from health impairments due to complex or
partial genetic components as well as to management faults in respects to
keeping, feeding and health prophylaxis against infectious diseases. This health
risks exist during the whole rearing period: from late pregnancy till far beyond
weaning. Health impairments reduce trade value and practical use, and interfere
with aspects of animal protection. In the field of breeding permission, first in
stallions, applied research ist needed. For horse farms a praxis-oriented
comprehensive advisory service should be established.
PMID- 10774069
TI - [Veterinary service and supervision of equine competitions].
AB - Because of the growing interest in animal health and welfare in breeding and
sport--specially in the horse--the regulation of the German Riding Association
(FN) was updated. The result--the LPO 2000--refer more functions to the
veterinarian. At first the permanent presence of the vet is necessary, at second
he controls the correct, new installed vaccination against influenza-virus. The
functions of vet-check, general horse-control and doping are wide up in number
and consultation. For this the veterinarian must decree about much experience and
good preparation. The organisations of the veterinarians of the countries and the
FN work together to develop the knowledge and competence in horse-sport for a
better protection.
PMID- 10774070
TI - [Pet markets: permits and surveillance].
AB - When pets are sold on pet markets there are frequently situations that are not
consistent with the laws concerned with animal welfare. Animals are not packed
properly, tropical animals needing certain temperatures are sold outdoors under
unsuitable weather conditions, animals are kept and transported in unsuitable
containers, shy animals not used to market conditions or sick animals are being
offered. Different possibilities to guarantee proper conditions for the animals
are being described involving the organizer as well as the local veterinary
authority surveying the market. Possible executive measures are presented.
PMID- 10774071
TI - [Pasture maintenance of cattle--administration measures].
AB - In order to keep cattle pasturing throughout the entire year they must be
supplied with a sufficient amount of feed an water, a robust constitution and the
provision of a adequate shelter. Examples of the possibility of ensuring these
minimum demands are given in the following report. Furthermore, administrative
measures used in the case of nonobservance are listed.
PMID- 10774072
TI - [CO2 stunning of broilers and turkey hens].
AB - Stunning of poultry is still not solved satisfactorily. This concerns the
requirements of animal welfare, meat quality and working conditions in the
lairage, stunning and debleeding area. In an investigation of combined CO2-/O2
stunning in a new gas stunning system stress reactions of the animals during the
induction phase and stunning effectivity were recorded in 7,000 chicken and 3.825
turkeys. During the induction phase (here: chicken 41 sek./turkeys 25-65 sec.)
the animals first staid calm and then showed beak-opening as a consequence of the
breathing stimulating effect of CO2. As a further sign of the aversiveness
against CO2 the animals showed head shaking and wing flapping. The used settings
of gas concentrations and stunning time in the system investigated lead to a very
deep stunning resp. Killing of the animals. Therefore the debleeding cut could be
performed late (chicken 44-55 sec., turkeys 54-90 sec.) after leaving the system
without animals regaining consciousness. The stunning of turkeys with a mixture
of CO2 and oxygen is an improvement according to animal welfare requirements
because unnecessary pain and suffering, happening very often with electrical
stunning, can be avoided. As far as animal welfare in chicken stunning is
concerned it must be evaluated if gas stunning means an improvement because
stress during the till now relatively long induction phase must be put into
relation with comparably lower stress caused by hanging upside down and a fast
and safe working electrical stunning unit.
PMID- 10774073
TI - [Computer simulation programs as an alternative for classical nerve, muscle and
heart experiments using frog tissues].
AB - Courses in Physiology include different methodical approaches such as exercises
with living animals, experiments using organs or tissues from killed or
slaughtered animals, application of diagnostic techniques in humans and
theoretical seminars. In addition to these classical approaches computer programs
for multimedia simulation of nerve, muscle and heart physiology are now a regular
component of courses in Physiology at the School of Veterinary Medicine in
Hannover. It is the aim of the present paper to give the first experiences about
these new components.
PMID- 10774074
TI - [Centralized examination of zoo shop owners, a Hessian model: first experiences
and perspectives].
AB - A public permission based on Section 11 of the Federal Animal Protection Act is
required for all owners of specialised zoo shops in Germany. The permission is
conceded only on the premises that the responsible person has given proof of his
professional skills and knowledge. A centralized examination procedure was
established for the state of Hessia. This paper reports on the experiences with
the procedure one year after its introduction.
PMID- 10774075
TI - [Keeping of pets--assessment of accessories].
AB - In keeping of pets accessories play an important role. They serve to improve the
conditions of pet keeping or even help to make it possible at all. Beyond that,
accessories enrich activity of the animals and thus may increase their well
being. But accessories can endanger health and life of the pets due to deficient
quality or due to inadequate use. This paper demonstrates the sources of danger
potentially arising from accessories by pointing out examples. On the other hand
exemplary paraphernalia and ways of pet keeping are presented which are qualified
to increase well-being of the pets and to avoid physical impairment.
PMID- 10774076
TI - Polio eradication in Kenya.
PMID- 10774077
TI - National immunisation days for polio eradication in Uganda: did immunisation
cards increase coverage?
AB - OBJECTIVE: To analyse the effect of cards and of vitamin A supplementation on
coverage for National Immunisation Days (NIDs). DESIGN: A retrospective
ecological study. SETTING: A countrywide NIDs coverage before and after
introduction of the NIDs cards and vitamin A supplementation in all districts of
Uganda. METHODS: NIDs for polio eradication commenced in Uganda in 1996. Two
rounds, one month apart are implemented yearly. During the second round of 1998
NIDs, cards were introduced nationally and vitamin supplementation was introduced
in 24 of the 45 districts. We compared NIDs coverage before and after NIDs cards
and NIDs coverage in districts that implemented vitamin A to those that did not.
RESULTS: After introduction of NIDs cards, the national coverage rose from 97.7%
to 106.9%, an increase of 9.2%. In those districts that implemented vitamin A
supplementation, the NIDs coverage rose from 100.1% to 111.5%, an increase of
10.4%. In those districts that did not implement vitamin A, the NIDs coverage
rose by 6.7% from 94.5% to 102.2%. Before the introduction of cards and vitamin A
in 1996 and 1997, the NIDs coverage was between 92-96%. CONCLUSION: NIDs cards
and vitamin A supplementation could have increased the NIDs national coverage.
PMID- 10774078
TI - Air pollution and respiratory health in Africa: a review.
AB - OBJECTIVE: To bring into focus the existence of respiratory hazards due to air
pollution as a result of industrialization, tobacco smoking (personal pollution),
domestic pollution and vehicular fuel combustion on the African continent; and to
stimulate health workers, and the various governments in Africa, to devote more
attention to the subject of air pollution by engaging in and encouraging
multidisciplinary research so that appropriate and effective control measures can
be put in place. DATA SOURCES: Medline literature search through internet using
the keywords: air pollution, cigarette smoking, domestic pollution, respiratory
morbidity, Africa. The author's contributions to the subject of air pollution and
respiratory morbidity are included. STUDY SELECTION: Relevant studies or articles
from eastern, western, northern, southern and central parts of Africa are
included in the review. DATA EXTRACTION: From individual study or article. DATA
SYNTHESIS: Evidence of respiratory hazards sequel to the four main sources of air
pollution in each part of Africa, are synchronised under the headings:
introduction, respiratory impairment and the future. CONCLUSIONS: Respiratory
impairment from the four main sources of air pollution is a major but highly
neglected problem on the African continent. There is need for concerted efforts
on the part of African governments, health administrators and health workers to
ensure that necessary attention is given to multidisciplinary research on the
subject so that meaningful control measures can be formulated, thereby ensuring
clean air for the people to breathe.
PMID- 10774079
TI - Sildenafil (Viagra) in the treatment of male erectile dysfunction in Nairobi.
AB - OBJECTIVE: To evaluate the effectiveness of sildenafil (Viagra) in the treatment
of male erectile dysfunction in Nairobi. DESIGN: Prospective open label extension
study. SETTING: Urology clinics at the Nairobi Hospital, Kenyatta National
Hospital and the author's private clinic in Hurlingham, Nairobi. PARTICIPANTS:
Two hundred and nineteen adult male patients with erectile dysfunction. RESULTS:
The age range was 33-80 years with a mean of 62.5 years and a peak incidence in
the 60-69 year age group. One hundred and nineteen patients (54.34%) had organic
causes, 85 patients (38.81%) had psychogenic causes and 15 patients had mixed
causes. Two hundred patients (91.32%) had improved sexual function after
treatment with viagra. This improvement was sustained during the study period of
sixteen weeks and included improved erectile and orgasmic functions and overall
sexual satisfaction. One hundred and fifty seven of these patients responded to
therapy with 50 mg of viagra; 40 patients with 25 mg and three patients with 100
mg of therapy. Nineteen patients (8.68%) had no improvement in sexual function
after viagra administration. Seven patients (3.2%) had adverse effects which were
mild and transient. They included mild headaches in three patients, mild
dyspepsia in two patients and facial flushing and nausea and vomiting in one
patient, respectively. CONCLUSION: Oral sildenafil (Viagra) is an effective well
tolerated and simple treatment for male erectile dysfunction in the majority of
cases. The cost of treatment at about ten United States dollars for the 50 mg
tablet is prohibitive and may limit its wide use by many deserving patients in
this locality.
PMID- 10774080
TI - Testicular cancer at Kenyatta National Hospital, Nairobi.
AB - OBJECTIVE: To determine the prevalence, clinical characteristics, management
methods and prognosis of testicular cancer at Kenyatta National Hospital. DESIGN:
Retrospective case study of testicular cancer patients over a fifteen year
period. SETTING: Kenyatta National Hospital, a referral and teaching hospital.
PARTICIPANTS: All histologically confirmed testicular cancer patients recorded at
the Histopathology Department of Kenyatta National Hospital between 1983 and
1997. RESULTS: The mean age was 34.8 years with a peak incidence in the 30-44
year age group. History of cryptochirdism was obtained in 10.26% of the patients.
Thirty one patients (79.49%) presented with painless testicular swellings, eleven
(28.08%) with pain, nine (23.08%) with scrotal heaviness, six (15.38%) with
abdominal swellings and one (2.56%) each with gynaecomastia and eye swelling. On
examination 32 patients (82.05%) had testicular masses, ten (25.64%) had
abdominal masses, seven (17.91%) had supraclavicular and cervical
lymphadenopathy, and one each (2.56%) had gynaecomastia and eye mass
respectively. More than eighty nine per cent had germ cell cancers with seminoma
accounting for 67.35%, teratoma 12.24%, embroyonal carcinoma 8.16%,
rhabdomyosarcoma 6.12% and malignant germ cell tumour, orchioblastoma and
dysgerminoma each accounted for 2.04%. Three patients (7.7%) had orchidectomy and
radiotherapy and chemotherapy, sixteen (41.03%) had orchidectomy and
radiotherapy, six (15.38%) had orchidectomy and chemotherapy, ten (25.64%) had
radiotherapy and chemotherapy, three (7.7%) and two (5.13%) had only chemotherapy
and radiotherapy respectively. No cisplastin based chemotherapy regime was used.
Follow up was effected for eighteen patients (46.15%) and seven patients (38.89%)
were alive after five years. CONCLUSION: Prognosis with current regimes was poor
with survival of only 38.89% after five years. Cisplastin based chemotherapy with
up to 90% cure rates should be included as a component of testicular cancer
management at Kenyatta National Hospital.
PMID- 10774081
TI - Naturalistic study of olanzapine in treatment-resistant schizophrenia and acute
mania, depression and obsessional disorder.
AB - BACKGROUND: Whereas the Fiji government provides all aspects of mental health
care services free of charge to its citizens, many schizophrenics have failed to
respond to classical antipsychotic drugs. OBJECTIVE: To assess the efficacy and
safety of olanzapine among various patients with severe psychiatric disorders.
SETTING: Naturalistic setting. DESIGN: Descriptive study. MEASUREMENTS: Outcome
was based on reduction of symptoms on the PANSS (> or = 40%) and CGI shift to 1
3. SUBJECTS: The were 64 patients (30 males) aged 17-77 years. Thirty six (56.3%)
had schizophrenia, eight mania, ten severe depression, four obsessive compulsive
disorder (OCD), one each had schizo-affective and delusional disorders, while the
remaining had chronic brain diseases. RESULTS: At weeks 3, 8, 12, the proportion
of subjects with 40% improvement was 60.6%, 79.9%, and 76.8%, respectively.
Positive and negative symptoms improved. Thirteen (48.1%) of the 27 long-stay
treatment--resistant schizophrenics achieved clinical recovery at eight weeks.
All with primary diagnosis of severe depression and mania achieved full clinical
recovery (mostly within two weeks). Two OCD cases achieved clinical recovery at
week eight. CONCLUSION: Olanzapine was safe for all categories of patients. There
was not a single case of extrapyramidal reaction among subjects who did not have
it pre-treatment; and the drug was safe in a suicidal overdose of 205 mg. Most
patients experienced weight gain; two adolescent girls had temporary amenorrhoea
and one subject had transient rise in liver transaminases which normalised
without discontinuing the drug.
PMID- 10774082
TI - Generational differences in male sexuality that may affect Zimbabwean women's
risk for sexually transmitted diseases and HIV/AIDS.
AB - OBJECTIVE: To determine generational differences in male sexuality, which could
predispose men's female sexual partners to STDs/HIV. DESIGN: Cross-sectional
study. SETTING: Harare, Zimbabwe. SUBJECTS: Three hundred and ninety seven male
adults aged eighteen years and above. MAIN OUTCOME MEASURES: Number of sexual
partners, condom use, likelihood of sharing information on HIV status with wife
or with other sexual partners, preference for women with dry vaginas prior to sex
and discussion about sexual satisfaction with wife or with girl friend. RESULTS:
Fewer men in the 27-39 year age group when compared to men aged 18-26 years
(22.2% versus 28.9%) had two or more sexual partners. The greatest proportion of
ever condom users were men aged 27-39 years, but this proportion was not
significantly different from the proportion of ever condom users aged 18-26 years
(76.5% versus 69.5%; Odds Ratio[OR] = 1.42, 95% Confidence interval [CI] 0.81
2.51). Men aged > or = 40 years (43.8%, OR = 0.34, 95% CI 0.20-0.84) were
significantly fewer than men aged 18-26 years in ever use of condoms. In the
event that they contracted HIV, 79.5%, 82.4% and 85.9% of men aged 18-26, 27-39
and 40 years and above respectively indicated that they would disclose their HIV
status to their wives. On the other hand, men aged 18-26 years (56.8%), 27-39
years (54.0%) and > or = 40 years (53.1%) indicated that they would disclose
their HIV status to girl friends or other sexual partners. Significantly, more
men aged 40 years (OR = 2.23; 95% CI 1.19-4.18) and 27-39 years (OR = 1.82; 95%
CI 1.00-3.32) in comparison to 18-26 year old men indicated their preference for
women with dry vaginas prior to sex. The greatest proportion of men who discussed
sexual satisfaction with their wives (85.7%) and girl friends or other sexual
partners (23.5%) were aged 27-39 years. CONCLUSION: It is recommended that public
health and behavioural scientists in Zimbabwe devote more time to understanding
the intricacies of male sexual behaviour at different stages of life. This would
provide the important insight needed to develop effective targeted interventions
to reduce the spread of STDs/HIV in Zimbabwe.
PMID- 10774083
TI - Randomised trial of alternative malaria chemoprophylaxis strategies among
pregnant women in Kigoma, Tanzania: I. Rationale and design.
AB - OBJECTIVE: The objective of the study was to assess the effectiveness of
alternative strategies of malaria chemoprophylaxis on the reduction of malaria
episodes and prevalence of parasitaemia among pregnant women in Kigoma urban
district in western Tanzania. DESIGN: Randomised antimalarial prophylactic trial.
SETTING: The study was conducted in an urban maternal and child health (MCH)
clinic in Kigoma town. SUBJECTS: All pregnant women attending antenatal care
services at Kigoma urban MCH clinic were eligible. Informed consent was sought
from each pregnant woman for participation in the study. INTERVENTION MEASURES:
The intervention measures were intermittent and continuous malaria
chemoprophylaxis using chloroquine and proguanil. MAIN OUTCOME MEASURES:
Reduction of malaria episodes and parasitaemia and haemoglobin levels among
participating pregnant women in Kigoma urban district. RESULTS: Baseline data
indicates that the overall mean haemoglobin concentrations among the
primigravidae and multigravidae women were similar within the intervention and
comparison groups (F-test (df = 5, N = 701) = 1.27, P = 0.27). Similarly, no
significant difference was observed in the prevalence of malaria parasitaemia
within the primigravidae intervention and comparison groups (chi 2 test (df = 5,
N = 701) = 5.4, P = 0.4). Hence, the process of randomisation produced comparable
intervention and comparison groups with balanced characteristics. Specific
results of the baseline studies are presented in the companion paper. CONCLUSION:
We conclude that the process of randomisation resulted in comparable intervention
and comparison groups. As malaria is a common cause of considerable morbidity and
mortality among pregnant women in Tanzania, the present study provided useful
data for improving reproductive health in Kigoma region, western Tanzania.
PMID- 10774084
TI - Randomised trial of alternative malaria chemoprophylaxis strategies among
pregnant women in Kigoma, Tanzania: II. Results from baseline studies.
AB - OBJECTIVE: To determine baseline data among pregnant women consenting to
participate in a randomised trial of alternative strategies of malaria
chemoprophylaxis in Kigoma urban district, western Tanzania. DESIGN: Cross
sectional study. SETTING: The study was conducted in an urban MCH clinic in
Kigoma town in western Tanzania. SUBJECTS: All consenting pregnant women who
fulfilled entry criteria were recruited into the study. BASELINE STUDIES:
Baseline data were collected prior to randomisation of women to antimalarial
prophylactic regimens. Baseline measurements included examination for blood
depleting parasitic infections (stool and urine examinations), haemoglobin
levels, haematocrit, sickling test, and blood slide for malaria parasites.
RESULTS: A total of 728 pregnant women consented to participate in the interview
and of these 705 participated in baseline studies constituting a participation
rate of 96.8%. The age of participating women ranged from 14 to 45 years with a
mean age of 23.7 years (standard deviation [SD] = 5.4) while the mean number of
pregnancies ranged from 1 to 13 with a mean of 3.2 (SD = 2.2). The prevalence of
malaria parasitaemia among the pregnant women examined was 9.4% (N = 705) while
the prevalence of anaemia (defined as Hb < 8.5 gdl-1) was 12.4% (N = 579). No
significant difference was observed in prevalence proportions of malaria
parasitaemia in relation to age, parity, marital status and use of mosquito
bednets. However the prevalence of anaemia among women in the age group 31-45
years was significantly lower than that observed among women in the age group 14
20 years (2.9% versus 18.9%; crude odds ratio [OR] = 0.13; 95% confidence
interval [CI], 0.02-0.55). Sickle cell disease (HbAS) was found in 2.3% (N = 564)
of the pregnant women examined. CONCLUSION: It is concluded that the prevalence
of malaria parasitaemia and anaemia was very high in this population suggesting
the need for interventions directed at controlling these major causes of maternal
morbidity and mortality in Tanzania.
PMID- 10774085
TI - Determination of drug susceptibility and DNA fingerprint patterns of clinical
isolates of Mycobacterium tuberculosis from Kampala, Uganda.
AB - OBJECTIVE: To ascertain the rate of initial drug resistance and transmission
patterns of Mycobacterium tuberculosis in Kampala, Uganda. SETTING: National
Tuberculosis (TB) Treatment Centre, Mulago Hospital, Kampala, Uganda and Case
Western Reserve University, Cleveland, Ohio, USA and McClellan Memorial Veterans
Hospital, Little Rock, Arkansas, USA. METHODS: Using a radiometric BACTEC 460 TB
system, susceptibility of 215 M. tuberculosis isolates from previously untreated
patients from Kampala, Uganda (age range, 17-48 years, mean, 28 years; 56% males
and 69% human immunodeficiency virus (HIV)-seropositive) was determined for
isoniazid, rifampin, streptomycin and ethambutol. Isolates from 73 patients,
selected on the basis of geographical location, were tested for strain diversity
or relatedness using the IS6110 DNA fingerprinting technique. RESULTS: Resistance
rates were as follows: isoniazid, 7.9% streptomycin, 6.1% rifampin, 1.4% and
ethambutol 0.9%. Twelve per cent of the strains were resistant to at least one of
the first line drugs tested and 4.7% were multiply resistant. There were no
significant differences in resistance rates between patients with and without HIV
infection. Using the number and size of DNA fragments containing IS6110, only
three clusters of isolates with identical RFLP patterns were found out of the 73
isolates tested (8.2%). Each cluster contained two isolates. Three (4.1%)
isolates had less than seven copies of IS6110. CONCLUSION: This study shows that
in Uganda initial drug resistance rates to anti-tuberculosis agents are low and
similar to other sub-Saharan African countries and that multiple strains of M.
tuberculosis have been transmitted within the community.
PMID- 10774086
TI - Onchocerciasis in Gilgel Ghibe River Valley southwest Ethiopia.
AB - OBJECTIVE: To determine the prevalence of onchocerciasis and the entomological
transmission indices such as the parous rate and annual transmission potential
(ATP). SETTING: Gilgel Ghibe village, Gilgel Ghibe River Valley Southwest
Ethiopia between April 1994 and March 1995. SUBJECTS: Two hundred twenty eight
subjects of the total 400 population in Gilgel Ghibe village were subjected to
parasitological and clinical examinations. METHOD: Two skin snips per person were
taken and examined for microfilariae of Onchocerca volvulus. Fly collections were
done from dawn to dusk from human baits seated in pairs at four representative
sites at the river bank and away from the river bank. Flies were dissected for
parity and infections with O. volvulus larvae. RESULTS: Among the 228 people
examined, the prevalence of the disease was low (17%), being higher in males
(19%) than in females (14%). The geometric mean of microfilarial density was 11.1
(range, 1-132) mf per skin snip. Itching followed by pigmentary changes were the
most common clinical signs and symptoms. The predominant anthropophilic blackfly
species was Simulium (Edwardsellum) damnosum s.l. The annual parous rate and ATP
were 74.7% and 1669.5, respectively, being higher at the river bank than at sites
further away suggesting a greater risk of infection by the river side.
CONCLUSION: The low prevalence of onchocerciasis in Gilgel Ghibe area vis-a-vis
the high ATP level could be due to the possible presence of bovine onchocerciasis
in the area. Further studies employing molecular techniques are thus required to
identify O. volvulus from other filariae in flies.
PMID- 10774087
TI - Anatomic heterogeneity of the rat amygdaloid complex.
AB - The amygdala is a nuclear complex composed of 13 nuclei and cortical areas and
their subdivisions. Tract-tracing studies performed over the past 20 years
demonstrate that each nucleus is uniquely connected with other brain areas.
Consistent with anatomic heterogeneity, the functions of the amygdala vary from
attention to memory to formation of emotional responses to sensory stimuli. Here,
we briefly review the principles of amygdaloid neuronal wiring that underlie the
computations necessary to perform such complex behavioural functions.
PMID- 10774088
TI - The morphological conditions of the permanent pacemaker lead extraction.
AB - Pacemaker lead extraction is the treatment of choice in infectious complications
regarding implantation procedure. The purpose of this study was to estimate the
safety of the extraction in relation to the morphological changes of the pacing
electrode. Research was carried out on materials consisting of 60 human hearts
from 45 to 95 years of age (average 63 +/- 15 yrs), with VVI or DDD pacing
(pacing duration 84 +/- 26 months) fixed in a formalin solution. Classical
macroscopic anatomical methods were applied. In 44 hearts (73.3%) from the
investigated group the posterior tricuspid leaflet was thickened only, and in 24
of these hearts the process regarded not only posterior leaflet but also the
septal one and especially commissure between them. In 52 hearts (86.6%)
inflammatory reaction spread also to the neighbouring part of the electrode. The
length of the neointima-inflammatory tissue ranged from 4 to 8 mm (average 5 +/-
2 mm). On the tip of the electrode in the right ventricle cavity in 56 hearts
(93.3%) we observed that endocardial leads were surrounded by fibrous thickening,
and partially covered by endocardial tissue. We concluded that from the
anatomical point of view the extraction of the pacing electrode seems to be
questionable, especially in long-term permanent pacing. The experimental traction
shows that only recently implanted electrodes were removed without any
complications and in others with fraction of the tip, myocardial tissue avulsion
or such removal was not successful at all.
PMID- 10774089
TI - The types of neurones in the neostriatum of the guinea pig (Cavia porcellus):
Golgi and Kluver-Barrera studies.
AB - The Golgi technique stain was used to reveal the cellular structure of the
neostriatum (nucleus caudatus and putamen) in the guinea pig. The computerised
reconstructions were made from Golgi impregnated neurones. On the basis of
various criteria, 4 types of neurones were distinguished in the guinea pig
neostriatum: 1. The rounded neurones (most numerous) with 5-8 thin dendritic
trunks; 2. The triangular nerve cells with 3 thick dendritic trunks; 3. Two types
of multipolar neurones differing in dendritic arborization pattern with 4-6 and 7
9 primary dendrites, respectively. 4. The pear-shaped cells, which divide into
two distinctly different subpopulations.
PMID- 10774090
TI - Effects of diet and fluoride on early phases of odontogenesis in rats.
AB - The influence of diet and fluoride on odontogenesis in rats was investigated. 20
foetuses, 20 days old, were divided into four groups. The control group was fed
with the standard diet and drank water with 0.16 mg F/l. The second, third and
fourth groups were fed with the deficit, experimental diet and drank distilled
water with 10 and 110 mg of natrium fluoride per litre or without fluoride. In
each group, the observed tooth-bud development assumed different stages. The less
advanced cap stage assumed the tooth-bud in the group fed with the deficit diet
and given distilled water without fluoride. In the remaining groups, the
development of observed first molars in mandible assumed the different level of
its advancement in the same stage of odontogenesis--bell stage.
PMID- 10774091
TI - About variability of Vieussen valve in the adult human heart.
AB - The Vieussen valve is situated at the ostium of the great cardiac vein to the
coronary sinus. There are no details about its shape in anatomic literature. The
tested material consisted of 150 adult human hearts of both sexes from 18 to 85
years of age, fixed in a formalin/ethanol solution. Classical macroscopic
anatomical methods were used. The Vieussen valve was found in about 65% of the
tested material. It showed a large variability in terms of morphology.
PMID- 10774092
TI - Claustrocingulate connections in the rabbit and rat--a stereological study.
AB - Unbiased stereological methods were used for estimating the numerical density and
the total number of claustral neurones projecting to the cingulate cortex in
rabbit and rat. In rat the numerical density of neurones projecting to the
retrosplenial granular cortex (RSG) differed significantly from those projecting
to the retrosplenial agranular (RSA) and cingulate (Cg) cortices while in rabbit
the numerical densities of retrogradely labelled neurones in the claustrum
following injections into various areas of the cerebral cortex did not differ
significantly. The total number of retrogradely labelled neurones in the
claustral limbic zones did not differ significantly in both species. The
quantitative analysis of claustral zones projecting to a different cingulate
cortex area, both in rabbit and rat, reveals that each of these zones is rather
homogeneous.
PMID- 10774093
TI - The role of longitudinal shortening in the general pattern of heart left
ventricle contraction.
AB - This paper constitutes a report of our experience in the assessment of left
ventricle contraction using MRI (Philips 0,5T Gyroscan T5/II) and includes a
suggestion of the study method directed towards establishing the role of
different patterns of ventricle contraction in general ventricle function. In 29
patients, 22 men and 7 women, (average age 55.3) with history of myocardial
infarction, electrocardiographically gated MR images encompassing the entire
heart in the anatomic long and short axis planes were acquired. Significant
positive correlations between long axis shortening and area length ejection
fraction were found on four chamber view images: r = 0.605 at p < 0.05 and on two
chamber view images: r = 0.554 at p < 0.05.
PMID- 10774094
TI - [Diagnostic evaluation of endouterine manual aspiration for the detection of
endometrial hyperplasia and cancer in patients with abnormal uterine bleeding].
AB - The objective was to determinate the diagnostic value of manual vacuum aspiration
with Karman cannula (MVA) for the detection of endometrial hyperplasia and cancer
in patients with abnormal uterine bleeding. Fifty patients with abnormal uterine
bleeding were evaluated with MVA prior to dilatation and curettage (D&C). The
needing of cervical dilatation was noted. A matched analysis of the histological
reports with Wilcoxon contrast test was performed. In order to calculate the
diagnostic value, the histological examination of the tissue recollected by D&C
was defined as gold-standard. Sensitivity, specificity, pre-test probability
(prevalence), post-test probabilities (predictive values) and likelihood-ratios
were calculated. No significant difference between either histological reports in
matched analysis and the insufficient samples proportion was detected. Cervical
dilatation was performed more frequently to D&C (p = 0.0002). The pre-test
probability (prevalence) of endometrial hyperplasia/cancer was 20%. Two cases of
hyperplasia were not detected by MVA (negative false 20%). The endometrial biopsy
for MVA showed a sensitivity of 71% and specificity 93%. The post-test
probabilities for an abnormal and normal biopsy (positive and negative predictive
values) were 62.5% and 95.2%, respectively. The corresponding likelihood-ratios
were 10.23 and 0.3, respectively. The endometrial biopsy for MVA has a high
diagnostic value, similar to D&C, in the detection of endometrial
hyperplasia/cancer in patients with abnormal uterine bleeding with the advantage
to be an office procedure without either risks and costs of D&C.
PMID- 10774095
TI - [Treatment of pelvic endometriosis with goserelin acetate or nafarelin acetate.
Comparative study].
AB - The medical treatment of the pelvic endometriosis includes the hormonal therapy
that attacks directly to the endometriosis lesions or indirectly it inhibits the
endometrial proliferation and it induces atrophy through the estrogenic
deprivation, or to inclination of a combination of these effects. The objective
of the present study was to evaluate the effects of two gonadotrophin release
analogs in the treatment of the endometriosis. 15 patients were studied in who
the diagnosis settled down of endometriosis by means of laparoscope; these were
formed two groups in aleatory form and there were administered to each one them
nafarelin acetate in dose of 200 or 400 micrograms each 12 hours or goserelin
acetate in dose of 3.6 mg every 21 days; the serum levels of the stimulating
follicle, luteinizing, estradiol and prolactin hormones were determined at
intervals of four weeks and the secondary effects of these drugs were reported.
There were carried out a second look laparoscope in 10 patients. The statistical
analysis was carried out by means of the test of hypothesis of Wilcoxon and X2.
Inside those results were found that as much the nafarelin as the Goserelin are
able to diminish the gonadotropins and estradiol serum levels. Both analogs are
effective for the control of the endometriotic lesions. The secondary symptoms
are smaller and better supported by the patients using nafarelin. In conclusion
as much the nafarelin as the goserelin are appropriate medications for the
treatment of the pelvic endometriosis and the election between one or another one
can settle down for the comfort of application, secondary effects and cost.
PMID- 10774096
TI - [Prevalence of gynecologic changes in patients with diabetes mellitus and their
correlation with other variables].
AB - The structural abnormalities of the genitourinary tract and cervical/vaginal
infections are common in patients with diabetes mellitus. The objective was to
determine the prevalence of gynecological abnormalities in diabetic women and to
investigate its association with different variables. Diabetic women, aged 20
years and older who were attending the diabetic outpatient clinic, were randomly
selected. All patients underwent a clinical and gynecological examination and a
urianalysis, and papanicolaou. Smear were obtained. A total of 98 women, 84.7%
type 2 diabetics, with a mean age of 57 +/- 13 years were included. Uretherocele,
cystocele and/or rectocele were present in 19% and cervicitis in 22% of the
patients. Urinary incontinence (OR 3.1, p = 0.03) and the history of multiparity
(OR 4.2, p = 0.03) were statistically associated with these structural
abnormalities. The symptom of vaginal discharge (OR 3.8, p = 0.01) was the only
one variable that correlated with cervicitis. By comparing patients with and
without cervicitis or gynecologic abnormalities, no significant differences were
observed related to the type, duration or treatment of diabetes, blood glucose
control or the evidence of leukocyturia in the urine sample. There is an elevated
prevalence (31%) of gynecological abnormalities (cervicitis and/or structural
abnormalities) in diabetic women, and are mostly asymptomatic.
PMID- 10774097
TI - [Assessment of a preconception preventive program in a community].
AB - Primary Health Care (PHC) is the basic health support that includes health
promotion and disease prevention, considering social and developmental factors.
It is the main axis to pregestational health programs with the basic elements for
the women's self-care. This study evaluated the impact on health behavior and
adherence to a community based pregestational preventive program in 224 women of
reproductive age from Mexico City. The women were exposed to a health education
intervention for twelve months, with free clinical examination every six months
in a mobile screening unit close to their homes. Food and hygiene one to one
orientation was offered, together with anthropometric, blood pressure and
biochemical evaluations. Program adherence was 55%. Most of the women were less
than 25 years of age, education above nine years, non-single, housework
occupation as housewives, from an extended family, with social security and two
or less live children and desire for more. No differences were found in the
evaluated factors between those who continued and those who left the program.
When comparing initial and final data, a significant larger proportion did breast
self-examination, while this was not the case for the Pap smear test, no
differences were found in prevalence of anemia or overweight. Drop-out was mainly
due to a lack of interest, school or work problems and change of address. While
breast self examination showed a positive effect, the negative or no effect on
the other factors requires the intervention of other health professionals and
implies more effort from the women. If one of the objectives of the PHC is health
promotion, nurse intervention is a prominent role in the community.
PMID- 10774098
TI - [Treatment of giant vulvar condylomata acuminata combining CO2 laser and
electrosurgery].
AB - Since no antiviral treatment exists for human papilloma viruses (HPV), the
clinician's role is to treat all detectable lesions in order to help the
patient's immune system fight the virus and to prevent transmission by contact
with lesions. HPV-associated lesions have been treated by a wide range of
modalities, which may be divided into chemical, surgical and immunity-stimulating
methods. We treated patients with large vulva lesions with Electrosurgery in
combination with laser CO2 vaporization. HPV-associated lesions have been treated
by a wide range of modalities, which may be divided into chemical, surgical and
immunity-stimulating methods.
PMID- 10774099
TI - [Vulvar angiomyofibroblastoma. Report of a case and review of the literature].
AB - Angiomyofibroblastoma is a rare mesenchymal tumor predominantly of vulvar
location. It is characterized being of superficial and slow-growth, low
propensity for local recurrence and often misdiagnosed as a Bartholin's gland
cyst, hydrocele of the canal of Nuck and aggressive angiomyxoma. A case of vulvar
angiomyofibroblastoma in a 56 year-old woman is presented. The specimen was
processed by structural and immunohistochemical analysis. It's important to
suspect the diagnosis and to distinguish it of aggressive angiomyxoma.
PMID- 10774101
TI - [Rectal catheter decompression in colonic pseudoobstruction (Ogilvie syndrome).
Report of a case and review of the literature].
AB - The Ogilvie's Syndrome is a major surgical complication. It is defined as a
severe dilatation of the colon, the cecum, ascendant and transverse, without the
presence air at the distal colon following abdominal surgery. The causes are
unknown. We described a clinical case of patient delivered by C-S who developed
this syndrome and a review of the literature. We emphasized on the importance of
the early diagnosis by the use of the traditional abdomen X-Rays and we described
a relatively new approach for this patients through the decompression by
colonoscopy using a Levin's catheter successfully. This is an alternative minimum
invasive treatment which could be of a great benefit for the patients with this
disease.
PMID- 10774100
TI - [Conservative treatment of interstitial ectopic pregnancy and endometriosis with
laparoscopic methotrexate and potassium chloride and complementary management
with nasal nafarelin. Report of a case and review of the literature].
AB - A case of a 30 year-old patient is presented with infertility, 56 days
opsomenorrhea, cervical tenderness, left adnexial mass, beta subunit of Human
Gonadotrophin Corionic (HGC) of 112 mUl/mL, endovaginal ultrasonogram showed
trophoblastic vascular flow with cardiac output, suggestive of ectopic gestation.
Laparoscopy confirmed the diagnostic of left ectopic interstitial pregnancy,
salpingocentesis was done with Methotrexate and potassium chloride and severe
endometriosis was found. The postoperative control with seric levels of beta
subunit HGC were negativized at 28 days. The treatment lasted 4 months with
Nafarelin. The second look Hysteroscopy-Laparoscopy showed complete resolution of
ectopic gestation, endometriosis improvement and bilateral tubal permeability.
PMID- 10774102
TI - [Effectiveness of acarbose in the control of glucose tolerance worsening in
pregnancy].
AB - Gestational diabetes is considered as a carbohydrate intolerance, first diagnosed
during pregnancy. A previous stage of carbohydrate impairement may precede its
abnormality; therefore it may be convenient to establish some management in order
to avoid the gestational diabetes. Six pregnant women who had moderate elevated
level of blood glucose at fasting and postprandial were treated with acarbose,
alpha-glucosidase inhibitor agent, given three times a day before meals. In all
patients fasting and postprandial glucose levels were normalized; pregnancies
went uneventful and the newborns were considered normal. Acarbose was associated
with intestinal discomfort which persisted during the whole pregnancy.
PMID- 10774103
TI - [Viral hepatitis A and postpartum acute renal failure. Report of a case and
review of the literature].
AB - Hepatitis A virus infection (HAV) has been perceived as a self-limited disease.
However, acute renal failure is an infrequent but well-described complication of
HAV infection. Although the mechanisms responsible are uncertain, they may be
related to the immune complex. In this report we describe a patient with HAV and
acute renal failure in the postpartum period.
PMID- 10774104
TI - [Conservative management in severe pre-eclampsia].
AB - A total of 58 women with severe preeclampsia between 28-33 weeks of gestation
were studied during the period from 1 October 1996 to 1 October 1997. Twenty-four
women (42%) developed maternal or fetal indications necessitating early delivery
within 48 hours, meanwhile the other 34 patients (58%) received expectant
management. The average pregnancy prolongation period in the conservative
management group was 6.4 days (range 3 to 18). The primary indications for
delivery in this group were maternal indications 16 (47%), fetal compromise 13
(39%), 34 weeks of gestation 3 (8%), abruption placentae 1 (3%) and preterm labor
1 (3%). The mean birth weight and Apgar score at 5 minutes were 1520 +/- 310 g
and 8, respectively. Expectant management was not associated with fetal death or
maternal complications. The only neonatal death was related with sepsis and
prematurity. The women in the early delivery group totaled two stillbirths and
three neonatal deaths.
PMID- 10774105
TI - [Perinatal morbidity and mortality secondary to systemic lupus erythematosus in a
tertiary care institution].
AB - INTRODUCTION: Autoimmune diseases occur more often in procreation age women,
being systemic lupus erythematosus (SLE) a multisystemic, chronic inflammatory
illness, the prototype of them. OBJECTIVE: Evaluate the behavior of perinatal
morbidity/mortality in a group of pregnant patients, identifying maternal and
secondary neonatal complications secondary to SLE. MATERIAL AND METHODS: Between
January 1992 and December 1997, seventy two cases of maternal SLE were seen at
the Instituto Nacional de Perinatologia in Mexico City. Maternal and neonatal
files were reviewed retrospectively in search of maternal and neonatal
complications secondary to SLE. RESULTS: Maternal SLE diagnosis was confirmed in
all cases: Ideal reproductive age was seen in 84.7% and extreme ages in 15.3% of
the maternal population. Effective prenatal control was carried out in 87% of the
pregnancies and 16.6% required at least one hospitalization during gestation. The
most frequent complications were infectious (37.5%), haematologic (13.9%) and
renal (5.5%). No mortality was seen in the maternal population. Normal weight for
gestational age was seen in 58.3% of the neonates and low weight for gestational
age in 41.6%; prematurity was seen in the same percentage (41.6%). The most
frequent complications in the neonatal population were haematologic (18.0),
respiratory (12.5%), metabolic (8.3%) and heart block and cutaneous lesions
(1.4%). Neonatal lupus was diagnosed in 8.3%, and survival was of 94.4%).
DISCUSSION: Maternal and neonatal morbidity secondary to SLE was seen in less
than 50% of the cases. Infectious complications, the most frequent in the
maternal population, is probably secondary to medical treatment. Of the patients
with neonatal lupus only 2.8% had heart block and cutaneous lesions. Maternal
outcome and neonatal repercussion of maternal SLE do not differ in relation to
other authors results. However it is necessary to evaluate the immunologic
behavior and genetic predisposition because each population has a different of
HLA antigens.
PMID- 10774106
TI - [Transcutaneous electric stimulation (TENS) to reduce pain after cesarean
section].
AB - The main goal of this work was to evaluate the efficacy of transcutaneous
electrical nerve stimulation (n = 25), comparatively with the effects induced by
the intravenous administration of 1 g of Dipyrone (n = 25), to reduce
postoperative pain during the immediate period (4 hours) following cesarean
section. We undertook a clinical study in order to analyze the following
variables: pain intensity, duration of pain, and additional consumption of
analgesic drugs. Our data showed that both treatments resulted insufficient in
order to eliminate completely postoperative pain, requiring the administration of
additional analgesic drugs. This study supports previous findings reporting that
transcutaneous electrical nerve stimulation induces a decrement of 50% on the
total amount of analgesic drugs employed. Transcutaneous electrical nerve
stimulation showed to effectively reduce the intensity and duration of pain of
cutaneous origin, as well as to reduce pain associated with voluntary movements,
in all patients. Perhaps due to the blocking of A peripheral fibers (somatic
pain). However, in 13 patients, this treatment was insufficient to block visceral
pain conducted by type C peripheral fibers. These actions may be related to the
position of the stimulus electrodes, as well as to the frequency of stimulation
used in our study. Taken together, our results are indicative that transcutaneous
electrical nerve stimulation constitutes an alternative treatment in order to
reduce postoperative pain during the immediate period following cesarean birth;
reduces the requirements of analgesic drugs; helps on keeping alert the mothers
and therefore able to attend the newborn; and avoids secondary effects of
analgesic drugs over mother-newborn relationship. Nevertheless, it is necessary
to further explore transcutaneous electrical nerve stimulation, changing the
position of the stimulus electrodes, and the frequency of stimulation, in order
to evaluate its effects on visceral pain.
PMID- 10774107
TI - [Clinical and metabolic effects of oral contraceptives].
AB - The oral contraception most employed, consists in a combination of estrogen and
progestin, the main action in the prevention of ovulation through the inhibition
of the secretion of luteinizing hormone (LH) and follicle stimulating hormone
(FSH). The progestin in combination with estrogen produces an endometrium not
receptive to the oocyte implantation and changes tubal, this affects capacitation
and acrosomal reaction. Since 1960s up to date the reports made had been
established that the OC had been developed adverse effects such as increase
concentration of HDL, increase of apolipoprotein B-100, insulin resistance,
increase in SHBG, atherogenicity, alteration in the coagulation factors and
increase in the risk of venous thromboembolic disease. This work was elaborated
with literature search on MEDLINE between 1985 to 1998, with the purpose to
search the collateral effects of Oral Contraceptives evaluated by other authors.
PMID- 10774108
TI - [Use of modified intrauterine device (IUD) TCu 380 with chromium filaments in the
immediate postpartum].
AB - Postpartum insertion of the intrauterine device (IUD) can provide an effective
and convenient means of contraception. As a result, the use of IUD's has steadily
increased, and the Family Planning Program recommends it because it offers many
advantages. However, a major risk associated with the use of IUD's is the
possibility of its expulsion, which ranges from 4 to 60%. Furthermore, 20% of
women who expelled IUD's were unaware that it occurred, thus increasing their
susceptibility to unwanted pregnancies. IUD's modified by the addition of
biodegradable strands of chromic suture at time of implantation are thought to be
less likely to be expelled, as the sutures anchor the IUD more firmly to the
endometrium, and it is possible that the use of these sutures may decrease the
risk of expulsion. Therefore we determined if the chromic extension to IUD
enhance retention and decreased the rate of expulsion. In one year of study, 150
women received a modified IUD (TCu 380) with chromic catgut number 0 (ccO) in the
transversal arm within 10 minutes of delivery of the placenta. However, only 84
women completed the follow-up study. To evaluate IUD expulsion, exploratory
examinations were conducted during the immediate postpartum, at 7 days postpartum
and at 6 weeks after delivery. We determined the presence or expulsion of the IUD
in these three periods postpartum. Other parameters such as parity, age and
marital status were also considered. A total of 14 modified IUD's (16.6%) were
expelled. This represents a similar frequency of expulsion both during the
immediate postpartum and the 7 days postpartum period. There was no significant
difference in the rate of expulsion between the two periods. Moreover, there was
no expulsion at 6 weeks postpartum. The primiparity women had the highest
percentage of expulsion (22.8%). Single mothers either living with or without
their sexual partner had expulsion rates of 20.6 and 20.5%, respectively. The
highest rate of expulsion when we considered age was in women younger than 30
years of age. There was only one case of expulsion where the mother was unaware
of its occurrence. The results described here indicate that age, parity and civil
status have no direct influence on expulsion of modified IUD's with chrome
extensions. In all postpartum periods studied the p-value was greater than 0.05.
Six weeks postpartum was the only time at which there was no IUD expulsion. This
is most likely a consequence of decreased uterine cavity size and closure cervix.
The modified IUD TCu 380 with chrome strands shows a rate of expulsion similar to
other modified IUD's as evidenced in the literature. However, there is a lower
rate of expulsion than in unmodified IUD's. It is an important to rote that
incomplete expulsion of modified IUD's in this study was considered a total
expulsion which represent loss of contraceptive effectiveness. On the contrary,
if we had considered only completely expelled IUD's in this study, the percentage
would have been significantly lower, as only one total expulsion was found.
Further studies are necessary to investigate consecutive expulsions of the TCu
380 modified IUD.
PMID- 10774109
TI - [Benign epithelial inclusions in pelvic lymph nodes. 2 case reports].
AB - A large number of lymph node inclusions excluding endometriosis have been
described in a variety of anatomical sites; they are usually epithelial and only
rarely non-epithelial. Their presence can give rise to an erroneous diagnosis of
metastasis. Recently the staging laparotomy has become a frequent procedure in
the management of neoplasms of the female genital tract, and involves abdominal
lymphadenectomy, inspection of the peritoneal surface, multiple biopsies and the
resection of suspicious lesions. During the surgery, and among the lesions
excised, the occasional presence of lymph node inclusions can lead to a
diagnostic error. In order to avoid this problem, it is necessary to be
adequately informed about these inclusions, including their anatomic sites, their
histologic characteristics and the knowledge that they can present in lymph nodes
related to an inflammatory process or a tumour. This revision is to alert
pathologist towards a group of lesions which can imitate metastatic carcinoma,
and specially towards those inclusions which present together with malignant
neoplasias of the female genital tract. Recently we received two cases of pelvic
lymph nodes, initially diagnosed as metastatic carcinoma, and eventually found to
correspond to mesothelial cell hyperplasia in one case, and to lymph node
inclusions in the other.
PMID- 10774111
TI - [Change].
PMID- 10774110
TI - [Effect of intrafollicular interleukin-6 levels on the secretion of estradiol and
progesterone in patients treated with in vitro fertilization and embryo
transfer].
AB - The objective was to evaluate the relationship between follicular fluid levels of
Interleukin-6 (IL-6) and the seric concentrations of estradiol and progesterone
during controlled ovarian hyper-stimulation. The levels of IL-6 were measured in
follicular fluid of 15 patients undergone to in vitro fertilization and embryo
transfer and correlated with the values of seric estradiol and progesterone.
There were a negative correlation between follicular levels of IL-6 and either
estradiol and progesterone. Four patients achieved pregnancy following embryo
transfer (pregnancy rate 26.6%), one of them aborted. As conclusion, the
increased levels of IL-6 may be a reaction to controlled ovarian hyper
stimulation and probably a protective response. According to the reduction of
estradiol, there may be a subtle reduction in aromatase action by effect of IL-6
and other cytokines.
PMID- 10774112
TI - [Viral hepatitis c and pregnancy].
PMID- 10774113
TI - [Postpartum sphincter rupture and anal incontinence: prospective study with 259
patients].
AB - AIMS: Damage to the anal sphincter has been considered as the cause of anal
incontinence after childbirth. The aims of the present study were to determine
prospectively the incidence of anal incontinence and anal sphincter damage after
childbirth, and their relationship with obstetric parameters in France. PATIENTS
AND METHODS: We studied 259 consecutive women six weeks before and eight weeks
after delivery. They were asked to fill out a questionnaire dealing with faecal
and urinary incontinence. Anal endosonography (B&K 7-10 MHz) was then performed.
Two independent observers analyzed internal and external anal sphincters.
RESULTS: Two hundred and thirty-three women (90%) were assessed, among whom 31
had had a caesarean section. De novo sphincter defects were observed in 19.3% (39
patients) in the postpartum period only after vaginal delivery (202 patients).
These disruptions occurred with the same incidence after the first and second
childbirth. Independent risk factors (odds ratio; 95% confidence interval) for
sphincter defect were forceps (odds ratio 11.9; 4.8-33.3), perineal tears (odds
ratio 16.1; 4.4-83.9), episiotomy (odds ratio 6.6; 1.7-34.2), and pauciparity <
or = 2 (odds ratio 8.8; 1-78.3), as revealed by multivariate analyses. The
overall rate of de novo anal incontinence was 9% (20 patients), and independent
risk factors involved forceps (odds ratio 4.5; 1.5-13), perineal tears (odds
ratio 3.9; 1.4-10.9), de novo sphincter defect (odds ratio 5.5; 5-15) and
prolonged labor (odds ratio 3.4; 1-11). Among the 20 women who had de novo anal
incontinence, only 45% (9 patients) had sphincter defects. CONCLUSION: De novo
anal incontinence after delivery is multifactorial and anal sphincter defects
account only for 50% of them. Primiparous and secundiparous women have the same
high-risk factor for sphincter disruption and anal incontinence. Since external
anal sphincter disruptions are more frequent than internal anal sphincter damage,
surgical repair should be discussed.
PMID- 10774114
TI - [Voluntary pregnancy termination during 1998 in a French general hospital].
AB - The authors analyzed the etiology of voluntary abortions in a general hospital
during one year. Age, family situation, nationality, children, previous
abortions, type of contraception, and the reasons for aborting were reviewed. The
goal is to determine the target population for effective prevention. Teenagers
(7%), women under 35 years (78%), women with children (64%), primarily with two
children (42%), women with poor use of contraception (pill or condom) (48%) and
women without contraception (36%) were concerned. Social and cultural causes
(unemployment, wedding difficulties, number of children, habitation) were often
associated and different factors are described. Practitioners have little control
over these sociocultural situations. A strong plan involving all the educational
roles is necessary to modify this difficult situation.
PMID- 10774115
TI - [Angiogenesis in cervical cancer].
AB - Angiogenesis is a factor of spread and metastatization. This fact has been
established for many malignancies, but the data concerning cervical cancer are
rather conflicting. In a study including 42 patients affected by cervical cancer
stages IB to IVA, the authors assess the mean capillary density and the
correlations between this parameter and the other anatomoclinical parameters: the
VEGF expression, tumoral oxygenation and the data obtained from dynamic MRI. The
histologic assessment of the capillary density and the data obtained by dynamic
MRI enable us at the same time to quantify the tumoral angiogenesis and establish
the prognosis. The two methods could be used routinely as markers of prognosis.
VGEF surely plays a role in angiogenesis linked with cervical cancer growth, but
its regulation is not definitively clear at the moment. The impact of tumoral
oxygenation (whose place as a prognostic marker is clearly established) on
tumoral angiogenesis and vessels' permeability as well as its control is
currently not clearly established. Further studies on larger populations are
necessary.
PMID- 10774116
TI - [Mammary fibromatosis (apropos of 1 case)].
AB - Fibromatosis (desmoid tumors) is a rare entity expressing a mesenchymatous
proliferation. The breast is an exceptional localisation. The origin is either
the gland itself or the breast is an extension of a desmoid tumor originating
from the chest wall or shoulder. Etiology is still unknown. Clinical and
radiological features mimic the breast carcinoma. Diagnosis is made by
histological studies which show a benign structure contrasting with its
aggressive potential. Surgery is the treatment of choice and consists of wide
excision which can lead to mutilation. Hormonotherapy is used if surgery is too
invasive. We report a case of a female patient aged 21 years who presented for a
mammary fibromatosis, treated by a large surgical excision. Evolution was marked
by the appearance of an other localisation in the contralateral breast.
PMID- 10774117
TI - [Cervix dysplasias: study of Rb and p53 gene expression and correlation with
mitotic activity].
AB - OBJECTIVE: Certain HPV types have transforming properties. These oncogenic
activities are related to the abilities of the viral proteins E6 and E7 to
inhibit the products of two cellular tumor suppressor genes (p53 and Rb
respectively). But the early steps of cervical carcinogenesis are not well known.
The goal of our study was to evaluate cervical intraepithelial neoplasia (CIN)
for the tumor suppressor genes p53 and pRb, the HPV status and the mitotic
activity, in order to better understand the mechanism of carcinogenesis. MATERIAL
AND METHODS: Twenty formalin-fixed paraffin-embedded cone biopsies were selected
because they contained adjacent to normal epithelium different grades of CIN.
Immunohistochemistry was performed for evaluation of PCNA, pRb and p53.
Expression of these different biomarkers was assessed with the help of an image
analysis system, in the different epithelial layers of the different normal and
pathological cervical areas. The results were compared to normal controls.
RESULTS: There is an increase of PCNA expression in normal epithelium adjacent to
CIN, compared to normal controls. As tissues progress from adjacent normal
epithelium to condylomatous lesion and to the different grades of CIN, PCNA
expression increases (mainly in the superficial epithelial layers). For p53 and
pRb, the expression is increased in the basal and parabasal layers of adjacent
normal epithelium and condylomatous lesions. The observance of histologic signs
of CIN is associated with a disappearance of p53 and pRB expression. CONCLUSIONS:
These results indicate that the early steps of cervical carcinogenesis involve
proliferative dysregulation in relation to the p53 and pRb modulatory mechanism.
So expression of viral proteins of HPV is probably the earlier step of
carcinogenesis in cervical carcinoma.
PMID- 10774118
TI - [Effects of automobile lead on the general growth and sexual activity of the
rat].
AB - To identify the active element of automotive exhaust gas responsible for
masculine infertility, previously proved by our laboratory, we undertook these
experiments. Four hundred young male and female rats were exposed during two
months (30 min/d) to three types of automotive exhaust gases. The first type
emanated from an engine running on gasoline with lead, the second from an
unleaded gasoline engine, the third from a diesel engine. These three engines had
the same power (5 horsepower vehicles < 3.5 tons). For the first type of
emissions, some lead deposits were found in the lungs by histologic techniques.
This gas also induced in male rats the atrophy of the testicle, seminal vesicle
and epididym, certain pathological changes in spermatogenesis shown by the
histologic study, and a decrease of the serum's testosterone level. In female
rats, the relative weights of the ovary and uterus, as well as the percentage of
the arrival of oestrus, were not affected by the gaseous treatment. Both the
second and third types of gases seemed less active on the masculine sex as far as
these parameters are concerned. Our study suggests that, for light vehicles,
leaded gasoline pollutes more than unleaded gasoline or diesel fuels, and that
the lead present only in the first type would be the active element responsible
for the masculine infertility and body weight gain reduction in rats.
PMID- 10774120
TI - [Genetics and ovarian cancer--surveillance of a woman belonging to a family at
risk for ovarian cancer].
PMID- 10774119
TI - [Prescription in the labor room: therapeutics in labor induction].
PMID- 10774121
TI - [For or against laparoscopy under local anesthesia?].
PMID- 10774123
TI - Benefits of color coding weapons symbology for an airborne helmet-mounted display
AB - We assessed the advantages of a color-coded weapons symbology for a helmet
mounted display over monochrome symbology by measuring military pilots'
performance while they flew air-to-air combat in a simulator. The pilots fired
missiles significantly sooner without sacrificing probability of kill when using
the color-coded symbology, demonstrating a substantial practical benefit of
color. Actual or potential applications of this work include the design of color
codes for helmet-mounted and other displays that use complex symbology to assist
performance on cognitively challenging tasks.
PMID- 10774122
TI - [Microlaparoscopy under local anesthesia using a laparoscope under local
anesthesia with sedation--arguments for!].
PMID- 10774124
TI - Target cuing in visual search: the effects of conformality and display location
on the allocation of visual attention.
AB - Two experiments were performed to examine how frame of reference (world
referenced vs. screen-referenced) and target expectancy can modulate the effects
of target cuing in directing attention for see-through helmet-mounted displays
(HMDs). In the first experiment, the degree of world referencing was varied by
the spatial accuracy of the cue; in the second, the degree of world referencing
was varied more radically between a world-referenced HMD and a hand-held display.
Participants were asked to detect, identify, and give azimuth information for
targets hidden in terrain presented in the far domain (i.e., the world) while
performing a monitoring task in the near domain (i.e., the display). The results
of both experiments revealed a cost-benefit trade-off for cuing such that the
presence of cuing aided the target detection task for expected targets but drew
attention away from the presence of unexpected targets in the environment.
Analyses support the observation that this effect can be mediated by the display:
The world-referenced display reduced the cost of cognitive tunneling relative to
the screen-referenced display in Experiment 1; this cost was further reduced in
Experiment 2 when participants were using a hand-held display. Potential
applications of this research include important design guidelines and
specifications for automated target recognition systems as well as any terrain
and-targeting display system in which superimposed symbology is included,
specifically in assessing the costs and benefits of attentional cuing and the
means by which this information is displayed.
PMID- 10774125
TI - Good vibrations: tactile feedback in support of attention allocation and human
automation coordination in event-driven domains.
AB - Observed breakdowns in human-machine communication can be explained, in part, by
the nature of current automation feedback, which relies heavily on focal visual
attention. Such feedback is not well suited for capturing attention in case of
unexpected changes and events or for supporting the parallel processing of large
amounts of data in complex domains. As suggested by multiple-resource theory, one
possible solution to this problem is to distribute information across various
sensory modalities. A simulator study was conducted to compare the effectiveness
of visual, tactile, and redundant visual and tactile cues for indicating
unexpected changes in the status of an automated cockpit system. Both tactile
conditions resulted in higher detection rates for, and faster response times to,
uncommanded mode transitions. Tactile feedback did not interfere with, nor was
its effectiveness affected by, the performance of concurrent visual tasks. The
observed improvement in task-sharing performance indicates that the introduction
of tactile feedback is a promising avenue toward better supporting human-machine
communication in event-driven, information-rich domains.
PMID- 10774126
TI - Effects of mission rehearsal simulation on air-to-ground target acquisition.
AB - Traditionally military aviators have prepared for air-to-ground bombing missions
with maps and aerial photographs of their targets. Mission rehearsal systems
augment these media by allowing pilots to view simulated ingress to their target,
as seen from the cockpit perspective. In the present experiment we assessed the
benefits of mission rehearsal with a task requiring observers to view recorded
approaches to target objects and to detect the target objects as quickly as
possible. Results indicated that premission simulations allowed observers to
detect target objects at greater stand-off ranges than did study with maps and
aerial photographs alone. Actual or potential applications of this research
include the deployment of a mission rehearsal system to assist aviators' mission
planning.
PMID- 10774127
TI - Wrist and forearm posture from typing on split and vertically inclined computer
keyboards.
AB - A study was conducted on 90 experienced office workers to determine how
commercially available alternative computer keyboards affected wrist and forearm
posture. The alternative keyboards tested had the QWERTY layout of keys and were
of three designs: split fixed angle, split adjustable angle, and vertically
inclined (tilted or tented). When set up correctly, commercially available split
keyboards reduced mean ulnar deviation of the right and left wrists from 12
degrees to within 5 degrees of a neutral position compared with a conventional
keyboard. The finding that split keyboards place the wrist closer to a neutral
posture in the radial/ulnar plane substantially reduces one occupational risk
factor of work-related musculoskeletal disorders (WMSDs): ulnar deviation of the
wrist. Applications of this research include commercially available computer
keyboard designs that typists can use and ergonomists can recommend to their
clients in order to minimize wrist ulnar deviation from typing.
PMID- 10774128
TI - Information structure and the relative efficacy of tables and graphs.
AB - Users and system designers often prefer to display information with graphs rather
than with tables. However, empirical studies that compared task performance with
the two display types frequently revealed either an advantage of tables over
graphs or no differences between the displays. This apparent contradiction may
result from previous studies in which the importance of the structure that
usually exists in displayed information is overlooked. We predict that graphic
displays will have an advantage over tables when the displayed information has
structure and when this structure is relevant for the task. These conditions
generally exist in the actual use of information displays, but have seldom been
assessed in experiments. In the present study participants in an experiment
performed an information extraction task and a prediction task with unstructured
or structured data and with different levels of prior information about the
structure. The results showed that the information structure and prior knowledge
about the existence of structure affected the advantage of graphic displays over
tables when task performance depended on the use of structure. Existing
approaches to the study of displays were analyzed in view of these findings.
Actual or potential applications of this research include the development of
better displays for process control and decision support and better operator
training programs.
PMID- 10774130
TI - Foot flare and foot axis.
AB - Most commercial footwear is designed and manufactured on a curved last, although
the amount of curvature of the last and the turning point of the last centerline
have not been formally determined. In this study, we used principal component
analysis to determine the foot axis so that lasts that match feet can be
produced, resulting in a good fit. In evaluating 50 Hong Kong Chinese
participants, we found that the center of the foot is located at approximately
52% of the foot length measuring from the back of the foot (SD = 0.65%) and that
Hong Kong participants have a mean inflare (inward curvature) of 3.2 degrees. The
foot center and inflare measures will help determine the fit between footwear and
feet. Applications of this research include the ability to incorporate foot flare
into the design and manufacture of footwear.
PMID- 10774129
TI - The persuasiveness of synthetic speech versus human speech.
AB - Is computer-synthesized speech as persuasive as the human voice when presenting
an argument? After completing an attitude pretest, 193 participants were randomly
assigned to listen to a persuasive appeal under three conditions: a high-quality
synthesized speech system (DECtalk Express), a low-quality synthesized speech
system (Monologue), and a tape recording of a human voice. Following the appeal,
participants completed a posttest attitude survey and a series of questionnaires
designed to assess perceptions of speech qualities, perceptions of the speaker,
and perceptions of the message. The human voice was generally perceived more
favorably than the computer-synthesized voice, and the speaker was perceived more
favorably when the voice was a human voice than when it was computer synthesized.
There was, however, no evidence that computerized speech, as compared with the
human voice, affected persuasion or perceptions of the message. Actual or
potential applications of this research include issues that should be considered
when designing synthetic speech systems.
PMID- 10774131
TI - A new class of auditory warning signals for complex systems: auditory icons.
AB - This simulator-based study examined conventional auditory warnings (tonal,
nonverbal sounds) and auditory icons (representational, nonverbal sounds), alone
and in combination with a dash-mounted visual display, to present information
about impending collision situations to commercial motor vehicle operators. Brake
response times were measured for impending front-to-rear collision scenarios
under 6 display configurations, 2 vehicle speeds, and 2 levels of headway.
Accident occurrence was measured for impending side collision scenarios under 2
vehicle speeds, 2 levels of visual workload, 2 auditory displays,
absence/presence of mirrors, and absence/presence of a dash-mounted iconic visual
display. For both front-to-rear and side collision scenarios, auditory icons
elicited significantly improved driver performance over conventional auditory
warnings. Driver performance improved when collision warning information was
presented through multiple modalities. Brake response times were significantly
faster for impending front-to-rear collision scenarios using the longer headway
condition. The presence of mirrors significantly reduced the number of accidents
for impending side collision scenarios. Subjective preference data indicated that
participants preferred multimodal displays over single-modality displays. Actual
or potential applications for this research include auditory displays and
warnings, information presentation, and the development of alternative user
interfaces.
PMID- 10774132
TI - The design of a visual display for the presentation of statistical quality
control information to operators on the plant floor.
AB - We applied human-centered design methodologies to enhance the presentation of
product quality information to operators on a manufacturing plant floor. First,
an initial visual display concept that integrated a pictorial representation of a
product with standard graphical and tabular information about the product's
quality was refined through iterative design and testing. A preliminary study was
then conducted to determine the specific features of such a display (termed a
pictorial control chart) from among eight candidate detail designs. Finally, a
formal study was conducted to compare the performance of operators using this
refined pictorial control chart design with their performance using a
conventional control chart. Operators completed a quality control task in
significantly less time using the pictorial control chart. There were no
significant differences in the number of errors committed with the two charts.
Subjective measures showed a significant preference for the pictorial control
chart. Actual or potential applications of this research include the development
of quality control tools that are useful to and usable by operators on the
manufacturing plant floor.
PMID- 10774134
TI - Work organization, job stress, and work-related musculoskeletal disorders.
AB - Recent studies indicate potential links among work organization, job stress, and
work-related musculoskeletal disorders (WRMDs). In this paper we propose several
pathways for a theoretical relationship between job stress and WRMDs. These
pathways highlight the physiological, psychological, and behavioral reactions to
stress that can affect WRMDs directly and indirectly. One model stipulates that
psychosocial work factors (e.g., work pressure, lack of control), which can cause
stress, might also influence or be related to ergonomic factors such as force,
repetition, and posture that have been identified as risk factors for WRMDs. In
order to fully understand the etiology of WRMDs, it is important to examine both
physical ergonomic and psychosocial work factors simultaneously. Smith and
Carayon-Sainfort (1989) have proposed a model of the work system for stress
management that provides a useful framework for conceptualizing the work-related
factors that contribute to WRMDs. Practical applications of this research include
practitioners taking into account psychosocial work factors and job stress in
their efforts to reduce and control WRMDs.
PMID- 10774133
TI - Young novice driver subtypes: relationship to high-risk behavior, traffic
accident record, and simulator driving performance.
AB - Two studies were undertaken to obtain empirical support for the existence of
driver subtypes in the young novice driver population. In Study 1, 198
participants (55% male) aged 16 to 19 completed an extensive self-report
questionnaire. Five novice driver subtypes were identified through a cluster
analysis of personality and driving-related measures. Two relatively high-risk or
deviant subtypes (Clusters 1 and 5) were identified, characterized by high levels
of driving-related aggression, competitive speed, driving to reduce tension,
sensation seeking, assaultiveness, and hostility. The individuals in Cluster 5
also reported low levels of emotional adjustment and high levels of depression,
resentfulness, and irritability. In Study 2, a subset of participants from each
of the subtypes drove several scenarios in a driving simulator. The subtypes
differed in their responses to an emergency situation and several potential
traffic hazards. They also differed in the proficiency with which they could
control their attention among concurrent tasks in high-workload situations. Most
of the significant differences were related to lower levels of driving skill
among the two most deviant subtypes (Clusters 1 and 5). The potential
applications of this research include the design of training programs and other
countermeasures to address the young novice driver crash problem.
PMID- 10774135
TI - Aurally aided visual search in three-dimensional space.
AB - We conducted an experiment to evaluate the effectiveness of spatial audio
displays on target acquisition performance. Participants performed a visual
search task with and without the aid of a spatial audio display. Potential target
locations ranged between plus and minus 180 degrees in azimuth and from -70
degrees to +90 degrees in elevation. Independent variables included the number of
visual distractors present (1, 5, 10, 25, 50) and the spatial audio condition (no
spatial audio, free-field spatial audio, virtual spatial audio). Results
indicated that both free-field and virtual audio cues engendered a significant
decrease in search times. Potential applications of this research include the
design of spatial audio displays for aircraft cockpits and ground combat
vehicles.
PMID- 10774137
TI - Trichoepithelioma papulosum multiplex.
AB - Trichoepithelioma papulosum multiplex is an uncommon autosomal dominant disorder
in which multiple trichoepitheliomas are seen. Its cause may be a defective tumor
suppressor gene. Studies have mapped this gene to the 9p21 locus. However, there
is a parallel or identical syndrome of multiple trichoepitheliomas and
cylindromas. Within a given family, some members may have cyclindromas whereas
others may have trichoepitheliomas or a combination of both. Although preliminary
evidence suggests a different gene is responsible, it is possible that TPM may be
caused by more than two independent genes, with some cases of TPM due to
impairment of the gene for cylindromatosis. This entity, as well as other
disorders with multiple appendageal tumors, may require clarification and
distinction from TPM.
PMID- 10774136
TI - Effect of lifting belts on trunk muscle activation during a suddenly applied
load.
AB - The National Institute for Occupational Safety and Health suggests there is
insufficient biomechanical or epidemiological evidence to recommend the use of
back belts in industry. From a biomechanical perspective, previous work suggests
that lifting belts stiffen the torso, particularly in the frontal and transverse
planes. To determine whether lifting belts stiffen the torso and alter the trunk
muscle response during a sudden loading event, we tested the hypotheses that (a)
lifting belts alter peak muscle activity recorded with electromyography (EMG)
during sudden loading and (b) lifting belts have a larger impact on trunk muscle
response when sudden loads are applied asymmetric to the torso's midsagittal
plane. A sudden load was delivered to 10 men and 10 women without history of low
back disorder via a cable attached to a thoracic harness; motion was restricted
to the lumbar spine. Results indicate that gender was not a significant factor in
this study. The lifting belt reduced the peak normalized EMG of the erector
spinae muscles on average by 3% during asymmetric loading, though peak normalized
EMG was increased by 2% during symmetric loading. Lifting belts have been shown
to slightly reduce peak erector spinae activity during asymmetric sudden loading
events in a constrained paradigm; however, the effects of lifting belts are too
small to provide effective protection of workers. Actual or potential
applications include the assessment of lifting belts as protective devices in
workers based on the effects of lifting belts on the trunk muscle activity.
PMID- 10774138
TI - Tinea capitis: current concepts.
AB - Tinea capitis is an important fungal infection that may at times be a clinical,
diagnostic and therapeutic challenge. It is common in childhood around the world,
becoming almost epidemic in some communities. The central European and American
experience with it is somewhat variable, due to different etiologic fungi. The
use of topical antifungal agents and other approaches is stressed as of value
alongside the use of systemic antifungal medication.
PMID- 10774139
TI - Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous
pemphigoid.
AB - Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated
by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This
study investigated BP-associated HLA-DR and -DQ genes among Japanese patients. We
analyzed HLA-DR and -DQ genes among 23 Japanese BP patients based on the
polymerase chain reaction-restriction fragment length polymorphism. Eighteen of
these 23 patients (78%) carried at least one allele of HLA-DRB1*04 or DRB1*1101,
with significant increases in HLA-DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and
DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles
DRB1*1101 and DQB1*0302 (corrected p < 0.05 for each comparison), when compared
to control subjects. These data differ from the accepted DQB1*0301 (DQ7)
association with the same disease among Caucasians. These findings indicate that
different HLA class II haplotypes genetically influence susceptibility to BP
among different ethnic groups. Our findings, together with previous reports on
Caucasian patients with the pemphigoid group of bullous diseases, suggest that
HLA-DRB1 molecules might participate in the regulation of autoimmune responses to
BP antigens.
PMID- 10774140
TI - Correlation between deposition of immuno-components and infiltration pattern of
polymorphonuclear leukocytes in the lesions of chronic urticaria.
AB - Urticaria is often associated with perivascular infiltration of leukocytes into
the lesions. Although mast cell-derived chemical mediators are considered to play
crucial roles in the infiltration of leukocytes as well as in the dermal edema,
other mechanisms for the leukocyte infiltration have not been well defined. This
study revealed that approximately 25% of the cases of chronic idiopathic
urticaria in whom wheals had continued for more than 12 h had deposition of
immuno-components in the lesions, although histological examination of the
lesions did not show leukocytoclastic vasculitis. In these lesions with
deposition of immuno-components, both neutrophils and eosinophils had infiltrated
at a constant ratio (approximately 2:1), whereas, in the lesions without
deposition, a variable population of leukocytes was seen. This result suggests
that activation of complements occurs in the lesions of a considerable percentage
of patients with chronic idiopathic urticaria and that the complement fragments
influence the infiltration patterns of polymorphonuclear leukocytes.
PMID- 10774141
TI - A case of allergic urticaria caused by erythritol.
AB - A case of allergic urticaria due to erythritol is herein reported. A 24-year-old
female presented with severe wheals over her whole body. The urticaria occurred
after she had drunk a glass of canned milk-tea. When the cause of her skin
reaction was examined, it was found that the drink contained erythritol; this was
determined to have caused her urticaria. Erythritol has recently been used as an
artificial sweetener in many kinds of foods and drinks because it contains no
calories. Food and drink additives should thus be included in the differential
diagnosis of allergic urticaria.
PMID- 10774142
TI - Granuloma annulare in herpes zoster scars.
AB - A 54-year-old Japanese female developed granuloma annulare twice in herpes zoster
scars. Soon after the second event, she developed ulcerative colitis, which was
well controlled by sulfonamides and corticosteroid suppository. She had no
history of diabetes mellitus. There was no recurrence of granuloma annulare by
June of 1999. Granuloma annulare might have contributed to the complications of
ulcerative colitis, although this had not been noticed before.
PMID- 10774143
TI - Cutaneous CD30 (Ki-1)-positive anaplastic large cell lymphoma preceded by
Hodgkin's disease.
AB - A 38-year-old female was diagnosed as Hodgkin's disease of the axillar lymph
nodes, nodular sclerosis type, as evidenced by the presence of Reed-Sternberg
cells positive for CD30 and CD15 and negative for CD3, CD20, and CD45. She
achieved complete remission after combination chemotherapy. Two years later, she
noticed a red papule on her public area without any lymph node involvement. The
biopsy specimens showed diffuse proliferation of large-sized atypical lymphoid
cells positive for CD30 and CD45, and negative for CD3, CD20 and CD15. These
findings were mostly compatible with CD30 (Ki-1)-positive anaplastic large cell
lymphoma (Ki-1 lymphoma). Our case is considered to be cutaneous Ki-1 lymphoma
preceded by Hodgkin's disease.
PMID- 10774144
TI - Pityriasis rubra pilaris (PRP): report of four cases.
AB - Four patients with pityriasis rubra pilaris are reported. The diagnosis in each
was based upon well-recognized clinical features. Two of them, a mother and son,
had the disease since childhood and were marked by relative remission in spring
and exacerbation in autumn. Moderate to severe pruritus was a common dominator.
Erythroderma was a presenting feature in one case. Although histopathology was
considered imperative, it only supplemented the clinical expression. Vitamin A in
heavy dosage, supplemented by vitamin E and stanozolol in tandem, was the
mainstay of treatment.
PMID- 10774145
TI - Myelodysplastic syndrome following treatment of malignant melanoma with
vincristine, ACNU, and dacarbazine.
AB - Therapy-related myelodysplastic syndrome is a rare adverse effect in melanoma
patients elicited by chemotherapy. We report a case of myelodysplastic syndrome
following treatment of malignant melanoma with alkylating agents. Peripheral
blood showed a remarkable suppression of three cell lineages, and the bone marrow
was slightly hypercellular. However, no morphological abnormalities were detected
in the peripheral blood or the bone marrow, and chromosomal analysis was normal.
PMID- 10774146
TI - Post-scabetic nodules: a lymphohistiocytic reaction rich in indeterminate cells.
AB - We studied six infants and two adult cases of nodular scabies with immunostains
and electron microscopy. All eight cases have had either direct (KOH) or family
histories of scabies and were treated with lindane 1% cream or permethrin 5%
cream. Family members responded very well, but our patients developed multiple
papulo-nodular lesions which were initially very pruritic and, in some cases,
persisted from several months to over one year. H & E stain of biopsied tissue
sections revealed a heavy perivascular and periappendageal lymphohistiocytic cell
infiltration. Immunophenotype of these cells was compatible with Langerhans
cells, i.e. CD1A (+), S-100 (+) and HLA-DR (+). Electron microscopy showed that
these histiocytic cells satisfied all the ultrastructural criteria of Langerhans
cells except for the absence of Birbeck's granules. Lag, a monoclonal antibody
for Birbeck's granules, was negative. "Persistent nodules in scabies" or "nodular
scabies" seems to represent a prolonged response of indeterminate cells
lymphocytes to mite antigens.
PMID- 10774147
TI - Eosinophilic pustular folliculitis: report of seven cases in Thailand.
AB - Seven cases of eosinophilic pustular folliculitis (EPF) were diagnosed at the
Institute of Dermatology within the seven years from 1989-1996. There were 4
males and 3 females, age 24-44 years, with durations of the disease before
diagnosis ranging from 3 months to 5 years. The face was the most commonly
involved area. Lesions also occurred simultaneously on other sites including the
chest, trunk, scalp, and palmoplantar areas. Diagnosis was made from clinical
features, hematologic examinations, and histopathologic pictures. Topical
piroxicam gel, 0.5%, and oral indomethacin gave good results; some lesions
subsided within a few days, and the remissions lasted for four months to five
years.
PMID- 10774149
TI - Localized multiple glomus tumors of the face and oral mucosa.
AB - We describe a 54-year-old patient with an unusual localization of localized
multiple glomus tumors. She had several nodules on the left mandibular area,
lower lip, and anterior part of the buccal mucosa. A biopsy taken from the left
mandibular area showed cystically dilated vessels lined by endothelial cells and
a few outer layers of glomus cells in the dermis to subcutis. Localized multiple
glomus tumors are rare, and both their facial and oral mucocal localization are
extremely rare.
PMID- 10774148
TI - A case of erythromelalgia successfully controlled by systemic steroids and
pentazocine--is it related to a unique subtype of neutrophilic dermatosis?
AB - Erythromelalgia is a rare cutaneous disorder characterized by erythema, burning
discomfort, and warmth of the extremities. Its form may be adult- or early-onset,
and it may be further classified as idiopathic or secondary. Its pathogenesis and
histopathologic findings have not yet been clearly defined. Various treatment
modalities have been tried, but, for the idiopathic type, none has been
successful. We present a case of adult-onset idiopathic erythromelalgia with
unusual histopathological findings which showed a remarkable response to
corticosteroids and pentazocine.
PMID- 10774150
TI - Solid facial edema in a patient with rosacea.
AB - We report a 53-year old man with symmetrical nonpitting edema, conjunctivitis,
and acneiform eruptions on the face. Histopathological examination showed
perifollicular lymphohistiocytic infiltration and telangiectasias in the upper
dermis. Loosely aggregated non-caseating granulomas were scattered through the
dermis; some of them were seen in the perifollicular regions. The patient was
treated with fleroxacin (100 mg/day, orally) for two weeks with a marked
reduction of both solid facial edema and periorbital edema.
PMID- 10774151
TI - Cassiopeia flap: modification of Limberg flap for saving normal skin.
AB - Local flaps have the advantages of texture matching and increased flap survival
rate. The proper local flap planning for each lesion causes the dermatologist to
be reluctant to employ them. We propose a modified local flap, the "Cassiopeia
flap", with three simple marking points made on the ends of the diameter and on
the equidistant point along the diameter; two points from equilateral triangles
form a "W (Cassiopeia)". We applied this modification to ten lesions on the face,
scalp, trunk and thigh with excellent results.
PMID- 10774152
TI - Hereditary wooly hair in an Indian family.
PMID- 10774153
TI - [Occlusal function and periodontal tissue].
PMID- 10774154
TI - [Current status of study on obturator prosthesis].
PMID- 10774155
TI - [Clinical study on risk management for dental implant treatment--Part 1. Clinical
retrospective study on the medically compromised patients at clinic for oral
implant].
AB - A retrospective study on medically compromised patients was made using 1,000
outpatients who visited the Clinic for Oral Implant, University Hospital, Faculty
of Dentistry, Tokyo Medical and Dental University between April 1995 and June
1998. The results were as follows: 1. 35.3% (353 patients: 140 males and 213
females) of the outpatients were medically compromised. 2. The greatest number of
medically compromised patients was in the 50-59 age group (118 cases), followed
by those in the 40-49 and 60-69 age groups. 3. The highest ratio of medically
compromised patients was in the 60-69 age group (48.2%), followed by those in the
70-79 and 50-59 age groups. 4. Among the 353 patients, 96 (27.2%) underwent
surgical treatment such as insertion of implant (68 cases), removal of implant,
extraction of tooth, and free gingival graft. 5. Among the 68 patients who
underwent insertion of implant, in a classification by type of disease, the
patients with cardiovascular diseases were the most numerous (33.9%), followed by
metabolic and digestive tract diseases. 6. All surgical treatments of implant
insertion were performed under local anesthesia, while monitoring cardiac and
respiratory function, and SpO2. Among the 68 patients, 9 underwent operation
under intravenous sedation and 2 under nitrous oxide inhalation sedation. All 11
patients had hypertension. The results suggested that identification of
preoperative risk factors, precise recognition of general condition, and
establishment of control system are important to manage medically compromised
patients for dental implant treatment.
PMID- 10774156
TI - [Growth analysis of experimentally-induced unilateral premature fusion of the
coronal suture in rat].
AB - The purpose of this study was to investigate the effect of early fixation of the
coronal suture on the skeletal growth pattern of maxillary complex in rat. Rats
were sacrificed at 2, 4, 6, and 8 weeks after operation and their dryskulls were
prepared. Computerized images of dorsoventral cephalograms were measured and
analyzed statistically. The left coronal suture in the experimental group was
fixed with cyanoacrylate adhesive at 4 days old, and the rats were fed with hard
diet after weaning. Their snout bent towards the operated side 4 weeks after
operation and then had a tendency to grow back towards the mid line. The left
palatine bone was the most affected in the maxillary complex. There were no
specific findings in the maxilla. Catch up growth of the left palatine and
premaxillary bone was found 4 weeks after operation. On the other hand, this
catch up growth was hardly found in another experimental group, which upper and
lower incisor edges were trimmed every other day and received a soft diet. A
number of direct measurements on the palatine and the premaxillary bone indicated
compensatory growth following the changing masticatory function such as incisor
edges trimming and diet difference. It was concluded that functional effects of
incisal occlusion might suppress skeletal deformity formed with unilateral
coronal synostosis.
PMID- 10774157
TI - [Study on health awareness of home helper for dependent elderly].
AB - The purpose of this study was to investigate the level of oral health awareness
and oral health care activities of home helper for dependent elderly. A
questionnaire was mailed to persons who took the profession course of care worker
training and education (second and third grade) for home helper and short term
course (special subject) at care worker support center foundation (33 branches).
Responses were obtained from 220 persons qualified as home helpers. Of 220 home
helpers, 104 (47.3%) had worked as a home helper for fewer than six years. One
hundred forty two (64.5%) were trained and educated for a home helper as a second
grade. The results were as follows: 1. One hundred eleven (50.5%) had used a
dental floss and an interdental brush. 2. Two hundred eighteen (99.1%) thought it
was necessary to perform oral cleaning of dependent elderly. 3. Two hundred
fifteen (97.7%) hoped to perform the oral cleaning of dependent elderly. 4. Two
hundred nine (95.0%) considered oral cleaning distasteful. 5. Two hundred three
(92.3%) recognized food debris between natural teeth and the denture of dependent
elderly who could perform oral cleaning themselves. 6. Two hundred three (92.3%)
recognized food debris between natural teeth and the denture of dependent elderly
who could not perform oral cleaning themselves. 7. One hundred twenty (54.5%) had
been trained in oral cleaning for dependent elderly. 8. Two hundred twelve
(96.4%) hoped to receive training in oral cleaning for dependent elderly.
PMID- 10774158
TI - [Concentration and individual variation of inorganic ions in unstimulated whole
saliva].
AB - The purpose of this study was to know the range of fluctuation of inorganic ion
concentrations and pH in the unstimulated whole saliva and also to know if there
is individual difference between subjects which surpasses this fluctuation. Whole
saliva was collected seven times between 9 AM and 4 PM at one- or two-hour
intervals from ten subjects aged 24 to 27 years. The inorganic ion concentrations
and pH were analyzed using an ion chromatogram and a pH electrode respectively.
The coefficients of variation of the inorganic ion concentrations were between
24% to 43%, indicating that it is misleading to interpret only one data obtained
as the true value of the subject. However, statistical analysis showed that the
pH value and inorganic ion concentrations were significantly different among many
of the subjects, in spite of the fluctuation within individual subjects. On the
other hand, most of the correlations were statistically significant among pH and
each of the inorganic ions. Above all, the correlation coefficient between
potassium and phosphate ion concentrations was high. In contrast, the sodium ion
did not have any significant correlation with most of the other ions. The results
were discussed in reference to the salivary secretion mechanism.
PMID- 10774159
TI - [Mechanical behavior of the cement layer of a cast crown--effect of the
mechanical properties of casting alloy].
AB - Experimental crowns with uniform thickness at their axial surfaces were made of
dental casting gold-silver-palladium alloy (12% gold) and dental casting gold
alloy (Type IV). They were cemented on model teeth for abutment and their
deformations under applied loads were measured with strain gages. The effect of
axial metal thickness on the crown's rigidity and the cement fracture strength
were examined. Among the structures of cemented crowns and abutment teeth, that
of the axial metal thickness of 0.3 mm had cement failure at the smallest loads.
As the metal thickness was increased, the crown's deformation decreased and the
cement failure load increased. For a thickness greater than 0.7 mm, however, the
increase in failure load was not obvious. The difference of the casting alloy had
no significant effect on the cement fracture. Accordingly, the rigidity of dental
prostheses should be one of the most important design factors for preventing
failure under occlusal load, and it is recommended that the thickness of the
axial surface should be more than 0.7 mm.
PMID- 10774160
TI - [A newly developed method for taking pictures of tooth crown cracks for clinical
records].
AB - It is very important to examine fine cracks on the crown surface of traumatized
tooth in the dental clinic because the presence of these cracks may cause
discomfort or hypersensitivity of the tooth. By the emission of routinely used
light, it is difficult to illuminate cracks, and the usual intraoral photography
using strobe light emission is not useful to make records of cracks in most
cases. In the present study, a method for taking pictures to record tooth crown
cracks was newly developed using LED as a light source, and applied to patients
with traumatized teeth in the dental clinic. The results were as follows: 1.
Cracks on the tooth surface could be confirmed with the LEDs of all the colors
used in this study. However, the blue LED enabled cracks in the incisal edge part
to be more easily confirmed, and the white LED enabled cracks in the cervical
part to be more easily confirmed. 2. Cracks of multiple modalities on the tooth
surface was illuminated more often when the LED light was emitted at 45 degrees
to the axis of the tooth than 90 degrees. 3. The light exposure field became
wider by the use of the LED of diameter 5 mm than that of diameter 3 mm. However,
the LED of diameter 3 mm was more favorable than that of diameter 5 mm for the
observation of the cracks because the former could more easily change the
direction of light emission.
PMID- 10774161
TI - [Study on regeneration of mandibular bone with bioabsorbable organic/inorganic
composite membrane].
AB - Guided bone regeneration (GBR) has attracted much attention as a means to treat
bone defects and congenital malformation. However, presently available materials
are not ideal and further improvements are necessary. Hence we have been
developing a novel bioabsorbable composite material beta-TCP/CPLA for the GBR
technique. The polymeric matrix is a copolymer of poly-L-lactide acid and fatty
polyester (CPLA) that is biodegradable by hydrolysis, and the ceramic filler is
beta-tricalcium phosphate (beta-TCP) that is bioabsorbable and has good
osteoconductivity. The materials were evaluated by in vivo and in vitro
experiments. Furthermore, animal experiments with mandibular bones defects in
dogs were carried out. Good bone regeneration was observed in the case of the
treatment with beta-TCP/CPLA membrane whereas almost no bone regenerated in the
cases without the membrane. beta-TCP/CPLA membranes were suggested to have
promising properties for bone defect treatment.
PMID- 10774162
TI - [Evaluation of masticatory comminute function using multiple variables--Part II:
Analysis of masticatory efficiency from EMG duration].
AB - For analysis of parameters, which can represent stomatognathic function, a
possibility for the estimation of masticatory efficiency without analyzing food
comminution was shown in Part I. Since there is a necessity for more precise
estimation of masticatory efficiency to enable comparison with other parameters,
the variance from the central value of food particle size was quantified and a
new evaluation of masticatory efficiency, which can be adapted to any comminuted
foods and has a good reproducibility was devised. The relationship between the
masticatory efficiency originating from the side of comminuted food and the
parameters that represent a variance of electromyogram (EMG) duration was
analyzed. Then, the total variances of EMG duration, originating from working
side masseter, corresponding to the task, which is consumed by food comminution,
were calculated. That is the masticatory efficiency, which can be found from the
side of EMG. A negative correlation between masticatory efficiencies, originating
from the sides of food comminution and power supply was found. Therefore,
estimation of masticatory efficiency using EMG measurements from the side of EMG
may be possible.
PMID- 10774163
TI - [The fate of epithelial cells during fusion of primary palate in vitro].
AB - It has been demonstrated that palatal shelf epithelium transforms into
mesenchymal cells during fusion of the secondary palate. However, the fate of
epithelial cells in primary palate formation is still unclear. To specify the
presumptive fusion area of the primary palate, focal labeling of epithelial cells
of medial nasal prominence (MNP), lateral nasal prominence (LNP) and maxillary
prominence (Mx) of gestational day 12.0 rat embryos was initially done with
fluorescent DiI, and they were cultured for 24 h. As a result, the presumptive
fusion area was identified and it was found that there was a difference of the
fusion process between MNP-Mx and MNP-LNP. Next, in order to elucidate the fate
of epithelial cells in the fusion areas, facial epithelium was labeled with a
recombinant adenovirus, Adex-LacZ in the whole embryo culture system and they
were observed over time (12 h, 24 h, 36 h and 48 h). LacZ positive cells were
observed in the fused region of MNP-Mx and MNP-LNP. Moreover, it was found that
there were not only double positive cells of LacZ and TUNEL staining of apoptosis
but also some TUNEL nonpositive cells. These findings indicated that a number of
epithelial cells in the fusion area become apoptosis, but some cells survive by
epithelial-mesenchymal transformation during primary palate formation.
PMID- 10774164
TI - [Immunohistochemical analysis of bronchial mucosa in severe asthmatics treated
with long-term, high-dose inhaled BDP].
AB - To analyze specific mucosal changes in asthmatic patients receiving long-term,
high-dose beclomethazone dipropionate (BDP) inhalation therapy, we performed
bronchial mucosal biopsies and immunohistochemical analysis of patients who had
been treated with or without BDP-inhalation. Our study enrolled 6 chronic severe
asthmatics who were treated with 1,800 micrograms/day or more of BDP with regular
use for more than 3 years (HD-BDP group), 6 mild asthmatics who were not treated
with BDP (non-BDP group), and 6 control subjects. Specimens of bronchial mucosa
were stained with anti-EG 2 (eosinophils), anti-UCHLA-1 (T lymphocytes) and anti
tryptase (mast cells). Although limited eosinophil infiltration was observed in
the HD-BDP and control groups, a significant increase was noted in the non-BDP
group. The infiltration of both T lymphocytes and mast cells exhibited a
statistically significant increase in the non-BDP group compared to the HD-BDP
and control groups. In chronic severe asthmatics, airway mucosal cell
infiltration was reduced by high-dose and long-term inhaled BDP therapy, and BDP
also relieved their asthmatic symptoms. However, in mild asthmatics, bronchial
mucosal cell infiltration remained high. For such patients, we concluded that
initiating BDP therapy from an early stage may bring clinical improvement and
help prevent cell infiltration.
PMID- 10774165
TI - [The role of endothelin-B receptors in hypoxic pulmonary hypertension].
AB - Endothelin-1 (ET-1) is a potent vasoactive peptide, and is thought to play an
important role in the regulation of pulmonary vascular tone. Previous studies
suggested that ET-1 can act as a vasoconstrictor via the endothelin-A and -B 2
receptors located on smooth muscle cells, and also act as a vasodilator through
the endothelin-B 1 receptor situated on endothelial cells in the pulmonary
circulation. To determine the role of endothelin-B receptors in hypoxic pulmonary
hypertension, we examined the hemodynamic effects of a selective endothelin-B
receptor agonist (IRL 1620) in chronic hypoxic pulmonary hypertensive rats. In
rat lungs perfused with a half-blood solution, vasoconstriction by KCl
administration was gradually reversed by IRL 1620 in normoxic rats, but not in
chronic hypoxic rats. In in vivo studies, small doses of IRL 1620 induced
transient vasodilation in normoxic rats, but had no obvious effects in chronic
hypoxic rats. A high dose of IRL 1620 mediated vasoconstriction only in chronic
hypoxic rats. Endothelin-B receptor messenger-RNA expression was lower in the
lungs of chronic hypoxic rats than in normoxic rats. These results suggested that
although the vasodilatory response mediated by endothelin-B receptor can be
expected to play a protective role in the development of pulmonary hypertension,
that response is diminished in hypoxic pulmonary hypertension.
PMID- 10774166
TI - [Clinical study of immunotherapy for bronchial asthma using purified mite feces
antigen].
AB - For many years, hyposensitization therapy was considered to be a radical therapy
for allergic diseases such as bronchial asthma. Adverse effects including the
inducement of asthma attacks or anaphylactic shock were attributed to the use of
crude antigen solution during treatment. To contribute to the establishment of
safer and more effective approaches, we conducted immunotherapy trials using
purified mite feces antigen. Among the antigen fractions that were separated and
purified for this purpose, the HM 2 antigen fraction with a molecular weight in
the 30-40 kD range was found to be the most suitable for use. Treatment utilizing
this fraction achieved favorable outcomes. Of 25 patients with nonseasonal
asthma, the clinical outcome of treatment was "markedly improved" in 7,
"moderately improved" in 11, "slightly improved" in 3, "unchanged" in 4, and
"worsened" in none. Also, 4 of 5 patients with seasonal asthma experienced a
cessation of seasonal attacks. Among factors that affect therapeutic efficacy,
high Df-RAST scores and a history of childhood asthma were considered to be
particularly important.
PMID- 10774167
TI - [Postural effects on electromyographic activity of the transversus abdominis
muscle].
AB - During breathing at rest in humans, electromyographic activity of the expiratory
muscles (EMGem), tidal volume (VT), and minute ventilation (V(I)) are higher when
standing than when supine. EMGem is known to correlate with VT and V(I). It is
not known whether increased EMGem when standing results directly from the change
in posture or indirectly from postural changes in ventilatory pattern. Moving
average electromyographic activity of the transversus abdominis (EMGta) was
recorded using a pair of fine wire electrodes during carbon dioxide (CO2)
rebreathing both while standing and while supine. At matched end-tidal CO2
(ETCO2), VT, or V(I) values, EMGta was significantly higher when standing than
when supine. Postural differences in EMGta had no correlation with increasing
ETCO2, VT, or V(I) during CO2 rebreathing. These results suggested that both the
direct effect of the postural change and an indirect effect through changes in
ventilatory pattern contribute to the increased EMGem observed when standing
compared to that when supine.
PMID- 10774168
TI - [Two cases of lung metastasis of malignant melanoma].
AB - We report 2 cases of lung metastasis of malignant melanoma. Patient 1 was a 71
year-old woman who had undergone an operation for enucleation of her left eye 13
years earlier. Chest magnetic resonance imaging (MRI) demonstrated intermediate
intensity including partially high intensity on T 1 weighted images, and high
intensity including partially low intensity on T 2 weighted images. Microscopic
findings from a transbronchial lung biopsy specimen disclosed melanotic melanoma.
Patient 2 was a 54-year-old man who had undergone surgery for malignant melanoma
in the left upper arm 4 years earlier. Chest MRI films demonstrated low intensity
on T 1 weighted images, and high intensity on T 2 weighted images. Microscopic
findings from specimens of the primary lesion in the left upper arm revealed
melanotic melanoma, but the findings from the lower right lobectomy disclosed
amelanotic melanoma. It has been reported that MRI is useful in the diagnosis of
malignant melanoma, and that melanin content reflects MRI signal intensity. The
MRI findings were consistent with the histopathologic findings in each of the 2
cases we reported.
PMID- 10774169
TI - [Acute eosinophilic pneumonia induced by cigarette smoking].
AB - The subject was a 24-year-old man who presented with acute fever, dry cough, and
dyspnea. Chest X-ray films revealed diffuse infiltrates in both lungs.
Bronchoalveolar lavage fluid specimens contained an increased number of
eosinophils. Transbronchial lung biopsy specimens demonstrated the infiltration
of eosinophils into alveolar walls and air spaces. These findings were consistent
with acute eosinophilic pneumonia. The patient recovered without medical
treatment. Eight days prior to admission, he had resumed smoking after 3 years of
abstention. It was suggested that the cause of acute eosinophilic pneumonia in
this case was associated with the resumption of smoking. To confirm that
association, a smoking challenge test is usually necessary. However, similar
symptoms also developed later, after the patient was passively exposed to
cigarette smoke. Therefore, we concluded that smoking was probably the etiologic
agent of his illness.
PMID- 10774170
TI - [Empyema thoracis accompanied by hyperammonemic encephalopathy].
AB - A 50-year-old man was admitted to our hospital due to consciousness disturbance.
On admission, he was comatose (200 on the Japan Coma Scale) but brain computed
tomographic (CT) scans were normal. Chest radiographs and CT scans on admission
revealed massive pleural effusion in the right hemithorax. A culture of purulent
pleural fluid yielded three species of anaerobes, including Bacteroides fragilis.
Laboratory examinations revealed markedly elevated WBC count, CRP, and serum
ammonia (586 micrograms/dl). However, liver function was almost normal and no
other metabolic disorders were demonstrated. After the initiation of antibiotic
therapy and pleural drainage, the patient's cousciousness level gradually
improved in parallel with decreasing serum levels of ammonia and CRP. Because no
other potential causes of hyperammonemia were observed, we concluded that the
consciousness disturbance was due to hyperammonemia presumably caused by a urease
producing anaerobe infecting the right pleural space.
PMID- 10774171
TI - [Thymic carcinoma successfully treated by a combination of intra-arterial
infusion chemotherapy and surgery].
AB - A 47-year-old man with thymic carcinoma that had invaded the inner pericardium
and adhered to the superior vena cava and right atrium at first operation was
treated with intra-arterial infusion chemotherapy (nedaplatin and adriamycin)
through the internal thoracic artery. After 2 courses of modified ADOC therapy
(nedaplatin, adriamycin, vincristine, and cyclophosphamide), chest computed
tomographic (CT) scans revealed a 47% reduction in tumor size. No adverse effects
due to the anticancer drugs were observed. Resection of the tumor included part
of the upper lobe of the right lung and pericardium. Examination of resected
tumor tissue specimens revealed viable cancer cells and extensive fibrosis. The
diagnosis was thymic anaplastic carcinoma. We concluded that intra-arterial
selective infusion chemotherapy utilizing an ADOC regimen can be of value as a
treatment for thymic carcinoma.
PMID- 10774172
TI - [Limited-form Wegener's granulomatosis without anti-neutrophil cytoplasmic
antibody].
AB - A 78-year-old woman was admitted because of dry cough and weight loss. A computed
tomographic (CT) scan of the thorax showed multiple masses in both lungs with and
without cavitation. No other organ lesions were detected. The patient was
seronegative for antineutrophil cytoplasmic antibody (ANCA) and a routine sputum
culture was normal. Because specimens from transbronchial and CT-guided
transluminal lung biopsies disclosed non-specific granuloma with necrosis, an
excisional biopsy of the mass by video-assisted thoracoscopic surgery was
performed. The specimens contained geographic basophilic necrosis with palisading
histiocytes, giant cells, and neutrophils. A limited form of Wegener's
granulomatosis was diagnosed on the basis of the clinical and pathological
features and effects of treatment.
PMID- 10774173
TI - [Sarcoidosis differentially diagnosed from mediastinal tumor by thoracoscopic
biopsy].
AB - A 46-year-old man presented with swallowing difficulty and dyspnea when in the
supine position. Chest X-ray and computed tomographic (CT) films disclosed left
pleural effusion and a tumor shadow extending invasively from superior to
anterior mediastinum around the heart and large arteries. These observations
called for a differential diagnosis from malignant lymphoma, invasive thymoma,
and small cell carcinoma. Bronchofiberscopy and percutaneous tumor biopsy were
performed, but the findings were inconclusive. Thoracoscopic biopsy yielded a
diagnosis of sarcoidosis. No extrathoracic lesions were detected. Corticosteroid
therapy (30 mg/day of prednisolone) was started. After 6 months of treatment (7.5
mg/day of prednisolone), the tumor shadow was reduced in size and the patient's
swallowing difficulty and dyspnea subsided. This was a rare case of sarcoidosis
extending invasively around the heart and large arteries, and that needed to be
differentiated from mediastinal tumor. Thoracoscopic biopsy should be actively
enlisted as a diagnostic procedure in difficult cases of this kind.
PMID- 10774175
TI - [Arteriovenous fistula associated with Staphylococcus aureus sepsis in a patient
with Rendu-Osler-Weber syndrome].
AB - A 58-year-old man with a history of cerebral infarction and bleeding due to
duodenal ulcer was admitted with fever and arthralgia. Methicillin-sensitive
Staphylococcus aureus (MSSA) was isolated from his peripheral blood. Bacteremia
with MSSA was diagnosed, and antibiotic therapy was started. However, chest X-ray
films and computed tomographic scans disclosed mass shadows in both lungs
accompanied by dilated vascular markings. Pulmonary arteriography and magnetic
resonance angiography revealed the existence of arteriovenous fistulas in both
lungs. Ga scintigraphy disclosed a hot spot in the left lower lobe, consistent
with the location of one fistula. This indicated that the fistula might be the
focus of MSSA sepsis. Because the patient also had telangiectasia in his gastric
mucosa, oral cavity, and nasal cavity, he was given a diagnosis of Rendu-Osler
Weber syndrome.
PMID- 10774174
TI - [Silicosis characterized by increasing serum CA 19-9 in parallel with progression
of lung fibrosis].
AB - In November 1997, a 61-year-old man was admitted to our hospital complaining of
dyspnea. He had worked as a miner for 10 years and had received medical treatment
based on a diagnosis of idiopathic interstitial pneumonia at our hospital since
1984. In conjunction with the progression of interstitial pneumonia, the
patient's serum CA 19-9 had gradually increased since 1992, reaching 9,920 U/ml
in 1997. Though cancer of the pancreas or other organs was suspected, an
extensive examination revealed no malignancy. In April 1998, the patient died of
bacterial pneumonia. Lung autopsy specimens disclosed severe interstitial
fibrosis with prominent silicotic nodules. Based on these findings, silicosis was
diagnosed. In immunohistochemical staining for CA 19-9, the lumina of severely
fibrotic lesions covered with epithelial cells stained positively with anti-CA 19
9 antibody. These findings suggested that serum CA 19-9 may have been produced in
the epithelial cells. We speculated that increased serum CA 19-9 levels in
patients with interstitial pneumonia may occasionally be more indicative of the
magnitude of destruction of lung architecture than the degree of disease
activity.
PMID- 10774176
TI - [Small cell lung cancer associated with anti-Hu antibody-positive paraneoplastic
neurologic syndrome].
AB - We report a case of small cell lung cancer with anti-Hu antibody-positive
paraneoplastic neurologic syndrome preceded by variable neurological symptoms. A
57-year-old man first noticed a numbness on the inner side of his right leg in
April 1998. He was later admitted to a hospital following the development of
polyneuropathy, cerebellar dysfunction, and psychological symptoms. Chest plain X
ray films and computed tomographic scans disclosed a mass shadow in the right
upper lobe, in addition to enlarged mediastinal lymph nodes. Small cell lung
cancer was suspected on the basis of pathologic findings on an enlarged right
supraclavicular lymph node and radiologic findings. The patient was referred to
our hospital in October 1998. Anti-Hu antibody was detected both in serum and
cerebrospinal fluid. Small cell lung cancer (clinical T1N3M0, stage IIIB) with
paraneoplastic neurologic syndrome was diagnosed. Three courses of combination
chemotherapy (carboplatin and etoposide) were administered with a partial
response. However, the patient's neurological symptoms were not alleviated. We
discussed the mechanism, clinical symptoms, and treatment of this disease.
PMID- 10774177
TI - [Mycobacterial infection within a pulmonary bulla].
AB - The patient was a 31-year-old man. Chest X-ray films and computed tomographic
(CT) scans disclosed fluid retention within an 11-cm diameter pulmonary bulla
that had been detected in the upper lobe of his left lung 1 year earlier. CT
films also disclosed a 1.5-cm nodular lesion in the apical segment of the left
lower lobe. The patient had no symptoms and laboratory examinations disclosed no
signs of inflammation. Thoracoscopic examination revealed a yellow-turbid fluid
with caseous necrosis within the bulla. Although Ziehl-Neelson staining of a
bulla tissue specimen was 1 on the Gaffky scale, culture of the fluid was
negative. Histologically, the bulla wall and pulmonary nodule revealed granuloma
with caseous necrosis, thus yielding a diagnosis of mycobacterial infection
within the bulla and lung. Following an operation, anti-tuberculous drugs were
administered and the patient was well without recurrence of tuberculosis 30
months afterward. We concluded that infectious bulla with few or no symptoms and
limited inflammatory findings may occasionally be caused by Mycobacterium
infection.
PMID- 10774178
TI - [Diagnostic pitfalls in evaluating MR images of the uterus].
AB - The pitfalls in evaluating MR images of the uterus are briefly reviewed. These
pitfalls are roughly divided into physiological conditions that simulate organic
lesions, benign conditions that simulate malignancy, and malignant diseases that
simulate benign conditions. It is important to distinguish these mimicking
lesions from real organic lesions.
PMID- 10774179
TI - [Pitfalls in diagnosing female genital tract: ovarian disease].
AB - Because the ovaries are composed of surface epithelial cells, germ cells, sex
cord stromal cells and stroma, tumors of various histopathologies arise from this
organ. In addition, a number of non-tumorous diseases form adnexal masses such as
endometriosis and tubo-ovarian abscess. Furthermore, tumors arising from other
pelvic organs are sometimes mis-diagnosed as ovarian tumors. Therefore, it is
difficult to predict the histological type of an adnexal mass prior to surgery
even though the MR characteristics of various ovarian tumors have been reported.
Because of the large number of patients, there are two 'common sense'
considerations in diagnosing female intrapelvic masses in daily practice: 1)
solid adnexal masses are malignant ovarian tumors, 2) predominantly cystic
intrapelvic masses originate from the ovaries. However, certain tumors do not
conform to common sense. For example, fibrothecomas and benign teratomas are
exceptions to 1), and subserosal pedunculated leiomyomas and cystic adenomyosis
are exceptions to 2). The MR characteristics, pitfalls to diagnosis, and clues to
correct imaging diagnosis are discussed in this review.
PMID- 10774180
TI - [Usefulness of temporal subtraction images of chest computed radiography for
detection of metastatic pulmonary nodules].
AB - Temporal subtraction is a technique by which a previous chest radiograph is
subtracted from a current radiograph in order to enhance interval changes. Our
purpose in this study was to evaluate the usefulness of temporal subtraction for
the detection of metastatic pulmonary nodules. We examined 19 cases of metastatic
nodules less than 15 mm in diameter (8.4 mm on average). Temporal subtraction
images were created based on the matching of local lung areas in pairs of chest
radiographs. By using the subtraction images, the detectability of nodules was
clearly improved in 5 cases and moderately improved in 8 cases; there was no
improvement in 6 cases. The subtraction images were especially useful for nodules
superimposed over normal structures, such as rib, mediastinum, and diaphragm, as
well as for small nodules. In 6 of the 19 cases, the nodules had been missed
clinically; however, the temporal subtraction images clearly demonstrated half of
missed small nodules. Temporal subtraction made it possible to enhance subtle
interval changes and helped in detecting small pulmonary metastases. This
technique seems promising for augmenting the capabilities of computed radiography
of the chest.
PMID- 10774181
TI - [Regional differences of in vivo proton MR spectroscopy in developing human
brain].
AB - The purpose of this study was to clarify regional differences in proton MR
spectroscopy (1H-MRS) in the developing human brain. Proton MR spectra were
obtained from 24 infants aged 0 to 24 months old. Proton MR spectroscopy was
performed on a 1.5 Tesla clinical MR unit using a 3D-chemical shift imaging
sequence (3D-CSI). MR spectra obtained from voxels in frontal white matter and
those in parietal white matter were compared. The NAA/Cho ratios of the frontal
region were lower than those of the parietal region at birth but increased
rapidly during the first six months of life. The rate of increase was reduced in
the second year of life. In contrast, NAA/Cho ratios in paracentral areas were
already high at birth but increased slowly through the first two years of life.
Cho/Cr ratios of the frontal region were stable during the first year of life and
started to decrease in the second year of life. In the parietal region, Cho/Cr
ratios were decreased throughout infancy. Regional differences in 1H-MRS spectra
were apparent during infancy, and these differences were suggested to reflect
regional differences in the maturation of the developing human brain.
PMID- 10774182
TI - [MRI of ductal carcinoma in situ of the breast: patterns of findings and
evaluation of disease extent].
AB - Ten cases of ductal carcinoma in situ (DCIS) or DCIS with microinvasion were
reviewed in order to evaluate the characteristic findings of DCIS and to evaluate
the extent of disease on MRI. A 1.5Tesla Signa or Horizon (GE Medical Systems)
unit was used with a dedicated receive-only breast coil. The pulse sequence based
on RARE was used with the fat suppression technique. After examining both breasts
with a large FOV (30 cm), the affected breast alone was examined with a smaller
FOV (18 cm) and larger matrix (512 x 384) with and without Gd-enhancement. DCIS
showed several types of findings on MRI: linear, spotty enhancement; gathering of
linear enhancement; enhanced area or mass without distortion of the surrounding
tissue; and well-circumscribed mass mimicking intraductal papilloma. Compared
with typical findings of invasive carcinoma, DCIS tended to be enhanced slowly.
After performing MR examination in addition to mammography and ultrasonography, a
more accurate diagnosis of disease extent was possible in 6 of 10 patients. MRI
was useful in providing more precise information on the disease extent of DCIS,
and it is considered useful in planning the type of surgery. Further study using
larger series and precise pathological correlations are necessary.
PMID- 10774183
TI - Postoperative radiation therapy for adenoid cystic carcinoma.
PMID- 10774184
TI - [Intranet-based integrated information system of radiotherapy-related images and
diagnostic reports].
AB - PURPOSE: To use an intranet technique to develop an information system that
simultaneously supports both diagnostic reports and radiotherapy planning images.
METHODS: Using a file server as the gateway a radiation oncology LAN was
connected to an already operative RIS LAN. Dose-distribution images were saved in
tagged-image-file format by way of a screen dump to the file server. X-ray
simulator images and portal images were saved in encapsulated postscript format
in the file server and automatically converted to portable document format. The
files on the file server were automatically registered to the Web server by the
search engine and were available for searching and browsing using the Web
browser. RESULTS: It took less than a minute to register planning images. For
clients, searching and browsing the file took less than 3 seconds. Over 150,000
reports and 4,000 images from a six-month period were accessible. Because the
intranet technique was used, construction and maintenance was completed without
specialty. CONCLUSION: Prompt access to essential information about radiotherapy
has been made possible by this system. It promotes public access to radiotherapy
planning that may improve the quality of treatment.
PMID- 10774185
TI - [Contribution of cochlear nucleus to 80Hz amplitude-modulation following
response].
AB - The steady-state response (SSR) evoked by a sinusoidally amplitude-modulated
(SAM) tone is known as an amplitude-modulation following response (AMFR). The
amplitude of the SSR which is elicited using clicks or tone bursts at a stimulus
rate of 40 Hz, decreases during sleep. The same trend is also observed for AMFR
at a modulation rate of 40 Hz. Thus it was difficult to analyzing SSR and AMFR is
therefore difficult in young children, since objective audiometry just be
performed while the child is asleep. Recent reports, however, have announced that
the AMFR can be clearly detected at higher MFs (modulation frequencies),
especially at frequencies between 80 and 100 Hz. This finding has proven useful
in objective audiometry for young children. Recent reports have also suggested
that AMFRs arise from multiple sources, including the auditory cortex and
auditory nuclei in the brainstem. However, the exact sources of AMFRs have not
been clarified. The purpose of this study is to clarify the contribution of the
cochlear nucleus in evoking AMFRs at a modulation frequency of 80 Hz. The near
field potentials elicited with a SAM tone were recorded from the ipsilateral
cochlear nucleus and its vicinity in cats. The near-field potential recorded by
bipolar electrodes consisted of two different components: a low frequency
component similar to the stimulus envelope (modulation), and a high frequency
component similar to the actual stimulus tone. A sequence of field potentials was
recorded using monopolar electrodes located at different sites within the
cochlear nucleus and in its vicinity and on the surface of the cerebellum to
confirm that near-field potentials elicited by SAM tones at a MF of 80 Hz in the
cochlear nucleus can be recorded at the surface of the cerebellum or at other
brain sites. The phase of the 80 Hz frequency component of the potentials
elicited by a SAM tone at a MF of 80 Hz was then analyzed using a fast Fourier
transformation. A contour map was produced using the means of the Fourier
component phases corresponding to the 80 Hz response. The contour lines showed a
rapid change in the phases recorded near the cochlear nucleus. These findings
suggest that the cochlear nucleus contributes to the generation of scalp recorded
AMFR at a MF of 80 Hz.
PMID- 10774186
TI - [Changes in the shape of choanal openings and airflow rates during development].
AB - The shape of the choanal openings were examined in 173 babies aged zero to six
months using digital video fiberscope inserted via nose. A numerical analysis and
the fluid mechanics were then calculated for each recorded choanal opening. The
choanal openings in one month old babies were a flat oval shape. Vertical
development was faster than that of horizontal development, and the choanal
openings changed from a flat oval to a round and finally a vertical oval shapes
as the babies aged from two to four months. Both the air resistance and airflow
ratio in the choanae can be calculated by Navier-Stoke's equation, if the choanae
are assumed to be an oval tube. Using this equation, it was calculated that the
air resistance ratio was one to five and the airflow ratio increased five times
from neonates to six month old babies.
PMID- 10774187
TI - [Second reconstructions after failure of free-tissue transfer in the head and
neck region].
AB - A retrospective study was performed on 74 patients seen in our hospital between
1990 and 1999 who underwent head and neck reconstructive surgery involving a free
flap. Reconstructive surgery was unsuccessful in 5 cases (6.8%). A pedicled
myocutaneus flap was used in two cases for the second reconstruction attempt,
while a second free flap (jejunum) was used in two other patients. In these
cases, a bilateral neck dissection was performed prior to the second free flap
reconstruction and neck infection was found. The head and neck artery and vein
were unsuitable as recipient vessels in the second operation. Instead, the
cephalic vein was used as a source of vein grafts and as a recipient vein.
PMID- 10774188
TI - [Oral allergy syndrome in patients with Japanese cedar pollinosis].
AB - Patients with pollinosis sometimes complain of oral symptoms (itching and
tingling with or without edema of the lips, mouth and tongue) after eating fresh
fruits and vegetables. This condition has been termed Oral Allergy Syndrome
(OAS). Twenty-three patients with Japanese cedar pollinosis and OAS for fresh
fruits and vegetables were included in this study. Their mean age was 31.3 years
(range = 5 to 62). The fruits that caused OAS in these patients included melon,
apple, peach, and kiwi fruit. Most patients with OAS exhibited hypersensitivity
to more than two foods. Specific IgE antibodies to inhaled allergens of mite,
Japanese cedar pollen, birch pollen, melon, apple, peach, and kiwi were evaluated
using the Pharmacia CAP system. Eleven of the 16 subjects with specific IgE
antibodies for birch pollen, did not suffer symptoms during the birch and alder
pollen season. In subjects with specific IgE antibodies for fruits, 13 out of 20
patients showed specific IgE antibodies for apple, and 8 out of 9 patients with
OAS for apples were also positive for specific IgE antibodies for apples. On the
other hand, 17 patients had no specific IgE antibodies for melon, and only two
patients and one patient showed specific IgE antibodies for kiwi fruit and peach,
respectively. These results suggest that the evaluation of specific IgE
antibodies to birch pollen and apple may be useful for diagnosing OAS in patients
with Japanese cedar pollinosis.
PMID- 10774189
TI - [The effects of sleep position change in sleep apnea syndrome].
AB - Changing the sleep position from supine to non-supine is a simple but effective
treatment for some patients with sleep apnea syndrome. In the present study, we
compared the clinical data for good responders (GRs), those who responded well to
the sleep position change, with those for poor responders (PRs), and also
evaluated the effect of surgical treatment on the positional improvement of
ventilation in the PR group. Forty-one adult patients with sleep apnea syndrome
(mean age: 47.1 years, mean obesity index: 125.8%) were divided into two groups
based on their polysomnographic responses to sleep position change. Thirty-two
patients were classified as the GR group, whose apnea-hypopnea index (AHI) in the
non-supine position declined to less than half of their AHI in the supine
position, and nine whose non-supine AHI remained greater than half of their
supine AHI were classified as the PR group. The AHI and the desaturation index
(DI) for the PR group were significantly higher than those for the GR group, and
the obesity index was also higher in the PR group. For the eight PRs who had
surgical therapy, their polysomnographic data improved much more in the non
supine position than in the supine position. Of six patients whose total AHI was
still 10 or more after surgery, four changed into GRs. The combination of surgery
and sleep position change seemed to be an effective treatment even for patients
with a little improvement before surgery.
PMID- 10774190
TI - [Endoscopic transnasal transsphenoidal surgery for pituitary tumors--intranasal
procedures].
AB - We have been performing intranasal procedures and postoperative nasal treatments
in patients undergoing microscopic transseptal pituitary surgery for the past
twenty years. This surgery is safe and minimally invasive and has become the
standard procedure for removing pituitary adenomas. Recent advances in optical
technology have increased the use of endoscopy in endonasal sinus surgery.
Several methods for endoscopic transnasal pituitary surgery have been reported.
Here, we report the results for 31 patients (34 operations) who were treated with
endoscopic transnasal pituitary surgery. This technique enables the area of
surgery to be visualized without requiring a sublabial incision or septal
ablation to be performed. Five of the cases were for recurrences after
microscopic surgery. A transsphenoidal surgical approach via a unilateral nasal
cavity was used in 32 cases. For the remaining two cases, a transsphenoidal
surgical approach via bilateral nasal cavities was used in 1 case, and a
transethmoidal-transsphenoidal surgical approach via a unilateral nasal cavity
was used in 1 case. Excellent results comparable to those of microscopic
transseptal surgery were obtained. Endoscopic transnasal transsphenoidal surgery
was found to have the following advantages: low-invasiveness, a wide and clear
surgical view, and a relatively short operating time in the nose and sinus,
especially for recurrent cases. This endoscopic procedure should therefore be
considered as the first choice for pituitary surgery.
PMID- 10774191
TI - [Chronic granulomatous disease accompanying a deep cervical abscess in a young
child].
AB - We report the diagnosis and otorhinological treatment of a rare case of cervical
abscess in association with chronic granulomatous disease (CGD). A 19-month-old
boy was admitted to our hospital's Department of Pediatrics with fever and a
swollen neck. Antibiotic treatment (FMOX PIPC, and PAPM) was ineffective, so the
patient was referred to our department for otorhinological treatment. A deep
cervical abscess was drained using paracentesis in the Outpatient Department, but
the condition did not improve. Surgery to drain the cavity was therefore
performed. The wound was irrigated with oxydol, and the surgery was a success.
Immunodeficiency was suspected, because of the antibiotic treatment's failure.
Further examination clarified that the disease was CGD, but this diagnosis was
difficult to establish. The result of the NBT test was 120%. However, some
examination demonstrated that active oxygen production was impaired. The
production of cytochrome b in this patient was confirmed using flow cytometric
analysis. Both parents were confirmed to be carriers upon examination. The
patient was therefore diagnosed as having CGD as a result of an autosomal
recessive inheritance.
PMID- 10774192
TI - [Study of alpha-herpesvirus: present state and future developments].
AB - The herpesvirus is a ubiquitous infectious agent present in a variety of
vertebrates including humans. The virus has a duplex DNA molecule of 120-240 kbp
within an icosahedral capsid surrounded by an envelope. Latency is a central
feature of herpesvirus biology. Studies of herpesviruses relate to 1) diagnosis,
prevention, and the treatment of diseases associated with herpesvirus infections,
2) elucidation of biological mechanisms of mammalian cells using herpesviruses,
3) construction of vaccine and vector systems for gene therapy, and 4)
establishment of putative associations of herpesviruses with host organisms
during evolution (suggesting the host-linked evolution of herpesvirus).
PMID- 10774193
TI - [Structure and classification of alpha-herpesvirus].
AB - Virion of herpesviruses (100 to 200 nm in diameter) consists of a core containing
a linear double-stranded DNA, an icosahedral capsid, an amorphous layer
designated as the tegument which surrounds the capsid, and a protein-containing
lipid membrane designated as the envelope. Terminal and internal reiterated
sequences are present on herpesvirus genomes, giving a diverse range of DNA
structures. The family Herpesviridae is divided into three subfamily of Alpah-,
Beta- and Gammaherpesvirinae. Herpesviruses seem to have diversified from a
common ancestor, in a manner mediating co-speciation of herpesviruses with host
species through species-specific latent infection.
PMID- 10774194
TI - [Molecular mechanism of alpha-herpesvirus proliferation].
AB - Among members of the subfamily alpha herpesviruses, herpes simplex virus (HSV) is
one of the most well-studied and the most important human pathogen. HSV is
reported to possess the large, double-stranded DNA genome which contains at least
80 genes. Recent studies have revealed the functions and roles of many gene
products in HSV-infected cells. This article briefly reviews the results of these
studies relating to HSV replication mechanism in cells and latent infection in
central nerve system (CNS).
PMID- 10774195
TI - [Regulation of alphaherpesvirus gene expression].
AB - Human alphaherpesviruses are common human pathogens associated with a variety of
diseases. The striking characteristics of the viruses are to establish a latent
infection in neurons after lytic infection at the periphery. The alphaherpesvirus
genes have been shown to fall into several major groups (designated alpha, beta,
and gamma) whose expression is coodinately regulated and sequentially ordered in
a cascade fashion during the lytic cycle of alphaherpesvirus infection. Recently,
cellular proteins which interact with alphaherpesvirus regulatory proteins have
been identified and the studies have revealed that the regulatory proteins
interact with and modulate a plethora of cellular components and functions
including transcription, cell cycle, protein degradation pathway, and
translation. These findings suggest that they are multifunctional protein and the
functions of the regulatory proteins result from the sum of these interactions.
PMID- 10774196
TI - [The functions of alpha herpesvirus gene products].
AB - Herpes simplex virus type 1(HSV-1), type 2(HSV-2) and varicella-zoster virus
(VZV) belong to alphaherpesvirus family. These herpesviruses have large DNA
genomes which contain at least 69 genes. These viral genes are divided into two
groups based on whether they are essential or dispensable for virus growth in
cell culture. The essential gene products include transcriptional factor, viral
DNA replication, DNA cleavage/packaging and virion components, while the
dispensable gene products include deoxyribonucleotides metabolism, protein
kinases, tegument proteins. This article briefly reviews the functions of
alphaherpesvirus gene products, particularly roles of viral encoded protein
kinases, tegument proteins and host immune evasion.
PMID- 10774197
TI - [Role of apoptosis induced by acute herpes simplex virus].
AB - Apoptosis is induced by acute herpes simplex viral infection in the adrenal
cortex, myenteric plexus of the gut, ovary, and liver of mice. Viral replication
is closely related to apoptosis. This apoptosis is increased in immunosuppressive
regions like the adrenal cortex and liver of macrophag-depleted mice. However,
the herpes simplex virus is known to possess US3 gene, which interferes with cell
apoptosis. In the liver of macrophage-depleted mice infected with US3 gene
deficient mutant herpes, the apoptosis is confined to within the narrow limits of
inflammatory cell infiltration, mainly of neutrophils, and it plays a part in the
restriction of virus multiplication. Thus, a possibility exists that apoptosis
works as a primitive immunity in herpes simplex virus infection.
PMID- 10774198
TI - [The relationship between gene function and virulence in alpha-herpesviruses].
AB - Virulent alpha-herpesvirus genes, though not essential for virus replication in
cell culture, play important roles in virus replication in vivo. In this paper, I
classify the virulent genes and discuss the relationship between gene function
and virulence. The products of the virulent genes of herpes simplex virus,
described in this paper, are enzymes (thymidine kinase, ribonucleotide reductase,
deoxyuridine triphosphatase, DNA polymerase, and two protein kinases),
glycoproteins (gC, gE), immediate early gene product (ICP47) and gamma 34.5. To
identify the virulent genes of varicellazoster virus, mutation in the Oka vaccine
strain was studied. The low levels of gV expression and mutation found in the
immediate early gene were predicted as the cause of the attenuation of the Oka
vaccine strain.
PMID- 10774199
TI - [The mechanisms for latency and reactivation of alpha herpesviridae].
AB - Alpha herpesviridae (herpes simplex virus, HSV and varicella zoster virus, VZV)
is a neurotropic phathogen of humans that establishes latent infection in the
sensory ganglia, and periodically reactivates from latently infected neurons.
Most of basic research for analyzing the mechanism of latency and reactivation of
herpes viruses has been carried out in HSV. According to the results from the
molecular analysis in the neurons latently infected with HSV, during latency, the
virus genome is quiescent, except for the transcription of the latency associated
transcripts (LATs). Thus, it has been considered that LATs play an important role
for latency and reactivation of the virus. It has been shown that LATs are
required for efficient reactivation from latency in vivo, and regulate the site
specificity for reactivation of the virus. Recent studies demonstrated that the
quantities of latent virus are correlated with the frequency of reactivation of
the virus. Moreover, it was suggested that the latency-related gene of bovine
herpesvirus 1 could inhibit the apoptosis of the several cells including neuronal
cells.
PMID- 10774200
TI - [Advanced methods for the manipulation of herpesvirus genomes].
AB - The Herpesviridae are a family of viruses which have a large genome of linear,
double-stranded DNA (> 120 kb). It has been quite difficult to clone and modify
herpesvirus genomes because of their large sizes. Recently, several groups of
investigators demonstrated successful cloning of infectious herpesvirus genomes
as bacterial artificial chromosomes (BACs). In this review, I describe the recent
development of methods to modify the cloned viral genomes. The methods are: (i)
homologous recombination in E. coli which allows targeted mutagenesis of any
specific viral sequence, and (ii) mutagenesis which allows random modification of
entire viral genomes. Both methods should facilitate both the study of herpes
viruses and the development of herpesvirus-based vector system.
PMID- 10774201
TI - [Herpes simplex type-1 virus-based vectors for gene therapy].
AB - Recent advances in recombinant nucleic acid technologies and the understanding of
the molecular biology of diseases provide the basis for gene therapy's ability to
impact on the clinical practice of medicine. Herpes simplex virus type 1 (HSV-1)
has features that make it suitable as a vector for gene therapy. These properties
include: 1) wide host range and high efficiency of gene transfer; 2) large
transgene capacity which is provided by deletion of genes unnecessary for viral
replication; 3) unique ability of entering a state of latency in neurons; 4)
specific oncolytic effect of some mutants by deletion of certain early genes.
Three types of vectors designed for gene therapy have been developed from this
virus, termed replication-defective vectors, replication-conditional vectors and
amplicon vectors. In this review, we describe the recent advances in HSV-1-based
vector systems and their applications for gene therapy.
PMID- 10774202
TI - [Seroepidemiology of alphaherpesviruses].
AB - The seroepidemiology of herpes simplex virus (HSV) type-1 and -2 was studied in
different Japanese populations, by applying HSV gG1 and gG2 type-specific
antibody assays. HSV-1 infections correlated mostly with age and was widely
prevalent among subjects over 40 years old. HSV-2 prevalence varied greatly among
subgroups defined by sexual activity and were associated with risk behaviors,
from 80% among prostitutes to 7% among pregnant women. Since HSV-1 infection
during childhood has been decreasing, primary genital HSV-1 or HSV-2 infection,
with its higher frequency of clinical manifestations, will become more important.
In contrast, antibody prevalence to varicella-zoster virus has been constantly
high in children, with no tendency to change in seroepidemiology of VZV
infections so far.
PMID- 10774203
TI - [Molecular epidemiology of human alpha-herpesvirus infection].
AB - Herpes simplex virus type 1, 2 (HSV-1, 2) and varicella-zoster virus(VZV) are
significant pathogens in humans. These three viruses belong to the alpha
herpesvirus subfamily. The molecular epidemiological analyses of the viruses are
based on the heterogeneity of each viral genome found in isolates. HSV-1, 2
strains are classified into genotypes as intratypic variations by gains or losses
of cleavage sites using restriction endonucleases recognizing 6-base pairs. On
the other hand, VZV strains can rarely be distinguished with respect to the
presence or absence of restriation sites, so that the numbers and/or patterns of
repeating units in the reinteration structures(R1, R2, R5) are also available to
differentiate VZV isolates. Recently, analysis of viral DNA fragments amplified
by polymerase chain reaction has been applied as an alternative method. The
epidemiological relation of strains has been determined in various clinical
conditions such as the transmission of the viruses by these molecular
epidemiological methods.
PMID- 10774204
TI - [Clinical statistics on alpha-herpesvirus in Japan].
PMID- 10774205
TI - [Diagnosis--serodiagnosis of alpha herpesviruses].
AB - Herpes simplex virus(HSV) serodiagnosis concerns type-common diagnosis and type
specific diagnosis. Primary HSV infections can be diagnosed by type-common
serological assays, and in the ideal case, in combination with virus isolation.
HSV type 1 and HSV type 2 are very similar except for glycoprotein G(gG). This
glycoprotein can be used to determine type-specific antibodies especially during
initial non-primary infections. However, antibody response to gG is late compared
to the response to type-common antibodies. A rapid diagnosis of acute varicella
zoster virus(VZV) infections are often needed in clinical settings and in these
situations, diagnosis is performed by methods for rapid viral detection, and not
by serology. Serological tests are usually used to screen for immunity against
VZV.
PMID- 10774206
TI - [DNA diagnosis of alpha-herpesvirinae infection].
AB - Herpesviruses have a characteristic of the latency after the primary infection.
Advanced study on the causal relation between the reactivation of latent virus
and the appearance of the symptoms would need both of the detection of viral
genome by the DNA diagnosis method and the analysis of the kinetics of the virus.
We developed a new quantitative method for the detection and the titration of
copy number in the viral genome using the combination of polymerase chain
reaction and microplate hybridization. The availability of the method was
confirmed by the several cases of alpha-herpesvirinae infections.
PMID- 10774207
TI - [Alpha-herpesvirus infection in the central nervous system].
AB - Herpes simplex virus type 1 (HSV1) encephalitis is commonly observed, but HSV1
myelitis is rare. On the other hand, HSV2 is common etiologic agent for ascending
necrotizing myelitis associated with diabetes mellitus, malignant tumors, AIDS
and immunocompromised hosts. It is suggested that latent infection of the virus
of root ganglia or primary infected virus is possibly followed by spread of
infection to the central nervous system, particularly in immunocompromised
patients. In this report, pathological findings and clinical symptoms of our
recent encephalitis and myelitis cases infected with HSV2 and HSV1 are described.
PMID- 10774208
TI - [Vertical transmission of alpha herpes virus].
AB - Alpha herpes viruses which infect human being are Herpes simplex virus(HSV) and
Varicella zoster virus(VZV). Both are known to infect fetus or neonate when their
mothers are infected by these viruses. However, the pathogenesis of these two is
quite different; HSV infection is usually limited to local area while VZV infect
systemically. Intrauterine infection of HSV occurs very rarely whereas that of
VZV at the rate of as much as 2.0% when mothers are infected during 13-20 weeks
of gestation. Half of newborns are infected by HSV when their mothers are
primarily infected around the delivery. About 30% of these infected babies are
mortal. Neonatal varicella, caused by transplacentally transmitted VZV, sometimes
results in serious prognosis especially when maternal varicella has an onset
between 5 days before and 2 days after delivery.
PMID- 10774209
TI - [Alpha-herpes virus infections--male genital herpes].
AB - In Japan, male genital herpes is the third popular male STD, the most popular one
being gonococcal infection and the second chlamydial infection. As specific
clinical findings, superficial ulcer lesions with pain are formed in the genital
area, especially in the prepuce. After HSV infection in genital mucocutaneous
sites, viral particles are transported to the neurons. The state of subsequent
HSV infection from external genitalia to the neurons is known as latent
infection. 76% of our cases of the first episode of genital herpes infection were
caused by HSV-2, and most of the recurrent episodes was caused by HSV-2. Oral
acyclovir administration for five to ten days has shortened the treatment period,
although about 20 days were required without any treatment. The remaining
problems are, asymptomatic HSV shedding, severe infections in immunocompromised
patients, transmission of HSV to sex partners and vertical infection to neonates.
PMID- 10774210
TI - [Sexually transmitted diseases of alpha herpes virus in women].
AB - Among two alpha herpes viruses, Herpes Simplex Virus(HSV) and Varicella Zoster
virus(VZV), HSV infects genital sites and is frequently transmitted by sexual
contact while VZV has quite different mode of transmission and rarely infects
genital site except herpes zoster at the vulva. Genital herpes is the second and
the third leading cause of STDs in women and men respectively. While 90% of male
genital herpes was caused by HSV-2, 55% of female genital herpes was by HSV-2 and
the remaining 45% by HSV-1. As for primary infection of female genital herpes,
60% was caused by HSV-1 and 40% by HSV-2. On the otherhand about 90% of recurrent
infection was by HSV-2 suggesting that HSV-2 is closely related to latent
infection of the female genital tract.
PMID- 10774211
TI - [Clinical manifestations of the subfamily alpha-herpesvirinae in childhood].
AB - Herpes simplex virus(HSV) and varicella-zoster virus(VZV) belonging to the
subfamily of alpha-herpesvirinae have the capacity to establish latent infection
in neural tissues and to reactivate from these sites. HSV infection is
characterized by a vesicular eruption, fever, and other constitutional symptoms
but frequently inapparent both in primary and recurrent infections. However, the
infection produces a wide spectrum of illness ranging from the trivial fever
blisters to the most severe fatal sporadic encephalitis and neonatal infection.
In contrast, VZV develops varicella, a common contagious disease of childhood
during primary infection and zoster by reactivation of latent virus acquired
during varicella. In normal children, the systemic symptoms of both diseases are
mild, whereas serious complications are often observed in children with
deficiencies in cell-mediated immunity. Acyclovir has been the drug of choice for
treatment of severe infection with HSV and VZV for approximately 2 decades. Now,
two new agents, valacyclovir and famciclovir will supplant acyclovir for certain
indications.
PMID- 10774212
TI - [Alphaherpesvininae--dermatology].
AB - The subfamily alphaherpesuvirinae contains herpes simplex virus(HSV) and
varicella-zoster virus(VZV) in the Dermatology. HSV infectious diseases are
herpetic gingivostomatitis, herpes labialis, facial herpes simplex, Kaposi's
varicelliform eruption, genital herpes, lumbosacral herpes simplex, and herpetic
whitlow. The primary form of VZV infection is varicella, and the reactivation
form is herpes zoster. These infectious diseases in the dermatological clinics
usually occur in adult. In this paper we mention clinical manifestations and
treatment.
PMID- 10774213
TI - [Ophthalmic area].
AB - Although herpes simplex virus type 1 or herpes zoster virus is generally
considered to cause ocular infection among alpha herpesviruses, herpes simplex
virus type 2(HSV-2) retinitis has been recently reported. Acute retinal
necrosis(ARN) syndrome is associated with herpesviruses, but the mechanisms
remain unclear. The representative ocular infection by alpha herpesviruses is
herpes simplex virus type 1(HSV-1) keratitis. The clinical types, ocular symptoms
and therapy are reviewed in herpetic ocular infections(HSV-1 blephalitis,
conjunctivitis, keratitis, retinitis). In addition, ocular infections caused by
herpes zoster virus are reviewed.
PMID- 10774214
TI - [Alpha herpes virus and facial palsy].
AB - Alpha herpes virus is the major causes of peripheral facial palsy such as Bell's
palsy or Ramsay Hunt syndrome. Ramsay Hunt syndrome is caused by varicella zoster
virus (VZV) infection, and can be diagnosed by facial nerve paralysis associated
with herpetic eruption on the pinna, and complication of by vestibulo-cochlear
dysfunction. On the other hand, Bell's palsy presents only facial palsy and its
diagnosis is made by the exclusion of known conditions. The causes of Bell's
palsy had been unknown for many years, however, recently it was revealed that
herpes simplex type 1 was the major cause of Bell's palsy by PCR. Because early
treatment with acyclovir and prednisone was proven to be effective, we should
make efforts to diagnose these diseases as early as possible.
PMID- 10774215
TI - [Orofacial alpha herpesvirus infection].
AB - The mouth is the most common site of primary and recurrent herpes simplex virus
(HSV) infection. The clinical appearance of recurrent intraoral HSV infection is
similar to that of recurrent aphthous stomatitis. Reactivation of HSV occurs in
bone marrow transplantation and is more frequent in patients conditioned with
total body irradiation than in patients conditioned without total body
irradiation. Although the effect of oral acyclovir to prevent recurrent herpes
labialis is not confirmed, recurrent HSV lesions can be treated with the ointment
formulation successfully. A therapeutic approach using replication-competent HSV
may be useful in the treatment of tumors of epithelial origin, such as carcinoma
of the upper aerodigestive tract.
PMID- 10774216
TI - [Transplantation associated alpha herpes virus infection].
AB - Immunosuppression after organ or bone marrow transplantation changes its severity
with the time lapse. After bone marrow transplantation, HSV infection occurs in
early period and VZV infection, in intermediate period. Aciclovir prophylaxis is
effective for preventing HSV in early period and also for elevating the
compliance of drug intake. It delays onset of VZV infection on the other hand.
VZV infection is usually very severe if it is occurred early, before 100 days
after transplant. There was some case of VZV infection with severe abdominal pain
without any skin involvement. The incidence of VZV infection in bone marrow
recipients was 29%. Even in stable period it caused considerable mental problems
in some patient.
PMID- 10774217
TI - [Alpha herpesvirus infections in AIDS patients].
AB - Alpha-herpesvirus infections by herpes simplex virus and varicella-zoster virus
among HIV-infected patients were summarized. These infections were occurred in a
high frequency and shown to be extensive lesions, prolonged virus excretion from
the lesions, generalized infection, and uncommon diseases as compared these of
with immunocompetent patients. Acyclovir-resistant viruses appeared. These
evidences supplied the profound understanding of the pathogenesis and new
subjects in the field of herpesvirus infection. Recent introduction of HAART
against HIV and the appropriate use of anti-herpesvirus drugs, however, reduced
the development of severe infection, and provided successful treatment,
respectively.
PMID- 10774218
TI - [Prophylaxis and treatment of alpha herpesvirus infection--vaccine].
AB - Vaccines for human alpha herpesviruses were reviewed. To prevent recurrent
genital herpes, inactivated virion vaccines, subunit vaccines, live vectored
vaccines, genetically-attenuated live virus vaccines, and DNA vaccines have been
developed for herpes simplex virus(HSV). Although clinical studies of these
vaccines were reported, successful results have not been confirmed. Further
improvements in target genes, adjuvants, and vaccine strategies are necessary for
clinically useful HSV vaccines. To prevent varicella, a live attenuated
vaccine(Oka strain) was developed in Japan and is now widely used in the world.
PMID- 10774219
TI - [DNA vaccines against alphaherpesvirus infections].
AB - DNA vaccines offer a number of unique and favorable features that distinguish
them from conventional live attenuated, killed whole, or subunit vaccines. DNA
vaccine has been used to elicit humoral and cellular immune responses against
viruses, bacteria, parasites and tumors in various animals. In particular, DNA
vaccine can induce cytotoxic T lymphocytes, which play an important role in
protection against alphaherpesvirus infections. Therefore DNA vaccine is likely
to be a new and better approach to protect human and animals from
alphaherpesvirus infections. In this paper, current knowledge on DNA vaccines
against alphaherpesvirus infections is summarized.
PMID- 10774220
TI - [Antiherpetic chemotherapy].
AB - Acyclovir has changed the concept of anti-herpetic chemotherapy by its mechanism
of action and clinical efficacy. Idoxyuridine, vidarabine, and acyclovir have
been used for herpes simplex virus and varicella-zoster virus infection for two
decades in Japan. Varaciclovir and famciclovir which are the prodrugs of
acyclovir and penciclovir, respectively, will be added to the choice of anti
herpetic chemotherapy. This review introduces their mechanism of action and their
comparative characteristics in chemotherapy, and the new development of anti
herpetic drugs.
PMID- 10774221
TI - [Vaccine application of recombinant herpesviruses].
AB - Recently, genetic engineering using recombinant DNA techniques has been applied
to design new viral vaccines in order to reduce some problems which the present
viral vaccines have. Up to now, many viruses have been investigated for
development of recombinant attenuated vaccines or live viral vectors for delivery
of foreign genes coding immunogenic antigens. In this article, we introduced the
new vaccine strategy using genetically engineered herpesviruses.
PMID- 10774222
TI - [Pain treatment of herpes zoster].
AB - Reactivation of varicella-zoster virus causes herpes zoster, which accompanies
severe pain in most patients. Treatment of pain is mandatory in herpes zoster.
Pain caused by herpes zoster is classified as acute herpetic pain and
postherpetic neuralgia. The mechanisms and treatments for the two pains are
different. Acute herpetic pain is inflammatory and nociceptive one. Treatment for
acute herpetic pain includes antiviral drugs, non-steroidal anti-inflammatory
drugs, opioids, and sympathetic nerve blockade. Postherpetic neuralgia is a
neuropathic pain and requires antidepressants, anticonvulsants, and anti
arrhythmic drugs to relieve the pain. Topical application of capsaicin and local
anesthetics may benefit some patients with postherpetic neuralgia.
PMID- 10774223
TI - [Pathogenesis of animal herpesviruses to human].
AB - More than 90 spices of herpes viruses have been isolated from wide variety of non
human animals. Among these herpes viruses, only B virus (Cercopithecine
herpesvirus 1), the natural host of which is macaque monkey, is severely
pathogenic to human. B virus infects human through handling infected monkey
tissues or by injury caused by infected monkey, and severe encephalitis ensues.
However, in 1997 mucocutaneous infection without injury was reported. The genome
structure and immunogenic property of B virus is similar to those of human
herpesvirus(HSV). And pathogenecity of B virus to monkey is also similar to that
of HSV to human. Although the natural host of pseudorabiesvirus (Suid herpesvirus
1) is swine, it infects wide range of animals and causes severe nervous symptoms.
However, the pathogenicity to human is controversial.
PMID- 10774224
TI - [Analysis of deep mycoses in autopsy cases].
AB - The deep mycosis in compromised patients is increasing. We examined 40 cases (3%)
of the deep mycoses out of 1170 autopsy cases experienced in Saint Luke's
International Hospital from 1987 to 1996. The deep mycosis was highly associated
with hematologic malignancies(23%) but not with solid tumors(2%). The common
mycoses were aspergillosis and candidiasis, which were observed in 27(68%) and 14
(35%) cases, respectively. Most of the patients received broad-spectrum
antibiotics, anticancer agents and corticosteroids, and showed granulocytopenia.
The symptoms of deep mycoses were non-specific, for example, pyrexia and/or
respiratory symptoms. The clinical diagnosis was established in 8 cases and the
appropriate antifungal agents were used in 12 cases(30%). Thus, empiric
amphotericin-B therapy should be started early in-patients with granulocytopenia,
respiratory symptoms, and pyrexia.
PMID- 10774225
TI - Morphometric evaluation of the human cervical motoneurons.
AB - Morphometric analysis of the human cervical large motoneurons in the anterior
horn was performed in 7 male cadavers with the help of an image-analyzer and the
use of a new tissue preparation method which minimizes shrinkage. This method
makes it possible to precisely evaluate the size of cervical motoneurons at each
level. Our study revealed a difference in number, average area and total area of
the motoneurons between C1-C3 and C4-C7 levels. This results can be of importance
in setting standard values for the understanding of morphological and functional
correlations.
PMID- 10774226
TI - Unmyelinated nerve fibre analysis of the human lesser splanchnic nerve.
AB - The aim of the present study is to analyse unmyelinated nerve fibres of the human
lesser splanchnic nerve in relation to the ageing process. With the help of an
image-analyser, we examined 30 human lesser splanchnic nerves. The analysis was
conducted with the use of a new staining method that makes it possible to
discriminate various structures of the nervous tissue. Our report provides for
the first time information on the ageing process of the human lesser splanchnic
nerve fibres. The results indicate that a decrease in transverse area and
perimeter of unmyelinated axons is one of the important changes occurring in the
human lesser splanchnic nerve during the ageing process.
PMID- 10774227
TI - Immunohistochemical localisation of epidermal growth factor, transforming growth
factor alpha and EGF receptor during organogenesis of the murine hypophysis in
vivo.
AB - In previous study of melanocyte-stimulating hormone (MSH) cell development in the
proliferating pars intermedia, which is in close apposition to the presumptive
pars nervosa, no direct cell-to-cell contact was found between the boundary
neurohypophyseal pituicytes (PIC), adenohypophyseal precursor stem cells (PSC)
and the related diencephalic mesenchymal cells. Here, we have used
immunohistochemistry to examine cytokine expression in the development of the
hypophysis during foetal stages II-IV. Light and confocal laser scanning
microscopy indicated diffuse expression of both TGF alpha and EGF in the
hypophysis at different foetal stages. While no findings indicative for temporary
changes of TGF alpha and EGF patterns were found in the foetal hypophysis, a
temporary increment of EGF molecules was distinct in the diencephalic mesenchyme
at stages III and IV. On the other hand, light microscopy intensively immuno
localized EGFR in the adenohypophysis and neurohypophysis at different
developmental stages. Immunoreactivity of EGFR in the cytoplasm and nucleus
suggested active proliferative events in the PIC and PSC of stages II-IV mouse
pituitaries.
PMID- 10774228
TI - Lamination of the masticatory muscles in the kangaroo according to their
innervation.
AB - An analysis of the laminations of the masseteric, zygomaticomandibular and
temporalis muscles of the Red Kangaroo (Macropus Rufus) and all of the
masticatory muscles of the Eastern Gray Kangaroo (Macropus Giganteus) was carried
out based on their innervation. The masseteric muscle was divided into
superficial and deep layers; the superficial layer was further subdivided into
three laminae from the rostro-lateral portion to caudo-internal portion. The deep
layer was divided into lateral, caudo-internal and rostro-internal laminae. The
zygomaticomandibular muscle which was located between the masseteric and temporal
muscles was divided into lateral, internal and rostral laminae, on the basis of
its innervation. The lateral and internal laminae were innervated by the nerve
which arises between the masseteric nerve and the posterior deep temporal nerve.
A small rostral portion of the muscle was innervated by masseteric nerves, which
passed through the internal lamina of the deep layer of the masseteric muscle.
The temporalis muscle was innervated by an anterior deep temporal nerve and
posterior deep temporal nerve. Only the most rostro-internal lamina of the
temporalis muscle was innervated by the anterior deep temporal nerve. The
anterior deep temporal nerve and lateral pterygoid nerve had a common trunk. We
believe that the rostro-internal lamina was closely related to the lateral
pterygoid muscle. The lateral pterygoid muscle displayed one lamina, whereas the
medial pterygoid muscle was divided into internal and lateral laminae. The
lateral lamina was further divided into rostro-internal and caudo-lateral
laminae.
PMID- 10774229
TI - Effects of ovariectomy on parafollicular cells in the rat.
AB - Changes in the parafollicular cells in the thyroid gland of ovariectomized rats
were investigated to clarify the relationship between the secretory function of
sex hormones and that of parafollicular cells. Compared with control rats, the
ovariectomized rats exhibited decreases in 1) the number of parafollicular cells
in the thyroid glands, 2) the number of secretory granules in the parafollicular
cells, and 3) the area occupied by the Golgi complex. These results suggest that
the lack of estrogen caused by ovariectomy reduces the synthesis and release of
calcitonin in parafollicular cells, which may be one of the causes of
osteoporosis.
PMID- 10774230
TI - Effects of KrF excimer laser irradiation on human dental enamel.
AB - Spectra of human dental enamel was recorded in the 200-400 nm UV region. It
showed the weak band at 280 nm which were present in enamel protein. Excimer
laser are gas lasers which emit light with photochemical decomposition. The
wavelength depends on the 248 nm with krypton-fluoride. The enamel surfaces of
extracted human teeth were exposed to KrF excimer laser by an energy density
range from 29.6 to 3200 J/cm2. The purpose of this study was to investigate the
changes with photo chemical reaction in enamel by light microscopy, SEM and X ray
diffraction method. Results of analyses suggested that the observed changes of
enamel exposed to this laser were the alpha and beta-tricalcium phosphate (TCP)
phase in small amounts. No histological changes were observed in grain boundaries
of cross sectioned lased enamel under light microscopy. The SEM examination
revealed a roughened surface with bubble formation at 800-3200 J/cm2. SEM of
etched enamel surface with 0.1 N HCl after laser irradiation at 400-800 J/cm2
showed the extension along the length of the rods. At 1600-3200 J/cm2, there
appeared to be a melting of prism structures, because of conversion of photon
energy into thermal energy. These results showed the KrF excimer laser
irradiation to dental enamel might be a new type of treatment modality and
diagnosis in preventive dentistry.
PMID- 10774231
TI - Macroscopic anatomy of the auditory tube diverticulum (guttural pouch) in the
thoroughbred equine--a silicon mold approach.
AB - The characteristics of the equine auditory tube diverticulum (guttural pouches)
were studied in detail by the naked eye and silicon mold method. First, we
examined the anatomical relationship between the guttural pouches and their
associated bones and muscles. Secondly, a silicon mold was fabricated to clarify
the three-dimensional aspect of the guttural pouches, paying a special attention
to the distribution of major arteries and nerves surrounding it. Thirdly, the
volume of the silicon mold was measured by immersing it in water. The guttural
pouches are a pair of pouches located dorso-posteriorly to the posterior pharynx.
The pouches had a close contact rostrally with the Os sphenoidale, ventrally with
the pharynx and the esophagus, and caudally with the Articulatio atlantoaxialis.
The left and right guttural pouches had almost the same capacity in each horse.
The A. carotis interna, cranial ganglia of cervical nerves and cervical Truncus
sympathicus, as well as the N. vagus, N. glossopharyngeus, N. hypoglossus, and
Radices spinales of the N. accessorius, were present in the mucosal crease
extending from the roof of the guttural pouches towards the middle of the caudal
wall. The N. facialis appeared from the Foramen stylomastoideum ran dorsocaudally
along the lateral recess. The N. mandibularis appeared from the Foramen lacerum
went over the muscular process of an ear bone, ran along the roof of the lateral
recess and finally continued with the rostral side of the guttural pouches. Lymph
nodes, scattered on the mucosal surface, appeared as tiny indentations with
approximately millet seed size on the silicon surface. The capacity of guttural
pouches in adult horses (472 +/- 12.4 cm3) was three-fold larger than that in
foals (145 +/- 9.4 cm3).
PMID- 10774232
TI - A case of an aberrant branch from the posterior brachial cutaneous nerve to the
latissimus dorsi: a vestigeal part of the dorsoepitrochlearis?
AB - During dissection, an aberrant muscular nerve to the small part of the latissimus
dorsi arising from the posterior brachial cutaneous nerve was found. Based on the
findings of the form and the innervation, the small part is considered to be a
vestige of the dorsoepitrochlearis in mammals. It is suggested that the posterior
brachial cutaneous nerve is derived from the nerve to the dorsoepitrochlearis
(Kasai et al., 1989, Acta Anat Nippon 64: 255-266). This case may be indirect
evidence indicating one of the patterns of development of cutaneous nerves in
man.
PMID- 10774234
TI - The human recurrent laryngeal nerve during the aging process.
AB - After a morphometric analysis of nerve fibers of the human recurrent laryngeal
nerve, which is connected with phonation, the authors discovered several changes
occurring in the axon during the aging process. These changes are mainly the
disappearance of large axons and a slenderization of all remaining axons. This is
the first time that such observation has been made.
PMID- 10774233
TI - Developmental changes in enzyme activities and in morphology of rat cortex
mitochondria.
AB - Development of mitochondria in rat brain cortex was investigated in terms of
mitochondrial respiratory enzyme activities, and structural and numerical
developments of mitochondria. Measurements of succinate-O2 and NADH-O2
oxidoreductase activities of mitochondria resulted in simultaneous changes of
activities in postnatal rat. Both oxidoreductase activities were still low at 0-5
days old, increased until 15 days, decreased slightly at 21 days and drastically
in adult mitochondria. In morphological study, the cross-sectional area of
mitochondrion per cell increased gradually until 21 days old, but decreased
drastically in adult. The area of a mitochondrion at 5 days increased about 1.5
fold in comparison with that at 0 days, and maintained at 15 and 21 days.
However, the values of area of one mitochondrion from 10 days and adult are about
half of a maximum value (21 days). Numbers of mitochondrion per cell were still
low at 0-5 days, and high constantly (about twice) at 10-21 days. These findings
suggest that the organelle division of mitochondria may be carried out at 5-10
days postnatal. The number of adult rat mitochondria decreased slightly. The
small and undeveloped mitochondria were observed at 0 day postnatal by use of
transmission electron microscopy (TEM). However, during development from 5 days
postnatal, larger and elongated mitochondria were observed, and the maximal
complexity of structure of cristae is observed at 15 days and 21 days by TEM. In
adult cortex, the small mitochondria were also observed with compact and dense
cristae. Our results indicate that the changes of activities of mitochondrial
respiratory enzymes in rat cortex is good correlated with the structural
maturation of mitochondria.
PMID- 10774235
TI - [Nosocomial surveillance--compass for infection control].
AB - The authors, after defining basic concepts, make the case that nosocomial
surveillance is an indispensable tool without which up-to-date infection control
is impossible. They provide an overview of the nosocomial surveillance practices
in many countries in Europe and overseas, comparing their methods, results and
protocols, keeping in mind cost effectiveness and quality assurance
considerations. The authors' view is that in Hungary two kinds of nosocomial
surveillance programs should be established: 1. There should be reliable surveys
to follow up the incidence of nosocomial infections. Without such data any
national infection control strategy is at best uncertain. Obtaining this
information is mostly in the interest of the government. Procedures should be
coordinated from a central office, financial backing for the surveys should be
provided, and the personal and institutional infrastructure should be built up in
a consensual manner, with much care and technical expertise, relying on domestic
and foreign experience. 2. Each institution should decide, based on their current
goals, which selective nosocomial surveillance method is most appropriate for a
given occasion. This decision should be voluntary and government regulation of
these activities would be counterproductive.
PMID- 10774236
TI - [Cross reactivities between food antigens of plant or animal origin].
AB - Knowledge about cross reactivities among food proteins of plant or animal origin
is getting more and more important. Cross reaction provoking often clinical
symptoms may be based on close taxonomical relations or on the presence of
"archaic", ubiquiter protein structures preserved during phylogenesis. The most
significant cross reactivities characterized by increasing incidence are between
pollens and foods of plant origin and between latex and fruits.
PMID- 10774237
TI - [Preliminary results of the study of the relationship between cricopharyngeal
incoordination and gastroesophageal reflux in infants].
AB - The authors summarise the results of barium swallow examinations and
polysomnographic studies performed on 66 infants (41 male, 25 female), average
age 63 days (26-130 days). Oesophageal pH monitoring was also performed as part
of the polysomnographic examination. The results showed the highest incidence of
cricopharyngeal incoordination (CPI) in the 6-10 weeks age group. Although they
failed to demonstrate statistical significance between CPI and increased gastro
oesophageal reflux, they consider the two entities to be most probably related.
No relation was found between CPI and abnormal polysomnographic results. They
give an overview of the literature on the pathology of the cricopharyngeal muscle
and with regard to the lack of uniformity in the terminology of previous
publications, they present their use of terminology.
PMID- 10774239
TI - [Successful surgical treatment of ruptured left ventricular aneurysm].
AB - Authors report on the successful surgical treatment of a ruptured left
ventricular aneurysm that resulted in cardiogenic shock. Pathogenesis and
complications of left ventricular aneurysm as well as the diagnostic and
treatment modalities are summarized. Authors emphasize that the quick and close
co-operation between their departments was a prerequisite of the success.
PMID- 10774238
TI - [An adult form of type-I. Gaucher's disease].
AB - A young woman with no previous history of any diseases was admitted for further
evaluation of a mild thrombocytopenia she has had for some months. No signs of
bleeding have so far occurred. Physical examination was normal except for a
moderately enlarged spleen. Routine investigations showed lower platelet count.
There was no laboratory evidence of disease conditions with
autoimmune/inflammatory or hematologic origin. Bone marrow aspirate indicated
Gaucher's-like cells raising the suspicion of Gaucher's disease. This was further
supported by electron microscopic demonstration of Gaucher's bodies (with the
characteristic tubular structures) in crista biopsy specimens. However,
definitive diagnosis was obtained by verifying deficient lysosomal
glucosylceramide-beta-D-glucosidase activity in peripheral blood leukocytes. Upon
the absence of neurologic involvement the patient was typical for the adult form
or type-1 Gaucher's disease.
PMID- 10774240
TI - [Is "evidence-based therapy" a new thing?].
PMID- 10774242
TI - [NK-cell tumors].
PMID- 10774241
TI - [Sentinel lymph node detection in primary hepatocellular carcinoma with patent
blue and and intraoperative gamma rays].
PMID- 10774243
TI - [Recent advances of differentiation-inducing therapy for leukemia].
PMID- 10774244
TI - [Molecular cytogenetics of stem cell].
PMID- 10774245
TI - [Transcription factors and leukemias].
PMID- 10774246
TI - [Plasma cell leukemia presenting with circulating villous lymphocytes and an
indolent clinical course].
AB - A 73-year-old man was admitted to our hospital in July 1996 because of
lymphoctyosis and lumbago. Physical examination revealed hepatomegaly and anemia.
Hematologic examination showed a hemoglobin concentration of 9.6 g/dl and a
leukocyte count of 32,700/microliter with 74% abnormal mononuclear cells. In
Wright-Giemsa stained blood films, these cells had short villi arising from 1 or
2 poles. Immunophenotyping of peripheral mononuclear cells showed moderate to
strong expression of CD10, CD24, CD38, and sIg lambda, but not of CD19, CD20, or
CD25. Southern blot analysis of the peripheral mononuclear cells demonstrated
rearranged monoclonal bands in the C lambda. Urine immunoelectrophoresis detected
a monoclonal band identifiable as lambda-type Bence Jones protein. In addition,
bone X-ray studies disclosed multiple osteolytic lesions. A diagnosis of plasma
cell leukemia was made, and the patient was placed on chemotherapy consisting of
cyclophosphamide and prednisolone. No notable improvement in laboratory findings
was seen but the patient experienced an indolent clinical course. He died of
pneumonia in January 1998. The morphological and clinical findings were unusual
for a case of plasma cell leukemia. This case study suggested that signs of
lymphocytosis require immunophenotypic and electron microscopic studies for the
differential diagnosis of plasma cell leukemia.
PMID- 10774247
TI - [Development of gamma-heavy chain disease during the course of diabetic
nephropathy].
AB - We reported a rare case of gamma-heavy chain disease. A 63-year-old man had been
given a diagnosis of diabetes mellitus at the age of 30 and had received
hemodialysis since the age of 55. The patient presented with swollen lymph nodes
in the neck. Lymph node biopsy findings suggested immunoblastic lymphadenopathy.
The patient was admitted to Kitasato University hospital. Serum protein
electrophoresis showed an increase of beta-fraction peak, and
immunoelectrophoresis revealed an increase of gamma-heavy chain protein. Further
studies of the gamma-heavy chain protein showed that it contained three different
components and that the molecular weight of the main component was 34,000 Da. The
patient died on the 11th day of hospitalization. The diagnosis at autopsy was
unclassified malignant lymphoma.
PMID- 10774248
TI - [Effect of lenograstim (glycosylated recombinant human granulocyte-colony
stimulating factor) on peripheral blood stem cell mobilization in healthy
volunteers].
AB - The efficacy and safety of high-dose lenograstim on CD34 positive (CD34+) cell
mobilization into peripheral blood were investigated in 18 healthy male
volunteers. The volunteers were divided into 3 lenograstim dose groups of 6
subjects each. Lenograstim was administered at a dose of 2, 5, or 10
micrograms/kg/day, b.i.d. by subcutaneous injection for a total of 5 days. The
median peak number of CD34+ cells/microliter of blood was 16.3, 53.9, and 96.6 in
the 2, 5, and 10 micrograms/kg/day groups, respectively. A positive correlation
was observed between the peak CD34+ level and dose of lenograstim (P = 0.002).
The percentage of volunteers achieving more than 50 CD34+ cells/microliter of
blood was significantly higher in the 10 micrograms/kg/day group (83.3%, P =
0.010) than in the 2 micrograms/kg/day group (0%). On the subject of safety, at
least 1 adverse drug reaction (ADR) was observed in each of the volunteers, and a
total of 12, 33, and 45 ADRs were observed in the 2, 5, and 10 micrograms/kg/day
groups, respectively. A dose-dependent increase in the number of ADRs was also
observed, including an elevation of LDH (P < 0.001), bone pain (P < 0.001), and
fatigue (P = 0.008). However, no volunteers required symptomatic treatment or
discontinuation of lenograstim. We concluded that administration of lenograstim
at a dose of 10 micrograms/kg/day for 5 days is highly effective for CD34+ cell
mobilization into peripheral blood and tolerable in healthy volunteers.
PMID- 10774249
TI - [Allogeneic bone marrow transplantation for primary myelofibrosis after
splenectomy].
AB - A 46-year-old woman was given a diagnosis of primary myelofibrosis (PMF) in 1996.
Because of the progression of anemia and splenomegaly, she was scheduled for
allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor in
April 1998. Cyclophosphamide and busulfan were used as the conditioning regimen.
Before BMT, the patient was treated with hydroxycarbamide, which did not resolve
splenomegaly. She then underwent a splenectomy, which was followed by massive
portal vein thrombosis without any significant clinical outcome. After BMT, the
patient obtained rapid hematologic engraftment. Moreover, the alleviation of
marrow fibrosis was confirmed 4 months after BMT. We concluded that allogenic BMT
can cure patients with PMF, but that the issue of splenectomy and the indications
for BMT need to be evaluated further.
PMID- 10774250
TI - [Three pediatric cases of erythroleukemia: review of the literature on prognostic
factors].
AB - We encountered 3 patients with erythroleukemia who showed differing outcomes. The
first patient was an 11-year-old girl who was treated with an ANLL 91 national
protocol followed by bone marrow transplantation from an HLA-identical brother.
She is still in complete remission after 6 years. The second patient was a 15
year-old girl. Treatment with low dose Ara-C was effective. She experienced a
relapse once, but achieved her second remission with low dose-Ara-C plus vitamin
D. Up to the present, she has maintained remission for 5 years. The third patient
was a 1-month-old girl who initially presented with an increase of
proerythroblasts with infiltration to the liver. Although her response to Ara-C
and etoposide was favorable, she died of a generalized fungal infection in the
leukopenic phase. Chromosomal analyses of bone marrow cells were normal for
patients 1 and 2, but patient 3 had an abnormal complex karyotype. We think the
prognosis for erythroleukemia in childhood is not necessarily poor in all cases.
Appropriate treatment should be based on the patient's age, the proportion of
proerythroblasts, and the presence of chromosomal abnormalities.
PMID- 10774251
TI - [An elderly patient with myelodysplastic syndrome successfully treated with
combination of granulocyte-colony stimulating factor and continuous-drip infusion
of low-dose cytarabine and etoposide].
AB - A 73-year-old man was given a diagnosis of myelodysplastic syndrome in October
1997. He was treated with red blood cell transfusion and granulocyte-colony
stimulating factor (G-CSF). In February 1998, he was admitted due to progression
of pancytopenia. Bone marrow aspiration revealed refractory anemia with excess of
blasts in transformation. The patient was treated with continuous-drip infusion
of low-dose cytarabine and etoposide with G-CSF (AVG therapy). Complete remission
(CR) was obtained after 2 courses of AVG therapy. Non-hematologic adverse effects
were mild enough to be tolerated. CR has been maintained for 16 months with 1
course of consolidation therapy and 3 courses of intensification therapy using
the AVG regimen.
PMID- 10774252
TI - [Myelodysplastic syndrome associated with polymyalgia rheumatica].
AB - A 69-year-old man was referred to us because of severe pain in both girdles. A
diagnosis of polymyalgia rheumatica was made, and low-dose prednisolone therapy
(20 mg/d) was started. The patient's muscle pain disappeared after 3 weeks. After
5 months of therapy, pancytopenia became prominent. A marrow aspirate smear
showed hypercellularity, trilineage dysplasia, and 7% blasts. The clinical
diagnosis was myelodysplastic syndrome, subtype refractory anemia with excess of
blasts. In elderly patients presenting with polymyalgia rheumatica, an underlying
hematologic malignancy should always be looked for when the disease demonstrates
clinical signs inconsistent with typical polymyalgia rheumatica.
PMID- 10774253
TI - [CD16+ CD56- indolent, NK cell-lineage granular lymphocyte proliferative disorder
with autoimmune hemolytic anemia].
AB - A 64-year-old man was given a diagnosis of CD16+ CD56- natural killer cell
lineage granular lymphocyte proliferative disorder (NK-GLPD) with Coombs-negative
autoimmune hemolytic anemia (AIHA). Two courses of 1,000 mg intravenous
methylprednisolone for 3 days were transiently effective for both AIHA and NK
GLPD. On the recurrence of AIHA, NK-GLPD also re-appeared. The same treatment was
effective in controlling both diseases again. This was a rare case of NK-GLPD
combined with autoimmune disease.
PMID- 10774255
TI - [Transdermal delivery of drugs and enhancement of percutaneous absorption].
AB - This paper describes 1) the drug delivery through the skin to produce systemic
effects, 2) the enhancement of percutaneous absorption by absorption enhancers,
heating and complex formation, 3) the mechanism for the enhancement effect by
enhancers, 4) the percutaneous absorption of peptides, and 5) the pharmacokinetic
analysis for percutaneous absorption. 1,3-Dinitroglycerin, indomethacin (IND) and
many drugs were efficiently absorbed via rat and rabbit skins in the presence of
some enhancers, and using a microporous membrane therapeutic plasma
concentrations were maintained for a long time. Enhancement of percutaneous
absorption by the complex formation with fatty acid was observed for propranolol
(PL) in vitro and in vivo. Heating at 42-45 degrees C also enhanced the
percutaneous absorption dramatically, with decreased activation energies. The
following mechanisms for the enhancement effect by enhancers were found: a) an
increase in the fluidity of the stratum corneum lipids and reduction in the
diffusional resistance to permeants, b) the removal of intercellular lipids and
dilation between adherent cornified cells, c) an increase in the thermodynamic
activity of drugs in vehicles, d) the exfoliation of stratum corneum cell
membranes, the dissociation of adherent cornified cells and elimination of the
barrier function. Peptides such as enkephalin, elcatonin and insulin were
effectively absorbed through the skin in the presence of some enhancers and
specific inhibitors, with no proteolytic degradation. The pharmacokinetic model
with two parallel absorption processes, lipidic and aqueous pore transport
pathways, in skin could adequately describe the percutaneous absorption of IND,
PL and valproic acid. With peptides, a kinetic model including zero-order input
rate, first-order permeation rate and first-order degradation rate was able to
describe well the steady-state flux of peptides.
PMID- 10774254
TI - [Studies on hemorrhagic toxins from the venoms of Trimeresurus mucrosquamatus,
Crotalus ruber ruber, Vipera aspis aspis and Agkistrodon acutus and arginine
ester hydrolases from Trimeresurus mucrosquamatus venom].
AB - Venom samples were corrected from several poisonous snakes, such as Bungarus
multicinctus, Trimeresurus mucrosquamatus, T. gramineus, T. flavoviridis, and
Agkistrodon acutus, and stored in a desiccator at room temperature for 25 to 31
years. Then they were compared with fresh venoms as to their biological
activities. The characteristic local symptoms produced by the bite of venomous
snakes of Crotalidae and Viperidae are hemorrhage, necrosis and muscular
degeneration. Hemorrhagic toxins were purified from Trimeresurus mucrosquamatus,
Crotalus ruber ruber, Vipera aspis aspis, and Agkistrodon acutus venoms and their
biological, biochemical, and pathological properties were investigated. Arginine
ester hydrolases are present in the venoms of Crotalidae and Viperidae, but are
not found in the venoms of Elapidae and Hydrophiidae. In this paper we describe
the enzymatic and biological activities of arginine ester hydrolases from a
Trimeresurus mucrosquamatus venom.
PMID- 10774256
TI - [New methods of constructing fluorinated organic compounds and their
application].
AB - This review summarizes several effective synthetic methods of fluorinated organic
compounds developed by our group. Two topics have been described in this review.
The first topic describes novel fluorinations using diethylaminosulfur
trifluoride (DAST). The treatment of tertiary cyclopropyl silyl ethers with DAST
caused ring opening and produced allylic fluorides. The reaction of DAST with a
tertiary cyclobutanol provided a fluorocyclobutane, a (fluoromethyl)cyclopropane
or a homoallylic fluoride. DAST reacted with cyclic ketoximes bearing
substituent(s) that can stabilize a carbocation to cause the fluorinative
fragmentation which produces fluorinated carbonitrile. The second topic describes
the novel syntheses of organic compounds containing the difluoromethylene moiety
using fluorinated building blocks. The indium-mediated coupling of aldehydes with
3-bromo-3,3-difluoropropene gives alpha,alpha-difluorohomoallylic alcohols in
high yields. alpha,alpha-Difluorohomopropargylic alcohols were also obtained from
the indium-mediated coupling of aldehydes with alpha-bromo-alpha,alpha
difluoropropargyl compounds. In the presence of a palladium(0) catalyst, several
nucleophiles regioselectively reacted with 3-bromo-3,3-difluoropropene at its
gamma-position, and reacted with 1-substituted-3-bromo-3,3-difluoropropenes at
their alpha-position. (+)-(R)-1-Amino-2,2-difluorocyclopropane-1-carboxylic acid
was synthesized via the lipase-catalyzed asymmetric acetylation of a pro-chiral
diol as a key step.
PMID- 10774257
TI - [Pharmacological role of isatin, an endogenous MAO inhibitor].
AB - Isatin (indole-2,3-dione) has been found in mammalian tissues as one of major
components of tribulin, a postulated endogenous marker of stress and anxiety. I
previously identified isatin as an endogenous inhibitor of monoamine oxidase
(MAO) in the human urine and the brain of stroke-prone spontaneously hypertensive
rats (SHRSP) using GC-MS. A single dose of isatin significantly increased
norepinephrine (NE) and 5-hydroxytryptamine (5-HT) concentrations measured 2 h
later in the various brain regions of normotensive Wistar Kyoto rats (WKY).
Striatal acetylcholine (ACh) and dopamine (DA) levels significantly increased 2 h
after the administration of isatin. Perfused through a microdialysis probe,
isatin also produced a significant and concentration-dependent increase in the
ACh and DA concentration in the perfusate from the rat striatum. In the patients
with Parkinson's disease, urinary isatin concentrations tended to increase
according to the severity of disease, as classified by the Hoehn and Yahr
criteria. Isatin significantly increased striatal DA levels in a rat model of
Parkinson's disease. Isatin may play a role in the regulation of the brain levels
of ACh and DA. Furthermore, isatin has a wide spectrum of biological properties:
(a) a marker of stress and anxiety, (b) an inhibitor of a number of enzymes, (c)
an anti-seizure agent, (d) an inhibitor of benzodiazepin receptors and ANP
binding to its receptors.
PMID- 10774258
TI - [Development of synthetic methods for 4-substituted indoles and their
applications for the syntheses of natural products].
AB - In our continuing work on synthesizing 4-substituted indole alkaloids as simple
as possible by creating suitable reactions, we developed synthetic methods for 4
substituted indoles having a nitrogen or oxygen functional group at the 4
position starting from indole-3-carbaldehyde and one step conversion method of
indole-3-carbaldehydes into indole-3-acetonitriles. Utilizing them, we could
establish a practical synthetic route to 1,3,4,5-tetrahydropyrrolo[4,3,2-de]
quinoline in three steps from indole-3-carbaldehyde. On the basis of these
results, short step total syntheses of marine indole alkaloids, such as
isobatzelline C, batzelline C, makaluvamine A, and damirones A and B, were
achieved. Furthermore, a novel preparative method of psilocin was established in
only five steps from indole-3-carbaldehyde. The syntheses of psilocin analogs
having a formyl group or bromine in the benzene part were also achieved.
PMID- 10774259
TI - [Study of macrolide, lincosamide, and streptogramin B antibiotics resistance in
Staphylococcus aureus].
AB - Macrolide antibiotics (Mac) consist of a 12- to 16-membered lactone ring combined
with a sugar moiety, and they inhibit protein synthesis via binding to 23S
ribosomal RNA in bacteria. The 14- and 16-membered Mac are used for treating
infectious diseases caused by Gram-positive and other bacteria; e.g., Haemophilus
influenzae, Bordetella pertussis, Legionella pneumophila, Campylobacter,
Treponema pallidum and Mycoplasma. Resistance to macrolide, lincosamide, and
streptogramin-B (MLS) antibiotics in staphylococci is known to have the following
mechanisms: 1) alteration of the target on ribosome due to dimethylation of a
specific adenine residue in the 23S ribosomal RNA by the product of the erm gene,
and consequently a decrease in binding of MLS antibiotics; 2) inactivation of
streptogramin-B (STG-B) and lincosamide by the products of the sbh (encoding
streptogramin B hydrolase) and linA' (encoding 3-lincomycin 4-clindamycin O
nucleotidyltransferase) genes, respectively; and 3) active efflux of Mac and STG
B antibiotics determined by the msrA and msrB genes in Staphylococcus epidermidis
and Staphylococcus xylosus, respectively, both of which appear to act as an ATP
dependent efflux pump. I have shown that Staphylococcus aureus 8325(pEP2104)
exhibits inducible resistance to PMS (partial macrolide and streptogramin B)
antibiotics [the 14-membered macrolides, erythromycin (EM), and oleandomycin
(OL), and the 16-membered macrolide mycinamicin (MCM) and STG-B]. The sequence of
the N-terminal amino acid residues of a 63 kDa protein (MsrSA) that appeared in
the membrane of PMS-resistant strains was identical to that of an MsrA
polypeptide related to enhanced efflux of [14C]EM. Ribosomes from PMS-resistant
strains showed a similar affinity for EM to those from the PMS-sensitive host
strain NCTC8325, and no inactivation of EM by 8325(pEP2104) was observed. In the
present study, I showed the DNA sequence of the msrSA region on the constitutive
PMS-resistant plasmid pMC38, PMS-inducible resistant plasmid pEP2104 and PMS
sensitive mutant plasmid pSP6, and the region that is essential for inducible
expression in PMS resistance. In addition, I investigated the relationship
between PMS resistance and intracellular accumulation of EM.
PMID- 10774260
TI - [Studies on membrane factors in iron-supported lipid peroxidation].
AB - Lipid peroxidation in biomembranes is mediated by free radical reactions. It
leads to membrane damage and has been proposed to be associated with the
pathogenesis to tissue injuries. Iron is known as a catalyst of lipid
peroxidation. Microsomal lipid peroxidation by both NADPH and iron-chelate, such
as Fe(3+)-ADP or Fe(3+)-PPi, is believed to be enzymatically associated with iron
reduction. On the other hand, the addition of free Fe2+ to microsomes or
liposomes produces a lag phase before the maximal rates of lipid peroxidation. We
examined the interaction of iron with membrane in iron-supported lipid
peroxidation and microsomal membrane components associated with iron reduction in
NADPH-supported lipid peroxidation. Iron-supported lipid peroxidation was
affected by the surface charges of liposomal membrane. Liposomes containing
phosphatidylserine (PS) were most sensitive to iron-supported lipid peroxidation.
The effect of PS on iron-supported lipid peroxidation indicates that iron
participates in binding to membrane surface charges and also indicates that Fe2+
at high level bound to membranes plays a role in producing a lag phase. The
mechanism producing a lag phase in Fe(2+)-PPi-supported lipid peroxidation is
discussed. In NADPH-supported lipid peroxidation in microsomes, it seemed
unlikely that superoxide may be involved in iron reduction. Alternatively, under
anaerobic conditions, NADPH-supported iron reduction in microsomes was not
dependent on cytochrome P450 content and not inhibited by CO. A cholate
solubilized fraction of microsomes was applied to a laurate-Sepharose column and
an active fraction for lipid peroxidation was obtained. Involvement of a heat
labile component, distinct from cytochrome P450, responsible for iron reduction
in microsomal lipid peroxidation was demonstrated.
PMID- 10774261
TI - [Estimation of adverse drug reactions by the evaluation scores of subjective
symptoms (complaints) and background of patients. III. Drug-induced leucopenia].
AB - OBJECTIVES: The purpose of this study was to develop, implement, and assess an
estimation procedure for preventing adverse drug reaction by subjective symptoms
(complaints) of patients. This time, we carried out this study focusing on drug
induced leucopenia. METHODS: We have built a database for CARPIS (Case Reports of
Adverse Drug Reaction and Poisoning Information System) since 1987, and the total
number of case reports of adverse drug reaction accumulated in the CARPIS
database amounts to about 16,000. Using the date obtained from 139 cases of drug
induced leucopenia accumulated in the CARPIS database, we investigated a
relationship between leucopenia and patients. The evaluation scores were created
based on the subjective symptoms and backgrounds of the patients. RESULTS: We
could estimate 91 cases (65.5%) in 139 cases to be drug-induced leucopenia by the
use of these evaluation scores. The validity of this evaluation scores was
estimated to be as follows; sensitivity = 65.5%, specificity = 80.0% and
predictive value of positive test (PVP) = 82.0%. The positive likelihood (LR)
ratio was 3.3 and negative likelihood ratio 0.43. CONCLUSIONS: In this study, PVP
and LR values were not good, because among the symptoms of leucopenia a very few
specific symptoms could be detected. But we reported previous by the evaluation
scores about drug-induced liver disorders. Therefore, in order to apply these
evaluation scores to the clinical practice, we prepared an evaluation form for
subjective symptoms and backgrounds of the patients with adverse drug reactions.
In the future, we plan to examine other adverse reactions which adds the data to
this form.
PMID- 10774262
TI - [Effects of psidium components on cytokine productions in helper T cells and type
I allergy].
AB - Psidium genus Myrtaceae (Psidium) is known to be a chinese medicine with an anti
allergy effect. In the present study, to identify active components in Psidium
and investigate mechanisms of its anti-allergy effect, effects of several
components isolated from Psidium on cytokine production in helper T cell
subtypes, Th1 and Th2 cells, were studied. All components, except methyl gallate,
suppressed cytokine production in both Th1 and Th2 cells. Then, effects of methyl
gallate on IgE production in a model mouse with type I allergy were studied.
Methyl gallate suppressed IgE production in the mouse. Only methyl gallate
selectively suppressed Th2-cytokine production.
PMID- 10774263
TI - Cefuroxime utilization evaluation: impact of physician education on prescribing
patterns.
AB - BACKGROUND: Cefuroxime is a second-generation cephalosporin antibiotic used
widely for the treatment of various infections. OBJECTIVES: To assess the
appropriateness of cefuroxime usage as well as the long-term impact of re-feeding
the results to prescribing physicians. METHODS: Drug utilization evaluation
involved three data-collecting periods, each comprising 6 weeks, during which all
patients receiving cefuroxime were evaluated. Results of phase I were distributed
to all physicians in a newsletter and departmental lectures; phase II was
announced and conducted 6 months later. An identical phase III was unannounced
and conducted one year after phase II. The study included all patients receiving
cefuroxime during the three phases. The main outcome measure was appropriateness
of initiation, and continuation beyond 3 days, of empirical treatment.
Appropriateness was determined according to a prepared list of indications based
on the literature and the hospital's protocols. RESULTS: Cefuroxime was initiated
appropriately in 104 of 134 patients (78%) in phase I, in 85 of 100 (85%) in
phase II, and in 93 of 100 (93%) in phase III (P < 0.001). Cefuroxime was
continued appropriately after 3 days in 58/134 (43%), 57/100 (57%) and 70/100
(70%) respectively (P < 0.001). The total number of appropriate treatment days
out of all treatment days increased from 516 of 635 (81%) in phase I, to 450 of
510 (88%) in phase II, to 485 of 509 (95%) in phase III (P < 0.001). The
principal reason for cefuroxime usage was community-acquired respiratory tract
infection. CONCLUSION: Drug utilization evaluation may provide valuable data on
the usage of a particular drug. This information, once re-fed to physicians, may
improve utilization of the particular drug. This positive effect may be prolonged
beyond the immediate period of observation.
PMID- 10774264
TI - Gender differences in the reactogenicity of measles-mumps-rubella vaccine.
AB - BACKGROUND: In trials comparing different formulations of measles vaccine, excess
non-specific mortality occurred in female children who received high titer
vaccine. These findings suggest a gender-specific effect of measles vaccine.
OBJECTIVES: To determine whether gender differences exist in the rates of adverse
reactions and morbidity in the month following immunization with measles
containing vaccine, and to evaluate whether there is a gender-specific
association between the humoral immune response to measles vaccination and post
vaccination morbidity. METHODS: Parents completed questionnaires on the health
status of 755 infants aged 15-20 months, during the month preceding and the month
following the measles-mumps-rubella vaccination. Blood samples were tested for
measles antibody titers in a subsample of 237 infants. RESULTS: After controlling
background morbidity in the infants, the relative risk of fever and rash
following vaccination was 2.35 in females and 1.36 in males. The geometric mean
antibody titers against measles were similar in both sexes and there was no
significant association between antibody titer and post-vaccination morbidity in
either sex. CONCLUSIONS: Our findings demonstrate higher rates of adverse effects
in females following vaccination with MMR vaccine, irrespective of the humoral
response. This study emphasizes the need to consider possible gender differences
when evaluating new vaccines.
PMID- 10774265
TI - Immunity to varicella zoster virus in young Israeli adults.
AB - BACKGROUND: Chickenpox is a highly contagious childhood infection caused by
varicella zoster virus, a virus of the herpes family. Although a mild and self
limiting disease in otherwise healthy children, chickenpox can be a complicated
and even life-threatening disease in adults, pregnant women and immunosuppressed
individuals. Among infants whose mothers had varicella during the first trimester
of pregnancy, 2-3% will develop a congenital VZV syndrome that includes a
combination of scarring, limb deformation, central nervous system impairment and
ocular injury. In 1974, a live attenuated virus vaccine against VZV was developed
in Japan and has been thoroughly tested for safety, efficacy and long-term
effects. In March 1995 the vaccine was licensed in the U.S. for use in healthy
children only. OBJECTIVES: To determine the rate of immunity to VZV in young
Israeli adults. METHODS: On the assumption that a randomly picked sample of 18
year-old army recruits in Israel is representative of the general Jewish
population, 900 sera samples were taken for 3 years (1985,1988,1992). The sera
were analyzed for IgG to VZV with a commercial ELISA kit using microwells coated
with VZV antigens. RESULTS: A total of 98% of the samples tested positive for VZV
antibodies. The difference in serologic values between the recruitment years was
not statistically significant. CONCLUSION: The majority of the Israeli population
reaches adulthood already immunized against VZV, with immigrants having slightly
lower immunity rates. Nonetheless, a few dozen cases of chickenpox are diagnosed
in the IDF annually. These data should be taken into account when a vaccination
program is devised. Should such a program be implemented, it would be interesting
to repeat the serosurvey for comparison. A shift in the peak occurrence age might
necessitate the administration of a booster vaccine at an older age.
PMID- 10774266
TI - The effect of endogenous dehydroepiandrosterone sulphate on antibody response to
hepatitis B vaccine in neonates.
AB - BACKGROUND: DHEAS, the most abundant steroid secreted by the adrenal cortex, is
suggested to have an important role in the development of immune reaction by
activating T cell function and increasing antibody response, and has been tried
as a vaccine adjuvant in elderly people. OBJECTIVES: We examined the correlation
between endogenous DHEAS and antibody response in the neonatal period by
comparing the serum DHEAS levels with the amount of antibody response against
hepatitis B vaccination in neonates. METHODS: Vaccine was administered to 12
healthy infants within 24 hours of birth (day 0), and blood specimens were
obtained on days 0 and 30 for determination of anti-hepatitis B surface antibody
concentration and DHEAS levels. RESULTS: DHEAS levels varied widely (range 0.38
3.70 micrograms/ml, mean +/- 1SD 2.14 +/- 0.98). While we could identify two
groups of patients--those with high DHEAS levels (2.90 +/- 0.56) and those with
lower levels (1.30 +/- 0.56)--there was no correlation between DHEAS levels and
the antibody response to hepatitis B vaccine (r = -0.05). CONCLUSIONS: In
neonates, antibody response to hepatitis B vaccine does not correlate with DHEAS
serum levels. These results do not support the usage of DHEAS as a vaccine
adjuvant in neonates.
PMID- 10774267
TI - Home visits to the housebound patient in family practice: a multicenter study.
Israeli General Practice Research Network.
AB - BACKGROUND: Most countries today are experiencing an accelerated pace of
population aging. The management of the elderly housebound patient presents a
special challenge to the family physician. OBJECTIVES: To investigate a series of
home visits to housebound patients, the therapeutic procedures used, the
equipment needed, and the diagnostic conclusions reached. METHODS: The details of
379 consecutive home visits to housebound patients were recorded by 91 family
doctors serving 125,000 patients in Israel. RESULTS: The average age of the
patients was 76.1 years. The vast majority of the visits were during office hours
(94%). In 24.1% it was the doctor who decided to make the home visit on his/her
own initiative. The most common initial reason for a home visit was undefined
general symptoms, but the doctor was usually able to arrive at a more specific
diagnosis after the visit. Medications were prescribed in 59.1% of the visits,
and in 23.5% the medication was administered directly by the physician. The
commonest drugs used were analgesics and antibiotics. In 19.3% of visits no
action at all, other than examination and counseling, was undertaken. The
equipment needed included prescription pads (73%), a stethoscope (81%),
sphygmomanometer (74.9%), and otoscope/torch (30.6%). Only 15% of visits resulted
in referral to hospital. CONCLUSIONS: Home visits to housebound patients serve as
a support to caregivers, provide diagnostic information, and help the family with
the decision as to when hospitalization is appropriate. The specific medical
cause for the patient being housebound had little effect on the process of home
visiting.
PMID- 10774268
TI - Diabetes and ischemic heart disease among Yemenite immigrants in Israel.
AB - BACKGROUND: The pattern of diabetes and ischemic heart disease among emigrants
from pre-industrialized societies to more developed countries may be explained by
both genetic and environmental factors. OBJECTIVES: To describe and interpret the
pattern of diabetes and ischemic heart disease among Yemenite immigrants in
Israel and their second-generation offspring. METHODS: Medical record charts of
adult Yemenites were surveyed in a primary care health center, and the data were
compared with prevalence rates derived from a non-Yemenite population. RESULTS:
There was a marked excess of non-insulin dependent diabetes mellitus among
Yemenite immigrants over 45 years of age, but not of hypertension or ischemic
heart disease. Yemenites with diabetes were far less likely to develop ischemic
heart disease than non-Yemenites with diabetes (odds ratio for non-Yemenites
compared with Yemenites, 3.5; confidence interval 1.54 < OR < 7.77). CONCLUSIONS:
There was less of an association between diabetes and ischemic heart disease
among Yemenites. This finding requires further investigation of the relative
roles of genetic and environmental factors.
PMID- 10774269
TI - Attempt to prevent the development of diabetes in non-obese diabetic mice by oral
vanadate administration.
AB - BACKGROUND: Despite current treatment protocols, the long-term complications of
insulin-dependent diabetes mellitus have prompted the investigation of strategies
for the prevention of IDDM. OBJECTIVES: To investigate the effect of oral
vanadate in reducing diabetes type I in non-obese diabetic mice. METHODS: Sodium
metavanadate, 3.92 mmol/L, was added to the drinking water of 8-week-old female
NOD mice. Blood glucose levels, water consumption and body weight were measured,
and the end point of the study was judged by the appearance of hyperglycemia in
the mice. RESULTS: Treatment with vanadate did not significantly reduce the
incidence of type I diabetes as compared to the control group. However, oral
vanadate therapy significantly reduced the blood glucose levels after the fourth
week of treatment compared to the control group (3.83 +/- 0.67 vs. 4.44 +/- 0.83
mmol/L, P < 0.03). There was a consistent and significant increase in body weight
of the vanadate-treated pre-diabetic NOD mice compared to the controls. Diabetic
mice treated with vanadate had significantly lower levels of serum insulin as
compared to control diabetic mice (104 +/- 27 vs. 151 +/- 36 mumol/L, P < 0.03).
Histologically, no significant differences were found in inflammatory response of
the islets of Langerhans between the control and treated groups. CONCLUSIONS:
This study suggests that the post-receptor insulin-like effect induced by
vanadate is not sufficient to prevent the development of diabetes and insulitis
in pre-diabetic NOD mice.
PMID- 10774270
TI - Effect of prolonged fasting on plasma lipids, lipoproteins and apolipoprotein B
in 12 physicians participating in a hunger strike: an observational study.
AB - BACKGROUND: Dyslipidemia and obesity serve as risk factors for the development of
atherosclerotic cardiovascular disease. Fasting is sometimes recommended for
treating these conditions. This study was undertaken to try to resolve
conflicting results reported in the literature. OBJECTIVES: To study the effect
of fasting (0 calories, with free intake of fluids) for 3-5 days on plasma
concentration of triglyceride, cholesterol and apolipoprotein B. METHODS:
Physicians, about to begin a hunger strike, were divided into four groups:
normolipidemic non-obese men (group 1), two moderately obese men and two men with
type IV hyperlipidemia (group 2), healthy non-obese women (group 3), and healthy
non-obese women on oral contraceptives (group 4). Adherence to fasting was
monitored daily by detailed interviews, loss of weight, drop in plasma glucose,
presence of ketonuria, progressive rise in serum creatinine and uric acid, and
decrease in plasma pH. We monitored their serum glucose, electrolytes, liver
function, lipids, lipoproteins and apolipoprotein B on days 0, 3, and 5. RESULTS:
Physicians who adhered to complete fasting lost more than 1.5% of their body
weight after 3 days of fasting (n = 12), and more than 3.2% at 5 days (n = 5).
All non-obese normolipidemic males and females (groups 1 and 3) showed an
increase in plasma triglyceride (by 28-162%) and very low density lipoprotein
cholesterol (by 22-316%) after 3 days of fasting. The obese and hyperlipidemic
men (group 2) showed a decrease of 17-63% in their VLDL cholesterol, and the
women on oral contraceptives (group 4) showed a 20% decrease in their plasma
triglyceride on day 3. Low density lipoprotein cholesterol increased by 13% in
group 2, decreased by 7.3% in group 4, and remained unchanged in group 1 and 3.
Apolipoprotein B level correlated well with LDL cholesterol in all groups. High
density lipoprotein cholesterol changes were inconsistent. CONCLUSIONS: These
results help to explain and reconcile previous published reports. The metabolic
background of the individual together with the amount of energy consumed affect
the behavior of plasma lipids and lipoproteins levels during fasting.
PMID- 10774271
TI - Appendicitis in the elderly: what has changed?
AB - BACKGROUND: The course and outcome of appendicitis in the elderly differs from
that of the general population. The rates of perforated appendices, error in
diagnosis, postoperative complications and mortality may be related to the time
lapse between onset of symptoms and admission, and hence delay in surgery.
OBJECTIVES: To evaluate if these factors have improved in recent years. METHODS:
A retrospective study was carried out of all 61 patients over age 60 who
underwent appendectomies in a major metropolitan hospital during 1988-98.
RESULTS: We found that most patients had appendectomies within the first 24 hours
of admission and within 3 days of symptoms. Rate of perforation was 43%, error
5.6%, morbidity 41%, and mortality 3.2%. CONCLUSIONS: The high rate of appendix
perforation in the elderly is not due to delay. The literature reveals little
improvement in the statistics of the disease over the last five decades, despite
advances in imaging and surgical technique. This may be explained by the
increasing inclusion of octogenarian patients.
PMID- 10774272
TI - Impact of virus infection on adults.
PMID- 10774273
TI - The good, the bad and the ugly of vaccination.
PMID- 10774274
TI - Neonatal lupus syndromes.
PMID- 10774275
TI - Treatment of psoriasis at the Dead Sea: why, how and when?
PMID- 10774276
TI - The cellular mechanisms contributing to lung edema clearance.
PMID- 10774277
TI - Reiter's syndrome after intravesical Bacillus Calmette-Guerin therapy for bladder
cancer.
PMID- 10774278
TI - Radiation-induced Chandler's syndrome.
PMID- 10774279
TI - Vocal cord paralysis in a patient with active systemic lupus erythematosus.
PMID- 10774280
TI - Adult non-traumatic plantar heel pain: do initial X-rays enhance or detract from
the diagnosis?
PMID- 10774281
TI - Peripheral arterial tonometry: a novel and sensitive non-invasive monitor of
brief arousals during sleep.
PMID- 10774282
TI - Acute shrinkage of a macroprolactinoma masquerading as pituitary apoplexy.
PMID- 10774283
TI - Endomyocardial fibrosis with pericardial effusion and endocardial calcification.
PMID- 10774284
TI - A paradigm shift--consequences and implications.
PMID- 10774285
TI - Managing Gaucher.
PMID- 10774286
TI - Inhibiting metalloproteinase inhibitors?
PMID- 10774287
TI - Gastric trichobezoar.
PMID- 10774288
TI - [Chronic, unexplained pain: from complaint to action].
AB - Every physician encounters patients with physical symptoms that remain
unexplained, despite appropriate investigations. Medical curricula and textbooks
fail to provide guidance about the management of such problems. Particularly
specialists tend to feel helpless; this often leads to more referrals and
unnecessary operations. Three patients, referred to a neurologist for a second
opinion, had chronic, unexplained, crippling pains: a woman aged 53 with low back
pain radiating to the right leg for 27 years, a man aged 31 with neck pain for 3
years and a woman aged 31 with pain in the left arm for 1.5 years. They had no
recognisable features of depression. Their illness behaviour reversed after the
neurologist reassured the patients and advised them to embark upon a strict
programme of gradually increasing activities. In two of the patients, the scheme
was supervised by the general practitioner. A follow-up interview (after a median
interval of 3 years) of 27 similar patients referred for a second opinion showed
some success with this approach in about half of them. In retrospect no
predictive factors at baseline could be identified other than age and duration of
symptoms. An indispensable first step in patients with unexplained, chronic pain
is unqualified recognition of the symptoms, reassurance, and an explanation that
avoids the mind-body division.
PMID- 10774289
TI - ['Decubitus' guideline of the Dutch College of Family Practice; response from
family practice].
AB - The guideline on pressure ulcers issued by the Dutch College of General
Practitioners gives a lot of practical information for the family doctor and the
practical nurse. The main thought is the treatment of decubitus in a moist
environment. Furthermore this guideline will help the doctor to make the right
choice in the chaos of supplies. It is of great interest that interdisciplinary
collaboration will take place on this issue, for a well developed communication
gives the best results of treatment.
PMID- 10774290
TI - ['Decubitus' guideline of the Dutch College of Family Practitioners: response
from internal medicine].
AB - The guideline on pressure ulcers by the Dutch College of General Practitioners is
good in the aspects of simplicity and giving very practical advice. It can be
used as a guideline for prevention as well as treatment of pressure ulcers. Some
aspects, however, are insufficiently dealt with. There is no summing up of the
differences in anti-pressure ulcer devices such as mattresses and cushions. Use
is made of the international classification of pressure ulcers in 4 stages, but
also of a kind of rating in three colours (red-yellow-black), of which it is
known that it underestimates the severity of pressure ulcers. There is an advice
to use the knowledge of surgeons, dermatologists and nursing home doctors in
difficult cases in the home care, where training and deployment of nurses
specialised in this specific field might be preferable. Nevertheless, the
guideline is well documented and useful in general practice.
PMID- 10774291
TI - [Summary of 'Decubitus' guideline of the Dutch College of Family Practitioners].
AB - The guideline 'Decubitus' published by the Dutch College of General Practitioners
contains guidelines with instructions for prevention, diagnosis and treatment of
pressure ulcers in primary care. The classification used for severity is: redness
of the skin, superficial damage, superficial ulcer, deep ulcer. This
classification follows the one used internationally and the one in the consensus
of the Dutch Institute for Health Care Improvement CBO. For each patient who
becomes (totally or partly) immobile measures to prevent pressure ulcers are
necessary, with emphasis on minimizing pressure and shearing forces acting upon
the skin. After a pressure ulcer has developed these measures remain important.
Guidelines for treatment are given for each level of severity of the pressure
ulcer; the main aim is to keep the ulcer moist, to remove necrosis and exudate
and to treat infection.
PMID- 10774292
TI - [Therapeutic angiogenesis as a new experimental treatment for vascular disease].
AB - Currently, our treatment modalities for patients with severe coronary artery
disease consist of combinations of medication, percutaneous transluminal coronary
angioplasty (PTCA) and coronary revascularization operations. Still, the number
of patients who cannot be treated adequately in these ways is growing. In recent
years progress has been made in the field of angiogenesis: the process of the
development of new capillaries. It is now known that blood vessel growth is an
essential phenomenon in a range of disease. It is possible to inhibit or
stimulate this process, offering hope for new treatments in a wide array of
diseases. Stimulation of angiogenesis has already been successful in animal
models of chronic peripheral and myocardial ischaemia. Results of experimental
treatments of coronary patients have been reported since 1998. 'Therapeutic
angiogenesis' may evolve as our fourth treatment modality for the treatment of
coronary artery insufficiency.
PMID- 10774293
TI - [Meperidine (pethidine) outdated as analgesic in acute pancreatitis].
AB - The most important symptom in acute pancreatitis is pain. This pain often is so
severe that treatment is started with opioid analgesics. In daily practice
meperidine is often the analgesic of first choice because it is supposed to cause
less spasm of the M. sphincter ampullae hepatopancreaticae (sphincter of Oddi).
Drawbacks of the use of meperidine compared with other opiods are myoclonias,
tremors and convulsions due to accumulation of the metabolite norpethidine, and
hypotension, tachycardia and erythema due to release of more histamine from mast
cells. From literature study it appeared that all opioids have a spasmogenic
effect on the sphincter of Oddi, that there are no good arguments to assume that
this effect is less when meperidine is used, and that there is no good evidence
that this spasmogenic effect of opioid analgesics influences the course of acute
pancreatitis in an unfavourable way. Since the profile of effects and side
effects of meperidine is unfavourable, we prefer the use of opioids with a larger
therapeutic width.
PMID- 10774294
TI - [Trends in incidence and treatment of ductal carcinoma in situ of the breast in
southeast Netherlands].
AB - OBJECTIVE: To analyse the incidence and treatment of ductal carcinoma in situ
(DCIS) of the breast in the population. DESIGN: Retrospective, descriptive.
METHOD: The incidence of DCIS in the period 1975-1997 in 8 hospitals in
southeastern North Brabant and northern Limburg, the Netherlands, was analysed,
using data from the Eindhoven Cancer Registry. Changes in the treatment of DCIS
in the period 1984-1997 were studied, using information from the Breast Cancer
Documentation Project. RESULTS: Between 1975 and 1997, 448 cases of DCIS were
detected in 442 women. After adjustment for age according to the European
Standard Population, the incidence rate of DCIS increased from 0.3 per 100,000 in
1975 to 13.4 in 1997. Of the 87 patients with DCIS between 50 and 69 years of age
in 1996 and 1997, 68% was detected by the screening programme. The proportion of
patients with DCIS undergoing ablation of the breast was 53% during the period
1984-1989, and varied around 45% thereafter. The other patients underwent local
excision. The proportion of patients receiving radiotherapy after local excision
decreased from 78% in the period 1984-1989 to 24% in the period 1994-1995 and
rose to 41% during the last few years. Substantial differences in the treatment
of DCIS were observed between the 8 hospitals.
PMID- 10774295
TI - [Experiences of relatives of donors with the donation procedure; comparison
between 1995 and 1998].
AB - OBJECTIVE: To determine the experience of the relatives of organ and tissue
donors, immediately before, during and soon after the donation procedure. DESIGN:
Questionnaire. METHOD: At two national one-day meetings at which about 10% of the
families of donors between 1991 and 1998 were represented, the participants
completed a questionnaire with questions about their appreciation of the
communication with the different health care professionals. The appreciation was
scored on a 7-point scale. RESULTS: Most relatives looked back with satisfaction
on the events in the hospital and soon thereafter; the appreciation was 'a little
satisfied' to 'satisfied'. The relatives in non-heart-beating kidney
transplantation were more satisfied compared to those confronted with the brain
death transplantation, with regard to the conversation in which the death was
announced as well as to the conversation regarding the donation procedure.
Relatives in 1998 were more positive about some specific aspects than in 1995,
notably concerning explanation of the phenomenon of brain death. Satisfaction was
primarily influenced by the way in which the news of death was conveyed and the
aftercare by the transplant coordinator. The moment donation was addressed and
the moment the relatives said 'good-bye' to their beloved were the next important
factors.
PMID- 10774296
TI - [Patient with Peutz-Jeghers syndrome and liver metastases from an unknown primary
tumor].
AB - In a 35-year old man with deep venous thrombosis liver metastases of an
adenocarcinoma were observed. The primary tumour was not found. The patient had
pigmentations on the lips and hamartomatous polyposis of the intestine. These
findings indicate Peutz-Jeghers syndrome. In this syndrome there is an increased
risk of, notably, gastrointestinal malignancy at an early age. Recent
investigations have shown that Peutz-Jeghers syndrome is associated with a
mutation in the STK11 gene on chromosome 19.
PMID- 10774297
TI - [Stress ulcer prophylaxis in the intensive care unit].
PMID- 10774298
TI - [Stress ulcer prophylaxis in the intensive care unit].
PMID- 10774299
TI - Comparative anatomy of the central representation of the facial nerve.
PMID- 10774300
TI - The facial nerve--peripheral and central connections of proprioception.
PMID- 10774301
TI - Facial nerve fiber orientation, linkage between central nervous organization and
muscular function.
PMID- 10774302
TI - Changing ratio between myelin thickness and axon caliber in developing human
facial nerves.
PMID- 10774303
TI - To what extent can poor functional recovery of denervated muscles be attributed
to incomplete as opposed to inappropriate reinnervation after surgical repair of
severed nerves?
PMID- 10774304
TI - Morphologic studies on human and rodent facial muscles.
PMID- 10774305
TI - Denervation and reinnervation of muscle: physiological effects.
PMID- 10774306
TI - Postdenervation muscular changes in facial paralysis.
PMID- 10774307
TI - Effects of electrostimulation therapie: enzyme-histological and myometric changes
in the denervated musculature.
PMID- 10774309
TI - Facial Assessment Scales: defining selective movement.
PMID- 10774308
TI - Rehabilitation of facial expression ("mime therapy").
PMID- 10774310
TI - Fine structure of degeneration and regeneration of peripheral nerve fibers.
PMID- 10774311
TI - Regulation of transferrin receptors and iron uptake in normal and injured nervous
system.
PMID- 10774312
TI - Clinical experience in nerve grafting.
PMID- 10774313
TI - Prognostic value of electroneurography in Bell's palsy.
PMID- 10774315
TI - Bell's palsy: synopsis by an otologist.
PMID- 10774314
TI - Role of laminin for axonal growth.
PMID- 10774316
TI - The role of microglia in regeneration.
PMID- 10774317
TI - The role of calcitonin gene-related peptide in the regenerating facial nucleus.
PMID- 10774318
TI - The role of astrocytes in facial nerve regeneration.
PMID- 10774319
TI - Pathophysiology of hemifacial spasm.
PMID- 10774320
TI - Anatomy and histology of the mimic muscles and the supplying facial nerve.
PMID- 10774321
TI - Motor innervation pattern of the orbicularis oris muscle in guinea pig.
PMID- 10774322
TI - Why does the frontalis muscle "never come back"? Functional organization of the
mimic musculature.
PMID- 10774323
TI - Affection of mimic muscles, simulating damage of the facial nerve in patients
with facioscapulohumeral muscular dystrophy.
PMID- 10774324
TI - Muscle ultrastructural changes in long-standing idiopathic total facial nerve
palsy.
PMID- 10774326
TI - Respiratory-related electromyographic activity of facial muscles.
PMID- 10774325
TI - Comparison of myosin in denervated and immobilized muscles.
PMID- 10774327
TI - Peripheral communication of the facial nerve at the angle of the mouth.
PMID- 10774328
TI - Trigeminal-facial nerve communication and its clinical application.
PMID- 10774329
TI - Observations on the geniculate ganglion in adult human dissections.
PMID- 10774330
TI - The role of physical therapy in patients with facial paralysis: state of the art.
PMID- 10774331
TI - Functional recovery and electromyographic/electroneurography evaluation in Bell's
and Ramsay-Hunt's palsy patients undergoing physical training.
PMID- 10774332
TI - Treatment of facial paralysis using electromyographic feedback--a case study.
PMID- 10774333
TI - Eutrophic electrical stimulation in long-standing facial palsy.
PMID- 10774334
TI - Management of facial paralysis with jump interposition graft hypoglossal-facial
anastomosis with gold lid weight.
PMID- 10774335
TI - Temporalis transfer for correction of lagophthalmos.
PMID- 10774336
TI - Pectoralis minor transplantation in The Netherlands.
PMID- 10774337
TI - An experimental model for complex dynamic control of the reinnervated face.
PMID- 10774338
TI - Steroid therapy for facial nerve palsy in children.
PMID- 10774339
TI - Developmental aspects of the facial canal: a light and scanning electron
microscopic study.
PMID- 10774340
TI - Vulnerability of the facial nerve in entrapment palsy: comparative study in
guinea pigs and humans.
PMID- 10774342
TI - Course of the facial nerve in congenital dysplasia of the external auditory
canal: a high-resolution computerized tomography study.
PMID- 10774341
TI - Melkersson-Rosenthal syndrome: report of two cases and review of literature.
PMID- 10774343
TI - The quantification of synkinesis and facial paralysis.
PMID- 10774344
TI - Development of a sensitive clinical facial grading system.
PMID- 10774345
TI - Development of a new paresis scoring system for pre- and postoperative evaluation
of facial paresis.
PMID- 10774346
TI - Prediction of prognosis in facial nerve palsy using constellation diagram.
PMID- 10774347
TI - Computer-assisted grading of facial function.
PMID- 10774348
TI - Treatment of hemifacial spasm with botulinum toxin.
PMID- 10774349
TI - Botulinum toxin treatment in patients with facial synkinesis.
PMID- 10774350
TI - Botulinum toxin: structure and pharmacology.
PMID- 10774351
TI - The utility of single-fiber electromyography in facial nerve paralysis.
PMID- 10774352
TI - Computer-aided neuromyography with repetitive stimuli for diagnosis of facial
nerve disorders.
PMID- 10774353
TI - Antidromically evoked facial nerve response in guinea pigs with partial nerve
injury.
PMID- 10774354
TI - Antidromically evoked facial nerve responses in human subjects: modification of
recording techniques.
PMID- 10774355
TI - Electrophysiological evidence for central hyperexcitability of facial motoneurons
in hemifacial spasm.
PMID- 10774356
TI - Prognostic diagnosis of peripheral facial palsy by an impedance method.
PMID- 10774357
TI - Electrical evaluation of the facial nerve in acoustic neuroma patients comparing
transcranial magnetic stimulation and electroneurography.
PMID- 10774358
TI - The prognostic value of electroneurography in Bell's palsy.
PMID- 10774359
TI - Bell's palsy and magnetic stimulation: longitudinal study.
PMID- 10774360
TI - Electromyography of evoked activity of the facial nerve in cerebellopontine angle
surgery.
PMID- 10774361
TI - Identification of the exact stimulated site in transcranial magnetic stimulation
of the facial nerve.
PMID- 10774362
TI - Pre- and postoperative electrophysiological and magnetic stimulation control of
facial nerve function in hemifacial spasm.
PMID- 10774363
TI - Influence of different electrodes on electric and magnetic stimulation of the
facial nerve.
PMID- 10774364
TI - Evaluation of peripheral facial palsy by transcranial magnetic stimulation.
PMID- 10774365
TI - Transcranial magnetic stimulation of the facial nerve in small and medium-sized
acoustic neurinomas.
PMID- 10774366
TI - Neurophysiological evaluation of Bell's palsy: electroneurography and
transcranial magnetic stimulation.
PMID- 10774367
TI - Magnetic stimulation in patients with essential blepharospasm and hemifacial
spasm.
PMID- 10774368
TI - Blink reflex investigation using magnetic stimulation.
PMID- 10774369
TI - Progressive facial palsy and neurinomas of the VIIth nerve.
PMID- 10774370
TI - Two cases of intratemporal facial neurofibroma.
PMID- 10774371
TI - Facial nerve neuromas: diagnosis and management of the large lesion.
PMID- 10774372
TI - End-to-end anastomosis versus nerve graft in intratemporal and intracranial
lesions of the facial nerve.
PMID- 10774373
TI - Primary facial nerve tumors: diagnostic and management dilemmas.
PMID- 10774374
TI - Gunshot injuries to the intratemporal facial nerve.
PMID- 10774375
TI - Microsurgical selective removal of benign neoplasms of the parotid gland.
PMID- 10774377
TI - Facial nerve neurinoma and otologic signs.
PMID- 10774378
TI - Facial paralysis induced by tumors.
PMID- 10774376
TI - Peripheral facial nerve paresis as the initial presenting manifestation of tumors
of unknown origin.
PMID- 10774379
TI - The facial nerve in congenital ear malformations.
PMID- 10774381
TI - The acoustic trauma in decompression surgery of facial nerve.
PMID- 10774380
TI - Facial nerve neuroma.
PMID- 10774382
TI - Intraoperative NIM-2 monitoring for facial nerve preservation in acoustic
neurinoma surgery.
PMID- 10774383
TI - Facial nerve monitoring of skull base and cerebellopontine angle lesions.
PMID- 10774384
TI - Intraoperative facial nerve monitoring by monopolar low constant current
stimulation and postoperative facial function in acoustic tumor surgery.
PMID- 10774385
TI - Intraoperative facial nerve monitoring in the infratemporal fossa approach:
improved preservation of nerve function.
PMID- 10774386
TI - Gadolinium-DTPA-enhanced MRI of the facial nerve.
PMID- 10774387
TI - Gadolinium-enhanced MRI and positron emission tomography in Bell's palsy: a
preliminary report.
PMID- 10774388
TI - Correlation between gadolinium-enhanced MRI and neurophysiology in Bell's palsy:
a preliminary study.
PMID- 10774389
TI - Gadolinium-DTPA-enhanced MRI in facial palsy.
PMID- 10774390
TI - Hemifacial spasm: evaluation and management options.
PMID- 10774391
TI - Idiopathic facial nerve palsy (Bell's palsy): morphological changes in MRI.
PMID- 10774392
TI - Contrast-enhanced MRI of the facial nerve in patients with Bell's palsy.
PMID- 10774393
TI - Gadolinium-enhanced magnetic resonance imaging in experimental facial nerve
paralysis.
PMID- 10774394
TI - Preoperative radiologic assessment of facial nerve in cochlear implant surgery.
PMID- 10774396
TI - Hemifacial spasm caused by posterior inferior cerebellar artery elongation-
diagnostic value of angiomagnetic resonance imaging.
PMID- 10774395
TI - Gadolinium-enhanced magnetic resonance imaging in Bell's palsy.
PMID- 10774397
TI - Computerized tomography demonstration of labyrinthine facial nerve decompression
viability by the transattical approach.
PMID- 10774398
TI - Clinical investigation of hypoglossal-facial nerve anastomosis.
PMID- 10774399
TI - Salvage decompression of the facial nerve.
PMID- 10774400
TI - Is facial nerve decompression surgery effective?
PMID- 10774401
TI - Surgical treatment of synkinesis.
PMID- 10774402
TI - Parotidectomy with the Nerve Integrity Monitor II.
PMID- 10774403
TI - Anastomosis of intratemporal facial nerve with fibrin tissue adhesive.
PMID- 10774404
TI - Expression and regulation of neuropeptides in rat facial motoneurons.
PMID- 10774405
TI - Human facial nucleus: choline acetyltransferase and calcitonin gene-related
peptide.
PMID- 10774406
TI - Nerve growth factor: morphological and morphometric findings on facial nerve
regeneration in the rabbit.
PMID- 10774407
TI - Observation of motoneurons after recovery from experimental facial nerve
paralysis.
PMID- 10774408
TI - Extracellular matrix arrangements of rat facial nerve.
PMID- 10774409
TI - Best method for facial nerve anastomosis.
PMID- 10774410
TI - An animal model of ischemic facial palsy.
PMID- 10774411
TI - Experimental studies on antidromic evoked potential of the facial nerve.
PMID- 10774412
TI - Ultracytological localization of K(+)-dependent, p-nitrophenylphosphatase
activity in cat facial nerve.
PMID- 10774413
TI - Degeneration and regeneration of neuromuscular junction in guinea pig mimic
muscle--a scanning electron microscopic study.
PMID- 10774414
TI - Nerve growth factor: optic and ultrastructural findings on facial nerve
degeneration in the rabbit.
PMID- 10774415
TI - Detection of varicella zoster virus DNA by polymerase chain reaction in clinical
samples from patients with Hunt's syndrome.
PMID- 10774416
TI - Etiopathogenesis of Bell's palsy: an immune-mediated theory.
PMID- 10774417
TI - T-lymphocyte subpopulations and HLA-DR antigens in patients with Bell's palsy,
hearing loss, neuronitis vestibularis, and Meniere's disease.
PMID- 10774418
TI - Electrophysiologic pattern and T-cell subsets in Bell's palsy.
PMID- 10774419
TI - Immunological findings in Bell's palsy.
PMID- 10774420
TI - Prevalence of Borrelia burgdorferi antibodies in Bell's palsy in a metropolitan
area of northern Italy.
PMID- 10774421
TI - Anti-Borrelia burgdorferi antibodies in sera of patients with facial paralysis.
PMID- 10774422
TI - Macrophages and Schwann cells in myelin disintegration.
PMID- 10774423
TI - Reaction of the vasa nervorum of the facial nerve during stimulation with
neurotransmitters.
PMID- 10774424
TI - Morphological changes in ischemic facial nerve paralysis.
PMID- 10774425
TI - Activation of intravascular coagulation in Bell's palsy.
PMID- 10774426
TI - Retinal videofluorescence-angiographic findings in Bell's palsy.
PMID- 10774427
TI - Virus isolation study of the human ganglion geniculi (nerve VII).
PMID- 10774428
TI - Virus-associated demyelination in the pathogenesis of Bell's palsy.
PMID- 10774429
TI - Histopathology of facial nerve neuritis caused by herpes simplex virus infection
in mice.
PMID- 10774430
TI - Herpes simplex virus and experimental facial paralysis.
PMID- 10774431
TI - Recent treatment of Ramsay Hunt syndrome.
PMID- 10774432
TI - Herpes zoster of the geniculate ganglion: therapeutic concepts.
PMID- 10774433
TI - Acyclovir versus steroids in the treatment of Bell's palsy.
PMID- 10774434
TI - Facial palsy and human immunodeficiency virus infection.
PMID- 10774435
TI - Management of Bell's palsy accompanied by diabetes mellitus.
PMID- 10774436
TI - Long-term results of severe facial paralysis.
PMID- 10774437
TI - Distribution of facial nerve conduction velocities in patients with Bell's palsy.
PMID- 10774438
TI - Recurrent facial paralysis associated with HIV infection.
PMID- 10774439
TI - Bilateral facial palsy in Wegener's granulomatosis.
PMID- 10774440
TI - Facial palsy in equatorial Africa.
PMID- 10774441
TI - Therapeutic policy for Bell's palsy and Hunt syndrome.
PMID- 10774442
TI - Stellate ganglion block for facial palsy.
PMID- 10774444
TI - Emotions in the first 99 days after the onset of facial paralysis: a single case
study.
PMID- 10774443
TI - Treatment comparison between dexamethasone and placebo for idiopathic facial
palsy.
PMID- 10774446
TI - Central and peripheral rearrangements following hypoglossal-facial crossover: an
electrophysiological study.
PMID- 10774447
TI - Recovery of normal excitability of the facial motor nucleus following facial
nerve decompression in hemifacial spasm.
PMID- 10774445
TI - Evaluation of facial palsy by Moire topography.
PMID- 10774448
TI - Peripheral facial paralysis: evaluation of effects in a case-study.
PMID- 10774449
TI - Inferior vena cava interruption: how and when?
AB - Interruption of the inferior vena cava (IVC) to prevent pulmonary embolism
arising from venous thrombi in the lower extremities has become widely used since
IVC filters became available about 30 years ago. However, reliable data regarding
efficacy and safety of IVC filters are still lacking. The first controlled
clinical trial of IVC filters demonstrated their effectiveness, but filters had
no detectable impact on mortality and were associated with an increased risk of
recurrent deep venous thrombosis. On the basis of the literature, indications for
IVC interruption can be classified as accepted, debated, and debatable. The
relevance of debated indications, more accurate identification of patients who
remain "very high-risk" despite preventive or curative anticoagulant treatment,
and selection of the most appropriate filter should be looked at in prospective
clinical studies.
PMID- 10774450
TI - Ductal carcinoma in situ of the breast.
AB - Ductal carcinoma in situ of the breast is a heterogeneous group of lesions with
diverse malignant potential. It is the most rapidly growing subgroup in the
breast cancer family; it is projected that more than 39,000 new cases will be
diagnosed in the United States during 1999. Most new cases are nonpalpable and
are discovered mammographically. Treatment is controversial and ranges from
excision only, to excision with radiation therapy, to mastectomy. Genetic changes
routinely precede morphologic evidence of malignant transformation. Medicine must
learn how to recognize these genetic changes, exploit them, and in the future,
prevent them.
PMID- 10774451
TI - Gene therapy for adenosine deaminase deficiency.
AB - The clinical gene therapy trials for adenosine deaminase (ADA) deficiency have
defined both the potential benefits and the present limitations of gene therapy
with hematopoietic stem cells (HSC). Current clinical results indicate that (a)
both umbilical cord blood and neonatal bone marrow HSC can be transduced with
murine retroviral-based vectors, (b) the transduced HSC can engraft in
nonmyeloablated patients, (c) the frequency of HSC transduction/engraftment is
low (1/10,000), (d) an in vivo selective advantage can exist for transduced T
lymphoid progeny, and (e) the transduced ADA gene is not expressed in nondividing
T lymphocytes. Improving the clinical results of gene therapy for ADA deficiency
and other genetic diseases involving HSC will require (a) developing new vectors
that express the transduced gene in nondividing cells and (b) increasing the
frequency of stable HSC transduction.
PMID- 10774452
TI - Acupuncture: an evidence-based review of the clinical literature.
AB - This chapter reviews the experimental literature on the effects of acupuncture
treatment. The review covers the 14 medical conditions for which the National
Institutes of Health Acupuncture Consensus Development Panel (NIHCDP) concluded
that acupuncture either is effective (2 conditions) or may be useful (12
conditions). My conclusions partially support those of the NIHCDP. There is
evidence that acupuncture is effective for the treatment of postoperative and
chemotherapy-induced nausea and vomiting. Also, some data indicate that
acupuncture may be useful for headache, low back pain, alcohol dependence, and
paralysis resulting from stroke (4 of the 12 conditions for which the NIHCDP
found that acupuncture may be useful). For most of the remaining conditions,
there is little evidence that acupuncture is either effective or ineffective. It
is recommended that workers in the field design double blind, sham controlled
trials using adequate acupuncture treatment regimens, with specific hypotheses,
and sample sizes sufficient to allow both positive and negative conclusions.
PMID- 10774453
TI - Role of telomerase in cell senescence and oncogenesis.
AB - The ends of linear chromosomes are capped by specialized nucleoprotein structures
termed telomeres. Telomeres comprise tracts of noncoding hexanucleotide repeat
sequences that, in combination with specific proteins, protect against
degradation, rearrangement, and chromosomal fusion events. Due to the polarity of
conventional DNA synthesis, a net loss of telomeric sequences occurs at each cell
division. It has been proposed that this cumulative telomeric erosion is a
limiting factor in replicative capacity and elicits a signal for the onset of
cellular senescence. To proliferate beyond the senescent checkpoint, cells must
restore telomere length. This can be achieved by telomerase, an enzyme with
reverse-transcriptase activity. This enzyme is absent in differentiated somatic
tissues, but telomerase reactivation has been detected in most tumors. Much
investigative effort is focusing on telomere dynamics with a view to possible
manipulation of cellular proliferative potential. In this article, we review the
role of telomeres and telomerase in senescence and tumor progression, and we
discuss the potential use of telomerase in diagnosis and treatment.
PMID- 10774454
TI - Coronary artery disease in the transplanted heart.
AB - Coronary artery disease in the transplanted heart limits the long-term success of
cardiac transplantation. Intravascular ultrasound studies reveal a dual
morphology with donor-transmitted and de novo plaques. Coronary vasomotor
dysfunction may occur independently of morphological alterations. The disease is
characterized by the interaction of activated T lymphocytes with cytokines and
donor epicardial and microvascular endothelium. Various noxious stimuli
contribute to the continuing inflammatory response. Consequently, adhesion
molecule expression is upregulated, leukocytes migrate into the allograft,
thrombocytes accumulate, and growth factors are expressed, finally resulting in
functional and morphological chronic allograft lesions. Blocking the activation
of T cells, CD4+ cytokines, and adhesion molecules may prevent endothelial injury
and subsequent intimal thickening. Strategies to decrease the formation of anti
endothelial and anti-HLA-DR antibodies may also be protective, as may
antiproliferative drugs, augmentation of endogenous nitric oxide bioactivity, and
new immunosuppressive regimens. Revascularization procedures have a limited role
in treating significant focal lesions. Retransplantation, the only definitive
treatment, remains ethically controversial.
PMID- 10774455
TI - Measures of success and health-related quality of life in lower-extremity
vascular surgery.
AB - Lower-extremity vascular surgery is most often indicated for patients with
critical leg ischemia but has increasingly been used for patients with disabling
intermittent claudication. This article reviews indications, follow-up protocols,
and procedure-related outcomes including perioperative and late mortality,
complications, and long-term patency rates, which vary with patient risk factors,
vascular disease severity, and hospital volume. Population-based studies have yet
to establish whether rates of limb-preserving bypass surgery are related to
overall amputation rates, partly because of the continued high rate of primary
amputation. The functional benefits of vascular surgery have been traditionally
assessed by treadmill protocols and batteries of physical tests. Claudication
treatment is increasingly being measured by both generic and disease-specific
functional and health-related quality-of-life questionnaires. Patient self
reported measures of physical functioning and walking ability are reviewed.
Finally, conclusions are presented about trends in lower-extremity bypass surgery
rates.
PMID- 10774456
TI - New horizons in the treatment of autoimmune diseases: immunoablation and stem
cell transplantation.
AB - The prevalence of autoimmune diseases (ADs) in Western countries is estimated to
be from 3-7%, and the treatment of severe, relapsing/refractory cases is still
not satisfactory. The concept of utilizing intense immunosuppression followed by
allogeneic or even autologous hemolymphopoietic stem cells (HSCs) to treat AD is
based on encouraging results in experimental animals and from serendipitous cases
of patients with both ADs and malignancies who were allotransplanted for the
latter. However, rare unexpected relapses despite donor immune engraftment have
been reported following HSC transplantation for AD. Autologous transplantation is
a more feasible procedure with lower toxicity than allogeneic transplantation.
This article analyzes the experimental basis for stem cell transplantation in AD
and discusses the most important clinical results of both allogeneic and
autologous HSC transplants.
PMID- 10774457
TI - The surgical treatment of Parkinson's disease.
AB - Surgical treatment of Parkinson's disease (PD) can provide gratifying symptomatic
improvements for many individuals who suffer from persistent disabling symptoms
despite the best available medical management. Current surgical therapies include
ablative techniques (thalamotomy and pallidotomy), augmentative techniques
(nondestructive) (deep brain stimulation), and restorative techniques (tissue
transplantation and gene therapy). Ablative procedures can provide substantial
clinical benefit, but the current trend is toward deep brain stimulation, which
can provide similar symptomatic improvement in a nondestructive manner.
Restorative techniques, such as tissue transplantation and gene therapy, are
exciting but have significant obstacles to overcome before their promise can be
realized. Until the underlying pathological defect of PD can be identified and
treated, surgical intervention is likely to remain important in the symptomatic
treatment of this disabling disease.
PMID- 10774458
TI - Atherogenic lipids and endothelial dysfunction: mechanisms in the genesis of
ischemic syndromes.
AB - Atherogenic lipids, particularly oxidized low-density lipoprotein, are
responsible for a wide range of cellular dysfunctions within the vessel wall. The
effects on endothelial cells disrupt normal control of vasomotion, with a
reduction of effective nitric oxide activity, the development of a procoagulant
surface, chronic low-grade inflammation, and abnormal cell growth. These changes
are central not only in the development of atherosclerosis but also in the
evolution of both stable and unstable ischemic syndromes. There is growing
evidence that these abnormal changes in cell function respond rapidly to changes
in the atherogenic lipids. Certain cell functions can improve within hours or
days of cholesterol lowering.
PMID- 10774459
TI - Management of patients with hereditary hypercoagulable disorders.
AB - The inherited hypercoagulable states can be divided into those that are common
and associated with a modest risk of thrombosis (i.e. factor V Leiden and G20210A
prothrombin gene) and those that are uncommon but associated with a high risk of
thrombosis. There is no convincing evidence that, independent of other clinical
factors, the presence of factor V Leiden or the prothrombin gene mutation should
influence the use of primary prophylaxis or the duration of anticoagulant therapy
following an episode of thrombosis. Indirect evidence suggests that the presence
of antithrombin, protein C deficiency, or protein S deficiency justifies avoiding
additional risk factors for thrombosis, such as estrogen therapy, and justifies
use of more aggressive primary prophylaxis when additional risk factors cannot
readily be avoided (e.g. pregnancy). The presence of one of these three
abnormalities also favors more prolonged anticoagulant therapy following venous
thrombosis. However, their presence or absence appears to have less influence on
the risk of recurrent venous thromboembolism than whether thrombosis was provoked
by a major reversible risk factor, such as surgery.
PMID- 10774460
TI - Neurocysticercosis: updates on epidemiology, pathogenesis, diagnosis, and
management.
AB - Neurocysticercosis is now recognized as a common cause of neurologic disease in
developing countries and the United States. The pathogenesis and clinical
manifestations vary with the site of infection and accompanying host response.
Inactive infection should be treated symptomatically. Active parenchymal
infection results from an inflammatory reaction to the degenerating cysticercus
and will also respond to symptomatic treatment. Controlled trials have not
demonstrated a clinical benefit for antiparasitic drugs. Ventricular
neurocysticercosis often causes obstructive hydrocephalus. Surgical intervention,
especially cerebrospinal fluid diversion, is the key to management of
hydrocephalus. Shunt failure may be less frequent when patients are treated with
prednisone and/or antiparasitic drugs. Subarachnoid cysticercosis is associated
with arachnoiditis. The arachnoiditis may result in meningitis, vasculitis with
stroke, or hydrocephalus. Patients should be treated with corticosteroids,
antiparasitic drugs, and shunting if hydrocephalus is present.
PMID- 10774461
TI - Anti-cytokine therapy for rheumatoid arthritis.
AB - Tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) are important in
mediating inflammation in rheumatoid arthritis (RA). Randomized phase II and III
clinical trials of anti-TNF reagents (infliximab and etanercept) have
demonstrated an acceptable safety profile and marked clinical efficacy in cases
of RA that have not responded adequately to conventional therapy. Combination
therapy with methotrexate (MTX) appears to be particularly effective in patients
whose disease activity persists despite prior disease-modifying antirheumatic
drugs (DMARDs) and ongoing MTX monotherapy. DMARD-recalcitrant disease may become
the main indication for the use of anti-TNF drugs in patients with RA. Trials of
IL-1 receptor antagonist show a relatively modest anti-inflammatory effect and a
possible retardation of joint damage. Whether anti-TNF therapy protects joints
from structural damage is under investigation. One anti-TNF reagent has already
been approved in the United States for the treatment of RA, and other cytokine
antagonists or agonists are under development.
PMID- 10774462
TI - Artificial skin.
AB - The skin is a complex organ that is difficult to replace when it is irreversibly
damaged by burns, trauma, or disease. Although autologous skin transplantation
remains the most common form of treatment in patients with significant skin loss,
there are now a number of commercially available products that can be used to
replace the skin temporarily or permanently. Here we describe several such
products under the rubric "artificial skin," focusing on two types of technology
that have been applied to the problem of permanent skin replacement.
PMID- 10774463
TI - Age-associated increased interleukin-6 gene expression, late-life diseases, and
frailty.
AB - Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly
regulated and expressed at low levels, except during infection, trauma, or other
stress. Among several factors that down-regulate IL-6 gene expression are
estrogen and testosterone. After menopause or andropause, IL-6 levels are
elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent
mediator of inflammatory processes, and it has been proposed that the age
associated increase in IL-6 accounts for certain of the phenotypic changes of
advanced age, particularly those that resemble chronic inflammatory disease
[decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin
and cholesterol, and increased inflammatory proteins such as C-reactive protein
(CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been
linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and
Alzheimer's disease. This overview discusses the data relating IL-6 to age
associated diseases and to frailty. Like the syndrome of inappropriate
antidiuretic hormone, it is possible that certain clinically important late-life
changes are due to an inappropriate presence of IL-6.
PMID- 10774464
TI - Streptococcal toxic shock syndrome associated with necrotizing fasciitis.
AB - Streptococcal toxic shock syndrome (strep TSS) with associated necrotizing
fasciitis is a rapidly progressive process that kills 30-60% of patients in 72-96
h. Violaceous bullae, hypotension, fever, and evidence of organ failure are late
clinical manifestations. Thus, the challenge to clinicians is to make an early
diagnosis and to intervene with aggressive fluid replacement, emergent surgical
debridement, and general supportive measures. Superantigens such as pyrogenic
exotoxin A interact with monocytes and T lymphocytes in unique ways, resulting in
T-cell proliferation and watershed production of monokines (e.g. tumor necrosis
factor alpha, interleukin 1, interleukin 6), and lymphokines (e.g. tumor necrosis
factor beta, interleukin 2, and gamma-interferon). Penicillin, though efficacious
in mild Streptococcus pyogenes infection, is less effective in severe infections
because of its short postantibiotic effect, inoculum effect, and reduced activity
against stationary-phase organisms. Emerging treatments for strep TSS include
clindamycin and intravenous gamma-globulin.
PMID- 10774465
TI - Role of cytokines in the pathogenesis of inflammatory bowel disease.
AB - Recent advances in the drug treatment of inflammatory bowel disease (IBD) have
paralleled our understanding of the pathophysiology of ulcerative colitis and
Crohn's disease. Several proinflammatory and immune-regulatory cytokines are
upregulated in the mucosa of patients with IBD, and differences and similarities
in the cytokine profiles of ulcerative colitis and Crohn's disease have been
elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor
necrosis factor-alpha) antibody have shown marked clinical benefit in the
majority of patients with Crohn's disease, verifying the importance of TNF-alpha
in the pathogenesis of Crohn's disease. In preliminary studies, treatment with
recombinant human interleukin-10 has been beneficial in Crohn's disease but not
in ulcerative colitis. Future treatment of IBD may include combination or
sequential cytokine and anticytokine administration in defined groups of patients
based on their mucosal cytokine profiles.
PMID- 10774466
TI - Anorexia and bulimia nervosa.
AB - Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by
abnormal patterns of weight regulation and eating behavior and by disturbances in
attitudes and perceptions toward weight and body shape. Etiologic research has
indicated substantial genetic influence on these disorders, suggesting
significant biological contributions to their development. Obsessional,
perfectionistic, and anxious personality styles may be premorbid traits that
contribute to this pathogenesis. Studies of neuroendocrine, neuropeptide, and
neurotransmitter functioning in patients with AN and BN indicate that
disturbances of these systems may contribute to the maintenance as well as the
etiology of these sometimes fatal disorders. The efficacy of psychological
treatments and pharmacotherapy has been more clearly established for BN than for
AN.
PMID- 10774467
TI - The role of protein traffic in the progression of renal diseases.
AB - Progression to irreversible renal parenchymal damage and end-stage renal disease
is the final common pathway of chronic proteinuric nephropathies and is
relatively independent of the type of initial insult. In animals, a reduction in
nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that
are intended to sustain renal function but may be detrimental in the long term.
High glomerular capillary pressure impairs glomerular permeability to proteins,
which are then filtered in excessive quantities and reach the lumen of the
proximal tubule. The secondary process of reabsorption of filtered proteins can
contribute substantially to renal interstitial injury by activating intracellular
events, including upregulation of vasoactive and inflammatory genes. The
corresponding molecules formed in excessive amounts by the renal tubules cause an
interstitial inflammatory reaction that normally precedes renal scarring and
correlates with declining function. In several clinical studies, the increase in
urinary protein excretion correlated with the tendency of the renal disease to
progress more than it correlated with the underlying renal disease itself.
Whenever urinary protein excretion is reduced, the decline in the glomerular
filtration rate (GFR) slows or stops. Thus, to the extent that angiotensin
converting enzyme inhibitors lower the rate of urinary protein excretion, they
effectively limit the progressive decline in GFR. If treatment is sufficiently
prolonged, the GFR decline can be effectively halted or reversed, even in
patients with remarkably severe disease, and remission is now achievable in some
patients.
PMID- 10774468
TI - Carotid artery dissection.
AB - Among the large variety of cerebrovascular syndromes, carotid artery dissections
remain often under-recognized. Many patients present with minor or transient
symptoms, some with local pain only, and some are asymptomatic. A useful rule is
that the coincidence of any local pain in neck or face with an ipsilateral
Horner's syndrome preceding transient or persistent retinal or cerebral ischemic
symptoms should alert physicians--notably those treating emergencies--to rule out
an underlying dissection of the ipsilateral carotid artery. In most cases the
extracranial part of the carotid artery is affected; therefore, this review will
focus on this main subgroup of patients. We review the pathological anatomy, as
well as possible underlying causes, clinical features, diagnostic tools,
differential diagnosis, treatment options, and outcome data.
PMID- 10774469
TI - Bacterial vaginosis.
AB - Bacterial vaginosis represents a unique upheaval of the complex vaginal bacterial
flora with disappearance of lactobacilli and overgrowth of Gardnerella vaginalis
and resident anaerobic vaginal bacteria. Little progress has occurred in
identifying causal factors, although the pathophysiology of this syndrome is
better understood. Although symptoms are easily recognizable, obstetric and
gynecologic complications continue to increase in number. Bacterial vaginosis is
far more than a nuisance infection. Problems with diagnosis continue to dominate
clinical practice, although new tests have been introduced. Therapeutic options
have increased, although recurrent disease remains common, and management of this
common complication constitutes a major challenge.
PMID- 10774470
TI - Current concepts in cobalamin deficiency.
AB - The application of sensitive metabolic tests, such as the deoxyuridine
suppression test and measurement of homocysteine and methylmalonic acid, to
cobalamin status has identified the entity of mild, preclinical cobalamin
deficiency. This state, common in the elderly, responds to cobalamin therapy.
Preclinical deficiency may exist within the nervous system as well, although this
requires further study. Nevertheless, it is well to remember that not all low
cobalamin levels and not all abnormal metabolite results reflect cobalamin
deficiency. Interpretation of metabolic results still requires caution, as do
proposals to raise the cut-off point for low cobalamin levels to capture some
normal levels that are associated with metabolic abnormality. The recognition of
mild, preclinical deficiency has opened up many important issues. These include
identifying its causes, what should be done about it, and what the clinical
impact of the hyperhomocysteinemia itself is. Although malabsorptive disorders,
especially food-cobalamin malabsorption, underlie about half of all cases of
preclinical deficiency, no cause can be found in the remainder of these cases;
poor dietary intake appears to be uncommon. In addition, unusual states of
neurologically symptomatic cobalamin deficiency are being recognized, such as
nitrous oxide exposure in patients with unrecognized deficiency and severe
deficiency in children of mildly deficient mothers. All of these have broadened
and complicated the picture of cobalamin deficiency while providing greater
opportunities for prevention.
PMID- 10774471
TI - Adjuvant therapy for breast cancer.
AB - Substantial progress has been made in the diagnosis and management of primary
breast cancer over the past three decades. As a result, mortality related to this
disease has been decreasing gradually for several years, treatment has become
more effective, and side effects and complications related to treatment have
decreased. In this report, we review the state of adjuvant therapy for breast
cancer.
PMID- 10774472
TI - Kidney transplantation from living unrelated donors.
AB - Kidney transplant candidates increasingly are looking to their relatives,
spouses, and even friends for a better chance at transplantation. The wait for a
cadaver kidney might be 2-5 years. Although kidneys from well-matched family
members have been transplanted with excellent results for many years, accepting
living donors who are genetically unrelated to the patient has not been
encouraged until recently. Results show that, among 1700 patients who received
kidney transplants from living unrelated donors in the United States from 1995
through 1998, the one- and projected ten-year graft survival rates were 92% and
67%, respectively. These results are superior to the 87% and 50% rates for more
than 26,000 cadaver kidney transplants during the same period. Risks to the donor
are low (< 0.005% mortality and < 0.3% serious complications) but not absent.
Thus, motivated spouses, friends, and adopted or step-family members can play an
important role in the rehabilitation of patients who need a kidney transplant.
PMID- 10774473
TI - Global epidemiology of influenza: past and present.
AB - Pandemics are the most dramatic presentation of influenza. Three have occurred in
the twentieth century: the 1918 H1N1 pandemic, the 1957 H2N2 pandemic, and the
1968 H3N2 pandemic. The tools of molecular epidemiology have been applied in an
attempt to determine the origin of pandemic viruses and to understand what made
them such successful pathogens. An excellent example of this avenue of research
is the recent phylogenetic analysis of genes of the virus that caused the
devastating 1918 pandemic. This analysis has been used to identify evolutionarily
related influenza virus genes as a clue to the source of the pandemic of 1918.
Molecular methods have been used to investigate the avian H5N1 and H9N2 influenza
viruses that recently infected humans in Hong Kong. Antigenic, genetic, and
epidemiologic analyses have also furthered our understanding of interpandemic
influenza. Although many questions remain, advances of the past two decades have
demonstrated that several widely held concepts concerning the global epidemiology
of influenza were false.
PMID- 10774474
TI - The spectrum of human herpesvirus 6 infection: from roseola infantum to adult
disease.
AB - Human herpesvirus 6 is the causative agent of roseola infantum, a generally
benign rash illness of infants. Most persons acquire HHV-6 infection by age 2
years, and HHV-6 infection is a common cause of fever and febrile seizures in
infants. In adults, primary infection with HHV-6 can produce a mononucleosis-like
illness and, more rarely, severe disease, including encephalitis. In addition to
primary infections, HHV-6 can cause clinical illness during reactivation,
particularly in immunocompromised persons.
PMID- 10774475
TI - Catheter ablation for atrial fibrillation.
AB - Atrial fibrillation is frequently disabling and resistant to antiarrhythmic
drugs. Curative treatment by catheter-based ablation has been shown to be
feasible either by achieving long linear lesions, mainly in the left atrium, or
by targeting the initiating focus, most frequently in the pulmonary veins. This
paper reviews the different ablation approaches, their results, potential
complications, and relative merits.
PMID- 10774476
TI - Genetic disorders affecting proteins of iron metabolism: clinical implications.
AB - Remarkable progress is being made in understanding the molecular basis of
disorders of human iron metabolism. Recent work has uncovered unanticipated
relationships with the immune and nervous systems, intricate interconnections
with copper metabolism, and striking homologies between yeast and human genes
involved in the transport of transition metals. This review examines the clinical
consequences of new insights into the pathophysiology of genetic abnormalities
affecting iron metabolism. The proteins recently found to be involved in the
absorption, transport, utilization, and storage of iron are briefly described,
and the clinical manifestations of genetic disorders that affect these proteins
are discussed. This chapter considers the most common inherited disorder in
individuals of European ancestry (hereditary hemochromatosis), a widespread
disease in sub-Saharan populations for which the genetic basis is still uncertain
(African dietary iron overload), and several less frequent or rare disorders
(juvenile hemochromatosis, atransferrinemia, aceruloplasminemia,
hyperferritinemia with autosomal dominant congenital cataract, Friedreich's
ataxia, and X-linked sideroblastic anemia with ataxia).
PMID- 10774477
TI - Genetics of psychiatric disease.
AB - Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are
at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA)
disorders, while relatives of schizophrenia (SZ) probands are at increased risk
for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared
genetic susceptibility. Recent genetic linkage studies have defined confirmed
susceptibility loci for BIP disorder for multiple regions of the human genome,
including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of SZ
kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13,
both of which are implicated in susceptibility to BIP disorder. Similarly,
confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong
statistical evidence for a 13q32 BIP susceptibility locus has been reported.
Thus, both family and molecular studies of these disorders suggest shared genetic
susceptibility. These two group of disorders may not be so distinct as current
nosology suggests.
PMID- 10774478
TI - The Marfan syndrome.
AB - The Marfan syndrome (MFS), initially described just over 100 years ago, was among
the first conditions classified as a heritable disorder of connective tissue. MFS
lies at one end of a phenotypic continuum, with people in the general population
who have one or another of the features of MFS at the other end, and those with a
variety of other conditions in between. Diagnosis of MFS and these other
conditions remains based on clinical features. Mutations in FBN1, the gene that
encodes fibrillin-1, are responsible for MFS and (in a few patients) other
disorders in the continuum. In addition to skeletal, ocular, and cardiovascular
features, patients with MFS have involvement of the skin, integument, lungs, and
muscle tissue. Over the past 30 years, evolution of aggressive medical and
surgical management of the cardiovascular problems, especially mitral valve
prolapse, aortic dilatation, and aortic dissection, has resulted in considerable
improvement in life expectancy.
PMID- 10774479
TI - Nonsteroidal anti-inflammatory drugs and cancer prevention.
AB - Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, appear to have
clinically significant anticarcinogenic effects in the gastrointestinal tract.
Epidemiological data indicate that use of these drugs is inversely associated
with the risk of sporadic colorectal cancer, and clinical trials among patients
with familial polyposis coli show that NSAIDs can lead to the regression of large
bowel adenomas. Animal studies have reported a similar efficacy of NSAIDs against
experimental carcinogenesis. A consistent pattern in this research is that
continued long-term use of NSAIDs is required for an anticancer effect--up to 15
or 20 years before a reduced risk of colorectal cancer appears. Epidemiological
data also suggest possible protective effects in the stomach and esophagus. The
mechanisms underlying any chemopreventive effect of NSAIDs are not clear.
Inhibition of cyclooxygenase is one possibility, but pathways independent of
cyclooxygenase and prostaglandins are also possible.
PMID- 10774480
TI - Lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer.
AB - The standard of care for the evaluation of axillary nodal involvement remains
complete lymph node dissection. Lymphatic mapping and sentinel lymph node (SLN)
biopsy are changing this long-held paradigm; indeed, several leading institutions
already reserve complete axillary dissection for patients with metastasis to the
SLN. In addition to reviewing the literature, this chapter describes our
lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research
Institute with 1147 breast cancer patients. Our results, in addition to a meta
analysis of data from 12 institutions comprising an additional 1842 patients
undergoing complete axillary dissection, demonstrate that SLN biopsy is an
accurate method of axillary staging. Although the results from small series may
exaggerate the probability of false negative results, the risk of nodal disease
based on tumor size and other risk factors should be evaluated when considering
the results of SLN sampling.
PMID- 10774481
TI - The genetics of the amyloidoses.
AB - The amyloidoses are diseases in which abnormalities in the secondary structure of
precursor proteins result in decreased solubility under physiologic conditions,
with subsequent organ compromise. A total of 18 proteins have been definitively
identified as amyloid precursors associated with human disease. Mutations in the
genes that encode some of these proteins produce autosomal dominant disease in
mid to late adult life. Until recently, the late onset has obscured the familial
nature of some of the disorders. This is especially true in the apparently
sporadic disease-producing deposits found even later in life. In many instances,
these deposits are derived from precursors encoded by wild-type genes (perhaps
influenced by alleles that are polymorphic in the normal population); in other
cases, they represent autosomal dominant disease with age-dependent penetrance.
The genetic aspects of amyloid diseases produced by the deposition of four
different proteins have been investigated in detail and provide insights into the
particular diseases and amyloidogenesis in general.
PMID- 10774482
TI - [Prevalence of HTLV-1 virus infection in Togo (Kozah prefecture and the
University Hospital Center of Lome].
AB - The aim of this study was to determine the prevalence of Human T cell Leukaemia
Virus Type 1 (HTLV1) in a representative population sample, in neurological and
non-neurological patients hospitalised in the Lome teaching hospital in order to
study the clinical manifestations of this retrovirus. There was no statistical
difference among the three groups concerning the prevalence of HTLV1 respectively
(1.2%: 21/1717, 1.8%: 15/828 and 1.6%: 4/244). Spastic paraparesis was the only
disease significantly linked to HTLV1 (15.5%: 9/58).
PMID- 10774483
TI - [In vitro sensitivity to antibiotics in 178 strains of genital mycoplasma
isolated from gynecology consultants in Dakar].
AB - The susceptibility to antibiotics of 144 strains of Ureaplasma urealyticum and 34
strains of Mycoplasma hominis isolated in Dakar, Senegal, was determinated by MIC
determination in a medium. Doxycyclin and minocyclin are active on more than 90%
of the strains of U. urealyticum, and more than 80% of M. hominis strains. Over
93% of U. urealyticum strains are susceptible to all the macrolids and apparented
tested (erythromycin, pristinamycin, josamycin), but the activity of lincomycin,
pristinamycin and josamycin on M. hominis was found only for 70% of the strains.
Fluoroquinolones, once adequately studied, could turn out to be a useful
alternative in therapeutics.
PMID- 10774484
TI - [Evaluation of a simple and rapid method of Plasmodium falciparum DNA extraction
using thick blood smears from Gabonese patients].
AB - In field-based studies, sometimes it is difficult to collect and store samples.
We have evaluated a method of malaria parasite deoxyribonucleic (DNA) extraction
from non-stained thick dried blood smears collected from 108 Gabonese patients.
This method of DNA isolation was compared to those using phenol/chloroform.
Patients parasitemia ranged from 0 to 240,000 parasites/microliter of blood. Both
methods of DNA preparation gave similar results. Of the 108 slides, 57% were
Plasmodium falciparum positive after PCR analysis of the MSA-2 gene and 34% were
positive by microscopical examination. Thirty-six and seventy-two blood smears
from patients were also tested after one and four weeks' storage respectively, at
room temperature, and the parasite DNA was successfully extracted. We conclude
that this simple method of collection and rapid procedure of parasite DNA
isolation are adequate and convenient in the field when a large number of samples
are required and in the case of repetitive samplings of patients.
PMID- 10774485
TI - [Infantile visceral leishmaniasis from Leishmania infantum MON-24: a reality in
Tunisia].
AB - The authors report the first documented observation of infantile visceral
leishmaniasis due to Leishmania infantum MON-24 zymodeme in Tunisia. This
zymodeme was isolated from a non-immunodepressed two-year-old child, with
visceral leishmaniasis, originating from Zaghouan, in northern Tunisia. This case
shows that beside L. infantum MON-1 and MON-80, L. infantum MON-24, the usual
parasite of cutaneous leishmaniasis, there exists also a causative agent of
visceral leishmaniasis in our country.
PMID- 10774486
TI - [Ocular damage during HIV infection at the University Hospital Center of
Casablanca. (Apropos of 400 cases)].
AB - The objective of this study was to report ocular manifestations in Moroccan
patients infected with HIV/AIDS. 400 patients were surveyed retrospectively from
1993 to 1998 as part of a co-operative study undertaken by the departments of
infectious diseases and ophtalmology of the Casablanca Teaching Hospital. Of the
400 patients, 127 had an infection of the posterior segment and 7 showed signs of
a palpebral infection. We also found 44 cases of opportunist retinal infections,
dominated by the Cytomegalovirus (CMV) (18 cases). Our sample study indicates an
intermediary position between western countries where the widespread use of the
tritherapy has increased the life expectancy of patients and sub-Saharan Africa
where epidemiological data are still characterised by high mortality and
increasing endemic disease.
PMID- 10774487
TI - [Toxoplasma serology in HIV infected patients and suspected cerebral
toxoplasmosis at the Central Hospital of Bobo-Dioulasso (Burkina Faso)].
AB - A study was conducted in the Internal Medicine unit of Bobo-Dioulasso Hospital.
Of the 1828 HIV positive patients admitted in medical wards, 268 presented
neurological symptoms. 25.4% had positive Toxoplasma gondii serology.
Encephalitis was associated with 12.5% of this latter group and intracranial
hypertension with focal neurological defects affected a further 47.5% of them.
Presumptive treatment of toxoplasmosis led to significant clinical improvement in
60% of cases. Toxoplasma gondii serology should be part of the standard check-up
for every HIV-infected patient, and toxoplasmosis chemoprophylaxis should be
given to those with positive toxoplasma serology. Presumptive therapy of
toxoplasmosis should be started for all HIV positive patients with focal
neurological manifestations in the absence of a cerebral scanner.
PMID- 10774488
TI - [Suspected palpebral anthrax in children. (Apropos of 3 cases)].
AB - Anthrax is an infectious disease caused by Bacillus anthracis. It is primarily a
disease of domestic animals. Human beings can be infected by contact with
infected animals, soiled objects, thorns or insect stings. In its cutaneous form,
it may produce lesions of the eyelids. The authors report three suspected cases
of palpebral anthrax in children. The clinical diagnosis was evident. Scraping
from the necrotic tissue showed thick Gram positive rods in two children. This
aspect evokes Bacillus. All the patients responded to the Penicillin G. No
complications were noted. Prevention of anthrax in Africa poses the difficult
problem of health education for the local population and immunization programs
for animals which can be infected by Bacillus anthracis.
PMID- 10774489
TI - [Granulomatous peritonitis from ascariasis: apropos of 1 case in a Benin child].
AB - We report a case of granulomatous peritonitis in a child, due to Ascaris
lumbricoides eggs. A 6 year-old child was admitted to the emergency ward with
acute abdomen pain. Upon performing a laparotomy, severe adhesive inflammation
and adenopathies were found and abdominal tuberculosis was diagnosed. Specific
treatment was administered. Later, the acurage diagnosis of Ascaris ova
peritonitis was made by histopathological examination of tissue removed during
the operation. The pathogenesis is briefly discussed.
PMID- 10774490
TI - [Cardiothyreosis: retrospective study of 32 cases in the cardiology and internal
medicine department at Ouagadougou, Burkina Faso (1993-1998)].
AB - Cardiothyreosis is a relatively frequent condition in Sub-Saharan Africa and
represents 1.7% of cardiac admissions in Ouagadougou. In this retrospective
study, our aim has been to describe clinical characteristics of the disease and
its cross-disciplinary management. Over a period of six years (1993-1998), we
observed 32 cases of cardiothyreosis at the Centre Hospitalier Yalgado Ouedraogo.
Average age was 43.3 +/- 14.7, with a clear majority of women (78.1%). Systolic
blood pressure was on average 136 +/- 5 mmHg and mean diastolic blood pressure
was 78 +/- 16 mmHg. Mean heart frequency was measured at 125 +/- 27 beats/minute
and we detected 13 cases (41%) of atrial fibrillation. Heart failure occurred in
22 cases (69%). Underlying mitral valvulopathy was found in 5 cases. Arrhythmia
was reduced in 53% of the cases, after treating with betablocker or cibenzoline
(4 cases). Eighteen out of 25 patients presented anaemia (72%), 64% had
hypocalcemia, and 50%--hypokaliemia. The average cardio-thoracic index was 0.63
+/- 0.09 with extremes of 0.75 and 0.40. An echocardiogramme was conducted for 10
patients and showed atrial dilation in 4 cases and ventricular dilation in one
case. This turned out to be Basedow illness in 62.5% of the cases and
multinodular goitre in 37.5%. Mean hospitalisation was 18.3 +/- 12.7 days.
Antithyroidian treatment led to a positive evolution in 97% of the cases (only
one death occurred through refractory heart failure).
PMID- 10774491
TI - [Botryoid rhabdomyosarcoma of the urogenital sinus. Apropos of 1 case in an 11
month old child].
AB - Rhabdomyosarcomas are the most common sarcomas of the soft tissues found in
children under 15 years. The reported observation is of a vaginal tumour having
developed in an eleven-month-year-old little girl. It was a typical botryoid
rhabdomyosarcoma, usually found in the hollow organs surrounded on the edges by
mucus. Rhabdomyosarcomas have many characteristics which vary greatly according
to the degree of their cellular differenciation. The majority of these tumours
can be classified into four histological categories: embryonic, botryoid,
alveolar or plemorphous. The treatment is exeresis surgery with radio- and
chemotherapy. Prognosis, however, remains dim despite the therapeutic advances of
the last few years.
PMID- 10774492
TI - [African human trypanosomiasis. Therapeutic strategies].
AB - Although therapeutic strategies for trypanosomiasis appear to be straightforward,
their application in the field raises a number of questions which are
successively examined below. After a quick reminder of the available drugs, we
discuss: Criteria for eligibility: problems of beginning treatment for
immunological suspects and determination of the development phase. Present-day
problems: availability of drugs; side effects; therapeutic failures. While
efforts should be continued to make existing drugs available, it is important
that fundamental research be carried out to enhance their utilisation as well as
to develop new active molecules.
PMID- 10774493
TI - [Prevalence of hepatitis A, B, C virus markers in Reunion (south hospital and
Saint Pierre prison)].
AB - We studied the prevalence of Hepatitis A, B, C in different groups in the
population of the South of Reunion Island. The aims of this study were the
following: to estimate the prevalence of Hepatitis C virus (HCV) (anti-HCV
antibodies) and Hepatitis B virus (HBV) (anti-HBc, HBs Ag and anti-HBs) in a
population of 1455 women, who delivered in the Centre hospitalier Sud Reunion
(CHSR), to estimate the prevalence of these two viruses in a population selected
for risk factors (100 prisoners), to estimate the prevalence of Hepatitis A in a
group of 400 persons (aged 0 to 19) hospitalised in CHSR since 1st January 1998
(100 for each 5-year age bracket), to research risks factors in these populations
and immunity. The overall prevalence of anti-HCV was 0.14% in pregnant women and
risk factor associated was found in 28.9% of this population (2.9% history of
transfusion, 0.21% drug users). In the group of prisoners seroprevalence was 2%,
far below that of prisoners in France. Anti-HCV seroprevalence is weak in Reunion
Island and very inferior to seroprevalence in the French population as in other
Indian Ocean islands. This is due to the low risk of parenteral transmission.
Anti-HBc was found in 90 serum samples from women (overall prevalence 6.35%) and
of these 90 positive samples, 9 were positive for HBs Ag (overall prevalence
0.63%), 68 were positive for anti-HBs (4.81%) and 22 (1.54%) were anti-HBc
isolated (without HBs Ag and anti-HBs). The overall prevalence of anti-HBs was
62.8%. In the population of 100 prisoners, 2 were HBs Ag positive, 10 anti-HBc
positive (2 anti-HBc isolated, 2 associated with HBs Ag, 6 with anti-HBs). The
prevalence of anti-HBs was 22%. The major risk factor observed in this population
of prisoners was tattooing and/or piercing (46%). These results show that:
Reunion island is an area of low endemicity for HBV virus. The measure of
protective inoculation is well followed. i.v. drug abuse and previous transfusion
are weak routes of transmission. In the group aged 0 to 19, overall prevalence of
anti-HAV was 11.9% with the highest rate found among 15 to 19 year-olds (25%).
Seroprevalence falls with socio-economic progress. At the present time, the
endemic is intermediate in Reunion Island. Given immunity levels within the young
population, there is a risk of outbreak. This risk is due to the conditions in
Reunion Island, but also to people who travel to other Indian Ocean countries
where endemicity is high. It is thus very important that a vaccination strategy
be determined.
PMID- 10774494
TI - [What are the indications in France for vaccination against Japanese
encephalitis?].
AB - Japanese encephalitis is a mosquito-borne viral disease occurring in rural and
rice-growing areas of Asia, where mosquitoes proliferate, transmitting the
Flavivirus from viremic animals, mostly pigs, to humans. Japanese encephalitis
has recently spread to previously non-affected regions, leading to serious
outbreaks among non-immune populations. Although it has a high proportion of
unsymptomatic infection, clinical encephalitis is usually severe, resulting in a
very high mortality rate, and neurologic sequellae are common among survivors.
Vaccines are used in several Asian countries. One of these vaccines is now
available to French travellers, but only in international vaccination centres
with an authorization from the French drug agency (Agence francaise de securite
sanitaire des produits de sante). The aim of this paper is to clarify the
recommendations for immunisation in each country of the affected regions. The
area can be divided into three epidemiological zones, with tropical, subtropical
and temperate characteristics. For the first two, vaccination is recommended
before a long stay in a rural area, especially during the rainy season; in
temperate climates, outbreaks occur in summer and autumn. However, local
variations such as intensive rice-growing or development of pig breeding may
interfere with these patterns. Long-term visitors should consult a local
physician and prevention of mosquito bites is always recommended.
PMID- 10774495
TI - [Epidemiologic surveillance of dengue fever: non specific alert system in the
hospital milieu in Cayenne].
AB - A retrospective study was carried out in the General Hospital of Cayenne, the
main city in French Guiana, where malaria is endemic and dengue fever constitutes
a permanent threat. The aim of this study was to test an alert system for
epidemic outbreaks of dengue fever. Patients attending the emergency ward and for
whom a search of Plasmodium was prescribed were included. In 90% of cases,
patients were febrile, presenting clinical symptoms compatible with malaria or
dengue fever-like syndrome. The period of survey covered 39 months (January 1996
to March 1999). Three indices were studied; two non specific: EMN (Emergency
Malaria Negative--UPN in French): number of negative malaria blood tests for
patients having consulted the emergency ward; EMNT (Emergency Malaria Negative
Thrombopenia--UPNT in French): UPN with platelets < 150.000; and one more
specific; number of hospitalised dengue fever cases according to data from a
hospital programme on medical systems information. EMN weekly follow-ups led to
three epidemic alerts, two of which turned out to be crucial for dengue.
Accounting for thrombopenia (EMNT) reinforced the specificity. This simple and
reactive alert system should incite increased serological and virological
surveillance and contribute to precocious antivectorial control measures in
districts where several dengue fever cases are suspected.
PMID- 10774496
TI - [Adult non-viral lymphocytic meningitis in Abidjan (Cote d'Ivoire)].
AB - Our prospective and longitudinal study aimed to analyse the aetiologies, clinical
features and prognostic of non viral lymphocytes meningitis (NVLM). We recruited
131 patients, 77 males (59%) and 54 females (41%) sex-ratio 1.4. The mean age was
35 years [15-67]. 117 patients were HIV positive (89%) and 14 (11%) were HIV
negative. Feverish meningoencephalitis was present in 85% of cases, with 7 days
for mean delay of admission into hospital. 80 germs were found in the C.S.F. 70
Cryptococcus neoformans, 4 Mycobacterium tuberculosis, 3 Streptococcus
pneumoniae, 1 Candida albicans, 1 Neisseria meningitis and 1 Trypanosoma
gambiense. 63 aetiologies were linked to lymphocytes meningitis by indirect
deduction: 41 cases of tuberculous meningitis with lung X-ray anomalies and M.
tuberculosis in sputum (11 times), 11 cases of cerebral malaria with Plasmodium
falciparum in blood, 11 cases of cerebral toxoplasmosis by significant features
with cerebral tomodensitometry. Letality was 53%, 35% of patients improved and
12% were lost to follow-up. Our study shows the difficulties in the management of
the NVLM, due to the delay of diagnosis, particularly for tuberculous meningitis.
PMID- 10774497
TI - [Results of treatment of 62 cases of Hodgkin's disease in Cote d'Ivoire].
AB - This study reports the follow-up after 22 years of 62 treated cases of Hodgkin's
disease. Complete remission was obtained in 66% of cases versus 31% of incomplete
remission and 3% of failures. Overall survival of patients ranged from 10 days to
48 months. Real event-free survival was difficult to estimate given that 40% were
completely lost to follow-up. The most frequently encountered disorders were
haematologic ones. The difficulties were directly linked to precarious socio
economic conditions for most patients.
PMID- 10774498
TI - [Acute childhood gastroenteritis study at Central University Hospital of Pointe-a
Pitre/Abymes, Guadeloupe, from November 1997 to March 1998].
AB - To determine the role of enteric pathogens in acute childhood diarrhoea in
Guadeloupe, 161 children (108 cases and 53 controls) from 0 to 2 years of age,
admitted to Pointe-a-Pitre/Abymes University Hospital, were evaluated over a five
month period. A known enteric pathogen was identified in 40.8% of children. The
most commonly identified aetiologic agents were Salmonella (16.7% of cases),
especially Haddar serotype and Rotavirus (20.5%). This virus was isolated more
often in the dry season. Adenovirus were detected in 3.6% of diarrhoeal stools
and were not significatively associated with diarrhoeal disease. No Shigella,
Campylobacter or parasites were found.
PMID- 10774499
TI - [Early neonatal mortality at the gynecological-obstetrical hospital of Hanoi,
Vietnam].
AB - A retrospective study was conducted of a series of 18,834 births at the
gynaecological-obstetrics hospital of Hanoi, Vietnam, from January 1-1991 to
December 31-1995. The mean early neonatal mortality rate was 24.4". During the
study period, a considerable decrease in rate was observed, which was attributed
to a change in patient profile. The registered causes of death were primarily due
to premature delivery and/or respiratory distress (70%). Forty-nine percent of
the early neonatal deaths occurred during the first day of life. The risk factors
for early neonatal death were assessed. Improved surveillance at the hospital of
delivery practices is necessary and the problem of prematurity should be
approached from a broad perspective.
PMID- 10774500
TI - [Imported Plasmodium falciparum malaria. "Ballad in the land of consensus"].
PMID- 10774501
TI - Measuring olfactory dysfunction from cadmium in an occupational and environmental
medicine office practice.
PMID- 10774502
TI - Pharmaceuticals--cost or investment? An employer's perspective.
AB - Employers are becoming increasingly concerned about rising pharmaceutical costs.
Are improved health and cost outcomes achieved as a result of increasing
pharmaceutical costs? One should approach this issue with a holistic view that
considers the overall impact that disease conditions have on health and
productivity. To illustrate, we first identified the "top ten" most expensive
physical and mental health concerns facing American businesses, using data from
over 60 firms from the 1996 MarketScan Private Pay Fee-For-Service Research
Database. For some of these top ten conditions, the literature already addresses
the drug cost versus investment issue, with mixed results. For conditions in
which uncertainty prevails and for other high-cost conditions, empirical analyses
should address the drug cost versus investment issue to minimize the risk of a
penny-wise and pound-foolish payment/coverage policy. A similar strategy should
be applied to individual corporate diagnostic assessments.
PMID- 10774503
TI - Evidence-based design: the ACOEM Practice Guidelines Dissemination Project.
AB - A steering committee and investigators from the American College of Occupational
and Environmental Medicine (ACOEM) designed and carried out the ACOEM Practice
Guidelines Dissemination Project to encourage adoption of the ACOEM Occupational
Medicine Practice Guidelines. The project also involved research on guideline
acceptance as well as potential improvements and additions to the guidelines. To
increase guideline adoption and use in improving the appropriateness and
consistency of practice and case management, the design was based on existing
research on guideline format, education, and adoption efforts. This article
summarizes that information and the needs assessment done prior to case-based
guidelines training. Other articles in this issue report on guideline adoption
and use and the results of the market research on the ACOEM guidelines.
PMID- 10774504
TI - Acceptance and self-reported use of national occupational medicine practice
guidelines.
AB - The authors conducted a survey to ascertain post-training attitudes and self
reported use of the American College of Occupational and Environmental Medicine
occupational medicine practice guidelines. Trainees were surveyed 3 to 4 months
after completing a case-based practice ACOEM occupational practice guidelines
seminar. Of 96 physician respondents, 95% reported that the guidelines improved
their practice in some manner. Fifty-two percent of physicians thought that
guideline use decreased medical costs. Seventy-one percent reported that their
care complied with the guidelines in 70% or more of their cases; however,
"actually considering the guidelines in particular cases" was reported by only
47%. Discussion of cases was frequent (92%) and involved physicians, patients,
and other health care providers. We concluded that physicians' attitudes toward
the guidelines are positive and that reported compliance is high. Guidelines are
discussed frequently.
PMID- 10774505
TI - Beliefs about and use of occupational medicine practice guidelines by case
managers and insurance adjusters.
AB - Workers' compensation case managers and adjusters have increased their use of
practice guidelines recently, partly in response to state regulations. However,
informally reported rates of use are not as high as desired for the best managed
care practices and the greatest reductions in lost work time. Although there are
several studies of physicians' use of guidelines, there are few if any studies
about case managers' and adjusters' beliefs about, and utilization of, either
general medical or occupational medical practice guidelines. Information about
attitudes, beliefs about practice guidelines, and actual use should help
developers make the guidelines more usable and bring about more effective
interaction among case managers, adjusters, treating physicians, and other health
professionals. This article reports on pre- and post-training surveys of a cohort
of case managers and adjusters who participated in a case-based guideline
training course. It then compares their responses to those of the physicians
whose cases they might manage.
PMID- 10774506
TI - Suggested improvements in practice guidelines: market research to support
clinical quality improvement.
AB - The American College of Occupational and Environmental Medicine's Practice
Guideline Dissemination Project included market research to better understand the
wants and needs of physicians, case managers, and insurance adjusters who used
the guidelines. We used structured and open-ended survey questions and focus
groups administered to a cohort of physicians, adjusters, and case managers
trained as part of the project. Respondents were generally satisfied with the
format and contents of the guidelines. They requested additional material on case
management and facilitation of effective treatment and return to work by other
health professionals. They also suggested a variety of formats to improve the
accessibility of the guidelines. The suggestions may be used in new product
development or for guideline revisions.
PMID- 10774507
TI - Rehabilitative care of war-related health concerns.
AB - The objective of this study was to pilot the effectiveness of a 3-week
rehabilitative intervention that used medical review, graded exercise, education
on Gulf War exposures, active coping, and nutrition to improve disability and
related distress for Gulf War veterans with persistent symptoms. One hundred and
nine veterans were assessed at program entry and exit and at 1 and 3 months after
program completion. Outcomes were physical symptoms, quality of life, physical
health concern, and psychosocial distress--contrasted across time and demographic
groups. After treatment, veterans showed modest and global improvements; women
were more likely than men to show improvement. The finding that Gulf War veterans
who completed specialized rehabilitative management experienced modest, short
term improvements is encouraging, given that veterans of the conflict remain
concerned about their future health. Controlled studies are needed.
PMID- 10774508
TI - Urinary 1-hydroxypyrene as a biomarker of polycyclic aromatic hydrocarbons
exposure of workers on a contaminated site: influence of exposure conditions.
AB - The aim of the study was to determine the exposure levels of workers to
polycyclic aromatic hydrocarbons on gasworks sites by the measurement of urinary
1-hydroxypyrene. Start-shift and end-shift urine samples were taken every day
during an entire week (Monday to Friday), once in November and a second time in
June. Four groups of workers were selected according to their activity. Increased
exposure was only found among volunteers involved in the remediation of a site,
0.16 to 2.31 mumol/mol creatinine in non-smokers. The median of the non-smoker
referent group was 0.02 mumol/mol creatinine (95% confidence interval, 0.01 to
0.04). Smokers had greater exposure levels than non-smokers in every group.
Within and between variability was around 200%. Assessment of the exposure of
persons on contaminated soil is possible, with the condition that the exposed
subjects come in direct contact with the soil.
PMID- 10774509
TI - Median neuropathy at the wrist: diagnostic utility of clinical findings and an
automated electrodiagnostic device.
AB - Clinical findings have limited value in predicting electrophysiologically
confirmed median neuropathy at the wrist (MNW). To determine the value of
clinical findings and an automated electrophysiologic neurodiagnostic device
(AEND) in diagnosing MNW, we studied two groups of 75 consecutive patients (an
initial group and a validation group, 150 total) referred to an academic
electrophysiology laboratory for upper extremity complaints. The definitive
standard for MNW was the neurologist's diagnosis after formal clinical and
electrodiagnostic evaluation. The neurologist was blinded to the results of the
AEND (NC-Stat, NeuroMetrix, Inc). In the validation group, the AEND yielded a
distal motor latency (DML) in 97% of hands with a conventional motor response,
and the correlation of the AEND DML with the conventional DML was 0.94 (P <
0.001). Of 248 symptomatic hands, the neurologist diagnosed 117 (47%) with MNW.
At 90% specificity, the AEND DML had a sensitivity of 86% for MNW. Age, body mass
index, sensory symptoms in digits 1 to 3, and nocturnal awakening were
independent clinical predictors of MNW. Each 1-msec increase in the adjusted AEND
DML was independently associated with an OR of 298 (95% confidence interval, 40
to 2233) for MNW. Each 1-msec increase in the F-wave latency was independently
associated with an OR of 2.6 (95% confidence interval, 1.3 to 4.9) for MNW.
Compared with a model based solely on clinical variables, an algorithm including
symptom variables plus the AEND DML had an odds ratio for correct diagnostic
classification of 6.3 (95% confidence interval, 3.8 to 12.3). The sensitivity at
90% specificity improved from 40% for the clinical model to 86% for the model
with DML. A practical method for integrating clinical and electrophysiologic
findings to assess the risk of MNW was proposed. This method correctly stratified
79% of control and MNW patients into very low- and high-risk groups,
respectively. We concluded that MNW diagnosis is significantly improved with an
AEND.
PMID- 10774510
TI - Neurologic evaluation of workers previously diagnosed with solvent-induced toxic
encephalopathy.
AB - We examined 52 railroad workers with long-term occupational solvent exposures
(average 22 years duration) who had been previously diagnosed by others as having
solvent-induced toxic encephalopathy. All described episodes of transient
intoxication associated with occupational solvent exposure. Persistent symptoms
developed, an average, 16 years after exposure onset and included impaired memory
(38), altered mood (21), imbalance (18), and headache (17). Thirteen workers had
mild mental status abnormalities, but none fulfilled conventional clinical
criteria for encephalopathy or dementia. None had abnormal blink reflex (51) or
abnormal electroencephalographic (39) studies. Eight of 47 magnetic resonance
imaging studies showed evidence of scattered ischemic lesions among workers with
known diabetes mellitus (2), elevated blood pressure (4), or peripheral vascular
disease (2). One magnetic resonance imaging scan showed mild cortical atrophy. In
stepwise multiple linear and logistic regression models, no statistically
significant (P < 0.05) dose-response relationships were found between exposure
duration and symptoms or signs that were suggestive of encephalopathy. However,
the number of symptoms (P < 0.001) and the number of signs (P = 0.05) were
associated with current use of central nervous system-active medications.
Further, lower Mini-Mental Status Examination scores were associated with a
history of alcohol abuse (P = 0.01) and lower educational level (P = 0.03). The
number of chief symptoms involving memory, mood, balance, or headache differed
significantly among workers in different geographic sites (F(3.48) = 2.94, P =
0.04), a finding that was not explained by job title or exposure duration. There
also was a significant (P = 0.0001) inverse relationship between initial exposure
year (r2 = 0.60) or total years of exposure through 1987 (r2 = 0.56) and interval
to major neurologic symptom onset, suggesting that factors other than solvent
exposure account in part for worker complaints. We found no objective neurologic
evidence supportive of toxic encephalopathy or any other uniform syndrome among
these individuals, and most complaints were explained by neuropsychological
factors or conditions unrelated to occupational solvent exposure.
PMID- 10774511
TI - Comparison of surrogate with self-respondents for occupational factors.
AB - Accurate assessment of occupational history is critical in case-control studies
of disease risk associated with employment. However, in some studies of rapidly
fatal diseases, a surrogate or next of kin is interviewed rather than the study
subject. In a unique re-interview study of subjects from a community-based case
control study originally interviewed 5 years earlier, we evaluated the level of
agreement between (1) subjects and their surrogates on re-interview among those
who had died since the first interview, and (2) subjects themselves and their
responses at re-interview among those still living (to use as a comparison)
regarding work history and specific occupational exposures. For employment start
and stop dates, number of years worked, and number of jobs reported in the 1980
interview, exact agreement was poor for surrogate respondents and for self
respondents in the re-interview, with percentages ranging from 4% to 40%.
Agreement was similar for surrogates and self-respondents for job and industry
worked the longest, but percent of agreement among surrogates was significantly
lower than among the self-respondents for job and industry worked last. Five
(28%) of the kappa values for the industry in which the subject worked had high
agreement (kappa > 0.75) for self-respondents and surrogates. None of the kappa
statistics for materials handled by subjects in their jobs had high agreement,
and 57% of the kappa statistics had poor agreement (kappa 0.0 to 0.39). This
study suggests that occupational histories obtained by interview are poorly
reproduced, and existing methods may need improvement to collect reliable
occupational data. Further, the findings indicate that caution should be
exercised when creating a job-exposure matrix based on such data.
PMID- 10774512
TI - Fire- and flame-related occupational fatalities in the United States, 1980-1994.
AB - The National Traumatic Occupational Fatalities surveillance system recorded 1518
fire- and flame-related occupational fatalities among the civilian workforce in
the United States between 1980 and 1994. The fatalities resulted from 1221
separate incidents, of which 122 involved more than one victim and accounted for
419 of 1518 deaths. Nearly 4 of 10 fatalities resulting from a multiple-victim
fire were workers in the manufacturing industry. Similarly, the highest frequency
of fatalities in single-victim events, over one fourth, were in manufacturing.
For one fourth of the fatalities within each event category, the usual occupation
of the deceased was a precision production, craft, and repair worker. Although
this study sheds light on selected characteristics of these fatalities,
additional research on the causal factors associated with single- and multiple
victim events is needed to present specific recommendations for prevention
efforts.
PMID- 10774513
TI - Pregnancy outcome of personnel in Swedish biomedical research laboratories.
AB - Possible hazardous effects of laboratory work on the reproduction outcomes of
female laboratory personnel in Sweden from 1990 to 1994 were investigated in a
questionnaire-based study (n = 1052) by comparison with personnel in non
laboratory departments. The individual woman constituted the primary sampling
unit, with her pregnancies defined as the unit of analysis. Allowance for
dependence between different pregnancies of the same woman was considered by
applying random effect models. With regard to spontaneous abortions, no elevated
odds ratio was found for laboratory work in general, but an odds ratio of 2.3 and
a 95% confidence interval of 0.9 to 5.9 (n = 856) was connected to working with
chloroform. The odds ratio for large for gestational age infants in association
with the mother's laboratory work was 1.9 (confidence interval, 0.7 to 5.2). The
result with regard to spontaneous abortion partly supports previously reported
increased risks of miscarriage related to laboratory work with solvents.
PMID- 10774514
TI - [Monitoring of minimal residual disease with the combined detection of PML/RAR
alpha and RAR alpha/PML rearrangements in acute promyelocytic leukemia].
AB - BACKGROUND: Molecular assay commonly used to detect the PML/RAR alpha
rearrangement in acute promyelocytic leukemia (APL) has the limited sensitivity
in comparison with the higher sensitivity of RAR alpha/PML detection. This
prompted us to perform both assays in parallel to monitor a group of APL.
PATIENTS AND METHODS: The study included 56 APL patients mainly treated according
with the PETHEMA LPA-96 protocol. The PML/RAR alpha was detected according with
Biondi's et al method and the RAR alpha/PML following the Grimwade's et al RT-PCR
method (Human Press Inc.). RESULTS: RAR alpha/PML rearrangement was detected in
90% (20/22) of the patients at diagnosis positives for PML/RAR alpha. RAR
alpha/PML was detected in 74% (14/19) of post-induction samples versus 37% (7/19)
of positives for PML/RAR alpha. Likewise RAR alpha/PML rearrangement was detected
in some post-consolidation samples (2/11) that all were PMI/RAR alpha negatives.
In patients in maintenance regimen a greater proportion of RAR alpha/PML
positives (6/28) versus PML/RAR alpha (2/28) were observed. In a patient in
complete remission RAR alpha/PML preceded the positivity of PML/RAR alpha and
persisted after PMI/RAR alpha negativization. The results of the patients
monitored since the diagnosis showed that RAR alpha/PML revert to negative one
month after PML/RAR alpha negativization. CONCLUSIONS: RAR alpha/PML
rearrangement is not expressed in the totality of the APL patients, but in only a
90% of them. RAR alpha/PML rearrangement was detected in a greater proportion of
samples than PML/RAR alpha. RAR alpha/PML rearrangement lasted longer than
PML/RAR alpha after treatment.
PMID- 10774516
TI - [Clinical analysis of unsuspected pulmonary thromboembolism at the emergency
department].
AB - OBJECTIVES: Evaluate the degree of suspicion of pulmonary embolism (PE) in the
emergency department (ED). PATIENTS AND METHODS: We analyzed the cases of
patients with TEP diagnosed during two years and compared group A (PE suspected)
with group B (PE was not initially suspected). RESULTS: 57 cases of PE were
admitted from ED. In 14 (25%) of them the PE was not suspected. There were
statistically significant differences in the signs of deep venous thrombosis
(more prevalent in group A), heart failure, and pleural effusion (more frequent
in group B). The alternative diagnosis were mostly heart failure and pneumonia.
CONCLUSIONS: The patients with unsuspected PE do not have a different clinical
profile. The PE is most of the times confused with heart failure and pneumonia.
PMID- 10774515
TI - [Estimate of HIV-1 infection prevalence in pregnant women and effectiveness of
zidovudine administered during pregnancy in the prevention of vertical
transmission].
AB - BACKGROUND: Despite the proven efficacy of zidovudine (ZDV) for reducing
perinatal transmission of HIV-1, questions remain about its implementation and
effectiveness in routine practice. The aims of this study were to assess the
impact of ZDV administered during pregnancy in preventing perinatal HIV-1
transmission, and to determine the proportion of early identification of maternal
HIV-1 infection over time. PATIENTS AND METHODS: We prospectively followed from
birth a cohort of children born between 1/1/1987 and 31/10/1997 to HIV-1-infected
mothers. Infant infection status was assessed by follow-up beyond 18 months or
HIV-PCR up to 3 months of age. RESULTS: 229 mothers and 248 infants were
identified in the cohort. ZDV was administered during pregnancy as monotherapy to
34 mothers for a mean of 4.7 (3.1) months prior to delivery. There were no
differences in baseline characteristics between the treated and untreated groups.
Mean (SD) CD4 cell count was 465 (261) cells x 10(6)/l. Factors associated with
transmission were a more prolonged time of rupture of obstetric membranes (median
6 vs 1.04 hours; p = 0.023) and ZDV treatment. Among the ZDV-treated mothers only
one child was infected (2.9%), whereas 37 children born to 212 untreated women
became infected. (OR: 0.14; 95% CI: 0.07-0.92). The estimated prevalence of HIV-1
in pregnant women in our area is about 0.39% (95% CI: 0.34-0.45). From 1987 to
1991, 9.7% of infected women were nor identified at the perinatal period, as
compared to 2.5% in the last 5 years of the study period (p = 0.034).
CONCLUSIONS: In this study, the estimated prevalence of HIV-1 infection is high.
ZDV during pregnancy is significantly associated with a decrease in perinatal
transmission in our setting. The awareness of an effective treatment might have
contributed to the increased identification of HIV-infected mothers prior to
delivery observed over time in our cohort of children born to HIV-infected
mothers.
PMID- 10774517
TI - [Dermatitis outbreaks caused by Pyemotes].
AB - BACKGROUND: We describe three outbreaks of pyemotes dermatitis. METHODS: We
undertook case-control studies and samples of several suspected materials were
taken. RESULTS: There were 126 cases, with no cases admitted in hospitals.
Contact which suspected vegetable materials were the only risk factor identified.
Among orange picker workers risk factor was the exposure to orange trees, where
Pyemotes mite was found. CONCLUSION: To our knowledge this kind of occupational
risk among orange pickers has not been described before.
PMID- 10774518
TI - [Vertical transmission of HIV-1. How much can we reduce it?].
PMID- 10774519
TI - [Emergency valvular replacement in infective endocarditis: hospital and long term
clinical course. Analysis of 45 patients].
AB - BACKGROUND: To define the evolution of patients with infective endocarditis who
require urgent valve replacement in our environment. PATIENTS AND METHODS: We
followed 45 consecutive cases of infective endocarditis that require valve
replacement during their hospitalization. 32 patients had native valve infective
endocarditis, 7 early prosthesis valve endocarditis and 6 late prosthesis valve
endocarditis. Patients were followed for a long-term period, clinical and
echocardiographycally. RESULTS: In 39 cases valve replacement was performed
before ending antibiotic therapy. The main indications for surgery were
refractory heart failure (24 patients) and shock (11 patients). The mortality
rate was 24%: 19% in native valve infective endocarditis, 43% in early prosthetic
valve endocarditis and 33% in late prosthesis valve endocarditis. The first cause
of death was septic shock (46%). We followed 31 over 34 survivors for a mean time
65 (DS 49) months. We found two relapses and six deaths (1 sudden death, 2
endocarditis) and 72% of patients presented class I NYHA. We detected 17%
prosthetic leaks (34% in the prosthetic valve endocarditis group). CONCLUSIONS:
The need of urgent valve replacement in the context of infective endocarditis is
associated with a high mortality rate, and should be considered a serious
condition. Long term prognosis is, however, acceptable, although 17% of patients
had prosthesis leak, specially those with prosthetic valve endocarditis.
PMID- 10774520
TI - [Active oncologic treatment of advanced and terminal neoplastic disease].
PMID- 10774521
TI - [Extradigestive manifestations of Helicobacter pylori infection. Science or
fiction?].
PMID- 10774522
TI - [Nasal type T/NK cell lymphoma with testicular presentation].
PMID- 10774523
TI - [Infections caused by environmental mycobacteria in Spain].
PMID- 10774524
TI - [Levofloxacin-induced tendinitis].
PMID- 10774525
TI - Social categorization and stereotyping: 'You mean I'm one of "them"?'.
AB - What happens when people discover that they are members of a group about which
they have previously formed some stereotype? To address this question, procedures
previously shown to induce negative stereotypes of minority groups were combined
with a social categorization manipulation. Participants in a distinctiveness
based illusory correlation paradigm (Hamilton & Gifford, 1976) either knew
nothing about their group membership, or learned that they were a member of the
minority group or the majority group either before or after being presented the
stereotype-engendering stimulus materials. Results revealed that social
categorization into the minority group before stimulus presentation eliminated
the perceived stereotype and reversed the evaluative bias, whereas social
categorization into the minority group after stimulus presentation had no effect
on the perceived stereotype and only a weak effect in reducing the evaluative
bias. Social categorization into the majority group either before or after
stimulus presentation had little effect on the perceived stereotype and
evaluative bias. These results clarify the process underlying the influence of
social categorization on stereotype formation, underscore the distinction between
affective and cognitive influences on stereotype formation and stereotype change,
and offer insights into 'autostereotyping' among members of minority groups.
PMID- 10774526
TI - Displacing place-identity: a discursive approach to locating self and other.
AB - Questions of 'who we are' are often intimately related to questions of 'where we
are', an idea captured in the environmental psychological concept of place
identity. The value of this concept is that it attends to the located nature of
subjectivity, challenging the disembodied notions of identity preferred by social
psychologists. The topic of place identity would thus seem to be a productive
point around which the sub-disciplines of social and environmental psychology
might meet, answering calls for greater disciplinary cross-fertilization. This
study contributes to this project by presenting a sympathetic but critical
evaluation of research on place-identity. It argues that such research is
valuable in that it has established the importance of place for creating and
sustaining a sense of self. However, drawing on recent developments in discursive
approaches to social psychology, the authors identify several limitations with
existing work on place-identity. This critique is then developed through analysis
of an ongoing research programme located in the changing landscapes of the new
South Africa.
PMID- 10774527
TI - In what sense are prejudicial beliefs personal? The importance of an in-group's
shared stereotypes.
AB - This experiment investigated the role that group membership and shared
stereotypes play in the expression of intergroup prejudice. In three independent
conditions schoolchildren (N = 96) used a checklist to describe Australian
Aborigines with reference to the cultural stereotype and their personal beliefs.
In two conditions Aborigines were also described with reference to the beliefs of
a relevant in-group (with or without group interaction). In all conditions an
independent prejudice measure was also completed. Following Devine and Elliot
(1995), personal beliefs were always better predictors of prejudice than the
cultural stereotype. However, shared group beliefs were better predictors of
prejudice than personal beliefs elicited in the abstract, and personal beliefs
were more predictive of prejudice in conditions where they were informed by a
salient group membership. These patterns suggest that personal beliefs are more
predictive of prejudice when they reflect stereotypic beliefs shared within an in
group rather than individuals' idiosyncratic views.
PMID- 10774528
TI - The effects of cognitive load on strategic self-handicapping.
AB - Past research has demonstrated that observers tend to underestimate the
importance of situational determinants (e.g. task difficulty) of the performances
of others. This tendency is particularly pronounced when observers are
unmotivated, distracted or otherwise 'cognitively busy' while making
attributional judgments. The objective of the present research was to determine
whether a similar tendency exists when actors are given the opportunity to choose
the tasks they will undertake in a self-presentational situation. Sixty-one
participants were given a choice between a difficult and a simple task, with
cognitive busyness being manipulated while this choice was being made.
Cognitively busy participants were significantly more likely to choose the simple
task than their non-busy counterparts.
PMID- 10774529
TI - The double negative effect: the (almost) paradoxical role of the individual self
in minority and majority members' information processing.
AB - The authors examined the interactive influence of accessibility of the individual
self and relative in-group size on group-level as opposed to individual-level
information processing. In Expt 1, the authors predicted and found that, when
accessibility of the individual self was low, minority members tended more
towards group-level information processing than did majority members. This was
not true when accessibility of the individual self was high. Contrary to the
authors' hypothesis, however, the disappearance of the minority-majority effect
in the high-accessibility condition did not result from a decrease in group-level
information processing among minority members, but from an increase among
majority members. Experiment 2 replicated this unexpected effect using two
different measures of group level information processing. It also provided
additional data on the dynamic interplay of the individual self and the
collective self which seems to be responsible for the observed effects.
PMID- 10774530
TI - Contested identities and schisms in groups: opposing the ordination of women as
priests in the Church of England.
AB - Schisms constitute a common characteristic of human groups. Nevertheless, they
have been neglected by social psychology, mainly because social psychological
theories either dismiss group consensus or else depict groups as monolithic. This
study proposes a social psychological approach to schism which integrates recent
developments of self-categorization theory (SCT) with work on category
argumentation. According to SCT, shared group identification leads to a process
by which members should reach agreement. However, it is suggested that where
members construe the positions of others as fundamentally altering group
identity, then consensus is impossible. The corollary of assuming that groups
will be consensual is that lack of consensus indicates the existence of different
groups. This idea is examined through an analysis of a video and booklet produced
for a rally organized by Forward in Faith, an organization opposed to the
ordination of women as priests within the Church of England. It is shown that the
existence of women priests is construed as changing the essence of the Church
both on a structural level (by dividing it from the rest of the Christian
community and turning it into a sect) and doctrinally. Such changes are seen as
threatening the very existence of the Church of England and therefore demanding
all out opposition. However, it is also shown that the decision of whether
opponents fight the changes from inside the Church or by splitting from it
depends upon the perception of whether they will be accorded the opportunity to
advance their position from within. Thus schism is associated with both a
perceived 'change of essence' and also with 'lack of voice'.
PMID- 10774531
TI - Essentialist beliefs about social categories.
AB - This study examines beliefs about the ontological status of social categories,
asking whether their members are understood to share fixed, inhering essences or
natures. Forty social categories were rated on nine elements of essentialism.
These elements formed two independent dimensions, representing the degrees to
which categories are understood as natural kinds and as coherent entities with
inhering cores ('entitativity' or reification), respectively. Reification was
negatively associated with categories' evaluative status, especially among those
categories understood to be natural kinds. Essentialism is not a unitary syndrome
of social beliefs, and is not monolithically associated with devaluation and
prejudice, but it illuminates several aspects of social categorization.
PMID- 10774532
TI - Social categorizations, social comparisons and stigma: presentations of self in
people with learning difficulties.
AB - Self-categorization theory stresses the importance of the context in which the
meta-contrast principle is proposed to operate. This study is concerned with how
'the pool of psychologically relevant stimuli' (Turner, Hogg, Oakes, Reicher &
Wetherell, 1987, p. 47) comprising the context is determined. Data from
interviews with 33 people with learning difficulties were used to show how a
positive sense of self might be constructed by members of a stigmatized social
category through the social worlds that they describe, and therefore the social
comparisons and categorizations that are made possible. Participants made
downward comparisons which focused on people with learning difficulties who were
less able or who displayed challenging behaviour, and with people who did not
have learning difficulties but who, according to the participants, behaved badly,
such as beggars, drunks and thieves. By selection of dimensions and comparison
others, a positive sense of self and a particular set of social categorizations
were presented. It is suggested that when using self-categorization theory to
study real-world social categories, more attention needs to be paid to the
involvement of the perceiver in determining which stimuli are psychologically
relevant since this is a crucial determinant of category salience.
PMID- 10774533
TI - Video game violence and aggression: comments on 'Video game playing and its
relations with aggressive and prosocial behaviour' by O. Wiegman and E. G. M. van
Schie.
PMID- 10774534
TI - Acute metobromuron poisoning with severe associated methemoglobinemia.
Identification of four metabolites in plasma and urine by LC-DAD, LC-ESI-MS, and
LC-ESI-MS-MS.
AB - A case of self poisoning with metobromuron, a urea derivative used as a
herbicide, is reported. Severe methemoglobinemia observed at the admission (80%)
disappeared only at day 11, and hemolysis appeared at day 4 and decreased slowly
to day 12. Metobromuron was analyzed by liquid chromatography with diode-array
detection. Initial plasma concentration and elimination half-life were 4.9 mg/L
and 5 h, respectively. Several metabolites were also detected, and four of those
were identified by liquid chromatography-electrospray mass spectrometry.
Normetobromuron, bromophenylurea, and bromoacetanilide were detected in plasma,
but only N-methyl bromophenylurea was detected in urine. Bromoacetanilide
probably results from acetylation of the intermediate bromoaniline.
Methemoglobinemia could result from metabolization of metobromuron to
bromoaniline and bromoacetanilide.
PMID- 10774535
TI - Sensitive and selective determination of tetracaine and its metabolite in human
samples by gas chromatography-mass spectrometry.
AB - A sensitive and reliable method was developed for the determination of tetracaine
and its metabolite, p-butylaminobenzoic acid, in human samples. Tetracaine and
the metabolite, effectively extracted using a liquid-liquid extraction procedure
from 0.5 g of sample, were analyzed by gas chromatography-mass spectrometry.
Tetracaine was analyzed without derivatization, and the metabolite was analyzed
after tert-butylolimethylsilyl derivatization. Dibucaine and p
dimethylaminobenzoic acid were used as internal standards for tetracaine and the
metabolite, respectively. The calibration curve for each compound was linear in
the concentration range from 10 to 1,000 ng/0.5 g, and the lower limits of
detection were 10 ng/g for tetracaine and 0.6 ng/g for the metabolite in whole
blood and tissues. The accuracy and precision of the method were evaluated in
whole blood and brain at the concentrations of 50 ng/0.5 g and 500 ng/0.5 g for
tetracaine and 10 ng/0.5 g and 100 ng/0.5 g for the metabolite. The coefficients
of variation ranged from 0.8 to 3.0% for tetracaine and 2.4 to 9.8% for the
metabolite. We used this method to determine tetracaine and its metabolite in
human whole blood and tissues of an autopsied patient who died during spinal
anesthesia induced by tetracaine.
PMID- 10774536
TI - The quantitation of 2-oxo-3-hydroxy lysergic acid diethylamide (O-H-LSD) in human
urine specimens, a metabolite of LSD: comparative analysis using liquid
chromatography-selected ion monitoring mass spectrometry and liquid
chromatography-ion trap mass spectrometry.
AB - This paper compares the potential forensic application of two sensitive and rapid
procedures (liquid chromatography-mass spectrometry and liquid chromatography-ion
trap mass spectrometry) for the detection and quantitation of 2-oxo-3-hydroxy
lysergic acid diethylamide (O-H-LSD) a major LSD metabolite. O-H-LSD calibration
curves for both procedures were linear over the concentration range 0-8,000 pg/mL
with correlation coefficients (r2) greater than 0.99. The observed limit of
detection (LOD) and limit of quantitation (LOQ) for O-H-LSD in both procedures
was 400 pg/mL. Sixty-eight human urine specimens that had previously been found
to contain LSD by gas chromatography-mass spectrometry were reanalyzed by both
procedures for LSD and O-H-LSD. These specimens contained a mean concentration of
O-H-LSD approximately 16 times higher than the LSD concentration. Because both LC
methods produce similar results, either procedure can be readily adapted to O-H
LSD analysis for use in high-volume drug-testing laboratories. In addition, the
possibility of significantly increasing the LSD detection time window by
targeting this major LSD metabolite for analysis may influence other drug-free
workplace programs to test for LSD.
PMID- 10774537
TI - The use of nuclear magnetic resonance spectroscopy in the detection of drug
intoxication.
AB - The use of nuclear magnetic resonance (NMR) spectroscopy as a method for drug
analysis has the advantages of reduced pre-analytical preparation time and the
potential to detect and quantitate drug conjugates and metabolites
simultaneously. NMR was investigated as a method to screen for organic substances
(and metabolites) in 25 patients who presented to the Emergency Department with
clinical indications of a drug overdose. Urine specimens were examined by 1H NMR
spectroscopy at 300 MHz and the results compared with gas chromatography-mass
spectrometry (GC-MS) results. There was a 56% concordance (14 of 25 samples)
between NMR and GC-MS. NMR identified acetaminophen, ibuprofen, aspirin,
valproate, carbamazepine, and pseudoephedrine as parent compounds or metabolites.
For a patient for whom GC-MS results were negative, NMR strongly suggested the
presence of erythromycin. NMR was most successful in identifying analgesics and
antiepileptic drugs (sensitivity 83-100%). In 10 patients, signals from 1,2
propanediol, a common vehicle for some pediatric medications, were observed by
NMR spectroscopy. NMR had 0% sensitivity in identifying tricyclic antidepressants
and antipsychotic drugs. In these samples, GC-MS detected a variety of compounds,
including tricyclic antidepressants and their metabolites and chlorpromazine. In
addition, other substances that had not been disclosed as having been ingested,
such as caffeine, diphenhydramine, and nicotine, were detected by GC-MS. NMR
spectroscopy represents an emerging supplementary analytical technique that is
applicable to a wide range of possible intoxicants and to the evaluation of the
intoxicated patient, particularly when larger amounts of the intoxicant (> 200
mg) are ingested.
PMID- 10774538
TI - Over-the-counter delta5 anabolic steroids 5-androsen-3,17-dione; 5-androsten
3beta, 17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione:
excretion studies in men.
AB - Studies of urinary steroids were performed in males after oral administration of
5-androsten-3,17-dione; 5-androsten-3beta,17beta-diol; dehydroepiandrosterone;
and 19-nor-5-androsten-3,17-dione. 5-Androsten-3,17-dione; 5-androsten
3beta,17beta-diol; and dehydroepiandrosterone amplify most endogenous steroids,
but to a lesser extent than their delta4 analogues do. Especially affected are
androsterone, etiocholanolone, dehydroandrosterone, dehydroepiandrosterone, and
isomeric 5-androstendiols. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol;
and dehydroepiandrosterone elevate the urinary testosterone to epitestosterone
(T/E) ratio by a factor of 2-3 a few hours after administration. This may cause a
positive T/E test (> 6) for individuals with normal T/E ratios higher than 2.
Most of the steroids return to their original concentrations in less than 24 h.
Etiocholanolone and 5beta-androstan-3alpha,17beta-diol remain elevated for
several days. A reduced androsterone to etiocholanolone (A/E) ratio may be an
indication of delta5 steroids abuse. 19-Nor-5-androsten-3,17-dione has a similar
effect, except that all metabolites in urine are 19-nor exogenous steroids.
Identification criteria for 19-nor-5-androsten-3,17-dione may be the same as
nandrolone, that is, detection of 19-norandrosterone and 19-noretiocholanolone.
Specific abundant metabolites of 19-nor-5-androsten-3,17-dione are 19
nordehydroandrosterone and 19-nordehydroepiandrosterone. In the later stages of
excretion, higher concentration of 1 9-noreticholanolone relative to 19
norandrosterone specifically indicates administration of 19-nor delta5 steroids.
PMID- 10774539
TI - Detection of triazolam and its hydroxy metabolites in rat hair by reversed-phase
liquid chromatography with electrospray ionization mass spectrometry.
AB - A sensitive method using reversed-phase liquid chromatography coupled with
electrospray ionization mass spectrometry (LC-ESI-MS) for simultaneous
determination of triazolam (TZ) and its hydroxy metabolites in hair has been
developed. After the addition of deuterium-labeled 1 -hydroxymethyltriazolam (1
HT-d4) as an internal standard, analytes in hair shaft and hair root samples were
extracted with a basic medium, CH2Cl2/MeOH/28% NH4OH (20:80:2), at room
temperature overnight. The chromatographic separation of the analytes was
achieved using a 3-microm micro HPLC column (100 x 2.0-mm i.d.) with a gradient
of acetonitrile in water containing 1% acetic acid as the mobile phase at a flow
rate of 0.15 mL/min. The mass spectrometer was operated in selected-ion
monitoring mode at quasi molecular ions [M+H]+ of TZ and its metabolites. Under
the proposed conditions, the ranges of quantitation of TZ, 1-HT, and 4-HT were
0.1-10 ng/0.2 mL. The method has been applied to determine the hair shaft and
hair root incorporation of TZ and its metabolites into Dark Agouti rats
administered with 3 mg/kg or 6 mg/kg intraperitoneally twice a day for five days.
Judging from the retention behavior by the chromatography and the mass spectra of
the peaks detected, TZ, 1-HT, and 4-HT were incorporated in the hair shaft and
the hair root. The concentration of 4-HT was the highest of all compounds
detected. An unknown substance thought to be 1,4-diHT also appeared in both hair
shaft and hair root samples. This substance was obtained from in vitro metabolic
studies of TZ using rat liver microsome fraction and was accompanied by the other
two metabolites, 1-HT and 4-HT. Structural elucidation was performed with online
high-performance liquid chromatography-MS after acetylation of the substance with
acetic anhydride and pyridine. This is the first report of the detection of the
hydroxy metabolites of TZ in hair. The method has been found to be useful as a
screening procedure of TZ intake in humans.
PMID- 10774540
TI - Tabulation of alcohol content of beer and malt beverages.
AB - We present data from the analysis of the alcohol content of 391 beers and malt
beverages available for sale in the State of Washington. The beverages were
tested by gas chromatography for their alcohol content. Considerable variability
in the alcoholic strength was found, even within the same class. Overall, the
range of concentrations was 2.92% (v/v) to 15.66% (v/v). The alcohol content of
beverages consumed is a critical factor in Widmark or volume-of-distribution-type
calculations used to estimate blood or breath alcohol content from patterns of
alcohol consumption. Using the correct alcohol content for beer, when the brand
is known, can make a significant difference in the reliability of the
calculation, and the data presented here should assist with optimizing the
accuracy of the calculation.
PMID- 10774541
TI - GC-MS identification of sympathomimetic amine drugs in urine: rapid methodology
applicable for emergency clinical toxicology.
AB - A method was developed that permitted rapid identification in urine of the
following sympathomimetic amines: amphetamine, benzphetamine, cathinone,
desmethylsegiline, diethylpropion, ephedrine, fenfluramine, mazindol,
methylenedioxyamphetamine, methylenedioxyethylamphetamine,
methylenedioxymethamphetamine, mescaline, methamphetamine, methcathinone,
methylaminorex, methylphenidate, pemoline, phendimetrazine, phenylepherine,
phentermine, phenylpropanolamine, pseudoephedrine, and selegiline. In addition,
two alpha-phenylethylamine-like monoamine oxidase inhibitors, phenelizine and
tranylcypromine, were studied. Those sympathomimetic amines containing a primary
or secondary amine, a hydrazine, and/or hydroxyl (except mazindol) functional
groups were derivatized effectively using an on-column derivatization technique
that used a reagent consisting of 10% fluoroanhydride in hexane, whereas the
other sympathomimetic amines, including mazindol, were analyzed underivatized.
Three different fluoroanhydrides, trifluoroacetic (TFAA), pentafluoropropionic
(PFPA), and heptafluorobutyric (HFBA), and three different injection-port
temperatures (160, 200, and 260 degrees C) were investigated. Both TFAA and PFPA
gave sympathomimetic amine derivatives with essentially identical retention
times, whereas HFBA gave longer retention times and better separation of
individual compounds. The base fragmentation ion was noted to increase 50 amu
(CF2) for each derivatized sympathomimetic amine as the length of the carbon
fluorine chain increased. Fragmentation ion abundance was maximized at an
injection-port temperature of 260 degrees C, and this enhanced sensitivity
coupled with the better chromatographic resolution of the individual
sympathomimetic amines prompted the selection of HFBA as the derivatizing agent
of choice. Assignments were made for the fragmentation ions produced by each
derivatized drug. The developed method was adapted to analyze urine specimens
that might be encountered in emergency toxicology testing. For identification of
sympathomimetic amines requiring derivatization, 0.1 mL of the patient specimen
had amphetamine-d5 and methamphetamine-d5 added as internal standard followed by
adjustment of pH to 9.3 with borate buffer, extraction with 9:1
chloroform/isopropanol, centrifugation and separation of the organic phase,
addition of 10% methanolic HCI and evaporation under nitrogen, reconstitution
with HFBA reagent, and on-column derivatization during gas chromatographic-mass
spectrometric (GC-MS) analysis. For those sympathomimetic amines not requiring
derivatization, 1.0 mL of urine specimen had diazepam-d5 added as internal
standard followed by the same extraction procedure and reconstitution
accomplished with ethyl acetate. Because precolumn derivatization was eliminated
and only 8 min was required for GC-MS analysis, complete analysis time was
approximately 30 min, making the method suitable for clinical emergency
toxicology purposes.
PMID- 10774542
TI - Using amphetamine isomer ratios to determine the compliance of amphetamine
abusers prescribed dexedrine.
AB - The amphetamine isomer ratios (l-amphetamine/d-amphetamine) in 373 urine
specimens submitted for analysis over a two-year period have been determined
using a chiral derivatizing agent in conjunction with a gas chromatograph fitted
with a nitrogen-specific detector. All of the specimens were collected from known
or suspected amphetamine abusers, some of which were prescribed dexedrine for
maintenance and detoxification. The mean (+/- 1 standard deviation [SD]) l/d
amphetamine isomer ratio for 147 specimens from compliant subjects prescribed
dexedrine was 15.0% (+/- 4.9%). The mean (+/- 1 SD) l/d-amphetamine isomer ratio
from 165 subjects abusing illicit amphetamine was 98.5 (+/- 27.5%). The
calculation of l/d-amphetamine isomer ratios in urine has been found to be a
rapid method for determining the compliance of subjects prescribed dexedrine and
is therefore a useful technique for the continued management of amphetamine
abusers. In addition, 17 specimens of illicit amphetamine powder (assumed to be a
racemic mixture) were submitted to the laboratory for analysis. Using a
combination of gas chromatography with and without chiral derivatization, the
powders were found to have a mean l/d-amphetamine isomer ratio of 89.2% (range
72.2% to 98.3%) and mean purity (w/w) of 21.5% (range 3.4% to 71.0%) relative to
pure dl-amphetamine substance.
PMID- 10774544
TI - Use of hospital discharge data to monitor uterine rupture--Massachusetts, 1990
1997.
AB - Uterine rupture (UR), a potentially life-threatening condition for both mother
and infant, occurs in <0.1% of all pregnant women and <1% of women attempting
vaginal birth after cesarean section (VBAC) (1-4). During 1990-1997, the
proportion of vaginal deliveries among women who had previous cesarean sections
(CS) in Massachusetts increased 50%, from 22.3% to 33.5% (5). Concern about a
corresponding increase in UR prompted the Massachusetts Department of Public
Health and CDC to initiate a state-wide investigation that included an assessment
of the validity and reliability of International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM) (6), codes in hospital discharge
data to identify UR cases. This report summarizes the results of the
investigation, which indicate that ICD-9-CM codes related to UR, designed before
increased concern about UR, lack adequate specificity for UR surveillance and
have not been applied consistently over time.
PMID- 10774543
TI - The application of supercritical fluid extraction to cocaine and its metabolites
in blood and urine.
AB - Supercritical fluid extraction (SFE) is emerging as a valuable analytical
technique for use as an alternative to conventional solid-phase (SPE) and liquid
liquid extraction techniques. It is a relatively new technique based on the use
of supercritical fluids for the isolation of analytes from various matrices and
is attracting great interest because of the increasing need for a simple, rapid,
environmentally friendly, automated, and selective extraction method. A new
method using SFE procedures for the extraction of cocaine and its major
metabolites, benzoylecgonine and ecgonine methyl ester, from whole blood and
urine was developed. This study has shown that cocaine and its metabolites can be
successfully extracted from blood and urine using SFE techniques. Levels measured
using SFE have shown analyte recovery better than 70% for cocaine, better than
40% for benzoylecgonine, and better than 85% for ecognine methyl ester from whole
blood and urine. Good run-to-run reproducibility was observed between each
extraction with limits of detection and quantitation of 1 ng and 10 ng based on
200 microL of blood and urine. A comparison between SPE and developed SFE
techniques was investigated to observe if a correlation existed between the two
methods. Studies proved that a correlation did exist between the two methods for
spiked blood and urine samples with comparative results. This paper details a
procedure for the extraction of cocaine and its metabolites from blood and urine.
PMID- 10774545
TI - Imported dengue--United States, 1997 and 1998.
AB - Dengue is a mosquito-transmitted acute viral disease caused by one of four dengue
virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Dengue is endemic in most
tropical areas of the world and has occurred in U.S. residents returning from
travel to such areas. CDC maintains a laboratory-based passive surveillance
system for imported dengue among U.S. residents. The system relies principally on
reports by clinicians to state health departments, which forward patient
specimens to CDC for diagnostic testing. This report summarizes information about
imported dengue cases among U.S. residents for 1997 and 1998, which indicates
that most persons with a known travel history probably acquired infection in the
Caribbean islands or Asia.
PMID- 10774546
TI - Progress toward poliomyelitis eradication--Democratic Republic of Congo, 1996
1999.
AB - In 1988, the World Health Assembly resolved to eradicate poliomyelitis by
December 31, 2000 (1). Although progress has been extraordinary (2), full
implementation of polio eradication strategies has been delayed in several
countries affected by war. The Democratic Republic of Congo (DRC) has experienced
continual armed conflict since October 1996. As a result, DRC is the last country
in the African Region of the World Health Organization (WHO) to implement
National Immunization Days (NIDs*). DRC is an important global reservoir for wild
poliovirus and shares more than 5580 miles (9000 km) of border with nine
countries; in at least seven of these countries polio is endemic. The large area
of DRC, substantial amount of poverty, weak health-care infrastructure, poor
transportation and communication, and competing demands for resources present
considerable challenges to polio eradication. This report summarizes information
on the existing health-care infrastructure and routine coverage, information from
NIDs carried out in 1999, and results from the recently established surveillance
system for acute flaccid paralysis (AFP).
PMID- 10774547
TI - Public opinion about public health--United States, 1999.
AB - Previous surveys have documented a substantial gap in the public's understanding
and attitudes about public health (1). The Pew Charitable Trusts, a Philadelphia
based philanthropy that supports nonprofit activities in the areas of culture,
education, the environment, health and human services, public policy, and
religion, commissioned two firms, the Mellman Group and Public Opinion
Strategies, to conduct both qualitative and quantitative research in 1999 to
characterize the public's attitudes about public health. In particular, the Pew
Charitable Trusts asked the groups to explore 1) perceptions about public health
in general, including levels of support and importance compared with other
national priorities; 2) opinions about environmental health and its role in
causing disease and promoting health; and 3) opinions about the public health
infrastructure. This report summarizes the results of this survey, which indicate
that the term "public health" is misunderstood, persons are concerned about the
quality of the public health system, increased government spending for public
health is a greater priority than other key national concerns, and that the
public regard environmental factors as important contributors to certain health
problems.
PMID- 10774548
TI - HIV eradication: thinking the unthinkable.
PMID- 10774549
TI - Coreceptor usage and RANTES sensitivity of non-syncytium-inducing HIV-1 isolates
obtained from patients with AIDS.
AB - OBJECTIVES: The biologic phenotype of HIV-1 primary isolates obtained from
approximately 50% of patients who progress to AIDS switches from non-syncytium
inducing (NSI) to syncytium-inducing (SI). We evaluated possible associations
between virus coreceptor usage, sensitivity to inhibition by beta-chemokines, and
disease progression of patients who continue to yield NSI isolates after
developing AIDS. STUDY DESIGN/METHODS: Sequential virus isolates were analyzed
for biologic phenotype using the MT-2 cell assay, for sensitivity to beta
chemokines using RANTES inhibition, and for coreceptor usage using U87.CD4 and
GHOST.CD4 cells expressing different chemokine/orphan receptors or donor
peripheral blood mononuclear cells (PBMC) defective in CCR5 expression. In
addition, the env V3 region was sequenced and the length of the V2 region
determined. RESULTS: All NSI isolates, regardless of patient status at time of
isolation, were dependent on CCR5 expression for cell entry. Furthermore, there
was no indication of broadened coreceptor usage of NSI isolates obtained from
persons with late-stage AIDS. A majority of NSI isolates remained RANTES
sensitive; however, virus variants with reduced sensitivity were observed. The V2
lengths and the V3 sequences exhibited no or minor changes at analysis of
sequential NSI isolates. CONCLUSIONS: Our data suggest that NSI isolates obtained
from AIDS patients remain CCR5 dependent (ie, R5) and, in many cases, also remain
sensitive to RANTES inhibition. However, virus variants with decreased
sensitivity to RANTES inhibition may evolve during disease progression, not only
as a result of a switch from NSI to SI but also in patients who develop AIDS
while continuing to maintain R5 isolates.
PMID- 10774550
TI - Molecular epidemiology of vertical human immunodeficiency virus type 1
transmission in Greece: evidence of non-B subtypes.
AB - OBJECTIVES: To investigate the subtype classification of the circulating virus
strains among human immunodeficiency virus type 1 (HIV-1)-infected children in
Greece. STUDY DESIGN/METHODS: Since the beginning of the acquired
immunodeficiency syndrome (AIDS) epidemic in Greece in 1982, 23 children have
been reported to be vertically infected with HIV-1. Blood samples were available
for 19 of these children, and the C2-C4 env region was successfully amplified by
nested polymerase chain reaction (PCR) for 16 subjects. HIV-1 subtype was
established by the heteroduplex mobility assay (HMA) in 16 subjects and confirmed
by DNA sequencing and phylogenetic analysis in 8 subjects. RESULTS: Most subjects
(9; 56%) fell into subtype B. However, a substantial proportion (44%) were
classified as subtypes A (3; 19%), C (1; 6%), D (1; 6%), and I (2; 12%).
According to epidemiologic information, 5 of 7 children infected with non-B HIV-1
subtypes were born to Greek parents. CONCLUSION: These findings clearly suggest
that non-B strains have been introduced into Greece, providing evidence that HIV
epidemic in this country will probably change profile over time. In addition,
subtype I was identified in 2 HIV-1-infected children, both of whom were born to
Greek parents.
PMID- 10774551
TI - Different outcomes in patients achieving complete or partial viral load
suppression on antiretroviral therapy.
AB - BACKGROUND: Potent combination antiretroviral therapy can reduce HIV plasma viral
load (VL) to levels below the detection limit for as long as 2 years or more. A
VL <500 HIV RNA copies/mL was until recently considered a reasonable therapeutic
goal. However, lower levels seem necessary if VL rebounds and development of drug
resistance are to be avoided. PATIENTS AND METHODS: The clinical and virologic
outcome at 1 year were prospectively examined in a group of 100 patients who
began a triple combination antiretroviral therapy regimen consisting of stavudine
(d4T), lamivudine (3TC), and indinavir (IDV). A modified ultrasensitive VL test
with a detection limit of 40 copies/mL and a point mutation nested polymerase
chain reaction (PCR) assay for detecting the codon 184 mutation conferring 3TC
resistance were used for testing samples collected longitudinally from these
individuals. RESULTS: Overall, VL values <40 copies/mL were reached in 45% and
32% of patients at nadir and at 12 months, respectively. More than half (24 of 45
persons) who achieved a level <40 copies/mL at nadir remained with undetectable
VL at 1 year, whereas this occurred in only one fourth (7 of 28 persons) of those
having levels of 40 to 500 copies/mL (P < .05). However, rebounds in VL to >500
copies/mL at 1 year were seen at similar rates (26.6% and 25%, respectively) in
persons achieving either complete (<40 copies/mL) or partial (40-500 copies/mL)
VL suppression at nadir. In contrast, the codon 184 mutation emerged more
frequently at 1 year in patients whose VL remained between 40 and 500 copies/mL
at nadir than in those who reached a level <40 copies/mL (30.7% versus 0%; P <
.05). CONCLUSION: Plasma VL at nadir after beginning highly active antiretroviral
therapy (HAART) predicts the 1-year outcome. The achievement of levels of viremia
<40 copies/mL are desirable during antiretroviral therapy if prolonged benefit is
to be obtained. Because more than two thirds of persons with residual viremia do
not show drug resistance, intensification strategies should be investigated for
those patients with a good virologic response but without complete suppression
during the first 6 months on HAART.
PMID- 10774552
TI - A novel JC virus variant found in the Highlands of Papua New Guinea has a 21-base
pair deletion in the agnoprotein gene.
AB - OBJECTIVES: This paper describes a unique JC virus (JCV) variant recovered from
the Highlands of Papua New Guinea that contains an inframe 21-bp deletion in the
agnoprotein gene. We characterize the mutation and suggest possible roles for the
deletion in JCV evolution. STUDY DESIGN/METHODS: JCV DNA was extracted from urine
and polymerase chain reaction (PCR) amplified using whole genome primers. PCR
products were cloned, and multiple clones were sequenced. The JCV agnogene was
PCR amplified to verify the presence of the agnogene deletion. RESULTS: This
mutation creates a 21-bp deletion near the 3' end, which alters the predicted
secondary structure of the messenger RNA and changes local codon usage at the 3'
end of the agnogene. Protein secondary structure predictions suggest the deleted
portion of the agnoprotein may be a flexible surface feature. CONCLUSIONS: We
describe the first stable coding region deletion in JCV that presumably signifies
a single evolutionary event that led to the split from other Highlands viral
groups and occurred well after the human expansions that led to the peopling of
the Southwest Pacific.
PMID- 10774553
TI - Chromosomal latency and expression at map unit 96 of a wild-type plus adeno
associated virus (AAV)/Neo vector and identification of p81, a new AAV
transcriptional promoter.
AB - OBJECTIVE: Human adeno-associated virus (AAV) is ubiquitous and known to
establish latency by chromosomal integration. We have constructed a wild-type
plus AAV vector, ins96-0.9Neo, containing the neomycin resistance gene open
reading frame (Neo ORF) of 960 bases in length at map unit 96 of the virus. Ins96
0.9Neo was constructed in an unconventional manner in that the Neo ORF lacked a
dedicated heterologous promoter. In this study, this wild-type plus AAV vector
was to used to test AAV's packaging capacity and ability for chromosome 19 AAVS1
integration. However, when it was discovered that ins96-0.9Neo also transduced
cells to G418 resistance, we also investigated the mechanism of Neo ORF
expression in this vector. STUDY DESIGN/METHODS: We investigated the ability of
ins96-0.9Neo to produce virus at high titers and to retain the Neo sequences by
Southern blot analysis. The ability of ins96 0.9Neo virus to transduce the Neo
gene into cells was analyzed by colony formation under G418 selection, and the
ability of ins96-0.9Neo to latently infect cells, including the AAVS1 region of
chromosome 19, was investigated by a series of polymerase chain reaction (PCR)
amplifications. Finally, the RNA expression of the Neo gene at map unit 96 was
investigated by reverse transcriptase primer extension (RTPE) analyses with two
different primers and by S1 nuclease protection. RESULTS: High titers of the
ins96-0.9Neo virus could be generated (10(9) infectious units [IU]/mL without
concentration), the Neo gene was retained in the encapsidated viral genome,
infection by this virus resulted in G418 resistance, and significant integration
was taking place within the AAVS1 sequences of human chromosome 19 on
transduction. Analysis of mRNA by RTPE using both primers and by the S1 nuclease
protection assay mapped the 5' end of the Neo transcripts to approximately 700
bases upstream of the Neo ATG at map unit 81 (nt 3793-3813), thus identifying a
new AAV promoter. CONCLUSIONS: These data demonstrate that ins96-0.9Neo will be
useful for studying wild-type AAV integration and suggest that such wild-type
plus recombinant AAV vectors may be useful for human gene therapy. The advantages
of using such wild-type plus AAV vectors over defective AAV vectors include the
ease in production of recombinant virus and the ability for site-specific
integration into chromosome 19. This study also uncovered a previously unknown
AAV promoter, p81. This finding suggests that the as yet uncharacterized ORF (nt
3922-4388) located just downstream of this promoter is likely an expressed gene.
Furthermore, these data support our earlier findings that the AAV virion can
package >900 bases more than can the wild-type.
PMID- 10774554
TI - Coxsackievirus B3-induced chronic myocarditis in outbred NMRI mice.
AB - OBJECTIVES: The pathogenesis of coxsackievirus B3 (CVB3)-induced myocarditis was
investigated in adult Han:NMRI mice. The outbred model, in comparison with inbred
models, represents better the natural variable susceptibility of the human
population. STUDY DESIGN/METHODS: We analyzed the replicating virus titer, the
antibody response in the acute and chronic phase of disease, the histology of
myocardial injury, and the persistence of viral RNA. RESULTS: NMRI mice infected
with 5000 plaque-forming units (PFU) of the CVB3 variant "P"D, a lytic variant to
human fibroblast lines, showed a peak of virus replication at day 14 and
developed a severe acute myocarditis. The chronic myocarditis was characterized
by progressive fibrosis, small foci of infiltrates, persistent viral RNA in the
heart, and detectable anti-CVB3 IgG production and neutralizing antibody response
up to day 98 postinfection. CONCLUSIONS: CVB3"P"D is able to induce chronic
myocarditis in NMRI mice. This model provides a method for examining and proving
the mechanisms of myocardial pathogenesis and of developing therapeutic
strategies.
PMID- 10774555
TI - Free energy and information contents of conformons in proteins and DNA.
AB - Sequence-specific conformational strains (SSCS) of biopolymers that carry free
energy and genetic information have been called conformons, a term coined
independently by two groups over two and a half decades ago [Green, D.E., Ji, S.,
1972. The electromechanochemical model of mitochondrial structure and function.
In: Schultz, J., Cameron, B.F. (Eds.), Molecular Basis of Electron Transport.
Academic Press, New York, pp. 1-44; Volkenstein, M.V., 1972. The Conformon. J.
Theor. Biol. 34, 193-195]. Conformons provide the molecular mechanisms necessary
and sufficient to account for all biological processes in the living cell on the
molecular level in principle--including the origin of life, enzymic catalysis,
control of gene expression, oxidative phosphorylation, active transport, and
muscle contraction. A clear example of SSCS is provided by SIDD (strain-induced
duplex destabilization) in DNA recently reported by Benham [Benham, C.J., 1996a.
Duplex destabilization in superhelical DNA is predicted to occur at specific
transcriptional regulatory regions. J. Mol. Biol. 255, 425-434; Benham, C.J.,
1996b. Computation of DNA structural variability--a new predictor of DNA
regulatory regions. CABIOS 12(5), 375-381]. Experimental as well as theoretical
evidence indicates that conformons in proteins carry 8-16 kcal/mol of free energy
and 40-200 bits of information, while those in DNA contain 500-2500 kcal/mol of
free energy and 200-600 bits of information. The similarities and differences
between conformons and solitons have been analyzed on the basis of the
generalized Franck-Condon principle [Ji, S., 1974a. A general theory of ATP
synthesis and utilization. Ann. N.Y. Acad. Sci. 227, 211-226; Ji, S., 1974b.
Energy and negentropy in enzymic catalysis. Ann. N.Y. Acad. Sci. 227, 419-437].
To illustrate a practical application, the conformon theory was applied to the
molecular-clamp model of DNA gyrase proposed by Berger and Wang [Berger, J.M.,
Wang, J.C., 1996. Recent developments in DNA topoisomerases II structure and
mechanism. Curr. Opin. Struct. Biol. 6(1), 84-90], leading to the proposal of an
eight-step molecular mechanism for the action of the enzyme. Finally, a set of
experimentally testable predictions has been formulated on the basis of the
conformon theory.
PMID- 10774556
TI - Color sensitive retina based on bacteriorhodopsin.
AB - Bacteriorhodopsin (BR), a membrane protein of a microorganism Halobacterium
salinarium has been studied since the 80's as a potential material for
information technology. The information processing applications of BR employ
either photochromic or photoelectric properties of the protein. In this study we
discuss about design principles and describe our study of the use of
bacteriorhodopsin as a sensor material for a color sensitive artificial retina.
This retina includes low-level processing of input information. The design of a
color sensitive matrix element, the self-organizing color adaptation algorithm
and a system model for the retina are presented.
PMID- 10774557
TI - Interrelated modification of excitatory and inhibitory synapses in three-layer
olivary-cerebellar neural network.
AB - The model of three-layer olivary-cerebellar neural network with modifiable
excitatory and inhibitory connections between diverse elements is suggested. The
same Hebbian modification rules are proposed for Purkinje cells, granule (input)
cells, and deep cerebellar nuclei (output) cells. The inverse calcium-dependent
modification rules for these cells and hippocampal/neocortical neurones or Golgi
cells are conceivably the result of the involvement of cGMP and cAMP in
postsynaptic processes. The sign of simultaneous modification of excitatory and
inhibitory inputs to a cell is opposite and determined by the variations in pre-
and/or postsynaptic cell activity. Modification of excitatory transmission
between parallel fibers and Purkinje cells, mossy fibers and granule cells, and
mossy fibers and deep cerebellar nuclei cells essentially depends on inhibition
effected by stellate/basket cells, Golgi cells and Purkinje cells, respectively.
The character of interrelated modifications of diverse synapses in all three
layers of the network is influenced by olivary cell activity. In the absence
(presence) of a signal from inferior olive, the long-term potentiation
(depression) in the efficacy of a synapse between input mossy fiber and output
cell can be induced. The results of the suggested model are in accordance with
known experimental data.
PMID- 10774558
TI - Use of a windows program for simulation of the progress curves of reactants and
intermediates involved in enzyme-catalyzed reactions.
AB - A program that performs simulation of the kinetics of enzyme-catalyzed reactions
with up to 32 species is described. The program is written in C++ for MS Windows
95/98/NT and uses a simple text file to define the kinetic model. The use of the
program is illustrated with some examples. WES is available free of charge on
request from the authors (e-mail: fgarcia@iele-ab.uclm.es).
PMID- 10774559
TI - Towards a closed description of observation processes.
AB - A closed description of observation processes must necessarily include the
observer, too. In order to find a basis for such a unified description, an
operator algebra is developed which enables a formal description of at least a
significant majority of cognitive processes. It is found that this operator
algebra, which is a noncommutative semiring of a type already known in
literature, has astonishing similarities with the usual operator algebras in
quantum theory. Combined with a method for the formal treatment of perspective
notions, the representation scheme proposed here may open a chance for a unified
description of a process itself together with the relevant cognitive processes on
the observer's side. By the description of parallel-processing systems on the
same basis an operational definition of 'internal time' becomes possible.
PMID- 10774560
TI - Breast cancer in elderly women (> or = 70 years): which treatment?
AB - Breast cancer is a disease that affects women >70 years of age much more
frequently than other age groups. Epidemiologic data show that more than 40% of
breast cancers occur in the elderly. The optimal primary treatment for elderly
patients with breast cancer is controversial and ranges from tamoxifen as sole
therapy to surgery. Despite the high prevalence of the disease, the elderly have
been excluded from clinical trials mainly for the presence of concurrent medical
conditions that adversely affect treatment strategies. Since life expectancy
continues to increase in western countries, an appropriate treatment that
respects quality of life needs to be determined for the elderly age group. In the
light of randomised and retrospective studies carried out to date, limited
surgery without axillary dissection plus adjuvant tamoxifen seems to achieve,
mainly for elderly patients with early stage breast cancer, a local-regional
control rate comparable to that obtained with more aggressive therapeutic
strategies. The results of ongoing prospective clinical trials will show whether
or not conservative surgery without axillary clearance and tamoxifen may be
routinely used for elderly patients with early breast cancer.
PMID- 10774561
TI - Sentinel lymph node mapping and biopsy for breast cancer: a review of the
literature relative to 4791 procedures.
AB - The status of axillary nodes is the most important prognostic factor in breast
cancer to select patient subgroups for adjuvant chemotherapy; the current
standard of care for surgical management of invasive breast cancer is complete
removal of the tumor by either mastectomy or lumpectomy followed by axillary
lymph node dissection (ALND). The recent introduction of intraoperative lymphatic
mapping and sentinel lymph node biopsy (SLND) represents a major new opportunity
for appropriate and less invasive surgical management of many tumors. There is an
almost uniformly enthusiasm concerning the potential of this technique in breast
carcinoma management, shown by published data. A peculiar attention to the so
called "sentinel node debate" in breast cancer surgery is a constant in the last
years issues of the major medical journals. Even patients have become more aware
about medical enthusiasm and their request of concise information on the topic
and the possibilities of this approach is an increasing reality in medical
practice. The aim of this paper is to review recent literature to offer an
overview about the main controversial methodological aspects and a wide analysis
of reported results. The most significative international literature papers from
Medline were retrieved from 1993 to September 1999, and 4782 procedures were
analysed. This extensive review of the literature has confirmed accuracy,
feasibility and reliability of the SN detecting technique in axillary mapping.
Provided a good proficiency in SN localisation and pathological evaluation, human
resources and efforts should be mainly focused on its clinical validation as an
alternative to ALND instead of on further phase I-lI clinical studies.
PMID- 10774562
TI - Risk of basal and squamous cell carcinomas of the skin in Sion, Switzerland: a
case-control study.
AB - AIMS AND BACKGROUND: Non-melanocytic skin cancers are the most common cancers in
white populations. Studies on populations of Anglo-Saxon and Mediterranean
origins highlighted different patterns of risk of basal-cell carcinoma and
squamous-cell carcinoma in relation to sunlight exposure, skin characteristics
and phenotype susceptibility. In Sion, and in Switzerland as a whole, the high
incidence suggests the possible presence of additional risk factors or of a
different pattern of exposure to solar radiation as well as different composition
of pigmentary traits and skin sensitivity to sun. METHODS AND STUDY DESIGN: We
conducted a case-control study of 146 cases (73% of eligible cases) and 144
controls (81% of eligible subjects) to further evaluate the relationship between
nonmelanocytic skin cancer and risk factors in the Sion population. Interviews
were conducted by trained interviewers with a standardized questionnaire.
RESULTS: Pigmentary characteristics such as blonde and red hair as well as
tendency to sunburn without tanning and number of sunburns showed a statistically
significant and independent risk increase in basal-cell carcinoma. Sun exposure
during recreational activities (outdoor sports) showed a risk increase in basal
cell carcinoma with borderline statistical significance. Analysis of squamous
cell carcinoma risk was limited by the small number of cases, but it was
positively associated with lifetime exposure to sun during outdoor work and with
skin characteristics. CONCLUSIONS: Results confirmed previous suggestions of a
different mechanism leading to malignant transformation of target cells from the
basal and squamous epidermal layers, mediated by different phenotypes, and
conditioning the ability to develop an effectively protective tan.
PMID- 10774563
TI - Mortality of parents of children with cancer: a population-based study in Turin,
Italy.
AB - AIMS AND BACKGROUND: A cohort study was conducted in order to measure cause
specific mortality among parents of children recorded in the Childhood Cancer
Registry of Piedmont. It is the first study carried out on the subject in
southern Europe. METHODS AND STUDY DESIGN: The study comprised the 740 children
resident in Turin and in whom a cancer had been diagnosed in the period 1967
1991. Nominal data were obtained for 723 fathers and 733 mothers. At the end of
the follow-up in 1995, 645 fathers were alive, 68 dead and 10 untraceable.
Corresponding figures for mothers were 700, 28 and 5. Cause of death was known
for 91 of 96 parents. RESULTS: The period of observation of parents started on
the birth of the index child, however mortality analyses were restricted to the
period after 1965 because of limited availability of local reference rates. Total
mortality was lower than expected among fathers (66 observed deaths vs 88.2
expected, P <0.05) and mothers (28 vs 31.4). Fathers showed deficits (not
statistically significant) of lung neoplasms (4 vs 9.9), cardiovascular diseases
(18 vs 27.1) and hepatic cirrhosis (2 vs 6.6). No statistically significant
variations in mortality were observed with time from diagnosis or according to
life status of the children. No cancer deaths occurred among the mothers of
sarcoma cases whereas 1.9 were expected. CONCLUSIONS: The data do not indicate
any increase in mortality from cancer or other causes end, on the contrary, show
a reduction in mortality which was more evident for the causes related to life
style.
PMID- 10774564
TI - A computerized database for head and neck cancer registry.
AB - AIMS: Over the last years, the management of patients with head and neck cancer
has become extremely complex, and the knowledge and information needed to care
for a patient can no longer be trusted to the memory or manual systems. Recent
advances in data processing technology offer the potential for creating ideal
instruments to organize, store and analyze such information. METHODS: We
developed a computerized database management system (H&N-CDMS) which fulfils the
following requisites: easy to use even by operators not expert in informatics;
minimum possibility of insertion of ambiguous data; use for clinical and research
purposes; can be interconnected in a network of similar database operating in
other centers; can be expanded to image processing. CONCLUSIONS: The
configuration of the system is described and its main characteristics are
discussed: data entry and coding facilities, data accuracy and standardization,
security and anonymity, data retrieval and analysis. H&H-CDMS is a user-friendly
tool for head and neck cancer data management in clinical and research
environments.
PMID- 10774565
TI - The concentrations of five tumor markers in both BAL fractions in lung cancer
patients in relation to cigarette smoking.
AB - BACKGROUND: Lung cancer is the leading cause of death from cancer. Tobacco is
related to the development of this type of tumor due to genetic alterations and
to the secretion of certain biological markers. Bronchogenic carcinomas secrete a
series of biological substances known as tumor markers. Some of these markers,
such as carcinoembryonic antigen, neuron-specific enolase, tissue polypeptide
antigen (TPA), tissue polypeptide-specific antigen (TPS) and CYFRA 21.1, possess
clear clinical value when analyzed in bronchoalveolar lavage (BAL) of patients
with lung malignancies, particularly when they are analyzed in the two BAL
fractions, bronchial (BF) and alveolar (AF), being more increased in the BF. For
this reason, we intend to demonstrate that smokers with cancer secrete more
biological substances in the BF and that the concentrations of these markers are
higher in the BAL of smokers than in that of non-smokers. METHODS: The five
aforementioned tumor markers were studied in the two BAL fractions of 52 lung
cancer patients (46 smokers and 6 non-smokers). We performed BAL using 150 ml of
0.9% saline solution divided in three aliquots of 50 ml. The fluid obtained from
the first 50 ml was the BF. The liquid from the other two aliquots was the AF.
The five tumor marker concentrations were calculated in accord with the
indications of the laboratory. RESULTS: The TPA and TPS levels in the BAL of lung
cancer patients were more increased in the BF than in the AF, even when the
patients were divided into smokers and non-smokers. When we compared smokers with
non-smokers, the smokers had higher levels of TPS in the BF and of TPA in the AF.
CONCLUSIONS: Thus, we believe that the cellular alterations produced by tobacco
are responsible for the secretion of these tumor markers.
PMID- 10774566
TI - Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant
chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or
intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic
tumor response.
AB - AIMS AND BACKGROUND: From 1986 to 1989, a study for the treatment of
nonmetastatic osteosarcoma of the extremity (IOR/OS-2) was carried out at the
Rizzoli Institute. The cumulative dose of doxorubicin delivered was 480 mg/m2,
and severe heart failure developed in 5 (3%) of the 164 treated patients. The
specific aim of the subsequent study was to assess the efficacy of a protocol,
similar to IOR/OS-2, but with a reduced cumulative dose of doxorubicin (390
mg/m2). Additional aims were to assess the role of the route of infusion
(intraarterial or intravenous) of cisplatin on histologic response of the primary
tumor and the use of ifosfamide as salvage chemotherapy in poor responders.
METHODS: The new chemotherapy regimen (IOR/OS-3) was comprised of a preoperative
phase with methotrexate (10 g/m2), cisplatin (120 mg/m2 intraarterially or
intravenously), and doxorubicin (60 mg/m2). After surgery, the same drugs were
administered, with the addition of ifosfamide (10 g/m2) in patients who had a
poor histologic response to primary chemotherapy. RESULTS: Ninety-five patients
entered the study. The rate of good histologic response was 64% with
intraarterial cisplatin and 43% with intravenous cisplatin (P = 0.05). The 8-year
event-free survival and overall survival were 54% and 61%, respectively, with no
significant difference according to the histologic response. No cases of clinical
doxorubicin-induced cardiopathy were recorded. Event-free and overall survival
did not significantly differ from those achieved with IOR/OS-2 (8-year disease
free and overall survival, respectively 63% and 72%). CONCLUSIONS: The reduction
in the doxorubicin cumulative dose avoided episodes of cardiotoxicity, without
consequences on the efficacy of treatment. The addition of ifosfamide was an
effective "salvage" therapy for poor responders. A better histologic response
with intraarterial cisplatin was observed, but owing to the availability of an
effective salvage therapy for poor responders, the advantages in terms of
histologic response did not compensate for the cost and discomfort for the
patients of this modality of infusion of cisplatin.
PMID- 10774567
TI - Concurrent modulation of 5-fluorouracil with methotrexate and L-leucovorin: an
effective and moderately toxic regimen for the treatment of advanced colorectal
carcinoma. A multicenter phase II study of the Southern Italy Cooperative
Oncology Group.
AB - AIMS AND BACKGROUND: Methotrexate (MTX) and leucovorin (LV) can enhance the
cytotoxicity of 5-fluorouracil (5FU) by modifying its metabolic pathway inside
target cells. Some preclinical studies and clinical trials have suggested that
the concurrent or sequential double modulation of 5FU by means of MTX and LV may
give a higher activity than single biochemical modulations. The purpose of our
phase II study was to assess the activity and toxicity of a biweekly regimen
including MTX, levo-LV and 5FU in colorectal cancer patients. METHODS: From July
1994 to May 1997, 100 consecutive patients affected by advanced or metastatic
colorectal carcinoma were given MTX, 750 mg/m2 iv (2-h infusion) on day 1, and
levo-LV, 250 mg/m2 iv (2-h infusion) followed by 5FU, 800 mg/m2 iv bolus on day
2, every two weeks. Patients were treated until complete response or progressive
disease was documented, or for a maximum of 16 courses. RESULTS: Among 97
eligible patients, 5 complete and 25 partial responses were obtained, giving an
overall response rate of 31% (95% exact confidence limits, 22-41%). Response rate
was significantly higher in patients with a good (ECOG scale 0) than with a poor
(ECOG scale 1 or 2) performance status (40% versus 17%, P <0.02). Median time to
treatment failure was 27 weeks, median survival time was 63 (95% confidence
limits, 54-71) weeks, and 2- and 3-year probability of survival were 34% and 12%,
respectively. Performance status was the only pretreatment characteristic
significantly affecting the outcome of patients. Indeed, median survival time was
94 weeks for patients with a performance status = 0 and 37 weeks for patients
with a performance status > or = 1 (P<0.05). Toxicity of the treatment was low
and manageable; grade 3 to 4 leukopenia affected 8% of patients, whereas grade 3
diarrhea and mucositis occurred in 5% and 4%, respectively. CONCLUSIONS: The
double biochemical modulation of 5FU by MTX and levo-LV is at least as effective
as, and probably more effective than, the single modulation by MTX or by LV. It
may therefore represent a therapeutic option for the palliative treatment of
patients with advanced colorectal carcinoma.
PMID- 10774568
TI - Intrahepatic chemotherapy with floxuridine, leucovorin and dexamethasone in
continuous infusion and mitomycin-C bolus in unresectable hepatic metastases from
colorectal cancer: a phase II study.
AB - BACKGROUND: Intrahepatic continuous infusion FUDR induces a 50% response rate in
patients with hepatic metastases from colorectal cancer. Lower rates have been
observed in pretreated patients. The combination of floxuridine plus leucovorin
has obtained over 70% responses, with high hepatic toxicity. The use of
dexamethasone can decrease hepatic toxicity. A randomized study reported an
increase in response rate and a decrease in hepatic toxicity in a group of
patients treated with floxuridine plus dexamethasone compared to a group
receiving only floxuridine. Moreover, the combination of mitomycin C, carmustine
and floxuridine is also effective in pretreated patients. METHODS: On such
premises, since July 1993 we have treated 39 patients affected by unresectable
hepatic metastases from colon carcinoma (26 patients) and rectal carcinoma (13
patients) with the combination continuous infusion of floxuridine (0.20 mg/kg per
day) + leucovorin (7.5 mg/m2/day) + dexamethasone (20 mg on days 1 to 14) and
bolus mitomycin C (10 mg/m2 on day 1) via the hepatic artery. Cycles were
administered every four weeks. There were as 28 males and 11 females, with a
median age of 64 years (range, 39-75) and a median PS = 0. Twenty-two patients
were pretreated with systemic chemotherapy including 5-fluorouracil plus
leucovorin. Total number of cycles was 189, with a median of 6 cycles per patient
(range, 1-12). RESULTS: Of 39 patients 37 were assessable for response (2
patients were not assessable because they stopped chemotherapy for occlusion of
the catheter after the first cycle). There were 3 complete responses (1 in a
naive patient and 2 in pretreated patients), 16 partial responses (11 in
pretreated patients and 5 in chemonaive patients), 4 minor responses, 4 stable
disease and 10 progressive disease. The overall response rate was 51.3% (95 Cl,
51.3-86.7%). Median time to progression was 6 months (range, 1-34+). Overall
survival was 18 months (range, 1-34+). Of 39 patients, 36 were assessable for
toxicity (WHO) (3 patients died after the first cycle for progression of
disease): diarrhea and nausea-vomiting grade 3-4 occurred respectively in 15
(41%) and 3 patients (8%); hepatic toxicity was mild. CONCLUSIONS: The treatment
we used showed an elevated activity in liver metastases from colorectal cancer
even in patients pretreated and resistant to systemic chemotherapy, although
toxicity grade 3-4 diarrhea occurred in approximately 40% of the patients.
PMID- 10774569
TI - Mitoxantrone, 5-fluorouracil and low-dose leucovorin in doxorubicin-resistant
advanced breast cancer patients: a phase II study.
AB - AIM: Twenty-two anthracycline-resistant advanced breast cancer patients were
entered from June 1995 till November 1997 in a phase II study to assess the
activity and tolerability of second-line chemotherapy consisting of mitoxantrone,
5-fluorouracil and low-dose leucovorin. STUDY DESIGN: Patients were eligible if
they failed to respond to doxorubicin-containing chemotherapy, given as first
line chemotherapy for metastatic disease. Treatment consisted of mitoxantrone, 12
mg/m2 iv infusion on day 1, and leucovorin, 50 mg iv 1 hr before 5-fluorouracil,
350 mg/m2 iv infusion on days 1-3, every three weeks. RESULTS: Nineteen patients
were eligible for response, 2 refused further therapy after 2 cycles, and 1 was
excluded because grade 3 myelotoxicity developed during the first cycle. Partial
remission of 15 months duration occurred in 1 patient, in 7/19 women disease
remained stable with a median duration of 11 months (range, 5-24), and 11/19
patients experienced progressive disease. Median time to disease progression was
2 months (range, 0-17), and median survival was 8 months (range, 0-24). Toxicity
was generally mild and acceptable. One patient was excluded because of grade 3
granulocytopenia and thrombocytopenia, and one due to cardiotoxicity assessed by
the drop of left ventricular ejection fraction to more than 20% below the initial
value. CONCLUSIONS: In spite of the very low objective response rate, almost one
fourth of our anthracycline-resistant patients achieved a disease stabilization
of 27 weeks duration during mitoxantrone-based second-line chemotherapy. Hence,
mitoxantrone in combination with 5-fluorouracil, especially continuous infusion,
should be further investigated in this setting, particularly if new and expensive
drugs, considered the most active, are not readily available.
PMID- 10774570
TI - Neoadjuvant chemotherapy in locally advanced breast cancer: a preliminary report.
Turkish Oncology Study Group.
AB - AIMS AND BACKGROUND: A pilot study of neoadjuvant chemotherapy with
cyclophosphamide-epirubicin-5-fluorouracil (FEC) was performed on 85 patients
with locally advanced breast cancer. METHODS AND STUDY DESIGN: Patients received
four cycles of neoadjuvant chemotherapy followed by surgery, radiotherapy and a
treatment with cyclophosphamide-methotrexate-5-fluorouracil for three cycles.
RESULTS: Major clinical response was obtained in 76 (89%) patients. Complete
response was documented in 14 (17%) patients at pathologic examination of
surgical specimen. Grade 1-2 nausea and vomiting was the most common (77%) side
effect. Grade 2-3 alopecia was 66%. Grade 2-3 neutropenia occurred in 16% of
patients. None of the patients developed febrile neutropenia. Sinus tachycardia
was observed only in one patient. Three patients had a more than 10% decrease in
the left ventricular ejection fraction without any clinical signs. Nine patients
had progressive or stable disease and 4 did not undergo surgery or receive
radiation therapy; thus 13 were excluded from survival analysis. After a median
followup of 31 months (range, 15-41), disease-free survival and overall survival
were 20 (range, 13-32) and 23 months (range, 17-32). CONCLUSIONS: The FEC
combination is safe and effective for a neoadjuvant setting in locally advanced
breast cancer. A longer follow-up is necessary for the end point results.
PMID- 10774571
TI - Subclinical ductal carcinoma in situ of the breast: treatment with conservative
surgery and radiotherapy.
AB - AIMS AND BACKGROUND: In spite of the fact that ductal carcinoma in situ (DCIS) of
the breast is a frequently encountered clinical problem, there is no consensus
about the optimal treatment of clinically occult (i.e., mammographic presentation
only) DCIS. Interest in breast conservation therapy has recently increased. Few
data are available in Italy on the conservative treatment with surgery and
adjuvant postoperative radiotherapy. METHODS: A retrospective multi-institutional
study was performed in 15 Radiation Oncology Departments in northern Italy
involving 112 women with subclinical DCIS of the breast treated between 1982 and
1993. Age of the patients ranged between 32 and 72 years (median, 50 years). All
of them underwent conservative surgery: quadrantectomy in 89, tumorectomy in 11,
and wide excision in 12 cases. The most common histologic subtype was
comedocarcinoma (37%). The median pathologic size was 10 mm (range 1 to 55 mm).
Axillary dissection was performed in 83 cases: all the patients were node
negative. All the patients received adjunctive radiation therapy with 60Co units
(77%) or 6 MV linear accelerators (23%) for a median total dose to the entire
breast of 50 Gy (mean, 49.48 Gy; range, 45-60 Gy). Seventy-six cases (68%)
received a boost to the tumor bed at a dose of 8-20 Gy (median 10 Gy) for a
minimum tumor dose of 58 Gy. RESULTS: At a median follow-up of 66 months, 8 local
recurrences were observed, 4 intraductal and 4 invasive. All recurrent patients
had a salvage mastectomy and are alive and free of disease at this writing. The
10-year actuarial overall, cause-specific, and recurrence-free survival was of
98.8%, 100%, and 91%, respectively. CONCLUSIONS: The retrospective multicentric
study, with a local control rate of more than 90% at 10 years with 100% cause
specific survival, showed that conservative surgery and adjuvant radiation
therapy is a safe and efficacious treatment for patients with occult, non
palpable DCIS.
PMID- 10774572
TI - Endocrinological study of the dopaminergic regulation of prolactin release in
metastatic breast cancer.
AB - AIMS AND BACKGROUND: Prolactin (PRL) may be a growth factor for breast cancer.
Abnormally high levels of PRL have been proven to be associated with a poor
prognosis in metastatic breast cancer. However, most studies have been limited to
the evaluation of basal levels of PRL rather than its response to the classical
endocrine dynamic tests. This study was performed to analyse the dynamic
secretion of PRL under stimulatory and inhibitory tests in metastatic breast
cancer. METHODS: The study included 10 untreated metastatic breast cancer women,
who were evaluated after the classical stimulatory and inhibitory tests for PRL
secretion with the antidopaminergic agent Metoclopramide (10 mg iv as a bolus)
and with L-dopa, respectively. Serum levels of PRL were measured by RIA before
and at subsequent intervals after drug administration. PRL levels were considered
to be elevated when they were higher than 25 ng/ml. RESULTS: Abnormally high
basal levels of PRL were seen in 6/10 patients. L-dopa was unable to inhibit PRL
secretion, whose mean concentrations paradoxically significantly increased in
response to L-dopa, with values comparable to those observed after the classical
stimulatory test with metoclopramide. CONCLUSIONS: This study confirm the
existence of hyperprolactinemia associated with metastatic breast cancer. In
addition, by showing a paradoxical rise of PRL in response to L-dopa, which
inhibits PRL secretion in physiological conditions, this study would suggest that
breast cancer-related hyperprolactinemia may depend at least in part on
endogenous disease-related neuroendocrine alterations.
PMID- 10774573
TI - Transpectoral anterior approach to the axilla for lymph node dissection in
association with mastectomy preserving both pectoral muscles and their
neurovascular bundles.
AB - In Patey's mastectomy, which is still the most common operation for breast
cancer, axillary node dissection (AND) is performed through the base of the
axilla after retracting the pectoralis major muscle and excising the pectoralis
minor muscle (some surgeons preserve the latter). This has the disadvantage of
inadequate exposure of the axilla and the risk of damage to the neurovascular
bundles supplying the pectoral muscles, which in the long run may lead to atrophy
of these muscles. A transpectoral anterior approach to the axilla for AND in
association with mastectomy was attempted in 115 cases to obviate the above
mentioned disadvantages. The approach included: 1) splitting of the pectoralis
major between the clavicular and sternal fibers; 2) mobilization and swinging of
the pectoralis minor into different directions by means of a sling to facilitate
AND at selected levels. The major advantages of this approach were: 1) total
preservation of both pectoral muscles with their neurovascular bundles maintained
the normal anatomy and function of the shoulder; 2) the axilla was directly
approached through the anterior wall instead of through the base; in this way the
axillary contents were exposed almost at surface level; 3) the dissection plane
could be limited to anterior to and below the axillary vein and the risk of
postoperative lymphedema could thus be minimized; 4) change of position of the
ipsilateral arm was not necessary; 5) the duration of surgery was reduced.
Monoblock ablation of significant and suspected tissues, maintaining the normal
anatomy and function of the shoulder, could be easily accomplished with this
approach.
PMID- 10774574
TI - Effects of gemcitabine in normal and transformed human lung cell cultures:
cytotoxicity and increase in radiation sensitivity.
AB - AIMS AND BACKGROUND: Several anticancer drugs increase cell sensitivity to
irradiation. Gemcitabine (2', 2' difluorodeoxycytidine) decreases the cellular
dNTP pools and thus significantly increases the sensitivity to the DNA damaging
effects of low-dose radiation. In this study we have investigated whether
gemcitabine may play a role as radiosensitizer also in lung adenocarcinoma
treatment. METHODS & STUDY DESIGN: We studied this nucleoside analogue in normal
and transformed human cell lines (fetal lung and lung adenocarcinoma). After drug
treatment, cell lines were irradiated with different doses. Cell damage following
drug treatment and/or irradiation was assessed by measuring intracellular ATP
level and by the colony forming assay. RESULTS: The two cell lines significantly
differed in their sensitivity to the toxic effects of the drug; the normal cell
line was much more resistant than its transformed counterpart. This difference
was observed in both assays, although it was more evident in the colony forming
assay. A low radiation dose (50-100 cGy) did not cause any significant damage to
transformed cells; normal cells were more resistant and doses up to 500 cGy
caused little damage. However, when transformed cells were pretreated for three
hours with gemcitabine, even a nontoxic concentration of the drug (1-10 nM)
caused a marked sensitization of the cells to irradiation (50-100 cGy). The
radiosensitizing effect of gemcitabine could be observed also in normal cells,
although these cells were more resistant to the damaging effects of both
anticancer treatments. CONCLUSIONS: This study demonstrates that gemcitabine, a
chemotherapeutic agent already used in the clinic, could be proposed as a
radiosensitizer for radiation therapy of lung adenocarcinoma, having a clearly
potentiating effect on lowdose radiation.
PMID- 10774575
TI - Amplification of the c-myc oncogene in non-small cell lung cancer.
AB - Fresh non-small cell lung carcinoma surgical specimens were taken from 17
patients and 3 controls and screened for genetic abnormalities of the c-myc
oncogene. Southern blot hybridization analysis demonstrated two- to fivefold
amplification of the c-myc gene in 10 cases, i.e., 7 of 13 epidermoid lung
carcinomas, 2 of 3 adenocarcinomas and 1 of 1 osteogenic sarcoma metastatic to
the lung. Two- to fivefold amplification was observed in tissues from stage III
and IV epidermoid carcinomas and adenocarcinomas of the lung. A correlation
between cancer stage and c-myc gene amplification was found.
PMID- 10774577
TI - Epithelioid hemangioendothelioma of the larynx.
AB - Epithelioid hemangioendothelioma is an uncommon vascular tumor of the soft
tissues. Several reports have described this tumor in visceral locations such as
liver, lung, and brain. To the best of our knowledge this is the first report of
an immunohistochemical and ultrastructural study of a primary epithelioid
hemangioendothelioma occurring in the larynx. Difficulties concerning the
differential diagnosis and clinical problems arising from surgical therapy in the
laryngeal area are also discussed.
PMID- 10774578
TI - Primary esophageal lymphoepithelioma.
AB - Lymphoepitheliomas are extremely rare outside the nasopharynx.
Extranasopharyngeal lymphoepithellomas may be located in the stomach or digestive
tract, and only one single case of esophageal location has been found in our
review. In many cases the tumor is related to Epstein-Barr virus infection. We
report a case of undifferentiated carcinoma of the distal third of the esophagus
in a 79 year-old man. Pathological examination of the esophagus revealed an
undifferentiated carcinoma with lymphold stroma (lymphoepithelioma). In situ
hybridization of the neoplastic cells was negative for Epstein-Barr virus. To our
knowledge, the present case is the first documented esophageal lymphoepithelioma
in Western countries.
PMID- 10774576
TI - Concurrent chemoimmunotherapy in metastatic clear cell sarcoma: a case report.
AB - Clear cell sarcoma is a rare tumor with a poor prognosis. The therapeutic
approach in the metastatic disease stage is controversial: to the authors'
knowledge the use of concurrent chemoimmunotherapy has not been previously
reported. We present a case of a 57-year-old male with metastatic clear cell
sarcoma treated simultaneously with subcutaneous interferon-a 2b and six courses
of chemotherapy according to the CyVEDIC regimen. Disease stabilization lasting
17 months was achieved.
PMID- 10774579
TI - Primary malignant melanoma arising in the parotid gland: case report and
literature review.
AB - Melanoma of the head and neck is an extremely rare disease, characterized by
difficult and late diagnosis and poor prognosis; moreover, the definition of
primary melanomas of the salivary glands remains controversial. In this paper we
describe an unusual case of primary melanoma arising in the parotid gland. A 60
year-old woman presented to us for the persistence of a parotid neoplasm
diagnosed as carcinoma by fine-needle aspiration and treated with radiation
therapy. Wide destructive surgery was performed and immunohistochemical analysis
of the surgical specimen led to a diagnosis of melanoma. Complete screening
excluded other primary tumor sites. After five years of follow-up the patient Is
alive and free of disease. Here we report the diagnostic procedures leading to
the diagnosis along with a critical analysis of the literature, emphasizing the
difficulties in the diagnosis and classification of melanoma as a primary tumor
in the parotid gland and the need for destructive surgery.
PMID- 10774581
TI - [CPT-11: new drug for metastatic colorectal cancer].
PMID- 10774580
TI - A spindle cell tumor of unknown origin and diffuse bone marrow involvement in a
patient with hypercalcemia.
AB - BACKGROUND: Metastasis of unknown origin in bone marrow is infrequent, although,
when it occurs, adenocarcinoma is the most common histologic type. Involvement of
bone marrow by a spindle cell tumor and presentation with hypercalcemia are very
rare. METHOD: This report describes a 21-year-old man with diffuse bone marrow
involvement from a spindle cell tumor. RESULTS: The patient presented with low
back pain, anemia, thrombocytopenia, azotemia, and hypercalcemia. Bone marrow
biopsy revealed a spindle cell tumor that was positive for vimentin staining but
whose primary site could not be identified. A bone marrow scan revealed absence
of uptake, which suggested systemic disease. We treated this case as a type of
sarcoma by giving combined chemotherapy consisting of vincristine, actinomycin-D
and cyclophosphamide. The patient showed a clinical response for seven months,
but the disease progressed despite chemotherapy and he died one year after
diagnosis. CONCLUSIONS: We have documented a rare case of spindle cell tumor
involving bone marrow without evidence of the tumor's primary site.
PMID- 10774582
TI - [Management of the oncologic patient: recent conferences].
PMID- 10774583
TI - [Anastrozolo: intracellular anti-aromatase activity and pharmacologic
interactions. Satellite Symposium AIOM 1999 - Roma].
PMID- 10774585
TI - Antiretroviral therapy: state of the HAART.
PMID- 10774584
TI - [Chemotherapy of solid tumors: pharmacologic activity or effectiveness?].
PMID- 10774586
TI - Inhibitory effects of EICAR on infectious pancreatic necrosis virus replication.
AB - Recently, the antiviral 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide
(EICAR) was shown to inhibit the replication of the infectious pancreatic
necrosis virus (IPNV). In order to obtain more information about the mechanism of
the antiviral action of EICAR we studied its effect on viral macromolecules
synthesis. EICAR was found to inhibit IPNV messenger and genomic RNA synthesis.
To inhibit viral RNA synthesis, EICAR must be added at least 3 h before the start
of RNA synthesis. This suggests that EICAR does not directly affect the viral RNA
polymerization process. Moreover, the antiviral action of EICAR was reversed by
the exogenous addition of guanosine (5-50 microg/ml), but not adenosine or
cytidine (10-100 microg/ml). Our findings suggest that the antiviral action of
EICAR is mediated by a reduction of the intracellular guanosine 5'-triphosphate
(GTP) pool level, as has been observed with ribavirin and EICAR in other
biological systems.
PMID- 10774587
TI - Enhanced antiviral benefit of combination therapy with lamivudine and famciclovir
against WHV replication in chronic WHV carrier woodchucks.
AB - Cell culture studies in our laboratory and others have previously demonstrated
synergistic antiviral activity for combinations of 3TC (lamivudine) and
penciclovir against Hepatitis B Virus (HBV) replication and the Duck Hepatitis B
Virus (DHBV). Based on these results, a study was designed to determine if an
enhanced antiviral effect with combinations of 3TC and famciclovir (FCV, oral
prodrug of penciclovir) could be demonstrated in vivo using the Woodchuck
Hepatitis Virus (WHV)/woodchuck experimental model of chronic HBV infection. Both
antiviral agents have been shown to be effective against WHV replication in WHV
chronic carriers in previous studies by our laboratories. The antiviral effects
of four different combinations of lamivudine and FCV were found to be greater
than those observed for the corresponding monotherapies. All four combination
treatments produced antiviral effects that were at least equal to that expected
for additive activity based on estimations generated by Bliss Independence
calculations. Two of the combination treatments produced antiviral effects that
were significantly greater than that expected for additive effects, indicative of
synergistic antiviral interactions. These studies demonstrate that combination
therapy of chronic WHV infection has enhanced antiviral benefit over
corresponding monotherapies and indicate that combination treatment of chronic
HBV infection can be superior to therapies using a single antiviral agent.
PMID- 10774588
TI - The role of natural killer cells in protection of mice against death and corneal
scarring following ocular HSV-1 infection.
AB - C57BL/6 mice depleted of NK (natural killer) cells with anti-asialo-GM1 antibody
were more susceptible to lethal HSV-1 ocular challenge (12% survival) than
control C57BL/6 mice (100% survival), CD4+ depleted mice (100% survival), CD8+
depleted mice (80% survival), or macrophage depleted mice (85% survival). NK
depletion also resulted in significantly higher levels of HSV-1 induced corneal
scarring than was seen with any of the other groups. C57BL/6 mice depleted of NK
cells with PK136 (anti-NK1.1 antibody which is more specific for NK cells than is
anti-asialo-GM1 antibody) were also more susceptible to HSV-1 ocular challenge
than T cell or macrophage depleted mice. Vaccination completely protected NK
depleted mice against death and corneal scarring. In contrast to C57BL/6 mice, in
BALB/c mice, NK depletion had no effect on survival or corneal scarring following
ocular HSV-1 challenge. Experiments with IFN-gamma knockout mice (IFN-gamma(o/o)
mice) suggested that IFN-gamma played a minor role in protection of naive mice
against death following HSV-1 challenge. However, IFN-gamma did not appear to be
an important factor in protection against HSV-1 induced eye disease. Thus,
protection against HSV-1 induced corneal scarring in naive mice appeared to be
due to a non-INF-gamma NK function. Our results therefore suggest that NK cells
were very important in protecting naive C57BL/6 mice but not vaccinated C57BL/6
mice against corneal scarring and death following ocular HSV-1 challenge.
PMID- 10774589
TI - Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV
infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199
study teams.
AB - RATIONALE: To determine the dosage requirements and pharmacokinetics of
atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N
dealkylated metabolite (N-ATV) during phase I studies in patients receiving
atevirdine alone or in combination with zidovudine. DESIGN: Two open label, phase
I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which
atevirdine was administered every 8 h with weekly dosage adjustments to attain
targeted trough plasma atevirdine concentrations. SETTING: Five Adult AIDS
Clinical Trials Units. PATIENTS: Fifty patients (ACTG 199; n = 20 and ACTG 187; n
= 30) with HIV-1 infection and < or =500 CD4+ lymphocytes/mm3. INTERVENTION: ACTG
199; 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough
atevirdine concentrations of 5-10 microM) and zidovudine (200 mg every 8 h). ACTG
187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve
escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31
microM). MEASUREMENTS: ACTG 199: atevirdine, N-ATV and zidovudine trough
determinations weekly (all patients) and intensive pharmacokinetics (selected
patients) prior to and at 6 and 12 weeks during combination therapy. ACTG 187:
atevirdine and N-ATV trough concentrations over a 12 week period. Intensive
pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during
atevirdine monotherapy in female patients. RESULTS: Atevirdine plasma
concentrations demonstrated considerable interpatient variability which was
minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to
achieve the desired trough concentrations. In ACTG 187, the mean number of weeks
to attain the target value, and the percentage of patients who attained the
target, was group I (5-11 microM): 2.7+/-2.4 weeks (92%); group II (12-21
microM): 2.6+/-1.8 (64%); and group III (22-31 microM): 7.0+/-5.6 weeks (27%). In
ACTG 199 it was 3.2+/-5.2 weeks (95%) to achieve a 5-10 microM trough. Atevirdine
demonstrated a mono- or bi-exponential decline among most of the patients studied
after the first dose. During multiple-dosing a number of patterns of atevirdine
disposition were observed including; rapid absorption with Cmax at 0.5-1 h,
delayed absorption with Cmax at 3-4 h; minimal Cmax to Cmin fluctuation and Cmax
to Cmin ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized
on day one by rapid appearance of the metabolite which peaked at 2-3 h after the
dose and declined in a mono- or bi-exponential manner. At steady-state N-ATV
patterns demonstrated minimal Cmax to Cmin fluctuations with some of the patients
having more stable plasma N-ATV concentrations, while others had greater
fluctuations week to week. CONCLUSIONS: Considerable interpatient variability was
noted in the pharmacokinetics of atevirdine. The variation in drug disposition
was reflected in the range of daily doses required to attain the targeted trough
concentrations. Atevirdine metabolism did not appear to reach saturation during
chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV
ratios in plasma and saturation was not an explanation for the variation in
dosing requirements. No apparent differences were noted between males and
females, and atevirdine did not appear to influence zidovudine disposition.
PMID- 10774590
TI - Effect of protease inhibitors on HIV-1 maturation and infectivity.
AB - The effects of HIV-1 protease inhibitors on proteolytic processing and
infectivity of virions produced from lymphocytes chronically infected with the
virus were studied. Protease inhibition was detected by the accumulation of the
polyprotein precursors Pr55gag and Pr160gag-pol and their cleavage intermediates.
Immunoblot analysis demonstrated that while the processing of Pr55gag was largely
irreversible, cleavage of Pr160gag-pol proceeded once the inhibitor was removed,
although it was not completed during 96 h of subsequent observation. Virions
produced during exposure of cells to protease inhibitors regained some degree of
infectivity post-withdrawal of the inhibitor, suggesting that the processing of
Pr160gag-pol following drug withdrawal resulted in the production of those
enzymes necessary to enable at least limited viral replication. When cells were
exposed to a protease inhibitor for 72 h then the inhibitor withdrawn, a lag
phase of up to 24 h occurred before these cells produced virions with equivalent
infectivity to virus produced from cells not exposed to drug. These observations
may reflect a clinical situation likely to occur as trough plasma concentrations
of protease inhibitors fall below the IC100 for HIV, highlighting the need for
adherence to drug regimens containing these inhibitors.
PMID- 10774592
TI - Susceptibility of protein kinase (ORF47)-deficient varicella-zoster virus strains
to anti-herpesvirus nucleosides.
AB - To clarify whether varicella-zoster virus (VZV) protein kinase (PK; ORF47) takes
part in phosphorylation of anti-herpesvirus nucleosides, thymidine kinase (TK)
deficient, and PK/TK double deficient recombinant VZV strains were isolated and
their susceptibility, and that of wild type and PK-deficient strains to various
nucleoside analogs was evaluated. The PK-deficient VZV strains showed a
sensitivity equal to that of the wild type strain against all compounds tested,
including ganciclovir. This indicates that PK is not involved in phosphorylation
of the tested nucleosides in VZV-infected cells.
PMID- 10774591
TI - Inhibitory effect of cycloSaligenyl-nucleoside monophosphates (cycloSal-NMP) of
acyclic nucleoside analogues on HSV-1 and EBV.
AB - The in vitro antiviral activity of a new series of cycloSal-pro-nucleotides
derived from the acyclic nucleoside analogues aciclovir and penciclovir against
herpes simplex virus type 1 (HSV-1), thymidine kinase deficient (TK-) HSV-1, and
Epstein-Barr virus (EBV) was evaluated. Using the XTT-based tetrazolium reduction
assay EZ4U, the cycloSal derivatives were examined for their antiviral and
cytotoxic effects in HSV-1 as well as HSV-1-TK--infected Vero cells. The anti-EBV
activity was assessed by means of an EBV DNA hybridization assay using a
digoxigenin-labeled probe specific for the Bam H1-W-fragment of the EBV genome
and by measuring viral capsid antigen (VCA) expression in P3HR-1 cells by
indirect immunofluorescence. Among the new cycloSal-phosphotriesters the three
aciclovir monophosphates proved to be potent and selective inhibitors of HSV-1
replication, EBV DNA synthesis and EB-VCA expression. Of interest is the
retention of activity of the aciclovir monophosphates in HSV-1-TK--infected
cells. Particularly 3-methyl-cycloSal-aciclovir monophosphate retained the same
effectiveness, as compared to the wild type virus strain. In contrast to the
aciclovir pro-nucleotides the penciclovir cycloSal-phosphotriesters exhibited at
best only a marginal antiviral effect on HSV and EBV replication.
PMID- 10774593
TI - Negative reactivity and attachment: Down syndrome's contribution to the
attachment-temperament debate.
AB - This longitudinal study investigated the relation between negative reactivity and
attachment in children with Down syndrome (DS). Specifically, we examined whether
extremely low negative reactivity is associated with the enactment and
organization of attachment behaviors. To address this issue 30 infants with DS
(13 female, 17 male) were observed in Ainsworth's Strange Situation at 19 and 27
months. The intensity and duration of distress reactions were coded in 15-s
intervals throughout each Strange Situation episode. Children's distress
intensity during separations from caregivers was used to place children into Low
versus Moderate/High Negative Reactivity groups. In addition, ratings of infants'
social interactive behaviors (contact maintenance, proximity seeking, distance
interaction, resistance, and avoidance) were made for each episode and used to
assess the quality of infants' attachment relationships. The data indicated that
there are high rates of Type A and D insecure attachments within the DS
population at each age studied. However, low negative reactivity was not
consistently related to the activation of the attachment behavioral system, or
associated with insecure attachment relationships. Alternative explanations for
the high rate of insecure attachments are discussed.
PMID- 10774594
TI - Prediction of externalizing behavior problems from early to middle childhood: the
role of parental socialization and emotion expression.
AB - Parental emotions and behaviors that contribute to continuity and change in
preschool children's externalizing problems were examined. Mothers and fathers
were observed interacting with their children, and child-rearing styles were
reported. Teachers, mothers, and children reported children's antisocial,
oppositional behavior. Externalizing problems showed strong continuity 2 and 4
years later. Proactive parenting (i.e., supportive presence, clear instruction,
and limit setting) predicted fewer behavior problems over time, after controlling
for initial problems; the converse was true for parental anger. In contrast, the
hypothesized ameliorative contribution of parents' positive emotion was not
found. Parental contributions were most influential for children whose initial
problems were in the clinical range. In particular, parental anger predicted
continuation of problems over time. Paternal, as well as maternal, influences
were identified. Examination of parental emotions and inclusion of fathers is
important to research and intervention with young antisocial children.
PMID- 10774595
TI - Emotion management skills in sexually maltreated and nonmaltreated girls: a
developmental psychopathology perspective.
AB - Research has demonstrated that children who experience familial sexual
maltreatment are at risk for developing psychological difficulties characterized
by emotional and behavioral dysregulation. Surprisingly, however, little
attention has been directed toward identifying processes in emotional development
that differ in maltreated and nonmaltreated children. From a developmental
psychopathology perspective, the present study examined emotion management skills
(i.e., emotional understanding, emotion regulation) in 21 sexually maltreated
girls and their nonmaltreated peers to determine how the experience of sexual
maltreatment may interfere with normative emotional development. Findings
indicated that sexually maltreated girls, in comparison to their nonmaltreated
peers, demonstrate lower emotional understanding and decreased ability to
regulate their emotions in accordance with cultural expectations. Further,
maltreated girls expected less emotional support and more relational conflict
from parents in response to sadness displays and from parents and peers in
response to anger displays. These findings will be discussed from the
functionalist approach to emotional development, emphasizing the importance of
social context (e.g., maltreating, nonmaltreating) in the development of
children's emotion management skills.
PMID- 10774596
TI - Factors influencing maltreated children's early adjustment in foster care.
AB - Internal representations of self and primary attachment figures may be one
mechanism by which maltreatment affects children's interpersonal behavior and
relationships with others. Research on the continuity and influence of maltreated
children's attachment representations, however, has not included youngsters
removed from abusive or neglectful home environments. This paper examines the
influence of maltreated children's maternal and self-representations on
subsequent relationships with foster mothers and behavioral adjustment in foster
care. Participants included 32 children, ages 9-13 years, who entered foster
placement for the first time after a sustained relationship with a maltreating
biological mother. Upon initially entering foster care, children's maternal and
self-representations were significantly related to each other and to severity of
maltreatment history but not to other factors believed to influence the quality
of parent-child relationship (e.g., maternal mental health, partner stability).
In addition, these representations significantly predicted children's subsequent
views of their relationships with foster mothers. Finally, children's behavior in
their foster homes was associated with maltreatment severity, internal
representations assessed at entry into foster care, and to concurrent perceptions
of their new foster mothers. These findings advance our understanding of foster
placement's role in maltreated children's development and provide preliminary
insight into the processes associated with the formation of potentially
compensatory relationships.
PMID- 10774597
TI - High "intelligence," low "IQ"? Speed of processing and measured IQ in children
with autism.
AB - The uneven profile of performance on standard assessments of intelligence and the
high incidence of savant skills have prompted interest in the nature of
intelligence in autism. The present paper reports the first group study of speed
of processing in children with autism (IQ 1 SD below average) using an inspection
time task. The children with autism showed inspection times as fast as an age
matched group of young normally developing children (IQ 1 SD above average). They
were also significantly faster than mentally handicapped children without autism
of the same age, even when these groups were pairwise matched on Wechsler IQ. To
the extent that IT tasks tap individual differences in basic processing
efficiency, children with autism in this study appear to have preserved
information processing capacity despite poor measured IQ. These findings have
implications for the role of general and specific cognitive systems in knowledge
and skill acquisition: far from showing that children with autism are unimpaired,
we suggest that our data may demonstrate the vital role of social insight in the
development of manifest "intelligence."
PMID- 10774598
TI - Hyperactive and antisocial behaviors: comorbid or two points in the same process?
AB - We hypothesized that hyperactivity defines the first stage and that antisocial
problems define a second stage in a progression that leads eventually to early
onset delinquency. As expected, a structural equation model (SEM) showed that a
latent construct for hyperactivity was significantly related to a latent
construct for antisocial problems. We hypothesized that this path reflected a
shared mechanism, disrupted parental discipline. A second SEM showed that the
relation between hyperactivity and antisocial behavior really reflected a shared
disruption in parental discipline. A third SEM showed that having antisocial
parents was uniquely correlated with antisocial children but not with
hyperactivity. A fourth SEM showed that early-onset delinquency was predicted by
a latent construct for antisocial child; but when this was partialed out, the
contribution for hyperactivity was nonsignificant.
PMID- 10774599
TI - The influence of positioning on spectroscopic measurements of brain oxygenation.
AB - This study was designed to evaluate the influence of body position during
neurosurgical and cerebrovascular operations on regional cerebral oxygen
saturation (rSO2). Awake volunteers (group I; n = 14), anesthetized patients
(group II; n = 48) undergoing lumbar discectomy, and 12 patients undergoing
carotid endarterectomy (group III) with internal carotid artery (ICA) stenosis
were studied. Anesthesia in the patient groups was performed with sevoflurane
(1.1 Vol% insp.) in N2O2/O2 mixture (FiO2 0.4) rSO2 was monitored with a INVOS
4100 cerebral oxymeter (Somanetics Corporation, Troy, MI). Measurements were done
in all groups in supine position with head turned to the right and left side.
Furthermore, in groups I and II, rSO2 was measured in right lateral, left
lateral, prone, or sitting position. In each position the parameters were
registered at three times (1, 3, and 5 min after taking up the position). In the
healthy volunteers, the mean rSO2 values of both hemispheres were 71.3 +/- 5.0%.
No significant changes of rSO2 were found interhemispherical and upon turning the
head to both sides or positioning to the prone and both lateral positions. After
assuming the sitting position, the decrease of rSO2 was not significant. In group
II, rSO2 decreased significantly in the sitting position. In group III, baseline
readings for rSO2 obtained from the side of ICA stenosis were significantly
lower, compared to the contralateral side. After turning the head to the
ipsilateral side, this difference diminished. In contrast, turning the head
toward the contralateral side, the rSO2 difference remained nearly constant, both
values decreasing constantly throughout the observation period. In conclusion,
after different positioning maneuvers awake and under anesthesia, alterations of
rSO2 can be registrated by near-infrared spectroscopy (NIRS).
PMID- 10774600
TI - Effects of olprinone on systemic and cerebral circulation in patients with
subarachnoid hemorrhage.
AB - Olprinone is a promising new drug used for treating cerebral vasospasm. To
clarify the effects of olprinone on systemic and cerebral circulation in patients
with subarachnoid hemorrhage, hemodynamic and oxygenation parameters were
evaluated as 12 such patients underwent surgery. After aneurysm clipping and
confirmation of hemostasis, olprinone was administrated at a dose of 10 microg/kg
over 5 minutes followed by 0.2 microg/kg/min for 25 minutes. Variables before and
after administration were compared by paired t tests. Heart rate and cardiac
index increased while no significant changes occurred in oxygen saturation of
mixed venous blood, or oxygen extraction ratio. Cortical blood flow increased and
cerebral vascular resistance decreased significantly, but oxygen saturation in
the jugular bulb, arterio-jugular difference of oxygen content, and lactate
oxygen index did not change significantly. In conclusion, olprinone increased
cardiac output and cortical blood flow in patients with subarachnoid hemorrhage,
but the balance between oxygen supply and consumption systemically and in the
brain did not change. This observation suggests the possibility that olprinone
increases cerebral metabolism.
PMID- 10774601
TI - S(+)-ketamine up-regulates neuronal regeneration associated proteins following
glutamate injury in cultured rat hippocampal neurons.
AB - In previous studies, racemic ketamine improved neurological outcome after
experimental brain injury and S(+)-ketamine demonstrated neuroprotective effects
in neurons after damage in vitro. We compared the expression of regeneration
associated proteins in rat hippocampal neurons after glutamate injury and
treatment with S(+)-ketamine versus racemic ketamine. Following an 8 minute
exposure to 100 microM glutamate, neurons were maintained untreated or in the
presence of S(+)-ketamine or racemic ketamine (10(-4) M, 10(-5) M, 10(-6) M) for
one week. Growth-associated protein-43 (GAP-43) and synaptosomal-associated
protein-25 (SNAP-25) was analyzed by Western Blotting, the mitochondrial
transmembrane potential (MTP) by fluorescence imaging, and [3H]2-deoxy-D-glucose
([3H]2-DG) uptake by scintillation spectrometry. Seven days after exposure, GAP
43 decreased to 15% and SNAP-25 to 30% in the glutamate-injured, untreated
neurons. The MTP declined to 50% and [3H]2-DG to 30%. Both S(+)-ketamine and
racemic ketamine at 10(-4) M and 10(-5) M minimized the decline in MTP, almost
maintaining it at control value. Additionally, S(+)-ketamine and racemic ketamine
decreased the reduction in [3H]2-DG. S(+)-ketamine at 10(-4) M and 10(-5) M and
racemic ketamine at 10(-4) M reduced the decline in SNAP-25 to 60% of controls (P
< .05). However, S(+)-ketamine at 10(-4) M and 10(-5) M only reversed the
decrease in GAP-43 to 50% and 40% of controls, respectively (P < .05). We
conclude that the synthesis of a growth-associated protein related to plasticity
and repair in the adult nervous system is increased by S(+)-ketamine but is not
increased by racemic ketamine.
PMID- 10774602
TI - Enhancement of brain tissue oxygenation during high dose isoflurane anesthesia in
the dog.
AB - It is reported that high dose desflurane can increase brain tissue oxygen
pressure (PtO2) in patients during cerebral aneurysm surgery. The purpose of this
study was to determine whether high dose isoflurane anesthesia can produce a
similar effect in dogs and the importance of cerebral perfusion pressure in
mediating this effect. Six dogs were anesthetized, and ventilated with isoflurane
inspired oxygen concentration of 40%. Following a craniotomy, a catheter was
inserted into the sagittal sinus for cerebral venous blood samples and a
Neurotrend probe was inserted into cortex brain tissue to measure PtO2, carbon
dioxide pressure (PtCO2), and pH (pHt). Brain tissue and arterial and sagittal
sinus blood gas tensions and pH were measured under the following conditions: 1 =
baseline 1.5% isoflurane, 2 = 1.5% isoflurane + increase mean arterial pressure
(MAP) by 50 mm Hg, 3 = 3% isoflurane anesthesia, 4 = 3% isoflurane anesthesia +
increase MAP 55 mm Hg, 5 = 1.5% isoflurane anesthesia, 6 = 1.5% isoflurane
anesthesia + increase MAP 35 mm Hg. In the first and second trial with 1.5% end
tidal isoflurane, PtO2 increased 15% during an increase in MAP without a change
in sagittal sinus oxygenation. At 3% isoflurane, PtO2 increased 90% and sagittal
sinus PO2 increased 38% during an increase in MAP. These results show that the
cerebral metabolic depression and cerebrovasodilatory effects of high dose
isoflurane can enhance brain tissue oxygenation. Normal brain vascular regulation
that limits hyperperfusion and hyperoxygenation of brain tissue is antagonized by
high dose isoflurane.
PMID- 10774603
TI - Inhibitory effects of halothane, isoflurane, sevoflurane, and pentobarbital on
the constriction induced by hypocapnia and bicarbonate in isolated canine
cerebral arteries.
AB - The effects of halothane, isoflurane, sevoflurane (0.5, 1 and 2 MAC) and
pentobarbital (10(-5) M, 10(-4) M and 3 x 10(-4) M) on hypocapnia- and
bicarbonate-induced constriction of isolated dog middle cerebral arteries were
investigated in vitro. The isometric tension of isolated cerebral arterial rings
was measured in an organ bath containing Krebs bicarbonate solution, aerated with
5% CO2 and 95% O2. Hypocapnia, induced by replacing the bathing solution with one
that had been equilibrated with 2.5% CO2 and 97.5% O2, produced a sustained
vasoconstriction (268 +/- 36 mg, mean +/- SEM). Exposure of arterial rings to a
bathing solution that contained double the concentration of NaHCO3 (50 mM)
elicited a phasic constriction followed by a gradual decrease in tension (309 +/-
34 mg). Although halothane, isoflurane, and sevoflurane attenuated both
hypocapnia- and bicarbonate-induced constrictions in a dose-dependent manner, the
inhibition of these constrictions was greater in rings treated with halothane
than in those treated with isoflurane or sevoflurane when compared at equipotent
concentrations. These alkaline-induced constrictions were attenuated by
pentobarbital only at the highest concentration of 3 x 10(-4) M. Halothane (1 and
2 MAC) attenuated the constriction induced by hypocapnia to a greater extent than
that induced by 15 mM KCl, whereas pentobarbital (10(-4) M and 3 x 10(-4) M)
attenuated hypocapnia-induced constriction less than KCl-induced constriction.
These results indicate that alkaline-induced constriction is more vulnerable to
halothane than other volatile anesthetics and pentobarbital. The mechanisms of
the inhibitory effects of halothane and pentobarbital on alkaline-induced
cerebral vasoconstriction seem to differ; the inhibitory effect of pentobarbital,
but not of halothane may be, in part, ascribed to its inhibitory effect on the
Ca++ influx.
PMID- 10774605
TI - Craniotomy performed with LMA: a case report.
AB - Since its introduction into clinical practice in 1988, the laryngeal mask airway
(LMA) has been used as an alternative device to achieve and maintain control of
the airway during anesthetics. The LMA has been used primarily in patients
undergoing peripheral procedures in the supine position. The authors describe its
use in an open intracranial neurosurgical procedure for a patient with a space
occupying lesion. To our knowledge, this is the first such description in the
literature.
PMID- 10774604
TI - Anesthetic management for two-stage computer-assisted, stereotactic thalamotomy
in a child with Hallervorden-Spatz Disease.
AB - We report the numerous management challenges surrounding the care of a child in
whom bilateral thalamotomies were used to treat end-stage Hallervorden-Spatz
Disease (HSD). The management of this patient was greatly facilitated by the use
of modern anesthetic agents and a multidisciplinary team to care for the patient.
The outcome was an improved life expectancy and quality of life.
PMID- 10774606
TI - Antecubital central venous catheter placement complicated by a persistent left
superior vena cava.
AB - A 14-year-old female in whom we encountered a persistent left superior vena cava
during placement of a central venous catheter is presented. The patient had a
history of coarctation of the aorta, but the left superior vena cava was unknown.
Since the incidence of persistent left superior vena cava in patients with
congenital heart disease is ten times as great as those without, in this patient
population it may be useful to obtain radiographic confirmation of catheter
position before use.
PMID- 10774607
TI - Airway obstruction due to a rigid cervical collar.
AB - Airway obstruction after anterior cervical discectomy and fusion (ACDF) is a
potentially life-threatening postoperative complication. We experienced a case of
airway obstruction after an ACDF attributable to the rigid cervical collar used
in the patient's postoperative care, which has not been reported previously.
PMID- 10774608
TI - Anesthetic management of severe chronic cardiopulmonary failure during
endovascular embolization of a PICA aneurysm: a case report.
AB - The authors present a case in which a 64-year-old female patient suffering from
severe cardiopulmonary dysfunction underwent endovascular embolization of an
aneurysm of the posterior inferior cerebellar artery (PICA). The anesthetic
management consisted of so-called dynamic akinetic sedation and controlled
hemodynamics (DASCH) using intravenous propofol and dopamine infusions and
invasive blood pressure monitoring. The details of the perioperative patient
management are described. The patient made a successful recovery.
PMID- 10774609
TI - The use of hyperventilation in the treatment of plateau waves in two patients
with severe traumatic brain injury: contrasting effects on cerebral oxygenation.
AB - We present the case reports of two patients with severe traumatic brain injury
who, in the absence of external stimuli, developed episodes of acute elevation of
intracranial pressure (plateau waves) associated with jugular bulb oxyhemoglobin
(SjO2) desaturation, severe reduction of cerebral tissue PO2 (PbrO2), and
deterioration of neurological status. In all of these episodes hyperventilation
was successful in extinguishing plateau waves, but in one patient it was
associated with an improvement of both the global (increased SjO2) and local
(increased PbrO2) cerebral perfusion, while in the other patient it was
associated with a reduction of both SjO2 and PbrO2. In both patients the effects
of hyperventilation (and other pharmacological treatments) were short-lived;
plateau waves reappeared and the patients had to be submitted to decompressive
craniotomy (first patient) and cerebrospinal fluid (CSF) drainage (second
patient). We conclude that hyperventilation can be useful as a temporary measure
to treat plateau waves, but cerebral oxygenation should always be monitored to
avoid iatrogenic cerebral ischemia.
PMID- 10774610
TI - Sevoflurane and anesthesia for neurosurgery: a review.
AB - This review assesses the extent to which sevoflurane fulfills the requirements of
the ideal inhalational agent for use in neuroanesthetic practice. Sevoflurane's
pharmacokinetic profile is outlined. Data from animal and human studies are used
to discuss its effects on cerebral hemodynamics, central nervous system
monitoring, and cardiovascular parameters. Where possible, sevoflurane is
compared with isoflurane, currently considered the inhalational agent of choice
in neuroanesthesia. Sevoflurane's potential for toxicity is reviewed.
PMID- 10774611
TI - A new frontier: magnetic resonance imaging-operating room.
AB - Developments in technology have led to the merger of two distinct environments,
that of magnetic resonance imaging and that of the operating room. The major
advantage of this merger for neurosurgical procedures is the ability to perform
real-time imaging to help guide surgery. This review discusses the role of the
anesthesiologist in the planning and administration of safe anesthesia in this
new and challenging environment.
PMID- 10774612
TI - Expression of the lactate transporter MCT1 in macrophages.
AB - This study evaluated macrophage expression of the stereospecific lactate
transporter, MCT1, and the effects of lipopolysaccharide (LPS), tumor necrosis
factor (TNFa), or nitric oxide (NO) on MCT1 mRNA and protein levels and lactate
transporter activity. Peritoneal and J774.1 macrophages were treated with either
saline, LPS (10 or 100 ng/mL), dexamethasone (100 nM), and dexamethasone + LPS.
Cells were harvested at 4, 8, and 16 h after treatment and processed for total
RNA and protein isolation. LPS treatment significantly increased macrophage MCT1
mRNA expression at 4 and 8 h compared with the saline-treated cells.
Dexamethasone did not alter MCT1 mRNA levels. Treatment of J774.1 macrophages
with TNFalpha (1 ng/mL) or nitric oxide (DETA-NO, 100 microM) also significantly
increased MCT1 mRNA levels at 4 and 8 h after treatment. LPS and TNFalpha
treatment significantly increased MCT1 protein levels at 8 and 16 h after
treatment. Lactate transporter activity in J774.1 macrophages was measured by
uptake of 14C-labeled lactate. LPS and TNFalpha treatment significantly augmented
lactate uptake, 12 h after administration; however, nitric oxide treatment did
not affect lactate uptake. Thus, our data demonstrated that stimulated peritoneal
and J774.1 macrophages express the lactate transporter, MCT, and that LPS and
TNFalpha regulate MCT1 mRNA and protein levels.
PMID- 10774614
TI - Mesenteric vasoconstriction in response to hemorrhagic shock.
AB - Previous studies indicate that cardiogenic shock (tamponade) in swine produces
selective mesenteric ischemia due to disproportionate mesenteric vasospasm
mediated primarily by the renin-angiotensin axis. Here, we characterized the
systemic and mesenteric hemodynamic responses to hypovolemic shock to better
understand the neurohumoral mechanisms controlling this response. Varying degrees
of hypovolemic shock were produced by graded levels of hemorrhage, from 12.5 to
50% of the calculated blood volume. Systemic and mesenteric pressures and blood
flows were measured, and corresponding vascular resistances were calculated. The
hemodynamic responses of the mesenteric vascular bed were compared with those of
the systemic (nonmesenteric) vasculature. These experiments were then repeated
after confirmed blockade either of the alpha-adrenergic nervous system
(phenoxybenzamine), of vasopressin (Manning compound), or of the renin
angiotensin axis (enalapril). Graded levels of hemorrhage produced corresponding
graded, reproducible, steady-state levels of systemic hypotension, hypoperfusion,
and peripheral vasoconstriction, i.e., hemorrhagic shock. This was associated
with disproportionate degrees of mesenteric ischemia due to disproportionate
mesenteric vasoconstriction. The selective component of this mesenteric
vasoconstrictive response was not attenuated by a-adrenergic blockade nor by
vasopressin blockade but was blocked by ablation of the renin-angiotensin axis
with enalapril. Like cardiogenic shock, hemorrhagic shock generates selective
mesenteric ischemia by producing a disproportionate mesenteric vasospasm that is
mediated primarily by the renin-angiotensin axis.
PMID- 10774613
TI - The effect of inducible nitric oxide synthase (iNOS) inhibition on smoke
inhalation injury in sheep.
AB - Recent studies on smoke inhalation injury have been focused on nitric oxide (NO)
as an essential factor of progressive lung injury. We studied the effects of
inducible nitric oxide synthase (iNOS) inhibition on inhalation injury in sheep.
Sheep (n = 14) were prepared surgically for chronic study. After recovery period,
the sheep received 48 breaths of cotton smoke. The animals were then randomised
into two groups: MEG group [30 mg/kg mercaptoethylguanidine (MEG), selective
inhibitor of iNOS and peroxynitrite scavenger, was given 1 h after injury and
then 8 h for 41 h, n = 7] and control group (0.9% NaCl, n = 7). All animals were
ventilated mechanically, and airway blood flow was measured using colored
microspheres. In the control group, following significant increase in airway
blood flow, deterioration in the PaO2/FiO2 ratio was observed. Whereas in the MEG
group, it was not observed. In addition, the MEG group did not show significant
increase in pulmonary vascular resistance and intrapulmonary shunt fraction. Lung
wet/dry ratios, a marker of pulmonary edema, were significantly lower in the MEG
group. At 48 h after injury, lung tissue-conjugated dienes, an index of lung
oxidative tissue injury, were significantly lower in the MEG group than in the
control group. Our data suggest that 1) iNOS-NO produced in the airway
circulation plays a major role on the significant increase in airway blood flow,
which may contribute to the spread of injury from injured airway to the lung
parenchyma; 2) iNOS-NO induced in the pulmonary circulation contributes to the
loss of hypoxic pulmonary vasoconstriction; and 3) iNOS-NO plays an important
role on the lung oxidative tissue injury.
PMID- 10774615
TI - Relative effects of glucose and glutamine on reactive oxygen intermediate
production by neutrophils.
AB - The energy source for neutrophils (PMNs) has long been believed to be glucose.
However, it has been shown recently that PMNs use glutamine as well as glucose.
Nevertheless, the comparative effects of glucose and glutamine on PMN function
remain to be clarified. This study investigated the relative effects of glucose
and glutamine on reactive oxygen intermediate (ROI) production by PMNs. In
experiment 1, PMNs (1 x 10(6)/mL) isolated from healthy volunteers were incubated
in RPMI 1640 medium containing neither glucose nor glutamine for 4, 12, 18, and
24 h at 37 degrees C. The medium was supplemented with 0 or 200 mg/dL (0 or 11
mM, respectively) glucose and glutamine (0, 0.5, 1, or 2 mM). PMN cell death was
assessed on the basis of hypodiploid DNA by flow cytometry using propidium iodide
DNA staining. ROI production by PMNs was determined by flow cytometry using
dihydrorhodamine 123. In experiment 2, isolated PMNs were cultured in RPMI 1640
medium containing neither glucose nor glutamine. The medium was supplemented with
glucose (0 or 11 mM) and a competitive inhibitor of glycolysis, 2-deoxy-D-glucose
(2-DG; 0 or 20 mM). Each medium was supplemented with glutamine (0, 0.5, 1, or 2
mM) and incubated for 12 h at 37 degrees C. Then, ROI production by PMNs was
measured. PMN cell death was not affected by glucose or glutamine in this
experiment. In contrast, ROI production by PMNs was greater at 11 mM glucose than
at 0 mM glucose at all incubation times studied. At 11 mM glucose, supplemental
glutamine enhanced PMN ROI production after 18 and 24 h culture. In contrast, at
0 mM glucose, glutamine augmented ROI production by PMNs after 12 h as well as
with 18 and 24 h incubations. PMN ROI production after 12 h culture was
significantly greater at 11 mM glucose without 2-DG than at both 11 and 0 mM
glucose with addition of 2-DG. In addition, supplemental glutamine enhanced ROI
production by PMNs when 2-DG was added at 11 and 0 mM glucose. Glucose is
essential for PMN ROI production. Under conditions of glucose depletion in vitro,
glutamine is of importance in ROI production by PMNs, whereas the enhancing
effect of glutamine on PMN ROI production is minor compared to that of glucose.
PMID- 10774616
TI - Hepatic injury and lipid peroxidation during ischemia and reperfusion.
AB - We determined the relationship between lipid peroxidation and alterations in
hepatic secretory and microsomal function during various periods of hepatic
ischemia/reperfusion. Rats were pretreated with alpha-tocopherol or vehicle and
then subjected to 30, 60, and 90 min, no-flow hepatic ischemia in vivo with 1 or
5 h of reperfusion. Serum aminotransferase (ALT) level, wet-dry weight ratio, and
lipid peroxidation were increased at 1 and 5 h of reperfusion, and these changes
were significantly attenuated by alpha-tocopherol. Na+, K+-ATPase activity, and
glucose-6-phosphatase activity were significantly decreased in 90-min ischemic
rats, and these decreases were ameliorated by alpha-tocopherol. After 90 min of
ischemia, bile flow, cholate output, and bilirubin output were markedly decreased
by ischemia/reperfusion, and alpha-tocopherol restored the secretion. Cytochrome
P450 content was decreased by ischemia/reperfusion and restored by alpha
tocopherol to the level of that found in the sham-operated group. Aminopyrine N
demethylase activity was decreased, and aniline p-hydroxylase was increased in 60
min ischemic rats. The changes in the activities of the two enzymes were
prevented by alpha-tocopherol. Our findings suggest that ischemia/reperfusion
diminishes hepatic secretory functions and microsomal drug metabolizing systems
in proportion to the duration of ischemia and reperfusion in vivo, and this is
associated with increased lipid peroxidation.
PMID- 10774617
TI - The complement regulators C1 inhibitor and soluble complement receptor 1
attenuate acute lung injury in rabbits.
AB - Because activation of the complement system plays a major role in the
pathogenesis of acute lung injury, the availability of new specific complement
inhibitors represents a promising therapeutic approach. In the present study we
investigated pulmonary edema formation and pulmonary artery pressure (PAP) in
acute complement-induced lung injury for possible therapeutic impact of the
complement regulators C1 inhibitor and soluble complement receptor 1. Eighteen
isolated and ventilated rabbit lungs were perfused with pooled normal human serum
(NHS, final concentration 35%) in Krebs-Henseleit buffer in a recirculating
system. Lung weight gain and PAP were continuously recorded. Complement
activation was blocked by the addition of C1 inhibitor (1.0 U/mL, n = 6) or sCR 1
(2.0 microg/mL, n = 6). Lungs that received NHS without inhibitors served as
controls (n = 6). This study was performed according to the Helsinki Declaration
and approved by the local government. Application of NHS resulted in an increase
of PAP within 20 min from 8+/-2 to 42+/-6 mmHg, which was significantly (P <
0.05) decreased by C1-Inh (25+/-5 mmHg) and sCRI (20 +/-3 mmHg). Moreover,
pulmonary edema formation after NHS, as assessed by overall weight gain, was
reduced by both C1-Inh and sCR1, compared with controls. These findings were
paralleled with significantly decreased thromboxane release rates and reduced
tissue deposition of C3c and C5b-9. C1 inhibitor and sCR1 attenuate the
complement-induced pulmonary capillary leakage and PAP increase, indicating the
protective effect of complement inhibition in isolated perfused rabbit lungs.
PMID- 10774618
TI - A porcine model of sepsis resulting from the combined insults of hemorrhage and
peritonitis.
AB - The physiological responses to either hemorrhage or sepsis have been well
documented, however, their simultaneous delivery, as often seen in penetrating
trauma, has not been extensively studied. A terminally-anesthetized porcine model
of fixed-volume hemorrhage combined with intraperitoneal sepsis was developed.
Large White pigs (45-60 kg) were bled 40% of blood volume and peritonitis was
induced using an E. coil (O18:K1:H7) culture. Three groups of animals were
sequentially studied. Group A (n = 8) received 10(8) bacteria, and Groups B (n =
4) and C (n = 5) received 10(10) organisms. All animals were maintained on a 2.5
mL/kg/h infusion of 0.9% saline. Group C was autotransfused at 1 h. Animals were
monitored for up to 24 h. Cardiovascular features of hypovolemia were recorded in
all animals. Animals in Group A improved clinically with little microbiological
evidence of systemic sepsis. Group B showed rapid cardiovascular collapse, early
E. coil-positive blood cultures, and an early rise in serum TNF-alpha levels.
Autotransfusion of Group C significantly improved cardiopulmonary parameters,
acid-base status, and survival. A reproducible model of hemorrhage and
peritonitis, appropriate for abdominal trauma, which allows investigation of
resuscitative and pharmacological interventions has been characterized.
PMID- 10774619
TI - Synergistic septicemic action of the gram-positive bacterial cell wall components
peptidoglycan and lipoteichoic acid in the pig in vivo.
AB - Despite the fact that gram-positive infections constitute around 50% of all cases
leading to septic shock, little is yet known about the mechanisms involved. This
study was carried out to find out more about the effects of cell wall components
peptidoglycan (PepG) and lipoteichoic acid (LTA) of the gram-positive bacterium
Streptococcus pyogenes in the pig. Specific pathogen-free pigs (20 kg bodyweight)
were pretreated with metyrapone (a cortisol-synthesis inhibitor) and then were
given 2-h infusions of 160 microg/kg of PepG (n = 5), 160 microg/kg LTA (n=5), or
a combination of both (LTA + PepG, 160 microg/kg each, n = 5). Four hours after
start of the infusions, the PepG, LTA, and LTA + PepG groups showed decreases in
mean arterial pressure (change of -11%, -25%, and -47% from baseline,
respectively), dynamic lung compliance (-18%, -24%, and -38%), arterial oxygen
tension (-10%, -16%, and -37%), changes in blood leukocyte numbers (+11%, -27%,
and -67%), and increases in pulmonary vascular resistance index (+7%, +106%, and
+307% from baseline) and metabolic acidosis (base excess values decreased with
1.8, 2.3 and 8.1 units). The differences between the PepG and LTA + PepG groups
were statistically significant (P < 0.05, Kruskal-Wallis tests), but not between
LTA and LTA + PepG groups. However, no changes in systemic nitric oxide (NO)
production could be detected, which is much in contrast to studies on lower order
animals. Moreover, comparison of the results obtained using this model with those
obtained in a model of endotoxin-induced septic shock showed distinct difference
in the mechanisms by which gram-positive and gram-negative bacterial components
exert their actions. For example, a marked fall in systemic blood pressure and
dynamic lung compliance is seen in both models, but in the present gram-positive
sepsis model, much less interleukin-8 and tumor necrosis factor-alpha are
produced. In conclusion, this study showed that PepG and LTA act synergistically
to cause respiratory failure and septic shock in the pig. The infusion of the
combination of PepG and LTA in the pig could serve as a new, well-controlled
model for studies of gram-positive sepsis.
PMID- 10774620
TI - Effects of the combined thromboxane receptor antagonist and synthase inhibitor
DTTX-30 on intestinal O2-exchange and energy metabolism during hyperdynamic
porcine endotoxemia.
AB - Sepsis may lead to deranged thromboxane-prostacyclin ratio with consecutive organ
dysfunction. Because of the suggested role of the gut in the pathogenesis of
septic shock and multiple organ failure, we investigated the effects of the novel
dual thromboxane synthase inhibitor and receptor antagonist DTTX-30 (TRASI) on
intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of
hyperdynamic, normotensive porcine endotoxemia. Before, 12, 18, and 24 h after
starting continuous i.v. endotoxin (LPS), we measured portal venous (PV) blood
flow, intestinal oxygen extraction (iO2ER), intracapillary hemoglobin O2
saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV lactate
pyruvate (L-P) ratio, and plasma levels of thromboxane and prostacyclin.
Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of
0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma
thromboxane levels and attenuated the LPS-induced fall in systemic vascular
resistance, resulting in hemodynamic stabilization. TRASI did not influence the
LPS-induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting
unchanged microcirculatory O2 availability and decreased iO2ER, possibly because
of reduced O2 requirements. Nevertheless, TRASI prevented the LPS-induced
increase in the PV L-P ratio, attenuated the progression of the ileal mucosal
arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence,
compounds like TRASI may beneficially influence LPS-related derangements of gut
energy metabolism.
PMID- 10774621
TI - Sodium arsenite induces the stress response in the gut and decreases bacterial
translocation in a burned mouse model with gut-derived sepsis.
AB - Bacteria translocation from the bowel to systemic organs after burn injury may
contribute to or be a cause of sepsis and multiple organ failure. The stress
response confers protection under stressful conditions that would otherwise lead
to cell damage or death. We investigated whether prior induction of the stress
response by sodium arsenite could affect bacterial translocation after thermal
injury. HSP-70, a highly stress-inducible protein, was used as a marker for
induction of the stress response. Balb/c mice were intravenously injected with 4
mg/kg of sodium arsenite and killed at selected times post-treatment. Other
treated mice were then gavaged with 10(10) E. coil or 10(10) 111In-labeled E.
coil followed by a 20% burn. Survival was observed for 10 days. Mice gavaged with
radiolabeled E. coil were killed 4 h post-burn to determine the effect of HSP-70
induction on microbial translocation in mesenteric lymph nodes (MLN), liver, and
spleen. Sodium arsenite-injected mice showed HSP-70 induction in the ileum that
increased in a time-dependent manner with peak expression 12 h post-injection.
Treated mice showed a significantly higher survival rate (93%) than controls
(46%; P < 0.05), and detection of 111In-labeled E. coli was significantly less in
the liver and spleen (P < 0.05). These data show that sodium arsenite induced HSP
70 expression in the small intestine. The stress response was associated with
significantly increased survival and significant decrease in detection of 111In
labeled E. coil in the liver and spleen in a burned mouse model with gut-derived
sepsis.
PMID- 10774622
TI - Reduced oxygen consumption precedes the drop in body core temperature caused by
hemorrhage in rats.
AB - This study examines the early time course in core temperature change and oxygen
consumption at 4 levels of hemorrhage. Chronically instrumented rats were
acclimatized to a respirometry chamber for 30 min. The rats were briefly (10 min)
removed from the chamber for a fixed volume hemorrhage of 0 mL/kg (sham), 8
mL/kg, 16 mL/kg, 24 mL/kg, or 32 mL/kg. Rats were then returned to the chamber,
and oxygen consumption and body core temperature were monitored for the next 2 h.
Oxygen consumption (control 1.26 mL O2/g/h) fell significantly 5 min after
hemorrhage in all but the sham and 8 mL/kg hemorrhage groups, with the decrease
proportional to the hemorrhage volume. The 32 mL/kg hemorrhage group showed the
greatest decrease, to 0.47 mL O2/g/h. Body core temperature (control 37.5 degrees
C) fell more gradually, declining to 35.6 degrees C 110 min after the 24 mL/kg
hemorrhage, and to 33.2 degrees C at 6 h after the 32 mL/kg hemorrhage. In the 16
mL/kg hemorrhage group, oxygen consumption fell significantly by 5 min after
hemorrhage, but a drop in body temperature was not seen until 25 min after
hemorrhage. The data from this study indicate that the drop in core temperature
does not cause the observed decrease in oxygen consumption. In fact, the timing
and magnitude of the drop in oxygen consumption indicate that the reduced
metabolic rate may mediate the hemorrhage-induced drop in body core temperature
in conscious rats.
PMID- 10774623
TI - Upregulation of inducible nitric oxide synthase and nitric oxide occurs later
than the onset of the hyperdynamic response during sepsis.
AB - Polymicrobial sepsis is characterized by an early, hyperdynamic phase (i.e., 2-10
h after cecal ligation and puncture [CLP]) followed by a late, hypodynamic phase
(16 h after CLP or later). Although nitric oxide (NO) plays an important role in
the pathophysiologic response during sepsis, it remains unknown how early NO is
upregulated after the onset of sepsis and which organs are responsible for
producing the increased amount of NO. To study this, male rats were subjected to
sepsis by CLP followed by fluid resuscitation. Blood samples were then taken at
2, 5, 10, or 20 h after CLP or sham operation. In additional groups of animals,
the kidneys, small intestine, heart, liver, and lungs were harvested at 5 or 10 h
after CLP. Plasma and tissue levels of nitrate and nitrite (NO3-/NO2-, stable
products of NO) were determined by using a colorimetric assay. Inducible NO
synthase (iNOS) mRNA was examined in various tissues harvested at 10 h after CLP
by reverse transcription-polymerase chain reaction (RT-PCR) technique. The
results indicate that plasma levels of NO3-/NO2- (mainly reflecting iNOS
activity) did not increase at 2-5 h but were significantly elevated at 10-20 h
after CLP. Tissue levels of NO3-/NO2- increased significantly in the kidneys,
small intestines, heart, and liver at 10 h but not at 5 h after CLP. Similarly,
iNOS gene expression was upregulated in the kidneys, small intestines, and liver.
Thus, the above organs appear to be important sites responsible for producing the
increased NO during sepsis. Because we previously showed that the hyperdynamic
response occurs as early as 2 h after CLP and because iNOS-derived NO production
is not upregulated earlier than 10 h after the onset of Sepsis, it appears that
factors other than NO are responsible for producing the hyperdynamic response
during sepsis.
PMID- 10774624
TI - Is therapeutic drug monitoring a case for optimizing clinical outcome and
avoiding interactions of the selective serotonin reuptake inhibitors?
AB - The selective serotonin reuptake inhibitors (SSRIs) comprise citalopram,
fluoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each
other in chemical structure, by pharmacokinetic properties and, most importantly,
with respect to enzyme-specific metabolism and interactions. Citalopram is
administered as a racemic mixture. The drug is oxidated to desmethylcitalopram in
the liver, partially by CYP2C19 and partially by CYP3A4. Fluoxetine is
administered as a racemate of R- and S-fluoxetine. Both R- and S-fluoxetine are
metabolized by CYP2D6 to the active metabolites R- and S-norfluoxetine.
Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6.
Paroxetine is metabolized to inactive metabolites partially by CYP2D6, and
accordingly the metabolism of paroxetine is dependent on the genetic polymorphism
of CYP2D6. Sertraline is metabolized to desmethylsertraline, probably by CYP3A4.
Several analytical methods have been described for all SSRIs. Most assays are
based on separation by high-performance liquid chromatography or gas
chromatography. Stereoselective methods for the analysis of racemic citalopram
and fluoxetine have been published. The SSRIs are generally well tolerated and
their therapeutic indices are large. In several studies there has not been found
a clear relationship between clinical efficacy and plasma concentration, nor any
threshold that defines toxic concentrations. The available data do not suggest
that any benefit be obtained from routine monitoring of SSRI plasma levels.
Therefore therapeutic drug monitoring (TDM) of the SSRIs may be useful mainly in
situations where poor compliance is suspected and when therapeutic failure or
toxic events are experienced at clinically relevant dosages. Further, in special
populations, such as in elderly patients, poor metabolizers of sparteine (CYP2D6)
or mephenytoin (CYP2C19), and patients with liver impairment, the measurement of
plasma concentrations may be useful.
PMID- 10774625
TI - Interactions between drugs and Asian medicine: displacement of digitoxin from
protein binding site by bufalin, the constituent of Chinese medicines Chan Su and
Lu-Shen-Wan.
AB - Asian medicines are widely used as alternative medicine. However, interactions
between drugs and Asian medicines have been poorly studied. Chan Su and Lu-Shen
Wan are Asian medicines that contain the cardiaoactive compound bufalin. Bufalin
is structurally similar to digitoxin and is also strongly bound to serum albumin.
The authors studied possible displacement of digitoxin from the protein binding
site by bufalin. The authors prepared three serum pools from patients taking
digitoxin and supplemented aliquots of each serum pool with no bufalin (control)
and 25 ng/mL, 50 ng/mL, 100 ng/mL, 250 ng/mL, 500 ng/mL, and 1000 ng/mL bufalin.
The authors observed significant displacement of digitoxin by bufalin as
evidenced by increased free digitoxin concentrations. For example, the
concentration of free digitoxin increased from a control value of 1.6 ng/mL to
2.5 ng/mL in the presence of 1000 ng/mL bufalin (total digitoxin: 36.3 ng/mL) in
the serum pool 1. The authors observed similar increases in free digitoxin
concentrations in other serum pools in the presence of various concentrations of
bufalin. The authors used a chemiluminescent assay and ACS:180 analyzer to
measure both total (in the original serum) and free (in the protein-free
ultrafiltrate) digitoxin concentrations because the chemiluminescent assay does
not cross-react with bufalin. When an acetone/water (1:1 by volume) extract of
Chan Su was added to a serum pool containing digitoxin, the authors observed a
significantly increased free digitoxin concentration, indicating that Chan Su can
displace digitoxin from the protein binding site in vitro. The authors conclude
that bufalin and acetone/water extract of Chan Su can cause significant
displacement of digitoxin from the protein binding site.
PMID- 10774626
TI - Cyclosporin assays, metabolite cross-reactivity, and pharmacokinetic monitoring.
AB - The range of cyclosporin (CsA) immunoassays has become the mainstay in many
therapeutic drug monitoring laboratories for delivering CsA concentration data to
support clinical care of patients after transplantation. However, these assays
have been criticized because of the varying degree of CsA-metabolite
interferences that introduce analytical errors. The introduction of another such
CsA assay (on the AXSyM analyzer) has been considered, as the manufacturer has
represented it as having a low CsA-metabolite cross-reactivity profile compared
with chromatographic methods. A case is presented to question how this apparent
result was obtained in view of the method using the same antibody as another CsA
method from the same manufacturer (fluorescence polarizaton immunoassay on the
TDx analyzer) which is well known to have poor performance in regard to CsA
metabolite cross-reactivity. The implications for this problem may be even more
serious as more patients are monitored using the CsA AUC strategies, rather than
the traditional trough concentration approach. Such issues reinforce the need for
the clinical laboratory to be critical of methods offered commercially based on
scientific/pharmacologic skills.
PMID- 10774627
TI - Digoxin level and clinical manifestations as determinants in the diagnosis of
digoxin toxicity.
AB - The aim of this study was to determine the relative importance of different risk
factors in the diagnosis of digitalis toxicity. The authors recruited inpatients
for whom serum digoxin level was requested and prospectively followed them for a
week to ascertain if they showed digitalis toxicity. The predictive value of
different factors for the assessment of digoxin toxicity was analyzed by multiple
logistic regression. Forty-one toxic and 58 nontoxic patients were included. In
the univariant analysis, intoxicated patients were older, most were women, and
they had worse renal function and higher digoxin level; but there were no
differences in serum electrolytes or other risk factors. In the multivariant
analysis, digoxin level was the only independent factor related to digitalis
toxicity. A different risk of toxicity for each clinical manifestation was found
for a certain digoxin level. Patients with signs of automaticity in the
electrocardiogram had a higher likelihood of being intoxicated than patients with
gastrointestinal symptoms, atrioventricular block, or bradycardia. Therefore, in
the population evaluated in this study, digoxin level is the key independent
factor in digoxin intoxication, although the probability of being intoxicated is
also a function of the type of clinical manifestations. A graphic approximation
of this probability based on these two factors is presented.
PMID- 10774628
TI - Limited sampling strategy for mycophenolic acid area under the curve.
AB - The immunosuppressive potential of mycophenolate mofetil (MMF), a prodrug for
mycophenolic acid, is related to the area under the time-concentration curve
(AUC). Full pharmacokinetic (PK) profiles are expensive and cumbersome, and
therefore a limited sampling technique would be favorable. The authors
retrospectively analyzed 114 full 10-point PK profiles from 61 pediatric patients
receiving MMF. Stepwise multiple regression analysis was used to calculate
limited sampling approaches. Correlation between AUC and predose trough
concentration was r2 = 0.29 (p < 0.0001), and between AUC and postdose trough
concentration was r2 = 0.48 (p < 0.0001). The best correlations were with the 2
hours (C2, r2 = 0.59, p < 0.0001), three hours (C3, r2 = 0.52, p < 0.0001), 1.5
hours (C1.5, r2 = 0.50, p < 0.0001), and six hours (C6 r2 = 0.43, p < 0.0001). No
combination of any two sampling points resulted in significantly better
correlation with AUC, but three-point estimates at C1, C2, and C6 resulted in
excellent correlation between predicted AUC and AUC from the full profile when
using the formula AUC = 10.75 + (0.98 x C1) + (2.38 x C2) + (4.86 x C6), Pearson
r = 0.93, 95% confidence interval 0.89 to 0.95. Bland and Altman analysis
revealed good agreement between predicted AUC and AUC from the full profile. The
AUC of mycophenolic acid can be predicted by limited sampling including C1, C2,
and C6.
PMID- 10774629
TI - Stereospecificity of antibody: quinine, the optical isomer of quinidine and anti
malarial drug chloroquine do not cross-react with quinidine immunoassays.
AB - Quinine is an optical isomer of quinidine. Both quinine and chloroquine (an
aminoquinoline derivative) are used in treating malaria. The authors studied
cross-reactivity of quinine and chloroquine with the quinidine immunoassays using
the TDx and AxSYM analyzers (Abbott Laboratories, Abbott Park, IL). The authors
observed no cross-reactivity of chloroquine with quinidine immunoassays (TDx and
AXSYM) even when drug-free serum was supplemented with 1000 microg/mL
chloriquine. The authors observed no cross-reactivity of quinine up to a
concentration of 250 microg/mL. At higher concentrations, the authors observed a
small cross-reactivity. The cross-reactivity of a substance should be studied in
the presence of the primary analyte. When serum pools prepared from patients
receiving quinidine were supplemented with various concentrations of quinine or
chloroquine, the authors observed statistically significant declines in quinidine
concentrations with higher concentrations of both quinine and chloroquine. The
authors observed significant cross-reactivity of L-amphetamine with the
amphetamine immunoassay also marketed by Abbott Laboratories and run on the AxSYM
analyzer. The authors conclude that although the antibody used in the quinidine
assay is stereospecific, the antibody used in the amphetamine assay by the same
manufacturer is not stereospecific.
PMID- 10774631
TI - Measurement of tafenoquine (WR 238605) in human plasma and venous and capillary
blood by high-pressure liquid chromatography.
AB - A simple, rapid, and accurate high-pressure liquid chromatographic method with
fluorescence detection is described for the measurement of tafenoquine (TQ) (also
known as WR 238605) from human plasma and venous and capillary blood. Tafenoquine
was measured in plasma and venous blood following protein precipitation.
Chromatographic separation was achieved using a Waters S5P Spherisorb phenyl
analytical cartridge (150 mm x 4.6 mm I.D., 5 microm particle size) (Waters,
Milford, MA, USA) and a mobile phase of 22 mM ammonium acetate, pH 4:acetonitrile
(45:55, vol/vol). The flow rate was 1.5 mL/min and the retention times were
approximately 3.5 min for WR VIIIAc (internal standard) and approximately 7.8 min
for TQ. The interday and intraday coefficients of variation of TQ over a
concentration range of 20-1000 ng/mL in plasma were < or =8.4% and in venous
blood were < or =9.6%. The mean percent difference between added concentration
and obtained concentration was 7.3% in plasma and 8.5% in venous blood over the
corresponding concentration range. The limit of quantitation for both fluids was
10 ng/mL. Tafenoquine concentrations were comparable between capillary and venous
blood with no significant difference between measurement in both biological
fluids. The clinical application of the method was demonstrated by measuring
plasma and whole blood concentrations of TQ from participants in a
chemosuppression trial of the drug against malaria infections in Thailand.
PMID- 10774630
TI - A simple high-performance liquid chromatography assay for simultaneous
measurement of adenosine, guanosine, and the oxypurine metabolites in plasma.
AB - To study the effect of pharmacologic agents on the biologic fate of adenosine, a
reversed-phase high-performance liquid chromatography (HPLC) assay coupled with a
solid-phase extraction (SPE) method was developed for simultaneous determination
of plasma adenosine, hypoxanthine, xanthine, inosine, guanosine, and uric acid.
The HPLC system consisted of a reversed phase C18 column, UV detector set at 254
nm, and a mobile phase composed of 0.01 M ammonium phosphate: methanol (9.5 :
0.5) vol/vol with the final pH adjusted to 3.9. The standard curves were linear
between 0.1-2 microg/mL for all the analytes (except uric acid 50-400 microg/mL),
with r2 > 0.99. The absolute recoveries were >60% and accuracy >85% in almost all
cases. The limit of detection was <1 ng based on absolute injection of the
analytes. The intraassay variations were <10% and interassay variations <15%. The
presence of a wide range of medications in plasma samples did not interfere with
the assay. The assay was applied successfully to measure plasma adenosine and the
oxypurine metabolites in humans and rats. It was noted that plasma concentrations
of adenosine and the oxypurine metabolites can vary considerably depending on the
method of blood sample collection, and that species differences are apparent.
PMID- 10774632
TI - Simultaneous plasma level analysis of clomipramine, N-desmethylclomipramine, and
fluvoxamine by reversed-phase liquid chromatography.
AB - A simple reversed-phase liquid chromatographic method enabling the simultaneous
analysis in plasma of the tricyclic antidepressant clomipramine, its demethylated
metabolite, and the selective serotonin reuptake inhibitor fluvoxamine, was
developed. The drugs and dibenzepine, the internal standard, were extracted from
1 mL plasma through an automated solid-phase procedure, eluted in a total
chromatographic time of approximately 14 min and detected by means of an
ultraviolet spectrophotometer preset at 254 nm. An assay sensitivity of 10
microg/L was observed for all analytes. Recoveries for these drugs and their
metabolites ranged between 65% and 98% and their coefficient of variation (within
day and day-to-day) between 1.9% and 2.9%. In spiked plasma, within-day and day
to-day imprecision data were less than 5%. The simultaneous determination of
clomipramine, N-desmethylclomipramine, and fluvoxamine with adequate sensitivity
and accuracy may be useful for the monitoring of drug treatment in depression and
obsessive-compulsive disorder, where combinations of such drugs are employed.
PMID- 10774633
TI - An improved gas chromatography assay for topiramate monitoring in pediatric
patients.
AB - An improved micromethod involving capillary gas chromatographic assay with liquid
liquid extraction and nitrogen phosphorus detection (GC/NPD) was developed and
validated for the determination of topiramate (TPM) in human body fluids. The
galactopyranose analog of TPM was used as the internal standard. Capillary gas
chromatographic conditions yielded typical retention times of 6.8 min for TPM and
7.2 min for the internal standard. Calibrations were linear between 1.0 and 32
microg/mL. Between-day precision (n = 17) for three serum controls (3.0, 10, and
24.5 microg/mL) resulted in coefficients of variation of 6.9%, 7.3%, and 4.9%,
respectively. The limit of detection was 0.42 microg/mL. There was an excellent
linear correlation between the fluorescence-polarization immunoassay (FPIA) and
GC/NPD determinations of 56 patient specimens (r2 = 0.981). Chromatograms showed
no interfering peaks with the respective blank human samples or from many
commonly prescribed drugs. Because of improved specificity and decreased sample
volume requirements, this micromethod should be particularly useful for
monitoring TPM therapy in pediatric patients, for patients with impaired renal
function, and for research studies.
PMID- 10774634
TI - Venlafaxine serum levels and CYP2D6 genotype.
AB - Thirty-three patients with depression treated with 225 mg venlafaxine were
genotyped for the polymorphic enzyme, debrisoquine 4-hydroxylase (CYP2D6). The
relationship between drug and metabolite levels and between genotype and clinical
response were investigated. Although the number of responders in this study is
insufficient for definite conclusions to be drawn, a target therapeutic
concentration ranging from 195-400 microg/L for the sum of venlafaxine and O
desmethylvenlafaxine is suggested. The ratio of O-desmethylvenlafaxine to
venlafaxine in the serum concentrations is a measure of metabolic turnover, and
can be used to distinguish between ultrarapid and poor metabolizers. All but one
of the nonresponders in this study had lower ratios than the responders. Three
patients (9%) had homozygous defective CYP2D6 alleles and did not readily
metabolize venlafaxine to O-desmethylvenlafaxine, pointing to poor metabolism. In
these patients, N-desmethylation was increased. Two out of four patients detected
by the ratio as potentially ultrarapid metabolizers were shown to have multiple
copies of a functional CYP2D6 gene.
PMID- 10774635
TI - Steady state plasma levels of the enantiomers of trimipramine and of its
metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients.
AB - Steady state plasma concentrations of the (L)- and (D)-enantiomers of
trimipramine (TRI), desmethyltrimipramine (DTRI), 2-hydroxytrimipramine (TRIOH)
and 2-hydroxydesmethyl-trimipramine (DTRIOH) were measured in 27 patients
receiving between 300 and 400 mg/day racemic TRI. The patients were phenotyped
with dextromethorphan and mephenytoin, and the 8-hour urinary ratios of
dextromethorphan/dextrorphan, dextromethorphan/3-methoxymorphinan, and (S)
mephenytoin/(R)mephenytoin were used as markers of cytochrome P-450IID6 (CYP2D6),
CYP3A4/5 and CYP2C19 activities, respectively. One patient was a CYP2D6 and one
was a CYP2C19 poor metabolizer. A stereoselectivity in the metabolism of TRI has
been found, with a preferential N-demethylation of (D)-TRI and a preferential
hydroxylation of (L)-TRI. CYP2D6 appears to be involved in the 2-hydroxylation of
(L)-TRI, (L)DTRI and (D)-DTRI, but not of (D)-TRI, as significant correlations
were measured between the dextromethorphan/dextrorphan ratios and the (L)-TRI/(L)
TRIOH (r = 0.45, p = 0.019), the (L)-DTRI/(L)-DTRIOH (r = 0.47, p = 0.014), and
the (D)-DTRI/(D)-DTRIOH (r = 0.51, p = 0.006), but not with the (D)-TRI/(D)-TRIOH
ratios (r = 0.29, NS). CYP2C19, but not CYP2D6, appears to be involved in the
demethylation pathway, with a stereoselectivity toward the (D)-enantiomer of TRI,
as a significant positive correlation was calculated between the mephenytoin
(S)/(R) ratios and the concentrations to dose-to-weight ratios of (D)-TRI (r =
0.69, p = 0.00006). CYP3A4/5 appears to be involved in the metabolism of (L)-TRI
to a presently not determined metabolite. The CYP2D6 poor metabolizer had the
highest (L)-DTRI and (D)-DTRI concentrations to dose-to-weight ratios, and the
CYP2C19 poor metabolizer had the highest (L)-TRI and (D)-TRI concentrations to
dose-to-weight ratios of the group.
PMID- 10774636
TI - Determination of ribavirin in serum using highly selective solid-phase extraction
and high-performance liquid chromatography.
AB - A rapid assay for determination of ribavirin in serum using solid-phase
extraction (SPE), high-performance liquid chromatography (HPLC), and UV-detection
was developed. The SPE uses phenylboronic acid columns with an approximately 100%
recovery for ribavirin. The concentration-peak area relation was linear (r >
0.995), from 1 to 64 microM in 100 microL serum. The limit of detection was 0.1
microM. The intraassay CV was 3.2% at treatment levels (9.7 microM) and 11.5% at
0.4 microM. The method is used to monitor patients undergoing ribavirin treatment
for hepatitis C (HCV). Samples from HCV-infected patients with and without renal
dysfunction have been analyzed without interference of endogenous compounds. It
is concluded that the method is useful for routine therapeutic drug monitoring.
PMID- 10774637
TI - Stereoselective HPLC-assay for citalopram and its metabolites.
AB - The racemic selective serotonin reuptake inhibitor citalopram (CIT) is
increasingly used for depressive disorders. As both enantiomers of CIT differ in
pharmacologic activity and demethylated metabolites might contribute to the
antidepressent action of CIT, a stereoselective assay for all active compounds is
needed, but will require that pharmacokinetic/pharmacodynamic relationships be
investigated. A stereoselective high-performance liquid chromatography (HPLC)
assay (Chirobiotic V column) with UV-detection (lambda = 240 nm) for R- and S-CIT
as well as both enantiomers of desmethyl(DM)-CIT and didesmethyl(DDM)-CIT was
developed. The calibration range was linear from 5 to 200 ng/mL and the lower
limit of detection averaged 2 ng/mL. Based on three quality controls (10, 75, and
150 ng/mL) the intraday and interday coefficients of variation ranged from 1.3%
to 9.0% for CIT and from 2.2% to 10.3% for DM-CIT and DDM-CIT. The assay was used
to analyze the trough steady state plasma levels of all 6 agents in 16 elderly
patients treated daily with 20 to 40 mg CIT. For the dose of 20 mg (n = 14) mean
values +/- SD of R- (and S-CIT) averaged 36.2+/-15.0 (27.4+/-13.1) ng/mL,
respectively (mean R/S-ratio: 1.4+/-0.4), for R- (and S-DM-CIT) 7.2+/-3.1 (7.7+/
3.8) ng/mL, respectively (R/S-ratio: 1.0+/-0.3) whereas DDM-CIT was only
detectable as R-enantiomer in 8 cases (13.2+/-12.1 ng/mL; range: 2.2-36.2 ng/mL).
Significant (p < 0.01) linear correlations could be found between both
enantiomers of CIT and DM-CIT as well as between parent drug and primary
metabolite for the R-enantiomers. Apparently R/S- and metabolic ratios increased
with dose; this might indicate that stereoselective disposition of CIT and DM-CIT
is concentration-dependent. The present assay allows a rapid, sensitive, and
reliable stereoselective determination of CIT and its (active) metabolites which
can be applied for assessing pharmacokinetic parameters and evaluating putative
relationships to clinical (side) effects.
PMID- 10774638
TI - Therapeutic drug monitoring of tacrine: simple and fast high-performance liquid
chromatography assay method for its determination in human plasma.
AB - A new high-performance liquid chromatography (HPLC) assay method was developed
for the therapeutic monitoring of tacrine. The method involved a simple protein
precipitation by means of either acetonitrile or cold methanol followed by a fast
isocratic separation on a CN column eluted in reversed-phase mode. The entire
sample preparation took place in an HPLC vial and no further liquid transfer was
required. The validation data showed that the assay method was precise, accurate,
and robust. Analysis of more than 1,000 plasma samples collected from patients
with Alzheimer disease demonstrates the suitability of the assay.
PMID- 10774639
TI - Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin
concentration with central nervous system intoxication.
AB - The authors report on a Japanese adult male patient with a long history of
partial seizures that were poorly controlled by conventional doses of phenytoin
and other drugs. His treatment was complicated by toxic symptoms and an excessive
serum phenytoin concentration, 32.6 microg/mL at a dose of 187.5 mg/day.
Polymerase chain reaction-restriction fragment length polymorphism analysis
disclosed heterozygosity involving cytochrome P450 subfamilies 2C9 (*1/*3) and
2C19 (*1/*3). Currently, it is generally accepted that the former mutation is
responsible for the CYP2C9 poor metabolizer phenotype. Pharmacokinetic parameters
were estimated by a kinetic analysis, MULTI, using 17 observed dose-concentration
data sets: a lower Vmax (5.6 mg/kg/day) and a higher Km (11.5 microg/mL) were
observed. Although phenytoin is metabolized predominantly by CYP2C9 with a minor
contribution of CYP2C19, patients with the Leu359 variant should be monitored
closely when treated with a moderate to high daily dose of phenytoin.
PMID- 10774640
TI - Systemic vancomycin overexposure in a patient with spinal cord injury who had
Staphylococcal sepsis and Clostridium difficile colitis.
PMID- 10774641
TI - Equity in sharing science and the ownership of knowledge.
PMID- 10774642
TI - Malaria in tree crop plantations in south-eastern and western provinces of
Thailand.
AB - During the past three decades almost half of the existing natural tropical
forests in Thailand were destroyed and replaced by cash crops, rubber, coffee,
fruit orchards (durian, rambutan, mangosteen) and other commercial plantations.
In order to determine the proportion of malaria cases contracted from such
commercial plantations, an epidemiological study was conducted between June 1996
to May 1997 in two districts, one in Pong Nam Ron, located in a south-eastern
province near the Cambodian border and another in Sai Yok, in a western province
along the Myanmar border. Data were collected by passive case detection from
patients attending the existing malaria clinics and active case detection by
monthly malariometric survey in selected villages. All malaria cases were
thoroughly investigated and classified according to exposure to different
ecotypes prior to onset of malaria symptoms in the preceding two weeks. Malaria
cases acquired from commercial plantations accounted for 35.2% and 11.2% in Pong
Nam Ron and in Sai Yok districts respectively. In such plantations, most of the
malaria cases were contracted from fruit orchards and to a lesser extent from
rubber and teak plantations. From this study it is evident that commercial
plantations provide a significant site of malaria transmission in addition to the
forest and foothills areas in Southeast Asia where efficient vectors such as An.
dirus and An. minimus are prevalent and have adapted to such changed ecosystems.
PMID- 10774643
TI - Low CD8+ T lymphocyte response to P. falciparum circumsporozoite protein in
naturally-exposed malaria endemic populations in Thailand.
AB - Cytotoxic T lymphocytes (CTLs) specific for epitope(s) within the
circumsporozoite (CS) protein of malaria sporozoite have been shown to play an
important role in protective immunity against malaria. Human CTLs against the
potential epitope at the carboxy terminal region of CS protein of Plasmodium
falciparum 7G8 strain (Pf7G8CS 368-390) were determined in thirty-six falciparum
malaria patients and ten healthy controls. Four of 36 individuals and none of the
healthy controls developed Pf7G8CS 368-390 specific CTL activity. The CTL
activity was antigen specific and CD8+ T cell dependent. Although low CTL
response has been determined, the study suggested that there was a correlation
between initial parasitemia and the specific Pf7G8CS 368-390 CTL activity. A
correlation between such CTL activity and anti-R32tet32 antibody levels among
individuals with previous malaria experience was found, which was in contrast to
those among individuals with recent malaria infection. All these 4 CTL positive
individuals had at least two episodes of clinical malaria experience while all 25
individuals who were exposed to malaria for the first time did not have such a
specific CTL response. These results showed that individuals with a history of
natural endemic exposure to P. falciparum sporozoite developed low specific CTL
responses to Pf7G8CS 368-390, so that previous but recent sporozoite exposure
might be a prerequisite for generation of such CS protein specific CTL response.
PMID- 10774644
TI - Complicated malaria is associated with differential elevations in serum levels of
interleukins 10, 12, and 15.
AB - Complicated malaria, caused by Plasmodium falciparum, is characterized by
multiple organ dysfunction. The pathogenesis of complicated malaria involves
complex host-parasite interactions that include polarized cytokine responses.
Recently, correlates between Th1-like and Th2-like cytokines, especially
interleukin-10 (IL), IL-12, and TNF-alpha, and specific types of organ
dysfunction have been noted. Here, we measured IL-10, IL-12, and for the first
time, IL-15, in 19 patients aged 16-55 years old with complicated malaria on days
0 (admission), 3, 7, and 14. For analysis, patients were grouped together or sub
categorized into hyperparasitemias or cerebral malaria (CM). For IL-10, a
dramatic increase was noted on admission, followed by a reduction toward control
values that closely paralleled parasite clearance. For IL-12, modest but
persistent increases were noted over the entire 14 day period that did not
correlate with parasitemia. In general, especially on days 0 and 3,
hyperparasitemic patients had, in comparison with CM patients, higher IL-10 and
IL-12 levels. In contrast, IL-15 was generally below detection in most samples.
These results provide further insight into the pathogenesis of complicated
malaria by strengthening the contention that cytokines such as IL-10 and IL-12
are involved in modulating the immune response to P. falciparum.
PMID- 10774645
TI - Acceptance of short course artesunate plus mefloquine drug combination by malaria
patients in rural Myanmar.
AB - A cross sectional study was carried out in a rural area of Myanmar to identify
malaria patients' acceptance of artesunate plus mefloquine drug combination and
to determine the cost borne by patients. The majority (88.5%) preferred this new
regimen rather than the other ones they had used before; conviction of drug
efficacy was the reason given for the preference by most of them. Traveling on
foot to rural health centers or a health assistant's residence for getting the
drugs was found to be the main route. Average cost incurred by a patient to get
the drug was found to be 274.22 Kyats. Among the cost items, drug cost was the
highest item that they had used.
PMID- 10774646
TI - Cost and performance of malaria sector: a case study at Malaria Sector 11, Tak
Province, Thailand.
AB - The objective of this study was to assess the cost and performance of each
operational unit at the malaria sector level and to calculate the unit cost of
each activity accordingly. Data were collected at Malaria Sector No.11 situated
at the western border of Thailand with Myanmar during the fiscal year of 1995.
The unit cost was calculated by dividing the total cost of each activity by its
output using appropriate units of analysis. The result showed that 67% of the
total cost of malaria sector was labor cost and 45% of the total cost was
allocated to diagnosis and treatment activities. Unit cost in terms of
cost/visit, cost/case found, cost/case of falciparum malaria treated, cost/case
of vivax malaria treated, cost/house spray and cost/impregnated net were US$1.85,
8.21, 10.07, 8.46, 2.24 and 1.54 respectively. The results of this study will
provide important information as to the best use of limited available resources
to determine which activities should be stopped, continued, increased or
decreased at the malaria sector level.
PMID- 10774647
TI - Cost-effectiveness analysis of lambdacyhalothrin-treated nets for malaria
control: the patients' perspective.
AB - The present study was undertaken to evaluate the cost-effectiveness of
lambdacyhalothrin-treated nets in comparison with conventional DDT-spraying as a
method of malaria control according to the patients' perspective among migrant
populations in a high-risk area along the Thai-Myanmar border in Thailand. Ten
hamlets comprising 243 houses with 948 inhabitants were given only treated nets.
Twelve hamlets comprising 294 houses and 1,315 inhabitants represented the DDT
treated area and another six hamlets with 171 houses and 695 inhabitants served
as controls. Information as to consumer costs was obtained by interviewing 3,214
patients seeking care at all levels of the health care system in the study area.
Analysis showed that the impregnated-net program was more cost-effective than the
DDT-spraying program or surveillance alone (US$ 0.59 vs US$ 0.74 vs US$ 0.79 per
1 case of prevented malaria). We conclude that in a high-risk area such as along
the Thai-Myanmar border in western Thailand, integrating the use of impregnated
nets with large-scale primary health care programs is likely to constitute the
most cost-effective method for controlling malaria according to the patients'
perspective.
PMID- 10774648
TI - Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic
area in Irian Jaya, Indonesia: influence of seasonal rainfall fluctuations.
AB - A malaria intervention study was carried out using permethrin impregnated bed
nets in the south-central part of Irian Jaya with perennial transmission, from
April 1993 to April 1995. Malariometric surveys were carried out periodically for
parasite prevalence by species and for spleen rates. Prior to intervention, the
percentage of Plasmodium falciparum infected inhabitants was significantly higher
in Hiripau, where permethrin-impregnated bed nets were used during the study,
than in the placebo-treated control village, Kaugapu. After two years of
intervention the situation was reversed and figures higher in the control village
(RR 0.19, 95% CI 0.10-0.36, p < 0.0001). Similarly, P. vivax infection rates,
12.4% in Hiripau vs 5.7% in Kaugapu in April 1993. were reversed in April 1995
(3.6% in Hiripau and 11.3% in Kaugapu, p < 0.001). In the treated village, pre
control hyperendemicity was reduced to a low mesoendemic level (spleen rate
12.5%) during two years of intervention, whereas the level was mesoendemic
(spleen rate 35.2%) in the control village. Impregnated bed nets were found an
effective intervention both in moderate (April 1993 through April 1994, 1,626 mm
rainfall) and high (April 1994 through April 1995/1995, 3,321 mm) transmission
seasons.
PMID- 10774649
TI - Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic
area in Irian Jaya, Indonesia: differentiation between two age groups.
AB - A malaria intervention trial was conducted for two years to evaluate the efficacy
of permethrin-impregnated bed nets in reducing malaria infection and splenomegaly
in two different age groups, ie below and over age of ten, in a hyperendemic area
in Irian Jaya, Indonesia. Permethrin-impregnated or placebo-treated bed nets were
provided to a treated and a control village, respectively. Immediately after
periods with moderate rainfall in the first year, treated bed nets decreased P.
falciparum and P. vivax density in the blood of children <10 years (group 1) but
did not reduce the percentage of infection with either species. Children >10 and
adults (group 2) showed significant reduction only in P. falciparum infection
rates and density, whereas P. vivax was not influenced. After an excessive
rainfall season in the second year, the risk for P. falciparum infections in both
age groups using treated nets was less than half of that in the control village.
P. vivax infection rates were significantly lower in the treated village at the
beginning of and after these heavy rainfalls. In the treated village, spleen
enlargement was markedly reduced in the younger age group during the second year.
PMID- 10774650
TI - Well-breeding Anopheles dirus and their role in malaria transmission in Myanmar.
AB - Mosquitos were collected with human and animal baits from March 1996 to January
1998 in four villages located along the Yadana gas pipe line in Yepyu township,
Dawae district, Tanintharyi Division, southern Myanmar. A total of 23 anopheline
species were collected. Anopheles dirus were abundant in pre-monsoon (May/June)
an post-monsoon (October) months. All An. dirus caught both humans and cattle
were assayed with specific, sporozoite enzyme-linked immunosorbent assays
(ELISAs). A total of 5/250 (2%) caught with human bait was found positive with
Plasmodium vivax from Eindayaza, Ohnbinkwin and Thaechaung during rainy and cool
dry months. Larval surveys also showed An. dirus larvae/pupae were caught from
domestic wells (6 to 46% found positive). Clinical surveys indicated that
transmission is hyperendemic and occur all year round in all four villages.
PMID- 10774651
TI - Differences in Anopheles composition and malaria transmission in the village
settlements and cultivated farming zone in Sarawak, Malaysia.
AB - Anopheles mosquitos were surveyed using three trapping technics in four longhouse
settlements and their respectively farming zone in western Sarawak, Malaysia. The
study area was mountainous with tropical rain forest. An. leucosphyrus and An.
donaldi were predominant in the farm huts. An. tessellatus and An. subpictus were
more abundant in the village settlements. In both ecotypes, human baited traps
yielded a significantly greater proportion of Anopheles mosquito than CDC light
traps and landing biting catches. Circumsporozoite antigen positively rate,
mosquito survival rate and parasite rate showed that malaria transmission is more
intense in farm huts than in longhouse settlements. The entomological inoculation
rate of An. donaldi and An. leucosphyrus in farm huts was 0.035 and 0.023,
respectively. No sporozoite infections were observed in the main settlements.
PMID- 10774652
TI - Insecticide cross-resistance spectra and underlying resistance mechanisms of Sri
Lankan anopheline vectors of malaria.
AB - Present status of insecticide resistance was investigated in two major vectors of
malaria; An. culicifacies and An. subpictus, collected from a high malaria
transmission area in Sri Lanka during 1996/1998. Adult and larval bioassays were
carried out to obtain log-probit mortality lines for malathion, propoxur,
permethrin and chlorpyrifos. Respective LD50 values were 4.45%, 0.002%, 0.16% and
0.001% for An. culicifacies and 0.66%, 0.004%, 0.004% and 0.04% for An.
subpictus. Adults were also tested for WHO standard discriminating dosages of
malathion, propoxur, permethrin, DDT, cypermethrin, deltamethlin and lambda
cyhalothrin. Both populations were highly resistant to DDT. An. culicifacies was
more resistant to malathion and An. subpictus was more resistant to chlorpyrifos.
About 25% of both populations were resistant to permethrin. An. culicifacies was
susceptible to propoxur, deltamethrin and lambda cyhalothrin and An. subpictus to
cypermethrin and lambda cyhalothrin. Adult mosquitos were individually tested for
their insecticide detoxifying enzyme activities and altered target-site,
acetylcholinesterase. High general esterase activity indicated the presence of
amplified esterase genes in both populations. Native gel electrophoresis resolved
one elevated esterase isoenzyme, with high affinity to organophosphates, from
each species. Malathion carboxylesterase mechanism was present in both
populations. Higher glutathione-S-transferase activity was marked in An.
subpictus. Synergistic studies showed the possible involvement of monooxygenases
in resistance in both species. Acetylcholinesterase activity of approximately 80%
of both populations was not inhibited by a standard dosage of propoxur. Low
resistance to carbamates shows that the impact of agricultural pesticides is not
significant in the development of resistance especially in An. culicifaies.
Pyrethroids, other than permethrin, can be successfully used in vector control
programs. Carbamates will be an alternative.
PMID- 10774653
TI - Larvicidal, adulticidal and repellent effects of Kaempferia galanga.
AB - Four fractions of Kaempferia galanga (hexane fraction, dichloromethane fraction
1, dichloromethane fraction 2 and methanolic fraction) were tested for larvicidal
activity toward fourth instar Culex quinquefasciatus. The hexane fraction was
found to exhibit the highest larvicidal effect with the LC50 of 42.33 ppm.
Testing for adulticidal activity, the hexane fraction did not show any promising
adulticidal effect. However, it caused a knockdown effect which might be useful
as a repellent. It was then tested for repellent activity in human volunteers
both in laboratory and field studies. In a laboratory study, the hexane fraction
possessed repellency against Aedes aegypti (ED50 value of 30.73 microg/cm2), and
provided biting protection for 3 hours. In a field study, it could protect
against certain mosquitos, ie, Armigeres subalbatus, Anopheles barbirostris, An.
aconitus, Mansonia uniformis, Cx. quinquefasciatus, Cx. gelidus, Cx.
tritaeniorhynchus and Ae. aegypti. The hexane fraction did not cause dermal
irritation when applied on human skin.
PMID- 10774654
TI - Cross-resistance to Bacillus sphaericus strains in Culex quinquefasciatus
resistant to B. sphaericus 1593M.
AB - Bacillus sphaericus 1593M resistant larvae of Culex quinquefasciatus were reared
in the laboratory since 1995. Resistance in the larvae was monitored by
subjecting selection pressure using B. sphaericus 1593M at every generation.
Bioassays were conducted with different strains of B. sphaericus (Bs 2297, Bs
2362 and Bs IAB 59) and confirmed cross-resistance in the present study. The
level ranged between 27.3 to 18.2 fold in comparison with susceptible larvae. But
Bacillus thuringiensis var israelensis strains (Bti PG14 and Bti 426) did not
show any cross-resistance in the larvae and it emphasized a need to study the
mode of action of B. sphaericus toxin that induces cross-resistance in the larval
strain.
PMID- 10774655
TI - Characterization of three microsatellite loci for Aedes aegypti (Diptera:
Culicidae) and their use for population genetic study.
PMID- 10774656
TI - Control of dengue fever with active surveillance and the use of insecticidal
aerosol cans.
AB - An interventional study was conducted in southern Vietnam to evaluate the
feasibility and effectiveness of a new approach to control dengue fever. The
approach consisted of active surveillance of dengue patients and the use of
insecticidal aerosol cans. Febrile patients were tested serologically at local
health centers and insecticidal aerosol cans were given to the family and
employed in the neighborhood of dengue patients instead of ultra low volume (ULV)
fogging with insecticide. The number of dengue IgM antibody positive cases among
febrile patients, the number of reported dengue hemorrhagic fever patients and
the total cost were compared in the 2 approaches (prompt focal ULV fogging and
the use of insecticidal aerosol cans) in 1997. The aerosol cans were employed 5
times (in June, July, August, September and October) in the study area. ULV
fogging in the control area was performed 5 times (in March, May, July, August
and September). Twenty-two serologically positive cases were found in the study
area which was about half that found in the control area (43 cases). A total of
16 dengue hemorrhagic fever patients was reported in the study area and 43 in the
control area. Compared with the reported numbers of the previous year, the
reduction rate in the number of dengue hemorrhagic fever cases was 71.4% in the
study area and 51.7% in the control area. There were statistically significant
differences in the morbidity of dengue fever and the reduction rate of dengue
hemorrhagic fever. The cost of the insecticidal aerosol cans was US$393 which was
lower than the cost of US$553 for ULV fogging. The findings suggest that
insecticidal aerosol cans were effective and feasible for dengue fever control.
PMID- 10774657
TI - Hepatitis viruses and chronic liver disease.
AB - We have investigated several groups of Thai patients diagnosed with chronic liver
disease including chronic hepatitis, cirrhosis and hepatocellular carcinoma, as
well as cholangiocarcinoma, for the prevalence of infection with either one of
the hepatitis viruses B, C, G and the novel hepatitis virus TT (TTV). The 168
patients tested comprised 120 men and 48 women with their median age ranging from
42.3 to 62.3 years. Screening for antibodies to HBV and HCV was performed by a
commercially available serological test kit, for the presence of HBV and TTV DNA
by PCR, and of HCV and HGV RNA by RT-PCR, respectively. There was a clear two
fold higher prevalence of HBV (49%) over HCV (27%) infection and a four-fold
higher frequency compared to HGV (13%) and TTV (11%) infection, respectively, in
those individuals with chronic hepatitis, cirrhosis, and hepatocellular
carcinoma, whereas all but one patient with cholangiocarcinoma the etiology of
which has been ascribed to parasitic infestation, were free of all viral markers.
In Thailand chronic HBV, and to a lesser extent, chronic HCV infection represent
the two most common causes of hepatitis potentially proceeding to chronic liver
disease, whereas the clinical significance pertinent to HGV and TTV remains to be
elucidated.
PMID- 10774658
TI - The risk of occupational HIV exposure among Thai healthcare workers.
AB - To analyze the incidence of occupational exposure to HIV in a large group of
healthcare workers at the 2 Thai Red Cross hospitals, prospectively collected
during a seven-year period in order to find out the causes and circumstances that
prone to exposure, the interventions that may minimize the exposure and the
consequences of the accidents. The first 200 incident reports from 198 hospital
workers of the Thai Red Cross Society who had occupational exposure to HIV
infected blood and body fluids during 1991-1997 were analyzed. We analyzed the
demographic data, the timing and place of exposure, the nature and cause of
exposure, HIV status at baseline and at follow-up at 3, 6 and 12 months as well
as the received antiretroviral prophylaxis. All of the 198 HCW had negative anti
HIV at baseline and remained negative throughout the one-year follow-up although
only 55% submitted the results of their anti-HIV testing at 6 months. However,
none claimed for work-related life insurance against HIV during those 7 years
indicating that nosocomial rate of transmission is less than 1 in 200 or less
than 0.5%. Analysis of the incidents indicated that the risk group was the 20-40
years old nursing personnel who worked in the medical wards during the regular
working hours. The procedures that were responsible for most of the injuries were
venepuncture, intravenous access, injection and waste collection. Most of the
injuries could be prevented if the work place safety guidelines were strictly
followed and if personnel were more careful at work. The results can be used to
implement more effective preventive measures for hospitals in Thailand.
Postexposure management at the Thai Red Cross hospitals conformed with the
international guidelines. However, only 78% of those who should receive
postexposure prophylaxis were recommended for treatment and only 69% of those
recommended actually took the treatment. This emphasizes the need to educate
clinicians involved in postexposure care as well as to ensure them and the
injured subjects about the safety of the antiretroviral prophylaxis.
PMID- 10774659
TI - Dengue infection with central nervous system manifestations.
AB - A prospective observational study was conducted over a seven years period to
determine the clinical and laboratory findings of dengue patients with central
nervous system manifestations. Thirty serologically confirmed dengue infected
patients with central nervous system manifestations were seen at the Department
of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok and at
Songkhla Hospital, Songkhla, Thailand. The age ranged between 3 months and 14
years with a mean age of 6.2 years. Seventeen were boys and thirteen were girls.
The central nervous system manifestations included alteration of consciousness
76.7%, seizures 63.3%, pyramidal tract signs 36.7%, meningeal signs 30% and
headache 26.7%. Eleven patients had primary while 19 had secondary dengue
infection. Cerebrospinal fluid examination showed lymphocytic pleocytosis in 6
out of 28 patients while presence of anti-dengue IgM antibodies was detected in 2
out of 19 specimens of cerebrospinal fluid tested. Two patients died, autopsy was
done on one patient and examination of the brain was compatible with viral
encephalitis.
PMID- 10774660
TI - Dengue virus infection during post-epidemic period in Delhi, India.
AB - Dengue fever (DF) and dengue hemorrhagic fever (DHF) are major public health
problems in India. During the period following an epidemic, a study was carried
out using virological and serological tests for confirmation of suspected cases
of dengue virus infection in fever cases presenting to the All India Institute of
Medical Sciences. Serum samples of suspected DF/DHF cases were processed from
January to December 1997. In 37 samples from patients with fever of less than 5
day duration, received on ice, virus isolation was attempted in C6/36 clone of
Aedes albopictus cell line, followed by indirect fluorescent antibody staining
with monoclonal antibodies to dengue viruses 1 to 4. One hundred and forty-three
serum samples from patients with more than 5 days fever were tested for dengue
specific IgM antibody by either MAC-ELISA or a rapid immunochromatographic assay.
Dengue virus type 1 was demonstrated by culture in 8 (21.6%) of 37 serum samples
and IgM antibody could be detected in 42 (29.4%) of the 143 serum samples by the
serological methods. The peak of dengue virus infection was seen from September
to November 1997.
PMID- 10774661
TI - A randomized comparative trial in order to assess the reactogenicity and
immunogenicity of a new measles mumps rubella (MMR) vaccine when given as a first
dose at 12-24 months of age.
AB - An open, randomized multi-center trial, involving 700 infants, was conducted in
order to compare a new measles mumps rubella (MMR) vaccine, SB MMR (containing a
Jeryl Lynn derived mumps strain RIT 4385) with a widely used vaccine, Merck MMR,
when given to children between 12-24 months. Infants were divided between 2
groups; group 1 received SB MMR while group 2 received Merck MMR. Solicited local
and general symptoms were recorded using diary cards and antibody levels were
measured using ELISA assays. There was a significantly lower incidence of redness
(p < 0.001) and swelling (p = 0.03) observed in group 1 compared with group 2.
The incidence of all other solicited local and general symptoms were comparable
between groups. In initially seronegative subjects equivalent seroconversion
rates and post-vaccination GMTs were observed between groups. In conclusion,
these results demonstrate that SB MMR is safe and well tolerated when given to
children at this age range, and has an equivalent immunogenic profile compared to
the widely used Merck MMR vaccine.
PMID- 10774662
TI - Cutaneous delayed-type hypersensitivity responsiveness in lepromatous and
borderline lepromatous leprosy patients as determined by MULTITEST CMI.
AB - To assess cell mediated immune (CMI) function in patients with lepromatous and
borderline lepromatous leprosy (LL and BL), 35 patients were examined with the
MULTITEST CMI system to evaluate cutaneous delayed-type hypersensitivity (DTH)
responsiveness to 7 recall antigens. Reactions were assessed quantitatively and
qualitatively. In addition, patients were classified as "responsive" (> or = 2
positive reactions), "hypo-responsive" (1 positive reaction), or anergic. Only
hyporesponsive and anergic patients were re-tested. In 23 patients tested before
treatment started (Group 1), 9 were responsive, 4 hypo-responsive, and 10
anergic. Upon re-testing, 10 of the 14 hyporesponsive-anergic subjects showed
improvement. In 12 patients assessed after therapy initiation (Group 2), 9 were
responsive and 3 others became responsive upon re-testing. Quantitative
assessment indicated variable deficiencies in cutaneous DTH reactivity that, in
many cases, improved with therapy. Correlations between reactivity and disease
severity (LL versus BL) or duration of disease were not observed. The MULTITEST
CMI system provided a convenient, safe, and reproducible method to assess
cutaneous DTH responsiveness in LL and BL patients. Our findings indicated that
most LL and BL patients are able to generate detectable but generally fewer and
less robust cutaneous DTH responses to recall antigens, many improving with
therapy. However, a semi-quantitative classification whereby patients that
reacted to 2 or more antigens were considered "responsive" showed little
difference between patients and controls. Overall, the data support the
contention that deficits in cutaneous DTH responsiveness probably neither
predispose nor necessarily accompany lepromatous disease, a practical
consideration as efforts to develop a leprosy vaccine continue.
PMID- 10774663
TI - Assay of iodine deficiency status in three ecological regions of Nepal by a
microdigestion method.
AB - Iodine deficiency disorders (IDD) are a global public health problem. In
continuation of the efforts to eliminate the iodine deficiency in different parts
of the world, IDD surveys are being conducted to assess the status of iodine
nutriture. A survey was conducted in Nepal in 1998 with assistance from UNICEF.
We present the status of the iodine nutriture, as assessed from urinary iodine
levels of casual samples by a micro-digestion method, in the three ecological
regions: Terai (flat region), Hilly region (300-3,000 m altitude) and mountainous
regions (>3,000 m altitude) of Nepal. Terai region is more affected, having
iodine deficiency in 18.6% of the population. The hilly and mountainous regions
were found to have 11.2% and 9% iodine deficient populations respectively. The
study shows improvement in iodine deficiency status with respect to previous
surveys yet it continued to be prevalent in the country as a major public health
problem which requires strengthening of preventive measures.
PMID- 10774664
TI - Secular increases in weight, height and body mass index among school children of
Hat Yai, Thailand: a 5 years follow-up study.
AB - Upward trend of growth and overweight has been reported from developed countries.
As Thailand has been undergoing rapid economic transition over the previous
decade, we conducted an analysis to demonstrate the secular changes of growth
over five years follow-up. Subjects were a cohort of 2,252 primary school
children recruited in 1992 for the Hat Yai childhood obesity study. Baseline
demographic and family data were collected by a questionnaire completed by
parents. To quantify the cohort effect, a generalized estimating equations
analysis for a cross sectional time series data was undertaken with weight,
height, and body mass index (BMI, kg/m2) as a dependent variable and containing a
quadratic term of age, sex, year of birth and family variables. One thousand and
ninety-four (48.5%) children completed 6 anthropometric measurements. Graphs of
median weight, height, BMI and overweight prevalence of each birth cohort against
age showed secular increases of growth and overweight, and an age effect. For
each one-year younger cohort, the median weight, median height and median BMI
increased by 1.22 kg, 1.25 cm and 0.23 kg/m2, respectively. An increasing trend
of childhood overweight reported here may signify a need for preventing
overweight and reducing weight in childhood adolescence in the future.
PMID- 10774665
TI - Prevalence of communicable disease among restaurant workers along a highway in
Assam, India.
AB - 105 workers of 29 roadside restaurants along a highway in Assam were interviewed
for their habits, educational status and were examined for their hygienic status
and presence of communicable diseases (STDs,TB etc). Most of them were young,
males with 40% literacy; more than half were unmarried. About 30% of them were
alcoholic and smokers and 2.9% were addicted to cannabis. The hygienic conditions
of the workers were poor. More than one third had sexual contact with multiple
sex partners or commercial sex workers and 2% were engaged in homosexual
activity. Most of them did not use condom. 25.7% of them had genital lesions
suggestive of sexually transmitted disease, 11.8% showed gram negative diplococci
in urethral smears and 5.1% were VDRL reactive. Skin infections followed by
gastrointestinal disorders and respiratory tract infections were other prevalent
problems. 70.6% were positive for intestinal parasites and 22.2% were sputum
positive for acid fast bacilli. However all the collected blood samples were
negative for HIV.
PMID- 10774666
TI - The serological status of Solomon Island blood donors.
AB - The serological status of Solomon Island blood donors in 1995 and in particular
the seroprevalence of antibodies to Hepatitis B and C and prevalence of risk
factors for these chronic infections was studied. A questionnaire of risk factors
for Hepatitis B and C was undertaken. All blood donors had been previously
screened for HIV antibody without any positive cases recorded. 598 donors had
serum collected of which 36 samples (6.0%) were third generation HCV EIA antibody
positive and 3 samples were RIBA positive but none were PCR positive. 25.1% of
samples were positive for HBsAg and anti-HBc antibody was found in 84.4%.
Elevated ALT levels (>35 U/l) were found in 6.5% of samples but there was no
statistically significant association with HCV or HBsAg status. 15.4% were TPHA
positive and 5.4% had RPR titers more than or equal to 1. Anti-HTLV-1 antibody
was positive in 12.3% randomly selected samples. All 10 positive samples were
then found to be antibody indeterminate with Western blot assay. Of the 585
samples with completed questionnaires, analysis of the relationship between anti
HCV status with tattoo status and ear piercing also failed to reach statistical
significance. Consistent with other studies from tropical malaria-prone
countries, a positive anti-HCV antibody test even by the third generation EIA is
probably a false positive test in most cases. In addition, high prevalence rates
of HBV, yaws or syphilis infection were demonstrated.
PMID- 10774667
TI - Analysis of blood culture isolates from hospitalized neonates in Nepal.
AB - Clinically suspected 77 cases of neonatal septicemia admitted to the pediatric
ward of BP Koirala Institute of Health Sciences, Dharan, Nepal, were evaluated by
blood culture. The blood culture was positive for bacterial growth in 46 (59.7%)
cases. Gram-negative bacteria were isolated in 33 (71.7%) cases, the most common
being Escherichia coli, followed by Klebsiella spp, Enterobacter spp.
Staphylococcus aureus was the most common gram-positive bacteria. The bacterial
isolates were most sensitive to gentamicin (74.5%) and ciprofloxacin (74.5%)
followed by chloramphenicol (59.9%). They were most resistant (78.8%) to
ampicillin. This study for the first time underlines the pattern of bacterial
isolates and their sensitivity pattern to antibiotics in this part of Nepal.
PMID- 10774668
TI - Impact of environmental change and schistosomiasis transmission in the middle
reaches of the Yangtze River following the Three Gorges construction project.
AB - With the construction of the Three Gorges high dam on the Yangtze River in China
in mind, a serious of ecological environmental factors that might affect the
transmission of Schistosoma japonicum in Jian Han Plain were investigated by
means of data collection, field surveys and observation in Hubei Province.
Several ecological factors including water level of the Yangtze River; riparian
water table, annual rainfall and yearly evaporation were investigated in relation
to the prevalence of schistosomiasis. The results suggest that after the dam
construction, middle water level flows (ie between flood flows and dry-weather
flows) will persist in the flood season due to a rise in the water table. The
investigation indicated that snail distribution and human schistosomiasis
prevalence differed significantly between years which had typically high, middle
and low typical water levels in the Yangzte. Moreover, the prevalence of the
disease showed a significant linear regression relationship with density of snail
intermediate hosts, water table, annual rainfall, yearly evaporation and ground
altitude in the survey area. Systematic and careful monitoring and surveillance
is necessary to investigate the impact of the environmental changes brought about
by the dam construction on schistosomiasis transmission.
PMID- 10774669
TI - Occurrence of myocarditis in rodents infected with Schistosoma mansoni.
AB - Myocarditis is a complication of Schistosoma mansoni infection, although the
literature does not provide much information regarding the frequency of
myocarditis. In order to analyze the relationship between myocarditis and S.
mansoni infection, different laboratory animals were infected with different dose
of cercariae. At different weeks of post infection the hearts of infected animals
were collected and processed for histopathological examination. Myocarditis was
characterized by interstitial inflammatory cell infiltration with or without
granuloma. ddY and ICR infected mice showed eosinophilic egg-granuloma in the
heart where as neither eosinophil nor egg-granuloma were observed in the heart of
infected gerbils. Higher number of eosinophils and greater size of the granuloma
were found in the ddY mice than ICR mice. The number of eosinophils was
significantly higher in severe myocarditis. Incidence of myocarditis was higher
in ddY mice (69% with 100) than ICR mice (35%) and gerbils (23%). The results
indicate that ddY mice were more susceptible to S. mansoni infection in the
development of myocarditis and myocardial severity was associated with greater
eosinophil infiltration. These findings suggest that eosinophils might be
involved in the development of myocarditis, although the involvement of
immunological reaction can not be ruled out.
PMID- 10774670
TI - Field trial of the ICT filariasis for diagnosis of Wuchereria bancrofti
infections in an endemic population of Thailand.
AB - The ICT Filariasis, a rapid card test format, which is based on qualitative
detection by monoclonal antibody of the circulating antigen of Wuchereria
bancrofti adult worm, is a new diagnostic test of choice for determining the
infections under field conditions. By using clinical and recall techniques and
microscopy (thick smear and capillary tube technique) as reference, we assessed
the efficiency of the ICT card test in sera from 225 subjects living in W.
bancrofti-endemic villages of Tak Province, Thailand, who were recruited during a
cross-sectional community survey. The ICT card test gave a 20% antigen positive
rate, while other tests gave lower positive rates of the same 5.8% by clinical
and recall techniques and thick smear, and 5.3% by capillary tube technique,
respectively. The ICT card test had a specificity of 100% when sera from
microfilaremic subjects were positive, as when sera from W. bancrofti non-endemic
subjects either with Brugia malayi microfilaremia or with other parasites, and
those from normal controls were all negative by the test. When done in W.
bancrofti microfilaremia sera, the ICT card test had a sensitivity of 100% using
a microscopy as reference, and 84.6% when using clinical and recall techniques.
However, the ICT card test was more sensitive than the others when done in
endemic normal sera (14% positive). Such findings compared well with findings in
endemic area of South America, suggested its usefulness to detect W. bancrofti
infections in endemic area, especially on the Thai-Myanmar border.
PMID- 10774671
TI - Evaluation of recombinant chitinase antigen in serological diagnosis and
surveillance of lymphatic filariasis.
AB - Apply recombinant chitinase fusion protein antigen, enzyme-linked immunosorbent
assays examined anti-filarial antibodies and evaluated of useful value in
serological diagnosis and surveillance of lymphatic filariasis. The test jirds
were immunized and infected by chitinase and B. malayi third stage larvae
respectively. Functional protein molecular of chitinase was analyzed by SDS-PAGE,
Western blot. The result shown that jirds from microfilaremia (mf) and donors
with Mf were directly to react with chitinase antigen that positive rate was
100%, but Mf-xt antigen was only 80%. Normal jirds and persons sera from
unepidemic control donors all were negative. False positives of 5% and 20%
reacted with chitinase and Mf-xt antigens respectively. The results indicate that
recombinant chitinase antigen is suitable for detection of active occult or
patent lymphatic filariasis with daytime blood samples in residents of endemic
areas, is easy to be performed and inexpensive.
PMID- 10774672
TI - Quantitative assessment of Ascaris lumbricoides infection in school children from
a slum in Visakhapatnam, south India.
AB - An epidemiological study was conducted on 217 school children aged between 7-13
years, from Relliveedhi a slum in Visakhapatnam, Andhra Pradesh, south India,
during August 1993 to August 1994. The children belonged to a socioeconomically
backward community-parental occupation being fishing or waged labor. Intensity
and prevalence estimations for Ascaris lumbricoides were done indirectly by
formalin-ethyl-acetate sedimentation technic and directly by worm expulsions
following albendazole administration at a single oral dose of 400 mg/child.
Prevalence rate was 73% while the intensity of infection ranged between low to
moderate. Boys had severe infection than girls due to their outdoor activities
and behavioral habits. Nine year old children had the highest prevalence rates.
Mean Ascaris worm intensity was 2.2 (+/-1.91) with an over-dispersed distribution
of the parasite in the host population. Reinfection study over a period of nine
month showed that the prevalence rates exceeded the pre-intervention level but
the intensity of infection was very low. Dual species intensity correlation
between Ascaris and Trichuris was consistently strong.
PMID- 10774673
TI - Chromosomes and C-banding of Opisthorchis viverrini.
AB - Chromosome of Opisthorchis viverrini was observed by air-drying and C-banding
techniques. The chromosome number was 2n=12 and n=6 consisting of one large-sized
metacentric, one medium-sized metacentric, one small-sized metacentric, one small
sized submetacentric or subtelecentric, one small-sized subtelocentric or
acrocentric and one small-sized acrocentric. The relative lengths of the
chromosomes were 32.02 +/- 2.52, 23.28 +/- 1.98, 15.24 +/- 3.40, 13.39 +/- 3.11,
10.18 +/- 1.56 and 5.82 +/- 0.59% respectively. After C-banding treatment, two of
the small-sized chromosomes showed a remarkable constitutive heterochromatin.
PMID- 10774674
TI - Immunoblotting and enzyme linked-immunosorbent assay for diagnosis of toxoplasma
infection in HIV Thai patients.
AB - Toxoplasma gondii has been recognized as an important cause of morbidity and
mortality among immunocompromised persons. The diagnosis of T. gondii infection
is most often based on serological tests results. Serological diagnosis can be
limited in AIDS patients because of depressed antibody responses. Fifty serum
samples were used in this study to investigate serological evidence of
toxoplasmosis in HIV positive Thai patients by Platelia kit, the commercial
enzyme-linked immunosorbent assay (ELISA) in which the membrane protein p-30 is
the predominant antigen and immunoblot technique (IB). Sera of HIV positive Thai
patients with Toxoplasma infection recognized the same antigenic component, the
32 kDa antigenic band, as is recognized by Toxoplasma positive sera from
immunocompetent patients and it may represent a specific marker for diagnosis of
Toxoplasma infection in HIV positive Thai patients.
PMID- 10774675
TI - Evaluation of direct agglutination test (DAT) as an immunodiagnostic tool for
diagnosis of visceral leishmaniasis in Nepal.
AB - Before field application of the direct agglutination test (DAT) for
leishmaniasis, it was assessed as a diagnostic tool. Fifteen confirmed visceral
leishmaniasis cases (bone marrow aspiration positive), 120 tuberculosis, 58
leprosy, 15 malaria, 26 intestinal parasitic infection cases, 24 endemic healthy
controls from adjacent to the study area, and 18 controls from Kathmandu (who had
never visited the VL endemic areas) were tested for anti-leishmanial antibody
agglutination titers. Two of the tuberculosis cases were positive for anti
leishmanial agglutinating antibodies at 1:800. All the visceral leishmaniasis
confirmed cases were reactive to anti-leishmanial antibody at > or = 1:3,200.
Other specimens were negative for serology. The sensitivity of the direct
agglutination test was 100% and the specificity was 99.2%. The direct
agglutination test had positive and negative predictive values of 100% and 99.2%
respectively. The direct agglutination test has been found to be simple, rapid,
reliable, economic, safe and adaptable to micro-techniques using microtiter
plates. It is specific and sensitive. The direct agglutination test is simple
enough for it to be performed in a field laboratory.
PMID- 10774676
TI - Horizontal conjugate gaze palsy in eosinophilic meningitis.
AB - Two cases of eosinophilic meningitis who presented with headache and strabismus
are reported. Pertinent physical examination revealed unilateral horizontal
conjugate gaze palsy with absence of doll's eye maneuver and hemiparesis. The
etiologic agent of eosinophilic meningitis is presumed to be Angiostrongylus
cantonensis and the infected location that produce horizontal conjugate gaze
palsy was a pontine lesion.
PMID- 10774677
TI - A study of liver fluke infection in Sukhothai, Thailand.
AB - A cross sectional survey on opisthorchiasis was conducted from August to
September 1933 in Tambon Nai Muang, Sawankhalok district, Sukhothai Province. The
1,964 villagers were stool examined and it was found that 384 of them had liver
fluke infection. Of these 1,608, who were older than 12 years, were interviewed
in order to detect potential risk factors of liver fluke infection. The study
found that the population at risk were those older than 24 years of age (p <
0.05) and the possible risk factor was eating incomplete cooked fresh water fish
(p < 0.05). The food prepared from incomplete cooked fish which was harmful to
the villagers were pickle fish so called pla ra (p < 0.05) and papaya salad with
pickle fish so called som tam pla ra (p < 0.05).
PMID- 10774679
TI - Two decades in the sun: the Welcome-Mahidol-Oxford venture.
PMID- 10774678
TI - Amebic liver abscess in an elderly AIDS patient.
AB - An elderly bisexual male AIDS patient, whose CD4 cell count was 128/mm3 and HIV
RNA was 3.0x10(5) copies/ml, was admitted because of amebic liver abscess and
poor nutritional condition. He was treated with daily doses of 1,500 mg of
metronidazole for 14 days for amebic liver abscess and with anti-HIV drugs; good
therapeutic results were observed. Our study indicates that amebic liver abscess
is easily treated by appropriate administration of metronidazole even in an old
AIDS patient receiving anti-HIV drugs with low CD4 cell counts and high HIV-RNA
values.
PMID- 10774680
TI - Twenty years of the Wellcome-Mahidol University, Oxford Tropical Medicine
Research Program.
PMID- 10774682
TI - Ex vivo blood schizontocidal activities of artemisinin derivatives against
Plasmodium falciparum.
AB - Serum samples collected at intervals from eight healthy volunteers after the
administration of the six regimens of artemisinin derivatives were investigated
for their ex vivo blood schizontocidal activities against K1 strain Plasmodium
falciparum. The regimens included single doses of (a) 300 mg oral artemether; (b)
300 mg intramuscular artemether; (c) 100 mg suppository artemether; (d) 300 mg
oral artesunate (Guillin formulation); (e) 300 mg oral artesunate (Arenco
formulation); (f) 300 mg oral dihydroartemisinin. Sera collected after various
regimens of artemisinin derivatives showed distinct degree of ex vivo blood
schizontocidal activities. Activity of sera after suppository dosing was
remarkably low and variable comparing to the other two formulations (oral,
intramuscular). Median values for Amax (the maximum activity normalized with
dose) of sera from oral dosing were 2.4- and 118-fold, while AUA (the area under
activity-time curve, normalized with dose) were 0.82- and 2,370-fold of that
after the intramuscular and suppository dosing, respectively. Sera from
artesunate-Arenco dosing exhibited significantly higher Amax and AUA (medians:
Amax 12.4 vs 5.13 nmol/l/mg dose; AUA: 21.9 vs 8.8 nmol x h/ml/mg dose), compared
to that from artesunate-Guillin dosing. Among the oral formulations of
artemisinin derivatives investigated (artemether, artesunate,
dihydroartemisinin), sera collected following a single dose of oral
dihydroartemisinin exhibited lowest bioactivity (Amax 2.35 nmol/l/mg dose; AUA:
44 nmol x h/ml/mg dose).
PMID- 10774681
TI - Investigations of incidence of pretreatment, drug sensitivity in vitro, and
plasma levels of pyrimethamine in patients with multidrug resistant falciparum
malaria following the three combination regimens of artemether/pyrimethamine.
AB - The study was carried out to investigate the status of in vitro susceptibility of
Plasmodium falciparum to pyrimethamine (PYR) in multidrug resistant area of the
Thai-Myanmar border, the incidence of unregulated use of the combination of PYR
with sulfadoxine (Fansidar) in this area and the relevance of pharmacodynamic and
pharmacokinetic factors in determining the treatment outcome from the three
combination regimens of ART/PYR (1-, 2- and 3-day regimens), in patients with
acute uncomplicated falciparum malaria. The majority of patients had baseline PYR
concentrations in the range of 1-100 (50.6%) or 100-500 (34.8%) ng/ml, while
concentrations of more than 500 ng/ml were found in only 1.1%. All of the
isolates exhibited high grade resistance to PYR with the minimum inhibition
concentration (MIC) of as high as 10(-5) M. No association was observed between
treatment outcome and the presence of baseline plasma PYR concentrations. In
addition, lack of association between plasma concentrations during the acute
phase (day-1 and -2) and treatment outcome was found.
PMID- 10774683
TI - Chloroquine concentration profile in the community of Mewat region, district
Gurgaon (Haryana), India.
AB - A survey was conducted to find chloroquine concentration profile in the community
of Mewat region district Gurgaon (Haryana) of India. 88 P. falciparum and 3 P.
vivax cases were detected out of 148 blood slides examined with a SPR of 61.48.
Plasma chloroquine and desethylchloroquine concentrations were determined in 55
P. falciparum and 2 P. vivax patients and 29 persons whose blood slides were
negative for malaria parasite before giving any treatment. Mean chloroquine
concentrations in cases with P. falciparum parasites and without malaria
parasites were 0.018 and 0.016 microg ml(-1) respectively. Chloroquine to
desethyl chloroquine ratio was between 2 and 3 in both groups. Only 10 malaria
parasite negative cases out of 29 had plasma chloroquine concentrations above
0.016 microg ml(-1) required for malaria chemoprophylaxis. Chloroquine was
undetectable in plasma samples of 8 out of 55 P. falciparum cases. Chloroquine
plasma concentrations in 21 P. falciparum cases were below therapeutically
effective concentration of 0.016 microg ml(-1) suggesting improper treatment
while in 29 P. falciparum cases, parasitemia recurred despite required
chloroquine concentration confirming chloroquine resistant status. Irregular
prophylaxis and lack of proper treatment was one of the major causes of malaria
outbreak in this area.
PMID- 10774684
TI - Surveillance of risk factors from imported cases of falciparum malaria in
Sichuan, China.
AB - With a sharp increase of the number of imported cases of falciparum malaria, the
potential risk of the reemergent transmission of this kind of malaria is
approaching imminently in Sichuan Province, China, where falciparum malaria had
completely been eliminated by the 1960s. It has been of concern whether the
epidemic would appear again, because there still exist malaria vectors and
vulnerable populations in Sichuan. By undertaking surveillance on 31 cases
returning from the endemic areas with falciparum malaria, and on their family
members and neighbors, we have not found out any introduced case of falciparum
malaria who was contracted from the imported ones. The vector monitoring results
suggested that the use of insecticide-impregnated bednets interfered with malaria
vectorial capacity and expectation of infective life. The epidemiological
characteristics of the imported cases and reasons why no consequent malaria case
was detected were analysed at dynastic level in detail.
PMID- 10774685
TI - Control strategies of malaria in Henan Province, China.
AB - Malaria had been one of the main problems of public health, with the highest
incidence rate of 16.94%, in Henan Province of China in 1970. The rate has been
very low (about 5 per 100,000) in the 1980s and the 1990s since malaria had been
controlled in the 1970s. But in recent years, malaria has resurged and outbreaks
occurred with an incidence rate of more than 40% in some local areas where An.
anthropophagus was the main vector, and falciparum malaria cases have been found.
At present, malaria control strategies should focus on surveillance of malaria,
management of population dynamics, health education and adopting practicable
integrated measures.
PMID- 10774686
TI - Clinical case definition of malaria at a secondary level hospital in northern
India.
AB - Malaria has re-emerged as a major public health problem in India. At present,
under the National guidelines; all fevers are presumed to be due to malaria and
chloroquine is given as presumptive treatment. This results in overtreatment. We
did a pilot study to see whether some clinical predictors of malaria could be
identified in the Indian setting. This case control study was done in a secondary
level hospital. All those with fever who were smear positive for malaria were
enrolled as cases and other patients fever who were smear negative for malaria
served as the controls. All the factors under study were ascertained by a history
or detailed clinical examination. A total of 41 cases and 95 controls were
enrolled. Of the 41 cases, 35 were positive for P. vivax and six were positive
for P. falciparum. After multivariate analysis, only splenomegaly (OR = 2.11; 95%
CI = 1.27-3.50) and pallor (OR = 2.01; 95% CI = 1.16-3.48) were significantly
associated with malaria. It appears that history of fever along with one or both
of these two signs can be a useful predictor of malaria in a secondary level
hospital in India. The utility and feasibility of a similar approach in a field
setting needs to be studied further.
PMID- 10774687
TI - An update on the prevalence of HIV/AIDS in Bangladesh.
AB - The National AIDS Committee was formed in 1985 to develop and support policies
that prevent transmission of human immunodeficiency virus (HIV). In 1990, the
Institute of Epidemiology, Disease Control and Research in the Ministry of Health
began sero-surveillance for AIDS/HIV infection. Convenience sampling was
conducted among prisoners, sailors, truckers, antenatal attendees, repatriated
Bangladeshi workers, and brothel-based prostitutes in Dhaka. In 1994, commercial
sex workers in other high-risk areas were included in surveillance activities.
Among over 75,700 HIV tests through 1998, 119 have been confirmed positive for
HIV. While the cumulative HIV prevalence rate was only 1.5/1,000 tests, it was
significantly higher among men (p < 0.0001) than among women. The rates among men
were as high as 28/1,000 tests in 1996 and 21/1,000 tests in 1997. Almost 50% of
the reported HIV cases are from cities on the border of India and Myanmar. It is
anticipated that HIV transmission will increase further given the high prevalence
of risk behaviors, core high-risk groups, and extreme poverty.
PMID- 10774688
TI - HIV transmission in sexual partners of persons with HIV/AIDS attending the
Infectious Diseases Hospital, Yangon.
AB - A study was conducted in the Infectious Diseases Hospital, Yangon, for one year
from August 1996 to 1997, to assess the extent and the factors related to HIV
transmission among sexual partners of HIV/AIDS cases. It was a cross-sectional
comparative study on 67 (61 males, 6 females) HIV positive individuals with or
without AIDS, and their sexual partners. Separate interviews of index cases and
partners were done, and clinical examination and laboratory tests for HIV and
sexually transmitted diseases (STDs) were performed. HIV transmission was found
in 41.8% of the partners. Male-to-female transmission was 39.3% (n=61) and female
to male transmission was 66.7% (n=6), Seven and one half percent of the partners
were suffering from AIDS. There were 4 (6.6%) pregnant mothers and 1 (25%) was
HIV positive. Though 75% of the partners did not use condoms during their married
life, HIV transmission was significantly reduced in the condom users (odds ratio
(OR) = 0.18, 95% confidence interval (CI) 0.02-0.98 p = < 0.05). The seropositive
men who were less than 30 years of age had greater HIV transmission (OR = 5.67,
95% CI 1.13-36.46). However, socio-demographic factors, number of marital
partners and age of first sex partners, duration of marriage, number of sexual
relationships between these couples, duration of HIV positivity and AIDS
infection, immunological status of the index group and STD positivity among
partners had no significant association with the transmission of HIV. This study
demonstrated that the transmission of HIV was high among the sexual partners of
persons with HIV infection. It also highlighted the requirement of effective
counseling and preventive measures against HIV infection among the couples.
PMID- 10774689
TI - Cytomegalovirus and Cryptosporidium infections in AIDS: a necropsy study.
AB - A case of coinfection of cytomegalovirus (CMV) and Cryptosporidium in an AIDS
patient is reported. Chronic diarrhea was the presenting symptom. Etiologic
agents were diagnosed only at postmortem evaluation. CMV intranuclear inclusions
were seen in the terminal ileum, colon and vermiform appendix. Cryptosporidium
oocysts were also present in the intestinal brush border of the colon.
Improvement of diagnostic procedures such as colonic biopsy and the use of
appropriate staining procedure for AIDS patients with diarrhea can help identify
the cause of illness.
PMID- 10774690
TI - Prevalences of human herpesvirus 6 and human herpesvirus 7 in normal Thai
population.
AB - Prevalences of human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) DNA
were investigated in normal Thai population. Peripheral blood mononuclear cells
(PBMC) and saliva were collected from 238 healthy adults in five provinces which
might be a representative of each part of the country, and 120 normal children in
one province. Prevalences of HHV-6 DNA PBMC were 45.5-74.3% in adults and 78.3%
in children, and in saliva, very low prevalences were detected; 5.7-8.6% in
adults and 15.0% in children, respectively. Additionally, all HHV-6 DNA detected
in this study were variant B. Comparingly to those of HHV-7 DNA, the prevalences
were significantly higher than those of HHV-6, ie, 82.9-91.4% in PBMC of adults,
85% in PBMC of children, 84.8-89.0% in saliva of adults and 92.5% in saliva of
children. HHV-6 and HHV-7 isolation from saliva specimens were also performed. No
HHV-6 could be isolated from any samples, whereas, in the present study, HHV-7
could be isolated as 90.0% from children and as 20.0-54.5% from adults.
PMID- 10774691
TI - Prevalence of cytomegalovirus antibodies among various age groups of Thai
population.
AB - The prevalence of CMV antibody in various groups of Thai population was studied.
Pregnant women and young children had been infected with CMV more than the other
studied groups. Children of both sex had equal chance of getting CMV infection
while the risk of CMV infection in adult between male and female was
significantly difference (p < 0.001). Pregnant women had higher chance to get CMV
infection than normal women. Prevalence of CMV antibody at present was similar to
previous studies.
PMID- 10774692
TI - Clearance of hepatitis TT virus infection among thalassemia children and IVDU.
AB - The novel transfusion transmissible hepatitis virus TTV first isolated by a group
from Japan has predominantly been detected in members of groups at high risk for
contracting blood borne viruses. Aside from elevated liver enzymes, the symptoms
associated with its infection have been reported to range from asymptomatic to
hepatic failure. The purpose of the present study was to determine if and to what
extent the host's immune response is capable of clearing TTV infection. Hence, we
extracted DNA from sera obtained from altogether 201 intravenous drug users
(IVDU) and 80 thalassemia children--both groups at high risk of parenteral
exposure--and performed PCR using semi-nested primers. Those positive for TTV DNA
were once again subjected to PCR after approximately one year in order to
determine how many still harbored the virus. Our results showed TTV DNA to be
absent in merely 20.6% of the formerly positive IVDU, whereas it was still
present in all the thalassemia children who could be tested for the second time.
Based on the small sample size and the high-risk environment, these results ought
to be interpreted with caution and definitely merit further investigation.
PMID- 10774693
TI - Prevalence of hepatitis a antibodies in western Indian population: changing
pattern.
AB - This report pertains to a retrospective study conducted between 1983 and 1995 at
three time points to evaluate the prevalence of hepatitis A virus (HAV) infection
in the population of Bhor Taluk, situated in western India. Serum samples from
children and adults were tested for anti-HAV antibodies using blocking ELISA
test. There was a significant decrease in anti-HAV prevalence among children aged
5-10 years in 1995 (87.36%) as compared to that of 1983 (97.58%) and 1987
(96.48%). All individuals >11 years of age were seropositive for anti-HAV
antibodies. Anti-HAV prevalence was similar in the users of well water, but was
significantly reduced in individuals supplied with piped water in 1995 (88.61%)
compared with that in 1983 (98.77%). A significant decrease in anti-HAV
positivity was noted in children from Bhor Taluk as compared to children from
Pune bled in 1992. These results underline the need for periodic surveillance of
seroepidemiology of hepatitis A to determine the measures for prevention and
control of the disease.
PMID- 10774694
TI - Three Japanese encephalitis cases in Okinawa, Japan, 1991.
AB - Since 1974, no Japanese encephalitis (JE) case had been reported on Okinawa
island in either Okinawan people or US servicemen. In 1991, three US marines
stationed on Okinawa island developed encephalitis symptoms. Neutralization (N)
test and IgM-capture ELISA were carried out on the serial samples of serum and
cerebrospinal fluid (CSF) taken from the patients. In each patient N test on both
serum and CSF samples gave a significant rise in JE antibody titer in the
comparison between the acute and convalescent phases, indicating that all the
cases were infected with JE virus. The IgM-capture ELISA also showed a
significant rise of antibody titer of the serum and CSF samples in the
convalescent phase in patients 2 and 3, while in patient 1 a significant rise in
IgM antibody was observed in the serum sample, but not in the CSF sample. None of
the patients had been administered JE vaccine. This report underscores the
importance of JE vaccination.
PMID- 10774695
TI - Recovery of poliovirus from cut surface of stored fresh papaya fruit.
AB - Poliovirus kept on the cut surfaces of fully ripe papaya cubes placed in an ice
box showed a sharp and significant reduction in the recovery of infectious virus
about 15 minutes after exposure. Thereafter, a very gradual decrease ensued and
infectious residual virus was detected up to the end of the 6-hour exposure
period. Papaya cubes washed or kept overnight before virus inoculation, and from
less ripe fruits produced a similar survival pattern. A very small proportion of
the inoculum was recovered from the mashed content of the inoculated papaya cubes
thus suggesting that most of the non-recovered virus particles were inactivated.
The results suggest that the importance of poliovirus-contaminated cut papayas as
a transmission vehicle for the virus is greatly reduced by the rapid decline in
the infectivity of a large proportion of the virus soon after contamination.
Nevertheless, the potential to transmit remains as a small residual pool of
infectious poliovirus is able to survive for a relatively long period.
PMID- 10774696
TI - Screening for TORCH infections in pregnant women: a report from Delhi.
AB - Primary TORCH infections (toxoplasmosis, rubella, cytomegalovirus and herpes
simplex virus type 1 and 2) in the mother can lead to severe fetal anomalies or
even fetal loss. A prospective study was designed to detect the seroprevalence of
IgM antibodies to Toxoplasma gondii, rubella virus and cytomegalovirus and IgG
antibodies to herpes simplex virus type 1 and 2. One hundred and twenty pregnant
women presenting to the antenatal clinic of a tertiary health center were
included in this study. Out of these 120 women 112 (93.4%) had evidence of one or
more infections. Prevalence of IgG antibodies to HSV was 70%. Seropositivities
for toxoplasmosis, rubella and CMV respectively were 11.6, 8.3 and 20.8%. Our
data demonstrating high frequency of primary infections during pregnancy support
the conclusion that routine prenatal TORCH screening is justified.
PMID- 10774697
TI - An epidemiological survey of female reproductive health status: gynecological
complaints and sexually-transmitted diseases.
AB - An epidemiological survey of gynecological and sexually-transmitted diseases was
conducted in 4 villages of Narmpong district, Khon Kaen, Thailand. It was focused
on the reproductive health status of rural women. A mobile gynecological clinic
was set up to collect materials and data including demographic characteristics,
physical examination and specimen collection. Vaginal swabs were examined by
microscope, Gram staining, pH measurement, KOH test and bacteriological
cultivation. Endocervical swabs were examined for Chlamydia trachomatis, herpes
simplex virus (HSV) and human papilloma virus (HPV) by polymerase chain reaction.
Papanicolaou's test was applied for diagnosis of cytological abnormalities. Blood
was tested by RPR and TPHA and urine was tested by LED test. The chief complaint
was dysmenorrhea (44.8%). The others ranging from 43.4-3.0% were lower abdominal
pain to genital ulcer. Prevalence of C. trachomatis, C. albicans, T. vaginalis,
T. pallidum and G. vaginalis were found in 4.6, 10.9, 5.1, 2.7 and 1.0% of 586
women and HSV and HPV were found in 6.4% and 1.4% of 110 women, respectively. The
three pathogens. C. trachomatis, C. albicans and T. vaginalis, were frequently
found among women in the age of 20-49 years. The number of marriages and sex
partners in the past year had an association with C. trachomatis infection while
vaginal pH > 4.5, marital status, number of marriages and itching of genitalia
had an association with T. vaginalis infection.
PMID- 10774699
TI - Dietary management during pregnancy, lactation and common childhood illnesses in
rural Bangladesh.
AB - Data were collected on nutritional aspects of women in general and during special
time frames such as pregnancy, lactation and common childhood illnesses
(diarrhea, acute respiratory infections and measles) from rural areas in
Bangladesh. A distinctive gender bias was evident regarding decision making and
food allocation within the household. Inadequate feeding practices were observed
during diarrhea with 22.2% of the mothers discontinuing breast-feeding. Breast
feeding and nutritional support were comparatively better during ARI and measles.
When the children were ill, 97% of the mothers administered a special diet with a
variety of food preferences, which were perceived to improve the symptoms of the
respective illness. Maternal education influenced both the occurrence of diarrhea
and the nutritional management of diarrhea and measles significantly. Therefore,
community health education should focus on the importance of breast-feeding and
continued nutritional support during illnesses. In order for this health
education to be effective, traditional beliefs noted in this study have to be
incorporated.
PMID- 10774700
TI - Cross over placebo control trial of dilazep in beta-thalassemia/hemoglobin E
patients.
AB - An attempt was made to find better symptomatic treatment for beta
thalassemia/hemoglobin E (beta-thal/Hb E) patients in order to reduce their blood
demand. Oral administration of dilazep was prescribed for these patients and a
clinical trial was conducted over a 2-year period as a cross over placebo control
study. Seventeen beta-thal/Hb E patients were enrolled in the study. All of them
received dilazep and placebo for 10 months at different periods of time and were
taken care of by the same doctor throughout the study. The blood demand of the
same patients during the period of receiving dilazep with the period of receiving
placebo, was 1.5 +/- 1.8 U/10 months versus 2.2 +/- 2.6 U/10 months,
respectively. Thus dilazep showed a benefit in decreasing the blood demand by
about 50% although the results did not reach statistical significance (p = 0.1).
There was a statistical difference in hemoglobin concentration of the patients
receiving dilazep compared with placebo (p = 0.038). While receiving dilazep the
mean +/- SD hemoglobin level was 5.82 +/- 0.8 g/dl, significantly higher than
while receiving placebo (5.66 +/- 0.9 g/dl) (p = 0.038). The liver, and renal
function tests, and cardiac enzyme levels of the patients showed no significant
changes throughout the study. However, one case had a problem with bleeding
following tooth extraction whilst receiving dilazep and needed 1 unit of blood
transfusion. In conclusion, administration of dilazep to patients with beta
thal/Hb E increased the patients' hemoglobin and reduced their blood demand with
few side effects.
PMID- 10774698
TI - Hepatitis B infection in Bangladeshi mothers and infants.
AB - In order to estimate the relative importance of perinatal transmission of
hepatitis B in rural Bangladesh a cross-sectional study was carried out. Paired
serum samples of infants aged 2-8 months old, a group of new born, and their
mothers were tested for hepatitis B markers using a commercial ELISA test kit. In
total, 107 (32.4%) positive for HBcAg, 18 (5.4%) for HBsAg, and 4 (1.2%) for
HbeAg. Of the infants, 35 (10.5%) positive for HBcAg, 1 (0.3%) for HBsAg, and
none for HBeAg. Of the 18 HBsAg positive mothers, 4 (22%) were HBeAg positive.
All 14 children of mothers who were HBeAg negative were negative for HBsAg. Only
one out of four (25%) of children of HBeAg positive mothers were HBsAg carriers
(8 months old), and in three children transmission did not occur (two 8 months,
one 6 months old). This survey indicates that hepatitis B is prevalent in rural
Bangladesh and that the perinatal transmission mode may be relatively low.
PMID- 10774701
TI - Comparative analysis of serological and molecular results for HLA-DR typing in
120 Thai subjects.
AB - In this study, serological HLA-DR typing results were compared to typing results
obtained with sequence-specific primers in the polymerase chain reaction (PCR
SSP). HLA-DR typing was performed on 120 random Thai individuals. Differences in
HLA-DR typing results were found in 18 out of 120, which were due to cross
reactive antibodies and the lack of potent antisera to define proper HLA-DR
splits by serology. Furthermore, PCR-SSP is fast and easy to perform as HLA-DR
typing results can be obtained within 2 hours. From the results of this study it
can be concluded that PCR-SSP is a reliable and promising technique for HLA-DR
typing which can replace the serological technique in routine clinical practice.
PMID- 10774702
TI - Substance abuse treatment policy implications derived from routine statistical
reports.
AB - Substance abuse poses both economic and social threats. Medical treatments for
substance abusers are considered as one of the main strategies to tackle with the
problems. For each episode of cases seeking medical treatments, data are
routinely collected and reported to the Department of Medical Services and copies
to the Office of Narcotics Control Board of Thailand. However, they are rarely
analyzed and used. This paper demonstrates an example how a basic analysis, with
occasional substantiation from other databases or basic knowledge, can lead to
meaningful policy options for medical treatments of substance abuse in the near
future.
PMID- 10774703
TI - The seasonal variation in the microbial agents implicated in the etiology of
diarrheal diseases among children in Lao People's Democratic Republic.
AB - During 1994-1995, the etiological structure of children's diarrhea was monitored
in outpatients at Mahosot Hospital, Vientiane, Lao PDR. Of the 191 children
studied, 42% had stool specimens positive for enteropathogens; 22% had rotavirus,
21.5% enteropathogenic E. coli, 4.7% Shigella flexneri, 2.9% Campylobacter
jejuni, 2.1% Shigella sonnei, and 0.5% each of Giardia intestinalis and Entamoeba
histolytica. No Vibrio cholerae and Salmonella spp. was detected in this
monitoring. In children under five years, rotaviruses were detected almost all
round the year with a maximum prevalence in January in the dry season. Shigella
species were highly detected in June to July in the rainy season.
PMID- 10774704
TI - An outbreak of salmonellosis linked to a marine turtle.
AB - In September 1998, an outbreak of gastroenteritis occurred in a coastal
Aboriginal community in the Northern Territory over a seven day period. An
investigation was conducted by the Center for Disease Control, Territory Health
Services. Thirty-six cases were detected and 17% (n=6) were hospitalized.
Salmonella chester was isolated from eight of nine stool specimens. Sixty-two
percent of cases interviewed (n=28) reported consumption of a green turtle
(Chelonia mydas) within a median of 24 hours prior to onset of illness. Of the
remainder, all but two were contacts of other cases. Salmonella chester was
isolated from a section of partially cooked turtle meat. There are no previous
published reports of salmonellosis associated with consumption of sea turtles
despite them being a popular food source in coastal communities in the Pacific.
PMID- 10774705
TI - Distribution of the larvae of blackflies (Diptera: Simuliidae) at Doi Inthanon
National Park, northern Thailand.
AB - The larvae of seventeen Simulium species consisting of thirteen known species,
three unnamed species and one new species were distributed in various localities
with different habitats at 400-2,460 meters above sea level in Doi Inthanon
National Park, Chiang Mai Province, northern Thailand. Simulium caudisclerum, S.
sp G and S. sp H were restricted to the high altitude of 2,460 m at the cool Ang
Kha habitat of the summit of Doi Inthanon. On the other hand, S. nakhonense and
S. rudnicki occurred only at low altitudes from 400 m-700 m. Some Simulium
species such as S. fenestratum, S. asakoae, S. inthanonense and S. sp J were
found in the warmer localities at 1,010 m-1,280 m altitudes. Moreover, S.
feuerborni and S. rufibasis were widely distributed species at different
altitudes from 700 m-2,460 m and 1,010 m-2,300 m respectively. Therefore, the
distribution and abundance of Simulium species seem to correlate with altitudes
as well as micro-habitat factors such as water temperature and water velocity.
PMID- 10774706
TI - Activation and germination of spores of Bacillus thuringiensis var israelensis by
alkaline pH and larval (Aedes aegypti) gut fluid.
AB - Alkaline activation of the spores of crystalliferous (Cry+) and acrystalliferous
(Cry-) strains of Bacillus thuringiensis var israelensis; wild type B. cereus and
its transcipient crystalliferous derivatives and wild type B. subtilis was
studied. Also the effect of larval (Aedes aegypti) gut fluid on the activation of
spores of these strains was studied. Only the spores of the crystal forming
strains were found to be activated by 0.1 M K2CO3 (pH 10) and by the larval gut
fluid. The process of alkaline activation was independent of whether crystals
were present with the spores in the activation solution. This indicates that
protoxin in the spore coat is responsible for the alkaline activation process and
may have ecological implications for the organism.
PMID- 10774707
TI - Schistosoma japonicum in the black rat, Rattus rattus mindanensis, from Leyte,
Philippines in relation to Oncomelania snail colonies with reference to other
endoparasites.
AB - This study examined the prevalence of Schistosoma japonicum infections in field
rats, Rattus rattus mindanensis, according to different trapping locations.
Between October 1995 and January 1996, traps were set in the municipality of
Palo, Leyte, Philippines to determine the correlation of rats infected with
schistosomiasis to the proximity of the intermediate snail host, Oncomelania
hupensis quadrasi, colonies. Of the 22 rats that were caught within a snail
colony, 21 (95.5%) were positive for schistosomiasis. Of the 23 rats that were
caught 100 meters from a snail colony, 13 (56.5%) were positive for
schistosomiasis. Of the 17 rats that were caught approximately 1 km from a snail
colony, zero (0%) were positive for schistosomiasis. Infection rates were highest
within the habitat of the intermediate host and lowest in rats captured far from
snail colonies. Captured rats were also examined for the presence of other
endoparasites. Infections of the following were found: Angiostrongylus
cantonensis, Gonylonema neoplasticum, Hymenolepis diminuta, Nippostrongylus
muris, Strongyloides ratti, Syphacia obvelata, Taenia crassicollis and Trichuris
muris, but there was no correlation between trapping location and prevalence.
None of the rats were infected with Moniliformis moniliformis, Trichinella
spiralis, Trypanosoma lewisi or Vampirolepis nana.
PMID- 10774708
TI - A simple and rapid non-radioactive oligonucleotide based hybridization assay for
the detection of Wuchereria bancrofti.
AB - Five biotin labeled oligonucleotides was designed based on a previously cloned
and characterized repetitive DNA sequence specific for Wuchereria bancrofti. The
oligonucleotide mix (containing five probes) when used in a hybridization assay,
detected as little as 100 pg of purified W. bancrofti, microfilarial DNA, a
single infective stage larva and a single microfilaria in 50 microl blood sample.
A simple protocol was followed for the hybridization assay. Blood samples lysed
with sterile distilled water and digested with proteinase K in the presence of a
detergent were directly applied on to nylon membranes for dot blot assays. The
DNA extract of mosquitos carrying infective stage larvae was eluted through
sephadex G-50 minicolumns prior to blotting. The assay was also able to detect
DNA extracted from microfilariae infected samples stored over five days at room
temperature (28 degrees C). This simple and rapid oligonucleotide hybridization
protocol with the highly sensitive chemiluminescent-based detection has
significant potential for the development of a field kit to detect W. bancrofti
infection.
PMID- 10774709
TI - Histochemical alterations of infective third-stage hookworm larvae (L3) in
vaccinated mice.
AB - To study the histochemical alterations of hookworm L3 administered in a challenge
dose to mice vaccinated previously with the larvae. Male Kunming strain mice
vaccinated subcutaneously with 500 living Ancylostoma caninum L3 once every 2
weeks for a total of three immunizations before a final challenge with 500 L3 one
week after the final immunization. The abdominal skin with underlying
subcutaneous tissue and muscle were removed from the site of percutaneous
challenge entry (from 2-3 mice), and fixed in absolute alcohol, cold acetone and
10% neutralized formalin. The tissue sections containing the L3 from the
challenge dose were then stained histochemically of glycogen, RNA, DNA alkaline
protein, acid mucopolysaccharide, collagen, reticulin, alkaline phosphatase (AKP)
and adenosine triphosphatase (ATPase). Skin samples from non-immunized mice that
were also subcutaneously inoculated with the L3 served as negative control. The
L3 identified in cutaneous sections from vaccinated mice at 6-72 hours post
challenge exhibited reductions in parasite glycogen, alkaline protein, RNA and
DNA, as well as reductions in acid mucopolysaccharide, collagen and reticulin
contents in the parasite cuticle. There were also reduced enzyme AKP and ATPase
activities. In contrast L3, identified in sections from non-immunized mice
exhibited a normal histochemical appearance, as did some L3 who survived in
vaccinated mice at 7-14 days post-challenge. Vaccination results in hookworm L3
damage which is manifested by reduced histochemical staining for the challenge
inoculum of parasites. There is also reduced hydrolytic enzyme activity. The
observed changes could reflect either host-mediated parasite structural damage
and disintegration or possibly anti-metabolic properties of the host immune
response.
PMID- 10774710
TI - Prevalence of trematode metacercariae in cyprinoid fish of Ban Pao district,
Chiang Mai Province, northern Thailand.
AB - The prevalence of trematode metacercariae in natural cyprinoid fish was carried
out in Ban Pao district, Chiang Mai Province, northern Thailand. Fish were
collected from both man-made water reservoirs and natural sources during July
1996-May 1997. Nine species of cyprinoid fish harbored the metacercariae of
Opisthorchis viverrini and small intestinal flukes of the family Heterophyidae,
ie Haplorchis taichui, H. pumilio and Centrocestus spp. Metacercariae of H.
taichui were found approximately 384 times more than O. viverrini. Among the fish
collected, Puntius leiacanthus contained the highest number of metacercariae of
H. taichui (182 metacercariae/fish) whereas P. orphoides contained the highest
number of metacercariae of O. viverrini (1.4 metacercariae/fish). Metacercariae
of H. taichui found in this area were year-round, with the highest and lowest
incidence rates being in winter and rainy season, respectively. The difference
between H. taichui and O. viverrini with respect to their prevalences are
discussed.
PMID- 10774711
TI - Potassium permanganate staining for differentiation the surface morphology of
Opisthorchis viverrini, Haplorchis taichui and Phaneropsolus bonnei eggs.
AB - Potassium permanganate staining method was developed for differentiation
Opisthorchis viverrini, Haplorchis taichui and Phaneropsolus bonnei eggs. The
surfaces of O. viverrini, H. taichui and P. bonnei eggs stained permanently and
temporarily were similar in appearance even the staining procedures were varied
both in concentration and time. Determined under light microscope set at 400x,
all of these eggs were oval-shaped, operculated at one pole and indistinct small
knob at posterior end. O. viverrini eggs showed the distinct musk-melon-like
prominent ridges on the surface. Haplorchis taichui eggs had a light striae
pattern while P. bonnei eggs had a smooth egg shell. Length of these trematode
eggs were significant different (chi2 test, p < 0.05). Mean +/- SD of O.
viverrini, H. taichui and P. bonnei eggs were 26.34 +/- 1.65 microm, 29.03 +/-
1.48 microm and 23.00 +/- 1.49 microm, respectively. Regarding of their width,
the mean +/- SD of O. viverrini, H. taichui and P. bonnei eggs were 15.54 +/-
0.69 microm. 14.94 +/- 0.91 microm and 12.25 +/- 1.02 microm, respectively. The
means of width of O. viverrini and H. taichui eggs were not significantly
different (chi2 test, p > 0.05), however, they were significantly different from
those of P. bonnei (chi2 test, p < 0.05). Temporary staining using 1% w/v
concentration and only 1 minute of time is useful in the mass fecal examination
survey for the prevalence and intensity of truly Opisthorchis infection.
PMID- 10774712
TI - Histopathological diagnosis of subcutaneous Dirofilaria repens infection in
humans.
AB - The host tissue response in humans, based on a study of biopsies of 14
subcutaneous nodules caused by Dirofilaria repens is described. The response was
characterized by accumulation of eosinophilic material or eosinophilic pus
adjacent to the parasite with surrounding granulomatous inflammation associated
with extensive eosinophil infiltration of the surrounding tissue. Unlike with
fungal lesions, fat necrosis was conspicuously absent. Nodules were all less than
3 cm in size. Fifteen percent of the smaller nodules (less than 1 cm) and 30% of
the larger nodules required extensive examination of tissue to visualize the
parasite. It is concluded that when typical tissue reactions are seen, extended
histological processing is indicated for accurate diagnosis of dirofilariasis, by
demonstrating the parasite.
PMID- 10774713
TI - Movability of advanced third-stage larva of Gnathostoma spinigerum exposed to
albendazole sulphoxide in vitro.
AB - Movability of advanced third-stage larvae of Gnathostoma spinigerum exposed to
albendazole sulphoxide (AlbSO), the active metabolite of albendazole, was
determined in vitro. Larvae in control groups moved actively with the whole body
for all 21 days of the study period. In larvae treated with AlbSO 1 microg/ml,
the movement was significantly reduced after 11 days exposed to the drug and to
be only a part of body on the 15th-21st days. In larvae treated with AlbSO 2
microg/ml, the movement was initiated in decreasing after 9th days and to be only
a part of body on the 12th-17th days. Finally, worms were immobile but not dead
on the 20th-21st days. Although there was no larvae died at 21st days exposed to
AlbSO in both concentrations; but all worms were sluggish and may die later.
These lethargic worms may not be able to migrate in patients and leading to cure.
Albendazole may not be benefit for acute symptom clearance; however, it can
prevent the recurrent migratory swelling after the treatment of 21 day-course.
PMID- 10774714
TI - Clinostomum trematode from human eye.
AB - The first human case of Clinostomum lacramalitis in Thailand is reported. A 38
year-old man visited an ophthalmology clinic after having itchy pain in the right
eye for two days. Ophthalmological examination revealed a living worm adhered to
the lacramal opening and after removal, it was identified as Clinostomum sp. The
patient admitted that he used to eat raw freshwater fish, he caught in Prachin
Buri Province where he lives.
PMID- 10774715
TI - Insufficient evidence of TT-viral etiology of post hepatitis aplastic anemia.
AB - Post-hepatitis aplastic anemia is a rather rare pathologic condition of as yet
unclear etiology especially as hepatitis viruses A to G have been excluded as the
potential agents responsible. The novel TT virus, a single-stranded DNA virus
first isolated from the serum of a patient with post-transfusion hepatitis in
Japan might cause this condition. Therefore, our group subjected the sera of two
children with post-hepatitis aplastic anemia to semi-nested PCR using primers
specific for detection of TTV DNA. Although TTV DNA was not detectable in either
sample it might be speculated that, like hepatitis viruses A to G, TTV could be
found associated with this condition whereas it certainly does not constitute its
sole etiologic agent.
PMID- 10774716
TI - Dating behavior of the retinal ganglion cell.
PMID- 10774717
TI - Insulation of signaling pathways: odor discrimination via olfactosomes?
PMID- 10774718
TI - LTP takes route in the hippocampus.
PMID- 10774719
TI - A plethora of taste receptors.
PMID- 10774720
TI - A new twist in the saga of charge movement in voltage-dependent ion channels.
PMID- 10774721
TI - Addiction, dopamine, and the molecular mechanisms of memory.
PMID- 10774722
TI - Nomenclature of voltage-gated calcium channels.
PMID- 10774723
TI - A genetic analysis of synaptic development: pre- and postsynaptic dCBP control
transmitter release at the Drosophila NMJ.
AB - Postsynaptic dCBP (Drosophila homolog of the CREB binding protein) is required
for presynaptic functional development. Viable, hypomorphic dCBP mutations have a
approximately 50% reduction in presynaptic transmitter release without altering
the Ca2+ cooperativity of release or synaptic ultrastructure (total bouton number
is increased by 25%-30%). Exogenous expression of dCBP in muscle rescues impaired
presynaptic release in the dCBP mutant background, while presynaptic dCBP
expression does not. In addition, overexpression experiments indicate that
elevated dCBP can also inhibit presynaptic functional development in a manner
distinct from the effects of dCBP loss of function. Pre- or postsynaptic
overexpression of dCBP (in wild type) reduces presynaptic release. However, we do
not observe an increase in bouton number, and presynaptic overexpression impairs
short-term facilitation. These data suggest that dCBP participates in a
postsynaptic regulatory system that controls functional synaptic development.
PMID- 10774724
TI - atonal regulates neurite arborization but does not act as a proneural gene in the
Drosophila brain.
AB - Drosophila atonal (ato) is the proneural gene of the chordotonal organs (CHOs) in
the peripheral nervous system (PNS) and the larval and adult photoreceptor
organs. Here, we show that ato is expressed at multiple stages during the
development of a lineage of central brain neurons that innervate the optic lobes
and are required for eclosion. A novel fate mapping approach shows that ato is
expressed in the embryonic precursors of these neurons and that its expression is
reactivated in third instar larvae (L3). In contrast to its function in the PNS,
ato does not act as a proneural gene in the embryonic brain. Instead, ato
performs a novel function, regulating arborization during larval and pupal
development by interacting with Notch.
PMID- 10774725
TI - Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple
aspects of retinocollicular mapping.
AB - Ephrin-A2 and -A5 are thought to be anteroposterior mapping labels for the
retinotectal/retinocollicular projection. Here, gene disruptions of both these
ephrins are characterized. Focal retinal labeling reveals moderate map
abnormalities when either gene is disrupted. Double heterozygotes also have a
phenotype, showing an influence of absolute levels. In vitro assays indicate
these ephrins are required for repellent activity in the target and also normal
responsiveness in the retina. In double homozygotes, anteroposterior order is
almost though not completely lost. Temporal or nasal retinal labelings reveal
quantitatively similar but opposite shifts, with multiple terminations scattered
widely over the target. These results indicate an axon competition mechanism for
mapping, with a critical role for ephrins as anteroposterior topographic labels.
Dorsoventral topography is also impaired, showing these ephrins are required in
mapping both axes.
PMID- 10774726
TI - Olfaction and odor discrimination are mediated by the C. elegans guanylyl cyclase
ODR-1.
AB - Animals in complex environments must discriminate between salient and
uninformative sensory cues. Caenorhabditis elegans uses one pair of olfactory
neurons called AWC to sense many different odorants, yet the animal can
distinguish each odorant from the others in discrimination assays. We demonstrate
that the transmembrane guanylyl cyclase ODR-1 is essential for responses to all
AWC-sensed odorants. ODR-1 appears to be a shared signaling component downstream
of odorant receptors. Overexpression of ODR-1 protein indicates that ODR-1 can
influence odor discrimination and adaptation as well as olfaction. Adaptation to
one odorant, butanone, is disrupted by ODR-1 overexpression. Olfactory
discrimination is also disrupted by ODR-1 overexpression, probably by
overproduction of the shared second messenger cGMP. We propose that AWC odorant
signaling pathways are insulated to permit odor discrimination.
PMID- 10774727
TI - The LIM homeobox gene ceh-14 confers thermosensory function to the AFD neurons in
Caenorhabditis elegans.
AB - In Caenorhabditis elegans three pairs of neurons, AFD, AIY, and AIZ, play a key
role in thermosensation. The LIM homeobox gene ceh-14 is expressed in the AFD
thermosensory neurons. ceh-14 mutant animals display athermotactic behaviors,
although the neurons are still present and differentiated. Two other LIM homeobox
genes, ttx-3 and lin-11, function in the two interneurons AIY and AIZ,
respectively. Thus, the three key thermosensory neurons are specified by three
different LIM homeobox genes. ceh-14 ttx-3 lin-11 triple mutant animals have a
basic cryophilic thermotaxis behavior indicative of a second thermotaxis pathway.
Misexpression of ceh-14 in chemosensory neurons can restore thermotactic behavior
without impairing the chemosensory function. Thus, ceh-14 confers thermosensory
function to neurons.
PMID- 10774728
TI - Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm.
AB - In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally
across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing
RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when
these metamorphic RGCs are grafted into embryos, they project contralaterally,
suggesting that the embryonic chiasm lacks signals that guide axons
ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but
not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm,
ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs.
Ephrin-B is also found in the chiasm of mammals, which have ipsilateral
projections, but not in the chiasm of fish and birds, which do not. These results
suggest that ephrin-B/EphB interactions play a key role in the sorting of axons
at the vertebrate chiasm.
PMID- 10774729
TI - GFRalpha-mediated localization of RET to lipid rafts is required for effective
downstream signaling, differentiation, and neuronal survival.
AB - The GDNF family ligands (GFLs: GDNF, neurturin, persephin, and artemin) signal
through RET and a gly-cosyl-phosphatidylinositol (GPI)-anchored coreceptor
(GFRalpha1-alpha4) that binds ligand with high affinity and provides specificity.
The importance of the GPI anchor is not fully understood; however, GPI-linked
proteins cluster into lipid rafts, structures that may represent highly
specialized signaling organelles. Here, we report that GPI-anchored GFRalpha1
recruits RET to lipid rafts after GDNF stimulation and results in RET/Src
association. Disruption of RET localization using either transmembrane-anchored
or soluble GFRalpha1 results in RET phosphorylation, but GDNF-induced
intracellular signaling events are markedly attenuated as are neuronal
differentiation and survival responses. Therefore, proper membrane localization
of RET via interaction with a raft-localized, GPI-linked coreceptor is of
fundamental importance in GFL signaling.
PMID- 10774730
TI - Analysis of relations between NMDA receptors and GABA release at olfactory bulb
reciprocal synapses.
AB - In the mammalian olfactory bulb, signal processing is mediated by synaptic
interactions between dendrites. Glutamate released from mitral cell dendrites
excites dendritic spines of granule cells, which in turn release GABA back onto
the mitral cell dendrites, forming a reciprocal synaptic pair. This feedback
synaptic circuit was shown to be mediated predominantly by NMDA receptors. We
further utilized caged Ca2+ compounds to obtain insight into the mechanism that
couples NMDA receptor activation to GABA release. Feedback inhibition elicited by
photo-release of caged Ca2+ in mitral cell secondary dendrites persisted when
voltage-gated Ca2+ channels were blocked by cadmium (Cd2+) and nickel (Ni2+).
These results indicate that Ca2+ influx through NMDA receptors can directly
trigger presynaptic GABA release for local dendrodendritic feedback inhibition.
PMID- 10774731
TI - Expression of cerebellar long-term depression requires postsynaptic clathrin
mediated endocytosis.
AB - Cerebellar long-term depression (LTD) is a cellular model system of information
storage that may underlie certain forms of motor learning. While cerebellar LTD
is expressed as a selective modification of postsynaptic AMPA receptors, this
might involve changes in receptor number/distribution, unitary conductance,
kinetics, or glutamate affinity. The observation that GluR2-containing synaptic
AMPA receptors could be internalized by regulated clathrin-mediated endocytosis
suggested that this process could underlie LTD expression. To test this
hypothesis, we postsynaptically applied dynamin and amphiphysin peptides that
interfere with the clathrin endocytotic complex and found that they blocked LTD
expression in cultured Purkinje neurons. In addition, induction of LTD and
attenuation of AMPA responses by stimulation of clathrin-mediated endocytosis
occluded each other. These findings suggest that the expression of cerebellar LTD
requires clathrin-mediated internalization of postsynaptic AMPA receptors.
PMID- 10774732
TI - Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent
receptor internalization.
AB - Redistribution of postsynaptic AMPA- (alpha-amino-3-hydroxy-5-methylisoxazole-4
propionic acid-) subtype glutamate receptors may regulate synaptic strength at
glutamatergic synapses, but the mediation of the redistribution is poorly
understood. We show that AMPA receptors underwent clathrin-dependent endocytosis,
which was accelerated by insulin in a GluR2 subunit-dependent manner. Insulin
stimulated endocytosis rapidly decreased AMPA receptor numbers in the plasma
membrane, resulting in long-term depression (LTD) of AMPA receptor-mediated
synaptic transmission in hippocampal CA1 neurons. Moreover, insulin-induced LTD
and low-frequency stimulation-(LFS-) induced homosynaptic CA1 LTD were found to
be mutually occlusive and were both blocked by inhibiting postsynaptic clathrin
mediated endocytosis. Thus, controlling postsynaptic receptor numbers through
endocytosis may be an important mechanism underlying synaptic plasticity in the
mammalian CNS.
PMID- 10774734
TI - GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic
hippocampal activity.
AB - In the hippocampus, interneurons provide synaptic inhibition via the transmitter
GABA, which can activate GABA(A) and GABA(B) receptors (GABA(A)Rs and GABA(B)Rs).
Generally, however, GABA released by a single interneuron activates only
GABA(A)Rs on its targets, despite the abundance of GABA(B)RS. Here, I show that
during hippocampal rhythmic activity, simultaneous release of GABA from several
interneurons activates postsynaptic GABA(B)Rs and that block of GABA(B)Rs
increases oscillation frequency. Furthermore, if GABA uptake is inhibited, even
GABA released by a single interneuron is enough to activate GABA(B)Rs. This
occurs also on cells not directly contacted by that interneuron, indicating that
GABA has to overcome uptake and exit the synaptic cleft to reach GABA(B)RS. Thus,
activation of extrasynaptic GABA(B)Rs by pooling of GABA is an important
mechanism regulating hippocampal network activity.
PMID- 10774733
TI - Modulation of GABAergic signaling among interneurons by metabotropic glutamate
receptors.
AB - Synapses between hippocampal interneurons are an important potential target for
modulatory influences that could affect overall network behavior. We report that
the selective group III metabotropic receptor agonist L(+)-2-amino-4
phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons
more than to pyramidal neurons. The L-AP4-induced depression is accompanied by
changes in trial-to-trial variability and paired-pulse depression that imply a
presynaptic site of action. Brief trains of stimuli in Schaffer collaterals also
depress GABAergic transmission to interneurons. This depression persists when
GABA(B) receptors are blocked, is enhanced by blocking glutamate uptake, and is
abolished by the group III metabotropic receptor antagonist (alpha-methylserine-O
phosphate (MSOP). The results imply that GABAergic transmission among
interneurons is modulated by glutamate spillover from excitatory afferent
terminals.
PMID- 10774735
TI - Four residues of the extracellular N-terminal domain of the NR2A subunit control
high-affinity Zn2+ binding to NMDA receptors.
AB - NMDA receptors are allosterically inhibited by Zn2+ ions in a voltage-independent
manner. The apparent affinity for Zn2+ of the heteromeric NMDA receptors is
determined by the subtype of NR2 subunit expressed, with NR2A-containing
receptors being the most sensitive (IC50, approximately 20 nM) and NR2C
containing receptors being the least sensitive (IC50, approximately 30 microM).
Using chimeras constructed from these two NR2 subtypes, we show that the N
terminal LIVBP-like domain of the NR2A subunit controls the high-affinity Zn2+
inhibition. Mutations at four residues in this domain markedly reduce Zn2+
affinity (by up to >500-fold) without affecting either receptor activation by
glutamate and glycine or inhibition by extracellular protons and Ni2+ ions,
indicating that these residues most likely participate in high-affinity Zn2+
binding.
PMID- 10774736
TI - A model for the topology of excitatory amino acid transporters determined by the
extracellular accessibility of substituted cysteines.
AB - Excitatory amino acid transporters (EAATs) function as both substrate
transporters and ligand-gated anion channels. Characterization of the
transporter's general topology is the first requisite step in defining the
structural bases for these distinct activities. While the first six hydrophobic
domains can be readily modeled as conventional transmembrane segments, the
organization of the C-terminal hydrophobic domains, which have been implicated in
both substrate and ion interactions, has been controversial. Here, we report the
results of a comprehensive evaluation of the C-terminal topology of EAAT1
determined by the chemical modification of introduced cysteine residues. Our data
support a model in which two membrane-spanning domains flank a central region
that is highly accessible to the extracellular milieu and contains at least one
reentrant loop domain.
PMID- 10774737
TI - Experience-dependent asymmetric shape of hippocampal receptive fields.
AB - We propose a novel parameter, namely, the skewness, or asymmetry, of the shape of
a receptive field to characterize two properties of hippocampal place fields.
First, a majority of hippocampal receptive fields on linear tracks are negatively
skewed, such that during a single pass the firing rate is low as the rat enters
the field but high as it exits. Second, while the place fields are symmetric at
the beginning of a session, they become highly asymmetric with experience.
Further experiments suggest that these results are likely to arise due to
synaptic plasticity during behavior. Using a purely feed forward neural network
model, we show that following repeated directional activation, NMDA-dependent
long-term potentiation/long-term depotentiation (LTP/LTD) could result in an
experience-dependent asymmetrization of receptive fields.
PMID- 10774738
TI - A stimulus-driven approach to object identity and location processing in the
human brain.
AB - The primate visual system is considered to be segregated into ventral and dorsal
streams specialized for processing object identity and location, respectively. We
reexamined the dorsal/ventral model using a stimulus-driven approach to object
identity and location processing. While looking at repeated presentations of a
standard object at a standard location, subjects monitored for any infrequent
"oddball" changes in object identity, location, or identity and location
(conjunction). While the identity and location oddballs preferentially activated
ventral and dorsal brain regions respectively, each oddball type activated both
pathways. Furthermore, all oddball types recruited the lateral temporal cortex
and the temporo-parietal junction. These findings suggest that a strict
dorsal/ventral dual-stream model does not fully account for the perception of
novel objects in space.
PMID- 10774739
TI - The bHLH gene Hes1 regulates differentiation of multiple cell types.
AB - For embryos that have small pancreas and lack brain, eyes and thymus, the defects
are caused by mutation of a single gene, Hes1. Hes1 encodes a basic helix-loop
helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH
genes such as the neuronal determination gene, Mash1. Misexpression of Hes1
inhibits cell differentiation and keeps cells at the precursor stage or
proliferative stage. Conversely, in the absence of Hes1, the expression of
positive bHLH genes is upregulated and cells differentiate prematurely without
sufficient cell growth. As a result, the development of many tissues such as the
brain, eye and pancreas is severely affected. Thus, Hes1 regulates tissue
morphogenesis by maintaining undifferentiated cells. In the case of T cell
development, Hes1 mutation leads to defects of expansion of early T cell
precursors and thereby suppresses T cell fate specification. Thus, Hes1 promotes
differentiation of some cell types in addition to maintenance of the
undifferentiated state. Interestingly, Hes1 expression is controlled by the
transmembrane protein Notch, which is activated by the ligands expressed on the
surface of neighboring cells. Taken together, these results indicate that the
Notch-Hes1 pathway, which is controlled by cell-cell interaction, plays an
essential role in differentiation of many cell types.
PMID- 10774740
TI - Molecular cloning of a cDNA encoding ribosome inactivating protein from
Amaranthus viridis and its expression in E. coli.
AB - In order to isolate a cDNA clone of ribosome inactivating protein (RIP), a cDNA
library was constructed in Uni-ZAP XL vector with poly(A) RNA purified from
leaves of Amaranthus viridis. To get the probe for screening the library, PCR of
phage DNA was conducted using the vector primer and degenerate primer designed
from a conserved putative active site of the RIPs. Twenty-six cDNA clones from
about 600,000 plaques were isolated, and one of these clones was fully sequenced.
It was 1,047 bp and contained an open reading frame encoding 270 amino acids. The
deduced amino acid sequence had a putative signal sequence of 17 amino acids and
a putative active site (AIQMVAEAARFFKYIE) conserved in other RIPs. E. coli cells
expressing A. viridis RIP cDNA did not grow well as compared to control cells,
indicating that recombinant A. viridis RIP presumably inactivated E. coli
ribosomes. In addition, recombinant A. viridis RIP cDNA produced by E. coli had
translation inhibition activity in vitro.
PMID- 10774741
TI - Cloning and sequence analysis of cDNA for diuretic hormone receptor from the
Bombyx mori.
AB - The insect diuretic hormone (DH) binds to their receptor in malpighian tubules,
and stimulates water secretion and cAMP synthesis. Complementary DNA encoding a
diuretic hormone receptor was cloned from the malpighian tubules of Bombyx mori.
The cloned cDNA encodes a protein consisting of 391 amino acid residues with the
seven transmembrane domains. The receptor protein is homologous with that of
other insects, and is structurally related to G-protein coupled receptors such as
corticotropin relating factor (CRF), secretin, and vasoactive intestinal peptide.
PMID- 10774742
TI - Chromosomal localization and sequence variation of 5S rRNA gene in five Capsicum
species.
AB - Chromosomal localization and sequence analysis of the 5S rRNA gene were carried
out in five Capsicum species. Fluorescence in situ hybridization revealed that
chromosomal location of the 5S rRNA gene was conserved in a single locus at a
chromosome which was assigned to chromosome 1 by the synteny relationship with
tomato. In sequence analysis, the repeating units of the 5S rRNA genes in the
Capsicum species were variable in size from 278 bp to 300 bp. In sequence
comparison of our results to the results with other Solanaceae plants as
published by others, the coding region was highly conserved, but the spacer
regions varied in size and sequence. T stretch regions, just after the end of the
coding sequences, were more prominant in the Capsicum species than in two other
plants. High G x C rich regions, which might have similar functions as that of
the GC islands in the genes transcribed by RNA PolII, were observed after the T
stretch region. Although we could not observe the TATA like sequences, an AT rich
segment at -27 to -18 was detected in the 5S rRNA genes of the Capsicum species.
Species relationship among the Capsicum species was also studied by the sequence
comparison of the 5S rRNA genes. While C. chinense, C. frutescens, and C. annuum
formed one lineage, C. baccatum was revealed to be an intermediate species
between the former three species and C. pubescens.
PMID- 10774743
TI - Regulatory properties of glutamate dehydrogenase from Sulfolobus solfataricus.
AB - The purified glutamate dehydrogenase (GDH) from Sulfolobus solfataricus showed
remarkable thermostability and retained 90-95% of the initial activity after
incubation at -20 degrees C, 4 degrees C, and 25 degrees C for up to 6 months.
Unlike mammalian GDHs, the activity of GDH from Sulfolobus solfataricus was not
significantly affected by the presence of various allosteric effectors such as
ADP, GTP, and leucine. Incubation of GDH with increasing concentration of o
phthalaldehyde resulted in a progressive decrease in enzyme activity, suggesting
that the o-phthalaldehyde-modified lysine or cysteine is directly involved in
catalysis. The inhibition was competitive with respect to both 2-oxoglutarate (Ki
= 30 microM) and NADH (Ki = 100 microM), further supporting a possibility that
the o-phthalaldehyde-modified residues may be directly involved at the catalytic
site. The modification of GDH by the arginine-specific dicarbonyl reagent
phenylglyoxal was also examined with the view that arginine residues might play a
general role in the binding of coenzyme throughout the family of pyridine
nucleotide-dependent dehydrogenases. The purified GDH was inactivated in a dose
dependent manner by phenylglyoxal. Either NADH or 2-oxoglutarate did not gave any
protection against the inactivation caused by a phenylglyoxal. This result
indicates that GDH saturated with NADH or 2-oxoglutarate is still open to attack
by phenylglyoxal. Phenylglyoxal was an uncompetitive inhibitor (Ki = 5 microM)
with respect to 2-oxoglutarate and a noncompetitive inhibitor (Ki = 6 microM)
with respect to NADH. The above results suggests that the phenylglyoxal-modified
arginine residues are not located at the catalytic site and the inactivation of
GDH by phenylglyoxal might be due to a steric hindrance or a conformational
change affected by the interaction of the enzyme with its inhibitor.
PMID- 10774744
TI - Dynamic chromatin remodeling in the vicinity of J chain gene for the regulation
of two stage-specific genes during B cell differentiation.
AB - Dynamic chromatin remodeling during B cell differentiation was identified in the
vicinity of J chain gene. In pre-B cells, the enhancer-containing DNase I
hypersensitive sites (HSSs) 3-4 were open. However, these HSSs 3-4 turned out to
be unassociated with J chain gene expression, as the J chain promoter-containing
HSS1 remained in a closed state. The open enhancer HSSs 3-4 in the pre-B cells
might be related to the expression of a pre-B cell-specific gene upstream of the
HSSs 3-4, which was identified in our Northern blot analyses. The HSSs 3-4 are
then closed in the next immature and mature B cell stages until the IL-2 opens
the HSSs 3-4 again as well as HSS1 to express J chain gene in the primary immune
responses. The dynamic regulation of chromatin structure during B cell
differentiation for the expression of two stage-specific genes will provide a
good model system for the study of B cell differentiation and gene expression.
PMID- 10774745
TI - Reactive oxygen species-specific mechanisms of drug resistance in paraquat
resistant acute myelogenous leukemia sublines.
AB - Reactive oxygen species (ROS)-specific mechanisms of drug resistance were
explored in paraquat (PQ)-resistant acute myelogenous leukemia cell (OCI/AML-2)
sublines. For this, PQ-resistant AML sublines, AML-2/PQ100 and AML-2/PQ400, were
selected in the presence of PQ concentrations of 100 microg/ml and 400 microg/ml,
respectively. They showed a moderate level of cross resistance to cisplatin and
doxorubicin. They were also slightly more resistant than the parental cell (AML
2/WT) to etoposide, camptothecin and daunorubicin. The resistance of PQ-resistant
AML-2 sublines to cisplatin seemed to be due to increased amounts of
metallothionein, which was not only supported by reversal of resistance to
cisplatin by propargylglycin (an inhibitor of metallothionein synthesis) but also
confirmed by Western blot analysis and reverse transcription-PCR assay. In
addition, both AML-PQ100 and /PQ400 sublines showed increased activities of Cu-,
Zn-containing superoxide dismutase (Cu,Zn-SOD) and Mn-containing superoxide
dismutase (Mn-SOD), whereas AML-2/PQ400, but not AML-2/PQ100, showed increased
glutathione S-transferase activity as compared to that of AML-2/WT. However,
there was no difference in other ROS-related cellular antioxidants between AML
2/WT and its PQ-resistant sublines. Taken together, these results strongly
suggest that increases in levels of metallothionein, glutathione S-transferase,
Cu,Zn-SOD and Mn-SOD play important roles in protective mechanisms against
toxicity of PQ or ROS in AML cells.
PMID- 10774746
TI - Identification and characterization of a bidirectional promoter from the
intergenic region between the human DDX13 and RD genes.
AB - The human DDX13 gene encodes a putative RNA helicase of the DExH-box family. In
an earlier report we showed that the human DDX13 and RD genes were arranged head
to-head in the class III MHC complex and their ATG start codons were separated by
745 base pairs. We have now analyzed the common 745 bp intergenic region in
detail and characterized their promoters. Northern blot analysis revealed that
DDX13 and RD exhibit distinct patterns of steady-state expression among multiple
human tissues. The promoter regions for DDX13 and RD genes were identified by
deletion analysis from 740 bp to 176 bp of the intergenic region fused to a
chloramphenicol acetyltransferase (CAT) reporter gene using transient
transfection assays. Results indicated that a promoter sequence as small as 176
bp is sufficient for basal expression of both genes in HeLa and HepG2 cells.
Functional analysis using a bidirectional reporter system demonstrates that the
sequence 262 bp proximal to the DDX13 gene is sufficient for concurrent
expression in both directions. However, the common 740 bp intergenic region
showed promoter activity in DDX13 only, suggesting the presence of a negatively
acting region for the RD gene within the region -267 to -744. It appears that RD
expression is controlled by a complex system of positively and negatively acting
elements present on distant portions of both genes.
PMID- 10774747
TI - Diversity of the p70 killer cell inhibitory receptor (KIR3DL) family members in a
single individual.
AB - NK cells and some T cells express members of a multigenic family of killer cell
inhibitory receptors (KIRs) including p70 KIR (KIR3DL) and p58 KIR (KIR2DL)
family that recognize polymorphic class I MHC molecules on target cells and
transmit an inhibitory signal to prevent killer cell-mediated cytoxicity. The
cDNA sequences of p70 KIR family members reported so far suggest that the p70 KIR
gene consists of a multigene complex and that each gene may exhibit certain
degrees of polymorphism. However, it is not clear how diverse the repertoire of
the p70 KIR family is, particularly in a single individual. To address this
question in more detail and to determine some indication as to the origin of the
diversity, we cloned p70 KIR cDNAs from a single individual. We identified nine
new KIRs that are different from the previously reported ones. A comparison of
the amino acid sequences with published sequences of p70 KIRs showed that two
clones belonged to the KIR3DL1 family, five clones belonged to the KIR3DL2
family, one clone belonged to the KIR2DL4 family, and one clone appeared to be an
alternatively spliced form of p70 KIR. These results suggested that the
repertoire of p70 KIR family members in a single individual is highly diverse. It
is not clear how the diverse receptors are generated in a single individual, but
a comparison of amino acid sequences of p70 KIR family members suggested that
some of them may be encoded by distinct genes or their alleles, while others may
be generated by a recombination mechanism and/or an alternative splicing
mechanism at the maturation of the mRNA transcripts.
PMID- 10774748
TI - Isolation of true Rbp9 null alleles by imprecise P element excisions.
AB - The P element has been widely used as a mutagen because of its convenience in
locating the site of mutagenesis. However, P element-induced mutations often
result in varied mutant phenotypes, making it difficult to identify the null
phenotype. Previously, three Rbp9 alleles were isolated using P element
mutagenesis. Although the coding regions of Rbp9 were disrupted by P elements in
all three cases, they showed different degrees of defects. In order to
characterize the null phenotype of Rbp9, Rbp9 alleles with chromosomal deletions
were created by inducing imprecise excisions of the P elements. All Rbp9 alleles
generated from imprecise excisions showed the same mutant phenotype: female flies
were sterile and cystocyte differentiation was blocked. This result reveals that
the primary function of Rbp9 resides in the regulation of cystocyte
differentiation. In addition, this result shows that a P element does not always
completely inactivate gene activity, even when it is incorporated into the coding
region.
PMID- 10774749
TI - Expression patterns of alpha-synuclein in human hematopoietic cells and in
Drosophila at different developmental stages.
AB - Alpha-synuclein, a presynaptic protein of the central nervous system, has been
implicated in the synaptic events such as neuronal plasticity during development
and learning, and neuronal degeneration under pathological conditions. As an
effort to understand the biological function of alpha-synuclein, we examined the
expression patterns of alpha-synuclein in various human hematopoietic cells, and
in Drosophila at different developmental stages. The alpha-synuclein was
ubiquitously expressed in all the tested hematopoietic cells including T cells, B
cells, NK cells, and monocytes, as well as in the lymphoma cell lines, Jurkat and
K562. A potential alpha-synuclein homologue was also expressed in Drosophila, and
its expression appeared to be temporally and spatially regulated during
development. Our data suggest that alpha-synuclein may function in invertebrates
as well as in vertebrates and its function may not be restricted to the neuron.
PMID- 10774750
TI - Mapping of altromycin B-DNA adduct at nucleotide resolution in the human genomic
DNA by ligation-mediated PCR.
AB - The ligation-mediated PCR was used to map DNA alkylation sites induced by
altromycin B at nucleotide resolution in genomic DNA purified from cultured human
colon carcinoma. Altromycin B, one of the pluramycin group of antitumor
antibiotics, is characterized as intercalator with the added ability to alkylate
N7 guanine. DNA adducts formed in genomic DNA were cleaved into DNA strand breaks
by hot piperidine treatment, and fragments containing ligatable breaks were then
amplified in a single-sided, ligation-mediated PCR. The alkylation sites observed
in exon 9 of the p53 gene revealed that the most high reactivity sites for
altromycin B were found to be N7 of guanine in a 5'-AG* sequence. Determination
of the DNA alkylation sites in naked radiolabeled plasmid DNA also showed that
altromycin B preferred N7 of guanine in a 5'-AG* sequence. Thus, it can be
concluded that the sequence selective DNA adduct formation induced by the
intercalating alkylator, altromycin B, in genomic DNA is similar to that observed
in naked plasmid DNA.
PMID- 10774751
TI - Transfer RNA identity change in anticodon variants of E. coli tRNA(Phe) in vivo.
AB - The anticodon sequence is a major recognition element for most aminoacyl-tRNA
synthetases. We investigated the in vivo effects of changing the anticodon on the
aminoacylation specificity in the example of E. coli tRNA(Phe). Constructing
different anticodon mutants of E. coli tRNA(Phe) by site-directed mutagenesis, we
isolated 22 anticodon mutant tRNA(Phe); the anticodons corresponded to 16 amino
acids and an opal stop codon. To examine whether the mutant tRNAs had changed
their amino acid acceptor specificity in vivo, we tested the viability of E. coli
strains containing these tRNA(Phe) genes in a medium which permitted tRNA
induction. Fourteen mutant tRNA genes did not affect host viability. However,
eight mutant tRNA genes were toxic to the host and prevented growth, presumably
because the anticodon mutants led to translational errors. Many mutant tRNAs
which did not affect host viability were not aminoacylated in vivo. Three mutant
tRNAs containing anticodon sequences corresponding to lysine (UUU), methionine
(CAU) and threonine (UGU) were charged with the amino acid corresponding to their
anticodon, but not with phenylalanine. These three tRNAs and tRNA(Phe) are
located in the same cluster in a sequence similarity dendrogram of total E. coli
tRNAs. The results support the idea that such tRNAs arising from in vivo
evolution are derived by anticodon change from the same ancestor tRNA.
PMID- 10774752
TI - Okadaic acid induces cycloheximide and caspase sensitive apoptosis in immature
neurons.
AB - Previous studies have shown that okadaic acid (OA) evokes tau phosphorylation and
neurofibrillary changes in vivo, and in cultured neurons, that resemble
Alzheimer's disease pathogenesis. In order to investigate the mechanism of OA
neurotoxicity, we treated cultured rat neurons with OA and examined nuclear
morphology, phosphatidylserine (PS) externalization, alpha-fodrin cleavage, and
the effects of cell death inhibitors. Our results demonstrated that cycloheximide
(CHX) and the broad-spectrum caspase inhibitor, ZVAD, significantly reduced cell
death in a dose-dependent manner. Nuclear fragmentation, a hallmark of apoptosis,
occurred after OA treatment and was inhibited by CHX or ZVAD. PS externalization
was apparent in 6-12 h in neurites and in cell bodies, and peaked at 24 h after
OA treatment. Cleavage of alpha-fodrin as visualized by the appearance of 150-
and 120-kDa bands appeared with a time course similar to PS externalization.
These results suggest that OA induce CHX and caspase sensitive neuronal
apoptosis.
PMID- 10774753
TI - Molecular detection of TEL-AML1 transcripts as a diagnostic tool and for
monitoring of minimal residual disease in B-lineage childhood acute lymphoblastic
leukemia.
AB - The chromosomal translocation t(12;21) (p12;q22) which results in the TEL-AML1
fusion gene is the most frequent genetic rearrangement in childhood B-lineage
acute lymphoblastic leukemia (ALL). The rearrangement in this locus, however, is
only rarely observed by routine karyotypic analysis. We established a nested
reverse transcriptase-polymerase chain reaction (nested-RT-PCR) technique for the
detection of the TEL-AML1 transcript, and used this to investigate the incidence
of the rearrangement, and to characterize the disease present in TEL-AML1
positive B-lineage ALL patients. The TEL-AML1 fusion transcript was detected in
nine of fourteen patients. These patients were relatively homogeneous in that
they were young and had low presenting leukocyte counts, both features of which
are associated with a favorable prognosis. Furthermore, we could detect the TEL
AML1 transcript in the peripheral blood of t(12;21)-positive patients and we used
this to assess minimal residual disease (MRD) in patients during chemotherapy.
The data demonstrate that nested-RT-PCR is a suitable tool for diagnosing
t(12;21)-positive ALL, that these patients constitute a clinically distinct
subgroup of ALL patients, and that the method could also be used to monitor MRD
in these patients.
PMID- 10774754
TI - Minimal core domain of HIV-1 integrase for biological activity.
AB - The human immunodeficiency virus type-1 (HIV-1) integrase (IN) mediates insertion
of viral DNA into human DNA, which is an essential step in the viral life cycle.
In order to study minimal core domain in HIV-1 IN protein, we constructed nine
deletion mutants by using PCR amplification. The constructs were expressed in
Escherichia coli, and the proteins were subsequently purified and analyzed in
terms of biological activity such as enzymatic and DNA-binding activities. The
mutant INs with an N-terminal or C-terminal deletion showed strong disintegration
activity though they failed to show endonucleolytic and strand transfer
activities, indicating that the disintegration reaction does not require the fine
structure of the HIV-1 IN protein. In the DNA-binding analysis using gel mobility
shift assay and UV cross-linking method, it was found that both the central and C
terminal domains are essential for proper DNA-IN protein interaction although the
central or C-terminal domain alone was able to be in close contact with DNA
substrate. Therefore, our results suggest that the C-terminal domain act as a DNA
holding motive, which leads to proper interaction for enzymatic reaction between
the IN protein and DNA.
PMID- 10774755
TI - Cloning, overexpression and purification of Bacillus subtilis elongation factor
Tu in Escherichia coli.
AB - To establish the overexpression and one-step purification system of Bacillus
subtilis elongation factor-Tu (EF-Tu), the EF-Tu gene was amplified with or
without own ribosome binding site (rbs) by PCR and the only PCR product without
rbs was subcloned successfully. For the expression of the EF-Tu gene cloned after
PCR amplification, a constitutive expression system and inducible expression
system with His6 tag at N-terminus or C-terminus, or glutathione-S-transferase
(GST) fusion system were examined in E. coli and B. subtilis. Except GST fusion
system in E. coli, however, all other trials were unsuccessful at the step of
plasmid construction for the EF-Tu expression. The GST/EF-Tu fusion proteins were
highly expressed by IPTG induction and obtained as both soluble and insoluble
form. From the soluble GST/EF-Tu fusion protein, EF-Tu was obtained to near
homogeneity by one-step purification with glutathione-sepharose affinity column
chromatography followed by factor Xa treatment. The purified EF-Tu showed high
GDP binding activity. These results indicate that the GST/EF-Tu fusion system is
favorable to overexpression and purification of B. subtilis EF-Tu.
PMID- 10774756
TI - Isolation and characterization of polymorphic cDNAs partially encoding ADP
glucose pyrophosphorylase (AGPase) large subunit from sweet potato.
AB - cDNA clones encoding sweet potato AGPase large subunit (iAGPLI) from the cDNA
library constructed from the tuberous root were isolated. Two clones were
characterized and named iAGPLI-a and iAGPLI-b. They were 1,661 bp and 1,277 bp in
length and contained partial open reading frames of 450 and 306 amino acids,
respectively. Both nucleic acid and amino acid sequence identities between iAGPLI
a and iAGPLI-b were 83.8% and 97.3%, respectively. Based on the amino acid
sequence analysis, iAGPLI-a and iAGPLI-b share the highest sequence identity
(81%) with potato AGPase large subunit. The iAGPLI-a and iAGPLI-b genes were
expressed predominantly in the stem and weakly in the tuberous root, and no
transcript was expressed in other tissues. The sweet potato genome contains
several copies of the iAGPLI gene.
PMID- 10774757
TI - Yeast asparagine (Asn) tRNA without Q base promotes eukaryotic frameshifting more
efficiently than mammalian Asn tRNAs with or without Q base.
AB - In this study, we compare the efficiency of Asn tRNA from mammalian sources with
and without the highly modified queuosine (Q) base in the wobble position of its
anticodon and Asn tRNA from yeast, which naturally lacks Q base, to promote
frameshifting. Interestingly, no differences in the ability of the two mammalian
Asn tRNAs to promote frameshifting were observed, while yeast tRNA(ASn)(-Q)
promoted frameshifting more efficiently than its mammalian counterparts in both
rabbit reticulocyte lysates and wheat germ extracts. The shiftability of yeast
Asn tRNA is therefore not due, or at least not completely, to the lack of Q base
and most likely the shiftiness resides in structural differences elsewhere in the
molecule. However, we cannot absolutely rule out a role of Q base in
frameshifting as wheat germ extracts and a lysate depleted of most of its tRNA
and supplemented with calf liver tRNA contain both Asn tRNA with or without Q
base.
PMID- 10774758
TI - Perinatal vasoconstrictive renal insufficiency associated with maternal
nimesulide use.
AB - A full-term newborn developed oliguric renal failure at 24 hr of life, which
persisted for several days. Her mother ingested therapeutic doses of nimesulide,
a non-steroidal anti-inflammatory (cyclo-oxygenase-2 inhibitor) drug, during the
last 2 weeks of pregnancy. She was found at delivery to have developed
oligohydramnion, esophagitis, and a bleeding peptic ulcer. The infant's
fractional excretion of sodium was very low (0.5%) pointing for a severe
vasoconstrictive mechanism involved. Renal sonogram showed hyperechogenic
medullary papillae, which resolved during convalescence. This case emphasizes the
importance of renal prostagandins in the control of vascular tone and sodium
homeostasis. This is the first report of an adverse effect of fetal renal
circulation by maternal ingestion of nimesulide.
PMID- 10774759
TI - Prenatal ultrasonographic diagnosis of conditions associated with potential
umbilical cord compression.
AB - The objective of this review is to assess the current literature pertaining to
prenatal ultrasonographic diagnosis of various conditions that predispose the
fetus to potential umbilical cord compression. We performed a MEDLINE search
utilizing the terms:umbilical cord compression, nuchal cord, cord entanglement,
and true knot. Additional sources were obtained through cross-referencing.
Prenatal ultrasound assists in the diagnosis of nuchal cord(s), true knot of the
umbilical cord, cord entanglement in monoamniotic twin gestations, and other
unusual etiologies that may lead to umbilical cord compression. Supplementary
ultrasonographic measures including color Doppler imaging, Doppler flow
velocimetry, and possibly three-dimensional ultrasound may further prenatal
diagnosis of these conditions. Doppler flow velocimetry may also assist in
detecting impaired or deteriorating umbilical artery flow reflecting increasing
cord compression prior to the onset of adverse and potentially nonreversible
effects upon the fetus. Close fetal surveillance in cases further complicated by
decreased fetal movements, decreased amniotic fluid volume, postdates, fetal
growth restriction, and impaired umbilical artery Doppler flow velocimetry may
assist in the management of such gestations. Although definitive prospective
studies investigating neonatal outcome following prenatal ultrasonographic
depiction of potential umbilical cord compression are not currently available,
review of the literature suggests that increased fetal surveillance may be
indicated in certain clinical conditions.
PMID- 10774760
TI - Infected cephalohematoma associated with sepsis and skull osteomyelitis: report
of one case.
AB - Osteomyelitis is rarely complicated by an infected cephalohematoma. We report a
case of an infected cephalohematoma associated with Escherichia coli sepsis and
osteomyelitis of the skull. This 37-day-old boy had E. coli sepsis, which had a
poor response to antibiotic treatment. An infected cephalohematoma was found when
he was 43 days old. Cranial computed tomography (CT) scanning showed
cephalohematoma with abscess formation and underlying bony destruction over the
left parietal region. Antibiotics alone could not eradicate the infection.
Extensive incision, drainage, and debridement of the necrotic bone resulted in
prompt improvement. Three weeks of ceftizoxime administered intravenously,
followed by 3 weeks of cefixime given orally completed the treatment course.
PMID- 10774761
TI - Transient hyperechogenicity of the renal medullary pyramids: incidence in the
healthy term newborn.
AB - A screening program was performed on 1881 clinically healthy term newborns, aimed
at detecting eventual pathological conditions not diagnosed during pregnancy.
Seventy-three cases of transient hyperechogenicity of the renal medullary
pyramids were observed, involving one or both kidneys with either sectorial or
diffuse pattern. None of the neonates examined had evidence of renal dysfunction
and follow-up ultrasound scans demonstrated complete resolution of the
sonographic picture. Medullary hyperechogenicity is not rare in healthy term
newborns (3.9%); it presents rapid resolution and should be considered in
differential diagnosis of pathological conditions.
PMID- 10774762
TI - Color Doppler of the splenic artery in the prenatal diagnosis of heterotaxic
syndromes.
AB - The objective of this paper is to determine whether color and pulsed Doppler of
the splenic artery is helpful in the prenatal diagnosis of polysplenia or
asplenia in heterotaxic syndromes. Over a 3-year period, localization of the
splenic artery by color and pulsed Doppler was attempted on all fetuses with the
diagnosis of heterotaxic syndromes. Postnatal follow-up was obtained on all
neonates. The diagnosis of heterotaxic syndromes was performed on eight fetuses
during the study period. Mean gestational age at diagnosis was 20.1 weeks. All
fetuses had situs ambiguous and complex cardiac abnormalities. All pregnancies
were managed expectantly and none were terminated. The splenic artery was imaged
by color and pulsed Doppler in 6 of 8 fetuses, all with one or multiple spleens
confirmed postnatally. The splenic artery could not be imaged in two fetuses,
both with asplenia confirmed postnatally. The perinatal mortality rate was 88% (7
of 8) and the one surviving infant is currently alive and well at 3 years of age.
Color and pulsed Doppler of the splenic artery can aid in the prenatal diagnosis
of heterotaxic syndromes. This information is of value and should result in
improved prenatal counseling and management of affected pregnancies.
PMID- 10774763
TI - Second-trimester presentation of placenta percreta.
AB - Placenta percreta is diagnosed usually in the third trimester as massive
postpartum hemorrhage when an attempt to remove the placenta reveals lack of a
cleavage plane. However, placenta percreta may present in the second trimester
with signs and symptoms of uterine rupture. The diagnosis of this event may be
difficult because of mild abdominal discomfort often associated with normal
pregnancy. We describe two cases that occurred in the second trimester with an
unusual presentation. Both patients suffered considerable surgical morbidity.
Other cases reported in the literature are mentioned as well. When a patient with
risk factors for abnormal placentation presents with abdominal pain and/or
vaginal bleeding in the second trimester of pregnancy, the diagnosis of placenta
percreta should be considered. A laparotomy is indicated immediately when
hemoperitoneum is suspected because uterine rupture has most likely occurred.
Placenta percreta in the second trimester is a potentially life-threatening
condition that warrants expeditious diagnosis to limit maternal postoperative
morbidity.
PMID- 10774764
TI - Current obstetrical practice and umbilical cord prolapse.
AB - The aim of this study was to assess the contribution of current obstetrical
practice to the occurrence and complications of umbilical cord prolapse. Maternal
and neonatal charts of 87 pregnancies complicated by true umbilical cord prolapse
during a 5-year period were reviewed. Twin gestation and noncephalic
presentations were common features (14 and 41%, respectively). Eighty-nine
percent (77) of infants were delivered by cesarean section of which 29% were
classical and 88% were primary. The mean gestational age at delivery was 34.0 +/-
6.0 weeks, and the mean birth weight was 2318 +/- 1159 g. Obstetrical
intervention preceded 41 (47%) cases (the obstetrical intervention group):
amniotomy (9), scalp electrode application (4), intrauterine pressure catheter
insertion (6), attempted external cephalic version (7), expectant management of
preterm premature rupture of membranes (14), manual rotation of the fetal head
(1), and amnioreduction (1). There were 11 perinatal deaths. Thirty-three percent
of the infants (32) had a 5-min Apgar score < 7 and 34% had a cord pH < 7.20.
Neonatal seizures, intracerebral hemorrhage, necrotizing enterocolitis, hyaline
membrane disease, persistent fetal circulation, sepsis, assisted ventilation, and
perinatal mortality were comparable in the "obstetrical intervention" and "no
intervention" groups. Most of the neonatal complications occurred in infants < 32
weeks' gestation. We conclude that obstetrical intervention contributes to 47% of
umbilical cord prolapse cases; however, it does not increase the associated
perinatal morbidity and mortality.
PMID- 10774765
TI - Hepatitis B carrier and perinatal outcome in singleton pregnancy.
AB - The objective of this article is to evaluate the effect of hepatitis B
antigenemia on perinatal outcome. Perinatal outcome of 824 women with hepatitis B
surface antigen (HbsAg) was compared with 6281 women without hepatitis B surface
antigen (control) from June 1996 to September 1998. The maternal characteristics
were comparable between the two groups. Perinatal outcome was comparable between
groups. The incidences of preterm birth, premature prelabor rupture of membranes,
prelabor rupture of membranes, small for gestational age, neonatal jaundice,
fetal distress, perinatal asphyxia, congenital abnormality, gastrointestinal
tract abnormality, and perinatal mortality were similar among the two groups. We
conclude that the presence of hepatitis B surface antigen in pregnant women does
not pose additional risk for the pregnancy.
PMID- 10774766
TI - Comparison of the effect of saturated and monounsaturated fat on postprandial
plasma glucose and insulin concentration in women with gestational diabetes
mellitus.
AB - The goal of this study was to determine whether the type of fat plays a role in
the glucose response to a meal, independent of the carbohydrate content. Ten
gestational diabetic women (gestational weeks 29-34) who were well controlled on
diet alone were randomized as to the order in which they would eat a meal, after
overnight fast, containing saturated fat (SF) or monounsaturated fat (MUFA).
Blood was drawn at 0, 60, 120, and 180 min for plasma glucose, insulin, lipid
profile (triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL
cholesterol) and free fatty acids. After 2 weeks, each patient received the other
type of meal. The test meal was composed of 20% of the total daily caloric needs
based on ideal body weight. The area under the curve showed a significantly lower
glucose concentration for SF meal (p = 0.001). Serum insulin concentrations
followed the glucose response with the peak at the 60-min time point and a
significantly lower concentration at the 180-min time point in the SF than in the
MUFA group. The present study demonstrated that the addition of SF to the meal
resulted in lower postprandial glucose and insulin than when the meal contained
MUFA. Thus, SF may be useful in controlling postprandial glucose.
PMID- 10774767
TI - Compressed air as a source of inhaled oxidants in intensive care units.
AB - Exhaled gas from mechanically ventilated preterm infants was found to have
similar oxidant concentrations, regardless of lung disease, leading to the
hypothesis that wall outlet gases were an oxidant source. Oxidants in compressed
room air and oxygen from wall outlets were assessed in three hospitals. Samples
were collected by flowing wall outlet gas through a heated humidifier and an ice
packed condenser. Nitric oxide (NO) was measured in intensive care room air and
in compressed air with and without a charcoal filter using a Sievers NOA280
nitric oxide analyzer (Boulder, CO). Oxidants were measured by spectrophotometry
and expressed as nMol equivalents of H2O2/mL. The quantity of oxidant was also
expressed as amount of Vitamin C (nMol/mL) added until the oxidant was
nondetectable. This quantity of Vitamin C was also expressed in Trolox Equivalent
Antioxidant Capacity (TEAC) units (mMol/L). Free and total chlorine were measured
with a Chlorine Photometer. Oxidants were not found in compressed oxygen and were
only found in compressed air when the compression method used tap water. At a
compressed room air gas flow of 1.5 L/min, the total volume of condensate was
20.2 +/- 1 mL/hr. The oxidant concentration was 1.52 +/- 0.09 nMol/mL equivalents
of H2O2/mL of sample and 30.8 +/- 1.2 nMol/hr; 17.9% of that found in tap water.
Oxidant reduction required 2.05 +/-0.12 nMol/mL vitamin C, (1.78 +/- 0.1 x 10(-3)
TEAC units). Free and total chlorine in tap water were 0.3 +/- 0.02 mg/mL and 2.9
+/- 0.002 mg/mL, respectively. Outlet gas contained 0.4 +/- 0.06 mg/mL and 0.07 +
0.01 mg/mL total and free chlorine, respectively; both 14% of tap water. When a
charcoal filter was installed in the hospital with oxidants in compressed air,
oxidants were completely removed. Nursery room air contained 12.4 +/- 0.5 ppb NO;
compressed wall air without a charcoal filter, 8.1 +/- 0.1 ppb and compressed air
with a charcoal filter 12.5 +/- 0.5 ppb. A charcoal filter does not remove NO.
(Table 3) We recommend that all compressed air methods using tap water have
charcoal filters at the compression site and the gases be assessed periodically
for oxidants.
PMID- 10774769
TI - Etiologic evidence and primary prevention of cancer.
AB - For many decades, primary prevention of cancer was implemented on the basis of
evidence for a causal relationship between exposure and human cancer that took
into consideration biological plausibility, but did not depend on the degree of
understanding of the underlying mechanisms. One of the credos of public health is
that primary prevention can be implemented before reaching a complete
understanding of mechanisms that could confirm/explain causality. Measures of
primary prevention are taken on the basis of what is recognized as causative
factors of human cancer. The most authoritative lists of recognized human
carcinogens are those compiled from the evaluations of carcinogenic risk carried
out by the International Agency for Research on Cancer (IARC) and the evaluations
that the U.S. National Toxicology Program (NTP) publishes in its periodical
Report on Carcinogens. Knowledge of mechanisms is accumulating at a fast pace,
and although it has not yet led to the definition of an efficient strategy for
primary prevention for the majority of cancer cases, it may drive the scientific
establishment toward a high-risk approach to prevention. The most reasonable and
socially acceptable development of primary prevention should be the blending of a
population approach; that is, the shifting of the distribution of risk factors
across an entire population in a favorable direction (e.g., a general decrease of
the levels of exposure to environmental carcinogens) with the high-risk approach
that will concern individuals with extreme values of genetically determined
weaknesses in the interactions with the environment.
PMID- 10774768
TI - Laboratory animal tests and human cancer.
AB - The use of the results of laboratory animal tests to predict human cancer is
effective in identifying potential human carcinogens before human exposure,
permitting measures to be taken to prevent that exposure, a foolproof way to
prevent human cancer. The purported, and highly publicized, faults of these
tests, when examined critically, are shown not to be significant. Most chemicals
are not carcinogenic; only about 1 in 10 are truly carcinogenic. The high doses
used to maximize sensitivity do not produce false positives. All human
carcinogens are carcinogenic in laboratory animals, and almost all animal
carcinogens for which there is human exposure, when analyzed by epidemiological
studies, show responses that are not statistically different. Most carcinogens
are not banned, some are regulated, but many are not. The claimed costs of these
health regulations are typically overestimated, and often greatly overestimated.
Using the results of laboratory animal studies is good science and good public
health.
PMID- 10774770
TI - Molecular and environmental causes of cancer.
AB - The multistep, clonal evolution model of cancer predicts fundamental mechanisms
by which chemicals may influence the cancer process. These are illustrated by
studies of the mechanisms of induction of carcinogenesis by estrogens and the
inhibition of carcinogenesis by caloric restriction.
PMID- 10774771
TI - Risk assessment for possible carcinogens: a critical look.
AB - Our overall understanding of mechanisms of toxicology in relation to human
disease, with prevention of disease as a major objective, depends in part on the
development of an adequate number of ways to assess risks, both short term and
long term. Despite the cost, the long duration of the test, and some pitfalls,
the long-term animal tests remain, to date, the only reliable assay for possible
carcinogens. Recent work has concentrated increasingly on the development of
short-term tests to replace the long-term tests. Such a development would be most
welcome from several points of view. To date, a variety of approaches have been
or are being used. These include (1) activation to an alkylating agent with DNA
as the most important target, generating possible mutations in DNA and DNA damage
with or without repair, (2) induction of cell proliferation, at least a few
cycles, with DNA synthesis as the major target, again favoring mutations, and (3)
decrease in cell-to-cell communication (gap-junctional intercellular
communication) as a supposed test for promotion. None of these proposed assays
are reliable indices for possible carcinogenic effects of chemicals or other
agents; the scientific basis for this negative conclusion is discussed.
PMID- 10774772
TI - Doses in rodent cancer studies: sorting fact from fiction.
AB - The belief that rodent cancer bioassays predict for human cancers is a
fundamental public health precept based on sound biological principles.
Nonetheless, it is appropriate to periodically debate this point as scientific
understanding of cancer causation advances. This presentation addresses one of
the many factors that determines the predictive value of rodent tumor bioassay
results for human health. This is the issue of dose. Examination of several
recent National Toxicology Program (NTP) studies demonstrates that the applied
dose often far overestimates the actual effective dose, or maximum blood
concentration attained in a rodent, when compared with similar relationships in
humans. Further examination of the NTP database on rodent toxicity and
carcinogenicity studies revealed summary information on factors that were pivotal
in prechronic studies for selecting doses for chronic studies. Contrary to
popular belief, target organ toxicity was a determining factor in only about half
of the studies. The typically minimal nature of the lesions which limit doses for
chronic studies is described for several common target sites. Taken together,
these facts paint a far different picture than the common public perception of
the "massive" doses used in chronic rodent studies and suggest that, in some
cases, dose limitations are actually so severe as to limit the sensitivity of a
chronic bioassay to detect a carcinogenic effect.
PMID- 10774773
TI - Using the NTP database to assess the value of rodent carcinogenicity studies for
determining human cancer risk.
AB - The large database of carcinogenicity results generated by the National
Toxicology Program (NTP) provides a unique opportunity to critically evaluate
important scientific issues such as (1) the frequency of positive outcomes, (2)
the interspecies correlation in carcinogenic response between rats and mice, (3)
the correlation between body weight and tumor incidence, (4) estimates of the
false-positive and false-negative rates, and (5) the frequency of decreasing
tumor incidences. Such database evaluations enable us to better understand the
value and limitations of rodent carcinogenicity studies for determining human
cancer risk. However, as the NTP database becomes increasingly accessible to the
general scientific community, there is also increased opportunity for misuse of
the database. This article reexamines and updates previous database evaluations,
presents four scientific principles that should be employed by anyone attempting
to use this database, and illustrates how failure to apply these principles can
lead to misleading results.
PMID- 10774774
TI - New issues in cancer risk assessment.
AB - When a nonlinear dose-response at low doses can be justified, an acceptable daily
intake for a carcinogen can be obtained by dividing a benchmark dose, associated
with a low incidence of tumors in animals, by uncertainty factors to account for
animal-to-human extrapolation, human variability, and risk reduction from a low
observed adverse-effect level. This approach can utilize mechanistic information
to justify smaller uncertainty factors than typical default values of 10. If a
nonlinear dose-response cannot be justified, traditional linear extrapolation
from the benchmark dose to zero sometimes gives similar results. This suggests a
unified risk-assessment procedure based on uncertainty factors. The issue of
cross-species extrapolation based on the risk relative to background risks,
rather than excess risk, is examined. The relative risk approach reduces the
estimates of cancer risk in humans based on common rodent tumors, such as the
liver in some strains of mice.
PMID- 10774775
TI - Dose-response analyses of experimental cancer data.
AB - Dose-response analysis provides a powerful tool to determine causality from
experimental cancer data, estimate low-dose risk, and evaluate mechanistic
hypotheses. However, the interpretation of cancer dose-response data can be
influenced by how the dose and response terms are characterized. Using the poly-3
quantal response method to adjust for the extensive and early development of
lethal lymphomas in butadiene-exposed mice provided a means of obtaining a better
representation of dose-response relationships for late-developing tumors induced
by this chemical. Fitting a Weibull model to survival-adjusted tumor data for
chloroprene and butadiene indicated similar carcinogenic potencies for these
chemicals in mice. In conjunction with the rodent toxicity and carcinogenicity
studies conducted by the National Toxicology Program, toxicokinetic studies are
performed to characterize relationships between exposure and tissue
concentrations of parent compound and metabolites. A physiologically based
pharmacokinetic model (PBPK) of butadiene dosimetry indicated that differences in
carcinogenic response between rats and mice are not simply due to differences in
tissue concentrations of epoxybutene, a mutagenic metabolic intermediate. Thus,
factors beyond tissue dosimetry of this metabolite must be important in butadiene
induced carcinogenesis. A PBPK model for isoprene indicated that blood
concentrations of isoprene epoxides are a better indicator of kidney cancer risk
than are measurements of isoprene-exposure concentrations. An evaluation of dose
response relationships for cytotoxicity, regenerative hyperplasia, and tumor
induction by trihalomethanes indicates that for this family of chemicals, cell
proliferation is not a reliable predictor of tumor response.
PMID- 10774776
TI - Thoughts on carcinogenesis testing: the FDA today.
AB - Prevention of human cancer in the future will depend on using the results of
epidemiologic and animal studies and strategies to minimize exposure. Changes are
occurring in the area of animal testing and research that potentially represent
significant steps toward reducing our dependence on the traditional 2-year
bioassay as our primary tool for identification of chemical carcinogens and
management of risk. Efforts to prevent cancer would be enhanced by more attention
to describing modes of action so that the development of tumors would not be the
only basis for predicting carcinogenic potential. These markers might also serve
for early detection of cancer at a stage more amenable to treatment. What
carcinogens do we want to detect through animal tests in the future? Whether the
goal is to identify weak or potent carcinogens, or both, there will still be a
need for 2-year bioassays, but hopefully for confirmatory rather than screening
purposes.
PMID- 10774777
TI - A commentary on the use of hepatocytes in drug metabolism studies during drug
discovery and development.
AB - Isolated hepatocytes and liver slices, in short-term suspension or longer-term
culture, offer the prospect of providing qualitative metabolic information and
quantitative pharmacokinetic parameters from key animal species and man at early
stages of the drug discovery-development continuum. The propensity for changes in
the fidelity of drug metabolism after removal of hepatocytes from the organ has
long been recognized. The many and varied approaches which have been undertaken
in an attempt to compensate for physiological shortcomings of in vitro hepatocyte
systems are reviewed. In this respect, short-term suspension culture may provide
a baseline against which to measure the success of extended culture methods, but
it should be remembered that even freshly isolated hepatocyte preparations have
deficiencies and liabilities that may affect the nature of information gathered.
This article discusses the current advances and shortcomings of hepatocyte
suspensions and cultures, along with liver slice technology, at both quantitative
and qualitative levels.
PMID- 10774778
TI - Metabolic activation capacity of neonatal mice in relation to the neonatal mouse
tumorigenicity bioassay.
AB - The neonatal mouse tumorigenicity bioassay is a well-developed animal model that
has recently been recommended as an alternative tumorigenicity bioassay by the
International Conference on Harmonization (ICH) for Technical Requirements for
the Registration of Pharmaceuticals for Human Use. There are sufficient data to
conclude that this animal model is highly sensitive to genotoxic chemical
carcinogens that exert their tumorigenicity through mechanisms involving the
formation of covalently bound exogenous DNA adducts that lead to mutation. On the
other hand, it is not sensitive to chemical carcinogens that exert tumorigenicity
through a secondary mechanism. The metabolizing enzymes present in the neonatal
mouse, particularly the cytochromes P450, are critical factors in determining the
tumorigenic potency of a chemical tested in this bioassay. However, compared to
the metabolizing enzymes of the adult mouse and rat, the study of the
metabolizing enzymes in neonatal mouse tissues has been relatively limited.
PMID- 10774779
TI - Endothelium-dependent and -independent vasoreactivity of rat basilar artery in
chronic heart failure.
AB - Alterations of vasoreactivity are a well-known phenomenon in chronic heart
failure (CHF), and activation of the endogenous endothelin (ET) system is
suspected to contribute significantly. Regional differences in alterations of
vasoreactivity exist; however, nothing is known about cerebrovascular reactivity
in CHF. This is of interest in view of increased stroke risk in CHF. Therefore,
12 weeks after coronary artery ligation to induce CHF in rats, studies of
vasoreactivity of the isolated basilar artery (BA) were performed and compared
with third-order branches (MA-A3) and the main trunk (MA) of the superior
mesenteric artery. Some of the animals received long-term ET-receptor antagonism
by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252
or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF,
endothelium-dependent relaxation by acetylcholine and A23187 as well as
endothelium-independent relaxation by sodium nitroprusside (SNP) was largely
unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without
change of maximal effect. ET-1-induced contraction did not differ in arteries
from CHF and control rats, either in placeboor ET-receptor antagonist-treated
animals. In summary, there was essentially no change of vascular reactivity in
similar sized arteries obtained from brain and mesentery. This is in contrast to
results on arteries from a variety of vascular regions published previously, thus
supporting the concept of organ- and probably time-related changes of vascular
function in the development of CHF. The absence of significant alteration of
cerebral vasoreactivity may be taken to indicate that changes in cerebral blood
flow and increased incidence of ischemic stroke in patients with CHF are caused
not by local alterations of vascular function.
PMID- 10774780
TI - AT-1015, a novel serotonin (5-HT)2 receptor antagonist, blocks vascular and
platelet 5-HT2A receptors and prevents the laurate-induced peripheral vascular
lesion in rats.
AB - The serotonin (5-HT2A) antagonistic activities and the protective effect on
laurate-induced peripheral vascular lesions of AT-1015, a novel 5-HT2 receptor
antagonist, were investigated. In platelet aggregation, AT-1015 selectively
inhibited in vitro 5-HT2A receptor-mediated aggregation, and the activity was
almost equivalent to that of ketanserin (5-HT2A/2C receptor antagonist) and 100
times more potent than sarpogrelate (5-HT2A receptor antagonist). AT-1015 also
inhibited 5-HT2A receptor-mediated aggregation by oral administration in rat, and
the dose required for inhibition was equivalent to ketanserin. In a 5-HT-induced
vasoconstriction study in rat, AT-1015 slightly reduced maximal contraction and
caused a rightward shift of the concentration-response curve (pKB value, 9.5),
which was unlike competitive inhibitors such as ketanserin and sarpogrelate (pA2
value, 9.3 and 8.7, respectively). Moreover, the ex vivo inhibitory activity
significantly remained after oral administration (1 mg/kg). In the rat peripheral
vascular lesion model, AT-1015 (1 mg/kg, p.o.) effectively prevented progression
of peripheral lesions, and it was more potent compared with ketanserin,
sarpogrelate, and cilostazol. These results suggest that AT-1015 is a potent 5
HT2A receptor antagonist, and its insurmountable antagonism may be relevant to
its therapeutic potential in peripheral vascular disease.
PMID- 10774781
TI - Furosemide inhibits thromboxane A2-induced contraction in isolated human internal
mammary artery and saphenous vein.
AB - Evidence suggests that, in addition to its diuretic property, furosemide also may
exert direct vascular effects. Because thromboxane A2 (TXA2) has a role in the
control of vascular tone, we investigated the effect of furosemide on the
contraction induced by U46619 (a stable TXA2 mimetic) on isolated human internal
mammary artery (IMA) and saphenous vein (SV). Concentration-response curves to
U46619 were performed in the absence (vehicle) or the presence of furosemide (0.1
1 mM) on rings of IMA and SV. In addition, the relaxant effect of furosemide (0.1
microM-1 mM) also was evaluated on U46619-precontracted IMA and SV. The
participation of cyclooxygenase derivatives was studied by pretreatment with
indomethacin. Furosemide (0.1-1.0 mM) caused parallel rightward shifts of U46619
concentration-response curves without affecting the maximal responses in both IMA
and SV. Treatment with indomethacin (1 microM) modified neither the inhibitory
effect of furosemide on U46619-induced contractions, nor the relaxant effect of
furosemide on U46619-induced contractions, nor the relaxant effect of furosemide
on U46619-precontracted IMA and SV. In conclusion, furosemide at high
concentrations inhibited U46619-induced contraction in human isolated IMA and SV
and relaxed U46619-precontracted IMA and SV by mechanisms independent of the
release of relaxant prostaglandins. These results suggest that blockade of TXA2
receptors by furosemide may contribute to explaining the therapeutic effects of
furosemide in the treatment of severe heart failure.
PMID- 10774782
TI - Effect of long-term ouabain treatment on contractile responses of rat aortae.
AB - Male Sprague-Dawley rats were infused with 50 microg/kg/day of ouabain for 4
weeks to address the question whether prolonged exposure to the drug affects
blood pressure, the in vitro contractile responses to agonists and high K+ of
their aortae, and the influence of endothelium on these responses. Systolic blood
pressure was not affected by ouabain treatment. The responsiveness of endothelium
intact aortae from ouabain-treated rats to endothelin-1 increased, that to
phenylephrine decreased, and that to high K+ was unchanged, as compared with
control. The responses of endothelium-free aortae to endothelin-1, phenylephrine,
and high K+ were lower in ouabain-treated than in control rats. The removal of
endothelium increased the response to phenylephrine and decreased that to high K+
in either control or ouabain-treated rat aortae, whereas it did not affect the
response to endothelin-1 in control rat aortae and decreased it in ouabain
treated rat aortae. The response to caffeine was unaffected by either ouabain
treatment or endothelium removal. Thus rat ouabain long-term treatment induces
opposing effects on the responsiveness of their intact aortae to an alpha
adrenergic agonist and endothelin-1. If these effects observed in the ex vivo
experiments occur also in vivo on rat microvasculature, they could balance out
and contribute to the lack of effect on systolic blood pressure of prolonged
ouabain treatment.
PMID- 10774783
TI - EDHF-mediated relaxation in rat gastric small arteries: influence of ouabain/Ba2+
and relation to potassium ions.
AB - In several blood vessels, endothelium-dependent vasorelaxation is in part
mediated by an endothelium-derived hyperpolarizing factor (EDHF), the nature of
which is as yet unknown. Experiments were performed to investigate whether the
recently raised hypothesis that EDHF might be identified as the potassium ion,
released by activation of endothelial K(Ca) channels and inducing relaxation by
stimulation of Na+/K+-pump and the inward rectifier K+ conductance, might be
valid for small rat gastric arteries. EDHF-induced relaxation (assessed as the
nitro-L-arginine/indomethacin resistant component of acetylcholine-induced
relaxation), but not nitroprus-side-induced relaxation is strongly inhibited in
the presence of ouabain (0.5 mM)/Ba2+ (30 microM), ouabain being responsible for
the greater part of the inhibition. This inhibition is reversible. Application of
increasing concentrations of K+ elicits transient relaxations in some
preparations, but in a greater part of the preparations, no or only small
relaxations. In membrane potential measurements, it was found that increasing
concentrations of extracellular K+ consistently depolarized smooth muscle cells,
whereas acetylcholine elicits hyperpolarization. The K(Ca) channel openers NS
1619 and 1-EBIO elicit relaxation effects that are not diminished after removal
of the endothelium and are not inhibited by ouabain/Ba2+. It is concluded that
EDHF-mediated relaxation is sensitive to inhibition by ouabain/Ba2+, but that the
relation of this inhibitory influence to an action of K+ as EDHF is uncertain.
PMID- 10774784
TI - Use of statins and blood pressure control in treated hypertensive patients with
hypercholesterolemia.
AB - High serum cholesterol has been frequently reported in patients with arterial
hypertension in whom it might influence the blood pressure control. The aim of
this study was to compare the extent of blood pressure changes in 41 patients
with hypertension and hypercholesterolemia, taking antihypertensive drugs and
treated for 3 months with statins (HC-S; pravastatin or simvastatin) and compared
with matched controls with high (HC-D; 44) or normal serum cholesterol (NC-D; 45)
undergoing antihypertensive treatment combined with dietary treatment alone.
After 3 months of follow-up, a greater reduction of systolic (SBP) and diastolic
(DBP) blood pressure values was observed in HC-S patients (ASBP/DBP, -11.3 +/-3/
10.6 +/- 2%) when compared with both HC-D (deltaSBP/DBP, -6.6 +/- 2/-6.1 +/- 2%;
p < 0.05) and NC-D (deltaSBP/DBP, -6.9 +/- 2/-6.8 +/- 1.5%; p < 0.05). In statin
treated patients, a slight linear relation has been found between the percentage
changes in DBP and those in plasma total cholesterol (R = 0.37, p = 0.043),
whereas no relation was found with SBP changes (R =0.11; p = 0.35). In
conclusion, the results of this study demonstrate that the use of statins in
combination with antihypertensive drugs can improve blood pressure control in
patients with uncontrolled hypertension and high serum cholesterol levels. The
additional blood pressure reduction observed in patients treated with statins is
clinically relevant and only partially related to the lipid-lowering effect.
PMID- 10774785
TI - Cardiovascular adverse drug reaction associated with combined beta-adrenergic and
calcium entry-blocking agents.
AB - Numerous studies have shown a beneficial effect of combination therapy with beta
blockers and calcium antagonists in patients with anginal syndrome and/or
hypertension. However, because both agents exert a negative chronotropic effect,
their combined use may cause bradyarrhythmias with resultant symptoms of
cerebral, coronary, and systemic hypoperfusion. We describe our clinical
experience with patients who had cardiovascular adverse drug reactions (CVADRs)
with combination therapy. This prospective study included 26 patients who had
CVADRs among 2,574 admissions during a 2-year period. The study group included 14
men and 12 women with a median age of 73 years. Various combinations of calcium
antagonists and beta-blockers were associated with the CVADRs. The most frequent
pharmacologic combination was diltiazem plus propranolol. The CVADRs were the
cause for hospital admission in 10 patients, an associated cause in nine
patients, and developed during hospitalization in seven patients. Cardiac
bradyarrhythmias were found in 22 patients. These rhythm abnormalities resolved
within 24 h after discontinuation of the offending drugs. Temporary transvenous
pacemaker insertion was necessary in only one patient with complete
atrioventricular block. Twenty-two patients recovered, two patients died of pump
failure not associated with CVADRs, and in two patients, the CVADRs contributed
to the patients' death. CVADRs are not uncommon in elderly patients with ischemic
heart disease and/or hypertension treated with the concomitant use of calcium
antagonist and beta-adrenergic blocking drugs. Use of calcium antagonist plus
beta-blocker may unpredictably cause serious hemodynamic events, marked
suppression of sinus node activity, and prolongation of atrioventricular
conduction in some patients. Enhanced therapeutic monitoring may be warranted
when calcium antagonists are combined with beta-blockers.
PMID- 10774786
TI - Molsidomine improves flow-dependent vasodilation in brachial arteries of patients
with coronary artery disease.
AB - Flow-mediated vasodilation (FMD) of human blood vessels is essential to
adaptation and regulation of peripheral blood flow, and is mediated by
endogenously produced nitric oxide. Endothelial function is impaired in many
pathologic states, especially in coronary heart disease. We questioned in this
study whether exogenous nitric oxide (NO) would restore endothelial dysfunction
in peripheral arteries of patients with coronary artery disease (CAD). In a
randomized double-blinded case-control assay, we used computerized A-mode
ultrasonography to measure diastolic diameters of the brachial artery before and
after hyperemia in two groups of 10 patients with CAD. Each group received orally
either placebo or 12 mg molsidomine a day for 48 h. In the molsidomine group, FMD
was improved with a 60% increase after the first intake of molsidomine, and the
same trend was observed after the last intake, although less pronounced.
Significant increase in diastolic diameter was observed after the last
molsidomine intake, but not after the first one. Thus molsidomine has an early
positive effect on FMD in addition to a delayed vasodilator effect. Improvement
of endothelial dysfunction by molsidomine in patients with CAD may uncover new
therapeutic perceptive in the use of nitrovasodilators.
PMID- 10774787
TI - Effects of angiotensin II type 1 receptor antagonist on nitric oxide synthase
expression and myocardial remodeling in Goldblatt hypertensive rats.
AB - We evaluated the effects of long-term treatment with TCV-116, an angiotensin II
type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS)
messenger RNA (mRNA) and protein expression in the left ventricle and its
relation to myocardial remodeling in Goldblatt hypertensive rats. Two-kidney, one
clip Goldblatt hypertensive rats (RHR) were assigned either to a TCV-116
treatment group (RHR-TCV, n = 8, 3 mg/kg/day, subdepressor dose) or to a group
without treatment (RHR-V, n = 7) after their kidneys had been clipped for 4
weeks. TCV-116 was administered to rats in the treatment group for 6 weeks, and
age-matched sham-operated rats (ShC, n = 7) served as a control group. Blood
pressure in RHR-V and RHR-TCV was similar and significantly higher than that in
ShC. The eNOS mRNA and protein levels and NOS activity in the left ventricle was
significantly decreased in RHR-V compared with ShC, and significantly increased
in RHR-TCV compared with ShC and RHR-V. RHR-V demonstrated a significant increase
in fibrosis factor (type I collagen) mRNA expression, perivascular fibrosis, and
myocardial fibrosis. These parameters in the microvasculature were improved
significantly by TCV-116. Subdepressor dose of TCV- 116 improved pathological
myocardial changes in RHR, which may be due in part to an increased eNOS mRNA and
protein expression and NOS activity in the left ventricle.
PMID- 10774788
TI - Cocaine induces apoptosis in human coronary artery endothelial cells.
AB - This study was designed to determine the direct cytotoxic effect of cocaine on
human coronary artery endothelial cells (HCAECs). Cocaine treatment of cultured
HCAECs induced a time- and dose-dependent increase in apoptotic cell death in
HCAECs. Cocaine-induced surface exposure of phosphatidylserine in HCAECs was seen
as early as at 6 h. With prolonged treatment < or =72 h, cocaine (10-500 microM)
produced a dose-dependent increase in apoptosis in the cells. Corresponding DNA
fragmentation induced by cocaine was demonstrated in situ by terminal
deoxynucleotidyl transferase (Tdt) UTP nick end-labeling TUNEL assay and by
electrophoresis of labeled DNA fragments, showing the characteristic apoptotic
ladders. Both caspase-9 (Z-LEHD-FMK) and caspase-3 (Ac-DEVD-CHO) inhibitors
blocked cocaine-induced apoptosis. In addition, cyclosporin A inhibited cocaine
induced apoptosis in a concentration-dependent manner with a median inhibitory
concentration (IC50) of 0.3 microM. The maximum of 62% inhibition was obtained
with 3 microM cyclosporin A. Cocaine-induced apoptosis also was blocked by
naloxone and nifedipine in a dose-dependent manner. These findings suggest that
cocaine induces apoptosis in cultured HCAECs, which may be mediated by opioid
receptors. The release of cytochrome c from the mitochondria and its subsequent
activation of caspase-9 and caspase-3 may play a key role in cocaine-induced
apoptosis.
PMID- 10774789
TI - Direct vasodilating effects of the new dopaminergic agonist Z1046 in human
arteries.
AB - Dopaminergic agonists remain of interest in the treatment of heart failure;
however, concomitant stimulation of alpha- and beta-receptors should be avoided.
This study evaluates the dopaminergic and adrenergic (vasodilating) properties of
Z1046, epinine (the active metabolite of ibopamine), and dopamine. Isotonic
contraction experiments were performed on human internal mammary artery rings in
vitro. alpha1-Antagonistic effects of Z1046 were demonstrated by performing
cumulative dose-response curves with the selective alpha1-agonist phenylephrine
in the presence of Z1046. Furthermore, both alpha1- and dopamine-mediated
receptor effects of Z1046, epinine, and dopamine were studied by performing
cumulative dose-response relations both at baseline and in precontracted artery
rings both with and without the D1-like antagonist SCH23390. In contrast to both
epinine and dopamine, Z1046 is devoid of alpha1-receptor-mediated contraction.
Furthermore, Z1046, epinine, and dopamine induced direct dopamine receptor
mediated vasodilation when interfering alpha1 effects were blocked. In contrast
to epinine and dopamine, Z1046 is devoid of vasoconstricting properties at higher
dosages. Because of its D1-like agonistic and alpha1-antagonistic properties,
Z1046 is an effective vasodilator in the whole dosage range. Because of its total
receptor profile, Z1046 appears to be more favorable for treatment of heart
failure than is ibopamine.
PMID- 10774790
TI - Antithrombotic activity of NSP-513, a novel selective phosphodiesterase 3
inhibitor, on femoral arterial thrombosis induced by physical stenosis and
electrical current: comparison of antithrombotic and hemodynamic effects.
AB - NSP-513, a novel potent and selective phosphodiesterase 3 (PDE 3) inhibitor, and
cilostazol, a previously developed PDE 3 inhibitor, were compared with respect to
antiplatelet, antithrombotic, and hemodynamic effects. In the in vitro
antiplatelet aggregation studies, NSP-513 and cilostazol inhibited collagen
induced canine platelet aggregation with median inhibitory concentration (IC50)
values of 0.093 and 3.1 miccroM, respectively, and inhibited adenosine
diphosphate (ADP)-induced canine platelet aggregation with IC50 values of 0.15
and 12 microM, respectively. For ADP-induced platelet aggregation, the presence
of prostaglandin E1 (PGE1; 3 and 10 nM) further decreased the IC50 values for NSP
513 to 0.11 and 0.032 microM, respectively. In ex vivo antiplatelet aggregation
studies, orally administered NSP-513 (0.03-1 mg/kg) and cilostazol (50 mg/kg)
inhibited collagen-induced canine platelet aggregation. In an in vivo canine
femoral arterial thrombosis model, intraduodenally administered NSP-513 (0.01
0.03 mg/ kg) dose-dependently prevented thrombus formation without any changes in
blood pressure, heart rate, or bleeding time. In conscious dogs, NSP-513 at oral
doses of > or =0.3 mg/kg produced hemodynamic changes such as decreased blood
pressure and increased heart rate and LVdP/dt(max). Thus the minimal
hemodynamically effective dose of NSP-513 was 0.3 mg/kg, and the hemodynamic
effects of this dose were comparable to those of 50 mg/kg of cilostazol. In
conclusion, these data suggest that NSP-513 has in vivo selectivity for
antiplatelet and antithrombotic activities over hemodynamic activity, and that
the selectivity of NSP-513 is higher than that of cilostazol in dogs.
PMID- 10774791
TI - EGF-genistein inhibits neointimal hyperplasia after vascular injury in an
experimental restenosis model.
AB - A murine model of vascular injury-induced neointimal hyperplasia was developed by
using a photoactive dye, rose bengal. Photoactivation of rose bengal induced
vascular injury to the femoral arteries of C57B1/6 mice and resulted in an
occlusive neointimal hyperplasia after 4 weeks. The cellular elements of the
hyperplastic neointima were found to be alpha-actin-positive vascular smooth
muscle cells expressing epidermal growth factor (EGF) receptor at high levels.
EGF-Gen, an EGF-R-specific inhibitor with potent anticancer activity, suppressed
the formation of hyperplastic neointima. Morphometric analysis of serial tissue
sections at 4 weeks after vascular injury showed that in 75% of the EGF-Gen
treated mice, the maximal stenosis index was only 0.44 +/- 0.13, whereas in 75%
of phosphate-buffered saline (PBS)-treated mice, the maximal stenosis index was
1.20 +/- 0.25. The mean neointima/media ratios for areas of maximum neointimal
hyperplasia were 0.59 +/- 0.16 (n = 24) for the EGF-Gen-treated group, 0.99 +/-
16 (n = 45) for the PBS group (EGF-Gen vs. PBS, p = 0.0017), and 1.03 +/- 18 (n =
8) for group treated with unconjugated genistein (EGF-Gen vs. Gen, p = 0.0088).
EGF-Gen treatment of mice with vascular injury to the left femoral artery was not
associated with any clinical signs of toxicity or histopathologic lesions in any
of the organs, including the uninjured right femoral artery. EGF-Gen also
inhibited VSMC migration in vitro, without affecting VSMC proliferation and
viability, suggesting that EGF-Gen is blocking neointima formation by inhibiting
cellular migration to vascular injury sites. In conclusion, EGF-Gen may be useful
as a nontoxic prophylactic agent for prevention of restenosis in clinical
settings.
PMID- 10774792
TI - Effects of aldose reductase inhibition on responses of the corpus cavernosum and
mesenteric vascular bed of diabetic rats.
AB - We examined the effects of 2 months of streptozotocin-induced diabetes mellitus
in rats on relaxation and contraction of corpus cavernosum and the mesenteric
vascular bed in vitro. A further diabetic group was treated from diabetes
induction with 10 mg/kg/day of the aldose reductase inhibitor, WAY121509. For
corpus cavernosum, maximal acetylcholine-induced relaxation was 35.5% reduced (p
< 0.001) by diabetes, and this deficit was completely prevented by WAY121509
treatment. Neither diabetes nor treatment affected contractile responses to field
stimulation of noradrenergic nerves; however, nonadrenergic noncholinergic nerve
relaxation responses were 32.9% decreased by diabetes and WAY 121509 attenuated
this by 84% (p < 0.001). For the mesenteric vascular bed, diabetes depressed
maximal endothelium-dependent vasodilation to acetylcholine by 25.2% (p < 0.001),
and this was partially (50.6%; p < 0.01) prevented by WAY121509. Nitric oxide
synthase blockade revealed endothelium-derived hyperpolarising factor-mediated
vasodilation to acetylcholine that was 73.5% (p < 0.001) depressed by diabetes;
WAY121509 provided partial (43.4%; p < 0.001) protection. Neither diabetes nor
treatment affected endothelium-independent vasorelaxation to the nitric oxide
donor, sodium nitroprusside, in corpus cavernosum or mesenteric vessels. Thus the
data show protective effects of WAY121509 on nitric oxide-mediated cavernosal
vasorelaxation responses and on mesenteric endothelium-derived hyperpolarising
factor responses. Together these findings could account for the beneficial
effects of aldose reductase inhibition on diabetic complications in experimental
models.
PMID- 10774793
TI - Mechanism of relaxations to dendroaspis natriuretic peptide in canine coronary
arteries.
AB - Experiments were designed to determine mechanisms by which Dendroaspis
natriuretic peptide (DNP) causes relaxations in coronary arteries. Rings of
canine left circumflex artery with and without endothelium were suspended in
organ chambers filled with Krebs-Ringer bicarbonate solution (37 degrees C,
bubbled with 95% O2/5% CO2). Concentration-response curves to DNP (10(-10) to 3 x
10(-7) M) were obtained in arteries contracted with prostaglandin (PGF(2alpha), 2
x 10(-6) M), either in the absence or the presence of C-ANP (10(-6) M) to inhibit
natriuretic clearance receptors; indomethacin to inhibit cyclooxygenase (INDO,
10(-5) M), N(G)-monomethyl-L-arginine to inhibit production of nitric oxide (L
NMMA; 10(-4) M), HS-142-1 to inhibit particulate guanylate cyclase (10(-5) M); 1H
[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one to inhibit soluble guanylate
cyclase (ODQ; 10(-5) M), or tetraethylammonium to inhibit potassium channels
(TEA; 10(-3) or 10(-2) M). Relaxations to DNP were greater in rings with than in
those without endothelium. C-ANP significantly attenuated relaxations to DNP only
in rings with endothelium. HS-146-1 but not INDO, L-NMMA, ODQ, and TEA
significantly reduced relaxations to DNP in rings with and without endothelium
contracted with PGF(2alpha). These results suggest that the endothelium augments
inhibitory effects of DNP and that natriuretic clearance receptors mediate this
component of the response to DNP in canine coronary arteries. In addition,
relaxations to DNP in canine arterial smooth muscle involve activation of
particulate guanylate cyclase but not hyperpolarization.
PMID- 10774794
TI - Effects of cerivastatin on human arterial smooth muscle cell proliferation and
migration in transfilter cocultures.
AB - Statins competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase activity reducing mevalonate synthesis. In this study,
antiproliferative and antimigratory effects of the new compound cerivastatin were
analyzed and compared with classic statins of the first and second generation
using mono- and cocultures of human arterial smooth muscle (haSMC) and
endothelial (haEC) cells. Effects on the mitotic index and mitochondrial activity
of haEC and haSMC monocultures were tested using BrdU enzyme-linked immunosorbent
assay (ELISA) and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide
(MTT) tests, respectively. In lactate dehydrogenase (LDH) assays, cytotoxicity of
statins was studied. Transfilter cocultures were performed for 14 days to
evaluate haSMC growth under the stimulatory effect of proliferating haEC, which
release growth factors [e.g., platelet-derived growth factor (PDGF)]. The
hydrophobic statins simvastatin, lovastatin, and atorvastatin significantly
inhibited haSMC and haEC growth in monocultures at 0.5-50 microM. However, most
potent effects were exerted by cerivastatin in 10- to 30-fold lower doses without
any significant cytotoxicity. More important, cerivastatin showed also
significant effects on haSMC proliferation and migration in transfilter
cocultures at extremely low doses (IC50, 0.04-0.06 microM), even when applied
exclusively to the endothelial side and in the presence of low-density
lipoprotein (LDL). Addition of mevalonate abolished the effects of cerivastatin
completely. Even in the presence of growth-stimulating haEC and LDL, cerivastatin
was found to be the most potent inhibitor of haSMC proliferation and migration in
doses that also can be reached in human serum after oral drug administration. The
results support the concept that statins seems to influence additional cellular
mechanisms beyond cholesterol reduction, which might also have a relevance for
the prevention of restenosis.
PMID- 10774795
TI - Specific augmentation of plantar skin blood flow by lipo-PGE1 assessed in
tetrodotoxin- and N(G)-nitro-L-arginine-treated rats.
AB - 1Vasodilating effects of prostaglandin E1 incorporated in lipid microspheres
(lipo-PGE1) were compared with those of prostaglandin E1 (PGE1) or its
cyclodextrin clathrated preparation (PGE1-CD) on plantar skin blood flow in rats
treated with tetrodotoxin and N(G)-nitro-L-arginine (L-NNA). Tetrodotoxin (50
microg/kg, i.v.) could totally inhibit the pressor response to electrical
stimulation of the spinal cord, and the reflex tachycardia due to the depressor
response to acetylcholine. Furthermore, L-NNA (30 mg/kg, i.v.) was used to
counteract the lowering of the systemic blood pressure and peripheral vascular
tone by elimination of sympathetic nerve activity, and to maintain the arterial
blood pressure at the control level. Lipo-PGE1 increased plantar skin blood flow
4 to 6 times more potently than PGE1-CD or PGE1 in the treated rats. Furthermore,
lipo-PGE1 increased plantar skin blood flow about 3 times more selectively than
PGE1-CD. We also assessed several vasodilators, including terbutaline,
nitroprusside, nicardipine, and papaverine in tetrodotoxin- and L-NNA-treated
rats. However, none of them could selectively increase plantar blood flow despite
the prominent depressor responses achieved. These results suggest that PGE1
preparations, especially lipo-PGE1 could potently and selectively increase
plantar skin blood flow in rats treated with tetrodotoxin and L-NNA.
PMID- 10774796
TI - Ischemia-induced action potential shortening is blunted by d-sotalol in a pig
model of reversible myocardial ischemia.
AB - The purpose of this study was to investigate, in an anesthetized pig model of low
flow myocardial ischemia, the electrophysiologic effects of the class III drug d
sotalol during myocardial ischemia. Serial monophasic action potential (MAPD90)
recordings and refractory period determinations from the anterior and posterior
left ventricular wall were taken in 25 pigs during baseline, after low-flow
posterior wall ischemia, after d-sotalol infusion under nonischemic conditions,
and after repeated posterior wall ischemia while continuing the drug.
Measurements were done at 60 and 150 beats/min after radiofrequency ablation of
atrioventricular conduction. At baseline, MAPD90 and refractory periods were
comparable in the anterior and posterior wall (323 +/- 15 vs. 318 +/- 10 ms, and
267 +/- 10 vs. 262 +/- 11 ms at 60 beats/min, respectively). In the absence of d
sotalol, low-flow regional ischemia was associated with a significant shortening
of MAPD90 in the posterior versus the anterior wall (267 +/- 20 vs. 317 +/- 20 ms
at 60 beats/min; p = 0.006). Similarly, ischemia-induced shortening of the
refractory periods in the posterior wall was apparent (230 +/- 16 ms in the
posterior wall vs. 274 +/- 14 ms in the anterior wall at 60 beats/min). In
contrast, ischemia was no longer associated with shortening of MAPD90 (360 +/- 17
ms posterior wall and 360 +/- 20 ms anterior wall at 60 beats/min) and refractory
periods (304 +/- 19 ms posterior wall vs. 316 +/- 15 ms anterior wall at 60
beats/min) during combined posterior wall ischemia and d-sotalol infusion.
Similar findings were obtained during pacing at 150 beats/min. d-Sotalol
attenuates ischemia-induced action potential shortening. This property should
decrease dispersion of cardiac repolarization and be antiarrhythmic. On the other
hand, longer APD under ischemic conditions may favor calcium overload, which may
trigger new arrhythmias.
PMID- 10774797
TI - Pharmacologic characterization of receptor types mediating coronary vasodilator
actions of sensory neuropeptides in the guinea pig.
AB - The receptor types mediating sensory neuropeptide-induced coronary vasodilatation
were elucidated on isolated guinea pig hearts perfused with isotonic buffer
containing 20 mM KCl. Substance P and the selective neurokinin-1 (NK1) receptor
agonist [Sar9, Met(O2)11]-substance P produced dose-dependent reductions in
perfusion pressure, but the selective NK2 receptor agonist [Nle10]-neurokinin A4
10 and the selective NK3 receptor agonist [MePhe7]-neurokinin B produced no
change. The vasorelaxant effects of substance P and the NK1 receptor agonist were
abolished by the selective NK1 receptor antagonist FK888 (N2-[(4R)-4-hydroxy-1-(1
methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-3-(2-naphthyl)-L
alaninamide), whereas the selective NK2 receptor antagonist SR48968 ((S)-N-methyl
N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl )-butyl] benzamide)
and the selective NK3 receptor antagonist SR142801 ((S)-(N)-( 1-(3-(1-benzoyl-3
(3,4-dichlorophenyl)piperidin-3-yl)propyl)4-p henylpiperidin-4-yl)-N
methylacetamide) produced partial inhibition on their responses. Calcitonin gene
related peptide (CGRP) produced dose-dependent vasodilatation on the guinea pig
coronary blood vessels, which was significantly (p = 0.0067) inhibited by the
selective CGRP1 receptor antagonist hCGRP8-37. The selective CGRP2 receptor
agonist [Cys(acetomethoxy)2,7]CGRP had no effect on perfusion pressure. These
results demonstrate that the sensory neuropeptides substance P and CGRP are
effective vasodilators of the guinea pig coronary vascular bed. The receptor
types mediating their vasorelaxant effects were identified to be the NK1
receptors and CGRP1 receptors, respectively.
PMID- 10774798
TI - Properties of the ventricular adrenergic signal transduction system during
ontogeny of spontaneous hypertension in rats.
AB - The purpose of this study was to characterize adrenergic receptors and associated
G proteins in ventricles of spontaneously hypertensive rats (SHRs) at different
stages of development. The beta- and alpha1-adrenoceptor densities and subtype
distribution, and beta-adrenoceptor-G protein coupling were studied by
radioligand binding, and levels of G(Salpha), G(ialpha), and G(q/11alpha) protein
species were determined by Western blotting in SHRs and Wistar-Kyoto (WKY)
control rats aged 3.5 weeks, 3 months, and 8 months. In 3.5-week-old SHRs, both
the beta-adrenoceptor density and the percentage of agonist high-affinity binding
sites were higher than in age-matched WKY rats. The beta1/beta2-subtype
distribution, the alpha1-adrenoceptor density, and the alpha1B/alpha1A-subtype
distribution were similar in rats of both strains at all ages. Although
essentially no differences in G(salpha) levels between SHRs and WKY rats were
detected, higher G(ialpha) and lower Gq/1alpha concentrations were found in 3.5
week-old SHRs. In 3-month-old SHRs, increased levels of Gq/11alpha proteins were
observed. In 8-month-old SHRs, none of the parameters was different from those of
controls. We conclude that the differences in properties of the adrenergic signal
transduction system between SHRs and WKY rats are exclusively observable before
and at the onset of the overt hypertension. Moreover, the hypertensive genotype
apparently affects G proteins more readily than adrenoceptors.
PMID- 10774799
TI - Electrophysiologic effects of a calcium sensitizer inotrope levosimendan
administered intravenously in patients with normal cardiac function.
AB - Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents
as heart failure therapy. Calcium sensitization of the myofilaments might
increase inotropy without influencing cardiac electrophysiology unless modified
by ancillary properties of the drugs. Electrophysiologic effects of a calcium
sensitizer inotrope levosimendan were examined in short-term intravenous
administration in humans. Variables were determined in 10 patients with normal
cardiac function during a preceding control phase and levosimendan infusion
yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan
increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus
node recovery time and AH interval. At the tested cycle lengths, levosimendan
shortened the effective refractory periods in the atrioventricular node by 40-63
ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9
ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action
potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90%
levels of repolarization on average. The QT interval during spontaneous rhythm
and atrial pacing remained unchanged although increased slightly when corrected
to sinus rate (p < 0.001). The observations indicate that levosimendan in short
term administration facilitates impulse formation and conduction in cardiac slow
response tissue, enhances recovery of excitability in the myocardium, and may
delay ventricular repolarization. The effects on the ventricle were not
substantial, and therefore the likelihood of provoking serious cardiac
arrhythmias is not estimated to be high.
PMID- 10774800
TI - Action of polygodial on agonist-induced contractions of the rat portal vein in
vitro.
AB - This study investigated the vasorelaxant action of the sesquiterpene polygodial,
isolated from the bark of Drymis winteri, on rat portal vein in vitro, contracted
by various agonists. Polygodial (21-342 microM) preincubated 20 min before,
produced graded antagonism of the contractile responses caused by bradykinin,
endothelin-1, noradrenaline, the stable analogue of thromboxane A2 U46619,
substance P, neurokinin B, and senktide (an NK3-selective agonist). Polygodial,
at the same concentration, also produced graded inhibition of the contractile
response induced by potassium chloride and by phorbol ester. At the median
inhibitory concentration (IC50) level, polygodial was approximately 114- to 177
fold more active in inhibiting mediated contractions to senktide and phorbol
ester. When assessed in the tonic contraction induced by endothelin-1 (0.5 nM) or
by phorbol (3 microM), polygodial (0.1-100 microM) produced concentration
dependent relaxation, with maximal inhibition (E(max)) of 62 +/- 2% and 100%,
respectively. Finally, polygodial (0.1-100 microM) inhibited the rhythmic
spontaneous contractions of the rat portal vein (E(max) of 75 +/- 2%). Taken
together, these results suggest that the vasorelaxant actions caused by
polygodial in rat portal vein are, at least in part, associated with inhibition
of calcium influx through voltage-sensitive channels and interaction with protein
kinase C-dependent mechanisms. In addition, these data confirm and extend our
previous suggestion that polygodial preferentially antagonizes tachykinin
mediated contraction, especially the NK3-mediated responses.
PMID- 10774801
TI - The path to the discoveries of human retroviruses.
AB - Paul Ehrlich, gifted with knowledge, vision, and the capacity to bring his
discoveries to practice, shaped the destiny of many biomedical scientific
disciplines, including immunology, chemotherapy, hematology, cytology, and cancer
research. His perceptive concept of receptors and ligands binding together in
highly specific reactions was introduced just over a century ago in 1898 and is
both fundamental and central to present day biomedical research. His mother
country, Germany, commemorates his seminal contributions to science and to human
welfare with an annual prize for achievements in fields that are related to his
work. The 1999 Paul Ehrlich and Ludwig Darmsteaedter Prize was awarded to Robert
C. Gallo, M.D. for his achievements in the pursuit of cancer related viruses and
the growth in culture of human T-cells which led to the discovery of the first
human retroviruses and, as a direct consequence, the discovery of the Human
Immunodeficiency Virus, the third known human retrovirus. Below, excerpted from
his acceptance lecture, is a concise personal history of those discoveries.
PMID- 10774802
TI - Inhibition of HIV-1 replication and infectivity by expression of a fusion
protein, VPR-anti-integrase single-chain variable fragment (SFv): intravirion
molecular therapies.
AB - OBJECTIVES: To deliver antiretroviral agents or other foreign proteins into
progeny virions and evaluate their inhibitory effect on human immunodeficiency
virus type 1 (HIV-1) replication. STUDY DESIGN/METHODS: HIV-1 encodes proteins in
addition to gag, pol, and env, some of which are packaged into virus particles.
One essential retroviral enzyme is integrase (IN), which has been used as a
target for developing agents that inhibit virus replication. In previous studies,
we demonstrated that intracellular expression of single-chain variable antibody
fragments (SFvs), which bind to IN, results in resistance to productive HIV-1
infection in T-lymphocytic cells. Because the highly conserved accessory HIV-1
Vpr protein can be packaged within virions in quantities similar to those of the
major structural proteins, this primate lentiviral protein may be used as a
fusion partner to deliver antiviral agents or other foreign proteins into progeny
virions. In these studies, the fusion proteins Vpr-chloramphenicol acetyl
transferase (CAT) and Vpr-SFv-IN have been developed. Stable transfectants
expressing these fusion proteins were generated from PA317 cells and SupT1 T
lymphocytic cells and analyzed using immunofluorescence microscopy. After
challenge of SupT1 cells with HIV-1, p24 antigen expression was evaluated. The
incorporation of these fusion proteins were evaluated by immunoprecipitation of
virions using a Vpr antibody. RESULTS: Expression of the fusion proteins was
confirmed by immunofluorescent staining in PA317 cells transfected with the
plasmids expressing Vpr-CAT and Vpr-SFv-IN proteins. Stable transfectants
expressing these fusion proteins were generated from SupT1 T-lymphocytic cells.
When challenged, HIV-1 replication, as measured by HIV-1 p24 antigen expression,
was inhibited in cells expressing Vpr-SFv-IN. It was demonstrated that Vpr
chloramphenicol acetyl transferase (Vpr-CAT and Vpr-SFv-IN proteins can be
efficiently packaged into the virions and that Vpr-SFv-IN also decreases the
infectivity of virions into which it is encapsidated. CONCLUSIONS: An anti
integrase single-chain variable fragment moiety can be delivered into HIV-1
virions by fusing it to Vpr. Vpr-SFv-IN decreases HIV-1 production in human T
lymphocytic cells. The benefits of "intravirion" gene therapy include
immunization of target cells as well as decreasing infectivity of HIV-1 virions
harboring the fusion construct. Thus, this approach to anti-HIV-1 molecular
therapies has the potential to increase inhibitory effects against HIV-1
replication and virion spread.
PMID- 10774803
TI - Interactions between human immunodeficiency virus type 1 reverse transcriptase,
tRNA primer, and nucleocapsid protein during reverse transcription.
AB - An early step in the life cycle of human immunodeficiency virus type 1 is the
reverse transcription of the viral RNA genome into double-stranded DNA, which is
subsequently translocated to the cell nucleus. It is then integrated into host
DNA and serves as a template for viral gene expression. Reverse transcription is
catalyzed by the viral enzyme reverse transcriptase and is a complex process
comprising a series of RNA-dependent DNA polymerization, DNA-dependent DNA
polymerization, and RNase H reactions. Strand transfer reactions are required to
complete the process. Reverse transcription is initiated when a molecule of host
cell tRNA(lys3), which serves as a primer, is bound to the primer binding site of
viral genomic RNA. The viral nucleocapsid protein is involved in each of the
initiation of reverse transcription and in subsequent strand transfer or template
switching events. We review the interactions among reverse transcriptase, viral
genomic RNA, the tRNA primer of reverse transcription, and viral nucleocapsid
protein in the various steps of reverse transcription, including primer
placement, initiation, and processive synthesis.
PMID- 10774804
TI - Improved conditions for extraction and amplification of human immunodeficiency
virus type 1 RNA from plasma samples with low viral load.
AB - OBJECTIVES: We attempted to define optimal conditions for amplification of low
copy number HIV-1 RNA sequences in plasma samples, applying improved conditions
for nucleic acid extraction and amplification. METHODS: Several methodologic
parameters were evaluated, including methods of RNA extraction, volumes of plasma
samples, proportion of extracted RNA used as a template for amplification, and
reverse transcriptase-DNA polymerase enzyme combination employed in cDNA
synthesis and polymerase chain reaction amplification. RESULTS: With this
improved assay, we were able to obtain sufficient amounts of amplified material
for direct sequencing in 97% of all plasma samples in our study, including 88% of
samples with viral loads <80 copies/mL, 78% of samples with viral loads <50
copies/mL, and even 2 (67%) of 3 samples with <20 copies/mL. CONCLUSIONS: This
procedure could be useful for testing resistance mutations in patients undergoing
highly active antiretroviral therapy, in which the viral load is commonly <400
copies/mL, and even if it is <20 RNA copies/mL.
PMID- 10774805
TI - Increased promoter diversity reveals a complex phylogeny of human
immunodeficiency virus type 1 subtype C in India.
AB - OBJECTIVE: To evaluate human immunodeficiency virus type 1 (HIV-1) long terminal
repeat (LTR) sequence diversity among distinct populations within India and to
determine the prevalent subtype. STUDY DESIGN/METHODS: Analysis of the 3'LTR was
conducted from 28 HIV-1-positive samples: 1992-1993 (Pune, New Delhi) and 1995
1996 (Pune, Mumbai and Vellore). Genomic DNA was extracted from cocultivated
peripheral blood mononuclear cells (PBMCs) and used for polymerase chain reaction
(PCR) amplification and sequencing using dye terminator chemistry. Sequences were
edited, aligned, and analyzed phylogenetically utilizing gap-stripped and
bootstrapping parameters. Mobility shift assays were used to confirm binding
activity. RESULTS: All nucleotide sequences were HWV-1 subtype C based on
phylogenetic analysis. The isolates from Pune/Delhi formed subclusters when
analyzed separately, irrespective of time or sample source. However, no
significant subclustering was observed with isolates from Mumbai or Vellore or
with the entire sample set when analyzed collectively. Subtype-specific enhancer
analysis revealed an expected third NF-kappaB site but also revealed six isolates
with insertions and deletions not previously described, one of which resembles an
AP-1 binding site. CONCLUSIONS: The results confirm the prevalence of HIV-1C and
suggest increasingly complex phylogeny of HIV-1C within India, such that the
previously observed subclustering may no longer adequately reflect the diversity
of isolates currently circulating throughout India.
PMID- 10774806
TI - CXCR4 and CCR5 expression on CD4+ T cells in vivo and HIV-1 antigen beta
chemokine production in vitro after treatment with HIV-1 immunogen (REMUNE).
AB - BACKGROUND: The chemokine receptors CXCR4 and CCR5 have been identified as the
major coreceptors for HIV-1 on CD4+ cells and macrophages. The natural ligands
for these receptors are SDF-1 and the beta-chemokines (MIP-1alpha, MIP-1beta,
RANTES), respectively, and are the products of a variety of immune cells,
including CD8+ T lymphocytes. STUDY DESIGN/METHODS: We hypothesized that the
ability to stimulate the natural ligands for these receptors using an immune
based therapy might influence in vivo chemokine receptor expression. RESULTS: In
vivo CXCR4 expression remained stable after treatment with an HIV-1 Immunogen
(REMUNE), whereas CCR5 expression on CD4+ T cells decreased (p < .05).
Furthermore, HIV-1 antigen-specific production of beta-chemokines in vitro was
also augmented (P < .05). CONCLUSIONS: These preliminary results suggest that
this HIV-1-specific immune-based therapy can stimulate antigen-specific beta
chemokine production in vitro and downregulate CCR5 receptor expression on CD4
cells in vivo.
PMID- 10774808
TI - The origins of the American Board of Toxicology.
PMID- 10774809
TI - The principles and practice of toxigenomics: applications and opportunities.
PMID- 10774807
TI - Genotypic and phenotypic diversity of rabies virus variants involved in human
rabies: implications for postexposure prophylaxis.
AB - OBJECTIVES: Rabies virus variants associated with silver-haired bats (SHBRV) are
responsible for most recent human rabies cases in the United States, which are
not associated with a history of exposure. We compared their genotype and
phenotype with those of dog rabies virus (DRV) variants, the classic cause of
rabies in humans, to determine whether differences in these strains might have
ramifications for therapeutic intervention, particularly vaccination. METHODS:
Eleven silver-haired bat and 8 dog rabies virus isolates were characterized by
sequencing the glycoprotein gene, by assessing their ability to replicate in
neuronal versus nonneuronal cultures at optimal and suboptimal temperatures, by
assessing their pathogenicity in mice, and by determining the resistance of these
viruses to therapeutic immunization with commercial vaccines. RESULTS: SHBRV
isolates were less genetically diverse, less neuronal cell specific, more
temperature sensitive, but as pathogenic, on average, as DRV isolates. Immune
protection was equivalent for SHBRV and DRV strains of similar pathogenicity.
CONCLUSIONS: SHBRV strains have unique characteristics that may explain their
exceptional association with human rabies but have little bearing on their
lethality in mice. The pathogenicity of a particular virus, rather than its
antigenic makeup, determines the outcome of immunization.
PMID- 10774810
TI - Dermatoxicokinetic modeling of p-nitrophenol and its conjugation metabolite in
swine following topical and intravenous administration.
AB - The development of a dermatotoxicokinetic (dTK) model for p-nitrophenol (PNP), a
common metabolite from a variety of compounds and a biomarker of organophosphate
(OP) insecticide exposure, may facilitate the kinetic modeling and risk
assessment strategy for its parent compounds. In order to quantify and then
clarify in vivo-in vitro correlation of PNP disposition, multicompartment kinetic
models were formulated. Female weanling pigs were dosed with [14C]PNP
intravenously (150 microg in ethanol, n = 4) or topically onto non-occluded
abdominal skin (300 microg/7.5cm2 in ethanol, n = 4). PNP and p-nitrophenyl-beta
D-glucuronide (PNP-G) profiles were determined in plasma and urine in addition to
total 14C quantitation in many other samples. Disposition parameters (rate
constants, Ftop, T12, T1/2Ka, AUC, Vss, Clp, MAT, and MRT) and the simulated
chemical mass-time profiles on the dosed skin surface and in the local, systemic,
and excretory compartments were also determined. Total recoveries of 97.17 +/-
4.18% and 99.80 +/- 2.41% were obtained from topical and intravenous experiments,
respectively. Ninety-six hours after topical and intravenous application, 70.92
+/- 9.72% and 98.65 +/- 2.43% of the dose were excreted via urine, and 0.55 +/-
0.16% and 0.51 +/- 0.10% via the fecal route, respectively. Peak excretion rate
and time were also determined. It was suggested by experimental observation and
modeling that urinary 14C excretion correlates with the systemic tissue depletion
profile well and may be used as a biomarker of PNP exposure. This study also
supports the strategy of using urinary PNP as a biomonitoring tool for OP
pesticide exposure, although some precautions have to be taken. The strategy used
in this study will be useful in comprehensive dTK modeling in dermal risk
assessment and transdermal drug delivery.
PMID- 10774812
TI - In vivo kinetics of trichloroacetate in male Fischer 344 rats.
AB - Trichloroacetate (TCA) is a toxicologically important metabolite of the
industrial solvents trichloroethylene and tetrachloroethylene, and a by-product
of the chlorination of drinking water. Tissue disposition and elimination of 14C
TCA were investigated in male Fischer 344 rats injected iv with 6.1, 61, or 306
micromol TCA/kg body weight. Blood and tissues were collected at various time
points up to 24 h. No metabolites were observed in plasma, urine, or tissue
extracts. Overall TCA kinetics in tissues were similar at all doses. Based on
similar terminal elimination rate constants, tissues could be divided into three
classes: plasma, RBC, muscle, and fat; kidney and skin; and liver, small
intestine, and large intestine. Nonextractable radiolabel, assumed to be
biologically incorporated metabolites in both liver and plasma, increased with
time, peaking at 6-9 h postinjection. The fraction of the initial dose excreted
in the urine at 24 h increased from 67% to 84% as the dose increased, whereas
fecal excretion decreased from 7% to 4%. The cumulative elimination of TCA as CO2
at 24 h decreased from 12% to 8% of the total dose. Two important kinetic
processes were identified: a) hepatic intracellular concentrations of TCA were
significantly greater than free plasma concentrations, indicating concentrative
transport at the hepatic sinusoidal plasma membrane, and b) TCA appears to be
reabsorbed from urine postfiltration at the glomerulus, either in the renal
tubules or in the bladder. These processes have an impact on the effective tissue
dosimetry in liver and kidney and may play an important role in TCA toxicity.
PMID- 10774811
TI - Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl
manganese tricarbonyl (MMT) in Sprague-Dawley rats.
AB - The toxicokinetics of manganese (Mn) was investigated in male and female rats
either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg),
or following a single oral dose of methylcyclopentadienyl manganese tricarbonyl
(MMT) (20 mg MMT/kg or 5.6 mg Mn/kg). The plasma concentrations of manganese were
quantified by atomic absorption spectrophotometry (AAS). Upon iv administration
of MnCl2, manganese rapidly disappeared from blood with a terminal elimination
t1/2 of 1.83 h and CL8 of 0.43 L/h/kg. The plasma concentration-time profiles of
manganese could be described by C = 41.9e(-424t) + 2.1e(-0.44t). Following oral
administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax
= 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT
resulted in a delayed Tmax(7.6 h), elevated Cmax (0.93 microg/ml), and prolonged
terminal t1/2 (55.1 h). The rats receiving MMT had an apparent clearance (CL/F =
0.09 L/h x kg) about 37-fold less than did those who were dosed with MnCl2.
Accordingly, the area under the plasma concentration-time curves (AUC) of
manganese in MMT-treated rats was about 37-fold greater than that in MnCl2
treated rats. A gender-dependent difference in toxicokinetic profiles of plasma
manganese was also observed. Female rats displayed a greater AUC than that of
male rats. Although the apparent volume of distribution of manganese was similar
in both sexes, the apparent clearance in males was about twice that observed in
females. The results indicated that after oral administration, the MMT-derived
manganese displayed higher and more prolonged plasma concentration-time profiles
than MnCl2-derived manganese. Thus, MMT-derived manganese appeared likely to
accumulate in the body following repeated exposure.
PMID- 10774813
TI - Comparative in vivo hepatic effects of Di-isononyl phthalate (DINP) and related
C7-C11 dialkyl phthalates on gap junctional intercellular communication (GJIC),
peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat and mouse liver.
AB - The short-term hepatic effects of DINP (CAS 68515-48-0, designated DINP-1) in
rats and mice were evaluated at tumorigenic and nontumorigenic doses from
previous chronic studies. Groups of male F344 rats were fed diets with DINP-1 at
concentrations of 0, 1000, or 12,000 ppm and male B6C3F1 mice at 0, 500, or 6000
ppm DINP-1. After 2 or 4 weeks of treatment, changes in liver weight, gap
junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX),
and replicative DNA synthesis were examined. In addition, hepatic and serum
concentrations of the parent compound and major metabolites were determined.
Relative to controls in both species, increased liver weight and PBOX at the high
dose of DINP-1 were consistent with peroxisomal proliferation. Hepatic GJIC was
inhibited and DNA synthesis was increased at the high dose of DINP-1, which is
also consistent with the tumorigenic response in rats and mice reported in other
chronic studies at these doses. These hepatic effects were not observed at the
low doses of DINP-1. At comparable low doses of DINP-1 in other chronic studies,
no liver tumors were observed in rats and mice. The monoester metabolite (MINP-1)
was detected in the liver at greater concentrations in mice than rats. This
result is also consistent with the dose-response observations in rat and mouse
chronic studies. Additionally, other structurally similar dialkyl phthalate
esters ranging from C7 to C11 were evaluated using a similar protocol for
comparison to DINP-1; these included an alternative isomeric form of DINP (DINP
A), di-isodecyl phthalate (DIDP), di-isoheptyl phthalate (DIHP), di-heptyl, nonyl
undecyl phthalate (D711P), and di-n-octyl phthalate (DNOP). Collectively, these
data indicate that in rats and mice, DINP-1 and other C7-C11 phthalates exhibit a
threshold for inducing hepatic cellular events. Further, where previous chronic
data were available for these compounds, these phthalates elicited hepatic
effects at doses that correlated with the tumorigenic response. Overall, these
studies suggest a good correlation between the inhibition of GJIC when compared
with the data on production of liver tumors in chronic studies.
PMID- 10774814
TI - Relationships between DNA incorporation, mutant frequency, and loss of
heterozygosity at the TK locus in human lymphoblastoid cells exposed to 3'-azido
3'-deoxythymidine.
AB - 3'-Azido-3'-deoxythymidine (AZT), a thymidine analogue widely used in the
treatment of AIDS patients and for prevention of the onset of AIDS in HIV
seropositive individuals, causes tumors in mice exposed as adults or in utero.
The purpose of this study was to investigate the potential mechanisms of AZT
mutagenicity and carcinogenicity by quantifying the incorporation of AZT into
cellular DNA, measuring AZT-induced thymidine kinase (TK) mutant frequencies
(Mfs), and determining the percentage of loss of heterozygosity (LOH) in
spontaneous or AZT-induced TK mutants in the human lymphoblastoid cell line, TK6.
Cells were exposed to 300 microM AZT for 0, 1, 3, or 6 days, or to 0, 33, 100,
300, or 900 microM AZT for 3 days (n = 5 flasks/group). The effects of exposure
concentration on incorporation of AZT into cellular DNA were evaluated by an AZT
radioimmunoassay, and the effects of duration and concentration of AZT exposure
on the TK Mfs were assessed by a cell-cloning assay. AZT was incorporated into
DNA in a dose-related manner at concentrations up to 300 microM, above which no
further increase was observed. TK Mf increased with the extended duration and
with incremental concentrations of AZT exposure. There was a positive correlation
(P = 0.036, coefficient = 0.903) between AZT-DNA incorporation and AZT-induced TK
Mfs, suggesting that AZT incorporation into cellular DNA has a direct role in the
genotoxicity of AZT. Southern blot analyses indicated that 84% (6.2 x 10(-6)/7.4
x 10(-6)) of AZT-induced mutants were attributable to LOH, consistent with the
known mechanism of AZT as a DNA chain terminator. Considering the importance of
LOH in human carcinogenesis, AZT-induced LOH warrants further study.
PMID- 10774815
TI - Hepatocarcinogenesis in female Sprague-Dawley rats following discontinuous
treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
AB - In this study, we investigated the time course of promotion of tumors and
putatively preneoplastic altered hepatic foci in the livers of diethylnitrosamine
(DEN)-initiated female Sprague-Dawley rats. These rats had been treated with
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) under different dosing regimens, but
we used the same administered biweekly dose of 1.75 microg/kg of body weight.
Animals were treated continuously for up to 60 weeks, or continuously for 30
weeks, followed by cessation of treatment for up to 30 weeks. In addition, TCDD
treatment in these groups was begun either 2 or 18 weeks after initiation with
DEN. Liver tumors were only observed in animals after 60 weeks on the study and
were increased by continuous TCDD treatment, relative to controls. The incidence
of hepatocellular adenoma and carcinoma combined, in animals treated with TCDD
for 30 weeks followed by no TCDD treatment for 30 weeks (17%), was lower than in
animals receiving either TCDD (79%) or vehicle control (corn oil) alone (55%) for
60 weeks. The lower liver-tumor incidence after cessation of TCDD treatment
paralleled time-dependent decreases in the volume fraction occupied by placental
glutathione S-transferase-positive altered hepatic foci and the number of foci
per unit volume, but not the mean focus volume that exhibited a time-dependent
increase after cessation of TCDD treatment. Cessation of TCDD treatment led to
reductions in liver TCDD levels, and these changes were reflected in a cessation
of reduced body weight because of TCDD treatment. These data indicate that liver
tumor promotion by TCDD in female rats is dependent upon continuous exposure to
TCDD, and that alterations in patterns of TCDD exposure can have significant
effects on tumor incidence not reflected by standard measures of dioxin exposure.
PMID- 10774816
TI - Evaluation of a Tier I screening battery for detecting endocrine-active compounds
(EACs) using the positive controls testosterone, coumestrol, progesterone, and
RU486.
AB - After previously examining 12 compounds with known endocrine activities, we have
now evaluated 4 additional compounds in a Tier I screening battery for detecting
endocrine-active compounds (EACs): a weak estrogen receptor (ER) agonist
(coumestrol; COUM), an androgen receptor (AR) agonist (testosterone; TEST), a
progesterone receptor (PR) agonist (progesterone; PROG), and a PR antagonist
(mifepristone; RU486). The Tier I battery incorporates 2 short-term in vivo tests
(5-day ovariectomized female battery; 15-day intact male battery) and an in vitro
yeast transactivation system (YTS). The Tier I battery is designed to identify
compounds that have the potential to act as agonists or antagonists to the
estrogen, androgen, progesterone, or dopamine receptors; steroid biosynthesis
inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis); or
compounds that alter thyroid function. In addition to the Tier I battery, a 15
day dietary restriction experiment was performed using male rats to assess
confounding due to treatment-related decreases in body weight. In the Tier I
female battery, TEST administration increased uterine weight, uterine stromal
cell proliferation, and altered hormonal concentrations (increased serum
testosterone [T] and prolactin [PRL]; and decreased serum FSH and LH). In the
male battery, TEST increased accessory sex gland weights, altered hormonal
concentrations (increased serum T, dihydrotestosterone [DHT], estradiol [E2], and
PRL; decreased serum FSH and LH), and produced microscopic changes of the testis
(Leydig cell atrophy and spermatid retention). In the YTS, TEST activated gene
transcription in the yeast containing the AR or PR. In the female battery, COUM
administration increased uterine weight, uterine stromal cell proliferation, and
uterine epithelial cell height, and increased serum PRL concentrations. In the
male battery, COUM altered hormonal concentrations (decreased serum T, DHT, E2;
increased serum PRL) and, in the YTS, COUM activated gene transcription in the
yeast containing the ER. In the female battery, PROG administration increased
uterine weight, uterine stromal cell proliferation, and uterine epithelial cell
height and altered hormonal concentrations (increased serum progesterone and
decreased serum FSH and LH). In the male battery, PROG decreased epididymis and
accessory sex gland weights, altered hormonal concentrations (decreased serum T,
PRL, FSH, and LH; increased serum progesterone and E2), and produced microscopic
changes of the testis (Leydig cell atrophy). In the YTS, PROG activated gene
transcription in the yeast containing the AR or PR. In the female battery, RU486
administration increased uterine weight and decreased uterine stromal cell
proliferation. In the male battery, RU486 decreased epididymis and accessory sex
gland weights and increased serum FSH and LH concentrations. In the YTS, RU486
activated gene transcription in the yeast containing the ER, AR, or PR. Dietary
restriction data demonstrate that confounding due to decrements in body weight
are not observed when body weight decrements are 10% or less in the Tier I male
battery. In addition, minimal confounding is observed at body decrements of 15%
(relative liver weight, T3, and T4). Hence, compounds can be evaluated in this
Tier I at levels that produce a 10% decrease in body weight without confounding
of the selected endpoints. Using the responses obtained for all the endpoints in
the Tier I battery, a distinct "fingerprint" was produced for each type of
endocrine activity against which compounds with unknown activity can be compared.
These data demonstrate that the described Tier I battery is useful for
identifying EACs and they extend the compounds evaluated to 16.
PMID- 10774817
TI - Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in
vitro.
AB - Although benign, uterine leiomyomas occur with high frequency and significant
morbidity in reproductive-age women, and they present a significant health
problem. Leiomyomas develop in the uterine myometrium and are sensitive to
ovarian hormones, making them potential target sites for endocrine disruptors.
Here we utilize cell lines derived from rat uterine leiomyomas to determine if a
panel of 7 organochlorine pesticides have potential agonist activity in
myometrial cells using cellular and molecular in vitro assays. The organochlorine
pesticides investigated have been previously characterized as having agonist
activity in other hormonally responsive tissues, but their effects have not been
studied in uterine myometrial cells. In Eker rat leiomyoma-derived cells, HPTE,
kepone, and the alpha isomer of endosulfan stimulated proliferation, an effect
dampened by the antiestrogen ICI 182,780. In addition, these compounds stimulated
transcription of the vitellogenin estrogen-response element via the ER in a
transcriptional reporter gene assay and induced the expression of an endogenous
estrogen-responsive gene, the progesterone receptor (PR). This contrasted with
the agonist profile of methoxychlor, dieldrin, toxaphene, and endosulfan-beta.
These compounds, unable to stimulate proliferation of uterine leiomyoma cells,
did exhibit agonistic activity in these cells at the transcriptional level in the
estrogen-sensitive reporter gene assay, and they were also able to upregulate PR
message. These data demonstrate that organochlorine pesticides act as estrogen
receptor agonists in Eker rat uterine myometrial cells, and they indicate a need
for further investigation of the potential tissue-specific agonist activity of
these pesticides and their role in the pathogenesis of uterine leiomyoma.
PMID- 10774818
TI - Microcystin-LR toxicodynamics, induced pathology, and immunohistochemical
localization in livers of blue-green algae exposed rainbow trout (oncorhynchus
mykiss).
AB - With this retrospective study, we investigated the temporal pattern of toxin
exposure and pathology, as well as the topical relationship between hepatotoxic
injury and localization of microcystin-LR, a potent hepatotoxin, tumor promoter,
and inhibitor of protein phosphatases-1 and -2A (PP), in livers of MC-gavaged
rainbow trout (Oncorhynchus mykiss) yearlings, using an immunohistochemical
detection method and MC-specific antibodies. H&E stains of liver sections were
used to determine pathological changes. Nuclear morphology of hepatocytes and
ISEL analysis were employed as endpoints to detect the advent of apoptotic cell
death in hepatocytes. Trout had been gavaged with lyophilized cyanobacteria
(Microcystis aeruginosa, strain PCC 7806) at acutely toxic doses of 5700 microg
microcystin (MC) per kg of body weight (bw), as described previously (Tencalla
and Dietrich, 1997). Briefly, 3 control and 3 test animal were killed 1, 3, 12,
24, 48, and 72 h after bolus dosing, and livers were fixed and paraffin embedded
for histological analysis and later retrospective histochemical analyses. The
results of the immunohistochemistry reported here revealed a time dependent,
discernible increase in MC-positive staining intensity throughout the liver,
clearly not concurring with the kinetics of hepatic PP inhibition observed in the
same fish and reported in an earlier publication by Tencalla and Dietrich (1997).
After 3 h, marked and increasing MC-immunopositivity was observed in the
cytoplasm, as well as the nuclei of hepatocytes. Apoptotic cell death could be
detected after 48 h, at the very earliest. These data suggest that accumulation
of MC and subsequent changes in cellular morphology, PP inhibition, and
hepatocyte necrosis represent the primary events in microcystin induced
hepatotoxicity and appear to be associated with the reversible interaction of MC
with the PP. In contrast, apoptotic cell death, as demonstrated here, seems to be
of only secondary nature and presumably results from the covalent interaction of
MC with cellular and nuclear PP as well as other thiol containing cellular
proteins.
PMID- 10774819
TI - Hemopoietic progenitor cells are sensitive targets of 2,3,7,8-tetrachlorodibenzo
p-dioxin in C57BL/6J mice.
AB - Treatment of adult C57BL6J mice with tetrachlorodibenzo-p-dioxin (TCDD) elicits
altered bone marrow hemopoietic cellular potentials and markedly reduced T
lymphoid-reconstituting activity. The latter has been hypothesized to play a role
in TCDD-induced thymic atrophy. To investigate cellular targets responsible for
reduced prothymocyte capacity, bone marrow cells from TCDD-treated C57BL/6J mice
were assessed for hemopoietic alterations within the lineage-negative (lin-)
compartment by the examination of Sca-1 and c-Kit levels. Lin- hemopoietic cells
from C57BL/6J mice, treated with 30 microg/kg of TCDD, were assessed for
phenotypic alterations following 24 h through 31 days. The responses of lin-
cells to TCDD doses ranging from 0.3 to 30 microg/kg were also assessed at 2 days
following TCDD treatment. The data reveal increases in the number of bone marrow
lin- Sca-1+ c-Kit+ cells, relative to control, over 24 h through 31 days
following treatment, as well as dose-dependent increases in this population when
examined at 2 days. Increases in lin- Sca-1+ c-Kit- cells occurred on a more
transient basis and were also dependent upon TCDD dose. These data suggest that
proliferation and/or differentiation processes of hemopoietic stem cells are
affected by TCDD and that these effects contribute to a reduced capacity of bone
marrow to generate pro-T lymphocytes.
PMID- 10774820
TI - Inhibition of CYP2E1 reverses CD4+ T-cell alterations in trichloroethylene
treated MRL+/+ mice.
AB - Trichloroethylene is an organic solvent that is primarily used as a degreasing
agent for metals. There is increasing evidence in both humans and animal models
that trichloroethylene promotes the development of autoimmunity, but little is
known about the mechanisms that mediate the effect of trichloroethylene on the
immune system. Metabolic activation of trichloroethylene is considered an
obligatory pathway for other known toxicities such as hepatotoxicity,
nephrotoxicity, and carcinogenicity. Trichloroethylene is metabolized by the
cytochromes P450, primarily cytochrome P450 2E1 (CYP2E1). To investigate whether
metabolism by CYP2E1 is required for immunomodulation, we treated autoimmune
prone MRL+/+ mice with trichloroethylene in the drinking water for 4 weeks, in
the presence or absence of diallyl sulfide, a specific inhibitor of CYP2E1. Using
an antibody that recognizes proteins covalently modified by a reactive metabolite
of trichloroethylene; two immunoreactive proteins were detected in liver
microsomes from trichloroethylene-treated mice. Formation of these
trichloroethylene-protein adducts, an indicator of metabolic activation, was
completely inhibited in animals that were concomitantly treated with
trichloroethylene and diallyl sulfide. The level of CYP2E1 apoprotein in liver
microsomes was significantly reduced in the presence of diallyl sulfide. The
enhanced mitogen-induced proliferative capacity of T cells from trichloroethylene
treated MRL+/+ mice was inhibited if the mice were also treated with diallyl
sulfide. In addition, the reduction in interleukin-4 levels secreted by activated
CD4+ T cells from trichloroethylene-treated mice was reversed if the mice were
also treated with diallyl sulfide. Taken collectively, metabolism of
trichloroethylene by CYP2E1 is responsible, at least in part, for the CD4+ T cell
alterations associated with exposure to this environmental toxicant.
PMID- 10774821
TI - Oxidative stress in female B6C3F1 mice following acute and subchronic exposure to
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly persistent trace
environmental contaminant and is one of the most potent toxicants known to man.
Hassoun et al. (1998, Toxicol. Sci. 42, 23-27) reported an increase in the
production of reactive oxygen species (ROS) in the brain of female B6C3F1 mice
following subchronic exposure to TCDD at doses as low as 0.45 ng/kg/day. In the
present study, oxidative stress was characterized in liver, spleen, lung, and
kidney following subchronic (0.15-150 ng/kg; 5 days/week for 13 weeks, po) or
acute exposure (0.001-100 microg/kg, po) to TCDD in order to investigate the
interaction between tissue concentration and time for production of ROS. Seven
days following acute administration of TCDD, mice were sacrificed; they
demonstrated increases in liver superoxide anion production (SOAP) and
thiobarbituric acid reactive substances (TBARS) at doses of 10 and 100 microg/kg,
associated with hepatic TCDD concentrations of 55 and 321 ng/g, respectively.
Liver obtained from mice following subchronic TCDD exposure demonstrated an
increase in SOAP and TBARS above controls at doses of 150 ng/kg/day with liver
TCDD concentration of only 12 ng/g. Interestingly, glutathione (GSH) levels in
lung and kidney following sub-chronic TCDD exposure were decreased at the low
dose of 0.15 ng/kg/day. This effect disappeared at higher TCDD doses. The data
suggest that higher tissue TCDD concentrations are required to elicit oxidative
stress following acute dosing than with subchronic TCDD exposure. Therefore, the
mechanism of ROS production following TCDD exposure does not appear to be solely
dependent upon the concentration of TCDD within the tissue. In addition, very low
doses of TCDD that result in tissue concentrations similar to the background
levels found in the human population produced an effect on an oxidative stress
endogenous defense system. The role of this effect in TCDD-mediated toxicity is
not known and warrants further investigation.
PMID- 10774822
TI - Effect of trichloroethylene and its metabolites, dichloroacetic acid and
trichloroacetic acid, on the methylation and expression of c-Jun and c-Myc
protooncogenes in mouse liver: prevention by methionine.
AB - Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid
(TCA) are environmental contaminants that are carcinogenic in mouse liver. 5
Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcription of
mRNA, including the protooncogenes, c-jun and c-myc. We have previously reported
that TCE decreased methylation of the c-jun and c-myc genes and increased the
level of their mRNAs. Decreased methylation of the protooncogenes could be a
result of a deficiency in S-adenosylmethionine (SAM), so that methionine, by
increasing the level of SAM, would prevent hypomethylation of the genes. For 5
days, female B6C3F1 mice were administered, daily by oral gavage, either 1000
mg/kg body weight of TCE or 500 mg/kg DCA or TCA. At 30 min after each dose of
carcinogen, the mice received, by ip injection, 0-, 30-, 100-, 300-, or 450-mg/kg
methionine. Mice were euthanized at 100 min after the last dose of DCA, TCA, or
TCE. Decreased methylation in the promoter regions of the c-jun and c-myc genes
and increased levels of their mRNA and proteins were found in livers of mice
exposed to TCE, DCA, and TCA. Methionine prevented both the decreased methylation
and the increased levels of the mRNA and proteins of the two pro-tooncogenes. The
prevention by methionine of DCA- TCA-, and TCE-induced DNA hypomethylation
supports the hypothesis that these carcinogens act by depleting the availability
of SAM. Hence, methionine would prevent DNA hypomethylation by maintaining the
level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, or TCE
must be sufficient to decrease the level of SAM in order for these carcinogens to
be active.
PMID- 10774823
TI - In vitro and in vivo assessment of the effect of impurities and chirality on
methamidophos-induced neuropathy target esterase aging.
AB - In vitro and in vivo studies evaluated neuropathy target esterase (NTE)
inhibition and aging (i.e., loss of reactivation potential) by analytical and
technical grade racemic and resolved L-(-) and D-(+) isomers of methamidophos
(O,S-dimethyl phosphoramidothioate). For studies in vitro, microsomal protein
from phenobarbital-induced livers was isolated from chick embryos and NTE
inhibition assays were performed using chick embryo brain homogenate treated with
1 or 5 mM methamidophos (with and without metabolic enzymes); for studies in
vivo, hens received 30 to 35 mg/kg methamidophos injected into the pectoral
muscle. NTE aging in hens was assessed 24 h later or after 30 min to 1 h
incubation in vitro using solutions of potassium fluoride (KF) reactivator.
Technical methamidophos produced significantly higher levels of aged-inhibited
NTE than analytical methamidophos or isolated optical isomers. In vivo, technical
methamidophos produced 61% total NTE inhibition with 18% aged and 43% unaged NTE;
hens receiving analytical grade averaged 6% aged, 52% unaged, and 58% total NTE
inhibition. Results for 1 mM analytical methamidophos in vitro were 5% aged, 54%
unaged, and 59% total inhibition; for 1 mM technical methamidophos, values
averaged 11% aged, 50% unaged, and 60% total NTE inhibition. The degree of NTE
aging obtained both in vivo and in vitro for the isolated D-(+) and L-(-) isomers
never exceeded that obtained using analytical grade. These data indicate that
impurities in methamidophos could contribute to OPIDN potential. The in vitro
methodology described could be applied to first tier screening for detection of
NTE inhibition and aging, thus reducing the need for whole-animal testing for
OPIDN.
PMID- 10774824
TI - Reproductive toxicity of 1-bromopropane, a newly introduced alternative to ozone
layer depleting solvents, in male rats.
AB - 1-Bromopropane has been newly introduced as an alternative to ozone-depleting
solvents. We aimed to clarify its dose-dependent reproductive toxicity in male
rats. Thirty-six Wistar male rats were randomly divided into 4 groups of 9. The
groups were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h
per day for 12 weeks. Epididymal sperm indices were evaluated after a 12-week
exposure. The testes, epididymides, seminal vesicle, prostate, and other organs
were weighed and examined histopathologically. Spermatogenic cells, in stage VII
seminiferous tubules, and retained spermatids, at the basal region of stages IX
XI seminiferous epithelium, were counted. Plasma testosterone levels were
measured by radioimmunoassay. The testicular weight did not significantly change,
but the weight of epididymides, seminal vesicle, and prostate dose-dependently
decreased. The weight of seminal vesicle decreased significantly at the lowest
concentration of 200-ppm and over. 1-Bromopropane induced a dose-dependent
decrease in the epididymal sperm count and in motility, as well as an increase in
tailless sperm and sperm with an immature head shape. The spermatogonia,
preleptotene spermatocytes, pachytene spermatocytes, and round spermatids did not
decrease significantly at stage VII. Retained, elongated spermatids near the
basement membrane at the postspermiation stages IX-XI increased dose-dependently.
Plasma testosterone levels significantly decreased at the 800-ppm dosage. 1
Bromopropane caused failure of spermiation. Its reproductive toxicity is
different from that of 2-bromopropane, which specifically impairs spermatogonia.
Thus, this solvent may have serious reproductive toxic effects in men, and should
be used very cautiously in the workplace.
PMID- 10774825
TI - In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters
postnatal development of seminal vesicle epithelium.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to alter male
reproductive development of laboratory animals through in utero and lactational
exposure. As a result of exposure, the accessory glands of the male reproductive
tract, including the seminal vesicle, are decreased in size as determined by
total weight of the tissue. Analysis of seminal vesicle weights over time
suggests that the changes may be transient. Administration of 1.0 microg/kg TCDD
during gestation caused a significant decrease in seminal vesicle weights of
offspring 8-11 months of age. We examined the effects of TCDD on seminal vesicles
from rats exposed in utero and lactationally. Pregnant Long Evans rats were
gavaged on gestation day 15 with 1.0 microg/kg TCDD in corn oil. Male pups were
euthanized and necropsied on postnatal days (PND) 15, 25, 32, 49, 63, and 120.
Seminal vesicles were weighed and then fixed in 10% neutral buffered formalin and
processed for microscopic examination. Seminal vesicle weights were not
significantly decreased until PND 32. Androgen receptor mRNA expression in PND 25
seminal vesicles was not different from control. In the present study, TCDD
exposure decreased seminal vesicle epithelial branching and differentiation.
Control epithelial cells had tall columnar morphology with relatively abundant
cytoplasm, whereas TCDD-treated cells had rounded nuclei and less cytoplasm. In
addition, immunolocalization of proliferating nuclear antigen was confined to
undifferentiated basal epithelial cells of controls but was found in both basal
and luminal cells of the treated seminal vesicle. Results indicate that the TCDD
induced impaired growth of the rat seminal vesicles is associated with a dramatic
decrease in the development of the epithelium.
PMID- 10774826
TI - Prenatal toxicity of inhaled polymeric methylenediphenyl diisocyanate (MDI)
aerosols in pregnant wistar rats.
AB - Mated Wistar rats, 25/group, were exposed to polymeric methylenediphenyl
diisocyanate (MDI) aerosol of respirable size for 6 h/day, on gestational days
(gd) 6 through 15, at 0, 1, 4, and 12 mg/m3. Maternal clinical signs, body
weights, and feed and water consumption were measured throughout gestation. At
scheduled sacrifice on gd 20, maternal body, gravid uterine, liver, and paired
lung weights were documented. Corpora lutea were counted, implantation sites were
identified: resorptions, dead and live fetuses, and placentas were weighed. All
live fetuses were counted, sexed, weighed, and examined for external alterations;
approximately 50% of the live fetuses/litter were preserved in Bouin's fixative
and examined for visceral alterations, and the remaining live fetuses/ litter
were cleared and stained with alizarin red S and examined for ossified skeletal
alterations. Maternal toxicity was observed at 12 mg/m3, including mortality (2
of 24 pregnant), damage to the respiratory tract, reduced body weights and weight
gain, reduced liver and increased lung weights, and reduced gravid uterine weight
(the last not statistically significantly different from the control value).
Developmental toxicity was also observed at 12 mg/m3, including reduced placental
and fetal body weights and an increased incidence of fetal skeletal variations
and skeletal retardations. There was no evidence of maternal or developmental
toxicity at 1 or 4 mg/m3. The no observed adverse effect concentration for
maternal and developmental toxicity was therefore 4 mg/m3. There were no
treatment-related teratogenic effects at any concentrations evaluated.
PMID- 10774827
TI - Variable pulmonary responses from exposure to concentrated ambient air particles
in a rat model of bronchitis.
AB - Chronic bronchitis may be considered a risk factor in particulate matter (PM)
induced morbidity. We hypothesized that a rat model of human bronchitis would be
more susceptible to the pulmonary effects of concentrated ambient particles
(CAPs) from Research Triangle Park, NC. Bronchitis was induced in male Sprague
Dawley rats (90-100 days of age) by exposure to 200 ppm sulfur dioxide (SO2), 6
h/day x 5 days/week x 6 weeks. One day following the last SO2 exposure, both
healthy (air-exposed) and bronchitic (SO2-exposed) rats were exposed to filtered
air (three healthy; four bronchitic) or CAPs (five healthy; four bronchitic) by
whole-body inhalation, 6 h/day x 2 or 3 days. Pulmonary injury was determined
either immediately (0h) or 18 h following final CAPs exposure. The study protocol
involving 0 h time point was repeated four times (study #A, November, 1997; #B,
February, 1998; #C and #D, May, 1998), whereas the study protocol involving 18 h
time point was done only once (#F). In an additional study (#E), rats were
exposed to residual oil fly ash (ROFA), approximately 1 mg/ m(3)x6 h/day x 3 days
to mimic the CAPs protocol (February, 1998). The rats allowed 18 h recovery
following CAPs exposure (#F) did not depict any CAPs-related differences in
bronchoalveolar lavage fluid (BALF) injury markers. Of the four CAPs studies
conducted (0 h time point), the first (#A) study (approximately 650 microg/m3
CAPs) revealed significant changes in the lungs of CAPs-exposed bronchitic rats
compared to the clean air controls. These rats had increased BALF protein,
albumin, N-acetyl glutaminidase (NAG) activity and neutrophils. The second (#B)
study (approximately 475 microg/m3 CAPs) did not reveal any significant effects
of CAPs on BALF parameters. Study protocols #C (approximately 869 microg/m3 CAPs)
and #D (approximately 907 microg/m3 CAPs) revealed only moderate increases in the
above mentioned BALF parameters in bronchitic rats exposed to CAPs. Pulmonary
histologic evaluation of studies #A, #C, #D, and #F revealed marginally higher
congestion and perivascular cellularity in CAPs-exposed bronchitic rats. Healthy
and bronchitic rats exposed to ROFA (approximately 1 mg/m3) did not show
significant pulmonary injury (#E). Analysis of leachable elemental components of
CAPs revealed the presence of sulfur, zinc, manganese, and iron. There was an
apparent lack of association between pulmonary injury and CAPs concentration, or
its leachable sulfate or elemental content. In summary, real-time atmospheric PM
may result in pulmonary injury, particularly in susceptible models. However, the
variability observed in pulmonary responses to CAPs emphasizes the need to
conduct repeated studies, perhaps in relation to the season, as composition of
CAPs may vary. Additionally, potential variability in pathology of induced
bronchitis or other lung disease may decrease the ability to distinguish toxic
injury due to PM.
PMID- 10774828
TI - Quantitation and localization of pulmonary manganese superoxide dismutase and
tumor necrosis factor alpha following exposure to ozone and nitrogen dioxide.
AB - Tumor necrosis factor a (TNFalpha) and manganese superoxide dismutase (MnSOD) are
thought to play critical roles in the process of lung injury, repair, and
disease. The induction of TNFalpha and MnSOD were examined in a model of
progressive pulmonary fibrosis along the length of the alveolar duct in rats
exposed for 1, 5, and 8 weeks to a combination of 0.8 ppm ozone and 14.4 ppm
nitrogen dioxide. This oxidant injury model results in a triphasic response with
an initial inflammatory stage during weeks 1-3, followed by a partial resolution
at weeks 4-5, and a final stage of rapidly progressive fibrosis during weeks 6-8.
Changes in TNFalpha and MnSOD labeling for the proximal and distal alveolar ducts
of the lungs were quantified using immunohistochemistry and morphometric
techniques at 1, 5, and 8 weeks of exposure. A significant elevation in MnSOD was
noted in alveolar macrophages and interstitial cells of the proximal and distal
portions of the alveolar duct following 8 weeks of exposure. Labeling for
TNFalpha only in the proximal region of the alveolar duct, was significantly
increased in alveolar macrophages after 1 and 8 weeks of exposure, while a
significant increase in TNFalpha labeling of interstitial cells in proximal
regions was noted at all time points. We conclude that MnSOD is elevated in areas
of focal injury as well as the more distal protected areas of the lungs, while
TNFalpha correlates strongly with both the temporal and spatial aspects of
greatest cellular injury in the lungs.
PMID- 10774829
TI - Environmental tobacco smoke, cardiovascular disease, and the nonlinear dose
response hypothesis.
AB - Two recent government reports have focused attention on the hypothesis that
environmental tobacco smoke (ETS) exposure increases the risk of cardiovascular
disease (CVD) in nonsmokers. The first report was published by the California
Environmental Protection Agency (CAEPA) in 1997. The second report was issued in
1998 by the Scientific Committee on Tobacco and Health (SCOTH) in the United
Kingdom. A meta-analysis of five large prospective epidemiology studies reports
that the relative risk for actively smoking 20 cigarettes per day is 1.78. Active
smoking exposes the smoker to approximately 16 times the ETS concentration, and
100- to 300-fold the total smoke dose experienced by a nonsmoker (Smith and
Ogden, 1998, JAMA 280, 32-33.). Despite the much lower smoke exposure, these
government reports estimate the relative risk for ischemic heart disease in ETS
exposed nonsmokers at 1.30 (CAEPA) and 1.23 (SCOTH). As an explanation for this
nonlinear dose-response anomaly, platelet aggregation is proposed to be a
plausible and quantitatively consistent mechanism. Herein, evidence is presented
suggesting that this low-dose hypothesis is inconsistent with the biochemistry
and physiology of platelets and with the literature on the cardiovascular
pathology of active smoking. In addition, several important biases and
confounders are ignored. These epidemiologic biases and confounders include the
following: misclassification of smokers as nonsmokers; improper use of death
certificates as surrogates for mortality statistics; underreporting of diabetes
and hypertension in the relatives of smokers; and additional atherogenic risk
factors in smoking households. Future field studies on ETS and CVD should
emphasize proximal markers of risk for thrombosis in exposed nonsmokers. Proximal
thrombogenic risk markers identified in field studies should be mechanistically
examined under controlled exposure conditions.
PMID- 10774830
TI - Succimer and the urinary excretion of essential elements in a primate model of
childhood lead exposure.
AB - Succimer is considered to be a safe and effective treatment for lead (Pb)
poisoning, since it reduces body Pb levels without an apparent diuresis of other
essential elements. However, while existing clinical data indicate that succimer
does not significantly increase the excretion of non-target elements, those
studies have also reported a wide range of outcomes. Therefore, we investigated
whether succimer treatment measurably increased the urinary excretion of
essential elements in a primate model of childhood Pb exposure. Infant rhesus
monkeys (Macaca mulatta) were exposed to Pb from birth through one year of age,
and presented blood Pb levels of approximately 40-50 microg/dL at the start of
treatment. Subsequently, they were treated with succimer (30 mg/kg/day x 5 days
followed by 20 mg/kg/day x 14 days, n = 15) or vehicle (n = 14) for 19 days.
Complete urine samples were collected over the first 5 days of treatment, and
were analyzed for levels of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe),
lead (Pb), magnesium (Mg), manganese (Mn), nickel (Ni), and zinc (Zn), using
trace metal-clean techniques and magnetic sector-ICP-MS. Succimer treatment
significantly (p < 0.05) reduced blood Pb levels when compared to the vehicle
group over the treatment period, and concomitantly produced a significant >4-fold
increase in urinary Pb excretion. Succimer treatment also significantly (p <
0.05, multivariate ANOVA) increased the urinary excretion of essential elements,
but only when the cumulative total excretion over treatment days 1-5 for all
elements were considered. None of these relative increases reached statistical
significance for any particular element x day, although increases in Zn (day 3)
excretion were only marginally non-significant (0.1 > p > 0.05). Multivariate
analyses of a subset of elements (Cu, Fe, Mn, Zn) similarly indicated no
significant effect of succimer treatment overall, although the urinary excretion
of Mn was significantly increased on day 3 of treatment. Collectively, these data
indicate that succimer does contribute to an increase in the urinary excretion of
essential elements, although not significantly for any single element considered
here. This may be important in Pb-exposed children, who can possess reduced trace
element reserves due to nutritional deficiencies.
PMID- 10774831
TI - Subchronic and chronic toxicological investigations on metiram: the lack of a
carcinogenic response in rodents.
AB - Metiram complex is a non-systemically acting fungicide of the group of
ethylenebisdithiocarbamates (EBDC). The subchronic and chronic toxicity and the
carcinogenic potential of metiram (containing 2% ethylene thiourea, ETU, as an
intentionally added impurity) were investigated. Doses in the
chronic/carcinogenicity rat study were 0, 5, 20, 80, or 320 ppm. In the
carcinogenicity study in mice, diets were administered for 89 weeks (females) or
95 weeks (males) at doses of 0, 100, 300, or 1000 ppm. No oncogenic response was
noted in either species. The subchronic studies in rats and mice further
investigated the thyroid as a target organ. Doses of 0, 5, 80, 320, or 960 ppm
were utilized in the rat study and a NOAEL of 80 ppm was established. In the
subchronic mouse study, diets containing 0, 300, 1000, 3000, or 7500 ppm were
utilized. A NOAEL of 300 ppm was established in this study. In summary, the
findings of these studies defined the toxicity of metiram in rodents and
demonstrated the lack of a carcinogenic response following chronic dietary
exposure in the rat and mouse. The NOAELs that were established in these studies
were consistent with the NOAELs established for thyroid toxicity/carcinogenicity
in studies on ethylenethiourea (ETU).
PMID- 10774832
TI - Toxicity of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in
diethylnitrosamine-initiated ovariectomized rats implanted with subcutaneous 17
beta-estradiol pellets.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatocarcinogen in female
but not in male rats. Several lines of evidence suggest a key role of ovarian
hormones, presumably estrogen, in the mechanism of TCDD-induced
hepatocarcinogenesis. The aim of this current study was to determine the toxicity
of co-treatment with TCDD and 17 beta-estradiol and assess the efficacy of 90-day
subcutaneous constant release 17 beta-estradiol pellets. Ovariectomized (OVX)
female Sprague-Dawley rats were initiated with diethylnitrosamine (DEN) and
treated with TCDD for 20 or 30 weeks in the presence and absence of 17 beta
estradiol. TCDD concentrations were equivalent in livers of TCDD-treated sham
operated and OVX rats following 20 weeks of treatment. Following 30 weeks of TCDD
treatment, liver TCDD concentrations were higher in OVX rats than in intact rats.
TCDD concentrations in livers of TCDD-treated OVX rats receiving supplemental 17
beta-estradiol were similar to intact rats following either 20 or 30 weeks of
treatment. Mean hepatic background TCDD concentrations in untreated rats were 2
fold higher in intact rats compared to OVX rats, regardless of 17-estradiol
exposure following 20, but not 30 weeks of treatment. Serum indicators of
hepatocellular and hepatobiliary toxicity indicated transient hepatotoxicity in
TCDD-treated OVX rats receiving 17 beta-estradiol. Histopathological alterations
indicated hepatotoxicity induced by exposure to TCDD following either 20 or 30
weeks of exposure. No excess hepatotoxicity was associated with 17 beta-estradiol
supplementation in TCDD-exposed OVX female Sprague-Dawley rats. Serum 17 beta
estradiol concentrations were not constant and resulted in supra-physiological
levels that decreased over time, resulting in target physiological serum 17 beta
estradiol concentrations following several weeks of release. Treatment with 17
beta-estradiol resulted in uterine weights and total body weights comparable to
sham-operated female rats. These data confirm the efficacy of supplemental
subcutaneous 17 beta-estradiol pellets on the induction of estrogenic responses
in TCDD-treated rats and indicate no increased hepatotoxicity associated with 17
beta-estradiol exposure in TCDD-treated rats.
PMID- 10774833
TI - Studies on the mechanisms of arsenic-induced self tolerance developed in liver
epithelial cells through continuous low-level arsenite exposure.
AB - Arsenic (As) is a human carcinogen. Our prior work showed that chronic (>18
weeks) low level (500 nM) arsenite (As3+) exposure induced malignant
transformation in a rat liver epithelial cell line (TRL 1215). In these cells,
metallothionein (MT) is hyper-expressible, a trait often linked to metal
tolerance. Thus, this study examined whether the adverse effects of arsenicals
and other metals were altered in these chronic arsenite-exposed (CAsE) cells.
CAsE cells, which had been continuously exposed to 500 nM arsenite for 18 to 20
weeks, and control cells, were exposed to As3+, arsenate (As5+), dimethylarsinic
acid (DMA), monomethylarsonic acid (MMA), antimony (Sb3+), cadmium (Cd2+),
cisplatin (cis-Pt), and nickel (Ni2+) for 24 h and cell viability was determined
by metabolic integrity. The lethal concentration for 50% of exposed cells (LC50)
for As3+ was 140 microM in CAsE cells as compared to 26 microM in control cells,
a 5.4-fold increase in tolerance. CAsE cells were also very tolerant to the acute
toxic effects of As5+ (LC50 > 4000 microM) compared to control (LC50 = 180
microM). The LC50 for DMA was 4.4-fold higher in CAsE cells than in control
cells, but the LC50 for MMA was unchanged. There was a modest cross-tolerance to
Sb3+, Cd2+, and cis-Pt in CAsE cells (LC50 1.5-2.0-fold higher) as compared to
control. CAsE cells were very tolerant to Ni2+ (LC50 > 8-fold higher). Culturing
CAsE cells in As(3+)-free medium for 5 weeks did not alter As3+ tolerance,
implicating an irreversible phenotypic change. Cellular accumulation of As was
87% less in CAsE cells than control and the accumulated As was more readily
eliminated. Although accumulating much less As, a greater portion was converted
to DMA in CAsE cells. Altered glutathione (GSH) levels were not linked with As
tolerance. A maximal induction of MT by Zn produced only a 2.5-fold increase in
tolerance to As3+ in control cells. Cell lines derived from MT normal mice
(MT+/+) were only slightly more resistant (1.6-fold) to As3+ than cells from MT
null mice (MT-/-). These results show that CAsE cells acquire tolerance to As3+,
As5+, and DMA. It appears that this self-tolerance is based primarily on reduced
cellular disposition of the metalloid and is not accounted for by changes in GSH
or MT.
PMID- 10774835
TI - Grandparent visitation rights.
PMID- 10774834
TI - The hepatic inflammatory response after acetaminophen overdose: role of
neutrophils.
AB - Acetaminophen overdose induces severe liver injury and hepatic failure. There is
evidence that inflammatory cells may be involved in the pathophysiology. Thus,
the aim of this investigation was to characterize the neutrophilic inflammatory
response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen. A time
course study showed that neutrophils accumulate in the liver parallel to or
slightly after the development of liver injury. The number of neutrophils in the
liver was substantial (209 +/- 64 PMN/50 high-power fields at 12 h) compared to
baseline levels (7 +/- 1). Serum levels of TNF-alpha and the C-X-C chemokines KC
and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in
controls during the injury process. In addition, mRNA expression of MIP-2 and KC
were upregulated in livers of acetaminophen-treated animals as determined by
ribonuclease protection assay. However, none of these mediators were generated in
large enough quantities to account for neutrophil sequestration in the liver.
There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on
circulating neutrophils. Moreover, an anti-CD18 antibody had no protective effect
against acetaminophen overdose during the first 24 h. These results indicate that
there is a local inflammatory response after acetaminophen overdose, including a
substantial accumulation of neutrophils in the liver. Because of the critical
importance of beta2 integrins for neutrophil cytotoxicity, these results suggest
that neutrophils do not contribute to the initiation or progression of AAP
induced liver. The inflammation observed after acetaminophen overdose may be
characteristic for a response sufficient to recruit neutrophils for the purpose
of removing necrotic cells but is not severe enough to cause additional damage.
PMID- 10774836
TI - Thomas G. Gutheil, MD: a president for the new millennium.
PMID- 10774837
TI - Ensuring that forensic psychiatry thrives as a medical specialty in the 21st
century.
AB - The author contends that forensic psychiatry will thrive as a legitimate medical
specialty in the 21st century only if it helps to fulfill the crucial requirement
of medical systems in the new health care era. The article presents six basic
requirements of future medical systems: effective, efficient, and responsible
organizations; quality educational programs of the appropriate type and size;
linkage to health care networks; primary care capacity and services; restructured
systems for research; and effective leadership. Specific opportunities for
forensic psychiatry to help meet these requirements are outlined. The author
presents major implications of these opportunities for forensic academicians and
practitioners as well as for the American Academy of Psychiatry and the Law.
PMID- 10774838
TI - The mental state at the time of the offense measure: its validation and
admissibility under Daubert.
AB - Melton et al. (Melton GB, Petrila J, Poythress NG, Slobogin C: Psychological
Evaluations for the Courts (ed 2). New York: Guilford, 1997) recently advocated
the use of the Mental State at the Time of the Offense (MSE-Offense) measure not
only as a screen for insanity evaluations but also as the sole measure in
"obvious" cases of insanity. Given this recommendation for expanding the role of
the MSE-Offense, the current authors have evaluated the available data based on
its construction and validation. We found fundamental flaws in its development
and grave shortcomings in its validation. Based on these limitations, we conclude
that the MSE-Offense is unacceptable under the Daubert standard (Daubert v.
Merrell Dow Pharmaceuticals, Inc., U.S. 113 S. Ct. 2786 (1993)) for either the
screening or determination of criminal responsibility.
PMID- 10774839
TI - Commentary on "The mental state at the time of the offense measure": should we
ever screen for insanity.
PMID- 10774840
TI - The future of criminal violence: juveniles tried as adults.
AB - Juveniles tried as adults (JTA) represent a select and small subsample of
juvenile offenders. This study seeks to provide a profile of habitually violent
JTAs transferred to the adult penal system and to compare them with their adult
counterparts. Twenty-nine incarcerated violent male juveniles tried as adults
were compared with a sample of 27 incarcerated violent male offenders across
demographic, neuropsychological, criminal history, psychopathy, and substance
abuse variables. The JTAs were characterized by a high rate of gang membership
(96%), substance abuse (alcohol, marijuana, and phenylcyclidene), and use of
guns. In the juvenile sample, 65 percent used guns in violence not leading to
arrest, and 93 percent used guns in a violent crime leading to arrest. Juvenile
offenders were similar to their adult counterparts in patterns of criminality,
although adult offenders had higher psychopathy scores. Both groups revealed
generally intact neuropsychological functioning with the exception of a higher
rate of perseverative responses in the adult sample. The results are discussed in
terms of the implication of the degree of violence in a young offender
population.
PMID- 10774841
TI - The guilty but mentally ill verdict: a review and conceptual analysis of intent
and impact.
AB - The purpose of this article is to review the law and literature involving the
guilty but mentally ill (GBMI) verdict to provide a clear conceptual examination
of the actual intent and impact of the verdict. Such an examination may help to
clarify continuing debates and confusion about the nature of GBMI and its success
in addressing perceived problems with insanity acquittals. This review suggests
that the actual intentions of the GBMI verdict are associated with minimal and
largely unsuccessful results. In addition, the typical absence of treatment for
defendants found GBMI appears unsurprising given that the provision of treatment
for mentally ill offenders is not a legal intention of the GBMI verdict. Finally,
the introduction of the GBMI verdict has had unintended negative consequences
that include increased confusion among jurors and the legal profession and
possible increased occurrence of inappropriate verdicts. In conclusion,
significant problems can be noted with regard to both the intent and impact of
the GBMI verdict.
PMID- 10774842
TI - Mass homicide: the civil massacre.
AB - Seven cases of mass homicide in Australia, New Zealand, and Britain between 1987
and 1996 are presented. These cases add to the world literature on these rare
crimes and balance previous, mostly North American reports. These acts were
committed by socially unsuccessful, self-absorbed, and resentful individuals.
Lengthy fantasy comprising identification, modeling, and rehearsal preceded the
incidents, even where the final acts had impulsive elements. Most had a long
standing fascination with firearms fueling their fantasies and providing the
means for mass killing. Their targets were mostly unprotected strangers. Overt
suicidal intent or a preparedness to die while committing the homicides was
invariable. Ethological theories of status acquisition may provide a useful
understanding of mass homicide.
PMID- 10774843
TI - Suicide, contributory negligence, and the idea of individual autonomy.
PMID- 10774844
TI - Suspected Munchausen's syndrome and civil commitment.
PMID- 10774845
TI - Diminished capacity and insanity in Washington State: the battle shifts to
admissibility.
PMID- 10774846
TI - Hubbart v. Superior Court of Santa Clara County.
PMID- 10774847
TI - Institutional failure in the life histories of men condemned to death.
PMID- 10774848
TI - The prosecution of Nathaniel Abraham--a minor.
PMID- 10774849
TI - Education, special needs, and medical exclusions: a good "IDEA"?
PMID- 10774850
TI - The role of forensic psychiatrists as expert witnesses in malpractice cases.
PMID- 10774851
TI - The Williamson v. Liptzin lawsuit.
PMID- 10774852
TI - Nerve distribution to the human knee joint: anatomical and immunohistochemical
study.
AB - The nerve distribution to the knee joints was analyzed in 5 cadavers and 10 joint
capsules specimens were resected during total knee arthroplasty. We found nerve
fibers immunoreactive for anti-substance P antibody in the articular capsule. By
confocal laser scanning microscopy, we evaluated the three-dimensional structures
of the Ruffini's corpuscles and the free nerve endings, both of which were
immunoreactive for anti-protein gene product 9.5.
PMID- 10774853
TI - Reproducibility of patellofemoral CT scan measurements.
AB - At least seven parameters have been described for the measurement of
patellofemoral malalignment on CT scanning; three of which measure lateral
patellar tilt, two lateral patellar shift and two femoral trochlear dysplasia. We
studied 22 knees in 18 patients complaining of patellofemoral pain in order to
investigate the reproducibility of these methods. CT scans of the patellofemoral
joint were performed in each knee at 0 degrees and 20 degrees of flexion. The
seven parameters were recorded from each scan by three independent observers in a
blind study. The reproducibility was studied by means of the intraclass
correlation coefficient (ICC). Parameters measuring lateral patellar tilt showed
excellent reliability (ICC>75%). The measurements of lateral patellar shift and
femoral trochlear dysplasia showed a fair or poor correlation (ICC<75%). We
suggest that parameters for measuring lateral patellar tilt only should be used
from CT scanning when planning treatment for patello-femoral malalignment.
PMID- 10774854
TI - Restoration of bone stock in revision surgery of the femur.
AB - Three hundred and four femoral revisions were performed from 1987 to the end of
1990. All were done with cementless titanium calcar replacement prostheses,
designed for proximal bone loading. Type III bone deficiencies were present in
160 femurs, all requiring supplemental cortical bone plates for bony
augmentation. All grafts united and provided increased bone stock in the long
term. Physiologic loading is important for graft remodeling and maturation. Hip
scores have improved from an average Harris Hip Score of 44 to 84. Current
survivorship at 10 years is 96%, and the revision rate is 3.2%. Thigh pain is
mild in 3% of cases. There have been no late failures or distal lysis noted to
date.
PMID- 10774855
TI - Cementless cup supporter for protrusio acetabuli in patients with rheumatoid
arthritis.
AB - The MC cup supporter is an acetabular reinforcement ring for the Harris-Galante
(HG) cementless porous-coated socket. This supporting ring has been used with
autogenous bone graft since 1991 in the management of protrusio acetabuli in
patients with rheumatoid arthritis (RA). We have reviewed 15 hips in 13 patients
at an average of 53.6 months (range 24-84 months) after operation. The clinical
results of total hip arthroplasty (THA) in protrusio acetabuli using this ring
were satisfactory. All grafts appeared to have united radiologically with no
radiolucent lines between graft and acetabulum.
PMID- 10774856
TI - Removal of the subchondral plate in acetabular preparation.
AB - Retention of the subchondral plate during acetabular preparation in total hip
replacement is believed to be an important part of modern cementing techniques.
We have constructed a two-dimensional finite element analysis to assess the
effect of retention and removal of this relatively stiff structure. The finite
element analysis demonstrates increased stiffness and stress concentrations at
the bone-cement interface that may have an adverse effect. Although further study
is required, it may be that subchondral bone retention is not advantageous.
PMID- 10774857
TI - The effect of anatomical positional relationships on kinetic parameters after
total hip replacement.
AB - The purpose of this study was to evaluate the significance of positional
relationships of the components on gait after total hip replacement (THR). Gait
was analysed using multicomponent force platforms integrated into a treadmill, in
conjunction with an optoelectric measuring system. 26 patients, after undergoing
total hip replacement, were classified according to the vertical and horizontal
positions of the centre of rotation, the vertical position of the femur and the
functional leg length, and compared with a control group. Deterioration in
parameters of gait was observed following cranialisation of the centre of
rotation or of the femur, whereas neither medial movement of the centre of
rotation nor leg lengthening by up to 1 cm had any effect. This study emphasises
the importance of considering, at the time of preoperative planning, the effect
of the position of the prosthesis on the functional parameters of gait.
PMID- 10774858
TI - Surgical treatment of old pelvic fractures.
AB - We report on 4 patients, aged 24-51 years, with untreated pelvic ring fractures.
The chief complaints were gait disturbances and pain in the buttocks and lower
limb. The period between the initial injury and the surgical treatment ranged
from 2.5 months to 3 years. Palsy was not improved, but pain and gait ability was
improved in all patients.
PMID- 10774859
TI - Supracondylar nailing of distal periprosthetic femoral fractures.
AB - Seven patients who sustained complex distal femoral fractures above total knee
arthroplasties all treated by supracondylar (retrograde) femoral nailing were
retrospectively evaluated. All the patients demonstrated uncomplicated
postoperative follow-ups and returned to weight bearing between 2 and 3 months
after surgery. No delayed healing occurred and alignment of the femur was
satisfactory.
PMID- 10774860
TI - The surgical treatment for degenerative disease of the ankle.
AB - Although a variety of surgical techniques are available for the surgical
treatment of early degenerative disease of the ankle, arthrodesis remains the
preferred treatment for severe cases. We studied 126 ankles with an average
follow up of 39 months of whom 25 with early disease underwent debridement and
cheilectomy, 18 with intermediate disease underwent lower tibial osteotomy and 83
with severe disease underwent either arthrodesis (78) or total ankle replacement
(5). In 96% of cases there was a satisfactory functional outcome.
PMID- 10774861
TI - Local anaesthetic injection with and without corticosteroids for subacromial
impingement syndrome.
AB - Fifty patients with impingement syndrome refractory to long-term conservative
treatment were randomized to three treatment groups. All patients received an
injection of 10 ml 0.5% bupivacaine, in group 1 without corticosteroid, in group
2 with crystalline corticosteroid and in group 3 with lipoid corticosteroid.
Treatment in group 1 had to be stopped because of inefficacy. In groups 2 and 3
favorable results were achieved in 19 out of 40 patients.
PMID- 10774862
TI - Restoration of elbow flexion by modified Steindler flexorplasty.
AB - A modified Steindler flexorplasty was used to restore elbow flexion in 8 patients
with post-traumatic flail elbow. In 5 patients there was associated loss of wrist
and finger extension, which was treated by tendon transfer and in 2 patients an
associated flail shoulder was treated by arthrodesis. The results were not
compromised in patients whose flexor tendons had been transferred for wrist and
finger extension. All patients had a stable and mobile elbow with marked
improvement of upper limb function. Modified Steindler flexorplasty is a simple,
effective and reliable procedure for the restoration of elbow flexion.
PMID- 10774863
TI - Pediatric stress fractures.
AB - Stress fractures in children are uncommon. This report describes the findings of
8 cases in 6 children. One patient had 3 stress fractures: 2 consecutive midshaft
stress fractures of the same tibia associated with one of the fibula. Signs and
symptoms may be misdiagnosed as malignant tumors or osteomyelitis. Serial
radiographs and computed tomography scans are the key to the diagnosis, although
bone scan and magnetic resonance imaging can be helpful. Biopsy is unnecessary
and might even be misleading.
PMID- 10774864
TI - Increasing age does not affect good outcome after lumbar disc replacement.
AB - From 1992 to 1998 fifteen Link-Charite SB III disc prostheses were implanted into
14 patients. The main indication was degenerative lumbar disc disease with
segmental instability. With a mean follow-up of 48 months (18-68 months); 12
patients had a good (10) or fair (2) outcome regarding pain relief, return to
employment and level of general physical activity. In contrast to previous
publications we felt that age over 45 years did not appear to adversely affect
the outcome.
PMID- 10774865
TI - Laminectomy performed using a micro bone saw.
AB - In 154 clinical cases requiring laminectomy at any part of the spinal column, the
laminae were removed using a micro bone saw. Immediately after the laminectomy
two surgeons using a microscope examined the field for any damage to the dura,
the spinal cord, the nerve roots and the epidural vessels. No injury to the
spinal cord or the nerve roots was observed. In 5 patients the dura were
lacerated for a length of up to 10 mm, and in all the patients adhesions were
present due to previous operations. Epidural vessels were severed in 18 cases.
The method is useful and less time-consuming than conventional laminectomy.
PMID- 10774866
TI - A new fracture of the forearm adjacent to a healing fracture.
AB - A 10-year-old girl sustained closed fractures of the distal radius and ulna. This
was manipulated and she was treated in an above-elbow plaster for 4 weeks. Two
weeks later she was discharged, only to have a second injury to the same forearm.
X-ray showed a new fracture distal to undisrupted callus.
PMID- 10774867
TI - Hormonal responses to whole-body vibration in men.
AB - The aim of this study was to evaluate the acute responses of blood hormone
concentrations and neuromuscular performance following whole-body vibration (WBV)
treatment. Fourteen male subjects [mean (SD) age 25 (4.6) years] were exposed to
vertical sinusoidal WBV, 10 times for 60 s, with 60 s rest between the vibration
sets (a rest period lasting 6 min was allowed after 5 vibration sets).
Neuromuscular performance tests consisting of counter-movement jumps and maximal
dynamic leg presses on a slide machine, performed with an extra load of 160% of
the subjects body mass, and with both legs were administered before and
immediately after the WBV treatment. The average velocity, acceleration, average
force, and power were calculated and the root mean square electromyogram (EMGrms)
were recorded from the vastus lateralis and rectus femoris muscles simultaneously
during the leg-press measurement. Blood samples were also collected, and plasma
concentrations of testosterone (T), growth hormone (GH) and cortisol (C) were
measured. The results showed a significant increase in the plasma concentration
of T and GH, whereas C levels decreased. An increase in the mechanical power
output of the leg extensor muscles was observed together with a reduction in
EMGrms activity. Neuromuscular efficiency improved, as indicated by the decrease
in the ratio between EMGrms and power. Jumping performance, which was measured
using the counter-movement jump test, was also enhanced. Thus, it can be argued
that the biological mechanism produced by vibration is similar to the effect
produced by explosive power training (jumping and bouncing). The enhancement of
explosive power could have been induced by an increase in the synchronisation
activity of the motor units, and/or improved co-ordination of the synergistic
muscles and increased inhibition of the antagonists. These results suggest that
WBV treatment leads to acute responses of hormonal profile and neuromuscular
performance. It is therefore likely that the effect of WBV treatment elicited a
biological adaptation that is connected to a neural potentiation effect, similar
to those reported to occur following resistance and explosive power training. In
conclusion, it is suggested that WBV influences proprioceptive feedback
mechanisms and specific neural components, leading to an improvement of
neuromuscular performance. Moreover, since the hormonal responses, characterised
by an increase in T and GH concentration and a decrease in C concentration, and
the increase in neuromuscular effectiveness were simultaneous but independent, it
is speculated that the two phenomena might have common underlying mechanisms.
PMID- 10774868
TI - Interindividual differences in the thermoregulatory response to cool exposure in
sleeping neonates.
AB - The responses of the thermoregulatory effectors vary greatly among neonates.
Therefore, we assume that a small decrease in air temperature from
thermoneutrality induces various thermoregulatory responses within neonates that
represent an energy cost due to the cold defence processes. To determine the
importance of this variability in nursing, 26 neonates were explored at
thermoneutrality and in a cool environment (-1.5 degrees C from thermoneutrality)
similar to that which occurs currently in clinical procedure. Oxygen consumption
(VO2), oesophageal and skin temperatures, as well as sleep parameters were
recorded continuously in both conditions. Analysis of all of the data from all of
the neonates revealed that the cool exposure induced thermal and sleep
disturbances, but VO2 did not increase and was not negatively correlated to body
temperature (as might be expected). Analyses of individual data showed large
variability in body temperature regulation: the neonates could be assigned to one
of three groups according to the direction of the individual slopes of VO2 versus
oesophageal or skin temperature. The groups also differed according to the sleep
changes recorded in the cool condition. The results show that the definition of
thermoneutrality should be revised by incorporating non only changes in the body
temperature, but also the sleep disturbances (increased wakefulness and active
sleep, decreased quiet sleep), which are criteria that are more sensitive to mild
cool exposure. Thermoneutrality should be defined for each individual, since the
results stress that the variability does not help to predict a general pattern of
thermoregulatory responses in cool-exposed neonates.
PMID- 10774869
TI - Blood distribution adaptations in paraplegics during posture changes: peripheral
and central reflex responses.
AB - The veno-arteriolar reflex (VAR) in spinal-cord-injured subjects (SCI) has been
attributed little interest, although it might contribute substantially to their
blood redistribution. This peripheral reflex response, which is based on an axon
reflex, consists of a reduction in limb blood flow following an increase in venal
transmural pressure. The purpose of the present investigation was to assess the
peripheral and central cardiovascular adaptations of paraplegics with high (HP)
and low (LP) spinal lesions to subsequent, passive posture changes involving leg
dependency and upright sitting, and to compare them to able-bodied (AB) subjects.
Lower-limb cutaneous vascular conductance (CVC) was evaluated from skin blood
flow measurements (laser Doppler flowmetry) taken from the dorsal foot, and from
ankle blood pressure. Cardiac stroke volume, heart rate and myocardial
performance were assessed using impedance cardiography and brachial blood
pressure. During leg dependency, a significant vasoconstriction was noted in all
three groups. The initial decrease in CVC was higher in HP (-76.82%) than in AB (
45.82%), the values for LP (-67.08%) lying in between these two (significant
group x time interaction: F = 2.832; P = 0.042). There were no differences for
parameters of central hemodynamics. No between-group differences were noted in
any parameter tested during upright sitting. CVC remained at a similar low level
as compared to leg dependency, stroke volume decreased, heart rate and blood
pressure increased, and myocardial performance remained constant. The present
results suggest that paraplegics have a peripheral VAR in their paralyzed lower
limbs, and that this contributes to their cardiovascular stability.
PMID- 10774871
TI - Mutual nervous influences between breathing and precision finger movements.
AB - The precision of short-term finger tracking flexions has been shown to vary with
the respiratory cycle. In the present study, we analysed the mutual effects
between breathing and short-term finger tracking movements (SFTM)--both flexions
and extensions. Moreover, we investigated the preferred phase relationships
between breathing and spontaneous single finger flexions and extensions. Two
types of experiments were carried out. Fifteen volunteers participated in the
finger tracking experiments. In one experimental session, a square-wave function
served as a tracking signal that required a rapid finger flexion, and in another
session it required a finger extension. In the second type of experiment, 14
volunteers performed spontaneous short-term finger flexions and extensions of a
pre-defined amplitude, with the starting point chosen at their convenience. SFTM
were associated with modulations in the time course of the respiratory cycle.
These were more pronounced for finger flexions than for extensions. Likewise, the
precision of finger flexions, but not extensions, showed significant respiratory
phase-dependent differences. The largest tracking errors occurred at the end of
expiration in finger flexions and at the end of inspiration in finger extensions.
Spontaneous finger flexions tended to start at around the respiratory phase
transitions. Spontaneous extensions, however, tended to start at early expiration
(12.5-37.5% of expiration time). The results demonstrate that both spontaneous
and tracking finger flexions and extensions are influenced by different stages of
a breath. However, spontaneous finger movements did not tend to start at the
stages of breaths that were associated with the highest movement precision in the
tracking tests. Moreover, these results suggest that finger flexions are more
closely related to the respiratory rhythm than are finger extensions.
PMID- 10774870
TI - Increased hypoxic ventilatory response during hypovolemic stress imposed through
head-up-tilt and lower-body negative pressure.
AB - The aim of this study was to quantify the influence of head-up-tilt (HUT) on the
isocapnic hypoxic ventilatory response (HVR) in man, and to investigate the
effect of orthostatic blood shifts separately from other gravitational effects by
the application of lower-body negative pressure (LBNP) with subjects in a
horizontal position. HVR was measured in 15 subjects during passive HUT from 0
degrees to 85 degrees as well as during -7 degrees head-down-tilt and while they
were in a sitting position. In a subgroup of eight subjects the effect of 85
degrees HUT was compared to a corresponding LBNP of -70 mbar on HVR. Moreover, by
imposing graded HUT (7 degrees, 15 degrees, 30 degrees, 50 degrees) and LBNP (
15, -30 mbar) we studied the effect of low-level orthostatic stress on HVR.
Ventilation, end-tidal partial pressure of CO2, heart rate and blood pressure
were recorded continuously for 1 min before, and during HVR. HVR was
significantly increased by approximately equal to 50% through both 85 degrees HUT
and -70 mbar LBNP as compared to 0 degrees and 0 mbar, respectively, at unchanged
mean arterial pressure. Low-level HUT and LBNP had no effect on HVR. It was
concluded that the orthostatic HVR increase may be attributable to caudal blood
shifts (i.e., central hypovolemia). This HVR increase requires a pronounced
hypovolemic stress but no decrease in arterial blood pressure. It is suggested
that a central interaction of arterial and cardiopulmonary baroreceptors is
underlying this response. Their separate contribution remains to be assessed.
PMID- 10774872
TI - The oxygen consumption associated with unloaded walking and load carriage using
two different backpack designs.
AB - The purpose of this study was to assess the energy expenditure associated with
load carriage using both a traditional rucksack and a new rucksack design, the
AARN rucksack, which incorporates front balance pockets. Nine volunteers walked
at 3 km h(-1) at various uphill and downhill gradients on a treadmill without a
load and carrying a load of 25.6 kg in each of the rucksacks. The oxygen
consumption associated with both of the loading conditions was significantly (P <
0.001) higher than that associated with unloaded walking at all downhill
gradients tested, although there was no significant difference between the two
loading conditions. During the uphill gradients the oxygen consumption associated
with the AARN pack was significantly (P < 0.05) lower than that associated with
the traditional pack at the 0%, 5%, 10% and 20% gradients. The mean (%)
differences at these gradients, expressed in ml x kg(-1) x min(-1) were 1.18
(9%), 1.45 (8%), 1.76 (8%) and 1.88 (6%), respectively. On average for the whole
protocol, the oxygen consumption associated with the AARN rucksack was 5% lower
than that associated with the traditional rucksack [mean (SD) 17.28 (7.46) ml x
kg(-1) x min(-1) for the AARN pack and 18.20 (7.84) ml x kg(-1) x min(-1) for the
traditional pack]. The findings of the present study suggest that a load carriage
system that allows the load to be distributed between the back and font of the
trunk is more appropriate for carrying relatively heavy loads than a system that
loads the back only.
PMID- 10774873
TI - Velocity specificity in early training of the knee extensors after anterior
cruciate ligament reconstruction.
AB - Resistance-training velocity specificity is known to occur in isotonic training
of uninjured subjects and in isokinetic training of injured patients. Whether
velocity specificity occurs with isotonic training in injured patients has not
been tested, despite the common use of this exercise mode in patients. Thirty-two
patients recovering from anterior cruciate ligament reconstruction (ACLR) surgery
were tested at approximately 2 and 6 weeks after surgery. The isokinetic
injured/uninjured strength ratios of the knee extensors were compared for the
test velocities of 60 degrees x s(-1) and 210 degrees x s(-1), as assessed before
and after a 4-week training period. Isotonic training of the knee extensors at 60
degrees x s(-1) was applied in formal sessions three times per week. The
isokinetic injured/uninjured strength ratios were compared for the two test
velocities, and there was no indication that training velocity specificity
occurred in these patients. Possible reasons for this finding, which contrasts
with previous work, are discussed.
PMID- 10774874
TI - Effects of hypobaric hypoxia on vascular endothelial growth factor and the acute
phase response in subjects who are susceptible to high-altitude pulmonary oedema.
AB - In order to investigate whether vascular endothelial growth factor (VEGF) and
inflammatory pathways are activated during acute hypobaric hypoxia in subjects
who are susceptible to high-altitude pulmonary oedema (HAPE-S), seven HAPE-S and
five control subjects were exposed to simulated altitude corresponding to 4000 m
in a hypobaric chamber for 1 day. Peripheral venous blood was taken at 450 m
(Zurich level) and at 4000 m, and levels of erythropoietin (EPO), VEGF,
interleukin-6 (IL-6) and the acute-phase proteins complement C3 (C3), alpha1
antitrypsin (alpha1AT), transferrin (Tf) and C-reactive protein (CRP) were
measured. Peripheral arterial oxygen saturation (SaO2) was recorded. Chest
radiography was performed before and immediately after the experiment. EPO
increased during altitude exposure, correlating with SaO2, in both groups (r =
0.86, P < 0.001). Venous serum VEGF did not show any elevation despite a marked
decrease in SaO2 in the HAPE-S subjects [mean (SD) HAPE-S: 69.6 (9.1)%; controls:
78.7 (5.2)%]. C3 and alpha1AT levels increased in HAPE-S during hypobaric hypoxia
[from 0.94 (0.11) g/l to 1.07 (0.13) g/l, and from 1.16 (0.08) g/l to 1.49 (0.27)
g/l, respectively; P < 0.05], but remained within the clinical reference ranges.
No significant elevations of IL-6, Tf or CRP were observed in either group. The
post-exposure chest radiography revealed no signs of oedema. We conclude that
VEGF is not up-regulated in HAPE-S and thus does not seem to increase critically
pulmonary vascular permeability during the 1st day at high altitude. Furthermore,
our data provide evidence against a clinically relevant inflammation in the
initial phase of exposure to hypoxia in HAPE-S, although C3 and alpha1AT are
mildly induced.
PMID- 10774875
TI - Quadriceps-hamstring EMG activity during functional, closed kinetic chain
exercise to fatigue.
AB - It has been hypothesized that the ability of the neuromuscular system to co
contract muscles for joint stabilization may be impaired during the development
of fatigue. The purpose of this study was to examine muscle activation of the
quadriceps and hamstring muscles during a prolonged closed kinetic chain
exercise, the forward lunge. Eight males and two females [mean (SD) age 26.0
(2.3) years, height 177.2 (13.6) cm, body mass 82.8 (17.1) kg] with no prior knee
pathology volunteered for this study. Subjects performed repeated forward lunges
onto their dominant leg at the cadence of one full lunge cycle every 2 s, until
the point of volitional failure. Digital switches were positioned to record foot
strike and knee-strike of the lunge leg at the midpoint of the lunge, as well as
heel-strike upon return to stance. During the lunge performance, surface
electromyographic (EMG) signals of the vastus lateralis (VL), vastus medialis
(VM), biceps femoris (BF), and semitendinosus (ST) muscles of the supporting leg
were measured. Heart rate was also monitored every 30 s during the performance.
All EMG data were full-wave rectified, partitioned into up and down phases, and
integrated over the entire exercise period. The results demonstrated a
significant increase in activation of the VL, VM, and BF during performance of
the forward lunge to volitional failure (P < 0.05). No significant increase was
shown for the ST. Heart rate increased significantly over the course of the
lunge. These findings suggest that activation of the VL, VM, and BF muscles
occurs as a unit during performance of the forward lunge during both concentric
and eccentric lunge phases.
PMID- 10774876
TI - Effect of brief maximal exercise on circulating levels of interleukin-12.
AB - Interleukin-12 (IL-12) is a cytokine that was originally identified as natural
killer cell stimulatory factor. It induces the activity of T-helper 1 (Th1) cells
and exhibits strong anti-tumor activity. In this study, we studied the effects of
brief anaerobic maximal exercise on circulating levels of IL-12. Six healthy
males [mean (SD) 25.2 (2.6) years] performed a modified Wingate test exercise
(resistance 0.075 kg/kg of body mass). The exercise consisted of five bouts of
maximal cycling for 10 s, with rest intervals of 50 s between them. Blood samples
were taken before, immediately after, 30 min after, 60 min after and 120 min
after the exercise. Plasma concentrations of IL-12 were measured using an enzyme
linked immunosorbent assay. Data were corrected for hemoglobin and hematocrit
measurements. Plasma concentrations of IL-12 averaged [mean (SD)] 234.2 (40.9)
pg/ml before, 305.2 (62.1) pg/ml immediately after, 202.8 (24.2) pg/ml 30 min
after, 239.7 (35.1) pg/ml 60 min after, and 199.6 (49.2) pg/ml 120 min after the
exercise. We showed that plasma concentrations of IL-12 increased significantly
immediately after brief anaerobic maximal cycle ergometer exercise (P < 0.01).
PMID- 10774877
TI - Critical power of knee extension exercises does not depend upon maximal strength.
AB - A possible dependence of critical power (CP) and the Y-intercept of the
work/exhaustion time relationship (Y(intercept)) on maximal muscular strength of
the same muscle group has been studied in nine endurance-trained subjects, seven
gymnasts, and seven weight-lifters. CP was calculated as being equal to the slope
of the linear relationship between exhaustion time and the work performed at
exhaustion on a knee extension ergometer. Y(intercept) was equal to the intercept
between this relationship and the work axis. The muscular strength of the knee
was evaluated by measuring the torques exerted on a Biodex knee isokinetic
dynamometer at four angular velocities: 0 degrees x s(-1) (T0), 90 degrees x s(
1) (T90), 180 degrees x s(-1) (T180) and 240 degrees x s(-1) (T240). The results
of the present study do not support the hypothesis that CP depends upon maximal
strength. Indeed, CP was not correlated with T0, T90, T180 or T240 (?r? < 0.01).
Y(intercept) was significantly and positively correlated only with T90.
PMID- 10774878
TI - Prognostic implications of infarct size assessed by myocardial perfusion single
photon emission tomography.
PMID- 10774879
TI - Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of
somatostatin radiotracers selected for scintigraphic and radiotherapeutic use.
AB - In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method
for the visualisation of human endocrine tumours and their metastases. Recently,
several new, alternative somatostatin radioligands have been synthesised for
diagnostic and radiotherapeutic use in vivo. Since human tumours are known to
express various somatostatin receptor subtypes, it is mandatory to assess the
receptor subtype affinity profile of such somatostatin radiotracers. Using cell
lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and
sst5, we have evaluated the in vitro binding characteristics of labelled (indium,
yttrium, gallium) and unlabelled DOTA-[Tyr3]-octreotide, DOTA-octreotide, DOTA
lanreotide, DOTA-vapreotide, DTPA-[Tyr3]-octreotate and DOTA-[Tyr3]-octreotate.
Small structural modifications, chelator substitution or metal replacement were
shown to considerably affect the binding affinity. A marked improvement of sst2
affinity was found for Ga-DOTA-[Tyr3]-octreotide (IC50 2.5 nM) compared with the
Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the
same range was also found for In-DTPA-[Tyr3]-octreotate (IC50 1.3 nM) and for Y
DOTA-[Tyr3]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr3]-octreotate bound
at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold
improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA
octreotide compared with their Tyr3-containing analogue, suggesting that
replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the
octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14
fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had
the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased
binding affinity for sst3 and sst5 was observed for DOTA-[Tyr3]-octreotide, DOTA
lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked
changes in subtype affinity profiles are due not only to the different chemical
structures but also to the different charges and hydrophilicity of these
compounds. Interestingly, even the coordination geometry of the radiometal
complex remote from the pharmacophoric amino acids has a significant influence on
affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr3]-octreotide
or [Tyr3]-octreotate. Such changes in sst affinity profiles must be identified in
newly designed radiotracers used for somatostatin receptor scintigraphy in order
to correctly interpret in vivo scintigraphic data. These observations may
represent basic principles relevant to the development of other peptide
radioligands.
PMID- 10774880
TI - In vivo imaging of herpes simplex virus type 1 thymidine kinase gene expression:
early kinetics of radiolabelled FIAU.
AB - Previous studies have shown that the herpes simplex virus type 1 thymidine kinase
gene (HSV1-tk), in combination with appropriate radiolabelled substrates (e.g.
[I*]-2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil, I*-FIAU, where
the asterisk indicates that any of the various radioactive iodine isotopes can be
used), can be used as a reporter gene for in vivo monitoring of gene transfer and
expression. The aim of our study was to examine the early kinetics of I*-FIAU and
the possibility of utilising iodine-123-labelled FIAU for imaging of gene
expression. CMS-5 fibrosarcoma cells were transduced in vitro with the retroviral
vector STK containing the HSV1-tk gene. BALB/c mice were inoculated
subcutaneously with HSV1-tk(+) and tk(-) cells into both flanks. FAU (2'-fluoro
2'-deoxy-1-beta-D-arabinofuranosyluracil was radioiodinated (123I, 125I) using
the iodogen method. High-performance liquid chromatography purification resulted
in high specific activity and radiochemical purity for both tracers ([123I]FIAU
and [125I]FIAU). Biodistribution studies and gamma camera imaging were performed
at 0.5, 1, 2 and 4 h p.i. In addition, the genomic DNA of the tumours was
isolated for measurement of the activity accumulation resulting from the
[125I]FIAU incorporation. Biodistribution studies 0.5 h p.i. showed tumour/blood
and tumour/muscle ratios of 3.8 and 7.2, respectively, for the HSV1-tk(+)
tumours, and 0.6 and 1.2, respectively, for negative control tumours. Fast renal
elimination of the tracer from the body resulted in rapidly increasing
tumour/blood and tumour/muscle ratios which reached values of 32 and 88 at 4 h
p.i., respectively. Tracer clearance from blood was bi-exponential, with an
initial half-life of 0.6 h followed by a half-life of 4.6 h. The tracer half-life
in herpes simplex viral thymidine kinase-expressing tumours was 35.7 h. The
highest activity accumulation (20.3%+/-5.7% ID/g) in HSV1-tk(+) tumours was
observed 1 h p.i. At that time, about 46% of the total activity found in HSV1
tk(+) tumours was incorporated into genomic DNA. Planar gamma camera imaging
showed a distinct tracer accumulation as early as 0.5 h p.i., with an increase in
contrast over time. These results suggest that sufficient tumour/background
ratios for in vivo imaging of HSV1-tk expression with [123I]FIAU are reached as
early as 1 h p.i.
PMID- 10774881
TI - Technetium-99m labelled antimicrobial peptides discriminate between bacterial
infections and sterile inflammations.
AB - The aim of this study was to select technetium-99m labelled peptides that can
discriminate between bacterial infections and sterile inflammations. For this
purpose, we first assessed the binding of various 99mTc-labelled natural or
synthetic peptides, which are based on the sequence of the human antimicrobial
peptide ubiquicidin (UBI) or human lactoferrin (hLF), to bacteria and to
leucocytes in vitro. In order to select peptides that preferentially bind to
bacteria over host cells, radiolabelled peptides were injected into mice
intraperitoneally infected with Klebsiella pneumoniae (K. pneumoniae) and the
amount of radioactivity associated with the bacteria and with the leucocytes was
quantitated. The next phase focussed on discrimination between bacterial
infections and sterile inflammatory processes using 99mTc-labelled peptides in
mice intramuscularly infected with various bacteria (e.g. multi-drug-resistant
Staphylococcus aureus) and in animals that had been injected with
lipopolysaccharides (LPS) of bacterial origin to create a sterile inflammatory
process. Also, we studied the distribution of 99mTc-labelled UBI 29-41 and UBI 18
35 in rabbits having an experimental thigh muscle infection with K. pneumoniae
and in rabbits injected with LPS. Based on the results of our in vitro and in
vivo binding assays, two peptides, i.e. UBI 29-41 and UBI 18-35, were selected as
possible candidates for infection imaging. The radiolabelled peptides can detect
infections with both gram-positive and gram-negative bacteria in mice as early as
5-30 min after injection, with a target-to-non-target (T/NT) ratio between 2 and
3; maximum T/NT ratios were seen within 1 h after injection. In rabbits, high
T/NT ratios (>5) for 99mTc-labelled UBI 29-41 were observed from 1 h after
injection. No accumulation of the selected 99mTc-labelled UBI-derived peptides
was observed in thighs of mice and rabbits previously injected with LPS.
Scintigraphic investigation into the biodistribution of 99mTc-labelled UBI
peptides revealed that these peptides were rapidly removed from the circulation
by renal excretion. Similar data were observed for 99mTc-labelled defensin 1-3.
Our data for 99mTc-labelled hLF and related peptides indicate that these
compounds are less favourable for infection detection. Taken together, 99mTc
labelled UBI 18-35 and UBI 29-41 enable discrimination between bacterial
infections and sterile inflammatory processes in both mice and rabbits. Based on
their characteristics, we consider these peptides the candidates of preference
for detection of bacterial infections in man.
PMID- 10774882
TI - Clinical evaluation of no-carrier-added meta-[123I]iodobenzylguanidine for
myocardial scintigraphy.
AB - In clinical and research studies, images obtained using carrier-added meta
[123I]iodobenzylguanidine (c.a. [123I]MIBG) have shown quite variable quality,
with varying levels of uptake in lung, liver and mediastinum; this is a
significant problem for quantification of the myocardial uptake by means of
region ratios. First experimental and preliminary human data in respect of no
carrier-added (n.c.a.) [123I]MIBG are indicative of improved imaging quality. The
aim of the present study was to evaluate the clinical value of myocardial
scintigraphy with n.c.a. [123I]MIBG in patients with tachyarrhythmias. The study
population comprised 24 patients with tachyarrhythmogenic diseases routinely
studied by cardiac single-photon emission tomography (SPET) with [123I]MIBG.
Twelve of the 24 patients were studied with c.a. [123I]MIBG (seven females and
five males; mean age 42+/-13 years, range 20-60 years), whereas the other 12 were
studied with n.c.a. [123I]MIBG (ten females, two males; mean age 41+/-11 years,
range 18-60 years, P=NS). For quantification of the specific uptake in the
different organs, count ratios were calculated on SPET images acquired 4 h p.i.
Visual analysis of all [123I]MIBG scans showed improved image quality (improved
contrast between heart and neighbouring organs) in n.c.a. studies as compared
with c.a. studies. A significantly higher heart/left atrial blood ratio was found
in the n.c.a. studies as compared with the c.a. studies (10.3+/-3.2 vs 5.3+/-1.3,
P=0.0003); furthermore, significantly higher heart/lung and heart/liver ratios
(2.5+/-0.6 vs 1.5+/-0.3, P=0.0002, and 0.8+/-0.2 vs 0.6+/-0.1, P=0.0006,
respectively) were obtained in the c.a. studies, whereas lung/left atrial blood
and liver/left atrial blood ratios showed no significant differences (4.2+/-1.3
vs 3.6+/-1.1, P=0.39, and 13.7+/-5.2 vs 9.6+/-2.2, P=0.21, respectively). In
conclusion, the use of n.c.a. [123I]MIBG yields a significantly higher myocardial
uptake associated with improvement in contrast between the heart and neighbouring
organs and is therefore superior to the commercially available c.a. [123I]MIBG
for use in clinical and research studies of the myocardial presynaptic
sympathetic nervous system. Furthermore, our data indicate that for
quantification the use of a left atrial blood reference region of interest, which
is only available on SPET studies, is to be recommended.
PMID- 10774883
TI - Detection of viable cortical neurons using benzodiazepine receptor imaging after
reversible focal ischaemia in rats: comparison with regional cerebral blood flow.
AB - To elucidate the utility of benzodiazepine receptor imaging for the detection of
viable cortical neurons, dual-tracer autoradiography using iodine-125 iomazenil
(IMZ) and iodine-123 N-isopropyl-4-iodoamphetamine (IMP) was performed in a model
of reversible focal ischaemia during the acute and subacute phases. The right
middle cerebral artery of anaesthetized rats was occluded for 60 min using an
intraluminal filament and reperfused. In the acute phase study, 125I-IMZ (370
kBq) was injected via the femoral vein at 2 h after reperfusion, and 123I-IMP (37
MBq) was injected at 50 min post-injection. Rats were sacrificed 10 min after the
injection of 123I-IMP. In the subacute phase study, the same procedure was
performed at 5 days after reperfusion. In the acute phase, the IMP uptake was
significantly decreased in almost all areas of the lesioned hemisphere, an
exception being the cerebellum; however, the IMZ uptake was significantly
decreased only in ischaemic cores. The discrepancy between IMZ and IMP uptake was
observed in the lateral neocortex and the lateral caudate putamen (CPu), which
were most frequently damaged in this ischaemic model. In the subacute phase, the
IMZ uptake in lesioned rats was significantly decreased only in the parietal lobe
and hippocampus, though the IMP uptake was decreased in many regions of lesioned
hemispheres (the frontal, parietal cortex, CPu, hippocampus and thalamus).
Histopathological findings indicated that both the IMP and the IMZ uptake was
markedly decreased in necrotic areas. Although the IMP uptake was significantly
decreased in the ischaemic areas, the IMZ uptake was maintained in these areas.
These results suggest that benzodiazepine receptor imaging is superior to
regional cerebral blood flow imaging for the detection of viable cortical neurons
in both the acute and subacute phases of ischaemia.
PMID- 10774884
TI - Indium-111 labelled platelet scintigraphy can predict the immunological origin of
fever in patients on dialysis carrying a non-functioning renal allograft.
AB - The purpose of this study was to evaluate the usefulness of labelled platelet
scintigraphy in the differential diagnosis of a prolonged febrile syndrome (PFS)
in patients on dialysis carrying a non-functioning renal allograft. We
prospectively performed an indium-111 mercaptopyridine-labelled platelet scan on
91 patients (54 men, 37 women; mean age 39.6+/-12 years). The mean duration of
PFS was 35 days (range 7-122). Forty-six of the 91 patients underwent steroid
therapy (2-10 mg/day). Platelet labelling was carried out following Thakur's
method. Platelet scans were performed 48 h after reinjection of labelled
platelets. The platelet uptake index (PUI) was calculated by dividing the
cpm/pixel in the allograft ROI by cpm/pixel in a mirror background ROI. The final
diagnosis of PFS was established depending on the outcome after treatment. In
61/91 patients the fever had an immunological origin because it disappeared after
graft embolisation or transplantectomy. In 30/91 patients the PFS disappeared
after antibiotic therapy (non-immunological origin). The PUI in patients with
immunological PFS was 1.80+/-0.7, while in patients with non-immunological PFS it
was 1.12+/-0.1 (P<0.05). When a PUI of > or =1.5 was considered as the threshold
to establish PFS of immunological origin, the sensitivity of platelet scan was
76%, the specificity 100%, and the negative and positive predictive values 69%
and 100%, respectively. In patients classified with immunological PFS who
underwent steroid therapy, the PUI was significantly lower than in patients
without steroids (P<0.05). These results suggest that 111In-labelled platelet
scintigraphy can accurately predict an immunological PFS in patients on dialysis
carrying a non-functioning renal allograft. Therapy with steroids could reduce
the sensitivity of 111In-labelled platelet scintigraphy in detecting
immunological PFS.
PMID- 10774885
TI - Non-invasive estimation of myocardial efficiency using positron emission
tomography and carbon-11 acetate--comparison between the normal and failing human
heart.
AB - The clearance kinetics of carbon-11 acetate, assessed by positron emission
tomography (PET), can be combined with measurements of ventricular function for
non-invasive estimation of myocardial oxygen consumption and efficiency. In the
present study, this approach was applied to gain further insights into
alterations in the failing heart by comparison with results obtained in normals.
We studied ten patients with idiopathic dilated cardiomyopathy (DCM) and 11
healthy normals by dynamic PET with 11C-acetate and either tomographic
radionuclide ventriculography or cine magnetic resonance imaging. A "stroke work
index" (SWI) was calculated by: SWI = systolic blood pressure x stroke
volume/body surface area. To estimate myocardial efficiency, a "work-metabolic
index" (WMI) was then obtained as follows: WMI = SWI x heart rate/k(mono), where
k(mono) is the washout constant for 11C-acetate derived from monoexponential
fitting. In DCM patients, left ventricular ejection fraction was 19%+/-10% and
end-diastolic volume was 92+/-28 ml/m2 (vs 64%+/-7% and 55+/-8 ml/m2 in normals,
P<0.001). Myocardial oxidative metabolism, reflected by k(mono), was
significantly lower compared with that in normals (0.040+/-0.011/min vs 0.060+/
0.015/min; P<0.003). The SWI (1674+/-761 vs 4736+/-895 mmHg x ml/m2; P<0.001) and
the WMI as an estimate of efficiency (2.98+/-1.30 vs 6.20+/-2.25 x 10(6) mmHg x
ml/m2; P<0.001) were lower in DCM patients, too. Overall, the WMI correlated
positively with ejection parameters (r=0.73, P<0.001 for ejection fraction;
r=0.93, P<0.001 for stroke volume), and inversely with systemic vascular
resistance (r=-0.77; P<0.001). There was a weak positive correlation between WMI
and end-diastolic volume in normals (r=0.45; P=0.17), while in DCM patients, a
non-significant negative correlation coefficient (r=-0.21; P=0.57) was obtained.
In conclusion non-invasive estimates of oxygen consumption and efficiency in the
failing heart were reduced compared with those in normals. Estimates of
efficiency increased with increasing contractile performance, and decreased with
increasing ventricular afterload. In contrast to normals, the failing heart was
not able to respond with an increase in efficiency to increasing ventricular
volume. The present data support the usefulness of the WMI for non-invasive
characterization of cardiac efficiency and may serve as a background for improved
evaluation of medical therapy for heart failure.
PMID- 10774886
TI - Relation between exercise-induced ventricular arrhythmias and myocardial
perfusion abnormalities in patients with intermediate pretest probability of
coronary artery disease.
AB - The significance of exercise-induced ventricular arrhythmias (VAs) is largely
dependent on the clinical characteristics of the studied population. The relation
between exercise-induced VAs and myocardial perfusion abnormalities has not yet
been evaluated in a homogeneous patient population with intermediate probability
of coronary artery disease (CAD). We studied 302 patients (mean age 54+/-9 years,
152 men and 150 women) with intermediate pretest probability of CAD (range=0.25
0.80, mean=0.43+/-0.20) by upright bicycle exercise stress test in conjunction
with technetium-99m single-photon emission tomography (SPET) imaging. Exercise
induced VAs (frequent or complex premature ventricular contractions or
ventricular tachycardia) occurred in 65 patients (22%). No significant difference
was found between patients with and patient without VAs regarding the pretest
probability of CAD (0.45+/-0.21 vs 0.43+/-0.20). Patients with exercise-induced
VAs had a higher prevalence of perfusion abnormalities (52% vs 26%, P=0.002) and
ischaemic electrocardiographic changes (31% vs 16%, P<0.05) compared to patients
without VAs. A higher prevalence of perfusion abnormalities in patients with VAs
was observed in both men (67% vs 35%, P<0.01) and women (38% vs 16%, P<0.05).
However, the positive predictive value of exercise-induced VAs for the presence
of myocardial perfusion abnormalities was higher in men than in women (67% vs
38%, P<0.05). The presence of abnormal myocardial perfusion was the only
independent predictor of exercise-induced VAs (OR 2.2; 95% CI, 1.2-4.2) by
multivariate analysis of clinical and stress test variables. It is concluded that
in patients with intermediate pretest probability of CAD, exercise-induced VAs
are predictive of a higher prevalence of myocardial perfusion abnormalities in
both men and women. However, the positive predictive value of exercise-induced
VAs for perfusion abnormalities is higher in men. Because of the underestimation
of ischaemia by electrocardiographic changes, exercise-induced VAs should be
interpreted as a marker of a higher probability of CAD.
PMID- 10774887
TI - Influence of exercise rehabilitation on myocardial perfusion and sympathetic
heart innervation in ischaemic heart disease.
AB - Exercise rehabilitation improves the clinical status in ischaemic heart disease.
The purpose of this study was to assess the influence of exercise rehabilitation
on myocardial perfusion and sympathetic heart innervation. Sixteen patients with
ischaemic heart disease and previous myocardial infarction were investigated by
means of exercise/rest tetrofosmin and metaiodobenzylguanidine (MIBG)
exercise/rest single-photon emission tomography (SPET) studies, before and 6
months after starting an exercise rehabilitation programme. Tomograms were
divided into 15 segments, and these were grouped into five myocardial anatomical
regions. Regional uptake of both tracers was quantified and expressed as a
percentage of maximum peak activity. The percentage < or =55% was chosen to
evaluate defect size, and the results were expressed as a percentage of left
ventricular mass. Areas with perfused and denervated myocardium and areas with
ischaemic myocardium were calculated. In addition, regions with <75% of peak
activity in the exercise perfusion study at baseline were divided into two groups
according to whether there was an increase in peak activity of >10% (representing
reversible regional defects) or an increase of <10% (representing fixed regional
defects) in the rest study. These percentages were compared with the percentages
obtained in the innervation study, and with the percentages obtained in
exercise/rest perfusion and innervation studies performed 6 months after starting
rehabilitation. Myocardial perfusion defects were significantly smaller than
myocardial innervation defects before and 6 months after starting exercise
rehabilitation. The area of ischaemia 6 months after starting exercise
rehabilitation was significantly smaller than that before rehabilitation (0.31%+/
1.4% vs 1.4%+/-1.6%, P<0.01). The size of innervation defects and the area of
perfused and denervated myocardium did not show significant differences between
the two studies performed before and 6 months after starting exercise
rehabilitation. In reversible regional defects the percentage of peak activity
was significantly increased 6 months after starting exercise rehabilitation in
exercise and rest studies (P<0.001), while in fixed regional defects it was
significantly increased only in exercise studies (P<0.001). There was no
significant change in the regional MIBG percentages. We conclude that in
ischaemic heart disease, exercise rehabilitation over a period of 6 months
improves myocardial perfusion, but does not cause changes in sympathetic
myocardial innervation.
PMID- 10774888
TI - Influence of drugs on myocardial iodine-123 metaiodobenzylguanidine uptake in
rabbit myocardium.
AB - About 15 years ago, iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging
was introduced for the evaluation of myocardial sympathetic nerve function. Two
uptake mechanisms for MIBG have so far been identified: uptake type I, a
saturable, energy-dependent mechanism, and uptake type II, a non-saturable,
energy-independent mechanism. We incubated isolated rabbit myocardial tissue
samples with 123I-MIBG in order to assess the uptake characteristics and the
influence of varying incubation conditions. Furthermore, we examined the effects
of several drugs and uptake inhibitors on the myocardial uptake of MIBG. The in
vitro myocardial uptake of MIBG reached a steady plateau at 23.87%+/-3.63% after
1 h, i.e. a concentration gradient of 10, in a thermo-independent manner within a
concentration range from 1.5 to 1500 microM. This indicates an unsaturable uptake
process in the tested concentrations. Preincubation with the following drugs
caused a significant inhibitory effect on myocardial MIBG uptake: haloperidol,
levomepromazine, metoprolol, labetalol and clomipramine. According to our
findings, the uptake mechanism seems to be an unspecific process, but the
concentration gradient of 10 makes passive diffusion unlikely. Further studies
with uptake-II-blocking substances as well as with isolated myocardial cells will
be needed to clarify the nature of the myocardial MIBG uptake mechanism.
PMID- 10774889
TI - [123I]FP-CIT binding in rat brain after acute and sub-chronic administration of
dopaminergic medication.
AB - The recently developed radioligand [123I]FP-CIT is suitable for clinical single
photon emission tomography (SPET) imaging of the dopamine (DA) transporter in
vivo. To date it has remained unclear whether dopaminergic medication influences
the striatal [123I]FP-CIT binding. The purpose of this study was to investigate
the influence of this medication on [123I]FP-CIT binding in the brain. We used an
animal model in which we administered dopaminomimetics, antipsychotics and an
antidepressant. In vivo [123I]FP-CIT binding to the DA and serotonin transporters
was evaluated after subchronic and acute administration of the drugs. The
administered medication induced small changes in striatal [123I]FP-CIT binding
which were not statistically significant. As expected, the DA reuptake blocker
GBR 12,909 induced a significant decrease in [123I]FP-CIT binding. [123I]FP-CIT
binding in the serotonin-rich hypothalamus was decreased only after acute
administration of fluvoxamine. The results of this study suggest that
dopaminergic medication will not affect the results of DA transporter SPET
imaging with [123I]FP-CIT.
PMID- 10774890
TI - Technetium-99m ethylene dicysteine: a new renal tubular function agent.
AB - Technetium-99m ethylene dicysteine (EC), a metabolite of ethylene cysteine dimer
(ECD), is a new technetium-labelled renal tubular function tracer introduced as
an alternative to ortho-iodohippurate (OIH) and with imaging qualities similar to
99mTc-mercaptoacetyltriglycine (MAG3). The elimination of 99mTc-EC is principally
via active tubular transport. It is available in lyophilised kit form which can
be easily prepared at room temperature, and the compound remains stable for at
least 8 h. Both in normal individuals and in patients, plasma clearance of 99mTc
EC has been reported to be around 0.75 of OIH clearance. Thus there is a very
strict correlation between 99mTc-EC and OIH clearance, and several algorithms are
available to estimate OIH clearance from 99mTc-EC clearance. The renal extraction
ratio of 99mTc-EC is 0.70. The distribution volume of 99mTc-EC is twice that of
99mTc-MAG3 (20% of body weight) and slightly higher than that of OIH. The plasma
protein-bound fraction of 99mTc-EC (30%) is significantly lower than that of
99mTc-MAG3 and OIH. The same applies to red blood cell binding of 99mTc-EC
(5.7%). There is negligible uptake in the liver and intestines. Within 1 h 70% of
99mTc-EC is excreted in the urine. 99mTc-EC provides the same scintigraphic
information as 99mTc-MAG3. The lower liver activity makes 99mTc-EC particularly
attractive in patients with renal failure. The 99mTc-EC clearance can be
accurately estimated from a single plasma sample obtained at 54 min after
injection. In conclusion, 99mTc-EC is a suitable renal imaging agent and for some
applications is even more attractive than OIH: it provides an index of tubular
function and yields high-quality images. The labelling procedure is easy,
radiochemical purity is high and the complex is stable for a long time. The
extent to which 99mTc-EC is adopted for clinical use will ultimately depend upon
its cost and availability.
PMID- 10774891
TI - Apoptotic cell death: its implications for imaging in the next millennium.
AB - Apoptosis, also known as programmed cell death, is an indispensable component of
normal human growth and development, immunoregulation and homeostasis. Apoptosis
is nature's primary opponent of cell proliferation and growth. Strict
coordination of these two phenomena is essential not only in normal physiology
and regulation but in the prevention of disease. Programmed cell death causes
susceptible cells to undergo a series of stereotypical enzymatic and morphologic
changes governed by ubiquitous endogenous biologic machinery encoded by the human
genome. Many of these changes can be readily exploited to create macroscopic
images using existing technologies such as lipid proton magnetic resonance (MR)
spectroscopy, diffusion-weighted MR imaging and radionuclide receptor imaging
with radiolabeled annexin V. In this review the cellular phenomenon of apoptotic
cell death and the imaging methods which can detect the process in vitro and in
vivo are first discussed. Thereafter an outline is provided of the role of
apoptosis in the pathophysiology of clinical disorders including stroke,
neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia
and inflammation, myelodysplastic disorders, organ transplantation, and oncology,
in which imaging may play a critical role in diagnosis and patient management.
Objective imaging markers of apoptosis may soon become measures of therapeutic
success or failure in both current and future treatment paradigms. Since
apoptosis is a major factor in many diseases, quantification and monitoring the
process could become important in clinical decision making.
PMID- 10774892
TI - Time to reconsider the PIOPED criteria?
PMID- 10774893
TI - We miss our krypton.
PMID- 10774894
TI - The practice of public health in the next few years.
PMID- 10774895
TI - Health care systems in transition III: the Indian subcontinent.
PMID- 10774896
TI - Health care systems in transition III. Bangladesh, Part I. An overview of the
health care system in Bangladesh.
PMID- 10774897
TI - Health care systems in transition III. Bangladesh, Part II. Bangladesh's response
to HIV-AIDS.
PMID- 10774898
TI - Health care systems in transition III. Sri Lanka, Part I. An overview of Sri
Lanka's health care system.
PMID- 10774899
TI - Health care systems in transition III. Sri Lanka, Part II. The current status of
HIV-AIDS in Sri Lanka.
PMID- 10774900
TI - Health care systems in transition III. India, Part I. The Indian experience.
PMID- 10774901
TI - Health care systems in transition III. India, Part II. The current status of HIV
AIDS in India.
PMID- 10774902
TI - Health care systems in transition III. Pakistan, Part I. An overview of the
health care system in Pakistan.
PMID- 10774903
TI - Health care systems in transition III. Pakistan, Part II. Pakistan's response to
HIV-AIDS.
PMID- 10774904
TI - For debate: the virtuous public health physician.
AB - This paper argues that although public health physicians have shown interest in
ethical dilemmas relating to specific problems within the specialty, few have
addressed the central ethical dilemma in public health, namely the conflict
between the rights of the individual and the responsibilities of society for all
its members. The paper reviews a number of public health programmes, where
different approaches have been taken to this central dilemma. It then examines a
number of schools of ethics, in an attempt to resolve the problem. Of these, only
virtue ethics, perhaps supported by the insights of feminism and the ethics of
care, appear to help with an irreconcilable conflict. The paper then makes an
attempt to apply the concept of virtue ethics in public health medicine and to
answer the question, 'what would a virtuous public health physician look like?'
Finally, it lists some of the consequences of such an approach.
PMID- 10774905
TI - Congenital anomalies in Glasgow between 1982 and 1989 and chromium waste.
AB - BACKGROUND: The former site of a factory in Glasgow and nearby areas were found
to be heavily polluted by chromium waste. This gave rise to local concern on
possible health effects. As part of a wider study answering this concern,
congenital malformations were investigated. METHODS: A descriptive geographical
study was carried out. A 10 km circle centred on the factory site was designated
as the study area and subdivided into one circle of 2 km radius and eight 1 km
wide rings. Significant differences in relative risk between the circle and rings
and a decreasing trend of risk with distance from the centre would point towards
a teratogenic role of the chromium waste. Relative risks by rings were obtained
by Poisson regression. Relative risks by deprivation categories were also
obtained, with most results adjusted by these categories. RESULTS: Significant
differences in risk appeared, with the area containing the polluted soil having
the lowest risk. Aggregations of rings showed a central area with a relatively
low risk, followed by an intermediate one with the highest risk and an external
area with risk also high. Relative risk appeared to increase sharply between the
most affluent category and the rest, then growing steadily with increasing
deprivation but decreasing slightly for the most deprived. CONCLUSIONS: Relative
risk shows a significant peak in an area 2-4 km away from the pollutant, which
does not point towards a possible teratogenic effect of the chromium waste.
Relative risk of congenital malformations for the more affluent sector of the
population appeared to be markedly lower than that for the rest.
PMID- 10774906
TI - Trends in sickness benefits in Great Britain and the contribution of mental
disorders.
AB - BACKGROUND: Government benefits paid to those unfit for work or the work market
as a result of ill health have been rising dramatically in Great Britain, in
parallel with increases throughout Europe and North America. Psychological
conditions are known to be an important cause of sickness absence. This study set
out to examine trends in government sickness and invalidity benefits in Britain
between April 1984 and April 1995. The importance of mental disorders as a cause
of 'incapacity' (the condition for which benefits are paid) was examined.
METHODS: Data from the Department of Social Security were used to chart trends in
incapacity according to gender, age group, employment category and cause. An
exploratory ecological analysis of associations between regional rates of
incapacity and socio-economic and health indices was also undertaken using
correlation analysis and multiple regression. RESULTS: Steadily increasing rates
of incapacity were observed, primarily reflecting increases in the longer-term
'invalidity' benefit. The non-employed made up a rising proportion of recipients.
Regional incapacity rate was most strongly associated with socio-economic
factors, particularly social class. Mental disorders were the second most
numerous causal category and consisted mainly of milder conditions, namely
depressive and neurotic disorders. CONCLUSION: The dramatic increase in
incapacity benefits is unlikely to be attributable to changes in population size
or structure. It contrasts with improvements in the objective health status of
the population. Mental disorders, and particularly milder conditions, account for
a substantial and increasing amount of incapacity. The data are consistent with
the hypothesis that sickness benefits increasingly represent disguised
unemployment.
PMID- 10774907
TI - Patients and procedures in short-stay independent hospitals in England and Wales,
1997-1998.
AB - BACKGROUND: Private hospitals' activities are not routinely reported, so what
services they provide and for whom is not known. This study describes the
clientele and case-mix of independent hospitals in England and Wales in 1997
1998. METHOD: Person, clinical and funding data were collected on samples of
patients admitted to 215 of 221 independent hospitals open in 1997-1998. Sample
numbers were weighted to reflect sampling duration, region, season and non
response. RESULTS: A total of 37,434 sampled records represented 828,422
admissions: 406,843 in-patients (5 per cent fewer than in 1992-1993) and 421,580
day cases (69 per cent more); 806,509 were residents of England and Wales (up 24
per cent); 16,628 came from overseas (down 20 per cent). Numbers increased in all
age groups except children; 25 per cent were 65 or over (18 per cent in 1992
1993). The commonest procedures were abortion (11 per cent), endoscopy of the
gastro-intestinal tract (10 per cent) or joints (5 per cent), lens operations (5
per cent), hernia repairs (3 per cent), and other common National Health Service
(NHS) elective operations. The NHS funded 84,561 patients (11 per cent of the
total) including 41,942 non-abortion cases (6 per cent). A total of 540,996 (76
per cent) paid through insurance; 119,101 (17 per cent) were self-funded
including 30 per cent of the over-75s. Ninety-five per cent of patients went
home, 0.3 per cent died and 0.2 per cent were transferred to NHS hospitals.
CONCLUSIONS: Demand for short-stay independent hospital care is rising. The
clientele is becoming older, and readier to pay out of pocket. Clinical activity
is mainly surgical and similar to NHS elective surgical demand. One year's
caseload equals 10 weeks' elective admissions to NHS hospitals, in that sense
relieving the NHS. The scale of transfer to NHS hospitals (three per day) is
small.
PMID- 10774908
TI - Working to keep school children healthy: the complementary roles of school staff
and school nurses.
AB - BACKGROUND: Against a background of future uncertainty for school nursing and
little previous research, this study aimed to identify and describe the
distinctive role of the school nurse in working to keep school children healthy.
Particular attention was paid to the 'interface' between nursing and the health
related work of teachers. The research was carried out in four health authority
areas in England. METHODS: Seventy-eight semi-structured interviews were carried
out with a range of respondents: school nurses, school Heads and teachers, health
authority purchasers and NHS Trust managers. Seven focus group discussions were
held with parents and eight with young people of secondary school age. RESULTS:
Four key elements of the school nurse role were identified: safeguarding the
health and welfare of children; health promotion; a pupils' confidante; and
family support. In each of these aspects of work, nurses and teachers had shared
or complementary roles. An over-arching role for the school nurse as 'health
adviser' to pupils, parents and teachers was also identified. Despite these
common elements, emphasis in the practice of individual school nurses varied
widely. Difficulties for school nurses in developing their role were identified.
Parents and young people saw school as an appropriate setting for health-related
work. CONCLUSION: The research identified key components of the school nursing
role and the complementary roles of nurses and school staff. To optimize school
nurses' contribution to child health, a more strategic approach is required, in
partnership with education, along with research into the effectiveness of school
nursing interventions.
PMID- 10774909
TI - The link between major risk factors and important categories of admission in an
ageing cohort.
AB - BACKGROUND: Record linkage of routine hospital data to population-based research
findings presents an opportunity to explore the relationships between classical
risk factors and hospital activity. METHODS: The objectives of this study were to
examine, in Paisley and Renfrew, the effect of risk factor variables on the
likelihood of experiencing an acute hospital admission with six major medical
conditions. The subjects were 8,349 women and 7,057 men, aged 45-64 in the early
to mid-1970s. The main outcome measures were acute hospital admission with
principal diagnosis of: any malignant neoplasm; malignant neoplasm of trachea,
bronchus and lung; ischaemic heart disease; respiratory disease; cerebrovascular
disease; or diabetes mellitus. RESULTS: Smokers were almost eight times more
likely to be admitted with lung cancer and, to a lesser extent, were more likely
to be admitted for the other conditions investigated with the exception of
diabetes mellitus. Forced expiratory volume was also an independent risk factor
for admission with lung cancer and strokes. Higher levels of cholesterol were
associated with increased risk of admission with ischaemic heart disease but less
with cancer (including lung cancer). With the exception of admissions for
cerebrovascular disease, deprivation category was found to have no independent
effect on the likelihood of experiencing any of the morbidity outcomes examined.
CONCLUSIONS: These data confirm that associations first established between risk
factors and mortality outcomes (e.g. smoking and lung cancer) are also found
between risk factors and hospital admissions for the same causes. This in itself
is unremarkable, but the results are of interest for three reasons. First, they
illustrate the potential of record linkage to map the effects of risk factors.
Second, they demonstrate the size of the effect risk factors have on the risk of
admission. Third, they provide a surprising finding that deprivation category
does not act as an independent risk factor for the majority of the categories of
admission investigated.
PMID- 10774910
TI - The effect of home visiting programmes on uptake of childhood immunization: a
systematic review and meta-analysis.
AB - BACKGROUND: The aim of the study was to evaluate the effectiveness of home
visiting programmes on the uptake of childhood immunization. METHODS: A
systematic review was carried out of the literature of controlled studies
evaluating home visiting programmes involving at least one post-natal visit,
which included tasks within the remit of British health visiting and reporting
outcomes relevant to British health visiting. Eleven studies were considered,
nine of which used socio-economically disadvantaged families. The outcome measure
was uptake of a range of childhood immunizations. RESULTS: Eleven studies
reported uptake of immunization. Effect sizes from nine studies were included in
the meta-analysis. Fixed effects models demonstrated a significant effect of home
visiting for all studies and also for several subgroups of studies, but with
significant heterogeneity of effect sizes. A random effects model failed to
demonstrate an effect of home visiting. CONCLUSIONS: Home visiting programmes
have not been shown to be effective in increasing the uptake of immunization.
Other methods of increasing uptake and reducing inequalities in uptake will need
to be explored.
PMID- 10774911
TI - Escherichia coli O157:H7; an economic assessment of an outbreak.
AB - BACKGROUND: The aim of the study was to assess the impact of an outbreak of
Escherichia coli O157:H7 that occurred in 1994 in a rural community, with a
population of approximately 107,000, to the west of Edinburgh. METHODS: The
impact of the outbreak was assessed during the acute phase of the illness and in
the subsequent 12 months. The method involved three surveys of confirmed cases
using general practice notes, hospital records and interviews with cases. Key
persons involved in the investigation and control of the outbreak were also
interviewed. The impact of the illness on cases and their families was estimated
and the resources used to treat cases and to control the outbreak were costed and
long-term costs projected. RESULTS: There were 71 cases whose ages ranged from 7
months to 84 years. The mortality rate was 1.4 per hundred cases. There were 10
cases of haemolytic uraemic syndrome (HUS) and one case of thrombotic
thrombocytopenia purpura (TTP). Two children were on long-term dialysis. Co
morbidity involving the immune system was associated with hospital admission. The
illness lasted on average 6.9 weeks. Twenty-six per cent of cases reported
symptoms 12 months later. The average cost per HUS case was 62,353 pound
sterlings, the TTP case cost 21,422 pound sterlings, non-HUS and non-TTP cases
cost 1,030 pound sterlings. The costs of investigating and controlling the
outbreak were 171,848 pound sterlings. The costs of cases projected over 30 years
were 11.9 million pound sterlings, or 168,032 pound sterlings per case.
CONCLUSIONS: The impact on the health of cases was considerable and the costs
were high. Every effort should be made to prevent the disease and to identify and
control outbreaks quickly.
PMID- 10774912
TI - A cost analysis of neonatal care in the UK: results from a multicentre study.
ECSURF Study Group.
AB - BACKGROUND: A number of papers have recently been published examining the
magnitude of scale economies in neonatal care and the level of activity at which
these become attainable. Although these agree there is scope for economies in the
production of neonatal care, they debate the extent to which such economies are
attainable and how they might best be detected. A major multicentre study of
neonatal units in the United Kingdom has produced costing and activity data
allowing these issues to be explored afresh. METHODS: A postal questionnaire was
used to determine neonatal cost and activity levels in 57 UK neonatal units.
Costs for the financial year 1990-1991 related to clinical staffing, support
(such as pathology) and overheads (such as heat, light, power and administrative
overheads). Activity related to the total number of care days provided and the
number of these that were intensive in nature. All data were scrutinized to
ensure consistent definitions. A multivariate regression analysis was used to
investigate the relationship between costs and activity. RESULTS: A double-log
function relating variations in total costs to total days, case-mix and an
interaction term provided the best fit to the data. The analysis suggests that
significant economies of scale are possible within the observed range of
provision of intensive care. CONCLUSIONS: Significant economies of scale may be
attainable. Nevertheless, these results should be carefully interpreted. In
particular, the costs of neonatal care should not be examined in isolation but in
relation to outcomes. In certain instances, units of inefficient scale but
acceptable outcome may be defensible on grounds of ease of access.
PMID- 10774913
TI - Outbreaks of influenza A in nursing homes in Sheffield during the 1997-1998
season: implications for diagnosis and control.
AB - Three recent outbreaks of influenza A in nursing and residential homes in
Sheffield were characterized by high attack rates among both residents and staff,
and a high mortality rate among residents. The epidemiology of the outbreaks was
unusual in that all three occurred towards the end of a quiet influenza season,
against a generally low level of community activity, and involved strains of
influenza that were not included in the current season's vaccine. The outbreak
investigation was aided by the use of a novel rapid diagnostic technique. In
future the combination of vaccination, surveillance, rapid diagnosis and new
antineuraminidase drugs should improve prospects for control of influenza within
closed communities.
PMID- 10774914
TI - Quarterly Communicable Disease Review July to September 1999. From the PHLS
Communicable Disease Surveillance Centre.
PMID- 10774915
TI - Ethnic groups and our healthier nation: whither the information base?
PMID- 10774916
TI - Probing metal-complexes with metallothioneins by reversed phase microbore
chromatography and capillary zone electrophoresis coupled with inductively
coupled plasma and electrospray mass spectrometry.
AB - Four different hyphenated techniques: microbore reversed phase (RP) HPLC-ICP MS,
CZE-ICP MS, RP HPLC-ES MS and CZE-ES MS were investigated for the
characterization of metallothionein-metal complexes under neutral pH conditions.
Particular attention was given to the differentiation between metallothionein and
artifact signals, identification of mixed-metal complexes, and the validity of
the molecular mass as the identification parameter of the different MT iso- and
sub-isoforms. Despite the similar morphology of chromatograms and
electrophoregrams mass spectrometry revealed different origin of the apparently
corresponding peaks. The performance of the four above mentioned techniques was
characterized using the example of rabbit liver MT-1 preparation. Reversed-phase
HPLC with post-column acidification prior to ES MS was judged to be the most
versatile technique for the characterization of metal complexes with
metallothioneins but other techniques offer valuable auxiliary information.
PMID- 10774917
TI - Application of electroanalytical methods to the characterization of
metallothioneins and related molecules.
AB - Electroanalytical methods have been applied to the characterization and to the
study of complexing properties of several Cd,Zn metallothioneins (MT) of
different mammalian origin, rabbit and rat liver and horse kidney and human
foetal liver and adult kidney. Differential pulse polarography (DPP) has been
selected as the most suitable technique for distinguishing the chemical form of
compounds and, assuming a diffusion controlled mechanism, monitoring the
evolution of different species as a function of parameters, such as the solution
pH and the gradual addition of cations, cadmium and/or zinc, initially contained
in the studied molecules. Due to the fact that the metallothioneins structure is
complex and often not perfectly known, the peptidic fragment Lys-Cys-Thr-Cys-Cys
Ala (56-61) MT-1 (FT) of the mouse liver has been taken as a model for MT
characterization. The study of FT alone and in the presence of Cd and/or Zn,
using several electroanalytical methods has been very useful for the
investigation of adsorption-diffusion processes and for the identification and
elucidation of electrochemical systems. The interpretation of voltammetric data
is very often not easy. For some cases, proper interpretation can be made using
chemometric techniques. Multivariate factor analysis has been applied to the
electroanalytical investigation of the complexing properties between cadmium
and/or zinc and FT, using results obtained by DPP and linear sweep voltammetry.
For more complex systems, like MT, the application of chemometry becomes more
complex.
PMID- 10774918
TI - Voltammetry on mercury and carbon electrodes as a tool for studies of
metallothionein interactions with metal ions.
AB - Rabbit liver Cd-metallothionein (CdMT) and Cd-complex of synthetically prepared
pentapeptide (gamma-Glu-Cys)2-Gly were studied as examples of animal and plant
metallothioneins. Using hanging mercury electrode, cathodic stripping voltammetry
after adsorptive accumulation of the Cd(II)-SR complex at different potentials,
is suitable for estimating changes occurring in metal coordination due to the
presence of metal ions such as Zn2+, Cu2+, Hg2+ or excessive Cd2+. Conditions
under which similar behaviour can be observed for both CdMT and Cd-pentapeptide
complex are specified. On carbon electrodes, detailed study of reduction
processes of Cd(II)-SR complexes is prevented by occurrence of a large catalytic
current; oxidation processes are more suitable for study at these electrodes.
Carbon composite paste electrode (10% SiO2) allows deposition of Cd(II)-SR
complex during its reduction, as was demonstrated with Cd-cysteine, CdMT or Cd
pentapeptide complex. After deposition, oxidation peak of the uncomplexed Cd2+
ions and one or two oxidation peaks corresponding to a formation of the RS-Cd(II)
complex are observed. Also, similarly as on Hg electrode, it was observed that
excessive Cd2+ or Zn2+ ions influence oxidation peaks of the RS-Cd(II) complex
formation. Combination of measurements on mercury electrode and composite paste
electrode is recommended for studies of metallothionein interactions with metal
ions or other metal complexes.
PMID- 10774920
TI - Metallothioneins in marine mammals.
AB - Metallothioneins (MTs) have been detected in livers and kidneys of 10 marine
mammals species (Pinnipeds and Odontocetes). Characterization of renal MTs of
striped dolphin has shown that the protein has two isoforms (MT-1 and MT-2) with
a molecular weight estimated around 6,800. MT concentrations also vary widely in
marine mammals tissues (from 58 to 1,200 microg x g(-1) ww) underlying the
numerous parameters involved: physiological status, pregnancy, age, diet. The
participation of this protein in metal detoxification has been investigated since
high levels of cadmium (Cd) and mercury (Hg) have been measured in livers and
kidneys of marine mammals. It has been suggested that those animals can mitigate
at least in part, the toxic effects of Cd and Hg through binding to MTs. The
percentage of the cytosolic Cd bound to MTs can reach almost 100%. On the
contrary, the percentage of hepatic and renal Hg bound to MT is very low
(generally less than 10%) and this metal is mainly associated with selenium
(HgSe) under a detoxified form in the insoluble fraction of the tissues. MTs
appear to play a minor role in the binding and detoxification of Hg by marine
mammals. On the contrary, close and dynamic interactions occur between Cd and
MTs. Cytosolic MTs appear as a potential short term way of detoxification of Cd
accumulated from diet. Long-term detoxification would imply a sequestration of
the metal under a precipitated form (e.g. in lysosomes).
PMID- 10774919
TI - Advantages and disadvantages of voltammetric method in studying cadmium
metallothionein interactions.
AB - A sensitive and chemical species-selective technique of differential pulse anodic
stripping voltammetry (DPASV) was applied in studying the cadmium-metallothionein
(Cd-MT) interaction. The amperometric titrations of the purified MT20 and MT10
fractions, isolated by verified biochemical procedures from the digestive gland
of cadmium-exposed mussels Mytilus galloprovincialis, with Cd2+ ions were
performed in the buffered sodium chloride solution of 0.59 M ionic strength, pH
7.9 and 25 degrees C. Applying the DPASV method at various cadmium to
metallothionein ratio several groups of chemical species were recorded. The data
on the available ligand concentration to complex cadmium ions (CL), the apparent
concentration stability constants (K,) of the respective complexes and the
reliability of the determined complexing parameters are discussed. In quantifying
the Cd-MT interaction the interference of dithiotreitol (DTT), which is used as
the reducing agent in isolation and purification of MTs, is documented.
PMID- 10774921
TI - Bivalve metallothionein as a biomarker of aquatic ecosystem pollution by trace
metals: limits and perspectives.
AB - Owing to their induction by metals metallothioneins (MTs) have been proposed as
biomarkers of the metallic contamination of the environment. On the other hand,
bivalves are regarded as very convenient bioindicators of the aquatic ecosystems
and an extensive literature has been dedicated to their response to metals. Among
studies supporting the involvement of MTs in metal detoxification some
discrepancy appears due to inter- and intra-specific variations, or to
heterogeneous exposure conditions. A lesser number of papers are dealing with the
use of metallothionein levels as biomarkers, and sometimes they evidence that
natural factors influencing metallothionein synthesis have to be taken into
account before final conclusions can been drawn. Moreover, there is still a large
number of non-intercalibrated protocols used to quantify amounts of
metallothioneins in organisms. As comparisons are necessary to assess the
relative abundance of metallothioneins in a studied species, more work has to be
completed before such comparisons could be validated. In the present paper we
wish to establish the limits of the use of mollusc metallothioneins as a
biomarker of aquatic ecosystem contamination by trace metals, using published and
recent data as support for our conclusions and perspectives.
PMID- 10774922
TI - Metallothioneins (MTs) in marine molluscs.
AB - The presence of MTs in marine molluscs was firstly hypothesized in oyster and in
mussel during the seventies, however mussel's and oysters' MTs were completely
purified and sequenced rather later. Already from the first studies it was
evident that the purification of molluscan MTs was more difficult than in
mammals. Mussel's MTs are characterized by the presence of a monomeric and a
dimeric form. Several physiological and biochemical parameters can influence the
concentration and the isolation of MT from molluscan tissues. Remarkable
variations in MT isolation and quantification might depend on the purification
and storage protocol. Because of possible artefacts due to the isolation
procedure the establishment of a standard protocol for MT quantification in
marine mollusc is still an important goal. In a few species the presence of very
low molecular weight metal binding ligands has also been reported, in these cases
it cannot be excluded that the native MT has been cleaved by the action of
proteases. This review aims to report: 1) importance of a standard method for MT
purification and quantification in molluscs; 2) distribution of MT among
molluscan species; 3) data concerning oyster's and mussel's MTs which are the two
more deeply investigated marine molluscs; 4) biotic and abiotic factors
influencing MT concentration, and 5) biological role of MT and use of MT as a
biochemical marker of heavy metal pollution.
PMID- 10774923
TI - Metallothioneins in terrestrial invertebrates: structural aspects, biological
significance and implications for their use as biomarkers.
AB - During the last few years the subject of metallothioneins (MTs) in terrestrial
invertebrates has gained increasing attention. One reason for this may be that
terrestrial invertebrates provide new insights into the biological diversity of
MTs, with the potential of discovering alternative models of structural and
functional relationships. Four groups of terrestrial invertebrates have been
studied in detail, namely nematodes, insects, snails and earthworms, with the
present article focusing on MTs from the latter two groups. Snails are
interesting because they possess distinct MT isoforms involved in different metal
specific tasks. In the Roman snail (Helix pomatia), for example, one isoform is
predominantly expressed in the midgut gland, accounting for the accumulation,
binding and detoxification of cadmium. The second isoform, which is present in
the snail's mantle, is substantially different regarding its primary structure.
Furthermore, it binds nearly exclusively copper, and thus is probably involved in
the homeostatic regulation of essential trace elements. Earthworm MTs merit our
attention because of another peculiarity: they seem to be much more unstable than
snail MTs, particularly under conventional conditions of preparation. The cDNA of
the brandling worm (Eisenia foetida), for instance, codes for a putative MT,
which is about twice the size of the actual protein. The isolated MT peptide
binds four Cd2+ ions and represents a one-domain MT entity that is stable and
functional in vitro. This strongly suggests that earthworm MTs are either
posttranslationally modified, or subjected to enzymatic cleavage during
preparation. Both snail and earthworm MTs are inducible by metal exposure,
especially by cadmium, thus supporting the idea of using them as potential
biomarkers for environmental metal pollution. Whilst snail MTs have already been
tested in this respect with some success, the use of earthworm MTs as biomarkers
still remains to be evaluated, especially in the light of the unknown
significance of their posttranslational instability.
PMID- 10774924
TI - Nuclear localization of metallothionein during cell proliferation and
differentiation.
AB - Although MT is detected as a cytoplasmic protein in hepatocytes of adult liver,
it can be localized in the hepatocyte nuclei in human fetal liver bound to zinc
and copper. Both nuclear and cytoplasmic localization of MT have been observed in
several human tumours, especially in regions of high proliferation. Transient co
localization of zinc and MT has been shown in differentiating myoblast and 3T3-L1
fibroblasts, and during the G1-/S-phase progression in cell cycle. Several
mechanisms have been proposed for the import and retention of MT in the nucleus,
including signal transduction pathways. The high levels of MT in the nucleus of
cells under certain conditions may be related to the increased requirement for
zinc for several metallo-enzymes and transcription factors during rapid growth.
The function of nuclear MT may be to protect the cell from DNA damage and
apoptosis, and also to regulate gene expression during certain stages of cell
cycle.
PMID- 10774925
TI - Nuclear trafficking of metallothionein: possible mechanisms and current
knowledge.
AB - Although metallothionein (MT) was first characterized as a cytoplasmic protein,
it is now known to be localized in the nucleus depending on various cellular
events, such as cell proliferation. The suggested roles of karyophilic MT are: to
1) regulate the biological pool of the essential metals zinc (Zn) and copper
(Cu), and especially to supply Zn to Zn-requiring enzymes/transcription factors
through activated cell proliferation, and 2) to protect DNA from oxidative stress
including those caused by antitumor agents. Translocation of MT to the nucleus
might be mediated, depending on cellular events, by a structural change in MT
itself or through the appearance of nuclear binding proteins. Supporting the
former possibility, MT is known to have some structural features, namely, highly
conserved lysyl residues, which are anticipated to act as nuclear localization
signal (NLS). In addition, concomitant appearance of non-acetylated MT, without
post-translational acetylation, and nuclear localization of MT, have been
reported. Supporting the latter possibility, MT-partner proteins might
participate in the nuclear trafficking of MT (i.e., an MT-nuclear translocator or
a nuclear chaperone of MT). We now provide an overview of the current knowledge
on both mechanisms.
PMID- 10774926
TI - Metals and cellular signaling in mammalian cells.
AB - A number of heavy metals are known to be essential for life, but most of these
can also be toxic to cells under certain circumstances, or at elevated levels.
Metals can directly induce gene expression through the actions of metal
responsive transcription factors. However, metals can also influence the response
to non-metal extracellular signals. Cells respond to extracellular signals
through a variety of different, but often interacting, signal transduction
pathways. Metals can alter cell behaviour by interacting with transcription
factors and transduction molecules, many of which are dependent on metals
(primarily zinc) for their action. In addition, metals can affect cells in more
nonspecific ways, for example, by inducing a generalized stress response or by
cross-linking cell surface thiol groups. The prominent role of zinc in signal
transduction combined with low intracellular free zinc levels has lead to the
speculation that cellular signaling and gene expression may be regulated, in
part, by zinc bioavailability. Experimental modification of the levels of the
intracellular metal-binding protein, metallothionein (MT), results in altered
responsiveness to extracellular signals. This observation suggests that MT is
capable of influencing gene expression, perhaps by regulating the level of
intracellular free zinc.
PMID- 10774927
TI - Intracellular sequestration of anti-tumor drugs by metallothionein.
AB - Acquired drug resistance is one of the most important problems in cancer
chemotherapy. One of the mechanisms proposed to contribute to this phenomenon is
the sequestration of alkylating agents by metallothionein (MT) in vivo. In this
study cadmium-induced human bladder tumor T24 cells were exposed to the
therapeutic agents chlorambucil and melphalan. MT-2a, was shown by capillary
electrophoresis to comprise 56% of the MT isoforms in induced cells, and drug
adducts of MT-2a were isolated and characterized by HPLC and electrospray
ionization mass spectrometry. One to four equivalents of drug were found to be
covalently adducted. Major binding sites on metallothionein were located in the C
terminal domain by peptide mapping, consistent with previous studies in vitro.
PMID- 10774928
TI - Metal transfer as a mechanism for metallothionein-mediated metal detoxification.
AB - High kinetic reactivity and high metal affinity of the metal-binding sites of
metallothionein are characteristics that would facilitate involvement of the
thionein-zinc metallothionein couple in metal transfer or exchange reactions.
Studies demonstrating thionein-metallothionein-mediated activation or inhibition
of various zinc metalloenzymes and transcription factors provide support for a
potential role for metallothionein in metal transfer reactions with receptor
molecules. Although a role in basal zinc regulation is currently a topic of
debate, less controversial is a role for metallothionein in the detoxification of
metals such as cadmium. The toxicity of metals can, in part, be due to
adventitious binding to charged sites of target proteins or the displacement of
zinc bound to zinc metalloproteins. Zinc metallothionein has the capability of
repairing such structures through abstraction of a toxic metal in the former case
or through a reciprocal metal transfer reaction that involves abstraction of the
toxic metal and donation of the essential metal zinc in the latter. This would
confer on metallothionein an active role in the protective response to metal
toxicity, rather than a passive one that is solely dependent on the high metal
affinity for binding free metal ions. The efficacy of such a mechanism for metal
detoxification has been demonstrated with enzymes, actin and zinc finger
proteins. With zinc finger proteins, zinc metallothionein can restore both
altered secondary structure and inhibited DNA-binding function to functional
states through a zinc for cadmium exchange.
PMID- 10774929
TI - Antioxidant role of metallothioneins: a comparative overview.
AB - Metallothioneins (MTs) are sulfhydryl-rich proteins binding essential and non
essential heavy metals. MTs display in vitro oxyradical scavenging capacity,
suggesting that they may specifically neutralize hydroxyl radicals. Yet, this is
probably an oversimplified view, as MTs represent a superfamily of widely
differentiated metalloproteins. MT antioxidant properties mainly derive from
sulfhydryl nucleophilicity, but also from metal complexation. Binding of
transition metals displaying Fenton reactivity (Fe,Cu) can reduce oxidative
stress, whereas their release exacerbates it. In vertebrates, MT gene promoters
contain metal (MRE) and glucocorticoid response elements (GRE), Sp and AP
sequences, but also antioxidant response elements (ARE). MT neosynthesis is
induced by heavy metals, cytokines, hormones, but also by different oxidants and
prooxidants. Accordingly, MT overexpression increases the resistance of tissues
and cells to oxidative stress. As for invertebrates, data from the mussel show
that MT can actually protect against oxidative stress, but is poorly inducible by
oxidants. In yeast, there is a Cu(I)-MT that in contrast to mammalCu-MT exhibits
antioxidant activity, possibly due to differences in metal binding domains.
Finally, as the relevance of redox processes in cell signaling is becoming more
and more evident, a search for MT effects on redox signaling could represent a
turning point in the understanding of the functional role of these protein.
PMID- 10774930
TI - Metallothionein isoform gene expression in zinc-treated human peripheral blood
lymphocytes.
AB - Zinc plays an important role in the maintenance of the immune system. While the
mechanisms of zinc ions interaction with immune cells are still poorly
understood, a striking concurrent effect of zinc is the induction of the
biosynthesis of metallothioneins (MT), a group of low molecular weight, cysteine
rich metal-binding proteins, believed to play a role in zinc homeostasis. In
humans, they are encoded by a family of genes, located at 16q13 containing 10
functional and 7 non-functional MT isoforms. In this work we analyzed the
spectrum of different isoforms in human peripheral blood lymphocytes. It was
demonstrated by RT-PCR that the MT-2a, MT-1a, MT-1e, MT-1f, MT-1g, MT-1h and MT
1x genes are expressed in these cells and that these isoforms are further
upregulated by zinc, as examined by quantitative RT-PCR. Surprisingly, RT-PCR
also showed the presence, even in unstimulated cells, of MT-3 transcripts, which
are considered as brain-specific isoforms. In an effort to determine whether
MTmRNA abundance is translated into MT protein, MT isolated from zinc-treated
lymphocytes by gel chromatography was resolved into 7 metal-binding fractions by
using RP-HPLC. Automatic Edman-degradation of the different fractions revealed
the presence of MT-2a, MT-1a, MT-1e, MT-1f, MT-1g, MT-1h, MT-1x and MT-1k, an
isoform which until now was only identified at the level of protein in human
liver and kidney tissue.
PMID- 10774931
TI - Effect of gamma irradiation on liver metallothionein synthesis and lipid
peroxidation in rats.
AB - Several studies have recently shown that metallothionein (MT), a protein
characterized by a high thiol content and that binds Zn2+ and Cu+, might be
involved in the protection against oxidative stress and can act as a free radical
scavenger. Oxidative stresses, such as irradiation, increase lipid peroxidation
(LP) and subsequent tissue damage through free radical production. The induction
of hepatic MT synthesis by gamma-irradiation (20 Gy) at 8, 24, 30 and 48 hrs.
post-irradiation in two different age groups of Sprague-Dawley rats (39-40 and 48
49 days old) was studied. LP measured by the thiobarbituric acid reactive
substances (TBARS) assay and Cu and Zn levels in liver have also been determined.
In the younger group, the gamma-irradiation induced hepatic MT synthesis and
increased LP that peaked 24 hrs. after irradiation. During the first 30 hrs. post
irradiation, a positive and statistically significant correlation between hepatic
MT content and LP level in liver was found. In the older group, liver MT
synthesis was only increased 1.7-fold and LP levels were not altered at 24 hrs.
post-irradiation compared with sham-irradiated rats. Therefore it appears that LP
is not necessary for induction of MT synthesis by gamma-irradiation.
PMID- 10774932
TI - Lack of involvement of metallothionein expression in pancreatic carcinogenesis by
N-nitrosobis (2-oxopropyl) amine in Syrian hamsters.
AB - The possible involvement of metallothionein (MT) in pancreatic ductal
carcinogenesis by N-nitrosobis(2-oxopropyl) amine (BOP) in hamsters was
investigated. Hamsters received subcutaneous (s.c.) injections with dissolved BOP
to 70 mg/kg body weight (BW) followed 7 days later by 20 mg/kg BW BOP and they
were sacrificed at 4, 11, 16 and 27 weeks after the beginning of the experiment.
MT expression was studied by immunohistochemistry and MT contents were assayed
biochemically. Pancreatic ductal hyperplasias were developed from 11 weeks on and
carcinomas from 16 weeks on, the incidence of the latter reaching 73% at the end
of experiment. However, while normal appearing proliferating duct cells were
sometimes positive, MT expression was not evident in hyperplasia (H), atypical
hyperplasia (AH) or carcinoma (C), and MT contents did not significantly differ
in pancreas of hamsters receiving saline or BOP at any time point. The results
suggest that MT is not involved in pancreatic duct carcinogenesis. However, the
presence of MT in proliferating ducts not related to carcinogenesis may suggest
some unknown role for MT in cellular homeostasis.
PMID- 10774933
TI - Toxicological aspects of metallothionein.
AB - Metallothionein (MT) is expressed to a certain extent in almost all mammalian
tissues. The biological significance of MT is related to its various forms MT-1,
MT-2, MT-3 and MT4. For MT-1 several isoforms of the protein exist and it is
likely that these isoforms are related to various functions involved in
developmental processes occurring at various stages of gestation. Toxicokinetics
and biochemistry of essential and toxic metals such as cadmium, zinc, mercury and
copper in organs e.g. kidney, CNS, are often related to metallothionein. It is
debated whether there is a relation or not for other metals e.g. selenium and
bismuth. For the toxicokinetics of cadmium, MT plays an important role. By
expanding techniques from experimental toxicology and biochemistry to include
molecular biology methods, more specific and relevant studies can be performed of
the actual role and biological function of MT. The present paper on toxicological
aspects of metallothionein, presents an overview and evaluation of present
knowledge concerning differences among organs and within organs of the expression
of MT and how this affects tissue sensitivity to toxicity.
PMID- 10774934
TI - Metallothionein in human disease.
AB - Evidence concerning a role for metallothionein (MT) in human disease is reviewed.
Current knowledge of MT is juxtaposed with our understanding of the pathogenesis
of disease. MT is known to modulate three fundamental processes: 1) the release
of gaseous mediators such as hydroxyl radical or nitric oxide; 2) apoptosis, and
3) the binding and exchange of heavy metals such as zinc, cadmium or copper. The
capability to specifically manipulate MT levels in cells and in mice is beginning
to provide answers regarding how MT could impact complex disease scenarios.
Associations among MT and several diseases, including cancer, circulatory and
septic shock, coronary artery disease, and Alzheimer's disease have been made.
Strong evidence exists that MT modulates the immune system. The primary function
of MT remains unknown.
PMID- 10774935
TI - A morphologic study of dermatofibrosarcoma protuberans: expansion of a histologic
profile.
AB - Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor of
intermediate malignancy characterized by a distinctive storiform growth pattern
and frequent local recurrences. In this study, we retrospectively reviewed 48
cases of DFSP diagnosed at the Cleveland Clinic Foundation between 1970 and 1999
to determine the prevalence of morphologic variations including the presence of
giant cell fibroblastoma (GCF)-like areas, multinucleated giant cells,
hypercellular zones and fibrosarcomatous change. RESULTS: The cohort consisted of
42 patients (20 males, 22 females) with a median age at diagnosis of 40 years
(range: 10-73 years). Forty-one primary tumors and seven recurrences were
evaluated from these 42 patients. Tumor sites included the trunk (22 cases), head
and neck (8 cases), upper extremities (7 cases) and lower extremities (6 cases).
GCF-like areas were identified in seven (14.6%), multinucleated giant cells in
ten (20.8%), hypercellular zones in 12 (25%) and fibrosarcomatous change in six
(12.5%) cases, respectively. Combinations included giant cells and GCF-like areas
(two cases), giant cells and hypercellular zone (two cases), and GCF-like areas
and hypercellular zones (one case). Our findings suggest that DFSP has a wider
range of morphologic features, including GCF-like areas, multinucleated giant
cells, hypercellular zones and fibrosarcomatous change, than has been previously
recognized in the literature.
PMID- 10774936
TI - Immunohistochemical analysis of cytokeratin expression in reactive eccrine
syringofibroadenoma-like lesion: a comparative study with eccrine
syringofibroadenoma.
AB - In addition to solitary eccrine syringofibroadenoma (ESFA), there is another type
of ESFA which is associated with underlying dermatoses (reactive ESFA-like
lesion). Five lesions in 4 patients of reactive ESFA-like lesion were analyzed by
an immunohistochemical method using 13 kinds of anti-cytokeratin (CK) antibodies.
Two cases of solitary ESFA were also studied by the same procedure for
comparison. Suprabasal staining pattern of AE1 and MNF116, which stain CKs 6, 16
and 17, markers of hyperproliferative state, was observed diffusely in 5 lesions
of reactive ESFA-like lesions except for focal negative staining in one case, and
was observed focally in one case of solitary ESFA. Furthermore, differentiation
specific cytokeratin expression was reduced in 3 of 5 lesions of reactive ESFA
like lesions. Both ESFA and reactive ESFA showed basically similar
immunoreactivity suggesting differentiation toward the dermal duct. The above
slight difference in immunoreactivity between both lesions may be explained due
to inflammatory infiltrates associated with underlying dermatoses.
PMID- 10774937
TI - Immunohistochemical evaluation of basal cell carcinoma and trichepithelioma using
Bcl-2, Ki67, PCNA and P53.
AB - Most basal cell neoplasms with follicular differentiation represent a
heterogenous group of tumors. Although may arise anywhere in the skin, these
neoplasms commonly occur on the head and neck regions. The majority of these
neoplasms are basal cell carcinomas (BCC) and trichoepitheliomas (TE).
Overlapping histopathologic features between these benign and malignant tumors
are occasionally seen which may create problems in rendering a definitive
diagnosis. The intent of this investigation was two-fold: 1) to examine whether
there are quantitative differences of the cellular expression of Bcl-2, Ki67,
PCNA and P53 between BCC and TE; and 2) to examine the value of these
immunostains in differentiating between BCC and TE. Twenty cases of BCC were
stained with antibodies for Bcl-2, Ki67, PCNA and P53. The positive cell indices
and staining characteristic of these immunostains were compared with those of 20
cases of TE. The cell indices for each group were analyzed statistically
utilizing the analysis of variance (ANOVA) technique. Intensity and patterns of
Bcl-2 and P53 expression were similar between BCC and TE. The ANOVA analysis
showed no statistically significant differences between cell indices for cases
stained with antibodies for Bcl-2 and P53 (p=0.49 and p=0.87 respectively) in the
two neoplastic groups. There were intense labelling and generalized patterns of
Ki67 and PCNA expression in BCC. Conversly, Ki67- and PCNA-labelled cells were
much fewer in TEs than those noted in BCCs. Additionally, Ki67- and PCNA-positive
cells were limited to the peripheral layers of the neoplastic islands of TEs.
There were statistically significant differences between cell indices for cases
stained with antibodies for Ki67 and PCNA (p=0.02 and p=0.05 respectively) in the
two neoplastic groups. BCC and TE exhibited comparable expressions of Bcl-2 and
P53 with similar intensity of labelling and patterns of distribution. This
suggests possible similar mechanisms of growth regulation in both neoplasms.
However, Ki67 and PCNA labelling was noted with significantly increased numbers
and recognizably different patterns in BCCs compared to TEs. This may help
explain the significant capabilities in tumor proliferation and the aggressive
behavior of BCC compared to the limited growth potential of TE. Additionally,
Ki67 and PCNA staining intensity and characteristics may have some value in
differentiating between BCC and TE.
PMID- 10774938
TI - Hyperthermia to normal human skin in vivo upregulates heat shock proteins 27, 60,
72i and 90.
AB - This study was performed to test the hypothesis that expression of heat shock
proteins (HSPs) exhibits a spatially selective response within intact human skin
following in vivo exposure to thermal stress. This response is believed to
protect cells and tissues from further damage. Using Western blotting and
immunohistochemistry, we studied the expression of a range of HSPs in normal
human skin of 5 subjects prior to and following heating in vivo. The skin was
heated to 41 +/- 0.5 degrees C for 1 h and biopsies were taken at 4, 8 and 24 h
and from control, untreated skin. HSPs 27, 60, 72i, 90, 110 and heat shock
constitutive (HSC)70 were expressed in normal skin, but the extent and
distribution of these HSPs showed considerable variation. HSP27, 60 and 72i were
found predominantly in the epidermis, whereas HSC70 showed weak epidermal
staining but strong dermal expression. Heating the skin in vivo resulted in an
increased skin content of HSP27, 60, 72i and 90, with maximal increase at 24 h
following hyperthermia, while the skin content of HSC70 and HSP110 were
unchanged. Significant increases in the content of HSP72i and HSP90 had occurred
by 4 h following hyperthermia, with a mean +/-SEM of 206 +/- 50% and 197 +/- 38%
of the control, untreated values, respectively (p<0.05). These findings indicate
the complexity of HSP dynamics in human skin, and suggest that heating within the
experimental range may protect the skin from further stresses for at least 24 h.
PMID- 10774939
TI - Failure of detection of mucin in the clear halos around the epidermotropic
lymphocytes in mycosis fungoides.
AB - Epidermotropic lymphocytes in mycosis fungoides typically reside in clear
lacunae. The material forming this space is unknown. Thirty specimens from 30
patients with mycosis fungoides were stained with alcian blue, modified Mowry's
colloidal iron and mucicarmine to determine if some form of mucin could be
identified. Using these stains, no form of mucin was noted in the lacunae
surrounding the epidermotropic lymphocytes of mycosis fungoides. The cause of the
clear spaces around epidermotropic lymphocytes in mycosis fungoides remains
unexplained, but is unlikely to represent mucin deposition.
PMID- 10774940
TI - Epithelioid sarcoma arising on the nose of a child: a case report and review of
the literature.
AB - A 4-year-old boy presented with a 6-month history of a red papule on the nasal
septum. Physical examination was otherwise unremarkable. A biopsy specimen showed
an epithelioid sarcoma characterized by nodular collections of epithelioid tumor
cells with central, tumor cell necrosis. By immunohistochemistry the tumor cells
were positive for cytokeratin, epithelial membrane antigen, vimentin, and CD34,
but negative for S-100, CD31, factor VIII-related antigen, CD68, actin, desmin
and myoglobin. Epithelioid sarcoma is an uncommon tumor of uncertain histogenesis
that typically arises in the extremities of young adults. Both the age of our
patient and the location of his tumor are unusual, emphasizing the spectrum of
presentations that may occur with epithelioid sarcoma. Epithelioid sarcoma should
be considered in the differential diagnosis of granulomatous diseases and
epithelioid tumors of children, even in unusual locations.
PMID- 10774941
TI - A case of localized follicular hamartoma: an ultrastructural and
immunohistochemical study.
AB - We report the case of a 22-year-old woman with a nevoid plaque that we termed
localized follicular hamartoma. The plaque was noticed at puberty on a unilateral
site of the face and scalp. Clinically, it revealed numerous, skin-colored to
light brown papules alone and in groups, occasionally bearing a single hair.
Histologically, branched epithelial nests of squamoid and/or basaloid cells were
revealed in connection with the interfollicular epidermis and the upper portions
of hair follicles, of which the lower portions showed normal structures.
Immunohistochemically, the epithelial nests showed the keratin expression
consisted with that of the infundibular epithelium. S-100-positive cells were
found in the epithelial nests and the stroma. Factor XIIIa-positive dendritic
cells were numerous in adjacent to the epithelial nests. Ultrastructurally,
immature melanocytes with a small number of premelanosomes and Merkel cells were
found in the nests. Stromal dendritic cells showed the adherent features of the
cytoplasmic processes to anchoring fibrils or basal lamina of the epithelial
nests. From these findings, our case is a hamartoma, which seems to be an
abortive growth of secondary hair germs with a limited differentiation to the
upper follicular portion.
PMID- 10774942
TI - Mixed syringocystadenoma papilliferum and papillary eccrine adenoma occurring in
a scrotal condyloma.
AB - This paper describes an unusual appendage tumour with mixed elements of
syringocystadenoma papilliferum (SCAP) and papillary eccrine adenoma (PEA)
occurring in a scrotal condyloma. The occurrence of SCAP in association with a
condyloma is an unusual event; however, the presence of SCAP in association with
PEA is of greater significance.
PMID- 10774943
TI - Expression of alpha3 beta1 integrin in suprabasal layers of the epidermis of
melanocytic tumors is due to epithelial hyperproliferation.
PMID- 10774944
TI - Apolipoprotein E polymorphism and central nervous system tumors: correlation with
cell proliferation indices and clinical outcome.
AB - AIMS: This study was designed to determine whether the polymorphism of
apolipoprotein E (apoE), one of the key regulatory proteins in cholesterol
metabolism, is related to varying susceptibility to central nervous system (CNS)
neoplasms, and to evaluate any possible interaction between this polymorphism and
tumor cell proliferation or clinical outcome. METHODS AND RESULTS: 53 CNS tumors
were selected. Follow-up and survival data were available for 36 patients. ApoE
genotypes and cell proliferation indices (nucleolar organizer regions, MIB-1,
PCNA, p53) were determined from paraffin-embedded tissue by standard methods.
Each of the indices of cell proliferation correlated positively with tumor grade
and negatively with duration of clinical follow-up and survival. There was a non
significant trend for apoE epsilon2 allele carriers to have high-grade tumors and
apoE epsilon4 allele carriers to have low-grade tumors. Possession of apoE
epsilon4 was associated with a more advanced age of disease presentation (p <
0.01) and a longer duration of follow-up (p < 0.04). No significant correlations
were found between possession of either apoE epsilon2 or apoE epsilon4 alleles
and indices of cell proliferation. CONCLUSIONS: These preliminary findings
suggest that possession of apoE epsilon4 allele may correspond to a more
favorable clinical course in terms of more advanced age of disease presentation,
and longer duration of follow-up and survival in patients with CNS neoplasms.
PMID- 10774945
TI - Olfactory neuroepithelioma arising from the olfactory placode.
AB - The patient was a 54-year-old man, who had lost his sense of smell 6 years
previously and had started to become forgetful about 6 months prior to presenting
at hospital. MRI admission showed a large multicystic tumor with Gd-DTPA
enhancement extending from the anterior cranial fossa through the sphenoid sinus
and into the nasal cavity. Histopathological examination revealed extensive
proliferation of small round cells that were divided by connective tissue septae.
The tumor cells occasionally formed tubular structures, although no basement
membranes were present. On immunostaining, round tumor cells were positive for
neuron-specific enolase, synaptophysin, and chromogranin A, while cells forming
tubules were positive for AE 1 and CAM 5.2. Almost all of the tumor cells were
positive for Ber-EP4, and some of the epithelioid cells surrounding the tubular
structures were also positive for luteinizing hormone-releasing hormone (LH-RH).
Electron microscopy demonstrated sporadic intercellular junctions, many
microtubules in the tumor cell processes, and clear- and dense-cored vesicles in
the cytoplasm. Based on the results, this case appears to be the first documented
neuroepithelioma with Ber-EP4- and LH-RH-positive cells arising from the
olfactory placode.
PMID- 10774946
TI - Inclusion body myositis (IBM).
AB - Clinical, histological, immunohistochemical and ultrastructural features of 5
cases of inclusion body myositis -4 sporadic (s-IBM) and one hereditary (h-IBM)
form are described. These patients (3 men, 2 women) had chronic progressive
weakness of varying severity in all 4 extremities with sparing of cranial
muscles. Elevation of CPK was noted in 2 patients. Electromyography revealed
features of myopathy in 4 and additional neurogenic changes in 2 subjects.
Clinical diagnosis was often other than inclusion body myositis. Presence of
characteristic eosinophilic inclusions within the vacuoles established the
diagnosis. The inclusions were congophilic and showed positivity to ubiquitin,
beta-amyloid and SMI-31 in the sporadic cases while congophila was absent in the
hereditary form. Immunostaining to hyperphosphorylated-tau was negative in both s
IBM and h-IBM. Membraneous whorls were observed at ultrastructural level. None of
the patients improved with steroids and trial with other immunosuppressants was
unsuccessful.
PMID- 10774947
TI - Effects of prenatal ethanol exposure on neuronal migration, neuronogenesis and
brain myelination in the mice brain.
AB - BACKGROUND: One of the most severe consequences of maternal alcohol consumption
is the damage to the developing central nervous system. MATERIAL AND METHODS: To
evaluate the effect of prenatal alcohol exposure on neuronal migration,
neuronogenesis and myelination in the brain, pregnant BALB/C mice were maintained
on either liquid diets containing ethanol (12 g/kg body weight) beginning on
gestation day 6 or isocoloric diet (control group). The dams were sacrificed on
gestation day 17 and the brain sections of the pups were analyzed using
immunohistochemical method to evaluate the number of neurons, oligodendrioglial
expression of myelin basic protein (MBP) and neuronal expression of neural cell
adhesion molecule (NCAM). RESULTS: Ethanol-exposed pups revealed significantly
weaker expression of MBP compared to the control group. In contrast, no
significant difference of NCAM expression and neuronal cell count were present
between ethanol-exposed pups and the control group. CONCLUSION: These data
demonstrate that alcohol exposure affects the level of MBP expression,
consequently causing a reduction in brain myelination that may lead to neuronal
dysfunction. The ineffectiveness of prenatal alcohol exposure on the number of
neurons in contrast to the previous reports might be due to the adequate sampling
of areas for cell counting. Although there is a view that NCAM is involved both
directly and indirectly in neuronal cell migration, we speculate that alcohol
neuroembryotoxicity uncouples this relationship. Other adhesion molecules, such
as L1, or extracellular matrix proteins, such as laminin, would be other
candidates for investigation.
PMID- 10774948
TI - Aqueductal stenosis and hydrocephalus in an infant due to aspergillus infection.
AB - Aqueductal stenosis is a common cause of hydrocephalus during infancy. We report
on an infant born with aplasia cutis congenita at the scalp vertex and
hypoplastic left heart syndrome developing systemic aspergillosis after cardiac
surgery. The infant died at the age of 76 days despite systemic antimycotic
therapy with a combination of flucytosine and amphotericin B. Therapy started at
post-operative day 17 and was also applied intrathecally. Post-mortem examination
revealed meningitis, multiple brain aspergillomas and microabscesses with focal
ependymitis, focal bronchopneumonia, and necrotizing enterocolitis. One of the
brain aspergillomas was located close to the aqueduct causing an aqueductal
stenosis and an obstructive hydrocephalus. Histologically, aspergillus hyphae
could only be detected in the aspergilloma of the aqueduct. To the best of our
knowledge, this is the first reported case of an aqueductal stenosis caused by an
aspergilloma.
PMID- 10774949
TI - Intradural spinal lipoma of the conus medullaris without spinal dysraphism.
AB - A 42-year-old man suffering from progressive left radicular sensory motor loss
(L4 level) underwent neurosurgical repair. Neuroimaging (RMI) had led to the
diagnosis of schwannoma of the filum terminale with lipomatous component.
Histological examination visualized a true mature lipoma associated with numerous
bundles of more or less dystrophic nerve fibers. This histological benign tumor
raised the problem of the genesis of intradural lipomas of spinal cord.
PMID- 10774951
TI - Melanotic differentiation in dysembryoplastic neuroepithelial tumor.
AB - Dysembryoplastic neuroepithelial tumor (DNT) is an uncommon intracranial tumor
which is usually encountered in patients with medically intractable complex
partial seizures of temporal lobe origin. Melanotic differentiation in a DNT has
not been reported previously. Herewith we report a case of DNT with unique
melanotic differentiation in a 23-year-old female who presented with medically
intractable epilepsy. She underwent craniotomy and tumor decompression with a
good outcome. We present the histopathological features of DNT with melanotic
differentiation and discuss its prognostic significance.
PMID- 10774950
TI - Intracranial malignant B-cell lymphoma of the dura.
AB - OBJECTIVE: Malignant B-cell lymphomas of the dura mater are very rare. A case of
primary centroblastic/centrocytic lymphoma of the dura mimicking a bilateral
convexity meningioma is presented. CLINICAL PRESENTATION: A 50-year-old woman was
referred to our institution with a 6-month history of headache and two Jacksonian
seizures. Computed tomography revealed a parafalcine and bilateral convexity
lesion. Cerebral angiography and magnetic resonance imaging were performed prior
to surgery. At surgery the tumor was removed subtotally. The patient was treated
postoperatively by combined chemo- and radiotherapy. CONCLUSION: Laboratory
studies and follow-up examinations revealed no evidence of systemic lymphoma nor
of any immunocompromised state. According to the presented case combined surgery
and chemoradiotherapy seems to be an effective treatment for this rare lesion.
PMID- 10774952
TI - Granular cell tumor of intracranial meninges.
AB - BACKGROUND: Granular cell tumor (GCT) is a benign neoplasm composed of a
proliferation of round or polygonal cells that contain eosinophilic granular
cytoplasm. The most common locations are tongue and subcutaneous tissue, but a
variety of other sites may be involved including the central nervous system
(CNS). Most CNS GCT arise in the pituitary, but rare cases involving brain and
leptomeninges have been described. Extracranial GCT are usually S-100-positive,
but those of the CNS, as well as the congenital variant of GCT, can be S-100
negative. CASE REPORT: We report an incidental autopsy finding of a 2.5 mm GCT
that arose in the intracranial meninges overlying the anterior superior
cerebellar vermis. RESULTS: The neoplasm had abundant eosinophilic, granular
cytoplasm that was PAS-positive and diastase-resistant. Immunohistochemical
studies showed that the neoplasm was positive for CD68 and negative for S-100,
GFAP, EMA, and keratin. Thus, the immunophenotype is consistent with non-neural
origin. CONCLUSION: Although this lesion in this circumstance was of no clinical
significance, knowledge of the occurrence of GCT at this site broadens the
differential diagnosis of eosinophilic lesions of the leptomeninges.
PMID- 10774953
TI - Solitary fibrous tumor of the meninges.
AB - Intracranial fibrous tumors are unusual growths that occur almost exclusively in
young individuals. Most of these lesions are intra-axial, however, on extremely
rare occasions they arise from the leptomeninges and compress the adjacent brain.
The authors report the case of a benign solitary fibrous tumor of the meninges in
a 14-year-old girl who presented with a 5-month history of generalized headaches.
NMR imaging displayed a left parietal mass, which mimicked a meningioma.
PMID- 10774954
TI - The millenium 2000; laboratory medicine--from where? to where?
PMID- 10774955
TI - Regulation of lipid and lipoprotein metabolism by PPAR activators.
AB - The peroxisome proliferator-activated receptors (PPARs) are ligand-activated
transcription factors belonging to the nuclear hormone receptor superfamily.
PPARalpha, the first identified PPAR family member, is principally expressed in
tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and
muscle. PPARgamma, on the other hand, is expressed at high levels in adipose
tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by
pharmacological drugs, such as fibrates for PPARalpha and glitazones for
PPARgamma. PPARalpha mediates the hypolipidemic action of fibrates in the
treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARalpha is
considered a major regulator of intra- and extracellular lipid metabolism. Upon
fibrate activation, PPARalpha down-regulates hepatic apolipoprotein C-III and
increases lipoprotein lipase gene expression, key players in triglyceride
metabolism. In addition, PPARalpha activation increases plasma HDL cholesterol
via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II
expression in humans. Glitazones exert a hypotriglyceridemic action via PPARgamma
mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play
also a role in intracellular lipid metabolism by up-regulating the expression of
enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty
acid entry into mitochondria and peroxisomal and mitochondrial fatty acid
catabolism. These observations have provided the molecular basis leading to a
better understanding of the mechanism of action of fibrates and glitazones on
lipid and lipoprotein metabolism and identify PPARs as attractive targets for the
rational design of more potent lipid-lowering drugs.
PMID- 10774956
TI - Laboratory screening for erythropoietin abuse in sport: an emerging challenge.
AB - The growing diffusion of banned practice to improve the athletic performances is
forcing clinical laboratories to identify and standardize reliable assays to
detect potential unfairness. Among the doping practices, the use of recombinant
human erythropoietin is becoming fairly popular, due to simplicity and safeties
of administration and troublesome detection. The heterogeneous response rate, the
presence of a little but significant amount of naturally occurring hormone, the
short half-life exhibited by recombinant human erythropoietin and the lack of
standardization of commercial assays appear the main problems to overcome. Aim of
the present article is to provide a critical review of some of the more
widespread laboratory techniques currently available for the screening for
erythropoietin abuse in sport.
PMID- 10774957
TI - Antioxidant enzyme activities and total nitrite/nitrate levels in the collar
model. Effect of nicardipine.
AB - There is a large body of literature describing the causative role of oxidative
stress mediated by increased levels of reactive oxygen species in the
pathogenesis of cardiovascular disease such as atherosclerosis, hypertension, and
restenosis after angioplasty. The positioning of a soft silicone collar around
the rabbit carotid artery elicits intimal thickening. The findings from recent
studies demonstrated that both intimal thickening and atherosclerosis lead to
synthesis of inducible nitric oxide synthase, resulting in abundant amounts of
nitric oxide. We investigated the effects of collaring and nicardipine treatment
on the activities of antioxidant enzymes, superoxide dismutase and catalase, and
total nitrite/nitrate levels, stable products of nitric oxide. Placing the collar
increased the total nitrite/ nitrate levels and decreased superoxide dismutase
activity in collared arteries. Treatment with nicardipine (20 mg/kg/day, s.c.)
prevented enhanced nitric oxide degradation without affecting superoxide
dismutase and catalase activities. Our results suggest that enhanced nitric oxide
production and superoxide anion are generated in response to the collaring,
resulting in oxidative stress within the segment in this model.
PMID- 10774958
TI - Enzyme immunoassays for fragments (epitopes) of human proatrial natriuretic
peptides.
AB - Several peptides derived from the N-terminal sequence of pro-atrial natriuretic
peptide (proANP) have been tested successfully as markers of heart disease. We
have developed specific and sensitive competitive enzyme immunoassays for
fragments [1-30] and [31-67] of proANP. Antisera were raised in sheep against
synthetic peptides predicted to be highly immunogenic. Binding specificity was
determined by epitope mapping. Microtiter plates were coated with antibody
specific for the Fc region of sheep IgG to capture the affinity-purified specific
anti-proANP antibodies in an oriented and reproducible form. Synthetic proANP
calibrators or diluted samples were incubated simultaneously with biotinylated
peptide and binding was quantitated using streptavidin-peroxidase and TMB.
Immunoreactive proANP could be measured in diluted plasma, serum and urine. The
detection limits of the proANP[1-30] and proANP[31-67] assays were 2.5 and 10
pmol/l respectively. The linearity of samples diluted beyond the recommended
assay conditions was good. Recoveries of added standard peptides ranged from 102
to 112%. Circulating concentrations of immunoreactive proANP in 115 healthy
subjects ranged from 0.11 to 0.47 nmol/l proANP[1-30] and 0.18 to 0.79 nmol/l
proANP[31-67]. In patients with cardiac disease, proANP levels were increased
significantly. The reference interval of proANP[31-67] in urine was 0.09 to 1.7
nmol/l, several-fold higher than proANP[1-30] ( or = 40 degrees C in an area at least 10 mm in depth. After
placement of the applicator into the common bile duct of anesthetized sheep,
endohyperthermia led to a consistent and repeatable heating of the surrounding
tissue to 40.5 +/- 0.5 degrees C at 1 cm distance, and 39.9 +/- 0.7 degrees C at
2 cm distance. Blood pressure, heart rate, and systemic temperature did not
change in vivo. Histological examination of the bile duct showed superficial
mucosal necrosis (depth 100-200 microm), microvascular damage with petechiae,
congestion and edema of the bile duct wall and adventitia after hyperthermia
treatment in vivo. CONCLUSIONS: The intraluminal endohyperthermia system produces
consistent and repeatable heating of the surrounding tissue. Since effective
thermal power can reach a depth of up to 2 cm, tumors may also be heated
adequately.
PMID- 10774971
TI - Diagnostic and therapeutic fistuloscopy: an adjuvant management in postoperative
fistulas and abscesses after upper gastrointestinal surgery.
AB - BACKGROUND AND STUDY AIMS: Postoperative fistulas and abscesses pose difficult
management problems. We report our experience in the use of fistuloscopy in
postoperative fistulas and abscesses after upper gastrointestinal surgery.
PATIENTS AND METHODS: From June 1993 to January 1997, nine patients (seven men,
two women; mean age 65) with postoperative fistulas and abscesses were treated
with therapeutic fistuloscopy. Diagnostic fistuloscopy was carried out using a 5
mm choledochoscope under fluoroscopic guidance. Therapeutic procedures included
mechanical debridement, irrigation, and sealing of fistula with fibrin sealant
and gelatin sponge. RESULTS: The patients were suffering from duodenal stump
fistula (three cases), gastrojejunostomy dehiscence after gastrectomy (three
cases), gastropleurocutaneous fistula (two cases), and subphrenic abscesses (two
cases). Fistuloscopy was performed 4-19 days (mean 12 days) after the diagnosis
of the fistula. The median number of sessions required was 2 (range 1-4). The
average daily fistula output prior to fistuloscopy was 154 ml (range 30-560 ml),
and all fistulas healed in an average of 18.7 days (range 2-46 days) after index
fistuloscopy. No procedure-related complications occurred. The mean hospital stay
was 61 days. During a mean follow-up period of 12 months, no recurrent abscesses
or fistulas developed. CONCLUSIONS: Fistuloscopy provides a new means of managing
patients with postoperative fistula and abscess formation.
PMID- 10774972
TI - Gastrointestinal bleeding due to worm infestation, with negative upper
gastrointestinal endoscopy findings: impact of enteroscopy.
AB - BACKGROUND AND STUDY AIMS: In cases of hookworm and roundworm infestation,
chronic occult bleeding is well known, but acute gastrointestinal bleeding is
rarely described. We report five patients with worm infestation who presented
with acute massive gastrointestinal bleeding. PATIENTS AND METHODS: Over 1 year,
we have encountered 15 patients with obscure gastrointestinal bleeding. All the
patients had normal findings on upper gastrointestinal endoscopy. Push
enteroscopy was performed in each patient and evaluation of the proximal 40-50 cm
of the jejunum was done. RESULTS: Five patients (four men, one woman; average age
50 yr, range 40-60) had worm infestation (two hookworm, three roundworm). All the
patients had gastrointestinal bleeding (five had melena, one hematemesis, and two
hematochezia) for a duration of 7-14 days. Hemoglobin ranged from 2.8 to 9 g/dl.
Push enteroscopy revealed fresh blood in the jejunum, multiple erosions, and
hookworms in two patients and roundworms in three patients. Hookworms were
retrieved endoscopically in two patients whereas roundworms could be retrieved in
only one patient. All the patients were treated with mebendazole (100 mg twice a
day for 3 days), iron, and folic acid. Gastrointestinal bleeding subsided in all
the patients. CONCLUSIONS: In developing countries, worm infestation should be
considered an important cause of obscure acute gastrointestinal bleeding.
Evaluation of the jejunum using an enteroscope will result in more frequent
diagnosis of worms as a cause of acute gastrointestinal bleeding which might have
been classified as obscure gastrointestinal bleeding.
PMID- 10774973
TI - Randomly alternating image presentation during laparoscopic training leads to
faster automation to the "fulcrum effect".
AB - BACKGROUND AND STUDY AIMS: The aim of this study was to evaluate four training
programmes intended to help laparoscopic surgeons automate to the "fulcrum
effect". METHODS: A total of 32 participants (16 men, 16 women), were randomly
assigned to one of four different image-viewing conditions: full binocular, y
axis inverted, normal laparoscopic and randomly alternating (between y-axis
inverted and normal laparoscopic). The subjects were requested to perform 10
trials of a simple laparoscopic cutting task, each lasting 2 minutes. Each then
completed a 2-minute test under normal laparoscopic imaging conditions. RESULTS:
In the final test trial, participants who trained under the randomly alternating
imaging conditions (y-axis inverted and normal laparoscopic) performed
significantly better than those from the other groups. CONCLUSION: Training under
a randomly alternating viewing condition helps laparoscopic trainees automate to
the "fulcrum effect" faster.
PMID- 10774974
TI - Treatment of esophagogastric tumors.
AB - Palliative endoscopic treatment of esophagogastric cancer is now possible using
expandable metal stents. The properties, advantages, and drawbacks of these
stents have been extensively analyzed, and there is no doubt that they are now
easy and safe to introduce, without serious morbidity. However, the frequency of
persistent thoracic pain and delayed complications, as well as the high rate of
repeat interventions required, justify limited use of the procedure. The major
indication for the procedure is dysphagia due to cancer in the esophagus or at
the cardia. Enteral stents have been used in the treatment of malignant duodenal
or jejunal stenoses, but the results are poor. A promising new area is the
treatment of benign stenoses using expandable and biodegradable stents. It may be
possible to use this technique for surgical anastomoses after tumor resection.
Careful endoscopic analysis of the mucosal surface is necessary to establish the
strict indications for endoscopic mucosal resection for mucosal malignancy.
Biopsy evidence of the relation between lesion diameter, a depressed surface
pattern and the depth of invasion into the submucosa, as well as the extent of
regional or distant lymphatic invasion, provides the best guidelines for safe
curative mucosectomy in gastric cancer. Endoscopic therapy is always safe in
lesions less than 1cm in diameter; for other lesions, resection is safe when the
depth of submucosal invasions is less than 300 microm. In other situations,
surgery is preferable in patients who are otherwise in good health. In Japan, the
results of the National Survey of Gastric Cancer, with cases detected by
screening, confirmed the benefits of adherence to these guidelines; most patients
were treated surgically, and only 7% with endoscopic therapy.
PMID- 10774975
TI - Minimally invasive surgery: hepatobiliary-pancreatic and foregut.
AB - This review is confined to the liver, biliary tract, pancreas, and foregut
(oesophagus and stomach). The issues relating to laparoscopic cholecystectomy
mainly concern the bile duct injuries associated with this operation. This review
provides some evidence that although the risk for this iatrogenic injury is
declining, it continues to be a problem and is accompanied by significant
morbidity, mortality, and a huge escalation in care costs. Laparoscopic clearance
of ductal stones is undoubtedly safe and effective, and issues have now focused
on comparisons between this form of management and orthodox endoscopic clearance.
Laparoscopic cardiomyotomy may well replace other forms of treatment of
achalasia, including balloon dilation and botulinum toxin injection. As the
results of laparoscopic antireflux surgery have been so good in the medium term,
the question of medical versus laparoscopic treatment is being addressed by two
randomized clinical trials. Gastric resection is established only in respect of
excision of mesenchymal tumours. Gastric surgery for advanced gastric cancer must
still be regarded as developmental. Laparoscopic liver resections and in situ
ablation are still confined to developing centres, but the early results are
promising. However, simpler hepatic procedures, such as de-roofing of symptomatic
simple hepatic cysts, are well established and in widespread practice. Only a few
centres have published their results on laparoscopic pancreatic surgery. The
early reported outcome for internal drainage of pancreatic pseudocysts,
enucleation of benign insulinomas, and distal pancreatic resections has been
good, but the experience is limited.
PMID- 10774976
TI - Minimal standard terminology for digestive endoscopy: results of prospective
testing and validation in the GASTER project.
AB - BACKGROUND AND STUDY AIMS: Standardization of the endoscopic report is a key
issue for future research in the field of digestive endoscopy. The Minimal
Standard Terminology (MST) has been proposed by the European Society for
Gastrointestinal Endoscopy (ESGE) as a structured language for production of
computerized endoscopic reports. The aim of this study was to validate version
1.0 of this terminology prospectively, by collecting cases in a multicenter,
multilingual trial. METHODS: Endoscopic cases (esophagogastroduodenoscopy [EGD],
colonoscopy, endoscopic retrograde cholangiopancreatography [ERCP]) were
prospectively collected in nine university hospitals in Europe, using the same
software. Reports were produced in the local language, but the software allowed
comparison of reports between languages, and global analysis of the database.
Outcome measures were the adequacy of terms proposed in the MST to describe
"reasons for performing an endoscopy", "findings", and "endoscopic diagnoses",
frequency of use and content of free-text fields, and types of lesions described.
RESULTS: A total of 6,232 reports were analyzed, including 3,447 gastroscopies,
1,743 colonoscopies, and 1,042 ERCPs. Overall, terms originally contained in the
MST were adequate to describe fully 91.0% of all examinations where "reasons for
endoscopy" were described, 99.5 % of examinations where "findings" were
described, 95.8% of all examinations containing descriptions of "endoscopic
diagnosis", 98.9% of examinations containing descriptions of "additional
diagnostic procedures", and 94.8 % of examinations containing descriptions of
"additional therapeutic procedures". Free-text fields were only used in the other
cases (less than 5% of cases in average). CONCLUSIONS: The MST appeared adequate
to cover a large part of routine endoscopy reports, and could thus be used as a
tool for standardization of endoscopic reports in clinical practice. The latter
could be significantly improved by the use of a structured and standardized
terminology for the production of endoscopic reports.
PMID- 10774977
TI - Gastric hyalinization as a possible consequence of corrosive injury.
AB - We report a case of gastric obstruction due to hyalinization of the antrum. The
endoscopic appearance of the lesion was suggestive of Crohn's disease or gastric
neoplasm. Biopsy showed pseudopolypous gastritis with ulceration and fibroid
granulation. Surgery was carried out to relieve the obstruction. Examination of
the resected specimen showed massive hyalinization of all layers of the antral
wall with circular collagenous infiltration and a normal duodenal bulb. The
question of hyaloid gastritis as a unique entity is raised. Subsequently,
information from the patient revealed the cause: voluntary acid ingestion causing
corrosive injury.
PMID- 10774978
TI - Eighteen-year surveillance of dysplasia-associated lesion in ulcerative colitis.
AB - The case of a 65 year old patient with ulcerative colitis is reported, who had a
dysplasia-associated lesion or mass (DALM) in her rectum. Refusing surgery after
detection of the lesion and on follow-up, she underwent surgery only 18 years
later when frank carcinoma (Dukes C) was detected. Even if DALM may take a
variable course, surgical excision is still highly recommended.
PMID- 10774979
TI - Treatment of achalasia by injection of botulinum toxin or sclerosants?
PMID- 10774980
TI - Use of endoscopic band ligation to treat a Dieulafoy's lesion of the esophagus.
PMID- 10774981
TI - Endoscopy-guided nasoenteral tube placement in infants by the stylet method.
PMID- 10774982
TI - Knot formation in a floppy-tipped guidewire in the common bile duct: an unusual
complication of ERCP.
PMID- 10774983
TI - A rectal carcinoid macroscopically simulating early cancer.
PMID- 10774984
TI - Internal gallbladder drainage in a patient with malignant cystic duct stenosis
due to sarcoma.
PMID- 10774986
TI - Endoscopic resection of early adenocarcinoma in Barrett's esophagus.
PMID- 10774985
TI - Leukemic rectosigmoiditis.
PMID- 10774987
TI - 5-Lipoxygenase inhibition: a new treatment strategy for Sjogren-Larsson syndrome.
AB - The Sjogren-Larsson syndrome (SLS) is a severe neurocutaneous disorder due to
fatty aldehyde dehydrogenase (FALDH) deficiency. The recent discovery of the role
of FALDH in the degradation of leukotriene B4 (LTB4) opened the way to the
development of a new therapeutic strategy for SLS, i.e. 5-lipoxygenase
inhibition. We treated one SLS patient with zileuton during five weeks. During
the treatment period we found decreased values of LTB4 and omega-OH-LTB4. The
severity of the pruritus diminished, and favorable changes in the child's
behavior were observed. The height of the prominent "lipid peak" of cerebral
white matter (that is characteristically found on proton magnetic resonance
spectroscopy in SLS patients) decreased during treatment, and increased again
when treatment was stopped. In conclusion, the beneficial effects of 5
lipoxygenase inhibition in SLS are very promising and encourage further research.
PMID- 10774988
TI - Botulinum toxin injection as an adjunct when planning hand surgery in children
with spastic hemiplegia.
AB - The usefulness of botulinum toxin A treatment when planning hand surgery in eight
children with spastic hemiplegia was evaluated. The hand function of the children
was assessed before and after treatment using a test battery consisting of
quantitative and qualitative functional assessment. The results of preoperative
botulinum treatment supported surgical intervention in four children and serial
botulinum treatment in three children. In one child, the preoperative botulinum
treatment provided no additional information. We conclude that preoperative
botulinum A treatment in most children with spastic hemiplegia, for whom hand
surgery is being considered, identifies the patients who would not benefit from
the planned surgery or for whom the functional benefit would probably not
outweigh the burden of surgical procedure and postoperative rehabilitation.
PMID- 10774989
TI - A KCNQ2 splice site mutation causing benign neonatal convulsions in a Scottish
family.
AB - Benign familial neonatal convulsions (BFNC) are one of the rare idiopathic
epilepsies with autosomal dominant mode of inheritance. Two voltage-gated
potassium channels, KCNQ2 on chromosome 20q13.3 and KCNQ3 on 8q24, have been
recently identified as the genes responsible for BFNC. Here we describe a large
family with BFNC in which we found a previously undescribed mutation in the KCNQ2
gene. A 1187(+2)T/G nucleotide exchange affects the conserved donor splice site
motif in intron 9. This mutation can be predicted to give rise to aberrant
splicing of the primary transcript. There was a wide range of clinical
manifestations in this family. An unusual clinical feature is the occurrence of
partial seizures in later life with corresponding focal neurological deficits.
PMID- 10774990
TI - Functional MRI in children with congenital structural abnormalities of the
occipital cortex.
AB - Functional MRI techniques were used to map the position of visual cortex in an
awake and a sedated child with congenital anomalies of the posterior hemispheres.
In one subject with cortical heterotopia, an activated cortex was found distinct
from the structurally abnormal area detected on conventional MRI. In a sedated
patient with holoprosencephaly, activated cortical areas in the posterior-medial
portions of the hemispheres were identified. This study demonstrates the utility
of functional MRI in such patients, both awake and sedated.
PMID- 10774991
TI - Effect of surfactant administration on cerebral haemodynamics and oxygenation in
premature infants--a near infrared spectroscopy study.
AB - OBJECTIVES: The aim of this study was to assess changes in cerebral haemodynamics
and oxygenation induced by surfactant administration using near infrared
spectroscopy (NIRS). METHODS: Eighteen premature infants, mean birth weight 960 g
(range 550-1560 g), mean gestation age 28 weeks (range 25-30 weeks), were studied
during 27 surfactant administrations. Porcine surfactant was administered to
treat respiratory distress syndrome in a bolus of 100 mg/kg. Manual bag
ventilation was performed for one minute after instillation. Heart rate, arterial
oxygen saturation measured by pulse oximetry, transcutaneous PO2 (TcPO2), and
PCO2 (TcPCO2), blood pressure, and cerebral oxygenated (O2Hb), deoxygenated
(HHb), and total haemoglobin (tHb) concentration changes obtained by NIRS were
registered every second from 15 minutes before until 30 minutes after surfactant
administration. RESULTS: During surfactant administration, there was a short
lasting but significant drop in heart rate and arterial oxygen saturation. NIRS
parameters remained constant during and up to 1 minute after administration. One
to three minutes after administration, heart rate, oxygen saturation, and TcPO2
increased significantly concomitantly with an increase in O2Hb and a decrease in
HHb. In 10 cases, TcPO2 increased above 100 mmHg. tHb--indicative of cerebral
blood volume--did not change significantly. Five to 30 minutes after surfactant
administration there was no difference of monitoring data from baseline levels.
TcPCO2 and blood pressure remained unchanged during the measurement period.
CONCLUSION: Cerebral blood volume remained constant in very-low-birth-weight
infants when surfactant was administered by bolus administration followed by
manual ventilation according to our protocol. Attention should be directed
towards rapid adaptation of inspiratory oxygen concentrations after surfactant
administration to avoid hyperoxaemia.
PMID- 10774992
TI - Functional magnetic resonance imaging of the normal and abnormal visual system in
early life.
AB - Functional magnetic resonance imaging (fMRI) in young children may provide
information about the development of the visual cortex, and may have predictive
value for later visual performance. The purpose of this study was to evaluate the
usefulness of fMRI for examining cerebral processing of vision in very young
infants and in infants with brain damage. We examined 15 preterm infants, 12
children suspected of having a cerebral visual impairment and 10 children with a
normal visual system, all of whom were either spontaneously asleep or sedated
with chloral hydrate. Cortical response to stroboscopic light stimulation could
be demonstrated in all technically acceptable data sets from children with a post
menstrual age (PMA) of > 41 weeks, but not in younger infants. Children < 60
weeks PMA showed either a blood oxygenation level-dependent (BOLD) signal
increase or decrease, while all older children showed a signal decrease. The
activated cortical volumes showed a linear relation to age for healthy children
younger than 90 weeks PMA, but were small in children with visual impairment. In
two children with unilateral damage to the optic radiations, activation was
strongly asymmetrical with greatest activation on the healthy side. In future
prospective studies, results from the period from birth to six months of age
should be interpreted with caution, as inter-individual variation of cortical
development may be confused with functional deficit.
PMID- 10774993
TI - Lymphocyte inclusions in Finnish-variant late infantile neuronal ceroid
lipofuscinosis (CLN5).
AB - Electron microscopic reinvestigation of archival samples of peripheral blood
lymphocytes of four patients with Finnish-variant late infantile neuronal ceroid
lipofuscinosis (CLN5) showed inclusions with dark globules and particles showing
fingerprint profiles. Findings, in contrast to an earlier report, show that the
lymphocytes in this disease carry pathognomonic cytosomes like all other forms of
neuronal ceroid lipofuscinosis in childhood.
PMID- 10774994
TI - 2-ketoglutarate dehydrogenase deficiency with intermittent 2-ketoglutaric
aciduria.
AB - 2-ketoglutarate dehydrogenase (KGD) deficiency is a rare disorder of the
tricarboxylic acid cycle. To date, 7 patients have been reported with clinical
symptoms suggesting a neurodegenerative disease. We report a new patient in whom
urinary excretion of 2-ketoglutaric acid (KGA) was intermittently found to be
within normal ranges. At birth, the male patient suffered from mild perinatal
asphyxia due to meconium aspiration. During the first months of life, he
developed an opisthotonus, hyperexcitability and truncal hypertonia. At the
present age of 14 months, these neurological symptoms became less pronounced. A
cranial MRI was normal. Urinary 2-KGA excretion was found to be intermittently
increased in 3 of 6 analyses between 2 weeks and 14 months of age (5-1700
mmol/mol creatinine, controls: < 340 mmol/mol creatinine). 2-KGA was not
increased in plasma and CSF. Diagnosis was confirmed by measurement of decreased
2-KGD activity in cultured skin fibroblasts. This report demonstrates that the
diagnosis of 2-KGD deficiency can easily be missed. In case of doubt, 2-KGD
activity should be measured in fibroblasts. The clinical and long-term outcome of
patients with 2-KGD deficiency is unknown. Further reports and long-term
evaluation are required.
PMID- 10774995
TI - Multisystem involvement in congenital insensitivity to pain with anhidrosis
(CIPA), a nerve growth factor receptor(Trk A)-related disorder.
AB - Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal
recessive disorder, is characterized by insensitivity to pain, self-mutilating
behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and
autonomic neuropathy, also classified as HSAN, due to a defect of the receptor
for nerve growth factor. CIPA is the first human genetic disorder caused by a
defect in the neurotrophin signal transduction system. This is the first clinical
report of CIPA patients characterized on molecular grounds. The clinical
phenotypes of our patients show that CIPA is characterized by a multisystem
involvement besides the nervous system, including bone fracture with slow
healing, immunologic abnormalities, such as low response to specific stimuli,
chronic inflammatory state ending in systemic amyloidosis. The molecular
characterization allows a better understanding of most of the clinical features.
PMID- 10774996
TI - Paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.
AB - Paraneoplastic cerebellar degeneration (PCD) is a rare neurological complication
in adults with extracerebral neoplasms. It is characterized by a diffuse
cerebellar dysfunction, usually leading to severe neurological sequelae. In
childhood, this complication is extremely rare. We report on PCD as primary
manifestation of Hodgkin disease (HD) in a thirteen-year old boy. On magnetic
resonance imaging, irreversible atrophy of the cerebellum developed within three
months. Antibodies against Purkinje cells were detectable at diagnosis and
normalised after successful treatment of the lymphoma. Cerebellar symptoms,
however, only partially resolved. The necessity of a search for a malignant
tumour is emphasised in the presence of an otherwise unexplained, subacutely
developing, diffuse cerebellar dysfunction.
PMID- 10774997
TI - MRI findings in succinic semialdehyde dehydrogenase deficiency.
PMID- 10774998
TI - Moyamoya disease (moyamoya syndrome) and coarctation of the aorta.
PMID- 10774999
TI - I-cell disease presenting with severe hypophosphatemia and cardiomyopathy.
PMID- 10775000
TI - Reexamining health effects of cigar smoking: fashionable, but may increase the
risk of coronary heart disease.
PMID- 10775001
TI - The 6-minute walk. A simple test with clinical application.
PMID- 10775002
TI - Hybrid therapy for atrial fibrillation.
PMID- 10775003
TI - Selection of patients with secundum atrial septal defects for transcatheter
device closure.
PMID- 10775004
TI - Twisting, untwisting and diastolic function in aortic valve disease.
PMID- 10775005
TI - Blood viscosity and the risk of death from coronary heart disease.
PMID- 10775006
TI - Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of
prospective studies of coronary heart disease.
PMID- 10775007
TI - Catabolism in chronic heart failure.
PMID- 10775008
TI - Improved long-term prognosis for patients with unstable coronary syndromes 1988
1995.
AB - AIMS: A more aggressive approach to unstable coronary syndromes has developed
over the last decade. We set out to examine the long-term outcome among patients
with acute coronary syndromes with respect to period of admission since 1988.
METHODS: 3918 patients with unstable angina or a non-Q wave myocardial infarction
who were admitted to the coronary care unit at Ostra Hospital in the period 1988
1997 were included. Standardized criteria were used to define a non-Q wave
myocardial infarction and included fulfilment of the following: (1) typical
enzyme changes (serial serum aspartate aminotransferase above 0.7 microkat x l(
1), serial creatine kinase above 3.3 microkat x l(-1) or serial creatine kinaseMB
subunit mass concentration above 15 microg x l(-1)), and at least one of the
following: (2) chest pain, shock, syncope or pulmonary oedema suggestive of a
myocardial infarction, (3) development of electrocardiographic changes with
serial ST-T changes without Q waves. The standardized criteria for unstable
angina pectoris were fulfilment of at least one of the following: (1) a clear
worsening of a previous stable pattern of angina pectoris, (2) chest pain at rest
or minimal effort with transient ST-segment elevation or depression on
electrocardiogram or elevation of cardiac enzymes not reaching the criteria for
myocardial infarction. Information on vital status and cause of death after
discharge was collected from the national cause-specific mortality register.
RESULTS: Two-year mortality decreased from 30% in 1988 to 19% in 1995 (relative
risk per year 0.94 (0.90-0.97), 95% confidence interval). The improvement was
consistent regardless of differences in age, prior myocardial infarction,
diabetes mellitus, hypertension, development of non-Q wave myocardial infarction,
treatment with heparin or thrombolytics or performance of acute coronary
angiograms. The cumulative survival at 10 years was 53% in the unstable angina
group and 36% in the non-Q wave myocardial infarction group (P<0.0001).
CONCLUSION: Against a background of a more aggressive approach to acute coronary
syndromes a decrease in long-term mortality is seen between 1988 and 1995.
PMID- 10775009
TI - Is the 6-minute walk test a reliable substitute for peak oxygen uptake in
patients with dilated cardiomyopathy?
AB - AIMS: The 6-min walk test may serve as a more simple clinical tool to assess
functional capacity in congestive heart failure than determination of peak oxygen
uptake by cardiopulmonary exercise testing. The purpose of the study was to
prospectively examine whether the distance ambulated during a 6-min walk test (i)
correlates with peak oxygen uptake, (ii) allows peak oxygen uptake to be
predicted, and (iii) provides prognostic information similar to peak oxygen
uptake in patients with dilated cardiomyopathy and left ventricular ejection
fraction < or = 35%. METHODS AND RESULTS: In 113 patients (age: 54+/-12 years,
NYHA: 2.2+/-0.8) with dilated cardiomyopathy (left ventricular ejection fraction
19+/-7%) a 6-min walk test and cardiopulmonary exercise testing were performed.
The 6-min walk test and peak oxygen uptake were closely correlated at the initial
visit (r=0.68, n=113), as well as after 263+/-114 (r=0.71, n=28) and 381+/-170
days (r=0.74, n=14). During serial exercise testing the 6-min walk test allowed
peak oxygen uptake to be reliably predicted (r=0.76 between calculated and real
peak oxygen uptake). After 528+/-234 days, 42 patients were hospitalized due to
worsening heart failure and/or died from cardiovascular causes. Compared to
clinically stable patients, these 42 patients walked a shorter distance (423+/
104 vs 501+/-95 m, P<0.001) and had a lower peak oxygen uptake (12.7+/-4.0 vs
17.4 + 5.6 ml x min(-1) x kg(-1), P<0.001). By univariate analysis the 6-min walk
test outperformed other prognostic parameters such as left ventricular ejection
fraction, cardiac index and plasma norepinephrine concentration and conferred a
prognostic power similar to peak oxygen uptake. This predictive value could be
further improved in a multivariate model, by combining the 6-min walk test with
independent variables, such as left ventricular ejection fraction or cardiac
index. CONCLUSION: The 6-min walk test correlated with peak oxygen uptake when
tested serially over the course of the disease. Although both tests define two
distinct domains of functional capacity, the 6-min walk test provides prognostic
information very similar to peak oxygen uptake in congestive heart failure
patients with dilated cardiomyopathy.
PMID- 10775010
TI - Endocardial mapping of atrial fibrillation in the human right atrium using a non
contact catheter.
AB - BACKGROUND: Endocardial mapping of atrial fibrillation in humans is limited by
its low resolution and by complexities in the arrhythmia and atrial anatomy.
METHODS AND RESULTS: A catheter mounted non-contact multielectrode was deployed
in the right atrium of 11 patients with atrial fibrillation and used to
reconstruct 3360 electrograms, superimposed onto a computer-simulated model of
the endocardium, using inverse solution mathematics. This allows construction of
isopotential maps of the right atrium. Patients had either sustained atrial
fibrillation (n=3) for >6 months or developed atrial fibrillation during the
study (n=8). Spontaneous initiation of atrial fibrillation was recorded in one
patient and was demonstrated by the non-contact system to arise from two
successive atrial ectopic beats from the site of a roving contact catheter.
Reconstruction of electrograms recorded during atrial fibrillation was validated
by comparison with contact electrograms with cross-correlation. During
established atrial fibrillation, four patients predominantly had a single right
atrial wave front, two had two wave fronts and five patients had three to five
wave fronts for most of the time. Periods of electrical silence were seen in the
right atrium in eight patients, after which, activity emerged from consistent
septal sites alone, suggesting a left atrial origin. During intravenous
administration of flecainide, atrial fibrillation in two patients terminated
spontaneously or following pacing manoeuvres, while in the remaining patient
sinus rhythm was restored via atrial tachycardia. CONCLUSION: Non-contact mapping
of the right atrium has demonstrated modes of initiation and termination of
atrial fibrillation, characterized different patterns of right atrial activation
in atrial fibrillation and suggests that the left atrium may sustain atrial
fibrillation in some patients. Simultaneous mapping of the right and left atrium
is required to further elucidate the mechanisms of human atrial fibrillation.
PMID- 10775011
TI - Catheter ablation of atrial flutter due to amiodarone therapy for paroxysmal
atrial fibrillation.
AB - AIMS: Antiarrhythmic drug treatment for atrial fibrillation can cause atrial
flutter-like arrhythmias. The aim of this study was to clarify the effect of
catheter ablation of the tricuspid annulus-vena cava inferior isthmus on
amiodarone-induced atrial flutter and to determine the incidence of atrial
fibrillation after catheter ablation of amiodarone-induced atrial flutter in
comparison to regular typical flutter. METHODS AND RESULTS: Among 92 consecutive
patients with typical atrial flutter who underwent isthmus ablation 28 patients
had atrial flutter without a history of previous atrial fibrillation (group I),
10 patients had atrial flutter following the initiation of amiodarone therapy for
paroxysmal atrial fibrillation (group II) and 54 patients had atrial flutter and
atrial fibrillation (group III). Atrial cycle length during atrial flutter in
amiodarone-treated patients (group II) (277+/-24 ms) was significantly longer as
compared to the cycle length of atrial flutter in group I (247+/-33 ms) and group
III patients (235+/-28 ms). The rate of successful transient entrainment and
overdrive stimulation to sinus rhythm was not different between patients with
(60%) or without amiodarone therapy (group I: 71%, group III: 53%). Successful
isthmus ablation with bidirectional conduction block eliminating right atrial
flutter was achieved in 90% of amiodarone-treated patients and 93% of patients
without amiodarone therapy. In the amiodarone-treated patient group atrial
conduction times during pacing in sinus rhythm were significantly prolonged by 20
30% before and after ablation in all regions of the reentrant circuit. During a
mean follow-up of 8+/-3 months post-ablation, atrial fibrillation recurred in two
of 10 patients on continued amiodarone therapy after successful isthmus ablation.
Thus, successful catheter ablation of atrial flutter due to amiodarone therapy
was associated with a markedly lower recurrence rate of paroxysmal atrial
fibrillation (20%) as compared to patients with atrial flutter plus preexisting
paroxysmal atrial fibrillation (76%) and was similar to the outcome of patients
with successful atrial flutter ablation without preexisting atrial fibrillation
(25%). CONCLUSION: These data suggest that isthmus ablation with bidirectional
block and continuation of amiodarone therapy is an effective therapy for the
treatment of atrial flutter due to amiodarone therapy for paroxysmal atrial
fibrillation.
PMID- 10775012
TI - Influence of atrial septal defect anatomy in patient selection and assessment of
closure with the Cardioseal device; a three-dimensional transoesophageal
echocardiographic reconstruction.
AB - BACKGROUND: The maximal diameter of the defect and the dimensions of the septal
rims are essential parameters for the selection of optimal cases for device
closure. Neither two-dimensional echocardiography nor balloon catheter sizing
provide optimal data. Unique three-dimensional echocardiography might help to
improve patient selection and assessment of results. Our aim was to optimize
transcatheter closure of secundum type atrial septal defects using three
dimensional echocardiography. METHODS: Sixteen patients enrolled in a protocol
for atrial septal defect transcatheter closure with the Cardioseal device
underwent transoesophageal two- and three-dimensional echocardiography. Maximal
diameter and tissue rim of the atrial septal defect were measured and compared by
both methods. In the 12 patients selected for closure, the balloon stretched
diameter was compared to three-dimensional echocardiography measurements. Device
placement was assessed by two- and three-dimensional echocardiography. RESULTS:
The shape of the atrial septal defect appeared variable on three-dimensional
views: round in nine patients but complex (oval, raquet-shaped, multiple) in
seven patients. The surface area of the atrial septal defect varied by 68+/-15%
during the cardiac cycle. The correlation between atrial septal defect maximal
diameters measured by two-dimensional transoesophageal echocardiography and three
dimensional echocardiography was better in round defects (y=1 x +1.6, r=0.99)
than in complex defects (y=0.7 x -0.5, r=0.88). The antero-superior rim could
only be properly assessed by three-dimensional echocardiography. In 12 patients
the correlation between stretched diameter and three-dimensional echocardiography
maximal diameter was poor (y=0.3 x +13, r=0.41). After placement of the device,
three-dimensional echocardiography enabled the mechanism of residual shunting to
be understood in three patients. CONCLUSIONS: Dynamic three-dimensional
echocardiography enhances the understanding of the anatomy and physiology of
atrial septal defect and should be an important process in future initiatives for
device closures.
PMID- 10775013
TI - Cardiac rotation and relaxation in patients with aortic valve stenosis.
AB - BACKGROUND: Diastolic dysfunction with delayed relaxation and abnormal passive
elastic properties has been described in patients with severe pressure overload
hypertrophy. The purpose of this study was to evaluate the time course of
rotational motion of the left ventricle in patients with aortic valve stenosis
using myocardial tagging. METHODS: Myocardial tagging is a non-invasive method
based on magnetic resonance which makes it possible to label ('tag') specific
myocardial regions. From the motion of the tag's cardiac rotation, radial
displacement and translational motion can be determined. In 12 controls and 13
patients with severe aortic valve stenosis systolic and diastolic wall motion was
assessed in an apical and basal short axis plane. RESULTS: The normal left
ventricle performs a systolic wringing motion around the ventricular long axis
with clockwise rotation at the base (-4.4+/-1.6 degrees) and counter-clockwise
rotation at the apex (+6.8+/-2.5 degrees) when viewed from the apex. During early
diastole an untwisting motion can be observed which precedes diastolic filling.
In patients with aortic valve stenosis systolic rotation is reduced at the base (
2.4+/-2.0 degrees; P<0.01) but increased at the apex (+12.0+/-6.0 degrees;
P<0.05). Diastolic untwisting is delayed and prolonged with a decrease in
normalized rotation velocity (-6.9+/-1.1 s(-1)) when compared to controls (
10.7+/-2.2 s(-1); P<0.001). Maximal systolic torsion is 8.0+/-2.1 degrees in
controls and 14.1+/-6.4 degrees (P<0.01) in patients with aortic valve stenosis.
CONCLUSIONS: Left ventricular pressure overload hypertrophy is associated with a
reduction in basal and an increase in apical rotation resulting in increased
torsion of the ventricle. Diastolic untwisting is delayed and prolonged. This may
explain the occurrence of diastolic dysfunction in patients with severe pressure
overload hypertrophy.
PMID- 10775014
TI - Acute and long-term results after TASH.
PMID- 10775015
TI - Anorectic-induced valvulopathy.
PMID- 10775016
TI - Natriuretic peptides in the evaluation of suspected heart failure: studies in
primary care are needed.
PMID- 10775017
TI - History and evolution of the monoamine hypothesis of depression.
AB - The symptoms of depression can be improved by agents that act by various
mechanisms to increase synaptic concentrations of monoamines. This finding led to
the adoption of the monoamine hypothesis of depression, first put forward over 30
years ago, which proposes that the underlying biological or neuroanatomical basis
for depression is a deficiency of central noradrenergic and/or serotonergic
systems and that targeting this neuronal lesion with an antidepressant would tend
to restore normal function in depressed patients. The hypothesis has enjoyed
considerable support, since it attempts to provide a pathophysiologic explanation
of the actions of antidepressants. However, in its original form it is clearly
inadequate, as it does not provide a complete explanation for the actions of
antidepressants, and the pathophysiology of depression itself remains unknown.
The hypothesis has evolved over the years to include, for example, adaptive
changes in receptors to explain why there should be only a gradual clinical
response to antidepressant treatment when the increase in availability of
monoamines is rapid. Still, the monoamine hypothesis does not address key issues
such as why antidepressants are also effective in other disorders such as panic
disorder, obsessive-compulsive disorder, and bulimia, or why all drugs that
enhance serotonergic or noradrenergic transmission are not necessarily effective
in depression. Despite these limitations, however, it is clear that the
development of the monoamine hypothesis has been of great importance in
understanding depression and in the development of safe and effective
pharmacologic agents for its treatment.
PMID- 10775018
TI - Depression: the case for a monoamine deficiency.
AB - The monoamine hypothesis of depression predicts that the underlying
pathophysiologic basis of depression is a depletion in the levels of serotonin,
norepinephrine, and/or dopamine in the central nervous system. This hypothesized
pathophysiology appears to be supported by the mechanism of action of
antidepressants: agents that elevate the levels of these neurotransmitters in the
brain have all been shown to be effective in the alleviation of depressive
symptoms. However, intensive investigation has failed to find convincing evidence
of a primary dysfunction of a specific monoamine system in patients with major
depressive disorders. Understanding of the etiology of depression has been
hampered by the absence of direct measurements of monoamines in humans. However,
the monoamine depletion paradigm, which reproduces the clinical syndrome, allows
a more direct method for investigating the role of monoamines. Results from such
studies show that antidepressant responses are transiently reversed, with the
response being dependent on the class of antidepressant. In contrast, monoamine
depletion does not worsen symptoms in depressed patients not taking medication,
nor does it cause depression in healthy volunteers with no depressive illness. In
conclusion, it is clear that antidepressant agents in current use do indeed
require intact monoamine systems for their therapeutic effect. However, some
debate remains as to the precise role that a deficiency in monoamine system(s)
may play in depression itself.
PMID- 10775019
TI - Evidence for a biochemical lesion in depression.
AB - The monoamine hypothesis of depression predicts an impairment in central
monoaminergic function. The lesion may comprise deficiencies in the absolute
concentrations of norepinephrine and/or serotonin (5-HT). Depletion studies have
shown a correlation between such deficiencies and depressive symptoms.
Measurement of the concentrations of the neurotransmitters and their metabolites
in cerebrospinal fluid, urine, and plasma of patients with depression has yielded
equivocal results regarding the possibility of altered metabolism of these
neurotransmitters. Other studies have investigated the possibility of altered
numbers and/or affinities of the serotonin and norepinephrine receptors and
uptake sites. For example, there is evidence for a reduction in the activity of
the serotonin reuptake transporter in patients with depression and an increase in
the density of 5-HT2 receptors in the brains of suicide victims. Similarly, in
the noradrenergic system, up-regulation of beta-adrenoceptors is consistently
observed. Most recently, attention has focused on the possibility that a lesion
may occur in the postreceptor, subcellular components of the monoamine systems,
such as the second messenger processes. Also, experimental evidence has shown
"cross-talk" between the noradrenergic and serotonergic systems. There is
therefore substantial clinical and experimental evidence that lesions in the
serotonergic and noradrenergic systems are responsible for depression and that
antidepressant treatment can reverse these alterations.
PMID- 10775020
TI - The case for an individual approach to the treatment of depression.
AB - Early reports of the discovery of antidepressants in the 1950s have remained as
little-known findings. Had the discovery of isoniazid, an agent with no clear
action on monoamine systems, and that of reserpine, which depletes monoamines,
been more widely known, then the monoamine lesion theories of depression, as
proposed by Schildkraut in 1965, may not have been written. If the lesion in
depression is lowered brain monoamine levels, then antidepressant agents that
increase monoamine levels should work for all patients. If this were the case,
optimizing treatment effect sizes with a minimum of side effects and some
demonstrable specificity to depressive disorders would be possible. This is not
the profile of antidepressants in clinical practice. Alternatively, if
antidepressants act on constitutional types to provide appropriate therapeutic
principles, then the efficacy would stem from an ability to suppress symptoms and
to elicit or maintain conditions that allow recovery in a subgroup of patients
who would otherwise remain nonresponsive. Current monoamine selective
antidepressant principles embody "get-up-and-go" (noradrenergic) and emotional
reactivity-reducing (serotonergic) principles. Different antidepressants are,
therefore, likely to have different treatment effect sizes in different
constitutional types. A further important aspect of antidepressant selectivity
will lie in the extent to which these agents promote a sense of well-being during
the maintenance phase of treatment.
PMID- 10775021
TI - Are all antidepressants the same?
AB - Historically, the clinician's choice of antidepressant agent has been determined
largely by consideration of tolerability, given the perception that the
therapeutic efficacy of the various antidepressants was broadly comparable.
However, with the advent of the newer, more selective antidepressants,
indications of variation in clinical efficacy have begun to emerge. The advent of
the selective serotonin reuptake inhibitors has been welcomed by patients,
largely owing to their superior tolerability profile compared with older
antidepressants. However, severely depressed patients appear to benefit
particularly from agents that include a noradrenergic mode of action, such as
tricyclic antidepressants and the modern dual-action antidepressants mirtazapine,
venlafaxine (at higher doses), and milnacipran. In addition, a noradrenergic
component may offer superior efficacy in social functioning. The recent
development of a novel, selective norepinephrine reuptake inhibitor (reboxetine)
with proven efficacy in a range of depressed patients will permit the
investigation of the relevance of the noradrenergic approach. Clinical
observations of the effects of the newer, more selective antidepressants are
important in our understanding of precise mode of action, variation in efficacy
and tolerability, and comparative usefulness in clinical practice.
PMID- 10775022
TI - Value of prothrombin fragment 1.2 (F 1.2) in the diagnosis of stroke in young
patients with antiphospholipid antibodies.
AB - The presence in the serum of antiphospholipid antibodies (aPL) is associated with
venous and arterial thrombosis. This observation has led to the search for these
antibodies in young patients with ischemic neurologic syndromes. However, 1% to
5% of healthy people may be found to have circulating aPL without necessarily
being at increased risk of thromboembolism. Thus, the finding of APLA in a
patient with cerebral ischemia does not necessarily provide an explanation for
the etiology of the clinical syndrome. The aim of this study was to determine
whether the presence of aPL in young patients with stroke or transient ischemic
attacks represents a possible cause of hypercoagulability as defined by ongoing
thrombin formation with resultant elevation of prothrombin fragment 1.2 (F1.2)
levels. This was a retrospective, case-control study involving 57 subjects.
Twenty-seven patients had a recent cerebrovascular ischemic event--either TIA or
a stroke. Fifteen were positive for aPL, and 12 were aPL-negative. Thirty
subjects, matched for age and sex with no history of cerebrovascular disease,
served as controls. Of this group, 20 were aPL-positive and 10 were aPL-negative.
Causes of hypercoagulability other than aPL were excluded by laboratory testing.
A positive test for aPL was repeated after a 6-week interval and two positive
tests were required for a patient to be regarded as being aPL-positive. Levels of
F1.2 were measured by an ELISA technique. There was a significant difference (p <
0.05) in the mean F1.2 levels between the aPL-positive group with a history of
cerebrovascular disease (mean F1.2 = 2.3733) and each of the other study groups.
There was no statistically significant difference between any of the other study
groups. Our findings suggest that F1.2 levels are elevated in young patients with
cerebrovascular syndromes who have aPL and in whom other causes of
hypercoagulability and atherosclerotic vascular disease are absent. Elevated F1.2
in these patients may be a potential marker of the hypercoagulable state
associated with aPL.
PMID- 10775023
TI - Platelet prothrombinase activity, a final pathway platelet procoagulant activity,
is overexpressed in type 1 diabetes: no relationship with mean platelet volume or
background retinopathy.
AB - There is overwhelming evidence that platelets from diabetic individuals are
hyperreactive, not only when microvascular complications are apparent, but
already at an early stage of the disease. There is still controversy about the
question of whether primary hyperreactive platelets may contribute to the origin
or progression of microangiopathy or whether diabetic platelet hyperfunctionality
is just a logical consequence of a continuous low-grade activation of platelets
by contact with a diseased microvascular wall. As a consequence of platelet
activation, the outer layer of its phospholipid membrane is more procoagulant
than in the quiescent state, stimulating thrombin formation in plasma. This
platelet function is called platelet procoagulant activity. We studied platelet
prothrombinase activity (PPA), a final pathway platelet procoagulant activity of
type 1 diabetic platelets, and looked for an eventual correlation with
microvascular disease (background retinopathy) and mean platelet volume (MPV).
Stypven clotting times (SCTs), reflecting PPA expression, and MPV of citrated
platelet-rich plasma (PRP), were measured in 21 patients with type 1 diabetes-10
with and 11 without background retinopathy-under clinically acceptable metabolic
control and compared them to 20 disease-free voluntary controls. We also compared
PPA expression and MPV in diabetic individuals with and without retinopathy. With
the SCT, a selective test adapted for studying PPA in PRP, we found
hyperexpression of PPA in all diabetic patients. We found no difference in MPV
between diabetic and control PRP. Comparing patients with and without background
retinopathy we found no significant difference in PPA expression. From these
results, we suggest that the phospholipid surface of diabetic platelets, more
than the surface of normal control platelets, stimulate the expression of PPA.
This diabetic platelet coagulant anomaly was not related to an increased platelet
mass (higher MPV) nor to the presence of microangiopathy. We conclude that PPA
hyperexpression is associated with patients with type 1 diabetes, already
occurring in an early stage of the disease, and not necessarily a consequence of
early-stage microvascular disease, because the anomaly is also demonstrable, in
the same degree, in patients with diabetes without microangiopathy.
PMID- 10775024
TI - Defibrotide in recurrent thrombotic thrombocytopenic purpura.
AB - Thrombotic thrombocytopenic purpura (TTP) is a common illness characterized by
platelet thrombi within the microvascularization. In its natural course, this
disease has had a mortality rate of 90%. Plasma infusion or exchange achieved a
survival rate of 70% to 90%. However, 10% to 30% of patients surviving the
initial TTP episode relapse at regular intervals. The treatment of recurrent
forms of the disease remains a challenge; several approaches have been shown to
induce medium to long term remissions. We describe a patient with recurrent TTP
whose disease remitted after administration of defibrotide.
PMID- 10775025
TI - Soluble P-selectin in human plasma: effect of anticoagulant matrix and its levels
in patients with cardiovascular disorders.
AB - P-Selectin represents a cell surface glycoprotein that is constitutively present
in the Weibel-Palade bodies of endothelial cells and in the alpha-granules of
platelets. In inflammation and thrombogenic conditions, plasmatic P-selectin
levels are markedly elevated, indicating the leakage of this marker from these
sites. In this study, a quantitative sandwich enzyme-linked immunosorbent assay
(ELISA) utilizing a monoclonal soluble P-selectin (sP-selectin) antibody was
employed to assess this marker in blood samples collected in various
anticoagulants such as heparin, hirudin, sodium citrate (3.2% and 3.8%), and
ethylenediaminetetraacetic acid (EDTA). The soluble P-selectin levels ranged from
26 ng/mL to 44 ng/mL. Sodium citrate (3.8%) was used to collect platelet-poor
plasma (PPP) from patients with heparin-induced thrombocytopenia (HIT), coronary
angioplasty (CA), or coronary atherectomy (CAT). In comparison with the control
group (approximately 30 ng/mL), all of these patient groups showed a marked
elevation of sP-selectin levels (HIT = 96 ng/mL [n = 18], CA = 46 ng/mL [n = 6]
and CAT = 60 ng/mL [n = 10]). In platelet-rich plasma (PRP) preparations using
various anticoagulants, the sP-selectin levels were markedly higher, ranging from
87 ng/ mL to 117 ng/mL (n = 10). In patients recruited into a clinical trial (the
argatroban [ARG] 911 Study), in which argatroban was used as an alternate
anticoagulant in patients with HIT, a 25% to 35% decrease in sP-selectin levels
was observed after 72 hours of argatroban treatment. In addition, the relative
ratio between levels in PRP and PPP in these patients differed, suggesting that
the anticoagulant matrix influences the sP-selectin levels. These data clearly
suggest that the anticoagulant matrix and blood collection procedures may
significantly influence the plasmatic P-selectin levels. Furthermore, in
different clinical conditions, elevation of this marker may reflect endogenous
platelet activation; however, optimal anticoagulant for blood collection is
important for proper diagnostic validation.
PMID- 10775026
TI - Rapid ELISA D-dimer testing in the exclusion of venous thromboembolism in
hospitalized patients.
AB - The clinical diagnosis of deep-vein thrombosis (DVT) and pulmonary embolism (PE)
is known to be unreliable. Until now, no biological marker has been found to
confirm thrombosis, but help can be gained from a biological marker ruling out
the diagnosis of DVT or PE, i.e., the sensitive measurement of D-dimer (DD)
species. This article summarizes our experience in introducing a rapid D-dimer
test (ELISA VIDAS D-dimeres test, bioMerieux) in a collaborative strategy for
thrombosis diagnosis during 9 consecutive months involving 1,131 measurements.
The efficacy of the DD test was very different according the type of patient, and
departments where the DD test provides a real diagnostic benefit were identified.
High clinical probability for thrombosis was encountered in 32 patients and
radiology was carried out, although D-dimer was negative: none of these patients
was found to have a thrombosis after radiologic examination. However, extensive
progress must be made in test prescription to reduce the excessive rate of
positive D-dimer tests (78%) and positive measurements that are not followed up
by radiology (42%).
PMID- 10775027
TI - Acquired hemophilia A in women postpartum: clinical manifestations, diagnosis,
and treatment.
AB - Acquired hemophilia A in women postpartum is diagnosed by a prolonged activated
partial thromboplastin time (APTT), low plasma levels of coagulant factor VIII,
and the detection of an inhibitor against factor VIII in the Bethesda assay.
Effective treatment of bleeding symptoms should be based upon the clinical
situation and depends on the inhibitor characteristics against human and porcine
factor VIII. Immunosuppression usually does not significantly affect the
disappearance of the factor VIII inhibitor antibody. The natural history of
acquired hemophilia postpartum is independent of immunosuppressive treatment and
featured by spontaneous disappearance of the inhibitor against factor VIII in the
majority of cases.
PMID- 10775028
TI - Risk of thrombosis in patients homozygous and heterozygous for factor V Leiden in
the East Bohemian region.
AB - A retrospective investigation on the frequency of thrombotic events in 227
heterozygous and 16 homozygous carriers for the factor V R506Q mutation (factor V
Leiden) from 102 unrelated families in the East Bohemian region is reported. A
majority of 130 of the 227 (57%) heterozygous and a minority of 5 of 16 (31%)
homozygous carriers for the factor V R506Q mutation remained asymptomatic. Deep
venous thrombosis without pulmonary embolism in a minority was the main and the
most frequent clinical manifestation in 97 of 243 carriers for the factor V R506Q
mutation. Deep venous thrombosis occurred in 92 of 227 (41%) heterozygous and in
11 of 16 (69%) homozygous carriers of the factor V R506Q. Spontaneous thrombosis
prevailed in symptomatic men. Thrombosis in women usually occurs during risk
situations well known to elicit venous thrombosis. Oral contraceptives and
pregnancy were significantly the most frequent risk factors in female carriers of
the factor V R506Q mutation, which in fact can readily explain the lower average
age for the first thrombotic event of 30.6 years in women compared to 37.1 years
in men.
PMID- 10775029
TI - Simple and safe method to prepare patients with prosthetic heart valves for
surgical dental procedures.
AB - Temporary discontinuation of high-intensity oral anticoagulant treatment is not
recommended in patients undergoing dental surgery. This policy is not based on
solid data from randomized clinical trials but on expert consensus. The
alternative, i.e., to continue treatment and treat patients with tranexamic acid
mouthwash, often is not applicable. A prospective cohort study was carried out to
evaluate bleeding and thromboembolic complications in patients bearing prosthetic
heart valves and registering International Normalized Ratio (INR) values between
2.0 and 4.5, who underwent dental procedures after a 2-day suspension of warfarin
treatment. One hundred four consecutive patients receiving high-intensity
anticoagulation underwent 123 dental procedures after 2 days' warfarin
withdrawal. No major bleeding complications occurred in the week after the
procedure; minor bleeding requiring local measures occurred in two patients. No
thromboembolic events and no cases of bacterial endocarditis were recorded in the
3 months after the procedure. A mean decrease in INR by approximately 1.0 U (from
2.95+/-0,59 to 1.87+/-0,46) occurred after 2 days' warfarin suspension. Seven
days after reinitiation of warfarin, INR values returned to the therapeutic range
in 90% of cases. The calculated average time spent at INR less than 2.0 (critical
value) was 28 hours. Two days' warfarin suspension is a simple and safe policy
for patients with prosthetic heart valves undergoing dental surgery.
PMID- 10775030
TI - Review and management of patients with the prothrombin G20210A polymorphism.
AB - A single mutation in the 3'-untranslated region of the prothrombin gene,
resulting in a G to A substitution, was recently reported. This finding added to
the growing list of genetic disorders thought to be responsible for familial
thrombophilia. Although most studies are in general agreement about the elevated
risk of venous thrombosis in individuals carrying this mutation, its role in the
first event of venous thromboembolism and recurrent events is unclear. Even less
clear is the role that this mutation plays in the formation of arterial
thrombosis (including coronary artery disease and cerebral ischemia), as studies
show contradicting results. Because of this, it is not recommended as part of the
routine screening of patients with venous thromboembolism. However, there are
certain subgroups of patients who should undergo testing. The discovery of this
prothrombin mutation has important clinical implications because it is the second
most common cause of genetic thrombophilia, second only to the factor V Leiden.
Moreover, its discovery likely will augment the clinician's ability to
systematically risk-stratify an individual's likelihood of developing spontaneous
thrombosis.
PMID- 10775032
TI - Prevalence of genetic mutations that predispose to thrombophilia in a Greek
Cypriot population.
AB - Several hereditary disorders, particularly those affecting the physiological
anticoagulation systems, have been well established as risk factors for venous
thromboembolism. In the present study, we investigated the prevalence of the
following thrombogenic mutations in a Greek-Cypriot population: the G1691 factor
V Leiden mutation, the G20210A mutation in the prothrombin gene, and the C677T
mutation in the methylenetetrahydrofolate reductase (MTHFR). All three variants
have been documented to be significant risk factors for various cardiovascular
conditions. Ninety unrelated subjects were screened. For the Leiden mutation, 11
subjects (12.2%) were heterozygous and one (1.1%) was homozygous. Seven subjects
(7.8%) were heterozygous for the G20210A variant in prothrombin; no homozygotes
were identified. The C677T mutation in MTHFR was found in 40 individuals in the
heterozygous state (44.4%), and in 16 individuals in the homozygous state
(17.8%). These data demonstrate that Greek-Cypriots have an increased frequency
of thrombogenic mutations, and suggest that screening for these mutations should
be seriously considered, especially when surgery or pregnancy is planned. This is
the first study for the frequency of mutations in risk factors that predispose to
thrombophilia on the island of Cyprus.
PMID- 10775031
TI - Hemostatic abnormalities in patients with thrombotic complications on maintenance
hemodialysis.
AB - Before hemodialysis (HD), plasma levels of tissue factor (TF), free-TF pathway
inhibitor (TFPI) and thrombomodulin (TM) were significantly higher in patients
with HD than in healthy volunteers. Plasma levels of (T-F) TFPI and plasmin
plasmin inhibitor complex (PPIC) were significantly higher in patients with HD
than in healthy volunteers. During HD, plasma levels of TF and (T-F) TFPI were
not significantly increased, but plasma levels of total TFPI and free TFPI at 1
hour after and at the end of HD were significantly increased, compared with
levels before start of HD. Plasma level of PPIC 1 hour after start of HD was
significantly higher than before start of HD, and plasma levels of thrombin
antithrombin complex (TAT), PPIC, D-dimer, TM, and protein C (PC) at the end of
HD were significantly higher than before start of HD. In patients with thrombosis
complications, plasma TF levels were significantly higher than in patients
without thrombotic complications during HD. Plasma levels of PC were
significantly lower in patients with thrombotic complications than in patients
without thrombotic complications. There was no significant difference between
both groups during HD in hemostatic parameters, with the exception of TF and PC.
Hemostatic abnormalities existed in patients with HD; especially, increased TF
and decreased PC might cause thrombotic complications.
PMID- 10775033
TI - Sudden cardiac death from thrombotic thrombocytopenic purpura.
AB - Clinical thrombotic thrombocytopenic purpura (TTP) is characterized by a pentad
of microangiopathic hemolytic anemia, thrombocytopenia, neurological symptoms,
renal involvement, and fever. A case of TTP in which early symptoms and signs
were suggestive of ischemic heart disease, renal failure, and severe
thrombocytopenia developed to a rapid outcome of death. The postmortem
examination revealed coronary artery microthrombi, typical of TTP. The clinical
presentation of this TTP was atypical: severe thrombocytopenia, striking renal
and CNS symptoms were present, but fever and anemia were not present. Thrombotic
thrombocytopenic purpura is an uncommon condition that carries a high fatality
rate if untreated. Awareness of this syndrome and its high risk of sudden death
underlines the importance of rapid diagnosis and treatment.
PMID- 10775034
TI - Acute myocardial infarction associated with the prothrombin G20210A mutation.
PMID- 10775035
TI - Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel
oncogenic character of the wild-type protein.
AB - The c-Raf-1 kinase is a downstream effector of Ras signaling. Both proteins are
highly oncogenic when they are mutationally activated, but only the Ras GTPase is
frequently mutated in naturally occurring tumors. Although the c-Raf-1 protein
was found to be amplified in different lung cancer cell lines, overexpression of
the wild-type c-Raf-1 protein was shown to be insufficient to transform cultured
cells. Here we have addressed the question of whether overexpression of the wild
type c-Raf-1 kinase can induce lung cancer in mice. We show that lung-targeted
expression of oncogenically activated or wild-type c-Raf-1 proteins induces
morphologically indistinguishable lung adenomas in transgenic mice. Compared with
mice transgenic for the activated c-Raf-1-BxB, tumor development is delayed and
occurs at a lower incidence in wild-type c-Raf-1 transgenic mice. Our studies
show that the c-Raf-1 expression level is a critical parameter in tumor
development and should be analyzed in more detail to evaluate its potential in
the induction of cancer.
PMID- 10775036
TI - Prolonged activation of the mitogen-activated protein kinase pathway is required
for macrophage-like differentiation of a human myeloid leukemic cell line.
AB - The role of the mitogen-activated protein kinase (MAPK) signal transduction
pathway in the proliferation of mammalian cells has been well established.
However, there are relatively few reports concerning cell differentiation being
mediated by MAPK. The effect of phorbol 12-myristate 13-acetate (PMA) on cell
differentiation and signal transduction in a human myeloid leukemia cell line, TF
1a, was investigated. When TF-1a cells were treated with 10(-6), 10(-7), 10(-8),
and 10(-9) M PMA for 24 h, they underwent 98, 93, 91, and 51% macrophage-like
differentiation, respectively. PMA treatment rapidly (10 min) induced
phosphorylation of MAPK kinase (MEK and p44/42 MAPK), which persisted for at
least 24 h. p44/42 MAPK immunoprecipitates from lysates of PMA-treated cells had
increased ability to phosphorylate the transcription factor Elk-1. This is
important because phosphorylated Elk-1 can be considered an "end-product" of the
MAPK pathway. In contrast, treatment of TF-1a cells with granulocyte/macrophage
colony stimulating factor induced only transient activation of MEK and p44/42
MAPK (10-20 min) and an increase (approximately 50%) in cell proliferation,
without any change in cellular differentiation. These results suggest that
macrophage-like differentiation may be dependent on prolonged activation of the
MAPK pathway. Additional support for this conclusion was obtained from
experiments showing that treatment of TF-1a cells with antisense oligonucleotides
for MEK1 coding sequences prior to adding PMA inhibited macrophage-like
differentiation. Furthermore, transient transfection with an inactive, dominant
negative MEK mutant also inhibited PMA-induced differentiation, whereas transient
transfection with a plasmid coding for constitutively activated MEK led to
macrophage-like differentiation in the absence of PMA.
PMID- 10775038
TI - Binding of 14-3-3beta to the carboxyl terminus of Wee1 increases Wee1 stability,
kinase activity, and G2-M cell population.
AB - Wee1 protein kinase plays an important regulatory role in cell cycle progression.
It inhibits Cdc-2 activity by phosphorylating Tyr15 and arrests cells at G2-M
phase. In an attempt to understand Wee1 regulation during cell cycle, yeast two
hybrid screening was used to identify Wee1-binding protein(s). Five of the eight
positive clones identified encode 14-3-3beta. In vivo binding assay in 293 cells
showed that both full-length and NH2-terminal truncated Wee1 bind with 14-3
3beta. The 14-3-3beta binding site was mapped to a COOH-terminal consensus motif,
RSVSLT (codons 639 to 646). Binding with 14-3-3beta increases the protein level
of full-length Wee1 but not of the truncated Wee1. Accompanying the protein level
increases, the kinase activity of Wee1 also increases when coexpressed with 14-3
3beta. Increased Wee1 protein level/enzymatic activity is accountable, at least
in part, to an increased Wee1 protein half-life when coexpressed with 14-3-3beta.
The protein half-life of the NH2-terminal truncated Wee1 is much longer than that
of the full-length protein and is not affected by 14-3-3beta cotransfection.
Biologically, 14-3-3beta/Wee1 coexpression increases the cell population at G2-M
phase. Thus, Wee1 binding with 14-3-3beta increases its biochemical activity as
well as its biological function. The finding reveals a novel mechanism by which
14-3-3 regulates G2-M arrest and suggests that the NH2-terminal domain of Wee1
contains a negative regulatory sequence that determines Wee1 stability.
PMID- 10775037
TI - An in vivo function for the transforming Myc protein: elicitation of the
angiogenic phenotype.
AB - The ability of neoplastic cells to recruit blood vasculature is crucial to their
survival in the host organism. However, the evidence linking dominant oncogenes
to the angiogenic switch remains incomplete. We demonstrate here that Myc, an
oncoprotein implicated in many human malignancies, stimulates neovascularization.
As an experimental model, we used Rat-1A fibroblasts that form vascular tumors
upon transformation by Myc in immunocompromised mice. Our previous work and the
use of neutralizing antibodies reveal that in these cells, the angiogenic switch
is achieved via down-modulation of thrombospondin-1, a secreted inhibitor of
angiogenesis, whereas the levels of vascular endothelial growth factor, a major
activator of angiogenesis, remain high and unaffected by Myc. Consistent with
this finding, overexpression of Myc confers upon the conditioned media the
ability to promote migration of adjacent endothelial cells in vitro and corneal
neovascularization in vivo. Furthermore, mobilization of estrogen-dependent Myc
in vivo with the appropriate steroid provokes neovascularization of cell implants
embedded in Matrigel. These data suggest that Myc is fully competent to trigger
the angiogenic switch in vivo and that secondary events may not be required for
neovascularization of Myc-induced tumors.
PMID- 10775039
TI - 1alpha,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion
associated proteases in cultured malignant cells.
AB - Vitamin D and its derivatives (deltanoids) are potent regulators of cell
proliferation and differentiation. Targeted production of proteolytic enzymes
like serine proteases and metalloproteinases is an important part of the invasive
process of cancer cells. Treatment with 1 alpha25-dihydroxyvitamin D3
[1alpha,25(OH)2D3] decreases the invasive properties of breast carcinoma cells.
Here we have analyzed the effects of 1alpha,25(OH)2D3 and its synthetic analogues
on the secretion and cell surface association of the components of the
plasminogen activator (PA) system and on the secretion of certain matrix
metalloproteinases (MMPs) and their inhibitors in MDA-MB-231 breast carcinoma
cells. Deltanoids were able to decrease the secretion of urokinase PA and tissue
type PA activity in a dose-dependent manner and to increase PA inhibitor 1
secretion, leading to reduced total PA activity. CB1093 was the most potent
analogue, effective at concentrations several logarithms lower than
1alpha,25(OH)2D3. Transient transfection of different urokinase PA promoter
reporter constructs to HT-1080 fibrosarcoma indicator cells indicated that
vitamin D-responsive sequences were located between nucleotides -2350 and -1870
in the 5' region of the promoter. Treatment of MDA-MB-231 cells with
1alpha,25(OH)2D3 or other deltanoids also resulted in decreased MMP-9 levels in
association with increased tissue inhibitor of MMP 1 activity. Membrane-type 1
MMP expression or proteolytic processing were not appreciably affected by
deltanoids. Vitamin D and its analogues caused a decrease in Matrigel invasion
assays of MDA-MB-231 cells. Cancer cell invasion is associated with coordinated
secretion of proteolytic enzymes and their inhibitors. Vitamin D and its
derivatives can evidently influence invasive processes by two means: (a)
decreasing the expression and activity of cell invasion-associated serine
proteases and metalloproteinases; and (b) inducing their inhibitors.
PMID- 10775040
TI - Global assessment of functioning (GAF) ratings: determinants and role as
predictors of one-year treatment outcomes.
AB - OBJECTIVE: To assess the adequacy of global ratings of patients' psychosocial
functioning, which are an integral part of the current system for obtaining
multidimensional psychiatric diagnoses and are embodied by the Global Assessment
of Functioning (GAF) Scale as AXIS V of the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (American Psychiatric Association, 1994).
METHOD: We identified a sample of 1,688 patients with substance use disorders,
many of whom also had psychiatric disorders; examined the determinants of GAF
ratings; and focused on how well these ratings predicted patients' one-year
symptom and psychosocial functioning outcomes. RESULTS: Patients' clinical
diagnoses and psychiatric symptoms were stronger predictors of GAF ratings than
was their social and occupational functioning. Moreover, GAF ratings were only
minimally associated with patients' one-year psychological, social, and
occupational functioning outcomes. CONCLUSIONS: These findings raise serious
questions about the conceptual and clinical value of the current standard method
of assessing psychiatric and substance abuse patients' global functioning.
PMID- 10775041
TI - Dependency and suicidality in psychiatric inpatients.
AB - One hundred fifty-two psychiatric inpatients (91 women and 61 men) completed
widely used objective (i.e., self-report) and projective measures of
interpersonal dependency; scores on these measures were compared to two indices
of suicidality derived from patients' chart records (i.e., number of past suicide
attempts and physician judgments of suicidality at admission). High objective
dependency scores were associated with high suicidality scores in women and men,
even when level of depression was controlled for statistically. Projective
dependency scores were unrelated to both suicidality indices.
PMID- 10775042
TI - Countertransference feelings and the psychiatric staff's self-image.
AB - This paper presents a study of associations between psychiatric staff's habitual
feelings towards their patients and the staff's self-image. At 22 psychiatric
treatment homes for psychotic and other severely disturbed patients, 163 male and
female staff recurrently rated their feelings towards the individual patients on
a feeling checklist. At the beginning of the study period, they also rated
different aspects of their self-image (the introject and the mother and father
images) using Structural Analysis of Social Behavior (SASB). Over time and over
patient, correlations between the individual staff ratings on the feeling
checklist and ratings on the SASB were studied for all staff and for male and
female staff separately. The analyses showed a number of associations between the
staff's feelings and aspects of their self-image. Staff who habitually tended to
feel helpful and autonomous towards their patients had a more positive image of
mother, whereas staff who tended to feel more rejecting, unhelpful, and
controlled had a combination of negative images of mother and father and a
protecting introject. Some notable differences between male and female staff were
found. Overall, self-image accounted for larger proportions of the male staff's
feelings than of the female staff's. Negative feelings for male staff were
associated more with a critical father image, whereas for female staff these
feelings were associated more with an image of the father as a freedom giving.
PMID- 10775043
TI - Relative size of the literatures for psychopathological disorders: number of
articles pertaining to DSM-IV diagnostic categories.
AB - A computerized search of the 1991-1997 PsycLIT database was used to quantify the
size of the literature for each of the DSM-IV mental disorders. The search
included DSM-IV/IIIR diagnoses and alternative terms for the disorders to provide
a complete assessment. Generally it was found that major disorders and those with
neurophysiological components were investigated a great deal (there were over
10,000 articles for both major depression and schizophrenia) while there were few
articles concerning rare or newly introduced disorders. Within diagnostic groups
certain disorders received the preponderance of research attention. Factors
related to the degree to which a mental disorder is investigated are discussed.
These findings should stimulate consideration of whether clinical research is
directing its efforts in a way that best promotes understanding of the nature and
treatment of mental disorders.
PMID- 10775044
TI - Object relations and reality testing in early- and late-onset schizophrenia.
AB - One hundred fifty-seven U.S. military veterans with schizophrenia were divided
into early-onset (i.e., onset at age 20 or before, n = 36) and late-onset (i.e.,
onset after age 30, n = 28) groups and completed the Bell Object Relations and
Reality Testing Inventory (BORRTI), the Positive and Negative Syndrome Scale, and
several representative neuropsychological instruments. Participants were compared
on background characteristics and test measures. The early-onset group
demonstrated significantly more object-relations and reality-testing deficits
than the late-onset group. In contrast, no significant group differences were
found on symptom or neuropsychological variables. An a posteriori three-group
analysis that included the middle age of onset group (i.e., ages 21 to 30) found
that the middle group had mean values that fell between early- and late-onset
groups on most variables. No distinct patterns of BORRTI subscale scores
distinguished the middle group. The finding that object-relations and reality
testing deficits are more pronounced in early-onset schizophrenia has
implications for the treatment and rehabilitation of schizophrenia.
PMID- 10775045
TI - The many methods of religious coping: development and initial validation of the
RCOPE.
AB - The purpose of this study was to develop and validate a new theoretically based
measure that would assess the full range of religious coping methods, including
potentially helpful and harmful religious expressions. The RCOPE was tested on a
large sample of college students who were coping with a significant negative life
event. Factor analysis of the RCOPE in the college sample yielded factors largely
consistent with the conceptualization and construction of the subscales.
Confirmatory factor analysis of the RCOPE in a large sample of hospitalized
elderly patients was moderately supportive of the initial factor structure.
Results of regression analyses showed that religious coping accounted for
significant unique variance in measures of adjustment (stress-related growth,
religious outcome, physical health, mental health, and emotional distress) after
controlling for the effects of demographics and global religious measures
(frequency of prayer, church attendance, and religious salience). Better
adjustment was related to a number of coping methods, such as benevolent
religious reappraisals, religious forgiveness/purification, and seeking religious
support. Poorer adjustment was associated with reappraisals of God's powers,
spiritual discontent, and punishing God reappraisals. The results suggest that
the RCOPE may be useful to researchers and practitioners interested in a
comprehensive assessment of religious coping and in a more complete integration
of religious and spiritual dimensions in the process of counseling.
PMID- 10775046
TI - Factor structure of the Beck Depression Inventory-Second Edition (BDI-II) in a
student sample.
AB - A confirmatory factor analysis was performed to evaluate the factorial validity
of the Beck Depression Inventory-Second Edition (BDI-II) in a large sample of
undergraduates (N = 576). Results suggest that the revised measure is internally
consistent and consists of two underlying factors assessing cognitive-affective
and somatic symptoms of depression. Results support the use of the BDI-II as a
severity measure of symptoms of depression.
PMID- 10775047
TI - Use of the California Verbal Learning Test to detect proactive interference in
the traumatically brain injured.
AB - Recent studies using the California Verbal Learning Test (CVLT) to investigate
the learning and memory capacities of traumatically-brain injured (TBI)
individuals have suggested that this population does not show the expected
buildup of proactive interference (PI). The purpose of this study was to
investigate whether PI could be detected on the CVLT, in a TBI sample, if PI were
calculated using alternative methods. CVLT data from 25 TBI individuals with
varying degrees of brain injury and 21 healthy controls were compared. Results
from the various analyses suggested that TBI individuals show buildup and release
from PI when learning and attempting to recall competing forms of information if
appropriate methods of analysis are used. Although the CVLT differs considerably
from traditional PI paradigms (e.g., Wickens, 1970), our results suggest it can
be used to detect PI in TBI individuals.
PMID- 10775048
TI - The Memory Assessment Scales and lateralized temporal lobe epilepsy.
AB - We report Memory Assessment Scales (MAS) performance in 101 patients with
unilateral temporal lobe epilepsy (TLE; left, n = 51; right, n = 50) with left
cerebral language dominance. A significant multivariate group effect was present
for the major summary indices (Verbal Memory, Visual Memory, and Global Memory, p
< .04). Univariate analyses revealed no significant differences for either the
Global Memory or Verbal Memory summary scores, although a significant group
difference was present for Visual Memory (p < .04). The Verbal Memory-Visual
Memory discrepancy score was significantly different between right and left TLE
groups (p < .004). Verbal Memory scores were at least 14 points lower than Visual
Memory scores in 34 patients (left = 20, 59%; right = 14, 41%). Visual Memory
scores were at least 14 points lower than Verbal Memory performance in 20
patients (left = 5, 25%; right = 15, 75%). Diagnostic efficiency statistics show
higher sensitivity but lower specificity in group classification for left TLE
patients. These data suggest that the MAS is sensitive to material-specific
memory deficits associated with a unilateral temporal lobe seizure focus.
However, over one-third of the patients (19/54) with at least a 14-point Verbal
Memory-Visual Memory discrepancy were classified incorrectly. The MAS, like other
material-specific memory measures, should be interpreted within the context of
other clinical findings.
PMID- 10775049
TI - Too many simple clerical scoring errors: the Rey Figure as an example.
AB - The clerical errors from 325 scored Rey Figure drawings were tabulated using the
procedures outlined in the Boston Qualitative Scoring System manual. The error
types investigated were avoidable quantitative scoring errors (e.g., addition,
using conversion tables, and plotting scores). The three scorers made errors on
18.3%, 22.4%, and 24.7% of the Rey Figures they scored.
PMID- 10775050
TI - Quality of life of persons with severe mental illness living in an intermediate
care facility.
AB - This study examined resident characteristics, clinical factors, and mental health
service utilization associated with quality of life (QOL) for residents living in
an Intermediate Care Facility (ICF). This study also utilized published
literature to compare the QOL of ICF residents to persons with psychiatric
disorders living in other residential settings. Chart review and interviews were
used to study 100 randomly selected residents living in an ICF with a chart
diagnosis of schizophrenia. Multivariate analyses suggest that higher levels of
QOL are associated with reports that psychological problems did not interfere
with work and activities and with lower levels of being a danger to others. Also,
a comparison of the QOL scores reported by ICF residents to other published
mentally ill populations suggests that residents of the ICF report somewhat
higher QOL scores than state hospital patients, but lower scores as compared to
other community samples. Data provide insight into the types of problems faced by
residents of an intermediate care facility. These findings have implications for
understanding the importance of mental health service utilization on QOL.
PMID- 10775051
TI - Interrater reliability of the Brief Psychiatric Rating Scale used at a community
based inpatient crisis stabilization unit.
AB - In 1993, the State of Georgia passed a law reforming the mental health system to
include more consumers of services and their families on local boards, to provide
services in the community, and to measure and report the outcomes of these
services. As mental health services expanded in the community, it became
necessary to extend the use of reliable and valid instruments appropriate to a
brief treatment setting. This field study investigates the usefulness of the
Brief Psychiatric Rating Scale (BPRS) using paired ratings to measure the level
of psychiatric symptoms of clients treated in an urban community inpatient crisis
stabilization unit. Interrater agreement for all paired assessments exceeded .85
comparing favorably with previous studies reported in the literature. The BPRS
was found to be a useful and efficient instrument in this community setting.
PMID- 10775052
TI - K-ras point mutations in spontaneously occurring endometrial adenocarcinomas in
the Donryu rat.
AB - The Donryu rat has been found to have a high incidence of spontaneous uterine
endometrial carcinomas. Moreover the histologic findings, biological nature and
pathogenesis of these rat tumors appear similar to those in humans. To determine
if the incidence of H- and K-ras gene mutations in these rat tumors is similar to
that in human endometrial cancers, we isolated DNA samples from 2 atypical
hyperplasias, 5 simple or complex hyperplasia without atypia, 9 adenocarcinomas
and 7 histologically normal tissues, amplified exons 1 and 2 of the H- and K-ras
genes by PCR and hybridized the products with allele specific oligonucleotide
probes. K-ras point mutations were observed in 1/2 of the atypical hyperplasia
(codon 12: GGT-->GTT) and 3/9 of the carcinoma (codon 12: GGT-->GAT, GGT-->AGT,
codon 61: CAA-->CAC), while they were not detected in 7 of the normal tissues and
in 5 of the simple or complex hyperplasia without atypia. H-ras point mutations
were not detected in any of these DNA samples. These frequencies in this rat
model are similar to those in humans. The absence of K-ras mutations from simple
and complex hyperplasia tissue samples suggests that these mutations are
associated with cytological atypia. Our findings suggest that alterations in the
K-ras gene may be one of the important initiating event in endometrial
carcinogenesis in some of the Donryu rat, like the human.
PMID- 10775053
TI - Four new human renal cell carcinoma cell lines expressing globo-series
gangliosides.
AB - Clinicopathological studies revealed that monosialosyl galactosyl globoside
(MSGG) and disialosyl galactosyl globoside (DSGG) expressed by renal cell
carcinoma (RCC) are one of the biochemical indicator related to the metastatic
potential. The present study examines the characteristics of four new human RCC
cell lines and compares the expression of MSGG and DSGG among them using TLC
immunostaining and flow cytometry. TOS-1 and TOS-2 were derived from metastatic
subcutaneous tissues. TOS-3 and TOS-3LN were derived from the primary lesion and
from metastatic lymph nodes respectively. Monolayer culture, light microscopy and
electron microscopy of these cells showed that these cell lines were derived from
RCC. TLC immunostaining and flow cytometric analysis revealed increased levels of
MSGG in TOS-2 and TOS-3LN, and increased DSGG in TOS-1 and TOS-3LN. These cell
lines would be useful for functional studies of globo-series ganglioside
expressed by RCC.
PMID- 10775054
TI - The expression of common fragile sites in peripheral blood lymphocytes of breast
and colorectal cancer patients with aphidicolin.
AB - The frequency and distribution of aphidicolin induced common fragile sites was
evaluated on chromosomes of peripheral blood lymphocytes in 10 breast and 10
colorectal cancer patients, and 10 healthy controls to determine correlation
between specific fragile sites and cancer breakpoints. Fifty complete metaphases
were screened from each culture and the results were evaluated by Student's t
test. The total number of fragile sites was found as 933 in breast cancer
patients, 950 in colorectal cancer patients and 501 in control group. Both the
number of aberrations per cell and number of aberrations per damaged cell were
significantly higher in the patient groups. These findings indicate that genetic
instability in the breast and colorectal cancer patients increased and fragile
sites may play a critical role in the pathogenesis of breast and colorectal
cancer.
PMID- 10775055
TI - Effects of short-term glycemic control, low protein diet and administration of
enalapril on renal hemodynamics and protein permselectivity in type 2 diabetic
patients with microalbuminuria.
AB - To determine whether each of glycemic control (GC), low protein diet (LPD) or
administration of angiotensin converting enzyme inhibitor (ACEI) has beneficial
effects on diabetic nephropathy through the different mechanisms, changes in
charge and size selectivity of glomerulus and renal hemodynamics were analyzed in
microalbuminuric type 2 diabetic patients after additive combination therapy
(first period: GC only, second period: GC-LPD, third period: GC+LPD+ACEI). To
detect improvement of the impairments of glomerular charge selectivity and size
selectivity, changes in the ratio of the renal clearance of two plasma proteins
with similar molecular radii and different isoelectric points (pIs)
(ceruloplasmin and IgG: CRL/IgG) and changes in the ratio of the renal clearance
of two plasma proteins with similar pIs and different molecular radii (alpha2
macroglobulin and albumin: alpha2/Alb) were examined before and after each
therapy. Creatinine clearance decreased significantly in the first and third
periods although slight but not significant decrease was detected in the second
period. Filtration fraction was significantly decreased only in the third period.
Although renal clearances of Alb, IgG and CRL were decreased in periods of all
three therapies, that of alpha2-macroglobulin with a large molecular radius was
decreased significantly only after the third therapy. Neither CRL/IgG nor
alpha2/Alb changed during these three therapies. These findings suggest that each
of three short-term therapies consisting of GC, GC+LPD and GC+LPD+ACEI, reduced
proteinuria in microalbuminuric type 2 diabetic patients not through the
improvement of renal size and charge selectivities, but through improvement of
renal hemodynamics.
PMID- 10775056
TI - Alpha-adrenergic blockade in preventing posttransplant edema of lung allograft.
AB - Effect of alpha-adrenergic blockers on pulmonary edema in lung transplantation
was studied with a rat model of syngeneic left lung transplantation. Prior to
harvesting, 0.1 mg of Prazosin or 0.4 mg of Yohimbine was given to the donor.
Pulmonary and systemic hemodynamics were measured under the right pulmonary
arterial occlusion (RPAO) at different time points after grafting. Wet to dry
weight ratio (W/D) of all transplants was also calculated. Same procedure was
conducted in rats with normal and ischemic lung and in transplanted animals
without any treatments. While RPAO did not increase W/D in normal lung with a
significant elevation in pulmonary arterial pressure (PAP), both these values
significantly increased in transplanted lung. Transplanted animals could not
tolerate RPAO 24 hours after grafting, but were tolerable later than 48 hours
with elevated W/D and PAP. On the contrary, animals given Prazosin or Yohimbine
were all tolerable at 24 hours postsurgery. Yohimbine significantly improved W/D.
Consequently, it was demonstrated that pulmonary edema of the graft reached its
peak during first 24 to 48 hours after transplantation and was alleviated by the
blockade of alpha-adrenergic receptor in the graft vessel.
PMID- 10775057
TI - Influence of clinical information on the detection of wrist fractures in
children.
AB - The purpose of this investigation is to assess the importance of clinical
information for the detection of non-displaced wrist fractures in children.
Twenty non-displaced fractures of the distal radius in children younger than 15
years of age and twenty age-matched controls were evaluated by five blinded
observers before and after giving clinical data, and a receiver operating
characteristic (ROC) analysis using a continuous rating scale with a line-marking
method was performed. The detection of the fractures was significantly improved
with clinical information, and the main reason for this was an increase in true
positive fraction. Availability of adequate clinical data should be emphasized
for interpreting radiography.
PMID- 10775058
TI - Acute tubulointerstitial nephritis following intravenous immunoglobulin therapy
in a male infant with minimal-change nephrotic syndrome.
AB - A boy aged 4 years with nephrotic syndrome (NS) was referred to our hospital
because of the third relapse of NS. Hypogammaglobulinemia associated with massive
proteinuria was observed at the presentation. Residual urinary tract infection
required intravenous piperacillin and immunoglobulin therapy (IVIG). Soon after
IVIG, he complained of high fever with chills, bilateral knee joint pain, dry
cough and chest discomfort. Although he did not develop renal insufficiency, a
transient increase in the urinary beta2-microglobulin and decrease in the serum
complement hemolytic activity were observed. These clinical manifestations
spontaneously ceased. A percutaneous renal biopsy for his NS performed 19 days
after the episode of allergic reaction revealed tubulointerstitial nephritis
(TIN) with marked eosinophil infiltrates. Glomeruli showed minor glomerular
abnormalities. Renal complications associated with IVIG treatment have been
reported to date, however, acute TIN has rarely been seen.
PMID- 10775059
TI - Extra-abdominal desmoid tumor of the hand: a case report and review of the
literature.
AB - Extra-abdominal desmoid tumor of the hand is rare and only 10 cases have been
described in the literature. We present a 14-year-old boy with a recurrent extra
abdominal desmoid tumor in the dorsal site of the right hand. MR image
demonstrated the tumor in the third dorsal interosseous muscle, and adhered to
the radial side of the forth metacarpal bone. The lesion revealed iso-signal
intensity on T1-weighted images and high intensity on T2. We performed a marginal
excision. Histological examination of the tumor showed proliferation of the
fibroblastic cells with abundant collagen bundles. He developed local recurrence
for the third time. The size of the third recurrent tumor has not been changed
for 2 years and 3 months. Therefore, we have not performed any additional
surgery. Since extensive resection markedly diminishes the function of the hand,
we consider that a marginal surgical margin is acceptable for the quality of
daily life of patients with a desmoid tumor of the hand.
PMID- 10775060
TI - Stabilization of a novel beta-turn-like motif by nonconventional intramolecular
hydrogen-bonding interactions in a model peptide incorporating beta-alanine.
AB - The chemical synthesis and x-ray crystal structure analysis of a model peptide
incorporating a conformationally adaptable unsubstituted beta-Ala residue: Boc
beta-Ala-Acc6-OCH3 (C16H28N2O5, molecular weight = 328.41; 1) has been described.
The peptide crystallized in the space group P2(1)2(1)2(1) a = 8.537 (3), b =
8.872 (10), c = 25.327 (8), alpha = beta = gamma = 90.0 degrees, Z = 4. An
attractive feature of the crystal structure analysis of 1 is an accommodation of
a significantly folded beta-Ala residue in a short linear peptide. The overall
peptide conformation is typically folded into a beta-turn-like motif. The
stabilization of the peptide backbone conformation by nonconventional C-H...O
weak intramolecular hydrogen-bonding interactions, involving the ester terminal
carbon atom and the ethereal oxygen of the Boc group, has been evoked. The
conformational constraint that seems most apparent is the phi, psi value of the
highly constrained hydrophobic Acc6 ring that may play a key role in inducing or
sustaining the observed pseudo type III or III' beta-turn structure. The
resulting 12-membered hydrogen bonding ring motif in 1 is distinctly different
from the one found in classical beta-turn structures, stabilized by a
conventional strong C=O...H-N intramolecular hydrogen bond, comprised of alpha
amino acids. The potential of the conformationally adaptable beta-Ala residue to
occupy i + 1 position (left corner) of the folded beta-turn-like structure and to
design and construct novel secondary structural features have been emphasized.
PMID- 10775061
TI - Fluorescence study on the interaction of a multiple antigenic peptide from
hepatitis A virus with lipid vesicles.
AB - The interaction of the multiple antigenic peptide MAP4VP3 with lipid membranes
has been studied by spectroscopic techniques. MAP4VP3 is a multimeric peptide
that corresponds to four units of the sequence 110-121 of the capsid protein VP3
of hepatitis A virus. In order to evaluate the electrostatic and hydrophobic
components on the lipid-peptide interaction, small unilamelar vesicles of
different compositions, including zwitterionic dipalmitoylphosphatidylcholine
(DPPC), anionic dipalmitoylphosphatidylcholine/phatidylinositol (DPPC:PI 9:1),
and cationic dipalmitoylphosphatidylcholine/stearylamine (DPPC:SA 9.5:0.5), were
used as membrane models. Intrinsic tryptophan fluorescence changes and energy
transfer experiments show that MAP4VP3 binds to all three types of vesicles with
the same stoichiometry, indicating that the electrostatic component of the
interaction is not important for binding of this anionic peptide. Steady-state
polarization experiments with vesicles labeled with 1,6-diphenyl-1,3,5-hexatriene
or with 1-anilino-8-naphtalene sulphonic acid indicate that MAP4VP3 induces a
change in the packing of the bilayers, with a decrease in the fluidity of the
lipids and an increase in the temperature of phase transition in all the
vesicles. The percentage of lipid exposed to the bulk aqueous phase is around 60%
in intact vesicles, and it does not change upon binding of MAP4VP3 to DPPC
vesicles, indicating that the peptide does not alter the permeability of the
membrane. An increase in the amount of lipid exposed to the aqueous phase in
cationic vesicles indicates either lipid flip-flop or disruption of the vesicles.
Binding to DPPC vesicles occurs without leakage of entrapped carboxyfluorescein,
even at high mol fractions of peptide. However, a time-dependent leakage is seen
with cationic DPPC/SA and anionic DPPC/PI vesicles, indicating that the peptide
induces membrane destabilization and not lipid flip-flop. Resonance energy
transfer experiments show that MAP4VP3 leakage from cationic vesicles is due to
membrane fusion, whereas leakage from anionic vesicles is not accompanied by
lipid mixing. Results show that MAP4VP3 interacts strongly with the lipid
components of the membrane, and although binding is not of electrostatic nature,
the bound form of the peptide has different activity depending on the membrane
net charge; thus, it is membrane disruptive in cationic and anionic vesicles,
whereas no destabilizing effect is seen in DPPC vesicles.
PMID- 10775062
TI - Terminal residues in protein chains: residue preference, conformation, and
interaction.
AB - The known protein structures have been analyzed to find out if there is any
pattern in the type of residues used and their conformation at the two terminal
positions of the polypeptide chains. While the N-terminal position is
overwhelmingly occupied by Met (followed by Ala and Ser), the preference for the
C-terminal is not as distinct, the residues with highest propensities being Lys,
Arg, Gln, and Asn. Only one main-chain torsion angle, psi, can be defined for the
N-terminal residue, which is found to be in the extended conformation due to a
favorable electrostatic interaction between the charged amino group and the
carbonyl oxygen atom. The distribution of the angle phi for the C-terminal
residue, on the other hand, is not much different from that of the nonterminal
residues. There are some differences in the distribution of the side-chain
torsion angle chi1 of both the terminal residues from the general distribution.
The terminal segments are generally flexible and there is a tendency for the more
ordered residues to have lesser solvent exposure. About 40% of the terminal
groups form a hydrogen bond with protein atoms--a slight preference is observed
for the side-chain atoms (more than half of which belong to charged residues)
over the main-chain ones. Although the terminal residues are not included in any
regular secondary structure, the adjacent ones have a high preference to occur in
the beta conformation. There is a higher chance of a beta-strand rather than an
alpha-helix to start within the first 6 positions from the N-terminal end. It is
suggested that the extended conformation observed for the N-terminal residue
propagates along the chain leading to the formation of beta-strand. In the C
terminal end, on the other hand, as one moves upstream the alpha and beta
structures are encountered in proportion similar to the average value for these
structures in the database. The cleavage site of the zymogen structures has a
conformation that can be retained by the N-terminal residue of the active enzyme.
PMID- 10775063
TI - 1H-nmr study of water dynamics in hydrated collagen: transverse relaxation-time
and diffusion analysis.
AB - Water proton transverse relaxation times (T2) and self-diffusion coefficients (D)
were measured in randomly oriented hydrated collagen fibers. Three T2 relaxation
times were discerned indicating the presence of at least three water fractions in
the collagen sample. The D values associated with each water fraction were
determined. The diffusion time dependence of D suggests water motion is
restricted by macromolecular structure. The experimental results are discussed
with reference to the structural properties of hydrated collagen fibers.
PMID- 10775064
TI - Synthesis of delta(E)Phe-containing tripeptide via photoisomerization and its
conformation in solution.
AB - A new synthetic route to (E)-beta-phenyl-alpha,beta-dehydroalanine (delta(E)Phe)
containing peptide was presented via photochemical isomerization of the
corresponding (Z)-beta-phenyl-alpha,beta-dehydroalanine (delta(Z)Phe)-containing
peptide. By applying this method to Boc-Ala-delta(Z)Phe-Val-OMe (Z-I: Boc, t
butoxycarbonyl; OMe, methoxy), Boc-Ala-delta(E)Phe-Val-OMe (E-I) was obtained.
The identification of peptide E-I was evidenced by 1H-nmr, 13C-nmr, and uv
absorption spectroscopy, elemental analysis, and hydrogenation. The conformation
of peptide E-I in CDCl3 was investigated by 1H-nmr spectroscopy (solvent
dependence of NH chemical shift and difference nuclear Overhauser effect).
Interestingly, peptide E-I differed from peptide Z-I in the hydrogen-bonding
mode. Namely, for peptide Z-I, only Val NH participates in intramolecular
hydrogen bonding, which leads to a type II beta-turn conformation supported by
hydrogen bonding between CO(Boc) and NH(Val). On the other hand, for peptide E-I,
two NHs, delta(E)Phe NH and Val NH, participate in intramolecular hydrogen
bonding. In both peptides, a remarkable NOE (approximately 11-13%) was observed
for Ala C(alpha) H-deltaPhe NH pair. Based on the nmr data and conformational
energy calculation, it should be concluded that peptide E-I takes two consecutive
gamma-turn conformations supported by hydrogen bonding between CO(Boc) and
NH(delta(E)Phe), and between CO(Ala) and NH(Val) as its plausible conformation.
PMID- 10775065
TI - Syntheses and biological activities of sandostatin analogs containing
stereochemical changes in positions 6 or 8.
AB - In a continuation of our research efforts on the design and synthesis of novel
peptidomimetic structures, we have synthesized a series of sandostatin amide
analogs in which stereoisomers of threonine and beta-hydroxyvaline(beta-Hyv) are
employed. The analogs D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Xaa6-Cys 7]-Xbb8-NH2 (Xaa =
allo-Thr, D-allo-Thr, D-beta-Hyv, beta-Hyv, D-Thr, and Xbb = Thr or Xaa = Thr and
Xbb = allo-Thr, D-allo-Thr, beta-Hyv, D-Thr) explore the effects on biological
activity of stereochemical modifications and beta-methylation at positions 6 or
8. By these modifications, we examine the role of the two residues in binding to
somatostatin receptors. We describe the synthesis and biological activity of
these analogs. In combination with the results of the conformational analysis,
this study provides new insights into the structural requirements for the binding
affinity of somatostatin amide analogs to somatostatin receptors [Mattern et al.,
Conformational analyses of sandostatin analogs containing stereochemical changes
in positions 6 or 8].
PMID- 10775067
TI - New analysis of the phylogenetic change of collagen thermostability.
AB - Recent data concerning the thermostability and the primary structure of type IV
collagens, some invertebrate collagens, and for the stability of synthetic
collagen-like polypeptides, show that our earlier analysis of the phylogenetic
change of thermostability has some shortcomings. The results of the analysis were
corrected and it has been shown that the dependence of denaturation temperature
Td on 4-hydroxyproline content is hyperbolic and the total Gly-Pro-Hyp sequence
content is a main, but not exclusive, factor influencing the change of collagen
thermostability. It appears possible that the same mechanism underlies the
thermostability of fibril-forming collagens of all animal life, ranging from
Antarctic ice fish to at least one annelid (Alvinella pompejana) living at very
high temperatures at the bottom of the ocean near thermal vents.
PMID- 10775066
TI - Conformational analyses of sandostatin analogs containing stereochemical changes
in positions 6 or 8.
AB - We report the conformational analysis by 1H nmr in DMSO and computer simulations
involving distance geometry and molecular dynamics simulations of analogs of the
cyclic octapeptide D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys 7]-Thr8-ol
(sandostatin, octreotide). The analogs D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Xaa6-Cys 7]
Xbb8-NH2 (Xaa = allo-Thr, D-allo-Thr, D-beta-Hyv, beta-Hyv, D-Thr, and Xbb = Thr
or Xaa = Thr and Xbb = allo-Thr, D-allo-Thr, beta-Hyv, D-Thr) contain
stereochemical changes in the Thr residues in positions 6 and 8, which allow us
to investigate the influence of the stereochemistry within these residues on
conformation and binding affinity. The molecular dynamics simulations provide
insight into the conformational flexibility of these analogs. The compounds with
(S)-configuration at the C(alpha) of residue 6 adopt beta-sheet structures
containing a type II' beta-turn with D-Trp in the i+1 position, and these
conformations are "folded" about residues 6 and 3. The structures are very
similar to those observed for sandostatin, and the disulfide bridge results in a
close proximity of the H(alpha) protons of residues 7 and 2, which confirms
earlier observations that a disulfide bridge is a good mimic for a cis peptide
bond. The compounds with (R)-configuration at the C(alpha) of residue 6 adopt
considerably different backbone conformations. The structures observed for these
analogs contain either a beta-turn about residue Lys and Xaa6 or a gamma-turn
about the Xaa6 residue. These compounds do not exhibit significant binding to the
somatostatin receptors, while the compounds with (S) configuration in position 6
bind potently to the sst2, 3, and 5 receptors. The nmr spectra of analogs with
(R) or (S) configuration at the C(alpha) of residue 8 are strikingly similar to
each other. We have demonstrated that the chemical shifts of protons of residues
3, 4, 5, and 6, which are part of the type II' beta-turn, and especially the
effect on the Lys gamma-protons are considerably different in active molecules as
compared to inactive analogs. Since the presence of a type II' beta-turn is
crucial for the binding to the receptors, the chemical shifts, the amide
temperature coefficients of the Thr residue and the medium strength NOE between
LysNH and ThrNH can be extremely useful as an initial screening tool to separate
the active molecules from inactive analogs.
PMID- 10775068
TI - Sclerosing encapsulating peritonitis in pediatric peritoneal dialysis patients.
AB - The aim of this study was to define the incidence and characteristics of
sclerosing encapsulating peritonitis (SEP) in pediatric peritoneal dialysis (PD)
patients in Japan. A questionnaire was sent to all dialysis units with at least
two pediatric PD patients. Among 687 patients registered, 11 cases (1.6%) of SEP
were diagnosed. The mean age of patients with SEP at the start of PD was 9.7+/
3.6 years and at SEP diagnosis, 19.1+/-3.8 years. All patients had undergone PD
for more than 5 years, and the mean PD duration was 9.6+/-3.3 years. SEP was
diagnosed in 6.6% and 12% of patients dialyzed for >5 years and >8 years,
respectively. The incidence of peritonitis among patients with SEP was not
different from that among the Japanese pediatric registry. All patients had
virtually no residual urine volume and 9 had impaired peritoneal ultrafiltration.
Peritoneal calcification was the most-frequent radiological finding. Peritoneal
biopsy was performed in 7 patients and confirmed sclerotic peritonitis in all.
Ten patients transferred to hemodialysis, and only 1 patient underwent surgery.
Three patients died. We recommend that patients on PD for more than 5 years who
have impaired peritoneal ultrafiltration or peritoneal calcification should be
carefully managed as presumptive cases of SEP.
PMID- 10775069
TI - Comparing a urea kinetic monitor with Daugirdas formula and dietary records in
children.
AB - The use of the online urea monitor has not been validated in children on
hemodialysis. We compared online measured Kt/V(urea) and protein catabolic rate
(PCR) with single- and double-pool Daugirdas formula (DF and eDF) based
Kt/V(urea) and with protein intake derived from dietary records (DPI). In 8
children aged 8-18 years, 26 measurements were performed with the online urea
monitor (UM 1000) with double-needle access. In 7 children, aged 4-14 years, 12
additional measurements were performed using single-needle dialysis. Pre-dialysis
serum urea was determined by the monitor in equilibrated ultrafiltrate, obtained
with ultrafiltration rates (UF) of 0.5 or 1.0 l/h, in 10 and 23 experiments
respectively, and compared with the laboratory results. Urea determination in
ultrafiltrate correlated well with blood sample urea: r=0.945 and 0.88 for UF
rates of 0.5 l/h and 1.0 l/h, respectively. The correlation of online Kt/V with
DF and eDF was 0.79 for double-needle and 0.21 for single-needle access. Bland
Altmann analysis showed a mean bias of 0.02 and 0.001, but levels of agreement of
+0.3 and -0.3 for double-needle and +0.77 and -0.77 for single-needle dialysis
respectively with DF. Maximum percentage error for double-needle access was 18%
and 59% for single-needle access. The correlation of DPI with PCR was 0.5. A
Bland-Altmann plot showed a mean bias of =0.22 with upper and lower limits of
agreement of +0.55 and -0.1, respectively. Online urea kinetic modelling is
feasible in children with double-needle hemodialysis only. Even with small
dialyzers, an accurate serum urea measurement is obtained. PCR underestimates
dietary protein intake.
PMID- 10775070
TI - Interleukin-8 alters glomerular heparan sulfate glycosaminoglycan chain size and
charge in rats.
AB - We have previously shown that the in vivo infusion of interleukin-8 (IL8) in rats
causes albuminuria and an increased catabolism of the heparan sulfate (HS)
glycosaminoglycans (GAG). The purpose of this study was to characterize further
the in vivo effect of IL8 on rat HSGAG. The left renal artery of male rats was
continuously infused with IL8 (750 ng/ml, 4 rats) or 1% bovine serum albumin (3
rats) using an osmotic pump. On the 5th day of infusion, 35sulfate (1.0 mCi/100
g) was given intraperitoneally and the rat was killed 8 h later. Glomerular HSGAG
was isolated and its size and charge was determined by liquid chromatography. The
HSGAG 35sulfate uptake was higher in IL8-treated rats than controls (387+/-138
vs. 246+/-15 cpm/1,000 glomeruli, mean +/- SD, P<0.05). No differences in HSGAG
size were observed between IL8-treated and control animals. However, after ion
exchange chromatography, there was a shift to the left in the elution profile of
IL8-treated rats, demonstrating the presence of chains with decreased negative
charge. IL8 infusion into rats results in a decreased total negative charge of
the HSGAG. Because IL8 has been found in the serum of some patients with minimal
lesion nephrotic syndrome, this finding may explain, at least in part, the
reported reduced glomerular charge barrier observed in these patients.
PMID- 10775071
TI - Fetal ontogeny and role of metanephric bradykinin B2 receptors.
AB - Previous studies in rats have shown that blockade of bradykinin B2 receptors
(B2R) in combination with a high-salt intake during gestation result in poor
postnatal survival and long-term hypertension in the offspring. In this study, we
examined the fetal ontogeny of B2R and determined the consequences of gestational
B2R blockade and high salt on kidney development. B2R gene expression is induced
on embryonic day (E16) of fetal metanephrogenesis and remains sustained until
term. The earliest expression of the B2R protein is observed on apical membranes
of ureteric bud branches and in capillary loop stage glomeruli. By the end of
gestation, B2R becomes restricted to more-differentiated tubules in the deep
cortex and medulla. Pairs of rats on normal (0.12 mmol/g) or high (0.84 mmol/g)
salt diets were mated at 14 weeks of age. The B2R antagonist, Icatibant
(previously known as Hoe-140) (300 nmol/kg per day) or saline (vehicle) was
infused intraperitoneally during gestation via osmotic minipumps. Fetuses were
examined on E20 (n=27-36 per group). No significant differences in litter size or
body weight were observed among the groups. Combined high-salt and Icatibant
treatment caused aberrant fetal renal development characterized by tubular
dysgenesis, widened stromal mesenchyme, and glomerular cysts. The dysgenetic
tubules stained positively for the distal nephron lectin, Dolichos biflorus, and
exhibited enhanced Bax expression and apoptosis. Renal microvascular development,
the number of mature glomeruli, and percentage of proliferating glomerular cells
were not affected. Gestational Icatibant or high salt alone had no deleterious
effects on fetal nephrogenesis. We conclude that gestational blockade of the
kallikrein-kinin system impairs fetal nephrogenesis if combined with an
intrauterine stressor such as high-salt intake. B2R may play a protective role
during segmental nephron differentiation.
PMID- 10775072
TI - Echo-enhanced ultrasound voiding cystography in children: a new approach.
AB - The development of echo-enhancing agents has significantly improved the detection
of the movement of fluid within the urinary tract by ultrasonography (US). The
purpose of our study was to compare ultrasound voiding cystography (USVC) for the
detection of vesicoureteric reflux (VUR) in children with direct radionuclide
voiding cystography (DRVC). Ninety-nine children, aged 1.1-12.3 years, with 198
potentially refluxing units, were investigated simultaneously by DRVC and USVC.
The indications for cystography were urinary tract infection, follow-up of a
previously detected VUR, and screening of siblings of children with VUR. During
the investigation an echo-enhancing agent (Levovist) was administered
intravesically through a catheter already in place for the DRVC. The movement of
both agents, radiotracer and Levovist, was registered simultaneously by a
computerized gamma camera and US, respectively. The results were analyzed with
DRVC representing the reference diagnostic test. The overall sensitivity and
specificity of USVC for the detection of VUR were 79% and 92%, respectively. USVC
may represent a reliable diagnostic tool for the detection and follow-up of VUR
in children.
PMID- 10775073
TI - Persistent hypoparathyroidism following magnesium repletion in burn-injured
children.
AB - Children suffering severe burns develop hypocalcemia, magnesium (Mg) depletion,
hypoparathyroidism, and renal resistance to parathyroid hormone (PTH) infusion.
We hypothesized that Mg depletion accounted for both the hypoparathyroidism and
the renal resistance to PTH, and that Mg repletion would improve both. Due to a
lack of PTH for infusion, we studied only the effect of Mg repletion on the
relationship between ionized Ca (iCa) and PTH in the serum of 14 sequentially
recruited children burned > or =40% total body surface area. All received a
urinary Mg retention test a median of 20 days post burn (range 8-137 days). Seven
(50%) of the children remained Mg depleted, which was not attributable to burn
size or to time from burn to study. Combined enteral and parenteral Mg intakes
were not different between the depleted and repleted groups, 12.2+/-4.4 (SD)
mg/kg per day and 14.2+/-6.2 mg/kg per day, respectively. Both groups had low
intact PTH levels in relation to serum iCa concentration, indicating persistent
hypoparathyroidism. We conclude that Mg depletion is not the chief cause of
hypoparathyroidism following thermal injury and we postulate that the persistent
hypoparathyroidism is consistent with a reduced set-point for Ca suppression of
PTH secretion.
PMID- 10775074
TI - Acyclovir prophylaxis of varicella in children with renal disease receiving
steroids.
AB - Varicella, or chickenpox, is very communicable and has been shown to be
transmitted to nearly 90% of household contacts. Severe varicella infections with
fatal complications have been noted in children receiving corticosteroids despite
the administration of varicella-zoster immune globulin (VZIG). The use of post
exposure acyclovir prophylaxis in immunocompetent children exposed to a household
contact with varicella has been shown to decrease the transmission rate of
varicella significantly. We studied the safety and efficacy of acyclovir
prophylaxis as an adjunctive preventive measure in 8 children (10 separate
exposures) receiving corticosteroids for renal disease. Four children (6 separate
exposures) served as controls. No adverse reactions were reported with the
acyclovir prophylaxis. The maximum change between pre- and study serum creatinine
levels was 0.1 mg/dl. None of the 8 patients who received acyclovir prophylaxis
developed chickenpox. One of these 8 patients developed humoral immunity to
varicella despite the absence of clinical infection. One of 4 patients who
received VZIG prophylaxis alone developed chickenpox. These data support the use
of acyclovir prophylaxis as an adjunctive measure to VZIG for the prevention of
potentially serious varicella infection in children receiving steroids.
PMID- 10775075
TI - Growth over 10 years following a 1-year trial of growth hormone therapy.
AB - The growth of short children with chronic renal failure (CRF) and renal
transplants was assessed over 10 years following entry into a 1-year trial of
recombinant human growth hormone (rhGH) therapy. Patients were divided into three
groups: 6 prepubertal patients with CRF (group 1), mean (range) age at start of
trial 7.7 (5.0-10.4) years; 6 prepubertal patients with renal transplants (group
2), age 11.9 (9.5-14.6) years; and 6 pubertal patients with renal transplants
(group 3), age 15.6 (14.1-18.3) years. In group 1, the mean (range) height
standard deviation score (Ht SDS) increased from -2.9 (-3.7 to -2.2) to -1.9 (
2.9 to -0.5) over 4.0 (0.3-9.1) years of rhGH (P=0.04), and was -1.6 (-2.9 to
0.4) after 10 years of follow-up (NS). In group 2 Ht SDS increased from -3.3 (
4.5 to -1.9) to -2.9 (-5.4 to -0.5) over 2.7 (1.0-6.0) years and was -3.0 (-6.3
to -0.1) at final height (NS). In group 3 Ht SDS increased from -3.4 (-4.3 to
2.6) to -3.0 (-3.4 to -2.2) over 1.4 (0.2-2.3) years (NS) and was -2.5 (-3.0 to
1.9) at final height (P=0.03 from stopping rhGH to final height). Final height
was attained in 13 patients, in whom Ht SDS increased from -3.2 (-4.3 to -1.9) to
-2.6 (-3.9 to -0.5) on rhGH (P=0.004) and to -2.2 (-4.4 to -0.1) after stopping
treatment (P=0.04). Four patients died, 2 have chronic hepatitis C, and 1 has had
surgery for parathyroid adenomata. In conclusion, the majority of patients had an
improvement in Ht SDS while on rhGH, which was maintained after stopping
treatment.
PMID- 10775076
TI - Maternal cocaine abuse and fetal renal arteries: a morphometric study.
AB - The purpose of the present study was to evaluate the pathological findings and
perform morphometric analysis of the renal arteries of fetuses exposed to cocaine
in utero. The control group consisted of 22 stillborn fetuses of unknown etiology
whose mothers' urine was negative for cocaine or any other vasoactive substances.
The study group comprised 29 stillborn fetuses whose mothers' urine was positive
only for cocaine on the day of admission. Sections of fetal kidneys (4 microm),
stained with hematoxylin and eosin and periodic acid-Schiff reagent, were
examined under light microscopy (x40) to identify interlobular arteries.
Morphometric analysis of these arteries was performed using a self-assembled
system with a touch-sensitive screen as an interactive peripheral. Their inner
and outer circumferences were measured by outlining them on the screen with a
stylus. The radius (r) was calculated from the measurement of the circumference
(2.pi.r). The difference of the radii of the outer and inner circumferences was
the thickness of the arterial wall. The interlobular arterial thickness was
significantly greater (P<0.001) in the cocaine-exposed group (mean 15.46+/-5.8
microm, 2SD) compared with the normal (mean 9.03+/-3.96 microm, 2SD). There was a
significantly (P<0.001) positive relation with advancing gestational ages in both
groups. The circumferences of the lumen of the arteries showed a significant
(P<0.05) relation with advancing gestational ages in the normal group only. In
the cocaine-exposed group, the arterial lumen circumference (mean 167.88+/-17.58
microm, 2SD) was significantly (P<0.001) smaller than in the normal group (mean
227.73+/-6.82 microm, 2SD). Thus, maternal cocaine abuse is associated with
thickening of the interlobular arterial wall of the fetal kidney and narrowing of
the lumen.
PMID- 10775077
TI - Oligohydramnion, renal failure and no pulmonary hypoplasia in glomerulocystic
kidney disease.
AB - Two newborns with glomerulocystic kidney disease manifesting as late onset
oligohydramnion and neonatal anuria, yet without severe respiratory distress, are
presented. They had a similar perinatal course and associated clinical
manifestations. No associated congenital or inherited malformation syndrome could
be defined. Both infants' parents were first degree cousins and belonged to the
same small Bedouin tribe, and neither they nor the infants' siblings had
polycystic kidneys or renal insufficiency, pointing to either a possible genetic
etiology or a common external toxic exposure.
PMID- 10775078
TI - Spontaneous clinical improvement in dense deposit disease.
AB - The clinical course and 3-year follow-up of a female patient aged 11 years who
presented with nephrotic syndrome and renal failure is described. The renal
biopsy revealed type II membranoproliferative glomerulonephritis or dense deposit
disease. She was treated with penicillin prophylaxis, frusemide and captopril,
and was not given immunosuppression, anticoagulation or antiplatelet therapy.
Despite poor prognostic clinical and pathological features, she had spontaneous
resolution of her renal failure and proteinuria, although her proteinuria
recurred 17 months post presentation. Her unusual progress, with improvement in
her disease activity and normalisation of her glomerular filtration rate, is
described.
PMID- 10775079
TI - Renal involvement in polyarteritis nodosa: evaluation of 26 Turkish children.
AB - Renal involvement is common in childhood polyarteritis nodosa (PAN). We report a
retrospective analysis of the presentation and clinical course of 26 patients
with PAN and renal involvement. The mean age was 9.3 years (range 1-14 years) and
there were 12 boys and 14 girls. Renal symptoms at presentation were as follows:
3 had isolated proteinuria, 9 had nephritic syndrome, 2 had nephritic and
nephrotic components, and 10 had renal failure with one of the above features.
Two patients with isolated hypertension were diagnosed by angiography and
classified as classical PAN. Patients either received prednisone p.o. alone
(n=9), or prednisone plus cyclophosphamide p.o. (n=11), or pulse steroids with
prednisone p.o. and cyclophosphamide (n=2); 4 did not receive any treatment.
Patients who were given cyclophosphamide had a significantly better outcome than
those who did not. We suggest that oral cyclophosphamide therapy and
corticosteroids are effective in the treatment of PAN. The overall 1-year and 5
year survival rates of the patients were 72.5% and 60%, respectively. In
conclusion, renal disease is a serious manifestation of PAN necessitating prompt
and aggressive treatment.
PMID- 10775080
TI - Hypocomplementemic urticarial vasculitis: report of a pediatric case.
AB - Hypocomplementemic urticarial vasculitis syndrome (HUVS) is well described in
adults but is quite rare in children. We report a pediatric case of HUVS
initially diagnosed as juvenile rheumatoid arthritis and then as Henoch-Schonlein
purpura. Beginning at 3 years of age, our patient developed polyarthritis with
hypocomplementemia. She subsequently experienced an intermittent purpuric rash
beginning at age 4 years, and she continued to have episodic arthritis and rash
for years. Hematuria and proteinuria were noted at 12 years of age; renal biopsy
revealed membranoproliferative glomerulonephritis with membranous features. Serum
complement evaluation revealed activation of the classical pathway, consistent
with HUVS. Therapy with oral dapsone led to improvement in proteinuria. HUVS
should be considered in the differential diagnosis of pediatric patients with
glomerulonephritis, urticarial rash, arthritis/arthralgias, and obstructive
pulmonary disease.
PMID- 10775081
TI - Neonatal hypertension: diagnosis and management.
AB - Hypertension in the term or preterm neonate may be seen in up to 2% of all
infants cared for in the modern neonatal intensive care unit. Although the
definition of hypertension in this age group has not been completely
standardized, recent studies have provided new normative data that may be used to
facilitate identification of such infants. Common causes of hypertension in
neonates include thromboembolic events related to umbilical catheterization,
congenital problems such as aortic coarctation, structural renal malformations
and renovascular disease, as well as acquired renal disease and certain
medications. A careful history and physical examination will usually identify the
probable cause in most cases without the need for extensive laboratory or
radiologic testing. Therapy of neonatal hypertension should be tailored to the
severity of the blood pressure elevation, and to the underlying cause of
hypertension as appropriate. A wide range of therapeutic agents are now available
for management of neonatal hypertension in both the acute and chronic settings.
In most cases hypertension will resolve, but some infants may require prolonged
treatment.
PMID- 10775082
TI - Evolution of secondary hyperparathyroidism after renal transplantation.
AB - Renal osteodystrophy is an important problem in children with chronic renal
failure, leading to skeletal deformities. The most-frequent type of renal
osteodystrophy is secondary hyperparathyroidism, and the main factors
contributing to the pathogenesis of this condition are completely or partially
corrected after successful renal transplantation. The present paper reviews data
on the evolution of secondary hyperparathyroidism after transplantation. Studies
in both adults and children suggest that secondary hyperparathyroidism and
increased bone remodelling activity may persist months after transplantation. The
severity of secondary hyperparathyroidism prior to transplantation, the duration
of dialysis, and the development of nodular and/or monoclonal hyperplasia of
parathyroid glands are the most-important factors that determine the phenomenon.
Important issues, which still need to be answered, are the possible roles of
growth factors, cytokines, VDR gene polymorphism (B/b allele), and type of
immunosuppressive regimen in the skeletal abnormalities observed.
PMID- 10775083
TI - The ethics of withholding and withdrawing dialysis therapy in infants.
AB - Pediatric nephrologists may encounter infants with renal failure who have either
unexpectedly survived lung hypoplasia at birth or whose renal failure could be
treated but comorbid conditions exist. As a member of the health care team, the
pediatric nephrologist may be asked to guide therapeutic intervention with
parents, family members, and other care-givers. We present a case study that
illustrates some of the difficulties that may arise when conflicting social and
economic pressures, as well as public opinion and legal authority, enter the
decision-making process. Clinical, theoretical, legal, and economic
considerations involved in the ethical decision process are presented. Some
tentative guidelines for approaching such dilemmas are offered bearing in mind a
goal of consensual decision making.
PMID- 10775084
TI - Extracellular fluid restoration in hypertonic dehydration.
PMID- 10775085
TI - Hypercalcemia in neonatal distal renal tubular acidosis.
PMID- 10775086
TI - Amykacin-related apneic episode in an infant on peritoneal dialysis.
PMID- 10775087
TI - Nano-electrospray ionization quadrupole time-of-flight tandem mass spectrometric
analysis of a ganglioside mixture from human granulocytes.
PMID- 10775089
TI - Characterization of combinatorially designed polyarylates by time-of-flight
secondary ion mass spectrometry.
AB - A series of 16 polyarylates, with well-controlled and systematically varying
chemistry, has been characterized by time-of-flight secondary ion mass
spectrometry (TOF-SIMS). The polymers are structurally identical except for the
incremental additions of C2H4 units to the backbone and sidechain. From the
spectra, peaks characteristic of all polyarylates are identified. Furthermore,
evaluation of the spectra and identification of unique signals allow
classification of the polyarylates according to sidechain and backbone chemistry.
PMID- 10775088
TI - Comparative analysis of ceramide structural modification found in fungal
cerebrosides by electrospray tandem mass spectrometry with low energy collision
induced dissociation of Li+ adduct ions.
AB - Fungal cerebrosides (monohexosylceramides, or CMHs) exhibit a number of ceramide
structural modifications not found in mammalian glycosphingolipids, which present
additional challenges for their complete characterization. The use of Li+
cationization, in conjunction with electrospray ionization mass spectrometry and
low energy collision-induced dissociation tandem mass spectrometry (ESI-MS/CID
MS), was found to be particularly effective for detailed structural analysis of
complex fungal CMHs, especially minor components present in mixtures at extremely
low abundance. A substantial increase in both sensitivity and fragmentation was
observed on collision-induced dissociation of [M + Li]+ versus [M + Na]+ of the
same CMH components analyzed under similar conditions. The effects of particular
modifications on fragmentation were first systematically evaluated by analysis of
a wide variety of standard CMHs expressing progressively more functionalized
ceramides. These included bovine brain galactocerebrosides with non-hydroxy and 2
hydroxy fatty N-acylation; a plant glucocerebroside having (E/Z)-delta8 in
addition to (E)-delta4 unsaturation of the sphingoid base; and a pair of fungal
cerebrosides known to be further modified by a branching 9-methyl group on the
sphingoid moiety, and to have a 2-hydroxy fatty N-acyl moiety either fully
saturated or (E)-delta3 unsaturated. The method was then applied to
characterization of both major and minor components in CMH fractions from a non
pathogenic mycelial fungus, Aspergillus niger; and from pathogenic strains of
Candida albicans (yeast form); three Cryptococcus spp. (all yeast forms); and
Paracoccidioides brasiliensis (both yeast and mycelium forms). The major
components of all species examined differed primarily (and widely) in the level
of 2-hydroxy fatty N-acyl delta3 unsaturation, but among the minor components a
significant degree of additional structural diversity was observed, based on
differences in sphingoid or N-acyl chain length, as well as on the presence or
absence of the sphingoid delta8 unsaturation or 9-methyl group. Some variants
were isobaric, and were not uniformly present in all species, affirming the need
for MS/CID-MS analysis for full characterization of all components in a fungal
CMH fraction. The diversity in ceramide distribution observed may reflect
significant species-specific differences among fungi with respect to cerebroside
biosynthesis and function.
PMID- 10775090
TI - Liquid chromatography/atmospheric pressure chemical ionization-mass spectrometric
analysis of benzoylurea insecticides in citrus fruits.
AB - A liquid chromatography (LC) method for the quantitative determination of three
benzoylurea insecticide residues (diflubenzuron, flufenoxuron and hexaflumuron)
in citrus fruits is described. Residues were successfully separated on a C18
column by methanol/water gradient elution. Detection was by negative-ion,
selected-ion monitoring atmospheric pressure chemical ionization-mass
spectrometry (APCI-MS); the main ions were [M - H]-, and the secondary fragment
ions were [M - H - HF]-. Useful confirmatory information can thus be obtained at
low extraction voltages from losses of HF. Detection limits for standard
solutions were 10 fg injected and good linearity and reproducibility were
obtained. The optimum LC/APCI-MS conditions were applied to the analysis of
benzoylureas in oranges. Samples were extracted using matrix solid phase
dispersion (MSPD), in which orange samples were homogenized with Cs, placed onto
a glass column and eluted with dichloromethane. Detection limits of 2 microg kg(
1) in the crop were obtained. Average recoveries from citrus fortified with
approximately (25-1000 microg kg(-1)) ranged from 87 to 102%. The method was
applied to field-treated orange samples and benzoylureas were sometimes detected
at concentration levels lower than maximum residue limits.
PMID- 10775091
TI - Benefits of 2.94 micron infrared matrix-assisted laser desorption/ionization for
analysis of labile molecules by Fourier transform mass spectrometry.
AB - A 2.94 microm Er:YAG laser was used together with a commercial Fourier transform
mass spectrometer to study labile biomolecules. The combination has shown
superior performance over conventional 337 nm ultraviolet matrix-assisted laser
desorption/ionization (UV-MALDI) Fourier transform mass spectrometry (FTMS),
especially for the analysis of peptides with post-translational modifications.
With succinic acid as a matrix, the sensitivity of the single-shot analysis was
increased by an order of magnitude to the low femtomole level, with significantly
less fragmentation observed. Intact molecular ions of a range of O-glycosylated
and sulfated peptides were detected. Urea was found to induce even less
fragmentation, although at the expense of the total ion yield. Molecular ions of
a noncovalent complex (vancomycin + diacetyl-L-Lys-D-Ala-D-Ala) have been
observed for the first time in MALDI-FTMS. 2.94 microm infrared (IR) MALDI also
produced abundant molecular ions of a range of nonbiological samples, including
C60 and C70 fullerenes as well as dimetal coordination complexes.
PMID- 10775092
TI - Analysis of intact tetraether lipids in archaeal cell material and sediments by
high performance liquid chromatography/atmospheric pressure chemical ionization
mass spectrometry.
AB - A method combining normal phase high performance liquid chromatography (HPLC)
with positive ion atmospheric pressure chemical ionization mass spectrometry
(APCI-MS) was developed for the analysis of intact glycerol dialkyl glycerol
tetraethers (GDGTs) in archaeal cell material and sediments. All GDGTs previously
reported to occur in the thermophilic archaeon Sulfolobus solfataricus could be
identified based on their mass spectra and retention time. Positive ion mass
spectra consisted of abundant protonated molecules and fragment ions
corresponding to loss of water and the glycerol moiety. In addition, two novel
GDGTs representing alternative combinations of biphytanyl moieties were observed.
Using this method, the tetraethers present in the thermophilic archaeon
Metallosphaera sedula and two sediment samples were characterized. This rapid
method will greatly contribute to the establishment of the sedimentary record of
these compounds and increase our understanding of archaea and their occurrence in
widely different environments.
PMID- 10775093
TI - Rapid identification of Mg-chelated chlorins by on-line high performance liquid
chromatography/atmospheric pressure chemical ionization mass spectrometry.
AB - On-line high performance liquid chromatography/atmospheric pressure chemical
ionization mass spectrometry (HPLC/APCI-MS) has been applied to the
identification of a number of tetrapyrrolic pigments as well as several magnesium
free analogs. Mass spectra, acquired both in positive (+) and negative (-)
ionization mode, allow not only the determination of the structural features of
the pigments, but also a very easy differentiation of the Mg-chelated pigments
from the free bases. In the positive ionization mode, all pigments show mainly a
[M + H]+ ion and a [M + H - C20H38]+ fragment ion corresponding to the loss of
the phytyl chain via a hydrogen rearrangement. In the negative ionization mode,
on the other hand, although all pigments give an abundant molecular anion [M]-*,
only the Mg-chelated chlorin spectra show a prominent fragment [M - C20H39]-
produced by a formal loss of the phytyl radical.
PMID- 10775094
TI - Structure of the lipid A of Bordetella hinzii ATCC 51730.
AB - Bordetella hinzii has recently been isolated from immunocompromised human hosts.
The structure of the lipid A of its endotoxin was investigated using chemical
analyses, nuclear magnetic resonnance (NMR), gas liquid chromatography/mass
spectrometry (GC/MS), plasma desorption mass spectrometry (PDMS) and matrix
assisted laser desorption/ionization (MALDI) mass spectrometry. The lipid A
contains the classical bisphosphorylated beta-(1-->6)-linked D-glucosamine
disaccharide with hydroxytetradecanoic acid (C14OH) in amide linkages. The lipid
A components of B. pertussis, B. bronchiseptica, and B. parapertussis all differ
in their acylation pattern but share a residue of tetradecanoyl-3
hydroxytetradecanoic acid in amide linkage at the C-2' position. However, in the
B. hinzii species, the tetradecanoic acid (C14) is stoichiometrically replaced by
a 2-hydroxytetradecanoic acid (2-C14OH). In the few reported examples of a
hydroxylated fatty acid in this position, the substitutions were only partial.
The B. hinzii lipid A differs from that of B. pertussis also by replacement of
the hydroxydecanoic acid (C10OH) by hydroxydodecanoic acid (C12OH) and by the
presence of a hexadecanoic acid (C16) to give a sixth fatty acid. The lipid A was
heterogeneous, being composed of three major molecular species: tetra-, penta-
and hexaacylated. The fatty acids in ester linkage were localized by PDMS of the
native and alkali-treated lipid A. The lipid A components isolated from the O
chain-linked lipopolysaccharides (LPSs) were shown to be more acylated than those
from the O-chain-free LPSs.
PMID- 10775095
TI - Investigating ion-surface collisions with a niobium superconducting tunnel
junction detector in a time-of-flight mass spectrometer
AB - The performance of an energy sensitive, niobium superconducting tunnel junction
(STJ) detector is investigated by measuring the pulse height produced by
impacting molecular and atomic ions at different kinetic energies. Ions are
produced by laser desorption and matrix-assisted laser desorption in a time-of
flight mass spectrometer. Our results show that the STJ detector pulse height
decreases for increasing molecular ion mass, passes through a minimum at around
2000 Da, and then increases with increasing mass of molecular ions above 2000 Da.
The detector does not show a decline in sensitivity for high mass ions as is
observed with microchannel plate ion detectors. These detector plus height
measurements are discussed in terms of several physical mechanisms involved in an
ion-surface collision.
PMID- 10775097
TI - Demonstrating the effect of the 'polarised grid geometry' for orthogonal
acceleration time-of-flight mass spectrometers
PMID- 10775096
TI - Determination of the fatty acid composition of saponified vegetable oils using
matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
AB - A method using matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry (MALDI-TOFMS) for the determination of the fatty acid composition of
vegetable oils is described and illustrated with the analysis of palm kernel oil,
palm oil, olive oil, canola oil, soybean oil, vernonia oil, and castor oil.
Solutions of the saponified oils, mixed with the matrix, meso
tetrakis(pentafluorophenyl)porphyrin, provided reproducible MALDI-TOF spectra in
which the ions were dominated by sodiated sodium carboxylates [RCOONa + Na]+.
Thus, palm kernel oil was found to contain capric acid, lauric acid, myristic
acid, palmitic acid, oleic acid, and stearic acid. Palm oil had a fatty acid
profile including palmitic, linoleic, oleic, and stearic. The relative
percentages of the fatty acids in olive oil were palmitoleic (1.2 +/- 0.5),
palmitic (10.9 +/- 0.8), linoleic (0.6 +/- 0.1), linoleic (16.5 +/- 0.8), and
oleic (70.5 +/- 1.2). For soybean oil, the relative percentages were: palmitoleic
(0.4 +/- 0.4), palmitic (6.0 +/- 1.3), linolenic (14.5 +/- 1.8), linoleic (50.1
+/- 4.0), oleic (26.1 +/- 1.2), and stearic (2.2 +/- 0.7). This method was also
applied to the analysis of two commercial soap formulations. The first soap gave
a fatty acid profile that included: lauric (19.4% +/- 0.8), myristic (9.6% +/-
0.5), palmitoleic (1.9% +/- 0.3), palmitic (16.3% +/- 0.9), linoleic (5.6% +/-
0.4), oleic (37.1% +/- 0.8), and stearic (10.1% +/- 0.7) and that of the second
soap was: lauric (9.3% +/- 0.3), myristic (3.8% +/- 0.5), palmitoleic (3.1% +/-
0.8), palmitic (19.4% +/- 0.8), linoleic (4.9% +/- 0.7), oleic (49.5% +/- 1.1),
and stearic (10.0% +/- 0.9). The MALDI-TOFMS method described in this
communication is simpler and less time-consuming than the established
transesterification method that is coupled with analysis by gas
chromatography/mass spectrometry (GC/MS). The new method could be used routinely
to determine the qualitative fatty acid composition of vegetable oils, and, when
fully validated by comparison with standard analytical methodologies, should
provide a relatively fast quantitative measurement of fatty acid mixtures and/or
soap formulations that contain saturated and unsaturated hydrocarbon moieties.
PMID- 10775098
TI - Orbital physics in transition-metal oxides
AB - An electron in a solid, that is, bound to or nearly localized on the specific
atomic site, has three attributes: charge, spin, and orbital. The orbital
represents the shape of the electron cloud in solid. In transition-metal oxides
with anisotropic-shaped d-orbital electrons, the Coulomb interaction between the
electrons (strong electron correlation effect) is of importance for understanding
their metal-insulator transitions and properties such as high-temperature
superconductivity and colossal magnetoresistance. The orbital degree of freedom
occasionally plays an important role in these phenomena, and its correlation
and/or order-disorder transition causes a variety of phenomena through strong
coupling with charge, spin, and lattice dynamics. An overview is given here on
this "orbital physics," which will be a key concept for the science and
technology of correlated electrons.
PMID- 10775099
TI - Advances in the physics of high-temperature superconductivity
AB - The high-temperature copper oxide superconductors are of fundamental and enduring
interest. They not only manifest superconducting transition temperatures
inconceivable 15 years ago, but also exhibit many other properties apparently
incompatible with conventional metal physics. The materials expand our notions of
what is possible, and compel us to develop new experimental techniques and
theoretical concepts. This article provides a perspective on recent developments
and their implications for our understanding of interacting electrons in metals.
PMID- 10775100
TI - Quantum criticality: competing ground states in low dimensions
AB - Small changes in an external parameter can often lead to dramatic qualitative
changes in the lowest energy quantum mechanical ground state of a correlated
electron system. In anisotropic crystals, such as the high-temperature
superconductors where electron motion occurs primarily on a two-dimensional
square lattice, the quantum critical point between two such lowest energy states
has nontrivial emergent excitations that control the physics over a significant
portion of the phase diagram. Nonzero temperature dynamic properties near quantum
critical points are described, using simple theoretical models. Possible quantum
phases and transitions in the two-dimensional electron gas on a square lattice
are discussed.
PMID- 10775101
TI - Sources of quantum protection in high-T(c) superconductivity
AB - The layer-structure cuprates with high superconducting transition temperatures
T(c) exhibit a number of anomalous electronic properties in both superconducting
and normal states. These anomalies are ascribed to the existence of independent
spectra of excitations for charge and for spin, signaling a collective state, a
"quantum protectorate."
PMID- 10775103
TI - Electronic structures of single-walled carbon nanotubes determined by NMR
AB - Single-walled carbon nanotubes were studied by (13)C nuclear magnetic resonance
(NMR). Two types of (13)C nuclear spins were identified with different spin
lattice relaxation rates. The fast-relaxing component, assigned to metallic
tubes, followed the relaxation behavior expected in metals, and the density-of
states at the Fermi level increased with decreasing tube diameter. The slow
relaxing component has a significantly lower density-of-states at the Fermi
level. Exposure to oxygen has a substantial effect on relaxation rates of both
components.
PMID- 10775105
TI - Tectonic implications of U-Pb zircon ages of the himalayan orogenic belt in nepal
AB - Metasedimentary rocks of the Greater Himalaya are traditionally viewed as Indian
shield basement that has been thrust southward onto Lesser Himalayan sedimentary
rocks during the Cenozoic collision of India and Eurasia. Ages determined from
radioactive decay of uranium to lead in zircon grains from Nepal suggest that
Greater Himalayan protoliths were shed from the northern end of the East African
orogen during the late Proterozoic pan-African orogenic event. These rocks were
accreted onto northern Gondwana and intruded by crustal melts during Cambrian
Ordovician time. Our data suggest that the Main Central thrust may have a large
amount of pre-Tertiary displacement, that structural restorations placing Greater
Himalayan rocks below Lesser Himalayan rocks at the onset of Cenozoic orogenesis
are flawed, and that some metamorphism of Greater Himalayan rocks may have
occurred during early Paleozoic time.
PMID- 10775104
TI - Crossed nanotube junctions
AB - Junctions consisting of two crossed single-walled carbon nanotubes were
fabricated with electrical contacts at each end of each nanotube. The individual
nanotubes were identified as metallic (M) or semiconducting (S), based on their
two-terminal conductances; MM, MS, and SS four-terminal devices were studied. The
MM and SS junctions had high conductances, on the order of 0.1 e(2)/h (where e is
the electron charge and h is Planck's constant). For an MS junction, the
semiconducting nanotube was depleted at the junction by the metallic nanotube,
forming a rectifying Schottky barrier. We used two- and three-terminal
experiments to fully characterize this junction.
PMID- 10775102
TI - Positional syntenic cloning and functional characterization of the mammalian
circadian mutation tau.
AB - The tau mutation is a semidominant autosomal allele that dramatically shortens
period length of circadian rhythms in Syrian hamsters. We report the molecular
identification of the tau locus using genetically directed representational
difference analysis to define a region of conserved synteny in hamsters with both
the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon
(CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro
expression and functional studies of wild-type and tau mutant CKIepsilon enzyme
reveal that the mutant enzyme has a markedly reduced maximal velocity and
autophosphorylation state. In addition, in vitro CKIepsilon can interact with
mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to
phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and
propose a mechanism by which the mutation leads to the observed aberrant
circadian phenotype in mutant animals.
PMID- 10775106
TI - New observational constraints for atmospheric hydroxyl on global and hemispheric
scales
AB - Dramatic declines in emissions of methyl chloroform (1,1, 1-trichloroethane)
resulting from the Montreal Protocol provide an unprecedented opportunity to
improve our understanding of the oxidizing power of Earth's atmosphere.
Atmospheric observations of this industrial gas during the late 1990s yield new
insights into the global burden and distribution of the hydroxyl radical. Our
results set firm upper limits on the global and Southern Hemispheric lifetimes of
methyl chloroform and confirm the predominance of hydroxyl in the tropics. Our
analysis suggests a global lifetime for methyl chloroform of 5.2 (+0.2, -0.3)
years, a Southern Hemispheric lifetime of 4.9 (+0.2, -0.3) years, and mean annual
concentrations of OH that are 15 +/- 10% higher south of the intertropical
convergence zone than those north of this natural mixing boundary between the
hemispheres.
PMID- 10775107
TI - Cardiovascular evidence for an intermediate or higher metabolic rate in an
ornithischian dinosaur.
AB - Computerized tomography scans of a ferruginous concretion within the chest region
of an ornithischian dinosaur reveal structures that are suggestive of a four
chambered heart and a single systemic aorta. The apparently derived condition of
the cardiovascular system in turn suggests the existence of intermediate-to-high
metabolic rates among dinosaurs.
PMID- 10775108
TI - A structural framework for deciphering the link between I-Ag7 and autoimmune
diabetes.
AB - Susceptibility to murine and human insulin-dependent diabetes mellitus correlates
strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ
alleles that lack an aspartic acid at position beta57. I-Ag7 lacks this aspartate
and is the only class II allele expressed by the nonobese diabetic mouse. The
crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex
with a high-affinity peptide from the autoantigen glutamic acid decarboxylase
(GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta57,
which accounts for distinct peptide preferences compared with other MHC class II
alleles. Loss of Asp(beta57) leads to an oxyanion hole in I-Ag7 that can be
filled by peptide carboxyl residues or, perhaps, through interaction with the T
cell receptor.
PMID- 10775109
TI - The eye injury of King Philip II and the skeletal evidence from the royal tomb II
at Vergina.
AB - The Royal Tomb II was discovered in Vergina, Greece, in 1977. It contained a male
skeleton and a rich array of grave goods. Evidence of trauma supposedly in the
orbital bones of the skull has been thought to correspond to an eye injury that
King Philip II is historically known to have suffered. However, reexamination of
the orbital morphology showed no evidence of such pathology. Therefore, the
skeleton does not belong to Philip II. New skeletal evidence shows that the
skeleton belongs to King Philip III Arrhidaeus. In this case, the tomb may well
contain some of the paraphernalia of Alexander the Great.
PMID- 10775110
TI - Emergence of genetic instability in children treated for leukemia.
AB - T cells from patients who had received chemotherapy for B-lineage acute
lymphocytic leukemia were studied to determine whether genetic instability, a
principal characteristic of cancer cells, can also occur in nonmalignant cells.
Consistent with expectations for a genetic instability phenotype, multiple
mutations were detected in the hypoxanthine-guanine phosphoribosyltransferase
(HPRT) reporter gene in independently isolated mutant T cells expressing
identical rearranged T cell receptor beta (TCRbeta) gene hypervariable regions.
These results indicate that cancer treatment can lead to genetic instability in
nonmalignant cells in some individuals. They also suggest a mechanistic paradigm
for the induction of second malignancies and drug resistance.
PMID- 10775111
TI - Homologs of small nucleolar RNAs in Archaea.
AB - In eukaryotes, dozens of posttranscriptional modifications are directed to
specific nucleotides in ribosomal RNAs (rRNAs) by small nucleolar RNAs (snoRNAs).
We identified homologs of snoRNA genes in both branches of the Archaea. Eighteen
small sno-like RNAs (sRNAs) were cloned from the archaeon Sulfolobus
acidocaldarius by coimmunoprecipitation with archaeal fibrillarin and NOP56, the
homologs of eukaryotic snoRNA-associated proteins. We trained a probabilistic
model on these sRNAs to search for more sRNAs in archaeal genomic sequences. Over
200 additional sRNAs were identified in seven archaeal genomes representing both
the Crenarchaeota and the Euryarchaeota. snoRNA-based rRNA processing was
therefore probably present in the last common ancestor of Archaea and Eukarya,
predating the evolution of a morphologically distinct nucleolus.
PMID- 10775113
TI - On the origin of internal structure of word forms.
AB - This study shows that a corpus of proto-word forms shares four sequential sound
patterns with words of modern languages and the first words of infants. Three of
the patterns involve intrasyllabic consonant-vowel (CV) co-occurrence: labial
(lip) consonants with central vowels, coronal (tongue front) consonants with
front vowels, and dorsal (tongue back) consonants with back vowels. The fourth
pattern is an intersyllabic preference for initiating words with a labial
consonant-vowel-coronal consonant sequence (LC). The CV effects may be primarily
biomechanically motivated. The LC effect may be self-organizational, with
multivariate causality. The findings support the hypothesis that these four
patterns were basic to the origin of words.
PMID- 10775112
TI - Transport of peptide-MHC class II complexes in developing dendritic cells.
AB - Major histocompatibility complex class II (MHC II) molecules capture peptides
within the endocytic pathway to generate T cell receptor (TCR) ligands. Immature
dendritic cells (DCs) sequester intact antigens in lysosomes, processing and
converting antigens into peptide-MHC II complexes upon induction of DC
maturation. The complexes then accumulate in distinctive, nonlysosomal MHC II+
vesicles that appear to migrate to the cell surface. Although the vesicles
exclude soluble lysosomal contents and antigen-processing machinery, many contain
MHC I and B7 costimulatory molecules. After arrival at the cell surface, the MHC
and costimulatory molecules remain clustered. Thus, transport of peptide-MHC II
complexes by DCs not only accomplishes transfer from late endocytic compartments
to the plasma membrane, but does so in a manner that selectively concentrates TCR
ligands and costimulatory molecules for T cell contact.
PMID- 10775114
TI - Illusions in reasoning about consistency.
AB - Reasoners succumb to predictable illusions in evaluating whether sets of
assertions are consistent. We report two studies of this computationally
intractable task of "satisfiability." The results show that as the number of
possibilities compatible with the assertions increases, the difficulty of the
task increases, and that reasoners represent what is true according to
assertions, not what is false. This procedure avoids overloading memory, but it
yields illusions of consistency and of inconsistency. These illusions modify our
picture of human rationality.
PMID- 10775115
TI - Publishing in the journals of the APS: why are authors charged fees?
PMID- 10775116
TI - Evaluation of aortic compliance in humans.
PMID- 10775117
TI - Right ventricular pressure and dilation during pressure overload determine
dysfunction after pressure overload.
AB - Volume expansion and inotropic stimulation are used clinically to augment cardiac
output during acute right ventricular (RV) pressure overload. We previously
showed that a brief period of RV pressure overload causes RV free wall
dysfunction that persists after normal loading conditions have been restored.
However, the impact of volume expansion and inotropic stimulation on the severity
of RV dysfunction after acute pressure overload is unknown. We hypothesized that
the severity of RV dysfunction after RV pressure overload would be related to the
level of RV free wall systolic stress during RV pressure overload, rather than to
the specific interventions used to augment RV function. Chloralose-anesthetized,
open-chest pigs were subjected to 1 h of RV pressure overload caused by pulmonary
artery constriction, followed by 1 h of recovery after release of pulmonary
artery constriction. A wide range of RV free wall systolic stress during RV
pressure overload was achieved by either closing or opening the pericardium (to
simulate volume expansion) and by administering or not administering dobutamine.
The severity of RV free wall dysfunction 1 h after RV pressure overload was
strongly and directly correlated with the values of two hemodynamic variables
during RV pressure overload: RV free wall area at peak RV systolic pressure
(determined by sonomicrometry) and peak RV systolic pressure, two of the major
determinants of peak RV free wall systolic stress. Opening or closing the
pericardium, and using or not using dobutamine during RV pressure overload, had
no independent effects on the severity of RV dysfunction. The findings suggest
that the goal of therapeutic intervention during RV pressure overload should be
to achieve the required augmentation of cardiac output with the smallest possible
increase in RV free wall systolic stress.
PMID- 10775118
TI - Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca(2+)](i)
in canine cerebral vascular muscle.
AB - Studies were designed to investigate effects of neutral sphingomyelinase (N
SMase) and ceramide analogs as well as phosphorylcholine on vascular tone and
Ca(2+) mobilization in isolated canine cerebral arterial smooth muscle. N-SMase
(0.001-0.1 U/ml) provoked a gradual but sustained vasoconstriction of arterial
rings in a concentration-related manner that was endothelium independent.
Incubation of denuded arterial rings in Ca(2+)-free medium or pretreatment with
verapamil in extracellular Ca(2+) resulted in a reduction of the N-SMase-evoked
constriction. Exposure of arterial rings to 1,2-bis(2-aminophenoxy)ethane-N,N,N',
N'-tetraacetic acid (BAPTA)-AM did not, however, result in a reduction of N-SMase
induced constriction. Both staurosporine and bisindolymaleimide I attenuated N
SMase-induced contractions to 66% and 72% of control, respectively. N-SMase
caused gradual and sustained rises in intracellular Ca(2+) concentration
([Ca(2+)](i)) in primary cultured cerebral vascular smooth muscle cells.
Pretreatment of these cultured cells with nimodipine and verapamil caused a
steady decline in N-SMase-induced rises in [Ca(2+)](i). Exposure of the cells to
Ca(2+)-free solution reversed the [Ca(2+)](i)-induced rise triggered by N-SMase
to the resting baseline. Both C(8) and C(16) ceramide (10(-9)-10(-6) M), but not
phosphorylcholine, constricted denuded canine arterial rings in a concentration
related manner and elevated [Ca(2+)](i). Our results suggest that the
sphingomyelin-signaling pathway, via a probable release of ceramide molecules,
may play an important role in regulation of cerebral arterial wall tone.
PMID- 10775119
TI - Thyroid hormone-induced overexpression of functional ryanodine receptors in the
rabbit heart.
AB - Modifications in the Ca(2+)-uptake and -release functions of the sarcoplasmic
reticulum (SR) may be a major component of the mechanisms underlying thyroid
state-dependent alterations in heart rate, myocardial contractility, and
metabolism. We investigated the influence of hyperthyroid state on the expression
and functional properties of the ryanodine receptor (RyR), a major protein in the
junctional SR (JSR), which mediates Ca(2+) release to trigger muscle contraction.
Experiments were performed using homogenates and JSR vesicles derived from
ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism,
with attendant cardiac hypertrophy, was induced by the injection of L-thyroxine
(200 microg/kg body wt) daily for 7 days. Western blotting analysis using cardiac
RyR-specific antibody revealed a significant increase (>50%) in the relative
amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca(2+)
dependent, high-affinity [(3)H]ryanodine binding was also significantly greater (
approximately 40%) in JSR from hyperthyroid rabbits. The Ca(2+ )sensitivity of
[(3)H]ryanodine binding and the dissociation constant for [(3)H]ryanodine did not
differ significantly between euthyroid and hyperthyroid hearts. Measurement of
Ca(2+)-release rates from passively Ca(2+)-preloaded JSR vesicles and assessment
of the effect of RyR-Ca(2+)-release channel (CRC) blockade on active Ca(2+)
uptake rates revealed significantly enhanced (>2-fold) CRC activity in the
hyperthyroid, compared with euthyroid, JSR. These results demonstrate
overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy.
Relative abundance of RyR may be responsible, in part, for the changes in SR
Ca(2+) release, cytosolic Ca(2+) transient, and cardiac systolic function
associated with thyroid hormone-induced cardiac hypertrophy.
PMID- 10775120
TI - Protection against endotoxemia by HSP70 in rodent cardiomyocytes.
AB - Clinical and experimental studies have shown that myocardial dysfunction is an
early event during endotoxemia or septic shock. Several reports have shown that
rodents submitted to a mild heat shock become resistant to lipopolysaccharides
(LPS) or sepsis. The most abundant of the heat shock proteins (HSP), the HSP70,
has been postulated to be the principal mediator of the observed protection
against endotoxemia. We have tested the hypothesis that a protective effect
against endotoxemia is achievable by the increased presence of the HSP70 in
rodent cardiomyocytes. We have found that a transgenic mouse line overexpressing
the rat HSP70 gene in the heart exhibits an increased tolerance to LPS treatment
(control estimated survival function [S(t)] = 0.538, transgenic S(t) = 0.787, P <
0.05). Interestingly, the increased presence of the HSP70 in the hearts of these
mice results in a decrease in the activation of the inducible nitric oxide
synthase (iNOS) after LPS treatment. We conclude that HSP70 protection against
LPS is most probably mediated through the modulation of iNOS activation and the
subsequent decreased synthesis of nitric oxide in cardiomyocytes.
PMID- 10775122
TI - Importance of bicarbonate transport for protection of cardiomyocytes against
reoxygenation injury.
AB - Isolated cardiomyocytes from adult rats were incubated in anoxic bicarbonate
buffered media at extracellular pH (pH(o)) 6.4 until a cytosolic Ca(2+) overload
and intracellular pH (pH(i)) of 6.4 were reached. On reoxygenation, the pH of the
medium was changed to 7.4 to activate the Na(+)/H(+)exchanger (NHE) and the Na(+)
HCO(-)(3) symporter (NBS). The reoxygenation was performed in the absence or
presence of the NHE inhibitor HOE-642 (3 micromol/l) and/or the NBS inhibitor
DIDS (0.5 mmol/l), as in bicarbonate-free media. In reoxygenated control cells
pH(i) rapidly recovered to the preanoxic level, and a burst of spontaneous
oscillations of cytosolic Ca(2+) occurred, accompanied by the development of
hypercontracture. When NBS and NHE were simultaneously inhibited during
reoxygenation, pH(i) recovery was prevented, Ca(2+) oscillations were attenuated,
and hypercontracture was abolished. Sole inhibition of NBS or NHE showed no
protection against hypercontracture. In the absence of cytosolic acidosis, HOE
642 or DIDS did not prevent hypercontracture induced by Ca(2+) overload. The
results demonstrate that simultaneous inhibition of NHE and NBS is needed to
protect myocardial cells against reoxygenation-induced hypercontracture.
PMID- 10775121
TI - Depressed tolerance to fluorocarbon-simulated ischemia in failing myocardium due
to impaired [Ca(2+)](i) modulation.
AB - The aim of this study was to investigate the tolerance of failing myocardium from
postinfarction rats to simulated ischemia. Myocardial infarction (MI) was induced
by ligation of the left coronary artery in male Wistar rats. Isometric force and
free intracellular Ca(2+) concentration ([Ca(2+)](i)) were measured in isolated
left ventricular papillary muscles from sham-operated and post-MI animals 6 wk
after surgery. Ischemia was simulated by using fluorocarbon immersion with
hypoxia. Results showed that mechanical performance was depressed during the
period of hypoxia in physiological salt solution (44 +/- 7% of baseline in sham
vs. 30 +/- 6% of baseline in MI, P < 0.05) or ischemia (16 +/- 2% of baseline in
sham vs. 9 +/- 1% of baseline in MI, P < 0.01) accompanied by no corresponding
decrease of peak [Ca(2+)](i) (hypoxia: 51 +/- 8% of baseline in sham vs. 46 +/-
7% of baseline in MI, P = NS; ischemia: 47 +/- 5% of baseline in sham, 39 +/- 7%
of baseline in MI, P = NS). After reoxygenation, [Ca(2+)](i) rapidly returned to
near preischemic basal levels, whereas developed tension in fluorocarbon remained
significantly lower. This dissociation between peak [Ca(2+)](i) and isometric
contractility was more pronounced in the failing myocardium from postinfarction
rats. In conclusion, more severe impairment of [Ca(2+)](i) homeostasis in the
failing myocardium from postinfarction rats increases susceptibility to ischemia
reperfusion injury.
PMID- 10775123
TI - Energy-wasteful total Ca(2+) handling underlies increased O(2) cost of
contractility in canine stunned heart.
AB - Postischemic myocardial stunning halved left ventricular contractility [end
systolic maximum elastance (E(max))] and doubled the O(2) cost of E(max) in
excised cross-circulated canine heart. We hypothesized that this increased O(2)
cost derived from energy-wasteful myocardial Ca(2+) handling consisting of a
decreased internal Ca(2+) recirculation, some futile Ca(2+) cycling, and a
depressed Ca(2+) reactivity of E(max). We first calculated the internal Ca(2+)
recirculation fraction (RF) from the exponential decay component of
postextrasystolic potentiation. Stunning significantly accelerated the decay and
decreased RF from 0.63 to 0. 43 on average. We then combined the decreased RF
with the halved E(max) and its doubled O(2) cost and analyzed total Ca(2+)
handling using our recently developed integrative method. We found a decreased
total Ca(2+) transport and a considerable shift of the relation between futile
Ca(2+) cycling and Ca(2+) reactivity in an energy-wasteful direction in the
stunned heart. These changes in total Ca(2+) handling reasonably account for the
doubled O(2) cost of E(max) in stunning, supporting the hypothesis.
PMID- 10775124
TI - Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat
mesenteric arteries.
AB - The vasodilator effects of thrombin depend on activation of proteinase-activated
receptor (PAR)-1 and the subsequent release of endothelin (ET)-1, which
stimulates the generation of nitric oxide and PGs. We recently showed that
thrombin released matrix metalloproteinase-2 (MMP-2) from rat arteries. We have
now studied the significance of this release for the vasodilator effects of
thrombin. Thrombin (>/=100 pmol), but not a PAR-1-activating peptide (TFLLR
NH(2)), produced a long-lasting (>10 min) vasorelaxation of rat mesenteric
arteries, as detected by a microperfusion bioassay. Thrombin induced a
simultaneous release of vascular MMP-2 into arterial perfusates, as revealed by
zymography. Interestingly, the vasodilator effects of thrombin were inhibited by
a tissue inhibitor of MMP-2 (TIMP-2, 10 pmol). Moreover, infusion of exogenous
MMP-2 (5 pmol) resulted in vasorelaxation. These vasodilatory effects of thrombin
and MMP-2 were significantly (P < 0.05) inhibited by endothelium denudation and
by PD-142893 (2 nmol), an antagonist of ET receptors. Furthermore, both thrombin
and MMP-2 constricted endothelium-denuded arteries. These results show that the
vasodilator effects of thrombin may depend, in part, on a release of vascular MMP
2 and downstream activation of ETs. Thus MMP-2-dependent signaling may complement
the PAR-1-dependent pathway of vasodilator action of thrombin.
PMID- 10775125
TI - Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat
skeletal muscle.
AB - Impaired vascular responsiveness in sepsis may lead to maldistribution of blood
flow in organs. We hypothesized that increased production of nitric oxide (NO)
via inducible nitric oxide synthase (iNOS) mediates the impaired dilation to ACh
in sepsis. Using a 24-h cecal ligation and perforation (CLP) model of sepsis, we
measured changes in arteriolar diameter and in red blood cell velocity (V(RBC))
in a capillary fed by the arteriole, following application of ACh to terminal
arterioles of rat hindlimb muscle. Sepsis attenuated both ACh-stimulated dilation
and V(RBC) increase. In control rats, arteriolar pretreatment with the NO donors
S-nitroso-N-acetylpenicillamine or sodium nitroprusside reduced diameter and
V(RBC) responses to a level that mimicked sepsis. In septic rats, arteriolar
pretreatment with the "selective" iNOS blockers aminoguanidine (AG) or S
methylisothiourea sulfate (SMT) restored the responses to the control level. The
putative neuronal NOS (nNOS) inhibitor 7-nitroindazole also restored the response
toward control. At 24-h post-CLP, muscles showed no reduction of endothelial NOS
(eNOS), elevation of nNOS, and, surprisingly, no induction of iNOS protein;
calcium-dependent constitutive NOS (eNOS+nNOS) enzyme activity was increased
whereas calcium-independent iNOS activity was negligible. We conclude that 1) AG
and SMT inhibit nNOS activity in septic skeletal muscle, 2) NO could impair
vasodilative responses in control and septic rats, and 3) the source of increased
endogenous NO in septic muscle is likely upregulated nNOS rather than iNOS. Thus
agents released from the blood vessel milieu (e.g., NO produced by skeletal
muscle nNOS) could affect vascular responsiveness.
PMID- 10775126
TI - Myogenic reactivity and resistance distribution in the coronary arterial tree: a
model study.
AB - The objectives of this study were to evaluate the myogenic behavior of blood
vessels and their interaction within the coronary arterial tree and to evaluate
the possible role of the myogenic response in autoregulation. The model consists
of 10 compartments in series, each representing a class of vessel sizes. Diameter
and resistance in each class are determined by their value at full dilation
(d(p,) R(p)) and by the myogenic response. Three distributions of R(p) and three
distributions of myogenic strength, M(i) (slope of pressure-diameter curve, range
-0.05 to -0.4%/mmHg) were evaluated (9 cases). It was found that larger vessels
attenuate the myogenic activity of smaller vessels and that myogenic
responsiveness is sufficient to achieve autoregulation. When M(i) has a maximum
in vessels of 84 microm, the maximum effect of perfusion pressure on active
diameter occurs in vessels between 123 and 181 microm, depending on the
distribution of R(p). Distribution of resistance and control mechanisms in the
coronary arterial tree are important for interpretation of individual vessel
responses as observed in vivo.
PMID- 10775127
TI - Differential regulation of cardiac ANP and BNP mRNA in different stages of
experimental heart failure.
AB - Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac
hormones that are involved in water and electrolyte homeostasis in heart failure.
Although both hormones exert almost identical biological actions, the
differential regulation of cardiac ANP and BNP mRNA in compensated and overt
heart failure is not known. To study the hypothesis that cardiac BNP is more
specifically induced in overt heart failure, a large aortocaval shunt of 30 days
duration was produced in rats and compared with compensated heart failure.
Compensated heart failure was induced either by a small shunt of 30 days duration
or by a large shunt of 3 days duration. Both heart failure models were
characterized by increased cardiac weight, which was significantly higher in the
large-shunt model, and central venous pressure. Left ventricular end-diastolic
pressure was elevated only in the overt heart failure group (control: 5.7 +/- 0.
7; small shunt: 8.6 +/- 0.9; large shunt 3 days: 8.5 +/- 1.7; large shunt 30
days: 15.9 +/- 2.6 mmHg; P < 0.01). ANP and BNP plasma concentrations were
elevated in both heart failure models. In compensated heart failure, ANP mRNA
expression was induced in both ventricles. In contrast, ventricular BNP mRNA
expression was not upregulated in any of the compensated heart failure models,
whereas it increased in overt heart failure (left ventricle: 359 +/- 104% of
control, P < 0.001; right ventricle: 237 +/- 33%, P < 0.01). A similar pattern of
mRNA regulation was observed in the atria. These data indicate that, in contrast
to ANP, cardiac BNP mRNA expression might be induced specifically in overt heart
failure, pointing toward the possible role of BNP as a marker of the transition
from compensated to overt heart failure.
PMID- 10775128
TI - Recombinant human, active site-blocked factor VIIa reduces infarct size and no
reflow phenomenon in rabbits.
AB - Oxygen free radicals induce de novo synthesis of tissue factor (TF), the
initiator of the extrinsic pathway of coagulation, within the coronary
vasculature during postischemic reperfusion. In the present study we wanted to
assess whether TF expression might cause myocardial injury during postischemic
reperfusion. Anesthetized rabbits underwent 30 min of coronary occlusion followed
by 5.5 h of reperfusion. At reperfusion the animals received 1) saline (n = 8),
2) human recombinant, active site-blocked activated factor VII (FVIIai, 1 mg/kg,
n = 8), or 3) human recombinant activated FVII (FVIIa, 1 mg/kg, n = 8). FVIIai
binds to TF as native FVII, but with the active site blocked it inhibits TF
procoagulant activity. The area at risk of infarction (AR), the infarct size
(IS), and the no-reflow area (NR) were determined at the end of the experiment.
FVIIai resulted in a significant reduction in IS and NR with respect to control
animals (28.1 +/- 11.3 and 11.1 +/- 6.1% of AR vs. 59.8 +/- 12.8 and 24.4 +/-
2.7% of AR, respectively, P < 0.01), whereas FVIIa resulted in a significant
increase in IS and NR to 80.1 +/- 13. 1 and 61.9 +/- 13.8% of AR, respectively (P
< 0.01). In conclusion, TF-mediated activation of the extrinsic coagulation
pathway makes an important contribution to myocardial injury during postischemic
reperfusion.
PMID- 10775129
TI - Contribution of cytochrome P-450 omega-hydroxylase to altered arteriolar
reactivity with high-salt diet and hypertension.
AB - The present study evaluated the contribution of cytochrome P-450 omega
hydroxylase in modulating the reactivity of cremaster muscle arterioles in
normotensive rats on high-salt (HS) and low-salt (LS) diet and in rats with
reduced renal mass hypertension (RRM-HT). Changes in arteriolar diameter in
response to ACh, sodium nitroprusside (SNP), ANG II, and elevated O(2) were
measured via television microscopy under control conditions and following
cytochrome P-450 omega-hydroxylase inhibition with 17-octadecynoic acid (17-ODYA)
or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on
either LS or HS diet, resting tone was unaffected and arteriolar reactivity to
ACh or SNP was minimally affected by cytochrome P-450 omega-hydroxylase
inhibition. In RRM-HT rats, cytochrome P-450 omega-hydroxylase inhibition reduced
resting tone and significantly enhanced arteriolar dilation to ACh and SNP.
Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and
O(2) in all the groups, although the degree of inhibition was greater in RRM-HT
than in normotensive animals. These results suggest that metabolites of
cytochrome P-450 omega-hydroxylase contribute to the altered reactivity of
skeletal muscle arterioles to vasoconstrictor and vasodilator stimuli in RRM-HT.
PMID- 10775130
TI - Endothelium modulates anion channel-dependent aortic contractions to iodide.
AB - Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The
substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br)
initially inhibited and then potentiated isometric contractile responses of rat
aortic rings to norepinephrine. Anion substitution alone produced a small
relaxation, which occurred despite a lack of active tone and minimal subsequent
contraction of endothelium-intact rings (4.2 +/- 1.2% of the response to 90 mM
KCl). Endothelium-denuded rings underwent a similar initial relaxation but then
contracted vigorously (I > Br). Responses to 130 mM I (93.7 +/- 1.9% of 90 mM
KCl) were inhibited by nifedipine (10(-6) M), niflumic acid (10(-5) M), tamoxifen
(10(-5) M), DIDS (10(-4) M), and HCO(-)(3)-free buffer (HEPES 10 mM) but not by
bumetanide (10(-5) M). Intact rings treated with N(omega)-nitro-L-arginine (10(
4) M) responded weakly to I (15.5 +/- 2.1% of 90 mM KCl), whereas hemoglobin (10(
5) M), indomethacin (10(-6) M), 17-octadecynoic acid (10(-5) M), and 1H-[1,2,
4]oxadiazole[4,3-a]quinoxalin-1-one (10(-6) M) all failed to augment the response
of intact rings to I. We hypothesize that VSM takes up I primarily via an anion
exchanger. Subsequent I efflux through anion channels having a selectivity of I >
Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated
vessels, this current is sufficient to activate voltage-dependent calcium
channels and cause contraction. Neither nitric oxide nor prostaglandins are the
primary endothelial modulator of these anion channels. If they are regulated by
an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450
metabolite.
PMID- 10775131
TI - Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human
endothelial cells.
AB - Cellular phenotype is determined not only by genetic transcription but also by
subsequent translation of mRNA into protein. Extracellular signals trigger
intracellular pathways that distinctly activate translation. The 70/85-kDa S6
kinase (pp70(S6k)) is a central enzyme in the signal-dependent control of
translation, but its regulation in endothelial cells is largely unknown. Here we
show that fluid flow (in the absence of an exogenous mitogen) as well as humoral
agonists activate endothelial pp70(S6k). Rapamycin, an inhibitor of the mammalian
target of rapamycin (mTOR), and wortmannin, a phosphatidylinositol 3-kinase
inhibitor, blocked flow-induced pp70(S6k) activation; FK-506, a rapamycin analog
with minimal mTOR inhibitory activity, and PD-98059, an inhibitor of the flow
sensitive mitogen-activated protein kinase pathway, had no effect. Synthesis of
Bcl-3, a protein whose translation is controlled by an mTOR-dependent pathway,
was induced by flow and inhibited by rapamycin and wortmannin. Transcriptional
blockade did not abolish the flow-induced upregulation of Bcl-3. Fluid forces may
therefore modify endothelial phenotype by specifically regulating translation of
certain mRNA transcripts into protein.
PMID- 10775132
TI - Energetics of rat papillary muscle during contractions with sinusoidal length
changes.
AB - The mechanical efficiency of rat cardiac muscle was determined using a
contraction protocol involving cyclical, sinusoidal length changes and phasic
stimulation at physiological frequencies (1-4 Hz). Experiments were performed in
vitro (27 degrees C) using rat left ventricular papillary muscles. Efficiency was
determined from measurements of the net work performed and enthalpy produced by
muscles during a series of 40 contractions. Net mechanical efficiency was defined
as the percentage of the total, suprabasal enthalpy output that appeared as
mechanical work. Maximum efficiency was approximately 15% at contraction
frequencies between 2 and 2.5 Hz. At lower and higher frequencies, efficiency was
approximately 10%. Enthalpy output per cycle was independent of cycle frequency
at all but the highest frequency used. The basis of the high efficiency between 2
and 2.5 Hz was that work output was also greatest at these frequencies. At these
frequencies, the duration of the applied length change was well matched to the
kinetics of force generation, and active force generation occurred throughout the
shortening period.
PMID- 10775133
TI - Amelioration with vessel dilator of acute tubular necrosis and renal failure
established for 2 days.
AB - Seventeen Sprague-Dawley rats had ischemic nonoliguric acute renal failure (ARF)
induced by vascular clamping resulting in their preischemic blood urea nitrogen
(BUN) and creatinine levels of 16 +/- 1 and 0.56 +/- 0.05 mg/dl to increase to
162 +/- 4 and 8.17 +/- 0.5 mg/dl, P < 0.001, respectively, at day 4 of
postischemia. Vessel dilator, a 37-amino-acid cardiac peptide hormone (0.3 microg
x kg(-1) x min(-1) ip), decreased the BUN and creatinine levels to 53 +/- 17
mg/dl and 0.98 +/- 0.12 mg/dl (P < 0.001) in another seven animals where ARF had
been established for 2 days. Water excretion doubled with ARF and was further
augmented by vessel dilator. Transthoracic echocardiography revealed left
ventricular dilation as a probable cause of the increase in vessel dilator in the
circulation with ARF, and vessel dilator infusion reversed this dilation. At day
6 of ARF, mortality decreased to 14% with vessel dilator from 88% without vessel
dilator. Acute tubular necrosis was <5% in the vessel dilator-treated rats
compared with 25% to >75% in the placebo-treated ARF animals. We conclude that
vessel dilator improves acute tubular necrosis and renal function in established
ARF.
PMID- 10775134
TI - Vagus nerve is involved in lack of blood reflow into sinusoids after rat hepatic
ischemia.
AB - Although recovery of microcirculation is an important determinant for ischemia
reperfusion injury, little information is available about hepatic blood flow
after ischemia. To examine regulatory mechanisms of postischemic hepatic
microcirculation, we studied the sinusoidal blood flow after portal triad
clamping of rat livers for 5, 15, or 30 min. Hepatic tissue blood flow and
erythrocyte blood flow in sinusoids were measured using a laser-Doppler flowmeter
and an intravital microspectroscope, respectively. There was a time of no blood
flow (lag time) in sinusoids after declamping, dependent on the ischemic time.
Cholinergic blockade agents eliminated the lag time, whereas nerve stimulation at
the hiatus esophagus or on the hepatoduodenal ligament during reperfusion
prolonged it. Chemical denervation with 10% phenol or surgical denervation on the
hepatoduodenal ligament eliminated the lag time. The prolongation of lag time by
nerve stimulation was completely abrogated by truncal vagotomy. These results
suggest that the cholinergic vagus nerve is involved in causing the lag time of
sinusoidal blood flow in hepatic ischemia-reperfusion.
PMID- 10775135
TI - Bradykinin mediates cardiac preconditioning at a distance.
AB - Preconditioning the heart by brief coronary (CAO) or mesenteric artery occlusion
(MAO) can protect against damage during subsequent prolonged CAO and reperfusion.
The role of bradykinin (BK) in remote cardiac preconditioning by MAO is
investigated by antagonizing the BK B(2) receptor [Hoechst 140 (HOE-140)] or
simulating local BK release by mesenteric intra-arterial infusion. Anesthetized
male Wistar rats (n = 6-8) were treated with HOE-140 or saline before starting
the preconditioning protocol, CAO, MAO, or non-preconditioned control. Infarct
size related to risk area [ratio of infarct area to area at risk (IA/AR)] was
determined after 3 h of reperfusion following a 60-min CAO. IA/AR was 62 +/- 5%
in controls and not affected by HOE-140 (58 +/- 6%). CAO as well as MAO
significantly protected the heart (IA/AR, 37 +/- 3 and 35 +/- 5%), which was
prevented by HOE-140 (IA/AR, 71 +/- 6 and 65 +/- 7%, respectively). Brief
intramesenteric BK infusion mimicked MAO (IA/AR, 26 +/- 3%). Pretreatment with
hexamethonium could abolish this protection (IA/AR, 67 +/- 4%). These data
indicate an important role for BK in remote preconditioning by MAO. Results
support the hypothesis that remote preconditioning acts through sensory nerve
stimulation in the ischemic organ.
PMID- 10775136
TI - Interaction of glutamine and arginine on cerebrovascular reactivity to
hypercapnia.
AB - Glutamine is purported to inhibit recycling of citrulline to arginine and to
limit nitric oxide release in vitro. However, vasoactive effects of glutamine
have not been clearly demonstrated in vivo. During hyperammonemia, impaired
cerebrovascular reactivity to CO(2) is related to glutamine accumulation. We
tested the hypotheses that 1) glutamine infusion in the absence of hyperammonemia
impairs cerebrovascular CO(2) reactivity and 2) arginine infusion preserves CO(2)
reactivity during glutamine infusion and during hyperammonemia. Pentobarbital
sodium-anesthetized rats were equipped with a closed cranial window for measuring
pial arteriolar diameter. Intravenous infusion of 3 mmol. kg(-1). h(-1) of L
glutamine for 6 h produced threefold increases in plasma and cerebrospinal fluid
concentrations. Dilation to hypercapnia was reduced by 45% compared with that of
a time control group at 6 h but not at 3 h of glutamine infusion. Coinfusion of 2
mmol. kg(-1). h(-1) of L-arginine with glutamine maintained the hypercapnic
vasodilation at the control value. Infusion of ammonium acetate at a rate known
to produce threefold increases in cortical tissue glutamine concentration
resulted in no significant hypercapnic vasodilation. Coinfusion of arginine with
ammonium acetate maintained hypercapnic vasodilation at 60% of the control value.
Arginine infusion did not augment hypercapnic vasodilation in a control group. We
conclude that glutamine modulates cerebrovascular CO(2) reactivity in vivo.
Glutamine probably acts by limiting arginine availability because the vascular
inhibitory effect required >3 h to develop and because arginine infusion
counteracted the vascular effect of both endogenously and exogenously produced
increases in glutamine.
PMID- 10775137
TI - Cardiac output increases independently of basal metabolic rate in early human
pregnancy.
AB - Early pregnancy is characterized by the institution of a high-flow low-resistance
circulation. In this study, we tested the hypothesis that these hemodynamic
changes develop independently of changes in basal metabolic rate. In 12 healthy
women, we determined and calculated once during the follicular phase (day 5 +/-
2) and at 6, 8, 10, and 12 wk of pregnancy the following variables: body weight
and length, body mass index, fat-free mass (FFM), mean arterial pressure (MAP),
heart rate (HR), stroke volume, cardiac output (CO), total peripheral vascular
resistance (TPVR), resting energy expenditure (REE), FFM REE (REE(FFM)), and
respiratory quotient (RQ). At 6 wk of gestational age, HR and CO had increased,
whereas MAP and TPVR had decreased. These changes persisted throughout the study
period. Meanwhile, REE, REE(FFM), RQ, FFM, and body weight did not change
consistently. The changes with pregnancy in hemodynamics did not correlate with
those in basal metabolic rate. In early pregnancy, the institution of a high-flow
low-resistance circulation develops without a concomitant rise in basal metabolic
rate. These findings support the concept that the hemodynamic changes in early
pregnancy develop independently of concomitant changes in basal metabolic rate.
PMID- 10775138
TI - Interstitial flow through the internal elastic lamina affects shear stress on
arterial smooth muscle cells.
AB - Interstitial flow through the tunica media of an artery wall in the presence of
the internal elastic lamina (IEL), which separates it from the subendothelial
intima, has been studied numerically. A two-dimensional analysis applying the
Brinkman model as the governing equation for the porous media flow field was
performed. In the numerical simulation, the IEL was modeled as an impermeable
barrier to water flux, except for the fenestral pores, which were uniformly
distributed over the IEL. The tunica media was modeled as a heterogeneous medium
composed of a periodic array of cylindrical smooth muscle cells (SMCs) embedded
in a fiber matrix simulating the interstitial proteoglycan and collagen fibers. A
series of calculations was conducted by varying the physical parameters
describing the problem: the area fraction of the fenestral pore (0. 001-0.036),
the diameter of the fenestral pore (0.4-4.0 microm), and the distance between the
IEL and the nearest SMC (0.2-0.8 microm). The results indicate that the value of
the average shear stress around the circumference of the SMC in the immediate
vicinity of the fenestral pore could be as much as 100 times greater than that
around an SMC in the fully developed interstitial flow region away from the IEL.
These high shear stresses can affect SMC physiological function.
PMID- 10775139
TI - Temporal gradient in shear-induced signaling pathway: involvement of MAP kinase,
c-fos, and connexin43.
AB - The effect of a temporal gradient in shear and steady shear on the activity of
extracellular signal-regulated protein kinases 1 and 2 (ERK1/ERK2), c-fos, and
connexin43 (Cx43) in human endothelial cells was investigated. Three laminar flow
profiles (16 dyn/cm(2)), including impulse flow (shear stress abruptly applied
for 3 s), ramp flow (shear stress smoothly transitioned at flow onset), and step
flow (shear stress abruptly applied at flow onset) were utilized. Relative to
static controls, impulse flow stimulated the phosphorylation of ERK1/ERK2 8.5- to
7.5-fold, respectively at 10 min, as well as the mRNA expression of c-fos 51-fold
at 30 min, and Cx43 8-fold at 90 min. These high levels of mRNA expression were
sustained for at least 4 h. In contrast, ramp flow was unable to significantly
induce gene expression and even inhibited the activation of ERK1/ERK2. Step flow,
which contains both a sharp temporal gradient in shear stress and a steady shear
component, elicited only moderate and transient responses, indicating the
distinct role of these fluid shear stimuli in endothelial signal transduction.
The specific inhibitor of mitogen-activated protein kinase kinase PD-98059
inhibited impulse flow-induced c-fos and Cx43 mRNA expression. Thus these
findings implicate the involvement of ERK1/ERK2, c-fos, and Cx43 in the signaling
pathway induced by the temporal gradient in shear.
PMID- 10775140
TI - Thrombin induces endothelin expression in arterial smooth muscle cells.
AB - Thrombin has been shown to stimulate endothelin release by endothelial cells, but
the ability of thrombin to induce endothelin in nonendothelial cells is less well
known. Incubation of rat aortic smooth muscle cells with thrombin resulted in a
stimulation of preproendothelin-1 (preproET-1) mRNA expression. This induction of
preproET-1 mRNA expression by thrombin was accompanied by the release of
immunoreactive peptide ET-1 into the extracellular medium. The synthetic thrombin
receptor activator peptide (TRAP) confirmed ligand-specific receptor action to
induce preproET-1 mRNA. Nuclear run-on analysis revealed that the transcriptional
rate of preproET-1 mRNA increases twofold after 1 h of incubation with thrombin.
In cells treated with thrombin, the half-life of preproET-1 mRNA was identical to
that in untreated control cells. These results demonstrated that thrombin
regulates endothelin synthesis at a transcriptional level but does not influence
mRNA stability. Inhibition of protein kinase C (PKC) with selective inhibitors
(chelerythrine and bisindolylmaleimide I) before thrombin stimulation failed to
significantly inhibit preproET-1 gene expression. Inhibition of mitogen-activated
protein (MAP) kinase kinase and protein tyrosine kinase decreased preproET-1 mRNA
expression in thrombin-stimulated smooth muscle cells. Furthermore, addition of
an activator of peroxisome proliferator-activated receptors-alpha (PPARalpha),
fenofibrate, prevented the preproET-1 gene induction in response to thrombin.
These results demonstrated that thrombin-induced endothelin gene transcription
involved MAP kinase kinase rather than the PKC cascade in smooth muscle cells,
which was repressed by PPARalpha stimulation.
PMID- 10775141
TI - Heme oxygenase modulates selectin expression in different regional vascular beds.
AB - Heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron, and
CO. The inducible isoform (HO-1) has been implicated as a modulator of the
inflammatory response. HO-1 activity can be induced by hemin and inhibited with
zinc protoporphyrin IX (ZnPP). Using these reagents, we assessed the possibility
that HO-1 modulates the inflammatory response by altering the expression of
endothelial cell adhesion molecules. Endotoxin (lipopolysaccharide, LPS)-induced
expression of P- and E-selectin expression was quantified in different vascular
beds of the rat using the dual radiolabeled monoclonal antibody technique.
Pretreatment with hemin attenuated, whereas ZnPP treatment exacerbated, the
increased selectin expression normally elicited by LPS. Biliverdin, at an
equimolar dosage, was as effective as hemin in attenuating LPS-induced selectin
expression in the lung, kidneys, liver, and intestines. These findings indicate
that the anti-inflammatory properties of HO-1 may be related to an inhibitory
action of P- and E-selectin expression in the vasculature. Biliverdin (or its
metabolite, bilirubin), rather than CO, may account for this action of HO-1 on
endothelial cell adhesion molecule expression.
PMID- 10775142
TI - Regulation of contraction and relaxation by membrane potential in cardiac
ventricular myocytes.
AB - Control of contraction and relaxation by membrane potential was investigated in
voltage-clamped guinea pig ventricular myocytes at 37 degrees C. Depolarization
initiated phasic contractions, followed by sustained contractions that relaxed
with repolarization. Corresponding Ca(2+) transients were observed with fura 2.
Sustained responses were ryanodine sensitive and exhibited sigmoidal activation
and deactivation relations, with half-maximal voltages near -46 mV, which is
characteristic of the voltage-sensitive release mechanism (VSRM) for sarcoplasmic
reticulum Ca(2+). Inactivation was not detected. Sustained responses were
insensitive to inactivation or block of L-type Ca(2+) current (I(Ca-L)). The
voltage dependence of sustained responses was not affected by changes in
intracellular or extracellular Na(+) concentration. Furthermore, sustained
responses were not inhibited by 2 mM Ni(2+). Thus it is improbable that I(Ca-L)
or Na(+)/Ca(2+) exchange generated these sustained responses. However, rapid
application of 200 microM tetracaine, which blocks the VSRM, strongly inhibited
sustained contractions. Our study indicates that the VSRM includes both a phasic
inactivating and a sustained noninactivating component. The sustained component
contributes both to initiation and relaxation of contraction.
PMID- 10775143
TI - Interstitial fluid pressure, composition of interstitium, and interstitial
exclusion of albumin in hypothyroid rats.
AB - Lack of thyroid hormones may affect the composition and structure of the
interstitium. Hypothyrosis was induced in rats by thyroidectomy 4-12 wk before
the experiments. In hypothyroid rats (n = 16), interstitial fluid pressure
measured with micropipettes in hindlimb skin and muscle averaged +0.1 +/- 0.2 and
+0.5 +/- 0.2 mmHg, respectively, with corresponding pressures in control rats (n
= 16) of -1.5 +/- 0.1 (P < 0.001) and -0.8 +/- 0.1 mmHg (P < 0.001). Interstitial
fluid volume, measured as the difference between the distribution volumes of
(51)Cr-EDTA and (125)I-labeled BSA, was similar or lower in skin and higher in
hypothyroid muscle. Total protein and albumin concentration in plasma and
interstitial fluid (isolated from implanted wicks) was lower in hypothyroid
compared with control rats. Hyaluronan content (n = 9) in rat hindlimb skin was
2.05 +/- 0.15 and 1.92 +/- 0.09 mg/g dry wt (P > 0.05) in hypothyroid and control
rats, respectively, with corresponding content in hindlimb skeletal muscle of
0.35 +/- 0.07 and 0.23 +/- 0. 01 mg/g dry wt (P < 0.01). Interstitial exclusion
of albumin in skin and muscle was measured after (125)I-labeled rat serum albumin
infusion for 120-168 h with an implanted osmotic pump. Relative excluded volume
for albumin (V(e)/V(i)) was calculated as 1 - V(a)/V(i), and averaged 28 and 28%
in hindlimb muscle (P > 0.05), 44 and 45% in hindlimb skin (P > 0.05), and 19 and
32% in back skin (P < 0.05) in hypothyroid and control rats, respectively.
Albumin mass was higher in back skin in spite of a lower interstitial fluid
albumin concentration, a finding explained by a reduced V(e)/V(i) in back skin in
hypothyroid rats. These experiments suggest that lack of thyroid hormones in rats
changes the interstitial matrix again leading to reduced interstitial compliance
and changes in the transcapillary fluid balance.
PMID- 10775144
TI - Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and
wild-type mice.
AB - We investigated the function of estrogen receptor-alpha in global myocardial
ischemia and reperfusion injury in male estrogen receptor-alpha knockout (ERKO)
and wild-type mice. Mouse hearts were subjected to 45 min of global ischemia
followed by 180 min of reperfusion. The hearts were excised, cannulated, and
maintained in a chilled (4 degrees C) cardioplegia solution until warm (37
degrees C) oxygenated Krebs-Henseleit bicarbonate buffer was perfused through the
coronary arteries. ERKO hearts started beating later and had a higher incidence
of ventricular fibrillation and/or tachycardia than control hearts. Coronary flow
rate was significantly lower in ERKO hearts during the 90- and 120-min periods of
reperfusion. Ca(2+) accumulation was significantly greater following 30, 90, 120,
150, and 180 min of reperfusion in ERKO hearts. Nitrite production was
significantly less in ERKO hearts following 90, 120, and 150 min of reperfusion.
Myocardial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide was significantly lower in experimental ERKO hearts. Marked interstitial
edema and contraction bands were seen in hematoxylin-eosin-stained sections of
ischemia-reperfused ERKO hearts but not in control tissues. Hematoxylin-basic
fuchsin-picric acid-stained sections from experimental ERKO hearts had fewer
viable myocytes compared with controls. Transmission electron microscopy revealed
swollen and fragmented mitochondria with amorphous and granular bodies, loss of
matrix, and rupture of cristae in experimental ERKO hearts. This is the first
demonstration that estrogen receptor-alpha plays a cardioprotective role in
ischemia-reperfusion injury in males.
PMID- 10775145
TI - Vagal modulation of the heart and central hemodynamics during handgrip exercise.
AB - Blood pressure and continuous electrocardiogram recordings were obtained from 12
participants during spontaneous breathing (SB1), dynamic handgrip exercise at 20%
(HG(20)) of maximal voluntary contraction (MVC), and spontaneous breathing (SB2)
and dynamic handgrip exercise at 60% (HG(60)) of MVC. Repeated-measures ANOVAs
were used to examine the effects of the exercise conditions on mean arterial
pressure (MAP), on mean standard deviation (SDNN), and on the coefficient of
variation of R-R intervals. The mean R-R interval responded to exercise in an
intensity-dependent manner. SDNN decreased with exercise but was not intensity
dependent. Coefficient of variation decreased during HG(20), and MAP increased
following HG(60). These data are consistent with the notion that changes in
cardiovascular function with low-intensity exercise are primarily mediated by
parasympathetic withdrawal, and as exercise intensity increases, additional
cardiovascular reactivity is mediated by increased sympathetic outflow. The
change in the coefficient of variation from rest to exercise was unique in
comparison to the changes in SDNN, and this merits further investigation.
PMID- 10775146
TI - Beating rate of isolated neonatal cardiomyocytes is regulated by the stable
microtubule subset.
AB - We investigated the roles of microtubule (MT) dynamics (growth and shrinkage),
the stable, nongrowing MT subset, the posttranslationally detyrosinated MT
subset, and artificially elevated tubulin levels in the negative regulation of
heart cell beating rate. We manipulated the MT populations in isolated, neonatal
cardiomyocytes obtained from normal animals in several ways and then measured
heart cell beating rate directly. We found that the stabilized population of MTs
was sufficient to maintain a normal beating rate, whereas MT dynamics and
detyrosination made no observable contribution. Furthermore, by directly and
acutely increasing the level of tubulin within otherwise normally beating cells,
we found that the increased tubulin (and MT) levels further depressed the beating
rate. In conclusion, the stabilized MT subset is sufficient to maintain the
normal beating rate in these cells, whereas increasing the MT density depresses
it.
PMID- 10775147
TI - Effects of diminished expression of connexin43 on gap junction number and size in
ventricular myocardium.
AB - Gap junction number and size vary widely in cardiac tissues with disparate
conduction properties. Little is known about how tissue-specific patterns of
intercellular junctions are established and regulated. To elucidate the
relationship between gap junction channel protein expression and the structure of
gap junctions, we analyzed Cx43 +/- mice, which have a genetic deficiency in
expression of the major ventricular gap junction protein, connexin43 (Cx43).
Quantitative confocal immunofluorescence microscopy revealed that diminished Cx43
signal in Cx43 +/- mice was due almost entirely to a reduction in the number of
individual gap junctions (226 +/- 52 vs. 150 +/- 32 individual gap
junctions/field in Cx43 +/+ and +/- ventricles, respectively; P < 0.05). The mean
size of an individual gap junction was the same in both groups.
Immunofluorescence results were confirmed with electron microscopic morphometry.
Thus when connexin expression is diminished, ventricular myocytes become
interconnected by a reduced number of large, normally sized gap junctions, rather
than a normal number of smaller junctions. Maintenance of large gap junctions may
be an adaptive response supporting safe ventricular conduction.
PMID- 10775149
TI - Role of endogenous nitric oxide in progression of atherosclerosis in
apolipoprotein E-deficient mice.
AB - This study investigated the role of endogenous nitric oxide (NO) in the
progression of atherosclerosis in apolipoprotein E-deficient [apoE-knockout (KO)]
mice. Mice were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) an
inhibitor of nitric oxide synthase (NOS) or with the NOS substrate L-arginine for
8 wk. L-NAME treatment resulted in a significant inhibition of NO-mediated
vascular responses and a significant increase in the atherosclerotic
plaque/surface area in the aorta of apoE-KO mice. L-arginine treatment had no
influence on endothelial function and did not alter lesion size. Mean arterial
blood pressure and serum lipid levels were not altered by the treatments. At the
beginning of the study impairment in endothelial function was only apparent in
the case of N(G)-nitro-L-arginine-induced, NO-mediated contraction, whereas ACh
induced, NO-mediated relaxation was not different between age-matched apoE-KO and
C57Bl/6J mice. After the 8-wk treatment with the NOS inhibitor, both NO-mediated
responses were significantly inhibited. The acceleration in lesion size
concomitant to the severely impaired NO-mediated responses indicates that lack of
endogenous NO is an important progression factor of atherosclerosis in the apoE
KO mouse.
PMID- 10775148
TI - I(NaCa) contributes to electrical heterogeneity within the canine ventricle.
AB - This study examines the amplitude of sodium-calcium exchange current (I(NaCa)) in
epicardial, midmyocardial, and endocardial canine ventricular myocytes. Whole
cell currents were recorded at 37( degrees )C using standard or perforated-patch
voltage-clamp techniques in the absence of potassium, calcium-activated chloride,
and sodium-pump currents. I(NaCa) was triggered by release of calcium from the
sarcoplasmic reticulum or by rapid removal of external sodium. I(NaCa) was large
in midmyocardial myocytes and significantly smaller in endocardial myocytes,
regardless of the method used to activate I(NaCa). I(NaCa) at -80 mV was -0.316
+/- 0. 013, -0.293 +/- 0.016, and -0.210 +/- 0.007 pC/pF, respectively, in
midmyocardial, epicardial, and endocardial myocytes when activated by the calcium
transient. When triggered by sodium removal, peak I(NaCa) was 0.74 +/- 0.04, 0.57
+/- 0.04, and 0.50 +/- 0.03 pA/pF, respectively, in midmyocardial, epicardial,
and endocardial myocytes. Epicardial I(NaCa) was smaller than midmyocardial
I(NaCa) when activated by removal of external sodium but was comparable to
epicardial and midmyocardial I(NaCa) when activated by the normal calcium
transient, implying possible transmural differences in excitation-contraction
coupling. Our results suggest that I(NaCa) differences contribute to transmural
electrical heterogeneity under normal and pathological states. A large
midmyocardial I(NaCa) may contribute to the prolonged action potential of these
cells as well as to the development of triggered activity under calcium-loading
conditions.
PMID- 10775150
TI - Leukocyte adhesion and microvessel permeability.
AB - To investigate the direct effect of leukocyte adherence to microvessel walls on
microvessel permeability, we developed a method to measure changes in hydraulic
conductivity (L(p)) before and after leukocyte adhesion in individually perfused
venular microvessels in frog mesentery. In 19 microvessels that were initially
free of leukocyte sticking or rolling along the vessel wall, control L(p) was
measured first with Ringer-albumin perfusate. Blood flow was then restored in
each vessel with a reduced flow rate in the range of 30-116 microm/s to
facilitate leukocyte adhesion. Each vessel was recannulated in 45 min. The mean
number of leukocytes adhering to the vessel wall was 237 +/- 22 leukocytes/mm(2).
At the same time, L(p) increased to 4.7 +/- 0.5 times the control value.
Superfusion of isoproterenol (10 microM) after leukocyte adhesion brought the
increased L(p) back to 1.1 +/- 0.2 times the control in 5-10 min (n = 9).
Superfusing isoproterenol before leukocyte adhesion prevented the increase in
L(p) (n = 6). However, the number of leukocytes adhering to the vessel wall was
not significantly affected. These results demonstrated that leukocyte adhesion
caused an increase in microvessel permeability that could be prevented or
restored by increasing cAMP levels in endothelial cells using isoproterenol. Thus
cAMP-dependent mechanisms that regulate inflammatory agent-induced increases in
permeability also modulate leukocyte adhesion-induced increases in permeability
but act independently of mechanisms that regulate leukocyte adhesion to the
microvessel wall. Application of ketotifen, a mast cell stabilizer, and
desferrioxamine mesylate, an iron-chelating reagent, attenuated the increase in
L(p) induced by leukocyte adhesion, suggesting the involvement of oxidants and
the activation of mast cells in leukocyte adhesion-induced permeability increase.
Furthermore, with the use of an in vivo silver stain technique, the locations of
the adherent leukocytes on the microvessel wall were identified quantitatively in
intact microvessels.
PMID- 10775151
TI - Endothelin-induced cardiac myocyte hypertrophy: role for focal adhesion kinase.
AB - Endothelin-1 (ET) produces neonatal rat ventricular myocyte (NRVM) hypertrophy
and activates focal adhesion kinase (FAK) in other cell types. In the present
study, we examined whether ET activated FAK in NRVM and whether FAK was necessary
and/or sufficient for ET-induced NRVM hypertrophy. Chronic ET-1 stimulation (100
nM, 48 h) increased protein-to-DNA and myosin heavy chain (MHC)-to-DNA ratios and
stimulated the assembly of newly synthesized MHC into sarcomeres. ET-1 also
induced the assembly of focal adhesions and costameres, as evidenced by increased
phosphotyrosine, FAK, and paxillin immunostaining. Acutely, ET treatment rapidly
increased tyrosine phosphorylation of FAK and paxillin. FAK was also activated by
phorbol 12-myristate 13-acetate (2 microM, 5 min). Pretreatment with
chelerythrine (5 microM) or rottlerin (10 microM) completely blocked ET-induced
FAK phosphorylation, indicating that protein kinase C activation was upstream of
ET-induced FAK activation. In contrast, ET-induced FAK activation was not
affected by blocking calcium influx via L-type voltage-gated calcium channels.
Adenoviruses (Adv) containing FAK and FAK-related nonkinase (FRNK) were used to
specifically define the role of FAK in ET-induced hypertrophy. ET stimulation
failed to increase total protein-to-DNA or MHC-to-DNA ratios or to stimulate
sarcomeric assembly in myocytes infected with Adv-FRNK. However, Adv-FAK alone
did not increase total protein-to-DNA or MHC-to-DNA ratios and failed to increase
the number or size of myofibrils as evidenced by double immunofluorescence
labeling for MHC and FAK. Thus, although FAK is necessary for ET-induced NRVM
hypertrophy, other ET-generated signals are also required to elicit the
hypertrophic phenotype.
PMID- 10775152
TI - Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density
in pacing-induced heart failure.
AB - Congestive heart failure is associated with cardiac adrenergic nerve terminal
changes and beta-adrenoceptor density downregulation. To study the temporal
sequence of these changes, we performed studies in rabbits at 2, 4, and 8 wk of
cardiac pacing (360 beats/min) and at 1, 2, and 4 wk after cessation of pacing.
Rapid pacing produced left ventricular (LV) dysfunction and an increase in plasma
norepinephrine (NE) in 1-2 wk. At week 2, NE uptake activity, NE uptake-1
density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl
imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, immunostained
tyrosine hydroxylase profile, beta-adrenoceptor density, and NE histofluorescence
did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV
function normalized quickly, followed by return of tyrosine hydroxylase and NE
profiles in 1 wk and adenylyl cyclase responses to agonists and NE uptake
activity in 2 wk. Myocardial beta-adrenoceptor density returned to normal by 4 wk
after cessation of pacing. Our results suggest that there is no permanent
structural neuronal damage in the myocardium within the first 8 wk of rapid
cardiac pacing. Abnormal myocardial NE reuptake mechanism may play an important
pathophysiological role in heart failure.
PMID- 10775153
TI - A new method of long-term preventive cardioprotection using Lactobacillus.
AB - Potential long-term cardioprotection was investigated in an extensive
experimental study. Lactobacillus cultivation components (LCC) were administered
intravenously in anesthetized rats 1, 7, and 21 days before global ischemia (GI).
GI was produced by full stop flow in isolated Langendorff-perfused hearts for 20
min and was followed by reperfusion. Control animals were injected with saline.
LCC reduced reperfusion tachyarrhythmia significantly and improved functional
recovery of the ischemized rat heart. These beneficial effects were associated
with reduction of release of norepinephrine (NE) and prostacyclin at the first
minute of reperfusion, activation of myocardial catalase, and overexpression of
70-kDa heat stress protein (HSP-70) at ischemia and reperfusion (P < 0.05). This
cardioprotection was documented up to 21 days after a single injection of LCC.
Thus Lactobacillus cultivation components are new nontoxic materials that produce
marked long-term cardioprotection against ischemia-reperfusion damage. This
effect is attributed to an activation of the cellular defense system, manifested
by activation of the antioxidant pathway and by expression of protective
proteins. NE is involved in this process, and the data also suggest a role for
prostacyclin in this model of cardioprotection. The potential of LCC and related
compounds working through similar mechanisms in the prevention and therapy of
various ischemic heart syndromes should be explored.
PMID- 10775155
TI - Is tumor necrosis factor alpha a trigger for the initiation of endometrial
prostaglandin F(2alpha) release at luteolysis in cattle?
AB - To determine the physiological significance of tumor necrosis factor alpha
(TNFalpha) in the regulation of luteolytic prostaglandin (PG) F(2alpha) release
by the bovine endometrium, the effect of TNF-alpha on PGF(2alpha) output by the
endometrial tissues in vitro was investigated and compared with the effect of
oxytocin (OT). Furthermore, the presence of specific receptors for TNFalpha in
the bovine endometrium during the estrous cycle was determined. Endometrial
slices (20-30 mg) taken from six stages of the estrous cycle (estrus: Day 0;
early I: Days 2-3; early II: Days 5-6; mid-: Days 8-12; late: Days 15-17; and
follicular: Days 19-21), as determined by macroscopic examination of the ovaries
and uterus, were exposed to TNFalpha (0.06-6 nM) and/or OT (100 nM). OT
stimulated PGF(2alpha) output at the follicular stage and at estrus (P < 0.001),
but not at the late luteal stage. On the other hand, the stimulatory effects of
TNFalpha on PGF(2alpha) output were observed not only at the follicular stage but
also at the late luteal stage (P < 0.001). When the endometrial tissues at late
luteal stage were simultaneously exposed to TNFalpha (0.6 nM) and OT (100 nM),
the stimulatory effect on PGF(2alpha) output was higher than the effect of
TNFalpha or OT alone (P < 0.05). Specific binding of TNFalpha to the bovine
endometrial membranes was observed throughout the estrous cycle. The
concentration of TNF-alpha receptor at the early I luteal stage was less than the
concentrations at other luteal stages (P < 0.01). The dissociation constant
(K(d)) values of the endometrial membranes were constant during the estrous
cycle. The overall results lead us to hypothesize that TNFalpha may be a trigger
for the output of PGF(2alpha) by the endometrium at the initiation of luteolysis
in cattle.
PMID- 10775154
TI - Orosomucoid has a cAMP-dependent effect on human endothelial cells and inhibits
the action of histamine.
AB - The plasma protein orosomucoid (alpha(1)-acid glycoprotein) has previously been
shown to constitute a critical component of the capillary barrier. The protein
has also been suggested to act as an anti-inflammatory mediator in a diversity of
experimental situations. Recently we reported that orosomucoid is synthesized by
the microvascular endothelial cells per se. In the present study, the effects of
orosomucoid on primary cultures of human umbilical vein endothelial cells (HUVEC)
were studied using the Cytosensor microphysiometer. We found that 1) orosomucoid
(0.01 g/l) increased the metabolic activity of HUVEC as reflected by the
increased acidification rate of +14 +/- 1%; 2) pretreatment with 0.5 mM 8-bromo
cAMP for 20 min markedly and reversibly inhibited the effect of orosomucoid,
whereas 8-bromo-cGMP did not; 3) histamine elicited a dose-dependent response
that was abolished by pretreatment with either cAMP or cGMP; and finally, 4)
pretreatment of HUVEC for 6 min with orosomucoid (0.01 g/l) inhibited the action
of histamine. In summary, this is the first report demonstrating that orosomucoid
affects human endothelial cells and that it does so by using cAMP as a second
messenger. This provides an explanation for previous findings of anti
inflammatory effects of the protein and shows that orosomucoid affects the
endothelium during both normal and pathophysiological conditions.
PMID- 10775156
TI - Production of prostaglandin f(2alpha) by cultured bovine endometrial cells in
response to tumor necrosis factor alpha: cell type specificity and intracellular
mechanisms.
AB - Tumor necrosis factor alpha (TNFalpha) has been shown to be a potent stimulator
of prostaglandin (PG) F(2alpha) secretion in the bovine endometrium. The aims of
the present study were to determine the cell types in the endometrium (epithelial
or stromal cells) responsible for the secretion of PGF(2alpha) in response to
TNFalpha, and the intracellular mechanisms of TNFalpha action. Cultured bovine
epithelial and stromal cells were exposed to TNFalpha (0.006-6 nM) or oxytocin
(100 nM) for 4 h. TNFalpha resulted in a dose-dependent increase of PGF(2alpha)
production in the stromal cells (P < 0.001) but not in the epithelial cells. On
the other hand, oxytocin stimulated PGF(2alpha) output in the epithelial cells
but not in the stromal cells. When the stromal cells were incubated for 24 h with
TNFalpha and inhibitors of phospholipase (PL) C or PLA(2), only PLA(2) inhibitor
completely stopped the actions of TNFalpha (P < 0.001). When the stromal cells
were exposed to TNFalpha and arachidonic acid, the action of TNFalpha was
augmented (P < 0.001). When the stromal cells were incubated for 24 h with a
nitric oxide (NO) donor (S-NAP), S-NAP stimulated the PGF(2alpha) production dose
dependently. Although an NO synthase (NOS) inhibitor (L-NAME) reduced TNFalpha
stimulated PGF(2alpha) production, an inhibitor of phosphodiesterase augmented
the actions of TNFalpha and S-NAP (P < 0. 05). The overall results indicate that
the target of TNFalpha for stimulation of PGF(2alpha) production in cattle is the
endometrial stromal cells, and that the actions of TNFalpha are mediated via the
activation of PLA(2) and arachidonic acid conversion. Moreover, TNFalpha may
exert a stimulatory effect on PGF(2alpha) production via the induction of NOS and
the subsequent NO-cGMP formation.
PMID- 10775157
TI - Secretion and gene expression of metalloproteinases and gene expression of their
inhibitors in porcine corpora lutea at different stages of the luteal phase.
AB - We hypothesize that spontaneous regression of corpora lutea (CL) involves short
lasting restructure of luteal tissue with an activation of matrix
metalloproteinases (MMPs) and their respective inhibitors (tissue inhibitors of
metalloproteinase, TIMPs). This was tested by determining the gene expression of
MMP-1, MMP-2, and MMP-9 and respective TIMP-1 and TIMP-2 in luteal tissue from
sows at the early, midluteal, and late luteal phase (Days 6-8, Days 9-11, and
Days 13-15 of estrous cycle). Gene expression of the three MMPs was low in early,
slightly higher in midluteal, and significantly elevated (P < 0.05) in regressing
CL. An inverse pattern was found for gene expression of TIMP-1 and TIMP-2. Under
culture conditions, the release of MMPs was determined from steroidogenic large
luteal cells (LLC). LLC harvested from regressing CL released significantly (P <
0.05) more active MMPs than cells obtained from CL at the early luteal phase. As
luteolysis can be induced by prostaglandin F(2alpha) (PGF(2alpha)) and tumor
necrosis factor alpha (TNF), we studied their effects on LLC under culture
conditions. Treatment of cells with PGF(2alpha) or TNF (10(-7) M or 3 x 10(-9) M,
respectively) induced a significantly higher release of MMPs, and gene expression
was also significantly stimulated in comparison to that in untreated LLC. The
gene expression of TIMPs remained unaffected by either treatment. It is concluded
that at the beginning of luteolysis, MMPs are expressed and released in high
amounts and that this is essential for the structural regression of the CL.
PMID- 10775158
TI - Molecular cloning and expression analysis of the complementary deoxyribonucleic
acid for chicken inhibin/activin beta(B) subunit.
AB - Inhibins and activins are dimeric peptide hormones that play an integral role in
the intraovarian regulation of folliculogenesis. The domestic hen, with its well
defined follicular hierarchy, provides a unique model in which to study the role
of these hormones in follicular development. In the present study, the complete
coding sequence and deduced amino acid sequence for the chicken inhibin/activin
beta(B) subunit has been determined from cDNA clones isolated from a chicken
ovarian granulosa cell library. This beta(B)-subunit cDNA predicts a precursor
protein of 392 amino acids containing the mature C-terminal 115 amino acid
beta(B) subunit. When compared to the beta(B) subunit isolated from a variety of
species, the chicken cDNA clone showed high nucleotide identity in the full
length coding region (>70%) and in the mature coding region (>80%). In addition,
the deduced amino acid sequence of chicken beta(B) subunit showed greater than
95% identity compared to other species in the mature peptide region. Expression
of the beta(B)-subunit mRNA was detected by reverse transcription-polymerase
chain reaction in both gonadal and extragonadal tissues. Northern blot analysis
detected expression in the gonadal tissues only, specifically in the granulosa
tissue from the F3-F5 follicles, small yellow follicles (SYF), large white
follicles, and immature and mature rooster testes. A major transcript of
approximately 4.1 kilobases (kb) and three minor transcripts of approximately 8.4
kb, 6.5 kb, and 1.7 kb were detected in the SYF granulosa samples. To examine the
expression pattern of the beta(B) subunit around the stage of follicle selection,
the SYF granulosa was subdivided into two groups: 6-8 mm and 9-12 mm.
Quantification of RNA expression (n = 3) showed that expression of the beta(B)
subunit was maximal in the 6-8 mm SYF. Activin B, as well as other intraovarian
signals, may regulate early follicle selection and/or development in the chicken.
PMID- 10775159
TI - Development rates of male bovine nuclear transfer embryos derived from adult and
fetal cells.
AB - This study compared the nuclear transfer (NT) embryo development rates of adult
and fetal cells within the same genotype. The adult fibroblast cells were
obtained from a 21-yr-old Brahman bull. The fetal cells were derived from a Day
40 NT fetus previously cloned using cells from the Brahman bull. Overall, similar
numbers of blastocysts developed from both adult (53 of 190; 28%) and fetal (39
of 140; 28%) donor cells. Improved blastocyst development rates were observed
when fetal cells were serum-starved (serum-fed 12% vs. serum-starved 43%; P <
0.01) whereas there was no similar benefit when adult cells were serum-starved
(both serum-fed and serum-starved 28%). Day 30 pregnancy rates were similar for
blastocysts derived from adult (6 of 26; 23%) or fetal (5 of 32; 16%) cells. Day
90 pregnancy rates were 3 of 26 for adult and 0 of 32 for the fetal cell lines.
One viable bull calf derived from a 21-yr-old serum-starved adult skin fibroblast
was born in August 1999. In summary, somatic NT embryo development rates were
similar whether adult or fetal cells, from the same genotype, were used as donor
cells. Serum starvation of these adult donor cells did not improve development
rates of NT embryos to blastocyst, but when fetal cells were serum-starved, there
was a significant increase in development to blastocyst.
PMID- 10775160
TI - Tissue-specific localization of cytochrome P450 aromatase in the equine embryo by
in situ hybridization and immunocytochemistry.
AB - Estrogen production by the preimplantation equine embryo is presumed to be
important in maternal-conceptus communication in the mare. The synthesis of C(18)
estrogens from C(19) androgens requires cytochrome P450 aromatase (P450(arom)) in
the conceptus, but little information is available on the specific tissue
location or potential developmental patterns of expression for the horse. The
goal of this research was to localize P450(arom) in the equine conceptus by
immunocytochemistry and in situ hybridization. Intact blastocyst-stage embryos
were collected by nonsurgical flush on Days 12-15 of pregnancy, fixed in 4%
paraformaldehyde, and paraffin-embedded. Aromatase protein was localized using
rabbit anti-human placental aromatase antiserum with a detection system utilizing
peroxidase and 3-amino-9-ethylcarbazole. For in situ hybridization, tissue
sections were incubated with sense or antisense [(35)S]UTP-labeled cRNA probes
prepared from equine aromatase cDNA. Aromatase protein and transcript were
abundant in the extraembryonic trophectoderm but absent from embryonic ectoderm.
No P450(arom) expression was detected in abembryonic endoderm or mesoderm.
Aromatase expression was demonstrated in the endoderm beneath the disc
(hypoblast). This pattern of P450(arom) expression in the equine blastocyst
closely resembles that seen transiently in the porcine embryo, suggesting that
regulatory mechanisms conferring tissue specificity may be conserved.
PMID- 10775161
TI - Qualitative and quantitative decline in spermatogenesis of the follicle
stimulating hormone receptor knockout (FORKO) mouse.
AB - Sertoli cells express functional receptors for FSH, one of the two pituitary
hormones that regulate spermatogenesis in mammals. We recently produced genetic
mutant (FORKO) mice that lack FSH receptor, in order to examine the effects on
testicular function and fertility. Mutant males exhibited weight loss of testis,
epididymis, and seminal vesicle as well as low levels of testosterone. Except for
reduced seminiferous tubular diameter, no gross changes were apparent upon
histological examination. Analysis of testicular germ cells by flow cytometry
revealed a significant increase in the percentage of 2C cells (spermatogonia and
non-germ cells) and a significant decrease in the percentage of HC cells
(elongated spermatids) of FORKO males. The absolute number of homogenization
resistant elongated spermatids was also significantly reduced in the mutant
males. A 2-fold increase in c-kit-positive 2C cells was recorded in the mutant
males. Elongated spermatids of FORKO males showed a dramatic increase in
propidium iodide binding suggesting reduced nuclear compaction. The increase in
size of the sperm head in mutants, as well as susceptibility to dithiothreitol
induced decondensation, suggests the inadequate condensation of sperm chromatin.
Sperm chromatin structure assay, a technique that reflects DNA stability,
revealed that sperm from FORKO males are susceptible to acid denaturation,
indicating the poor quality of sperm. These data allow us to conclude that
genetic disruption of FSH receptor signaling in the rodent induces major changes
that might contribute to reduced fertility.
PMID- 10775162
TI - Identification of components of the intrafollicular bradykinin-producing system
in the porcine ovary.
AB - As a step in elucidating the biological role of plasma kallikrein (PK) present in
the follicular fluid of mammalian ovaries, we examined pig ovary fluid to
determine its constituent activators and substrates. Using the inactive precursor
form of plasma kallikrein (prePK) as a substrate, we purified an enzyme capable
of activating this protein. The prePK-activating enzyme was shown to be the
active enzyme blood coagulation factor XIIa. We also isolated high molecular
weight kininogen (HMW-K) from the same fluid. Incubation of HMW-K with the
ovarian follicular fluid PK resulted in the production of the nanopeptide
bradykinin (BK). Expression of prePK, blood coagulation factor XII, and HMW-K was
examined by Northern blot analysis using ovary and liver poly(A)(+) RNA. All
these transcripts were found in the liver, but none were found in the ovary. In
addition, it was found that BK levels in the fluid derived from the small
follicles were approximately 6 times higher than those from medium and large
follicles. These results demonstrate the presence of a BK-producing system in the
ovarian follicles and suggest the physiological importance of this peptide
hormone in the early stages of follicular development and at ovulation.
PMID- 10775163
TI - Induction of glucose-regulated protein 78 in rat uterine glandular epithelium
during uterine sensitization for the decidual cell reaction.
AB - Endometrial receptivity for implantation and sensitization for decidualization in
rodents is a transient state under the control of the ovarian steroids estrogen
and progesterone. It is unclear, however, what molecular events mediate the onset
of uterine receptivity. Messenger RNA differential display was performed on
endometrial RNA from ovariectomized rats differentially sensitized for
decidualization. Maximally sensitized uteri were at the equivalent of Day 5 of
pseudopregnancy, and temporally nonsensitized uteri at Day 4 or 6; hormonally
nonsensitized uteri were from animals on Day 5 treated with low or high doses of
estradiol on Day 4. A cDNA with endometrial expression restricted to maximally
sensitized uteri was isolated, cloned, and sequenced. The cDNA matched the
sequence for glucose-regulated protein 78 (GRP78), a heat shock 70-related
protein that resides in the lumen of the endoplasmic reticulum (ER) and has roles
in several cellular processes including multimeric protein assembly, the
degradation of proteins, and the storage and regulation of ER luminal calcium.
Northern blot analysis indicated a dramatic increase in GRP78 mRNA levels
restricted to the sensitized, Day 5 endometrium, suggesting a role in the onset
of the sensitized phase. In situ hybridization and immunohistochemistry
experiments localized the up-regulation of GRP78 within the receptive endometrium
to the glandular epithelium.
PMID- 10775164
TI - Polymerization of nonfilamentous actin into microfilaments is an important
process for porcine oocyte maturation and early embryo development.
AB - Actin is one of the major proteins in mammalian oocytes. Most developmental
events are dependent on the normal distribution of filamentous (F-) actin.
Polymerization of nonfilamentous (G-) actin into F-actin is important for both
meiosis and mitosis. This study examined G- and F-actin distribution in pig
oocytes and embryos by immunocytochemical staining and confocal microscopy. Actin
protein was quantified by electrophoresis and immunoblotting. G-Actin was
distributed in the whole cytoplasm of oocytes and embryos irrespective of their
stages. F-Actin was distributed at the cortex of oocytes and embryos at all
stages, at the joint of blastomeres in the embryos, in the cytoplasm around the
germinal vesicle (GV), and in the perinuclear area of 2- to 4-cell-stage embryos.
No differences in the amount of actin protein were found among oocytes and
embryos. Oocytes cultured in medium with cytochalasin D (CD), an inhibitor of
microfilament polymerization, underwent GV breakdown and reached metaphase I but
did not proceed to metaphase II. Two- to 4-cell-stage embryos cultured in medium
with CD did not develop to blastocysts. When GV-stage oocytes or 2- to 4-cell
stage embryos treated with CD for 6 h were re-cultured in media without CD,
oocytes or embryos re-assembled actin filaments and underwent a meiotic
maturation or blastocyst formation similar to that of controls. These results
indicate that it is the polymerization of G-actin into F-actin, not actin protein
synthesis, that is important for both meiosis and mitosis in pig oocytes and
embryos.
PMID- 10775165
TI - Spindle formation and dynamics of gamma-tubulin and nuclear mitotic apparatus
protein distribution during meiosis in pig and mouse oocytes.
AB - This work focuses on the assembly and transformation of the spindle during the
progression through the meiotic cell cycle. For this purpose, immunofluorescent
confocal microscopy was used in comparative studies to determine the spatial
distribution of alpha- and gamma-tubulin and nuclear mitotic apparatus protein
(NuMA) from late G2 to the end of M phase in both meiosis and mitosis. In pig
endothelial cells, consistent with previous reports, gamma-tubulin was localized
at the centrosomes in both interphase and M phase, and NuMA was localized in the
interphase nucleus and at mitotic spindle poles. During meiotic progression in
pig oocytes, gamma-tubulin and NuMA were initially detected in a uniform
distribution across the nucleus. In early diakinesis and just before germinal
vesicle breakdown, microtubules were first detected around the periphery of the
germinal vesicle and cell cortex. At late diakinesis, a mass of multi-arrayed
microtubules was formed around chromosomes. In parallel, NuMA localization
changed from an amorphous to a highly aggregated form in the vicinity of the
chromosomes, but gamma-tubulin localization remained in an amorphous form
surrounding the chromosomes. Then the NuMA foci moved away from the condensed
chromosomes and aligned at both poles of a barrel-shaped metaphase I spindle
while gamma-tubulin was localized along the spindle microtubules, suggesting that
pig meiotic spindle poles are formed by the bundling of microtubules at the minus
ends by NuMA. Interestingly, in mouse oocytes, the meiotic spindle pole was
composed of several gamma-tubulin foci rather than NuMA. Further, nocodazole, an
inhibitor of microtubule polymerization, induced disappearance of the pole
staining of NuMA in pig metaphase II oocytes, whereas the mouse meiotic spindle
pole has been reported to be resistant to the treatment. These results suggest
that the nature of the meiotic spindle differs between species. The axis of the
pig meiotic spindle rotated from a perpendicular to a parallel position relative
to the cell surface during telophase I. Further, in contrast to the stable
localization of NuMA and gamma-tubulin at the spindle poles in mitosis, NuMA and
gamma-tubulin became relocalized to the spindle midzone during anaphase I and
telophase I in pig oocytes. We postulate that in the centrosome-free meiotic
spindle, NuMA aggregates the spindle microtubules at the midzone during anaphase
and telophase and that the polarity of meiotic spindle microtubules might become
inverted during spindle elongation.
PMID- 10775166
TI - Distribution and activation of uterine mononuclear phagocytes in peripartum
endometrium and myometrium of the mouse.
AB - The present study tested the hypothesis that macrophage distribution and
activation are enhanced in the uterus before term. Mid-uterine horn tissue strips
from mice on Days 15 and 18 of pregnancy, the day of birth (= Day 19), and one
day postpartum were paraffin-embedded and then sectioned, stained with a
monoclonal pan-macrophage marker (BM8), and processed for visualization and
quantification of resident macrophages per nuclear area. Macrophages were
dispersed throughout the endometrium and subluminal epithelium; cell numbers
declined on the day before term, then increased postpartum. Within myometrium,
macrophages congregated in stroma surrounding muscle bundles, and staining was
enhanced near term. Macrophage numbers were similar in pregnant and postpartum
uteri, enhanced more than 2-fold over those in nonpregnant controls. Uterine
sections were also analyzed by laser-scanning cytometry to enumerate activated
macrophages (i.e., those that express the intercellular adhesion molecule marker
CD54+) and to determine cell cycle (propidium iodide fluorescence). Activated
macrophages were directly proportional to cell numbers and, by cell cycle
analysis, were not terminally differentiated. Highest cell numbers occurred on
Day 15: 4-fold greater than those in nonpregnant controls and 2-fold higher than
those at Day 18 or in postpartum groups. These findings indicate a decline in
endometrial macrophage numbers at least one day before the onset of parturition
and raise the possibility that trafficking of this immune cell may contribute to
onset of labor.
PMID- 10775167
TI - A monoclonal antibody to human SP-10 inhibits in vitro the binding of human sperm
to hamster oolemma but not to human Zona pellucida.
AB - SP-10 is a sperm intra-acrosomal protein, specific to the testis, that is
believed to play an important role in egg-sperm binding. While the molecular
characterization of the SP-10 protein has been clarified, little is yet known of
its functional role in fertilization. We therefore established a monoclonal
antibody (mAb pep-SP10) against a peptide (pep-SP10) that included the most
hydrophilic portion of human SP-10 between the 135th and 149th amino acids. Human
SP-10 was found to be localized in the equatorial region of acrosome-reacted
sperm by immunofluorescent staining using our mAb pep-SP10. Monoclonal Ab pep
SP10 inhibited sperm-oolemma binding in the zona-free hamster egg penetration
test, but it did not inhibit sperm-zona binding in the hemizona assay.
Furthermore, we demonstrated that the oolemmal ligands of human SP-10 did not
include beta(1) integrins, the most promising candidates for oocyte ligands
involved in sperm-oolemma binding, based on the findings of a human sperm
cultured cell binding assay using F9 mouse embryonal carcinoma cells and F9
transformed cells lacking beta(1) integrins. In conclusion, our present data
suggest that human SP-10, expressed on the equatorial region of acrosome-reacted
sperm, indeed mediates sperm-oolemma binding in a beta(1) integrin-independent
manner, but not sperm-zona binding.
PMID- 10775168
TI - Morphological and biochemical identification of apoptosis in small, medium, and
large bovine follicles and the effects of follicle-stimulating hormone and
insulin-like growth factor-I on spontaneous apoptosis in cultured bovine
granulosa cells.
AB - The first objective of this study was to determine whether the death of bovine
granulosa cells (GC) isolated from small ( 8 mm) follicles during follicular atresia occurs by apoptosis. The second
objective was to establish an in vitro model system to elucidate the
developmental (GC from follicles of different sizes) and hormonal (FSH and
insulin-like growth factor-I [IGF-I]) regulation of bovine GC apoptosis during
follicular atresia. Bovine ovaries were obtained from a nearby slaughterhouse.
Follicles were classified by morphometric criteria as healthy or atretic.
Apoptosis in GC from follicles of different sizes was analyzed by both
morphological and biochemical methods. Bovine GC were cultured for 48 h at a
density of 5 x 10(6) cells/ml in serum-free media at 39 degrees C to determine
the effects of FSH and IGF-I on apoptosis. The results showed that apoptosis
occurred in GC from all sizes of follicles. Apoptosis in GC was also detected in
some healthy follicles. Degenerate GC displayed the morphological characteristics
of apoptosis, including nuclei with marginated chromatin, a single condensed
nucleus, multiple nuclear fragments, and/or membrane-bound structures containing
variable amounts of chromatin and/or cytoplasm (apoptotic bodies). All GC
classified as apoptotic on the basis of their morphology contained fragmented DNA
measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end
labeling (TUNEL) technique. Cells that had undergone apoptosis were observed
mainly in GC and in scattered theca cells. Throughout the GC layer, apoptotic
cell death was more prevalent among antral GC than among mural GC. Interestingly,
morphological results showed that no apoptosis occurred in cumulus cells. A time
dependent, spontaneous onset of apoptosis occurred in GC from small, medium, and
large follicles during in vitro serum-free culture. The rate of DNA fragmentation
in the culture of GC from small follicles was higher than that from medium and
large follicles. FSH attenuated apoptotic cell death in GC from medium follicles
more effectively than in those from small follicles. IGF-I also suppressed
apoptosis in cultured GC from small follicles. In conclusion, this study showed
that 1) GC death during bovine follicular development and atresia occurs by
apoptosis; 2) apoptosis occurs in GC and theca cells; however, apoptosis does not
occur in cumulus cells even in atretic antral follicles; 3) GC from all small,
medium, and large follicles undergo spontaneous onset of apoptosis when cultured
under serum-free conditions; and 4) FSH and IGF-I can attenuate apoptosis in
cultured bovine GC.
PMID- 10775169
TI - Maturation of mouse primordial follicles by combination of grafting and in vitro
culture.
AB - Cryopreservation of ovarian cortical tissue and subsequent transplantation or in
vitro culture of follicles are technologies under development with the aim to
safeguard fertility in patients with gonadal failure. In the present study, we
investigated whether primordial follicles could be triggered to full maturation
by a combination of in vivo transplantation and in vitro culture in a mouse
model. In a first step, newborn mouse ovaries containing only primordial
follicles were allotransplanted under the renal capsule of ovariectomized
recipient mice. The second step was to mechanically isolate growing preantral
follicles from the graft and culture these in vitro to maturity. In our
experiment, one newborn mouse ovary was transplanted under the renal capsule of
each 8- to 12-wk-old F1 (C57Bl/6j x CBA/Ca) female ovariectomized recipient (n =
26). Two weeks after transplantation, all 26 grafts were recovered. Four grafts
were processed for histology and showed that developmental stages of follicles in
14-day-old ovarian grafts were comparable to those in 14-day-old mouse ovaries.
The 22 remaining grafts were used for mechanical isolation of preantral
follicles. As a control group, preantral follicles isolated from ovaries of 14
day-old mice were used. The mean preantral follicle yield per ovary was 11 in the
transplant group versus 33 in the control group. Follicles were cultured
individually in 20-microliter droplets of alpha-MEM supplemented with 100 mIU
rFSH and 5% fetal bovine serum for 12 days under an atmosphere of 5% CO(2) in air
at 37 degrees C. By Day 12 of culture, 66.5% of follicles retained their oocytes
in the grafting group versus 97.5% in the control group (P < 0.001). Final oocyte
maturation was induced by addition of 2.5 IU/ml hCG. At 14-16 h post-HCG, the
percentages of oocytes showing germinal vesicle breakdown and polar body
extrusion were significantly higher in the control group (90.6% and 82.8%)
compared to the grafting group (60% and 45%). The mean diameter of the mature
oocytes of the grafting group (69.9 +/- 4.45 micrometer) was similar to that of
oocytes from the control group (70.5 +/- 2.35 micrometer). Our results suggest
that maturation of mouse primordial follicles is feasible by combination of in
vivo transplantation and in vitro culture. This two-step strategy may be an
attractive model for promoting the growth and maturation of primordial follicles
from other species.
PMID- 10775170
TI - Activin A in JEG-3 cells: potential role as an autocrine regulator of
steroidogenesis in humans.
AB - Activin A has been shown to exert several regulatory functions on human placenta.
In the present study, we tested the hypothesis that activin A is an autocrine
regulator of trophoblast using a choriocarcinoma cell line, JEG-3, as a model.
Messenger RNAs for activin beta(A) subunit, activin binding protein
(follistatin), and various activin receptors, including ActR-IA, ActR-IB, ActR
IIA, and ActR-IIB, were detected in JEG-3 cells by reverse transcription
polymerase chain reaction. The expression of activin A in JEG-3 cells was further
confirmed by Western blot analysis using an antibody against activin beta(A)
subunit. Using Northern blot analysis, Smad-2 and Smad-4 mRNAs were also observed
in JEG-3 cells. These data suggest that JEG-3 cells produce activin A and express
activin binding proteins and receptors, as well as potential downstream signals.
In cultured JEG-3 cells, basal progesterone production was stimulated by activin
A but inhibited by follistatin-288. Similarly, in the presence of
androstenedione, estradiol production was enhanced by activin A but decreased by
follistatin-288. On the other hand, neither activin A nor follistatin affected
JEG-3 cell growth. Taken together, these findings strongly suggest that activin A
is an autocrine factor that is involved in the regulation of progesterone and
estradiol production in JEG-3 cells.
PMID- 10775171
TI - Evidence for the involvement of calmodulin in mouse sperm capacitation.
AB - Although Ca(2+) is of fundamental importance in mammalian sperm capacitation, its
downstream targets have not been definitively demonstrated. The purpose of this
study was to use the calmodulin (CaM) antagonists W7 and calmidazolium (CZ) to
investigate the possible role of CaM, a Ca(2+)-specific binding protein, in
capacitation. Sperm membrane changes associated with capacitation were assessed
by the B pattern after chlortetracycline staining and by the ability to undergo
the acrosome reaction (AR) in response to lysophosphatidylcholine (LPC). The
percentage of B pattern sperm was significantly inhibited by W7 or CZ in a
concentration-dependent manner. At 100 microM W7 or 10 microM CZ, these
inhibitors also significantly reduced the sperm's ability to undergo the LPC
induced AR. Inhibition of the B pattern and the LPC-induced AR was overcome by
exogenous cAMP analogues. Treatment of the sperm with 100 microM W7 also resulted
in a significant decrease in their ability to fertilize eggs in vitro. At 100
microM, W5, a less potent dechlorinated W7 analogue, had no effect on the B
pattern, LPC-induced AR, or fertilization competence. Sperm viability and protein
tyrosine phosphorylation were not substantially affected by 100 microM W7
(relative to 100 microM W5) or 10 microM CZ; however, the percentages of motile
and hyperactivated sperm were significantly reduced. The antagonist-inhibited
sperm motility was restored by dilution in control medium, but not by cAMP
analogues. These results suggest that CaM participates in the regulation of
membrane changes important for mouse sperm capacitation, at a point upstream from
cAMP, and that this pathway is at least partially separable from pathways
controlling tyrosine phosphorylation and hyperactivation.
PMID- 10775173
TI - Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic
male lamb.
AB - This study tested the hypothesis that LH secretion is modulated by insulin and
that the responsiveness to hypoinsulinemia is enhanced by sex steroids. The model
was the developing male lamb (12-26 wk of age) rendered diabetic by chemically
induced necrosis of insulin-secreting tissue (streptozotocin). Our approach was
to monitor LH secretion under diabetic conditions, with or without insulin
supplementation, either in the presence or in the absence of gonadal steroids.
The first experiment determined if chronic insulin supplementation could sustain
LH secretion in diabetic lambs. After documentation of the induced diabetic
condition, twice-daily treatment with a long-acting insulin preparation (Lente)
minimized diabetes-induced hyperglycemia, sustained growth, and maintained LH
pulse frequency at levels comparable to pre-diabetic conditions. A second
experiment evaluated the acute regulation of LH secretion by insulin. Twenty-four
hours of insulin withdrawal decreased LH pulse frequency, increased circulating
glucose levels, increased the concentration of plasma non-esterified fatty acids
(NEFAs), and increased urinary output of ketones. LH pulse frequency continued to
decline after 96 h of insulin withdrawal. By contrast, 24 h of insulin re
supplementation increased LH pulse frequency, reduced circulating glucose and
NEFA concentrations, decreased plasma cortisol, and reduced urinary output of
ketones. After 96 h of insulin re-supplementation, LH pulse frequency increased
further, to levels comparable with those before insulin withdrawal. A third
experiment determined if the effects of insulin withdrawal on LH secretion are
influenced by the presence of gonadal steroids. The same individuals were treated
with a physiologic dose of estradiol (Silastic capsule, s.c.) and subsequently
monitored for changes in LH secretion in the presence and in the absence of
exogenous insulin. Prior to insulin withdrawal, estradiol decreased both LH pulse
frequency and pulse amplitude. Moreover, after 96 h of insulin withdrawal,
estradiol potentiated the decline in LH pulse frequency (47% reduction in LH
pulse frequency in the presence of estradiol versus 26% reduction in LH pulse
frequency in the absence of estradiol). These findings support the contention
that insulin and/or insulin-dependent changes in glucose availability modulate
LH(GnRH) pulse frequency, and that such effects are potentiated by, but not
dependent upon, gonadal steroids.
PMID- 10775172
TI - Deletion of follicle-stimulating hormone (FSH) receptor residues encoded by exon
one decreases FSH binding and signaling in the rat.
AB - The rat FSH receptor (rFSHR) shares considerable homology with the rat LH
receptor (rLHR), yet binds human FSH (hFSH) with high fidelity, suggesting that
the binding determinant encoded by the rFSHR gene shares no homology with the
analogous rLHR primary sequence, thereby affording specificity of ligand binding.
Two such regions of primary sequence have been previously identified and studied
by peptide challenge tests and immunoneutralization studies. We therefore
implemented site-directed mutagenesis to delete the regions S9-N30 and D300-F315
of the mature rFSHR sequence. The mutant receptor (DeltarFSHR) cDNAs were
expressed in insect cells. The large deletion DeltarFSHRS9-N30 and a smaller
deletion, DeltarFSHRS9-S18, did not bind (125)I-hFSH. However, DeltarFSHRK19-R29
and DeltarFSHRD300-F315 bound (125)I-hFSH with an affinity indistinguishable from
wild-type rFSHR. The deletion mutants DeltarFSHR S9-N30 or DeltarFSHRS9-S18 were
not detectable on the cell surface by flow cytometry unless cells were sheared.
Although (125)I-hFSH binding to DeltarFSHRK19-R29 was normal, this form of the
receptor was defective for signal transduction whereas DeltarFSHRD300-F315 was
not. Furthermore, neither region seems to be a specificity determinant, since
their removal did not result in high-affinity binding of hCG to DeltarFSHR.
PMID- 10775174
TI - Central action of insulin regulates pulsatile luteinizing hormone secretion in
the diabetic sheep model.
AB - This study tested the hypothesis that central mechanisms regulating luteinizing
hormone (LH) secretion are responsive to insulin. Our approach was to infuse
insulin into the lateral ventricle of six streptozotocin-induced diabetic sheep
in an amount that is normally present in the CSF when LH secretion is maintained
by peripheral insulin administration. In the first experiment, we monitored
cerebrospinal fluid (CSF) insulin concentrations every 3-5 h in four diabetic
sheep given insulin by peripheral injection (30 IU). The insulin concentration in
the CSF was increased after insulin injection, and there was a positive
relationship between CSF and plasma concentrations of insulin (r = 0.80, P <
0.01). In the second experiment, peripheral insulin administration was
discontinued, and the sheep received either an intracerebroventricular (i.c.v.)
infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5
days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated
to approximate the increase in CSF insulin concentration found after peripheral
insulin treatment. To monitor LH secretory patterns, blood samples were collected
by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days
after the start of i.c.v. insulin infusion. To monitor the increase in CSF
insulin concentrations, a single CSF sample was collected one and four days after
the start of the central infusion. The i.c.v. insulin infusion increased CSF
insulin concentrations above those in saline-treated animals (P < 0.05) and
maintained them at or above the peak levels achieved after peripheral insulin
treatment. Central insulin infusion did not affect peripheral (plasma) insulin or
glucose concentrations. LH pulse frequency in insulin-treated animals was greater
than that in saline-treated animals (3.5 +/- 0.2 vs. 2.3 +/- 0.3 pulses/4 h, P <
0.01), but it was less than that during peripheral insulin treatment (4.8 +/- 0.2
pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central
insulin supplementation are able to increase pulsatile LH secretion in diabetic
sheep with low peripheral insulin. These results are consistent with the notion
that central insulin plays a role in regulating pulsatile GnRH secretion.
PMID- 10775175
TI - Regulation of ovarian steroidogenesis in vitro by follicle-stimulating hormone
and luteinizing hormone during sexual maturation in salmonid fish.
AB - The regulation of ovarian steroidogenesis in vitro by coho salmon FSH and LH was
investigated in intact coho salmon follicles and isolated follicular layers at
various stages of oocyte maturation, from late vitellogenesis until the
completion of germinal vesicle breakdown (GVBD). In granulosa layers from all
stages, LH, but not FSH, stimulated 17alpha,20beta-dihydroxy-4-pregnen-3-one (17,
20beta-P) production. In theca-interstitial layers from all stages, FSH and LH
stimulated steroid production, LH being more potent than FSH. The basal steroid
output of intact follicles was significantly lower than that of isolated
follicular layers, and their response to FSH and LH also differed. First, the
intact follicles produced 17alpha-hydroxyprogesterone in response to FSH during
the central germinal vesicle stage while theca-interstitial layers did not.
Second, estradiol-17beta production was not inhibited by LH during final oocyte
maturation in intact follicles, as observed for granulosa layers. Our results
indicate that LH is the determining factor regulating the production of the
maturation-inducing steroid, 17,20beta-P, and the induction of GVBD in the
salmonid ovary. In summary, we have provided evidence for maturation-associated
changes in the effects of FSH and LH in the salmonid ovary, which further
supports the hypothesis that FSH and LH have distinct functions in the teleost
ovary.
PMID- 10775176
TI - The proteasome is involved in the first metaphase-to-anaphase transition of
meiosis in rat oocytes.
AB - The proteasome engages in protein degradation as a regulatory process in
biological transactions. Among other cellular processes, the proteasome
participates in degradation of ubiquinated cyclins in mitosis. However, its role
in meiosis has not been established. Resumption of meiosis in the oocyte involves
the activation of maturation promoting factor (MPF), a complex of p34cdc2 and
cyclin B. Inactivation of this factor, occurring between the two meiotic
divisions, is associated with degradation of cyclin B. In this study, we examined
the possible involvement of the proteasome in regulation of the exit from
metaphase I in spontaneously maturing rat oocytes. We found that upon resumption
of meiosis, proteasomes translocate to the spindle apparatus. We further
demonstrated that specific inhibitors of proteasome catalytic activity, MG132 and
lactacystin, blocked polar body extrusion. Chromosome and microtubule fluorescent
staining verified that MG132-treated oocytes were arrested at metaphase I.
Intervention of proteasomal action with this inhibitor also resulted in
accumulation of cyclin B and elevated activity of MPF. These data demonstrate
that proteasomal catalytic activity is absolutely essential for the decrease in
MPF activity and completion of the first meiotic division. Its translocation to
the spindle apparatus may facilitate the timely degradation of cyclin B.
PMID- 10775177
TI - Identification of a novel testis-specific leucine-rich protein in humans and
mice.
AB - A novel testis-specific protein, termed LRTP, was identified by screening both
human and mouse testis and mouse pachytene spermatocyte cDNA libraries. Sequence
analyses (GenBank accession number: AF092208) revealed that LRTP contains an
amino terminus leucine-rich repeat domain. There are several acidic regions rich
in glutamic acid in the C-terminus. The sequence, by GenBank search, shows
similarities to LANP and SDS22+, leucine-rich repeat proteins localized to the
nucleus and involved in the regulation of protein phosphatases. In mouse, the
mRNA is first detected at about Day 14 postpartum, presumably when mid-pachytene
spermatocytes are first seen. In situ hybridization confirmed the expression of
the LRTP mRNA at this stage of spermatogenesis. Immunohistochemical analysis
revealed that the protein is most abundant in the cytoplasm of pachytene and
diplotene cells, corresponding to late prophase of meiosis I. Immunohistochemical
localization is markedly reduced in secondary spermatocytes, suggesting a
functional association of LRTP with meiosis. An LRTP cDNA probe did not bind to
mouse ovary RNA in a dot blot assay.
PMID- 10775178
TI - Blockade of the alpha(v)beta(3) integrin adversely affects implantation in the
mouse.
AB - The role of endometrial and embryonic integrins during implantation remains
unresolved although work in animal models and in humans supports their
involvement in this process. Temporal and spatial distribution of the
alpha(v)beta(3) integrin on both embryo and endometrium in women and mice
coincides with the time of initial attachment during implantation. In mice, the
endometrial and embryonic alpha(v)beta(3) integrin is present at the time of
implantation, as shown by reverse transcription-polymerase chain reaction and
immunohistochemistry. In situ hybridization demonstrates the presence of the
alpha(v)beta(3) integrin on the subluminal stromal cells of the uterus.
Functional blockade of this integrin on the day of implantation by intrauterine
injection of neutralizing monoclonal antibodies against alpha(v) or beta(3)
integrin subunits, arg-gly-asp (RGD)-containing peptides, or of the disintegrin
echistatin, reduced the number of implantation sites compared to controls
receiving BSA. These studies demonstrate that, like the human, the murine
alpha(v)beta(3) integrin is expressed at the time of implantation in the
endometrium and on the blastocyst, and may play a critical role in the cascade of
events leading to successful implantation.
PMID- 10775179
TI - Induction of interleukin-1alpha production in murine Sertoli cells by interleukin
1.
AB - In the present study we examined the involvement of interleukin (IL)-1alpha,
1beta, FSH, and lipopolysaccharide (LPS) in the regulation of IL-1alpha and
1beta production by Sertoli cells under in vitro conditions. Sertoli cell
cultures from immature mice produced constitutively basal levels of intracellular
IL-1alpha. Stimulation of Sertoli cell cultures with LPS (5 microgram/ml)
resulted in a maximal production of intracellular IL-1alpha 2 h after the
stimulation. Thereafter, these levels decreased but remained significantly higher
within 24 h after stimulation than those in control cultures. The effect of LPS
on IL-1alpha production was dose dependent. FSH did not show any effect on
intracellular IL-1alpha production by Sertoli cells. IL-1alpha could not be
detected in supernatants of unstimulated or stimulated Sertoli cell cultures.
Sertoli cell cultures stimulated with recombinant IL-1alpha induced optimal
intracellular levels of IL-1alpha within 2 h of stimulation. These levels
remained high 24 h after stimulation. However, stimulation of Sertoli cell
cultures with IL-1beta induced a peak of IL-1alpha production 8 h after
stimulation. These levels decreased 24 h after the stimulation but were still
found to be significantly higher than those in control cultures. The addition of
IL-1 receptor antagonist (IL-1ra) to Sertoli cell cultures did not significantly
alter their capacity to produce IL-1alpha. However, the stimulatory effects of
recombinant IL-1alpha on IL-1alpha production by Sertoli cell cultures were
reversed by the concomitant addition of recombinant IL-1ra. No immunoreactive IL
1beta could be detected in lysates or conditioned media of immature murine
Sertoli cells under any of the stimulatory conditions outlined. Our results may
suggest the involvement of physiological (IL-1) and pathophysiological factors
(LPS) in the regulation of spermatogenesis and spermiogenesis processes and male
fertility.
PMID- 10775180
TI - A premature increase in circulating cortisol suppresses expression of 11beta
hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid in the adrenal of
the fetal sheep.
AB - We have investigated the effect of intrafetal cortisol administration, before the
normal prepartum cortisol surge, on the expression of 11beta hydroxysteroid
dehydrogenase (11betaHSD) type 2 mRNA in the fetal adrenal. We also determined
whether increased fetal cortisol concentrations can stimulate growth of the fetal
adrenal gland or increase expression of adrenal steroidogenic enzymes. Cortisol
(hydrocortisone succinate: 2.0-3.0 mg in 4.4 ml/24 h) was infused into fetal
sheep between 109 and 116 days of gestation (cortisol infused; n = 12), and
saline was administered to control fetuses (saline infused; n = 13) at the same
age. There was no effect of cortisol infusion on the fetal adrenal:body weight
ratio (cortisol: 101.7 +/- 5.3 mg/kg; saline: 108.2 +/- 4.3 mg/kg). The ratio of
adrenal 11betaHSD-2 mRNA to 18S rRNA expression was significantly lower, however,
in the cortisol-infused group (0.75 +/- 0.02) compared with the group receiving
saline (1.65 +/- 0.14). There was no significant effect of intrafetal cortisol on
the relative abundance of adrenal CYP11A1, CYP17, CYP21A1, and 3betaHSD mRNA. A
premature elevation in fetal cortisol therefore resulted in a suppression of
adrenal 11betaHSD-2. Increased intra-adrenal exposure to cortisol at this stage
of gestation is, however, not sufficient to promote adrenal growth or
steroidogenic enzyme gene expression.
PMID- 10775181
TI - Multiple effects of retinoids on the development of Sertoli, germ, and Leydig
cells of fetal and neonatal rat testis in culture.
AB - We investigated the effect of retinoids on the development of Sertoli, germ, and
Leydig cells using 3-day culture of testes from fetuses 14.5 and 18.5 days post
conception (dpc) and from neonates 3 days postpartum (dpp). Addition of 10(-6) M
and 3.10(-8) M retinoic acid (RA) caused a dose-dependent disruption of the
seminiferous cords in 14.5-day-old fetal testes, without any change in the 5
bromo-2'-deoxyuridine (BrdU) labeling index of the Sertoli cells. RA caused no
disorganization of older testes, but it did cause hyperplasia of the Sertoli
cells in 3-dpp testes. Fragmentation of the Sertoli cell DNA was not detected in
control or RA-treated testes at any age studied. The cAMP produced in response to
FSH was significantly decreased in RA-treated testes for all studied ages. Both
10(-6) M and 3.10(-8) M RA dramatically reduced the number of gonocytes per 14.5
dpc testis. This resulted from a high increase in apoptosis, which greatly
exceeded the slight increase of mitosis. RA caused no change in the number of
gonocytes in testes explanted on 18.5 dpc (the quiescent period), whereas it
increased this number in testes explanted on 3 dpp (i.e., when gonocyte mitosis
and apoptosis resume). Lastly, RA and retinol (RE) reduced both basal and acute
LH-stimulated testosterone secretion by 14.5-dpc testis explants, without change
in the number of 3beta-hydroxysteroid dehydrogenase-positive cells per testis.
Retinoids had no effect on basal or LH-stimulated testosterone production by
older testes. In conclusion, RE and RA are potential regulators of the
development of the testis and act mainly negatively during fetal life and
positively during the neonatal period on the parameters we have studied.
PMID- 10775183
TI - Growth and antrum formation of bovine preantral follicles in long-term culture in
vitro.
AB - Culture of preantral follicles has important biotechnological implications
through its potential to produce large quantities of oocytes for embryo
production and transfer. A long-term culture system for bovine preantral
follicles is described. Bovine preantral follicles (166 +/- 2.15 micrometer),
surrounded by theca cells, were isolated from ovarian cortical slices. Follicles
were cultured under conditions known to maintain granulosa cell viability in
vitro. The effects of epidermal growth factor (EGF), insulin-like growth factor
(IGF)-I, FSH, and coculture with bovine granulosa cells on preantral follicle
growth were analyzed. Follicle and oocyte diameter increased significantly (P <
0.05) with time in culture. FSH, IGF-I, and EGF stimulated (P < 0.05) follicle
growth rate but had no effect on oocyte growth. Coculture with granulosa cells
inhibited FSH/IGF-I-stimulated growth. Most follicles maintained their morphology
throughout culture, with the presence of a thecal layer and basement membrane
surrounding the granulosa cells. Antrum formation, confirmed by confocal
microscopy, occurred between Days 10 and 28 of culture. The probability of
follicles reaching antrum development was 0.19 for control follicles. The
addition of growth factors or FSH increased (P < 0.05) the probability of antrum
development to 0.55. Follicular growth appeared to be halted by slower growth of
the basement membrane, as growing follicles occasionally burst the basement
membrane, extruding their granulosa cells. In conclusion, a preantral follicle
culture system in which follicle morphology can be maintained for up to 28 days
has been developed. In this system, FSH, EGF, and IGF-I stimulated follicle
growth and enhanced antrum formation. This culture system may provide a valuable
approach for studying the regulation of early follicular development and for
production of oocytes for nuclear/embryo transfer, but further work is required.
PMID- 10775182
TI - Progesterone modulation of osteopontin gene expression in the ovine uterus.
AB - Osteopontin (OPN) is an acidic phosphorylated glycoprotein component of the
extracellular matrix that binds to integrins at the cell surface to promote cell
cell attachment and cell spreading. This matrix constituent is a ligand that
could potentially bind integrins on trophectoderm and endometrium to facilitate
superficial implantation and placentation. OPN mRNA increases in the endometrial
glandular epithelium (GE) of early-pregnant ewes, and OPN protein is secreted
into the uterine lumen. Therefore, progesterone and/or interferon-tau (IFNtau)
may regulate OPN expression in the uterine GE. Cyclic ewes were ovariectomized
and fitted with intrauterine (i. u.) catheters on Day 5 and treated daily with
steroids (i.m.) and protein (i.u.) as follows: 1) progesterone (P, Days 5-24) and
control serum proteins (CX, Days 11-24); 2) P and ZK 136.317 (ZK; progesterone
receptor [PR] antagonist, Days 11-24) and CX proteins; 3) P and recombinant ovine
IFNtau (roIFNtau, Days 11-24); or 4) P and ZK and roIFNtau. All ewes were
hysterectomized on Day 25. Progesterone induced the expression of endometrial OPN
mRNA in the GE and increased secretion of a 45-kDa OPN protein from endometrial
explants maintained in culture for 24 h. Administration of ZK ablated
progesterone effects. Intrauterine infusion of roIFNtau did not affect OPN gene
expression or secretion in any of the steroid treatments. Interestingly, OPN mRNA
positive GE cells lacked detectable PR expression, although PR were detected in
the stroma. Results indicate that progesterone regulates OPN expression in GE
through a complex mechanism that includes PR down-regulation, and we suggest the
possible involvement of a progesterone-induced stromal cell-derived growth
factor(s) that acts as a progestamedin.
PMID- 10775184
TI - Differential splicing of three gonadotropin-releasing hormone transcripts in the
ovary of seabream (Sparus aurata).
AB - Previous studies demonstrated the presence of high-affinity GnRH binding sites
and compounds with GnRH-like activity in the ovary of seabream, Sparus aurata,
providing evidence for the role of GnRH as a paracrine/autocrine regulator of
ovarian function in this species. In the present study, the expression of three
forms of GnRH (salmon, chicken-II, and seabream) genes in this marine teleost
species was demonstrated for the first time. Moreover, there is evidence for
differential splicing and intronic expression of cGnRH-II and sbGnRH. Treatment
of seabream follicle-enclosed oocytes with salmon GnRH stimulated reinitiation of
oocyte meiosis, whereas chicken GnRH-II treatment was without effect. Novel
information was also provided about organization of cGnRH-II and seabream GnRH
transcripts, confirming that GnRH gene organization is maintained through
evolution, despite changes in the size and sequence of exons and introns.
PMID- 10775185
TI - Intrafollicular concentrations of steroids and steroidogenic enzymes in relation
to follicular development in the mare.
AB - The objective of the present study was to determine the changes in follicular
fluid steroid concentrations and in granulosa cell steroidogenic enzyme
expression during the follicular phase, in relation to follicular size and
physiological status in the mare. Follicular fluid and follicular cells were
recovered by ultrasound-guided follicular punctures either around the time of
emergence of the dominant follicle, at the end of the dominant follicle growth,
or at the preovulatory stage, after injection of gonadotropin to induce
ovulation. Cellular relative amounts of steroidogenic acute regulatory protein
(StAR), P450-side chain cleavage (P450(scc)), 3beta-hydroxysteroid dehydrogenase
(3betaHSD), 17alpha-hydroxylase, and aromatase were assessed by semiquantitative
Western blot and densitometry. Follicular fluid was assayed for cholesterol
concentrations by colorimetric assay and for progesterone, testosterone, and
estradiol-17beta concentrations by RIA. Intrafollicular concentrations of
progesterone and estradiol-17beta significantly increased in the dominant
follicle during growth. After injection of gonadotropin, follicular maturation
was characterized by a decrease in estradiol-17beta concentrations and a further
increase in progesterone concentrations. Granulosa cells from dominant follicles
had increased levels of StAR, P450(scc), 3betaHSD, and aromatase during growth,
but decreased levels during maturation. Levels of StAR, P450(scc), 3betaHSD, and
aromatase, as well as progesterone and estradiol-17beta, were lower in granulosa
cells from subordinate than from dominant follicles. We did not observe a
relationship between the steroidogenic activity of follicles and the capacity of
their enclosed oocytes to complete meiosis in vitro.
PMID- 10775186
TI - Cloning and expression analysis of testis-specific cyclic 3', 5'-adenosine
monophosphate-responsive element modulator activators in the nonhuman primate
(Macaca fascicularis): comparison with other primate and rodent species.
AB - The cAMP-responsive element modulator (CREM) gene encodes a transcription factor
that is essential for spermatogenesis. In mouse testis, several CREM repressors
and activators have been identified. In contrast to the situation for the mouse,
however, little is known about CREM isoforms in the primate testis. We analyzed
CREM isoforms and mRNA expression in a clinically relevant primate model, the
cynomolgus monkey (Macaca fascicularis). A cDNA library was generated from monkey
testis; and two activator isoforms (tau2 with and without exon gamma) were
identified, which displayed high sequence identity to mouse and human isoforms.
The insertion of exon gamma was observed for the first time in the primate
testis. CREM activator expression was confined to the testis, where it was seen
in late pachytene spermatocytes and round spermatids in specific spermatogenic
stages, as revealed by in situ hybridization. Comparison of the mRNA and the
recently described protein expression indicated a lack of translational delay of
CREM expression. Comparative analysis of testicular CREM expression by reverse
transcription-polymerase chain reaction yielded several transcripts in the rat,
mouse, hamster, and marmoset; two transcripts in cynomolgus and rhesus monkeys;
and one transcript in men. These findings suggest an evolutionary trend from
multiple activator isoforms to a single activator transcript in men.
PMID- 10775188
TI - Identification of isoforms of a mitotic motor in mammalian spermatogenesis.
AB - We have isolated the full-length coding sequence for mouse KIFC5A (kinesin family
c-terminal 5A) cDNA, encoding a motor protein found in the testes. The complete
sequence of the KIFC5A cDNA is homologous to a group of carboxyl-terminal motors,
including hamster CHO2, human HSET, and mouse KIFC1 and KIFC4. The KIFC5A and
KIFC1 cDNAs are nearly identical except for the presence of two additional
sequence blocks in the 5'-end of KIFC5A and a number of single base-pair
differences in their motor domains. Polymerase chain reaction amplification and
sequencing of the 5'-end of KIFC5A identified 3 distinct RNA species in testes
and other tissues. Sequence comparison and genetic mapping confirmed the
existence of a small multi-gene family in the mouse and suggest possible
mechanisms of alternative splicing, genetic duplication, and separate genetic
loci in the generation of these motors. In order to examine the possible role of
these motors in germ cells of the testes, an antibody to a shared epitope was
used to localize this group of proteins to different spermatogenic cell types.
These experiments suggest that KIFC5-like motor proteins are associated with
multiple microtubule complexes in male germ cells, including the meiotic spindle,
the manchette, and the flagella.
PMID- 10775187
TI - A novel secretory protein produced by rat spongiotrophoblast.
AB - The placenta secretes various factors in stage- and cell-specific manners. We
have identified a cDNA encoding a novel protein with 124 amino acids, which was
named spongiotrophoblast specific protein (SSP). SSP is highly homologous to
mouse 4311, showing 81% and 59% similarity at the nucleotide and amino acid
levels, respectively. Northern blot analysis showed that SSP mRNA was first
detected on Day 14 of pregnancy, peaked on Day 16, and remained elevated until
term. In situ hybridization analysis showed that SSP mRNA was specifically
expressed in spongiotrophoblast cells of Day 20 placenta but not in Day 12
placenta. No expression was detected from the differentiated or undifferentiated
rat choriocarcinoma Rcho-1 cell line. Native SSP was detected as a 19-kDa
molecule by Western blotting in cell extracts prepared from the junctional zone.
SSP was predicted to be a secretory protein, because 1) a hydropathy test
revealed that SSP contained an N-terminal hydrophobic region and 2) native SSP
was also detected in the cultured media of junctional zone explants. To further
investigate a potential signal peptide of this protein, sets of recombinant SSP
were generated using a COS7 transfection system. The N-terminal amino acid
sequence of secreted recombinant SSP confirmed that the N-terminal 17 amino acids
had been cleaved to produce a secretory protein. Thus, we have identified and
cloned a novel secretory protein, SSP, which is specifically expressed by rat
spongiotrophoblast cells during the latter half of pregnancy.
PMID- 10775189
TI - Injection of sperm cytosolic factor into mouse metaphase II oocytes induces
different developmental fates according to the frequency of [Ca(2+)](i)
oscillations and oocyte age.
AB - Intracellular calcium ([Ca(2+)](i)) rises are a hallmark of mammalian
fertilization and are associated with normal activation of embryonic development.
Injection of mammalian sperm cytosolic factor (SCF) into oocytes has been shown
to trigger [Ca(2+)](i) rises similar to those observed during fertilization, and
to initiate normal embryonic development. However, Ca(2+) release has also been
shown to be associated with cell death, but the mechanisms of the detrimental
effects of Ca(2+) stimulation on development have not yet been investigated.
Thus, studies were undertaken using SCF to test the effects of [Ca(2+)](i)
oscillations on oocyte activation in freshly ovulated and aged oocytes.
Injections of 1 mg/ml SCF into freshly ovulated mouse metaphase II oocytes, which
evoked Ca(2+) responses with low frequency and short duration, induced normal
activation and cleavage to the two-cell stage. Conversely, injection of 15 mg/ml
SCF, which triggered high-frequency and persistent Ca(2+) responses, induced
abnormal activation that was characterized by abnormal chromatin configurations,
inhibition of DNA synthesis, and lack of first mitotic spindle assembly. More
importantly, fertilization-like Ca(2+) responses induced by injection of 1 mg/ml
SCF triggered cell death, rather than activation, in in vitro-aged oocytes. These
oocytes exhibited extensive cytoplasmic and DNA fragmentation that was
accompanied by activation of protein caspases, all of which are signs of
apoptotic cell death. Fewer similarly aged oocytes that were either unstimulated
or activated with 7% ethanol underwent fragmentation. Together, these results
suggest that [Ca(2+)](i) oscillations are required to activate freshly ovulated
oocytes, but if initiated at abnormally high frequency and duration or if induced
in aged oocytes, the [Ca(2+)](i) oscillations may trigger premature termination
of embryonic development.
PMID- 10775190
TI - Induction of a sodium ion influx by progesterone in human spermatozoa.
AB - In human spermatozoa, progesterone (P(4)) induces a depolarization of the plasma
membrane, a rapid calcium (Ca(2+)) influx, and a chloride efflux. The sodium ion
(Na(+)) was partly responsible for the P(4)-induced depolarizing effect but was
not required for calcium influx. We used fluorescent probes for
spectrofluorometry to investigate whether P(4) induced a Na(+) influx and whether
voltage-operated channels were involved in Na(+) and/or Ca(2+) entries. We found
that 10 microM P(4) significantly increased intracellular Na(+) concentration
from 17.8 +/- 2.0 mM to 27.2 +/- 1. 6 mM (P < 0.001). Prior incubation of
spermatozoa with 10 microM flunarizine, a Na(+) and Ca(2+) voltage-dependent
channel blocker, inhibited the sodium influx induced by 10 microM P(4) by 84.6 +/
15.4%. The Ca(2+) influx induced by 10 microM P(4) was also significantly
inhibited in a Na(+)-containing medium by 10 microM flunarizine or 10 microM
pimozide (P < 0.01). In contrast, flunarizine had no inhibitory effect on the
Ca(2+) influx induced by 10 microM P(4) in spermatozoa incubated in Na(+)
depleted medium. The P(4)-promoted acrosome reaction (AR) was significantly
higher when spermatozoa were incubated in Na(+)-containing medium as compared to
Na(+)-depleted medium. These data demonstrate that P(4) stimulates a Na(+) influx
that could be involved in the AR completion. They also suggest that voltage
dependent Na(+) and Ca(2+) channels are implicated in P(4)-mediated signaling
pathway in human spermatozoa.
PMID- 10775191
TI - Nitric oxide synthase in the rabbit uterus and vagina: hormonal regulation and
functional significance.
AB - The effects of estrogen (E(2)), progesterone (P(4)), and E(2) and P(4)
(E(2)+P(4)) on uterine, vaginal, and cerebellar nitric oxide synthase (NOS) were
examined. Additionally, experiments were done to investigate whether NOS
containing nerves were present in the uterus and vagina and the extent to which
vaginal smooth muscle response was dependent on nitric oxide (NO). Cytosolic NOS
was determined by the formation of [(14)C]citrulline from [(14)C]arginine, and
NOS localization was visualized by immunohistochemistry. Vaginal smooth muscle
relaxation was induced by electrical field stimulations (EFS). NOS activity in
the uterus was markedly down-regulated in all hormone-treated groups. Vaginal NOS
activity was nearly 4-fold higher than the uterine NOS activity and was
considerably reduced by E(2) or E(2)+P(4) treatment. In contrast to findings in
the uterus, P(4) treatment up-regulated vaginal NOS. Hormone treatment had no
significant effect on cerebellar NOS. NOS-containing nerves could be demonstrated
in the uterus and vagina by immunohistochemistry. Vaginal smooth muscle responded
with relaxation after EFS, which was inhibited by N(G)-nitro-L-arginine. A
relatively high vaginal NOS, a down-regulation by E(2), an up-regulation by P(4),
and NO-dependent response of vaginal smooth muscle suggest a tissue-specific
physiological role.
PMID- 10775192
TI - Levels and interactions of p27, cyclin D3, and CDK4 during the formation and
maintenance of the corpus luteum in mice.
AB - The cyclin-dependent kinase (CDK) inhibitor p27, the regulator of the cell cycle,
is required for proper functioning of luteinizing/luteinized cells in vivo. Since
different members of the CDK family may be targeted by p27 during luteinization
associated cell cycle exit, this in vivo study further analyzed the organization
of the network of cell cycle regulators that may underlie both the establishment
and maintenance of the luteal phenotype. Most importantly, it shows that the
luteinization process is associated with down-regulation of CDK2 and cyclin D1,
and up-regulation of p27 and cyclin D3. Both p27 and cyclin D3 proteins not only
accumulated during initial phases of luteinization, but they remained elevated
until termination of the luteal function. Along with its accumulation, p27 lost
physical contact with CDK2 and instead became associated with CDK4. In fully
luteinized cells, all cyclin D3 was incorporated into complexes with p27, some
complexes being p27/cyclin D3/CDK4 trimers. Despite the significant amounts of
CDK4 and CDK6, only nonphosphorylated forms of retinoblastoma protein were
detectable in fully luteinized cells. Together, our data indicate that while
inhibition of proliferation is underlaid by the progressive loss of positive
regulators of the cell cycle, including cyclins and CDK2, maintenance of the
luteal phenotype is driven by up-regulated levels of p27 and cyclin D3, at least
partially owing to formation of p27/cyclin D3/CDK4 trimers.
PMID- 10775193
TI - Meiotic competence in horse oocytes: interactions among chromatin configuration,
follicle size, cumulus morphology, and season.
AB - Horse oocytes were collected from an abattoir over a 15-mo period. After
classification of follicle size and cumulus morphology, oocytes were either fixed
immediately (0 h) or matured in vitro (24 h). There was no effect of season on
the number of antral follicles present on the ovaries, or on oocyte maturation
rate for any class of oocyte. The proportion of oocytes having condensed
chromatin at 0 h increased with increasing follicle size. The oocyte maturation
rate also increased with follicle size, and for follicles /= 4 mm in
diameter were measured by daily ultrasonography in HGAIN and LGAIN heifers during
one follicular wave before realimentation (Wan) and in two waves (W-2, W-1)
immediately before the wave resulting in first ovulation or luteinization (W0).
Ovaries of M heifers were evaluated to determine the day of ovulation of the
second-wave dominant follicle (DF). Resumption of ovulation after realimentation
occurred 23 days earlier in HGAIN than in LGAIN. Maximum diameter, growth rate,
and persistence of dominant follicles increased, while persistence of first
subordinate follicles decreased between anovulation and resumption of ovulation
in anovulatory heifers. Concentrations of LH in serum were similar for HGAIN and
LGAIN and gradually increased during realimentation. The increase in estradiol
before the first ovulation was less in realimented heifers compared with cyclic
heifers. Concentrations of insulin-like growth factor-I (IGF-I) in HGAIN and
LGAIN gradually increased during realimentation but were lower than
concentrations of IGF-I in cyclic heifers at ovulation. Increased diameter,
growth rate, and persistence of the DF were associated with increased
concentrations of LH, estradiol, and IGF-I during the transition from
nutritionally induced anovulation to resumption of ovulatory cycles.
PMID- 10775199
TI - Opposing effects of androgen and estrogen on pituitary-adrenal function in
nonpregnant primates.
AB - Maternal administration of androstenedione produces a sustained fall in maternal
plasma adrenocorticotropic hormone (ACTH) concentrations in the pregnant nonhuman
primate. We hypothesize a negative feedback influence on the maternal hypothalamo
pituitary-adrenal (HPA) axis by androgens in primates. This may reflect an
important maternal adaptation during pregnancy in primates preventing premature
induction of labor by maternal stress. However, androstenedione is precursor for
placental estradiol-17beta synthesis, and infusion of androstenedione into
pregnant primates elevates maternal plasma estradiol-17beta to term
concentrations. Thus, it could be argued that 1) the effects attributed to
androstenedione on the maternal HPA axis are mediated by estrogen rather than by
androgen and 2) the negative influence of androgens may be on placental ACTH
rather than, or in addition to, pituitary ACTH. To discriminate between
androgenic and estrogenic effects of androstenedione on pituitary and/or
placental ACTH function in primates we measured plasma ACTH, cortisol, and
dehydroepiandrosterone sulfate (DHEAS) concentrations in nonpregnant baboons
after treatment with either androstenedione or estradiol-17beta. Nine female
baboons were studied between 14 and 22 days postpartum prior to estrous cycling.
After 2 days of baseline, a continuous i.v. infusion of androstenedione (1.5
mg/kg per h in 10% intralipid, IL) was started at 0900 h and maintained for 9
days in 3 baboons. A similar protocol was carried out in another 3 baboons that
received a continuous i.v. infusion of estradiol-17beta (10 microg/kg per h in
10% IL) instead of androstenedione. Three additional baboons received continuous
i.v. IL vehicle alone and served as controls. Arterial blood samples (0.5 ml) for
measurement of plasma hormones were taken during baseline and after 1, 3, 5, 7,
and 9 days of infusion. Baseline plasma ACTH, DHEAS, and cortisol concentrations
were similar among all groups. Plasma ACTH did not change during IL, increased
following estradiol-17beta, and fell during androstenedione treatment.
Accordingly, plasma cortisol and DHEAS concentrations were also unaltered by IL,
and both steroids increased during estradiol-17beta treatment. In contrast,
plasma cortisol and DHEAS remained unaltered from baseline during androstenedione
treatment, despite the fall in plasma ACTH measured at this time. These data in
the nonpregnant baboon 1) are consistent with negative feedback on pituitary ACTH
by androgens and 2) demonstrate a positive influence on pituitary-adrenal
function by estrogen in primates.
PMID- 10775200
TI - Circadian rhythm of the preovulatory surge of luteinizing hormone and its
relationships to rhythms of body temperature and locomotor activity in turkey
hens.
AB - Simultaneous measurements of plasma LH, body temperature, and locomotor activity
were made in laying turkey hens and are reported. Blood samples were remotely
collected using a jugular cannula system, and body temperature and locomotor
activity were remotely monitored using a radiotelemetry system in freely moving
laying turkeys. Under a photoschedule of 14L:10D, the period for preovulatory
surges of LH was 25.7 +/- 0.4 h while the periods for peak body temperature and
onset of sustained locomotor activity were 24.9 +/- 0.4 and 25.7 +/- 0.5 h,
respectively. During exposure to constant light, the periods for preovulatory
surges of LH, peak body temperature, and onset of sustained locomotor activity
increased to 27.9 +/- 0.9, 26.7 +/- 0.7, and 27.4 +/- 0.7 h, respectively. With
the 14L:10D photoschedule, initiation of LH surges was restricted to the
scotophase, but after 8 days of constant light, initiation of LH surges had
dispersed throughout the 24-h subjective day and night. With constant light, the
amplitude of the peak body temperature rhythm decreased, while the duration of
the locomotor activity rhythm became broadened and, in some birds, disorganized.
Peak body temperature and onset of locomotor activity rhythms and LH surges did
not coincide, even though peak body temperature, onset of locomotor activity, and
LH surges had similar periods. It is concluded that 1) the photoschedule
influences the periods of the LH surge, peak body temperature, and onset of
locomotor activity; and 2) a specific or direct relationship between the rhythms
of LH surge, body temperature, and locomotor activity remains to be determined in
laying turkey hens.
PMID- 10775201
TI - Ultrastructural morphometry of bovine compact morulae produced in vivo or in
vitro.
AB - The objective of this study was to compare the ultrastructure of bovine compact
morulae produced in vivo or in vitro using morphometric analysis. Compact morulae
produced in vivo were obtained from superovulated Holstein cows. Compact morulae
produced in vitro were obtained from cumulus-oocyte complexes aspirated from
ovaries of Holstein cows. The complexes were matured and fertilized in vitro. At
20 h postinsemination (hpi), zygotes were distributed into 1 of 3 culture media:
1) IVPS (in vitro produced with serum): TCM-199 + 10% estrous cow serum (ECS); 2)
IVPSR (in vitro produced with serum restriction): TCM-199 + 1% BSA until 72 hpi
followed by TCM-199 + 10% ECS from 72 to 144 hpi; 3) mSOF (modified synthetic
oviductal fluid): SOF + 0.6% BSA. At 144 hpi, five grade 1 compact morulae from
each of the four treatments were prepared for transmission electron microscopy.
The volume density occupied by cellular components was determined by the point
count method using a sampling of seven to nine random micrographs from each
compact morula. The volume density of lipid was greater (P < 0.05) in compact
morulae from IVPS, IVPSR, and mSOF treatments compared with those produced in
vivo. There was a reduced proportional volume of total mitochondria in compact
morulae from the IVPS treatment compared with those produced in vivo (P < 0.05).
For compact morulae from the IVPS culture treatment, the volume density of
vacuoles was greater than that for compact morulae produced in vivo (P < 0.05).
The cytoplasmic-to-nuclear ratio for compact morulae from the IVPS treatment was
increased (P < 0.05) compared with the ratio for those produced in vivo. In
conclusion, compact morulae produced in vitro differed ultrastructurally from
those produced in vivo. Compact morulae produced in IVPS culture medium possessed
the greatest deviations in cellular ultrastructure.
PMID- 10775202
TI - Smoking and the brain.
PMID- 10775203
TI - Assessing the risk of violence in patients.
PMID- 10775204
TI - Fighting biological warfare.
PMID- 10775205
TI - General practitioners and cancer.
PMID- 10775206
TI - Periodic fevers enter the era of molecular diagnosis.
PMID- 10775207
TI - Clinton fires latest salvo in medicare drug benefit war.
PMID- 10775208
TI - College recommends new post of healthcare practitioner.
PMID- 10775209
TI - Dutch tighten their rules on advertising of alcohol.
PMID- 10775211
TI - FDA committee recommends approval for viagra rival.
PMID- 10775212
TI - Rich countries accused of breaking promises on debt.
PMID- 10775213
TI - AIDS patients in South Africa to get free drug.
PMID- 10775214
TI - BMA launches review on UK healthcare spending.
PMID- 10775215
TI - UK juniors advised to accept new pay offer.
PMID- 10775216
TI - Smoking and dementia in male British doctors: prospective study.
AB - OBJECTIVE: To assess the possible association between smoking and dementia.
DESIGN: Prospective study. SETTING: Cohort of British male doctors followed up
since 1951. SUBJECTS: 34 439 male British doctors, with 24 133 deaths recorded.
RESULTS: For all types of dementia combined the relative risk was 0.96 (95%
confidence interval 0.78 to 1.18), based on 473 deaths at a mean age of 81 years.
For probable or definite Alzheimer's disease, the relative risk in continuing
smokers was 0.99 (0.78 to 1.25), based on 370 deaths at a mean age of 82 years.
In aggregate, however, the other prospective studies indicate a direct, although
not clearly significant, association between smoking and the onset of dementia in
general and of Alzheimer's disease in particular. CONCLUSIONS: Contrary to
previous suggestions persistent smoking does not substantially reduce the age
specific onset rate of Alzheimer's disease or of dementia in general. If
anything, it might increase rather than decrease the rate, but any net effect on
severe dementia cannot be large in either direction.
PMID- 10775217
TI - Educational differences in smoking: international comparison.
AB - OBJECTIVE: To investigate international variations in smoking associated with
educational level. DESIGN: International comparison of national health, or
similar, surveys. SUBJECTS: Men and women aged 20 to 44 years and 45 to 74 years.
SETTING: 12 European countries, around 1990. MAIN OUTCOME MEASURES: Relative
differences (odds ratios) and absolute differences in the prevalence of ever
smoking and current smoking for men and women in each age group by educational
level. RESULTS: In the 45 to 74 year age group, higher rates of current and ever
smoking among lower educated subjects were found in some countries only. Among
women this was found in Great Britain, Norway, and Sweden, whereas an opposite
pattern, with higher educated women smoking more, was found in southern Europe.
Among men a similar north-south pattern was found but it was less noticeable than
among women. In the 20 to 44 year age group, educational differences in smoking
were generally greater than in the older age group, and smoking rates were higher
among lower educated people in most countries. Among younger women, a similar
north-south pattern was found as among older women. Among younger men, large
educational differences in smoking were found for northern European as well as
for southern European countries, except for Portugal. CONCLUSIONS: These
international variations in social gradients in smoking, which are likely to be
related to differences between countries in their stage of the smoking epidemic,
may have contributed to the socioeconomic differences in mortality from ischaemic
heart disease being greater in northern European countries. The observed age
patterns suggest that socioeconomic differences in diseases related to smoking
will increase in the coming decades in many European countries.
PMID- 10775219
TI - A golden rule: Looking first.
PMID- 10775218
TI - Evaluating "payback" on biomedical research from papers cited in clinical
guidelines: applied bibliometric study.
AB - OBJECTIVES: To develop a methodology for evaluating the impact of research on
health care, and to characterise the papers cited on clinical guidelines. DESIGN:
The bibliographic details of the papers cited in 15 clinical guidelines,
developed in and for the United Kingdom, were collated and analysed with applied
bibliometric techniques. RESULTS: The median age of papers cited in clinical
guidelines was eight years; most papers were published by authors living in
either the United States (36%) or the United Kingdom (25%)-this is two and a half
times more than expected as about 10% of all biomedical outputs are published in
the United Kingdom; and clinical guidelines do not cite basic research papers.
CONCLUSION: Analysis of the evidence base of clinical guidelines may be one way
of tracking the flow of knowledge from the laboratory to the clinic. Moreover,
such analysis provides a useful, clinically relevant method for evaluating
research outcomes and different strategies in research and development.
PMID- 10775220
TI - Assessment of aggression in psychiatric admissions: semistructured interview and
case note survey.
PMID- 10775221
TI - Worsening of symptoms of multiple sclerosis associated with carbamazepine.
PMID- 10775222
TI - Immune complex haemolytic anaemia associated with sulfasalazine.
PMID- 10775224
TI - A Texan prayer.
PMID- 10775223
TI - Decision making, evidence, audit, and education: case study of antibiotic
prescribing in general practice.
AB - OBJECTIVES: To describe a group general practice's implementation of a decision
to prescribe 3 day courses of 200 mg trimethoprim twice daily for urinary tract
infections in women and to compare 3 day courses with 5 and 7 day courses.
DESIGN: Record review, audit of trimethoprim prescribing for urinary tract
infections, and critical appraisal of evidence originally presented in support of
3 day course. SETTING: Group general practice in Newcastle upon Tyne. DATA
SOURCES: The records of all female patients aged 12 years and older who were
prescribed trimethoprim for uncomplicated urinary tract infections during a 12
month period were reviewed. 271 valid records were identified. DATA EXTRACTION:
Prescribing rates for different courses of trimethoprim, rates of patients
returning for second consultations, rates of urine cultures, results of cultures,
results of critical appraisal of evidence. RESULTS: 114 of 271 (42%)
prescriptions written at the first visit were for 3 day courses. 16 of 114 (14%)
patients who had had a 3 day course of treatment returned for a second
consultation compared with 6/83 (7.2%) of those who had had a 5 day course and
8/74 (11%) who had had a 7 day course. The difference between 3 day and 5 day
courses in rates of returning for second consultations was 6.8% (95% CI -1.7% to
12.6%) and between 3 day and 7 day courses was 3.2% (-3.6% to 10.0%). Appraisal
of the original evidence on which the practice based its recommendations showed
that it was flawed. Additional evidence was found in the Cochrane Library.
CONCLUSIONS: Our original decision, made by consensus at a meeting of the
practice's partners, had not led to a consistent change in practice. We did not
find a significant increase in treatment failures among patients treated with the
3 day regimen.
PMID- 10775225
TI - Ulcerative colitis.
PMID- 10775226
TI - ABC of arterial and venous disease. Renal artery stenosis.
PMID- 10775227
TI - Use and interpretation of ambulatory blood pressure monitoring: recommendations
of the British hypertension society.
PMID- 10775228
TI - What is the optimal age for starting lipid lowering treatment? A mathematical
model.
PMID- 10775229
TI - Damages claimed for antenatal injuries.
PMID- 10775230
TI - Is infestation with the common bedbug increasing?
PMID- 10775231
TI - Use of hypericum as antidepressant. Valid measure of antidepressant efficacy in
primary care is needed.
PMID- 10775232
TI - Article about Canadian guidelines on proton pump inhibitors was misleading.
PMID- 10775233
TI - Doctors and theologians. There is abundance in religion but scarcity in the NHS.
PMID- 10775234
TI - Caring for marginalised people. Appropriate external intervention is needed.
PMID- 10775235
TI - Doctors and complementary medicine. "Deep model" that is probably true should be
used.
PMID- 10775236
TI - Surgeons should have to demonstrate competence as pilots do.
PMID- 10775237
TI - Deaths attributed to haemochromatosis are rare in Britain.
PMID- 10775238
TI - Differences in suicide rates may be even more pronounced.
PMID- 10775239
TI - Scottish group is developing guideline for managing pregnant women with epilepsy.
PMID- 10775240
TI - Waiting time for cardiac surgery in Scotland is relatively short.
PMID- 10775241
TI - More work is needed to explain why patients ask for amputation of healthy limbs.
PMID- 10775242
TI - Openness is fine but deferred responsibility is not.
PMID- 10775243
TI - Could the GMC institute an appeal procedure?
PMID- 10775244
TI - Unlike GMC, GP did not follow line of political correctness.
PMID- 10775246
TI - Obituaries.
PMID- 10775245
TI - Drivers who take insulin must tell driver and vehicle licensing agency.
PMID- 10775248
TI - Death, Hope and Sex.
PMID- 10775247
TI - Inequalities in Health: The Evidence.
PMID- 10775249
TI - Why I am not a Christian.
PMID- 10775250
TI - Stronger campaign needed to end female genital mutilation.
PMID- 10775251
TI - The new kids.
PMID- 10775253
TI - Smoking has little net effect on the incidence of severe dementia.
PMID- 10775252
TI - Of smokers, enthusiasts, and bedbugs.
PMID- 10775255
TI - UK clinical guidelines tend to cite UK research.
PMID- 10775254
TI - Smoking is most prevalent among people of low education.
PMID- 10775256
TI - Violent thoughts are common among psychiatric inpatients but rarely asked about.
PMID- 10775257
TI - GPs need to critically appraise evidence before adopting it.
PMID- 10775258
TI - Ambulatory blood pressure monitoring can lead to less drug treatment.
PMID- 10775259
TI - Transcriptional control by the TGF-beta/Smad signaling system.
PMID- 10775260
TI - Crystal structure of the catalytic domain of human complement c1s: a serine
protease with a handle.
AB - C1s is the highly specific modular serine protease that mediates the proteolytic
activity of the C1 complex and thereby triggers activation of the complement
cascade. The crystal structure of a catalytic fragment from human C1s comprising
the second complement control protein (CCP2) module and the chymotrypsin-like
serine protease (SP) domain has been determined and refined to 1.7 A resolution.
In the areas surrounding the active site, the SP structure reveals a restricted
access to subsidiary substrate binding sites that could be responsible for the
narrow specificity of C1s. The ellipsoidal CCP2 module is oriented
perpendicularly to the surface of the SP domain. This arrangement is maintained
through a rigid module-domain interface involving intertwined proline- and
tyrosine-rich polypeptide segments. The relative orientation of SP and CCP2 is
consistent with the fact that the latter provides additional substrate
recognition sites for the C4 substrate. This structure provides a first example
of a CCP-SP assembly that is conserved in diverse extracellular proteins. Its
implications in the activation mechanism of C1 are discussed.
PMID- 10775261
TI - Structure and mechanism of the aberrant ba(3)-cytochrome c oxidase from thermus
thermophilus.
AB - Cytochrome c oxidase is a respiratory enzyme catalysing the energy-conserving
reduction of molecular oxygen to water. The crystal structure of the ba(3)
cytochrome c oxidase from Thermus thermophilus has been determined to 2.4 A
resolution using multiple anomalous dispersion (MAD) phasing and led to the
discovery of a novel subunit IIa. A structure-based sequence alignment of this
phylogenetically very distant oxidase with the other structurally known
cytochrome oxidases leads to the identification of sequence motifs and residues
that seem to be indispensable for the function of the haem copper oxidases, e.g.
a new electron transfer pathway leading directly from Cu(A) to Cu(B). Specific
features of the ba(3)-oxidase include an extended oxygen input channel, which
leads directly to the active site, the presence of only one oxygen atom (O(2-),
OH(-) or H(2)O) as bridging ligand at the active site and the mainly hydrophobic
character of the interactions that stabilize the electron transfer complex
between this oxidase and its substrate cytochrome c. New aspects of the proton
pumping mechanism could be identified.
PMID- 10775262
TI - Supercomplexes in the respiratory chains of yeast and mammalian mitochondria.
AB - Around 30-40 years after the first isolation of the five complexes of oxidative
phosphorylation from mammalian mitochondria, we present data that fundamentally
change the paradigm of how the yeast and mammalian system of oxidative
phosphorylation is organized. The complexes are not randomly distributed within
the inner mitochondrial membrane, but assemble into supramolecular structures. We
show that all cytochrome c oxidase (complex IV) of Saccharomyces cerevisiae is
bound to cytochrome c reductase (complex III), which exists in three forms: the
free dimer, and two supercomplexes comprising an additional one or two complex IV
monomers. The distribution between these forms varies with growth conditions. In
mammalian mitochondria, almost all complex I is assembled into supercomplexes
comprising complexes I and III and up to four copies of complex IV, which guided
us to present a model for a network of respiratory chain complexes: a
'respirasome'. A fraction of total bovine ATP synthase (complex V) was isolated
in dimeric form, suggesting that a dimeric state is not limited to S.cerevisiae,
but also exists in mammalian mitochondria.
PMID- 10775263
TI - Polyunsaturated fatty acids are potent neuroprotectors.
AB - Results reported in this work suggest a potential therapeutic value of
polyunsaturated fatty acids for cerebral pathologies as previously proposed by
others for cardiac diseases. We show that the polyunsaturated fatty acid
linolenic acid prevents neuronal death in an animal model of transient global
ischemia even when administered after the insult. Linolenic acid also protects
animals treated with kainate against seizures and hippocampal lesions. The same
effects have been observed in an in vitro model of seizure-like activity using
glutamatergic neurons and they have been shown to be associated with blockade of
glutamatergic transmission by low concentrations of distinct polyunsaturated
fatty acids. Our data suggest that the opening of background K(+) channels, like
TREK-1 and TRAAK, which are activated by arachidonic acid and other
polyunsaturated fatty acids such as docosahexaenoic acid and linolenic acid, is a
significant factor in this neuroprotective effect. These channels are abundant in
the brain where they are located both pre- and post-synaptically, and are
insensitive to saturated fatty acids, which offer no neuroprotection.
PMID- 10775264
TI - Protein trafficking to the plastid of Plasmodium falciparum is via the secretory
pathway.
AB - The plastid of Plasmodium falciparum (or 'apicoplast') is the evolutionary
homolog of the plant chloroplast and represents a vestige of a photosynthetic
past. Apicoplast indispensability indicates that it still provides essential
functions to parasites. Similar to plant chloroplasts, the apicoplast is
dependent on many nucleus-encoded genes to provide these functions. The
apicoplast is surrounded by four membranes, two more than plant chloroplasts.
Thus, protein targeting to the apicoplast must overcome additional membrane
barriers. In P.falciparum we have analyzed apicoplast targeting using green
fluorescent protein (GFP). We demonstrate that protein targeting is at least a
two-step process mediated by bipartite N-terminal pre-sequences that consist of a
signal peptide for entry into the secretory pathway and a plant-like transit
peptide for subsequent import into the apicoplast. The P.falciparum transit
peptide is exceptional compared with other known plastid transit peptides in not
requiring serine or threonine residues. The pre-sequence components are removed
stepwise during apicoplast targeting. Targeting GFP to the apicoplast has also
provided the first opportunity to examine apicoplast morphology in live P.
falciparum.
PMID- 10775265
TI - The role of the sid1p kinase and cdc14p in regulating the onset of cytokinesis in
fission yeast.
AB - Coordination of mitosis and cytokinesis is crucial for ensuring proper chromosome
segregation and genomic stability. In Schizosaccharomyces pombe, the sid genes
(cdc7, cdc11, cdc14, spg1, sid1, sid2 and sid4) define a signaling pathway that
regulates septation and cytokinesis. Here we describe the characterization of a
novel protein kinase, Sid1p. Sid1p localizes asymmetrically to one spindle pole
body (SPB) in anaphase. Sid1p localization is maintained during medial ring
constriction and septum synthesis and disappears prior to cell separation.
Additionally, we found that Cdc14p is in a complex with Sid1p. Epistasis analysis
places Sid1p-Cdc14p downstream of Spg1p-Cdc7p but upstream of Sid2p. Finally, we
show that cyclin proteolysis during mitosis is unaffected by inactivating the sid
pathway; in fact, loss of Cdc2-cyclin activity promotes Sid1p-Cdc14p association
with the SPB, possibly providing a mechanism that couples cytokinesis with
mitotic exit.
PMID- 10775266
TI - Nek2B, a novel maternal form of Nek2 kinase, is essential for the assembly or
maintenance of centrosomes in early Xenopus embryos.
AB - Nek2, a NIMA-related kinase, has been postulated to play a role in both the
meiotic and mitotic cell cycles in vertebrates. Xenopus has two Nek2 splice
variants, Nek2A and Nek2B, which are zygotic and maternal forms, respectively.
Here we have examined the role of Nek2B in oocyte meiosis and early embryonic
mitosis. Specific inhibition of Nek2B function does not interfere with the
oscillation of Cdc2 activity in either the meiotic or mitotic cell cycles;
however, it does cause abortive cleavage of early embryos, in which bipolar
spindle formation is severely impaired due to fragmentation or dispersal of the
centrosomes, to which endogenous Nek2B protein localizes. In contrast, inhibition
of Nek2B function does not affect meiotic spindle formation in oocytes, in which
functional centrosomes are absent. Thus, strikingly, Nek2B is specifically
required for centrosome assembly and/or maintenance (and hence for normal bipolar
spindle formation and cleavage) in early Xenopus embryos. Finally, (ectopic)
Nek2A but not Nek2B is very labile in cleaving embryos, suggesting that Nek2A
cannot replace the centrosomal function of Nek2B in early embryos.
PMID- 10775267
TI - Signal transduction and transforming properties of the TEL-TRKC fusions
associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute
myelogenous leukemia.
AB - The TEL-TRKC fusion is expressed as a consequence of t(12;15)(p13;q25), and is
associated with two human cancers: congenital fibrosarcoma and acute myelogenous
leukemia (AML). We report that the T/T(F) and T/T(L) fusion variants associated
with congenital fibrosarcoma and AML, respectively, are constitutively tyrosine
phosphorylated, and confer factor-independent growth to the murine hematopoietic
cell line Ba/F3. Retroviral transduction of T/T(L) causes a rapidly fatal
myeloproliferative disease in a murine bone marrow transplant (BMT) model,
whereas T/T(F) causes a long-latency, pre-B-cell lymphoblastic lymphoma. TEL-TRKC
variants are potent activators of the MAP kinase pathway, but neither variant
activates Stat5 or other Stat family members. T/T(L), but not T/T(F), induces
tyrosine phosphorylation of phospholipase Cgamma (PLCgamma), phosphoinositol-3
kinase and SHC. However, mutation analysis demonstrates that PLCgamma tyrosine
phos phorylation by T/T(L) is dispensable for induction of the myeloproliferative
phenotype by T/T(L). Collectively, these data demonstrate that the TEL-TRKC
fusion variants are oncoproteins that activate the MAP kinase pathway, and do not
require activation of either PLCgamma or Stat5 for efficient induction of a
myeloproliferative phenotype in the murine BMT model.
PMID- 10775268
TI - The p300/CBP acetyltransferases function as transcriptional coactivators of beta
catenin in vertebrates.
AB - Wnt growth factors regulate a variety of developmental processes by altering
specific gene expression patterns. In vertebrates beta-catenin acts as
transcriptional activator, which is needed to overcome target gene repression by
Groucho/TLE proteins, and to permit promoter activation as the final consequence
of Wnt signaling. However, the molecular mechanisms of transcriptional activation
by beta-catenin are only poorly understood. Here we demonstrate that the closely
related acetyltransferases p300 and CBP potentiate beta-catenin-mediated
activation of the siamois promoter, a known Wnt target. beta-catenin and p300
also synergize to stimulate a synthetic reporter gene construct, whereas
activation of the cyclin D1 promoter by beta-catenin is refractory to p300
stimulation. Axis formation and activation of the beta-catenin target genes
siamois and Xnr-3 in Xenopus embryos are sensitive to the E1A oncoprotein, a
known inhibitor of p300/CBP. The C-terminus of beta-catenin interacts directly
with a region overlapping the CH-3 domain of p300. p300 could participate in
alleviating promoter repression imposed by chromatin structure and in recruiting
the basal transcription machinery to promoters of particular Wnt target genes.
PMID- 10775269
TI - Regulation of plastid rDNA transcription by interaction of CDF2 with two
different RNA polymerases.
AB - The plastid genome is known to be transcribed by a plastid-encoded prokaryotic
type RNA polymerase (PEP) and by a nucleus-encoded phage-type RNA polymerase
(NEP). The spinach plastid rrn operon promoter region harbours three different,
overlapping promoters. Two of them are of the prokaryotic type. The third
promoter is a non-consensus-type NEP promoter. We separated three different
transcriptional activities from spinach chloroplasts: PEP, the phage-type RNA
polymerase NEP-1, and a third, hitherto undescribed transcriptional activity (NEP
2). NEP-2 specifically transcribes the rrn operon in the presence of the
transcription factor CDF2. CDF2 was previously shown to recruit PEP to the rrn
promoter to repress transcription. Together, our results suggest the existence of
a third RNA polymerase in plastids and a mechanism of rDNA transcriptional
regulation that is based on the interaction of the transcription factor CDF2 with
two different transcriptional systems.
PMID- 10775270
TI - A small protein that mediates the activation of a two-component system by another
two-component system.
AB - The PmrA-PmrB two-component system of Salmonella enterica controls resistance to
the peptide antibiotic polymyxin B and to several antimicrobial proteins from
human neutrophils. Transcription of PmrA-activated genes is induced by high iron,
but can also be promoted by growth in low magnesium in a process that requires
another two-component system, PhoP-PhoQ. Here, we define the genetic basis for
the interaction between the PhoP-PhoQ and PmrA-PmrB systems. We have identified
pmrD as a PhoP-activated gene that mediates the transcriptional activation of
PmrA-regulated genes during growth in low magnesium. When transcription of pmrD
is driven from a heterologous promoter, expression of PmrA-activated genes occurs
even at repressing magnesium concentrations and becomes independent of the phoP
and phoQ genes. The PmrD effect is specific for PmrA-regulated genes and requires
functional PmrA and PmrB proteins. A pmrD mutant is sensitive to polymyxin if
grown in low magnesium, but resistant if grown in high iron. The PmrD protein
controls the activity of the PmrA-PmrB system at a post-transcriptional level.
PMID- 10775272
TI - Association of GCN1-GCN20 regulatory complex with the N-terminus of eIF2alpha
kinase GCN2 is required for GCN2 activation.
AB - Stimulation of GCN4 mRNA translation due to phosphorylation of the alpha-subunit
of initiation factor 2 (eIF2) by its specific kinase, GCN2, requires binding of
uncharged tRNA to a histidyl-tRNA synthetase (HisRS)-like domain in GCN2. GCN2
function in vivo also requires GCN1 and GCN20, but it was unknown whether these
latter proteins act directly to promote the stimulation of GCN2 by uncharged
tRNA. We found that the GCN1-GCN20 complex physically interacts with GCN2,
binding to the N-terminus of the protein. Overexpression of N-terminal GCN2
segments had a dominant-negative phenotype that correlated with their ability to
interact with GCN1-GCN20 and impede association between GCN1 and native GCN2.
Consistently, this Gcn(-) phenotype was suppressed by overexpressing GCN2, GCN1
GCN20 or tRNA(His). The requirement for GCN1 was also reduced by overexpressing
tRNA(His) in a gcn1Delta strain. We conclude that binding of GCN1-GCN20 to GCN2
is required for its activation by uncharged tRNA. The homologous N-terminus of
Drosophila GCN2 interacted with yeast GCN1-GCN20 and had a dominant Gcn(-)
phenotype, suggesting evolutionary conservation of this interaction.
PMID- 10775271
TI - A dual role for BBP/ScSF1 in nuclear pre-mRNA retention and splicing.
AB - The MSL5 gene, which codes for the splicing factor BBP/ScSF1, is essential in
Saccharomyces cerevisiae, yet previous analyses failed to reveal a defect in
assembly of (pre)-spliceosomes or in vitro splicing associated with its
depletion. We generated 11 temperature-sensitive (ts) mutants and one cold
sensitive (cs) mutant in the corresponding gene and analyzed their phenotypes.
While all mutants were blocked in the formation of commitment complex 2 (CC2) at
non-permissive and permissive temperature, the ts mutants showed no defect in
spliceosome formation and splicing in vitro. The cs mutant was defective in (pre)
spliceosome formation, but residual splicing activity could be detected. In vivo
splicing of reporters carrying introns weakened by mutations in the 5' splice
site and/or in the branchpoint region was affected in all mutants. Pre-mRNA
leakage to the cytoplasm was strongly increased (up to 40-fold) in the mutants. A
combination of ts mutants with a disruption of upf1, a gene involved in nonsense
mediated decay, resulted in a specific synthetic growth phenotype, suggesting
that the essential function of SF1 in yeast could be related to the retention of
pre-mRNA in the nucleus.
PMID- 10775273
TI - Evolutionarily conserved binding of ribosomes to the translocation channel via
the large ribosomal RNA.
AB - During early stages of cotranslational protein translocation across the
endoplasmic reticulum (ER) membrane the ribosome is targeted to the
heterotrimeric Sec61p complex, the major component of the protein-conducting
channel. We demonstrate that this interaction is mediated by the 28S rRNA of the
eukaryotic large ribosomal subunit. Bacterial ribosomes also bind via their 23S
rRNA to the bacterial homolog of the Sec61p complex, the SecYEG complex.
Eukaryotic ribosomes bind to the SecYEG complex, and prokaryotic ribosomes to the
Sec61p complex. These data indicate that rRNA-mediated interaction of ribosomes
with the translocation channel occurred early in evolution and has been
conserved.
PMID- 10775274
TI - Conservation of polyamine regulation by translational frameshifting from yeast to
mammals.
AB - Regulation of ornithine decarboxylase in vertebrates involves a negative feedback
mechanism requiring the protein antizyme. Here we show that a similar mechanism
exists in the fission yeast Schizosaccharomyces pombe. The expression of
mammalian antizyme genes requires a specific +1 translational frameshift. The
efficiency of the frameshift event reflects cellular polyamine levels creating
the autoregulatory feedback loop. As shown here, the yeast antizyme gene and
several newly identified antizyme genes from different nematodes also require a
ribosomal frameshift event for their expression. Twelve nucleotides around the
frameshift site are identical between S.pombe and the mammalian counterparts. The
core element for this frameshifting is likely to have been present in the last
common ancestor of yeast, nematodes and mammals.
PMID- 10775275
TI - Structure of the fMet-tRNA(fMet)-binding domain of B. stearothermophilus
initiation factor IF2.
AB - The three-dimensional structure of the fMet-tRNA(fMet) -binding domain of
translation initiation factor IF2 from Bacillus stearothermophilus has been
determined by heteronuclear NMR spectroscopy. Its structure consists of six
antiparallel beta-strands, connected via loops, and forms a closed beta-barrel
similar to domain II of elongation factors EF-Tu and EF-G, despite low sequence
homology. Two structures of the ternary complexes of the EF-Tu small middle
dotaminoacyl-tRNA small middle dot GDP analogue have been reported and were used
to propose and discuss the possible fMet-tRNA(fMet)-binding site of IF2.
PMID- 10775276
TI - Beyond Burkitt--is diverticular disease more than just cereal fibre deficiency?
PMID- 10775278
TI - Rickettsial diseases: the typhus group of fevers--a review.
PMID- 10775277
TI - Impact of HIV infection on tuberculosis.
AB - Tuberculosis is increasing in prevalence in many countries and is now the leading
infectious cause of death world wide, being responsible for three million deaths
annually. Infection with HIV, likewise increasing in prevalence, has emerged as
the most important predisposing factor for developing overt tuberculosis in
people co-infected with Mycobacterium tuberculosis. Owing to the widespread
geographical overlap of these two infections, it is estimated that in 1999, HIV
related tuberculosis will reach one million cases and will cause 30% of the
expected 2.5 million AIDS related deaths. Tuberculosis in HIV infected
individuals may have unusual clinical features and can cause diagnostic
difficulties. Despite the effectiveness of modern short course treatment, the
mortality of HIV related tuberculosis during and after treatment remains high,
and this may be due to other HIV related infections. The "cursed duet" of
infection with both HIV and M tuberculosis is generating a threat to human health
of unparalleled proportions which, if not taken seriously by health workers and
decision makers, could become totally unmanageable.
PMID- 10775279
TI - Role of smoking in inflammatory bowel disease: implications for therapy.
AB - The relationship between smoking and inflammatory bowel disease is now firmly
established but remains a source of confusion among both patients and doctors. It
is negatively associated with ulcerative colitis but positively associated with
Crohn's disease. In addition, it has opposite influences on the clinical course
of the two conditions with benefit in ulcerative colitis but a detrimental effect
in Crohn's disease. These differences have been the subject of much interest and
scrutiny with the hope that they may offer some insight into the pathogenesis of
the two conditions and possibly lead to alternative therapeutic options. Nicotine
is probably the principal active ingredient in smoking responsible for the
association; trials have shown it to be of some benefit in ulcerative colitis,
but further research is required to establish its therapeutic role, and the
relevant mechanisms responsible for its action. In this article, we review the
role of smoking in inflammatory bowel disease and its implication for therapy.
PMID- 10775280
TI - Alcoholic liver disease.
AB - Alcohol is a major cause of liver cirrhosis in the Western world and accounts for
the majority of cases of liver cirrhosis seen in district general hospitals in
the UK. The three most widely recognised forms of alcoholic liver disease are
alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic
cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear
but immune mediated and free radical hepatic injury are thought to be important.
There is increasing interest in genetic factors predisposing to hepatic injury in
susceptible individuals. Diagnosis is based on accurate history, raised serum
markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and
liver histology when obtainable. Abstinence is the most important aspect of
treatment. Newer drugs such as acamprosate and naltrexone are used to reduce
alcohol craving. Vitamin supplements and nutrition are vital while
corticosteroids have a role in acute alcoholic hepatitis where there is no
evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has
excellent results in abstinent patients with end stage liver disease but there
are concerns about recidivism after transplant.
PMID- 10775281
TI - Heterogeneity of anti-PR3 associated disease in Hong Kong.
AB - Thirty seven patients tested positive for antibody against proteinase 3 (anti
PR3) using either one of the two in-house ELISA methods at the Immunology
Laboratory, University of Hong Kong. All except three were Chinese. Systemic
vasculitis was diagnosed in 13 patients. However, the positive predictive value
of anti-PR3 for Wegener's granulomatosus was low (22%). The commonest presenting
feature was respiratory (32%). Both respiratory and renal symptoms were commonly
reported in anti-PR3 positive patients as in previous studies. In this largely
Chinese population, there is marked variability in the spectrum of diseases
associated with anti-PR3; though many had vasculitic diseases, some were
diagnosed with other conditions such as inflammatory bowel diseases and
respiratory infection. In contrast with series in white people,
antimyeloperoxidase rather than anti-PR3 associated disease is more prevalent in
Chinese patients.
PMID- 10775282
TI - Unreliability of cardiothoracic ratio as a marker of left ventricular impairment:
comparison with radionuclide ventriculography and echocardiography.
AB - BACKGROUND: The size of the heart assessed by cardiothoracic ratio on chest
radiography is often used as a screening test for the presence of heart failure
and for assessing its severity. METHODS: We compared cardiothoracic ratio (CTR),
left ventricular ejection fraction (LVEF) from radionuclide ventriculography, and
left ventricular dimensions from echocardiography in a population of 91 patients
(aged 60.4 (SD 9.6) years) with a diagnosis of chronic heart failure. RESULTS:
There was a weak relation between CTR and LVEF (R = 0.33) and fractional
shortening from echocardiography (R = 0.22). LVEF and fractional shortening
correlated more closely (R = 0.55). No measure of left ventricular function
correlated with exercise capacity as measured by peak oxygen consumption. For the
group of patients with a normal fractional shortening (n = 17), the left
ventricle was dilated in all but two (mean end diastolic dimension 5. 9 (0.7)
cm). The two with normal dimensions had a low ejection fraction. For the 12
patients with a CTR in the normal range, the left ventricular end diastolic
dimension was only slightly smaller than for the rest (6.2 (0.9) v. 6.9 (1.2); p
= 0.045). CONCLUSIONS: Chest radiography is not a reliable indicator of the
degree of left ventricular dysfunction. Echocardiography and radionuclide
ventriculography are more appropriate investigations for assessing cardiac
function.
PMID- 10775283
TI - Causes of anorexia in untreated hyperthyroidism: a prospective study.
AB - Seventeen consecutive patients (mean (SD) 46 (11) years) with untreated
hyperthyroidism and anorexia and 29 patients (35 (9) years) with untreated
hyperthyroidism without anorexia were studied. The study was conducted at the
thyroid clinic of the PUMC Hospital, Beijing, China from March to August 1997.
The patients' ages, serum free calcium, liver function and emotional state,
specifically the level of anxiety (using the self anxiety scale, Chinese
version), were compared before and/or after antithyroid drug treatment in the two
groups. This prospective study suggested that the causes of anorexia in untreated
hyperthyroidism are complicated. Older age, abnormal liver function, and the
level of anxiety are significantly related to anorexia in untreated
hyperthyroidism, but hypercalcaemia was not confirmed to be related to anorexia
in the study.
PMID- 10775284
TI - Diagnosis of malignant melanoma by general practitioners and hospital
specialists.
AB - The aim of this study was to audit all malignant melanomas confirmed
histologically in the Scarborough Health District over six years, prompted by the
continuing rise in incidence rate nationally and relatively high number of
malignant melanomas excised by general practitioners (GPs) in this area. A total
of 157 malignant melanomas were diagnosed (60% from females and 40% from males)
over the six years; primary excisions being carried out by GPs (37%) and hospital
specialists (63%). The clinical diagnosis of malignant melanoma was made in 9% of
GP cases and 35% of the hospital specialist cases. However another 45.5% of GP
cases, and 38% of hospital specialist cases were regarded as suspicious pigmented
lesions clinically. The histological diagnosis was of superficial spreading
malignant melanoma in 72% of the GP and 69% of the hospital specialist cases.
Most of the GP melanomas were excised with a lateral margin of 2 mm or less
(71%); around half of the hospital excisions had a margin of over 2 mm (49%).
Most melanomas were 2 mm or less in depth (Breslow depth) in both the GP (81%)
and hospital specialist (75%) series. Over the six year period (1993-98) the
incidence of malignant melanomas has continued to rise, but Breslow depth at
diagnosis has not changed significantly. It is therefore important to continue
with early recognition of this condition by GPs in the first instance, reduction
in its incidence being the long term goal. During five years of the study there
were only 67 lesions thought clinically to be malignant melanoma (26 GP and 41
hospital specialist cases), but which proved to be benign histologically.
PMID- 10775285
TI - Crohn's colitis and idiopathic thrombocytopenic purpura.
AB - A 17 year old girl with active Crohn's colitis developed idiopathic
thrombocytopenic purpura that was managed with intravenous immune globulins and
cyclosporin A. The possible association between Crohn's disease and immune
thrombocytopenia is explored.
PMID- 10775286
TI - Osteomyelitis and possible endocarditis secondary to Lactococcus garvieae: a
first case report.
AB - Although osteomyelitis is commonly caused by staphylococcal infection, the first
case of a lumbar osteomyelitis secondary to Lactococcus garvieae is reported. The
case was complicated by possible endocarditis of an aortic valve prosthesis.
PMID- 10775287
TI - Phaeochromocytoma unearthed by fluoxetine.
AB - Non-specific noradrenaline reuptake inhibition by high dose selective serotonin
reuptake inhibitors, along with catecholamine release from phaeochromocytoma, may
lead to a hypertensive paroxysm. This may unmask a clinically silent
phaeochromocytoma. Hypertensive paroxysm induced by paroxetine leading to
detection of phaeochromocytoma has been reported. The first patient in whom
fluoxetine unmasked a phaeochromocytoma is reported.
PMID- 10775288
TI - Reversible sensorineural hearing loss after non-otological surgery under general
anaesthetic.
AB - Acute sensorineural hearing loss can occur after both otolaryngological and non
otolaryngological procedures. The mechanism of such hearing loss remains
unproved; but nitrous oxide has been implicated and where used, attendants should
be aware of its potential damage to hearing. It is essential that patients with
sudden hearing loss are identified as soon as possible as the recovery rate had
been shown to be higher in those who presented early; and as our case
demonstrates, complete recovery is possible. Anaesthetists, non-otolaryngological
surgeons, and ward nurses must be aware of this early postoperative complication
if appropriate treatment is to be instituted.
PMID- 10775289
TI - Progressive breathlessness in an 18 year old male.
PMID- 10775291
TI - Diffuse swelling of the penis in a young adult.
PMID- 10775290
TI - Sleeping eyes.
PMID- 10775292
TI - Hypercalcaemia in a 63 year old man.
PMID- 10775294
TI - Progressive breathlessness in an 18 year old male
PMID- 10775295
TI - Sleeping eyes
PMID- 10775293
TI - Subacute haemorrhage into the spinal cord.
PMID- 10775297
TI - Hypercalcaemia in a 63 year old man
PMID- 10775296
TI - Diffuse swelling of the penis in a young adult
PMID- 10775298
TI - Subacute haemorrhage into the spinal cord
PMID- 10775299
TI - Risperidone implicated in the onset of tardive dyskinesia in a young woman.
AB - The aim of this case report is to highlight that risperidone may cause and
ameliorate tardive dyskinesia. A 16 year old white women with a 12 month history
of schizophrenia, developed buccolingual masticatory tardive dyskinesia after
receiving risperidone 6 mg. She had received small dosages of typical
antipsychotics before and during receiving risperidone for short periods.
Recommencement of risperidone with 2 mg and increasing to 6 mg resulted in
improvement in tardive dyskinesia and up until now she remains free of any
abnormal involuntary movements.
PMID- 10775300
TI - Gap junctions in the cardiovascular and immune systems.
AB - Gap junctions are clusters of intercellular channels directly connecting the
cytoplasm of adjacent cells. These channels are formed by proteins named
connexins and are present in all metazoan organisms where they serve diverse
functions ranging from control of cell growth and differentiation to electric
conduction in excitable tissues. In this overview we describe the presence of
connexins in the cardiovascular and lympho-hematopoietic systems giving the
reader a summary of the topics to be covered throughout this edition and a
historical perspective of the discovery of gap junctions in the immune system.
PMID- 10775301
TI - The molecular basis of selective permeability of connexins is complex and
includes both size and charge.
AB - Although gap junction channels are still widely viewed as large, non-specific
pores connecting cells, the diversity in the connexin family has led more
attention to be focused on their permeability characteristics. We summarize here
the current status of these investigations, both published and on-going, that
reveal both charge and size selectivity between gap junction channels composed of
different connexins. In particular, this review will focus on quantitative
approaches that monitor the expression level of the connexins, so that it is
clear that differences that are seen can be attributed to channel properties. The
degree of selectivity that is observed is modest compared to other channels, but
is likely to be significant for biological molecules that are labile within the
cell. Of particular relevance to the in vivo function of gap junctions, recent
studies are summarized that demonstrate that the connexin phenotype can control
the nature of the endogenous traffic between cells, with consequent effects on
biological effects of gap junctions such as tumor suppression.
PMID- 10775302
TI - Connexin hemichannels and cell-cell channels: comparison of properties.
AB - Connexin46 (Cx46) forms functional hemichannels in the absence of contact by an
apposed hemichannel and we have used these hemichannels to study gating and
permeation at the single channel level with high time resolution. Using both cell
attached and -excised patch configurations, we find that single Cx46 hemichannels
exhibit some properties expected of half of a gap junction channel, as well as
novel properties. Cx46 hemichannels have a large unitary conductance
(approximately 300 pS) and a relatively large pore as inferred from permeability
to TEA. Both monovalent cations and anions can permeate, but cations are
substantially more permeable. The open channel conductance shows marked inward
rectification in symmetric salts. We find that the conductance and permeability
properties of Cx46 cell-cell channels can be explained by the series addition of
two hemichannels. These data suggest that the pore structures of unapposed
hemichannels and cell-cell channels are conserved. Also like cell-cell channels,
unapposed Cx46 hemichannels are closed by elevated levels of H+ or Ca2+ ions on
the cytoplasmic face. Closure occurs in excised patches indicating that the
actions of these agents do not require a soluble cytoplasmic factor. Fast (<0.5
ms) application of H+ to either side of the open hemichannel causes an immediate
small reduction in unitary conductance followed by complete closure with
latencies that are dependent on H+ concentration and side of application;
sensitivity is much greater to H+ on the cytoplasmic side. Closure by cytoplasmic
H+ does not require that the hemichannel be open. Thus, H+ ions readily permeate
Cx46 hemichannels, but at high enough concentration close them by acting at a
cytoplasmic site(s) that causes a conformational change resulting in complete
closure. Extracellular H+ may permeate to act on the cytoplasmic site or act on a
lower affinity extracellular site. Thus, the unapposed hemichannel is a valuable
tool in addressing fundamental questions concerning the operation of gap junction
channels that are difficult to answer by existing methods. The ability of Cx46,
and perhaps other connexins, to form functional unapposed hemichannels that are
opened by moderate depolarization may represent an unexplored role of connexins
as mediators of transport across the plasma membrane.
PMID- 10775303
TI - Modulation of intercellular communication by differential regulation and
heteromeric mixing of co-expressed connexins.
AB - Intercellular communication may be regulated by the differential expression of
subunit gap junction proteins (connexins) which form channels with differing
gating and permeability properties. Endothelial cells express three different
connexins (connexin37, connexin40, and connexin43) in vivo. To study the
differential regulation of expression and synthesis of connexin37 and connexin43,
we used cultured bovine aortic endothelial cells which contain these two
connexins in vitro. RNA blots demonstrated discordant expression of these two
connexins during growth to confluency. RNA blots and immunoblots showed that
levels of these connexins were modulated by treatment of cultures with
transforming growth factor-ss1. To examine the potential ability of these
connexins to form heteromeric channels (containing different connexins within the
same hemi-channel), we stably transfected connexin43-containing normal rat kidney
(NRK) cells with connexin37 or connexin40. In the transfected cells, both
connexin proteins were abundantly produced and localized in identical
distributions as detected by immunofluorescence. Double whole-cell patch-clamp
studies showed that co-expressing cells exhibited unitary channel conductances
and gating characteristics that could not be explained by hemi-channels formed of
either connexin alone. These observations suggest that these connexins can
readily mix with connexin43 to form heteromeric channels and that the
intercellular communication between cells is determined not only by the
properties of individual connexins, but also by the interactions of those
connexins to form heteromeric channels with novel properties. Furthermore,
modulation of levels of the co-expressed connexins during cell proliferation or
by cytokines may alter the relative abundance of different heteromeric
combinations.
PMID- 10775304
TI - Identification of a protein kinase activity that phosphorylates connexin43 in a
pH-dependent manner.
AB - The carboxyl-terminal (CT) domain of connexin43 (Cx43) has been implicated in
both hormonal and pH-dependent gating of the gap junction channel. An in vitro
assay was utilized to determine whether the acidification of cell extracts
results in the activation of a protein kinase that can phosphorylate the CT
domain. A glutathione S-transferase (GST)-fusion protein was bound to Sephadex
beads and used as a target for protein kinase phosphorylation. A protein extract
produced from sheep heart was allowed to bind to the fusion protein-coated beads.
The bound proteins were washed and then incubated with 32P-ATP. Phosphorylation
was assessed after the proteins were resolved by SDS-PAGE. Incubation at pH 7.5
resulted in a minimal amount of phosphorylation while incubation at pH 6.5
resulted in significant phosphorylation reaction. Maximal activity was achieved
when both the binding and kinase reactions were performed at pH 6.5. The protein
kinase activity was stronger when the incubations were performed with manganese
rather than magnesium. Mutants of Cx43 which lack the serines between amino acids
364-374 could not be phosphorylated in the in vitro kinase reaction, indicating
that this is a likely target of this reaction. These results indicate that there
is a protein kinase activity in cells that becomes more active at lower pH and
can phosphorylate Cx43.
PMID- 10775305
TI - Regulation of intercellular coupling in acute and chronic heart disease.
AB - Effective pump function of the heart depends on the precise control of spatial
and temporal patterns of electrical activation. Accordingly, the distribution and
function of gap junction channels are important determinants of the conduction
properties of myocardium and undoubtedly play other roles in intercellular
communication crucial to normal cardiac function. Recent advances have begun to
elucidate mechanisms by which the heart regulates intercellular electrical
coupling at gap junctions in response to stress or injury. Although responses to
increased load or injury are generally adaptive in nature, remodeling of
intercellular junctions under conditions of severe stress creates anatomic
substrates conducive to the development of lethal ventricular arrhythmias.
Potential mechanisms controlling the level of intercellular communication in the
heart include regulation of connexin turnover dynamics and phosphorylation.
PMID- 10775306
TI - Biophysical characteristics of gap junctions in vascular wall cells: implications
for vascular biology and disease.
AB - The role gap junction channels play in the normal and abnormal functioning of the
vascular wall is the subject of much research. The biophysical properties of gap
junctions are an essential component in understanding how gap junctions function
to allow coordinated relaxation and contraction of vascular smooth muscle. This
study reviews the properties thus far elucidated and relates those properties to
tissue function. We ask how biophysical and structural properties such as gating,
permselectivity, subconductive states and channel type (heteromeric vs homotypic
vs heterotypic) might affect vascular smooth muscle tone.
PMID- 10775307
TI - Gap junctions in isolated rat aorta: evidence for contractile responses that
exhibit a differential dependence on intercellular communication.
AB - Connexin43 (Cx43) is a major gap junction protein present in the Fischer-344 rat
aorta. Previous studies have identified conditions under which selective
disruption of intercellular communication with heptanol caused a significant,
readily reversible and time-dependent diminution in the magnitude of alpha1
adrenergic contractions in isolated rat aorta. These observations have
indentified a significant role for gap junctions in modulating vascular smooth
muscle tone. The goal of these steady-state studies was to utilize isolated rat
aortic rings to further evaluate the contribution of intercellular junctions to
contractions elicited by cellular activation in response to several other
vascular spasmogens. The effects of heptanol were examined (0.2-2.0 mM) on
equivalent submaximal ( approximately 75% of the phenylephrine maximum) aortic
contractions elicited by 5-hydroxytryptamine (5-HT; 1-2 microM), prostaglandin
F2alpha (PGF2alpha; 1 microM) and endothelin-1 (ET-1; 20 nM). Statistical
analysis revealed that 200 microM and 500 microM heptanol diminished the maximal
amplitude of the steady-state contractile responses for 5-HT from a control
response of 75 +/- 6% (N = 26 rings) to 57 +/- 7% (N = 26 rings) and 34.9 +/- 6%
(N = 13 rings), respectively (P<0.05), and for PGF2alpha from a control response
of 75 +/- 10% (N = 16 rings) to 52 +/- 8% (N = 19 rings) and 25.9 +/- 6% (N = 18
rings), respectively (P<0.05). In contrast, 200 microM and 500 microM heptanol
had no detectable effect on the magnitude of ET-1-induced contractile responses,
which were 76 +/- 5. 0% for the control response (N = 38 rings), 59 +/- 6.0% in
the presence of 200 microM heptanol (N = 17 rings), and 70 +/- 6.0% in the
presence of 500 microM heptanol (N = 23 rings) (P<0.13). Increasing the heptanol
concentration to 1 mM was associated with a significant decrease in the magnitude
of the steady-state ET-1-induced contractile response to 32 +/- 5% (21 rings;
P<0.01); further increasing the heptanol concentration to 2 mM had no additional
effect. In rat aorta then, junctional modulation of tissue contractility appears
to be agonist-dependent.
PMID- 10775308
TI - Chronic hypertension alters the expression of Cx43 in cardiovascular muscle
cells.
AB - Connexin43 (Cx43), the predominant gap junction protein of muscle cells in
vessels and heart, is involved in the control of cell-to-cell communication and
is thought to modulate the contractility of the vascular wall and the electrical
coupling of cardiac myocytes. We have investigated the effects of arterial
hypertension on the expression of Cx43 in aorta and heart in three different
models of experimental hypertension. Rats were made hypertensive either by
clipping one renal artery (two kidney, one-clip renal (2K,1C) model) by
administration of deoxycorticosterone and salt (DOCA-salt model) or by inhibiting
nitric oxide synthase with N G-nitro-L-arginine methyl ester (L-NAME model).
After 4 weeks, rats of the three models showed a similar increase in intra
arterial mean blood pressure and in the thickness of the walls of both aorta and
heart. Analysis of heart mRNA demonstrated no change in Cx43 expression in the
three models compared to their respective controls. The same 2K,1C and DOCA-salt
hypertensive animals expressed twice more Cx43 in aorta, and the 2K, 1C rats
showed an increase in arterial distensibility. In contrast, the aortae of L-NAME
hypertensive rats were characterized by a 50% decrease in Cx43 and the carotid
arteries did not show increased distensibility. Western blot analysis indicated
that Cx43 was more phosphorylated in the aortae of 2K,1C rats than in those of L
NAME or control rats, indicating a differential regulation of aortic Cx43 in
different models of hypertension. The data suggest that localized mechanical
forces induced by hypertension affect Cx43 expression and that the cell-to-cell
communication mediated by Cx43 channels may contribute to regulating the
elasticity of the vascular wall.
PMID- 10775309
TI - Sera from chronic chagasic patients depress cardiac electrogenesis and
conduction.
AB - We report results obtained with sera from 58 chronic chagasic patients that were
evaluated for effects on heart rate and atrioventricular (AV) conduction in
isolated rabbit hearts and screened for the presence of muscarinic and beta
adrenergic activity. We show that sera from 26 patients decreased heart rate,
while 10 increased it and 22 had no effect. Additionally, sera from 20 of the 58
patients blocked AV conduction. Muscarinic activation seems to be involved in
both effects, but is not the only mechanism, since atropine did not antagonize
the decrease in heart rate in 23% of sera or AV block in 40%. Sera from patients
with complex arrhythmias were significantly more effective in depressing both
heart rate and AV conduction. Sera that induce increases in heart rate seem to
operate exclusively through beta-adrenergic activation. Two of these sera,
evaluated with respect to intercellular communication in primary cultures of
embryonic cardiomyocytes were able to block gap junction conductance evaluated by
a dye injection technique after 24-h exposure. The mechanisms underlying this
uncoupling effect are currently being investigated.
PMID- 10775310
TI - Gap junctions in cells of the immune system: structure, regulation and possible
functional roles.
AB - Gap junction channels are sites of cytoplasmic communication between contacting
cells. In vertebrates, they consist of protein subunits denoted connexins (Cxs)
which are encoded by a gene family. According to their Cx composition, gap
junction channels show different gating and permeability properties that define
which ions and small molecules permeate them. Differences in Cx primary sequences
suggest that channels composed of different Cxs are regulated differentially by
intracellular pathways under specific physiological conditions. Functional roles
of gap junction channels could be defined by the relative importance of permeant
substances, resulting in coordination of electrical and/or metabolic cellular
responses. Cells of the native and specific immune systems establish transient
homo- and heterocellular contacts at various steps of the immune response.
Morphological and functional studies reported during the last three decades have
revealed that many intercellular contacts between cells in the immune response
present gap junctions or "gap junction-like" structures. Partial characterization
of the molecular composition of some of these plasma membrane structures and
regulatory mechanisms that control them have been published recently. Studies
designed to elucidate their physiological roles suggest that they might permit
coordination of cellular events which favor the effective and timely response of
the immune system.
PMID- 10775311
TI - Gap junction modulation by extracellular signaling molecules: the thymus model.
AB - Gap junctions are intercellular channels which connect adjacent cells and allow
direct exchange of molecules of low molecular weight between them. Such a
communication has been described as fundamental in many systems due to its
importance in coordination, proliferation and differentiation. Recently, it has
been shown that gap junctional intercellular communication (GJIC) can be
modulated by several extracellular soluble factors such as classical hormones,
neurotransmitters, interleukins, growth factors and some paracrine substances.
Herein, we discuss some aspects of the general modulation of GJIC by
extracellular messenger molecules and more particularly the regulation of such
communication in the thymus gland. Additionally, we discuss recent data
concerning the study of different neuropeptides and hormones in the modulation of
GJIC in thymic epithelial cells. We also suggest that the thymus may be viewed as
a model to study the modulation of gap junction communication by different
extracellular messengers involved in non-classical circuits, since this organ is
under bidirectional neuroimmunoendocrine control.
PMID- 10775312
TI - Molecular tennis--flat smashes and wicked cuts.
AB - Molecular photodissociation typically produces open-shell photofragments that
have angular momentum. This Account explores how the measurement of the
directional nature of photofragment angular momentum can provide us with a new
viewpoint for seeing and understanding the process whereby molecules fall apart
under irradiation. Although the photodissociation process is more complicated
than might be imagined at first, the measurements reveal detail that approaches
conventional bound-state spectroscopy, enhancing our understanding of the
chemical bond and even allowing us to manipulate the ultimate fate of a
photofragment by selecting the wavelength and the polarization of the photolysis
source.
PMID- 10775313
TI - High-pressure pulse radiolysis as a tool in the study of transition metal
reaction mechanisms.
AB - The unique combination of high-pressure and pulse radiolysis kinetic techniques
enables detailed mechanistic insight for a large variety of chemical processes to
be gained. Typical examples for transition metal reactions are presented. These
include ligand substitution, electron transfer, reactions of complexes with
uncommon oxidation states, and reactions with radicals, including the formation
and decomposition reactions of complexes with metal-carbon sigma bonds. The
volumes of activation and volume profiles obtained form the basis of a critical
analysis of different plausible reaction mechanisms.
PMID- 10775314
TI - Synthesis of diverse and complex molecules on the solid phase.
AB - In this paper we summarize our efforts toward optimizing key reactions on the
solid phase which tolerate a variety of functional groups. These groups were
sequentially modified, allowing the production of novel and diverse compound
libraries on the solid phase.
PMID- 10775315
TI - Low-valent ruthenium and iridium hydride complexes as alternatives to Lewis acid
and base catalysts.
AB - The discovery of a new chemical reaction often leads to new applications and new
chemical principles. Low-valent ruthenium and iridium hydride complexes are
highly useful redox Lewis acid and base catalysts. Nitriles are activated by
these catalysts and undergo reactions with either nucleophiles or electrophiles
under neutral conditions. Hydration of nitriles, esterification of nitriles with
alcohols, and amidation of nitriles with amines can be performed catalytically
together with formation of ammonia. The catalytic reactions of pronucleophiles
such as nitriles and carbonyl compounds with electrophiles such as alkenes,
alkynes, carbonyl compounds, imines, and nitriles take place generally.
PMID- 10775316
TI - Design of luminescent inorganic materials: new photophysical processes studied by
optical spectroscopy.
AB - Recent spectroscopic results in the emerging area of transition-metal NIR-to
visible upconversion are related. The examples of Ti(2+)-, Re(4+)-, and Os(4+)
doped materials showing upconversion illustrate GSA/ESA, GSA/ETU, and photon
avalanche multiphoton excitation mechanisms, respectively. Strategies for
manipulation of such upconversion processes using the spectroscopic or magnetic
properties of the host material are described. High-resolution low-temperature
continuous-wave absorption and emission and time-resolved emission experiments
combine to yield information about energy splittings, intensities, and excited
state dynamics, and assist in the design and development of luminescent materials
showing novel multiphoton excitation properties.
PMID- 10775317
TI - Mechanistic aspects of beta-bond-cleavage reactions of aromatic radical cations.
AB - The mesolytic cleavage of a beta-C-X bond (ArCR(2)-X(*+) --> ArCR(2)(*/+) +
X(+/*)) is one of the most important reactions of alkylaromatic radical cations.
In this Account, our group's results concerning some fundamental aspects of this
process (cleavage mode, structural and stereoelectronic effects, competitive
breaking of different beta-bonds, nucleophilic assistance, possible
stereochemistry, carbon vs oxygen acidity in arylalkanol radical cations) are
presented and critically discussed for reactions where X = H, CR(3), SR, and
SiR(3). Several examples illustrating how this information was exploited as a
tool to detect electron-transfer mechanisms in chemical and enzymatic oxidations
are also reported.
PMID- 10775318
TI - Long-range charge transfer in DNA: transient structural distortions control the
distance dependence.
AB - Damage to DNA is often caused by oxidative reactions. In one such process, an
electron is lost from a base, forming its radical cation. Further reaction of the
radical cation can lead to permanent change, which results in mutation. This
Account is a report on oxidative damage to DNA caused by irradiation of
anthraquinone derivatives, which are either randomly bound to the DNA or attached
to it covalently at specific locations. Radical cations introduced in the DNA by
the excited quinone cause damage both near to it and far away. We describe a
mechanism for long-range charge transport in DNA that depends on its spontaneous
structural distortion, which we call phonon-assisted polaron hopping. This
mechanism, and its extension, provides a framework for understanding the
reactions and charge-transport properties of DNA.
PMID- 10775319
TI - Toxicity of epoxy fatty acids and related compounds to cells expressing human
soluble epoxide hydrolase.
AB - Soluble epoxide hydrolase (sEH) is suggested to alter the mode of action and
increase the toxic potency of fatty acid epoxides. To characterize the structural
features necessary for sEH-dependent epoxy fatty acid toxicity, 75 aliphatic
compounds were assayed for cytotoxicity in the presence and absence of sEH. Three
groups of aliphatic epoxide-diol pairs were described by their observed
differential toxicity. Group I compounds were typified by terminal epoxides whose
toxicity was reduced in the presence of sEH. Group II compounds were toxic in
either their epoxide or diol form, but toxicity was unaffected by sEH. Group III
compounds exhibited sEH-dependent toxicity and were therefore used to investigate
the structural elements required for cytotoxicity in this study. The optimal
structure for group III compounds appeared to be a fatty acid 18-20 atoms long
(e.g., a carbon backbone plus a terminal heteroatom) with an epoxide positioned
between C-7 and C-12. In the absence of sEH, replacement of epoxides with a
vicinal diol was required for toxicity. While diol stereochemistry was
unimportant, vicinal diol-induced toxicity exhibited fewer positional constraints
to toxicity than sEH-dependent epoxide toxicity. Tested fatty acids and esters
with neither an epoxide nor a vicinal diol were not toxic. These data support the
hypothesis that long-chain epoxy fatty acid methyl esters are potential pro
toxins metabolized by sEH to more toxic diols. Furthermore, our results suggest
that the endogenous compounds, leukotoxin methyl ester, 9,10(Z)-epoxyoctadec
12(Z)-enoic acid methyl ester, and isoleukotoxin methyl ester, 12, 13(Z)
epoxyoctadec-9(Z)-enoic acid methyl ester, are structurally optimized to elicit
the observed effect.
PMID- 10775320
TI - Identification and characterization of a reaction product of 2'-deoxyoxanosine
with glycine.
AB - 2'-Deoxyoxanosine (dOxo) is a novel DNA lesion produced from dGuo by reaction
with nitrous acid or nitric oxide [Suzuki, T., Yamaoka, R., Nishi, M., Ide, H.,
and Makino, K. (1996) J. Am. Chem. Soc. 118, 2515-2516]. We investigated the
reaction of dOxo with glycine (Gly) under physiological conditions. When 5 mM
dOxo was incubated with 500 mM Gly in 100 mM sodium phosphate buffer (pH 7.4) at
37 degrees C, an unknown product was formed exclusively. The yield of the product
was 86% at an incubation time of 3 h. Using spectrometric data, it was identified
as a ring-opened adduct containing an amide bond between the carbonyl group of
dOxo and the amino group of Gly. The adduct was very stable (t(1/2) = 1280 h)
under physiological conditions. Furthermore, dOxo in oligodeoxynucleotide reacted
with Gly, yielding the same adduct. These results suggest that dOxo formed in DNA
may react with Gly present in cells, resulting in adduct formation in vivo.
PMID- 10775321
TI - Polymorphism- and species-dependent inactivation of glutathione transferase zeta
by dichloroacetate.
AB - Glutathione transferase zeta catalyzes the glutathione-dependent oxidation or
conjugation of a range of alpha-haloacids. Repeated administration of
dichloroacetate to human subjects increases its plasma elimination half-life, and
the activity of glutathione transferase zeta is decreased in rats given
dichloroacetate. The objective of the studies presented here was to investigate
the kinetics and mechanism of the dichloroacetate-induced decrease in glutathione
transferase zeta activity. The rate constants (k(inact)) for the dichloroacetate
dependent inactivation of glutathione transferase zeta in liver cytosol are in
the following order: rat > mouse > human; the half-maximal inhibitory
concentration (K(inact)) of DCA did not differ among the species that were
studied. In contrast to dichloroacetate, chlorofluoroacetate produced much less
inactivation of mouse liver glutathione transferase zeta activity. Moreover, the
addition of N-acetyl-L-cysteine or potassium cyanide did not fully block the
dichloroacetate-induced inactivation of glutathione transferase zeta. The
k(inact) values for the dichloroacetate-induced inactivation of four polymorphic
variants of recombinant human glutathione transferase zeta (hGSTZ1-1) were in the
following order: variant 1a-1a < 1b-1b approximately 1c-1c approximately 1d-1d.
The dichloroacetate-induced inactivation of hGSTZ1-1 was irreversible. The
binding of radioactivity from [1-(14)C]dichloroacetate and from
[(35)S]glutathione to recombinant hGSTZ1c-1c was demonstrated, indicating
covalent modification of the protein. These results show that dichloroacetate is
a mechanism-based inactivator of glutathione transferase zeta and is
biotransformed to electrophilic metabolites that covalently modify and, thereby,
inactivate the enzyme.
PMID- 10775322
TI - Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat
hemoglobin beta-chains in vivo.
AB - Disulfiram (DSF) is a drug used in aversion therapy to treat alcoholics and acts
by inhibiting mitochondrial low-K(m) aldehyde dehydrogenase. Investigations into
the mechanisms for in vivo inactivation suggest that the DSF metabolite S-methyl
N, N-diethylthiocarbamate sulfoxide reacts irreversibly with an active site Cys.
This work aimed to determine if DSF generates monothiocarbamate adducts on
cysteine residues in vivo by examining hemoglobin. Sprague-Dawley rats were
treated with DSF po for 2, 4, and 6 weeks. Rats have four different globin beta
chains, of which three (beta-1-3) contain two cysteine residues each. MALDI-TOF
MS analysis of two new globin species from DSF-treated rats collected by HPLC
revealed increments of 99 Da above the mass of the unmodified chains (beta-2 and
beta-3). In a separate experiment, the globin mixture was digested for 2 h with
Glu-C and reanalyzed by MALDI-TOF MS. Results showed a peptide at m/z 2716.3
having a mass 99 Da higher than a known Cys-containing peptide. Subsequently, the
Glu-C digest was analyzed using Q-TOF tandem MS, enabling observation of the +4
charge state of the peptide with m/z 2716.3. This peptide was fragmented to
produce y-sequence ions that located the modification to Cys-125 (present on both
beta-2 and beta-3). Cys-125 is the most reactive of two cysteine residues on
these beta-chains. To confirm the structure of the modification, globin was
hydrolyzed with 6 N HCl at 110 degrees C for 18 h. The adduct survived these
conditions so that S-(N,N-diethylcarbamoyl)cysteine was detected in the
hydrolysates of treated rats on the basis of comparison with the tandem MS
spectrum of a standard. These results extend the findings of others obtained
using glutathione conjugates and demonstrate the ability of DSF to covalently
modify Cys residues of proteins in a manner consistent with the production of S
methyl-N, N-diethylthiocarbamate sulfoxide, or sulfone, intermediates.
PMID- 10775323
TI - Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz
and its derivatives, and sulforaphane.
AB - Recent studies have demonstrated that two chemoprotective agents, oltipraz (OPZ),
a synthetic derivative of the natural compound 1, 2-dithiole-3-thione (D3T), and
sulforaphane (SF), an isothiocyanate, are not only inducers of glutathione S
transferases but also inhibitors of some major cytochrome P450 enzymes (P450s)
involved in xenobiotic metabolism. We examined P450 inhibition by the two
compounds and compared two OPZ metabolites (OPZ M(3) and M(8)) and D3T using
human P450s expressed in Escherichia coli membranes. OPZ was a more potent
inhibitor than D3T or SF, in the following order of inhibition: P450 1A2 > 3A4 >
1A1 approximately 1B1 > 2E1. OPZ M(3) also inhibited P450s 1A2, 1A1, 1B1, and 3A4
but not more effectively than OPZ. OPZ M(8) was not inhibitory. OPZ behaved as a
competitive inhibitor of P450 1A2, with a K(i) of 1.5 microM. Incubation of P450
1A2 with OPZ and NADPH led to a first-order loss of the P450 spectrum, and the
loss was not blocked by glutathione. No such time-dependent loss of P450 was seen
with P450 1A2 and D3T, P450 1A2 and OPZ M(3), P450 1A2 and SF, P450 3A4 and OPZ,
P450 3A4 and D3T, P450 2E1 and OPZ, or P450 2E1 and D3T. The time- and
concentration-dependent loss of P450 1A2 activity in the presence of OPZ was
characterized with a K(i) of 9 microM and a k(inactivation) of 0.19 min(-)(1).
The activation of 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline (MeIQ) in an E.
coli lac-based mutagenicity tester system containing functional human P450 1A2
was inhibited by OPZ (IC(50) < 1 microM) but not appreciably by 40 microM D3T.
Our results indicate that OPZ is a competitive and mechanism-based inhibitor of
P450 1A2, and the extent of this inhibition is significantly greater than that of
other chemoprotective chemicals with P450 1A2 or other human P450s.
PMID- 10775324
TI - Transalkylation of phosphotriesters using Cob(I)alamin: toward specific
determination of DNA-phosphate adducts.
AB - The supernucleophilic cobalt compound, cob(I)alamin, has been kinetically
characterized with respect to its ability to bring about transalkylation of
adducts to DNA phosphates (phosphotriesters). The reactivity of cob(I)alamin
toward different phosphotriesters (model compounds and methylated DNA), as well
as its specificity toward DNA-phosphate adducts, has been investigated. Through
nucleophilic displacement on the alkyl by cob(I)alamin, the alkyl groups (methyl
and ethyl) were transferred from phosphotriesters within minutes at room
temperature. In contrast, methylated nucleosides (base adducts) were stable in
the presence of cob(I)alamin.
PMID- 10775325
TI - Preparation of a methylated DNA standard, and its stability on storage.
AB - Several methods are available for the determination of low levels of O(6)
methylguanine in DNA; this base arises after methylation by environmental
carcinogens. The reliability of these assays is much improved by the use of a
standard. We have prepared such a standard by treating calf thymus DNA with [(3)H
methyl]-N-methyl-N-nitrosourea. We characterized the methylated bases by
hydrolysis of a sample to nucleosides, followed by liquid chromatography and
liquid scintillation counting of the tritium content. The level of O(6)
methylguanine was 0.6 per one million nucleotides. This base is stable, and its
level was unchanged after storage for 5 years at -20 degrees C. The methylated
DNA also contained 7-methylguanine and 3-methyladenine, which are slowly cleaved
from the DNA on standing. The half-life for loss of 7-methylguanine at neutral pH
was estimated to be 70 h at 39 degrees C, 460 h at 22 degrees C, 3800 h at 10
degrees C, and about 4 years at -20 degrees C.
PMID- 10775326
TI - Mechanism-based inactivation of cytochrome P450 2B1 by 7-ethynylcoumarin:
verification of apo-P450 adduction by electrospray ion trap mass spectrometry.
AB - 7-Ethynylcoumarin was synthesized as a potential mechanism-based inhibitor, and
it was found to be an effective inactivator of 7-ethoxy-4
(trifluoromethyl)coumarin (7EFC) O-deethylation catalyzed by purified,
reconstituted P450 2B1. In contrast, 7-ethynylcoumarin demonstrated minimal
inactivation of P450 2A6-mediated 7-hydroxycoumarin formation. The inactivation
of P450 2B1 demonstrated pseudo-first-order kinetics and was NADPH- and inhibitor
dependent. The maximal rate constant for the inactivation of 2B1 was 0.39 min(
)(1) at 30 degrees C, and thus, the time required to inactivate 50% of the P450
2B1 that was present (t(1/2)) was 1.8 min. The estimated concentration which led
to half-maximal inactivation (K(I)) was 25 microM. No protection from
inactivation was seen in the presence of nucleophiles (glutathione and sodium
cyanide), an iron chelator (deferroxamine), or superoxide dismutase and catalase.
Addition of the substrate (7EFC) protected P450 2B1 from inactivation, in a
concentration-dependent manner. The partition ratio for P450 2B1 was 25; i.e.,
the number of metabolic events was 25-fold higher than the number of inactivating
events. Incubations of 7-ethynylcoumarin with P450 2B1 for 10 min resulted in an
80% loss in enzymatic activity, while 90% of the ability to form a reduced-CO
complex remained. This activity loss was not recovered following dialysis,
indicative of irreversible inactivation. Covalent attachment of the entire
inhibitor and oxygen to apo-P450 2B1, in a 1:1 ratio, was shown via electrospray
ion trap mass spectrometry. This method also verified the absence of modification
to the heme or the cytochrome P450 reductase. Taken together, the
characterization of the inhibition seen with P450 2B1 and 7-ethynylcoumarin was
consistent with all of the criteria required to distinguish a mechanism-based
inactivator. In addition, electrospray ion trap mass spectrometry has the
potential to be applied to protein adducts above and beyond those associated with
the mechanism-based inactivation of cytochrome P450s.
PMID- 10775327
TI - Determination of r-7,t-8,9,c-10-tetrahydroxy-7,8,9, 10-tetrahydrobenzo[a]pyrene
in human urine by gas chromatography/negative ion chemical ionization/mass
spectrometry.
AB - r-7,t-8,9,c-10-Tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (trans-anti-BaP
tetraol) is the major hydrolysis product of r-7, t-8-dihydroxy-t-9,10-epoxy
7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), the principal ultimate carcinogen
of the environmental pollutant benzo[a]pyrene (BaP). As part of a program to
establish activation/detoxification profiles of urinary metabolites of BaP in
humans, we developed a method for quantifying trans-anti-BaP-tetraol. Urine was
collected from three groups of individuals exposed to BaP: psoriasis patients
treated with a coal tar-containing ointment, steel workers, and smokers.
[(2)H(12)]-trans-anti-BaP-tetraol was added to the urine as an internal standard.
The urine was treated with beta-glucuronidase and sulfatase, and then the BaP
tetraols were enriched by reverse-phase and phenylboronic acid solid-phase
extraction. The resulting fraction was treated with sodium hydride and
methylmethane sulfonate to convert BaP-tetraols to the corresponding tetramethyl
ethers (BaP-TME). The mixture was purified by normal-phase HPLC and analyzed by
gas chromatography/negative ion chemical ionization/mass spectrometry with
selected ion monitoring. [(13)CH(3)](4)-trans-anti-BaP-TME was used as an
external standard. Ions at m/z 376, 380, and 388 were monitored for quantitation
of trans-anti-BaP-TME, [(13)CH(3)](4)-trans-anti-BaP-TME, and [(2)H(12)]-trans
anti-BaP-TME, respectively. The instrumental detection limit was approximately 1
fmol of trans-anti-BaP-TME. trans-anti-BaP-tetraol (as trans-anti-BaP-TME) was
detected in 20 of 20 individuals receiving coal tar therapy (mean, 16 fmol/mL of
urine), 13 of 13 exposed steel workers (mean, 4.1 fmol/mL of urine), and nine of
21 cigarette smokers (mean, 0.5 fmol/mL of urine). The means in these groups were
significantly different (P < 0.0001). The urine of steel workers was also
analyzed for cis-anti-BaP-tetraol and cys-syn-BaP-tetraol, but neither was found.
The results of this study provide a quantitative method for determination of
parts per trillion levels of trans-anti-BaP-tetraol in human urine. Ultimately,
this method can be employed as part of a phenotyping approach for assessing BaP
metabolites in human urine.
PMID- 10775328
TI - Mutagenic activity of surface soil and quantification of 1,3-, 1,6-, and 1,8
dinitropyrene isomers in soil in Japan.
AB - To clarify the mutagenic potential of nonagricultural surface soil in Japan, 110
soil samples were collected from five geographically different areas between
November 1996 and March 1997, and organic extracts of the soil samples were
examined by the Ames/Salmonella assay. Most of the soil extracts showed
mutagenicity toward both strains TA98 and TA100 in the presence and/or absence of
a mammalian metabolic activation system (S9 mix), suggesting that surface soil is
largely contaminated with environmental mutagens. Soil samples collected at
Hekinan, Kobe, and Osaka were highly mutagenic toward both strains, and their
potencies toward TA98 without S9 mix were extremely high, inducing more than 12
000 revertants per gram of soil. On the other hand, soil samples from Muroran
showed strong mutagenicity toward TA100 with S9 mix. Furthermore, 1, 3
dinitropyrene (DNP), 1,6-DNP, and 1,8-DNP in soil samples collected at 10
sampling sites in three metropolitan areas were quantified by fluorometric
detection of the corresponding diaminopyrene isomers using high-performance
liquid chromatography (HPLC). Three DNP isomers were detected in all soil
samples, and the amounts of 1,3-, 1,6-, and 1,8-DNP isomers in the soil samples
were 12-3270, 14-5587, and 13-6809 pg/g, respectively. The gross amount of three
DNP isomers in surface soil collected at Hekinan was more than 10 ng per gram of
soil. The highest contribution ratios of DNP isomers to the mutagenicity of soil
extracts were observed for the samples collected at Osaka, and the total of the
contribution ratios of three DNP isomers was about 50%. These results suggest
that surface soil is largely contaminated with mutagenic compounds and that DNP
isomers are one class of major mutagenic and carcinogenic compounds contaminating
surface soil.
PMID- 10775329
TI - Kinetic and mechanistic studies of the peroxynitrite-mediated oxidation of
oxymyoglobin and oxyhemoglobin.
AB - Kinetic studies of the peroxynitrite-mediated oxidations of oxymyoglobin
(MbFeO(2)) and oxyhemoglobin (HbFeO(2)) showed that the mechanisms of these
reactions are more complex than what had previously been reported; both reactions
proceed in two steps. For myoglobin, we found that the small amount of
deoxymyoglobin (MbFe(II)) which is in equilibrium with MbFeO(2) is first oxidized
by peroxynitrous acid to ferryl myoglobin (MbFe(IV)=O). Then, in the second step,
MbFe(IV)=O is reduced by peroxynitrous acid to metmyoglobin (metMb). The second
order rate constant values obtained at pH 7.3 and 20 degrees C for the two steps
are (5.4 +/- 0.2) x 10(4) and (2.2 +/- 0.1) x 10(4) M(-)(1) s(-)(1),
respectively. Analogous studies with hemoglobin suggest that its reaction with
peroxynitrite follows the same mechanism. In this case, the second-order rate
constant values measured at pH 7.0 and 20 degrees C for the two steps are (8.8 +/
0.4) x 10(4) and (9.4 +/- 0.7) x 10(4) M(-)(1) s(-)(1), respectively. A possible
mechanism in the absence as well as in the presence of CO(2) and the relevance of
these reactions in vivo are discussed.
PMID- 10775330
TI - 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) inhibits peroxynitrite
mediated phenol nitration.
AB - Peroxynitrite (PN), a very reactive oxidant formed by the combination of
superoxide and nitric oxide, appears to play a role in producing tissue damage in
a number of inflammatory conditions. Pharmacological scavenging and decomposition
of PN within these areas has therapeutic value in several tissue injury models.
Recently, we have been interested in nitroxide free radical-containing compounds
as possible scavengers of PN decomposition products. Nitroxides can undergo redox
reactions to the corresponding hydroxylamine anion or oxoammonium cation in
biological systems as shown by its ability to react with superoxide, leading to
the formation of hydrogen peroxide and molecular oxygen. We found that 4-hydroxy
2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) inhibits PN-mediated nitration of
phenolic compounds in the presence of a large molar excess of PN, suggesting a
catalytic-like mechanism. In these experiments, Tempol inhibited PN-mediated
nitration over the pH range of 6.5-8.5. This inhibition was specific for
nitration and had no effect on hydroxylation. After the inhibition of PN-mediated
nitration, Tempol was recovered from the reaction mixtures unmodified. In
addition, Tempol was effective in protecting PC-12 cells from death induced by
SIN-1, a PN-generating compound. The exact mechanism of Tempol's interaction with
PN is not clear; however, we propose that an intermediate in this reaction may be
a nitrogen dioxide radical-Tempol complex. This complex could react with water to
form either nitrite or nitrate, or with a phenol radical to produce nitrophenol
or nitrosophenol products and regenerate the nitroxide.
PMID- 10775331
TI - Formation of N-nitrosamines and N-nitramines by the reaction of secondary amines
with peroxynitrite and other reactive nitrogen species: comparison with
nitrotyrosine formation.
AB - Reactive nitrogen species, including nitrogen oxides (N(2)O(3) and N(2)O(4)),
peroxynitrite (ONOO(-)), and nitryl chloride (NO(2)Cl), have been implicated as
causes of inflammation and cancer. We studied reactions of secondary amines with
peroxynitrite and found that both N-nitrosamines and N-nitramines were formed.
Morpholine was more easily nitrosated by peroxynitrite at alkaline pH than at
neutral pH, whereas its nitration by peroxynitrite was optimal at pH 8.5. The
yield of nitrosomorpholine in this reaction was 3 times higher than that of
nitromorpholine at alkaline pH, whereas 2 times more nitromorpholine than
nitrosomorpholine was formed at pH <7.5. For the morpholine-peroxynitrite
reaction, nitration was enhanced by low concentrations of bicarbonate, but was
inhibited by excess bicarbonate. Nitrosation was inhibited by excess bicarbonate.
On this basis, we propose a free radical mechanism, involving one-electron
oxidation by peroxynitrite of secondary amines to form amino radicals (R(2)N(*)),
which react with nitric oxide ((*)NO) or nitrogen dioxide ((*)NO(2)) to yield
nitroso and nitro secondary amines, respectively. Reaction of morpholine with
NO(*) and superoxide anion (O(2)(*)(-)), which were concomitantly produced from
spermine NONOate and by the xanthine oxidase systems, respectively, also yielded
nitromorpholine, but its yield was <1% of that of nitrosomorpholine. NO(*) alone
increased the extent of nitrosomorpholine formation in a dose-dependent manner,
and concomitant production of O(2)(*)(-) inhibited its formation. Reactions of
morpholine with nitrite plus HOCl or nitrite plus H(2)O(2), with or without
addition of myeloperoxidase or horseradish peroxidase, also yielded nitration and
nitrosation products, in yields that depended on the reactants. Tyrosine was
nitrated easily by synthetic peroxynitrite, by NaNO(2) plus H(2)O(2) with
myeloperoxidase, and by NaNO(2) plus H(2)O(2) under acidic conditions. Nitrated
secondary amines, e.g., N-nitroproline, could be identified as specific markers
for endogenous nitration mediated by reactive nitrogen species.
PMID- 10775332
TI - DNA damage by dimethylformamide: role of hydrogen peroxide generated during
degradation.
AB - Dimethylformamide (DMF) has been suspected to associate with cancers in exposed
workers, whereas there has been inadequate evidence for carcinogenicity in
experimental animals. We demonstrated that H(2)O(2) was generated during the
degradation of DMF under aerobic conditions, and that the amount of H(2)O(2) was
enhanced by exposure to solar light or by the contamination of trace metal.
Experiments using (32)P-5'-end-labeled DNA fragments revealed that the degraded
DMF induced DNA damage in the presence of Cu(II). However, purified DMF did not
induce DNA damage even in the presence of Cu(II). Addition of purified DMF
enhanced DNA damage induced by H(2)O(2) in the presence of Cu(II). The degraded
DMF caused Cu(II)-mediated DNA cleavage frequently at thymine and cytosine
residues. The similar pattern of site-specific DNA damage was observed with
purified DMF and H(2)O(2). Bathocuproine and catalase inhibited the DNA damage,
indicating the involvement of Cu(I) and H(2)O(2). A typical free hydroxy radical
scavenger showed no inhibitory effect on the DNA damage. Addition of purified DMF
enhanced about 3-4-fold 8-oxo-7, 8-dihydro-2'-deoxyguanosine formation induced by
H(2)O(2) and Cu(II). ESR spectroscopic study demonstrated that carbon-centered
radicals and nitrogen-centered radicals were generated in the reaction mixture of
DMF, H(2)O(2), and Cu(II). Inhibitory effects of scavengers on radical formation
and DNA damage suggest that carbon-centered radicals and/or nitrogen-centered
radicals may contribute to the DNA damage. These results suggest that H(2)O(2)
generation during DMF degradation is related to the possible carcinogenic
activity of DMF.
PMID- 10775333
TI - Meeting announcements
PMID- 10775334
TI - Editor's change of address
PMID- 10775335
TI - Pesticide residues in grapes, wine, and their processing products.
AB - In this review the results obtained in the 1990s from research on the behavior of
pesticide residues on grapes, from treatment to harvest, and their fate in
drying, wine-making, and alcoholic beverage processing are reported. The
fungicide residues on grapes (cyproconazole, hexaconazole, kresoxim-methyl,
myclobutanil, penconazole, tetraconazole, and triadimenol), the application rates
of which were of a few tens of grams per hectare, were very low after treatment
and were not detectable at harvest. Pyrimethanil residues were constant up to
harvest, whereas fluazinam, cyprodinil, mepanipyrim, azoxystrobin, and
fludioxonil showed different disappearance rates (t(1/2) = 4.3, 12, 12.8, 15.2,
and 24 days, respectively). The decay rate of the organophosphorus insecticides
was very fast with t(1/2) ranging between 0.97 and 3.84 days. The drying process
determined a fruit concentration of 4 times. Despite this, the residue levels of
benalaxyl, phosalone, metalaxyl, and procymidone on sun-dried grapes equalled
those on the fresh grape, whereas they were higher for iprodione (1.6 times) and
lower for vinclozolin and dimethoate (one-third and one-fifth, respectively). In
the oven-drying process, benalaxyl, metalaxyl, and vinclozolin showed the same
residue value in the fresh and dried fruit, whereas iprodione and procymidone
resides were lower in raisins than in the fresh fruit. The wine-making process
begins with the pressing of grapes. From this moment onward, because the
pesticide on the grape surface comes into contact with the must, it is in a
biphasic system, made up of a liquid phase (the must) and a solid phase (cake and
lees), and will be apportioned between the two phases. The new fungicides have
shown no effect on alcoholic or malolactic fermentation. In some cases the
presence of pesticides has also stimulated the yeasts, especially Kloeckera
apiculata, to produce more alcohol. After fermentation, pesticide residues in
wine were always smaller than those on the grapes and in the must, except for
those pesticides that did not have a preferential partition between liquid and
solid phase (azoxystrobin, dimethoate, and pyrimethanil) and were present in wine
at the same concentration as on the grapes. In some cases (mepanipyrim,
fluazinam, and chlorpyrifos) no detectable residues were found in the wines at
the end of fermentation. From a comparison of residues in wine obtained by
vinification with and without skins, it can be seen that their values were
generally not different. Among the clarifying substances commonly used in wine
(bentonite, charcoal, gelatin, polyvinylpolypyrrolidone, potassium caseinate, and
colloidal silicon dioxide), charcoal allowed the complete elimination of most
pesticides, especially at low levels, whereas the other clarifying substances
were ineffective. Wine and its byproducts (cake and lees) are used in the
industry to produce alcohol and alcoholic beverages. Fenthion, quinalphos, and
vinclozolin pass into the distillate from the lees only if present at very high
concentrations, but with a very low transfer percantage (2, 1, and 0.1%,
respectively). No residue passed from the cake into the distillate, whereas
fenthion and vinclozolin pass from the wine, but only at low transfer percentages
(13 and 5%, respectively).
PMID- 10775336
TI - Role of hydroxyl radicals and singlet oxygen in the formation of primary radicals
in unsaturated lipids: a solid state electron paramagnetic resonance study.
AB - Primary radicals were generated by UV photolysis of samples of trilinolein, at 77
K and under a controlled atmosphere. The resulting EPR spectra clearly show that
the amount of radicals is dependent on the purity of the lipid, the exposure to
visible light in the presence of a photosensitizer and oxygen, and, finally, the
presence of an antioxidant. These solid state EPR experiments indicate that if
all of the elements for the production of singlet oxygen (Rose Bengal, molecular
oxygen, and visible light) are not present, primary radicals are practically not
generated. They also point out the various steps of the oxidation mechanism:
formation of singlet oxygen, which reacts with the lipid to form a hydroperoxide;
and photolytic formation of the hydroxyl radical, which reacts with the frozen
lipid to generate primary lipidic radicals. This constitutes a new method for
investigating lipid oxidation and studying the influence of photosensitizers and
molecules that are likely to react with singlet oxygen.
PMID- 10775338
TI - Variation in total and soluble beta-glucan content in hulless barley: effects of
thermal, physical, and enzymic treatments.
AB - Total and soluble beta-glucan content and effects of various treatments of barley
grain on extractability and molecular characteristics of soluble beta-glucan were
studied. Four types of hulless barley (normal, high amylose, waxy, and zero
amylose waxy) from 29 registered and experimental genotypes were analyzed. For
each, moisture, protein, amylose, 100 kernel weight, starch, beta-glucan (total
and soluble), beta-glucanase activity, and slurry viscosity were determined.
Significant differences in total beta-glucan were observed among the groups, with
average values of 7. 49%, 6.86%, 6.30%, and 4.38% for high amylose, waxy, zero
amylose waxy, and normal barley, respectively. The extractability of beta-glucan
in high amylose barley was relatively low (20.6-29.7%) compared to that in normal
(29.8-44.3%), zero amylose waxy (34.0-52. 5%), and waxy (36.7-52.7%) barley
genotypes. Viscosity of barley flour slurries was affected by the content of
soluble beta-glucans, beta-glucanase activity, and molecular weight of beta
glucans. Hydrothermal treatments (autoclaving and steaming) of barley had no
effect on extractability of beta-glucans, but prevented enzymic hydrolysis of
beta-glucans, and thereby substantially improved their molecular weight. The
addition of enzymes (protease and esterase) during extraction and/or physical
treatments (sonication) increased extractability of beta-glucans from barley.
PMID- 10775337
TI - Identification of oxidation products of (-)-epigallocatechin gallate and (-)
epigallocatechin with H(2)O(2).
AB - (-)-Epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) are two
important antioxidants in tea. They also display some antitumor activities, and
these activities are believed to be mainly due to their antioxidative effects.
However, the specific mechanisms of antioxidant action of tea catechins remain
unclear. In this study are isolated and identified two novel reaction products of
EGCG and one product of EGC when they were reacted separately with H(2)O(2).
These products are formed by the oxidation and decarboxylation of the A ring in
the catechin molecule. This study provides unequivocal proof that the A ring of
EGCG and EGC may also be an antioxidant site. This study also indicates an
additional reaction pathway for the oxidation chemistry of tea catechins.
PMID- 10775339
TI - Preparation of novel functional oligophosphopeptides from hen egg yolk phosvitin.
AB - Novel hen egg phosvitin phosphopeptides (PPP) with molecular masses of 1-3 kDa
were prepared from tryptic hydrolysis following partial alkaline
dephosphorylation. The phosvitin treated with various NaOH concentrations (0.05
0.4 N) resulted in different dephosphorylated proteins ranging from 17.5 to 96.3%
of phosphate retention. The protein was digested into 10-20 amino acid peptides
with trypsin. Calcium-binding properties of PPP were compared with those of
commercial casein phosphopeptides in vitro. The PPP with 35% phosphate retention
is shown to be effective for enhancing calcium binding capacity and inhibiting
the formation of insoluble calcium phosphate. The results provide potential novel
functional oilgophosphopeptides as nutraceuticals.
PMID- 10775340
TI - Isolation of immunoglobulin from egg yolk by anionic polysaccharides.
AB - Isolation conditions of immunoglobulin in egg yolk (IgY) were optimized by the
addition of various levels of Na-alginate (Alg), lambda-carrageenan (lambda-Cg),
Na-carboxymethyl cellulose (CMC), and pectin (PC) to 6-fold diluted yolk. The
mixtures were then reacted at pH 4.0-6.0 for 30 min. The optimal isolation
conditions of IgY for Alg, lambda-Cg, and CMC were at the 0.1% level and at pH
5.0, while those for PC were at the 0.15% level and at the same pH. The remaining
lipid and remaining protein in the supernatants thus obtained was 0.5-3.8% and 10
17%, respectively, and more than 90% of lipoproteins were precipitated. The IgY
recovery was determined to be 33-74% by means of single radial immunodiffusion
method when IgY was isolated under the optimal conditions. PC showed the best
recovery of IgY, while lambda-Cg provided the least. The interactions between
polysaccharides and lipoproteins were mainly ionic bonds, hydrophobic
interactions, and hydrogen bonds as determined by the addition (0-2.0 M) of NaSCN
or urea to the polysaccharide-lipoprotein precipitates.
PMID- 10775341
TI - Identification and quantification of aminophospholipid-linked Maillard compounds
in model systems and egg yolk products.
AB - While the Maillard reaction of free amino acids and proteins is a well
established process, no defined structures from the nonenzymatic browning of
aminophospholipids in foodstuffs have been described so far.
Phosphatidylethanolamine (PE)-linked glucosylamines (Schiff-PE), Amadori products
(Amadori-PE), 5-hydroxymethylpyrrole-2-carbaldehydes (Pyrrole-PE), and
carboxymethyl (CM-PE) as well as carboxyethyl (CE-PE) derivatives were detected
and quantified by liquid chromatography- electrospray mass spectrometry (LC
(ESI)MS). Model incubations of soy-PE and D-glucose were employed to firmly
establish the LC-(ESI)MS procedure. Analyses of spray-dried egg yolk powders and
lecithin products derived therefrom show one-fourth of the native D-glucose
content of egg yolk to be transformed to Amadori-PE, corresponding to a PE
derivatization quota of 11-15.5 mol %. Schiff-PE and Pyrrole-PE were present only
in low amounts, no CM-PE and CE-PE could be identified in any of the investigated
samples. The high glycation rate of egg yolk PE will influence the emulsifying
properties and perhaps even the oxidation resistance of the respective products.
PMID- 10775342
TI - Rotational and translational mobility of small molecules in sucrose plus
polysaccharide solutions.
AB - The effect of different polysaccharides on the rotational (D(rot)) and
translational diffusion (D(trans)) coefficients of small molecules in
concentrated systems (sucrose solutions) was investigated. Dextran (1 or 10% w/w)
with different molecular masses (from 10(4) to 2 x 10(6) Da), gum arabic, or
pullulan was added to solutions of sucrose (57.5% w/w). Viscosity measurements of
the diffusion medium studied (sucrose and sucrose plus polysaccharide) were made
using a Rheometric Scientific viscometer in a temperature range from 20 to -10
degrees C. The rotational mobility of nitroxide radicals (Tempol) dispersed in
the concentrated systems was measured by electron spin resonance. The
translational diffusion coefficient of fluorescein was determined by the
fluorescence recovery after photobleaching method. The studied temperature range
for the latter two techniques was from 20 to -16 degrees C. For these conditions
of concentration and temperature, there was no ice formation in the samples. No
effect of the molecular mass of dextran on D(rot) and D(trans) was observed when
solutions with the same dry matter content were compared. Only pullulan and gum
arabic, at 10%, had a significant effect on D(trans)( )()of fluorescein.
Temperature and total dry matter content were observed to be the most important
factors controlling D(rot) and D(trans) in these concentrated systems.
PMID- 10775343
TI - Physicochemical changes and mechanism of heat-induced gelation of arrowtooth
flounder myosin.
AB - Physicochemical changes of myosin during heating were investigated to elucidate
the mechanism of heat-induced gelation of arrowtooth flounder (ATF) myosin at
high ionic strength. Changes in dynamic properties indicated ATF myosin formed a
gel in three different stages as shown by the first increase in G' (storage
modulus) at 28 degrees C, followed by the decrease at 35 degrees C and the second
increase at 42 degrees C. DSC thermogram showed the onset of myosin denaturation
at 25 degrees C with two maximum transition temperatures at 30 and 36 degrees C.
The decrease in alpha-helical content indicated ATF myosin began to unfold at 15
degrees C and the unfolding continued until it reached 65 degrees C. Turbidity
measurement showed myosin began to aggregate at 23 degrees C and the aggregation
was complete at 40 degrees C. Surface hydrophobicity increased consistently in
the temperature range studied, 20-65 degrees C. Sulfhydryl contents decreased
significantly at 20-30 degrees C due to the formation of disulfide linkages but
remained constant at temperatures >30 degrees C. ATF myosin was shown to be
extremely sensitive to heat, resulting in denaturation at lower temperature than
other fish myosin. Denaturation was initiated by unfolding of the alpha-helical
region in myosin followed by exposure of hydrophobic and sulfhydryl residues,
which are subsequently involved in aggregation and gelation processes.
PMID- 10775344
TI - Effects of proteolysis and mechanism of gel weakening in heat-induced gelation of
fish myosin.
AB - Addition of papain decreased the onset temperature and the rate at which G'
developed during heat-induced gelation of arrowtooth flounder myosin. Frequency
sweep results revealed that G' markedly decreased in proportion to the amount of
papain added. However, use of E-64, a cysteine proteinase inhibitor, reversed the
effects of papain and protected myosin heavy chain from degradation. DSC
thermograms indicated papain significantly decreased the enthalpy required to
induce myosin denaturation without significant changes in onset and maximum
transition temperatures. Thermal denaturation kinetics indicated decreases in
both the activation energy and the rate of myosin denaturation. CD studies
revealed a rapid decrease in alpha-helical content, indicating the initial
degradation of myosin molecules mostly occurred in the tail region. These results
suggested that proteolysis affected thermal properties and reactivity of myosin
during heating. Although myosin gel could be formed, structural disruption
resulted in lower gelling ability and rigidity of the formed gel.
PMID- 10775345
TI - Solvent effects on the crystallization behavior of milk fat fractions.
AB - The high- and medium-melting fractions of milk fat (HMF and MMF, respectively)
were crystallized in the presence of various solvents, including the low-melting
fraction of milk fat (LMF), canola oil (CO), hexane, and ethyl acetate. Choice of
solvent was shown to have a strong influence on phase behavior and
crystallization kinetics. Dilution and solubilization effects were observed for
all the blends. More solids were formed in the HMF and MMF blends with LMF than
with CO, and complexes were formed between the milk fat fractions possibly
because of molecular complementarity. Solids were slightly higher for the more
polar ethyl acetate than for hexane. Crystallization proceeded more rapidly in
the presence of LMF and ethyl acetate than in the presence of CO and hexane,
respectively. According to the Hildebrand equation, HMF and MMF were ideally
soluble in LMF and CO. X-ray diffraction spectroscopy (XRD) revealed the
existence of liquid-state structure in mixtures of HMF/CO, HMF/LMF, MMF/CO, and
MMF/LMF. The observed liquid-state structure was reminiscent of liquid crystals.
No differences were observed in the structure of the liquid phase between LMF-
and CO-containing mixtures.
PMID- 10775346
TI - A comparison of color formation and maillard reaction products of a lactose
lysine and lactose-N(alpha)-acetyllysine model system.
AB - The formation of color and Maillard reaction products in two model systems
consisting of lactose and lysine or N(alpha)-acetyllysine has been investigated.
During heating, the blockage of the N(alpha) group of lysine determined a faster
color and antioxidative ability development compared to the system with free
lysine. This is combined to a greater amount of melanoidin formation in the
acetylated lysine system, while in the free lysine system a higher amount of
pyrraline and hydroxymethyl furfural were detected. The pattern of low molecular
weight products suggests that 3-deoxyglucosone and 1-deoxyglucosone degradation
pathways are favored for free lysine and N(alpha)-acetyllysine, respectively.
Whole data allow us to hypothesize that in a lactose-N(alpha)-acetyllysine model
system the formation of colored high molecular weight polymer proceeds faster
because less material is dispersed in reaction pathways, mainly the Strecker
degradation, which leads to small and intermediate molecular weight products.
PMID- 10775347
TI - Dietary docosahexaenoic acid can alter the surface expression of CD4 and CD8 on T
cells in peripheral blood.
AB - The effect of dietary docosahexaenoic acid (DHA) on T cell states in peripheral
blood was investigated. Weanling male C57Bl/6N mice were kept on one of three 10%
fat diets containing various amounts of DHA and linoleic acid for 4 weeks.
Changing the concentration of dietary DHA did not alter the proportion of T cells
expressing CD4 or CD8. However, increasing the concentration of dietary DHA
lowered the expression of CD4 and CD8 on the cell surface. The decreased
expression of these surface molecules involved in T cell proliferation has
serious implications in the role of DHA as an immunosuppressant.
PMID- 10775348
TI - Purification and some properties of catalase from wheat germ (Triticum aestivum
L.).
AB - Two isoforms of catalase, CAT-1 and CAT-2, were purified from wheat germ after
extraction, ammonium sulfate precipitations, hydrophobic chromatography, and two
ionic-exchange chromatographies. The global yields and the purification factors
were close to 3% and 50 for CAT-1 and close to 6% and 100 for CAT-2. Both
isoforms exhibit an optimum activity at pH 7. When pH was decreased from 7 to
5.6, CAT-1 showed a decreasing affinity for its substrate, whereas the opposite
was found for CAT-2. Both isoforms were irreversibly denaturated when exposed to
acidic pH, CAT-1 being more sensitive than CAT-2. Conversely, CAT-2 appeared to
be more sensitive to inhibitors. The rate as well as the extent of denaturation
during incubation with 3-amino-1,2,4-triazole (AT) were higher with CAT-2 than
with CAT-1. Guaiacol is a competitive inhibitor more potent with respect to CAT
2. The difference in affinity for hydrogen peroxide as well as the poor stability
of CAT-1 in acidic medium suggests that this isoform could be less effective
during dough mixing.
PMID- 10775349
TI - Antiphotooxidative activity of protoberberines derived from Coptis japonica
makino in the chlorophyll-sensitized photooxidation of oil.
AB - Antiphotooxidative components were isolated from the methanolic extract of Coptis
japonica Makino by liquid-liquid partitioning fractionation, subsequent column
chromatography on Sephadex LH-20 and silica gel, and preparative silica gel TLC.
The isolated compounds were identified as coptisine, jatrorrizhine, berberine,
and magnoflorine by a combination of spectroscopic studies using UV-visible, IR,
mass-spectrometry, and NMR. Coptisine, jatrorrizhine, and berberine isolated from
Coptis japonica Makino showed strong antiphotooxidative activity in the
chlorophyll-sensitized photooxidation of linoleic acid. However, these compounds
did not show either inhibitory activity against lipid peroxidation in rat liver
microsomes nor DPPH radical scavenging activity, indicating that their
antiphotooxidative activity was not due to the radical chain reaction breaking
ability but due to singlet oxygen quenching activity. Commercially available
authentic protoberberines (berberine chloride and palmatine chloride) also showed
strong antioxidative activity in the chlorophyll-sensitized photooxidation of
linoleic acid. The antiphotooxidative activities of the berberine chloride and
palmatine chloride were significantly higher than that of ascorbyl palmitate in
the chlorophyll-sensitized photooxidation of linoleic acid. These results clearly
showed for the first time the antiphotooxidative properties of protoberberines in
chlorophyll-sensitized photooxidation of oil.
PMID- 10775350
TI - Preparation and characterization of films from pea protein.
AB - The conditions for protein film preparation from an alkaline dispersion of a pea
protein isolate were investigated in the presence of polyols as plasticizers.
Mechanical and barrier properties of resulting films were studied as a function
of protein dispersion conditions, protein and plasticizer concentrations and
ratios, chain length of the plasticizer, and pH and composition of the alkaline
medium. Neither the mode of protein hydration nor the pea isolate origin had a
significant effect on the mechanical properties of pea protein films. However,
increasing the plasticizer chain length induced slightly higher surface
hydrophobicity but poor mechanical properties. Addition of monoglycerides to film
forming solution allowed a significant improvement of the films during aging.
Both tensile strength and surface hydrophobicity increased when ammonium
hydroxide was used as protein dispersing agent instead of sodium hydroxide.
PMID- 10775351
TI - Purification and characterization of broad bean lipoxygenase isoenzymes.
AB - Two lipoxygenase isoenzymes, BBL-1 and BBL-2, were purified from broad beans.
Fractionation of globulins and albumins by ionic strength was preferred to the
classical water extraction system and the ammonium sulfate fractionation as
initial purification steps. From the albumin fraction, BBL-1 and BBL-2 were
purified 17.6 and 35. 7-fold, respectively, by conventional gel filtration and
ion-exchange chromatography. The molecular weight of both BBL-1 and BBL-2 was 97
kDa with a maximal activity around pH 5.8; however, they showed a significant
difference in their K(m) values for linoleic acid: 2.3 and 0.25 mM for BBL-1 and
BBL-2, respectively. BBL-1 produced hydroperoxides and ketodienes while BBL-2
produced exclusively hydroperoxides.
PMID- 10775352
TI - Phenolic composition of grape stems.
AB - Grape stems contain significant amounts of polyphenolic compounds, especially
phenolic acids, flavonols, and flavanonols such as astilbin. The tannin content
was characterized after the depolymerization reaction thiolysis. Tannins
consisted of polymeric proanthocyanidins (up to 27 units) mainly consisting of (
)-epicatechin units along with smaller amounts of (+)-catechin, (-)-epicatechin
gallate, and (-)-epigallocatechin. Flavanonols (astilbin) have been identified
for the first time in stem and characterized by LC/MS and NMR. All phenolic
compounds in grape stems were quantified by HPLC: quercetin 3-glucuronide was the
most important, followed by catechin, caffeoyltartaric acid, and dihydroquercetin
3-rhamnoside (astilbin). Comparison was made of proanthocyanidin characteristics
in different white and red grape varieties and also among parts of the cluster
(skin, seed, and stem). Stem-condensed tannins were qualitatively intermediate
between seed and skin but could not be differentiated between red and white
varieties.
PMID- 10775353
TI - Characterization of the nitrogen compounds released during yeast autolysis in a
model wine system.
AB - The nitrogen composition of wines aged with yeast for a long period of time, as
in the case of sparkling wines, depends on the composition of the base wine and
on the compounds released by the yeast. In this paper, the release of the
different classes of nitrogen compounds during autolysis of one of the strains of
yeast used in the manufacture of sparkling wines has been studied. The yeast,
Saccharomyces bayanus, was suspended in a model wine buffer, pH 3.0 and 10%
ethanol, and incubated at 30 degrees C. Samples of the autolysate were taken
after 4, 24, 48, 72, 168, and 360 h of autolysis. An electrophoretic and
chromatographic study was conducted of the proteins, peptides with molecular
weights higher and lower than 700 Da, and amino acids released during the
autolysis. Using SDS-PAGE, it was observed that it was predominantly polypeptides
with molecular weights lower than 10 000 that were released. Through HPLC of the
fraction lower than 10 000 Da, it was observed that it is polypeptides with
molecular weights of between 10 000 and 700 Da that are released first and that
these later break up to give rise to peptides with molecular weights lower than
700 Da, which in turn break down into amino acids. This indicates that the nature
of the nitrogen compounds present in wines aged with yeast depends on the aging
time, being less polymerized as the aging time increases.
PMID- 10775354
TI - Saccharomyces cerevisiae mannoproteins that protect wine from protein haze:
evaluation of extraction methods and immunolocalization.
AB - Yeast-derived haze-protective mannoprotein material (HPM) offers protection to
white wines from commercially unacceptable turbidities. HPM extraction methods
have been evaluated using three winemaking strains of Saccharomyces cerevisiae.
Digestion with Zymolyase of cells pretreated with DTE and EDTA gave the greatest
yields of active material. Heat treatment of cells with SDS also released active
material but the quantities were low. Treatment of the cells in an autoclave or
with a French pressure device was less effective. A detailed study was conducted
on the strain Maurivin PDM. SDS was not necessary to extract HPM from PDM;
boiling the cells for 5 min in Tris buffer was sufficient. HPM could also be
extracted with EDTA during the pretreatment of the cells prior to Zymolyase
digestion. The data suggest that HPM was noncovalently linked to other cell wall
components and loosely associated with the cell wall. An immunological
investigation showed that a specific mannoprotein with haze-protective activity,
HPF1, was located primarily on the outermost and innermost layers of the cell
wall.
PMID- 10775355
TI - Vitis vinifera must varietal authentication using microsatellite DNA analysis
(SSR).
AB - A microsatellite DNA-based method for Vitis vinifera grape must authentication is
presented. Five of the most important port wine producing grape cultivars (Tinta
Roriz, Tinto Cao, Touriga Francesa, Touriga Nacional, and Tinta Barroca) were
typed at four microsatellite loci described by Bowers et al. (Genome 1996, 39,
628-633) and Thomas and Scott (Theor. Appl. Genet. 1993, 86, 985-990). The
corresponding 5 varietal musts and 26 must mixtures that result from the
combination of the five varieties were also typed at the four loci. There were no
differences between the corresponding leaf and varietal must profiles. All must
combinations showed the expected band profiles corresponding to the sum of the
varietal band profile components. Among the 26 must mixtures, 8 could be
discriminated using the four loci.
PMID- 10775356
TI - Identification of new steroidal hydrocarbons in refined oils and the role of
hydroxy sterols as possible precursors.
AB - The dehydration of sterols during the refining process of vegetable oils results
in the formation of steroidal hydrocarbons (sterenes or steradienes) with two
double bonds in the ring system. Other steroidal hydrocarbons whose structures
were in agreement with the presence of three double bonds in the ring system were
detected in the sterene fractions of refined vegetable oils. The 5alpha-, 7alpha
, and 7beta-hydroxy derivatives of cholesterol and phytosterols have been
dehydrated in n-butanol/H(3)PO(4) to form steroidal hydrocarbons with three
double bonds at the 2, 4, and 6 positions in the ring system. These hydrocarbons
had the same relative retention time and mass spectra as those present in the
sterene fractions of refined oils. The dehydration of the hydroxy sterols
dissolved in extra virgin olive oil and in the presence of 1% bleaching earths at
80 degrees C for 1 h results in the formation of the same steroidal hydrocarbons
found in the refined oils.
PMID- 10775357
TI - Relation of acidity and sensory quality with sterol content of olive oil from
stored fruit.
AB - Composition of the sterol fraction, fatty acid, acidity, and the sensorial
evaluation of virgin olive oils were studied in two eastern Spanish varieties
grown and processed under the same conditions. Fruits were stored at 5 degrees C
and ambient temperature for different times. During fruit storage, there was no
significant variation (P = 0.05) in fatty acid composition. However, the sterol
composition of the oil varied markedly (in particular, there was an increase in
stigmasterol), acidity increased, and there was a very significant decrease in
sensorial quality. The stigmasterol content presented a high correlation with the
acidity and sensory evaluation (P < 10(-)(6)). The total sterol content increased
gradually with olive storage time. Oils with stigmasterol greater than
campesterol are graded to a low level (lampant). It is of interest that sensorial
quality is revealed by stigmasterol content, a fact unknown until now.
PMID- 10775358
TI - Properties of tofus and soy milks prepared from soybeans having different
subunits of glycinin.
AB - The contribution of soybean protein to the physical properties of tofu, a product
manufactured by curdling soy milk with coagulants such as calcium or magnesium
chloride, was studied by comparing the properties of soy milk prepared from
soybeans with different subunits (I, IIa, and IIb) of glycinin with amino acid
residues deleted. The breaking stress value of the tofu curds prepared from
soybeans having group I was higher than those without group I. The soy milks
having group I contained more protein particles and showed more sensitivity to
calcium and magnesium ions than those without group I. The amounts of glycinin
and protein particles were higher in the soy milks having group I than those in
the soy milks without group I. To elucidate the influence of each group on the
breaking stress, the glycinin content was adjusted to an identical level in soy
milks having each group. Among the tofu curds from three groups, their order of
hardness according to their breaking stress was IIa, IIb, and I. The order of
particle content among these soy milks was also IIa, IIb, and I. Therefore, the
results suggested that the breaking stress value of the tofu curd is dependent
upon the number of protein particles in the soy milk and that the number of the
particles is determined by the proportion and structure of glycinin in the
soybean.
PMID- 10775359
TI - Thermal stabilities of lupin seed conglutin gamma protomers and tetramers.
AB - Various experimental approaches have been used in this work to assess the thermal
stabilities of lupin seed conglutin gamma at two pH values, 4.5 and 7.5, at which
the protein exists as a protomer and a tetramer, respectively. The patterns of
thermal unfolding at the two pH values differed significantly; the tetramer
aggregated and became insoluble, whereas the protomer was still soluble after
thermal treatment. Also, the midpoint transition temperatures were dramatically
different, being 60.3 and 75.1 degrees C for the protomer and tetramer,
respectively. The behavior of conglutin gamma at neutral pH was also affected by
disulfide formation/interchange, in that some unfolded protein molecules became
covalently stabilized. More detailed analyses by differential scanning
calorimetry and indirect fluorescence measurements, using 8-anilino-1
naphthalenesulfonic acid as a probe, confirmed the remarkable differences
observed in the thermal stabilities of the two protein forms and allowed models
for their unfolding patterns to be drawn.
PMID- 10775360
TI - Application of response surface methodology to the study of methyl glucoside
polyester synthesis parameters in a solvent-free system.
AB - Response surface methodology (RSM) and 3-level-3-factor fractional factorial
design were used to evaluate the effects of synthesis parameters, including
reaction time (4 to 8 h), temperature (110 to 130 degrees C), and substrate molar
ratio of fatty acid methyl esters (FAME) from soybean oil to methyl glucoside
(4:1 to 6:1) on the percent molar conversion to methyl glucoside polyester
(MGPE), utilizing 15 g of methyl glucoside as the reactant in a solvent-free
system. All synthesis variables (reaction time, temperature, and substrate molar
ratio) exhibited significant effects on percent molar conversion to MPGE in the
experimental range. Optimization of the synthesis reaction was suggested by ridge
max analysis to compute the estimated ridge of optimum response for increasing
radii from the center of the original design. Based on the ridge max analysis,
optimum conditions were: reaction time 6.3 h, synthesis temperature 123.8 degrees
C, and substrate molar ratio 5.9:1. The predicted molar conversion was 55.68%
(i.e., 15 g methyl glucoside yielded 56.5 g MGPE) at the optimum point.
PMID- 10775361
TI - Measuring antioxidant efficiency of wort, malt, and hops against the 2,2'
azobis(2-amidinopropane) dihydrochloride-induced oxidation of an aqueous
dispersion of linoleic acid.
AB - This paper presents a simple, convenient method for determining the efficiency of
antioxidants in aqueous systems. Production of conjugated diene hydroperoxide by
oxidation of linoleic acid in an aqueous dispersion is monitored at 234 nm. 2, 2'
Azobis(2-amidinopropane) dihydrochloride is used as a free radical initiator.
Among 12 antioxidants tested, phenolic compounds proved to be the most efficient,
both kinetically and in terms of the inhibition time (T(inh)). Applied to wort,
malt, and hops, the method confirmed a significant antioxidant activity in such
products, especially hops. This assay can be used to follow oxidative changes
throughout the brewing process and to understand the contribution of each raw
material.
PMID- 10775362
TI - A capillary electrophoresis laser-induced fluorescence method for analysis of
potato glycoalkaloids based on a solution-phase immunoassay. 1. Separation and
quantification of immunoassay products.
AB - Solution-phase immunoassays are typically faster and more precise than ELISAs.
This research developed a solution-phase for the immunoassay of potato
glycoalkaloids (GAs) based on quantification by capillary electrophoresis (CE)
with laser-induced fluorescence (LIF) detection. Solanidine coupled to 4'
(aminomethyl)fluorescein and a polyclonal antibody solution were used as the
immunoreagents. Unbound fluorescent solanidine was detected by CE-LIF (excitation
488 nm, emission 520 nm). Optimum resolution of immunoassay products was achieved
with a buffer consisting of 50 mM phosphate, 10% (v/v) methanol, and 1.5 mM SDS,
pH 7.5. A plot of signal vs log [GA] produced a sigmoidal curve typical of
immunoassays. Analysis of extracts of sprouted Yukon Gold potato tubers and
nonsprouted Yukon Gold tubers resulted in total [GA] of 98 microg/g (RSD 9%) and
55 microg/g (RSD 9%), respectively. The findings indicated that CE-LIF coupled
with a solution-phase immunoassay can be used to quantify total GA in potatoes.
PMID- 10775363
TI - Direct thermal desorption-gas chromatography and gas chromatography-mass
spectrometry profiling of hop (Humulus lupulus L.) essential oils in support of
varietal characterization.
AB - The use of direct thermal desorption-gas chromatography-mass spectrometry (DTD-GC
MS) and DTD-GC-flame ionization detection (DTD-GC-FID) for characterization of
hop essential oils is described. Four hop varieties (Nugget, Galena, Willamette,
and Cluster) from the Yakima valley (Yakima, WA) 1998 harvest were analyzed by
DTD-GC-MS and DTD-GC-FID methodology. Approximately 1 g of hops was needed for
the analysis. Hop samples were prepared for GC-MS and/or GC-FID profiling in
approximately 20 min. More than 100 volatile compounds have been identified and
quantified for each hop variety. The results were found to be in good agreement
with conventional steam distillation-extraction (SDE) data. A calibration curve
for determination of essential oil content in hops by DTD-GC-FID has been
generated. Quantitation of hop oil content by DTD-GC-FID was shown to be in good
agreement with conventional SDE data. The recovery of key oil components valuable
for varietal identification was demonstrated to be highly reproducible and
characteristic of each variety analyzed when DTD-GC-FID was used for analysis.
PMID- 10775364
TI - Antioxidant activities of astaxanthin and related carotenoids.
AB - The antioxidant activities of astaxanthin and related carotenoids have been
measured by employing a newly developed fluorometric assay. This assay is based
on 4,4-difluoro-3,5-bis(4-phenyl-1, 3-butadienyl)-4-bora-3a,4a-diaza-s-indacene
(BODIPY 665/676) as an indicator; 2,2'-azobis-2,4-dimethylvaleronitrile (AMVN) as
a peroxyl radical generator; and 6-hydroxy-2,5,7, 8-tetramethylchroman-2
carboxylic acid (Trolox) as a calibrator in an organic and liposomal media. By
employing this assay, three categories of carotenoids were examined: namely, the
hydrocarbon carotenoids lycopene, alpha-carotene, and beta-carotene; the hydroxy
carotenoid lutein; and the alpha-hydroxy-ketocarotenoid astaxanthin. The relative
peroxyl radical scavenging activities of Trolox, astaxanthin, alpha-tocopherol,
lycopene, beta-carotene, lutein, and alpha-carotene in octane/butyronitrile (9:1,
v/v) were determined to be 1.0, 1.0, 1.3, 0.5, 0.4, 0.3, and 0.2, respectively.
In dioleoylphosphatidyl choline (DOPC) liposomal suspension in Tri-HCl buffer (pH
7.4 at 40 degrees C), the relative reactivities of astaxanthin, beta-carotene,
alpha-tocopherol, and lutein were found to be 1.00, 0.9, 0.6, and 0.6,
respectively. When BODIPY 665/676 was replaced by 4,4-difluoro-5-(4-phenyl-1,3
butadienyl)-4-bora-3a, 4a-diaza-s-indacene-3-undecanoic acid (BODIPY 581/591
C(11)) as an indicator, astaxanthin showed the highest antioxidant activity
toward peroxyl radicals. The relative reactivities of Trolox, astaxanthin, alpha
tocopherol, alpha-carotene, lutein, beta-carotene, and lycopene were determined
to be 1.0, 1.3, 0.9, 0.5, 0.4, 0.2, and 0.4, respectively.
PMID- 10775366
TI - Quantitative determination of polycyclic aromatic hydrocarbons in barbecued meat
sausages by gas chromatography coupled to mass spectrometry.
AB - A method is described for the analysis of the 16 polycyclic aromatic hydrocarbons
(PAHs) prioritized by the USA EPA in meat sausages grilled under common barbecue
practices. Quantification was done by GC-MS using perdeuterated internal
standards (IS). Validation was done by spiking the matrix at the 0.5 and 1.0
microg/kg levels. The average of expected values ranged from 60 to 134% (median
84%) at the 0.5 microg/kg level and from 69 to 121% (median 96%) at the 1.0
microg/kg level. The median of the limits of detection and quantification were
0.06 and 0.20 microg/kg, respectively, for a 4-g test portion. The carcinogenic
PAHs were below the quantification limit in all products except one lamb sausage.
Comparison of estimates when either 1, 5, or 16 perdeuterated PAHs were used as
IS showed that the most accurate determination of PAHs required that each
compound be quantified against its corresponding perdeuterated analogue.
PMID- 10775365
TI - Measurement of 2-thiobarbituric acid values in dark chicken meat through
derivative spectrophotometry: influence of various parameters.
AB - Several variables (kind of filter paper, amount of sample, antioxidant addition,
stability of the spectrophotometric measurement, and handling and storage of
samples) were found to influence 2-thiobarbituric acid (TBA) values in dark
chicken meat when an acid aqueous extraction method with derivative
spectrophotometry was used. Filter papers with larger pore diameter or increasing
sample weight led to lower TBA values. After incubation of reaction mixtures at
70 degrees C and ice-cooling, tempering for 45 min at room temperature was
necessary to stabilize the spectrophotometric measurement. Furthermore, addition
of butylated hydroxytoluene (BHT) and ethylenediaminetetraacetic acid disodium
salt (EDTA) in the early steps of the method prevented artifactual formation of
TBA reactive substances during analysis. Vacuum packaging and storage of samples
at -20 degrees C were useful to avoid sample oxidation. The method finally
proposed has a coefficient of variation of 3.81 or 4.13% for raw or cooked
samples, respectively.
PMID- 10775367
TI - Application of high-temperature gas chromatography-mass spectrometry to the
investigation of glycosidically bound components related to cashew apple
(Anacardium occidentale L. Var. Nanum) volatiles.
AB - Free and bound volatile components of a Brazilian cashew apple variety
(Anacardium occidentale L. var. nanum) were obtained by simultaneous distillation
extraction (SDE) and XAD-2 adsorption. According to gas chromatography-mass
spectrometry (GC-MS) analyses and retention indices, 62 free volatile
constituents were characterized and quantified. They were esters (40%), terpenes
(20%), hydrocarbons (14%), fatty acids (9%), aldehydes (8%), alcohols (3%),
lactones (3%), ketones (1%), phenols (1%), and norisoprenoids (1%). The
glycosidically bound volatile precursors were analyzed by high-temperature GC-MS,
after room temperature silylation. Several conjugated alcohols and cinnamic acids
were detected and reported as cashew apple glycosyl constituents for the first
time.
PMID- 10775368
TI - Quantification of free and bound pantothenic acid in foods and blood plasma by a
stable isotope dilution assay.
AB - A stable isotope dilution assay for quantification of pantothenic acid in food
and blood plasma uses a 4-fold labeled isotopomer of the vitamin as an internal
standard. Pantothenic acid and its labeled analogue were detected as
trimethylsilyl derivatives by gas chromatography-mass spectrometry, showing a
minimized spectral overlap. In starch a detection limit of 44 microg/kg, an
intrasample relative standard deviation of 6.7%, and recovery values ranging
between 97.5 and 99.4% were determined. Total pantothenic acid content was
determined in rice, milk powder, apple juice, and blood plasma after enzymatic
hydrolysis of the vitamin's conjugates; free pantothenic acid was quantified
prior to enzyme treatment. Almost all results were found to be in good agreement
with literature data.
PMID- 10775369
TI - Rapid evaluation of phenolic component profile and analysis of oleuropein aglycon
in olive oil by atmospheric pressure chemical ionization-mass spectrometry (APCI
MS).
AB - Epidemiological studies have linked the Mediterranean diet with a low incidence
of cardiovascular diseases. Olive oil, the major fat component of this diet, is
characterized by antioxidant properties related to their content in catecholic
components, particularly oleuropein aglycon. Therefore quantification of these
components in edible oils may be important in determining the quality, and
consequently its commercial value. The present method allows us to obtain the
profile of the phenolic components of the oil from the methanolic extracts of the
crude olive oil. In particular tyrosol, hydroxytyrosol, elenolic acid,
deacetoxyligstroside and deacetoxyoleuropein aglycons, ligstroside and oleuropein
aglycons, and 10-hydroxy-oleuropein are clearly identified by atmospheric
pressure chemical ionization-mass spectrometry (APCI-MS). Moreover, oleuropein
and its isomers present in the oil are quantified by APCI-MS/MS analysis of the
extracts without preliminary separation from other phenolic compounds.
PMID- 10775370
TI - Determination of the enantiomeric composition of gamma-lactones in edible oils by
on-line coupled high performance liquid chromatography and gas chromatography.
AB - A new method is proposed for the determination of the enantiomeric composition of
gamma-lactones in different vegetable edible oils (i. e., olive oil, almond oil,
hazelnut oil, peanut oil, and walnut oil), and its potential for authenticity
control is underlined for a limited number of samples. The method is based on the
direct injection (i.e., without requiring a sample pretreatment step) in on-line
coupled reversed phase liquid chromatography to gas chromatography (RPLC-GC)
using a chiral stationary phase in the GC-step. Different experimental values for
both speed of sample introduction into GC and volume of the transferred fraction
are considered to improve the recoveries obtained. Relative standard deviations
lower than 10% and detection limits ranging from 0.06 to 0.22 mg/L were achieved
for the investigated gamma-lactones.
PMID- 10775371
TI - Phenolic compounds in virgin olive oil. 2. Reappraisal of the extraction, HPLC
separation, and quantification procedures.
AB - The extraction procedures (solid/liquid SPE and liquid/liquid LLE) and HPLC
separation and quantification methods of polyphenolic compounds have been checked
in virgin olive oils in order to explain the differences in content reported in
the literature. The work has been carried out on oils prepared from one cultivar
and produced under the same protocol. The extraction methods are practically
equivalent, but the SPE technique is more favorable because it is faster and
simpler. It has been proved that the chromatographic features and the method of
chemical expression of the concentrations may greatly affect the final values.
Thus, under the same analytical method, the total concentration values of
polyphenols of the same oil show variations from 18% to 80%, according to the
formality of expression as gallic acid, caffeic acid, or tyrosol equivalents. The
role of the nature and spectrophotometric features of the phenols and of the
internal standard is also discussed, and it was found to be an important source
of reported variation. A gradient separation with an eluent mixture acetonitrile
sulfuric acid (0.1 mol/L), detection at 225 nm, and quantitative calculation of
polyphenolic compounds in oils (expressed as tyrosol equivalents, THY(eq)) is
proposed.
PMID- 10775372
TI - Comparison among differential pulse voltammetry, amperometric biosensor, and
HPLC/DAD analysis for polyphenol determination.
AB - Polyphenols are widespread in vegetables and fruits. They can play an important
role in human diet and health, and they influence the sensorial properties of
many foods, and act as natural antioxidants. This study was conducted using
HPLC/DAD, tyrosinase biosensor, and differential pulse voltammetry (DPV) analyses
to detect polyphenolic compounds in natural complex matrices. The analyses were
applied to a series of both standards and natural extracts derived from grape,
olives, and green tea. The pure compounds include phenolic acids, flavones,
flavonols, catechins, tannins, and oleuropein. HPLC/DAD, DPV, and the biosensor
approach were used as independent analytical techniques. Bare graphite screen
printed electrodes were employed in DPV and in the biosensor analysis. The most
accurate data were obtained by HPLC/DAD analysis, while the DPV approach using
screen-printed electrodes could represent a quick screening method for the
determination of polyphenols in natural extracts. Use of the biosensor for the
analysis of complex matrices needs further study in order to improve its
performance.
PMID- 10775373
TI - Relationship between the reduction of tetrazolium salt XTT and DNA strand
breakage with aminosugars.
AB - Dihydropyrazine derivatives formed by the self-condensation reaction of D
glucosamine have the DNA breaking activity. To establish the monitoring method of
the biological active dihydropyrazines, we investigated the relationship between
the XTT (3'-[1-[(phenylamino)-carbonyl]-3, 4-tetrazolium]bis(4-methoxy-6
nitro)benzensulfonic acid hydrate) reducibility and the DNA breaking activity of
aminosugars. Aminosugar in 50 mM sodium phosphate buffer (pH 7.4) was incubated
at 37 degrees C. At a given time, the XTT reducibility and the DNA breaking
activity of the incubated aminosugar were measured. Both XTT reducibility and DNA
breaking activity showed a maximum value within 1-4 h after the incubation and
then gradually decreased with the incubation time. Superoxide anion was suggested
to involve in both of the DNA breaking activity and the XTT reducibility by the
addition of the radical scavengers into those assay mixtures. The quantity of
remaining covalently closed circular DNA and the XTT reducibility of all
aminosugars showed a good correlation (r = 0.825, n = 26). This means that the
XTT assay is applicable for the monitoring of those biologically active products
derived from aminosugars when the participation of superoxide anion in DNA
scission is recognized.
PMID- 10775374
TI - Monoclonal-based ELISA for the identification of herbicidal cyclohexanedione
analogues that inhibit graminaceous acetyl coenzyme-A carboxylase.
AB - Cyclohexanediones are one of four known structural classes of herbicides that
inhibit graminaceous acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2). Five
monoclonal antibodies were raised against cyclohexanediones conjugated to bovine
serum albumin. Cross-reactivity studies using a homologous competitive indirect
enzyme-linked immunosorbent assay (ciELISA) against 24 cyclohexanedione analogues
revealed that two monoclonal antibodies (mAb A and mAb B) could segregate the
analogues into active and inactive ACCase inhibitors on the basis of the analogue
concentration required to inhibit 50% of antibody binding to the coating
conjugate (IC(50)). Both mAb A and mAb B were also found to cross-react with
various members of the indolizidinedione structural class of ACCase inhibitors in
ciELISA, suggesting that both cyclohexanediones and indolizidinediones possess
features recognized by monoclonal antibodies important for the inhibition of
ACCase activity. In conclusion, pharmacophore-specific antibodies may be
potentially valuable screening tools for the identification of new lead
chemistries in a pesticide discovery program.
PMID- 10775376
TI - Comparison of in-line connected diode array and electrochemical detectors in the
high-performance liquid chromatographic analysis of coenzymes Q(9) and Q(10) in
food materials.
AB - In-line connected electrochemical (EC) and diode array (DAD) detectors were
compared in the reversed-phase high-performance liquid chromatographic (RP-HPLC)
analysis of coenzymes Q(9) and Q(10) in some food materials (beef steak, beef
heart, Baltic herring fillet, and rye flour). Coenzymes Q(9) and Q(10) were
extracted from the samples using a 5:1 n-hexane-ethanol mixture. Coefficient of
variation (CV%) of quadruplicate or quintuplicate determined samples for
coenzymes Q(9) and Q(10) was <10 by both EC detector and DAD. Responses of the
detection systems were linear in the range evaluated, 10-200 ng/injection, and
had correlation coefficients exceeding 0.999. Recoveries of added coenzymes Q(9)
and Q(10) varied 73-105% for DAD and 74-103% for EC detector, respectively.
Detection limits for coenzymes Q(9) and Q(10) using the DAD system were 4 and 6
ng/injection, respectively, and 0.2 and 0.3 ng/injection by EC detection. Results
derived from the two detection systems were generally similar. However, although
EC detector was 20-fold more sensitive, the selectivity was, in some cases,
poorer than that of DAD.
PMID- 10775375
TI - Development and evaluation of an immunological approach for the identification of
novel acetyl coenzyme-A carboxylase inhibitors: assay optimization and pilot
screen results.
AB - Cyclohexanediones, aryloxyphenoxypropionates, indolizidinediones, and
triazinediones are four known structural classes of herbicides that inhibit
acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2). An immunological study to
determine the potential of ACCase inhibitor-specific monoclonal antibodies as
screening tools to identify novel lead chemistry was undertaken. Using two
cyclohexanedione-specific monoclonal antibodies (mAb A and mAb B; Webb, S. R.;
Hall, J. C. J. Agric. Food Chem. 2000, 48, 1210-1218) and three different
cyclohexanedione hapten coating conjugates, competitive indirect enzyme-linked
immunosorbent assays (ciELISA) were developed. Cross-reactivity of the monoclonal
antibodies with four structural classes of ACCase inhibitors revealed that the
ciELISA using mAb A and a modified cyclohexanedione hapten coating conjugate
detected analogues from all four known classes of ACCase inhibitors. A pilot
screen using this ciELISA format identified two novel ACCase inhibitors,
demonstrating the potential for antibodies as rapid and cost-effective screening
tools for identifying novel lead chemistry in pesticide discovery programs.
PMID- 10775377
TI - Separation of biologically active lipids from red wine.
AB - A number of lines of evidence suggest that red wine exerts a protective effect
against coronary heart disease, but the nature of the protective compounds is
unclear and the mechanism is incompletely understood. In this study, total lipids
of a Greek red wine were separated into neutral and polar lipids. Polar lipids
were further separated into glyco- and phospholipids, which were fractionated by
HPLC. Each lipid fraction was tested in vitro for its ability to inhibit platelet
activating factor (PAF) and thrombin-induced washed rabbit platelet aggregation
and/or to cause platelet aggregation. A significant number of glyco- and
phospholipids that exerted the above biological activities were detected.
Structural data of an active phosphoglycolipid are also provided. trans
Resveratrol demonstrated also a dose-dependent inhibition of PAF-induced platelet
aggregation along with the already reported inhibitory activity against thrombin
and adenosine-5'-diphosphate. Because it has already been reported that PAF is
involved in atheromatosis generation, the existence of PAF inhibitors in red wine
may contribute to the protective role of red wine against atherosclerosis.
PMID- 10775378
TI - Analysis of benzothiazole in Italian wines using headspace solid-phase
microextraction and gas chromatography-mass spectrometry.
AB - Benzothiazoles are a part of the molecular structure of a large number of natural
products, biocides, drugs, food flavors, and industrial chemicals. They also
appear in the environment mainly as a result of their production and use as
rubber vulcanization accelerators. A new headspace solid-phase microextraction
(HS-SPME) method for analysis of benzothiazole (BTH) in wine is described. This
method is fast, inexpensive, and does not require solvents. The detection limit
of BTH in wine was 45 ppt with linearity up to 100 ppb. The quantification of BTH
is performed by the standard additions method and does not require the use of an
internal standard. We have analyzed 12 wines from different grape varieties grown
in several regions, using SPME extraction and gas chromatography-mass
spectrometry (GC-MS) detection. Under these experimental conditions,
benzothiazole was found in all wines analyzed. Concentration levels in samples
varied from 0.24 microg/L (Vermentino) to 1.09 microg/L (Franciacorta).
PMID- 10775379
TI - Occurrence of resveratrol in edible peanuts.
AB - Resveratrol has been associated with reduced cardiovascular disease and reduced
cancer risk. This phytoalexin has been reported in a number of plant species,
including grapes, and may be one of the compounds responsible for the health
benefits of red wine. Analytical methods for measuring resveratrol in wine and
peanuts were adapted to isolate, identify, and quantify resveratrol in several
cultivars of peanuts. Aqueous ethanol (80% v/v) extracts from peanuts without
seed coats were purified over alumina/silica gel columns and analyzed by reversed
phase HPLC using a C-18 column. Peanuts from each market type, Virginia, runner,
and Spanish, produced in four different locations contained from 0.03 to 0.14
microg of resveratrol/g. Seed coats from runner and Virginia types contained
approximately 0.65 microg/g of seed coat, which is equivalent to <0.04
microg/seed. Quantitative analysis of 15 cultivars representing 3 peanut market
types, which had been cold stored for up to 3 years, indicated a range of 0.02
1.79 microg/g of peanut compared to 0.6-8.0 microg/mL in red wines.
PMID- 10775380
TI - Characterization and esterification of hemicelluloses from rye straw.
AB - Hemicelluloses were extracted with 10% KOH/0.5% Na(2)B(4)O(7). 10H(2)O from
delignified rye straw. Esterification of the hemicelluloses with various acyl
chlorides was performed in a homogeneous N,N-dimethylformamide and lithium
chloride system using 4-(dimethylamino)pyridine catalyst and triethylamine as a
neutralizer. The degree of substitution was controlled between 0.37 and 1.65.
Under an optimum condition (sample 14, molar ratio 3:1), >90% of the free
hydroxyl groups in native hemicelluloses were stearoylated at 75 degrees C for 40
min. Meanwhile, the products were characterized by FT-IR and GPC techniques as
well as their solubilities. The molecular mass measurements (31400-123300 g mol(
)(1)) showed only a minimal degradation of the macromolecular hemicelluloses
during rapid reactions at 48-75 degrees C for 20-40 min.
PMID- 10775381
TI - Delignification of maize stems by peroxymonosulfuric acid, peroxyformic acid,
peracetic acid, and hydrogen peroxide. 1. Physicochemical and structural
characterization of the solubilized lignins.
AB - Water-treated maize stems were subjected to delignification with
peroxymonosulfuric acid at 20 degrees C for 144 h, with peroxyformic acid at 80
degrees C for 6 h, with peracetic acid at 50 degrees C for 6 h, and with 2%
hydrogen peroxide at 45 degrees C for 12 h at pH 1.5, 4.4, 9.5, 11.5, 12.0, and
12.6, respectively, which solubilized 47.1, 91.3, 33.3, 16.6, 15.9, 17.4, 86.2,
87.7, and 91. 3% of the original lignin, respectively. Substantial lignins were
released during the treatment with peroxyformic acid and hydrogen peroxide at pH
> or =11.5, whereas an insignificant effect on delignification was observed by
using peroxymonosulfuric acid, peracetic acid, and hydrogen peroxide under
acidic, natural, and weakly alkaline media conditions. The structures of the
isolated lignin preparations were investigated by chemical analysis, gel
permeation chromatography, and UV, FT-IR, and (13)C NMR spectroscopy.
PMID- 10775382
TI - Volatile composition of some Brazilian fruits: umbu-caja (Spondias citherea),
camu-camu (Myrciaria dubia), Araca-boi (Eugenia stipitata), and Cupuacu
(Theobroma grandiflorum).
AB - Twenty-one volatile compounds were identified for the first time by GC-MS in umbu
caja and in camu-camu, plus 30 volatile compounds were identified in araca-boi
samples. Terpenic compounds predominated among the volatile compounds in these
fruit samples, with the major compounds being identified as cis-beta-ocimene and
caryophyllene in the northeastern fruit; alpha-pinene and d-limonene were the
most abundant volatile compounds in the headspace of the Amazonian fruit camu
camu. Sesquiterpenes were the most abundant compounds in the araca-boi sample,
with germacrene D presenting a higher relative percentage. The chemical class of
esters predominated in the cupuacu sample. Ethyl butyrate and hexanoate were the
major compounds in the headspace of this Amazonian fruit.
PMID- 10775383
TI - Chemical composition of essential oils from needles and twigs of balkan pine
(Pinus peuce grisebach) grown in Northern Greece.
AB - The composition of essential oils from twigs and needles of Balkan pine (Pinus
peuce Gris.) grown in northern Greece was investigated. The compounds were
identified by using GC-MS analysis. The twig oil was rich in alpha-pinene
(7.38%), beta-pinene (12.46%), beta-phellandrene (26.93%), beta-caryophyllene
(4.48%), and citronellol (12.48%), and the needle oil was rich in alpha-pinene
(23.07%), camphene (5.52%), beta-pinene (22.00%), beta-phellandrene (6.78%),
bornyl acetate (9.76%), beta-caryophyllene (3.05%), and citronellol (13.42%). The
mean oil yield was 2.85% for twigs and 0. 57% for needles.
PMID- 10775384
TI - Flavor compounds of pine sprout tea and pine needle tea.
AB - Flavor compounds of pine sprout tea and pine needle tea were analyzed and
identified in this study. Eighty-one and 39 kinds of flavor compounds were
detected in pine sprout tea and pine needle tea by GC, respectively. Among them,
55 and 29 flavor compounds were identified by GC-MS, respectively. Major flavor
compounds of pine sprout tea were alpha-pinene, myrcene, beta-thujene, terpinene
4-ol, and delta-cadinene, and major flavor compounds of pine needle tea were
alpha-pinene, isoamyl alcohol, trans-caryophyllene, terpinene-4-ol, alpha
terpineol, and delta-cadinene.
PMID- 10775385
TI - Effect of pH on retention of aroma compounds by beta-lactoglobulin.
AB - Interactions between volatile compounds and BLG in aqueous solution were studied
using static and dynamic headspace techniques (exponential dilution). The
intensity of interactions between methyl ketones (C7-C9), ethyl esters (C6-C9),
limonene, myrcene, and beta-lactoglobulin (BLG) were estimated by determination
of the relative infinite dilution activity coefficients (gamma(r)). For a
constant pH value, the methyl ketones retention by BLG increased significantly
with the hydrophobicity of the volatiles, whereas the retention reached a maximum
for ethyl octanoate in the ester series, indicating a possible steric hindrance.
For limonene and myrcene an unexpected increase in headspace concentration or
"salting out" effect was noticed for acid pH. The variations of the retention
according to the pH increase of the medium from pH 3 to pH 11 could be related to
structural modifications of the BLG. The retention increase observed between pH 3
and pH 9 resulted from the flexibility modification of the protein, allowing
better accessibility to the primary or the secondary hydrophobic sites, whereas
the dramatic decrease observed at pH 11 was the consequence of the alkaline
denaturation of BLG. Electrostatic interactions occurring at pH 7.5 could also
explain the observed retention increase.
PMID- 10775386
TI - Modeling flavor release from aqueous sucrose solutions, using mass transfer and
partition coefficients.
AB - The penetration theory of interfacial mass transfer was used to model flavor
release from aqueous solutions containing different concentrations of sucrose.
The mass transfer coefficient and the gas/solution partition coefficient are the
main factors of the model influencing the release in time. Parameters governing
the isolation by a purge and trap method at mouth conditions (volume,
temperature, and artificial saliva) were used in the model description of the
flavor release. Viscosities of the different sucrose solutions (0-60 w/v %) at 37
degrees C were estimated, and their influence on the mass transfer coefficients
was determined. The gas/solution partition coefficients for ethyl acetate, methyl
butanoate, ethyl butanoate, hexanal, and octanal were measured for the different
sucrose concentrations at 37 degrees C. At lower sucrose concentrations the
partition coefficient primarily controls flavor release during a purge time of 10
min, whereas at higher sucrose concentrations the influence of the mass transfer
coefficient is more important.
PMID- 10775387
TI - Unsaturated hydrocarbons with fruity and floral odors.
AB - Hydrocarbons usually do not exhibit odors of interest or well-defined character.
However, certain cyclic alkenes have been associated with typical and pleasant
notes, such as fruity, green, and floral. One of the best known examples is
represented by the isomeric megastigmatrienes, endowed with a pleasant smell of
tropical fruits. From the structures of these odorants, 24 analogues and
homologues, most of them cyclic alkenes, but including also some open-chain
alkenes, have been synthesized to define structural parameters related to the
characteristic odors of these compounds. The number and position of double bonds,
the substitution on the ring, and the size of the ring are the variables taken
into account. Most of the new compounds present a mainly fruity character,
associated in several cases with floral and green notes, producing an overall
sensation described as "tropical fruit".
PMID- 10775388
TI - Effects of vine or bunch shading on the glycosylated flavor precursors in grapes
of Vitis vinifera L. Cv. syrah.
AB - Effects of the modification of vine or bunch environment on glycoconjugates were
studied in Syrah berries over two years. Vines were shaded from berry set to
maturity, with black polyethylene nets of different mesh size to obtain 30 and
50% of the direct sunlight. Bunches were naturally shaded by the leaves or
artificially with 90% shade bags. Sun-exposed berries were chosen as control
berries. A quantitative decrease in levels of glycoconjugates was observed in
shaded bunches, particularly for phenolic and C(13)-norisoprenoidic glycosides.
In the same way, vine shading caused a decrease in the contents of glycosides of
terpenols, phenols, and C(13)-norisoprenoids in berries, but the grape
environment (microclimate) affected the berry composition more than the vine
environment. A cluster thinning experiment confirmed the independence of grapes
with regard to the plant for the biosynthesis of the C(13)-norisoprenoid
glycosides.
PMID- 10775389
TI - Quantitation of flavor-related alkenylbenzenes in tobacco smoke particulate by
selected ion monitoring gas chromatography-mass spectrometry.
AB - Little is known about the possible health effects associated with inhaling
alkenylbenzenes through cigarette smoking, even though these flavor-related
compounds have known toxic effects in animals. We developed a rapid and sensitive
solid-phase extraction (SPE) method to quantify seven alkenylbenzenes and
piperonal in mainstream cigarette smoke particulate. The smoke particulate
fraction of a single cigarette was collected on Cambridge filter pads, solvent
extracted, concentrated, purified with SPE, and analyzed by selected ion
monitoring gas chromatography-mass spectrometry. We positively identified and
quantified five alkenylbenzenes compounds (eugenol, isoeugenol, methyleugenol
myristicin, and elemicin) and piperonal in the smoke particulate from eight U.S.
brands with mean levels (measured in triplicate) ranging from 6.6 to 4210 ng per
cigarette. Additionally, complete blocking of nearly invisible ventilation holes
in the cigarette filter increased 2- to 7-fold the percent transfer of
alkenylbenzenes from tobacco to the particulate fraction of mainstream smoke.
PMID- 10775390
TI - Critical comparison of three olfactometric methods for the identification of the
most potent odorants in cooked mussels (Mytilus edulis).
AB - Three olfactometric methods (olfactometry global analysis, OSME, and AEDA) were
compared to evaluate the main impact odorants of cooked mussels. The results
obtained from these methods were very similar and well correlated. On the basis
of the three techniques, 42 odor-active compounds were detected and 28 were
identified. Among these compounds, 6 odorants seem to contribute actively to the
aroma of mussels: 2,3-butanedione (4) (buttery, caramel-like odor), (Z)-4
heptenal (14) (boiled potato-like odor), (E)-2-penten-1-ol (17) (mushroom-like
odor), 2-ethylpyrazine (19) (nutty odor), methional (25) (boiled potato-like
odor), and (E,E)-2,4-octadienal (32) (cucumber-like odor).
PMID- 10775391
TI - Antioxidant changes and sensory properties of carrot puree processed with and
without periderm tissue.
AB - Carrot purees were thermally processed with and without the periderm tissue after
a long and short blanch time, with and without vacuum deaeration treatments.
Samples were stored at an elevated temperature (40 degrees C for 4 weeks) to
determine physicochemical changes affecting antioxidant activity (AOX), as
measured by the coupled oxidation of beta-carotene and linoleic acid assay, and
overall quality characteristics. Differences in AOX between treatments before
thermal processing and during storage were associated with increased levels of
phenolic acids and the subsequent development of numerous compounds thought to be
oxidation products of phenolic acids. Samples processed with periderm tissue
contained higher levels of phenolic acids, total carotenoids, and sugars than
samples processed without periderm tissue. Strained carrot color was adversely
affected by a long blanch time compared to a short blanch in treatments with and
without periderm tissue, indicating improved color with reduced preprocessing
heating. Sensory analyses by a quantitative descriptive analysis panel indicated
increased musty/moldy and terpene flavors in samples processed with periderm
tissue that were seemingly related to elevated levels of phenolic acids and
volatile terpenoids. Terpenoid levels were reduced with deaeration steps prior to
thermal processing. Processing carrots without removal of periderm tissue has
proven to be a viable option when short blanch times and deaeration steps are
employed.
PMID- 10775392
TI - Physicochemical behaviors of sugars, lipids, and gluten in short dough and
biscuit.
AB - The structure of short dough and biscuit has been characterized at a macroscopic
level (dimensions, bulk structure) and a microscopic level (starch damage,
protein aggregates, microstructure) by physical and biochemical methods. The
baking process of short dough induces a large decrease of the product bulk
density from 1.26 to 0. 42 (+/-0.01) g.cm(-)(3) for final biscuit, leading to a
cellular solid with a thin colored surface and a porous inner structure. Proteins
appear aggregated in biscuit when compared to short dough, whereas starch
granules remain almost intact in biscuits. The components which are involved in
the cohesiveness of short dough and biscuit final structure have been identified.
They suggest that short dough is a suspension of solid particles in a liquid
phase being an emulsion of lipids in a concentrated sugar solution. The role of
sugars in biscuit structure suggest that biscuit structure is a composite matrix
of protein aggregates, lipids and sugars, embedding starch granules.
PMID- 10775393
TI - Effect of sucrose on the thermomechanical behavior of concentrated wheat and waxy
corn starch-water preparations.
AB - The rheological behavior of concentrated starch preparations from two different
origins (wheat and waxy corn) was studied in the presence of sucrose by dynamic
mechanical thermal analysis (DMTA). Moisture contents ranged from 30 to 60% (w/w
wsb), and samples contained 0, 10, or 20 g of sucrose for 100 g of the starch
water mixture. The storage modulus (G') changes during heating depended strongly
on water content (in the moisture range studied), and the importance of these
variations was dependent upon the starch type. Sucrose addition resulted in a
shift to higher temperatures of the increase in G' during heating. Differential
scanning calorimetry (DSC) and electron-spin resonance (ESR) analyses were
performed in parallel in order to relate the viscoelastic changes to water
migrations and to structural disorganization of starch. Sucrose was found to
increase the gelatinization temperature and enthalpy of both starches, implying a
stabilization of the granular structure during heating. The sugar-water
interactions do not appear to be the only way by which sucrose delays starch
gelatinization. The obtained results suggest that sugar-starch interactions in
the amorphous and/or the crystalline regions of the starch granules should be
envisaged.
PMID- 10775394
TI - Spice extracts as dose-modifying factors in radiation inactivation of bacteria.
AB - Three spices, chili, black pepper, and turmeric, were tested for the effect of
their aqueous extracts on the sensitivity of three bacteria, Escherichia coli,
Bacillus megaterium, and Bacillus pumilusspores, to gamma-radiation. It was found
that the extracts of the three spices offered protection to these organisms
against inactivation by gamma-radiation. These spice extracts were also tested
for their protection of naked plasmid DNA. Radiation-induced degradation of
plasmid pUC18 DNA was reduced in the presence of the spice extracts. The maximum
protection was offered by the chili extract followed by that of black pepper and
turmeric. The two known antioxidants, curcumin and piperine from turmeric and
black pepper, respectively, were shown to protect the plasmid DNA from the
degradation by gamma-radiation. Experiments with the plasmid pUC18 DNA indicated
that the spice extracts probably protected microorganisms by protecting their
DNA. These studies indicated the importance of spices among ingredients in food
as dose-modifying factors during radiation processing.
PMID- 10775395
TI - Predictive study on Tuscan extra virgin olive oil stability under several
commercial conditions.
AB - Industries aim to ensure extra virgin olive oil (EVOO) stability especially
during commercial activities up to use by end consumers. The objective of this
work was to set up predictive models of EVOO stability during commercial
activities. Stability was studied on five lots of a batch of Tuscan virgin olive
oil to simulate different commercial activities. Chemical, physical, and sensory
analyses were carried out on EVOO samples. Experimental data were processed by
multivariate analyses to select significant parameters and by regression analyses
to set up kinetic models. A few parameters were found to be significant:
hydroxytyrosol and tyrosol contents, carotenoid absorbance at 475 and 448 nm,
alpha-tocopherol content, Rancimat induction time, and K(232). It was also shown
that the stability of this EVOO was not significantly influenced by different
uncontrolled bottling, transport, and storage conditions in supermarkets.
Empirical models were set up to predict the time to reach a reference value for
K(232).
PMID- 10775396
TI - Influence of lactic acid on the solubilization of protein during corn steeping.
AB - The role of lactic acid (LA) in corn wet-mill steeping is not well understood.
Because LA is known to improve wet-milling starch yields and steepwater contains
a large amount of proteinaceous material, one of the effects of LA in steeping
may be to help break down the endosperm protein matrix. Protein solubilization
was studied for four different steeping solutions containing LA, sulfur dioxide
(SO(2)), a combination of LA and SO(2), or no added chemicals at temperatures
between 44 and 60 degrees C with steep times of up to 48 h. The accumulation of
proteinaceous material in steepwater with time was sigmoidal regardless of the
steeping chemicals or temperature. The initial slow rate of solubilization
appeared to be due to incomplete kernel hydration. Significantly greater amounts
of protein were released in the presence of LA than in its absence, with the
greatest amounts found when steeping was performed with both LA and SO(2). The
increase of proteinaceous material in steepwater containing LA was not due to low
pH, because steeping solutions containing other organic and inorganic acids did
not increase steepwater protein. The effect of LA concentration was also studied.
In the absence of SO(2), higher concentrations of LA resulted in higher
steepwater protein concentrations. The opposite trend was observed in the
presence of SO(2). Similar steepwater protein concentrations were obtained with
DL-lactic acid and L-lactic acid, indicating that the additional protein release
was not sensitive to isomeric effects.
PMID- 10775397
TI - Development of ochratoxin A during robusta (Coffea canephora) coffee cherry
drying.
AB - The occurrence and formation of ochratoxin A (OTA) in Robusta coffee was studied
for three consecutive seasons under tropical conditions in Thailand. Sun drying
of coffee cherries consistently led to OTA formation in the pulp and parchment
(husks) of the cherries. In replicated trials, dried coffee beans (green coffee)
were shown to contain on average OTA concentrations that were approximately 1% of
those found in husks. OTA contamination of green coffee depended on cherry
maturity, with green cherries being the least, and overripe cherries the most
susceptible. Defects, and in particular the inclusion of husks, are the most
important source of OTA contamination. OTA contamination occurred independently
of whether cherries were placed on concrete, on bamboo tables, or on the ground.
The study suggests that better raw material quality, an appropriate drying and
dehulling procedure combined with a reduction of green coffee defects can
effectively contribute to the reduction of OTA in green coffee.
PMID- 10775398
TI - Antioxidant activity and general fruit characteristics in different ecotypes of
Corbarini small tomatoes.
AB - Sixteen ecotypes of Corbarini small tomatoes were studied. The antioxidant
activity was evaluated with the DMPD (N, N-dimethyl-p-phenylenediamine) method in
the water-soluble fraction (S-AA) and with the ABTS [2, 2'-azinobis(3
ethylbenzothiazoline-6-sulfonic acid)] method in the water-insoluble fraction (I
AA). S-AA and I-AA were strongly related to each other, varying to a large extent
between the ecotypes considered. They were also significantly correlated with
fruit weight, total solids, and refractive index. The combination of the latter
variables (by multiple regression analysis) accounted for 36% and 44% of the
total variability of S-AA and I-AA, respectively. Moreover, when the ecotypes
were subdivided according to their shape (round, pear-shaped, oval, and long), S
AA and I-AA were both significantly higher in round tomatoes and lower in the
long ones. In conclusion, the antioxidant activity varies to a considerable
extent between different ecotypes of Corbarini small tomatoes. These differences
are related to shape and some other fruit characteristics.
PMID- 10775399
TI - Soybean meal fermented by Aspergillus awamori increases the cytochrome P-450
content of the liver microsomes of mice.
AB - The effect of soybean meal fermented by Aspergillus awamori on the acute
lethality of acetaldehyde, pentobarbital sleeping time, and cytochrome P-450
content of the hepatic microsomes was studied in mice. Most of the daidzin and
genistin in soybean meal (SBM) were converted into the respective aglycones,
daidzein and genistein, by fermentation. In experiment 1, mice were fed
isonitrogenic test diets with one of the following five protein sources for 28 d:
casein, SBM, fermented and hot-air-dried SBM (FSBM-HD), fermented and freeze
dried SBM (FSBM-FD), or methanol-extracted FSBM-FD (FSMB-FD-R). The acute
lethality of acetaldehyde in mice fed the FSBM-FD diet was significantly lower
than that in mice fed the SBM, FSBM-HD, or FSBM-FD-R diet. In experiments 2 and
3, mice were fed isonitrogenic test diets with one of the following four protein
sources for 28 d: casein, SBM, FSBM-FD, and FSBM-FD-R. The pentobarbital sleeping
time was significantly shorter and the cytochrome P-450 content was significantly
higher in the mice fed the FSBM-FD diet than the respective value in mice fed the
other test diets. In experiment 4, mice were fed one of eight diets which
contained different levels of aglycone obtained by varying the proportion of FSBM
FD and FSBM-FD-R, for 28 d. The cytochrome P-450 content in hepatic microsomes
increased as the dietary level of isoflavonoid aglycones increased, but there was
a saturation phenomenon. These results suggest that soy isoflavonoid aglycones
are more potent inducers of cytochrome P-450 than isoflavonoid glycosides.
PMID- 10775400
TI - New analogue of gymnodimine from a Gymnodinium species.
AB - A spiroimine, gymnodimine B (1), was isolated from cells recovered by filtration
from cultures of a marine dinoflagellate, Gymnodinium sp. Its structure was
identified by one- and two-dimensional NMR spectroscopy and mass spectrometry.
Gymnodimine B is similar in structure to gymnodimine (2) but contains an
exocyclic methylene at C-17 and an allylic hydroxyl group at C-18.
PMID- 10775401
TI - Occurrence of Fusarium species and mycotoxins in nepalese maize and wheat and the
effect of traditional processing methods on mycotoxin levels.
AB - Maize (Zea mays) and wheat (Triticum aestivum) collected in the foothills of the
Nepal Himalaya Mountains were analyzed for Fusarium species and mycotoxins:
fumonisins, nivalenol (NIV), and deoxynivalenol (DON). Predominant species were
Gibberella fujikuroi mating population A (F. moniliforme) in maize and F.
graminearum in maize and wheat; G. fujikuroi mating population D (F.
proliferatum), F. acuminatum, F. avenaceum, F. chlamydosporum, F. equiseti, F.
oxysporum, F. semitectum, and F. torulosum were also present. Strains of G.
fujikuroi mating population A produced fumonisins, and strains of F. graminearum
produced NIV or DON. By immunoassay or high-performance liquid chromatography,
fumonisins were >1000 ng/g in 22% of 74 maize samples. By immunoassay or
fluorometry, NIV and DON were >1000 ng/g in 16% of maize samples but were not
detected in wheat. Fumonisins and DON were not eliminated by traditional
fermentation for producing maize beer, but Nepalese rural and urban women were
able to detoxify contaminated maize by hand-sorting visibly diseased kernels.
PMID- 10775402
TI - Structure-antifeedant activity relationship of clerodane diterpenoids.
Comparative study with withanolides and azadirachtin.
AB - A structure-antifeedant activity relationship (SAR) study of clerodane
diterpenoids was carried out. Attention was focused on the feeding-deterrent
activities exhibited toward Tenebrio molitor by clerodane diterpenoids and
withanolides. Azadirachtin was chosen as a reference compound. SAR studies on the
clerodane compounds indicate that the stereoelectronic factors are more important
than the hydrophobic aspects as determinants of antifeedant activity. A furan
ring in the side chain and a carbonyl alpha,beta-unsaturated (or spiro-epoxide)
group appear to be indispensable for the biological response. A conformational
study indicate that the optimum interatomic distance between these moieties is a
range between 9.5 and 10.5 A. In addition, a similar stereoelectronic response
was found among withanolides and azadirachtin. On the basis of these results it
is reasonable to imagine a closely related chemical mechanism for these
compounds.
PMID- 10775403
TI - Molecular design of antibrowning agents.
AB - Tyrosinase inhibitory and antioxidant activity of gallic acid and its series of
alkyl chain esters were investigated. All inhibited the oxidation of L-3,4
dihydroxyphenylalanine (L-DOPA) catalyzed by mushroom tyrosinase. However, gallic
acid and its short alkyl chain esters were oxidized as substrates yielding the
colored oxidation products. In contrast, the long alkyl chain esters inhibited
the enzyme activity without being oxidized. This indicates that the carbon chain
length is associated with their tyrosinase inhibitory activity, presumably by
interacting with the hydrophobic protein pocket in the enzyme. On the other hand,
the esters, regardless their carbon chain length, showed potent scavenging
activity on the autoxidation of linoleic acid and 1,1-diphenyl-2-p-picryhydrazyl
(DPPH) radical, suggesting that the alkyl chain length is not related to the
activity. The effects of side-chain length of gallates in relation to their
antibrowning activity are studied.
PMID- 10775404
TI - Cyclopenta[b]benzofurans from Aglaia species with pronounced antifungal activity
against rice blast fungus (Pyricularia grisea).
AB - Eight flavaglines, six cyclopenta[b]benzofurans, a cyclopenta[bc]benzopyran, and
a benzo[b]oxepine, together with an aromatic butyrolactone were isolated from
Aglaia odorata, A. elaeagnoidea, and A. edulis (Meliaceae) and tested against the
three plant pathogens Pyricularia grisea, Fusarium avenaceum, and Alternaria
citri for antifungal properties. Using the microdilution technique linked with
digital image analysis of germ tubes, the benzofurans displayed strong activity,
whereas the benzopyran, benzoxepine, and butyrolactone were inactive at the
highest concentration tested. P. grisea, responsible for rice blast disease, was
the most susceptible fungus against all benzofurans, with rocaglaol as the most
active derivative. Based on EC(50), EC(90), and MIC values, the antifungal
activity of rocaglaol was clearly higher than of the reference compounds,
blasticidin S and Benlate.
PMID- 10775405
TI - Analysis of metal cations and inorganic anions in olive oil mill waste waters by
atomic absorption spectroscopy and ion chromatography. Detection of metals bound
mainly to the organic polymeric fraction.
AB - Metal cations were quantitatively detected by atomic absorption spectrometry in
samples of olive oil mill waste waters obtained by a pressure process (omww(1))
(K, 17.1; Mg, 2.72; Ca, 2.24; Na, 0.40; Fe, 0.123; Zn, 0.0630; Mn, 0.0147; Cu,
0.00860 g L(-)(1)) and a centrifugation process (omww(2)) (K, 9.80; Mg, 1.65; Ca,
1.35; Na, 0. 162; Fe, 0.0330; Zn, 0.0301; Mn, 0.00910; Cu, 0.00980 g L(-)(1)).
The inorganic anions, determined in the same samples by ion chromatography,
proved to be Cl(-), H(2)PO(4)(-), F(-), SO(4)(2)(-), and NO(3)(-) (1.61, 1.05,
0.66, 0.52, and 0.023 g L(-)(1), respectively, in omww(1) and 0.61, 0.40, 0.25,
0.20, and 0.0090 g L(-)(1), respectively, in omww(2)). Most of the metal cations
were revealed to be bound to the omww organic polymeric fraction (opf), composed
of polysaccharides, phenol polymers, and proteins. Opf relative molecular weight
was substantially estimated in the range between 1000 and 30000 Da for
approximately 75% and in the range from 30000 to 100000 Da for approximately 25%.
The free residual cations pool proved to be neutralized by the inorganic
counteranions. Finally, the possible exploitation of this material in agriculture
and in environmental biotechnology processes is also discussed in the light of
its chemical and biochemical oxygen demand parameters.
PMID- 10775406
TI - Effect of culture acclimation on the kinetics of aldicarb insecticide degradation
under methanogenic conditions.
AB - This study reports on the kinetics of aldicarb transformation under methanogenic
conditions using batch reactors containing acclimated and unacclimated cultures
under controlled conditions. Culture acclimation was accomplished by exposing
anaerobic microorganisms maintained in a semi-batch reactor to low concentrations
of aldicarb. Results of the kinetic studies showed that in an anaerobic system
aldicarb is converted to aldicarb nitrile by the hydrolytic pathway. Analysis of
the hydrolysis/dehydration rate constants showed that anaerobic cultures enhanced
the rate of conversion of aldicarb by 4-fold for acclimated cultures and by 2
fold for unacclimated cultures compared to the rate of abiotic hydrolysis (p <
0.05). Only the acclimated cultures were able to further mineralize the reaction
intermediate aldicarb nitrile. Michaelis-Menten and Monod kinetics adequately
defined the aldicarb nitrile degradation.
PMID- 10775407
TI - A hairy root culture of melon produces aroma compounds.
AB - Musk melon is the favorite fruit with a high market value in Japan, and the
fragrance is one of the major factors determining the fruit quality of melon. In
this study, mutant melon hairy roots which had been induced by means of the T-DNA
insertion mutagenesis were found to produce volatile compounds with the fruity
fragrance of mature melon. The volatile compounds were extracted and identified
by GLC-mass spectrometry. Some essential oils such as (Z)-3-hexenol, (E)-2
hexenal, 1-nonanol, and (Z)-6-nonenol were stably synthesized by these hairy
roots despite the increased number of subcultures. The productivity of these
compounds by the best hairy root line was shown to be considerably higher than
naturally ripened melon fruits.
PMID- 10775408
TI - Nitric oxide production and mitochondrial dysfunction during rat thymocyte
apoptosis.
AB - Production of nitric oxide (NO) by mitochondrial membranes as methemoglobin
formation sensitive to N(G)-methyl-l-arginine inhibition and mitochondrial O(2)
consumption in metabolic states 3 and 4 and the respiratory control (state
3/state 4) were measured at early stages of rat thymocyte apoptosis. Programmed
cell death was induced by addition of methylprednisolone and etoposide to
thymocyte suspensions. Increased NO production by mitochondrial membranes was
observed after 30 min of methylprednisolone and etoposide addition and was
accompanied by mitochondrial respiratory impairment as an early phenomenon in
apoptotic thymocytes. The respiratory control in isolated mitochondria from
untreated thymocytes was 4.2 +/- 0.2 and decreased to 3.1 +/- 0.2 and 1.9 +/- 0.3
after 1 h of methylprednisolone and etoposide treatment, respectively. The low
mitochondrial respiratory control was accompanied by a marked decrease in GSH and
cytochrome c content. Moreover, an inhibitory effect in the amount of apoptosis
due to thymocyte pretreatment with N(G)-methyl-l-arginine and N(omega)-nitro-(l)
arginine (l-NNA), indicate that nitric oxide production is closely involved in
the signaling of rat thymocyte apoptosis.
PMID- 10775409
TI - Exercise preconditioning against hydrogen peroxide-induced oxidative damage in
proteins of rat myocardium.
AB - Both regular physical exercise and low levels of H(2)O(2) administration result
in increased resistance to oxidative stress. We measured the accumulation of
reactive carbonyl derivatives and the activities of proteasome complex and DT
diaphorase in cardiac muscle of trained and untrained rats after chronic i.p.
administration of 1 ml t-butyl H(2)O(2) (1 mmol/kg for 3 weeks every second day).
Twenty-four rats were randomly assigned to a control group administered with
saline, control administered with H(2)O(2), and exercised administered either
saline or H(2)O(2). The activity of DT-diaphorase significantly increased in
H(2)O(2) administered and exercised groups, indicating that an increase in
H(2)O(2) levels stimulate the activity of this enzyme. The cardiac muscle of
H(2)O(2) administered nonexercised animals accumulated significantly more
carbonyl than control group (P < 0.05). The exercise and H(2)O(2) administration
resulted in less oxidatively modified protein than found in nonexercised groups
(P < 0.05). The peptide-like activity of proteasome complex was induced by the
treatment of H(2)O(2) and exercise and exercise potentiate the effect of
H(2)O(2). On the other hand, the chymotrypsin-like and trypsin-like activities
were stimulated only by physical training and H(2)O(2) administration. The data
suggest that chronic administration of H(2)O(2) after exercise training decreases
the accumulation of carbonyl groups below the steady-state level and induces the
activity of proteasome and DT-diaphorase. Hence, the stimulating effect of
physical exercise on free radical generation is an important phenomenon of the
exercise-induced adaptation process since it increases resistance to oxidative
stress. Regular exercise training is a valuable physiological means of
preconditioning the myocardium to prolonged oxidative stress.
PMID- 10775410
TI - Efficient production of recombinant brazzein, a small, heat-stable, sweet-tasting
protein of plant origin.
AB - Brazzein is a 54-amino-acid sweet-tasting protein first isolated from the fruit
of Pentadiplandra brazzeana Baillon found in West Africa. Brazzein, as isolated
from the fruit, is 500 times sweeter than sucrose on a weight basis (9500 times
sweeter on a per-molecule basis). A minor component of brazzein from fruit, des
pGlu1-brazzein, has 53 amino acid residues and has twice the sweetness of the
parent protein. We have designed a gene for des-pGlu1- brazzein that incorporates
codons that are optimal for protein production in Escherichia coli. Production of
brazzein from the chemically synthesized gene resulted in recombinant protein
with sweetness similar to that of brazzein isolated from the original source. The
best yields were achieved by producing brazzein as a fusion with staphylococcal
nuclease with a designed cyanogen bromide cleavage site. Because of its intense
sweetness and stability at high pH and temperature, brazzein is an ideal system
for investigating the chemical and structural requirements involved in sweet
taste properties. This efficient protein production system for brazzein will
facilitate such investigations.
PMID- 10775411
TI - Sweetness determinant sites of brazzein, a small, heat-stable, sweet-tasting
protein.
AB - Brazzein, originally isolated from the fruit of the African plant Pentadiplandra
brazzeana Baillon, is the smallest, most heat-stable and pH-stable member of the
set of proteins known to have intrinsic sweetness. These properties make brazzein
an ideal system for investigating the chemical and structural requirements of a
sweet-tasting protein. We have used the three-dimensional structure of the
protein (J. E. Caldwell et al. (1998) Nat. Struct. Biol. 5, 427-431) as a guide
in designing 15 synthetic genes in expression constructs aimed at delineating the
sweetness determinants of brazzein. Protein was produced heterologously in
Escherichia coli, isolated, and purified as described in the companion paper
(Assadi-Porter, F. M., Aceti, D., Cheng, H., and Markley, J. L., this issue).
Analysis by one-dimensional (1)H NMR spectroscopy indicated that all but one of
these variants had folded properly under the conditions used. A taste panel
compared the gustatory properties of solutions of these proteins to those of
sucrose and brazzein isolated from fruit. Of the 14 mutations in the des-pGlu1
brazzein background, four exhibited almost no sweetness, six had significantly
reduced sweetness, two had taste properties equivalent to des-pGlu1-brazzein (two
times as sweet as the major form of brazzein isolated from fruit which contains
pGlu1), and two were about twice as sweet as des-pGlu1-brazzein. Overall, the
results suggest that two regions of the protein are critical for the sweetness of
brazzein: a region that includes the N- and C-termini of the protein, which are
located close to one another, and a region that includes the flexible loop around
Arg43.
PMID- 10775412
TI - Disulfide connectivity in cerebroside sulfate activator is not necessary for
biological activity or alpha-helical content but is necessary for trypsin
resistance and strong ligand binding.
AB - Cerebroside sulfate activator (CSAct) protein is exceptionally resistant to heat
denaturation and proteolytic digestion. Although water soluble the protein binds
membrane-associated lipids. Its biological role is thought to be to transfer
certain lipids between membranes and to facilitate their catabolism in the
lysosomes. An example of the latter is the removal of the sulfate group from
cerebroside sulfate by arylsulfatase A. The mechanism of lipid sequestration from
membranes and presentation of the lipid-protein complex to catabolic enzymes is a
crucial aspect of the function of this protein. The widespread occurrence of the
protein class of which CSAct is one of the best known members underscores the
significance of this protein. The preparation, purification and chemical and
biological properties of a stable disulfide blocked derivative of CSAct is
described. The pyridoethylated protein was susceptible to tryptic attack and
devoid of a significant population of solvent-protected exchange resistant
protons. It apparantly formed a CS complex. However, unlike the complex with the
native protein, this was not sufficiently stable to remain intact during size
exclusion chromatography. The disulfide-blocked protein had a similar CD spectrum
as native protein, indicating similar alpha-helical content. Unexpectedly, the
activities of disulfide-blocked protein in the arylsulfatse A catalyzed sulfate
hydrolysis from cerebroside sulfate were substantial. Hitherto, it had been
assumed that the disulfide connectivities were essential for the protein to
maintain a correctly folded configuration to bind lipid ligands and potentiate
their hydrolysis. Some revision of our thoughts on the importance of the
disulfide connectivities in the structure and function of the protein are
necessary.
PMID- 10775413
TI - Association and dissociation of the tripeptidyl-peptidase II complex as a way of
regulating the enzyme activity.
AB - Tripeptidyl-peptidase II is an unusually large exopeptidase. The subunits (M(r) =
138,000) form an active complex with an M(r) > 10(6). This paper demonstrates
that the complex can spontaneously dissociate in vitro into dimers which retain
110th of the original specific activity. The dissociated enzyme can reassociate
at elevated temperatures, provided the protein concentration is sufficiently
high. This reassociation was accompanied by a reactivation. The rate of
reactivation was increased by the presence of competitive peptide inhibitors. It
is speculated that association/dissociation may be a way of regulating the enzyme
activity in vivo.
PMID- 10775414
TI - Characterization of a novel transcription factor binding to the regulatory
regions of the human pro-alpha1(I) collagen gene.
AB - We have identified a novel transcription factor TGP (TG Binding Protein) that
binds to the consensus sequence 5'-TGTGGGGTGG-3' in the promoter and intron of
the human pro-alpha1(I) collagen gene. This recognition sequence, or sequences
closely resembling these sequences, was also identified in the pro-alpha1(I) and
pro-alpha2(I) collagen genes of other species. Competition experiments revealed
that TGP is related to but distinguishable from the Ap4/5 family of transcription
factors and that it can be separated from Ap4/5 according to size.
PMID- 10775415
TI - Sds22p is a subunit of a stable isolatable form of protein phosphatase 1 (Glc7p)
from Saccharomyces cerevisiae.
AB - Protein phosphatase 1 (PP1) is one of the major protein phosphatases in
eukaryotic cells. PP1 activity is believed to be controlled by the interaction of
PP1 catalytic subunit with various regulatory subunits. The essential gene GLC7
encodes the PP1 catalytic subunit in Saccharomyces cerevisiae. In this study,
full-length GLC7(1-312), C-terminal deletion mutants, and C-terminally poly-his
tagged mutants were constructed and expressed in a GLC7 knockout strain of S.
cerevisiae. Viability studies of the GLC7 knockout strains carrying the plasmids
expressing GLC7 C-terminal deletion mutants and their tagged forms showed that
the mutants 1-295 and 1-304 were functional, whereas the mutant 1-245 was not.
The C-terminally poly-his tagged Glc7p with and without an N-terminal
hemagglutinin (HA) tag was partially purified by immobilized Ni(2+) affinity
chromatography and further analyzed by gel filtration and ion exchange
chromatography. Phosphatase activity assays, SDS-PAGE, and Western blot analyses
of the chromatographic fractions suggested that the Glc7p associated with
regulatory subunits in vivo. A 40-kDa protein was copurified with tagged Glc7p
through several chromatographic procedures. Monoclonal antibody against the HA
tag coimmunoprecipitated the tagged Glc7p and the 40-kDa protein. This protein
was further purified by a reverse phase HPLC column. Analysis by CNBr digestion,
peptide sequencing, and electrospray mass spectrometry showed that this 40-kDa
protein is Sds22p, one of the proteins proposed to be a regulatory subunit of
Glc7. These results demonstrate that Sds22p forms a complex with Glc7p and that
Sds22p:Glc7p is a stable isolatable form of yeast PP1.
PMID- 10775416
TI - Disruption of cytoplasmic and mitochondrial folylpolyglutamate synthetase
activity in Saccharomyces cerevisiae.
AB - Similar to other eukaryotes, yeasts have parallel pathways of one-carbon
metabolism in the cytoplasm and mitochondria and have folylpolyglutamate
synthetase activity in both compartments. The gene encoding folylpolyglutamate
synthetase is MET7 (also referred to as MET23) on chromosome XV and appears to
encode both the cytoplasmic and mitochondrial forms of the enzyme. In order to
determine the metabolic roles of both forms of folylpolyglutamate synthetase, we
disrupted the met7 gene and determined that the strain is a methionine auxotroph
and an adenine and thymidine auxotroph when grown in the presence of
sulfanilamide. The met7 mutant becomes petite under normal growth conditions but
can be maintained with a grande phenotype if the strain is tup and all media are
supplemented with dTMP. A met7 gly1 strain is auxotrophic for glycine when grown
on glucose but prototrophic when grown on glycerol. A met7 ser1 strain cannot use
glycine to suppress the serine auxotrophy of the ser1 phenotype. A met7 shm2
strain is nonviable. In order to disrupt just the mitochondrial
folylpolyglutamate synthetase activity, we constructed mutants with an
inactivated chromosomal MET7 gene complemented by genes that express only
cytoplasmic folylpolyglutamate synthetase, including the Lactobacillus casei folC
gene and the yeast MET7 gene with its mitochondrial leader sequence deleted
(MET7Deltam). All the genes providing cytoplasmic folylpolyglutamate synthetase
complemented the methionine auxotrophy as well as the synthetic lethality of the
shm2 strain and the synthetic glycine auxotrophy of the gly1 strain. The strains
lacking the mitochondrial folylpolyglutamate synthetase had longer doubling times
than the isogenic wild-type strains but retained the function of the
mitochondrial folate-dependent enzymes to produce formate, serine, and glycine.
Mutants complemented by the bacterial folC gene or by the MET7Deltam gene on a
2mu plasmid remained grande without the tup mutation and supplementation and
dTMP. Mutants complemented by the MET7Deltam gene integrated in single copy
became petites under those conditions, indicating a deficiency in dTMP production
but this is likely due to lower expression of cytoplasmic folylpolyglutamate
synthetase by the MET7Deltam gene.
PMID- 10775417
TI - Chemical modification of SH groups of E. coli phosphofructokinase-2 induces
subunit dissociation: monomers are inactive but preserve ligand binding
properties.
AB - Modification of Escherichia coli phosphofructokinase-2 (Pfk-2) with N-(1
pyrenil)maleimide results in an enzyme form that is inactive. However, the rate
of modification is drastically reduced in the presence of the allosteric effector
MgATP. The stoichiometry of the label incorporation was found to be 2.03 +/-
0.035 mol of the reagent/mol of subunit, in agreement with the number of
titratable SH groups by 5,5'-dithiobis(2-nitrobenzoic acid) in the labeled
protein. HPLC gel filtration experiments demonstrate that native Pfk-2 is a dimer
in the absence of ligands, while in the presence of MgATP a dimer-tetramer
transition is promoted. In contrast, the modified enzyme eluted as a monomer and
the presence of MgATP was not able to induce aggregation. Although the modified
monomers are inactive, the dissociation constants for the substrates and the
allosteric effector MgATP, measured by following the fluorescence of the binding
probe, are the same as for the native enzyme. Quenching of pyrene fluorescence
emission of labeled phosphofructokinase-2 monomers by acrylamide gave downward
curved Stern-Volmer plots, with very similar quenching efficiencies for the
control and for the fructose-6-P and MgATP-enzyme complexes. These results show
the presence of SH groups in the interface of Pfk-2 subunits, critical for
subunit interactions, and that conformational changes occurring through the
dimers are essential for catalytic activity.
PMID- 10775418
TI - Activation of transcription factors in zebrafish cell cultures by environmental
pollutants.
AB - Many classes of environmental pollutants are found at significant levels in the
aquatic environment. We are designing a fish model as an inexpensive and
efficient system for the assessment of aquatic pollution. Three classes of
environmental pollutants-halogenated and nonhalogenated aromatic hydrocarbons,
heavy metals, and potent electrophiles-are known to upregulate particular
mammalian genes via the activation of specific DNA motifs called aromatic
hydrocarbon (AHREs), heavy metal (MREs), and electrophile (EPREs) response
elements, respectively. We have made plasmid constructs, using these mammalian or
trout response elements to drive the luciferase reporter gene. Here we show that
transient transfection of the zebrafish ZEM2S cell line with these reporter
constructs imparts dose-dependent gene induction upon exposure to a variety of
chemicals within each of these three classes of inducers: [a] (AHRE-mediated)
2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, 3,4,5,3',4',5'
hexabromobiphenyl, Aroclor 1254, and benzo[a]pyrene; [b] (MRE-mediated) Cd(2+),
Zn(2+), Hg(2+), and Al(3+); and [c] (EPRE-mediated) tert-butylhydroquinone,
Hg(2+), Pb(2+), As(3+), Cu(2+), and Cd(2+). As expected, some agents gave a
response to only one of the three classes, whereas others gave a mixed (AHRE-
plus EPRE-mediated or MRE- plus EPRE-mediated) response. In response to several
environmental agents, we found that differences in the electrophoretic mobility
shift assay, using the AHRE or MRE as probe, were consistent with the degree of
transcriptional activation seen with the reporter constructs. Our data suggest
that these reporter constructs might be valuable for the generation of transgenic
zebrafish in order to carry out mechanistic and developmental studies of
transcriptional activation by environmental contaminants; moreover, such
transgenic zebrafish lines might be useful as a sentinel for assessing aquatic
pollution.
PMID- 10775419
TI - Renal excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine in Wistar rats with
increased O(2) consumption due to cold stress.
AB - DNA damage by reactive oxygen species is of special interest in the development
of cancer and in aging. The renally excreted amount of 8-oxo-7,8-dihydro-2'
deoxyguanosine (oxo(8)dG) is a potential noninvasive marker of oxidative DNA
damage. The respiratory chain of mitochondria is one source for the formation of
reactive oxygen species. In the present study we investigated in Wistar rats (n =
7; mean body weight at start, 307.4 +/- 11 g) the effect of an increased O(2)
consumption, i.e., energy expenditure, due to cold stress on the renally excreted
amount of oxo(8)dG. First, the rats were housed for 4 days at 23.5 degrees C
(basic period, BP), and then for 6 days at 10 degrees C (cold stress period,
CSP), and finally for 3 days at 23.5 degrees C (recovery period, RP). The O(2)
consumption (L O(2)/day/kg weight) was significantly (P < 0.0001) on average 50%
higher in CSP (69.0 +/- 3.9) than in BP (45.8 +/- 4.8), and similar in BP and RP
(44.3 +/- 5.4). The average renal excretion of oxo(8)dG (pmol/day/kg weight) was
significantly (P < 0.025) on average 13% higher in CSP (375.5 +/- 27.7) than in
BP (333.2 +/- 47. 4) and similar in BP and RP (331.8 +/- 34.3). Maximum increase
in oxo(8)dG excretion of on average 17% was on the third to fifth day of the CSP.
This study reveals that an increase in O(2) consumption of 50% resulted in a much
lower increase in the renal excretion of oxo(8)dG.
PMID- 10775420
TI - Reaction of uric acid with peroxynitrite and implications for the mechanism of
neuroprotection by uric acid.
AB - Peroxynitrite, a biological oxidant formed from the reaction of nitric oxide with
the superoxide radical, is associated with many pathologies, including
neurodegenerative diseases, such as multiple sclerosis (MS). Gout (hyperuricemic)
and MS are almost mutually exclusive, and uric acid has therapeutic effects in
mice with experimental allergic encephalomyelitis, an animal disease that models
MS. This evidence suggests that uric acid may scavenge peroxynitrite and/or
peroxynitrite-derived reactive species. Therefore, we studied the kinetics of the
reactions of peroxynitrite with uric acid from pH 6.9 to 8.0. The data indicate
that peroxynitrous acid (HOONO) reacts with the uric acid monoanion with k = 155
M(-1) s(-1) (T = 37 degrees C, pH 7.4) giving a pseudo-first-order rate constant
in blood plasma k(U(rate))(/plasma) = 0.05 s(-1) (T = 37 degrees C, pH 7.4;
assuming [uric acid](plasma) = 0.3 mM). Among the biological molecules in human
plasma whose rates of reaction with peroxynitrite have been reported, CO(2) is
one of the fastest with a pseudo-first-order rate constant k(CO(2))(/plasma) = 46
s(-1) (T = 37 degrees C, pH 7.4; assuming [CO(2)](plasma) = 1 mM). Thus
peroxynitrite reacts with CO(2) in human blood plasma nearly 920 times faster
than with uric acid. Therefore, uric acid does not directly scavenge
peroxynitrite because uric acid can not compete for peroxynitrite with CO(2). The
therapeutic effects of uric acid may be related to the scavenging of the radicals
CO(*-)(3) and NO(*)(2) that are formed from the reaction of peroxynitrite with
CO(2). We suggest that trapping secondary radicals that result from the fast
reaction of peroxynitrite with CO(2) may represent a new and viable approach for
ameliorating the adverse effects associated with peroxynitrite in many diseases.
PMID- 10775421
TI - Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear
factor kappaB in cancer cells versus normal cells.
AB - Green tea has shown remarkable anti-inflammatory and cancer chemopreventive
effects in many animal tumor bioassays, cell culture systems, and epidemiological
studies. Many of these biological effects of green tea are mediated by
epigallocatechin 3-gallate (EGCG), the major polyphenol present therein. We have
earlier shown that EGCG treatment results in apoptosis of several cancer cells,
but not of normal cells (J. Natl. Cancer Inst. 89, 1881-1886 (1997)). The
mechanism of this differential response of EGCG is not known. In this study, we
investigated the involvement of NF-kappaB during these differential responses of
EGCG. EGCG treatment resulted in a dose-dependent (i) inhibition of cell growth,
(ii) G0/G1-phase arrest of the cell cycle, and (iii) induction of apoptosis in
human epidermoid carcinoma (A431) cells, but not in normal human epidermal
keratinocytes (NHEK). Electromobility shift assay revealed that EGCG (10-80
microM) treatment results in lowering of NF-kappaB levels in both the cytoplasm
and nucleus in a dose-dependent manner in both A431 cells and NHEK, albeit at
different concentrations. EGCG treatment was found to result in a dose-based
differential inhibition of TNF-alpha- and LPS-mediated activation of NF-kappaB in
these cells. The inhibition of NF-kappaB constitutive expression and activation
in NHEK was observed only at high concentrations. The immunoblot analysis also
demonstrated a similar pattern of inhibition of the constitutive expression as
well as activation of NF-kappaB/p65 nuclear protein. This inhibition of TNF-alpha
caused NF-kappaB activation was mediated via the phosphorylative degradation of
its inhibitory protein IkappaBalpha. Taken together, EGCG was found to impart
differential dose-based NF-kappaB inhibitory response in cancer cells vs normal
cells; i.e., EGCG-mediated inhibition of NF-kappaB constitutive expression and
activation was found to occur at much higher dose of EGCG in NHEK as compared to
A431 cells. This study suggests that EGCG-caused cell cycle deregulation and
apoptosis of cancer cells may be mediated through NF-kappaB inhibition.
PMID- 10775422
TI - Transport of alpha-ketoisocaproate in rat cerebral cortical neurons.
AB - Transport of alpha-ketoisocaproic acid (KIC), the product of leucine
transamination, was studied in the cerebral cortex cells isolated from the adult
rat brain. The process of [(14)C]KIC accumulation was followed in the presence of
aminooxyacetate, an inhibitor of transaminases. Accumulation of KIC was not
affected by Na(+) replacement, its initial velocity was observed to be higher
upon lowering of external pH. Addition of KIC promoted acidification of
cytoplasmic pH, monitored with 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein.
The detected inhibition of KIC accumulation by alpha-cyano-4(OH)cinnamate pointed
to an involvement of one of monocarboxylate transporters (MCT), although 4,4'
diisothiocyano-2,2'-stilbenedisulphonate was without effect. Accumulation of KIC
was inhibited by lactate; the effect of pyruvate was detected to be much weaker.
Other branched-chain alpha-ketoacids (ketoisovalerate, keto-methylvalerate), as
well as beta-hydroxybutyrate and valproate decreased the transport of KIC by 30,
60, and 80%, respectively. The observed characteristics of KIC accumulation in
the cortical neurons indicate an involvement of one of the MCT transporters. A
crucial role of SH group(s) in the process of KIC accumulation, excluding MCT2,
indicates the MCT1, although an involvement of another isoform of MCT in the
process of KIC transport in neurons from cerebral cortex of adult brain has not
been definitely excluded.
PMID- 10775423
TI - Aristolochene synthase: purification, molecular cloning, high-level expression in
Escherichia coli, and characterization of the Aspergillus terreus cyclase.
AB - Aristolochene synthase catalyzes the cyclization of farnesyl diphosphate (6) to
(+)-aristolochene (1). The Aspergillus terreus enzyme has been purified 75-fold
to homogeneity in six steps. Based on the sequence of 3 internal peptides
obtained by Lys-C digestion of the native protein, a set of degenerate PCR
primers was used to amplify a 550-bp segment of cDNA corresponding to a portion
of the aristolochene synthase transcript. A second round of PCR using specific
primers was used to prepare a (32)P-labeled 180-bp segment, which was used to
screen an A. terreus cDNA library prepared using lambdaZapII, resulting in the
identification and sequencing of the A. terreus aristolochene synthase cDNA.
Aristolochene synthase was encoded by an open reading frame (ORF) of 960 bp,
corresponding to a protein of 320 amino acids with a predicted M(D) of 36,480.
Comparison of the A. terreus ORF with the sequence of the previously described
aristolochene synthase from Penicillium roqueforti revealed a 66% of identity at
the nucleic acid level and a 70% identity at the deduced amino acid level between
the aristolochene synthases from the two different fungal sources. PCR was used
to insert the A. terreus aristolochene synthase gene into the T7lac expression
vector pET11a. Cloning of the resultant construct into Escherichia coli XL1-Blue
and subcloning into the expression host E. coli BL21(DE3)/pLysS gave, after
induction with IPTG, soluble aristolochene synthase as 5-10% of total protein.
The recombinant aristolochene synthase, which was purified 13-fold to
homogeneity, appeared to be identical in all respects with the native A. terreus
enzyme, displaying essentially the same steady-state kinetic parameters, with a
K(m) of 15 nM and k(cat) 0.015 s(-1). Using PCR to amplify the aristolochene
synthase gene (Aril) from A. terreus genomic DNA revealed the presence of 2
introns, identical in relative location but different in both sequence and length
compared to the corresponding Ari1 gene of P. roqueforti.
PMID- 10775424
TI - Peroxynitrite modulates the activation of p38 and extracellular regulated kinases
in PC12 cells.
AB - Although peroxynitrite appears to contribute to neuronal dysfunction in several
neurodegenerative disorders, little is known about how peroxynitrite affects
cellular signaling processes. This study investigated if peroxynitrite affects
the mitogen-activated protein kinases, extracellular-regulated kinases 1 and 2
(ERK1/2) and p38. Exposure of PC12 cells to 500 microM peroxynitrite activated
ERK1/2 and p38 within 5 min and this was followed by gradual decreases in
activation over the next 25 min. Activation of ERK1/2 by peroxynitrite was
mediated by activation of the epidermal growth factor (EGF) receptor in a
calcium/calmodulin-dependent kinase II- and src family tyrosine kinase-dependent
manner, as it was blocked by the selective EGF receptor inhibitor AG1478, by
KN62, an inhibitor of calcium/calmodulin-dependent kinase II, and by PP1, a src
family tyrosine kinase inhibitor. Activation of p38 by peroxynitrite was
independent of the EGF receptor, required activation of calcium/calmodulin
dependent kinase II and src family tyrosine kinases, and was modulated by nerve
growth factor (NGF) in a time-dependent manner. Pretreatment with NGF (2 h)
attenuated, whereas cotreatment with NGF potentiated, peroxynitrite-induced
activation of p38. Thus, peroxynitrite activates ERK1/2 and p38, activation of
EGF receptors, calcium/calmodulin-dependent kinase II, and src family tyrosine
kinases participate in these signaling responses to peroxynitrite, and
peroxynitrite- and NGF-induced signaling activities converge on p38.
PMID- 10775425
TI - A distinct ganglioside composition of rat pancreatic islets.
AB - Gangliosides in rat pancreatic tissue and isolated pancreatic islets were
examined by methods including glycolipid-overlay techniques. The content of
gangliosides in isolated pancreatic islets was approximately 6-fold higher than
that in pancreatic tissue when compared on a protein basis. While N
glycolylneuraminic acid amounted to 7.2% of total lipid-bound sialic acids of
pancreatic tissue, this molecular species was not detected in that of pancreatic
islets. A remarkable difference in ganglioside composition was observed between
pancreatic tissue and pancreatic islets. Pancreatic tissue showed a complex
ganglioside pattern with GM3 as the largest ganglioside component, whereas
isolated pancreatic islets had a simpler ganglioside profile without detectable
amounts of GM3 and some other components. Pancreatic gangliosides were further
examined by thin-layer chromatographic immunostaining with a monoclonal antibody
A2B5 that reacts specifically with c-series gangliosides. Pancreatic tissue and
pancreatic islets showed almost identical ganglioside patterns consisting of GT3,
GT2, GQ1c, and GP1c. The concentration of c-series gangliosides in pancreatic
islets was calculated to be more than 250-fold higher than that of pancreatic
tissue. These results shows that pancreatic islet cells have a distinct
ganglioside composition in rat pancreas.
PMID- 10775426
TI - Prooxidants open both the mitochondrial permeability transition pore and a low
conductance channel in the inner mitochondrial membrane.
AB - Mitochondria can be induced by a variety of agents/conditions to undergo a
permeability transition (MPT), which nonselectively increases the permeability of
the inner membrane (i.m.) to small (<1500 Da) solutes. Prooxidants are generally
considered to trigger the MPT, but some investigators suggest instead that
prooxidants open a Ca(2+)-selective channel in the inner mitochondrial membrane
and that the opening of this channel, when coupled with Ca(2+) cycling mediated
by the Ca(2+) uniporter, leads ultimately to the observed increase in
mitochondrial permeability [see, e.g., Schlegel et al. (1992) Biochem. J. 285,
65]. S. A. Novgorodov and T. I. Gudz [J. Bioenerg. Biomembr. (1996) 28, 139]
propose that the i.m. contains a pore that, upon exposure to prooxidants, can
open to two states, one of which conducts only H(+) and one of which is the
classic MPT pore. Given the current interest in increased mitochondrial
permeability as a factor in apoptotic cell death, it is important to determine
whether i.m. permeability is regulated in one or multiple ways and, in the latter
event, to characterize each regulatory mechanism in detail. This study examined
the effects of the prooxidants diamide and t-butylhydroperoxide (t-BuOOH) on the
permeability of isolated rat liver mitochondria. Under the experimental
conditions used, t-BuOOH induced mitochondrial swelling only in the presence of
exogenous Ca(2+) (>2 microM), whereas diamide was effective in its absence. In
the absence of exogenous inorganic phosphate (P(i)), (1) both prooxidants caused
a collapse of the membrane potential (DeltaPsi) that preceded the onset of
mitochondrial swelling; (2) cyclosporin A eliminated the swelling induced by
diamide and dramatically slowed that elicited by t-BuOOH, without altering
prooxidant-induced depolarization; (3) collapse of DeltaPsi was associated with
Ca(2+) efflux but not with efflux of glutathione; (4) neither Ca(2+) efflux nor
DeltaPsi collapse was sensitive to ruthenium red; (5) collapse of DeltaPsi was
accompanied by an increase in matrix pH; no stimulation of respiration was
observed; (6) Sr(2+) was able to substitute for Ca(2+) in supporting t-BuOOH
induced i.m. depolarization, but not swelling; (7) in addition to being
insensitive to CsA, the collapse of DeltaPsi was also resistant to
trifluoperazine, spermine, and Mg(2+), all of which block the MPT; and (8)
DeltaPsi was restored (and its collapse was inhibited) upon addition of
dithiothreitol, ADP, ATP or EGTA. We suggest that these results indicate that
prooxidants open two channels in the i.m.: the classic MPT and a low-conductance
channel with clearly distinct properties. Opening of the low-conductance channel
requires sulfhydryl group oxidation and the presence of a divalent cation; both
Ca(2+) and Sr(2+) are effective. The channel permits the passage of cations,
including Ca(2+), but not of protons. It is insensitive to inhibitors of the
classic MPT.
PMID- 10775427
TI - Characterization of ecdysteroid 26-hydroxylase: an enzyme involved in molting
hormone inactivation.
AB - Insect molting hormone (ecdysteroid) inactivation occurs by several routes,
including 26-hydroxylation and further oxidation to the 26-oic acids. Thus, the
ecdysteroid 26-hydroxylase is a critical enzyme involved in precise regulation of
ecdysteroid titers during insect development. Administration of the ecdysteroid
agonist, RH-5849 (1,2-dibenzoyl, 1-tert-butyl hydrazone), or 20-hydroxyecdysone
to the tobacco hornworm, Manduca sexta, results in induction of ecdysteroid 26
hydroxylase activity in midgut mitochondria and microsomes. The biochemical and
kinetic properties of the ecdysteroid 26-hydroxylase were investigated. The
mitochondrial enzyme was found to have optimal activity at a pH of 7. 5 in a
Hepes or sodium phosphate buffer at 30-37 degrees C. The apparent K(m) of the
microsomal 26-hydroxylase for 20-hydroxyecdysone substrate was lower than that of
the mitochondrial enzyme for either 20-hydroxyecdysone or ecdysone substrate. The
V(max) of the 26-hydroxylase in both subcellular fractions was slightly higher
using 20-hydroxyecdysone as substrate compared to ecdysone. Demonstration that
activity of the mitochondrial 26-hydroxylase was inhibited by incubation in a CO
(or N(2)) atmosphere, taken together with the requirement for reducing cofactor
and the efficacy of the P450 inhibitors, ketoconazole and fenarimol, provided
strong evidence that the hydroxylase is cytochrome P450-dependent. Indirect
evidence suggested that the mitochondrial and microsomal ecdysteroid 26
hydroxylase(s) could exist in a less active dephosphorylated state or more active
phosphorylated state. Using Escherichia coli alkaline phosphatase to remove
covalently bound phosphate groups, the activity of the 26-hydroxylase was
decreased and, conversely, activity was enhanced using a cAMP-dependent protein
kinase with appropriate cofactors. In addition, the protein kinase was shown to
reactivate the 26-hydroxylase activity in alkaline phosphatase-treated fractions.
PMID- 10775429
TI - Purification and characterization of hepatic and intestinal phenol
sulfotransferase with high affinity for benzo[a]pyrene phenols from channel
catfish, Ictalurus punctatus.
AB - Cytosol from channel catfish liver and intestinal mucosa has high
sulfotransferase activity with low concentrations of 3-, 7-, or 9
hydroxybenzo[a]pyrene. To further investigate this conjugation pathway,
sulfotransferase activity toward 9-hydroxybenzo[a]pyrene was isolated from
catfish intestinal and hepatic cytosol by chromatography on anion exchange and
PAP-agarose affinity columns. SDS-PAGE of the active fractions showed that one
major band with molecular size of about 41,000 Da was isolated from intestine,
while two bands of about 41,000 and 31,000 Da were obtained from liver.
Antibodies against human phenol-sulfating sulfotransferase cross-reacted strongly
with the 41,000-Da bands from liver and intestine, but weakly with the hepatic
31,000-Da protein. N-Terminal sequence information could not be obtained from the
pure proteins. Following digestion, an internal sequence of 20 amino acid
residues was obtained from the hepatic 41,000-Da protein, which matched a
sequence found in several mammalian sulfotransferases. No fish sulfotransferase
sequences were available for comparison. The identity of the hepatic 31,000-Da
protein was not established. The purified 41,000-Da proteins had very high
activities with 3-, 7-, or 9-hydroxybenzo[a]pyrene, with K(m) values in the 40
100 nM range and V(max) 125-300 nmol/min/mg of protein. Substrate inhibition was
observed when the concentrations of hydroxylated benzo[a]pyrenes were above 0.5
microM. As well as benzo[a]pyrene phenols, the purified 41,000-Da
sulfotransferases catalyzed sulfation of 2-naphthol, 4-nitrophenol, 4
methylumbelliferone, 7-(hydroxymethyl)-12-methylbenz[a]anthracene,
dehydroepiandrosterone, estrone, and 17beta-estradiol. Phenolic compounds were
the preferred substrates for the purified enzymes.
PMID- 10775428
TI - Identification and characterization of an animal delta(12) fatty acid desaturase
gene by heterologous expression in Saccharomyces cerevisiae.
AB - We have cloned a Caenorhabditis elegans cDNA encoding a Delta12 fatty acid
desaturase and demonstrated its activity by heterologous expression in
Saccharomyces cerevisiae. The predicted protein is highly homologous both to the
cloned plant genes with similar function and to the published sequence of the C.
elegans omega-3 fatty acid desaturase. In addition, it conforms to the structural
constraints expected of a membrane-bound fatty acid desaturase including the
canonical histidine-rich regions. This is the first report of a cloned animal
Delta(12) desaturase gene. Expression of this cDNA in yeast resulted in the
accumulation of 16:2 and 18:2 (linoleic) acids. The increase of membrane fluidity
brought about by this change in unsaturation was measured. The production of
polyunsaturated fatty acids in yeast cells and the concomitant increase in
membrane fluidity was correlated with a modest increase in growth rate at low
temperature and with increased resistance to ethanol and oxidative stress.
PMID- 10775430
TI - Metabolism of monoepoxides of methyl linoleate: bioactivation and detoxification.
AB - Leukotoxin (ltx) and isoleukotoxin (iltx) methyl esters, are metabolites of
methyl linoleic acid, an essential fatty acid. They have been associated with
acute respiratory distress syndrome. The observed toxicity of ltx and iltx is, in
fact, due to the metabolism of the epoxides to their corresponding diols by
soluble epoxide hydrolase (sEH). Herein, we demonstrate that ltx/iltx are toxic
in a time-dependent manner to human sEH expressing cells with a LT(50) of 10.6 +/
0.8 h and that ltx and iltx have K(M) of 6.15 +/- 1.0 and 5. 17 +/- 0.56 microM,
respectively, and V(max) of 2.67 +/- 0.04 and 1. 86 +/- 0.06 micromol/min/mg,
respectively, which can be inhibited by sEH inhibitors. We show that four major
metabolites of ltx/iltx are formed in our system, including ltx/iltx free acid,
ltxd/iltxd, free acid, and phosphotidylcholine and phosphotidylethanolamine
containing the carboxylic acid forms of both ltx/iltx and ltxd/iltxd, but that
the only metabolite associated with toxicity is the carboxylic acid form of
ltxd/iltxd, suggesting the involvement of cellular esterases. We demonstrate that
a serine esterase inhibitor provides some protection from the toxicity of epoxy
fatty esters to sEH expressing cells as do intercellular free sulfhydryls, but
that this protection is not due to glutathione conjugation. With these data, we
have proposed an extension of the metabolic pathway for ltx/iltx in eukaryotic
cells.
PMID- 10775431
TI - Selenoprotein P: properties, functions, and regulation.
AB - Selenoprotein P (SeP) is a plasma protein which contains 10 selenocysteine
residues per polypeptide. It accounts for more than 50% of the selenium content
in rat and human plasma but its function is still not completely understood.
However, a function as an extracellular antioxidant seems most probable. A
protective function of SeP in human plasma against the potent endotoxin
peroxynitrite and phospholipid hydroperoxide reducing activity was demonstrated
in vitro. An association of SeP with the vascular endothelium, a prime target of
peroxynitrite toxicity, was shown in vivo. SeP of bovine serum acts as a survival
promoting factor in neuronal cell culture. Analysis of the human SeP promoter
indicates a transcriptional regulation of SeP by inflammatory mediators.
PMID- 10775432
TI - N-(cyclohexanecarboxyl)-O-phospho-l-serine, a minimal substrate for the dual
specificity protein phosphatase IphP.
AB - Three dual-specific phosphatases [DSPs], IphP, VHR, and Cdc14, and three protein
tyrosine phosphatases [PTPs], PTP-1B, PTP-H1, and Tc-PTPa, were challenged with a
set of low molecular weight phosphoesters to probe the factors underlying the
distinct substrate specificities displayed by these two mechanistically
homologous families of protein phosphatases. It was observed that beta-naphthyl
phosphate represented an excellent general substrate for both PTPs and DSPs.
While DSPs tended to hydrolyze alpha-naphthyl phosphate at rates comparable to
that of the beta-isomer, the PTPs PTP-1B and Tc-PTPa did not. PTP-H1, however,
displayed high alpha-naphthyl phosphatase activity. Intriguingly, PTP-H1 also
displayed much higher protein-serine phosphatase activity in vitro, 0.2-0.3% that
toward equivalent tyrosine phosphorylated proteins, than did PTP-1B or Tc-PTPa.
The latter two PTPs discriminated between the serine- and tyrosine-phosphorylated
forms of two test proteins by factors of >/=10(4)-10(6). While free phosphoserine
represented an extremely poor substrate for all of the DSPs examined, the
addition of a hydrophobic "handle" to form N-(cyclohexanecarboxyl)-O-phospho-l
serine produced a compound that was hydrolyzed by IphP with high efficiency,
i.e., at a rate comparable to that of free phosphotyrosine or p-nitrophenyl
phosphate. VHR also hydrolyzed N-(cyclohexanecarboxyl)-O-phospho-l-serine (1 mM)
at a rate approximately one-tenth that of beta-naphthyl phosphate. None of the
PTPs tested exhibited significant activity against this compound. However, N
(cyclohexanecarboxyl)-O-phospho-l-serine did not prove to be a universal
substrate for DSPs as Cdc14 displayed little propensity to hydrolyze it.
PMID- 10775433
TI - Redox cycling of 2-(x'-mono, -di, -trichlorophenyl)- 1, 4-benzoquinones,
oxidation products of polychlorinated biphenyls.
AB - Polychlorinated biphenyl (PCB) preparations are complete liver carcinogens in
rodents and efficacious promoters in two-stage hepatocarcinogenesis. Cytochrome
P450 isozymes catalyze the oxidation of PCBs to mono- and dihydroxy metabolites.
The potential for further enzymatic or nonenzymatic oxidation of ortho- and para
dihydroxy PCB metabolites to (semi)quinones raises the possibility that redox
cycling involving reactive oxygen species may be involved in PCB toxicity. Seven
synthetic 2-(x'-chlorophenyl)-1, 4-benzoquinones (containing one to three
chlorines) were investigated for their participation in oxidation-reduction
reactions by following the oxidation of NADPH. These observations were made: (i)
NADPH alone directly reduced all quinones but only 2-(2'-chlorophenyl)- and 2-(4'
chlorophenyl)-1,4-benzoquinone supported NADPH consumption beyond that required
to quantitatively reduce the quinone. (ii) For all quinones, superoxide dismutase
increased NADPH oxidation in excess of the amount of quinone, demonstrating the
participation of the superoxide radical. (iii) The presence of microsomal enzymes
from rat liver increased the rate of NADPH consumption, but only 2-(2'
chlorophenyl)- and 2-(4'-chlorophenyl)-1,4-benzoquinone autoxidized. (iv) The
combination of superoxide dismutase with microsomal enzymes accelerated
autoxidation from 1.6- to 6.8-fold higher than that found in the absence of
microsomal protein. These data support the concept that in the absence of
microsomal protein, there occurs a two-electron reduction of the quinone by NADPH
to the corresponding hydroquinone that comproportionates with the large reservoir
of quinone to initiate autoxidation. In the presence of microsomes, enzymatic one
electron reduction generates a semiquinone radical whose autoxidation with oxygen
propagates the redox cycle. These results show the potential of some 2-(x'
chlorophenyl)-1, 4-benzoquinones to initiate the wasteful loss of NADPH.
PMID- 10775434
TI - Plant natriuretic peptide immunoreactants modulate plasma-membrane H(+) gradients
in Solanum tuberosum L. leaf tissue vesicles.
PMID- 10775435
TI - The human OGG1 gene: structure, functions, and its implication in the process of
carcinogenesis.
AB - A particularly important stress for all cells is the one produced by reactive
oxygen species (ROS) that are formed as byproducts of cell metabolism. Among DNA
damages induced by ROS, 8-hydroxyguanine (8-OH-G) is certainly the product that
has retained most of the attention in the past few years. The biological
relevance of 8-OH-G in DNA has been unveiled by the study of Escherichia coli and
Saccharomyces cerevisiae genes involved in the neutralization of the mutagenic
effects of 8-OH-G. These genes, fpg and mutY for E. coli and OGG1 for yeast, code
for DNA glycosylases. Inactivation of any of those genes leads to a spontaneous
mutator phenotype, characterized by the increase in GC to TA transversions. In
yeast, the OGG1 gene encodes a DNA glycosylase/AP lyase that excises 8-OH-G from
DNA. In human cells, the OGG1 gene is localized on chromosome 3p25 and encodes
two forms of hOgg1 protein which result from an alternative splicing of a single
messenger RNA. The alpha-hOgg1 protein has a nuclear localization whereas the
beta-hOgg1 is targeted to the mitochondrion. Biochemical studies on the alpha
hOgg1 protein show that it is a DNA glycosylase/AP lyase that excises 8-OH-G and
Fapy-G from gamma-irradiated DNA. Several approaches have been used to study the
biological role of OGG1 in mammalian cells, ranging from its overexpression in
cell lines to the generation of homozygous ogg1-/- null mice. Furthermore, to
explore a possible role in the prevention of cancer, the cDNA coding for alpha
hOgg1 has been sequenced in human tumors. All these results point to 8-OH-G as an
endogenous source of mutations in eukaryotes and to its likely involvement in the
process of carcinogenesis. A review of the recent literature on the mammalian
Ogg1 proteins, the main repair system involved in the elimination of this
mutagenic lesion, is presented.
PMID- 10775436
TI - p-Cresol sulfate is the dominant component of urinary myelin basic protein like
material.
AB - Multiple sclerosis (MS) is clinically heterogeneous and has an uncertain natural
history. A high priority for more effective treatment of MS is an objective and
feasible laboratory test for predicting the disease's course and response to
treatments. Urinary myelin basic protein (MBP)-like material (MBPLM), so
designated because it is immunoreactive as a cryptic epitope in peptide 83-89 of
the human MBP molecule of 170 amino acids, is present in normal adults, remains
normal in relapsing-remitting, but increases in progressive MS. In the present
investigation, MBPLM was purified from urine and characterized. p-Cresol sulfate
is the major component of urinary MBPLM. This conclusion is based on the
following: (1) MBPLM and p-cresol sulfate both have a mass of 187 on negative
scans by electrospray ionization mass spectrometry, the same fragments on tandem
mass spectrometry of 80 (SO(-)(3)) and 107 (methylphenol), and similar profiles
on multiple reaction monitoring; (2) (1)H and (13)C nuclear magnetic resonance
spectroscopy revealed identical spectra for MBPLM and p-cresol sulfate; (3)
purified p-cresol sulfate reacted in parallel with MBP peptide 83-89 in the same
radioimmunoassay for MBPLM; and (4) p-cresol sulfate has the same behavior on
preparative HPLC columns as urinary MBPLM. The unexpected immunochemical
degeneracy permitting a cross-reaction between p-cresol sulfate and a peptide of
an encephalitogenic myelin protein is postulated to be based on shared
conformational features. The mechanisms by which urinary p-cresol sulfate,
possibly derived from tyrosine-SO(4), reflects progressive worsening that is
disabling in MS are unknown.
PMID- 10775437
TI - Characterization of a structural model of membrane bound cytochrome c-550 from
Bacillus subtilis.
AB - A structural model of Bacillus subtilis cytochrome c-550 has been built based
upon hydropathy analysis, sequence alignment, homology modeling, and energy
minimization. The model has a single transmembrane alpha-helix and a water
soluble domain folded around covalently attached heme C. Physical measurements on
purified, recombinant cytochrome c-550 have been made to test aspects of the
model. Excitation at either 280 or 295 nm yields fluorescence with an emission
maximum at 334 nm and a quantum yield of 25% relative to n-acetyltryptophanamide.
The model places one (i.e., W115) of the two tryptophans of cytochrome c-550 in
the heme domain and the second (i.e., W3) in the transmembrane domain. The indole
ring of W115 is within 5 A of the heme macrocycle and is expected to be highly
quenched via resonance energy transfer to the heme. In contrast, W3 is at the
start of the putative transmembrane helix and could be located a considerable
distance from the heme. Forster theory assigns a distance of 42 A from W3 to the
heme. This distance is important in adjusting the relative positions of the
membrane-spanning and heme-binding domains. Circular dichroism measurements in
the ultraviolet region indicate increased alpha-helical content of B. subtilis
cytochrome c compared to mitochondrial cytochrome c in support of an alpha
helical transmembrane domain. The ionic strength dependence of redox kinetics for
cytochrome c-550 indicates an overall negative charge that is consistent with a
calculated pI of 5.4. However, the charge distribution specified by the model
indicates a surface for electron exchange that is different from the classical
front face used by mitochondrial cytochrome c.
PMID- 10775438
TI - A four-way junction with triple-helical arms: design, characterization, and
stability.
AB - The formation of the four-way junction containing four triple-helical arms has
been demonstrated using chemical methods (polyacrylamide gel electrophoresis and
chemical footprinting using OsO(4) as a probe) and physical methods (UV
absorbance melting and DSC). The junction J(T1T3) was assembled from two 20-mer
purine strands and two 44-mer pyrimidine strands. To determine the contribution
of the different arms to the stability of the complete structure of J(T1T3), the
junction was compared to two simplified substructures, J(T1) and J(T3),
respectively. Common to these complexes is the underlying double-helical four-way
junction Js. Addition of Na(+) had a profound effect on stabilizing and
subsequently folding the junctions into the stacked X-structures. The following
results support the structure present: (i) The native polyacrylamide
electrophoresis exhibits only a single band(s) corresponding to one species
present when all four single strands are mixed in equal amounts. (ii) OsO(4)
modifications were investigated at pH 5.0 and in the presence of 10 mM Mg(2+) and
100 mM Na(+). There is no cleavage of thymine residues at the branch point and
throughout the structure. (iii) The thermal unfolding of J(T1) and J(T3)
illustrates that the triple-helical arms are more stable than the double-helical
arms which are contained in these junctions and that J(T1T3) with four triple
helical arms is slightly more stable than J(T1) and J(T3). (iv) The calorimetric
transition enthalpies determined for the arms of J(T1T3) are comparable to those
associated with the unfolding of its corresponding arms in J(T1) and J(T3). The
results also illustrate that the formation of the junctions is not restricted by
the pH, [Na(+)], sequence composition of the arms, and/or the loop position.
PMID- 10775439
TI - Electrochemical reduction of flavocytochromes 2B4 and 1A2 and their catalytic
activity.
AB - The present study shows that cytochromes P450 2B4 and 1A2 with a covalently
attached riboflavin (semisynthetic flavocytochromes RfP450 2B4 and RfP450 1A2)
can be reduced electrochemically on rhodium-graphite electrodes at a potential of
-500 mV (vs Ag/AgCl). In the presence of substrates such as aminopyrine, aniline,
7-ethoxyresorufin, and 7-pentoxyresorufin, N-demethylation, p-hydroxylation, and
O-dealkylation reactions proceeded, as was confirmed by product analysis. Rates
of electrocatalytically driven reactions are comparable to those obtained using
NAD(P)H as the source of reducing equivalents. These results suggest the
practicality of developing flavocytochrome P450s as catalysts for oxidation
reactions with different classes of organic substrates.
PMID- 10775440
TI - Kinetics of methionine transport and metabolism by Trypanosoma brucei brucei and
Trypanosoma brucei rhodesiense.
AB - Methionine is an essential amino acid for both prokaryotic and eukaryotic
organisms; however, little is known concerning its utilization in African
trypanosomes, protozoa of the Trypanosoma brucei group. This study explored the
Michaelis-Menten kinetic constants for transport and pool formation as well as
metabolic utilization of methionine by two divergent strains of African
trypanosomes, Trypanosoma brucei brucei (a veterinary pathogen), highly sensitive
to trypanocidal agents, and Trypanosoma brucei rhodesiense (a human pathogenic
isolate), highly refractory to trypanocidal arsenicals. The Michaelis-Menten
constants derived by Hanes-Woolf analysis for transport of methionine for T. b.
brucei and T. b. rhodesiense, respectively, were as follows: K(M) values, 1. 15
and 1.75 mM; V(max) values, 3.97 x 10(-5) and 4.86 x 10(-5) mol/L/min. Very
similar values were obtained by Lineweaver-Burk analysis (K(M), 0.25 and 1.0 mM;
V(max), 1 x 10(-5) and 2.0 x 10(-5) mol/L/min, T. b. brucei and T. b.
rhodesiense, respectively). Cooperativity analyses by Hill (log-log) plot gave
Hill coefficients (n) of 6 and 2 for T. b. brucei and T. b. rhodesiense,
respectively. Cytosolic accumulation of methionine after 10-min incubation with
25 mM exogenous methionine was 1.8-fold greater in T. b. rhodesiense than T. b.
brucei (2.1 vs 1.1 mM, respectively). In African trypanosomes as in their
mammalian host, S-adenosylmethionine (AdoMet) is the major product of methionine
metabolism. Accumulation of AdoMet was measured by HPLC analysis of cytosolic
extracts incubated in the presence of increasing cytosolic methionine. In
trypanosomes incubated for 10 min with saturating methionine, both organisms
accumulated similar amounts of AdoMet (approximately 23 microM), but the level of
trans-sulfuration products (cystathionine and cysteine) in T. b. rhodesiense was
double that of T. b. brucei. Methionine incorporation during protein synthesis in
T. b. brucei was 2.5 times that of T. b. rhodesiense. These results further
confirm our belief that the major pathways of methionine utilization, for
polyamine synthesis, protein transmethylation and the trans-sulfuration pathway,
are excellent targets for chemotherapeutic intervention against African
trypanosomes.
PMID- 10775441
TI - Characterization of the responsive elements to hormones in the rat aldolase B
gene.
AB - Transcription of the aldolase B gene, AldB, in the liver is regulated by hormones
such as insulin and glucagon. To characterize the elements that are responsive to
these hormones in the upstream region of AldB, plasmids carrying various length
of the upstream region of this gene were constructed and transfected to primary
cultured rat hepatocytes. The promoter activities were gradually increased by
progressive deletion of the 5'-upstream region, and high activities were observed
for constructs carrying the sequence between -408 and -85 bp, suggesting the
presence of suppressive element(s) in the upstream region of -409 bp. The
transcription activities of the mutants containing the sequences between -228 and
-85 bp were enhanced by insulin, and glucagon suppressed the transcription
activities of those containing the sequence between -764 and -85 bp. Two sequence
elements similar to the cAMP-responsive element (CRE), one from -89 to -82 bp and
another from +13 to +20 bp, were found in the upstream sequence of the gene. The
latter element is not functional because its deletion did not affect either the
transcription efficiency or glucagon response. However, the deletion of the
former element diminished both functions. A gel retardation assay showed that the
nuclear factor binds to the former element, which was competitive with authentic
CRE oligonucleotide but not with the mutant CRE one. These results suggest that
the CRE-like element in the promoter region is prerequisite for both fundamental
transcription efficiency of the gene and suppression by glucagon in hepatocytes.
PMID- 10775442
TI - Differential impairment of 20S and 26S proteasome activities in human
hematopoietic K562 cells during oxidative stress.
AB - The 20S proteasome and the 26S proteasome are major components of the cytosolic
and nuclear proteasomal proteolytic systems. Since proteins are known to be
highly susceptible targets for reactive oxygen species, the effect of H(2)O(2)
treatment of K562 human hematopoietic cells toward the activities of 20S and 26S
proteasomes was investigated. While the ATP-independent degradation of the
fluorogenic peptide suc-LLVY-MCA was not affected by H(2)O(2) concentrations of
up to 5 mM, the ATP-stimulated degradation of suc-LLVY-MCA by the 26S proteasome
began to decline at 400 microM and was completely abolished at 1 mM oxidant
treatment. A combination of nondenaturing electrophoresis and Western blotting
let us believe that the high oxidant susceptibility of the 26S proteasome is due
to oxidation of essential amino acids in the proteasome activator PA 700 which
mediates the ATP-dependent proteolysis of the 26S-proteasome. The activity of the
26S-proteasome could be recovered within 24 h after exposure of cells to 1 mM
H(2)O(2) but not after 2 mM H(2)O(2). In view of the specific functions of the
26S proteasome in cell cycle control and other important physiological functions,
the consequences of the higher susceptibility of this protease toward oxidative
stress needs to be considered.
PMID- 10775443
TI - Interaction of Ap1, Ap2, and Sp1 with the regulatory regions of the human pro
alpha1(I) collagen gene.
AB - In the pro-alpha1(I) collagen gene a number of cis-regulatory elements, which
interact with a variety of trans-acting factors, are present in the promoter and
first intron. We have undertaken a comprehensive study of Sp1, Ap1, and Ap2
binding in the region spanning -442 to +1697 nt. DNase I footprinting analysis
revealed these factors bind with varying affinities to some of the potential
sites: Sp1 binds to 16 of 34 potential sites, Ap2 binds to 22 of 40 potential
binding sites, and Ap1 binds to its only potential site. The Sp1 sites were
mostly clustered in the intron region, while the Ap2 sites were clustered in the
promoter region. Transmission electron microscopic analysis of DNA-protein
complexes not only confirmed these results, but also clearly showed that
heterologous and/or homologous protein-protein interactions between Sp1 and/or
Ap2 bring the promoter and intron in contact with each other, with the resulting
looping out of the intervening DNA. This strongly suggests that the DNA-looping
model is an explanation for the orientation preference of the enhancing element
in the first intron as these interactions possibly create an optimum environment
for the binding of the rest of the transcriptional machinery.
PMID- 10775444
TI - Determination of a cAMP-dependent protein kinase phosphorylation site in the C
terminal region of human endothelial actin-binding protein.
AB - Three different C-terminal regions of human endothelial actin-binding protein-280
(ABP-280 or ABP; nonmuscle filamin) were subcloned and efficiently expressed in
the Escherichia coli BL21 (DE3) system as indicated by sodium dodecyl sulfate
polyacrylamide gel electrophoresis. As predicted by the aminoacid sequence one of
the fragments, a 109-kDa peptide (residues 1671-2647), contained a calpain
cleavage site and two potential cAMP-dependent protein kinase (PKA)
phosphorylation sites (serine 2152 and threonine 2336). A second fragment, a 74
kDa peptide (residues 1671-2331), contained a calpain cleavage site and one of
the three presumptive PKA phosphorylation sites (serine 2152). The third
fragment, a 48-kDa peptide (residues 2223-2647), contained only one of the PKA
sites (threonine 2336). Phosphorylation of these truncated peptides indicated
that only the fragments containing serine 2152 incorporated phosphate after PKA
treatment. Site-directed mutagenesis analysis confirmed that serine 2152 is the
unique substrate for PKA in the C-terminal region of ABP. The functional
significance of phosphorylation of this residue, which belongs to a serine
proline motif, is discussed.
PMID- 10775446
TI - Comparison of mono- and dichlorinated tyrosines with carbonyls for detection of
hypochlorous acid modified proteins.
AB - Hypochlorous acid is a potent oxidant capable of oxidizing and chlorinating
proteins. Based on its indiscriminant reactivity, it is proposed to play a major
role in tissue damage associated with a range of inflammatory diseases. We have
determined the relative tendencies for formation of protein carbonyls,
chlorinated tyrosine residues, and epitopes recognized by an antibody raised
against hypochlorous acid oxidized protein (HOP-1) when albumin is treated with
hypochlorous acid. We have also tested the specificity of the HOP-1 antibody by
measuring how effectively it recognizes proteins oxidized by hypobromous acid. 3
Chlorotyrosine, along with a new marker of hypochlorous acid dependent protein
modification, 3, 5-dichlorotyrosine, was formed at the lowest doses of
hypochlorous acid that were capable of generating protein carbonyls.
Comparatively high doses of hypochlorous acid were needed to generate epitopes
recognized by HOP-1, which were also produced by hypobromous acid. Our study
demonstrates that it is advantageous to measure protein carbonyls and HOP-1
epitopes in conjunction with chlorinated tyrosines when attempting to identify
the oxidants responsible for inflammatory tissue damage.
PMID- 10775445
TI - Activation of m3 muscarinic receptors induces rapid tyrosine phosphorylation of
p125(FAK), p130(cas), and paxillin in rat pancreatic acini.
AB - Tyrosine phosphorylation plays a key role in transmembrane and cytoplasmic signal
transduction mechanisms stimulated by oncogenes, integrins, growth factors,
neuropeptides, and bioactive lipids. Moreover, recent studies show that
stimulation of odd-numbered muscarinic receptors increases the tyrosine
phosphorylation of several proteins in different cellular types. The present
study was aimed at examining whether activation of m3 muscarinic receptors in rat
pancreatic acini evokes tyrosine phosphorylation of p125(FAK), and its
substrates, p130(cas) and paxillin. Results show that stimulation of pancreatic
acini with carbachol resulted in a rapid and transient increase in tyrosine
phosphorylation of p125(FAK), p130(cas), and paxillin. Tyrosine phosphorylation
of these proteins occurred in a time- and concentration-dependent manner.
Simultaneous blockage of both PKC activation and increases in [Ca(2+)](i)
partially decreased p125(FAK), p130(cas), and paxillin tyrosine phosphorylation
stimulated by carbachol. Pretreatment of pancreatic acini with Clostridium
botulinum C3 transferase, which specifically inactivates p21(rho), partially
inhibited carbachol-induced p125(FAK), p130(cas), and paxillin tyrosine
phosphorylation. In contrast, this treatment had no effect on amylase release
stimulated by carbachol. Cytochalasin D, which disrupts actin microfilaments
network, completely inhibited carbachol stimulated tyrosine phosphorylation of
these proteins without having significant effects in carbachol-stimulated amylase
secretion. These results dissociate tyrosine phosphorylation of p125(FAK),
p130(cas), and paxillin from amylase secretion after m3 muscarinic receptors
occupation in rat pancreatic acini. Taken together, these data suggest that (a)
activation of m3 muscarinic receptors in rat pancreatic acini increases tyrosine
phosphorylation of p125(FAK) and its substrates, p130(cas) and paxillin by
diacylglycerol-activated PKC- and calcium- dependent, and independent pathways,
(b) these responses require activation of p21(rho) and an intact actin
cytoskeleton, and (c) p125(FAK), p130(cas), and paxillin are unlikely related to
secretion in rat pancreatic acinar cells.
PMID- 10775448
TI - Tight binding of pyridoxal 5'-phosphate to recombinant Escherichia coli
pyridoxine 5'-phosphate oxidase.
AB - Escherichia coli pyridoxine (pyridoxamine) 5'-phosphate oxidase (PNPOx) catalyzes
the oxidation of pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate to
pyridoxal 5'-phosphate (PLP) using flavin mononucleotide (FMN) as the immediate
electron acceptor and oxygen as the ultimate electron acceptor. This reaction
serves as the terminal step in the de novo biosynthesis of PLP in E. coli.
Removal of FMN from the holoenzyme results in a catalytically inactive apoenzyme.
PLP molecules bind tightly to both apo- and holoPNPOx with a stoichiometry of one
PLP per monomer. The unique spectral property of apoPNPOx-bound PLP suggests a
non-Schiff base linkage. HoloPNPOx with tightly bound PLP shows normal catalytic
activity, suggesting that the tightly bound PLP is at a noncatalytic site. The
tightly bound PLP is readily transferred to aposerine hydroxymethyltransferase in
dilute phosphate buffer. However, when the PNPOx. PLP complex was added to
aposerine hydroxymethyltransferase suspended in an E. coli extract the rate of
reactivation of the apoenzyme was several-fold faster than when free PLP was
added. This suggests that PNPOx somehow targets PLP to aposerine
hydroxymethyltransferase in vivo.
PMID- 10775447
TI - N-Hydroxyguanidine compound 1-(3,4-dimethoxy- 2-chlorobenzylideneamino)-3
hydroxyguanidine inhibits the xanthine oxidase mediated generation of superoxide
radical.
AB - We here show that the novel N-hydroxyguanidine derivative PR5 (1-(3, 4-dimethoxy
2-chlorobenzylideneamino)-3-hydroxyguanidine) is acting as an alternative
electron acceptor in xanthine oxidase catalyzed oxidation of xanthine. The
reduction product is the corresponding guanidine derivative 1-(3, 4-dimethoxy-2
chlorobenzylideneamino)guanidine (PR9). The reaction occurs under both anaerobic
and aerobic conditions. Moreover, EPR measurements show that the action of PR5 is
associated with the inhibition of superoxide radical formation seen under aerobic
conditions. PR5 also supports xanthine oxidase catalyzed anaerobic oxidation of
NADH. Kinetic studies indicate that increasing xanthine concentration
significantly increases the apparent K(m) of PR5, but it remains unaltered by
changing NADH concentration. Moreover, the molybdenum center inhibitor
allopurinol inhibits the PR5-sustained oxidation of xanthine and NADH equally
well, whereas the flavin adenine dinucleotide site inhibitor diphenyliodonium
(DPI) markedly inhibits only the PR5-sustained oxidation of NADH. We suggest that
PR5 binds and becomes reduced at the molybdenum center of the xanthine oxidase.
We also found that both PR5 and its reduction product PR9 can inhibit the oxygen
sustained xanthine oxidase reaction. The properties of PR5 suggest that it is a
member of a novel class of compounds which we have termed xanthine oxidase
electron acceptor-inhibitor drugs. The potential use of xanthine oxidase electron
acceptor-inhibitors in the prevention of free radical mediated tissue damage in
organ ischemia-reperfusion diseases is discussed.
PMID- 10775449
TI - N-Bromoacetylethanolamine phosphate as a probe for the identification of a liver
microsomal glucose-6-phosphate transporter peptide in rats and Ehrlich ascites
tumor-bearing mice.
AB - Hepatic microsomal glucose-6-phosphatase is a multicomponent system composed of
substrate/product translocases and a catalytic subunit. Previously we (Foster et
al. (1996) Biochim. Biophys. Acta 12, 244-254) demonstrated that N
bromoacetylethanolamine phosphate (BAEP) is a time-dependent, irreversible
inhibitor of glucose-6-phosphate hydrolysis in intact but not disrupted
microsomes. We proposed that BAEP manifests its inhibitory effect by binding with
a glucose-6-phosphate translocase protein of the glucose-6-phosphatase system.
Here we provide additional evidence that BAEP inhibits glucose-6-phosphate
transport in microsomal vesicles and utilize [(32)P]BAEP as an affinity label in
the identification of a glucose-6-phosphate transport protein. In this study, we
identify 51-kDa rat and mouse liver microsomal proteins involved in glucose-6
phosphate transport into and out of microsomal vesicles by utilizing (1) an
Ehrlich ascites tumor-bearing mouse model, which displays a decreased sensitivity
to the time-dependent inhibitory effect of BAEP, and (2) another glucose-6
phosphate translocase inhibitor, tosyl-lysine chloromethyl ketone, in conjunction
with [(32)P]BAEP as an affinity label.
PMID- 10775450
TI - Initiation of rapid, P53-dependent growth arrest in cultured human skin
fibroblasts by reactive chlorine species.
AB - Oxidants produced by neutrophils have been implicated in causing cancers
associated with chronic inflammation. Hypochlorous acid is the most potent
oxidant produced by these cells in appreciable amounts. It reacts with amines to
form chloramines, which are weaker oxidants but are mutagenic. Recently, we
showed that sublethal doses of hypochlorous acid increased levels of the
transcription factor protein 53 (p53) and the wild-type activating fragment
1/cyclin-dependent kinase inhibitory protein-1 (WAF1/CIP1) in cultured human skin
fibroblasts. WAF1/CIP1 is an important intermediate in the pathway leading to
growth arrest. We now show that low doses of hypochlorous acid and physiological
chloramines lead to an inhibition of both DNA synthesis and division of cultured
human skin fibroblasts. Inhibition of DNA synthesis occurred within 1 h of
hypochlorous acid treatment, was maintained for 24 h, and returned to a normal
rate after 48 h. Cell division was inhibited by hypochlorous acid and chloramines
for 48 h and returned to normal 72 h after treatment. Growth arrest was dependent
on p53 because it was blocked when cells were transfected with a p53-binding
oligonucleotide. We propose that reactive chlorine species will initiate
WAF1/CIP1-dependent growth arrest that will counteract their mutagenic effects
and minimize the possibility of the malignant transformation of cells surrounding
sites of inflammation.
PMID- 10775451
TI - Specificity and mechanism analysis of hepatitis C virus RNA-dependent RNA
polymerase.
AB - The RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene
has been expressed as a nonfusion protein in bacterial cells and purified to
homogeneity using sequential chromatographic columns. The purified NS5B protein
exhibited RNA-dependent RNA polymerase activity using poly(A) template and the
K(m) and V(max) were determined as 8.4 microM and 1976 pmol/mg-min, respectively.
This full-length NS5B protein exhibited much stronger binding affinity toward the
30-mer poly(G) than other homopolymeric RNAs of the same size. For the first
time, we demonstrate that the HCV NS5B was able to bind various ribonucleotides.
Using a panel of oligonucleotides varying in length, we studied the NS5B
catalytic efficiency and proposed the size of the NS5B active site to be 8-10
nucleotides. The multifunctional nature of NS5B protein is also discussed and
compared with other viral RNA polymerases.
PMID- 10775452
TI - In vivo upregulation of interleukin-4 is one mechanism underlying the
immunoregulatory effects of 1,25-dihydroxyvitamin D(3).
AB - The active form of vitamin D (1,25-(OH)(2)D(3)) is a potent immune system
regulator. In vivo the oral administration of 1, 25-(OH)(2)D(3) completely
prevents experimental autoimmune encephalomyelitis (EAE), significantly prolongs
allograft survival, and prevents collagen-induced arthritis. 1,25-(OH)(2)D(3)
given to mice increased IL-4 protein and transcript levels. We have now tested
the efficacy of 1,25-(OH)(2)D(3) on EAE development and allograft survival in IL
4-deficient [knockout (ko)] mice. 1, 25-(OH)(2)D(3) was found to be much less
effective in the absence of IL-4, suggesting that IL-4 production is a
significant factor in the action of 1,25-(OH)(2)D(3) on the immune system.
PMID- 10775453
TI - A low molecular weight factor from dividing cells activates phospholipase D in
caveolin-enriched membrane microdomains.
AB - Phospholipase D (PLD) activity is elevated in Ras-transformed NIH 3T3 cells. This
difference in PLD activity between Ras-transformed and nontransformed parental
cells disappeared in isolated membranes from these cells. In reconstitution
experiments, heat-denatured cytosolic fractions from Ras-transformed, but not
parental, NIH 3T3 cells elevated PLD activity in isolated membranes. This heat
resistant PLD-stimulating activity from the Ras-transformed cells was sensitive
to proteases and passed through a 1-kDa MW cutoff membrane, suggesting that the
factor is a peptide of less than 10 amino acids. The ability of this PLD
stimulating factor, designated PLD-SF, to elevate PLD activity in isolated
membranes was restricted to the caveolin-enriched light membranes, where many
signaling molecules are localized. PLD-SF was also elevated in v-Src- and v-Raf
transformed cells and in serum-stimulated NIH 3T3 cells. PLD-SF was detected in a
variety of rat tissues but was highest in testes, where a large percentage of
cells are dividing. A similar low molecular weight PLD-stimulating activity was
found in actively dividing, but not stationary yeast, cells. The data here
provide evidence for a highly conserved PLD-stimulating peptide that is elevated
in response to mitogenic stimuli.
PMID- 10775454
TI - Role of the carbonate radical anion in tyrosine nitration and hydroxylation by
peroxynitrite.
AB - Peroxynitrite has been receiving increasing attention as the pathogenic mediator
of nitric oxide cytotoxicity. In most cases, the contribution of peroxynitrite to
diseases has been inferred from detection of 3-nitrotyrosine in injured tissues.
However, presently it is known that other nitric oxide-derived species can also
promote protein nitration. Mechanistic details of protein nitration remain under
discussion even in the case of peroxynitrite, although recent literature data
strongly suggest a free radical mechanism. Here, we confirm the free radical
mechanism of tyrosine modification by peroxynitrite in the presence and in the
absence of the bicarbonate-carbon dioxide pair by analyzing the stable tyrosine
products and the formation of the tyrosyl radical at pH 5.4 and 7.4. Stable
products, 3-nitrotyrosine, 3-hydroxytyrosine, and 3, 3-dityrosine, were
identified by high performance liquid chromatography and UV spectroscopy. The
tyrosyl radical was detected by continuous-flow and spin-trapping electron
paramagnetic resonance (EPR). 3-Hydroxytyrosine was detected at pH 5.4 and its
yield decreased in the presence of the bicarbonate-carbon dioxide pair. In
contrast, the yields of the tyrosyl radical increased in the presence of the
bicarbonate-carbon dioxide pair and correlated with the yields of 3-nitrotyrosine
under all tested experimental conditions. Taken together, the results demonstrate
that the promoting effects of carbon dioxide on peroxynitrite-mediated tyrosine
nitration is due to the selective reactivity of the carbonate radical anion as
compared with that of the hydroxyl radical. Colocalization of 3-hydroxytyrosine
and 3-nitrotyrosine residues in proteins may be useful to discriminate between
peroxynitrite and other nitrating species.
PMID- 10775455
TI - A novel female-specific member of the CYP3A gene subfamily in the mouse liver.
AB - Expression of a female-specific CYP3A in the adult mouse liver was observed on
immunoblotting analysis. To characterize this cytochrome P450, we determined the
primary structure of its cDNA and examined its expression profile. This
cytochrome P450 consisted of 504 amino acids and showed 92, 68, 88, and 69% amino
acid sequence identity with mouse CYP3A11, 3A13, 3A16, and 3A25, respectively,
and was designated as CYP3A41, a new mouse CYP3A gene. In the female liver,
levels of CYP3A41 mRNA expression were comparable to those of CYP3A11, the major
CYP3A enzyme in the adult mouse liver. Expression of CYP3A41 mRNA was detected
immediately after birth in the livers of animals of both sexes, but increased
with age in females, whereas it was gradually reduced in males, resulting in
predominantly female-specific expression in livers. Lesser amounts of CYP3A41
mRNA were detected in the kidneys of female mice, with traces in the stomach,
ovary, and heart of female mice and in the testis of male mice. Gonadectomy and
sex hormone treatment indicated that estradiol and testosterone were able to
induce and suppress the expression of CYP3A41 mRNA in the liver, respectively.
Among the classical CYP3A inducers, dexamethasone, rifampicin, and 3
methylcholanthrene did not affect the level of CYP3A41 mRNA in the liver of
either sex. On the other hand, pregnenolone 16alpha-carbonitrile and
phenobarbital suppressed CYP3A41 level to half that of untreated female mice.
These observations indicated that CYP3A41 is a female-specific CYP3A and one of
the major CYP3A forms in the female mouse liver.
PMID- 10775456
TI - Molecular dynamics simulation and nuclear magnetic resonance studies of the
terminal glucotriose unit found in the oligosaccharide of glycoprotein
precursors.
AB - The trisaccharide alpha-d-Glcp-(1 --> 2)-alpha-d-Glcp-(1 --> 3)-alpha-d-Glcp-OMe,
a model for the terminal glucotriose in Glc(3)Man(9)GlcNAc(2) in glycoprotein
precursors, has been investigated by computer simulations and NMR spectroscopy.
Molecular dynamics simulations were performed for 1 ns in aqueous solution and 20
ns in vacuo using the CHARMM-based force fields PARM22 and CHEAT95. An additional
Monte Carlo simulation with the HSEA force field was also carried out.
Experimental NMR data in water solution was obtained from measurement of long
range (1)H,(13)C heteronuclear trans-glycosidic coupling constants, (3)J(H,C),
using one-dimensional Hadamard spectroscopy. Calculation of the (3)J(H,C) values
from the simulations showed a varying degree of agreement to experimental data.
It could be shown from simulation that the φ torsion angles differed, which
was corroborated by the NMR measurements. Analyses were done of radial
distribution functions and of hydrogen bonds. It was suggested that
intermolecular hydrogen bonds were present, but in contrast to simulation the
results from NMR spectroscopy did not support any major contribution. Hence,
their influence on the conformation of the trisaccharide is rather small.
Comparison of (1)H NMR chemical shifts for the trisaccharide and the glucotriose
in Glc(3)Man(8)GlcNAc revealed high similarity. However, the derived conformation
of the model substance in this work differed at one glycosidic torsion angle
compared to the glucotriose on a large oligosaccharide.
PMID- 10775457
TI - Protein kinase C-stimulated formation of ethanolamine from
phosphatidylethanolamine involves a protein phosphorylation mechanism: negative
regulation by p21 Ras protein.
AB - Mammalian cells express a phospholipase D (PLD)-like enzyme which forms
ethanolamine from phosphatidylethanolamine (PtdEtn) by a protein kinase C-alpha
(PKC-alpha)-activated, presently unknown, mechanism. Now we report that addition
of a PKC-alpha-enriched purified PKC preparation or recombinant PKC-alpha to a
plasma membrane-enriched membrane fraction, isolated from leukemic HL60 cells,
greatly ( approximately 6.5-fold stimulation) enhanced PtdEtn hydrolysis if the
PKC activator phorbol 12-myristate 13-acetate (PMA) and ATP were both present;
this was accompanied by PKC-mediated phosphorylation of several membrane
proteins. The combined effects of PKC-alpha, ATP, and PMA on [(14)C]PtdEtn
hydrolysis were inhibited by GF 109203X (10 microM), an inhibitor of catalytic
activity of PKC. In this membrane fraction, PMA alone also had a smaller (
approximately 3.5-fold) stimulatory effect on PtdEtn hydrolysis which was not
affected by adding ATP or GF 109203X to the membranes. These results suggest that
PMA can stimulate PtdEtn hydrolysis via a PKC-catalyzed phosphorylation mechanism
as well as by a phosphorylation-independent process. Transformation of NIH 3T3
fibroblasts by H-ras reduced the effect of PMA on PtdEtn hydrolysis. Furthermore,
in NIH 3T3 fibroblasts, scrape-loaded Y13-259 anti Ras antibody enhanced PMA
stimulated hydrolysis of PtdEtn. These results suggest that activation of the
PtdEtn-hydrolyzing PLD enzyme by PKC-alpha is inhibited by p21 Ras.
PMID- 10775458
TI - A second dihydroorotate dehydrogenase (Type A) of the human pathogen Enterococcus
faecalis: expression, purification, and steady-state kinetic mechanism.
AB - We report the identification, expression, and characterization of a second
Dihydroorotate dehydrogenase (DHODase A) from the human pathogen Enterococcus
faecalis. The enzyme consists of a polypeptide chain of 322 amino acids that
shares 68% identity with the cognate type A enzyme from the bacterium Lactococcus
lactis. E. faecalis DHODase A catalyzed the oxidation of l-dihydroorotate while
reducing a number of substrates, including fumarate, coenzyme Q(0), and
menadione. The steady-state kinetic mechanism has been determined with menadione
as an oxidizing substrate at pH 7.5. Initial velocity and product inhibition data
suggest that the enzyme follows a two-site nonclassical ping-pong kinetic
mechanism. The absorbance of the active site FMN cofactor is quenched in a
concentration-dependent manner by titration with orotate and barbituric acid, two
competitive inhibitors with respect to dihydroorotate. In contrast, titration of
the enzyme with menadione had no effect on FMN absorbance, consistent with
nonoverlapping binding sites for dihyroorotate and menadione, as suggested from
the kinetic mechanism. The reductive half-reaction has been shown to be only
partially rate limiting, and an attempt to evaluate the slow step in the overall
reaction has been made by simulating orotate production under steady-state
conditions. Our data indicate that the oxidative half-reaction is a rate-limiting
segment, while orotate, most likely, retains significant affinity for the reduced
enzyme, as suggested by the product inhibition pattern.
PMID- 10775459
TI - Suppression of CYP2C11 gene transcription by interleukin-1 mediated by NF-kappaB
binding at the transcription start site.
AB - Inflammatory cytokines cause the down-regulation of multiple cytochrome P450
mRNAs, but the transcriptional mechanisms involved are not known. We investigated
the role of a putative negative NF-kappaB-responsive element, nkappaB-RE1, in the
down-regulation of the CYP2C11 gene in rat hepatocytes. This sequence spans the
transcription start site of CYP2C11, from positions -2 to +8. Electrophoretic
mobility shift assays showed that nuclear extracts from livers of rats treated
with bacterial lipopolysaccharide, or from hepatocytes treated with interleukin
1beta, formed a protein complex with an oligonucleotide probe containing the
nkappaB-RE1, and that this complex contained predominantly the p50 subunit of NF
kappaB. Binding of NF-kappaB to the nkappaB-RE1 probe was of lower affinity than
to a probe containing the prototypic NF-kappaB enhancer of the immunoglobulin
kappa chain gene. Mutations in the 5'-end of the nkappaB-RE1, and to a lesser
extent the 3'-end, reduced the affinity of NF-kappaB for this element.
Introduction of the 5'-mutation into nkappaB-RE1 abolished the response of the
200-CYP2C11-chloramphenicol acetyltransferase reporter construct to interleukin-1
or lipopolysaccharide. We conclude that nkappaB-RE1 is a functional negative
regulatory element that participates in the inflammatory suppression of CYP2C11.
PMID- 10775460
TI - Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase?
AB - The hepatic cytosolic hemoprotein tryptophan 2,3-dioxygenase (TDO) is the rate
limiting enzyme in tryptophan catabolism and thus plays a key role in regulating
the physiological flux of tryptophan into relevant metabolic pathways. The TDO
protein is induced by corticosteroids such as dexamethasone (DEX) and is
stabilized by its prosthetic heme. In rats, acute chemically induced hepatic heme
depletion reduces the functional hepatic TDO levels to 25-30% of basal levels
within 1 h, and this decrease persists beyond 28 h of heme depletion at which
time only 25-30% of the protein is available for heme incorporation. Since this
could stem from impaired de novo synthesis and/or instability of the newly
synthesized apoTDO protein in the absence of heme, we examined the specific role
of heme in these events in a previously validated rat model of acute hepatic heme
depletion triggered by the P450 suicide substrate 3, 5-dicarbethoxy 2,6-dimethyl
4-ethyl-1,4-dihydropyridine. We now show that exogenous heme can reverse the
functional impairment of the enzyme observed during hepatic heme depletion and
fully restore the impaired DEX-mediated induction of the enzyme to normal.
Furthermore, through Northern/slot blot analyses coupled with nuclear run-on
studies, we now document that this heme regulation of TDO is exerted primarily at
the transcriptional level. Immunoblotting analyses also reveal corresponding
changes in the TDO protein, thereby establishing that heme is necessary for DEX
inducible TDO mRNA transcription and subsequent translation. Thus, the TDO gene
may contain heme-regulatory elements in addition to the reported glucocorticoid
responsive elements. Together, these findings suggest that clinically, hepatic
heme deficiency may enhance the tryptophan flux into synthetic (serotonergic)
pathways, not only by depriving prosthetic heme for a functionally competent TDO
hemoprotein, its primary catabolic enzyme, but also by impairing the de novo
synthesis of this enzyme.
PMID- 10775461
TI - Arsenic inhibits NF-kappaB-mediated gene transcription by blocking IkappaB kinase
activity and IkappaBalpha phosphorylation and degradation.
AB - The inflammatory cytokine, TNF-alpha, induces IL-8 gene transcription via a
mechanism involving proteasome-mediated IkappaBalpha degradation and NF-kappaB
activation. Here, we investigated whether arsenic, which has been shown to
inhibit the ubiquitin-proteasome pathway, could inhibit TNF-alpha-mediated
increases in IL-8 expression. Using RT-PCR, we show that the addition of TNF
alpha to human bronchial epithelial (BEAS 2B) or embryonic kidney (HEK293) cells
resulted in increased steady-state levels of IL-8 mRNA. This was preceded by a
rapid decrease in cellular IkappaBalpha levels, as demonstrated by Western
analysis, and an increase in nuclear levels of NF-kappaB, as demonstrated by gel
shift analysis. Further demonstrating the activation of NF-kappaB, TNF-alpha
induced the transcription of a NF-kappaB-dependent reporter gene. Exposing the
cells to 500 microM arsenite, prior to adding TNF-alpha, completely inhibited
IkappaBalpha degradation, NF-kappaB translocation, NF-kappaB-dependent gene
transcription, and transcription of the endogenous gene for IL-8. In comparison
with the proteasome inhibitor MG-132, which does not affect the phosphorylation
and ubiquitination of IkappaBalpha, arsenite inhibited the phosphorylation of
IkappaBalpha. Furthermore, arsenite directly blocked the activity of IKK, the
kinase responsible for IkappaBalpha phosphorylation. These studies demonstrate
that high levels of arsenic may inhibit NF-kappaB-mediated gene transcription by
specifically blocking IKK activity, thereby limiting the phosphorylation and
subsequent degradation of the NF-kappaB inhibitor, IkappaBalpha.
PMID- 10775462
TI - Veterinary institutions - lessons from history?
PMID- 10775463
TI - Hunting for prions in cyprus-important needles in the TSE haystack.
PMID- 10775465
TI - The pathogenesis of ostertagiosis-worm or host-mediated changes?
PMID- 10775464
TI - Adherence and pathogenesis of pasteurella multocida--a sticky problem.
PMID- 10775467
TI - The Brown Animal Sanatory Institution--historical lessons for the present?
AB - This article briefly reviews the history of the Brown Institution (1871-1944), a
remarkable but short-lived and now largely forgotten veterinary centre of
research and clinical practice. As well as providing a broad-based clinical
service for the surrounding area of London, the Brown Institution was also the
home of some of the most distinguished contributors to comparative medicine and
physiology. Many of its aspirations, achievements and difficulties are relevant
and comparable to those faced by the profession today.
PMID- 10775466
TI - Feline infectious pneumonia: a short literature review and a retrospective
immunohistological study on the involvement of Chlamydia spp. and distemper
virus.
AB - A short literature review of feline infectious pneumonia, feline Chlamydia and
Paramyxoviridae is presented. In a retrospective study (from 1987 to 1996) 245
cases of feline pneumonia or conjunctivitis/rhinitis were investigated:
histological diagnoses and aetiologies were compared; all lungs were examined
immunohistologically for the occurrence of chlamydia and of canine distemper
virus (CDV), but neither pathogen could be demonstrated. The results confirm
previous reports indicating that feline chlamydia is not a primarily pulmonary
pathogen and that CDV is not a causative agent of pneumonia in cats as it is in
large felids. The review provides a summary of the known causes and pathology of
infectious pneumonia in cats (in order of frequency), although some remain
aetiologically uncertain. It focuses on chlamydia and distemper virus - a
recognized and as yet unknown cause of feline pneumonia. The role and especially
the frequency of chlamydia as a cause of feline pneumonia are controversial but
distemper virus, known to cause pneumonia in dogs and large felids, has not as
yet been demonstrated in cats. The aims of the retrospective study were to
determine the occurrence of chlamydia in 245 cases of feline pneumonia or
conjunctivitis/rhinitis, and to investigate the presence of CDV in these lungs.
PMID- 10775468
TI - Evidence for a parasite-mediated inhibition of abomasal acid secretion in sheep
infected with Ostertagia leptospicularis.
AB - The acid secretory capacity of the abomasal mucosa was studied in sheep
experimentally infected with Ostertagia leptospicularis. The acidity of the
abomasal contents, permanently recorded by a pH probe located inside the
abomasum, decreased markedly to mean levels between pH 5 and 6. Subcutaneous
administration of histamine or carbachol successfully stimulated acid secretion
(pH 3.4). The results indicate that the abomasal mucosa harboured a population of
functional parietal cells which were also identified immunohistochemically
(H(+)/K(+)-ATPase). Ultrastructural investigation before stimulation revealed
that the majority of these cells was in a resting state. Despite high serum
gastrin levels, the acid secretion was blocked either at the level of the
parietal cell or the enterochromaffin-like cell by an unknown factor, possibly
mediated by the parasites. This is the first report of a parietal cell
dysfunction associated with a nematode infection in the abomasum. It is suggested
that the parasites induce changes in their environment which favour their
survival and/or increase their reproduction.
PMID- 10775469
TI - Blood lactate responses to submaximal field exercise tests in thoroughbred
horses.
AB - The associations between velocity during a standardized, submaximal 800-m
exercise test and blood lactate concentration after exercise were investigated in
Thoroughbred racehorses on sand and grass racetracks. Predicted lactate
concentrations for each horse's exercise test velocity were calculated from the
line of best fit derived from results at each racetrack. The repeatability of the
differences between the measured and predicted blood lactate response to exercise
was also investigated. Exercise tests were conducted at speeds ranging from 12.8
to 16.6 m/s. The variability of velocity within the exercise test was expressed
as the coefficient of variation (CV) of the times for the four 200-m sections.On
the sand track, the coefficient of determination for the lactate-speed
relationship was highest for an exponential regression equation [lactate (mmol/L)
= 0.08e(0.33x)(m/s);r(2)= 0.58, P< 0.05;n = 21]. Similar coefficients of
determination were calculated for linear (r(2)= 0.56) and second order polynomial
equations (r(2)= 0. 57). On the grass racetrack, the relationship was best
described by a second order polynomial equation [lactate (mmol/L) = -0.87x(2)+
28. 17x - 211.41;r(2)= 0.57, P< 0.05;n = 25]. The mean differences between the
measured and predicted blood lactate concentrations in repeated tests were 1.9 +/
1.8 (SD) and 1.8 +/- 1.7 ( SD) on the sand and grass racetracks. There were no
significant associations between the velocity of the exercise and the CV on
either racetrack. Differences between measured and predicted blood lactate
concentrations, based on track-specific lines of best fit, have potential
application in field studies of fitness in Thoroughbred horses.
PMID- 10775470
TI - Intrauterine infusion of PGF(2alpha) at insemination enhances reproductive
performance of sows during the low fertility season.
PMID- 10775471
TI - Immunization with a Streptococcus bovis vaccine administered by different routes
against lactic acidosis in sheep.
AB - Streptococcus bovis is an important lactic acid bacterium in the rumen, which
contributes to the development of lactic acidosis. This study was designed to
test the efficacy of immunization with S. bovis primed either intramuscularly
(i.m.) or intraperitoneally (i.p. ) against lactic acidosis. Forty-five wethers
were allocated to three treatment groups. Two groups were injected with a S.
bovis vaccine by either the i.m. or i.p. route for primary immunization; both
groups were further immunized by the same route(s) (oral and/or i.m.) for
boosters. The third group was not immunized (control). Antibody concentrations
were measured in saliva prior to and following animals being fed a grain diet,
and also in the rumen fluid, before the animals were suddenly introduced to a
grain diet. The average antibody concentration in the animals of the i.m. group
was higher than the i.p. group (P< 0.05). The antibody concentration in the rumen
fluid of immunized sheep was higher than the control animals (P< 0.01). The
difference in the rumen fluid antibody concentration between the i.m. and i.p.
groups was not statistically significant (P> 0.05). In the i.m. group, there was
a significantly greater feed intake, higher rumen pH, lower diarrhoea scores, and
less increase in blood packed cell volume following grain feeding than in the
animals of the control group. The severity of diarrhoea and the increase of blood
packed cell volume in the animals of the i. p. group were also less than in the
animals of the control group. The results suggest that the risk of lactic
acidosis can be reduced by immunization against S. bovis, and that the
immunization primed i. m. is more effective than the immunization primed i.p.
PMID- 10775472
TI - Western blot detection of PrP(Sc)in Cyprus sheep with natural scrapie.
PMID- 10775473
TI - In vitro study of Pasteurella multocida adhesion to trachea, lung and aorta of
rabbits.
AB - In vitro experiments were undertaken to study the adhesion and colonization to
tracheal mucosa, lung and aorta explants from freshly killed rabbits of two
different strains of Pasteurella multocida. Serotype A:3 (capsulated, fimbriae +,
haemagglutination -, dermonecrotic toxin -) isolated from a rabbit with rhinitis,
and serotype D:1 (non-capsulated, fimbriae +, haemagglutination +, dermonecrotic
toxin +) isolated from a dead rabbit with septicaemia, were used. When the
explants were observed under the scanning electron microscope, the type D strain
was highly adherent to trachea and aorta explants compared to the type A strain.
Adhesion to lung explants was best achieved by the type A strain after 45 min
incubation, but after 2 h incubation no significant difference was observed
between the strains. Our data indicate that the presence of fimbriae and the
absence of capsule seem to enhance the adherence of P. multocida type D strain to
tracheal tissue. The capsular material of P. multocida type A strain and the
toxin of the type D strain seem to influence the adherence to lung tissue in
rabbit. Adhesion of strain D to aorta may indicate the expression of receptors on
the endothelium to that strain and may also explain the ability of certain
strains to cause septicaemia.
PMID- 10775474
TI - Developmental competence of frozen-thawed blastocysts from fair-quality bovine
embryos cultured with beta-mercaptoethanol.
AB - Two-hundred-and-thirty-one fair-quality embryos at the compacted morula stage
collected from 89 superovulated cows were cultured in TCM199 or Brinster's BMOC-3
medium with or without 100 microM beta-mercaptoethanol (beta-ME). After 24 h
culture, a total of 142 fair-quality embryos developed to the blastocyst stage,
of which 106 were subsequently frozen with 1.8 M ethylene glycol. The mean cell
number and development rates of frozen-thawed blastocysts from the fair-quality
embryos cultured in TCM199 containing beta-ME were higher than those of the fair
quality embryos directly frozen without culture. The pregnancy rates obtained
with frozen blastocysts from fair-quality embryos tended to be lower than those
of non-cultured fresh fair-quality embryos and cultured fresh blastocysts. These
results indicate that the inclusion of beta-ME in pre-freezing culture media
improve the development of frozen-thawed blastocysts from fair-quality embryos,
but not the pregnancy rate.
PMID- 10775475
TI - Plasma profiles of progesterone and conceptus proteins in cows with spontaneous
embryonic/fetal mortality as diagnosed by ultrasonography.
PMID- 10775476
TI - Application of ultrasonographic examination of the ovine fetus in normal sheep
and those presenting with obstetrical problems.
PMID- 10775477
TI - Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic
injury and heart failure.
AB - Apoptosis is "suicidal" programmed cell death followed by necrosis, i.e. cellular
degradation. This review presents a critical evaluation of the methods used for
detection of apoptosis and on data regarding the role of apoptosis in ischemia
and heart failure. METHODS: DNA laddering by electrophoresis and the TUNEL method
in histology for the final stage of apoptosis, Annexin V labeling, evidence of
caspase activation, cleavage of substrates, measurements of mitochondrial pro
apoptotic and anti-apoptotic factors (Bcl-2, Bax and others) and determination of
the mitochondrial transitional pore potential. Much work has been carried out
regarding the mechanism and the importance of apoptosis in ischemia and heart
failure but many issues still remain unsolved: (1)Time needed for completion of
apoptosis from stimulus to DNA fragmentation? (2)Importance of mitochondrial
pathway considering the fact that cardiomyocytes contain the highest volume
density of mitochondria of all mammalian cells (25% in humans, 37% in mice)?
(3)Means of removal of dead cells, disconnection at the intercalated disc from
neighbouring myocytes, time frame of this process? (4)Reversibility of apoptosis?
(5)Differences between physiological (postnatal differentiation of the conduction
system) v pathological apoptotic cell death? (6)Why do cells, under ischemic
conditions, die by either apoptosis or oncosis? (7)Is apoptosis an epiphenomenon
or a true cause of heart failure? (8)Quantification of the rate of apoptosis in
different pathophysiological situations? Clarification of these unresolved issues
will then allow an estimation of the importance of apoptosis in cardiac
pathophysiology and, if necessary because the role of apoptosis has been
established, the development of new therapeutic concepts.
PMID- 10775478
TI - No involvement of endogenous nitric oxide in classical ischemic preconditioning
in swine.
AB - Endogenous nitric oxide (NO) is involved in the protection by classical ischemic
preconditioning (IP) against ischemia-induced arrhythmias in anesthetized dogs.
Furthermore, NO triggers and mediates protection against infarction and stunning
in delayed IP in conscious rabbits. Up to now it is unclear whether or not
endogenous NO is also involved in the protection against infarction by classical
IP in vivo. In 45 enflurane-anesthetized swine, severe left anterior descending
coronary artery hypoperfusion for 90 min followed by 2 h of reperfusion resulted
in an infarct size (IS, triphenyl tetrazolium chloride-staining) of 20.5+/-5.4%
(S.E.M.) of the area at risk. Inhibition of NO synthase by l -nitro arginine (l
NA, 30 mg/kg i.v.) increased left ventricular (LV) peak pressure from 93+/-3 to
120+/-1 mmHg (P<0.05), but did not alter IS (22.4+/-5. 6%). With aortic
constriction to match the increase in LV peak pressure with l -NA, IS was
unchanged (18.1+/-5.1%). IP by 10 min ischemia and 15 min reperfusion preceding
the 90 min target ischemia reduced IS to 2.0+/-0.8% (P<0.05 v. non-preconditioned
groups). This reduction of IS by IP was not affected by l -NA (1.3+/-0.9%, P<0.05
v. non-preconditioned groups). Area at risk and myocardial blood flow
(microspheres) during ischemia were not different among groups. Relationships
between IS and subendocardial blood flow with l -NA or aortic constriction,
respectively, were not different from that with placebo, but were significantly
shifted downwards by IP with and without l -NA. Thus, endogenous NO does not
alter infarct size development per se and is not involved in the protection
against infarction by classical IP in pigs in vivo.
PMID- 10775479
TI - Length-tension relationships of sub-epicardial and sub-endocardial single
ventricular myocytes from rat and ferret hearts.
AB - In vivo the sub-epicardial myocardium (EPI) and sub-endocardial myocardium (ENDO)
operate over different ranges of sarcomere length (SL). However, it has not been
previously shown whether EPI and ENDO work upon different ranges of the same or
differing length-tension curves. We have compared the SL-tension relationship of
intact, single ventricular EPI and ENDO myocytes from rat and ferret hearts.
Cells were attached to carbon fibres of known compliance in order to stretch them
and to record force at rest (passive tension) and during contractions (active
tension). In both species, ENDO cells were significantly stiffer (i.e. had
steeper SL-passive tension relationships) than EPI cells. Ferret ENDO cells had
significantly steeper SL-active tension relationships than EPI cells; rat cells
tended to behave similarly but no significant regional differences in active
properties were observed. There were no inter-species differences in the active
and passive properties of EPI cells, but ferret ENDO cells displayed
significantly steeper passive and active SL-tension relationships than rat ENDO.
We conclude that in vivo, ferret EPI and ENDO myocytes will function over
different ranges of different SL-tension curves. There is a close relationship
between SL and active tension (the Frank-Starling law of the heart), and our
observations suggest that regional differences in the response to ventricular
dilation will depend on both the change in SL and differing regional slopes of
the SL-active tension curves.
PMID- 10775480
TI - Sarcoplasmic reticulum Ca(2+)ATPase and cell contraction in developing rabbit
heart.
AB - The purpose of the present study was to determine whether age-related changes in
the expression and function of the cardiac isoform of the sarcoplasmic reticulum
Ca(2+)-ATPase (SERCA2a) play a role in SR Ca(2+)release and cell contraction.
SERCA2a protein levels and subcellular localization were compared between fetal,
neonatal, juvenile and adult New Zealand White rabbits. Studies of SERCA function
in isolated myocytes were performed in situ by examining the rate of reloading of
the SR Ca(2+)stores following caffeine-induced depletion. We found that
significant quantities of SERCA2a were present early in immature heart and that
SERCA2a expression reached adult levels within 15-30 days after birth.
Furthermore, SERCA2a protein is present as a series of transverse striations
within the cell as early as 1 day of age. In contrast to previous studies of
SERCA in vitro, the SERCA protein function in situ was found to be comparable
between neonatal and adult myocytes in maintaining SR Ca(2+)stores. These results
indicate that the paucity of SR Ca(2+)release in immature ventricular cardiac
myocytes is not the result of immaturity in SERCA2a expression.
PMID- 10775481
TI - Insulin administered at reoxygenation exerts a cardioprotective effect in
myocytes by a possible anti-apoptotic mechanism.
AB - The metabolic cocktail of glucose-insulin-potassium (GIK) has been shown to
reduce mortality in humans and reduce infarct size in the rat when administered
from the onset of reperfusion following an ischemic insult. The mechanisms
underlying GIK mediated cardioprotection are, however, still unclear. Recent data
implicates insulin "alone" as the major protagonist of cardioprotection when
administered at the time of reperfusion. We have therefore begun to investigate
an insulin activated signalling pathway and the putative role of apoptosis in
this insulin-induced cardioprotection. Simulated ischemia and reoxygenation were
induced in rat neonatal cardiocyte experiments. The administration of insulin
[0.3 mU/ml] at the moment of reoxygenation (Ins(R)) enhanced myocardial cell
viablility as assessed by trypan blue exclusion compared to vehicle alone treated
control myocytes (Ins(R)50+/-2%v controls 70+/-1%, P<0.001). This insulin
mediated cardioprotection was due, in part to a reduction in myocyte apoptosis as
measured by TUNEL (Ins(R)29+/-2%v controls 49+/-3%, P<0.001) and Annexin V
staining (Ins(R)34+/-2%v controls 65+/-3%, P<0.001). These cardioprotective and
anti-apoptotic effects of insulin were completely abolished by the tyrosine
kinase inhibitor lavendustin A and by the phosphatidylinositol 3-kinase (PI3
kinase) inhibitor wortmannin. Thus, we conclude that the early administration of
insulin appears to be an effective modality to reduce reoxgygenation injury in
cardiocytes, in part, via the attenuation of ischemia/reoxygenation-induced
apoptosis. Moreover, the cardioprotective and anti-apoptotic effects of insulin
are mediated via tyrosine kinase and PI3-kinase signalling pathways.
PMID- 10775482
TI - Outside-in signalling of fibronectin stimulates cardiomyocyte hypertrophy in
cultured neonatal rat ventricular myocytes.
AB - Cardiac hypertrophy involves the accumulation of extracellular matrix proteins,
such as fibronectin, leading to increasing myocardial stiffness, ventricular
dysfunction and heart failure. To better understand the possible role of
extracellular matrix-evoked intracellular signalling in ventricular myocytes, we
investigated the effect of fibronectin on myocyte hypertrophic responses using
cell culture models. Cell size in myocytes cultured on fibronectin-coated dishes
was three times larger than that grown on non-coated dishes. However, the number
of cells on fibronectin-coated dishes was not changed throughout the experiment.
Protein synthesis was significantly increased by fibronectin, as were synthesis
of atrial and brain natriuretic peptides. Fibronectin also elicited actin
reorganization, co-localization of beta 1 integrin and vinculin, formation of
focal adhesions and tyrosine phosphorylation of focal adhesion kinase in
myocytes. These fibronectin-mediated effects were inhibited in a dose-dependent
manner by GRGDSP, a competitive antagonist of the fibronectin receptors; GRGDSP
had no effect on cell number or viability. Blocking antibody for beta 1 and beta
3 integrin significantly suppressed fibronectin-induced secretion of natriuretic
peptides. Myocyte hypertrophy was observed in myocyte-nonmyocyte co-culture that
reflects more closely the myocyte environment in vivo. GRGDSP may also suppress
the myocyte hypertrophic response in the co-culture. These findings demonstrate
that the interaction of fibronectin and RGD-dependent integrins is involved in
the hypertrophic responses of myocyte in vitro, and suggest that extracellular
matrix proteins such as fibronectin are not merely passive adhesive molecules but
are active participants in processes leading to myocyte hypertrophy.
PMID- 10775483
TI - Expression of plasma membrane calcium ATPases in phenotypically distinct canine
vascular smooth muscle cells.
AB - Our laboratory has identified at least two types of vascular smooth muscle cells
(VSMCs) that exist in canine arteries and veins: type 1 cells, located in the
media express muscle specific proteins but do not proliferate in culture; and
type 2 cells, located in both media and adventitia, do not express muscle
specific protein but proliferate in culture. Plasma membrane Ca(2+)-ATPases
(PMCAs) have been implicated in proliferation control. The present study examines
the expression of PMCA isoforms and calmodulin-binding domain splice variants in
these two types of canine VSMCs. PMCA protein was found in both type 1 and type 2
cells. Reverse transcriptase-polymerase chain reaction assays were developed for
canine PMCA calmodulin-binding domain splice variants. We cloned and sequenced
isolates corresponding to PMCA1b, 4a and 4b from canine VSMCs. PMCA 2 and 3 were
not detected. Freshly isolated type 1 cells expressed PMCA 1b, 4a and 4b, while
freshly isolated type 2 cells expressed PMCA1b and 4b. Upon placement in culture,
type 2 cells originating from either carotid artery or saphenous vein
demonstrated a time-dependent upregulation of PMCA4a mRNA. Treatment with the
phosphoinositide 3-kinase inhibitor wortmannin produced concentration-dependent
inhibition of both PMCA4a upregulation and [(3)H]thymidine incorporation. These
findings suggest a role for phosphoinositide 3-kinase in regulating PMCA
expression, which may be important in the control of Ca(2+)-sensitive VSMC
functions.
PMID- 10775484
TI - Sensitivity of mechanical and metabolic functions to changes in coronary
perfusion: A metabolic basis of perfusion-contraction coupling.
AB - Experimental evidence indicates a metabolic basis of contraction-perfusion
coupling during an increase in cardiac work load. This study aims to characterize
adjustment of myocardial energy metabolism in response to acute low flow ischemia
(LFI), and to determine its involvement in perfusion-contraction coupling.
Intracellular parameters were measured in isolated rat hearts by NMR spectroscopy
and biochemical methods during 30 min of graded LFI and reperfusion as compared
to continuous perfusion (control). Oxygen pressure was set to reach maximal
oxygen extraction at 70% coronary flow rate (CFR), therefore oxygen limitation
was proportional to coronary underperfusion. At 69, 38 and 10% CFR left
ventricular pressures decreased to 71, 43 and 25% of pre-ischemic values
respectively (P<0.005 v 97% in control) without an increase in diastolic tone,
and recovered to 92+/-3% after 30 min of reperfusion. Despite hydrolysis of high
energy phosphates and cellular acidification, ADP concentrations were stable in
underperfused hearts. At 69, 38 and 10% CFR, cytosolic phosphorylation potentials
(PP) decreased from 74+/-10 m M(-1)during pre-ischemia to 40+/-6, 25+/-4 and 14+/
4 m M(-1)respectively (P<0.05 v 63+/-9 m M(-1)in control), and lactate efflux
increased to 256+/-18, 386+/-22 and 490+/-43 micromol /gdw respectively (P<0.005
v 186+/-22 micromol/gdw in control). Glycogen contents decreased (P<0.005 v
control) and accounted for 27-30% of lactate efflux. These results indicate: (a)
proportionate depression of contraction force and glycogen contents, and
increased glucose uptake and anaerobic energy production in the underperfused
myocardium. Coordinated modulation of these parameters attributes cytosolic PP a
regulatory function; (b) resetting of cytosolic PP to lower levels mediates
perfusion-contraction coupling during graded LFI. The data are consistent with
the concept that glycolytic energy production improves myocardial tolerance to
ischemia.
PMID- 10775485
TI - Identification of genes regulated during mechanical load-induced cardiac
hypertrophy.
AB - Cardiac hypertrophy is associated with both adaptive and adverse changes in gene
expression. To identify genes regulated by pressure overload, we performed
suppressive subtractive hybridization between cDNA from the hearts of aortic
banded (7-day) and sham-operated mice. In parallel, we performed a subtraction
between an adult and a neonatal heart, for the purpose of comparing different
forms of cardiac hypertrophy. Sequencing more than 100 clones led to the
identification of an array of functionally known (70%) and unknown genes (30%)
that are upregulated during cardiac growth. At least nine of those genes were
preferentially expressed in both the neonatal and pressure over-load hearts
alike. Using Northern blot analysis to investigate whether some of the identified
genes were upregulated in the load-independent calcineurin-induced cardiac
hypertrophy mouse model, revealed its incomplete similarity with the former
models of cardiac growth.
PMID- 10775486
TI - Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in
transgenic mice.
AB - The beta(1)-adrenergic receptor (AR) is the dominant subtype in non-failing and
failing myocardium. beta(1)-AR signaling, by the endogenous neurotransmitter
norepinephrine, is central to the regulation of myocardial contractility. In
heart failure, the beta(1)-AR undergoes subtype-selective downregulation which
may protect against the increased cardiac adrenergic drive associated with this
pathophysiological state. To examine the hypothesis that chronically increased
beta(1)-AR mediated signaling has adverse myocardial effects, transgenic mice
overexpressing the human beta(1)-AR in a cardiac-selective context were produced,
utilizing an alpha-myosin heavy chain (MHC) promoter. In these mice, beta(1)-AR
protein abundance was approximately 24-46-fold (1-2 pmol/mg protein) that of wild
type mice. Histopathological examination of young (4 months old) and old
(approximately 9 months old) transgenic mouse hearts consistently demonstrated
large areas of interstitial replacement fibrosis, marked myocyte hypertrophy and
myofibrilar disarray. In addition, increased expression of the pre-apoptotic
marker, Bax, was observed coincident with regions of fibrosis accompanied by an
increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice
exhibited a slight tendency towards a decreased fractional shortening, whereas
older beta(1)-AR transgenic mice had a marked reduction in fractional shortening
(%FS approximately 30) as determined by echocardiography. Additionally, older
beta(1)-AR transgenic mice had an increased left ventricular chamber size. In
summary, cardiac-directed overexpression of the human beta(1)-AR in transgenic
mice leads to a significant histopathological phenotype with no apparent
functional consequence in younger mice and a variable degree of cardiac
dysfunction in older animals. This model system may ultimately prove useful for
investigating the biological basis of adrenergically-mediated myocardial damage
in humans.
PMID- 10775487
TI - Length-dependence of cross-bridge mediated activation of the cardiac thin
filament.
AB - Length-dependent Ca(2+)activation of the thin filament plays a critical role in
the steep force-length relationship of cardiac muscle (Frank-Starling relation).
Recent evidence indicates that the increase in myofilament Ca(2+)sensitivity and
Ca(2+)-troponin C affinity that occurs with increase in sarcomere length results
from a cooperative activation of the thin filament by attached cross-bridges. At
short sarcomere length the Ca(2+)sensitivity is lower because the access of cross
bridges for actin is reduced. The aim of this study was to determine the length
dependence of myosin-mediated thin filament activation in skinned bovine
ventricular muscle, as assayed by the generation of force with progressive
reduction of MgATP concentration in the absence of Ca(2+). If the interaction
between myosin and actin is weaker at short sarcomere length there should be a
lower MgATP concentration needed to maintain the relaxed state. Contrary to
expectation, the force-pMgATP relationship was not significantly influenced by
change in sarcomere length. However this relationship became length-sensitive in
the presence of phosphate analogs which stabilize weak-binding cross-bridges. We
suggest that sarcomere length modulates Ca(2+)sensitivity by controlling the size
of the population of thin filament regulatory units in the weakly-bound state.
PMID- 10775488
TI - Differentiation of cardiomyocytes in floating embryoid bodies is comparable to
fetal cardiomyocytes.
AB - Embryonic stem cells will cluster and differentiate into embryoid bodies, which
can develop spontaneous rhythmic contractions. From these embryoid bodies,
cardiomyocytes can be isolated based on density by a discontinuous Percoll
gradient. These cardiomyocytes differentiate into ventricular myocytes, which is
demonstrated by the expression of the ventricular specific isoform of the myosin
light chain 2 gene. In this study the functional expression of ion channels was
compared between fetal cardiomyocytes (in vivo) and stem cell derived
cardiomyocytes (in vitro). Sodium and calcium currents together with transient
potassium currents could be detected in early developmental stages ( 1 SD below the mean age of onset for those of known APOE
genotype (36.4 +/- 2.3 years, mean +/- SD), and > 2 SDs below the mean age of
onset for the pedigree as a whole (37.4 +/- 1.7 years, mean +/- SD). APOE
genotype may therefore modulate age at onset in this pedigree.
PMID- 10775536
TI - Clinical and molecular genetic characteristics of patients with cerebrotendinous
xanthomatosis.
AB - Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a
deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to
mutations in its gene. In this study we report on mutations in 58 patients with
CTX out of 32 unrelated families. Eight of these were novel mutations, two of
which were found together with two already known pathogenic mutations. Twelve
mutations found in this patient group have been described in the literature. In
the patients from 31 families, mutations were found in both alleles. In the
literature, 28 mutations in 67 patients with CTX out of 44 families have been
described. Pooling our patient group and the patients from the literature
together, 37 different mutations in 125 patients out of 74 families were
obtained. Identical mutations have been found in families from different ethnic
backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the
region of exons 6-8. This region encodes for adrenodoxin and haem binding sites
of the protein. Of these 125 patients, a genotype-phenotype analysis was done for
79 homozygous patients harbouring 23 different mutations, out of 45 families. The
patients with compound heterozygous mutations were left out of the genotype
phenotype analysis. The genotype-phenotype analysis did not reveal any
correlation.
PMID- 10775537
TI - Insights into the functional specificity of the human corpus callosum.
AB - Patient VP underwent complete callosotomy for the control of intractable epilepsy
at the age of 27 years. Subsequent MRI, however, revealed spared callosal fibres
in the rostral and splenial ends of the corpus callosum. We report a series of
experiments designed to determine whether these fibres support functional
transfer of information between the two cerebral hemispheres. Although we found
no evidence for transfer of colour, shape or size information, there is good
evidence for transfer of word information. This suggests that the spared splenial
fibres in VP's corpus callosum are material-specific. The results of these
experiments illustrate the remarkable degree of functional specificity within the
corpus callosum
PMID- 10775539
TI - Compensatory strategies for reaching in stroke.
AB - A major prerequisite for successful rehabilitation therapy after stroke is the
understanding of the mechanisms underlying motor deficits common to these
patients. Studies have shown that in stroke patients multijoint pointing
movements are characterized by decreased movement speed and increased movement
variability, by increased movement segmentation and by spatial and temporal
incoordination between adjacent arm joints with respect to healthy subjects. We
studied how the damaged nervous system recovers or compensates for deficits in
reaching, and correlated reaching deficits with the level of functional
impairment. Nine right-hemiparetic subjects and nine healthy subjects
participated. All subjects were right-hand dominant. Data from the affected arm
of hemiparetic subjects were compared with those from the arm in healthy
subjects. Seated subjects made 40 pointing movements with the right arm in a
single session. Movements were made from an initial target, for which the arm was
positioned alongside the trunk. Then the subject lifted the arm and pointed to
the final target, located in front of the subject in the contralateral workspace.
Kinematic data from the arm and trunk were recorded with a three-dimensional
analysis system. Arm movements in stroke subjects were longer, more segmented,
more variable and had larger movement errors. Elbow-shoulder coordination was
disrupted and the range of active joint motion was decreased significantly
compared with healthy subjects. Some aspects of motor performance (duration,
segmentation, accuracy and coordination) were significantly correlated with the
level of motor impairment. Despite the fact that stroke subjects encountered all
these deficits, even subjects with the most severe motor impairment were able to
transport the end-point to the target. All but one subject involved the trunk to
accomplish this motor task. In others words, they recruited new degrees of
freedom typically not used by healthy subjects. The use of compensatory
strategies may be related to the degree of motor impairment: severely to
moderately impaired subjects recruited new degrees of freedom to compensate for
motor deficits while mildly impaired subjects tended to employ healthy movement
patterns. We discuss the possibility that there is a critical level of recovery
at which patients switch from a strategy employing new degrees of freedom to one
in which motor recovery is produced by improving the management of degrees of
freedom characteristic of healthy performance. Our data also suggest that stroke
subjects may be able to exploit effectively the redundancy of the motor system.
PMID- 10775538
TI - The central role of the prefrontal cortex in directing attention to novel events.
AB - The physiological basis for the striking decrease of attention to novel events
following frontal lobe injury is poorly understood. In this study, event-related
potentials (ERPs) were recorded from patients with frontal lobe damage and
matched subjects, who controlled the duration of viewing of background, novel and
target stimuli. Frontal lobe patients did not differ from normal controls in
terms of age, education, estimated IQ or mood. However, they were judged to be
more apathetic as measured by self-report and informants' ratings. Patients with
frontal lobe damage exhibited markedly reduced amplitude of the novelty P3
response and the duration of viewing of novel stimuli. In contrast, injury to the
frontal lobes had a limited impact on P3 amplitude and behavioural responses
(viewing duration and reaction time) to target stimuli. A strong correlation was
found between measures of apathy and both attenuated P3 amplitude and viewing
duration in response to novel but not target stimuli. Differences in amplitude of
the novelty P3 response explained a large portion of the variance associated with
duration of viewing of novel stimuli. After controlling for the influence of P3
amplitude, there was no association between frontal lobe injury and reduced
viewing of novel stimuli. The results of this study suggest that frontal lobe
damage leads to diminished visual attention to novel events through its
disruption of neural processes underlying the novelty P3 response. These
processes appear to regulate the allocation of attentional resources and early
exploratory behaviours, and are not limited to immediate orienting responses.
Damage to the frontal lobes may prevent the generation of a signal which
indicates that a novel event in the environment requires additional attention due
to its potential behavioural significance. The disruption of these processes is
likely to contribute to the apathy observed in patients after injury to the
frontal lobes.
PMID- 10775540
TI - Participation of the left posterior inferior temporal cortex in writing and
mental recall of kanji orthography: A functional MRI study.
AB - To examine the neuropsychological mechanisms involved in writing kanji
(morphograms), we used functional MRI (fMRI) in 10 normal volunteers, all right
handed, native Japanese speakers. The experimental paradigms consisted of kana-to
kanji transcription, mental recall of kanji orthography and oral reading and
semantic judgement of kana words. The first two tasks require manual and mental
transcription of visually presented kana words into kanji, respectively, whereas
the last two tasks involve language processing of the same set of stimulus words
without recall of kanji. The transcription and mental recall tasks yielded
lateralized activation of the left posterior inferior temporal cortex (PITC). By
contrast, neither oral reading nor semantic judgement produced similar activation
of the area. These results, in good accordance with lesion data, provide
converging evidence that the left PITC plays an important role in writing kanji
through retrieval of their visual graphic images, and suggest language-specific
cerebral organization of writing. The set of fMRI experiments also provides new
neuroimaging data on the cortical localization of basic language functions in
people using a non-alphabetical language.
PMID- 10775541
TI - The age-range of risk of developing multiple sclerosis: evidence from a migrant
population in Australia.
AB - The prevalence of multiple sclerosis in the Australian-born population in five
different regions of Australia has a strong correlation with latitude, the
disease becoming increasingly prevalent with increasing south latitude. In this
study, the prevalence in the migrant population from the UK and Ireland (UKI) in
the different regions also showed a significant correlation with latitude, but
this relationship was strongly influenced by the high prevalence in Hobart.
Except for Hobart, the prevalence in migrants was considerably less than that in
their countries of origin. The prevalence of multiple sclerosis among those
migrating before the age of 15 years from the high-risk UKI to lower-risk
Australia was not significantly different to that among those migrating at or
after that age, and this finding was confirmed in a case-control study which
demonstrated little association between age at migration and risk of developing
multiple sclerosis. These findings suggest that the risk from environmental
factors in multiple sclerosis may operate over a period of many years and not
only in childhood and early adult life.
PMID- 10775542
TI - Familial British dementia with amyloid angiopathy: early clinical,
neuropsychological and imaging findings.
AB - Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant
condition characterized by a dementia, progressive spastic tetraparesis and
cerebellar ataxia with onset in the sixth decade. A point mutation in the BRI
gene has been shown to be the genetic abnormality. Genealogical work with the
large family originally reported by Worster-Drought and updated by Plant has
identified nine generations dating back to the late eighteenth century. The
pedigree now includes six living affected patients, 35 historical cases, and 52
descendants at risk of having inherited the disease. A common ancestor has been
identified between the large pedigree and a case report of 'familial cerebellar
ataxia with amyloid angiopathy'. An autopsy case from a separate family with an
identical condition is described but no common ancestor with the large pedigree
has been found. Case histories have been researched and updated in each pedigree.
Eleven individuals at risk of FBD, aged between 44 and 56 years, agreed to
undergo a clinical and neuropsychological assessment along with MRI brain imaging
in order to clarify early diagnostic features. Five of the eleven were thought to
show early clinical signs of the disease. Neurological examination was abnormal
in three, with limb and gait ataxia and mild spastic paraparesis. Three had
impaired recognition and recall memory and another had mild impairment of delayed
visual recall. All affected individuals had an abnormal MRI of the brain,
consisting of deep white-matter hyperintensity (T(2)-weighted scans) and lacunar
infarcts, but no intracerebral haemorrhage. The corpus callosum was affected
particularly, and in one patient it was severely atrophic.
PMID- 10775543
TI - The effects of a volatile anaesthetic on the excitability of human corticospinal
axons.
AB - The recovery of excitability following a conditioning volley and the strength
duration properties of corticospinal axons were measured in 10 neurologically
normal patients in whom corticospinal function was being monitored during
scoliosis surgery. Corticospinal volleys were produced using transcranial
electrical stimulation of the motor cortex, and recorded from the spinal cord
using epidural leads. Administration of a volatile anaesthetic, sevoflurane 2%,
increased the threshold current required to produce a submaximal test volley by
35.8% (P = 0.0005), indicating that the anaesthetic depressed the excitability of
the site at which the transcranial stimulus activated the corticospinal system.
Following a strong transcranial stimulus, axons were relatively refractory for
conditioning-test intervals up to approximately 2.5 ms, and then superexcitable
for intervals of >10 ms. In two patients, the time course and extent of
refractoriness and superexcitability did not differ when receiving sevoflurane 2%
and after its withdrawal. Strength-duration properties were determined by
measuring the stimulus current required to produce a submaximal corticospinal
volley of fixed amplitude using test stimuli of different duration, from 50
micros to 1 ms. Strength-duration curves were well described by a hyperbolic
function, with which there is a linear relationship between stimulus charge and
stimulus duration. In the absence of sevoflurane, the strength-duration time
constant (tau(SD)) was 432.2 +/- 70.5 micros. When sevoflurane 2% was
administered to 6 patients, tau(SD) decreased to 203.7 +/- 93.8 micros, a change
that was significant (P = 0.04). The decrease in tau(SD) was accompanied by an
increase in rheobase. These findings imply that the lowest-threshold component of
the corticospinal volley produced by transcranial electrical stimulation probably
arises from nodes of Ranvier of corticospinal axons, where it would not be
affected by changes in the excitability of cortical neurons. It is suggested that
the increase in threshold produced by sevoflurane is due to depression of Na(+)
currents at the nodes of Ranvier of corticospinal axons.
PMID- 10775544
TI - Mutation-dependent alteration in cellular distribution of peripheral myelin
protein 22 in nerve biopsies from Charcot-Marie-Tooth type 1A.
AB - The hereditary demyelinating neuropathy Charcot-Marie-Tooth type 1A is caused by
duplication or by point mutations of the PMP22 gene. Histopathological
differences in these genotypes suggest distinct disease mechanisms. In the
present investigation we demonstrate a pathologically altered cellular
distribution of PMP22 in sural nerve biopsies of patients with PMP22 point
mutations. In these patients, in contrast to findings in patients with PMP22
duplication, PMP22 partially accumulates in the Schwann cells instead of being
inserted in the myelin sheath. These findings may explain the different
histopathology and may suggest different mechanisms of pathogenesis in these
genotypes.
PMID- 10775545
TI - Auditory evoked potentials to spectro-temporal modulation of complex tones in
normal subjects and patients with severe brain injury.
AB - In order to assess higher auditory processing capabilities, long-latency auditory
evoked potentials (AEPs) were recorded to synthesized musical instrument tones in
22 post-comatose patients with severe brain injury causing variably attenuated
behavioural responsiveness. On the basis of normative studies, three different
types of spectro-temporal modulation were employed. When a continuous 'clarinet'
tone changes pitch once every few seconds, N1/P2 potentials are evoked at
latencies of approximately 90 and 180 ms, respectively. Their distribution in the
fronto-central region is consistent with generators in the supratemporal cortex
of both hemispheres. When the pitch is modulated at a much faster rate (
approximately 16 changes/s), responses to each change are virtually abolished but
potentials with similar distribution are still elicited by changing the timbre
(e.g. 'clarinet' to 'oboe') every few seconds. These responses appear to
represent the cortical processes concerned with spectral pattern analysis and the
grouping of frequency components to form sound 'objects'. Following a period of
16/s oscillation between two pitches, a more anteriorly distributed negativity is
evoked on resumption of a steady pitch. Various lines of evidence suggest that
this is probably equivalent to the 'mismatch negativity' (MMN), reflecting a pre
perceptual, memory-based process for detection of change in spectro-temporal
sound patterns. This method requires no off-line subtraction of AEPs evoked by
the onset of a tone, and the MMN is produced rapidly and robustly with
considerably larger amplitude (usually >5 microV) than that to discontinuous pure
tones. In the brain-injured patients, the presence of AEPs to two or more complex
tone stimuli (in the combined assessment of two authors who were 'blind' to the
clinical and behavioural data) was significantly associated with the demonstrable
possession of discriminative hearing (the ability to respond differentially to
verbal commands, in the assessment of a further author who was blind to the AEP
findings). Behavioural and electrophysiological findings were in accordance in
18/22 patients, but no AEPs could be recorded in two patients who had clear
behavioural evidence of discriminative hearing. The absence of long-latency AEPs
should not, therefore, be considered indicative of complete functional deafness.
Conversely, AEPs were substantially preserved in two patients without behavioural
evidence of discriminative hearing. Although not necessarily indicative of
conscious 'awareness', such AEP preservation might help to identify sentient
patients who are prevented by severe motor disability from communicating their
perception.
PMID- 10775546
TI - Abnormal reciprocal inhibition between antagonist muscles in Parkinson's disease.
AB - Disynaptic Ia reciprocal inhibition acts, at the spinal level, by actively
inhibiting antagonist motor neurons and reducing the inhibition of agonist motor
neurons. The deactivation of this pathway in Parkinson's disease is still
debated. Disynaptic reciprocal inhibition of H reflexes in the forearm flexor
muscles was examined in 15 control subjects and 16 treated parkinsonian patients
at rest and at the onset of a voluntary wrist flexion. Two patients were
reassessed 18 h after withdrawal of antiparkinsonian medication. At rest, the
level of Ia reciprocal inhibition between the wrist antagonist muscles was not
significantly different between patients and controls. In contrast, clear
abnormalities of this inhibition were revealed by voluntary movements in the
patients. In normal subjects, at the onset of a wrist flexion, Ia reciprocal
inhibition showed a large decrease, and we argue that this decrease is
supraspinal in origin. On the less affected sides of the patients the descending
modulation was still present but lower than in controls; on the more affected
sides this modulation had vanished almost completely. These movement-induced
abnormalities of disynaptic Ia reciprocal inhibition were closely associated with
Parkinson's disease but were probably not dependent on L-dopa. They could play a
role in the disturbances of precise voluntary movements observed in Parkinson's
disease.
PMID- 10775547
TI - Kurtzke scales revisited: the application of psychometric methods to clinical
intuition.
AB - When developing his disability scales for multiple sclerosis, Kurtzke
demonstrated perception and insight. However, 45 years later, the evaluation of
his clinically derived scales remains limited, particularly for more disabled
patients. Indeed, many of Kurtzke's assumptions underpinning the development of
the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) are
untested. This study aims to build on previous work and provide a more detailed
examination using psychometric methods of the EDSS and FS. There are three study
objectives: (i) to examine comprehensively the psychometric properties of the
EDSS in more disabled people with multiple sclerosis undergoing in-patient
rehabilitation; (ii) to examine the reliability of the FS and test Kurtzke's
assumptions that they measure different aspects of the neurological examination
and measure different constructs from that measured by the EDSS; and (iii) to
examine whether the FS can be summed to generate a summary score. The EDSS was
examined for its acceptability (score distributions), reliability (inter- and
intra-rater reproducibility, standard error of measurement), validity (convergent
and discriminant validity, measurement precision, discrimination between
individuals) and responsiveness (effect size). The FS were examined for their
reliability (inter- and intra-rater reproducibility), intercorrelations,
correlations with the EDSS and the extent to which they satisfy Likert's criteria
as a summed rating scale. In this more disabled sample of people with multiple
sclerosis, the EDSS is an acceptable measure but demonstrates limited
variability. Inter-rater reproducibility (intraclass correlation coefficient; ICC
= 0.78) is adequate for group comparison studies, but intra-rater reproducibility
is variable (ICC = 0.62-0.94). Convergent and discriminant validity for the EDSS
is supported, but its measurement precision relative to the Functional
Independence Measure is limited (56%). Also, the EDSS has a limited ability to
distinguish between individuals in terms of their disability and its
responsiveness is poor (effect size = 0.10). Results indicate that the FS measure
constructs distinct from each other (intercorrelations = -0.23 to +0. 52) and
from the EDSS (correlations = -0.10 to +0.59). Intra-rater, but not inter-rater
reproducibility is adequate for group comparison studies. The FS do not satisfy
criteria as an eight-, seven- or six-item summed rating scale. Despite being
based on sound clinical intuition, the lack of psychometric input into the
development of the EDSS and FS has limited their usefulness as evaluative outcome
measures in multiple sclerosis.
PMID- 10775548
TI - Neuropsychological consequences of cerebellar tumour resection in children:
cerebellar cognitive affective syndrome in a paediatric population.
AB - Acquired cerebellar lesions in adults have been shown to produce impairments in
higher function as exemplified by the cerebellar cognitive affective syndrome. It
is not yet known whether similar findings occur in children with acquired
cerebellar lesions, and whether developmental factors influence their
presentation. In studies to date, survivors of childhood cerebellar tumours who
demonstrate long-term deficits in cognitive functions have undergone surgery as
well as cranial irradiation or methotrexate treatment. Investigation of the
effects of the cerebellar lesion independent of the known deleterious effects of
these agents is important for understanding the role of the cerebellum in
cognitive and affective development and for informing treatment and
rehabilitation strategies. If the cerebellar contribution to cognition and affect
is significant, then damage in childhood may influence a wide range of
psychological processes, both as an immediate consequence and as these processes
fail to develop normally later on. In this study we evaluated neuropsychological
data in 19 children who underwent resection of cerebellar tumours but who
received neither cranial irradiation nor methotrexate chemotherapy. Impairments
were noted in executive function, including planning and sequencing, and in
visual-spatial function, expressive language, verbal memory and modulation of
affect. These deficits were common and in some cases could be dissociated from
motor deficits. Lesions of the vermis in particular were associated with
dysregulation of affect. Behavioural deficits were more apparent in older than
younger children. These results reveal that clinically relevant
neuropsychological changes may occur following cerebellar tumour resection in
children. Age at the time of surgery and the site of the cerebellar lesion
influence the neurobehavioural outcome. The results of the present study indicate
that the cerebellar cognitive affective syndrome is evident in children as well
as in adults, and they provide further clinical evidence that the cerebellum is
an essential node in the distributed neural circuitry subserving higher-order
behaviours.
PMID- 10775549
TI - The cerebellum contributes to higher functions during development: evidence from
a series of children surgically treated for posterior fossa tumours.
AB - We present data on the intellectual, language and executive functions of 26
children who had undergone surgery for the removal of cerebellar hemisphere or
vermal tumours. The children with right cerebellar tumours presented with
disturbances of auditory sequential memory and language processing, whereas those
with left cerebellar tumours showed deficits on tests of spatial and visual
sequential memory. The vermal lesions led to two profiles: (i) post-surgical
mutism, which evolved into speech disorders or language disturbances similar to
agrammatism; and (ii) behavioural disturbances ranging from irritability to
behaviours reminiscent of autism. These data are consistent with the recently
acknowledged role of the cerebellum as a modulator of mental and social
functions, and suggest that this role is operative early in childhood.
PMID- 10775550
TI - Department of Veterans Affairs hypertension meeting : a proposal for improved
care.
AB - A major invitational hypertension meeting was hosted by the Department of
Veterans Affairs (VA) in Washington, DC, on May 26 to 28, 1999. It followed a
report that only 25% of hypertensive veterans had adequate levels of treated
blood pressure and focused on how control of hypertension could be improved both
immediately and in the future. After the presentation of brief outlines of 5
unresolved basic science questions, 2 general topics were considered: (1) 30
years of change in hypertension and its treatment and (2) current healthcare
delivery mechanisms and how to improve them. Since 1970, the severity of
hypertension has decreased, malignant hypertension has disappeared, and the
prognostic roles of systolic and diastolic blood pressure have been reversed as
hypertension became milder. Five VA Cooperative Studies have provided important
data: the 1970 Freis Trial report demonstrated the value of treatment, 2 trials
showed that some controlled patients can decrease or even discontinue
pharmacological treatment without recrudescent hypertension, a blinded trial was
performed on the efficacy of different antihypertensive drugs, and an unblinded
trial showed that diuretics and beta-blockers are the most effective agents when
caregivers choose the agent and dose. Two healthcare models were considered: (1)
the patient-friendly VA Hypertension Screening and Treatment Program that was
introduced in 1972, which controls 80% of patients at the goal of the Joint
National Committee on Detection, Evaluation, and Treatment of High Blood Pressure
with diuretics and keeps patients in the program an average of 7.5 years, and (2)
the newer primary care health maintenance organization-like model in the VA and
throughout the United States. Choosing a regimen and monitoring control of blood
pressure and compliance with therapy were discussed. The meeting was closed with
6 general recommendations for improving the care of hypertensive patients.
PMID- 10775551
TI - National Heart, Lung, and Blood Institute Workshop on Sodium and Blood Pressure :
a critical review of current scientific evidence.
PMID- 10775552
TI - Association of insulin resistance with salt sensitivity and nocturnal fall of
blood pressure.
AB - Insulin resistance was demonstrated in hypertensive patients and in salt
sensitive subjects. It was recently reported that the salt-sensitive state was
related to a reduced fall in blood pressure during the night in essential
hypertension. In the present study, the relationship among insulin sensitivity,
blood pressure response to salt intake, and nocturnal fall in blood pressure was
examined in 20 subjects with nondiabetic and nonobese essential hypertension
during a low-salt and a high-salt diet. The subjects were maintained on a low
salt diet (50 mmol/d) and a high-salt diet (255 mmol/d) for 1 week each, in
random order. On the sixth day of each diet, blood pressure was measured every
hour for 24 hours with an automatic device. Insulin sensitivity was measured
according to the steady-state plasma glucose (SSPG) method on the seventh day of
each diet. Salt-induced increase in blood pressure, which we defined as the
change in 24-hour mean arterial pressure between the low and the high dietary
salt intakes, was significantly correlated with SSPG (r=0.60, P<0.01) during the
high-salt period. There was a significant negative correlation (r=-0.61, P<0.01)
between SSPG and a nocturnal fall in mean arterial pressure during the high-salt
period. Salt-induced increase in blood pressure was inversely correlated with a
nocturnal fall in mean arterial pressure (r=-0.52, P<0.02) with the high-salt
diet. These results suggest that insulin resistance, salt sensitivity, and failed
nocturnal fall in blood pressure are associated with each other in subjects with
essential hypertension.
PMID- 10775553
TI - Sodium sensitivity of blood pressure in long-term detoxified alcoholics.
AB - To investigate whether sodium sensitivity of blood pressure participates in the
relationship of arterial hypertension to chronic alcohol consumption, 30
alcoholics detoxified from 6 to 12 months and 30 teetotaler controls underwent a
dietary sodium manipulation study. They received a daily 55 mmol sodium diet for
7 days, followed by a 260 mmol sodium diet for 7 days. Changes in 24-hour urinary
sodium excretion between the end of each period were similar in alcoholics and
controls (202+/-16 SEM mmol and 227+/-11, respectively). Plasma renin activity in
alcoholics was lower than in controls at both low (2.4+/-0.4 ng angiotensin
I/mLxh(-1) versus 3. 7+/-0.2, P<0.003) and high sodium intake (0.47+/-0.10 versus
0. 82+/-0.10, P<0.05), with smaller variations in alcoholics (-1.9+/-0. 3 versus
2.9+/-0.2, P<0.009). In alcoholics, alteration in sodium intake was followed by
greater changes in both systolic and mean blood pressure (ambulatory blood
pressure monitoring), which rose by 10.6+/-2.2 mm Hg and 7.3+/-1.5 versus 4.7+/
1.4 and 3.9+/-1.0 in controls, respectively (P<0.03 for systolic and P<0.05 for
mean blood pressure). The ratio of changes in mean blood pressure to those in 24
hour urinary sodium excretion was higher in alcoholics (0.044+/- 0.011 mm
Hgxmmol(-1) versus 0.018+/-0.0041, P<0.005). Our data show that in detoxified
alcoholics, there is an abnormal response of both blood pressure and plasma renin
activity to variations in salt intake similar to that in sodium-sensitive
arterial hypertension. The precise relationship between the sodium sensitivity of
blood pressure in detoxified alcoholics and the long-term influence of alcohol on
blood pressure remains to be elucidated.
PMID- 10775555
TI - Effects of work stress on ambulatory blood pressure, heart rate, and heart rate
variability.
AB - Work stress has repeatedly been associated with an increased risk for
cardiovascular disease. This study tested whether this relationship could be
explained by exaggerated cardiovascular reactivity to work or impaired recovery
in leisure time. Vagal tone was assessed as a possible determinant of these work
stress effects. Participants included 109 male white-collar workers (age, 47.2+/
5. 3) who were monitored on 2 workdays and 1 nonworkday for ambulatory blood
pressure, heart rate, and heart rate variability. Chronic work stress was defined
according to Siegrist's model as (1) high imbalance, a combination of high effort
and low reward at work, or (2) high overcommitment, an exhaustive work-related
coping style indexing the inability to unwind. All findings were adjusted for
possible differences in posture and physical activity between the work stress
groups. High imbalance was associated with a higher heart rate during work and
directly after work, a higher systolic blood pressure during work and leisure
time, and a lower 24-hour vagal tone on all 3 measurement days. Overcommitment
was not associated with an unfavorable ambulatory profile. Logistic regression
analysis revealed that heart rate [odds ratio 1-SD increase 1.95 (95% CI, 1.02 to
3.77)] and vagal tone [odds ratio 1-SD decrease 2.67 (95% CI, 1.24 to 5.75)] were
independently associated with incident mild hypertension. Surprisingly, the
values during sleep were more predictive for mild hypertension than the values
during work. The results from the present study suggest that the detrimental
effects of work stress are partly mediated by increased heart rate reactivity to
a stressful workday, an increase in systolic blood pressure level, and lower
vagal tone.
PMID- 10775554
TI - Role of citrate synthase in aldosterone-mediated sodium reabsorption.
AB - Aldosterone and other mineralocorticoids increase citrate synthase activity in
the kidney and enhance renal sodium reabsorption, but it is unclear whether the
increased citrate synthase activity is involved in renal sodium transport. We
used the Wistar-Furth rat, an inbred strain found to be deficient in renal
citrate synthase activity, as an experimental model to investigate this issue. We
confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth
rats was decreased compared with that from control Wistar rats (by 28%).
Similarly, urinary citrate excretion was 23% lower in Wistar-Furth rats.
Subnormal citrate formation in Wistar-Furth rats could not be accounted for by
differences in systemic pH or circulating potassium levels. Because renal citrate
synthase activity was reduced in Wistar-Furth rats, we hypothesized that renal
sodium excretory responses to mineralocorticoids would be reduced as well. Four
hour sodium excretion after intraperitoneal injection of 5 microg of aldosterone
was reduced by 56% in adrenalectomized Wistar rats and by 52% in adrenalectomized
Wistar-Furth rats (both P<0.01 compared with vehicle injection). Similarly, the
pattern of urinary sodium excretion in response to subcutaneous injections of
deoxycorticosterone acetate over a 2-week period was similar in adrenalectomized
Wistar and Wistar-Furth rats. In summary, acute and chronic antinatriuretic
responses to mineralocorticoids are maintained in Wistar-Furth rats at the level
of Wistar rats, despite the marked reduction in citrate synthase activity. These
findings are not consistent with an important role for citrate synthase activity
in mineralocorticoid-mediated renal sodium transport.
PMID- 10775556
TI - Mental stress-induced increase in blood pressure is not related to baroreflex
sensitivity in middle-aged healthy men.
AB - The baroreflex that acts to blunt blood pressure (BP) variations through opposite
variations in heart rate should limit the BP increase produced by an emotional
challenge. However, relations between baroreflex sensitivity and BP reactivity
induced by a psychological stress in a large group of adults have never been
firmly established. In 280 healthy men, rest (10 minutes) and stress (5 minutes)
BP and heart rate were recorded beat to beat by a blood pressure monitor. The
mental stress was elicited by a well-standardized computerized version of a word
color conflict stress test (Stroop Color Test). Rest and stress baroreflex
sensitivity was assessed by the cross-spectral analysis of BP and heart rate and
by the sequence method. The stress-induced increase in systolic BP (22.4+/-0.1 mm
Hg) was not correlated with resting baroreflex sensitivity but was slightly
correlated (r=0.2, P<0.001) with BP variability assessed either by standard
deviation or by mid-frequency band spectral power. Our results suggested that a
centrally mediated sympathetic stimulation overcame cardiac autonomic regulation
and emphasized the role of the sympathetic vasoconstriction in the pressure
response at the onset of the stressing stimulation. During the sustained
sympathoexcitatory phase, the cardiac baroreflex blunts BP variations but at a
lower sensitivity.
PMID- 10775557
TI - Diurnal blood pressure variation in progressive autonomic failure.
AB - To investigate the role of the autonomic nervous system (ANS) in the generation
of the circadian blood pressure (BP) variation, the degree of impairment of the
ANS was related to the results of ambulatory BP recordings in 212 patients with
progressive autonomic failure due to familial amyloid polyneuropathy. On the
basis of BP and/or heart rate (HR) responses to the Valsalva maneuver, 60 degrees
head-up tilting, deep-breathing tests, and plasma norepinephrine levels, 4 groups
of patients were distinguished. In all patients and in 38 age-matched control
subjects, ambulatory BP was monitored. Patients of group I (n=40, aged 32+/-3 y),
with no evidence yet of impairment of their ANS, had circadian BP and HR
variations indistinguishable from controls. Patients of group II (n=41, aged 34+/
5 y) had a variable degree of impairment of their parasympathetic ANS, but their
sympathetic ANS was still intact. Twenty-four-hour HR was higher in these
patients than in controls (88+/-11 versus 78+/-7 bpm, P<0.01). Their circadian HR
variation was maintained, but their circadian BP variation was diminished (10+/
6/11+/-4 versus 17+/-6/16+/-4 mm Hg in controls, P<0.01) because of an
attenuation of the nocturnal BP decline. Patients of group III (n=69, aged 36+/-6
y), with parasympathetic failure and intermediate sympathetic dysfunction, had a
blunted diurnal BP variation, whereas patients of group IV (n=62, aged 38+/-6 y),
with parasympathetic failure and severe sympathetic dysfunction, had an absent
diurnal BP variation. In patients of groups III and IV, a decrease in daytime BP
accounted for the blunted circadian BP variation. This extensive study in
progressive autonomic failure confirms the important role of the ANS in the
generation of circadian BP variation. For the maintenance of a normal circadian
BP pattern, not only an intact sympathetic but also an intact afferent
parasympathetic ANS is a prerequisite.
PMID- 10775558
TI - Arterial hypertension, microalbuminuria, and risk of ischemic heart disease.
AB - Albumin excretion in urine is positively correlated with the presence of ischemic
heart disease and atherosclerotic risk factors. We studied prospectively whether
a slight increase of urinary albumin excretion, ie, microalbuminuria, adds to the
increased risk of ischemic heart disease among hypertensive subjects. In 1983 and
1984, blood pressure, urinary albumin/creatinine concentration ratio, plasma
total and HDL cholesterol levels, body mass index, and smoking status were
obtained in a population-based sample of 2085 subjects, aged 30 to 60 years, who
were free from ischemic heart disease, diabetes mellitus, and renal or urinary
tract disease. Untreated arterial hypertension or borderline hypertension was
present in 204 subjects, who were followed until 1993 by the National Hospital
and Death Certificate Registers with respect to development of ischemic heart
disease. During 1978 person-years, 18 (9%) of the hypertensive subjects developed
ischemic heart disease. Microalbuminuria, defined as a urinary albumin/creatinine
ratio above the upper decile (1.07 mg/mmol), was the strongest predictor of
ischemic heart disease, with an unadjusted relative risk of 4.2 (95% CI 1.5 to
11.9, P=0.006) and a relative risk of 3.5 (95% CI 1.0 to 12.1, P=0.05) when
adjusted for all other atherosclerotic risk factors, including age and gender. In
conclusion, microalbuminuria confers a 4-fold increased risk of ischemic heart
disease among hypertensive or borderline hypertensive subjects. Urinary albumin
excretion should be measured regularly in a hypertension clinic, and a rigorous
control of blood pressure and of other atherosclerotic risk factors is
recommended in hypertensive patients with microalbuminuria.
PMID- 10775559
TI - Platelet-derived nitric oxide and coronary risk factors.
AB - Platelet aggregation is inhibited through a negative feedback mechanism by the L
arginine/nitric oxide (NO) pathway found in platelets themselves. We have shown
that long-term smoking impairs the bioactivity of platelet-derived NO (PDNO),
resulting in an increased platelet aggregability. However, little is known about
the relation between other coronary risk factors and PDNO release. Accordingly,
this study was undertaken to examine whether other coronary risk factors are
related to the impairment of PDNO bioactivity. We measured collagen-induced PDNO
release with an NO-selective electrode in 61 subjects (mean age 47 years, range
24 to 74 years) who underwent complete physical and laboratory examinations.
There was a significant inverse correlation between PDNO release and the number
of coronary risk factors (r=-0.61, P<0. 001). Univariate analysis showed a
significant inverse correlation between PDNO release and age (r=-0.33, P<0.01),
mean arterial pressure (r=-0.40, P<0.002), total cholesterol level (r=-0.31, P<0.
02), and LDL-cholesterol level (r=-0.33, P<0.02). PDNO release was significantly
lower in long-term smokers than in nonsmokers (P<0. 001). With multiple stepwise
regression analysis, PDNO release correlated significantly and independently
(r(2)=0.51), with smoking (F=37.8), age (F=7.1), and mean arterial pressure
(F=5.1). Thus, we demonstrated that coronary risk factors are associated with an
impairment of PDNO release by human platelets. Our findings may contribute to the
understanding of the pathophysiological link between coronary risk factors and
atherothrombotic disease.
PMID- 10775560
TI - Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan
of hypertensive rats.
AB - In this study, we investigated the outcome of lifelong treatment with the
angiotensin II type 1 receptor (AT(1)) blocker fonsartan (HR 720) in young stroke
prone spontaneously hypertensive rats (SHR-SP). In addition to the primary end
point, lifespan, and to determine the mechanisms involved in the treatment
induced effects, parameters such as left ventricular hypertrophy, cardiac
function/metabolism, endothelial function, and the expression/activity of
endothelial nitric oxide synthase and of angiotensin-converting enzyme (ACE) were
also investigated. Ninety 1-month-old SHR-SP were allotted to 2 groups and
treated via drinking water with an antihypertensive dose of fonsartan (10 mg. kg(
1). d(-1)) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP,
which was comparable to the lifespan of normotensive Wistar-Kyoto rats. After 15
months, a time when approximately 80% of the placebo group had died, left
ventricular hypertrophy was completely prevented in fonsartan-treated animals.
Furthermore, cardiac function and metabolism as well as endothelial function were
significantly improved. These effects were correlated with increased endothelial
nitric oxide synthase expression in the heart and carotid artery and with
markedly decreased tissue ACE expression/activities. Lifespan extension and
cardiovascular protection by long-term AT(1) blockade with fonsartan led to
similar beneficial effects, as observed with long-term ACE inhibition.
PMID- 10775561
TI - N-Acetyl-L-cysteine potentiates interleukin-1beta induction of nitric oxide
synthase : role of p44/42 mitogen-activated protein kinases.
AB - We have reported previously that N-acetyl-L-cysteine facilitated interleukin
1beta-induced nitric oxide synthase (iNOS) expression in rat vascular smooth
muscle cells. The present study compares the effect of N-acetyl-L-cysteine with
other antioxidants and tested the possibility that N-acetyl-L-cysteine
potentiates iNOS induction by a mechanism involving activation of p44/42 mitogen
activated protein kinases (MAPKs). The effect of N-acetyl-L-cysteine on
potentiating interleukin-1beta-induced nitrite production and iNOS expression was
mimicked either by the enantiomers, L-cysteine and D-cysteine, or by a non-thiol
containing antioxidant, L-ascorbic acid. Interleukin-1beta activated p44/42 MAPK,
and this activation was enhanced in the presence of N-acetyl-L-cysteine.
Inhibition of p44/42 MAPK phosphorylation by the selective inhibitor PD98059
clearly inhibited iNOS expression induced by interleukin-1beta either in the
absence or in the presence of N-acetyl-L-cysteine. These observations, combined
with previous results, indicate that p44/42 MAPK activation is required for
interleukin-1beta induction of iNOS and that N-acetyl-L-cysteine may act as a
reducing agent and facilitate interleukin-1beta-induced iNOS expression through a
reduction/oxidation-related mechanism involving potentiation of cytokine
activation of the p44/42 MAPK signaling pathway.
PMID- 10775562
TI - Physical exercise, aortic blood pressure, and aortic wall elasticity and
composition in rats.
AB - With a training schedule (8 weeks' treadmill running at 30 m/min up a 10% incline
5 d/wk for 90 min/day), we investigated whether exercise modifies aortic wall
dimensions, composition (calcium and elastin content), or stiffness in
normotensive 6-month-old male Wistar WAG/Rij rats. Maximal oxygen uptake was
measured in half of the rats (n=10 per group). Wall stiffness was evaluated in
the other half (9 trained and 10 untrained) on the basis of changes in
thoracoabdominal pressure pulse wave velocity and differences in amplitude
between the peripheral and central aortic pressure signals. Experiments were
performed in nonanesthetized, unrestrained rats and then after pithing. The
impact of exercise on the oxidative capacity of the plantaris muscles was
evaluated with the measurement of citrate synthase activity. Training increased
maximal oxygen uptake by 34% and citrate synthase activity by 40%. Mean
peripheral aortic pressure increased by 6% and 19% in trained rats, under awake
and pithed conditions, whereas mean central aortic pressure increased by 16%,
after pithing only. All indexes of aortic stiffness were similar in trained and
control rats, as were aortic wall dimensions, composition, cardiac mass, and
heart rate. In conclusion, physical exercise in young rats appears to have no
effect on aortic stiffness.
PMID- 10775564
TI - Cellular hypertrophy in subcutaneous small arteries of patients with renovascular
hypertension.
AB - Structural alterations of small arteries in patients with essential hypertension
are characterized by inward eutrophic remodeling. However, small arteries in
patients with secondary hypertension, as well as in experimental models of
hypertension with high circulating renin, are characterized by inward
hypertrophic remodeling, which is characterized by smooth muscle cell hypertrophy
in animal models. The aim of our study was to determine whether remodeling of
subcutaneous small arteries in patients with secondary forms of hypertension is
associated with smooth muscle cell hypertrophy and/or alterations in the elastic
modulus of the vessel wall. Fifteen patients with renovascular hypertension, 9
with primary aldosteronism, and 13 with essential hypertension and 9 normotensive
subjects were included in the study. A biopsy of subcutaneous fat was taken from
all subjects. Small arteries were dissected, and morphology was determined on a
micromyograph. Unbiased estimates of cell volume and number were made in fixed
material. From the resting tension-internal circumference relation of the small
arteries, the incremental elastic modulus was calculated and plotted as a
function of wall stress. Blood pressure was greater in patients with essential
hypertension, renovascular hypertension, or primary aldosteronism than in
normotensive subjects, but no significant difference was observed among the 3
groups of hypertensive patients. The media/lumen ratio, the medial cross
sectional area, and the smooth muscle cell volume were significantly greater in
patients with renovascular hypertension than in normotensive subjects and
patients with essential hypertension. No difference in cell number or in the
elastic properties was observed among the 4 groups of subjects. In conclusion,
our data demonstrate for the first time that a pronounced activation of the renin
angiotensin-aldosterone system is associated with vascular smooth muscle cell
hypertrophy in human hypertension in a manner similar to that found in animal
models.
PMID- 10775563
TI - Shear stress-induced release of prostaglandin H(2) in arterioles of hypertensive
rats.
AB - The nitric oxide-mediated portion of shear stress-induced dilation of rat
gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive
rats (SHR). Because shear stress-induced dilation is primarily mediated by
endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized
that in the cremasteric vascular bed the mediation of shear stress-induced
dilation by prostaglandins is altered in hypertension. At a constant intraluminal
pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles
of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0+/-3.1 and
51.7+/-3.6 microm, respectively, whereas their passive diameters were 109.4+/-4.4
and 101.9+/-6.7 microm, respectively. Dilations to increases in shear stress
elicited by increases in intraluminal flow (from 0 to 25 microL/min) were
significantly less (P<0.05) in cremasteric arterioles isolated from SHR than from
WKY. Arachidonic acid (10(-5) mol/L) elicited constrictions in SHR arterioles but
dilations in WKY arterioles. The prostaglandin H(2)/thromboxane A(2)
(PGH(2)/TxA(2)) receptor antagonist SQ 29,548 (10(-6) mol/L) significantly
increased basal diameter by 11% and normalized the attenuated shear stress
induced dilation in SHR, whereas it did not affect basal diameter and arteriolar
responses of WKY. Furegrelate, a specific inhibitor of TxA(2) synthase, did not
affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid-induced
constriction to dilation in SHR arterioles, whereas it did not affect the dilator
response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619
(a PGH(2)/TxA(2) receptor agonist) were not different. These results demonstrate
that in cremasteric arterioles of hypertensive rats, shear stress elicits an
enhanced release of PGH(2), resulting in a reduced shear stress-dependent
dilation. Thus, augmented hemodynamic forces can alter the shear stress-induced
synthesis of prostaglandins, which may contribute to the elevated vascular
resistance in hypertension.
PMID- 10775566
TI - Role of reactive oxygen species in bradykinin-induced mitogen-activated protein
kinase and c-fos induction in vascular cells.
AB - Bradykinin stimulates proliferation of aortic vascular smooth muscle cells
(VSMCs). We investigated the action of bradykinin on the phosphorylation state of
the mitogen-activated protein kinases p42(mapk) and p44(mapk) in VSMCs and tested
the hypothesis that reactive oxygen species (ROS) might be involved in the signal
transduction pathway linking bradykinin activation of nuclear transcription
factors to the phosphorylation of p42(mapk) and p44(mapk). Bradykinin (10(-8)
mol/L) rapidly increased (4- to 5-fold) the phosphorylation of p42(mapk) and
p44(mapk) in VSMCs. Preincubation of VSMCs with either N-acetyl-L-cysteine and/or
alpha-lipoic acid significantly decreased bradykinin-induced cytosolic and
nuclear phosphorylation of p42(mapk) and p44(mapk). In addition, the induction c
fos mRNA levels by bradykinin was completely abolished by N-acetyl-L-cysteine and
alpha-lipoic acid. Using the cell-permeable fluorescent dye dichlorofluorescein
diacetate, we determined that bradykinin (10(-8) mol/L) rapidly increased the
generation of ROS in VSMCs. The NADPH oxidase inhibitor diphenylene iodonium
(DPI) blocked bradykinin-induced c-fos mRNA expression and p42(mapk) and
p44(mapk) activation, implicating NADPH oxidase as the source for the generation
of ROS. These findings demonstrate that the phosphorylation of cytosolic and
nuclear p42(mapk) and p44(mapk) and the expression of c-fos mRNA in VSMCs in
response to bradykinin are mediated via the generation of ROS and implicate ROS
as important mediators in the signal transduction pathway through which
bradykinin promotes VSMC proliferation in states of vascular injury.
PMID- 10775565
TI - Pharmacological concentrations of ascorbic acid are required for the beneficial
effect on endothelial vasomotor function in hypertension.
AB - Increased production of superoxide anion may contribute to impaired bioactivity
of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of
scavenging superoxide anion; however, experimental studies have shown that high
physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent
superoxide-mediated vascular dysfunction. To seek kinetic evidence that
superoxide anion contributes to endothelial vasomotor dysfunction in human
hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra
arterial infusions on forearm blood flow responses to methacholine or sodium
nitroprusside in 30 patients with hypertension and 22 age-matched controls.
Endothelium-dependent vasodilation to methacholine was significantly impaired in
the hypertensive patients, with a response to the highest dose of methacholine
(10 microg/min) of 12.3+/-6.7 compared with 16.1+/-5.8 mL. min(-1). dL tissue(-1)
in the controls (P<0.001). The response to sodium nitroprusside was equivalent in
the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood
flow response to methacholine in hypertensive patients with a peak response of
16.1+/-7.1 mL. min(-1). dL tissue(-1) (P=0.001). This dose produced a cephalic
vein ascorbic acid concentration of 3.2+/-1. 4 mmol/L. In contrast, ascorbic acid
at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both
doses had no effect on the vasodilator response to sodium nitroprusside in
hypertensive patients or the methacholine response in the controls. These results
agree with the predicted kinetics for superoxide anion-mediated impairment of
endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to
impaired endothelium-dependent vasodilation in patients with hypertension.
PMID- 10775567
TI - Inhibition of vascular smooth muscle cell migration by elevation of extracellular
potassium concentration.
AB - The effect of potassium on the migration of vascular smooth muscle cells was
analyzed in media made with extracellular potassium concentrations of 3, 4, 5,
and 6 mmol/L. The migration of cultured porcine coronary artery cells was
stimulated with platelet-derived growth factor (PDGF)-BB. In the first study,
cells were exposed to PDGF-BB at concentrations of 0, 10, or 20 ng/mL for 5 hours
with the use of a Boyden chamber. Cells were quiescent overnight in 0.5% fetal
bovine serum in Dulbecco's modified Eagle's medium with an extracellular
potassium concentration of 4 mmol/L. With increasing potassium concentration,
migration was significantly inhibited (P<0. 02, 2-way ANOVA). In the cells
exposed to 10 ng/mL PDGF-BB, migration ranged from 500+/-86% to 294+/-44% (value
in wells with 0 ng/mL PDGF-BB and 4 mmol/L potassium concentration=100%) in
medium containing 3 to 6 mmol/L extracellular potassium concentration (P<0. 03).
Long-term potassium exposure was investigated in cells grown in 5% serum in
Dulbecco's modified Eagle's medium with an extracellular potassium concentration
of 3, 4, 5, or 6 mmol/L for 3 to 4 weeks. Migration was assessed with 0 or 20
ng/mL PDGF-BB. Migration was significantly inhibited by the elevation of
extracellular potassium concentration (P<0.01, 2-way ANOVA). With 20 ng/mL PDGF
BB, the migration rates ranged from 152+/-11% in medium with 3 mmol/L potassium
to 69+/-5% in 6 mmol/L potassium (P<0.01). Increases in extracellular potassium
concentration within the physiological range significantly and directly inhibit
vascular smooth muscle cell migration.
PMID- 10775568
TI - Glomerular hyperfiltration, high renin, and low- extracellular volume in high
blood pressure.
AB - Abnormal renovascular resistance and glomerular filtration rate are
characteristic of established hypertension and may also be involved in its
pathogenesis. To determine renal and body fluid correlates of the predisposition
to high blood pressure, we examined 100 healthy young adults with high or low
blood pressure. Within each group, half had parents with high blood pressures,
and half had parents with low blood pressures. Renal function and hemodynamics,
body fluid volumes, and relevant hormones and genotypes were measured. Subjects
with high personal and parental blood pressures had the highest levels of
glomerular filtration rate (P<0.02) and plasma active renin concentration and low
levels of exchangeable sodium and plasma volume (P<0.02). High glomerular
filtration rate was not associated with differences in urinary kallikrein or
prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and
angiotensinogen genes were not associated with differences in glomerular
filtration rate or renin. Subjects with high personal, but low parental, blood
pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal
glomerular filtration rates. In this population, extracellular volume depletion
and high renin are correlates of high blood pressure in early adulthood, and
glomerular hyperfiltration is a feature of those who also have familial
predisposition to high blood pressure.
PMID- 10775569
TI - Cyclophilin B expression in renal proximal tubules of hypertensive rats.
AB - Rat cyclophilin-like protein (Cy-LP) is a candidate hypertension gene initially
identified by differential hybridization and implicated in renal mechanisms of
salt retention and high blood pressure. We report the molecular characterization
of rat cyclophilin B (CypB) and demonstrate, through sequence analysis and an
allele-specific polymerase chain reaction primer assay, that CypB but not Cy-LP
is expressed in rat kidney. CypB is an endoplasmic reticulum-localized prolyl
isomerase that interacts with elongation initiation factor 2-beta, an important
regulator of protein translation and a central component of the endoplasmic
reticulum stress response to hypoxia or ATP depletion. Active renal transport of
sodium is increased in the spontaneously hypertensive rat (SHR), and there is
evidence that this coincides with hypoxia and ATP depletion in the renal cortex.
In the present studies we have examined expression of CypB in rat proximal
tubules, which contributes to the increased renal sodium reabsorption in this
model of hypertension. We report that CypB transcript abundance is significantly
elevated in proximal convoluted tubules from SHR compared with the control Wistar
Kyoto strain. This upregulation occurs in weanling animals and precedes the
development of hypertension, indicating that it is not a simple response to
hypertension in SHR. Further, CypB expression is also higher in a proximal tubule
cell line derived from SHR compared with a similar line derived from Wistar-Kyoto
rats, indicating that this difference is genetically determined. No sequence
differences were observed in the CypB cDNA from these 2 strains. These
observations suggest that a genetically determined alteration in proximal tubules
from SHR occurs that leads to increased expression of CypB. In view of evidence
linking CypB to the regulation of elongation initiation factor-2, the
upregulation of CypB may result from metabolic stress.
PMID- 10775570
TI - Effects of renal medullary and intravenous norepinephrine on renal
antihypertensive function.
AB - Increasing renal arterial pressure activates at least 3 antihypertensive
mechanisms: reduced renin release, pressure natriuresis, and release of a
putative renal medullary depressor hormone. To examine the role of renal
medullary perfusion in these mechanisms, we tested the effects of the infusion of
norepinephrine, either infusion into the renal medullary interstitium or
intravenous infusion, on responses to increased renal arterial pressure in
pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which
allows renal arterial pressure to be set to any level above or below systemic
arterial pressure. With renal arterial pressure initially set at 65 mm Hg,
intravenous and medullary interstitial norepinephrine (300 ng. kg(-1). min(-1))
similarly increased mean arterial pressure (by 12% to 17% of baseline) and
reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to
19%), but only medullary norepinephrine reduced medullary perfusion (by 28%).
When renal arterial pressure was increased to approximately 160 mm Hg, in steps
of approximately 65 mm Hg, urine output and sodium excretion increased
exponentially, and plasma renin activity and mean arterial pressure fell.
Medullary interstitial but not intravenous norepinephrine attenuated the
increased diuresis and natriuresis and the depressor response to increased renal
arterial pressure. This suggests that norepinephrine can act within the renal
medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing
medullary perfusion. These observations support the concept that medullary
perfusion plays a critical role in the long-term control of arterial pressure by
its influence on pressure diuresis/natriuresis mechanisms and also by affecting
the release of the putative renal medullary depressor hormone.
PMID- 10775571
TI - Effects of cardiac natriuretic peptides on oxidized low-density lipoprotein- and
lysophosphatidylcholine-induced human mesangial cell migration.
AB - The objectives of the present study were (1) to determine whether oxidized LDL
and lysophosphatidylcholine (lyso-PtdCho), a major phospholipid component of
oxidized LDL, stimulate the migration of cultured human mesangial cells and (2)
to investigate the possible effects on mesangial cell migration of the cardiac
natriuretic peptides atrial and brain natriuretic peptide (ANP and BNP). Oxidized
LDL (10 and 100 microg/mL) and lyso-PtdCho (10(-7) to 10(-5) mol/L) stimulated
migration in a concentration-dependent manner. In contrast, the effects of native
LDL and phosphatidylcholine were modest or nonexistent. Protein kinase C (PKC)
inhibitor and downregulation of PKC activity by phorbol ester inhibited oxidized
LDL- and lyso-PtdCho-induced migration. Human ANP(1-28) and human BNP-32
significantly inhibited oxidized LDL- and lyso-PtdCho-induced migration in a
concentration-dependent manner. C-ANF (des
[Glu(18),Ser(19),Gly(20),Leu(21),Gly(22)]ANP(4-23)), a specific ligand for ANP
clearance receptors, could not inhibit oxidized LDL- and lyso-PtdCho-induced
migration. Inhibition by ANP and BNP of lyso-PtdCho-induced migration was
paralleled by an increase in the cellular level of GMP. Oxidized LDL- and lyso
PtdCho-induced migrations were inhibited by 8-bromo-cGMP. The results suggest
that oxidized LDL and lyso-PtdCho stimulate the migration of human mesangial
cells, at least in part, through a PKC-dependent process and that ANP and BNP
inhibit this stimulated migration, probably through a cGMP-dependent process.
PMID- 10775572
TI - Angiotensin II and alpha(v)beta(3) integrin expression in rat neonatal cardiac
fibroblasts.
AB - We recently demonstrated that alpha(v)beta(3) integrins are involved in the
mechanisms of angiotensin II (Ang II)-induced DNA synthesis and collagen gel
contractions in rat cardiac fibroblasts (CFBs), cellular mechanisms that are
relevant for cardiac remodeling. The aim of the present study was to elucidate
the effect of Ang II and other growth factors on the regulation of the
alpha(v)beta(3) integrins in fibroblasts from neonatal rat hearts. The
alpha(v)beta(3) integrin receptor expression was significantly increased (P<0.05)
at the mRNA level after treatment with Ang II, transforming growth factor-beta(1)
(TGF-beta(1)), and platelet-derived growth factor (PDGF) for 8 and 16 hours. The
surface expression of the alpha(v) and beta(3) integrin subunits was elevated
after 32 and 48 hours (P<0.05) as determined with flow cytometry. To investigate
fibroblast motility, we performed chemotaxis experiments with transwell chambers.
Ang II was chemotactic for CFBs, as tested with checkerboard experiments. The
chemotactic effect was concentration dependent and was completely blocked by Ang
II type 1 receptor blockers but not by Ang II type 2 receptor blocker PD 123319.
Ang II- and PDGF-BB-mediated chemotaxis could be significantly inhibited by RGD
peptides and the blocking antibodies against alpha(v)beta(3) integrin (both
P<0.01). Adhesion of CFBs to vitronectin was partially inhibited by an antibody
to alpha(v)beta(3) integrin but was mainly mediated by an alpha(v)beta(5)
integrin. Relevant in vivo expression of alpha(v)beta(3) integrin by CFBs was
confirmed with in situ hybridization with probes for alpha(v) and beta(3) mRNA in
rat hearts. The present study demonstrates that the expression of alpha(v)beta(3)
integrin is augmented by Ang II, PDGF, and TGF-beta(1) in neonatal CFBs.
Furthermore, this integrin is involved in the chemotaxis, motility, and adhesion
of CFBs. The present findings support the current concept that integrins
participate in the control of fibroblast behavior during cardiac remodeling
mechanisms.
PMID- 10775573
TI - Increased cardiac angiotensin II levels induce right and left ventricular
hypertrophy in normotensive mice.
AB - Angiotensin II is a potent arterial vasoconstrictor and induces hypertension.
Angiotensin II also exerts a trophic effect on cardiomyocytes in vitro. The goals
of the present study were to document an in vivo increase in cardiac angiotensins
in the absence of elevated plasma levels or hypertension and to investigate
prevention or regression of ventricular hypertrophy by renin-angiotensin system
blockade. We demonstrate that high cardiac angiotensin II is directly responsible
for right and left ventricular hypertrophy. We used transgenic mice
overexpressing angiotensinogen in cardiomyocytes characterized by cardiac
hypertrophy without fibrosis and normal blood pressure. Angiotensin-converting
enzyme inhibition and angiotensin II type 1 receptor blockade prevent or
normalize ventricular hypertrophy. Surprisingly, in control mice, receptor
blockade decreases tissue angiotensin II despite increased plasma levels. This
suggests that angiotensin II may be protected from metabolization by binding to
its receptor. Blocking of the angiotensin II type 1 receptor rather than enhanced
stimulation of the angiotensin II type 2 receptor may prevent remodeling and
account for the beneficial effects of angiotensin antagonists.
PMID- 10775574
TI - Synergistic effects of AT(1) and ET(A) receptor blockade in a transgenic,
angiotensin II-dependent, rat model.
AB - Angiotensin II and endothelin may participate in increasing blood pressure and
inducing end-organ damage, but the evidence is conflicting. We tested the
hypothesis that endothelin(A) receptor blockade would ameliorate blood pressure
and end-organ damage in a rat model of human renin-dependent hypertension. We
studied rats that were transgenic for both the human renin and angiotensinogen
genes. Experimental groups (n=12 each) of untreated transgenic rats, transgenic
rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats
receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and
nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was
measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic
peptide, collagen III, and ACE was measured. The mortality rate in untreated
transgenic rats was 42%, which is consistent with previous observations in this
line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat
per group (8%), without significantly lowering blood pressure. In the combination
group, blood pressure was normalized and all rats survived. The drug combination
also decreased elevated water intake in transgenic rats to normal levels and
significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs
decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III
gene expression. We suggest that endothelin participates in this model of
angiotensin II-induced hypertension and end-organ damage. Our findings may have
clinical implications and provide a rationale for combining angiotensin II type 1
receptor and endothelin(A) receptor blockade to obtain a synergistic effect.
PMID- 10775575
TI - Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by
noradrenaline in man.
AB - Angiotensin-(1-7) has been suggested to be a novel vasodilating peptide. We
investigated the direct vascular effect of angiotensin-(1-7) in human forearm
resistant vessels, particularly with regard to the interaction with angiotensin
II, in healthy normotensive men by strain-gauge venous occlusion plethysmography
with intra-arterial infusions of peptides. Intra-arterial infusion of angiotensin
(1-7) at 0.1 to 2000 pmol/min did not cause vasodilatation but rather reduced
forearm blood flow by approximately 10% at the highest dose. A placebo-controlled
study showed that angiotensin-(1-7) at 0.5 to 40 nmol/min caused weak but
significant vasoconstriction (P=0.0016 by ANOVA). Angiotensin-(1-7) at 100
pmol/min, but not at 10 pmol/min, significantly shifted the angiotensin II dose
response curve toward the right (mean+/-SD of percent changes in forearm blood
flow: -19+/-17%, -33+/-22%, -55+/-12%, -63+/-10%, and -68+/-5% at 5, 10, 25, 50,
and 100 pmol/min of angiotensin II, respectively, with saline; 5+/-13%, 0. 9+/
18%, -40+/-16%, -54+/-9%, and -61+/-6% with angiotensin-(1-7), P=0.0021 by
ANOVA). Angiotensin-(1-7) did not affect the dose-response curve of noradrenaline
[3+/-12%, 5+/-16%, -20+/-22%, -31+/-18%, and -40+/-12% at 25, 50, 100, 300, and
600 pmol/min of noradrenaline, respectively, with saline; -4+/-15%, -2+/-23%,
29+/-22%, -34+/-16%, and -42+/-9% with angiotensin-(1-7)]. Our results suggest
that angiotensin-(1-7) antagonizes vasoconstriction by angiotensin II in human
resistant vessels and might act as an endogenous angiotensin II antagonist.
PMID- 10775576
TI - Elevated intraluminal pressure inhibits vascular tissue plasminogen activator
secretion and downregulates its gene expression.
AB - We recently discovered that patients with essential hypertension have a markedly
impaired capacity for stimulated release of tissue plasminogen activator (tPA)
from vascular endothelium. This defect may reduce the chance of timely
spontaneous thrombolysis in case of an atherothrombotic event. We now
investigated whether increased intraluminal pressure as such may depress vascular
tPA release or downregulate its gene expression. Segments of human umbilical
veins were studied in a new computerized vascular perfusion model under steady
laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high
or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear
stress (10 dyne/cm(2)). Quantitative immunohistochemical evaluation of cellular
tPA immunoreactivity was performed on paraffin-embedded 5-microm vascular
sections. tPA mRNA in endothelial cells was quantified with reverse transcription
real-time TaqMan polymerase chain reaction with GAPDH as endogenous control.
Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western
blotting, followed by densitometric quantification. High-pressure perfusion
downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (P=0.01)
compared with vessels perfused under normal intraluminal pressure. tPA release
into the perfusion medium was markedly suppressed by high pressure (P<0.01
ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3
hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein
expression and inhibits its release from the endothelium independently of shear
stress. The defective capacity for stimulated tPA release that we demonstrated in
patients with essential hypertension might thus be an effect of the elevated
intraluminal pressure per se.
PMID- 10775578
TI - Hypertension online only : april 2000
PMID- 10775577
TI - Development of hypertension in a rat model of diet-induced obesity.
AB - Although obesity is a risk factor for hypertension, the relationship between
these 2 conditions is not well understood. Therefore, we examined some parameters
of hypertension and cardiovascular disease in a dietary model of obesity. Male
Sprague-Dawley rats were provided either a control diet (C) or a diet containing
32% kcal as fat (similar to a Western diet) for 1, 3, or 10 weeks. Rats in the
latter group diverged based on body weight gain into obesity-prone (OP) and
obesity-resistant (OR) groups. Systolic blood pressure in OP rats was
significantly higher after 10 weeks of the diet (149+/-4. 8 mm Hg) compared with
both OR and C groups (131+/-3.7 and 129+/-4.5 mm Hg, respectively). The aortic
wall area of OP rats was significantly increased, indicating arterial
hypertrophy, and a 2-fold increase in plasma renin activity was found in OP rats
compared with OR and C rats. The lipid profile showed a significant increase in
plasma and VLDL triglycerides of OP versus OR and C groups as early as 3 weeks on
the diet. Plasma and LDL-cholesterol levels were increased in the OP group versus
the OR and C groups after 3 weeks of the diet, but the difference was blunted
after 10 weeks. Lipid peroxidation (thiobarbituric acid-reactive substances) in
OP rats was increased 2-fold in LDL and 1.5-fold in aortic wall compared with OR
rats, suggesting an increased oxidative stress in these animals. Periodic acid
Schiff staining of the kidney showed mesangial expansion and focal sclerosis that
were more prominent in OP rats than in OR rats. The results suggest that
hypercholesterolemia, but not hypertriglyceridemia, is linked to the diet; that
hypertension and renin-angiotensin system activation are associated with obesity;
and that lipid peroxidation and renal damage are the results of both factors.
PMID- 10775579
TI - Induction of cellular genes is mediated by the Bel1 transactivator in foamy virus
infected human cells.
AB - To gain insight into human foamy virus (HFV; also called spumaretrovirus)-induced
alterations of cellular genes, the expression profiles of defined genes in HFV
infected primary human cells were analyzed by cDNA array assays. Several distinct
cellular genes activated by HFV infection were identified; the identities of the
cellular genes were confirmed by RNA blot analyses. Compared with mock-infected
controls, the concentrations of cellular Kip2, Egr-1, COUP-TF1, insulin-like
growth factor II (IGF-II), and EphB3 mRNAs were significantly increased in HFV
infected cells and showed a gene-specific and time-dependent induction.
Immunoblot analyses with antibodies against some of the cellular gene products
revealed increased levels of the corresponding proteins. To investigate
mechanisms of HFV-induced alterations in cellular gene expression, the capacity
of known HFV genes to increase expression of defined cellular genes was analyzed
by transient expression experiments. Plasmids that encode the HFV Bel1
transcriptional transactivator were necessary and sufficient to strongly increase
expression of p57Kip2, IGF-II, and EphB3 genes in 293T cells. Potential
mechanisms and consequences of activation of cellular genes during HFV infection
and Bel1 transactivation of the Kip2 gene are discussed.
PMID- 10775580
TI - The human immunodeficiency virus type 1 gp120 V2 domain mediates gp41-independent
intersubunit contacts.
AB - The envelope protein of human immunodeficiency virus type 1 HIV-1 undergoes
proteolytic cleavage in the Golgi complex to produce subunits designated gp120
and gp41, which remain noncovalently associated. While gp41 has a well
characterized oligomeric structure, the maintenance of gp41-independent gp120
intersubunit contacts remains a contentious issue. Using recombinant vaccinia
virus to achieve high-level expression of gp120 in mammalian cells combined with
gel filtration analysis, we were able to isolate a discrete oligomeric form of
gp120. Oligomerization of gp120 occurred intracellularly between 30 and 120 min
after synthesis. Analysis by sedimentation equilibrium unequivocally identified
the oligomeric species as a dimer. In order to identify the domains involved in
the intersubunit contact, we expressed a series of gp120 proteins lacking various
domains and assessed the effects of mutation on oligomeric structure. Deletion of
the V1 or V3 loops had little effect on the relative amounts of monomer and dimer
in comparison to wild-type gp120. In contrast, deletion of either all or part of
the V2 loop drastically reduced dimer formation, indicating that this domain is
required for intersubunit contact formation. Consistent with this, the V2 loop of
the dimer was less accessible than that of the monomer to a specific monoclonal
antibody. Previous studies have shown that while the V2 loop is not an absolute
requirement for viral entry, the absence of this domain reduces viral resistance
to neutralization by monoclonal antibodies or sera. We propose that the
quaternary structure of gp120 may contribute to resistance to neutralization by
limiting the exposure of conserved epitopes.
PMID- 10775581
TI - CD8(+)-Cell antiviral factor activity is not restricted to human immunodeficiency
virus (HIV)-specific T cells and can block HIV replication after initiation of
reverse transcription.
AB - CD8(+) lymphocytes from human immunodeficiency virus (HIV)-infected patients can
suppress in vitro HIV replication in CD4(+) T cells by a noncytolytic mechanism
involving secreted CD8(+)-cell antiviral factor(s) (CAF). Using an HIV Nef
specific cytotoxic-T-lymphocyte (CTL) line and autologous CD4(+) T cells infected
with a nef-deleted HIV-1 virus, we demonstrated that, after a priming antigenic
stimulation, this suppression does not require the presence of the specific
antigen during the effector phase. Furthermore, using an Epstein-Barr virus (EBV)
specific CTL line from an HIV-seronegative donor, we demonstrated that the
ability to inhibit HIV replication in a noncytolytic manner is not restricted to
HIV-specific effector cells; indeed, EBV-specific CTL were as efficient as HIV
specific effectors in suppressing R5 or X4 HIV-1 strain replication in vitro.
This HIV-suppressive activity mediated by a soluble factor(s) present in the
culture supernatant was detectable for up to 14 days following stimulation of EBV
specific CD8(+) cells with the cognate epitope peptide. Following acute infection
of CEM cells with an X4 strain of HIV-1, EBV-specific CTL line supernatant
containing HIV-suppressive activity did not block virus entry but was shown to
interfere with virus replication after the first template switching of reverse
transcription. Our results suggest that the noncytolytic control of HIV
replication by EBV-specific CD8(+) T lymphocytes corresponded to a CAF-like
activity and thus demonstrate that CAF production may not be restricted to CTL
induced during HIV disease. Moreover, CAF acts after reverse transcription at
least for X4 isolate replication inhibition.
PMID- 10775582
TI - Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents
recognition of transgene products by CD8(+) cytotoxic T lymphocytes.
AB - The in vivo persistence of gene-modified cells may be limited by the development
of a host immune response to vector-encoded proteins. Herpesviruses evade
cytotoxic T-lymphocyte (CTL) recognition by expressing genes which interfere
selectively with presentation of viral antigens by class I major
histocompatibility complex (MHC) molecules. Here, we studied the use of
retroviral vectors encoding herpes simplex virus ICP47, human cytomegalovirus
(HCMV) US3, or HCMV US11 to decrease presentation of viral proteins and transgene
products to CD8(+) CTL. Human fibroblasts and T cells transduced to express the
ICP47, US3, or US11 genes alone exhibited a decrease in cell surface class I MHC
expression. The combination of ICP47 and US11 rendered fibroblasts negative for
surface class I MHC and allowed a class I MHC-low population of T cells to be
sorted by flow cytometry. Fibroblasts and T cells expressing both ICP47 and US11
were protected from CTL-mediated lysis and failed to stimulate specific memory T
cell responses to transgene products in vitro. Our findings suggest that
expression of immunoregulatory viral gene products could be a potential strategy
to prolong transgene expression in vivo.
PMID- 10775583
TI - An evolutionarily conserved positively charged amino acid in the putative
membrane-spanning domain of the foamy virus envelope protein controls fusion
activity.
AB - Foamy viruses (FVs) are highly fusogenic, and their replication induces massive
syncytium formation in infected cell cultures which is believed to be mediated by
expression of the envelope (Env) protein. The FV Env is essential for virus
particle egress. The unusually long putative membrane-spanning domain (MSD) of
the transmembrane subunit carries dispersed charged amino acids and has an
important function for particle envelopment. To better understand the capsid
envelope interaction and Env-mediated cell fusion, we generated a variety of FV
MSD mutations. C-terminal deletions revealed the cytoplasmic domain to be
dispensable but the full-length MSD to be required for fusogenic activity. The N
terminal 15 amino acids of the MSD were found to be sufficient for membrane
anchorage and promotion of FV particle release. Expression of wild-type Env
protein rarely induced syncytia due to intracellular retention. Coexpression with
FV Gag-Pol resulted in particle export and a dramatic increase in fusion
activity. A nonconservative mutation of K(959) in the middle of the putative MSD
resulted in increased fusogenic activity of Env in the absence of Gag-Pol due to
enhanced cell surface expression as well as structural changes in the mutant
proteins. Coexpression with Gag-Pol resulted in a further increase in the fusion
activity of mutant FV Env proteins. Our results suggest that an interaction
between the viral capsid and Env is required for FV-induced giant-cell formation
and that the positive charge in the MSD is an important determinant controlling
intracellular transport and fusogenic activity of the FV Env protein.
PMID- 10775584
TI - Posttranscriptional inhibition of class I major histocompatibility complex
presentation on hepatocytes and lymphoid cells in chronic woodchuck hepatitis
virus infection.
AB - Woodchuck hepatitis virus (WHV), similar to human hepatitis B virus, causes acute
liver inflammation that can progress to chronic hepatitis and hepatocellular
carcinoma. WHV also invades cells of the host lymphatic system, where it persists
for life. We report here that acute and chronic hepadnavirus hepatitis is
characterized by a profound difference in the expression of class I major
histocompatibility complex (MHC) molecules on the surface of infected hepatocytes
and, notably, lymphoid cells. While acute WHV infection is accompanied by the
enhanced hepatocyte surface presentation of class I MHC antigen and upregulated
transcription of the relevant hepatic genes, inhibition of class I antigen
display on liver cells is a uniform hallmark of chronic WHV infection. This
inhibition in chronic hepatitis occurs despite augmented (as in acute infection)
expression of hepatic genes for class I MHC heavy chain, beta(2)-microglobulin,
and transporters associated with antigen processing (TAP1 and TAP2). Further, the
class I antigen inhibition is not related to the histological severity of
hepatocellular injury, the extent of lymphocytic infiltrations, the level of
intrahepatic gamma interferon induction, or the hepatic WHV load. Importantly,
the antigen expression is also inhibited on organ lymphoid cells of chronically
infected hosts. The results obtained in this study demonstrate that the defective
presentation of class I MHC molecules on cells supporting persistent WHV
replication is due to viral posttranscriptional interference. This event may
diminish the susceptibility of infected hepatocytes to virus-specific T-cell
mediated elimination, hinder virus clearance, and deregulate the class I MHC
dependent functions of the host immune system. This multifarious effect could be
critical for perpetuation of liver damage and evasion of the antiviral
immunological surveillance in chronic infection and therefore could be supportive
of hepadnavirus persistence.
PMID- 10775585
TI - The carboxyl terminus of v-Abl protein can augment SH2 domain function.
AB - Abelson murine leukemia virus (Ab-MLV) transforms NIH 3T3 and pre-B cells via
expression of the v-Abl tyrosine kinase. Although the enzymatic activity of this
molecule is absolutely required for transformation, other regions of the protein
are also important for this response. Among these are the SH2 domain, involved in
phosphotyrosine-dependent protein-protein interactions, and the long carboxyl
terminus, which plays an important role in transformation of hematopoietic cells.
Important signals are sent from each of these regions, and transformation is most
likely orchestrated by the concerted action of these different parts of the
protein. To explore this idea, we compared the ability of the v-Src SH2 domain to
substitute for that of v-Abl in the full-length P120 v-Abl protein and in P70 v
Abl, a protein that lacks the carboxyl terminus characteristic of Abl family
members. Ab-MLV strains expressing P70/S2 failed to transform NIH 3T3 cells and
demonstrated a greatly reduced capacity to mediate signaling events associated
with the Ras-dependent mitogen-activated protein (MAP) kinase pathway. In
contrast, Ab-MLV strains expressing P120/S2 were indistinguishable from P120 with
respect to these features. Analyses of additional mutants demonstrated that the
last 162 amino acids of the carboxyl terminus were sufficient to restore
transformation. These data demonstrate that an SH2 domain with v-Abl substrate
specificity is required for NIH 3T3 transformation in the absence of the carboxyl
terminus and suggest that cooperativity between the extreme carboxyl terminus and
the SH2 domain facilitates the transmission of transforming signals via the MAP
kinase pathway.
PMID- 10775586
TI - Inhibition of human immunodeficiency virus type 1 replication prior to reverse
transcription by influenza virus stimulation.
AB - It is now recognized that, in addition to drug-mediated therapies against human
immunodeficiency virus type 1 (HIV-1), the immune system can exert antiviral
effects via CD8(+) T-cell-generated anti-HIV factors. This study demonstrates
that (i) supernatants from peripheral blood mononuclear cells (PBMC) stimulated
with influenza A virus inhibit replication of CCR5- and CXCR4-tropic HIV-1
isolates prior to reverse transcription; (ii) the HIV-suppressive supernatants
can be generated by CD4- or CD8-depleted PBMC; (iii) this anti-HIV activity is
partially due to alpha interferon (IFN-alpha), but not to IFN-gamma, IFN-beta,
the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES, or interleukin-16; (iv)
the anti-HIV activity is generated equally well by PBMC cultured with either
infectious or UV-inactivated influenza A virus; and (v) the antiviral activity
can be generated by influenza A-stimulated PBMC from HIV-infected individuals.
These findings represent a novel mechanism for inhibition of HIV-1 replication
that differs from the previously described CD8 anti-HIV factors (MIP-1alpha, MIP
1beta, RANTES, and CD8 antiviral factor).
PMID- 10775587
TI - The minimal replicator of Epstein-Barr virus oriP.
AB - oriP is a 1.7-kb region of the Epstein-Barr virus (EBV) chromosome that supports
the replication and stable maintenance of plasmids in human cells. oriP contains
two essential components, called the DS and the FR, both of which contain
multiple binding sites for the EBV-encoded protein, EBNA-1. The DS appears to
function as the replicator of oriP, while the FR acts in conjunction with EBNA-1
to prevent the loss of plasmids from proliferating cells. Because of EBNA-1's
role in stabilizing plasmids through the FR, it has not been entirely clear to
what extent EBNA-1 might be required for replication from oriP per se, and a
recent study has questioned whether EBNA-1 has any direct role in replication. In
the present study we found that plasmids carrying oriP required EBNA-1 to
replicate efficiently even when assayed only 2 days after plasmids were
introduced into the cell lines 143B and 293. Significantly, using 293 cells it
was demonstrated that the plasmid-retention function of EBNA-1 and the FR did not
contribute significantly to the accumulation of replicated plasmids, and the DS
supported efficient EBNA-1-dependent replication in the absence of the FR. The DS
contains two pairs of closely spaced EBNA-1 binding sites, and a previous study
had shown that both sites within either pair are required for activity. However,
it was unclear from previous work what additional sequences within the DS might
be required. We found that each "half" of the DS, including a pair of closely
spaced EBNA-1 binding sites, had significant replicator activity when the other
half had been deleted. The only significant DNA sequences that the two halves of
the DS share in common, other than EBNA-1 binding sites, is a 9-bp sequence that
is present twice in the "left half" and once in the "right half." These nonamer
repeats, while not essential for activity, contributed significantly to the
activity of each half of the DS. Two thymines occur at unique positions within
EBNA-1 binding sites 1 and 4 at the DS and become sensitive to oxidation by
permanganate when EBNA-1 binds, but mutation of each to the consensus base,
adenine, actually improved the activity of each half of the DS slightly. In
conclusion, the DS of oriP is an EBNA-1-dependent replicator, and its minimal
active core appears to be simply two properly spaced EBNA-1 binding sites.
PMID- 10775588
TI - A novel polyomavirus (goose hemorrhagic polyomavirus) is the agent of hemorrhagic
nephritis enteritis of geese.
AB - We have identified the etiological agent of hemorrhagic nephritis enteritis of
geese (HNEG), a fatal disease of European geese. HNEG has been recognized in
almost all goose breeding areas, with an epizootic pattern, and up to now, the
infectious agent has remained unknown. In order to identify the causative agent,
infected tissues from HNEG-affected geese were inoculated to 1-day-old goslings,
which then developed clinical signs typical of HNEG. Tissue homogenates from
these birds were subjected to Freon extraction followed by sucrose density
gradient ultracentrifugation. The resulting main band was examined by electron
microscopy and consisted of spherical, naked, papovavirus-like particles
approximately 45 nm in diameter. The virus was isolated and propagated in goose
kidney cell primary culture. Tissue- or culture-purified virus allowed the
experimental reproduction of the disease in goslings. Random PCR amplification of
viral nucleic acid produced a 1,175-bp fragment which was shown to be associated
with field samples collected from geese affected by HNEG on commercial farms in
France. Sequence analysis of the PCR product revealed a unique open reading
frame, showing 63 to 72% amino acid similarity with the major capsid protein
(VP1) of several polyomaviruses. Finally, based on phylogenetic analysis, we
conclude that the causative agent of HNEG is closely related to but clearly
distinct from other polyomaviruses; we thus have named this newly identified
virus Goose hemorrhagic polyomavirus.
PMID- 10775589
TI - Identification and analysis of a novel heparin-binding glycoprotein encoded by
human herpesvirus 7.
AB - Human herpesvirus 6 (HHV-6) and HHV-7 are closely related betaherpesviruses that
encode a number of genes with no known counterparts in other herpesviruses. The
product of one such gene is the HHV-6 glycoprotein gp82-105, which is a major
virion component and a target for neutralizing antibodies. A 1.7-kb cDNA clone
from HHV-7 was identified which contains a large open reading frame capable of
encoding a predicted primary translational product of 468 amino acids (54 kDa)
with 13 cysteine residues and 9 potential N-linked glycosylation sites. This
putative protein, which we have termed gp65, was homologous to HHV-6 gp105 (30%
identity) and contained a single potential membrane-spanning domain located near
its amino terminus. Comparison of the cDNA sequence with that of the viral genome
revealed that the gene encoding gp65 contains eight exons, spanning almost 6 kb
of the viral genome at the right (3') end of the HHV-7 genome. Northern (RNA)
blot analysis with poly(A)(+) RNA from HHV-7-infected cells revealed that the
cDNA insert hybridized to a single major RNA species of 1.7 kb. Antiserum raised
against a purified, recombinant form of gp65 recognized a protein of roughly 65
kDa in sucrose density gradient-purified HHV-7 preparations; treatment with
PNGase F reduced this glycoprotein to a putative precursor of approximately 50
kDa. Gp65-specific antiserum also neutralized the infectivity of HHV-7, while
matched preimmune serum did not do so. Finally, analysis of the biochemical
properties of recombinant gp65 revealed a specific interaction with heparin and
heparan sulfate proteoglycans and not with closely related molecules such as N
acetylheparin and de-N-sulfated heparin. At least two domains of the protein were
found to contribute to heparin binding. Taken together, these findings suggest
that HHV-7 gp65 may contribute to viral attachment to cell surface proteoglycans.
PMID- 10775590
TI - Identifying the determinants in the equatorial domain of Buchnera GroEL
implicated in binding Potato leafroll virus.
AB - Luteoviruses avoid degradation in the hemolymph of their aphid vector by
interacting with a GroEL homolog from the aphid's primary endosymbiotic bacterium
(Buchnera sp.). Mutational analysis of GroEL from the primary endosymbiont of
Myzus persicae (MpB GroEL) revealed that the amino acids mediating binding of
Potato leafroll virus (PLRV; Luteoviridae) are located within residues 9 to 19
and 427 to 457 of the N-terminal and C-terminal regions, respectively, of the
discontinuous equatorial domain. Virus overlay assays with a series of
overlapping synthetic decameric peptides and their derivatives demonstrated that
R13, K15, L17, and R18 of the N-terminal region and R441 and R445 of the C
terminal region of the equatorial domain of GroEL are critical for PLRV binding.
Replacement of R441 and R445 by alanine in full-length MpB GroEL and in MpB GroEL
deletion mutants reduced but did not abolish PLRV binding. Alanine substitution
of either R13 or K15 eliminated the PLRV-binding capacity of the other and those
of L17 and R18. In the predicted tertiary structure of GroEL, the determinants
mediating virus binding are juxtaposed in the equatorial plain.
PMID- 10775591
TI - Directional transneuronal infection by pseudorabies virus is dependent on an
acidic internalization motif in the Us9 cytoplasmic tail.
AB - The Us9 gene is conserved among most alphaherpesviruses. In pseudorabies virus
(PRV), the Us9 protein is a 98-amino-acid, type II membrane protein found in the
virion envelope. It localizes to the trans-Golgi network (TGN) region in infected
and transfected cells and is maintained in this compartment by endocytosis from
the plasma membrane. Viruses with Us9 deleted have no observable defects in
tissue culture yet have reduced virulence and restricted spread to
retinorecipient neurons in the rodent brain. In this report, we demonstrate that
Us9-promoted transneuronal spread in vivo is dependent on a conserved acidic
motif previously shown to be essential for the maintenance of Us9 in the TGN
region and recycling from the plasma membrane. Mutant viruses with the acidic
motif deleted have an anterograde spread defect indistinguishable from that of
Us9 null viruses. Transneuronal spread, however, is not dependent on a dileucine
endocytosis motif in the Us9 cytoplasmic tail. Through alanine scanning
mutagenesis of the acidic motif, we have identified two conserved tyrosine
residues that are essential for Us9-mediated spread as well as two serine
residues, comprising putative consensus casein kinase II sites, that modulate the
rate of PRV transneuronal spread in vivo.
PMID- 10775592
TI - Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency
virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse
enveloped viruses.
AB - Cyanovirin-N (CV-N) is a cyanobacterial protein with potent neutralizing activity
against human immunodeficiency virus (HIV). CV-N has been shown to bind HIV type
1 (HIV-1) gp120 with high affinity; moreover, it blocks the envelope glycoprotein
mediated membrane fusion reaction associated with HIV-1 entry. However, the
inhibitory mechanism(s) remains unclear. In this study, we show that CV-N blocked
binding of gp120 to cell-associated CD4. Consistent with this, pretreatment of
gp120 with CV-N inhibited soluble CD4 (sCD4)-dependent binding of gp120 to cell
associated CCR5. To investigate possible effects of CV-N at post-CD4 binding
steps, we used an assay that measures sCD4 activation of the HIV-1 envelope
glycoprotein for fusion with CCR5-expressing cells. CV-N displayed equivalently
potent inhibitory effects when added before or after sCD4 activation, suggesting
that CV-N also has blocking action at the level of gp120 interaction with
coreceptor. This effect was shown not to be due to CV-N-induced coreceptor down
modulation after the CD4 binding step. The multiple activities against the HIV-1
envelope glycoprotein prompted us to examine other enveloped viruses. CV-N
potently blocked infection by feline immunodeficiency virus, which utilizes the
chemokine receptor CXCR4 as an entry receptor but is CD4 independent. CV-N also
inhibited fusion and/or infection by human herpesvirus 6 and measles virus but
not by vaccinia virus. Thus, CV-N has broad-spectrum antiviral activity, both for
multiple steps in the HIV entry mechanism and for diverse enveloped viruses. This
broad specificity has implications for potential clinical utility of CV-N.
PMID- 10775593
TI - Expression of an antigenic adenovirus epitope in a group B coxsackievirus.
AB - Group B coxsackieviruses (CVB) cause human myocarditis, while human adenovirus
type 2 (Ad2) is implicated as an agent of this disease. The L1 loop of the Ad2
hexon protein has been demonstrated to be antigenic in rabbits. To evaluate the
feasibility of a multivalent vaccine strain against the CVB and Ad2, we cloned
the sequence encoding the Ad2 hexon L1 loop, flanked by dissimilar sequences
encoding the protease 2A (2Apro) recognition sites, into the genome of an
attenuated strain of CVB type 3 (CVB3/0) at the junction of 2Apro and the capsid
protein 1D. Progeny virus (CVB3-PL2-Ad2L1) was obtained following transfection of
the construct into HeLa cells. Replication of CVB3-PL2-Ad2L1 in diverse cell
cultures demonstrated that the yield of the chimeric virus was between 0.5 to 2
log units less than the parental strain. Western blot analyses of the CVB3 capsid
protein 1D in CVB3-PL2-Ad2L1-infected HeLa cells demonstrated production of the
expected capsid protein. Viral proteins were detected earlier and in
approximately fourfold greater amounts in CVB3-PL2-Ad2L1-infected HeLa cells than
in CVB3/0-infected cells. Cleavage of the CVB3-PL2-Ad2L1 polyprotein by 2Apro was
slowed, accompanied by an accumulation of the fusion 1D-L1 loop protein. Reverse
transcription-PCR sequence analysis of CVB3-PL2-Ad2L1 RNA demonstrated that the
Ad2 hexon polypeptide coding sequence was maintained in the chimeric viral genome
through at least 10 passages in HeLa cells. Mice inoculated with CVB3-PL2-Ad2L1
demonstrated a brief viremia with no replication detectable in the heart but
prolonged replication of virus in the pancreas in the absence of pathologic
changes in either organ. CVB3-PL2-Ad2L1 induced binding and neutralizing anti-Ad2
antibodies, in addition to antibodies against CVB3 in mice. CVB3-PL2-Ad2L1 was
used to challenge mice previously inoculated with CVB3/0 and with preexisting
anti-CVB3 neutralizing-antibody titers; anti-Ad2 neutralizing and binding
antibodies were induced in these mice at higher levels than in mice without anti
CVB3 immunity. The data demonstrate that a CVB vector can stably express an
antigenic polypeptide of Ad2 from within the CVB open reading frame that results
in the induction of protective immune responses against both viruses.
PMID- 10775594
TI - Replicase complex genes of Semliki Forest virus confer lethal neurovirulence.
AB - Semliki Forest virus (SFV) is a mosquito-transmitted pathogen of small rodents,
and infection of adult mice with SFV4, a neurovirulent strain of SFV, leads to
lethal encephalitis in a few days, whereas mice infected with the avirulent
A7(74) strain remain asymptomatic. In adult neurons, A7(74) is unable to form
virions and hence does not reach a critical threshold of neuronal damage. To
elucidate the molecular mechanisms of neurovirulence, we have cloned and
sequenced the entire 11,758-nucleotide genome of A7(74) and compared it to the
highly neurovirulent SFV4 virus. We found several sequence differences and sought
to localize determinants conferring the neuropathogenicity by using a panel of
chimeras between SFV4 and a cloned recombinant, rA774. We first localized
virulence determinants in the nonstructural region by showing that rA774
structural genes combined with the SFV4 nonstructural genome produced a highly
virulent virus, while a reciprocal recombinant was asymptomatic. In addition to
several amino acid mutations in the nonstructural region, the nsp3 gene of rA774
displayed an opal termination codon and an in-frame 21-nucleotide deletion close
to the nsp4 junction. Replacement in rA774 of the entire nsp3 gene with that of
SFV4 reconstituted the virulent phenotype, whereas an arginine at the opal
position significantly increased virulence, leading to clinical symptoms in mice.
Completion of the nsp3 deletion in rA774 did not increase virulence. We conclude
that the opal codon and amino acid mutations other than the deleted residues are
mainly responsible for the attenuation of A7(74) and that the attenuating
determinants reside entirely in the nonstructural region.
PMID- 10775595
TI - Identification of a cis-acting replication element within the poliovirus coding
region.
AB - The replication of poliovirus, a positive-stranded RNA virus, requires
translation of the infecting genome followed by virus-encoded VPg and 3D
polymerase-primed synthesis of a negative-stranded template. RNA sequences
involved in the latter process are poorly defined. Since many sequences involved
in picornavirus replication form RNA structures, we searched the genome, other
than the untranslated regions, for predicted local secondary structural elements
and identified a 61-nucleotide (nt) stem-loop in the region encoding the 2C
protein. Covariance analysis suggested the structure was well conserved in the
Enterovirus genus of the Picornaviridae. Site-directed mutagenesis, disrupting
the structure without affecting the 2C product, destroyed genome viability and
suggested that the structure was required in the positive sense for function.
Recovery of revertant viruses suggested that integrity of the structure was
critical for function, and analysis of replication demonstrated that nonviable
mutants did not synthesize negative strands. Our conclusion, that this RNA
secondary structure constitutes a novel poliovirus cis-acting replication element
(CRE), is supported by the demonstration that subgenomic replicons bearing lethal
mutations in the native structure can be restored to replication competence by
the addition of a second copy of the 61-nt wild-type sequence at another location
within the genome. This poliovirus CRE functionally resembles an element
identified in rhinovirus type 14 (K. L. McKnight and S. M. Lemon, RNA 4:1569
1584, 1998) and the cardioviruses (P. E. Lobert, N. Escriou, J. Ruelle, and T.
Michiels, Proc. Natl. Acad. Sci. USA 96:11560-11565, 1999) but differs in
sequence, structure, and location. The functional role and evolutionary
significance of CREs in the replication of positive-sense RNA viruses is
discussed.
PMID- 10775596
TI - Isolation of Borna disease virus from human brain tissue.
AB - Serological and molecular epidemiological studies indicate that Borna disease
virus (BDV) can infect humans and is possibly associated with certain
neuropsychiatric disorders. We examined brain tissue collected at autopsy from
four schizophrenic patients and two healthy controls for the presence of BDV
markers in 12 different brain regions. BDV RNA and antigen was detected in four
brain regions of a BDV-seropositive schizophrenic patient (P2) with a very recent
(2 years) onset of disease. BDV markers exhibited a regionally localized
distribution. BDV RNA was found in newborn Mongolian gerbils intracranially
inoculated with homogenates from BDV-positive brain regions of P2. Human
oligodendroglia (OL) cells inoculated with brain homogenates from BDV-positive
gerbils allowed propagation and isolation of BDVHuP2br, a human brain-derived
BDV. Virus isolation was also possible by transfection of Vero cells with
ribonucleoprotein complexes prepared from BDV-positive human and gerbil brain
tissues. BDVHuP2br was genetically closely related to but distinct from
previously reported human- and animal-derived BDV sequences.
PMID- 10775597
TI - Design and packaging of adeno-associated virus gene targeting vectors.
AB - Adeno-associated virus (AAV) vectors can transduce cells by several mechanisms,
including (i) gene addition by chromosomal integration or episomal transgene
expression or (ii) gene targeting by modification of homologous chromosomal
sequences. The latter process can be used to correct a variety of mutations in
chromosomal genes with high fidelity and specificity. In this study, we used
retroviral vectors to introduce mutant alkaline phosphatase reporter genes into
normal human cells and subsequently corrected these mutations with AAV gene
targeting vectors. We find that increasing the length of homology between the AAV
vector and the target locus improves gene correction rates, as does positioning
the mutation to be corrected in the center of the AAV vector genome. AAV-mediated
gene targeting increases with time and multiplicity of infection, similar to AAV
mediated gene addition. However, in contrast to gene addition, genotoxic stress
did not affect gene targeting rates, suggesting that different cellular factors
are involved. In the course of these studies, we found that (i) vector genomes
less than half of wild-type size could be packaged as monomers or dimers and (ii)
packaged dimers consist of inverted repeats with covalently closed hairpins at
either end. These studies should prove helpful in designing AAV gene targeting
vectors for basic research or gene therapy.
PMID- 10775599
TI - Influenza virus assembly and lipid raft microdomains: a role for the cytoplasmic
tails of the spike glycoproteins.
AB - Influenza viruses encoding hemagglutinin (HA) and neuraminidase (NA)
glycoproteins with deletions in one or both cytoplasmic tails (HAt- or NAt-) have
a reduced association with detergent-insoluble glycolipids (DIGs). Mutations
which eliminated various combinations of the three palmitoylation sites in HA
exhibited reduced amounts of DIG-associated HA in virus-infected cells. The
influenza virus matrix (M(1)) protein was also found to be associated with DIGs,
but this association was decreased in cells infected with HAt- or NAt- virus.
Regardless of the amount of DIG-associated protein, the HA and NA glycoproteins
were targeted primarily to the apical surface of virus-infected, polarized cells.
The uncoupling of DIG association and apical transport was augmented by the
observation that the influenza A virus M(2) protein as well as the influenza C
virus HA-esterase-fusion glycoprotein were not associated with DIGs but were
apically targeted. The reduced DIG association of HAt- and NAt- is an intrinsic
property of the glycoproteins, as similar reductions in DIG association were
observed when the proteins were expressed from cDNA. Examination of purified
virions indicated reduced amounts of DIG-associated lipids in the envelope of HAt
and NAt- viruses. The data indicate that deletion of both the HA and NA
cytoplasmic tails results in reduced DIG association and changes in both virus
polypeptide and lipid composition.
PMID- 10775600
TI - Rotavirus-induced structural and functional alterations in tight junctions of
polarized intestinal Caco-2 cell monolayers.
AB - We provide here new insights into rotavirus (RRV) pathogenicity by showing that
RRV infection promotes structural and functional injuries localized at the tight
junctions (TJ) in the cell-cell junctional complex of cultured polarized human
intestinal Caco-2 cells forming monolayers. RRV infection resulted in a
progressive increase in the paracellular permeability to [(3)H]mannitol as a
function of the time postinfection. We observed a disorganization of the TJ
associated protein occludin as a function of the time postinfection, whereas
distribution of the zonula adherens associated E-cadherin was not affected. These
structural and functional RRV-induced TJ injuries were not accompanied by
alteration in cell and monolayer integrity, as assessed by the lack of change in
transepithelial membrane resistance and lactate dehydrogenase release. Finally,
using the stabilizer of actin filaments Jasplakinolide, we demonstrated that the
RRV-induced structural and functional alterations in TJ are independent of the
RRV-induced apical F-actin rearrangements.
PMID- 10775598
TI - Identification of a key target sequence to block human immunodeficiency virus
type 1 replication within the gag-pol transframe domain.
AB - Although the full sequence of the human immunodeficiency virus type 1 (HIV-1)
genome has been known for more than a decade, effective genetic antivirals have
yet to be developed. Here we show that, of 22 regions examined, one highly
conserved sequence (ACTCTTTGGCAACGA) near the 3' end of the HIV-1 gag-pol
transframe region, encoding viral protease residues 4 to 8 and a C-terminal Vpr
binding motif of p6(Gag) protein in two different reading frames, can be
successfully targeted by an antisense peptide nucleic acid oligomer named
PNA(PR2). A disrupted translation of gag-pol mRNA induced at the PNA(PR2)
annealing site resulted in a decreased synthesis of Pr160(Gag-Pol) polyprotein,
hence the viral protease, a predominant expression of Pr55(Gag) devoid of a fully
functional p6(Gag) protein, and the excessive intracellular cleavage of Gag
precursor proteins, hindering the processes of virion assembly. Treatment with
PNA(PR2) abolished virion production by up to 99% in chronically HIV-1-infected
H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1
isolates with the multidrug-resistant phenotype. This particular segment of the
gag-pol transframe gene appears to offer a distinctive advantage over other
regions in invading viral structural genes and restraining HIV-1 replication in
infected cells and may potentially be exploited as a novel antiviral genetic
target.
PMID- 10775601
TI - Successful vaccine-induced seroconversion by single-dose immunization in the
presence of measles virus-specific maternal antibodies.
AB - In humans, maternal antibodies inhibit successful immunization against measles,
because they interfere with vaccine-induced seroconversion. We have investigated
this problem using the cotton rat model (Sigmodon hispidus). As in humans,
passively transferred antibodies inhibit the induction of measles virus (MV)
neutralizing antibodies and protection after immunization with MV. In contrast, a
recombinant vesicular stomatitis virus (VSV) expressing the MV hemagglutinin (VSV
H) induces high titers of neutralizing antibodies to MV in the presence of MV
specific antibodies. The induction of neutralizing antibodies increased with
increasing virus dose, and all doses gave good protection from subsequent
challenge with MV. Induction of antibodies by VSV-H was observed in the presence
of passively transferred human or cotton rat antibodies, which were used as the
models of maternal antibodies. Because MV hemagglutinin is not a functional part
of the VSV-H envelope, MV-specific antibodies only slightly inhibit VSV-H
replication in vitro. This dissociation of function and antigenicity is probably
key to the induction of a neutralizing antibody in the presence of a maternal
antibody.
PMID- 10775602
TI - Activation of transcription factors NF-kappaB and NF-IL-6 by human
immunodeficiency virus type 1 protein R (Vpr) induces interleukin-8 expression.
AB - Human immunodeficiency virus (HIV)-positive individuals express elevated levels
of interleukin-8 (IL-8), which is believed to be responsible for some of the
clinical manifestations occurring during AIDS. We report here that virion-derived
HIV type 1 (HIV-1) protein R (Vpr) increased IL-8 expression in primary T cells
and macrophages, as well as in the T-cell line Jurkat, the monocytic cell line
U937, and the epithelial cell line A549. Vpr appeared to increase IL-8 expression
and IL-8 promoter activity by activating transcription factors NF-kappaB and NF
IL-6. Elevated Vpr was also shown to increase transcription of the NF-kappaB and
NF-IL-6 enhancer-containing viral promoters for HIV, cytomegalovirus, and simian
virus 40, as well as increase the expression of IL-6 and IL-10 in primary
macrophages and in A549 cells, tumor necrosis factor alpha expression in primary
T cells, and IL-6 and gamma interferon expression in U937 cells. These results
suggest a new role for Vpr in the pathogenesis of HIV infection, namely, the
activation of transcription factors NF-IL-6 and NF-kappaB.
PMID- 10775603
TI - Functional differences between human and bovine immunodeficiency virus Tat
transcription factors.
AB - Transcriptional transactivation of the human immunodeficiency virus type 1 (HIV
1) long terminal repeat (LTR) promoter element by the essential viral Tat protein
requires recruitment of positive transcription elongation factor b (P-TEFb) to
the viral TAR RNA target. The recruitment of P-TEFb, which has been proposed to
be necessary and sufficient for activation of viral gene expression, is mediated
by the highly cooperative interaction of Tat and cyclin T1, an essential
component of P-TEFb, with the HIV-1 TAR element. Species, such as rodents, that
encode cyclin T1 variants that are unable to support TAR binding by the Tat
cyclin T1 heterodimer are also unable to support HIV-1 Tat function. In contrast,
we here demonstrate that the bovine immunodeficiency virus (BIV) Tat protein is
fully able to bind to BIV TAR both in vivo and in vitro in the absence of any
cellular cofactor. Nevertheless, BIV Tat can specifically recruit cyclin T1 to
the BIV TAR element, and this recruitment is as essential for BIV Tat function as
it is for HIV-1 Tat activity. However, because the cyclin T1 protein does not
contribute to TAR binding, BIV Tat is able to function effectively in cells from
several species that do not support HIV-1 Tat function. Thus, BIV Tat, while
apparently dependent on the same cellular cofactor as the Tat proteins encoded by
other lentiviruses, is nevertheless unique in terms of the mechanism used to
recruit the BIV Tat-cyclin T1 complex to the viral LTR promoter.
PMID- 10775605
TI - The cHS4 insulator increases the probability of retroviral expression at random
chromosomal integration sites.
AB - Retroviruses are highly susceptible to transcriptional silencing and position
effects imparted by chromosomal sequences at their integration site. These
phenomena hamper the use of recombinant retroviruses as stable gene delivery
vectors. As insulators are able to block promoter-enhancer interactions and
reduce position effects in some transgenic animals, we examined the effect of an
insulator on the expression and structure of randomly integrated recombinant
retroviruses. We used the cHS4 element, an insulator from the chicken beta-like
globin gene cluster, which has been shown to reduce position effects in
transgenic Drosophila. A large panel of mouse erythroleukemia cells that bear a
single copy of integrated recombinant retroviruses was generated without using
drug selection. We show that the cHS4 increases the probability that integrated
proviruses will express and dramatically decreases the level of de novo
methylation of the 5' long terminal repeat. These findings support a primary role
of methylation in the silencing of retroviruses and suggest that cHS4 could be
useful in gene therapy applications to overcome silencing of retroviral vectors.
PMID- 10775604
TI - Octamerization enables soluble CD46 receptor to neutralize measles virus in vitro
and in vivo.
AB - A chimeric fusion protein encompassing the CD46 ectodomain linked to the C
terminal part of the C4b binding protein (C4bp) alpha chain (sCD46-C4bpalpha) was
produced in eukaryotic cells. This protein, secreted as a disulfide-linked homo
octamer, was recognized by a panel of anti-CD46 antibodies with varying
avidities. Unlike monomeric sCD46, the octameric sCD46-C4bpalpha protein was
devoid of complement regulatory activity. However, sCD46-C4bpalpha was able to
bind to the measles virus hemagglutinin protein expressed on murine cells with a
higher avidity than soluble monomeric sCD46. Moreover, the octameric sCD46
C4bpalpha protein was significantly more efficient than monomeric sCD46 in
inhibiting virus binding to CD46, in blocking virus induced cell-cell fusion, and
in neutralizing measles virus in vitro. In addition, the octameric sCD46
C4bpalpha protein, but not the monomeric sCD46, fully protected CD46 transgenic
mice against a lethal intracranial measles virus challenge.
PMID- 10775606
TI - Cell-specific modulation of papovavirus replication by tumor suppressor protein
p53.
AB - Small DNA tumor viruses like human papillomaviruses, simian virus 40, and
adenoviruses modulate the activity of cellular tumor suppressor proteins p53
and/or pRB. These viruses replicate as nuclear multicopy extrachromosomal
elements during the S phase of the cell cycle, and it has been suggested that
inactivation of p53 and pRb is necessary for directing the cells to the S phase.
Mouse polyomavirus (Py), however, modulates only the pRB protein activity without
any obvious interference with the action of p53. We show here that Py replication
was not suppressed by the p53 protein indeed in all tested different mouse cell
lines. In addition, E1- and E2-dependent papillomavirus origin replication was
insensitive to the action of p53 in mouse cells. We show that in hamster (Chinese
hamster ovary) or human (osteosarcoma 143) cell lines the replication of both Py
and papillomavirus origins was efficiently blocked by p53. The block of Py
replication in human and hamster cells is not caused by the downregulation of
large T-antigen expression. The deletion analysis of the p53 protein shows that
the RPA binding, proline-rich regulatory, DNA-binding, and oligomerization
domains are necessary for p53 action in both replication systems. These results
indicate that in mouse cells the p53 protein could be inactive for the
suppression of papovavirus replication.
PMID- 10775607
TI - Retrovirus vectors bearing jaagsiekte sheep retrovirus Env transduce human cells
by using a new receptor localized to chromosome 3p21.3.
AB - Jaagsiekte sheep retrovirus (JSRV) is a type D retrovirus associated with a
contagious lung tumor of sheep, ovine pulmonary carcinoma. Other than sheep, JSRV
is known to infect goats, but there is no evidence of human infection. Until now
it has not been possible to study the host range for JSRV because of the
inability to grow this virus in culture. Here we show that the JSRV envelope
protein (Env) can be used to pseudotype Moloney murine leukemia virus (MoMLV)
based retrovirus vectors and that such vectors can transduce human cells in
culture. We constructed hybrid retrovirus packaging cells that express the JSRV
Env and the MoMLV Gag-Pol proteins and can produce JSRV-pseudotype vectors at
titers of up to 10(6) alkaline phosphatase-positive focus-forming units/ml. Using
this high-titer virus, we have studied the host range for JSRV, which includes
sheep, human, monkey, bovine, dog, and rabbit cells but not mouse, rat, or
hamster cells. Considering the inability of the JSRV-pseudotype vector to
transduce hamster cells, we used the hamster cell line-based Stanford G3 panel of
whole human genome radiation hybrids to phenotypically map the JSRV receptor
(JVR) gene within the p21.3 region of human chromosome 3. JVR is likely a new
retrovirus receptor, as none of the previously identified retrovirus receptors
localizes to the same position. Several chemokine receptors that have been shown
to serve as coreceptors for lentivirus infection are clustered in the same region
of chromosome 3; however, careful examination shows that the JSRV receptor does
not colocalize with any of these genes.
PMID- 10775608
TI - An adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis
complexes with dynein and a small GTPase.
AB - Adenoviruses (Ad) code for immunoregulatory and cytokine regulatory proteins, one
of which is the early region 3, 14.7-kDa protein (Ad E3-14.7K), which has been
shown to inhibit tumor necrosis factor alpha-induced apoptosis. In an effort to
understand the mechanism of action of Ad E3-14.7K, we previously searched for
cell proteins with which it interacted. Three Ad E3-14.7K-interacting proteins
(FIP-1, -2, and -3) were isolated. FIP-1 is a small GTPase which was used in this
report as bait in the yeast two-hybrid system to find other interacting cell
targets. The search resulted in the isolation of a protein, which we called GIP-1
(GTPase-interacting protein) that subsequently was shown to be identical to one
of the light-chain components of human dynein (TCTEL1). FIP-1 was able to bind
both TCTEL1 and Ad E3-14.7K simultaneously and was necessary to form a complex in
which the viral protein was associated with a microtubule-binding motor protein.
The functional significance of these interactions is discussed with respect to
the steps of the Ad life cycle which are microtubule associated.
PMID- 10775609
TI - Alteration of substrate and inhibitor specificity of feline immunodeficiency
virus protease.
AB - Feline immunodeficiency virus (FIV) protease is structurally very similar to
human immunodeficiency virus (HIV) protease but exhibits distinct substrate and
inhibitor specificities. We performed mutagenesis of subsite residues of FIV
protease in order to define interactions that dictate this specificity. The I37V,
N55M, M56I, V59I, and Q99V mutants yielded full activity. The I37V, N55M, V59I,
and Q99V mutants showed a significant increase in activity against the HIV-1
reverse transcriptase/integrase and P2/nucleocapsid junction peptides compared
with wild-type (wt) FIV protease. The I37V, V59I, and Q99V mutants also showed an
increase in activity against two rapidly cleaved peptides selected by cleavage of
a phage display library with HIV-1 protease. Mutations at Q54K, I98P, and L101I
dramatically reduced activity. Mutants containing a I35D or I57G substitution
showed no activity against either FIV or HIV substrates. FIV proteases all failed
to cut HIV-1 matrix/capsid, P1/P6, P6/protease, and protease/reverse
transcriptase junctions, indicating that none of the substitutions were
sufficient to change the specificity completely. The I37V, N55M, M56I, V59I, and
Q99V mutants, compared with wt FIV protease, all showed inhibitor specificity
more similar to that of HIV-1 protease. The data also suggest that FIV protease
prefers a hydrophobic P2/P2' residue like Val over Asn or Glu, which are utilized
by HIV-1 protease, and that S2/S2' might play a critical role in distinguishing
FIV and HIV-1 protease by specificity. The findings extend our observations
regarding the interactions involved in substrate binding and aid in the
development of broad-based inhibitors.
PMID- 10775610
TI - Core protein phosphorylation modulates pregenomic RNA encapsidation to different
extents in human and duck hepatitis B viruses.
AB - To clarify the role of core protein phosphorylation in pregenomic-RNA
encapsidation of human and duck hepatitis B viruses (HBV and DHBV, respectively),
we have examined the phosphorylation states of different forms of intracellular
HBV core protein and the phenotypic effects of mutations in the phosphorylation
sites of HBV and DHBV core proteins. We show that HBV core protein is
phosphorylated to similar extents in the form of protein dimers and after further
assembly in pregenomic RNA-containing capsids. Individual and multiple
substitutions of alanine and aspartic acid for serine in the phosphorylation
sites of HBV core protein resulted in site-specific and synergistic effects on
RNA encapsidation, ranging from 2-fold enhancement to more than 10-fold
inhibition. Core protein variants with mutations in all phosphorylation sites
exhibited dominant-negative effects on RNA encapsidation by wild-type protein.
The results suggest that the presence of phosphoserine at position 162 of HBV
core protein is required for pregenomic-RNA encapsidation, whereas phosphoserine
at position 170 optimizes the process and serine might be preferable in position
155. Examination of the pregenomic-RNA-encapsidating capacities of DHBV core
protein variants, in which four phosphorylation sites were jointly mutated to
alanine or aspartic acid, suggests that phosphorylation of DHBV core protein at
these sites may optimize pregenomic-RNA encapsidation but that its impact is much
less profound than in the case of HBV. The possible mechanisms by which RNA
encapsidation may be modulated by core protein phosphorylation are discussed in
the context of the observed differences between the two viruses.
PMID- 10775611
TI - Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human
papillomavirus-specific CD8(+) cytotoxic T lymphocytes.
AB - Interleukin-10 (IL-10) is widely known as an immunosuppressive cytokine by virtue
of its ability to inhibit macrophage-dependent antigen presentation, T-cell
proliferation, and Th1 cytokine secretion. However, several studies have
challenged the perception of IL-10 solely as an immunosuppressive cytokine. As
part of an investigation on potentiation of the cytotoxic activity of human
papillomavirus E7-specific CD8(+) cytotoxic T lymphocytes (CTL) for adoptive
transfusions to cervical cancer patients, we found that IL-10 in combination with
IL-2, unlike several other combinations, including IL-2 with IL-12, gamma
interferon (IFN-gamma), tumor necrosis factor alpha, and transforming growth
factor beta, was able to consistently increase cytotoxicity. This augmentation in
cytotoxic activity correlated with a significant increase in the cytoplasmic
accumulation of perforin as detected by fluorescence-activated cell sorter.
Surface expression of both the alpha and beta chains of the CD8 heterodimeric
coreceptor and CD56 molecules was increased by exposure of CTL to IL-10. More
importantly, we found that administration of IL-10 in combination with IL-2 after
antigen stimulation consistently increased the intracellular expression of Th1
cytokines (i.e., IFN-gamma and IL-2) compared to results for control CD8(+) T
cells cultured in IL-2 alone. In kinetic studies, proliferation, intracellular
perforin levels, cytotoxic activity, and IFN-gamma expression were consistently
elevated in CTL cultures containing IL-10 compared to control cultures, both at
early and late time points following stimulation. In contrast, intracellular IL-2
expression was consistently increased only at early time points following
stimulation with autologous tumor cells or solid-phase anti-CD3 antibody. Taken
together, these data support the use of IL-10 in combination with IL-2 for the in
vitro expansion and potentiation of tumor-specific CTL for clinical use in the
therapy of cancer.
PMID- 10775612
TI - Tomato yellow leaf curl geminivirus (TYLCV-Is) is transmitted among whiteflies
(Bemisia tabaci) in a sex-related manner.
AB - Tomato yellow leaf curl virus (TYLCV) is the name given to a complex of
geminiviruses infecting tomato cultures worldwide. TYLCV is transmitted by a
single insect species, the whitefly Bemisia tabaci. Herein we show that a TYLCV
isolate from Israel (TYLCV-Is) can be transmitted among whiteflies in a sex
dependent manner, in the absence of any other source of virus. TYLCV was
transmitted from viruliferous males to females and from viruliferous females to
males but not among insects of the same sex. Transmission took place when insects
were caged in groups or in couples, in a feeding chamber or on cotton plants, a
TYLCV nonhost. The recipient insects were able to efficiently inoculate tomato
test plants. Insect-to-insect virus transmission was instrumental in increasing
the number of whiteflies capable of infecting tomato test plants in a whitefly
population. TYLCV was present in the hemolymph of whiteflies caged with
viruliferous insects of the other sex; therefore, the virus follows, at least in
part, the circulative pathway associated with acquisition from infected plants.
Taken as a whole, these results imply that a plant virus can be sexually
transmitted from insect to insect.
PMID- 10775614
TI - Deletion of a short, untranslated region adjacent to the polypurine tract in
Moloney murine leukemia virus leads to formation of aberrant 5' plus-strand DNA
ends in vivo.
AB - Experiments were performed to determine the function of a 28-nucleotide
untranslated sequence lying between the envelope gene and the polypurine tract
(PPT) sequence in the Moloney murine leukemia virus (Mo-MuLV) genome. A mutant
virus carrying a deletion of this sequence (Mo-MuLVDelta28) replicated more
slowly than wild-type (wt) virus and reverted by recombination with endogenous
sequences during growth in NIH 3T3 cells. We show that this deletion did not
affect the level of viral protein expression or genomic RNA packaging. Mo
MuLVDelta28 served as a helper virus as efficiently as the wt virus; in contrast,
a retroviral vector harboring this mutation exhibited reduced transduction
efficiency, indicating that the mutation acts not in trans but in cis. Analysis
of acutely infected cells revealed that reduced levels of viral DNA were
generated by reverse transcription of the Mo-MuLVDelta28 RNA as compared to the
wt RNA. Analysis of DNA circle junctions revealed that plus-strand DNA of Mo
MuLVDelta28 but not wt virus often retained the PPT and additional upstream
sequences. These structures suggest that aberrant 5' ends of plus-strand DNA were
generated by a failure to remove the PPT RNA primer and/or by mispriming at sites
upstream of the PPT. These data demonstrate that the major role of the sequences
immediately upstream of the PPT is specifying efficient and accurate plus-strand
DNA synthesis.
PMID- 10775613
TI - Modifications that stabilize human immunodeficiency virus envelope glycoprotein
trimers in solution.
AB - The functional unit of the human immunodeficiency virus type 1 (HIV-1) envelope
glycoproteins is a trimer composed of three gp120 exterior glycoproteins and
three gp41 transmembrane glycoproteins. The lability of intersubunit interactions
has hindered the production and characterization of soluble, homogeneous envelope
glycoprotein trimers. Here we report three modifications that stabilize soluble
forms of HIV-1 envelope glycoprotein trimers: disruption of the proteolytic
cleavage site between gp120 and gp41, introduction of cysteines that form
intersubunit disulfide bonds, and addition of GCN4 trimeric helices.
Characterization of these secreted glycoproteins by immunologic and biophysical
methods indicates that these stable trimers retain structural integrity. The
efficacy of the GCN4 sequences in stabilizing the trimers, the formation of
intersubunit disulfide bonds between appropriately placed cysteines, and the
ability of the trimers to interact with a helical, C-terminal gp41 peptide
(DP178) support a model in which the N-terminal gp41 coiled coil exists in the
envelope glycoprotein precursor and contributes to intersubunit interactions
within the trimer. The availability of stable, soluble HIV-1 envelope
glycoprotein trimers should expedite progress in understanding the structure and
function of the virion envelope glycoprotein spikes.
PMID- 10775615
TI - Complement depletion facilitates the infection of multiple brain tumors by an
intravascular, replication-conditional herpes simplex virus mutant.
AB - Intravascular routes of administration can provide a means to target gene- and
virus-based therapies to multiple tumor foci located within an organ, such as the
brain. However, we demonstrate here that rodent plasma inhibits cell transduction
by replication-conditional (oncolytic) herpes simplex viruses (HSV), replication
defective HSV, and adenovirus vectors. In vitro depletion of complement with mild
heat treatment or in vivo depletion by treatment of athymic rats with cobra venom
factor (CVF) partially reverses this effect. Without CVF, inhibition of cell
infection by HSV is observed at plasma dilution as high as 1:32, while plasma
from CVF-treated animals displays anti-HSV activity at lower dilutions (1:8).
When applied to the therapy of intracerebral brain tumors, in vivo complement
depletion facilitates the initial infection (assayed at the 2-day time point) by
an intra-arterial replication-conditional HSV of tumor cells, located within
three separate and distinct human glioma masses. However, at the 4-day time
point, no propagation of HSV from initially infected tumor cells could be
observed. Previously, we have shown that the immunosuppressive agent,
cyclophosphamide (CPA), facilitates the in vivo propagation of an oncolytic HSV,
delivered intravascularly, within infected multiple intracerebral masses, by
inhibition of both innate and elicited anti-HSV neutralizing antibody response
(K. Ikeda et al., Nat. Med. 5:881-889, 1999). In this study, we thus show that
the addition of CPA to the CVF treatment results in a significant increase in
viral propagation within infected tumors, measured at the 4-day time period. The
concerted action of CVF and CPA significantly increases the life span of athymic
rodents harboring three separate and large glioma xenografts after treatment with
intravascular, oncolytic HSV. Southern analysis of viral genomes analyzed by PCR
reveals the presence of the oncolytic virus in the brains, livers, spleens,
kidneys, and intestine of treated animals, although none of these tissues
displays evidence of HSV-mediated gene expression. In light of clinical trials of
oncolytic HSV for malignant brain tumors, these findings suggest that antitumor
efficacy may be limited by the host innate and elicited humoral responses.
PMID- 10775616
TI - The spread of herpes simplex virus type 1 from trigeminal neurons to the murine
cornea: an immunoelectron microscopy study.
AB - An animal model has been developed to clarify the mechanism for spread of herpes
simplex virus (HSV) from neuron to epithelial cells in herpetic epithelial
keratitis. HSV was introduced into the murine trigeminal ganglion via stereotaxic
guided injection. After 2 to 5 days, the animals were euthanized. Ganglia and
corneas were prepared for light and electron microscopic immunocytochemistry with
antisera to HSV. At 2 days, labeled axons were identified in the stromal layer.
At 3 days, we could detect immunoreactive profiles of trigeminal ganglion cell
axons that contained many vesicular structures. By 3 and 4 days, the infection
had spread to all layers of epithelium, and the center of a region of infected
epithelium appeared thinned. At 5 day, fewer basal cells appeared infected,
although infection persisted in superficial cells where it had expanded
laterally. Mature HSV was found in the extracellular space surrounding wing and
squamous cells. Viral antigen was expressed in small pits along the apical
surfaces of wing and squamous cells but not at the basal surface of these cells
or on basal cells. This polarized expression of viral antigen resulted in the
spread of HSV to superficial cells and limited lateral spread to neighboring
basal cells. The pathogenesis of HSV infection in these mice may serve as a model
of the human recurrent epithelial disease in the progression of focal sites of
infection and transfer from basal to superficial cells.
PMID- 10775617
TI - Genomic determinants of cardiovirulence in coxsackievirus B3 clinical isolates:
localization to the 5' nontranslated region.
AB - Coxsackievirus B3 (CVB3) infections can cause myocarditis in humans and are
implicated in the pathogenesis of dilated cardiomyopathy. The natural genetic
determinants of cardiovirulence for CVB3 have not been identified, although using
strains engineered in the laboratory, cardiovirulence determinants have been
identified in the CVB3 5' nontranslated region (5'NTR) and capsid. The
myocarditic phenotypes of two CVB3 clinical isolates were determined using an
established murine model of inflammatory heart disease. The 5'NTRs and capsid
proteins of the noncardiovirulent CVB3/CO strain and cardiovirulent CVB3/AS
strain were examined to determine their influence on the cardiovirulence
phenotype. Six intratypic chimeric viruses were constructed in which 5'NTR and
capsid sequences of the infectious cDNA copy of the cardiovirulent CVB3/20 genome
were replaced by homologous sequences from CVB3/CO or CVB3/AS. Chimeric strains
were tested for cardiovirulence by inoculation of C3H/HeJ mice. Sections of
hearts removed at 10 days postinoculation were examined for evidence of
myocarditis by light microscopy and assayed for the presence of virus.
Replacement of the CVB3/20 capsid coding region by that from the homologous
region of CVB3/CO resulted in no change in the cardiovirulent CVB3/20 phenotype,
with virus recoverable from the heart at 10 days postinoculation. However,
recombinant virus containing the CVB3/CO 5'NTR alone or the 5'NTR and capsid
sequences together were not myocarditic, and infectious virus was not recovered
from the myocardium. Chimeric viruses containing the CVB3/AS 5'NTR alone, capsid
sequence alone, or both together preserved the myocarditic phenotype. These data
support the 5'NTR as the primary site in the determination of the natural
cardiovirulence phenotype of CVB3.
PMID- 10775618
TI - Identification of critical amino acid residues in human immunodeficiency virus
type 1 IN required for efficient proviral DNA formation at steps prior to
integration in dividing and nondividing cells.
AB - Human immunodeficiency virus type 1 integrase (HIV-1 IN) is thought to have
several putative roles at steps prior to integration, such as reverse
transcription and nuclear transport of the preintegration complex (PIC). Here, we
investigated new functional aspects of HIV-1 IN in the context of the viral
replication cycle through point mutagenesis of Ser, Thr, Tyr, Lys, and Arg
residues conserved in IN, some of which are located at possible phosphorylation
sites. Our results showed that mutations of these Ser or Thr residues had no
effect on reverse transcription and nuclear transport of PIC but had a slight
effect on integration. Of note, mutations in the conserved KRK motif (amino acids
186 to 189), proposed previously as a putative nuclear localization signal (NLS)
of HIV-1 IN, did not affect the karyophilic property of HIV-1 IN as shown by
using a green fluorescent protein fusion protein expression system. Instead,
these KRK mutations resulted in an almost complete lack of viral gene expression
due to the failure to complete reverse transcription. This defect was
complemented by supplying wild-type IN in trans, suggesting a trans-acting
function of the KRK motif of IN in reverse transcription. Mutation at the
conserved Tyr 143 (Y143G) resulted in partial impairment of completion of reverse
transcription in monocyte-derived macrophages (MDM) but not in rhabdomyosarcoma
cells. Similar effects were obtained by introducing a stop codon in the vpr gene
(DeltaVpr), and additive effects of both mutations (Y143G plus DeltaVpr) were
observed. In addition, these mutants did not produce two-long terminal repeat
DNA, a surrogate marker for nuclear entry, in MDM. Thus, the possible impairment
of Y143G might occur during the nuclear transport of the PIC. Taken together, our
results identified new functional aspects of the conserved residues in HIV-1 IN:
i) the KRK motif might have a role in efficient reverse transcription in both
dividing and nondividing cells but not in the NLS function; ii) Y143 might be an
important residue for maintaining efficient proviral DNA formation in nondividing
cells.
PMID- 10775619
TI - H-1 parvovirus-associated replication bodies: a distinct virus-induced nuclear
structure.
AB - We have identified a nuclear structure that is induced after infection with the
autonomous parvovirus H-1. Using fluorescence microscopy, we observed that the
major nonstructural protein (NS1) of H-1 virus which is essential for viral DNA
amplification colocalized with virus-specific DNA sequences and sites of ongoing
viral DNA replication in distinct nuclear bodies which we designated H-1
parvovirus-associated replication bodies (H-1 PAR-bodies). In addition, two
cellular proteins were shown to accumulate in H1 PAR-bodies: (i) the
proliferating cell nuclear antigen (PCNA) which is essential for chromosomal and
parvoviral replication and (ii) the NS1-interacting small glutamine-rich TPR
containing protein (SGT), suggesting a role for the latter in parvoviral
replication and/or gene expression. Since many DNA viruses target preexisting
nuclear structures, known as PML-bodies, for viral replication and gene
expression, we have determined the localization of H-1 PAR- and PML-bodies by
double-fluorescence labeling and confocal microscopy and found them to be
spatially unrelated. Furthermore, H-1 PAR-bodies did not colocalize with other
prominent nuclear structures such as nucleoli, coiled bodies, and speckled
domains. Electron microscopy analysis revealed that NS1, as detected by indirect
immunogold labeling, was localized in ring-shaped electron-dense nuclear
structures corresponding in size and frequency to H-1 PAR-bodies. These
structures were also clearly visible without immunogold labeling and could be
detected only in infected cells. Our results suggest that H-1 virus does not
target known nuclear bodies for DNA replication but rather induces the formation
of a novel structure in the nucleus of infected cells.
PMID- 10775620
TI - Liver-specific alpha 2 interferon gene expression results in protection from
induced hepatitis.
AB - The current therapy for hepatitis B and C is based on systemic administration of
recombinant human alpha interferon (r-hIFN-alpha). However, systemic delivery of
r-hIFN-alpha is associated with severe side effects, but more importantly, it is
effective in only a small percentage of patients. In an effort to maximize IFN
alpha antiviral efficacy, we have explored the therapeutic potential of murine
IFN-alpha2 (mIFNalpha2) selectively expressed in the liver. To this end, we have
developed a helper-dependent adenovirus vector (HD) containing the mIFN-alpha2
gene under the control of the liver-specific transthyretin promoter (HD-IFN).
Comparison with a first-generation adenovirus carrying the same mIFN-alpha2
expression cassette indicates that at certain HD-IFN doses, induction of
antiviral genes can be achieved in the absence of detectable circulating mIFN
alpha2. Challenge of injected mice with mouse hepatitis virus type 3 showed that
HD-IFN provides high liver protection. Moreover, liver protection was also
observed in acute nonviral liver inflammation hepatitis induced by concanavalin A
at 1 month postinfection. These results hold promise for the development of a
gene therapy treatment for chronic viral hepatitis based on liver-restricted
expression of IFN-alpha2.
PMID- 10775621
TI - Structure-function analysis of hepatitis C virus envelope-CD81 binding.
AB - Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease.
We have recently found that the large extracellular loop (LEL) of human CD81
binds HCV. This finding prompted us to assess the structure-function features of
HCV-CD81 interaction by using recombinant E2 protein and a recombinant soluble
form of CD81 LEL. We have found that HCV-E2 binds CD81 LEL with a K(d) of 1.8 nM;
CD81 can mediate attachment of E2 on hepatocytes; engagement of CD81 mediates
internalization of only 30% of CD81 molecules even after 12 h; and the four
cysteines of CD81 LEL form two disulfide bridges, the integrity of which is
necessary for CD81-HCV interaction. Altogether our data suggest that neutralizing
antibodies aimed at interfering with HCV binding to human cells should have an
affinity higher than 10(-9) M, that HCV binding to hepatocytes may not entirely
depend on CD81, that CD81 is an attachment receptor with poor capacity to mediate
virus entry, and that reducing environments do not favor CD81-HCV interaction.
These studies provide a better understanding of the CD81-HCV interaction and
should thus help to elucidate the viral life cycle and to develop new strategies
aimed at interfering with HCV binding to human cells.
PMID- 10775622
TI - Rescue of mumps virus from cDNA.
AB - A complete DNA copy of the genome of a Jeryl Lynn strain of mumps virus (15,384
nucleotides) was assembled from cDNA fragments such that an exact antigenome RNA
could be generated following transcription by T7 RNA polymerase and cleavage by
hepatitis delta virus ribozyme. The plasmid containing the genome sequence,
together with support plasmids which express mumps virus NP, P, and L proteins
under control of the T7 RNA polymerase promoter, were transfected into A549 cells
previously infected with recombinant vaccinia virus (MVA-T7) that expressed T7
RNA polymerase. Rescue of infectious virus from the genome cDNA was demonstrated
by amplification of mumps virus from transfected-cell cultures and by subsequent
consensus sequencing of reverse transcription-PCR products generated from
infected-cell RNA to verify the presence of specific nucleotide tags introduced
into the genome cDNA clone. The only coding change (position 8502, A to G) in the
cDNA clone relative to the consensus sequence of the Jeryl Lynn plaque isolate
from which it was derived, resulting in a lysine-to-arginine substitution at
amino acid 22 of the L protein, did not prevent rescue of mumps virus, even
though an amino acid alignment for the L proteins of paramyxoviruses indicates
that lysine is highly conserved at that position. This system may provide the
basis of a safe and effective virus vector for the in vivo expression of
immunologically and biologically active proteins, peptides, and RNAs.
PMID- 10775624
TI - Cytoplasmic trafficking of the canine parvovirus capsid and its role in infection
and nuclear transport.
AB - To begin a successful infection, viruses must first cross the host cell plasma
membrane, either by direct fusion with the membrane or by receptor-mediated
endocytosis. After release into the cytoplasm those viruses that replicate in the
nucleus must target their genome to that location. We examined the role of
cytoplasmic transport of the canine parvovirus (CPV) capsid in productive
infection by microinjecting two antibodies that recognize the intact CPV capsid
into the cytoplasm of cells and also by using intracellular expression of
variable domains of a neutralizing antibody fused to green fluorescence protein.
The two antibodies tested and the expressed scFv all efficiently blocked virus
infection, probably by binding to virus particles while they were in the
cytoplasm and before entering the nucleus. The injected antibodies were able to
block most infections even when injected 8 h after virus inoculation. In control
studies, microinjected capsid antibodies did not interfere with CPV replication
when they were coinjected with an infectious plasmid clone of CPV.
Cytoplasmically injected full and empty capsids were able to move through the
cytosol towards the nuclear membrane in a process that could be blocked by
nocodazole treatment of the cells. Nuclear transport of the capsids was slow,
with significant amounts being found in the nucleus only 3 to 6 h after
injection.
PMID- 10775623
TI - A Rev-independent human immunodeficiency virus type 1 (HIV-1)-based vector that
exploits a codon-optimized HIV-1 gag-pol gene.
AB - The human immunodeficiency virus (HIV) genome is AU rich, and this imparts a
codon bias that is quite different from the one used by human genes. The codon
usage is particularly marked for the gag, pol, and env genes. Interestingly, the
expression of these genes is dependent on the presence of the Rev/Rev-responsive
element (RRE) regulatory system, even in contexts other than the HIV genome. The
Rev dependency has been explained in part by the presence of RNA instability
sequences residing in these coding regions. The requirement for Rev also places a
limitation on the development of HIV-based vectors, because of the requirement to
provide an accessory factor. We have now synthesized a complete codon-optimized
HIV-1 gag-pol gene. We show that expression levels are high and that expression
is Rev independent. This effect is due to an increase in the amount of gag-pol
mRNA. Provision of the RRE in cis did not lower protein or RNA levels or
stimulate a Rev response. Furthermore we have used this synthetic gag-pol gene to
produce HIV vectors that now lack all of the accessory proteins. These vectors
should now be safer than murine leukemia virus-based vectors.
PMID- 10775625
TI - Lymphoid organs as a major reservoir for human T-cell leukemia virus type 1 in
experimentally infected squirrel monkeys (Saimiri sciureus): provirus expression,
persistence, and humoral and cellular immune responses.
AB - The aim of this study was to investigate the distribution of human T-cell
leukemia virus type 1 (HTLV-1) in various organs of serially sacrificed squirrel
monkeys (Saimiri sciureus) in order to localize the reservoir of the virus and to
evaluate the relationship between viral expression and the humoral or cellular
immune response during infection. Six squirrel monkeys infected with HTLV-1 were
sacrificed 6, 12, and 35 days and 3, 6, and 26 months after inoculation, and 20
organs and tissues were collected from each animal. PCR and reverse transcription
PCR (RT-PCR) were performed with gag and tax primers. Proviral DNA was detected
by PCR in peripheral blood mononuclear cells (PBMCs) of monkeys sacrificed 6 days
after inoculation and in PBMCs, spleens, and lymph nodes of monkeys sacrificed 12
and 35 days and 3, 6, and 26 months after inoculation. Furthermore, tax/rex mRNA
was detected by RT-PCR in the PBMCs of two monkeys 8 to 12 days after inoculation
and in the spleens and lymph nodes of the monkey sacrificed on day 12. In this
animal, scattered HTLV-1 tax/rex mRNA-positive lymphocytes were detected by in
situ hybridization in frozen sections of the spleen, around the germinal centers
and close to the arterial capillaries. Anti-HTLV-1 cell-mediated immunity was
evaluated at various times after inoculation. Anti-p40(Tax) and anti-Env
cytolytic T-cell responses were detected 2 months after infection and remained
detectable thereafter. When Tax peptides were used, this response appeared to be
directed against various Tax epitopes. Our results indicate that squirrel monkeys
represent a promising animal model for studying the early events of HTLV-1
infection and for evaluating candidate vaccines against HTLV-1.
PMID- 10775626
TI - Variable sensitivity of CCR5-tropic human immunodeficiency virus type 1 isolates
to inhibition by RANTES analogs.
AB - Aminooxypentane (AOP)-RANTES efficiently and specifically blocks entry of non
syncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1
(HIV-1) into host cells. Inhibition appears to be mediated by increased
intracellular retention of the CCR5 coreceptor- AOP-RANTES complex and/or
competitive binding of AOP-RANTES with NSI R5 HIV-1 isolates for CCR5. Although
AOP-RANTES and other beta-chemokine analogs are potent inhibitors, the extreme
heterogeneity of the HIV-1 envelope glycoproteins (gp120 and gp41) and variable
coreceptor usage may affect the susceptibility of variant HIV-1 strains to these
drugs. Using the same peripheral blood mononuclear cells (PBMC) with all
isolates, we observed a significant variation in AOP-RANTES inhibition of 13
primary NSI R5 isolates; 50% inhibitory concentrations (IC(50)) ranged from 0.04
nM with HIV-1(A-92RW009) to 1.3 nM with HIV-1(B-BaL). Experiments performed on
the same isolate (HIV-1(B-BaL)) with PBMC from different donors revealed no
isolate-specific variation in AOP-RANTES IC(50) values but did show a
considerable difference in virus replication efficiency. Exclusive entry via the
CCR5 coreceptor by these NSI R5 isolates suggests that variable inhibition by AOP
RANTES is not due to alternative coreceptor usage but rather differential CCR5
binding. Analysis of the envelope V3 loop sequence linked a threonine or arginine
at position 319 (numbering based on the HXB2 genome) with AOP-RANTES resistance.
With the exception of one isolate, A319 was associated with increased sensitivity
to AOP-RANTES inhibition. Distribution of AOP-RANTES IC(50) values with these
isolates has promoted ongoing screens for new CCR5 agonists that show broad
inhibition of HIV-1 variants.
PMID- 10775627
TI - Transdominant activity of human immunodeficiency virus type 1 Vpr with a mutation
at residue R73.
AB - The 96-amino-acid-long human immunodeficiency virus type 1 virion-encoded
accessory protein Vpr is of particular interest, as this protein, which is found
in association with viral particles, can exert a regulatory effect on both virus
replication and host cell function. Evidently, Vpr, through interaction with
several host regulatory proteins, can modulate transcription from the viral long
terminal repeat promoter. Expression of Vpr in cells results in deregulation of
cell proliferation during the cell cycle pathway at the G(2) stage. Vpr has
unique structural features consisting of multiple functional domains. In this
study, we have focused on the leucine/isoleucine-rich domain near the carboxyl
terminus of Vpr at residue 73 (arginine) and have demonstrated that alterations
at this residue result in ablation of transcriptional activity of Vpr and its
ability to block cell cycle events at the G(2) stage. Interestingly, substitution
mutations at R73 have resulted in a peptide with dominant negative activities on
wild-type functions in transcription and host proliferation events. Results from
in vitro and in vivo protein-protein interaction studies have revealed that
functionally inactive mutant Vpr can be associated with wild-type protein,
presumably through the N-terminal regions of the protein which have been shown to
be important for Vpr oligomerization. Thus, it is likely that complexation of the
mutant Vpr with wild-type protein functionally inactivates Vpr. The importance of
these findings in light of the development of therapeutic strategies is
discussed.
PMID- 10775629
TI - Cross-reactive T-helper responses in patients infected with different subtypes of
human immunodeficiency virus type 1.
AB - Immunization with a recombinant glycoprotein 160 envelope immunogen derived from
a virus of genetic subtype B induced strong specific T-helper cell responses in
asymptomatic human immunodeficiency virus (HIV) carriers infected with subtypes B
to G. This indicates that the HIV-specific T-helper immunity, which is the basis
for development of antibodies and cytotoxic T lymphocytes, can be improved by
both homologous and heterologous antigens. It also suggests that a particular
immunogen can be effective against many different HIV strains.
PMID- 10775628
TI - Machinery to support genome segment inversion exists in a herpesvirus which does
not naturally contain invertible elements.
AB - In many herpesviruses, genome segments flanked by inverted repeats invert during
DNA replication. It is not known whether this inversion is a consequence of an
inherently recombinagenic replicative mechanism common to all herpesviruses or
whether the replication enzymes of viruses with invertible segments have
specifically evolved additional enzymatic activities to drive inversion. By
artificially inserting a fusion of terminal sequences into the genome of a virus
which normally lacks invertible elements (murine cytomegalovirus), we created a
genome composed of long and short segments flanked by 1,359- and 543-bp inverted
repeats. Analysis of genomic DNA from this virus revealed that inversion of both
segments generates equimolar amounts of four isomers during the viral propagation
necessary to produce DNA for analysis from a single viral particle. We conclude
that a herpesvirus which naturally lacks invertible elements is able to support
efficient segment inversion. Thus, the potential to invert is probably inherent
in the replication machinery of all herpesviruses, irrespective of genome
structure, and therefore genomes with invertible elements could have evolved
simply by acquisition of inverted repeats and without concomitant evolution of
enzymatic activities to mediate inversion. Furthermore, the recombinagenicity of
herpesvirus DNA replication must have some importance independent of genome
segment inversion.
PMID- 10775630
TI - Cell-dependent requirement of human immunodeficiency virus type 1 gp41
cytoplasmic tail for Env incorporation into virions.
AB - Growth kinetics in lymphocytic H9 and M8166 cells of two mutants of human
immunodeficiency virus type 1 (HIV-1) with deleted gp41 cytoplasmic tails were
examined. While the mutant viruses designated CTdel-44 and CTdel-144 were able to
grow in M8166 cells, they were unable to grow in H9 cells. Transfection and
single-round infectivity assays demonstrated that they are defective in the early
phase of viral replication in H9 cells. Analysis of the mutant virions revealed
drastically reduced incorporation of Env gp120 (compared with the incorporation
of wild-type virions) in H9 cells but normal incorporation in M8166 cells. These
results indicate that the HIV-1 cytoplasmic tail of gp41 determines virus
infectivity in a cell-dependent manner by affecting incorporation of Env into
virions and suggest the involvement of a host cell factor(s) in the Env
incorporation.
PMID- 10775631
TI - Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated
prion protein accumulation.
AB - We report that lysosomotropic agents and cysteine protease inhibitors inhibited
protease-resistant prion protein accumulation in scrapie-infected neuroblastoma
cells. The inhibition occurred without either apparent effects on normal prion
protein biosynthesis or turnover or direct interactions with prion protein
molecules. The findings introduce two new classes of inhibitors of the formation
of protease-resistant prion protein.
PMID- 10775632
TI - L* protein of Theiler's murine encephalomyelitis virus is required for virus
growth in a murine macrophage-like cell line.
AB - We sought to confirm the importance of L* protein for growth of Theiler's murine
encephalomyelitis virus (TMEV) in a macrophage-like cell line, J774-1. The
protein is out of frame with the polyprotein and synthesized in DA but not GDVII
subgroup strains of TMEV. A recombinant virus, DANCL*/GD, which substitutes the
DA 5' noncoding and L* coding regions for the corresponding regions of GDVII and
synthesizes L* protein, grew with little restriction in J774-1 cells. In
contrast, another recombinant virus, DANCL*-1/GD, which has an ACG rather than an
AUG as the starting codon of L* protein at nucleotide 1079, resulting in no
synthesis of L* protein, did not grow well. No significant difference between the
rates of adsorption to J774-1 cells of these viruses was observed. RNase
protection assay demonstrated that DANCL*/GD viral RNA significantly increased,
whereas only a minimal increase was observed for DANCL*-1/GD. The present study
suggests that L* protein is required for virus growth in macrophages.
PMID- 10775633
TI - Interspecies major histocompatibility complex-restricted Th cell epitope on foot
and-mouth disease virus capsid protein VP4.
AB - T-cell epitopes within viral polypeptide VP4 of the capsid protein of foot-and
mouth disease virus were analyzed using 15-mer peptides and peripheral blood
mononuclear cells (PBMC) from vaccinated outbred pigs. An immunodominant region
between VP4 residues 16 and 35 was identified, with peptide residues 20 to 34
(VP4-0) and 21 to 35 (VP4-5) particularly immunostimulatory for PBMC from all of
the vaccinated pigs. CD25 upregulation on peptide-stimulated CD4(+) CD8(+) cells
dominated by Th memory cells in the pig-and inhibition using anti-major
histocompatibility complex class II monoclonal antibodies indicated recognition
by Th lymphocytes. VP4-0 immunogenicity was retained in a tandem peptide with the
VP1 residue 137 to 156 sequential B-cell epitope. This B-cell site also retained
immunogenicity, but evidence is presented that specific antibody induction in
vitro required both this and the T-cell site. Heterotypic recognition of the
residue 20 to 35 region was also noted. Consequently, the VP4 residue 20 to 35
region is a promiscuous, immunodominant and heterotypic T-cell antigenic site for
pigs that is capable of providing help for a B-cell epitope when in tandem, thus
extending the possible immunogenic repertoire of peptide vaccines.
PMID- 10775634
TI - Maternally transferred antibodies from DNA-immunized avians protect offspring
against hepadnavirus infection.
AB - The outcome and protective efficacy of maternal antibodies elicited by DNA
immunization to the large (L) hepadnavirus envelope protein were studied using
the duck hepatitis B virus (DHBV) model. Following genetic immunization of
breeding ducks with a DHBV L protein gene-bearing plasmid, specific and highly
neutralizing antibodies were transferred from the sera of immunized ducks, via
the egg yolk, to the progeny of vaccinees. Interestingly, large amounts (60 to
100 mg/egg) of high-titer and L protein-specific yolk immunoglobulins
(immunoglobulin Y) accumulated in the egg yolk. These results suggest that eggs
from genetically immunized avians may represent a potent source of DNA-designed
antibodies specific to viral antigen. Importantly, these antibodies are
vertically transmitted and protect offspring against high-titer DHBV challenge.
PMID- 10775636
TI - Characterization of two divergent lineages of macaque rhadinoviruses related to
Kaposi's sarcoma-associated herpesvirus.
AB - We have cloned and characterized the entire DNA polymerase gene and flanking
regions from Kaposi's sarcoma-associated herpesvirus (KSHV) and two closely
related macaque homologs of KSHV, retroperitoneal fibromatosis-associated
herpesvirus-Macaca nemestrina (RFHVMn) and -Macaca mulatta (RFHVMm). We have also
identified and partially characterized the corresponding genomic region of
another KSHV-like herpesvirus, provisionally named "M. nemestrina rhadinovirus
type 2 (MneRV-2)," with close similarity to rhesus rhadinovirus (RRV). A sequence
comparison of these four macaque viruses and two KSHV-like gammaherpesviruses
recently identified in African green monkeys, Chlorocebus rhadinovirus types 1
and 2 (ChRV-1 and ChRV-2) reveals the presence of two distinct lineages of KSHV
like rhadinoviruses in Old World primates. The first rhadinovirus lineage
consists of KSHV and its closely related homologs RFHVMn, RFHVMm, and ChRV-1,
while the second more distantly related lineage consists of RRV, MneRV-2, and
ChRV-2. Our findings raise the possibility of the existence of another human KSHV
like herpesvirus belonging to the second rhadinovirus lineage.
PMID- 10775635
TI - Human papillomavirus type 16 E7 oncoprotein represses transcription of human
fibronectin.
AB - The E7 oncoprotein encoded by human papillomavirus (HPV) type 16 repressed the
transcription of fibronectin, a key component of the extracellular matrix. This
repression, detected in several HPV-positive nontumorigenic and tumorigenic cell
lines, was abolished when the Cys-X-X-Cys repeats in E7 were disrupted.
PMID- 10775637
TI - A frequent, naturally occurring mutation (P130T) of human hepatitis B virus core
antigen is compensatory for immature secretion phenotype of another frequent
variant (I97L).
AB - A frequent mutation at codon 97 of human hepatitis B virus core antigen has been
shown to cause an "immature secretion" phenotype, featuring nonselective and
excessive secretions of virions containing immature viral genome. Our current
study demonstrates that this abnormality can be efficiently offset by another
frequent core mutation, P130T.
PMID- 10775639
TI - Resignation editorial
PMID- 10775640
TI - In appreciation of professor R. G. Edwards, founding editor of the human
reproduction journals
PMID- 10775638
TI - Distinct mechanisms of entry by envelope glycoproteins of Marburg and Ebola
(Zaire) viruses.
AB - Since the Marburg (MBG) and Ebola (EBO) viruses have sequence homology and cause
similar diseases, we hypothesized that they associate with target cells by
similar mechanisms. Pseudotype viruses prepared with a luciferase-containing
human immunodeficiency virus type 1 backbone and packaged by the MBG virus or the
Zaire subtype EBO virus glycoproteins (GP) mediated infection of a comparable
wide range of mammalian cell types, and both were inhibited by ammonium chloride.
In contrast, they exhibited differential sensitivities to treatment of target
cells with tunicamycin, endoglycosidase H, or protease (pronase). Therefore,
while they exhibit certain functional similarities, the MBG and EBO virus GP
interact with target cells by distinct processes.
PMID- 10775641
TI - Multiplex PCR of polymorphic markers flanking the CFTR gene; a general approach
for preimplantation genetic diagnosis of cystic fibrosis.
AB - Cystic fibrosis (CF) is the first monogenic disorder for which single cell
preimplantation genetic diagnosis (PGD) has been successfully applied. The
spectrum of mutations in CF is extremely heterogeneous, and hence, the
development of mutation-specific PGD protocols is impracticable. The current
study reports the development and evaluation of a general multiplex marker
polymerase chain reaction (PCR) protocol for PGD of CF. Four closely linked
highly polymorphic (CA)(n) repeat markers D7S523, D7S486, D7S480 and D7S490,
flanking the cystic fibrosis transmembrane regulator (CFTR) gene, were used. In
99% of the single cells tested (100 leukocytes and 50 blastomeres), multiplex PCR
results were obtained and the overall allelic drop out (ADO) rate varied from 2
to 5%. After validation for the presence of ADO and additional alleles, 95% of
the multiplex PCR results were accepted to construct the marker genotypes.
Depending on the genotype of the couple, and taking into account the embryos lost
for transfer due to validation criteria (5%), ADO (0-2%) and single recombination
(1.1-3%), in general >90% of the embryos could be reliably genotyped by PGD using
a single blastomere. The risk of misdiagnosis equals the chance of a double
recombination between informative flanking markers and is <0.05%. Therefore, this
polymorphic and multi-allelic marker system is a reliable and generally
applicable alternative for mutation-directed PGD protocols. Furthermore, it
provides a test for the origin of the detected genotype and also gives an
indication of the chromosomal ploidy status of the blastomere tested.
PMID- 10775642
TI - Evidence for nitric oxide acting as a luteolytic factor in the human corpus
luteum.
AB - The aims of the present study were to characterize the expression and cellular
localization of isoforms of nitric oxide synthase (NOS) in the human corpus
luteum (CL) and to determine the effects of nitric oxide (NO) on CL
steroidogenesis. Immunoblotting analyses revealed that endothelial NOS (eNOS) is
the most abundant isoform in human CL with highest values during the late luteal
phase. Immunoreactive eNOS was localized predominantely in the theca lutein
layer, being particularly abundant in endothelial cells, but with positive
staining also in some steroidogenic cells. Immunoreactive inducible NOS (iNOS)
was also detected, but to lesser degree, and did not display apparent phase
specific changes. The effect of NO on CL steroid synthesis was examined using
human chorionic gonadotrophin (HCG)-stimulated dispersed CL cells cultured in
vitro. Progesterone production was significantly decreased (P < 0.05) by the NO
donor spermine NONOate (10(-5) mol/l) in cells of the late, but not mid-, luteal
phase. To investigate a potential link between NO and the local prostaglandins
(PG), concentrations of PGF(2alpha) and PGE(2) were measured in culture medium.
NO significantly increased (P < 0.05) concentrations of both PGF(2alpha) and
PGE(2) during the late luteal phase. It is concluded that NO may be luteolytic in
the human CL of menstruation.
PMID- 10775643
TI - Distinct regulation of nitric oxide and cyclic guanosine monophosphate production
by steroid hormones in the rat uterus.
AB - It has previously been reported that uterine nitric oxide (NO) production is
enhanced during rat pregnancy compared to non-pregnant, labouring or postpartum
states. The present hypothesis is that these changes in uterine NO production
during pregnancy are caused by the interplay of oestrogen and progesterone. It is
further postulated that changes in cyclic guanosine monophosphate (cGMP)
production closely follow the changes in uterine NO synthesis. To test these
hypotheses a variety of hormonal regimens (17beta-oestradiol, progesterone and
combinations) were applied to different rat models (prepubertal, non-pregnant
intact and ovariectomized as well as pregnant rats). The production of nitric
oxide (NO) as well as basal and in-vitro NO-stimulated cGMP tissue content were
measured in parallel. NO production was measured by the accumulation of nitrites
and nitrates in a 24 h incubation medium as analysed by Greiss reaction. cGMP
content was measured by radioimmunoassay. Diethylenetriamine/NO (DETA/NO) was
used as NO donor. NO production in the rat uterus was markedly increased by
pregnancy compared to other physiological (prepubertal, or cycling dioestrus) and
experimentally induced (OVX) states. In contrast, uterine cGMP was significantly
decreased in pregnancy. Pregnancy also inhibited the elevation in uterine cGMP
after in-vitro NO challenge. Chronic 17beta-oestradiol treatment in prepubertal
and/or OVX models increased NO production and also mimicked the effect of
pregnancy on cGMP. Administration of progesterone in prepubertal rats induced a
parallel decrease in both uterine NO and cGMP. In conclusion, sex steroid
hormones distinctly regulate uterine NO and cGMP production depending upon the
dose and regimen used, as well as the animal's reproductive state.
PMID- 10775644
TI - Cloning and characterization of bonnet monkey GnRH receptor.
AB - Gonadotrophin releasing hormone (GnRH) plays an important role in the
reproductive processes of both males and females. It is synthesized by the
hypothalamus and binds to a specific receptor on the pituitary to bring about the
release of the gonadotrophins, lutineizing hormone and follicle stimulating
hormone, which in turn bring about the release of the gonadal steroids. Although
the structure of the GnRH receptor (GnRHR) has been elucidated from a number of
sources, no information is available about the receptor from the non-human
primate species. Here we report the cloning and characterization of the receptor
from the pituitary of the bonnet monkey. Antiserum to a bacterially expressed
recombinant fragment was used in Western blot analysis and fluorescence
microscopy to demonstrate the presence of GnRHR in both human and monkey
placentae and pituitary.
PMID- 10775645
TI - GP-83 and GP-39, two glycoproteins secreted by human epididymis are conjugated to
spermatozoa during maturation.
AB - Surface glycoconjugates of spermatozoa are modified during epididymal maturation,
which is closely related to the development of sperm function. In addition,
recognition of surface glycoconjugates is one of very critical events in sperm
oocyte interaction. The binding of carbohydrate-specific lectins to the human
sperm surface during epididymal maturation has been investigated. However, the
glycoproteins responsible for lectin binding in sperm maturation are not well
documented. This study used wheat germ agglutinin (WGA), peanut agglutinin (PNA)
and concanavalin A (Con-A) to identify sperm maturation-related glycoproteins in
human epididymis. Histochemical localization revealed that the binding sites of
WGA, PNA and Con-A were mainly in the principal cells and luminal contents of the
human epididymis, but not in the interstitial regions. Each lectin displayed a
fairly distinct regional localization. On Western blots probed with WGA and Con
A, glycoproteins of 83 kDa (GP-83) and 39 kDa (GP-39) were identified in the
sperm extracts, epididymal fluid and tissue extracts of the corpus and cauda
epididymides, but not in the caput. PNA identified GP-83 in the same manner as
WGA and Con-A, but did not recognize GP-39. These results suggest that lectin
binding glycoproteins GP-83 and GP-39 found on mature spermatozoa may be secreted
by the principal cells of corpus and cauda epididymis, and conjugated to
spermatozoa during their transit in human epididymis.
PMID- 10775646
TI - Purification of GP-83, a glycoprotein secreted by the human epididymis and
conjugated to mature spermatozoa.
AB - Epididymal secretions are critical for mammalian spermatozoa to acquire both
forward motility and an ability to recognize and penetrate oocytes. Previous
studies identified two glycoproteins, GP-83 and GP-39, which were secreted by the
human epididymis and may be related to maturation of sperm function. In this
study, GP-83 was purified from human seminal fluid by DEAE-ion exchange, gel
filtration chromatography and preparative gel elution. The isoelectric point (pI)
of purified GP-83 was 6.57. Monospecific antiserum to GP-83 was induced in male
New Zealand rabbits and confirmed on immunoblots. GP-83 was found in fluid,
tissue and sperm extracts of corpus and cauda epididymis, but not in the caput.
Immunohistochemical localization identified GP-83 in the luminal contents and in
the supranuclear region and cell membrane of principal cells of the corpus and
cauda epididymis. GP-83 was found on the anterior acrosome in ejaculated
spermatozoa, and shifted to the equatorial region after capacitation and the
acrosome reaction.
PMID- 10775647
TI - Characterization of calcium-mobilizing, purinergic P2Y(2) receptors in human
ovarian cancer cells.
AB - In human ovarian EFO-21 and EFO-27 carcinoma cells, extracellular ATP induced a
concentration-dependent rise in intracellular calcium concentration
([Ca(2+)](i)), suggesting the expression of a purinoreceptor. ATP and UTP were
equipotent in generating [Ca(2+)](i) signals, followed by ATP-gamma-S and ADP,
whereas beta, gamma-ATP, 2 methyl 1 thio-ATP, 3'-o-(4-benzoyl) benzoyl-ATP, AMP,
and adenosine were ineffective. This pharmacological profile suggested the
presence of the P2Y(2) subtype in both cell types, and this was confirmed by
reverse transcription-polymerase chain reaction (RT-PCR) analysis using P2Y(2)
primers. ATP-induced [Ca(2+)](i) signals were composed of two phases: an early
and extracellular calcium-independent phase, followed by a sustained plateau
phase that was dependent on capacitative calcium influx. In addition to the rise
in the [Ca(2+)](i), a time- and concentration-dependent increase in
phosphatidylethanol accumulation was observed in ATP-stimulated cells, indicating
an increase in phospholipase D activity. RT-PCR analysis identified the
expression of a transcript for the phospholipase D-1 subtype of this enzyme.
Activation of these receptors by a slowly degradable analogue, ATP-gamma-S,
attenuated basal and fetal calf serum-induced cell proliferation in a time- and
concentration-dependent manner. These results indicate that ATP may act as an
extracellular messenger in controlling the ovarian epithelial cell cycle through
P2Y(2) receptors.
PMID- 10775648
TI - Distribution of steroidogenic enzymes involved in androgen synthesis in
polycystic ovaries: an immunohistochemical study.
AB - To find an explanation for the possible working mechanism of laparoscopic ovarian
electrocautery for the treatment of anovulation in polycystic ovarian syndrome
(PCOS), we evaluated the distribution of steroidogenic enzymes involved in the
synthesis of ovarian androgens in surgical pathology specimens of entire
polycystic ovaries. A total of 13 formalin-fixed and paraffin-embedded samples of
the ovaries of patients with clinically proven PCOS were immunostained with
specific antibodies against cholesterol side-chain-cleavage enzyme (P450scc),
3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17alpha-hydroxylase (P450c17) and
adrenal 4-binding protein (Ad4BP), a transcription factor of steroidogenic
enzymes. Follicular theca cells of all ovaries demonstrated marked
immunoreactivity for Ad4BP, P450scc, 3beta-HSD and P450c17. Granulosa cells of
seven ovaries expressed Ad4BP, while granulosa cells of three ovaries also showed
P450scc. In the granulosa cells of all ovaries, 3beta-HSD and P450c17
immunoreactivity was not observed. In the stroma, luteinized cells of most
ovaries demonstrated Ad4BP, P450scc, 3beta-HSD and P450c17 immunoreactivity, but
at a much lower level compared with the follicular theca cells. Non-luteinized
stromal cells sporadically demonstrated Ad4BP, P450scc, 3beta-HSD and P450c17
immunoreactivity. The stromal steroidogenic cells were mainly located in the
ovarian cortex, except for some hilus steroidogenic cells. These data demonstrate
that in polycystic ovaries, androgens are mainly produced in the follicular theca
cells and to some extent in luteinized stromal cells. This suggests that the
working mechanism of laparoscopic electrocautery of the ovary is primarily
explained through the reduction of ovarian hyperandrogenism by coagulation of
follicular theca cells and concomitant stroma.
PMID- 10775649
TI - Quantification of mRNA in single oocytes and embryos by real-time rapid cycle
fluorescence monitored RT-PCR.
AB - Deciphering the complex series of regulatory events that occur during early
development depends partly on the ability to accurately quantify stage-specific
mRNA species. However, the paucity of biological material coupled with the lack
of sensitivity and/or reproducibility of the currently available quantitative
methods had been severe limitations on single cell analysis. Rapid cycle DNA
amplification is a highly sensitive technique for amplification of specific DNA
sequences. With the addition of fluorescence probes, it is possible to monitor
the log-linear phase of amplification during which the most useful quantitative
data is obtained. Unknown concentrations are extrapolated from standards co
amplified producing a standard curve. Furthermore, micro volume capabilities
allow for the analysis of minute samples. Consequently, this approach is ideally
suited to the needs of the clinical IVF laboratory. Rapid fluorescence monitored
cycling was used to examine expression levels of the housekeeping genes beta
actin and hypoxanthine guanine phosphorlbosyltransferase in individual
murine/human oocytes and/or embryos. Results obtained compared favourably with
those attained by others and followed the predicted temporal patterns of
expression. Once informative reproductive molecular markers are identified by
micro-array analysis, minimally invasive techniques can be developed to biopsy
cytoplasm and/or polar bodies for clinical evaluation using rapid fluorescence
monitored reverse transcription-polymerase chain reaction methods.
PMID- 10775650
TI - Surface-expressed E-cadherin, and mitochondrial and microtubule distribution in
rescue of mouse embryos from 2-cell block by aggregation.
AB - E-cadherin (uvomorulin)-mediated cell interactions are essential for
preimplantation development in mammals. We observed that E-cadherin is expressed
at contact sites between blastomeres of 2-cell mouse embryos of non-blocking
genotype (CBA x C57BL F1) explanted at 32 h post human chorionic gonadotrophin
(HCG) and cultured in vitro, while blastomere rounding and reduced zones of
contact and E-cadherin-staining were observed in embryos of a blocking strain
(MF1) arrested at the 2-cell stage. Embryos of MF1 strain can be rescued by
aggregation with four 2-cell embryos of the non-blocking genotype. An early event
in rescue is E-cadherin expression at contact zones between adjacent embryos of
different genotype in aggregation chimeras. E-cadherin-mediated signalling
appears important for the rescue (including formation of adherens-like contacts,
cell polarization and morphogenetic processes) since there is no rescue when E
cadherin-specific antibodies are present during phytohaemagglutinin-mediated
aggregation and subsequent culture. In blocked embryos, the distribution of
microtubules is disturbed and concomitantly mitochondria cluster around the
nucleus. Rescue by aggregation retains normal mitochondrial distribution in the
presence of a dense microtubular lattice in all blastomeres. Therefore, E
cadherin-mediated signalling and its downstream effects on cytoskeletal
organization are essential in the rescue of blocking embryos by aggregation.
Normal preimplantation development appears to be dependent on the polarized
expression of surface E-cadherin and the microtubule-mediated dispersal of
mitochondria.
PMID- 10775651
TI - The DAZL1 gene is expressed in human male and female embryonic gonads before
meiosis.
AB - The human DAZL1 gene (known also as DAZH or DAZLA) is the autosomal homologue of
the Y-chromosomal DAZ gene which has been found to be deleted in azoospermic
males. Evidence suggests that the role of DAZL1 may not be restricted to
spermatogenesis, but may include oogenesis as well. In order to study the
function of human DAZL1 gene in the ovary, we observed its expression pattern
during embryonic development. RNA in-situ hybridization showed that DAZL1
transcripts were localized to a subset of cells (somatic versus germ cells) in
human embryonic ovary (23 weeks of gestation) and testis (21 weeks gestation). In
the ovary, DAZL1 transcripts were found in oogonia and in oocytes and granulosa
cells of primordial follicles. In the testis, DAZL1 transcripts were identified
exclusively in the germ cells. Our results demonstrate high similarity between
the human DAZL1 and the mouse Dazl1 gene expression patterns during embryonic
development, suggesting that the human gene functions at the first phase of
gametogenesis, just as in the mouse, where Dazl1 mutations cause male and female
sterility.
PMID- 10775652
TI - Cell proliferation effect of lactoferrin in human endometrial stroma cells.
AB - The aim of this study was to evaluate the effect of lactoferrin (LF) on the
proliferation of human endometrial stroma cells. In addition, we compared the
effect of LF, oestradiol and epidermal growth factor (EGF) on the proliferation
of human endometrial stroma cells. Human endometrial tissue was obtained from
patients with a normal menstrual cycle in the proliferative phase and the stroma
cells were isolated and cultured in vitro. When LF was added to the culture
medium, the rate of cell proliferation increased significantly in comparison to
controls (P < 0.01). The enhanced rate of proliferation induced by LF was
neutralized by the addition of anti-LF monoclonal antibody. The effect of LF on
cell proliferation at a concentration of 100 ng/ml was similar to that of 10
nmol/l oestradiol, but less than that of 10 mg/ml EGF. When LF was added in
combination with either oestradiol or EGF, no additive effects on cell
proliferation were observed. Based on the present results, it is suggested that
LF has a potential biological effect in the proliferation of human endometrium.
PMID- 10775653
TI - Polymorphisms in biotransformation enzymes and the risk for recurrent early
pregnancy loss.
AB - An imbalance between phase I drug metabolizing enzymes and phase II
detoxification enzymes may contribute to the development of pre-eclampsia.
Polymorphic variants in the phase I enzyme, cytochrome P450 genes may lead to
increased toxification, whereas polymorphisms in the phase II enzyme, glutathione
S-transferase genes may result in impaired detoxification. Most abundant in
placenta and decidua is glutathione S-transferase P1-1, which may therefore be of
particular importance in reproduction. We studied the frequencies of polymorphic
variants in those enzymes in 187 women with recurrent early pregnancy loss and in
109 women with an uncomplicated obstetric history. DNA was extracted and
subsequently polymerase chain reaction based genotyping assays were used. chi(2)
Analysis and Fisher's exact test were used for statistical evaluation. The
glutathione S-transferase P1b-1b genotype was found significantly more often in
women with recurrent early pregnancy loss than in controls (12% versus 5%, P =
0.03), in particular in those who consumed coffee (P = 0.02) or smoked cigarettes
(P = 0.04). Polymorphisms in other glutathione S-transferase and cytochrome P450
genes occurred equally frequently in cases and controls. In conclusion, the
occurrence of the glutathione S-transferase P1b-1b genotype, leading to lower
glutathione S-transferase Pi enzyme activity and consequently to impaired
placental detoxification, may represent a risk factor for recurrent early
pregnancy loss.
PMID- 10775654
TI - Matrix metalloproteinases -2 and -9 and their endogenous tissue inhibitors in
fetal membrane repair following fetoscopy in a rabbit model.
AB - The cellular mechanisms underlying fetal membrane repair are poorly understood.
Matrix metalloproteinases (MMP) and the endogenous tissue inhibitors of
metalloproteinases (TIMP) play a key role in the control of turnover of
extracellular matrix in fetal membranes at normal parturition and preterm
prelabour rupture of the fetal membranes (PPROM). The time course of secretion of
MMP-2 (72 kDa, gelatinase A) and MMP-9 (92 kDa, gelatinase B) and TIMP into extra
embryonic coelomic, allantoic and amniotic fluids in a rabbit model was examined.
Furthermore, to evaluate their role in fetal membrane repair, the changes induced
by fetoscopy at mid-gestation (23 days; gestation length is 32 days) were
investigated. Zymography showed predominantly secretion of latent MMP-2 at 18, 23
and 30 days of gestation in all gestational compartments. Reverse zymography
detected a broad range of TIMP activity with molecular weights of 27-30 kDa (TIMP
1, glycosylated TIMP-3 and TIMP-4), 24 kDa (unglycosylated TIMP-3) and 21 kDa
(TIMP-2). Following fetoscopy, both MMP-2 and TIMP increased significantly in
amniotic fluid and extra-embryonic coelomic fluid, but not in allantoic fluid, as
demonstrated by densitometric analyses. These findings indicate a modulating role
for MMP and TIMP in the repair processes following a surgically induced fetal
membrane defect.
PMID- 10775655
TI - NMR study of the differential contributions of residues of transforming growth
factor alpha to association with its receptor.
AB - A heteronuclear NMR study of human transforming growth factor alpha (TGFalpha) in
complex with the epidermal growth factor receptor extracellular domain (EGFR-ED)
provided an effective method for delineating the relative contributions of the
residues of the ligand to its affinity for the receptor. In conjunction with
previously obtained mutagenesis data, these results indicate that while a large
number of residues are involved in complex formation and make up the binding
interface, a small subset contribute most of the binding energy. They also show
that while the residues which contribute to receptor binding are localized on one
face of the molecule, the specific residues that play the major role in the
affinity of TGFalpha in the complex are in two distinct regions of TGFalpha. This
suggests that two small functional epitopes each composed of two residues exist
within a larger structural epitope presented on the binding face. These results
give the most detailed picture to date of the receptor binding determinants and
yield further insight into the formation of the ligand-receptor complex.
PMID- 10775656
TI - Simplified amino acid alphabets for protein fold recognition and implications for
folding.
AB - Protein design experiments have shown that the use of specific subsets of amino
acids can produce foldable proteins. This prompts the question of whether there
is a minimal amino acid alphabet which could be used to fold all proteins. In
this work we make an analogy between sequence patterns which produce foldable
sequences and those which make it possible to detect structural homologs by
aligning sequences, and use it to suggest the possible size of such a reduced
alphabet. We estimate that reduced alphabets containing 10-12 letters can be used
to design foldable sequences for a large number of protein families. This
estimate is based on the observation that there is little loss of the information
necessary to pick out structural homologs in a clustered protein sequence
database when a suitable reduction of the amino acid alphabet from 20 to 10
letters is made, but that this information is rapidly degraded when further
reductions in the alphabet are made.
PMID- 10775657
TI - The CATH Dictionary of Homologous Superfamilies (DHS): a consensus approach for
identifying distant structural homologues.
AB - A consensus approach has been developed for identifying distant structural
homologues. This is based on the CATH Dictionary of Homologous Superfamilies
(DHS), a database of validated multiple structural alignments annotated with
consensus functional information for evolutionary protein superfamilies (URL:
http://www. biochem.ucl.ac.uk/bsm/dhs). Multiple structural alignments have been
generated for 362 well-populated superfamilies in the CATH structural domain
database and annotated with secondary structure, physicochemical properties,
functional sequence patterns and protein-ligand interaction data. Consensus
functional information for each superfamily includes descriptions and keywords
extracted from SWISS-PROT and the ENZYME database. The Dictionary provides a
powerful resource to validate, examine and visualize key structural and
functional features of each homologous superfamily. The value of the DHS, for
assessing functional variability and identifying distant evolutionary
relationships, is illustrated using the pyridoxal-5'-phosphate (PLP) binding
aspartate aminotransferase superfamily. The DHS also provides a tool for
examining sequence-structure relationships for proteins within each fold group.
PMID- 10775658
TI - Analysis of structural and physico-chemical parameters involved in the
specificity of binding between alpha-amylases and their inhibitors.
AB - Enzyme-inhibitor specificity was studied for alpha-amylases and their inhibitors.
We purified and cloned the cDNAs of two different alpha-amylase inhibitors from
the common bean (Phaseolus vulgaris) and have recently cloned the cDNA of an
alpha-amylase of the Mexican bean weevil (Zabrotes subfasciatus), which is
inhibited by alpha-amylase inhibitor 2 but not by alpha-amylase inhibitor 1. The
crystal structure of AI-1 complexed with pancreatic porcine alpha-amylase allowed
us to model the structure of AI-2. The structure of Zabrotes subfasciatus alpha
amylase was modeled based on the crystal structure of Tenebrio molitor alpha
amylase. Pairwise AI-1 and AI-2 with PPA and ZSA complexes were modeled. For
these complexes we first identified the interface forming residues. In addition,
we identified the hydrogen bonds, ionic interactions and loss of hydrophobic
surface area resulting from complex formation. The parameters we studied provide
insight into the general scheme of binding, but fall short of explaining the
specificity of the inhibition. We also introduce three new tools-software
packages STING, HORNET and STINGPaint-which efficiently determine the interface
forming residues and the ionic interaction data, the hydrogen bond net as well as
aid in interpretation of multiple sequence alignment, respectively.
PMID- 10775659
TI - Factors enhancing protein thermostability.
AB - Several sequence and structural factors have been proposed to contribute toward
greater stability of thermophilic proteins. Here we present a statistical
examination of structural and sequence parameters in representatives of 18 non
redundant families of thermophilic and mesophilic proteins. Our aim was to look
for systematic differences among thermophilic and mesophilic proteins across the
families. We observe that both thermophilic and mesophilic proteins have similar
hydrophobicities, compactness, oligomeric states, polar and non-polar
contribution to surface areas, main-chain and side-chain hydrogen bonds.
Insertions/deletions and proline substitutions do not show consistent trends
between the thermophilic and mesophilic members of the families. On the other
hand, salt bridges and side chain-side chain hydrogen bonds increase in the
majority of the thermophilic proteins. Additionally, comparisons of the sequences
of the thermophile-mesophile homologous protein pairs indicate that Arg and Tyr
are significantly more frequent, while Cys and Ser are less frequent in
thermophilic proteins. Thermophiles both have a larger fraction of their residues
in the alpha-helical conformation, and they avoid Pro in their alpha-helices to a
greater extent than the mesophiles. These results indicate that thermostable
proteins adapt dual strategies to withstand high temperatures. Our intention has
been to explore factors contributing to the stability of proteins from
thermophiles with respect to the melting temperatures (T(m)), the best descriptor
of thermal stability. Unfortunately, T(m) values are available only for a few
proteins in our high resolution dataset. Currently, this limits our ability to
examine correlations in a meaningful way.
PMID- 10775660
TI - Remarkable thermal stability of doubly intramolecularly cross-linked hen
lysozyme.
AB - In order to examine how a protein can be effectively stabilized, two
intramolecular cross-links, Glu35-Trp108 and Lys1-His15, which have few
unfavorable interactions in the folded state, were simultaneously introduced into
hen lysozyme. Both of the intramolecularly cross-linked lysozymes, 35-108 CL and
1-15 CL, containing cross-links Glu35-Trp108 and Lys1-His15, respectively, showed
increases in thermal stability of 13.9 and 5.2 degrees C, respectively, over that
of wild type, at pH 2.7. On the other hand, a doubly cross-linked lysozyme showed
an increase in thermal stability of 20.8 degrees C over that of wild type, under
identical conditions. Since the sum of the differences in denaturation
temperature between wild type and each of the cross-linked lysozymes was nearly
equal to that between wild type and the doubly cross-linked lysozyme, we suggest
that the efficient stabilization of the lysozyme molecule was the direct result
of the double intramolecular cross-links.
PMID- 10775661
TI - Homology modeling and identification of serine 160 as nucleophile of the active
site in a thermostable carboxylesterase from the archaeon Archaeoglobus fulgidus.
AB - The hyperthermophilic Archaeon Archaeoglobus fulgidus has a gene (AF1763) which
encodes a thermostable carboxylesterase belonging to the hormone-sensitive lipase
(HSL)-like group of the esterase/lipase family. Based on secondary structure
predictions and a secondary structure-driven multiple sequence alignment with
remote homologous proteins of known three-dimensional structure, we previously
hypothesized for this enzyme the alpha/beta-hydrolase fold typical of several
lipases and esterases and identified Ser160, Asp 255 and His285 as the putative
members of the catalytic triad. In this paper we report the building of a 3D
model for this enzyme based on the structure of the homologous brefeldin A
esterase from Bacillus subtilis whose structure has been recently elucidated. The
model reveals the topological organization of the fold corroborating our
predictions. As regarding the active-site residues, Ser160, Asp255 and His285 are
located close each other at hydrogen bond distances. The catalytic role of Ser160
as the nucleophilic member of the triad is demonstrated by the
[(3)H]diisopropylphosphofluoridate (DFP) active-site labeling and sequencing of a
radioactive peptide containing the signature sequence GDSAGG.
PMID- 10775662
TI - Improved efficiency of site-specific copper(II) ion-catalysed protein cleavage
effected by mutagenesis of cleavage site.
AB - The peptide sequence (N)DKTH(C) was previously investigated as a site for
efficient, specific cleavage of a fusion protein by cupric ions using a humanized
gamma1 Fab' as a model protein. Here we show that conservative mutations to three
of the residues in the introduced cleavage site resulted in cleavage sites that
were significantly improved. They were cleaved more efficiently by Cu(2+), such
that cleavage reactions could be shorter, of lower pH or at a lower temperature.
Some were even found to be measurably cleaved by Ni(2+). Use of these new
cleavage sequences along with cupric ions may provide a more rapid and less harsh
method for cost-effective, large-scale proteolytic cleavage of fusion proteins
and peptides.
PMID- 10775663
TI - Citrobacter freundii tyrosine phenol-lyase: the role of asparagine 185 in
modulating enzyme function through stabilization of a quinonoid intermediate.
AB - Asn185 is an invariant residue in all known sequences of TPL and of closely
related tryptophanase and it may be aligned with the Asn194 in aspartate
aminotransferase. According to X-ray data, in the holoenzyme and in the Michaelis
complex Asn185 does not interact with the cofactor pyridoxal 5'-phosphate, but in
the external aldimine a conformational change occurs which is accompanied by
formation of a hydrogen bond between Asn185 and the oxygen atom in position 3 of
the cofactor. The substitution of Asn185 in TPL by alanine results in a mutant
N185A TPL of moderate residual activity (2%) with respect to adequate substrates,
L-tyrosine and 3-fluoro-L-tyrosine. The affinities of the mutant enzyme for
various amino acid substrates and inhibitors, studied by both steady-state and
rapid kinetic techniques, were lower than for the wild-type TPL. This effect
mainly results from destabilization of the quinonoid intermediate, and it is
therefore concluded that the hydrogen bond between Asn185 and the oxygen at the C
3 position of the cofactor is maintained in the quinonoid intermediate. The
relative destabilization of the quinonoid intermediate and external aldimine
leads to the formation of large amounts of gem-diamine in reactions of N185A TPL
with 3-fluoro-L-tyrosine and L-phenylalanine. For the reaction with 3-fluoro-L
tyrosine it was first possible to determine kinetic parameters of gem-diamine
formation by the stopped-flow method. For the reactions of N185A TPL with
substrates bearing good leaving groups the observed values of k(cat) could be
accounted for by taking into consideration two effects: the decrease in the
quinonoid content under steady-state conditions and the increase in the quinonoid
reactivity in a beta-elimination reaction. Both effects are due to
destabilization of the quinonoid and they counterbalance each other. Multiple
kinetic isotope effect studies on the reactions of N185A TPL with suitable
substrates, L-tyrosine and 3-fluoro-L-tyrosine, show that the principal mechanism
of catalysis, suggested previously for the wild-type enzyme, does not change. In
the framework of this mechanism the observed considerable decrease in k(cat)
values for reactions of N185A TPL with L-tyrosine and 3-fluoro-L-tyrosine may be
ascribed to participation of Asn185 in additional stabilization of the keto
quinonoid intermediate.
PMID- 10775664
TI - Chemical engineering of a three-fingered toxin with anti-alpha7 neuronal
acetylcholine receptor activity.
AB - Though it possesses four disulfide bonds the three-fingered fold is amenable to
chemical synthesis, using a Fmoc-based method. Thus, we synthesized a three
fingered curaremimetic toxin from snake with high yield and showed that the
synthetic and native toxins have the same structural and biological properties.
Both were characterized by the same 2D NMR spectra, identical high binding
affinity (K(d) = 22 +/- 5 pM) for the muscular acetylcholine receptor (AChR) and
identical low affinity (K(d) = 2.0 +/- 0.4 microM) for alpha7 neuronal AchR.
Then, we engineered an additional loop cyclized by a fifth disulfide bond at the
tip of the central finger. This loop is normally present in longer snake toxins
that bind with high affinity (K(d) = 1-5 nM) to alpha7 neuronal AchR. Not only
did the chimera toxin still bind with the same high affinity to the muscular AchR
but also it displayed a 20-fold higher affinity (K(d) = 100 nM) for the neuronal
alpha7 AchR, as compared with the parental short-chain toxin. This result
demonstrates that the engineered loop contributes, at least in part, to the high
affinity of long-chain toxins for alpha7 neuronal receptors. That three-fingered
proteins with four or five disulfide bonds are amenable to chemical synthesis
opens new perspectives for engineering new activities on this fold.
PMID- 10775665
TI - Mineral oil metal working fluids (MWFs)-development of practical criteria for
mist sampling.
AB - Not all mineral oil metalworking fluids (MWFs) in common use form stable airborne
mists which can be sampled quantitatively onto a filter. This much has been known
for some time but no simple method of identifying oils too volatile for customary
filter sampling has been developed. Past work was reviewed and experiments were
done to select simple criteria which would enable such oils to be identified. The
sampling efficiency for a range of commercial mineral oil MWF were assessed by
drawing clean air through spiked filters at 2 l. min(-1) for periods up to 6 h
before analysis. The physical properties of MWF are governed by their composition
and kinematic viscosity was found to be the most practical and easily available
index of the potential for sample loss from the filter. Oils with viscosities
greater that 18 cSt (at 40 degrees C) lost less than 5% of their weight, whereas
those with viscosities less than 18 cSt gave losses up to 71%. The losses from
the MWF were mostly aliphatic hydrocarbons (C(10)-C(18)), but additives such as
alkyl benzenes, esters, phenols and terpene odorants were also lost. The main
recommendation to arise from the work is that filter sampling can be performed on
mineral oils with viscosities of 18 cSt (at 40 degrees C) or more with little
evaporative losses from the filter. However, sampling oils with viscosities less
than 18 cSt will produce results which may significantly underestimate the true
value. Over a quarter of UK mineral oil MWFs are formulated from mineral oils
with viscosities less than 18 cSt (at 40 degrees C). The problem of exposure
under-estimation and inappropriate exposure sampling could be widespread. Further
work is being done on measurement of mixed phase mineral oil mist exposure.
PMID- 10775666
TI - Separation efficiency of a wood dust collector-field measurement using a
fluorescent aerosol.
AB - Given the dangerous nature of the dust emitted in the wood industry, the quality
of the recycled air in the work premises after cleaning must be strictly
controlled.A method of measuring the efficiency of a wood dust collector as a
function of the particle diameter has been developed using a fluorescein tracer
aerosol generated upstream of the equipment. The separation efficiency is
determined from the particle size mass distribution of the tracer, both upstream
and downstream, measured by means of two cascade impactors. The mass efficiency
measured by tracer technique was compared on a test rig to the number efficiency
measured using a reference method based on optical counting. The agreement
between the two efficiencies is quite good; nevertheless, the tracer method leads
to results that are slightly below those obtained using the reference method. The
method was applied to measure the efficiency of a 11 500 m(3) h(-1) wood dust
collector. The results are presented along with those obtained from a sample of
plane filter media making up the bags of the dust collector.
PMID- 10775667
TI - Exposure to organic solvents among car painters in Bergen, Norway.
AB - Car painters are exposed to organic solvents during their work. Several sets of
official regulations have therefore been adopted in Norway in recent years to
reduce the exposure. This study evaluated some of the effects of these
regulations, by measuring the levels of exposure to organic solvents in six car
painting garages and relating them to the limit values in Norway. Both stationary
and personal monitoring were performed. In addition, the occurrence of acute
symptoms in the nervous system, skin and upper airways, the use of personal
protective equipment and the workers' satisfaction with the ventilation were
determined using the results of a questionnaire survey among the car painters
from 11 car-painting garages (N=28). A control group of unexposed workers (N=18)
was used for comparison. All air samples showed low levels of exposure, far below
the limit values. The highest levels were found for toluene; about half the limit
value in two garages (11.5 and 12.5 ppm). No significant difference was found
between the exposed and unexposed workers in the frequency of acute symptoms.
Most workers reported to always use gloves, overalls and respiratory protective
equipment during the car painting. The study indicates that the exposure to
organic solvents is low in the examined car-painting garages, and the risk of
adverse health effects related to organic solvents is probably low in these
workplaces.
PMID- 10775668
TI - On the use of computational fluid dynamics in the prediction and control of
exposure to airborne contaminants-an illustration using spray painting.
AB - Computational fluid dynamics (CFD) is employed to simulate breathing-zone
concentration for a simple representation of spray painting a flat plate in a
cross-flow ventilated booth. The results demonstrate the capability of CFD to
track correctly changes in breathing-zone concentration associated with work
practices shown previously to be significant in determining exposure. Empirical
data, and models verified through field studies, are used to examine the
predictive capability of these simulations and to identify important issues in
the conduct of such comparisons. A commercially available CFD package is used to
solve a three-dimensional turbulent flow problem for the velocity field, and to
subsequently generate particle trajectories for polydisperse aerosols. An in
house algorithm is developed to convert the trajectory data to breathing-zone
concentrations, transfer efficiencies and aerosol size distributions. The mesh
size, time step, duration of the simulation, and number of particles per size
interval are all important variables in achieving convergent results.
PMID- 10775669
TI - Computational fluid dynamics as a method for assessing fume cupboard performance.
AB - A commercially available computational fluid dynamic (CFD) software program,
specific for HVAC systems, was used to study the performance of an aerodynamic
fume cupboard. The numerical results showed good qualitative agreement with
physical measurements giving confidence in the CFD model to simulate and predict
overall fume cupboard performance. However, there were some quantitative
differences specifically around 'aerodynamic' features that could not be
accurately simulated by the software code. The CFD model was clearly able to
demonstrate differences in performance between good and bad cupboard designs, and
show the importance of using rear baffles and lipfoils. It also showed the
importance of good design features when a 'worker' was standing against the front
edge or when there were draughts in front of the aperture. The computer model was
used to simulate the gas tracer containment test method described in BS 7258
(1994) [Laboratory Fume Cupboards], and had a much greater sensitivity than the
recommended physical measuring instruments. The results given in this paper
demonstrate the potential for using a commercially available software package for
the optimisation of fume cupboard design and testing. It also indicates the
economy of using CFD compared with building a prototype and testing a model.
PMID- 10775670
TI - Contaminant dispersion in the vicinity of a worker in a uniform velocity field.
AB - The transportation of gaseous contaminant from a low and moderate low impulse
(momentum<1 m s(-1)) source to the breathing zone was studied in a uniform air
stream flow. Results of the effects of the direction and the velocity of
principal air flow, convection due to a human body, arm movement of a human being
and the type of source on the concentration profiles are presented. Three
important results were obtained. Firstly, for a given low and moderate impulse
low impulse contaminant source in the near field of a worker, his/her orientation
relative to the principal air flow direction is the most important factor in
reducing occupational exposure, with an air velocity of about 0.3 m s(-1).
Secondly, the effect of convection resulting from body heat on air flow was lower
than expected. Thirdly, arm movements influence contaminant dispersion, and
should be included when models assessing exposure are developed. The present data
can also be used to validate existing computational fluid dynamic (CFD) models.
PMID- 10775671
TI - Fit factors for quarter masks and facial size categories.
AB - Respirator fit testing is necessary before entering hazardous working
environments to ensure that the respirator, when worn, satisfies a minimum fit
and that the wearer knows when the respirator fits properly. In the many
countries that do not have fit testing or total inward leakage regulations
(including Korea), however, many workers wearing respirators may be potentially
exposed to hazardous environments. It is necessary to suggest a useful tool to
provide an alternative for fit testing in these countries. This study was
conducted to evaluate fitting performance for quarter-mask respirators, and fit
factors in facial size categories based on face lengths and lip lengths of the
wearers. A total of 778 subjects (408 males, 370 females) were fit tested for
three quarter masks: Sejin Co. SK-6 (Ulsan, Korea), Yongsung Co. YS-2010 S
(Seoul, Korea), and 3 M Co. Series 7500 Medium (MN, USA) masks with a PortaCount
8020 (TSI Co., USA). A facial dimension survey of the subjects was conducted to
develop facial size categories, on the basis of face length and lip length.
Geometric mean fit factors (GMFFs) of Series 7500 Medium were found to be the
highest of the three respirators. All of the respirators were more suitable for
males than females in fitting performance. The Series 7500 Medium fitted a large
number of the males tested, since the GMFFs for males were above 100 for every
box of facial size categories, and high pass proportion rates were shown at an
individual fit factor level of 100. The YS-2010 S provides an adequate fit for
males in a limited range of facial dimensions. The Series 7500 Medium is more
limited in providing adequate fit for females at specific facial dimensions than
for males. For adequate fitting performance, the SK-6 is not preferentially
recommended for Korean male and female workers due to low GMFFs and pass
proportions. The result of this study indicates that after more accurate studies
are performed, facial size categories, on the basis of facial dimensions, could
be a useful tool to assist in the selection of adequately fitting respirators for
workers in the countries having no fit testing requirements.
PMID- 10775672
TI - Identification of matrix metalloproteinases and their tissue inhibitors type 1
and 2 in human masseter muscle.
AB - Changes in masticatory muscle structure and function are either developmental, as
seen in anomalies of facial form, or adaptive, as seen during procedures such as
orthognathic surgery and functional-appliance orthodontic therapy. Remodelling of
muscle extracellular matrix is pivotal in these processes. This turnover is
mediated via members of the family of enzymes known as matrix metalloproteinases
(MMP) and inhibited by the tissue inhibitors of metalloproteinases (TIMP). The
aim here was to investigate the in vivo pattern of expression and distribution of
MMPs and TIMPs in masseter muscle of humans with both normal and abnormal facial
forms. Masseter muscle biopsies were taken from 10 patients, four with long-face
syndrome and six normal controls as confirmed by cephalometry.
Immunohistochemical techniques were used to show the pattern and distribution of
MMPs and TIMP proteins in the muscle. Zymography of tissue extracts was used to
determine the presence of MMP activity. Reverse transcriptase-polymerase chain
reaction (RT-PCR) was used to detect the presence of MMP and TIMP-2 mRNA. MMP-1
was expressed around the individual muscle fibres, especially in those fibre
surfaces in contact with the interstices of the connective tissue and around
blood vessels. MMP-9 staining was less intense and was expressed in the
interstices of the connective tissue and around blood vessels. Zymography of
protein extracts confirmed that MMP-9 activity was present. MMP-2 and MMP-3 were
not expressed in the samples, although MMP-2 mRNA could be detected by RT-PCR and
its activity could be detected by zymography. Intense TIMP-1 staining was present
around each muscle fibre, in the interstices of the connective tissue and
surrounding blood vessels; TIMP-2 mRNA could be detected in all samples. These
staining patterns were seen in all biopsies examined and were irrespective of the
facial form of the donor. These findings provide evidence that the mechanisms
required for matrix remodelling are present in the human masseter muscle.
PMID- 10775673
TI - Immunohistological and morphometric analysis of intra-epithelial lymphocytes and
Langerhans cells in healthy and diseased human gingival tissues.
AB - Periodontal diseases are histologically characterized by an infiltration of
several inflammatory cell populations into the gingival epithelium and connective
tissue, associated with degradation of extracellular matrix components. The
purpose of this in situ study was to evaluate the inflammatory state of gingival
tissues by the number of intra-epithelial lymphocyte (IEL) subsets and the area
fraction (AA%) occupied by collagen fibres in the upper gingival connective
tissue, and also to evaluate the number of CD1a+ Langerhans cells (LC) in order
to show correlation(s), if any, between these histological findings. The gingival
samples were from 10 clinically healthy controls (group C), 8 patients with
gingivitis (group G) and 9 with chronic adult periodontitis (group P). A
quantitative evaluation of the number of cell populations (CD1a+, CD45RB+, CD3+,
CD8+, CD20+, TIA-1+ and GrB+ cells) and the area fraction (AA%) occupied by
collagen fibres in the upper gingival connective tissue was made by morphometric
and automated image analysis. The results showed that, compared with group C, all
IEL subset numbers were significantly increased (p<0.05) in G and P groups, CD20+
excepted. In addition, there was a significant increase in the cytotoxic TIA-1+
IEL number (p<0.05) in group P when compared with group G. The study also showed
a significant decrease in the number of CD1a+ LC in groups G and P (p<0.02 and
p<0.001, respectively) when compared with group C. No significant difference was
found in CD1a+ LC number between groups G and P. The determination of
coefficients of correlation (r) with data obtained for each patient showed that
in group G, CD1a+ LC number was significantly correlated with CD45RB+ (p<0.05)
and CD3+ (p<0.01) IEL numbers whereas during periodontitis, CD1a+ LC number was
significantly and inversely correlated with CD20+ (p<0.01), cytotoxic TIA-1+
(p<0.01) and with activated cytotoxic GrB+ (p<0.01) IEL numbers. Moreover, in
group P a significant (p<0.05) positive correlation was shown between CD1a+ LC
number and the AA% occupied by collagen fibres. This work demonstrates a decrease
in CD1a+ LC number according to the severity of the periodontal disease estimated
by the number of IEL and by the area fraction occupied by collagen fibres in
human gingiva. The decrease of such cells could represent a way to avoid immune
overstimulation.
PMID- 10775674
TI - The effect of stimulus form and dimensions on the oral size illusion in humans.
AB - Previous work has shown that individuals overestimate the diameter of holes
presented to the tongue when they use their fingers to select matching holes from
a range of comparators. This disparity is known as the oral size illusion. The
hypothesis that this illusion arises from the greater pliability of the tongue
surface compared with that of the fingertip was tested here. Two experiments were
carried out on 64 participants. In experiment 1 (n=32), the stimuli were two sets
of holes, 1 and 5 mm deep and 2.4, 5.6, 8.2, 12 mm dia. , which were presented to
the tongue. The comparator was a series of holes 5 mm deep and 0.8-15 mm dia.,
which were explored manually. Participants significantly overestimated all
diameters of the 1- and 5-mm deep stimulus holes (p<0.05). Apart from the 2.4-mm
dia. holes, there were no significant differences between the illusions produced
with the holes 1 mm and 5 mm deep (p0.7). In experiment 2 (n=32) individuals were
tested with small cylinders ('pegs') 1 mm high and 2.6, 5.2. 7.6, 12.6 mm dia.
and also with the four 5-mm deep stimulus holes used in experiment 1. The 'peg'
stimuli presented to the tongue were matched against a similar set of 1-mm pegs,
2-18 mm dia., explored with the fingers. The comparator series for the 5-mm deep
holes was the same as for experiment 1. Participants consistently overestimated
the size of the 5-mm holes (p<0.001). However, there was no illusion with the peg
stimuli (p=0.08), except for the 7.6-mm dia. stimulus (p<0.05). The results of
experiment 1 did not support the experimental hypothesis that the oral size
illusion was due to the greater pliability of the tongue surface. The result of
experiment 2 suggests that the oral size illusion does not occur when peg stimuli
are used instead of holes. The form and diameter of the stimulus is thus
important in determining the magnitude of the oral size illusion.
PMID- 10775675
TI - Quantification of human chewing-cycle kinematics.
AB - This study introduces new methods of quantifying and evaluating the human chewing
cycle. These methods were validated on a sample of 26 young adults (11 women and
15 men) between 20-35 years of age. Movements of the mandibular central incisors
were recorded (100 Hz) using an optoelectric computer system while the
participants chewed gum. A subsample of 10 cycles was automatically selected,
based on multiple objective criteria to ensure representative cycles for each
individual. Once representative cycles had been identified, multilevel
statistical models were used to evaluate and describe the sample's kinematic
patterns. The multilevel procedures allow for missing observations, they do not
assume equal intervals, and variation can be partitioned hierarchically. Two
level models showed significantly shorter cycle duration for males (835 msec)
than females (973 msec). Inferior-superior (IS) cycle range was 2.6 mm larger and
maximum IS velocity was 19.6 mm/sec faster in males than females. There were no
significant differences in medial-lateral (ML) and anteroposterior (AP) excursive
ranges or velocities. With the exception of cycle duration and ML ranges of
motion, random variation was three to five times larger between individuals than
between cycles. The three-level models showed that eighth-order polynomials were
necessary to describe IS, AP, and ML chewing movements of the entire cycle. The
models identified highly significant sex differences in cycle kinematics
(excursions, velocities, accelerations, etc.) for each aspect of movement (AP,
IS, and ML). It is concluded that this approach provides several important
advantages over existing methods, including (a) its objectivity, (b) a more
complete description of kinematic patterns, (c) a hierarchical description of
variation, and (d) its ability to test hypotheses statistically.
PMID- 10775676
TI - Promotion of selective cell attachment by the RGD sequence in dentine matrix
protein 1.
AB - Dentine matrix protein 1 (DMP1) is an important component of the non-collagenous
extracellular matrix of developing teeth and bones. Functions of DMP1 other than
a putative role in the initiation of mineralization are largely unknown. A first
report on the DNA and deduced amino acid sequence showed that DMP1 has a single
Arg-Gly-Asp (RGD) sequence. Here, whether the RGD sequence functions as a cell
attachment domain was tested. Using site-directed mutagenesis, two mutant
recombinant DMP1 proteins with specific alterations at the RGD site were created.
In the first mutant protein the RGD sequence was altered to a RGE (RGE) sequence;
in the second the RGD domain was deleted (DEL). Mutated proteins were confirmed
to be DMP1 by partial protein sequencing and dot-blot analysis with an anti-DMP1
antibody. Attachment of RPC-C2A (dental pulp cells), MC3T3-E1 (calvarial cells)
or CHO (Chinese hamster ovary cells) to non-tissue-culture plastic coated with
either DMP1, RGE or DEL proteins was compared. Bovine serum albumin and
fibronectin served as negative and positive controls, respectively. The RGD
containing native DMP1 protein effectively allowed cell attachment and spreading.
The RGE and DEL proteins with the altered and deleted RGD sites were
significantly less effective in promoting cell attachment than the recombinant
DMP1. Both RPC-C2A pulp cells and MC3T3-E1 cells showed similar reductions in
attachment to mutated proteins. Treatment of RPC-C2A cells with a RGD-containing
peptide prior to plating on DMP1-coated chambers abolished DMP1-mediated cell
attachment. In contrast to RPC-C2A and MC3T3-E1cells, CHO cells, which normally
do not express DMP1, failed to attach to DMP1. These data demonstrate that DMP1
promotes cell attachment through the RGD domain and that the attachment is cell-
and tissue-specific. A basis for these observations is proposed using computer
generated models of the polypeptides within the DMP1 protein containing the RGD,
RGE or DEL sequences.
PMID- 10775677
TI - Age-associated changes in decorin in rat mandibular condylar cartilage.
AB - The small proteoglycan decorin strongly binds the fibrils of collagen types I and
II; this interaction is thought to play a part in the maintenance of tissue
integrity and biomechanical properties. In limb articular cartilage, there is
evidence that decorin synthesis increases with age and that it is elevated in
response to increased loading or in osteoarthritic cartilage. The aim here was to
characterize the presence and relative amount of decorin in the condylar
cartilage of the temporomandibular joint (TMJ) with maturation by Western
blotting, and to assess its tissue localization by immunohistochemistry.
Comparative data were obtained from tibial articular cartilage, which has been
extensively studied. Cartilage from the mandibular condyle and tibial plateau was
harvested from 24-day-old (growing) and 161-day-old (young adult) female Sprague
Dawley rats. In growing animals, decorin appeared slightly more abundant in the
mandibular condylar cartilage than in articular cartilage, whereas in young adult
animals the decorin content in the TMJ cartilage was noticeably less than in limb
articular cartilage. Although there was an increase in decorin abundance with age
at the TMJ, the increase in decorin with age in limb articular cartilage was
considerably more pronounced. These data indicate that, although decorin is
present in mandibular condylar cartilage, its abundance in adults is less than in
limb articular cartilage; thus, maturation-associated changes may be dissimilar
in magnitude from those documented for limb articular cartilage.
PMID- 10775678
TI - Autoradiographic investigation of the effect of 1-hydroxyethylidene-1, 1
bisphosphonate on matrix protein synthesis and secretion by secretory ameloblasts
in rat incisors.
AB - Seven daily subcutaneous injections of 1-hydroxyethylidene-1, 1-bisphosphonate
(HEBP) can induce enamel hypoplasia. Several enamel-free zones were observed
along the crown-analogue side of rat incisors during the secretory stage of
amelogenesis. Ameloblasts related to the enamel-free zones lay directly on the
abnormally non-mineralized mantle dentine, whereas the adjacent ameloblasts,
which were forming the enamel matrix layer, were associated with the region where
mineralization of dentine was proceeding. The further purpose of this study was
to investigate the synthetic and secretory activity of these two groups of
ameloblasts and to trace the fate of the radioactively labelled proteins. [(3)H]
proline was administered to Wistar rats 12 h after the last injection of HEBP.
Light-microscopic autoradiography was performed. Quantitative analysis indicated
that the ameloblasts of the enamel-forming zones in the drug-treated group showed
a distribution pattern of silver grains similar to that of the controls. The
ameloblasts of the enamel-free zones also demonstrated incorporation of [(3)H]
proline at the same level. There was some labelling over the non-mineralized
mantle dentine, which was supposed to indicate the penetration of ameloblast
products. From these results, it is concluded that HEBP does not affect the
ameloblast activity in protein synthesis. The complete failure of enamel-layer
formation in some specific regions is probably due to the failure in protein
secretion and protein deposition. This study provides additional evidence that
the mineralization of dentine is an essential factor in successful enamel matrix
secretion and deposition.
PMID- 10775679
TI - The effect of epidermal growth factor on the fetal rabbit mandibular condyle and
isolated condylar fibroblasts.
AB - The load-bearing surface of the mandibular condyle presents a unique arrangement
of tissues consisting of an avascular layer composed largely of collagen bundles.
Fibroblasts are interspersed amongst these bundles and are generally agreed to
produce the collagen. The mechanisms controlling development of these tissues
have not been determined. This study was conducted to explore the role of
epidermal growth factor (EGF), which appears to be important in the development
of many oral tissue types as well as in the growth and differentiation of the
mandibular condyle. Superficial cells of the fibrous zone of the condyle were
isolated from fetal rabbit condyles and [(3)H]thymidine incorporation into DNA
measured. The application of EGF produced a significant increase in radiolabel
incorporation after 2 days compared to 4 days in the controls, suggesting that
EGF induced cells to enter S-phase more rapidly. Fetal condyles were also
cultured on gelfoam surgical sponges for up to 21 days. Autoradiography of
cultured condyles showed that cells of all three zones may potentially replicate,
as indicated by incorporation of [(3)H]thymidine. All three regions displayed
greater increases in cell numbers in samples exposed to EGF than in control
samples. The measurement of zone thickness in condyles cultured on gelfoam
sponges with or without EGF showed that this peptide was able to re-establish
thickness, bringing it in line with the relation observed when the condyles were
isolated initially, particularly of the intermediate zone over a period of 21
days. As very little autoradiographic labelling occurred at this time-point in
any of the zones, the increase in thickness must primarily be due to matrix
production. It is concluded that EGF is one factor potentially regulating both
replication and differentiation in mandibular condyle and its associated cells.
PMID- 10775680
TI - Human lateral pterygoid muscle activity on the return phase of contralateral and
protrusive jaw movements.
AB - Normal function of the lateral pterygoid muscle is not well understood. The
principal aim of this study was to determine whether there is a progressive
decrease in lateral pterygoid activity as the condyle moves posteriorly and
superiorly during the return phase of a contralateral or protrusive jaw movement,
as would be expected if the muscle is involved in controlling or stabilizing the
condyle during the return phase of these movements. In seven humans,
electromyographic activity was recorded in the superior (SHLP) and inferior
(IHLP) heads of the lateral pterygoid, the masseter, anterior temporal, posterior
temporal and submandibular group of muscles, together with condylar movement,
during contralateral and protrusive jaw movement. In most individuals, there was
a progressive decrease in rectified and smoothed IHLP activity in relation to
condylar movement during the return phase of contralateral and protrusive jaw
movement. However, this pattern usually was not seen when SHLP activity was
studied in relation to condylar movement. Further, there was a high correlation
coefficient between condylar displacement and the rectified and smoothed IHLP and
anterior temporal muscle activities during the return phase of contralateral or
protrusive jaw movement, while SHLP presented a much lower correlation. For
example, the mean (+/-SD) correlation coefficient between posterior condylar
movement (along anteroposterior axis) and IHLP activity during the return phase
of a protrusive jaw movement was -0.73+/-0.36 (for contralateral movement:
0.71+/-0.56), for the anterior temporal 0.69+/-0.21 (contralateral: 0.81+/-0.09),
and for the submandibular muscles, -0. 77+/-0.15 (contralateral: -0.34+/-0.71).
For the SHLP, masseter and posterior temporal, values were -0.34+/-0.61
(contralateral: -0. 48+/-0.37), -0.24+/-0.57 (contralateral: 0.16+/-0.80), and
0.16+/-0. 77 (contralateral: 0.64+/-0.14), respectively. These findings suggest
an important role for the IHLP and anterior temporal in controlling the movement
of the condyle to the glenoid fossa on the return phase of contralateral and
protrusive jaw movements. Further studies are needed to clarify the function of
the lateral pterygoid muscle during these and other jaw movements.
PMID- 10775681
TI - Late review of the use of silver sulphadiazine dressings for the treatment of
fingertip injuries.
AB - The management of finger tip injuries is controversial. We sent out to review the
long term outcome on conservative treatment with Silver Sulphadiazine dressings.
21 patients were reviewed at between 2 and 8 years after injury. All patients
were satisfied with the treatment and the cosmetic results were good. We
recommend this method of treatment.
PMID- 10775682
TI - Prehospital stabilization of the cervical spine for penetrating injuries of the
neck - is it necessary?
AB - The purpose of this study was to assess the specific indications, benefits and
risks associated with cervical spine stabilization during pre-hospital care of
penetrating neck injuries. We retrospectively reviewed hospital charts and
autopsy reports of 44 military casualties in Israel with a penetrating neck
injury during a period of 4.5 years. A review of the literature was also carried
out. In eight of 36 hospitalized casualties (22%) a life-threatening sign was
diagnosed in the exposed neck - large or expanding haematoma, or subcutaneous
emphysema. Surgical stabilization of the cervical spine was not performed for any
of the casualties. It was concluded that life threatening complications due to
penetrating neck injury are common and may be overlooked if the neck is covered
by a stabilization device. It is extremely rare for a penetrating injury to
result in an unstable cervical spine. New management guidelines concerning pre
hospital stabilization are suggested.
PMID- 10775683
TI - The role of fluoroscopy in avoiding rotational deformity of treated femoral shaft
fractures: an anatomical and clinical study.
AB - In the first part of the study we examined the accuracy of femoral anteversion
(AV) determined by fluoroscopy, simulating a method used in closed intramedullary
femoral nailing. Twenty cadaveric femora were used. The condyles and posterior
trochanteric area were resting on a horizontal table. The proximal femur was
imaged using a C-arm image intensifier with horizontal X-ray beam at an angle of
30, 45, or 60 degrees to the long axis of the femoral shaft. To evaluate the
reliability of the measurements, the real AV angle was determined by radiography.
A small difference (mean 2 degrees ) was found between the real AV angle and the
angle between the horizontal plane and the central head-neck axis (NH angle) as
displayed by the image intensifier. In a separate clinical study, the NH angle
was assessed and used as a guide to intraoperative rotational reduction in ten
patients with femoral shaft fracture using the aforementioned method. Follow-up
examinations of the AV angle showed that rotational deformities of clinical
significance were avoided.
PMID- 10775684
TI - Missile injuries of the knee joint.
AB - The results of the treatment of missile injuries of 170 knees in 162 patients are
analyzed. The injuries were caused by infantry weapon missiles in 52(32.1%) and
by fragments of mine or explosive devices in 110(67.9%) patients. The most
frequent were penetrating injuries of the joint with multifragment fractures
which in 15.8% cases were associated with injuries of the neurovascular bundle.
Stabilization of bone fragments was required in 111(65.3%) knees. Stabilization
was done by external fixation in 42(37.8%) and by plaster of Paris in 69(62.2%)
knees. Additional mini osteosynthesis was required in 13(30.9%) knees stabilized
by external fixation and in 3(4.3%) knees stabilized by plaster of Paris.
Amputations were performed in 13(7. 6%) injured knees. During the postoperative
period local and general complications occurred in 27(16.6%) patients. The most
frequent local complications were suppurative articular infections requiring
repeated surgery. Soft tissue defect covering was necessary in 53(33. 1%)
patients. The poor late results were present in missile fractures of the knee.
The most frequent were degenerative changes with bone defects. The possible
surgical solutions in such cases are arthrodesis or total endoprosthesis
implantation.
PMID- 10775685
TI - The value of the axial view in assessing calcaneal fractures.
AB - We studied the value of the axial view of the calcaneum in diagnosing fractures.
Fifty sets calcaneal radiographs were studied by four senior trauma staff and
four orthopeadic trainees on two occasions 2-3 weeks apart. On the first occasion
only the lateral view was studied; on the second, both lateral and axial views
were studied. The axial view did not improve the sensitivity or specificity of
the lateral view alone. Senior staff were more accurate in assessing the
radiographs. We suggest that the axial view should not be used routinely in
assessing a patient with a possible calcaneal fracture.
PMID- 10775686
TI - Outcome after hemi-arthroplasty for displaced intracapsular femoral neck fracture
related to mental state.
AB - This study was performed to assess mortality and functional outcome after hemi
arthroplasty for displaced intracapsular femoral neck fractures in relation to
mental state. Between 1991 and 1995, 202 consecutive patients over 70 years of
age were followed for at least two years or until death. Thirty-nine patients
were known with senile dementia at the time of admission. The four-month
mortality rate was 11.7% for the mentally normal patients and 33.3% for the
mentally impaired patients. After one year the mortality rate was 19. 6% for the
mentally normal patients and 43.6% for the mentally impaired patients. This
difference is statistically significant (p<0. 001). Of the 141 surviving mentally
normal patients, who had been mobile before operation, 16 (11.3%) were not mobile
four months after operation. Of the 24 surviving mentally impaired patients, who
had been mobile before operation, 18 (75.0%) were not mobile four months after
operation. This difference is statistically significant (p<0.001). The conclusion
of our study is that mental state has a statistically significant effect on
mortality and functional outcome after hemi-arthroplasty for displaced
intracapsular femoral neck fractures. For demented patients, hemi-arthrplasty is
a too major operation and less invasive methods of internal fixation should be
considered.
PMID- 10775687
TI - Endoscopic osteosynthesis after thoracic spine trauma: a report of two cases.
AB - Modern concepts of treating thoracic diseases suggest more and more the use of
minimally invasive thoracoscopic techniques to reduce morbidity and save costs.
For treatment of specific lesions at the thoracic spine, several thoracoscopic
procedures have been performed successfully. The present report examines the
feasibility of thoracoscopic osteosynthesis in two patients with ventral
hyperextension injuries and anterior instability of the thoracic spine. After
initial correction of the anatomical deformity, autologous bone was harvested
from the anterior iliac crest. Using a ventral, thoracoscopic approach, the main
location of the ventral, damaged spinal segment was identified by the covering
pleural haematoma. After endoscopic ventral bone grafting, osteosynthesis was
performed, using dynamic compression plates, cardan drills and screw drivers. The
perioperative course was uneventful, and follow up examinations after 3 years and
9 months, respectively, revealed an unchanged stable spinal segment. Our results
show thoracoscopic osteosynthesis to be technically possible, with a potential
for yielding satisfying long-term results.
PMID- 10775688
TI - Abdominal CT scanning for trauma: how low can we go?
AB - PURPOSE: computed tomography (CT) of the abdomen is an established, albeit
expensive and perhaps overused, diagnostic modality for the evaluation of the
injured patient. We developed a practice management guideline for blunt abdominal
trauma intended to reduce the percentage of negative CT scans, yet minimize
delayed recognition of injury and non-therapeutic laparotomy. PROCEDURES: between
April 1996 and March 1997, 1147 adult patients at risk for blunt abdominal injury
were admitted to our Level I trauma centre and underwent abdominal evaluation
according to the practice management guideline. MAIN FINDINGS: abdominal CT was
performed in 522 patients (45%), and 441 scans were negative (85%). Delayed
recognition of injury and non-therapeutic laparotomy rates were low, 4% and 1.6%,
respectively. PRINCIPAL CONCLUSION: abdominal CT scanning in trauma patients can
achieve low non-therapeutic laparotomy and delayed recognition of injury rates
but at the expense of high negative CT scan rates. Greater reliance on the
physical examination and perhaps abdominal ultrasound may reduce negative CT scan
rates and yet preserve low non-therapeutic laparotomy and delayed recognition of
injury rates.
PMID- 10775689
TI - Centralization of ulna for infected nonunion of radius with extensive bone loss.
A modified Hey-Groves procedure.
AB - We describe a case of infected nonunion of the radius with extensive bone loss in
an 11-year-old boy treated by centralization of the ulna. The technique used
differs from the original Hey Groves procedure in that it preserves the distal
end of the ulna with its important triangular fibrocartilage complex, thereby
retaining stability and contour of the wrist joint. Our patient obtained a
functionally and cosmetically satisfactory, stable forearm and wrist. We present
the technique as a useful armament in the management of extensive bony defect of
the radius arising from trauma or infection.
PMID- 10775690
TI - Image intensifier position for hand and wrist fractures.
PMID- 10775691
TI - The aetiology and epidemiology of clavicular fractures. A prospective study
during a two-year period in Uppsala, Sweden.
AB - In a prospective study, the age- and gender-specific incidence and features of
clavicular fractures were studied during 1989 and 1990. The population at risk
consisted of about 200,000 individuals aged 15 or above in the county of Uppsala,
Sweden. There were 187 clavicular fractures in 185 patients corresponding to an
annual incidence of 50/100,000 (males 71/100,000, women 30/100,000). Males were
significantly younger and sustained comminuted fractures more often than women.
The fracture incidence decreased with age in both genders, although the reduction
was significant only in men. Bicycle accidents most frequently caused clavicular
fractures in both genders, whereas sports activities were significantly more
common in men. Right and left clavicles were almost as frequently fractured, and
a direct fall on the shoulder was the most frequent mechanism of injury for both
genders. There was no difference between genders in the anatomical location with
about three of four fractures occurring through the middle part and one of four
through the acromial part of the clavicle. Ninety-five percent healed
uneventfully, while non-union developed in 5% - evenly distributed between the
middle part of the clavicle and the acromial part.
PMID- 10775692
TI - Implant failure in tibial nailing.
AB - Between 1991 and 1995 five hundred and twenty tibial diaphyseal fractures were
treated with intramedullary nailing in Northern Ireland. We retrospectively
reviewed three hundred and thirty eight patients in three out of the four
fracture units in Northern Ireland. Within this group there were three hundred
and forty fractures and we identified twenty five episodes of implant failure.
This group of patients had a higher percentage of open injuries with a higher
degree of comminution and had been treated with smaller diameter nails when
compared with the group of patients, who had no implant failure. Failure occurred
most frequently at the transverse proximal locking screw when a single screw was
used. Fractures in the distal third of the tibia had a higher incidence of nail
breakage. We would recommend early elective dynamisation and the use of
statically locked larger diameter nails, especially in comminuted or distal third
fractures.
PMID- 10775693
TI - Proto-oncogene expression during fracture repair.
AB - The possibility that proto-oncogenes play a role in fracture repair has been
investigated in this study. Closed fractures were created in the tibiae of NZW
rabbits and treated with a plaster cast. At intervals of 1 and 2 weeks, sections
of the fracture callus were obtained and stained using an immunocytochemical
technique which localised c-myc and c-jun. Osteogenic cells of the periosteum,
endosteum, Haversian canal and new bone trabeculae expressed proto-oncogenes
while hypertrophic chondrocytes were generally immunoreactive negative. The
results suggest that proto-oncogene expression may be involved in post-fracture
osteogenesis but not in the chondrogenic processes which precede endochondral
bone formation. This could be used as a tool for diagnosing slow healing in the
early stages of fracture repair.
PMID- 10775694
TI - Healing of closed femoral shaft fractures treated with the AO unreamed femoral
nail. A comparative study with the AO reamed femoral nail.
AB - Out of a hundred and seven closed femoral fractures, fifty-three were treated
with the unreamed femoral nail and fifty-four with the reamed femoral nail. There
were four delayed unions in the Unreamed Femoral Nail group (UFN) and three in
the Reamed Femoral Nail group (RFN). There were no cases of infection or
malunion. Implant failure was the cause of implant conversion in one patient of
the UFN group. Healing time of the femoral fractures was 19.2 weeks in the UFN
group and 19.6 weeks in the RFN group. Due to the significant decrease in
operating time with the UFN (70 min) in comparison with the RFN (125 min) and the
possible risk of posttraumatic pulmonary oedema (ARDS) with reaming techniques,
the authors recommend the UFN for the treatment of acute closed femoral shaft
fractures.
PMID- 10775695
TI - Chronic traumatic anterior knee pain.
AB - Chronic anterior knee pain following a direct injury to the front of the knee is
common. The persistent symptoms can be troublesome. There is a paucity of
documentation regarding its definition, natural history and prognosis. We have
reviewed 46 (92%) of a consecutive series of 50 patients with chronic traumatic
anterior knee pain, in which other significant acute knee pathology was excluded.
After a mean follow-up of 4 years and 8 months only 4% of patients were pain
free, 68% had moderate or severe pain and 28% mild pain. Twenty percent felt they
were improving, 59% were static and 17% were deteriorating. The commonest
clinical findings were patello-femoral crepitus (96%), local tenderness (72%) and
difficulty in squatting or kneeling (72%). Few patients improve beyond 2 years
and continued improvement is unlikely. In patients referred for specialist advice
this is a clinical syndrome characterised by persistent debilitating symptoms
resistant to treatment.
PMID- 10775696
TI - Urological pitfalls in unstable pelvic fractures.
PMID- 10775697
TI - Traumatic rupture of the superior gluteal artery with a stable pelvic fracture.
PMID- 10775698
TI - Acute compartment syndrome masked by intravenous morphine from a patient
controlled analgesia pump.
PMID- 10775699
TI - Acute slipped capital femoral epiphysis in the eightieth year of life: a case
report.
PMID- 10775700
TI - Pancreaticogastrostomy for trauma: an alternative to distal pancreatectomy.
PMID- 10775701
TI - Heritability of lateralization in fish: concordance of right-left asymmetry
between parents and offspring.
AB - The poeciliid fish Girardinus falcatus shows a consistent population bias to
detour a vertical-bar barrier preferentially leftwise when approaching a dummy
predator to inspect it; the asymmetry seems to be due to a preferential use of
the lateral field of the right eye during fixation of biologically relevant
stimuli such as a predator. In order to unravel the origins of this lateral bias,
we took advantage of the individual variability present in the natural population
to perform artificial selection experiments. Males and females that scored
similarly at the detour test were mated together and their progeny were tested in
the same task. Results showed that there was a striking similarity in the
strength and in the direction of the asymmetries between parents and offspring.
Correlation was highly significant and the estimate of heritability was greater
than 0.5. This represents the first demonstration of heritability of the
direction of a behavioural asymmetry outside the primate order. The finding paves
the way to the use of a novel and suitable animal model for the neuro-genetics of
lateralization and to the possible identification of homologous and/or analogous
genes underlying brain asymmetry among vertebrates.
PMID- 10775702
TI - Modulation of slow brain potentials by working memory load in spatial and
nonspatial auditory tasks.
AB - Slow event-related brain potentials were recorded from the human scalp during
spatial and nonspatial auditory delayed matching-to-sample and n-back tasks to
find out whether there are differences in the distribution of slow potentials
during the retention of audiospatial and pitch information. The performance of
both the location and pitch tasks produced slow potentials during the delay phase
of the memory tasks. The delay-related slow potential was modulated by the amount
of information to be processed during the tasks at the parietal-occipital sites.
The distribution of mnemonic modulation was, however, not different between the
tasks. The results suggest that there is integration of auditory information
processing in the neuronal networks engaged in mnemonic processing of pitch and
location.
PMID- 10775703
TI - Ideomotor apraxia, visuomotor control and the explicit representation of posture.
AB - Ideomotor apraxia is normally viewed as a disorder of the representation or
execution of action. However, the evidence from gesture imitation is that apraxic
patients are unable to reproduce the final posture of a gesture but may not show
abnormality in movement kinematics. This supports a hypothesis that impaired
gesture imitation is due to a deficit in a conceptual representation of body
posture rather than indicating a disorder specific to action control. The present
study evaluated whether other aspects of apraxic behaviour might also be most
consistent with a deficit in the representation of posture. Patients with left
hemisphere damage and apraxia on gesture imitation had difficulty in reproducing
a series of actions due to failure to adopt the required configuration of the
hand whereas there was no consistent reduction in speed of response once the
actions had been learned. They also tended to use an abnormal, clumsy grasp when
using a spoon but this dissociated from accurate performance on other tests of
manual dexterity where there was less scope for variation in configuration of the
hand. These data suggest that the most common deficit in ideomotor apraxia is
impaired ability to perform tasks where the goal is to reproduce or adopt complex
hand configurations and that impaired execution of some types of action is
secondary to this problem. This is consistent with a role for the human left
parietal lobe in providing an explicit representation of posture which is used to
guide some actions and to supplement a more primitive system of direct visuomotor
control.
PMID- 10775704
TI - Visual motion sensitivity in dyslexia: evidence for temporal and energy
integration deficits.
AB - In addition to poor literacy skills, developmental dyslexia has been associated
with multisensory deficits for dynamic stimulus detection. In vision these
deficits have been suggested to result from impaired sensitivity of cells within
the retino-cortical magnocellular pathway and extrastriate areas in the dorsal
stream to which they project. One consequence of such selectively reduced
sensitivity is a difficulty in extracting motion coherence from dynamic noise, a
deficit associated with both developmental dyslexia and persons with
extrastriate, dorsal stream lesions. However the precise nature of the
mechanism(s) underlying these perceptual deficits in dyslexia remain unknown. In
this study, we obtained motion detection thresholds for 10 dyslexic and 10
control adults while varying the spatial and temporal parameters of the random
dot kinematogram (RDK) stimuli. In Experiment 1 stimulus duration was manipulated
to test whether dyslexics are specifically impaired for detecting short duration,
rather than longer stimuli. Dot density was varied in Experiment 2 to examine
whether dyslexics' reduced motion sensitivity was affected by the amount of
motion energy present in the RDKs. Dyslexics were consistently less sensitive to
coherent motion than controls in both experiments. Increasing stimulus duration
did not improve dyslexics' performance, whereas increasing dot density did. Thus
increasing motion energy assisted the dyslexics, suggesting that their motion
detectors have a lower signal to noise ratio, perhaps due to spatial
undersampling.
PMID- 10775705
TI - Minding the facts: a comment on Thompson-Schill et al.'s "A neural basis for
category and modality specificity of semantic knowledge".
AB - In this comment on a recent paper by Thompson-Schill et al. (1999) I argue that
the authors failed to consider important empirical facts that are at variance
with their favored theory of the causes of semantic category-specific deficits. I
also argue that the predictions they make about fusiform gyrus activation on the
basis of the interactive modality-specific hypothesis of semantic organization do
not obviously follow from that model. I point out that simulations are needed in
order to derive predictions from the model. Finally, I argue that the fMRI
results they obtained are not obviously relevant to our understanding of the
causes of semantic category-specific deficits.
PMID- 10775706
TI - Intact spatial updating during locomotion after right posterior parietal lesions.
AB - One function of the posterior parietal cortex (PPC) is to monitor and integrate
sensory signals relating to the current pointing direction of the eyes. We
investigated the possibility that the human PPC also contributes to spatial
updating during larger-scale behaviors. Two groups of patients with brain
injuries either including or excluding the right hemisphere PPC and a group of
healthy subjects performed a visually-directed walking task, in which the subject
views a target and then attempts to walk to it without vision. All groups walked
without vision accurately and precisely to remembered targets up to 6 m away; the
patient groups also performed similarly to the healthy controls when indicating
egocentric distances using non-motoric responses. These results indicate that the
right PPC is not critically involved in monitoring and integrating non-visual
self-motion signals, at least along linear paths. In addition, visual perception
of egocentric distance in multi-cue environments is immune to injury of a variety
of brain areas.
PMID- 10775707
TI - The dynamics of shifting visuospatial attention revealed by event-related
potentials.
AB - We developed a behavioral task for spatial orienting of attention in which the
same physical stimulus cued covert peripheral shifts of attention to either the
left or the right visual fields in different conditions. The design enabled us to
record the brain activity engaged during spatial shifts of covert attention that
was independent from the physical characteristics of the cueing stimulus using
event-related potentials (ERPs). ERPs elicited by foveal cues differed according
to the predicted target location starting ca. 160 ms, and differences persisted
until the occurrence of the target stimuli. Multiple processes were linked to
shifting spatial attention during the cue-target interval. The earliest effects
consisted of enhanced negative potentials over the posterior scalp contralateral
to the cued location. Later effects were concentrated over the right anterior
scalp sites, where activity associated with shifts to the right visual field
elicited larger positive potentials. The results extend our understanding of the
neural system that orients spatial attention by providing valuable information
about the temporal dynamics and hemispheric asymmetries of activity within its
posterior and anterior regions.
PMID- 10775708
TI - Prospective remembering of Korsakoffs and alcoholics as a function of the
prospective-memory and on-going tasks.
AB - Prospective memory is assumed to rely more on the frontal lobes than
retrospective memory. Since Korsakoff patients are known to suffer from a general
cerebral atrophy and a frontal lobe atrophy in particular, they are expected to
show considerably impaired prospective memory. In Experiment 1, the performance
of Korsakoff patients on a semantic prospective-memory task (which was embedded
in a perceptual on-going task) was particularly bad in Session 1; in Session 2,
the Korsakoff patients improved substantially, to reach the performance level of
nonamnesic alcoholics. In Experiment 2, prospective memory of the Korsakoff
patients and nonamnesic alcoholics was better when the on-going task was more
similar to the prospective-memory task; particularly striking was the much better
prospective memory in the semantic prospective-memory task when the on-going task
requires a semantic analysis than when the on-going task requires perceptual
processing. The findings are in agreement with a task-appropriate processing
explanation but also in partial agreement with the attention hypothesis of the
instance theory of automaticity. Contrary to the frontal lobe hypothesis,
prospective memory of the Korsakoff patients was surprisingly good in several
aspects of the two experiments.
PMID- 10775709
TI - Noun imageability and the temporal lobes.
AB - We used positron emission tomography to investigate brain activity in response to
hearing or reading nouns of varying imageability. Three experiments were
performed. Activity increased with noun imageability in the left mid-fusiform
gyrus, the lateral parahippocampal area in humans, and in the rostral medial
temporal lobes close to or within perirhinal cortex. The left mid-fusiform
activation has been observed in previous imaging studies of single word
processing. Its functional significance was variously attributed to semantic
processing, visual imagery, encoding episodic memories, or the integration of
lexical inputs from different sensory modalities. These hypotheses are not
mutually exclusive. The more rostral medial lobe response to noun imageability
has not been observed previously. However, lesions in perirhinal cortex impair
knowledge about objects in non-human primates, and bilateral rostral ventromedial
temporal lobe potentials in response to object nouns were observed with human
intracranial recordings. Imageable (object) nouns are learnt with reference to
sensory experiences of living and non-living objects, whereas acquisition of the
meaning of low imageable (abstract) nouns is more dependent on their context
within sentences. Parahippocampal and perirhinal cortices are reciprocally
connected with, respectively, second and third order sensory association
cortices. We conclude that access to the representations of word meaning is
dependent on heteromodal temporal lobe cortex, and that during the acquisition of
object nouns one route is established through ventromedial temporal cortical
regions that have reciprocal connections with all sensory association cortices.
PMID- 10775710
TI - Information processing deficits in head injury assessed with ERPs reflecting
early and late processing stages.
AB - ERPs provide informative measures of slowed information processing in head
injury. While several studies have reported changes in long latency ERPs (N2, P3)
in head injury, the data on early ERP components related to attention selection
are inconclusive. The problem may be partly methodological because the standard
oddball paradigm does not give an adequate basis for discriminating components
contributing to the N1 and P2 waveforms. Following a suggestion by Garcia-Larrea
et al. [10: Garcia-Larrea L, Lukasziewicz A-C, Maugiere F. Revisiting the oddball
paradigm. Non-target vs neutral stimuli and the evaluation of ERP attention
effects. Neuropsychologia 1992;30:723-741] we used an extended oddball paradigm
to study measures of early processing (N1-average, P250) as well as conventional
cognitive ERPs (N1, P2, N2, P3) in a group of head injured patients and controls.
We found evidence of deficits in early processing of neutral and non-target
stimuli in the patient group, and interpret the findings as an indication that
the patients are less efficient in terminating processing of irrelevant stimuli.
The results further indicate that processing deviations affect both target and
non-target stimuli in the oddball paradigm and thus the allocation of attention
in the task as a whole.
PMID- 10775711
TI - The effects of anterior lesions on performance on a story comprehension test:
left anterior impairment on a theory of mind-type task.
AB - Participants with unilateral anterior or posterior lesions were compared to a
healthy group on a theory of mind-type task that involved explaining the words or
actions of story characters in a series of brief vignettes. Participants also
carried out a set of non-social neuropsychological tests. Those with left
anterior brain lesions (n=6) showed impairment relative to those with right
anterior (n=13), left (n=4) and right (n=8) posterior lesions and healthy
participants (n=60) in story comprehension, and their errors commonly involved
failure to make non-literal interpretations. The left anterior lesion
participants also showed impairment on some measures of executive function. The
implications of the findings for our understanding of impairments in story
comprehension after brain injury are discussed in terms of models of executive
function and theory of mind.
PMID- 10775712
TI - Hemispheric lateralisation in a manual-verbal task combination: the role of
modality and gender.
AB - Differences in hemispheric lateralisation between males and females were tested
using a manual-verbal task combination. The manual task was finger tapping and
the verbal task required reciting words. Words were presented either visually or
aurally in order to examine a possible role of modality of presentation on
hemispheric lateralisation. The influence of the verbal task on motor task
performance was evaluated by changes in the number of taps from single to dual
task condition. The influence of the motor task performance on the verbal task
was examined by changes in the number of words recalled. Cognitive performance
differences between males and females were also examined in a mental rotation
task. The results showed a greater right finger (RH) tapping than left finger
(LH) tapping interference, but only when the verbal task was presented in the
visual mode. There was no difference in this pattern between males and females,
both showing a greater RH tapping than LH tapping interference. The interference
in finger tapping for both RH and LH was greater when the verbal task was
presented aurally than when presented visually. Furthermore, females compared to
males showed a greater interference in finger tapping when the verbal task was
presented aurally than when presented visually. Later recall of verbal
information was impaired equally by concurrent RH or LH tapping; however, later
recall was better when the verbal task was presented visually than when presented
aurally. No gender differences were found in delayed recall. Performance in the
mental rotation task was better in males than in females. The data are discussed
on the basis of theories of dual task interference and/or of brain asymmetry.
PMID- 10775713
TI - Digitizing the moving face during dynamic displays of emotion.
AB - Humans typically decode facial signals during dynamic interactions in which the
face moves. In this study, we digitized real time video signals in order to
examine movement asymmetries across the face during emotional and nonemotional
expressions. Forty dextral males were tested. For each expression, a 400 ms video
segment was analyzed for changes in signal value (pixel intensity) over
consecutive frames. The upper and lower face regions were examined separately due
to differences in the cortical enervation of facial muscles in the upper
(bilateral) vs lower face (contralateral). Results revealed distinctly different
movement asymmetries over the lower and upper hemiface. In the upper face, more
movement occurred over the right side for most facial expressions, regardless of
emotionality. The latter finding questions the assumption that muscles of the
upper face are symmetrical and/or bilaterally enervated in a symmetrical manner.
In the lower face, negative expressions linked to fight-flight emotions (i.e.
fear, anger) were associated with greater left sided movement, whereas happiness
tended to be associated with more right sided movement. No consistent pattern of
movement asymmetry occurred for nonemotional expressions. Although the valence
related movement asymmetries in the lower face are consistent with
neuropsychological models of emotional expressivity, it remains unclear whether
they reflect activation or inhibitory hemispheric mechanisms. Taken together,
these data suggest that multiple factors may contribute to expressive movement
asymmetries of the face.
PMID- 10775714
TI - Laterality of tail resting posture in three species of New World primates.
AB - A variety of mammalian species including prosimian and simian primates wrap their
tails around their bodies as a means of thermoregulation and for reasons of
comfort during resting or sleep. Adopting such a resting posture requires an
animal to move its tail either to the right or to the left of the midline of its
body, and thus to perform a lateralized behavior. The purpose of this study was
to assess the occurrence of lateral biases in tail resting posture in three
species of New World primates. Twenty squirrel monkeys, spider monkeys, and
howler monkeys, respectively, were observed and data on tail resting posture were
collected and analyzed. The results demonstrate (1) that individual squirrel
monkeys and spider monkeys exhibit highly significant lateral biases in tail
resting posture; (2) a lack of a lateral bias at the group level; (3) that howler
monkeys fail to show side preferences in tail wrapping; (4) a lack of sex
differences in this behavior in all three species; and (5) a lack of significant
correlations between preferred side of tail resting posture and preferred side of
hand use in simple reaching tasks which had been assessed with a subset of
animals in previous studies. Thus, the present study provides evidence for a
behavioral asymmetry which is well-known to occur in rats but has not been
described so far in nonhuman primates, and which might offer an additional
approach to the investigation of the mechanisms underlying functional cerebral
asymmetries.
PMID- 10775715
TI - Hand response differences in a self-face identification task.
AB - Evidence has indicated that the right frontal cortex is preferentially involved
in self-face recognition. To test this further, we employed a face identification
task and examined hand response differences (N=10). Pictures of famous faces were
combined with pictures of the participants' faces (self) and their co-workers'
faces (familiar). These images were presented as a 'movie' in which one face
transformed into another. Under the first instruction set, the movies began with
either the participant's face or a co-worker's face, and the sequences gradually
morphed into a famous face. When told to stop the movie when the face in the
sequence became famous, a significantly later 'frame' was identified when the
movies were composed of self-faces and the participants responded with their left
hand. When the movies started with the famous faces and participants had to stop
the movie when it became their own or their familiar co-worker's image
(Instruction set 2), a significantly earlier frame was identified in the 'Self:
Left hand' condition. The data suggest that participants are inclined to identify
images as their own when the right hemisphere is preferentially accessed.
PMID- 10775716
TI - The cerebellum and cognition: cerebellar lesions impair sequence learning but not
conditional visuomotor learning in monkeys.
AB - Claims that the cerebellum contributes to cognitive processing in humans have
arisen from both functional neuroimaging and patient studies. These claims
challenge traditional theories of cerebellar function that ascribe motor
functions to this structure. We trained monkeys to perform both a visuomotor
conditional associative learning task and a visually guided sequence task, and
studied the effects of bilateral excitotoxic lesions in the lateral cerebellar
nuclei. In the first experiment three operated monkeys showed a small impairment
in post-operative retention of a visuomotor associative task (A) but were then
not impaired in learning a new task (B). However, the impairment on A could have
been due to a problem in making the movements themselves. In a second experiment
we therefore gave the three control animals a further pre-operative retest on
both A and B and then tested after surgery on retention of both tasks. Though
again the animals showed motor problems on task A, they reached criterion, and at
this stage could clearly make both movements satisfactorily. The critical test
was then retention of task B, and they were not impaired. In the final experiment
(serial reaction time task) the monkeys response times on a repeating visuomotor
sequence were compared with those for a pseudo-random control sequence. After
bilateral nuclei lesions they were slow to execute the pre-operatively learned
sequence but were still faster on this than on the control task. However, when
they were then given a new repeating sequence to learn, they never performed the
sequence as quickly as they had on retention of the first sequence. We conclude
that the cerebellum is not essential for the learning or recall of stimulus
response associations but that it is crucially involved in the process by which
motor sequences become automatic with extended practice.
PMID- 10775717
TI - Multiple perceptual distortions and their modulation in leftsided visual neglect.
AB - There is an ongoing debate concerning the perception and neural representation of
space in neglect. Four experiments are here reported designed to further
investigate the nature of perceptual distortions and their modifiability in
patients with neglect. In Experiment 1 it was found that neglect patients, in
contrast to left- or right-hemisphere lesioned control patients and normal
subjects, show similar distortions of perceived visual space when judging the
extension of horizontal distances (space distortion) as compared to the
horizontal size of objects (size distortion). Similar deficits were present in
most neglect patients in a newly developed space bisection task. These results
attest that neglect patients have perceptual distortions related to within-object
(size) and between-object (distance) spatial processing in their horizontal
plane. Objects were oversized by 33% and distances by 19% horizontally in neglect
patients, whereas all control groups showed nearly veridical spatial coding
(deviations<5%). In Experiment 2 the modifiability of these distortions was
tested by the use of slow visual background motion. Leftward, coherent background
motion transiently restored normal horizontal size and distance coding in neglect
patients, whereas rightward motion aggravated the deficit significantly in the
distance task, but not in the size task. None of the other subject groups showed
any influence of background motion on spatial judgments. Experiment 3 evaluated
possible effects of simultaneous vs successive stimulus presentation in
perceptual distortions, thus modulating attentional factors. Neglect patients
performed significantly better - although not normal - with a successive
presentation of the spatial stimuli (2 s, 10 s delay) as compared to the
simultaneous condition in the size judgment task, but not in the distance task.
In contrast, this manipulation had no effects in any of the control groups.
Experiment 4 reports more detailed results of subject J.S., a neglect patient
with a right mediotemporal lesion, who showed a marked horizontal size
distortion, but normal horizontal distance judgments. Despite some fluctuation in
J.S.'s size judgments he showed a significant overestimation of horizontal object
size by +22% to +40% across several test blocks and testing sessions. Thus,
performance fluctuations due to attentional or other reasons cannot fully account
for J.S.'s dissociation in size vs distance judgments. He thus shows that the
visual coding of horizontal spatial extension within an object can be dissociated
from that of the spatial extension between objects along the horizontal plane.
Finally, performance in the three spatial tasks (used in Experiment 1) was found
to correlate significantly with three typical tests of spatial neglect (line
bisection, cancellation, copying, r=0.42-0.77), thereby indicating a significant
relationship to the neglect syndrome.Together, the results of the four
experiments are interpreted in support of multiple spatial-perceptual distortions
in visual neglect, which are influenced by visual motion and attention.
Perceptual distortions relating to objects and space between objects are present
in most neglect patients, but may dissociate, as in case J.S. It is argued that
these might reflect the existence of several, partially overlapping and diverging
neural maps for the representation of different spatial attributes in the
horizontal plane. Furthermore, it is hypothesized that these perceptual
distortions constitute an important element of the spatial-perceptual deficits
encountered in the syndrome, contribute to its severity, but are not the key
deficit of the disorder.
PMID- 10775718
TI - Processing of illusion of length in spatial hemineglect: a study of line
bisection.
AB - Bisection of horizontal lines and of the Brentano form of the Muller-Lyer
illusion was investigated in six right brain-damaged patients with left spatial
hemineglect, and in six control subjects. Patients bisected the lines to the
right of the objective mid-point. Comparable illusory effects on line bisection
were however found in both patients and control subjects. Relative to the
baseline condition, in both groups the subjective midpoint was displaced towards
the side expanded by the illusion, both leftwards and rightwards. By contrast,
line length and spatial position of the stimulus had differential effects. In
neglect patients, the rightward bisection error increased disproportionately with
line length, and when the stimulus was located in the left, neglected, side of
egocentric space. Control subjects showed no such effects. The suggestion is made
that the visual, non-egocentric, processes underlying these illusory effects of
length may be spared in patients with left spatial neglect. The possible neural
basis of this dissociation is discussed.
PMID- 10775719
TI - Identification of Poppelreuter-like pictures as indexed by blinking.
AB - Blinking was recorded in 28 adult participants during the identification of
superimposed pictures (similar to Poppelreuter figures), some of which had been
presented individually in an earlier study phase. Participants were required to
name the pictures at the end of the identification phase. The percentage of
correct identifications was greater for combinations formed by old than new
pictures, and decreased as the number of pictures in the combination increased.
Attentional demands associated with mental load (number of pictures) affected
both the rate of blinks produced during the identification process and the
latency of the first blink produced after the stimulus onset. The first blink
latency increased as the number of pictures increased, and also depended on
material to be identified, with longer latencies associated with novel
combinations. We suggest that blinking may be used as an index of memory
processes involved in visual identification, even in absence of overt (verbal)
responses.
PMID- 10775720
TI - Antepartum detection of macrosomic fetus: clinical versus sonographic, including
soft-tissue measurements.
AB - OBJECTIVE: To compare clinical and sonographic estimates of birth weights with
five new estimation techniques that involve measurements of soft tissue, for
identifying newborns with birth weights of at least 4000 g. METHODS: Over 1 year,
each woman at or after 36 weeks' gestation and suspected of having a macrosomic
fetus had clinical and sonographic estimates of fetal weight (EFW) based on femur
length (FL) and head and abdominal circumference, followed by five additional
ways to identify excessive growth: cheek-to-cheek diameter, thigh soft tissue,
ratio of thigh soft tissue to FL, upper arm subcutaneous tissue, and EFW derived
from it. Areas (+/- standard error) of receiver operating characteristic (ROC)
curves were calculated and compared with the area under the nondiagnostic line. P
<.05 was considered statistically significant. RESULTS: Among 100 women
recruited, 28 newborns weighed 4000 g or more. The areas under the ROC curves
with clinical (0.72 +/- 0.06) and sonographic predictions using biometric
characteristics (0.73 +/- 0.06) had the highest but similar accuracies (P.05).
Three of the five newer methods (upper arm or thigh subcutaneous tissue and ratio
of thigh subcutaneous tissue to FL) were poor diagnostic tests (range of areas
under ROC 0.52 +/- 0.06 to 0.58 +/- 0.07). Estimated fetal weight based on upper
arm soft tissue thickness and cheek-to-cheek diameter (areas 0.70 +/- 0.06 and
0.67 +/- 0.06, respectively) were not significantly better than clinical
predictions (P.05) for detecting macrosomic fetuses. About 110 macrosomic and
nonmacrosomic infants combined would be needed to have 80% power to detect a
difference between ROC curves with areas of 0.58 (thigh subcutaneous tissue) and
0.72 (clinical estimate). CONCLUSION: ROC curves indicated that measurements of
soft tissue are not superior to clinical or sonographic predictions in
identifying fetuses with weights of at least 4000 g.
PMID- 10775721
TI - Diagnosis of anal sphincter tears by postpartum endosonography to predict fecal
incontinence.
AB - OBJECTIVE: To determine whether anal endosonography immediately after vaginal
delivery can predict subsequent fecal incontinence. METHODS: We studied
nulliparas who delivered vaginally and had no anal sphincter tears (third- or
fourth-degree perineal tears) diagnosed clinically by endosonography before any
suture of the perineum. The sonographer was unaware of delivery details and the
obstetrician and the women were not informed of endosonography results.
Therefore, the suture of the perineum and the outcomes were not influenced by
sonographer's diagnoses. Three months after delivery, we assessed fecal
incontinence by self-administered questionnaires. RESULTS: Clinically undetected
tears of the anal sphincter were diagnosed by anal endosonography in 42 of 150
women (28%). The external anal sphincter alone was involved in 30 women (20%),
the internal anal sphincter alone in two (1.3%), and both in ten (7%). The postal
questionnaire was returned by 144 women. Incontinence was reported by 22 (15%,
95% confidence interval [CI] 10%, 22%), consisting mainly of incontinence to
flatus only (16 of 22, 73%, 95% CI 50%, 89%). Clinically undetected anal
sphincter tears diagnosed by endosonography were associated with incontinence 3
months after delivery (odds ratio [OR] 8.8; 95% CI 2.9, 26.5). The sensitivity of
anal endosonography was 68% (95% CI 49%, 88%) and the positive predictive value
37% (95% CI 22%, 51%). CONCLUSION: Anal endosonography immediately after vaginal
delivery allows diagnosis of clinically undetected anal sphincter tears that
might be associated with subsequent fecal incontinence.
PMID- 10775722
TI - Epidural analgesia for cephalic version: a randomized trial.
AB - OBJECTIVE: To determine if epidural analgesia improves the success rate of
external cephalic version. METHODS: Women with singleton fetuses in breech or
transverse presentation of at least 37 weeks' gestation were offered enrollment
in a randomized trial. Inclusion criteria included maternal age of 18 years or
older, nonvertex presentation confirmed by ultrasound, intact membranes, reactive
fetal nonstress test, and estimated fetal weight (EFW) between 2000 and 4000 g.
Women in the epidural group had lumbar epidural catheters inserted, through which
2% lidocaine and 100 microg of fentanyl were infused. External cephalic version
attempts were done with ultrasound guidance in a standard fashion for both
groups. The primary outcome variable was the successful version of the fetus to a
cephalic presentation. RESULTS: There were no statistically significant
differences between groups in gestation at time of procedure, placental location,
fetal lie, gravity, parity, EFW, or amniotic fluid index. External cephalic
version was successful in 32 of 54 women (59%) with epidural anesthesia compared
with 18 of 54 (33%) with no anesthesia (relative risk [RR] 1.8, 95% confidence
interval [CI] 1.2, 2.8, P <.05). Vaginal delivery occurred in 29 of 54 women
(54%) in the epidural group and 16 of 54 women (30%) in the control group (RR
1.9, 95% CI 1.2, 2.9, P <.05). CONCLUSION: Epidural analgesia increased the
success rate of external cephalic version and the likelihood of subsequent
vaginal delivery.
PMID- 10775723
TI - Amniocentesis for selection before rescue cerclage.
AB - OBJECTIVE: To determine whether diagnostic amniocentesis should be part of
evaluations of women under consideration for rescue cerclage. METHODS: We
reviewed the obstetric records of 25 candidates for rescue cerclage seen between
June 30, 1995, and July 1, 1997. Rescue cerclage was defined as a procedure on a
cervix with an internal os dilated at least 2 cm and 50% effaced, with membranes
visible at the external os. Transabdominal amniocentesis was offered as part of
the preoperative evaluation, and amniotic fluid (AF) was sent for glucose and
lactate dehydrogenase level determinations, Gram staining, and culture for
aerobic and anaerobic bacteria. Placentas were examined for histopathologic
evidence of inflammation. The women were divided into three groups. Eleven women
had rescue cerclage after amniocentesis, seven had rescue cerclage after
declining amniocentesis, and seven had amniocentesis but were treated
conservatively because of AF markers of infection. Analysis of variance and
chi(2) statistics were used. RESULTS: The group that had rescue cerclage after
amniocentesis had a significantly longer mean admission-to-delivery interval,
higher mean gestational age at delivery, higher mean birth weight, and higher
neonatal survival rate than did the group that had rescue cerclage without
amniocentesis and the group that had no cerclage after amniocentesis (P <.001).
CONCLUSION: Amniocentesis before rescue cerclage placement identified women with
subclinical chorioamnionitis who would not benefit from cerclage.
PMID- 10775724
TI - Growth pattern of twins of different chorionicity evaluated by sonographic
biometry.
AB - OBJECTIVE: To determine differences between growth patterns of monochorionic and
dichorionic twins, and of concordant and discordant twins of both chorionicities.
METHODS: We studied 70 cases of concordant twins (24 monochorionic, 46
dichorionic) and 45 cases of discordant twins (25 monochorionic, 20 dichorionic).
In each case, growth was measured longitudinally by ultrasound biometry and the
growth pattern was depicted. RESULTS: There were no differences in incremental
growth between concordant monochorionic and dichorionic twins. The growth curve
of concordant twins of both chorionicities was almost the same as that of a
singleton until 34 weeks' gestation. However, in the discordant twins, the growth
of the larger twin matched the growth curve of a singleton or concordant twin,
but the growth of the smaller twin gradually decreased to the range of growth
restriction. The growth curves for monochorionic discordant twins appeared to be
representative of two groups, one of which had onset of discordancy before 24
weeks. CONCLUSION: It is clinically important to determine chorionicity early in
twin pregnancies, to calculate the percentage of discordancy between the fetuses,
and to examine longitudinal fetal growth curves in each chorionicity.
PMID- 10775725
TI - Maternal urine beta-core hCG fragment level and small for gestational age
neonates.
AB - OBJECTIVE: To determine whether second-trimester urine beta-core fragments of hCG
predict small for gestational age (SGA) neonates. METHODS: Spot urine beta-core
levels were measured in 733 nonhypertensive women with singleton pregnancies who
presented for amniocentesis and had karyotypically normal fetuses. The beta-core
level was standardized to urine creatinine and expressed as multiples of the
median. The area under a receiver operating characteristics curve was used to
determine the screening efficiency of the urine analyte for prediction of small
for gestational age (SGA) births. In a subgroup of cases, serum markers (alpha
fetoprotein [AFP], hCG, and unconjugated estriol) were compared using stepwise
regression analysis to urine beta-core fragment for SGA prediction. RESULTS:
There were 23 (3.0%) SGA neonates. The mean +/- standard deviation (SD) gestation
at urine collection was 16.4 +/- 1.3 weeks and collection to delivery interval
was 23.0 +/- 2.2 weeks. Mean beta-core (+/- SD) fragment levels were
significantly higher in those who later had SGA infants compared with
appropriately grown infants (2982.8 ng/mg creatinine versus 1447.4 ng/mg
creatinine, P <.001). Stepwise logistic regression found that urine beta-core
fragment and serum AFP were the only significant predictors of SGA, with
statistically significant chi(2) values (P <.001 and P =.038, respectively). The
urine analyte was significantly superior. Second-trimester urine beta-core
fragment had a 78.3% sensitivity and 70% specificity for SGA prediction.
Exclusion of preeclamptic cases resulted in a sensitivity of 84.2% and a
specificity of 71.2%. CONCLUSION: Second-trimester elevated maternal urine beta
core fragment of hCG predicted SGA infants, and was superior to other serum
analytes in that prediction.
PMID- 10775726
TI - Amniotic fluid soluble fas levels in intra-amniotic infection.
AB - OBJECTIVE: Membrane Fas can induce apoptosis in sensitive cells. It has been
reported that soluble Fas (sFas) is elevated in septicemia. We examined amniotic
fluid (AF) sFas levels in patients with and without intra-amniotic infection.
METHODS: Forty-two AF specimens were studied. Intra-amniotic infection was
defined as the presence of a positive AF culture. Twenty-one specimens were from
patients with intra-amniotic infection and 21 were from patients without intra
ammotic infection. Amniotic fluid sFas was determined by an enzyme immunoassay
and normalized by AF creatinine levels. The Mann-Whitney U test, contingency
table method, and Spearman's rank correlation test were used for statistical
analyses. Data were expressed as median with ranges. RESULTS: There were no
significant differences in maternal age, gestational age, parity, and race
between the groups. The median AF sFas was significantly higher with intra
amniotic infection than without it (5.07 U/mL, range 0.32-13. 25 compared with
1.95 U/mL, range 0.01-5.35; P =.004). After normalizing to AF creatinine,
infected fluids also had significantly higher median sFas/creatinine than
uninfected amniotic fluids (289.1 U/mg creatinine, range 16.6-920.5 compared with
126.8 U/mg creatinine, range 0.5-546.2; P =.01). Amniotic fluid sFas and
sFas/creatinine were positively correlated with AF leukocytes and negatively
correlated with AF glucose. CONCLUSION: Elevated AF sFas is associated with intra
amniotic infection. High production of AF sFas in intra-amniotic infection may
play a role in the inhibition of apoptosis of AF leukocytes, leading to the
persistence of inflammation.
PMID- 10775727
TI - Serum intercellular adhesion molecule-1 levels and histologic chorioamnionitis.
AB - OBJECTIVE: To compare the diagnostic value of intercellular adhesion molecule
(ICAM)-1 with that of C-reactive protein (CRP) and white blood cell (WBC) count
for detecting histologic chorioamnionitis in serum of women with preterm labor.
METHODS: Maternal blood was collected from 97 consecutive women admitted with
preterm delivery before 37 weeks' gestation, and 50 women after normal term
delivery (38-41 weeks' gestation). Intercellular adhesion molecule-1, CRP, and
WBC count were measured before delivery. RESULTS: Histologic chorioamnionitis was
diagnosed in 48 of 97 women (48%) who delivered preterm and in none who delivered
at term. Maternal serum levels of ICAM-1 (median 169 ng/mL, range 94-510 ng/mL, P
<.001), CRP (median 2.8 ng/mL, range 0.5-13.2 mg/dL, P <.001) and WBC count (12.6
x 10(3)/microL, range 6.4-30.6 x 10(3)/microL, P <.02) were statistically
significantly higher in women with histologic chorioamnionitis than those without
it (ICAM-1 median 70 ng/mL, range 23-107 ng/mL; CRP median 0.7 mg/dL, range 0.5
6.7 mg/dL; WBC count median 10.9 x 10(3)/microL, range 4.3-22.2 x 10(3)/microL).
The sensitivity and specificity of maternal serum ICAM-1 (cutoff 106 ng/mL), CRP
(cutoff 1.1 mg/dL), and WBC count (cutoff 11.8 x 10(3)/microL) for diagnosing
histologic chorioamnionitis were 98.0% and 93.8%, 75.5% and 71.4%, and 63.3% and
61.2%, respectively. CONCLUSION: In women with preterm labor, ICAM-1 is a more
reliable indicator of histologic chorioamnionitis than CRP or WBC count.
PMID- 10775728
TI - Placental expression and serum concentrations of cytokeratin 19 in preeclampsia.
AB - OBJECTIVE: To evaluate cytokeratin 19 as a serum marker of preeclampsia. METHODS:
Serum cytokeratin 19 levels were measured in 46 women with preeclampsia and 46
controls matched for gestational age and parity, using an immunoradiometric
assay. Cytokeratin 19 was evaluated immunohistochemically in placental specimens
from 28 healthy pregnant women and 24 women with preeclampsia. RESULTS:
Cytokeratin 19 was identified in the syncytiotrophoblast in 13 (46. 4%) of 28 and
23 (95.8%) of 24 placental specimens from controls and women with preeclampsia,
respectively (P =.03). Median serum levels of cytokeratin 19 in controls and
women with preeclampsia were 1.7 (range 0.3-4.7) microg/mL and 2.7 (range 0.8
8.2) microg/mL, respectively (P <.001). Cytokeratin 19 significantly influenced
the odds of presenting with preeclampsia (P <.001) and the odds of developing
severe disease (P <.001). Serum cytokeratin 19 correlated inversely with fetal
birth weight (Kendall tau-b correlation coefficient = -0.2, P =.007). Compared
with healthy pregnant women, women with severe preeclampsia had significantly
higher and more rapidly increasing cytokeratin 19 serum levels throughout the
third trimester (P <.001). CONCLUSION: Placental stimulation of cytokeratin 19,
and release of it into maternal circulation, seem to be a feature of
preeclampsia. Correlations with clinical characteristics suggest that cytokeratin
19 is a marker of disease severity.
PMID- 10775729
TI - Human papillomaviruses and vulvar vestibulitis.
AB - OBJECTIVE: To assess the relationship between human papillomavirus (HPV)
infection and vulvar vestibulitis syndrome. METHODS: From November 1995 to
December 1997, 135 women with vulvar vestibulitis were compared with 322 controls
who had no evidence of vulvar vestibulitis. Human papillomavirus DNA was
amplified by polymerase chain reaction and detected with liquid-capture molecular
assay. RESULTS: Human papillomavirus DNA was found in 29.6% of cases and in 23.9%
of controls (relative risk [RR] 1.4; 95% confidence interval [CI].8, 2.2). The
prevalence of HPV tended to decrease with increasing duration of pain among
cases. Thus, prevalences were 37. 5%, 29.6%, and 22.0% for pain durations of 3-6
months, 7-12 months, and 13-24 months, respectively (P =.14). Prevalence of HPV
also tended to increase with pain intensity among cases, but that association was
not statistically significant (P =.57). Prevalence percentages for women with
low, moderate, or severe pain were 27.5%, 28.8%, and 34.4%, respectively.
Prevalence of HPV was slightly higher in cases with the most severe pain (34.4%)
than in controls (23.9%) (RR 1.8; 95% CI.8, 4.0). In cases with the most pain in
the shortest time (3-6 months), prevalence of HPV was double that of controls
(50% versus 23.9%) (RR 3.5; 95% CI 1.0, 12.7; P =.054). CONCLUSION: There was
little support for the idea that HPV might be related to vulvar vestibulitis.
PMID- 10775730
TI - Adenomyosis: symptoms, histology, and pregnancy terminations.
AB - OBJECTIVE: To correlate symptoms of uterine adenomyosis with histopathologic
features. METHODS: One hundred eleven specimens of uteri and cervices that
weighed under 280 g were reevaluated. When adenomyosis was identified, assessment
included depth of adenomyotic foci, graded as deep (above 80%), intermediate (40
80%), and superficial (under 40%), and number of adenomyotic foci. Clinical data
were collected from patient records. RESULTS: Specimens were categorized in four
groups, 17 with adenomyosis alone, 19 with adenomyosis with leiomyomas, 39 with
leiomyomas alone, and 36 with neither. Among women with adenomyosis alone, 58.8%
had pregnancy terminations and 47.4% of women with adenomyosis and leiomyomas had
terminations, compared with 20.5% of women with leiomyomas alone (P <.01) and
22.2% in those with neither (P <.01). The number of foci correlated significantly
with depth within the myometrium in specimens with adenomyosis alone (r =.46, P
=.05) or combined with leiomyomas (r =.66, P <.001). The median number of foci
associated with dysmenorrhea was 10 compared with 4.5 without it (P <.003); in
menorrhagia the respective median numbers were 7 and 7 (P =.25). Menorrhagia and
dysmenorrhea presented in 36.8% and 77.8% of deep, compared with 13.3% (P <.001)
and 12.5% (P <.001) of intermediate depths, respectively. Superficial depth was
not associated with menorrhagia or dysmenorrhea. CONCLUSION: Pregnancy
termination might affect the pathogenesis of adenomyosis. The number of foci and
their myometrial depths correlated to each other and to dysmenorrhea, but only
myometrial depth correlated to menorrhagia.
PMID- 10775731
TI - Computed tomography in endometrial carcinoma.
AB - OBJECTIVE: To determine the value of computed tomography (CT) scans for
preoperatively detecting extrauterine-nodal disease and postoperative recurrent
disease in patients with endometrial cancer. METHODS: We reviewed records of 702
women with primary endometrial carcinoma that was diagnosed between 1979 and
1993. Preoperative CT findings were compared with pathologic findings to assess
nodal disease. The yield of postoperative CT was reviewed in clinically
suspicious and routine settings. RESULTS: Among 492 women eligible for analysis,
178 (36%) had a total 326 CT scans. Among 56 women who had preoperative CT scans
and lymph node samplings, positive and negative predictive values for nodal
involvement were 50% and 94%, respectively, and sensitivity and specificity were
57% and 92%, respectively. Preoperative CT findings altered treatment plans in
only six patients (8%). Forty-five asymptomatic women had 73 routine CT scans,
and recurrence was diagnosed by CT in only two (4.4%). Thirty-seven women had CT
scans for suspicion of recurrence, which was confirmed in 17 (46%). Kaplan-Meyer
analysis showed no survival advantage in women with subclinical recurrences
diagnosed by CT scan. CONCLUSION: Routine preoperative CT scanning rarely alters
treatment and is a poor predictor of nodal disease. Computed tomography in the
postoperative period might be helpful for detection and follow-up of recurrent
disease, but there was no difference in survival when subclinical recurrence was
found by CT. Thus, CT scanning of any woman with endometrial cancer should be
discouraged unless it is to evaluate symptoms.
PMID- 10775733
TI - Risk factors for hypercarbia, subcutaneous emphysema, pneumothorax, and
pneumomediastinum during laparoscopy.
AB - OBJECTIVE: To determine independent predictors for the development of
hypercarbia, subcutaneous emphysema, pneumothorax, and pneumomediastinum during
laparoscopy. METHODS: We reviewed 968 laparoscopic cases between January 1, 1997,
and December 31, 1998. Patients who had hypercarbia (end-tidal carbon dioxide of
50 mmHg or greater), pneumothorax/pneumomediastinum, and subcutaneous emphysema
were compared with controls according to age, operative time, type of surgery,
extraperitoneal or intraperitoneal approach, preexisting medical conditions, body
mass index, sex, use of Hasson technique, and number of surgical ports. Maximum
positive end-tidal CO(2) (PETCO(2)) was added as an independent variable for
subcutaneous emphysema, pneumothorax, and pneumomediastinum. Data were analyzed
using univariate analysis and then subjected to multivariate analysis using
multiple logistic regression analysis. RESULTS: Incidence rates were 5.5% for
hypercarbia, 2.3% for subcutaneous emphysema, and 1.9% for pneumothorax/
pneumomediastinum. Independent risk factors for development of hypercarbia were
operative time greater than 200 minutes (odds ratio [OR] 2.02), patient age
greater than 65 years (OR 2.19), and Nissen fundoplication surgery (OR 3.18).
Predictors of the development of subcutaneous emphysema were PETCO(2) greater
than 50 mmHg (OR 3.49), operative time greater than 200 minutes (OR 5.27), and
the use of six or more surgical ports (OR 3.06). Variables that predicted the
development of pneumothorax and/or pneumomediastinum were PETCO(2) greater than
50 mmHg (OR 4. 15) and operative time greater than 200 minutes (OR 20.49).
CONCLUSION: Longer operative times, higher maximum measured end-tidal CO(2),
greater number of surgical ports, older patient age, and Nissen fundoplication
surgery predispose patients to hypercarbia-related complications during
laparoscopy.
PMID- 10775732
TI - Modulation of endometrial steroid receptors and growth regulatory genes by
tamoxifen.
AB - OBJECTIVE: We investigated tamoxifen's effects on the expression of growth
regulatory genes in the endometrium to identify the mechanism by which tamoxifen
induces proliferation. METHODS: Using immunohistochemical techniques, we analyzed
39 endometrial specimens for expression of Ki-67, lactoferrin, transforming
growth factor-alpha, tumor necrosis factor receptor-II, adrenomedullin, estrogen
receptors, and progesterone receptors. Twenty specimens were obtained from
postmenopausal breast cancer patients treated with tamoxifen (20 mg/day) for at
least 6 months to include two endometrial adenocarcinoma specimens. Five
secretory phase, three proliferative phase, and seven atrophic endometrial
specimens were used as controls. In addition, four endometrial adenocarcinoma
specimens were reviewed from patients not treated with tamoxifen. Intensity of
immunostaining was quantified using digitized imaging techniques. RESULTS:
Overexpression of both estrogen receptors and progesterone receptors, and an
elevated proliferative index were the most consistent effects observed in benign
endometrial specimens from tamoxifen-treated patients compared with atrophic
controls (P <. 003). This staining pattern was also evident in adenocarcinomas
from patients who received tamoxifen. Benign endometrium from tamoxifen-treated
patients also expressed transforming growth factor-alpha, tumor necrosis factor
receptor-II, lactoferrin, and adrenomedullin at levels comparable with those
found in proliferative endometrial specimens. CONCLUSION: These data provide
further documentation that the uterotropic effects of tamoxifen may be due, at
least in part, to the induction of estrogen receptors and progesterone receptors,
as well as other genes associated with the proliferative phase. Furthermore,
analysis of estrogen receptors, progesterone receptors, and Ki-67 may be useful
in identifying postmenopausal individuals on tamoxifen, who are at increased risk
for developing endometrial cancer.
PMID- 10775734
TI - Urinary tract infections in women with bacterial vaginosis.
AB - OBJECTIVE: To evaluate the risk of urinary tract infections in women with
bacterial vaginosis. METHODS: One hundred twenty-nine women who presented for
routine gynecologic examinations were evaluated for bacterial vaginosis and
urinary tract infections between June 1998 and March 1999. RESULTS: Sixty-seven
women had bacterial vaginosis and 62 women did not. Fifteen women with bacterial
vaginosis (22.4%) had urinary tract infections, compared with six (9.7%) of those
without it. Bacterial vaginosis was associated with an increased risk of urinary
tract infections (odds ratio 2.79; 95% confidence interval 1.05, 8.33).
CONCLUSION: Women with bacterial vaginosis are at increased risk for urinary
tract infections.
PMID- 10775735
TI - Racial differences in the structure and function of the stress urinary continence
mechanism.
AB - OBJECTIVE: To compare the structure and function of the urethral sphincter and
the urethral support in nulliparous black and white women. METHODS: Eighteen
black women (mean age 28.1 years) and 17 white women (mean age 31.3 years)
completed this cross-sectional study. The following assessments were made:
urethral function using multichannel cystometrics and urethral pressure
profilometry, pelvic muscle strength using an instrumented speculum, urethral
mobility using the cotton-swab test and perineal ultrasound, and pelvic muscle
bulk using magnetic resonance imaging. RESULTS: Black women demonstrated a 29%
higher average urethral closure pressure during a maximum pelvic muscle
contraction (154 cm H(2)O versus 119 cm H(2)O in the white subjects; P =.008).
Although not statistically significant, black women had a 14% higher maximum
urethral closure pressure at rest (108 cm H(2)O versus 95 cm H(2)O; P =.23) and a
21% larger urethral volume (4818 mm(3) versus 3977 mm(3); P =.06). In addition,
there was a 36% greater vesical neck mobility measured with the cotton-swab test
(blacks 49 degrees versus whites 36 degrees; P =.02) and a 42% difference in
ultrasonically measured vesical neck mobility during a maximum Valsalva effort
(blacks = -17 mm versus whites -12 mm; P =.08). CONCLUSION: Functional and
morphologic differences exist in the urethral sphincteric and support system of
nulliparous black and white women.
PMID- 10775736
TI - Dry mouth with conventional and controlled-release oxybutynin in urinary
incontinence. The Ditropan XL Study Group.
AB - OBJECTIVE: To compare the efficacy and safety of controlled-release oxybutynin
with conventional, immediate-release oxybutynin and determine rates of dry mouth.
METHODS: Patients (n = 226) who were known to be responsive to anticholinergic
therapy and who had seven or more urge incontinence episodes per week were
randomized to receive controlled-release oxybutynin or immediate-release
oxybutynin. After an initial placebo run-in period, dosing in each began at 5 mg
per day and increased weekly by 5 mg per day to a maximum of 20 mg per day or
when a balance between improvement of incontinence symptoms and tolerability of
side effects was achieved. Rates of urge incontinence and dry mouth were
compared. Post hoc Kaplan-Meier survival analysis was used to describe
elimination of incontinence episodes by dose and to analyze dry mouth risk by
dose. RESULTS: Reductions in urge urinary incontinence episodes from baseline to
the end of treatment were 18.6 to 2.9 per week (83% mean decrease) and 19.8 to
4.4 per week (76% mean decrease) in the controlled- and immediate-release
oxybutynin groups (P =.36), respectively. At equal doses, comparable proportions
of patients in both groups reported the absence of urge incontinence (P =.85).
The incidence of dry mouth increased with dose in both groups, but there was no
difference in dry mouth rates between the groups: 47.7% and 59.1% for the
controlled- and immediate-release oxybutynin (P =.09), respectively. However,
Kaplan-Meier analysis to examine first report of dry mouth at a given dose
revealed that a significantly lower proportion of patients taking controlled
release oxybutynin had moderate to severe dry mouth (P =.007) or any dry mouth (P
=.003) compared with those taking immediate-release oxybutynin. CONCLUSION: At
the same daily dose, controlled- and immediate-release oxybutynin demonstrated
comparable efficacy in reduction of urge incontinence episodes. The incidence of
dry mouth was dose dependent but equal in both groups; first report of moderate
to severe dry mouth was significantly lower in the controlled-release group.
PMID- 10775737
TI - Relationship between body fat distribution and bone mineral density in
premenopausal Japanese women.
AB - OBJECTIVE: To investigate the relationship between body fat distribution and bone
mineral density (BMD). METHODS: Subjects were 282 premenopausal women (mean age
+/- standard deviation [SD], 38.8 +/- 8.5 years; range, 20-51 years) with regular
menstrual cycles. Baseline characteristics included age, age at menarche, height,
weight, body mass index ([BMI], weight/height(2)), and parity. Anthropometric
characteristics including the ratio of trunk fat mass to leg fat mass (trunk-leg
fat ratio), percentage of body fat, and total body lean mass were measured by
whole-body scanning with dual-energy x-ray absorptiometry. Lumbar spine BMD (L2
4) was also measured by dual-energy x-ray absorptiometry. Correlations of BMD to
baseline and anthropometric characteristics were investigated using univariate
and multivariate analysis. RESULTS: Although height, trunk-leg fat ratio, and
total body lean mass were positively correlated with lumbar spine BMD (r =.18, P
<.01; r =.17, P <.01; and r =.25, P <.001; respectively), age at menarche was
inversely correlated with BMD (r = -.19, P <.01). On multivariable analysis,
trunk-leg fat ratio, height, age at menarche, and total body lean mass were still
independently correlated with lumbar spine BMD (P <. 05). However, total fat mass
was not correlated with BMD. CONCLUSION: Upper body fat distribution rather than
overall adiposity is associated with lumbar spine BMD in premenopausal women.
Humoral factors associated with body fat mass appear to influence lumbar spine
BMD.
PMID- 10775738
TI - Initial 17beta-estradiol dose for treating vasomotor symptoms.
AB - OBJECTIVE: To compare the efficacy of different doses of 17beta-estradiol (E2)
for relief of vasomotor symptoms in menopausal women. METHODS: This was a
randomized, double-masked, placebo-controlled, 12-week study in which 333
menopausal women with moderate or severe hot flushes were assigned to treatment
with 0.25 mg, 0.5 mg, 1 mg, or 2 mg oral micronized 17beta-E2, or placebo. The
number and severity of hot flushes were recorded daily. RESULTS: There was a
significant linear correlation between increased dosage of 17beta-E2 and
decreased moderate to severe hot flushes per week (P <.001). Rapid reduction in
moderate to severe hot flushes was only achieved with 1 and 2 mg, showing a
significant difference from placebo at week 4 (P <.05). At week 4, half the women
on placebo had reduced moderate to severe hot flushes of at least 52%; the
corresponding figures were 56%, 69%, 86%, and 91% for 0.25, 0.5, 1, and 2 mg,
respectively. At week 12, all doses except 0.25 mg were significantly better than
placebo for reducing moderate to severe hot flushes (P <.001). Although there
were no significant differences, twice as many women in the 2-mg group
discontinued treatment due to adverse events, compared with the placebo group.
CONCLUSION: Oral micronized 17beta-E2 showed a dose-response effect for reducing
moderate and severe hot flushes in menopausal women. 17beta-E2 1 mg appeared to
be the most useful initial dose.
PMID- 10775739
TI - Estrogen therapy in women undergoing coronary artery bypass grafting: effect on
surgical complications.
AB - OBJECTIVE: To determine whether estrogen therapy at the time of coronary artery
bypass grafting affects postoperative complications. METHODS: Consecutive
postmenopausal women who had coronary artery bypass grafting between 1992 and
1997 were identified and their medical records were reviewed. Outcome measures
included mortality, perioperative cardiac morbidity, and early and late
postoperative complications. RESULTS: Estrogen therapy was noted in 13.9% of 734
women. Those using estrogen replacement were younger (63.9 +/- 0.27 versus 68.8
+/- 0.64 years) and had higher ejection fractions (2.8 +/- 0.11 versus 3.1 +/-
0.04) and fewer vessels bypassed. Mortality rates were 2.9% for estrogen users
and 7.4% for nonusers (odds ratio [OR] 0.38; confidence interval [CI] 0.07,
1.21). Perioperative cardiac morbidity rates were 5.8% for estrogen users and 11%
for nonusers (OR 0.52; CI 0.23, 1.7). Early complication rates were 0. 98% for
estrogen users and 1.11% for nonusers. Late inpatient complications were noted in
6.8% of treated women and 14.8% of those untreated (OR 0.42; CI 0.16, 0.96).
Stepwise logistic regression confirmed age, New York Heart Association angina
classification, and ejection fraction as significant variables for mortality,
perioperative cardiac morbidity, and late complications. Estrogen therapy did not
influence mortality, perioperative cardiac morbidity, or early or late
complications. CONCLUSION: Age, ejection fraction, and New York Heart Association
angina classification predicted mortality, perioperative cardiac morbidity, and
late complications. Estrogen therapy at the time of admission for coronary artery
bypass grafting did not influence surgical mortality, perioperative cardiac
morbidity, or early or late complications.
PMID- 10775740
TI - Steroid hormone contraception and bone mineral density: a cross-sectional study
in an international population. The WHO Study of Hormonal Contraception and Bone
Health.
AB - OBJECTIVE: To evaluate relationships between bone mineral density and use of
steroid hormonal contraceptives. METHODS: This was a multicenter cross-sectional
study in seven centers in three regions of the developing world from April 1994
to June 1997. Women 30-34 years old attending family planning clinics, with at
least 24 months of lifetime use of combined oral contraceptives (OC), depot
medroxyprogesterone acetate (DMPA), or levonorgestrel implants, or no or only
short-term (less than 6 months) use of steroid hormonal contraceptives, had bone
mineral density (BMD) measured at the distal radius and the midshaft of the ulna
using single-photon x-ray absorptiometry. RESULTS: In the study, 2474 women were
examined. For OC use, adjusted mean BMD was significantly higher in short-term,
current users compared with women who never used hormonal contraceptives. For
DMPA and levonorgestrel implants, adjusted mean BMD was statistically
significantly lower in short-term current users compared with those who never
used hormonal contraceptives. For all three hormonal methods, there were no
significant differences in BMD between past users of hormonal contraceptives and
never users, even among those who had used the methods for 4 or more years. The
magnitude of changes in BMD was small and less than one standard deviation (SD)
from the mean of those who never used steroid contraceptives. CONCLUSION: This
study suggests that hormonal contraceptive use by young adult women is associated
with small changes in BMD that occur early after initiation of use and are
reversible.
PMID- 10775741
TI - Cost-effectiveness of elective cesarean delivery after one prior low transverse
cesarean.
AB - OBJECTIVE: This analysis was undertaken to better understand the costs and health
consequences of a trial of labor after cesarean when compared with a policy of
routine elective repeat cesarean delivery. METHODS: A decision-tree model
incorporating a Markov analysis was used to examine the reproductive life of a
hypothetical cohort of 100,000 pregnant women whose only prior pregnancy was
delivered through a low transverse cesarean incision. Using this model, the
policy of performing routine elective cesarean delivery was compared with a
policy of allowing a trial of labor. Main outcome measures were maternal and
neonatal morbidity and mortality, total costs to the health care system, and cost
per major neonatal complication avoided (death or permanent neurologic sequelae).
RESULTS: The consequences of routine elective cesarean delivery for a second
birth are significant, with an additional 117,748 cesarean deliveries, 5500
maternal morbid events, and $179 million incurred during the reproductive life of
100,000 women. The prevention of one major adverse neonatal outcome requires 1591
cesarean deliveries and $2.4 million. Sensitivity analysis confirms the
robustness of the analysis. CONCLUSION: Routine elective cesarean for a second
delivery for women with a prior low transverse cesarean incision results in an
excess of maternal morbidity and mortality and a high cost to the medical system.
PMID- 10775742
TI - Preterm birth in two urban areas of Ukraine.
AB - OBJECTIVE: To determine whether the preterm birth rate was elevated in two urban
areas of Ukraine, a former eastern bloc country that experienced serious
economic, social, and health problems during its transition from a socialist
republic. METHODS: We identified every pregnancy in a defined period in two urban
sites where a separate study of pregnancy and childhood was being conducted. We
obtained gestational age and vital status at delivery for each. Information about
onset of labor and conduct of delivery was available for the subgroup enrolled in
the collaborating study. RESULTS: Among 17,137 pregnancies, all but 6774 were
terminated voluntarily. Among the continuing pregnancies, the preterm birth rate
was 6.6% for live-born singletons of 20 or more weeks' gestation. Only 12% of
preterm births involved medical intervention, the rest were idiopathic. The
preterm birth rate was higher than in Europe (4.0% to 5.4%) and Canada (5.9%) but
lower than for whites in the United States (8.4%). CONCLUSION: Live-born preterm
birth rates are influenced by whether infants survive to be included in
calculations. The high fetal mortality rate in Ukraine causes many preterm births
to be excluded, thus lowering the rate. Frequent pregnancy termination and lack
of ultrasound dating in Ukraine also might cause the preterm birth rate to be
lower. Preterm birth rates, especially among live-born infants, are difficult to
interpret and treacherous to compare across nations. Survival of the fetus and
its health and development at birth are better indicators of reproductive
outcome.
PMID- 10775743
TI - A survey of obstetrician-gynecologists on their patients' alcohol use during
pregnancy.
AB - OBJECTIVE: To examine knowledge, attitudes, current clinical practices, and
educational needs of obstetrician-gynecologists regarding patients' alcohol use
during pregnancy. METHODS: A 20-item, self-administered questionnaire on
patients' prenatal alcohol use was sent to 1000 active ACOG fellows. Responses
were analyzed using univariate and multivariate statistical techniques. RESULTS:
Of the 60% of the obstetrician-gynecologists who responded to the survey, 97%
reported asking their pregnant patients about alcohol use. When a patient reports
alcohol use, most respondents reported that they always discuss adverse effects
and always advise abstinence. One fifth of the respondents (20%) reported
abstinence to be the safest way to avoid all four of the adverse pregnancy
outcomes cited (ie, spontaneous abortion, central nervous system impairment,
birth defects, and fetal alcohol syndrome); 13% were unsure about levels
associated with all of the adverse outcomes; and 4% reported that consumption of
eight or more drinks per week did not pose a risk for any of the four adverse
outcomes. The two resources that respondents said they needed most to improve
alcohol-use assessment were information on thresholds for adverse reproductive
outcomes (83%) and referral resources for patients with alcohol problems (63%).
CONCLUSION: Efforts should be made to provide practicing obstetrician
gynecologists with updates on the adverse effects of alcohol use by pregnant
women and with effective methods for screening and counseling women who report
alcohol use during pregnancy.
PMID- 10775744
TI - Complications in pregnancy, labor, and delivery with uterine leiomyomas: a
population-based study.
AB - OBJECTIVE: To determine the extent to which uterine leiomyomas are associated
with characteristics of pregnancy, labor, and neonatal outcome recorded on birth
certificates. METHODS: In a population-based series of women who delivered
singleton live infants in Washington state from 1987-1993, we linked computerized
birth certificates and hospital discharge records to investigate the relationship
between uterine leiomyomas and complications in pregnancy and delivery. Subjects
were 2065 women with uterine leiomyomas noted on computerized hospital discharge
records. From the remaining records, a comparison group of women without uterine
leiomyomas diagnoses were selected at random and frequency-matched by birth year
to women with leiomyomas. We used unconditional logistic regression to estimate
odds ratios (ORs) and 95% confidence intervals (CIs) of pregnancy or delivery
complications in relation to uterine leiomyomas after multivariate adjustment.
RESULTS: Women with leiomyomas were more likely than controls to be over age 35
at delivery, nulliparous, or black. We observed independent associations between
uterine leiomyomas and abruptio placentae (OR 3. 87, 95% CI 1.63, 9.17), first
trimester bleeding (OR 1.82, 95% CI 1. 05, 3.20), dysfunctional labor (OR 1.85,
95% CI 1.26, 2.72), and breech presentation (OR 3.98, 95% CI 3.07, 5.16). The
risk of cesarean was also higher among women with uterine leiomyomas (OR 6. 39,
95% CI 5.46, 7.50), but a portion of the excess risk might have been due to
biased detection of leiomyomas at cesarean delivery. CONCLUSION: Leiomyomas
appear to increase likelihood of complications during pregnancy, labor, and
delivery.
PMID- 10775745
TI - Postpartum contraceptive use among adolescent mothers.
AB - OBJECTIVE: To compare the incidence of repeat pregnancy and method continuation
rate at 12 months postpartum in young women who chose either depot
medroxyprogesterone acetate or oral contraceptives (OCs) as contraception.
METHODS: We conducted a prospective cohort study of 122 postpartum women younger
than 18 years of age who delivered between January 8, 1997 and December 31, 1997.
Patients choosing depot medroxyprogesterone acetate (n = 76) and OCs (n = 46)
were accrued for 12 months and were followed-up for a minimum of 12 months. Main
outcome measures were median contraceptive method continuation and the incidence
of repeat pregnancy at 12 months postpartum. RESULTS: There was no difference in
mean age at delivery (P =.47), parity (P =.84), or gravidity (P =.78) between
depot medroxyprogesterone acetate and OC users. At 12 months postpartum, 27.4% of
OC users and 55.3% of depot medroxyprogesterone acetate users were still using
contraception. Median time to contraceptive discontinuation was longer for those
choosing depot medroxyprogesterone acetate compared with OCs (17.8 vs 7.4 months,
respectively, P =.002). The overall incidence of repeat pregnancy at 12 months
postpartum was 10.6%. Among OC and depot medroxyprogesterone acetate users,
respectively, 24% and 2.6% became pregnant again, producing a relative risk (RR)
of 9.09 (95% confidence interval [CI] 2.1, 39.2) for repeat pregnancy among OC
users. The mean time to repeat pregnancy (this was reported instead of the median
time whenever the pregnancy rate had not reached 50% at the end of the follow-up
period) was longer for depot medroxyprogesterone acetate compared with OC users
(17.1 months vs 13.2 months, respectively, P <.001). CONCLUSION: Adolescent
mothers using depot medroxyprogesterone acetate injection for contraception have
a higher method continuation rate and a lower incidence of repeat pregnancy at 12
months postpartum than those selecting OCs during the same period.
PMID- 10775746
TI - Nausea and vomiting in early pregnancy: its role in placental development.
AB - Nausea and emesis in early pregnancy is a common phenomenon affecting between 50%
and 70% of pregnant women, but little is known about the etiology and possible
function of this common and often incapacitating condition. Morning sickness has
been reported to have a positive effect on pregnancy outcome and is associated
with a decreased risk of miscarriage, preterm birth, low birth weight (LBW), and
perinatal death. Both human and animal studies have shown that reduced energy
intakes in early pregnancy are associated with increased placental weight. Based
on evidence from the literature, a hypothesis is proposed that suggests a
functional role for the nausea and emesis of pregnancy in stimulating early
placental growth. It is suggested that morning sickness, resulting from secretion
of hCG and thyroxine, reduces maternal energy intake. As a result, maternal
levels of the anabolic hormones, insulin, and insulin growth factor-1 (IGF-1) are
lowered. By suppressing maternal tissue synthesis in early pregnancy, we propose
that nausea and vomiting in pregnancy helps ensure that nutrient partitioning
favors the developing placenta. Evidence is also presented that suggests there
may be a positive relationship between morning sickness and preconceptional body
mass index (BMI), such that women who are underweight will experience less severe
symptoms of morning sickness compared with women with normal preconceptional
BMIs.
PMID- 10775747
TI - Teaching and evaluating surgical skills.
AB - OBJECTIVE: To examine how surgical skills are taught and evaluated in obstetrics
gynecology residency programs in the United States. METHODS: A questionnaire was
mailed to the directors of all 266 residency programs in the United States and to
second contact names at 51 sites. Directors were asked to evaluate how surgical
skills are taught and evaluated and to rate the importance of specific techniques
and procedures for residents at given points in resident training. RESULTS: Two
hundred twenty-three surveys were returned (70%), representing 203 of 266
programs (76%). Among responding programs, 99% reported teaching surgical skills
in operating rooms, 88% in lectures, 68% with bench procedures, and 54% with
animal surgery. Twenty-nine percent indicated they had formal surgical skills
curricula. A significantly higher percentage of those programs with formal
curricula used animal surgery laboratories (81% versus 42%, P <.001) and were
more likely to conduct formal skills assessments (88% versus 69%, P =.005) than
programs without formal curricula. Overall, 74% of programs evaluated surgical
skills. Of those, 56% reported using subjective faculty evaluations, 12% written
evaluations (eg, checklists), 4% written and oral assessments, and 1% a test.
Regardless of formal curricula, there was much agreement in respondents' ratings
of 60 different skills and procedures as "essential," "important," "nice to
know," or "unimportant. CONCLUSION: Most programs teach surgical skills in the
operating room and through lectures. Only 29% of reporting programs provide
formal surgical curricula. Evaluation of surgical skills is usually done by
subjective evaluation, a technique with unknown validity and poor reliability.
PMID- 10775748
TI - Evaluation of 11-[3H]-tetrodotoxin use in a heterologous receptor binding assay
for PSP toxins.
AB - This report describes the preparative scale production of 11-[3H]-tetrodotoxin
(TTX) and its evaluation as a substitute for [3H]-saxitoxin (STX) as the
radioligand in a receptor binding assay for paralytic shellfish poisoning (PSP)
toxins. Restrictions on the world-wide distribution of [3H]-STX imposed by the
international Chemical Weapons Convention served as the primary impetus for this
study. We have incorporated on a preparative scale, a nonexchangeable tritium
label into the TTX molecule at a specific activity of 12.90 Ci/mmol and recovered
material of high radiochemical purity (98%). The resulting 11-[3H]-TTX was found
to exhibit site-specific binding characteristics in the receptor assay
(dissociation constant(K(d))=4.77+/-1.54nM; maximum binding(B(max))=1. 62+/
0.24pmol/mg of synaptosomal protein). The inhibition constant (K(i)) for the
assay was 1.46+/-0.28 nM STX equiv. (n=6), with an estimated detection limit of
ca. 2-4 ng STX equiv./ml in a sample extract. Moreover, quantitative comparisons
indicated that 11-[3H]-TTX could be used interchangeably with [3H]-STX in the
receptor assay for determination of PSP toxicity in shellfish and algal extracts
without compromising assay performance. We conclude that the 11-[3H]-TTX produced
and evaluated herein exhibits physical, chemical and biological characteristics
suitable not only for use in the PSP receptor binding assay, but likely for other
applications employing [3H]-STX as the radioligand.
PMID- 10775749
TI - Haemorrhagic protein of Russell's viper venom with fibrinolytic and esterolytic
activities.
AB - A haemorrhagic toxin specifically active on skin and muscle at the site of
introduction in mice has been purified from Vipera russelli russelli (Indian
subspecies of Russell's viper) venom by CM-Sephadex C-50 ion exchange
chromatography and size exclusion (SE)-HPLC. This toxic protein also has strong
fibrinolytic and arginine esterolytic activities. The purified preparation was a
single polypeptide chain of molecular weight 73,000, as revealed by SDS-PAGE and
SE-HPLC under native and denatured conditions. It has been named as VRR-73.
Atomic absorption spectrometry indicated the existence of Mg(2+) in a mol per mol
ratio. Antiserum was effective in neutralizing haemorrhage when administered
immediately following VRR-73 but was ineffective in inhibiting fibrinolytic and
esterolytic activities. On the other hand phenylmethyl sulphonyl fluoride and
EDTA inhibited fibrinolysis and esterolysis but did not affect haemorrhage.
Thermal denaturation of VRR-73, after exposure at 100 degrees C for 10 min, led
to inactivation of all of its activities. Fibrinolytic and esterolytic
activities, but not the haemorrhagic activity, were slowly regained after cooling
at 25 degrees C. Thus the two pathological activities of VRR-73 appear to be
associated with two different regions of the molecule.
PMID- 10775750
TI - Influence of environmental and nutritional factors on growth, toxicity, and toxin
profile of dinoflagellate Alexandrium minutum.
AB - The toxic dinoflagellate Alexandrium minutum T1 was isolated from southern Taiwan
in February 1996, grown under various environmental and nutritional conditions,
and then examined for growth, toxicity, and toxin profile. It was found that the
optimal environmental conditions for cell growth and toxin production of A.
minutum T1 was as follows: temperature 25 degrees C, pH 7.5, light strength 120
microEm(-2) s(-1), and salinity 15 ppt. The optimal level of nutrients
supplemented in the 50% natural seawater medium was as follows: phosphate 0.002%,
nitrate 0.01%, cupric ion 5.0 ppb, ferric ion 270 ppb and humic acid free. Both
cell toxicity and total toxicity reached the maximum level at the post-stationary
growth phase and decreased quickly. The toxic components of A. minutum T1 were
assayed by high performance liquid chromatography, and found to be gonyautoxin
(GTX) 1-4 only. Among these four toxin components, toxins GTX 1 and 4 were the
predominant components throughout the growth curve when the cells were grown in
the optimal environmental and nutritional conditions. But toxins GTX 2 and 3
increased when the cells were cultured in high salinity medium.
PMID- 10775751
TI - Structure and biological activities of eumenine mastoparan-AF (EMP-AF), a new
mast cell degranulating peptide in the venom of the solitary wasp (Anterhynchium
flavomarginatum micado).
AB - A new mast cell degranulating peptide, eumenine mastoparan-AF (EMP-AF), was
isolated from the venom of the solitary wasp Anterhynchium flavomarginatum
micado, the most common eumenine wasp found in Japan. The structure was analyzed
by FAB-MS/MS together with Edman degradation, which was corroborated by solid
phase synthesis. The sequence of EMP-AF, Ile-Asn-Leu-Leu-Lys-Ile-Ala-Lys-Gly-Ile
Ile-Lys-Ser-Leu-NH(2), was similar to that of mastoparan, a mast cell
degranulating peptide from a hornet venom; tetradecapeptide with C-terminus
amidated and rich in hydrophobic and basic amino acids. In fact, EMP-AF exhibited
similar activity to mastoparan in stimulating degranulation from rat peritoneal
mast cells and RBL-2H3 cells. It also showed significant hemolytic activity in
human erythrocytes. Therefore, this is the first example that a mast cell
degranulating peptide is found in the solitary wasp venom. Besides the
degranulation and hemolytic activity, EMP-AF also affects on neuromuscular
transmission in the lobster walking leg preparation. Three analogs EMP-AF-1
approximately 3 were snythesized and biologically tested together with EMP-AF,
resulting in the importance of the C-terminal amide structure for biological
activities.
PMID- 10775752
TI - Purification and characterization of anticoagulation factors from the venom of
Agkistrodon acutus.
AB - Two anticoagulants from five-pace snake (Agkistrodon acutus) venom,
anticoagulation factor I (ACF I) and anticoagulation factor II (ACF II), have
been purified by a multiple-step chromatography procedure of anion-exchange
chromatography, gel permeation chromatography and cation-exchange chromatography.
Each of them is shown to be homogeneous as judged by PAGE, SDS-PAGE and mass
spectrometry. In vitro, both proteins show equivalent anticoagulant activity, and
are devoid of proteolytic, esterolytic, L-amino acid oxidase, phospholipase A,
thrombin-like, fibrinolytic, hemorrhagic and lethal activities. They have similar
amino acid compositions with similar absorption coeffecients (A(1%)(280)) (30.5
for ACF I and 30.0 for ACF II). Both are disulfide-linked consisting of two 14.7
kD chains for ACF I and two 14.6 kD chains for ACFII. ACF I has a molecular mass
of 29,604+/-8 atomic mass units (amu) compared to 29,468+/-6 amu for ACF II,
determined by mass spectrometry. The isoelectric points of ACF I and ACF II are
5.7 and 7.0, respectively. We conclude that the two isoforms possess equivalent
biological activities with similar amino acid compositions and molecular masses,
but different isoelectric points.
PMID- 10775753
TI - Antibacterial properties of KwaZulu natal snake venoms.
AB - The objective was to ascertain whether local snake venoms have antibacterial
properties. The venoms of the common night adder (Causus rhombeatus), gaboon
adder (Bitis gabonica), puff adder (Bitis arietans), black mamba (Dendroaspis
polylepis), eastern green mamba (Dendroaspis augusticeps), forest cobra (Naja
melanoleuca), snouted cobra (Naja annulifera) and Mozambique spitting cobra (Naja
mossambica) were collected and, by gel diffusion, tested against the bacteria
Staphylococcus aureus, Escherichia coli, Pseudomonas aeriginosa, Bacteriodes
fragilis, Bacteroides intermedius, Clostridium sordellii and Clostridium
perfringens. All snake venoms showed antibacterial activity, with the adders
showing most activity against the aerobes while the cobras showed lesser, but
equal activity against the aerobes and anaerobes. Black mamba venom only showed
activity against C. perfringens. In conclusion, local snake venoms have
antibacterial properties which are dependent on the venom and bacterial type; and
in the Naja spp., for anaerobic bacteria, diminish in winter. There is liable to
be more than one toxin component responsible.
PMID- 10775754
TI - Role of kinins and nitric oxide on the rabbit arthritis induced by Bothrops
jararaca venom.
AB - The effects of the nitric oxide synthase inhibitor N(omega)Nitro-L-arginine
methyl ester (L-NAME) and of the bradykinin B(2) receptor antagonist HOE 140 were
evaluated in the inflammatory reaction induced by Bothrops jararaca venom (BjV)
in New Zealand White rabbits. Arthritis was induced by injecting 0.5 ml of a
sterile solution of BjV (1-64 microg/ml) into the knee intraarticular cavity. The
contralateral joint was injected with bovine serum albumin (BSA) diluted in
sterile saline. At selected times thereafter (4, 24 and 48 h), the vascular
permeability and the leukocyte influx in both the synovial fluid and synovium
were evaluated. BjV caused a dose-dependent increase in both leukocyte influx and
protein extravasation which reached a maximal response at 16 microg. Bothrops
jararaca venom also induced the increase in the leukocyte accumulation in the
synovium and in the concentration of both NO(2)/NO(3) in the synovial fluid.
Chronic administration of L-NAME (20 mg/kg/day in the drinking water for 2 weeks)
markedly reduced the leukocyte accumulation (90%), protein leakage (44%), and
NO(2)/NO(3) (50%) levels in the synovial fluid, measured at the 4th h. Hoe 140,
given i.v. (0.3 mg/kg, 30 min before) also reduced leukocyte accumulation (75%),
protein leakage (48%), and NO(2)/NO(3) (79%) levels in the synovial fluid,
measured at the 4th h. Similar results were obtained with acute administration of
L-NAME (30 mg/kg, i.v., 30 min before). These results indicate that arthritis
induced by BjV is triggered by kinin formation and that the increase in both
vascular permeability and leukocyte accumulation is modulated by NO release.
PMID- 10775756
TI - The antihemorrhagic factor, erinacin, from the European hedgehog (Erinaceus
europaeus), a metalloprotease inhibitor of large molecular size possessing
ficolin/opsonin P35 lectin domains.
AB - From muscle extracts of the European hedgehog, Erinaceus europaeus, an
antihemorrhagic factor, erinacin, was purified by ammonium sulfate precipitation
followed by chromatography on DEAE-cellulose, hydroxylapatite and gel filtration
columns. A purification of approx. 1400-fold was achieved with an overall yield
of 21% in antihemorrhagic activity. The molecular weight of erinacin determined
by gel filtration was approx. 1000 kDa. SDS-PAGE of erinacin under reducing
conditions indicates that it consists of two types of subunits, alpha and beta,
with molecular weights of 37 and 35 kDa, respectively, in a ratio of 1:2. In the
presence of 6 M guanidine-HCl, erinacin dissociates into alpha-subunits and beta
subunit decamers. From these results the subunit assembling of erinacin has been
formulated as alpha(10).2beta(10). The molecular weight of the subunits and of
the beta-subunit decamer was confirmed by MALDI-TOF mass spectrometry. Erinacin
inhibits the hemorrhagic and proteolytic activity of the major hemorrhagic
metalloprotease from the venom of Bothrops jararaca. Complete inhibition was
achieved in an equimolar mixture of inhibitor and enzyme suggesting an equimolar
complex. Erinacin is not inhibiting serine proteases such as trypsin and
chymotrypsin, it was characterized to be a metalloprotease inhibitor. In
electronmicroscopy, flower bouquet-like structures characteristic for some animal
lectins were observed. Amino acid sequence analysis indicated that both subunits
are almost identical and are composed of common amino terminal, collagen- and
fibrinogen-like domains homologous to proteins of the ficolin/opsonin P35 lectin
family.
PMID- 10775755
TI - Ca(2+) and Na(+) contribute to the swelling of differentiated neuroblastoma cells
induced by equinatoxin-II.
AB - Equinatoxin-II (EqTx-II), a cytotoxic protein (mol.wt 20 kDa) isolated from the
sea anemone Actinia equina, was found to consistently increase the three
dimensional projected area of differentiated neuroblastoma (NG108-15) cells
provided Ca(2+) was present in the medium. No swelling was detected when external
NaCl was replaced by sucrose, but replacement of NaCl by Na-isethionate did not
prevent the swelling, as revealed by confocal laser scanning microscopy. In
addition, microspectrofluorometric measurements in cells preloaded with the
Ca(2+) indicator fura-2/AM revealed that EqTx-II (100 nM) markedly increased the
fluorescence (F(340)/F(380)) ratio indicating a rise of intracellular Ca(2+)
concentration ([Ca(2+)](i)). The elevation of [Ca(2+)](i) exhibited two
components that seem to be related to the kinetics of EqTx-II-induced Ca(2+)
entry since pretreatment of cells with Ca(2+)-ATPase inhibitors (thapsigargin),
Ca(2+) channel blockers (nifedipine and Gd(3+)) or prolonged exposure to a high
K(+) (75 mM) medium did not alter EqTx-II-induced Ca(2+) signals. As far as we
know, this is the first demonstration that EqTx-II causes swelling of
neuroblastoma cells and that this effect is correlated both with an increase of
[Ca(2+)](i) and needs the presence of extracellular Na(+). It is suggested that
EqTx-II has the ability to insert into the plasma membrane of neuroblastoma cells
and to form pores altering the membrane permeability and the intracellular
osmolality, inducing a marked influx of water into the cells.
PMID- 10775757
TI - Toxinological studies on the nematocyst venom of Chrysaora achlyos.
AB - Nematocyst venoms from both oral arms and lappets of Chrysaora achlyos were
prepared and found to have factors producing mouse lethality, hemolysis and
hepatocyte toxicity. These venoms had less potency than those of Chrysaora
quinquecirrha a phylogenetic, congeneric cousin. Envenomated bathers had
significant species-specific anti venom IgG and also cross-reacting antibody to
Chrysaora quinquecirrha nematocyst venoms. There were similarities and contrasts
in the capillary electropherograms and sodium dodecyl sulfate (SDS) gels between
C. achlyos nematocyst venoms and those of their C. quinquecirrha counterparts.
PMID- 10775758
TI - Disseminated intravascular coagulation after cerastes vipera envenomation in a 3
year-old child: a case report.
AB - This study presents a case of severe disseminated intravascular coagulation (DIC)
in a 3-year-old child following envenomation by the snake, Cerastes vipera. A
literature search revealed very few similar cases. We describe a child who was
bitten in his left foot by a snake identified as a C. vipera. Initial symptoms
were relatively benign. Local signs included a hemorrhagic vesicle at the site of
the bite with marked swelling of the entire leg. Twenty-four hours later, the
child developed severe bleeding due to DIC, which lasted 5 days and required
repeated administration of blood and blood products and total exchange
transfusion. The patient was discharged from the hospital after 7 days in good
condition. To the best of our knowledge, severe DIC following envenomation by a
C. vipera has not been previously described in the literature. Treatment was
essentially supportive. The case report indicates that a specific antivenin
against this snake's venom should be made available in our area.
PMID- 10775759
TI - Dinophysistoxin-2: a rare diarrhoeic toxin associated with Dinophysis acuta.
AB - Okadaic acid and dinophysistoxin-2 have been found yearly in Portuguese
shellfish. Their presence was correlated with the occurrence of Dinophysis spp:
Dinophysis acuminata has until now been found to be responsible only for OA
contamination, while Dinophysis acuta contributes with OA and the rare diarrhetic
toxin DTX2. Differences in toxicity levels may reflect different cell toxicities
and different non-toxic phytoplankton availability as food source to shellfish.
PMID- 10775760
TI - Neural electrophysiological effect of crude venom of conus textile from the south
China Sea.
AB - In the present study, we characterized effects of the crude venom from Conus
textile, a marine molluscivorous snail collected from the South China Sea, on
neural electrophysiological activity in insect, molluscan and mammalian species.
Our results demonstrate that the venom reversibly blocks the cholinergic synaptic
transmission of cockroach Periplaneta americana central nervous system, partially
blocks Na(+) currents in rat hippocampal CA(1) pyramidal neurons, and enhances
the excitability and spontaneous activity of the giant neurons of garden snail
Achatina fulica.
PMID- 10775761
TI - Mass spectrophotometric evidence for P-III/P-IV metalloproteinases in the venom
of the Boomslang (Dispholidus typus).
AB - The Boomslang, Dispholidus typus, is a mid- to rear-fanged arboreal colubrid
widely distributed throughout much of the African continent. Envenoming by this
species is rare although deaths have been recorded. Typical symptoms associated
with envenoming include diffuse intravascular coagulation (DIC) caused by
fibrinogen consumption and consequent incoagulable blood together with
haemorrhage into tissues such as muscle and brain; together, these procoagulant
and haemorrhagic effects of the venom result in a very poor prognosis in patients
who receive a large dose of venom and who are not treated with antivenom. Renal
failure may also result from acute tubular necrosis resulting from pigment
nephropathy. Little is known about the toxic components present in the venom;
however, proteolytic activity has been reported although the proteinases involved
have not been identified. In this study we provide LC/MS/MS (liquid
chromatography/mass spectrometry/mass spectrometry) data supporting the presence
of class P-III/P-IV snake venom metalloproteinases (SVMPs) in Boomslang venom.
Using a polyclonal antibody raised against the P-III haemorrhagic toxin
(Jararhagin) obtained from the venom of the Brazilian pit viper, Bothrops
jararaca, we identified by western blot a 65 kDa protein from Boomslang venom
which cross-reacted with the jararhagin antibody. A corresponding band from SDS
PAGE was subjected to tryptic digestion followed by LC/MS/MS sequence analysis of
the digestion mixture. A variety of peptide sequences were identified in the
digest, one of which was clearly homologous with a highly conserved region of the
disintegrin-like domains of P-III/P-IV SVMPs. These data provide the first
structural evidence for the presence of SVMPs in Boomslang venom; it is possible
that SVMPs may also be present in the venoms of other colubrids, which cause
similar symptoms in envenomed humans. In other snake venoms, most notably those
of the Viperinae and Crotalinae subfamilies, many of the coagulopathic and
haemorrhagic syndromes associated with systemic and local envenoming are
attributed to SVMPs. The identification of a P-III/P-IV SVMP sequence in D. typus
venom suggests that many of the pathological signs resulting from envenoming by
this species may also be due to the presence of SVMPs in the venom. It is hoped
that these results may accelerate research into colubrid venoms and may provide
new insights into novel and more efficacious treatments for colubrid envenoming.
PMID- 10775762
TI - Multiple forms of phospholipase D in plants: the gene family, catalytic and
regulatory properties, and cellular functions.
AB - Multiple Phospholipase D (PLD) genes have been identified in plants and encode
isoforms with distinct regulatory and catalytic properties. Elucidation of the
genetic and biochemical heterogeneity has provided important clues as to the
regulation and function of this family of enzymes. Polyphosphoinositides, Ca(2+),
and G-proteins are possible cellular regulators for PLD activation. PLD-mediated
hydrolysis of membrane lipids increases in response to various stresses. Recent
studies suggest that PLD plays a role in the signaling and production of hormones
involved in plant stress responses.
PMID- 10775763
TI - Biochemistry of lipid metabolism in olive and other oil fruits.
PMID- 10775764
TI - Interactions of peptides with liposomes: pore formation and fusion.
AB - Leakage from liposomes induced by several peptides is reviewed and a pore model
is described. According to this model peptide molecules become incorporated into
the vesicle bilayer and aggregate reversibly or irreversibly within the surface.
When a peptide aggregate reaches a critical size, peptide translocation can occur
and a pore is formed. With the peptide GALA the pores are stable and persist for
at least 10 minutes. The model predicts that for a given lipid/peptide ratio, the
extent of leakage should decrease as the vesicle diameter decreases, and for a
given amount of peptide bound per vesicle less leakage would be observed at
higher temperatures due to the increase in reversibility of surface aggregates of
the peptide. Effect of membrane composition on pore formation is reviewed. When
cholesterol was included in the liposomes the efficiency of inducation of leakage
by the peptide GALA was reduced due to reduced binding and increased
reversibility of surface aggregation of the peptide. Phospholipids which contain
less ordered acyl-chains and have a slightly wedge-like shape, can better
accommodate peptide surface aggregates, and consequently insertion and
translocation of the peptide may be less favored. Demonstrations of antagonism
between pore formation and fusion are presented. The choice of factors which
promote vesicle aggregation, e.g., larger peptides, increased vesicle and peptide
concentration results in enhanced vesicle fusion at the expense of formation of
intravesicular pores. FTIR studies with HIV-1 fusion peptides indicate that in
systems where extensive vesicle fusion occurred the beta conformation of the
peptides was predominant, whereas the alpha conformation was exhibited in cases
where leakage was the main outcome. Antagonism between leakage and fusion was
exhibited by 1-palmitoyl-2-oleoylphosphatidylglycerol vesicles, where the order
of addition of peptide (HIV(arg)) or Ca(2+)dictated whether pore formation or
vesicle fusion would occur. The current study emphasizes that the addition of
Ca(2+), which promotes vesicle aggregation can also reduce peptide translocation
in isolated vesicles.
PMID- 10775765
TI - Ontogeny of G-protein expression: control by beta-adrenoceptors.
AB - Cardiac cell homeostasis is maintained in the face of excessive beta-adrenoceptor
stimulation through the process of desensitization. Desensitization is not an
inherent property of these cells but rather is acquired during development;
neonates given beta-agonists actually show heterologous sensitization, involving
changes in the expression and catalytic activity of adenylyl cyclase (AC) as well
as an increased receptor/G-protein coupling. The current study examines the role
of specific G-protein components, G(s)alpha and G(i)alpha, in the ontogeny of
beta-adrenoceptor responses and in the transition from agonist-induced
sensitization to desensitization. Between postnatal days (PN) 6 and 15 there was
a significant decrease in the 52 kDa isoform of G(s)alpha with no accompanying
change of the 45 kDa form; over the same period, G(i)alpha3 also declined
substantially. In contrast, the 45 kDa isoform of G(s)alpha and G(i)alpha1,2
remained fairly constant over the same period and fluoride-stimulated AC activity
increased. Treatment with isoproterenol on PN2-5 did not result in any
significant changes in G(s)alpha expression but robustly decreased G(i)alpha1,2.
These changes were accompanied by heterologous sensitization of AC activity at
the level of AC itself, evidenced by equivalent increases in the enzymatic
response to fluoride and forskolin-Mn2+. Isoproterenol given to older animals
(PN11-14) also caused specific loss of G(i) protein, in this case targeting
G(i)alpha3, whereas G(s)alpha again was unchanged; in contrast to the younger
group, the older animals displayed heterologous desensitization of AC at the
level of G-protein function (specific loss of the fluoride response). These
results indicate that the normal ontogenetic increase of cardiac beta
adrenoceptor coupling to AC is not dependent on the absolute amount of G
proteins, nor on the relative balance of stimulatory (G(s)) and inhibitory (G(i))
subunits. However, the ability of receptor stimulation to downregulate
G(i)alpha1,2, an event which is specific to immature cardiac cells, is likely to
be an important component of the resistance of the fetal/neonatal heart to
agonist-induced desensitization and hypertrophy. The maintenance of cardiac beta
adrenoceptor signaling in the face of intense stimulation is likely to play an
important role in the physiologic adaptations necessary to the perinatal
transition.
PMID- 10775766
TI - Antisense knockdown of calcium-dependent K+ channels in developing cerebellar
Purkinje neurons.
AB - Normal developmental upregulation of K(Ca) channel activity in cultured rat
cerebellar Purkinje neurons was selectively inhibited by antisense
oligonucleotide sequence (3 microM) targeted against the rslo transcript. The
knockdown was specific; delayed rectifier and apamin-sensitive K+ channel
abundances in Purkinje neurons were not affected by rslo antisense. Sense
oligonucleotides (3 microM), used as a control, had no effect on channel
abundance. Quantitative morphometric analyses of anti-calbindin-labeled Purkinje
neurons showed no differences between neurons in control, sense and antisense
treatment groups, and confirmed that the presence of the added oligonucleotide in
the sense and antisense treatment conditions had no discernable toxic effects on
neuronal health, for which neurite outgrowth is a sensitive indicator. These
results confirm the identification of the developmentally regulated K(Ca) channel
as the product of the gene rslo in cerebellar Purkinje neurons.
PMID- 10775767
TI - Dynamic changes in cerebral glucose metabolism in conscious infant monkeys during
the first year of life as measured by positron emission tomography.
AB - Recently, advances in spatial resolution have provided the opportunity to utilize
positron emission tomography (PET) to examine local cerebral metabolic rates for
glucose (lCMR(glc)) in large animals noninvasively, thereby allowing repeated
lCMR(glc) measurements in the same animal. Previous studies have attempted to
describe the ontogeny of cerebral glucose metabolism in anesthetized nonhuman
primates using [18F]fluorodeoxyglucose (FDG) and PET. However, the use of
sedation during the tracer uptake period may influence lCMR(glc). This study was
conducted to describe lCMR(glc) in conscious infant vervet monkeys (Cercopithecus
aethiops sabaeus) during the first year of life utilizing FDG-PET. Cross
sectional studies (n=23) displayed lowest and highest lCMR(glc) in all structures
at the 2-3 and 8-9 month age groups, respectively. The metabolic pattern
suggested an increase in lCMR(glc) values between 2 and 8 months of age with
decreased metabolism observed at 10-12 months of age in all regions. Peak
lCMR(glc) values at 8 months were an average of 84+/-24% higher than values seen
at the youngest age examined quantitatively (2-3 months). The regions of greatest
and smallest increases in lCMR(glc) at 8 months were the cerebellar hemispheres
(90%) and the thalamus (39%), respectively. Longitudinal analysis in 4 animals
supported this developmental pattern, demonstrating the ability to detect changes
in cerebral glucose metabolism within animals and the potential for FDG-PET in
nonhuman primate models of brain maturation. By determining the normative profile
of lCMR(glc) during development in monkeys, future application of FDG-PET will
provide the opportunity to longitudinally assess the effects of environmental or
pharmacological intervention on the immature brain.
PMID- 10775769
TI - Expression of sulfoglucuronyl (HNK-1) carbohydrate and its binding protein (SBP
1) in developing rat cerebellum.
AB - Sulfoglucuronyl carbohydrate (SGC) is expressed on several glycoproteins of the
immunoglobulin superfamily of cell-adhesion molecules. Developmental expression
of SGC and its binding protein, SBP-1, was studied in the rat cerebellum by
immunocytochemistry to understand the function of SBP-1 and the significance of
its interaction with SGC. During early postnatal development (postnatal day (PD)
3-10) SBP-1 was strongly expressed in the granule neurons of the external and
internal granule cell layers (EGCL and IGCL). This expression declined by PD 15,
and disappeared in the adult. Between PD 3 and 15, SGC was expressed in cellular
processes surrounding the granule neurons in the IGCL, and it also declined and
disappeared with development. SGC expression, however, continued in Purkinje
cells and their dendrites in the molecular layer in adults. The expressions of
SBP-1 and SGC were developmentally regulated and appeared to be chronologically
co-ordinated with granule neuron migration from EGCL to IGCL. High magnification
confocal microscopy showed that SBP-1 was primarily localized in nuclei and
plasma membranes of granule neurons, whereas SGC in the IGCL was localized on
neuronal plasma membranes, dendrites and glial processes, but not in cell soma.
The relative localization of SBP and SGC was confirmed by cellular and
subcellular markers in vivo and with dissociated cerebellar cells in culture. It
is proposed that SBP-1 on plasma membranes of granule neurons interacts with SGC
on the surrounding processes and membranes and this interaction could provide a
potential mechanism for guidance and cell signaling, in the processes of granule
neuron migration and differentiation.
PMID- 10775768
TI - The previously identified r3/r5 repressor may require the cooperation of
additional negative elements for rhombomere restriction of Hoxb1.
AB - Hoxb1 has several rhombomere-specific roles in hindbrain development and may
contribute to development of a small number of tissues outside the hindbrain. To
gain insight into the regulation of late Hoxb1 expression in these structures,
several regions of the Hoxb1 locus were systematically evaluated for their
ability to control late Hoxb1 expression in transgenic mouse embryos. This was
achieved by progressive enlargement of the portion of the Hoxb1 locus used to
control reporter gene expression. Unexpectedly, the previously identified
rhombomere 4 (r4) enhancer and r3/r5 repressor that were thought to be sufficient
for r4 restriction of Hoxb1 produced continuous expression throughout much of the
length of the central nervous system (CNS) and in several structures outside the
nervous system. However, adjacent regions of the Hoxb1 locus, in combination with
the r4 enhancer and r3/r5 repressor were capable of restricting most expression
to r4 in the hindbrain, and to gut epithelium/mesoderm, caudal spinal cord and
caudal paraxial mesoderm outside the hindbrain. Expression that occurred outside
r4 in the brains of the majority of founder embryos was confined to scattered
cells in specific regions. These cells may have arisen in r4 and then migrated
into adjacent brain regions as rhombomere lineage restrictions dissipated.
Alternatively, these dispersed stained cells may have originated outside r4
implying that Hoxb1 cannot be accurately regulated in a consistent manner outside
the Hox complex.
PMID- 10775770
TI - Alterations in respiratory behavior, brain neurochemistry and receptor density
induced by pharmacologic suppression of sleep in the neonatal period.
AB - The present study examined if drug suppression of active sleep (AS) in the
neonate affected the development and expression of respiratory behavior.
Secondly, we assessed brain neurochemistry and receptor density in specific supra
medullary brain regions to identify coincident biochemical alterations. Sprague
Dawley newborn rat pups were randomized and divided among six rat mothers
(n=10/mother/group), each mother housed separately. Two untreated control (UC)
groups received either no interventions or were fed milk vehicle twice daily and
were handled similarly to the drug intervention animals. Pharmacological
disruption of sleep was achieved by administration (2 groups of each) of either
clonidine (CLO) 100 microm/kg, or scopolamine (SCO) 800 microm/kg, given orally
twice daily for the first 7 days of life. On postnatal (P) days P10 and P19 of
life, pups were assessed for metabolism, minute ventilation (VE), tidal volume
(Vt) and frequency (f). On P21 (14 days after the end of drug exposure), pups
from each condition were sacrificed and punch biopsies of the frontal cortex,
hypothalamus, and hippocampus were examined for hydroxytryptophan (5-HT), and
norepinepherine (NE) by HPLC. An equal number of pups were sacrificed and brains
examined for muscarinic acetylcholine (mAch), alpha2-adrenergic and I1
imidazoline receptor density. RESULTS: Both CLO and SCO exposed animals had a
lower V(t) and respiratory quotient than UC animals (p<0.01). CLO animals
exhibited a higher f (p<0.01) and both CLO and SCO exhibited a lower V(t)
(p<0.05) than the UC groups; VE was reduced in the SCO groups, compared with CLO
and UC groups (p<0.01). Pattern of breathing in response to brief hypoxia
exposure was altered for CLO and SCO. The normal decline in VE during sleep was
not observed in CLO rats. Both drug exposures resulted in a comparable reduction
in hypothalamic NE and 5-HT levels (p<0.05), while in the frontal cortex, and the
hippocampus variable changes in NE and 5-HT, occurred. In CLO and SCO rats mAch
receptors were increased in cortex, and reduced in hypothalamus; I1-imidazoline
receptors were increased in hypothalamus and decreased in hippocampus (p<0.05 for
each). In contrast, alpha2-adrenergic receptors were increased in cortex for both
CLO and SCO, decreased in hypothalamus for CLO, and decreased in hippocampus for
SCO (p<0.05 for each). CONCLUSIONS: these data show that drug-induced neonatal
sleep suppression will alter ventilatory pattern, metabolism, and site-specific
concentrations of adrenergic neurotransmitters and in receptor density, perhaps
as a result of suppression of neonatal AS.
PMID- 10775771
TI - The effect of periaqueductal gray lesions on responses to age-specific threats in
infant rats.
AB - During early ontogeny infant rats show specific responses to a variety of age
dependent threatening situations. When isolated from nest and dam, they emit
ultrasonic vocalizations and show decreased reactivity to noxious stimulation, or
analgesia. When exposed to an unfamiliar adult male, they become immobile and
analgesic. The midbrain periaqueductal gray (PAG) is an important area within the
circuitry that controls responses to threatening stimuli in the adult. Little is
known about the functions of the PAG in early life. It was hypothesized that the
PAG mediates the responses to the age-specific threats social isolation and male
exposure in the infant rat. Rat pups were lesioned electrolytically either in the
lateral or the ventrolateral PAG on postnatal day 7, tested in social isolation
on day 10, and exposed to a male on day 14. On day 10 during isolation,
ultrasonic vocalizations and isolation-induced analgesia were decreased in both
lesion groups. On day 14, male-induced immobility and analgesia were decreased in
ventrally lesioned animals. In conclusion, the PAG seems to play a
developmentally continuous role in age-specific responses to threat such as
ultrasonic vocalization, analgesia, and immobility.
PMID- 10775772
TI - Serum-free culture of rat post-natal and fetal brainstem neurons.
AB - Serum-free medium is essential for cell culture studies in which complete control
of the environment is required. Primary culture of post-natal brainstem neurons
in defined medium has not been described in the literature, and successful
culture of primary brainstem neurons is typically restricted to embryonic ages
E14-E18. This study describes a method for culture of fetal and post-natal
brainstem neurons using a serum-free culture medium. The culture system is based
on Neurobasal medium supplemented with antioxidant-rich B27. Media and
supplements are commercially available products from Life Technologies. Neuron
survival was optimized by replacing glutamine with GlutaMaxI, by matching
osmolality with neuronal age, and by using Hibernate medium to increase neuron
survival during tissue dissociation. Fetal E14, E16, E20, and post-natal P3 and
P6 cultures were examined after 4, 7, and 9 days in culture. Neuron and glial
cells present in the cultures were identified using immunocytochemistry with
antibodies raised against microtubule-associated protein 2 (MAP2) and glial
fibrillary acidic protein (GFAP), respectively. Fetal E14 cultures had more
bipolar neurons than multipolar neurons compared with developmentally older P6
cultures. Early fetal cultures had a higher percentage of neurons than late fetal
and early post-natal cultures. Neuron survival was similar between 4 and 9 days
in culture for all age groups tested. This is the first reliable, defined culture
medium that supports brainstem neurons from late fetal and early post-natal
stages of the rat for up to 6 days post-partum.
PMID- 10775773
TI - Conversion and storage of somatostatin are established before response to
secretagogue stimuli in P19 neurons.
AB - In mature neurons, neuropeptides are synthesized via limited proteolysis of
propolypeptides by convertases. The bioactive peptides are then stored in
secretory granules until they are released extracellularly upon the induction of
a fusion between granules and the plasma membrane, in response to secretagogues.
We used the mouse P19 embryonic carcinoma cells as a model to determine if the
capacities to convert and store neuropeptides and to secrete them in a regulated
fashion are established coordinately during neuronal differentiation. We have
previously shown that both undifferentiated P19 cells and their neuronal
derivatives express the largely distributed furin, PACE4 and PC5 convertases,
whereas only neuronal derivatives express the neuroendocrine convertase PC2. In
addition, undifferentiated cells displayed furin- rather than PC2-like converting
capacities. The present work demonstrates that day 8 P19 neurons mainly convert
prosomatostatin (proSS) to somatostatin-14 (SS-14) using HPLC and
radioimmunoassay (RIA) analyses, indicating that P19 cells acquire PC2-like
converting capacities as a consequence of neuronal differentiation. SS-14 was
predominantly intracellular in neuronal cells which were shown to express several
granins, markers of granules, by Western blotting. However, cell membrane
depolarization with 50 mM K+, a general secretagogue stimulus, evoked the release
of SS-14 by day 12, but not by day 8, P19 neurons. The results thus demonstrate
that capacities to convert and store neuropeptides can be established before
coupling of stimulus-secretion during neuronal differentiation.
PMID- 10775775
TI - Ethanol inhibits development of dendrites and synapses in rat hippocampal
pyramidal neuron cultures.
AB - Evidence suggests that some neuropathologic manifestations of Fetal Alcohol
Syndrome (FAS) result from the disruption of neuromorphogenesis and synapse
formation in the hippocampus. Prior research in this laboratory has shown that
ethanol in the medium during the first 24 h in culture increases the number of
minor processes (the precursors of axons and dendrites) and accelerates the rate
at which axons are formed in low-density cultures of embryonic rat hippocampal
neurons. The current study examined the effects of ethanol on the subsequent
development of dendrites and synapses in these cultures. Quantitative
morphometric analysis utilized double-immunofluorescent staining for MAP2 and
synapsin I to visualize dendrites and synaptic specializations, respectively. Six
days of ethanol (200, 400 or 600 mg/dl) in the medium, beginning at the time of
plating, resulted in decreases in total dendritic length per cell, dendrite
number per cell, length of individual dendrites and synapse number per innervated
dendrite but had no effect on cell survival. The decrease in synapse number was
correlated with dendrite length, suggesting that ethanol's effects on synapse
number are secondary to its effects on dendritogenesis. Taken together with our
previous findings, these results are the first to demonstrate that ethanol has
differential effects on axonal and dendritic growth in a culture model of neurons
that are vulnerable to ethanol-induced cytoarchitectural abnormalities during
development in vivo.
PMID- 10775774
TI - Synaptic connectivity in hippocampal neuronal networks cultured on micropatterned
surfaces.
AB - Embryonic rat hippocampal neurons were grown on patterned silane surface in order
to organize synapse formations in a controlled manner. The surface patterns were
composed of trimethoxysilylpropyl-diethylenetriamine (DETA) lines separated by
tridecafluoro-1,1,2,2-tetrahydrooctyl-1-dimethylchlorosilane (13F) spaces. Pre-
and post-synaptic specializations were identified by immunostaining for synapsin
I and microtubule-associated protein-2 (MAP-2). Functional synaptic connections
were examined by recording simultaneously from pairs of neurons using the whole
cell configuration of the patch-clamp technique. Spontaneous and evoked synaptic
currents were recorded in neurons cultured for 2-14 days. The formation of
functional connections was accompanied by the appearance of spontaneous synaptic
currents (SSCs), which could be detected after approximately 3 days in culture in
the absence of evoked synaptic currents (ESCs). ESCs were detected only after
approximately 7 days in culture, mostly in the form of unidirectional synaptic
connections. Other forms of synaptic connectivity, such as bidirectional and
autaptic connections, were also identified. Both transient GABAergic and
glutamatergic signals mediated the transmissions between communicating cells.
These results demonstrate the combination of various types of synaptic
connections forming simple and complex networks in neurons cultured on line
(DETA)-space (13F) patterns. Finally, precisely synchronized SSCs were recorded
in neuron pairs cultured on pattern indicating the existence of a fast-acting
feedback mechanism mediated by pre-synaptic GABA(A) receptors.
PMID- 10775776
TI - Estrogen receptor alpha, but not beta, is expressed in the interneurons of the
hippocampus in prepubertal rats: an in situ hybridization study.
AB - Estradiol is involved in the differentiation and plasticity of hippocampal
neurons. In the CA1 region, estrogen treatment increases dendritic spines and
synapse density on pyramidal cells. In the adult hippocampus, immunoreactivity
for estrogen receptor alpha (ERalpha) has been reported in inhibitory
interneurons, but neither in the pyramidal neurons nor in granule cells.
Estrogens also mediate aspects of sexual differentiation of the hippocampus. To
examine the possibility that an alteration in expression of the two types of
estrogen receptors (ERalpha and ERbeta) in the hippocampus underlies different
roles of estrogen and/or ERs during development and in adult life, we applied non
isotopic, digoxigenin (dig)-labeled, in situ hybridization histochemistry (ISHH)
for the both ER forms and examined the distribution pattern of their messages in
serial, frontal sections over the postnatal period and in the adult. ERalpha mRNA
expression was found scattered throughout the hippocampus especially in the hilar
region of the dentate gyrus, and in the strata radiatum and pyramidale in the
cornus ammonis at postnatal days (PND) 14, 21 and 35. In the hilus of the dorsal
hippocampus, the density of ERalpha-labelled cells was greater in the rostro
medial aspect, while less in the lateral and the caudal region. In the ventral
hippocampus the signals for ERalpha mRNA were also found in relatively high
density in the hilus. No significant sex difference in distribution and intensity
of the ERalpha mRNA positive cells were detected. The hippocampal distribution of
ERalpha mRNA expression at PND 14 remained the same on PND 21 and 35 and in
adulthood. As reported for adults, ERalpha mRNA signals appear to be in
interneurons of the hippocampus but neither in the pyramidal cells nor in the
dentate granular cells based on their size and location. In contrast to the
result of ERalpha, no clear signals for ERbeta mRNA were detected in the
hippocampus across all ages examined, whereas they were clearly detected in the
hypothalamus.
PMID- 10775778
TI - Pre- or postnatal testosterone and flutamide effects on sexually dimorphic nuclei
of the rat hypothalamus.
AB - Utilizing the sexually dimorphic nature of hypothalamic nuclei, a determination
of the effects of pre- or postnatal flutamide and testosterone treatments were
examined in male and female rats. Statistical analysis compared treatments, sex,
and time of injection in terms of the sexually dimorphic nucleus of the preoptic
area (SDN-POA) and the anteroventral periventricular nucleus (AVPV) volumes and
lengths. The present findings establish that pre- or postnatal hormonal
environments are crucial in influencing sexual morphology on the developing
brain.
PMID- 10775779
TI - Isolation of a retinal pigment epithelial cell-derived fraction which promotes
Muller cell proliferation.
AB - Retinal pigment epithelial cells (RPE) secrete a factor(s) in vitro which
promotes Muller cell proliferation. To begin the isolation of the active factor,
medium conditioned by cultured RPE (RPE-CM) was fractionated by fast protein
liquid chromatography. The fractions were tested in an assay for Muller cell
proliferation and it was found that one fraction contained biological activity
comparable to that of complete RPE-CM. Gel electrophoresis demonstrated that this
fraction consisted of proteins with approximate molecular masses of 35-88 kDa. An
affinity assay revealed that only an 88-kDa protein in the RPE-CM binds to Muller
cells. This protein was also present in the active fraction; therefore, it is the
most likely source of the mitogenic activity of RPE-CM.
PMID- 10775777
TI - Different effects of acute neonatal stressors and long-term postnatal handling on
stress-induced changes in behavior and in ornithine decarboxylase activity of
adult rats.
AB - A transient increase in brain polyamine (PA) metabolism, termed the PA-stress
response (PSR), is a common response to stressful stimuli. Previous studies have
implicated the PSR as a component of the adaptive and/or maladaptive brain
response to stressful events. Ample evidence indicates that stressful experiences
during early life can alter normal developmental processes and may result in
pathophysiological and behavioral changes in the adult. The aim of the present
study, therefore, was to determine whether strong acute neonatal stressors (3
mg/kg dexamethasone, or 2 h restraint stress at day 7), as compared to mild long
term intermittent maternal separation and handling (15 min, twice a day between
postnatal days 2 and 25), would lead in adult Wistar rats to different PSR and
behavioral reactivity to novelty stress. Changes in ornithine decarboxylase (ODC)
activity and in tissue PA concentrations served as markers of the PSR, and
behavioral alterations in an open-field arena indicated the reactivity to novelty
stress. Animals subjected to acute neonatal stressors, showed reduced behavioral
reactivity in the open-field test, indicative of increased emotional reactivity
to novelty. In these animals, the increase in ODC activity after dexamethasone
challenge was attenuated in the brain, but exaggerated in the liver. In the
thymus and adrenal gland of these animals, the basal enzyme activity was
significantly increased, but a similar reduction was observed after dexamethasone
challenge. In contrast, long-term postnatal handling led in adults to novelty
induced changes indicative of reduced emotional behavior, yet the alterations in
ODC activity after dexamethasone challenge in these animals were similar to those
in animals after acute stressors. The concentrations of tissue polyamines in
adults were not affected by any of the postnatal stressors. The results justify
the following conclusions: (1) Strong acute neonatal stressors can lead to
increased emotional behavior in adults, while mild long-term intermittent
handling, may result in adaptation and reduced emotionality. (2) Attenuated
stress-induced increase of ODC activity in the brain, but exaggerated increased
activity in the liver, may be implicated in altered emotional behavior reactivity
to stressors.
PMID- 10775780
TI - Influenza vaccination coverage in old people's home in Carmarthenshire, UK,
during the winter of 1998/99.
AB - A mailed questionnaire survey was undertaken in old people's (nursing and
residential) homes in Carmarthenshire, UK to determine the influenza vaccine
uptake during the 1998/99 season. Out of the total 60 questionnaires circulated,
response was received from 47 homes giving an overall response rate of 78%.
Amongst the 1399 residents, 1132 (81%) received influenza vaccine in the winter
of 1998/99. Uptake was higher in nursing homes (89%) than in residential homes
(79%) or dual registered homes (81%). The most common reason for not receiving
influenza vaccination was refusal by the residents themselves, although the
vaccine was offered to 99% of residents. This study suggests that strategies to
improve communication and provision of educational materials outlining the
benefits of influenza vaccine to elderly residents and health professionals may
help increase the likelihood of vaccine uptake.
PMID- 10775781
TI - Effect of sequence variation in meningococcal PorA outer membrane protein on the
effectiveness of a hexavalent PorA outer membrane vesicle vaccine.
AB - Though meningococcal serogroup C conjugate vaccines have been introduced into the
UK infant immunisation schedule, there is currently no vaccine solution for
serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B
vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has
been evaluated in phase I and II trials with promising results. This vaccine
contains six different PorA OMPs each representing a different serosubtype.
However, considerable sequence variation occurs in the variable regions (VRs)
encoding these serosubtypes. By using recombinant P1.5,10 PorA variants we have
demonstrated that the killing of this particular serosubtype combination was due
mainly to the induction of antibody to the VR2 (P1.10) epitope region, and that
after three or four doses of vaccine there was a significant reduction in the
killing of variants P1.10a (three doses, p<0.0001; four doses, p = 0.003) and
P1.10f (three doses, p<0.0001; four doses, p = 0.002), as compared to responses
to the P1.10 strain, when the P1.10 serosubtype was used as the immunogen. Since
large numbers of serosubtype variants are known to exist, this finding may have
implications for the use of PorA as a meningococcal serogroup B vaccine.
PMID- 10775782
TI - In vivo antibody response and in vitro CTL activation induced by selected measles
vaccine candidates, prepared with purified Quil A components.
AB - Semipurified Quil A and purified Quil A were used to prepare well-characterized
subunit vaccine candidates against measles. Variation in the relative amounts of
the measles virus (MV) fusion (F) protein, Quil A-components and lipids did not
influence induction of antibody responses in mice, but had a pronounced effect on
the capacity to induce cytotoxic T cell (CTL) activity of a CD8(+) MV F-protein
specific human T cell clone in vitro. A characteristic MV iscom preparation based
on the combined use of HPLC-purified Quil A-components QA-3 and QA-22 (QA-3/22)
efficiently induced CTL activity in vitro. Comparable results were obtained by
mixing beta-propiolactone inactivated MV with iscom-matrix QA-3/22 or free QA-22.
On the basis of the data presented it was concluded that these three preparations
are interesting MV vaccine candidates for further evaluation in pre-clinical
experiments in a primate model.
PMID- 10775783
TI - Immune response to caprine arthritis-encephalitis virus surface protein induced
by coimmunization with recombinant vaccinia viruses expressing the caprine
arthritis-encephalitis virus envelope gene and caprine interleukin-12.
AB - The objective of this study was to determine if interleukin (IL)-12 can focus an
antigen specific type 1 immune response characterized by activation of Th1
lymphocytes and production of IgG2 antibodies in vivo. Saanen goats co-immunized
with recombinant vaccinia viruses expressing caprine IL-12 (rRB-IL12) and the
caprine arthritis-encephalitis virus (CAEV) envelope (env) gene (rWR-63) were
evaluated for development of immune responses to the CAEV env encoded surface
glycoprotein (SU). Immune responses were defined by: (i) SU antibody titers; (ii)
the ratio of SU IgG1 and IgG2 antibodies; (iii) interferon gamma (IFNgamma) and
IL-4 gene expression and proliferative response of SU stimulated lymph node
mononuclear cells (LNMC). Apart from enhancement of IFNgamma and IL-4 gene
expression in SU stimulated LNMC, rRB-IL12 did not affect the immune response to
rWR-63 encoded SU. Thus, localized production of exogenous species specific IL-12
at the site of immunization did not focus initial priming of antigen reactive Th
lymphocytes. These results are in contrast to previous studies using inbred mice
and raise questions regarding the use of cytokine adjuvants to focus immune
responses in outbred animals.
PMID- 10775784
TI - Safety and immunogenicity of a three-component blood-stage malaria vaccine in
adults living in an endemic area of Papua New Guinea.
AB - A Phase I safety and immunogenicity study with a three-component blood-stage
malaria vaccine was conducted in adult male subjects living in an endemic area of
Papua New Guinea. The preparations were recombinant proteins which corresponded
to parts of the two merozoite surface proteins of Plasmodium falciparum (MSP1 and
2), and of the ring-infected erythrocyte surface antigen (RESA). The three
proteins were emulsified with the adjuvant Montanide ISA720. Ten subjects were
injected twice (four weeks apart) with the vaccine formulation and two with the
adjuvant alone. Mild pain at the site of injection was reported by about half of
the subjects but no systemic reaction related to the formulation occurred. There
was a sharp rise in geometric mean stimulation index after the second dose
compared to baseline for MSP1 and RESA, while the rise was small for MSP2.
Geometric mean antibody titres increased for MSP1 during the study, whereas they
hardly changed for MSP2 and RESA. The vaccine formulation was safe when used in
an already immune population. The vaccine induced good cellular responses,
especially for MSP1 and RESA. Boosting of humoral responses was weak, probably
because of high baseline antibody levels.
PMID- 10775785
TI - Induction of protective immunity against toxoplasmosis in mice by DNA
immunization with a plasmid encoding Toxoplasma gondii GRA4 gene.
AB - GRA4 is a dense granule protein of Toxoplasma gondii that is a candidate for
vaccination against this parasite. We have inserted the entire coding sequence of
GRA4 into an eukaryotic expression vector to determine whether DNA immunization
can elicit protective immune response to T. gondii. Susceptible C57BL/6 mice were
then vaccinated intramuscularly with GRA4 DNA and orally challenged with a lethal
dose of 76 K T. gondii strain cysts. Immunization with pGRA4 resulted in a 62%
survival of C57BL/6 infected mice. Mice immunized with GRA4 DNA developed high
levels of serum anti-GRA4 immunoglobulin G antibodies as well as a cellular
immune response, as assessed by splenocyte proliferation, in response to
recombinant GRA4 protein restimulation in vitro. The cellular immune response was
associated with IFN-gamma and IL-10 synthesis, suggesting a modulated Th1-type
response. Splenocyte proliferation was strongly enhanced and protection slightly
higher by inoculation with GRA4 DNA combined with a granulocyte-macrophage colony
stimulating factor expressing vector. This is the first report that demonstrates
the establishment of a DNA vaccine-induced protective immunity against the acute
phase of T. gondii infection.
PMID- 10775786
TI - Humoral immune responses to DNA vaccines expressing secreted, membrane bound and
non-secreted forms of the Tania ovis 45W antigen.
AB - The antibody response to DNA vaccines expressing secreted, membrane bound and non
secreted forms of the same antigen was investigated. The antigen gene selected
for these studies was the full length 45W antigen gene from Taenia ovis. This
gene encodes a host protective membrane bound antigen with a native secretion
signal at the amino terminus and a hydrophobic anchor domain at the carboxyl
terminus. Full length and rationally truncated forms of the 45W antigen gene were
generated and used to construct DNA vaccines encoding membrane bound, secreted
and non-secreted forms of the 45W antigen. The cellular localisation of these
antigen forms was confirmed by Western blot studies. BALB/c mice were immunised
intramuscularly with plasmid DNA and serum antibody responses measured by enzyme
linked immunosorbant assay (ELISA). The cellular localisation of DNA vaccine
antigen had a significant effect on the magnitude but not the subclass of
antibody responses. Immunisation with DNA expressing secreted 45W generated three
fold higher antibody titres than immunisation with DNA expressing membrane bound
45W, and 18-fold higher antibody titres than DNA expressing non-secreted 45W. All
mice generated a predominantly IgG1 antibody response indicative of a TH-2 type
immune response. These results indicate that the optimal induction of humoral
immune responses to intramuscular genetic immunisation with the 45W antigen,
requires the active secretion of antigen. This observation may be of value during
the design of DNA vaccines in the future.
PMID- 10775787
TI - Expression library immunization protects mice against a challenge with virulent
rodent malaria.
AB - Although several candidate vaccine antigens have been developed for malaria,
there is as yet no effective single vaccine available. There is a growing
consensus that the ultimate malaria vaccine will be multivalent, requiring the
identification of a suitable cocktail of antigens. However, evaluation of the
multitude of potential malaria vaccine antigens in suitable combinations is a
daunting task. Here we describe the validation of expression library immunization
(ELI) as a tool for the discovery of sequences protective against malaria
infection. A genomic Plasmodium chabaudi expression library was constructed
comprising ten separate pools of 3000 plasmids. Over three vaccine trials using
biolistic delivery of pools composed of 616 to 30,000 plasmids we report up to
63% protection of mice from a challenge with P. chabaudi adami DS, a highly
virulent strain. Overall, ELI protected 36% of vaccinated mice against virulent
challenge compared with only 3.2% survival of control mice. These results
demonstrate that ELI is a suitable approach for screening the malaria genome to
identify the components of multivalent vaccines.
PMID- 10775788
TI - Immunization with Streptococcus bovis protects against lactic acidosis in sheep.
AB - Lactic acidosis is a gastrointestinal disorder resulting from the rapid
overgrowth of lactic acid-producing bacteria when ruminants are suddenly
introduced to grain feed. The present study has investigated the ability of live
and killed bacterial vaccines to reduce lactic acidosis in sheep, via a
stimulation of specific antibody production against lactic acid-producing
bacteria. Forage-fed sheep were immunized with live or killed Streptococcus bovis
Sb-5 vaccine, with or without adjuvant, via intramuscular injection. After the
primary immunization, three boosters were given at 2-4 week intervals. Sheep were
subsequently challenged by a sudden switch to a grain-based diet. Following
challenge, vaccinated sheep maintained significantly higher feed intake, and had
higher rumen pH, lower L-lactate concentrations, and less severe diarrhoea scores
than non-vaccinated control sheep. Higher rumen pH, lower mortality and less
severe diarrhoea were found in the animals immunized with live vaccine compared
to the animals immunized with killed vaccines. Significant increases in mucosal
and systemic antibody responses were observed after boosting; the S. bovis
specific antibody concentrations were significantly higher in samples of saliva,
rumen fluid and serum from sheep immunized with live vaccine than with killed
vaccines. These results demonstrate that lactic acidosis can be reduced by
immunization against S. bovis, and that live Sb-5 vaccine is effective in
invoking mucosal as well as systemic antibody responses.
PMID- 10775789
TI - Purified dengue 2 virus envelope glycoprotein aggregates produced by baculovirus
are immunogenic in mice.
AB - The full-length dengue 2 virus envelope glycoprotein (Egp) was expressed in
insect cells by recombinant (r) baculovirus and found to form multimeric
aggregates that were recovered in the void volume of gel filtration columns and
by ultracentrifugation. An immunoblot confirmed that rEgp aggregrates disrupted
with SDS sample buffer released a monomeric form that migrated with a molecular
weight similar to native dengue 2 virus Egp on polyacrylamide gels. The rEgp
aggregates reacted strongly with a panel of monoclonal antibodies specific for
the native Egp and which identify critical structural and functional epitopes.
The rEgp aggregates were purified by ultracentrifugation through 30% sucrose, and
were shown to be the major protein band on a polyacrylamide gel and corresponding
immunoblot. Purified rEgp aggregates in combination with aluminum hydroxide
induced high titer neutralizing antibodies in adult mice. The generation of full
length dengue 2 rEgp aggregates in insect cells facilitated development of a
simple, effective procedure for purification of the recombinant protein, and
represents a good approach for producing highly immunogenic dengue 2 rEgp as a
component of a subunit vaccine.
PMID- 10775790
TI - Protection against influenza virus infection by nasal vaccination in advance of
sublethal irradiation.
AB - The effect of sublethal gamma-ray irradiation on the protection conferred by a
nasal influenza vaccine was investigated in BALB/c mice. A radiation dose of 7 Gy
was selected as the sublethal dose as this caused exacerbation of the influenza
but was not lethal in the mouse model. Mice were irradiated 7 days before, on the
same day as, and 7 days after, administration of a nasal influenza vaccine, and
were then infected with a lethal dose of the virus 4 weeks after vaccination.
Almost all mice irradiated 7 days before or on the same day as vaccination died
from viral pneumonia around 7 days after the challenge infection, whereas all
mice irradiated 7 days after vaccination survived with no sign of infection. In
mice irradiated 7 days after vaccination, both local anti-viral IgA and systemic
IgG antibodies were produced in parallel with a marked reduction in lung viral
titer, although no antibody production and no reduction in lung viral titer were
detected in mice irradiated 7 days before, or on the same day as, vaccination.
These results clearly demonstrate that vaccination with influenza virus before
irradiation can protect mice from subsequent infection. This may be applicable to
patients due to receive sublethal irradiation for bone marrow transplantation.
PMID- 10775791
TI - Effect of different promoters on immune responses elicited by HIV-1 gag/env
multigenic DNA vaccine in Macaca mulatta and Macaca nemestrina.
AB - pCMV-NL(Deltapol) and pAKV-NL(Deltapol) expressed human immunodeficiency virus
type 1 (HIV-1) gag and env under the regulation of the human cytomegalovirus
(CMV) immediate-early (IE) promoter/enhancer and the endogenous AKV murine
leukemia viral long terminal repeat (LTR), respectively. Analysis of the immune
responses elicited by direct DNA injection of pCMV-NL(Deltapol) and pAKV
NL(Deltapol) in macaques indicated that generation of the humoral and T-cell
proliferative responses correlated directly with the promoter strength of the
vaccine DNAs. In Macaca mulatta, pCMV-NL(Deltapol) generated stronger humoral
responses and T-cell proliferative responses to Gag and Env using less DNA and
fewer number of injections than pAKV-NL(Deltapol). Similarly, in Macaca
nemestrina pCMV-NL(Deltapol) elicited high humoral responses, which persisted
long-term and were boostable. Injection of large amounts of pAKV-NL(Deltapol), in
general, failed to produce antibody levels comparable to pCMV-NL(Deltapol).
However, injection of a control animal with large amounts of vector DNA produced
a generalized enzyme-linked immunosorbent assay (ELISA) reactivity to HIV-1. The
results indicated that generation of high immune responses to HIV-1 cannot be
achieved by increasing the vaccine DNA dose and may require high protein
expression from the DNA by including a strong promoter or by the use of other
boosting agents. Furthermore, safety concerns may arise with increasing the DNA
dose that could need additional investigation.
PMID- 10775792
TI - Differing serologic responses to an haemophilus influenzae type b polysaccharide
neisseria meningitidis outer membrane protein conjugate (PRP-OMPC) vaccine in
australian aboriginal and caucasian infants - implications for disease
epidemiology.
AB - This study compared Hib antibody responses to a single lot of PRP-OMPC vaccine
given at 2, 4 and 12 months to 57 Aboriginal infants in rural areas of the
Northern Territory and 56 Caucasian infants in Sydney, Australia. The Aboriginal
infants had lower levels of antibody in cord blood (P>0.05), which were
significantly lower (P<0.02) by 2 months of age. Antibody responses to one or two
doses of vaccine, measured at 4 and 12 months of age, were similar but the
geometric mean titre following the booster dose in Aboriginal infants was
significantly lower (1.98 vs. 6.04 mcg/ml, P = 0.002). Low preimmunisation
antibody is consistent with the early onset of Hib disease in Aboriginal infants
before immunisation. Lower responses to boosting could correlate with persistence
of Hib colonisation in indigenous populations.
PMID- 10775793
TI - Strategies for inducing protection against avian influenza A virus subtypes with
DNA vaccines.
AB - The cross-species transfer of a H5N1 influenza virus from birds to humans, and
the systemic spread of this virus in mice, has accelerated the efforts to devise
protective strategies against lethal influenza viruses. DNA vaccination with the
highly conserved nucleoprotein gene appears to provide cross protection against
influenza A viruses in murine models. Whether such vaccines would protect human
hosts against different influenza A viruses, including strains with pandemic
potential, is unclear. Our aim in this study is to evaluate the ability of a
combination DNA vaccine consisting of two plasmids encoding the HA genes from two
different subtypes and a DNA vaccine encoding the viral nucleoprotein gene from a
H5 virus to induce protection against highly lethal infection caused by H5 and H7
influenza viruses in chickens. Chickens given a single dose of plasmids
expressing H5 and H7 hemagglutinins protected the birds from infection by either
subtype. However, birds immunized with nucleoprotein DNA and challenged with
either A/Ck/Vic/1/85(H7N7) or A/Ty/Ir/1/83 (H5N8) showed definite signs of
infection, suggesting inadequate immunity against viral infection. Fifty percent
of the nucleoprotein DNA immunized birds survived infection by influenza
A/Ty/Ir/1/83 (H5N8) virus (virus of same subtype) while 42% survived infection by
influenza A/Ck/Vic/1/85/(H7N7) virus (virus of a different subtype). These
studies demonstrate that immunization with DNA encoding a type-specific gene may
not be effective against either homologous or heterologous strains of virus,
particularly if the challenge virus causes a highly lethal infection. However,
the combination of HA subtype vaccines are effective against lethal infection
caused by viruses expressing any of the HA subtypes used in the combination
preparation.
PMID- 10775794
TI - An investigation of the intradermal route as an effective means of immunization
for microparticulate vaccine delivery systems.
AB - Among the common routes of parenteral immunization, the skin is the only site
that can function as an immune organ. Skin-associated lymphoid tissue contains
specialized cells that enhance the immune response. The intercellular space in
the skin interstitium provides a connection to the lymphatic capillaries and
vessels that terminate in peripheral immune organs like the lymph nodes and
spleen. The potential of intradermal immunization with microparticulate vaccine
delivery systems was investigated in this study. The microparticulates used were
muramyl dipeptide (MDP) loaded ovalbumin microspheres (OVA-MSs) and fluorescent
latex microspheres of fixed sizes of 2.3 and 2.1 microm diameter, respectively.
Similar doses of OVA-MSs were injected subcutaneously (s.c.) and intradermally
(i.d.) in mice. The induced OVA-specific IgG antibody immune response was found
to be significantly higher in i.d. immunized mice as compared to those injected
s.c. The sc and i.d. administration of fluorescent latex microspheres in mice
demonstrated that the uptake and translocation of microspheres from the site of
injection depends primarily upon the surface area of the microspheres. The
enhancement in antibody production upon i.d. administration was explained on the
basis of (i) an increased surface area of microspheres and a lower number of
microspheres per injection site, and (ii) an increased probability of interaction
with the immune cells of the skin. Efficient lymph node targeting observed from
the id administered microspheres may be the result of both of these factors. The
results of this study demonstrated that the intradermal route is an effective
means of immunization for microparticulate vaccine delivery systems, requiring
lower doses and resulting in a higher immune response as compared to the
traditionally used sc route.
PMID- 10775795
TI - Strain-dependent induction of cytokine profiles in the gut by orally administered
Lactobacillus strains.
AB - Different Lactobacillus strains are frequently used in consumer food products. In
addition, recombinant lactobacilli which contain novel expression vectors can now
be used in immunotherapeutic applications such as oral vaccination strategies and
in T cell tolerance induction approaches for autoimmune disease. Both for food
and clinical applications of lactobacilli, proper selection of wild type strains
is crucial. For that purpose, eight different common Lactobacillus strains were
analysed with respect to mucosal induction of pro- and anti-inflammatory
cytokines, IgA-producing plasma cells in the gut, as well as systemic antibody
responses against a parenterally administered antigen. Immunohistochemical
analysis of cytokine-producing cells in the gut villi showed no significant
induction of the cytokines IL-1alpha, IFN-gamma, IL-4 or IL-10 after oral
administration of wild type Lactobacillus strains. In contrast, oral
administration of L. reuteri and L. brevis induced expression of the
proinflammatory/Th1 cytokines TNF-alpha, IL-2 and/or IL-1beta. Oral
administration of these two strains and L. fermentum also significantly enhanced
the IgG response against parenterally administered haptenated chicken gamma
globulin (TNP-CGG). The five other strains did not show this adjuvanticity. L.
reuteri induced relatively high levels of IgG2a compared to L. murines, a
nonadjuving Lactobacillus strain. These findings imply that different
Lactobacillus strains induce distinct mucosal cytokine profiles and possess
differential intrinsic adjuvanticity. This suggests that rational Lactobacillus
strain selection provides a strategy to influence cytokine expression and thereby
influence immune responses.
PMID- 10775796
TI - Cell death of spinal interneurones.
AB - The occurrence of neuronal death during development is well documented for some
neuronal populations, such as motoneurones and dorsal root ganglion cells, whose
connecting pathways are clearly defined. Cell survival is thought to be regulated
largely by target and input connections, a process that serves to match the size
of synaptically linked neuronal populations. Far less is known about
interneurones. It is assumed that most interneurone populations are excluded from
this process because their connections are more diffuse. Recent studies on the
rat spinal cord have indicated that interneurone death does occur, both naturally
during development and induced following peripheral nerve injury. Here the
evidence for spinal interneurone death is reviewed and the factors influencing it
are discussed. There are many functional types of interneurones in the spinal
cord that may differ in vulnerability to cell death, but it is concluded that for
most spinal interneurones the traditional view of target regulation is unlikely.
Instead it is proposed that developmental interneurone death in the spinal cord
forms part of a plastic response to altered sensory activation rather than a size
matching exercise. There is also emerging evidence that interneurone death may
play a more direct role in some neurodegenerative diseases than hitherto
considered.
PMID- 10775797
TI - On the design of neural networks in the brain by genetic evolution.
AB - Hypotheses are presented of what could be specified by genes to enable the
different functional architectures of the neural networks found in the brain to
be built during ontogenesis. It is suggested that for each class of neuron (e.g.,
hippocampal CA3 pyramidal cells) a small number of genes specify the generic
properties of that neuron class (e.g., the number of neurons in the class, and
the firing threshold), while a larger number of genes specify the properties of
the synapses onto that class of neuron from each of the other classes that makes
synapses with it. These properties include not only which other neuron classes
the synapses come from, but whether they are excitatory or inhibitory, the nature
of the learning rule implemented at the synapse, and the initial strength of such
synapses. In a demonstration of the feasibility of the hypotheses to specify the
architecture of different types of neuronal network, a genetic algorithm is used
to allow the evolution of genotypes which are capable of specifying neural
networks that can learn to solve particular computational tasks, including
pattern association, autoassociation, and competitive learning. This overall
approach allows such hypotheses to be further tested, improved, and extended with
the help of neuronal network simulations with genetically specified architectures
in order to develop further our understanding of how the architecture and
operation of different parts of brains are specified by genes, and how different
parts of our brains have evolved to perform particular functions.
PMID- 10775798
TI - The evolution of temporal processing in the medial superior olive, an auditory
brainstem structure.
AB - A basic concept in neuroscience is to correlate specific functions with specific
neuronal structures. By discussing a specific example, an alternative concept is
proposed: structures may be linked to rules of processing and these rules may
serve different functions in different species or at different stages of
evolution. The medial superior olive (MSO), a mammalian auditory brainstem
structure, has been thought to solely process interaural time differences (ITD),
the main cue for localizing low frequency sounds. Recent findings, however,
indicate that this is not its only function since mammals that do not hear low
frequencies and do not use ITDs for sound localization also possess a MSO.
Recordings from the bat MSO indicate that it processes temporal cues in the milli
and submillisecond range, based on monaural or binaural inputs. In bats, and
most likely in other small mammals, this temporal processing is related to
pattern recognition and echo suppression rather than sound localization. However,
the underlying mechanism, coincidence detection of several inputs, creates an
epiphenomenal ITD sensitivity that is of no use for small mammals like bats or
ancestral mammals. Such an epiphenomenal ITD sensitivity would have been a pre
adaptation which, when mammals grew larger during evolution and when localization
of low frequency sounds became a question of survival, suddenly gained relevance.
This way the MSO became involved in a new function without changing its basic
rules of processing.
PMID- 10775799
TI - Cadherins in the central nervous system.
AB - The central nervous system (CNS) is divided into diverse embryological and
functional compartments. The early embryonic CNS consists of a series of
transverse subdivisions (neuromeres) and longitudinal domains. These embryonic
subdivisions represent histogenetic fields in which neurons are born and
aggregate in distinct cell groups (brain nuclei and layers). Different subsets of
these aggregates become selectively connected by nerve fiber tracts and, finally,
by synapses, thus forming the neural circuits of the functional systems in the
CNS. Recent work has shown that 30 or more members of the cadherin family of
morphoregulatory molecules are differentially expressed in the developing and
mature brain at almost all stages of development. In a regionally specific
fashion, most cadherins studied to date are expressed by the embryonic
subdivisions of the early embryonic brain, by developing brain nuclei, cortical
layers and regions, and by fiber tracts, neural circuits and synapses. Each
cadherin shows a unique expression pattern that is distinct from that of other
cadherins. Experimental evidence suggests that cadherins contribute to CNS
regionalization, morphogenesis and fiber tract formation, possibly by conferring
preferentially homotypic adhesiveness (or other types of interactions) between
the diverse structural elements of the CNS. Cadherin-mediated adhesive
specificity may thus provide a molecular code for early embryonic CNS
regionalization as well as for the development and maintenance of functional
structures in the CNS, from embryonic subdivisions to brain nuclei, cortical
layers and neural circuits, down to the level of individual synapses.
PMID- 10775800
TI - Identification of human estrogen-inducible transcripts that potentially mediate
the apoptotic response in breast cancer.
AB - Hormone manipulation has been used for several decades with the purpose of
inducing breast cancer regression. On the one hand, hormone ablation and
antiestrogen administration were used on the rationale that estrogens induce
proliferation of their target cells. Before the advent of the antiestrogen
tamoxifen, on the other hand, the estrogen agonist DES was used to obtain
clinical remissions. The rationale for the use of diethylstilbestrol (DES) was
totally empirical. In fact, the efficacy of both treatments was comparable. A
mechanistic explanation for estrogen-induced regression is urgently needed in
order to provide a rationale for its use in therapeutic fields, and to develop
markers to identify this phenotype in order to recognize responsive tumors. In
this report, we use E8CASS cells (a MCF7 variant) as a model to study estrogen
mediated regression. The proliferation rate of E8CASS cells is decreased by
estrogens. In order to isolate mRNA sequences induced by estradiol, a subtracted
library was prepared from E8CASS cells grown in the presence and absence of
estrogens. Twenty nine differentially expressed unique sequences were found.
Seven of them were homologous to known genes, 12 of them were homologous to
expressed sequence tags (EST), and 10 sequences had no homologues in the
databases. The two sequences showing the highest induction by estradiol (E9 and
E43) were chosen for further analysis. The sequence of the E43 coding region has
96% homology to the bovine actin2 gene and 100% identity to bovine actin2
protein, and it is homologous to the human actin-related protein 3 (Arp3). It has
been suggested that Arp3 is involved in actin nucleation. The phenotype of E8CASS
cells is clearly affected by estrogen treatment. It is likely that E43 may be
involved in these morphological changes. The E9 cDNA is a putative zinc-finger
protein of the PHD family of transcriptional transactivators. A member of this
family, Requiem, is involved in apoptosis. The E9 mRNA is highly expressed in
E8CASS cells treated with estrogens, a treatment which results in decreased
proliferation rate and increased DNA degradation. This correlation suggests that
E9 may be a mediator of estrogen-induced regression of breast cancer.
PMID- 10775801
TI - Down-regulation of AP1 activities after polarization of vas deferens epithelial
cells correlates with androgen-induced gene expression.
AB - Vas deferens epithelial cell subcultures were used to study the sequential
regulation of jun/fos proto-oncogene expression and AP1 activities during cell
proliferation, polarization and androgen-induced expression of a terminal
differentiation marker, i. e. the mvdp gene. Proliferation of epithelial cells is
associated with a high expression in the nucleus of most Jun and Fos
oncoproteins. After cell seeding on an extracellular matrix which allows
polarization and expression of the mvdp gene in response to androgens, AP1
protein accumulation is greatly altered and consists in a loss of JunB, Fra1,
FosB and a decrease in c-Fos, c-Jun and Fra2, while JunD remained at the same
level. This was correlated with a drop in AP1 binding activity as evaluated by
gel shift assay using either AP1 consensus sequence or AP1 binding sites of the
mvdp gene promoter region, and in AP1 transactivating activity, as estimated by
stable transfection experiments using an AP1 responsive promoter (TRE-TK-luc).
Androgens did not significantly influence AP1 activities. On the contrary,
stimulation of AP1 proteins by the tumor-promoting phorbol ester caused a
decrease in androgen-induced mvdp mRNA accumulation, and this effect was reversed
by staurosporine, a potent inhibitor of PKC. Our data suggest that a down
regulation of AP1 activities induced by epithelial cell differentiation is a
prerequisite to androgen-induced mvdp gene expression. The high AP1 activities
observed during proliferative state or induced in TPA-treated polarized cells,
exert a repressive effect on androgen action.
PMID- 10775803
TI - Vitamin D receptor interactions with positive and negative DNA response elements:
an interference footprint comparison.
AB - Interference footprinting protocols were utilized to examine the interactions of
the vitamin D receptor (VDR) with either a positive or a negative vitamin D
response element (VDRE). A sequence from the human osteocalcin (hOC) gene was
chosen for the prototypical positive DR+3 VDRE, while an analogous sequence
linked to the avian parathyroid hormone gene (aPTH) was used as the negative
VDRE. Both types of response elements were examined for phosphate backbone
contacts, as well as base-specific interactions with guanine and thymine
residues. Sources of VDR included partially purified canine intestinal
preparations, as well as extracts of recombinant human VDR and retinoid X
receptor alpha prepared from baculovirus-infected Sf9 insect cells. Cold
competition experiments using variable amounts of these oligonucleotides in the
mobility shift assay revealed that the hOC element was a five-fold better
competitor for heterodimer complex binding than the negative VDRE. Interference
footprints revealed extensive strong contacts to the phosphate backbone and
individual guanine and thymine nucleotides of the hOC element. The composite hOC
footprint was asymmetric for the number and strength of interactions observed
over each of the respective direct repeat half-sites. In contrast, the aPTH VDRE
footprints revealed fewer points of DNA contact that were limited to the
hexanucleotide repeat regions and were strikingly weaker in nature. The alignment
of DNA contact points for both elements produced a 5' stagger that was indicative
of successive major groove interactions, and consistent with dimer binding. DNA
helical representations indicate that the heterodimer contacts to these response
elements are substantially different and provide insight into functional aspects
of each complex.
PMID- 10775802
TI - Impaired transactivation of the glucocorticoid receptor cloned from the Guyanese
squirrel monkey.
AB - Squirrel monkeys are among a diverse group of New World primates that demonstrate
unusually high levels of circulating corticosteroids and glucocorticoid receptor
(GR) insensitivity. Recent evidence suggests that overexpression of an
immunophilin impairs dexamethasone binding to GR in the Bolivian squirrel monkey
(Saimiri boliviensis). Here we describe the cloning, expression, and functional
characterization of GR from the closely related Guyanese squirrel monkey (S.
sciureus). The cloned Guyanese squirrel monkey GR (gsmGR) cDNA closely resembles
human GR (hGR) cDNA, and yields a high affinity dexamethasone binding receptor
when expressed in COS-1 cells. Transactivation analysis of hGR and gsmGR
expressed in CV-1 cells and cultured squirrel monkey kidney (SMK) cells indicates
that: (1) SMK cells elaborate a functional high activity GR from human GR cDNA;
(2) gsmGR is an order of magnitude less efficient than hGR at transactivation in
CV-1 and SMK cells; and (3) maximal transactivation by gsmGR is attenuated in
both cell lines. Glucocorticoid resistance in S. sciureus is at least partly
attributable to a naturally occurring mutation in the GR gene that results in
impaired GR transactivation.
PMID- 10775805
TI - Catecholestrogens excretion in smoking and non-smoking postmenopausal women
receiving estrogen replacement therapy.
AB - Estrogens are involved in the etiology of breast cancer. Their blastomogenic
influence may be partly realized through their conversion into catecholestrogens,
rate of which may be modified by smoking. The risk of having breast cancer
diagnosed can increase in women using estrogen replacement therapy (ERT). The
principal aim of this investigation was to compare the excretion of classical
estrogens and catecholestrogens in smoking and non-smoking postmenopausal women
receiving Progynova (estradiol valerate, 2 mg/day, 1 month). Total 16 women were
studied before and after treatment. Urinary estrogen profile method based on
isotope dilution capillary gas chromatography-mass spectrometry was used. Before
ERT, significantly lower excretion of 16-epiestriol and 4-hydroxyestrone (4-OHE1)
and lower ratio of 4-OHE1/E1 were revealed in smokers. After ERT, much higher
excretion of 2-OHE1, and 4-hydroxyestradiol (4-OHE2), higher ratios of 2-OHE1/E1
and 4-OHE1/E1 and lower ratio of 2-methoxyestrone/2-OHE1 were discovered in
smokers as compared to non-smoking women. In conclusion only combination of ERT +
smoking and not smoking itself leads to the specific prevalence of
catecholestrogens (2-OH- and carcinogenic and DNA-damaging 4-OH-metabolites) that
may increase risk of genotoxic variant of hormone-induced breast carcinogenesis
without influence on the total morbidity.
PMID- 10775806
TI - Expression and activity of dehydroepiandrosterone sulfotransferase in human
gastric mucosa.
AB - Dehydroepiandrosterone sulfotransferase (DHEA-ST) is a key enzyme in the
formation of Dehydroepiandrosterone sulfate (DHEAS) and is thought to be involved
in the conversion of various substances such as bile acids and cholesterol. The
existence of DHEA-ST in the small intestine in addition to the adrenal gland and
liver in adult humans was recently reported. As the sulfotransferases can act on
toxic or potentially toxic substances to reduce their biological activity, we
attempted to clarify the significance of DHEA-ST in gastrointestinal tract. We
examined surgically resected human stomach for the presence of DHEA-ST and
attempted to determine its possible biological significance. DHEA-ST activity
ranged widely from 6 to 84 pmoles/mg protein/90 min in 7 cases. Immunoblotting
revealed one single band of a 35-kDa protein corresponding to the moleculr weight
of DHEA-ST. Both DHEA-ST immunoreactivity and mRNA hybridization signals were
localized in parietal cells of the gastric glands. The results of our present
study demonstrated that the sulfation of DHEA by DHEA-ST occurs in the gastric
glands. The localization of DHEA-ST in parietal cells suggests that this enzyme
is correlated to mucosal function in the human stomach in addition to
detoxification of exogenous substances.
PMID- 10775804
TI - The expression of androgen receptor messenger RNA is regulated by tri
iodothyronine in lizard testis.
AB - The network of hormonal and non-hormonal signals required for testicular activity
during the reproductive cycle of the seasonal breeding lizard, Podarcis sicula,
are not yet well understood. Androgens are significantly involved in meiosis and
spermiogenesis, and such an effect is mediated through their receptor (AR).
Estrogens also affect the testicular activity down-regulating the expression of
AR mRNA. Since over the last few years, extensive works have reported, in
mammals, a clear influence of tri-iodothyronine (T(3)), the biologically active
thyroid hormone, on Sertoli cell activities, we carried out a study to shead
light on the effect/s exerted by T(3) in lizard testis. A thyroid hormone
receptor mRNA (TR mRNA) has been found in the testis indicating that T(3) might
be involved in the regulation of gonadal activity. In in vivo experiments,
injection of T(3) to male lizards, captured during the recrudescence period
(March) and maintained under experimental photothermal conditions (24 degrees C
and 15 h daylight), increased the expression of AR mRNA. The in vitro results
confirmed the stimulatory effect of T(3) on AR mRNA levels. Thus, in testosterone
(T) exposed cells, the highest values of AR mRNA were observed in T(3)-primed
animals, indicating that T and T(3) increase AR gene transcription independently.
The present data suggest that, in lizards, the combined action of androgens,
estrogen and T(3) might regulate testicular activity, modulating AR mRNA levels.
PMID- 10775808
TI - Insulin attenuates the stimulatory effects of tumor necrosis factor alpha on
11beta-hydroxysteroid dehydrogenase 1 in human adipose stromal cells.
AB - Obesity is frequently associated with insulin-resistance and abnormal glucose
homeostasis. Recent evidence indicates that TNFalpha may play a role in mediating
the insulin-resistance of obesity through its overexpression in adipose tissue.
Previously, we have shown that human adipose stromal cells contain 11beta
hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity. The present
study was designed to examine the effects of insulin on 11beta-HSD1 expression in
human adipose stromal cells under basal and TNFalpha-stimulated conditions. The
cells were obtained from breast adipose tissue by collagenase digestion, and
grown to confluence under replicating conditions in 10% fetal bovine serum. The
cells were transferred to serum-free medium for 24 h prior to treatment with
either TNFalpha, insulin or both for a further 24 h. The level of 11beta-HSD1
reductase activity was determined by measuring the conversion of [(3)H]-cortisone
to [(3)H]-cortisol at a substrate concentration of 10 nM. Treatment with TNFalpha
at concentrations of 0.1-10 ng/ml resulted in a dose dependent increase in 11beta
HSD1 reductase activity from 1.5 to 10-fold. Insulin (0.1-100 nM) had no effect
under basal conditions, but inhibited the stimulatory effects of TNFalpha (5
ng/ml) on 11beta-HSD1 reductase activity in a dose dependent fashion (8-66%)
inhibition). Northern blot analysis revealed corresponding changes in the level
of 11beta-HSD1 mRNA, suggesting that the effects of TNFalpha and insulin on
11beta-HSD1 activity are mediated at the level of gene transcription. The
interaction between insulin and TNFalpha suggests that local and systemic factors
may act in a concerted fashion to modulate glucocorticoid activity in adipose and
other peripheral tissues.
PMID- 10775807
TI - Chronic administration of corticosterone impairs LH signal transduction and
steroidogenesis in rat Leydig cells.
AB - The mechanism involved in the inhibitory actions of chronic corticosterone
treatment on Leydig cell steroidogenesis was studied in adult Wistar rats. Rats
were treated with corticosterone-21-acetate (2 mg/100 g body weight, i.m., twice
daily) for 15 days and another set of rats was treated with corticosterone plus
ovine luteinizing hormone (oLH) (100 microg/kg body weight, s.c., daily) for 15
days. Chronic treatment with corticosterone increased serum corticosterone but
decreased serum LH, testosterone, estradiol and testicular interstitial fluid
(TIF) testosterone and estradiol concentrations. Administration of LH with
corticosterone partially prevented the decrease in serum and TIF testosterone and
estradiol. Leydig cell LH receptor number, basal and LH-stimulated cAMP
production were diminished by corticosterone treatment which remained at control
level in the corticosterone plus LH treated rats. Activities of steroidogenic
enzymes, 3beta- and 17beta-hydroxysteroid dehydrogenase (3beta-HSD and 17beta
HSD) were significantly decreased in corticosterone treated rats. LH plus
corticosterone treatment did not affect 3beta-HSD activity but decreased 17beta
HSD activity, indicating a direct inhibitory effect of excess corticosterone on
Leydig cell testosterone synthesis. The indirect effect of corticosterone, thus,
assume to be mediated through lower LH which regulates the activity of 3beta-HSD.
Basal, LH and cAMP-stimulated testosterone production by Leydig cells of
corticosterone and corticosterone plus LH treated rats were decreased compared to
control suggesting the deleterious effect of excess corticosterone on LH signal
transduction and thus steroidogenesis.
PMID- 10775810
TI - Sympathetic reinnervation of sinus node and left ventricle after heart
transplantation in humans: regional differences assessed by heart rate
variability and positron emission tomography.
AB - BACKGROUND: Orthotopic heart transplantation (HTx) results in complete cardiac
denervation. Reestablished partial sympathetic nerve function has been found in
patients some years after HTx. However, the atrial and ventricular regional
patterns of reinnervation have not been established. METHODS: Two parallel
methods were used to evaluate the regional restoration of sympathetic nerves in
the myocardium. Patients were investigated with respect to ventricular
reinnervation (VI) using positron emission tomography (PET) and the
norepinephrine analogue C-11-hydroxyephedrine (HED). Tracer uptake was quantified
using dynamic imaging protocols, yielding regional HED retention fraction. A
regional value above 7%/minute ( +/- 2.5 SD above the mean value of denervated
hearts) was considered evidence of sympathetic reinnervation. Spectral analysis
of heart rate variability (HRV) served as a quantitative marker for reinnervation
at the sinus node (SI). Spectra of HRV during positive head-up tilt were
calculated. The low frequency (LF) power spectral density (0.05 to 0.18 Hz) was
evaluated. RESULTS: After HTx (4. 6 +/- 3.9 years; range, 0.2 to 13.6 years), 38
patients (aged 50.9 +/- 7.6 years; range, 37 to 65 years) were investigated by
PET imaging and HRV. Twenty-two patients with a mean HED retention of 10. 7 +/-
2.6%/minute were classified as left ventricular reinnervated. Sixteen patients
with a mean HED retention of 4.8 +/- 0.8%/minute did not reach the threshold. The
time difference after HTx was significant for these 2 groups, 5.3 +/- 3.0 years
vs 3.8 +/- 4.7 years ( p < 0.05 ). The LF power spectral density of the
ventricular reinnervated patients was 5.9 +/- 8.6 ms(2), and 1.8 +/- 4.4 ms(2) (p
<0.005 ) for those not reinnervated. Low frequency showed small values and narrow
distribution for the patients not reinnervated, assuming sinus node denervation,
and showed extended distribution for the reinnervated, suggesting a heterogeneous
reinnervation pattern. CONCLUSIONS: Two non-invasive parallel methods were used
to investigate regional reestablishment of cardiac nerves in the myocardium in
HTx patients. Left VI assessed by PET imaging and SI by HRV was congruent in 60%
of HTx patients. Lack of SI paralleled absence of VI. Our results suggest that
partial VI occurs prior to SI.
PMID- 10775811
TI - A prospective study of plasma nitrates following human heart transplantation
relevance to myocardial function.
AB - BACKGROUND: Nitric oxide (NO) has been shown to affect myocardial function in
positive and negative inotropic ways. Expression of inducible nitric oxide
synthase and release of nitric oxide into the circulation has been associated
with acute rejection in animal studies. The role of NO and the associated
myocardial dysfunction seen during acute rejection in humans has not been
adequately defined. In a prospective sequential study, we have studied the
relationship between plasma nitrate and biopsy-proven acute rejection, and
systolic and diastolic function after heart transplantation. METHODS: Biopsies
were performed weekly and then fortnightly up to 12 weeks after transplantation
and on clinical indication of rejection in 37 patients. Plasma nitrates were
obtained on the morning of each biopsy (total 341). An echocardiogram was
performed immediately prior to each biopsy in which the systolic parameters,
ejection fraction (EF) and fractional shortening (fs), and the diastolic
parameters, isovolumetric relaxation time (IVRT), mitral valve pressure half-time
(MVPHT), mitral valve deceleration time (MVDT), e:a ratio, and a wave duration,
were measured. RESULTS: Plasma-nitrate level showed no significant correlation
with the systolic parameters, EF or fs, or with changes in EF or fs. No
significant correlation was found between plasma-nitrate level and the diastolic
parameters IVRT, MVPHT, MVDT, mitral valve a wave duration, or e:a ratio.
CONCLUSIONS: This study has shown no correlation between plasma nitrate and
impaired systolic or diastolic function after heart transplantation. Instead
there was a weak trend for elevated nitrate to be associated with better systolic
function.
PMID- 10775812
TI - Sleep apnea in heart transplant recipients: type, symptoms, risk factors, and
response to nasal continuous positive airway pressure.
AB - BACKGROUND: We determined the type, symptoms, and risk factors for sleep apnea in
heart transplant recipients and the response to nasal continuous positive airway
pressure. METHODS: A retrospective study on heart transplant recipients with
sleep apnea was conducted in a tertiary care medical center with follow-up
telephone interviews. Between February 1988 and August 1998, 147 patients
underwent orthotopic heart transplantation at our institution. Seventeen patients
(11.6%) who were suspected of having sleep apnea underwent polysomnography at a
mean interval of 17.5 months after transplantation. RESULTS: All were diagnosed
with sleep apnea: 13 had obstructive sleep apnea and 4 had mixed sleep apnea.
Mean age at polysomnography was 50.8 years (range, 24-67 years). The patients
presented with snoring (100%), excessive daytime somnolence (65%), witnessed
apneas (53%), and morning fatigue (53%). Sixteen (94%) had a mean weight gain of
10.4 kg after transplantation, and 1 patient lost 14.6 kg. In the 11 patients
with obstructive sleep apnea who underwent nasal continuous positive airway
pressure titration, significant improvements occurred in the apnea-hypopnea index
(decreased from 37.6 to 10.4; p = 0.01) and mean arousal index (decreased from
44.5 to 19.4; p = 0.01). Only 2 of the 8 patients with sleep apnea for whom nasal
continuous positive airway pressure was recommended continued to use it at the
time of telephone follow-up. CONCLUSIONS: Sleep apnea, especially obstructive
sleep apnea, occurs frequently in heart transplant recipients. Obstructive sleep
apnea appears to present in the typical manner, and although a positive response
to nasal continuous positive airway pressure can be documented by
polysomnography, long-term use of nasal continuous positive airway pressure may
be low.
PMID- 10775813
TI - Efficacy of tacrolimus in patients with steroid-resistant cardiac allograft
cellular rejection.
AB - BACKGROUND: Tacrolimus is an immunosuppressive agent that is gaining widespread
use in solid organ transplantation. This study was undertaken to evaluate the
efficacy of tacrolimus in treating steroid-resistant cellular myocardial
rejection. METHODS: We retrospectively analyzed the incidence of rejection and
clinical outcome of 21 heart transplant recipients who were electively converted
from cyclosporine to tacrolimus for recurrent episodes of steroid-resistant
cellular rejection. These were compared to a historic group of 6 hemodynamically
stable patients who were treated electively with Orthoclone OKT3 (Muromonab/CD3)
for recurrent rejection. RESULTS: Eighty five percent (56/66) of the episodes of
rejection occurred within the first 3 months after heart transplantation.
Tacrolimus was started 2. 4 +/- 2.0 months post-transplant, and the mean follow
up duration on tacrolimus was 11.0 +/- 7.0 months. After conversion, a
significant decline was noted in both the number of episodes of acute rejection
per patient (3.14 +/- 0.85-0.57 +/- 0.87, p < 0.0001), and the incidence of acute
rejection per 100 patient-days (6.39 +/- 3.96-0. 25 +/- 0.47, p < 0.0001). In
comparison, OKT3 was started 5.25 +/- 9. 20 months post-transplant. Similarly,
there was a significant decrease in the incidence of acute rejection per 100
patient-days (8. 69 +/- 5.65-0.20 +/- 0.23, p < 0.0001). The average hospital
charges per patient for the OKT3-treated group was $33,339 +/- $10,511. There was
no significant difference in the actuarial 1-year survival between the tacrolimus
and OKT3-treated groups (93% vs 80%, p = 0.5). CONCLUSIONS: Outpatient conversion
to tacrolimus is safe, well tolerated, and an effective therapeutic strategy for
the treatment of steroid-resistant cellular rejection in heart transplant
recipients. It is more cost-effective than OKT3 in the hemodynamically stable
patient and outcomes are similar.
PMID- 10775814
TI - Increased morbidity and high variability of cyclosporine levels in pediatric
heart transplant recipients.
AB - OBJECTIVES: This study analyzed the relationship of variability in routine trough
cyclosporine (CSA) levels to morbidity after pediatric cardiac transplantation.
BACKGROUND: Due to high interindividual variation between dosage and blood
concentrations, trough surveillance CSA levels are routinely performed after
cardiac transplantation to adjust dosages. In addition, trough CSA levels have
been used as a measure of patient compliance in transplant recipients. Recent
investigations have demonstrated a relationship between late rejection and
mistimed CSA dosing intervals, which could also lead to CSA levels that are
incorrectly presumed to be trough levels. METHODS: Trough surveillance whole
blood CSA levels were retrospectively reviewed in 49 pediatric heart transplant
recipients who had a median follow-up of 42 months (range 6 to 138 months). All
patients received the same immunosuppression regimen (CSA, azathioprine, and
steroids), the same CSA-level surveillance protocol, and the same stabilization
of CSA dose and level in the therapeutic range (150 to 300 ng/ml) prior to
hospital discharge. CSA levels drawn because of coexisting phenomena (drug
interaction, gastroenteritis) that could cause CSA-level fluctuation were
excluded from analysis. Cyclosporine variability was measured as the percentage
of CSA levels that were considered sub-therapeutic (< or = 100 ng/ml), toxic (>
or = 450 ng/ml), or both. Cyclosporine-level variability was then analyzed in
respect to demographic and outcome variables. RESULTS: For the group, the median
percentage of sub-therapeutic levels was 3% (range, 0% to 16%); the median
percentage of toxic levels was 5% (range, 0% to 36%); the median of the
combination of sub-therapeutic and toxic levels was 10% (0% to 38%). Eight of the
49 patients (16%) has a high (>20%) percentage of sub-therapeutic + toxic levels
or high CSA variability. High CSA variability was significantly associated with
recipients > 12 months of age (p = 0.028), and recipients with a history of non
compliance (p < 0.001). Patients with high CSA variability had a significantly
higher median number of hospitalized days per year of follow-up (p = 0.036),
higher rate of recurrent rejection (> or = 2 episodes; p = 0.0003), and higher
death rate more than 6 months after transplant (p = 0.01). CONCLUSIONS: Although
this study could not determine cause, high variability in trough CSA levels was a
marker for pediatric heart transplant recipients at greater risk for recurrent
rejection and hospitalization after transplantation.
PMID- 10775815
TI - Hepatitis C transmission and infection by orthotopic heart transplantation.
AB - BACKGROUND: The transmission and clinical consequences of hepatitis C viral (HCV)
infection acquired by orthotopic heart transplantation (OHT) from an HCV-infected
donor to an HCV-naive recipient have not been well described. We report our
experience in 5 HCV-naive patients who were transplanted with hearts from HCV
positive donors. All transplants occurred within a 1-year period. METHODS: After
cardiac transplantation we retrospectively examined the recipients' clinical
course, liver-associated enzymes, HCV-antibody serology, quantitative HCV RNA
level, and HCV genotype. RESULTS: Five subjects with rapidly deteriorating heart
failure and negative serum antibodies to HCV received an emergent OHT from a
donor known to be infected with HCV. Liver-associated enzymes peaked at 2 to 6
weeks post-transplant: mean peak alanine aminotransferase was 180 U/L (normal, 9
to 52) and aspartate aminotransferase was 111 U/L (normal, 14 to 36). Liver
enzymes had returned to normal limits by 6 and 12 months post-OHT. At a mean 15
months after transplantation, only 1 of 5 patients has developed antibodies to
HCV, but 4 of 5 have evidence of infection, as shown by serum HCV RNA. No patient
has developed evidence of liver failure. CONCLUSIONS: (1) Transmission of HCV
from an HCV-positive donor to an HCV-naive recipient at the time of OHT is
likely. (2) Antibodies to HCV post-OHT may remain negative for more than 1 year
in these patients. (3) Hepatitis C viral RNA using polymerase chain reaction
should be the test of choice for diagnosis of HCV infection post-OHT. (4)
Hepatitis C viral donor hearts should be limited to critically ill patients in
extremis until the long-term consequences of acquisition of HCV by an OHT
recipient are known.
PMID- 10775816
TI - Comparison of the efficacy and cost effectiveness of pre-emptive therapy as
directed by CMV antigenemia and prophylaxis with ganciclovir in lung transplant
recipients.
AB - BACKGROUND: CMV disease remains a major complication of lung transplantation and
attempts to prevent it have met with marginal success. In a previous study we
documented that universal prophylaxis did not prevent CMV disease but merely
delayed it, and was very costly. METHODS: We compared the efficacy and cost of
pre-emptive therapy with ganciclovir, guided by CMV antigenemia, to that of
historic controls that received universal prophylaxis with ganciclovir. CMV
antigenemia assay was done routinely and pre-emptive therapy was initiated if
greater than 25 CMV positive cells per 100,000 polymorphonuclear cells were
found. RESULTS: Nineteen patients were enrolled; 6 of of whom received 12 courses
of pre-emptive therapy. The incidence of CMV disease was 26% compared to 38% for
the historical controls (p = 0.51). None of the patients that received pre
emptive therapy developed CMV disease following that therapy. Antigenemia failed
to predict disease in 5 patients that developed it, and thus it is unknown if pre
emptive therapy could have prevented it. There was no mortality in either the
study patients or historic controls directly related to CMV. The net savings with
pre-emptive therapy was $2569 per patient. CONCLUSIONS: We conclude that pre
emptive therapy with ganciclovir is as safe and effective as universal
prophylaxis in preventing CMV disease in lung transplant recipients, and is less
expensive. The appropriate surveillance technique and timing remain to be
determine to optimize the efficacy of pre-emptive therapy.
PMID- 10775818
TI - L-arginine during long-term ischemia: effects on cardiac function, energetic
metabolism and endothelial damage.
AB - BACKGROUND: We have evaluated the addition of L-arginine, a precursor of nitric
oxide, to a cardioplegic solution (named CRMBM) designed for long-term heart
preservation. METHODS: Isolated isovolumic-perfused rat hearts (n = 22) were
arrested with the CRMBM solution either with (Arg) or without L-arginine (2
mmol/L) (Arg group, n = 12, vs control group n = 10), submitted to 8 hours of
cold storage (4 degrees C) in the solution, and then reperfused for 60 minutes at
37 degrees C. In 11 hearts, we evaluated the quality of cardiac preservation with
P-31 magnetic resonance spectroscopy and the measure of function and cellular
integrity. Endothelium-dependent and independent vasodilatations were measured in
11 other hearts, using 5-hydroxytryptamine and papaverine to assess endothelial
and smooth muscle function. RESULTS: Adding L-arginine to the cardioplegic
solution improved functional recovery during reflow, as shown by the rate
pressure product (31% +/- 3% for control vs 47% +/- 3% for Arg, p = 0.003)
together with higher coronary flow and diminished contracture. Purine release in
coronary effluents during reperfusion was lower in the Arg group. During ischemia
and reflow kinetics of intracellular pH and high-energy phosphates were similar
in both groups. Coronary endothelium-dependent vasodilatation was similarly
impaired in both groups, but smooth muscle was less altered with L-arginine.
CONCLUSIONS: As an additive to the CRMBM cardioplegic solution, L-arginine
provides a protective effect for long-term heart preservation. Our data do not
show coronary endothelial protection as the prominent mechanism.
PMID- 10775819
TI - The effect of FR167653 on pulmonary ischemia-reperfusion injury in rats.
AB - BACKGROUND: A novel synthesized organic compound, FR167653, has been
characterized as a potent suppressant of interleukin-1 and tumor necrosis factor
alpha. We designed this experimental study to evaluate the effect of FR167653 on
ischemia-reperfusion injury of the rat lung. METHODS: Following general
anesthesia, the left bronchus, pulmonary artery and vein were clamped for 1 hour.
FR167653 was administered continuously beginning 30 minutes before the onset of
ischemia and extending for 2 hours after reperfusion. Thirty-eight Wistar rats
were divided into 4 groups according to the dose of FR167653 at the rate of 0.1,
0.05 and 0.025 mg/kg/hr in each group. After the optimal dose was obtained from
the result of 1-week survival rate, the group with the optimal dose was compared
with a control group by using such parameters as arterial oxygen saturation
(SaO(2)), arterial oxygen tension (PaO(2)), cytokines, the expression of p38 MAP
kinase and histologic study. RESULTS: Survival rate of the group received FR at
the rate of 0.1 mg/kg/hr (FR0.1 group) was best among the 4 groups. SaO(2) levels
and PaO(2) levels after 2-hour of reperfusion were significantly (p < 0.05,
respectively) higher in the FR0.1 group than in the control group. After 2-hour
reperfusion, IL-1 beta was lower in the FR0.1 group than in the control group,
and the expression of p38 MAP kinase was reduced in the FR0.1 group compared with
the control group. In histologic study after 2-hour of reperfusion, alveolar
damage with edema and interstitial thickening localized along the alveolar duct
were observed in the control group, whereas these findings were remarkably less
evident in the FR0.1 group. CONCLUSIONS: We concluded that FR167653 ameliorates
ischemia-reperfusion injury of the lung and may inhibit the production of
proinflammatory cytokines by means of the inhibition of p38 MAP kinase.
PMID- 10775817
TI - Accuracy of dobutamine tetrofosmin myocardial perfusion imaging for the
noninvasive diagnosis of transplant coronary artery stenosis.
AB - BACKGROUND: Exercise stress myocardial perfusion scintigraphy has been used for
the diagnosis of transplant coronary artery stenosis (TCAS) in cardiac allograft
recipients. However, the role of pharmacologic stress myocardial perfusion
imaging has not been evaluated. Aim of the study is to assess the accuracy of
dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the
diagnosis of TCAS in heart transplant recipients. PATIENTS AND METHODS: We
studied 50 patients (age 56 +/- 8 year, 45 men) at a mean of 6.4 +/- 2.8 years
after cardiac transplant with dobutamine (up to 40 ig/kg/min) stress 99m
technetium tetrofosmin SPECT. Resting images were acquired 24 hours after the
stress study. Significant TCAS was defined as > or =50% luminal diameter stenosis
by coronary angiography. RESULTS: Significant TCAS was detected in 30 patients
(60%). Myocardial perfusion abnormalities (reversible and/or fixed defects) were
detected in 27 of the 30 patients with and in 9 of the 20 patients without
significant TCAS (sensitivity = 90%, CI 82-98, specificity = 55% CI 41-69,
positive predictive value = 75%, CI 63-87, negative predictive value = 79%, CI 67
90 and accuracy = 76%, CI 64-88). Patients with multivessel TCAS had a larger
stress perfusion defect score (5.6 +/- 3.1 vs 3.2 +/- 2.4, p < 0.05) compared to
patients with single vessel TCAS. Among patients with abnormal perfusion who had
no significant TCAS, 2 had lesions <50%, 2 had luminal irregularities and 5 had
no abnormalities at angiography. Therefore specificity was 62% (8/13) in patients
without any detectable angiographic abnormalities. CONCLUSIONS: Dobutamine stress
tetrofosmin myocardial perfusion imaging is a highly sensitive method for the
detection of TCAS in recipients of cardiac allografts. The high negative
predictive value of the test indicates that patients who demonstrate normal
perfusion by this method may be excluded from further invasive studies.
PMID- 10775820
TI - Pretreatment of brain dead rabbits with pinacidil before prolonged cold-storage
with an extracellular solution alters aortic endothelial function.
AB - OBJECTIVE: Endothelial injury occurs during heart transplantation and contributes
to the development of cardiac allograft vasculopathy. We have evaluated in a
brain death model in the rabbit whether pre-treatment with the potassium channel
opener (PCO) pinacidil before prolonged hypothermic storage with an extracellular
solution would improve vascular endothelial recovery. METHODS: Rabbits were
randomized into 4 experimental groups (n = 8 per group). In the control group
(CTRL), abdominal aortic rings were assessed immediately after 90 minutes of
anesthesia. In the brain death group (BD), aortic rings were assessed immediately
after 90 minutes of brain death. In the STH group, aortic rings taken from brain
dead rabbits were stored for 24 hours at 4 degrees C with the extracellular
preservation solution of St. Thomas Hospital (STH) before assessment. In the STH
+ PCO group, the potassium channel opener pinacidil, 1 mg/kg, was administered
intravenously to brain dead rabbits 10 minutes before explantation. Aortic rings
were then stored for 24 hours at 4 degrees C with the STH solution before
evaluation. Brain death was induced by rapid inflation of a sub-durally placed
balloon and validated by clinical and electroencephalographic data. Concentration
response curves to acetylcholine (ACH, 10(-9) to 10(-4) mol/liter) and
nitroglycerin (NGL, 10(-9) to 10(-5) mol/liter) were constructed in
phenylephrinepre-contracted rings. RESULTS: ACH evoked a similar concentration
dependent relaxation in the CTRL (E(max): 95.8 +/- 2.9%; EC(50): -6.86 +/- 0.13
log M) and BD groups (E(max): 90.8 +/- 3.8%; EC(50): -6.75 +/- 0.15 log M). The
concentration-relaxation curve was shifted rightward in the STH group (E(max):
76.7 +/- 7.1%; EC(50): -6.75 +/- 0.16 log M) in comparison with the CTRL and BD
groups, but there were no significant differences in either E(max) or EC(50)
values. After pinacidil pre-treatment, there was a further significant shift to
the right of the concentration-relaxation curve to ACH (E(max): 77.4 +/- 5.0%;
EC(50): -6.14 +/- 0.19 log M, p < 0.05 vs CTRL, BD and STH). There were no
significant differences between groups in the concentration-relaxation curves to
NGL in endothelium-intact and endothelium-denuded vascular rings (either E(max)
or EC(50)). CONCLUSION: Pre-treatment of brain dead rabbits with pinacidil before
prolonged cold-storage with STH solution significantly impaired endothelium
dependent vasorelaxation in comparison to storage with STH solution. The role of
PCO pre-treatment in the context of cardiac transplantation needs to be
reconsidered.
PMID- 10775821
TI - Skeletal muscle dysfunction in lung transplantation.
PMID- 10775823
TI - Funding adolescent medicine fellowship training
PMID- 10775822
TI - Maximizing thoracic organ transplant opportunities: the importance of efficient
coordination.
AB - BACKGROUND: In Australia, despite large distances and one of the world's lowest
multiorgan donor rates (11.4/million population/year), the thoracic organ
transplant (TOTx) rate of 9.6/million population/year is one of the world's
highest. METHODS: As an example of the Australian approach, a system of
transplant coordination and organ allocation has evolved at the Alfred Hospital.
Donor organs are assigned locally, or between the 4 major TOTx units on rotation.
The recipient team then selects appropriate recipients, matching by blood group,
size, cytomegalovirus (CMV) status, prospective cross matching and clinical
status. An experienced recipient coordinator takes responsibility for
organization of the retrieval and transplant process, including all operating
room staff, all medical personnel, and transport for the donor team and the
potential TOTx recipients. RESULTS: Between February 1989 and February 1999, 307
hearts, 48 heart/ lung, 124 single and 116 bilateral lung transplants were
performed from 452 donor offers (52% beyond 500 miles). This represents 1.74
organs transplanted/thoracic donor and compares favourably to American United
Network for Organ Sharing (1.43) and European (1.3) figures. CONCLUSIONS: The
Australia TOTx model has enabled high transplant rates by efficiently using the
available donor organs. This has been achieved through an enlarged, experience
TOTx team, the optimizing of donor acceptance criteria and improving coordination
logistics to allow multiple thoracic procedures simultaneously.
PMID- 10775824
TI - Bone mineral status in adolescent girls: effects of eating disorders and
exercise.
AB - PURPOSE: To compare whole-body, lumbar, total spine, and pelvis bone mineral
density (BMD), body mass index (BMI), body composition, energy expenditure for
physical activity, and dietary intake of adolescents, aged 16-22 years. METHODS:
Three study groups included 25 girls with histories of eating disorderd, 25 girls
with no histories of eating diso rders who exercised < or = 7 hours/week, and 15
girls with no history of eating disorders who exercised > 7 hours/week. Bone
mineral density was measured by dual-energy x-ray absorptiometry (DEXA), body
composition by bioelectric impedance and DEXA, energy expenditure by Personal
Activity Computer, nutrient intake by 4-day dietary recalls/records, and BMI by
measures of height/weight. General linear models, LSM +/- SEM, Student's t-tests,
and correlation analyses were used to determine group differences. RESULTS: No
significant differences in whole-body, spinal, and pelvis BMD were found among
the three groups. Mean body fat (percent) was significantly higher (p =.0001) for
the group with histories of eating disorders than other groups. Dietary intakes
of adolescents with histories of eating disorders were significantly lower for
energy (p =.0001), fat (p =.0001), calcium (p =.0007), vitamin D (p =.0180), and
zinc (p =.0057) than those without eating disorder histories who exercised or =20 identified individuals likely to
have an eating disorder, including anorexia nervosa and bulimia nervosa. RESULTS:
402 women completed surveys for a response rate of 47%. Based on the EAT-26
scores greater than 20, 17% of our population had scores predictive of an eating
disorder. Four test questions correlated with positive EAT-26 scores: "How many
diets have you been on in the past year?"; "Do you feel you should be dieting?";
"Do you feel dissatisfied with your body size?"; and "Does your weight affect the
way you feel about yourself?" CONCLUSIONS: These four test questions in written
format screen for disordered eating among female college students in primary care
settings.
PMID- 10775827
TI - Use of hormone replacement therapy to reduce the risk of osteopenia in adolescent
girls with anorexia nervosa.
AB - PURPOSE: To assess how commonly hormone replacement therapy (HRT) and other
measures are prescribed for the treatment of osteopenia in children and
adolescents with anorexia nervosa (AN). METHODS: A self-administered
questionnaire was distributed and completed by allopathic and osteopathic
physician members of the Society for Adolescent Medicine at its 1998 annual
meeting. The questionnaire was also mailed and E-mailed between March 1998 and
February 1999. Descriptive statistics included percentages and measures of
central tendency. RESULTS: The questionnaire was completed by 394 of the 1029
physicians surveyed (38.3%). Of the 268 respondents who treated patients with AN
under the age of 18 years, 77.6% prescribed HRT. The decision to prescribe HRT
was influenced by patient's age but not by bone mineral status. Among those who
prescribed HRT, additional therapies included increased caloric intake (89.4%),
weight gain (82.2%), increased calcium intake (84.1%), a change in exercise
patterns (59.1%), and vitamin D supplementation (37.0%). Only 59 (22.0%) did not
use HRT as a treatment modality. One-third of nonprescribers cited the lack of
evidence of efficacy of HRT in preventing osteopenia. More recent medical
graduates were less likely to prescribe HRT. CONCLUSIONS: This survey suggests
that practitioners caring for adolescent females with AN commonly prescribe HRT
for the treatment of osteopenia despite the paucity of evidence demonstrating
that it effectively prevents or reverses bone loss associated with this disorder.
PMID- 10775828
TI - Bibliography of journal articles (January to June 1998).
PMID- 10775829
TI - Eating behavior, depression, and self-esteem in high school students.
AB - OBJECTIVE: In a representative sample of 4700 Slovene high school students, we
examined their eating behavior and its correlations with some psychosocial and
psychological characteristics with the aim of identifying the main risk factors
for disordered eating. METHOD: Using a questionnaire which also included Zung's
Self-rating Depression Scale and Rosenberg's Self-Esteem Scale, we compared girls
(n = 2507) and boys (n = 2193) with regard to their satisfaction with their body
weight, weight-reducing activities, and frequency of binge eating. We assessed
their family relationships, abuse of alcohol and other psychoactive drugs,
suicidal ideation, and suicidal tendences, as well as their level of depression
and self-esteem. RESULTS: The results showed significant differences between
girls and boys, between groups of those who were satisfied and those who were
dissatisfied with their body weight, and also between groups which indulged in
frequent binge eating and those which did not. CONCLUSION: Within a general
population of adolescents, there is a substantial number of subjects with
disordered eating behavior, some part of whom are at high risk for eating
disorders.
PMID- 10775830
TI - A differential display protocol to identify differentially expressed mRNAs in
potassium-deprived cerebellar granule cells.
AB - Differential display (DD) has become a popular technique for the identification
of differentially expressed genes. Here we present a DD protocol for studying
mRNA expression changes during neuronal apoptosis. Neuronal apoptosis is
typically dependent on macromolecular synthesis, thus suggesting that regulation
of gene expression is involved in control of the activation of the cell-death
machinery. In order to identify some of the genes involved, we employed the
widely used cell culture model in which apoptosis is induced in rat cerebellar
granule cells (CGCs) using potassium deprivation. Although DD has been applied
productively in the study of various biological phenomena, the method has its
drawbacks. In particular, the cloning and verification of cDNA fragments is
frequently described as problematic or laborious, and often produces many "false
positives". Here we report the successful use of DD including an efficient
protocol for cDNA clone screening and verification. This protocol avoids some of
the problems presented by heterogeneous DD bands, which may be a major cause of
false-positive results. To identify the desired clones, we apply single-stranded
conformational polymorphism (SSCP) and slot blot techniques.
PMID- 10775831
TI - Measurement of intracellular calcium levels by the fluorescent Ca(2+) indicator
Calcium-Green.
AB - The fluorescent calcium-sensitive indicators, such as the Calcium Green-1, allow
one to detect small calcium transients at low indicator concentrations. The
protocol reported here is a rapid and sensitive method that facilitates the
measurement of intracellular free-calcium in cell suspensions. Using this assay,
we were able to detect and quantify the variations in intracellular calcium
concentration during microglial cell activation induced by the fragment peptides
beta25-35 and PrP106-126.
PMID- 10775832
TI - Improved selective, simple, and contrast staining of acidophilic neurons with
vanadium acid fuchsin.
AB - Acidophilia is one of the hallmarks of acute neuronal damage and death in brain
ischemia, excitotoxic and traumatic lesions and epileptic seizures. We here
describe a novel and simple method for visualizing acidophilic neurons on
paraffin sections, using vanadium acid fuchsin (VAF) staining and toluidine blue
or hematoxylin counterstaining. Paraffin sections of the brain fixed in ethanol
formalin-acetic acid mixture are stained in 0.1% acid fuchsin containing 0.125%
of ammonium metavanadate and 1% of glacial acetic acid, differentiated if
overstained in 0.01% of borax solution, and counterstained with 0.05-0.025% of
toluidine blue in acetate buffer (pH 3.3) or Gill's II hematoxylin. The sections
are dehydrated, cleared in xylene and mounted in Canada balsam or any synthetic
mounting media for light microscopy. VAF combined with toluidine blue or
hematoxylin results in highly selective and reproducible color contrast staining
of acidophilic neurons as well as glial nuclei and hyperchromatic neurons. As a
progressive method, acid fuchsin staining usually does not require
differentiation. The red acidophilic neurons are clearly visible on the
background of non-damaged cells, which significantly facilitates the
identification, and localization of damaged neurons, even at low magnification
under the light microscope.
PMID- 10775833
TI - Autoradiographic characterisation of beta-adrenoceptors in chick brain using
[3H]CGP 12177.
AB - An autoradiographic method for labelling beta(1)- and beta(2)-adrenoceptors using
[3H]CGP 12177 as a radioligand is described as well as the procedure for an
autoradiographic saturation kinetic study. The method afforded higher quality
autoradiographs as well as an improvement in the tissue preservation when assayed
in birds and chick embryos. The results confirmed the K(d) values previously
reported for membrane homogenate binding. The use of different radioligands to
characterise beta-adrenoceptors, the higher B(max) values found with
autoradiography than those obtained by the membrane homogenate binding method and
the typical errors in quantifying autoradiography are discussed. It is concluded
that the method described here considerably improves autoradiographic beta
adrenergic characterisation.
PMID- 10775834
TI - Gas-tissue autoradiography using [15O] molecular oxygen for visualization of
mitochondrial oxygen fixation in brain slices.
AB - We have developed a novel in vitro autoradiographic method of visualizing oxygen
fixation using [15O]O(2). Brain slices (400 microm) are preincubated in Krebs
Ringer phosphate buffer and exposed to [15O]O(2) with carrier O(2) for 10 min on
slide glass or on a Millicell-CM membrane in a chamber. After the 15O(2)
exposure, the brain slices are placed in contact with an imaging plate. The
autoradiograms are analyzed with MacBas to obtain images of the distribution of
radioactivity. The [15O]O(2) fixation was more extensive in the gray matter
(striatum, thalamus and cerebral cortex) than in the white matter. The fixation
of [15O]O(2) in brain slices decreased dose dependently with NaCN concentration.
These results indicate that [15O]O(2) is converted into [15O]H(2)O in the brain
tissue according to the activity of mitochondrial electron transfer and remains
in the tissue. This method provides information regarding the basic oxygen
consumption of brain slices of rat and mouse under conditions of sufficient O(2)
delivery, which reflects mitochondrial electron transport.
PMID- 10775835
TI - Methods to induce primary and secondary traumatic damage in organotypic
hippocampal slice cultures.
AB - Organotypic brain slice cultures have been used in a variety of studies on
neurodegenerative processes [K.M. Abdel-Hamid, M. Tymianski, Mechanisms and
effects of intracellular calcium buffering on neuronal survival in organotypic
hippocampal cultures exposed to anoxia/aglycemia or to excitotoxins, J. Neurosci.
17, 1997, pp. 3538-3553; D.W. Newell, A. Barth, V. Papermaster, A.T. Malouf,
Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and
glucose deprivation in organotypic hippocampal cultures, J. Neurosci. 15, 1995,
pp. 7702-7711; J.L. Perez Velazquez, M.V. Frantseva, P.L. Carlen, In vitro
ischemia promotes glutamate mediated free radical generation and intracellular
calcium accumulation in pyramidal neurons of cultured hippocampal slices, J.
Neurosci. 23, 1997, pp. 9085-9094; L. Stoppini, L.A. Buchs, D. Muller, A simple
method for organotypic cultures of nervous tissue, J. Neurosci. Methods 37, 1991,
pp. 173-182; R.C. Tasker, J.T. Coyle, J.J. Vornov, The regional vulnerability to
hypoglycemia induced neurotoxicity in organotypic hippocampal culture: protection
by early tetrodotoxin or delayed MK 801, J. Neurosci. 12, 1992, pp. 4298-4308.].
We describe two methods to induce traumatic cell damage in hippocampal
organotypic cultures. Primary trauma injury was achieved by rolling a stainless
steel cylinder (0.9 g) on the organotypic slices. Secondary injury was followed
after dropping a weight (0.137 g) on a localised area of the organotypic slice,
from a height of 2 mm. The time course and extent of cell death were determined
by measuring the fluorescence of the viability indicator propidium iodide (PI) at
several time points after the injury. The initial localised impact damage spread
24 and 67 h after injury, cell death being 25% and 54%, respectively, when slices
were kept at 37 degrees C. To validate these methods as models to assess
neuroprotective strategies, similar insults were applied to slices at relatively
low temperatures (30 degrees C), which is known to be neuroprotective [F.C.
Barone, G.Z. Feuerstein, R.F. White, Brain cooling during transient focal
ischaemia provides complete neuroprotection, Neurosci. Biobehav. Rev. 1, 1997,
pp. 31-44; V.M. Bruno, M.P. Goldberg, L.L. Dugan, R.G. Giffard, D.W. Choi,
Neuroprotective effect of hypothermia in cortical cultures exposed to oxygen
glucose deprivation or excitatory aminoacids, J. Neurochem. 4, 1994, pp. 387-392;
G.C. Newman, H. Qi, F.E. Hospod, K. Grundhmann, Preservation of hippocampal brain
slices with in vivo or in vitro hypothermia, Brain Res. 1, 1992, pp. 159-163;
J.Y. Yager, J. Asseline, Effect of mild hypothermia on cerebral energy metabolism
during the evolution of hypoxic ischaemic brain damage in the immature rat,
Stroke, 5, 1996, pp. 919-925.]. Low temperature incubation significantly reduced
cell death, now being 9% at 24 h and 14% at 67 h. Our results show that these
models of moderate mechanical trauma using organotypic slice cultures can be used
to study neurodegeneration and neuroprotective strategies.
PMID- 10775836
TI - Expression analysis of Escherichia coli lacZ reporter gene in transgenic mice.
AB - To define a gene expression mechanism, it is often advantageous to use a reporter
gene and transgenic mouse. The lacZ reporter gene is particularly useful for
studies of the cis-regulatory element for tissue-specific expression in
transgenic mice because of the ease of the enzyme assay and visualization on
sections. In this report, we describe our method for examining the cis-regulatory
element in transgenic mice, including choice of the lacZ gene, generation of
transgenic mice, and analysis of beta-galactosidase activity.
PMID- 10775837
TI - PCR amplification in bisulfite methylcytosine mapping in the GC-rich promoter
region of amyloid precursor protein gene in autopsy human brain.
AB - Alterations in DNA 5-methyldeoxycytidine pattern influence gene expression for
certain mammalian genes in development, differentiation, carcinogenesis, and
aging. Detection of DNA methylation at the promoter region, which generally
represses transcription activity, is one important element in studying changes in
molecular expression with aging and age-associated disorders. Bisulfite genomic
sequencing is a useful method for mapping methylated cytosines. However, PCR
amplification for bisulfite-treated DNA does not yield a sufficient amount of
products that have a sufficient level of specificity, especially in the GC-rich
sequences usually seen at the promoter regions of house keeping genes. We present
a method for increasing the sensitivity and specificity of PCR amplification in
bisulfite methylcytosine mapping in an extremely GC-rich promoter region of
amyloid precursor protein (APP) gene from the cerebral cortex of human autopsy
brain. The PCR used consists of two cycles using the lower primer alone to
amplify the sense sequence, and then eight cycles at a theoretical annealing
temperature (60 degrees C) and 30 cycles at a lower annealing temperature (50
degrees C) using both the upper and lower primers. The present method likely can
also be applied to other GC-rich genomic sequences.
PMID- 10775838
TI - An in vitro model for the study of taste papillae morphogenesis using branchial
arch explants.
AB - It is generally accepted that innervation is required for the maintenance of
taste papillae and taste buds, but it is not entirely clear what role, if any,
innervation plays in papillae and taste bud formation. Events in taste papillae
formation and differentiation take place almost entirely in utero and, therefore,
the study of the role of innervation in these events requires a suitable in vitro
model. In the past, investigators have made use of various culture techniques to
study mammalian taste papillae development in vitro and the role of innervation
in this process with varying success. All of these models examined papillae
development in isolated tongue or tongue fragments and have lacked the ability to
manipulate the innervation of developing taste papillae in these explants. We
have established a protocol for an in vitro model of taste papillae morphogenesis
using branchial arch explants and roller tube culture methodology. Our results
demonstrate that this model supports the morphogenesis of the circumvallate
papilla with an integrated nerve. In addition, the use of branchial arch explants
allows the inclusion or exclusion of geniculate and petrosal ganglia to examine
directly the effects of the presence or absence of innervation on papillae
formation and maintenance.
PMID- 10775839
TI - A simple method using 31P-NMR spectroscopy for the study of protein
phosphorylation.
AB - Nonradioactive 31P-NMR spectroscopy has previously been used for the study of
protein phosphorylations. However, the procedures does not seem to be easy for
non-experts of this field, hence, this approach has not been widely used. We
introduce here a simple protocol with 31P-NMR spectroscopy to study in vitro
phosphorylation in receptor proteins. The effectiveness of this method was
verified using synthetic peptides and recombinant proteins of the C-terminus of
the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor, whose
phosphorylations are considered to have important roles in synaptic plasticity.
We show that a decrease in the pH of the sample solution after the
phosphorylation reaction is critical for the separation of the phosphorylation
signals. In the analysis of the C-terminal portion of the GluR2 AMPA receptor,
the phosphorylation sites of which had not hitherto been well clarified, we found
the presence of at least three protein kinase C (PKC) phosphorylation sites.
Furthermore, this method allows prediction of the origins of each of the
phosphorylation peaks. Thus, the techniques we described here is useful for
examination of protein phosphorylation and permits us to safely conduct
repetitive experiments.
PMID- 10775840
TI - A sensitive quantification method for evaluating the level of hepatocyte growth
factor and c-met/HGF receptor mRNAs in the nervous system using competitive RT
PCR.
AB - Conventional RNA quantification methods such as Northern blots or RNase
protection assays are often not sufficiently sensitive to measure mRNA levels in
a small neuronal region. The reverse transcription-polymerase chain reaction (RT
PCR) is a sensitive alternative that can be used to determine the relative amount
of mRNAs in tissues or cells. However, this method does not directly yield the
absolute value of mRNA abundance because of the exponential nature of PCR. Using
synthetic RNA competitors, we developed a competitive RT-PCR to evaluate the
absolute amount of hepatocyte growth factor (HGF) and c-met/HGF receptor mRNAs in
neural tissues. Here we describe the procedures we used to measure HGF and c-met
mRNA levels in the punched ventral horn of the mouse spinal cord. This protocol
provides a rapid, sensitive and accurate means of measuring mRNA levels and
allows for comparison of the expression of related genes at one time and in a
tiny piece of sample from a specific neuronal region.
PMID- 10775842
TI - The salicylate hydroxylation assay to measure hydroxyl free radicals induced by
local application of glutamate in vivo or induced by the Fenton reaction in
vitro.
AB - The direct measurement of hydroxyl radicals in vivo is extremely difficult.
Therefore, the indirect determination of hydroxyl radicals using salicylate (2
hydroxybenzoate) is widely accepted. Reverse microdialysis with glutamate led to
a dose-dependent production of hydroxyl free radicals indicated by the
hydroxylation adduct of salicylate, namely 2,3-dihydroxybenzoic acid. The local
stimulation of hydroxyl free radical formation seems to be suitable to
investigate a radical-scavenging property of potential neuroprotective drugs. In
vitro experiments using the Fenton reaction may be a helpful tool to assess
whether or not a substance is able to act as a radical scavenger in a cell free
environment, which is easy to handle and a simple screening method before in vivo
experiments were performed. In the present study we present an in vivo approach
using local application of glutamate into the striatum and an in vitro screening
using the Fenton reaction to induce hydroxyl radical formation. The main goal is
to reliable measure hydroxyl free radicals, which are the most reactive oxygen
radicals in biology and medicine.
PMID- 10775841
TI - Progressive calibrated pressure device to measure cutaneous blood flow changes to
external pressure strain.
AB - The present methodological paper describes a simple and useful device for local,
external pressure application. The mechanical devices, the difficulties, the time
required, the possibilities and limitations of the technique to apply a
progressive calibrated pressure and to measure cutaneous blood flow with a laser
Doppler probe at the same site are discussed. This technique was used to study
the effects of local pressure on the cutaneous blood flow with laser Doppler
technique. Use of this protocol has provided evidence for a transient cutaneous
vasodilation in the human hand during progressive externally applied pressure
strain. Results from our laboratory thus far suggest that this vasodilator
response is mediated by small sensory nerve fibres in the skin.
PMID- 10775843
TI - Application of real-time polymerase chain reaction for the quantitation of
interleukin-1beta mRNA upregulation in brain ischemic tolerance.
AB - Differential gene expression plays an important role in normal development and
pathophysiological conditions. The accurate quantitation of mRNA expression is
critical to assess the differential gene expression. While a number of
techniques, such as Northern analysis, (semi-)quantitative reverse transcription
polymerase chain reaction (RT-PCR) and in situ hybridization, are available to
measure the levels of mRNA expression, certain limitations exist, including the
insensitive and inaccurate quantitation of mRNA expressed at low abundance. In
the present study, we describe the application of a recently developed TaqMan
real-time quantitative RT-PCR for the detection of interleukin-1beta (IL-1beta)
mRNA expression in rat cortical tissue after a short duration of ischemia (i.e.,
ischemic preconditioning). The principle of the TaqMan real-time detection is
based on the fluorogenic 5' nuclease assay that allows simple and rapid
quantitation of a target sequence during the extension phase of PCR
amplification. Using a cloned plasmid DNA as a standard and normalizing RNA
samples with a housekeeping gene for the TaqMan real-time PCR, we detected the
significant induction in absolute copy numbers of IL-1beta mRNA in the
ipsilateral cortex after preconditioning, suggesting a potential role of this
inflammatory cytokine in ischemic brain tolerance.
PMID- 10775844
TI - Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors.
AB - Investigative interest in atypical nevi and familial melanoma has contributed to
the identification of several candidate melanoma loci within the human genome.
Molecular defects in both tumor suppressor genes and oncogenes have been
pathogenically linked to melanoma in recent studies. Of the loci currently
characterized, the major gene resides on chromosome 9p and encodes a tumor
suppressor designated p16. This gene, which is also known as CDKN2A, is either
mutated or deleted in a large majority of melanoma cell lines, as well as in many
uncultured melanoma cells and in the germline of melanoma kindreds. A novel
aspect of the p16 locus is that it encodes not just one but two separate gene
products that are transcribed in alternative reading frames. Both products
function as negative regulators of cell cycle progression. The p16 protein itself
executes its effects by competitively inhibiting cyclin-dependent kinase 4, which
is a factor necessary for cellular progression through a major regulatory
transition of the cell division cycle. Inherited and acquired deletions or point
mutations in the p16 gene increase the likelihood that potentially mutagenic DNA
damage will escape repair before cell division. Notably, the second product of
the locus, ARF (for alternative reading frame), regulates cell growth through
independent effects on the p53 pathway. Although there is little evidence that
ARF by itself is involved in the pathogenesis of melanoma, deletions at the p16
locus disable two separate pathways that control cell growth. These recent
advances open up the possibility of genetic testing for melanoma susceptibility
in the setting of familial melanoma and suggest novel therapeutic strategies for
melanoma based on gene therapy or small molecule mimicry targeted to the
correction of defects in the p16 regulatory pathway. (J Am Acad Dermatol
2000;42:705-22.) LEARNING OBJECTIVE: At the conclusion of this learning activity,
participants should be familiar with the historical aspects of melanoma genetics
and should have a greater understanding of the CDKN2A(p16)/ARF tumor suppressor
genes.
PMID- 10775845
TI - Fat redistribution in HIV disease.
AB - BACKGROUND: Abnormal distributions of body fat have been reported in association
with HIV infection, including cases of both regional loss and gain of fat.
OBJECTIVE: We describe the spectrum of abnormal fat distribution in HIV-positive
patients. METHODS: Patients were included if they demonstrated a lack of
subcutaneous fat in the cheeks in the absence of generalized wasting. Patients
were examined fully and photographed, and medical records were reviewed. RESULTS:
Fourteen patients were seen. Further abnormalities of body fat distribution were
noted in all patients. We found a consistent pattern of fat loss in the cheeks,
temples, and extremities as well as fat gain over the neck, upper back, mastoid
processes, chest, and visceral abdomen. CONCLUSION: A consistent syndrome of body
fat redistribution is seen in HIV-positive patients. A characteristic pattern of
fat loss in the cheeks may serve as a specific marker of HIV-related fat
redistribution.
PMID- 10775846
TI - Amelanotic melanoma: the great masquerader.
AB - BACKGROUND: Cutaneous melanoma is often recognized by its dark color, but some
tumors have little or no pigmentation. OBJECTIVE: We present the clinical
findings of 4 cases of primary cutaneous amelanotic melanoma in which the
clinical diagnosis was unsuspected and one case of amelanotic metastatic
melanoma. METHODS: Five cases of melanoma are reviewed. The clinical morphology
of the lesions is presented and discussed. We surveyed the literature regarding
conditions that mimic amelanotic melanoma, and we discuss the treatment and
prognosis for amelanotic melanoma. RESULTS: Amelanotic melanoma may masquerade as
a variety of other conditions leading to a delay in the diagnosis or an
inappropriate biopsy technique. The prognosis of amelanotic primary tumors is no
different from that for its pigmented counterpart. CONCLUSION: The clinician
should be familiar with the presentation of amelanotic melanoma to facilitate
prompt diagnosis.
PMID- 10775847
TI - Fine needle aspiration in the diagnosis of metastatic melanoma.
AB - BACKGROUND: Fine needle aspiration is an accurate technique to diagnose
metastatic melanoma. Few reports exist in the literature describing its
usefulness in many patients with melanoma confirmed by open biopsy. OBJECTIVE:
The purpose of this study was to determine the utility and predictive value of
fine needle aspiration in patients with malignant melanoma who presented with
lesions suspected to be metastatic. METHODS: We retrospectively reviewed 99 cases
of fine needle aspiration and the corresponding histologic findings obtained by
open biopsy in 82 patients. RESULTS: Of the 99 cases, 86 were positive for
melanoma, 12 were negative, and one was indeterminate. The positive predictive
value of fine needle aspiration was 99%. One patient had a false-positive
diagnosis. CONCLUSION: Fine needle aspiration is a rapid, accurate, and minimally
invasive procedure that is useful in the diagnosis of metastatic melanoma.
Patients with a positive aspirate of palpable regional nodes can proceed directly
to surgery, bypassing the need for an open biopsy.
PMID- 10775848
TI - The expression of p16(INK4a), the product of a tumor suppressor gene for
melanoma, is upregulated in human melanocytes by UVB irradiation.
AB - BACKGROUND: The genetic locus CDKN2A has been linked to familial melanoma, and
mutations or deletions in its coding sequence are seen in some cases of sporadic
and familial melanomas. The protein encoded by CDKN2A, p16(INK4a), functions as a
negative regulator of cell cycle progression and as a tumor suppressor, but the
regulatory mechanisms involved in controlling its expression remain poorly
defined. OBJECTIVE: This study tested the hypothesis that UVB irradiation, which
transiently inhibits the growth of human melanocytes, is one of the regulators of
p16(INK4a) expression. METHODS: Cultured human melanocytes were irradiated with
UVB over a sublethal dosage range, and p16(INK4a) protein and mRNA levels were
quantified at varying times thereafter by quantitative immunostaining and by
Western and Northern blotting. RESULTS: Levels of p16(INK4a) protein in
melanocytes increased significantly after sublethal UVB irradiation as compared
with nonirradiated cells. Northern analysis indicated that p16(INK4a) messenger
RNA coordinately increased in a dose-dependent manner more than 2-fold in
irradiated cells at the tested doses. CONCLUSION: UVB irradiation
transcriptionally activates the expression of p16(INK4a) in cultured human
melanocytes. Therefore the growth arrest that occurs with irradiation of
melanocytes could be mediated, in part, by upregulation of p16(INK4a). This
transient arrest may allow repair of UVB-induced DNA damage before cell division.
Conversely, hereditary or acquired defects in CDK4A that give rise to functional
insufficiency of p16(INK4a) could permit the premature propagation of melanocytes
harboring potentially carcinogenic DNA damage.
PMID- 10775849
TI - Summertime sun protection used by adults for their children.
AB - BACKGROUND: Because an estimated 50% to 80% of the skin's lifetime sun damage is
thought to occur in childhood and adolescence, it is during these critical
periods that intense, intermittent sun exposure causing burning increases
melanoma risk. METHODS: A 1997 telephone survey of 503 households evaluated
parental attitudes about their child having a tan, and ease of practicing sun
protection, sun protection methods used, and sunburning on 5 successive summer
weekends. RESULTS: In a random sample of 1 child from each household, 13% of
children sunburned during the past week or weekend, and 9% of their parents
experienced a sunburn during the past weekend. Children's sunburn was
significantly associated with sunburn in the adult respondent, increasing age of
the child, having fair skin, being white, and using sunscreens. Duration and peak
hours of sun exposure were associated for children and parents. Sunscreen with a
sun protection factor of at least 15 was the predominant form of sun protection
used. Sunscreen use in children was significantly associated with longer duration
of sun exposure, sunny weather conditions, younger age, fair skin, a history of
sunburns before this study, a family history of skin cancer, and a higher family
income. Feeling that a tan appeared healthy was associated with male gender of
the adult and increasing age of the child. Complimenting the child on the
appearance of a tan was associated with male gender of the adult, older children,
children with skin type reported as olive or dark, and lower educational levels.
CONCLUSION: Although there has been a promising initial effort to alert parents
to the need to protect their children from sunburns, many view a tan as healthy
and do not effectively implement sun protection behaviors for their children,
which results in sunburns. Sun protection that prevents sunburning could be
achieved by more children seeking shade, wearing protective clothing, limiting
exposure during peak hours, and effectively using sunscreen.
PMID- 10775850
TI - Detection of artificial changes in mole size by skin self-examination.
AB - BACKGROUND: The efficacy of the skin self-examination (SSE) to detect artificial
changes in the size of nevi has not been evaluated in a controlled setting.
OBJECTIVE: Our purpose was to determine the sensitivity and specificity of the
SSE in detecting artificial changes in mole size in patients at high risk for
melanoma. METHODS: In a single-center, single-blinded cross-over study, patients
who had been performing the SSE confidently for at least 1 year examined their
backs after the diameter of an existing mole was increased artificially in random
order by 0, 2, or 4 mm. RESULTS: The specificity of the SSE was 62% (95%
confidence interval [CI], 53%-72%) (N = 103). The sensitivity of the 2 mm change
was 58% (95% CI, 49%-68%) and that of the 4 mm change was 75% (95% CI, 66%-83%).
SSE performance was not related to perceived risk, number of moles, gender, age,
or frequency of self-examination. CONCLUSION: Even in our highly motivated and
selected group of high-risk patients, 25% could not detect an obvious increase in
the diameter of an existing nevus, whereas 38% incorrectly identified a change
when none was made. The SSE is only a moderately effective tool for the detection
of acute, large, changes in mole size. The usefulness of the SSE in detection of
new lesions or changes in existing lesions is likely due to a combination of
factors or due to factors other than size, such as color, border irregularity,
and texture, among others.
PMID- 10775851
TI - Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and
the Q-switched ruby laser.
AB - BACKGROUND: Monobenzylether of hydroquinone is used worldwide to remove residual
pigment in patients with vitiligo universalis. Because of the side effects
reported with this drug, the use of monobenzylether of hydroquinone has been
restricted in The Netherlands. OBJECTIVE: Our purpose was to evaluate the long
term effectiveness and safety of a combination therapy consisting of topical 4
methoxyphenol (4-MP) cream and Q-switched ruby (QSR) laser in 16 patients with
vitiligo universalis. METHODS: In a retrospective study, patient record forms
were evaluated. Data were collected regarding history as well as physical and
histologic examination. The patients came to the institute for a follow-up visit
after a treatment-free period of 2 to 36 months. RESULTS: Thirteen patients
received both therapies. Three patients only used the cream. None of the areas
was treated by the cream and QSR laser at the same time. In 11 of the 16 patients
(69%; 95% confidence interval [CI], 41%-89%) total depigmentation was achieved
using the 4-MP cream. Onset of depigmentation was between 4 and 12 months. Four
of the 5 patients who did not respond to the 4-MP cream had successful
depigmentation with the QSR laser. Mild burning or itching was reported with the
cream in 4 cases (25%). Of the 11 patients who responded to the 4-MP cream, 4 had
recurrence of pigmentation (relapse rate of 36%; 95% CI, 11%-69%) after a
treatment-free period of 2 to 36 months. In 9 of the 13 patients (69%; 95% CI,
39%-91%) total depigmentation was achieved after QSR laser therapy. Onset of
depigmentation was between 7 and 14 days after the treatment. Three of the 4
unresponsive patients showed total depigmentation after application of the 4-MP
cream. No side effects were observed. Of the 9 patients who responded to QSR
laser therapy, 4 had recurrence of pigmentation (relapse rate of 44%; 95% CI, 14%
79%) after a treatment-free period of 2 to 18 months. These patients had a
negative Koebner phenomenon. CONCLUSION: Depigmentation therapy using a 4-MP
cream and/or QSR laser therapy is an effective and safe method to remove
disfiguring residual pigment in patients with vitiligo universalis. Patients
should be warned that repigmentation may occur, even after total depigmentation
has been achieved.
PMID- 10775852
TI - Teledermatoscopy in Switzerland: a preliminary evaluation.
AB - BACKGROUND: Since devices for digital epiluminescence microscopy and for
telemedicine have become affordable, a critical evaluation of this new method has
been needed. OBJECTIVE: Our aim was a critical evaluation of teledermatoscopy
under routine conditions in private practice. METHODS: Pigmented skin lesions
(PSLs) scheduled for excision were documented with a digital epiluminescence
microscopy (DELM) system. Images were sent to the PSL consultation at the
Department of Dermatology of the University Hospital Geneva, where a diagnosis
was established. The histopathologic report including the initial diagnosis was
sent afterward. Both approaches were compared concerning diagnostic accuracy.
RESULTS: Over a period of 6 months, 55 lesions on 51 patients have been included
in this study. Picture quality was good or very good in more than 90%. Diagnostic
accuracy of the teledermatoscopy approach was superior to that of the
conventional approach for malignant melanocytic lesions. CONCLUSION: We have
shown the feasibility of a teledermatoscopic consultation. The gain of diagnostic
accuracy in this teledermatoscopic approach, especially for malignant melanocytic
lesions, suggests that patients might benefit directly from such a consultation
at distance.
PMID- 10775853
TI - Assessment of the accuracy of low-cost store-and-forward teledermatology
consultation.
AB - BACKGROUND: Telemedicine has the potential to revolutionize the delivery of
dermatologic care to underserved areas. OBJECTIVE: Our purpose was to compare
diagnoses from two types of dermatology consultations: telemedicine using store
and-forward (SAF) technology, and traditional face-to-face (FTF) office visits.
METHODS: Skin conditions were imaged with a consumer-grade digital camera. A
standardized template was used to collect historical data. Information was stored
in a secured database for access by 2 or 3 board-certified dermatologists.
Results from the FTF visit were used to assess the accuracy of the SAF diagnoses.
RESULTS: A total of 106 dermatologic conditions in 92 patients were included.
Concordance between FTF and SAF diagnoses was high, ranging from 81% to 89% for
all 3 dermatologists. Clinically relevant disagreement occurred in only 4% to 8%
of cases. Remaining disagreements did not affect patient care. Diagnostic
confidence and image quality affected agreement. When cases of high confidence
were analyzed separately, agreement increased to 88% to 100%. This increase was
substantiated by means of a chi-square test between the high confidence and low
confidence groups, which demonstrated statistical significance (P <. 005) for all
dermatologists. Similarly, when cases of above average image quality were
considered, agreement increased to 84% to 98%. Again this difference was
substantiated by means of a chi-square test between adequate and poor images,
with statistical significance for two dermatologists (P <.001). Accuracy was
comparable between disease types with the exception of benign neoplasms, which
demonstrated agreement of 22% to 46%. CONCLUSION: These data support the use of
existing digital technology to construct an accurate SAF teledermatology system.
The inexpensive camera and widely available computer equipment make this an
extremely affordable system. Furthermore, participating dermatologists appear
well aware of system limitations, as reflected in the increased agreement for
high confidence cases. Additional investigation of the accuracy of
teledermatology for benign neoplasms is warranted.
PMID- 10775854
TI - Accessibility and reliability of cutaneous laser surgery information on the World
Wide Web.
AB - The World Wide Web has provided the public with easy and affordable access to a
vast range of information. However, claims may be unsubstantiated and misleading.
The purpose of this study was to use cutaneous laser surgery as a model to assess
the availability and reliability of Web sites and to evaluate this resource for
the quality of patient and provider education. Three commercial methods of
searching the Internet were used, identifying nearly 500,000 possible sites. The
first 100 sites listed by each search engine (a total of 300 sites) were
compared. Of these, 126 were listed repeatedly within a given retrieval method,
whereas only 3 sites were identified by all 3 search engines. After elimination
of duplicates, 40 sites were evaluated for content and currency of information.
The most common features included postoperative care suggestions, options for
pain management or anesthesia, a description of the way in which lasers work, and
the types of lasers used for different procedures. Potential contraindications to
laser procedures were described on fewer than 30% of the sites reviewed. None of
the sites contained substantiation of claims or referrals to peer-reviewed
publications or research. Because of duplication and the prioritization systems
of search engines, the ease of finding sites did not correlate with the quality
of the site's content. Our findings show that advertisements for services exceed
useful information.
PMID- 10775855
TI - Quantitative nailfold capillary microscopy findings in patients with acrocyanosis
compared with patients having systemic sclerosis and control subjects.
AB - BACKGROUND: The morphologic capillary microscopy (capillaroscopy) pattern of
acrocyanosis is characterized by hemorrhages, pericapillary edema, and widened
capillaries. These findings can result in a difficult differential diagnosis with
systemic sclerosis (SSc). OBJECTIVE: We sought to quantify the characteristics of
the capillaroscopy pattern that distinguishes patients with acrocyanosis from
patients with SSc and control subjects. METHODS: A videomicroscope with
fiberoptic illumination and personal computer-based image processing was used to
measure capillary density, giant capillaries, loop width, and arterial and venous
limbs in 10 patients with acrocyanosis, 10 patients with SSc, and 10 healthy
control subjects. RESULTS: Acrocyanotic patients differed in every quantitative
parameter both from control subjects and patients with SSc. In particular,
capillary density, which was reduced compared with that of control subjects, was
much higher than that of patients with SSc: one giant capillary per finger was
observed in 2 patients with acrocyanosis, whereas more than 2 giant capillaries
per finger were observed in each patient with SSc. CONCLUSION: These differences
may aid in making the distinction between the capillaroscopy patterns in
acrocyanosis and SSc.
PMID- 10775856
TI - Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic
correlation.
AB - BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease
that tends to affect certain ethnic groups. It is characterized by recurrent,
self-limited attacks of peritonitis, pleuritis, and synovitis. Erysipelas-like
erythema (ELE) is the pathognomonic skin manifestation. Lesions are characterized
by tender erythematous plaques, usually located on the lower legs. They may be
triggered by physical effort and subside spontaneously within 48 to 72 hours of
bed rest. Fever and leukocytosis may accompany this condition. OBJECTIVE: The
purpose of this study was to describe the histology and the immunofluorescence
findings in ELE and to discuss these observations in relation to the clinical
findings in FMF. METHODS: We studied 7 patients with FMF in whom ELE developed.
In all patients a biopsy was performed within 18 hours from onset of the lesion.
In addition to routine hematoxylin and eosin stains, immunohistochemistry to
evaluate the infiltrate and direct immunofluorescence were performed. Patients
were followed up for their ELE lesions. RESULTS: Histologic examination revealed
edema of the superficial dermis and sparse perivascular infiltrate composed of a
few lymphocytes, neutrophils, and nuclear dust. Vasculitis was not observed.
Direct immunofluorescence showed, in all cases, deposits of C3 in the wall of the
small vessels of the superficial vascular plexus. In some cases fibrinogen and
IgM were also observed. CONCLUSION: These findings are in accordance both with
those found previously in the erysipelas-like phenomenon and those in the
peritoneum of patients with FMF. The sparse infiltrate and the deposition of C3
also are compatible with the clinical picture of self-resolving lesions of short
duration. It also suggests that erysipelas-like erythema belongs to the spectrum
of neutrophilic dermatoses and supports a pathogenesis that involves abnormal
inhibition of the inflammatory cascade.
PMID- 10775857
TI - Clearance is not a realistic expectation of psoriasis treatment.
AB - BACKGROUND: Psoriasis is a disease with many manifestations for which numerous
treatments are available. OBJECTIVE: The purpose of this article is to assess
whether complete clearance is a realistic expectation given the currently
available treatments for psoriasis. METHODS: Clinical trials of the treatment of
psoriasis were identified from the medical literature, and the reported rates of
clearance were compared. RESULTS: The percentage of patients who experienced
complete clearing of their psoriasis varied with the different monotherapy
treatments from 2% with tazarotene gel to a maximum of 86% with narrow-band UVB.
Combinations of systemic retinoids (etretinate, acitretin) and photochemotherapy
(PUVA) attained the maximum reported clearance rate as combination therapy.
CONCLUSION: The new treatments available for psoriasis give physicians new
opportunity to control the severity of psoriasis. Despite the availability of
novel treatments for psoriasis, complete clearing of psoriasis is obviously not a
realistic expectation of topical treatment. Phototherapy and systemic therapy
provide greater improvement, but studies rarely report complete clearing of the
disease as an endpoint. At this time, optimal therapy consists of using
combinations of different treatments to obtain short-term improvement and long
term control of the disease.
PMID- 10775858
TI - Squaric acid immunotherapy for warts in children.
AB - BACKGROUND: Warts are a common pediatric skin infection caused by human
papillomavirus (HPV). Spontaneous clearance of warts involves anti-HPV immunity,
which may be enhanced by contact sensitizers. Squaric acid dibutylester (SADBE)
is a nonmutagenic sensitizing agent useful for immunotherapy of alopecia areata.
OBJECTIVE: We hypothesized that SADBE home application might be effective therapy
for warts. METHODS: An open-label, retrospective study of 61 children with warts
was performed. Sensitization with 2% SADBE on the forearm was followed with home
application of 0.2% SADBE to warts 3 to 7 nights per week for at least 3 months.
RESULTS: Complete clearing occurred in 34 patients (58%), with a mean duration of
therapy of 7 weeks. Partial clearing occurred in 11 (18%), and no response in 14
(24%). Clearance correlated with plantar distribution, wart duration under 2
years (P <.05), and first-line therapy with SADBE. Mild side effects occurred in
one third of patients, were limited most commonly to mild erythema at the site of
sensitization, and necessitated discontinuation of therapy in only 2 patients.
CONCLUSION: SADBE topical immunotherapy is a safe, effective option for home
therapy of warts in children.
PMID- 10775859
TI - Treatment of capillary hemangiomas of early childhood with a new method of
cryosurgery.
AB - BACKGROUND: Capillary hemangiomas in young children are difficult to treat. They
are a recognized proliferation of benign vascular cells and may be disfiguring
because of their predilection for the head and neck. OBJECTIVE: In contrast to an
earlier "wait and see" approach to treating capillary hemangiomas in young
children, we sought to determine whether these vascular lesions would respond to
a new method of cryosurgery. METHODS: In this trial 19 young patients with 24
hemangiomas were treated with contact cryosurgery at a constant applicator tip
temperature of only -32 degrees C. RESULTS: Our study demonstrates that this
method, used early in the treatment of capillary hemangiomas, in particular
capillary and mixed capillary-cavernous hemangiomas, will yield excellent to good
response in terms of complete remission and regression without leaving side
effects such as scarring or hypopigmentation. CONCLUSION: Results of our study
suggest that capillary hemangioma has an excellent response to even mild
cryosurgery.
PMID- 10775860
TI - Unplanned incomplete Mohs micrographic surgery.
AB - BACKGROUND: Incomplete Mohs micrographic surgery (MMS) is the cessation of MMS
while the tumor margins are known to be still positive. OBJECTIVE: Our purpose
was to examine the factors behind unplanned incomplete MMS and to identify means
of avoiding and managing this situation when it arises. METHODS: We performed a
retrospective case review examining clinical presentations, histologic features,
and management of incomplete MMS. RESULTS: Fifteen of 10,346 procedures (0.15%)
were identified as incomplete MMS. Complete records were available in 14 cases.
The age range was 30 to 90 years; the study comprised 10 men and 4 women. The
tumors included 9 basal cell and 4 squamous cell carcinomas and 1
dermatofibrosarcoma protuberans. The sites involved were nose, medial canthus,
ear, scalp, and lower eyelid. Twelve cases dealt with unresectable disease,
whereas two patients were unable to tolerate further surgery. Of the unresectable
cases, MMS was terminated because of ongoing multifocal positive skin margins,
bony invasion, or extension of tumor to other locations. Surgical defects were
repaired, whereas residual disease was managed with a variety of methods.
CONCLUSION: Incomplete MMS is a rare problem of either unresectable disease or
inability of the patient to tolerate the procedure. Preoperative planning may
help to identify both subgroups of patients. A multispecialty approach to
managing these cases is often necessary.
PMID- 10775861
TI - Management of melanoma with a multidisciplinary melanoma clinic model.
PMID- 10775862
TI - Surgical pearl: scroll-shaped electrode for electrodesiccation of actinic
cheilitis.
PMID- 10775863
TI - Treatment with anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody
dramatically decreases the clinical activity of psoriasis lesions.
AB - We treated a 57-year-old woman for refractory inflammatory bowel disease with a
humanized anti-tumor necrosis factor alpha monoclonal antibody (Infliximab). The
patient also had a 15-year history of Crohn's disease and a 20-year history of
moderate to severe psoriasis. She received a single infusion of Infliximab (5
mg/kg). Two weeks after the infusion her psoriasis had dramatically improved in
appearance. To our knowledge, our case is the first reported instance of
successful anti-tumor necrosis factor alpha therapy in psoriasis.
PMID- 10775864
TI - Malignant melanoma arising in a seborrheic keratosis.
AB - We report a case of malignant melanoma associated with seborrheic keratosis. This
has been reported rarely in the literature, with disagreement regarding whether
it is coincidental or whether malignant transformation occurs. Because seborrheic
keratoses are common and association with malignant melanoma is very rare, we
conclude that the association is coincidental. However, because of the
association of other malignancies, a biopsy of any suspect or changing seborrheic
keratosis is essential.
PMID- 10775865
TI - Teledermatology as a new tool in sub-saharan Africa: an experience from Tanzania.
AB - Large areas of sub-Saharan Africa suffer a substantial lack of skin care. Hence
teledermatology, meaning the online visual exchange of clinical and histologic
data, could develop into a powerful medical resource. We report the first
established teledermatologic connection in this area: between the Regional
Dermatology Training Centre (RDTC) in Moshi, Northern Tanzania, and the
Department of Dermatology, University Hospital of Zurich, Switzerland. This
report illustrates local difficulties as well as the considerable potential of
teledermatology in such a setting.
PMID- 10775866
TI - Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with
mycophenolate mofetil.
AB - Mycophenolate mofetil (MMF), a widely used immunosuppressant in organ
transplantation, is a recent addition to the therapeutic armamentarium of
autoimmune and inflammatory skin disorders in dermatology. We describe 5 patients
with moderate to severe chronic plaque psoriasis and 6 patients with psoriatic
arthritis that was refractory to conventional systemic and/or topical
antipsoriatic treatment who were treated with MMF monotherapy (2 g/d) in a 10
week study. Although MMF was tolerated well in all patients, only patients with
moderate psoriasis and psoriatic arthritis improved with therapy, whereas
patients with severe psoriasis did not respond to MMF. Although MMF seems to be
effective and safe for blistering autoimmune diseases and pyoderma gangrenosum,
our data do not allow optimistic statements on the use of MMF in severe plaque
stage psoriasis. However, MMF may develop into an interesting therapeutic
alternative for patients with psoriatic arthritis.
PMID- 10775867
TI - Lack of efficacy of topical mycophenolic acid in psoriasis vulgaris.
AB - Mycophenolic acid is effective for systemic treatment of psoriasis. However,
there is no report about its topical use in this cutaneous disorder so far. We
undertook a randomized, placebo-controlled, within subject comparison of
mycophenolic acid 1% incorporated in an ointment base and the corresponding
vehicle alone (placebo) using the psoriasis plaque test in 7 patients with plaque
type psoriasis over a period of 3 weeks. Scoring of erythema and induration was
performed 3 times weekly. After 3 weeks of occlusive treatment there was a
reduction of the sum score for erythema and induration in the mycophenolic acid
treated sites of 23% and of 5.7% in the vehicle-treated sites, which was not
statistically significant. No adverse advents were noted during the time of
study. We conclude that mycophenolic acid is ineffective when applied topically
in psoriasis even under occlusion.
PMID- 10775868
TI - Antiepiligrin cicatricial pemphigoid.
AB - Cicatricial pemphigoid is a chronic subepithelial autoimmune blistering disease
of mucous membranes and skin. Recently, a subtype of cicatricial pemphigoid with
autoantibodies to epiligrin was identified. We describe a Taiwanese patient who
presented with ocular, oral, and cutaneous involvement. Direct immunofluorescence
showed IgG and C3 deposition in epidermal basement membrane; indirect
immunofluorescence showed circulating IgG autoantibodies reactive with the dermal
side of 1 mol/L sodium chloride-split skin. Immunoblotting of laminin 5 isolated
from the extracellular matrix of cultured human keratinocytes showed no specific
reactivity. In contrast, with immunoprecipitation of the conditioned culture
media from biosynthetically radiolabeled human keratinocytes, this patient's
serum clearly reacted with a series of disulfide-linked polypeptides that
correspond to laminin 5(alpha3beta3gamma2) and laminin 6(alpha3beta1gamma1). This
is the first confirmed case of a patient of Chinese ancestry with this disease
entity.
PMID- 10775869
TI - Melanoma in situ of the oral mucosa in an adolescent with dysplastic nevus
syndrome.
AB - We describe a case of melanoma in situ occurring on the oral mucosa in an
adolescent male patient who has dysplastic nevus syndrome. This association has
not been previously reported and is of interest both because of the rarity of
melanoma involving the oral mucosa, particularly in childhood, and because of the
lack of any previous reports of oral mucosal melanoma in association with the
dysplastic nevus syndrome.
PMID- 10775871
TI - Ciprofloxacin-induced bullous pemphigoid.
PMID- 10775872
TI - Orf contamination may occur during religious events.
PMID- 10775873
TI - Finasteride and the hair cycle.
PMID- 10775874
TI - Calciphylaxis and antiphospholipid antibody syndrome.
PMID- 10775875
TI - Treatment of spider veins with the 595 nm pulsed-dye laser.
PMID- 10775878
TI - Nonconventional amide bond formation catalysis: programming enzyme specificity
with substrate mimetics.
AB - This article reports on the design and characteristics of substrate mimetics in
protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide
synthesis and the general advantages of substrate mimetics over common acyl donor
components are described. The binding behavior of these artificial substrates and
the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl
transfer, protein-ligand docking, and molecular dynamics studies on the trypsin
model. The general validity of the substrate mimetic concept is illustrated by
the expansion of this strategy to trypsin-like, glutamic acid-specific, and
hydrophobic amino acid-specific proteases. Finally, opportunities for the
combination of the substrate mimetic strategy with the chemical solid-phase
peptide synthesis and the use of substrate mimetics for non-peptide organic amide
synthesis are presented.
PMID- 10775879
TI - Steps in the formation of neurites and synapses studied in cultured leech
neurons.
AB - Leech neurons in culture have provided novel insights into the steps in the
formation of neurite outgrowth patterns, target recognition and synapse
formation. Identified adult neurons from the central nervous system of the leech
can be removed individually and plated in culture under well-controlled
conditions, where they retain their characteristic physiological properties, grow
neurites and form specific chemical or electrical synapses. Different identified
neurons develop distinctive outgrowth patterns that depend on their identities
and on the molecular composition of the substrate. On native substrates, the
patterns displayed by these neurons reproduce characteristics from the adult or
the developing neurons. In addition, the substrate may induce selective directed
growth between pairs of neurons that normally make contact in the ganglion. Upon
contact, pairs of cultured leech neurons form chemical or electrical synapses, or
both types depending on the neuronal identities. Anterograde and retrograde
signals during membrane contact and synapse formation modify the distribution of
synaptic terminals, calcium currents, and responses to 5-hydroxytryptamine.
PMID- 10775880
TI - Coexistence of potentiation and fatigue in skeletal muscle.
AB - Twitch potentiation and fatigue in skeletal muscle are two conditions in which
force production is affected by the stimulation history. Twitch potentiation is
the increase in the twitch active force observed after a tetanic contraction or
during and following low-frequency stimulation. There is evidence that the
mechanism responsible for potentiation is phosphorylation of the regulatory light
chains of myosin, a Ca2+-dependent process. Fatigue is the force decrease
observed after a period of repeated muscle stimulation. Fatigue has also been
associated with a Ca2+-related mechanism: decreased peak Ca2+ concentration in
the myoplasm is observed during fatigue. This decrease is probably due to an
inhibition of Ca2+ release from the sarcoplasmic reticulum. Although potentiation
and fatigue have opposing effects on force production in skeletal muscle, these
two presumed mechanisms can coexist. When peak myoplasmic Ca2+ concentration is
depressed, but myosin light chains are relatively phosphorylated, the force
response can be attenuated, not different, or enhanced, relative to previous
values. In circumstances where there is interaction between potentiation and
fatigue, care must be taken in interpreting the contractile responses.
PMID- 10775881
TI - A micromethod for quantitation of debrisoquine and 4-hydroxydebrisoquine in urine
by liquid chromatography.
AB - We describe a new simple, selective and sensitive micromethod based on HPLC and
fluorescence detection to measure debrisoquine (D) and 4-hydroxydebrisoquine (4
OHD) in urine for the investigation of xenobiotic metabolism by debrisoquine
hydroxylase (CYP2D6). Four hundred microl of urine was required for the analysis
of D and 4-OHD. Peaks were eluted at 8.3 min (4-OHD), 14.0 min (D) and 16.6 min
for the internal standard, metoprolol (20 microg/ml). The 5-microm CN-reverse
phase column (Shimpack, 250 x 4.6 mm) was eluted with a mobile phase consisting
of 0.25 M acetate buffer, pH 5.0, and acetonitrile (9:1, v/v) at 0.7 ml/min with
detection at lambdaexcitation = 210 nm and lambdaemission = 290 nm. The method,
validated on the basis of measurements of spiked urine, presented 3 ng/ml (D) and
6 ng/ml (4-OHD) sensitivity, 390-6240 ng/ml (D) and 750-12000 ng/ml (4-OHD)
linearity, and 5.7/8.2% (D) and 5.3/8.2% (4-OHD) intra/interassay precision. The
method was validated using urine of a healthy Caucasian volunteer who received
one 10-mg tablet of Declinax(R), po, in the morning after an overnight fast.
Urine samples (diuresis of 4 or 6 h) were collected from zero to 24 h. The
urinary excretion of D and 4-OHD, Fel (0-24 h), i.e., fraction of dose
administered and excreted into urine, was 6.4% and 31.9%, respectively. The
hydroxylation capacity index reported as metabolic ratio was 0.18 (D/4-OHD) for
the person investigated and can be compared to reference limits of >12.5 for poor
metabolizers (PM) and <12.5 for extensive metabolizers (EM). In parallel, the
recovery ratio (RR), another hydroxylation capacity index, was 0.85 (4-OHD:
SigmaD + 4-OHD) versus reference limits of RR <0.12 for PM and RR >0. 12 for EM.
The healthy volunteer was considered to be an extensive metabolizer on the basis
of the debrisoquine test.
PMID- 10775882
TI - Comparison of AutoSet and polysomnography for the detection of apnea-hypopnea
events.
AB - The use of the flow vs time relationship obtained with the nasal prongs of the
AutoSettrade mark (AS) system (diagnosis mode) has been proposed to detect apneas
and hypopneas in patients with reasonable nasal patency. Our aim was to compare
the accuracy of AS to that of a computerized polysomnographic (PSG) system. The
study was conducted on 56 individuals (45 men) with clinical characteristics of
obstructive sleep apnea (OSA). Their mean (+/- SD) age was 44.6 +/- 12 years and
their body mass index was 31.3 +/- 7 kg/m2. Data were submitted to parametric
analysis to determine the agreement between methods and the intraclass
correlation coefficient was calculated. The Student t-test and Bland and Altman
plots were also used. Twelve patients had an apnea-hypopnea index (AHI) <10 in
bed and 20 had values >40. The mean (+/- SD) AHI PSG index of 37.6 (28.8) was
significantly lower (P = 0.0003) than AHI AS (41.8 (25. 3)), but there was a high
intraclass correlation coefficient (0.93), with 0.016 variance. For a threshold
of AHI of 20, AS showed 73.0% accuracy, 97% sensitivity and 60% specificity, with
positive and negative predictive values of 78% and 93%, respectively.
Sensitivity, specificity and negative predictive values increased in parallel to
the increase in AHI threshold for detecting OSA. However, when the differences of
AHI PSG-AS were plotted against their means, the limits of agreement between the
methods (95% of the differences) were +13 and -22, showing the discrepancy
between the AHI values obtained with PSG and AS. Finally, cubic regression
analysis was used to better predict the result of AHI PSG as a function of the
method proposed, i.e., AHI AS. We conclude that, despite these differences, AHI
measured by AutoSettrade mark can be useful for the assessment of patients with
high pre-test clinical probability of OSA, for whom standard PSG is not possible
as an initial step in diagnosis.
PMID- 10775883
TI - Induction of Fos protein immunoreactivity by spinal cord contusion.
AB - The objective of the present study was to identify neurons in the central nervous
system that respond to spinal contusion injury in the rat by monitoring the
expression of the nuclear protein encoded by the c-fos gene, an activity
dependent gene, in spinal cord and brainstem regions. Rats were anesthetized with
urethane and the injury was produced by dropping a 5-g weight from 20.0 cm onto
the exposed dura at the T10-L1 vertebral level (contusion group). The spinal cord
was exposed but not lesioned in anesthetized control animals (laminectomy group);
intact animals were also subjected to anesthesia (intact control). Behavioral
alterations were analyzed by Tarlov/Bohlman scores, 2 h after the procedures and
the animals were then perfused for immunocytochemistry. The patterns of Fos-like
immunoreactivity (FLI) which were site-specific, reproducible and correlated with
spinal laminae that respond predominantly to noxious stimulation or injury:
laminae I-II (outer substantia gelatinosa) and X and the nucleus of the
intermediolateral cell column. At the brain stem level FLI was detected in the
reticular formation, area postrema and solitary tract nucleus of lesioned
animals. No Fos staining was detected by immunocytochemistry in the intact
control group. However, detection of FLI in the group submitted to anesthesia and
surgical procedures, although less intense than in the lesion group, indicated
that microtraumas may occur which are not detected by the Tarlov/Bohlman scores.
There is both a local and remote effect of a distal contusion on the spinal cord
of rats, implicating sensory neurons and centers related to autonomic control in
the reaction to this kind of injury.
PMID- 10775884
TI - Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's
disease in a Southern Brazilian population.
AB - Apolipoprotein E (protein: apo E; gene: APOE) plays an important role in the
multifactorial etiology of both Alzheimer's disease (AD) and lipid level
concentrations. The polymerase chain reaction (PCR) was used to investigate the
APOE gene polymorphism in 446 unrelated Caucasians, among them 23 AD patients,
and 100 Afro-Brazilians living in Porto Alegre, Brazil. The frequencies of the
APOE*2, APOE*3 and APOE*4 alleles were 0.075, 0.810 and 0.115 in Caucasians and
0.075, 0.700 and 0.225 in Afro-Brazilians, respectively (chi2 = 8.72, P = 0.013).
A highly significant association was observed between the APOE*4 allele and AD in
this population-based sample. The APOE*4 frequency in AD patients (39%) was about
four times higher than in the general Caucasian population (11.5%). The influence
of each of the three common APOE alleles on lipid traits was evaluated by the use
of the average excess statistic. The E*2 allele is associated with lower levels
of triglycerides and of total and non-HDL cholesterol in both men and women.
Conversely, the E*4 allele is associated with higher levels of these traits in
women only. The effect of APOE alleles was of greater magnitude in women.
PMID- 10775885
TI - Relation of the disaccharidases in the small intestine of the rat to the degree
of experimentally induced iron-deficiency anemia.
AB - Hypolactasia associated with severe iron-deficiency anemia has been reported in
several studies. The objective of the present study was to determine whether
hypolactasia is associated with the degree and duration of iron-deficiency
anemia. Newly weaned male Wistar rats were divided into a control group receiving
a diet supplemented with iron (C) and an experimental group (E) receiving a diet
not supplemented with iron (iron-deficiency diet). The animals were studied on
the 3rd, 5th, 7th, 14th, 21st, 28th and 35th days of the experiment, when overall
and iron nutritional status and disaccharidase activity in the small intestine
were determined by the Dahlqvist method. A reduction in weight occurred in the
anemic animals starting on the 5th day of the study. Anemia was present in the
experimental animals, with a progressive worsening up to the 14th day
(hemoglobin: C = 13.27 and E = 5.37) and stabilizing thereafter. Saccharase and
maltase activities did not differ significantly between groups, whereas lactase
showed a significant reduction in total (TA) and specific activity (SA) in the
anemic animals starting on the 21st day of the study. Median lactase TA for the C
and E groups was 2.27 and 1.25 U on the 21st day, 2.87 and 1. 88 U on the 28th
day, and 4.20 and 1.59 U on the 35th day, respectively. Median lactase SA was
0.31 and 0.20 U/g wet weight on the 21st day, 0.39 and 0.24 U/g wet weight on the
28th day, and 0.42 and 0.23 U/g wet weight on the 35th day, respectively. These
findings suggest a relationship between the enzymatic alterations observed and
both the degree and duration of the anemic process. Analysis of other studies on
intestinal disaccharidases in anemia suggests that the mechanism of these changes
may be functional, i.e., that the enterocytes may suffer a reduction in their
ability to synthesize these enzymes.
PMID- 10775886
TI - Upper esophageal sphincter pressure in patients with Chagas' disease and primary
achalasia.
AB - The most important component of the upper esophageal sphincter (UES) is the
cricopharyngeal muscle. During the measurement of sphincter pressure the catheter
passed through the sphincter affects the pressure value. In Chagas' disease and
primary achalasia there is an esophageal myenteric plexus denervation which may
affect UES pressure. We measured the UES pressure of 115 patients with Chagas'
disease, 28 patients with primary achalasia and 40 healthy volunteers. We used a
round manometric catheter with continuous perfusion and the rapid pull-through
method, performed in triplicate during apnea. Pressures were measured in four
directions, and the direction with the highest pressure (anterior/posterior) and
the average of the four directions were measured. The highest UES pressure in
Chagas' disease patients without abnormalities upon radiologic esophageal
examination (N = 63) was higher than in normal volunteers (142.8 +/- 47.4 mmHg vs
113.0 +/- 46.0 mmHg, mean +/- SD, P<0.05). There was no difference in UES
pressure between patients with primary achalasia and patients with Chagas'
disease and similar esophageal involvement and normal volunteers (P>0.05). There
was no difference between patients with or without esophageal dilation. In the
group of subjects less than 50 years of age the UES pressure of primary achalasia
(N = 21) was lower than that of Chagas' disease patients with normal radiologic
esophageal examination (N = 41), measured at the site with the highest pressure
(109.3 +/- 31.5 mmHg vs 149.6 +/- 45.3 mmHg, P<0.01) and as the average of the
four directions (64.2 +/- 17.1 mmHg vs 83.5 +/- 28.6 mmHg, P<0.05). We conclude
that there is no difference in UES pressure between patients with Chagas'
disease, primary achalasia and normal volunteers, except for patients with minor
involvement by Chagas' disease, for whom the UES pressure at the site with the
highest pressure was higher than the pressure of normal volunteers and patients
with primary achalasia.
PMID- 10775887
TI - Long-term outcome of 25 children and adolescents with severe aplastic anemia
treated with antithymocyte globulin.
AB - Severe aplastic anemia (SAA) is probably an immune-mediated disorder, and
immunosuppressive therapy is recommended for patients with no available donor for
bone marrow transplant. Between October 1984 and November 1987, 25 consecutive
children and adolescents with SAA with no HLA-compatible marrow donor received
equine antithymocyte globulin (ATG) (15 mg kg-1 day-1) for 10 days. The patients
were evaluated 6 weeks, 6 months, and 12 months after starting ATG treatment.
Thereafter, patients were evaluated yearly until July 1998. Median age was 10
years (range, 1.5-20 years), granulocyte counts on referral ranged from 0.032 to
1.4 x 10(9)/l (median 0.256 x 10(9)/l), and 12 patients had granulocyte counts
<0.2 x 10(9)/l. At a median follow-up of 9.6 years (range, 8.6-11.8 years), 10
patients (40%) remained alive with good marrow function. No morphologic evidence
of hematological clonal disorders has been observed, although two patients
probably have acquired clonal chromosomal abnormalities (trisomy 8 and del(6)q21,
respectively). Responses to ATG were observed between 6 weeks and 6 months from
the start of treatment in 60% of evaluable patients. The response rate was not
different in patients whose granulocyte count at diagnosis was <0.2 x 10(9)/l, or
in those who were <10 years of age. This study supports the view that, when
compared with supportive measures, ATG is an effective treatment for children or
adolescents with SAA. Although these results are inferior to those reported for
marrow transplantation or more intensive immunosuppressive regimens, these
patients who responded to ATG are long-term survivors with stable peripheral
blood counts and a low rate of relapse.
PMID- 10775888
TI - Differential regulation of vitamin D receptor expression in distinct leukemic
cell lines upon phorbol ester-induced growth arrest.
AB - A close correlation between vitamin D receptor (VDR) abundance and cell
proliferation rate has been shown in NIH-3T3 fibroblasts, MCF-7 breast cancer and
in HL-60 myeloblastic cells. We have now determined if this association occurs in
other leukemic cell lines, U937 and K562, and if VDR content is related to c-myc
expression, which is also linked to cell growth state. Upon phorbol myristate
acetate (PMA) treatment, cells from the three lineages (HL-60, U937 and K562)
differentiated and expressed specific surface antigens. All cell lines analyzed
were growth inhibited by PMA and the doubling time was increased, mainly due to
an increased fraction of cells in the G0/G1 phase, as determined by flow
cytometry measurements of incorporated bromodeoxyuridine and cell DNA content. C
myc mRNA expression was down-regulated and closely correlated to cell growth
arrest. However, VDR expression in leukemic cell lines, as determined by
immunofluorescence and Northern blot assays, was not consistently changed upon
inhibition of cell proliferation since VDR levels were down-regulated only in HL
60 cells. Our data suggest that VDR expression cannot be explained simply as a
reflection of the leukemic cell growth state.
PMID- 10775889
TI - Expression of anti-Z-DNA single chain antibody variable fragment on the
filamentous phage surface.
AB - We describe the expression of an anti-Z-DNA single chain variable region antibody
fragment (scFv) on a filamentous phage surface. Four vectors for phage display
were constructed. Two of them are able to display multiple copies of the antibody
fragment, and the others can be used to make monovalent libraries. The vectors
use different promoter/leader sequences to direct the expression of the fused
proteins. All were able to promote the assembly of fusion virion particles. In
this paper we also show the affinity selection (biopanning) of those phage
antibodies based on the capacity of their products to recognize the antigen. We
used biotinylated Z-DNA and the selection was performed in a solution phase
fashion. The data presented here indicate that these vectors can be further used
to construct anti-nucleic acid antibody fragment libraries that can be used to
study the basis of nucleic acid-protein interaction and its role in autoimmunity
mechanisms.
PMID- 10775890
TI - Effects of tryptophan depletion on anxiety induced by simulated public speaking.
AB - Several lines of evidence point to the participation of serotonin (5HT) in
anxiety. Its specific role, however, remains obscure. The objective of the
present study was to evaluate the effect of reducing 5HT-neurotransmission
through an acute tryptophan depletion on anxiety induced by a simulated public
speaking (SPS) test. Two groups of 14-15 subjects were submitted to a 24-h diet
with a low or normal content of tryptophan and received an amino acid mixture
without (TRY-) or with (TRY+) tryptophan under double-blind conditions. Five
hours later they were submitted to the SPS test. The state-trait anxiety
inventory (STAI) and the visual analogue mood scale (VAMS) were used to measure
subjective anxiety. Both scales showed that SPS induced a significant increase in
anxiety. Although no overall difference between groups was found, there was a
trend (P = 0.078) to an interaction of group x gender x phases of the SPS, and a
separate analysis of each gender showed an increase in anxiety measured by the
STAI in females of the TRY- group. The results for the female TRY- group also
suggested a greater arousing effect of the SPS test. In conclusion, the
tryptophan depletion procedure employed in the present study did not induce a
significant general change in subjective anxiety, but tended to induce anxiety in
females. This suggests a greater sensitivity of the 5HT system to the effects of
the procedure in this gender.
PMID- 10775891
TI - The cardiopulmonary reflexes of spontaneously hypertensive rats are normalized
after regression of left ventricular hypertrophy and hypertension.
AB - Cardiopulmonary reflexes are activated via changes in cardiac filling pressure
(volume-sensitive reflex) and chemical stimulation (chemosensitive reflex). The
sensitivity of the cardiopulmonary reflexes to these stimuli is impaired in the
spontaneously hypertensive rat (SHR) and other models of hypertension and is
thought to be associated with cardiac hypertrophy. The present study investigated
whether the sensitivity of the cardiopulmonary reflexes in SHR is restored when
cardiac hypertrophy and hypertension are reduced by enalapril treatment.
Untreated SHR and WKY rats were fed a normal diet. Another groups of rats were
treated with enalapril (10 mg kg-1 day-1, mixed in the diet; SHRE or WKYE) for
one month. After treatment, the volume-sensitive reflex was evaluated in each
group by determining the decrease in magnitude of the efferent renal sympathetic
nerve activity (RSNA) produced by acute isotonic saline volume expansion.
Chemoreflex sensitivity was evaluated by examining the bradycardia response
elicited by phenyldiguanide administration. Cardiac hypertrophy was determined
from the left ventricular/body weight (LV/BW) ratio. Volume expansion produced an
attenuated renal sympathoinhibitory response in SHR as compared to WKY rats. As
compared to the levels observed in normotensive WKY rats, however, enalapril
treatment restored the volume expansion-induced decrease in RSNA in SHRE. SHR
with established hypertension had a higher LV/BW ratio (45%) as compared to
normotensive WKY rats. With enalapril treatment, the LV/BW ratio was reduced to
19% in SHRE. Finally, the reflex-induced bradycardia response produced by
phenyldiguanide was significantly attenuated in SHR compared to WKY rats. Unlike
the effects on the volume reflex, the sensitivity of the cardiac chemosensitive
reflex to phenyldiguanide was not restored by enalapril treatment in SHRE. Taken
together, these results indicate that the impairment of the volume-sensitive, but
not the chemosensitive, reflex can be restored by treatment of SHR with
enalapril. It is possible that by augmenting the gain of the volume-sensitive
reflex control of RSNA, enalapril contributed to the reversal of cardiac
hypertrophy and normalization of arterial blood pressure in SHR.
PMID- 10775892
TI - Kallikrein-like amidase activity in renal ischemia and reperfusion.
AB - We assessed a kallikrein-like amidase activity probably related to the kallikrein
kinin system, as well as the participation of leukocyte infiltration in renal
ischemia and reperfusion. Male C57BL/KSJmdb mice were subjected to 20 or 60 min
of ischemia and to different periods of reperfusion. A control group consisted of
sham-operated mice, under similar conditions, except for ischemia induction.
Kallikrein-like amidase activity, Evans blue extravasation and myeloperoxidase
activity were measured in kidney homogenates, previously perfused with 0.9% NaCl.
Plasma creatinine concentration increased only in the 60-min ischemic group.
After 20 min of ischemia and 1 or 24 h of reperfusion, no change in kallikrein
like amidase activity or Evans blue extravasation was observed. In the mice
subjected to 20 min of ischemia, edema was evident at 1 h of reperfusion, but
kidney water content returned to basal levels after 24 h of reperfusion. In the
60-min ischemic group, kallikrein-like amidase activity and Evans blue
extravasation showed a similar significant increase along reperfusion time.
Kallikrein-like amidase activity increased from 4 nmol PNA mg protein-1 min-1 in
the basal condition to 15 nmol PNA mg protein-1 min-1 at 10 h of reperfusion. For
dye extravasation the concentration measured was near 200 microg of Evans blue/g
dry tissue in the basal condition and 1750 microg of Evans blue/g dry tissue at
10 h of reperfusion. No variation could be detected in the control group. A
significant increase from 5 to 40 units of DeltaAbs 655 nm g wet tissue-1 min-1
in the activity of the enzyme myeloperoxidase was observed in the 60-min ischemic
group, when it was evaluated after 24 h of reperfusion. Histological analysis of
the kidneys showed migration of polymorphonuclear leukocytes from the vascular
bed to the interstitial tissue in the 60-min ischemic group after 24 h of
reperfusion. We conclude that the duration of ischemia is critical for the
development of damage during reperfusion and that the increase in renal cortex
kallikrein-like amidase activity probably released from both the kidney and
leukocytes may be responsible, at least in part, for the observed effects,
probably through direct induction of increased vascular permeability.
PMID- 10775905
TI - Social and Economic Effects of Bariatric Surgery.
AB - One to 5 years after gastric restrictive surgery and subsequent weight loss, 79
bariatric surgery patients were compared with a similar group of 54 non-operated
patients. The operated group had a significantly higher proportion of employment,
more working hours, and a higher income. They were also more active in different
physical and social activities and had a better sexual life. They required less
medical care, had fewer days of sick leave or sick pension, and gave a much
higher score in assessment of their general health. The results indicate that
obesity surgery is highly cost-effective.
PMID- 10775906
TI - Single-shot Intercostal Nerve Block as an Adjunct to Post-operative Pain Control
for Upper Abdominal Surgery in the Obese Patient.
AB - One-hundred and ninety-two obese patients presented for upper abdominal surgery,
of which 110 received general anesthesia with opioid analgesia and 82 patients
received general anesthesia with opioid analgesia plus a single-shot intercostal
nerve block of 0.5% bupivacaine in 1: 200,000 adrenaline. A significant increase
in the time to first post-operative opioid dose and a significant reduction in
the number of doses over the first 12 and 24 h periods were noted in the patients
receiving intercostal nerve block.
PMID- 10775907
TI - Wound Complications Following Vertical Banded Gastroplasty: report of experience
and review of the literature.
AB - This prospective study was undertaken to evaluate wound management and outcome in
76 morbidly obese patients undergoing vertical banded gastroplasty through a
detailed protocol to determine the nature and incidence of wound complications
and to evaluate these results relative to the surgical literature. Early wound
complications can be infrequent. Late wound failures often occur in patients not
experiencing early wound complications. Mechanical factors, such as size-related
tension across the incision, undoubtedly play a major role in late wound failure.
A long suture length to wound length ratio mitigates mechanical factors involved
in late wound failure. With attention to technical factors and detail, wound
complications can be minimized, though not eliminated.
PMID- 10775908
TI - Revision of Staple Line Failure Following Roux-en-Y Gastric Bypass for Obesity: a
follow-up of weight loss.
AB - Eighty-one patients with primary Roux-en-Y gastric bypass for obesity underwent
revisional surgery for staple-line failure. All patients (100%) were included in
the follow-up. Two years later, patients had an excess weight loss of 77%; 91% of
the patients had a final weight loss of 50% or more of their excess weight.
Weight loss of revision patients was comparable to that reported for patients
with primary operations. It was concluded that revision for staple line failure
is clearly justified.
PMID- 10775909
TI - Aorta and Iliac Arterial Sizes in Pre-operative Morbidly Obese Patients: a
preliminary report.
AB - Central blood flow and cardiac output are increased in most morbidly obese
patients. This may be reflected in abnormal vessel sizes. Other influences such
as smoking, age, weight, vertebral size, hypertension and age at onset of obesity
may also be operative. Abnormal aorta and common iliac artery diameters were
retrospectively measured on abnormal computer-assisted axial tomography scans of
44 morbidly obese, vascular disease-free females prior to their bariatric
surgery. They were compared at standardized aortic and ileac levels with normal
weight, similar age, control patients. There was no correlation between patient
body weight, body mass index, percent excess body weight or age at onset of
obesity versus any of the aortic or iliac diameters. Pearson's correlation
analysis of smoking, age and hypertension each showed a significant positive
relationship with aorto-iliac diameters (p < 0.05). Vertebral coronal body widths
revealed a significant correlation with age (p < 0.05) but not with body weight,
aortic or iliac diameters at any level. We conclude that the aortic and iliac
arterial diameters of morbidly obese patients are significantly enlarged relative
to normal weight controls. Smoking, age and hypertension also appear to have some
degree of influence on aorto-iliac diameters in morbidly obese middle-aged women.
PMID- 10775910
TI - Jejunoileal Bypass Operations With a Side-to-side Anastomosis in the Treatment of
Morbid Obesity.
AB - In order to avoid a stagnant loop syndrome in intestinal bypass operations for
morbid obesity, we have tried a jejunoileal bypass with a side-to-side
anastomosis in a pilot study. Seven patients were operated on with this method,
which resulted in a very high incidence of liver damage. The study puts a
question mark to the blind loop syndrome as an etiological factor in producing
liver damage.
PMID- 10775911
TI - Effects of Eicosapentaenoic Acid on Lipid Metabolism in Obesity Treatment.
AB - In this study, we investigated the hypolipidemic action of eicosapentaenoic acid
(EPA) and its mechanism. Three types of 5% fat diets (stearic acid, linoleic
acid, and EPA) were prepared in our laboratory. Rats that weighed 170-190 g were
fed one of these diets for 20 weeks at an equivalent calorie value (groups S, L,
and E). Weight gain occurred in the following order: group E < group S < group L.
Serum levels of total cholesterol, triglycerides, phospholipids and total lipids
were significantly lower in group E than in the other groups. Analysis of the
fatty acid composition of adipose tissue showed that the level of C18:1 was
significantly higher in group S, that of C18:2 was significantly higher in group
L, and that of C16:0 was significantly higher in group E than in the other
groups. These results indicated that EPA had a hypolipidemic action, higher
ketogenicity, and lower lipogenicity than the other fatty acids. Inclusion of EPA
in the diet of hyperlipidemic subjects may thus help in the primary prevention of
hyperlipidemia and, in turn, morbid obesity.
PMID- 10775912
TI - Obesity Stereotypes Among Physicians, Medical and College Students, Bariatric
Surgery Patients and Families.
AB - Cultural indoctrination throughout childhood largely defines adult value systems
including stereotypic attitudes towards the obese. It is possible that medical
education may alter physicians' earlier stereotypes of obesity. 156 subjects,
comprising sex distinct adult groups, morbidly obese persons, their family
members and significant others. college undergraduates, medical students, medical
and surgical residents, and medical school faculty, were surveyed with a
questionnaire. It required that each of 32 bipolar adjectives describing obese
persons be answered on a -0 to 9-point scale. The adjectives were selected to
provide a sweeping array of attributes used commonly to note differences among
people (e.g. intelligent-unintelligent, happy-sad, complex-simple) with low
values corresponding to the first, usually more favorable, adjective of each
pair. Discriminant analysis identified only 5 of 32 adjective pairs (16%) as
useful (p < 0.05) in isolating the respondent groups. Although it reached
statistical significance, the magnitudes of these differences were not very
substantive with reference to a 9-point scale. We conclude that obesity appears
to carry a burdensome degree of societal prejudice, as reflected by negative
stereotypes, which is largely unaffected by undergraduate or postgraduate medical
education.
PMID- 10775913
TI - Psychological Profile and Outcome in Patients Undergoing Gastroplasty for Morbid
Obesity.
AB - Eighteen out of 22 consecutive patients undergoing vertical banded gastroplasty
were reviewed with regard to preoperative psychological assessment and
postoperative outcome. Each patient was initially evaluated by a consultant
liaison psychiatrist with regard to previous or ongoing psychological
disturbance, and suitability for bariatric surgery. Patients could be grouped
into three broad categories: Group A (seven patients) those with no psychiatric
abnormality; Group B (six patients) those with minor psychiatric disorders such
as sociopathic teenage behavior, outpatient treatment for depression; and Group C
(five patients) those with a history of major psychiatric disturbance such as
depressive psychosis and drug dependency. Psychiatric morbidity had no adverse
effect in terms of postoperative outcome or weight loss. Mean weight loss of 26%,
30% and 33% was recorded in groups A, B and C respectively after a mean follow-up
period of 33 months following gastroplasty. The occurrence of postoperative
psychiatric problems correlated closely with none of seven patients in group A
but in four of the five patients in Group C requiring psychiatric management. Our
findings indicate that psychiatric illness is not associated with poor outcome
following surgery for morbid obesity and such patients should not be excluded if
psychiatric support is available before and after surgery.
PMID- 10775914
TI - Why the Operation I Prefer is Vertical Banded Gastroplasty 5.0.
AB - Vertical banded gastroplasty (VBG) is easy for the patient, requiring no nasal
gastric tube, gastrostomy, feeding enterostomy, or central venous line. Clear
liquids are begun the first morning and pursed foods the second day. VBG with a
5.0 cm collar and a 13 ml pouch provides sufficient weight control with minimal
risk and side effects. Splenectomy risk is 0.3%, peritonitis from leak 0.6% and
operative mortality 0.24%. VBG causes no malabsorption or bacterial overgrowth
because there are no blind segments. VBG does not predispose to difficult to
diagnose, lethal, closed segment obstruction because of the absence of exclusion.
VBG minimizes risk of acid peptic disease by preserving normal feedback control
of acid secretion. Revisions have been less than 2% per year. The first 250
patients to be followed for 5 years with VBG-5.0 showed an 80% success in
achieving 25% of excess weight loss without revision. For these successful
patients the average percentage excess weight loss was 60% for the morbid obese
(MO 160 to 225% of ideal) and 52% for the super (SO over 225% of the ideal).
Absolute weight averages changed from 122 to 86 kg for MO and from 159 to 110 kg
for SO.
PMID- 10775915
TI - Why the Operation I Prefer is Silastictrade mark Ring Vertical Gastroplasty.
AB - The author prefers Silastictrade mark ring vertical gastroplasty because it is a
rapid and safe method for vertical gastroplasty, with minimal complications and a
success rate comparable to the other operations.
PMID- 10775916
TI - Why the Operation I Prefer is Adjustable Gastric Banding.
AB - The author discusses why he performs adjustable gastric banding. Advantages cited
are simplicity, and ability to control weight loss by adjusting stomal diameter
PMID- 10775917
TI - Why I Prefer Gastric Bypass Distal Roux-en-Y Gastroileostomy.
AB - Gastric bypass distal or extended Roux-en-Y has been our preferred primary
procedure since April 1985. The common channel of the Roux-en-Y is shortened to 5
7 ft of ileum. This procedure has been used not only on our new patients, but on
patients regaining weight or with incomplete weight loss after other bariatric
operations.
PMID- 10775918
TI - An Apparatus for Visualizing and Videotaping Obesity Operations.
AB - A video camera has difficulty in gaining access for obesity operations. A 7-ft
aluminum arm (boom) has been mounted on a sturdy tripod. A camera at one end of
the boom enables easy direct videotaping, without interfering with the operating
table
PMID- 10775919
TI - Reporting our Results.
AB - Morbid obesity is a life-threatening disease that has reached epidemic
proportions, especially in the upper midwestern part of the USA. The surgical
treatment of morbid obesity is generally effective while the non-surgical
treatment is usually not effective. Yet many of our colleagues and much of the
public have not accepted these facts for a variety of reasons. Chief among them
is the perception that we, as bariatric surgeons, do not really know our results.
At times we have been too quick to report on a few early spectacular results, and
much too slow to come forward with poor results. We can do something about this.
My purpose today is to examine the way in which we should report our results. In
approaching a subject, one can take a historical, a philosophical or a scientific
approach, but I am not a historian, a philosopher or a statistician. With this
denial, I will now feel perfectly comfortable to dabble in all three areas.
Historically, I recall that the bearer of bad news is forever an orphan.
Philosophically, it is the open mouth that catches the flies. In spite of these
warnings, I propose to examine the subject by asking and answering, at least to
some extent, a series of questions. Some answers are more obvious and shorter
than others.
PMID- 10775920
TI - Pulmonary Changes in Obesity: surgical implications. A Literature Review.
AB - Obesity affects approximately one-third of the population of the United States.
Pulmonary complications are common following upper abdominal surgery, and
constitute the most frequent postoperative complication in the obese surgical
patient. This literature review addresses the pathophysiology of the pulmonary
changes associated with simple obesity and examines intraoperative and
postoperative changes which occur in this patient group. Measures used
prophylaxis and management of these complications are reviewed.
PMID- 10775921
TI - Gastrointestinal Surgery for Severe Obesity.
AB - The National Institutes of Health Consensus Development Conference on
Gastrointestinal Surgery for Severe Obesity brought together surgeons,
gastroenterologists, endocrinologists, psychiatrists, nutritionists, and other
health care professionals as well as the public to address the nonsurgical
treatment options for severe obesity, the surgical treatments for severe obesity
and the criteria for selection, the efficacy and risks of surgical treatments for
severe obesity, and the need for future research on and epidemiological
evaluation of these therapies. Following 2 days of presentations by experts and
discussion by the audience, a consensus panel weighed the evidence and prepared
their consensus statement. Among their findings, the panel recommended that 1)
patients seeking therapy for severe obesity for the first time should be
considered for treatment in a nonsurgical program with integrated components of a
dietary regimen, appropriate exercise, and behavioral modification and support,
2) gastric restrictive or bypass procedures could be considered for well-informed
and motivated patients with acceptable operative risks, 3) patients who are
candidates for surgical procedures should be selected carefully after evaluation
by a multidisciplinary team with medical, surgical, psychiatric, and nutritional
expertise, 4) the operation be performed by a surgeon substantially experienced
with the appropriate procedures and working in a clinical setting with adequate
support for all aspects of management and assessment, and 5) lifelong medical
surveillance after surgical therapy is a necessity. The full text of the
consensus panel's statement follows.
PMID- 10775922
TI - Renal Tubular Acidosis after Jejunoileal Bypass for Morbid Obesity: role of
secondary hyperparathyroidism.
AB - The effect of calcium infusion was studied in patients with renal tubular
acidosis (RTA) and secondary hyperparathyroidism. Both developed after
jejunoileal bypass operation (JIB) for morbid obesity. In three of four cases the
acidification defect was abolished, probably due to a decrease of serum
parathyroid hormone. As we found RTA in 9% (95% confidence limits 2-21%) of our
patients, screening for acidosis is recommended in obesity patients after
malabsorptive operations. RTA can be verified through an ammonium loading test.
Before deciding on re-establishing bowel continuity due to RTA, we suggest that
patients be evaluated for secondary hyperparathyroidism and vitamin D deficiency
by measurement of serum calcium, parathyroid hormone and vitamin
1.25(OH)&inf2D&inf3;, and any calcium and vitamin D deficiency be corrected. An
intravenous calcium loading test can predict the outcome of oral calcium and
vitamin D supplementation. If RTA can be abolished through correction of calcium
homeostasis, reoperation may be avoided. Before deciding on re-establishing bowel
continuity in JIB patients with RTA, we therefore suggest that patients be
evaluated for secondary hyperparathyroidism and any calcium deficiency be
corrected.
PMID- 10775923
TI - The Mechanism of Weight Loss after Ileo-gastrostomy for Morbid Obesity.
AB - Twelve patients (weight 107-178 kg and age range 19-43 years) were investigated
following ileo-gastrostomy for morbid obesity. A number of variables were studied
prospectively, pre- and postoperatively, to determine the cause of weight loss
previously attributed to malabsorption or decreased caloric intake. Weight loss
of 10.9-36.5 kg, mean 22.9 kg, occurred. Three-day calorie counts demonstrated a
postoperative decrease in daily caloric consumption of 320-3870, mean 1975 cal.
Analysis of body compartment composition after derivation of lean body mass (from
calculation of total body water with tritiated water) showed a mean decrease in
adipose tissue of 17.7 kg. Postoperative weight loss, mainly fat, could not all
be accounted for by decreased caloric consumption or steatorrhea (72-h stool fat
increased by a mean of 30 g). Pulmonary studies showed no significant change in
respiratory quotient, but a large decrease in both postoperative utilization of
oxygen and the production of carbon dioxide. This may indicate an alternate,
anaerobic, energy cycle utilization. Other statistically significant variables
included a large fall in cholesterol, LDH cholesterol and triglycerides, and
smaller decrease in HDL cholesterol. Changes in gastro-intestinal (GI) hormones
and cell counts in stomach and small intestine were also measured and will be
reported later.
PMID- 10775924
TI - Radiological Features after Vertical Banded Gastroplasty.
AB - More than 1300 vertical banded gastroplasty operations have been performed at our
hospital since November 1982. We describe the radiologic findings based on 159 of
these patients, who were referred for radiologic contrast studies. Patients were
referred because of abdominal pain, excess vomiting, excess weight loss,
inadequate weight loss or regain of weight. The pre-contrast plain film was an
important indicator of staple-line abnormalities. The radiographic findings could
be divided into: abnormalities of the partition, abnormalities of the banded
outlet, and ulcers and extragastric leaks.
PMID- 10775925
TI - The Effect of Gastric Banding on Weight Loss in Patients with Morbid Obesity.
AB - The results following operation for morbid obesity in 41 patients (8 men and 33
women) during the period 1983-1989 are reported. The median preoperative body
mass index (BMI) was 43.6 (median excess weight 81%). All patients were
preoperatively evaluated at the Department of Internal Medicine, and they had all
tried several conservative regimens in order to lose weight. They were all
operated on with gastric banding, creating a gastric stoma of 15 mm. Pneumonia
developed in 10 patients, one patient got a wound infection, and one patient died
postoperatively from a massive coronary embolism. The immediate postoperative
weight loss was satisfactory, median BMI being reduced from 43.6 preoperative to
30.5 after 9 months. Median BMI after 3 and 5 years was 34 and 32 (median excess
weight 42 and 41%, respectively). Six patients were reoperated, four having their
band removed, two being converted to vertical gastric banding. In conclusion,
gastric banding gives satisfactory results for most of the patients. The
reoperation rate is, however, high and the long-term result is not favorable for
all patients
PMID- 10775926
TI - Gastric Banding for Morbid Obesity: the St Paul's experience.
AB - A group of 300 consecutive morbidly obese patients who underwent a gastric
banding procedure (gastric segmentation) by a single surgeon (F.S.W.) has been
analyzed as to their sex, age, hospitalization, complications and sequelae,
reversal or reoperation, and weight loss. The time frame was born August 1984 to
January 1991. Eighty-eight percent were females and the average age was 37 years.
The operative mortality was zero, and the complications were minor (1%). Eight
women have had one or more normal pregnancies after the operation. Thirty-eight
cases (12.7%) have had a reversal or a reoperation. Thirty-one patients (10.3%)
were lost to follow-up. 271 cases have been operated on for more than 1 year and
up to 6.5 years. In those patients not lost to follow-up or who have not had a
reoperation, 109 or 54% had a weight loss of 30% or more and 140 or 68% had a
weight loss of 25% or more. We conclude that in our setting, the gastric banding
is successful in promoting weight loss with a minimum risk and an acceptable
reoperation or reversal rate.
PMID- 10775927
TI - Orally-administered Serum Ranitidine Concentration after Biliopancreatic
Diversion for Obesity.
AB - Stomal ulcer occurs in about 5% of patients after biliopancreatic diversion
(BPD). Seven females were given 150 or 300 mg of ranitidine orally. Blood samples
found a pharmacologically effective concentration from 0.5 to 8 h after both
doses. Intestinal absorption of ranitidine is maintained after BPD.
PMID- 10775928
TI - Roux-Y Gastric Bypass: an effective anti-reflux procedure.
AB - Gastric limiting procedures have made an improvement in the lives of those
patients in whom they have been successful. Not only have there been marked
improvements in diabetes, hypertension, and arthritis, but there have been a
number a number of other 'spin-offs', not the least of which is control of reflux
esophagitis by totally eliminating the secretion of the parietal cell mass of the
stomach from rising into the esophagus. We compared a group of 100 obese patients
with reflux esophagitis who underwent Roux-Y gastric bypass (RYGBP) to a
normalisized group of 23 patients on whom we had done Nissen fundoplications in
the past. Visick grading I-II of 100% vs 87%, respectively, may indicate a
superiority of RYGBP over the Nissen procedure. Although the groups and time
periods are too divergent to draw statistically significant conclusions, one can
see that the RYGBP population was apparently better served considering their cure
of 'heartburn' and other reflux symptoms as well as their achievement of
sustained weight loss.
PMID- 10775929
TI - The Needle Catheter Jejunostomy: a useful and cost-effective adjunct in bariatric
surgery.
AB - The safety and efficacy of the needle catheter jejunostomy (NCJJ) is evaluated in
200 consecutive, prospectively studied gastric bypass procedure patients with a
follow-up of 6 months to 9.5 years. The NCJJ was used in place of intravenous
fluid administration from the first postoperative day to supplement oral fluids
for 6 weeks postoperatively and for complete temporary supplementation in 16
patients with viral illness or pouch outlet obstruction, thus avoiding re
hospitalization for rehydration. We did not use X-ray confirmation of the
catheter placement. Analysis revealed no major complications with no catheter
dislodgment, associated intra-abdominal sepsis or late bowel obstruction. There
were 24 (12%) subcutaneous infections, only four (2%) of which required minor
incisions and drainage under local anesthesia. Risk factors for the infections
were insulin-dependent diabetes mellitus and the actual withdrawal of the NCJJ
(50% of the infections occurred at this time). The NCJJ has been a safe, useful
and cost-effective adjunct in the operative management of the morbidly obese
patient.
PMID- 10775930
TI - Why the Operation We Prefer is the Roux-Y Gastric Bypass.
AB - Roux-Y gastric bypass with transection in an anterio-posterior oblique fashion
and an 11-12 mm internal diameter gastrojejunostomy supported by an external
strip of linea alba fascia is safe and effective as a primary or revision
procedure, with a very low failure and revision rate.
PMID- 10775931
TI - Why the Operation I Prefer is Biliopancreatic Diversion (BPD).
AB - The author discusses why his operation of choice is biliopancreatic diversion
(BPD). BPD is the most effective in obtaining long-term weight loss and permits
unchanged eating habits. Although BPD is technically demanding, revisions for
protein malnutrition or stomal ulcer have not been difficult and have become
infrequent. However, lifelong follow-up must be guaranteed.
PMID- 10775932
TI - A Technique for Converting the Roux-en-Y Gastric Bypass to a Modified
Biliopancreatic Diversion.
AB - Our group has performed the Roux-en-Y gastric bypass (RYGB) in 1450 patients
since 1983: 805 patients had primary operations, and 645 were converted from
previous gastroplasty procedures, i.e. horizontal gastroplasty, vertical banded
gastroplasty, and gastrogastrostomy. Within the last 2 years, 38 patients who
failed the RYGB were converted to a modified biliopancreatic diversion (BPD)
using a technique that did not require dismantling a major portion of the
original gastric exclusion. A 24-month follow-up has demonstrated a significant
and sustained weight loss in all patients. In addition, the modified BPD
completely eliminated the problem of reflux bile gastritis in those patients with
a short Roux-en-Y jejunal limb.
PMID- 10775933
TI - Modification of Gastric Banding, Using a Fundal Suture.
AB - Many forms of gastric banding have been described and high reoperation rates
reported. These can be mainly attributed to excess vomiting associated both with
and without stenosis. Reflux esophagitis and the 'sump' effect may be other
causes. This paper examines the problems associated with banding leading to
revisional surgery and introduces a new technique, 'fundal supporting suture', to
correct these problems. Preliminary results on 126 bandings without the
modification and 22 with the modification are presented.
PMID- 10775934
TI - The Accuracy of Scales Used to Weigh Patients.
PMID- 10775935
TI - Remedial Operations Following Surgery for Morbid Obesity.
PMID- 10775936
TI - Conversion of Jejunoileal Bypass to Silastic Ring Vertical Gastroplasty.
AB - A gastric restrictive procedure is usually performed simultaneous with takedown
of a jejunoileal bypass (JIB) to prevent weight regain. However, the preferred
gastric restrictive procedure has not been established. Currently, we combine JIB
takedown with silastic ring vertical gastroplasty (SRVG), and report our
experience with 36 patients treated over a 5-year period. Indications for JIB
takedown were diarrhea (69%), arthralgias (53%), liver disease (34%),
nephrolithiasis (25%), and increasing weight (33%). Mean weight at the time of
JIB takedown was 232+/-12 (SEM) lb (105 +/- 5 kg) (77 +/- 8% EBW (excess body
weight)). Follow-up was complete in 33 (92%) patients. Post-reversal weight was
202 +/- 14 lb (92 +/- 6 kg) (55 +/- 8% EBW) at 1 year and 218 +/- 12 lb (99 +/- 5
kg) (67 +/- 8% EBW) (not significant) at a mean follow-up of 2.9 years. Twenty
one (64%) patients lost weight or were stable (+/-% EBW), while 12 (36%) gained a
mean of 39 +/- 7 lb (18 +/- 3 kg) (range 16-80 lb (7 +/- 36 kg)). Resolution of
preoperative complaints was noted in all patients with diarrhea and 53% with
migratory arthralgias. Major early postoperative morbidity occurred in 11%, with
no mortality. We conclude that SRVG is a safe and effective procedure to combine
with JIB takedown.
PMID- 10775938
TI - Weight Loss Curve Analysis.
AB - The purpose of this study was to develop a mathematical model to describe weight
loss trend over time and to determine differences, if any, among various weight
loss trends. Weight change was studied following Roux-en-Y gastric bypass (RGB)
and vertical banded gastroplasty (VBG). The total number of patients analyzed was
3172, 63.5% VBG and 36.5% RGB. Median age (years) for VBG was 36 (range 18-70)
and RGB 38 (range 18-66). Median operative body mass index (BMI) (kg/m(2)) for
VBG was 45.0 (range 30.1-90.5) and RGB 43.3 (range 30.4-80.6). Females
represented 87% of the VBG patients and 89% of RGB patients. Obesity category
percentages for each operative type were: super-VBG 20%, RGB 14%; morbid-VBG 78%,
RGB 80%; obese-VBG 2%, RBG 6%. The development of a mathematical model to study
weight loss over time was a two-stage process. First, weight loss trend was
determined as evidenced by individual patient BMI values plotted over time. It
was observed that plots represented quadratic curves, so the model BMI = B&inf0;
+ B&inf1;(time) + B&inf2;(time)(2) was used. Second, the estimated beta's
(B&inf0;, B&inf1;, B&inf2;) were treated as response variables to estimate weight
loss trend for the combination effect of three independent variables: gender
(male and female), obesity category (super, morbid, obese) and operative type
(VBG and RGB). It was found that the three independent variables simultaneously
interact with patient weight loss (p = 0.0001).
PMID- 10775937
TI - Silicone Elastomere Ring Vertical Gastroplasty: extended follow-up.
AB - Statistically significant long-term data have been noticeably scarce in the
evaluation of various bariatric procedures. Bariatric patients who lost weight
frequently experience drastic life-style changes and often exhibit denial to the
extent that follow-up is impaired. In this study, a cohort of 100 consecutive
patients who underwent silicone elastomere ring vertical gastroplasty is
evaluated at 46-55 months post-surgery with 90% follow-up. Results indicate that
the 24-month figure of 36% loss of the preoperative weight level deteriorates to
32% at 46-55 months, and the failure rate increases slightly to 25% (or less),
primarily due to anatomic failure of the procedure. Failure due to lack of
patient compliance occurs but is less common than previously thought. Silicone
elastomere ring vertical gastroplasty remains one of the safest of the effective
procedures available to the bariatric surgeon.
PMID- 10775939
TI - Biliopancreatic Diversion with Gastrectomy as Surgical Treatment of Morbid
Obesity.
AB - The best procedure for the treatment of morbid obesity has not yet been defined.
Biliopancreatic diversion is one of the techniques available, but its results
have not been sufficiently documented and the addition of a subtotal gastrectomy
to the diversion so as to avoid leaving a blind non-functioning stomach, is still
questionable. The purpose of this paper is to report our experience with our
first 149 consecutive patients who were treated by biliopancreatic diversion with
subtotal gastrectomy for morbid obesity. Operative mortality was 3% and morbidity
12%. The weight loss was marked during the first 6 months and decreased during
the following 12 months. The weight stabilized at 2 years and there was
subsequently a small increase. In only two out of 48 cases was the weight loss
less than 25% of the initial weight at 2 years. The undesirable side-effects were
diarrhea in 6%, vomiting in 9% and dyspepsia in 4%. The intervention leads to a
malabsorption of carotene, iron, albumin and calcium. Except for carotene the
deficiencies were corrected by oral supplement. In two patients, with resistant
deficiencies, the diversion was reversed. Eighty-eight percent of the patients
are satisfied with this intervention. At 2 years, 70% have reached their weight
loss objective without any major side-effects or nutritional deficiencies, but in
14% the outcome of the procedure must be considered unsatisfactory.
Biliopancreatic diversion with subtotal gastrectomy is a major operation, but it
gives encouraging results so far.
PMID- 10775940
TI - Vertical Banded Gastroplasty-Gastric Bypass: preliminary report.
AB - Vertical banded gastroplasty-gastric bypass is a surgical technique combining the
advantages of the vertical banded gastroplasty with those of gastric bypass. The
procedure was performed on 148 morbidly obese individuals: 83% were female, and
17% were male. Ages ranged from 15 to 64 years, with a mean age of 35. Mean
percentage weight was 215% of ideal. The vertical banded gastroplasty is
constructed by creating a 10 cc vertical pouch along the lesser curvature with a
5.5 cm supporting band. The pouch is fashioned in a way that the lower portion is
free and mobile. This free segment of stomach is anastomosed by triangulation to
a Roux-en-Y loop of jejunum, which is brought up in a retrocolic, retrogastric
fashion. With 100% follow-up in the 19 patients who have reached 1 year, average
excess weight loss has been substantial. There was one early postoperative
complication requiring surgery. Two patients required late revisional operations.
Vertical banded gastroplasty-gastric bypass is a relatively simple procedure to
perform and has a low rate of complications. Gastric bypass in combination with a
small banded pouch along the lesser curvature should result in substantial and
permanent weight loss.
PMID- 10775942
TI - A Review of Seven Years' Experience with Silicone Gastric Banding.
AB - Since January 1983, silicone gastric banding (SGB) has been used with very low
morbidity in 311 extremely obese patients to produce and maintain significant
weight loss for as long as 7 years. A small meal-sizing pouch with reinforced
small stoma is created with placement of the silicone band around the stomach.
The basic operative technique involving no cutting or crushing of either the
stomach or the small intestines has not changed. Strict quality control of the
banding is permitted by specialty designed calibration devices and other
instruments. To permit correction of changes in stoma diameter occurring with the
passage of time, the band was modified in 1986 by adding an adjustable portion
(stoma adjustable silicone gastric banding or SASGB). Adjustment to proper size
is done percutaneously through the injection port. SASGB allows correction of
most stoma-related problems non-operatively and significantly improved weight
loss. One-hundred and seventy three original SGB patients (125 primary, 48
conversion) and 138 SASGB patients (93 primary, 45 conversion) were operated. At
60 months, 65 primary SGB patients averaged 47% excess weight loss (EWL). At 36
months, average EWL was significantly greater for 37 primary SASGB patients than
four 94 primary SGB (64.3% vs 49.3%, p = 0.01); 84% of SASGB patients had EWL >
and 57% achieved EWL > 60%. SASGB generates weight loss comparable to that
produced by more extensive bariatric procedures. Excellent weight loss and
maintenance combined with the stoma size non-surgical adjustment ability makes
SASGB attractive for use in treating bariatric patients.
PMID- 10775941
TI - Radiological Investigations in Vertical Banded Gastroplasty Patients.
AB - In our institute we have performed 124 vertical banded gastroplasties. Patients
with a follow-up beyond 3 months were studied with a barium meal, in order to
evaluate the efficiency of surgery and the eventual complications. Seventy-nine
patients have had one or more X-ray investigations at various times after surgery
(for a total of 136 studies). The first 20 patients were routinely studied at 1,
2 and 3 years after the operation; the next 32 patients were studied for features
such as vomiting, poor weight loss or low food intake; the last 27 patients were
studied with an early overlook beginning 3 months after surgery. We noted
gastroesophageal reflux in eight (10.1%) cases, outlet dilatation in four (5%)
cases, outlet substenosis (diameter 6-8 mm) in 13 (16.4%) cases, outlet stenosis
(diameter 40) is associated with an increased risk of a
variety of health problems, many of them potentially life-threatening or life
shortening. Vertical banded gastroplasty (VBG) is currently the most frequently
performed surgical procedure used to restrict food intake, and assist with weight
loss. After massive weight loss, however, redundant abdominal and breast tissue
can result in physiological and psychological problems related to an unusual body
habitus. Patients complain of difficulties with daily activities, choice of
clothing, social acceptance, etc. Body contouring has proven to be an important
part of the rehabilitation of the morbidly obese patient, and we have therefore
reviewed the records of 55 patients who experienced massive weight loss following
VBG and then underwent abdominoplasty with or without mammoplasty/mastoplexy, in
order to assess the parameters which will be seen more frequently in the future
by plastic surgeons as bariatric surgery becomes more widely accepted and
performed
PMID- 10775945
TI - Effect of Weight Loss in the Morbidly Obese Patient with Severe Disability.
AB - An impairment can result in disability which can result in handicap. In Canada,
disabilities have been based on 17 activities of daily living (ADL), nine of
which may be due to massive obesity. Severe disability (SD) is inability to
perform three or more of these ADL. During 1985, all patients with SD who
underwent weight loss surgery were surveyed. Of 120 morbidly obese patients, 44
fulfilled the SD criteria. Effect of weight loss was observed over 5 years in 42
SD patients (initial mean body mass index 47.8 final 27.8), two being lost to
follow-up. Disability became moderate (unable to do one or two of the ADL) in
three, mild (difficult but able to perform) in 17, and disappeared in 22
patients. Two who regained lost weight redeveloped SD.
PMID- 10775946
TI - Why the Operation I Prefer is Silastic Ring Vertical Gastric Bypass.
AB - Silastic ring vertical gastric bypass is a composite operation which maximizes
the advantages of the vertical banded gastroplasty and the gastric bypass
operations. It is our operation of choice because it appears to date to be the
only operation that addresses the medical and psychosocioeconomic problem of
severe obesity. Acute complications include wound infection, wound seroma and
anastomotic leaks. Late complications include marginal ulcers (6%), staple-line
breakdown (4%), iron deficiency, vitamin B&inf1;&inf2; deficiency and anemia. The
operation is relatively simple, safe, effective and acceptable to the patients
and doctors.
PMID- 10775947
TI - Percutaneous Examination of the Bypassed Stomach.
AB - Gastric partitioning procedures utilized in bariatric surgery, which completely
segment or transect the stomach, have the disadvantage of preventing direct
access to the excluded stomach for evaluation of possible pathologic changes or
the management of such diseases as peptic ulcer. Retrograde endoscopy is not
possible where the combined length of the efferent jejunal limb and proximal
jejunum exceeds that of the excluded stomach, and their adaptation to allow
direct percutaneous endoscopy are described.
PMID- 10775948
TI - Mechanical Retraction in Obesity and Esophagogastric Surgery.
AB - A slotted retractor blade (two vertical limbs, with one shorter), to maximize
esophagogastric exposure and minimize trauma to surrounding tissues, is
described.
PMID- 10775949
TI - Using a Full-depth Wound Drainage System to Decrease Wound Infection Rates in the
Morbidly Obese.
AB - The morbidly obese surgical patient is at increased risk for wound complications
due to mechanical stresses from a deep and heavy subcutaneous tissue layer that
create dead spaces in which hematomas and seromas can form. To drain the full
depth of this layer, we revised an existing wound drainage system using cut
segments of a Davol drain and added a Velcro binder to minimize lateral stress on
the wound. We used the full-depth drain for all 384 morbidly obese patients who
underwent vertical banded gastroplasty during a 10-year period. No patient
developed a wound infection in the hospital; however, three patients had wound
abscesses one month postoperatively, an infection rate of 0.78%. We believe that
the drain system was an important factor in producing the low infection rate.
PMID- 10775950
TI - Gastroplasty for Morbid Obesity after Cardiac and Renal Transplantation.
AB - The success of vertical banded gastroplasty (VBG) in the obese transplanted
population is measured by a low operative morbidity and mortality in the context
of a good record of permanent weight loss and an enhanced quality of life.
Selection of transplanted patients for gastroplasty should be guided by the
prevailing standards for the general population. VBG is the procedure of choice
because of proven efficacy and has the benefit over gastric bypass of not
producing malabsorption. The operation causes early satiety while allowing
consistent absorption of immunosuppressive medication from the upper
gastrointestinal tract, essential in these patients. This risk of hypertension,
diabetes mellitus, hyperlipidemia, and immunosuppressive medication toxicity may
be decreased by substantial long-term weight loss afforded morbidly obese
transplant patients by gastric restrictive surgery. Cardiac risk factors
associated with morbid obesity and immunosuppressive therapy are lessened with
sustained weight reduction.
PMID- 10775951
TI - Erosion of Marlex Mesh Collar after Vertical Banded Gastroplasty.
AB - Marlex mesh, as opposed to silastic ring, when used as a collar in the bariatric
procedure of vertical banded gastroplasty, has been reported rarely to erode into
the gastric lumen. We report two cases of such an erosion, of which one ended as
a complete internalization of the collar into the stomach. In one of the patients
we observed a wider than expected portion of tissue that had been encircled by
the collar, which might have caused a local inflammatory reaction leading to the
later erosion.
PMID- 10775952
TI - Obesity Surgery Poly-parametric Patient Auto-evaluation.
AB - A simple auto-evaluation sheet is presented for the proper assessment of the
patient's condition after surgery. Stress is put not only on the weight loss, but
on other important factors as well.
PMID- 10775953
TI - Epidemiology of central nervous system infections.
AB - The radiologist frequently is asked to contribute to the diagnosis of a patient
with central nervous system infections, although radiologic findings usually are
nonspecific. The radiologist can consider diagnostic possibilities with more
accuracy if the clinician includes accurate demographic and epidemiologic
information. This article organizes a broad range of central nervous system
infections into demographic and epidemiologic perspective.
PMID- 10775954
TI - Imaging of cranial meningitis and ventriculitis.
AB - A spectrum of infectious diseases may affect the cranial meninges. Contrast
enhanced MR imaging and fluid-attenuated inversion-recovery MR techniques are
superior to contrast-enhanced computed tomography for detecting and
characterizing most pathologic meningeal conditions. In patients with meningitis,
a major role of medical imaging is to identify potential complications such as
hydrocephalus, extra-axial mass-forming infectious collections, parenchymal
infarcts related to arteritis, ventriculitis, and associated underlying
parenchymal abscesses or granuloma formations. Early diagnosis of such
complications may reduce the rate of morbidity and mortality in this group of
patients.
PMID- 10775955
TI - Encephalitis, cerebritis, and brain abscess: pathophysiology and imaging
findings.
AB - This article discusses the imaging findings of encephalitis, cerebritis, and
brain abscess in immunocompetent patients. MR imaging is the procedure of choice
in evaluating suspected intracranial infections because of its inherent contrast
resolution, multiplanar capability, improved sensitivity in the posterior fossa,
sensitivity to the presence of subacute, and chronic hemorrhage, and its
sensitivity to the detection of meningeal disease on postcontrast images.
Discussion of pathologic conditions and imaging features of encephalitis are
based on the most common causative agents of each type of disease. Imaging
features and pathologic conditions of cerebritis and brain abscesses also are
reviewed with emphasis on pyogenic bacteria.
PMID- 10775956
TI - Central nervous system tuberculosis: imaging manifestations.
AB - Tuberculosis of the brain is a disease of pathologic complexity and clinical
subtlety-characteristics that manifest in the radiologic presentation of the
disease and may make the task of interpreting radiologic data difficult. Much of
the difficulty, however, reflects differences between the pathologic processes of
tuberculosis and other infective diseases of the brain, and once these
differences are appreciated, interpreting radiologic images becomes clearer.
PMID- 10775957
TI - Imaging of rickettsial, spirochetal, and parasitic infections.
AB - This article reviews the clinical signs, symptoms, and neuroimaging findings of
the commonly known rickettsial, spirochetal, and parasitic infections
(cysticercosis is covered elsewhere in this issue). Differential diagnoses and
significant imaging characteristics are reviewed to help narrow the diagnostic
possibilities. Several of the infections in this disparate group are not seen as
commonly as they once were because of advances in early diagnosis, treatment,
improvements in sanitation, and prevention of epidemics. Many of the infections,
however, are endemic to certain parts of the world and are seen with increasing
frequency in immunocompromised individuals.
PMID- 10775958
TI - Imaging of neurocysticercosis.
AB - Neurocysticercosis produces a variety of neurologic syndromes resulting from the
cysticerci infestation of the central nervous system by the larvae of Taenia
solium. Because of increased immigration to the United States from endemic areas,
the incidence of neurocysticercosis has increased, especially in California,
Texas, Arizona, and other southwestern states. Neuroimaging studies play a
significant role in the diagnosis and management of patients with
neurocysticercosis.
PMID- 10775959
TI - Fungal infections of the central nervous system.
AB - The diagnosis and treatment of central nervous system fungal infections typically
pose problems for the clinician. With an increased incidence of fungal infections
in immunocompromised patients, neuroradiologic imaging has become essential in
determining complications and outcomes. This article provides a summary of the
more common organisms encountered in fungal infections of the central nervous
system and the imaging features primarily seen with CT and MR imaging.
PMID- 10775960
TI - Central nervous system infections in the pediatric population.
AB - Central nervous system infections and sequelae in the pediatric population may
present differently depending on the patient's stage of development. Infections
contracted from conception through the neonatal period may affect central nervous
system formation, whereas infections acquired later tend to cause parenchymal
destruction. This article discusses congenital, focal parenchymal, extra-axial,
and diffuse parenchymal infections and their effect on the developing brain.
PMID- 10775961
TI - Treatment of central nervous system infections: a neurosurgical perspective.
AB - Almost any microorganism has the potential to infect the human central nervous
system. Neurosurgical intervention may be required for tissue assay, to establish
a microbiologic diagnosis, for decompression of space-occupying lesions with
significant mass effects, or for definitive treatments such as cerebrospinal
fluid diversion. This article surveys the surgical management of intracranial
infections with special emphasis on subdural and epidural empyema, brain
abscesses, mycotic aneurysms, and neurocysticercosis.
PMID- 10775962
TI - [A controlled, double-blind, randomized pilot clinical trial of nicardipine as
compared with a placebo in patients with moderate or severe head injury].
AB - INTRODUCTION: One of the factors involved in the occurrence of ischemic cerebral
lesions following head injury is cerebral vasospasm. We analyze the effect of
intravenous nicardipine on the prevention and treatment of posttraumatic cerebral
vasospasm. PATIENTS AND METHODS: We made a placebo-controlled, randomised, double
blind pilot study of the effect of nicardipine (intravenously 5 mg/hour for one
week) on patients with moderate or severe head injury who presented with cerebral
vasospasm, defined as an average Doppler flow velocity (DFV) of 100 cm/second or
more. The main variable assessed was the evolution of the DFV and the secondary
criteria were the evolution of the arterial blood pressure, coma scales, the
findings on the Glasgow Coma Scale and the safety of the drug. RESULTS: Eleven
patients were included in each homogeneous group. The DFV was found to have
become normal on the first day of treatment with nicardipine and on the third day
with the placebo (p = 0.023). During the first day of treatment the percentage of
cerebral hemispheres diagnosed as having suspected spasm was 11.1% for
nicardipine and 64.3% for the placebo (p = 0.02881). The average time for
recovery (DFV < 100 cm/second) was 3.33 days with the placebo and 1.22 days with
nicardipine (p = 0.0039). The patients treated with nicardipine had 8.89 times
more chance of recovery from vasospasm. The incidence of adverse effects was
greater with the placebo (p = 0.014). CONCLUSION: Nicardipine is effective in the
reversal and prevention of increased Doppler flow velocity in patients with
moderate or severe head injury.
PMID- 10775963
TI - [Vascular hemichorea: clinical-radiological correlation].
AB - INTRODUCTION: Hemichorea is uncommon in acute cerebrovascular accidents. Its
appearance is in relation to the contralateral involvement of the basal ganglia,
particularly the striate ganglion. With current neuroimaging techniques it is
possible to identify the lesions responsible for these abnormal movements.
Magnetic resonance (MR) is the technique of choice for detection of small sized
lesions. OBJECTIVE: We have analysed our series of patients to try to relate the
site of the lesion to the appearance of chorea. PATIENTS AND METHODS: We made a
retrospective study of the cases of hemichorea of vascular origin admitted
between January 1993 and April 1999. In all cases, cerebral CAT and/or MR had
been done to find the site of the lesion. RESULTS: A total of 10 patients with an
average age of 72.5 years (range: 55-85) was found. In eight of them (80%)
lesions were found in the basal ganglia, half of which were of ischemic type and
the other half hemorrhagic. The sites were: caudate nucleus in one case (10%),
thalamus in two cases (20%) and capsulo-lenticular lesions in five cases (50%).
All lesions were contralateral to the side of the body affected except in one
case with a left thalamic haematoma and homolateral hemichorea. CONCLUSIONS: The
lesions found were very varied in site. In 20% of the cases they were not
detected by conventional neuroimaging techniques. This fact supports the concept
of a functional global network of the basal ganglia which may be interrupted at
several points and lead to the same clinical findings.
PMID- 10775964
TI - [Immunological study in patients with severe myoclonic epilepsy in childhood].
AB - OBJECTIVE: Clinical and experimental data support the role of immune mechanisms
in the pathogeny of childhood epilepsy. The purpose of this report is to study
the immunological aspects in severe myoclonic epilepsy in infancy (SMEI).
PATIENTS AND METHODS: 12 patients selected according to the following criteria:
no previous personal history of disease, frequent familial history of epilepsy,
beginning in the first year of life with seizures usually febriles, onset of
afebrile seizures between 18 months and 4 years, normal EEG and psychomotor
development are at the onset, seizures resistant to antiepileptic drugs. The
following immunological evaluation, has been carried out: granulocytes phagocytic
activity, lymphocytics subpopulations, serum immunoglobulins and IgG subclasses,
hemolytic capacity of complement, lymphocytic transformation test. RESULTS: In
five cases the immunological study was normal; five cases had IgA deficiency,
associated in two to high serum IgG1 levels and in two to high IgG1 and low IgG2
levels; one case shows an IgM increase associated to hemolytic capacity of
complement deficiency (CH50); four cases have a reduced response to different
mitogens. CONCLUSIONS: The value of this results is doubtful. It is possible that
genetical and environmental factors are involved in SMEI and that the
immunological abnormalities found favor the hyperergic reactions in given
circumstances.
PMID- 10775965
TI - [Status epilepticus in the childhood. A review of seven years].
AB - INTRODUCTION: Status epilepticus is a neurological emergency that requires early
and prompt treatment. PATIENTS AND METHODS: This retrospective study includes 32
children treated for status epilepticus at Hospital Geral de Santo Antonio, from
January 1992 to December 1998. We evaluated the clinical features, duration,
aetiology and prognostic. RESULTS: Symptomatic or criptogenetic aetiology was
present in 53% of children and idiopathic in 47%. 27% of episodes of status
epilepticus were induced by fever. The most common neurological sequel was
epilepsy (onset of new epilepsy in 20%; aggravated in 25%). Two children (10%)
had major neurological sequelae after status epilepticus. CONCLUSION: In our
study the duration of status epilepticus and sequelae seems to be related with
aetiology.
PMID- 10775966
TI - [Transient global amnesia and vascular risk factors].
AB - INTRODUCTION: Transient global amnesia (TGA) is a clinical syndrome determined by
an episode of less than 24 hours consisting of temporo-spatial disorientation
with retrograde and anterograde amnesia followed by complete recovery.
OBJECTIVES: To determine whether the presence or absence of vascular risk factors
(VRF) in patients with TGA is associated with different clinical data and/or
examination findings. PATIENTS AND METHODS: A retrospective study was made of two
groups of 13 and 12 patients with TGA, who presented with and without VRF,
respectively. The following variables were determined: VRF, age, a previous
history of migraine, triggering factors, duration and repetition of the episodes,
associated neurological symptoms and findings obtained by neuroimaging, eco
Doppler of the supra-aortic trunks and transcranial Doppler. The data were
subjected to statistical analysis by univariate analysis with Fischer's exact
probability test. RESULTS: The statistical studies showed no significant
differences between the variables obtained in the two groups of patients.
CONCLUSIONS: Transient global amnesia has been particularly related to migraine,
epilepsy and cerebral vascular pathology, although its aetiology has not been
fully determined. In this study we compare clinical data between the two groups
of patients with and without VRF who have had TGA. The lack of significant
differences between them tends to rule out a vascular aetiology as the sole cause
of this syndrome. Recently Leao's propagated depression has been suggested as the
physiopathological mechanism involved. According to this theory, the vascular
pathology might act as the trigger but probably not as the aetiological factor.
The findings of our study may support this thesis.
PMID- 10775967
TI - [Clinical semiology associated with increased creatinine kinase in patients
attending emergency department].
AB - INTRODUCTION: The prognosis of rhabdomyolysis is conditioned by the development
of acute renal failure which depends of quick preventive measures. Rhabdomyolysis
is diagnosed by measuring plasma creatinkinase and it is usually suspected by the
presence of previous putative causal factors like traumatisms. Non traumatic
rhabdomyolysis usually lacks of clinical relevant antecedents and the syndrome
should be suspected by patient clinical symptomatology; unfortunately, this one
has been scarcely studied. OBJECTIVES: To describe the semiology observed in
patients experiencing non traumatic rhabdomyolysis and to identify which symptoms
induced to the subject to go to the emergency room in order to facilitate the
diagnostic procedure. PATIENTS AND METHODS: We studied the patients with non
traumatic rhabdomyolysis (creatinkinase > 1,000 IU/l) which attended the
emergency room in a one year period. We collected data regarding their clinical
symptomatology as well as which of them was responsible of his/her coming to the
emergency unit. Symptoms were classified in four groups: muscular, urinary,
neurological and others. RESULTS: We evaluated 49 patients. The relative
frequency of each kind of symptoms was the following: muscular 51%, urinary 18%,
neurological 67%, and others 47%. The absolute frequency of the symptoms which
caused the consultation were: muscular 16%, urinary 2%, neurological 48%, others
22%, muscular and neurological associated 6%, and neurological and other
associated 6%. CONCLUSION: CK serum levels should be measured in all of the
patients attending the emergency unit who exhibit some type of neurological
manifestation.
PMID- 10775968
TI - [The Mini-Mental State Examination as a selected diagnostic test for dementia: a
Colombian population study. GENECO].
AB - INTRODUCTION: Folstein's Mini Mental State Examination (MMSE) is widely used as
screening test for cognitive impairment. OBJECTIVE: To test a Spanish version of
the MMSE in a population of high illiteracy rate. MATERIAL AND METHODS:
Population-based survey of a stratified random sample of urban and rural
residents of five regions of Colombia, followed by neurological and
neuropsychological evaluation of suspect cases (phase 2). Dementia was diagnosed
using DSM-IV criteria. RESULTS: 1,611 subjects age 50 or older filled out both
the WHO Protocol for Epidemiologic Studies of Neurological Disorders and a
Spanish version of the MMSE; 55.2% of them had three or less years of schooling;
536 individuals with scores below cutoff points were sent to phase 2. Of the
population with satisfactory scores in MMSE 366 (34.0%) were evaluated by
neurologists to exclude other neurological conditions. Twelve cases of dementia
were diagnosed among individuals with scores below cutoff point and one among
subjects with high scores. Age-adjusted prevalence was 8.1 per thousand subjects
age 50 or over (95% CI: 3.7-12.5); and 34.2 per thousand for ages 75 or over (95%
CI: 12.2-56.2). Sensitivity and specificity were 92.3 and 53.7%; 16 of the 19
questions show significant differences (p < 0.001) according to educational
level. A gender gap is significant in low educational levels (p < 0.001) but not
in subjects with more than five years of schooling. CONCLUSIONS: MMSE scores
correlated closely with level of education. Low specificity leads to many non
demented subjects with low educational status requiring further investigation.
PMID- 10775970
TI - [Dysembryoplastic neuroepithelial tumors].
AB - INTRODUCTION: The dysembryoplastic neuroepithelial tumors tend to occur in young
patients, with partial complex partial seizures which is refractory to medical
treatment. These are stable lesions, with defined histological features,
specially with clinical data corroboration. CLINICAL CASES: The clinical,
imagiological, operative, and histopathological data of six patients with proved
dysembryoplastic neuroepithelial tumors were reviewed. All patients had seizures
with age at onset ranged from 7 to 27 years. Five lesions were located in the
temporal lobe and one in the parietal lobe. Common features included cortical to
subcortical location, low density in CT-scan, very low signal intensity on T1
weighted images and high signal on T2-weighted images. Calcification occurred in
two lesions, and three showed contrast enhancement. Complete resection of the
tumor was performed in three cases, and subtotal resection in other three cases.
Pathological features included oligodendroglial-like cells, glioneural component,
and few cases showed dysplastic cortical disorganization. The postoperative
period of follow-up ranged from 2 to 18 months. Four patients were seizure free,
two of which had subtotal resection of the lesion. The remaining two patients
maintained seizures. CONCLUSIONS: The clinical, imagiological and
histopathological data of the six cases presented are generally compatible with
those of the reports reviewed by the authors. The imagiological features are
nonspecific. Surgical treatment permits histological diagnosis and epilepsy
control.
PMID- 10775969
TI - [Giant subarachnoid cysts due to neurocysticercosis: two cases reported fro a
rural area in Extremadura].
AB - INTRODUCTION: Neurocysticercosis is the commonest cerebral parasitosis. The most
recent cases reported in Spain have occurred in patients from endemic countries.
The formation of giant subarachnoid cysts (GSC) is an uncommon complication of
neurocysticercosis and its treatment is the subject of debate. We report two
cases seen recently in the Valle del Jerte, a rural district in Extremadura.
CLINICAL CASES: Case 1. A 64 year old man had had complex partial crises (CPC)
since 1985. In 1987 he was diagnosed as having neurocysticercosis with
parenchymatous cysts and treated with praziquantel. In 1996, on CAT and MR a left
frontal GSC was diagnosed and also two parenchymatous active cysts. The cyst was
removed surgically and he was subsequently treated with albendazol. Case 2. A 72
year old man had generalized crises and CPC since 1970. In 1987 and 1991 on CAT
and MR several parenchymatous lesions compatible with neurocysticercosis were
seen. In 1997 he presented with headache and subacute cognitive impairment. On
CAT and MR a left temporal GSC was seen with several active parenchymatous
lesions. The patient was treated with albendazol and dexamethasone. Both patients
improved, although radiological resolution of the GSC in case 2 took a year.
CONCLUSIONS: Neurocysticercosis is a condition still present in Spain. GSC
respond to treatment with albendazol, whilst surgical treatment is the best
option when severe intracranial hypertension occurs.
PMID- 10775971
TI - [An unusual presentation of herpetic encephalitis].
AB - INTRODUCTION: Herpetic encephalitis (HE) is the commonest cause of acute sporadic
encephalitis in the United States and Europe. In 20% of cases, the clinical
course is atypical and this may lead to delay in diagnosis and treatment.
CLINICAL CASE: A 24 year old patient presented with aseptic meningitis, which had
been present for the previous 10 days and which then became complicated by fever
and aphasia. The cerebrospinal fluid (CSF) showed marked pleocytosis and
increased protein. Cerebrospinal puncture was found to be positive for DNA of the
herpes simplex virus. Magnetic resonance (MR) imaging showed a temporal lesion
with intense uptake of contrast. Treatment was started with acyclovir and the
patient improved over the days following this. CONCLUSIONS: At present the
diagnosis of herpetic encephalitis is based on polymerase chain reaction (PCR)
studies of the CSF and MR imaging. The correlation between patients with HE with
cerebrospinal puncture showing positive for herpes and alterations on MR is 89%.
In view of the 20% of atypical forms, a high degree of clinical suspicion is
necessary to try to obtain early diagnosis and treatment.
PMID- 10775972
TI - [Essential mixed cryoglobulinemia as a cause of ischemic cerebrovascular
accident].
AB - INTRODUCTION: Involvement of the central nervous system in patients with
essential mixed cryoglobulinaemia is rare, and there are few cases described in
the medical literature. Moreover, the mechanism by which lesions are produced in
the central nervous system is still not clear. CLINICAL CASE: We describe the
case of a 35 year old woman who presented with dysarthria, weakness and
paraesthesia of her left limbs and left central facial paralysis of sudden onset.
Vascular studies showed the presence of IgG-IgM polyclonal positive cryoglobulins
and polymerase chain reaction (PCR) showed hepatitis C virus to be present.
Cerebral magnetic resonance showed ischemic lesions in the tail of the right
caudate nucleus and right corona radiata and the posteromedial part of the right
putamen. Other investigations were negative or normal. CONCLUSIONS: In young
patients with cerebral vascular pathology the possibility of hepatitis C and
essential mixed cryoglobulinemia should be considered, especially when the
transaminases are raised as in our patient. We consider that the
physiopathological mechanisms must be related to factors which determine a
prothrombotic state in the arterial bed involved.
PMID- 10775973
TI - [Central nervous system mycotic infections].
AB - INTRODUCTION: There has been an increased number of cases of fungal diseases of
the central nervous system (CNS) during the past few years. This paper reviews
current literature about these conditions, with emphasis on recent advances on
diagnosis and therapy. DEVELOPMENT: While some fungi may cause disease in normal
hosts, most of these microorganisms are opportunistics and affect
immunocompromised hosts. With the exception of Candida albicans, that is a normal
inhabitant of the intestinal tract, most fungi enter the body by inhalation or
through skin abrasions. Common fungal diseases include aspergillosis,
blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis,
mucormycosis, paracoccidioidomycosis, and phaeohyphomycosis. In general terms,
fungal invasion of the CNS may produce one or more of the following clinical
syndromes: subacute or chronic meningitis, encephalitis, parenchymal brain
abscesses or granulomas, stroke, or myelopathy. Diagnosis may be difficult on
clinical grounds, and data provided by neuroimaging studies or CSF examination is
non-specific. Definitive diagnosis usually rest on the demonstration of the
causal agent on body fluids or tissue samples. Early administration of
amphotericin B, associated or not with the new azoles, is indicated to arrest the
often fatal course of these conditions. CONCLUSIONS: Formerly considered rare
diseases, the acquired immunodeficiency syndrome (AIDS) epidemic and the
widespread use of corticosteroids and cytotoxic agents, have caused an increase
in the prevalence of CNS mycosis. Development of potent antimycotic drugs have
improved the prognosis of fungal diseases of the CNS. However, due to diagnostic
delays or the presence of debilitating conditions, some patients still have
torpid clinical courses despite proper therapy.
PMID- 10775975
TI - [Cognitive evaluation in illiterate persons].
AB - INTRODUCTION: Approximately a third of the world population is illiterate. The
analysis of illiterate patients' performance in cognitive tasks is an important
part of neuropsychology. OBJECTIVE: To show that cognitive evaluation tests, both
psychological and neuropsychological, are extremely sensitive to the educational
level of the subject. DEVELOPMENT AND CONCLUSIONS: It has been suggested that
schooling may in some way modify the cerebral organization of cognitive activity.
Although education does not alter the hemisphere dominance of language and other
cognitive functions, there does seem to be increased lateralization of these
functions in literate people. In neuropsychological testing, schooling is an even
more significant variable than age. However, education does have a lineal effect
on the scores obtained in neuropsychological tests. More precisely, the
relationship between schooling and performance of neuropsychological tests shows
an negatively accelerated curve.
PMID- 10775974
TI - [Physiopathology of cerebral ischemia].
AB - INTRODUCTION: Knowledge of physiopathological mechanisms permits understanding of
neuro-imaging changes during the various phases of cerebral ischaemia and the
mechanisms of action on which many aspects of treatment are based. DEVELOPMENT:
The physiopathology of cerebral ischemia is different in the white and grey
matter of the brain. In the grey matter, obstruction of a blood vessel causes an
ischemic gradient. In the more peripheral zones, known as the ischemic penumbra,
functional alterations occur in the neurons and the glia, although the structural
integrity is maintained for some time. Liberation of glutamate and the entrance
of calcium into the cells leads to a series of biochemical processes which end in
neurone death. In the white matter, loss of energy alters the direction of the
ion exchange pumps, resulting in calcium entering the axon. Liberation of GABA
activates specific receptors which protect the nerve fibres from the consequences
of anoxia. CONCLUSIONS: The cerebral oedema which accompanies ischemia has a
double mechanism: initially it is cytotoxic and then vasogenic. Both contribute
to increase the neurological damage caused by cerebral ischaemia.
PMID- 10775976
TI - [Neuropsychological evaluation of patients with perceptual and/or motor
deficits].
AB - INTRODUCTION: The task of neuropsychology should be based on confirmation of the
suspected deterioration, definition of the degree of deterioration and
differentiation between focal and diffuse lesions, and should also apply to the
results obtained in different evolutionary assessments. In subjects with
particular characteristics--such as is the case of persons with motor and/or
sensory deficits--neuropsychological evaluation should take into account the
possible defects and be adapted more closely to each individual patient. In spite
of the rigorous methodology necessary in all evaluations, the application of
protocols should be adapted to each case. The examination of the patient should
be varied according to what is required and the particular condition of each
patient. We must consider that some aspects of neuropsychological evaluation are
specifically related to the neurological function--muscle, tone, reflexes,
sensitivity, perception, etc.--which may be affected. Residual disability often
includes motor difficulties and problems of perception which should be
considered. DEVELOPMENT: In this paper we show the need for the relevant
selection of tests and careful interpretation of the results in persons with
sensory and/or motor defects, and we describe some tests which are useful for the
neuropsychological evaluation of general functions in patients with visual and
auditory functions respectively. CONCLUSIONS: It is necessary to know exactly
which dysfunction is involved and whether the person is conscious of the deficit.
Evaluation should also cover cognitive, social and affective-emotional aspects.
It is necessary to work on creating specific tests for particular populations.
PMID- 10775977
TI - [Neurological evaluation of behavior].
AB - INTRODUCTION: The evaluation of behavior is becoming increasingly important in
neurology, mainly because the behavior disorders are an important factor in
overburdening carers and leading to institutionalization of patients with
dementia. DEVELOPMENT: In this article we review the methodology and scope of the
evaluation of conduct in cognitive deterioration and in dementia, with special
attention to Alzheimer's disease. We also describe the instruments for evaluation
which the author considers to be most relevant. From an initial broad concept,
the scales of evaluation have been reduced to a limited concept of behavior
disorder, which is an equivalent phenomenon to a 'psychiatric disorder'. The
behavioral manifestations of the different dementias overlap completely, so that
there is only limited usefulness in the evaluation of behavior for differential
diagnosis. However, detailed evaluation of behavior contributes to a more
rational approach to these patients, which would reduce the career's burden.
CONCLUSION: Development of sensitive scales during all the phases of
deterioration and of instruments which allow one to investigate the genesis of
the different disorders are urgently needed, preferably with an intercultural
approach.
PMID- 10775978
TI - [Evaluation of epilepsy surgery].
AB - INTRODUCTION: Neuropsychology is a discipline included in the neurosciences
which, over the past twenty years, has shown its value in the assessment and
rehabilitation of cognitive functions in different disorders. In particular, in
epilepsy it has permitted the description of the different factors which affect
cognitive deterioration; permitted the establishment of profiles of cognitive
deterioration and also the evaluation of the adverse effects of some anti
epileptic drugs on cognition. DEVELOPMENT: In this paper we confirm the value of
neuropsychology in an Epilepsy Unit and describe different procedures for
evaluation, as well as the cognitive consequences of the surgery of epilepsy.
PMID- 10775979
TI - [Acalculia. Neurological bases, evaluation and disorders].
AB - OBJECTIVE: To make a review of the literature on alterations in mathematical
ability secondary to structural cerebral lesions. DEVELOPMENT AND CONCLUSIONS: We
refer to the initial classification of acalculia of Berger (secondary acalculia
when this is due to broader neuropsychological deficits and primary acalculia
when it occurs alone) to the classical division of Hecaen (alexia and numerical
agraphia with or without alterations in reading and writing of letters and words,
visuo-spatial acalculia due to alterations in the spatial organization of multi
digit figures and the partial results of arithmetical operations, anarithmetia or
primary failure in mathematical ability) and the most recent classifications
based on neurocognitive models, which subdivide the acalculias into those
secondary to changes in the system for processing numbers and those due to
changes in the cognitive system for mathematics (McCloskey and Caramazza).
Similarly, we review the correlations between the clinical changes in mathematics
and the cerebral localization of the causative lesions (left parieto-temporal,
right and including frontal and subcortical associative areas) together with the
association of acalculia and other neuropsychological deficits. Finally we review
the neuropsychological instruments available for the evaluation of acalculias,
with particular reference to the tools validated and scaled for our language and
sociocultural setting.
PMID- 10775980
TI - [Procesing of faces: neurological bases, disorders and evaluation].
AB - INTRODUCTION AND DEVELOPMENT: The processing of faces and recognition of familiar
faces involves activity in many regions of the brain: 1. The visual association
cortex in the act of constructing the perceived object; 2. Hippocampus and
frontotemporal regions in the process of comparing what has been perceived with
remembered images to activate sentiments of familiarity; 3. The temporoparietal
regions in the semantic memory related to people, and 4. The left hemisphere in
the activation of linguistic structures which codify information for access to
the name. Lesions in any of these structures may give rise to alterations in the
different steps of the cerebral processing of faces, amongst which prosopagnosia
and prosopamnesia stand out. CONCLUSION: The psychophysiological and functional
neuroimaging studies will permit, in the near future, evaluation and trial of
cognitive models and advances in the understanding of cerebral processing of
faces, their evaluation and disorders.
PMID- 10775981
TI - [Attention and neglect: neurological basis, assessment and disorders].
AB - OBJECTIVE: Attention phenomenology is a wide subject, in this revision we will
explain attention and its relationship with behavioral neglect. DEVELOPMENT:
Selective attention is the ability to throw the focus of awareness toward
behaviorally relevant events in the personal and extrapersonal space. Severe
alteration of these mechanisms constitutes unilateral neglect in patients with
contralateral brain damage. Unilateral neglect is one of the most behaviorally
devastating syndrome. There are different behavioral neglect: attentional
(perceptual), intentional (motor), motivational and representational aspects of
unilateral neglect. Left side neglect after right hemisphere lesions is more
common (31 to 46%) than right sided neglect following lesions in the left
hemisphere (2 to 12%). CONCLUSION: One year after a cerebrovascular accident only
1/3 of the patients with unilateral neglect persist with this handicap.
PMID- 10775982
TI - [Spanish neurology during "The Illumination". The work of Gaspar Casal].
AB - During 'The Illustration', Spanish medicine broke free of its cultural isolation
and sought to participate in the new European tendencies. Sydenham's medicine,
based on observation as opposed to the dogmatism of Galenism, was practised in
our country by Gaspar Casal of Gerona. His posthumous work Historia Natural y
Medica del Principado de Asturias is an outstanding example of observation and
theory based on the evidence. Famous for his description of the clinical picture
of pellagra (mal de la rosa) it includes chapters in which his clinical acumen
was applied to neurological conditions such as hysteria, epilepsy and apoplexy.
PMID- 10775983
TI - [Disseminated intraperenchymal neurocycsticercosis].
PMID- 10775984
TI - [Subdural empyema: a case report].
PMID- 10775985
TI - [Epileptic crises associated with trisomy of the short arm of chromosome 7
(46,XY,7p+].
PMID- 10775986
TI - [BVD approach: vaccination and eradication].
AB - The vulnerability of cattle populations that do not have adequate levels of
antibodies against the bovine virus diarrhoea (BVD) virus was demonstrated in
February 1999, when a contaminated vaccine against infectious bovine
rhinotracheitis (IBR) was accidentally used. Only cattle with antibodies against
BVD survived this unintentional challenge. A BVD infection can be detected easily
with currently available laboratory techniques, but the virus is less easy to
eliminate. The risk of financial loss is small, and the costs are limited, if
mainly seronegative cattle, selected on the basis of sampling, are given the live
vaccine. Over the last 7 years this approach has been applied to about twenty
dairy farms. This approach would be compatible with a BVD eradication programme.
PMID- 10775987
TI - Complicated third stage of labor: time to switch on the scanner.
AB - This Editorial chronicles the current experience in ultrasound usage during
pathologic events occurring in the third stage of labor. Further improvement in
the technology for carrying out clinical research will improve our knowledge so
that more information can be gleaned from this modality to bestow optimal
management for such potentially dangerous conditions. Awareness of the
capabilities of sonography may provide the motivation for its use, and
obstetricians are encouraged to scan the third stage of normal deliveries for
better recognition of normal findings and improved assessment of abnormal ones.
Although final decisions should be based mainly upon sound clinical judgement, we
contend that complicated third stage of labor warrants turning on the scanner.
PMID- 10775988
TI - Extended field-of-view and B-flow ultrasound: fashion or future?
PMID- 10775989
TI - Blood flow velocity waveforms from fetal peripheral pulmonary arteries in
pregnancies with preterm premature rupture of the membranes: relationship with
pulmonary hypoplasia.
AB - OBJECTIVES: To measure fetal peripheral pulmonary artery velocity waveforms by
Doppler ultrasonography in pregnancies complicated by premature rupture of
membranes under 24 weeks' gestation and to relate the Doppler indices to the
development of fetal pulmonary hypoplasia. DESIGN: A prospective longitudinal
study of fetal peripheral pulmonary artery velocity waveforms from premature
rupture of membranes to delivery. SUBJECTS: Twenty pregnancies complicated by
premature rupture of membranes before 24 weeks of gestation and delivering after
26 weeks. METHODS: Peripheral pulmonary artery velocity waveforms were recorded
by Doppler technique at weekly intervals until delivery and Pulsatility Index
(PI) calculated. Pregnancies were managed conservatively according to an
institutional management protocol. Pulmonary hypoplasia was defined at autopsy by
lung/body weight ratios and radial alveolar counts. Pulsatility Indices of
fetuses developing pulmonary hypoplasia were compared with those with a normal
lung development. RESULTS: After premature rupture of membranes PI values were
higher than normal reference limits for gestation, but no differences were found
between the six fetuses which developed pulmonary hypoplasia and the remaining 14
fetuses with normal lung development. In this latter group PI values
progressively decreased with advancing gestation (ANOVA for repeated measurements
F = 11.61; P < or = 0.001), while they increased in fetuses developing pulmonary
hypoplasia (F = 8.44; P < or = 0.001). As a consequence of these opposite trends
significant differences in PI values were present between the two groups of
fetuses from 2 weeks after the premature rupture of membranes. Two weeks after
the premature rupture of membranes a PI value from the peripheral pulmonary
arteries above the 95th centile had a sensitivity of 62.5%, specificity of 94.6%,
positive predictive value of 83.3%, negative predictive value of 78.5% and
relative risk of 3.88 (95th confidence interval 1.34-11.28) for the prediction of
pulmonary hypoplasia. CONCLUSION: The measurement of peripheral pulmonary
velocity waveforms may help to establish the risk of developing pulmonary
hypoplasia in pregnancies complicated by premature rupture of membranes.
PMID- 10775990
TI - The association between congenital heart disease and Down syndrome in prenatal
life.
AB - OBJECTIVE: To assess the relationship between congenital heart disease (CHD) and
Down syndrome (DS) in utero. DESIGN: Retrospective case series. SUBJECTS: Fifty
two fetuses with a cytogenetic diagnosis of DS managed at our Fetal Cardiology
Unit in the study period. In particular, two populations of fetuses with DS were
studied: a group of 41 DS fetuses referred to our unit for fetal echocardiography
due to the chromosomal anomaly and a second group of 274 fetuses referred because
of suspected CHD, 11 of which were found to have DS. METHODS: All fetuses were
submitted to detailed ultrasound evaluation of fetal anatomy. Associated
extracardiac anomalies, and presence and type of CHD, were recorded for all
fetuses. Karyotyping was obtained by means of cordocentesis or amniocentesis.
Necropsy or neonatal echocardiograms were sought for confirmation of the prenatal
diagnosis. RESULTS: In the group of 41 fetuses with known DS, the incidence of
CHD was 56% ([atrioventricular septal defect (AVSD) 44%, ventricular septal
defect (VSD) 48%], the remainder having other heart defects). Conversely,
considering the incidence of DS in fetuses with CHD, 43% of all AVSDs (53% of
AVSD with normal visceral situs) were associated with DS, whereas none of the 39
cases of VSD was associated with trisomy 21. Ventricular septal defects were
diagnosed only in fetuses referred to our center with a known diagnosis of
aneuploidy. CONCLUSIONS: We have confined that more than half of the fetuses with
DS bear a CHD, which is an AVSD in 44% of cases. Conversely, 43% of fetuses with
an AVSD have trisomy 21. For VSDS, the situation is controversial, due to the
relatively low detection level of this heart defect at the routine mid-trimester
obstetric scan.
PMID- 10775991
TI - The cervix as a predictor of preterm delivery in 'at-risk' women.
AB - OBJECTIVE: To examine the relationship between ultrasound-determined cervical
status and pregnancy outcome in women 'at-risk' of spontaneous preterm delivery.
DESIGN: A prospective cohort study of 120 pregnant women considered to be 'at
risk' of spontaneous preterm delivery by their clinician. Transvaginal ultrasound
of the cervix was used to assess overall cervical length, closed endocervical
canal length, diameter and internal os dilatation in the second trimester. The
main outcome measure was occurrence of spontaneous preterm birth (< 34 and < 37
weeks of gestation). RESULTS: The overall preterm delivery rate (< 37 weeks
gestation) in these women was 35% (n = 42) with 20% (n = 24) delivering < 34
weeks gestation. Of the 71 women with a normal cervix, 8 (11%) delivered < 34
weeks, whereas of the 49 women with an abnormal cervix, 16 (33%) delivered < 34
weeks (RR 2.90; 95% CI 1.35-6.24). Using linear regression, closed endocervical
canal length of < 21 mm before 20 weeks is associated with delivery < 34 weeks in
95% of women, and with delivery < 37 weeks in 95% of women if the canal length is
< 33 mm. Logistic regression showed closed endocervical canal length to be the
only significant factor in those women who delivered < 34 weeks after controlling
for possible confounders. CONCLUSIONS: A strong relationship is demonstrated
between cervical status and pregnancy outcome, particularly the cervical findings
before 20 and 24 weeks of gestation. The length of the closed portion of the
endocervical canal is the best predictor. A beneficial effect of this approach to
'at-risk' women is the reduction in unnecessary interventions in those with
normal cervical findings.
PMID- 10775992
TI - Prenatal diagnosis of single umbilical artery: determination of the absent side,
associated anomalies, Doppler findings and perinatal outcome.
AB - OBJECTIVE: To determine the absent side of a single umbilical artery and its
association with malformations and abnormal karyotypes. METHODS: We prospectively
studied 102 fetuses from 13 to 39 weeks of gestational age with a prenatally
identified single umbilical artery. The absent side, pregnancy data, Doppler
findings and the perinatal outcome were reviewed. RESULTS: (1) The left umbilical
artery was absent in 71 (69.6%) and the right in 31 (30.4%) fetuses; (2) Single
umbilical artery as an isolated finding occurred in 59 (57.8%) pregnancies and
was not associated with aneuploidy. The mean gestational age at delivery in this
group was 38.4 weeks and the mean birth weight was 3047 g. Six (10.2%) fetuses
were small for gestational age, all of them with normal umbilical and uterine
Doppler findings; and (3) Chromosomal abnormalities were diagnosed in 10 of 43
fetuses with single umbilical artery and congenital malformations. In nine of 10
fetuses with aneuploidy the left umbilical artery was not developed. Absence of
the left artery occurred in 21 of 33 fetuses with sonographic anomalies and
normal karyotype. Pathologic Doppler measurements of the umbilical artery were
found in only one case of nonchromosomal abnormality. CONCLUSION: Our data
suggest that in fetuses with single umbilical artery the absence of the left
artery is more frequent than the absence of the right artery. The association
with additional malformations seems to be equal on each side.
PMID- 10775993
TI - Prediction of discordant twins by real-time ultrasonography combined with
umbilical artery velocimetry.
AB - OBJECTIVE: To evaluate the role of umbilical Doppler velocimetry combined with
ultrasonographic intertwin differences derived from estimated fetal weight,
biparietal diameter, abdominal circumference and femur length as a comprehensive
test for the prediction of discordancy. METHODS: The sets of twins were studied
with real-time ultrasonography for morphometric measurements and with duplex
Doppler velocimetry for the S/D ratio of the umbilical artery in third trimester.
The following cutoff values were used to indicate abnormal test results: delta
biparietal diameter > 6 mm, delta abdominal circumference > 20 mm, delta femur
length > 5 mm, delta estimated fetal weight > 15% and delta systolic/diastolic
ratio > 15%. Discordancy was identified when the birth weight difference exceeded
15%. RESULTS: Among the 52 sets of twin pregnancies studied, 40 sets of twins
fulfilled the study criteria. Thirteen sets of twins were discordant (32.5%) The
mean gestational age at delivery was 37.15 +/- 2.24 weeks (range 28-41 weeks).
The diagnostic accuracy provided by ultrasonographic morphometries was not
significantly different from that provided by umbilical Doppler velocimetry.
Overall the best predictors appeared to be the presence of either delta
systolic/diastolic ratio > 15% or delta estimated fetal weights > 15% with
sensitivity and specificity values of 92% and 70%, respectively. CONCLUSION: Real
time ultrasonography combined with umbilical artery velocimetry is useful in
predicting discordant twins.
PMID- 10775994
TI - The application of three-dimensional ultrasound to nuchal translucency
measurement in early pregnancy (10-14 weeks): a preliminary study.
AB - OBJECTIVES: The aims of this prospective screening study were to calculate the
success rate and to assess the intraoperator variability of fetal nuchal
translucency measurement by using three-dimensional ultrasound. SUBJECTS AND
METHODS: Eighty-six women, each with a singleton pregnancy undergoing routine
nuchal translucency measurement between 10 weeks and 14 weeks plus 6 days
gestational age. Three-dimensional transvaginal sonography was performed. A new
method of nuchal translucency measurement was applied from three volumetric data
sets using four steps. RESULTS: In all cases good sagittal views of the fetus
were obtained, the fetal skin could be distinguished from the amnion and the
nuchal translucency thickness could be measured. The new measurement procedure
could be standardized. The overall time required for the examination was 5 min.
The procedure caused no discomfort to the woman and was easily performed by the
examiner. Intra-operator variability was low (P = 0.862). CONCLUSION: Three
dimensional ultrasound is a useful and easily applicable tool for nuchal
translucency measurement during early pregnancy (10-14 weeks plus 6 days). Its
advantages still need further evaluation.
PMID- 10775995
TI - On-to-on versus on-to-out nuchal translucency measurements.
AB - OBJECTIVE: To analyze variables affecting the differences between on-to-on and on
to-out methods of nuchal translucency measurement. DESIGN: Prospective comparison
of two methods of caliper placement. SUBJECTS: A total of 245 women undergoing
transabdominal and 37 women undergoing transvaginal nuchal translucency scanning.
METHODS: Nuchal translucency was measured using both on-to-on and on-to-out
methods of caliper placement on the same frozen images. Differences between the
methods were evaluated according to fetal size, nuchal thickness and mode of
examination. Regression analysis was performed for the calculation of the
expected difference between the methods at various combinations. Results among
1254 singleton pregnancies were used to set 50th, 95th and 97.5th centiles for
the on-to-on method. The calculated differences were used to set 50th, 95th and
97.5th centiles for the on-to-out method. RESULTS: The mean difference between on
to-out and on-to-on nuchal translucency, using transabdominal scanning, was 0.95
+/- 0.14 mm. The differences were shown to correlate directly with fetal size and
with nuchal thickness. In addition, scans performed transvaginally exhibited a
smaller difference between the methods (0.90 mm vs. 0.94 mm; P < 0.05).
CONCLUSION: The difference between on-to-on and on-to-out nuchal translucency
measurements may have a considerable effect on the calculated risk for
aneuploidy.
PMID- 10775996
TI - Relationship between fetal femur diaphysis length and neonatal crown-heel length:
the effect of race.
AB - OBJECTIVE: To determine whether racial differences affect the relationship
between the fetal femur diaphysis length and the neonatal crown-heel length.
DESIGN: A prospective study in a teaching hospital with a multiracial population.
SUBJECTS: Four hundred and fifty pregnant women (150 Malays, 150 Chinese and 150
Indians) who delivered live infants. METHODS: Ultrasound scan measurement of the
fetal femur diaphysis length was carried out within 48 h of delivery in all
cases. The relationship between the neonatal crown-heel length and the femur
diaphysis length was obtained by regression using the method of least squares.
Dummy or indicator variables were used to determine the effect of race on the
relationship. RESULTS: The relationship between the neonatal crown-heel length
and the femur diaphysis length in all three races was well described by a linear
model but a quadratic model described the relationship better. There was no
significant difference in relationship of the neonatal crown-heel length and the
femur diaphysis length between the Malay and Chinese populations, but the
relationship in the Indian population was significantly different was from both
the Chinese and Malay. For a given femur diaphysis length, the crown-heel length
of the Indian population was found on average to be 1.1 cm shorter than the crown
heel length of the Malay and Chinese populations. CONCLUSION: Differences in
fetal body proportions exist between some races. The longer femur diaphysis
length noted in certain races does not necessarily imply that the corresponding
crown-heel length is longer. These inter-racial differences may increase the
error of fetal weight and length estimates if formulae, which have been derived
from samples racially dissimilar to that of the target population are used.
PMID- 10775997
TI - Gray scale and color Doppler sonography in the third stage of labor for early
detection of failed placental separation.
AB - OBJECTIVE: The purpose of this study was the characterization of normal and
abnormal third stage placental separation using gray scale and color Doppler
sonography. METHODS: The third stage of labor was examined in 62 patients using
gray scale and color Doppler sonography. After identification of placental basal
plate vessels by color Doppler sonography, the placentation site was examined
throughout the third stage with combined gray scale and color Doppler mode.
Placental separation from the myometrium was defined clinically and correlated to
cessation of color Doppler detected blood flow in basal plate vessels. RESULTS:
Three sonographic phases of placental separation were: (1) latent = interval
between delivery of the fetus and beginning placental separation; (2) detachment
= mono- or multiphasic shearing off of the placenta and (3) expulsion = interval
between completed separation and vaginal delivery of the placenta. In 57 cases
with clinically normal placental separation blood flow between placenta and
myometrium ceased immediately after delivery of the fetus during the latent
period. In five cases manual or instrumental removal was necessary because of
placenta adhaerens in one case and placenta accreta in four cases. The latter
showed maternal blood flow from the myometrium deep into the placenta beyond the
latent phase. CONCLUSION: Cessation of blood flow between the basal placenta and
myometrium following delivery of the baby is the sonographic hallmark of normal
placental separation. Persistent blood flow demonstrated by color Doppler
sonography is suggestive of placenta accreta.
PMID- 10775998
TI - Comparison of Lerner score, Doppler ultrasound examination, and their combination
for discrimination between benign and malignant adnexal masses.
AB - OBJECTIVE: To determine whether the combined use of Lerner's morphologic score
and color Doppler ultrasound examination results in better discrimination of
benign and malignant adnexal masses than the use of Lerner's score alone or
Doppler variables alone. DESIGN: One hundred and seventy-three consecutive women
with a pelvic mass judged clinically to be of adnexal origin underwent
preoperative ultrasound examination including color and spectral Doppler
techniques. One hundred and forty-nine tumors were benign and 24 malignant. The
sensitivity and false-positive rate with regard to malignancy were calculated for
Lerner's score, six Doppler variables and combinations of Lerner's score and
Doppler variables. Previously defined gray scale and Doppler criteria of
malignancy were used and tested prospectively. The best method was defined as
that detecting most malignancies with the lowest false-positive rate. RESULTS:
Lerner's score had a sensitivity of 92% and a false-positive rate of 36%. The
best Doppler variable--time-averaged maximum velocity--had similar diagnostic
properties with a sensitivity of 100% and a false-positive rate of 41%. Combining
Lerner's score with Doppler measurement of time-averaged maximum velocity--i.e.
requiring both Lerner's score and time-averaged maximum velocity to indicate
malignancy for a malignant diagnosis to be made--had a sensitivity of 92% and a
false-positive rate of 19%. CONCLUSIONS: The combined use of Lerner's score and
measurement of time-averaged maximum velocity is a better method for
discrimination of benign and malignant adnexal masses than the use of Lerner's
score alone or Doppler ultrasound examination alone. The clinical value of the
combined method needs to be cross-validated prospectively in a new series of
tumors.
PMID- 10775999
TI - Demonstration of a recto-vaginal fistula with the ultrasound contrast medium
Echovist.
AB - The demonstration of a recto-vaginal fistula in a patient with Crohn's disease is
described. The patient was examined by vaginal ultrasound using the contrast
medium Echovist-200 (SHU 454, Schering AG, Berlin). This agent had not been used
before under these circumstances and proved to be successful.
PMID- 10776000
TI - Prenatal ultrasonographic diagnosis of posteromedial bowing of the leg: two case
reports.
AB - Congenital posteromedial bowing of the leg was prenatally detected in two
pregnancies, at 20 and 31 weeks of gestation. Posteromedial bowing is a rare
anomaly of unknown etiology. The prenatal course, monitored by ultrasonography,
and the postnatal clinical and radiographic outcomes are discussed and show a
complex differential diagnosis. The initial postnatal therapy is conservative.
Leg length discrepancy can eventually be treated by lengthening or epiphysiodesis
on the contralateral side.
PMID- 10776001
TI - Early prenatal ultrasound diagnosis of cleidocranial dysplasia.
AB - A woman was referred in the first trimester of her third pregnancy because of a
family history of cleidocranial dysplasia. An ultrasound examination at 14 weeks
4 days revealed a fetus with appropriate biometric measurements. However, the
clavicles were noted to be hypoplastic and the cranium appeared less well
ossified than expected for gestational age, suggesting the diagnosis of
cleidocranial dysplasia. On subsequent examination at 21 weeks, the findings were
essentially unchanged. Induced vaginal delivery owing to decreased amniotic fluid
volume occurred at 37 weeks, and a female weighing 3200 g was delivered. The
infant had clinical and X-ray signs of cleidocranial dysplasia.
PMID- 10776002
TI - Extended field-of-view ultrasound imaging in obstetrics and gynecology:
preliminary experience.
PMID- 10776003
TI - Prenatal diagnosis of ventriculo-coronary fistula in a late first-trimester fetus
presenting with increased nuchal translucency.
PMID- 10776004
TI - New application of B-flow sono-angiography in perinatology.
PMID- 10776005
TI - Aspirin and prevention of vascular complications: there are still indications.
PMID- 10776006
TI - Mid-trimester uterine artery Doppler screening as a predictor of adverse
pregnancy outcome in high-risk women.
AB - OBJECTIVE: To assess the value of uterine artery Doppler ultrasound screening,
when performed in a clinical setting, to predict complications of impaired
uteroplacental blood flow in high-risk women. DESIGN: A prospective audit.
SUBJECTS: A total of 116 pregnancies in 114 women at high risk of pre-eclampsia
and/or small-for-gestational-age (SGA) babies attending a maternal-fetal medicine
clinic at National Women's Hospital, a tertiary referral hospital, Auckland, New
Zealand. METHODS: Uterine artery Doppler screening was performed as part of
clinical practice between 22 and 24 weeks' gestation. A resistance index (RI) was
calculated from each uterine artery and the presence or absence of a notch was
determined. An RI of > 0.58 was defined as abnormal and an RI of > or = 0.7 was
defined as very abnormal. The main outcome measures were: pre-eclampsia, SGA baby
(birth weight < 10th centile), placental abruption, intrauterine death, 'all' and
'severe' outcomes. RESULTS: Thirty-two (27.5%) women developed pre-eclampsia, 31
(26.7%) had SGA babies, 23 (20%) were delivered at < 34 weeks because of
pregnancy complications, and there were three (2.6%) placental abruptions and
three (2.6%) perinatal deaths. The sensitivity of any RI of > 0.58 for pre
eclampsia, SGA, 'all' outcomes and 'severe' outcome was 91%, 84%, 83% and 90%,
respectively. The specificity of any RI of > 0.58 for these outcomes was 42%,
39%, 47% and 38%, respectively. The positive predictive value of any RI of > 0.58
for the same outcomes was 37%, 33%, 58% and 24%, respectively. Among women with
both RI values of > or = 0.7, 58%, 67%, 85% and 58% developed pre-eclampsia, SGA,
'all' and 'severe' outcomes, respectively. In women with bilateral notches, 47%,
53%, 76% and 65% developed the respective outcomes. Women with both RI values of
> or = 0.7 and women with bilateral notches had relative risks of 11.1 (95% CI
2.6-46.4) and 12.7 (95% CI 4.0-40.4) for developing severe outcome, respectively.
Only 5% of women with both RI values of < 0.58 developed a severe outcome.
CONCLUSION: In high-risk women, uterine artery Doppler waveform analysis
performed best in the prediction of severe adverse outcome and was better than
clinical risk assessment in the prediction of pre-eclampsia and SGA babies.
Further studies are necessary to determine how information from uterine artery
Doppler studies should modify current practice in high-risk women.
PMID- 10776007
TI - A prospective management study of slow-release aspirin in the palliation of
uteroplacental insufficiency predicted by uterine artery Doppler at 20 weeks.
AB - OBJECTIVE: To investigate the effect of low-dose, slow-release aspirin in
reducing the incidence and/or severity of pregnancy complications in women
identified as high risk of developing problems associated with uteroplacental
insufficiency, namely pre-eclampsia or delivering a small-for-gestational age
(SGA) baby. DESIGN: A prospective, randomized management study. One thousand and
twenty-two women of mixed parity underwent color flow/pulsed Doppler (CFPD)
imaging of the uterine arteries at the time of the 17-23 week (mean 19.9) anomaly
scan. Women who were screen positive were randomized to a control or treatment
group. The treatment group was given 100-mg slow-release aspirin (Disprin CV)
daily and followed up at regular intervals. Women in the routine group received
routine antenatal care. Main outcome measures were pre-eclampsia and SGA < 3rd
centile. Secondary outcome measures were: SGA < 10th centile, pre-eclampsia
requiring delivery before 34 weeks, placental abruption, an Apgar score < 7 at 5
min, admission to neonatal intensive care unit or a pregnancy that resulted in a
stillbirth or neonatal death. Odds ratios (OR) with 95% confidence intervals (CI)
were calculated for severe and any complications. RESULTS: Two hundred and
sixteen women were screen positive according to the defined criteria. One hundred
and three women were assigned to the treatment group and 113 to the control
group. The difference in the incidence of pre-eclampsia and SGA < 3rd centile
between the control and treatment groups did not reach statistical significance.
There was a statistically significant reduction in any (OR 0.41 (CI 0.35-0.45), P
< 0.01) and severe pregnancy complications (OR 0.43 (CI 0.21-0.84), P < 0.05) in
the treatment group compared with the controls. CONCLUSIONS: The administration
of slow-release aspirin to women identified as high risk, using color Doppler
imaging of the uterine arteries at 20 weeks' gestation, did not significantly
alter the incidence of pre-eclampsia or delivery of a SGA baby. It did, however,
improve the outcome by reducing the overall incidence of complications associated
with uteroplacental insufficiency.
PMID- 10776008
TI - Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy:
results of a randomized, placebo-controlled, double-blind trial.
AB - OBJECTIVE: This study was conducted to evaluate uteroplacental and fetal
hemodynamics in fetuses exposed to low-dose aspirin (100 mg/d). DESIGN:
Randomized, placebo-controlled, double-blind trial. SUBJECTS: The study protocol
included singleton pregnancies of less than 20 gestational weeks at risk for pre
eclampsia or fetal growth restriction. Exclusion criteria were diabetes mellitus,
pre-existing proteinuric hypertension or fetal malformations. Forty-three
pregnant women were randomly allocated to daily treatment with 100 mg aspirin (n
= 22) or placebo (n = 21). METHODS: Pulsed Doppler measurements of the uterine
artery, fetal middle cerebral artery, fetal aorta, ductus arteriosus and
atrioventricular valves were performed longitudinally at 14 day intervals
starting from 18 gestational weeks until delivery. Results were expressed as
group medians (aspirin vs. placebo) and were analyzed by Mann-Whitney U-test.
RESULTS: There was no difference in uterine, umbilical, aortic, middle cerebral
and ductus arteriosus blood flow between the aspirin group and controls. Median
ductal peak flow velocities increased with gestational age in both groups, but
differences between groups did not reach significance. In the third trimester of
pregnancy, ductal peak velocities > 140 cm/s were occasionally observed in both
groups. However, end diastolic velocities > 35 cm/s or atrioventricular valve
regurgitation never occurred. CONCLUSIONS: Daily administration of low-dose
aspirin during the second and third trimesters of pregnancy does not alter
uteroplacental or fetoplacental hemodynamics and does not cause moderate or
severe constriction of the ductus arteriosus.
PMID- 10776009
TI - Prenatal diagnosis of placenta previa accreta by transabdominal color Doppler
ultrasound.
AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of transabdominal
color Doppler ultrasound in diagnosing placenta previa accreta. DESIGN: Eighty
patients with persistent placenta previa underwent transabdominal B-mode and
color Doppler ultrasound evaluation in the second and third trimesters because
they had a high risk of placenta accreta. Color Doppler imaging criteria used
included diffuse intraparenchymal placental lacunar flow; focal intraparenchymal
placental lacunar flow; bladder-uterine serosa interphase hypervascularity;
prominent subplacental venous complex; and loss of subplacental Doppler vascular
signals. The color Doppler images were interpreted prospectively for signs of
placenta previa accreta according to the exhibited color Doppler sonographic
features. RESULTS: Sixteen of the 80 patients exhibited characteristic color
Doppler imaging patterns highly specific for placenta accreta according to the
preceding criteria, and 14 of these had histopathological proof of placenta
accreta. Two patients had false-positive color Doppler imaging evidence mistaken
for interphase hypervascularity caused by bladder varices. Thirteen patients
underwent hysterectomy in the group suspicious for accreta. Of the 64 patients
with negative color Doppler imaging results, three had placenta accreta, while
two required cesarean hysterectomy; the remaining patient underwent uterine
artery ligation for bleeding from the lower uterine segment. The sensitivity of
color Doppler imaging in the diagnosis of placenta previa accreta was 82.4%
(14/17) and the specificity was 96.8% (61/63). The positive and negative
predictive values were 87.5% (14/16) and 95.3% (61/64), respectively.
CONCLUSIONS: Variable vascular morphological patterns of placenta previa accreta
were exhibited and categorized by transabdominal color Doppler sonography in the
antenatal period. The identification of these specific vascular patterns had a
positive impact on the peripartum clinical management of the affected patients.
PMID- 10776010
TI - Customized fetal weight limits for antenatal detection of fetal growth
restriction.
AB - OBJECTIVE: To define cut-off limits for individually adjustable fetal weight
standards for the detection of intrauterine growth restriction. DESIGN:
Retrospective study, with the outcome measures small-for-gestational age (SGA)
birth weight, operative delivery for fetal distress, umbilical artery pH < 7.15,
and admission to the neonatal intensive care unit. SUBJECTS AND METHODS: Two
hundred and fifteen women considered to be at increased risk of uteroplacental
insufficiency were recruited to a study of serial ultrasound scans. Fetal weights
were derived using standard formulae and, retrospectively, weight percentiles
were calculated after individual adjustment for maternal height, weight in early
pregnancy, ethnic group, parity and fetal sex. INTRODUCTION: One or more
antenatal scans indicative of fetal weight below the 10th customized percentile
were predictive for a SGA neonate at birth (P < 0.001), operative delivery for
fetal distress (P < 0.01) and admission to neonatal intensive care (P < 0.01) but
not for a low umbilical artery pH (P = 0.6). Receiver-operator curves showed the
optimal customized fetal weight percentile limit for predicting an SGA neonate to
be the 18th percentile (sensitivity 83%, specificity 79%, positive predictive
value 63% and negative predictive value 92%). For the prediction of operative
delivery for fetal distress and admission to neonatal intensive care, the
optional customized cut-off value was the 8th percentile. CONCLUSIONS: The
assessment of fetal weight using ultrasound and an individually-adjusted standard
is predictive of growth restriction and perinatal events associated with hypoxia
or diminished reserve. The optimal cut-off value for predicting operative
delivery for fetal distress or admission to the neonatal intensive care unit
suggests that the 10th customized percentile is a good limit for clinical use.
PMID- 10776011
TI - Gestational age in pregnancies conceived after in vitro fertilization: a
comparison between age assessed from oocyte retrieval, crown-rump length and
biparietal diameter.
AB - OBJECTIVE: To compare gestational age (GA) and day of delivery estimated from the
time of in vitro fertilization (IVF) (oocyte retrieval + 14 days), the ultrasonic
measurement of the crown-rump length (CRL) and the biparietal diameter (BPD) in
pregnancies conceived in an IVF setting. DESIGN: Included were 208 singletons and
72 twin pregnancies conceived after IVF. GA estimated from the time of IVF was
compared with the GA estimated from the ultrasonic measurement of the CRL in the
first trimester and the BPD in the second trimester. RESULTS: In singletons the
mean difference in gestational age was 0.9 days between IVF and CRL estimates and
2.1 days between IVF and BPD estimates. The gestational age as estimated from CRL
or BPD was shorter than the GA estimated from IVF. There was no systematic
variation in the mean differences in GA between the methods. In three pregnancies
there was a difference of more than 7 days between the gestational age estimated
from IVF and CRL and in 22 pregnancies between gestational age estimated from IVF
and BPD. A difference of > 14 days for any of the estimates was not found in any
case. In singletons there was a high correlation in the gestational age at birth
assessed from the time of IVF and from CRL, from the time of IVF and from BPD.
CONCLUSION: Assessment of gestational age from the time of IVF, CRL and BPD in
pregnancies conceived after IVF shows equally high agreement between the three
methods. This supports the use of ultrasound as a reliable method for estimation
of gestational age.
PMID- 10776012
TI - Fetal transverse cerebellar diameter measurements in normal and reduced fetal
growth.
AB - OBJECTIVES: To establish the increase in fetal transverse cerebellar diameter
(TCD) relative to gestational age during normal and restricted fetal growth; to
determine the significance of TCD and TCD/AC relationship in predicting fetal
outcome as expressed by perinatal mortality. DESIGN: A retrospective cross
sectional study. SUBJECTS: Three hundred and sixty normally developing fetuses
between 17 and 34 weeks of gestation and 73 growth-restricted fetuses between 24
and 34 weeks of gestation. METHODS: Ultrasonographic measurements included head
circumference (mm), abdominal circumference (mm) and transverse cerebellar
diameter (mm). A gestational age-related normal reference chart was produced for
TCD. RESULTS: Statistically significant relationships between transverse
cerebellar diameter and gestational age, abdominal circumference and head
circumference were found. The normal fetal TCD exhibited a more than twofold
increase in size during the second half of pregnancy. Twenty-six per cent of the
small-for-gestational age (SGA) fetuses displayed a reduced TCD and 82% of the
SGA fetuses demonstrated raised TCD/AC values. No statistically significant
difference in perinatal mortality or birth weight was found between the subsets
of growth-restricted fetuses with reduced or normal TCD; or between the subsets
with normal or raised TCD/AC values. CONCLUSIONS: In the normally developing
fetus the TCD increases with advancing gestational age. Increased TCD/AC values
are suspicious of fetal growth restriction. The perinatal mortality in growth
restricted fetuses with a small cerebellum is increased twofold over that of
other fetuses.
PMID- 10776013
TI - Patient acceptance of endovaginal ultrasound.
AB - OBJECTIVE: To assess women's experiences and attitudes regarding endovaginal
ultrasound. METHODS: Women attending the obstetrics and gynecology clinics at the
University of Florida were asked to complete an anonymous questionnaire. RESULTS:
Of respondents who had had a prior endovaginal ultrasound examination, 26%
reported that 'it hurt a lot' and 50% reported that 'it hurt a little'. In
contrast, only 23% of patients had experienced any pain with a prior abdominal
ultrasound (P < 0.001). Multivariate analysis showed that discomfort with a prior
vaginal ultrasound was related to patient age category, with less discomfort
being experienced with increasing ages (P = 0.001). A history of unwanted sex,
sexual or physical abuse, or dyspareunia was not associated with more painful
examinations. Most patients were willing to undergo a future vaginal ultrasound
investigation if it were recommended by their doctor. Multivariate analysis
showed that more willingness was associated with older age category (P = 0.004),
a history of dyspareunia (P = 0.03) and bleeding in a current pregnancy (P =
0.005). Of the patients (less than half) who had a preference, most preferred a
female sonographer for endovaginal sonography (P < 0.001) and most preferred that
a doctor, rather than a nurse or technician, perform the examination (P < 0.001).
CONCLUSIONS: The majority of women who had experienced a vaginal ultrasound
examination found it somewhat uncomfortable, but almost all women who returned
the questionnaire expressed a willingness to undergo endovaginal ultrasound if it
were recommended.
PMID- 10776015
TI - Alobar holoprosencephaly at 9 weeks gestational age visualized by two- and three
dimensional ultrasound.
AB - We present the ultrasound detection of alobar holoprosencephaly (HPE) with
cyclopia in an embryo of 9 weeks 2 days last menstrual period (LMP)-based
gestational age; the crown-rump length (CRL) was 22 mm. The use of three
dimensional (3-D) ultrasound made additional diagnostic ultrasound tomograms
possible, and the volume reconstructions improved the imaging and the
understanding of the condition.
PMID- 10776016
TI - Prenatal diagnosis of a bronchogenic cyst in an unusual site.
AB - We report a rare case of a subdiaphragmatic cyst, diagnosed prenatally during
routine ultrasound screening at 25 weeks' gestation. Serial ultrasonographic
evaluation demonstrated a slight increase in the size of the cyst during
pregnancy. On the basis of the anatomic site and the sonographic features of the
lesion, four diagnostic hypotheses were postulated: cystic neuroblastoma, adrenal
hemorrhage, duplication of the inferior third of the esophagus and
retroperitoneal cystic lymphangioma. A healthy baby, weighing 3300 g and with
Apgar scores of 8 and 9, was delivered vaginally at term. He underwent successful
surgery at the age of 3 months. The post-operative course was uneventful and the
baby is currently doing well. Histology revealed a bronchogenic cyst.
PMID- 10776014
TI - Ultrasound in cyberspace.
PMID- 10776018
TI - First-trimester prenatal diagnosis of a thoracic cystic lesion associated with
fetal skin edema.
AB - An unusual case of chest cyst diagnosed at the end of the first trimester in a
dizygotic twin pregnancy and managed conservatively is reported. Between 11 and
14 weeks of gestation, ultrasound revealed a relatively large echopoor lung cyst
occupying the left side of the chest, displacing the mediastinum and the heart.
This was associated with increased nuchal translucency thickness and generalized
skin edema. Subsequent sonograms showed complete resolution of the cyst together
with the skin edema. The fetuses were delivered at term and had an uncomplicated
postnatal outcome. This case emphasizes the role of reduced venous return as a
cause of early fetal hydrops. Diagnosis and follow-up of a congenital lung cyst
from the end of the first trimester should enable early intervention to be made.
PMID- 10776017
TI - Prenatal diagnosis of tracheal obstruction: possible association with maternal
pertussis infection.
AB - A fetus with the sonographic appearance of echogenic and enlarged lungs and
dilated trachea and bronchi, indicating laryngotracheal obstruction, is reported.
Additionally, the fetus had ascites and subcutaneous edema and the amniotic fluid
volume was reduced. Doppler flow investigation of the systemic venous circulation
revealed signs of heart failure, and color Doppler visualized possible increased
pulmonary flow. Following termination of pregnancy, autopsy confirmed the
sonographic observations and revealed a hypoplastic thymus. During the present
pregnancy the mother suffered from sustained cough, and serological tests
revealed acute pertussis infection. Polymerase chain reaction investigation for
Bordetella pertussis in the amniotic fluid was negative. The possibilities of
pertussis toxins as noxious factors and of an atypical presentation of DiGeorge
anomaly are discussed.
PMID- 10776019
TI - Prenatal ultrasound evaluation of fetal diastematomyelia: two cases of type I
split cord malformation.
AB - Isolated diastematomyelia is a rare form of spinal dysraphism characterized by a
sagittal cleft in the spinal cord, conus medullaris and/or filum terminale with
splaying of the posterior vertebral elements. This condition is the result of the
presence of an osseous or fibrocartilaginous septum producing a complete or
incomplete sagittal division of the spinal cord into two hemicords. It may be
isolated or associated with other segmental anomalies of the vertebral bodies.
Prenatal diagnosis of this anomaly is possible in the early midtrimester by
sonography, thus allowing for early surgical intervention and a favorable
prognosis. Two cases of fetal diastematomyelia diagnosed by prenatal sonography
are presented, each demonstrating the typical sonographic features diagnostic of
this condition. The first case, detected at 28 weeks' gestation, presented with
disorganization of the bony processes of the vertebral column with a midline
echogenic focus. The second fetus, diagnosed at 17 weeks' gestation, had a
similar appearance with widening of the posterior elements and the presence of a
midline echogenic bony spur. Postnatally, both infants underwent magnetic
resonance imaging for a definitive diagnosis. Surgical repair of the defect was
performed in the neonatal period in both cases.
PMID- 10776020
TI - The use of chorionic villus biopsy catheters for saline infusion
sonohysterography.
AB - BACKGROUND: Saline infusion sonohysterography is one of the recent refinements of
ultrasonography that has the ability to enhance imaging of the uterine cavity in
a safe, inexpensive and expedient manner. The technique can be difficult in women
with a stenotic cervical os. This report describes a single-pass technique using
chorionic villus sampling (CVS) catheters for saline infusion sonohysterography.
METHOD: Saline infusion sonohysterography requires the transcervical passage of a
catheter, through which saline is infused. The subsequent distension of the
uterine cavity enhances the ability to detect intrauterine pathology with
ultrasonography. In women with cervical stenosis, a catheter can be used in place
of the more conventional two-pass technique, which requires the use of a uterine
sound or probe followed by a conventional catheter. EXPERIENCE: We have used CVS
catheters in women with cervical stenosis on 12 occasions. All have been
successful and without significant discomfort to the patient. CONCLUSION: The use
of CVS catheters for saline infusion sonohysterography in women with cervical
stenosis can alleviate the need to remove the cervical probe prior to
introduction of the catheter.
PMID- 10776021
TI - Do not judge the fetus only by the calipers.
PMID- 10776022
TI - Holoprosencephaly at 10 weeks 2 days (CRL 33 mm).
PMID- 10776024
TI - [Family model and mental anorexia. Part II. Intergenerational pattern of
relationships].
AB - Concepts analysing intergenerational transmission in families of anorectic
patients are presented. The researches indicate that the problems associated with
the autonomy process in patients with anorexia nervosa may be rooted in
experiences of former generations and connected with specific patterns of family
relationships. From among these, mourning and suffering bonds, sense of justice,
value of sacrifice philosophy and particular delegations addressed to daughters
seem essential. Such a selection emphasises co-evolutional character of
separation-individuation process and justifies the place of family therapy in
therapeutic process.
PMID- 10776023
TI - [Family models and mental anorexia. Part I. Patterns in patient's family origin].
AB - The paper presents family models which associate the development of anorexia
nervosa with the specific functioning of the patient's family of origin. The
described conceptions are based on systems theory which assumes circular
conception of family relations. This allows for avoiding one-sidedness of
approach, i.e. perceiving a patient as a victim of the family system. In fact,
these models emphasize the patient's part in the specific "game" taking place
within the family. The conceptions indicate a number of characteristic patterns
of relations between the patient's parents as a married couple as well as between
the patient and her parents, which, in the period of adolescence become the
source of a crisis that assumes the form of anorexia nervosa. The presented
approach, focussed on an analysis of family relations, does not question the
importance of other aetiological factors. It only points out that the dynamics of
mutual relations within a family is an important mechanism influencing the
development of the patient's identification and her psychosexual role as well as
the course of the separation/individuation process. These aspects seem pivotal
for understanding and treatment of anorexia nervosa.
PMID- 10776025
TI - [Osteoporosis in anorexia nervosa: a literature review].
AB - Osteoporosis is now established as one of common and early physical complications
of anorexia nervosa (a.n.). The etiology of bone demineralisation in a.n. is
multifactorial. Various studies suggest that long duration of a.n. and
amenorrhea, early onset of illness and amenorrhea, low body mass index, low lean
and fat mass in body, inadequate calcium, vit D3 and protein intake,
hypoestrogenemia and hypercortisolemia are related to decreased bone mineral
density (BMD). The severity of bone mass deficit is sufficient in some patient to
result in pathological fractures of spine, hip or long bones. Fractures may occur
after 7-15 years of a.n duration. Crucial for increase of BMD is restoration of
weight and resumption of menses. The issue of reversibility of osteopenia,
indications and methods of treatment for patients with decreased BMD are of
clinical importance.
PMID- 10776026
TI - [Multiple EEG examinations in patients with refractory endogenous depression
after unilateral ECT].
AB - In 37 inpatients /27 females and 10 males, mean age--49.8 +/- +/- 10.3 years/,
with the diagnosis of refractory endogenous depression, after completing a course
of unilateral ECT /u-ECT/, multiple EEG examinations were performed during a year
of observation. Routine EEG examinations were carried out after a washing out
period of two weeks, using an 8 channel Medicor-Orion EEG device. The patients
were examined before treatment and 2, 4 and 6 weeks and then 3, 6 and 12 months
after the course of ECT. The mean number of ECT which the patients received
during a therapeutic session was 8.4 +/- +/- 2.8. Two weeks after completing the
course of U-ECT, pathologic tracings in the EEG were found in 17 patients--mainly
slowing of the basic alpha activity and slow theta waves. A month after the
course of U-ECT in the majority of patients--32 there was a normal EEG tracing.
After 6 weeks changes in EEG were found in 2 patients. In one of them they were
still present after completion of U-ECT. No significant relationship between the
persistence of EEG changes and the number of U-ECT received during the last
therapeutic session or the quantity of ECT treatments in the past was detected.
The result of this work may support the hypothesis that changes in the biological
activity of the brain after ECT therapy are reversible in nature and most
probably are a reflection of functional changes in the neurons, partly connected
with the therapeutic process or without any relationship with that occurring from
a wide spectrum of neurochemical activity of the method of treatment.
PMID- 10776027
TI - [ECT versus transcranial magnetic stimulation (TMS): preliminary data of computer
modeling].
AB - The essential issue of electroshock therapy (ECT) is the activity of physical
stimulus, i.e., the electric current, on the disturbed structures of the brain.
ECT sessions--when chronically applied for evoking antidepressive effects--are
responsible for the appearance of excessive incitement in the neuronal net in the
brain tissue in a form of self-sustaining after-discharge (SSAD) (convulsive
attack characteristic for ECT). The study presents the computer research on basic
biophysical phenomena of electroshock therapy (flow of electric current in the
structures of the head just before convulsive attack). Five-layer 3-D model of
the head was created in OPERA-3D (Vector Fields Ltd., Oxford), general 3
dimensional issues solver. Geometrical dimensions and electrophysical properties
of each layer correspond with natural properties. The model was subjected to the
action of electric stimulation (parameters identical to those applied in clinical
conditions). Analysis of the flow in particular layers revealed the
crawling/spreading effect present not only in the scalp layer but also in the
layer of cerebrospinal fluid. The effect is conditioned by "deeper situated"
lesser conduction of electricity-respectively skull bones, brain tissue. Crawling
effect is the reason why only 5-15% of the electricity applied on the surface of
the head reaches the surface of the brain. Electro-stimulation examinations also
showed that the values of the so called density of the current in layers of brain
tissue balanced between 1-10 mA/mm2. The current parameters of ECT were effective
in evoking subsequent convulsive attack and safe for the brain tissue. The model
was subjected to the action of magnetic stimulation according to the parameters
of neurologic technique of transcranial magnetic stimulation (TMS). ELECTRA
module was used to solve wire-current issues. The examination showed more regular
distribution of current vectors in all layers of the head. The density of
cerebral cortex was 0.1-1 mA/mm2, confirming markedly lesser current charge than
that observed during ECT. The problem of magnetic stimulation efficacy in
irritating deep structures of the brain demands further studies.
PMID- 10776028
TI - [A case of frontal lobe syndrome of post-traumatic origin].
AB - The paper discusses the case of a patient who was subjected to forensic and
psychiatric observation and was charged with appropriation of money to the
detriment of the company she worked for by District Public Prosecutor's Office.
History data indicate that she was employed in the said company over the period
of 20 years as an accountant and until the disclosure of the crime she had had
the company's full confidence. She enjoyed a fine reputation at the place of her
residence as well. Several months before undertaking criminal actions she had
sustained a head and chest injure as a result of a car accident. She was not
subjected to hospitalisation then. Before she had not been penalized
administratively or legally. She had not suffered from head injuries with a loss
of consciousness. During forensic and psychiatric observation, psychiatric,
psychological, neurological and electroencephalographic examinations were carried
out, skull and chest plain films were taken and computerised tomography of head
was conducted. Clinically it was diagnosed as a frontal organic brain damage
syndrome complicated by depression. Experts' examinations were steered by
psychopathological image, especially axial symptoms of defective function of the
frontal lobe, i.e. lack of initiative and spontaneity, deficiency of higher
emotions, decline of criticism and lowering of psychomotor drive. Although
psychological examination showed that intelligence quotient and the results of
'organic tests' were within normal range, qualitative analysis of the structure
of mental functions disclosed impairment of abstract thinking, especially using
associative processes. Essential data were gathered from computerised tomography
of head which demonstrated cortical atrophy of frontal and temporal lobes and
pericentral gyri. However, neurological and electroencephalographic examinations
and skull plain film did not bring any significant information.
PMID- 10776029
TI - [Chronic subdural hematoma with psychopathological manifestations].
AB - A seventy-one-year old male patient was consulted by psychiatrist at the request
of family physician on account of growing dementia. The first examination
revealed deteriorated verbal contact, deficiency of memory and intellect and
problems with sense of locality. Neither hallucinations nor delusions were found.
However, after a detailed examination it was established that deterioration in
verbal contact was due to aphasia and not dementia. Also, right side hemiparesis
of small degree was detected. In spite of these symptoms the patient was able to
move by himself. After admission to neurological department, computer tomography
of brain was performed. It showed big subdural hematoma whose size was 13.2 by
2.9 cm. Adequate surgery was carried out and the patient was discharged from
hospital ten days after operation. During supervisory examination, performed two
months after intervention, no psychopathological problems were found. Also,
deficiencies of memory, intellect and concentration were normal for the patient's
age. The presented instance is a good argument for thorough examination of mental
and neurological state, even in apparently evident cases. This description is
illustrated with two tomograph pictures of brain.
PMID- 10776030
TI - [Mental disorders in the course of neuroborreliosis: own observation].
AB - Three cases of psychic disorders in the course of Lyme borreliosis were
described. Two cases were connected with Lyme meningitis, one of them with
chronic Lyme arthritis. These cases were described to discuss the possible
occurrence of mental disturbances in the course of Lyme borreliosis, directly or
indirectly connected with the central nervous system.
PMID- 10776031
TI - [Transmission of Borna disease virus as etiopathogenetic factor in schizophrenia
and affective disorders].
AB - Borna Disease Virus (BDV) is a negative single-stranded ribonucleic acid (RNA)
virus, showing strong neurotropism. BDV may infect many different warm-blooded
animal species, causing neurological and behavioral disorders.
Seroepidemiological studies suggest the existence of human infections with BDV
and their higher prevalence in psychiatric patients. Using different serological
assays, anti-BDV antibodies were found in about 10%-20% of patients with
schizophrenia, and in 1%-2% of the control group of healthy subjects. There are
also reports on BDV antigens and BDV RNA in peripheral blood mononuclear cells of
human subjects, and in the brain tissue examined during the autopsy in patients
with psychiatric disorders. Higher prevalence of BDV infection markers was also
found in the group of patients with affective illness. A hypothesis was put
forward on the activation of BDV-infection in patients with affective illness
during acute episode. There are also reports on higher BDV-seropositivity in
various psychiatric disorders compared with healthy control subjects. It also
would be purposeful to study a possibility of BDV infections in patients with
psychiatric disturbances, having their onset in childhood or adolescence.
PMID- 10776033
TI - [Lyme borreliosis: disease diagnosed by the one who thinks of it].
PMID- 10776034
TI - [Reversible posterior leukoencephalopathy syndrome].
PMID- 10776032
TI - [Sex reassignment and other kinds of treatment in case of transsexualism].
AB - This report discusses the recent literature on the sex reassignment and
psychotherapy in the case of patients with transsexualism. On the basis of a
literature review, the author provides guidelines for evaluating, referring to
and treating patients who request surgical operation (e.g. hormonal reassignment,
monitored "real life test"). Medical and psychological risk of the sex surgery is
indicated. The status of psychotherapy in the treatment of severe gender
dysphoria (transsexualism) is also presented. Psychoanalytical, behavioral or
cognitive therapy is rather rarely recommended as the possible alternative in the
treatment of transsexuals. Sometimes psychotherapy is included as a part of
treatment both before and after surgery. Although the outcomes of the sex surgery
still remain unclear it is a widely used method of curing transsexualism.
PMID- 10776035
TI - [Migratory erythema (Lyme borreliosis). Clinicoepidemiologic features of 50
patients].
AB - BACKGROUND AND OBJECTIVE: Erythema migrans (EM) is the earliest and most common
manifestation of the infection caused by B. burgdorferi (Lyme borreliosis). The
objective of the present work was to report the clinicoepidemiological features
in a series of patients. PATIENTS AND METHODS: Retrospective collection of
clinicoepidemiological features of the first fifty patients diagnosed of EM at La
Rioja Hospital (March 1989-September 1998). RESULTS: In our series, no
differences were observed regarding sex or living in a rural or urban area. Mean
age was 41 years (range 9 to 78). In 70% of patients the antecedent of a tick
bite was obtained and the incubation period was 6.48 days (1 to 15 days). The
mean size of the lesions was 14.3 cm (5 to 40) and in 16% of patients satellite
cutaneous lesions were observed. The areas where EM appeared were lower limbs and
the perineal region (60%), chest (24%), head and neck (10%) and upper limbs (6%).
Forty-eight percent of patients reported extra-cutaneous manifestations. All
cases occurred during the spring, summer and autumn months, with a peak in June.
The most common referred antecedent was walking in forest areas. All patients
responded to antibiotic therapy. CONCLUSIONS: EM is common in the studied
environment and presents with a marked polymorphism.
PMID- 10776036
TI - [Proximal vein by-pass in the treatment of venous stenosis in expanded
polytetrafluoroethylene prosthesis for hemodialysis].
AB - OBJECTIVE: To show the long-term results of 97 politetraflouroethylene dialysis
grafts submitted to a graft by-pass to treat graft-vein stenosis. MATERIALS AND
METHODS: Venous stenoses were studied and diagnosed by means of fistulography in
cases with fistula dysfunction or during surgery for graft thrombectomy. Both
early and late complication rates were studied, as well as primary and secondary
patency rates. RESULTS: Number of cases, 97. Mean age, 58 years (7-79). Diabetic
nephropathy: 19.5%. Types of grafts in which stenoses developed: straight
forearms 13; loop forearm 9; 6 mm upper arm 36; 6-8 mm upper arm 34; brachio
jugular 4; femoro-femoral 1. Overall follow-up time: 2,427 graft-months. Mean
follow-up time: 21 +/- 5 months. Late complication rate: 0.30 episodes per graft
year of follow-up. Re-stenosis rate: 0.12 graft-year of follow-up. Primary
cumulative patency rate: 70%, 62%, 51%, 45% at one, two, three and four years,
respectively. Secondary cumulative patency rate: 87%, 79%, 74% and 71% at one,
two, three and four years, respectively (p < 0.0016). No differences were
observed between secondary patency observed after by-pass to treat dysfunction or
thrombosis (p = 0.09259). DISCUSSION: In our experience, by-pass to proximal vein
is associated with good results both at short and long term, probably because the
intimal hyperplasia area is excluded and because by-pass is performed on an
already dilated vein. The procedure can be performed under local anesthesia and
in an outpatient basis between dialysis, with little discomfort for the patient.
PMID- 10776037
TI - [Recurrence and prognostic factors after treatment with antithyroid agents in
Graves-Basedow disease. Multicenter study in Northern Spain].
AB - Therapy with anti-thyroid drugs is the initial option mostly used in our country
for the treatment of hyperthyroidism due to Graves-Basedow disease. To evaluate
the long term results of this kind of therapy, a total of 773 patients were
studied who were diagnosed from 1975 to 1994 in three hospitals in Northern Spain
(Hospital Central de Asturias, Hospital de Cruces and Hospital de Navarra) after
a mean follow-up time after anti-thyroid drug withdrawal of 46 +/- 33.1 months.
The results showed a likelihood of hyperthyroidism relapse of 42.9%, 59.8%, 67.9%
and 78.9% at one, three, five and ten years, respectively. Goitre size was
correlated very significantly with the likelihood of relapse (p < 0.0001). In
contrast, only TBII positivity at the end of therapy among the remaining
parameters (age, sex, goitre size, length of therapy, positivity of anti-thyroid
antibodies and TBII) influenced significantly on the relapse likelihood (p <
0.05). In conclusion, after a long term follow-up after anti-thyroid therapy, a
high relapse rate of hyperthyroidism in Graves-Basedow disease, which amounts up
to 79% at ten years, was observed. Goitre size was the main predictive factor for
this relapse.
PMID- 10776038
TI - [Effectiveness of treatment with metformin in patients with type 2 diabetes
mellitus poorly controlled with insulin treatment].
AB - Combined treatment with insulin plus metformin could be a good alternative to
improve the glycemic control in patients with type 2 diabetes mellitus poorly
controlled with insulin therapy. We retrospectively studied 21 obese insulin
treated type 2 diabetic patients with deficient metabolic control (HbA1c 9.2 +/-
1.2%) who were treated with metformin for a minimum of 8 months. After 4 months
of treatment, a significant decrease in the percentage of HbA1c was observed
(delta HbA1c -1.07 +/- 1.12%; p < 0.01), with maintained values since then. Non
changes in body weight or insulin requirement were noted. Our results suggest
that the addition of metformin to insulin treatment is a safe and effective
strategy for the improvement of glycemic control among obese type 2 diabetic
patients.
PMID- 10776039
TI - [Hereditary thrombophilia in venous thromboembolic disease].
PMID- 10776040
TI - [Intensification of antiretroviral treatment].
PMID- 10776041
TI - [Rescue antiretroviral therapy].
PMID- 10776042
TI - [Extensive cutaneous induration in dorsal region].
PMID- 10776043
TI - [Subocclusion case in patient with congenital digestive disorders].
PMID- 10776044
TI - [Ankle pain and tumefaction in a patient with rheumatoid arthritis].
PMID- 10776045
TI - [32-year old male with hepatic focal lesions and pleural effusion].
PMID- 10776046
TI - [Long-standing unilateral muco-purulent rhinorrhea in young adult].
PMID- 10776047
TI - [Dangers of self-exploration].
PMID- 10776048
TI - [Bilateral pseudothrombophlebitis].
PMID- 10776049
TI - [Light cigarettes do not reduce the risks for the smoker].
PMID- 10776050
TI - [Endocarditis in patients with pacemakers].
PMID- 10776051
TI - [Paresis of the sixth nerve following spinal anesthesia].
PMID- 10776052
TI - [Inappropriate antidiuretic hormone secretion syndrome associated with the use of
selective serotonin reuptake inhibitors].
PMID- 10776053
TI - [Geriatric psychiatry--relevance for the general practitioner].
AB - The older population, the group of the very old in particular, is increasing and
thus the risk group for the two most important psychiatric disorders, dementia
and depression. Many individuals become mentally ill for the first time late in
life, mainly because of losses, loneliness and somatic diseases. Therefore,
beside physical examination, screening for depression and cognitive testing are
very important for the general practitioner. Relatives and caregivers often play
a keyrole. They have to be involved in evaluation and therapy and their needs for
support and advice should be considered.
PMID- 10776054
TI - [New antidepressive drugs].
AB - Five of the available eight substance groups known as antidepressants has been
developed during the last years: selective serotonin reuptake inhibitors (SSRI),
selective serotonin and norepinephrine reuptake inhibitors (SNRI), serotonin
antagonists, reversible selective inhibitors of monoaminooxidase A (RIMA) and St.
Johns word. Two main ideas were important for their development: more specific
biochemical effects and less side effects. This development is going further.
During the next years at least three new substance groups with new biochemical
effects will come on the market. The growing spectrum of antidepressants is
important for avoiding therapy resistant depression.
PMID- 10776055
TI - [Alzheimer dementia].
AB - Alzheimer's disease is the most common form of dementia in the elderly. This
review describes diagnosis, differential diagnosis, etiology and course of
Alzheimer's dementia. Genetic and non-genetic risk factors are presented. In
addition to the already available symptomatic therapies with acetylcholinesterase
inhibitors, new therapeutic approaches with protective and restorative substances
are currently being developed.
PMID- 10776056
TI - [Transient ischemic attacks and prolonged reversible ischemic neurologic deficit.
Diagnosis, differential diagnosis and treatment].
AB - Cerebral and ocular ischemic events are classified according to their duration
and localisation in transient (< 24 hours) or permanent (> or = 24 hours)
cerebral (transient ischemic attack (TIA), cerebral infarct) and ocular
(amaurosis fugax, retinal infarct) deficits. The terms "Prolonged Reversible
Ischemic Neurological Deficit" (PRIND, > or = 24 hours to < or = 7 days) and
"Reversible Ischemic Neurological Deficit" (RIND, > or = 24 hours to < or = 3
days) are no longer used. The differential diagnosis of TIAs and ischemic strokes
is discussed. Ischemic strokes are an emergency and should be referred within
five hours at the latest to a centre, which offers around the clock acute
therapies such as fibrinolysis and an organised stroke management. Secondary
stroke prevention after TIA or stroke encompasses the treatment of vascular risk
factors, carotid endarterectomy, anticoagulation in the presence of cardiac
embolism (target international normalised ratio, 2.5; range 2.0-3.0) and the
administration of platelet inhibitors. Carotid endarterectomy is indicated, when
luminal narrowing is at least 70%, and not indicated when it is less than 50%.
The benefit of endarterectomy in 50-69% stenoses decreases, and individual
predictors of the operation risk are useful for choosing the appropriate
treatment. Patients without indication for carotid endarterectomy or oral
anticoagulation are treated with platelet inhibitors. We use the combination
dipyridamole-aspirin as first choice drug, because it has been shown to be
superior to aspirin and dipyridamole alone. In the presence of adverse effects or
contraindications for dipyridamole we prescribe aspirin (100-300 mg daily). We
administer clopidogrel (75 mg daily) if dipyridamole and aspirin are not
indicated, have caused adverse effects, or did not prevent ocular or cerebral
ischemic events.
PMID- 10776057
TI - [Musculature--an overlooked organ!].
PMID- 10776058
TI - [Metabolic capacity of skeletal muscles and health].
AB - The metabolic capacity of skeletal muscle plays a significant role for insulin
sensitivity and the blood lipid profile. The metabolic capacity of the muscle is
a function of the individual's physical activity level. This is also true for the
content of type IIx muscle fibres, which is reduced and the number of
capillaries, which is elevated with muscle usage. Several of these skeletal
muscle features are risk factors for or linked with life style-induced diseases
such as type II diabetes, hypertension, hyperlipidaemia and obesity. This central
role of the skeletal muscle and its functional metabolic capacity for life style
diseases highlights the importance of people maintaining daily physical activity.
This article focuses on the link between the metabolic capacity of skeletal
muscle and the metabolic syndrome and briefly discusses possible metabolic
explanations for this relationship. An important aspect is that when skeletal
muscle has a high capacity for lipid oxidation more saturated fatty acids are
oxidized and more unsaturated fatty acids are built into the phospholipid
fraction of the plasma membrane, giving it more fluidity and improved insulin
sensitivity. Moreover, the article points at the role of these fatty acids in
activating genes via the PPAR-receptor system essential for enzyme and transport
proteins in the lipid metabolism.
PMID- 10776059
TI - [Physical activity--what minimal level is sufficient seen from health
perspective?].
AB - Physical inactivity represents an important risk factor for development of
cardiovascular and metabolic disease and is tightly coupled to a reduced energy
expenditure both at work and during leisure activities. Although comprehensive
physical training is known to influence oxygen uptake capacity, muscle strength
and metabolic factors, also increased weekly energy expenditure achieved through
activities with moderate intensity will influence risk factors such as
hypertension, insulin resistance, oxidative metabolism in skeletal muscle and a
low HDL/total cholesterol ratio beneficially and improve metabolic fitness. To
achieve this, all adults should aim at a total of 30 min of moderate physical
activity daily, preferentially through activities that can be a natural part of
daily living (walking, cycling or gardening). This recommendation can also be
achieved through accumulation of several minor activity periods of 5-10 min each.
Further increase in amount or intensity of physical activity above the minimal
recommendations improves the morbidity preventive effect further, although
several risk factors show a curvelinear and levelling-off pattern of their dosis
response curve between training and risk factors.
PMID- 10776060
TI - [Physical activity and obesity].
PMID- 10776061
TI - [Diagnosis of muscular disease].
AB - Diagnostic evaluation of muscle disease has gained considerably from the
expanding development in molecular science in the last decade. This paper gives
an overview of current diagnostic procedures in the evaluation of patients with
muscle disease. The role of the clinical examination, genetic and serological
tests, neurophysiological examination, muscle imaging, muscle histology and
exercise tests for the diagnosis of muscle disease are discussed.
PMID- 10776063
TI - [Physical activity and immune system--a stress model].
PMID- 10776062
TI - [Chronic musculoskeletal pain syndromes].
PMID- 10776064
TI - [Physical training in the treatment of type 2 diabetes].
PMID- 10776065
TI - [Electric stimulation in muscle training of the lower extremities in persons with
spinal cord injuries].
AB - Spinal cord injured persons have limited possibilities to perform physical
training. By use of computerized, feed-back controlled electrical stimulation of
the gluteal, the hamstrings and the quadriceps muscles cycle ergometry can be
performed by the spinal cord injured individual. The cardiovascular demands of
this training is higher than with voluntary upper body training using the intact
innervated muscles. The inactivity related conditions caused by the spinal cord
injury are reversed in part by regular electrically stimulated training. An
increase is seen in maximal oxygen consumption, in the insulin stimulated glucose
uptake and in the muscular mass and bone mineral content of the lower
extremities. Electrically induced cycle ergometry is thoroughly investigated,
relatively safe, but time consuming. As this training in addition results in the
same well being as seen by training in able bodied individuals it can be
recommended for motivated patients.
PMID- 10776067
TI - [Muscular function in the elderly. Effect of training].
PMID- 10776066
TI - [Improved function of the hand in persons with tetraplegia using electric
stimulation via implanted electrodes].
AB - Functional Electrical Stimulation (FES) is a controlled use of electrical
stimulation of muscle contractions to obtain function. FES is utilised today in
the treatment of spinal cord injured individuals for diaphragmatic pacing,
bladder and bowel management, ejaculation, walking and hand function, as well as
conditioning. We present The Freehand System, which consists of implanted
electrodes to arm and hand muscles. This system has now been implanted in the
first two Nordic tetraplegics. Candidates are tetraplegics with C5-6 lesions.
After implantation it may take 6-8 months before the tetraplegic person can
expect to use The Freehand System completely in daily life. The tetraplegic
individual can choose between two grasps. The Freehand System can for some few
very physically disabled tetraplegics be a good aid to increase their level of
activities of daily living and independence. Continued development in the coming
years may broaden the indications with benefit for more individuals.
PMID- 10776068
TI - [Creatine--a dietary supplement beneficial for the performance and also of
medical interest].
PMID- 10776069
TI - [Fatal outcome with cerebral edema following abuse of anabolic steroids].
AB - The usual side effects of anabolic steroid abuse are thromboembolic, hepatic,
cardiac, reproductive and psychiatric disorders. We report a case of lethal
cerebral oedema associated with massive abuse of anabolic steroids in a
previously healthy 21 year old man.
PMID- 10776070
TI - [Picture of the month. Muscular dystrophy].
PMID- 10776071
TI - [High-intensity strength training of fragile elderly persons].
PMID- 10776072
TI - Preparing advanced nurse practitioners: challenges for nephrology.
PMID- 10776073
TI - The concept of leadership.
PMID- 10776074
TI - A quantitative study comparing adjustment and acceptance of illness in adults on
renal replacement therapy.
AB - Adjustment and acceptance of illness are major factors influencing quality of
life in different modes of renal replacement therapy. A quantitative tool was
used to compare adjustment and acceptance of illness in adult patients on
maintenance dialysis to those with a functioning renal transplant. A
questionnaire incorporating Felton's Acceptance of Illness Scale was sent to 273
patients receiving replacement therapy for end stage renal disease (ESRD) in
Leicester, UK. The instrument examined the effects of a variety of clinical and
social parameters on the Acceptance of Illness Scale Score (AISS). Patients with
a functioning renal transplant had a significantly higher AISS than patients on
hemodialysis (HD) or peritoneal dialysis (PD) (P < 0.0001). Patients in
employment or full-time education had a higher AISS than other patients (P <
0.01). White/Caucasian ethnic origin had a higher AISS than Asian (P = 0.011).
There were weak inverse correlations between age and AISS, and between AISS and
perception of 'choice' in treatment modality. Health care professionals need to
be aware of all variables that affect patient acceptance of illness in order to
administer optimum clinical care.
PMID- 10776075
TI - Perceptions of kidney transplant by persons with end stage renal disease.
AB - This prospective, descriptive research study sought to identify factors that
influence the pursuit of kidney transplant by persons with end stage renal
disease (ESRD). Four research questions explored various areas about kidney
transplants, including overall knowledge, reasons for wanting/not wanting a
kidney transplant, sources of information, views of how one's life could change,
and interest in receiving a transplant. A prospective, descriptive study was
designed that used both quantitative and qualitative methods of data collection.
A random sample of 115 persons from a total population of 450 individuals,
currently undergoing treatment in 1 of 3 dialysis facilities in a mid-Atlantic
state. was obtained. Two nurse interviewers used four instruments during a 1
hour, structured interview completed at the facility. The results show that: (a)
two-thirds of the sample population underestimated the current success rate of
transplantation; and (b) over half never discussed transplants with family
members. Implications for health care providers are discussed in this article.
PMID- 10776076
TI - The psychosocial meanings of living related kidney organ donation: recipient and
donor perspectives--literature review.
AB - There is a shortage of information about the psychosocial influences that impact
family decision making for a living related donor kidney transplant. This article
reviews research findings related to the psychosocial meanings of donation.
potential recipient's decisions about the kidney donor, and families' roles and
expectations. The social meaning of organ donation as a "gift" and family
dynamics involved in decision making are addressed. The findings show that
families make decisions about kidney donation in different ways. Emotional
responses of potential kidney recipients include ambivalence, passivity, and
denial of the severity of their illness. Emotional responses of potential family
donors range from unrestrained willingness to ambivalence and concerns of
coercion. Improved accuracy of health assessment and awareness of the importance
of psychosocial perspectives is needed. Assessment questions addressing the fears
and concerns of potential recipient and donor are suggested.
PMID- 10776077
TI - Reducing complications during hemodialysis using gradient ultrafiltration with
gradient sodium dialysate.
AB - The objective of this study was to determine if patient complications and nursing
interventions during hemodialysis could be reduced using gradient ultrafiltration
and gradient sodium dialysate. Twenty outpatients who had been on hemodialysis
for at least 3 months, and using gradient sodium dialysate for at least 1 month,
participated. Patients received either ultrafiltration at a constant hourly rate
or gradient ultrafiltration, in which the ultrafiltration rate was set higher
initially, then decreased step-wise mid-dialysis. Patients received each protocol
for 3 months, using a randomized cross-over design. Both protocols used gradient
sodium dialysate (150 mEq/L x 3 hrs, 140 mEq/L x 1 hr). There were significantly
fewer complications and interventions using gradient ultrafiltration, as compared
to constant ultrafiltration. No differences were found in interdialytic weight
gain, intradialytic weight loss, or orthostatic blood pressure. These results
indicate that gradient ultrafiltration combined with gradient sodium dialysate
enhances patient well-being and reduces nursing interventions during
hemodialysis.
PMID- 10776078
TI - Guarded alliance relationships between hemodialysis patients and their health
care providers.
AB - To further understand the complex patient-nurse relationships surrounding end
stage renal disease. Thorne and Robinson's (1987: 1988a, 1988b) framework of
guarded alliance was found to be most useful. In this study, we interviewed five
patients regarding their perceptions of the patient-nurse relationships they had
experienced while receiving hemodialysis treatment. Our study finds that this
model is very useful in understanding these ever-changing relationships. Content
analysis of the transcribed interviews indicated that patients experienced all of
Thorne and Robinson's relationship stages including naive trust, disenchantment,
and guarded alliance. Interestingly, we also found that patients may experience
the same stages of "relationship" with their dialysis machine as well.
PMID- 10776079
TI - Overcoming language barriers for non-English speaking patients.
AB - Although some of the resources or services listed may seem expensive, it is
cheaper to use these than to face a malpractice suit for failure to provide
patients with limited English access to services equal to those provided to
English speakers. The University of California at San Francisco (UCSF), one of
the top three ranking research hospitals in the U.S., had a suit filed against it
by the American Civil Liberties Union (ACLU) claiming failure to provide adequate
translation services for the patient population. The university is now a
participant in a statewide effort to provide access to well-trained translator
services to the patient population. This effort and the development of an in
house interpreter services department has contributed to a competitive edge for
UCSF in the area of patient services and satisfaction as well as attracting more
Medicaid patients, which increases their revenues.
PMID- 10776080
TI - Iron management: innovative solutions to persistent challenges--focus on
Ferrlecit.
AB - The use of sodium ferric gluconate in sucrose injection (Ferrlecit) in the
treatment of anemia in patients with end stage renal disease (ESRD) was the major
topic at the symposium "Iron Management: Innovative Solutions to Persistent
Challenges," held April 14, 1999 during the annual ANNA 30th National Symposium
in Baltimore, Maryland. Chairperson Susan Vogel, MHA, RN, CNN, addressed the
challenges of anemia management and the limitations of oral iron supplements. She
described available intravenous (i.v.) iron therapies and reviewed clinical trial
data that demonstrated an excellent safety and efficacy profile for the newly
approved i.v. iron supplement, sodium ferric gluconate. Suzanne Schweitzer, RPh,
MPH, discussed iron metabolism and the U.S. labeling for sodium ferric gluconate,
with a focus on dosing and administration. In the final presentation, Suzanne
Seiler, RN, described her clinic's experience with sodium ferric gluconate and
provided an experimental dosing and monitoring protocol. Together, these
presentations suggest that sodium ferric gluconate is an important new tool for
meeting the challenges of iron management in ESRD patients.
PMID- 10776081
TI - Intravenous iron products.
AB - Intravenous iron has been used extensively and successfully as part of the
treatment of anemia in dialysis patients. Iron dextran can be used safely,
however, there is a slight risk of severe, anaphylactoid reactions. Iron
gluconate and iron sucrose are less likely to cause hypersensitivity reactions.
These products should be safe and effective alternatives to iron dextran.
PMID- 10776082
TI - Hormone replacement therapy (HRT) in ESRD.
PMID- 10776083
TI - Vascular access thrombosis: etiology and prevention.
AB - Vascular access thrombosis has been the Achilles heel of patients with end-stage
renal disease since the inception of maintenance hemodialysis. Although many
factors have been implicated in the etiology of access thrombosis, data indicate
that the primary risk factors include an increased use of synthetic
polytetrafluoroethylene grafts, lack of surgical expertise in access
construction, advanced age, systolic hypotension, and high levels of serum
lipoprotein (a). The occurrence and severity of access problems can be modified
by ongoing nurse monitoring and prompt intervention to proactively correct
evolving problems.
PMID- 10776084
TI - Knowledge and power.
PMID- 10776085
TI - Research ethics, the establishment of a nursing research profile--who owns the
knowledge?
PMID- 10776086
TI - Reflective writing: a strategy to foster critical inquiry in undergraduate
nursing students.
AB - Whilst nursing has recognised the importance of reflective practitioners, few
strategies designed to achieve this outcome are currently apparent in nursing
education literature. Writing, forwarded as one way to enhance the development of
critical thinking and reflection in undergraduate nursing students, is the focus
of this article. The article describes a project undertaken to explore the ways
writing could be incorporated into an undergraduate curriculum as a strategy to
enhance and extend personal and professional meaning-making. It examines a number
of strategies utilised in the project and offers some insightful understandings
developed by the team.
PMID- 10776087
TI - Developing a collaborative preceptor program involving registered nurses, student
nurses and faculty.
AB - This paper addresses a collaborative preceptorship program involving a group of
undergraduate nursing students, their registered nurse preceptors employed on the
paediatric ward of an acute care hospital, and academic staff from a university
school of nursing. The project utilised a fourth generation evaluation model,
adapted from action research methods, which comprised a series of parallel
focussed group discussions with a registered nurse preceptor group and a student
nurse group. During the project, members of the two groups explored the issues
around the supervision of students in practice in an acute paediatric context.
This resulted in the development of innovative approaches to the supervisory
practices utilised by preceptors. It also highlighted the benefits of
collaboration between universities and hospital staff in developing preceptorship
programs which respond appropriately to the needs of both preceptors and
students.
PMID- 10776088
TI - Comparing professional and patient outcomes for the same episode of care.
AB - Following an acute hospital admission, patients' perceptions of the acceptability
of their own outcomes were compared with professionally derived outcomes of care
developed for the same patients by nurses. Professional opinion was obtained from
the Nursing Practice--Casemix and Outcomes Project undertaken by the Sydney
Metropolitan Teaching Hospitals Nursing Consortium, where patient outcomes were
classified by nurses into three groups: Outcomes Acceptable; Outcomes Not
Acceptable but Justified and Outcomes Not Acceptable and Not Justified. Fifteen
male patients in the present study discussed their outcomes following recent
orthopaedic surgery at a series of focus groups organised according to the three
outcome categories. Findings from the study showed the majority of patients were
satisfied with their outcomes. Patient agreement with nurses regarding the
acceptability of outcomes was highest for patients from the Outcomes Acceptable
group and lowest for those from the Outcomes Not Acceptable and Not Justified
group. This work is significant in that it is one of the first nursing studies to
compare outcomes developed by practitioners for a particular group of patients
with actual outcomes experienced by the same group of patients.
PMID- 10776089
TI - Venturing on-line for an emergency management course.
PMID- 10776090
TI - Cybernurse-on-line URLs.
PMID- 10776091
TI - Venepuncture versus heel prick for the collection of the Newborn Screening Test.
AB - This study compared the heel prick with venepuncture of a superficial vein on the
dorsum of the hand to collect the Newborn Screening Test. Midwives at two
different maternity centres collected the blood samples, with midwives at each
centre using only one of the two blood collecting approaches being studied. The
time taken to collect the Newborn Screening Test and four crying parameters
(amount of crying, percentage of crying, length of first cry and cry latency)
were measured. Thirty-six infants were assigned to either a control or
experimental group and their Newborn Screening Tests were recorded on audiotape.
Analysis of the results found a shorter sample collection time, length of crying,
duration of the first cry, a lower percentage of crying, and increased cry
latency for the venepuncture group; all significant at the P < 0.05 level. These
findings suggest that venepuncture should be the preferred technique for midwives
to collect the Newborn Screening Test.
PMID- 10776092
TI - Manual handling practices and injuries among ICU nurses.
AB - This paper describes manual handling practices and injuries among Intensive Care
Units (ICU) nurses working in a large tertiary referral medical centre in
Australia. The objectives of this study were to identify patterns of manual
handling activities; the incidence, types of injury and body site injured; and
establish the consequences of injuries. The rate of manual handling injuries
among ICU nurses was unacceptably high (52.2%), as was back injury (71.4% of all
injuries). In order to reduce manual handling injuries, employers should provide
lifting assistance devices; design workplaces so as to minimise the need for ICU
nurses to twist, bend and/or lift items from the floor; introduce regular
equipment maintenance procedures; provide adequate staffing to assist with
lifting patients; and implement processes that facilitate more detailed
statistics on manual handling activities and outcomes.
PMID- 10776093
TI - Measuring outcomes--what's meaningful?
PMID- 10776094
TI - Time to toot your horn.
PMID- 10776095
TI - The 1999 Scope of Practice for Diabetes Educators and the Standards of Practice
for Diabetes Educators. American Association of Diabetes Educators.
PMID- 10776096
TI - Management of children with diabetes in the school setting. American Association
of Diabetes Educators.
AB - The AADE recognizes the special needs of children with diabetes in the school
setting. This position statement has been developed to provide basic guidelines
to assist these children, their parents, school personnel, and healthcare workers
in promoting a safe school environment and successful learning experience for the
child with diabetes. Diabetes educators are encouraged to support this endeavor
by sharing their knowledge and resources with school personnel whenever possible.
PMID- 10776097
TI - Special considerations for the education and management of older adults with
diabetes. American Association of Diabetes Educators.
PMID- 10776098
TI - Assessing the effectiveness of a clinical fellowship on diabetes in enhancing
diabetes care in North Carolina.
PMID- 10776099
TI - Is it compliance or is it memory?
PMID- 10776100
TI - Race, ethnicity, and diabetes care: where to from here?
PMID- 10776101
TI - Development and evaluation of an intervention program: "Control on Campus".
AB - PURPOSE: This study was designed to develop and test an intervention for college
students with type 1 diabetes. METHODS: A diabetes program, "Control on Campus,"
and guide were developed based on the Expanded Health Belief Model and Social
Learning Theory. Diabetes knowledge, attitudes, and behaviors were assessed
preprogram, postprogram, and at follow-up for 3 intervention cohorts and a
control group. RESULTS: Reporting of HbA1c values and diabetes knowledge improved
significantly as a result of the intervention compared with no increase in the
control group. Furthermore, participants reported feeling more support on campus
after the intervention, appeared to have overcome their fears associated with
testing their blood glucose, reported an increased frequency of blood glucose
testing, and were more likely to test when they felt their blood glucose level
was low. CONCLUSIONS: Overall, this research yielded substantial insight into the
characteristics of college students with diabetes and was successful in designing
and evaluating an intervention trial for this population.
PMID- 10776102
TI - Coping and psychosocial adjustment of women with diabetes.
AB - PURPOSE: The purpose of this study was to investigate relationships between
coping styles and psychosocial adjustment for women with diabetes. METHODS: The
sample consisted of 115 community-residing women with diabetes. Coping was
measured by the Revised Jalowiec Coping Scale and psychosocial adjustment by the
Psychosocial Adjustment to Illness Scale. Pearson's product moment correlation
was used to assess relationships between coping and adjustment. RESULTS: The most
frequently and effectively used coping styles were optimistic, confrontive, self
reliant, and supportant. The psychological, social, and health care domains
showed the most problems; the fewest were in the extended family, sexual, and
vocational domains. Relationships were found between women's coping styles and
psychosocial adjustment, with better adjustment associated with effective use of
confrontive, supportant, optimistic, self-reliant, and palliative coping styles.
CONCLUSIONS: Important relationships exist between the ways women cope with
diabetes and their level of psychosocial adjustment to the illness. Knowledge of
these relationships can help diabetes educators assist clients in making
lifestyle changes.
PMID- 10776103
TI - A community diabetes education and gardening project to improve diabetes care in
a Northwest American Indian tribe.
AB - PURPOSE: The purpose of this study was to design a culturally appropriate
education program for a Northwest American Indian tribe. METHODS: Needs
assessment revealed that a community approach rather than clinic-based education
would address multiple barriers to diabetes care. Both process and outcome
information are described for community and individual level evaluations.
RESULTS: This intervention design consisted of community diabetes workshops
called "How Healthy Am I?--Treating the Whole Person." The workshops represented
a traditional view of health and included 4 specific themes: (1) taking care of
the body, with an emphasis on diabetes care and physical activity; (2) mental
health needs; (3) foods for healthy living; and (4) spirituality and healing the
whole person. Workshops were designed to be social and informational, and involve
all community members. A community garden was established to improve access to
fresh produce and encourage exercise. CONCLUSIONS: Prior to implementation of the
community workshops and evaluations, the tribal government chose to discontinue
receiving the federal funding for this project. Elements of a mutually respectful
collaboration are outlined and discussed based on the experiences of this
project.
PMID- 10776104
TI - Diabetes in urban African Americans: assessment of diabetes-specific locus of
control in patients with type 2 diabetes.
AB - PURPOSE: This study was conducted to examine the applicability and relationship
to glycemic control of the Diabetes Locus of Control (DLC) Scales in a low
literacy, economically deprived, African American population with type 2
diabetes. METHODS: The DLC Scales were administered orally to African American
patients with type 2 diabetes who had been referred to the diabetes unit of a
large urban public hospital. Reliability, interscale correlations, and
associations with patient characteristics were compared with those originally
obtained for a better educated, predominately Caucasian population. RESULTS: The
structure and correlates of the DLC Scales in the African American population
were more similar than different from those originally obtained from a primarily
well-educated, Caucasian population. However, comprehension of some items was
difficult for up to 10% of the low-literacy population. A significant
relationship was found between belief in chance and both glycemic control at the
6-month follow-up and the change in glycemic control over time. CONCLUSIONS:
Although the DLC Scales operate similarly in an urban African American population
with limited education, further modification is needed to enhance the prediction
of glycemic control and provide direction for developing targeted interventions.
PMID- 10776105
TI - The latest developments in insulin injection devices.
AB - The next several years promise dramatic changes in the treatment of diabetes,
many of which will be driven by rapidly developing technology. Today's patient
with diabetes has ready access to more information about the disease and its
treatment options. As a result of this increased knowledge base, insulin-treated
patients have become more autonomous in the management of their diabetes and may
be better prepared to participate in making informed choices regarding insulin
delivery devices. As with any insulin regimen, diabetes educators are encouraged
to provide ongoing patient education and follow-up to assure optimal use of these
new technologies.
PMID- 10776106
TI - Communicating in style: using the Internet in gastroenterology nursing practice.
PMID- 10776107
TI - Patient satisfaction with an outpatient endoscopic service.
AB - The competitive health care market, increasing demand for patient involvement in
establishing directions for health care and implementation of hospital
accreditation have all driven hospitals toward evaluation of patient satisfaction
with the service they receive from the health care venue. Although the concept of
patient involvement in health care evaluation and quality assurance is not new,
relatively little literature exists on patient satisfaction with outpatient
endoscopic services. This study was designed to explore patient satisfaction with
endoscopic services and factors influencing their perceptions. The sample (N =
151) included patients undergoing outpatient endoscopic examination over a 1
month period. The 14-item questionnaire included demographics and patients'
perceptions of their experiences pre, interim, and postprocedure. Patients' age,
referral source, procedure characteristics, perception of the quality of
preprocedure information all influenced perceptions of the service provided by
the endoscopic unit. Overall, service satisfaction was good. The results of this
study have provided the multidisciplinary team with direction for planning
improvements in care, and they may be relevant to other outpatient endoscopic
services.
PMID- 10776108
TI - Therapeutic potential of infliximab in inflammatory bowel disease.
AB - Traditional treatment approaches for patients with inflammatory bowel disease
involve 1) pharmacologic management with aminosalicylates, corticosteroids,
immunomodulatory agents, and antibiotics; and 2) nonpharmacologic management by
surgical and dietary means. Complications and inadequate responses to current
treatment modalities have resulted in the development of new and more specific
biologic therapies. The proinflammatory cytokine tumor necrosis factor alpha (TNF
alpha) is present in elevated concentrations in patients with inflammatory bowel
disease; therefore, it has been targeted for treatment approaches. Infliximab is
a chimeric, monoclonal antibody to TNF alpha developed to inhibit the interaction
of TNF alpha with its receptor, to result in amelioration of inflammation. This
biologic agent has received the most attention and is the most studied of those
for the treatment of patients with Crohn's disease. This article reviews the
symptoms of inflammatory bowel disease, the traditional treatment approaches
used, the role of TNF alpha in disease pathogenesis, and the value of infliximab
in treatment.
PMID- 10776109
TI - Endoscopic ultrasound for chronic abdominal pain and gallbladder disease.
AB - Endoscopic ultrasound (EUS) is a major advance in gastrointestinal endoscopy.
EUS, which is invaluable in the diagnosis and staging of gastrointestinal cancer,
is now being used in the diagnosis of chronic upper abdominal pain. EUS combined
with stimulated biliary drainage (EUS/SBD) aids in the diagnosis of
choledocholithiasis, cholecystitis, microlithiasis, and various conditions of the
upper gastrointestinal tract. This article describes the EUS/SBD procedure and
nursing care. Two case histories illustrating potential benefits to patients are
presented.
PMID- 10776110
TI - Internet tools for gastroenterology nurses and associates.
AB - The Internet is a worldwide network of computers with powerful communication
capabilities. Electronic mail, World Wide Web, search engines, Usenet, listservs,
and databases are tools to send, receive, and search for information via the
Internet. This article defines common Internet terminology and describes the
basic Internet tools that can enhance the practice of gastroenterology nurses and
associates.
PMID- 10776111
TI - The role of the gastroenterology nurse in colorectal cancer screening.
AB - This article provides an overview of the incidence of colorectal cancer in the
United States and describes personal and familial factors that increase a
person's risk for developing colorectal cancer. Recommendations for each
classification of patient risk group are outlined. An in depth review of
screening justification for colorectal cancer is presented as well as the
American Cancer Society's recommendations for screening. Descriptions of and
recommended frequency for fecal occult blood tests, flexible sigmoidoscopy,
double contrast barium enema, and colonoscopy are explained as well as the
advantages and disadvantages of each test. The role and fundamental
responsibilities of the nurse endoscopist are presented based on the author's
personal experience. Factors that influence patient compliance are also
described, including the role of the gastroenterology nurse in facilitating
colorectal cancer screening.
PMID- 10776112
TI - Performance of gastrointestinal manometry studies and provocative testing. The
Society of Gastroenterology Nurses and Associates, Inc.
PMID- 10776113
TI - When cancer strikes a member of the family or a close friend, the word itself
takes on a different meaning.
PMID- 10776114
TI - Native women and cancer.
AB - Literature regarding cancer patterns in American Indians and Alaska Native women
is reviewed and attention is paid to promising research initiatives to improve
cancer prevention and control as well as approaches to enhance exchange of
knowledge through a new national resource center. Lung, breast, and colorectal
cancer are the leading cause of cancer deaths in American Indians and Alaska
Native women. There continues to be a disproportionate death rate from cervical
cancer. Enhanced availability for breast and cervical cancer screening in
conjunction with community education is showing promising trends toward reversing
the patterns of late diagnosis. Communities can benefit from sharing their
collective resources in a new national resource center called "Native
C.I.R.C.L.E." housed in the Mayo Cancer Center.
PMID- 10776116
TI - Pap prevalence and cervical cancer prevention among Alaska Native women.
AB - The goals of the Alaska Native Women's Health Project (WHP) were to determine the
following: (1) Pap prevalence based on chart review before and during an
intervention period; (2) the level of understanding of cancer and cancer
screening services with emphasis on cervical cancer; (3) use and satisfaction
with current health maintenance services; and (4) improvement in knowledge and
cancer screening rates following intervention. A random sample of 481 Alaska
Native (Eskimo, Aleut, Indian) women living in Anchorage were interviewed face to
face about their understanding of cancer risk factors (tobacco use, sexually
transmitted diseases (STDs), reproductive issues), cancer screening examinations
(Pap test, breast self-examination (BSE), breast exam by a provider,
mammography), and their attitudes about health care and health care services.
Sixty-two percent of control women were documented to have had at least one Pap
test within the 3-year period prior to the beginning of the study; however, only
9% were documented to have had annual Pap screening. The intervention included
distribution of educational materials, counseling on any woman's health issue,
special evening clinics, and reminders (mail/phone call) of scheduled Pap
appointments.
PMID- 10776115
TI - Characteristics of American Indian women cigarette smokers: prevalence and
cessation status.
AB - A high rate of cigarette smoking is documented among the American Indian
population in California, but data on Indian women smokers have not been widely
studied. This paper reports on a survey conducted in a smoking cessation project
implemented and evaluated as part of a National Cancer Institute (NCI)
cooperative agreement. Characteristics of Indian women smokers are presented and
cessation status is examined. The overall goal of the project was to increase
long-term smoking cessation among American Indian populations through a
reproducible clinic-based smoking cessation program. To ascertain smoking
prevalence and tobacco use patterns, a self-administered survey was completed by
1,369 adult male and female American Indian health clinic users in Northern
California. Study results reported several important characteristics of Indian
women smokers. Single and divorced participants had a higher smoking rate (40.4%
and 42%) than married participants (34.4%); 54.5% of unemployed women smoked; and
level of education was strongly associated with smoking status (p = .011). Almost
80% (79.9%) of women former smokers quit using the "cold turkey" method. Fewer
than 50% of Indian women smokers reported willingness to quit at the following
smoking cessation stages: "immediately" or "ready" (12.4%), "in one month"
(10.5%), and "in six months" (25.2%). This points to a need for effective tobacco
cessation interventions for American Indians, which will take into consideration
Indian women smokers' demographic characteristics, lenient attitudes toward
smoking, and smoking behaviors.
PMID- 10776117
TI - The Alaska Native Women's Wellness Project.
AB - Alaska Native women have encountered many obstacles in the health care system
which deter them from adhering to cancer screening recommendations. To improve
access, it was necessary for us to listen to them and their attitudes about
health care. As a result of this assessment, we changed our approach resulting in
an overall increase in screening rates from 14% to 62%. A case example is
presented to demonstrate barriers to cancer screening and our techniques for
overcoming them.
PMID- 10776118
TI - Measures of American Indian traditionality and its relationship to cervical
cancer screening.
AB - The goal of this study was to evaluate the relationship between culture and
attitudes about cervical cancer screening among young American Indian women
living and working in northeast Oklahoma. A cohort of 199 American Indian women,
ages 18-40, were surveyed to determine their blood quantum, self-identification,
and beliefs and practices regarding traditional behavior in order to develop a
traditional behavior scale (the degree to which an individual maintained
traditional tribal ways or behaviors). The use of this scale indicated that the
degree of American Indian blood quantum, blood quantum for primary tribe, and
self-identification are correlated to the traditional behavior scale. The scale,
however, was unable to predict intention to get a Pap test. Results indicate that
it is useful to understand the variation of traditional behavior within the
specific population group to be served when planning and implementing culturally
appropriate interventions for American Indian women. It is also useful to
evaluate which segments of the population current programs are reaching.
PMID- 10776119
TI - Native American cancer survivors.
AB - This paper provides a brief review of cancer survival data for both Native
American men and women, information about cancer survivor support groups,
survivor resources, and some examples of how cancer is perceived by some Native
Americans.
PMID- 10776121
TI - Eight strategies to stretch your educational resources.
AB - Despite the reduction in resources for staff development in home care, the need
of the clinical staff for orientation and continuing education remains. Meeting
educational needs cost-effectively in the current environment will require
creativity, innovation, and a commitment to explore new options.
PMID- 10776120
TI - The importance of qualitative research in addressing cultural relevance:
experiences from research with Pacific Northwest Indian women.
AB - Across Indian communities, the spirit of self-determination is in the air. Tribes
are contracting with the federal government in order to take responsibility for
health and governance as sovereign nations. For too long others have defined
tribal needs, conceptualized tribal problems, and used their theoretical models
in implementing interventions. In this age of self-determination, more tribal
communities want to partner with others in studies affecting their communities.
Qualitative research offers an approach that can be responsive to community
needs. The strength of one qualitative method, Grounded Theory, for example, is
presented here as one such tool. Using Grounded Theory in two Pacific Northwest
tribal communities, the first study looked at attitudes about Papanicolaou (Pap)
test screening and the second looked at conceptualization of pain. It is
suggested that qualitative research is of particular value to the design of
culturally relevant interventions.
PMID- 10776122
TI - Latex allergies: what is your responsibility as a manager?
AB - Natural Rubber Latex (NRL) is found in over 40,000 products and presents many
challenges for the home care manager who is faced with the task of providing
"reasonable accommodations" to keep the employee safe in the work environment. In
addition, patient care must also be modified in order to keep latex sensitive
patients safe. This article presents the background of latex allergies and
describes how to better manage both the employee and the patient with this
allergy based on the most current information.
PMID- 10776123
TI - Doing the right thing: administrative ethics.
PMID- 10776124
TI - Death of a home care agency: is there an educator in the house?
PMID- 10776125
TI - Back to basics. A review of selected certification and coverage fundamentals.
AB - Attention to the basics can often eliminate, or at least minimize, problems
experienced throughout an organization, saving critical resources for more
positive endeavors such as quality improvement and service development. Agencies
with a good grip on the basics spend less time fixing problems, and more time on
innovation and quality.
PMID- 10776126
TI - HHS announces expanded "senior patrol" grants to help spot waste, fraud, and
abuse in Medicare and Medicaid.
PMID- 10776127
TI - [Means of communicating one's last will and testament].
PMID- 10776128
TI - [Andree Coulombe, a woman made to order for intensive care. Interview by Danielle
Stanton].
PMID- 10776129
TI - [The prenatal period for primiparous couples].
PMID- 10776130
TI - So you can't afford a commercial package? Innovate, collaborate, improve.
AB - Traditional classroom mandatory review classes do not actively involve the
learner; require considerable instructor time for development, implementation,
and tracking; and are costly to the institution. This article describes the
creation and implementation of a computer-assisted instruction (CAI) mandatory
review package using the medical center's intranet system. The CAI mandatory
review package allows employees to complete mandatory review at a computer
terminal at their worksite and at their convenience.
PMID- 10776131
TI - Implementing differentiated practice: personal values and work satisfaction among
hospital staff nurses.
AB - This project was part of a collaborative model for nursing staff development and
student education. Personal values and work satisfaction of 49 staff nurses
working on three hospital units were compared. One of the units employed
differentiated practice. Results revealed high similarity in personal values
among all nurses. Work satisfaction was significantly higher among nurses working
on the unit employing differentiated practice. The importance of assessing
personal values of nurses emerged as an important aspect of staff development,
and differentiated practice appeared to be related to staff nurse satisfaction.
PMID- 10776132
TI - Dosage calculation testing for competency in ambulatory care.
AB - The scope of services provided by the Staff Development Department or clinical
educators in healthcare settings includes, but is not limited to, employee
orientation, continuing education, and competency assessment. The critical issue
of ascertaining competency of nursing staff in medication dosage calculation
encompasses each of these functions. The authors describe the process of pilot
testing a dosage calculation test in an ambulatory care setting, adapting it
based on feedback, using it with orientees and current staff, and using the
educational process with nurses needing assistance in dosage calculation.
PMID- 10776134
TI - A comparison of three teaching methods on learning and retention.
AB - The purpose of this study was to examine the relationship of the teaching method
used with cognitive learning and learning retention outcomes of nurses when
instructed in Imogene King's Theory of Goal Attainment. This study's
quantitative, quasi-experimental design examined relationships and/or differences
between variables or groups. Cognitive learning and learning retention outcomes
were measured by pre-, post- and 1-week posttests. Statistically significant
learning took place in all three methods. However, no statistically significant
difference was found between teaching method used and cognitive learning or
retention. The information gained from this study may provide a stepping stone
for enhanced education in the orientation phase of employment, and will provide
the impetus for further study.
PMID- 10776133
TI - Six hospitals describe decentralization, cost containment, and downsizing.
AB - Decentralization, cost containment, and downsizing continue in full force as
healthcare organizations continue to adapt to constant economic change. Hospitals
are forced to take a second and third look at how health care is managed in order
to survive. Six Northwest Florida hospitals were surveyed in an effort to explore
current changes within the healthcare delivery system. This article provides both
managers and staff with an overview of recent healthcare changes in an area of
the country with implications for staff development.
PMID- 10776135
TI - The orientation experiences of urgent care nurses: sources of learning.
AB - The purpose of this qualitative study was to characterize and explain the unique
features relating to the orientation of newly hired nurses in an urgent care
setting. The learning needs of professionally experienced nurses are examined as
nurses change their context of work. The methodology for this study was
exploratory, using descriptive and evaluative case studies. Nurses identified how
additional knowledge was learned when they recognized gaps between what they know
and what they need to know. The findings included an urgent care nursing
perspective of orientations and consisted of four sources of learning: natural,
self-directed, peer-directed, and organization-directed. The narratives shared by
these nurses strengthen and advance the communication of those who help adults
learn.
PMID- 10776136
TI - Report of the Task Force on advanced practice in nursing continuing education and
staff development.
PMID- 10776137
TI - Building nursing science.
PMID- 10776138
TI - An overview of the need-driven dementia-compromised behavior model.
PMID- 10776139
TI - Wandering. A dementia-compromised behavior.
AB - The wandering behavior of individuals with dementia is a puzzling behavior, and
strategies for responding to it often are poorly grounded. However, advances in
the understanding of neuro-cognitive factors contributing to wandering now may
provide important clues for designing nursing approaches. In this article, such
advances are summarized, and implications and strategies for practice are
delineated.
PMID- 10776140
TI - Problematic vocalizations in institutionalized individuals with dementia.
PMID- 10776141
TI - Passive behaviors in dementia. Clinical application of the need-driven dementia
compromised behavior model.
PMID- 10776142
TI - The measurement of need-driven dementia-compromised behavior. Achieving higher
levels of interrater reliability.
PMID- 10776143
TI - Some musings of an aging researcher.
PMID- 10776144
TI - How is the practice of gerontological nursing changing in your field or setting?
How do you see your role evolving in the next 5 years?
PMID- 10776145
TI - The thief called dementia.
PMID- 10776147
TI - Predicting pressure ulcer sore risk.
PMID- 10776146
TI - There's good news and bad.
PMID- 10776148
TI - Individualized music intervention protocol.
PMID- 10776149
TI - Creutzfeldt-Jakob disease. Assessment and management update.
PMID- 10776151
TI - The meaning of leisure.
AB - Although leisure plays a significant role in older adults' lives, little is known
about the meaning of leisure for this population. Thus, the purpose of this
grounded theory study was to conceptualize the meaning of leisure for older
adults in a continuing care retirement community. Theoretical sampling included
40 retirement home residents of Dutch heritage living in a suburban, midwestern
area of the United States. Data collection consisted of participant observation
and intensive interviews, and data analysis involved constant comparison method.
This method facilitated development of a conceptual model of authoring leisure.
The model of authoring leisure highlights older adults' definition of leisure,
strategies used to author leisure, and the consequence of authoring leisure. The
resulting conceptual refinement of leisure facilitates validation of leisure
related nursing diagnoses and provides empirically based knowledge for
gerontological nursing practice.
PMID- 10776150
TI - Infection with HIV in the elderly population.
AB - Infection with HIV among older adults in the United States needs to be
investigated in greater detail because little substantive knowledge currently is
available about HIV/AIDS in the elderly population. The Centers for Disease
Control and Prevention reports that 10% of all cases of diagnosed HIV/AIDS are in
people age 50 and older. The problem is that very little is known about the
effects of HIV/AIDS in this population. The majority of the literature is based
on limited case reports, and very little empirical research is available. This
lack of knowledge limits health care professionals' ability to properly diagnose
and adequately treat individuals who may be infected. This article considers
various sources of infection, potential risk factors, the difficulty of
diagnosis, and the rapid progression of the disease process in older adults.
Signs and symptoms of common opportunistic infections are explored. Treatment
challenges, nursing care of older adults infected with HIV, and psychosocial
aspects of the disease are discussed.
PMID- 10776152
TI - Measuring nursing work in long-term care. The reliability and validity of the
Leatt Measure of Nursing Technology.
AB - A projected 400% increase in the number of people age 85 and older by the year
2010, with one fourth of them needing nursing home care, forces attention on long
term care. This study establishes the validity and reliability of the Leatt
Measure of Nursing Technology (LMNT) as a measure of the nature of nursing work
in long-term care settings. The LMNT subscales measure the amount of uncertainty,
instability, and variability of work which includes, but is not limited to, the
technical equipment used. The LMNT was administered to licensed nursing staff in
nine long-term care facilities in the Seattle area to evaluate its use in this
environment. The nursing homes represented both for-profit and not-for-profit,
and large (more than 250 beds) and small (70 beds) facilities. A total of 113
usable questionnaires were returned (45% response rate). Cronbach's alpha for
subscales were .71 for Uncertainty, .66 for Instability, and .56 for Variability,
with .77 for the total scale. Construct validity was evaluated by factor
analysis, which confirmed the original factor structure. Content validity was
evaluated using focus group discussions with key informants at each facility. A
comparative analysis was used to determine major and minor themes in each of the
instrument subscale topic areas. Qualitative analysis, combined with reliability
and item level analyses, resulted in suggested minor changes in the instrument to
make it more usable in long-term care settings. While some revisions are
suggested, a concerted effort must be made to preserve the ability to compare
findings with those obtained using the LMNT in acute care settings by retaining
the general structures and factors of the measure.
PMID- 10776153
TI - What are the critical success factors for providing quality dementia care in
assisted living?
PMID- 10776154
TI - Hands.
PMID- 10776155
TI - A perfect death.
PMID- 10776157
TI - The lived experience of being at home. A phenomenological investigation.
AB - OBJECTIVE: To describe the essential structure of the lived experience of feeling
at home for older adults relocated to alternative care settings which provide
some degree of supervision. METHODS: A purposive sample of 10 relocated older
adults in three settings (i.e., one life care and two long-term care facilities)
was studied using a qualitative design. Data were gathered through interviews and
analyzed using Giorgi's (1985) method of phenomenology. FINDINGS: Fourteen themes
existing in a dialectic of "at home" versus "not at home" emerged and were
integrated into the essential structure of the phenomenon of home. Elders who
felt at home had strong feelings of satisfaction with their lives, security,
autonomy, and purpose. Those older adults who did not feel at home were anxious,
angry, and depressed, and were consumed by a desire to be elsewhere. CONCLUSIONS:
Some individuals have great difficulty establishing a sense of home in
alternative settings. Methods of assessing older adults and designing
interventions that contribute to establishing a sense of home could prove
valuable in enhancing the quality of life for those who must spend their
remaining years in settings other than their traditional homes.
PMID- 10776158
TI - Family perspectives on dying in long-term care settings.
AB - Dying is a central experience in the life of a family. Yet there are few studies
of dying in long-term care and the role of a family. The dynamic relationships
among families, staff, and residents in long-term care facilities related to the
process of dying is an area where research is needed. As part of a larger study
of death and dying in long-term care settings, 11 family members who recently had
experienced the loss of a relative in the long-term care setting were
interviewed. The purpose of this study was to describe family perspectives on
death and dying in long-term care facilities and to discuss ways staff may be
helpful to families in coping with the loss of a family member. Analyzing death
and dying from the family perspective offers health care providers an opportunity
to expand the understanding of the phenomenon of death in long-term care
facilities and to incorporate care activities that families view as helpful.
Major themes emerged from this study, including the caring behaviors of staff,
participating in the dying process, and providing spiritual support. The themes
and practice implications are discussed in this article.
PMID- 10776156
TI - Doris Schwartz: an exemplar of personal, social, and creative courage.
PMID- 10776159
TI - Individualized interventions to prevent bed-related falls and reduce siderail
use.
AB - Five categories of problems that often result in siderail use: memory disorder,
impaired mobility, injury risk, nocturia/incontinence, and sleep disturbance. As
nursing homes work toward meeting the Health Care Financing Administration's
mandate to examine siderail use, administrators and staff need to implement
interventions that support safety and individualize care for residents. While no
one intervention represents a singular solution to siderail use, a range of
interventions, tailored to individual needs, exist. This article describes the
process of selecting individualized interventions to reduce bed-related falls.
PMID- 10776160
TI - Observed behaviors of patients with probable Alzheimer's disease who are
hospitalized for diagnostic tests.
AB - This study examines observed behaviors of hospitalized patients with probable
Alzheimer's disease (AD) undergoing invasive diagnostic procedures. Data was
obtained from nursing documentation in the medical records of 30 patients, 10 in
each stage of AD (i.e., mild, moderate, severe). In general, analysis of the data
revealed that changes in behavior occurred immediately prior to, during, and
following these procedures. Specifically, the moderately impaired patients showed
the most significant curve over the 5-day observation period, while patients in
the mildly impaired group showed a high peak of behavioral change on the test
day. The severely impaired group of patients had a higher sustained level of
activity throughout the 5-day period. Routine assessment of the patients' usual
behaviors, care-givers' knowledge of the stage of disease, and awareness of the
potential impact that diagnostics may have on cognitively impaired patients could
help care providers decide what interventions most likely would lead to
successful outcomes.
PMID- 10776161
TI - Deceiving appearances. Communicating with facially inexpressive older adults.
AB - The term "facially inexpressive" is introduced to describe individuals who have
lost the ability to produce facial expressions as a result of a neuromuscular
disorder. Difficulties in communication may be compounded by presentation of this
condition in individuals of mature appearance because the expectation of
diminished functioning may increase. Practical techniques are offered to
circumvent inaccurate and potentially detrimental assumptions both practitioners
and laypeople tend to make when communicating with older adults whose conditions
prevent the normal yield of social cues. A case study is presented and
implications for the wider geriatric population are discussed.
PMID- 10776162
TI - Use of the Iowa Self-Assessment Inventory with older hospitalized patients.
AB - This study examined the utility of the Iowa Self-Assessment Inventory (ISAI) as a
multidimensional screening tool for older adults in the acute care hospital
setting. A sample of 98 patients age 60 and older were administered the ISAI, the
Short Geriatric Depression Scale, and the Mini-Mental State Examination. The
findings suggest the ISAI is useful for screening for depression but does not
detect differences in cognition. However, qualitative data and literature review
support the continued search for a holistic, humanistic screening tool to
increase the quality and effectiveness of patient care.
PMID- 10776163
TI - Agnes.
PMID- 10776164
TI - Prostate cancer elder alert. Epidemiology, screening, and early detection.
PMID- 10776165
TI - Planning an osteoporosis education program for older adults in a residential
setting.
PMID- 10776166
TI - The changing role of grandparenthood.
AB - For many grandparents in America, caring for grandchildren has become a full-time
responsibility that has led to multiple stresses. Raising grandchildren may cause
financial stress, cramped living quarters, role restriction, and social isolation
among this group. However, advantages to this role among grandparents can include
greater life satisfaction and a positive influence on the other generations
within the family. Nurses and other health providers can play an essential role
in assisting grandparents caring for grandchildren by strategically building
family strengths and cohesiveness.
PMID- 10776167
TI - Consequences of not recognizing delirium superimposed on dementia in hospitalized
elderly individuals.
AB - OBJECTIVE: The purpose of this study was to describe the recognition and
management of delirium in hospitalized patients with and without dementia.
DESIGN: A descriptive, exploratory design was used with a convenience sample of
20 hospitalized older patients who were observed indepth using qualitative
interviews and observations of 13 family members and 11 staff members. SETTING:
This research was conducted on the medical-surgical units of a 550-bed,
nonprofit, state-supported teaching hospital in the southeastern United States.
The facility provides primary and tertiary care with five intensive care units
and eight medical-surgical units. PARTICIPANTS: This study did not exclude
individuals with dementia or pre-existing delirium. Subjects were not excluded on
the basis of race or gender. Twenty patients in the sample underwent observation
and mental and functional status testing. Thirteen family members and 11 staff
members were interviewed and observed. MEASUREMENTS: In Phase 1 of the study,
patients had daily mental status testing performed by the investigator. In Phase
2, family members and staff members were interviewed about the confusion event.
For each patient, demographics and information regarding their health status and
current diagnosis and treatment were obtained. The Mini-Mental State Examination
(MMSE) and the Confusion Assessment Method were completed on each subject within
36 hours of being admitted to the hospital. The Cornell Depression Scale and Katz
Activities of Daily Living scale were completed within 48 hours of admission.
RESULTS: The prevalence of delirium in this study was 60%. The incidence, or new
onset of delirium, was 30%. The presence of delirium was associated with new
onset incontinence, lower baseline MMSE scores, depression, weight loss, and
comorbidity. Of the eight individuals with delirium superimposed on dementia, 63%
(n = 5) were re-admitted to the hospital within 30 days, compared to none of the
individuals with delirium in the absence of dementia. Delirium superimposed on
dementia also was less likely to be recognized by nurses and physicians.
CONCLUSIONS: Delirium in individuals with dementia should be assessed and treated
routinely because the failure to recognize delirium superimposed on dementia
promptly has significant negative personal, social and financial consequences.
PMID- 10776168
TI - Practical uses of peripheral intravenous nutrition. Three case studies.
PMID- 10776169
TI - Policy recommendations for family caregiver support.
PMID- 10776170
TI - The elderly immigrant. An isolated experience.
PMID- 10776171
TI - Priscilla Pierre Ebersole. Pathfinder in gerontological nursing.
PMID- 10776172
TI - Family Involvement in Care for individuals with dementia protocol.
PMID- 10776173
TI - Prostate cancer elder alert. Living with treatment choices and outcomes.
PMID- 10776174
TI - Grief responses of senior and elderly widows. Practice implications.
PMID- 10776175
TI - Alcohol use in elderly women. Nursing considerations in community settings.
PMID- 10776176
TI - In what ways is technology assisting you with your practice?
PMID- 10776177
TI - Lactation consulting in an ideal world: a personal view.
PMID- 10776178
TI - Mammary candidosis in lactating women.
AB - Though perceived to be a growing problem by lactation professionals, fungal
infection of the breast (mammary candidosis) is largely unstudied. Candida
albicans, a commensal organism encountered frequently in the vagina and
gastrointestinal tract of humans, has been reported to be responsible for both
superficial (cutaneous) and localized (ductal) infection of the mammary gland in
lactating women, though the latter association is not universally accepted.
Severe pain is considered to be characteristic of yeast infection of the breast
and may be a cause of premature weaning among lactating mothers. Given that pain
is often the complaint that prompts mothers to consult lactation professionals,
it is important that healthcare providers working with lactating women be
knowledgeable about this disease. In this article, current research regarding
yeast infection of the breast is summarized, including morphology and pathology,
diagnosis, risk factors, and common treatment options.
PMID- 10776179
TI - A multidisciplinary approach to promoting a Baby Friendly environment at an urban
university medical center.
PMID- 10776181
TI - Weight change during lactation does not alter the concentrations of chlorinated
organic contaminants in breast milk of women with low exposure.
AB - The purpose of this longitudinal study was to evaluate whether a loss of body fat
during lactation between 4 and 20 wk postpartum increases the concentration of
environmental contaminants in breast milk. We examined this relationship in two
different cohorts of exclusively breastfeeding women: (1) California women with
low exposure to contaminants (n = 10 whose weight was stable [mean change, 0.0 +/
0.2 kg] and n = 11 who lost weight [mean loss, -4.1 +/- 0.4 kg]) and (2)
Hispanic women (n = 30) who had recently immigrated to North Carolina, primarily
from Mexico, and were presumed to have a higher prior exposure to contaminants.
Breast milk samples were analyzed for hexachlorobenzene (HCB) and DDT and its
related products. There was no significant relationship between change in body
composition and change in milk contaminant concentrations in either California or
North Carolina women. Concentrations of HCB were similar between the California
and North Carolina women, but those of DDT and related products were higher in
the North Carolina subjects. Results suggest that moderate weight loss in
lactating women with low exposure to environmental contaminants does not increase
contaminant concentration in breast milk.
PMID- 10776180
TI - Mastitis and immunological factors in breast milk of human immunodeficiency virus
infected women.
AB - Human milk contains important immunological factors that protect the breast from
infection and are thought to protect infants from infection, including human
immunodeficiency virus (HIV) infection. Human milk immunological factors have not
been well characterized in HIV-infected lactating women. Lysozyme, secretory
leukocyte protease inhibitor (SLPI), sodium (an indicator of mastitis), and HIV
were measured in breast milk of 334 HIV-infected women at 6 weeks postpartum.
Women with mastitis, as indicated by elevated breast milk sodium concentrations,
had higher median levels lysozyme (290 vs 221 mg/L, p < 0.04), SLPI (38 vs 19
mg/L, p < 0.0001) and HIV (920 copies/mL vs undetectable, p < 0.0001) compared
with women without mastitis. Lower total plasma carotenoid levels (p < 0.02) and
higher maternal HIV load (p < 0.006) by quartile were risk factors for mastitis.
Mastitis, as indicated by elevated breast milk sodium levels, is associated with
high concentrations of immunological factors and higher HIV load in breast milk.
PMID- 10776182
TI - Maternal perception of lactogenesis time: a clinical report.
AB - A study evaluating the time between delivery and the surge in milk production
(lactogenesis time) determined whether lactogenesis time (LT) is affected by
parity, factors in pregnancy and delivery, and especially cesarean section. Forty
six primiparous mothers and 81 multiparous mothers reported the time of sensation
of milk production after delivery. The mean LT in the entire sample was 50 +/- 15
hours. The mean LT in 46 primiparous mothers was 59 +/- 14 hours, and in 81
multiparous mothers 45 +/- 12 hours (by student t test, p < 0.01). Mean LT did
not decrease as parity increased in the multiparous mothers. By multivariate
analysis, mean LT was 44 hours in multiparous mothers who delivered vaginally
without medication, 11 hours longer if primiparous, 6 hours longer if delivery by
cesarean section, and 13 hours longer if sedative or pain medication were given
during labor.
PMID- 10776184
TI - Patient with insufficient glandular tissue experiences milk supply increase
attributed to progesterone treatment for luteal phase defect.
AB - A case report is presented on the experience of a mother diagnosed with
insufficient glandular tissue at 3 months postpartum with her first child who
then went on to breastfeed her second child (fifth pregnancy) without
supplementation of any kind. The mother had difficulty becoming pregnant and
maintaining a pregnancy. She was diagnosed with a luteal phase defect and was
thus treated with natural progesterone during her fifth pregnancy. The authors
speculate that this treatment may have stimulated the development of her mammary
alveolar cells, allowing lactation to progress normally.
PMID- 10776183
TI - Connection and pleasure, disruption and distress: women's experience of
breastfeeding.
AB - Interview data collected in a recent study of first time motherhood were used to
explore the experience of breastfeeding. Twenty-five Australian women
participated in a series of semistructured interviews begun during late pregnancy
and continuing until 6 months postpartum. Discourse analysis was used to examine
the transcribed data. The analysis revealed that breastfeeding was central to
these women's experience of motherhood. The majority of women were strongly
committed to breastfeeding. Their decision to breastfeed was influenced by a
range of public and professional discourses. Breastfeeding was also an embodied
experience that was difficult to articulate. For some, this embodied experience
was connected, harmonious and pleasurable and for others, disruptive, unpleasant,
and violent. This paper describes the embodied experience of breastfeeding and
highlights the complexity of the relationship between embodied experience and
contemporary meanings and context of breastfeeding.
PMID- 10776185
TI - Is pasteurized mother's own or donor milk an answer to the HIV crisis?
PMID- 10776187
TI - Recent references.
PMID- 10776186
TI - Use of cough and cold preparations during breastfeeding.
AB - Adverse reactions in infants from maternal drug ingestion depend largely on the
amount of milk consumed by the infant, timing of breastfeeding in relation to
dosing, dose of the medication, dosing interval, and duration of therapy. When
taking medications, breastfeeding mothers should be instructed to take their
medication after breastfeeding, at the lowest effective dose and for the shortest
duration. Overall, there are few data from human studies on the use of
antihistamines, decongestants, and cough products during breastfeeding. Studies
of pseudoephedrine, triprolidine, and loratadine in humans conclude that low
levels of each drug would reach a breastfed infant. Since triprolidine and
pseudoephedrine are also considered compatible with breastfeeding by the AAP,
these 2 drugs should be the first-line choices. Codeine is considered compatible
with breastfeeding by the AAP, and would be an acceptable choice for short-term
use as a cough suppressant. It is important to note that many of the liquid cough
and cold products contain alcohol. In addition, many of the combination products
are a mixture of an antihistamine and a decongestant and may also contain
aspirin, acetaminophen, ibuprofen, or caffeine. It is preferable for nursing
mothers to only take medications that are necessary and to avoid such combination
products. The AAP considers alcohol, acetaminophen, ibuprofen, and caffeine
compatible with breastfeeding. Aspirin has been associated with significant
negative effects on some nursing infants, and the AAP recommends giving aspirin
to nursing mothers with caution. Mothers taking cough and cold products should
watch for adverse events in their breastfed infants. Infants may experience
paradoxical central nervous stimulation from antihistamines and irritability and
insomnia from decongestants.
PMID- 10776188
TI - Faculty and clinicians collaborate to teach basic intravenous skills to senior
baccalaureate nursing students.
AB - Faculty in baccalaureate programs must adapt their curricula to meet the needs of
students entering health care settings where rapid change means increased
responsibility for the staff nurse. One of these changes is in the area of
intravenous therapy, where it has become an expectation that staff nurses perform
peripheral IV starts. In response to this need, faculty at Boston College School
of Nursing chose to develop an IV Therapy Practicum by collaborating with IV
nurse specialists from The Lahey Clinic. This practicum was incorporated into the
senior-level Synthesis Clinical Course, for which students are mentored by a
baccalaureate-prepared nurse preceptor.
PMID- 10776189
TI - Alpha 1-antitrypsin deficiency and the impact of nursing interventions and
treatment with intravenous therapy. An overview.
AB - The primary function of alpha1-antitrypsin is to protect the alveoli in the lung
from harmful destruction from proteolytic enzymes, which prevent optimal elastic
recoil of the lungs and destroy the lungs. Insufficient serum levels of alpha1
antitrypsin eventually lead to early onset of emphysema in the third, fourth, or
fifth decade of life. Treatment of alpha1-antitrypsin deficiency by intravenous
administration of an enzyme inhibitor known as alpha1-proteinase inhibitor, a
human-derived blood product, can be administered to help replace the enzymes
required to maintain lung function. Early detection, nursing intervention, and
clinical management slow the progression of this hereditary disease.
PMID- 10776190
TI - Prostacycline (Flolan). Intravenous nursing responsibilities in the care of the
patient with primary pulmonary hypertension.
AB - Primary, or unexplained, pulmonary hypertension is an extremely rare lung
disorder. For no apparent reason, blood pressures in the pulmonary artery
increase far in excess of normal levels. Prostacycline (Flolan, epoprostenol) has
proved effective in the long-term care of patients with Type III or Type IV
primary pulmonary hypertension (PPH). These patients require intensive
intravenous therapy-related education in the safe and compliant administration of
prostacycline. The IV nurse's multiple roles in the care of these patients are
clearly delineated: instructor, advocate, and clinical resource specialist.
PMID- 10776191
TI - The role of systemic lidocaine in neuropathic pain management.
AB - Pain management is rapidly changing as the mysteries of how healthy and damaged
nervous systems work to communicate pain to the brain become better understood.
The role of subcutaneous or intravenous lidocaine in the management of
neuropathic pain has been increasingly studied. Patients with a variety of pain
have been shown to benefit from this therapy, including patients with cancer,
postherpetic neuralgia, second degree burns, strokes, and diabetes. As research
and experience grow, so too will the practitioner's ability to successfully use
intravenous and subcutaneous lidocaine therapy for their patients with pain.
PMID- 10776192
TI - Latex allergy. Prevention is the key.
AB - Latex allergy has been recognized as the new allergy of the 1990's, an allergy
identified in patients and health care workers. The primary cause is the use of
powdered latex gloves. Many of the medical supplies used by the intravenous nurse
specialist are made of latex. This allergy is potentially preventable for both
the patient and nurse. The IV nurse specialist needs to be aware of the
prevalence, symptoms, risk factors, diagnosis, and treatment of latex allergy.
PMID- 10776193
TI - The role of chloride in acid-base balance.
AB - The role of chloride in acid-base balance is described. Chloride is defined, and
its functions, regulation, and normal values are discussed. Chloride shift is
explained. Hypochloremia and hyperchloremia and their implications in acid-base
balance are discussed, including etiology, assessment, types of metabolic
acidosis, treatment, and nursing considerations.
PMID- 10776194
TI - Stress and school: helping children cope.
PMID- 10776195
TI - Hepatitis B vaccine.
AB - Hepatitis B virus (HBV) infection is a health problem that affects numerous
infants and children in the United States. Approximately 4000 to 6000 new
infections occur each year in children and adolescents; most often they become
infected without obvious clinical manifestations. Some persons become chronically
infected, and this asymptomatic chronically infected population serves as a
reservoir for HBV. Immunization of all newborn infants and adolescents for HBV is
a vital step toward eradicating HBV from the general population. Pediatric nurse
practitioners are in a strategic position to provide education and the carry out
immunization efforts that will dramatically decrease the morbidity associated
with HBV.
PMID- 10776196
TI - Update of the health care management needs of infants with sickle cell disease.
AB - This article describes the characteristics, clinical manifestations, and health
care management of infants with sickle cell disease. Also discussed are parent
education issues and stressors related to coping with the health care management
needs of infants with sickle cell disease. Special emphasis is given to
literature focused on the concept of anticipatory grief often experienced by
parents of chronically ill children.
PMID- 10776197
TI - Management of children with swallowing disorders.
AB - Early diagnosis and treatment of feeding and swallowing problems may improve a
child's health status and quality of life and reduce health care costs. Pediatric
nurse practitioners have a salient role in the early diagnosis of children at
risk for feeding and swallowing problems. Increased knowledge about the normal
swallowing process, children at risk for feeding and swallowing disorders, and
associated symptoms enhances early diagnosis and treatment. The child's general
health history and physical evaluation, along with additional diagnostic tests,
provide the basis for the formulation of an individualized feeding program by an
interdisciplinary team. Pediatric nurse practitioners, through their knowledge
about dysphagia and participation on a interdisciplinary team, can provide
support for family members and assist them in adapting to and caring for a child
with a swallowing impairment.
PMID- 10776198
TI - The usefulness of an assessment of emotional involvement of HIV-positive mothers
and their infants.
AB - INTRODUCTION: A positive mother-infant relationship is crucial for optimal child
development; however, many factors may interfere with the development of a such a
relationship. One group at risk for compromised mother-infant interactions is
women with HIV infection. The purposes of this study were (a) to examine the
usefulness of the Attachment During Stress scale (ADS) for measuring the
emotional involvement of HIV-positive mothers with their infants during a clinic
visit and (b) to explore the effects of maternal health status, age, parity, and
educational level on mother-infant involvement. METHOD: A descriptive,
longitudinal study was conducted with 57 primarily African American HIV-positive
mothers and their infants who were patients at 1 of 2 regional referral centers.
The ADS was completed during the child's physical examination at 3, 6, and 12
months of age, and mothers completed questionnaires during these visits. RESULTS:
Maternal age, education level, health status, and parity were not related to
maternal emotional involvement. However, the emotional involvement of the mother
and infant were correlated (r = 0.73, P < .001). DISCUSSION: These findings
suggest that the ADS may be a useful screening tool to supplement the nurse's
clinical judgment in a pediatric outpatient setting. The ADS provides some useful
information about the emotional involvement of the mother and infant, although it
does not provide a comprehensive assessment of their relationship.
PMID- 10776200
TI - Malocclusion: how important is that bite?
PMID- 10776201
TI - Stealing/shoplifting.
PMID- 10776202
TI - Evaluation of attention deficit hyperactivity disorder.
PMID- 10776199
TI - The San Antonio Biethnic Children's Blood Pressure Study: auscultatory findings.
AB - INTRODUCTION: The purpose of this study were to: (a) examine for possible
ethnicity-related and gender-related differences in blood pressure (BP) in
Mexican American and non-Hispanic White schoolchildren; (b) compare auscultatory
and oscillometric BP levels; and (c) establish auscultatory BP standards using
the width of the BP cuff based on the circumference of the arm in schoolchildren
in K-12. METHODS: Participants were 6259 schoolchildren in kindergarten through
12th grade in the San Antonio, Texas, area. Auscultatory and oscillometric BP
readings were obtained in random sequence, using BP cuff width 40% to 50% of the
circumference of the upper arm. Averages of 3 readings were used for statistical
analyses. RESULTS: Auscultatory systolic pressures (SPs) in preadolescent Mexican
American boys and girls were higher (1 to 3 mm Hg) auscultatory (SP) than in
their White counterparts, but the difference was clinically not important.
Diastolic pressures (DP) showed no important differences. Auscultatory SPs in 13-
to 18-year-old boys of both ethnic groups were significantly (P < .05) higher (3
to 12 mm Hg) than they were for girls, with no ethnic differences. Oscillometric
SP was higher than auscultatory SP in children of all ages studied. Oscillometric
(DP) was slightly lower (0 to 5 mm Hg) than was auscultatory K4 and higher (4 to
5 mm Hg) than was auscultatory K5 DP. DISCUSSION: No important ethnicity-related
difference was found for auscultatory BP, but significant gender-related
differences (boys greater than girls) were found in SP in subjects ages 13 to 18
years. Differences in BP readings by oscillometric and auscultatory methods do
not allow interchange of readings. This study provides, for the first time,
auscultatory BP standards using BP cuff width 40% to 50% of the arm
circumference.
PMID- 10776203
TI - Dysfunctional voiding.
PMID- 10776204
TI - Good news for women and babies: folic acid prevents birth defects.
PMID- 10776205
TI - Playing to learn: the work of children and their parents.
PMID- 10776206
TI - Child's drawing: grandfather in the emergency department.
PMID- 10776207
TI - Reviewing the case for debridement.
PMID- 10776208
TI - The management of a patient with complex wounds.
PMID- 10776209
TI - The use of proteases as prognostic markers for the healing of venous leg ulcers.
AB - Abnormally high levels of some proteases are associated with pathological changes
in the wound bed of venous leg ulcers. This study involved two experiments which
measured proteases in wound fluid harvested from leg ulcers in order to predict
healing. In the first experiment, neutrophil elastase, a protease, was harvested
from wound fluid extracted from the bandages of seven patients with leg ulcers.
This was undertaken once a week over a period of up to six weeks. The amount of
elastase recovered from the bandages showed wide variation between patients and
there was no consistent correlation between the activity of elastase and healing
of the ulcers, as determined nine months after sampling for the enzyme. The
second experiment determined the stability of neutrophil elastase that was added
to bandages for one week. The stability was found to vary from approximately 50%
to 100%, depending on the type of bandage used. In addition to the possibility of
using protease measurements to predict healing, the procedure was found to be
simple, non-invasive and relatively inexpensive, and could be performed routinely
in the clinic.
PMID- 10776210
TI - Interface pressure measurements during ambulance journeys.
AB - This study investigated the risk of developing pressure damage associated with
surfaces used in ambulances. One subject's journey in an ambulance was evaluated
to identify the intensity of interface pressures (in mmHg) at particularly
susceptible areas (the ischial tuberosities, sacrum and heels) while the vehicle
was both stationary and moving. Interface pressures measured on a standard
ambulance stretcher and a spinal board were also compared. Results indicate that
the pressure readings obtained are likely to lead to capillary occlusion with the
potential development of pressure damage. Manufacturers of ambulances therefore
need to consider incorporating pressure-relieving surfaces in seats and
stretchers in the future.
PMID- 10776212
TI - Wound debridement, Part 2: Sharp techniques.
PMID- 10776211
TI - The structure and composition of chronic wound eschar.
AB - Wounds with a covering of eschar require debridement before optimal wound healing
can proceed. There are several different methods available but these have been
derived empirically with no direct evidence of the structure or composition of
the tissue they are designed to remove, or of the potential autolytic mechanisms
which are the targets for some of these treatments. The aim of this study
therefore was to determine the composition of chronic wound eschar and hence
identify potential targets for the induction of autolytic debridement. Chronic
wound eschar was removed by surgical debridement and analysed using
immunohistochemistry, polyacrylamide gel electrophoresis (PAGE) and gelatin
zymography. Immunohistochemistry using antibodies specific for extracellular
matrix (ECM) proteins revealed a definite tissue structure, consisting of many
fibrous regions and fine fibrillar elements separated by areas of tissue which
were of a more irregular and amorphous nature. An antibody specific for all
leucocytes revealed the presence of leucocytes in the region of tissue closest to
the wound bed. The presence of this leucocyte population correlated to elevated
levels of gelatinase activity as identified by gelatin zymography. PAGE analysis
identified various protein species in the range 3.5-60 kDa molecular weight.
These data indicate that wound debridement is likely to require multiple enzyme
specificities to degrade the eschar and that these enzymes may be supplied by
inflammatory leucocytes infiltrating the eschar from the wound bed. The various
protein species demonstrated by PAGE may represent ECM proteins, those with lower
molecular weight possibly representing the degradation products of autolytic
debridement.
PMID- 10776213
TI - How compression therapy works.
PMID- 10776214
TI - Paste-impregnated bandages.
PMID- 10776215
TI - Short-stretch bandaging in the treatment of venous leg ulcers.
PMID- 10776216
TI - The challenge of outcome measures in chronic wounds.
PMID- 10776217
TI - The aetiology and management of pilonidal sinus.
AB - Although there are various treatment regimens and dressing techniques for the
management of pilonidal disease, we recommend the 'open' technique for patients
with an uncomplicated sinus. Patients with more complex sinuses or recurrent
pilonidal disease should be treated by plastic surgeons.
PMID- 10776218
TI - The economics of preventing and treating pressure ulcers: a pilot study.
AB - A pilot economic evaluation of a projected pressure ulcer prevention policy was
carried out in a 252-bed geriatric unit in Glasgow. The aim was to set up a
framework for evaluating and comparing the costs and benefits of current care and
a potential prevention programme. Data were collated from prevalence and
incidence studies. Prevalence results showed that 41% of the patient population
suffered pressure damage to some extent and incidence data showed that 45% of
these were potentially preventable. Evaluation of the costs and benefits shows
that the prevention programme would be cost-effective. The cost would be between
17,606 Pounds and 28,669 Pounds but the benefits would range from 305,506 Pounds
to 342,510 Pounds. The authors conclude that economic appraisal is feasible.
PMID- 10776219
TI - The use of aromatherapy in wound care.
PMID- 10776220
TI - Beds and mattresses.
PMID- 10776221
TI - Nutritional intake in community patients with pressure ulcers.
AB - Nutritional status has been associated with the development and healing of
pressure ulcers. This study aimed to examine the dietary intake of adults who had
pressure ulcers (n = 75) and a control group with no pressure ulcers (n = 100),
randomly selected from those receiving treatment from community nurses. All
participants were considered to be at risk of developing pressure damage. Dietary
intake was assessed using a 24-hour recall method (completed by 84 participants)
and a nutritional questionnaire (completed by all 175 participants). The mean age
of participants was 79 +/- 6 years and 70% were women. Patients who had pressure
ulcers had a lower energy intake (mean difference -185 kcal, 95% confidence
interval -413 to 43) and intake of protein (mean difference -6.73 g/day, 95% CI
16.20 to 2.74) but neither factor achieved a standard level of statistical
significance. However, when protein was categorised into quartiles, a
significantly higher proportion of participants with low intake had pressure
ulcers on chi-squared analysis (p = 0.043). More participants who had pressure
ulcers required assistance with eating (odds ratio 4.55, 95% CI 1.53 to 13.54)
and more had experienced recent taste changes (odds ratio 3.28, 95% CI 1.19 to
9.10). While these differences were significant, there were few major differences
between those who had pressure ulcers and the control group. A number of
participants in both groups had poor nutritional intake and other risk factors
for malnutrition were also found. Poor nutrition is a problem for all patients
receiving community nursing care, not just those with pressure ulceration. Due to
acknowledged difficulties in recording nutritional intake in elderly patients,
further assessment of dietary intake in those receiving community nursing
services should be undertaken to support these results.
PMID- 10776222
TI - Comparative study of a foam mattress and a water mattress.
AB - In order to determine the effectiveness of high-quality foam replacement
mattresses in the treatment of pressure ulcers, one such mattress (TheraRest) was
compared with a water mattress (Secutex). One hundred and twenty nursing home
patients with pressure ulcers were randomised into two groups and nursed on one
of the mattresses for four weeks. After four weeks, 45% of the patients using the
foam mattress were completely healed, compared with 48.3% of those using the
water mattress. This difference is not significant. Since high-quality foam
mattresses are cheaper in the long term than water mattresses, and are easier for
nursing staff to manage, it is suggested that these mattresses are preferable.
PMID- 10776223
TI - The identification and treatment of slough.
PMID- 10776224
TI - Honey in wound care.
PMID- 10776225
TI - Cell biology of chronic wounds: the role of inflammation.
PMID- 10776226
TI - Autologous keratinocytes cultured on benzylester hyaluronic acid membranes in the
treatment of chronic full-thickness ulcers.
AB - Keratinocytes were obtained from three patients with chronic full-thickness
ulcers of different aetiologies. The cells were isolated, cultured and then
seeded on to a membrane composed of benzylester hyaluronic acid. Once the
keratinocytes had become subconfluent, the keratinocyte-containing matrix sheets
were then applied as autologous grafts to the patients' ulcers. Results indicate
that autologous grafting of keratinocytes cultured on benzylester hyaluronic acid
membranes provides improved graft handling, reduces total time required for
tissue cultivation and enhances cellular vitality because of the possibility of
grafting at a subconfluent non-differentiated stage.
PMID- 10776227
TI - Developing guidelines for pressure ulcer prevention and management.
PMID- 10776228
TI - The development of a leg ulcer care programme.
PMID- 10776229
TI - Prescribing for leg ulcers in general practice, Part 1.
PMID- 10776230
TI - [Munchhausen by proxy syndrome].
PMID- 10776231
TI - [Introduction to healing with precious stones].
PMID- 10776232
TI - [The child in a chaotic society].
PMID- 10776233
TI - [Bilirubinemia in the newborn--is it a disease?].
PMID- 10776234
TI - [Is there a depository for the nurse's empathy outside the nursery room?].
PMID- 10776235
TI - [Faked sick leave can lead to legal dispute].
PMID- 10776236
TI - [Campylobacter soon as no. 1 infection?].
PMID- 10776237
TI - [New protocol on the prevention of bacterial endocarditis].
PMID- 10776238
TI - Remember maternal mortality.
PMID- 10776239
TI - Poor and pregnant in Africa: safe motherhood and human rights.
AB - Currently almost 600,000 women die in the world each year owing to the effects of
childbirth. The greater proportion of these deaths occur in developing countries.
This issue is considered in the light of human rights and equity. This paper was
presented in a Plenary session at the Perinatal Society of Australia and New
Zealand's third annual congress in Melbourne, March 1999.
PMID- 10776240
TI - Towards an understanding of the cultural roots of homophobia in order to provide
a better midwifery service for lesbian clients.
AB - Research has indicated that homophobia amongst health professionals, including
midwives, has negative consequences for the care received by lesbian clients.
Social scientists recognise that homophobia is neither inevitable nor universal,
rather it is culturally specific and culturally constructed. This recognition is
potentially very positive, since it suggests that homophobia in midwifery
practice may successfully be theorised and critiqued in order to support the
development of better services for lesbian clients. In this paper discourse
analysis methodology from the cultural and social sciences is used to interrogate
textual evidence of the nature of homophobia in British and North American
culture. The analysis results in the identification of five 'themes' underlying
cultural expressions of homophobia: anxiety about sexual difference, fear of
female sexuality, the sexualisation of lesbianism, the characterisation of
lesbianism as 'sick' or 'unnatural', and the inability to identify lesbians with
any certainty. In the context of midwifery, these themes emerge as particularly
powerful, suggesting that, while the deep-rooted nature of homophobia is
resistant to rapid change, midwives may be uniquely well placed to develop
appropriate professional services for the growing minority of their clients who
are lesbian.
PMID- 10776241
TI - An ethnographic study of women's experience of partnership caseload midwifery
practice: the professional as a friend.
AB - OBJECTIVES: To explore the experience of a known midwife for labour and birth as
provided through the partnership caseload model of care in women who had a
previous baby under an alternative system of care. DESIGN: A qualitative study
using an ethnographic approach. Data were collected by tape-recorded interviews.
SETTING: The maternity unit at Leicester Royal Infirmary NHS Trust, Leicester, UK
in 1998. PARTICIPANTS: 10 multiparous women cared for by Birth Under Midwifery
Practice Scheme (BUMPS) midwives were interviewed between eight- and 12 weeks'
postpartum. KEY FINDINGS: Women's perceptions and experiences were predominantly
influenced by the relationships they had with their midwives who they described
as 'friends'. All other themes were filtered through these relationships,
including previous negative experiences of maternity care, the valuing of a known
midwife for labour and birth, their positive birth experiences, expressions of
delight at their care, their liking of home antenatal care, and the appreciation
of their existing children and partners meeting their midwives. IMPLICATIONS FOR
PRACTICE: Partnership caseload midwifery practice has significant positive impact
on women's experience of childbirth. The midwife/woman relationship that has
evolved in this context is highly valued by women and challenges traditional
professional roles. The model should be explored in other settings to see if its
benefits to women are transferable.
PMID- 10776242
TI - Fears associated with pregnancy and childbirth--experiences of women who have
recently given birth.
AB - OBJECTIVE: To describe fears associated with pregnancy and childbirth and to see
whether women who have recently given birth feel that their fears were justified.
DESIGN: A qualitative study. Data were collected by semi-structured interviews.
Data interpretation was based on the method of content analysis. SETTING: The
maternity units of two university hospitals in Finland. PARTICIPANTS: A
convenience sample of 20 women, 10 primiparae and 10 multiparae. The interviews
were held 2 or 3 days after childbirth. FINDINGS: The most common fears
associated with pregnancy and childbirth were concerned with the baby's well
being, the course of pregnancy, and childbirth. The fears found expression in
different kinds of behaviours, emotions and physical sensations. Many of the
participants felt that their fears had not been justified, but some maintained
that their fears had been justifiable. KEY CONCLUSIONS AND IMPLICATIONS FOR
PRACTICE: There was much inter-individual variation in the fears associated with
pregnancy and childbirth. It is important that diagnosis during pregnancy is
undertaken sensitively and that midwifery staff remember that pregnant women may
have very serious fears associated with pregnancy and childbirth. The
participants in this study felt that fears associated with pregnancy and
childbirth also had positive meanings. It may not be essential to try to protect
women against these fears or to remove them altogether, but to give every
pregnant women the opportunity to deal with her own fears and to obtain the help
she needs in her situation.
PMID- 10776243
TI - Evaluation of midwife-led care provided at the Royal Bournemouth Hospital.
AB - OBJECTIVE: To compare the outcome of care given to women 'booking' for delivery
in a midwife-led maternity unit with that for comparable women 'booking' for care
in a consultant obstetric unit. DESIGN AND METHOD: Prospective cohort study with
a quasi-experimental design and data extracted from case notes. SETTING: East
Dorset, midwife-led maternity unit at Royal Bournemouth Hospital and consultant
led maternity unit at Poole General Hospital. SUBJECTS: Two cohorts of women who
satisfied the criteria for 'booking' at the Royal Bournemouth Hospital. Of these
794 'booked' at Bournemouth from 1 November 1992 to 30 June 1993 and 705 'booked'
at Poole over the same period. MAIN PROCESS AND OUTCOME MEASURES: Care given,
morbidity in women and their babies, transfers during the antenatal period and in
labour. FINDINGS: Of the women who initially 'booked' for Bournemouth, 62.3%
actually delivered there, 27.1% transferred before labour and a further 9.2%
transferred during labour. No differences were seen between those 'booked' for
Bournemouth or Poole in the proportions of low birthweight babies, babies who
were transferred to special care or babies who had congenital abnormality. Higher
proportions of babies whose mothers 'booked' for delivery in Poole were
resuscitated and had one minute Apgar scores below seven but there was no
difference in the five minute scores. Similar proportions of women had perineal
tears but fewer of the women 'booked' for delivery in Bournemouth had an
episiotomy. 'Booking' for Poole was associated with higher rates of induction and
augmentation of labour and greater use of anesthesia. 'Booking' for Bournemouth
was associated with a shorter first stage and a longer third stage of labour.
Women 'booked' for delivery in Bournemouth were no more likely to be delivered by
a midwife than those 'booked' for Poole. CONCLUSIONS: There was very little
difference between the groups of women who initially 'booked' for delivery at the
two units. There were differences in the patterns of care received, but no major
differences in the outcome for the women or their babies were detected.
PMID- 10776244
TI - A study of student midwives' experiences during their two-year education
programme.
AB - OBJECTIVE: To explore the opinions, feelings and views of student midwives of
their education as they progressed through their two-year programme in Ireland,
with the intention of interpreting and understanding the working and learning
world of the participants so that future students might be assisted to improve
their educational experiences. DESIGN: Triangulation, using quantitative and
qualitative methods. A phenomenological approach was used to guide the
qualitative section of the study. SETTING: All seven midwifery schools in
Southern Ireland. PARTICIPANTS: All students in the first intake of 1995 in every
midwifery school (n = 125). DATA COLLECTION: Individual and group interviews,
diary-keeping and questionnaires. The design and conduct of the study are
described in this paper and the findings will be presented at a later date.
PMID- 10776245
TI - Migration and motherhood: a response to Barclay and Kent (1998)
AB - A recent paper by Barclay and Kent (1998) raised various issues with regards to
motherhood and recent immigration. They expressed reservations with
conceptualizing extreme misery in new mothers as depression, and with screening
for postnatal distress in women from non-English-speaking backgrounds (NESB).
They argued that a common self-report measure for postnatal distress screening,
the Edinburgh Postnatal Depression Scale (EPDS), was flawed. They also argued
that the concept of postnatal depression implies a medical aetiology and, thus,
fails to recognise the socio-cultural aspects experienced by NESB women. We
address these issues, by demonstrating that the EPDS is not flawed, and by
arguing that screening for postpartum distress results in more NESB women being
identified and, consequently, offered a service, than if such screening does not
occur. We also disagree with the view that the term 'postnatal depression'
necessarily implies any aetiology, and that work by our unit, as well as others
around the world, indicates that the psychosocial and cultural aspects related to
distress in new immigrant mothers is being recognised and acted upon.
PMID- 10776246
TI - The Perinatal Society of Australia and New Zealand--third annual congress, 21-24
March 1999, Melbourne, Australia.
PMID- 10776247
TI - Slipping away: nephrologists are losing control of managing their renal patients.
PMID- 10776248
TI - A healthier picture for dialysis patients.
PMID- 10776249
TI - Gathering data in the dialysis unit: what do you need? What do you need it for?
PMID- 10776250
TI - Can higher hematocrits prove of value for ESRD patients?
PMID- 10776251
TI - Chronicling three decades on dialysis.
PMID- 10776252
TI - Dare to Dream dialysis patient completes cross-country cycling tour.
PMID- 10776253
TI - The public's investment in renal care: what are the obligations of the patient?
PMID- 10776254
TI - Licensed, certified, accredited: what are the differences for the dialysis unit?
PMID- 10776255
TI - Bridging the barriers to renal rehabilitation.
PMID- 10776256
TI - Holistic nursing. Interview by Roxana Huebscher.
PMID- 10776257
TI - Identifying outcomes.
AB - The author describes the importance of outcome management in nurse practitioner
practice. A scheme for the development of outcome management projects is
presented. Obstacles in the use of outcome management are discussed.
PMID- 10776258
TI - Challenges for nurse practitioners: realistic health outcomes for developmentally
disabled individuals.
AB - Developing, measuring, and reporting clinical outcomes is challenging for all
health care providers. Nurse practitioners are qualified and suited to work with
developmentally disabled clients and their special needs. A review of current
literature shows that several isolated studies on clinically relevant topics have
been published. Strategies are explained here to assist nurse practitioners in
developing systems for tracking individual client data and for creating outcome
based networks to increase the generalizability of findings.
PMID- 10776259
TI - Is anyone listening? Does anyone care? Menopausal and postmenopausal health
risks, outcomes, and care.
AB - Healthy People 2000, the national strategy for improving the health of
individuals in the United States, provides direction for the prevention of
chronic illnesses, injuries, and infectious diseases by specifying desired
outcomes for specific populations. The authors focus on outcomes for several
illnesses and conditions known to significantly affect the health of women who
are menopausal or postmenopausal. These include osteoporosis, hypertension,
cardiovascular disease, stroke, diabetes mellitus type 2, congestive heart
failure, and obesity. Suggestions for advanced nurse practitioner assessment and
intervention are provided for the reader.
PMID- 10776260
TI - Health outcomes for persons with diabetes.
AB - New practice guidelines for the diagnosis and management of diabetes mellitus
published by the American Diabetes Association (ADA) reflect stringent goals for
blood glucose control. Although the rationale is sound, such goals are difficult,
if not impossible, to attain. It is proposed that focusing on the goals rather
than one's attempts to approach the goals can lead to failure. This article
examines the need to help patients focus on attempting to approach rather than on
meeting the goals set forth by the ADA.
PMID- 10776261
TI - Outcomes for patients at risk for inheritable breast cancer: how the nurse
practitioner can determine the proper course of action to ensure desired
outcomes.
AB - The topic of genetics and genetic testing pertaining to diseases such as
hereditary breast cancer is an issue of which nurse practitioners need to be
aware. In the general primary care practice where patients are seen daily with
questions about genetic testing, the nurse practitioner is in an ideal setting to
educate and counsel these men and women for an outcome that is acceptable to both
practitioner and patient.
PMID- 10776262
TI - Back injury in primary care: three sides of the coin.
AB - Low-back pain is the most common job-related injury in the United States. This
diagnosis is often accompanied by complexities that make effective treatment
options varied and inconclusive. The primary care nurse practitioner who manages
industrial injuries must consider 3 perspectives: the patient, the employer, and
the practitioner providing care. This research study compares 2 treatment
options: conservative and active physical rehabilitation for the patient with an
acute first-time low-back injury. Recommendations are made for customizing
treatment plans to individual practice settings.
PMID- 10776263
TI - Where do we go from here? Future directions for positive health outcomes.
AB - The history of nursing and its perspective on the individual as a part of a
family and community, nursing's basic professional preparation as generalists,
the advanced preparation of Nurse Practitioners, and direct access to clients
position the NP to be the premier professional in health promotion. Suggestions
for action in education and in practice offer methods for acquiring the
recognition of this professional competence as a hallmark of the primary care
Nurse Practitioner.
PMID- 10776264
TI - [Assurance of nursing quality--what does it really mean? Discussion on the
subject "quality of health care". Interview by Harald Verworner].
PMID- 10776265
TI - [Standards for local therapy of skin lesions].
PMID- 10776266
TI - [Improving teaching evaluation at the school for general health care and patient
care at the East Vienna Center for Social Medicine].
PMID- 10776267
TI - [Daily work at a hospital or for a "confused state"].
AB - This article intends to contribute for a reflection on 'conflictual dynamics'
that exists among the normalized, the instituted and the custodian work of the
nursing team at the hospital. We have tried to emphasise the need of
comprehending the human dimension at a 'confusional environment', revealed
through the diversity of interests, feelings and contradictions that make no good
to the intended homogenisation.
PMID- 10776268
TI - [The question of interdisciplinary work in the daily work of a nurse in a mental
health day care center].
AB - This study aim is the nurses perceptions inside the mental health daily attention
centre and the interdisciplinary aspect their work. This study has emerged from
the necessity of understanding the work and participation of the nurses who act
in those new places together with a interdisciplinary group, taking into
consideration that graduation does not educate nurses for this kind of work. The
interdisciplinary work has been seen as a sine qua non condition for optimising
care for people who suffer from serious psychological illness as it is in the II
National Conference of Mental Health, the Caracas Conference and the Health
Ministry 224 Edict. Quantitative study has been used in order to value each nurse
experience as well as his/her professional history in Mental Care Exercise.
PMID- 10776269
TI - [Relaxation: a strategy in the context of nursing care].
AB - This work has evaluated the application of relaxation as a strategy of nursing
care; it has also sought for a theoretical framework that could base this
technique application to assist the needs of a client facing his illness status,
as well as a resource to be used by nurses in dealing with stressing situations,
regarding to their professional praxis. We have worked upon conceptual aspects,
the etymology, the aims, relaxation application and its implication in nursing
care. We have concluded that relaxation technique is an ability that needs to be
learned and pratice in order to improve well-being. It is a therapeutic modality,
not pharmacologic, can be associated to traditional therapeutics and is of
preventive value. It increases the options of efficient therapy for nurses. It is
a coping technique in relation to stress. For inserting it into nursing praxis it
is demanding that the nurse perceive the client and himself as a whole for both
are benefitted by this strategy use.
PMID- 10776270
TI - [Communications by health professionals to patients undergoing diagnostic tests
with new technologies].
AB - Descriptive exploratory study with quanti-qualitative approach accomplished at
public and private net units in Goiania--GO from August to September, 1997 aiming
at observing clients understanding of communication of the professionals who
perform high technology exams and identifying whether any orientation provided to
clients about the exams that are to be performed and their impressions during
their performance. The population is of clients of both sexes who have undergone
high technology diagnosis examinations. The data have been collected by the
authors and research aids through semistructured interviews among the study
subject clients. By the results, we have concluded that the majority of the
clienta does not receive any orientation, lacked information about the exam that
is to be performed for several reasons, including fear of the unknown.
Communication was restrict. Fear of pain, of the result, discomfort have also
been reported.
PMID- 10776271
TI - [Evaluation of the teaching of nursing within a new liberating idea].
AB - Intending to offer new teaching technologies the Nursing Master Course at the
Federal University of Ceara have been integrating the graduation and
postgraduation courses. The study aimed at evaluating a subject in Nursing
Graduation Course in a critical and transforming point of view. The used
methodology involves SAUL's (1995) emancipating evaluation paradigm contemplating
three moments: reality description, reality criticism and collective
construction. The most significant results were: the constaint be compatible with
the schedule, with methodological renewal and evaluation decentralization. The
study has been concluded perceiving the methodological deficiency adopted by the
subject as a critical point. It is certain that this investigation brings
contribution for teaching-learning relationship where professor and students are
process subjects, eliminating, so, the student position of a mere system
manipulated object and copy copiers.
PMID- 10776272
TI - [Nursing attendants: why? How long?].
AB - Qualification for nursing professionals is important for they deal with lives
that need qualified care. This study aims at analysing health professionals
opinions about nursing attendants. It was accomplished between March and July,
1997. Nurses, physicians, nursing aids and technicians at public and
philanthropic hospitals in Fortaleza--CE were interviewed. The outcomes show that
nursing attendants, most times, perform the same procedures as the nursing aids
and may interfere with the provided service quality and cause iatrogenics; others
consider them as important at institutions for their practice; some others
express themselves completely against the non-qualified professionalization
process; anothers express themselves for this process, but disagree on how it is
accomplished for they do not perceive any change in their professional profile
after being qualified. We do understand that this question is deserving of
immediate attitudes for it is related to nursing principal subject: Caring.
PMID- 10776273
TI - [The use of the quality function deployment (QFD) in the planning of care].
AB - This research aimed at suggesting an alternative to achieve quality in Nursing
Service through an exploratory-descriptive study with 114 patients. A planning
model was has been elaborated the steps and actions outlined by the Quality
Function Deployment Method. It was based on Total Quality Control management
approach. Seventeen steps has been established in order to seek clients' needs
and through successive deployment and priority, the main Quality Features and
Procedures which supported standardisation and monitoring of proposed actions has
been determined. The outcomes showed that this method is feasible for Nursing
Service Quality Planning because it has enabled to review the context as a whole,
providing major degree of certainty on decisions.
PMID- 10776274
TI - [Auditorship and errors: emphasis on nursing records].
AB - This study examines 34 procedure billing reports collected at health care
facilities that participated in SIA-SIH/SUS activities in Rio Branco--Acre in
1994/1995. It aims at identifying and analyzing any errors found in the procedure
notes. This study also used sub-categories which were defined through content
similarity. A total of 491 errors were found in the procedure billing reports.
This represents an average of 14.4% of errors per procedure billing report. When
the procedure billing reports were analyzed using 8 criteria, 198 (40.6%)
administrative errors, 121 (24.6%) doctors errors, 99 (20.2%) nurses errors, and
51 (10.2%) accounting errors were detected. When the nurses' errors were further
examined, it was detected that 34 (34.3%) were due to nurses notes and 15 (15.1%)
as a result of erroneous medication administration. It was concluded that nursing
staff is not following the standard note taking procedures. This places not only
the patients at risk but also health care professionals and health care
facilities which are responsible for patient care.
PMID- 10776275
TI - [Nurses and the Mercosul regulations and control of professional practice].
AB - A study comparing the regulation and control of the professional practice of
nurses in Brasil, Argentina, Uruguay and Paraguay, delineating their
particularities, differences and similarities in the perspective of the
implementation of the Cone Sul Common Market, which presupposes the free
circulation of workers in the workplaces of the member-countries of the Ascnsion
Treaty.
PMID- 10776276
TI - [Self-concept and the nurses' desire for social identity].
PMID- 10776277
TI - [Mental health of surgical patients: development of nursing activities through
support groups].
AB - The use of support groups as a resource for caring patients has been an usual
modality of nursing assistance. This study aimed at using the support group for
approaching the surgical in-patient in order to diminish present anxiety in these
situations. The research has been developed at a surgical clinic at HCFM-UFG with
41 patients. The data collection has been done through individual interviews,
groups emergent material and field diary. Generally speaking, we have observed
that the patients show themselves actually involved with the work, demonstrating
the group efficiency as a resource to deal with anxiety, fear and tension that
are present during international process. We have pointed out the importance of
the nurse to practice his/her role as a group co-ordinator, especially to deal
with difficult handling situations. Meetings supervision as for their thematic
constaint and performance are also indispensable.
PMID- 10776278
TI - [Life style and health: the every day life of alumnae from the Anna Nery nursing
school in the decade of the twenties].
PMID- 10776279
TI - [Care of women under chemotherapy treatment. Comprehensive analysis of care].
AB - This study was developed upon my reflections as a nurse working at the
Antineoplastic Chemotherapy Center at Luiza Gomes de Lemos Hospital of the
National Cancer Institute (Inca), and as a Master course student at Anna Nery
Nursing School. Developing my Master thesis on Martin Heidegger's philosophical
thinking it has enabled me to reflect about the nursing care, considering this
philosopher's thinking. In this study, I have registered some situations that
occurred on my working days, in the scenery mentioned above, and reflected about
them, seeking to analyze their proximity and distance from Heidegger's
philosophical thinking. This study was also a reflection about questions emerging
from the research process and care practice which leaded me to another
understanding of nursing care to women who are submitted to chemotherapy
treatment. Then, I was able to see nursing care in another way, that one of
comprehension as a possibility of professional action.
PMID- 10776280
TI - [Ethical behavior of nurses in university hospitals].
AB - The aims of this study were to analyse the conception of ethics in the nurse's
speech and practice, to verify its influence on nurses formation, and to
investigate the nurses views regarding to the contribution of ethics to the
comprehension of the moral reality and to the critical analysis of the nursing
practice. The methodology focused on the qualitative analyses of data collected
through the techniques of: document collection and analysis, group interviews,
and observations of the nurses ethical behaviour during their practice. According
to he results, the nurses conception of ethics relates in satisfaction to their
work, to professional discrimination, and to corporate issues of health team. No
reference was made to citizenship concerns. There is also a setting away from
ethics understanding while moral behaviour and a critical view of the profession
and of health care.
PMID- 10776281
TI - [Nursing assistance by a home care team after the death of the patient].
AB - This is report about an experience of continuation of home assistance to families
after the patient's death who had determined the beginning of assistance. The
present article shows the criteria used to provide a family with an "Assistance
service and support to families of chronical patients of HUM" as well as
discussions emerged and feelings experienced by the team when subjected to the
possibility/proposal of the continuation of assistance. Furthermore the article
considers the visitor's reaction at first visit made after death and finally it
also presents the importance of continuation of assistance based on reports of
verbal manifestation of the family and on evaluation of team members. The authors
believe that due to the fact that the assistance to the family is still regarded
as a topic which has been very little explored, discussions that might contribute
somehow to the consolidation of its practicability must be made possible and
stimulated.
PMID- 10776282
TI - [The infected partners view of AIDS].
AB - Our objective was to reflect upon the HIV contamination in women who has a stable
relationship. We have used semi-structure interview with an ethnographic way of
focussing to the women from Infections diseases hospital, also STD's at the State
of Ceara. At the interview questions about prevention in the couple relationship,
the HIV positive result reaction, the feelings toward children and living with
family and friends have been made. The interview analysis has identified the
absence of prevention, the lack of search about HIV information, the wives wrath
and the worries about the children, and also the difficult situation between
family and friends.
PMID- 10776283
TI - [Teaching development and professional identity in nursing: the system of
concepts as a mediator in learning].
AB - The focus of this study is characterisation of the representations socially
constituted about the concepts "Nursing" and "Nursing and context". The
interpretative mental schemes were sequentially configured during the Graduation
course starting from the written answers supplied by students to the following
questions: "How do you judge Nursing?" and "What is the relation between the
profession and social context? "We have used interpretation schemes based on the
contain analysis. As a result, we have identified a peculiar development of
schemes formed by means of structures that were involved with forming system and
used system of human resources as reference which promote distinct perspectives
of professional performance. The components nucleuses of each stage of conception
expressed the logical structure which were incorporated to subsequent
construction, that configures a evolution determined by selective adhesion of
students to the graduation or to the practice field. There has been a movement
alongside to those systems resulting from discrepancy between the experience and
personal schemes.
PMID- 10776284
TI - [An object study about the teaching of psychiatric nursing and mental health].
AB - This article approaches the construction of a study object about the psychiatric
nursing teaching and mental health. It is supported on the Marxist theoretical
methodological referential making a re-dimension of concepts as teaching--as a
reproduction and resistance practice--ideology/counter-ideology, actors/social
subjects, mental health and the psychiatric reform.
PMID- 10776285
TI - [From care of the soul to care of the body--a new understanding of the history of
nursing].
AB - This study relates to the birth and the development of the Company of the Sisters
of Charity of Sao Vicente de Paulo in France since 1633. This study has as its
objective historically rebuild the process of creation of the Company of the
Sisters of Sao Vicente de Paulo and the role of Luiza de Marillac and Father
Vicente de Paulo in this process, and discuss the importance of this Company for
the proposal of a pre-professional nursing care, imposing the bases of what would
be called later the nursing techniques. It is a study of social and historical
nature, to which I will use Michel Foucault preconceived ideas, regarding the
analysis and discussion of the documents under the light of the genealogical
analysis. This study focuses mainly the aspects that concern to implementation of
a nursing practice towards the care of the sick body, and to the catechisation of
the poor and the sick people. It focuses also the importance of Luiza de Marillac
as a nurse, master and guide to the other Sisters.
PMID- 10776286
TI - [Health care: the place for the invention of a new scientific paradigm].
AB - It is an essay about Care, basis of the practice and research, as place of
invention, test, criticism and reconstruction of the Nursing specific knowledge.
Health and well-being, quality, "L'etat de l'art" and, yet, the experience of
caring at the patients and Nurses' bodies are discussed.
PMID- 10776287
TI - [Use of alternative therapies by nursing teachers].
AB - The necessity of the health professionals to understand the health illness
process in a different paradigm of the valid bio-medical model is more and more
present. The objective of this work was verify what are the alternatives
practices utilised for Nursing teachers for themselves and/or in their respective
family relatives and if these teachers have been utilised the practices and if
they talk about this subject with their students. The population of this study
were 59 Nursing graduate teachers from Sao Paulo City placed in four different
teaching institutions that answered a questionnaire. The people that answered the
questionnaire were chosen at random and the data were collected in October, 1996.
Among the results, we verified that 39 (66.1%) of them referred that they used
the APH, in fact, the more usual alternative practice is the homeopathy (24
times), floral (21) and the eastern massage (13). The people did not use the APH
are for its use in specific situations; 56 (94.9%) teachers were for its
teaching, but only 31 (52.5%) talk about APH to their students.
PMID- 10776288
TI - [Occupational nursing specialization: proposed change of paradigm].
AB - The course of Labour Nursing aimed at preparing nurses for companies security and
workers health. It started in 1974 as a result of the efforts of DESP/EEAN/UFRJ
and ABEn close to the Ministry of Labour in Rio de Janeiro and based on the
Resolution 112/59--OMS/OIT. Later, this course was spread out to other
Universities and Brazil's regions and 13 courses have been provided until 1985.
In the beginning, the courses follwed the orientation and control of FUNDACENTRO,
until 1996 and were directed to the industry. From this time on, these courses
register was sent to CORENs and accomplished independently at Nursing Schools,
based on Resolution 12/86--MEC, Rec. 161/93--OIT. Instructions from the Ministry
of Labour and Ministry of Health. At the EEAN, up to 1995, 11 Specialisation
Courses have been accomplished, based on ANENT orientations and fundamental by
the subjects: Scientific Investigation Methodology, Methodology of Nursing
Teaching and Education for Health; Worker's Health Politics; Labour
Organisational and Social Sciences; Environment Sanitation; Work Safety and
Hygiene and Human Ecology; Ergonomy; Labour Process; Occupational Risks; Labour
Accidents and Illnesses; Labour Legislation; Labour Nursing; Technical Visits and
Practice in Workers Health Services at Companies Programmes and Public Health.
The course enables nurses of essential, educative, managing and investigative
activities and their formation culminates with a dissertation that has as a study
object, emerging problems of nursing practice for workers. This programme has
been studied by the author herself aiming at a better adjustment for these
professionals insertion into the work market.
PMID- 10776289
TI - [Nursing performance in materials management in intensive care units].
AB - This study had as a goal to identify the nursing practice in management of
material resources in a general hospital. It is a descriptive work of quanti
qualitative nature, performed in four ICU's (Intensive Care Units) among the
largest general hospitals in Salvador-Bahia. It has been observed that (only) in
three out of four Units, there was the presence of nurses in the commission of
material purchase and selection. In addition, the participation of the nursing
group in the process of material prevision and control is the lowest, there is
lack of evaluation of purchased material; resulting, in turn, in the not
occasional presence, of second line, useless and of low quality materials which
directly or indirectly affect the provided care. It has been noticed that the
nursing performance in material resources management became restrict, only for
the reposition of these consumed materials, without, therefore, an effective and
efficient insertion in the process of prevision, selection, purchasing and
controlling.
PMID- 10776290
TI - [Leisure and recreation in a clinical unit: what the participating patients think
and feel about it].
AB - This paper is a report of experience, accomplished with intern patients at two
units of a University Hospital (H.U.), whose main objective was identifying how
the intern patients perceived leisure activities and recreation during their
hospitalisation, and what was these activities effect on the patients involved.
PMID- 10776292
TI - [The nursing school of the Federal University of Minas Gerais: from its creation
until today].
AB - The purpose of this work was to bring back some historical aspects of the Federal
University of Minas Gerais Nursing School--EEUFMG, since its creation in 1933
until 1998.
PMID- 10776291
TI - [There should be freedom in nursing].
AB - The title of this effort has reminded us of the Inconfidencia Mineira, that had
Jose Joaquim da Silva Xavier, the Tiradentes as its leader. It was a movement
that longed for freedom, like nursing that, along the years, has been building
its history and has been walking in search of its autonomy. This study has aims
at investigating the ways nursing has gone through, while a science, it searches
for its autonomy and mediates about nurse's performance while an autonomous and
creative professional. This study had the historical materialism as support. It
was accomplished from May to August, 1997 with nurses from Ceara that were
involved with the profession historical process. The results originated a central
category, professional practice, and the other three ones: autonomy, creativity
and disposition to face challenges, that favour a better comprehension about the
paths nursing tracked, besides permitting us to understand that the nurse can be
autonomous and free.
PMID- 10776293
TI - [The process of health care in Brazil in the context of current transformations
in the sphere of labor. Study in a teaching institution. Doctors thesis in
sociology and human sciences. State University of Campinas, 1996 (Review)].
PMID- 10776294
TI - [Visual stimulation for premature newborns: a nursing intervention].
AB - Vision allows us to assimilate the environment, helping us to construct
knowledge. New-borns need time to develop some organs and senses, among them
vision. The early premature visual stimulation may prevent its psycho-motor and
social development from being late. In this study an experimental group has been
submitted to stimulation process and visual evaluation and other group, the
control one, was only evaluated. Data analysis considered exposure time, tool
used, number of days and stimulation response. It has been verified that new
borns submitted to visual stimulation are alert, active and attentive; those from
the control group are uninterested and stimulus little active. It has been
noticed that the stimulation programme will permit visual disturbances to be
detected b constant response evaluation.
PMID- 10776295
TI - [Nursing: a special way of developing, being, thinking and doing].
AB - The present essay tries to stimulate nurses and graduation and post-graduation
students in obtaining knowledge more and more and being prouder and prouder of
Nursing. It synthetically explains Nursing as a profession, discipline, science,
art, technology and goes beyond science and arts. It considers Nursing as
something that nurses bring up when caring for someone through professional
knowledge and a proper way of being a nurse.
PMID- 10776296
TI - [Constructing the meaning of breast feeding through nursing care].
AB - From the referential of Symbolic Interactionism and Dada Based Theory we have
searched to achieve the objectives of comprehending the meaning, attributed by
the nursing student to breastfeeding and to nursing interventions in this
process. The study was accomplished with graduation students from Sao Paulo
University (USP) Nursing School. The study results show that the student
experience his relation to breastfeeding and to his learning process in assisting
the nutrice and her child expressed by two themes: BUILDING UP A VIEW OVER
BREASTFEEDING and BUILDING UP ASSISTANCE TO BREASTFEEDING. These themes portrait
students' conceptual and technical evolutive process about breastfeeding
assistance and their perception of being a nurse, attributing meanings to their
performance in the process that is experienced by woman and her child.
PMID- 10776297
TI - [A path to freedom: an experience in semiology and semiotechnique].
AB - The work reports the experience of planning the course: Semiology and
Semiotechnique which is part of Nursing new curriculum. The objectives were:
stimulating creativity and sensitivity that care bears in techniques development;
valuing feelings and emotions in the establishment of nurse and patient
relationship, allowing some reflection and self-knowledge in collective
experience, and establishing relationship between professors and students based
upon partnership, compromise and on mutual feeling/doing/learning. Methodological
work and art creativity privileged sensitivitiness as the necessary step for
formation process and together with this developed from arts and creativity and
understand these workshops performance and developing a critical as well as
dynamic group. The results show that it is an experience as an opportunity of
developing critical potential, critical and theoretical, creative towards
conscience which leads to Liberty in Nursing.
PMID- 10776298
TI - [AIDS and school: proposal for institutional and interdisciplinary prevention].
AB - The project AIDS and School emerges as an institutional and interdisciplinary new
proposal for HIV/AIDS combat. In 1992, Rio de Janeiro State University
represented by Social Work and Nursing Faculties and by Adolescent Health Studies
Nucleus and Education and Health State Secretaries and yet Oswaldo Cruz
Foundation (FIO-CRUZ), thought about a way of preventively intervene with the age
where the contact with the virus is mostly contacted. The adolescent should be
worked on but for achieving a great number of students, a teacher was needed.
From this, the project was designed and its development started in 1994 with '1
degree and 2 degrees graus' teachers capacitation in six districts of Rio de
Janeiro. The work is of relevance for its supervision characteristics and support
to GEPAE (AIDS and School Project Executive Group). At the workshops themes are
worked with the teachers, such as: Loss and Death; Sexuality; Sexuality in AIDS
times; Technical Information and Applied Methodology. This project is sponsored
by the World Bank through Health Ministry. Nowadays, we are evaluating the
project and we have already detected that for its performance and characteristics
it will be turned into a Programme.
PMID- 10776299
TI - [Hospitals: place for the sick and other challenged persons].
AB - The hospitals were, since its source, a place of retirement and shelter of sick
people. The Church, in Middle Age, founded hospitals in their monasteries, where
sick people took care and a assistance, more religious than therapeutic. In the
final of Middle Age the hospital became an exclusion's place for the crazy
people, the leprous people, the bec people and the sick people were guided to.
With de arisemens hospital became privilegious space where sick people could be
observed and the art of care was consolidate. The apprehension of care practices
by the capitalism way of production changed the welcoming character of the
hospital that would be an instrument of work, productive space not only of
treatment but, foremost, of values.
PMID- 10776300
TI - [Nurses interacting therapeutically with elderly patients in chronic depression].
AB - In a humanist care model we searched to analyse experiences lived by nurses
interacting with chronic depression patients. There was a female patient who was
being assisted by Psycho-social Support Nucleus (NAP), 60 years old, presenting
depressive symptoms, proper for her age, probably stressed by her suffering
experiences in life. It was a therapeutic interaction as matters of the patient's
interest (not the nurses interest) have been presented; the pace of communication
has been determined b the patient herself; the nurse (except in the very
beginning when the patient was a little anxious) followed her communication,
physically approaching her whenever it was necessary; intervened only at
necessary moments; inspired confidence that was necessary for the patient to talk
about her intimate feelings; helped her to recover when she was out of control;
conducted her safely, but with comprehensive attitude until the patient felt easy
to leave her; demonstrated that she could help her in other moments if she
thought it was necessary. Interaction achieved its aims helping the patient and
being technically adequate for therapeutic and diagnosis aspects.
PMID- 10776301
TI - [Mental suffering of nurses who care for cancer patients].
AB - In this qualitative study, four nurses of a teaching hospital in the city of
Campinas, Sao Paulo-Brazil, all of them working with oncological patients were
interviewed in order to verify the situation that most caused mental suffering in
the day by day with these patients. Data collection were performed as proposed by
the ethnographic approach and the non-directive interview and the direct
observation was employed. The contain analysis has been utilized to the data
analysis. The results have shown that many situations of the relationship nurses
oncological patients cause mental suffering in that professional. Those
situations are tied to the work of the nurses, to the kind of patient treated by
those professionals and to the kind of sickness presented by the patient. That
study has shown that, many times, the nurses utilize defense mechanisms against
that mental suffering. This work aims to contribute to the knowledge of the
subject and therefore be itself a base in which one could elaborate measures that
can make these problems that occur with the nurses that work in the Oncology area
lighter. With that study to contribute to the comprehension of the challenge that
the cancer, sickness that make professional and population frightened, is.
PMID- 10776302
TI - [Bed baths--an initiation ritual for the nurse].
AB - It's a experience, at the Fundamental Nursing Laboratory, for the "Bath in the
Bed" practice with 22 graduating from the UERJ nursing course, the object was to
record the teaching strategy procedure, identify the students representations and
feelings with her own bath and characterize, after the sensibility dynamic
developed in "LIVING EXPERIENCES", her feelings. The explorer-qualitative
research was implemented in 1997. Among the results there are the proper
categories of the knowledge construction on the "Bath in the Bed": Incentive for
body dirt cleaner; Incentive to pleasure--the relax body; Incentive to comfort-
free body and Incentive to sensations--dynamic body. Conclusion, the students
carry from their reality common sense knowledge for "dirt" and "clean" when
representing their own body. When experiment to "touch" humors and perceives the
client bad odors, even of symbolic way, their reactions are different and re
extend a cultural and scientific knowledge.
PMID- 10776303
TI - [Brazilian Nursing Magazine--a history of resistance].
AB - Part of the conquest of ANEDB, since 1920 the REBEn itself inserting in the
professional dispute about the diffusion of the nursing facts. Ought to Edith
Magalhaes Fraenkel and Rachel Haddock Lobo the inspiration and initiative for the
creation, since 1929, within the participation in the I Quadrienal of ICN
congress, in Montreal where were discussed facilities, difficulties and advance
of nursing newspaper. The ANNAES of nursing, edited by the newspaper "Journal do
Brasil--R.J.", in 1932, was the precursor of the REBEn. With her existence,
readers, students and Professionals greediness for extend his specifics
knowledge, constructors of the historic documentation and the knowledge
profession, responsible by the scientific and technologic development and by the
concept emission of different period of the Brazilian nursing, has learned to
take advantage on his benefits. With more of 50 volumes and 200 edited copies the
REBEn has acquired a reference status in the domestic and international of health
and human science areas. Already consolidate; spread dissertation results,
thesis, and work papers, presented or showed in Brazilian congresses of nursing.
It's the most consulted newspaper as source and field scientific investigation.
It provides the readers growth, organizer in the editorial process and counselors
formation "ad hoc" through the permanent criticism and evaluation.
PMID- 10776305
TI - [History of nursing in Parana].
PMID- 10776304
TI - [Project of introduction of nursing records at the pediatric intensive care
unit].
AB - The project, performed at the Infantile General Hospital ITU, in Curitiba,
Parana, enabled to experience nursing practices in caring for seriously ill in
hospital children and, also in concrete day by day situations. At beginning we
have notice the absence of nursing care records of any kind, through many
situations, that sometimes, put children's treatment in risk for nursing
information records precariously and for the Tailorized way of nursing care. From
nursing records process diagnosis, was discussed the project build, we have
elaborated a record form and two manuals (Nursing records and Pharmacology
Notions) for professionals training and follow-up. The project introduction has
provided a better interaction between patient and nursing assistance and has
encouraged, through the systematized way of information records, a
interdisciplinary work, besides organization of nursing assistance, resulting in
a better assistance quality and credibility.
PMID- 10776306
TI - [Alternative medicine today].
PMID- 10776307
TI - [Higher professional education as a means for development in nursing].
AB - The author reflects on how higher training contributes to development in Nursing,
understanding by this term the discipline but also the set of professionals which
exercise it. Therefore, the author analyzes those elements which are part of
professional development; be this intrinsic, professional discourse, excellent
professional exercise, market dominance, syndical capacity or representation. The
author ends her article with a very simple proposal: make a world full of care,
with a recognition of successes, a correction of errors and a deepening of
attitudes.
PMID- 10776308
TI - [Urinary incontinence in patients with acute ictus].
AB - This project won the "Ausonia" Incontinence First Prize among those projects
submitted during 1999. This article analyzes the prevalence of urinary
incontinence among patients diagnosed as suffering acute ictus after 3 months, 6
months and 12 months. The authors also investigate those factors associated with
acute ictus incontinence, how incontinence influences a patient's evolution, and
how incontinence affects the environment where recuperation occurs, at home or in
an institution, while the patient is recovering. The results confirm that acute
urinary incontinence is a forecasting factor, independent of the poor middle and
long range functional prognosis, and that the potential prognosis is superior
than the seriousness of the neurological deficit at the moment a patient enters a
hospital.
PMID- 10776309
TI - [Importance of mental health nursing in the Baleares].
PMID- 10776310
TI - [Tick bites. Poisoning].
AB - Various aspects related to lesions and infections produced in humans due to the
bites of ticks which live in our country are focused on in this article. Some
kinds of ticks found here are described and identified. The author also points
out the possible infections these ticks can transmit, mentioning their symptoms,
the corresponding treatment in situ as well as in health centers along with
preventive measures one can take to avoid at risk situations.
PMID- 10776311
TI - [Performance of two new closed ostomy bags of unique design with two different
types of cutaneous protectors].
AB - The authors study the performance of two closed bags, Almarys Optima and Almaris
Quiet, in ostomized patients in Spain. The behavior of both cutaneous protectors
in the two bags is analyzed based on the characteristics of the ostomized
patients; security, discretion and comfort levels have been evaluated. It has
been evaluated if the characteristics of the ostomized patients influence in the
valuation of these new bags. The study has been prospective, multicentric and
single blinded. The authors concluded that the valuation of both bags is very
positive as much by the users as by the sanitary professionals in charge to carry
out the study, although the opportunity stands out to approach the use of one or
another one of the bags based on the type of skin and of the physical activity
made by the user.
PMID- 10776312
TI - [Medical technology: its impact on the physician-patient relationship].
AB - The Nuestra Senora del Remedio Clinic is celebrating the 75th anniversary of the
arrival of the San Jose de Gerona order at the clinic. Dr. Vallbona was invited
to present a conference which we transcribe in this article, superficially
reviewing the problems which may compromise the doctor-patient relationship as
well as the rights and responsibilities each member of this relationship has.
PMID- 10776314
TI - [Diabetes mellitus: reasons for hope].
PMID- 10776313
TI - [Septicemias related to intravascular catheters].
AB - Catheter-Related Septicemia (SRC) is an important health problem which depends
on, to a large degree, a nurse's care, both concerning the insertion technique
employed in cases involving peripheral catheters and centers of peripheral access
(PICC) and concerning the manipulation, maintenance and treatment applied no
matter what type of catheter is used. The challenge for nurses consists in
minimizing the number of complications which occur. Catheter-Related Septicemia
can be prevented. In order for this prevention to occur, we must unify our
criteria and exercise the utmost care in carrying out our assistance to patients.
Therefore, strict asepsis while inserting catheters and manipulating blood
vessels acquires maximum importance.
PMID- 10776315
TI - [The necessity of improving care].
PMID- 10776316
TI - [Palliative care nurses: humanizing the end of life].
PMID- 10776318
TI - [Drugs and the nurse's role].
PMID- 10776317
TI - [Drugs and the nurse's role. What one has to know about the drug].
PMID- 10776319
TI - [May nurses institute an analgesic treatment?].
PMID- 10776320
TI - [Reconstitution of chemotherapies in the hospital].
PMID- 10776321
TI - [Gastrointestinal disorders: functional digestive disorders].
PMID- 10776322
TI - [Urinary incontinence in a population of nurses].
PMID- 10776323
TI - [Education of nursing personnel on transfusion safety].
PMID- 10776324
TI - [The French Committee for Health Education].
PMID- 10776325
TI - [The headache of antibiotics].
PMID- 10776326
TI - [Jalmalv: caring for life until death].
PMID- 10776328
TI - [Temporary, education and mandate: a sometimes difficult combination]
PMID- 10776327
TI - [Private nurses and the nomenclature of professional activities].
PMID- 10776329
TI - [Education in gerontology: a tool for life planning].
PMID- 10776330
TI - The balanced budget: a doubled-edged sword?
PMID- 10776331
TI - Spinal cord impairment: acute transverse myelitis.
AB - Acute transverse myelitis (ATM) is an unusual inflammatory disease involving the
entire thickness of the spinal cord. It results in loss of motor and sensory
function below the level of injury. The prognosis is variable. The following
paper reviews the literature, clinical consideration, and nursing interventions
of this puzzling condition.
PMID- 10776332
TI - Factors influencing functional outcome and discharge disposition after thoracic
spinal cord injury.
AB - The purpose of this retrospective study was to describe the relationships among
level of injury, completeness of impairment, age, complexity of coexistent
disease, functional outcomes, and discharge disposition in persons with traumatic
thoracic spinal cord injury (SCI). The sample consisted of 41 persons with acute
traumatic thoracic SCI discharged from a 48-bed rehabilitation unit between 1992
and 1997. Persons with complete SCI had significantly lower Functional
Independence Measure scores than persons with incomplete SCI (p < .05). The
effect of the completeness of injury did not persist to discharge FIM scores.
Persons discharged to home without a home-health referral (HHR) had higher FIM
scores than those discharged to home with one. Persons discharged to home with an
HHR had higher FIM scores than those discharged to skilled nursing facility
units, although these were not statistically significant. The findings of this
study suggest that rehabilitation goals and discharge disposition planning for
persons with traumatic thoracic SCI cannot be based on level and completeness of
injury alone. The interdisciplinary team must understand the abilities, needs,
and disposition of this population to develop rehabilitation goals and
interventions that are feasible and realistic.
PMID- 10776333
TI - Me, an entrepreneur?
PMID- 10776334
TI - Revisiting latex allergies.
PMID- 10776335
TI - How do I find what I want on the Internet?
PMID- 10776336
TI - Sampling.
PMID- 10776337
TI - Nurturing decisions.
PMID- 10776338
TI - The universal specialty.
PMID- 10776339
TI - The lingo of chemo. How language misleads patients with cancer.
PMID- 10776340
TI - Corticosteroids for cancer pain.
PMID- 10776341
TI - The family as restraint?
PMID- 10776342
TI - The family as restraint?
PMID- 10776343
TI - Radial artery harvesting.
PMID- 10776344
TI - The octopus and me. The nursing insight gleaned from a battle with cancer.
PMID- 10776345
TI - A hard pill to swallow. A handy guide to medications that must be swallowed
whole.
PMID- 10776346
TI - Adjusting to breast cancer.
PMID- 10776347
TI - Three days.
PMID- 10776348
TI - Malnutrition in hospitals. Who's assessing what patients eat?
PMID- 10776349
TI - The mask and the meaning.
PMID- 10776350
TI - Nutrition: the forgotten ingredient in cancer care.
PMID- 10776351
TI - The cancer survival toolbox.
PMID- 10776352
TI - Emergency. Chemotherapy-induced hypersensitivity reaction.
PMID- 10776353
TI - Spotlight on the uninsured.
PMID- 10776354
TI - Book of the year awards. The most valuable texts of 1999 as chosen by AJN's panel
of judges.
PMID- 10776355
TI - The 'ethics' of instinct.
PMID- 10776356
TI - Does JCAHO see the truth? How nurses can alert JCAHO surveyors to staffing
problems.
PMID- 10776358
TI - Chemotherapy on the unit. Protecting the provider as well as the patient.
PMID- 10776357
TI - Nurses. Then and now. Oncology nursing.
PMID- 10776359
TI - Perspectives on isolated systolic hypertension in elderly patients.
AB - Until the mid-20th century, clinicians' concern was directed mainly to the
systolic component of blood pressure. Later, however, when systolic blood
pressure was found to be elevated with advancing age and decreased compliance of
the arterial wall, it began to be considered an inevitable consequence of aging.
Based on this belief, physicians often concluded that only the diastolic blood
pressure elevation, which reflected peripheral vascular resistance, was harmful,
while systolic hypertension was innocuous. Therapeutic intervention was practiced
mainly for diastolic hypertension, and research protocols were based on the
levels of diastolic blood pressure alone. In the 1950s, even when life insurance
companies' actuarial data revealed that systolic and diastolic blood pressure
elevations were hazardous to health, few clinicians took heed. In 1962, the World
Health Organization also defined hypertension as a blood pressure level of 165/95
mm Hg or higher for intervention purposes. However, until the 1991 Systolic
Hypertension in the Elderly Program (SHEP) trial, many physicians were reluctant
to pay credence to the need for therapy of elevated systolic blood pressure (vide
infra).
PMID- 10776360
TI - Part-time physicians. Physician workload and patient-based assessments of primary
care performance.
AB - OBJECTIVE: To examine the relationship between the number of hours physicians
work and patients' assessment of the physician. DESIGN: Cross-sectional study
with physician and patient surveys. SETTING: Primary care practices in
Massachusetts. PARTICIPANTS: A random sample of 6810 Massachusetts state
employees in 15 different health plans. MAIN OUTCOME MEASURES: Eleven summary
scales measuring 7 essential elements of primary care. Information was derived
from the Primary Care Assessment Survey, a validated patient-completed
questionnaire. RESULTS: Physicians were classified into 3 groups according to
their reported hours of work: "overtime" (> 65 h/wk), "full time" (40-65 h/wk),
and "part time" (< 40 h/wk). There was no statistically significant difference
between the 3 groups of physicians in 10 of the 11 measures of primary care
performance. Physicians who worked more than 65 hours per week were found to
score significantly higher in the visit-based continuity of care category than
physicians working fewer hours. Physicians working more than 65 hours per week
were also found to be significantly less satisfied with the amount of time they
had for family and personal life than the other 2 groups. CONCLUSIONS: Part-time
physicians perform as well as full-time physicians in most aspects of primary
care, including all interpersonal aspects of care, as reported by patients.
Patients of physicians working more than 65 hours per week experienced higher
levels of visit-based continuity of care than patients of physicians working
fewer hours, but this appears to carry a cost to those physicians in the area of
personal and professional satisfaction. Subsequent research should examine the
relationship between physician workload and technical aspects of care.
PMID- 10776361
TI - The effect of continuity of care on emergency department use.
AB - OBJECTIVE: To examine whether continuity of care with an individual health care
provider is associated with the number of hospital emergency department (ED)
visits in a statewide Medicaid population. DESIGN: A cross-sectional study based
on a 100% sample of Delaware Medicaid claims for 1 year (July 1, 1993, to June
30, 1994). Continuity with a single provider during the year was computed for
each participant. SETTING: The state of Delaware. PARTICIPANTS: Continuously
enrolled Medicaid clients aged 0 to 64 years who had made at least 3 physician
office visits during the study year (N = 11,474). INTERVENTION: None. MAIN
OUTCOME MEASURES: Likelihood of making a single ED visit or multiple ED visits
during the study year. RESULTS: In multivariate analysis, continuity is
associated with a significantly lower likelihood of making a single ED visit
(odds ratio, 0.82; 95% confidence interval, 0.70-0.95), and is even more strongly
associated with a lower likelihood of making multiple ED visits (odds ratio,
0.65; 95% confidence interval, 0.56-0.76). CONCLUSIONS: This study demonstrates
that high provider continuity is associated with lower ED use for the Medicaid
population. This suggests that strategies to improve continuity of care may
result in lower ED use and possibly reduced health care costs. Such strategies
may be more acceptable than current managed care policies that attempt to control
costs by denying access to emergency care.
PMID- 10776362
TI - An office-based instrument for exercise counseling and prescription in primary
care. The Step Test Exercise Prescription (STEP).
AB - BACKGROUND: Available evidence suggests that despite physicians' positive
attitudes toward exercise as an important part of promoting a healthy lifestyle,
few physicians actually prescribe exercise for their patients. One barrier may be
lack of a standard office instrument. OBJECTIVES: To determine the (1) exercise
counseling habits among a large group of Canadian family physicians and (2)
acceptance and utilization of an exercise counseling instrument geared to primary
care practice. DESIGN: Randomized control trial. SETTING: Primary care practice.
PARTICIPANTS: Family physicians (N = 400) from 3 regions of Canada, representing
both rural and urban practice (ratio of 1:3). Patients (10 per practice) were
healthy community dwellers older than 65 years obtained as a convenience sample
in their family practice. INTERVENTIONS: In phase 1, 400 physicians listed as
being in general or family practice by their provincial registries were randomly
selected from a larger group listed by these registries and contacted by
telephone. A total of 362 completed a 10-minute questionnaire that detailed
practice demographics, preventive practice, and exercise counseling habits. In
phase 2, 293 agreed to further participate in the administration of an exercise
prescription randomly assigned to them by the study team. Two methods of exercise
prescription were compared: counseling using the American College of Sports
Medicine guidelines (control) and counseling using guidelines and an office-based
step test (Step Test Exercise Prescription [STEP]) to determine fitness level and
prescribe an exercise training heart rate. Physicians were asked to deliver their
assigned exercise prescription to a convenience sample of the next 10 healthy
patients older than 65 years who presented to the office. MAIN OUTCOME MEASURES:
Primary outcome measures were physician exercise counseling confidence and
knowledge before and after the study. Secondary outcomes included details of the
exercise counseling sessions (e.g., time required). RESULTS: In phase 1, more
than 90% of the 362 physicians claimed to practice preventive health counseling,
and 70% claimed to include exercise counseling. Only 67.4% felt confident
regarding their exercise prescribing, and most (93.8%) were interested in
improving their exercise prescribing skills. The leading barriers to exercise
prescription were described in order as inadequate time, lack of necessary skills
and tools, and lack of reimbursement. In phase 2, no difference in physician
profile, patient profile, or indications for exercise counseling were observed
between control (n = 145) and STEP (n = 148) groups. STEP was significantly
longer (16.4 vs 12.9 min; P = .001) to administer; however, improvement in
physician confidence (P = .01) and knowledge (P = .009) were significantly
greater compared with controls. CONCLUSIONS: Most family physicians practiced
preventive exercise counseling but reported lack of time and skills as barriers
to this practice. Physicians randomized to the STEP group took longer to deliver
exercise advice but felt more confident and knowledgeable compared with controls.
PMID- 10776363
TI - Randomized trial of a depression management program in high utilizers of medical
care.
AB - BACKGROUND: High utilizers of nonpsychiatric health care services have
disproportionally high rates of undiagnosed or undertreated depression.
OBJECTIVE: To determine the impact of offering a systematic primary care-based
depression treatment program to depressed "high utilizers" not in active
treatment. DESIGN: Randomized clinical trial. SETTING: One hundred sixty-three
primary care practices in 3 health maintenance organizations located in different
geographic regions of the United States. PATIENTS: A group of 1465 health
maintenance organization members were identified as depressed high utilizers
using a 2-stage telephone screening process. Eligibility criteria were met by 410
patients and 407 agreed to enroll: 218 in the depression management program (DMP)
practices and 189 in the usual care (UC) group. INTERVENTION: The DMP included
patient education materials, physician education programs, telephone-based
treatment coordination, and antidepressant pharmacotherapy initiated and managed
by patients' primary care physicians. MAIN OUTCOME MEASURES: Depression severity
was measured using the Hamilton Depression Rating Scale (Ham-D) and functional
status using the Medical Outcomes Study 20-item short form (SF-20) subscales.
Outpatient visit and hospitalization rates were measured using the health plan's
encounter data. RESULTS: Based on an intent-to-treat analysis, at least 3
antidepressant prescriptions were filled in the first 6 months by 151 (69.3%) of
218 of DMP patients vs 35 (18.5%) of 189 in UC (P < .001). Improvements in Ham-D
scores were significantly greater in the intervention group at 6 weeks (P = .04),
3 months (P = .02), 6 months (P < .001), and 12 months (P < .001). At 12 months,
DMP intervention patients were more improved than UC patients on the mental
health, social functioning, and general health perceptions scales of the SF-20 (P
< .05 for all). CONCLUSION: In depressed high utilizers not already in active
treatment, a systematic primary care-based treatment program can substantially
increase adequate antidepressant treatment, decrease depression severity, and
improve general health status compared with usual care.
PMID- 10776365
TI - Correlates of physicians' prevention-related practices. Findings from the Women
Physicians' Health Study.
AB - BACKGROUND: Determinants of physicians' prevention-related counseling and
screening practices are not well understood. Such determinants are worth knowing
because we can then intervene on malleable variables and produce physicians with
stronger prevention-related skills. Of the few such variables that have been
examined, they have typically only been studied in univariate analyses or in
small or otherwise limited populations and have been especially sparsely studied
in women physicians. OBJECTIVE: To explore the effect of potential counseling-
and screening-related variables in 4501 respondents to the Women Physicians'
Health Study, a questionnaire-based study of a representative sample of US women
MDs. RESULTS: Being a primary care practitioner and practicing a related health
habit oneself were significantly correlated with reporting counseling and
screening for all prevention-related variables examined. Current attempts to
improve a related habit oneself, ethnicity, region, practice site, and amount of
continuing medical education were sometimes significantly correlated with
counseling and screening; most other variables studied (i.e., personal health
status, a personal or family history of disease, control of work environment, and
career satisfaction) were rarely significantly correlated. CONCLUSIONS: Being a
primary care practitioner and having related healthy habits oneself were the most
significant correlates of US women physicians' self-reported prevention-related
counseling and screening practices. These findings suggest potential new
directions for physician training.
PMID- 10776364
TI - Recreational firearm use and hearing loss.
AB - OBJECTIVE: To assess the relation between recreational firearm use and high
frequency hearing loss in a population of older adults. DESIGN: Cross-sectional,
population-based cohort study. SETTING: The midwestern community of Beaver Dam,
Wis. PARTICIPANTS: A population-based sample of 3753 participants (83% of those
eligible), aged 48 to 92 years, participated in the baseline phase of the
Epidemiology of Hearing Loss Study. INTERVENTION: None. MAIN OUTCOME MEASURES:
Lifetime and past year self-reported firearm use during target shooting and
hunting were assessed by interview. Hearing thresholds were measured by pure-tone
audiometry. RESULTS: After age and other factors were adjusted for, men (n =
1538) who had ever regularly engaged in target shooting (odds ratio, 1.57; 95%
confidence interval, 1.12-2.19) or who had done so in the past year (odds ratio,
2.00; 95% confidence interval, 1.15-3.46) were more likely to have a marked high
frequency hearing loss than those who had not. Risk of having a marked high
frequency hearing loss increased 7% for every 5 years the men had hunted (odds
ratio, 1.07; 95% confidence interval, 1.03-1.12). Thirty-eight percent of the
target shooters and 95% of the hunters reported never wearing hearing protection
while shooting in the past year. CONCLUSIONS: These results indicate that use of
recreational firearms is associated with marked high-frequency hearing loss in
men. There is a need for further education of users of recreational firearms
regarding the risk of hearing impairment associated with firearm use and the
availability and importance of appropriate hearing protection.
PMID- 10776366
TI - Enhancing influenza immunization. Postcard and telephone reminders and the
challenge of immunization site shift.
AB - OBJECTIVE: To determine if postcard and telephone reminders increased the rate of
influenza immunization of Medicare beneficiaries. DESIGN: Before and after trial
(postcard reminders) with systematically allocated control group (telephone
reminder intervention). SETTING: A semirural family practice residency program.
PATIENTS AND OTHER PARTICIPANTS: All 475 noninstitutionalized persons older than
65 years who had received at least 1 office service in the previous 2 years.
INTERVENTION: In September 1996, each of 475 patients received a postcard urging
prompt influenza immunization. Those not responding within 1 month were
systematically allocated either to a group receiving further telephone contact or
to a control group. At the time of telephone contact, any offered information
about influenza immunization received outside the Smoky Hill Family Practice
Center, Salina, Kan, was recorded. MAIN OUTCOME MEASURES: We measured the
percentage of change in practice-administered influenza immunizations compared
with the baseline rate of the preceding 2 years; the difference in immunization
rates between the telephone intervention group and controls; and the number of
patients contacted by telephone who reported receiving influenza immunization at
a site other than the Family Practice Center. RESULTS: Twenty-eight percent of
patients who received a postcard obtained office influenza immunizations within 1
month, but no additional immunizations could be attributed to the telephone
intervention. Thirty-five percent of patients contacted by telephone reported
receiving influenza immunization at a site other than the Family Practice Center.
CONCLUSIONS: The postcard intervention was associated with a significant increase
in the office immunization rate. This increase may have been confounded by "site
shift" in which individuals came to the office for an immunization that they
might otherwise have received at other community sites.
PMID- 10776367
TI - Follow-up radiographs to detect callus formation after fractures.
PMID- 10776368
TI - Reducing antihypertensive medication use in nursing home patients.
AB - Of the 1.5 million nursing home residents, about 40% are aged 85 years or older,
and a similar percentage have hypertension. The rates of incorrect diagnoses from
the "white coat" effect and from errors in blood pressure evaluation are as
frequent in older persons as in younger persons. The benefits of antihypertensive
treatment and the risks of lowering blood pressures in the very old (> or = 85
years) are uncertain. Elderly patients experience adverse effects from drug
treatment that are unique to their age group and that complicate management
problems associated with polypharmacy and multiple comorbid conditions. Trials to
withdraw or lower the dosage of antihypertensive medications have been successful
in up to 40% of elderly persons when combined with salt restriction and weight
loss, but such studies are lacking in nursing home patients. The management of
hypertension should be reevaluated in nursing home patients.
PMID- 10776369
TI - Prescription of proton pump inhibitors before endoscopy. A potential cause of
missed diagnosis of early gastric cancers.
AB - BACKGROUND: Early gastric cancer is frequently seen with nonspecific dyspeptic
symptoms and subtle endoscopic features. Treatment at this stage of the disease
produces a high chance of cure. If the diagnosis is missed at this early stage,
then the prognosis may be much poorer depending on the subsequent delay in
reaching a diagnosis. OBJECTIVES: To report the healing effect of proton pump
inhibitors on early gastric cancer. METHODS: This article reports a case series
of 7 patients with ulcerated early gastric cancers indistinguishable as malignant
gastric ulcers at endoscopy who were inadvertently prescribed a short course of a
proton pump inhibitor prior to a second confirmatory endoscopy. The cases studied
were patients with dyspeptic symptoms referred from primary care physicians for
upper gastrointestinal endoscopy. RESULTS: In each case the patient became
asymptomatic, the endoscopic signs seen at the first endoscopy had resolved, and
the lesions could not be recognized even by an experienced endoscopist. If the
proton pump inhibitors had been prescribed by the referring physician before the
first endoscopy, the diagnosis probably would have been missed. These cases
demonstrate the potentially serious masking effect of prescribing a short course
of these drugs before making an endoscopic diagnosis. Even though the patient has
been referred for endoscopy, the endoscopist may fail to identify the lesion and
thus miss the diagnosis. CONCLUSIONS: Primary care physicians must resist the
pressures to prescribe proton pump inhibitors before endoscopy, particularly in
patients older than 45 years, if the diagnostic yield of gastric cancer in the
early curable stages is to be maximized.
PMID- 10776370
TI - Vagally mediated atrial fibrillation in a young man.
AB - Atrial fibrillation may be provoked by either vagal or sympathetic stimulation.
Sympathetic effects are common in middle-aged and elderly patients with
underlying heart disease. However, in the young, non-diseased heart, vagal
influences are more likely to predominate. Recognition of vagally mediated atrial
fibrillation in young adults as a unique clinical entity has diagnostic and
therapeutic implications.
PMID- 10776371
TI - Fast fixes for bad service.
PMID- 10776372
TI - Talk or sue?
PMID- 10776373
TI - Empowering patients.
PMID- 10776374
TI - Forces that will change health care.
PMID- 10776376
TI - Web targets nurses.
PMID- 10776375
TI - Truer takes on kids.
PMID- 10776377
TI - Paramedics--above & beyond.
PMID- 10776378
TI - Ten risk management challenges for 2000.
PMID- 10776379
TI - Bandwidth & bandwagon.
PMID- 10776380
TI - The CEO's guide to the Internet.
PMID- 10776381
TI - A listing of key market. Sectors & players.
PMID- 10776382
TI - Confronting HIPAA.
PMID- 10776383
TI - A better ending.
PMID- 10776384
TI - Genomics.
PMID- 10776385
TI - Taking it to the top.
PMID- 10776386
TI - Breast cancer guidelines in action.
PMID- 10776387
TI - The management of acute myocardial infarction: a ray of sunshine.
PMID- 10776388
TI - The international consensus statement on cerebral palsy causation.
PMID- 10776389
TI - Healthcare services for low-incidence anomalies.
PMID- 10776390
TI - The effect of mammographic screening on invasive breast cancer in Western
Australia.
AB - OBJECTIVE: To determine whether mammographic screening has affected the
presentation of invasive breast cancer in Western Australia. DESIGN: Population
based reviews of the presentation of all invasive breast cancers diagnosed in
Western Australia in 1989 and 1994. SETTING: Western Australia (population 1.8
million). Active recruitment of women aged 50-69 years for mammographic screening
began in 1989. MAIN OUTCOME MEASURES: Size and stage of invasive breast cancers
at diagnosis. RESULTS: From 1989 to 1994, the age-standardised incidence rose
from 109 to 123 per 100,000 woman-years, based on 584 and 750 cases,
respectively. The proportion of all invasive breast cancers detected as a result
of a mammogram increased from 9.2% in 1989 to 34.5% in 1994. Among the cases
where relevant information was recorded, the proportion of "impalpable" tumours
increased from 7.7% in 1989 to 27.6% in 1994, and the average size of palpable
tumours fell. There was an unexpected increase in the proportion of tumors that
were negative on assays for oestrogen and progesterone receptors. CONCLUSIONS: A
relatively simple and inexpensive clinical review has boosted confidence that the
outlay of public monies required to establish and conduct screening in Australia
appears likely to yield the reductions in mortality from breast cancer that would
be predicted on the basis of the earlier controlled trials of mammography.
PMID- 10776391
TI - Stated and actual management of acute myocardial infarction among different
specialties.
AB - OBJECTIVES: To examine the variation in stated management of acute myocardial
infarction (AMI) among clinicians of different specialties, and to compare stated
with actual practice. DESIGN: Mail survey using a hypothetical case history, and
review of medical records. SETTING: 47 public hospitals in New South Wales.
SUBJECTS: 224 cardiologists, general/other physicians and general practitioners
(GPs) who manage patients with AMI; 390 patients admitted for AMI between
February and June 1996. OUTCOME MEASURES: Stated and actual use of treatments and
investigations for AMI. RESULTS: Stated use of aspirin, thrombolysis and beta
blockers (95%-100%, 95%-100% and 80%-86%, respectively) was high in all three
specialties. Cardiologists were significantly more likely than GPs to state use
of heparin (87% v 57%; P < 0.001), ACE inhibitors (84% v 49%; P < 0.001) and
echocardiography or gated pool heart scan (79% v 26%; P < 0.001). Stated use of
nitrates by cardiologists was significantly lower compared with the other
specialties (29% v 50% and 44%; P = 0.027). Actual use of aspirin was high (>
80%) in all specialties. Actual use of thrombolysis was similar to stated use
after adjusting for factors such as time to hospital arrival and ST-segment
elevation. There were substantial differences between stated and actual use.
CONCLUSIONS: There were differences in practice patterns between and among
clinicians of different specialties in NSW, consistent with findings from other
countries. The high stated and actual use of aspirin and thrombolysis is
encouraging.
PMID- 10776393
TI - Deaths due to brain injury among footballers in Victoria, 1968-1999.
AB - OBJECTIVES: To determine the frequency and nature of fatal brain injuries
occurring in Australian football. SETTING: State of Victoria, January to July
1999. DESIGN: Retrospective case series of football-related deaths identified
from the coronial autopsy records of the Victorian Institute of Forensic Medicine
(1990-1999) and newspaper reports (1968-1989). MAIN OUTCOME MEASURES: Coronial
autopsy findings and circumstances of injury. RESULTS: 25 deaths associated with
Australian football were identified, nine due to brain injury. Coronial findings
in the brain-injury deaths were intracranial haemorrhage in eight patients and
infarct in the territory of the middle cerebral artery in one. In three of four
cases of subarachnoid haemorrhage, vertebral artery trauma was noted. In all but
one case, injury occurred as an accidental part of play. CONCLUSIONS: The most
common findings in deaths due to brain injury in Australian football were
intracranial haemorrhage, including subarachnoid haemorrhage from vertebral
artery injury.
PMID- 10776392
TI - Implementing clinical practice guidelines: a community-based audit of breast
cancer treatment. Australian Capital Territory and South Eastern New South Wales
Breast Cancer Treatment Group.
AB - OBJECTIVE: To improve breast cancer management by facilitating implementation of
treatment guidelines. DESIGN: A prospective, longitudinal study (developed by
clinicians and consumers) of all patients with newly diagnosed breast cancer.
Four locally agreed breast cancer management guidelines were established (based
on 1995 National Health and Medical Research Council guidelines) as practice
indicators. SETTING: Breast cancer treatment facilities and medical practices in
the Australian Capital Territory and South Eastern New South Wales, May 1997 to
July 1998. MAIN OUTCOME MEASURES: Actual treatment received by patients for
primary breast cancer during the study period. RESULTS: During the 14 months of
the study, 19 clinicians registered 221 new patients with a proven diagnosis of
breast cancer. Of 191 women with localised invasive breast cancer, 112 (59%) had
tumours 2 cm or less in diameter. Axillary surgery in 173 (91%) of these women
showed 107 (56%) had no axillary lymph node involvement. Of 87 women treated with
breast-conserving surgery for locally invasive cancer, 85 (98%) also received
postoperative radiotherapy. Some form of systemic adjuvant therapy was indicated
in 99 women (axillary nodes positive or tumours > 2 cm diameter) and this
treatment was received by 95 (96%). All 27 women aged under 50 years with node
positive disease received adjuvant chemotherapy. CONCLUSIONS: Enhancing uptake of
breast cancer management guidelines is feasible at a regional level with an audit
program and broad support among clinicians and consumers.
PMID- 10776395
TI - Osteoporosis prevention and treatment.
AB - Patients with low bone density or any prior low trauma fracture should be
considered for therapeutic intervention. Oestrogen replacement therapy remains
the first choice for prevention of bone loss in early postmenopausal women with
low bone density. In postmenopausal women with existing fractures, the rank order
of treatments is firstly alendronate, secondly raloxifene and thirdly less potent
bisphosphonates, such as etidronate, or active vitamin D metabolites, such as
calcitriol. For men with osteoporosis, if hypogonadism is present, it should be
treated with testosterone replacement therapy. Despite limited data, a
bisphosphonate should then be considered in conjunction with calcium.
Supplementation with simple vitamin D should be considered in elderly patients
who are housebound or live in institutions, as they are at risk of vitamin D
deficiency and osteomalacia.
PMID- 10776394
TI - Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus
guidelines for androgen prescribing.
AB - Androgen replacement therapy (ART) is usually life-long, and should only be
started after androgen deficiency has been proven by hormone assays. The
therapeutic goal is to maintain physiological testosterone levels. Testosterone
rather than synthetic androgens should be used. Oral 17 alpha-alkylated androgens
are hepatotoxic and should not be used for ART. There is no indication for
androgen therapy in male infertility. Although androgen deficiency is an uncommon
cause of erectile dysfunction, all men presenting with erectile dysfunction
should be evaluated for androgen deficiency. If androgen deficiency is confirmed,
investigation for the underlying pathological cause is required.
Contraindications to androgen therapy are prostate and breast cancer. Precautions
include using lower starting doses for older men and induction of puberty.
Intramuscular injections should be avoided in men with bleeding disorders.
Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid
overload need to be considered. Competitive athletes should be warned about the
risks of disqualification. ART should be initiated with intramuscular injections
of testosterone esters, 250 mg every two weeks [corrected]. Maintenance requires
tailoring treatment modality to the patient's convenience. Modalities currently
available include testosterone injections, implants, or capsules. Choice depends
on convenience, cost, availability and familiarity. There is no convincing
evidence that, in the absence of proven androgen deficiency, androgen therapy is
effective and safe for older men per se, in men with chronic non-gonadal disease,
or for treatment of non-specific symptoms. Until further evidence is available,
such treatment cannot be recommended.
PMID- 10776396
TI - Transport and health: en route to a healthier Australia?
AB - We have been slow to recognize the impact that decisions about transport, land
use and infrastructure have on health. Apart from encouraging a sedentary
lifestyle, reliance on motor vehicle transport has a range of adverse health
effects (traffic accidents, air and noise pollution, and greenhouse gas
emissions). Physical activity equivalent to 30 minutes (in total) of brisk
walking on all, or most, days of the week provides preventive and protective
benefits for a wide range of health conditions (including cardiovascular disease,
diabetes, depression and osteoporosis). "Active transport"--walking, cycling
and/or using public transport instead of car travel--could have dual health
benefits by providing physical activity and reducing the adverse health effects
of motor vehicle transport. Doctors, medical administrators and health advocates
can encourage the use of "active transport", and influence community-based
programs and policy development about land use planning and travel demand
management.
PMID- 10776397
TI - Uterine artery embolisation for symptomatic fibroids.
AB - Traditional operative treatments for symptomatic fibroids--hysterectomy and
myomectomy--involve considerable morbidity. Although morbidity is reduced with
endoscopic surgery, this technique is not widely available, and has limitations.
Embolisation of the pelvic vasculature is not a new procedure, having been used
to treat postpartum and postsurgical bleeding for 20 years. It has only recently
been used to treat symptomatic fibroids. Uterine artery embolisation can produce
a mean reduction of 29%-51% in uterine volume at the time of the three-month
review, with longer follow-up showing continued shrinkage and no regrowth. The
range of shrinkage is highly variable, which needs to be explained to all
potential candidates. Symptomatic relief is a more certain outcome, with relief
of pelvic pressure symptoms in 91%-96% of women. There is a small risk of
complications requiring hysterectomy, and the long-term effect on ovarian
function is unknown.
PMID- 10776398
TI - Delayed diagnoses of cystic fibrosis in a screened population.
PMID- 10776399
TI - Communicating prognosis in early breast cancer: do women understand the language
used?
PMID- 10776400
TI - Communicating prognosis in early breast cancer: do women understand the language
used?
PMID- 10776401
TI - Do management algorithms improve chest pain triage?
PMID- 10776402
TI - Do management algorithms improve chest pain triage?
PMID- 10776403
TI - Homeless young people: an important risk group for sexually transmitted
infections.
PMID- 10776404
TI - Ciprofloxacin-resistant Campylobacter jejuni infections.
PMID- 10776405
TI - Quantitative heel ultrasound as a predictor for osteoporosis.
PMID- 10776406
TI - The medicolegal assessment: a risk factor for overdose?
PMID- 10776407
TI - Internet postgraduate education.
PMID- 10776408
TI - An email from Borneo.
PMID- 10776409
TI - A pneumococcal conjugate vaccine for infants and children.
PMID- 10776410
TI - Curosurf.
PMID- 10776412
TI - [Incidence of end-stage renal disease in Ile de France: a prospective
epidemiological survey].
AB - OBJECTIVES: To evaluate incidence and prevalence of patients with end-stage renal
disease (ESRD) treated with maintenance dialysis in the Ile de France district in
1998. METHODOLOGY: Prospective epidemiologic inquiry with the cooperation of the
91 nephrology departments and dialysis facilities of the Ile de France district
(total population: 10,695,300 inhabitants in March 1999), from January 1st to
December 31st, 1998. Evaluation of the demographic and clinical characteristics
of the 1155 patients accepted on maintenance dialysis in 1998, and recording of
the total number of dialyzed patients at the beginning and at the end of the same
year. RESULTS: The total number of ESRD patients was 1155, including 29 (2.5%)
children aged < or = 17 years and 86 (7.4%) returns to dialysis following kidney
graft failure. Incidence of ESRD in first-dialyzed patients was 100/million/year
and overall incidence, including returns from transplantation, was
108/million/year. Mean age of the 1040 adult first-dialysis patients was 59 +/-
16.8 years, with a proportion of those aged > or = 75 years of 21.6%. Patients
with vascular renal disease were 22.5% and those with diabetic nephropathy 20.6%.
As a whole, 36.5% of patients were referred to the nephrologist < 6 months of
starting dialysis. Prevalence of patients on supportive dialysis increased from
417 to 433 per million inhabitants (a 3.8% increase) from the beginning to the
end of 1998, with the proportion of patients treated with self-care dialysis or
peritoneal dialysis rising by 10%. From January 1995 to January 1999, prevalence
of dialysis-treated ESRD patients rose by nearly 4% per year as a mean.
CONCLUSION: Incidence of ESRD patients requiring maintenance dialysis in the Ile
de France district reached 100/million in 1998, an increment of 4% per year over
the past 4 years. The increase in incidence results from the increasing number of
older patients, parallel to the ageing of general population, these patients
having a high comorbidity mainly due to diabetes and atherosclerosis. Prevalence
of dialysis-treated patients was 433/million population at the end of 1998. It
rose at a similar rate as did incidence, although with a growing proportion of
out-center dialysis.
PMID- 10776411
TI - [Rapid diagnosis of the type of meningitis (bacterial or viral) by the assay of
serum procalcitonin].
AB - OBJECTIVE: It has been shown that serum procalcitonin (PCT) can be used to
differentiate bacterial from viral meningitis in children in all cases. The aim
of this study was to demonstrate the interest of PCT in the management of
suspected meningitis in adults. PATIENTS AND METHODS: We conducted a prospective
study including 179 consecutive patients admitted to the emergency department for
suspected meningitis. All samples were taken at patient admission. The
discriminant potential between bacterial and viral meningitis was studied for
cerebrospinal fluid parameters (cytology, protein, glucose, lactate) and serum
parameters (C reactive protein, PCT). RESULTS: Thirty-two patients had bacterial
meningitis, 90 had viral meningitis and meningitis was ruled out in 57. Among all
studied parameters, the most discriminant for distinguishing between bacterial
and viral meningitis in 100% of the cases proved to be serum procalcitonin with a
threshold value of 0.93 ng/ml. CONCLUSION: Serum procalcitonin is an interesting
parameter in the emergency department for management of meningitis suspicion in
adults.
PMID- 10776413
TI - [Meningeal metastases of ovarian cancer. Contribution of imaging].
AB - BACKGROUND: Secondary meningeal localizations are uncommon and may disclose
reactivation of a malignant disease. Most meningeal metastases occur in breast
cancer, exceptionally in primary ovarian cancer. CASE REPORT: We report 2 cases
of secondary meningeal localizations of ovarian cancer. The diagnosis was
clinical, supported by cerebrospinal fluid analysis and computed tomography and
magnetic resonance imaging. DISCUSSION: Establishing the diagnosis of
carcinomatous meningitis may be difficult. Clinical signs and biological data are
not always conclusive. If spinal tap is contraindicated or negative, imaging,
particularly magnetic resonance imaging is highly contributive in establishing
the diagnosis of secondary localization. A precise evaluation of the invaded
tissues is quite helpful in guiding therapeutic management based on chemotherapy,
tumor resection or radiotherapy.
PMID- 10776414
TI - [Exposure to blood accidents in a university hospital. Results of 1-year
surveillance].
PMID- 10776415
TI - [Severe cytomegalovirus enteritis in AIDS. Favorable outcome of medical
treatment].
PMID- 10776416
TI - [Hypercalcemia due to septic bone metastasis].
PMID- 10776417
TI - [Type 1 diabetes: long-term effects of intensive insulin therapy on diabetic
retinopathy and nephropathy].
PMID- 10776418
TI - [Isoprostanes: new markers of oxidative stress in human diseases].
AB - BACKGROUND: Most of the traditional methods used to assess oxidative stress in
clinical setting are non specific, unreliable or inaccurate. Recently, a novel
family of prostaglandin F2 isomers, called F2-isoprostanes, produced in vivo by a
free radical peroxidation of arachidonic acid, has been described. These
compounds may produce physiological or pathological effects due to their ability
to alter smooth muscle and platelet functions. The quantification of the two
major isoforms (isoprostaglandin F2 alpha type-III and VI) in biological fluids
and tissues as markers of lipid peroxidation appears to be an important advance
in our ability to explore the role of free radicals in the pathogenesis of human
disease. CLINICAL DATA: Urinary excretion of F2-isoprostanes is correlated with
age, indicating increased oxidative stress during the normal aging process. High
F2-isoprostanes concentration has been described in diseases such as ischemic
heart disease, diabetes, Alzheimer's disease and hepatic cirrhosis. The
correlation of F2-isoprostane concentrations and human diseases severity in
hepatic cirrhosis, cardiac failure and diabetes suggest that these compounds may
be of interest as predictive markers. PERSPECTIVES: Preliminary studies suggest
the use of F2-isoprostanes as prognosis markers. In addition, F2-isoprostanes
quantification offers promising potential as intermediate endpoints for clinical
studies of antioxidant therapies.
PMID- 10776419
TI - [Penetrating atheromatous ulcers of the aorta].
AB - THORACIC PAINFUL SYNDROME: Penetrating atherosclerotic aortic ulcers represent a
condition in which an atherosclerotic plaque ulcerates and disrupts the internal
elastic lamina, allowing intramural hematoma formation into the aortic media.
Recently individualized as an entity from all vascular thoracic painful
syndromes, they affect preponderantly the elderly patients with a medical
hypertensive and atherosclerotic history and with multiple cardiovascular risk
factors. The descending thoracic aorta is most frequently involved. IMAGING:
Computed tomography scanning and magnetic resonance imaging tend to replace
aortography in providing an accurate diagnosis of the ulceration and of its
parietal extent. Moreover, they allow the discrimination with aortic dissection
or with intramural hematoma without intimal rupture which outcome and treatment
should differ. RISKS: In the absence of complication, progressive aneurysmal
dilatation at the level of the ulcer is a rule. Pseudoaneurysms formation,
embolization, and acute transmural aortic rupture can however occur and may
justify, in selected cases, a preventive or curative surgical treatment. STENT
GRAFTING: Endovascular stent-grafting techniques may appear as a safe and
effective less invasive choice in high-risk patients with suitable anatomical
conditions.
PMID- 10776420
TI - [Surgery of epilepsy: current status].
AB - PRELIMINARY EXPLORATIONS: The advent of magnetic resonance imaging and its
capacity to detect fine structural injury and SPECT and PET functional imaging as
well as the generalization of EEG-video and the simplification of intracranial
electrode implantation techniques has given a whole new life to surgery in
epilepsy. Preoperative explorations are shorter and less invasive, allowing
surgery without implantation of intracranial electrodes in more than 70% of the
cases. SURGERY: New surgical techniques (subpial transection, neuro
navigation...) and improvement in well-known procedures (amygdalo
hippocampectomy...) has made it possible to propose lower risk procedures with
minimal trauma (overall complication rate < 10%), particularly for temporal
epilepsy where the success rate is greater than 80%. FUNDAMENTAL RULE: The key to
success however directly depends on rigorous application of the fundamental rule
of anatomo-electro-clinical correlation.
PMID- 10776421
TI - [Surgical treatment of stress urinary incontinence in women].
AB - INDICATION FOR SURGERY: Exercise-induced urinary incontinence is responsible for
more than 75% of all cases of urinary incontinence in women. Surgery can provide
excellent cure if the initial indication is established properly. SURGICAL
PROCEDURES: The aim is to correct the mechanical alterations leading to urine
leakage: sphincter anomalies and cervico-urethral hypermobility. Colpo-suspension
using the indirect Burch procedure and the direct Goebell-Stoeckel procedure are
indicated for physically active patients. For sphincter failure, an artificial
sphincter with a fixed bladder neck is indicated. Simplified transvaginal colpo
suspension is indicated for elderly women. TENSION FREE VAGINAL TAPE: The
recently developed, this new technique appears extremely promising for the
treatment of urethral hypermobility.
PMID- 10776422
TI - [Imaging in medicine. Intra-somatic vertebral vacuum].
PMID- 10776423
TI - The meaning of surgery.
PMID- 10776424
TI - Surgery and meaning.
PMID- 10776425
TI - Stimulated apoptosis as an anti-neoplastic strategy.
PMID- 10776426
TI - Obstruction and perforation in colorectal adenocarcinoma: an analysis of
prognosis and current trends.
AB - BACKGROUND: In adenocarcinoma of the colon and rectum, obstruction and
perforation may occur either alone or together at the site of the neoplasm or
proximally. Both events carry a poor prognosis. This retrospective study sought
to determine whether a correlation exists between perforation and obstruction,
and between these conditions and different clinicopathological factors in
colorectal adenocarcinoma. METHODS: The medical records of 1950 patients with
colorectal adenocarcinoma treated in our hospital during a 7-year period were
retrospectively analyzed. One hundred patients (5%) were excluded from this study
because of a loss of follow-up. Data on clinicopathological factors including
age, sex, tumor location, surgical mortality, pathological type, stage, and long
time cancer-free rate were simultaneously analyzed. Patients were grouped as
follows: Group 1, complete colonic obstruction without perforation (n = 120).
Group 2, complete obstruction with perforation at the site of the cancer (n =
35); Group 3, complete obstruction with perforation proximal to the cancer (n =
13); and Group 4, nonobstructing, nonperforated cancers (n = 1682). RESULTS: When
compared with Group 4, Group 1 had a more advanced Dukes' stage, older age,
greater incidence of colonic versus rectal cancers, and a poorer cancer-free
survival (P < or = .005). Groups 2 and 3 had a greater incidence of colonic
versus rectal cancers (P < or = .004), and Group 3 had a greater operative
mortality (P < .001). No significant differences were found between Groups 1, 2,
and 3. Multivariate analysis revealed that the independent factors favorable to
cancer-free survival (> 5-year survival) were female gender (P = .035), well
differentiated pathology (P < .001), uncomplicated cases (P = .004), colon versus
rectal location (P < .001), and early stage (P < .001). CONCLUSIONS: The
perioperative mortality rate for perforated colorectal cancer at the site of the
cancer was 9%; for obstructive colorectal cancer, 5%. Perioperative mortality was
much greater for perforations of the colon and rectum occurring proximal to the
cancer (31%). Survival was worse (P < .001) for patients with obstruction (33%)
or perforation proximal to the cancer (33%). The site of perforation did not
appear to impact the 5-year survival, although the numbers are relatively small.
PMID- 10776428
TI - Liver metastases from breast cancer: long-term survival after curative resection.
AB - BACKGROUND: Liver metastases from breast cancer are associated with a poor
prognosis (median survival < 6 months). A subgroup of these patients with no
dissemination in other organs may benefit from surgery. Available data in the
literature suggest that only in exceptional cases do these patients survive more
than 2 years when given chemohormonal therapy or supportive care alone. We report
the results of liver resection in patients with isolated hepatic metastases from
breast cancer and evaluate the rate of long-term survival, prognostic factors,
and the role of neoadjuvant high-dose chemotherapy. PATIENTS AND METHODS: Over
the past decade, 17 women underwent hepatic metastectomy with curative intent for
metastatic breast cancer. The follow-up was complete in each patient. The median
age at the time breast cancer was diagnosed was 48 years. Neoadjuvant high-dose
chemotherapy (HDC) with hematopoietic progenitor support was used in 10 patients
before liver resection. Perioperative complications, long-term outcome, and
prognostic factors were evaluated. RESULTS: Seven of the 17 patients are
currently alive, with follow-up of up to 12 years. Four of these patients are
free of tumors after 6 and 17 months and 6 and 12 years. The actuarial 5-year
survival rate is 22%. One patient died postoperatively (mortality rate, 6%) of
carmustine-induced fibrosing pneumonitis. There was no further major morbidity in
the other patients. The liver was the primary site of recurrent disease after
liver resection in 67% of the patients. Patients in whom liver metastases were
found more than 1 year after resection of the primary breast cancer had a
significantly better outcome than those with early (< 1 year) metastatic disease
(P = .04). The type of liver resection, the lymph node status at the time of the
primary breast cancer resection, and HDC had no significant impact on patient
survival in this series. CONCLUSIONS: Favorable 22% long-term survival can be
achieved with metastasectomy in this selected group of patients. Careful
evaluation of pulmonary toxicity from carmustine and exclusion of patients with
extrahepatic disease are critical. Improved survival might be achieved with
better selection of patients and the use of liver-directed adjuvant therapy.
PMID- 10776427
TI - Seasonal changes in calcium homeostasis affect the incidence of postoperative
tetany in patients with Graves' disease.
AB - BACKGROUND: We have found that postoperative tetany occurs in patients with
Graves' disease who have secondary hyperparathyroidism caused by a deficiency in
calcium and vitamin D concomitant with transient hypoparathyroidism after
surgery. There are seasonal variations in serum 25-hydroxyvitamin D (25[OH]D)
concentrations. The purpose of this study was to investigate the effects of
seasonal changes in calcium homeostasis on the incidence of postoperative tetany
in patients with Graves' disease who undergo subtotal thyroidectomy. PATIENTS AND
METHODS: A prospective study was carried out to investigate sequential changes in
serum levels of intact parathyroid hormone (iPTH), calcium and other
electrolytes, 25(OH)D, and 1,25-dihydroxyvitamin D (1,25[OH]2D) in female
patients with Graves' disease who underwent subtotal thyroidectomy during the
summer (n = 89) and during the winter (n = 89). RESULTS: The serum levels of
calcium, magnesium, and 25(OH)D were significantly higher, but iPTH levels and
1,25(OH)2D levels were lower in summer than in winter. The percentage of vitamin
D deficiency (25(OH)D < 25 nmol/L) was 23% in summer and 62% in winter (P <
.001). iPTH was below the detection limit on the first postoperative day in 15
patients (13.8%) in summer and in 13 patients (11.4%) in winter. In summery,
tetany developed in only 4 of 15 patients and in one patient whose iPTH level was
below normal (incidence of tetany, 5.6%). In winter, however, tetany developed in
6 of 13 patients and in 4 patients whose iPTH level was below normal (incidence
of tetany, 11.2%). CONCLUSIONS: Patients with Graves' disease are more
susceptible to calcium and vitamin D deficiency during the winter than during the
summer, resulting in the tendency toward a higher incidence of postoperative
tetany in winter.
PMID- 10776429
TI - Positive end-expiratory pressure and response to inhaled nitric oxide: changing
nonresponders to responders.
AB - BACKGROUND: Inhaled nitric oxide (INO) has been shown to improve oxygenation in
two thirds of patients with acute respiratory distress syndrome (ARDS). Failure
to respond to INO is multifactorial. We hypothesized that the addition of
positive end expiratory pressure (PEEP) might modify the response to INO in
patients who had previously failed to respond to INO. METHODS: Patients with ARDS
who failed to respond to INO at 1 ppm (PaO2 increase of < 20%) were selected.
Each patient underwent a PEEP trial using an improvement in static lung
compliance as the end point. One hour after the new PEEP level was reached,
hemodynamic and blood gas values were obtained. INO was then reinstituted at 1
ppm, and hemodynamic and blood gas variables were obtained 1 hour later. RESULTS:
Six of nine patients demonstrated an increase in PaO2/FIO2 (161 +/- 27 to 186 +/-
29) with a mean increase in PEEP of 3.7 cm H2O. Each patient responding to PEEP
further improved PaO2/FIO2 (186 +/- 29 to 223 +/- 36) with INO at 1 ppm. The
three patients who failed to improve after the PEEP increase also failed to
respond to a second trial of INO. There were no changes in cardiac output or
systemic vascular resistance. Pulmonary artery pressures decreased slightly (39
+/- 5 vs 38 +/- 7 vs 35 +/- 9 mm Hg). Pulmonary vascular resistance decreased
significantly after reintroduction of INO (298 +/- 131 vs 310 +/- 122 vs 249 +/-
105 dynes/sec/cm-5) in patients who responded positively. CONCLUSIONS: The
response of ARDS patients to INO can be improved if optimum alveolar recruitment
is achieved by the addition of PEEP. PEEP and INO have a synergistic effect on
PaO2/FIO2. Patients who fail to respond to INO may benefit from an optimum PEEP
trial.
PMID- 10776430
TI - Evaluation of morbidity and mortality after resection for hilar
cholangiocarcinoma--a single center experience.
AB - BACKGROUND: Hilar resection, especially in combination with liver resection,
results in substantial morbidity and mortality, which clearly influences the
overall outcome. In the present study, patients who underwent resection of a
proximal bile duct tumor were analyzed with the aim of identifying risk factors
for morbidity and mortality. METHODS: Between 1983 and 1998, 112 consecutive
patients underwent a local resection, which in 32 patients was combined with a
hemihepatectomy (11 extended resections). Eighty-four percent of the patients
underwent preoperative (endoscopic) drainage. For evaluation of different
treatment strategies during the study, the period was divided in three 5-year
intervals. RESULTS: Postoperative complications occurred in 65% of the patients.
The overall hospital mortality was 15% for local resections and 25% for hemi
hepatectomies. There was a significantly lower morbidity and no mortality after
hilar resection during the last 5 years. A higher Bismuth classification showed
significant correlation with postoperative morbidity. Extended liver resections
and vascular resections and a preoperative albumin level below 35 g/L were found
to be significant predictors of increased mortality in univariate analysis.
CONCLUSIONS: The overall morbidity and mortality rate in this series is higher
than most recently published series. More (extended) liver resections resulted in
an increased rate of microscopic tumor-free resections, at the cost of higher
hospital morbidity and mortality. Improved preoperative work-ups will result in a
selection of patients who might benefit from these extensive resections.
PMID- 10776431
TI - A comparison of laparoscopic and open cholecystectomy in patients with
compensated cirrhosis and symptomatic gallstone disease.
AB - BACKGROUND: The purpose of this study was to compare the risks and benefits of
performing open cholecystectomy (OC) and laparoscopic cholecystectomy (LC) in
patients with compensated cirrhosis. METHODS: Data on 50 patients who underwent
cholecystectomy for the treatment of symptomatic gallstone disease between 1990
and 1997 were collected retrospectively. These patients were divided into 2
groups: Group I included 24 patients who underwent OC, and Group II included 26
patients who underwent LC. The cohorts were well-matched for age, sex, race,
clinical presentation, and Child-Turcotte-Pugh (CTP) class. Twelve patients in
Group I had a concomitant surgical procedure in contrast to only 2 patients in
Group II. No patient in this study had CTP Class C cirrhosis. RESULTS: There was
no operative mortality. Conversion to OC was necessary in 3 patients (12%) during
LC because of uncontrollable liver bed bleeding in 2 of the patients and
insufficient visualization of the anatomy in 1 of the patients. Mean surgical
times were significantly longer in Group I when comparing patients from both
groups without concomitant surgical procedures (mean +/- SD, 177 +/- 91.3 minutes
vs 116.8 +/- 42.3 minutes, P = .037). No patient in Group II required any blood
component replacement in contrast to 9 patients (38%) in Group I. Intraoperative
bleeding remained significantly higher in Group I when comparing patients without
concomitant surgical procedures (P = .043). No patients in Group II had a wound
complication, compared with 2 patients (8%) in Group I. The 12 patients without
concomitant surgical procedures in Group I had significantly longer hospital
stays when compared with 24 patients without concomitant surgical procedures in
Group II (mean +/- SD, 6.9 days +/- 3.3 [median 6] vs 2.4 days +/- 1.8 [median
2.0]); P = .001. CONCLUSIONS: Our results demonstrate that laparoscopic
cholecystectomy can be performed safely in patients with CTP Class A and B
cirrhosis. It offers several advantages over open cholecystectomy, including
lower morbidity, shorter operative time, and reduced hospital stay with less need
for transfusions.
PMID- 10776432
TI - Beta adrenoceptor regulation of macrophage arginase activity.
AB - BACKGROUND: Arginase, which metabolizes L-arginine within the urea cycle, is
essential for production of polyamines and affects production of nitric oxide by
depletion of L-arginine, the common substrate for both arginase and nitric oxide
synthase. Having shown that trauma increases splenic macrophage arginase
activity, we seek to define the mechanisms for this. RAW macrophage arginase
activity and expression are increased by 8-bromo-cAMP in vitro. We hypothesize
that since catecholamines increase cAMP, trauma-induced splenic arginase activity
may be mediated by post-injury catecholamine release. METHODS: RAW 264.7
macrophage arginase activity was measured in vitro in response to 4
catecholamines with or without propranolol or lipopolysaccharide (LPS). C57BL/6
mice underwent laparotomy as a model of moderate trauma after propranolol
treatment, with and without intraperitoneal Escherichia coli LPS administration
as a simulated pro-inflammatory stimulus. RESULTS: Macrophage arginase activity
increased in vitro in response to catecholamines or LPS (P < .05). Propranolol
pretreatment blocked macrophage arginase activity induced by epinephrine (10
mumol/L) in vitro (P < .05). Trauma or LPS alone increased splenic arginase
activity in vivo (P < .05). Propranolol did not alter LPS-induced splenic
arginase activity but did significantly reduce trauma-induced splenic arginase
activity (P < .05). CONCLUSIONS: Catecholamines alone increase macrophage
arginase activity through beta-adrenoceptor activation. Increased splenic
arginase activity induced by moderate trauma is decreased by beta-adrenoceptor
blockade, suggesting that trauma-induced arginase activity is partly mediated by
endogenous catecholamines.
PMID- 10776433
TI - Trauma increases extrahepatic arginase activity.
AB - BACKGROUND: Although expressed primarily in the liver, arginase activity also is
present in extrahepatic tissues and specifically in macrophages, where it may
play diverse physiologic roles in wound healing, cellular proliferation, and the
regulation of nitric oxide production. Arginase activity in immune cells is
upregulated by certain cytokines such as IL-4, IL-10, and TGF-beta and by
catecholamines. Since the release of these substances is increased after trauma,
we hypothesized that arginase activity would also be increased in immune cells
after trauma. The current work tests this hypothesis. METHODS: A model of
surgical trauma was created in C3H/HeN mice by performing an exploratory
laparotomy. Tissue arginase activity and arginase I protein expression were
determined. As a control, arginase activity and expression were also stimulated
with the use of endotoxin. In addition, we evaluated the expression of inducible
nitric oxide synthase and the accumulation of nitric oxide metabolites in plasma.
RESULTS: Surgical trauma was associated with a significant increase in arginase
activity in splenic and renal tissues (P < .05). Splenic macrophages from trauma
animals exhibited arginase activity levels approximately 10 times those of
controls (P < .05). Endotoxin alone increased arginase activity in the spleen,
but this increase was less than that of trauma alone (P < .05). Arginase activity
remained elevated after trauma for up to 4 days and normalized by day 7. Arginase
I expression was upregulated by trauma in both splenic and renal tissue and by
endotoxin in the spleen only. Despite upregulation of inducible nitric oxide
synthase in trauma animals, circulating nitric oxide metabolites were decreased 2
days after trauma compared with controls (P < .05). Endotoxin-induced nitric
oxide metabolites were also reduced in trauma animals compared with endotoxin
treatment alone (P < .05), but this normalized by day 4. CONCLUSIONS:
Extrahepatic arginase expression and activity is increased after trauma and may
provide the necessary precursors for cellular proliferation and repair or may
play a regulatory role in the production of nitric oxide.
PMID- 10776434
TI - Frequency and time course of pancreatic and extrapancreatic bacterial infection
in experimental acute pancreatitis in rats.
AB - BACKGROUND: Infectious complications in severe pancreatitis are the main factors
determining clinical course and outcome. The taurocholate model for acute
necrotizing pancreatitis was evaluated for frequency and time course of
pancreatic and extrapancreatic bacterial infection. METHODS: Sixty-five male
Wistar rats were divided into 5 groups of 13 animals each. Specimens for
bacteriologic examination were taken, and pancreatitis was induced by intraductal
infusion of 3% taurocholate under sterile conditions. Animals were killed 8, 16,
24, or 32 hours thereafter, and bacteriologic examination was performed. A
control group of animals with intraductal infusion of 0.9% saline solution were
killed after 32 hours. RESULTS: There was no significant pancreatic infection in
the control group and in the 8-hour group (1 of 13 rats). Sixteen and 24 hours
after induction of pancreatitis, infection and inflammation of the pancreas were
found in 77% (10 of 13 rats), and after 32 hours pancreatic infection occurred in
69% (9 of 13 rats). Extrapancreatic bacterial infection after 16 hours occurred
in the liver (62%), spleen (62%), and mesenteric lymph nodes (46%). Bacteria
infecting the pancreas reflected the bacterial spectrum of the large bowel and
terminal ileum before induction of pancreatitis (Escherichia coli [77%], Proteus
[43%], Enterococcus [37%], and Staphylococcus [23%]). CONCLUSIONS: Pancreatic
infection is an early and frequent finding in the taurocholate model of acute
necrotizing pancreatitis. Infection occurs between 8 and 16 hours after induction
of pancreatitis. The source of infecting bacteria seems to be the large bowel or
the terminal ileum. We present a useful model of severe pancreatitis in which to
study bacterial translocation, the further route of spread, and therapeutic
approaches.
PMID- 10776435
TI - Fistulation method: simple and safe pancreaticojejunostomy after
pancreatoduodenectomy.
AB - BACKGROUND: A pancreatic leak from the pancreaticojejunostomy after
pancreatoduodenectomy has a potential risk of serious complications. We devised a
simplified fistulation method for pancreaticojejunostomy. METHODS: The
fistulation method, which uses a pancreatic drainage tube as a stent without
pancreatic duct-to-jejunal mucosa anastomosis, was applied to 162 consecutive
patients. They were divided into 3 groups according to the state of the
pancreatic remnant: group 1, soft and normal parenchyma (n = 71); group 2, firm
and thickened parenchyma (n = 40); group 3, hard and atrophic parenchyma (n =
51). The consistency in relation to the incidence of pancreatic leak and
mortality were analyzed. Morphologic changes of the pancreatic remnant in long
term survivors of group 1 were assessed with computed tomography. RESULTS: A
pancreatic leak occurred in 3 patients from group 1, in 2 patients from group 2,
and in no patients from group 3 (leak rate, 3%). No operative mortality and 5
hospital deaths (3%) unrelated to a pancreatic leak were observed. The parenchyma
of the pancreatic remnant was well preserved in 52% of the long-term survivors
and the pancreatic duct was not dilated in 63%. CONCLUSIONS: The fistulation
method can be performed safely and easily regardless of the state of the
pancreatic remnant, and it provides every surgeon with a low incidence of
pancreatic leak among patients.
PMID- 10776436
TI - Effect of uric acid on liver injury during hemorrhagic shock.
AB - BACKGROUND: It remains unproven whether nitric oxide (NO) exerts a toxic effect
on hepatocytes directly or through the formation of a more toxic compound during
hemorrhagic shock (HS). NO reacts at a very high rate constant with superoxide to
give peroxynitrite, a potentially toxic molecule. In this study, we investigated
whether or not peroxynitrite contributed to tissue injury in the liver during HS.
METHODS: Male Sprague-Dawley rats were subjected to decompensated HS followed by
resuscitation. In addition to the time course of tissue injury and inducible NO
synthase (iNOS) messenger RNA (mRNA) expression in the liver during HS, we
investigated the effect of N6-(iminoethyl)-L-lysine(LNIL) (a specific inhibitor
of iNOS) and also that of uric acid (a natural scavenger of peroxynitrite) on
tissue injury and nitrotyrosine formation (a footprint of peroxynitrite) in the
liver. RESULTS: The liver injury, evaluated by plasma aminotransferase levels and
histology, became evident at the end of the shock period and had significantly
increased 1 hour after the start of resuscitation (Shock-1 h). There was no iNOS
mRNA expression in the liver at baseline, and it had clearly increased by Shock-1
h. Treatment with LNIL or uric acid significantly attenuated the tissue injury
with a prominent reduction in nitrotyrosine formation in the liver. CONCLUSIONS:
These lines of evidence suggest that one of the mechanisms by which NO production
causes liver injury during HS may be its reaction with superoxide to form
peroxynitrite.
PMID- 10776437
TI - Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes
in a bioartificial liver.
AB - BACKGROUND: This study was designed to determine if an anti-necrotic compound,
glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and
function of hepatocytes in a bioartificial liver. METHODS: Isolated rat
hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and
cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine
alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of
glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined
after anoxic exposure (0-20 hours). Cell functionality (measured by urea
production), cell viability (quantitated by vital staining with fluorescein
diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified
by electron microscopy and DNA fragmentation studies) were determined for each
condition. RESULTS: The viability of GERH declined gradually and then stabilized
12 hours after hepatocyte isolation. The rate of urea production by GERH was
directly proportional to the number of viable hepatocytes. Apoptotic death
predominated at low cell density, and necrotic cell death became significant at
high cell density. Hepatocyte necrosis became more significant after exposure to
longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose
dependent cytoprotection to GERH with an optimum benefit at a concentration of 60
mumol/L. After anoxic exposure or under high cell density culture, glycine
demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3
mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive.
CONCLUSIONS: The metabolic activity of a hepatocyte bioartificial liver may
benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.
PMID- 10776438
TI - Gadolinium pretreatment decreases survival and impairs liver regeneration after
partial hepatectomy under ischemia/reperfusion in rats.
AB - BACKGROUND: Modulation of Kupffer cell functions by treatment with gadolinium
chloride protects the liver against reperfusion injury. However, its effect on
liver regeneration after hepatectomy under ischemia/reperfusion has not been
studied. Using a common clinical ischemia/reperfusion technique, we examined the
effect of gadolinium on liver regeneration after hepatectomy in rats. METHODS:
After an initial 15-minute ischemia and 15-minute reperfusion, 70% hepatectomy
was performed during the second 15-minute ischemia period in gadolinium
pretreated (gadolinium group) and saline solution--pretreated (control group)
rats. The 24-hour survival rate, relative liver weight, DNA synthesis rate, and
hepatic adenosine triphosphate level were examined immediately after hepatectomy
and on postoperative days (PODs) 1, 2, 3, and 7. Serum levels of total bilirubin,
glutamic pyruvic transaminase, and endotoxin were also measured. RESULTS: The 24
hour survival rate was significantly lower in the gadolinium group (67%) than in
the control group (100%). On POD 1, the relative liver weight and DNA synthesis
rate were significantly lower in the gadolinium group than in the control group.
On POD 1, serum total bilirubin and endotoxin levels were significantly higher in
the gadolinium group than in the control group. Immediately after hepatectomy,
the hepatic adenosine triphosphate level was significantly lower in the
gadolinium group than in the control group. CONCLUSIONS: Under
ischemia/reperfusion, gadolinium pretreatment impairs liver regeneration and
energy status after hepatectomy and decreases postoperative survival.
PMID- 10776439
TI - The lidocaine (MEGX) test as an index of hepatic function: its clinical
usefulness in liver surgery.
AB - BACKGROUND: The purpose of this study was to evaluate the clinical usefulness of
the lidocaine test, as an index of hepatic function, in the different fields of
liver surgery. METHODS: The lidocaine (MEGX [monoethylglycinexylidide]) test,
which was performed in 200 patients with different liver diseases and in 23 organ
donors, was compared with common laboratory tests. The MEGX value was related to
postoperative complications in patients who undergo liver resection and to the
survival of patients with cirrhosis who are awaiting transplantation. In organ
donors, the test was related to the outcome of patients who underwent
transplantation. RESULTS: The MEGX value was significantly higher in patients
without cirrhosis compared to patients with cirrhosis (77.8 +/- 25 ng/mL vs 35.6
+/- 30 ng/mL; P < .05); among patients with cirrhosis, there was a significant
difference between those patients classified Child A and those classified Child B
and C (43.3 +/- 25 ng/mL vs 11.5 +/- 7.1 ng/mL; P < .05). The patients classified
Child A who underwent liver resection with MEGX value less than 25 ng/mL had a
significantly higher rate of postoperative complications compared with other
patients (P < .001). Patients with cirrhosis who were awaiting liver
transplantation and who had a MEGX value of less than 10 ng/mL had a life
expectancy of no longer than 1 year. CONCLUSIONS: The MEGX test is a reliable
index of hepatic function. Patients carrying hepatocellular carcinoma with MEGX
value of less than 25 ng/mL have a high risk of liver insufficiency after hepatic
resection. Patients with decompensated cirrhosis who have an MEGX value of less
than 10 ng/mL should undergo transplantation as soon as possible.
PMID- 10776440
TI - Gallbladder carcinoma with a tumor thrombus in the common bile duct: an unusual
cause of obstructive jaundice.
PMID- 10776441
TI - Small bowel obstruction resulting from mesh plug migration after open inguinal
hernia repair.
PMID- 10776442
TI - On the lung injury and disseminated intravascular clotting seen after liver
trauma.
PMID- 10776443
TI - Endoscopic ultrasonography in the evaluation of thyroid cancer invasion into the
esophagus.
PMID- 10776444
TI - Comparison of hypergravity and microgravity effects on rat physiology: an
overview.
PMID- 10776445
TI - Comparison of hyper- and microgravity on rat muscle, organ weights and selected
plasma constituents.
AB - BACKGROUND: Centrifugation has been proposed to be one possible countermeasure
for the skeletal muscle, organ, hormonal, and plasma chemistry adaptations
associated with chronic unloading (e.g., during spaceflight). HYPOTHESIS: Our
hypothesis was that there would be a continuum of physiological and morphological
responses from zero gravity to hypergravity. METHODS: Adult male rats were
centrifuged continuously at 2G for 14 d and the weights of limb muscles and
organs, and the levels of plasma constituents were compared with the same
measurements from rats flown on a 14-d spaceflight (Cosmos 2044). RESULTS: Mean
body weights of centrifuge rats did not change, whereas age-matched controls grew
21%. There was a sparing of muscle protein in the centrifuge rats; the absolute
weights of predominantly slow muscles in the hindlimb were maintained and the
relative weights (expressed relative to body weight and as a percent difference
from control) of almost all muscles studied were larger than control. In
contrast, spaceflight resulted in a decrease in the relative weights of most
extensor, but not flexor, hindlimb muscles studied. Relative organ weights, in
general, were elevated in centrifuge rats compared with control rats. Relative
organ weights in flight rats were similar to control, except for a decrease in
testes weight. Plasma thyroxine and testosterone levels were significantly
reduced following flight, whereas only thyroxine was decreased after
centrifugation. Centrifugation resulted in a decrease in most other plasma
chemistry measurements, whereas flight rats showed no change or an elevation in
these measures. DISCUSSION: These data indicate that the physiological responses
to micro- and hypergravity are often in the opposite direction, suggesting that
in general there is a continuum of physiological and morphological effects from
microgravity to 1G to hypergravity. These data further suggest that the
imposition of hypergravity conditions on animals that are in a microgravity
environment may have a beneficial effect in maintaining some physiological
systems at or near control levels.
PMID- 10776446
TI - Effect of centrifugation at 2G for 14 days on metabolic enzymes of the tibialis
anterior and soleus muscles.
AB - BACKGROUND: The enzyme composition of different muscle types vary greatly,
leading to different changes of enzyme level caused by exposure to various
stimuli. METHODS: Male Wistar rats were centrifuged at 2G in a 12-ft radius
centrifuge for 14 d. Tibialis anterior (TA) and soleus muscles from four
centrifuge and four control rats were analyzed for three enzymes characteristic
of fast twitch muscles (phosphofructokinase, glycerol-3-phosphate dehydrogenase,
and pyruvate kinase), and four enzymes characteristic of slow twitch muscles
(hexokinase, mitochondrial thiolase, B-hydroxyacyl CoA dehydrogenase, and citrate
synthase). RESULTS: The centrifuged TA muscles lost 15% of their weight; the
corresponding soleus muscles gained 4%. Calculated on the basis of dry weight,
the fast twitch enzyme activities were reduced 3-15% in the TA muscles but
increased 10-23% in the soleus muscles. The slow twitch enzymes were reduced 18
30% in TA muscles but were almost unchanged in the soleus muscles. When
calculated on the basis of total muscle weight, all of the enzymes in TA muscles
were significantly reduced by centrifugation. In contrast, in soleus muscles, on
the basis of total muscle weight, centrifugation caused an average increase of
22% in the fast twitch enzymes but only marginal changes in the slow twitch
enzymes.
PMID- 10776447
TI - The effects of increased gravity and microgravity on cardiac morphology.
AB - BACKGROUND: Our previous study of rats exposed for 14 d to microgravity on Cosmos
2044 revealed morphological changes consistent with cardiac atrophy. METHODS: In
the current comparison study, light and electron microscopic studies were
performed on cardiac muscle from 10 rats exposed to hypergravity (continuous
centrifugation at 2G) for 14 d. RESULTS: Myofiber area was significantly greater
in the 2G papillary muscle as compared with muscle from 10 control rats of the
same strain and size. This contrasts with the significant decrease in myofiber
area previously seen in the rats exposed to microgravity. At the electron
microscopic level, general morphological features were similar in both groups and
resembled tissue from control rats from the previous Cosmos studies. However,
mitochondria from papillary and ventricular muscle from the 2G rats revealed
signs of fatigue typical of the early stage of hypertrophy. These results are
consistent with a state of adaptive cardiac hypertrophy for the 2G group.
PMID- 10776448
TI - Cortical bone responses to 2G hypergravity in growing rats.
AB - BACKGROUND: Rat cortical bone adaptation to chronic hypergravity (2G) was studied
using young growing male Wistar rats (60 d). METHODS: Animals (10 rats) were
subjected to chronic hypergravity (14 d) in order to understand the plastic
nature of bone under a constant hypergravity stress using a special rodent
habitat that was attached to a 12-ft. radius centrifuge. Also, an equal number of
stationary controls were housed in a rodent vivarium containing identical cages
that were used for centrifugation. After 14 d of centrifugation, femur bones were
excised and prepared for morphological and biochemical measurements. RESULTS:
Results showed that 2G had significantly shortened the femurs (3%) and reduced
the cortical bone area (13%). In particular, hypergravity induced significant
reductions in the thicknesses of cortical bone at the anterior (13%) and medial
regions (15%) of the mid-diaphysis. However, femoral bone density, collagen and
calcium concentrations were unaltered. The content of mature, stable bone
collagen cross-links hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), were
significantly greater in bones from centrifuged animals. CONCLUSION: Our findings
suggest that short term exposure to 2G does not enhance bone formation or induce
changes in cortical bone composition, or alter specific gravity. These data also
suggest that bone maturation as reflected by collagen cross-linking is
upregulated. However, it is undetermined at this time whether the enhanced
content of mature bone collagen in the centrifuged rats is a result of either an
increased rate of cross-linking or reduction in the degradation of "older
collagen."
PMID- 10776449
TI - Effects of 2 weeks hypergravity on the composition of the intervertebral disc.
AB - BACKGROUND: The effects of loading on connective tissues similar to the
intervertebral disk have primarily been studied using articular cartilage organ
culture in vitro techniques. The effects of in vivo loading on the intervertebral
disk are less well documented. METHODS: The lumbar annuli of rats centrifuged at
2G for 2 wk were compared with those of similar rats kept under analogous
conditions at 1G. The studies involved the water, hydroxyproline (collagen), and
uronic acid (proteoglycan, PG) content of the L4-5 and L5-6 annuli. Comparisons
were also made between the 2G animals and the previous Cosmos 2044 spaceflight
animals at 0G. RESULTS: The water content of annuli did not differ between the
control and 2G annuli; however, the PG content of the tissue was decreased in the
2G animals and the collagen content slightly increased, resulting in an increased
collagen-PG ratio in the 2G animals. When the annuli were immersed in water for 2
h, more PG leached from the annuli of the 2G animals than the control animals,
suggesting an alteration in the nature of the PG population comprising the
annuli. Interestingly, the direction of changes in the 2G annuli was identical to
that of the previous Cosmos 2044 0G animals when they were compared with their
respective controls. Therefore, directly opposite experimental conditions (2G and
0G) produced similar results. CONCLUSION: Previous studies regarding PG synthesis
and content in cartilaginous tissues suggest alterations in intratissue pH and
hydration to be among the factors involved in controlling the PG population. If
the observed changes are permanent, they may affect the integrity of the
intervertebral disk although it is likely they are totally reversible on return
to 1G after an interim period, providing injuries are avoided.
PMID- 10776450
TI - Cyclic AMP-receptor responses to hypergravity.
AB - BACKGROUND: Altered gravity (G) encountered during spaceflight causes physiologic
changes in humans and in experimental animals. In addition to weightlessness (0G)
in space, sharply increased G forces are exerted on the spacecraft during the
lift-off and reentry phases. Previous studies showed major changes in cAMP
associated activity of rat heart muscle after spaceflight, indicating that
(hormone) signaling pathways may have been affected. HYPOTHESIS: The present
study was designed to test the hypothesis that cAMP-related cellular responses of
exocrine glands after simulated hypergravity (centrifugation at 1.7G) differ from
the effects of 0G. METHODS: A portion of the parotid and lachrymal gland tissue
was fixed for morphologic and immunocytochemical study, and another was used for
biochemical determinations. A short-term tissue culture was established from each
gland to determine the effects of stimulation by norepinephrine. Heart muscle
(ventricle) was also studied. Soluble and particulate fraction extracts of tissue
homogenates were prepared, photoaffinity labeled with the [32P]8-N3-analog of
cAMP, proteins separated by electrophoresis and the cAMP-reactive proteins (cARP)
identified by autoradiography. RESULTS: Differences were seen in protein banding
patterns of the gland extracts and in altered cARP distribution in the 1.7G
samples of heart ventricle and exocrine gland tissues, when compared with 1G
controls. In the heart, cARP increased in the soluble fraction, while the
particulate fraction extract showed no change. In acinar cells of the parotid,
labeled cARP had accumulated, but decreased after stimulation to the level of the
1G controls. Immunogold labeling showed an increased content of amylase in the
secretory granules of the 1.7G animals, while morphologic observation revealed
few changes in the structure of parotid acinar cells. The response in the
lachrymal gland was translocation of an isoform of cARP from the particulate to
the cytoplasmic compartment. CONCLUSIONS: Changes distinct from those due to 0G,
but specific for hyper-G were found in cARP activity, protein synthesis, as well
as in an apparent inhibition of regulated secretion.
PMID- 10776451
TI - Rat anterior pituitary hormone cells: responses to variable gravity.
AB - BACKGROUND: While life science data dealing with effects of hypogravity are
accumulating, relatively little is known about the effects of hypergravity at the
level of either the whole animal or the individual cell. The purpose of this
experiment was to compare data collected on cells of anterior pituitaries from
animals centrifuged at 2G using an experimental design that was identical to that
of a spaceflight experiment performed in 1989. HYPOTHESIS: Centrifugation of the
animal at 2G for 14 d alters the function and morphology of cells of the anterior
pituitary in subsequent in vitro tests at 1G. METHODS: Intact rats were
centrifuged at twice Earth's gravity for 14 d in a specially designed animal
centrifuge as part of the Cosmos 2G study. This study was designed to replicate a
previous spaceflight experiment so that direct comparisons between hyper-
(centrifugation, 2G) and hypogravity (spaceflight, 0.001G) could be made.
Anterior pituitary cells were then evaluated for cell function and morphology in
a variety of post-flight tests. RESULTS: Growth hormone cells from centrifuged
animals released less bioactive, but not immunoreactive, growth hormone (GH) than
cells from non-centrifuged animals. This was also true for GH released in
response to provocative stimulation by a synthetic peptide (growth hormone
releasing hormone, GHRH) that causes GH release after binding to cell membrane
receptors. Cell morphology was also different between cells from centrifuged and
control animals; cells in the experimental group were smaller and less
granulated. However, another type of hormone-producing cell contained in these
preparations, viz. prolactin cells, was not affected by centrifugation.
CONCLUSIONS: Centrifugation of animals for 14 d alters both the in vitro release
of GH and GH cell morphology relative to corresponding controls from non
centrifuged animals. Because prolactin cells are not affected by centrifugation,
the response is specific to the GH cell.
PMID- 10776452
TI - Adaptation of rat gastrocnemius muscles to 2 weeks of centrifugation: myofibers
and extracellular matrix.
AB - BACKGROUND: The effect of 2 wk of exposure to centrifugation (2G) on
gastrocnemius muscles of rats was investigated by morphometric and computer
assisted image analysis of muscle fiber areas and non-contractile tissue
components (extracellular matrix). RESULTS: Muscle atrophy was seen in the
myofibers from 2G rats which had decreased in cross-sectional area by 26%. In
contrast, the non-contractile tissue component actually increased by 13%. These
results were compared with soleus muscle atrophy seen following 2 wk of unloading
by tail-suspension. In all cases, the extracellular matrix increased in
proportion to the decrease in fiber area. A theoretical model was developed to
assess the effect of changes in myofiber cross-sectional area on the relative
content of the extracellular matrix. The experimental results from both rat
gastrocnemius and soleus muscles were consistent with the model with slight
variations due to the known differences in connective tissue content of different
muscles in the rat. CONCLUSION: Thus, the gastrocnemius muscle atrophy seen after
2 wk of centrifugation results from loss of contractile and other myofiber
specific proteins while the extracellular matrix remains relatively constant. The
loss in myofiber content was greater than expected from changes in muscle wet
weight and more than required to adapt to a decrease in body weight.
PMID- 10776453
TI - Hypergravity does not affect testicular function.
AB - BACKGROUND: A previous study revealed that exposure of rats to microgravity for
14 d on Cosmos 2044 reduced production of testosterone by > 80%, although
spermatogenesis remained essentially normal. METHODS: To ascertain if testicular
function was altered in hypergravity, 60-d-old rats were randomly assigned to 2
groups (10 per group) and subjected to 14 d of centrifugation to expose them to a
total of 2G, or held at unit gravity in similar cages without centrifugation
(control). RESULTS: After 14 d, body weight of 2G rats was essentially unchanged,
whereas that of control rats had increased; 310 vs. 377 g (p < 0.05). Testes
weight, production and secretion of testosterone, diameters of seminiferous
tubules and their lumina, data from subjective evaluation of spermatogenesis, and
counts of homogenization-resistant spermatids all were similar for 2G and control
rats. CONCLUSION: It was concluded that exposure of male rats to 2G for 14 d had
no major effect on testicular function whereas, based on earlier studies,
exposure to microgravity (< 10(-3) x gravity) for 11-14 d suppressed production
of testosterone by Leydig cells and reduced concentrations of anabolic steroids
available to peripheral tissues.
PMID- 10776454
TI - Reduction of pituitary AVP and OT contents in rats following spaceflight.
AB - BACKGROUND: Responses of pituitary concentrations of vasopressin (AVP) and
oxytocin (OT) during spaceflight have been variable, possibly due to differences
in flight conditions or in age and strain of flight animals. METHODS: We reviewed
findings of three space-flights of varying flight and recovery durations in which
rats of different ages and strains were used. Male rats ranging in weight from
248-396 g were flown in space for 7-14 d. Flight animals were then compared with
vivarium controls and synchronous controls. Parallel ground-based studies
(hypergravity and simulated hypogravity) were conducted. RESULTS: Pituitary
content of AVP was significantly (p < or = 0.05) decreased by spaceflight (6.3 +/
0.3 micrograms.mg-1 protein in flight vs. 8.3 +/- 0.5 micrograms.mg-1 protein in
vivarium). OT content was also reduced during spaceflight (4.3 +/- 0.2
micrograms.mg-1 protein in flight vs. 6.1 +/- 0.3 micrograms.mg-1 protein in
vivarium). Vivarium and synchronous control rats showed no difference in
pituitary contents. Flight duration or recovery times did not appear to influence
pituitary hormone contents. Strain of rat had an effect on content but not on
responses to spaceflight. Age of animals confounded the response to spaceflight:
pituitary contents of AVP and OT were not altered in young animals (< or = 60 d
old). Hindlimb suspended animals showed no difference in AVP but OT content was
decreased. Ground-based exposure to hypergravity (2 G) did not alter content of
AVP or OT in young animals. CONCLUSIONS: Decreases in pituitary content of AVP
and OT with spaceflight may be due to a variety of factors unique to the
microgravity environment. Differences between studies may be due in part to
differences in size and age of rats used.
PMID- 10776455
TI - Ivan Petrovich Pavlov (1849-1936)
PMID- 10776456
TI - Neural regulation of glucose homeostasis.
AB - The regulation of blood glucose is generally stated to be under the control of
the endocrine system. But the endocrine secretion is itself regulated by the
central nervous system, especially the hypothalamus. The brain can sense the
energy status of the body by using neural afferent signals and metabolic cues
such as glucose. A variety of experimental evidences have been put forth to
support the postulate that there are "glucoreceptors", sensitive to blood glucose
and glucose utilization, in the hypothalamus. Gastrointestinal afferents, which
carry information about the energy intake, reach the hypothalamic regions and
interact with the glucose sensitive mechanisms. Available evidence suggests that
obesity and decreased body weight, resulting from lesions of the hypothalamic
'satiety' and 'feeding' centres respectively, are not only due to altered food
intake, but also to derangement in glucose homeostasis. The medial preoptic area
does the fine tuning of energy balance (regulation of food intake) in response to
alterations in the temperature, locomotor activity and sleep wakefulness. Thus
the hypothalamus regulates energy balance through its control of energy intake on
the one hand, and its expenditure and storage on the other. Neuroendocrine system
and autonomic nervous system deal with storage and expenditure of energy.
PMID- 10776457
TI - Averaged evoked potentials: event related potentials (ERPs) and their
applications.
AB - Endogenous potentials are evoked responses that occur independent of the stimulus
evoking them. They are related to different aspects of information processing.
Two types of event related potentials (ERPs) are recorded, the P300 wave and
contingent negative variation (CNV). The P300 wave is the most frequently studied
factor in various clinical diseases and also for neurological research. Different
tasks, paradigms can be used of which the oddball paradigm, consisting of target
and non-target stimuli and their variations is most popular. The effect on P300
of physiological factors like age, IQ, pregnancy, exercise and others along with
the clinical application in various neurophysiological and psychiatric disorders
are discussed. This review deals with various aspects of (ERPs), their
methodology with a broad view of the scope and clinical horizon as regard their
application in neurophysiological research.
PMID- 10776458
TI - The characteristics and determinants of maximal expiratory pressure in young,
healthy, Indian males.
AB - Maximal expiratory pressure (MEP) can be used as an index of respiratory muscle
strength and of the ability of an individual to cough effectively. The influence
of anthropometry, nutritional status and ethnicity on MEP was studied in 113
young healthy Indian males and 53 Tibetans between 18 and 30 years of age. All
subjects underwent an anthropometric assessment. Anthropometric variables (BMI,
log BMI) explained only 12.5% of the variance in MEP. MEP was significantly lower
in chronically undernourished subjects when compared with anthropometrically
similar underweight subjects (P < 0.05). The Indian subjects had significantly
lower MEP's than BMI matched Tibetan subjects (P < 0.01). This difference may
have been due to the higher chest circumferences in the Tibetans (P < 0.01).
While general muscle strength (maximal hand grip) and MEP were significantly
correlated (r = 0.26, P < 0.01), the strength of the correlation was relatively
low, suggesting that the determinants of the two measures were considerably
different.
PMID- 10776459
TI - Increased sweet taste preference following the lesion of basolateral nucleus of
amygdala (BLA) in rat.
AB - A study of gustatory preference was carried out in Wistar strain albino rats by
electrolytically lesioning the basolateral nucleus of amygdala. The intake of
sweet tasting saccharin (Sn-0.1% soln w/v), NaCl solutions (1% Soln w/v) and tap
water, were tested in single bottle, 2 bottle choice and 3 bottle choice
situations. The consumption of fluids both before and after the stereotaxic
surgery was recorded and statistically analysed. Lesion of BLA increased the
intake of all fluids in the single bottle tests (P < 0.01). But the increase in
the group provided with saccharin was more than that in other two groups. When
taste preference was tested using 2-bottle and 3-bottle choice situations, the
lesioned rats were seeking Sn solution. In our previous study, we found that the
lesion of BLA increased fluid intake in rats. The intake, in the present study
was more in those animals provided with Sn solution. When choice was given, the
rats shifted their preference from water to the Sn following the lesion. Thus
this study confirms that BLA is involved in the preference for sweet tasting
solution over the NaCl or plain water.
PMID- 10776460
TI - Neuronal responses of periaqueductal gray to peripheral noxious stimulation.
AB - Central pathways transmit pain from peripheral regions to one of the most
important area of the descending pain modulatory system, the Periaqueductal gray
(PAG). Independent discoveries in the past suggest that the PAG contains afferent
input, output neurons and intrinsic interneurons. An attempt was made in the
present study to find out the effects of more than one kind of noxious stimulus
on the PAG neuronal activity. Experiments were conducted in rhesus monkeys and
the effects of noxious mechanical, thermal and tooth-pulp stimulation on the
activity of 14 neurons were studied. The neurons responded to more than one kind
of noxious stimuli by increasing or decreasing its firing rate. No limb
specificity could be identified and homogeneous distribution of the excitatory
and inhibitory neurons was found.
PMID- 10776461
TI - Yoga training and motor speed based on a finger tapping task.
AB - A finger tapping task was used to assess motor speed (MS) of both hands in 53
adults and 152 children before and after yoga training and in 38 adults of a non
yoga (control) group. All subjects were right hand dominant. The 30-second
tapping speed (TS) test was considered as three time intervals, i.e. 0-10 second
(TS1), 10-20 seconds (TS2) and 20-30 seconds (TS3). There was a significant
(Student's t-test) increase in all three TS values following 10 days of yoga in
children and 30 days of yoga in adults. However for both groups at baseline and
final assessments, TS2 and TS3 were significantly lower than TS1. Hence the TS
was increased after yoga training during the first 10-seconds of the test but not
during the next 20 seconds. These results suggest an increase in motor speed for
repetitive finger movements following yoga training, but not in strength or
endurance, as the increase was not sustained over 30 sec.
PMID- 10776462
TI - Sudomotor sympathetic hypofunction in Down's syndrome.
AB - General sympathetic dysfunction has been proposed as an explanation for the
inability to reach normal heightened attention in Down's syndrome (DS). The
present study on 15 DS subjects (group average age +/- SD, 14.3 +/- 3.6 years; 11
males) and in an equal number of age- and gender-matched normal subjects (NS),
evaluated activity in different subdivisions of the sympathetic nervous system.
DS subjects had (i) lower skin conductance levels (i.e., lower sudomotor
sympathetic activity) and (ii) higher heart rates than NS. In response to
auditory stimuli, DS subjects showed abnormal SSR responses (also indicating
sudomotor sympathetic activity) but normal cutaneous vasoconstriction. Hence the
results suggest that sympathetic dysfunction in DS is restricted to the sudomotor
subdivision, activity of which has been associated with attention and
recognition.
PMID- 10776463
TI - Spirometric impairments in undernourished children.
AB - The present study elucidates the effect of undernutrition on pulmonary functions
in children. The study was carried out in healthy normals, wasted, wasted and
stunted children. Spirometry was performed with Vitalograph Compact-II
spirometer. Wasted, wasted and stunted children showed lower lung volumes, forced
mid expiratory flow time and inspiratory flow rates than healthy normals. Wasted
and stunted children had lower VC, FVC and FIF50% than wasted children. The
reduction in lung volumes and flow rates in wasted children may be due to
ventilatory muscle wasting. But in wasted and stunted children along with
muscular wasting diminished skeletal growth is also a reason for lower lung
functions. No airflow limitation was observed in undernourished children.
PMID- 10776464
TI - A synergistic decline in humoral and cellular immunity of diabetic mice on
exposure to polluted air.
AB - It is clinically known that diabetic patients are more prone to infectious
diseases, due to low immune status. Since, some of the common air pollutants are
reported to suppress immune system, how exposure to artificially polluted air
influences the immune responses in experimental diabetic mice was studied. A
diabetic state was induced by alloxan and mice were exposed to artificially
polluted air for 30 days. During the period of exposure, the humoral (antibody
titer) and cellular (foot and swelling) immune responses to antigenic challenges
with sheep RBC were investigated. The exposure to polluted air produced a
significant decline in the immune responses in non-diabetic mice whereas a
synergistic decline was observed in diabetic group. Since, daily oral treatment
with vitamin E (150 mg/kg) significantly prevented the pollution induced
immunosuppression, the involvement of free radicals is suggested.
PMID- 10776465
TI - Effects of L-arginine on picrotoxin-induced increase in brain ammonia
concentrations and convulsions in rats.
AB - The effect of L-arginine (840 mg/kg) pre- (30 min before challenge) and post
treatment (5 min after challenge) period was tested on picrotoxin-induced
increase in ammonia concentrations in brain regions (cerebral cortex, brain stem
and cerebellum) and the accompanying convulsive responses in adult male rats. The
combined effect of L-arginine and diazepam was also tested against picrotoxin
induced convulsions. Picrotoxin-induced increase in ammonia was reverted
partially by L-arginine pretreatment. However, L-arginine pretreatment did not
show anticonvulsant effect independently or concurrently with diazepam. On the
other hand, L-arginine post-treatment reverted ammonia to control level in all
brain regions. A partial but significant inhibition of convulsion responses was
found in these animals. The combined effect of diazepam and L-arginine post
treatment was much greater than that produced by these agents independently.
These findings suggest that ammonia has a partial but significant participation
in the convulsant action of picrotoxin. L-arginine has a potential to revert
brain ammonia to control level in picrotoxin-treated animals and thereby it has
produced a partial protection. The data further indicate that the duration of
action of L-arginine is considerably short and has an additive anticonvulsant
action with diazepam.
PMID- 10776466
TI - Bronchodilatory and anti-allergic effect of PulmoFlex--a proprietary herbal
formulation.
AB - PulmoFlex, a poly-herbal anti-asthmatic formulation has been reported to possess
antihistaminic, mast cell stabilizing, anti-anaphylactic and antiallergic
properties in experimental animals and clinical trials. The present study was
undertaken to determine the effect of PulmoFlex on isolated perfused rat lung.
The lung tissues were perfused at a pressure of 50 mmHg using oxygenated Krebs
solution at 37 degrees C. PulmoFlex (1 & 2 mg/ml) increased the pulmonary
perfusion flow indicating its bronchodilatory action. PulmoFlex (500 mcg)
significantly prevented histamine (50 mcg), acetylcholine (50 mcg) and C-48/80
(10 mcg), induced bronchoconstriction indicating its antihistaminic,
anticholinergic and mast cell stabilizing actions on pulmonary vascular beds and
bronchioles, respectively. Lung tissue of sensitized (BSA) rats treated with
PulmoFlex (20 mg/kg x 10 days) showed better perfusion following Ex vivo
antigenic challenge as compared to untreated rats. This indicates the possibility
of suppression of IgE mediated immune reaction by PulmoFlex. Thus, the present
findings, suggest that PulmoFlex acts as an antiasthmatic by its bronchodilatory,
membrane stabilizing, antihistaminic, anticholinergic and immunomodulatory
(reaginic antibody mediated) effects.
PMID- 10776467
TI - The effect of acute noise stress on neutrophil functions.
AB - The effect of acute noise stress on albino rats was studied by estimating the
plasma corticosterone level, total leukocyte count and differential leukocyte
count. Neutrophil function was assessed by Candida phagocytosis and Nitroblue
tetrazolium reduction test. The total leukocyte count was significantly
decreased. No significant changes were observed in the differential count of the
leukocytes. A significant increase in the plasma corticosterone level, Candida
phagocytosis and Nitroblue tetrazolium reduction was observed indicating acute
noise to be a potent stressor in albino rats.
PMID- 10776468
TI - Ventilatory functions in stone quarry workers of Rajasthan.
AB - Ninety two stone quarry workers from nearby villages of Jodhpur town were,
assessed for their lung functions which included measurement of Forced vital
capacity (FVC), Forced expiratory volume in Ist second (FEV1), and Peak
expiratory flow rate (PEFR). A detailed questionnaire was administered to all the
workers, who were divided into group I (cutting the stone) and group II (loading
and unloading the stone) depending on the nature of their Job. The presenting
complaints included cough with sputum (55%), chest pain (79%), bodyache (31%) and
21% gave the history as suffering from tuberculosis. Comparison of the lung
function results between two groups indicated a significant decrement of FEV1 and
PEFR in group II as compared to group I workers. The observed lung functions were
also found to be lower on comparison with the normative data from Rajasthan.
However, no difference in observed lung function results of smokers and
nonsmokers were obtained. Thus the reported lower values of lung functions
independent of smoking habits, may be due to occupational stone dust exposure.
PMID- 10776469
TI - Antibiotic prophylaxis in elective cholecystectomy: a randomized, double blinded
study comparing ciprofloxacin and cefuroxime.
AB - A prospective, randomised and double blind study was undertaken to compare the
prophylactic efficacy of ciprofloxacin and cefuroxime in 155 patients undergoing
elective cholecystectomy. Patients with past history of jaundice or presence of
jaundice, diabetes mellitus, common bile duct stones and previous biliary tract
surgery were excluded. Patients were allocated to the following groups: group A
no antibiotic (n = 30); group B-ciprofloxacin (200 mg i/v before surgical
incision and a second dose after 12 hrs) (n + 45); group C-ciprofloxacin given
only post operatively (200 mg i/v, 12 hourly X 2 days followed by oral 500 mg
twice daily X 3 days) (n = 35); group D-cefuroxime (750 mg i/v before surgical
incision and a second dose after 12 hrs) (n = 45). Efficacy of the antibiotic was
defined as a patient being free of post operative wound infection. Maximum
numbers of infection occurred in group A (26.67%) and group C (25.71%). The
incidence of wound infection was significantly lower when ciprofloxacin was used
as prophylaxis (group B) than when used post operatively (group C) only (P <
0.05). Patients who received ciprofloxacin (group B) and cefuroxime (group D) as
prophylaxis had significantly reduced incidence of infection (4.44% and 6/67%
respectively); no statistically significant difference was found between these
groups. Ciprofloxacin could be used as prophylactic antimicrobial in elective
cholecystectomy in developing countries because of its effectiveness, economy and
ready availability.
PMID- 10776470
TI - Effect of Panax ginseng and diazepam on brain 5-hydroxytryptamine and its
modification by diclofenac in rat.
AB - Wistar male rats pretreated with anti-stress agents like, Panax ginseng (Pg) and
diazepam (Diaz) were stressed by restraining for 1 h and 5-HT content of brain
and hypothalamus as well as plasma corticosterone were measured
spectrophotoflurometrically. Diclofenac (DICLO), a prostaglandin (PG) synthesis
inhibitor was used to confirm the role of prostaglandin in restraint stress
induced elevation of central 5-HT correspondingly confirmed by elevation of
plasma corticosterone and modification of the above anti-stress agents. Pg, Diaz
and DICLO per se did not modify brain and hypothalamic 5-HT in control rats. But
they attenuated stress-induced elevation of brain and hypothalamic 5-HT. Anti
stress action of both Pg and Diaz reflected by inhibition of stress-induced
elevation of brain and hypothalamic content of 5-HT as also stress-induced
concurrent elevation of plasma corticosterone were further diminished by DICLO.
The mediatory action of 5-HT in anti-stress effects of Pg and Diaz may be
modulated through prostaglandins.
PMID- 10776471
TI - Hypoglycaemic and anti-oxidant activity of Salacia oblonga Wall. extract in
streptozotocin-induced diabetic rats.
AB - The petroleum ether extract of the root bark of S. oblonga Wall. (Celastraceae)
(SOB) was studied in streptozotocin (STZ) diabetic rats and anti-lipid
peroxidative activity of the same was studied in the cardiac tissue. SOB
prevented significantly the streptozotocin-induced hyperglycaemia and
hypoinsulinaemia. It also produced a significant decrease in peroxidation
products viz. thiobarbituric acid reactive substances (P < 0.001), conjugated
dienes (P < 0.05), hydroperoxides (P < 0.001). The activity of antioxidant
enzymes such as superoxide dismutase (P < 0.001), catalase (P < 0.001), GSHPxase
and GSSGRase was found to be increased in the heart tissue of diabetic animals
treated with SOB. These results suggest that S. oblonga root bark extract
possesses anti-diabetic and anti-oxidative activity in streptozotocin-diabetic
rats.
PMID- 10776472
TI - Possible reasons for spontaneous incidence of micronucleus in rodents.
PMID- 10776473
TI - Effect of N-acetylcysteine and sodium nitrite on myocardial reperfusion injury.
PMID- 10776474
TI - Basal autonomic functions in males and females.
PMID- 10776475
TI - The effects of regular exercise on lipid and lipoprotein profile in men.
PMID- 10776477
TI - Influence of different types of stress on selected cardiovascular parameters in
rats.
AB - Wistar strain male albino rats were exposed to different types of stressors like
isolation, immobilization, overcrowding and forced swimming, for a duration of
one day, 7 days, 15 days and 30 days and the effect on heart weight, adrenal
weight, heart rate, P-R interval and serum transaminase levels were studied.
There was a significant increase in the heart weight and adrenal weight in most
of the stress subgroups. Tachycardia was seen in all the types of stress upto 7
days, except in the case of overcrowding stress. Serum transaminase level
increased significantly in all the types of stress. Among the different types of
stress, immobilization and forced swimming had greater effect on the heart weight
and heart rate. Increase in the heart rate and heart weight was observed only in
the initial period of exposure to a stressor and when the animals were exposed to
a prolonged stressor like 15 days and 30 days, there was no further increase in
the heart weight and heart rate which may be due to the adaptation of the animal
to a chronic stressor.
PMID- 10776476
TI - A perspective of smooth muscle contractility through actions of vanadium
compounds.
AB - Smooth muscle contraction has a characteristic step-response with successive
additions of stimulating compounds, and instant reversal on withdrawing the
stimulus, indicative of an equilibrium situation wherein continuous, rapid
reactions are occurring. Vanadium compounds, ortho- and meta-vanadates,
decavanadate and peroxovanadate, were found to contract a variety of smooth
muscles. Their actions were analyzed with respect to activation of receptors,
increase in the intracellular calcium concentration, and increase in calmodulin
dependent myosin light chain phosphorylation leading to contraction. A new
perspective of smooth muscle contractility has emerged from the studies with
vanadium compounds suggesting control mechanisms involving phosphorylation for
contraction and redox for relaxation.
PMID- 10776478
TI - A simultaneous ex vivo model of embryogenesis: I. Organogenesis.
AB - In vivo culture of chick embryo was carried out to develop an experimental
interphase between in vitro and in vivo study of embryonic physiology. In the
process, a simultaneous model of vasculogenesis and organogenesis has been worked
out, which is impossible to achieve in mammalian system. Both early (40 hours of
incubation) and late (64 & 88 hours of incubation) hours of cultures were
conducted for morphological and morphometric studies. A new combination of stains
was used in place of conventional haematoxylin and eosin in 40 hours old whole
mount of embryos. Semithin plastic sections were etched for haematoxylin/pyronin
stain in addition to paraffin (both normal and enblock) sections. Specific stains
(histological, enzyme histochemical or immunohistochemical) were chosen according
to the specific organs/areas studied. Immunohistochemistry and NADPH-diaphorase
activity were standardized in whole-mount of embryos. Morphometry was done using
camera lucida and quantitative image analysis system. A parallel preparation of
extra embryonic whole-mounts, paraffin and semithin plastic sections with
different types of stainings provides evidence for the scope of the simultaneous
study of vasculogenesis. Thus the morphological and morphometric data presented
in this and the succeeding article describe the scope and avenues for the use of
ex vivo model in various aspects of embryonic physiology, preliminary drug
trials/metabolism, radiology, teratology and toxicology.
PMID- 10776479
TI - A simultaneous ex vivo model of embryogenesis: II. Vasculogenesis.
AB - Vasculogenesis was simultaneously studied with embryogenesis in in ovo chick
embryo culture, which was harvested at 40 hours. Endodermal cells and vascular
endothelial cells were studied using a new combination of stains,
immunohistochemistry (for nuclei and basement membrane) and NADPH-diaphorase
activity in whole-mounts, paraffin sections and etched semithin sections. The
model can be used for the study of developmental process of blood vessels as well
as embryonic physiology of blood vessels vis-a-vis organogenesis in response to
different angiogenic agents, drug trials, cancer therapy by angiostatic
chemicals/radiations and toxins. Considering that vasculogenesis/angiogenesis as
one of the fundamental phenomena in physiology, pathophysiology, toxicology and
pharmacology of developmental sciences, the model in developing embryo is
presented.
PMID- 10776480
TI - Hypothalamo-limbic involvement in modulation of tooth-pump stimulation evoked
nociceptive response in rats.
AB - The hypothalamo-limbic system has been implicated in recognizing the affective
significance of pain and elicitation of related emotional responses. Several
evidences from different studies support a role of these areas in endogenous
analgesic mechanisms for pain modulation as elucidated by different pain tests in
more than one animal model. In the above context, the aim of this study was to
investigate the relative effectiveness of the pain modulatory action of
hypothalamic and limbic structures in rat using similar stimulation parameters,
and studying the effect on tooth pulp stimulation evoked jaw opening reflex (TP
JOR). To achieve the objective, unilateral stimulation of hypothalamic (lateral =
LH; ventromedial = VMN; anterior = AH) and limbic areas (amygdala = AMYG;
hippocampus = HIPP) was done on the TP-JOR test. A significant reduction in the
amplitude of EMG recorded from the digastric muscle (dEMG) as a result of tooth
pulp stimulation was observed on stimulation of LH, VMN, AMYG and HIPP but not
from AH. Also, the magnitude of this effect was almost similar from these areas.
The results suggest that these areas (except AH) have an antinociceptive role in
tooth-pulp stimulation evoked pain response.
PMID- 10776481
TI - Effect of ethanol/arrack on the lipid metabolism of mammary gland during
pregnancy and lactation in rats.
AB - Female rats were exposed to arrack (12.0 ml/kg body weight/day) and ethanol (4.0
g/kg body weight/day) before conception and throughout gestation and lactation.
On 19th day of gestation and 21st day of lactation there was increase in the
cholesterol phospholipids, triglycerides and free fatty acids in the mammary
gland of rats administered arrack/ethanol in comparison with the controls. The
lipoprotein lipase activity showed significant increase in the treated groups, in
which the activity decreased on 21st day in comparison with 19th day. The
absolute and relative weight of mammary gland also showed a significant decrease
in ethanol/arrack treated group. The biochemical alterations produced in the
mammary gland by arrack and its equivalent alcohol were different showing that
non-alcoholic portion of arrack interferes with the toxicity induced by alcohol.
Arrack was found to be a potent hyperlipidemic agent than ethanol.
PMID- 10776482
TI - Analgesic effect of environmental noise: a possible stress response in rats.
AB - Environmental noise is a known stress, which induces alterations of various
physiological responses in individuals exposed to it. Stress has been shown to
cause changes in the perception of various sensations including pain and stress
induced analgesia has been observed following exposure to a diverse set of
stimuli. To examine the algesic behavior of rats exposed to loud environmental
noise, for long duration, we used an environment simulating chamber and conducted
the tail flick test for the assessment of pain. The rats were divided into groups
and subjected to loud noise for test sessions lasting 1 h, 2 h or 3 h in trials
of 5 consecutive days. The noise was of two kinds--a continuous shrill noise
(pure tone 92 dB & 98 dB) and an intermittent heavy artillery noise (white noise
102 dB). 15 min before and after each test session, tail flick latencies (TFL)
were recorded at 5 min interval. The TFL recorded were normalised to an Index of
Analgesia (IA) and the readings statistically analyzed using the F test (ANOVA),
the significance being obtained by Tukey's test (at 5% level). The results
revealed a significant increase in the TFL and the IA (P < 0.0001) in all the
test groups demonstrating a significant analgesic response in rats subjected to
noise stress. The analgesia was maximum immediately after noise exposure and
declined with time. It was found to be directly related to the duration of
exposure, the intensity and the characteristics of the noise with loud
intermittent (white) noise and longer duration of exposure producing more
analgesia.
PMID- 10776483
TI - A study of forced vital capacity and its predictors among the sand stone quarry
workers.
AB - The study assesses the relationship of selected demographic, anthropometric,
radiological, work-history and smoking-history related variables with Forced
Vital Capacity (FVC) in a sample of 168 sand stone quarry workers in a desert
environment. Except the variables related to smoking behaviour, all are found
significantly associated with FVC. The predictors of FVC screened through the
multiple regression analysis were age, weight, height, profusion of opacities in
chest X-ray and duration of work. Mean FVC was found significantly lower as
compared to the healthy adult population. On an average FVC% was 90% of predicted
(Percentage deviation of 10%). A clear increasing trend in FVC% along
age/duration of work was observed among the young workers, which may be due to
building of muscles in this job. Percentage deviation of 20% or more in FVC was
significantly associated with presence of radiological opacities suggestive of
silicosis (odds Ratio = 3.3). The diagnostic utility of the same is also
assessed.
PMID- 10776484
TI - Somatostatin (SRIF) like immunoreactivity in median eminence (ME) of female rat
brain: evidence of compartmentalization in ME.
AB - Somatostatin (SRIF) immunoreactivity was observed in rostrocaudal extent (Bregma
levels-1.8 mm to -3.8 mm) of the median eminence (ME) in female rat brain using
Avidin-Biotin Complex (ABC) method (Hsu et al, 1981). SRIF immunoreactivity (IR)
was observed in entire-rostrocaudal extent of both internal (IZ) and external
zone (EZ) of ME. Image analysis of SRIF stained sections showed that in rostral
ME (Bregma -1.8 to -2.3 mm) dense immunoreactive nerve terminals were observed in
EZ. In medial ME (Bregma -2.3 mm to 3.3 mm) SRIF-IR was low in IZ and dense in
EZ. In this region dense immunoreactive nerve terminals were observed in lateral
margin of EZ. In caudal ME (Bregma -3.3 mm to -3.8 mm) nerve terminals in lateral
EZ and median IZ and EZ showed dense reactivity in nerve terminals. These results
led us to hypothesize that each region-lateral IZ and EZ and medial IZ and EZ are
independent functional units in ME. Six functionally independent compartments
could be identified-Compartment I and III of IZ and IV in EZ (Lateral margins in
ME), Compartment V (IZ) and Compartment VI (medial EZ).
PMID- 10776485
TI - Heart rate and blood lactate in 400 m flat and 400 m hurdle running: a
comparative study.
AB - This study was conducted on a group of male sprinters (n = 8) to compare heart
rate (HR) and blood lactate (La) response in 400 m flat and 400 m hurdle running
during weekly trial race. Durations of the flat and hurdle races were 51.65 +/-
1.51 and 58.27 +/- 1.97 sec respectively. Peak HR attained at the end of the flat
and hurdle races were 192.4 +/- 5.3 and 193.6 +/- 4.1 beats/min, whereas, average
HR during the events were 173.6 +/- 22.6 and 176.7 +/- 19.6 beats/min
respectively. La level following the flat event (18.84 +/- 1.57 mmol/L) was found
significantly (P < 0.05) higher than the post-hurdle race (16.14 +/- 1.97
mmol/L). The study indicates that cardiovascular stress is similar in both the
events although flat race impose higher anaerobic glycolytic demand than hurdle
run.
PMID- 10776486
TI - A study of P300-event related evoked potential in the patients of major
depression.
AB - Many studies involving various electrophysiological parameters have been
conducted in psychiatric disorders like schizophrenia and dementia to assess
their cognitive dysfunctions. Not much reports are available in major depression.
The present study was conducted in 20 patients of major depression to evaluate
their cognitive functions in terms of P300. P300 or P3 wave of auditory event
related evoked potentials (ERPs) is usually seen around 300 msec of presenting of
target stimulus, if the subject is responding to it. Auditory ERPs were recorded
using the standard 'odd ball' paradigm. The latencies of various components of
ERPs N1, N2, P1, P2, and P3 were recorded and compared with those of 20 normal
age and sex matched controls. The latency of P300 was found to be significantly
delayed in cases of major depression as compared to that of controls. Other waves
were also delayed in cases of depression but the difference was not statistically
significant. Our results suggest that P300 latency is longer in the patients of
major depression disorders which could be due to constitutive altered 'cognitive
neuronal pool' or a neurotransmitter/neuropeptide imbalance. Further studies
involving larger populations are required to elucidate the diagnostic and
predictive role of latency of P300 in the cases of depression.
PMID- 10776487
TI - Role of nitric oxide on insulin induced seizures in mice.
AB - The role of nitric oxide (NO) on acute hypoglycemia-induced seizures in mice was
investigated using insulin as the hypoglycemic agent. The NO precursor L-arginine
in the doses of 150, 500 and 750 mg/kg exhibited a dose-dependent protective
effect against seizures induced by 8 mu/kg insulin. The NO synthase inhibitor (L
NMMA) at the doses of 50 and 100 mg/kg potentiated the subconvulsive doses of
insulin (2 mu/kg). The onset, duration, number of seizures and the mortality were
noted in a 2 hr study period. The results of this study suggest than NO plays an
important protective role in acute hypoglycemia induced seizures which are known
to occur through the activation of NMDA receptors.
PMID- 10776488
TI - Cognitive dysfunction induced by phenytoin and valproate in rats: effect of
nitric oxide.
AB - Phenytoin (PHT) and Valproate (VPA) are known to induce cognitive dysfunction, in
terms of long term memory loss. Nitric oxide (NO) on the other hand is said to
help in long term potentiation and hence enhance memory. The effects of nitric
oxide donor L-arginine (L-Arg) and nitric oxide synthase inhibitor N-W-L
Nitroarginine (L-NOARG) were studied on the cognitive dysfunction, induced by PHT
and VPA in normal healthy rats, using the step-through passive avoidance test
(PAT). It was observed that combining L-Arg with PHT significantly enhanced long
term memory while, combining PHT with L-NOARG decreased it, as compared to PHT
alone. When combined with VPA, L-Arg and L-NOARG increased the retention latency
as compared to PVA alone but this was not statistically significant. We conclude
that the No donor L-Arg is able to increase the difference in LTE in acquisition
and retention trials with both PHT and VPA, but with VPA the increase is not
statistically significant.
PMID- 10776489
TI - Cognitive dysfunction in NIDDM: P3 event related evoked potential study.
AB - P3 component of the endogenous cerebral evoked response is a sophisticated,
objective and quantitative approach to assess higher functions of the brain. This
test was employed using auditory 'odd ball' paradigm to assess cognitive
functions in thirty non insulin dependent diabetic patients (NIDDM) aged 43.6 +/-
9 yrs with poor blood glucose control. (HbAlc. 9.9 +/- 1.0%). The peak latencies
of N2, P3 components of event related evoked potentials obtained in these
patients were compared with 30 age and sex matched non diabetic healthy controls.
Latencies of these potentials were: N2 = 248.0 +/- 36.3, P3 = 391.6 +/- 49.9 msec
in NIDDM as compared to 220.6 +/- 26.4, 326.2 +/- 26.8 msec in controls and were
highly significant (P < 0.001). The duration of disease, blood glucose level or
the physical parameters of height, weight and blood pressure did not show any
correlation with N2 or P3 latencies or amplitude. These findings provide an
electrophysiological evidence of delayed cognition in poorly controlled NIDDM
cases.
PMID- 10776490
TI - Evaluation of the activity of receptor-operated Ca2+ channels in rat portal vein
in induced hyperthyroidism.
AB - The activity of receptor-operated Ca2+ channels (ROCCs) was studied in rat portal
vein in L-thyroxine-induced experimental hyperthyroidism. The following
parameters were evaluated: 1. NE-stimulated 45Ca influx. 2. CaCl2-induced
contractile responses in Ca2+ free NE-stimulated tissues to calculate EC50 value
of CaCl2. The NE (10(-6)mol) stimulated 45Ca influx and the mean EC50 value of
CaCl2 did not differ significantly in portal veins isolated from hyperthyroid
rats as compared to those of euthyroid control rats. The study revealed no
significant change in the functional status of ROCCs in experimental
hyperthyroidism.
PMID- 10776491
TI - Peak expiratory flow rate (PEFR) in hairdressers.
AB - The present cross sectional study with comparison group was undertaken to assess
the lung function of hairdressers by Peak Expiratory Flow Rate (PEFR) using
Wright peak flow meter. Total 385 hairdressers and 770 controls were included in
the study. PEFR was observed to be reduced in hairdressers compared with
controls. The difference was significant (P < 0.01) above 45 years of age. Also
with increasing duration of exposure observed PEFR was reduced than expected.
Above 20 years of length of service, the difference was statistically significant
(P < 0.01). Smokers in hairdressing occupation had reduced PEFR than in control
group, though this difference was not significant. Thus, we conclude that
hairdresser's environment adversly affects their lung function and smoking may
potentiate the adverse effect.
PMID- 10776492
TI - Effects of short-term administration of Tulsi leaves on sexual behaviour in
female rats.
PMID- 10776493
TI - Tamarind as a sailogogue.
PMID- 10776494
TI - Data acquisition and analysis using conventional multimedia computer: a cost
effect method for computerising electrophysiological data.
PMID- 10776495
TI - PEFR in cement pipe factory workers.
PMID- 10776496
TI - Hypervitaminosis E.
PMID- 10776497
TI - Study of coagulase positive and negative Staphylococci in clinical samples.
AB - A total of 983 patients samples (pus, urine, sputum, throat swabs, blood culture,
CSF, vaginal swabs, ear swabs) were studied for a period of one year. The
incidence of coagulase positive Staphylococci was highest in pus and the
incidence of coagulase negative Staphylococci was highest in conjunctival swabs.
Antibiotic Sensitivity pattern of routinely used antibiotics was studied.
Coagulase positive Staphylococci was found to be most sensitive to Ciprofloxacin
followed by Norfloxacin and Gentamycin. Coagulase negative Staphylococci showed
maximum sensitivity to Ciprofloxacin followed by Norfloxacin and Chloramphenicol.
PMID- 10776498
TI - Confidential communications in medical care.
AB - Since the legal consequences taking in consideration of Indian evidence Act 1857
of an unwarranted release of confidential information are uncertain and even the
consequences may be serious, it is necessary that a physician be most cautious
when divulging any information about a patient. Although there are exceptions to
the proposition that all confidential information acquired from a patient should
be kept secret, the basic rule to remember is that confidential information
should not be revealed without obtaining the patient's consent unless law of the
land like provision in criminal procedure code of India requires the physician to
report the information, to any person or insurance company. Whenever a physician
believes it is necessary to reveal a professional secret to protect the welfare
of a patient, a third person, or the community, he should exercise caution in the
method of disclosure. The following suggestions have been made to guide
physicians under these circumstances: 1. Assure yourself that the person informed
is sometime entitled to the information, such as the patient's parent or
guardian. 2. Do not give information by telephone if you do not recognize the
voice of the person making the request. 3. Avoid the use of telegrams or letters
to communicate medical information of patient. 4. If you are in doubt about your
right to release the information consult your legal council. 5. A person in
police custody as an undertrial prisoner has the right not to permit the doctor
who has examined him, to disclose the nature of his illness to any person. If a
person is convicted, he has no right and the doctor can disclose the result to
the authorities. 6. Never release the treatment history without written consent
from patient or its legal heirs to any insurance company.
PMID- 10776499
TI - Prevalence of HBsAg positivity in staff and patients at MGM Medical College and
Hospital, Navi-Mumbai.
AB - Prevalence of HBsAg was studied by Elisa test in 166 hospital employees, 170
patients at random and 1042 voluntary blood donors. Prevalence of HBsAg among
doctors was 3.33% in nurses and lab-technicians 0%, in nursing students 1.53% and
in ward-boys 15%. Less incidence in staff members other than ward boys is because
of HBsAg vaccination. Prevalence of the HBsAg in random patients was 7.65% and in
voluntary blood donors was 2.11%.
PMID- 10776500
TI - Awareness and health seeking behaviour of rural adolescent school girls on
menstrual and reproductive health problems.
AB - A study was conducted on 130 girl students aged 13-17 years in Haryana to assess
their awareness and health seeking behaviour regarding menstrual and reproductive
health. Mean age at menarche of the girls was 13.6 +/- 0.83 years. Awareness
about the process of menstruation was poor. Commonest reported menstrual problem
was dysmenorrhoea (40.7%) followed by irregular menses (2.3%) of which only 5.3%
consulted a doctor and 22.4% took over the counter medications from the chemist
shops. Knowledge about normal duration of pregnancy and need for extra food
during pregnancy was poor. Most of the girls knew about importance, duration of
child spacing and need for three medical examinations during pregnancy. Major
sources of information were television (73.1%), radio (37.1%) and parents
(36.1%). Girls preferred to consult parents (49.2%) and doctors (44.6%) for help
at times of having reproductive health problems. This study highlights the need
for educating school girls about adolescent health, pregnancy and reproductive
health problems through schools and parents by the health professionals.
PMID- 10776501
TI - Simple and essential nutritional requirement to control hypertension--the silent
killer non drug treatment of hypertension.
PMID- 10776502
TI - Heart failure--role of ACE inhibitors and beta-blocker in its treatment.
PMID- 10776503
TI - First cervical cancer vaccine--from pipe dream to pipeline.
PMID- 10776504
TI - 50 years of influenza surveillance: much still to do to stop a common killer.
PMID- 10776505
TI - Acute respiratory infection in children: a survey in the rural community.
AB - The prevalence of Acute Respiratory Infections was 7.6% in a total of 10,951
children below 5 yrs surveyed. The annual incidence was estimated to be 2.6
episodes per child. The prevalence was highest in the 6 months--2 yrs of age.
Majority of the episodes were mild in nature (86.2%), while only 1.7% episodes
were severe in nature. A substantial number of episodes (27.3%) did not receive
any treatment. There was no association between the severity of ARI episodes and
the treatment received. Registered medical practitioners were the main source of
treatment. Far distance of the hospital was the reason for not receiving any
treatment among untreated cases. The outcome was better in those episodes treated
by a qualified MBBS doctor, as compared to other sources of treatment.
PMID- 10776506
TI - Antiovarian antibody in premature ovarian failure.
AB - Premature ovarian failure is a syndrome consisting of primary or secondary
amenorrhoea, hypergonodotropiremia and hypoestrogenemia in women under the age of
40. An autoimmune mechanism was suggested as possible etiology when Vallolton and
Forbes in 1966-67 found antibodies to the cytoplasm of rabbit ova in 29 of 232
tested sera. Immune mechanism in the pathogenesis of premature ovarian failure
(POF) is suggested by association of autoimmune phenomenon with POF in some cases
and demonstration of circulating antibodies to ovary in serum samples from women
with POF. The incidence of presence of antiovarian antibody of POF patients has
been reported earlier. Evidence of autoimmunity is present in 18-92% of patients
with POF. In the present study we have studied 18 cases of POF without any overt
manifestation of autoimmune disorder but the antiovarian antibody was detected,
with the idea that this autoantibody might be the cause of ovarian dysfunction
which is evident in POF. Presence of antiovarian antibody in 16.67% cases with
POF in our study that ovarian antibodies may play a role in or reflect an
autoimmune process responsible for the development of POF.
PMID- 10776507
TI - Multidrug resistant Salmonella.
AB - A total of 326 salmonella strains was isolated and studied from suspected enteric
fever cases in Mumbai (Bombay) during a 2 year period from May 1992 to July 1994.
These were identified using standard biochemical and serological tests.
Bacteriophage typing, antibiotic sensitivity and conjugation experiments were
also carried out. S. typhi was the most common serotype accounting for 75.46% of
the strains. Among S. typhi strains 87% were biotype I and 13% were biotype II.
9.5% strains were of S. paratyphi A, 5.52% of S. typhimurium, 4.60% of S.
worthington, 4.30% of S. havana and 0.62% of S. enteritidis. The commonest
bacteriophage type of S. typhi was E1, and of S. paratyphi A type 1, whereas
88.88% strains of S. typhimurium were untypable. Most of the strains were
multidrug resistant including commonly used antibiotics such as chloramphemicol,
ampicillin, and cotrimaxazole. Quinolone derivatives such as Ciprofloxacin were
found to be the most effective drugs. In the conjugation experiments there was
direct transfer of resistance pattern and enbloc transfer of resistance was
observed in most strains. Salmonella typhi is still the most commonly encountered
species. There is an alarming increase in multidrug resistance.
PMID- 10776508
TI - Management of advanced breast cancer: a case report.
PMID- 10776509
TI - Review on human leptospirosis.
PMID- 10776510
TI - Attention deficit hyperactivity disorder--a review.
PMID- 10776511
TI - Psychosocial characteristics of literate blinds: a study.
AB - Blindness leaves a person in a state of physical, psychosocial and economic
dependence. Aberrant mental attitudes and even frank mental illnesses can develop
among the aged blinds. The present study shows that acceptance towards their
disability was much higher (in 68.75% cases) among the aged blinds in group 'A'
(mean age 42.2 years) than the younger student (in 47% cases) in group 'B' (mean
age 17.6 years) All the younger blinds were found to be optimistic for their
future but the level for this mental attitude among older subjects was relatively
lower (in 68.75% cases). The aberrant mental attitude like rejection, guilt and
aggressiveness which reflected negative attitude towards life were more prevalent
among students. Older blinds were found to be relatively more shameful for their
disability (in 43.75% cases). The negative attitude towards life was evaluated to
be present among 12.5% cases in group 'A' and among 76.5% cases in group 'B'.
Anxiety and depression were the mental illnesses evaluated among blind and were
displayed by 6.25% and 0% cases in group 'A' i.e. the group of teachers and
trained workers and in 35.3% and 43.7% cases among group 'B' i.e. the group of
blind students respectively. Aberrant mental attitudes have shown no definite
relation with the age at the onset of blindness or otherwise they appeared to
change with age.
PMID- 10776512
TI - Awareness of urban slum mothers regarding home management of diarrhoea and
symptoms of pneumonia.
AB - A total of 635 mothers of under five children from urban slum area of Nanded city
were assessed to know their awareness about home management of diarrhoea and
symptoms of pneumonia. 48.5% of the mothers were unaware of any method of
rehydrating the child with diarrhoea at home level followed by 36.2% mothers who
were knowing home available fluids for rehydrating the child. 50.4% of the
mothers were not knowing a single symptom of pneumonia followed by 35.1% mothers
who were aware rapid abdominal movements (Pet Udna) as a symptom of pneumonia.
PMID- 10776513
TI - Use of nitrate in angina.
PMID- 10776514
TI - Humoral and cell mediated immune responses in patient with tuberculous
meningitis.
AB - A study was carried out to find out the humoral and cell mediated immunity levels
in patients with TBM and healthy controls. For humoral immunity, the amounts of
immunoglobulins--IgG, IgM and IgA were quantitated by SRID method. For cell
mediated immunity, percentages of total T cells, Th cells and Ts cells and the
ratio of Th:Ts cells was studied. Hypergammaglobulinemia of all three
immunoglobulins was observed together with a decrease in the total T cells and Th
cells, and a lower Th:Ts cell ratio indicating a deficiency or a defect in the
immune system of patients infected with TBM.
PMID- 10776515
TI - Incidence of Vibrio cholerae in different age groups and sex in Aurangabad
Province isolated during January 1994 to December 1994.
AB - In our study age group 1-10 years was mostly affected as also in 1992 and 1993
because of low health consciousness and poor personal hygiene at this age.
PMID- 10776516
TI - Knowledge and attitude of medical students in Delhi on postmortem examination.
AB - A survey proforma with multiple choice questionnaire was designed and asked to be
filled in by two hundred medical students belonging to 3rd and 4th year of MBBS
curriculum of a University medical college in Delhi. One hundred thirty-three
(66.5) students responded. A large majority of 129 (96.9%) students were aware of
the major use of the postmortem examination/autopsy. All students have the
knowledge that postmortem involves examination of a body in detail both
externally and internally. Sixty-four (48.1%) feel that it does not cause
disfigurement of the body. One hundred fifteen (86.4%) students were the view
that they possess satisfactory level of knowledge on postmortems. The main source
of knowledge and information on the subject is teaching during medical curriculum
as informed by 76 (57.1%) students. More than 50% were willing ti permit autopsy
on the self/relative. While, only 7 (5.3% students showed reluctance to watch
autopsy.
PMID- 10776517
TI - Reproductive tract infections among rural women in Meerut.
AB - The present study was done among 500 women of reproductive age group. Study
revealed overall prevalence rate of RTI of 44.8%. Excessive vaginal discharge was
the most common presenting symptom (42.0%). Inspite of such an high prevalence of
reproductive tract infections, only 22.8% of the women sought treatment for their
problem. The study suggests to improve the awareness about RTI and its treatment
facility among women and also recommends to develop a strategy to train and
reorient the health personnel.
PMID- 10776518
TI - Using antileukotrienes in asthma therapy.
PMID- 10776519
TI - Takayasu's arteritis.
AB - This paper reviews the literature of Takayasu's arteritis (T.A.). The concept of
this disease has evolved considerably over the past decades. T.A. was first
described by Mikito Takayasu in 1908, and was thought to be restricted to south
east Asia. But due to the increasing reports from all over the world, it is well
established that T.A. has world-wide distribution. Clinical presentation varies
according to the location of the arterial lesions. In Europe brachiocephalic
trunk lesions prevail and are best managed by an arterial reconstruction.
Historical background, epidemiology, etiology, pathology, clinical findings,
diagnosis, classification, treatment and long-term prognosis are discussed.
PMID- 10776520
TI - Colorectal cancer cells in the liver: from micro- to macrometastatic disease.
PMID- 10776521
TI - Comparison between open and closed repair for abdominal aortic aneurysms: a word
of caution.
PMID- 10776522
TI - Postoperative lavage and on demand surgical intervention in the treatment of
acute necrotizing pancreatitis.
AB - OBJECTIVE: To analyse our experience with a combined approach of postoperative
local lavage and on demand surgical intervention in the treatment of acute
necrotizing pancreatitis. PATIENTS AND METHODS: All patients operated on for
acute pancreatitis in a tertiary hospital between June 1993 and July 1997 were
studied retrospectively. Demographic data, Ranson score, APACHE II score at
admission were recorded. Hospital charts and clinical courses were reviewed.
RESULTS: Seventeen patients were treated surgically because of end stage multiple
organ failure (MOF) (n = 13) or infected necrosis (n = 4). APACHE II and Ranson
scores were 26.2 +/- 9.25 and 7.33 +/- 1.35 respectively. All patients had
protracted clinical courses, and required aggressive intensive care therapy.
Forty-eight surgical interventions were performed in 17 patients. Early mortality
was 36 percent. Complications were numerous, and mostly consisted of intra
abdominal abscesses. Young age (under 55) was associated with significantly
better outcome (22% vs. 87% mortality, p = 0.015). CONCLUSION: Continuous local
lavage after surgical debridement, with on demand re-laparotomy, proves to be a
valuable approach in patients with necrotizing pancreatitis with acceptable
morbidity and mortality rates. It appears however, that the role of surgery for
acute pancreatitis is limited to patients with infected necrosis or end stage
MOF.
PMID- 10776523
TI - Ischaemic colitis following aortoiliac surgery.
AB - Ischaemic colitis following aortoiliac surgery is a feared complication. Its
frequency varies from 7% after repair of ruptured abdominal aortic aneurysm (AAA)
to 0.6% after bypass for aortoiliac occlusive disease (AOD). In order to analyse
predisposing factors and outcome of ischaemic colitis, the authors reviewed their
clinical experience from 1988 to 1998. It concerns 28 cases (16 ruptured AAA, 7
elective AAA, 5 OAD) of clinically evident colonic ischaemia. This means an
incidence of 7% after repair of ruptured AAA, 0.6% after elective AAA repair, and
0.8% after bypass for AOD. Transmural necrosis (grade 3) was observed in 21
patients, grade 2 ischaemia in 5 patients, and grade 1 ischaemia in 2 patients.
Fifteen patients with grade 3 ischaemia underwent colectomy (Hartmann's
procedure) with a mortality rate of 66%. All non operated grade 3 patients died.
Overall, 16 of the 28 patients died at hospital (57% mortality rate). None of the
patients with mild (grade 2 or 1) colonic ischaemia died. Profound hypovolaemic
shock and inflammatory AAA were the only significant predisposing factors leading
to colonic ischaemia. Associated colon revascularization could not avoid the
evolution to colon necrosis in four patients. Reimplantation of a patent inferior
mesenteric artery or an internal iliac artery was performed in only 4.8% of all
aortoiliac reconstructions, and did not influence the development of ischaemic
colitis. The authors conclude that a more liberal use of postoperative
sigmoidoscopy could allow detecting colonic ischaemia at an earlier stage and
reduce ensuing mortality. A reinforced effort to restore or preserve colonic
vascularization could lower the incidence of colonic ischaemia following
aortoiliac surgery.
PMID- 10776525
TI - Diaphragmatic Morgagni hernia in adulthood: correct preoperative diagnosis is
possible with newer imaging techniques.
AB - Morgagni hernia is a rare type of diaphragmatic hernia. It is frequently
associated with elusive clinical and radiological findings in the adult and
consequently, diagnosis and appropriate therapy are usually delayed. We describe
a case in which a Morgagni hernia presented as a right sided cardiophrenic mass
on a routine chest X-ray. The diaphragmatic defect was further confirmed by
computed tomography (CT), by a magnetic resonance imaging (MRI) of the chest. The
defect was closed by a prolene mesh.
PMID- 10776524
TI - An unusual cause of thigh pain in colonic cancer. Inflammatory oncotaxis?
AB - Colonic carcinoma metastasis in order of frequency to the liver, lung, bone and
brain. Metastases elsewhere are unusual. We report a very rare case of metastatic
spread to skeletal muscle and skin. There follows a review of the theories of
anomalous metastatic localization. Inflammatory oncotaxis is offered as the most
likely explanation of this phenomenon. The importance of good history taking in
colorectal cancer follow up clinics is emphasised.
PMID- 10776526
TI - Splenic abscess after appendicitis.
AB - We report an appendicitis complicated by a splenic abscess in a patient with
polycystic kidneys and multiple cystic lesions in the liver. Clinical decision
making for operative intervention was made difficult by the extensive intra
abdominal abnormalities seen on computer tomography. Finally curation was
achieved by splenectomy and appendectomy.
PMID- 10776527
TI - Early surgical suction and washout for treatment of cytotoxic drug
extravasations.
AB - This case report is presented to assess safety and efficiency of early suction
and saline washout of extravasated cytotoxic drugs. Through multiple small skin
incisions, the area of extravasation is first suctioned and subsequently
extensively washed out with saline. Incisions are left open and the arm is
elevated for 24 hours. A complete healing was obtained in five days without any
skin or soft tissue loss. No additional treatment was needed. Early referral and
surgical treatment by suction and washout is a safe and reliable treatment
protocol for major cytotoxic drug extravasation injuries.
PMID- 10776528
TI - Primary composite tumour with bipartite differentiation of the esophagus.
AB - Primary small cell carcinoma of the esophagus is a rare tumour. A primary
composite tumour of the esophagus is even rarer and only four cases had been
reported in the literature up to August 1998. The definitive histogenesis of this
tumour remains controversial in spite of the additional information provided by
electron microscopy and immunohistochemistry. In the presented case,
histologically, the tumour tissue was composed of two malignant components:
approximately 50% of a moderately differentiated squamous cell carcinoma, and
approximately 50% of a small cell carcinoma. A lot of morphological transition
zones were observed between the squamous cell carcinoma components and the small
cell carcinoma components in some areas in the squamous cell carcinoma component.
Histochemically and immunohistochemically, the small cell carcinoma cells
demonstrated argyrophil granules, and Cytokeratin and Chromogranin A reactivity,
but the squamous cell carcinoma cells demonstrated only Cytokeratin reactivity.
Negative reactivity for argentaffin granules, neuron-specific enolase and S-100
were observed in both the small cell carcinoma and the squamous cell carcinoma
components. Histological, histochemical and immunohistochemical findings suggest
that a primary composite tumour of the esophagus may be derived from a totipotent
primitive cell in the basal region of the squamous mucosa of the esophagus. The
patient received chemotherapy preoperatively but died one month after the initial
diagnosis.
PMID- 10776529
TI - [1H-NMR analysis of heteroassociation of caffeine with antibiotic actinomycin D
in the aqueous solution].
AB - The molecular basis of the action of caffeine as a complex forming agent, an
interceptor of aromatic drugs intercalating into DNA was studied by the example
of the an anticancer antibiotic actinomycin D examined. The hetero-association of
caffeine and actionomycin D was studied by one- and two-dimensional 1H-NMR
spectroscopy (500 MHz). Concentration and temperature dependences of the proton
chemical shifts of molecules in aqueous solution were measured. The equilibrium
reaction constant of hetero-association of caffeine with actinomycin D (K = 246
+/- 48 M-1), the limiting chemical shifts of caffeine protons in complexes were
determined. The most favourable structure of the 1:1 caffeine-actinomycin D
hetero-complex in aqueous solution was constructed using the calculated values of
the induced proton chemical shifts of molecules and the quantum-mechanical iso
shielding curves for caffeine and actinomycin D. The thermo-dynamical parameters
of the hetero-complex formation between caffeine and actinomycin D were also
determined. The structural and thermo-dynamical analysis showed that dispersive
forces and hydrophobic interactions play the major role in hetero-association of
caffeine and actinomycin D in aqueous-salt solution. The relative content of
different complexes in mixed solutions containing caffeine and actinomycin D was
calculated and distinctive features of the dynamic equilibrium of caffeine
actinomycin D hetero-associates were revealed as a function of concentration and
temperature. It is concluded that hetero-association of caffeine and actinomycin
D molecules a lowers the effective concentration of the drug in solution and
hence the pharmacological activity of actinomycin D.
PMID- 10776530
TI - [Analysis of log-normal components of fluorescence spectra of prodan and
acrylodan bound to proteins].
AB - Steady-state fluorescence spectra of prodan and acrylodan covalently bound to
cystein residue of Lys-Cys-Phe tripeptide in solvents of different polarity were
analyzed. It was shown that the shape of spectral bands is well described by a
log-normal function. Linear relations between three shape-determining parameters
of the log-normal function (namely, the positions of spectral maximum and two
half-maximum amplitudes) were revealed and evaluated for both fluorophores. This
finding enabled us to present the shape of spectral bands of these fluorophores
in any environment as analytical log-normal functions depending on only two
parameters, the maximum position and the peak amplitude. The empirical
uniparametric log-normal curve was used for the analysis of composite
fluorescence spectra of prodan bound to bovine serum albumin and acrylodan
covalently attached to actin or subfragment 1 of myosin.
PMID- 10776531
TI - [How do point amino acid substitutions affect the protein structure?].
AB - In order to estimate the influence of point mutations on the protein structure,
552 pairs of structurally aligned proteins with pairwise sequence identities
greater than 60% were analyzed. We selected all isolated point mismatches from
these alignments. The statistics of local conformational changes corresponding to
these mismatches was studied. This study revealed two surprising aspects: (a)
only an extremely minor fraction (< 3%) of all observed mutations leads to
significant changes in local conformations; (b) observed substitutions, which
affect local conformation are more frequently those of similar (high scoring)
amino acid pairs rather than the substitutions thought of as "hazardous" (low
scoring), although the overall average score of the changing substitutions is
still lower than the corresponding average score for the substitutions that leave
the structure unchanged.
PMID- 10776532
TI - [Temperature compensation for enzyme activity in homoiothermal animals].
AB - The dependence of lactate gehydrogenase activity on body temperature of
homoiothermal animals upon hypothermia was studied. New data indicating the
induction of thermal compensation for enzymic activity in warm-blooded under
these conditions were obtained.
PMID- 10776533
TI - [Effect of treated with weak magnetic field aqueous salt solutions on the
intrinsic fluorescence of bovine serum albumin. Isolation from solutions and
partial characterization of the biologically active fluorescing fraction].
AB - It was shown that water with additions of Ca2+, Na+, K+ and Cl- ions
preliminarily treated with weak combined constant (42 microT) and low-frequency
alternating (0.06 microT) magnetic fields affects the intrinsic fluorescence of
bovine serum albumin, the magnitude of the effect being dependent on the
frequency of the alternating field and ionic composition of the aqueous salt
solution. A practically complete transfer of the effect through a small portion
of the solution treated with magnetic fields was revealed. It was also found that
after magnetic treatment, the solution contains a rather large (molecular mass
700-900 D) and stable molecular associate, which possesses, at least partially,
the properties and characteristics inherent in the whole solution that were as
acquired as a result of magnetic treatment.
PMID- 10776534
TI - [Effect of weak magnetic fields on the capacity of various proteins and polyamino
acids to form complexes with DNA].
AB - It was shown that preliminary treatment of the protein component (histone H3,
protamine sulfate, polyarginine) of a DNA-protein complex with weak combined (42
microT) and low-frequency (3.5-5.0 Hz) alternating (0.06 microT) magnetic fields
adjusted formally to the cyclotron resonance of amino acid ions charged under
natural conditions leads to substantial changes in complex formation and
formation of complexes of a different type than without treatment.
PMID- 10776535
TI - [Formation of complexes between DNA and cationic amphiphile molecules by the
fluorescent probe method].
AB - The formation of complexes of DNA with dodecylamine, dodecyltrimethylammonium,
tetradecyltrimethylammonium, and hexadecyltrimethylammonium was studied using a
fluorescent probe pyrene. The dependences of the spectral parameters of the
hydrophobic pyrene probe on the concentration of the cationic amphiphile in the
presence and absence of DNA were obtained and analyzed. It is shown that, in the
absence of DNA, these dependences exhibit only one S-shaped region, which
corresponds to the micelle formation of the amphiphile, whereas in the presence
of DNA there are two S-shaped regions, which indicates the cooperative formation
of two types of DNA-cationic amphiphile complexes. For each of the four cationic
amphiphiles, the critical concentrations for the micelle formation in the absence
of DNA (C0) and the concentrations at which the first (Cd1) and the second
complex with DNA are formed were determined. It was found that the Cd1 value is
15-40 times lower than C0. The Cd1 value does not depend on DNA concentration and
is determined only by the length of the hydrocarbon chain and the structure of
the amphiphile ionic fragment. The Cd1 value increases as the length of the
aliphatic chain decreases and upon replacement of mobile hydrogen atoms in the
ammonium fragment by methyl groups. It was shown that hydrophobic clusters of
amphiphile arising upon complex formation with DNA play the role of cross-links
promoting DNA aggregation, or DNA compactization in the case of dilute solution
of high-molecular weight DNA. The structures of the first and second DNA-cationic
amphiphile complexes are proposed, and the mechanism and nature of interactions
that determine their formation are discussed.
PMID- 10776536
TI - [Catalysis of 'dark' stage of cis-trans-isomerization of betaine stilbazole by
myoglobin].
AB - The back thermal cis-trans isomerization reaction of stilbazole betaine in the
presence of metmyoglobin was studied. The catalytic effect of metmyoglobin heme
on the back thermal cis-trans isomerization reaction of stilbazole betaine was
observed.
PMID- 10776537
TI - [Structure formation of water insoluble fullerene amino acid derivatives in
organic solvents].
AB - The time-dependent structure formation of the fullerene derivative of p-amino
benzoic acid in organic solvents was studied by scanning electron microscopy. It
was shown that, during storage of solutions, the structures are destroyed.
PMID- 10776538
TI - [Possible states of photosystem II reaction center and thermoluminescence of the
higher plants. I. Analysis of thermoluminescence models and their applicability
to the description of experimental data].
AB - A method for the deconvolution of experimental glow curves into overlapping bands
and determination of the activation energies for these bands is proposed. The
model includes the S-states of the water-splitting complex, tyrozine Z and P680
on the donor side, pheophytine, primary and secondary quinone acceptors on the
acceptor side, and takes into account the connection between different states of
the reaction center complex. The rate constants of forward electron transport and
the activation energies of backward reactions of electron transfer in photosystem
II reaction center, included into the model, are estimated from the known
experimental data using the proposed approach.
PMID- 10776539
TI - [A model of electron transport in chloroplasts taking into account the Mitchell Q
cycle. A numerical experiment].
AB - A mathematical model of electron transfer Je coupled with transmembrane transport
of protons JH in chloroplasts is proposed. It is taken into account that a part
of the whole electron flow can be involved in the circle around the b/f-complex.
This allows one to explain the experimental dependences of Je and JH on pH inside
and outside thylakoid.
PMID- 10776540
TI - [Polymyxin B and Ca(2+) induce conductance fluctuations in the dipalmitoyl
phosphatidic acid bilayer lipid membrane].
AB - Polymyxin B in micromolar concentrations induces current fluctuations in liquid
crystalline bilayer lipid membranes from dipalmitoylphosphatidic acid identified
as ion channels. The appearance of ion channels correlates with phase separation
of the lipid in the presence of peptide polycations detected by differential
scanning calorimetry. Ca2+ also induces the formation of ion channels in liquid
crystalline bilayer lipid membranes from dipalmitoylphosphatidic acid followed by
the phase transition of the phospholipid. The capacitive current, which indicates
the possibility of structural transformations of bilayer-non-bilayer type
(hexagonal phase II), precedes the formation of Ca(2+)-induced channels in
bilayer lipid membranes from dipalmitoylphosphatidic acid.
PMID- 10776541
TI - [Phosphorescent analysis of lipid peroxidation products in isolated human
erythrocyte membranes].
AB - The room temperature phosphorescence of lipid peroxidation products in the
composition of isolated human erythrocyte membranes was registered, and its
kinetic parameters were determined. The excitation and emission spectra of
phosphorescence of lipid peroxidation products in the composition of erythrocyte
membranes at 0 degree C measured. The nature of lipid peroxidation products
possessing the phosphorescencing capacity was discussed. Based on the analysis of
temperature dependences of the intensity and lifetimes of phosphorescence of
lipid peroxidation products in the range -2 divided by 26 degrees C, it is
concluded that the deactivation of excited triplet states of lipid chromophores
was realized by the dynamic type.
PMID- 10776543
TI - [Modeling of the two wave response of ATP receptors to jumps of the agonist
concentration in pheochromocytoma cells].
AB - A model for the kinetics of conformational transitions of ionotropic ATP
receptors in pheochromocytoma cells was elaborated. The contribution of the
states of ionotropic receptors (upon the blockage of the "open" channel state) to
the kinetics of postsynaptic currents was estimated at mediator concentrations
studied. The model enables one to determine the contribution of various
conformational states of the receptor, in particular in the "closed" state, to
the dynamics of ionic current that is registered upon stimulation of ATP
receptors. It is shown that after the cessation of the agonist application, a
secondary current wave can arise. The rate constants for conformational
transitions of ATP receptors were determined.
PMID- 10776542
TI - [Structural modification of erythrocyte membranes during oxidative stress and
activity of membrane bound NADH-methemoglobin reductase].
AB - The activity of NADH-methemoglobin reductase (metHb-reductase) in membranes
isolated from human erythrocytes treated with phenylhydrazine at its sublytic
concentration was studied. A decrease in the activity of membrane-bound metHb
reductase was shown to depend on the concentration of phenylhydrazine.
Simultaneously, an increase in the level of membrane-bound methemoglobin and a
change in the fluorescence parameters of membrane-bound 4,4'-diisothiocy
anatostilbene-2,2'-disulfonic acid were registered. In the case when Hb-free
erythrocyte ghosts were treated with 0.2-2.0 mM phenylhydrazine, the activity of
metHb-reductase did not change. The obtained results indicate that the inhibition
of the activity of membrane-bound metHb-reductase by phenylhydrazine-induced
oxidative stress in human erythrocytes is not caused by the direct action of the
oxidant on the enzyme. The reason for this is the interaction of the products of
hemoglobin oxidation with erythrocyte membrane (protein band 3) and structural
changes in membrane proteins.
PMID- 10776544
TI - [Modeling of the effect of modulated electromagnetic radiation on animal cells].
AB - Frequency-dependent modifications of intracellular free calcium concentration
([Ca2+]i) in neutrophils exposures to modulated extremely high frequency
electromagnetic radiation were analyzed using a special mathematical model for
[Ca2+]i oscillations. The model took into account the activation of Ca2+ influx
into the cell by cytosolic Ca2+ and Ca(2+)-induced Ca2+ release from
intracellular stores. The calcium channels of plasma membrane were chosen as a
target for the influence of harmonic signal and additive noise in the model. The
model simulation showed that in response to modulating signal, the rise in
[Ca2+]i, has frequency dependence and phase dependence in relation to the moment
of chemical stimulation. The phase-frequency dependence of the effect was
observed at a certain sequence of delivery of chemical stimulus and modulating
signal to the cell. At intensities of modulating signals exceeding the threshold,
a rise in [Ca2+]i, reaching a level of more than 50% of the initial level, was
observed at a frequency of about 1 Hz and in the phase range of 0.3-2.5 radians.
The effect was found only at high intensities of chemical stimulus. The additive
noise introduced into the system modified qualitatively and quantitatively the
phase-frequency characteristics of the cell response to the modulating signal. An
increase in noise intensity resulted in a displacement of the average frequency
of the band of rise in [Ca2+]i, and then the emergence of a set of bands with a
greater Q-factors. The analysis of dynamics of the nonlinear system in terms of
the stability theory showed that, as the intensity of chemical stimulus
increases, the system transits by means of a series of bifurcations from regular
driving to chaotic, and then to oscillations, induced by a modulating harmonic
signal. The boundary of the transition of oscillations from chaotic to induced
ones corresponds to a specific "threshold" of the intensity of chemical stimulus
for the significant rise in [Ca2+]i in response to the modulating signal. The
results of the model analysis are in good correspondence with the experimental
data obtained earlier, namely, with the effects of modulated extremely high
frequency electromagnetic radiation on neutrophils, which were observed only in
the presence of Ca2+ in extracellular medium and at high concentrations of
calcium ionophore A23187. Thus, as the characteristic frequency of the quasi
periodic process of calcium signalling in the cell coincides with the frequency
of external field, a narrow-band rise in [Ca2+]i is observed, which can result in
a modification of the functional activity of the cell.
PMID- 10776545
TI - [Distribution of porphyrin sensitizers among protein and cellular blood
elements].
AB - The distribution of porphyrin pigments between plasma proteins and blood cells
was studied. It was shown that the relative fraction of sensitizer bound by blood
cells changed significantly depending on the physicochemical features of pigment
molecules. This parameter strongly correlates with porphyrin polarity. Polar
watersoluble tetraphenylporphin derivatives, chlorine e6 and hematoporphyrin are
bound by plasma proteins only. The decrease in pigment polarity by substitution
of polar side groups results in a drastic increase of pigment affinity to blood
cells. The binding of extremely apolar pigments by cells in blood occurs for a
long period of time, probably as a result of a low rate of pigment redistribution
between serum proteins and cellular membrane. The data obtained show that blood
cells may be involved into the control of pigment transport and distribution in
organism during photodynamic therapy. The parameters of porphyrin distribution
between plasma proteins and cells in blood are of certain importance when the
pharmacokinetic behavior of various sensitizers is compared.
PMID- 10776546
TI - [Microcalorimetric study of human serum].
AB - It was established that albumin of donor blood serum denatures in two temperature
ranges. It is shown that the first stage of denaturation with Td = 61.5 degrees C
is dominant and corresponds to melting of regions not bound to fatty acids. The
second stage with Td = 80 degrees C corresponds to melting of regions bound to
fatty acids. Serum denaturation heat is equal to 20.2 J/g dry protein. A change
in denaturation heat capacity is 0.21 J/(g.K). Analysis of thermal parameters of
deconvolution peaks showed that albumin of donor blood serum is in a fatless
state and its multiple binding centers are essentially free as compared with
freshly isolated albumin and may play an important role in binding of ligands in
vivo. The thermal parameters of denaturation of some important human blood serum
proteins including gamma-globulins, transferrin ceruloplasmin and protease
inhibitors were also determined.
PMID- 10776547
TI - [Independent denaturation of albumin and globulins in human serum].
AB - The independent melting of albumin, gamma-globulin, transferrin, and protease
inhibitors in the composition of donor blood serum was studied by differential
scanning microcalorimetry. It was found that the number of domains in gamma
globulin in donor blood serum and in diluted solutions is the same, whereas the
number of domains of albumin in solution and in the composition of blood serum is
three and two, respectively. In blood serum, the N-terminal domain melts by the
"all-or-none" mechanism. Therefore, the decomposition of peaks of the
denaturation curve was made under the assumption that the denaturation of blood
serum proteins occurs by the "all-or-none" principle. It is assumed that
comparing the calculated melting parameters (Td, delta Td, delta Hd, delta Cd) of
domains of blood serum proteins of donor with the corresponding parameters of
patients with oncological and nononcological diseases can be used as a basis for
a more precise diagnostics of these diseases.
PMID- 10776548
TI - [The informational role of regular low amplitude movements in the formation of
visual signals].
AB - The role of tremor and drift in the formation of primary receptive fields and
signals of space-frequency transformations at the level of retina fovea
centralies cells was investigated. The mechanism of organization of direct
informational connection between photoreceptors, horizontal and bipolar cells was
determined, and the formulas for the synthesis of visual information signals were
derived taking into account the frequency of participation of image elements. It
is shown that tremor and drift are those mechanophysical processes whose mutual
cooperation leads to the formation of the hysteresis signal informationally
sufficient for monochrome and polychrome visual recognition.
PMID- 10776549
TI - [The branching structure of the bistable dendrite].
AB - A branching structure consisting of three bistable cylindrical branches was
considered. Both stable and unstable solutions for the voltage distribution in
such a structure, were obtained using the method developed in our laboratory.
This made it possible to calculate the input current-voltage characteristic of
the bistable branching structure, including unstable segments of this
characteristic. Possible stable states of the structure when its proximal end is
loaded by a resistance were determined. It is shown that the binary exclusive-OR
could be accomplished by the elementary branching structure of a bistable
dendrite. A model with overexcitation carried out by Ca-dependent K channels was
developed. It is shown that the model parameters do not fall outside the
physiological range of values.
PMID- 10776550
TI - [Effect of insulin on the myocardium of the active, hibernating and wakening
ground squirrel Citellus undulatus].
AB - The effect of insulin (0.1-100 nM) on isometric force of contraction in isolated
ground squirrel papillary muscle was investigated. In summer, autumn and winter
active animals, insulin had a negative inotropic effect on papillary muscles,
decreasing the amplitude of contraction by about 30% of the control value. In
some cases, predominantly in the summer group of animals, insulin produced
different effects on contractility: low doses (0.1-0.5 nM) caused a transient
activation of isometric contraction by about 10-15% of control, whereas high
doses produced a negative inotropic effect by about 30% of the control level.
During deep hibernation (at 5-6 degrees C of heart temperature) and during
arousal from hibernation (from 3 to 20 degrees C), insulin had no significant
effect on contractility. Opposite inotropic effects of insulin at concentrations
of 0.1-50 nM were found during arousal: from 26 to 31 degrees C of heart
temperature--a positive inotropic effect by about 20-25% of control, and from 32
to 36 degrees C--a negative one by about 30-40% of the control value.
PMID- 10776551
TI - [Dependence of the fish school movement and plankton special distribution on the
phytoplankton growth rate].
AB - In this paper we investigate the spontaneous emergence and the dynamics of
patchiness in spatially distributed communities of plankton, which plays a key
role in the matter rotation on earth. Patchiness is often supposed to be due to
hydrodynamical factors (diffusion and advection). In contrast to this approach,
we consider the formation of plankton patches as a result of interactions in the
trophic chain nutrient--phytoplankton--zooplankton-fish. We present a
mathematical model of such interactions, which combines a continuous description
of the plankton spatio-temporal dynamics and a discrete description of the fish
school movement. We show that the fish school can give rise to plankton patches.
In turn, fish school walks are shown to depend on phytoplankton growth rate. We
show also that the Hurst exponent characterizing the fish school movement in the
diffusion approximation depends on phytoplankton growth rate.
PMID- 10776552
TI - [Effect of inorganic phosphate on photosynthesis in bean leaves].
AB - It was shown that raising pod seedlings by the hydroponics method on KH2PO4
solutions at concentrations between 10(-7) and 10(-5) M leads to an increase in
the rate of oxygen release (delta O2/delta t), with the chlorophyll content in
leaves being unchanged. The values of the parameters FM/FT of slow fluorescence
induction and B/A of photoinduced changes in ESR1 signals from pod leaves
correlate with the delta O2/delta t value.
PMID- 10776553
TI - [Electrical characteristics of the peritoneum in various body states].
AB - It is shown that carcinogenesis can be identified from the first day of
development of the process against the background of inflammation response by
measuring the electric resistance of the peritoneum.
PMID- 10776554
TI - [Carotenoid functions--a subject for the biophysical research].
AB - Progress, problems and outlooks in studies of functions of carotenoids in cells
of living beings.
PMID- 10776555
TI - [Platelet antigens and antibodies against them].
PMID- 10776556
TI - [Changes in blood flow in vessels of the inferior vena cava region under negative
intrathoracic pressure].
PMID- 10776557
TI - [Lack of energy balance as typical patho- and sanogenic responses during nervous
system diseases].
PMID- 10776558
TI - [Effect of ximedone on posttraumatic survival of sensory neurons].
PMID- 10776559
TI - [Free radical oxidation during experimental pneumonia].
PMID- 10776560
TI - [Changes in somatosensory evoked potentials and reflex responses of human hand
muscles during pain stimulation of the index finger before and after its
ischemia].
PMID- 10776561
TI - [Interrelation between changes in parameters of the knee reflex and functional
biomechanical disturbances in the pelvic region].
PMID- 10776562
TI - [Lung NADH diaphorase activity in rats with respiratory distress syndrome].
PMID- 10776563
TI - [Effects of ricin and its B-subunit on calcium responses in human lymphocytes].
PMID- 10776564
TI - [Elevated selenium glutathione peroxidase activity in blood from patients with
ischemic heart disease during treatment with selenium-containing antioxidant
preparation Adrusen zinco].
PMID- 10776566
TI - [Hepatoprotective effect of soy proteins and its use in the diet therapy of
chronic toxic hepatitis].
PMID- 10776565
TI - [Activity of cytochrome p450-1A in the liver of CBA and CC57BR during long-term
multiple induction by o-aminoazotoluene].
PMID- 10776567
TI - [Reaction of hypochlorite-anion with unilamellar phosphatidylcholine liposomes by
UV absorption spectrophotometry].
PMID- 10776568
TI - [Effect of endothelin-1 on DNA synthesis in various cell populations in newborn
rats].
PMID- 10776569
TI - [Effect of endothelin-1 on DNA synthesis in the epithelium and smooth muscle
cells in the trachea of newborn white rats].
PMID- 10776570
TI - [Disturbed functioning of enzyme systems of microsomal oxidation, glucuro-, and
glutathione conjugation of xenobiotics in the liver of rats intoxicated by
deoxycholate and their correction].
PMID- 10776571
TI - [Anti-arrhythmia effect of the GABA derivative TZ-50-2 during neuronal atrial
fibrillation].
PMID- 10776572
TI - [Effect of benzodiazepines on Ca(2+) transport in synaptoneurosomes in mice with
various stress response phenotype].
PMID- 10776573
TI - [Protein spectra and lipid bilayers of erythrocyte membranes in children with
insulin-dependent diabetes mellitus (data from polyacrylamide gel electrophoresis
and fluorescent analysis)].
PMID- 10776574
TI - [Membranotropic effects of glucocorticoids. Effect of cortisol on D-glucose
uptake by isolated hepatocytes].
PMID- 10776575
TI - [Modeling of hepatitis C viral infection in vivo and in vitro].
PMID- 10776576
TI - [Accumulation of a factor sharply stimulating glia proliferative activity in the
aging mammalian brain].
PMID- 10776577
TI - [Use of glutamic acid during alcoholic intoxication under unfavorable
environmental conditions].
PMID- 10776578
TI - [Temperature-dependent activity of acetylcholinesterase in synaptic membranes
from the rat brain during hypothermia].
PMID- 10776579
TI - [Emergence and development of uterine dysplasia of the cervix epithelium].
PMID- 10776580
TI - [Surgical treatment of children with large deep burns based on the use of
cultivated allogenic fibroblasts].
PMID- 10776581
TI - [Effects of phospholipid hepatoprotective agents in experimental Reye syndrome].
PMID- 10776582
TI - [Cytologic characteristics of the red bone marrow from BALB C mice after
implantation of the human fetal tissue].
PMID- 10776583
TI - [Blood plasma chemiluminescence and activity of alveolar macrophages during
experimental pneumonia].
PMID- 10776584
TI - [Pathomorphologic and endoscopic analysis of large bronchi during lung cancer].
PMID- 10776586
TI - [Mathematical model of the human body surface area].
PMID- 10776585
TI - [Ultrastructure of epithelial cells from the mouth mucosa lavage].
PMID- 10776587
TI - [Dye sorption as an indicator of the membrane damage and the prehemolytic
erythrocyte state].
PMID- 10776588
TI - Education Committee of the International Union of Biochemistry and Molecular
Biology.
PMID- 10776589
TI - Cells on the move: a dialogue between polarization and motility.
AB - Throughout evolution, both prokaryotic and eukaryotic cells have developed a
variety of biochemical mechanisms to define the direction and proximity of
extracellular stimuli. This process is essential for the cell to reply properly
to the environmental cues that determine cell migration, proliferation, and
differentiation. Chemotaxis is the cellular response to chemical attractants that
direct cell migration, a process that plays a central role in many physiological
situations, such as host immune responses, angiogenesis, wound healing,
embryogenesis, and neuronal patterning, among others. In addition, cell migration
takes part in pathological states, including inflammation and tumor metastasis.
Indeed, tumor progression to invasion and metastasis depends on the active
motility of the invading cancer cells and the endothelial cell bed during tumor
neovascularization. Cell migration switches "off" and "on," based on quantitative
differences in molecular components such as adhesion receptors, cytoskeletal
linking proteins, and extracellular matrix ligands, and by regulating the
affinity of membrane-bound chemoattractant receptors. A clear understanding of
how cells sense chemoattractants is, therefore, of pivotal importance in the
biology of the normal cell as well as in prevention of malignant cell invasion.
Here we offer a perspective on cell migration that emphasizes the relationship
between cell polarization and cell movement and the importance of the equilibrium
between the signals that drive each process for the control of tumor cell
invasion.
PMID- 10776590
TI - Kaposi's sarcoma-associated herpesvirus: from cell biology to pathogenesis.
AB - Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is linked to the
etiopathogenesis of Kaposi's sarcoma, a plasma-blastic variant of Castleman's
disease and primary effusion lymphoma. KSHV is related to a number of non-human
primate viruses. Only a limited number of KSHV proteins are expressed in tumor
cells. Here we discuss the putative role of these proteins in KSHV pathogenesis.
PMID- 10776591
TI - Carbon nanotubes: a future material of life.
AB - The synthesis and applications of carbon nanotubes, a new form of crystalline
carbon, are reviewed. In particular, the results obtained in the authors'
laboratory are summarized, including the preparation of highly crystalline multi
walled carbon nanotubes; also discussed are the valence band and core level
structures, the nonlinear optical limiting behavior, the band gap measurement,
and the hydrogen uptake by carbon nanotubes, which has been greatly enhanced by
alkali-doping.
PMID- 10776592
TI - Genomic organization of the serine protease light chain of mouse complement
factor I gene.
AB - A portion of the mouse complement factor I (mCFI) gene encoding for the mCFI
light chain was cloned from a mouse 129/SVJ1 bacterial artificial chromosome
library. It contains five exons and four introns. The intron sizes are remarkably
different from the human homolog. Several polymorphisms were found in exon 13.
One polymorphism was in the coding region, which causes a threonine in the Balb/c
mCFI to be replaced by an isoleucine in the 129/SVJ1 mCFI. The other two
polymorphisms are located in the 3' untranslated region. The organization of the
serine protease domain in mCFI is similar to that of trypsin but very different
from that of the other complement serine proteases.
PMID- 10776593
TI - Kinetic characteristics of ATP hydrolysis by a detergent-solubilized alkaline
phosphatase from rat osseous plate.
AB - Polidocanol-solubilized alkaline phosphatase was purified to homogeneity with a
specific activity of 822.3 U/mg. In the absence of Mg2+ and Ca2+ ions and at pH
9.4, the enzyme hydrolyzed ATP in a manner that could be represented by biphasic
curves with V = 94.3 U/mg, K0.5 = 17.2 microM, and n = 1.8 and V = 430.3 U/mg,
K0.5 = 3.2 mM, and n = 3.2 for high- and low-affinity sites, respectively. In the
presence of saturating concentrations of Mg2+ or Ca2+ ions, the hydrolysis of ATP
also followed biphasic curves. However, the specific activity increased to as
much as 1,000 U/mg, whereas the K0.5 and n values remained almost unchanged. In
the presence of nonsaturating concentrations of metal ions, the hydrolysis of ATP
was similar to that observed in the absence of these ions, but with a marked
decrease in K0.5 values. At pH 7.5, the enzyme also hydrolyzed ATP with K0.5 =
8.1 microM and V = 719.8 U/mg. Apparently, alkaline phosphatase was able to
hydrolyze ATP in vivo, either at pH 7.5 or pH 9.4. These data contribute to the
knowledge of the biological properties of skeletal alkaline phosphatase and
suggest that this enzyme may have a high-affinity binding site for ATP at
alkaline pH.
PMID- 10776594
TI - Lessons from sequenced genomes. Overlapping genes in Methanococcus jannaschii?
AB - This paper describes our finding on overlapping genes in Methanococcus jannaschii
genome. We found that one of the open reading frames (ORFs) within the M.
jannaschii genome contains the nucleotide sequence of tRNA(Ser), which raises a
serious question of the correctness of the initiation codon assignment for that
ORF. We suggest that there are two other possible AUG initiation codons
downstream from the TTG triplet, which was initially considered as a translation
start site. Only one of the AUG triplets is preceded by the Shine-Dalgarno
sequence that seems to be required for binding the ribosome and initiation of
translation.
PMID- 10776595
TI - Biochemical characterization of dichlorvos-induced delayed neurotoxicity in rat.
AB - In vitro and in vivo studies were carried out to assess the delayed neurotoxicity
potential of dichlorvos. In vitro, dichlorvos caused a concentration and time
dependent decrease in the activity of neuropathy target esterase (NTE). The Ki of
dichlorvos for NTE was calculated to be 1.28 x 10(3) M-1 min-1. In vitro
reactivation and ageing studies revealed that dichlorvos-inhibited NTE became
refractory to activation by potassium fluoride after 5 min in the ageing medium,
thus indicating the formation of an aged complex between dichlorvos and NTE. In
vivo also, dichlorvos (200 mg/kg body wt) given as a single subcutaneous dose
inhibited NTE in brain at various intervals after exposure (24 h, 10 days, and 21
days). The delayed neurotoxicity potential of dichlorvos was finally confirmed by
the rota rod test, which revealed severe motor deficit in all the exposed
animals.
PMID- 10776596
TI - High-yield expression of fully bioactive N-terminal parathyroid hormone analog in
Escherichia coli.
AB - A fully active analog of human parathyroid hormone (hPTH) has been produced by
recombinant expression in Escherichia coli. Initially, a nucleotide sequence
encoding hPTH(1-34)-Asp-Pro was ligated to a proinsulin gene in the plasmid pUC8,
for the eventual expression of a fusion protein of 137 amino acids. Unexpectedly,
the proinsulin gene and 340 bp downstream were deleted by an unknown mechanism
during transformation of the E. coli. This resulted in a new plasmid encoding a
small (72-amino acid) fusion product of hPTH(1-34)-Asp35-Pro36-X, where X is a 36
residue "arbitrary" downstream sequence of pUC8. The fusion product was
efficiently expressed and the hPTH analog, [Asp35]hPTH-(1-35), was readily
released by acid cleavage, with a yield of 100 mg/L. This analog had an effective
concentration for half-maximal adenylyl cyclase stimulation (EC50) in rat
osteosarcoma cells of 14 nM, which was identical to that for hPTH-(1-34). In the
ovariectomized rat model of osteoporosis, [Asp35]hPTH-(1-35) was fully active as
a bone anabolic agent.
PMID- 10776597
TI - Vanadium-binding protein excreted by vanadate-reducing bacteria.
AB - A vanadium-binding protein was isolated from the culture medium of the vanadium
reducing bacterium Pseudomonas isachenkovii by utilizing vanadate as the terminal
electron acceptor upon anaerobic respiration. The protein was associated with
vanadium at a molar ratio of approximately 1:20. It was purified to homogeneity
and separated into three components by treatment with 1 M HCl followed by gel
filtration: a protein, a vanadium-binding ligand, and inorganic vanadium.
Electron paramagnetic resonance analysis showed that vanadium was associated with
the protein in the 4+ oxidation state. The distribution of vanadium within the
cell was studied by electron microscopy and x-ray microanalysis of P.
isachenkovii cells. The results suggest that vanadium, accumulated in special
swells on the surface of the cell membranes, is reduced and excreted to the
medium.
PMID- 10776598
TI - Two systems for phosphate uptake in Yarrowia lipolytica cells grown at acidic
conditions.
AB - Inorganic phosphate (Pi) is accumulated by Yarrowia lipolytica cells grown at
acidic pH conditions by two kinetically discrete H+/Pi-cotransport systems with
apparent K(m) values for Pi of 12-18 microM and 2-3 mM Pi at pH 5.5,
respectively. One of these is derepressible and operates at low external Pi
concentrations; the other is most likely constitutively expressed and comes into
play at high Pi concentrations. The derepression of the high-affinity Pi
transport system is under the control of available extracellular Pi as well as
the amount of intracellular polyphosphates stores. Characteristics of the Pi
transport behavior in Yarrowia lipolytica are discussed.
PMID- 10776599
TI - Effect of buffer solutions on activation of Shamouti orange pyrophosphate
dependent phosphofructokinase by fructose 2,6-bisphosphate.
AB - Shamouti phosphofructokinase (PFP) activation depends on the presence of fructose
2,6-bisphosphate (Fru-2,6-P2) in the glycolytic reaction. The effect of
activation by Fru-2,6-P2 differs considerably, however, according to the buffer
(pH 8.0) in which the reaction is performed: Ka = 2.77 +/- 0.3 nM in Hepes-NaOH
and 7.75 +/- 1.49 nM in Tris-HCl. The presence of chloride ions (39 mM) in the
Tris-HCl buffer inhibits PFP. Indeed, when using a Hepes-NaOH buffer and then
adding 39 mM NaCl, Ka = 8.12 +/- 0.52 nM. The Ki for chloride ions is
approximately 21.7 mM. In the gluconeogenic reaction, Shamouti PFP generally
showed a high endogenous activity. Addition of Fru-2,6-P2 did not modify the
velocity and the Vmax of the enzyme; however, its presence increased the affinity
of the enzyme for Fru-1,6-P2 from 200 +/- 15.6 microM in absence of Fru-2,6-P2 to
89 +/- 10.3 microM in its presence (10 microM). In the presence of chloride (39
mM), the affinity for the substrate decreased with K(m) = 150 +/- 14 microM. The
calculated Ki for chloride ions equals 56.9 mM. In both the glycolytic and the
gluconeogenic reactions, Vmax is not affected; therefore, the inhibition mode of
chloride is competitive.
PMID- 10776600
TI - Epitope-tagged constructs of the yeast plasma-membrane H(+)-ATPase.
AB - In this study, two different epitope tags (HA, c-myc) were introduced near the N
terminus of the yeast PMA1 H(+)-ATPase. The resulting proteins were
indistinguishable from the wild-type ATPase in their ability to travel through
the secretory pathway, as judged by quantitative immunoblotting of isolated
secretory vesicles. Furthermore, there were no significant abnormalities in
ATPase activity (including K(m) for MgATP, Vmax, pH optimum, and IC50 for
inhibition by vanadate) or in ATP-dependent proton pumping. Finally, the epitope
tagged ATPases could support normal growth and displayed the expected activation
by glucose.
PMID- 10776601
TI - Narrative and interactional process for preventing harmful struggle in therapy:
an integrative empirical model.
AB - Resistance or struggle in therapy looms large as a predictor of treatment
outcomes. This study organizes the significant empirical data on struggle into a
coherent, operational framework for use by therapists in preventing and/or
ameliorating harmful struggle in therapy. First, we review the prevalence and
significance of struggle. Second, we offer a historical and conceptual overview,
with emphasis on a contemporary interactional/systemic perspective on struggle.
Third, we provide a synthesis of peer-reviewed research, profiling struggle at
speech-act and episode levels of interaction process and across
assessment/joining, intervention, and integration-consolidation phases of
therapy. Fourth, based upon this review, we propose a three-factor model-
consisting of eliciting dialogue, enactments, and accommodation--for successful
therapy process relative to the occurrence of struggle.
PMID- 10776602
TI - The effective use of enactments in family therapy: a discovery-oriented process
study.
AB - In this investigation we examine the elements of enactments--in-session dialogues
used to observe and modify family interactions in structural family therapy.
Twenty-one videotaped segments of 18 therapy sessions with different families
were used to compile detailed descriptions of therapist techniques and client
responses. Enactments were analyzed as consisting of three distinct phases-
initiation, facilitation, and closing--each of which required more numerous and
complex interventions than are usually described in the clinical literature.
Judges were able to reliably describe therapist interventions that led to
successful enactments as well as what therapists did or failed to do that led to
unproductive outcomes. Clinical implications of these findings are discussed.
PMID- 10776603
TI - The Power Equity Guide: attending to gender in family therapy.
AB - In the past two decades, feminist scholars have challenged the field of family
therapy to incorporate the organizing principle of gender in its theory,
practice, and training. In this paper, we introduce a training, research, and
therapeutic tool that provides guidance for addressing or observing gender and
power differentials in the practice of family therapy. As a training tool, the
Power Equity Guide helps trainees to translate their theoretical understanding of
feminist principles into specific behaviors in therapy. Researchers and
supervisors can use the Power Equity Guide to evaluate the practice of gender
informed family therapy. We also provide specific suggestions for its use by
trainers, supervisors, therapists, and researchers.
PMID- 10776604
TI - Systemic effects of trauma in clinic couples: an exploratory study of secondary
trauma resulting from childhood abuse.
AB - Clinical literature suggests that those close to a trauma survivor may experience
intrapersonal and interpersonal distress because of indirect or secondary effects
of the trauma. The focus of this study is on the association between reported
childhood physical and sexual abuse and current individual stress symptoms,
relationship satisfaction, and family adjustment. The participants included 96
clinic couples who reported a history of childhood physical or sexual abuse in
one or both partners and 65 clinic couples in which neither partner reported such
abuse. Couples in which one or both partners reported childhood abuse reported
significantly lower marital satisfaction, higher individual stress symptoms, and
lower family cohesion than couples with no abuse history. No significant
differences were found between individuals who reported a history of abuse and
their partners who reported no history of childhood abuse, suggesting support for
secondary trauma theory. Clinical and future research implications are discussed.
PMID- 10776605
TI - Healing bittersweet legacies: revisiting contextual family therapy for
grandparents raising grandchildren in crisis.
AB - Over the past decade, grandparents have become primary caregivers for their
grandchildren at an unprecedented rate. Drug/alcohol abuse, poor mental health,
financial instability, chronic illness, and early death have left parents
unavailable for childrearing, leaving their elder generation responsible for
tending vulnerable children. While grandparents' resources have been overtaxed
with this arrangement, family therapists have been caught off guard in adapting
traditional family therapy methods to this population. This paper revisits
Contextual Family Therapy for what it has to offer grandparents in crisis. The
purpose is to restore appropriate "give and take" while compensating for a
"skipped" parenting generation.
PMID- 10776606
TI - Spiritual issues in family therapy: a graduate-level course.
AB - With the advent of the biopsychosocial approach in family therapy, the domain of
spiritual issues is increasingly being recognized as important to families. This
article will describe a graduate-level seminar on Spiritual Issues in Family
Therapy at the University of San Diego that offers family therapy students the
opportunity to examine issues of spirituality, religion, and meaning and their
place in therapy. One premise of the course is that research has demonstrated
that most clients consider their spiritual life to be relevant to personal
problems and would prefer a therapist who is comfortable with such topics. The
goals of the course include (1) training in opening a dialogue with individuals
and families about spiritual issues and discerning when referral may be
appropriate; (2) expanding an awareness of wisdom traditions through use of
comparative religions material; and (3) identifying from current practice many of
the spiritual issues that may arise in the clinical setting.
PMID- 10776607
TI - The spiritual genogram in family therapy.
AB - Spiritual and religious issues often surface during marital and family therapy.
In this article, I describe a spiritual genogram that is a multigenerational map
of family members' religious and spiritual affiliations, events, and conflicts.
Used as a tool in family therapy, the spiritual genogram enables clients to make
sense of their families' religious/spiritual heritage and to explore the ways in
which their experiences impact present couple or family issues.
PMID- 10776608
TI - Spiritual ecomaps: a new diagrammatic tool for assessing marital and family
spirituality.
AB - This paper develops a new diagrammatic spiritual assessment tool, the spiritual
ecomap, for use with individuals, couples, and families. While a genogram
portrays a family's history over time, a spiritual ecomap provides a valuable
supplement by depicting a family's current relationships to critical ecological
systems in space. The spiritual ecomap is based upon an anthropological framework
conceptualized in the spiritual formation tradition and can be used with families
from diverse spiritual traditions. I use a case study to familiarize the reader
with the instrument, and offer suggestions for its application.
PMID- 10776609
TI - Postmodernism and the sacred: reclaiming connection in our greater-than-human
worlds.
AB - This article addresses the many faces of postmodernism and offers the critique
that postmodernism taken up in a particular extremist way can tend to sacrifice
the sacred, the spiritual, and the recognition of our "greater than human" worlds
in a quest for the particular. In response to this critique, I speak to a
postmodern family therapy practice that is informed by values of connectedness,
community, and communion; enacted through love and pragmatics; and committed to
recognition of our obligation to ecological practice.
PMID- 10776610
TI - The influence of religious and ethnic differences on marital intimacy:
intermarriage versus intramarriage.
AB - The influence of religious and ethnic differences on marital intimacy was
examined by administering the Personal Assessment of Intimacy in Relationships
and a demographic/attitudinal questionnaire to 25 Jewish couples (intramarried)
and 25 couples with one Jewish partner (intermarried). All couples were childless
and in the first 5 years of their first marriage. Results indicated that the
groups did not differ regarding couple level of intimacy, similarity of intimate
experience, or mutual understanding. However, in-depth interviews revealed
differences in the pathways by which these two groups arrived at a similar level
of intimacy. Intramarried couples appear to experience greater personal
similarity and mutual understanding rooted in their ethnic bond, which aids the
development of intimacy. Intermarried couples appear to find that the very
process of negotiating ethnic differences leads to greater mutual understanding
and intimacy. These findings indicate that clinicians and religious leaders
should not assume that intermarriage constrains levels of intimacy. Nor should it
be assumed that intramarriage assures high intimacy.
PMID- 10776611
TI - The fifth Holocaust Dialogue Interactive Group session: lessons to be learned.
AB - This article describes the fifth Holocaust Dialogue Group meeting between
descendants of both victims and perpetrators. This process began in 1994 and has
continued into 1999. It is held in conjunction with the annual International
Association of Family Therapy Conference. Those in attendance report that this
process has facilitated their catharsis regarding long-repressed issues and
feelings of shame and guilt, enabled them to ask probing questions of relatives,
and contributed to a profoundly desired healing. Repetitive themes that have
emerged in the sessions are highlighted.
PMID- 10776612
TI - [Physiology of microbial cell and metabolic engineering].
AB - This review is devoted to the problems of the physiology and cell biology of
microorganisms in relation to metabolic engineering. The latter is considered as
a branch of fundamental and applied biotechnology aimed at controlling microbial
metabolism by methods of genetic engineering and classical genetics and based on
intimate knowledge of cell metabolism. Attention is also given to the problems
associated with the metabolic limitation of microbial biosyntheses, analysis and
control of metabolic fluxes, rigidity of metabolic pathways, the role of
pleiotropic (global) regulatory systems in the control of metabolic fluxes, and
prospects of physiological and evolutionary approaches in metabolic engineering.
PMID- 10776613
TI - [About nannobacteria].
AB - Bacterial nanocells 0.2-0.3 micron in size and hundreds of a cubic micron in
volume have been revealed in natural habitats and obtained in pure cultures. The
taxonomic analysis of naturally occurring nanobacteria showed that they belong to
the known taxa of the kingdom Eubacteria. The results of the cytological
investigation of nanocells suggest that they are universally formed in response
to stress impacts.
PMID- 10776614
TI - [On the mechanism of autotrophic fixation of carbone dioxide by Chloroflexus
aurantiacus].
AB - The activity of two carboxylating enzymes was studied in the green filamentous
bacterium Chloroflexus aurantiacus. The carboxylation reaction involving pyruvate
synthase was optimized using 14CO2 and cell extracts. Pyruvate synthase was shown
to be absent from cells of Cfl. aurantiacus OK-70 and present (in a quantity
sufficient to account for autotrophic growth) in cells of Cfl. aurantiacus B-3.
Differences in the levels of acetyl CoA carboxylase activity were revealed
between cells of the strains studied grown under different conditions. The data
obtained confirm the operation of different mechanisms of autotrophic CO2
assimilation in Cfl. aurantiacus B-3 and Cfl. aurantiacus OK-70: in the former
organism, it is the reductive cycle of dicarboxylic acids, and in the latter one,
it is the 3-hydroxy-propionate cycle.
PMID- 10776615
TI - [Synergistic effect of rib80 and hit mutations on riboflavin biosynthesis and
iron transport in the yeast Pichia guilliermondii].
AB - Mutant strains of the yeast Pichia guilliermondii, carrying both rib80 and hit
mutations in a haploid genome, were derived from previously obtained strains with
defective rib80 or hit genes, exerting negative control of the riboflavin
biosynthesis and iron transport in Pichia guilliermondii. The double mutant
rib80hit strains exhibited an increased level of riboflavin biosynthesis and
higher activities of GTP cyclohydrolase and riboflavin synthetase. Iron
deficiency caused an additional increase in riboflavin overproduction. These
results suggest the synergistic interaction of the rib80 and hit mutations. A
combination of both mutations in a single genome did not affect iron assimilation
by the cells: ferrireductase activity, the rate of 55Fe uptake, and the iron
content in cells of the double mutants remained at the level characteristic of
the parent strains.
PMID- 10776616
TI - [Specific control over the synthesis of plasmin-like and plasminogen-activating
proteinases in marine bacteria].
AB - The biosynthesis of proteinases with various substrate specificities was studied
in Bacillus firmus 44b and Bacillus oligonitrophilus 21p as influenced by the
growth conditions and growth phases of the bacteria. The period of the maximum
synthesis of plasmin-like enzymes was observed 6 h later than the period of the
maximum growth rate period of B. firmus 44b, and 3 h as compared to the growth
rate of B. oligonitrophilus 21p. The periods of the maximum accumulation of
activating enzymes were delayed 9 and 12 h, respectively, as compared to the
rapid growth periods of these two bacteria. Catabolite repression of proteinase
synthesis and stimulation of the latter with substrate proteins were
insignificant. The production of both plasmin-like and plasminogen-activating
enzymes was most sensitive to repression by nitrogen deficiency. The production
of plasminogen-activating proteinases was less dependent on the carbon source
than the production of plasmin-like enzymes.
PMID- 10776617
TI - [The effect of carbon sources and mononucleotides on the production of
extracellular alkaline phosphatase by Bacillus intermedius].
AB - The biosynthesis of extracellular alkaline phosphatase in the streptomycin
resistant strains Bacillus intermedius S3-19 and S7 in the presence in the medium
of 5'-nucleoside monophosphates and different sources of carbon--glucose, sodium
pyruvate, sodium lactate, or glycerol--was studied. It was established that, in
the presence of mononucleotides, the content of extracellular alkaline
phosphatase in both strains increased; the maximal effect was caused by 5'-AMP at
a concentration of 20 micrograms/ml. In medium with a low orthophosphate content,
where active biosynthesis of alkaline phosphatase occurred, 1% glucose and 0.5%
pyruvate stimulated this process 2.5-4 times, and 2% sodium lactate and sodium
pyruvate, on the contrary, inhibited it by 20-40%. Analysis of the dynamics of
growth and accumulation of extracellular phosphatase in the presence of different
sources of carbon in the medium gives evidence of an interrelationship between
the biosynthesis of alkaline phosphatase and carbon metabolism in Bacillus
intermedius.
PMID- 10776618
TI - [Localization of alkaline phosphatase in cells of Bacillus intermedius].
AB - Alkaline phosphatase, an enzyme secreted by Bacillus intermedius S3-19 cells to
the medium, was also detected in the cell wall, membrane, and cytoplasm. The
relative content of alkaline phosphatase in these cell compartments depended on
the culture age and cultivation medium. The vegetative growth of B. intermedius
on 0.3% lactate was characterized by increased activity of extracellular and
membrane-bound phosphatases. The increase in lactate concentration to 3% did not
affect the activity of membrane-bound phosphatase but led to a decrease in the
activity of the extracellular enzyme. Na2HPO4 at a concentration of 0.01%
diminished the activity of membrane-bound and extracellular phosphatases. CoCl2
at a concentration of 0.1 mM released membrane-bound phosphatase into the medium.
By the onset of sporulation, phosphatase was predominantly localized in the
medium and in the cell wall. As is evident from zymograms, the multiple molecular
forms of phosphatase varied depending on its cellular localization and growth
phase.
PMID- 10776619
TI - [Isoelectric characterization of extracellular polygalacturanases of various
Aspergillus alliaceus strains].
AB - The composition of pectin hydrolase complexes produced by various Aspergillus
alliaceus strains was studied under the conditions of induction, catabolite
repression, or constitutive synthesis. The strains were found similar in terms of
the polygalacturonase spectrum and different with regard to the levels of endo-
and exoenzyme activities. The analysis of the zymograms of inducible
polygalacturonases revealed that all tested cultures contained at least 24
molecular forms of polygalacturonase. Taking into account only the three
molecular forms typical of all analyzed strains of A. alliaceus with pI values of
5.7, 5.9, and 6.3, one can use the spectrum of constitutive, catabolite
repression-resistant polygalacturonases as an additional taxonomic species
criterion.
PMID- 10776620
TI - [Microbial destruction of cyanide and thiocyanate].
AB - The role played by a bacterial community composed of Pseudomonas putida, strain
21, Pseudomonas stutzeri, strain 18, and Pseudomonas sp., strain 5, and by
physical and chemical factors in the degradation of CN- and SCN- was studied. It
was shown that the degradation of CN- is determined both by the action of
bacteria and by abiotic physical and chemical factors (pH, O2, temperature, the
medium agitation rate, etc.). The contribution of chemical degradation was found
to increase drastically at pH below 9.0; when air was blown through the medium
(irrespective of the pH value); under active agitation of the medium; and when
the medium surface interfacing air was increased. Even at elevated pH values (9.0
9.2), suboptimal for bacterial growth, the microbial degradation could account
for at most 20-25 mg/l of CN-, regardless of its initial concentration. When CN-
and SCN- were concurrently present in the medium, the former compound was the
first to be degraded by microorganisms. The rate of bacterial degradation of SCN-
under continuous cultivation in a chain of reactors was found to depend on its
concentration, the medium flow rate, agitation rate, and the pattern of carbon
source supply and could exceed 1 g/(1 day). CN- and SCN- are utilized by bacteria
solely as nitrogen sources. The mechanism of CN- and SCN- degradation by the
microbial community is discussed.
PMID- 10776621
TI - [The function of anabiosis autoinductors in microorganisms under blockade of
metabolism].
AB - Alkyl-substituted hydroxybenzenes (AHBs), which are auto-inducers of microbial
dormancy (d1 factors), were found to stabilize the structure of protein
macromolecules and modify the catalytic activity of enzymes. In vitro experiments
showed that C6-AHB at concentrations from 10(-4) to 10(-2) M, at which it occurs
in the medium as a true solution and a micellar colloid, respectively,
nonspecifically inhibited the activity of chymotrypsin, RNase, invertase, and
glucose oxidase. C6-AHB-induced conformational alterations in protein
macromolecules were due to the formation of complexes, as evidenced by
differences in the fluorescence spectra of individual RNase and C6-AHB and their
mixtures and in the surface tension isotherms of C6-AHB and trypsin solutions.
Data on the involvement of dormancy auto-inducers in the post-translational
modification of enzymes and their inhibition will provide further insight into
the mechanisms of development and maintenance of dormant microbial forms.
PMID- 10776623
TI - [Extracellular factors affecting the adhesion of Pseudomonas fluorescens cells to
glass surface].
AB - Two factors affecting the adhesion of Pseudomonas fluorescens to glass surfaces
were revealed in the culture liquid (CL) of this bacterium. One of these factors,
adhesin, which is responsible for cell adhesion, was found to be a protein
substance located both at the cell surface and in the CL. Bacterial cells grown
in rich LB medium were less adhesive than cells grown in minimal M9 medium. The
adhesive capacity of cells was independent of the growth phase. The other factor,
anti-adhesion (AA), which reduces cell adhesion, was found only in the CL. AA
concentration in the CL increased with the culture age.
PMID- 10776622
TI - [Stabilization of enzymes by anabiosis autoinducers as a possible mechanism of
resistance of resting microbial forms].
AB - Alkyl-substituted hydroxybenzenes (AHBs), auto-inducers of microbial dormancy (or
d1 factors), were found to stabilize the structure of protein macromolecules,
making them metabolically less active and more resistant to stresses. In vitro
experiments with the Bacillus intermedius ribonuclease and chymotrypsin showed
that the degree of the physical and chemical stability of these enzymes treated
with AHBs depends on their concentration and incubation time. Experiments with
RNase, which is capable of refolding, i.e., renaturation after heat denaturation,
revealed that AHBs efficiently interact with both intact and denatured proteins.
The data obtained allow the inference to be made that d1 factors may play the
role of natural chemical chaperons, blocking metabolism in dormant cells through
the formation of catalytically inactive thermostable complexes with enzymes.
PMID- 10776624
TI - [Properties of adhesin and antiadhesin from Pseudomonas fluorescence].
AB - Some properties of the adhesion-modifying factors of Pseudomonas fluorescens are
described. Adhesin, which promotes the adhesion of P. fluorescens cells, is a
hydrophobic compound of a protein nature with a molecular mass of more than 10
kDa located either at the cell surface or in the medium. Anti-adhesion, which
suppresses the adhesion of P. fluorescens cells, is a thermolabile hydrophobic
compound of a nonprotein nature with a molecular mass of less than 3 kDa. Heating
makes anti-adhesin hydrophilic. The role of adhesion and anti-adhesion in the
adhesion and adaptation of P. fluorescens cells is discussed.
PMID- 10776625
TI - [Factor of salinity and adaptive capacity of recombinant strains of Escherichia
coli and Bacillus subtilis].
AB - Effect of different concentrations of salts on natural and recombinant strains of
Bacillus subtilis and Escherichia coli was studied. The recombinant strain of B.
subtilis was found to be more osmotolerant than the wild-type strain of this
bacterium, whereas the opposite situation was observed for the recombinant and
wild-type strains of E. coli. Some salts exerted a bacteriostatic effect on E.
coli and B. subtilis. The adaptive capacity of recombinant strains depended on
the number of plasmid copies in the cells. The introduction of recombinant
bacteria into model ecosystems resulted in the generation of their variants with
increased osmotolerance.
PMID- 10776626
TI - [Cell division in the volume of Flavobacterium sp.22 colonies].
AB - Six-day-old colonies of Flavobacterium sp. 22 were studied by electron
microscopy. Direct evidence was obtained of bacterial cell division across the
entire colony volume, indicating that the colony growth of Flavobacterium sp. 22
is not purely peripheral. It is argued that the colony shape is determined not
only by peripheral growth but also by physical forces acting upon a droplet of
liquid on the surface. For bacterial colonies developing on solid nutrient media,
the intercellular matrix plays the role of such a liquid.
PMID- 10776627
TI - [Effect of chitosan derivatives on the reproduction of Coliphages T2 and T7].
AB - The effect of chitosan derivatives with different degrees of polymerization and
deamination, as well as of chitosan 6-O-sulfate and chitosan N-succinate-6-O
sulfate, on the reproduction of coliphages T2 and T7 in Escherichia coli and on
the growth of this bacterium was studied. Chitosan derivatives decreased the
yield of coliphages and exhibited bactericidal activity. The efficiency of
inhibition of viral infection and the bactericidal activity of chitosan were
found to be dependent on the degree of its polymerization. At the same time,
there was no correlation between the degree of chitosan deamination and the
extent of inhibition of viral infection. Anionic chitosan derivatives virtually
did not possess antiviral or bactericidal activity. It is assumed that chitosan
blocks some stages of phage reproduction. The decrease in the phage-producing
ability of E. coli may also be due to the bactericidal effect of chitosan.
PMID- 10776629
TI - [Effect of chitosan derivatives on the development of phage infection in cultured
Bacillus thuringiensis].
AB - The influence of chitosan fragments with different degrees of polymerization and
some chemical chitosan derivatives on the infection of Bacillus thuringiensis by
phage 1-97A was studied. It was shown that chitosan inhibits phage infection and
inactivates phage particles. The extent of inhibition of phage infection
inversely depended on the degree of polymerization of chitosan fragments. On the
contrary, the extent of inactivation of phage virulence was proportional to the
degree of polymerization. Chitosan derivatives did not inhibit the growth of
bacilli. Deaminated chitosan derivatives at a concentration of 100 mg/ml
efficiently inhibited phage reproduction, exhibiting no correlation between the
degree of deamination and antiviral activity. The anionic derivative chitosan
sulfate and N-succinate-6-O-sulfate did not inactivate phage, did not influence
bacterial growth, and did not inhibit the process of viral infection.
PMID- 10776628
TI - [Coliphages inactivation using chitosan derivatives].
AB - The effect of chitosan fragments with different degrees of polymerization and the
chemical derivatives of chitosan differing in the number of amino groups and
total molecule charge on phages T2, T4, and T7 was studied. The interaction of
chitosan with bacteriophage particles inactivated them to the extent dependent on
the chemical properties of chitosan and its concentration. Phage T2 was found to
be most susceptible to inactivation by chitosan. The polycationic nature of
chitosan plays an important role in the inactivation of phages. It is assumed
that the abnormal rearrangement of the basal plate of phages, the loss of long
tail fibers, and probably, modification of the receptor-recognizing phage
proteins may be responsible for the inactivation of coliphages by chitosan.
PMID- 10776631
TI - [A new yeast species Candida anutae sp.nov. from the fruiting bodies of
agaricus].
AB - Among the yeasts isolated from the fruiting bodies of different species of
agarics picked in forests near Moscow and Turku (Finland) in 1995-1998,
populations of an earlier unknown species, morphologically similar to
Metschnikowia lunata but differing from it by physiological characteristics and
the absence of asci with spores, were constantly found. Description of the new
species is given within the genus Candida Berkhout.
PMID- 10776630
TI - [The study of heterogeneity of plasmid-bearing and plasmid-f ree populations of
Bacillus subtilis under different environmental conditions].
AB - The population heterogeneity of recombinant and plasmid-free Bacillus subtilis
strains introduced into aquatic microcosms was studied. After introduction, the
population of the plasmid-free strain B. subtilis 2335 in microcosms has long
been represented by both vegetative cells and spores, whereas, already ten days
after introduction, the population of the recombinant strain B. subtilis 2335/105
(Km[symbol: see text]nf+) was represented only by spores. The number of plasmid
copies in the spore isolates of the recombinant strain was the same as before
introduction, but the plasmid abundance in the vegetative isolates of this strain
decreased. The isolates of B. subtilis 2335/105 obtained from microcosms and the
variants of this strain obtained by ten successive subcultures on M9 and 0.1 x M9
media with and without kanamycin (Km) differed in the number of plasmid copies,
Km resistance, and maximum biomass yield during batch cultivation. Irrespective
of the presence of Km, more than 50% of the variants subcultured on M9 medium
showed reduced plasmid abundance. At the same time, about 70% of the variants
subcultured on 0.1 x M9 medium with Km and 90% of the variants subcultured on the
same medium without Km retained the initial number of plasmid copies. The
variants subcultured on media with Km retained the initial biomass level. In more
than 70% of the variants isolated from media without Km, the biomass yield
increased.
PMID- 10776632
TI - [Discrimination of the soil yeast species Williopsis saturnus and Williopsis
suaveolens by the polymerase chain reaction using nonspecific primers].
AB - Thirty-five yeast strains of the genus Williopsis, analyzed by the polymerase
chain reaction with the universal primer N21, were found to belong to two sibling
species, W. saturnus and W. suaveolens. Such affiliation of the strains studied
agrees well with the results of genetic and physiological investigations.
PMID- 10776633
TI - [Taxonomy of denitrifying bacteria in soddy podzolic soil].
AB - The taxonomic composition of denitrifying bacteria in soddy podzolic soil was
studied by the succession analysis method. This method revealed a significant
variation in the taxonomic composition of denitrifying microorganisms in the
course of succession. In contrast to succession analysis, the single
microbiological analysis of soil samples reflected only the late stage of
succession and thus led to an underestimation of the major members of succession.
Myxobacteria were found to be the most active denitrifiers at the early stages of
succession, whereas bacilli dominated at its late stages. The bacilli were
represented by three facultatively anaerobic species, Bacillus cereus, Bac.
circulans, and Bac. polymyxa.
PMID- 10776634
TI - [The degree of halophily in Rhodococcus erythropolis and Halobacterium salinarum
depends on the partial pressure of oxygen].
PMID- 10776635
TI - [Adhesive and growth characteristics of R and S variants of Pseudomonas
Fluorescens].
PMID- 10776636
TI - [The formation of the right and left heart ventricles from the ventricular
portion of the heart tube in embryogenesis].
AB - It has been generally assumed that the initial rudiment of the heart ventricle is
divided by the longitudinal interventricular septum into the right and left
ventricles. This paper presents evidence for the hypothesis that the right and
the left ventricles are produced during normal development from different
sequentially located segments of the cardiac tube. These segments yielding
rudiments of the right and left ventricles could be detected even during early
embryogenesis. This hypothesis requires a new explanation for the process of the
formation of two separate outlets from the heart ventricles.
PMID- 10776637
TI - [The genetic control aspects of the development of the autonomic nervous system].
AB - This article provides a review of current views about the role of cell genetic
machinery in the control of development of neurons of the autonomous nervous
system. Some of the genes defining migration and specification of these neurons
are described. We give a schematic presentation of the genetically determined
organization of the neuronal networks, which are a basis of the intramural
nervous machinery and sympathetic ganglia. We describe the distribution of
neurons with different transmitter specificity in the cell populations comprising
the neuronal networks.
PMID- 10776638
TI - [Inorganic ion dynamics in the microspore and pollen grain of tobacco during the
development of the male gametophyte].
AB - We studied the dynamics of mobile potassium, chloride, and nitrate ions during
development of the micro-spore and differentiation of the pollen grain in
Nicotiana tabacum L. by measuring their concentration in aqueous extracts from
cells destroyed by freezing-thawing using ion-selective electrodes. Stage
specific changes in the ion content and intracellular concentration in the male
gametophyte were found. A relationship of the dynamics of ions to growth
processes and changes in metabolic activity during gametophytogenesis has been
discussed. The changes in the potassium and chloride ion concentrations have been
interpreted as regulatory changes controlling protein synthesis in the pollen
grain vegetative cell.
PMID- 10776639
TI - [Ooplasmic segregation and morphological axis formation in the polychaete Nereis
virens embryo].
AB - Ooplasmic segregation is of great importance in the development of Annelida. The
mechanisms of this process are very diverse in different groups of polychaetes,
oligochaetes, and leeches (Fernandez et al., 1998). Ooplasmic segregation in
Nereis virens is connected with the first meiotic spindle formation and animal
vegetative axis appearance. Spherical polyaxial symmetry of the oocyte transforms
into radial stratified symmetry in the course of ooplasmic segregation. There are
two main steps of ooplasmic segregation in Nereis virens. The first step begins
after the cortical reaction when the central clear cytoplasm reaches the surface
of the oocyte. The movement of the cytoplasm is sensitive to nocodazole,
colchicine, and cytochalasin B and appears to be mediated by microtubules and,
partly, by microfilaments. The second step is not sensitive to the microtubule
inhibitors and is mediated mainly by actin filaments. Ooplasmic segregation in
Nereis virens may be considered as a primitive form of ooplasmic segregation in
Annelida.
PMID- 10776640
TI - [The possible functional interaction of serotonin and neuropeptides in
embryogenic regulatory processes (experiments on embryos of the mollusk Tritona
diomedea)].
AB - Ritanserin and inmecarb hydrochloride, antagonists of serotonin, act
cytostatically and teratogenically on early embryos of Tritonia diomedea, a
nudibranch mollusk. On the basis of a pharmacological analysis and the type of
developmental abnormalities observed, this action appears to be due to
disturbances in the functional activity of endogenous serotonin and is associated
with damage of to the cytoskeleton. The effects of ritanserin and inmecarb are
prevented or attenuated by lipophilic serotonin analogs (serotoninamides of
polyenoic fatty acids), as well as by polypeptides isolated from neurons Pd5 and
Pd6 of the pedal ganglia of the adult Tritonia. In late embryos (stage of
veligers), serotonin and to a lesser extent its lipophilic analogs strongly
increase embryonic motility. This effect of serotonin is potentiated by some
neuropeptides and inhibited by others. These results provide evidence for
functional interaction between serotonin and neuropeptides in the control
processes of embryogenesis.
PMID- 10776641
TI - [The effect of the composition of the culture media on bovine oocyte maturation
and embryo development in vitro].
AB - We studied the capacity of the cattle oocyte for the resumption of meiosis and
achievement of metaphase II in various protein-free culture media (DMEM, TCM-199,
Ham's F-10, and Ham's F-12) and the pattern of influence of the estrous serum on
in vitro development of fertilized cattle oocytes, with special reference to the
time of its addition to the synthetic oviduct fluid containing BSA. In the first
experimental series, it was shown that the highest number of oocytes (76.1%)
resumed meiosis in DMEM medium. Meiosis was not resumed in Ham's F-12.
Intermediate results were obtained for TCM-199 (55.1%), which is commonly used
for maturation of cattle oocytes in vitro, and for Ham's F-10 (51.7%). The
oocytes reached metaphase II in DMEM at a higher rate (45.3%) than in TCM-199 or
Ham's F-10 (29.4 and 8.6%, respectively). In the second experimental series, the
estrous serum was added to the culture medium within 20 h (control) or 42 h
(experiment) after the beginning of fertilization. The estrous serum did not
inhibit the first cleavage division (the percentage of cleaving embryos did not
differ reliably: 32.7 and 37.9%, respectively). However, a later serum addition
to the culture medium (within 42 h after the beginning of fertilization) reliably
increased the percentage of embryos that reached the blastocyst stage (6.5% in
the control and 17.8% in the experiment) and the hatched blastocyst stage (2 and
9.2%, respectively).
PMID- 10776643
TI - [The history of modern chromosome analysis. The founding contribution of the
works of Caspersson].
AB - Chromosome analysis based on the studies of individual chromosomes is widely used
in medical genetics, selection, and molecular biology. The "Human Genome" program
based on studies of individual chromosomes is aimed at the complete sequencing of
the human genome. The nature of the differential stainability of the chromosomes
of different organisms (Rodionov, 1999) and the identity or difference of
individual types of their banding are discussed.
PMID- 10776642
TI - [The effect of a periovulatory prolactin imbalance on prolactin receptor
expression in rat ovary cell].
AB - Using the technique of immunohistochemistry in combination with cytophotometry,
we have studied the effect of periovulatory hyper- and hypoprolactinemia on the
expression of prolactin receptors in various cell types of rat ovaries during
early estrus. It has been shown that intense specific staining of oocytes is
positively controlled by prolactin. The maximal intensity of specific staining
was found in cells of the cumulus and the inner layer of granulosa cells in
mature follicles; staining intensity gradually diminished towards the outer
boundary cell layer. Postovulatory follicles are distinct from those mature
follicles in which there was no ovulation in their more intense manifestation of
prolactin receptors in cells of the inner layer and cumulus, as well as in
increased positive staining (after prolactin administration) only in the
granulosa layer cells closest to theca. In follicles which did not ovulate by the
time of the early estrus, prolactin administration leads to a proportional growth
of specific immunoreactivity in all cell layers of the granulosa. The
administration of bromocryptin, an inhibitor of prolactin secretion, leading to a
10-fold decrease in prolactin level in blood, results in a twofold decrease in
the intensity of specific staining of all cell layers of the granulosa in either
type of follicle. Corpora lutea of the previous cycle have irregularly positioned
luteocytes with weak and strong specific staining, the intensity of which is not
changed in response to prolactin and diminishes slightly after the administration
of bromocryptin. We conclude that the most intense changes in the content of
prolactin receptors under the conditions of imbalance of this hormone during the
periovulatory period are observed in those follicles where the oocyte did not
ovulate by the time of early estrus.
PMID- 10776644
TI - [Idiopathic pulmonary fibrosis].
PMID- 10776645
TI - [Circadian rhythms of hypophysis-thyroid hormones secretion in patients with
bronchial asthma].
AB - AIM: To examine circadian rhythms of hypophysiothyroid system in patients with
bronchial asthma and effects of exogenic glucocorticoids on thyroid function.
MATERIALS AND METHODS: Free T3, T4 and TTH were measured in plasma using
immunochemiluminescence in 16 patients with nonallergic bronchial asthma running
a severe course. The plasma samples were taken each 6 hours for 48 hours.
RESULTS: In patients with severe bronchial asthma (SBA) thyroid functional
activity changed. Production of T3 increased while that of T4 dropped at night.
TTH concentration rhythm for 24 hours was like that in healthy subjects.
Glucocorticoids induced no significant changes in circadian rhythms of
hypophysiothyroid system in SBA patients. CONCLUSION: In SBA functional activity
of the hypophysiothyroid system changes with rearrangement of hormonal production
at night.
PMID- 10776646
TI - [Membrane-receptor disorders in adrenergic and histaminergic systems under
peroxide exposure in bronchial asthma patients].
AB - AIM: To characterize membrane-receptor peculiarities in adrenergic and
histaminergic systems under model peroxide effect in bronchial asthma (BA).
MATERIALS AND METHODS: 172 patients with BA, 17 patients with nonpulmonary
allergy, 38 healthy men and 19 healthy blood relatives of BA patients were
examined for peroxide resistance of erythrocytic membrane to modulation with
adrenergic and histaminergic agonists and antagonists. The modified method by A.
A. Abramov and A. A. Pokrovsky was used. RESULTS: In atopic BA the phenomenon of
inversion of the effect of beta-adrenoblocker (obzidan) and of combined effect of
histamine and H1-antagonist (dimedrol) was revealed. The same phenomenon was
registered at the stage of preasthma and at the preclinical stage of BA. In
infection-dependent BA this phenomenon occurred less frequently being rare in
remission. In both BA variants the shift of H1/H2-histaminergic balance to
increased H1-activity exists which is more significant in atopic BA, preasthma
and preclinical BA. CONCLUSION: Peroxide effects modelled on red cell membranes
enabled to characterize reactivity of adrenergic and histaminergic systems not
only in BA but also in preasthma and preclinical BA.
PMID- 10776647
TI - [Bronchial reactivity as factor of effectiveness of new antiasthmatic drugs].
AB - AIM: To evaluate bekotid and bekodisk effects on bronchial reactivity and
sensitivity. MATERIALS AND METHODS: Bronchial reactivity and sensitivity were
studied in a comparative study of two corticosteroids for inhalation--bekotid and
bekodisk--in 37 patients with bronchial asthma. Unlike bekotid, bekodisk does not
contain freon which irritates mucosa of the upper respiratory tracts and bronchi.
The examination included clinical and allergological tests, provocative
inhalation tests, peak flowmetry, assessment of bronchial resistance and external
respiration function. RESULTS: Bekodisk treatment reduced the number of asphyxia
episodes, sensitivity to carbacholine, the need in inhalation sympathomimetics,
improved external respiration function. CONCLUSION: Determination of reactivity
and sensitivity of the bronchi is essential for comparison of drugs against
bronchial asthma. Bekodisk significantly lowers reactivity to nonspecific
mediatory substances, is simple and available in application, is more tolerable
than bekotid.
PMID- 10776648
TI - [Influence of berotec inhalations on pulmonary gas exchange in patients with
bronchial asthma].
AB - AIM: To determine mechanisms inducing changes in lung gas exchange after berotec
inhalation in patients with bronchial asthma (BA). MATERIALS AND METHODS: A study
was made of external respiration function including estimation of lung transfer
factor (TLCO sbh.) and its components--transfer coefficient (KCO), membrane
diffusion capacity (DM), pulmonary capillary blood volume (Vc)--by the single
breath holding method on CO in 14 healthy persons and 39 patients with BA before
and after berotec inhalation. The data were obtained in the absolute values and
their changes after berotec inhalation were measured in percent to initial ones.
RESULTS: In healthy subjects we did not observe changes of TLCO sbh. and its
components after berotec inhalation, only an insignificant decrease of VA eff.
was registered (p < 0.01). After berotec inhalation a considerable improvement in
Sgaw, FEV1, RPV and a decrease of TLCO sbh., KCO were observed. Changes in TLCO
sbh. were caused by a decrease in DM without changes in VA eff. in BA patients
with initial normal values of KCO. In patients with smaller initial values of KCO
moderate improvement of bronchial permeability without changes in KCO, PaO2 were
observed. These changes occurred due to a decrease of VA eff. CONCLUSION: Changes
of the transfer factor and its components in patients with BA reflect two types
of adaptation reactions in response to berotec inhalation and their role in
mechanisms of compensation of gas exchange in the lungs.
PMID- 10776649
TI - [Use of nebulizer in berodual treatment of patients with chronic obstructive
bronchitis in exacerbation].
AB - AIM: To study efficiency and safety of berodual in solution for inhalations
delivered with the help of nebulizer in patients with exacerbation of chronic
bronchitis (CB). MATERIALS AND METHODS: 12 patients with chronic bronchitis who
had not responded to oral methylxantines in combination with expectorants
received berodual for 10 days (1 ml 3 times a day). RESULTS: In the course of
berodual treatment all the CB symptoms relieved and external respiration function
improved. CONCLUSION: Berodual is effective as monotherapy of chronic obstructive
bronchitis.
PMID- 10776650
TI - [Effectiveness of antiinflammatory therapy in patients with interstitial lung
diseases using re-assay of biomarker mucin 3EG5].
AB - AIM: To investigate a potential of a new marker of activity of interstitial
pulmonary diseases (IPD)--mucin 3EG5--in monitoring of effectiveness of the
antiinflammatory therapy. MATERIALS AND METHODS: Serum mucin antigen 3EG5
(glycolyl-sialylated glycoprotein) was assessed with sandwich immunoassay
constructed using a monoclonal antibody 3E1.2 (Medical Innovations, Australia)
and affinity-purified polyclonal antibody G5 (Xema, Russia) against total mucin
antigen family. The level of serum 3EG5 was studied in 16 IPD patients (9 had
idiopathic pulmonary fibrosis and 7--chronic hypersensitivity pneumonitis) before
and after 6 months of immunosuppressive therapy. By changes in pulmonary function
tests during 6 months of steroid treatment all the patients were divided into two
groups: responders (a 15% increase in FVC, 20% increase in DLCO and reduction in
the PA-aO2 of 5 mm Hg) and nonresponders (worsening or insignificant changes in
these indices). RESULTS: In responders (n = 7) after treatment serum levels of
3EG5 fell from 230 +/- 97 to 88 +/- 40 units/ml (p < 0.01). In nonresponders
serum 3EG5 was not different before and after therapy: 249 +/- 153 and 247 +/-
170 units/m, although in this group two patients with unchanged lung function
showed a significant decrease in 3EG5, so the accuracy of changes in serum 3EG5
to reflect response to therapy was 88%. There was a significant difference
between the posttreatment levels of 3EG5 of the two groups of patients (p =
0.03). CONCLUSION: Successive measurements of serum mucin 3EG5 may be used for
monitoring of the response to immunosuppressive therapy in IPD patients.
PMID- 10776651
TI - [History of pneumonia studies].
PMID- 10776652
TI - [Quality of life as a research object in pulmonology (materials of the
international congress INTERASTHMA-98 and 8th National congress on respiratory
diseases). (lecture)].
PMID- 10776653
TI - [Myocardial revascularization and drug therapy of ischemic heart disease
(lectures)].
PMID- 10776654
TI - [Respiratory water release and significance of its investigation in pulmonology].
PMID- 10776655
TI - [Nebulizer in treatment of chronic obstructive lung diseases].
PMID- 10776656
TI - [Pharmacoeconomic aspects of bronchial asthma].
PMID- 10776657
TI - [Noninvasive lung ventilation in acute respiratory failure in patients with
chronic obstructive lung disease].
PMID- 10776658
TI - [Antithrombotic therapy in acute coronary syndrome].
PMID- 10776659
TI - [Chronic bronchitis and obstructive lung disease: analytical assay].
PMID- 10776660
TI - Association between ethanol and sucrose intake in the laboratory mouse:
exploration via congenic strains and conditioned taste aversion.
AB - BACKGROUND: A substantial body of literature indicates that intakes of "sweet"
solutions and ethanol are positively correlated across inbred strains of rats and
mice but there has been speculation that the correlation is fortuitous and there
is no agreement on the underlying mechanism. METHODS AND RESULTS: We assessed the
correlation between intake of sucrose and ethanol in congenic mice created by
backcrossing alleles favoring sucrose intake from the BXD RI-5 strain into
DBA/2J. In addition, to probe more specifically the interrelationship between
intake of the two solutions, we examined aversion generalization from sucrose to
ethanol in C57BL/6J mice. Among the congenic mice, a statistically significant
product-moment correlation of r = 0.36 (p < 0.02) was found between 6-hr intake
of sucrose corrected for differences in baseline water intake and preference for
10% ethanol presented in a 96-hr 2-bottle test. Furthermore, C57BL/6J male mice
conditioned to avoid a 0.2 M sucrose solution generalized their aversion to a 10%
ethanol solution presented in the same 2-bottle test, drinking 42.1 +/- 9.38%
(mean +/- SE) of their total fluid intake from the ethanol tube, compared with
the control group mean of 69.86 +/- 8.84%. CONCLUSIONS: The positive association
between intake of sucrose and ethanol in congenic mice provides strong evidence
that the previously demonstrated genetic correlation between intake of these
solutions is not the result of fortuitous fixation of unrelated alleles and
provides suggestive evidence that, at least in the B6/D2 lineage, the genetic
association between intakes of the two solutions reflects close linkage or the
pleiotropic effects of the same genes. The demonstration that a conditioned taste
aversion to sucrose generalized to ethanol in the C57BL/6J inbred mouse strain is
an extension of similar observations in outbred rats and specifically
demonstrates that intake of the two solutions is controlled by some of the same
physiologic or neurological processes and thus is consistent with the pleiotropic
interpretation of the genetic correlation.
PMID- 10776661
TI - Effect of chronic alcohol consumption on total plasma homocysteine level in rats.
AB - BACKGROUND: Chronic alcoholism in humans is associated with the development of
hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of
hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6.
Population-based studies indicate that folate is the strongest vitamin
determinant of hyperhomocysteinemia and, in most settings, folate supplementation
effectively lowers elevated homocysteine levels. However, it is not clear whether
folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS:
In the present study, 10 male Sprague Dawley rats were fed ethanol-containing
Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This
represents a folate intake more than 20 times the basal requirement. Ethanol
represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol).
The same number of rats were pair-fed with isocaloric control diets that
contained an identical level of folate in which ethanol was entirely replaced by
maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any
significant reduction in plasma or hepatic folate concentrations, plasma
pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the
other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/-
4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76
micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S
adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS:
Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is
related to interference with one-carbon metabolism, and not through vitamin
depletion.
PMID- 10776662
TI - Analysis of heritability of hormonal responses to alcohol in twins: beta
endorphin as a potential biomarker of genetic risk for alcoholism.
AB - BACKGROUND: Hormonal responses to alcohol have been reported to differ in
subjects with and without a family history of alcoholism which suggests that
alcohol-induced hormonal changes might be used to identify individuals who are at
elevated genetic risk for developing alcoholism. However, before a biological
response can be used as a marker of genetic risk for disease, it must first be
demonstrated that the response is, in fact, heritable. The present study was
designed to determine whether hormonal responses to alcohol are heritable.
METHODS: The adrenocorticotropic hormone (ACTH), beta-endorphin (beta-E),
cortisol (CORT), and prolactin (PRL) responses to alcohol were examined in male
and female identical (monozygotic or MZ) and fraternal (dizygotic or DZ) twin
pairs. Male subjects consumed 0.35 g ethanol/kg body weight (BW) and females
consumed 0.325 g ethanol/kg BW in each of two alcohol drinking sessions
administered 1 hr apart (total dose of 0.7 g/kg BW in males and 0.65 g/kg BW in
females). Plasma hormone content was analyzed in samples collected before
(resting conditions) and at 15, 60, 75, 120, 180, and 240 min after onset of
drinking. Hormonal responses to alcohol were examined with twin analyses using
the TWINAN90 program. A separate analysis was performed for each of the four
hormones. A subset of subjects from each zygosity was seen on two separate
occasions to establish retest reliability. Heritability of hormonal responses to
alcohol was estimated using the intraclass correlation approach before and after
removing the contribution of covariates that have the potential of influencing
the plasma levels of these hormones. RESULTS: Resting plasma levels of all four
hormones were within the expected range, and the beta-E, ACTH, and PRL responses
to the alcohol challenge evidenced good test-retest reliability. Of the four
hormones examined, the only one that showed significant heritability after
alcohol drinking was beta-E. Heritability estimates were not altered for any of
the four hormones after removal of the variance contributed by covariates, such
as gender and age. CONCLUSIONS: Taken together with other recent findings, the
results suggest that the beta-E response to alcohol may represent a new biomarker
that can be used to identify individuals who are at elevated genetic risk for
developing alcoholism.
PMID- 10776663
TI - P rats develop physical dependence on alcohol via voluntary drinking: changes in
seizure thresholds, anxiety, and patterns of alcohol drinking.
AB - BACKGROUND: It has been proposed that the alcohol-preferring P rat meets many of
the criteria for an animal model of alcoholism. However, the development of
alcohol dependence has not been explored in rats that self-administer ethanol for
less than 15-20 weeks. The present study investigated the development of physical
dependence upon alcohol after 2-6 weeks of voluntary alcohol intake. Changes in
bicuculline-induced seizure thresholds, microstructure of alcohol drinking, and
anxiety-related behavior were used as indices of alcohol dependence. In addition,
we evaluated the microstructure of alcohol drinking associated with the
development of physical dependence upon alcohol. METHODS: Alcohol (10% ethanol
solution) was measured in graduated drinking tubes with both alcohol and water
available continuously. Microstructure of alcohol intake was monitored by a
computerized drinkometer. Physical dependence upon alcohol was determined by
measuring bicuculline-induced seizure thresholds after alcohol withdrawal.
Anxiety-related behavior of P rats after alcohol withdrawal was determined by the
social interaction and elevated plus maze tests. RESULTS: Initial alcohol intake
in the alcohol-preferring P rat was relatively modest (3.9 +/- 0.4 g/kg/day).
Four days of forced alcohol exposure (initiation) followed by 6 weeks of
voluntary drinking resulted in an increase of alcohol intake to 5.5 +/- 0.2
g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks,
produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure
thresholds during alcohol withdrawal. Alterations in the microstructure of
alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared
to the baseline [p < 0.001] with no change in bout frequency) were associated
with the development of alcohol dependence. Termination of alcohol intake after 6
weeks of voluntary alcohol consumption resulted in increased anxiety according to
both the social interaction and elevated plus maze tests. CONCLUSIONS: The
results of this study indicate that 6 weeks of voluntary alcohol intake are
sufficient for the development of physical dependence upon alcohol in the alcohol
preferring P rats as measured by susceptibility to bicuculline-induced seizures.
This time is much shorter than the 15-20 weeks reported earlier. Development of
physical dependence to alcohol was associated with an increase in daily alcohol
intake (40% over the baseline), an increase in alcohol intake during each
drinking bout (90% over the baseline), and elevated anxiety during alcohol
withdrawal.
PMID- 10776664
TI - MK-801 blocks the development of behavioral sensitization to the ethanol.
AB - BACKGROUND: Studies have indicated that MK-801 (a noncompetitive N-methyl-D
aspartate receptor antagonist) participates in the long-term neural changes
responsible for sensitization to stimulant drugs. It is known that repeated
administration of low doses of ethanol sensitizes animals to its stimulant
effect. In this work we investigated whether MK-801 alters the development of
behavioral sensitization to ethanol. METHODS: Groups of male Swiss mice were
treated with saline or ethanol (2.0 g/kg) plus saline or MK-801 (0.25 mg/kg) for
21 days. On day 25, all animals received an ethanol challenge injection (2.0
g/kg). We measured locomotor activity on days 1, 7, 14, 21) and 25. In addition,
we assessed the effects of different doses of MK-801 on the response to a low
dose of ethanol (2.0 g/kg). RESULTS: Ethanol-treated mice developed sensitization
to the locomotor-stimulating effect of the drug, whereas those concomitantly
receiving ethanol and MK-801 did not. All doses of MK-801 that were used
stimulated the locomotor activity of both ethanol and saline-treated animals.
CONCLUSIONS: The findings support the hypothesis that N-methyl-D-aspartate
receptors have an important role in the development of sensitization to drugs of
abuse.
PMID- 10776665
TI - Ethanol suppresses NK cell activation by polyinosinic-polycytidylic acid (poly
I:C) in female B6C3F1 mice: role of endogenous corticosterone.
AB - BACKGROUND: Acute administration of EtOH suppresses basal NK cell lytic function
in mice, and this suppression is caused, in part, by neuroendocrine mediators
induced by EtOH. There is also evidence that a smaller part of the suppression is
caused by direct action of EtOH. However, activation of NK cells to higher levels
of lytic activity may be more important than basal NK cell lytic function in
resistance to cancer or infectious agents. Therefore, the study described here
examined the effects of acute EtOH exposure on activation of NK cells by
polyinosinic-polycytidilic acid (poly I:C). METHODS: Ethanol was administered by
gavage as a 32% solution in water, and poly I:C was administered to activate NK
cells. NK cell activity was measured using a standard 4 hr 51Cr release assay
with YAC-1 tumor cells. The effects of corticosterone were evaluated by
administration of a glucocorticoid antagonist (RU 486) or a dosage of
corticosterone previously shown to induce similar blood levels as treatment with
EtOH. RESULTS: EtOH at 5-7 g/kg suppressed poly I:C-induced increases in NK cell
lytic activity, and at least the lower end of this dosage range yields blood EtOH
levels that are relevant for humans (0.25-0.3%). This suppression was partially
blocked in mice that were pretreated with a glucocorticoid antagonist, and
administration of exogenous corticosterone also suppressed NK cell activation.
CONCLUSIONS: EtOH-induced increases in corticosterone are apparently involved in
the suppression of NK cell activation. This conclusion was supported by the lack
of a direct effect of EtOH or its major metabolites (acetaldehyde and acetate) on
NK cell activation by poly I:C in vitro.
PMID- 10776666
TI - Early postnatal ethanol exposure has long-term effects on the performance of male
rats in a delayed matching-to-place task in the Morris water maze.
AB - BACKGROUND: There is concern that, in the absence of full-blown fetal alcohol
syndrome, binge drinking during pregnancy might produce long-term cognitive
deficits in offspring. Spatial working memory might be particularly vulnerable in
this regard. This is the first study to address this issue in an animal model of
binge exposure during the brain growth spurt using a delayed matching-to-place
(DMTP) task in the Morris water maze. METHODS: Infant male rats were
gastrostomized and reared artificially from postnatal days (PD) 5 to 18. From PD
6 to 9 they were fed either 6.5 g x kg(-1) x d (-1) ethanol (EtOH) in a binge
exposure model (BAC 302 mg/dl) or an isocaloric maltose-dextrin solution (MD).
The study included a third suckled control group (SC) that was reared normally.
The rats were tested on a series of problems in the DMTP task, first as juveniles
(PD 35) and then twice again as adults. Each problem included an initial search
trial and a subsequent test trial. The first two phases of testing used delays of
either 0 sec or 60 sec between these two trials. The third phase increased this
delay to 60 sec and 2 hr. In addition, the rats were tested on a cued task in the
water maze. RESULTS: EtOH rats were impaired relative to controls in their
ability to relocate the hidden platform on the second trial, which followed the
search trial. In Phases 1 and 2, there was no differential effect of ethanol on
performance across the 0-sec and 60-sec delay conditions. However, EtOH rats were
more affected by the longer 2-hr delay in Phase 3. There were no group
differences on the search trial, in swimming speed, or cued-task performance.
CONCLUSIONS: These findings establish that binge exposure to ethanol during the
brain growth spurt results in a long-lasting impairment on the DMTP performance
of rats in the water maze.
PMID- 10776667
TI - Avian genetic background modulates the neural crest apoptosis induced by ethanol
exposure.
AB - BACKGROUND: Ethanol-induced neural crest apoptosis likely contributes to the
distinctive craniofacial phenotype that results from prenatal alcohol exposure.
The mechanism responsible for this apoptosis is incompletely understood. A
serendipitous change in poultry production flocks led to the discovery that, in
chick, the embryo's genetic background modulates its susceptibility to ethanol
induced apoptosis. METHODS: We examined the level of ethanol-induced neural crest
apoptosis in 11 chick layer strains or crosses, using acridine orange uptake.
RESULTS: Holding the ethanol dose and exposure stage constant, strains were
classified into very sensitive (Babcock ISA, HyLine W98, Babcock B300/Hampshire
Red cross [BxHR]), moderately sensitive (Spafas, HyLine W36, Babcock B300), and
nonresponsive (DeKalb White and Black, Shaver White and 2000, DcKalb
White/Hampshire Red cross). Detailed examination of two susceptible strains (W98,
BxHR) and a resistant strain (DcKalb White) revealed that the DeKalb's
nonresponse was not caused by a shift in timing of apoptosis, or to a lower
alcohol exposure at either time of injection or time of death. Strains had
identical stage distributions at the time of injection and at apoptosis; housing
and diet were held constant. CONCLUSIONS: Factors within the embryo and/or egg
environment can affect the susceptibility to ethanol-induced apoptosis. These
sensitive and resistant strains will be important tools to dissect the molecular
mechanism of ethanol-induced apoptosis, and for understanding how these losses
affect subsequent development.
PMID- 10776668
TI - Effect of ethanol on brain metallothionein in transgenic mice.
AB - BACKGROUND: Three isoforms of metallothionein (MT-I, -II, and -III) have been
detected in mice brain but little is known on their inducibility. Therefore,
changes in MT levels in brain were investigated in MT-I overexpressing transgenic
mice (MT-I*) and wild type mice of the same strain (C57BL/6J) after oral
administration of ethanol. METHODS: All experimental mice were given 4 g/kg of
ethanol by gastric intubation. In addition, to account for the stress of animal
handling, both groups of mice (MT-I* and C57) were given distilled water by
gastric intubation and used as controls. At different times after ethanol/water
treatment, the mice were killed and the brains were dissected into six regions.
The total amount of MT in the brain and different regions were measured by a
cadmium-binding assay. Zinc and copper were measured by atomic absorption
spectrometry. The results were compared with untreated mice and corresponding
control mice. RESULTS: In C57BL/6J mice, the whole brain MT was increased by
approximately 1.29-fold at 12 hr and approximately 1.27-fold at 18 hr after
ethanol administration compared with basal levels. In MT-I* male mice, the whole
brain MT was increased by approximately 1.64-fold at 12 hr and approximately 1.62
fold at 18 hr after ethanol administration, whereas in MT-I* female mice, it was
increased by approximately 1.57-fold at 12 hr and approximately 1.61-fold at 18
hr after ethanol administration. Although the zinc and copper levels in the whole
brain were not altered, the zinc level in the cerebellum at 12 and 18 hr in male
and female MT-I* mice were increased, and zinc levels in the hippocampus of male
MT-I* mice were increased at 12 and 18 hr after ethanol treatment. CONCLUSIONS:
Acute or chronic ethanol administration can cause generation of oxygen free
radical and oxidative stress to the brain. The generation of free radicals is
thought to be one of the causes of cell injury after ethanol administration. The
mechanism of induction of MT in brain after oral ethanol administration may be
associated with oxidative stress caused by ethanol or its metabolites, and can be
considered as a protective mechanism against ethanol toxicity.
PMID- 10776670
TI - Pronounced hepatic free radical formation precedes pathological liver injury in
ethanol-fed rats.
AB - BACKGROUND: The role of free radicals in alcoholic liver injury remains
uncertain. These experiments were conducted to measure radical formation in rats
that were fed alcohol along with either fish oil or saturated fats, which cause
different types of liver pathology. METHODS: Liquid diets containing alcohol or
isocaloric dextrose were administered to rats by intragastric infusion for 2
weeks. Radical intermediates detected by spin trapping were measured in bile.
RESULTS: In rats that were fed alcohol plus fish oil, biliary concentrations of
trapped radicals, which most likely originated from lipids, were 6-fold higher
than in controls that were fed fish oil plus dextrose. High rates of radical
formation persisted 24 hr after alcohol withdrawal, when all alcohol had been
metabolized. In contrast, diets containing alcohol and medium chain triglycerides
did not stimulate lipid radical formation. CONCLUSIONS: High rates of lipid
radical formation were observed only in rats that were fed alcohol in combination
with a fish oil diet, and a persistent flux of radical formation continued after
alcohol withdrawal. These radical phenomena precede serious liver pathology,
which develops after longer periods of fish oil plus alcohol diets.
PMID- 10776669
TI - Impaired protein synthesis induced by acute alcohol intoxication is associated
with changes in eIF4E in muscle and eIF2B in liver.
AB - BACKGROUND: Acute alcohol intoxication in rats decreases protein synthesis in
skeletal muscle and, to a lesser extent, in liver. The purpose of the present
study was to examine potential mechanisms for the inhibitory effect of acute
ethanol exposure. METHODS: Rats were injected intraperitoneally with either
ethanol (75 mmol/kg) or saline, and tissues were examined 2.5 hr later. Rates of
protein synthesis in vivo were determined by [3H]phenylalanine incorporation into
protein, and various eukaryotic initiation factors (eIFs) were quantitated by
Western blot analysis to identify possible mechanisms for regulating translation.
RESULTS: Protein synthesis in gastrocnemius and liver was decreased (39% and 21%,
respectively) after alcohol administration, compared with saline-injected control
animals. Alcohol administration did not alter tissue RNA content but diminished
translational efficiency in muscle (43%) and liver (24%). Hepatic eIF2B activity
was decreased 24% in alcohol-treated rats, and this was associated with a 95%
increase in eIF2alpha phosphorylation. However, alcohol did not alter the amount
of 4E-binding protein 1 (4E-BP1) bound to eIF4E, cIF4E bound to eIF4G, or the
phosphorylation state of either 4E-BP1 or eIF4E. In contrast to liver, neither
eIF2B activity nor the phosphorylation of eIF2alpha was affected in muscle of
alcohol-treated rats. However, acute alcohol intoxication increased binding of 4E
BP1 to eIF4E (113%), decreased the amount of cIF4E bound to cIF4G (81%), and
decreased the amount of 4E-BP1 in the phosphorylated gamma-form (77%). The plasma
concentrations of insulin and insulin-like growth factor-I were unchanged by
alcohol, but muscle insulin-like growth factor-I messenger ribonucleic acid
abundance was decreased 35%. CONCLUSIONS: These data suggest that acute alcohol
intoxication decreases translation initiation and protein synthesis in liver and
muscle via different mechanisms. Changes in eIF2B appear to predominate in liver,
whereas alterations in eIF4E availability appear more critical in skeletal muscle
for controlling translation initiation.
PMID- 10776671
TI - Alcohol and aldehyde dehydrogenase genotypes in Korsakoff syndrome.
AB - BACKGROUND: Previous studies have suggested a genetic predisposition to the
development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome
commonly associated with alcoholism; however, little is known about this genetic
risk factor. METHODS: To test the hypothesis that altered alcohol or aldehyde
regulation is related to the development of WKS, the genetic polymorphisms of
aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined
in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic
subjects without any WKS symptoms and 175 nonalcoholic controls. RESULTS:
Although the frequencies of the ALDH2 genotypes and alleles did not differ
significantly between alcoholic subjects with WKS and alcoholics without WKS, the
ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS.
CONCLUSIONS: These findings suggest that the ADH2*1/2*1 genotype is a risk factor
for the development of WKS in alcoholic patients.
PMID- 10776672
TI - An association study between alcoholism and the serotonergic receptor genes.
AB - BACKGROUND: Linkage and association studies of alcoholism using DNA makers have
been conducted without conclusive results. The comorbidity of alcoholism with
affective disorder indicates that dysfunction of the serotonergic system may play
an important role in developing alcoholism. METHODS: We studied the genetic
association between alcoholism and alleles of the HTR1A, HTR2A, and HTR2C genes.
The subjects were 91 biologically unrelated alcoholics and 90 controls.
Polymorphisms of these genes were determined by polymerase chain reaction
restriction fragment length polymorphisms, and the data were analyzed by chi2
tests. RESULTS: We found no significant association between alcoholism and the
HTR1A, HTR2A, and HTR2C genes. CONCLUSIONS: The study results suggest that these
serotonergic receptor genes may not directly contribute to the etiology of
alcoholism.
PMID- 10776673
TI - Association study between genetic polymorphisms in the 14-3-3 eta chain and
dopamine D4 receptor genes and alcoholism.
AB - BACKGROUND: The dopaminergic system may be involved in the development of
alcoholism. As part of our ongoing studies on the association between alcoholism
and dopaminergic genes, we report herein a mutation analysis of the 14-3-3 eta
chain gene (YWHAH) and an association study between alcoholism and the YWHAH and
dopamine D4 receptor gene (DRD4) polymorphisms. METHODS: Nucleotide mutations
were investigated using single-strand conformation polymorphism methods.
Associations were analyzed using a case-control design involving 185 Japanese
alcoholics and 286 Japanese controls. RESULTS: Five polymorphisms, -147G>A,
134(GCCTGCA)2-4, IVS1+31(G)7-8, IVS1+73-74ins(G), and 753A>G, were detected on
the YWHAH, and three of them were novel. No significant associations were found
between alcoholism and these polymorphisms or two additional polymorphisms on
DRD4 exon III and DRD4 -521C/T. CONCLUSIONS: YWHAH and DRD4 do not appear to play
a major role in the development of alcoholism.
PMID- 10776674
TI - Differential display of ethanol-induced gene in N18TG2 cells.
AB - BACKGROUND: Recent advances in molecular biology, such as polymerase chain
reaction (PCR) differential display, have enabled the screening of mRNAs
transcriptionally regulated by chronic ethanol treatment. Screening of gene
expression after ethanol exposure will be the most needed for new biological
insights into alcoholism. METHODS: We used PCR differential display to detect
differentially expressed RNAs in N18TG2 cells treated for 4 days with physiologic
concentrations of ethanol (25 mM). RESULTS: We succeeded in identifying two
differentially expressed RNAs in the ethanol-treated cells. The increase in the
expression of the two RNAs was verified by Northern hybridization analysis.
Sequence analyses and searches of the sequence databases revealed that one of the
RNAs was that of the heat shock cognate protein 73 (HSC73) gene and that the
other was the product of a novel gene. The increase in the level of HSC73 mRNA
after ethanol administration was consistent with similar reports from other
laboratories, and indicated that our assay system would be applicable to the
screening of up-regulated gene expression during ethanol treatment. Rapid
amplification of cDNA 5'-ends (5'-RACE) allowed us to determine the upstream
sequence of the uncharacterized mRNA that would code for a protein of 113 amino
acids. A homology search by MPsrch indicated very low homology to the calcium
channel L-type alpha I subunit. CONCLUSIONS: The function of this new gene
product is presently unknown, but our results indicate that an investigation of
the pathophysiological significance of the gene in alcoholism would be
worthwhile. Identification of genes that are influenced by chronic ethanol will
certainly increase of the molecular mechanisms underlying physiologic dependence.
PMID- 10776675
TI - Ethanol improves decreased filterability of human red blood cells through
modulation of intracellular signaling pathways.
AB - BACKGROUND: Deformability of red blood cells (RBCs) is one of the most important
factors in maintaining the microcirculation system. In vitro studies have
revealed that ethanol seriously impairs the deformability of RBCs at
concentrations far higher than those easily achievable in the blood after alcohol
consumption. We examined the effect of ethanol on deformability at the
physiologically achievable concentrations. METHODS: To impair deformability
quantitatively, washed RBCs from healthy young male volunteers were mechanically
stressed by being injected rapidly through a fine needle. The deformability of
RBCs was evaluated by measuring the filterability through a nickel mesh filter.
The activities of protein kinase A and protein kinase C in RBCs were measured by
the ELISA method using an antibody for the phosphorylated substrate of the
kinases. RESULTS: Ethanol exhibited a biphasic effect on the mechanically
impaired filterability of human RBCs, that is, an improvement at concentrations
from 0.02% to 0.2% (v/v) and a marked deterioration at 0.5% and higher. Without
mechanical stress, ethanol decreased filterability at concentrations of 0.5% and
higher. Ethanol increased the protein kinase A and protein kinase C activities of
the mechanically stressed RBCs at concentrations of 0.02% and higher and those of
the RBCs without mechanical stress at concentrations of 0.05% and higher.
CONCLUSIONS: The present results suggest a beneficial effect of ethanol on blood
rheology at concentrations that are physiologically achievable in the blood and
indicate the importance of intracellular signaling pathways in regulating the
deformability of RBCs.
PMID- 10776676
TI - Acute and chronic effect of alcohol on Ca2+ channels in hepatic stellate cells.
AB - BACKGROUND: Hepatic stellate cells have been reported to play important roles in
the regulation of hepatic microcirculation via cell contraction. Increase in
intracellular calcium concentration is required to induce cell contraction. We
have already reported the existence of L-type voltage-operated Ca2+ channels
(VOCC), such as smooth muscle cells. On the other hand, alcohol has been known to
disturb hepatic microcirculation. In this study, we evaluated the effect of acute
and chronic treatment of alcohol on VOCC in rat hepatic stellate cells. METHODS:
Stellate cells isolated from rats were cultured with or without 100 mM ethanol
for up to 14 days. VOCC were detected by the patch clamp technique. Cells
cultured for 14 days without ethanol were exposed to ethanol to investigate
calcium current during membrane depolarization. alpha-Smooth muscle actin (alpha
SMA) was stained by indirect immunofluorescence. RESULTS: In the control model,
VOCC were recognized in cells cultured for more than 7 days. Detection of VOCC
increased from 9% on day 7 to 55% on day 14. On the other hand, VOCC in cells
treated chronically with 100 mM ethanol appeared earlier than in the control and
the incidences were significantly higher than those of the control accompanied
with an early activation of cells. In contrast, simultaneous exposure to ethanol
during the membrane depolarization inhibited Ca2+ current. CONCLUSIONS: The
expression of Ca2+ channels in stellate cells were up-regulated by the chronic
treatment of alcohol accompanied with the transformation to myofibroblast-like
phenotype. However, alcohol itself inhibited Ca2+ current.
PMID- 10776677
TI - Changes in dopamine transporter and c-Fos expression in the nucleus accumbens of
alcohol-tolerant rats.
AB - BACKGROUND: We have shown that neurochemical functions of 5-HT3 receptors in
regulating dopamine (DA) release in the nucleus accumbens (ACC) after alcohol
exposure compensate for the dysfunction of serotonergic activity to restore the
original properties in processing alcohol tolerance, and that the development of
alcohol dependence may be mediated by ACC 5-HT3 receptors. In the present study,
the effects of chronic alcohol consumption on the functions of the dopamine
transporter (DAT) and the expression of c-Fos proteins were investigated using in
vivo brain microdialysis and immunocytochemistry. METHODS: Perfusion of cocaine
and 1-(2-Bis-(4-fluorophenyl) methoxy) ethyl)-4-(3-phenylpropyl) piperizine (GBR
12909) through the microdialysis probe membrane increased the extracellular
levels of DA in ACC of alcohol-treated rats that had developed alcohol tolerance
by drinking 10% EtOH for 30 days. RESULTS: The magnitudes of DA reuptake or DAT
inhibitors, cocaine, and GBR 12909 that induced DA availability in the ACC were
significantly higher in alcohol-treated rats than in controls. When compared with
control rats, the alcohol-treated rats exhibited higher levels of DA and its
metabolite, DOPAC, in the ACC. Increased expression of the c-Fos-like protein was
found in the ACC of alcohol-treated rats. These results show that (1) chronic
alcohol consumption desensitizes or decreases the DAT of DA terminals in the ACC
and that (2) EtOH causes cellular hyperexcitability of ACC dopaminergic neurons
with increased Fos expression during alcohol tolerance. CONCLUSION: The findings
suggested that an abnormality of the dopaminergic neurons in the ACC that are
involved with DAT dysfunction is associated with the development of alcohol
tolerance.
PMID- 10776678
TI - Involvement of mu-opioid receptor in the salsolinol-associated place preference
in rats exposed to conditioned fear stress.
AB - BACKGROUND: Salsolinol, a condensation product of dopamine with acetaldehyde (the
initial oxidation product of ethanol), has long been discussed as an endogenous
opioid system-activating factor contributing to the etiology of alcoholism.
Moreover, psychological stress has been considered to play an important role in
the development of alcoholism. METHODS: Male Sprague Dawley rats were subjected
to conditioned fear stress (at 24 hr after electric footshock exposure), and then
salsolinol or saline was injected intraperitoneally. For conditioning, rats were
immediately confined to the nonpreferred compartment after salsolinol injection
and to the preferred compartment after saline injection on alternate days. This
conditioning session was repeated twice daily (for 8 days). Test session was
carried out 1 day after the last conditioning session. RESULTS: Salsolinol [10
mg/kg, but not 1, 3, or 30 mg/kg, intraperitoneally (ip)] without conditioned
fear stress induced a slight, but significant, place preference. In contrast,
salsolinol (1, 3, and 10 mg/kg, ip) with conditioned fear stress induced a marked
and significant place preference. The nonselective opioid receptor antagonist
naloxone hydrochloride (which can pass into the brain), but not the nonselective
peripheral opioid receptor antagonist naloxone methiodide (which cannot pass into
the brain), significantly attenuated the salsolinol (3 mg/kg, ip)-induced place
preference under conditioned fear stress. Moreover, the selective mu-opioid
receptor antagonist beta-funaltrexamine significantly attenuated the salsolinol
induced place preference. Furthermore, 0.3 mg/kg salsolinol (which produced no
significant place preference) combined with the mu-opioid receptor agonist
morphine [0.1 mg/kg, subcutaneously (sc)], at the dose which alone produced no
significant place preference, produced a marked and significant place preference.
Both naloxone hydrochloride and beta-funaltrexamine significantly attenuated the
salsolinol plus morphine-induced place preference. CONCLUSIONS: Salsolinol may
have some rewarding effect, and its rewarding effect may be potentiated by
psychological stress. In addition, the rewarding effect of salsolinol especially
under psychological stress may involve the endogenous central opioid system,
i.e., mu-opioid receptor.
PMID- 10776679
TI - Before-discharge intervention method in the treatment of alcohol dependence.
AB - BACKGROUND: Alcoholics have the fundamental problem of denying dependence on
alcohol and minimizing their alcohol-related problems. Therapeutic interventions
often fail to help alcoholics become aware of their drinking problem and remain
in long-range treatment programs, which is a prerequisite for recovery from
alcohol dependence. METHODS: Inpatients were assigned to either group 1 or 2
depending on which day of the week they were admitted to the hospital. A newly
developed structured intervention method (Before-Discharge Intervention Method,
or BDIM) was employed with select (nonrandomized) hospitalized alcoholics in
group 1 and their family members before the patients were discharged from the
hospital. None of the patients in group 2 received the BDIM. With this
intervention method, the alcoholic's family members delivered to him or her
verbal messages that conveyed concern about the alcoholic's problem drinking,
their observations of the alcoholic's past episodes of drinking problems, and
wishes and support for abstinence. Unless patients died during hospitalization or
would not be able to attend the hospital follow-up clinic and local self-help
groups (Danshukai) after discharge, outcome evaluations were carried out on all
patients in groups 1 and 2 during two calendar months, 3 months after the last
BDIM patient left the hospital. Outcome measures included patient's and family
members' attendance at hospital outpatient follow-up sessions and self-help group
meetings, and patient's abstinence. RESULTS: Family members' attendance at
hospital follow-up sessions and/or self-help group meetings was significantly
higher in group 1 than in group 2. Among the three subgroups of discharged
patients in either group 1 or 2-that is, those who lived with their spouse, those
who lived with someone other than their spouse, and those who lived alone-only
those in group 1 who lived with their spouse did significantly better than their
counterparts in group 2 in three treatment outcome measures. However, patients'
maintenance of abstinence was significantly better only when they and their
family members both attended hospital outpatient follow-up sessions and/or self
help group meetings. We noted no other statistically significant difference
between groups 1 and 2 in any of the other two subgroups of discharged or
patients in any of the three treatment outcome variables. Irrespective of the
BDIM, patients who lived alone did significantly more poorly than either those
who lived with their spouse or those who lived with someone other than their
spouse in terms of attendance at hospital follow-up sessions and local self-help
group meetings and abstinence. CONCLUSIONS: This intervention method can help the
alcoholic face the reality of his or her drinking problems and alcohol dependence
and thus remain longer in long-range rehabilitation programs, which is a
prerequisite for successful recovery from alcohol dependence.
PMID- 10776680
TI - Japanese national survey of adolescent drinking behavior in 1996.
AB - BACKGROUND: Despite legal prohibition of drinking by minors, there has been no
systematic attempt to monitor drinking by young Japanese. This research, the
first Japanese national survey of Japanese adolescent drinking behaviors, was
conducted in 1996. METHODS: In this survey, information on drinking frequency was
obtained from questionnaires completed by 42,183 junior high school and 72,396
senior high school students in randomly selected schools representing all areas
of Japan. RESULTS: Sixty percent of junior high school students and 70% of senior
high school students reported having drinking experiences; 5% of junior high
school students and 10% of senior high school students drank one or more times
per week. Many of the junior high school students usually drank with their
families and consumed small amounts, but many of senior high school students
drank on various occasions and consumed larger amounts. These Japanese high
school students reported being offered alcohol frequently by their parents, found
it easy to buy alcoholic beverages, and believed that they had the right to
determine whether to drink. Japanese adolescents' drinking has increased over the
past 20 years, whereas drinking by U.S. adolescents has decreased. CONCLUSIONS:
Japanese policies aimed at decreasing adolescent drinking are inadequate. A
system for monitoring and potentially modifying adolescent drinking behavior is
needed.
PMID- 10776681
TI - Is heavy alcohol consumption an attributable risk factor for cancer-related
deaths among Japanese men?
AB - BACKGROUND: Over the past four decades, per capita alcohol consumption in Japan
has increased 4-fold. Age-adjusted cirrhosis mortality rates for men have also
increased, whereas the rates for women have declined gradually. This widening
difference in mortality could be due to a decreasing prevalence of viral
hepatitis infection for both sexes and to differences in alcohol consumption
between the sexes. Difficulties in estimating the impact of increased alcohol
consumption on mortality rates in Japan also arise from changes in the prevalence
of non-alcohol-related risk factors. METHODS: To measure the relative
contribution of alcohol to death from cirrhosis, liver cancer, esophageal cancer,
and head and neck cancer among Japanese men, we used the mortality rate for
Japanese women as the standard because alcohol consumption for women has been
low. We used published vital statistics data from 1992 to 1996 to calculate the
attributable risk percent (ARP) in 5-year cohorts of Japanese men age 20 and
older. RESULTS: Among Japanese men, heavy alcohol consumption accounted for 70.7%
of deaths due to cirrhosis, 76.8% of liver cancer deaths, 88.5% of esophageal
cancer deaths, and 87.4% of head and neck cancer deaths. When we examined ARPs by
age group, ARPs for these four diseases were approximately 80% in the middle age
groups. However, for older groups, the ARPs for cirrhosis and liver cancer were
much lower than those for esophageal cancer and head and neck cancer. The
prevalence of previous hepatitis C virus infection, considered to be the major
cause of cirrhosis and liver cancer, increased with age. CONCLUSIONS: The results
support previous epidemiologic studies conducted in Japan. Heavy alcohol
consumption is a major public health problem among younger Japanese men,
accounting for approximately 80% of the deaths for the four diseases examined.
PMID- 10776682
TI - Prospective study on alcohol intake and risk of subarachnoid hemorrhage among
Japanese men and women.
AB - BACKGROUND: Few prospective data are available to evaluate potential risk factors
of subarachnoid hemorrhage among the Japanese, although several prospective
studies conducted in the United States and in Europe have shown a positive
relationship between alcohol intake and the risk of subarachnoid hemorrhage.
METHODS: A 9.4 year follow-up study was conducted on 12,372 men and women age 40
to 69 years who had no history of stroke, in six communities in Japan. The
incident cases of subarachnoid hemorrhage were confirmed with computed tomography
findings and/or clinical findings. Alcohol intake and other cerebrovascular risk
factors were measured at the baseline examination. A Cox proportional hazard
analysis was used to estimate the relative risks and 95% confidence intervals of
the incidence of subarachnoid hemorrhage. RESULTS: During the follow-up
assessment, 71 cases of subarachnoid hemorrhages occurred. For men, heavy
drinking appeared to be an independent risk factor for subarachnoid hemorrhage;
multivariate-adjusted relative risk was 4.3 (95% confidence interval [CI]: 1.1
16.8; p = 0.04). Among women, no excess risk was found for heavy drinking,
probably due to the small number of heavy drinkers (n = 15). The combination of
heavy drinking with smoking or hypertension increased the risk of subarachnoid
hemorrhage substantially for men; the multivariate-adjusted relative risk was 6.0
(95% CI: 1.8-20.1;p = 0.004) for heavy drinking smokers and 13.0 (95% CI: 3.9
43.9; p < 0.001) for heavy drinking hypertensives. CONCLUSIONS: A reduction in
alcohol intake, smoking cessation, and control of hypertension are important in
preventing subarachnoid hemorrhage among Japanese men.
PMID- 10776683
TI - Effect of acute ethanol administration on the intestinal absorption of endotoxin
in rats.
AB - BACKGROUND: Endotoxin has been implicated in the pathogenesis and progression of
alcoholic liver disease. Not only inactivation of reticuloendothelial function,
which reduces clearance of endotoxin, but also an increase in absorption of
endotoxin from the intestine may be involved in mechanisms of ethanol-induced
endotoxemia. However, it is unclear how ethanol affects absorption of endotoxin
from the intestine in vivo. METHODS: We gave 10 mg/kg of lipopolysaccharides to
rats with water (group 1), 5% ethanol (group 2), or 20% ethanol (group 3) using
an intubation tube to the stomach. Blood samples were collected and plasma
endotoxin levels were measured. We used fluorescence spectrophotometer to examine
permeability of the gut to macromolecules (fluorescein isothiocyanate-dextran;
4,000 Da [FD4] or 20,000 Da [FD20]). RESULTS: Plasma endotoxin levels were not
different between group 1 (9 +/- 2 pg/ml) and group 2 (14 +/-3 pg/ml), whereas
they significantly increased in group 3 with a peak at 60 min (87 +/- 35 pg/ml).
Acute ethanol administration did not affect clearance of endotoxin in rats.
Hemorrhagic erosions of the proximal small intestine with epithelial cell loss
were observed in group 3 at 4 hr, but no significant histological change was
observed at 30 min by light microscopy. Acute ethanol administration (20%)
increased the permeability of the small intestine to FD4 and FD20 in 30 min when
no hemorrhagic erosions of the proximal small intestine with epithelial cell loss
were observed. CONCLUSIONS: Acute ethanol administration increases intestinal
permeability before pathological changes are revealed by light microscopy. Acute
ethanol ingestion, especially at high concentrations, facilitates the absorption
of endotoxin from rats' small intestine via an increase in intestinal
permeability, which may play an important role in endotoxemia observed in
alcoholic liver injury.
PMID- 10776684
TI - Immediate and delayed effects of treatment at the Dead Sea in patients with
psoriatic arthritis.
AB - The purpose of this study was to evaluate the immediate and delayed effects of
balneotherapy at the Dead Sea on patients with psoriatic arthritis (PsA). A total
of 42 patients with PsA were treated at the Dead Sea for 4 weeks. Patients were
randomly allocated into two groups: group 1 (23 patients) and group 2 (19
patients). Both groups received daily exposure to sun ultraviolet rays and
regular bathing at the Dead Sea. Group 1 was also treated with mud packs and
sulfur baths. Patients were assessed by a dermatologist and a rheumatologist 3
days before arrival, at the end of treatment, and at weeks 8, 16, and 28 from the
start of treatment. The clinical indices assessed were morning stiffness, right
and left hand grip, number of tender joints, number of swollen joints, Schober
test, distance from finger to floor when bending forward, patient's self
assessment of disease severity, inflammatory neck and back pain and psoriasis
area and severity index (PASI) score. Comparison between groups disclosed a
similar statistically significant improvement for variables such as PASI, morning
stiffness, patient self-assessment, right and left grip, Schober test and
distance from finger to floor when bending forward. For variables such as tender
and swollen joints, and inflammatory neck and back pain, improvement over time
was statistically significant in group 1. Addition of mud packs and sulfur baths
to sun ultraviolet exposure and Dead Sea baths seems to prolong beneficial
effects and improves inflammatory back pain.
PMID- 10776685
TI - A longitudinal study of autoantibodies against central nervous system tissue and
gangliosides in connective tissue diseases.
AB - Our objective was to investigate longitudinally, antibodies against central
nervous tissue (anti-CNS) derived from bovine brain and gangliosides GM 1, GD1a,
GD1b, and GT1b in 91 patients with connective tissue diseases (systemic lupus
erythematosus, n = 38; mixed connective tissue disease, n = 16; primary Sjogren's
syndrome, n = 7; progressive systemic sclerosis, n= 13;
polymyositis/dermatomyositis, n=4; overlap syndrome, n = 5; undifferentiated
connective tissue disease, n = 8). Anti-CNS and anti-ganglioside antibodies,
measured by enzyme-linked immunosorbent assay, were found in 73% and 63% of
patients, respectively. Anti-CNS positive sera were also reactive in Western
blotting in 74% of cases and recognized up to 14 different polypeptides from 29
to 130 kDa. Anti-CNS and anti-ganglioside antibodies reflected only in a limited
extent the disease activity. In 27 of 58 patients, anti-CNS antibodies remained
positive independently of disease activity and antibody levels did not correlate
with the phases of exacerbations. A total of 36 of 60 anti-CNS-positive patients,
in contrast to two of 22 anti-CNS-negative patients, had major neuropsychiatric
manifestations (P < 0.001). Anti-ganglioside antibodies were not significantly
associated with neuropsychiatric manifestations. In conclusion, our longitudinal
data suggest that anti-CNS antibodies may be an important marker for the
diagnosis of cerebral involvement in connective tissue diseases, but the
pathogenic role of these autoantibodies remains to be determined.
PMID- 10776686
TI - Spondylitis is the most common pattern of psoriatic arthritis in Korea.
AB - We assessed the prevalence and clinical features of psoriatic arthritis (PsA) in
Korean patients with psoriasis. The prevalence of PsA in patients with psoriasis
was 9%. Patients with PsA were older and had a longer duration of skin disease
than those with psoriasis alone (median age, 40 vs 35 years, P = 0.03, and 15.3
vs 11.7 years, P = 0.04, respectively). Spondylitis was the most common pattern
of PsA (50%). Nail change, dactylitis, and enthesopathy were observed in 36%,
15.4%, and 15.6% of patients with PsA, respectively. Increased erythrocyte
sedimentation rate (ESR), antinuclear antibody, and radiological sacroiliitis
were more frequent in patients with PsA than in those with uncomplicated
psoriasis (25.8% vs 10.3%, P = 0.04; 37.9% vs 16.7%, P = 0.02; and 37.8% vs 1.1%,
P < 0.01, respectively). The onset ages of psoriasis and arthritis in the
spondylitis group were significantly lower than those in the non-spondylitis
group (median age, 21.5 vs 31 years, P = 0.03, and 28.5 vs 43.5 years, P = 0.01,
respectively). HLA-B27 was prevalent in 8% of patients with PsA.
PMID- 10776687
TI - Expression of kappa-opioid receptor mRNA in human peripheral blood lymphocytes
and the relationship between its expression and the inflammatory changes in
rheumatoid arthritis.
AB - The expression of the kappa-opioid receptor on human peripheral blood cells (in
rheumatoid arthritis cases and normal volunteers) was examined using reverse
transcriptase polymerase chain reaction (RT-PCR), and the relationship between
its expression and the inflammatory activity or chronic pain in patients with
rheumatoid arthritis (RA) was determined. RT-PCR was performed on the peripheral
blood cells obtained from 37 patients with RA and 13 healthy volunteers. kappa
Opioid receptor mRNA expression was exhibited on the blood cells of 37% of RA
patients (14/ 37) and 54% of healthy volunteers (7/13) , and the levels of
expression were lower in the RA patients than in the healthy volunteers.
Regarding the relationship between the expression of kappa-opioid receptor mRNA
and the symptoms in RA patients, it was noted that the expression of the receptor
mRNA was significantly decreased in RA patients in whom erythrocyte sedimentation
rate (ESR), Lansbury index, and visual analogue pain scores were high. The kappa
opioid receptor mRNA was expressed on four cell types, namely, T and B cells,
macrophages, and natural killer (NK) cells in RA patients; however, it was
expressed only on the T and B cells and macrophages (and not on NK cells) in the
healthy volunteers. Our findings suggest that the levels of expression of kappa
opioid receptor mRNA were decreased in RA patients in comparison with those in
healthy volunteers; and that they were significantly related to the inflammatory
activity or chronic pain in the RA patients. The higher the mRNA expression
level, the less severe the inflammatory changes of RA. The kappa-opioid receptor
may thus play a role in the modulation of nociception and anti-inflammatory
changes in chronic inflammatory disorders.
PMID- 10776688
TI - Serum levels of IL-10, IL-6, IL-1ra, and sIL-2R in patients with psoriatic
arthritis.
AB - Our objective was to evaluate the levels of interleukin-6 (IL-6), soluble
receptors of IL-2 (sIL-2R), IL-10, and IL-1 receptor antagonists (IL-1ra) in the
serum of patients with psoriatic arthritis (PsA) and to assess the correlation
between these levels and parameters of clinical activity of skin and joint
disease. In total, 34 patients with PsA and ten healthy volunteers participated
in the study. Assessment of joint disease included duration of morning stiffness,
number of tender and swollen joints, right and left grip, the presence of
inflammatory spinal back pain, and Schober test. Current severity of skin disease
was graded according to the psoriasis area and severity index (PASI). Erythrocyte
sedimentation rate (ESR) was determined as a marker of disease activity. Serum
levels of IL-6, sIL-2R, IL-1ra, and IL-10 were measured by an enzyme immunoassay
kit. Significantly higher serum levels of IL-6, sIL-2R, IL-1ra, and IL-10 were
found in patients with PsA in comparison with healthy volunteers. A statistically
significant correlation was found between levels of sIL-2R and PASI, whereas no
association was found with clinical parameters of joint severity. Levels of IL
lra correlated with the number of tender and swollen joints. No correlation was
found between levels of IL-6, IL-10, and clinical parameters of skin and joint
severity. In the group of patients with PsA, serum levels of sIL-2R clearly
correlated with severity of skin disease, whereas levels of IL-1ra were
associated with joint severity.
PMID- 10776689
TI - Rheumatoid factors in systemic lupus erythematosus: association with clinical and
laboratory parameters. SLE study group.
AB - The prevalence and clinical and laboratory associations of IgM, IgG and IgA
rheumatoid factors (RF) were determined in 352 patients with systemic lupus
erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%,
and 20.5% of the sera, respectively. RF were associated with sicca syndrome,
hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and
SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with
nephritis and livedo racemosa. Moreover, we observed an association of RF and
parameters of inflammatory activity such as elevated erythrocyte sedimentation
rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that
laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA
DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients
characterized by distinct autoimmune phenomena and high disease activity in the
absence of nephritis.
PMID- 10776690
TI - Influence of cyclosporin A on radiological progression in early rheumatoid
arthritis patients: a 42-month prospective study.
AB - The aim of this study was to evaluate whether cyclosporin A (CsA) influences the
radiological disease progression in early rheumatoid arthritis (RA) patients in
comparison with other disease-modifying drugs (DMARDs). A total of 103 early RA
patients, without prior use of DMARDs, were randomized to receive CsA (3 mg/kg
per day) or methotrexate (MTX) (0.15 mg/kg per week). In addition, all patients
received prednisone (7.5 mg/day). After 42 months of treatment, pairs of hand and
wrist radiographs of 41 patients treated with CsA and 42 treated with MTX were
evaluated blindly and separately by two investigators, using reference
radiographs for scoring. A scale scoring similar to Larsen's standard radiographs
with minor modifications was used. The studied radiographs were obtained at the
beginning and 42 months after therapy in both groups. Patients in both groups
responded beneficially to the above treatment regimens. In the CsA group, 37
patients (71 %) remained radiographically stable and 4 worsened, while in the MTX
group 39 patients (76%) remained stable and 3 deteriorated. No significant
radiological worsening was found in the CsA-treated patients as compared to those
treated with MTX. Early immuno-intervention in RA patients appears to be crucial
for the future development of joint damage: CsA can delay radiological disease
progression and may inhibit joint damage deterioration in early RA patients.
PMID- 10776691
TI - The MEK inhibitor, PD98059, reduces survival but does not block acute myeloid
leukemia blast maturation in vitro.
AB - The appearance of blasts in acute myeloid leukemia (AML) reflects a shift from
cellular processes inducing maturation and cell death to those favouring survival
and accumulation. We have monitored changes in the growth factor signalling
molecule MAPKinase, in the cytoprotective protein Bcl-2 and in the cell death
protein Bax, during maturation of proliferating and non-proliferating AML blasts
in vitro. Eighteen AML samples were cultured for 7 d in serum-free medium with or
without a supplement of recombinant cytokines comprising c-kit ligand, IL3 and
GMCSF. Maturation of AML blasts, as assessed by morphology on Romanowsky-stained
slides of 7/18 samples and by changes in surface CD markers on all 18 leukemias,
occurred in both the absence and presence of cytokines. Cell numbers decreased to
a mean of 71% after 7 d of cytokine-free culture, but increased to 210% in
cytokine-supplemented cultures. The proportion of CD15-positive cells, assessed
by flow cytometry, increased over 7 d in 17/18 samples, from a mean of 22% to 68%
in cytokine-free cultures and to 72% in cytokine-supplemented cultures (p = <
0.0001 for both). By immunofluorescence/flow cytometry, there was no significant
change in Bcl-2 over 7 d of culture, while Bax increased, particularly in
cytokine-free cultures (2.2-fold), which led to a significant decrease in the Bcl
2/Bax ratio. Immunoblotting demonstrated that ERK was briefly phosphorylated
after seeding AML blasts into culture. PD98059, an inhibitor of MAPKinase kinase
(MEK) which activates MAPKinase, inhibited this transient ERK phosphorylation but
was unable to block maturation as measured by acquisition of CD15 in samples from
12 patients with low starting numbers of CD15-positive cells. PD98059, however,
reduced cell numbers in 7-d liquid culture and, in cytokine-supplemented
cultures, this was associated with a 1.3-fold increase in Bcl-2 (p = 0.012) and a
1.4-fold increase in Bax (p = 0.02). Overall, these data demonstrate that most
leukemic populations can partially differentiate in vitro without the need for
cytokines or inducers. The MAPKinase pathway is not required for this maturation,
but it does maintain cell viability in the absence or presence of cytokines. A
rise in Bcl-2 may not protect AML blasts in the face of elevated Bax.
PMID- 10776692
TI - Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune
thrombocytopenic purpura.
AB - We investigated the levels of various cytokines and soluble factors in ITP
patients, in order to determine the influence of these factors on the
pathogenesis of ITP. We found increases in IL-2, IL-6, IFN-gamma, and M-CSF
levels in ITP patients compared with those in healthy individuals. On lymphocyte
phenotype analysis, we found no clear difference in total T cell population (CD2+
CD19- cells) or cytotoxic T cell frequency (CD8+ CD11b- cells) between these two
groups. The frequency of helper/inducer T cells (CD4+ CD8- cells) was decreased
in ITP patients. There was a significant increase in activated T cells (CD3+ HLA
DR+ cells) in ITP patients. Furthermore, frequencies of NK cells of potent
activity (CD16+ CD56+ cells) were significantly elevated in ITP patients.
Seventeen of the 54 ITP patients (31.5%) had elevated levels of sFas, and 11 of
the 54 patients (20.4%) of sFasL. In addition, a significant increase of sFasL
was observed in sFas-positive ITP patients, and in these patients the sFasL level
was correlated with that of sFas (r = 0.687, p < 0.01). We found significant
increases in IL-2 and sIL-2R levels in sFas-positive ITP patients. For other
factors examined, however, there were no differences in level between sFas
positive and -negative ITP patients. Percentages of activated T cells (CD3+ and
HLA-DR+ cells) and NK cells (CD16+ and CD56+ cells) were significantly higher in
sFas-positive ITP patients than in sFas-negative ITP patients. These findings
suggests that the pathogenesis of ITP includes alteration of the Fas/FasL
pathway.
PMID- 10776693
TI - Thrombopoietin activates the growth of megakaryoblasts in patients with chronic
myeloproliferative disorders and myelodysplastic syndrome.
AB - The effects of thrombopoietin (TPO) on cell proliferation and differentiation,
and the relation between these effects and the expression of c-mpl on leukemia
cells were studied in seven acute myelogeneous leukemia cell lines and seven
myelogeneous blast cell preparations from patients with chronic
myeloproliferative disorders (CMPDs) and myelodysplastic syndrome (MDS). Among
the leukemia cells, five preparations of megakaryoblastic leukemia cells from
patients and one megakaryoblastic cell line, CMK 11.5, proliferated in response
to TPO in vitro. CMK 11.5 and the blastic cells from one patient diagnosed with
MDS with myelofibrosis differentiated with increasing expression of CD41a in
response to TPO. However, TPO had no effect on the cells lacking megakaryocytic
characteristics. Some patients with CMPD and MDS develop acute transformation
with blasts demonstrating megakaryocytic features, and some of these cells show
growth in response to TPO. Therefore, in vivo administration of TPO should be
considered carefully for patients with CMPD or MDS, since TPO may induce leukemic
cell proliferation.
PMID- 10776694
TI - Incidence of iron-deficiency anaemia in infants in a prospective study in Jordan.
AB - A high prevalence of iron-deficiency anaemia has been reported in Jordanian
infants. A prospective study of infants in downtown Amman examined the
relationship between anaemia in pregnancy and iron deficiency in infancy. The
iron status of infants born to 107 anaemic (Hb < 11 g/dl) and 125 non-anaemic
mothers was reviewed at 3, 6, 9 and 12 months. Indicators to define iron
deficiency anaemia were Hb < 11 g/dl and either plasma ferritin < 12 microg/l or
zinc protoporphyrin (ZPP) > 35 microg/dl whole blood. Haemoglobin electrophoresis
excluded haemoglobinopathy. There was 72% iron-deficiency anaemia throughout the
year, significantly higher in infants born to anaemic mothers (81%; n = 91)
compared with controls (65%; n = 112). At 12 months, 72% of the infants tested (n
= 195) were anaemic. While 57% were identified as iron-deficient by research
criteria of either ferritin or ZPP, only 37% were identified by ferritin alone,
40% by ZPP alone and 29% if both ferritin and ZPP were required to meet criteria.
Most infant anaemia was identified as due to iron deficiency, supporting
contextual setting as assisting diagnosis: infants in developing countries are
recognised as vulnerable to iron deficiency. Using multiple criteria, more cases
were identified when either ferritin or ZPP were abnormal than when one alone, or
both parameters were required to meet research criteria.
PMID- 10776695
TI - Beta-thalassaemia intermedia in Lebanon.
AB - Approximately one third of thalassaemia patients on record in Lebanon have
thalassaemia intermedia. We have analysed three factors in a panel of 73 patients
with this less severe form of the disease in our population: mild beta-globin
gene mutations, deletions in the alpha-globin gene and the presence of a
polymorphism for the enzyme Xmn I in the Ggamma-promoter region. The results show
that the most important contributing factor is the beta-genotype: 68% of patients
have a mild beta+ mutation (IVSI-6, cd29, -88 or -87), while 26% of patients are
positive for the Xmn I polymorphism associated with increased production of HbF,
which showed strong linkage to particular mutations (IVSII-1, cd8 and cd30).
However, the genotype phenotype correlation is difficult, because many patients
were initially misdiagnosed as thalassaemia major and were started early on
regular blood transfusions, which was stopped later on. This illustrates well the
importance of an early accurate diagnosis of thalassaemia intermedia for
appropriate clinical management.
PMID- 10776696
TI - Characteristics of haemopoietic progenitor cells related to CD34 epitope class
expression.
AB - Haemopoietic progenitor cells (HPCs) express the CD34 molecule, a heavily
glycosylated transmembrane protein displaying three main classes of epitopes. The
CD34 epitope class expression may vary between different subsets of HPCs. The aim
of this study was to characterise the subsets of HPCs expressing CD34 class II
and III epitopes. The cells were studied for coexpression of activation-, lineage
and adhesion-associated molecules, and their clonogenic ability and
morphological features were examined. CD34+ HPCs expressing class III epitopes
outnumbered those expressing class II. Class III expressing HPCs were enriched
for CFU-GM and BFU-E and cells coexpressing CD13, CD33, c-kit and CD71 compared
to class II expressing HPCs. CD34+ cells exclusively expressing class III
epitopes uniformly displayed CD13 and CD33; they had a high clonogenic capacity
and morphological characteristics of promyelocytes and myelocytes. The data show
that class III epitopes are distributed more broadly on CD34+ HPCs than are class
II epitopes, and that lack of class II epitopes is confined to CD34+ HPCs at a
late stage of myeloid differentiation. The higher number of class III expressing
HPCs coexpressing c-kit and CD71 suggests that these cells exhibit a higher
proliferative or differential potential than do HPCs expressing class II
epitopes.
PMID- 10776697
TI - A quantitative reverse transcriptase polymerase chain reaction method for the
detection of leukaemic cells with t(8;21) in peripheral blood.
AB - We evaluated the usefulness of a recently developed real-time reverse
transcriptase polymerase chain reaction (RT-PCR) system to detect minimal
residual diseases (MRD) in patients with acute myelogenous leukaemia (AML) with
chromosomal translocation t(8:21). The method was simple, rapid and reproducible
for the quantity of chimeric AML1-ETO (MTG8) transcripts. The ratio of the
absolute copy number of a target gene (AML1-ETO) to a control gene
(glyceraldehyde-3-phosphate dehydrogenase, GAPDH) was calculated by using a
fluorescence curve prepared from amplicons of serially diluted standard RNA. The
relative points of MRD in bone marrow (BM) of 8 patients in the acute phase of
the disease was from 0.85 to 3.0, whereas those of MRD in complete remission (CR)
decreased to below 6.4 x 10(-3). This method was also applied to evaluate
chimeric transcripts in peripheral blood (PB) samples. The values in patients
with t(8;21) AML were from 0.97 to 2.0 in the acute phase, whereas those in CR
showed less than 2.2 x 10(-4). There was 10(-5)-fold difference in AML1-ETO mRNA
expression between PB samples in the acute phase and those in CR. The results
suggest that we may easily monitor MRD in patients with t(8;21) AML through
quantitative analysis of AML1-ETO transcripts in blood samples.
PMID- 10776698
TI - Different alterations in lactate dehydrogenase activity and profile of peripheral
blood mononuclear cells in Hodgkin's and non-Hodgkin's lymphomas.
AB - The enzyme lactate dehydrogenase (LDH) activity of peripheral blood mononuclear
cells (PBMC), LDH isotype H and M pattern and PBMC spontaneous LDH release
activity were examined in 55 non-Hodgkin's lymphoma (NHL) patients, 46 Hodgkin's
disease (HD) patients and 47 controls. The intracellular LDH and M isotype
activity of PBMC, their spontaneous LDH release activity significantly increase
(p < 0.01) in NHL with progressing histological grade of malignancy. Contrary to
this, all classical HD patients have a significant elevation (p < 0.05) of each
of these parameters. Furthermore, unlike HD, in NHL clinical stage is associated
with significant (p < 0.05) increase in the level of spontaneous LDH release
activity in each histological form. It is also shown that spontaneous LDH release
activity of PBMC for HD and NHL patients demonstrates significant positive
correlation (p < 0.005) with serum LDH level, although elevation of spontaneous
LDH release precedes serum LDH increase in both diseases. The results obtained
regarding alterations in intracellular, isotype and spontaneously released LDH
activity of circulating PBMC show that these parameters are dependent, in NHL
patients, on the grade of malignancy and tumor burden, while they are
persistently present in HD patients.
PMID- 10776699
TI - Acute promyelocytic leukemia and pregnancy.
AB - In acute promyelocytic leukemia (APL), the use of all-trans-retinoic acid (ATRA)
as a differentiating agent induces complete remission in a high percentage of
patients. In pregnancy, however, this drug bears the risk of severe
teratogenicity to the child. We report the case of a 23-yr-old woman at 21 weeks'
gestation suffering from APL. She was treated with ATRA (45 mg/m2) for 40 d and
two courses of standard chemotherapy. The mother achieved complete remission
within 22 d of treatment. Fetal development was normal, and a healthy premature
girl was born in the 35th week of pregnancy. In a review of the literature we
have identified 14 cases of APL in pregnancy treated with ATRA alone or in
combination with chemotherapy. ATRA has been used as early as in the 3rd week of
gestation and in no case have malformations or other teratogenic effects
occurred. Side-effects, however, ranged from fetal cardiac arrhythmias to
induction of labour. Although known to exhibit severe teratogenic effects during
the first trimester of pregnancy, ATRA seems to be reasonably safe during the
second and third trimesters in the treatment of APL. However, careful obstetric
follow-up is mandatory regarding fetal cardiac complications.
PMID- 10776700
TI - Intravenous iron polymaltose complex for treatment of iron deficiency anaemia in
pregnancy resistant to oral iron therapy.
PMID- 10776702
TI - Hypokalemia, hypophosphatemia and hypouricemia due to proximal renal tubular
dysfunction in acute myeloid leukemia.
PMID- 10776703
TI - Iron overload in thalassaemias and genetic haemochromatosis.
PMID- 10776701
TI - 3H9, a monoclonal antibody capable of discriminating neutrophilic from basophilic
and eosinophilic granulocytes.
PMID- 10776704
TI - Transplantation versus coronary artery bypass in patients with severe ventricular
dysfunction. Surgical outcome and quality of life.
AB - BACKGROUND: The purpose of this study is to evaluate the quality of life,
functional status and survival rate of patients with left ventricular ejection
fraction (LVEF) < or = 20% following coronary bypass (CABG) versus heart
transplantation. METHODS: EXPERIMENTAL DESIGN: comparative study, mean follow-up
of 20 months. SETTING: division of cardiac surgery at a McGill University-based
hospital in Montreal, Canada. PATIENTS: the charts of 65 consecutive patients
with angiographic LVEF < or = 20% were reviewed. Among these patients, 14/65 were
referred for transplantation but instead underwent CABG (Group I) after
consultation with the transplant committee. The charts of 14 matched transplant
patients (Group II) were reviewed. The SF-36 and Duke's questionnaire forms were
mailed to both groups in order to evaluate their quality of life and functional
capacity, respectively. INTERVENTIONS: comparison between coronary bypass and
heart transplantation. MEASURES: main outcome measures were mortality, quality of
life, and functional capacity. RESULTS: Results are expressed as mean+/-SEM. The
in-hospital mortality rate of CABG among all patients with LVEF < or = 20% was
4.6% (3/65). Among the 14 CABG patients initially referred for transplantation,
perioperative mortality was 1/14 (7.1%), same as in the matched transplant group.
Three additional group I patients were reported by family to have died of cardiac
events at follow-up period. Postoperative death identified at follow-up was
assigned the lowest life quality score. The transformed quality of life scores
were as follows: physical functioning: I=42.5+/-10.6, II=73.2+/-7.2, p=0.029;
physical role: I=35.0+/-13.5, I=61.4+/-13.2, p=0.180; bodily pain: I=54.0+/-14.0,
II=69.8+/-8.5, p=0.349; general health: I=34.7+/-9.2, II=84.6+/-5.2, p=0.0003;
vitality: I=36.5+/-9.3, II=60.0+/-5.2, p=0.045; social functioning: I=55.0+/-4.0,
II=87.5+/-5.1, p=0.050; emotional role: I=36.7+/-15.3, II=87.9+/-6.8, p=0.009;
mental health: I=52.8+/-12.4, II=81.5+/-4.2, p=0.054. Duke's activity status
index: I=16.8+/-4.2, II=31.8+/-4.2, p=0.021. CONCLUSIONS: Heart transplant is
associated with a significantly superior postoperative quality of life and
functional capacity than bypass surgery. However, in patients with LVEF < or =
20%, CABG can be performed with an acceptable perioperative mortality of 4.6%
7.1%, similar to the rate for transplantation.
PMID- 10776705
TI - Hemodynamic effects of alpha-human atrial natriuretic polypeptide on patients
undergoing open-heart surgery.
AB - BACKGROUND: A cardiac hormone, alpha-human atrial natriuretic polypeptide (alpha
hANP), acts as a vasodilator and a diuretic by activating cyclic GMP formation.
We studied the hemodynamic effects of continuous intravenous infusion of alpha
hANP on patients undergoing open-heart surgery. METHODS: A total of 15 patients,
including 7 with CABG, 4 with AVR, 2 with CABG plus AVR, and 2 with AVR plus MVR
were involved in the study. They underwent open-heart surgery in our institute
between July 1996 and April 1997. The mean age of patients was 68 years, ranging
from 63 to 77. A dosage of 0.05 microg/kg/min of alpha-hANP was administered to
all patients on postoperative day 1. Hemodynamics and blood and urine samples
were measured at the following times: 2 hours before continuous intravenous
infusion of alpha-hANP, 0, 1, 2, 3, 6, 12 and 24 hours after continuous
intravenous infusion. We concomitantly measured urine volume and the plasma
concentration of alpha-hANP. RESULTS: The plasma concentration of alpha-hANP
increased sufficiently after the beginning of continuous intravenous infusion
without any side effects, and the urine volume increased too. The administration
of alpha-hANP induced a decrease in central venous pressure, pulmonary capillary
wedged pressure and the pulmonary vascular resistance index. Systemic vascular
resistance index and cardiac output remained unchanged. CONCLUSIONS: It is useful
for the management of patients with associated volume overload following open
heart surgery because the administration of alpha-hANP decreases preload and
facilitates satisfactory urination.
PMID- 10776706
TI - Surgical correction for sinus of Valsalva aneurysm.
AB - BACKGROUND: To evaluate the efficacy of surgical correction of sinuses of
Valsalva aneurysms, 24 patients operated on from 1974-1994 were reviewed. Mean
age was 42.2+/-16.7 years; 17 were males. METHODS: Right coronary sinus was
affected in 13 patients and noncoronary sinus in 8. Intracardiac fistula was
detected in 16 patients: into the right atrium in 8; right ventricle in 5; left
ventricle in 2; and left atrium in 1. Repair was performed via an aortic approach
in 11 patients and a combined aortic and intracardiac approach in 13 patients.
Suture closure of the fistula was via the aortic side in 10 cases and the
intracardiac side in 6. Ten patients had patch closure via the aortic side.
RESULTS: Follow-up was 92% complete at a mean of 8.4 years with 3 late cardiac
and 1 noncardiac deaths. Eighty-eight percent of patients are in New York Heart
Association functional class I or II; none underwent reoperation. CONCLUSIONS:
Sinuses of Valsalva aneurysm repair have low operative mortality and morbidity
risks with excellent early and late results. Surgical approach is dependent upon
the presenting pathology.
PMID- 10776707
TI - What are the predictors of restoration of sinus rhythm after combined treatment
with surgical repair for organic heart disease and the Maze procedure for atrial
fibrillation?
AB - BACKGROUND: Recently, combined treatment using the Maze procedure for organic
heart disease and atrial fibrillation has been reported, but there have been few
studies of cardiac rhythm after combined treatment. Predictors of cardiac rhythm
after combined surgical treatment have been unknown. METHODS: Thirty patients who
underwent cardiac surgery with the Maze procedure were retrospectively enrolled
in this study. Two groups consisted of the patients with restoration of sinus
rhythm after surgery (SR: n=15, 6 males and 9 females, mean age of 64 years), and
the patients with maintenance of atrial fibrillation (AF; n=15, 5 males and 10
females, mean age of 61 years). Before cardiac surgery, all patients underwent
exercise testing with measurement of atrial natriuretic peptide (ANP) before and
after exercise testing, two-dimensional echocardiography, and right and left
heart catheterization. RESULTS: The mean maximal heart rate and the ANP level
after exercise testing in SR were significantly higher than those in AF. The left
atrial dimension and right atrial and pulmonary capillary wedge pressures were
significantly higher in AF than in SR. These findings indicate that subjects in
SR exhibited less impaired atrial function which were evaluated by exercise
testing with measurement of ANP, echocardiography, and cardiac catheterization.
CONCLUSIONS: The atrial function of patients with sinus rhythm after the Maze
procedure may be less impaired than that of patients remaining in atrial
fibrillation.
PMID- 10776708
TI - Chronic pulmonary artery balloon counterpulsation in sheep via percutaneous
route.
AB - BACKGROUND: In clinical practice pulmonary artery balloon counterpulsation (PABC)
has been utilized only in the operative setting with the balloon housed in a
graft attached to the pulmonary artery. Clearly, percutaneous insertion of a
dedicated pulmonary artery balloon is a desirable goal for patients requiring
temporary assist for right ventricular failure. METHODS: To address the question
of right sided cardiopulmonary tolerance for a chronic indwelling pulmonary
artery balloon, six adult ewes underwent percutaneous placement of an 11 ml
pulmonary artery balloon, via the femoral vein. Effective pumping and timing were
monitored for 48 hours at which time the animals were sacrificed. At autopsy
gross and microscopic study of all right heart structures, the pulmonary arteries
and the lungs were studied for adverse effects. RESULTS: There were
inconsequential minor abrasions to right heart structures in most animals. The
pulmonary artery in five of six animals revealed ecchymoses and some transmural
hemorrhage, but no necrosis or perforation. There was no pulmonary injury that
could not be ascribed to postoperative atelectasis. CONCLUSIONS: This study
demonstrates that chronic pulmonary artery balloon counterpulsation can be
carried out for a period of 48 hours without significant injury to right heart
and pulmonary structures in the ovine model
PMID- 10776709
TI - IL-8, IL-6 and ICAM-1 in serum of paediatric patients undergoing cardiopulmonary
bypass with and without cardiocirculatory arrest.
AB - BACKGROUND: The aim of the present study was to evaluate the systemic
inflammatory response to CPB in paediatric patients undergoing surgical
correction of congenital heart diseases. METHODS: EXPERIMENTAL DESIGN:
comparative investigation. SETTING: paediatric cardiology hospital INTERVENTION:
ICAM-1, IL-8, and IL-6 production were analysed before and during CPB, and after
surgery in 9 paediatric patients, submitted to cardiocirculatory arrest (Group
A); and in 11 without cardiocirculatory arrest (Group B). MEASURES: ICAM-1, IL-8,
and IL-6 production were analysed from arterial samples before and during CPB,
and after surgery. RESULTS: In group A vs group B a significant increase of IL-8
was detected during (297+/-250 vs 11+/-19 pg x ml(-1), p<0.001) and after (100+/
230 vs n.d. pg x ml(-1)) surgery and was correlated with the duration of
operation (r=0.759; p=0.0001) and clamping time (r=0.738; p<0.05). After surgery
in group A, IL-6 levels (35+/-43 pg x ml) were higher than those in group B (2+/
5 pg x ml), and a good correlation was observed between IL-6 and duration of
aortic clamping (r=0.714; p=0.048), cardiac arrest, (r=0.714; p=0.048), and
length of surgery (r=0.867; p=0.04). CONCLUSIONS: In children who underwent CPB
with cardiocirculatory arrest cytokine production seems related to duration of
operation and amplified by ischemia-reperfusion phenomena.
PMID- 10776710
TI - Effect of Celsior and University of Wisconsin solutions on myocardial metabolism
and function after warm ischemia.
AB - BACKGROUND: Optimal preservation of donor hearts remains a significant concern
during transplantation. Organ shortage led to an increase in the use of damaged
hearts. METHODS: To study the effect of preservation solutions on recovery of
myocardial metabolism and function after warm ischemia, 10 dogs underwent 30
minutes of warm global ischemia under cardiopulmonary bypass. The animals were
then administered 1 liter of Celsior (5 dogs), an extracellular crystalloid
solution or 1 liter of University of Wisconsin solution (5 dogs), cooled at 4
degrees C, followed by 60 minutes of cold preservation and 30 minutes of warm
blood reperfusion. Interstitial myocardial pH and pO2 changes were measured. The
left ventricle dP/dt was measured before and after the ischemic episode, as where
creatine kinase, troponine T and lactate serum levels. RESULTS: Tissue pH
averaged 6.9+/-0.1, 6.2+/-0.1, 6.7+/-0.1 and 6.8+/-0.1 before and after warm
ischemia, following the 60 minutes of cold preservation and the reperfusion
period in animals treated with the Celsior solution, compared to 6.8+/-0.1, 6.4+/
0.1, 7+/-0.1 and 6.8+/-0.2 respectively in dogs treated with the University of
Wisconsin solution (p<0.05). Oxygen tension in the myocardium averaged 36+/-8
mmHg before warm ischemia and 59+/-31 mmHg after in animals that received Celsior
compared to 30+/-10 mmHg and 49+/-7 mmHg in dogs treated with University of
Wisconsin (p>0.05). Global myocardial function decreased significantly following
reperfusion compared to baseline in both groups of animals. The serum levels of
creatine kinase, troponine T and lactate increased significantly during the
experiment although there was no significant difference between the 2 groups.
CONCLUSION: Both preservation solutions (Celsior and University of Wisconsin)
resulted in suboptimal recovery of myocardial function and metabolism when
administered after a period of warm ischemia. Strategies to improve recovery of
damaged donor hearts remain to be appropriately defined.
PMID- 10776711
TI - Estimation of functional liver reserve in patients before cardiac surgery using
antipyrine plasma clearance test.
AB - BACKGROUND: Hyperbilirubinemia is not uncommon and is sometimes fatal after
valvular surgery. One important cause of it is a poor functional liver reserve,
however, conventional tests reflect hepatic blood flow and do not offer precise
evaluation of the pure functional liver reserve. Antipyrine has particular
pharmacological properties, and its plasma clearance represents quantitatively
the functional capacity of the liver. In this study, we measured antipyrine
plasma clearance in cardiac surgical patients and evaluated the feasibility of
using this parameter as a predictor of the risk of postoperative
hyperbilirubinemia. METHODS: The plasma clearance of antipyrine was measured
preoperatively in 40 cardiac patients undergoing mitral and/or tricuspid valvular
surgery and its relations with hemodynamics or postoperative course were studied.
RESULTS: Antipyrine clearance in preoperative patients was 0.365+/-0.175 (mean +/
SD) ml/min/kg, lower than the normal range (0.405+/-0.04 ml/min/kg), and showed
no correlation with cardiac index, while the plasma disappearance rate of
indocyanine green depended on the cardiac index. The maximum postoperative total
bilirubin level showed significant correlation with antipyrine clearance (r=
0.699); this correlation coefficient was greater than that with indocyanine green
(-0.477). The correlation was more prominent in patients with cardiac
dysfunction. Furthermore, antipyrine clearance showed significant predictability
of the duration of ICU stay. CONCLUSIONS: Antipyrine clearance provides a precise
estimate of functional liver reserve which is independent of hemodynamics and
predicts the risk of postoperative hyperbilirubinemia in preoperative cardiac
patients.
PMID- 10776712
TI - Gauze swabs left intrapericardially following cardiac surgery.
AB - The occurrence of surgical gauze swabs left in the body following operations is
not as rare as one would suspect, however the actual incidence is difficult to
estimate. This accident seems to be occurring most frequently in general and
gastro-intestinal surgery followed by operations in gynaecology and obstetrics
and orthopaedics. There have been only a few papers in the literature dealing
with the topic of foreign bodies left in place after cardiac surgical procedures.
In this paper two cases of gauze swabs left intrapericardially following cardiac
surgery are presented. The issue goes far beyond professional significance alone,
but raises important and critical questions of medical ethics let alone legal
implications.
PMID- 10776713
TI - The utility of selective screening for carotid stenosis in cardiac surgery
patients.
AB - PURPOSE: To determine if any of 8 categorical clinical variables can be used to
select patients and improve the yield of a screening program for severe carotid
stenosis (> or = 80%) in elective cardiac surgery patients. METHODS: A
prospective cohort analysis of 200 consecutive patients prior to elective cardiac
surgery for the following variables: age, gender, smoking carotid bruit,
peripheral vascular disease, hyperlipidaemia, previous neurologic symptoms and
diabetes mellitus. All patients were subsequently screened with carotid duplex
scanning for the presence of severe carotid stenosis. Positive scans were
confirmed by angiography. RESULTS: Sixteen patients (8%) were identified with
severe carotid stenosis. Univariate analysis identified three variables that
increase risk for carotid stenosis: carotid bruit (relative risk (RR)=16.4, 5.4
57.6 95% confidence interval, p<0.001), neurological history (RR=10.3, 3.9-23.2,
p<0.001) and peripheral vascular disease (RR=5.3, 1.9-14.9, p<0.001). Stepwise
logistic regression analysis identified previous neurologic history and carotid
bruit as independent predictors of stenosis. If screening for carotid stenosis
was limited to patients with these two variables, then 37 (18.5% of total)
patients would have been screened. Fourteen of these 37 (37.8%) had a severe
carotid stenosis. Two patients with stenosis (12.5% of those with carotid
stenosis, 1% of total patient population) would not have been screened.
CONCLUSIONS: Clinical variables can be used to improve the yield of a
preoperative screening program for carotid stenosis.
PMID- 10776714
TI - Toward a rational management of concomitant carotid and coronary artery disease.
AB - BACKGROUND: Patients with angina undergoing carotid endarterectomy have a high
perioperative mortality. Our aim was to assess the outcome of carotid
endarterectomy in patients with concomitant coronary artery disease, in
particular, to examine the timing of carotid endarterectomy and CABG. METHODS: A
retrospective study was performed at a tertiary and secondary referral centre for
cardiovascular disease. Over a five-year period 71 carotid endarterectomies and
6,590 coronary artery bypasses were performed. Significant (>70%) internal
carotid stenoses were found in 35 (0.5%) patients due for CABG. Of these, 23
patients underwent Combined procedures (Carotid and CABG), 9 Reverse staged (CABG
then Carotid), and 3 Prior staged carotid endarterectomies (Carotid then CABG).
36 other carotid endarterectomies were in patients evaluated cardiologically, but
did not require CABG (Isolated group). Risk factors, 30 day perioperative outcome
including hospital inpatient stay and early follow-up are reported. RESULTS: The
Combined group 30-day perioperative mortality rate was 4.3% and permanent stroke
rate 8.6%. There were no major complications in Reverse or Prior staged cases.
Isolated group mortality was 2.7% with no strokes. Risk factors were more
prevalent in the combined group; 56% previous myocardial infarction, 39%
hypertension, 35% a history of raised cholesterol and 46% intermittent
claudication. All cases were followed up for a mean of 18.4 months, with no
carotid stroke related events. Overall hospital stay for staged patients was a
mean 19.3 days (SE=2.4) days compared to mean 9.8 days for combined patients
(SE=0.97, p<0.001). CONCLUSIONS: Patients with combined cardiac and carotid
disease benefit from assessment of both systems in order to stage CABG and
carotid endarterectomy. Risk factors were more prevalent in the combined group; a
combined procedure offered a median difference of 8 days less hospital inpatient
stay compared to the staged cases. Our experience suggests that carefully planned
management of concomitant coronary and carotid disease can achieve better
results.
PMID- 10776715
TI - Does saphenous vein arterialisation prevent major amputation in critical leg
ischaemia? A comparative study.
AB - BACKGROUND: Arterialisation of the great saphenous vein has been suggested to
improve distal circulation in patients with critical leg ischaemia not accessible
for reconstructive surgery. As the technique has been a matter of controversy the
aim was to assess the outcome of a series of own patients treated with
arterialisation and compare them with conservatively treated patients. METHODS:
EXPERIMENTAL DESIGN: a retrospective cohort study. SETTING: an academic referral
centre (Department of Surgery, Helsinki University Central Hospital) together
with a district hospital (Peijas-Rekola Hospital). PATIENTS AND INTERVENTIONS: 14
consecutive patients with critical leg ischaemia treated with arterialisation of
the great saphenous vein in the district hospital were compared with 14 age, sex,
diabetes and symptom severity-matched controls with critical leg ischaemia
treated conservatively in the academic referral centre. MEASURES: major
amputations and patient survival. RESULTS: The leg salvage rate was 57% at one
year in the arterialisation group and 54% in the conservative group (NS) but the
survival rate at one year was 92% in the operative group and 64% in the control
group (NS). CONCLUSIONS: Arterialisation did not have any effect on leg salvage.
The results of this study do not support the use of arterialisation as a
treatment for critical leg ischaemia
PMID- 10776716
TI - Carotid endarterectomy without protective measures in patients with occluded and
non occluded contralateral carotid artery.
AB - BACKGROUND: Comparison of carotid endarterectomy in patients with and without
occluded contralateral carotid artery. METHODS: DESIGN: evaluation of results
without using shunt or patch. SETTING: <> Hospital, Medical School,
University of Athens. SUBJECTS: 235 patients, divided into group I of 40 patients
with and group II of 195 patients without occluded contralateral carotid artery.
INTERVENTION: carotid endarterectomy under general anesthesia. MAIN OUTCOME
MEASURES: heparin administration, stable hemodynamic status during clamping,
short duration monitoring postoperatively. RESULTS: Postoperative morbidity of
both groups was 2.5% (6/235) and mortality 1.7% (4/235). Group I: mortality rate
was 2.5% (1/40) major and minor stroke each 2.5% (1/40) and group I: 1.5% (3/195)
and 1% (2/195) respectively (NS). Four to 108 months later, 30% (12/40) of group
I and 21% (41/195) of group II died. CONCLUSIONS: Endarterectomy of the carotid
artery under general anesthesia without use of shunt and patch in patients with
or without occlusion of the contralateral carotid artery presented the same
comparative results. Candidates for carotid endarterectomy should be screened
systematically for coronary disease preoperatively and annual stress testing
postoperatively, tactics which may improve early and late mortality rate after
carotid surgery.
PMID- 10776717
TI - Flow capacity of inferior epigastric artery in composite arterial grafts.
AB - BACKGROUND: In the effort to expand the use of arterial conduits for myocardial
revascularization, 'Y-graft' techniques are utilized with increasing frequency,
although the physiology of this type of composite arterial grafts is not yet
fully understood. The aim of this study was to measure changes in blood flow
through a 'Y-graft' constructed by anastomosing a segment of inferior epigastric
artery (IEA) off the side of an in situ internal thoracic artery (ITA). METHODS:
Twenty-two patients who underwent CABG were enrolled in this prospective study.
Exclusion criteria were age > 70 years, poor left ventricular function (Ejection
Fraction < 0.25) and need for associated cardiac procedures. Blood flow in the
TrA-IEA 'Y-graft' was measured in the operating room after completion of left ITA
to left anterior descending artery (LAD) and IEA to marginal or diagonal branch
anastomoses. Follow-up evaluation was performed at 3 and 12 months
postoperatively. RESULTS: After completion of surgery, blood flow in ITA and IEA
as measured downstream from the Y anastomosis was 45+/-7 and 39+/-6 ml/min
respectively. Temporary occlusion of either branch did not significantly affect
flow in the other side of the arterial Y. All patients were discharged from the
hospital in excellent condition. At follow-up no cases of angina recurrence were
recorded. CONCLUSIONS: Composite ITA-IEA arterial grafts provide excellent short
term clinical results. Blood flow on either side is not affected by run off in
the other side branch. Information from this study may be used to understand the
role that undivided ITA side branches play in reducing flow rate in an ITA graft
harvested during minimally invasive CABG procedures.
PMID- 10776718
TI - Insidious symptomatology and misleading physical findings in popliteal artery
entrapment syndrome. A case report.
AB - A patient presented with an ischemic right forefoot. She suffered rest pain but
had relief on walking and on flexing her leg. Popliteal and pedal pulses were
palpable. The underlying condition was popliteal artery entrapment. Compression
of the popliteal artery occurred with extension of the knee and additional
contraction of the gastrocnemius muscles only and was released with flexion.
Distal embolizations into all three lower leg arteries had caused acute ischemia.
As the emboli had travelled through both tibial vessels very distally pedal
pulses were found to be normal. Treatment was operatively by resection of a tiny
lateral portion of the medial gastrocnemic tendon which crossed the artery
dorsally as the vessel pierced the tendon.
PMID- 10776719
TI - Takayasu's aortitis treated surgically by extensive aortic replacement. A case
report.
AB - A case report of Takayasu's arteritis with aneurysmal involvement of the
ascending aorta, aortic arch and descending thoracic aorta is presented. The
patient underwent successful two-stage operation by use of Elephant trunk
technique. During the first operation, replacement of ascending aorta and aortic
arch was done under selective cerebral perfusion. During the second-stage
operation, replacement of the descending thoracic aorta was performed under
partial cardiopulmonary bypass. The postoperative course was uneventful and one
year after surgery the patient is doing well. Specific conditions and operative
strategy required in case of extensive aortic involvement in Takayasu's arteritis
are discussed.
PMID- 10776720
TI - Spontaneous rupture of the iliac vein.
AB - Two unusual cases of iliac vein spontaneous rupture into the retroperitoneum are
presented together with 18 cases reported by the literature. In one patient of
ours, entrapment of clots in an IVC filter and proximal iliac vein involvement
into the scar tissue surrounding the left limb of an aortoiliac bifurcation graft
might have caused flow disturbances and subsequent predisposition to rupture of
the thrombosed external iliac vein. Inflammatory parietal changes, including
infiltration of macrophages, T and B lymphocytes producing elastin degradation by
means of cytokines, may have led ultimately to vein disruption. Despite clinical
features and CT scan findings, the physician's awareness of this disease remains
the most important factor for the early treatment.
PMID- 10776721
TI - Pseudo-aneurysm of the carotid bifurcation secondary to radiation.
AB - Pseudoaneurysms of the extracranial carotid vessels have a varied
etiopathogenesis. Cases have been attributed to spontaneous rupture, following
tonsillectomy or peritonsillar abscesses, trauma, postanastamotic and, rarely,
postirradiation, and ECMO. The authors present a case of a pseudoaneurysm
involving the carotid artery bifurcation following radiation therapy. A saphenous
vein graft was used to establish continuity between the common and the internal
carotid arteries. A vascular shunt was used to maintain cerebral perfusion during
surgery. This case highlights the technical difficulties encountered in
correcting this condition. This case exemplifies the technical difficulties that
are encountered in a complicated case such as this. Numerous previous operations
and radiotherapy compounded the hazards of the surgical procedure. Although
technically challenging, every attempt must be made to resect pseudoaneurysms
caused by radiation induced vascular damage.
PMID- 10776722
TI - Rupture of Dacron aorto-femoral graft. Case report.
AB - A 74-year-old patient was admitted to our department in a serious general
condition due to massive bleeding. He had been treated 10 years previously in
another hospital with an aorto-bifemoral bypass for obstructive disease using a
knitted-Dacron graft. A large pulsating mass was present in the right iliac fossa
as well as enormous pulsating enlargement of the scrotum. Echo color-Doppler
investigation detected dilation up to 5 cm in diameter of the right branch of the
graft and a large perigraft hematoma communicating with a similar mass in the
scrotum. The patient was submitted to emergency surgery and a large rupture of
the graft was found. The dilated segment was resected and replaced by a new 8 mm
Dacron graft. Postoperative course was uneventful.
PMID- 10776723
TI - Aorto-iliac steal syndrome. A rare case of renal hypoperfusion.
AB - In aorto-iliac occlusive disease a diversion of blood flow from visceral arteries
to lower limbs rarely occurs. This condition is known as aorto-iliac steal
syndrome. This report is about the case of a male patient affected by chronic
atherosclerotic occlusion of the aorta associated with an aorto-iliac steal
supported by an anomalous vessel coming from the left renal artery to the
homolateral external iliac artery to the detriment of the renal blood flow. Renal
sequential scintiscan (RSS) at rest and after stress test was employed to assess
renal blood flow and excretory functions before and after an aorto-bifemoral
bypass. Surgical revascularization permitted reversal of the steal phenomenon and
the improvement of left renal blood flow.
PMID- 10776724
TI - Postoperative pneumoperitoneum for prolonged air leaks and residual spaces after
pulmonary resections.
AB - BACKGROUND: Postoperative air leaks and pleural residual spaces are often
encountered during partial lung resections and may adversely affect the immediate
outcome prolonging the hospital stay. At present the only treatment consists of
maintenance of the chest drainage under suction until resolution of the leaks.
METHODS: From January 1995 to December 1997 the authors have operated on and
subsequently treated 12 patients presenting prolonged air leaks with residual
pleural spaces after lobectomies for lung cancer. The patients underwent
respectively: left or right lower lobectomies (n=7), left upper lobectomies
(n=3), right upper lobectomies (n=2). In this study the air leak was considered
prolonged if it continued and delayed the discharge after surgery beyond the
postoperative day 8. The pneumoperitoneum was carried out under local anesthesia.
The air was insufflated through a needle inserted just above the umbilical scar
as for laparoscopic surgery access up to an amount of about 1200 cc-1300 cc.
RESULTS: We have obtained in all cases and without complications an immediate
reduction in the air leaks and a complete resolution of the residual pleural
spaces. Chest drainages were removed from 3 to 4 days after the procedure.
CONCLUSIONS: The good results achieved suggest that this procedure might be
considered for selected cases, being a minor procedure, performed under local
anesthesia and with minimum discomfort for the patient.
PMID- 10776726
TI - Extended thymectomy for myasthenia gravis in an octogenarian. A case report.
AB - An 86-year-old woman with myasthenia gravis successfully underwent an extended
thymectomy. The patient had a 2-year history of generalized myasthenia and had
limited response to anticholinesterases and steroids. An extended thymectomy was
successfully performed in the usual fashion. The postoperative course was
uneventful except for an episode of psychosis probably due to postoperative
steroid therapy. The steroid dosage was gradually reduced to 5 mg/day over seven
months after the operation, during which she became fully asymptomatic. No
symptoms due to myasthenia have surfaced for over 2 years after surgery. Although
elderly patients are usually considered to be less responsive to an operation,
thymectomy may sometimes be the treatment of choice for myasthenia gravis even in
octogenarians.
PMID- 10776725
TI - Double lung cancer combined with idiopathic thrombocytopenic purpura. A case
report.
AB - A 68-year-old woman was admitted because of two abnormal lung shadows, which
later proved to be differentiated double cancer. Preoperative hematology tests
showed a low platelet count and the result of bone marrow aspiration was
compatible with idiopathic thrombocytopenic purpura (ITP). A normal platelet
count was once obtained by preoperative percutaneous partial splenic arterial
embolization (PSE). However, as there was a tendency for the platelet count to
decrease just before surgery, one shot high-dose immunoglobulin (Ig) was
administered, which is thought to have a short term effect. The operation was
performed successfully. After resection of lung cancer, her platelet count was
maintained at around 15x10(4) mm3 without taking drugs for ITP. These findings
suggest a relationship between lung cancer and ITP.
PMID- 10776727
TI - Combined approach to intrathoracic lesions invading the spinal cord.
AB - The treatment of intrathoracic lesions invading the spine has two main issues:
the surgical route to be preferred and the incidence of complications following
the operation. As a matter of fact surgical treatment, performed in two stages,
has a higher risk of cord accidents. Some authors have proposed a combined
thoraco-vertebral surgical route which allows the exposition of both the spine
and the chest. We experienced the utility of such a surgical approach in the
treatment of two endothoracic lesions invading the thoracic spine and requiring
the stabilization of the rachis. Satisfactory results were achieved without
morbidity.
PMID- 10776728
TI - Incarcerated postraumatic intercostal lung hernia. Case report and review of the
literature.
AB - Traumatic lung hernia is a rare diagnosis. A 52-year-old female motorvehicle
passenger was admitted as a trauma patient after a motorvehicle accident. She was
found to have an incarcerated lung hernia. Size of the hernia, incarceration and
respiratory insufficiency mandated immediate surgical intervention with
reposition, drainage and stabilisation of the chest wall. The postoperative
course was uneventful. The management of the patient is discussed and the
available literature reviewed.
PMID- 10776729
TI - Entrapment of a Swan Ganz catheter in an IVC filter requiring caval exploration.
A case report.
AB - The placement of Swan Ganz (SW) catheters and inferior vena cava (IVC) filters
are common procedures performed in critically ill patients. Many reports describe
the independent misplacement of SG catheters and IVC filters, and others have
reported migration of IVC filters and entanglement of various intravascular
devices in IVC filter. Our patient is a 70-year-old Caucasian woman who underwent
an aortic valve replacement and coronary artery bypass grafting. The patient
developed a deep venous thrombosis and an infrarenal IVC filter was placed
without incident. A Swan Ganz catheter was placed later in the postoperative
period and became entangled in the IVC filter. We advised operative removal after
several unsuccessful percutaneous attempts to retrieve the catheter. IVC filters
are indicated for prevention of fatal pulmonary emboli in patients with a
contraindication to anticoagulants or with recurrent embolism despite adequate
anticoagulant therapy. Complications of IVC filters include caval thrombosis,
retroperitoneal hemorrhage and perforation of the IVC, hepatic veins, duodenum
and aorta. We describe our evaluation and operative approach and make
recommendations for prevention of entangling the SG into the IVC filter.
PMID- 10776730
TI - Pericardial cysts of the mediastinum.
AB - Pericardial cysts are an uncommon benign disease. Their treatment, in the past,
was based on excision by thoracotomy or, in selected cases, on percutaneous
aspiration. The progress of video-assisted thoracoscopy gave new possibilities,
but most surgeons still consider the thoracotomic approach as the treatment of
choice. The aim of this study is to report our experience and to discuss the role
of different therapeutic procedures in the management of pericardial cysts.
Between 1970 and 1996, 24 patients with pericardial cysts were treated at the
first Department of Surgery of the University of Rome <>. Of 24
cysts, six were located in the right cardiophrenic angle, three in the left
cardiophrenic angle, two in the subcarenal areas, one in the paracardiac area and
one on the posterior mediastinum. Ten patients were asymptomatic. Diagnosis was
performed preoperatively only in patients with cysts typically located in the
cardiophrenic angle. Twenty-three patients were surgically treated by a standard
posterolateral thoracotomy or limited thoracotomy with sparing of muscles. One
patient underwent CT-guided transparietal fine-needle aspiration. There were no
cases of operative mortality. Morbidity was 12.5% and consisted of retained
secretions, moderate hypoxemia and partial atelectasis. All patients were
submitted to a long-term follow-up and no cyst recurrences were found. We
conclude that excision via thoracotomy is an optimal treatment for pericardial
cysts. Limited thoracotomy with sparing muscles offers a good cosmetic result and
a rapid functional respiratory recovery. Percutaneous cyst aspiration may be, in
selected patients, an attractive alternative to surgery.
PMID- 10776731
TI - Invasive thymoma with intracaval growth extending and directly invading the right
atrium.
AB - We report an extremely rare case of an invasive thymoma with intracaval growth
extending and directly invading the right atrium. Enbloc excision of the tumor
with lobectomy and combined resection of the right atrium, and graft replacement
of the superior vena cava were successfully performed during cardiopulmonary
bypass. Invasive thymoma with this type of intracaval and intra-atrial
progression is extremely rare.
PMID- 10776732
TI - Definition and classification of the antiphospholipid syndrome.
PMID- 10776733
TI - Blunt trauma of the brachial artery.
PMID- 10776734
TI - Sex and science.
PMID- 10776735
TI - Place of aspirin in prophylaxis of venous thromboembolism.
PMID- 10776736
TI - Aprotinin: pharmacological reduction of perioperative bleeding.
PMID- 10776737
TI - Can paternal mtDNA be inherited?
PMID- 10776738
TI - Which influences cognitive function: living alone or being alone?
PMID- 10776739
TI - Prediction of pregnancy loss.
PMID- 10776740
TI - Atypical varieties of chronic inflammatory demyelinating neuropathies.
PMID- 10776741
TI - Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin:
Pulmonary Embolism Prevention (PEP) trial.
AB - BACKGROUND: Previous trials of antiplatelet therapy for the prevention of venous
thromboembolism have individually been inconclusive, but a meta-analysis of their
results indicated reductions in the risks of deep-vein thrombosis and of
pulmonary embolism in various high-risk groups. The aim of this large randomised
placebo-controlled trial was to confirm or refute these apparent benefits.
METHODS: During 1992-1998, 148 hospitals in Australia, New Zealand, South Africa,
Sweden and the UK randomised 13,356 patients undergoing surgery for hip fracture,
and 22 hospitals in New Zealand randomised a further 4088 patients undergoing
elective arthroplasty. Study treatment was 160 mg daily aspirin or placebo,
started preoperatively and continued for 35 days. Patients received any other
thromboprophylaxis thought necessary. Follow-up was of mortality and of in
hospital morbidity up to day 35. FINDINGS: Among the patients with hip fracture,
allocation to aspirin produced proportional reductions in pulmonary embolism of
43% (95% CI 18-60; p=0.002) and in symptomatic deep-vein thrombosis of 29% (3-48;
p=0.03). Pulmonary embolism or deep-vein thrombosis was confirmed in 105 (1.6%)
of 6679 patients assigned aspirin compared with 165 (2.5%) of 6677 assigned
placebo, which represents an absolute reduction of 9 (SE 2) per 1000 and a
proportional reduction of 36% (19-50; p=0.0003). Similar proportional effects
were seen in all major subgroups, including patients receiving subcutaneous
heparin. Aspirin prevented 4 (1) fatal pulmonary emboli per 1000 patients (18
aspirin-group vs 43 placebo-group deaths), representing a proportional reduction
of 58% (27-76; p=0.002), with no apparent effect on deaths from any other
vascular cause (hazard ratio 1.04 [95% CI 0.86-1.26]) or non-vascular cause (1.01
[0.84-1.23]). Deaths due to bleeding were few (13 aspirin vs 15 placebo), but
there was an excess of 6 (3) postoperative transfused bleeding episodes per 1000
patients assigned aspirin (p=0.04). Among elective-arthroplasty patients, rates
of venous thromboembolism were lower, but the proportional effects of aspirin
were compatible with those among patients with hip fracture. INTERPRETATION:
These results, along with those of the previous meta-analysis, show that aspirin
reduces the risk of pulmonary embolism and deep-vein thrombosis by at least a
third throughout a period of increased risk. Hence, there is now good evidence
for considering aspirin routinely in a wide range of surgical and medical groups
at high risk of venous thromboembolism.
PMID- 10776742
TI - Aprotinin and transfusion requirements in orthotopic liver transplantation: a
multicentre randomised double-blind study. EMSALT Study Group.
AB - BACKGROUND: Intraoperative hyperfibrinolysis contributes to bleeding during adult
orthotopic liver transplantation. We aimed to find out whether aprotinin, a
potent antifibrinolytic agent, reduces blood loss and transfusion requirements.
METHODS: We did a randomised, double-blind, placebo-controlled trial in which six
liver-transplant centres participated. Patients undergoing primary liver
transplantation were randomly assigned intraoperative high-dose aprotinin,
regular-dose aprotinin, or placebo. Primary endpoints were intraoperative blood
loss and transfusion requirements. Secondary endpoints were perioperative fluid
requirements, postoperative blood transfusions, complications, and mortality.
FINDINGS: 137 patients received high-dose aprotinin (n=46), regular-dose
aprotinin (n=43), or placebo (n=48). Intraoperative blood loss was significantly
lower in the aprotinin-treated patients, with a reduction of 60% in the high-dose
group and 44% in the regular-dose group, compared with the placebo group
(p=0.03). Total amount of red blood cell (homologous and autologous) transfusion
requirements was 37% lower in the high-dose group and 20% lower in the regular
dose group, than in the placebo group (p=0.02). Thromboembolic events occurred in
two patients in the high-dose group, none in the regular-dose group, and in two
patients in the placebo group (p=0.39). Mortality at 30 days did not differ
between the three groups (6.5%, 4.7%, and 8.3%; p=0.79). INTERPRETATION:
Intraoperative use of aprotinin in adult patients undergoing orthotopic liver
transplantation significantly reduces blood-transfusion requirements and should
be routinely used in patients without contraindications.
PMID- 10776743
TI - Adult psychosocial outcomes in long-term survivors of acute lymphoblastic
leukaemia and Wilms' tumour: a controlled study.
AB - BACKGROUND: Variability in methods and deficits in design have contributed to
conflicting findings about adult psychosocial functioning after childhood cancer.
We did a controlled study of psychosocial outcomes in adult survivors of
childhood acute lymphoblastic leukaemia (ALL) and Wilms' tumour to address
previous methods limitations. METHODS: We assessed 102 survivors of childhood ALL
and Wilms' tumour, who had been free from relapse for 5 years and were aged 19-30
years, and 102 unrelated healthy controls. We used standard measures of adult
psychiatric disorder, interpersonal and social-role performance, and intellectual
ability to assess past and current functioning. FINDINGS: Cancer survivors had no
increased rates of psychiatric disorder. Mean scores of cancer survivors were
significantly higher (indicating poorer functioning) than those of controls for
love/sex relationships (mean difference 0.87 [95% CI 0.53-1.22]), friendships
(0.37 [0.07-0.67]), non-specific social contacts (0.40 [0.20-0.60]), and day-to
day coping (0.35 [0.14-0.57]). Cancer survivors were more likely than controls to
have a combination of deficits in love/sex relationships and friendships (ALL
survivors odds ratio 10.83 [95% CI 3.87-30.82], Wilms' tumour survivors 4.85
[1.43-16.47]), which was associated with more recent treatment (p=0.005). Poor
coping was associated with lower intellectual ability scores (p=0.018).
INTERPRETATION: Childhood ALL and Wilms' tumour have long-term effects on
interpersonal functioning and coping, probably mediated by different mechanisms.
Prospective studies with each of these tumour groups are needed with similar
adolescent and adult outcome measures.
PMID- 10776744
TI - Influence of social network on occurrence of dementia: a community-based
longitudinal study.
AB - BACKGROUND: Few data are available on the effect of social ties on dementia
development. This study explored whether single social network components and
different degrees of the social connections affect dementia incidence. METHODS: A
community-based cohort of 1203 non-demented people, living at home in the
Kungsholmen district of Stockholm, Sweden, and who had good cognition, was
followed for an average period of 3 years. On the basis of medical and
psychological data, 176 patients were diagnosed with dementia according to the
criteria of the third edition revision of the Diagnostic and Statistical Manual
of Mental Disorders. Information on social network was obtained by personal
interview by trained nurses at baseline. The covariates included in the analysis
were age, sex, education, cognitive and functional status, depressive symptoms,
and vascular diseases. FINDINGS: Those individuals living alone, and those
without any close social ties, both had an adjusted relative risk for developing
dementia of 1.5 (95% CI 1.0-2.1 and 1.0-2.4, respectively). Compared with married
people living with someone, single people and those living alone had an adjusted
relative risk of 1.9 (95% CI 1.2-3.1). Infrequent contacts with network resources
did not increase the risk of the disease if such contacts were experienced as
satisfying. When all components were combined in an index, a poor or limited
social network increased the risk of dementia by 60% (95% CI 1.2-2.1), and a
significant gradient was found for the four degrees of social connections
(p=0.0009). INTERPRETATION: An extensive social network seems to protect against
dementia. Confirmation of this finding and further investigation to clarify the
mechanisms are worthwhile due to the implications for prevention.
PMID- 10776745
TI - Oral artemether for prevention of Schistosoma mansoni infection: randomised
controlled trial.
AB - BACKGROUND: Chemotherapy with praziquantel is the current strategy of choice to
control schistosomiasis. However, in view of concern about praziquantel tolerance
or resistance, new drugs are needed. Artemether, a derivative of the antimalarial
drug artemisinin, kills immature schistosomes of Schistosoma japonicum, and
reduces the incidence of infection in field trials. Laboratory studies have also
showed activity by this drug against S. mansoni. We report a randomised double
blind placebo-controlled clinical trial of artemether to prevent S. mansoni
infection. METHODS: The trial was done in an area of western Cote d'Ivoire
endemic for S. mansoni. 354 schoolchildren were enrolled. Stool specimens were
screened over four consecutive days, followed by two mass treatments with
praziquantel 4 weeks apart. All S. mansoni negative children were randomly
assigned to placebo (n=151) or artemether 6 mg/kg (n=138) orally six times once
every 3 weeks. Adverse events were assessed 24 h after treatment. Perceived
illness episodes were recorded once a week by interviewing the children with a
standardised questionnaire. 3 weeks after the final medication S. mansoni
infections were assessed by screening stool samples. Blood samples were examined
for Plasmodium falciparum before the first and after the last artemether
treatment. FINDINGS: Oral artemether showed no adverse reactions. The group that
received artemether had a significantly lower incidence of S. mansoni infection
(31/128 versus 68/140, relative risk: 0.50 [95% CI 0.35-0.71], p=0.00006). The
geometric mean egg output among positive children in the artemether group was
significantly lower than in placebo recipients (19 vs 32 eggs/g stool, p=0.017).
There was also a significant reduction in the prevalence of P. falciparum.
INTERPRETATION: Oral artemether is safe and shows a prophylatic effect against S.
mansoni. The use of artemether may be recommended in appropriated situations as
an additional tool for more effective schistosomiasis control measures. However
the application needs to be carefully assessed especially in view of the concern
that it could select for resistant plasmodia.
PMID- 10776746
TI - Relation between decreased anandamide hydrolase concentrations in human
lymphocytes and miscarriage.
AB - BACKGROUND: Endocannabinoids such as anandamide are thought to have adverse
effects on pregnancy and embryonic development. The activity of the degradative
enzyme anandamide hydrolase may therefore be crucial for prevention of excessive
concentrations of anandamide in the uterus, and thus prevention of pregnancy
failure or female infertility. We tested this hypothesis in a preliminary study,
and then used the results to find out whether anandamide hydrolase activity could
predict miscarriage in a group of pregnant women. METHODS: We assessed anandamide
hydrolase activity in peripheral lymphocytes from 50 healthy, pregnant women at
weeks 6-11 of gestation by a specific radiochromatographic method. The expression
of the enzyme at the protein level was measured by ELISA with specific polyclonal
antibodies. In a further study, we measured anandamide hydrolase concentration in
120 women who were 7-8 weeks pregnant and compared these findings with subsequent
pregnancy outcome. FINDINGS: In the first study, seven of the 50 women had a
miscarriage. Anandamide hydrolase activity was lower in the seven women who
miscarried than in the 43 who did not (60.43 pmol/min per mg protein [SD 29.34]
vs 169.60 pmol/min per mg protein [30.20]; difference 109.17 pmol/min per mg
protein [95% CI 26.64-191.70]; p<0.0001 by the Mann-Whitney test). Enzyme
activity correlated with enzyme concentration, and a threshold concentration
represented by an optical density (after ELISA) of 0.15 absorbance units at 450
nm separated the women who had miscarriages from those who did not. In the second
study, 15 women had anandamide hydrolase concentrations below the threshold, and
105 had concentrations at or above the threshold. All 15 women in the low
anandamide hydrolase group had miscarriages, compared with one of the 105 women
with high concentrations (p<0.0001 by Fisher's exact test). INTERPRETATION:
Decreased anandamide hydrolase activity and expression in peripheral lymphocytes
is an early (<8 weeks of gestation) marker of spontaneous abortion, and may prove
useful as a diagnostic tool for large-scale, routine monitoring of gestation. Our
results also suggest that endocannabinoids might be critical in regulating the
lymphocyte-dependent cytokine network associated with human fertility and
successful pregnancy.
PMID- 10776747
TI - When sugar is not so sweet.
PMID- 10776748
TI - Immune repopulation after HAART in previously untreated HIV-1-infected children.
Paediatric European Network for Treatment of AIDS (PENTA) Steering Committee.
AB - In 25 vertically HIV-infected children receiving highly-active antiretroviral
therapy, a 3-log10 reduction in plasma HIV RNA load was maintained for 1 year and
was associated with a doubling of the CD4-cell percentage. Most (75%) new CD4
cells carried the CD45RA marker of naive cells and there was only a small rise in
memory cells (CD45RO). This pattern of immune restoration differs from adults,
and may be due to the presence of a functioning thymus in children.
PMID- 10776749
TI - Sleep attacks (sleep episodes) with pergolide.
AB - Increased sedation, somnolence, and sleep episodes seem to occur with several, if
not all, dopamine agonists and dopaminergic treatment. Patients at risk of sleep
episodes can be identified by well-chosen questions, and could be managed by
appropriate measures including dose reduction.
PMID- 10776750
TI - Sleep attacks and Parkinson's disease treatment.
AB - Three patients with Parkinson's disease had so-called sleep attacks at the wheel
while taking bromocryptine, lisuride pergolide, or piribedil. We believe that all
dopamine agonists can induce sleep attacks.
PMID- 10776751
TI - Adoptive transfer of vitiligo after allogeneic bone marrow transplantation for
non-Hodgkin's lymphoma.
AB - Vitiligo developed in a 50-year-old man 9 months after allogeneic transplantation
from his HLA-identical sister who had had this disease for several years. Our
findings suggest adoptive transfer of vitiligo by haematopoietic stem cell
transplantation, and lend support to the autoimmune nature of this disease.
PMID- 10776752
TI - Cavernosal arterial insufficiency and erectile dysfunction in recipients of high
dose chemotherapy and total body irradiation for multiple myeloma.
AB - Five patients with multiple myeloma who had an autologous bone marrow/stem cell
transplant were studied to assess the cause of the erectile dysfunction by
assessing markers of gonadal function and cavernosal vascular measurements by
flow Doppler study.
PMID- 10776753
TI - Use of in-vitro fertilisation embryos cryopreserved for 5 years or more.
AB - Human embryos cryopreserved after in-vitro fertilisation can be stored initially
for 5 years, and the storage period may be extended to a maximum of 10 years. Of
1344 embryos cryopreserved between 1988 and 1994 at two centres in Manchester,
67% (904 embryos) have had to be destroyed at the end of the first 5-year
interval, even if the couples involved remain childless.
PMID- 10776754
TI - "Working draft" of human genome available by June.
PMID- 10776755
TI - Spinal-cord repair: are we getting closer?
PMID- 10776756
TI - UK government rejects advice to update drug laws.
PMID- 10776757
TI - South Africa's Medicines Control Council contradicts Health Minister.
PMID- 10776758
TI - Spain approves HIV/AIDS drug-resistance tests.
PMID- 10776759
TI - UK's position on human cloning provokes hostile reaction in Europe Union.
PMID- 10776761
TI - White blood cells 1: non-malignant disorders.
AB - Disorders of white cells are very common in clinical practice. White-cell
development and numbers are controlled by a mixture of external stimuli including
cytokines, matrix proteins, and accessory cells. Several different white-cell
lineages are recognised; each has a role in host defence. Both white-cell
deficiency and overproduction can lead to disease. Some forms of inherited white
cell deficiency are potentially treatable with gene therapy.
PMID- 10776760
TI - Directly observed therapy and treatment adherence.
AB - Direct observation of patients taking their medication is a strategy to improve
completion rates for tuberculosis treatment, but the programmes to implement this
approach consist of a complex array of inputs aimed at influencing adherence.
Policy makers need a clear understanding of these inputs to succeed. We
systematically identified and reviewed published reports of direct observation
therapy (DOT) programmes and compared inputs with WHO's short-course DOT
programme. DOT programmes frequently consist of more than the five elements of
WHO's strategy, including incentives, tracing of defaulters, legal sanctions,
patient-centred approaches, staff motivation, supervision, and additional
external funds. Focusing on direct observation as a key factor in the promotion
of adherence seems inappropriate. Multiple components might account for the
success of DOT programmes, and WHO should make these explicit.
PMID- 10776762
TI - Pharmacogenetics and future drug development and delivery.
PMID- 10776763
TI - Systemic cause of unstable atherosclerotic plaques.
PMID- 10776764
TI - Systemic cause of unstable atherosclerotic plaques.
PMID- 10776765
TI - Systemic cause of unstable atherosclerotic plaques. Atorvastatin and
Thrombogenicity of Carotid Atherosclerotic Plaque (ATROCAP) study group.
PMID- 10776766
TI - Temperature monitoring with ThermoSpots in Malawi.
PMID- 10776767
TI - Allergic reactions to icodextrin in patients with renal failure.
PMID- 10776768
TI - Cortical origins of pathological pain.
PMID- 10776769
TI - Physicians for peace.
PMID- 10776770
TI - Physicians for peace.
PMID- 10776771
TI - Physicians for peace.
PMID- 10776772
TI - Fetal growth restriction.
PMID- 10776773
TI - Fetal growth restriction.
PMID- 10776774
TI - Aneurysmal walls in unruptured intracranial aneurysms.
PMID- 10776775
TI - Medicine and Austria.
PMID- 10776776
TI - Medicine and Austria.
PMID- 10776777
TI - Medicine and Austria.
PMID- 10776778
TI - Spironolactone and congestive heart-failure.
PMID- 10776779
TI - Quality of cancer services.
PMID- 10776780
TI - Breastfeeding and the prevention of infant mortality.
PMID- 10776781
TI - Information dominance over disease.
PMID- 10776782
TI - Between circular and cul-de-sac epidemiology.
PMID- 10776783
TI - How did life start on earth?
PMID- 10776784
TI - Japan lags behind in classroom comfort.
PMID- 10776785
TI - Value of anecdotes.
PMID- 10776786
TI - Biologic functions and signaling of the interleukin-4 receptor complexes.
AB - IL-4 is a pleiotropic cytokine which plays a pivotal role in shaping immune
responses. The effects of IL-4 are mediated after binding to high affinity
receptor complexes present on hematopoietic as well as non-hematopoietic cells.
This review will summarize the current knowledge on the molecular structure of
the different types of IL-4 receptor (IL-4R) complexes as well as the signal
transduction mechanisms induced by IL-4 leading to cellular proliferation and /
or gene activation. IL-4 effects are modulated by soluble forms of the respective
receptor molecules which are produced by several immune cells in a regulated
manner. The biological impact of recently described IL-4R allotypes of mice and
humans as well as the results of studies with IL-4R knockout mice will be
particularly emphasized.
PMID- 10776787
TI - HIV-1 gp41: role in HIV entry and prevention.
PMID- 10776788
TI - HIV-2 transmembrane protein gp36 binds to the putative cellular receptor proteins
P45 and P62.
AB - Based on the findings that two cellular proteins of 45 kDa (P45) and 62 kDa (P62)
serve as the putative receptor molecules for binding of HIV-1 transmembrane
protein gp41 to human T, B lymphocytes and monocytes, we examined whether HIV-2
gp36 and HIV-1 gp41 share the putative receptor proteins P45 and P62. In SPR
assay (SPR: surface plasmon resonance), the recombinant soluble gp36 (rsgp36: Env
aa518-678 from clone ROD) like the recombinant soluble gp41 (rsgp41: Env aa539
684 from clone BH10) was binding to P45 and P62. By affinity capillary
electrophoresis (ACE)-analysis, formation of stable rsgp36-P45 and rsgp36-P62
complexes were confirmed, and the interactions of rsgp36 with P45 and P62 is
quite strong with a fast association rate and a slow dissociation rate. These
results indicate that HIV-2 gp36 and HIV-1 gp41 have the common putative cellular
receptor proteins P45 and P62, and the binding of gp36 to human lymphocytes and
monocytes could be based on the interaction between gp36 and P45 and P62.
PMID- 10776789
TI - Epitope-vaccines: a new strategy to induce high levels of neutralizing antibodies
against HIV-1.
AB - Based on the experimental evidence that gp120 subunit vaccine did not protect
individuals from HIV-1 infection, we suggested that epitope-vaccines of HIV-1
gp41 may be a new strategy to induce high levels of neutralizing antibodies
against HIV-1, and characterised immunogenicity of epitope-vaccines. Two
epitopes, RILAVERYLKD-epitope (aa586-596) on the N-domain and ELDKWA-epitope
(aa669-674) on the C-domain of gp41, were demonstrated by us and others to induce
protective activity. After vaccination course, the RILAVERYLKD-dimer epitope
vaccine [C(RILAVERYLKDG)2-BSA] induced strong epitope-specific antibody response
by about 1:25,600 dilution, and the ELDKWA-tetramer epitope-vaccine [C-(ELDKWAG)4
BSA] could yet induce strong antibody response to ELDKWA-epitope by 1:12,800
25,600 dilution of antisera in mice, while rgp41 subunit vaccine induced very
weak antibody response to both epitopes (1:400). In rabbit experiments, the
titres of ELDKWA-epitope-specific antibody induced by ELDKWA-epitope-vaccine [C
(ELDKWAG)4-BSA] reached to 1:6,400, while rgp41 subunit vaccine induced very weak
antibody response to this epitope and to P1 and P2 peptides (1:400). Moreover,
the ELDKWA-epitope-specific antibodies in mice and rabbit antisera induced by
epitope-vaccine could very strongly interact with P2 peptide sequence
corresponding to the C-domain of gp41 (dilution by 1:25,600), and the RILAVERYLKD
epitope-specific antibodies in mice antisera induced by epitope-vaccine could
also very strongly interact with P1 peptide sequence-corresponding to the N
domain of gp41 (dilution by 1:102,400). All these results provided experimental
evidence that epitope-vaccine may be a new general strategy to induce high levels
of neutralizing antibodies against HIV-1 or other viruses.
PMID- 10776790
TI - Consequences of antigen self-presentation by tumor-specific cytotoxic T cells.
AB - CD8-positive cytotoxic T cells (CTL) recognize antigenic peptides in combination
with major histocompatibility complex (MHC) class I molecules on the surface of
syngeneic antigen presenting cells (APC). In the present paper we show that cells
from tumor antigen-specific CTL clones present their cognate antigenic peptide to
other CTL from the same clone. Inter-CTL peptide presentation resulted in
activation of the cells of one CTL clone to MHC-unrestricted lysis of bystander
cells. In contrast to the behaviour of this clone, another CTL clone did not lyse
bystander cells after incubation with the cognate peptide, but was activated to
self-destruction. The human herpes virus Epstein-Barr virus is involved in the
pathogenesis of a broad spectrum of human neoplasias. Using freshly established
non-clonal T cells with specificity for a peptide derived from an Epstein-Barr
virus encoded antigen we found again lysis of MHC mismatched bystander cells as a
consequence of inter-CTL peptide presentation, indicating that bystander lysis
following antigen self-presentation is not a phenomenon restricted to long-term
in vitro cultured T cell clones. The potential implications for
immunosurveillance against cancer and for tumor escape mechanisms are discussed.
PMID- 10776791
TI - Molecular, genetic and epidemiologic studies on selective complete C1q deficiency
in Turkey.
AB - Selective complete C1q deficiencies (SCDC1q) of the complement component C1q are
rare genetic disorders with high prevalence of lupus-erythematosus-like symptoms
and recurrent infections. Among the 41 published cases from 23 families, 10
derive from 6 Turkish families. One particular mutation leading to a stop codon
in the C1q A gene was first identified in members of a Gypsy family from the
Slovac Republic. Later the same mutation has been found in all cases in four
SCDC1q families from Turkey suggesting that one particular defective allele may
be present in the populations of Southeastern Europe and Turkey. This study was
undertaken to investigate the frequency of C-->T mutation in exon II of C1qA gene
in Turkish population by using allele-specific polymerase chain reaction (PCR)
and PCR-restriction fragment length polymorphism (PCR-RFLP). Among the 1544
patients from 15 pediatric departments and an additional 89 SLE patients of
various ages no C1qA gene mutation was found. There were 43 heterozygous and 4
homozygous mutations in 161 family members or relatives investigated from the 4
families known with SCDC1q. Among the 223 inhabitants who were nonrelative to the
3 SCDC1q families living in the same village were screened for mutation and one
heterozygous individual was observed. Although this mutant allele appears to be
at a low prevalence in the population tested, individuals with recurrent
infections or symptoms of lupus erythematosus-like syndrome should be tested for
this mutation to rule out this type of C1q deficiency.
PMID- 10776792
TI - Different influence of macrophage migration inhibitory factor (MIF) in signal
transduction pathway of various T cell subsets.
AB - It has been shown that macrophage migration inhibitory factor (MIF) modulates not
only macrophage functions, but also T cell functions. However, detailed analysis
of the MIF function on responses of various T cell subpopulations remained to be
elucidated. In this report, using a neutralizing anti-MIF monoclonal antibody
(mAb) we examined MIF functions on various T cell lineages. It was shown that
anti-MIF mAb inhibited antigen-specific responses of both IFN-gamma producing and
IL-4 producing T cells. The inhibition appeared to be related to blockade of the
signal pathway via T cell receptor (TCR) but not that via IL-2 receptor (IL-2R).
However, the anti-MIF mAb showed no inhibitory effect on NK-T cell responses
stimulated through TCR. These results suggest that MIF is involved in the signal
pathway via TCR in mainstream T cells but not in NK-T cells.
PMID- 10776793
TI - Serum antibodies against the heat shock protein 60 are elevated in patients with
osteosarcoma.
AB - Osteosarcoma is the most frequent malignant bone tumor, mainly occurring in the
second and third decade of life. Diagnosis is limited to clinical symptoms,
radiology and histology, but so far no diagnostic laboratory tests are available.
Heat shock proteins (hsp), highly conserved proteins performing vital
intracellular chaperoning functions and preventing cells from death, have been
shown to be involved in tumor immunity. We analyzed 75 sera from 23 patients with
high-grade osteosarcoma, 8 patients with chondrosarcoma, 10 patients with Ewing's
sarcoma, 5 patients with soft tissue sarcoma, 11 patients with benign bone tumors
at the time of diagnosis and from 18 healthy controls with an indirect one-site
enzyme linked immunosorbent assay (ELISA) for the presence of anti-hsp60 and 70
antibodies. In these assays 10/23 osteosarcoma patients (43%) had anti-hsp60
antibodies with a mean +/- S.D. titer of 0.382 +/- 0.243 U/ml. Only one of the 18
healthy controls (1/18, 5.6%; titer 0.22 U/ml), two of the Ewing's sarcoma
patients (2/10, 20%; titer 0.2 +/- 0.09 U/ml), two of the patients with a benign
bone tumor (2/11, 18%; titer 0.22 +/- 0.16 U/ml) and one of the chondrosarcoma
patients (1/8, 12.5%; titer 0.14 U/ml) were positive, whereas all others,
including all soft tissue sarcomas were negative throughout. Anti-hsp60
antibodies in patients with osteosarcoma are therefore significantly increased (p
< 0.05). 19/23 (83%) of osteosarcoma biopsy specimens expressed hsp60
immunohistochemically and all specimens from patients with a positive anti-hsp60
serum titer expressed hsp60. The level of the anti-hsp60 antibodies did not
correlate with clinical parameters such as response to preoperative chemotherapy,
duration of symptoms, age, gender, tumor size, serum alkaline-phosphatase levels
and metastases. Although no difference in anti-hsp70 antibodies could be observed
between sera from patients and healthy controls, a positive correlation was found
for the presence of anti-hsp70 serum antibodies and lung metastases at the time
of diagnosis in osteosarcoma patients. These data suggest an increase of anti
hsp60 antibodies at the time of first diagnosis of osteosarcoma. These findings
should therefore give rise to further investigations on a group of new markers
for the diagnosis of osteosarcoma.
PMID- 10776794
TI - Induction of apoptosis in lymphoid tissues of mice after intramuscular injection
of enterotoxigenic Escherichia coli enterotoxin.
AB - Although it has been reported that intravenous injection of Escherichia coli
enterotoxin induces atrophies of the thymus and spleen by necrosis, the toxin
injected intramuscularly to mice induced atrophies of both tissues, which were
associated with apoptosis of lymphocytes. Apoptosis predominantly occurred in the
thymus and increased in a time-dependent manner up to 26 h and faint ladder band
patterns of DNA were observed at 36 h. Although the high dose of toxin also
induced in vitro apoptosis in cultured thymocytes, the toxin was not detected in
the serum at levels sufficient to cause in vitro apoptosis after intramuscular
administration. By flow cytometric analysis, CD4+ CD8+ double-positive T cell and
CD45+ positive B cell numbers were found to be mainly decreased in thymus and
spleen, respectively, of mice. These results suggest that the atrophies of thymus
and spleen by intramuscular administration of the toxin to mice are due to
apoptosis of CD4+ CD8+ double-positive T and CD45+ positive B cells,
respectively, but the toxin does not reach these cells via the circulation. A
different mechanism from that in vitro in cultured cells might be involved in the
induction of apoptosis in vivo.
PMID- 10776795
TI - Lipopeptides as immunoadjuvants and immunostimulants in mucosal immunization.
AB - In previous studies we have shown that lipopeptides constitute potent
immunoadjuvants in mice, rabbits and other species: in parenteral immunization,
lipopeptide adjuvants were comparable, or in some cases superior to Freund's
adjuvant, and were devoid of the side effects of this additive. Here we
demonstrate that lipopeptides also constitute adjuvants for mucosal
immunizations. The serum antibody responses against the wheat storage protein
gliadin, the bee venom constituent melittin, or the hen egg protein ovalbumin
could in most cases be enhanced more than 100-fold by the lipopeptide P3CSK4,
applied via the nasal route. An enhanced specific antibody level could also be
detected in supernatants of cell cultures prepared from spleens, Peyer's patches,
lungs and mesenteric lymph nodes of immunized mice. Moreover, the lipopeptide
P3CSK4 enhanced chemiluminescence in mouse spleen cells and peritoneal
macrophages in vitro, indicating a macrophage-activating effect. Finally, nasal
application of lipopeptide increased protection against a lethal infection of
influenza. Our findings are of importance for the improvement of immunizations
and might lead to more effective vaccines.
PMID- 10776796
TI - Comparison of two laboratory methods for the determination of serum resistance in
Borrelia burgdorferi isolates.
AB - A growth inhibition assay (GIA) and an immunofluorescence test detecting
deposited complement components C6 and C9 were compared for their ability to
classify Borrelia isolates with respect to their resistance to non-immune human
serum (NHS). In both assays a total of 34 Borrelia isolates of all three human
pathogenic genospecies were tested. Interestingly, 95% of the serum-sensitive or
intermediate serum-sensitive isolates belonged to the genospecies B. burgdorferi
s. s. and B. garinii, whereas most B. afzelii isolates (83%) proved serum
resistant. Consequently, a strong correlation between the assignment of the
isolates to the different genospecies and their degree of serum sensitivity was
seen. These findings were supported strongly by the quantitative analysis of the
deposited complement components and the location of the terminal complement
complex on the bacterial surface as detected by means of immunoelectron
microscopy. The GIA displayed an obvious lack of sensitivity to slow growing
isolates, whereas the IFA allowed classification of all Borrelia isolates.
Discrimination between serum-sensitive and serum-resistant isolates in the IFA
was the most specific provided that the detection of C6 and C9 was incorporated
into the final classification of isolates. Accordingly, both assays, turned out
to be effective and reliable tools for the investigation of borrelial serum
sensitivity. The IFA, however, is regarded as superior to the GIA owing to the
obvious ease of performance and its rapid capability for the classification of
even very slow growing isolates.
PMID- 10776797
TI - C3 synthesis and CRs expression during differentiation of a murine stem cell
line.
AB - C3 production, release and CRs expression during the neutrophilic differentiation
of a murine non tumorigenic cell line is investigated. The murine non tumorigenic
cell line 32DCl3(G) which undergoes terminal differentiation into
polymorphonuclear granulocytes when cultured in presence of G-CSF was selected as
a suitable in vitro model for this study. The results show that as the cells
progress into the differentiation program, levels of C3 mRNA increase,
accompanied by increased C3 production. As differentiation progresses the cells
gradually express CRs on their surface; these are undetectable on the surface of
undifferentiated cells. As a consequence of CRs appearance, cells become able to
bind C3 through receptorial binding. Differences were found in the modality of C3
secretion: differentiated cells tend to store C3 in their intracellular
compartments rather than secrete it continuously into the medium and they respond
to membrane stimulation with increased secretion of C3. Treatment of 32DCl3(G)
with TNF-alpha increased C3 production in a time- and dose-dependent fashion.
Cell response to this stimulus progressively increases during the differentiation
process suggesting that they acquire functionality in the signal transduction
mechanisms.
PMID- 10776798
TI - Delayed clearance of zymosan-induced granuloma and depressed phagocytosis of
macrophages with concomitant up-regulated kinase activities of Src-family in a
human monocyte chemoattractant protein-1 transgenic mouse.
AB - A human monocyte chemoattractant protein-1 (hMCP-1) transgenic mouse (Tgm) line
which constitutively produces a large amount of hMCP-1 (7-13 ng/ml in the serum)
was established. Although expression of the transgene was detected in various
tissues, an accumulation of macrophages (Mphi) was seen in only lymphoid organs
which might be attributed to the high concentration of hMCP-1 in these organs. A
reduced phagocytosis by peritoneal Mphi in vivo and a delayed clearance of
granulomas in the liver following zymosan administration were observed in these
Tgm. However, peritoneal exudate cells (PEC) from Tgm exhibited normal in vitro
phagocytic activity and nitric oxide (NO) production upon stimulation with IFN
gamma as compared with those from non-Tgm. In addition, high activities of src
family protein tyrosine kinases (PTK), Fgr and Hck, were also noted in the
peritoneal resident cells from Tgm, whereas the level of mitogen-activated
protein kinase (MAPK) activity was almost the same as that of non-Tgm. It was
suggested that the low functional activities of Tgm Mphi seen in vivo were
attributed to down-regulation of the unique transducing system of hMCP-1 signals
under the influence of a high concentration of the hMCP-1. It seemed that the
depressed functions were recovered when the peritoneal cells were released ex
vivo from such a high hMCP-1 environment.
PMID- 10776799
TI - Accessory function and costimulatory molecule expression of alveolar macrophages
in patients with pulmonary tuberculosis.
AB - An effective immune response against M. tuberculosis requires a coordinated
interaction of alveolar macrophages (AM) and lymphocytes. Secondary signals, such
as accessory function (AF) of antigen presenting cells and interaction of
costimulatory molecules are also important for T cell activation. In the present
study we determined the AF and the expression of CD11a, CD54, CD58, CD80, CD86
and HLA-DR costimulatory molecules by AMs lavaged from patients with pulmonary
tuberculosis and controls. We hypothesized that alterations in AF and
costimulatory molecule expression may influence the presentation of tuberculosis.
Therefore these parameters were also correlated with the radiographic extension
of the disease. AMs of patients with tuberculosis exhibited an increased AF and a
significantly increased expression of co-stimulatory molecules compared with
controls. Furthermore, we observed that the expression of CD54 (ICAM-1) decreased
with the course of the disease. We conclude that the infection by M. tuberculosis
results in an increased AF of AMs and the activity of AMs remains uninfluenced by
the extension of the disease. Clear-cut changes of patterns of costimulatory
molecule expression by AMs could not be observed with the progression of
tuberculosis.
PMID- 10776800
TI - Phenotypic pattern of B cells in the appendix: reduced intensity of CD19
expression.
AB - The lymphoid tissue of the appendix is considered as part of the gut-associated
lymphoid tissue (GALT). In order to understand better the immunological
significance of the appendix we analyzed the cellular composition of normal and
inflamed human appendix tissue by flow cytometer with special attention to
expression of the CD19 and CD5 markers on B cells. Cellular analysis was also
performed on peripheral and appendical vein blood samples as well as on omentum
and peritoneal fluid samples. The study population included seventeen patients
aged 2-15 yr. (mean age - 11.5 yr.) undergoing appendectomy. Ten children were
diagnosed with acute appendicitis while 7 had a normal appendix. RESULTS:
Compared to the peripheral blood, the appendix contained a significantly higher
percentage of CD19 cells (47.6% of total lymphocytes versus 15%, p<0.0001), and
B1 cells (4.98% of total lymphocytes versus 2.42%, p=0.001). In addition, the
intensity of CD19-staining was markedly decreased in the appendix (mean - 395.7),
and also in the omentum (mean - 398.2) as compared to peripheral lymphocytes
(mean - 497.7, p<0.0001 for both comparison). Comparison between the inflamed and
the non-inflamed appendices revealed that the inflamed appendix contained a
significantly higher proportion of B1 cells (5.64% of total lymphocytes versus
3.53%, p=0.032), and also a higher B1/b cell ratio (0.13 vs. 0.07, p=0.01).
CONCLUSIONS: These results indicate that the appendix tissue contains higher
number of B1 (and B) cells compared to the peripheral blood and that these cells
play a role in the primary immune response to acute infection/inflammation in the
appendix. Appendiceal B cell population is unique in term of CD19 intensity
expression on their surface.
PMID- 10776801
TI - Cleavage of the fifth component of complement and generation of a functionally
active C5b6-like complex by human leukocyte elastase.
AB - Activation by complement C3/C5 convertases of the fifth component of human
complement, C5, leads to two active cleavage products: C5a, a chemotactic
peptide, and C5b, the activated form of C5. Human leukocyte elastase (HLE) has
long been known to also release from C5 a chemotactic, C5a-like fragment. This,
however, cannot be identical with C5a, since HLE does not cleave peptide bonds at
the carboxyl group of arginine, the cleavage site that separates C5a and C5b
after the exposure to the complement convertases. Therefore, the question arose
whether HLE is capable of releasing a functionally C5b-like product from C5. The
results show that this is, indeed, so. Treatment of human C5 with HLE in the
presence of C6 leads to the formation on an active C5b6-like complex that lyses
non-sensitized guinea pig red cells upon addition of the terminal components C7,
C8, and C9. However, since C6 is highly sensitive to the hydrolytic action of
HLE, the yield of the activation complex is rather low. The results offer a third
possibility for the activation of C5: 1) classical cleavage at Arg74 by
complement convertases, 2) oxidation of methionine residues without cleavage,
and, as shown here, 3) cleavage by elastase at (a) site(s) distal from Arg74. The
three procedures may modulate the relative yield of the two activities generated
from C5, C5a-like and C5b-like effects.
PMID- 10776802
TI - Reduced pteridine derivatives induce apoptosis in human neuronal NT2/HNT cells.
AB - Elevated concentrations of the pteridine compound neopterin, usually accompanied
by 7,8-dihydroneopterin were found in cerebrospinal fluids of patients with
neurodegenerative diseases and central nervous system infections. Here, the
potential of pteridines to induce apoptosis of the human neuronal cell line (NT2)
was investigated. Reduced neopterin, biopterin- and folate derivatives led to a
time-dependent increase of apoptosis of cells. In contrast, non-reduced
pteridines did not significantly alter cell survival. After differentiation of
neuronal precursor cells to neurons and astrocyte-like cells, similar effects
were detected. Antioxidants partly protected NT2 from pteridines-induced
apoptosis, suggesting the involvement of reactive oxygen intermediates. In vitro
experiments using dichlorofluorescin-diacetate further indicated a direct
formation of reactive oxygen species in cells. Results implicate that high
concentrations of reduced pteridines, might contribute to the loss of neuronal
cells in neurodegenerative diseases.
PMID- 10776803
TI - Long-acting calcium channel antagonist pranidipine prevents ventricular
remodeling after myocardial infarction in rats.
AB - The purpose of this study was to examine the effects of the long-acting calcium
channel antagonist pranidipine on ventricular remodeling, systolic and diastolic
cardiac function, circulating humoral factors, and cardiac mRNA expression in
myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of
the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was
randomly administered to the infarcted rats. Hemodynamic measurements, Doppler
echocardiographic examinations, analyses of the plasma levels of humoral factors,
and myocardial mRNA expression were performed at 4 weeks after myocardial
infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous
pressure (CVP) increased to 24.2 +/- 1.2mmHg and 5.4 +/- 0.6 mmHg. Pranidipine
reduced LVEDP and CVP to 13.6 +/- 1.4mmHg (P < 0.01) and 2.5 +/- 0.4mmHg (P <
0.01). The weight of the left and right ventricles in MI was significantly higher
than in the sham-operated rats (sham, 2.02 +/- 0.04 and 0.47 +/- 0.02g/kg; MI,
2.18 +/- 0.05 and 0.79 +/- 0.04g/ kg; P < 0.01). Left ventricular end-diastolic
dimension (LVDd) in MI increased to 10.3 +/- 0.3mm (P < 0.01) (sham, 6.4 +/-
0.3mm). Pranidipine prevented an increase in the weight of the left and right
ventricles (2.02 +/- 0.04 and 0.6 +/- 0.03g/kg, P < 0.01) and LVDd (7.9 +/-0.2mm,
P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine,
norepinephrine, and dopamine concentrations in MI were higher than those of the
sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels
of the myocardial infarcted rats to the level of the sham-operated rats.
Moreover, the rats in MI showed systolic dysfunction, shown by decreased
fractional shortening (sham, 31 +/- 2% vs MI, 15 +/- 1%; P < 0.01) and diastolic
dysfunction shown by the E-wave deceleration rate (sham, 12.8 +/- 1.1 m/s2; MI,
32.6 +/- 2.1 m/s2; P < 0.01). Pranidipine significantly prevented systolic and
diastolic dysfunction. The increases in beta-myosin heavy chain (MHC), alpha
skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left
ventricle and right ventricle at 4 weeks after the myocardial infarction were
significantly suppressed by the treatment with pranidipine. On the other hand,
depressed alpha-MHC was restored to normal levels by pranidipine in both regions.
In conclusion, pranidipine prevents the left ventricular remodeling process
accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac
gene expression after myocardial infarction.
PMID- 10776804
TI - Effects of repeated brief episodes of ischemia and reperfusion in isolated
perfused rat hearts.
AB - The effects of ischemia and reperfusion on the coronary endothelium and
myocardium as well as tolerance to ischemia/reperfusion injury were assessed
using isolated retrogradely perfused rat hearts. Repeated brief episodes of
myocardial ischemia followed by reperfusion is known to have a protective effect
against subsequent myocardial infarction. However, no studies have been performed
with perfusion in the absence of blood cells to determine the effect of repeated
ischemia and reperfusion on the coronary endothelium and myocardium. Using the
Langendorff perfusion technique, rat hearts were subjected to a 30-, 10-, 5-, or
2-min period of low-flow perfusion by reducing the coronary flow to 3 ml/min
followed by reperfusion at 20 ml/min for the same period of time. Control
perfusion was then performed at a constant flow rate of 20 ml/ min for 60 min.
Acetylcholine-induced coronary vasodilation was significantly (P < 0.05) lower in
hearts subjected to 30 min of ischemia and 30 min of reperfusion when compared
with the control hearts. Myocardial creatinine kinase (CK) activity was
significantly reduced (P < 0.01) in hearts subjected to ischemia and reperfusion
for either 30, 10, or 5 min. To assess the effect of repeated episodes of
ischemia and reperfusion, the following protocols were used: a control study with
constant perfusion for 60 min (group A), 30 min of ischemia and 30 min of
reperfusion (group B), three 10-min episodes of ischemia and reperfusion (group
C), six 5-min episodes of ischemia and reperfusion (group D), and 15 2-min
episodes of ischemia and reperfusion (group E). Acetylcholine-induced coronary
vasodilation was significantly inhibited in group B (80% +/- 12%, P < 0.05) and
group C (70% +/- 13%, P < 0.01), but did not change significantly in either group
D (123% +/-19%) or group E (142% +/- 15%), compared with the control group (group
A; 127% +/- 15%, mean +/-SEM). Nitroglycerin-induced coronary vasodilation was
not altered by ischemia/reperfusion in any group. In contrast, myocardial CK
activity was significantly lower in group B (3.6 +/- 0.6IU/mg protein, P < 0.01),
group C (3.2 +/- 0.1 IU/mg protein, P < 0.01), and group D (3.3 +/- 0.21U/mg
protein, P < 0.01) than in group A (47 +/- 6.7 IU/mg protein). The myocardial CK
activity of group E was not significantly different from that of group A, but was
significantly higher than in groups B, C, and D (P < 0.01). In isolated perfused
rat hearts, both the coronary endothelium and myocardium are damaged by repeated
episodes of ischemia and reperfusion. However, the coronary endothelium is more
resistant to such damage than is the myocardium.
PMID- 10776806
TI - H2-blocker modulates heart rate variability.
AB - The use of H2-blockers in the treatment of patients with peptic ulcer has become
popular. However, this treatment has adverse cardiovascular effects. The aim of
this study was to investigate proarrhythmic rhythm and autonomic nervous activity
by analyzing heart rate variability in patients treated with omeprazole,
ranitidine, and plaunotol. Nineteen patients (mean age 67.5 +/- 2.7 years) with
active gastric ulcer were treated with omeprazole (20 mg/day) for 8 weeks, then
ranitidine (300 mg/day) for the next 4 months, and finally plaunotol (240
mg/day). At each stage of the treatment, Holter electrocardiography was
performed, and heart rate variability and arrhythmias analyzed. Heart rate
variability yielded power in the low- (0.04-0.15 Hz) and high-frequency
components (0.15-0.4 Hz). Although both ranitidine and omeprazole induced little
change in cardiac rhythm, the high-frequency power was higher (10.3 +/- 0.8 vs
8.6 +/- 0.6 ms, P < 0.05) and the ratio of low-to-high frequency power was lower
(1.41 +/-0.10 vs 1.59 +/- 0.09. P < 0.05) during ranitidine than during plaunotol
treatment. Cosinor analysis of heart rate variability revealed a decreased
amplitude of low-frequency power during omeprazole compared with during
ranitidine and plaunotol treatment. Ranitidine modulated high-frequency power
which may be related to the adverse cardiovascular effects of H2-blocker.
PMID- 10776805
TI - SD3212, a new antiarrhythmic drug, raises atrial fibrillation threshold in
isolated rabbit hearts.
AB - SD3212 is a new antiarrhythmic drug which has class I, III, and IV effects. The
purpose of this study was to elucidate the electrophysiological effects of this
compound on a rabbit atrial fibrillation model, and to test a hypothesis that
atrial fibrillation threshold is a quantitative indicator of atrial
vulnerability. Whole hearts were excised from rabbits, and the aortas cannulated
to perfuse the coronary arteries. Atrial fibrillation was induced with a burst
stimulation of 50 Hz for 1 s while 3 microM acetylcholine (ACh) was perfused.
When the right atrial appendage was paced at 200-ms intervals, SD3212 prolonged
interatrial conduction time: control 30 +/- 1.2 ms, ACh 33 +/- 1.4 ms, ACh + SD 1
microM 37 +/- 2.4 ms, ACh + SD 3 microM 52 +/- 8.1 ms. The drug also prolonged
the effective refractory period: control 80 +/-3.0 ms, ACh 48 +/- 3.8 ms, ACh +
SD 1 microM 65 +/- 4.7 ms, ACh + SD 3 microM 98 +/- 15 ms. The rate of induction
of atrial fibrillation by rapid pacing was 26% in Tyrode's solution, 85% in the
presence of ACh, and 38% in the presence of ACh + SD 1 microM. The atrial
fibrillation threshold decreased from 8.6 +/- 0.8mA (control) to 2.5 +/- 0.7 mA
in the presence of ACh. It increased again to 7.8 +/- 1.0 mA in the presence of
SD3212 (1 microM). SD3212 prolonged both the conduction time and refractory
period. A reversed use-dependency was not prominent. These features caused
antifibrillatory effects. Thus, the atrial fibrillation threshold seems to be a
good quantitative indicator of atrial vulnerability.
PMID- 10776807
TI - Assessment of endothelium-mediated vasodilation of the peripheral circulation by
transcutaneous ultrasonography and venous occlusion plethysmography.
AB - Transcutaneous ultrasonography is a non-invasive technique with the ability to
measure the volumetric blood flow of the peripheral circulation. Peripheral blood
flow can be determined by high-resolution imaging of vessel diameter coupled with
Doppler assessment of flow velocity. This method, however, has not been validated
in vivo. Accordingly, brachial artery flow in response to intraarterial infusion
of vasodilators was assessed by ultrasonography in 16 healthy subjects and
compared to values obtained simultaneously by venous occlusion plethysmography.
Blood flow calculated from ultrasound-derived vessel diameter and flow velocity
was found to highly correlate with plethysmographic flow, with r values ranging
from 0.83 to 0.99. Using this ultrasound technique combined with plethysmography,
the response of conduit and resistance vessels to endothelium-mediated
vasodilation was characterized. Doppler velocity rose dramatically with
endothelium-dependent acetylcholine (970%), but only modestly with endothelium
independent vasodilators, nitroglycerin (292%) and nitroprusside (340%). Despite
eliciting the greatest overall forearm flow response, acetylcholine resulted in a
smaller increase in conduit diameter (15.4%) than nitroglycerin (21.8%), and only
a comparable change than nitroprusside (14.6%). Taken together, these results
suggest that acetylcholine acts predominantly on resistance vessels, whereas
nitrovasodilators affect mainly conduit vessels. In summary, transcutaneous
ultrasonography can be used reliably to assess flow changes in the peripheral
circulation. Combined with plethysmography, this technique is useful for
determining the relative contribution of conduit and resistance vessels to
peripheral flow, particularly in the assessment of endothelium-mediated
vasodilation.
PMID- 10776808
TI - Relationship between left atrial spontaneous echo contrast and the features of
middle cerebral artery territory in nonvalvular atrial fibrillation.
AB - We investigated the relationship between left atrial spontaneous echo contrast
(SEC) and cerebrovascular features in nonvalvular atrial fibrillation (NVAF). Few
reports have been published to compare cardiac and cerebrovascular imaging in
patients with NVAF. Forty-four patients with NVAF were studied using
transesophageal echocardiography and non-invasive imaging including magnetic
resonance imaging (MRI), magnetic resonance angiography (MRA), and transcranial
color Doppler imaging (TCD) in the middle cerebral artery (MCA) territory. The
symptomatic severity was divided into asymptomatic, transient ischemic attack
(TIA), and stroke. The severity of the MRI findings was divided into normal,
small, and large infarcts. The severity of the MRA findings was divided into
normal, attenuation, and occlusion. MCA was bilaterally scanned and a side-to
side asymmetry ratio of pulsatility index (PI) was measured. The severity of SEC
was divided into normal, SEC, and thrombi. Five patients with other
thromboembolic risk or poor results of TCD were excluded. SEC and thrombi were
detected in 12 (30%) and in 3 patients (5%), respectively. TIA and stroke were
detected in 8 (21%) and in 17 patients (44%), respectively. Small and large
infarcts were detected in 9 (23%) and in 18 patients (46%), respectively, on MRI.
Attenuation and occlusion were detected in 14 (36%) and in 8 patients (21%),
respectively, on MRA. PI ratio was 1.21 +/- 0.25. SEC severity was highly
associated with PI ratio and MRA severity in monovariate analysis (P < 0.005), P
< 0.01, respectively). SEC severity was highly associated with PI ratio and MRA
severity in stepwise multiple regression analysis (P = 0.0001, r = 0.630, n =
39). In patients with NVAF, left atrial SEC was highly related to attenuation or
occlusion on MRA and imbalance of cerebral blood flow on TCD in the MCA
territory.
PMID- 10776809
TI - Pulmonary blood flow distribution after the total cavopulmonary connection for
complex cardiac anomalies.
AB - In total cavopulmonary connection (TCPC), the anastomotic portion of the caval
veins to the pulmonary artery (PA) is decided empirically based on personal
experience. To compare the pulmonary flow distribution from both caval veins in
various types of cavopulmonary anastomosis, intrapulmonary ventilation-perfusion
distribution after TCPC was studied using lung scanning. We studied 11 patients,
2 to 37 years old, at 30-84 months after TCPC. Lung scanning was performed by
administering 185 MBq of xenon-133 saline solution from their upper extremities
and, after xenon-133 was washed out, from their lower extremities. Radionuclide
counts on both lungs were obtained and intrapulmonary ventilation-perfusion
distribution was assessed. In 4 patients whose superior vena cava (SVC)-PA
anastomosis was on the right side of the inferior vena cava (IVC)-PA anastomosis,
the blood flow distribution of the right and left lungs was 57.4%: 42.6%. In 3
patients whose SVC-PA anastomosis was on the left side of the IVC-PA anastomosis,
the blood flow distribution of the right and left lungs was equal in both lungs
(right, 53.1%; left, 46.9%). Systemic arterial oxygen saturation increased after
TCPC (before TCPC, 85.3% +/- 2.7% and after TCPC, 89.8% +/- 2.3% (P < 0.05) in
group R; before TCPC, 86.1% +/- 2.8% and after TCPC, 93.6% +/- 0.6% (P < 0.02) in
group L). After TCPC, the value in group L had a tendency to be greater than that
in group R (P < 0.04), in spite of the same values of systemic arterial oxygen
saturation before TCPC and cardiac index (group R, 2.9 +/- 0.96; group L, 3.4 +/-
0.37). Lung scanning with xenon-133 revealed the distribution of pulmonary blood
flow in the patients after TCPC quantitatively, and in the patients whose SVC-PA
anastomosis was on the left side of the IVC-PA anastomosis, the right and left
balance of the pulmonary blood flow distribution appeared to be more balanced
compared with patients whose connection was done the opposite way.
PMID- 10776810
TI - Confocal microscopic estimation of GABAergic nerve terminals in the central
nervous system.
AB - We describe a method for estimating the average proportion of GABAergic terminal
area relative to total nerve terminal area with confocal microscopy. Nerve
terminal regions were identified with dual colour immunofluorescence on Vibratome
sections with an antibody to synaptophysin (SYN), and GABAergic processes,
including axon terminals, were identified with an antibody to glutamic acid
decarboxylase (GAD). Sections were viewed in an Olympus AX70 microscope attached
to a Biorad 1024 MRC scanning confocal system. Images were collected with a 100 x
objective from the same tissue locations and imported into the NIH-Image program,
where black and white binary images were obtained for co-localisation and
quantitation. Measurements were made separately of areas of SYN/GAD (GABAergic
terminals) and SYN labelling (all terminals). The relative proportion of
GABAergic terminal areas in visual cortex (6.1+/-1%; mean +/- SE), CA1
hippocampus (2.6+/-0.5%) and deep cerebellar nuclei (46.6+/-3%) are consistent
with what is known of the relative levels of inhibitory input to these
structures. The assumptions that SYN labelling is restricted to axon terminals,
and that SYN labels all axon terminals was tested by ultrastructural localisation
of SYN in the three brain regions examined. Only 7.4+/-0.4% of SYN-labelled
profiles could not be positively identified as synaptic vesicle-containing axon
terminals, and between 93.4 and 99.2% of vesiculated axon profiles were SYN
positive. These results suggest that SYN is a very reliable marker for axon
terminals, and validates the confocal analytical approach. The confocal method
allows rapid sampling of many brain regions and would be suitable for examining
terminals containing any neurotransmitter that can be detected
immunocytochemically.
PMID- 10776811
TI - Rabbit and monkey visual cortex: more than a year of recording with up to 64
microelectrodes.
AB - In the visual cortex of rabbits and a marmoset monkey, 32 and 64 microwires,
respectively, were chronically implanted by an indirect insertion method so that
the cortex was penetrated from the white matter. For more than 1 year recordings
of action potentials of good quality were obtained at most electrodes. Recording
stability was judged by spike shape, spike train autocorrelograms, and spike
rates: within recording sessions, stability was essentially perfect. Periods in
which the signals of several electrodes were stable could last for several days.
A method of in vivo reconstruction of the electrode locations by micro-X-rays and
subsequent stereophotogrammetry is presented. The aspect of animal welfare is
considered.
PMID- 10776813
TI - Analysis of spatial patterns in histological sections of brain tissue using a
method based on regression.
AB - A method of determining the spatial pattern of any histological feature in
sections of brain tissue which can be measured quantitatively is described and
compared with a previously described method. A measurement of a histological
feature such as density, area, amount or load is obtained for a series of
contiguous sample fields. The regression coefficient (beta) is calculated from
the measurements taken in pairs, first in pairs of adjacent samples and then in
pairs of samples taken at increasing degrees of separation between them, i.e.
separated by 2, 3, 4,..., n units. A plot of beta versus the degree of separation
between the pairs of sample fields reveals whether the histological feature is
distributed randomly, uniformly or in clusters. If the feature is clustered, the
analysis determines whether the clusters are randomly or regularly distributed,
the mean size of the clusters and the spacing of the clusters. The method is
simple to apply and interpret and is illustrated using simulated data and studies
of the spatial patterns of blood vessels in the cerebral cortex of normal brain,
the degree of vacuolation of the cortex in patients with Creutzfeldt-Jacob
disease (CJD) and the characteristic lesions present in Alzheimer's disease (AD).
PMID- 10776812
TI - Purification of chick retinal ganglion cells for molecular analysis: combining
retrograde labeling and immunopanning yields 100% purity.
AB - Retinal ganglion cells (RGCs) from embryonic and posthatch chickens were 100%
purified by a novel combination of three steps: (1) Retrograde labeling by
injection of the fluorescent carbocyanine tracer DiI into the optic nerve, (2)
immunopanning of dissociated retinal cells with Thy1 antibodies, and (3) micro
aspiration of labeled RGCs into glass capillaries. The retina was dissected and
dissociated with trypsin 12-15 h after the injection of DiI. DiI-labeled cells
were identified on immunopanned dishes by fluorescence and collected for
molecular analysis within 3 h after dissociation. This technique allowed the
collection of up to 500 RGCs per capillary tube and 1500 labeled RGCs per retina.
Extraction of RNA and molecular analysis by RT-PCR from 600 RGCs shows that
expression of rare genes, such as those of neurotrophic factors, can be detected.
This is the first description of a rapid and reliable technique for a 100%
purification of RGCs with sufficient yield for molecular analysis of rare gene
expression. The protocol can be modified for the purification of other cell
types. The advantages and limitations of the three-step purification method are
compared with previous RGC purification protocols.
PMID- 10776814
TI - Computer-controlled impalement of cells in retinal wholemounts visualized by
infrared CCD imaging on an inverted microscope.
AB - We present a computer-guided microelectrode positioning system that is routinely
used in our laboratory for intracellular electrophysiology and functional
staining of retinal neurons. Wholemount preparations of isolated retina are kept
in a superfusion chamber on the stage of an inverted microscope. Cells and layers
of the retina are visualized by Nomarski interference contrast using infrared
light in combination with a CCD camera system. After five-point calibration has
been performed the electrode can be guided to any point inside the calibrated
volume without moving the retina. Electrode deviations from target cells can be
corrected by the software further improving the precision of this system. The
good visibility of cells avoids prelabeling with fluorescent dyes and makes it
possible to work under completely dark adapted conditions.
PMID- 10776815
TI - A combined system for measuring animal motion activities.
AB - In this study, we have developed a combined animal motion activity measurement
system that combines an infrared light matrix subsystem with an ultrasonic phase
shift subsystem for animal activity measurement. Accordingly, in conjunction with
an IBM PC/AT compatible personal computer, the combined system has the advantages
of both infrared and ultrasonic subsystems. That is, it can at once measure and
directly analyze detailed changes in animal activity ranging from locomotion to
tremor. The main advantages of this combined system are that it features real
time data acquisition with the option of animated real time or recorded
display/playback of the animal's motion. Additionally, under the multi-task
operating condition of IBM PC, it can acquire and process behavior using both IR
and ultrasound systems simultaneously. Traditional systems have had to make
separate runs for gross and fine movement recording. This combined system can be
profitably employed for normative behavioral activity studies and for
neurological and pharmacological research.
PMID- 10776816
TI - Quantification of GABA(A) receptor subunit mRNAs by non-radioisotopic competitive
RT-PCR utilizing plate-based EIA methodology.
AB - We developed a non-radioisotopic quantitative competitive RT-PCR method for the
measurement of gamma-aminobutyric acid (GABA) type A receptor subunit mRNA
levels. The specificity of the method was optimized by the use of four subunit
specific oligonucleotides in the sequential steps: reverse transcription,
polymerase chain reaction (PCR), and detection. The biotinylated PCR products
were bound on streptavidin-coated microtiter plates allowing detection of the
products using dinitrophenyl (DNP)-labeled probes and anti-DNP alkaline
phosphatase conjugate. The method was set up for the six major cerebellar GABA(A)
receptor subunits: alpha1; alpha6; beta2; beta3; gamma2 and delta. The method is
quantitative and rapid. With a large dynamic range from 10 fg to 1 ng of subunit
mRNA, the accuracy was 12 and 19% (intra- and interassay coefficients of
variation, respectively), which might be improved by using a smaller range of
standards. The use of a double logarithmic standard curve [log (standard to
competitor signal) vs. log (standard mRNA originally present)] requires only one
reaction from each sample, allowing the analysis of a large number of samples in
one experiment.
PMID- 10776817
TI - The rotating pole test: evaluation of its effectiveness in assessing functional
motor deficits following experimental head injury in the rat.
AB - Neurological motor dysfunction is often an integral component of the neurological
sequelae of traumatic brain injury (TBI). In experimental TBI, neurological motor
testing is an outcome measure used to monitor severity of injury, and the
response to treatment. This study evaluates the effectiveness and sensitivity of
the rotating pole test (RP) to characterize and evaluate the temporal course of
motor deficits after lateral fluid percussion (FP) injury to the rat brain. The
results are compared with the previously characterized and widely used composite
neuroscore of motor function (NS). The animals were required to walk across an
elevated wooden pole that was either stationary or rotating to left or right
directions at different speeds. Male Wistar rats underwent lateral FP injury of
moderate severity (mean 2.4 atm, n = 9) or sham surgery (n = 9), and were tested
at 48 h and 7 days post-injury using the NS and RP. The results of the NS
directly correlated to the results of the RP, showing a significant injury effect
at both 48 h and 7 days. This is the first study to show that the RP-test detects
neurological motor deficits after lateral FP injury, and suggests that this
technique is a reliable behavioral tool for evaluating neurological motor
function in the acute period after experimental TBI.
PMID- 10776818
TI - The problem of the morphological noise in reconstructed dendritic arborizations.
AB - For technical, instrumental and operator-related reasons, three-dimensional (3D)
reconstructions of neurons obtained from intracellularly stained neuronal pieces
scattered in serial sections are blurred by some morphological noise. This noise
may strongly invalidate conclusions drawn from models built using the 3D
reconstructions and it must be taken into account when retrieving digitized
neurons from available databases. We analyse on several vertebrate neurons
examples the main noise-generating sources and the consequences of the noise on
the 'quality' of the data. We show how the noise can be detected and evaluated in
any database, if sufficient information is presented in this database.
PMID- 10776819
TI - Surgery for tricuspid valve endocarditis: a selective approach.
AB - The authors report their 18-year experience in the surgical treatment of
infective tricuspid endocarditis. Between January 1981 and January 1999, 238
cases of infective endocarditis were seen. with a tricuspid involvement in 21
cases (8.8%). Tricuspid valve repair was performed in 9 patients with infective
lesions involving one single leaflet. The surgical principle of the repair was to
avoid any prosthetic material implantation. Posterior leaflet vegetectomy was
performed in another 2 patients with infected intracavitary leads. Tricuspid
valve replacement was performed in 10 patients with involvement of the whole
valvular apparatus. One patient died of septic shock 3 days postoperatively. All
the other patients had a good postoperative recovery. Follow-up ranged between 12
and 155 months (mean 68.9 +/- 55 months). Five cases of late mortality were
observed: 3 for cardiac reasons and 2 of cancer. All the other patients are
alive. Late postoperative echocardiography in the patients with tricuspid repair
showed tricuspid regurgitation to be absent in 6 patients, mild in 2, moderate in
1, and severe in 1. No recurrent infections were observed either in patients with
valve repair or in those with valve replacement. Good early and long-term results
can be achieved in the surgical treatment of tricuspid endocarditis as long as
complete excision of the infected tissue is performed and risk factors are
controlled.
PMID- 10776821
TI - Development of a servo-controller of heart rate using a cycle ergometer.
AB - In exercise training, precise control of exercise intensity would maximize the
training efficacy while minimizing risks. To adjust work rate, heart rate (HR)
has been used as a measure of exercise intensity. Thus, we developed a servo
controller of HR using a cycle ergometer. After estimating the transfer function
from work rate to HR, we optimized feedback parameters for achieving a quick and
stable HR response by means of a computer simulation. We then examined the
performance of the servo-controller of HR in 55 healthy volunteers. We set the
target HR at 60% and 75% of the age-predicted maximum HR. Times required for HR
to reach 90% of the target HR were 136 +/- 33 and 137 +/-22s in the respective
protocols. Standard deviations of the steady-state difference between the target
and measured HRs were 2.5 +/- 0.6 and 3.8 +/- 1.1 beats/min. We conclude that the
developed servo-controller makes it possible to precisely regulate HR and,
thereby, exercise intensity.
PMID- 10776820
TI - Endomyocardial biopsy findings in patients with atrioventricular block in the
absence of apparent heart disease.
AB - The purpose of this study was to examine the histopathological findings of right
ventricular endomyocardial biopsies from ten patients less than 60 years of age
(47 +/- 9.8 (mean +/- SD) years) with documented atrioventricular block but
without apparent heart disease. They underwent electrophysiological testing,
echocardiography, coronary angiography, and right ventricular endomyocardial
biopsy. Biopsy specimens were assessed for morphologic changes in myocyte
diameter, fibrosis, disarray, and degeneration. Electrophysiological testing
demonstrated atrioventricular nodal block in 2, intra-His bundle block in 2, and
infra-His bundle block in 6 patients. Histology revealed evidence of myocardial
fibrosis with either myocyte hypertrophy or disarray in 7 of the 10 patients. The
results of electrophysiological testing did not correlate with the
histopathological findings or severity. In one patient, heart failure appeared
during the follow-up period. We conclude that patients with atrioventricular
block of unknown etiology have histological abnormalities of the ventricular
endomyocardium in addition to the conduction system disturbances. We consider
such cases as constituting one of the disease groups of cardiomyopathy, and
suggest that it is necessary to follow up the clinical course in these patients.
PMID- 10776822
TI - Mathematical simulation of the Wenckebach phenomenon in Purkinje fibers.
AB - We were able to simulate the Wenckebach phenomenon using a model of a one
dimensional cable, consisting of 20 serially connected Purkinje fiber cells
represented by the model of McAllister, Noble, and Tsien. The internal resistance
between the 10th and 11th cells was modified to five times the normal. To
reconstruct the action potential, the derivative equation was solved using a
fourth-order Runge-Kutta algorithm. When the first cell of the cable was
stimulated, periodically, at an interval of 610 ms, a 9:8 Wenckebach pattern was
elicited in the conduction between the tenth and 11th cells. Lower order 5:4,
4:3, 3:2 Wenckebach patterns were observed at pacing cycle length of 605, 600
595, and 590-575 ms, respectively. At a pacing cycle length of 570ms or less, 2:1
block was elicited. In another simulation, only when INa, was 0 could the
Wenckebach phenomenon be elicited in a cable model. in which internal cell
resistance and membrane capacitance were uniformly set, but in which the INa of
the center two cells of the cable were alternated between 1 and 0. A localized
increase in internal resistance, a relatively long time constant of deactivation
of the delayed rectifier outward current, and a relatively rapid rate of pacing
cycle length was necessary to evoke the Wenckebach phenomenon. The conductance of
the delayed rectifier current at the end of an action potential increased
progressively, except after a dropped beat when it was allowed to decrease. It
was concluded that the change of conductance affected the cable property of the
fiber and consequently evoked the Wenckebach phenomenon.
PMID- 10776823
TI - Equations for estimating muscle fiber stress in the left ventricular wall.
AB - Left ventricular muscle fiber stress is an important parameter in cardiac
energetics. Hence, we developed equations for estimating regional fiber stresses
in rotationally symmetric chambers, and equatorial and apical fiber stresses in
prolate spheroidal chambers. The myocardium was modeled as a soft incompressible
material embedding muscle fibers that support forces only in their longitudinal
direction. A thin layer of muscle fibers then contributes with a pressure
increment determined by the fiber stress and curvature. The fiber curvature
depends on the orientation of the fibers, which varies continuously across the
wall. However, by assuming rotational symmetry about the long axis of the
ventricle and including a longitudinal force balance, we obtained equations where
fiber stress is completely determined by the principal curvatures of the middle
wall surface, wall thickness, and cavity pressure. The equations were validated
against idealized prolate spheroidal chambers, whose wall thicknesses are such
that the fiber stress is uniform from the equator to the apex. Because the apex
is free to rotate, the resultant moment about the long axis of the LV must be
zero. By using this constraint together with our fiber-stress equations, we were
able to estimate a muscle fiber orientation distribution across the wall that was
in qualitative agreement with published measurements.
PMID- 10776824
TI - A case of acute pulmonary embolism and acute myocardial infarction with suspected
paradoxical embolism after laparoscopic surgery.
AB - We describe the case of a 59-year-old Japanese man who had an acute pulmonary
embolism in addition to acute myocardial infarction after a laparoscopic
cholecystectomy. The posterior descending coronary artery was totally occluded.
and direct percutaneous transluminal balloon angioplasty was performed. The
pulmonary embolism was diagnosed by lung perfusion scanning and was treated with
anticoagulant therapy. A patent foramen ovale and right-to-left atrial shunting
of blood were detected by contrast transesophageal echocardiography. Paradoxical
embolism is a rare complication of pulmonary embolism and may have been
responsible for the acute myocardial infarction in our patient.
PMID- 10776825
TI - Coronary sinus long sheath catheter system: a new device for transfemoral
coronary sinus catheterization.
AB - Coronary sinus catheterization requires an approach into the right atrium via the
superior vena cava. This study contains information regarding a coronary sinus
long sheath catheter (CS sheath) system, a new device for cannulation of the
coronary sinus through the femoral approach. This method was successful in 96.9%
of the cases attempted. Furthermore, cannulation using the CS sheath allowed us
not only to insert several catheters into the coronary sinus for clinical use and
investigation, but also to access the great and small cardiac veins easily and
selectively.
PMID- 10776826
TI - Antitumour effects of bisphosphonates: first evidence and possible mechanisms.
AB - Bisphosphonates have been used successfully for many years in the treatment of
hypercalcaemia and to reduce skeletal complications of metastases. In the first
years of bisphosphonate use the efficacy of these substances was thought to lie
purely in the inhibition of osteoclasts. However, there is recent evidence to
suggest that an antitumour effect may also play a role. As well as having an
apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert
a similar influence on macrophages and tumour cells. Whether this effect (at low
doses) also plays a role in vivo remains unclear and requires further
investigation. Improvements in the survival time of certain subpopulations have
been found in many phase III studies with bisphosphonates to date, both in the
setting of metastatic breast cancer and in multiple myeloma. However, because
survival time in subgroups of patients was neither a primary nor a secondary
objective in these studies, these advantages could only be seen as important
pointers for future studies. Some preclinical studies have shown that down
regulation of bone metabolism by bisphosphonates is associated with a lower
incidence of bone metastases and destruction in animals, whereas activation is
correlated with a higher number of metastases. However, varying results were
found in animal experiments with regard to the effect of bisphosphonates on the
incidence and growth pattern of non-osseous metastases. The results of 3
randomised studies in patients with primary breast cancer who received clodronate
1600 mg/day orally have now been evaluated and presented. All 3 studies arrived
at different results. In the Heidelberg study there was a reduction in both
osseous and non-osseous metastases, whereas in a much larger study performed in
Great Britain, Canada and Scandinavia there was a reduction only in the incidence
of skeletal metastases. A third study from Finland found no effect on bone
metastases, but an increase in the number of visceral metastases and a
deterioration in overall survival. Because the dosage was identical in all 3
studies, the differing results can only be either random or methodological (for
example inclusion criteria or sample size). Overall, the results are very
promising, but there is a need for further studies.
PMID- 10776827
TI - What is new in the treatment of multiple sclerosis?
AB - Multiple sclerosis (MS) is considered an autoimmune disease associated with
immune activity directed against central nervous system antigens. Based on this
concept, immunosuppression and immunomodualtion have been the mainstays of
therapeutic strategies in MS. During the last decade new therapies have been
shown to significantly improve MS disease course. The effective therapies have
led to a better understanding of MS pathogenesis and further development of even
more efficient therapeutic interventions. Recombinant interferon (IFN)beta
represents the first breakthrough in MS therapy. Three large placebo-controlled,
double-blind studies and several smaller studies have demonstrated the efficacy
of different forms of IFNbeta administrated by either subcutaneous or
intramuscular routes and at different doses in patients with active relapsing
remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and
two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had
unique features and differences that make direct comparisons difficult, the
aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses
and probability of sustained clinical disability progression in patients with RR
MS. All forms of IFNbeta therapy had beneficial effects on the disease process
measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also
showed benefit in slowing or preventing the development of MS related brain
atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate
salt of a mixture synthetic polypeptides thought to mimic the myelin basic
protein showed a significant positive results in reducing the relapse rate in
patients with RR-MS. Follow up of these patients for approximately 3 years
continued to show a beneficial effect on disease relapse rate. Recent MRI data
supported the beneficial clinical results seen with glatiramer acetate in
patients with RR-MS. Recent studies using intravenous immune globulin (IVIG)
suggest that IVIG could be effective to some degree in patients with RR-MS.
However, there is not enough evidence that IVIG is equivalent to IFNbeta or
glatiramer acetate in the treatment of patients with RR-MS. There have also been
recent therapeutical advances in secondary progressive MS (SP-MS). A recent large
phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS
convincingly documented that IFNbeta-1b slowed progression of the disease
independent of the degree of the clinical disability at the time of treatment
initiation and independent of presence of superimposed relapses. Mitoxantrone, an
anthracenedione synthetic agent, was also shown to be effective as treatment for
active SP-MS. It is well tolerated but the duration of treatment is limited by
cumulative cardiotoxicity. There is a growing consensus that disease-modifying
therapies should be initiated early in the course of the disease before
irreversible clinical disability has developed. Different therapies should be
considered and tailored based on patient condition. Combination therapies could
be considered as a therapeutic option for patients that failed therapies with
IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies
testing safety and/or efficacy of different combination regimens (i.e.
azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of
intravenous cyclophosphamide with IFNbeta). Determining the effect of different
therapies on the course of the disease within large clinical studies appears
easier than determining individual responsiveness. Therefore, standardised
methods for evaluating individual patients receiving disease-modifying therapies
and development of effective therapeutic algorithms are needed.
PMID- 10776830
TI - Treatment of sexually transmitted bacterial diseases in pregnant women.
AB - Testing for and treating sexually transmitted diseases (STDs) in pregnant women
deserves special attention. Treatment possibilities are limited because of
potential risks for the developing fetus, and because effects can differ in
pregnant compared with non-pregnant women, re-infection may be missed because of
the intrinsic delicacy of contact-tracing during pregnancy and because pregnant
women are more reluctant to take the prescribed medication in its full dose, if
at all. However, the devastating effects of some of these genital infections far
outweigh any potential adverse effects of treatment. Although active syphilis has
become a rarity in most Western countries, it is still prevalent in South
America, Africa and South-East Asia. Benzathine benzylpenicillin (2.4 million
units once or, safer, twice 7 days apart) is the treatment of choice, although
patients with syphilis of longer standing require 3 weekly injections as well as
extensive investigation into whether there has been any damage due to tertiary
syphilis. Despite declining rates of gonorrhea, the relative rate of
penicillinase-producing strains is increasing, especially in South-East Asia. The
recommended treatment is intramuscular ceftriaxone (125 or 250 mg) or oral
cefixime 400 mg. Despite good safety records after accidental use,
fluoroquinolones are contraindicated during pregnancy. An alternative to a
fluoroquinolone in pregnant women with combined gonorrhea and chlamydial
infection is oral azithromycin 1 or 2 g. Azithromycin as a single 1 g dose is
also preferable to a 7 day course of erythromycin 500 mg 4 times a day for
patients with chlamydial infection. Eradication of Haemophilus ducreyi in
patients with chancroid can also be achieved with these regimens or intramuscular
ceftriaxone 250 mg. Trichomonas vaginalis, which is often seen as a co-infection,
has been linked to an increased risk of preterm birth. Patients infected with
this parasite should therefore received metronidazole 500 mg twice daily for 7
days as earlier fears of teratogenesis in humans have not been confirmed by
recent data. Bacterial vaginosis is also associated with preterm delivery in
certain risk groups, such as women with a history of preterm birth or of low
maternal weight. Such an association is yet to be convincingly proven in other
women. The current advice is to treat only women diagnosed with bacterial
vaginosis who also present other risk factors for preterm delivery. The treatment
of choice is oral metronidazole 1 g/day for 5 days. The possible reduction of
preterm birth by vaginally applied metronidazole or clindamycin is still under
investigation. In general, both test of cure and re-testing after several weeks
are advisable in most pregnant patients with STDs, because partner notification
and treatment are likely to be less efficient than outside pregnancy and the
impact of inadequately treated or recurrent disease is greater because of the
added risk to the fetus. Every diagnosis of an STD warrants a full screen for
concomitant genital disease. Most ulcerative genital infections, as well as
abnormal vaginal flora and bacterial vaginosis, increase the sexual transmission
efficiency of HIV, necessitating even more stringent screening for and treating
of STD during pregnancy.
PMID- 10776828
TI - Pharmacological therapy for glaucoma: a review.
AB - For some time the medical treatment of glaucoma has consisted of topical beta
blockers, adrenergic agents, miotics and oral carbonic anhydrase inhibitors
(CAIs). However, the therapeutic arsenal available for the medical treatment of
glaucoma has recently extended with new classes of ocular hypotensive agents i.e.
prostaglandins, local CAIs and alpha2-adrenergic agents. Beta-blockers are still
the mainstay in glaucoma treatment and are first line drugs. However, even if
they are applied once daily, as with timolol in gel forming solution and
levobunolol, the possible cardiopulmonary adverse effects of beta-blockers remain
a cause for concern. When monotherapy with beta-blockers is ineffective in
reducing intraocular pressure (IOP) or is hampered by adverse effects, a change
of monotherapy to prostaglandins, local CAIs, alpha2-adrenergic agonists
(brimonidine) or to dipivalyl epinephrine is advised. Prostaglandins, local CAIs
and alpha2-adrenergic agonists, such as brimonidine, may in time become first
line drugs because they reduce IOP effectively and until now systemic adverse
effects have rarely been reported with these agents. The development of a pro
drug of either a local CAI or an alpha2-adrenergic agonist with a sustained and
continuous effect on IOP level, which could be applied once a day is suggested.
Because of these new developments, miotics, i.e. pilocarpine and carbachol, are
recommended as second or third line drugs. The cholinesterase inhibitors are
considered third line drugs as better agents with fewer local and systemic
adverse effects have become available. Oral CAIs may be used temporarily in
patients with elevated IOPs e.g. postsurgery or post-laser, or continuously in
patients with glaucoma resistant to other treatment. Combining ocular hypotensive
drugs is indicated when the target pressure for an individual patient cannot be
reached with monotherapy. Combination therapy of beta-blockers is additive with
prostaglandins, topical CAIs and miotics. Prostaglandins such as latanoprost can
be combined with beta-blockers, adrenergic agents, local CAIs and miotics.
Combinations with brimonidine or local CAIs need further investigation. Treatment
of glaucoma with the new ocular hypotensive agents, either in monotherapy or
combination therapy, may provide lower IOPs and delay or postpone the need for
surgery.
PMID- 10776831
TI - Drugs used to treat spasticity.
AB - Spasticity is a common and disabling symptom for many patients with upper motor
neuron dysfunction. It results from interruption of inhibitory descending spinal
motor pathways, and although the pathophysiology of spasticity is poorly
understood, the final common pathway is overactivity of the alpha motor neuron.
Therapy for spasticity is symptomatic with the aim of increasing functional
capacity and relieving discomfort. Any approach to treatment should be
multidisciplinary, including physical therapy, and possibly surgery, as well as
pharmacotherapy. It is important that treatment be tailored to the individual
patient, and that both patient and care giver have realistic expectations.
Pharmacotherapy is generally initiated at low dosages and then gradually
increased in an attempt to avoid adverse effects. Optimal therapy is the lowest
effective dosage. Baclofen, diazepam, tizanidine and dantrolene are currently
approved for use in patients with spasticity. In addition, clonidine (usually as
combination therapy), gabapentin and botulinum toxin have shown efficacy,
however, more studies are required to confirm their place in therapy. Intrathecal
baclofen, via a surgically implanted pump and reservoir, may provide relief in
patients with refractory severe spasticity.
PMID- 10776832
TI - A review of the epidemiology and approaches to the treatment of social anxiety
disorder.
AB - This review presents current literature on the epidemiology and treatment of
social anxiety disorder (social phobia). This illness has been demonstrated to be
the most common anxiety disorder with a 1-year prevalence of 7 to 8% and a
lifetime prevalence of 13 to 14% in patients aged between 15 and 54 years. Social
anxiety disorder can be classified into 2 subtypes, discrete and generalised.
Morbidity is high with this disorder, and 70 to 80% of patients have co-morbid
mental disorders. Although effective treatments are available, social anxiety
disorder is under-recognised and under-treated. Treatments that have been
systemically studied and have shown efficacy in patients with social anxiety
disorder include pharmacotherapy (selective serotonin reuptake inhibitors,
monoamine oxidase inhibitors, reversible inhibitors of monoamine-A and
benzodiazepines) and short term psychotherapies (cognitive behaviour therapy,
social skills training and exposure in vivo therapy). Beta-blockers are useful in
treating performance-related anxiety. Few published data are available on the
treatment of social anxiety disorder with a combination of pharmacotherapy and
psychotherapy. We conclude this review by discussing proposed algorithms for
treating both subtypes of social anxiety disorder.
PMID- 10776833
TI - Alosetron.
AB - Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist
which has been evaluated for the management of irritable bowel syndrome (IBS). It
blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and
submucosal neurons in vitro, with half-maximal inhibition at approximately 55
nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension
in conscious or anaesthetised dogs. It increased the compliance of the colon to
distension in patients with IBS and delayed colonic transit in patients with IBS
or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg
increased in vivo fluid absorption in normal human small intestine. In clinical
trials in patients with IBS, alosetron 1 mg twice daily was effective in
relieving abdominal pain and discomfort. Alosetron was most effective in female
patients and particularly in those with diarrhoea-predominant IBS. In patients
with IBS and healthy volunteers who received alosetron, the most common adverse
event was constipation.
PMID- 10776835
TI - Levobupivacaine: a review of its pharmacology and use as a local anaesthetic.
AB - Based on findings that the cardiotoxicity infrequently observed with racemic
bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)
enantiomer, the S(-)-enantiomer (levobupivacaine) has been developed for clinical
use as a long acting local anaesthetic. The majority of in vitro, in vivo and
human pharmacodynamic studies of nerve block indicate that levobupivacaine has
similar potency to bupivacaine. However, levobupivacaine had a lower risk of
cardiovascular and CNS toxicity than bupivacaine in animal studies. In human
volunteers, levobupivacaine had less of a negative inotropic effect and, at
intravenous doses >75 mg, produced less prolongation of the QTc interval than
bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with
levobupivacaine. Levobupivacaine is long acting with a dose-dependent duration of
anaesthesia. The onset of action is < or = 15 minutes with various anaesthetic
techniques. In studies of surgical anaesthesia in adults, levobupivacaine
provided sensory block for up to 9 hours after epidural administration of < or =
202.5 mg, 6.5 hours after intrathecal 15 mg, and 17 hours after brachial plexus
block with 2 mg/kg. Randomised, double-blind clinical studies established that
the anaesthetic and/or analgesic effects of levobupivacaine were largely similar
to those of bupivacaine at the same dose. Sensory block tended to be longer with
levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes
with epidural administration and approximately 2 hours with peripheral nerve
block. With epidural administration, levobupivacaine produced less prolonged
motor block than sensory block. This differential was not seen with peripheral
nerve block. Conditions satisfactory for surgery and good pain management were
achieved by use of local infiltration or peribulbar administration of
levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for
pain management during labour, and was effective for the management of
postoperative pain, especially when combined with clonidine, morphine or
fentanyl. The tolerability profiles of levobupivacaine and bupivacaine were very
similar in clinical trials. No clinically significant ECG abnormalities or
serious CNS events occurred with the doses used. The most common adverse event
associated with levobupivacaine treatment was hypotension (31%). CONCLUSIONS:
Levobupivacaine is a long acting local anaesthetic with a clinical profile
closely resembling that of bupivacaine. However, current preclinical safety and
toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical
data comparing levobupivacaine with ropivacaine are needed before the role of the
drug can be fully established. Excluding pharmacoeconomic considerations,
levobupivacaine is an appropriate choice for use in place of bupivacaine.
PMID- 10776834
TI - Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus.
AB - Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths
postprandial peak plasma glucose levels and thus improves glycaemic control,
which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral
antihyperglycaemic agent is indicated for the treatment of patients with type 2
diabetes mellitus. Miglitol is generally well tolerated and, unlike the
sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia
when administered as monotherapy. The drug is systemically absorbed but is not
metabolised and is rapidly excreted via the kidneys. Clinical trials with
miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes
mellitus consistently demonstrated a significant improvement in glycaemic control
for periods of 6 to 12 months. There were also marked reductions in postprandial
serum insulin levels, although miglitol generally had no effect on fasting
insulin levels. In comparative studies miglitol had similar efficacy to acarbose,
but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In
addition, although sulphonylurea agents provided superior reductions in HbA1c
levels, miglitol provided similar or superior reductions in fasting and
postprandial plasma glucose levels. In combination with other oral antidiabetic
agents or insulin, miglitol improved glycaemic control in patients in whom
metabolic control was suboptimal despite dietary and pharmacological
intervention. Most adverse events associated with miglitol treatment involve
disturbances of the gastrointestinal tract (most common effects are flatulence,
abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to
moderate in severity, occur at the onset of treatment, decline with time and
resolve promptly on discontinuation of the drug or with dosage adjustment. As
monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use
with other oral antidiabetic agents may necessitate dosage adjustment of the
other agents. Miglitol had no significant effects on renal, cardiovascular,
respiratory or haematological parameters in long term studies. No dosage
adjustments are required in elderly patients, in those with hepatic impairment or
in those with mild to moderate renal insufficiency. CONCLUSIONS: In long term,
well designed trials miglitol reduces fasting and postprandial plasma glucose
levels, thus improving glycaemic control, which is reflected in a reduced HbA1c
level in patients with type 2 diabetes mellitus. Most adverse events associated
with miglitol involve disturbances of the gastrointestinal tract. This agent is a
useful first-line therapy in patients with type 2 diabetes mellitus
insufficiently controlled by diet alone and as second-line or as adjuvant therapy
in those insufficiently controlled with diet and sulphonylurea agents. Miglitol
may prove particularly beneficial in elderly patients and those with hepatic
impairment or mild to moderate renal impairment, in whom other oral antidiabetic
agents are contraindicated or need to be used with caution.
PMID- 10776836
TI - Nelfinavir: an update on its use in HIV infection.
AB - Nelfinavir is one of several currently available protease inhibitors used to
limit viral replication and improve immune function in HIV-infected individuals.
It is administered in combination with other antiretroviral agents. Nelfinavir
has been evaluated as first-line therapy with nucleoside reverse transcriptase
inhibitors (NRTIs) in treatment-naive patients, or as an additional
antiretroviral agent in protease inhibitor-naive patients already receiving
NRTIs. These studies have shown good efficacy in terms of HIV viral load
reduction and increased CD4+ cell counts. When used in combination with NRTIs,
nelfinavir 1250 mg twice daily produced similar results to 750 mg 3 times daily.
The more convenient twice-daily dosage schedule, which is now approved in the US,
may be beneficial in improving patient adherence to therapy. Nelfinavir has also
been used successfully in combination with non-nucleoside reverse transcriptase
inhibitors and/or other protease inhibitors, with or without NRTIs. Resistance to
nelfinavir has been observed in vitro and in clinical isolates from patients
experiencing insufficient or waning viral suppression during treatment.
Nelfinavir primarily selects for the D30N mutation, which is not seen with other
protease inhibitors, and alone does not cause resistance to other protease
inhibitors in vitro. Several studies have shown that patients who experience
virological failure while receiving nelfinavir can respond to salvage therapy
with other protease inhibitors. Diarrhoea is the most frequent adverse event in
patients receiving nelfinavir-based combination therapy, but was generally mild
and resulted in minimal discontinuation of therapy in clinical trials. Diarrhoea
can usually be controlled with drugs that slow gastrointestinal motility.
Metabolic disturbances associated with protease inhibitor use
(hypercholesterolaemia, hyperglycaemia and lipodystrophy) have also been reported
with nelfinavir. Nelfinavir is associated with a number of clinically significant
drug interactions and coadministration of some drugs (e.g. astemizole, cisapride,
triazolam) is contraindicated. Coadministration of nelfinavir with other protease
inhibitors generally resulted in favourable pharmacokinetic interactions (usually
increased area under the concentration-time curve for both drugs). CONCLUSION:
Nelfinavir, in combination with reverse transcriptase inhibitors and/or other
protease inhibitors, is effective in limiting HIV replication and increasing CD4+
cell counts in HIV-infected adults and children. The convenience of its dosage
administration, the low incidence of adverse events, and the potential for
salvage therapies indicate that nelfinavir (as part of combined antiretroviral
therapy regimens) should be considered as a first-line option in protease
inhibitor-naive patients and in those unable to tolerate other protease
inhibitors.
PMID- 10776837
TI - Docetaxel: an update of its use in advanced breast cancer.
AB - Docetaxel, a semisynthetic member of the taxoid class of antineoplastic agents,
is effective in the treatment of patients with advanced (locally advanced or
metastatic) breast cancer. Reported objective response rates for docetaxel 100
mg/m2 ranged from 54 to 69% and 53 to 82% as first-line monotherapy or
combination therapy, respectively. Objective response rates of 23 to 65% and 30
to 81% have been reported for docetaxel as second-line monotherapy or combination
therapy, respectively. In Japanese studies, second-line docetaxel 60 mg/m2
produced objective response rates of 42 to 55%. At the recommended dose of 100
mg/m2 given as a 1-hour intravenous (i.v.) infusion every 3 weeks, docetaxel had
significantly greater efficacy than doxorubicin, mitomycin plus vinblastine and
methotrexate plus fluorouracil, and similar efficacy to fluorouracil plus
vinorelbine in pretreated patients with advanced breast cancer. In chemotherapy
naive patients, first-line combined therapy with docetaxel and doxorubicin had
significantly greater efficacy than doxorubicin plus cyclophosphamide. Promising
results have been achieved in phase I/II trials of a weekly regimen of docetaxel
(generally 30 to 45 mg/m2). Preliminary data indicate a potential role for
docetaxel in the neoadjuvant therapy of early breast cancer. The major dose
limiting adverse event associated with docetaxel is neutropenia. Although other
adverse events are common, the tolerability profile of docetaxel is generally
acceptable in the majority of patients, particularly in comparison with other
antineoplastic regimens. CONCLUSIONS: Although no single standard regimen has
been identified as optimal for the treatment of advanced breast cancer, phase III
trials have shown that docetaxel has improved efficacy over doxorubicin alone
(considered one of the current gold standards), methotrexate/fluorouracil and
mitomycin/vinblastine in second-line therapy. In combination with doxorubicin,
docetaxel has demonstrated better efficacy than doxorubicin/cyclophosphamide in
first-line therapy. These results provide a basis for therapy choice in advanced
breast cancer. Clinical trials comparing docetaxel monotherapy versus paclitaxel
monotherapy and versus docetaxel combination therapy are warranted. The role of
docetaxel in the adjuvant and neoadjuvant treatment of early breast cancer is
being evaluated.
PMID- 10776838
TI - Meropenem: a review of its use in patients in intensive care.
AB - Meropenem is a carbapenem antibacterial agent that has antimicrobial activity
against gram-negative, gram-positive and anaerobic micro-organisms. In vitro
studies involving isolates from patients in intensive care units (ICUs) indicate
that meropenem is more active against most gram-negative pathogens than other
comparators (including imipenem), although, compared with imipenem, meropenem is
less active against most gram-positive organisms. Resistance to meropenem is
uncommon in most bacteria. Treatment with meropenem as initial empirical
monotherapy was effective in a range of serious infections in adult and
paediatric ICU patients. Meropenem monotherapy was as effective as
imipenem/cilastatin in 4 comparative trials in terms of satisfactory clinical and
bacteriological responses. Meropenem monotherapy was significantly more effective
than ceftazidime-based combination treatments in 2 trials in patients with
nosocomial lower respiratory tract infections (LRTIs) in terms of both clinical
and bacteriological responses. Meropenem was also more active than ceftazidime
based treatments against both gram-positive and gram-negative organisms. However,
2 studies in patients with a range of serious infections found no significant
differences between meropenem and cephalosporin-based treatments in terms of
clinical or bacteriological response. Meropenem was also as effective as
cephalosporin-based treatments in comparative trials in children with serious
infections. Meropenem is well tolerated as either a bolus or an infusion, and
clinical trials have shown similar incidences of adverse events to those observed
with cephalosporin-based treatments. It is well tolerated by the CNS, with
seizures reported infrequently, and can therefore be used at high doses and in
patients with meningitis. The incidence of drug-related nausea and vomiting is
low and, in contrast to imipenem/cilastatin, does not increase with dose or speed
of administration. CONCLUSIONS: Meropenem is a well tolerated broad spectrum
antibacterial agent that, when used as initial empirical monotherapy, is as
effective as imipenem/cilastatin in the treatment of a range of serious
infections (including nosocomial) in adults and children in ICUs. Compared with
cephalosporin-based combination treatments, meropenem monotherapy may be more
effective in the treatment of nosocomial LRTIs and can be used as monotherapy.
Meropenem has an important role in the empirical treatment of serious infections
in adults and children in ICUs.
PMID- 10776829
TI - Kinase inhibitors in cancer therapy: a look ahead.
AB - The most essential kinases involved in cell membrane receptor activation, signal
transduction and cell cycle control or programmed cell death and their
interconnections are reviewed. In tumours, the genes of many of those kinases are
mutated or amplified or the proteins are overexpressed. The use of key kinases
offers the possibility to screen in vitro for synthetic small molecule kinase
inhibitors. In view of the many interconnections of cellular kinases, their role
in preventing or inducing programmed cell death and the possibility that a
considerable number of signal transducing proteins are still unknown, cellular
test systems are recommended in which the respective key kinase or one of its
main partner molecules are overexpressed.
PMID- 10776840
TI - Inhibitory effect of oral administration of Lactobacillus casei on 3
methylcholanthrene-induced carcinogenesis in mice.
AB - The present study was designed to determine whether tumor induction by 3
methylcholanthrene (MC), a carcinogenic hydrocarbon, can be inhibited by oral
administration of Lactobacillus casei strain Shirota (LC). C3H/HeN mice were
divided into four groups and assigned to the following treatments: treated with
MC and given control or LC-containing diet; treated with vehicle only and given
control or LC-containing diet. MC (1 mg) was injected intradermally at 7 weeks of
age and the tumor incidence was monitored; LC was mixed into a diet at a
concentration of 0.05% (w/w) and the diet was fed from the day of MC injection
throughout the study. Spleen cells were analyzed for the immune parameters at 12
and 16 weeks after the MC injection. Oral feeding of mice with LC reduced tumor
incidence (P < 0.05). MC treatment lowered the in vitro response to concanavalin
A (Con A) of spleen cells, the secretion of interleukin-2 in spleen cell culture
after stimulation of the cells with Con A and the proportions of CD3+ CD4+ and
CD8 + splenic cells. However, the analysis of the spleen cells obtained from the
mice treated with MC and given the LC-containing diet revealed that these
disrupted host immune parameters were maintained at the level of normal controls.
These results suggest that oral feeding of mice with LC inhibits MC-induced
tumorigenesis by modulating the disrupted host immune responses during MC
carcinogenesis.
PMID- 10776841
TI - Candidacidal activity of shortened synthetic analogs of amoebapores and NK-lysin.
AB - Natural antimicrobial peptides and synthetic analogs thereof have emerged as
compounds with potentially significant therapeutical application against human
pathogens. Amoebapores are 77-residue peptides with cytolytic and antibacterial
activity considered to act by forming ion channels in cytoplasmic membranes of
the victim cells. A functionally and structurally similar peptide named NK-lysin
exists in mammalian lymphocytes. Several synthetic analogs of amoebapores and NK
lysin, which are substantially reduced in size compared to the parent molecules,
were tested for their ability to inhibit the growth of and to kill Candida
albicans. Some of the peptides displayed potent activity against a clinical
isolate as well as against defined culture strains. Among the most active
peptides found are some shortened substitution analogs of amoebapore C and a
cationic core region of NK-lysin. As these peptides are also highly active
against Gram-positive and Gram-negative bacteria but are of low cytotoxicity
towards a human keratinocyte cell line they may provide promising templates for
the design of broad-spectrum peptide antibiotics.
PMID- 10776839
TI - Lenograstim: an update of its pharmacological properties and use in chemotherapy
induced neutropenia and related clinical settings.
AB - Lenograstim is the glycosylated recombinant form of human granulocyte colony
stimulating factor. The drug is used to reduce the risk of life-threatening
infection in patients with neutropenia, particularly after cytotoxic
chemotherapy. Lenograstim accelerates neutrophil recovery significantly after
chemotherapy, with beneficial effects on clinical end-points such as incidence of
laboratory-confirmed infection and length of hospital stay. Chemotherapy dose
intensity has also been increased in patients receiving lenograstim, notably
those with breast or small cell lung cancer, although improvements in tumour
response and survival have not been demonstrated. Lenograstim also assists
neutrophil recovery in patients undergoing bone marrow transplantation, and
stimulates the production of peripheral blood stem cells (PBSCs) for autologous
transfusion after aggressive chemotherapy. Lenograstim also mobilises CD34+ cells
more efficiently in unit dose terms than filgrastim and has been used
successfully to mobilise PBSCs from healthy donors for allogeneic
transplantation. Randomised trials have shown increases in rates of disease
remission after lenograstim therapy in patients with acute myeloid leukaemia,
with no evidence of stimulation of malignant blasts. The drug has also shown
potential in the mobilisation of nonmalignant PBSCs for autotransplantation in
patients with chronic myeloid leukaemia. Other studies show efficacy of
lenograstim in patients with acute lymphoblastic leukaemia, aplastic anaemia, in
children with severe chronic neutropenia and in the reversal of neutropenia
related to antiviral therapy in patients with AIDS, although data are not
extensive. Cost analyses of lenograstim have been carried out from a hospital
perspective, although results have been inconclusive. Cost-effectiveness or cost
benefit data are lacking at present. Lenograstim is well tolerated, with bone
pain and injection site reactions being reported most frequently in clinical
trials. CONCLUSIONS: Lenograstim has been confirmed as a valuable adjunct to
minimise the haematological toxicity of myelosuppressive chemotherapy in patients
with malignant disease. The drug also enhances neutrophil recovery in patients
undergoing stem cell rescue, and assists PBSC mobilisation. Data indicate
clinical benefit with lenograstim in myeloid disorders, with no evidence of
malignant blast cell proliferation. Further studies are required to assess more
fully the pharmacoeconomic implications of the use of lenograstim and other
recombinant growth factors, to provide more data on the efficacy of the drug in
the management of disease-related neutropenia, and to clarify fully its position
relative to filgrastim.
PMID- 10776842
TI - Loss of pathogenic potential after cloning of the low-passage Borrelia
burgdorferi ZS7 tick isolate: a cautionary note.
AB - To study clonal polymorphism of Borrelia hurgdorferi antigens in the course of an
experimental infection sequence, the low-passage tick isolate ZS7 was cloned by
two rounds of agar subsurface plating. The resulting clones showed a variable
pathogenic potential after experimental infection of C.B-17. scid mice. The test
clone 4.2.II, selected for virulence by two passages in immunodeficient scid
mice, failed to establish a successful infection in immunocompetent AKR/N mice,
indicating the loss of pathogenicity traits required for evasion of the specific
immune response. Cloning of natural or clinical B. burgdorferi isolates is a
prerequisite for analyzing genetic and antigenic variation of the pathogen.
However, the inevitable propagation in artificial media during cloning may lead
to a loss of pathogenic features rendering the subsequent experimental infection
of animals impossible. A combined procedure of in vitro cloning and in vivo
selection also does not solve the dilemma because B. burgdorferi variants arise
by recombinatorial processes in the pathogen's dynamic genome during the course
of infection. Consequently, the resulting bacterial isolates from infected animal
tissues represent again non-clonal, heterogeneous B. burgdorferi populations. In
principle, cloning of a B. burgdorferi population is the appropriate method to
analyze the polymorphism of individual molecules during infection. As a caveat,
however, one has to envisage that during propagation of individual clones in
vitro and in vivo independent genetic variations
PMID- 10776843
TI - One-step polymerase chain reaction-based typing of Helicobacter pylori vacA gene:
association with gastric histopathology.
AB - Heterogeneity of the Helicobacter pylori vacA gene may be associated with
bacterial virulence and presentation. In this study, the possible correlation
between vacA genotypes and gastric histopathology was investigated. Using a
modified one-step polymerase chain reaction (PCR)-based method, 122 of 131 H.
pylori isolates obtained from 63 of 67 patients from Germany were classified into
distinct vacA genotypes according to their signal sequence (s1 or s2) and their
midregion alleles (m1 or m2). A possible subtype of ml, now alluded to as m3, was
identified in one-third of the isolates. Signal sequence s1 was significantly
associated with higher H. pylori density but not with gastric inflammation
parameters as compared with s2. Compared with m2, ml initially appeared to
correlate with higher mononuclear cell scores in corpus, although not with H.
pylori density. Upon differentiation between ml and m3, however, only the latter
was associated with the high cell scores. Moreover, m3 also correlated with a
higher antral H. pylori density. Positive cagA status correlated significantly
with vacA signal sequence s1, and higher gastric mononuclear cell scores and
corpus neutrophil score. H. pylori density was always associated with enhanced
gastric neutrophil and corpus mononuclear cell scores. These data indicate a
significant association of specific vacA genotypes with enhanced bacterial
density and gastric inflammation. PCR-based identification of the respective
alleles can now easily be performed in the diagnostic laboratory using a one-step
PCR assay.
PMID- 10776844
TI - An improved recombinant IgG immunoblot for serodiagnosis of Lyme borreliosis.
AB - We have previously described the use of the following recombinant antigens for
serodiagnostic immunoblots: p83/100, p39, OspC and p41 (flagellin) internal
fragment [Wilske et al. (1993) Med Microbiol Immunol 182:255-270; Rossler et al.
(1997) J Clin Microbiol 35:2752-2758]. In our currently used immunoblot p83/100
is derived from strain PKo (Borrelia afzelii), p39 (BmpA) and OspC from strains
PKa2 (B. hurgdorferi sensu stricto), PKo and PBi (B. garinii), respectively; the
p41 (flagellin) internal fragments were cloned from strains PKo and PBi. In this
study we describe the use of two additional recombinantly expressed highly
immunogenic proteins Osp 7 (derived from PKo) and p58 (derived from PBi). A
clinically well-defined panel of sera from 147 Lyme borreliosis patients and 139
controls previously tested by a standardized whole cell lysate immunoblot [Hauser
et al. (1997) J Clin Microbiol 35:1433-1444] was investigated in the recombinant
immunoblot without (old recombinant immunoblot) and with Ospl7 and p58 (new
recombinant immunoblot) for IgG antibodies. The sensitivity of the recombinant
IgG immunoblot for diagnosis of stage II and stage III could be significantly
improved by addition of Osp17 and p58 without loss of specificity. With the
exception of sera from patients with erythema migrans the diagnostic sensitivity
is comparable to the whole cell lysate IgG immunoblot. The main advantage of the
recombinant immunoblot is the easy identification of diagnostic bands, whereas
the identification of bands in the whole cell lysate immunoblot is difficult. The
recombinant immunoblot is especially suitable where large series of sera need to
be investigated.
PMID- 10776845
TI - Coexistence of ehrlichiae of the phagocytophila group with Borrelia burgdorferi
in Ixodes ricinus from Southern Germany.
AB - Human granulocytic ehrlichiosis (HGE) is an emerging infectious disease
recognized in the Western hemisphere. HGE is well known to occur in North
America, but records from outside the United States are sparse. The great
majority of data from Europe are restricted to seroprevalence studies and
molecular biological detection of granulocytic ehrlichiae (GE) in ticks and
mammals, but include defined cases from Slovenia. They argue for the existence of
this disease in many parts of Europe. In the present study, 510 Ixodes ricinus
ticks collected in five different regions of Southern Germany were investigated
for the presence of GE and Borrelia burgdorferi sensu lato using polymerase chain
reaction. In all, 8 (1.6%) of the 492 ticks that could be evaluated (193 females,
208 males, and 91 nymphs) contained GE and 178 (36.2%) B. burgdorferi s.l.. Four
of these ticks were infected with both pathogens. Interestingly, all ehrlichia
infected ticks were adults and all were collected in the English Garden, a
recreational park area located in the city of Munich. Sequencing of the 16S rDNA
(bp 1 1101) of four of the GE showed 100% sequence identity to each other and
greater than 99.9% identity with the published sequence of the HGE agent. The
four GE differed in respect to other hitherto described GE by a nucleotide
exchange at position 336. These results show that GE that are closely related to
the HGE agent are present in Southern Germany, and that coinfection with B.
burgdorferi is common in GE-infected ticks. However, in contrast to B.
burgdorferi which is endemic everywhere in Southern Germany, the distribution of
GE seems to be focal.
PMID- 10776846
TI - Anti-recombinant V antigen serum promotes uptake of Yersinia enterocolitica
serotype 08 by macrophages.
AB - Phagocytosis resistance even in the presence of opsonizing antibodies is a key
feature of pathogenic Yersinia spp. Nevertheless, antibodies against the secreted
V antigen and the outer membrane protein YadA are known to mediate protection
against Y. enterocolitica serotype 08 in a mouse model with intravenous
infection. To investigate the impact of anti-V antigen serum on the interaction
of Y. enterocolitica and phagocytic cells, gentamicin kill assays and
immunofluorescence staining were performed. In contrast to anti-YadA, the
presence of V antigen-specific antibodies resulted in an increased uptake of
yersiniae by macrophages. The inhibition of phagocytosis by cytochalasin D
suppressed the anti-V antigen-mediated uptake. The uptake-promoting effect of
anti-V antigen was more distinct for macrophages than for polymorphonuclear
leukocytes. The findings of the passive immunization experiments using an
orogastric infection model were in agreement with those of cell-culture
experiments. In the first 3 days of infection both antisera exhibit no protective
effect on the multiplication of the bacteria in the Peyer's patches. Only mice
passively immunized with anti-V antigen survived lethal oral infections with Y.
enterocolitica serotype 08. Taken together, the results support the assumption
that V antigen might be part of the translocation apparatus and that anti-V
antigen inhibits the Yop translocation. In addition, antisera against in-frame
deleted recombinant V antigen were generated. Protection experiments using these
antisera suggested that the type-specific region (amino acids 225-232) of the V
antigen might not be a protective epitope.
PMID- 10776847
TI - Domestic and personal accidents. Prevention in the absence of professional
supervision.
AB - This paper provides a review of a selection of recent papers, most of which
derive from presentations given at the 4th World Conference on Injury Prevention
and Control or the 6th International Conference on Product Safety Research, both
of which took place in Amsterdam in May 1998. What all the accidents studied in
these papers have in common is the absence of professional supervision. Everyone
immediately involved in the incident--whether as injured party, unintended cause
or informal supervisor is an 'amateur'. It is proposed that the term 'domestic
and personal accidents' should be used to describe this group of accidents, the
study of which has been neglected in comparison to transport and occupational
injuries. It is argued that domestic and personal activities are more
heterogeneous than ones with an element of professional supervision and are
therefore more difficult to prevent. Nevertheless examples are given of where
'horizontal' approaches to analysis and prevention of these accidents have proved
possible.
PMID- 10776848
TI - Consumer affairs and the valuation of safety.
AB - An appraisal of past work on the value of a statistical life has been conducted
for the purpose of assisting decisions in the consumer safety sector. Although
contingent valuation is nowadays often cited as the preferred approach for
valuing the dominant, human cost, element of safety, a range of other valuation
techniques is recognised and used, both in Britain and elsewhere. It is argued
that all valuation techniques entail considerable uncertainty for a variety of
reasons, some methodological and some attributable to the fact that the value of
safety is an ill-defined and fuzzy concept for the individual. In view of this,
plus the need to appeal to a diverse constituency, it is proposed that the value
of consumer safety be based upon a broad appreciation of the outcomes from the
various techniques which exist, rather than pinning all hopes upon any single
methodology. Furthermore, in the interests of sound consumer risk management
practice and public credibility, it is recommended that uncertainty be openly
acknowledged by expressing the value of safety as a range rather than a point
value. The range proposed is from Pound Sterling 1 million to Pound Sterling 10
million, with the expectation that for most consumer applications values used
might lie within a narrower bandwidth from about Pound Sterling 2 million to
Pound Sterling 4 million. It is suggested that the specification of a range,
while not everyone's nor every sector's preferred approach, nonetheless has a
number of useful attributes. These include endowing decision makers with a degree
of flexibility in arriving at safety decisions, considered to be an important
issue within the consumer safety sphere where complex contextual factors
frequently arise, and which are arguably best handled by a thoughtful and
sensitive approach and negotiation, rather than by the application of any more
formulaic recipe.
PMID- 10776849
TI - Near miss and minor injury information--can it be used to plan and evaluate
injury prevention programmes?
AB - AIM: To assess the usefulness of collecting information on near miss and minor
injuries for use in planning and evaluating injury prevention programmes for
children aged under 5 years in the home environment. METHOD: The research was set
within the context of a controlled intervention study based in 36 general
practices across Nottingham. All parents of children aged between 3 and 12 months
who had completed the intervention study questionnaire (n = 1594) were used as
the sampling frame for the diary study. A diary, developed specifically for the
main intervention study, was administered to a systematically assigned sample of
434 parents. Information provided by the Home Accident Surveillance System on 252
randomly selected children, of the same age and sex, who had attended an accident
and emergency department, was used to compare the circumstances surrounding near
miss and minor injuries with those of medically attended injuries. The children
whose parents had completed a diary were followed over a two year time period.
The children who had had a medically attended injury were identified from a
search of the child's general practice records and the Queens Medical Centre
accident and emergency records. The definition of a near miss used in the study
was: A near miss incident is something your child does or that happened to your
child which could have resulted in him/her being hurt, but fortunately it did
not. RESULTS: Overall two hundred and thirty one (53%) diaries were completed and
returned. Three hundred and fifty incidents were recorded of which 207 were near
misses and 143 minor injuries. The circumstances surrounding near miss and minor
injuries, although not identical when compared to medically attended injuries,
were very similar. The relationship between the occurrence of near miss, minor
injuries and future medically attended injuries appeared weak, for all categories
the negative predictive value was higher than the positive predictive value.
CONCLUSION: Although the circumstances surrounding all the incident categories
were similar, the numbers were too small to see whether specific injury
mechanisms predict future injuries of the same type. It appeared that near miss
and minor injuries are of limited use in predicting medically attended injuries,
however this hypothesis needs to be tested on a much larger sample.
PMID- 10776850
TI - Burn injuries in The Netherlands.
AB - The amount and type of burn injuries in The Netherlands are described using
Surveillance Systems on treatments at an Accident and Emergency (A&E) department,
hospital admissions and fatal injuries and a national survey (to asses treatments
by a general practitioner). These data show an estimated 420 persons/year/100,000
inhabitants that are medically treated for burn injuries due to home and leisure
accidents in The Netherlands. Fifty percent of all burn injuries concern scalds.
But almost all the fatal injuries are caused by fire and flames. From this
analysis, three risk groups were identified. Children aged 0-4 and elderly above
84 years have the highest risk of getting admitted to the hospital because of
burn injuries. Among the children admitted to hospital, 75% suffer scalds. For
injuries treated at an A&E department, people aged 15-24 years appear to have a
higher incidence than average. Through a series of surveys among these risk
groups, we were able to describe main accident scenarios of burn injuries and
their causes. Among young children, 80% of all scald injuries are caused by
pushing down or dropping a hot liquid. Parents most frequently reported lack of
the supervision (e.g. attention distracted by others) to be one of the causes of
the injury. Among the age group 15-29 years and the elderly, most injuries occur
during cooking. Clumsiness and inattention are major causes of injuries among
young adults. Among the elderly, a quarter of all victims reported health
problems or handicaps to be a cause of their injury. Based on the results of our
analysis, preventive measures were suggested.
PMID- 10776851
TI - Risk perception in consumer product use.
AB - In the literature, at least two distinct connotations of risk can be found: so
called objective risk, defined as the ratio of a particular number of accidents
and a measure of exposure, and subjective risk, defined as the perception and
awareness of risks by the person(s) involved. This article explores the
significance of risk perception and awareness in understanding and clarifying how
and why accidents involving consumer products occur. Based on empirical evidence
from video-recorded reconstructions of accidents with consumer products, the risk
perception and awareness of users in relation to featural and functional product
characteristics, and their influence on actual product use culminating in an
accident, is addressed. In contrast with what is usually assumed in the
literature, the findings show that the majority of the subjects had no idea that
they were running any risk of injuring themselves while they operated the
product. In several accidents, the product either offered functionalities not
anticipated in the design or did not adequately reflect its condition. The
implications of the findings for design practice as well as for risk research are
discussed.
PMID- 10776852
TI - Validating recall of falls by older people.
AB - Falls among older people are a priority issue for accident analysis because they
are relatively common, carry a significant burden of morbidity and mortality,
affect lifestyle choices, are a high cost to the community, and are potentially
preventable.
PMID- 10776853
TI - Epidemiology of personal watercraft-related injury on Arkansas waterways, 1994
1997: identifying priorities for prevention.
AB - Personal watercraft (PWC) use has increased rapidly in the past ten years.
Consequences of the increased use are collisions and injuries. This study was
conducted to determine the etiology and the characteristics surrounding PWC
collisions and injury associated with the use of these popular water recreational
vehicles and determine countermeasures. Methods included obtaining boating
accident reports limited to PWCs from the Arkansas Game and Fish Commission for
the years 1994 through 1997. Results show that there were 126 incidents involving
141 vessels and over $156,000 (US) in property damage. Almost two-fifths of PWC
users were injured, mainly head trauma and fractures to the lower limbs. There
were five reported fatalities. Study suggests that PWC collisions and injury are
increasing. With increased use and popularity, this trend will continue unless
sustained efforts in prevention are established. Changes in policy, education and
manufacturing standards need to be considered and initiated to provide for safe
PWC operation and boating environment.
PMID- 10776854
TI - Risk factors for severe injuries associated with falls from playground equipment.
AB - A case control study design was used to determine the risk factors for severe
injuries associated with falls from playground equipment. Children presenting to
the Hospital for Sick Children in Toronto because of falls from playground
equipment (1995-1996) were identified through daily review of admissions and
emergency department visits. Cases were defined as children with a severe injury
(AIS > or = 2), whereas, controls were children with a minor injury (AIS < 2).
Data on age, sex, socioeconomic status, prior experience on the equipment,
previous playground injury, type of equipment, height of fall, undersurface,
nature of injury, body part involved, and disposition were collected via
telephone interview, field trip measurement, and mailed questionnaire. A total of
126 children were studied--67 cases and 59 controls. There were no differences
between the two groups on age, sex, socioeconomic status, prior exposure to the
equipment, or previous playground injury. Extremity fractures predominated in the
case group, while, facial lacerations predominated in the control group. The
median height of fall for cases was 199 cm, compared with 160 cm for controls (P
= 0.021). Cases were also more likely to have fallen from a height of > 150 cm
(73%), compared with controls (54%), P = 0.027. The majority of cases (82%) and
controls (86%) fell onto an impact absorbing undersurface (P = 0.540). The median
depth of impact absorbing undersurface, however, for both case and control
injuries was 3 cm--well below the recommended safety standards. Height of fall
was an important risk factor for severe injury associated with falls from
playground equipment. Above 150 cm, the risk of severe injury was increased 2
fold.
PMID- 10776855
TI - What you don't know can hurt you: household products and events.
AB - Product safety is affected by product design and by the knowledge of the user,
either through the user's own background or through instructions and warnings
presented with the product. Given adequate knowledge, warnings can serve
primarily to remind individuals of the hazards and precautions that can be taken.
This study examined people in the USA (represented by two diverse samples) to
evaluate their knowledge about the hazards associated with common household
products and situations using both multiple choice and open-ended surveys. The
results indicated that the respondents were aware of a substantial number of
hazards, but their knowledge often did not extend to the specific circumstances
that could produce personal injury and property damage. Further, comparisons of
cued and non-cued responses suggested some hazards are not well recognized
without the cue. The results indicate warnings are needed both as reminders and
to provide safety information.
PMID- 10776856
TI - Stay on Your Feet Safety Walks Group.
AB - The Safety Walks Group is an initiative that evolved from the Stay on Your Feet
Program. The strategies used in this program target both behavioural and
environmental change and are based on the five areas for action under the Ottawa
Charter (WHO, 1986) and Jakarta Declaration (WHO, 1997). The Safety Walks Group
addresses the issue of public hazards via the use of a standard checklist
covering pedestrian areas, business houses and accommodation. The project
provided a forum for seniors to be proactive, working with the authorities to
address the issue of public hazards and make the environment safer.
PMID- 10776857
TI - Analysis of climbing accidents.
AB - The fall of a climber is analyzed by realistic and comprehensive model
calculations. Various parameters that define such a fall and the action of the
belaying system to stop it are included in an equation describing the balance
between the energy gained by the fall and the various channels of dissipation.
The result is a representative overview about the interplay between the various
parameters. From this understanding, important consequences and recommendations
for safety in climbing are deduced.
PMID- 10776858
TI - Smoking as a risk factor for accident death: a meta-analysis of cohort studies.
AB - This meta-analysis discusses the consistency, strength, dose-response,
independence, and generalizability of published cohort data on accident death
relative risks in smokers. To locate data, three authors independently searched
MEDLINE, and bibliographies of the pertinent studies found, for data which
allowed estimation of an appropriate cigarette smoker accident death relative
risk (and 95% confidence interval). Relative risks and dose-response were
summarized by fixed effects and Poisson modeling, respectively. Four pertinent
cohort studies including eight populations were located. Cigarette smoking
predicted summary accident death relative risks of 1.51 (95% confidence interval
1.27-1.78) versus never smokers and 1.35 (1.17-1.57) versus ex-smokers. Summary
dose-response trends were significant (P = 0.0000) versus never or least smoking
referents. In individual studies, the smoking/accident death association
persisted after adjustment or, in effect stratification, for age, race, sex, and
occupation; occupation and time period; or numerous cardiac risk factors. This
meta-analysis found significant, consistent, dose-response, often strong and
independent (of age, race, and sex), prospective associations of smoking with
accident death, internationally. Further studies and warnings of the
smoking/accident death associations seem merited.
PMID- 10776859
TI - Burn properties of fabrics and garments worn in India.
AB - A full-scale human form dummy was designed for studying the burning of common
dress assemblies (i.e. combination of garments) worn in India. The dummy was made
in eight parts; each made of a steel shell filled with water so as to replicate
properties of skin-tissue combination. Four thermocouples were fixed on the dummy
for measuring torso, neck and face temperatures. The dummy was clothed separately
in three women's dress assemblies (saree, salwar-khameez and nightgown) and men's
dress assemblies (kurta-pyjama, shirt-pant and lungi), and ignited at the feet by
a flat flame. The tests showed that loose fitting garments burnt easily. Once
completely burnt, all dress assemblies result in third degree burns over most of
the body. The burning process of synthetics is radically different from cottons
or cotton-polyester blends. However, flame duration and temperatures produced on
the skin are not radically different, suggesting that on the whole synthetics are
no worse than cotton garments. Thick garments, such as, jeans and khadi, do not
ignite easily and are inherently safer than similar garments made of light
fabric. The studies show that results of standard flammability tests using single
fabric strips do not correlate with the burning observed in garments as part of a
dress where multilayering is common. Standards/codes for fire safety of garments
and garment-dress assembly combinations need to be evolved to adequately address
their fire safety.
PMID- 10776860
TI - Karate injuries in children and adolescents.
AB - OBJECTIVES: To identify risk factors for injury and to establish safety
guidelines for children in Uechi-Ryu karate. DESIGN: A 1-year retrospective
survey of injuries. SETTING: A private karate school (Uechi-Ryu style) in
Plymouth, MA. PATIENTS: A total of 68 athletes (age 6-16 years; mean age 10
years) who participated in karate during the 1995-1996 season. INTERVENTIONS:
None. MAIN OUTCOME MEASURES: The presence or absence of injury, with grading of
injuries as major, moderate or minor. The types of injuries and body region
involved were also analyzed. RESULTS: Twenty eight percent of athletes sustained
at least one injury. All injuries were minor, with no time off from training
required. The injuries consisted primarily of bruises (11 of 19). Other injuries
included mild sprains or strains (5 of 19) and having their 'wind knocked out' (3
of 19). Most injuries were localized to the extremities. Logistic regression
analysis identified risk factors for injury. Risk of injury increased with number
of years of training (odds ratio 2.95; 95% confidence interval 1.81-4.82;
P<0.0001), number of hours per week (odds ratio 2.12; CI 1.15-4.21; P = 0.016)
and rank, specifically brown belt versus lower belts (odds ratio 6.56; CI 2.02
21.26; P = 0.006). CONCLUSIONS: Karate is a relatively safe sport for children
and adolescents when properly taught. Risk of injury increases with experience;
therefore, greater supervision is required of higher ranks. Injury increases with
weekly training; however, 3 h a week or less appears to be associated with a low
risk of significant injury in this age group.
PMID- 10776862
TI - Diagnosis and monetary quantification of occupational injuries by indices related
to human capital loss: analysis of a steel company as an illustration.
AB - Prevention of occupational injuries is an important task of human resource
management. In this study, new indices of human capital loss of occupational
injury including cumulative injury rate, proportion of potential workdays lost,
and potential salary lost were applied to the analysis of registry data of
occupational injuries from 1986 to 1994 of a steel company in Taiwan. In
addition, we compared these indices with disabling frequency rate and severity
rate. The results showed that the average disabling frequency rate and cumulative
injury rate of the whole company were 4.12 and 0.41, respectively; and the
average disabling severity rate and proportion of potential workdays lost of the
whole company were 563 and 229 x 10(-6), respectively, during 1986-1994. There
was no consistent improvement in occupational safety in this period. The average
potential salary lost of the whole company was more than US$ 2 million per year
with a discount rate of 0.04, which was equivalent to 92 times of average annual
income of a worker. The major monetary loss were due to non-traffic injuries of
operators and traffic injuries of non-operators, which amounted to US$ 145 and
152 per person per year. As the new indices can provide additional information on
lifetime occupational risk and human capital loss in monetary values, we
concluded that they may be useful supplementary tools for monitoring and
analyzing occupational injury data in a company.
PMID- 10776861
TI - An impact evaluation of a falls prevention program among older people.
AB - The aim of this evaluation study was to assess the impact of peer-presented
education sessions on the falls-related attitude, knowledge and behaviour of
older people. The evaluation was undertaken on the Bellarine Peninsula in
Victoria, Australia, and adopted a non-randomised pre-test post-test design.
Baseline, 3 and 12 months follow-up data were collected for 107 individuals who
attended the education sessions and 116 controls, matched by age range and sex.
The groups were not strictly equivalent at baseline, with the intervention group
having a greater knowledge about falls and falls prevention. Analyses which
controlled for baseline differences showed that those who attended the education
sessions maintained a greater knowledge of factors that can prevent falls at 12
months follow-up. The intervention group also made more changes in and around
their home to prevent falls by 3 and 12 months follow-up. Younger participants
who reported a previous history of falls and having taken action to prevent falls
were most likely to take additional action. The results can help target this type
of education program and suggest that their major benefit may lie in providing
those who voluntarily attend with the impetus to take the most effective
preventative action.
PMID- 10776863
TI - Multiple attribute entropy classification of school-age injuries.
AB - The data exploration task in epidemiology of school children injuries is aimed at
defining specific risk groups that can be further analyzed for definition of
prevention measures. These groups are selected by means of entropy classification
of relevant data collected in the Koprivnica district, Croatia. The necessary
pruning procedure for the entropy classification tree is proposed for: (a)
entropy increase for uniformly populated classes, and (b) entropy decrease for
the case of zeros in a class. The second reason for pruning is emphasized for
multiple (> 3) attribute descriptions of injury events because the number of
classes increases exponentially with the number of attributes. Four possible
prevention groups have been found by entropy classification: (1) dislocation,
sprain and strain injuries, mostly on legs of both age groups of boys (7-10
years, 11-14 years) in/around the house activities; (2) arm fractures of all boys
in/around the house activities; (3) open wounds mostly of the head, in younger
boys at school, and open wounds in younger boys in road traffic; and (4)
contusions mostly on arms, of older girls at school and contusions in older boys
in road traffic accidents. These groups comprise 57.2% of all considered cases.
PMID- 10776864
TI - Pedestrians on slippery surfaces during winter--methods to describe the problems
and practical tests of anti-skid devices.
AB - Every year there are thousands of pedestrians in Sweden who are injured because
of slippery pavements and roadways. Using an appropriate anti-skid device may
reduce the risk of slips and falls on ice and snow. Methods to describe
functional problems in walking on different slippery surfaces during winter have
been developed as rating scales for evaluating walking safety and walking balance
and an observation method to observe posture and movements during walking.
Practical tests of all 25 anti-skid devices on the market in Sweden were carried
out on different slippery surfaces; gravel, sand, salt, snow and ice. The anti
skid devices were described according to the subjects' perception of walking
safety, walking balance and priority for own use. The postures and movements
during walking were analysed by an expert physical therapist. The wholefoot
device 'studs' was perceived as the best according to walking safety and walking
balance and had the highest priority for own use.
PMID- 10776865
TI - The community safety approach in Falun, Sweden--is it possible to characterise
the most effective prevention endeavours and how long-lasting are the results?
AB - The safe community concept was put into practice in order to reduce the number of
unintentional injuries occurring in the Falun municipality. A community-based
injury prevention programme was initiated in 1989 and has been gradually built up
since that time. The prevention endeavours were based primarily on active
intervention strategies through the provision of information, supervision,
education and training. After 5 years of an active intervention programme, a
significant effect was found as regards the injury rates for both outpatients as
well as patients discharged from hospitals. The objectives of this study were: to
examine whether the character of the prevention endeavours was a determining
factor on the outcome (recorded as in-patient injury cases); to evaluate the
effects of this programme, which is still in practice, compared to long-term
historical trends; and to draw comparisons with other community-based programmes.
A category of 'most targeted risks' was identified as being different with
respect to how the injury mechanisms involved were targeted through the programme
activities. The development within the injury rates for this group, comprised
predominantly of injuries caused by falls at the same level, was significantly
different than those for the groups categorized as 'less targeted' and 'non
targeted'. The general effect of the programme appeared to be a neutralization of
an otherwise upward trend in the injury rates. A particular effect was
demonstrated in the number of fall injuries, including femoral fractures. It was
also noted that there was still a reduction in injuries after 7 years. However,
it was possible to surmise a waning effect during the last 2 years of the
programme while still in progress. This observation suggests that a community
based injury prevention programme must be continuously renewed and reinforced.
PMID- 10776866
TI - Crisis in surgical quality.
PMID- 10776867
TI - Clearing the cervical spine in victims of blunt assault to the head and neck:
what is necessary?
AB - A number of guidelines have been proposed to aid in determining the need for
radiologic evaluation of the cervical spine (c-spine) in victims of blunt trauma.
Mechanism of injury has not been shown to be an independent predictor of injury
or the lack thereof. The current study was undertaken to determine the incidence
of clinically relevant c-spine injuries in patients who sustained a blunt assault
to the head and neck. The trauma registry of an urban Level 1 trauma center was
used to identify patients who suffered a blunt assault to the head and neck and
were admitted to the hospital over a 30-month period. One hundred two patients
were identified. Only 8 patients met criteria for clinical clearance of the c
spine. Eighty patients were unable to be evaluated because of head injury or
intoxicants; 14 patients had neck pain on initial examination. These 94 patients
underwent plain film examination of their c-spine. Twelve required CT scanning to
supplement visualization. The possibility of ligamentous injury was investigated
by MRI or flexion/extension radiographs in 26 patients. No clinically significant
c-spine injuries were identified. Although many victims of a blunt assault to the
head and neck region may have a decreased LOC or neck pain, the likelihood of a
ligamentous injury is so low that plain-film X-ray evaluation of the c-spine is
all that is necessary to rule out injury in this patient population.
PMID- 10776868
TI - Nonoperative management of blunt liver trauma: the value of follow-up abdominal
computed tomography scans.
AB - Our hypothesis was that follow-up abdominal CT scans are not routinely necessary
in patients with blunt liver injury treated nonoperatively. We conducted an 8
year retrospective review of hospital chart and outpatient clinic records. We
reviewed all admission and follow-up CT scans. There were 42 adults and 12
children. There were 1 (2%) grade I, 15 (28%) grade II, 28 (52%) grade III, 8
(15%) grade IV, and 2 (4%) grade V liver injuries. Two patients died during the
first 24 hours, both from associated injuries. Nonoperative management was
successful in 51 (98%) of the remaining 52 patients. No follow-up abdominal CT
scans were performed on 21 (40%) patients; none developed hepatic complications.
An initial follow-up CT scan was obtained in 31 (60%) patients. Information from
these scans directly affected management in 3 (9%) patients; in each case, the
scans were prompted by a change in clinical status. One significant biloma with
bile leak was managed by nasobiliary stenting and percutaneous drainage. One
hepatic artery-to-portal vein fistula was obliterated by transarterial
embolization. A single missed diaphragm rupture necessitated laparotomy.
Additional late follow-up CT scans were obtained in 13 patients; no clinically
useful information was evident on any of these examinations. We conclude that
follow-up abdominal CT scans are not routinely necessary in patients with liver
injuries treated nonoperatively. Selective criteria based on the severity of
liver injury, presence of associated intra-abdominal pathology, and clinical
parameters should dictate the need for follow-up imaging studies.
PMID- 10776870
TI - Further evaluation of colostomy in penetrating colon injury.
AB - Our objective was to compare, in a randomized prospective format, complication
rates associated with primary repair versus fecal diversion in penetrating colon
injury. During a 72-month period, 181 patients with penetrating colon injuries
were entered in a randomized prospective study at an urban Level I trauma center.
After intraoperative identification of colon injuries, patients were randomized
to a primary repair or a diversion group. Randomization was independent of
previously identified risk factors, including severity of colon injury, presence
of hypotension, blood loss, extent of fecal contamination, and time from injury
to operation. Five patients initially entered in the study protocol were removed
because they died in the immediate postoperative period (< 24 hours). One hundred
seventy-six patients were studied, of which 89 were randomized to primary repair
and 87 to diversion. The average age in the diversion group was 26.4 years and it
was 28.0 years in the primary repair group (P > 0.05). The average Penetrating
Abdominal Trauma Index for the diversion group was 22.3, and it was 23.7 for the
primary repair group (P > 0.05). There were 18 (21%) septic related complications
in the diversion group and 16 (18%) in the primary repair group (P > .05). With
respect to risk factors, complication rates were not higher in one study group
versus the other. We conclude that, in the civilian population, all penetrating
colon injuries should be managed with primary repair.
PMID- 10776871
TI - Hypothermia-induced coagulopathy during hemorrhagic shock.
AB - A porcine model of hemorrhagic shock was used to study the effect of hypothermia
on hemodynamic, metabolic, and coagulation parameters. The model was designed to
simulate the events of severe blunt injury with hemorrhage occurring initially,
to a systolic blood pressure of 30 mm Hg, followed by simultaneous hemorrhage and
crystalloid volume replacement, followed by cessation of hemorrhage and blood
replacement. Half of the animals were rendered hypothermic by external
application of ice, and half remained normothermic. There was seven pigs in each
group. Two deaths occurred in each during the hemorrhage phase. The hypothermic
pigs demonstrated larger reduction in cardiac output than normothermic pigs.
Volume replacement in the normothermic group restored cardiac output to baseline
values. In the hypothermic group, cardiac output remained depressed despite
volume replacement. Prothrombin times and partial thromboplastin times showed
significantly more prolongation in the hypothermic group. Furthermore, this was
not corrected by replacement of shed blood in the hypothermic group, as was seen
in the normothermic group. We conclude that when shock and hypothermia occur
together, their deleterious effect on hemodynamic and coagulation parameters are
additive. The effects of hypothermia persist despite the arrest of hemorrhage and
volume replacement. Thus, it is necessary to aggressively address both shock and
hypothermia when they occur simultaneously.
PMID- 10776869
TI - Changing times and the treatment of liver injury.
AB - We hypothesized that the frequency, diagnosis and treatment of liver injury have
changed dramatically in the past 30 years. Patients with liver injuries treated
in an urban level I trauma center were analyzed for three separate time periods,
namely, 1969-1970, 1981-1982, and 1997-1998. The injuries were categorized by
etiology; Abbreviated Injury Score severity, and type of treatment, including
observation (Ob), laparotomy without treatment of liver injury (OR No Rx), suture
repair (Sut), tractotomy with intraperipheral hemostasis (Tr), dearterialization
(HAL), and resection (Re) (See Table, below). There were 249 patients in 1969
1970, 70, 79 in 1981-1982, and 116 in 1997-1998. Stab wounds and gunshot wounds
decreased from 235 patients in 1969-1970 to 61 patients in 1997-1998. Blunt
injuries increased from 14 patients in 1969-1970 to 55 patients in 1997-1998.
Major injuries (Abbreviated Injury Score 4-5) fell from 104 to 25 to 20 during
the decade. Laparotomy was done in all patients in 1969-1970 and 1981-1982,
whereas most blunt injuries were observed in 1997-1998; only 9 of 65 blunt
injuries in 1997-1998 required hemostasis. [table in text] We conclude the
following: 1) Central urban depopulation reduces experience with liver trauma, 2)
abdominal CT increases the diagnosis of liver injury, and 3) observation of
stable patients with blunt liver injury is now the standard.
PMID- 10776872
TI - Human endothelial cell cultures from progenitor cells obtained by leukapheresis.
AB - Although improved prosthetic graft patency with endothelial cell (EC) seeding has
been shown in animal models, the clinical application of this technique requires
a convenient source of ECs. We have evaluated EC cultures derived from the
mononuclear cell (MNC) fraction obtained during large-volume leukapheresis and
compared this with cultures grown from peripheral blood cells obtained by
phlebotomy. Leukapheresis was performed in healthy adult volunteers (n = 7) using
software designed to increase the percentage of MNCs harvested. Blood (40-293 mL)
was drawn from a peripheral vein in healthy adult volunteers (n = 13), and the
MNCs were obtained by differential centrifugation using a Lymphoprep gradient.
Significantly more MNCs were obtained by leukapheresis than by phlebotomy. Each
leukapheresis procedure yielded 12.5 to 23 mL, which contained 2.29 +/- 0.35 x
10(9) MNCs, compared with 2.16 +/- 0.50 x 10(8) MNCs, for each phlebotomy (P <
0.001). EC colonies developed in significantly more cultures from leukapheresis
derived MNCs (6 of 7) than phlebotomy-derived MNCs (4 of 13; P = 0.008).
Leukapheresis-derived cells developed EC morphology at 15.5 +/- 2 days compared
with 21 +/- 3.4 days for cells obtained by phlebotomy (P = not significant). EC
were identified by positive factor VIII and vascular endothelial growth factor
receptor immunostaining. Leukapheresis significantly increases the number of
progenitor cells available for differentiation into EC compared with phlebotomy
and avoids the need for any surgical procedure to harvest a peripheral vein as a
direct source of ECs.
PMID- 10776873
TI - Phyllodes tumors of the breast: a review of 32 cases.
AB - Most general surgeons involved in breast cancer care have limited experience with
phyllodes tumors. We analyzed a comprehensive database incorporating 8567 breast
cancer cases treated surgically in the Tulsa, Oklahoma, region between 1969 and
1993. This yielded 32 cases of phyllodes tumors (0.37%) in 31 patients. The
median age was 57 years (range, 18-91). There were 9 low-grade (28%), 2
intermediate-grade (6%), and 21 high-grade (66%) lesions. Size distribution
consisted of 23 (72%) lesions 5 cm or less and 9 (28%) greater than 5 cm (mean,
3; range, 1.2-17.5 cm). Of 137 resected nodes in 13 patients, none were positive
for metastatic disease. Surgical management consisted of wide excision or
mastectomy. No patients received adjuvant chemoradiation therapy. The disease
free, locoregional disease-free, and overall mean survival rates were 80, 81, and
97 months, respectively. Ten-year disease-free survival (DFS), locoregional
disease-free survival (LRDFS), and overall survival (OS) rates were 66, 72, and
55 per cent, respectively. Although there was a tendency toward a higher rate of
locoregional recurrences and metastases with high-grade lesions, this was not
statistically significant and did not affect DFS, LRDFS, or OS rates. Similarly,
size of lesion did not affect DFS, LRDFS, or OS rates. Three patients (9.6%) had
metastatic disease at presentation, and a further two (6.4%) developed metastases
during follow-up. Overall, nine (28.1%) recurrences developed in eight patients,
seven locoregional and two distant. Four patients (12.9%) died with evidence of
disease. These findings indicate prolonged survival in this patient population
with cystosarcoma phyllodes. Wide local excision of primary and recurrent lesions
remains the mainstay of therapy. Neither regional lymph node dissection nor
adjuvant chemoradiation adds significant benefit.
PMID- 10776875
TI - The role of hepatic resection in the management of bile duct injuries following
laparoscopic cholecystectomy.
AB - The creation of a specialized hepatobiliary surgery unit at our medical center
has resulted in referral of 16 patients with bile duct complications following
laparoscopic cholecystectomy over the last 18 months. No patient required
conversion to open cholecystectomy. Although no injury was recognized at the time
of surgery, 15 of 16 patients became symptomatic within the first 30 days. Two
patients died from sepsis and multisystem organ failure after protracted hospital
courses. Endoscopic retrograde cholangiopancreatography and/or percutaneous
transhepatic cholangiography determined diagnosis and level of injury. Six of
seven patients with cystic duct leak underwent successful endoscopic stent
placement and one patient sealed spontaneously after percutaneous drainage of a
large biloma. Nine patients required surgery that included hepaticojejunostomy
(five), T-tube insertion and drainage of abscess (two), or segmental hepatic
resection (two). Timely recognition of bile duct complications following
laparoscopic cholecystectomy is critical to a successful long-term outcome.
Although the majority of cystic duct leaks can be managed with endoscopic
stenting, patients with ductal injuries require hepaticojejunostomy. Segmental
liver resection may serve an important role in the management of carefully
selected patients with high intrahepatic injuries to avoid long-term transhepatic
stenting and complications such as episodic cholangitis and late stricture
formation.
PMID- 10776874
TI - Opioid and benzodiazepine withdrawal syndrome in adult burn patients.
AB - The prolonged use of continuous intravenous sedation [benzodiazepines (BZDs)] and
pain medication [opioids (OPs)] is now common in intensive care units. Few
studies have evaluated the characteristics that may lead to an acute withdrawal
syndrome when these long-term medications are withdrawn. Those studies that have
made recommendations for weaning rates to prevent withdrawal have given these
recommendations with minimal data to support their recommendations. The purpose
of this study was to retrospectively review the records of adult burn patients
for the presence of acute BZD or OP withdrawal syndrome and to characterize
whether patterns of BZD or OP administration or weaning rates contribute to the
development of acute withdrawal syndrome. We found no relation of acute
withdrawal syndrome to peak dose, total dose, or duration of dose of BZD/OP
before the terminal withdrawal phase. There was a significant relationship
between the rate of BZD/OP weaning in the terminal drug withdrawal phase and the
percentage of days that patients experienced withdrawal symptoms (P < 0.005).
Those patients who underwent a prolonged terminal weaning from these medications
experienced fewer symptoms. The optimal rate of weaning that would allow
decreased ventilator and intensive care unit length of stay without development
of acute withdrawal symptoms is yet to be determined.
PMID- 10776876
TI - Pancreatic carcinoma deemed unresectable at exploration may be resected for cure:
an institutional experience.
AB - Only a minority of patients with a diagnosis of pancreatic adenocarcinoma (PA)
have disease amenable to curative resection. Between April 1987 and March 1999,
40 patients with pancreatic adenocarcinoma deemed unresectable at exploration at
other institutions were considered for neoadjuvant treatments and then re
evaluated for possible re-exploration. We retrospectively compared the clinical
outcomes, including overall survival (OS), among three groups: Group A, 22
previously unresectable patients who were subsequently successfully resected, 20
after induction therapy; Group B, 31 patients who received preoperative
chemoradiotherapy before their only operation; and Group C, 33 patients who were
primarily resected, 27 of whom were then treated with adjuvant therapy. Of those
resectable from Group A, 5 required portal venorrhaphy and 3 had hepatic artery
reconstruction. Eighteen of the 40 patients were unresectable because of
progression of disease with a mean OS of 8 months; 12 were assessed at second
laparotomy; 6 were excluded from second operation on the basis of preoperative
imaging studies. Kaplan-Meier curves showed no differences in OS among the three
groups: OS in Group A was 34 months; Group B, 21; and Group C, 13 (P = 0.15).
Margin status was comparable in all three groups (P = 0.52). As expected, nodal
positivity was greatest in Group C (P = 0.001). There were no operative
mortalities in Group A, and the morbidity rate was comparable with that of Groups
B and C. Upon re-evaluation, many tumors (54%) previously deemed "unresectable"
were surgically extirpated for cure with a median survival comparable with that
of patients who did not undergo previous exploration.
PMID- 10776878
TI - Hypocaloric parenteral nutrition support in elderly obese patients.
AB - Hypocaloric nutritional support has been successfully used to achieve positive
nitrogen balance in obese patients. However, advanced age is associated with
changes in substrate metabolism. To evaluate the efficacy of this practice in
elderly patients, we retrospectively reviewed 30 obese patients requiring
parenteral nutrition support. Total caloric requirements (TCR) were calculated on
the basis of the Harris-Benedict equation. Patients were given a minimum of 1.5
g/kg/day protein, 75 per cent of TCR when current body weight was >120 and < or
=150 per cent of ideal body weight (IBW), and 60 per cent of TCR if current body
weight was >150 per cent of IBW. The patients were divided into two groups: Group
I (N = 18) patients were age <60 and Group II (N = 12) patients were > or =60
years of age. Only one of the Group I patients (143.2 +/- 25.7% IBW, received
18.2 +/- 3.7 kcal/kg/day and 1.6 +/- 0.4 g/kg/day protein), but five of the Group
II patients (141.3 +/- 14.4% IBW, received 18.3 +/- 2.6 kcal/kg/day and 1.7 +/-
0.3 g/kg/day protein), had negative nitrogen balance (P = 0.025). Apparently,
elderly obese patients have limited capacity to mobilize their fat stores as
energy sources and may continue to undergo protein catabolism with hypocaloric
high-protein nutrition support. Therefore, this form of nutritional support
should be used with caution in elderly obese patients.
PMID- 10776877
TI - Preoperative chemoradiation and coloanal J pouch reconstruction for low rectal
cancer.
AB - Our objective was to determine clinical outcomes of treatment of low rectal
adenocarcinoma with neoadjuvant chemoradiation, rectal excision, and coloanal J
pouch reconstruction. A retrospective review of 69 patients with stage B2 or
higher lesions was performed. Preoperative chemoradiation was followed by low
anterior resection and coloanal J pouch anastomosis, with end loop ileostomy.
Data were analyzed using the SPSS computer software. There were 46 males and 23
females, with a median age of 63 years. Pathologic staging showed no tumor in the
specimen, i.e.: stage 0, 14 per cent; stage A, 14 per cent; stage B, 53 per cent;
stage C, 18 per cent; and stage D, 1.4 per cent. Postoperative mortality was 2.8
per cent, and the pelvic leak rate was 4.3 per cent. After curative resection, 89
per cent patients are alive and 83 per cent are disease free with a mean follow
up of 50 months. The local recurrence rate is 7.2 per cent. Nodal status was the
most important predictor of survival and disease-free survival. Most (96%) have
fewer than two bowel movements a day and are satisfied with the functional
results. We conclude that preoperative chemoradiation and coloanal J pouch
reconstruction can achieve low recurrence rates and prolonged survival for most
patients with low rectal cancer with an acceptable quality of life.
PMID- 10776879
TI - Do angiogenesis and growth factor expression predict prognosis of esophageal
cancer?
AB - A retrospective study of surgically resectable esophageal cancers was undertaken
to determine the relationship between angiogenesis score and growth factor
expression with tumor size, histology, degree of differentiation, depth of
invasion, nodal disease, and the presence of Barrett's esophagus. The office and
hospital charts of 27 patients who had esophageal resection for carcinoma between
1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data
collection included patient demographics, survival, tumor size, histology,
differentiation, depth of invasion, nodal metastases, and the presence of
Barrett's esophagus. The pathology specimens were immunostained for von
Willebrand factor (factor VIII-related antigen). Immunostaining was also
performed for vascular endothelial growth factor and transforming growth factor
alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score
was determined by counting vessels under conventional light microscopy at x200
magnification, and growth factor expression was graded on a scale of 1 to 4.
Cancers had higher angiogenesis and growth factor expression than controls (P =
0.01). Patient age, tumor size, histology, differentiation, depth of invasion,
and Barrett's esophagus did not correlate with angiogenesis score or tumor growth
factor expression. Lymph node status did correlate with both angiogenesis score
and growth factor expression (P < or = 0.02). We conclude that high angiogenesis
score and growth factor expression correlate with the presence of lymph node
metastases. This may help select patients for preoperative radiation and
chemotherapy or determine the extent of surgery performed for esophageal
carcinoma.
PMID- 10776880
TI - Laparoscopic ultrasound enhances diagnostic laparoscopy in the staging of intra
abdominal neoplasms.
AB - Routine laparoscopy and laparoscopic ultrasound (LUS) for staging intra-abdominal
malignancies remains controversial. Thus, we undertook a prospective study to
assess the value of preoperative laparoscopy with LUS for patients with intra
abdominal tumors judged resectable by preoperative studies. Laparoscopy was
successfully performed in 76 of 77 patients, and 60 underwent LUS. Of 33 patients
with presumed pancreatic cancer, laparoscopic findings changed the operative
management of 11 patients, and LUS altered the management of an additional 6
patients. Laparotomy was avoided in 9 patients (27%). Among 14 patients with
hepatobiliary tumors, laparotomy was avoided in 9 patients in whom laparoscopy
and/or LUS revealed either benign or advanced disease. Operative management was
altered in 4 of 18 patients with gastric or esophageal cancer by laparoscopic
findings. LUS did not add to the management of these patients. Of 12 patients
with presumed intra-abdominal lymphoma, 9 were diagnosed with lymphoma and 3 with
benign disease, without laparotomy in all but 1 case. Laparoscopy and LUS are
valuable tools for evaluating the resectability of pancreatic and hepatobiliary
tumors. Laparoscopy, and to a lesser degree LUS, greatly facilitates diagnosing
patients with intra-abdominal lymphomas and spares an occasional patient with
esophagogastric carcinoma from undergoing laparotomy.
PMID- 10776882
TI - The solitary pulmonary nodule.
PMID- 10776881
TI - Liver resection for colorectal cancer: liver metastases in the aged.
AB - The purpose of this study was to determine the morbidity and mortality in elderly
patients undergoing liver resections for metastatic colon cancer and compare them
with those of a control group of younger patients. The charts of all patients
undergoing liver resection for colon cancer were retrospectively reviewed.
Patients less than 70 years of age (Group A) were compared with patients 70 years
of age or older (Group B). Between 1971 and 1995, 167 liver resections were
performed for metastatic colorectal cancer. Of these, 41 patients were in Group A
and 126 patients were in Group B. The mean age of Group A was 74.5 years, and
that of Group B was 57 years. American Society of Anesthesiologists (ASA)
classification was similar for both groups (Groups A and B were 75.6% and 81.1%
ASA class II, respectively). Anatomic resections were performed in 49 per cent
and wedge resections in 51 per cent of patients in Group A, and 68 and 32 per
cent in Group B, respectively. Estimated blood loss was slightly less for Group A
(1575 vs 1973 cm3), as was operative time (4.0 vs 4.7 hours). In-hospital
mortality rate was 7.3 per cent for Group A and 2.4 per cent for Group B. The
major morbidity rates were 29 and 17.5 per cent, respectively. Intensive care
unit care was necessary in 73 per cent (mean length of stay 3.9 days) for Group A
and 62.6 per cent (mean length of stay 2.0 days) for Group B. The average length
of hospitalization was 13.1 days for Group A and 16.6 days for Group B. The
recurrence rates were similar for the two groups [56% (Group A) vs 66% (Group
B)], but mean survival was longer for younger patients (22.9 vs 33.5 months). We
conclude that liver resection for colorectal cancer liver metastases in properly
selected patients older than 70 years of age can be performed with acceptable
morbidity and mortality rates. The long-term survival for older patients is less
than that for younger patients, but is still a significant length of time.
Therefore, we conclude that age alone is not a contraindication to liver
resection for colorectal cancer metastases in patients older than 70.
PMID- 10776883
TI - The solitary pulmonary nodule: radiologic considerations.
AB - The solitary pulmonary nodule is a commonly encountered radiologic finding that
might represent lung cancer, particularly in individuals at high risk to develop
lung cancer. Morphological characteristics including lesion size, contour and
edge, calcification and nodule density, and contrast enhancement may be helpful
in the attempt to differentiate malignant from benign nodules. In certain
instances, the combination of morphological characteristics indicates a specific
diagnosis, sometimes precluding the need for further workup. Growth rate is of
paramount importance in evaluating the nature of a solitary pulmonary nodule, and
2-year stability is traditionally considered an indicator of benignity. Screening
for lung cancer using low-dose CT has led to the detection of small pulmonary
nodules in a large number of high-risk individuals. In the workup of these
nodules, lung cancer, when present, should be diagnosed as early as possible,
while unnecessary surgery and needle biopsies should be avoided. Computer
analysis may prove to be a valuable tool in the evaluation of these nodules.
PMID- 10776884
TI - Computer-aided diagnosis of small pulmonary nodules.
AB - Computer-aided methods are now being developed for the detection and
characterization of pulmonary nodules found in CT images, based on techniques
from computer vision, image processing, and pattern classification. With the
increasing resolution of modern CT scanners, computer methods provide continually
improving accuracy, reproducibility, and utility in analyzing the larger numbers
of images acquired in a lung screening exam or diagnostic study. This article
describes the fundamental tools and issues involved in computer-aided nodule
detection and characterization, as we move from two-dimensional toward three
dimensional automated methods. In particular, we focus on the new domain of
"small" pulmonary nodules.
PMID- 10776885
TI - Role of nuclear medicine in the evaluation of the solitary pulmonary nodule.
AB - Tomographic imaging with either F-18 fluoro deoxyglucose (FDG) (a
nonmetabolizable glucose analog that reflects tumor increased glucose metabolism)
or technetium Tc-99m Depreotide (a synthetic peptide that binds with high
affinity to cell surface receptors with increased expression on certain tumor
cells) provides improved sensitivity and specificity in the differential
diagnosis of solitary pulmonary nodules (SPN) compared with noninvasive and some
invasive procedures. F-18 FDG requires instrumentation capable of coincident
imaging whereas Tc-99m Depreotide can be imaged on standard gamma cameras
equipped to perform single photon emission computed tomography (SPECT) imaging.
Either technique performs better than CT alone, and both are cost effective on
the basis of reducing unnecessary biopsies and thoracotomies in patients with
negative studies indicating that the SPN is nonmalignant.
PMID- 10776886
TI - Comparison of biopsy techniques in assessment of solitary pulmonary nodules.
AB - A wide variety of diagnostic tests are available to evaluate solitary pulmonary
nodules, ranging from noninvasive to invasive. Given the virulence of lung
cancer, those techniques that can provide cytological and pathological
information are often chosen. However, the choice of which procedure to perform
is complicated by numerous factors, including the sensitivity and specificity of
the test, as well as the prevalence of disease. Additional considerations also
include complications, availability and expertise in performing procedures, and
overall cost of the diagnostic algorithm. Rather than make specific
recommendations for diagnostic workup, it is more appropriate to consider that
this will vary from institution to institution based on the above factors.
PMID- 10776887
TI - The radiologic appearance of solitary pulmonary nodules and their cytologic
histologic correlation.
AB - In this article, we review the various causes of solitary pulmonary nodules.
Based on the underlying histology, we attempt to account for the radiologic
pattern associated with each. This includes features related to density, edge
characteristics, and texture. Similarly, the radiologic appearance of the nodule
can be helpful to the cytologist when interpreting cytological samples obtained
through image guidance.
PMID- 10776888
TI - Endurance sports after total knee replacement: a biomechanical investigation.
AB - PURPOSE: No biomechanical evaluation of total knee designs exists for loads
occurring during sports activities. It was the purpose of the present study to
evaluate the contact stress distribution and contact area of different knee joint
designs for loads that occur during four common recreational endurance
activities. METHODS: Three different total knee designs were evaluated for loads
occurring during cycling (1.2 body weight (BW) at 80 degrees of knee flexion),
power walking (4 BW at 20 degrees), hiking (8 BW at 40 degrees), and jogging (9
BW at 50 degrees) using Fuji pressure-sensitive film. The designs consisted of a
flat tibial inlay, a curved inlay, and an inlay with mobile bearings. Five
measurements were conducted for each load. The pressure sensitive films were
scanned and analyzed using an image analysis program. RESULTS: During cycling,
the area with stress levels above the yield point of polyethylene (overloaded
area) was below 15 mm2 for each design. During power walking, the mobile bearing
design showed no overloaded area, whereas it was below 50 mm2 for the flat and
curved design. During downhill walking and jogging, more than 140 mm2 were
overloaded for each design. CONCLUSIONS: It was concluded that patients after
total knee replacement should alternate activities such as power walking and
cycling. For mountain hiking, patients are advised to avoid descents or at least
use ski poles. Jogging or sports involving running should be discouraged after
total knee replacement.
PMID- 10776889
TI - Cardiorespiratory and metabolic responses to exercise in HbSC sickle cell
patients.
AB - PURPOSE: Relative to healthy control individuals with normal hemoglobin (Hb),
patients carrying the double heterozygous form of sickle cell disease (HbSC)
display an impaired oxygen transport capacity. The present study was undertaken
to determine the influence of the decreased oxygen availability associated with
the presence of HbSC on the cardiorespiratory and metabolic responses to
endurance exercise. METHODS: Eleven black men affected by the double heterozygous
form of the sickle cell disease (HbSC group) and seven healthy subjects with
normal Hb (HbAA group) of the same ethnic origin submitted successively to an
incremental exercise test to exhaustion on a cycle ergometer for the
determination of their maximal tolerated power and to a 20-min endurance
exercise. RESULTS: The HbSC had a significantly lower exercise tolerance than the
HbAA. During the endurance exercise, they exhibited furthermore significantly
lower VO2, VCO2, and minute ventilation V(E) than the HbAA. Despite the fact that
the HbSC exercised at a significantly lower mean absolute work rate than the
HbAA, except for the ventilatory equivalent for CO2 (V(E)/VCO2), which was higher
(P < 0.001) in the HbSC group, the other parameters recorded during the 20-min
endurance exercise (heart rate, arterial PaO2, PaCO2, pH, lactate, and VE/VO2,
the ventilatory equivalent for O2) and during the subsequent recovery (blood
lactate) were similar for both groups. CONCLUSION: The study underscores the
importance of considering relative work rate as well as absolute work rate to
arrive at a correct interpretation of exercise and recovery data. The results
give evidence that the modifications of homeostasis brought into play by exercise
were shifted toward distinctly lower absolute work rates in HbSC patients.
PMID- 10776890
TI - Incidence of exercise-induced bronchospasm in Olympic winter sport athletes.
AB - PURPOSE: The purpose of this project was to determine the incidence of exercise
induced bronchospasm (EIB) among U.S. Olympic winter sport athletes. METHODS:
Subjects included female and male members of the 1998 U.S. Winter Olympic Team
from the following sports: biathlon, cross-country ski, figure skating, ice
hockey, Nordic combined, long-track speedskating, and short-track speedskating.
Assessment of EIB was conducted in conjunction with an "actual competition"
(Olympic Trials, World Team Trials, World Cup Event, U.S. National Championships)
or a "simulated competition" (time trial, game), which served as the exercise
challenge. Standard spirometry tests were performed preexercise and at 5, 10, and
15 min postexercise. An athlete was considered EIB-positive based on a
postexercise decrement in FEV1 > or = 10%. RESULTS: For the seven sports
evaluated on the 1998 U.S. Winter Olympic Team, the overall incidence of EIB
across all sports and genders was 23%. The highest incidence of EIB was found in
cross-country skiers, where 50% of the athletes (female = 57%; male = 43%) were
diagnosed with EIB. Across the seven sports evaluated, the prevalence of EIB
among the female and male athletes was 26% and 18%, respectively. Among those
individuals found to be EIB-positive were athletes who won a team gold medal, one
individual silver medal, and one individual bronze medal at the Nagano Winter
Olympics. CONCLUSIONS: These data suggest that: 1) EIB is prevalent in several
Olympic winter sports and affects nearly one of every four elite winter sport
athletes; 2) the winter sport with the highest incidence of EIB is cross-country
skiing; 3) in general, EIB is more prevalent in female versus male elite winter
sport athletes; and 4) athletes may compete successfully at the international
level despite having EIB.
PMID- 10776891
TI - Growth, dietary intake, and trace element status in pubescent athletes and
schoolchildren.
AB - PURPOSE: To examine interactions between club-level sports training, dietary
intake, and nutritional status during puberty. METHODS: A 2-yr prospective study
was undertaken with 64 boys (40 ice hockey players, 24 controls) and 71 girls (28
gymnasts, figure skaters, and runners, 43 controls). The boys' age in the
beginning of the study was 12-13 yr, whereas the girls were 11-12 yr. The
following variables were measured in the beginning, and after 1 and 2 yr:
physical activity level (record), dietary intake (record), blood hemoglobin
concentration, serum ferritin, zinc and copper concentration, anthropometric
indices (height, weight, skinfolds, upper arm muscle girth), and biological
maturation (self-report). RESULTS AND CONCLUSIONS: The changes in the
anthropometric variables throughout the study period were not different between
the athletes and controls (P = 0.09). The athlete boys had higher mean energy,
iron and zinc intakes, and higher mean serum zinc concentration than the controls
(P < or = 0.003). The athlete and control girls' dietary intakes and biochemical
indices of trace element status were not different from each other (P < or =
0.13). Moreover, sports participation was not associated with the longitudinal
changes in trace element status (P > or = 0.08). These data suggest that club
level sports training does not affect growth, maturation or nutritional status
during puberty.
PMID- 10776892
TI - Cardiac responses to exercise in competitive child cyclists.
AB - PURPOSE: Cardiovascular responses to exercise in highly trained child endurance
athletes have not been well-defined. This study compared hemodynamic responses
with progressive cycle exercise in seven competitive child cyclists (mean age
11.9 yr) compared with 39 age-matched untrained boys. METHODS: Doppler
echocardiography and gas exchange variables were utilized to assess
cardiovascular changes during submaximal and maximal exercise. RESULTS: Mean
VO2max was 60.0 (+/-6.0) and 47.0 (+/-5.8) mL x kg(-1) x min(-1) in the cyclists
and nonathletes, respectively. At rest and maximal exercise, the cyclists
demonstrated greater stroke index than the untrained subjects (resting mean 59
(+/-6) vs 44 (+/-9) mL x m(-2); maximal mean 76 (+/-6) vs 60 (+/-11) mL x m(-2)),
but the ratio of maximal:rest stroke index was similar in both groups (1.31 for
cyclists, 1.41 for nonathletes). Both groups showed a plateau in stroke volume
beyond low-intensity work levels. No significant difference was observed in
maximal arteriovenous oxygen difference. CONCLUSIONS: These findings indicate
that 1) maximal stroke volume is the critical determinant of the high VO2max in
child cyclists and 2) factors that influence resting stroke volume are important
in defining VO2max differences between child endurance athletes and untrained
boys.
PMID- 10776893
TI - The role of skeletal muscle in lactate exchange during exercise: introduction.
PMID- 10776894
TI - An enzymatic approach to lactate production in human skeletal muscle during
exercise.
AB - PURPOSE: This paper examines the production of lactate in human skeletal muscle
over a range of power outputs (35-250% VO2max) from an enzymatic flux point of
view. The conversion of pyruvate and NADH to lactate and NAD in the cytoplasm of
muscle cells is catalyzed by the near-equilibrium enzyme lactate dehydrogenase
(LDH). As flux through LDH is increased by its substrates, pyruvate and NADH, the
factors governing the production of these substrates will largely dictate how
much lactate is produced at any exercise power output. In an attempt to
understand lactate production, flux rates through the enzymes that regulate
glycogenolysis/glycolysis, the transfer of cytoplasmic reducing equivalents into
the mitochondria, and the various fates of pyruvate have been measured or
estimated. RESULTS: At low power outputs, the rates of pyruvate and NADH
production in the cytoplasm are low, and pyruvate dehydrogenase (PDH) and the
shuttle system enzymes (SS) metabolize the majority of these substrates,
resulting in little or no lactate production. At higher power outputs (65, 90,
and 250% VO2max), the mismatch between the ATP demand and aerobic ATP provision
at the onset of exercise increases as a function of intensity, resulting in
increasing accumulations of the glycogenolytic/glycolytic activators (free ADP,
AMP, and Pi). The resulting glycolytic flux, and NADH and pyruvate production, is
progressively greater than can be handled by the SS and PDH, and lactate is
produced at increasing rates. Lactate production during the onset of exercise and
10 min of sustained aerobic exercise may be a function of adjustments in the
delivery of O2 to the muscles, adjustments in the activation of the aerobic ATP
producing metabolic pathways and/or substantial glycogenolytic/glycolytic flux
through a mass action effect.
PMID- 10776895
TI - Muscle as a consumer of lactate.
AB - Historically, muscle has been viewed primarily as a producer of lactate but is
now considered also to be a primary consumer of lactate. Among the most important
factors that regulate net lactate uptake and consumption are metabolic rate,
blood flow, lactate concentration ([La]), hydrogen ion concentration ([H+]),
fiber type, and exercise training. Muscles probably consume more lactate during
steady state exercise or contractions because of increased lactate oxidation
since enhancements in lactate transport due to acute activity are small. For
optimal lactate consumption, blood flow should be adequate to maintain ideal [La]
and [H+] gradients from outside to inside muscles. However, it is not clear that
greater than normal blood flow will enhance lactate exchange. A widening of the
[La] gradient from outside to inside muscle cells along with an increase in
muscle [La] enhances both lactate utilization and sarcolemmal lactate transport.
Similarly, a significant outside to inside [H+] gradient will stimulate
sarcolemmal lactate influx, whereas an increased intramuscular [H+] may stimulate
exogenous lactate utilization by inhibiting endogenous lactate production.
Oxidative muscle fibers are metabolically suited for lactate oxidation, and they
have a greater capacity for sarcolemmal lactate transport than do glycolytic
muscle fibers. Endurance training improves muscle capacity for lactate
utilization and increases membrane transport of lactate probably via an increase
in Type I monocarboxylate transport protein (MCT1) and perhaps other MCT isoforms
as well. The future challenge is to understand the regulatory roles of both
lactate metabolism and membrane transport of lactate.
PMID- 10776896
TI - Quantitative assessment of pathways for lactate disposal in skeletal muscle fiber
types.
AB - Quantifying the contribution of the various skeletal muscle fiber types toward
lactate disposal has proven elusive. In part, this can be attributed to the lack
of adequate preparations for the study of all potential metabolic pathways
involved. Toward this end our laboratory developed several perfused muscle
preparations that are homogeneous for specific fiber types. This paper briefly
reviews our findings regarding the influence of fiber type on lactate disposal in
resting skeletal muscle and the metabolic pathways involved. Perfusing over a
range of lactate concentrations, 1-12 mM, all fiber types were shown to switch
from net production at low lactate concentrations to net consumption at higher
concentrations. This transition occurred at lower lactate concentrations for Type
I and IIa fibers, when compared with IIb fibers. For Type I and IIa fibers
oxidation was observed to be the primary route of disposal accounting for
approximately 50% of the lactate removed. For all fiber types, transamination was
a significant pathway for the disposal of lactate carbon, whereas glyconeogenesis
was the primary pathway for disposal in Type IIb fibers. The glyconeogenic
capacity was quantitatively similar for Type IIa and IIb fibers but was
negligible for Type I fibers. The pathway for glyconeogenesis in skeletal muscle
was shown to be substantially different from that employed in hepatic
glyconeogenesis. Results indicated that neither the TCA cycle nor
phosphoenolpyruvate carboxykinase is involved in skeletal muscle glyconeogenesis.
Our findings suggested that PEP formation in skeletal muscle glyconeogenesis
occurs by "reversal" of the pyruvate kinase reaction.
PMID- 10776897
TI - Lactate transporters (MCT proteins) in heart and skeletal muscles.
AB - Lactate traverses the cell membranes of many tissues, including the heart and
skeletal muscle via a facilitated monocarboxylate transport system that functions
as a proton symport and is stereoselective for L-lactate. In the past few years,
seven monocarboxylate transporters have been cloned. Monocarboxylate transporters
are ubiquitously distributed among many tissues, and the transcripts of several
monocarboxylate transporters are present within many of the same tissues. This
complicates the identification of their metabolic function. There is also
evidence that that there is some species specificity, with differences in MCT
tissue distributions in hamsters, rats, and humans. MCT1 and MCT3-M/MCT4 are
present in rat and human muscles, and MCT1 expression is highly correlated with
the oxidative capacity of skeletal muscles and with their capacity to take up
lactate from the circulation. MCT1 is also present in heart and is located on the
plasma membrane (in subdomains), T-tubules, and in caveolae. With training, MCT1
is increased in rat and human muscle, and in rat hearts, resulting in an
increased uptake of lactate from the buffers perfused through these tissues and
an increase in lactate efflux out of purified vesicles. In humans, the training
induced increases in MCT1 are associated with an increased lactate efflux out of
muscle. MCT3-M/MCT4 is not correlated with the muscles' oxidative capacities but
is equally abundant in Type IIa and IIb muscles, whereas it is markedly lower in
slow-twitch (Type I) muscles. Clearly, we are at the threshold of a new era in
understanding the regulation of lactate movement into and out of skeletal muscle
and cardiac cells.
PMID- 10776898
TI - Intra- and extra-cellular lactate shuttles.
AB - The "lactate shuttle hypothesis" holds that lactate plays a key role in the
distribution of carbohydrate potential energy that occurs among various tissue
and cellular compartments such as between: cytosol and mitochondria, muscle and
blood, blood and muscle, active and inactive muscles, white and red muscles,
blood and heart, arterial blood and liver, liver and other tissues such as
exercising muscle, intestine and portal blood, portal blood and liver, zones of
the liver, and skin and blood. Studies on resting and exercising humans indicate
that most lactate (75-80%) is disposed of through oxidation, with much of the
remainder converted to glucose and glycogen. Lactate transport across cellular
membranes occurs by means of facilitated exchange along pH and concentration
gradients involving a family of lactate transport proteins, now called
monocarboxylate transporters (MCTs). Current evidence is that muscle and other
cell membrane lactate transporters are abundant with characteristics of high Km
and Vmax. There appears to be long-term plasticity in the number of cell membrane
transporters, but short-term regulation by allosteric modulation or
phosphorylation is not known. In addition to cell membranes, mitochondria also
contain monocarboxylate transporters (mMCT) and lactic dehydrogenase (mLDH).
Therefore, mitochondrial monocarboxylate uptake and oxidation, rather than
translocation of transporters to the cell surfaces, probably regulate lactate
flux in vivo. Accordingly, the "lactate shuttle" hypothesis has been modified to
include a new, intracellular component involving cytosolic to mitochondrial
exchange. The intracellular lactate shuttle emphasizes the role of mitochondrial
redox in the oxidation and disposal of lactate during exercise and other
conditions.
PMID- 10776899
TI - EPO, red cells, and serum transferrin receptor in continuous and intermittent
hypoxia.
AB - PURPOSE: Erythropoietic response in 10 healthy nonsmoking volunteers exposed to
normobaric hypoxia continuously or intermittently 12 h daily for 7 d was
evaluated in a randomized cross-over study. METHODS: An oxygen content of 15.4%
corresponding to an altitude of 2500 m was created by adding nitrogen into room
air in a flat. Venous blood samples for hemoglobin (Hb), hematocrit (Hct),
reticulocytes, serum erythropoietin (S-EPO), red cell 2,3-diphosphoglycerate (2,3
DPG), serum ferritin (S-Ferrit), and serum soluble transferrin receptor (S
TransfR) were drawn at 8:00 a.m. RESULTS: S-EPO was increased from baseline
values of 22.9+/-9.6 and 20.5+/-10.1 U x L(-1) to 40.7+/-12.9 (P < 0.05) and 35+/
14.3 U x L(-1) (P < 0.05) after the first night in continuous and intermittent
hypoxia, respectively, and remained elevated throughout both exposures. Hb and
Hct values did not show any significant changes. Red cell 2,3-DPG rose from
baseline a value of 5.0+/-0.8 to 5.9+/-0.7 mmol x L(-1) (P < 0.05) after the
first day in continuous hypoxia and from 5.2+/-0.7 mmol x L(-1) to 6.1+/-0.5 mmol
x L(-1) on day 3 (P < 0.05) during intermittent hypoxia. The reticulocyte count
rose significantly (P < 0.05) after 5 d in both experiments. S-transferrin
receptor level rose significantly from 2.2+/-0.4 and 2.1+/-0.5 mg x L(-1) to
2.6+/-0.5 mg x L(-1) and 2.3+/-0.6 mg x L(-1) on day 5 (P < 0.05), to 2.7+/-0.5
mg x L(-1) and 2.5+/-0.6 mg x L(-1) on day 7 (P < 0.05) under continuous and
intermittent hypoxia, respectively. CONCLUSIONS: We suggest that intermittent
exposure to moderate normobaric hypoxia 12 h daily for 1 wk induces a similar
stimulation of erythropoiesis as continuous exposure.
PMID- 10776900
TI - Effects of aerobic fitness on fat oxidation and body fatness.
AB - OBJECTIVE: This study investigated the contributions of physical fitness and body
composition to 24-h fat oxidation in adults under sedentary conditions in a whole
room calorimeter. METHODS: The following measurements were studied in 109 adults
(49 male/45 female) at least 36 h after a bout of exercise: 1) aerobic fitness
level assessed by VO2max, 2) body composition determined by underwater weighing,
3) resting metabolic rate (RMR) after an overnight fast, and 4) 24-h energy
expenditure (EE) and substrate oxidation determined in a whole-room calorimeter.
While in the calorimeter, subjects were provided with a diet (15% protein, 30%
fat, and 55% carbohydrate) estimated to produce energy balance on a sedentary day
and of similar nutritional composition to their daily dietary intake. RESULTS: We
found strong negative correlations between VO2max and % body fat in both male and
female subjects, but no relationship between VO2max and 24-h EE under the
sedentary conditions of this study. In male subjects, VO2max (mL O2 x kg(-1) fat
free mass x min(-1)) was negatively related to fat oxidation (r = -0.397, P <
0.005), and fat oxidation was more closely related to fat mass (r = 0.434, P <
0.0002) than to fat-free mass (r = 0.165, NS). In contrast, none of these
relationships were significant in females. CONCLUSION: The results show that in
male subjects under sedentary conditions, 24-h fat oxidation is positively
related to body fat mass and negatively related to VO2max (the marker used here
for level of physical fitness). This supports our hypothesis that regularly
active males maintain lower body fat stores as the low contribution to daily fat
oxidation from a lower body fat mass is counterbalanced by the high contribution
to fat oxidation from daily physical activity. The lack of a relationship between
VO2max and 24-h EE under the sedentary conditions of this study suggests that the
major effects of physical activity on total daily EE and fat oxidation may occur
during and relatively quickly after an exercise bout. Further, these data also
suggest that cessation of regular exercise will likely be associated with a high
risk of positive fat balance and weight gain.
PMID- 10776901
TI - Contributions of lower extremity joints to energy dissipation during landings.
AB - PURPOSE: The purpose of the study was to investigate changes in lower extremity
joint energy absorption for different landing heights and landing techniques.
METHODS: Nine healthy, active male subjects volunteered to perform step-off
landings from three different heights (0.32 m, 2.5 m(-s); 0.62 m, 3.5 m(-s); and
1.03 m, 4.5 m(-s)) using three different landing techniques (soft, SFL; normal,
NML; and stiff landing, STL). Each subject initially performed five NML trials at
0.62 m to serve as a baseline condition and subsequently executed five trials in
each of the nine test conditions (3 heights x 3 techniques). RESULTS: The results
demonstrated general increases in peak ground reaction forces, peak joint
moments, and powers with increases in landing height and stiffness. The mean
eccentric work was 0.52, 0.74, and 0.87 J x kg(-1) by the ankle muscles, and
0.94, 1.31, and 2.15 J x kg(-1) by the hip extensors, at 0.32, 0.62, and 1.03 m,
respectively. The average eccentric work performed by the knee extensors was
1.21, 1.63, and 2.26 J x kg(-1) for the same three heights. CONCLUSIONS: The knee
joint extensors were consistent contributors to energy dissipation. The ankle
plantarflexors contributed more in the STL landings, whereas the hip extensors
were greater contributors during the SFL landings. Also a shift from ankle to hip
strategy was observed as landing height increased.
PMID- 10776902
TI - Decreased EMG median frequency during a second bout of eccentric contractions.
AB - PURPOSE: Others have reported preferential recruitment of fast motor units in
muscles during performance of eccentric contractions and there is evidence that
fast muscle fibers are more susceptible to eccentric contraction-induced injury.
We tested the hypothesis that during a second bout of maximal eccentric
contractions 1 wk after the first, there would be a reduction in the
electromyographic (EMG) median frequency (MF) with minimal change in the EMG root
mean-square (RMS), indicating greater reliance on slower motor units. This could
provide an explanation for the enhanced resistance to eccentric contraction
induced injury after a single bout of eccentric exercise. METHODS: Human subjects
performed 50 maximal voluntary eccentric (N = 10) or concentric (N = 10)
contractions of the anterior crural muscles on two occasions separated by 1 wk.
To determine whether MF changes during the second bout could be a consequence of
injury to fibers in fast motor units, the anterior crural muscles of mice were
electrically stimulated to perform 50 maximal eccentric (N = 10) or concentric (N
= 9) contractions on two occasions separated by 1 wk. In both the humans and
mice, torque production and tibialis anterior muscle RMS and MF were measured
during the two exercise bouts. RESULTS: In human tibialis anterior muscle, MF was
30% lower (P < 0.01) during the second eccentric bout although RMS was the same.
In the mice, RMS and MF were unchanged at any time after the first eccentric bout
despite torque deficits similar to those observed in the humans. CONCLUSIONS: The
data indicate that with repetition of maximal voluntary eccentric contractions,
there is an increased activation of slow motor units and a concomitant decrease
in activation of fast units.
PMID- 10776903
TI - Muscle forces and spinal loads at C4/5 level during isometric voluntary efforts.
AB - PURPOSE: The goal of this study was to determine neck muscle forces and spinal
loads that result from isometric muscle contractions. METHODS: Electromyographic
(EMG) activity of the neck musculature and a three-dimensional biomechanical
model of the neck were used. The model was EMG-based and estimated muscle forces
and spinal loads at the C4/5 level. EMG signals were collected from eight sites
at the C4/5 level of the neck using Ag-AgCl surface electrodes from 10 adult male
subjects. The subjects performed isometric contractions gradually developing to
maximum efforts in flexion, extension, left lateral bending, and right lateral
bending. RESULTS: During maximum voluntary contraction (MVC) trials most muscles
generated high levels of EMG signal during cervical rotation. The posterior
surface of the neck (trapezius) was the only electrode site at which maximum
activity EMG consistently occurred by the same method (rotation) in all subjects.
Variations in the EMG patterns were observed in different experiments that
produced overall neck moments of equal magnitudes. With these data the model
computed variations in load distribution among the agonist muscles. Consistent
also with EMG distributions, the model also computed co-contractions of
antagonist muscles. The average (+/- SD) magnitudes of peak moments were 28.3 (+/
3.3) Nm in extension, 17.7 (+/- 3.1) Nm in flexion, 16.9 (+/- 2.8) Nm in left
lateral bending, and 17.0 (+/- 2.9) Nm in right lateral bending. The model
predicted C4/5 joint compressive forces during peak moments were 1372 (+/- 140) N
in extension, 1654 (+/- 308) N in flexion, 956 (+/- 169) N in left lateral
bending, and 1065 (+/- 207) N in right lateral bending. CONCLUSIONS: Results
suggest that higher C4/5 joint loads than previously reported are possible during
maximum isometric muscle contractions.
PMID- 10776904
TI - Influence of fatigue on EMG/force ratio and cocontraction in cycling.
AB - PURPOSE: The purpose of the present study was to observe force and power losses
and electromyographic manifestations of fatigue during repeated sprints performed
on a friction-loaded cycle ergometer. METHODS: Ten subjects performed 15 maximal
5-s sprints with 25-s rests between them. Power, velocity, and torque were
measured during sprints 1 and 13 and during two submaximal constant-velocity (50
rpm) periods of cycling performed before and after the sprints. The EMG signals
of five leg muscles were stored to determine the EMG/force ratio of power
producer muscles and the coactivation of antagonist muscles. The power producer
muscles were activated to the same level during sprints 1 and 13, despite a loss
of force, whereas the vastus lateralis muscle was recruited more during the
submaximal cycling period under fatigue conditions. RESULTS: This led to an
increased EMG/force ratio for the power producer muscles, indicating the
peripheral fatigue status of these muscles. Antagonist muscles were less
activated during the sprints after fatigue; whereas they stayed unchanged during
the last submaximal cycling period. CONCLUSIONS: This suggests that there is a
decrease in coactivation as agonist force is lost. This decrease in coactivation
under fatigue conditions has not been previously reported and is probably due to
the training status of the subjects. Subjects may have learned to better use
their antagonist muscles to efficiently transfer force and power to the rotating
pedal. This coordination can be adapted to cope with fatigue of the power
producer muscles.
PMID- 10776905
TI - Prediction of triathlon race time from laboratory testing in national
triathletes.
AB - PURPOSE: Four days after competing in an Olympic-distance National Triathlon
Championship (1500-m swim, 40-km cycle, 10-km run), five male and five female
triathletes underwent comprehensive physiological testing in an attempt to
determine which physiological variables accurately predict triathlon race time.
METHODS: All triathletes underwent maximal swimming tests over 25 and 400 m, the
determination of peak sustained power output (PPO) and peak oxygen uptake
(VO2peak) during an incremental cycle test to exhaustion, and a maximal treadmill
running test to assess peak running velocity and VO2peak. In addition, submaximal
steady-state measures of oxygen uptake (VO2), blood [lactate], and heart rate
(HR) were determined during the cycling and running tests. RESULTS: The five most
significant (P < 0.01) predictors of triathlon performance were blood lactate
measured during steady-state cycling at a workload of 4 W x kg(-1) body mass (BM)
(r = 0.92), blood lactate while running at 15 km x h(-1) (r = 0.89), PPO (r =
0.86), peak treadmill running velocity (r = 0.85), and VO2peak during cycling (r
= 0.85). Stepwise multiple regression analysis revealed a highly significant (r =
0.90, P < 0.001) relationship between predicted race time (from laboratory
measures) and actual race time, from the following calculation: race time (s) = -
129 (peak treadmill velocity [km x h(-1)]) + 122 ([lactate] at 4 W x kg(-1) BM) +
9456. CONCLUSION: The results of this study show that race time for top
triathletes competing over the Olympic distance can be accurately predicted from
the results of maximal and submaximal laboratory measures.
PMID- 10776906
TI - Exercise intensity during competition time trials in professional road cycling.
AB - PURPOSE: To estimate, upon competition heart rate (HR), exercise intensity during
time trials (TT) in professional road cycling. METHODS: Eighteen world-class
cyclists completed an incremental laboratory cycling test to assess maximal power
output (Wmax), maximal HR (HRmax), onset of blood lactate accumulation (OBLA),
lactate threshold (LT), and a HR-power output relationship. An OBLA(ZONE)
(HR(OBLA) +/- 3 beats x min(-1)) and a LT(ZONE) (HR(LT) +/- 3 beats x min(-1))
were described. HR was monitored during 12 prologue (<10 km, PTT), 18 short (<40
km, STT), 19 long (>40 km, LTT), eight uphill (UTT), and seven team (TTT) time
trials. A HR-power output relationship was computed to estimate each cyclist's
power output during TT racing from competition HR. Competition training impulse
(TRIMP) values were estimated from HR and race duration. RESULTS: %HRmax were
89+/-3%, 85+/-5%, 80+/-5%, 78+/-3%, and 82+/-2% in PTT, STT, LTT, UTT, and TTT,
respectively. The amount of TRIMP were, respectively, 21+/-3, 77+/-23, 122+/-27,
129+/-14, and 146+/-6. Competition HR values relative to HR(OBLA) and HR(LT)
were, respectively, 100+/-3%, 114+/-8% in PTT, 95+/-7%, 108+/-9% in STT, 89+/-5%,
103+/-8% in LTT, 87+/-2%, 101+/-5% in UTT, and 91+/-4%, 105+/-11% in TTT.
CONCLUSIONS: %HRmax, TRIMP and time distribution around HR(OBLA) and HR(LT)
reflected the physiological demands of different TT categories. HR(OBLA) and
HR(LT) were accurate intensity markers in events lasting, respectively, < or =30
(PTT and STT) and > or =30 min (LTT, UTT, TTT).
PMID- 10776907
TI - Use of bioelectrical impedance analysis to estimate body fluid compartments after
acute variations of the body hydration level.
AB - Physiological measurements including body mass, plasma osmolality, natremia,
plasma volume measured by Evans Blue dilution, and total body water (TBW) and
extracellular water (ECW) volumes estimated by bioelectrical impedance analysis
(BIA) were recorded in eight healthy young Caucasian subjects before and after
acute variations of their body hydration state on four separate occasions: 1)
euhydration or control trial (C); 2) heat-induced dehydration of 2.8% body mass
(D); 3) exercise-induced dehydration of 2.8% body mass (E); and 4) glycerol
hyperhydration (H). Heart rate, rectal and mean skin temperatures were also
recorded throughout the experiment. The main result of the study is that BIA only
half predicted the body water loss after exercise, although conditions were
standardized (electrode placement, side of the body, limb position, posture, and
ambient temperature). Differences in body temperatures cannot explain such an
unexpected result, nor did the study of plasma osmolality and sodium
concentration. If BIA appears to adequately predict changes in TBW after heat
induced dehydration and glycerol hyperhydration, further studies including
measures of TBW and ECW by dilution tracer methods would be necessary to
establish the validity of using the BIA method to measure such changes and to
interpret ECW variations.
PMID- 10776908
TI - Reliability of treadmill measures and criteria to determine VO2max in prepubertal
girls.
AB - PURPOSE: The main objective of this study was to determine the reliability of
measuring treadmill exercise economy (VO2submax) and the maximal oxygen uptake
(VO2max) in prepubertal girls tested twice, 6 wk apart. We also wanted to examine
the percentage of young girls who were able to reach the criteria for achieving
VO2max and to describe methods that would allow a high proportion of young
children to achieve criteria for reaching a true VO2max. METHODS: We studied 61
normal-weight, prepubertal girls with a mean (+/- SD) age 7.3+/-1.3 yr (range 4.8
to 10.3 yr). VO2submax was determined while walking for 4 min at 2.5 mph with 0%
grade. VO2max was measured during a progressive, all-out, continuous treadmill
test using standardized procedures and criteria. Heart rate (HR) was measured
using a Polar monitor. Respiratory rate (RR), respiratory exchange ratio (RER),
ventilation (V), and VO2 were measured using a Sensormedics metabolic monitor.
RESULTS: There were no significant differences between visits I and 2 in mean HR,
RR, RER, V, VO2submax (421 vs 422 mL x min(-1), respectively), and VO2max (1036
vs 1049 mL x min(-1), respectively). Intra-individual coefficients of variation
(CV) between visits 1 and 2 for submaximal tests were: HR = 5.1%, RR = 12.4%, RER
= 7.2%, V = 12.5%, and VO2 = 12.4%. Intra-individual CVs for the maximum tests
were: HRmax = 2.1%, RRmax = 10.8%, RERmax = 5.3%, Vmax = 11.7%, and VO2max =
7.5%. A high proportion of the girls reached criteria for VO2max [RER> 1.00,
HR>85% of age predicted maximum, and plateauing of VO2max] in both visits: 99%
reached one of three criteria, 92% reached two of three criteria, and 70% reached
all three criteria. Twenty girls [mean age 7.2+/-1.2 yr] reached at least two
criteria in both visits, whereas 32 girls [mean (+/- SD) age 8.6+/-1.0 yr]
reached three criteria in both visits. CONCLUSION: Exercise measurements using
treadmill testing were reliable in healthy, normal-weight, prepubertal girls.
Older girls when compared to the younger girls were able to reach criteria for
VO2max more often. Thus, we recommend that one testing should give researchers an
accurate measure of walking economy and aerobic capacity, and that two criteria
are enough for determining VO2max.
PMID- 10776909
TI - New graphical method for evaluating gas exchange in congestive heart failure.
AB - PURPOSE: The purpose of this study was to determine the usefulness of a new
graphical method for evaluating gas exchange (GE), as applied to three common
averaging techniques used during rest, exercise, and recovery in patients with
congestive heart failure (CHF). METHODS: Fifty patients' resting, exercise, and
recovery GE graphs were evaluated using a new graphical method to determine
oxygen consumption (VO2), ventilation (VE), and respiratory exchange ratio (RER).
Precision of the new method was evaluated by repeated measures using the same
investigator, an additional investigator, and an untrained student. A 1-min
rolling time average (RTA) updated every 20 s was used as the reference to the
graphical method and the metabolic cart's computer analysis. Breath-by-breath
data were evaluated using three averaging techniques, average 5 of 7 breaths
(5/7), average of 8 breaths (AVG 8), and 30-s average (30-s). Differences between
the computer and the graphical method were assessed by two-sided t-tests; ANOVA
was used between the three investigators and also between the three averaging
techniques. RESULTS: There were no significant differences of repeated measures
between trained and untrained investigators. The graphical method results were
significantly different than the computer results. The only difference with RTA
involved computer resting values, which were also different than the graphical
method. CONCLUSION: In conclusion, the graphical method may be used to
standardize GE evaluation because it displays excellent intrainvestigator
precision and good interinvestigator precision between experienced and
inexperienced investigators. Averaging techniques less than 30 s have greater
bias when using computer-derived values, although when incorporating the
graphical method the averaging technique chosen has little influence on all
measures.
PMID- 10776910
TI - Team physician consensus statement.
AB - The objective of the Team Physician Consensus Statement is to provide physicians,
school administrators, team owners, the general public, and individuals who are
responsible for making decisions regarding the medical care of athletes and teams
with guidelines for choosing a qualified team physician and an outline of the
duties expected of a team physician. Ultimately, by educating decision makers
about the need for a qualified team physician, the goal is to ensure that
athletes and teams are provided the very best medical care. The Consensus
Statement was developed by the collaboration of six major professional
associations concerned about clinical sports medicine issues: American Academy of
Family Physicians, American Academy of Orthopaedic Surgeons, American College of
Sports Medicine, American Medical Society for Sports Medicine, American
Orthopaedic Society for Sports Medicine, and the American Osteopathic Academy of
Sports Medicine. These organizations have committed to forming an ongoing project
based alliance to "bring together sports medicine organizations to best serve
active people and athletes."
PMID- 10776911
TI - Ethanol reduces metabolic uncoupling following experimental head injury.
AB - Previous investigations have shown that ethanol is neuroprotective following
experimental traumatic brain injury (TBI). This study sought to determine if the
neuroprotective effects of ethanol in a controlled cortical impact (CCI) injury
model are related to its effects on cerebral glucose metabolism and blood flow.
Adult rats were given ethanol (1.0 g/kg) or saline by intraperitoneal injection
followed 40 min later by injury. Regional cerebral blood flow (CBF) and cerebral
metabolic rates of glucose (CMRglc) were determined immediately, and at 3, 6, 12,
24, and 72 h postinjury using quantitative autoradiography. Immediately after
injury, CMRglc in the contusion core and penumbra was reduced in the ethanol
group compared to the saline group: (core CMRglc: 52.2 +/- 16.0 versus 94.2 +/-
14.1 micromol/100 g/min, respectively,p < 0.001; penumbral CMRglc: 58.2 +/- 12.8
versus 82.8 +/-19.7 micromol/100 g/min, respectively; p < 0.05) However, at 24
and 72 h postinjury, penumbral CMRglc in the ethanol group was increased compared
to the saline group (p < 0.05 and p < 0.001, respectively). Regarding CBF,
contusion core values in the ethanol group were elevated compared to the saline
group immediately postinjury, (70.4 +/- 17.1 versus 31.5 +/- 27.8 mL/100 g/min,
respectively (p < .05), and at 6, 12, and 24 h postinjury (p < 0.05). Penumbral
CBF was also higher at 6 and 72 h in the ethanol group compared to the saline
group (p < 0.05). These results indicate that low-dose ethanol is associated with
a marked attenuation of immediate postinjury hyperglycolysis and with more normal
glucose metabolism in the injury penumbra over the ensuing 3 days.
Simultaneously, the reduction in CBF typically seen within the contusion core and
penumbra after CCI is less severe when ethanol is present. The net effect of
these changes is a decreased degree of uncoupling between glucose metabolism and
CBF that otherwise occurs in the absence of ethanol. These changes may likely
explain the neuroprotective effect of ethanol.
PMID- 10776912
TI - Long-term dysfunction following diffuse traumatic brain injury in the immature
rat.
AB - Children often suffer sustained cognitive dysfunction after severe diffuse
traumatic brain injury (TBI). To study the effects of diffuse injury in the
immature brain, we developed a model of severe diffuse impact (DI) acceleration
TBI in immature rats and previously described the early motor and cognitive
dysfunction posttrauma. In the present study, we investigated the long-term
functional ability after DI (150 gm/2 m) compared to sham in the immature (PND
17) rat. Beam balance and inclined plane latencies were measured daily for 10
days after injury to assess gross vestibulomotor function. The Morris water maze
(MWM) paradigm was evaluated monthly up to 3 months after DI and sham injuries.
Reduced latencies on the balance beam and inclined plane were observed in DI rats
(p < 0.05 vs. sham [n = 10 per group]) at 24 h and persisted for 10 days
postinjury. DI produced sustained MWM performance deficits (p < 0.05 vs. sham) as
indicated by the greater latencies to find the hidden platform remarkably through
90 days after injury. Lastly, the brain and body weights of the injured animals
were less than sham (p < 0.05) after 3 months. We conclude that a diffuse TBI in
the immature rat: (a) created a consistent, marked, but reversible motor deficit
up to 10 days following injury; (b) produced a long-term, sustained performance
deficit in the MWM up to 3 months posttrauma; and (c) affected body and brain
weight gain in the developing rat through 3 months after injury. This TBI model
should be useful for the testing of novel therapies and their effect on long-term
outcome and development in the immature rat.
PMID- 10776913
TI - Stretch injury causes calpain and caspase-3 activation and necrotic and apoptotic
cell death in septo-hippocampal cell cultures.
AB - Traumatic brain injury (TBI) results in numerous central and systemic responses
that complicate interpretation of the effects of the primary mechanical trauma.
For this reason, several in vitro models of mechanical cell injury have recently
been developed that allow more precise control over intra- and extracellular
environments than is possible in vivo. Although we recently reported that calpain
and caspase-3 proteases are activated after TBI in rats, the role of calpain
and/or caspase-3 has not been examined in any in vitro model of mechanical cell
injury. In this investigation, varying magnitudes of rapid mechanical cell
stretch were used to examine processing of the cytoskeletal protein alpha
spectrin (280 kDa) to a signature 145-kDa fragment by calpain and to the
apoptotic-linked 120-kDa fragment by caspase-3 in septo-hippocampal cell
cultures. Additionally, effects of stretch injury on cell viability and
morphology were assayed. One hour after injury, maximal release of cytosolic
lactate dehydrogenase and nuclear propidium iodide uptake were associated with
peak accumulations of the calpain-specific 145-kDa fragment to alpha-spectrin at
each injury level. The acute period of calpain activation (1-6 h) was associated
with subpopulations of nuclear morphological alterations that appeared necrotic
(hyperchromatism) or apoptotic (condensed, shrunken nuclei). In contrast, caspase
3 processing of alpha-spectrin to the apoptotic-linked 120-kDa fragment was only
detected 24 h after moderate, but not mild or severe injury. The period of
caspase-3 activation was predominantly associated with nuclear shrinkage,
fragmentation, and apoptotic body formation characteristic of apoptosis. Results
of this study indicate that rapid mechanical stretch injury to septo-hippocampal
cell cultures replicates several important biochemical and morphological
alterations commonly observed in vivo brain injury, although important
differences were also noted.
PMID- 10776914
TI - Traumatic spinal cord injury produced by controlled contusion in mouse.
AB - Previous work from this laboratory has described a rat spinal cord injury (SCI)
model in which the mid-thoracic spinal cord is subjected to a single rapid and
calibrated displacement at the site of a dorsal laminectomy. Injury is initiated
at the tip of a vertical shaft driven by an electromagnetic shaker. Transducers
arranged in series with the shaft record the patterns of displacement and force
during the impact sequence. In the present study, this device and the relevant
surgical procedures were adapted to produce a spinal contusion injury model in
laboratory mice. The signal generator for the injury device has also been
converted to a computer-controlled interface to permit extension of the model to
other laboratories. Mice were subjected to SCI across a range of severities by
varying the amplitude of displacement and the magnitude of measured preload force
on the dural surface. A moderate injury produced by displacement of 0.5 mm over
25 msec resulted in initial paralysis and recovery of locomotion with chronic
deficits in hindlimb function. The magnitude of the peak force, impulse, power,
and energy generated at impact were correlated with behavioral outcome at 1 day
postinjury, while peak displacement and impulse were the best predictors of
behavioral outcome at 28 days postinjury. The shape of the force recording proved
to be a highly sensitive measure of subtle variations in the spinal compartment
that were otherwise difficult to detect in this small species. The results
demonstrate that the electromagnetic spinal cord injury device (ESCID) can be
used to produce a well-controlled contusion injury in mice. The unique features
of controlled displacement and monitoring of the biomechanical parameters at the
time of impact provide advantages of this model for reducing outcome variability.
Use of this model in mice with naturally occurring and genetically engineered
mutations will facilitate understanding of the molecular mechanisms of
pathophysiology following traumatic spinal cord injury.
PMID- 10776915
TI - Posttraumatic hypothermia reduces polymorphonuclear leukocyte accumulation
following spinal cord injury in rats.
AB - The present study addresses the effects of moderate posttraumatic hypothermia (32
degrees C) on the temporal and regional profile of polymorphonuclear leukocyte
(PMNL) accumulation after traumatic spinal cord injury (SCI). We hypothesized
that posttraumatic hypothermia would reduce the degree of inflammation by
reducing PMNL infiltration. Rats underwent moderate spinal cord injury at T10
using the NYU impactor device. In the first study, the temporal profile of
myeloperoxidase (MPO) activity (a marker of neutrophil accumulation) under
normothermic (37 degrees C) conditions was determined. The animals were allowed
to survive for 3 or 24 h, or 3 or 7 days after SCI. Spinal cords were dissected
into five segments rostral and caudal to the injury site. Additional animals were
studied for the immunocytochemical visualization of MPO. In the second study,
rats were sacrificed at 24 h after a monitoring period of normothermia (36.5
degrees C/3 h) or hypothermia (32.4 degrees C/3 h) with their controls. In the
time course studies, MPO enzymatic activity was significantly increased at 3 and
24 h within the traumatized T10 segment compared to controls. MPO activity was
also increased at 3 h within the rostral T8 and T9 segments and caudal T11 and
T12 segments compared to controls. At 24 h after trauma, MPO activity remained
elevated within both the rostral and caudal segments compared to control. By 3
days, the levels of MPO activity were reduced compared to the 24-h values but
remained significantly different from control. Neutrophils that exhibited MPO
immunoreactivity were seen at 6 and 24 h, with a higher number at 3 days. PMNLs
were located within the white and gray matter of the lesion and both rostral and
caudal to the injury site. Posttraumatic hypothermia reduced MPO activity at 24 h
in the injured spinal cord segment, compared to normothermic values. The results
of this study indicate that a potential mechanism by which hypothermia improves
outcome following SCI is by attenuating posttraumatic inflammation.
PMID- 10776916
TI - Spinal cord injury in ICAM-1-deficient mice: assessment of functional and
histopathological outcome.
AB - Adhesion molecule-mediated adhesion and extravasation of leukocytes may
constitute a mechanism of secondary tissue damage following spinal cord injury
(SCI). The objective of the present study was to determine to what extent genetic
deficiency in the adhesion molecule ICAM-1 influences functional and
histopathological measures of outcome following SCI. ICAM-1-/- (n = 11) and wild
type (n = 9) mice were subjected to a compression-type SCI. Assessment of hind
limb motor function was done on days 1, 2, 4, 7, 10, and 14 after injury, using a
motor function scoring system. Injury resulted in a drastically impaired hind
limb motor function at day one after injury followed by a partial recovery during
the observation period. No significant functional differences were found between
the experimental groups at any time-point. Fourteen days after injury the animals
were sacrificed and the spinal cords were processed for histopathological and
immunohistochemical evaluation. Luxol-stained, MAP2-, GFAP- and iba-1
immunostained cross-sectional areas were quantitated using a computerized image
analysis system to investigate white matter damage, neuronal loss, astrocytic
response and microglial activation respectively. None of these parameters
differed significantly between the groups. Separate experiments revealed that the
early (24 h postinjury) infiltration of polymorphonuclear leukocytes was
significantly reduced in white matter but not in the grey matter of ICAM-1-/-
mice, compared to injured controls. In summary, these results do not support the
concept that ICAM-1 alone mediates secondary tissue damage following traumatic
SCI in the mouse.
PMID- 10776917
TI - ATP-dependent astrocyte-endothelial calcium signaling following mechanical damage
to a single astrocyte in astrocyte-endothelial co-cultures.
AB - In the brain, endfeet of perivascular astrocytes make close contact with
capillary endothelial cells that form the blood-brain barrier. The aim of the
present work was to investigate whether and how calcium signals can be
communicated from astrocytes to endothelial cells following acute mechanical cell
damage. The experiments were performed on astrocyte-endothelial co-cultures
prepared from primary rat brain astrocytes and an endothelial cell line (ECV304).
A single astrocyte was acutely damaged by mechanical stimulation of sufficient
strength with a micropipette, and the resulting cytoplasmic calcium changes were
monitored using fura-2 and digital calcium imaging. Mechanical damage to a single
astrocyte triggered a large intercellular calcium wave that propagated to
surrounding astrocytes and also to even remotely located (several hundred
micrometers) endothelial cells. Astrocyte-endothelial calcium waves induced by
mechanical cell damage were largely deflected by fast superfusion, were able to
cross a cell-free lane, were dose-dependently inhibited by suramin, a P2
purinoceptor blocker, and were largely reduced in size in the presence of the ATP
degrading enzyme apyrase. Our results indicate that mechanical damage to a single
astrocyte can produce far reaching calcium signals that are propagated by the
release of a calcium mobilizing P2-purinergic agonist and that can be
communicated to endothelial cells. As endothelial cytoplasmic calcium is an
important factor in the regulation of blood-brain barrier permeability and
transport, mechanical cell damage-induced astrocyte-endothelial calcium signals
are hypothesized to play a role in the initiation of brain edema and the
stimulation of brain glucose uptake.
PMID- 10776918
TI - Magnetic resonance imaging with gadolinium DTPA enhancement in patients with
acute head injury.
AB - Gadolinium-enhanced magnetic resonance (MR) imaging in patients with acute head
injury was conducted to study if contrast extravasation was associated with
development of hemorrhagic lesions. A series of 60 head-injured patients were
admitted to our emergency unit. Computerized tomography (CT) scans and skull x
ray films were taken as rapidly as possible after hospitalization. Injury
severity on admission was evaluated using the Glasgow Coma Scale (GCS) score,
motor score, and pupillary examination, while overall outcome was assessed with
the Glasgow Outcome Scale (GOS) 3 months after injury. Of all patients admitted,
MR imaging with gadolinium enhancement was performed in 18 patients who were at
high risk of developing hemorrhagic lesion within 6 h after injury. In these
patients we investigated whether contrast extravasation was associated with
development of hemorrhagic lesions. All 18 patients presented abnormal findings
on their admission CT scans. Admission GCS score in those patients who underwent
MR imaging with gadolinium enhancement was 13 or more in 12 patients, 9-12 in
four patients, and 8 or less in two patients. Fourteen of 18 patients showed
contrast extravasation, corresponding with an evolution of lesion size. Nine of
14 patients who demonstrated extravasation of the contrast medium required
surgical treatment. The results of the current study suggest that extravasation
of contrast medium indicates a continuance of posttraumatic bleeding. Thus, MR
imaging with gadolinium enhancement in acutely head-injured patients may
constitute a reasonable strategy for predicting the development of hemorrhagic
lesions.
PMID- 10776919
TI - Comparison of morphological measurements extracted from digitized dental
radiographs with lumbar and femoral bone mineral density measurements in
postmenopausal women.
AB - BACKGROUND: We set out to determine whether morphologic measurements extracted
from digitized images of bite-wing radiographs correlated with lumbar and femoral
bone mineral density (BMD) measurements in 45 postmenopausal women who had no or
only mild periodontal disease (no probing depths >5 mm). METHODS: Lumbar spine
and femoral BMDs were determined by dual-energy x-ray absorptiometry. Vertical
bite-wing radiographs were taken and digitized. Crestal and apical regions of
interest (ROIs) were drawn on the digital images of the maxillary and mandibular
alveolar bone on the patient's right and left sides. For each patient, a single
morphologic measurement was made for each of 8 ROIs. Correlation analysis was
performed to determine the strengths of the relationships between the morphologic
measurements made at the 8 locations and between these morphologic measurements
and BMD measurements. RESULTS: The correlations (r) between the morphologic
operator (MO) measurements and lumbar spine and femoral BMDs were weak (mean r =
0.02, range = 0.32 to -0.26) and not statistically significant, with no clear
trends discernible. Correlations between MO measurements made at the 8 alveolar
sites were also weak (mean r = 0.05, range = 0.35 to -0.38) and not statistically
significant. CONCLUSIONS: The MO measurements used in this study were weakly
correlated with lumbar spine and femoral BMDs, with no clear trends discernible
in this population of postmenopausal women with no or mild periodontal disease.
PMID- 10776920
TI - A histochemical investigation of the bone formation process by guided bone
regeneration in rat jaws. Effect of PTFE membrane application periods on newly
formed bone.
AB - BACKGROUND: Guided bone regeneration (GBR) has been widely utilized for the
promotion of bone augmentation in bone loss areas. However, little information
has been available regarding chronological changes in newly formed bone and
alterations in the nature of newly formed bone after removal of a barrier
membrane. The present study attempted to establish a GBR model for rat maxillae.
We also examined the effects of membrane application periods on newly formed bone
and its remodeling process after removal of the membrane in this experimental
model. METHODS: Thirty-five Wistar rats were divided into 2 groups: a membrane
application group and a membrane removal group. The chronological changes of
newly formed bone were evaluated histologically and statistically. RESULTS: At 2
weeks after the GBR procedure, bony cavities had completely filled the newly
formed bone in the experimental side. In the control side, corticalization on the
surface of the newly formed bone proceeded with a decrease in the bone marrow
cavity, whereas the bone marrow space had enlarged by 12 weeks post-surgery in
the experimental side. In the membrane removal group, the osteoblasts appeared on
newly formed bone at 1 week after membrane removal. Comparatively thick compact
bone had formed on the surface of the newly formed bone at 4 weeks after membrane
removal, and corticalization proceeded later. CONCLUSIONS: The long-term
application of a barrier membrane induces the enlargement of the bone marrow
spaces. We suggest that PTFE membrane removal in adequate time promotes the
corticalization and maturation of the newly formed bone by the GBR technique.
PMID- 10776921
TI - Analysis of in situ protease activity in chronic adult periodontitis patients:
expression of activated MMP-2 and a 40 kDa serine protease.
AB - BACKGROUND: Periodontitis is characterized by extensive destruction of the
gingival tissues and associated supporting structures of the teeth. Although the
pathogenesis of the various forms of this disease is not completely understood,
host-derived proteases are believed to have an important role. In this study, we
analyzed human tissue samples from chronic adult periodontitis patients to assess
the levels of specific proteases and determine the effect of pH and tetracyclines
on their activity. METHODS: Gingival tissue samples were obtained from patients
with chronic adult periodontitis (probing depths ranged from 5 to 9 mm) and
periodontally healthy controls. Tissue extracts were prepared and analyzed for
protease activity by zymography and Western blotting. RESULTS: Maximal protease
activity from clinically normal and diseased tissues was observed at pH 8. Latent
matrix metalloproteinase (MMP)-9 and MMP-2 were expressed in all samples
examined, while active MMP-2 was detected only in tissues obtained from patients
with clinical disease. The MMP activities were differentially inhibited by
derivatives of tetracycline. At pH 6, a protease with a mass of approximately 40
kDa was observed in diseased samples. The enzymatic activity was inhibited by
phenylmethylsulfonyl fluoride, suggesting it is a serine protease. CONCLUSIONS:
The results of the current study substantiate the proposed role of host-derived
proteases in the pathogenesis of chronic adult periodontitis. Specifically, they
indicate that activated MMP-2 and a 40 kDa serine protease are involved in tissue
destruction associated with this form of periodontal disease and also suggest
that tissue pH influences protease activity in situ.
PMID- 10776922
TI - The association of calprotectin level in gingival crevicular fluid with gingival
index and the activities of collagenase and aspartate aminotransferase in adult
periodontitis patients.
AB - BACKGROUND: Calprotectin, a major cytosol protein of leukocytes, exists in plasma
and other body fluids of healthy human subjects. Since the calprotectin
concentration rises markedly in some inflammatory diseases including rheumatoid
arthritis, this protein has been thought to be a marker of inflammatory disease.
Recently, we identified calprotectin in human dental calculus and gingival
crevicular fluid (GCF), and found that the calprotectin concentration in GCF from
patients with periodontitis was significantly higher than that in GCF from
healthy subjects. In the present study, the association of GCF calprotectin level
with GCF volume, gingival index (GI), and levels of biochemical markers including
collagenase and aspartate aminotransferase (AST) in GCF was investigated to
clarify the relationship between GCF calprotectin level and periodontal
inflammation. METHODS: Ninety GCF samples collected from periodontal pockets with
a probing depth of more than 4 mm in 54 patients with adult periodontitis were
used for these assays. The GCF volume was measured, and GI in each site was
recorded. The calprotectin content in GCF samples was determined by ELISA using a
specific antibody. The activity of collagenase or AST was measured by a
respective assay kit. RESULTS: The total amount of calprotectin and GCF volume
showed a highly significant correlation (r = 0.64, P <0.0001), whereas the
calprotectin concentration had no correlation with the GCF volume (r = 0.01, P=
0.924). The mean calprotectin concentration in GCF increased with the degree of
GI, and the concentration in individual samples was significantly correlated with
the GI score (r = 0.56, P<0.0001). Significant positive correlations were
observed in GCF calprotectin versus collagenase (r = 0.57, P <0.0001) and GCF
calprotectin versus AST levels (r = 0.40, P <0.005). CONCLUSIONS: From the
present results and our previous findings, it is shown that the GCF calprotectin
level significantly correlates not only with clinical indicators but also with
current biochemical marker levels and that calprotectin may be a useful marker
for periodontal inflammation.
PMID- 10776923
TI - Bactericidal activity of a monoclonal antibody against a recombinant 40-kDa outer
membrane protein of Porphyromonas gingivalis.
AB - BACKGROUND: We have cloned the gene for a 40-kDa outer membrane protein (40-kDa
OMP) from Porphyromonas gingivalis 381. The recombinant (r)40-kDa OMP has become
the subject of considerable interest because of its potential role in the
development of a vaccine useful for passive immunization. To develop such a
vaccine, it is essential to fully understand the functions of anti-r40-kDa OMP
antibody in the host defense against P. gingivalis. To that end, we developed a
panel of monoclonal antibodies by immunizing mice with purified r40-kDa OMP. The
objective of this study was to determine the bactericidal activity on P.
gingivalis by the IgG1 monoclonal antibody Pg-ompA2. METHODS: Bacterial growth
measurement, a complement-mediated anti-P. gingivalis assay based on
[3H]thymidine uptake, and a 14C-release assay were performed to test the
bactericidal activity of Pg-ompA2 to P. gingivalis. RESULTS: In the presence of
complement, Pg-ompA2 was lethal to P. gingivalis 381 as well as to the more
virulent P. gingivalis strains, including ATCC 53977 and W83. Using component
deficient complement, we determined that Pg-ompA2 killed P. gingivalis by
activating both the classical and alternative complement pathways. CONCLUSIONS:
Pg-ompA2 has an in vitro complement-mediated bactericidal activity to P.
gingivalis. Pg-ompA2 may contribute to the development of a local immunotherapy
that can be applied in the gingival crevice of a patient with P. gingivalis
related periodontitis, or be a vaccine candidate.
PMID- 10776924
TI - Herpesviruses and periodontopathic bacteria in Trisomy 21 periodontitis.
AB - BACKGROUND: Little is known about the etiology and pathogenesis of periodontal
disease in Trisomy 21 patients. This study determined the occurrence of
herpesviruses and putative periodontopathic bacteria in Trisomy 21 periodontitis.
METHODS: Nineteen Trisomy 21 patients (17 to 37 years of age) contributed
subgingival samples from molar and bicuspid teeth presenting interproximal
periodontitis lesions (probing depths, 5 to 8 mm) and from shallow periodontal
sites (probing depths, 1 to 3 mm). Samples were obtained at baseline, and at 1
and 4 weeks after subgingival debridement by means of hand instruments and
ultrasonic scalers. Epstein-Barr virus type 1 and 2 (EBV-1 and EBV-2), human
cytomegalovirus (HCMV), and herpes simplex virus (HSV) were identified by
sensitive and specific nested polymerase chain reaction. Putative
periodontopathic bacteria were identified by means of non-selective and selective
culture. RESULTS: Of 19 Trisomy 21 periodontitis lesions, 6 (32%) were positive
for EBV-1, 5 (26%) were positive for HCMV, 3 (16%) were positive for HSV, and 2
(11%) showed viral co-infection. Of 19 shallow periodontal sites, only one
revealed HCMV. Prevotella intermedia, Bacteroides forsythus, and Capnocytophaga
species were detected in higher proportions in deep than in shallow periodontal
pockets (P = 0.02). Subgingival debridement did not reduce genomic herpesvirus
presence but caused a decrease in proportions of Porphyromonas gingivalis and
Capnocytophaga species. CONCLUSIONS: Periodontal herpesvirus-bacteria
coinfections may play important roles in the pathogenesis of destructive
periodontal disease in Trisomy 21 patients. Herpesviruses may reduce the
periodontal defense and promote growth of subgingival bacteria capable of causing
periodontal breakdown.
PMID- 10776925
TI - Comparison of four methods of assessing root surface debridement.
AB - BACKGROUND: While there is great interest in measuring the efficacy of root
surface debridement, there is little consensus on how this might be best
achieved. The aim of this study was therefore to compare four different methods
of assessing root surface debridement in their ability to discriminate between
ultrasonically instrumented root surfaces and non-instrumented control surfaces.
METHODS: Single-session subgingival root debridement was performed by an
experienced operator on 30 teeth prior to their extraction. Following extraction,
efficacy of root surface debridement was measured by percentage of remaining
calculus, instrument efficiency, modified instrument efficiency, and percentage
apical plaque border. In addition, the effect of probing depth landmark (apical
plaque border versus connective tissue attachment) on outcomes was assessed.
RESULTS: The results indicated that percentage apical plaque border demonstrated
highly statistically significant differences between instrumented and control
surfaces (P= 0.02). No other assessment method was able to discriminate between
instrumented and non-instrumented surfaces, and this may be a function of the low
amount of root surface calculus in the experimental sample. In addition, choice
of probing depth landmark had a notable effect on the outcomes for instrument
efficiency and modified instrument efficiency. Ninety-five percent limits of
agreement of interexaminer reproducibility were found to be much higher than
intra-examiner measurement for all four methods of assessment. CONCLUSIONS:
Percentage apical plaque border appeared to be potentially more useful than other
methods for assessing the efficacy of debridement of periodontally involved root
surfaces, particularly for measuring instrument penetrability.
PMID- 10776926
TI - Changes in the periodontal status of patients undergoing bone marrow
transplantation.
AB - BACKGROUND: Patients receiving an HLA-matched bone marrow transplant (BMT) from a
relative or unrelated donor undergo a permanent alteration of their immune
system, followed by a prolonged period of immunodeficiency. This study aimed to
examine alterations in the periodontal status of patients over 6 months post-bone
marrow transplantation. METHODS: Thirty-seven patients scheduled for bone marrow
transplantation participated in this study. One calibrated examiner carried out
periodontal examinations (clinical and radiographic) immediately prior to and at
3 and 6 months after transplantation. All patients followed an intense oral care
program. Subgingival plaque samples were analyzed by enzyme-linked immunosorbent
assay (ELISA) for the presence of Porphyromonas gingivalis, Actinobacillus
actinomycetemcomitans, and Prevotella intermedia. Data were subjected to
statistical analyses to determine the relationships between the frequency
distribution of the radiographic and clinical variables over time. RESULTS: Gains
in clinical attachment level (CAL) of > or =2 mm at 4 or more sites from baseline
to 6 months post-BMT were noted in 9/16 patients (56%), while 6/16 (38%) patients
experienced a loss of CAL > or =2 mm at 4 or more sites in the same period. At a
site level, 4.8% of sites exhibited a gain in CAL > or =2 mm between baseline and
3 months post-BMT while 2.3% of sites showed a loss of CAL > or =2 mm in the same
period. From baseline to 6 months, a gain in CAL of > or =2 mm was recorded at
3.1% of sites, and 2.4% of sites experienced a loss of > or =2 mm. A significant
improvement in the gingival index occurred between all sequential time periods
when assessed at a site level. At a patient level, 11/18 (61%) patients showed a
significant change in gingival index between baseline and 3 months and 10/16
(63%) between baseline and 6 months. There was no significant relationship
between clinical changes and the prevalence of the periodontal pathogens at the
various time periods. CONCLUSIONS: An improvement in periodontal health was
recorded between baseline and 6 months post-transplantation. Most of the
improvement in periodontal status was noted in the first 3 months after BMT, with
a slight decline in periodontal health between 3 and 6 months post-transplant. No
significant alteration was noted in the prevalence of periodontal pathogens
during the study period.
PMID- 10776927
TI - The relationship between gingivitis and colonization by Porphyromonas gingivalis
and Actinobacillus actinomycetemcomitans in children.
AB - BACKGROUND: Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans are
closely associated with the onset and severity of adult periodontal disease.
However, little is known regarding the colonization by, and host antibody
response to, these microorganisms in children. METHODS: Plaque and sera were
obtained from 40 healthy children, 2 to 18 years old. Gingival health was
assessed by the periodontal disease index (PDI), papillary bleeding score (BS)
and the modified total papillary margin attachment index (M-PMA). P. gingivalis
and A. actinomycetemcomitans in plaque samples were detected by slot
immunoblotting (SIB). Serum antibody levels against these microorganisms were
evaluated using ELISA. RESULTS: More than 60% of the children had detectable
levels of P. gingivalis in their plaque. Those having detectable levels had more
gingival inflammation than those having none; however, these differences were
significant only in children over the age of 12 years (PDI, BS). In contrast,
while 75% of the children had detectable A. actinomycetemcomitans, there were
significant differences in gingival inflammation associated with colonization in
children from 3 to 7 years of age (PDI) and over 12 years of age (M-PMA). Serum
antibody levels to P. gingivalis were inversely correlated with gingival
inflammation in all age groups, while A. actinomycetemcomitans titers were
positively correlated with gingival inflammation only in the children over 12
years. No significant relationship between the presence of either A.
actinomycetemcomitans or P. gingivalis and antibodies to them was found.
CONCLUSIONS: Our findings show that P. gingivalis and A. actinomycetemcomitans
are readily detected as early as 3 years of age and that their presence is
associated with the onset and severity of gingivitis.
PMID- 10776928
TI - Tissue engineered bone formation using chitosan/tricalcium phosphate sponges.
AB - BACKGROUND: Chitosan is a biodegradable natural polymer that has been shown to
improve wound healing. This study aimed to develop chitosan/tricalcium phosphate
(TCP) sponges as tissue engineering scaffolds for bone formation by three
dimensional osteoblast culture. METHODS: The sponges were prepared by freeze
drying and cross-linking a mixture of chitosan solution with TCP. Fetal rat
calvarial osteoblastic cells were isolated, cultured, and seeded into the
sponges. The cell-sponge constructs were cultured for 56 days. Cell
proliferation, alkaline phosphatase (ALPase) activity, and calcium deposition in
the cell-sponge constructs were measured at 1, 7, 14, 28, and 56 days. Histologic
examination was performed with light microscopy and scanning electron microscopy.
RESULTS: Chitosan/TCP sponges supported the proliferation of osteoblastic cells
as well as their differentiation as indicated by high ALPase activities and
deposition of mineralized matrices by the cells. Light and scanning electron
microscopic examination indicated that seeded osteoblastic cells were well
attached to sponge matrices and proliferated in a multi-layer fashion. Small bone
like spicules were observed on the sponge matrix at 14 days. Seeded cells
appeared to be embedded in the newly formed tissue matrix, which is
characteristic of the osteoblast differentiation and their progression into
osteocytic cells. The amount of mineralized tissue formed in the sponge at 56
days was significant. CONCLUSIONS: These results suggest that the chitosan/TCP
sponge is a feasible tool as a scaffolding material to grow osteoblast in a three
dimensional structure for transplantation into a site for bone regeneration.
PMID- 10776929
TI - The bone regenerative effect of platelet-derived growth factor-BB delivered with
a chitosan/tricalcium phosphate sponge carrier.
AB - BACKGROUND: In order to achieve optimal effects, growth factors including
platelet-derived growth factor (PDGF) should be delivered with a biodegradable
carrier that will release therapeutic concentrations over a sufficient length of
time. The purpose of this study was to evaluate the bone regenerative effect of
PDGF-BB delivered with a chitosan/tricalcium phosphate (TCP) sponge carrier in a
rat calvarial defect model. METHODS: The PDGF-BB-loaded chitosan/TCP sponge
carrier was fabricated by freeze-drying a mixture of chitosan solution and TCP
powder and soaking in a PDGF-BB solution. The release kinetics of PDGF-BB loaded
onto the sponge were measured in vitro with 125I-labeled PDGF-BB. Chitosan/TCP
sponges with and without PDGF-BB were implanted into 8 mm calvarial defects in
rats. Rats were sacrificed at 2 and 4 weeks following implantation, and
histologic and histomorphometrical examinations were performed. RESULTS: In vitro
evaluation demonstrated that an effective therapeutic concentration of PDGF-BB
following a high initial burst release was maintained throughout the examination
period. In the histologic examination, the chitosan/TCP sponge carrier promoted
osseous healing of the rat calvarial defects as compared to controls. The
addition of PDGF-BB to the carrier further enhanced bone regeneration. Evidence
of the degraded sponge matrix was observed mingled within the newly formed bone
without connective tissue encapsulation. CONCLUSIONS: The results of this study
support the use of chitosan/TCP sponges as a delivery system for growth factors
and demonstrate that PDGF-BB loaded onto chitosan/TCP sponge carriers has an
osteogenic effect on bone regeneration in vivo.
PMID- 10776930
TI - Volatile components of cigarette smoke: effect of acrolein and acetaldehyde on
human gingival fibroblasts in vitro.
AB - BACKGROUND: Tobacco and some of its volatile and non-volatile components have
been found to affect many types of cells including gingival fibroblasts. Since
normal gingival fibroblast functioning is fundamental to the maintenance of the
periodontal connective tissue, as well as to wound healing, we examined the
effect of acrolein and acetaldehyde, volatile components of cigarette smoke, on
proliferation, attachment, and ultrastructure of human gingival fibroblasts
(HGFs) in culture. METHODS: Human gingival fibroblast (HGF) strains derived from
healthy individuals with non-inflamed gingiva were used in this study. The cells
were incubated in the presence of different concentrations of acrolein and
acetaldehyde. Cell attachment and proliferation were evaluated after incubation
for 3 hours and 5 days, respectively. In addition, the cells were examined with a
transmission electron microscope in order to evaluate their morphology. RESULTS:
The results show that acrolein and acetaldehyde produced dose-dependent
inhibition of HGF attachment and proliferation. The cytotoxic effect was,
however, reversible when both substances were removed, after 3 days, from the
medium. The main ultrastructural finding for the HGF cytoplasm was the presence
of vacuoles and lysosomal structures that became prominent with increasing
concentration of acrolein and acetaldehyde. CONCLUSIONS: Our experimental data
suggest that acrolein and acetaldehyde, volatile components of tobacco smoke, are
detrimental to HGF survival and consequently to the oral connective tissue.
According to our morpho-functional evidence, these findings corroborate clinical
and epidemiological investigations demonstrating smoke as a risk factor in the
development of periodontal disease.
PMID- 10776931
TI - Effect of smoking on periodontal health in molar teeth.
AB - BACKGROUND: It is generally accepted that the primary cause of periodontitis is
bacterial infection of long duration. In addition, there are several risk factors
that may increase the probability and severity of periodontitis. For example, an
increased breakdown of alveolar bone has been observed in smokers compared to
never-smokers. The objective of this study was to investigate the association
between cigarette smoking and periodontal health, in particular, furcation
involvement in molar teeth. METHODS: One hundred twenty (120) adult regular
dental patients, presenting with at least 20 teeth each, third molars excluded,
were evaluated. Sixty of the subjects consumed an average (+/- SD) of 16.8 +/-
3.8 cigarettes daily and had smoked for 21.4 +/- 5.7 years. The remaining
subjects presented a negative history of smoking. Periodontal conditions for the
molar teeth were recorded at the first and second mandibular molar buccal
furcation area. RESULTS: Oral hygiene standards and dental care habits did not
differ notably between smokers and never-smokers. Smokers exhibited significantly
fewer molar teeth than never-smokers (2.2 +/- 1.1 versus 3.0 +/- 0.8; P<0.01).
Also, smokers exhibited significantly advanced gingival recession, probing depth,
clinical attachment loss, furcation involvement, and tooth mobility compared to
never-smokers (P<0.01). CONCLUSIONS: The results of this study suggest that long
term cigarette smoking significantly worsens periodontal health including degree
and incidence of furcation involvement in molar teeth.
PMID- 10776932
TI - Effects of combined oral treatments with cyclosporine A and nifedipine or
diltiazem on drug-induced gingival overgrowth in rats.
AB - BACKGROUND: Cyclosporine A (CsA) and calcium channel blockers induce gingival
overgrowth in humans and animals. Recently, nifedipine and diltiazem have often
been used to control CsA-related hypertension in organ transplant patients. The
purpose of this study was to examine the effects of a combined oral treatment of
CsA and nifedipine or diltiazem on the severity of gingival overgrowth in rats.
METHODS: Fifteen-day-old Fischer rats were treated orally with single or combined
applications of CsA, nifedipine, and/or diltiazem for 40 days; and induced
gingival overgrowth, rat growth, and blood drug levels were compared among the
different experimental groups. The experiment consisted of 6 groups: one control
group (group A) and 5 test groups treated with CsA (group B), nifedipine (group
C), and diltiazem (group D), as well as those concurrently treated with CsA and
nifedipine (group E), and CsA and diltiazem (group F). Gingival overgrowth was
determined by measuring the depth of the gingival sulcus. RESULTS: The mandibular
buccal gingival sulcus depth of group A was 365 +/- 41.2 microm. Among the test
groups, the most remarkable gingival overgrowth was seen in group E (1,020 +/-
63.3 microm), followed by group F (895 +/- 43.8 microm), group B (870 +/- 48.3
microm), group C (525 +/- 116 microm), and then group D (505 +/- 83.2 microm).
Rat body weight gain was reduced significantly by oral CsA treatment. Neither
nifedipine nor diltiazem suppressed rat growth when used independently; however,
rat growth reduced by CsA was further suppressed by a combined use of diltiazem,
but not nifedipine. CsA blood levels were reduced by concurrent oral treatment
with nifedipine or diltiazem along with the blood levels of those calcium channel
blockers when treatment was in combination with CsA. CONCLUSIONS: These results
suggest that gingival overgrowth is induced in rats as a side effect of CsA,
nifedipine, or diltiazem, and the combined use of these drugs influences rat
growth, blood drug levels, and the severity of gingival overgrowth.
PMID- 10776933
TI - Actinobacillus actinomycetemcomitans in destructive periodontal disease. Three
year follow-up results.
AB - BACKGROUND: Convincing data exist that A. actinomycetemcomitans is an etiologic
agent of periodontal disease. The purpose of this longitudinal study was to
evaluate A. actinomycetemcomitans as a diagnostic indicator for periodontal
disease in treated and periodontally maintained patients. METHODS: Following
comprehensive mechanical/surgical and supportive amoxicillin plus metronidazole
therapy in 13 subjects with A. actinomycetemcomitans-associated destructive
periodontal disease, we monitored subgingival A. actinomycetemcomitans at 4
individual sites in each patient up to 3 years post-therapy. The periodontal
status was determined, and A. actinomycetemcomitans levels were quantitatively
enumerated on TSBV agar in CFU/ml. Six patients with a persistence of subgingival
A. actinomycetemcomitans at each reexamination within 3 years post-therapy were
selected to be at risk for minor periodontal treatment outcomes and further
recurrence of periodontal disease (test group). Seven subjects with a complete
suppression of A. actinomycetemcomitans at each post-therapy visit served as
controls. RESULTS: The periodontal parameters decreased from overall values of
6.39 mm (probing depth, PD) and 7.64 mm (clinical attachment level, CAL) at the
outset to 3.81 mm (PD) and 5.62 mm (CAL) 2 years post-therapy (Friedman, P< or
=0.05). At the 3-year reexamination, the PD/CAL scores increased to 4.03/5.78 mm.
Among the 6 individuals (46%) with persistence of subgingival A.
actinomycetemcomitans at the final 3-year visit (test group), periodontal status
yielded increased levels of 4.45 mm (PD) and 6.60 mm (CAL). The control subjects
(n = 7) revealed lower values of 3.67 mm (PD) and 5.09 mm (CAL). However, on a
patient level, during the 3-year observational trial, the periodontal status of
the 13 individuals was not statistically affected by subgingival infection with
A. actinomycetemcomitans. CONCLUSIONS: Although in advanced periodontal disease,
comprehensive mechanical and antimicrobial treatment is an appropriate regimen
for sustained improvement of periodontal health, long-term control of subgingival
infection with A. actinomycetemcomitans could not be achieved. In the maintenance
care of destructive periodontitis, the persistence of A. actinomycetemcomitans is
not a diagnostic parameter for periodontal disease.
PMID- 10776934
TI - Ante-dependence modeling in a longitudinal study of periodontal disease: the
effect of age, gender, and smoking status.
AB - BACKGROUND: It is generally accepted that periodontal disease progresses by a
series of bursts that are interspersed by periods of stability or even gain of
attachment. In order to analyze longitudinal data on a patient's disease
experience, it is necessary to use models which accommodate serial dependence.
Ante-dependence between the results of a series of periodontal examinations over
time can be modeled using a Markov chain. This model describes temporal changes
in patients' levels of disease in terms of transition probabilities, which allow
for both regression and progression of the disease. The aim of the present study
was to demonstrate the use of a Markov chain model to analyze data from a
longitudinal study investigating the progression of periodontal disease in an
adult population. METHODS: The study population consisted of 504 volunteers;
however, only 456 were included in the analysis because the remaining 48 subjects
did not give consecutive data. Subjects were examined at baseline, 6 months, and
1, 2, and 3 years. Probing depths (PD) were recorded using an automated probe.
Disease was defined as four or more sites with PD > or = 4 mm. Markov chain
modeling was used to determine the effect of age, gender, and smoking on the
natural progression and regression (healing) of periodontal disease. RESULTS:
Smoking and increasing age had no effect on the progression of disease in this
population, but did have a significant effect (P values < or = 0.05) in reducing
the regression of disease; i.e., their effect on disease appears to be inhibition
of the natural healing process. Gender had no significant effects. CONCLUSIONS:
These results demonstrate how ante-dependence modeling of longitudinal data can
reveal effects that may not be immediately apparent from the data, with smoking
and increasing age being seen to inhibit the healing process rather than promote
disease progression.
PMID- 10776935
TI - The importance of data presentation regarding gingival crevicular fluid
myeloperoxidase and elastase-like activity in periodontal disease and health
status.
AB - BACKGROUND: The enzymatic profile of gingival crevicular fluid (GCF) is being
analyzed with increasing interest, but related studies lack a general consensus
on most methodological points, including the appropriate mode of data
presentation. METHODS: GCF myeloperoxidase (MPO) and elastase-like activity (ELA)
levels were spectrophotometrically determined on a total of 60 subjects who were
divided into three equal subgroups as early-onset periodontitis (EOP), adult
periodontitis (AP), and healthy. GCF enzyme levels were calculated and evaluated
both as total enzyme activity and enzyme concentration. The correlations between
these GCF enzymes and clinical periodontal status were also analyzed. RESULTS:
With both modes of data presentation, the results regarding MPO activity were
consistent. When presented either as total MPO activity or MPO concentration, the
periodontally healthy group showed significantly lower MPO activity than the two
patient groups (P<0.05). However, two modes of data presentation did not match
when GCF ELA was concerned. When data were reported as total ELA, the healthy
group exhibited lower enzyme activity (0.02 +/- 0.001 U) than EOP (0.04 +/- 0.01
U) and AP (0.06 +/- 0.02 U) groups; but when reported as concentration, the
highest ELA levels were seen in the healthy group (221 +/- 31.53 nmol/min/ml),
followed by AP (98.63 +/- 23.03 nmol/min/ml) and EOP (70.49 +/- 12.02
nmol/min/ml) (P<0.05). A strong-positive and significant correlation existed
between GCF MPO and ELA. Correlations with clinical parameters were mostly
observed with total activities. CONCLUSIONS: The findings of the present study
confirm the relationship between GCF ELA and MPO activity and periodontal disease
and also support the functional relativity between the two enzymes. Furthermore,
based on these findings, it can be suggested that data presentation by use of
total activity seems to be more sensitive in both the reflection of the actual
enzymatic profile of GCF and also the existing clinical periodontal status. For
each GCF component, the validity of different modes of data presentation should
be considered.
PMID- 10776936
TI - The immune modulation of B-cell responses by Porphyromonas ginginvalis and
interleukin-10.
AB - BACKGROUND: Polyclonal B-cell activation induced by periodontopathic bacteria has
been cited as being important for elevated numbers of B cells, but the role of
bacteria in the pathogenesis of periodontal disease remains unknown. In this
study, we used an in vitro model to investigate the activation of immune cells by
the periodontopathic bacterium Porphyromonas gingivalis in healthy subjects.
METHODS: Peripheral blood mononuclear cells (PBMC) or purified subsets of
lymphocytes were stimulated with sonicated extracts of P. gingivalis for 24
hours. Cells were harvested and monitored for expression of CD69 by flow
cytometry. Cytokine production (IL-10, IL-12, and IL-15) in P. gingivalis
stimulated PBMC cultures was measured by ELISA. To identify IL-10 producer cells,
a cell depletion experiment was used and confirmed by the ability of the purified
cell population to produce IL-10. To evaluate the effect of P. gingivalis and IL
10, the proliferative response of purified B cells was assessed by [3H] thymidine
uptake. RESULTS: PBMC cultured with P. gingivalis led to a large number of
activated B and natural killer (NK) cells as monitored by CD69 expression. When
positively sorted cells were used, the bacterium itself could directly activate
only B cells but not NK cells, alphabeta, and gammadelta T cells. Measurement of
B-cell regulatory cytokine production in P. gingivalis-stimulated PBMC cultures
revealed a large amount of IL-10 but no detectable IL-12 or IL-15; the major
producing cells were monocytes, not B cells or alphabeta T cells. When IL-10 was
added to B cells in the presence of bacteria, significantly increased B-cell
proliferative responses were observed. CONCLUSIONS: These results suggest that P.
gingivalis, both directly and indirectly via macrophage IL-10, may play an
important role in polyclonal B-cell activation associated with periodontal
disease.
PMID- 10776937
TI - Experimental stress suppresses recruitment of macrophages but enhanced their P.
gingivalis LPS-stimulated secretion of nitric oxide.
AB - BACKGROUND: Epidemiological studies have suggested that stress can alter the
onset and progression of periodontal disease. However, the mechanisms involved
are not clear. The present study was designed to examine whether the functional
response of mouse macrophages stimulated by Porphyromonas gingivalis
lipopolysaccharide (LPS) is affected by experimental stress, and to investigate
the role of corticosterone (CS) in the stress-related effects. METHODS: Two
models of stress were used: emotional (isolation) and physical (cold). We
measured thioglycollate-induced macrophage recruitment in vivo, and LPS-induced
nitric oxide (NO) secretion by the macrophages in vitro. Two groups of mice were
exposed to the stress conditions: isolation or cold. A third group was injected
daily with CS, and a fourth group was used as a control (no stress). After 3 days
of stress conditions, thioglycollate was injected into the peritoneal cavity.
Four days later, peritoneal macrophages were isolated, counted, and cultured. The
secretion of NO by the cultured cells was evaluated with and without P.
gingivalis LPS stimulation. RESULTS: The number of cells in the peritoneal lavage
of stressed mice was significantly reduced in comparison to macrophages isolated
from non-stressed animals. The number of macrophages from CS-treated mice did not
differ from controls. NO secretion from unstimulated macrophages did not differ
between the stressed and control groups. Stimulation of the macrophages with P.
gingivalis LPS significantly enhanced NO secretion by macrophages from the
control and stressed animals, but not by the CS-treated group. NO levels secreted
by P. gingivalis-stimulated cells from the two stressed groups were significantly
higher than the levels secreted by controls, and the isolation group released
significantly higher levels than the cold group. Stimulation of the macrophages
with P. gingivalis LPS and interferon (IFN)-gamma resulted in enhanced NO
secretion in the 4 groups compared to LPS alone, with no significant differences
between the groups. CONCLUSIONS: The results suggest that experimental stress
modulates the response of macrophages to inflammatory stimulants, and that CS is
not the sole mediator involved. The presence of IFN-gamma in the culture may mask
the functional differences induced by stress. The stress-induced upregulation of
NO secretion might be involved in the accelerated periodontal destruction in
stressed subjects.
PMID- 10776938
TI - Expression of estrogen receptors in desquamative gingivitis.
AB - BACKGROUND: Most cases of chronic desquamative gingivitis (CDG) are shown by
direct immunofluorescence (DIF) to be immune mediated diseases. Some patients
present with similar clinical and microscopic findings as CDG but DIF staining is
negative. It has been suggested that those cases of CDG may be hormone (estrogen)
mediated and may be treated with estrogens with favorable results. METHODS:
Gingival tissue from 24 cases of CDG and one case of ordinary gingivitis were
studied for estrogen receptor (ER) expression using immunohistochemical
techniques. Twenty-four of the 25 cases were female. Using standard DIF analysis,
11 of the CDG cases were diagnosed as benign mucous membrane pemphigoid, 10 as
lichen planus or lichenoid mucositis (LP), and one as pemphigus. The remaining 3
cases were not diagnostic for a specific disorder (idiopathic). Five of the
females had a history of estrogen substitute therapy. RESULTS: Twenty-two of 23
female CDG cases were positive for ER, although the degree of staining varied. A
32-year-old female with ordinary gingivitis, whose gingivitis varied with her
menstrual cycle, did not stain for ER. A 50-year-old male and a 76-year-old
female, both with gingival LP, also had negative staining for ER. CONCLUSIONS:
There appears to be no correlation between diagnosed diseases (immunological
versus idiopathic) and expression of ER in CDG gingiva. ER expression in the
gingiva is probably not related to the presence or absence of estrogen
supplementation. The results of this study do not support the use of estrogen in
the treatment of idiopathic CDG.
PMID- 10776940
TI - Radiographic and digital imaging in periodontal practice.
AB - This review defines terms such as accuracy, validity, and reliability, which are
used to describe the quality of methods for taking x-rays and for analyzing
digital images. Values for these parameters are described for techniques of
taking standardized x-rays such as ear-rod fixation and fixation by use of teeth
with a dental impression. In addition, values are given for linear measurements
on digitized images and for quantitative image subtraction. Differences are
addressed between quantitative subtraction with a reference ramp and relative
subtraction using the computer-assisted densitometric image analysis (CADIA)
system. The relationship between radiographic bone height and clinical attachment
level is also discussed. Finally, present and future use in the periodontal
office of linear radiographic measurements on digital images and digital
subtraction is discussed.
PMID- 10776939
TI - Ridge augmentation following implantation of recombinant human bone morphogenetic
protein-2 in the dog.
AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an
absorbable collagen sponge (ACS) carrier induces bone for reconstruction of
skeletal defects. The rhBMP-2/ACS implant is prepared by administering a rhBMP-2
solution to dry ACS. Once prepared, rhBMP-2/ACS forms a moldable, cohesive, and
adhesive implant. However, rhBMP-2/ACS does not have sufficient structural
strength to withstand soft tissue compression at specific anatomic sites. To more
fully understand the mechanisms that affect bone induction by rhBMP-2/ACS in the
presence of soft tissue compression, it would be useful to have a preclinical
model that appropriately simulates such circumstances in patients. This pilot
study evaluated one such potential model. METHODS: Bilateral, Class III alveolar
defects were surgically produced in 4 adult mongrel dogs following extraction of
the mandibular fourth premolars and reduction of the alveolar ridge. After an 8
week healing interval, mucoperiosteal flaps were elevated and rhBMP-2/ACS or
rhBMP-2/ACS combined with hydroxyapatite (HA) was implanted into contralateral
defects. The animals were euthanized at 12 weeks post-augmentation and block
biopsies processed for histologic evaluation. RESULTS: Limited augmentation
followed implantation of rhBMP-2/ACS (0.7 +/- 0.6 mm). In contrast, sites
receiving rhBMP-2/ACS/HA exhibited clinically relevant ridge augmentation (5.5 +/
1.6 mm). Defects implanted with rhBMP-2/ACS exhibited dense trabeculation within
the corpus of the reduced alveolar process. The cortices appeared intact without
evidence of expansion into the defect area. Three defects receiving rhBMP
2/ACS/HA exhibited sparse bone trabeculae amidst HA particles, fibrovascular
tissue, and marrow. Commonly, the HA particles were encapsulated by fibrous
tissue. Some particles were observed in contact with bone. CONCLUSIONS: The
results suggests that rhBMP-2/ACS has limited effect alone in this augmentation
model of Class III alveolar ridge defects. Inclusion of HA into the rhBMP-2
construct results in clinically relevant augmentation, however, the quality of
bone is compromised.
PMID- 10776941
TI - Non-Hodgkin's lymphoma and periodontitis. A case report.
AB - BACKGROUND: We describe an unusual case of extra-nodal non-Hodgkin's lymphoma
that developed in the maxillae associated with localized severe periodontitis in
a 64-year-old Caucasian male. The lymphoma was diagnosed less than 2 years
following routine periodontal surgery and 8 weeks after the extraction of
hopeless teeth in the associated area. METHODS: Two months following the
extractions, the patient experienced pain and swelling in the maxillary right
edentulous area mimicking an abscess, and reported for emergency care. An
expansile lesion measuring 2.0 x 2.5 cm in diameter was noted on radiographic
examination to extend into the right maxillary sinus. A definitive biopsy
diagnosis of high-grade, small, non-cleaved, diffuse non-Hodgkin's lymphoma of
the right posterior maxillae was established. The patient was subsequently
treated by a combination of radiation, chemotherapy, and bone marrow
transplantation. RESULTS: The maxillary tissues healed uneventfully, and the
patient has been closely observed for approximately 5 years without symptoms or
recurrence of the lymphoma. CONCLUSIONS: This case highlights the need for
careful debridement of extraction sockets associated with severe periodontitis
and argues for the routine submission of extracted teeth with adjacent soft
tissue for microscopic analysis, to assist in the early diagnosis of potentially
life-threatening malignancies.
PMID- 10776942
TI - Therapy for a patient with oligodontia: case report.
AB - Oligodontia, the congenital absence of numerous teeth, presents many problems for
both patient and therapist. Chief among these is the sequence and timing of
orthodontic therapy, implant placement, and restorative dentistry. The absence of
teeth can pose not only functional but psychosocial problems for young people.
This report details a young woman who was diagnosed with oligodontia at age 9,
treated using a multidisciplinary approach, and followed for 12 years.
PMID- 10776944
TI - Nutritional aspects of chronic liver disease and liver transplantation in
children.
PMID- 10776943
TI - Foreign body granuloma following placement of hard tissue replacement material: a
case report.
AB - The placement of grafting material in extraction sites for ridge preservation is
an increasingly common practice among clinicians. This is a case report of a
patient presenting with a symptomatic, foreign body granuloma following the
placement of hard tissue replacement (HTR) in extraction sockets. The surgical
specimen revealed numerous histiocytes and foreign body type giant cells. The
grafting material was surgically removed and the patient's symptoms were
alleviated. Although biocompatibility of HTR has previously been shown, specific
applications may be contraindicated or some patients may exhibit sensitivity to
this material.
PMID- 10776945
TI - Liver disease does not affect lipolysis as measured with the 13C-mixed
triacylglycerol breath test in children with cystic fibrosis.
AB - BACKGROUND: Liver disease associated with cystic fibrosis may not only limit the
solubilisation and absorption of the products of fat digestion, but also may
depress the activity of pancreatic lipase. The purpose of this study was to
measure the effect of liver disease on triacylglycerol lipolysis using the 13C
mixed triacylglycerol breath test. METHODS: Forty children with cystic fibrosis
took 13C-mixed triacylglycerol with a standard breakfast and the child's normal
pancreatic enzyme replacement therapy. Breath samples were collected before and
every 30 minutes after ingestion for 6 hours. The cumulative percentage dose of
13C recovered at 6 hours was calculated from sequential measurements of 13C
enrichment of breath CO2, measured by isotope ratio mass spectrometry. Liver
abnormalities and portal hypertension were defined by ultrasound scan and
clinical examination. RESULTS: Twenty-four children had liver abnormalities,
including 5 with portal hypertension. No difference was found between cumulative
percentage dose of 13C recovered at 6 hours in 16 children with no liver
abnormality (mean, 21.4%+/-11.1%), 19 children with liver abnormalities (22.2%+/
10.0%) and 5 children with portal hypertension (20.9%+/-7.1%). CONCLUSION:
Intestinal lipolysis is not reduced in cystic fibrosis liver disease when
measured using the 13C mixed triacylglycerol breath test. These findings affirm
the test's use as an indirect measure of fat digestion that is not affected by
inadequate intraluminal bile salts or liver disease.
PMID- 10776946
TI - Thickening infant formula with digestible and indigestible carbohydrate:
availability of calcium, iron, and zinc in vitro.
AB - BACKGROUND: Regurgitation is common in infants and is usually due to
gastroesophageal reflux. Often parental reassurance and dietary management by
feeding thickened formulas are the only therapeutic steps necessary. Adding
fibers may interfere with the absorption of micronutrients. METHODS: A continuous
flow dialysis in vitro method with a preliminary intraluminal digestive phase,
modified to simulate the conditions of infants less than 6 months of age and
children from 6 months of age on, was used to study the availability of calcium,
iron, and zinc from thickened and nonthickened first-and second-age infant
formulas. Pooled mature human milk was used as the reference standard. The
elemental content of the samples and dialysate fractions of calcium, iron, and
zinc after digestion was determined by atomic absorption spectrometry. RESULTS:
In human milk, calcium, iron, and zinc were highly available for absorptive
processes. Availability of calcium, iron, and zinc from nonthickened first- and
second-age infant formulas tends to be significantly better than in the
corresponding products thickened with locust bean gum. Thickening infant formulas
with pregelatinized rice starch, however, does not affect the availability of
calcium, iron, and zinc. CONCLUSIONS: It appears that human milk provides optimal
conditions for the availability of calcium, iron, and zinc. Availability of
calcium, iron, and zinc seems to lower when infant formulas are thickened with
indigestible carbohydrates, whereas it does not by adding digestible
carbohydrates.
PMID- 10776947
TI - Antibody reactivity against human and guinea pig tissue transglutaminase in
children with celiac disease.
AB - BACKGROUND: Highly discriminatory markers for celiac disease are needed to
identify children with early mucosal lesions. The purposes of this study were to
evaluate the clinical potential of circulating anti-tissue transglutaminase (tTG)
immunoglobulin (Ig)A antibodies in the diagnosis of childhood celiac disease and
to investigate the extent of autoreactivity of these antibodies. METHODS:
Included in this retrospective study were samples from 22 children with biopsy
verified celiac disease, 23 control subjects with disease, and 22 healthy control
subjects without any known gastrointestinal or inflammatory disorders. An enzyme
linked immunosorbent assay (ELISA) was used to measure the serum levels of IgA
antibodies specific for human and guinea pig tTGs. All samples were also analyzed
for antibodies to gliadin and endomysium (EMA). RESULTS: The concentrations of
IgA specific for human and guinea pig tTGs correlated with the small intestinal
villous structure and the serum levels of IgA EMA. The tTG ELISAs exhibited a
high specificity and sensitivity for detection of untreated celiac disease. The
human erythrocyte IgA tTG ELISA had the highest sensitivity (100%) and a
specificity of 98%. The IgA EMA method had a sensitivity of 95% and the highest
specificity (100%) of all tests. CONCLUSIONS: Our results provide additional
support to the concept that anti-tTG IgA antibodies can be used as a highly
discriminatory serologic marker for celiac disease and that measurements of these
autoreactive antibodies may in the future be used as an alternative to the EMA
test.
PMID- 10776948
TI - Prevalence of hepatitis G virus in healthy children in liver disease, and human
immunodeficiency virus-1 infection: response to interferon.
AB - BACKGROUND: A new virus of the Flaviviridae family, the hepatitis G virus
(HGV/HGBV-C), has been identified recently. The purpose of this study was to
determine the prevalence of HGV infection in healthy children, in patients with
liver disease, and in human immunodeficiency virus (HIV)-1-infected patients. The
role of HGV in the clinical course of chronic HCV, the response to interferon
alpha2b, and the possible implications of intravenous gamma-globulin in the
transmission of the virus were also evaluated. METHODS: Fifty healthy children,
66 patients with a variety of liver diseases, 19 patients with acquired immune
deficiency syndrome (AIDS), and various batches of commercial intravenous
immunoglobulins were investigated. Viral HGV RNA (5'NCR-NS5) and anti-HGV
envelope protein E2 were assayed. RESULTS: The prevalence of HGV infection was 6%
in the healthy children and 42% in the liver disease group. Viremia and anti-E2
were found in 11% and 79% of patients with AIDS. Four (27%) of 15 patients with
chronic HCV, receiving treatment with interferon, were coinfected by HGV and
became HGV-RNA negative during therapy. One year after the end of interferon
therapy, three of them were again HGV RNA positive. CONCLUSIONS: The prevalence
of HGV infection is high in healthy children higher in children affected with
liver disease, but its potential pathologic implication is questionable, and
further studies are warranted. Hepatitis G virus is sensitive to interferon
therapy, although the infection often recurs after discontinuation of treatment.
PMID- 10776949
TI - Screening by anti-endomysium antibody for celiac disease in diabetic children and
adolescents in Austria.
AB - BACKGROUND: Unrecognized celiac disease (CD) may be found in a substantial
proportion of patients with type I diabetes mellitus. METHODS: A cohort of 403
Austrian children and adolescents with type I diabetes mellitus (210 males and
193 females; age range, 1-22 years) was screened for celiac disease using the IgA
anti-endomysium antibody test (EMA) and the immunoglobulin (Ig)G anti-gliadin
(AGA-IgG) and IgA anti-gliadin (AGA-IgA) antibody test. RESULTS: Twelve patients'
sera (2.98%) yielded positive EMA results and two patients' sera (0.49%) with IgA
deficiency had high AGA-IgG values. All but one of these patients underwent
intestinal biopsy. Six (1.49%) had clear histologic evidence of CD (flat mucosa),
whereas three (0.74%) showed minor histologic changes (increase in
intraepithelial lymphocytes) and four (0.99%), including the EMA-negative
patients with IgA deficiency, had a normal mucosa. When the cases with silent and
potential CD were combined, the overall prevalence in the current cohort was
2.98%. There was no difference in the hemoglobin (Hb)A1c level between antibody
positive and -negative patients, and subsequent gluten-free diet did not change
this metabolic parameter. CONCLUSION: The prevalence of clinically unrecognized
CD, found by EMA screening, is much higher in Austrian children with diabetes
than in a comparable population without diabetes. The prevalence of CD in
diabetic children in Austria is distinctly lower, however, than in several other
countries.
PMID- 10776950
TI - Gastric metaplasia: a frequently overlooked feature of duodenal biopsy specimens
in untreated celiac disease.
AB - BACKGROUND: Duodenal gastric metaplasia is rarely reported in untreated celiac
disease, although it is seen in 60% to 100% of duodenal biopsy specimens in
nonceliac patients with histologic duodenitis. The low incidence could represent
underreporting, a decreased incidence in pediatric patients generally, or the
more distal sampling site that is customary for most biopsy specimens that are
obtained to diagnose celiac disease. It could also be a unique feature of the
inflammatory reaction that characterizes this disease. The purpose of this study
was to examine the incidence of gastric metaplasia in duodenal specimens from
children with untreated celiac disease with special reference to patient age and
biopsy site. METHOD: Formalin-fixed paraffin-embedded specimens of duodenal
mucosa were selected from the pathology department's archival material. Sections
were either stained histochemically or by immunochemical methods, according to an
antigen-retrieval protocol. Forty-four duodenal specimens from untreated patients
with celiac disease (n = 22) and control subjects of similar age with normal
histology (n = 22) were examined. Ten of each were obtained during upper
endoscopy from the proximal duodenum (proximal site) and 12 of each by Crosby
capsule near the ligament of Treitz (distal site). RESULTS: All specimens from
patients with celiac disease exhibited marked villous atrophy. None had been
noted to have gastric metaplasia during routine examination of sections stained
by hematoxylin and eosin. Fifteen (68%) of 22 of the celiac specimens and 2 of 22
(9%) control specimens contained gastric metaplasia, identified as patches of
gastric-type cells containing MUC5AC (gastric mucin), pS2 (gastric trefoil
factor) and neutral (periodic acid-Schiff-positive) mucin. Five of the seven
celiac specimens that had no metaplasia showed increased numbers of goblet cells
expressing gastric markers. The incidence of gastric metaplasia was not different
for endoscopic (70%) or capsule (67%) specimens. Sixty-eight percent (7/11) of
patients aged less than 3 years had gastric metaplasia. CONCLUSION: The presence
of gastric metaplasia has been previously underreported in celiac disease
specimens. Detection would be improved by the routine use of period acid-Schiff/
alcian blue staining. The incidence of gastric metaplasia in celiac disease is
not significantly influenced by biopsy site or age at time of the biopsy.
PMID- 10776951
TI - Complications of removing percutaneous endoscopic gastrostomy tubes in children.
AB - BACKGROUND: Little information has been reported regarding the frequency and type
of complications arising from removal of percutaneous endoscopic gastrostomy
(PEG) tubes in children. METHODS: The records of 397 patients who had PEG tubes
placed from 1993 through 1998 were reviewed for complications after removal. Data
collected included length of time the tube was in place, age of the patient at
insertion, type of tube removed, and patient diagnosis. RESULTS: Fifty-four
children had the PEG tube removed by traction or endoscopy. The only complication
was persistent leaking through a gastrocutaneous fistula in 13 patients (24%).
Leaking ceased in 6 children coincident with H2-antagonist therapy and silver
nitrate cautery, and surgical closure of the fistula was required in 7 patients.
Comparison of these 7 children with those who did not require surgery (n = 47)
showed a longer duration of tube placement (mean +/- SE of 20.6+/-3.6 months,
range 11-31 months vs. 11.1+/-1.3 months, range 1-35 months; P<0.05). Further
analysis showed no child with a PEG tube removed before 11 months (n = 23) after
insertion required surgery, whereas 7 (23%) of 31 children with a PEG tube
removed after 11 or more months required surgery. Age at insertion, type of
feeding device removed, and patient diagnoses were not different between the two
groups. CONCLUSIONS: These data indicate that persistent leaking necessitating
surgical closure of a gastrocutaneous fistula does not occur in children with a
PEG tube removed within 11 months of insertion. In contrast, 23% of children with
a PEG tube removed 11 or more months after insertion require surgery. In patients
identified as candidates for tube removal, this time frame may be important in
clinical decision making.
PMID- 10776952
TI - Feeding tolerance in premature infants fed fortified human milk.
AB - BACKGROUND: To evaluate feeding tolerance in premature infants immediately after
the addition of human milk fortifier (HMF) to their expressed human milk diet.
METHODS: Data on milk intake, feeding tolerance, and related assessments and
growth milestones from a prospective study of feeding strategies in premature
infants were analyzed. The database was searched for the first day HMF was added
to the feeding of infants receiving human milk exclusively. The following
assessments were tabulated for the 5 days before and the 5 days after the
addition of HMF: milk intake, the number of episodes of abdominal distension,
gastric residual volume (GRV) more than 2 ml/kg and more than 50% of the volume
fed in the prior 3 hours. bile-stained gastric residual, emesis or regurgitation,
blood in the stool, the number of abdominal radiographs, the number of episodes
of apnea and bradycardia, changes in findings in the clinical examination, and
the number of hours feeding was withheld. The time to achieve full tube feeding,
complete oral feeding, and hospital discharge were recorded. RESULTS: Seventy-six
exclusively human milk-fed premature infants (birth weight, 1065+/-18 g;
gestational age, 27+/-0.1 weeks; mean +/- SEM) who received HMF beginning 22+/
0.8 days of age were evaluated. There were significant increases in milk intake
and in the number of episodes of GRV more than 2 ml/kg and emesis after the
addition of HMF. There were no differences in the number of hours feeding was
withheld or any other assessment after the addition of HMF. Infants with
increases in GRV more than 2 ml/kg and/or emesis after the addition of HMF were
not more likely to be delayed in the time to achieve full tube feeding, complete
oral feeding, or hospital discharge than infants who did not experience these
events. CONCLUSION: These data suggest that, when all feeding and related
assessments and the time to achieve important growth milestones are considered,
the addition of HMF does not adversely affect the outcome of the premature
infant.
PMID- 10776953
TI - Dyspepsia in children and adolescents: a prospective study.
AB - BACKGROUND: Dyspepsia is poorly characterized in the pediatric population. The
goal of the current study was to describe the clinical constellation and natural
history of dyspepsia in children and adolescents seen in a pediatric
gastroenterology practice. METHODS: A standardized questionnaire was administered
by a pediatric gastroenterologist to all subjects 5 or more years of age (and
their parents or guardians) treated in a referral pediatric gastroenterology
practice for 1 month or more of abdominal pain or discomfort, nausea, or
vomiting. Subjects with dyspepsia and dyspepsia subtypes (ulcer-like, dysmotility
like) were identified by using previously defined adult criteria. Evaluation and
treatment were performed at the discretion of the attending pediatric
gastroenterologist. RESULTS: During a 1-year period, 257 patients were screened
with 127 subjects fulfilling criteria for dyspepsia (59% girls, 85% white; median
age, 11.7 years; median duration of symptoms, 8 months). Symptoms were ulcer-like
in 26% and dysmotility-like (nausea predominance) in 15% of subjects. In those
with dyspepsia, irritable bowel syndrome and gastroesophageal reflux were noted
in 24% and 43%, respectively. Esophagogastroduodenoscopy and biopsy were
performed in 56 subjects with 21 (38%) having mucosal inflammation (Helicobacter
pylori in 5). The remaining 35 subjects (62%) were considered to have functional
dyspepsia. Duration of symptoms less than 1 year and vomiting were risk factors
for mucosal inflammation. Follow-up at 6 months to 2 years revealed 70% of
subjects were either asymptomatic or much improved regardless of the cause of
dyspepsia. CONCLUSION: Most children and adolescents with dyspepsia do not have
serious disease. In our referral population H. pylori infection was unusual, and
no peptic ulceration was found. Most subjects with functional dyspepsia have
improvement of symptoms over time.
PMID- 10776954
TI - Portosystemic shunting in children during the era of endoscopic therapy: improved
postoperative growth parameters.
AB - BACKGROUND: Surgical portosystemic shunting has been performed less frequently in
recent years. In this retrospective study, recent outcomes of portosystemic
shunting in children are described, to evaluate its role in the era of endoscopic
therapy. METHODS: Retrospective chart review of children who underwent surgical
portosystemic shunt procedures between October 1994 and October 1997. RESULTS:
Twelve children (age range, 1-16 years) underwent shunting procedures. The causes
of portal hypertension were extrahepatic portal vein thrombosis (n = 6),
congenital hepatic fibrosis (n = 2), hepatic cirrhosis (n = 2), and other (n =
2). None of the patients were immediate candidates for liver transplantation.
Types of shunt included: distal splenorenal (n = 10), portocaval (n = 1), and
other (n = 1). Median follow-up was 35 months (range, 24-48 months). All patients
are currently alive and well with patent shunts. The mean hospital stay was 8
days. Three patients required readmission for further interventions because of
shunt stenosis in two and small bowel obstruction in the other. Mild
portosystemic encephalopathy was seen in one child with pre-existing
neurobehavioral disturbance. Excluding a patient who underwent placement of a
portosystemic shunt for a complication of liver transplantation, mean weight-for
age z score in nine prepubertal patients improved from -1.16 SD to +0.15 SD (P =
0.023), and mean height-for-age z score from -1.23 SD to 0.00 SD (P = 0.048) by 2
years after surgery. CONCLUSIONS: Surgical portosystemic shunting is a safe and
effective method for the management of portal hypertension in childhood. Patients
show significant improvements in growth parameters after the procedure. Surgical
portosystemic shunting should be actively considered in selected children with
portal hypertension.
PMID- 10776955
TI - Clinical quiz. Chilaiditi's sign.
PMID- 10776956
TI - Seroprevalence of Helicobacter pylori infection in cystic fibrosis and its cross
reactivity with anti-pseudomonas antibodies.
AB - BACKGROUND: The prevalence of Helicobacter pylori infection and its role in
gastroduodenal disease in cystic fibrosis (CF) are controversial. Additionally,
serologic determination of infection in this population may be inaccurate because
of cross-reactivity with other bacterial species. The seroprevalence of H. pylori
in a cohort of patients with CF and its cross-reactivity with Pseudomonas
antibodies were investigated. METHODS: A research enzyme-linked immunosorbent
assay (ELISA), and three commercial serologic assays (PyloriStat; BioWhittaker,
Walkersville, MD, U.S.A.; Flexsure; SmithKline Diagnostics, Inc., San Jose, CA,
U.S.A.; and HM-CAP; EPI, Stony Brook, NY, U.S.A.) at three independent
laboratories determined the seroprevalence of anti-H. pylori IgG antibodies in 70
patients with CF. Cross-reactivity between solid-phase H. pylori antigens and
Pseudomonas antibodies was ascertained by a competitive inhibition assay,
preadsorbing sera of patients with CF with whole cell proteins from different
Pseudomonas species, and serum reanalysis by each assay. Western blot analysis
before and after adsorption was performed to identify potential cross-reactive
antigens. RESULTS: The research ELISA, Flexsure, Pyloristat, and HM-CAP initially
showed H. pylori seropositivity of 47%, 28%, 24%, and 37%, respectively.
Postadsorption seropositivity declined to 8%, 0%, 0%, and 15%, respectively. All
patients with research ELISA true-positive results were confirmed endoscopically
to have H. pylori infection. Western blot analysis showed a 31-kDa H. pylori
protein with antigenic epitopes common to both bacterial species. CONCLUSIONS:
Cross-reactivity between solid-phase H. pylori antigens and anti-Pseudomonas
antibodies occurs in patients with CF. A high index of suspicion should be
assumed in evaluating results of serologic H. pylori tests in this population.
Preadsorption of CF sera with Pseudomonas proteins should be used in serologic
testing.
PMID- 10776957
TI - Spontaneous bowel perforation in infants and young children: a clinicopathologic
analysis of pathogenesis.
AB - BACKGROUND: In children beyond the neonatal stage, spontaneous bowel perforation
with no specific cause is rare. It has attracted little notice and does not fit
into any established clinical category. This often results in treatment delays.
To determine the underlying pathogenesis, a clinicopathologic analysis of this
group of patients was performed. METHODS: From 1984 through 1997, 15 previously
healthy children (10 boys and 5 girls) with bowel perforations were enrolled in
this study. Children in whom the specific cause was established were excluded.
The ages of the patients ranged from 3 months to 5 years, 5 months (average age:
2 years, 4 months). Data on clinical course, surgical and pathologic findings,
and outcomes were analyzed. RESULTS: All the patients had high fever and acute,
watery diarrhea with clinical dehydration. Abdominal distension developed and
bowel perforation ensued 5 to 30 days after the onset of diarrhea. In all cases,
the perforation consisted of either an isolated patch of bowel (n = 8) or patchy
lesions in a segment (n = 7), which was confined to one of the following three
anatomic watershed areas: the splenic flexure (n = 7); the lower sigmoid (n = 3);
and the ileocecal region (n = 5). One patient died, and three had major sequelae
including intra-abdominal abscess, adhesion ileus, and peristomal fistula.
Specimens from 13 patients were submitted for histopathologic evaluation. All
specimens had acute suppurative inflammation diffusely around the perforation
site. Seven had areas of coagulation necrosis of the muscularis propria,
especially in the inner circular muscle layer. CONCLUSION: In acute diarrheal
diseases, dehydration may cause bowel ischemia and lead to perforation.
Physicians should be alert to the possibility of this abdominal catastrophe when
progressive abdominal distension followed by acute diarrheal episodes occurs in
children.
PMID- 10776958
TI - Vomiting-induced hematemesis in children: Mallory-Weiss tear or prolapse
gastropathy?
PMID- 10776959
TI - Efficacy of octreotide in children with chronic gastrointestinal bleeding.
PMID- 10776960
TI - Familial colonic varices.
PMID- 10776961
TI - Recurrent perianastomotic ileo/jejuno-colic ulceration.
PMID- 10776962
TI - An uncommon and often overlooked cause of failure to thrive: diencephalic
syndrome.
PMID- 10776963
TI - Prolapse gastropathy in the pediatric patient.
PMID- 10776965
TI - Study of two ectopeptidases in the susceptibility to celiac disease: two newly
identified polymorphisms of dipeptidylpeptidase IV.
PMID- 10776964
TI - Infantile colonic Crohn's disease: a report of four cases in one family.
PMID- 10776966
TI - Failure to imbibe in otherwise normal infants.
PMID- 10776967
TI - Pseudomembranous viral colitis.
PMID- 10776968
TI - Analysis of autopsy evaluations of ovarian cancer patients treated at the
National Cancer Institute, 1972-1988.
AB - Between 1972 and 1988, more than 500 women were treated for ovarian cancer at the
National Cancer Institute in Bethesda, Maryland on approved experimental
treatment protocols. Of these, 73 underwent autopsy evaluation on the National
Cancer Institute campus. We have analyzed the autopsy reports of those
individuals to determine the patterns of disease spread at death. By comparison
with the literature, the demographics of the cohort did not differ from
previously published reports, other than the extent of chemotherapy received
antemortem. Median survival of the cohort was 15.6 months (range, 1.7-108.3
months), and median age at diagnosis was 55 years (range, 24-74 years). The
median number of treatments regimens received was two (range, 1-6). The pattern
of disease spread at autopsy was different from that in previously published work
in that there was a higher proportion of patients with disease found in liver
parenchyma, lung pleura, and the pericardium. Patients who received cisplatin as
part of their initial treatment regimen had a higher incidence of metastases to
the adrenal glands, thoracic nodes, bladder, and liver parenchyma, which was not
explained by differences in survival. Median survival for patients who received
cisplatin as part of their initial therapy was 15.6 months, compared with a
median of 15.4 months for patients who did not. These data suggest a changing
pattern of disease spread in patients with ovarian cancer receiving aggressive
chemotherapy. This may be caused by some effect of platinum-based therapy on the
metastatic potential of the tumor.
PMID- 10776969
TI - Phase I study of vinorelbine by 96-hour infusion in advanced metastatic breast
cancer.
AB - The purpose of this study was to evaluate the maximum tolerated dose and the
toxicity profile of vinorelbine administered by continuous infusion for 96 hours
to patients who had received prior chemotherapy for metastatic breast cancer.
Forty-three patients with metastatic breast cancer were treated with vinorelbine
8 mg intravenously for 10 minutes (day 1) followed by continuous infusion of
vinorelbine for 96 hours. Treatments were repeated every 3 weeks. Eighty-eight
percent of the patients had had two or more prior chemotherapeutic regimens: 91%
had prior doxorubicin therapy and 77% had prior paclitaxel therapy. All 43
patients were evaluable for toxicity. The median age was 49 years. All patients
had a performance status less than or equal to 2 and a life expectancy more than
12 weeks. Eight dose levels were evaluated, and a total of 182 cycles were given.
National Cancer Institute grade III or IV granulocytopenia was observed in 64
(35%) cycles, neutropenic fever in 27 (15%) cycles, fatigue (National Cancer
Institute grade III or IV) in 18 (10%) cycles, and hand-foot syndrome in 8 (4%)
cycles. In 17 (9%) cycles, patients were hospitalized. The maximum tolerated dose
of this regimen was determined to be vinorelbine 8 mg intravenously for 10
minutes (day 1) followed by continuous vinorelbine infusion 11 mg/m2 for 96
hours. The dose-limiting toxicity was neutropenic fever and stomatitis.
PMID- 10776970
TI - Adjuvant sequential chemotherapy with doxorubicin plus cyclophosphamide,
methotrexate, and fluorouracil (ACMF) with concurrent radiotherapy in resectable
advanced breast cancer.
AB - Doxorubicin (Adriamycin) is an anthracycline effective in breast cancer. Despite
a worldwide acceptance of Adriamycin in the adjuvant chemotherapy to maximize the
survival benefit in the higher risk patients with breast cancer with promising
results, oncologists in general do not favorably consider anthracyclines in the
adjuvant treatment setting because of concern about the acute and chronic drug
related toxicity. For high-risk patients with breast cancer with more than three
positive axillary lymph nodes, this series adopted a modified sequential regimen
of ACMF first with Adriamycin (A) as a single agent in 3-weekly administration
for three courses, and then a combination of cyclophosphamide, methotrexate,
fluorouracil (CMF) every 3 to 4 weeks for six courses given in an outpatient
setting concurrent with radiation therapy as an adjuvant treatment. A total of 56
patients underwent modified radical mastectomy and 3 others breast conservation
surgery for their invasive breast cancer. Forty-seven (84%) patients completed
the intended adjuvant treatment and 1 patient died of infection from treatment
related neutropenia. As a whole, the 3-year overall survival and disease-free
survival rates of 56 patients analyzed were 82.3% and 64.4%, respectively. In
this high-risk group, patients with four to nine positive nodes showed a slightly
better trend of survival than those with 10 or more positive nodes without
reaching statistically significant difference (36-month overall survival: 90.9%
vs. 72.5%, p = 0.06; disease-free survival: 78.7% vs. 47.8%, p = 0.38). In this
entire group of patients, locoregional recurrence was absent. A total of 55
episodes of grade III and IV hematologic toxicity were observed, with only one
death from neutropenic sepsis. This modified ACMF regimen offers a good survival
rate in breast cancer patients with more than three positive axillary lymph
nodes. When these patients are carefully managed, the morbidity and mortality
related to the treatment are low.
PMID- 10776971
TI - Combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in
previously treated patients with advanced/recurrent head and neck cancer: a phase
II feasibility study.
AB - The purpose of this phase II feasibility trial was to determine the efficacy and
toxicity of docetaxel combined with cisplatin and 5-fluorouracil in patients with
locally advanced and/or recurrent squamous cell carcinoma of the head and neck.
Nineteen patients entered the study. The majority had received prior radiotherapy
but were chemotherapy naive. Treatment consisted of docetaxel 80 mg/m2 day 1,
cisplatin 40 mg/m2 days 2 and 3, and 5-fluorouracil 1,000 mg/m2 by continuous
infusion days 1 to 3. The cycle was repeated every 28 days. Most patients
received granulocyte colony-stimulating factor, 150 microg/m2/day subcutaneously
between days 4 and 8. The median number of chemotherapy cycles per patient was
four. Dose reduction was done in three patients with no treatment delays. Of the
16 evaluable for response, seven patients (44%) demonstrated an objective
response, including two complete and five partial ones; eight patients (50%) had
stable disease; and one patient had progressive disease. The median time to
progression was 7.5 months (range: 4-17.5 months). The median survival was 11
months (range: 1-18 months) and 1-year survival was 49%. Febrile neutropenia was
recorded in 15% of courses. There were no toxic deaths. In conclusion, the
combination of docetaxel, cisplatin, and 5-fluorouracil is an active regimen
against previously treated squamous cell carcinoma of the head and neck with
acceptable toxicity.
PMID- 10776973
TI - Malignant thymoma with metastases to the gastrointestinal tract and ovary: a case
report and literature review.
AB - This is the first clinical case report of a thoracic invasive thymoma metastatic
to the ovary with disease noted in the entire abdomen including the pelvis 5 1/2
years after initial diagnosis. The involved areas of metastases include the
distal ileum, peritoneal and serosal surfaces (including the surface of the
distal colon, bladder, and pelvis), and the surface of the right ovary. The
patient survived 13 years after her initial diagnosis and 7 1/2 years after
discovery of her metastases. Thymomas are rare tumors but comprise the most
common primary tumor of the anterior mediastinum. Extrathoracic metastases of
malignant thymomas are also rare, and the literature reports that the most common
sites for metastases are the liver, lung, lymph nodes, and bone. Extrathoracic
disease is associated with a poor prognosis. The average time of survival after
the diagnosis of metastases is 1.5 years.
PMID- 10776972
TI - Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer
patients: a phase II study.
AB - Docetaxel has proven effective in advanced breast cancer. Myelosuppression and
cumulative fluid retention syndrome are troublesome, potentially avoidable
toxicities. In this consecutive cohort study, docetaxel (100 mg/m2 by 1 hour i.v.
infusion, q3 weeks) activity and toxicity was explored in 56 anthracycline
pretreated patients (eligible: 55: median age: 51 years [range: 28-68 years];
median performance status: 0 [range: 0-3]) with metastatic breast cancer, using
two different granulocyte colony-stimulating factor and steroid pre- and
postmedication schedules. Twenty-nine patients (group A) received a 5-day oral
prednisone premedication, and 26 (group B) received 4-day low-dose i.m.
dexamethasone; group B patients also received prophylactic granulocyte colony
stimulating factor. All patients were evaluable for toxicity and 53 for response.
Prophylactic granulocyte colony-stimulating factor significantly lowered the
incidence of grade III-IV neutropenia and neutropenic fever (p = 0.0001 and 0.01,
respectively). The incidence of moderate-severe fluid retention syndrome was
lower in patients receiving i.m. dexamethasone (p = 0.08). Overall response rate
was 53% (4 complete responses/24 partial responses, 95% confidence interval 39.4
66.2%); 32% have stable disease and 15% progressive disease. In 21 anthracycline
refractory/resistant patients, as well as in 10 paclitaxel-pretreated patients,
the overall response rate was 50%. Docetaxel is highly active in anthracycline-
and paclitaxel-pretreated metastatic breast cancer, with manageable toxicity.
Optimal use of both granulocyte colony-stimulating factor support and steroid
premedication deserves further investigation.
PMID- 10776974
TI - Randomized comparison of prophylactic antidiarrheal treatment versus no
prophylactic antidiarrheal treatment in patients receiving CPT-11 (irinotecan)
for advanced 5-FU-resistant colorectal cancer: an open-label multicenter phase II
study.
AB - Delayed diarrhea is the main toxicity of irinotecan at the currently recommended
dose of 350 mg/m2 30-minute intravenous infusion, once every 3 weeks. This phase
II, multicenter, open-label, randomized study was primarily designed to evaluate
the effect of a 15-day Tiorfan (racecadotril) treatment on the incidence and
severity of irinotecan-induced delayed diarrhea. One hundred thirty-six patients
with metastatic colorectal cancer who failed to respond to a 5-fluorouracil-based
treatment received 714 cycles of irinotecan. The patients were randomly allocated
either to group A (68 patients) and received Tiorfan (300 mg/day) from D0 to D15
or to group B (68 patients) with no prophylactic treatment. Delayed diarrhea
occurred in 197 of 355 cycles (55%) in Group A and 203 of 344 cycles (59%) in
Group B. grade III-IV diarrhea was reported in 17 of 40 compliant patients (42%)
in group A and 31 of 68 evaluable patients (45%) in group B. No difference was
observed between the two groups for delayed diarrhea characteristics, incidence,
or severity. The response rate in 99 evaluable patients was 12.1% (6.4%-20.2%).
This study has shown that Tiorfan given prophylactically at 300 mg/day has no
effect on delayed diarrhea.
PMID- 10776975
TI - Uninterrupted moderately accelerated radiotherapy in the treatment of
unresectable/advanced head and neck cancer: one institution's experience and a
comparative review.
AB - Conventional radiotherapy alone in treatment of unresectable or locally advanced
head and neck cancer has poor results. To improve outcome without significant
increase in acute and late morbidity, we began a moderately accelerated
hyperfractionation radiation therapy protocol without breaks for treatment of
unresectable/advanced head and neck malignancies. From August 1984 to June 1995,
48 patients with unresectable or advanced carcinoma of the head and neck were
treated using a protocol of accelerated hyperfractionation radiation therapy at
Kaiser Permanente Medical Center, Los Angeles. Patients were treated twice a day
using 150 cGy per fraction, 4 days per week, to a final dose of 60 Gy. Two
patients were excluded from this analysis because they did not complete
treatment. With a median follow-up of 33 months, 31 (67%) patients have had
disease recurrence, 30 (65%) of whom had a locoregional component to their
failures. At the last follow-up, 12 patients (26%) were alive with no evidence of
disease, 30 patients had died of disease, and 4 had died of intercurrent disease
without recurrence. Nine (19%) patients required treatment interruptions
averaging 8 days in duration. This accelerated regimen resulted in outcomes
similar to those with conventional radiotherapy, most likely because of a
conservative total dose. Further refinement of fractionation schedules with
potential incorporation of chemotherapy must be investigated.
PMID- 10776976
TI - Treatment of recurrent glioblastoma multiforme using fractionated stereotactic
radiosurgery and concurrent paclitaxel.
AB - Despite the progress in neurosurgery and radiotherapy, almost all patients
treated with malignant gliomas develop recurrent tumors and die of their disease.
Eighty-eight patients (median age 56 years) with recurrent glioblastoma (median
tumor volume 32.7 cm3) were treated with noninvasive fractionated stereotactic
radiosurgery and concurrent paclitaxel used as a sensitizer. The median interval
between diagnosis of primary glioblastoma and salvage radiosurgery was 7.8
months. Four weekly treatments (median dose: 6.0 Gy) were delivered after the 3
hour paclitaxel infusion (median dose: 120 mg/m2). Survival was calculated by the
Kaplan-Meier method from radiosurgery treatment. Overall median survival was 7.0
months, and the 1-year and 2-year actuarial survival rates were 17% and 3.4%,
respectively. When grouped by performance status, there was no difference in
survival between the patients with low and high Karnofsky score. Patients with
tumor volume less than 30 cm3 survived significantly longer than those with tumor
greater than 30 cm3 (9.4 vs. 5.7 months, p = 0.0001). Their 1-year survival rate
was 40% and 8%, respectively. Eleven patients (11%) had reoperation because of
expanding mass. Stable disease was seen in 40% of patients (n = 34), and increase
in radiographically detected mass was observed in 41 patients (48.8%). Although
the treatment of recurrent GBM is mostly palliative, the fractionated
radiosurgery offers a chance for prolonged survival, especially in patients with
a smaller tumor volume.
PMID- 10776977
TI - Thoracic reirradiation for symptomatic relief after prior radiotherapeutic
management for lung cancer.
AB - Limited information is available in the medical literature on thoracic
reirradiation for patients with recurrent/persistent lung carcinoma or new
primary lung tumors. Controversy exists regarding the retreatment because of
concerns regarding the risk of radiation toxicity. The medical and
radiotherapeutic records of more than 1,500 patients with lung cancer seen in the
Department of Radiation Oncology at Thomas Jefferson University Hospital from
1982 through 1997 were searched. Twenty-three patients with history of previous
thoracic radiation therapy underwent thoracic reirradiation for either biopsy
proven and/or radiographically evident tumor recurrence, metastasis, or second
lung primary. Most patients were reirradiated because of progressive dyspnea,
cough, thoracic pain, or hemoptysis. Each of these symptoms was evaluated
separately with regard to the subjective response to reirradiation. The median
follow-up time from completion of reirradiation to last correspondence with the
patient and/or family was 3.2 months, with a range of 0 to 17.5 months. In six
patients with hemoptysis, a decrease or resolution of this symptom was noted. Of
five patients with thoracic pain attributed to carcinoma, four noted an
improvement in pain after reirradiation. Of 15 patients with cough, 9 had an
improvement in cough, and of 15 patients with dyspnea, 11 had an improvement.
Thoracic reirradiation is an effective modality in patients with hemoptysis,
thoracic pain, cough, and dyspnea attributed to a radiographically defined
recurrence and/or progression of lung cancer.
PMID- 10776978
TI - Positron emission tomography: an independent indicator of radiocurability in head
and neck carcinomas.
AB - Positron emission tomography (PET) is a biochemical-imaging tool that uses the
uptake of the glucose analog 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) to detect
head and neck tumor proliferation. The aim of this study is to determine if
quantitation of either primary tumor metabolic activity or tumor response using
PET scans could predict local control and overall survival in patients with head
and neck cancer undergoing primary radiotherapy. Twelve patients with squamous
cell carcinomas of the head and neck underwent PET scans before and 6 weeks after
completion of radiation therapy. Tumor metabolic activity was quantitated using
the metabolic ratio method. Mean follow-up was 40 months (range: 18-55 months).
In our series, tumors with metabolic rates greater than that of the cerebellum
are associated with significantly better local control (p < 0.05) and survival.
Posttreatment PET imaging was falsely positive in one patient with clinical signs
of severe inflammation. Tumors with greater than 50% decrease in metabolic
activity with irradiation had improved local control. Clinically, nine patients
had excellent response to irradiation. These results suggest that pretreatment
PET findings may have prognostic implications in determining which patients will
achieve long-term local control with primary radiation therapy. This may help
identify those at increased risk of recurrence that may benefit from more
aggressive altered fractionation schemes or combined modality therapy.
PMID- 10776979
TI - Oligodendroglioma: an analysis of prognostic factors and treatment results.
AB - This study, an analysis of variable prognostic factors affecting the treatment
outcome for patients with oligodendroglioma, included a retrospective analysis of
the medical charts of patients diagnosed with oligodendroglioma treated at our
institution between 1975 and 1997. The endpoints analyzed were the progression
free survival (PFS), as well as the overall survival. The factors analyzed
included extent of surgery, postoperative radiotherapy, pathologic grade,
performance status, age, and sex. Of a total of 37 cases, 19 were male and 18
were female. The median age at diagnosis was 30 years. The most common presenting
symptoms were headache (78%), seizures (43%), motor symptoms (38%), and to a
lesser extent behavioral changes (16%). The median duration of symptoms was 9
months. The most common location on computed tomography or magnetic resonance
imaging scans was the frontal region (43%). Low grade tumors (grades I and II)
were found in 60% of patients, and the remaining 40% had high grade tumors
(grades III and IV). Eight patients had complete surgical excision, whereas 27
patients had partial excision, and two patients had biopsy only. The operative
mortality rate was 14%. There were 24 patients who received postoperative
radiotherapy, and only 3 patients received adjuvant chemotherapy. The median
postoperative radiation dose was 5,580 cGy. With a median follow-up of 7 years,
the 5-year PFS and overall survival for the whole group were 58% and 67%,
respectively. The pathologic grade of the tumor was the only prognostic factor
significantly affecting both PFS and overall survival. The 5-year PFS for
patients with low grade tumors was 79% in comparison to 32% for patients with
high grade tumors (p < 0.01). Patients with good performance status at initial
presentation (performance status of 1 and 2) had a higher 5-year PFS in
comparison to those with poor performance status (62% vs. 38%, respectively);
however, this difference did not reach statistical significance. Similarly,
patients who were subjected to complete surgical excision had a marginally higher
PFS in comparison to those who had biopsy or partial excision (75% vs. 53%).
There was no difference in the 5-year PFS between patients who received
postoperative irradiation versus those who did not (51% vs. 47%, respectively).
Patients with high grade oligodendrogliomas have a relatively poor prognosis. The
pathologic grade of the tumor was the single most important prognostic factor
significantly affecting both the PFS and overall survival. A prospective
randomized clinical trial is needed to address the impact of postoperative
irradiation on PFS of those tumors. In view of the poor outcome for patients with
high grade oligodendroglioma, the use of adjuvant systemic chemotherapy should be
studied in future multicenter randomized trials.
PMID- 10776980
TI - Preliminary results of three-dimensional conformal radiotherapy as salvage
treatment for a rising prostate-specific antigen level postprostatectomy.
AB - The purpose of this study is to determine the effectiveness of three-dimensional
conformal radiotherapy delivered to the fossa of the prostate and seminal
vesicles as salvage treatment for a prostate-specific antigen (PSA) level that
becomes undetectable and subsequently begins to rise postprostatectomy. Between
August 1994 and December 1997, 14 patients with prostate cancer whose PSA became
undetectable after a radical prostatectomy subsequently developed a rising PSA,
had no evidence of metastatic disease, and were treated with three-dimensional
conformal radiotherapy at the University of California, Davis Cancer Center.
Gleason scores ranged from 4 to 9 (29% of the patients had a Gleason score > or
=8). The seminal vesicles were involved in three (21%) cases and the surgical
margins were involved in seven (50%) cases. PSA values ranged from 0.3 to 6.7
(median: 0.7) ng/ml at the start of radiotherapy. Daily 1.8-2.0-Gy fractions were
administered to total doses at isocenter ranging from 60.6 to 74.2 (median: 64.9)
Gy. None of the patients received hormonal therapy. Follow-up ranged from 13 to
36 (median: 22) months. For patients with a preradiotherapy Hybritech PSA < or =
1.0 ng/ml, the Kaplan-Meier estimate of the 2-year biochemical disease-free
survival rate is 67%, whereas for patients with a preradiotherapy PSA more than
1.0 ng/ml, the 2-year biochemical disease-free survival rate is 20% (p = 0.17).
Because of the small number of patients, the difference is not statistically
significant. A positive microscopic margin had no impact on the results obtained
with salvage radiotherapy. Only one of four patients with a poorly differentiated
adenocarcinoma remains free of disease. Acute toxicity was mild and did not
require medication (Radiation Therapy Oncology Group grade I): four (29%)
patients experienced genitourinary morbidity and three (21%) patients experienced
gastrointestinal morbidity. With regard to late toxicity, one (7%) patient
developed a urethral stricture requiring dilatation (Radiation Therapy Oncology
Group grade III). All five patients who were potent at the start of radiotherapy
remain potent. Medicare's median reimbursement for salvage three-dimensional
conformal radiotherapy in this study ($7,512 in 1999 U.S. dollars) is equivalent
to its reimbursement for a 17-month course of goserelin hormonal therapy.
Patients with prostate cancer who develop an undetectable followed by a rising
PSA postprostatectomy should be referred for salvage treatment with radiotherapy
when their PSA is still less than or equal to 1.0 ng/ml. Salvage three
dimensional conformal radiotherapy is well tolerated and is less expensive than
more than 17 months of goserelin.
PMID- 10776981
TI - Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged.
AB - Multiple or recurrent squamous cell skin carcinoma is a rare tumor in the aged.
These patients are currently treated with 5-fluorouracil (5-FU) cream as a local
chemotherapy; in cases in which the disease progresses, few treatments are
available. Two reports deal with the treatment of progressive squamous cell skin
carcinoma with systemic 5-FU, but in only eight patients age less than 70 years.
We prospectively investigated oral 5-FU therapy in 14 consecutive patients
(average age 76 1/2 years) with histologically proven squamous cell skin
carcinoma. The disease was aggressive, multiple, or recurrent and had not been
eradicated by surgery, radiation therapy, topical 5-FU cream, and non-5-FU
chemotherapy. Oral 5-FU was administered as mannitol-coated 5-FU tablets at the
daily dose of 175 mg/m2 for 3 weeks every 5 weeks. Toxicity, effectiveness,
quality of life, and compliance to therapy were evaluated. Total cycles amounted
to 55 (range: 2-6, mean: 4 for each patient) at an average dose intensity of 740
mg/m2/week for from 12 to 36 weeks. Only gastrointestinal toxicity World Health
grade I occurred. Quality of life and compliance to therapy were 90%. Therapy
induced measurable improvement in nine patients (64.3%): two partial remissions
(14.3%), three minimal remissions (21.4%), and four arrests of disease (28.6%)
with a median duration of 30+ months. The study ended because of a lack of
patients. We can conclude that, if elderly patients require chemotherapy because
of progressive multiple or advanced squamous cell skin carcinoma, appreciable
results may be obtained with oral 5-FU as a single agent.
PMID- 10776982
TI - Comparative efficacy of three 5-HT3 antagonists (granisetron, ondansetron, and
tropisetron) plus dexamethasone for the prevention of cisplatin-induced acute
emesis: a randomized crossover study.
AB - The purpose of this study was to compare the antiemetic efficacy of three 5-HT3
antagonists (granisetron, ondansetron, tropisetron) plus dexamethasone for the
prevention of acute emesis induced by high-dose cisplatin chemotherapy. This was
a randomized, open label, crossover study. Recruited into the study were 94
chemotherapy-naive patients of whom five were excluded because chemotherapy was
not given, noncisplatin regimen was used instead, or presence of anticipatory
vomiting. The remaining 89 evaluable patients were mostly (86.5%) male, and were
all treated for head and neck cancers. The antiemetic regimens consisted of 1)
granisetron 3 mg i.v. and dexamethasone 20 mg i.v. on day 1 (GRADEX); 2)
tropisetron 5 mg i.v. and dexamethasone 20 mg i.v. on day 1 (TRODEX); and 3)
ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. to be followed by ondansetron
8 mg p.o. x 2 on day 1 (ONDEX). Patients were randomized to receive one of the
three regimens in the first cycle, and treatment was crossed over to the other
two regimens in subsequent cycles. Antiemetic efficacy was assessed using self
report diaries recording the number of vomiting episodes as well as duration and
severity of nausea within the first 24 hours. Complete response was defined as no
vomiting with or without mild nausea, and major response was defined as one
vomiting episode and/or moderate to severe nausea. Major efficacy refers to
either complete or major response. A total of 219 cycles was given to 89
patients: 16 received one cycle only, 16 received two cycles, and 57 received
three cycles. No carryover effects were observed between cycles. Using pooled
data from all cycles, the complete response rates to GRADEX, TRODEX, and ONDEX
were 81%, 68%, and 71%, respectively (p = 0.11); the corresponding major efficacy
rates were 91%, 93%, and 86%, respectively (p = 0.36). When only the first cycle
was considered, the complete response rates to GRADEX, TRODEX, and ONDEX were
81%, 75%, and 74%, respectively (p = 0.58); the corresponding major efficacy
rates were 92%, 94%, and 84%, respectively (p = 0.38). Analysis of the crossover
data showed that the majority of patients achieved complete response or major
efficacy with the different pairs of regimens, and there were no significant
differences between different regimens in terms of complete response or major
efficacy. The only exception was GRADEX versus TRODEX, in which 15.5% of patient
achieved complete response with GRADEX as compared with 1.7% with TRODEX (p =
0.025). The majority of patients (53%) did not report any preference, whereas 14%
preferred GRADEX, 15% preferred TRODEX, and 18% preferred ONDEX. The three 5-HT3
antagonists, when used in combination with steroids, had similar major efficacy
for prophylaxis against cisplatin-induced acute emesis. Although GRADEX was
superior to TRODEX in terms of complete response, this may not be of clinical
significance. The choice of antiemetic regimens should therefore depend on
patient preference and drug cost.
PMID- 10776983
TI - Phase I-II study of high dose epirubicin plus cisplatin in unresectable non-small
cell lung cancer: searching for the maximal tolerated dose.
AB - The purpose of this study was to search for the maximal tolerated dose of
cisplatin in the cisplatin plus high-dose epirubicin combination for patients
with non-small-cell lung cancer. The following range of cisplatin dosages were
tested in a phase I study: 75, 90, 105, and 120 mg/m2 in combination with
epirubicin 120 mg/m2 every 3 weeks. Eligibility consisted of previously untreated
stage IIIb or IV non-small-cell lung cancers, Eastern Cooperative Oncology Group
Performance Status less than or equal to 2, age less than or equal to 70 years,
measurable disease, adequate blood counts, chemistry, cardiac function, and no
brain metastasis. The maximal tolerated dose was defined as the dose level of
cisplatin for which two of three patients or three of six patients developed one
or more limiting toxicities during the first course of therapy. Afterward, the
maximal tolerated dose of cisplatin was adopted in a subsequent phase II study.
Three centers enrolled 42 patients: 18 in phase I and 24 in phase II. The maximal
tolerated dose was almost reached at the last dose level (i.e., 120 mg/m2).
Taking into account the total duration of the treatment, the real dose intensity
for patients treated at the fourth dose level (120 mg/m2) did not differ from
that of the third dose level (105 mg/m2). The latter dosage was therefore
considered as the maximal tolerated one. In the subsequent phase II study, the
median number of cycles received per patient was three (range: one to eight).
Fifty percent required a dose reduction of either epirubicin, cisplatin, or both.
The main toxicity was neutropenia, resulting in 10 episodes of febrile grade IV
neutropenia requiring readmission. Other toxicities were mild to moderate. There
was no toxic-related death. On intent-to-treat analysis, 10 patients (33%)
achieved an objective response. Among them were three complete responders. Median
survival was 8 months. We observed neither detraction nor improvement of quality
of life as assessed using the European Organization for Research and Treatment of
Cancer QLQ-C30-LC13. Given every 3 weeks in combination with epirubicin 120
mg/m2, the maximal tolerated cisplatin dose is 105 mg/m2. This combination yields
activity in non-small-cell lung cancer.
PMID- 10776984
TI - A phase II study of combined chemoradiotherapy for limited disease-small-cell
lung cancer.
AB - A study to evaluate the efficacy of cisplatin, doxorubicin, and etoposide
chemotherapy with combined radiotherapy was undertaken in 26 patients with
limited disease-small-cell lung cancer. Patients were treated with cisplatin (80
mg/m2) intravenously (i.v.) on day 1, doxorubicin (30 mg/m2) i.v. on day 1, and
etoposide (80 mg/m2) i.v. on days 1, 3, and 5, every 4 weeks for four cycles.
Thoracic irradiation of 40 Gy in 20 fractions was delivered during 4 weeks to the
primary site starting on day 8 of the second cycle of chemotherapy. The objective
response rate was 100%. A complete response was observed in 10 patients (38%).
The median survival time was 23 months, and the 3-year survival rate was 42%.
Seven patients (27%) continued to survive at least 8 years and remain free from
disease. Grade III/IV leukopenia was observed in 25 patients (96%). Grade III/IV
thrombocytopenia developed in 19 patients (73%). Grade III/IV esophagitis was not
seen. Interstitial pneumonitis occurred in two patients. This regimen is
effective and has acceptable toxicity for use in the treatment of limited disease
small-cell lung cancer.
PMID- 10776985
TI - Choriocarcinoma arising in a squamous cell carcinoma of the esophagus.
AB - Extragonadal germ cell tumors are rare neoplasms with histologic features
comparable to those of gonadal origin. Squamous cell carcinoma of the esophagus
was diagnosed in a 53-year-old male patient, and was palliated for a short period
by cisplatin plus 5-fluorouracil. Clinical deterioration and development of
gynecomastia led to diagnosis of hormone-secreting choriocarcinoma that
originated within the squamous cell tumor of the esophagus. Salvage chemotherapy
affected the markers but not the tumor. Extragonadal choriocarcinoma is a
chemosensitive tumor, but when arising within squamous cell carcinoma of the
esophagus it may be chemoresistant, and lead to a fatal outcome.
PMID- 10776986
TI - Accelerated hyperfractionation for bronchogenic cancer: Radiation Therapy
Oncology Group 9205.
AB - RTOG 92-05 was a phase II trial developed to evaluate the feasibility, toxicity,
and acceptance of a three times daily accelerated hyperfractionation radiation
therapy schedule delivering 110 cGy, three times daily, to 79.2 Gy uncorrected
tumor dose in 72 fractions, in 24 treatment days, in patients with bronchogenic
cancer. The radiographically visible tumor received accelerated
hyperfractionation and the other radiation volume received standard
hyperfractionation. Three times a day, a dose of 110 cGy was delivered, with an
interfractional interval of 4 hours; the middle fraction was a gross tumor boost.
This schedule allowed treatment to be completed in approximately 4 1/2 weeks in
an effort to minimize repopulation, to have a better biologically modeled
therapeutic ratio than other schedules that have been completed in cooperative
groups, and to use doses within cooperative group experience. In 33 months 35
patients were entered into the study; 15 of the patients had squamous cell
carcinomas, 10 had adenocarcinomas, 8 had large-cell undifferentiated carcinomas,
and 2 had unspecified non-small-cell cancers. Nineteen patients had AJCC stage
IIIB; 13, IIIA; 14, T4; 10, T3; 13, N2; and 7, N3. Twenty-one patients (60%) had
greater than 5% weight loss. The Karnofsky performance status was 90 to 100 in 12
patients and 70 to 80 in 23 patients. Treatment was completed in 91% of patients.
Acute toxicity >RTOG grade II occurred in three patients: one skin, one lung, and
two esophagus (one each III and IV, the only grade IV in the study). Overall late
toxicity > or = grade III occurred in six patients: three lung, one thyroid, one
esophagus, and one subcutaneous tissue (all grade III). The median survival was
10.5 months, 1-year survival was 42%, and 3-year survival was 18%. The outcome in
this group of patients with many adverse prognostic variables compared favorably
to prior RTOG radiation-alone studies.
PMID- 10776987
TI - CA 125: a clinically useful tumor marker in the management of colorectal
carcinoma metastatic to the liver in patients with normal carcinoembryonic
antigen.
AB - Two patients with colon carcinoma metastatic to the liver had normal plasma
carcinoembryonic antigen (CEA) levels (<1.0 ng/ml) but elevated CA 125 levels.
Treatment of the metastatic disease with chemotherapy, plus surgery in one case,
led to declines in the CA 125 levels. These decreases were associated with tumor
regression, as confirmed by clinical and radiologic evidence. These findings lead
us to conclude that the measurement of CA 125 for patients with normal CEA levels
is useful in the management of colorectal carcinoma.
PMID- 10776988
TI - The roles of placental growth hormone and placental lactogen in the regulation of
human fetal growth and development.
AB - The human growth hormone (hGH)/human placental lactogen (hPL) gene family, which
consists of two GH and three PL genes, is important in the regulation of maternal
and fetal metabolism and the growth and development of the fetus. During
pregnancy, pituitary GH (hGH-N) expression in the mother is suppressed; and hGH
V, a GH variant expressed by the placenta, becomes the predominant GH in the
mother. hPL, which is the product of the hPL-A and hPL-B genes, is secreted into
both the maternal and fetal circulations after the sixth week of pregnancy. hGH-V
and hPL act in concert in the mother to stimulate insulin-like growth factor
(IGF) production and modulate intermediary metabolism, resulting in an increase
in the availability of glucose and amino acids to the fetus. In the fetus, hPL
acts via lactogenic receptors and possibly a unique PL receptor to modulate
embryonic development, regulate intermediary metabolism and stimulate the
production of IGFs, insulin, adrenocortical hormones and pulmonary surfactant.
hGH-N, which is expressed by the fetal pituitary, has little or no physiological
actions in the fetus until late in pregnancy due to the lack of functional GH
receptors on fetal tissues. hGH-V, which is also a potent somatogenic hormone, is
not released into the fetus. Taken together, studies of the hGH/hPL gene family
during pregnancy reveal a complex interaction of the hormones with one another
and with other growth factors. Additional investigations are necessary to clarify
the relative roles of the family members in the regulation of fetal growth and
development and the factors that modulate the expression of the genes.
PMID- 10776989
TI - Turner's syndrome and thyroid disease: a transverse study of pediatric patients
in Brazil.
AB - An increased prevalence of autoimmune thyroid disease (AITD) has been described
in Turner's syndrome (TS), but the extent of this association is still
controversial. Some studies also suggest that AITD is more frequent among
patients with X-isochromosome. In order to determine the prevalence of AITD among
girls with TS, and to look for an association with age and karyotype, we
evaluated 71 patients with a mean age of 11.4 years (range 0-19.9). 15.5% (11/71)
were hypothyroid, 17 (23.9%) were positive for thyroid peroxidase (TPO) and/or
thyroglobulin (Tg) antibodies, and 24 (33.8%) had thyromegaly. No abnormality was
observed before 4 years, and the highest frequencies were observed after 16
years. There were no significant differences concerning thyroid findings among
patients with a 45,X karyotype, mosaics, and structural rearrangements. Half of
the patients (35/71) exhibited one or more abnormalities, which demonstrates the
importance of careful evaluation of thyroid function in all girls with TS.
PMID- 10776990
TI - The rising incidence of childhood type 1 diabetes in New South Wales, Australia.
AB - OBJECTIVES: 1. To determine the incidence of type 1 (insulin dependent) diabetes
in children aged 0-14 years who were resident in the state of New South Wales,
Australia over the period 1992-1996. 2. To analyse the trends in incidence over
the period 1990-1996. METHODS: Primary ascertainment of patients was performed
using a prospective incidence register established in 1990. The secondary source
of ascertainment was the National Diabetes Supply Scheme, a government subsidised
scheme for diabetic supplies. RESULTS: There were 1,230 patients identified over
the five-year period. Using the capture-recapture method, ascertainment was
estimated to be 99% complete. The lowest incidence occurred in 1992 (16.9 per
10(5) person years) and the highest incidence was in 1995 (21.7 per 10(5)). The
crude incidence of IDDM from 1990-1996 was 17.8 per 10(5) and there was a
statistically significant rise in the incidence of type 1 diabetes over this
period (p=0.0003). The annual incidence has increased on average by 3.2% per year
since 1990. CONCLUSION: The incidence of childhood type 1 diabetes in NSW has
increased significantly since 1990.
PMID- 10776991
TI - Prolactin secretion abnormalities in patients with the "syndrome of spotty skin
pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex).
AB - Carney complex is a multiple neoplasia and lentiginosis syndrome. Acromegaly due
to growth hormone (GH)-producing adenomas has been considered the only pituitary
related manifestation of the complex. In the present study, seven patients with
Carney complex, who belonged to three unrelated kindreds and had relatives with
acromegaly, were investigated for the presence of GH and prolactin (PRL)
secretion abnormalities (familial cases). In addition, four patients with the
complex and no family history of the complex were studied (sporadic cases). Seven
of the patients were female and four were male; their mean age was 24.27 +/- 4.34
years. Sampling every 20 min for one hour in the morning and under fasting and
unstimulated conditions was performed in all patients, for determination of serum
PRL levels. Insulin-like growth factor-I (IGF-I) levels and magnetic resonance
imaging (MRI) of the pituitary were also obtained. Patients who had elevated IGF
I levels underwent investigation for acromegaly by oral glucose tolerance test
and thyrotropin-releasing hormone. Seven of the 11 patients (63.6%) had
moderately high PRL levels (mean Z score value 2.12 +/- 0.66); three of these
patients also had elevated IGF-I levels but a negative investigation for
acromegaly. All patients had negative pituitary MRI. The patient with the highest
PRL levels underwent 24-hour sampling every 20 min, which demonstrated a higher
baseline secretion of this hormone with preservation of its circadian
pulsatility. Hyperprolactinemia was present in two siblings and a parent-child
pair. We conclude that prolactin hypersecretion, albeit mild, appears to be
frequent in patients with Carney complex, is inherited in an autosomal dominant
manner in kindreds with the syndrome, and may be associated with elevated IGF-I
levels in some, but not all, patients.
PMID- 10776992
TI - Is statural growth predictable in utero? Follow-up from the second trimester of
gestation to the 8th year of life.
AB - BACKGROUND: It is well known that birth weight is related to later childhood
growth and adult height. It can therefore be hypothesized that this relationship
exists also for fetal size before birth. OBJECTIVE: To verify whether a child's
final height can be predicted by sonographic biometry in utero. SUBJECTS: We
evaluated in 116 healthy children both ultrasound measurements in utero and
postnatal measurements at a mean age of 6.0 +/- 1.4 years. METHODS: The following
fetal ultrasound measurements were obtained: crown-rump length in the first
trimester; biparietal diameter, head circumference and femur length in the second
and third trimester. RESULTS: Midparental height of the children was correlated
both with crown-rump length in the first trimester and with femur length (FL) in
the second and third trimester. Predicted adult height was correlated both with
FL in the second and third trimester, while present height of the child was
correlated with FL only at the third trimester. CONCLUSIONS: FL showed a close
relationship with postnatal measurements. For the extreme values of FL, it seems
possible to make quite an accurate prediction of the limits of future height. We
can reasonably speculate, therefore, that the basis for the future growth of the
child can be found in utero.
PMID- 10776993
TI - Postnatal growth in southern Chinese children with symptomatic congenital heart
disease.
AB - Many Western children with congenital heart disease (CHD) show significant growth
retardation. In this study postnatal growth was examined in Chinese children with
symptomatic CHD in Hong Kong, in relation to their diagnosis and the time of
surgery. 363 children of four years old or younger, who were admitted at Grantham
Hospital, Hong Kong, in 1994 and 1995, were subdivided into six diagnostic
categories and categorised into cyanotic and acyanotic groups. While a reduced
birth weight SDS was present in 18% of patients, at the time of operation
approximately 40% of them had subnormal weight and height values. Girls were more
impaired in weight and weight-for-height than boys (-1.90 SDS vs -1.52 SDS, and
0.90 SDS vs -0.46 SDS, respectively). Children with acyanotic lesions were more
affected in growth than those with cyanotic lesions, but they were also operated
on at an older age than children in the latter group. Left to right shunt and
common intracardiac mixing were particularly associated with wasting;
transposition of the great arteries and pulmonary outflow tract obstruction with
stunting; while children with left ventricular outflow obstruction revealed a
proportional growth retardation in weight and height. Age at operation did not
seem to have an independent effect on postnatal growth in children with CHD. As
with Western children, growth retardation is a common feature in Chinese children
with symptomatic cardiac defects. Haemodynamics, age at operation and nutritional
influences are discussed as potential aetiologic factors.
PMID- 10776994
TI - Symptomatic versus substitution growth hormone therapy in short children: from
auxology towards a comprehensive multidimensional assessment of short stature and
related interventions.
AB - There is an ongoing debate as to whether symptomatic growth hormone treatment
(GHT) in short children without growth hormone deficiency (GHD) is justified,
since there is no substitutional indication. The increasing evidence that final
height cannot be normalized in these patients (e.g. in Ullrich-Turner syndrome)
reinforces this controversy. We have focused on the empirical evidence on the
psychosocial and physical meaning of being short in childhood as well as on the
underlying assumptions of the different GHT indications. The indication for GHT
in patients with non-GHD may be seen as a pharmacotherapeutic intervention in
order to prevent the developmental, physical and psychosocial risks associated
with short stature. This requires a qualitative shift in methodological
assessment with respect to the psychosocial and physical impact of being short as
well as of the potential benefit of new treatment indications in terms of a more
comprehensive evaluation including health-related quality of life for these
patients.
PMID- 10776995
TI - Psychosocial outcome in growth hormone deficient patients diagnosed during
childhood.
AB - Social disabilities have been described in GHD patients. The aim of this study
was to evaluate the social outcome of a group of adult hypopituitary patients
diagnosed and treated during childhood. Seventy patients were interviewed at a
mean age of 25.6 years (range 18-50 yr). They answered a semistructured
questionnaire and the Beck Depression Inventory test. Patients were compared for
academic achievement, marital status and employment with the nearest age sibling.
We found high levels of school repeaters, school was often not completed, and
around 50% were overprotected by teachers and teased by peers. 32% were
unemployed, while 58% of those employed work with their families. 80% still live
with their parents; only 16% are married and 9% have children. 44% had no dating
experience and 52% had never had sexual intercourse. Depression was common,
especially in hypogonadic subjects. Juvenilization was the most common complaint.
We did not found differences in maximal educational achievements and levels of
employment between patients and siblings, but significantly more married siblings
were found. Depression, social isolation and dependent life style were found in
GHD patients. Appropriate medical and psychological counseling should be included
for patients and their families as part of treatment.
PMID- 10776997
TI - Serum leptin concentrations in children with Prader-Willi syndrome and non
syndromal obesity.
AB - There is limited information on the underlying physiological mechanisms promoting
obesity in patients with Prader-Willi syndrome (PWS). The aim of this study was
to investigate whether body fat regulation in children with PWS is similar to
that in children with non-syndromal obesity and non-obese children. We studied
three groups: 1) 72 non-obese children and adolescents; 2) 68 children with non
syndromal obesity; and 3) 11 patients with PWS. Height and weight were measured
and body mass index (BMI) and BMI SDS were calculated. Fasting serum leptin
concentrations were determined. Median leptin serum concentrations were similar
in PWS patients and children with non-syndromal obesity. Median leptin serum
concentrations were higher in these two groups than in the non-obese group. Log
leptin serum concentrations and BMI SDS showed significant correlations in the
three groups of patients; correlation coefficients were 0.525, 0.285 and 0.854,
respectively. In conclusion, median leptin serum concentrations are similar in
PWS patients and children with non-syndromal obesity. The relationship between
log serum leptin concentrations and BMI SDS was different in the three groups of
patients studied.
PMID- 10776996
TI - Nocturnal integrated gonadotropin concentrations in evaluating pubertal
transition in girls.
AB - We assessed the utility of measuring the physiological levels of gonadotropins as
a diagnostic tool for pubertal onset in girls. Two methods of gonadotropin
measurements were compared: the standard frequent sampling method, in which blood
samples were drawn every 20 min, and the multiple integrated sampling method, in
which samples were obtained continuously at 30 min intervals by a withdrawal
pump. The two methods were examined simultaneously overnight in a group of eight
girls at different stages of puberty. The following parameters of both LH and FSH
secretion, calculated by PULSAR program, were highly correlated between these
methods: area under the curve (AUC), mean levels, mean from smoothed baseline and
mean peak height. The diagnostic value of multiple integrated sampling of
gonadotropins (performed over 6 h) was then assessed in five prepubertal girls
and six girls at early puberty (Tanner stages 2 and 3), in whom peak
gonadotropins levels in response to GnRH stimulation test were in the prepubertal
range. Several parameters of LH (but none of FSH) were significantly higher
(p<0.05) in early pubertal compared to prepubertal girls: AUC (5.61 +/- 2.40 vs
2.39 +/- 1.41), mean levels (0.52 +/- 0.21 vs 0.23 +/- 0.14), smoothed mean level
(0.43 +/- 0.18 vs 0.18 +/- 0.11) and peak area (0.27 +/- 0.08 vs 0.11 +/- 0.06).
We conclude that the technically simple method of multiple integrated sampling is
useful in detecting pubertal transition and is superior to the GnRH-stimulation
test. This method can be used in selective cases when the stimulation test yields
equivocal results.
PMID- 10776998
TI - Chronic hypoxemia leads to reduced serum IGF-I levels in cyanotic congenital
heart disease.
AB - Cyanotic congenital heart disease in children commonly causes more pronounced
growth retardation in comparison with acyanotic congenital heart disease. Chronic
hypoxemia has been suggested as the cause of poor growth in these patients, but
the relationship between serum IGF-I levels and chronic hypoxemia is unclear.
Serum IGF-I concentrations, oxygen saturation and nutritional status were
evaluated in 29 patients with cyanotic congenital heart disease, and serum IGF-I
levels were compared with a group of 20 well-nourished, age-matched control
children to assess the relationship between IGF-I levels and chronic hypoxemia.
The nutritional status of each patient was determined by using anthropometric
parameters and calorie and protein intake ratios. The patients were divided into
malnourished and well-nourished groups (21 and 8 patients, respectively)
according to their nutritional status. Serum IGF-I concentrations were measured
in the two patient groups and the controls. The malnourished group had the lowest
IGF-I levels (48.14 +/- 21.8 ng/ml, p<0.05). However, the well-nourished group's
IGF-I levels were significantly lower than the control subjects' despite improved
nutritional status (85.5 +/- 30.2 and 107 +/- 19.7 ng/ml, respectively, p<0.05).
In addition, we found a positive correlation between serum IGF-I levels and
oxygen saturation of the patients (r=0.402, p<0.05). These findings indicate that
chronic hypoxemia has a direct or indirect effect to reduce serum IGF-I
concentrations and this may be a cause of the increased growth failure in
patients with cyanotic congenital heart disease.
PMID- 10776999
TI - Syndrome of inappropriate antidiuretic hormone secretion and "designer drugs"
(ecstasy).
PMID- 10777000
TI - Osteopenia in children and adolescents with hyperprolactinemia.
AB - Three patients with hyperprolactinemia due to pituitary adenomas (two patients)
or empty sella (one patient) and osteopenia are described. Their ages at
presentation ranged from 8 to 17 years. Each patient was treated with
cabergoline. Serum prolactin levels became normal in all patients within one
month. Bone density and pubertal stage improved after 12 months of treatment.
PMID- 10777001
TI - Hypothalamic hamartoma as a cause of precocious puberty in neurofibromatosis type
1: patient report.
AB - Precocious puberty resulting from hypothalamic hamartoma is well known.
Neurofibromatosis type 1 can also present with precocious puberty. However,
hypothalamic hamartoma as the cause of precocious puberty in patients with
neurofibromatosis type 1 has never been described in the literature. This rare
occurrence of these two together in a patient with precocious puberty is
reported.
PMID- 10777002
TI - Insulin-like growth factor serum concentrations reflect insufficient growth in a
hypoplastic infant with partial trisomy 9q in the 12th week of life.
AB - This report presents changes of IGFs and IGFBPs in a female infant with partial
trisomy 9q in the 12th week of life. Studying deficient growth in this
hypoplastic infant (birth weight 1405 g, birth length 36 cm) with dysmorphic
features, the following changes in IGFs and IGFBPs were detected (microg/l): IGF
I: 26.5 vs 48.1 in healthy infants; IGF-II: 420 vs 728; IGFBP-2: 931 vs 524;
IGFBP-3: 800 vs 1070. This demonstrates that IGFs and IGFBPs may reflect
individual insufficient growth even at this early age.
PMID- 10777003
TI - Seizures following clonidine test for growth hormone reserve: unusual
presentation of benign partial epilepsy.
PMID- 10777004
TI - Gastric cancer: what responsibility is borne by Helicobacter pylori? Should it be
combated in the African context?
PMID- 10777005
TI - Risk factors for pre-cancerous lesions of the cervix.
AB - Studies on risk factors for pre-cancerous lesions of the uterine cervix have
shown strong association with sexual practice. Women with multiple sexual
partners and intercourse at early age are at high risk. A role of male partners
in further enhancing the risk has been identified. All these support the
hypothesis relating to a sexually transmissible aetiological agent. An extensive
review of the literature on the risk factors for pre-cancerous lesions of cervix
has been carried out. The risk factors were grouped into genital, sexual,
chemical, dietary and life factors. Human papilloma virus (HPV) is the major
infectious aetiological agent associated with the development of pre-cancerous
lesions of cervix. Other co-factors such as multiple sexual partners of the male
as well as the female and early age of first intercourse are also involved at the
critical aetiological step of progression from low-grade to high-grade lesions.
The role of other infectious agents in terms of supportive or interactive effects
is not clear. No independent effect for herpes simplex virus 2 on risk is
observed. Other risk factors include cigarette smoking, oral contraceptive usage,
certain nutritional deficiencies and poor personal hygiene. However, it is not
clear whether these factors operate independently from HPV. There is no
consistency in the independent effect of these factors on the development of low-
to high-grade lesions of cervix. There is a similarity in the patterns of risk
between pre-cancerous lesions of the cervix and cervical cancer. Monogamy, late
commencement of sexual activity, personal hygiene and use of barrier
contraceptive methods help towards primary prevention. In the long-term, primary
prevention of cervical neoplasia through HPV immunization of population may be a
possibility.
PMID- 10777006
TI - Mammographic densities and the prevalence and incidence of histological types of
benign breast disease. Reference Pathologists of the Canadian National Breast
Screening Study.
AB - There is now a large amount of evidence indicating that women with extensive
areas of mammographic densities are 4-6 times more likely to develop breast
cancer than those with little or no density in the mammogram. We have examined
one potential biological explanation for this association by estimating the
incidence of various histological types of benign breast disease in relation to
mammographic density. We studied the large cohort of women taking part in the
National Breast Screening Study (NBSS), a randomized trial of screening with
mammography. Mammograms from subjects with biopsies (n = 423) and from a
comparison group of subjects randomly selected from the NBSS (n = 465) were
included. Histological slides from biopsied subjects (n = 353) were classified
independently by the pathologists of the NBSS and by a review pathologist
(H.M.J.). Mammographic density in more than 75% of the breast area was associated
with an increased risk of incidence of hyperplasia without atypia, and of
atypical hyperplasia and/or carcinoma in situ. The classifications of the review
pathologist showed that, compared to women with no density, the relative risk of
incident lesions for women with density in more than 75% of breast was 13.85 (95%
CI 2.65-72.49) for hyperplasia, and 9.23 (95% CI 1.66-51.48) for atypical
hyperplasia and/or carcinoma in situ. These findings suggest that the association
between extensive mammographic density and breast cancer risk may, at least in
part, be attributable to biological processes in the breast that give rise to
these histological features that are known to be related to breast cancer risk.
PMID- 10777007
TI - Predictors of non-attendance in a population-based mammography screening
programme; socio-demographic factors and aspects of health behaviour.
AB - The aim of this study was to identify predictors of non-attendance in a
population-based mammography-screening programme in central Sweden, on the basis
of telephone interviews with 434 non-attendees and 515 attendees identified in a
mammography register. Non-attendance was studied in relation to sociodemographic
factors, indicators of general health behaviour, self-rated health and experience
of cancer in others and own cancer or breast problems. Being single or being non
employed were the only important socio-demographic predictors of non-attendance.
Non-attendance was more likely among women who never visited a dentist, had not
visited a doctor in 5 years, had never used oral contraceptives or hormone
replacement therapy, had never had cervical smear tests, never drank alcohol,
smoked regularly, reported no breast cancer in family or friends or own breast
problems. We conclude that socio-demographic factors alone do not appear to
constitute strong predictors of non-attendance. General health behaviour and
previous experience of cancer and breast disease seem to be more important
factors. Our results suggest that in the setting of population-based outreach
mammography programmes, previous contacts with the health care system and
encouragement from health professionals represent determinants of attendance.
PMID- 10777009
TI - K-ras mutations, rectal crypt cells proliferation, and meat consumption in
patients with left-sided colorectal carcinoma.
AB - It has been suggested that N-nitroso compounds derived from meat may increase the
risk of K-ras mutations in the human colon. We sought evidence of associations
between red meat consumption, frequency and type of K-ras mutations in resected
tumours, and the rate of crypt cell proliferation (CCP) in the normal mucosa of
patients with left-sided colorectal carcinoma. Meat consumption was assessed by
food frequency questionnaire, and CCP was determined in rectal biopsies obtained
prior to surgery. K-ras mutations in the resected tumours were determined using a
PCR-based oligonucleotide hybridization assay. Fifteen K-ras mutations were
detected in tumours from 43 patients; 13/15 in codon 12, 3/15 in codon 13, and
1/15 in both codons 12 and 13. All mutations were G-->A or G-->T transitions.
There was no statistically significant difference between intakes of red meat in
patients with a K-ras mutation (92.4 +/- 9.7 g/day) and those without (82.3 +/-
7.7 g/day). Rectal CCP was significantly higher in patients than in healthy
controls, but there was no correlation with meat consumption or K-ras mutation.
These data do not support the hypothesis that meat consumption is a risk factor
for acquisition of K-ras mutations during colorectal carcinogenesis.
PMID- 10777008
TI - Lung cancer risk in Venice: a population-based case-control study.
AB - Populations resident in the historical town of Venice and in the inland
industrial city of Mestre are at different risk of exposure to environmental
pollutants. This case-control study compares the risk of developing lung cancer
in the two populations in relation to known risk factors for this neoplasm. A
retrospective study of 305 incident cases of lung and 447 frequency-matched
population controls was conducted through a standard questionnaire on main risk
factors for lung cancer. Completeness of cases was checked against the Venetian
Cancer Registry files. The results indicate that lung cancer risk associated with
tobacco smoking was high in both areas, although more elevated in Venice islands
among heavy smokers. An elevation of risk was associated with housing without a
heating system, possibly suggesting a role of worse hygienic conditions. An
increased risk associated with exposure to occupational carcinogens was detected
in the inland area. In conclusion, lung cancer risk due to tobacco smoking
largely affects both the populations, while other risks such as occupation or
housing conditions appear to be more population-specific.
PMID- 10777010
TI - Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer:
results from the Canadian Enhanced Surveillance System case-control project.
Canadian Cancer Registries Epidemiology Research Group.
AB - The relationship between alcohol, tobacco and coffee consumption and pancreatic
cancer was investigated using population-based case-control data obtained from
eight Canadian provinces. Our findings are based on analyses performed on 583
histologically confirmed pancreatic cancer cases and 4813 controls. Questionnaire
data were obtained directly from 76% of the cases. Male subjects with 35 or more
cigarette pack-years had an increased risk of developing pancreatic cancer
relative to never smokers (OR= 1.46, 95% CI 1.00-2.14). Similarly, women
reporting at least 23 cigarette pack-years of smoking had an odds ratio of 1.84
(95% CI 1.25-2.69). For the most part, consumption of total alcohol, wine, liquor
and beer was not associated with pancreatic cancer. Coffee drinking was not
related to pancreatic cancer. More work is needed to clarify the role of these
and other potentially modifiable risk factors as a means to reduce the incidence
of this disease for which treatment results remain disappointing.
PMID- 10777011
TI - Medical history and risk of Hodgkin's and non-Hodgkin's lymphomas.
AB - The relationship between a history of selected medical conditions and risk of
lymphomas was investigated in a hospital-based case-control study conducted in
Northern Italy on 429 incident, histologically confirmed cases of non-Hodgkin's
lymphoma (NHL), 158 cases of Hodgkin's disease (HD) and 1157 controls admitted to
hospitals for acute conditions. The odds ratios (OR) for NHL were above unity in
patients with a history of infectious mononucleosis (OR 2.9), herpes zoster (OR
1.8), pyelonephritis (OR 4.9), tuberculosis (OR 1.8), malaria (OR 1.9), any
chronic bacterial diseases (OR 1.7), rheumatoid arthritis (OR 1.7) and psoriasis
(OR 2.5). With reference to HD, the ORs were 4.0 for infectious mononucleosis,
2.9 for herpes zoster, 3.3 for pyelonephritis, 2.3 for tuberculosis, 1.4 for
chronic bacterial diseases, 2.4 for rheumatoid arthritis, 2.7 for psoriasis and
2.1 for diabetes. The association of NHL and HD with herpes zoster was restricted
to the first ten years since the onset of the disease. The relationships between
NHL and mononucleosis (OR 12.9), malaria (OR 2.8) and psoriasis (OR 14.0) were
stronger for cases aged > or = 60 years, and that with tuberculosis (OR 3.5) was
stronger for younger cases. For HD, the positive association was stronger for
cases aged > or = 40 years for herpes zoster (OR 3.8) and diabetes (OR 2.6). An
increased risk of NHL was found in association with poliomyelitis (OR 1.6)
(restricted to cases aged > or = 60 years, OR 4.0) and BCG immunizations (OR
1.6), but not with vaccination against smallpox, tetanus and diphtheria;
increased risks of HD were found in relation to poliomyelitis and BCG
immunization in cases aged > or = 40 years (OR respectively 2.5 and 2.1), or > or
= 50 years (OR 4.3 and 2.2). Thus, our results confirm the association between a
history of several chronic infectious and inflammatory diseases and the risk of
NHL or HD, and are compatible with a role of chronic immunological alterations in
the aetiology of lymphomas.
PMID- 10777012
TI - International symposium: way of life and cancer.
PMID- 10777013
TI - Marshmallow--a unique food.
PMID- 10777014
TI - The New York State project: a leap to the future.
PMID- 10777015
TI - The cochlear implant field is slowly approaching the time when electrophysiologic
measures will be widely used in cochlear implant fitting.
PMID- 10777016
TI - The New York State universal newborn hearing screening demonstration project:
introduction and overview.
AB - OBJECTIVE: To determine the feasibility of universal newborn hearing screening,
including intervention of identified infants, in the state of New York. DESIGN:
The New York State Department of Health issued a request for proposals that
invited regional perinatal centers to apply for funding to implement universal
newborn hearing screening. Hospitals were free to choose their own protocols but
were to use physiologically based measures to screen infants for possible hearing
loss. Criteria for passing the screening measures were common across sites.
Infants failing the screening were to have diagnostic testing. Identified infants
were to be followed by the state's Early Intervention Program and its associated
Infant-Child Health Assessment Program. RESULTS: Seven regional perinatal centers
(eight hospitals) representing the various regions of the state were funded for 3
yr to implement universal newborn hearing screening and follow-up of identified
infants. Detailed data analysis was performed for inpatient, outpatient, and
intervention outcome measures and for the various protocols. Most of the outcome
measures were analyzed in terms of year of program operation, nursery type, and
geographic region of the state. CONCLUSIONS: Universal newborn hearing screening
was feasible in regional perinatal centers across the state of New York. The
average ages of identification of hearing loss, hearing aid fitting, and
enrollment in early intervention were less than those reported in published
studies where universal newborn hearing screening was not in place.
PMID- 10777017
TI - New York State universal newborn hearing screening demonstration project:
inpatient outcome measures.
AB - OBJECTIVE: To evaluate the feasibility of universal newborn hearing screening by
examining inpatient outcome measures from 8 hospitals located in geographically
diverse areas of New York State over a 3-yr period. DESIGN: Funding was provided
by the New York State Department of Health to implement predischarge hearing
screening programs in the neonatal intensive care units (NICUs) and well-baby
nurseries (WBNs) of eight hospitals. Various screening protocols including
transient evoked otoacoustic emissions alone or in combination with conventional
auditory brain stem response or screening auditory brain stem response were
implemented by each site. Measured outcomes included rate of misses, refusals,
and fails. Results were analyzed as a function of year of operation, nursery
type, and geographic location. RESULTS: Six out of eight hospitals successfully
implemented universal hearing screening during the first year, and the remaining
2 hospitals implemented programs during the second year of the project. Over a
period of 3 yr, 69,761 newborns were screened at the eight hospitals representing
96.9% of all live births. The overall fail rate (4.04%) combined with the miss
rate (2.61%) resulted in 6.63% of infants referred for outpatient follow-up. Mean
data indicated that inpatient outcome measures improved with year of operation,
with most individual hospitals also showing improvements. Both fail and miss
rates were higher in the NICU than in the WBN and for hospitals located in New
York City than in other regions of the state. CONCLUSIONS: Inpatient outcome
measures of a universal newborn hearing screening project, which involved
multiple centers across geographically diverse regions of New York State, were
acceptable in terms of successfully screening a high percentage of live births
and attaining low refer rates for outpatient screening. This study adds to the
growing body of literature supporting the feasibility of screening all newborns
before hospital discharge.
PMID- 10777018
TI - The New York State universal newborn hearing screening demonstration project:
outpatient outcome measures.
AB - OBJECTIVE: To investigate outpatient outcome measures of a multi-center, state
wide, universal newborn hearing screening project. DESIGN: Eight hospitals
participated in a 3-yr, funded project. Each hospital designed its own protocol
using common criteria for judging whether an infant passed a hearing screening.
Infants were tested in the hospital, and those either failing the in-hospital
screening or who were not tested in the hospital (missed) were asked to return 4
to 6 wk after hospital discharge for outpatient rescreening. Those infants
failing the outpatient rescreening were referred for diagnostic auditory brain
stem response testing. Each hospital used its own audiological equipment and
criteria to determine whether a particular infant had a hearing loss. All data
were collected and analyzed for individual hospitals, as well as totaled across
all hospitals. Data were analyzed in terms of year of program operation, nursery
type, and geographic region. RESULTS: Seventy-two percent of infants who failed
the in-hospital screening returned for outpatient testing. The percentage of in
hospital fails returning for retesting was significantly higher than the
percentage of in-hospital misses returning for retesting. The percentage of
infants returning for retesting increased with successive years of program
operation. Some differences were noted in the percentage of infants returning for
retesting among hospitals and geographic regions of the state. Some differences
in outpatient outcome measures also were noted between infants originally born
into the neonatal intensive care unit (NICU) and the well-baby nursery (WBN). The
percentage of infants from the NICU who returned for retesting was slightly
higher than that for infants from the WBN. The percentage of infants from the WBN
passing the outpatient rescreening was higher than that for the NICU infants. The
overall prevalence of hearing loss was 1.96/1000, with that in the NICU being
8/1000 and that in the WBN being 0.9/1000. Positive predictive value for
permanent hearing loss based on inpatient screening was approximately 4% and
based on outpatient rescreening was approximately 22%. CONCLUSIONS: Several
outpatient outcome measures changed with successive years of program operation,
suggesting that programs improve over time. Also, some outpatient outcome
measures differ between NICU and WBN populations. The differences noted across
regions of the state in the percentage of infants returning for outpatient
retesting require further research to determine whether differences are due to
demographic and/or procedural differences.
PMID- 10777019
TI - The New York State universal newborn hearing screening demonstration project:
ages of hearing loss identification, hearing aid fitting, and enrollment in early
intervention.
AB - OBJECTIVE: To determine the ages of hearing loss identification, hearing aid
fitting, and enrollment in early intervention through a multi-center, state-wide
universal newborn hearing screening project. DESIGN: Universal newborn hearing
screening was conducted at eight hospitals across New York State. All infants who
did not bilaterally pass hearing screening before discharge were recalled for
outpatient retesting. Inpatient screening and outpatient rescreening were done
with transient evoked otoacoustic emissions and/or auditory brain stem response
testing. Diagnostic testing was performed with age appropriate tests, auditory
brain stem response and/or visual reinforcement audiometry. Infants diagnosed
with permanent hearing loss were considered for hearing aids and early
intervention. Ages of hearing loss identification, hearing aid fitting, and
enrollment in early intervention were investigated regarding nursery type, risk
status, unilateral versus bilateral hearing loss, loss type, loss severity, and
state regions. RESULTS: The prevalence of infants diagnosed with permanent
hearing loss was 2.0/1000 (85 of 43,311). Of the 85 infants with hearing loss,
61% were from neonatal intensive care units (NICUs) and 67% were at risk for
hearing loss. Of the 36 infants fitted with hearing aids, 58% were from NICUs and
78% were at risk for hearing loss. The median age at identification and
enrollment in early intervention was 3 mo. Median age at hearing aid fitting was
7.5 mo. Median ages at identification were less for infants from the well-baby
nurseries (WBNs) than for the NICU infants and for infants with severe/profound
than for infants with mild/moderate hearing loss, but were similar for not-at
risk and at-risk infants. Median ages at hearing aid fitting were less for well
babies than for NICU infants, for not-at-risk infants than for at-risk infants,
and for infants with severe/ profound hearing loss than for infants with mild/
moderate hearing loss. However, median ages at early intervention enrollment were
similar for nursery types, risk status, and severity of hearing loss.
CONCLUSIONS: Early ages of hearing loss identification, hearing aid fitting, and
enrollment in early intervention can be achieved for infants from NICUs and WBNs
and for infants at risk and not at risk for hearing loss in a large multi-center
universal newborn hearing screening program.
PMID- 10777020
TI - New York State universal newborn hearing screening demonstration project: effects
of screening protocol on inpatient outcome measures.
AB - OBJECTIVE: To examine differences among various test protocols on the fail rate
at hospital discharge for infants in the well-baby nursery (WBN) and neonatal
intensive care unit (NICU) who received hearing screening through a universal
newborn hearing screening demonstration project. DESIGN: The outcomes of several
screening protocols were examined. Two technologies were used: transient evoked
otoacoustic emissions (TEOAEs) alone or in combination with the auditory brain
stem response (ABR). The performance of test protocols in both nurseries within
eight hospitals was examined over a 2- to 3-yr period. In the WBN, six hospitals
used a screening protocol of TEOAE technology first followed by an ABR (automated
or conventional) technology screening for newborns who referred on TEOAE
screening. Two hospitals used TEOAE only in the WBN. Seven hospitals used
screening protocols in the NICU that used a combination of TEOAE and ABR
technologies (TEOAE technology administered first or second, before or after
TEOAE, or TEOAE and ABR tests on all infants). Only one hospital used TEOAE
technology exclusively for hearing screening. RESULTS: Significant differences
among screening protocols were found across hospitals in the first, second, and
third years of the program. The combination of TEOAE technology and ABR
technology (a two-technology screening protocol) resulted in a significantly
lower fail rate at hospital discharge than the use of a single-technology
(TEOAE). Fail rates at discharge were twice as high using the one-technology
protocol versus two-technology protocol, even when the best outcomes from program
year 3 were considered exclusively. Results of two-technology versus one
technology protocols were similar in the NICU. Use of a second technology for
screening TEOAE fails significantly reduced every hospital that used the
protocol's fail rate at discharge. CONCLUSIONS: A two-technology screening
protocol resulted in significantly lower fail rates at hospital discharge in both
the WBN and NICU nurseries than use of a single-technology (TEOAE) hearing
screening protocol.
PMID- 10777021
TI - Binaural gap duration discrimination in listeners with impaired hearing and
normal hearing.
AB - OBJECTIVE: This study was designed to measure the ability of listeners with and
without sensorineural hearing loss to discriminate silent gaps between noise band
markers of different frequencies presented in an anechoic and a reverberant
listening environment. DESIGN: A two-interval, two-alternative, forced-choice
paradigm was used to measure gap discrimination ability for six listeners with
normal-hearing and six listeners with sensorineural hearing impairment. Marker
stimuli were narrow bands of noise centered at frequencies from 500 to 7000 Hz.
The center frequency of the leading marker was held constant at 2000 Hz and the
center frequency of the trailing marker was varied randomly across runs. Stimuli
were presented in two virtual listening environments (anechoic and reverberant).
The listeners' task was to indicate which interval contained the marker pair
separated by the larger silent gap. Gap discrimination was measured as a function
of the center frequency of the trailing marker and as a function of listening
environment. RESULTS: Gap discrimination thresholds (msec) varied as a function
of the center frequency of the trailing marker. As the trailing marker frequency
increased above and decreased below the leading marker frequency (2000 Hz), gap
thresholds increased significantly. Hearing loss and listening environment did
not have a significant effect on gap discrimination thresholds. Analysis of the
gap discrimination functions revealed significantly steeper slopes for trailing
marker frequencies below 2000 Hz than for trailing marker frequencies above 2000
Hz. A possible age effect was observed in the data and significant correlations
were found between age and function slopes for several conditions. CONCLUSIONS:
Gap discrimination becomes more difficult as the frequency disparity between
leading and trailing noise bands increases. This pattern of results occurs
independent of hearing loss but may be influenced by listener age.
PMID- 10777023
TI - Comparison of EAP thresholds with MAP levels in the nucleus 24 cochlear implant:
data from children.
AB - OBJECTIVE: The purpose of this study is to examine the relationship between the
electrically evoked compound action potential (EAP) thresholds and the MAP
thresholds (T-levels) and maximum comfort levels (C-levels) in children implanted
with the Nucleus 24 device. DESIGN: EAP thresholds were measured using the Neural
Response Telemetry system of the Nucleus 24 device. Twenty children implanted
with the Nucleus 24 cochlear implant participated in this study. EAP thresholds
were compared with the behavioral measures of T- and C-level used to construct
the MAP these children used on a daily basis. For these subjects, both EAP and
MAP T- and C-levels were obtained the same visit, which occurred at 3 to 5 mo
postconnection. RESULTS: EAP thresholds were shown to fall between MAP T- and C
level for 18 of 20 subjects tested; however, considerable variability across
subjects was noted. On average, EAP thresholds fell at 53% of the MAP dynamic
range. Correlations between EAP threshold and MAP T- and C-level improved
substantially when combined with behavioral measures obtained from one electrode
in the array. CONCLUSIONS: Moderate correlations were found between EAP
thresholds and MAP T- and C-levels for the children participating in this study.
However, a technique is described for improving the accuracy of predictions of
MAP T- and C-levels based on EAP data combined with a small amount of behavioral
information.
PMID- 10777022
TI - The relationship between EAP and EABR thresholds and levels used to program the
nucleus 24 speech processor: data from adults.
AB - OBJECTIVE: The objective of this study was to determine the relationship between
electrically evoked whole nerve action potential (EAP) and electrical auditory
brain stem response (EABR) thresholds and MAP threshold (T-level) and maximum
comfort level (C-level) for subjects who use the Nucleus 24 cochlear implant
system. DESIGN: Forty-four adult Nucleus 24 cochlear implant users participated
in this study. EAP thresholds were recorded using the Neural Response Telemetry
System developed by Cochlear Corporation. EABR thresholds were measured for a
subset of 14 subjects using standard evoked potential techniques. These
physiologic thresholds were collected on a set of five electrodes spaced across
the cochlea, and were then compared with behavioral measures of T-level and C
level used to program the speech processor. RESULTS: EAP thresholds were
correlated with MAP T- and C-levels; however, the correlation was not strong. A
technique for improving the correlation by combining measures of T- and C-levels
made on one electrode with the EAP thresholds was presented. Correlations between
predicted and measured T- and C-levels using this technique were 0.83 and 0.77,
respectively. Similar results were obtained using the EABR thresholds for a
smaller set of subjects. In general, EABR thresholds were recorded at levels that
were approximately 4.7 programming units lower than EAP thresholds. CONCLUSIONS:
Either EAP or EABR thresholds can be used in combination with a limited amount of
behavioral information to predict MAP T- and C-levels with reasonable accuracy.
PMID- 10777024
TI - Quantitation of the five forms of plasma high molecular weight angiotensinogen in
women with pregnancy-induced hypertension.
AB - In the human pregnant state a high molecular weight form of angiotensinogen
(HMrA) is present in significant quantities in addition to the usual low
molecular weight angiotensinogen (LMrA). In a previous study involving a small
number of white women, it was found that women who had developed pregnancy
induced hypertension (PIH) had significantly higher levels of plasma HMrA. It has
been determined that there are five isoforms of HMrA. The objectives of this
study were to expand the previous study with the inclusion of black women and to
determine which isoform(s) of plasma HMrA are elevated in PIH. Plasma LMrA and
HMrA were quantitated in 24 normotensive pregnant women and 65 women with PIH.
The PIH group had higher levels of HMrA and somewhat lower levels of LMrA than
the normotensive group. The HMrA/LMrA ratio was elevated in 47% of the PIH group.
The five isoforms of HMrA were quantitated in plasma from 10 white women with
PIH, 10 black women with PIH, and 6 normotensive pregnant white women. Half of
both the white and black women with PIH had an elevated HMrA/LMrA ratio. The
relative proportion of the HMrA isomers was similar in all groups. These studies
show that half the women with PIH have a distinct abnormality in their renin
angiotensin system. Both white and black women show this abnormality. In those
women who have an elevated total HMrA, all five isoforms of HMrA are equally
elevated.
PMID- 10777025
TI - Left ventricular geometry in pregnancy-induced hypertension.
AB - The changes induced by transient hypertension upon cardiac geometry (G) are
unclear. Pregnancy-induced hypertension (PIH) offers a natural and spontaneous
model of this condition. To assess geometric changes according to two
dimensionally guided M-mode echocardiography, we compared patients with PIH with
normal pregnant women (NPW). Fifty-five women, aged 28.5 +/- 7.5 years, with PIH
(defined as blood pressure >140/90 mm Hg in the third trimester of pregnancy and
without a history of hypertension) were compared with 57 NPW aged 30.7 +/- 7.5
years. Left ventricular mass index (LVMI) (Devereux formula) and relative wall
thickness (RWT) (Ganau formula) were calculated by means of echocardiography done
in the left lateral decubitus 2 to 4 days postpartum. Subjects were considered to
have: normal geometry (NG) if both LVMI and RWT fell below the mean +/- 1 SD or 2
SD; concentric hypertrophy (CH) if both were elevated; eccentric hypertrophy (EH)
if LVMI was elevated and RWT was normal; and concentric remodeling (CR) if LVMI
was normal and RWT was elevated. Comparisons were performed by the Student t
test. Patients with PIH had higher LVMI (106 +/- 29.4 v 90.6 +/- 19.8 g/m2; P <
.05) and RWT (0.41 +/- 0.07 v 0.38 +/- 0.05; P < .05). Considering the mean +/- 1
SD of NPW as the limit of normality the G pattern was NG in 26 (47%) and abnormal
in 29 (53%), of which 14 (25.5%) had EH, 11 (20%) had CR, and four (7%) had CH.
If we considered the mean +/- 2 SD, the G pattern was NG in 46 (84%) and abnormal
G in nine (16%), EH in four (7%), CR in three (5%), and CH in 2 (4%). According
to these data, women with PIH had higher LVMI and RWT compared with NPW. The most
frequent abnormal G patterns were EH and CR.
PMID- 10777026
TI - Hypertension after liver transplantation: a predictive role for pretreatment
hemodynamics and effects of isradipine on the systemic and renal circulations.
AB - Hypertension developing after liver transplantation during immunosuppression with
cyclosporine A reflects an unusual hemodynamic transition from peripheral
vasodilation to systemic and renal vasoconstriction. Although dihydropyridine
calcium channel blockers are often administered for their efficacy in promoting
vasodilation, some liver transplant recipients report marked symptomatic
intolerance to these agents. In the present study we examined systemic and renal
responses to isradipine using systemic (thoracic bioimpedance) and renal
hemodynamic measurements in 15 liver transplant recipients studied at the time of
initial diagnosis of posttransplant hypertension and after 3 months of treatment.
Circadian blood pressure patterns were examined by overnight ambulatory blood
pressure monitoring before and during antihypertensive therapy. During isradipine
administration, blood pressure decreased from 151 +/- 3/91 +/- 2 to 130 +/-3/81
+/- 2 mm Hg (P < .01) without change in renal blood flow (406 +/- 43 to 425 +/-
52 mL/min/1.73m2, P = NS) or renal vascular resistance index (25,674 +/-3312 to
20,520 +/- 2311 dynes x sec x cm(-5)/m2, P = NS). Pre-treatment differences in
systemic vascular tone persisted during treatment and predicted the tendency for
symptomatic tachycardia and flushing, predominantly in those with hyperdynamic
circulations. Twice daily dosing of isradipine was associated with partial and
significant restoration of the nocturnal decrease in blood pressure (systolic
blood pressure decreased 5.5%, normal 13%), usually absent early after
transplantation. Our results demonstrate the ability of hemodynamic measurements
to predict the symptomatic response to antihypertensive therapy in the
posttransplant setting.
PMID- 10777027
TI - Insulin and hypertension in the NHLBI Family Heart Study: a sibpair approach to a
controversial issue.
AB - The association between insulin and hypertension remains equivocal. We therefore
investigated insulin levels in 3037 normotensive and 1067 hypertensive subjects
from the National Heart, Lung and Blood Institute (NHLBI) Family Heart Study
(FHS) by two different approaches. First, we compared insulin levels between
normotensive and 275 untreated hypertensive subjects. Insulin levels unadjusted
as well as adjusted for age, sex, and center were significantly higher in
hypertensives. After adjustment for body mass index (BMI), insulin remained
significantly higher only in the diastolic hypertensive group (mean +/- SD 77.0
+/-36.7 pmol/L, P < .01) but not in the isolated systolic hypertensive group
(67.0 +/- 38.2 pmol/L) when compared to normotensives (63.2 +/- 29.1 pmol/L). A
sibpair analysis was then used that compared the intra-sibpair differences in
insulin concentrations to the intra-sibpair differences in blood pressure (BP)
levels. This approach was intended to control for the effects of genetic and
residual shared environmental variance upon insulin levels. The intra-sibpair
difference in insulin concentrations between concordant (diastolic and systolic
deltaBP < 5 mm Hg) and discordant sibpairs (diastolic and systolic deltaBP > 15
and > 20 mm Hg, respectively) was no longer significantly different when adjusted
for BMI (2.7 v 5.9 pmol/L for diastolic and -1.7 v -1.8 pmol/L for systolic BP).
Even the random selection of one sibpair from each of the 326 families
independently of insulin and BP levels did not result in a significant
correlation between the intrasibpair differences in insulin and BP. Using an
insulin resistance index instead of insulin did not change our findings. Our
investigation in the FHS sample of families suggests that there is only a small,
if any, influence of insulin levels on BP after adjustment for obesity-related
sources of variation.
PMID- 10777028
TI - Marked weight reduction lowers resting and exercise blood pressure in morbidly
obese subjects.
AB - Obesity and high blood pressure (BP) often coexist. Weight reduction lowers
resting BP but its effect on BP during exercise (a predictor of target organ
damage) has not been evaluated. Blood pressure was measured at rest and during
cycling, before and after weight reduction induced by gastric restriction.
Nineteen subjects (4 male), 41 +/-2 (SEM) years of age and body mass index (BMI)
of 43 +/- 0.9 kg/m2, were studied. On each occasion BP was measured at rest, at a
steady state of 0 and 25 watts, at peak exercise and 1 min into recovery. Body
weight was reduced by 28% +/- 6% and BMI decreased from 43.3 +/- 0.9 to 31.5 +/-
0.7 kg/m2 (P < .01). Both BP and heart rate, at rest and at all exercise
intensities, were significantly lower after weight reduction. Resting BP
decreased from 133 +/-4/87 +/- 3 mm Hg to 115 +/- 4/77 +/- 2 mm Hg (P < .001),
and BP at peak exercise decreased from 181 +/- 8/98 +/- 4 to 162 +/- 6/83 +/- 5
mm Hg (P < .001). The change in resting systolic BP did not correlate with the
change in body weight or with the change in heart rate, but it correlated with
the baseline systolic BP (R = 0.61; P < .005). It is concluded that marked weight
reduction reduces BP at rest and at all exercise intensities. Gastroplasty should
be considered as an option in morbidly obese hypertensive patients who are not
well controlled with conventional treatment, and who fail to lose or to maintain
a reduced weight by calorie restriction alone.
PMID- 10777029
TI - Transvascular albumin leakage and forearm vasodilatation to acetylcholine in
essential hypertension.
AB - The impact of hypertension on microvascular permeability and nitric oxide
mediated endothelial vasomotion in humans has been studied by measuring either
the transcapillary albumin escape rate (TERalb, a measure of permeability through
systemic capillary endothelium where most of the albumin permeation takes place)
and forearm vasodilatation to locally infused acetylcholine (used as a probe for
the nitric oxide-releasing potential of arteriolar endothelial cells). It is
unknown, however, how the two parameters relate to each other in the same
hypertensive subject. This piece of evidence may enhance our understanding about
the relative effect of hypertension on two biological functions (ie, permeability
and nitric oxide-mediated vasomotion), both dependent on vascular endothelium,
and also may allow to appreciate in greater detail the profile of parameters
frequently used as markers of microvascular dysfunction in human hypertension.
For these reasons, TERa1b (the 1-h decline rate of intravenous 125I-albumin) and
forearm vasodilatation (strain gauge venous plethysmography) to graded
intraarterial acetylcholine infusion were measured in 44 never-treated men with
uncomplicated essential hypertension, and 15 male normotensive controls with
comparable age, lipids, and proportion of current smokers. TERalb was increased
in patients, whereas acetylcholine-mediated vasodilatation did not differ
significantly between the two groups, indicating a heterogeneous impact of
elevated blood pressure on capillary permeability and endothelial vasomotion in
still uncomplicated mild to moderate essential hypertensive patients. The
dissociation between TERalb and forearm responsiveness to acetylcholine also
demonstrates that different endothelial-dependent biologic parameters do not
behave uniformly in human hypertension.
PMID- 10777030
TI - The relationship of electronically monitored physical activity to blood pressure,
heart rate, and the circadian blood pressure profile.
AB - We studied how closely changes in electronically monitored physical activity are
reflected in changes in blood pressure and heart rate in a group of untreated
hypertensive subjects. Thirty-nine hypertensive patients (office blood pressure >
140/ 90 mm Hg) of mean age 57 +/- 10 years (mean +/-SD) wore an ambulatory blood
pressure monitor and a wrist actigraph simultaneously. Both average and peak
activity for 5 min before each valid blood pressure reading were determined, as
was average activity for awake and sleep periods, determined by patient kept
diaries. For the overall group, awake and 24-h activities were inversely
correlated to age (n = 39, r = -0.42; P = 0.01 and n = 39, r = -0.38; P = 0.01,
respectively). No correlation was found between group awake activity and group
average blood pressure or heart rate. For individual patients, there was marked
variation in the degree of correlation between awake activity measures (both peak
and average) and blood pressure and heart rate. The strongest positive
correlation was between activity levels and the heart rate-pressure product.
Nondipper profile hypertensives had higher sleep activity than dipper
hypertensives (44 +/- 28 units/min v 25 +/- 20 units/min, df = 37, t = 2.12; P =
0.04), but awake activity levels were similar. The higher sleep activity remained
after adjustment for age. These findings indicate that the relationship between
actigraphic activity and hemodynamic parameters is highly variable and that the
rate-pressure product is the strongest correlate of short-term activity.
Furthermore, hypertensives with the nondipper profile have higher sleep activity
than dipper hypertensives. These findings stress the need for further study into
the role of day-to-day activity in determining ambulatory blood pressure and
heart rate variability.
PMID- 10777031
TI - Reference values of indices of spontaneous baroreceptor reflex sensitivity.
AB - Spontaneous baroreceptor reflex sensitivity (BRS) is a well established method
for determining baroreflex function, which can be used to assess the potential
impact on survival after myocardial infarction, to detect autonomic dysfunction
in diabetic patients and in human essential hypertension. The assessment of
impaired spontaneous baroreflex function in individual patients contains
important clinical information, but age-dependent reference values are still
lacking. In the present study we evaluated spontaneous BRS in healthy human
controls to determine reference values as a function of age. Two hundred and
sixty-two healthy volunteers divided into six age groups (I: <20 years, f = 11, m
= 9, II: 20-29 years, f = 42, m = 37, III: 30-39 years, f = 23, m = 37, IV: 40-49
years, f = 27, m = 22, V: 50-59 years, f = 19, m = 17, VI: 60-69 years, f = 5, m
= 13). Electrocardiograms (ECG) and finger arterial BP were measured with each
subject in the supine position (sup, 7 min) and during deep breathing (dB, 6/min,
15 cycles). BRS was assessed using the sequence technique and the alpha
coefficients as obtained from a power spectrum density estimate. Due to the
normal logarithmic distribution of the BRS, the limits for impaired baroreflex
function at rest were defined from logarithmic data. The limits for the BRS at
rest (P = .025) were calculated as (-0.0283 x age) + 2.5198 for the sequence
technique. We did not find significant differences in BRS among the female and
male healthy volunteers. Our analysis of the six age groups showed the expected
significant decrease in BRS, which was most prominent at the transition from
group III (<40 years) to group IV (<50 years). BRS at rest and during deep
breathing as well as sequential and spectral BRS indices did differ
significantly. The results underline the necessity of reference values to
evaluate impaired baroreflex function in individual patients.
PMID- 10777032
TI - Measurement variation among 12 electronic home blood pressure monitors.
AB - Although there are AAMI and BHS standards for accuracy of electronic home
electronic blood pressure monitors (HBPM), patient composition differences and
differences in manufacturer's algorithm for calculation of the systolic and
diastolic measurement may result in measurement differences between monitors. The
aim of this study was the measurement of differences among HBPM. Paired
comparisons were performed between the Omron 712c electronic home monitor and
each of 12 other HBPM (Sunbeam 7654, Sunbeam 7623, Omron 711, Omron 432c, A&D
UA767, Lumiscope 1085M, Omron 725CIC, Assure A30, Lumiscope 1083N, Omron 815,
Omron 605, and Assure BD-W20), in addition to comparison to the auscultatory
method by trained observers. Measurements were made in normotensive subjects in
an ambulatory setting. The main outcome measures were systolic and diastolic
blood pressure measurements. All of the HBPM, except for the Sunbeam 7654 and the
Assure A30/ BD-W20 (wrist) models, demonstrated small differences of <4/4 mm Hg
for systolic/diastolic measurements with pulse measurement differences of <3
beats/min. These differences were less than the differences previously reported
for office BP auscultation of 6/5-10 mm Hg for systolic/diastolic measurements.
The Omron 712c, passing previous AAMI and BHS standards, measured the systolic
reading within 2 mm Hg of auscultatory mercury or aneroid measurement and under
measured the diastolic by 6-9 mm Hg. Differences in the patient composition
studied could account for the difference. The wrist and finger manometers
performed clinically similar to the Omron 712c, except for the Assure BD-W20,
which overmeasured the diastolic by 7 mm Hg. It is concluded that the small
differences among the various HBPM, which are less than those in clinical office
auscultation, should encourage greater use of electronic manometers in the office
and at home.
PMID- 10777033
TI - Renin-angiotensin system in two genetically normotensive strains of Lyon rats.
AB - Compared to the Lyon normotensive (LN) controls, adult Lyon hypertensive rats
(LH) exhibit a renin-angiotensin system (RAS) dependent hypertension despite a
low renin secretion. This discrepancy could be explained by the elevated slow
pressor response to angiotensin II (AII) found in LH rats compared to LN
controls. To evaluate more precisely the pathophysiological importance of this
increased response, the present work aimed at determining whether the
characteristics of the RAS were identical in LN and low blood pressure (LL) rats,
the other normotensive control strain simultaneously selected with LH rats.
Plasma and kidney renin and prorenin were measured in 11-week-old LN and LL rats.
Aortic blood pressure (BP) was recorded at 15 weeks of age in freely moving rats
of both strains either untreated or having received an angiotensin converting
enzyme inhibitor, perindopril (3 mg/kg/day orally) since the age of 3 weeks.
Acute dose-response curves were constructed for AII and norepinephrine (NE). The
long-term pressor effects of AII (200 ng/kg/ min) and NE (1000 ng/kg/min) were
measured after chronic infusions in perindopril-treated LN and LL rats. LN and LL
rats exhibited similar mean BP level before (114 +/- 2 and 117 +/- 2 mm Hg,
respectively) and after perindopril treatment (91 +/-3 and 93 +/- 1 mm Hg,
respectively). Plasma and kidney renin and prorenin were decreased in LL rats. In
acute conditions, LL rats exhibited an unspecific hypersensitivity to AII and NE.
Chronically given AII exerted a greater pressor effect in LL than in LN rats
after 4 weeks (113 +/- 3 v 97 +/- 5 mm Hg in LL and LN rats respectively, P <
.05) and, even more, after 8 weeks of infusion (144 +/- 9 v 124 +/- 4 mm Hg in LL
and LN rats respectively, P < .05). The NE was devoid of chronic pressor effects.
In conclusion, 1) the increased slow pressor response to AII may not be a
critical pathogenetic factor in the development of hypertension, as it also
exists in normotensive LL rats; 2) LN and LL rats have the same normal BP despite
marked differences in their RAS, thus suggesting that there could be several
forms of normotension as known for hypertension; and 3) the simple comparison
between one genetically hypertensive strain and one single normotensive control
strain does not allow one to conclude that a phenotypic difference is of
pathophysiological significance.
PMID- 10777034
TI - The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II
receptor antagonist on insulin resistance in fructose-fed rats.
AB - The aim of this study was to compare the effects of an angiotensin-converting
enzyme (ACE) inhibitor and an angiotensin II receptor (AT) antagonist on insulin
resistance, especially on muscle fiber composition in fructose-induced insulin
resistant and hypertensive rats. Six-week-old male Sprague-Dawley rats were fed
either normal rat chow (control) or a fructose-rich diet (FFR). For the last two
weeks of a six-week period of either diet, the rats were treated with gum arabic
solution as a vehicle (control or FFR), angiotensin-converting enzyme inhibitor
(FFR+ACE), temocapril (1 mg/kg/ day) or an angiotensin II receptor antagonist
(FFR+AT), CS-866 (0.3 mg/kg/day), by gavage, and then the euglycemic
hyperinsulinemic glucose clamp technique was performed to evaluate insulin
sensitivity. At the end of the glucose clamp, the soleus muscle was dissected for
determination of the muscle fiber composition by ATPase methods. Blood pressure
at the glucose clamp in the FFR group was significantly higher than that of the
control group, and both temocapril and CS-866 significantly lowered the blood
pressure of the FFR group. The average rate of glucose infusion during the
glucose clamp, as a measure of insulin sensitivity (M value), was significantly
lower in the FFR rats compared to the controls (15.4 +/- 0.4, 10.9 +/- 0.6
mg/kg/min, for control and FFR, respectively, P < .01). Both temocapril and CS
866 partially improved the M values compared to FFR (13.2 +/- 0.7, 12.8 +/- 0.5
mg/kg/min, for FFR+ACE, FFR+AT, respectively, P < .01 compared with FFR, P < .05
compared with control). The composite ratio of type I fibers of the soleus muscle
was decreased significantly in the FFR rats compared with the controls (82% +/-
2%, 75% +/- 2%, for control and FFR, respectively, P < .01), and both temocapril
and CS-866 restored a composite ratio of type I fibers to the same level as that
of the controls (81% +/- 1%, 80% +/- 1% for FFR+ACE and FFR+AT, respectively).
The M value was significantly correlated with the composition of type I and type
II fibers. These results suggest that the fiber composition of skeletal muscle is
correlated to insulin resistance, and that both ACE inhibitors and AT antagonists
may modulate the muscle fiber composition in a hypertensive and insulin-resistant
animal model, fructose-fed rats, to the same extent.
PMID- 10777035
TI - Renal-protective effect of nondepressor dose of cicletanine in diabetic rats with
hypertension.
AB - We assessed the renal and cardiac benefits of cicletanine (CIC), a furopyridine
derivative drug with diuretic and antihypertensive properties, in diabetic
spontaneously hypertensive rats with renal impairment. Uninephrectomized
streptozotocin (STZ)-diabetic spontaneously hypertensive Izmo rats (SHRIzm) (10
weeks old) were randomly assigned to receive vehicle or CIC (100 mg/kg/day,
orally), and age-matched, uninephrectomized STZ diabetic Wistar-Kyoto Izmo rats
(WKYIzm) were assigned to receive vehicle for up to 12 weeks. Blood pressure
increased progressively in diabetic SHRIzm but not in diabetic WKYIzm. Urinary
albumin excretion increased significantly in both diabetic SHRIzm and diabetic
WKYIzm throughout the experiment. The antihypertensive effect of CIC was not
significantly observed in diabetic SHRIzm. However, the subdepressor doses of CIC
significantly decreased urinary albumin excretion, serum creatinine, and blood
urea nitrogen in diabetic SHRIzm. These results were confirmed by morphological
analysis of kidneys in each group of rats. The index of focal glomerular
sclerosis (FGS) in diabetic SHRIzm was significantly higher than that in diabetic
WKYIzm. The CIC treatment significantly and effectively protected against an
increase in the index of FGS in diabetic SHRIzm. Moreover, CIC treatment
significantly attenuated the increase in the heart weight to body weight ratio in
diabetic SHRIzm. Treatment with CIC did not affect urinary and blood glucose
concentrations at this dose. These results suggest that CIC has a renal
protective action, which is not related to improvement of diabetes or improvement
of high blood pressure in diabetic rats with hypertension. The action might be
due to the reduction of intraglomerular capillary pressure or protection of the
renal glomerular vascular endothelial cell injury and mesangial cell injury
through stimulation of PGI2 generation or elimination of free radicals, although
the mechanism remains to be further investigated.
PMID- 10777036
TI - Interaction of alcohol and an alpha1-blocker on ambulatory blood pressure in
patients with essential hypertension.
AB - Ingestion of alcohol acutely decreases vascular resistance and blood pressure
(BP) with activation of the sympathetic nervous system in Orientals. Although
alpha1-blockers are widely used in the treatment of hypertension, the possible
interaction between alcohol and alpha1-blockers has not been clarified. We
examined the effects of prazosin on the alcohol-induced BP changes in Japanese
men with mild hypertension. Ten hypertensive patients (54 +/- 3 years, mean +/-
SE) were given 1 mL/kg of alcohol or isocaloric control drink with a light meal
in the evening before and 5 to 7 days after treatment with prazosin (1 mg three
times daily). Ambulatory BP monitoring was carried out every 30 min for 24 h in
each period using Colin ABPM-630. Blood samples were obtained before and 2 h
after intake of alcohol or control drink. Before prazosin treatment, alcohol
ingestion decreased BP for several hours with a significant reduction in average
24-h BP, whereas it increased heart rate, plasma norepinephrine, and plasma renin
activity. Treatment with prazosin caused a significant decrease in 24-h BP (136.3
+/- 4.0/82.8 +/- 2.5 v 131.6 +/- 3.2/80.0 +/- 2.3 mm Hg). The alcohol-induced
hypotension at 2-4 h after ingestion was enhanced by prazosin (-18.0 +/- 3.7/
11.8 +/- 2.7 v -24.4 +/- 4.9/-17.8 +/- 2.8 mm Hg, P < .05 for diastolic BP).
These results suggested that inhibition of the sympathetic nervous system with
alpha1-blockers accentuates alcohol-induced hypotension. Ingestion of alcohol may
cause a marked BP reduction in hypertensive Orientals treated with alpha1
blockers.
PMID- 10777037
TI - Population advice on salt restriction: the social issues.
PMID- 10777038
TI - "Salt": a commentary.
PMID- 10777040
TI - Effect of three programmes for the treatment of endometritis on the reproductive
performance of a dairy herd.
AB - Three management programmes to improve the reproductive performance of a dairy
herd were compared in a prospective controlled field study on one commercial
farm. A total of 542 cows were examined for endometritis 22 to 28 days postpartum
and assigned to one of three treatment groups: in group 1 the cows with signs of
endometritis were treated with an intrauterine infusion of 100 ml of a 2 per cent
polycondensated m-cresolsulphuric acid formaldehyde solution; in group 2 the cows
with signs of endometritis were treated with an intrauterine infusion of 125 ml
of a 20 per cent eucalyptus compositum solution; and in group 3 all the cows were
injected intramuscularly with 0.75 mg of tiaprost, an analogue of prostaglandin
F2alpha (PGF2alpha) at two-week intervals, starting on day 43, until they were
inseminated. Thirty-four per cent of the cows showed signs of endometritis. In
group 3, oestrus detection efficiency was significantly higher than in groups 1
and 2 (P<0.05), the interval to first service was shorter, and the cows had fewer
days open than the cows in groups 1 and 2 (P<0.05). The results indicate that
management programmes based on the strategic use of PGF2alpha are an effective
alternative to traditional programmes based on rectal palpations and intrauterine
infusions to control endometritis at a herd level.
PMID- 10777039
TI - Detection of polymorphisms in the prion protein gene in a population of Irish
Suffolk sheep.
AB - Natural scrapie is associated with polymorphisms in the prion protein (PrP) gene.
In Suffolks, codon 171 is the codon at which most variation is found; RR171 is
thought to be associated with resistance to developing the clinical signs of the
disease and QQ171 is associated with susceptibility to the disease. The
objectives of this study were first to determine the PrP genotypes of Suffolk
stock rams in Ireland, and secondly to compare the genotype profiles of ram lambs
from flocks where a breeding programme based on the genotype AA136RR154RR171 had
been initiated and from flocks where there was no breeding programme based on PrP
genotype. Approximately 13 per cent of the stock rams genotyped in the Irish
population were genetically susceptible to showing the clinical signs of the
disease. However, lambs from farms that had initiated a selective breeding
strategy for RR171 over the past year had a larger proportion of RR171 and a
smaller proportion of QQ171 than the stock rams or ram lambs from farms not
applying a breeding strategy.
PMID- 10777041
TI - Omphalocele in a foal.
AB - An omphalocele was detected at birth in a male Arabian foal. The mass contained
small intestine and after releasing a constricting band at the body wall, the
contents slipped easily back into the abdomen. On the outside was the hairless
pink membrane. The interior, now empty of small intestine, contained the
umbilical arteries and vein, and a large urachus that extended from the bladder
to the opening at the extremity of the mass. Six days after corrective surgery
the foal was sent home and remained healthy.
PMID- 10777042
TI - Detectability and prevalence of Brachyspira species in herds rearing health class
feeder pigs in Finland.
AB - Faeces samples were taken three times at two-week intervals, from the farrowing
units of four herds of known Brachyspira (formerly Serpulina) status and one of
unknown Brachyspira status. Brachyspira hyodysenteriae, Brachyspira pilosicoli,
Brachyspira intermedia and Brachyspira group III were isolated from the faecal
samples from the weaners in the herds using either a maximum of 50 ppm of
olaquindox or no feed additives. The detection rates were relatively consistent.
However, B hyodysenteriae was not detected at one sampling in a known positive
herd. The prevalence of Brachyspira species was also studied in feeder pigs
originating from LSO 2000 health class farrowing units, comparable with specific
pathogen-free herds. These farms were free from swine dysentery, sarcoptic mange,
swine enzootic pneumonia and progressive atrophic rhinitis. Fifty of 428 herds
were sampled once. B hyodysenteriae was not isolated from any of them, but B
intermedia, B pilosicoli and Brachyspira group III were isolated from five, 14
and 37 of the herds, respectively. The detection of Brachyspira species did not
relate to the prevalence of diarrhoea in the herds, as judged by the farmers. The
herds using carbadox (40 to 50 ppm) had a lower prevalence of Brachyspira species
than those using olaquindox (40 to 50 ppm).
PMID- 10777043
TI - Extensive fibrinous pleurisy associated with Streptococcus dysgalactiae mastitis
in two ewes.
PMID- 10777044
TI - Inflammatory cytokine profiles of calves and lambs with strongyloidosis.
PMID- 10777045
TI - Efficacy and pharmacokinetics of levamisole hydrochloride in goats with nematode
infections.
PMID- 10777046
TI - Correlation between MRI, computed tomographic findings and clinical signs in a
case of ovine coenurosis.
PMID- 10777047
TI - Attitudes to animal welfare.
PMID- 10777049
TI - NVQ training scheme.
PMID- 10777048
TI - Attitudes to animal welfare.
PMID- 10777050
TI - Grass sickness research.
PMID- 10777051
TI - Highly pathogenic avian influenza (H7N1) in ostriches farmed in Italy.
PMID- 10777052
TI - Effects of nutritional stress conditions on the ploidy and behavior of human
amniotic cells.
PMID- 10777053
TI - Unexpected effects of albumin on apoptosis induction by deferoxamine in vitro.
PMID- 10777054
TI - Selection, establishment and characterization of cell lines derived from a
chemically-induced rat mammary heterogeneous tumor, by flow cytometry,
transmission electron microscopy, and immunohistochemistry.
AB - In order to isolate, characterize, and establish culture cell lines with
different diagnostic and prognostic significance, derived from multiclonal
neoplasms, a ductal infiltrating mammary tumor was induced in rats by 7,12
dimethylbenz[a]anthracene. Clones with different DNA/protein content, being the
DI of 1.16, 1.30, and 1.60, respectively, were observed in the primary tumor.
Biparametric flow cytometry suggested that the clone at 1.30 is made up of two
subpopulations with different protein and slightly different DNA contents. The
culture, after a few passages, exhibited the presence of aneuploid cells and the
absence of diploid components, demonstrating that only tumor cells survived. The
limiting dilution method gave rise to four lines with DI of 1.16, 1.25, 1.30, and
1.50; a mean chromosome number of 45, 46, 47, and 88, respectively; and different
morphological and ultrastructural features. These characteristics were stable
during the experimental procedure, that is, for about 20 passages. Conversely,
the detection of cytoskeletal proteins indicated that the tumor epithelial cells
underwent early dedifferentiation into sarcoma-like cells showing markers of
stromal cell type and thus exhibiting phenotypic instability in vitro, a feature
reported in many advanced human breast cancers in vivo. In conclusion, this
cellular model represents the in vivo situation and appears suitable for in vitro
studies of tumor cell characteristics and might be used to predict clinical
behavior.
PMID- 10777055
TI - In vitro proliferation and in vivo malignancy of cell lines simultaneously
derived from a chemically-induced heterogeneous rat mammary tumor.
AB - Identification of clones in primary tumors responsible for proliferation,
invasion, and metastasis was carried out. Four different aneuploid established
cell lines derived from a ductal infiltrating mammary rat tumor induced by 7,12
dimethylbenz[a]anthracene were studied for proliferative and growth features in
vitro and for tumorigenic and metastatic potential in vivo in nude mice. Clones,
named RM1, RM2, RM3, and RM4, were characterized by different proliferative
activity. Clone RM1 showed the highest proliferative activity by both tritiated
thymidine incorporation and S-phase flow cytometry, followed by clone RM4.
Conversely, clones RM2 and RM3 showed a lower proliferation rate. Growth
promoting activity, tested on 3T3 Swiss cells, was high in all clones, although
RM1 showed significantly lower growth factors-releasing activity. Nude mice
tumorigenesis demonstrated a strong tumor induction of line RM1 (100% of the mice
after 47 +/- 7 d) and a slightly lower tumor induction of line RM4 (70% of the
mice after 69 +/- 9 d). Line RM3 showed tumor induction in 40% of the mice after
186 +/- 16 d. Lines RM2 showed no tumor induction. Metastasis occurred in mice
treated with line RM1 only. Therefore, tumorigenesis and metastasis correlate
with proliferation but not with the release of growth factors. In conclusion,
flow cytometry monitoring of clones from heterogeneous primary tumors proved to
be a suitable model for the study of in vivo malignancy and in vitro
proliferation.
PMID- 10777056
TI - Effect of electrical stimulation on beta-adrenergic receptor population and
cyclic amp production in chicken and rat skeletal muscle cell cultures.
AB - Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic
AMP (cAMP) synthesis are important components of the signaling system that
controls muscle atrophy and hypertrophy, and the goal of this study was to
determine if electrical stimulation in a pattern simulating slow muscle
contraction would alter the betaAR response in primary cultures of avian and
mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and
rat skeletal muscle cells that had been grown for 7 d in culture were subjected
to electrical stimulation for an additional 2 d at a pulse frequency of 0.5
pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells,
the betaAR population was not significantly affected by electrical stimulation;
however, the ability of these cells to synthesize cyclic AMP was reduced by
approximately one-half. In contrast, the betaAR population in rat muscle cells
was increased slightly but not significantly by electrical stimulation, and the
ability of these cells to synthesize cyclic AMP was increased by almost twofold.
The basal levels of intracellular cyclic AMP in neither rat muscle cells nor
chicken muscle cells were affected by electrical stimulation.
PMID- 10777057
TI - Adhesion of Drosophila imaginal disc cells in vitro.
AB - We have used our imaginal disc cell lines to carry out in vitro studies on the
cell-cell and cell-substrate adhesion of Drosophila leg and wing disc cells.
Single cells were allowed to reaggregate in roller culture, and this process was
found to be partially dependent on the presence of magnesium and calcium ions in
the suspension medium. Varying rates of reaggregation were observed in cells from
different stages of a passage, correlating with the pattern of morphogenesis
which occurs during the passage. We have demonstrated that cloned cell lines can
be produced showing certain selected characteristics, such as reduced cell
adhesiveness.
PMID- 10777058
TI - Cell-cell and cell-substrate adhesion in cultured Drosophila imaginal disc cells.
AB - Drosophila imaginal disc cell lines were used to investigate various aspects of
cellular adhesion in vitro. The distribution of PS integrins and their
involvement in cell-cell and cell-substrate adhesion were assessed with the
monoclonal antibody aBG-1 against the betaPS subunit, and both forms of adhesion
were found to be impeded by the presence of the antibody. Adhesion to a number of
extracellular matrix components was investigated, and the cells were found to
adhere to human fibronectin. This adhesion was inhibited by aBG-1. The adhesion
molecule fasciclin III was also found in these cells. Given that the cells are
competent to perform cell-cell and cell-substrate adhesion, it was thought that
apical basal polarity might be restored when other suitable conditions were
provided, i.e., an artificial basement layer with feeder cells to provide
nutrients basally to the cells, and some features of apical-basal morphology were
seen in cells cultured under these conditions.
PMID- 10777059
TI - Characterization of cancer cell lines established from two human metastatic
breast cancers.
AB - Cell lines are valuable resources for the study of the malignancy and potential
therapy of human breast cancer. A major problem with adapting fresh breast tumor
specimens to grow in vitro is contamination by fibroblasts. Previously, we have
reported a technique to overcome this problem (Nayak, S. K; Dillman, R. O. Clin.
Biotechnol. 3:237-242; 1991). We have recently established two new breast cancer
cell lines, HH315 and HH375, that were derived from abdominal and supraclavicular
lymph node metastases from two patients. They were characterized by (1) growth
kinetics; (2) staining with monoclonal antibodies (MoAbs) to cytokeratin-19,
epithelial membrane antigen (EMA), anticarcinoembryonic antigen (CEA), breast
cancer antigen 1 (BRST-1), breast cancer antigen 2 (BRST-2), Her2/neu, and p53;
(3) expression of domains of urinary plasminogen activator (uPA), neural cell
adhesion molecule (NCAM), and haptoglobin (Hp) (Harvey et al., 1997); and (4)
karyotypic analysis. Growth kinetic studies showed that doubling times for both
lines ranged from 48 to 96 h. These two cell lines were found to have
characteristics of the metastatic breast cancer cells. Both lines stained
positive with MoAbs to cytokeratin-19 and EMA, thus confirming their epithelial
origin. They also strongly reacted with the pan-breast carcinoma MoAbs BRST-1 and
BRST-2, and carcinoembryonic CEA MoAb. Both cell lines overexpressed the oncogene
proteins Her2/neu and p53. The tumor cells were negative for estrogen and
progesterone receptors. HH315 cells were poorly differentiated, whereas the HH375
cells exhibited adenocarcinoma morphology. Both cell lines showed intense cell
surface and some cytoplasmic staining for uPA, NCAM, and Hp domains, which is a
characteristic of malignant neoplasms (Harvey et al., 1997). The HH375 cell line
showed two cell types, of which 60% were hyperdiploids with 60-70 chromosomes and
5-10 marker chromosomes. The remaining cells were polyploid with more than 200
chromosomes. Cell line HH315 consisted of only a polyploid population. These cell
lines may be useful in breast cancer research.
PMID- 10777060
TI - Quantitative assessment of marine sponge cells in vitro: development of improved
growth medium.
AB - As sources of natural products with potential human therapeutic value, marine
sponges are important subjects for cell culture studies. A critical component of
any cell culture system is its growth medium. Proceeding from the hypotheses that
the thawed, cryopreserved, primary cells would display detectable differential
responses and that those responses could be comparatively quantified, this study
has established that multiwell screening assays are useful tools for improving
medium formulations in cell cultures of the marine sponge, Teichaxinella
morchella. Fluorescent probe signals were correlated with known cell densities
and viabilities in a 96-well format. Analysis of variance and post-test methods
were applied to judge the significance of signal differences seen in a variety of
medium formulations. Results from a series of experiments suggested that reducing
glutamine and selenium concentrations in the standard medium would result in
greater DNA, protein, and esterase activity signals. This was confirmed by the
direct comparison of the standard and improved medium formulations. Significantly
higher protein content and esterase activity were associated with the improved
medium. DNA content was also higher, though not significantly. The result is a
new medium formulation that may be more able to support cell growth and division,
providing an improved cell culture system for marine sponge cell studies. The
assays can be used in additional studies to further improve the in vitro
conditions for marine sponge cell culture.
PMID- 10777061
TI - A human skin equivalent model that mimics the photoproduction of vitamin D3 in
human skin.
AB - A human skin equivalent was prepared by culturing human keratinocytes on the
surface of nylon filtration meshes containing human skin fibroblasts and by
growing the epidermal cells at the air-liquid interface. This human skin
equivalent model was used to mimic the photoproduction of vitamin D3 in human
skin. It was found that the concentration of 7-dehydrocholesterol and its
photoconversion to previtamin D3 and its subsequent thermal isomerization to
vitamin D3 in the human skin equivalent was essentially identical to that of
human skin. The 7-dehydrocholesterol content in the skin equivalent and human
skin was 2187 +/- 296 and 2352 +/- 320 ng/cm2, respectively. The percentage of
the major photoproducts of 7-dehydrocholesterol in the skin equivalent following
ultraviolet B radiation (0.5 J/cm2) was 35% pre-vitamin D3, 29% lumisterol, and
6% tachysterol; 30% remained as 7-dehydrocholesterol. Similarly, in human skin
they were 36%, 29%, 7%, and 28%, respectively. After incubation at 37 degrees C
for 30 min, 11% and 12% of the previtamin D3 had thermally isomerized to vitamin
D3 in the skin equivalent and human skin. In conclusion, compared with cultured
keratinocytes or fibroblasts, the human skin equivalent model provides a superior
in vitro system that better mimics the physiology and biochemistry of the
photosynthesis of vitamin D3 in human skin.
PMID- 10777062
TI - Expression of the green fluorescent protein carried by Autographa californica
multiple nucleopolyhedrovirus in insect cell lines.
AB - A recombinant AcMNPV containing the green fluorescent protein (gfp) gene under
the polyhedrin promoter (polh) was used to investigate the expression of the gfp
gene as well as the production of recombinant extracellular virus in 14
continuous insect cell lines, including Heliothis virescens (BCIRL-HV-AM1),
Helicoverpa zea (BCIRL-HZ-AM1), Anticarsia gemmatalis (BCIRL-AG-AM1),
Trichoplusia ni (TN-CL1), Spodoptera frugiperda (IPLB-SF21), Spodoptera exigua
(BCIRL/AMCY-Se-E1 and BCIRL/AMCY-Se-E5), Bombyx mori (BMN), Sf9 (a clone of IPLB
SF21), and five cell line clones of BCIRL-HV-AM1. The susceptibility of the cell
lines to the recombinant virus (AcMNPV.GFP) was ascertained by calculating the
mean percentage number of green light-emitting cells as well as by TCID50
titration of extracellular virus with fluorescence as a sign of infection. Of the
14 cell lines tested, all were permissive with varying degrees to AcMNPV.GFP,
except BCIRL-HV-AMCL2 and BCIRL-HZ-AM1, both grown in serum-containing medium,
and BMN, grown in serum-free medium, which were nonpermissive to the virus.
Except for BCIRL/AMCY-Se-E1, IPLB-SF21, and four of the five BCIRL-HV-AM1 clones,
all the other cell lines (BCIRL-HV-AM1, BCIRL-AG-AM1, TN-CL1, Se-E5, and Sf9)
expressed detectable levels of GFP by 48 h postinoculation. The BCIRL/AMCY-Se-E1
and IPLB-SF21 cells, grown in serum-free medium (Ex-Cell 401), expressed
detectable levels of GFP at 72 h postinoculation. By contrast, in BCIRL/AMCY-Se
E1 in serum-containing medium (Ex-Cell 401 + 10% FBS [fetal bovine serum]), GFP
was detected at 48 h postinoculation. Furthermore, TN-CL1 cells produced the
largest mean percentage number of fluorescent (76.6%) cells in both serum
containing and serum-free medium (64.8%) at 120 h postinoculation. All the BCIRL
HV-AM1 clones showed no GFP expression until 96 h postinoculation, and only then
about 1% of the cell population fluoresced. The mean extracellular virus (ECV)
production at 120 h postinoculation was highest in BCIRL/AMCY-Se-E5 cells grown
in Ex-Cell 401 + 10% FBS (37.8 x 10% TCID50/ml) followed by BCIRL-HV-AM1 in TC199
MK (33.4 x 10(6) TCID50/ml). Only the BCIRL-HV-AMCL3 clone produced any
substantial level of ECV at 120 h postinoculation (16.9 x 10(6) TCID50/ml).
However, there was no significant correlation between ECV production and the mean
percentage number of fluorescent cells. This study provides further information
on the susceptibility of 14 insect cell lines to a recombinant AcMNPV containing
the green fluorescent protein gene. This information might avail researchers with
information to facilitate decisions as to what other cell lines are available for
in vitro studies of the gfp gene.
PMID- 10777064
TI - Influence of milk centrifugation, brining and ripening conditions in preventing
gas formation by Clostridium spp. in Gouda cheese.
AB - This study examined milk centrifugation, increased salt concentration, and low
ripening temperature as potential strategies to prevent late blowing caused by
gas-forming Clostridium spp. in Gouda cheese. The survival of clostridia spores
in cheese brine and their ability to enter Gouda cheese during brining was also
evaluated. Centrifugation (3000 x g for 30 s) of contaminated milk resulted in >
60% spore reduction, with increased spore reduction at greater centrifugal
forces. Low levels of C. tyrobutyricum and C. sporogenes spores survived in
saturated (23%, w/v) brine with 2% (v/v) added whey at 15 degrees C for 63 days,
while C. beijerinckii and C. butyricum spores were not detectable on days 4 and
35, respectively. Spores of C. tyrobutyricum in brine infiltrated Gouda cheese
during 2 h of brining at 13 degrees C resulted in production of small gas holes
during ripening. In Gouda cheese slurry stored at 13 degrees C, three C.
tyrobutyricum strains plus one of three C. sporogenes strains germinated in the
slurry with no added salt. Of three C. tyrobutyricum strains stored at 13 degrees
C in slurries with higher water-phase salt concentrations of 2.4 and 3.6%, two
strains and one strain germinated, respectively. No germination of spores was
detected in any cheese slurry stored at 5 or 8 degrees C. Milk centrifugation,
increased percent water-phase salt, absence of spores in brine, and decreased
ripening temperature are all potentially important measures against gas
production by Clostridium spp. in Gouda cheese.
PMID- 10777063
TI - Corticotropin releasing hormone and related peptides can act as bioregulatory
factors in human keratinocytes.
AB - Following previous findings in human skin of the functional expression of genes
for the corticotropin releasing hormone (CRH) receptor type 1 (CRH-R1) and CRH
itself, we searched for local phenotypic effects for peptides related to CRH. We
now report that CRH, sauvagine, and urocortin inhibit proliferation of human
HaCaT keratinocytes in a dose-dependent manner. The peptides produced variable
cyclic adenosine 3':5'-monophosphate stimulation, with CRH having the highest
potency. Binding of iodine 125 CRH to intact keratinocytes was inhibited by
increasing doses of CRH, sauvagine, or urocortin, all showing equal inhibitory
potency. Immunocytochemistry identified CRH-R1 immunoreactivity in HaCaT
keratinocytes. In conclusion, CRH (exogenous or produced locally) and the related
urocortin and sauvagine peptides can modify human keratinocyte phenotype through
a receptor-mediated pathway.
PMID- 10777065
TI - Comparative detection of Cryptosporidium parvum oocysts from apple juice.
AB - Drinking unpasteurized apple juice (or cider) has been associated with
cryptosporidiosis, the diarrheal disease caused by the small protozoan parasite,
Cryptosporidium parvum. This report compares detection of C. parvum oocysts from
apple juice by acid-fast staining (AFS), direct immunofluorescence assay (DIFA),
and polymerase chain reaction (PCR), following sample concentration by formalin
ethyl acetate sedimentation or sucrose flotation. Flotation was more efficient
than sedimentation in recovering oocysts, and DIFA consistently detected lower
numbers of oocysts than AFS. In combination, flotation-AFS could detect 3000 to
10,000 oocysts inoculated into 100 ml of apple juice while flotation-DIFA was
able to detect as few as 100 oocysts. The highest sensitivity, 10 to 30 oocysts
per 100 ml of apple juice, was achieved by DIFA following immunomagnetic capture
(IC) of oocysts from samples concentrated by the flotation method. The detection
limit of PCR following flotation or flotation IC was 30 to 100 oocysts; sequence
analysis of the amplicon demonstrated that the PCR amplicon was C. parvum
specific.
PMID- 10777066
TI - Evaluation of the hygienic quality of raw milk based on the presence of
bifidobacteria: the cow as a source of faecal contamination.
AB - Fifty-eight samples of raw milk from three different farms were examined for the
presence of bifidobacteria. Isolates were identified and compared with
bifidobacteria isolated from dung of the cows that provided the milk. Of the raw
milk samples, 88% harboured Bifidobacterium pseudolongum subsp. globosum, as did
95% of the dung samples.
PMID- 10777067
TI - A combined discrete-continuous model describing the lag phase of Listeria
monocytogenes.
AB - Food microbiologists generally use continuous sigmoidal functions such as the
empirical Gompertz equation to obtain the kinetic parameters specific growth rate
(mu) and lag phase duration (lambda) from bacterial growth curves. This approach
yields reliable information on mu; however, values for lambda are difficult to
determine accurately due, in part, to our poor understanding of the physiological
events taking place during adaptation of cells to new environments. Existing
models also assume a homogeneous population of cells, thus there is a need to
develop discrete event models which can account for the behavior of individual
cells. Time to detection (t(d)) values were determined for Listeria monocytogenes
using an automated turbidimetric instrument, and used to calculate mu. Mean
individual cell lag times (tL) were calculated as the difference between the
observed t(d) and the theoretical value estimated using mu. Variability in tL for
individual cells in replicate wells was estimated using serial dilutions. A
discrete stochastic model was applied to the individual cells, and combined with
a deterministic population-level growth model. This discrete-continuous model
incorporating tL and the variability in tL (expressed as standard deviation;
S.D.(L)) predicted a reduced variability between wells with increased number of
cells per well, in agreement with experimental findings. By combining the
discrete adaptation step with a continuous growth function it was possible to
generate a model which accurately described the transition from lag to
exponential phase. This new model may serve as a useful tool for describing
individual cell behavior, and thus increasing our knowledge of events occurring
during the lag phase.
PMID- 10777068
TI - In vitro susceptibility of Enterococcus faecium isolated from food to growth
promoting and therapeutic antibiotics.
AB - A total of 76 E. faecium strains, isolated at retail level from raw poultry meat,
cheese, raw pork, and preparations of cheese and raw pork, were tested for their
susceptibility and resistance to growth-promoting antibacterials used in animals
and antibiotics used therapeutically in humans. All strains were uniformly
susceptible to the growth promoters bambermycin and avilamycin. Resistance
against bacitracin, virginiamycin and narasin was high among strains from poultry
meat. With tylosin, a macrolide antibiotic used therapeutically and for growth
promotion, resistance was mainly detected in strains originating from poultry
meat, though also in some strains from pork and from pork and cheese
preparations. The therapeutic antibiotic dalfopristin/quinupristin did not show
full cross-resistance with the growth-promoting antibiotic virginiamycin. With
dalfopristin/quinupristin two different levels of resistance were found. Only one
E. faecium strain isolated from poultry was resistant to the glycopeptides
avoparcin and vancomycin. Only one poultry meat strain was highly resistant to
ampicillin. However, nearly all poultry meat strains showed decreased
sensitivity. Only 3 out of 24 poultry strains were susceptible to minocycline,
while all strains from other origins were susceptible to this tetracycline
antibiotic. High-level streptomycin resistance was seen in strains of all
origins, though infrequently. High-level gentamicin resistance was not found.
PMID- 10777069
TI - Characterisation of Micrococcaceae isolated from different varieties of chorizo.
AB - A total of 426 strains of Micrococcaceae bacteria isolated from chorizo (a
traditional Spanish fermented sausage) were identified. The chorizos were sampled
from three regions of Castilla and Leon in Spain: Burgos, Segovia and Salamanca.
Two factories were chosen in each region and the samples were taken at three
stages of ripening. Staphylococcus xylosus was the most predominant species
isolated (95%). Twelve strain types of S. xylosus were established according to
their fermentation patterns, and two of them, S. xylosus type 2 and S. xylosus
type 5, made up the majority of the strains of S. xylosus isolated (27 and 52%).
Production of acetoin, nitrate reductase, urease activity, proteolytic and
lipolytic activity were determined for all isolates. The percentage of strains of
S. xylosus producing acetoin depends on the manufacturing location. In general,
the proteolytic and lipolytic activities of the S. xylosus isolated from chorizo
from Castilla and Leon were low and moderate; 97% of the strains showed nitrate
reductase and urease activity. According to our results and to previous
investigations, it seems that S. xylosus type 5, showing nitrate reductase and
urease activity, low-moderate proteolytic and lipolytic activities and not
producing acetoin would be suitable as a starter culture. Of the strains isolated
in this study, 38% comply with these requirements.
PMID- 10777070
TI - Vancomycin-resistant enterococci isolated from animals and food.
AB - One hundred and one chicken products, boiled ham and turkey cold meat were
acquired from 18 different supermarkets in Spain during October 1997 to June 1998
and were analyzed for vancomycin-resistant enterococci (VRE). In the same way, 50
intestinal chicken samples from a slaughterhouse were also studied. VRE were
detected in 25 of 92 samples of food of chicken origin (27.2%), but no VRE were
found in cooked pork or turkey products. VRE were also detected in 8 of 50
intestinal chicken samples from the slaughterhouse (16%). VRE were identified as
Enterococcus durans (n = 11), Enterococcus faecalis (n = 10), Enterococcus
faecium (n = 10) and Enterococcus hirae (n = 2). All these strains were
characterized as belonging to the vanA genotype by polymerase chain reaction.
Ampicillin, quinupristin/dalfopristin and high level aminoglycoside resistance
were frequently found among these strains. Heterogeneity was observed in
susceptibility patterns among VRE strains, even in those of the same species. The
high rate of colonization of chicken products by vanA containing enterococci
detected 6 months to 1 year after the banning of avoparcin as a growth promoter,
supports other studies suggesting that the food chain could be a source of VRE
colonization in humans and thus a source of VRE infections.
PMID- 10777071
TI - The use of immuno-magnetic separation (IMS) as a tool in a sample preparation
method for direct detection of L. monocytogenes in cheese.
AB - A sample preparation procedure was developed for direct detection of L.
monocytogenes in cheese. The sample preparation protocol consisted of a 10-fold
dilution and homogenization, a centrifugation step to precipitate large food
particles, passage of the supernatant over a sieve and through a separatory
funnel to further eliminate food particles and fat, a centrifugation step to
recover the bacterial pellet and finally enzymatic digestion of the suspension to
degrade the remaining small food particles. Recovery of L. monocytogenes was
confirmed by plating on Oxford medium and confirmation of suspected colonies.
This protocol enabled direct detection (without prior enrichment) of low numbers
of L. monocytogenes (0.5-1.5 cfu/g cheese) from different types of cheese. The
performance of Dynabeads Anti-Listeria (Dynal, Oslo, Norway) for selective
recovery of L. monocytogenes and their applicability in the above mentioned
procedure for direct detection of low numbers of L. monocytogenes from cheese was
evaluated. IMS could not separate and recover L. monocytogenes from the food
particles in the concentrated suspension. The use of IMS after a 24 h enrichment
procedure (as recommended by the manufacturer) allowed for the detection of low
numbers of L. monocytogenes (< 10 cfu/g). However, experiments in broth cultures
showed that although the detection limit of IMS with Dynabeads Anti-Listeria was
40-100 cfu/ml, the ratio of L. monocytogenes to non-Listeria flora was not
increased. Thus, selective enrichment or concentration of L. monocytogenes was
not obtained.
PMID- 10777072
TI - Occurrence of clostridia in glass bottled foods.
AB - Forty-one marketed samples of imported and domestic glass bottled foods were
tested for clostridia contamination. It was detected in nine (22%) samples.
Clostridia were isolated from fish sauce (Nam pla, Nuoc-mam), dressing, mustard,
hot and sour soup mix (Tom Yum), mysids boiled down in soy, and salmon flakes.
The origin of all clostridia positive samples was Asia. Clostridium botulinum and
C. perfringens were not detected. The frequency of occurrence was higher by
enrichment broth culture detection methods than by agar plate or pouch methods.
These findings suggest that the number of bacteria in most of these clostridia
positive food samples is very low, and the use of enrichment methods for
detection of clostridia is essential.
PMID- 10777073
TI - Bibliography of food microbiology.
PMID- 10777074
TI - Molecular epidemiology of tuberculosis: coming of age.
PMID- 10777075
TI - Transmission of tuberculosis in San Francisco and its association with
immigration and ethnicity.
AB - OBJECTIVE: To determine tuberculosis transmission dynamics in San Francisco and
its association with country of birth and ethnicity. METHODS: Restriction
fragment length polymorphism (RFLP) typing was performed on Mycobacterium
tuberculosis isolates from culture-positive pulmonary tuberculosis patients in
San Francisco (1991 through 1996), using IS6110 as a probe. Patients were
assigned to clusters based on mycobacterial isolates with identical DNA
fingerprints. Clusters were assumed to have arisen from recent transmission. A
transmission index was defined as the average number of culture-positive
pulmonary tuberculosis cases generated by a single source case and calculated for
subgroups. RESULTS: The transmission index was higher in US-born (0.59) than in
foreign-born groups (0.21), and was highest in blacks, in particular those aged
under 35 years. The increased transmission index among blacks was not explained
by smear-positivity, human immunodeficiency virus infection, or increased
susceptibility to disease progression. CONCLUSION: US-born tuberculosis cases
generated more secondary cases than immigrants. Young blacks appear to be a high
risk group for tuberculosis transmission. These results suggest the need to
develop interventions targeted towards this risk group.
PMID- 10777076
TI - A prospective evaluation of the clinical value of nation-wide DNA fingerprinting
of tuberculosis isolates in Denmark.
AB - SETTING: Denmark, a country with a low incidence of tuberculosis (TB). OBJECTIVE:
To evaluate the value of the nation-wide DNA fingerprinting of Mycobacterium
tuberculosis isolates performed in Denmark since 1992. DESIGN: Prospective study
of consecutive patients with culture-verified TB from five large TB Departments
in Denmark during a 7-month period in 1998. Results of IS6110 RFLP and
spoligotyping were compared to those in the nation-wide Danish DNA-fingerprint
database which covers approximately 95% of all culture-verified TB cases from
1992 onwards. Questionnaires asking about contact tracing and epidemiological
links were sent to the patients' treating physicians. RESULTS: Of the 177
patients included in the study, 57 were Danes, one was from Iceland, 111 were
immigrants, and eight were from Greenland. Responses to the questionnaires were
obtained from 163 patients (92%). Four cases of unsuspected transmission were
detected: one of nosocomial spread of TB, one of occupational acquisition of TB
and two of transmission in an international school, leading to further contact
tracing among 75 schoolchildren. These four cases were all the result of short
term contacts. In 22 cases, contact with one or more TB patient(s) was reported.
In six of these, the DNA-fingerprint result revealed that the presumed contact
could not be the source of infection, even though in two of the cases the known
TB contact was from the household. CONCLUSION: Nation-wide DNA fingerprinting of
TB isolates provides information that could not have been obtained otherwise, and
contribute to the understanding of TB transmission in Danish society. In some
cases the results lead to further contact tracing. Short-term contact can
apparently result in transmission of TB.
PMID- 10777077
TI - Pulmonary tuberculosis in Norwegian patients. The role of reactivation, re
infection and primary infection assessed by previous mass screening data and
restriction fragment length polymorphism analysis.
AB - SETTING: Norwegian patients with pulmonary tuberculosis notified to the National
Tuberculosis Register in 1975, 1985 and 1995. OBJECTIVE: To assess the proportion
of cases attributable to endogenous reactivation, exogenous re-infection and
primary infection. DESIGN: We reviewed patients notified with sputum smear and/or
culture confirmed pulmonary tuberculosis in 1975 (50% random sample, 95 cases),
1985 (133 cases) and 1995 (70 cases). Information on previous chest X-ray,
tuberculin and BCG status was collected from mass screening data files. Strains
from 54 patients in 1995 were analysed by IS6110 restriction fragment length
polymorphism (RFLP) typing and compared with culture-positive patients notified
between 1994 and 1997. RESULTS: Most patients had previously had tuberculosis
(65% in 1975, 53% in 1985 and 61% in 1995), either notified with tuberculosis or
with X-ray findings indicating previous tuberculosis. Another 10% had a prior
infection, but normal X-rays. No previous tuberculosis infection or disease was
found in 10% in 1975, 19% in 1985, and 16% in 1995. Of 54 patients with RFLP
results, three were caused by laboratory contamination. Of the remaining 51,
eight (16%) belonged to a cluster. Among 45 patients with results of both RFLP
typing and mass screening, 37 (82.2%) were probably caused by reactivation, six
(13.3%) by re-infection and two (4.4%) by primary infection. CONCLUSION:
Pulmonary tuberculosis in Norwegian patients can mainly be attributed to
reactivation, predominantly in persons with previous changes on chest X-ray.
PMID- 10777078
TI - Analysis of Mycobacterium tuberculosis transmission patterns in a homeless
shelter outbreak.
AB - SETTING: From July 1997 through May 1998, ten tuberculosis (TB) cases were
reported among men in a Syracuse New York homeless shelter for men. OBJECTIVE AND
DESIGN: Investigation to determine extent of, and prevent further, transmission
of Mycobacterium tuberculosis. RESULTS: Epidemiologic and laboratory evidence
suggests that eight of the ten cases were related. Seven cases had isolates with
matching six-band IS6110 DNA fingerprints; the isolate from another case had a
closely related fingerprint pattern and this case was considered to be caused by
a variant of the same strain. Isolates from eight cases had identical
spoligotypes. The source case had extensive cavitary disease and stayed at the
shelter nightly, while symptomatic, for almost 8 months before diagnosis. A
contact investigation was conducted among 257 shelter users and staff, 70% of
whom had a positive tuberculin skin test, including 21 with documented skin test
conversions. CONCLUSIONS: An outbreak of related TB cases in a high-risk setting
was confirmed through the use of IS6110 DNA fingerprinting in conjunction with
spoligotyping and epidemiologic evidence. Because of the high rate of infection
in the homeless population, routine screening for TB and preventive therapy for
eligible persons should be considered in shelters.
PMID- 10777079
TI - The design of multi-stage tuberculin surveys: some suggestions for sampling.
AB - SETTING: Tuberculin surveys of children to estimate national or regional
infection prevalences are commonly designed as multi-stage surveys. These surveys
require strategies for the efficient sampling of sub-units at each stage.
OBJECTIVES: To develop guidelines for sampling in tuberculin surveys. DESIGN:
Sampling theory was used to develop a simple and efficient sampling strategy for
planning and analysing tuberculin surveys. The issue of sample sizes is
considered. RESULTS: Formulae for the calculation of infection prevalences and
their confidence intervals are developed. Sample sizes are discussed. CONCLUSION:
We recommend that districts be sampled using sampling proportional to size, in
which larger units have a larger probability of being included in the sample.
Schools are sampled next using simple random sampling, where each school within a
district has the same probability of being included in the sample. In each school
all eligible children are Mantoux tested. The number of children tested per
district should be approximately constant. Increasing the number of selected
districts is usually more efficient for increasing the precision of the estimate
than increasing the number of children per district beyond several hundred to a
few thousand.
PMID- 10777080
TI - Tuberculin skin testing to assess the occupational risk of Mycobacterium
tuberculosis infection among health care workers in Abidjan, Cote d'Ivoire.
AB - SETTING: Tuberculin skin test (TST) survey of health care workers (HCWs) in
selected clinical services in Abidjan, Cote d'Ivoire. OBJECTIVE: To assess
whether HCWs in Abidjan are at increased risk for occupationally acquired
Mycobacterium tuberculosis infection. DESIGN: From October 1996 to January 1997,
consenting HCWs from four services where tuberculosis (TB) prevalence among
patients was high and two services where it was low were evaluated with a
questionnaire, TST (including evaluation of anergy) and chest radiograph.
RESULTS: Of the 512 participants, 405 (79%) had a TST reaction of > or =10 mm,
eight (2%) were anergic, five (1%) had a radiograph compatible with TB, and two
had confirmed TB. Using a cut-off of 10 mm, we found a higher prevalence of TST
positivity in services with high TB prevalence than in those with low TB
prevalence (92% vs 72%; odds ratio [OR] 4.3; 95% confidence interval [CI] 2.3
8.0]) and among HCWs with direct (87%; OR 2.9; 95%CI 1.6-5.1) and indirect
patient contact (80%, OR 1.7; 95%CI 1.0-2.3) than among those with minimal
patient contact (69%). CONCLUSION: These findings indicate that TST positivity
among HCWs is related to level of exposure to TB patients, and suggest that HCWs
in Abidjan are at risk for the nosocomial transmission of TB.
PMID- 10777081
TI - Care seeking behaviour and diagnostic processes in patients with smear-positive
pulmonary tuberculosis in Malawi.
AB - SETTING: Government hospitals in five districts in Malawi. OBJECTIVE: To
determine care seeking behaviour and diagnostic processes in patients newly
diagnosed with smear-positive pulmonary tuberculosis (PTB). DESIGN: Structured
questionnaires completed by interview between January to September 1998. RESULTS:
During the study period 1,518 patients were registered with PTB, of whom 1,099
(72%) were interviewed. The median delay between onset of cough and diagnosis was
8 weeks. There was a variable pattern of care seeking behaviour, with 70% of
patients initially visiting a place of orthodox medical care and 30% visiting
traditional healers, grocery shops, etc. Of these, 867 (79%) patients had one or
more subsequent contacts for help, with these visits targeted more to orthodox
medical care. At all stages, antibiotics resulted in symptomatic improvement in
up to 40% of cases. There was a median time of 7 weeks between cough and first
submission of sputum specimens. Almost all patients received sputum smear results
after a median length of 4 days; 474 (43%) of patients were only aware of their
diagnosis at the time of receiving smear results, this observation being
significantly associated with lack of schooling and not knowing another person
with TB. CONCLUSION: More needs to be done to educate communities and non
orthodox care providers about the diagnosis and treatment of TB.
PMID- 10777082
TI - Evaluation of a unified treatment regimen for all new cases of tuberculosis using
guardian-based supervision.
AB - SETTING: Ntcheu District, Malawi, using an oral antituberculosis treatment
regimen. OBJECTIVE: To determine whether directly observed treatment (DOT) during
the initial phase of treatment supervised either in hospital, at health centres
or by guardians in the community, was associated with 1) satisfactory 2-month and
8-month treatment outcomes, and 2) with a reduction of in-patient hospital-bed
days. DESIGN: Prospective data collection of all tuberculosis (TB) patients
registered between 1 April 1996 and 30 June 1997, with 2-month and 8-month
treatment outcomes, sputum smear conversion in smear-positive pulmonary TB
patients (PTB) and in-patient hospital-bed days. RESULTS: Among the 600 new
patients, 302 had smear-positive PTB, 150 smear-negative PTB and 148
extrapulmonary TB (EPTB). Eight-month treatment completion was 65% for smear
positive PTB patients, which was significantly higher than in patients with smear
negative PTB (45%) and EPTB (54%), due mainly to high 8-month mortality rates.
The site of the intensive phase was determined in 596 patients: 178 (30%)
received DOT from guardians, 115 (19%) from a health centre and 303 (51%) in
hospital. At 2 months, mortality rates were significantly higher in hospitalised
patients. Two-month treatment outcomes (including sputum smear conversion rates
in smear-positive PTB patients) were similar between patients receiving DOT at
health centres or from guardians. Decentralised DOT resulted in a 25% reduction
in hospital-bed days in patients alive at 2 months compared with that predicted
using the old regimens. CONCLUSION: Decentralising DOT to health centres and to
guardians during the intensive phase is associated with satisfactory treatment
outcomes.
PMID- 10777083
TI - Resolution of the acute-phase response in West African patients receiving
treatment for pulmonary tuberculosis.
AB - SETTING: The Komfo Anokye Teaching Hospital, Kumasi, Ghana, West Africa.
OBJECTIVE: To evaluate simple and commonly used parameters of the acute-phase
response as correlates of successful resolution of smear-positive pulmonary
tuberculosis (PTB) during drug treatment. DESIGN: Serum C-reactive protein (CRP)
concentration, erythrocyte sedimentation rate (ESR), body weight, and blood
haemoglobin were measured in human immunodeficiency virus (HIV) negative Ghanaian
patients with PTB (n = 15) and in age- and sex-matched healthy controls (n = 15).
These parameters were subsequently measured in patients after 1, 2 and 3 months
of antituberculosis treatment. Serum concentrations of soluble interleukin-2
receptor-alpha (sCD25) were also measured as a comparative index of resolution of
the systemic inflammatory process. RESULTS: Anti-tuberculosis treatment resulted
in sputum smear conversion in all 15 patients. After one month of treatment,
reductions in serum CRP concentration (>20%) and increases in haemoglobin
concentration (>0.4 g/dl) occurred in the majority of patients and correlated
with steep reductions in serum levels of sCD25. In contrast, weight loss and
elevated ESR were slower to resolve, and were insensitive early markers of
response to treatment. CONCLUSION: A fall in serum CRP and a rise in blood
haemoglobin are correlates of the initial response to drug treatment of PTB.
These parameters may assist in the evaluation of empiric trials of treatment in
microbiologically unconfirmed cases of suspected PTB.
PMID- 10777084
TI - High rate of non-compliance with anti-tuberculosis treatment despite a retrieval
system: a call for implementation of directly observed therapy in Saudi Arabia.
AB - SETTING: Taif Chest Hospital, Taif, Saudi Arabia. OBJECTIVES: Non-compliance with
anti-tuberculosis drug therapy is recognised as a major cause of treatment
failure, drug resistance and relapse. In Saudi Arabia, the problem of non
compliance is frequent and has serious implications which need urgent attention
from the health-care authority. The objectives of this study were to define
factors that affect compliance rate and to determine the appropriate methods to
modify these factors. DESIGN: We designed and tested a retrieval system to
improve patient return for follow-up and drug collection after an initial
hospital admission period in a large chest hospital in the western region of the
country. RESULTS: Of 628 patients, 358 (57%) did not attend the first out-patient
clinic visit. The retrieval system was successful in bringing back only 83
patients, reducing the default rate by only 13.2%. Various factors that may
affect compliance were analysed in the remaining 275 (43.8%) non-compliant
patients. CONCLUSION: Because many of these factors are difficult to change, we
strongly support implementation of the WHO-recommended directly observed
treatment (DOT) strategy in Saudi Arabia and other countries facing similar
problems with tuberculosis control.
PMID- 10777085
TI - Referral times of Vietnamese refugees with tuberculosis in camps in Hong Kong.
AB - SETTING: Two closed camps in Hong Kong for Vietnamese refugees. OBJECTIVE: To
determine the referral times by clinicians (doctor's delay) of cases of
tuberculosis (TB) from refugee camp clinics to the hospital/chest clinic. DESIGN:
Retrospective case-note study of 97 Vietnamese patients receiving treatment for
tuberculosis. RESULTS: The sites of TB were pulmonary (n = 61), glandular (n =
15), pleural effusion (n = 15), and other (n = 6). The median referral time was
18 days (range 0-417). Median consultations numbered three (range 1-16). Fifty
three (54.6%) patients were prescribed antibiotics. Thirty-nine (40%) patients
were referred within 10 days; of these, 18 were referred the same day. These 39
patients were less likely to have received antibiotics (9/39 [23.1%] vs 44/58
[75.9%], relative risk [RR] 0.3 95% confidence interval [CI] 0.17-0.55), but were
equally likely to have been physically examined (RR 0.66, 95%CI 0.39-1.1).
Sixteen (16.5%) patients were referred after 90 days. They attended the clinic
more often (median attendances 6.5 vs 3, P = 0.0002), and were prescribed more
antibiotic courses (mean antibiotic prescriptions 1.6 vs 0.7, P = 0.03).
CONCLUSION: Referral times by these clinicians varied widely, with long delays
for approximately 60% of patients. Guidelines pertinent to primary care
clinicians are needed to heighten their awareness of tuberculosis to prevent
referral delays and subsequent TB treatment.
PMID- 10777086
TI - Anti-tuberculosis drug resistance in the West Province of Cameroon.
AB - SETTING: All 15 district hospitals of the West Province of Cameroon, between July
1997 and June 1998. OBJECTIVE: To determine the prevalences of initial and
acquired resistance to the main anti-tuberculosis drugs 2 years after the
implantation of a tuberculosis control programme in the province. METHODS: A
total of 615 adults consecutively admitted to the 15 district hospitals with
sputum smear-positive pulmonary tuberculosis were systematically studied. Sputum
specimens collected from each patient were cultured on Lowenstein-Jensen medium.
Testing of susceptibility to the major anti-tuberculosis drugs was performed by
the indirect proportion method. RESULTS: Growth of Mycobacterium tuberculosis
complex strains was obtained from specimens of 566 (92%) of the 615 patients. The
overall resistance rate (one or more drugs) was 26.9%, with initial resistance
being 19.7% (86/437) and acquired resistance 51.1% (66/129). Initial resistance
to isoniazid was the most common (12.1%), followed by streptomycin (11.7%),
ethambutol (2.5%) and rifampicin (2.1%). Initial resistance was noted as 13.5% to
one drug, 4.3% to two, 1.1% to three and 0.7% to four. Acquired resistance to
isoniazid was the most frequent (41.1%), followed by streptomycin (26.4%),
rifampicin (14.7%) and ethambutol (9.3%). Acquired resistance was 25.6% to one
drug, 14.7% to two, 7% to three and 3.9% to four. CONCLUSION: The proportion of
resistant tuberculosis in the West Province is quite high. This underscores the
need for the improvement of the control programme by introducing the DOTS
strategy.
PMID- 10777087
TI - Rapid and efficient detection of extra-pulmonary Mycobacterium tuberculosis by
PCR analysis.
AB - SETTING: The diagnosis of extra-pulmonary tuberculosis (EPTB) remains an
important clinical problem, primarily because of the inadequate sensitivity of
conventional bacteriologic methods for detecting Mycobacterium tuberculosis in
extra-pulmonary specimens. OBJECTIVE: To evaluate whether a IS6110-based
polymerase chain reaction (PCR) method can be utilized to detect M. tuberculosis
in non-pulmonary specimens. DESIGN: Specimens from 286 Mexican patients with a
presumptive clinical diagnosis of EPTB were prospectively examined by Ziehl
Neelsen staining, mycobacterial culture on Lowenstein-Jensen slants, and by PCR.
The DNA for PCR was extracted by the buffer lysis method and phenol-guanidine
thiocyanate-chloroform. Primers that amplify a 200 bp fragment from the insertion
like M. tuberculosis sequence element IS6110 were utilized. RESULTS: Our results
demonstrate that this PCR method is highly specific (100%) for identifying M.
tuberculosis from a variety of specimens including cerebrospinal fluid (CSF),
pleural fluid, ascitic fluid, pericardial fluid, urine, and lymph node exudate.
Moreover, the sensitivity of PCR for detecting M. tuberculosis in CSF (94%),
pleural fluid (94%), ascitic fluid and other extrapulmonary specimens (93%)
greatly exceeds the sensitivity of conventional smear and culture methods.
CONCLUSION: These results demonstrate that PCR can be a highly specific and
sensitive aid in the detection of M. tuberculosis from extra-pulmonary specimens.
PMID- 10777088
TI - Bleach sedimentation method for increased sensitivity of sputum smear microscopy:
does it work?
AB - SETTING: A non-governmental organisation (NGO) supported tuberculosis control
programme in Bangladesh with good smear microscopy. OBJECTIVE: To verify whether
bleach sedimentation method increases the sensitivity of sputum smear microscopy
for acid-fast bacilli (AFB), and if so, how. DESIGN: Duplicate smears from
successive routine specimens, peripheral centres examining direct smears, and
blind examination of bleach sediment smears at central laboratories. RESULTS:
When all 3,287 sputum samples were examined in duplicate and the International
Union Against Tuberculosis and Lung Disease cut-off for positivity was applied,
more positives were not found by bleach sedimentation. Using the much lower
American Thoracic Society (ATS) threshold, the percentage positives rose slightly
from 15.5% for direct smear to 16.6% after bleach. The gain was more evident when
suspect examinations only were taken into consideration, as bleach missed many
positives identified by direct follow-up smear. When patients rather than
individual smears were counted, more suspects were detected by bleach (10% gain
on average), but with considerable variation between the centres (range 6-16%).
To arrive at this gain, the ATS cut-off was used, with corrections for false
results. Under routine conditions, however, this threshold is too low in view of
possible transfer of AFB. CONCLUSIONS: Bleach sedimentation can increase the
diagnostic yield, but only to a minor extent if all other factors have been
optimised already; it is not a panacea. Precautions against false negatives as
well as false positives should be taken, and the additional workload is not
negligible.
PMID- 10777089
TI - 45/47 kilodalton (APA) antigen capture and antibody detection assays for the
diagnosis of tuberculosis.
AB - SETTING: APA complex (45/47 kDa) is an antigen specifically excreted by
Mycobacterium tuberculosis and could therefore be a good candidate for diagnosis.
OBJECTIVES: To develop three APA immunocapture ELISA assays using monoclonal
antibodies (Mabs) and one IgG anti-APA ELISA test, and to determine their
usefulness for the diagnosis of tuberculosis in Madagascar. DESIGN: For the Ag
assays, 23 negative sputum and serum samples and 64 pairs of sputum and serum
from active smear-positive patients (PTM+) were tested. For antibody assay, 116
negative controls, 143 PTM+ and 54 extra-pulmonary tuberculosis patients were
tested. RESULTS: The sensitivities of the APA antigen detection assays were low
(less than 40%) for a specificity of 95.6%, using either monoclonal antibodies or
clinical specimens. The anti-APA serology was more sensitive (76.9% for PTM+
patients) but less specific (73.2%). Due to their poor predictive values, these
tests cannot be recommended for the routine diagnosis of tuberculosis in
Madagascar.
PMID- 10777090
TI - DOT field worker fooled by a 9-year-old child who did not take her TB medications
and relapsed with cavitary TB seven years later.
PMID- 10777091
TI - Definitions and treatment regimens for recurrent tuberculosis.
PMID- 10777092
TI - TB control and directly observed therapy (DOT) from a public health/human rights
perspective.
PMID- 10777093
TI - HLA haplotypes are associated with differential susceptibility to Trypanosoma
cruzi infection.
AB - We explored a possible role of HLA class II genes in determining the
susceptibility to Trypanosoma cruzi infection as well as in the development of
chagasic heart disease in a rural mestizo population from Arequipa (Southern
Peru). HLA-DRB1 and DQB1 polymorphisms were determined in 85 seropositive
(asymptomatic, n=52; cardiomyopathic, n=33) and 87 seronegative individuals. We
observed that the DRB1*14-DQB1*0301 haplotype correlates with not having T. cruzi
infection in a highly endemic area (OR= 0.26 (0.124.63); Pc=0.01). This
protective association is a dominant trait. We found no differences in the
allelic or haplotypic distributions we examined between asymptomatic and
cardiomyopathic patients in this population. Our data offer indirect but
compelling evidence that polymorphism in HLA region is involved in a differential
susceptibility to T. cruzi chronic infection.
PMID- 10777094
TI - Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in
Japanese: clinical phenotypes and gender as important factors.
AB - The purpose of this study was to clarify the association of HLA-DRB1 and -DPB1
alleles with multiple sclerosis (MS) in Japanese, to determine whether optico
spinal MS (OS-MS) and conventional MS are immunogenetically distinct, and to
verify the role of gender difference in HLA associations of MS. We studied HLA
DRB1 and -DPB1 polymorphisms in 166 Japanese patients with MS. Forty-seven
patients were classified as having the optico-spinal MS (OS-MS) and 119 as having
conventional MS. A lack of DPB1*0301 and a higher frequency of DPB1*0501 compared
with controls (corrected P<0.0074; odds ratio=9.48) were found in OS-MS. By
contrast, we found for the first time an association of DPB1*0301 with
conventional MS in Japanese (corrected P=0.0444; odds ratio=3.28). Logistic
analysis, adjusted for sex and age, revealed independent associations of
DPB1*0301 (P=0.0004, adjusted odds ratio (aOR)=4.70), DPB1*0501 (P=0.0081, aOR=
2.50) and DRB1*1501 (P=0.0252, aOR=2.21) with conventional MS. However, the
frequencies of DRB1*1501 and DPB1*0501 in male patients with conventional MS were
equal to those in male controls while the DPB1*0301 frequency was increased in
both male and female patients. We did not find any association of these HLA
alleles with disease course and severity. In conclusion, OS-MS is a DPB1*0501
associated distinct subtype of MS, and DPB1*0301 is the most strongly associated
allele with conventional MS in Japanese. In addition, gender plays an important
role in HLA association with MS.
PMID- 10777095
TI - Genetic polymorphisms in the cell growth regulated gene, SC1 telomeric of the HLA
C gene and lack of association of psoriasis vulgaris.
AB - Psoriasis vulgaris is associated with the HLA-Cw6 and Cw7 antigens. We have
previously narrowed down the critical region most likely to contain the psoriasis
vulgaris gene to 111 kb spanning 89 kb to 200 kb telomeric of the HLA-C locus by
microsatellite mapping. This segment includes three known genes (POU5F1, SC1 and
S) and four new expressed genes. Among them, SC1 (TCF19) is the cell growth
regulated gene possibly with trans-activator activity. Since psoriasis vulgaris
is a common skin disorder characterized by hyperproliferation of epidermal cells,
it is tempting to speculate that the SCI gene is one of the strong candidate
genes responsible for the development of psoriasis vulgaris. Here, we
investigated genetic polymorphisms in the SC1 gene by direct DNA sequencing and
polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP)
techniques. Three single nucleotide polymorphisms in exon 2, two of which are
accompanied by amino-acid substitutions, were identified. Further, one 4-bp
deletion polymorphism was detected around the acceptor site of the lariat-shaped
structure necessary for RNA splicing in intron 2. No significant difference in
the dimorphic or haplotypic distribution at these four polymorphic sites was
observed between the patients with psoriasis vulgaris and healthy controls. This
suggests that the susceptible gene for psoriasis vulgaris is not the SC1 gene
itself, although a unique homozygous haplotype was identified in the patients.
PMID- 10777096
TI - alpha-Interferon treatment induces quantitative modifications of HLA class I
associated peptides eluted from cultured cancer cell lines.
AB - Interferons upregulate the expression of HLA class I antigens on cancer cells.
Nevertheless, little is known about the panel of HLA class I antigen-associated
peptides presented by recombinant alpha-interferon (r(alpha)-IFN)-treated cells.
For this reason, peptides were eluted from five cancer cell lines (four melanoma
and one non-small cell lung cancer) following treatment with r(alpha)-IFN. High
performance liquid chromatography (HPLC) profiles of the peptide fractions were
compared with those obtained from untreated cells. No significant differences in
peptide characteristics (detectable on the basis of retention times) were
observed, but significant differences in terms of peptide quantities were
observed. Mass spectrometry performed on HPLC peaks allowed not only the
detection of three different peptides (two derived from the MAGE family of genes
and one from the mart-1) both in untreated and in treated cells, but also gave an
indication of the number of peptides within one HPLC peak. This data demonstrates
that r(alpha)-IFN-treated cells express a similar peptide pattern as untreated
cells, with significant quantitative differences. Interestingly, this finding
also explains the higher susceptibility to lysis (mediated by specific cytolytic
lymphocytes, which recognize cancer cells in an HLA-restricted fashion) of
r(alpha)-IFN-treated cells.
PMID- 10777097
TI - The isolation and characterisation of human monoclonal HLA-A2 antibodies from an
immune V gene phage display library.
AB - Molecular cloning techniques and V gene phage display have revolutionised the
production of human monoclonal antibodies. Antibodies of a defined specificity
can be obtained by selecting phage display libraries on antigen in a process
known as panning. We have applied these techniques to the isolation of three HLA
A2-specific single chain variable domain fragments (scFv) from a patient
alloimmunised by blood transfusion. Analysis of specificity with cells of HLA
genotyped donors revealed the following: i) in addition to the major reactivity
with HLA-A2, cross-reactivity with the HLA-A28 epitope; and ii) inhibition of
scFv binding to the antigen by the patients' antibodies. The heavy chain variable
genes of all three were derived from the germline gene Cos-3, carry the hallmarks
of somatic hypermutation, and are most likely derived from clonally related B
cells. The light chain variable domains were encoded by DPK1 and DPK8 from the
VkappaI family. These data show that phage display can be used to clone HLA
specific alloantibodies that recognise the native antigen from alloimmunised
patients.
PMID- 10777098
TI - Molecular characterization and applications of recombinant scFv antibodies to
CD152 co-stimulatory molecule.
AB - Recombinant human monoclonal antibodies against CD152 have been generated by
selecting a synthetic phage scFv library with purified CD152-Ig fusion protein.
Sixteen scFv fragments were isolated which specifically react with CD152 by
enzyme-linked immunoabsorbent assay (ELISA) and Western blot resulting in their
clustering into two groups recognizing different antigenic determinants. One
group of scFvs (#3, #13, #40, #44, #47, #51, #57, #80 #83) recognized an epitope
on CD152 dimer whereas another group (#15, #18, #31, #35, #54, #72, #81)
recognized an epitope on both dimeric and monomeric CD152 molecule suggesting
their possible use in understanding the subunit structure of CD152 which is still
controversial. Sequencing of the VH genes revealed that all the scFvs belonged to
the VH3 gene family but they were different in CDR3 length and composition. It
was possible to correlate specific CDR3 sequences with reactivity of the two
groups of scFvs. Four scFvs, #3, #40, #81 and #83, each representative of one
specific CDR3, were selected for further analysis. Competition ELISA experiments
showed that they recognize CD152 in its native configuration and bound to
different epitopes from the CD80/CD86 interaction site. The scFvs were able to
stain human T lymphocytes stimulated either with anti-CD3 and CD28 antibodies or
PHA, PMA and ionomycin by cytofluorimetry suggesting that they can be useful
reagents for monitoring the kinetics of surface-bound and intracellular CD152.
PMID- 10777099
TI - HLA genes in Arabic-speaking Moroccans: close relatedness to Berbers and
Iberians.
AB - The gene profile of Arabic-speaking Moroccans has been compared with those of
other Mediterranean populations in order to provide additional information about
the history of their origins. Our HLA data suggest that most Moroccans are of a
Berber (Imazighen) origin and that Arabs who invaded North Africa and Spain in
the 7th century A.D. did not substantially contributed to the gene pool; however,
they imposed their advanced culture and their religion. Present-day Egyptians are
also related to Moroccan Berbers and this supports an ancient Saharan origin for
part of the present-day Mediterraneans, particularly for the Arabic-speaking ones
(also Algerians) and also for the older substratum of Mediterranean people.
PMID- 10777100
TI - HLA-A*02 allele frequencies and haplotypic associations in Koreans.
AB - We have investigated the frequencies of HLA-A*02 alleles and their haplotypic
associations with HLA-B and -DRB1 loci in 439 healthy unrelated Koreans,
including 214 parents from 107 families. All of the 227 samples (51.7%) typed as
A2 by serology were analyzed for A*02 alleles using polymerase chain reaction
(PCR)-low ionic strength-single-strand conformation polymorphism (LIS-SSCP)
method. A total of six different A*02 alleles were detected (A*02 allele
frequency 29.6%): A*0201/9 (16.6%), *0203 (0.5%), *0206 (9.3%), *0207 (3.0%), and
one each case of *0210 and *02 undetermined type. Two characteristic haplotypes
showing the strongest linkage disequilibrium were A*0203-B38-DRB]*1502 and A*0207
B46-DRB1*0803. Besides these strong associations, significant two-locus
associations (P<0.001) were observed for A*0201 with B61, DRB1*0901 and
DRB1*1401, and for A*0206 with B48 and B61. HLA haplotypes carrying HLA-A2 showed
a variable distribution of A*02 alleles, and all of the eight most common A2-B-DR
haplotypes occurring at frequencies of > or =1% were variably associated with two
different A*02 alleles. These results demonstrate that substantial heterogeneity
is present in the distribution of HLA-A*02 alleles and related haplotypes in
Koreans.
PMID- 10777101
TI - DLA-DQA1 polymorphisms in dogs defined by sequence-specific oligonucleotide
probes (SSOP).
AB - Several recent studies have identified DNA sequences for alleles of the DLA-DQA1
locus in the dog. To date, 10 DQA1 alleles have been reported. No data exists on
the frequencies of these alleles within the general dog population, nor is there
any indication of whether alleles are breed specific. We have addressed this
issue by establishing a molecular-based sequence-specific oligonucleotide probing
(SSOP) method to identify all published DQA1 alleles and have used these methods
to type a large number of dogs. Oligonucleotide probes were designed to detect
all the polymorphic sites in exon 2. This allowed assignment at the allele level.
Three hundred and thirty dogs were typed for DQA1. All but two of the published
DQA1 alleles were identified in these animals. One new allele was identified, and
confirmed by DNA cloning and sequencing. This typing method provides a powerful
tool for generating data that will be essential for studies investigating the
genetic relationships between different breeds.
PMID- 10777102
TI - Identification of the novel allele HLA-A*6813 in two members of a family of
Syrian origin: implications for bone marrow transplantation.
AB - The identification of the new allele HLA-A*6813, which was found in a woman of
Syrian origin and her son, is described. In the sequence analysis the new allele
differs from A*68011 by positions 259 (A>G) and 261 (C>G) in exon 2. As the
structure is thus identical to the HLA-A consensus sequence it is likely that the
new allele originated by gene conversion. At the protein level, the new allele
has one amino acid difference from A*6801 (Asn63Glu), which results in a distinct
banding pattern in one dimensional-isoelectric focusing. Amino acid residue 63
contributes to the formation of pocket A and B and is thus important for peptide
binding. A*6813 was serologically detectable only by two of six polyclonal, but
by three monoclonal antisera. The restricted serological A68 activity may be
explained by altered peptide binding as presented peptides can affect the
serological recognition of major histocompatibility complex (MHC) class I
molecules. Moreover, our findings suggest that a possible mismatch with the other
known A*68 variants may impair clinical outcome of bone marrow transplantation.
PMID- 10777103
TI - Routine HLA-B genotyping with PCR-sequence-specific oligonucleotides (PCR-SSO)
detects eight new alleles: B*0807, B*0809, B*1551, B*3529, B*3532, B*4025, B*5304
and B*5508.
AB - This paper describes eight new alleles (B*0807, B*0809, B*1551, B*3529, B*3532,
B*4025, B*5304 and B*5508) that have been found by routine HLA-B genotyping with
sequence-specific oligonucleotides (SSOs). All of the new alleles have variations
which cause changes in residues that occur within antigen binding pockets and T
cell recognition sites of the antigen. The new polymorphisms within these new
alleles may affect the nature and specificity of peptide binding and cause
differential T-cell activation, which may have an affect in transplantation.
PMID- 10777104
TI - HLA-DRB1*04 and susceptibility to type 1 diabetes mellitus in a German/Belgian
family and German case-control study. The Belgian Diabetes Registry.
AB - HLA-DR4 is a primary disease association marker in type 1 diabetes mellitus
(IDDM). We therefore analyzed the transmission of 228 DR4+ haplotypes in 183
families with an IDDM proband (95 from Germany and 88 from Belgium). In a
separate case-control data set, we investigated the HLA-DRB1*04 and DQ allele
distribution in 245 IDDM patients and 177 controls from Germany, all DR4
positive. HLA-DRB1 *0401 and *0402 linked to DQB1 *0302 were significantly more
often transmitted to patients in the studied families (81% and 89%) in contrast
to DRB1 *0401-DQB1 *0301 (33%). The case-control study of HLA-DQB1 *0302+
individuals revealed -DRB1 *0405 to be more frequent in patients with IDDM and
HLA-DRB1 *0403 and -DRB1 *0404 to be less frequent. HLA-DQA1 *0102-DQB1 *0602 and
-DQA1 *0501-DQB1 *0301 in trans complementation with DRB1 *0401-DQB1 *0302 were
also significantly less frequent in IDDM patients (P<3x 10(-7) and P<0.02). In
conclusion, HLA-DRB1 *0403 and -DQB1*0301 alleles in cis as well as protective DQ
haplotypes in trans, confer dominant protection against IDDM in a German /
Belgian population.
PMID- 10777105
TI - Novel associations among HLA-DQA1 and -DQB1 alleles, revealed by high-resolution
sequence-based typing (SBT).
AB - Althought it is a valuable tool for the identification of HLA alleles, sequence
based typing (SBT) presents difficulties when used to determine HLA-DQA1 and
DQB1 alleles. Specifically, some HLA-DQA1 alleles have a three-base deletion at
codon 56 of exon 2 that interferes with the sequencing read. Moreover, the
frequently used primers for HLA-DQB1 may co-amplify the HLA-DQB2 pseudogene. To
overcome these problems, we amplified DQA1 exon 2 using five group-specific
polymerase chain reactions (PCRs) which allowed separation of deleted from non
deleted DQA1 alleles. DQB1 exon 2 was amplified using two group-specific
amplifications. To increase typing resolution, we also analyzed DQA1 exons 1, 3
and 4 and DQB1 exon 3 by PCR using sequence-specific primers (PCR-SSP) or SBT
analysis. Using this method we found some important associations between DQA1 and
DQB1 alleles: DQA1*05011 and DQB1*0201, DQA1*0505 and DQB1*03011, DQA1*01021 and
DQB1*06, DQA1*01022 and DQB1*0502.
PMID- 10777106
TI - IMGT/HLA database--a sequence database for the human major histocompatibility
complex.
AB - The IMGT/HLA Database is a specialist database for sequences of the human major
histocompatibility (MHC) system. It includes all the HLA sequences officially
recognised and named by the WHO Nomenclature Committee for Factors of the HLA
System. The database provides users with online tools and facilities for the
retrieval and analysis of these sequences. These include allele reports,
alignment tools and a detailed database of all source cells. The online IMGT/HLA
submission tool allows the submission of both new and confirmatory allele
sequences directly to the WHO Nomenclature Committee for Factors of the HLA
System. The latest version (release 1.4.1, November 1999) contains 1,015 HLA
alleles from over 2,270 component sequences derived from the EMBL/GenBank/DDBJ
databases. From its release in December 1998 until December 1999 the IMGT/HLA
website received approximately 100,000 hits. The database currently focuses on
the human major histocompatibility complex but will be used as a model system to
provide specialist databases for the MHC sequences of other species.
PMID- 10777107
TI - Extracellular fatty acid binding protein (Ex-FABP) modulation by inflammatory
agents: "physiological" acute phase response in endochondral bone formation.
AB - Ex-FABP, extracellular fatty acid binding protein, is a 21 kDa lipocalin
expressed in hypertrophic cartilage, muscle and heart during chick embryo
development and in granulocytes. Ex-FABP synthesis was increased in chondrocyte
and myoblast cultures by inflammatory agents (LPS; IL6) and repressed by
antiinflammatory agents. Expression of Ex-FABP and specific gelatinases is
paralleled in hypertrophic cartilage; LPS specifically induced high molecular
weight gelatinase ( > 200 kDa). LPS-treated hypertrophic chondrocytes showed
increased chemotactic activity for endothelial cells paralleled by increased
expression of transferrin. A high amount of Ex-FABP was expressed in adult
pathological cartilage both in dyschondroplastic and osteoarthritic chickens.
Controls were negative. Ex-FABP could represent a stress protein physiologically
expressed in tissues where active remodelling is taking place during development
and in tissues characterized by an acute phase response due to pathological
conditions. We also suggest that during endochondral bone formation other
responses characteristic of a local inflammatory status, such as gelatinase
production and angiogenic factor secretion, are "physiologically" activated.
PMID- 10777108
TI - Expression of NRL/NGAL (neu-related lipocalin/neutrophil gelatinase-associated
lipocalin) during mammalian embryonic development and in inflammation.
AB - The neu-related lipocalin (NRL) is a protein overexpressed in rat mammary cancer
induced by activated neu (HER-2/c-erbB2). This protein belongs to the family of
the lipocalins or low molecular weight proteins able to bind and transport small
hydrophobic molecules. The NRL homologue in mouse is SIP24, an acute phase
protein induced in the animal by turpentine injection; the human homologous
protein is NGAL expressed in granulocytes and epithelial cells in pathological
conditions, such as inflammation and malignancy. We have investigated NRL
expression in developing rat embryos. By immunolocalization we have shown
localization of the protein in the hypertrophic region of growth plate cartilage.
NRL was particularly enriched in prehypertrophic chondrocytes. In addition, we
observed localization of the protein in forming skeletal muscle fibres and in the
myocardium of developing heart. In agreement with the immunolocalization data, by
in situ hybridization we have demonstrated the presence of the specific mRNA in
the same tissues. At an early stage of differentiation, cultured rat embryo
derived chondrocytes did not express NRL; nevertheless expression of the protein
was induced in these cells by treatment with an inflammatory agent, such as LPS.
By Western blot analysis with specific antibodies we showed protein synthesis by
cultured myoblasts also in the absence of LPS treatment, but only when forming
myotubes were observed in culture. Stimulation of myoblast cultures with LPS
resulted in an enhancement of the NRL expression in well formed myotubes. Our
data suggest a role of NRL in cartilage and muscle differentiation. NRL
expression was induced by inflammatory agents. We wish to propose that the
expression of NRL in hypertrophic chondrocytes and forming myotubes is part of a
"physiological" acute phase response occurring during cartilage and muscle
development. In this manuscript we also report that NRL is not detectable by
immunolocalization in adult cartilage (both articular and tracheal) from normal
subjects. On the contrary articular cartilage from osteoarthritic patients was
highly positive for the presence of NRL/NGAL. Interestingly the expression of
this protein is also activated during neoplastic transformation of chondrogenic
lineage cells.
PMID- 10777109
TI - Synthesis of proteoglycans is augmented in dystrophic mdx mouse skeletal muscle.
AB - Mdx mice uniquely recover from degenerative dystrophic lesions through an intense
myoproliferative response. The onset and progression of this process are
controlled by a complex set of interactions between myoblasts and their
environment. The presence of the extracellular matrix is essential for normal
myogenesis. Proteoglycans are abundant components of the extracellular matrix.
The synthesis of proteoglycans in mdx mice during skeletal muscle regeneration
was evaluated. Incorporation of radioactive sulfate demonstrated a significant
increase in the synthesis of several types of proteoglycans in mdx animals
compared to age-matched controls. The size and charge of proteoglycans
synthesized by the mdx mice remained unchanged. In particular, one of the up
regulated proteoglycans, the small chondroitin/dermatan sulfate proteoglycan
decorin which is known to bind and to sequester transforming growth factor-beta,
was investigated. Immunocytolocalization and in situ hybridization studies showed
that decorin mainly accumulated in the endomysium, i.e. around individual
skeletal muscle fibers from M. tibialis anterior and diaphragm.
PMID- 10777110
TI - Visualization of the secretory process involved in Ca2+-activated fluid secretion
from rat submandibular glands using the fluorescent dye, calcein.
AB - The central feature of fluid and electrolyte secretion by salivary acinar cells
is transepithelial Cl- movement as a driving force for the secretion. However,
little is known about the membrane localization and regulation by agonists of
various anion channels. To characterize the anion transport and fluid secretion,
we visualized the secretory process induced by the cholinergic agonist, carbachol
(CCh), using the anionic fluorescent dye, calcein, under a confocal laser
scanning microscope. The fluorescence of calcein loaded into the isolated acini
was spread diffusely throughout the cytoplasm and was less intense in the
secretory vesicles which occupied the apical pole. Cytoplasmic calcein was
released into intercellular canaliculi just after the addition of CCh, depending
upon a rise in [Ca2+]i by Ca2+ release from intracellular stores. Thereafter, the
formation of watery vacuoles connected with intercellular canaliculi was
visualized in the calcein-loaded acini, depending upon external Ca2+. Both the
calcein release and vacuole formation were inhibited by suppressing the Ca(2+)
activated K+ efflux. The calcein release was also affected by the external anion
substitution, suggesting that calcein is released through an anion channel. In
the isolated, perfused glands, CCh-induced fluid secretion was sustained in two
phases, whereas the loaded calcein was initially and transiently released into
the saliva. By revealing the [Ca2+]i dependence and sensitivities to channel
blockers, our results suggest that the initial phase of CCh-induced fluid
secretion was evoked in association with the release of the organic anion,
calcein, and the late phase of fluid secretion, during which calcein is less
permeable, was associated with the formation of watery vacuoles. Thus, the anion
channels possessing the distinct property of anion permeation may be activated in
the initial phase and late phase. These results indicate that the anionic
fluorescent dye, calcein, is useful for visualizing the process of Ca(2+)
dependent fluid secretion, and for clarifying the relation between fluid
secretion and anion transport.
PMID- 10777111
TI - Sequence of lethal events in HeLa cells exposed to the G2 blocking cytolethal
distending toxin.
AB - The bacterial cytolethal distending toxin (CDT) was previously shown to block the
cell cycle of several cell lines at stage G2 through inactivation of the cyclin
dependent kinase Cdkl and without induction of DNA strand breaks. In the present
study, we have analyzed, using various methods of analytical cytometry, the
progressive transformation and delayed lethal events in the tumor-derived HeLa
cell line temporarily exposed to CDT. The cell proliferation arrest induced by
CDT was irreversible but, starting about two days after exposure, the G2 block
released partially, concomitantly with a decline in the level of Cdkl
phosphorylation. This partial release resulted in endoreduplication, leading to
the emergence of a significant subpopulation of cells with a 8C DNA content, and
by multipolar abortive mitosis which accounted for the mortality recorded 2 and 3
days after exposure. The other major lethal event was a micronucleation process
which started to be significant about 3 days after exposure and amplified later
on. Both multipolar abortive mitosis and micronucleation appeared topologically
related to centrosomal amplification.
PMID- 10777112
TI - Pre-ribosomal RNA is processed in permeabilised cells at the site of
transcription.
AB - The available data concerning the subnucleolar localisation of the individual
steps of precursor-ribosomal RNA (pre-rRNA) processing are ambiguous. According
to in situ hybridisation studies, the late steps of pre-rRNA processing have been
located into the granular component of the nucleolus, but factors engaged in
these events were found being enriched in the dense fibrillar component. In this
study, by utilisation of permeabilised human cells, we demonstrate that the newly
synthesised, bromouridine-labelled pre-rRNAs reside at, or near, the sites of
transcription. We provide evidence that processing of pre-rRNA occurs in
permeabilised mammalian cells and that the incorporated bromouridine residues do
not interfere with pre-rRNA maturation. Our results suggest that the maturation
process of ribosomal RNA in permeabilised cells takes place at, or nearby, the
site of transcription and that the processing complex is assembled during or
early after the rRNA transcription.
PMID- 10777114
TI - HIV risk factors, HIV antibody testing, and AIDS knowledge among African
Americans age 55 years and older.
AB - This study uses data from the 1992 AIDS Knowledge and Attitudes Supplement to the
National Health Interview Survey to assess AIDS knowledge, prevalence of HIV
testing, and HIV risk factors among 745 African Americans age 55 years and older.
The results revealed that only one of the six respondents who reported an HIV
risk factor had been tested for HIV. Overall, the respondents were very
knowledgeable about the major modes of transmission, but they still had
misconceptions about the likelihood of transmission through casual contact.
Prevention programs aimed at African Americans age 55 years and older should
focus on dispelling misconceptions about the transmission of HIV through casual
contact, and enhancing their knowledge about the effectiveness of condoms in
preventing the spread of AIDS.
PMID- 10777113
TI - CALNUC (nucleobindin) is localized in the Golgi apparatus in insect cells.
AB - A mouse monoclonal antibody 12B1 was raised against Golgi fractions from Sf21
insect cells and selected as Golgi-specific by immunostaining of the cells. The
antigen was purified from the cells by immunoaffinity chromatography with the
monoclonal antibody, and its N-terminal and internal amino acid sequences were
determined. Based on the partial amino acid sequences, cDNA encoding the antigen
protein was cloned and sequenced. The amino acid sequence deduced from the cDNA
nucleotide sequence showed a homology to those of CALNUC family proteins, CALNUC
(or nucleobindin, a calcium-binding Golgi protein with DNA-binding activity) and
protein NEFA (a cell surface protein with DNA-binding, EF-hand, and acidic
domains). The insect protein had two EF-hand loops at the same sites as the
mammalian CALNUC family proteins, but had no leucine zipper which the mammalian
homologues commonly have. An electron microscopic immunoperoxidase study
demonstrated that the insect protein was localized in the cis-Golgi cisternae and
cis-Golgi networks. Since this localization is identical to that of mammalian
CALNUC, the insect protein was considered to be a homologue of CALNUC rather than
that of NEFA. Assays involving proteinase K digestion, sodium carbonate
extraction and Triton X-114 extraction revealed that the insect CALNUC-like
protein was a soluble protein tightly associated with the luminal surface of
Golgi membranes as reported for mammalian CALNUC. The insect protein was also
shown to have calcium-binding activity as does mammalian CALNUC. These data
verify that the insect protein is CALNUC. The existence of CALNUC in insect cells
suggests that CALNUC is an essential calcium-binding Golgi protein in a wide
range of the animal kingdom. A phylogenetic tree analysis, however, suggested
that NEFA was derived from CALNUC long after the segregation of a mammalian
ancestor from an insect ancestor.
PMID- 10777115
TI - Assessments of the coverage of HIV-related care by public programs: a survey of
AIDS service organizations.
AB - AIDS service organizations (ASOs) were surveyed to identify effective services
covered, and effective services not covered, by the Medicaid and Medicare
programs, as well as programs funded by Title I and II of the Ryan White CARE
Act. The Medicaid programs cover a range of effective health services, with
prescription drug coverage mentioned most frequently by the ASOs. In addition to
prescription drugs and physician services, the Title II programs offer a range of
support-related services. The ASOs identified a blend of health and social
services funded by Title I as most effective at meeting the needs of people with
HIV illness. The Medicare program covers a range of health services necessary for
the treatment of acute illness, except for prescription drugs. The ASOs
identified the lack of Medicare coverage of prescription drugs as a major problem
for people with HIV illness.
PMID- 10777116
TI - Psychosocial needs of women infected with HIV.
AB - This article describes an exploratory social work study that examined the
psychosocial needs of HIV seropositive (HIV+) Caucasian women. A questionnaire
was used to obtain both qualitative and quantitative data from the sample of 12
women. Further, more substantive data were obtained through in-depth interviews
with 6 of the sample. Analysis of the data indicated a variety of needs which
were both psychosocial and instrumental in nature. These included: information
and support (especially at the time of diagnosis); assistance from health care
professionals and friends; planning for present and future care of children;
financial assistance; adjustment to the loss of employment; and finding
accommodations. A majority of the women wanted increased contact with other HIV+
women. The need for more counselling and services specific to women and mothers
was also expressed. Three interviewees were older widows whose husbands had died
of AIDS. They appeared to have some unique issues. A number of dominant themes
emerged from the in-depth interviews: the experience of being HIV+; experience
with professional and service providers; help and support; experiences of
parents; and finally, the emotional impact of being HIV+.
PMID- 10777117
TI - Autonomy, choice, and decision making: how nursing home social workers view their
role.
AB - Open-ended interviews with 17 social workers from rural and urban Minnesota
nursing homes explore how the practitioners perceive their roles in fostering the
autonomy and decision making of residents. The social workers' espoused theory of
practice is organized under three dimensions of autonomy: free action (supporting
residents' choices), decision making (helping residents deliberate effectively),
and continuity (maintaining a sense of self). The interviewees strongly identify
with an advocacy role; helping residents make decisions appears less salient. The
discussion explores the interviewees' perspectives and strategies, and suggests
further research questions.
PMID- 10777118
TI - Cohesion and organization patterns among family members coping with rheumatoid
arthritis.
AB - The effects of rheumatoid arthritis (RA) on family functioning are described from
two perspectives, cohesiveness and organization. These concepts are believed to
be essential for assessing levels of family stability following the onset of a
life crisis. In this study we characterized the ways in which families organize
their daily activities and achieve family cohesiveness. Fifteen families
participated in the study. The data showed family members have positive
perceptions about their family cohesiveness and organizational behaviors, which
were characterized in personal interviews. Families also discussed active and
passive coping styles in response to RA. Implications for social work practice
and issues for future research are presented.
PMID- 10777119
TI - New treatment possibilities in rheumatoid arthritis.
AB - It is very difficult to predict future treatment modalities especially in
diseases like rheumatoid arthritis (RA) with unknown etiology and pathogenesis.
In the near future, traditional disease-modifying antirheumatic drugs (DMARD)
alone, in combination with each other, or together with cyclosporine, FK506,
Rapamycin, or Leflunomide, will probably be the main treatment for RA. Currently
biological anti-TNFalpha agents like humanized MAb and recombinant TNF-receptor
constructs are now launched in the market. This therapy alone, or in combination
with methotrexate is very effective in RA patients. There are, however, concerns
over increase in serious infections. Autologous stem cell transplantation will
probably be used in certain patient with serious autoimmune diseases.
PMID- 10777120
TI - Glucocorticoid-like anti-inflammatory versus immunosuppressive effects of CPH 82
as a single drug therapy of moderately active rheumatoid arthritis patients.
PMID- 10777122
TI - Cyclosporine A versus methotrexate in the treatment of polymyositis and
dermatomyositis.
AB - OBJECTIVE: To determine the effectiveness and tolerance of treatment with
cyclosporine A (CyA) or methotrexate (MTX) added to corticosteroids in patients
with severe, active polymyositis (PM) and dermatomyositis (DM). PATIENTS AND
METHODS: Thirty-six patients (20 with DM, 16 with PM) were enrolled into the
study and randomized in MTX (n = 17) and CyA (n = 19) groups. Muscle endurance
and functional test (MEFT), clinical assessment (CA), global patient's assessment
(GPA), muscle MRI, serum CK, myoglobin, IL-1Ra, and autoantibody status were used
to assess the response to therapy after 1, 3, and 6 months. RESULTS: Significant
improvement in MEFT, CA, GPA, and muscle MRI was found in both groups. Patients
treated with MTX showed insignificantly better response than patients with CyA.
CK levels in the MTX group decreased significantly after 1, 3, and 6 months,
whereas a significant reduction in the CyA group was first observed after 6
months. IL-1Ra serum levels significantly dropped in the CyA group after two
weeks, whereas in the MTX group the significant decrease was first seen after 3
months of treatment. Good correlation was found between each of the clinical
parameters (MEFT, CA, and GPA), none of them showed any correlation with CK or IL
1Ra levels. CONCLUSIONS: Administration of MTX or CyA added to corticosteroids
was associated with clinical and laboratory improvement. Changes in CK and IL-1Ra
levels were not associated with parameters of clinical disease severity measured
in this study.
PMID- 10777121
TI - Endocrine effects of the podophyllotoxine derivative drug CPH 82 (Reumacon) in
patients with rheumatoid arthritis.
AB - CPH 82 is a non-steroid antirheumatic drug containing two benzylidenated
podophyllotoxin glucosides with no affinity for the glucocorticoid receptor.
Treatment with CPH 82 as single drug therapy significantly decreased serum and
urinary cortisol and cortisol metabolites, serum adrenal androgens and urinary
androgen metabolites, plasma ACTH and serum interleukin-6 (IL-6) and tumor
necrosis factor alpha (TNF-alpha), and increased serum levels of sex hormone
binding globulin (SHBG). Significant positive correlations were found between
serum TNF-alpha and plasma ACTH and between serum IL-6 and TNF-alpha on the one
hand and serum and urinary cortisol and cortisol metabolites on the other. The
initial action of CPH 82 on adrenal steroidogenesis may be a reduction in
cytokine levels due to the drugs' antiinflammatory effect. This causes decreased
ACTH stimulation, resulting in a reduced adrenocortical steroid secretion.
Accumulation of the drug in the adrenal cortex may also affect adrenal
steroidogenesis. The elevated SHBG levels may be caused by a weak estrogenic
activity of the drug.
PMID- 10777123
TI - Reproduction in women reporting chronic musculoskeletal disorders.
AB - The present population based study assessed aspects of female health as a part of
a national cardiovascular screening program in 40-42 year old women in the Sor
Trondelag county. Fertility, events related to the menstrual cycle, reproduction,
and the use of contraceptive methods in women reporting musculoskeletal diseases
(MSD) were compared to women without these disorders (references). A higher
proportion of women with MSD reported subfertility. No significant difference in
mean age of menarche or menstrual cycling pattern was found, however women
reporting MSD had significantly more often metrorrhagia than references. Mother's
age at birth of the first and last child differed from references only in two of
the patient groups, and interval between pregnancies was longer in women with
MSD. Women with MSD more often chose sterilisation as a contraceptive method.
CONCLUSION: Reproduction was altered in women with MSD. It remains to elucidate
the interrelationship between rheumatic disorders and gynecological dysfunction.
PMID- 10777124
TI - Dynamic magnetic resonance imaging of the metacarpophalangeal joints in
rheumatoid arthritis, early unclassified polyarthritis, and healthy controls.
AB - OBJECTIVE: To introduce dynamic magnetic resonance imaging (MRI) as an indicator
of inflammatory activity in the metacarpophalangeal (MCP) joints of patients with
rheumatoid arthritis (RA) or early unclassified polyarthritis, and to compare the
results with a healthy control group. MATERIALS AND METHODS: We examined 42 RA
and 23 early unclassified polyarthritis patients, and 12 healthy controls in a
cross-sectional study. Dynamic MRI (repeated FLASH-MR images after injection of a
contrast agent) was performed through the 2nd to the 5th MCP joint. Two methods
for identification of the enhancing synovial membrane were compared: 1) outlining
of enhancing synovial membrane on subtraction images and 2) automated recognition
by principal component analysis (PCA). The early enhancement (EE) rate was
calculated on the basis of the first method. RESULTS: Method 1) and 2) were
closely associated (P<0.00001). From the healthy control group, an upper limit
(mean+2SD) of normal enhancement was established for the 2nd to 5th MCP joints,
which served to identify abnormal EE rates in the corresponding joints of
patients. The patients had higher EE rates in the 2nd to 5th MCP joints than had
the healthy controls (P<0.01). There were no significant differences between the
two patient groups (P>0.09). CONCLUSION: PCA seems to be a promising method for
automated identification of enhancing tissue. EE rates of the finger joints may
be useful in the assessment of the inflammatory activity in the joints of
patients with RA and early unclassified polyarthritis and may reflect other
aspects of disease activity than clinical evaluation.
PMID- 10777125
TI - Ro 52kD autoantibodies are detected in a subset of ANA-negative sera.
AB - To define Ro 52kD, Ro 60kD, and La specificities of autoantibodies within ANA
negative sera, samples from 64 ANA-negative but SSA positive patients undergoing
investigation due to suspected CTD were analysed, using recombinant antigens and
synthetic peptides by immunoblotting and ELISA. The sera were selected from 4025
sera submitted for routine ANA analysis. Antibodies to Ro or La were detected in
42/64 sera (65%). Anti-Ro 52kD antibodies occurred most frequently and were
present in 42/64 sera (65%). This was the only specificity of autoantibody
detected in 18 sera. No patient had only anti-La or anti-Ro 60 antibodies. In
total 18.64 patients (28%) had Ro 60 antibodies and 14/64 had anti-La antibodies
(21%). Eight patients had antibodies reacting with all three antigens. We used
the same set of sera to test the antigenicity of different regions of Ro 52kD
represented by deletion clones and peptides derived from the Ro 52kD sequence.
Out of 30 sera reacting with a recombinant deletion clone encompassing as
residues 136-227, 12 sera reacted with a peptide corresponding to a 200-239. Some
sera gave a low positive OD value with a peptide of a 176-196. Based on the
results of this study in which we demonstrate Ro 52kD autoantibodies in 65% of
selected ANA negative sera and define an autocephitope within the Ro 52kD protein
composed of the leucine zipper domain, we suggest that testing for Ro 52kD
antibodies could be included in an extended investigation of ANA negative
patients with suspected connective tissue disease.
PMID- 10777126
TI - Impaired collagen gel contraction with cultured skin fibroblasts from patients
with systemic sclerosis.
AB - We investigated the capacity of skin fibroblasts, derived from 9 patients with
systemic sclerosis (SSc), to contract collagen lattices in a three-dimensional
culture system. In comparison with control fibroblasts (N = 8), more than 30% of
SSc fibroblasts exhibited markedly impaired ability to contract collagen
lattices. The expression of alpha2beta1 integrins and integrin-mediated signals
were not significantly different between normal and SSc fibroblasts. Although the
underlying mechanisms remain to be determined, our present data provide evidence
that certain aspects of interaction with collagen are impaired in SSc
fibroblasts.
PMID- 10777127
TI - Chlamydia pneumoniae not detected in temporal artery biopsies from patients with
temporal arteritis.
AB - In a recent report Chlamydia pneumoniae (C. pneumoniae), examined with both
immunohistochemistry and polymerase chain reaction (PCR), was detected in
positive temporal artery biopsies from patients with temporal arteritis (TA). Our
aim was to examine whether C. pneumoniae could be detected in patients with TA
recruited from a high endemic area of TA in southern Norway. Twenty paraffin
embedded temporal artery biopsies showing convincing inflammation in the vessel
wall with lymphocytic infiltration (giant cells in 12 biopsies) from 20 patients
with TA were examined for the presence of C. pneumoniae using an established PCR
technique. All examined TA patients (mean age 74.4 (SD 7.5) years, 75% females)
fulfilled the ACR-1990 criteria. C. pneumoniae was not detected in any of the
biopsies. In conclusion, our results indicate that C. pneumoniae, at least in the
population of southern Norway, does not have any pathogenetic role in TA.
PMID- 10777128
TI - Renal amyloidosis as a first manifestation of Familial Mediterranean Fever.
AB - Amyloid nephropathy was the presenting symptom in a case of Familial
Mediterranean Fever (FMF). As recent progress in molecular pathology permits the
detection of asymptomatic FMF individuals, it is suggested that relevant cases of
renal amyloidosis should be tested for FMF mutations.
PMID- 10777129
TI - Concurrent Henoch-Schonlein purpura and papular-purpuric gloves-and-socks
syndrome.
AB - The case of a young teenager with manifestations consistent with both Henoch
Schonlein purpura and papular-purpuric gloves-and-socks syndrome is described.
The illness was associated with acute parvovirus infection. Similarities and
differences among the two conditions are discussed.
PMID- 10777130
TI - Acute non-purulent inflammatory arthropathy associated with Staphylococcus aureus
abscess.
AB - Case 1. A 20-year-old woman presented 4 weeks post-partum with widespread
symmetrical inflammatory polyarthropathy with marked synovitis. Investigations
revealed grossly raised CRP with negative immunology screen. A few days before
presentation she saw her general practitioner with left-sided mastitis, which
then developed into a Staphylococcus breast abscess. Surgical drainage of this
led to almost immediate resolution of the joint complaints and return of CRP to
normal. Case 2. A 27-year-old man developed widespread symmetrical inflammatory
arthropathy. A few days prior to this he had developed folliculitis with a
furuncle on his neck. Swab grew Staphylococcus aureus. His arthritis settled
immediately following spontaneous drainage of his abscess and a full course of
antibiotic. The pathogenic mechanism is unclear but could be toxin-mediated.
PMID- 10777131
TI - Dental caries and caries-associated microorganisms in Uruguayan preschool
children.
AB - The prevalence of dental caries was studied in 3-5-year-old Uruguayan children (n
= 76) living in 2 areas with different socioeconomic and cultural conditions.
More children from the low socioeconomic area of Las Acacias had caries (68%)
than children from the middle- to high-class neighborhood of Pocitos (19%). They
also had poorer oral hygiene and a significantly higher caries prevalence (P <
0.05) than those from Pocitos. The occurrence of mutans streptococci and
lactobacilli was determined in whole unstimulated saliva and compared with that
in debris collected with a loop from the dorsum of the tongue. Mutans
streptococci were detected in 42% of the children with significant correlations
between the salivary levels of the microorganism and caries experience.
Lactobacilli were recovered less frequently (18%). The detection of mutans
streptococci in the tongue-loop samples was significantly correlated with that in
whole saliva.
PMID- 10777132
TI - Use of xylitol chewing gum among Finnish schoolchildren.
AB - The preventive, and partly the remineralizing, effect of xylitol was shown in
Finland in the Turku Sugar Studies in 1971-73. Since then, several clinical
trials in many countries have confirmed these results. In Finland, oral health
personnel have recommended daily use of xylitol chewing gum in their dental
health education. Moreover, commercial companies have advertised xylitol,
emphasizing in particular its caries preventive effects. All Nordic dental
associations have given their recommendations for xylitol use. The aim of this
study was to describe how this health habit has been adopted by Finnish
schoolchildren. The study was part of the comprehensive cross-national survey on
Health Behavior in School-aged Children (HBSC Study)--a WHO Collaborative Study.
The data were collected using standardized questionnaires to which pupils in
grades 5 (11 years), 7 (13 years) and 9 (15 years) responded anonymously in
school classrooms during the spring term 1998. The response rate varied between
87% (15-year-old boys) and 94% (11- and 13-year-old girls). Among boys, the
percentages of daily users of xylitol chewing gum were 47% (11 years), 46% (13
years), and 44% (15 years), and among girls, 57% (11 years), 65% (13 years), and
69% (15 years), respectively. Use of sugar-sweetened chewing gum was very rare
(1%), as also was use of chewing gum with other artificial sweeteners (1%). It
may be concluded that since 1991 the use of xylitol chewing gum has further
increased in Finland and currently more than a half of all schoolchildren benefit
from it.
PMID- 10777133
TI - Direction of shrinkage of light-curing resin composites.
AB - It is occasionally stated in the dental literature that light-curing resin
composites shrink towards the light source. As light travels at the speed of
light, this dictum is not obvious. It was the purpose of the present study to
investigate the direction of shrinkage of a light-curing resin composite in
relation to the attachment and the thickness of the material. The resin composite
was applied in cylindrical brass molds in such a manner that a flash, serving as
attachment, was produced at one side of the specimens, while the material was
flush with the mold at the other side. The specimens were now irradiated from
either the flash or the flush side, and the convexity or the concavity of the
specimens was measured. At a material thickness of 3 mm, the shrinkage was
towards the light source, irrespective of the position of the flash. At 4 and 5
mm thickness of the molds, the direction of shrinkage could be directed towards
or away from the light source, depending on the position of the flash. The number
of light quanta emitted from the light source and passing through the material
was compared with the number of molecules of camphorquinone present in a resin
composite of 3, 4, or 5 mm thickness. It was concluded that under the conditions
of the present study, the direction of shrinkage was the result of an interplay
between the direction of the light, the attachment of the material, and the
thickness of the material.
PMID- 10777134
TI - Cytotoxic effects of extracts of compomers.
AB - We have studied the cytotoxicity of 10 commercially available compomers. Extracts
were taken in cell culture medium of non-cured, freshly-cured, and aged samples.
Murine L-929 fibroblasts were exposed to the extracts for 24 h and the
cytotoxicity was evaluated using dimethylthiazol diphenyltetrazolium (MTT) assay
and neutral red uptake (NRU). Extracts were rated as severely, moderately, or
slightly cytotoxic when the activity relative to controls was less than 30%,
between 30% and 60%, or greater than 60%, respectively. Extracts of non-cured
materials were rated severely toxic with both methods, with one exception. All
but one freshly-cured material exhibited moderate to severe toxicity in both
assays. Aged test specimens were rated moderately to severely toxic. Non-cured
materials were generally more toxic than cured, with two exceptions. Aging and
polishing the samples to remove non-polymerized surface film affected
cytotoxicity to a varying degree. Curing reduced cytotoxicity in the MTT test
from severe to moderate in 7 of 9 materials, but had relatively little effect in
the NRU assay. Aging and polishing, however, had little effect on cytotoxicity
evaluated by the MTT test, but markedly reduced cytotoxicity in NRU in 6 of 8
extracts. To conclude, extracts made from compomers used for dental fillings were
found to be cytotoxic both before and after setting.
PMID- 10777135
TI - Current concepts on the theories of the mechanism of action of fluoride.
AB - The caries-preventive effect of fluoride is mainly attributed to the effects on
demineralization/remineralization at the tooth oral fluids interface. Sub ppm
levels of fluoride in saliva are effective in shifting the balance from
demineralization, leading to caries, to remineralization. This is attributed to
the fluoride-enhanced precipitation of calcium phosphates, and the formation of
fluorhydroxyapatite in the dental tissues. Low fluoride levels are found in
saliva after toothbrushing with fluoride containing dentifrices. Similar
concentrations are ineffective in interfering with processes of growth and
metabolism of bacteria, and also do not result in a significantly reduced
dissolution of tooth mineral as a result of (firmly bound) fluoride
incorporation. Comparative studies of fluoride efficacy have shown that higher
concentrations in solution are needed in pH-cycling studies of dentine than in
enamel to maintain the mineral balance or to induce remineralization. This is
attributed to the greater solubility of the dentine and the smaller size of the
dentine crystallites compared to enamel. Fluoride slow-release devices, in the
form of fluoride-releasing restorative materials, may serve to increase the
fluoride levels in saliva and plaque to levels at which caries can be prevented,
also in high-risk patients. Research questions for the next millennium and future
perspectives for fluoride applications should be found in the retention and slow
release of fluoride after various combinations of fluoride treatment, the
combination of fluoride and anti-microbial treatment, the individualization of
caries prevention, and the combination of preventive schemes with new
developments in caries diagnosis.
PMID- 10777136
TI - Fluoride in the oral environment.
AB - A predominant part of the cariostatic activity of fluoride is a function of its
concentration in the fluid environment of the teeth. The fluoride exposure
results in a slightly elevated steady-state level of fluoride in the oral fluids,
primarily in saliva and plaque fluid. So far, however, little is known about the
intra-oral fluoride concentration necessary to achieve a cariostatic effect at
the site of action. Following fluoride intake, the fluoride remaining in the oral
cavity is diluted by the saliva pool. The remaining fluoride may be found in
several compartments in the oral cavity. It may be ionized in saliva, ionized in
plaque (plaque fluid), bound in plaque, bound as calcium fluoride, bound to
enamel, and bound to soft tissues. Fluoride is also distributed to the oral
tissues and into the dental plaque by diffusion. It is well established that
plaque, after fluoride exposure, becomes a fluoride reservoir which stores for
some time and releases fluoride. The present review gives an insight into the
important parameters that determine the disposition and fate of fluoride in the
oral environment. To achieve in-depth understanding, and hence formulation of the
optimal fluoride therapy, more information is needed to consolidate our
understanding of the distribution, retention, and elimination of fluoride in the
oral cavity. Such knowledge will form a better basis for providing our patients
with more effective dental fluoride products and regimens.
PMID- 10777137
TI - Experimental intra-oral caries models in fluoride research.
AB - The use of experimental intra-oral caries models has increased in fluoride
research. This paper focuses on the pre-clinical intra-oral models, the in situ
and in vivo models, the various types, their benefits and disadvantages. Both
preparation and sterilization of the hard tissue substrates can affect the
substrates and therefore the results. Care needs to be taken that dentine samples
are not exposed to drying and consequently shrinking during preparation and
evaluation. Sterilization by gamma-radiation is at present the least tissue
damaging method. The most realistic experimental model is the in vivo model,
followed by the in situ model using specimens with natural surfaces. The most
accurate and direct evaluation technique for demineralization and
remineralization studies is quantitative transversal microradiography, whereas
confocal laser scanning microscopy (CLSM) is the most sensitive qualitative
evaluation technique. Other evaluation techniques discussed are microhardness
testing and the iodine permeability test. In light of the present skewed caries
situation in western countries we suggest that fluoride research focuses on
experimental caries models that can mimic severe cariogenic challenge. Testing of
fluoride combinations and dosages that can prevent lesion development rather than
promote remineralization would then be a practical consequence.
PMID- 10777138
TI - Government policies on fluoride utilization in the Nordic countries.
AB - In most but not all the Nordic countries, the National Boards of Health have
issued guidelines governing the utilization of fluoride. The purpose of this
paper is to outline the process of policy formation, describe the current
fluoride guidelines in the Nordic countries, and discuss compliance with and
appropriateness of the guidelines. The fluoride guidelines summarize current
knowledge and make recommendations on choice of fluoride preparations
(supplements, toothpaste, and varnish) and doses. Fluoride policies in the Nordic
countries in the late 1990s state that use of fluoride toothpaste twice a day is
the preferred and sufficient source of fluoride for the majority of the
population. The policies of the Nordic countries are similar, but there are
differences, some of them self-explanatory others not so obvious. In the case of
supplements, for example, there are differences in the recommended dosage
schedules. In the case of toothpaste, it is unclear what concentrations of
fluoride are recommended both for children and for adults. Starting time for the
use of fluoride, whether toothpaste or supplements, varies between countries. The
clinicians' compliance with fluoride guidelines has not been systematically
evaluated. Comparing the advice and treatments offered by dentists in the Nordic
countries with current guidelines suggests that national policies influence the
practice of clinicians. For government policy to be appropriate, it is imperative
that the guidelines are based on sound scientific evidence. It is thus concluded
that if nonevidence-based elements are included in national guidelines, this
should be clearly stated to prevent confusion and enhance compliance from
professionals and the public.
PMID- 10777139
TI - Efficiency of fluoride programs in the light of reduced caries levels in young
populations.
AB - Since the late 1930s, when the efficacy of fluoride in caries prevention was
first detected, various efficient methods for fluoride delivery have been
developed. Nowadays, fluoride is used for caries prevention on a global scale,
the most widely used methods being fluoridated toothpaste and water fluoridation.
The latter is a typical community-based prevention method, whereas the former
method relies on individual motivation. The goal of an efficient community-based
fluoride program is to maintain a constant low level of fluoride in as many
mouths as possible at as low a cost as possible. Initially, water fluoridation
and other community-based programs were highly efficient, but nowadays in
societies in which the major part of the population is using fluoride toothpaste
and caries levels are low, population-based programs show a low efficiency. As an
example, even though water fluoridation was withdrawn in Kuopio, there have been
no dramatic effects on the dental health of children and youths. In societies
with well-attended, community-based, free dental health care for children and
youths, the dental motivation of individuals is, in general, very high and the
use of fluoride for caries prevention may be taken care of at the individual
level.
PMID- 10777140
TI - Fluoride prospects for the new millennium--community and individual patient
aspects.
AB - Over the past 2 decades, it has been suggested that with the generalized
availability of fluoridated dentifrices, and coupled with a possible increased
likelihood of fluorosis, the benefits of community-based fluoridation have
receded. However, while this may be so for dentally motivated populations, there
are convincing data to suggest that the least fortunate amongst us could still
benefit from communally delivered fluoride. Furthermore, the deleterious effects
of such program withdrawals have been demonstrated and, with respect to fluorosis
fears, client assessment of their own fluorosis status has indicated few
concerns. Alternative, centrally delivered means of fluoride dispensing, e.g. via
schools, etc., although effective in the short-term, are impractical over longer
time-spans. Nonetheless, at the individual level, fluoride supplements and
dentifrices, in particular, are successful caries inhibitors. This is especially
so if these vehicles are employed in their most effective, proven manners.
Finally, fears relating to disfiguring fluorosis should be allayed, but where
fluoride abuses result in mild mottling, a simple remineralizing technique
obviates the need for traumatic restorative procedures.
PMID- 10777141
TI - Genetic subtypes of HIV type 1 in Hungary.
AB - We examined the diversity of HIV-1 subtypes in 11 adults from Hungary, using the
heteroduplex mobility assay (HMA) and DNA sequencing. HMA results showed that HIV
1 gp120 sequences from 10 patients were of subtype B, whereas 1 patient, infected
in Africa, carried a subtype C strain. DNA sequencing confirmed the HMA results
and revealed a high intrasubtype diversity in the C2V3 region of env in different
clade B isolates, which suggests multiple introduction of subtype B to Hungary.
This study shows that subtype B is the predominant HIV-1 clade in Hungary.
PMID- 10777142
TI - Long-term exposure of HIV type 1-infected cell cultures to combinations of the
novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of
nonnucleoside reverse transcriptase inhibitors.
AB - The novel quinoxaline GW420867X has been combined with a variety of nucleoside
reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase
inhibitors (NNRTIs) in HIV-1(IIIB)-infected CEM cell cultures. Whereas the
antiviral efficacy of combinations of GW420867X with the NRTIs lamivudine (3TC)
and abacavir (ABC) proved additive when administered to HIV-1-infected cells in a
short-term (4-day) infection experiment, combination of GW420867X with the NRTIs
3TC and ABC resulted in a marked delay of virus breakthrough compared with the
single drugs alone in a long-term (2-month) infection experiment. Delay of virus
breakthrough was less pronounced for combinations of GW420867X with the NNRTIs.
Combination of GW420867X with the NRTIs and NNRTIs resulted in additive
inhibitory effects on recombinant HIV-1 reverse transcriptase as evident from
isobolograms. Lamivudine plus GW420867X selected for the 3TC-specific M184I
mutation and a number of NNRTI-characteristic mutations (i.e., V106A, V108I, and
Y188H). Abacavir plus GW420867X selected only for NNRTI-specific mutations (i.e.,
K101E, K103R, V106A, and Y181C), including the novel L100V mutation. Combination
of GW420867X with five different NNRTIs selected solely for NNRTI-specific
mutations, and also for the L100V mutation in the combined presence of efavirenz,
nevirapine, or emivirine, respectively. Five single-, two double-, and two triple
mutated HIV-1 strains that emerged from this study were evaluated for their
sensitivity/resistance to AZT, lamivudine, and seven different NNRTIs. In all
cases, efavirenz, GW420867X, and UC-781 retained pronounced antiviral potency.
Our data suggest that combinations of GW420867X with 3TC, ABC, and NNRTIs (e.g.,
efavirenz) would be worth pursuing as therapeutic modalities against HIV-1
infections.
PMID- 10777144
TI - Enhancement of HIV type 1 antigen-specific CD4+ T cell memory in subjects with
chronic HIV type 1 infection receiving an HIV type 1 immunogen.
AB - We examined HIV-1 specific memory helper T immune responses in chronically HIV
infected subjects who received an immune-based therapy (HIV-1 immunogen, Remune).
Subjects in this study exhibited significant increases (p < 0.05) in the
frequency of helper T memory cells expressing interferon gamma (IFN-gamma) and
tumor necrosis factor alpha (TNF-alpha) in response to HIV-1 antigens in vitro.
The frequencies of HIV-specific memory T cells increased after successive
immunizations and exhibited a correlation with the standard tritiated thymidine
incorporation lymphocyte proliferation assay (r = 0.72, p < 0.0008). These
results support the notion that HIV-specific memory immune responses can be
stimulated in subjects with chronic HIV infection. Further investigations are
warranted to determine whether the induction of such responses is associated with
virologic control.
PMID- 10777143
TI - Baseline HIV type 1 genotypic resistance to a newly added nucleoside analog is
predictive of virologic failure of the new therapy.
AB - We evaluated the predictive value of baseline HIV-1 genotypic resistance
mutations for failure of a nucleoside reverse transcriptase inhibitor (NRTI)
containing therapy. The change in therapy of 88 HIV-1-infected patients was
analyzed retrospectively, relating the genotypic resistance profile at baseline
to the evolution of viral load and CD4+ T cell counts. Genotypic resistance at
baseline and at 6 months was evaluated with the LiPA HIV-1 RT, which detects
mutations at codons 41, 69, 70, 74, 184, and 215. At 1 to 3 months after change
in therapy, patients without preexisting resistance mutations to the new drug
(group S) had a significantly better evolution in viral load (reduction of 0.37
log(10)) compared with patients with known preexisting resistance mutation(s)
(group R) (increase of 0.08 log(10)). This difference was particularly striking
for patients with the baseline M184V mutation and whose treatment was modified by
the addition of lamivudine. After 6 months the median difference in viral load
evolution between the two groups increased to 0.61 log(10): the viral load of
patients of group S was still 0.18 log(10) below baseline while patients of group
R had an increase of 0.43 log(10) in viral load above baseline. Changes in CD4+ T
cell counts were not significantly different. The evolution in viral load in HIV
1-infected patients with and without baseline resistance mutation(s) toward a
newly added NRTI is significantly different at 1-3 months and at 6 months after
changing or adding one NRTI.
PMID- 10777145
TI - Expression of the novel T cell activation molecule hpH4 in HIV-infected patients:
correlation with disease status.
AB - We have described hpH4, a surface glycoprotein selectively expressed by activated
T cells and mature thymocytes and displaying weak lateral association with CD4.
The hpH4 expression pattern and biochemical features, together with analysis of
its tryptic digest by peptide mass searching using MALDI-MS, suggested that it is
a novel molecule. The aim of this work was to evaluate the peripheral blood T
cell expression of hpH4 in HIV-infected patients and the interplay between HIV
gp120 and hpH4, since both molecules interact with CD4. hpH4 expression during
HIV-1 infection was evaluated by assessing 55 patients at various disease stages
and following up 3 patients with primary infection and 3 patients with AIDS. hpH4
expression displayed a peak in the early phase of primary infection, dropped to
control levels in the asymptomatic phase, and was newly expressed, at low levels,
as AIDS developed. The expression kinetics were different than those shown by HLA
DR, CD25, and CD38. The most striking findings were the transient hpH4 expression
peak displayed in the earliest stage, which was unique for hpH4. Incubation of T
cells from normal donors with HIV gp120 induced transient hpH4 expression in
resting CD4+ T cells and potentiated the hpH4 lateral association with CD4 in
activated T cells. Moreover, hpH4 triggering inhibited gp120-induced death of
CD4+ cells. Therefore, H4 expression may be a response to avoid apoptosis induced
by HIV products.
PMID- 10777147
TI - Molecular characterization of feline interleukin 16: chemotactic activity and
effect on feline immunodeficiency virus infection and/or replication.
AB - Interleukin 16 (IL-16) has been shown to diminish HIV and SIV replication through
inhibition of HIV and SIV mRNA transcription. To evaluate its role in the FIV cat
model, we cloned and expressed feline IL-16 and determined its ability to induce
chemotaxis as well as to inhibit FIV replication in cultured PBMCs. Sequence
comparison of rfIL-16 with human, African green monkey, rhesus macaque, and mouse
IL-16 showed 84.2, 84.5, 84.4, and 79.4% identity at the nucleotide sequence
level and 93, 91.5, 90.7, and 87.2% identity at the amino acid sequence level,
respectively. Biocharacterization of rfIL-16 revealed potent induction of
chemotaxis (p < 0.05). In addition, p24 production from feline PBMCs infected
with FIV Zurich 2 in vitro was decreased up to 87% (p < 0.05). These data
demonstrate biologic and antiviral functionality of rfIL-16.
PMID- 10777146
TI - Decreased HIV-associated T cell apoptosis by HIV protease inhibitors.
AB - Antiretroviral treatment of patients infected with HIV results in improvements in
CD4+ T cell number. Emerging evidence suggests that some of the improvements in
CD4+ T cell number that occur in response to protease inhibitor (PI) therapy may
not be accounted for solely by enhanced viral suppression, implying that PI may
directly affect T cell survival. Since HIV T cell depletion is associated with
enhanced apoptosis, we analyzed the effect of PIs on T cell apoptosis. In vitro
treatment of peripheral blood lymphocytes (PBLs) from HIV-infected but untreated
patients with reverse transcriptase inhibitors (RTIs) does not alter apoptosis,
whereas PI treatment rapidly reduces CD4+ and CD8+ T cell apoptosis. In contrast,
PI treatment does not alter apoptosis in PBL blasts from HIV-negative patients,
or in Jurkat T cells. Consistent with this observation, 8 days of PI therapy in
HIV-infected patients does not significantly alter plasma viremia, yet results in
significant inhibition of CD4+ and CD8+ T cell apoptosis. The inhibitory effects
of PI on apoptosis have implications concerning the treatment of HIV and its
pathogenesis.
PMID- 10777148
TI - Construction of an SIV/HIV type 1 chimeric virus with the human interleukin 6
gene and its production of interleukin 6 in monkey and human cells.
AB - The switch from a Th1- to a Th2-type cytokine response is reported to be involved
in human immunodeficiency virus (HIV) disease progression. To study the effect of
IL-6, one of the Th2-type cytokines, on AIDS pathogenesis, we constructed an
SIV/HIV-1 chimeric virus (SHIV) having the human IL-6 gene (SHIV-IL6) SHIV-IL6
could replicate in M8166, a human T cell line, as well as in monkey and human
peripheral blood mononuclear cells (PBMCs). Along with the SHIV-IL6 replication,
IL-6 was detected in the culture supernatant by ELISA. The maximum level of IL-6
was 35, 15, and 8 ng/ml in M8166, human PBMCs, and monkey PBMCs, respectively.
The expressed IL-6 was biologically active as shown by the proliferation of IL-6
dependent murine hybridoma (MH-60) cells. The inserted IL-6 gene was stable for
at least four passages (45 days after the initial infection) in M8166 cells,
suggesting the ability to achieve stable expression of IL-6 in long-term
experiments. Therefore, we successfully established an SHIV system expressing IL
6, and this is the first report of an SHIV expressing a Th2-type cytokine. With
this system, IL-6 should be expressed in the regions where the virus replicates,
and therefore the inoculation of macaque monkeys with SHIV-IL6 is expected to
provide further information on the etiology of AIDS.
PMID- 10777149
TI - IgG subclass distribution in serum and various mucosal fluids of HIV type 1
infected subjects.
AB - We measured total IgG1, IgG2, IgG3, and IgG4 concentrations by ELISA in serum
(S), total saliva (TS), cervicovaginal secretions (CVS), seminal secretions
(SPE), and rectal secretions (RS) from either CDC II/III HIV-1-infected subjects
or healthy volunteers. Human serum albumin was measured in parallel to calculate
the relative coefficient of excretion (RCE). Levels of IgG1 and IgG3 directed
against gp120 MN also were measured by ELISA in all samples, and the specific
activity (SA) calculated. HIV-1-specific IgG2 and IgG4 were not compared, as
total IgG2 and total IgG4 levels in HIV-1-infected subjects were found to be
lower than in the healthy controls. Despite substantial interindividual
variability, total IgG1 and IgG3 concentrations in all fluids were greater in the
HIV-1-infected subjects than in the healthy controls. Calculations of RCE
indicated predominantly a transudative origin for IgG subclasses in the different
mucosal fluids, except for CVS, in which IgG1, IgG2, and IgG4 was produced
locally. The transduction behavior of IgG3 in secretions appears to be different
from that of other IgG subclasses. HIV-1-infected subjects were considered
positive for IgG1 and IgG3 antibodies against gp120 MN if their antibody levels
exceeded the maximum titer measured in the control group. Positive levels of anti
gp120 MN IgG1 were detected for 100% of HIV-1-infected individuals in S, CVS, and
SPE, 97% in TS, and 75% in RS. Fewer subjects had positive levels of IgG3 to
gp120 MN in their secretions (maximum 67% in CVS). Despite the low concentrations
of total IgG3, mean SA values for IgG3 to gp120 MN were greater in secretions
than in serum. No significant difference in the SA values for IgG1 to gp120 MN
was observed between the different fluids. Only CVS had a local production of HIV
specific IgG1 Our results highlight the importance of an HIV-specific IgG1 and
IgG3 immune response in mucosal fluids from HIV-1-infected subjects.
PMID- 10777150
TI - False positivity of enzyme-linked immunosorbent assay for measurement of
secretory IgA antibodies directed at HIV type 1 antigens.
AB - We have determined that polymeric IgA in saliva of HIV-1-uninfected individuals
binds in varying degrees to components of culture supernatants containing HIV-1
recombinant proteins when ELISA is used for the determination. This finding did
not extend to salivary IgG antibodies. Further, such problems were not
encountered in Western blot. Binding did not appear to be mediated by salivary
proteins known to bind to IgA, including secretory component, amylase,
lactoferrin, lysozyme, galactosyl transferase, or secretory leukocyte protease
inhibitor, and was not influenced by blocking reagents or by changes in secondary
anti-IgA antibodies. Although these findings will not likely impact on the use of
saliva as a diagnostic fluid for HIV-1 infection (the HIV-1 response in saliva is
mostly of the IgG isotype), they indicate that assessments of this secretion as
an indicator of IgA mucosal immune responses to HIV-1 vaccines should be
undertaken with caution.
PMID- 10777151
TI - Identification of all HIV type 1 group M subtypes in Senegal, a country with low
and stable seroprevalence.
AB - A total of 343 HIV-1-positive samples obtained between June 1996 and March 1999
was genetically characterized in the envelope region by HMA and/or sequencing.
The env subtype distribution was as follows: 290 (84.6%) A, 22 (6.5%) B, 16
(4.7%) C, 8 (2.5%) D, 1 (0.03%) E, 1 (0.03%) F1, 4 (1.2%) G, and 1 (0.03%) H. For
77 samples the p24 region from the gag gene was also sequenced, and for 9 (11.6%)
the subtypes between env and gag were different. Phylogenetic tree analysis
showed the predominance of AG-IBNG-like viruses among gag and env subtype A
sequences. HMA is relatively simple and requires less sophisticated technical
facilities compared with sequencing, and in Senegal 323 (94.2%) of the 343
samples could be identified by this technique. However, in the actual
configuration of the assay, discrimination between the recombinant AG-IBNG-like
recombinant viruses, which are predominant in Senegal, and the nonrecombinant
subtype A viruses is not possible.
PMID- 10777152
TI - Large-scale ex vivo expansion of primary T lymphocytes in late-stage AIDS
patients.
PMID- 10777153
TI - Recent advances in endoscopic ultrasonography.
AB - Endoscopic ultrasonography is recognized as an important tool in the diagnosis
and staging of esophageal, gastric, colorectal, pancreatic, and biliary tumors.
It also is a reliable method for the evaluation of submucosal tumors of the
gastrointestinal tract, the differentiation between benign and malignant giant
gastric folds, the evaluation of gastric ulcer healing, and the detection of
common bile duct stones. The recent introduction of endoscopic ultrasonographic
fine-needle aspiration provides for the cytologic and histologic diagnosis of
gastrointestinal submucosal and extraluminal tumors and regional lymph nodes.
This new technique may also be used for the intrasphincteric injection of
botulinum toxin in the treatment of achalasia, for the steroid injection
treatment of refractory esophageal strictures, for celiac nerve block, for
pseudocyst drainage, and for drug delivery into pancreatic tumors. High-frequency
thin ultrasonic probes can be used to make a more accurate diagnosis of
superficial carcinomas of the gastrointestinal tract and for intraductal
ultrasonography of the extrahepatic bile duct and pancreatic duct. In the future,
three-dimensional imaging of gastrointestinal tumors will provide more accurate
information regarding cancer extent. Endoscopic ultrasonography is a powerful
tool which can be used in the diagnosis and treatment of a variety of
gastrointestinal diseases.
PMID- 10777154
TI - Esophageal mucosal acid sensitivity can coexist with normal pH recording in
healthy adult volunteers.
AB - We aimed to determine whether healthy volunteers with normal pH monitoring study
results experienced heartburn or discomfort during an esophageal acid perfusion
test. We performed an esophageal acid perfusion test, followed by ambulatory
esophageal pH monitoring, in 15 healthy and asymptomatic volunteers (aged 19 to
34 years). The results of the acid perfusion test were correlated with those of
the pH monitoring. Three subjects (20%) reported chest discomfort during acid
perfusion. The pH data in all subjects were within our laboratory reference
ranges; the median (range) percent total time at pH < 4 being 1.7 (0.2-4.0)%
[laboratory reference, median (range), 3.0 (0.2-4.0)%]. We concluded that direct
infusion of acid onto the distal esophagus can produce discomfort akin to that of
gastroesophageal reflux disease in asymptomatic adult volunteers, even in the
absence of excessive esophageal acid exposure.
PMID- 10777155
TI - Proliferation and apoptosis in gastric antral epithelial cells of patients
infected with Helicobacter pylori.
AB - We measured cell proliferation and apoptosis in the antral epithelial cells of
Helicobacter pylori-infected and H. pylori-uninfected persons, and examined these
processes in relation to diagnosis and the histologic parameters of inflammation
to investigate their role in cellular turnover in diseases of the upper
gastrointestinal tract. The subjects were: 25 patients with antral gastric
cancers, 20 with antral gastric ulcers, 18 with duodenal ulcers, and 28 with
chronic gastritis, and 4 subjects with normal gastric mucosa. Seventy-two
subjects were infected with H. pylori, and 23 subjects, including the 4 with
normal gastric mucosa, were uninfected. H. pylori infection was associated with
increased apoptosis and cell proliferation in the gastric mucosa, which
correlated with the degree of acute inflammation and the density of H. pylori,
and these latter two factors correlated with each other. Intestinal metaplasia
and glandular atrophy were significantly higher in gastric cancers and gastric
ulcers than in duodenal ulcers. Cell proliferation was significantly lower in
gastric cancers than in gastric ulcers, but the apoptotic count did not show a
significant difference between these diseases. This decreased proliferation in
the adjacent mucosa in gastric cancers compared with findings in the other
diseases is thought to be closely related to the relatively decreased acute
inflammation, which may, partly, contribute to glandular atrophy in the adjacent
mucosa of gastric cancer.
PMID- 10777156
TI - High prevalence of anticardiolipin antibodies in hepatitis C virus infection:
lack of effects on thrombocytopenia and thrombotic complications.
AB - Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities.
Recently, an association between HCV infection and antiphospholipid syndrome,
including thrombocytopenia, has been reported. However, the precise relationship
between thrombocytopenia and anticardiolipin antibodies in patients with chronic
HCV infection is not fully understood; likewise, the association of
antiphospholipid syndrome and various liver diseases is not well understood. To
evaluate the prevalence and importance of antiphospholipid antibodies in various
chronic liver diseases, we determined the levels of anticardiolipin antibodies,
platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and
thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection,
chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC).
The prevalence of anticardiolipin antibodies in patients with HCV infection was
significantly higher than that in control subjects or individuals with the other
liver diseases examined. However, there was no significant correlation between
anticardiolipin antibodies and platelet counts or TAT. The frequency of
thrombotic complications was similar in anticardiolipin antibody-positive and
negative patients with chronic HCV infection. Further, sera from all but one
anticardiolipin antibody-positive HCV patient were negative for phospholipid
dependent anti-beta2 glycoprotein I antibodies. Our results suggest that
anticardiolipin antibodies are frequently found in patients with chronic HCV
infection, but they do not appear to be of clinical importance. Immunologic
disturbances induced by HCV or prolonged tissue damage in systemic organs as a
result of the extrahepatic manifestations of HCV infection may induce the
production of antibodies to various cardiolipin-binding proteins or
phospholipids.
PMID- 10777157
TI - A new variant deletion of a copper-transporting P-type ATPase gene found in
patients with Wilson's disease presenting with fulminant hepatic failure.
AB - A candidate gene (ATP7B) for Wilson's disease, an autosomal recessive disorder of
copper transport, has recently been identified. We examined the ATP7B gene in two
Japanese sisters with Wilson's disease presenting with fulminant hepatic failure
but who did not exhibit Kayser-Fleischer rings or abnormal neurological findings.
Genomic DNA was isolated from the whole blood of the patients and their family.
Entire exons of ATP7B, and their associated splice junctions, were amplified by
polymerase chain reaction. The sequencing of all exons was performed by a non
radioactive sequencing method. The sequencing of exon 12 of ATP7B revealed a 9-bp
deletion. The mutation deleted 922Gly, 923Tyr, and 924Phe, and three residues
conserved in the Menkes gene, ATP7A, located in the fifth transmembrane region.
Of the 14 family members tested, 7 were normal and 7 were heterozygous for the
deletion. Mean serum copper and cerulopasmin levels were significantly lower in
the family members who were heterozygous for the deletion than in the normal
family members, and two heterozygous family members showed abnormally low
ceruloplasmin levels; however, there were no differences in mean aspartate
aminotransferase or alanine aminotransferase levels between the two groups.
PMID- 10777158
TI - Intraductal ultrasonographic assessment of coagulation depth during endoscopic
microwave coagulation therapy in a canine model.
AB - In order to examine the feasibility of endoscopic microwave coagulation therapy
(MCT) for the treatment of common bile duct cancer in humans, we investigated the
safety and effectiveness of endoscopic MCT with the assistance of intraductal
ultrasonography (IDUS). We performed MCT in the canine small intestine as a model
because of its similarity in size to the obstructed human common bile duct.
Multiple coagulation lesions were made in anesthetized dogs, with the endoscope
inserted through a jejunostomy. Under condition "A", the tip of the MCT probe was
kept in a fixed position in contact with the mucosa of the intestine, and
coagulation was performed with an output of 30 or 50 W for 30 or 10 s,
respectively. Under condition "B", the tip of the MCT probe was moved along the
intestinal mucosa, and coagulation was performed with an output of 50, 40, or 30
W, all for 10 s. After coagulation, a thin-caliber ultrasonic probe was inserted
endoscopically for observation of the effects of coagulation. Each coagulation
under condition "A" resulted in degeneration of all layers of the intestine.
Coagulation under condition "B" resulted in more localized degeneration,
extending from the mucosal layer to the proper muscle layer. By comparison with
histologic observations, the accuracy of IDUS in assessing depth of degeneration
was 87.5%. Endoscopic microwave coagulation was considered safe and effective,
and IDUS was able to accurately assess the effects of microwave coagulation.
PMID- 10777159
TI - Gastric varices with splenic vein occlusion treated by splenic arterial
embolization.
AB - A 53-year-old man was admitted to our hospital in August 1997 with enlarged
gastric varices. Computed tomography (CT) showed splenic vein occlusion, gastric
varices, and extra-gastric wall collateral veins. Color flow images of gastric
varices were clearly visualized, and the velocity in the gastric varices was 19.6
cm/s via endoscopic color Doppler ultrasonography (ECDUS). The patient was
diagnosed with gastric varices according to angiographic findings of splenic vein
occlusion, and splenic arterial embolization was performed. Two weeks after the
splenic arterial embolization, CT showed peripheral areas of low attenuation in
the spleen, due to splenic infarction, with 70% of the spleen volume showing low
attenuation. Eight months after the splenic arterial embolization, ECDUS revealed
a decrease in gastric variceal color flow images, with the velocity in the
gastric varices being 10.3 cm/s.
PMID- 10777160
TI - Efficacy of oral adsorbent for treatment of peristomal fistula associated with
Crohn's disease.
AB - Perianal fistulae are frequently seen complications in Crohn's disease. Although
surgical procedures such as Seton's method have been devised, many patients still
suffer from fistulae that are resistant to conventional therapy. We administered
oral adsorbent to a patient with disease Crohn's who had a complicated peristomal
fistula that did not improve with conventional therapy. Six grams of oral
adsorbent (AST-120) were added daily to a regimen of elemental diet therapy and
prednisolone. The fistula gradually decreased in size after the administration of
the oral adsorbent, and had healed completely after 40 days' treatment. There
were no side effects from the oral adsorbent. This case report suggests that oral
adsorbent is an effective treatment for peristomal fistula associated with
Crohn's disease.
PMID- 10777161
TI - Rifampicin-associated pseudomembranous colitis.
AB - We report a case of pseudomembranous colitis that developed in a patient with
liver cirrhosis during anti-tuberculosis therapy with rifampicin and isoniazid.
The association between rifampicin and pseudomembranous colitis has been
controversial; this report, however, supports the association. Colonoscopy
performed 3 days after the onset of the pseudomembranous colitis revealed only
reddish patches and a few aphthoid lesions, but 4 days later pseudomembranes were
apparent. The pseudomembranous colitis was successfully controlled by
discontinuation of the anti-tuberculosis agents, along with the administration of
lactic acid bacteria, without vancomycin or metronidazole. Possible predisposing
factors for the development of pseudomembranous colitis in this patient are also
discussed.
PMID- 10777162
TI - Inflammatory pseudotumor of the liver with primary sclerosing cholangitis.
AB - Inflammatory pseudotumor (IPT) of the liver is a rare benign variant of hepatic
masses, and its exact etiology has not been elucidated. We report a case of IPT
associated with primary sclerosing cholangitis (PSC). The patient was a 50-year
old man admitted to our hospital because of jaundice. Abdominal ultrasonography
(US) and computed tomography showed multiple dilations of the intrahepatic bile
ducts and multiple masses in the liver. On magnetic resonance imaging, the masses
were slightly hypointense on T1-weighted images and slightly hyperintense on T2
weighted images. On T1-weighted images after the bolus infusion of Gd chelate,
the masses had no contrast enhancement, and they were hypointense in the arterial
phase and portal venous phase. However, they were slightly enhanced and became
almost isointense relative to the surrounding normal liver parenchyma in the
delayed phase. Endoscopic retrograde cholangiography demonstrated multiple
irregular strictures and dilations of the intrahepatic bile ducts. Angiography
demonstrated no abnormal findings, but, interestingly, subsequent dynamic CO2
enhanced US showed a strongly hyperechoic string, indicating that an artery had
penetrated through the hypoechoic mass. A US-guided percutaneous needle biopsy
revealed that the lesions were morphologically comparable to IPT. After
cholangiography and microscopic analysis of the tumor, the final diagnosis was
determined to be IPT of the liver with PSC. A number of previous reports have
suggested a possible relationship between IPT and PSC, based on pathological
findings. This report confirmed, based on clinical findings, that PSC is one of
the causes of hepatic IPT.
PMID- 10777163
TI - Esophageal mucosal acid sensitivity--normal or abnormal?
PMID- 10777164
TI - Alteration of cellular turnover in Helicobacter pylori-infected gastric mucosa.
PMID- 10777165
TI - Clarithromycin-susceptible Helicobacter pylori with mutation in 23S rRNA gene by
PCR-RFLP method.
PMID- 10777166
TI - The Extraesophageal Complications of Gastroesophageal Reflux Disease (GERD).
Proceedings of the Yale University Workshop. Westport, Connecticut, USA. October
22, 1999.
PMID- 10777167
TI - Protective mechanisms against supraesophageal GERD.
PMID- 10777168
TI - Gastroesophageal reflux disease and asthma.
AB - Gastroesophageal reflux (GER) and asthma occur together frequently. The
relationship has been recognized for more than 2,000 years but has not been
appreciated until recently. Attempts to determine the number of asthmatics that
currently have GER (prevalence) have shown a higher-than-expected prevalence. Of
the approximately 200 published studies on the relationship between GER and
asthma, the true prevalence of GER in asthmatics, however, can be estimated from
fewer than 20 of the studies. These studies, which comprise highly selected
referred populations, are unlikely to reflect the overall population of patients
with asthma. Nevertheless, the estimated prevalence of GER in asthmatics is
between 60-80% in adults and 50-60% in children. No attempts have been made to
determine the incidence of GER in asthmatics. To identify asthmatics who develop
GER over time would be a formidable task, requiring decades of close follow-up of
asthmatics who do not now have GER. Despite the lack of data on the incidence of
GER, data on the prevalence raise an important issue: If the prevalence of GER in
adult asthmatics is similar to the prevalence of GER in child asthmatics, what is
the true incidence of GER? There are two potential answers: (1) all of the child
asthmatics with GER grow up to become the adult asthmatics with GER (GER
incidence = 0%); and (2) some child asthmatics with GER outgrow either the GER or
the asthma; some adults with asthma develop GER while others with GER develop
asthma (low, medium, or high incidence depending on the numbers). It is not
unreasonable to suspect that some child asthmatics with GER become adult
asthmatics with GER, and that children with GER who apparently "outgrow" their
asthma surface later as adults with both asthma and GER. Because most children
leave their pediatricians after adolescence, the information required to
demonstrate continued asthma or GER is lost. As a result, the medical community
sees two completely different populations, each with very similar conditions:
childhood asthma with GER and adult asthma with GER. If the high prevalence of
GER in asthmatics is clinically relevant, it should be readily explainable. We
suggest that the GER/asthma relationship consists of a self-propagating situation
whereby reflux aggravates asthma, which in turn induces further reflux. In the
early course of the disease, asthma may not be apparent, as aspiration-induced
pulmonary symptoms may occur very infrequently-perhaps once or twice a year. With
time, however, aspiration may become more frequent, and the pulmonary tree may
become hypersensitive. The individual may be diagnosed as having asthma. The
pulmonary tree becomes increasingly hypersensitive, to a variety of stimuli. In
such a scenario, the initial contribution of acid aspiration is no longer
apparent, as the primary focus is on the asthma. In any individual patient, the
emphasis may be placed on the GER if reflux symptoms predominate or on asthma if
pulmonary symptoms predominate. The result is confusion over whether a patient
with GER has asthma or whether a patient with asthma has GER. The unending debate
about whether GER is a cause of the asthma or a result of the asthma becomes the
focus of attention. At such a point, the question of whether GER exists in
asthmatics or whether pulmonary symptoms exist in refluxers is irrelevant. For
the individual patient, gastric contents refluxed into the pulmonary tree is an
undesirable event, whether cause or effect, and it is up to the physician to
determine how such events can be stopped.
PMID- 10777169
TI - Laryngeal complications of GERD.
AB - Anatomic proximity of the larynx and hypopharynx make these structures
particularly susceptible to acid and bile exposure due to gastroesophageal reflux
disease (GERD). There is an increasingly expansive list of signs and symptoms
that can occur on the larynx and upper airway as a consequence of GERD. A high
index of suspicion must be maintained to property diagnose and manage the
laryngeal complications of GERD. Reflux of gastric contents into the
laryngopharynx is best demonstrated by a dual- or triple-sensor pH probe study.
Alternatively, an empiric trial of proton pump therapy as a diagnostic test has
sensitivity/specificity that is comparable to pH studies. This approach provides
both diagnostic and therapeutic advantage. Following improvement of symptoms,
reduction of the medication should be attempted, with the target of either
withdrawing therapy or using the lowest dose to control symptoms. Surgical
intervention for laryngeal complications is predictably better in patients who
have responded to proton pump inhibitor (PPI) therapy.
PMID- 10777170
TI - Oral and pharyngeal complications of gastroesophageal reflux disease: globus,
dental erosions, and chronic sinusitis.
PMID- 10777171
TI - Chest pain and gastroesophageal reflux disease.
AB - Gastroesophageal reflux disease (GERD) is the most common gastrointestinal cause
of "noncardiac chest pain." Following exclusion of a cardiac cause of chest pain,
an evaluation of the esophagus is, therefore, appropriate. Barium studies,
endoscopy, and esophageal manometry have little value in the diagnosis of GERD
induced chest pain. Twenty-four-hour pH monitoring with a symptom-index
correction may define an association but does not prove causality between the
patient's chest pain and GERD. Recent studies have implied that high-dose proton
pump inhibitor (PPI) therapy for one week is an effective approach. The PPI test
has excellent sensitivity/ specificity and economic savings (due to reduction in
diagnostic procedures) and, accordingly, should be the diagnostic/ therapeutic
approach of choice for patients with suspected GERD-induced chest pain.
PMID- 10777172
TI - Medical therapy of extraesophageal gastroesophageal reflux disease.
AB - Patients with extraesophageal gastroesophageal reflux disease (GERD) are often
more difficult to treat than patients with typical GERD. Effective treatment
almost always requires the use of proton pump inhibitors, often in higher doses
than traditionally used to treat patients with heartburn and erosive esophagitis
and for a longer period of time. Long-term maintenance therapy is usually
required as relapse is almost universal when therapy is discontinued. This paper
reviews the treatment options and suggested approach to management of these
patients with extraesophageal GERD.
PMID- 10777173
TI - Surgical therapy for atypical symptoms of GERD: patient selection and
preoperative evaluation.
AB - Patients are selected for surgery for extraesophageal manifestations of
gastroesophageal reflux disease (GERD) after medical therapy failure, medical
noncompliance, or because of a desire to change from medical therapy.
Preoperative assessment of patients with extraesophageal manifestations of GERD
is tailored to the four types of symptoms: noncardiac chest pain, pulmonary,
laryngeal, and oropharyngeal. Prior to surgery, all patients should undergo 24
hour pH testing and manometry. Indicators of a good response to surgery are an
initial response to medication and positive 24-hour pH test results.
PMID- 10777174
TI - Surgical therapy for GERD: selection of procedures, short- and long-term results.
AB - Surgical options for the supraesophageal complications of gastroesophageal reflux
disease (GERD) should be considered in all patients. Although the majority can be
managed successfully with medical therapy, patients with severe complications,
refractory disease, or with a severely incompetent lower esophageal sphincter
should be referred for surgical evaluation. The laparoscopic Nissen
fundoplication achieves the same short-term outcome as the open procedure but has
associated significantly less morbidity, shorter hospital stay, and more rapid
return to normal function. Patients who respond to medical therapy of
supraesophageal GERD complications have a predictably better response than
nonresponders to antireflux surgery.
PMID- 10777175
TI - Workshop consensus report on the extraesophageal complications of
gastroesophageal reflux disease.
PMID- 10777176
TI - Diabetes mellitus: a predictor of cirrhosis in chronic viral hepatitis.
PMID- 10777178
TI - Radiation therapy in pancreatic cancer: current practice and future trends.
AB - Treatment options for pancreatic cancer remain limited due to the large
proportion of patients presenting with advanced disease at the time of diagnosis.
Surgery offers the best chance for cure. Localized chemoradiation modestly
improves median survival in both localized and locally advanced disease.
Interstitial brachytherapy and intraoperative radiotherapy improve local control
without providing significant impact on overall survival. Technological advances
now allow us to deliver three dimensional conformal external beam irradiation
with improved efficacy and decreased morbidity. Novel treatment approaches, such
as intraoperative photoelectron radiation (Photon Radiosurgery System; PeC
Photoelectron Corporation) and the development of more effective
radiosensitizers, are presently under investigation.
PMID- 10777177
TI - Fecal impaction: not always a benign condition.
PMID- 10777179
TI - Antiviral therapy of HBV- and HCV-induced liver cirrhosis.
AB - Antiviral therapy is generally indicated in patients who have histologic evidence
of chronic hepatitis and ongoing viral replication. The aim of treatment is to
normalize alanine aminotransferase levels and to eliminate virus replication.
Interferon-alfa (IFN-alpha) is the most used agent. The standard treatment
regimen for hepatitis B e antigen (HBeAg)-positive cirrhosis is based on IFN
alpha given alone, but the efficacy of new antivirals (famciclovir, lamivudine)
with or without IFN-alpha is currently under investigation. Conversely, the
therapy of antiHBe-positive cirrhosis is far from being satisfactory. The results
of treatment of patients affected by type C cirrhosis with IFN-alpha alone have
been disappointing, as 10-15% of treated patients shows a sustained virologic
response. Although current evidence suggests that the combination of ribavirin
and IFN-alpha might be more efficacious than IFN alone in increasing the response
rate in patients in the advanced fibrotic stage, the efficacy of this regimen for
patients with well-compensated HCV-related cirrhosis is still unknown and
prospective well-designed studies are urgently needed. Patients with
decompensated cirrhosis are not generally treated unless they are included in
liver transplantation programs. Prospective long-term trials with large sample
sizes are needed to determine if responders to IFN-alpha have a low incidence of
liver-related complications and hepatocellular carcinoma.
PMID- 10777180
TI - The differential diagnosis of eosinophilic esophagitis.
AB - Eosinophilic esophagitis is a morphologic finding that may result from a wide
spectrum of clinical conditions. The distinctive histological features
accompanying eosinophilic esophagitis may facilitate the diagnosis of the
underlying disease entity. Unfortunately, there are no pathognomonic histologic
characteristics associated with eosinophilic esophagitis. Clinical signs and
symptoms, immunological markers, endoscopic findings, and response to therapy may
help establish or confirm the diagnosis of a clinical condition that results in
eosinophilic esophagitis. The following discussion outlines the causes of
eosinophilia in an esophageal biopsy sample.
PMID- 10777181
TI - Collagenous colitis and lymphocytic colitis.
AB - The most recently recognized and least understood forms of inflammatory bowel
disease are two types of idiopathic microscopic colitis-collagenous colitis and
lymphocytic colitis. These disorders share many clinical and histologic features,
but they have a few notable differences. Whether these are two distinct entities
or different presentations of the same disease remains controversial. Bismuth
subsalicylate is effective in some patients and treatment is symptomatic and
empirical in others. Unlike ulcerative colitis and Crohn's disease, these forms
of inflammatory bowel disease rarely require surgery. Ileostomy with or without
colectomy is curative for the rare patient with severe symptoms that are
refractory to medical measures. Collagenous and lymphocytic colitis are not
associated with an increased risk of malignancy.
PMID- 10777182
TI - Diabetes mellitus as a risk factor of liver cirrhosis in patients with chronic
hepatitis B virus infection.
AB - Liver cirrhosis may occur in chronic hepatitis B surface antigen (HBsAg)
carriers. Diabetes mellitus (DM)-associated chronic hepatitis may also
occasionally lead to cirrhosis; however, its role in the course of chronic HBsAg
carriers has not been studied. A cohort of 500 HBsAg carriers (398 men; mean age
at entry, 42 +/- 15 years) were followed up longitudinally. After a mean follow
up of 5.8 +/- 3.3 years, 71 (14.2%: 70 men) patients developed cirrhosis.
Increased risks of cirrhosis were found among men and the elderly (p < 0.001).
Fifteen (21.1%) cirrhotic patients were noted to have had DM for 2-15 years
before the development of cirrhosis. By contrast, only eight (1.9%; p < 0.001 )
of the patients without cirrhosis developed DM. When cirrhotic patients were
compared to 102 age- and sex-matched non-cirrhotic controls, DM and elevation of
serum alanine transaminase levels were found to be independent factors associated
with the advent of cirrhosis in multivariate analysis. Other factors, including
acute exacerbation, bridging hepatic necrosis, and superinfection by hepatitis C
or D viruses, were insignificant. Our results suggest that DM may play a role in
the progression to liver cirrhosis in chronic HBsAg carriers. High-risk subjects
should be closely monitored for late complications.
PMID- 10777183
TI - Familial intrahepatic cholestatic cirrhosis with positive antimitochondrial
antibody: familial primary biliary cirrhosis.
AB - We present three siblings (out of four) with intrahepatic cholestatic disease and
cirrhosis. Two of the siblings, a 33-year-old woman and a 34-year-old man had
advanced liver disease- with the liver histology showing established cirrhosis
with chronic cholestasis and excess copper accumulation. Both died two years
later due to hepatic encephalopathy. The third sibling, a 37-year-old man on
routine check-up was found to have abnormal liver functions. The liver biopsy
showed marked bile ductular proliferation with bridging fibrosis, reduction in
interlobular bile ducts, and excess copper accumulation. The presence of
antimitochondrial antibody in the serum in 1 in 320 dilutions in all three
patients and 1 in 80 dilutions in the oldest healthy sibling and
hypergammaglobulinemia in all the siblings confirmed the diagnosis of familial
primary biliary cirrhosis. Antinuclear and smooth muscle antibodies were not
present. Clinical and biochemical improvement has been noted in the third sibling
after therapy with ursodeoxycholic acid.
PMID- 10777184
TI - Respective value of alkaline phosphatase, gamma-glutamyl transpeptidase and 5'
nucleotidase serum activity in the diagnosis of cholestasis: a prospective study
of 80 patients.
AB - We studied the value of alkaline phosphatase (AP), gamma-glutamyl transpeptidase
(GGT), and 5'-nucleotidase (5'-NU) activities in the diagnosis of intrahepatic
(IHC) versus extra-hepatic cholestasis (EHC). Eighty patients were included
prospectively. All presented with cholestasis as defined by a concomitant
increase in at least two of three cholestatic enzymes (AP, GGT, 5'-NU), a low
cytolytic ratio (alanine aminotransferase/AP [xN/xN] < or = 5), and no evidence
for associated liver tumor. We compared 43 patients with IHC due to chronic liver
disease to 37 patients with EHC due to main bile duct obstruction. Fasting blood
samples for activity determination (AP, GGT, 5'-NU) were taken before performing
liver biopsy in cases of IHC and before endoscopic or surgical management in
cases of EHC. Enzyme activities were compared using univariate and multivariate
analysis. AP (276 IU/L [35-3,140] vs. 123 IU/L [37-699]: p < 0.0001), GGT (595
IU/L [98-5,200] vs. 211 IU/L [38-925]; p < 0.0001), and 5'-NU (32 IU/L [10-142]
vs. 16 IU/L [4-107]: p < 0.0003) were significantly higher in EHC when compared
to IHC. Only in GGT and 5'-NU activities were independent variables significantly
linked to the mechanism of cholestasis. In IHC, the ratio GGT/5'-NU (xN/xN) was
significantly lower than in EHC (2.8 [0.7-7.2] vs. 3.7 [1.8-10.5]: p < 0.006). A
threshold of GGT/5'-NU < 1.9 had a sensitivity of 40% and a specificity of 100%
for the diagnosis of IHC. Although such hepatobiliary enzymes cannot be regarded
as diagnostic, they can provide useful information to orientate the clinician in
the diagnosis of cholestasis.
PMID- 10777185
TI - Morbidity, mortality, and risk factors for esophagitis in hospital inpatients.
AB - Esophagitis is a common endoscopic finding, although its prevalence and
contribution to morbidity and mortality in hospital inpatients has not been
systematically evaluated. This study aimed to determine the prevalence of
esophagitis among hospital inpatients referred for upper gastrointestinal
endoscopy, to assess factors associated with the presence of esophagitis, and to
determine the mortality of patients with esophagitis. All inpatients referred for
upper gastrointestinal endoscopy in a district general hospital were assessed
prospectively for one year. The reason for referral, endoscopy findings, and one
month mortality were determined together with a history of nasogastric
intubation, periods spent supine, and drug use. Of 595 inpatients who underwent
gastroscopy, 58% were referred for investigation of acute upper gastrointestinal
bleeding. Esophagitis was found in 196 (33%). Esophagitis was significantly
associated with wide-bore nasogastric intubation (p = 0.021; relative risk, 2.61;
95% CI, 0.64-6.06) but not with fine-bore nasogastric intubation. Esophagitis was
also significantly associated with being nursed supine (p = 0.015; relative risk,
1.41; 95% CI, -1.75-6.72). There was no association between esophagitis and
specific drug therapy. Mortality among patients with esophagitis was higher than
those without esophagitis (p = 0.04; relative risk, 1.38; 95% CI, 0.34-3.22).
Reflux esophagitis is common in hospital inpatients who are endoscoped. Although
the underlying diseases are likely to account for the high mortality, the
associations of wide-bore nasogastric intubation and being nursed supine should
alert caregivers to an increased risk. If nasogastric intubation is required for
feeding only, fine-bore tubes should be considered.
PMID- 10777186
TI - Peristaltic pressure profiles of the human esophagus.
AB - Using a low-compliance pneumohydraulic infusion system, we mapped the entire
esophagus of nine volunteers with no history of esophageal disease, centimeter by
centimeter, to see if there was pressure symmetry throughout the esophagus during
5 mL wet swallows. We found that esophageal length varied from 21-25 cm. The
esophageal low-pressure zone (LPZ) varies in distance from the upper esophageal
sphincter (UES) (4-8 cm). The length of this LPZ is 2-3 cm in most subjects but
low pressures (<50 mmHg) may occur for longer intervals in some. The amplitudes
of most paired swallows were within 10 mmHg of each other, and in only 10% of
swallows was the pressure difference more than 15 mmHg. We conclude that there is
radial pressure symmetry throughout the normal esophagus. The LPZ coincides
closely to the 50-50 point where the percentage of striated and smooth muscle
distribution in the circular and longitudinal muscles is equal.
PMID- 10777187
TI - The electromyographic behavior of the thyroarytenoid muscle during swallowing.
AB - The electromyographic (EMG) behavior of the laryngeal adductors (e.g., the
thyroarytenoid [TA] muscle) during swallowing has been scarcely studied. However,
the detailed analysis of TA muscle is important to understand the physiology of
swallowing. We investigated 14 healthy adult subjects. Activation of the TA
laryngeal adductor muscle was compared with the mechanically measured laryngeal
up-down movement and with the onset of excitation of laryngeal elevators, such as
submental (SM) muscles, during swallowing. The laryngeal adductor of TA and
laryngeal elevators of SM muscles were electromyographically
(integrated/rectified) recorded. The vertical laryngeal movements during
swallowing were recorded using a piezoelectric sensor. The EMG behavior of the TA
muscle revealed three different activities during swallowing. The basic activity
was stable; it almost started with the upward movement of larynx and after the SM
EMG onset. A fore-burst was recorded just before the upward movement of the
larynx and a late-burst appeared just after the downward movement. The fore-burst
was proposed to be related with oral-laryngeal reflexes, and the late-burst could
be a rebound activity after a short expiration of swallowing, while the basic
activity is accepted to be a part of activity of central-pattern generator of
swallowing program.
PMID- 10777188
TI - Triage of patients with acute gastrointestinal bleeding for intensive care unit
admission based on risk factors for poor outcome.
AB - This study's aim was to determine the prognostic factors and to develop a triage
system for intensive care unit (ICU) admission of patients with gastrointestinal
bleeding (GIB). This prospective, observational study included 411 adults
consecutively hospitalized for GIB. Each patient's selected clinical findings and
laboratory values at presentation were obtained. The Acute Physiology and Chronic
Health Evaluation (APACHE) II scores were calculated from the initial findings in
the emergency department. Poor outcome was defined as recurrent GIB, emergency
surgery, or death. The role of hepatic cirrhosis, APACHE II score, active GIB,
end-organ dysfunction, and hypotension in predicting outcome was evaluated. Chi
square, Student's t, Mann-Whitney U, and logistic regression analysis tests were
used for statistical comparisons. Poor outcome developed in 81 (20%) patients; 39
died, 23 underwent emergency surgery, and 47 rebled. End-organ dysfunction,
active bleeding, hepatic cirrhosis, and high APACHE II scores were independent
predictors of poor outcome with odds ratios of 3:1, 3:1, 2:3, and 1:1,
respectively. The ICU admission rate was 37%. High APACHE II score, active
bleeding, end-organ dysfunction, and hepatic cirrhosis are independent predictors
of poor outcome in patients with GIB and can be used in the triage of these
patients for ICU admission.
PMID- 10777189
TI - Is gastric nodularity a sign for gastric inflammation associated with
Helicobacter pylori infection in children?
AB - The aim of this study was to investigate the accuracy of using gastric nodularity
(GN) as a marker for gastric inflammation associated with Helicobacter pylori
infection in children. A retrospective analysis of 395 upper endoscopies done in
children between 1990-1996 was performed. Demographics, clinical symptoms,
endoscopic features, rapid urease test (RUT), and histological results were
collected from each report. GN was found in 13 (3.5%) children. GN showed a
significant correlation with age but not with gender. Multiple regression
analysis showed a significant correlation between GN and gastritis with RUT but
not with other histological determinants alone (gastritis, RUT, or H. pylori
organisms). Nevertheless, GN had a poor accuracy rate to determine H. pylori
associated gastritis (sensitivity, 61%; positive predictive value, 12%). GN is a
poor predictor for gastric inflammation associated with H. pylori infection in
children. During endoscopy, gastric biopsies should always be obtained in
children to establish the presence of mucosal inflammation.
PMID- 10777190
TI - Primary small bowel malignancies: single-center results of three decades.
AB - We highlight one medical center's experiences with primary malignancies of the
small bowel. During a 27-year period, 79 patients were treated for small bowel
tumors. Of these, 15 (20%) were lost to follow-up; thus, 64 patients were
reviewed retrospectively with emphasis on histological distribution and their
topography, perioperative complications, overall survival, and prognostic
factors. In our 64-patient series, 33 (51.6%) presented with adenocarcinoma; 10
(15.5%), lymphoma; 8 (12.1%), leiomyosarcoma; 5 (7.6%), neurogenic tumor; 2 (3%),
unclassified carcinoma; 5 (7.6%), other types of sarcoma; and 1 patient presented
with synchronous adenocarcinoma and lymphoma. Of all patients, 30 (46.9%) were
curatively treated, whereas 34 (53.1%) underwent palliative procedures. Hospital
lethality was 9.4% and mainly occurred in patients operated on under emergency
circumstances. Reoperation rate was 29.7%. The observation period lasted at least
five years or until death; three patients were alive less than five years
postoperatively. Cumulative five-year survival rate was 22.5% in the
adenocarcinoma group, 33.3% in the lymphoma group, 33.3% in the leiomyosarcoma
group, and 22.2% in patients with other tumors. The uncharacteristic symptoms
presented by patients suffering from small intestinal malignancies make early
diagnosis difficult. Therefore, especially in patients with long-standing bowel
diseases, malignancy should be considered. Early diagnosis and surgical treatment
lead to a good prognosis as shown by our study.
PMID- 10777191
TI - Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease
in children.
AB - Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6
mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this
study was to evaluate whether these drugs healed pediatric perianal Crohn's
disease. Records of pediatric Crohn's patients were retrospectively reviewed for
significant perianal disease treated with AZA or 6-MP for > or =6 months. The
patient's perianal disease was reviewed and evaluated for fistulas, drainage,
induration, and tenderness. In addition, the patients were given a score using
the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively
scored upon initiation of treatment and after six months of therapy. Possible
scores ranged from 0-20. Twenty patients met the study criteria. Five patients
were considered treatment failures. One patient required a colostomy after 1.5
months of therapy, one developed pancreatitis, and three were noncompliant with
therapy. Of the remaining 15 patients who were treated for > or =6 months, 67%
had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in
fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/-
1.72 after six months of therapy. The improvement was statistically significant
(p < 0.001). AZA and 6-MP are effective treatments for healing significant
perianal Crohn's disease in pediatrics.
PMID- 10777192
TI - Pernicious anemia, gastric carcinoid, and autoimmune thrombocytopenia in a young
woman.
AB - The association between gastric carcinoid tumors and pernicious anemia is well
recognized. Such tumors occur in the presence of achlorhydria, chronic atrophic
gastritis, hypergastrinemia, and enterochromaffin-like cell hyperplasia. In this
case report, a 29-year-old woman with pernicious anemia and autoimmune
thrombocytopenia who developed gastric carcinoid tumors of the gastric body is
described. This is the second description of pernicious anemia associated with
autoimmune thrombocytopenia. This association in a young woman together with the
therapeutic options and decisions that were taken in the treatment of the patient
are discussed.
PMID- 10777193
TI - Heterotopic gastric tissue in the duodenal bulb.
AB - Heterotopic gastric tissue in the duodenal bulb is a rare congenital lesion. Its
prevalence has been reported to be 0.5-2%. It must be differentiated from gastric
metaplasia of the duodenal bulb because the two entities have different clinical
implications. During one year, we found three cases of gastric heterotopia of the
duodenal bulb. In one of the cases, active acid-secreting gastric mucosa was
documented by performing the pentagastrin Congo red dye test. The differences
between gastric heterotopia of the duodenal bulb and gastric metaplasia of the
duodenal bulb have been discussed.
PMID- 10777194
TI - Nonfunctioning islet cell carcinoma of the pancreas with high serum CEA & CA19-9,
K-ras codon 12 mutation, and microsatellite instability.
AB - A 55-year-old man with nonfunctioning islet cell carcinoma showing elevation of
serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9)
levels is described with genetic analyses. Pathological examination of the
resected specimen revealed two independent islet cell carcinomas, one in the body
and the other in the tail of the pancreas. It was proved immunohistochemically
that the tumor cells, particularly those in the tail, were immunoreactive to CEA
and CA 19-9 and had the property of duct cells, as well as endocrine cells.
Gastrin was demonstrated immunohistochemically in these tumor cells, although its
level in serum was not elevated. Genetic analyses of the fresh specimens from the
tumor in the body revealed K-ras codon 12 mutation and microsatellite
instability. These findings are consistent with its progressive clinical course
and strongly suggest that these tumors originate, not from the islet cells of
Langerhans, but from protodifferentiated cells, capable of giving rise to all the
pancreatic cell types.
PMID- 10777195
TI - Bilateral hydronephrosis due to fecaloma in an elderly woman.
AB - By computer search of the literature, we found few cases of hydronephrosis due to
fecal impaction. Because such a complication is extremely rare, we describe an 81
year-old woman with dementia, gallstones, arterial hypertension, and
diverticulosis of the sigma who was hospitalized for severe constipation,
fecaloma, and bilateral hydronephrosis. Through simultaneous lavage by two rectal
tubes and manual disimpaction of fecaloma, bilateral hydronephrosis was resolved.
We also briefly review the appropriate literature.
PMID- 10777196
TI - Urethral obstruction and bilateral ureteral hydronephroses secondary to fecal
impaction.
AB - We present a case report of the first adult woman reported to suffer from both
urethral obstruction and bilateral ureteral hydronephroses secondary to fecal
impaction. The work-up suggested that hypothyroidism might be the cause for fecal
impaction. Urinary tract obstruction caused by hypothyroidism-induced fecal
impaction has never been reported. Fecal impaction should be considered as one of
the causes for urinary tract obstruction.
PMID- 10777197
TI - Ascending cholangitis as a cause of pyogenic liver abscesses complicated by a
gastric submucosal abscess and fistula.
AB - Ruptures of nonamebic (pyogenic) liver abscesses into the thorax and peritoneum
are very uncommon; but, hepatoduodenal and hepatocolonic fistulas are ever more
rare. We report a case where ascending cholangitis was associated with pyogenic
liver abscess formation and a gastric fistula. Drainage into the stomach was
demonstrated by gastroduodenal endoscopy for gastric bleeding. After fistula
formation, we could successfully treat the inflammation caused by infection of
Citrobacter freundii and Candida albicans with intravenous infusion of both
antibiotic and antifungal agents.
PMID- 10777198
TI - Gabapentin "add-on therapy" for idiopathic chronic hiccup (ICH).
AB - The efficacy of cisapride, omeprazole, and baclofen (COB) for treatment of
idiopathic chronic hiccup (ICH). was proven in several studies. The combination
is considered, at present, to be "therapy of choice" for this condition.
Substituting gabapentin for baclofen in baclofen resistant ICH cases can
occasionally be successful. We present here cases where gabapentin was used
successfully in combination with cisapride and omeprazole (COG/one patient) or as
an "add-on" with cisapride, omeprazole, and baclofen (COBG/three patients). We
conclude that, with baclofen and gabapentin, we are in possession of two
substances that are, as a part of a combination therapy, quite effective for ICH.
Because of the far more extensive experience with baclofen, we use it as a first
line therapy, together with omeprazole and cisapride. In cases where the results
are not entirely satisfactory, the addition of gabapentin should be considered.
PMID- 10777199
TI - Adult celiac disease presented with celiac crisis: severe diarrhea, hypokalemia,
and acidosis.
AB - An acute severe onset of celiac disease is very uncommon in adults. We describe a
patient with adult celiac disease who presented with acute diarrhea that lead
rapidly to a life threatening hypokalemia and acidosis, the so-called celiac
crisis. Celiac crisis, described mainly in children younger than two years of
age, has become very rare due to earlier diagnosis and effective therapy of the
disease. The case described is an example of the heterogeneous clinical course of
celiac disease and emphasizes the need to consider it in the differential
diagnosis, even in adults suffering from acute diarrhea and acidosis.
PMID- 10777200
TI - Relief of small bowel obstruction following colonoscopy in a case of gallstone
ileus.
AB - We describe a patient who presented with mechanical obstruction of the small
bowel secondary to impaction of the ileocecal valve from a gallstone. The stone
impaction of the ileocecal valve was confirmed by colonoscopy. Although the stone
was disimpacted, it could not be trapped and extracted during colonoscopy.
Thereafter, the patient's small bowel obstruction was relieved with no further
intervention. Even though surgery is the gold standard for the management of
gallstone ileus. colonoscopy can be useful in management of patients with
gallstone ileus in whom surgery is contraindicated. A review of the literature is
also presented.
PMID- 10777201
TI - Lower gastrointestinal bleeding secondary to Dieulafoy-like lesion of the rectum.
AB - Two cases of gastrointestinal hemorrhage resulting from Dieulafoy-like lesion of
the rectum are presented. Both patients developed acute episodes of massive lower
gastrointestinal hemorrhage requiring transfusions. Colonoscopy was performed in
both instances and lesions were localized. The patients were successfully treated
by alcohol and epinephrine injection. Colonoscopy assisted in earlier diagnosis
and added therapeutic options to the treatment regimen for this lesion.
PMID- 10777202
TI - Autoimmune hepatobiliary disease in trisomy 21.
AB - Two patients with abnormal liver biochemistry are presented with hepatobiliary
disorders rarely described in trisomy 21. The first was considered to have
primary sclerosing cholangitis (PSC) and Crohn's disease. Liver biochemistry was
normal after six months' treatment with ursodeoxycholic acid and diarrhea
resolved after sulfasalazine. The second patient had autoimmune hepatitis that
responded to immunosuppression. Autoimmune hepatobiliary disorders, highlighted
by this report, occur in trisomy 21 but are rare. A high index of suspicion for
these potentially treatable disorders is required.
PMID- 10777203
TI - Primary peritonitis due to group A streptococcus.
AB - Primary peritonitis is a rare condition occurring, by definition, in patients
without underlying causes, such as perforated viscus, pre-existing ascites, or
nephrosis. We report a case of primary peritonitis and shock due to group A beta
hemolytic streptococcus, a rare etiology. A review of the world's literature
shows a predilection for women to have this condition. The entry site is obscure
in most cases. Asymptomatic genital tract colonization may be a portal of entry
in some women. Shock or toxic shock syndrome often accompany the abdominal
findings. Laparotomy to exclude a perforated viscus may be unavoidable. Despite
the significant morbidity, expeditious and appropriate antibiotic therapy is
curative.
PMID- 10777204
TI - Gastroduodenal tuberculosis presenting with massive hematemesis in a pregnant
woman.
PMID- 10777205
TI - Low reinfection rate of Helicobacter pylori infection in Turkey.
PMID- 10777206
TI - Ranitidine bismuth citrate plus azithromycin for Helicobacter pylori eradication.
PMID- 10777207
TI - Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence
specific DNA-binding site.
AB - KILLER/DR5, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
death receptor gene, has been shown to be induced by DNA damaging agents and
radiation in a p53-dependent manner. Although TRAIL is a potential therapeutic
agent for cancer, the induction mechanism of its receptors is poorly understood.
Here we show the identification of three p53 DNA-binding sites in the KILLER/DR5
genomic locus located upstream (BS1; -0.82 Kb) of the ATG site, within Intron 1
(BS2; +0.25 Kb downstream of the ATG) and within Intron 2 (BS3; +1.25 Kb
downstream of the ATG). A modified p53-binding and immunoselection protocol using
a wild-type p53-expressing adenovirus vector (Ad-p53) was used to identify the
binding sites and to show that each binding site can bind specifically to wild
type p53 protein (wt-p53). A reporter assay revealed that only BS2 could enhance
luciferase expression driven by a basal promoter. We constructed a reporter
plasmid carrying the genomic regulatory region of KILLER/DR5 including the three
p53 DNA-binding sites but no additional basal promoter. The genomic fragment
showed basal transcriptional activity which was induced by wt-p53 but not by
mutant p53, and human papilloma virus E6 inhibited the p53-dependent activation.
Mutation of BS2 abrogated not only the binding activity of wt-p53 but also the
induction of the KILLER/DR5 genomic promoter-reporter gene, indicating that BS2
is responsible for the p53-dependent transactivation of KILLER/ DR5. In p53-wild
type but not -mutant or -null cell lines, doxorubicin treatment stabilized p53
protein, and increased specific binding to BS2 as revealed by EMSA, and
upregulated the KILLER/DR5 promoter-luciferase reporter gene. These results
suggest that the transactivation of KILLER/DR5 is directly regulated by exogenous
or endogenous wt-p53 and establishes KILLER/DR5 as a p53 target gene that can
signal apoptotic death.
PMID- 10777208
TI - ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1
(ABI1) that is fused to MLL in t(10;11)+.
AB - Translocations of the chromosomal locus 11q23 that disrupt the MLL gene
(alternatively ALL-1 or HRX) are frequently found in children's leukemias. These
events fuse the MLL amino terminus in frame with a variety of unrelated proteins.
Up to date, 16 different fusion partners have been characterized and more are
likely to exist. No general unifying property could yet be detected amongst these
proteins. We show here that the frequent MLL fusion partner ENL at 19p13.1
interacts with the human homologue of the mouse Abl-Interactor 1 (ABI1) protein.
ABI1 in turn, is fused to MLL in the t(10;11)(p11.2;q23) translocation. ABI1 was
identified as an ENL binding protein by a yeast two-hybrid screen. The
interaction of ENL and ABI1 could be verified in vitro by far-Western blot assays
and GST-pulldown studies as well as in vivo by co-immunoprecipitation
experiments. A structure-function analysis identified an internal region of ENL
and a composite motif of ABI1 including an SH3 domain as mutual binding partners.
These data introduce novel aspects that might contribute to the understanding of
the process of leukemogenesis by MLL fusion proteins.
PMID- 10777209
TI - B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks
cellular transformation by Ras and Fos.
AB - B-ATF is a nuclear basic leucine zipper protein that belongs to the AP-1/ATF
superfamily of transcription factors. Northern blot analysis reveals that the
human B-ATF gene is expressed most highly in hematopoietic tissues. Interaction
studies in vitro and in vivo show that the leucine zipper of B-ATF mediates
dimerization with members of the Jun family of proteins. Chimeric proteins
consisting of portions of B-ATF and the DNA binding domain of the yeast activator
GAL4 do not stimulate reporter gene expression in mammalian cells, indicating
that B-ATF does not contain a conventional transcription activation domain. Jun/B
ATF dimers display similar DNA binding profiles as Jun/Fos dimers, with a bias
toward binding TRE (12-O-tetradecanolyphorbol-13-acetate-response element) over
CRE (cyclic AMP-response element) DNA sites. B-ATF inhibits transcriptional
activation of a reporter gene containing TRE sites in a dose-dependent manner,
presumably by competing with Fos for Jun and forming transcriptionally inert
Jun/B-ATF heterodimers. Stable expression of B-ATF in C3H10T1/2 cells does not
reduce cell viability, but does result in a reduced cellular growth rate when
compared to controls. This effect is dominant in the presence of the growth
promoting effects of the H-Ras or the v-Fos oncoproteins, since expression of B
ATF restricts the efficiency of focus formation by these transforming agents.
These findings demonstrate that B-ATF is a tissue-specific transcription factor
with the potential to function as a dominant-negative to AP-1.
PMID- 10777210
TI - Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein
Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and
invasive growth.
AB - The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has a
significant role in initiating EBV-associated lymphoproliferative disease and EBV
related malignancies. In view of clinical features related to the type of EBV
latency, LMP1 may influence invasiveness of EBV associated tumors categorized as
types II and III as represented on nasopharyngeal carcinoma (NPC). To screen for
genes associated with invasion of epithelial cells transformed by LMP1, Madin
Darby canine kidney (MDCK) epithelial cells were transformed by LMP1. Stable
transfection of a LMP1 gene into MDCK cells induced morphological change from
cobblestone to a long spindle-shape, reduced cell-cell adhesion and caused high
cell motility. Parental MDCK cells, which form spherical cysts in three
dimensional collagen gel matrix, form branching tubules following exposure to
hepatocyte growth factor (HGF). MDCK cells transformed by LMP1 showed invasive
growth to form branching tubules into collagen gel without HGF-treatment. mRNA
differential display and Northern hybridization identified plasminogen activator
inhibitor-1 (PAI-1), urokinase type plasminogen activator (uPA) and ets1 as genes
upregulated during transformation by LMP1. Expression of a dominant negative type
of Etsl in LMP1-transformed cells downregulated uPA expression and cell motility.
Deletion of LMP1 cytoplasmic carboxy-terminal activating region 1 (CTAR1) domain
abolished transformation, but a deletion mutant lacking CTAR2 domain still
retained transforming and uPA-inducing ability. Expression of Ets1 was
immunolocalized in tumor cells of NPC tissue which frequently express LMP1. Taken
together, it is suggested that LMP1 induces expression of Ets1 which may
contribute to invasion of NPC by stimulating cell motility and uPA expression.
PMID- 10777211
TI - Down-regulation of the extracellular matrix protein SPARC in vSrc- and vJun
transformed chick embryo fibroblasts contributes to tumor formation in vivo.
AB - In vitro transformation of primary cultures of chick embryo fibroblasts by the
membrane-bound vSrc or the nuclear vJun oncoproteins is correlated with a down
regulation of the secreted glycoprotein SPARC (also called BM-40 or osteonectin).
This protein is a nonstructural component of the extracellular matrix that is
thought to regulate cell-matrix interaction during development, wound repair, and
carcinogenesis. Its precise function remains unclear. To estimate the
contribution of SPARC down-regulation to the major aspects of the transformed
phenotype, we have reexpressed this protein from a self-replicating retrovirus
Rcas, designated R-SPARC, in the transformed cultures. These R-SPARC-infected
cultures display the following main properties: (i) they accumulate the SPARC
protein to a level identical to or only slightly higher than the level in normal
chick embryo fibroblasts; (ii) they retain the main phenotypic properties
characteristic of in vitro transformed cells, that is, altered morphology,
capacity to grow in a reduced amount of serum, and capacity to develop colonies
from single cells in agar; (iii) they display a clearly reduced capacity to
develop local fibrosarcomas in vivo. Taken together, these data strongly suggest
that down-regulation of SPARC contributes to the transformed phenotype triggered
by vSrc and vJun in primary avian fibroblasts, by facilitating in vivo
tumorigenesis.
PMID- 10777212
TI - Bcl-xS and Bax induce different apoptotic pathways in PC12 cells.
AB - Apoptosis is regulated by the action of the Bcl-2 family of proteins, which
includes anti- and pro-apoptotic members such as Bcl-xS and Bax. These proteins
may differ from each other in structure, mechanism of action and interactions
with anti-apoptotic signaling. The mechanism whereby Bax induces cell death has
been studied in some cellular systems, but the mechanism of Bcl-xS-induced
apoptosis is largely unknown. In this study we investigated and compared the
apoptotic effects of Bcl-xS and Bax in the pheochromocytoma cell line, PC12 (a
useful model system for studying neuronal apoptosis), and the extent to which
they are protected by the survival factor, nerve growth factor (NGF). PC12 cells
express endogenous Bcl-xS, Bax and Bcl-xL proteins. Subcellular fractionation
revealed that Bax is presented mainly in the cytosolic and the heavy membrane
fractions, Bcl-xS is present only in the cytosol, and the anti-apoptotic protein
Bcl-xL is located mainly in the heavy membrane fraction. In contrast to the
cytosolic localization of endogenous Bcl-xS, the exogenously overexpressed Bcl-xS
is localized to the mitochondria. Overexpression of Bcl-xS or Bax induces cell
death in the transfected cells. The cell death induced by overexpression of Bcl
xS was inhibited by coexpression of Bcl-xS with Bcl-2 or Bcl-xL, or by treatment
with the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoro
methylketone (Z-VAD-FMK) or with NGF. The Bcl-2 mutants deltaC22, which lacks the
transmembrane domain, and G145A (mI-3) were able to inhibit the death-inducing
effect of Bcl-xS. These results therefore suggest that the apoptotic pathway
induced by overexpression of Bcl-xS in PC12 cells can be controlled by Bcl-2 and
Bcl-xL, is mediated by caspases, and can be inhibited by the NGF signaling
pathway. The Bax-induced cell death was inhibited by co-expression of Bax with
Bcl-2 or Bcl-xL, but was not inhibited by Z-VAD-FMK, NGF, or the Bcl-2 ml-3 or
deltaC22 mutants. These results therefore suggest that Bax induces a caspase
independent cell death pathway which is blocked by Bcl-2 but not by the NGF
signaling pathway. They further suggest that Bcl-xS and Bax induce different cell
death pathways in PC12 cells.
PMID- 10777213
TI - Fas-dependent tissue turnover is implicated in tumor cell clearance.
AB - The apoptosis-inducing Fas receptor has been shown to be down-regulated in
various types of tumors, while its ligand (FasL) appears to be frequently up
regulated. Here we provide evidence that there is a strong selective pressure in
vivo against Fas-expressing, tumorigenic NIH3T3 cells, favoring survival,
proliferation and eventually tumor formation by Fas-negative cells. Importantly,
re-expression of Fas in these cells results in either the complete abolishment of
tumor development, or in a significant extenuation of the latency period of tumor
outgrowth. In addition, we found that environmental conditions which prevail
during tumorigenesis, such as limiting amounts of survival factors and the lack
of cell adhesion, are markedly sensitizing tumor cells to Fas-mediated suicide.
Our data suggest that in addition to T cell-mediated immune responses, mechanisms
of Fas-dependent tissue turnover are also centrally implicated in tumor cell
clearance.
PMID- 10777214
TI - Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein
associated with Hepatitis B virus X antigen.
AB - EBNA-3 (also called EBNA-3A) is one of the EBV encoded nuclear antigens that are
necessary for B-cell transformation. EBNA-3 is known to target RBPs, nuclear
proteins that also interacts with EBNA-2, EBNA-4 and EBNA-6. In order to identify
additional EBNA-3 targets, an EBV-transformed human lymphocyte cDNA library was
screened in the yeast two-hybrid system with N-terminus truncated EBNA-3 that
cannot interact with RBP-Jkappa. A clone, encoding Xap-2 protein, a cellular
partner of Hepatitis B virus X-antigen was isolated. This protein is also known
as the p38 subunit of the aryl hydrocarbon receptor complex (ARA9). The specific
binding to EBNA-3 was confirmed by showing that the GST-Xap-2 precipitated EBNA-3
from CV1 cells that were infected with recombinant vaccinia virus expressing EBNA
3. Deletion of the C-terminus of Xap-2 eliminated the binding. Fusion with green
fluorescent protein showed that Xap-2 is preferentially cytoplasmic but
translocates to the nucleus upon expression of EBNA-3.
PMID- 10777215
TI - A murine ATFa-associated factor with transcriptional repressing activity.
AB - The ATFa proteins, which are members of the CREB/ATF family of transcription
factors, have previously been shown to interact with the adenovirus E1a
oncoprotein and to mediate its transcriptional activity; they heterodimerize with
Jun, Fos or related transcription factors, possibly altering their DNA-binding
specificity; they also stably bind JNK2, a stress-induced protein kinase. Here we
report the identification and characterization of a novel protein isolated in a
yeast two-hybrid screen using the N-terminal half of ATFa as a bait. This 1306
residue protein (mAM, for mouse ATFa-associated Modulator) is rather acidic (pHi
4.5) and contains high proportions of Ser/Thr (21%) and Pro (11%) residues. It
colocalizes and interacts with ATFa in mammalian cells, contains a bipartite
nuclear localization signal and possesses an ATPase activity. Transfection
experiments show that mAM is able to downregulate transcriptional activity, in an
ATPase-independent manner. Our results indicate that mAM interacts with several
components of the basal transcription machinery (TFIIE and TFIIH), including
RNAPII itself. Together, these findings suggest that mAM may be involved in the
fine-tuning of ATFa-regulated gene expression, by interfering with the assembly
or stability of specific preinitiation transcription complexes.
PMID- 10777216
TI - Ectopic expression of cyclin E allows non-endomitotic megakaryoblastic K562 cells
to establish re-replication cycles.
AB - Megakaryocytes become polyploid by entering a truncated cell cycle, consisting of
alternate S phases and abortive mitoses. We have investigated the regulation of
the G1/S transition by comparing two megakaryoblastic cell lines, HEL and K562,
which respectively do or do not become polyploid in response to phorbol esters. A
pronounced downregulation of cyclin A, and to a lesser extent of cyclin E,
occurred in K562 cells during the first 24 h after TPA treatment, in contrast
with re-replicating HEL cells, in which both cyclins were present in individual
G2/M cells. Transactivation experiments suggested that the absence of cyclin A in
differentiated K562 cells could be due to a TPA-mediated inhibition of its
transcription. To investigate the potential role of cyclin E in the establishment
of re-replication cycles, we isolated K562 clones constitutively expressing
cyclin E. The resulting clones, and also K562 cells transiently expressing cyclin
E, entered re-replication cycles when treated with TPA. The transcriptional
activity of the cyclin A promoter was not inhibited after TPA treatment, and
although the levels of cyclin A fluctuated during further re-replication cycles,
they never decreased below S phase levels. We conclude that the presence of
cyclin E in megakaryoblastic G2/M cells determines cyclin A expression and allows
the entrance into an extra S phase.
PMID- 10777217
TI - Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically
resemble the deletion of the proline-rich domain.
AB - The p53 tumor suppressor protein induces apoptosis through a mechanism that may
involve the transcriptional activation of cellular genes, including the PIG3
gene. A p53 protein lacking the proline-rich region (p53delta62-91) induces many
p53-responsive genes but not PIG3. In parallel, this mutant induces growth arrest
but not apoptosis. We show here that the replacement of the N-terminal (amino
acids 1-80) or C-terminal (amino acids 344-393) domains of p53 with heterologous
domains does not interfere with transcription from the PIG3 promoter, but these
chimeras still require the proline-rich region for PIG3 activation. The p53
homolog p73beta also activated the PIG3 promoter, but in contrast to p53, the
proline-rich domain of p73beta (residues 81-113) was dispensable to induce the
PIG3 promoter. Some tumor-derived p53-mutants, especially M246I, retained the
ability to activate transcription of mdm2 but specifically failed to induce the
PIG3 promoter, thus resembling p53delta62-91. Further, p53delta62-91 and p53M246I
were defective for induction of apoptosis. Finally, p53delta62-91 and p53M246I
both showed reduced binding to the DNA of the PIG3 promoter and also to the DNA
of the mdm2 and p21 promoters in vitro. Correspondingly, at low expression
levels, p53delta62-91 and p53M246I poorly activated the mdm2 promoter when
compared to wild type p53. Our results suggest that the proline-rich domain of
p53 affects the ability of the central domain to bind DNA. Moreover, some tumor
derived mutations within the central DNA binding domain of p53 mimic the loss of
the proline-rich domain.
PMID- 10777218
TI - Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53.
AB - Dickkopf-1 (Dkk-1), a secreted glycoprotein, has been found to be necessary and
sufficient for inducing amphibian head formation. Interestingly, the mechanism by
which Dkk-1 does this is the ability of Dkk-1 to antagonize the Wnt signaling
pathway. Wnt, itself a proto-oncoprotein, can promote cell proliferation and
transformation when mutated or overexpressed, leading to tumor formation. p53 is
a tumor suppressor and loss of p53 function accelerates mammary tumorigenesis by
Wnt. In this study, we found that Dkk-1 is induced by wild-type p53 but not
mutant p53(R249S). In addition, DNA damage upregulates Dkk-1 in cell lines that
harbor an endogenous wild-type p53 gene but not in cell lines that are p53-null
or harbor an endogenous mutant p53 gene. We also found a potential p53 responsive
element located approximately 2100 nucleotides upstream of the Dkk-1
transcription start site and we show that p53 binds specifically to this element
both in vitro and in vivo. Furthermore, we have established several cell lines
derived from H1299 lung carcinoma and U118 glioma cells that inducibly express
Dkk-1 under a tetracycline-regulated promoter. We found that Dkk-1 has no effect
on proliferation of cells that are not transformed by Wnt. Taken together, these
results suggest that Dkk-1 may mediate p53 tumor suppression by antagonizing the
Wnt signaling pathway.
PMID- 10777219
TI - Lack of germline CDK6 mutations in familial melanoma.
AB - Germline mutations in genes encoding several components of the retinoblastoma
pathway have been linked with inherited predisposition to melanoma. Most
commonly, such mutations involve CDKN2A, a cyclin-dependent kinase inhibitor of
two kinases, CDK4 and CDK6, which phosphorylate the retinoblastoma protein (pRB)
and thereby promote passage through the G1/S cell-cycle restriction point. Less
frequently, germline mutations in the CDK4 gene have also been linked with an
increased risk of melanoma. Despite the sequence and functional homology between
CDK4 and CDK6, the role of germline mutations in CDK6 in melanoma predisposition
is unknown. We detected no CDK6 mutations within the p16 (CDKN2A) binding domain
in index cases from 60 melanoma-prone kindreds that lacked germline mutations in
the coding regions of either CDKN2A or within the entire CDK4 coding region. We
conclude that germline mutations in CDK6 do not make a significant contribution
to melanoma predisposition.
PMID- 10777220
TI - Role of basal calcium in the EGF activation of MAP kinases.
AB - The role of intracellular Ca2+ pools in the regulation of growth factor signal
transduction pathways and mitogenesis is not well understood. We have examined
the roles of basal and transiently mobilized Ca2+ in the regulation of MAP
kinases by EGF. To assess the influence of Ca2+ transients we utilized Plcg1-/-
and Plcg1+/+ mouse embryonic fibroblasts, while BAPTA/AM was employed to chelate
total intracellular Ca2+ in the same cell lines. The MAP kinases erk-1, erk-2 and
erk-5 exhibited similar patterns of activation in wild-type and Plcg1-/- cells
treated with EGF. However, pretreatment with BAPTA/AM significantly increased and
prolonged erk-1 and erk-2 activation in both cell types. In contrast, BAPTA/AM
prevented the EGF activation of erk-5 in wild-type and Plcg1-/- cells. These data
indicate that basal Ca2+, but not growth factor provoked Ca2+ transients, has a
significant influence on the activation of these MAP kinases. AG1478, a specific
EGF receptor kinase inhibitor, abolished the prolonged erk-1 and erk-2 activation
produced by EGF in cells pretreated with BAPTA/AM. This indicates that the
prolonged activation of erk-1 and erk-2 produced in the presence of BAPTA/AM
requires continuous signaling from the EGF receptor kinase.
PMID- 10777221
TI - Another Y2K problem: New Zealand's ageing drivers.
PMID- 10777222
TI - Gallstone prevalence in Christchurch: risk factors and clinical significance.
AB - AIMS: To determine the frequency, risk factors and clinical significance of
gallstones in a New Zealand population. METHODS: One thousand names were randomly
selected from the Christchurch electoral rolls to recruit controls for a study on
the prevalence of gallstones in diabetics. Three hundred and eighteen subjects
(169 females, 149 males) were recruited and in this study we analyse this control
group for gallstone disease. All subjects completed a questionnaire, provided a
fasting blood sample and underwent an ultrasound examination of their gallbladder
unless they had previously undergone a cholecystectomy. RESULTS: Overall
gallstone disease, defined as previous cholecystectomy or a positive scan for
gallstones was seen in 20.75% of the 318 subjects recruited. Gallstone disease
was more frequent in females (23.1%) compared to males (18.1%) but this
difference was not statistically significant. For both genders there was a
significant increase in gallstones with age. On univariate analysis, risk factors
for gallstone disease included age, increased body mass index, family history of
gallstones and decreased alcohol intake in females. However, only age and family
history were significant on multiple logistic regression. There was no difference
in the frequency of dyspeptic symptoms or abdominal pain between those with or
without gallstones confirmed on scanning. The ratio of cholecystectomy to silent
gallstones was higher in females (46.2%) than in males (22.2%). CONCLUSION:
Gallstones are prevalent in the New Zealand Community (20.8% overall). Risk
factors are increasing age and family history. Gallstones detected on scanning
were not associated with an increased incidence of dyspeptic symptoms or
abdominal pain.
PMID- 10777223
TI - An evaluation of the National Cervical Screening Programme Otago site.
AB - AIM: To evaluate progress of the Otago Cervical Screening Programme towards
achieving its goal of reducing cervical cancer incidence and mortality using data
routinely collected by the National Cervical Screening Register (NCSR), and to
investigate whether all data required for this task are available from the NCSR.
METHOD: Non-identifying data for Otago women aged 20-69 years were obtained from
the New Zealand National Cervical Screening Register for the period 1 July 1993
to 30 June 1996. For each five-year age group, proportion screened in three
years, short interval re-screening estimates and age-specific reporting rates for
squamous atypia of uncertain significance (ASCUS), low-grade intraepithelial
lesions (LGIL) and high-grade intraepithelial lesions (HGIL) were calculated. Age
specific reporting rates were also calculated for 20-69 year-old New Zealand
women for the same period and compared to the Otago rates. RESULTS: The
proportion of eligible women screened was 82.5%, slightly less than the target
85%. Women aged 55 years or more were underscreened, short interval rescreening
was more common among younger women, age-specific reporting rates for ASCUS, LGIL
and HGIL had increased since 1991/92, and the rate of HGIL was higher than
expected in the 20-34 year age group. CONCLUSIONS: In order to maximise the
effectiveness and efficiency of the Otago Cervical Screening Programme, it is
recommended that participation amongst older women be increased and frequent
screening be reduced in the younger age groups. Unexpected elevated rates of HGIL
amongst 20-34 year-old women were not adequately explained and require further
investigation. Not all data required for an outcome evaluation were available
through the NCSR.
PMID- 10777225
TI - A series of outbreaks of food poisoning?
AB - A series of independently occurring episodes which were notified individually as
'food poisoning' were, after investigation, linked to a common source water
supply.
PMID- 10777224
TI - Are New Zealand schools smoke-free? Results from a national survey of primary and
intermediate school principals.
AB - AIMS: To document policies and practices developed by primary and intermediate
schools in response to the Smoke-free Environments Act 1990 and estimate levels
of staff support for legislation requiring totally smoke-free schools. METHODS:
Questionnaires were mailed to a random national sample of 10% of principals of
all primary and intermediate schools. RESULTS: There were 209 questionnaires
returned, a response rate of 87%. While 97% of principals reported that their
school had a written policy for smoking, only 58% provided a copy. Only 49% of
principals said that their school smoking policy was prominently displayed. Most
(82 %) claimed that school buildings were smoke-free, but only 44% said that this
applied to buildings and grounds. Overall, 62% considered that school staff would
support legislation that required schools to be totally smoke-free in buildings
and grounds. School policies ranged from total prohibition of smoking in school
buildings and grounds to the provision of designated smoking areas for staff.
CONCLUSIONS: Compliance with current smoke-free legislation appears to be
variable. Consistency in the meaning of smoke-free status in schools is lacking.
There appears to be good staff and parent support for making all schools totally
smoke-free. The best way to achieve universal, permanent and totally smoke-free
status for New Zealand schools would be to amend current legislation to include
specific requirements for all school premises.
PMID- 10777226
TI - The diagnostic significance of polyclonal lymphocytosis in pleural effusions.
AB - AIM: To evaluate the diagnostic contribution and clinical relevance of analysing
subpopulations of lymphocytes in pleural effusions. METHODS: Forty patients (age
>60 years) with newly diagnosed, polyclonal, lymphocyte-rich pleural effusions
were evaluated. The following data were collected: demographic characteristics,
associated diseases, fluid type, fluid white blood cells count, differential
morphology and immunephenotyping, and final diagnosis. RESULTS: Of the 33
patients for whom biochemical data were available, 18 had exudative effusion,
while 15 had transudate. Thirty-three fluids contained mostly T cells and only
one was B-cell rich. (The lymphocytes of five patients with malignant epithelial
cells in the effusion were not subtyped.) Thirty-two of the 33 T-cell rich fluids
contained mainly CD4+ lymphocytes. The most common causes of pleural effusion
were congestive heart failure (17 patients) and epithelial malignant diseases
(eight patients), while none of the patients had tuberculosis. Since most
effusions were CD4+ rich, no correlation could be detected between lymphocyte
subtyping and diagnosis or the biochemical type of the fluids. Congestive heart
failure was significantly associated with transudates, while malignant diseases
correlated with exudates. CONCLUSIONS: Most patients with pleural polyclonal
lymphocytosis, especially those with transudates, have congestive heart failure.
The presence of exudative, lymphocyte-rich effusion is an indication for further
evaluation, since it is most commonly associated with malignancy. The clinical
value of lymphocyte subtyping is low and this procedure should not be used
routinely.
PMID- 10777227
TI - Outpatient treatment of pneumonia.
AB - In children, pneumonia must be differentiated from bronchiolitis and asthma.
Pneumonia is the only one of these three conditions for which antibiotics are
indicated. Clinical signs are more useful than radiological or laboratory
investigations for differentiating pneumonia from bronchiolitis and asthma. A
child has pneumonia if s/he has tachypnoea or indrawing and is not wheezing. The
child's age and the severity of the illness episode predict the aetiology of the
pneumonia. The majority of children with community-acquired pneumonia can be
managed in primary care. The antibiotic of choice for children < or = 5 years of
age is oral amoxycillin and for older children and adolescents is oral
erythromycin. Antibiotics will not prevent pneumonia in a child with an upper
respiratory tract infection. Up to 80% of adults with pneumonia can be managed as
outpatients. Indicators of morbidity and mortality from pneumonia are well
described. Clinical features and radiology do not reliably predict the causative
agent in adults with pneumonia, thus initial treatment is empirical.
Streptococcus pneumoniae is the most common cause of pneumonia in all studies.
The initial antibiotic treatment should be active against this organism.
Penicillin oramoxycillin or erythromycin are all suitable. Erythromycin has the
advantage of being active against Mycoplasma pneumoniae and Legionella species.
Follow-up of patients is important to decide whether they are responding to the
empirical treatment.
PMID- 10777228
TI - The Accident Insurance Act--a desirable reform or market madness?
PMID- 10777229
TI - PHARMAC and good science?
PMID- 10777230
TI - PHARMAC at what cost?
PMID- 10777231
TI - Home visits and palliative care.
PMID- 10777233
TI - Gamma hydroxybutyric acid "fantasy"--drug of abuse.
PMID- 10777232
TI - "Elder abuse"--more common than reported.
PMID- 10777234
TI - Medical Council Ethical Guidelines for doctors' duties in an environment of
competition or resource limitation.
PMID- 10777235
TI - Peripheral arterial occlusive disease: clinical data for decision making.
Introduction.
PMID- 10777236
TI - Intermittent claudication: a condition with underrated risks.
AB - Intermittent claudication (IC) is a symptom of peripheral arterial occlusive
disease (PAOD); it is subjective and therefore difficult to measure reliably.
Both the WHO/Rose Questionnaire and the Edinburgh Questionnaire have been used
widely, but they have a low sensitivity and therefore underestimate the true
prevalence of IC. The addition of a clinical examination does not necessarily
eliminate errors found on questionnaires alone. The single most important part of
the physical examination to confirm a diagnosis of IC is the palpation of the
patient's peripheral pulses, which alone appears to be more sensitive, but less
specific, than the questionnaires. The most useful noninvasive test is the ankle
brachial pressure index (ABPI), and it has been suggested that a resting ABPI of
0.9 is up to 95% sensitive in detecting angiogram-positive disease, and almost
100% specific in identifying apparently healthy individuals. An ABPI of 0.9 or
less is believed to be associated with 50% or greater vessel stenosis. The
incidence of IC varies depending on the methodology used to define it, but there
is a general pattern of a gradual increase in incidence up to the age of at least
70 years. For a chronic disease, the prevalence is a more relevant indicator of
how common it is. The prevalence of IC is 3% to 6% in men aged 60 years and
increases with age. The prevalence of asymptomatic PAOD may be as high as 20% in
the adult population, using noninvasive testing. This is important because, as
will be seen in later articles, PAOD, whether symptomatic or asymptomatic, is a
serious risk factor for cardiovascular morbidity and mortality.
PMID- 10777237
TI - Predictors of early disease in the lower limbs.
AB - Increasing age and male gender are unavoidable risk factors for peripheral
arterial occlusive disease (PAOD). A number of studies have looked at classical
risk factors for atherosclerosis, such as diabetes, hypertension, lipid
abnormalities, and smoking, as well as some more recently identified
associations, such as plasma fibrinogen levels, impaired glucose tolerance, and
hyperhomocysteinemia. However, most "risk factors" are really associations. A
causal relationship may only reasonably be firmly established if a prospective
controlled study shows that removing the risk factor significantly alters the
course of the disease, as with smoking. Smoking is probably the strongest risk
factor for intermittent claudication (IC), but hyperhomocysteinemia also appears
to be strongly associated with the development of PAOD. Moderate alcohol intake
and regular physical exercise appear to have a protective effect. A genetic risk
factor is suggested but not as yet confirmed. The magnitude of the association
varies from odds ratios of 2 to 3 for smoking and diabetes. There is insufficient
evidence for hyperhomocysteinemia, but the effect may be even greater. The
association with hypertension and lipid abnormalities is surprisingly
inconclusive.
PMID- 10777238
TI - Lower-extremity arteriosclerosis as a reflection of a systemic process:
implications for concomitant coronary and carotid disease.
AB - Peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and
cerebrovascular disease (CVD) are all manifestations of atherosclerosis or
atherothrombosis, and therefore it is not surprising that the three conditions
commonly occur together. Knowledge of the magnitude of co-existing cardiovascular
disease and its prognosis is essential for the physician treating IC so that he
can treat the local disease in its systemic context. The prevalence of CAD in
patients with IC is 40% to 60%, although this may be asymptomatic and increases
with the severity of the PAOD. Not surprisingly, the converse is also true; among
individuals with CAD, the prevalence of PAOD is higher than in non-CAD
individuals. The link between PAOD and CVD seems to be weaker than that with CAD,
but again up to 60% of claudicants have some evidence of CVD. The prevalence of
patients with CVD increases as the ABPI decreases. The evidence available from
all of the relevant studies suggests that approximately 60% of patients with PAOD
will have significant disease in the cardiac or cerebral circulation, and
approximately 40% of patients with coronary disease or significant cerebral
circulatory disease also will have PAOD.
PMID- 10777239
TI - The natural history of claudication: risk to life and limb.
AB - Although a patient with intermittent claudication (IC) will fear progression to
severe disease and amputation, this is a relatively rare outcome of claudication,
with only 1% to 3% of claudicants ever requiring major amputation over a 5-year
period. Indeed, in one study, 50% of claudicants became symptom free during 5
years' follow-up. All the new evidence over the last 40 years has not altered the
impression that only about one fourth of patients with IC will ever significantly
deteriorate, and that deterioration is most frequent during the first year after
diagnosis (6 to 9%) compared with 2% to 3% per annum thereafter. Smoking is the
most important risk factor for the progression of local disease in the legs, with
an amputation rate 11 times greater in smokers than nonsmokers. Diabetes, male
gender, and hypertension are also important risk factors for progression. Because
cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral
arterial occlusive disease (PAOD) coexist, PAOD and IC should be regarded as a
marker for increased risk from fatal and nonfatal cardiovascular event, and 2% to
4% of claudicants have a nonfatal cardiovascular event every year. The risk is
higher in the first year after developing IC than in a long-standing stable
claudicant, and the average claudicant is more likely to have a nonfatal
myocardial infarction (MI) or stroke in the next year that of ever requiring a
major amputation for his leg ischemia. The mortality in claudicants is 30% at 5
years, 50% at 10 years, and 70% at 15 years, without any clear decrease in these
figures over the last 30 to 40 years. The mortality of claudicants is
approximately two and a half times that of an age-matched general population.
PMID- 10777240
TI - Predicting which patients will develop chronic critical leg ischemia.
AB - Although numerically far less than claudicants, patients with critical leg
ischemia (CLI) demand a disproportionately large commitment both in medical
effort and economically and represent the major workload for vascular surgical
units. The incidence and prevalence of CLI is approximately 500 to
1,000/million/year. The risk factors for the development of CLI are largely the
same as those for the progression of local disease in IC, the most important,
apart from age, being smoking and diabetes. Major amputation is more common
amongst claudicants who are heavy smokers and who continue to smoke, and although
stopping smoking slows down the vascular changes and reduces the likelihood of
symptomatic progression, it does not reduce the risk of major amputation over the
following 2 to 3 years. Diabetic PAOD patients are about 10 times more likely to
come to amputation than nondiabetic PAOD patients, and the prevalence of gangrene
is 20 to 30 times higher in individuals with diabetes and PAOD compared with
nondiabetics with PAOD. There is some evidence that most of these effects of risk
factors are additive.
PMID- 10777241
TI - The fate of patients with critical leg ischemia.
AB - In some highly specialized and aggressive units, 90% of patients with critical
leg ischemia (CLI) will undergo some form of surgical or endovascular procedure;
however, in most, the figure is nearer 50 to 60%. The primary amputation rate
varies from around 10% to 40%. The mortality rate in these patients with standard
therapy is around 20% at 1 year and between 40% and 70% at 5 years. Virtually all
(95%) patients who present with ischemic gangrene, and 80% of those presenting
with rest pain, are dead within 10 years. There appears to be a decline in
overall major amputation rates associated with a corresponding increase in
revascularizations. However, although technical advances may have resulted in a
steadying or even decrease in amputations, comparisons of total amputations over
a longer period suggest an increase, presumably attributable to an aging
population. Some forward projections predict that major amputations will be
doubled in the next 30 years.
PMID- 10777242
TI - Acute limb ischemia.
AB - Although there is little information on the incidence of acute limb ischemia
(ALI) in the general population, it is estimated to be 14 per 100,000 and to
compose 10% to 16% of the vascular workload. Also, as surgical intervention has
become an option for ALI, the numbers actually referred appear to be increasing.
The two main causes of ALI are either an embolism or a thrombosis, and
differentiation based on history and clinical examination alone may be clinically
impossible in 10% to 15% of cases. However, with the advent of thrombolysis, the
distinction between emboli and thrombotic occlusions has become less important
from the point of view of management. The natural history of ALI has remained
largely unchanged despite the advent of the Fogarty catheter and thrombolysis.
Patients presenting with ALI continue to have a particularly severe short-term
outlook both in terms of loss of the leg and mortality, with 30-day amputation
rates of between 10% and 30% and a mortality rate of around 15%. A patient with
an embolic cause for an ischemic leg is at a higher risk of death because of the
associated underlying cardiac disease, whereas patients with a thrombotic cause
are more likely to lose a limb. The fact that overall mortality rates after
intervention for acute ischemia have not improved dramatically over the past 20
years no doubt reflects the severity of the underlying diseases in these high
risk patients.
PMID- 10777243
TI - Major amputations: clinical patterns and predictors.
AB - The major amputation rate is approximately 200 to 500/million/yr and occurs in
patients presenting with an acute onset of critical leg ischemia (CLI) rather
than in patients who steadily progress through increasingly severe claudication
to rest pain and ulcers. Diabetics, who form only 2% to 5% of the population,
form 40% to 45% of all amputees. Although it is widely believed that a below-knee
(BK) to above-knee (AK) amputation ratio of 2.5 is the minimum acceptable for
units providing a lower limb amputation service, the ratio is in fact usually
very much below the recommended figure. The data suggest that primary healing of
BK amputations ranges from 30% to 92% and the reamputation rate from 4% to 30%.
If a popliteal pulse is palpable, then there is only a 10% failure rate, and
bleeding during the operation does not seem to predict healing. Of the 30% of BK
amputees whose wounds do not heal primarily, about half will need a higher major
amputation, but once a BK major amputation has healed, only 4% of such patients
ever need a higher amputation. A total of 90% of AK major amputations heal, 70%
primarily. Two to three times as many BK amputees achieve full mobility than AK
amputees, and there has not been any dramatic change in 20 years. The fate of the
amputee 2 years after a successful BK amputation will be that 15% will have been
converted to an AK amputation, another 15% will have had a contralateral major
amputation, and 30% will be dead.
PMID- 10777244
TI - Canadian Network of Toxicology Centres (CNTC) executive summary--annual research
symposium, 29-30 March 1999.
PMID- 10777245
TI - In vitro cleavage by asbestos fibers of the fifth component of human complement
through free-radical generation and kallikrein activation.
AB - Chrysotile and crocidolite fibers incubated in normal human plasma (NHP)
generated from the C5 component of complement C5a-type fragments that stimulated
polymorphonuclear leukocyte (PMN) chemotaxis. Absorption of NHP with antiserum
against C5a totally abolished neutrophil chemotactic activity. Asbestos fibers
also produced C5a small peptides in the presence of ethylene glycol bis(beta
aminoethyl ether) N,N,N'N'-tetraacetic acid (EGTA) but not ethylene diamine
tetraacetic acid (EDTA). Activation of C5 was significantly inhibited when
asbestos fibers were pretreated with iron chelators such as sodium dithionite
(DTN), deferoxamine (DFX), or ascorbate (AA). Concentration-related inhibition of
C5 activation was also observed when asbestos fibers were added concurrently to
plasma in the presence of DFX, 1,3-dimethyl-2-thiourea (DMTU), a strong hydroxyl
scavenger, or aprotinin (APR), a specific protease inhibitor. Further, chrysotile
and crocidolite significantly increased plasma kallikrein activity. Data
demonstrate that asbestos-induced C5 activation plays a role in inflammatory
reactions characteristic of asbestosis through mechanisms involving iron ions,
hydroxyl radicals, and oxidized C5-ike fragments. The ferrous ions present at the
asbestos fiber surface trigger this activation and catalyze, via Fenton reaction,
the production of hydroxyl radicals, which in turn convert native C5 to an
oxidized C5-like form. This product is then cleaved by kallikrein, activated by
the same asbestos fibers, yielding an oxidized C5a with the same functional
properties as C5a.
PMID- 10777246
TI - Effects of selenium dioxide on blood and femoral bone marrow of rats.
AB - This study was undertaken to investigate the effects of selenium dioxide (SeO2)
on rat blood and femoral bone-marrow oxidant mechanisms. Treatment with SeO2, 67
microg Se/kg i.p. daily for 14 d, significantly decreased lipid peroxidation and
the concentrations of Fe in serum and bone marrow. The concentrations of Se in
serum and bone-marrow cells were significantly increased after SeO2 treatment.
The activities of glutathione peroxidase (GPx) in blood and bone-marrow cells
were markedly increased. The levels of oxyhemoglobin in blood were significantly
increased, while the concentrations of methemoglobin were decreased after SeO2
administration. The fragility of erythrocytes membranes was significantly
decreased in SeO2-treated rats compared to controls. Data suggest that treatment
with a low dose of SeO2 may provide antioxidant nutrients to blood and bone
marrow.
PMID- 10777247
TI - Possible immunotoxic effects of organochlorines in polar bears (Ursus maritimus)
at Svalbard.
AB - Associations between immunoglobulin G (IgG) levels and the organochlorine
contaminants (OCs) polychlorinated biphenyls (PCBs), chlordanes, 1,1-dichloro-2,2
bis(4-chlorophenyl) ethylene (DDE), hexachlorobenzene (HCB), and
hexachlorocyclohexanes (HCHs) in blood plasma from polar bears caught at Svalbard
were determined. The blood samples were collected from free-living polar bears of
different age and sex between 1991 and 1994. The IgC concentration increased with
age and was significantly higher in males than in females. IgG was negatively
correlated with sigmaPCB level and with three individual PCB congeners, IUPAC
numbers 99, 194, and 206. HCB was also negatively correlated with IgG. The
significant negative OC correlation with IgG levels may indicate an immunotoxic
effect.
PMID- 10777248
TI - Toxic effects of zinc from trout farm sediments on ATP, protein, and hemoglobin
concentrations of Limnodrilus hoffmeisteri.
AB - Zinc (Zn) is a nutritionally essential metal, and deficiency results in severe
health consequences to aquatic organisms. In this study toxicity data for
Limnodrilus hoffmeisteri produced by Zn in systems using three natural sediments
(trout farms: El Oyamel, El Truchon, and El Potrero) are presented. Hemoglobin,
adenosine triphosphate (ATP), and protein concentrations were measured in L.
hoffmeisteri exposed to spiked sediments, as indicators of exposure.
Physicochemical characteristics of water and sediments were also considered. Zn
concentrations were measured in water and sediment. El Oyamel, El Truchon, and El
Potrero pond sediments did not have similar physicochemical characteristics. Zn
concentrations of water obtained from the rustic ponds were near 0.4575 mg/L;
however, this metal was always found to be higher in the sediments (0.0271-0.9754
mg/kg). The bioassay with worms demonstrated that pond sediments from El Oyamel,
El Potrero, and El Truchon produced toxicity since ATP and protein concentrations
were low compared to controls (organisms without metal). All spiked sediments had
a significant reduction effect on ATP, protein, and hemoglobin concentrations.
This investigation clearly shows that sediments of El Truchon, El Oyamel, and El
Potrero possess toxicity potential. These results suggest the usefulness of these
bioassays to evaluate the toxicity of sediments polluted with heavy metals.
PMID- 10777249
TI - Reduced antioxidant defense capacity in myocardial tissue from guinea pigs
treated with 5-fluorouracil.
AB - Antioxidant defense capacity was investigated in myocardial tissue from guinea
pigs treated with 5-fluorouracil (5-FU) at a dose of 400 mg/kg/d daily for 5 d
administered intraperitonally. Treatment with 5-FU lowered the activities of
cardiac superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)
accompanied by higher catalase (CAT) activity. Further, antioxidant potential
(AOP) values were lower but oxidation resistance (OR) and malondialdehyde (MDA)
levels were higher in the 5-FU-treated tissue. With regard to myocardial iron
(Fe) and copper (Cu) levels, no significant differences were found between the
groups. Results suggest that 5-FU treatment causes impairment in the myocardial
antioxidant defense system and leads to cardiac peroxidation. It has been
postulated that these changes might be responsible for the 5-FU cardiotoxicity
seen in some patients, and antioxidant therapy might provide a therapeutic
advantage.
PMID- 10777250
TI - Do common childhood infections 'teach' the immune system not to be allergic?
PMID- 10777251
TI - T cells at the turn of the twenty-first century.
PMID- 10777252
TI - Feasibility study: transesophageal echocardiography with a 10F (3.2-mm)
multifrequency (5.5- to 10-MHZ) ultrasound catheter in a small rabbit model.
PMID- 10777253
TI - The field of nuclear cardiology.
PMID- 10777254
TI - Interference of rheumatoid factor activity by aspartame, a dipeptide methyl
ester.
AB - Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc
portions of normal, polyclonal IgG antibodies are frequently present in humans
with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe
(aspartame or APM) was found to relieve pain and improve joint mobility in
subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and
Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical
observations prompted the testing of the inhibition by APM of the binding
interactions of human IgM RFs with IgG Fc regions. The propensity of APM to
inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid
phase human IgG. Ten RA serum samples and three purified monoclonal
cryoglobulins, all of which had RF activity, were tested in this system. We found
that the presence of APM significantly reduced the binding of IgM RFs. The
inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by
the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding
of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative,
indicating that the methyl ester is not required for APM's interaction with IgM
antibodies. A human (Mez) IgM known to bind octameric peptides derived from the
Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the
Pepscan method of combinatorial chemistry. The relative binding constants of Asp
Phe and Phe-Asp were ranked among the highest values for 400 possible
combinations of the 20 most common amino acids. Possible blocking interactions of
APM were explored by computer-assisted docking studies with the model of a
complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary
immune complexes revealed a few key residues, which could act as molecular
recognition sites for APM. A structural hypothesis is presented to explain the
observed interference with RF reactivity by APM. Extrapolations of the current
results suggest that APM may inhibit the binding of IgG in a substantial
proportion of IgM RFs. Interference of RF reactivity, especially in RA patients,
may alleviate the pain and immobility resulting from chronic inflammation of the
joints.
PMID- 10777256
TI - The 1st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer
Therapeutics. Washington DC, USA. 16-19 November 1999. American Association for
Cancer Research. European Organisation for Research and Treatment of Cancer.
PMID- 10777255
TI - US advocacy group moves into Europe.
PMID- 10777257
TI - Link between HPV and invasive cervical cancer strengthened.
PMID- 10777258
TI - [Care of a patient with anorexia nervosa--from the viewpoint of the pediatric
nurse].
PMID- 10777259
TI - Pencillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson's
disease.
PMID- 10777260
TI - A case of cutaneous polyarteritis nodosa associated with ulcerative colitis.
PMID- 10777261
TI - Hypertrophic osteoarthropathy associated with pyoderma gangrenosum.
PMID- 10777262
TI - CD8-positive mycosis fungoides presenting as capillaritis.
PMID- 10777263
TI - Intraoperative detection of 5-aminolaevulinic acid-induced protoporphyrin
fluorescence in lymph node metastases after oral administration.
PMID- 10777264
TI - Low specificity of cytokeratin 20 in the diagnosis of extramammary Paget's
disease.
PMID- 10777266
TI - Normolipaemic xanthomas in association with human immunodeficiency virus
infection.
PMID- 10777265
TI - Congenital papular xanthoma.
PMID- 10777267
TI - Cutaneous squamous cell carcinoma with zosteriform metastases in a human
immunodeficiency virus-infected patient.
PMID- 10777268
TI - Combined ultraviolet A1 radiation and acitretin therapy as a treatment option for
pityriasis rubra pilaris.
PMID- 10777269
TI - Pemphigoid nodularis associated with nifedipine.
PMID- 10777270
TI - Acute generalized exanthematous pustulosis following use of ticlopidine.
PMID- 10777271
TI - Is systemic autoimmune disease a risk factor for terbinafine-induced erythema
multiforme?
PMID- 10777272
TI - Intranasal betamethasone induced acne and adrenal suppression.
PMID- 10777273
TI - Treatment of haemodialysis-associated pseudoporphyria with N-acetylcysteine:
report of two cases.
PMID- 10777274
TI - Severe course of chronic urticaria, arthralgia, fever and elevation of
erythrocyte sedimentation rate: Schnitzler's syndrome without monoclonal
gammopathy?
PMID- 10777276
TI - Pustular psoriasis exacerbated by pregnancy and controlled by cyclosporin A.
PMID- 10777275
TI - High-dose intravenous immune globulin is also effective in linear IgA disease.
PMID- 10777278
TI - Melanoma follow-up: protocols and practice.
PMID- 10777277
TI - Photodistributed chickenpox mimicking polymorphic light eruption.
PMID- 10777280
TI - Seasonal variation in herpes zoster infection.
PMID- 10777279
TI - Elastotic change in the subpapillary and mid-dermal layers in pseudoxanthoma
elasticum-like papillary dermal elastolysis.
PMID- 10777281
TI - Photopatch testing in photosensitive patients.
PMID- 10777282
TI - Thyroid eye disease associated with athyria.
PMID- 10777283
TI - Leber's hereditary optic neuropathy and maturity onset diabetes mellitus: is
there a metabolic association.
PMID- 10777284
TI - Free conjunctival autograft harvested from the fornix for repair of leaking
blebs.
PMID- 10777285
TI - Five cases of thelaziasis.
PMID- 10777286
TI - Fish hook injury of the eyelid: an unusual case.
PMID- 10777287
TI - Methaemoglobinaemia after peribulbar blockade: an unusual complication in
opthalmic surgery.
PMID- 10777288
TI - Women's health. Summary remarks.
PMID- 10777289
TI - Women's health. Keynote address.
PMID- 10777290
TI - Heart disease framework aims to cut deaths in England.
PMID- 10777291
TI - Managing self poisoning. Common sense makes no sense.
PMID- 10777292
TI - Managing self poisoning. Guidelines for accident and emergency departments are
needed.
PMID- 10777293
TI - Managing self poisoning. Body packers need careful treatment.
PMID- 10777294
TI - Managing self poisoning. Indications for the use of whole bowel irrigation are
weak.
PMID- 10777295
TI - Managing self poisoning. Poisons database is still not on the NHS net.
PMID- 10777296
TI - Differentiating between audit and research. Clinical audit is research.
PMID- 10777297
TI - Hospital of the future. Maybe hospitals are not needed at all.
PMID- 10777298
TI - Seasonality of birth in children with diabetes. Maternally transmitted infection
might increase risk of diabetes.
PMID- 10777299
TI - PFI rides again. Scheme was the lesser of two evils.
PMID- 10777300
TI - PFI rides again. The future does not bode well.
PMID- 10777301
TI - PFI rides again. Whatever happened to the NHS's response to the BMJ's articles.
PMID- 10777302
TI - PFI rides again. We're still waiting.
PMID- 10777303
TI - Choosing between home and hospital delivery. There is no evidence that hospital
is the safest place to give birth.
PMID- 10777304
TI - Choosing between home and hospital delivery. Risk of home birth in Britian cannot
be compared with data from other countries.
PMID- 10777305
TI - Helicobacter pylori and myocardial infection. Exclusion criteria were
inappropriate.
PMID- 10777306
TI - Treatment of schizophrenia. What in fact is schizophrenia?
PMID- 10777307
TI - Treatment of schizophrenia. Review should have paid more attention to
psychosocial interventions.
PMID- 10777308
TI - Treatment of schizophrenia. Review was based on fashion, not evidence.
PMID- 10777309
TI - More research is needed into the origins of pressure sores.
PMID- 10777310
TI - Carbon monoxide poisoning. Doctors should inform employment Medical Advisory
Service.
PMID- 10777311
TI - Student publications. Students should seek to publish not just in medical
journals.
PMID- 10777312
TI - Student publications. Students' letters in all journals need to be included.
PMID- 10777313
TI - Xenotransplantation. Public health risk must not be dismissed.
PMID- 10777314
TI - Xenotransplantation. Research in xenotransplantation will line drug industry's
pockets.
PMID- 10777315
TI - Antibiotic prophylaxis after percutaneous endoscopic gastrotomy insertion. All
encompassing study is needed.
PMID- 10777316
TI - Antibiotic prophylaxis after percutaneous endoscopic gastrotomy insertion.
Widespread routine use of prophylactic antibiotics might predispose to increased
risk of resistant organisms.
PMID- 10777317
TI - Antibiotic prophylaxis after percutaneous endoscopic gastrotomy insertion. Long
acting antibiotic is superior in reducing systemic complication.
PMID- 10777318
TI - Eugenics debate. Other slippery slopes become apparent.
PMID- 10777319
TI - Eugenics debate. What is immoral about the eugenics article?
PMID- 10777320
TI - Training for NHS Direct staff needs funding.
PMID- 10777321
TI - ICAP agenda of concern to developing countries.
PMID- 10777322
TI - Start of the new year.
PMID- 10777323
TI - CQ sources/bibliography.
PMID- 10777324
TI - Reply to Burdick: constraining physician discretion.
PMID- 10777325
TI - Diuretic use and abuse in systolic cardiac failure: a recipe for renal
impairment?
PMID- 10777326
TI - HIV/AIDS infection.
PMID- 10777327
TI - [New dimension in the care of type 2 diabetes].
PMID- 10777328
TI - Gene therapy: a rocky start to the new millennium.
PMID- 10777329
TI - A homegrown solution, via Ireland?
PMID- 10777330
TI - Bench research versus clinical trials: where should Canadian grant dollars go?
PMID- 10777331
TI - Ones that got away.
PMID- 10777332
TI - Ones that got away.
PMID- 10777333
TI - Air sampling--why, where, and how to do it!
PMID- 10777334
TI - Paper alert. Microbiology.
PMID- 10777335
TI - Web alert. Host-microbe interactions: bacteria.
PMID- 10777336
TI - Successful protection of humans exposed to rabies infection. Postexposure
treatment with the new human diploid cell rabies vaccine and antirabies serum.
1976.
PMID- 10777337
TI - Supplementation of vitamin D plus calcium is effective in corticosteroid-induced
osteoporosis management.
PMID- 10777338
TI - Commentary on letter titled: 'pain memory'.
PMID- 10777339
TI - PEDro.
PMID- 10777340
TI - Manual therapists-quo vadis?
PMID- 10777341
TI - The future and lung cancer: room for optimism?
PMID- 10777342
TI - The National Library of Medicine.
PMID- 10777343
TI - [HIV therapy: toxic liver injuries caused by protease inhibitors?].
PMID- 10777344
TI - [Paternalism, dominant knowledge, teamwork--changes in hospital and clinical
structure since 1900].
PMID- 10777345
TI - Imaging of head and neck tumors.
PMID- 10777346
TI - In memoriam Robert Huebner.
PMID- 10777347
TI - Gene therapy: back to the drawing board?
PMID- 10777348
TI - Increased funding doesn't add up to more GI grants in 2000.
PMID- 10777349
TI - Image of the Month. Pyoderma gangrenosum caused by ulcerative colitis.
PMID- 10777350
TI - Which is the hen and which is the egg?
PMID- 10777351
TI - Brain-gut interactions in ulcerative colitis.
PMID- 10777352
TI - When should endoscopic screening in familial adenomatous polyposis be started?
PMID- 10777353
TI - Consequences of the sex difference in rates of fetal growth.
PMID- 10777354
TI - The impact of diagnosis of hepatitis C virus on quality of life.
PMID- 10777355
TI - Serum alanine transaminase level is a good predictor of response to interferon
alfa therapy for chronic hepatitis B in human immunodeficiency virus-infected
patients.
PMID- 10777356
TI - Lack of membrane expression of interleukin-2 receptor alpha chain (CD25) in
mycosis fungoides: application of laser scanning cytometry for phenotyping of
skin infiltrating lymphocytes.
PMID- 10777357
TI - Marie Unna hereditary hypotrichosis gene maps to human chromosome 8p21 near
hairless.
PMID- 10777358
TI - A novel 5' (4041insA) mutation in a patient with numerous manifestations of
Cowden disease.
PMID- 10777359
TI - Expression of IL-18 in human keratinocytes.
PMID- 10777361
TI - The heritability of high myopia: a reanalysis of Goldschmidt's data.
PMID- 10777360
TI - Further characterization of the Sho-saio-to-mediated anti-tumor effect on
melanoma developed in RET-transgenic mice.
PMID- 10777362
TI - No evidence of germline PTEN mutations in familial prostate cancer.
PMID- 10777363
TI - Mutation analysis of H19 and NAP1L4 (hNAP2) candidate genes and IGF2 DMR2 in
Beckwith-Wiedemann syndrome.
PMID- 10777364
TI - A novel mutation in the CFTR gene correlates with severe clinical phenotype in
seven Hispanic patients.
PMID- 10777365
TI - The continuing failure to recognise Alstrom syndrome and further evidence of
genetic homogeneity.
PMID- 10777366
TI - Clinical and radiographic features of a family with hypochondroplasia owing to a
novel Asn540Ser mutation in the fibroblast growth factor receptor 3 gene.
PMID- 10777367
TI - Screening British CADASIL families for mutations in the NOTCH3 gene.
PMID- 10777368
TI - Correlation between mutations and age in cystic fibrosis in a French Canadian
population.
PMID- 10777369
TI - Progressive neurological deterioration in a child with distal arthrogryposis and
whistling face.
PMID- 10777370
TI - Chromosomal duplication of band 10p14 segregating through four generations.
PMID- 10777371
TI - Somatic mosaicism associated with a mild Alport syndrome phenotype.
PMID- 10777372
TI - Existing and emerging mechanisms for transport of iron and manganese to the
brain.
AB - The metals iron (Fe) and manganese (Mn) are essential for normal functioning of
the brain. This review focuses on recent developments in the literature
pertaining to Fe and Mn transport. These metals are treated together because they
appear to share several transport mechanisms. In addition, several neurological
diseases such as Alzheimer's Disease, Parkinson's Disease, and Huntington's
Disease are all associated with Fe mismanagement in the brain, particularly in
the striatum and basal ganglia. Similarly, Mn accumulation in brain also appears
to target the same brain regions. Therefore, stringent regulation of the
concentration of these metals in the brain is essential. The homeostatic
mechanisms for these metals must be understood in order to design neurotoxicity
prevention strategies.
PMID- 10777373
TI - Discordant results indicating monosomy 8 from FISH and trisomy 8 from chromosome
analysis in a patient with chronic lymphocytic leukemia.
PMID- 10777374
TI - Proceedings of the 9th International Congress on Renal Nutrition and Metabolism.
Vienna, Austria. August 29-September 1, 1998.
PMID- 10777375
TI - Early hormonal therapy in prostate cancer.
PMID- 10777376
TI - Secretin treatment for autism.
PMID- 10777377
TI - Secretin treatment for autism.
PMID- 10777378
TI - Secretin treatment for autism.
PMID- 10777379
TI - Secretin treatment for autism.
PMID- 10777380
TI - Unilateral renal agenesis in a family with medullary thyroid carcinoma.
PMID- 10777381
TI - Endoscopy.
PMID- 10777382
TI - Endoscopy.
PMID- 10777383
TI - Endoscopy.
PMID- 10777384
TI - Prolonged asymptomatic HIV-1 infection.
PMID- 10777385
TI - Death of a president.
PMID- 10777386
TI - TR3 death receptor expression in the normal and ischaemic brain.
AB - Members of the death receptor family may play a prominent role in developmental
and pathological neuronal cell death. We report the expression of the TR3 and TR7
death receptors in the adult human and rat central nervous system. Whereas
expression of TR3 appears to be high in the human cerebellum, with lower levels
in other brain regions, robust expression is observed in many regions of the rat
brain. We also analyzed modulation of death receptor expression in an in vivo rat
model of acute stroke. In contrast to tumor necrosis factor receptor 1, Fas and
p75(NGFR), which all show up-regulation specifically in lesioned cortex of the
permanent middle cerebral artery occlusion model of stroke. TR3 shows a rapid
global increase in both lesioned and unlesioned brain. In comparison, the
recently described death receptor TR7 shows no change in this model. These data
indicate that the death receptors show clear differences in patterns of
expression in response to ischemic injury. ? 2000 IBRO. Published by Elsevier
Science Ltd.
PMID- 10777388
TI - Dental Society of the State of New York. New members.
PMID- 10777387
TI - Off the mark.
PMID- 10777389
TI - Bertran S. Bildner: a new leader in a new century.
PMID- 10777390
TI - A resolution for the new millennium.
PMID- 10777391
TI - Bodes well for the future.
PMID- 10777392
TI - The resuscitation greats. Claude Beck and ventricular defibrillation.
PMID- 10777393
TI - Intra-aortic administration of epinephrine above aortic occlusion does not alter
outcome of experimental cardiopulmonary resuscitation.
PMID- 10777394
TI - Paleontology. Florida meeting shows perils, promise of dealing for dinos.
PMID- 10777395
TI - Stealth genome rocks rice researchers.
PMID- 10777396
TI - Hot pepper receptor could help manage pain.
PMID- 10777397
TI - Genome sequencing. Claim and counterclaim on the human genome.
PMID- 10777398
TI - Public health. A mold's toxic legacy revisited.
PMID- 10777399
TI - Angiogenesis research. Cancer drugs found to work in new way.
PMID- 10777400
TI - Biotechnology. Transgenic crops report fuels debate.
PMID- 10777401
TI - The rise of the mouse, biomedicine's model mammal.
PMID- 10777402
TI - A mouse chronology.
PMID- 10777403
TI - Academic facilities. The mouse house as a recruiting tool.
PMID- 10777404
TI - Property claims. A deluge of patents creates legal hassles for research.
PMID- 10777405
TI - Origins of vertebrate success.
PMID- 10777406
TI - Dynamic and permanent.
PMID- 10777407
TI - Antiscrapie drug action.
PMID- 10777408
TI - DNA banks for endangered animal species.
PMID- 10777409
TI - Language. Who's got rhythm?
PMID- 10777410
TI - Neurobiology. Stay the executioner's hand.
PMID- 10777411
TI - Infectious history.
PMID- 10777412
TI - [Predecessors: veterinarians from earlier times. 36. Giovanni Battista Ercolani
(1817-1883)].
PMID- 10777414
TI - Angel's stigma.
PMID- 10777415
TI - Wrestling with the covenant.
PMID- 10777416
TI - Recurrent priapism during treatment with clozapine and olanzapine.
PMID- 10777417
TI - Editor's note: whither occupational health and safety?
PMID- 10777418
TI - The shortage.
PMID- 10777419
TI - Recommended practices for traffic patterns in the peroperative practice setting.
Association of periOperative Registered Nurses.
PMID- 10777420
TI - Normal values of laboratory tests in elderly onset psoriatic arthritis.
PMID- 10777421
TI - RS3PE syndrome. The relation with HLA B7.
PMID- 10777422
TI - Intra-articular corticosteroids in septic arthritis: beneficial or barmy?
PMID- 10777423
TI - [Classification of finger deformities due to muscle-tendon imbalance].
AB - We have developed a 4 stages classification comprising: purely dynamic imbalance
(Stage 1); tenodesis effect (Stage 2); articular rigidity without cartilage
lesion (Stage 3); articular rigidity with bone and cartilage destruction (Stage
4). This classification is easy to remember and general enough to be used for
most deformities due to musculo-tendinous imbalance, whatever their type or
etiology. We believe that this assessment will help to clarify the therapeutic
indications and allow better interpretation of the results.
PMID- 10777424
TI - The effect of 5-fluorouracil on Dupuytren fibroblast proliferation and
differentiation.
AB - INTRODUCTION: Dupuytren's disease is a proliferative disease with contractile
properties, prone to recur after surgery. Intra-operatively applied 5
fluorouracil has been used to avoid scar problems in the eye after glaucoma
filtration surgery and was therefore investigated as a means to inhibit
proliferation and myofibroblast differentiation in Dupuytren fibroblasts in
vitro. METHOD: Primary cell lines were obtained by explants from Dupuytren's
tissue (n = 6), non-diseased palmar fascia from patients with Dupuytren's disease
(n = 3) and carpal ligament from patients undergoing carpal tunnel release (n =
3). The effect of 5-fluorouracil on proliferation was assessed by cell counting.
Myofibroblast differentiation, an intergral part of Dupuytren's contracture, was
investigated by staining for alpha smooth muscle actin, a marker for contractile
cells, using immunohisto-chemical methods. RESULTS: A single exposure to 5
fluorouracil caused a sustained inhibition of proliferation in Dupuytren's and
non-diseased fascia cultures, whilst the effect on carpal ligament cultures was
transient. Untreated Dupuytren's fibroblasts exhibited the highest myofibroblast
differentiation, whilst differentiation in non-diseased fascia cultures was shown
to be proportional to cell density and virtually non-existent in carpal ligament
cultures. After 5-fluorouracil exposure, the differentiation was significantly
reduced in Dupuytren's fibroblasts cultures, reduced at high cell densities in
non-diseased fascia and unchanged in carpal ligament cell cultures. DISCUSSION: 5
fluorouracil inhibits both proliferation and myofibroblast differentiation in
Dupuytren's cell cultures and may have a potential use as an adjuvant treatment
to Dupuytren surgery in order to reduce the rate of recurrence and contracture.
PMID- 10777425
TI - [Results of nerve sutures in the wrist in children].
AB - INTRODUCTION: Wounds involving the peripheral nerves cause serious damage in the
upper limb. The prognosis for recovery remains uncertain despite microsurgery. It
is commonly accepted that the results are far better in children than in adults.
We sought to confirm this idea on the basis of objective recovery criteria,
discriminating between peripheral axonal regeneration and the child's own
capacity to adapt. In other words, do nerves regenerate better in children?
MATERIALS AND METHODS: The clinical results of 25 nerve sutures of the wrist, in
children under 15, were analysed with a minimum follow-up of 12 months. The
subjects were reviewed clinically and had an electromyogram. The resulting data
was compared to that for adults found in the literature. RESULTS: Clinically, the
overall function of the hand was always satisfactory. The sensory results were
often excellent (S4 or S3+ in 23 cases/25). The mean value muscular testing was
between M2 and M3. With respect to the EMG results, the values we recorded were
rarely representative of the functional results. The motor recordings were mostly
poor, demonstrating that the nerve supply was compensated by a phenomenon
involving collateral innervation. DISCUSSION: The poor results of peripheral
nerve surgery are only due to the quality of the restored innervation. Dellon and
Mackinnon demonstrated that they were also due to the incapacity of the nerve
centres to integrate a change in the profile of sensory information. It would
therefore seem that not only the quantity of nerve tissue repair is insufficient,
but also the quality. Children have a superior cerebral capacity to adapt than
adults and probably benefit from better cortical acquisition processes and are
thus capable of putting the changes in the nerve messages to better use. The
analysis of the clinical and EMG results also reveals a trend demonstrated
partial nerve repair in children. We think that the functional results suggest
that children have a better central capacity to adapt.
PMID- 10777426
TI - [Surgical repair of the axillary nerve. Results of a five-year follow-up].
AB - INTRODUCTION: We report a series of 19 cases of axillary nerve lesions, which
were operated between 1981 and 1995. MATERIAL AND METHODS: There were 14 isolated
lesions of the axillary nerve and in 5 patients the lesion to the axillary nerve
was associated either with a lesion of the radial nerve or with a lesion of the
suprascapular nerve. Fourteen patients sustained shoulder stretch injury, three
had fractures of the scapular girdle and two anterior shoulder dislocation.
Patients were operated on 9 months after trauma through a combined anterior and
posterior approach. The lesion was located in the quadrilateral space. In 17
cases the neuroma was excised and the nerve was reconstituted, using sural nerve
grafts. In two cases the nerve was only freed from the surrounding scar tissue.
RESULTS: Results were considered as satisfactory in 10 out of 14 isolated
axillary nerve lesions. According the Constant score there were 2 very good, 8
good and 2 fair results. In this study, neurolysis and axillary nerve associated
with suprascapular nerve lesions gave poor results. DISCUSSION: The successfully
reinnervated deltoid muscle adds strength and endurance to the affected shoulder.
Electromyographic study remains important in detecting spontaneous return of
muscle function and determining the most favorable operative period before severe
amyotrophy appears.
PMID- 10777427
TI - [Surgical treatment of carpometacarpal joint osteoarthritis of the thumb by
trapeziectomy-interposition-ligamentoplasty].
AB - INTRODUCTION: Osteoarthritis of the carpometacarpal joint of the thumb is a
common pathology. Several surgical methods exist, including trapeziectomy,
arthrodesis, cemented or cementless prosthesis. Therefore, one must question the
legitimacy of non prosthetic surgery. The authors have tried to answer this
question. METHOD: Surgery consisted in trapeziectomy and ligament reconstruction
with tendon interposition arthroplasty (LRTI). Authors reviewed 47 cases with
five years follow-up. Patients were evaluated using a functional score, including
pain, professional and domestic activities, and leisure involving the hand.
Objective data were also assessed: thumb opposition, radiographic
scaphometacarpal mobility, key and tip pinch, grasp strength. RESULTS: Functional
results ranged from good to excellent in 42 cases. Opposition was satisfactory in
46 cases. Scapho-metacarpal range of motion was 16 degrees. Pinch strength was
4.2 kg and grasp strength was 23 kg. There were no complications. Loss of pinch
strength was 1 to 2 kg as compared to our reference group. Such a loss does not
impair patients' daily life. Age and operated side do not influence results.
Scores do not decrease with time. Radiographic staging seems to be linked with
scoring. Reducing the trapezial space does not influence results. We had none of
the complications described in other techniques: synovitis, ossifications,
loosening and reflex sympathetic dystrophy. DISCUSSION: This study, as well as
literature, confirms that trapeziectomy and ligament reconstruction with tendon
interposition arthroplasty gives satisfactory functional results which are stable
with time and without complication. For all these reasons, the authors prefer
this technique in degenerative osteoarthritis.
PMID- 10777428
TI - [Qualitative retrospective study comparing 43 advanced-rotated flaps to 19 island
type Venkataswami-Subramanian flaps].
AB - OBJECTIVE: In case of a fingertip trauma, the surgeon'aim is to give the finger a
good function, that means a fingertip with good sensibility and trophicity. The
purpose of this study was to follow-up three different types of flaps used for
fingertip reconstruction, and to analyse their sensibility and functional
results. METHOD: 62 fingertip-flaps performed in 60 patients were included in
this series. Patients were mainly males (45-60), adults (42-60), middle age (mean
age = 40), right-handed (55-60) and home-injured (32-60). The dominant side was
injured more often (43-60), by section (27-60) or crush (25-60). Patients were
reviewed by the same investigator. Various types of flaps were used: 31 Atasoy
flaps, 19 neurovascular island unipedicled flaps and 12 Hueston flaps. Sensory
results were evaluated using static and moving two-point discrimination tests,
and pain and hot-cold discrimination. Esthetic and functional results were also
evaluated. RESULTS: The tactile sensibility was good or excellent in 63% of flaps
and the nail looked good in 70% of flaps. Among all flaps, the Atasoy flap
obtained the best results. DISCUSSION: This study showed the good quality of
Atasoy and Hueston flaps in fingertip reconstruction. Neurovascular island flaps
gave poor results without taking in account the severity of initial trauma.
PMID- 10777429
TI - [Composite nail transfer by the traditional method].
AB - INTRODUCTION: We have retrospectively reviewed our experience in the treatment of
traumatic loss of the whole nail complex. METHOD: Contraindications for our
technique are cases suitable for microsurgical transfer and cases with a poorly
vascularised recipient bed. Under local anaesthesia, we harvested the nail unit
composed of the eponychiurn matrix, nail table, hyponychium and lateral folds.
The transfer to the recipient finger was also performed under local anaesthesia.
Post operative cryotherapy for 72 hours was combined with a prostaglandin E1
infusion (50 micrograms per day during 3 days). The functional result was
assessed by the coin test and the cosmetic result by VAS (from 1 to, 10). RESULT:
Eleven patients were operated on according to the technique between April 1995
and June 1997. Minimum follow-up was 6 months. Average follow-up was 13 months.
There were 9 men and 2 women with a mean age of 31 years (range: 13-40). Among
the 14 injured fingers, the index was involved 2 times, the middle finger 5
times, the ring finger 3 times and little finger 4 times. The aetiology was a
burn in one case and direct trauma in the other 13. We obtained 11 good results;
2 nails with slight dystrophy and one failure secondary to an infection (the burn
case). The coin test was good in 13 cases and the mean cosmetic VAS was 8/10.
DISCUSSION: Our technique is easy and well accepted by the patient. It gave 11
good results out of 14 cases. According to the literature, this method has fallen
into disuse due to its unpredictable results. It seems to us that this technique
has to be put into balance with microvascular transfer; a much more sophisticated
operation and with a nail prosthesis which is not always well accepted and is
very difficult to fix. A major prerequisite remains a well vascularised recipient
bed. Cryotherapy in the post operative period decreases the metabolism and avoids
ischaemia during the phase of revascularisation, and explains the quality of our
results.
PMID- 10777430
TI - [Soft tissue metastatic tumors of the fingers. Six cases].
AB - Soft tissue metastases of the fingers are rare. The authors report six new cases.
The clinical presentation is variable and can cause difficulty in diagnosis. The
bad prognosis of these lesions is emphasized.
PMID- 10777431
TI - Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind,
placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.
AB - Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in
patients with partial seizures. In this study, the efficacy and tolerability of
VGB as adjunctive therapy were evaluated in patients with refractory epilepsy.
Adult patients with a definite diagnosis of complex partial seizures and/or
partial seizures secondarily generalized were recruited from 10 Canadian centres.
Patients were randomized to receive either active medication or placebo in a
double- blind fashion and entered a 36-week titration and maintenance phase with
regularly scheduled visits. Both efficacy parameters and safety assessments were
monitored. Clinical laboratory, evoked potential studies, MRI, and
neuropsychological tests were also performed. Forty-eight percent of VGB-treated
patients vs. 26 percent of placebo-treated patients had a 50 percent or greater
reduction in the frequency of complex partial seizures and partial seizures
secondarily generalized. Vigabatrin was well tolerated by the majority of
patients. Minor neurological side effects were observed in a number of patients
in both treatment groups. No serious systemic toxicity was observed. No changes
in evoked potential studies or MRI findings were noted. Vigabatrin was found to
be an effective and well-tolerated antiepileptic drug when used as adjunctive
therapy in patients with difficult to control complex partial seizures and for
partial seizures secondarily generalized. Vigabatrin is a selective irreversible
inhibitor of the GABA- degradating enzyme GABA transaminase and has shown
efficacy in a number of clinical trials in patients with difficult to control
partial seizures. Vigabatrin has been found most effective against complex
partial and secondarily generalized tonic-clonic seizures in both adults and
children. Vigabatrin has also been shown to reduce infantile spasms secondary to
various aetiologies and is most effective in spasms associated with tuberous
sclerosis. The aim of this study was to further extend the clinical experience
with VGB as adjunctive therapy in the treatment of adult patients with difficult
to control complex partial seizures and/or partial seizures secondarily
generalized. In addition to the assessments of efficacy and tolerability to VGB,
neuropsychological evaluations were also carried out.
PMID- 10777432
TI - Interspecific Competition, Environmental Gradients, Gene Flow, and the
Coevolution of Species' Borders.
AB - Darwin viewed species range limits as chiefly determined by an interplay between
the abiotic environment and interspecific interactions. Haldane argued that
species' ranges could be set intraspecifically when gene flow from a species'
populous center overwhelms local adaptation at the periphery. Recently,
Kirkpatrick and Barton have modeled Haldane's process with a quantitative genetic
model that combines density-dependent local population growth with dispersal and
gene flow across a linear environmental gradient in optimum phenotype. To address
Darwin's ideas, we have extended the Kirkpatrick and Barton model to include
interspecific competition and the frequency-dependent selection that it
generates, as well as stabilizing selection on a quantitative character. Our
model includes local population growth, movements over space, natural selection,
and gene flow. It simultaneously addresses the evolution of character
displacement and species borders. It reproduces the Kirkpatrick and Barton single
species result that limited ranges can be produced with sufficiently steep
environmental gradients and strong dispersal. Further, in the absence of
environmental gradients or barriers to dispersal, interspecific competition will
not limit species ranges at evolutionary equilibrium. However, interspecific
competition can interact with environmental gradients and gene flow to generate
limited ranges with much less extreme gradient and dispersal parameters than in
the single-species case. Species display character displacement in sympatry, yet
the reduction in competition that results from this displacement does not
necessarily allow the two species to become sympatric everywhere. When species
meet, competition reduces population densities in the region of overlap, which,
in turn, intensifies the asymmetry in gene flow from center to margin. This
reduces the ability of each species to adapt to local physical conditions at
their range limits. If environmental gradients are monotonic but not linear, the
transition zone between species at coevolutionary equilibrium occurs where the
environmental gradient is steepest. If productivity gradients are also introduced
into the model, then patterns similar to Rapoport's rule emerge. Interacting
species respond to climate change, as it affects the optimal phenotype over
space, by a combination of range shifts and local evolution in mean phenotype,
while solitary species respond solely by range shifts. Finally, we compare
empirical estimates for intrinsic growth rates and diffusion coefficients for
several species to those needed by the single-species model to produce a stable
limited range. These empirical values are generally insufficient to produce
limited ranges in the model suggesting a role for interspecific interactions.
PMID- 10777433
TI - The Distribution of Abundance in Neutral Communities.
AB - The patterns of abundance generated by a simple stochastic birth-death
immigration model are described in order to characterize the diversity of neutral
communities of ecologically equivalent species. Diversity is described by species
number S and the variance of frequency or log abundance q~. The frequency
distribution of abundance is very generally lognormal, skewed to the left by
immigration and resembling descriptions of natural communities. Increased
immigration and community size always cause S to increase. Their effect on q~ is
more complicated, but given biologically reasonable assumptions, S and q~ will be
positively correlated in most circumstances. Larger samples contain more species;
the graph of log S on log individuals, equivalent to a species-area curve, is
generally convex upward but becomes linear with a slope of about +0.25 when
immigration is low and births exceed deaths. When individuals invade a new,
vacant environment, both S and q~ increase through time. Thus, a positive
correlation between S and q~ will usually be generated when sites of differing
size or age are surveyed. At equilibrium, communities maintain roughly constant
levels of S and q~ but change in composition through time; composition may remain
similar, however, for many generations. Many prominent patterns observed in
natural communities can therefore be generated by a strictly neutral model. This
does not show that community structure is determined exclusively by demographic
stochasticity, but rather demonstrates the necessity for an appropriate null
model when functional hypotheses are being tested.
PMID- 10777434
TI - Species Diversity and Biomass Stability.
AB - With the current accelerating rate of biodiversity extinction, there is great
interest in how species diversity influences ecosystem properties. In this
article, we investigate the relationship between species diversity and the
stability of community biomass in the face of stochastic perturbations of
species' abundances. The model explicitly includes species' interactions. We show
that the pattern of species' interactions affects whether the relationship
between diversity and biomass stability is positive or negative. In particular,
assumptions about community structure influence the relationship between species
diversity and community biomass, which in turn influences the diversity-stability
relationship. We also discuss the relationship between diversity and another type
of stability, the proportional change in community biomass with the extinction or
introduction of a species. Regardless of community type, diversity buffers the
change in biomass when a species is added or removed.
PMID- 10777435
TI - Dispersal, Environmental Correlation, and Spatial Synchrony in Population
Dynamics.
AB - Many species exhibit widespread spatial synchrony in population fluctuations.
This pattern is of great ecological interest and can be a source of concern when
the species is rare or endangered. Both dispersal and spatial correlations in the
environment have been implicated as possible causes of this pattern, but these
two factors have rarely been studied in combination. We develop a spatially
structured population model, simple enough to obtain analytic solutions for the
population correlation, that incorporates both dispersal and environmental
correlation. We ask whether these two synchronizing factors contribute additively
to the total spatial population covariance. We find that there is always an
interaction between these two factors and that this interaction is small only
when one or both of the environmental correlation and the dispersal rate are
small. The interaction is opposite in sign to the environmental correlation; so,
in the normal case of positive environmental correlation across sites, the
population synchrony will be lower than predicted by simply adding the effects of
dispersal and environmental correlation. We also find that population synchrony
declines as the strength of population regulation increases. These results
indicate that dispersal and environmental correlation need to be considered in
combination as explanations for observed patterns of population synchrony.
PMID- 10777436
TI - Coevolution of Contrary Choices in Host-Parasitoid Systems.
AB - We investigate patch selection strategies of hosts and parasitoids in
heterogeneous environments. Previous theoretical work showed that when host
traits vary among patches, coevolved populations of hosts and parasitoids make
congruent choices (i.e., hosts and parasitoids preferentially select the same
patches) and exhibit direct density dependence in the distribution of percent
parasitism. However, host-parasitoid systems in the field show a range of
patterns in percent parasitism, while behavioral studies indicate that hosts and
parasitoids can exhibit contrary choices (i.e., hosts avoid patches favored by
the parasitoid). We extend previous theory by permitting life-history traits of
the parasitoid as well as the host to vary among patches. Our analysis implies
that in coevolutionarily stable populations, hosts preferentially select patches
that intrinsically support higher host equilibrium numbers (i.e., the equilibrium
number achieved by hosts when both populations are confined to a single patch)
and that parasitoids preferentially select patches that intrinsically support
higher parasitoid equilibrium numbers (i.e., the equilibrium number achieved by
the parasitoids when both populations are confined to a patch). Using this
result, we show how variation in life-history traits among patches leads to
contrary or congruent choices or leads to direct density dependence, inverse
density dependence, or density independence in the distribution of percent
parasitism. In addition, we determine when populations playing the
coevolutionarily stable strategies are ecologically stable. Our analysis shows
that heterogeneous environments containing patches where the intrinsic rate of
growth of the host and the survivorship rate of the parasitoid are low result in
the coevolved populations exhibiting contrary choices and, as a result, promote
ecological stability.
PMID- 10777437
TI - The Time Value of Leaf Area.
AB - When a plant invests in construction of a leaf, the revenue-stream that accrues
is shaped by three variables: first, the light-capture area per milligram dry
mass invested, analogous to a potential rate of return on investment; second, the
longevity of the leaf, analogous to the expected duration of the revenue stream;
and third, a time-discount rate, quantifying the fact that light-capture area
deployed in the immediate future is more valuable to the plant than the same area
deployed at some later time. Recent comparative data make it possible to quantify
the cross-species trade-off between the first variable and the second variable.
Here we develop an approach through which the consequences of the third variable,
the time-discount rate, can be related to the trade-off between the first
variable and the second variable. The approach involves an equal-benefit set, the
cross-species equivalent of a fitness set. A wide spread of strategies is
actually observed to coexist in vegetation, from low to high light capture area
per gram and, correspondingly, from high to low leaf longevity. The coexistence
suggests that the different observed strategies do not have a clear-cut advantage
over the other. The equal-benefit set can be used to investigate what levels of
time discount would make it the case that neither the highest-longevity nor the
highest light-capture area per milligram strategies would have a clear advantage
over the other, with regard to the time-discounted value of the revenue stream
generated per milligram invested in leaf.
PMID- 10777438
TI - Spatial Variation in the Selective Scenarios of Hormathophylla spinosa
(Cruciferae).
AB - The effects of multispecific systems containing both mutualistic and antagonistic
interacting organisms on the evolution of plant traits have seldom been analyzed.
We studied the selection exerted by several species of herbivores and pollinators
in three populations of Hormathophylla spinosa (Cruciferae) in the Sierra Nevada
(Spain) over 4 yr by using path analyses and structural equation modeling (SEM).
The main selective pressures in our study sites were ungulates and pollinators.
However, the importance of each kind of interacting organism differed among
populations. Our results indicate a selection mosaic among populations of H.
spinosa in the Sierra Nevada caused by the spatial variation in the relative
importance of different interactions as selective pressures. We found two main
selective scenarios, depending on the presence or absence of ungulates. In the
populations with low ungulate pressure, there was positive phenotypic selection
in flower number per plant and in flower density (mediated by nectarivorous
pollinators). In the two populations with high ungulate pressure, there was a
strong positive, ungulate-mediated selection in thorn density. Our results
suggest that the application of SEM to several populations simultaneously
monitored might help to isolate the major selection pressures on local
populations and identify potential differences in selection among populations,
becoming a useful exploratory approach to study the geographical variation of
selection in complex systems.
PMID- 10777439
TI - Predator and Prey Models with Flexible Individual Behavior and Imperfect
Information.
AB - To begin identifying what behavioral details might be needed to characterize
community dynamics and stability, we examined the effect of prey behavioral
responses to predation risk on community dynamics and stability. We considered
the case of prey altering their foraging effort to trade off energy gain and
predation risk. We used state-dependent dynamic optimization to calculate the
optimal trade-off for four models of prey behaviorally responding to predation
risk. We consider a fixed behavior model in which prey use constant levels of
foraging effort and three flexible behavior models in which prey change their
foraging effort according to their physiological state and their perceived level
of predation risk. Flexible behavior was destabilizing at the community level as
evidenced by higher predator-prey oscillations and lower community persistence
times. The mechanisms by which prey estimated predation risk also affected
community stability. We found that community dynamics resulting from prey with
flexible behavior and fixed perception of risk approximated community dynamics
resulting from prey with flexible behavior and perfect information about
predation risk, however neither approximated the community dynamics resulting
from prey with flexible behavior and flexible perception of risk. Thus, whether
it might be possible to abstract complex behavior with simpler rules when
modeling community dynamics depends on the prey's behavioral mechanisms, which
are empirically poorly known.
PMID- 10777440
TI - Recruiters and Joiners: Using Optimal Skew Theory to Predict Group Size and the
Division of Resources within Groups of Social Foragers.
AB - I apply skew theory to the division of resources within multimember social
foraging and antipredator groups. Resource division is modeled as a game between
an individual controlling resources (recruiter) and a potential joiner to the
group. If a recruiter benefits from the presence of a joiner, it will allocate
sufficient resources to the joiner so that the joiner gains as much from group
foraging as it would from foraging alone. Joiners should receive a greater
proportion of resources controlled by the recruiter when benefits to grouping are
low. If group success is a concave-down function of group size, this framework
can be used to predict the stable group size. The stable group size is larger
than the optimal group size, given equal division of resources, and smaller than
the stable group size, given equal division of resources. Furthermore, both
current group members and potential joiners agree on the stable group size, so
long as the recruiter is able to control resource division. If the recruiter
cannot control resource division, there may be conflict over group size and the
opportunity for group members to contribute less to group success than they are
able.
PMID- 10777441
TI - Species Diversity, Species Extinction, and Ecosystem Function.
PMID- 10777442
TI - Is The Barley Endosperm a Water Reservoir for the Embryo When Germinating Seeds
Are Dried?
AB - The water content of germinating seeds fluctuates in response to water potential
changes in the surrounding environment. We tested the hypothesis that the
endosperm functions as a water reservoir when imbibed seeds experience drying,
and we characterized water uptake and movement within barley (Hordeum vulgare cv.
Triumph) caryopses (hereafter referred to as seeds). Water movement into and
through germinating barley seeds during imbibition and drying was determined
gravimetrically and with the fluorescent dye trisodium 8-hydroxy-1,3,6
pyrenetrisulfonate (PTS). During imbibition, embryo tissues hydrated more rapidly
and reached a higher water content (g H20/g dry weight) than did the endosperm,
although the endosperm eventually contained nine times as much total water. When
barley seeds that had imbibed for 12 h were exposed to moderate (-4 MPa) drying,
PTS solution moved from the endosperm into the shoot meristem, radicle, and
scutellum, but not vice versa. Radicle emergence and elongation proceeded for up
to 8 h. With harsh (-150 MPa) drying, PTS concentrated almost exclusively in the
radicle. These data illustrate that the endosperm is at least a temporary water
storage compartment external to the embryo itself. We speculate that water
supplied by the endosperm may be important in reducing the harmful effects of
drying during the critical transition period when a germinating seed changes from
a desiccation-tolerant to a desiccation-intolerant organism.
PMID- 10777443
TI - Pollination and embryo development in Brassica rapa L. in microgravity.
AB - Plant reproduction under spaceflight conditions has been problematic in the past.
In order to determine what aspect of reproductive development is affected by
microgravity, we studied pollination and embryo development in Brassica rapa L.
during 16 d in microgravity on the space shuttle (STS-87). Brassica is self
incompatible and requires mechanical transfer of pollen. Short-duration access to
microgravity during parabolic flights on the KC-135A aircraft was used initially
to confirm that equal numbers of pollen grains could be collected and transferred
in the absence of gravity. Brassica was grown in the Plant Growth Facility flight
hardware as follows. Three chambers each contained six plants that were 13 d old
at launch. As these plants flowered, thin colored tape was used to indicate the
date of hand pollination, resulting in silique populations aged 8-15 d
postpollination at the end of the 16-d mission. The remaining three chambers
contained dry seeds that germinated on orbit to produce 14-d-old plants just
beginning to flower at the time of landing. Pollen produced by these plants had
comparable viability (93%) with that produced in the 2-d-delayed ground control.
Matched-age siliques yielded embryos of equivalent developmental stage in the
spaceflight and ground control treatments. Carbohydrate and protein storage
reserves in the embryos, assessed by cytochemical localization, were also
comparable. In the spaceflight material, growth and development by embryos
rescued from siliques 15 d after pollination lagged behind the ground controls by
12 d; however, in the subsequent generation, no differences between the two
treatments were found. The results demonstrate that while no stage of
reproductive development in Brassica is absolutely dependent upon gravity, lower
embryo quality may result following development in microgravity.
PMID- 10777444
TI - Is There a Genetic Basis for Fluctuating Asymmetry and Does it Predict Fitness in
the Plant Lotus corniculatus Grown in Different Environmental Conditions?
AB - Fluctuating asymmetry (FA) is considered to be a good measure of developmental
stability. We measured the asymmetry of leaves and flowers of 16 different
genotypes of Lotus corniculatus grown in four different experimental environments
to estimate the plasticity or developmental stability of asymmetry itself. We
found that an index of FA (absolute difference between size of left and right
sides, corrected for trait size) differed significantly across environments, with
the treatment CO2+/N+ inducing the greatest FA for both flowers and leaves.
Genotypes did not differ in FAs. Individual plants showed significantly different
FAs only for flowers. At the individual level, we found no significant
relationship between flower FA and fitness. Previous work indicates that change
in asymmetry in a poor or perturbing environment versus a good environment could
reflect the intrinsic quality of a particular genotype. However, in our
experiment, genotype effect was significant only for change in asymmetry of
leaves, and this last trait was not significantly correlated with our fitness
estimate for each genotype in either the most or the least perturbing
environment.
PMID- 10777445
TI - 2n+n Hybridization of Apomictic Paspalum dilatatum with Diploid Paspalum Species.
AB - Common dallisgrass (Paspalum dilatatum) is an apomictic pentaploid (2n=5x=50) of
hybrid origin with irregular meiosis and with the genome formula IIJJX. The I and
J genomes are homologous to those of diploid P. intermedium and P. jurgensii,
respectively, but the source of the X genome is unknown. Members of the X genome
may have genes of special biological significance, including those controlling
apomixis. Common dallisgrass was crossed with several diploid Paspalum species in
an attempt to identify the source of the X genome. Since common dallisgrass is
apomictic, all hybrids produced will be formed by fertilization of an unreduced
egg (2n+n). Any hybrid showing 30 chromosome bivalents at meiosis would indicate
that the male diploid parent has a chromosome set that is homologous to the X
genome of dallisgrass. Over 36,000 spikelets of dallisgrass were emasculated and
dusted with pollen of 15 different diploid species (diploid species bearing I or
J genomes were excluded). Only five (P. chaseanum, P. equitans, P. fasciculatum,
P. notatum, and P. simplex) produced 2n+n hybrids with P. dilatatum. Meiotic
chromosome behavior was similar in all hexaploid hybrids showing ca. 20 bivalents
and 20 univalents. Results indicated a very low rate of 2n+n hybridization; none
of the five diploid species possessed the X genome. Because several diploid
species failed to hybridize with 5x dallisgrass, other methods should be
attempted. Molecular markers specific for the X genome may help solve the
question.
PMID- 10777446
TI - Genetics of Ustilago violacea. XXXV. Transposition in Haploid and Diploid
Sporidia and Germinating Teliospores.
AB - Ustilago violacea sporidia of the white (w) MAD strain (a-2 w lys-3 ino-1 thi)
incubated on minimal medium containing 100 mM KClO3 (potassium chlorate) produced
only colonies with the pink phenotype. Sporidia from these colonies retained
their pink color on complex medium. Sporidia of the diploid D1 strain (a-1 y nic
1 thi/a-2 w met-1 arg-f Chl70 thi) and of the diploid D2 strain (a-1 y his-1 glu
1 thi/a-2 w lys-3 ino-1 thi) produced pink colonies on complex medium. Streaks of
diploid D1 sporidia from the pink colonies were stable on complex medium. In
contrast, streaks of diploid D2 sporidia, which are heterozygous for the MAD
strain, were unstable, initially producing pink colonies on complex medium but
then, with continued incubation, producing white termini. Sporidia from the white
termini with diploid morphology continued to yield white colonies. Teliospore
colonies from three crosses with the MAD strain as a common parent were uniformly
pink or had a pink sector instead of the expected uniformly white colonies or
colonies having a white sector. Four of 20 and 13 of 20 teliospore colonies,
respectively, from two of the three crosses had both a-1 and a-2 sporidia, and
the remaining colonies had only a-1 or only a-2 sporidia. All 40 teliospore
colonies from the third cross had only a-1 or only a-2 sporidia. All of these
observations indicated that the MAD strain may have two autonomous, transactive
transposable elements in different chromosomes and that insertional mutations in
at least two haplolethal loci were responsible for the teliospore colonies with
only a-1 or only a-2 mating type. Crossing over between a haplolethal locus and
the centromere would account for teliospore colonies with both a-1 and a-2
sporidia.
PMID- 10777447
TI - Investigations into the Genetic Variation, Population Structure, and Breeding
Systems of the Fern Asplenium trichomanes subsp. quadrivalens.
AB - The genetic structure of five populations of the tetraploid fern Asplenium
trichomanes subsp. quadrivalens in northern Switzerland was analyzed. Asplenium
trichomanes subsp. quadrivalens is one of the most common and most widespread
ferns in Europe. In this study we have combined genetic investigations, spatial
autocorrelation, and breeding experiments to investigate in detail five
populations from natural rock faces. Enzyme electrophoresis revealed very low
genetic variability within and among the populations. The small amount of
variation was partitioned mainly among the localities, indicated by high Fst
values up to 0.764. Overall means of the proportion of polymorphic loci
(P=0.076), the mean number of alleles per locus (A=1.086), and the mean expected
heterozygosity (H=0.018) were low compared with other ferns (e.g., Kirkpatrick et
al. 1990). Very few heterozygous individuals were found. Values of the fixation
index (F) were high, ranging between 0.732 and 1.000 and indicating substantial
inbreeding. Spatial autocorrelation showed different patterns of substructure in
populations of A. trichomanes subsp. quadrivalens with a tendency for patches in
short distances (up to 1.5 m). The breeding experiments with isolated prothalli
and prothalli pairs showed that a mean of 56.4% of the isolated prothalli were
successful in sporophyte formation. The highest rate in one population was 83.3%.
We conclude that genetic load must be low in A. trichomanes subsp. quadrivalens.
Sporophyte formation was statistically more successful in the experiments with
gametophyte pairs than in isolates, indicating that additional cross
fertilization occurred. The latter agreed with the occurrence of few heterozygote
samples and the small number of multilocus phenotypes found in natural habitats.
Asplenium trichomanes subsp. quadrivalens is shown to be a highly inbreeding
taxon with the capability of single spore colonization and subsequent founding of
new populations. Such features can be hypothesized to have contributed to the
postglacial colonization and the widespread distribution of this taxon in Europe.
PMID- 10777448
TI - Nectar Production in Louisiana Iris Hybrids.
AB - Nectar is an important attractant for pollinators, and a plant's success in
sexual reproduction can be influenced by the amount and concentration of nectar
produced by its flowers. We studied nectar production over flower lifetime in
Iris fulva, Iris brevicaulis, and four classes of hybrids-reciprocal F1's and
backcrosses-between these species. Iris fulva produced less concentrated nectar
than did I. brevicaulis, whereas I. brevicaulis flowers had a shorter life span.
Hybrids were not intermediate, but they had the high nectar concentration of I.
brevicaulis combined with the long life span of I. fulva flowers. Nectar
production and concentration declined after the first day in all classes, but
flowers continued to produce nectar until they were completely wilted.
Backcrosses did not show a shift in mean or increased variation for the
characters that distinguished the parental species; backcrosses toward I. fulva
retained the high nectar concentration of I. brevicaulis, and backcrosses toward
I. brevicaulis did not have a reduced flower life span. Overall, F1 hybrid
flowers produced the highest amounts of nectar and nectar sugar over their life
spans. These results, together with previously obtained data on pollinator choice
in mixed arrays of the same flower classes, show that F1 hybrids between these
species do not suffer from reduced attractiveness to pollinators. F1 individuals
produced more nectar and nectar sugar than did their parents, and thus, they are
possibly even more attractive to pollinators that forage for nectar.
PMID- 10777449
TI - Hummingbird-Syndrome Traits, Breeding System, and Pollinator Effectiveness in Two
Syntopic Penstemon Species.
AB - Red-flowered, tubular Penstemon barbatus and Penstemon pinifolius, which have
probably adapted independently to hummingbird pollinators, coflower on recently
burned high-elevation slopes in the Chiricahua Mountains in Arizona. Hummingbirds
visit both species but visit P. barbatus at a higher rate. We compared several
traits and asked whether the species differed in specialization for hummingbird
pollination. The corollas of P. pinifolius were 30% narrower than those of P.
barbatus, but they were similar in tube length. Although a narrower corolla
appeared to decrease access by large insects, small halictid bees were the only
common insect visitors, and they gathered nectar from both species. Species
differences in nectar production rate and concentration were minor, being smaller
than within-species differences between dry and rainy periods. Taller
inflorescences and a wider corolla tube may contribute to greater hummingbird use
of P. barbatus. Penstemon pinifolius was fully self-compatible and weakly
autogamous, whereas P. barbatus was strongly self-incompatible and had a longer
flower life. Exclusion of hummingbirds reduced seed set fourfold in both species,
supporting the inference from morphology and rewards that hummingbirds are the
primary pollinators. In the absence of hummingbirds, halictids increased the seed
set of P. barbatus relative to exclusion of all visitors, but they did not
increase the seed set of P. pinifolius. Despite sharing the basic set of
hummingbird-syndrome traits, the two species differed in degree of investment in
individual flowers and in adaptations for outcrossing.
PMID- 10777450
TI - 9,10-Anthraquinone Reduces the Photosynthetic Efficiency of Oscillatoria
perornata and Modifies Cellular Inclusions.
AB - The natural compound 9,10-anthraquinone was found to inhibit the growth of the
musty odor-producing cyanobacterium Oscillatoria perornata at a low concentration
(1 uM) in previous laboratory studies. In this study, the mode of action of 9,10
anthraquinone was investigated by observing ultrastructural changes in O.
perornata and by monitoring chlorophyll fluorescence as an indicator of
photosynthetic efficiency. Results indicate that 9,10-anthraquinone inhibits
photosynthetic electron transport, probably at PSII, and thereby affects growth.
Moreover, 9,10-anthraquinone treatment caused thylakoid disorganization and
reduced the number of ribosomes in O. perornata. The thylakoid disorganization is
identical to reported modification in a cyanobacterium treated with simazine, a
PSII inhibitor.
PMID- 10777451
TI - Influence of Drought-Induced Water Stress on Soybean and Spinach Leaf Ascorbate
Dehydroascorbate level and Redox Status.
AB - We examined the influence of water stress (water deficit) induced by drought on
the steady state levels of ascorbic acid (ASC), dehydroascorbate (DHA), and the
ASC&rcolon;DHA redox status in leaflets of Glycine max (soybean) and leaves of
Spinacia oleracea (spinach). Two soybean cultivars (cv. Essex and cv. Forrest)
and one spinach cultivar (cv. Nordic) were grown in high-light growth chambers (
approximately 1000-1200 umol m-2 s-1) or in the greenhouse during May, June, and
July 1999. The cultivars were supplied with water until approximately 25-29 d
postemergence, at which time one-half of the plants were not watered for a period
of from 4.5 to 7.5 d; the other half of the plants were provided water daily and
served as controls. On designated days, leaf water potential (PsiLeaf) was
measured, and leaf disks of constant area were excised in the period between
approximately 1230 and 1330 hours. Leaf disk samples were immediately frozen in
liquid N2, samples were extracted, and ASC and DHA levels were measured and
expressed as umol per gram dry mass per time point. For the soybean cultivars,
low PsiLeaf values ( approximately -3.00 to -3.95 MPa) were accompanied by slight
decreases in ASC levels and slight increases in DHA levels per gram dry mass. In
some cases, leaflet ASC levels of water-stressed soybeans were similar to
controls or were even increased by as much as 1.2 times. In soybeans, the mole
fraction of ASC remained at 93-99 mol% of the total ascorbate (ASC+DHA),
indicating that most of the total ascorbate remained in the reduced form even at
low water potential. In spinach plants subjected to water stress (-1.8 to -2.6
MPa), leaf ASC decreased as much as 38%, but the ASC remained at 96-99 mol% of
the total ascorbate. It is concluded that during water stress, enzymes of the
ascorbate-glutathione cycle in leaf mesophyll cells, as well as in the system
that generates reductant to support DHA to ASC recycling, e.g., photosynthetic
electron transport in chloroplasts, is able to remain active enough to maintain
reduction of DHA to ASC.
PMID- 10777452
TI - Effects of Light and Sucrose Levels on the Anatomy, Ultrastructure, and
Photosynthesis of Gardenia jasminoides Ellis Leaflets Cultured in vitro.
AB - This article reports the effect of growing conditions on the anatomical and
ultrastructural changes associated with the development of photoautotrophy in
Gardenia jasminoides Ellis plantlets during shoot multiplication in vitro. Two
photosynthetic photon flux densities (PPFD) (50 and 100 umol m-2 s-1 PPFD: L50
and L100, respectively) and two sucrose concentrations in the culture medium (5
and 30 g L-1: S5 and S30, respectively) were assayed. An increase in PPFD
stimulated the development of photosynthetic tissues and led to higher
photosynthesis and dark respiration regardless of the sucrose level assayed.
However, the effect of sucrose in the medium depended on the PPFD. For the high
PPFD treatment, a low sucrose concentration in the medium stimulated the
development of photosynthetic tissues, whereas the opposite effect of sucrose was
observed at low PPFD. This study demonstrated that an increase in light intensity
to moderate values such as L100 has a beneficial effect on the development of
structural changes associated with photoautotrophy. Such an effect is stimulated
by low sucrose (S5) levels in the medium. These modifications of usual growing
conditions (such as L50 combined with S30) for micropropagation may prove to be
useful in mass propagation of gardenia. However, the use of a low sucrose level
in addition to conventional growing PPFD may be counterproductive.
PMID- 10777453
TI - Ultrastructure of the Host-Pathogen Relationship in Entomosporium Leaf Spot
Disease of Photinia.
AB - Entomosporium mespili appears to be a hemibiotroph on infected Photinia leaves.
This fungal pathogen produced distinctive haustoria in living host cells in young
lesions. Each haustorium possessed a long slender neck with a single septum and
an enlarged distal body that contained a single nucleus. A collar of host cell
wall material was associated with the haustorial neck. Intact haustoria also were
found in necrotic cells of older lesions. However, by this stage of disease
development, the pathogen also possessed an extensive system of branched, septate
hyphae that grew indiscriminately between and through dead and dying host cells.
These hyphae eventually gave rise to a subcutaneous layer of sporogenous cells
that formed conidia.
PMID- 10777454
TI - Structural Fruit Coloration in Delarbrea michieana (Araliaceae).
AB - The brilliant blue fruit color of Delarbrea michieana (F. Muell.) F. Muell.
(Araliaceae), a Queensland understory rain forest tree, is caused by iridisomes
(structures) in the epidermal cells that are produced beneath the cell wall and
probably outside of the cytoplasm. Layers within these iridisomes are of such a
thickness that they interfere constructively with light at 420-440 nm and produce
the color. Such color production may aid in attracting mammals and large
frugivorous birds (which may disperse the fruits) and may also allow ripe fruits
to continue photosynthetic carbon assimilation.
PMID- 10777455
TI - Cuticle Micromorphology of Pinus krempfii Lecomte (Pinaceae) and Additional
Species from Southeast Asia.
AB - Cuticle micromorphology of the unusual Vietnamese pine, Pinus krempfii Lecomte,
and three additional endemic southeast Asian species of Pinus L. (Pinaceae) is
characterized for the first time. Taxa studied include (1) P. krempfii, typically
placed in its own subgenus Ducampopinus (Chevalier) Ferre ex Little &
Critchfield; (2) the endemic Vietnamese species Pinus dalatensis Ferre and (3)
the southeast Asian species Pinus kwantungensis Chun ex Tsiang, both of subgenus
Strobus; and (4) the widespread Asian species Pinus kesiya Royle ex Gordon of
subgenus Pinus. The current and previous studies demonstrate that the genus Pinus
and its subgenera are delimited by unique combinations of cuticular characters,
although some of these characters may occur individually in other conifers.
Cuticular micromorphology supports taxonomic assignment of P. krempfii to
subgenus Strobus rather than to its own subgenus, a result that is also indicated
by other anatomical studies and recent molecular studies. Sectional affinities of
P. krempfii are usually with Parrya, subsection Krempfianae. An alternative
classification of P. krempfii with subsection Gerardianae can be supported by
micromorphological characters including broad cuticular bridges between stomata,
details of the intercellular flanges of the epidermal cells, and usually an
amphistomatic stomatal distribution. Features of other Asian species studied are
consistent with their taxonomic assignments. The study demonstrates the utility
of cuticle micromorphology to taxonomic delimitation within the family Pinaceae.
PMID- 10777456
TI - Seed Size and Dispersal Systems of Early Cretaceous Angiosperms from Famalicao,
Portugal.
AB - Seeds and fruits of Early Cretaceous (Barremian-Aptian) angiosperms from the
Famalicao locality in Portugal were analyzed to establish seed and fruit size
(volume) distributions and to infer the proportion of animal-dispersed fruits. On
the basis of a sample of 106 angiosperm fruit and seed taxa, the average seed
size was 0.78 mm3 (range 0.02-6.86 mm3), whereas the average fruit size was 2.06
mm3 (range 0.12-8.34 mm3). Variation in seed size among taxa is smaller than in
modern plant communities, but within-taxon variation is similar to that known for
extant plants. No significant difference in the size of "fleshy" versus other
fruits was observed. The proportion of fleshy fruits was 24.5%. This high figure
was surprising and indicates that the significance of animal dispersal during an
early stage in angiosperm evolution has been underestimated. We suggest that
reptiles and multituberculates, and perhaps other mammals and birds as well, were
the likely seed dispersers and that the early angiosperms from Famalicao probably
were herbs or small shrubs that inhabited a semiopen coniferous woodland.
PMID- 10777457
TI - Cones, Seeds, and Foliage of Tetraclinis Salicornioides (Cupressaceae) from the
Oligocene and Miocene of Western North America: A Geographic Extension of the
European Tertiary Species.
AB - The cupressaceous genus Tetraclinis is recognized from the Oligocene and Miocene
of western North America on the basis of co-occurring seed cones, seeds, and
foliage branches. Morphological and anatomical comparisons with the two
previously recognized European Tertiary species indicate that the North American
specimens are morphologically inseparable from Tetraclinis salicornioides (Unger)
Kvacek. The North American taxon is treated as a new variety, T. salicornioides
(Unger) Kvacek var. praedecurrens (Knowlton) comb. et stat. nov., and is
distinguished from the European representatives, T. salicornioides (Unger) Kvacek
var. salicornioides, by slight anatomical differences in the leaf epidermis.
Although cones and seeds of the fossil species are closely similar to those of
extant Tetraclinis articulata, the foliage is more "spreading," composed of
flattened segments with fused facial and lateral leaves that are apparently
adaptive for a more mesic climate. The recognition of T. salicornioides in
western North America along with the absence of Tetraclinis in the fossil and
recent flora of eastern Asia provide evidence for communication of the species
across the North Atlantic during the early or middle Tertiary.
PMID- 10777458
TI - Introduction
PMID- 10777459
TI - Screening for lung cancer revisited and the role of sputum cytology and
fluorescence bronchoscopy in a high-risk group.
AB - Lung cancer is an epidemic disease that is underrepresented in the research
funding for early detection and chemoprevention arenas. Screening programs have
been discouraged for both financial and political reasons. Yet, increasing
evidence suggests that screening and early detection may improve outcome in lung
cancer. Sputum cytology examination has been shown in several studies to lead to
detection of lung cancer at an earlier stage, resulting in an improved 5-year
survival rate. Monoclonal antibody detection, fluorescence bronchoscopy, and low
dose spiral CT increase diagnostic sensitivity and improve the ability to
localize early-stage lesions. Utilizing these new techniques and improving the
definition of high-risk groups may improve the success and cost-effectiveness of
early detection based on sputum cytology. The ultimate goal of improving long
term survival in lung cancer will be achieved only when cancer can be detected in
its early stages and lesions can be localized in large numbers. Advances in the
last 15 years offer an encouraging vision for the value of early detection and
effective treatment for lung cancer.
PMID- 10777460
TI - Diagnosis of lung cancer: pathology of invasive and preinvasive neoplasia.
AB - The histopathologic appearance of lung carcinoma remains an important guide to
prognosis and treatment. The newly revised World Health Organization
classification retains the broadest pathologic categories of the older
classification but includes several revisions, including the elimination of the
small cell, intermediate cell type category; the addition of large cell
neuroendocrine and spindle/giant cell categories; and an extended consideration
of preneoplastic lesions. The histopathologic classification of lung cancer is
expected to continue to change as clinical practice and biological understanding
of these tumors change. The application of immunohistochemical testing to
histologic material not only provides new assistance with conventional histologic
classification, but also permits new ways to subclassify tumors, the full
clinical significance of which is yet to be realized. The significance of
expression of neuroendocrine markers, histologic grading of response to
chemotherapy, and delineation of morphologic changes preceding the occurrence of
invasive carcinoma are all areas where understanding microscopic cellular changes
in the airways will be critical for clinical advance.
PMID- 10777461
TI - Imaging bronchogenic carcinoma.
AB - Imaging plays an integral role in diagnosing, staging, and following patients
with lung cancer. Most lung tumors are detected on chest radiographs, but
unfortunately, the majority of patients have advanced stage disease at
presentation. There is a wide spectrum of radiologic manifestations of lung
cancer, and recognition of these findings is essential for patient management. As
we continue to understand more about tumor biology, new imaging techniques should
emerge and have the potential to significantly improve our diagnostic
capabilities.
PMID- 10777462
TI - Clinical and surgical staging of non-small cell lung cancer.
AB - The necessity for a compulsive attitude toward preoperative assessment of lung
cancer is to be emphasized, since rational treatment and prognosis depend largely
on the stage of disease at the time of diagnosis. In the preoperative setting,
the techniques used should be sequential, logical, and help to identify patients
suitable for treatment with curative intent. With regard to the primary tumor (T
status), the accuracy of CT or MRI to predict the need for extended resections is
limited. Similarly, all noninvasive methods to determine the nodal status (N) are
valuable, but mediastinoscopy has a greater sensitivity and specificity than
either CT or MRI. The role of routine organ screening for the detection of
distant occult metastasis in the asymptomatic patient is still controversial.
Ultimately, the prognosis of the resected patient with lung cancer is based on
complete intraoperative staging, which can be done by either systematic node
sampling or complete lymphadenectomy. At present, neither of these techniques has
been shown to improve the quality of staging or survival.
PMID- 10777463
TI - Surgical therapy of early non-small cell lung cancer.
AB - Approximately 45% of all lung carcinomas are limited to the chest, where surgical
resection is not only an important therapeutic modality, but in many cases, the
most effective method of controlling the disease. Patients with T1N0 and T2N0
tumors have early lung cancer, and most are curable by resection, with 5-year
survival rates in the range of 75 to 80% for patients with T1N0 status. Patients
with smaller tumors do better than patients with larger ones, while visceral
pleural invasion does not seem to influence survival. Histologic type is also a
significant prognostic variable, with squamous tumors having a better prognosis
than tumors of nonsquamous histology. Other known prognostic factors are age and
gender of the patient and completeness of resection. The "gold standard" of
surgery remains lobectomy, regardless of tumor size at presentation. Stage T1N1
and T2N1 carcinomas represent a group of patients where the disease involves
hilar and bronchopulmonary nodes. This group is best treated by complete
resection with mediastinal lymphadenectomy. Tumor size and histology are
significant prognostic variables, and 5-year survival after complete resection is
in the range of 40 to 50%. Postoperative radiation therapy may improve local
control, while chemotherapy results in a slightly reduced risk of death.
PMID- 10777464
TI - Postoperative adjuvant therapy for patients with resected non-small cell lung
cancer: still controversial after all these years.
AB - Patients with clinical stage I and II non-small cell lung cancer (NSCLC)
generally are considered candidates for surgical resection, with cure rates as
high as 80% reported for some subsets. Locoregional and systemic adjuvant
therapies have been evaluated in patients with lymph node involvement or
pathologic T3 status, although considerable controversy regarding an appropriate
standard of care continues to exist. Several trials have evaluated postoperative
radiation therapy, the majority of which suggest that overall survival may be
only minimally improved with this adjuvant therapy, but local failure is probably
reduced. Trials evaluating the role of adjuvant chemotherapy have been few, often
enrolling small numbers of patients. Several recent reviews summarizing the
results of these trials suggest that, although some adjuvant chemotherapy
regimens may have biological activity, results have not been consistent, and
further study is warranted for regimens that include newer chemotherapy agents.
CNS relapse is one of the most common sites of metastasis in NSCLC, and
prophylactic cranial irradiation (PCI) has been evaluated in a number of trials
to reduce the risk of local failure at this site. Data from these trials strongly
suggest that a prospective trial of PCI in patients with NSCLC at high risk for
isolated CNS relapse is warranted. Future clinical trials evaluating new
radiographic, immunologic, and molecular technologies for early detection of
second primary tumors also should be considered, particularly in patients with
resected T1N0M0 lesions.
PMID- 10777465
TI - Adjuvant and neoadjuvant chemotherapy for non-small cell lung cancer: a time for
reassessment?
AB - Surgical resection has limited success in curing non-small cell lung cancer
(NSCLC), particularly among patients with locally advanced disease (stage IIIA).
Combined modality regimens, utilizing surgery, radiotherapy, and chemotherapy,
have improved response rates, although they have not been shown to significantly
impact survival among patients with completely resected stage I and II NSCLC.
Future improvements in NSCLC therapy, currently under investigation, are likely
to come from newer agents shown to be active in this disease and from alternative
schedules, such as neoadjuvant or concurrent combined modality treatments.
Neoadjuvant cisplatin-based chemotherapy has already been shown to increase cure
rates in stage IIIA NSCLC, from 10 to 15% to 25 to 30%. Newer active agents, such
as paclitaxel, vinorelbine, and gemcitabine, may be able to advance the cure rate
even further. Radiotherapy, which has been shown to decrease the rate of local
recurrence, may play a role as well.
PMID- 10777466
TI - Locally advanced, unresectable non-small cell lung cancer: new treatment
strategies.
AB - Approximately 40% of non-small cell lung cancer (NSCLC) patients present with
locally advanced, unresectable lesions. Treatment with thoracic radiotherapy
yields survivals averaging just 9 to 10 months, and long-term survival at 5 years
is poor. Recent studies indicate that chemotherapy followed by thoracic
radiotherapy improves 5-year survival by three- to fourfold. Nevertheless, most
patients do ultimately die of the underlying disease. New strategies designed to
enhance local tumor control-use of radiation-sensitizing drugs, three-dimensional
treatment planning techniques, or altered radiation fractionation schedules-may
further improve survival outcome. In addition, newer cisplatin-based regimens
containing either paclitaxel or vinorelbine improve survival over that achieved
with older vinca alkaloid or podophyllotoxin combination regimens. Accordingly,
the newer drug regimens combined with radiotherapy can be expected to further
improve survival in this subset of NSCLC patients. Prospective studies are
underway to test this conjecture.
PMID- 10777467
TI - Combined modality therapy for unresectable stage III non-small cell lung cancer:
new chemotherapy combinations.
AB - Over the last decade, we have witnessed improved outcome among patients with non
small cell lung cancer (NSCLC), principally through the use of new and novel
treatment programs. A meta-analysis of randomized clinical trials comparing
combined chemotherapy and radiation to radiation therapy alone clearly has shown
a survival benefit with platinum-based combination chemotherapy administered
sequentially or concurrently with thoracic radiation therapy over radiation
therapy alone. In addition, combining thoracic radiation therapy with novel drugs
or new drug combinations has yielded improvements in median survival duration and
long-term survival rates in locally advanced unresectable NSCLC. Paclitaxel and
carboplatin are two novel agents that have undergone extensive clinical
evaluation at various doses and schedules in combination with thoracic radiation
therapy in patients with locally advanced disease. There remains a need, however,
for further improvement in metastatic control and prevention of locoregional
recurrences. This will likely be achieved through the optimization of
chemotherapy regimens to be used in combined modality therapy with thoracic
radiation therapy.
PMID- 10777468
TI - Evolution of cisplatin-based chemotherapy in non-small cell lung cancer: a
historical perspective and the eastern cooperative oncology group experience.
AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death
in most industrialized nations, including the United States. Frequently, patients
with unresectable disease are treated with symptomatic care alone or, in the case
of locally advanced, unresectable lesions, with radiotherapy alone. In general,
chemotherapy is viewed as ineffective, and therefore rarely recommended except by
medical oncologists. Over the past 2 decades, however, it has become clear that
chemotherapy, and in particular cisplatin-based chemotherapy, provides a modest
survival advantage. In addition, recent studies indicate that chemotherapy can
improve tumor-related symptoms and quality of life. With modern chemotherapy,
median survival averages around 9 to 10 months in advanced NSCLC, a figure
comparable to that achieved with treatment of extensive-stage small cell lung
cancer, a malignancy generally viewed as chemotherapy sensitive. Importantly,
existing data indicate that chemotherapy is also cost-effective. Given these
observations, it is appropriate today for patients with advanced NSCLC to receive
chemotherapy.
PMID- 10777469
TI - New combinations in the treatment of lung cancer: a time for optimism.
AB - Strides have been made in the treatment of lung cancer in the last decade that
warrant a more optimistic outlook toward the disease. The recent development of
several new agents with single-agent activity, including paclitaxel, docetaxel,
vinorelbine, gemcitabine, and irinotecan, is important, and those agents offer
even greater potential when they are used in combination chemotherapy regimens or
in combined-modality programs. The experience to date with therapy results with
these agents in the treatment of lung cancer is reviewed and is compared to
results documented with the current standard treatments for lung cancer, namely,
cisplatin and cisplatin-based combination regimens. Published and ongoing trials
are outlined, and directions for future research and the future goals of lung
cancer therapy are outlined. The availability of newer chemotherapeutic agents
that are active in lung cancer has led to response rates as high as 40% in the
treatment of non-small cell lung cancer. These drugs have been shown to be active
in combination drug regimens as well as when combined with radiotherapy. Future
research will focus on using these agents in two- and three-drug regimens as
radiation sensitizers and in combination programs with new drugs and biological
agents with apparent activity against this disease.
PMID- 10777470
TI - Paclitaxel and docetaxel combinations in non-small cell lung cancer.
AB - Paclitaxel, the first of the taxanes, has exhibited unique and encouraging single
agent activity in the treatment of non-small cell lung cancer (NSCLC). Yet, with
single-agent response rates approaching 25%, it was logical to examine the impact
of paclitaxel in combination chemotherapy regimens. In trials evaluating the
activity of paclitaxel in combination with one of the platinum compounds,
cisplatin or carboplatin, response rates have ranged from 35 to > 50% and were
significantly better than response rates observed with etoposide/cisplatin, the
previous standard regimen for treatment of NSCLC. Docetaxel is a newer taxane
that also has exhibited notable single-agent activity and response rates ranging
from 20 to 50% when combined with cisplatin. Future research will look to refine
the use of taxane combinations in NSCLC and to examine the potential of these
unique and promising drugs when combined with newer agents that are active
against this disease.
PMID- 10777471
TI - Paclitaxel in advanced non-small cell lung cancer : an alternative high-dose
weekly schedule.
AB - STUDY OBJECTIVES: Sequential phase I and phase II trials of paclitaxel using an
extended weekly schedule were performed to explore its effect on tolerance,
limits of dose intensity, and activity at maximum dose intensity in disseminated
non-small cell lung cancer (NSCLC). DESIGN: Patients with stage IIIB/IV NSCLC
were eligible if they had a performance status of 0 to 2, no previous
chemotherapy, and normal organ function. Paclitaxel was administered as a 3-h
infusion weekly for 6 weeks of an 8-week cycle. Doses were modified for toxicity
observed on the day of treatment. MEASUREMENTS AND RESULTS: Paclitaxel, 100 to
200 mg/m(2)/wk, was administered in the phase I trial. Dose escalation was
limited primarily by neutropenia, and a relationship between dose and response
was noted. A phase II trial of paclitaxel, 175 mg/m(2)/wk, the maximum tolerated
dose, was initiated; data are available for the first 25 patients. Eighty-three,
75, 58, and 50% of intended doses were delivered during cycles one to four,
respectively. Grade 2 or 3 neuropathy occurred in nine patients, but improved in
all following dose reduction. Platelet counts rose by 17,000/microL/wk. Partial
responses occurred in 14 of 25 patients (56%; confidence interval, 46 to 66%).
The duration of response was 6 months, and 1-and 2-year survival rates were 53%
and 18%, respectively. CONCLUSION: Paclitaxel administered on a weekly schedule
allows enhanced dose intensity, has a protective or stimulatory effect on
platelets, and is active in NSCLC.
PMID- 10777472
TI - New chemotherapy agents for small cell lung cancer.
AB - BACKGROUND: Approximately 45,000 new cases of small cell lung cancer (SCLC) will
be diagnosed in the United States this year. Combination chemotherapy is the
cornerstone of treatment for all stages of this disease and results in high
response rates (65 to 85%), leading to a meaningful survival advantage for these
patients. Patients with limited-stage disease enjoy a median survival of 10 to 15
months with chemotherapy, as compared to 3 months without drug therapy. With
addition of chest radiotherapy, survival is further prolonged to 12 to 20 months.
Patients with extensive-stage disease experience an average survival of 1.5
months without chemotherapy and 7 to 11 months with chemotherapy. However, no
further improvement in survival has been demonstrated since combination
chemotherapy regimens were introduced in the late 1970s and early 1980s, despite
evaluating numerous strategies; the 5-year survival for all patients remains
dismal at 5%. Clearly, new chemotherapy agents with novel mechanisms of action
are needed. FOCUS: This article will review the experience to date with six new
agents that are active against SCLC. It includes two taxanes (paclitaxel and
docetaxel), vinorelbine, two camptothecin derivatives (topotecan and irinotecan),
and gemcitabine. Single-agent activity as well as combination regimens with other
agents and radiotherapy will be discussed. The role of maintenance therapy with
oral matrix metalloproteinase inhibitors also is evaluated.
PMID- 10777473
TI - New therapeutic strategies for lung cancer: biology and molecular biology come of
age.
AB - The current understanding of the biology and molecular biology of lung cancer
pathogenesis and progression is reviewed. Awareness of the influence of growth
factors, oncogenes, and tumor suppressor genes as well as signal transduction and
angiogenesis pathways on the natural history of cancer cells has led to attempts
to develop new therapeutic strategies directed at interrupting tumor cell growth.
Treatments utilizing monoclonal antibodies, matrix metalloproteinase inhibitors,
and gene transfer and alteration are currently being investigated. The rationale
and effectiveness of these treatments in early trials are explored, and
recommendations for future directions in cell biology research are presented.
Interest in the biology and molecular biology of tumor cells has led to some
important findings that may provide opportunities for new treatments. Several of
these new directions for anticancer therapy are already being examined in phase I
clinical trials.
PMID- 10777474
TI - New developments in smoking cessation.
AB - Research on smoking has increased in the past several years, and many new
therapeutic modalities have been developed. Primary intervention for smoking
cessation begins with systematic identification of smokers and a formal diagnosis
of nicotine dependence. Providing self-help brochures without clinical advice has
marginal efficacy, but these can be useful as an adjunct to clinician
intervention. Several large studies have shown that physician advice alone can
lead to quit rates of up to 10%, and follow-up for patients trying to quit can
double cessation rates. Behavioral therapy alone has demonstrated cessation rates
of approximately 20% for those willing to participate. Drug therapy remains the
most attractive method of smoking cessation for many patients. The standard
approach has been nicotine substitution using one of the four forms of nicotine
replacement (gum, patches, nasal spray, inhaler) currently available. The
efficacy of nicotine replacement products is similar, with each agent providing a
doubling of the cessation rate. Thus, the choice of agent depends on patient
factors and preference. Bupropion is the first nonnicotine-containing agent
approved for smoking cessation, with cessation rates ranging from 10.5 to 24.4%,
depending on dose. One-year follow-up suggests a continued benefit with this
agent. The combination of bupropion and transdermal nicotine has also been shown
to be effective for smoking cessation in clinical trials. Effective approaches to
smoking cessation should combine identification of smokers, provision of advice
at each visit, and widespread availability of treatment.
PMID- 10777475
TI - Activated ADP-ribosylation factor assembles distinct pools of actin on golgi
membranes.
AB - The small GTP-binding protein ADP-ribosylation factor (ARF) has been shown to
regulate the interaction of actin and actin-binding proteins with the Golgi
apparatus. Here we report that ARF activation stimulates the assembly of distinct
pools of actin on Golgi membranes. One pool of actin cofractionates with coatomer
(COPI)- coated vesicles and is sensitive to salt extraction and the plus end
actin-binding toxin cytochalasin D. A second ARF-dependent actin pool remains on
the Golgi membranes following vesicle extraction and is insensitive to
cytochalasin D. Isolation of the salt-extractable ARF-dependent actin from the
Golgi reveals that it is bound to a distinct repertoire of actin-binding
proteins. The two abundant actin-binding proteins of the ARF-dependent actin
complex are identified as spectrin and drebrin. We show that drebrin is a
specific component of the cytochalasin D-sensitive, ARF-dependent actin pool on
the Golgi. Finally, we show that depolymerization of this actin pool with
cytochalasin D increases the extent of the salt-dependent release of COPI-coated
vesicles from the Golgi following cell-free budding reactions. Together these
data suggest that regulation of the actin-based cytoskeleton may play an
important role during ARF-mediated transport vesicle assembly or release on the
Golgi.
PMID- 10777476
TI - Mechanism of reaction of myeloperoxidase with nitrite.
AB - Myeloperoxidase (MPO) is a major neutrophil protein and may be involved in the
nitration of tyrosine residues observed in a wide range of inflammatory diseases
that involve neutrophils and macrophage activation. In order to clarify if
nitrite could be a physiological substrate of myeloperoxidase, we investigated
the reactions of the ferric enzyme and its redox intermediates, compound I and
compound II, with nitrite under pre-steady state conditions by using sequential
mixing stopped-flow analysis in the pH range 4-8. At 15 degrees C the rate of
formation of the low spin MPO-nitrite complex is (2.5 +/- 0.2) x 10(4) m(-1) s(
1) at pH 7 and (2.2 +/- 0.7) x 10(6) m(-1) s(-1) at pH 5. The dissociation
constant of nitrite bound to the native enzyme is 2.3 +/- 0.1 mm at pH 7 and 31.3
+/- 0.5 micrometer at pH 5. Nitrite is oxidized by two one-electron steps in the
MPO peroxidase cycle. The second-order rate constant of reduction of compound I
to compound II at 15 degrees C is (2.0 +/- 0.2) x 10(6) m(-1) s(-1) at pH 7 and
(1.1 +/- 0.2) x 10(7) m(-1) s(-1) at pH 5. The rate constant of reduction of
compound II to the ferric native enzyme at 15 degrees C is (5.5 +/- 0.1) x 10(2)
m(-1) s(-1) at pH 7 and (8.9 +/- 1.6) x 10(4) m(-1) s(-1) at pH 5. pH dependence
studies suggest that both complex formation between the ferric enzyme and nitrite
and nitrite oxidation by compounds I and II are controlled by a residue with a
pK(a) of (4.3 +/- 0.3). Protonation of this group (which is most likely the
distal histidine) is necessary for optimum nitrite binding and oxidation.
PMID- 10777477
TI - Histone deacetylases specifically down-regulate p53-dependent gene activation.
AB - p53, the most commonly mutated gene in cancer cells, directs cell cycle arrest or
induces programmed cell death (apoptosis) in response to stress. It has been
demonstrated that p53 activity is up-regulated in part by posttranslational
acetylation. In agreement with these observations, here we show that mammalian
histone deacetylase (HDAC)-1, -2, and -3 are all capable of down-regulating p53
function. Down-regulation of p53 activity by HDACs is HDAC dosage-dependent,
requires the deacetylase activity of HDACs, and depends on the region of p53 that
is acetylated by p300/CREB-binding protein (CBP). These results suggest that
interactions of p53 and HDACs likely result in p53 deacetylation, thereby
reducing its transcriptional activity. In support of this idea, GST pull-down and
immunoprecipitation assays show that p53 interacts with HDAC1 both in vitro and
in vivo. Furthermore, a pre-acetylated p53 peptide was significantly deacetylated
by immunoprecipitated wild type HDAC1 but not deacetylase mutant. Also, co
expression of HDAC1 greatly reduced the in vivo acetylation level of p53.
Finally, we report that the activation potential of p53 on the BAX promoter, a
natural p53-responsive system, is reduced in the presence of HDACs. Taken
together, our findings indicate that deacetylation of p53 by histone deacetylases
is likely to be part of the mechanisms that control the physiological activity of
p53.
PMID- 10777478
TI - Endogenous c-N-Ras provides a steady-state anti-apoptotic signal.
AB - We report that c-N-Ras possesses an isoform-specific, functional role in cell
survival under steady-state conditions. This function includes protection from
programmed cell death by serum deprivation or upon treatment with apoptosis
inducing agents. The data demonstrate that c-N-Ras may play a functional role in
the regulation of steady-state phosphorylated Akt and serine 136-phosphorylated
Bad (Ser(136)-pBad). Immortalized N-Ras knockout fibroblasts possess nearly
undetectable levels of steady-state Ser(136)-pBad. In contrast, wild-type control
cells and the N-Ras knockout cells ectopically expressing c-N-Ras at control
levels maintained easily detectable levels of Ser(136)-pBad both at steady-state
and following treatment with tumor necrosis factor alpha. Similar results were
seen with Ser(112)-pBad. These differences did not arise from differences in
total Bad protein levels. These data correlate with the observation that the N
Ras knockout cells exhibit a heightened susceptibility to the induction of
apoptosis. Ectopic expression of c-N-Ras in the N-Ras knockout cells at
endogenous levels, compared with control cells, significantly rescues the
apoptotically sensitive phenotype. Elevated expression of either c-Kirsten A-Ras
or c-Kirsten B-Ras did not reverse the apoptotic sensitivity of the N-Ras
knockout cells or result in increased levels of either phospho-Akt or phospho
Bad. Our results indicate that, at steady state, c-N-Ras possesses an isoform
specific, functional role in cell survival.
PMID- 10777479
TI - Truncation of a mammalian myosin I results in loss of Ca2+-sensitive motility.
AB - MYR-1, a mammalian class I myosin, consisting of a heavy chain and 4-6 associated
calmodulins, is represented by the 130-kDa myosin I (or MI(130)) from rat liver.
MI(130) translocates actin filaments in vitro in a Ca(2+)-regulated manner. A
decrease in motility observed at higher Ca(2+) concentrations has been attributed
to calmodulin dissociation. To investigate mammalian myosin I regulation, we have
coexpressed in baculovirus calmodulin and an epitope-tagged 85-kDa fragment
representing the amino-terminal catalytic "motor" domain and the first calmodulin
binding IQ domain of rat myr-1; we refer to this truncated molecule here as
MI(1IQ). Association of calmodulin to MI(1IQ) is Ca(2+)-insensitive. MI(1IQ)
translocates actin filaments in vitro at a rate resembling MI(130), but unlike
MI(130), does not exhibit sensitivity to 0.1-100 micrometer Ca(2+). In addition
to demonstrating successful expression of a functional truncated mammalian myosin
I in vitro, these results indicate that: 1) Ca(2+)-induced calmodulin
dissociation from MI(130) in the presence of actin is not from the first IQ
domain, 2) velocity is not affected by the length of the IQ region, and 3) the
Ca(2+) sensitivity of actin translocation exhibited by MI(130) involves 1 or more
of the other 5 IQ domains and/or the carboxyl tail.
PMID- 10777480
TI - Elucidation of binding determinants and functional consequences of Ras/Raf
cysteine-rich domain interactions.
AB - Raf-1 is a critical downstream target of Ras and contains two distinct domains
that bind Ras. The first Ras-binding site (RBS1) in Raf-1 has been shown to be
essential for Ras-mediated translocation of Raf-1 to the plasma membrane, whereas
the second site, in the Raf-1 cysteine-rich domain (Raf-CRD), has been implicated
in regulating Raf kinase activity. While recognition elements that promote
Ras.RBS1 complex formation have been characterized, relatively little is known
about Ras/Raf-CRD interactions. In this study, we have characterized interactions
important for Ras binding to the Raf-CRD. Reconciling conflicting reports, we
found that these interactions are essentially independent of the guanine
nucleotide bound state, but instead, are enhanced by post-translational
modification of Ras. Specifically, our findings indicate that Ras farnesylation
is sufficient for stable association of Ras with the Raf-CRD. Furthermore, we
have also identified a Raf-CRD variant that is impaired specifically in its
interactions with Ras. NMR data also suggests that residues proximal to this
mutation site on the Raf-CRD form contacts with Ras. This Raf-CRD mutant impairs
the ability of Ras to activate Raf kinase, thereby providing additional support
that Ras interactions with the Raf-CRD are important for Ras-mediated activation
of Raf-1.
PMID- 10777481
TI - Autophosphorylation of type I phosphatidylinositol phosphate kinase regulates its
lipid kinase activity.
AB - Phosphatidylinositol phosphate kinases (PIPKs) have important roles in the
production of various phosphoinositides. For type I PIP5Ks (PIP5KI), a broad
substrate specificity is known. They phosphorylate phosphatidylinositol 4
phosphate most effectively but also phosphorylate phosphatidylinositol (PI),
phosphatidylinositol 3-phosphate, and phosphatidylinositol (3,4)-bisphosphate
(PI(3, 4)P(2)), resulting in the production of phosphatidylinositol (4, 5)
bisphosphate (PI(4,5)P(2)), phosphatidylinositol 3-phosphate,
phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P(2)), phosphatidylinositol (3,5)
bisphosphate (PI(3,5)P(2)), and phosphatidylinositol (3,4,5)-trisphosphate. We
show here that PIP5KIs have also protein kinase activities. When each isozyme of
PIP5KI (PIP5KIalpha, -beta, and -gamma) was subjected to in vitro kinase assay,
autophosphorylation occurred. The lipid kinase-negative mutant of PIP5KIalpha
(K138A) lost the protein kinase activity, suggesting the same catalytic mechanism
for the lipid and the protein kinase activities. PIP5KIbeta expressed in
Escherichia coli also retains this protein kinase activity, thus confirming that
no co-immunoprecipitated protein kinase is involved. In addition, the
autophosphorylation of PIP5KI is markedly enhanced by the addition of PI. No
other phosphoinositides such as phosphatidylinositol phosphate,
phosphatidylinositol bisphosphate, or phosphatidylinositol trisphosphate have
such an effect. We also found that the PI-dependent autophosphorylation strongly
suppresses the lipid kinase activity of PIP5KI. The lipid kinase activity of
PIP5KI was decreased to one-tenth upon PI-dependent autophosphorylation. All
these results indicate that the lipid kinase activity of PIP5KI that acts
predominantly for PI(4,5)P(2) synthesis is regulated by PI-dependent
autophosphorylation in vivo.
PMID- 10777482
TI - Calcineurin Co-regulates contractile and metabolic components of slow muscle
phenotype.
AB - Activation of the transcription factor nuclear factor of activated T cells by the
calcium-sensitive serine/threonine phosphatase calcineurin has been proposed as
one of the molecular mechanisms by which motor nerve activity establishes the
slow muscle phenotype. To investigate whether the calcineurin pathway can
regulate the large spectrum of slow muscle characteristics in vivo, we treated
rats for three weeks with cyclosporin A (an inhibitor of calcineurin). In soleus
(slow muscle), but not in plantaris (fast muscle), the proportion of slow myosin
heavy chain (MHC-1) and slow sarcoplasmic reticulum ATPase (SERCA2a) was
decreased, whereas that of fast MHC (MHC-2A) and fast SERCA1 increased,
indicating a slow to fast contractile phenotype transition. Cytosolic isoforms of
creatine kinase and lactate dehydrogenase (most abundant in fast fibers), as well
as mitochondrial creatine kinase and citrate synthase activities (elevated in
fast/oxidative fibers) were dose dependently increased by cyclosporin A treatment
in soleus muscle, with no change in plantaris. Calcineurin catalytic subunit was
more abundant in soleus muscle fibers compared with plantaris. Taken together
these results suggest that the calcineurin pathway co-regulates a set of
multigenic protein families involved in the transition between slow oxidative
(type I) to fast oxidative (type IIa) phenotype in soleus muscle.
PMID- 10777483
TI - Phosphorylation and regulation of a Gq/11-coupled receptor by casein kinase
1alpha.
AB - Agonist-mediated receptor phosphorylation by one or more of the members of the G
protein receptor kinase (GRK) family is an established model for G-protein
coupled receptor (GPCR) phosphorylation resulting in receptor desensitization.
Our recent studies have, however, suggested that an alternative route to GPCR
phosphorylation may be an operation involving casein kinase 1alpha (CK1alpha). In
the current study we investigate the involvement of CK1alpha in the
phosphorylation of the human m3-muscarinic receptor in intact cells. We show that
expression of a catalytically inactive mutant of CK1alpha, designed to act in a
dominant negative manner, inhibits agonist-mediated receptor phosphorylation by
approximately 40% in COS-7 and HEK-293 cells. Furthermore, we present evidence
that a peptide corresponding to the third intracellular loop of the m3-muscarinic
receptor (Ser(345)-Leu(463)) is an inhibitor of CK1alpha due to its ability to
both act as a pseudo-substrate for CK1alpha and form a high affinity complex with
CK1alpha. Expression of this peptide was able to reduce both basal and agonist
mediated m3-muscarinic receptor phosphorylation in intact cells. These results
support the notion that CK1alpha is able to mediate GPCR phosphorylation in an
agonist-dependent manner and that this may provide a novel mechanism for GPCR
phosphorylation. The functional role of phosphorylation was investigated using a
mutant of the m3-muscarinic receptor that showed an approximately 80% reduction
in agonist-mediated phosphorylation. Surprisingly, this mutant underwent agonist
mediated desensitization suggesting that, unlike many GPCRs, desensitization of
the m3-muscarinic receptor is not mediated by receptor phosphorylation. The
inositol (1,4, 5)-trisphosphate response did, however, appear to be dramatically
potentiated in the phosphorylation-deficient mutant indicating that
phosphorylation may instead control the magnitude of the initial inositol
phosphate response.
PMID- 10777484
TI - Nitric oxide inhibits the tumor necrosis factor alpha -regulated endocytosis of
human dendritic cells in a cyclic GMP-dependent way.
AB - Tumor necrosis factor-alpha (TNFalpha)-induced maturation of dendritic cells
(DC), with down-regulation of their endocytic ability, has been reported to be
mediated by the accumulation of the lipid messenger ceramide. We have now studied
the effects and mechanisms of action of NO on endocytosis, investigated with
fluorescein isothiocyanate-labeled dextran using human monocyte-derived DC, both
immature and after treatment with TNFalpha. Exposure of DC to NO, released by
either bystander phagocytes or NO donors, reversed the inhibition of endocytosis
induced by TNFalpha. The intracellular accumulation of ceramide induced by
TNFalpha was also inhibited by NO. In addition, NO was found to exert an
inhibitory effect downstream of the TNFalpha-triggered ceramide accumulation,
because NO donors reversed the inhibition of endocytosis induced by the cell
permeant C(2)-ceramide. These effects of NO were mimicked by the membrane
permeant cyclic GMP analogue, 8-Br cyclic GMP, and prevented by inhibition of the
soluble guanylyl cyclase. At variance with rodents, the inducible isoform of the
NO synthase was expressed neither in immature human DC nor after cell treatment
with TNFalpha, interferon-gamma, and lipopolysaccharide, suggesting that
regulation of these cells depends on exogenous NO. NO, working through cyclic
GMP, might therefore prolong the ability of human DC to internalize antigens at
the site of inflammation and thus modulate the initial steps leading to antigen
specific immune responses.
PMID- 10777485
TI - Transport properties of a system y+L neutral and basic amino acid transporter.
Insights into the mechanisms of substrate recognition.
AB - The properties of system y(+)L-mediated transport were investigated on rat system
y(+)L transporter, ry(+)LAT1, coexpressed with the heavy chain of cell surface
antigen 4F2 in Xenopus oocytes. ry(+)LAT1-mediated transport of basic amino acids
was Na(+)-independent, whereas that of neutral amino acids, although not
completely, was dependent on Na(+), as is typical of system y(+)L-mediated
transport. In the absence of Na(+), lowering of pH increased leucine transport,
without affecting lysine transport. Therefore, it is proposed that H(+), besides
Na(+) and Li(+), is capable of supporting neutral amino acid transport. Na(+) and
H(+) augmented leucine transport by decreasing the apparent K(m) values, without
affecting the V(max) values. We demonstrate that although ry(+)LAT1-mediated
transport of [(14)C]l-leucine was accompanied by the cotransport of (22)Na(+),
that of [(14)C]l-lysine was not. The Na(+) to leucine coupling ratio was
determined to be 1:1 in the presence of high concentrations of Na(+). ry(+)LAT1
mediated leucine transport, but not lysine transport, induced intracellular
acidification in Chinese hamster ovary cells coexpressing ry(+)LAT1 and 4F2 heavy
chain in the absence of Na(+), but not in the presence of physiological
concentrations of Na(+), indicating that cotransport of H(+) with leucine
occurred in the absence of Na(+). Therefore, for the substrate recognition by
ry(+)LAT1, the positive charge on basic amino acid side chains or that conferred
by inorganic monovalent cations such as Na(+) and H(+), which are cotransported
with neutral amino acids, is presumed to be required. We further demonstrate that
ry(+)LAT1, due to its peculiar cation dependence, mediates a heteroexchange,
wherein the influx of substrate amino acids is accompanied by the efflux of basic
amino acids.
PMID- 10777486
TI - Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin
by iron deficiency.
AB - A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested
by its ferroxidase activity and by the tissue iron overload in hereditary Cp
deficiency patients. In addition, plasma Cp increases markedly in several
conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle
cell disease, pregnancy, and inflammation. However, little is known about the
cellular and molecular mechanism(s) involved. We have reported that iron
chelators increase Cp mRNA expression and protein synthesis in human
hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp
mRNA is due to increased rate of transcription. We here report the results of new
studies designed to elucidate the molecular mechanism underlying transcriptional
activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was
cloned from a human genomic library. A 4774-base pair segment of the Cp
promoter/enhancer driving a luciferase reporter was transfected into HepG2 or
Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10
fold compared with untreated cells. Examination of the sequence showed three
pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation
analysis showed that a single HRE was necessary and sufficient for gene
activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by
gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding
to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore,
iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4
hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of
a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to
bind the Cp HRE in nuclear extracts from these cells. These results are
consistent with in vivo findings that iron deficiency increases plasma Cp and
provides a molecular mechanism that may help to understand these observations.
PMID- 10777487
TI - Isoforms of kalirin, a neuronal Dbl family member, generated through use of
different 5'- and 3'-ends along with an internal translational initiation site.
AB - Kalirin is a neuron-specific GDP/GTP exchange factor for Rho subfamily GTP
binding proteins. The major Kalirin transcripts in adult rat brain were
identified. Most include a Sec14p-like putative lipid-binding motif followed by
nine spectrin-like repeats and a Dbl homology/pleckstrin homology (DH-PH) domain.
Kalirin proteins with four different NH(2) termini are generated through the use
of five different 5'-ends; three of the proteins differ only at the extreme NH(2)
terminus, and one is truncated because translation is initiated at a methionine
in the 5th spectrin repeat. Four different 3'-ends yield Kalirin proteins with
additional functional domains. Kalirin-7 (7-kilobase pair mRNA) terminates with a
PDZ-binding motif, which in Kalirin-8 is replaced by an SH3 domain. Kalirin-9
contains another pair of DH-PH and SH3 domains. Kalirin-12 additionally encodes a
putative Ser/Thr protein kinase. Antisera specific for different COOH termini
established Kalirin-7 as the most abundant in cortex, with significant amounts of
Kalirin-9 and Kalirin-12; Kalirin-7 was less prevalent in cerebellum and
olfactory bulb. Kalirin proteins lacking the Sec14p-like domain and first four
spectrin-like repeats were much less prevalent. Form-specific antisera
demonstrated that different forms of Kalirin were localized to distinct
subcellular regions of cultured neurons. Members of the family of Kalirin
proteins may subserve different functions at these different locations.
PMID- 10777488
TI - Insulin and insulin-like growth factor-I induce vascular endothelial growth
factor mRNA expression via different signaling pathways.
AB - In this study we have investigated the molecular mechanisms of insulin and
insulin-like growth factor-I (IGF-I) action on vascular endothelial growth factor
(VEGF) gene expression. Treatment with insulin or IGF-I for 4 h increased the
abundance of VEGF mRNA in NIH3T3 fibroblasts expressing either the human insulin
receptor (NIH-IR) or the human IGF-I receptor (NIH-IGFR) by 6- and 8-fold,
respectively. The same elevated levels of mRNA were maintained after 24 h of
stimulation with insulin, whereas IGF-I treatment further increased VEGF mRNA
expression to 12-fold after 24 h. Pre-incubation with the phosphatidylinositol 3
kinase inhibitor wortmannin abolished the effect of insulin on VEGF mRNA
expression in NIH-IR cells but did not modify the IGF-I-induced VEGF mRNA
expression in NIH-IGFR cells. Blocking mitogen-activated protein kinase
activation with the MEK inhibitor PD98059 abolished the effect of IGF-I on VEGF
mRNA expression in NIH-IGFR cells but had no effect on insulin-induced VEGF mRNA
expression in NIH-IR cells. Expression of a constitutively active PKB in NIH-IR
cells induced the expression of VEGF mRNA, which was not further modified by
insulin treatment. We conclude that VEGF induction by insulin and IGF-I occurs
via different signaling pathways, the former involving phosphatidylinositol 3
kinase/protein kinase B and the latter involving MEK/mitogen-activated protein
kinase.
PMID- 10777489
TI - Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one
associated with extracellular signal-regulated kinase activation and the other
with G2/M accumulation or protein phosphatase 1/2A inhibition.
AB - Protein kinase C activators and microtubule-damaging drugs stimulate BCL2
phosphorylation, which has been associated with either enhancement or inhibition
of cell viability. In a Burkitt lymphoma cell line, both types of agents likewise
stimulated phosphorylation of myeloid cell leukemia 1 (MCL1), another viability
promoting BCL2 family member. However, while MCL1 phosphorylation induced by the
protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), did not
affect its electrophoretic mobility, microtubule-damaging agents, such as taxol,
induced MCL1 phosphorylation associated with a band shift to decreased mobility.
Inhibitors of extracellular signal-regulated kinase (ERK) activation blocked TPA
induced MCL1 phosphorylation but not the taxol-induced band shift. TPA-induced
MCL1 phosphorylation occurred rapidly and was not associated with decreased
viability, while the taxol-induced band shift occurred upon extended exposure as
cells accumulated in G(2)/M followed by cell death. Protein phosphatase 1/2A
inhibitors also induced the MCL1 band shift/phosphorylation. Thus, MCL1 undergoes
two distinct types of phosphorylation: (i) TPA-induced, ERK-associated
phosphorylation, which does not alter the electrophoretic mobility of MCL1, and
(ii) ERK-independent phosphorylation, which results in an MCL1 band shift and is
induced by events in G(2)/M or protein phosphatase 1/2A inhibitors.
PMID- 10777490
TI - Human damage-specific DNA-binding protein p48. Characterization of XPE mutations
and regulation following UV irradiation.
AB - Damage-specific DNA binding (DDB) activity purifies from HeLa cells as a
heterodimer (p127 and p48) and is absent from cells of a subset (Ddb(-)) of
xeroderma pigmentosum Group E (XPE) patients. Each subunit was overexpressed in
insect cells and purified. Both must be present for the damaged DNA band shift
characteristic of the HeLa heterodimer. However, overexpressed p48 peptides
containing the mutations found in three Ddb(-) XPE strains are inactive, and wild
type p48 restores DDB activity to extracts from a fourth XPE Ddb(-) strain,
GM01389, in which compound heterozygous mutations in DDB2 (p48) lead to a L350P
change from one allele and a Asn-349 deletion from the other. Although these
results indicate that these mutations are each responsible for the loss of DDB
activity, they do not affect nuclear localization of p48. In normal fibroblasts,
a 4-fold increase in p48 mRNA amount was observed 38 h after UV irradiation,
preceding a similar elevation in p48 protein and DDB activity at 48 h, implying
that p48 limits DDB activity in vivo. Because DNA repair is virtually complete
before 48 h, a role for DDB other than DNA repair is suggested.
PMID- 10777491
TI - Nuclear transport of human DDB protein induced by ultraviolet light.
AB - Human damage-specific DNA-binding (DDB) protein can be purified as a heterodimer
(p48 and p127) that binds to DNA damaged by ultraviolet light. We report here the
effects of UV irradiation on the cellular localization of each DDB subunit as a
function of time using green fluorescent fusion proteins in three diploid
fibroblast strains: repair-proficient IMR-90 and two repair-deficient xeroderma
pigmentosum group E strains (XP95TO and XP3RO). Although p48 remained in the
nucleus after UV irradiation, a dynamic nuclear accumulation of p127 from the
cytoplasm was found after 24 h. In IMR-90 cells, the nuclear localization of p127
corresponded to the up-regulation of p48 mRNA and protein levels and of DDB
activity. XP3RO cells showed delayed but similar kinetics with less transport,
whereas XP95TO cells appeared to have different kinetics, suggesting that these
cells exhibit different defects in p127 translocation. We propose that p48 might
act as the transporter for nuclear entry of p127 but that a third factor might be
necessary for efficient transportation.
PMID- 10777492
TI - Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3.
AB - We studied the regulation of three closely related members of Ras family G
proteins, R-Ras, TC21 (also known as R-Ras2), and M-Ras (R-Ras3). Guanine
nucleotide exchange of R-Ras and TC21 was promoted by RasGRF, C3G, CalDAG-GEFI,
CalDAG-GEFII (RasGRP), and CalDAG-GEFIII both in 293T cells and in vitro. By
contrast, guanine nucleotide exchange of M-Ras was promoted by the guanine
nucleotide exchange factors (GEFs) for the classical Ras (Ha-, K-, and N-),
including mSos, RasGRF, CalDAG-GEFII, and CalDAG-GEFIII. GTPase-activating
proteins (GAPs) for Ras, Gap1(m), p120 GAP, and NF-1 stimulated all of the R-Ras,
TC21, and M-Ras proteins, whereas R-Ras GAP stimulated R-Ras and TC21 but not M
Ras. We did not find any remarkable difference in the subcellular localization of
R-Ras, TC21, or M-Ras when these were expressed with a green fluorescent protein
tag in 293T cells and MDCK cells. In conclusion, TC21 and R-Ras were regulated by
the same GEFs and GAPs, whereas M-Ras was regulated as the classical Ras.
PMID- 10777493
TI - A novel 3-methyladenine DNA glycosylase from Helicobacter pylori defines a new
class within the endonuclease III family of base excision repair glycosylases.
AB - The cloning, purification, and characterization of MagIII, a 3-methyladenine DNA
glycosylase from Helicobacter pylori, is presented in this paper. Sequence
analysis of the genome of this pathogen failed to identify open reading frames
potentially coding for proteins with a 3-methyladenine DNA glycosylase activity.
The putative product of the HP602 open reading frame, reported as an endonuclease
III, shares extensive amino acid sequence homology with some bacterial members of
this family and has the canonic active site helix-hairpin-helix-GPD motif.
Surprisingly, this predicted H. pylori endonuclease III encodes a 25,220-Da
protein able to release 3-methyladenine, but not oxidized bases, from modified
DNA. MagIII has no abasic site lyase activity and displays the substrate
specificity of the 3-methyladenine-DNA glycosylase type I of Escherichia coli
(Tag) because it is not able to recognize 7-methylguanine or hypoxanthine as
substrates. The expression of the magIII open reading frame in null 3
methyladenine glycosylase E. coli (tag alkA) restores to this mutant partial
resistance to alkylating agents. MagIII-deficient H. pylori cells show an
alkylation-sensitive phenotype. H. pylori wild type cells exposed to alkylating
agents present an adaptive response by inducing the expression of magIII. MagIII
is thus a novel bacterial member of the endonuclease III family, which displays
biochemical properties not described for any of the members of this group until
now.
PMID- 10777494
TI - Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs.
AB - Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide
exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated
by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. A third
member of the family, Repac (GFR), which lacks the cAMP dependent regulatory
sequences, is a constitutive activator of both Rap1 and Rap2. In contrast to
Epac1, Epac2 contains a second cAMP binding domain at the N terminus, as does the
Epac homologue from Caenorhabditis elegans. Affinity measurements show that this
distal cAMP binding domain (the A-site) binds cAMP with much lower affinity than
the cAMP binding domain proximal to the catalytic domain (the B-site), which is
present in both Epac1 and Epac2. Deletion mutant analysis shows that the high
affinity cAMP binding domains are sufficient to regulate the GEFs in vitro.
Interestingly, isolated fragments containing the B-sites of either Epac1 or
Epac2, but not the A-site from Epac2, inhibit the catalytic domains in trans.
This inhibition is relieved by the addition of cAMP. In addition to the cAMP
binding domains, both Epac1 and Epac2 have a DEP domain. Deletion of this domain
does not affect regulation of Epac1 activity but affects membrane localization.
From these results, we conclude that all three members of the Epac family
regulate both Rap1 and Rap2. Furthermore, we conclude that the catalytic activity
of Epac1 is constrained by a direct interaction between GEF and high affinity
cAMP binding domains in the absence of cAMP. Epac1 becomes activated by a release
of this inhibition when cAMP is bound.
PMID- 10777495
TI - Aquaporin adipose, a putative glycerol channel in adipocytes.
AB - Adipose tissue is a major site of glycerol production in response to energy
balance. However, molecular basis of glycerol release from adipocytes has not yet
been elucidated. We recently cloned a novel member of the aquaporin family,
aquaporin adipose (AQPap), which has glycerol permeability. The current study was
designed to examine the hypothesis that AQPap serves as a glycerol channel in
adipocytes. Adipose tissue expressed AQPap mRNA in high abundance, but not the
mRNAs for the other aquaglyceroporins, AQP3 and AQP9, indicating that AQPap is
the only known aquaglyceroporin expressed in adipose tissue. Glycerol release
from 3T3-L1 cells was increased during differentiation in parallel with AQPap
mRNA levels and suppressed by mercury ion, which inhibits the function of AQPs,
supporting AQPap functions as a glycerol channel in adipocytes. Fasting increased
and refeeding suppressed adipose AQPap mRNA levels in accordance with plasma
glycerol levels and oppositely to plasma insulin levels in mice. Insulin dose
dependently suppressed AQPap mRNA expression in 3T3-L1 cells. AQPap mRNA levels
and adipose glycerol concentrations measured by the microdialysis technique were
increased in obese mice with insulin resistance. Accordingly, negative regulation
of AQPap expression by insulin was impaired in the insulin-resistant state.
Exposure of epinephrine translocated AQPap protein from perinuclear cytoplasm to
the plasma membrane in 3T3-L1 adipocytes. These results strongly suggest that
AQPap plays an important role in glycerol release from adipocytes.
PMID- 10777496
TI - Interaction of two classes of ADP-ribose transfer reactions in immune signaling.
AB - CD38 is a bifunctional ectoenzyme predominantly expressed on hematopoietic cells
where its expression correlates with differentiation and proliferation. The two
enzyme activities displayed by CD38 are an ADP-ribosyl cyclase and a cyclic
adenosine diphosphate ribose (cADPR) hydrolase that catalyzes the synthesis and
hydrolysis of cADPR. T lymphocytes can be induced to express CD38 when activated
with antibodies against specific antigen receptors. If the activated T cells are
then exposed with NAD, cell death by apoptosis occurs. During the exposure of
activated T cells to NAD, the CD38 is modified by ecto-mono-ADP
ribosyltransferases (ecto-mono-ADPRTs) specific for cysteine and arginine
residues. Arginine-ADP-ribosylation results in inactivation of both cyclase and
hydrolase activities of CD38, whereas cysteine-ADP-ribosylation results only in
the inhibition of the hydrolase activity. The arginine-ADP-ribosylation causes a
decrease in intracellular cADPR and a subsequent decrease in Ca(2+) influx,
resulting in apoptosis of the activated T cells. Our results suggest that the
interaction of two classes of ecto-ADP-ribose transfer enzymes plays an important
role in immune regulation by the selective induction of apoptosis in activated T
cells and that cADPR mediated signaling is essential for the survival of
activated T cells.
PMID- 10777497
TI - Psr1p/Psr2p, two plasma membrane phosphatases with an essential DXDX(T/V) motif
required for sodium stress response in yeast.
AB - Regulation of intracellular ion concentration is an essential function of all
cells. In this study, we report the identification of two previously
uncharacterized genes, PSR1 and PSR2, that perform an essential function under
conditions of sodium ion stress in the yeast Saccharomyces cerevisiae. Psr1p and
Psr2p are highly homologous and were identified through their homology with the
endoplasmic reticulum membrane protein Nem1p. Localization and biochemical
fractionation studies show that Psr1p is associated with the plasma membrane via
a short amino-terminal sequence also present in Psr2p. Growth of the psr1psr2
mutant is severely inhibited under conditions of sodium but not potassium ion or
sorbitol stress. This growth defect is due to the inability of the psr1psr2
mutant to properly induce transcription of ENA1/PMR2, the major sodium extrusion
pump of yeast cells. We provide genetic evidence that this regulation is
independent of the phosphatase calcineurin, previously implicated in the sodium
stress response in yeast. We show that Psr1p contains a DXDX(T/V) phosphatase
motif essential for its function in vivo and that a Psr1p-PtA fusion purified
from yeast extracts exhibits phosphatase activity. Based on these data, we
suggest that Psr1p/Psr2p, members of an emerging class of eukaryotic
phosphatases, are novel regulators of salt stress response in yeast.
PMID- 10777499
TI - DE1, a 12-base pair cis-regulatory element sufficient to confer dark-inducible
and light down-regulated expression to a minimal promoter in pea.
AB - We found a cis-regulatory element of 12 base pairs (bp) (GGATTTTACAGT) capable of
conferring light responsiveness to a minimal promoter, CaMV 35S46, in pea. The 12
bp sequence is located in the 5' upstream region of the light down-regulated gene
pra2, which encodes a small GTPase belonging to the YPT/rab family. Here we
examined gain-of-function analyses using synthetic promoter-luciferase constructs
in a transient assay and found that the 12-bp element alone was sufficient to
confer dark induction, as well as light down-regulation on the minimal promoter.
We named this dark inducible element DE1. Effects of various light conditions on
the reporter gene activity showed that DE1 received signals from phytochrome A,
phytochrome B, and blue light photoreceptors. Using phytochrome-deficient
mutants, we showed that the pra2 protein level in seedlings was also regulated by
these photoreceptors. The changes in the immunoblotting pattern of the pra2
protein in these mutants were correlated with the changes in epicotyl elongation.
Results from transient assays using these mutants showed that the DE1 received
signals from phytochromes A and B, demonstrating that this element is indeed a
light-responsive element. To our knowledge, this is the first cis-element that by
itself confers light responsiveness to a minimal promoter.
PMID- 10777498
TI - Interaction of murine BiP/GRP78 with the DnaJ homologue MTJ1.
AB - The activity of Hsp70 proteins is regulated by accessory proteins, among which
the most studied are the members of the DnaJ-like protein family. BiP/GRP78
chaperones the translocation and maturation of secreted and membrane proteins in
the endoplasmic reticulum. No DnaJ-like partner has been described so far to
regulate the function of mammalian BiP/GRP78. We show here that murine BiP/GRP78
interacts with the lumenal J domain of the murine transmembrane protein MTJ1 (J
MTJ1). J-MTJ1 stimulates the ATPase activity of BiP/GRP78 at stoichiometric
concentrations. The C-terminal tail of BiP/GRP78 is not required for the
interaction with J-MTJ1, leaving the function of this portion of the molecule
still unclear. Physical interactions between J-MTJ1 and BiP/GRP78 are stable and
can be abolished by a single histidine --> glutamine substitution in the highly
conserved HPD motif shared by all DnaJ-like proteins. The J-MTJ1 fragment, but
not the mutant J-MTJ1:H89Q fragment, stimulates the ATPase activity of
Escherichia coli DnaK, although at a higher concentration than its genuine
partner DnaJ. Full-length DnaJ does not stimulate BiP over the range of
concentrations investigated. These results indicate that the J domain of MTJ1 is
sufficient for its interaction with BiP/GRP78 and cannot be substituted by E.
coli DnaJ.
PMID- 10777500
TI - Distinct Ca2+ binding properties of novel C2 domains of plant phospholipase
dalpha and beta.
AB - Of the isoforms of plant phospholipase D (PLD) that have been cloned and
characterized, PLDalpha requires millimolar levels of Ca(2+) for optimal
activity, whereas PLDbeta is most active at micromolar concentrations of Ca(2+).
Multiple amino acid sequence alignments suggest that PLDalpha and PLDbeta both
contain a Ca(2+)-dependent phospholipid-binding C2 domain near their N termini.
In the present study, we expressed and characterized the putative C2 domains of
PLDalpha and PLDbeta, designated PLDalpha C2 and PLDbeta C2, by CD spectroscopy,
isothermal titration calorimetry, and phospholipid binding assay. Both PLD C2
domains displayed CD spectra consistent with anticipated major beta-sheet
structures but underwent spectral changes upon binding Ca(2+); the magnitude was
larger for PLDbeta C2. These conformational changes, not shown by any of the
previously characterized C2 domains of animal origin, occurred at micromolar
Ca(2+) concentrations for PLDbeta C2 but at millimolar levels of the cation for
PLDalpha C2. PLDbeta C2 exhibited three Ca(2+)-binding sites: one with a
dissociation constant (K(d)) of 0.8 microm and the other two with a K(d) of 24
micrometer. In contrast, isothermal titration calorimetry data of PLDalpha C2
were consistent with 1-3 low affinity Ca(2+)-binding sites with K(d) in the range
of 590-470 micrometer. The thermodynamics of Ca(2+) binding markedly differed for
the two C2 domains. Likewise, PLDbeta C2 bound phosphatidylcholine (PC), the
substrate of PLD, in the presence of submillimolar Ca(2+) concentrations, whereas
PLDalpha C2 did so only in the presence of millimolar levels of the metal ion.
Both C2 domains bound phosphatidylinoistol 4,5-bisphosphate, a regulator of PC
hydrolysis by PLD. However, added Ca(2+) displaced the bound phosphatidylinoistol
4,5-bisphosphate. Ca(2+) and PC binding properties of PLDalpha C2 and PLDbeta C2
follow a trend similar to the Ca(2+) requirements of the whole enzymes, PLDalpha
and PLDbeta, for PC hydrolysis. Taken together, the results suggest that the C2
domains of PLDalpha and PLDbeta have novel structural features and serve as
handles by which Ca(2+) differentially regulates the activities of the isoforms.
PMID- 10777501
TI - Uracil-DNA glycosylase in the extreme thermophile Archaeoglobus fulgidus.
AB - Uracil-DNA glycosylase (UDG) is an essential enzyme for maintaining genomic
integrity. Here we describe a UDG from the extreme thermophile Archaeoglobus
fulgidus. The enzyme is a member of a new class of enzymes found in prokaryotes
that is distinct from the UDG enzyme found in Escherichia coli, eukaryotes, and
DNA-containing viruses. The A. fulgidus UDG is extremely thermostable,
maintaining full activity after heating for 1.5 h at 95 degrees C. The protein is
capable of removing uracil from double-stranded DNA containing either a U/A or
U/G base pair as well as from single-stranded DNA. This enzyme is product
inhibited by both uracil and apurinic/apyrimidinic sites. The A. fulgidus UDG has
a high degree of similarity at the primary amino acid sequence level to the
enzyme found in Thermotoga maritima, a thermophilic eubacteria, and suggests a
conserved mechanism of UDG-initiated base excision repair in archaea and
thermophilic eubacteria.
PMID- 10777502
TI - Recruitment of nuclear receptor corepressor and coactivator to the retinoic acid
receptor by retinoid ligands. Influence of DNA-heterodimer interactions.
AB - Ligand activation of retinoic acid receptors (RARs) involves coordinated changes
in their interaction with coregulatory molecules. Binding of the agonist all
trans-retinoic acid to the RAR results in increased interaction with coactivator
molecules as well as a decreased interaction with corepressor molecules. Thus, an
all-trans-retinoic acid antagonist might function either by preventing agonist
induction of such events or, additionally, by actively increasing repression via
corepressor recruitment. We demonstrate that the repression of the
transcriptional activity of a constitutively active RARgamma-VP-16 chimeric
receptor by the inverse agonist AGN193109 requires a functional Co-R box and that
binding of this ligand to RARgamma leads to an increased interaction with the
corepressor N-CoR both in glutathione S-transferase pull-down and yeast two
hybrid analyses. Detection of nuclear receptor corepressor (N-CoR) association
with RARgamma was greatly facilitated by inclusion of a RARE oligonucleotide in
coimmunoprecipitation analyses, a result of an increase in association of the
ternary complex consisting of RAR, RXR, and DNA. Similarly, this DNA-dependent
increase in heterodimer formation likewise resulted in an increase in agonist
mediated recruitment efficiency of the coactivator SRC-1. Under conditions which
favor ternary complex formation, a RAR neutral antagonist is distinguished from
an inverse agonist with respect to corepressor recruitment as is a RAR partial
agonist distinguished from an agonist with respect to coactivator recruitment.
These results indicate that it is possible to design RAR ligands with distinct
recruitment capabilities for coregulators, both coactivators as well as
corepressors. In addition, using this recruitment assay, we show that SRC-1 and
the related coactivator molecule ACTR associate with the ternary complex via
utilization of different helical motifs within their conserved receptor
interaction domains.
PMID- 10777503
TI - Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous
xanthomatosis in mice with congenital hyperlipidemia.
AB - Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular
cholesterol. To investigate the role of ACAT-1 in atherosclerosis, we have
generated ACAT-1 null (ACAT-1-/-) mice. ACAT activities were present in the liver
and intestine but were completely absent in adrenal, testes, ovaries, and
peritoneal macrophages in our ACAT-1-/- mice. The ACAT-1-/- mice had decreased
openings of the eyes because of atrophy of the meibomian glands, a modified form
of sebaceous glands normally expressing high ACAT activities. This phenotype is
similar to dry eye syndrome in humans. To determine the role of ACAT-1 in
atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein
(apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models
susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous
xanthomatosis with loss of hair in both ACAT-1-/-:apo E-/- and ACAT-1-/-:LDLR-/-
mice. Free cholesterol content was significantly increased in their skin. Aortic
fatty streak lesion size as well as cholesteryl ester content were moderately
reduced in both double mutant mice compared with their respective controls. These
results indicate that the local inhibition of ACAT activity in tissue macrophages
is protective against cholesteryl ester accumulation but causes cutaneous
xanthomatosis in mice that lack apo E or LDLR.
PMID- 10777504
TI - Selective interaction of complexin with the neuronal SNARE complex. Determination
of the binding regions.
AB - Complexins are evolutionarily conserved proteins that specifically bind to
soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)
complexes and thus may regulate SNARE function. Using purified proteins, we have
performed a detailed analysis of the structure of complexin and of its
interaction with SNARE proteins. NMR spectroscopy revealed that isolated
complexins have no tertiary structure but contain an unusual alpha-helical middle
domain of approximately 58 amino acids that overlaps with the most highly
conserved region of the molecules. Complexins form a stable stoichiometric
complex with the central domain of the ternary SNARE complex, whereas no binding
was observed to monomeric SNAREs. Using a combination of limited proteolysis,
deletion mutagenesis, and NMR spectroscopy, we found that the helical middle
region of complexin is responsible for binding to the SNARE complex. Binding was
highly sensitive to substitution of syntaxin 1 or synaptobrevin 2 with other
SNARE homologs but less sensitive to substitution of SNAP-25. In addition, a
stretch of 12 amino acids in the middle of the SNARE motif of syntaxin 1A was
able to confer binding activity to the non-binding relative syntaxin 4.
Furthermore, disassembly of ternary complexes is not affected by complexins. We
conclude that complexins are specific ligands of the neuronal core complex that
bind with a central alpha-helical domain, probably to the middle of the surface
groove formed by synaptobrevin and syntaxin. Complexins may regulate the function
of ternary complexes and control membrane fusion through this interaction.
PMID- 10777505
TI - Lipid phosphorylation in chloroplast envelopes. Evidence for galactolipid CTP
dependent kinase activities.
AB - Lipid phosphorylation takes place within the chloroplast envelope. In addition to
phosphatidic acid, phosphatidylinositol phosphate, and their corresponding lyso
derivatives, we found that two novel lipids underwent phosphorylation in
envelopes, particularly in the presence of carrier-free [gamma-(32)P]ATP. These
two lipids incorporated radioactive phosphate in chloroplasts in the presence of
[gamma-(32)P]ATP or [(32)P]P(i) and light. Interestingly, these two lipids were
preferentially phosphorylated in envelope membranes in the presence [gamma
(32)P]CTP, as the phosphoryl donor, or [gamma-(32)P]ATP, when supplemented with
CDP and nucleoside diphosphate kinase II. The lipid kinase activity involved in
this reaction was specifically inhibited in the presence of cytosine 5'-O
(thiotriphosphate) (CTPgammaS) and sensitive to CTP chase, thereby showing that
both lipids are phosphorylated by an envelope CTP-dependent lipid kinase. The
lipids were identified as phosphorylated galactolipids by using an acid
hydrolysis procedure that generated galactose 6-phosphate. CTPgammaS did not
affect the import of the small ribulose-bisphosphate carboxylase/oxygenase
subunit into chloroplasts, the possible physiological role of this novel CTP
dependent galactolipid kinase activity in the chloroplast envelope is discussed.
PMID- 10777506
TI - Switching agonist/antagonist properties of opiate alkaloids at the delta opioid
receptor using mutations based on the structure of the orphanin FQ receptor.
AB - In an earlier study, we have demonstrated that by mutating five amino acid
residues to those conserved in the opioid receptors, the OFQ receptor could be
converted to a functional receptor that bound many opioid alkaloids with
nanomolar affinities. Surprisingly, when the reciprocal mutations, Lys-214 -->
Ala (TM5), Ile-277 --> Val/His-278 --> Gln/Ile-279 --> Val (TM6), and Ile-304 -->
Thr (TM7), are introduced in the delta receptor, neither the individual mutations
nor their various combinations significantly reduce the binding affinities of
opioid alkaloids tested. However, these mutations cause profound alterations in
the functional characteristics of the mutant receptors as measured in guanosine
5'-3-O-(thio)triphosphate binding assays. Some agonists become antagonists at
some constructs as they lose their ability to activate them. Some alkaloid
antagonists are transformed into agonists at other constructs, but their
agonistic effects can still be blocked by the peptide antagonist TIPP. Even the
delta inverse agonist 7-benzylidenenaltrexone becomes an agonist at the mutant
containing both the Ile-277 --> Val/His-278 --> Gln/Ile-279 --> Val and Ile-304 -
> Thr mutations. Thus, although the mutated residues are thought to be part of
the binding pocket, they are critically involved in the control of the delta
receptor activation process. These findings shed light on some of the structural
bases of ligand efficacy. They are also compatible with the hypothesis that a
ligand may achieve high affinity binding in several different ways, each having
different effects on receptor activation.
PMID- 10777507
TI - The role of arachidonic acid in steroidogenesis and steroidogenic acute
regulatory (StAR) gene and protein expression.
AB - This study was conducted to examine the mechanism for arachidonic acid (AA)
regulation of steroidogenic acute regulatory (StAR) protein expression and the
relationship between AA and cAMP in hormone-induced steroidogenesis. Dibutyryl
cyclic AMP (Bt(2)cAMP)-stimulated MA-10 Leydig cells were treated with AA and/or
the phospholipase A(2) inhibitor, dexamethasone. Dexamethasone significantly
reduced Bt(2)cAMP-stimulated progesterone production, StAR promoter activity,
StAR mRNA, and StAR protein. The inhibitory effects of dexamethasone were
reversed by the addition of 150 microm AA to MA-10 cells. In addition, MA-10
cells were treated with the lipoxygenase inhibitor, nordihydroguaiaretic acid
(NDGA), the 5-lipoxygenase inhibitor, AA861, the epoxygenase inhibitor,
miconazole, and the cyclooxygenase inhibitor, indomethacin. Both NDGA and AA861
inhibited progesterone production and StAR protein expression. AA861-inhibited
progesterone synthesis and StAR protein were partially reversed by addition of
the 5- lipoxygenase metabolite, 5(S)-hydroperoxy-(6E,8Z,11Z, 14Z)
eicosatetraenoic acid. Inhibition of epoxygenase activity inhibited progesterone
production significantly, but StAR protein was only slightly reduced.
Indomethacin enhanced StAR protein expression and significantly increased
progesterone production. Inhibition of AA release or lipoxygenase activities did
not affect protein kinase A activity, whereas inhibition of protein kinase A
activity using H89 reduced Bt(2)cAMP-induced StAR protein. AA alone did not
induce StAR protein expression nor steroid production. These results demonstrate
the essential role of AA in steroid biosynthesis and StAR gene transcription and
suggest the possible involvement of the lipoxygenase pathway in steroidogenesis.
This study further indicates that AA and cAMP transduce signals from trophic
hormone receptors to the nucleus through two separate pathways and act to co
regulate steroid production and StAR gene expression and indicates that both
pathways are required for trophic hormone-stimulated steroidogenesis.
PMID- 10777508
TI - p300/CBP-associated factor histone acetyltransferase processing of a peptide
substrate. Kinetic analysis of the catalytic mechanism.
AB - p300/CBP-associated factor (PCAF) is a histone acetyltransferase that plays an
important role in the remodeling of chromatin and the regulation of gene
expression. It has been shown to catalyze preferentially acetylation of the
epsilon-amino group of lysine 14 in histone H3. In this study, the kinetic
mechanism of PCAF was evaluated with a 20-amino acid peptide substrate derived
from the amino terminus of histone H3 (H3-20) and recombinant bacterially
expressed PCAF catalytic domain (PCAF(cat)). The enzymologic behavior of full
length PCAF and PCAF(cat) were shown to be similar. PCAF-catalyzed acetylation of
the substrate H3-20 was shown to be specific for Lys-14, analogous to its
behavior with the full-length histone H3 protein. Two-substrate kinetic analysis
displayed an intersecting line pattern, consistent with a ternary complex
mechanism for PCAF. The dead-end inhibitor analog desulfo-CoA was competitive
versus acetyl-CoA and noncompetitive versus H3-20. The dead-end analog inhibitor
H3-20 K14A was competitive versus H3-20 and uncompetitive versus acetyl-CoA. The
potent bisubstrate analog inhibitor H3-CoA-20 was competitive versus acetyl-CoA
and noncompetitive versus H3-20. Taken together, these inhibition patterns
support an ordered BiBi kinetic mechanism for PCAF in which acetyl-CoA binding
precedes H3-20 binding. Viscosity experiments suggest that diffusional release of
product is not rate-determining for PCAF catalysis. These results provide a
mechanistic framework for understanding the detailed catalytic behavior of an
important subset of the histone acetyltransferases and have significant
implications for molecular regulation of and inhibitor design for these enzymes.
PMID- 10777509
TI - Nuclear mitogen-activated protein kinase activation by protein kinase czeta
during reoxygenation after ischemic hypoxia.
AB - We examined the upstream kinases for mitogen-activated protein kinase (MAPK)
activation during ischemic hypoxia and reoxygenation using H9c2 cells derived
from rat cardiomyocytes. Protein kinase C (PKC)zeta, an atypical PKC isoform
mainly expressed in rat heart, has been shown to act as an upstream kinase of
MAPK during ischemic hypoxia and reoxygenation by analyses with PKC inhibitors,
antisense DNA, a dominant negative kinase defective mutant, and constitutively
active mutants of PKCzeta. Immunocytochemical observations show PKCzeta staining
in the nucleus during ischemic hypoxia and reoxygenation when phosphorylated MAPK
is also detected in the nucleus. This nuclear localization of PKCzeta is
inhibited by treatment with wortmannin, a phosphoinositide 3-kinase inhibitor
that also inhibits MAPK activation in a dose-dependent manner. This is supported
by the inhibition of MAPK phosphorylation by another blocker of phosphoinositide
3-kinase, LY294002. An upstream kinase of MAPK, MEK1/2, is significantly
phosphorylated 15 min after reoxygenation and observed mainly in the nucleus,
whereas it is present in the cytoplasm in serum stimulation. The phosphorylation
of MEK is blocked by PKC inhibitors and phosphoinositide 3-kinase inhibitors, as
observed in the case of MAPK phosphorylation. These observations indicate that
PKCzeta, which is activated by phosphoinositide 3-kinase, induces MAPK activation
through MEK in the nucleus during reoxygenation after ischemic hypoxia.
PMID- 10777510
TI - Molecular and functional characteristics of APJ. Tissue distribution of mRNA and
interaction with the endogenous ligand apelin.
AB - We have recently identified apelin as the endogenous ligand for human APJ. In
rats, the highest expression of APJ mRNA was detected in the lung, suggesting
that APJ and its ligand play an important role in the pulmonary system. When
apelin-36 and its pyroglutamylated C-terminal peptide, [ Ala, Asn(10) --> Ala or Gln, Leu(11) --> Arg,
Gly(12) --> Ala, His(14) --> Trp) enhanced activity 2-10-fold. These effects were
additive, as [Ala(3),(10,12),Arg(11), Trp(14)] rPTH(1-14)NH(2) was 220-fold more
potent than rPTH(1-14)NH(2) (EC(50) = 0.6 +/- 0.1 and 133 +/- 16 micrometer,
respectively). Native rPTH(1-11) was inactive, but [Ala(3,10), Arg(11)]rPTH(1
11)NH(2) achieved maximal cAMP stimulation (EC(50) = 17 micrometer). The modified
PTH fragments induced cAMP formation with hP1R-delNt in COS-7 cells as potently
as they did with hP1R-WT; PTH(1-34) was 6,000-fold weaker with hP1R-delNt than
with hP1R-WT. The most potent analog, [Ala(3,10,12),Arg(11), Trp(14)]rPTH(1
14)NH(2), stimulated inositol phosphate production with hP1R-WT. The results show
that short NH(2)-terminal peptides of PTH can be optimized for considerable gains
in signaling potency through modification of interactions involving the regions
of the receptor containing the transmembrane domains and extracellular loops.
PMID- 10777514
TI - Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial
membrane potential and reduced mitochondrial function.
AB - Cardiolipin (CL) is a unique phospholipid which is present throughout the
eukaryotic kingdom and is localized in mitochondrial membranes. Saccharomyces
cerevisiae cells containing a disruption of CRD1, the structural gene encoding CL
synthase, have no CL in mitochondrial membranes. To elucidate the physiological
role of CL, we compared mitochondrial functions in the crd1Delta mutant and
isogenic wild type. The crd1Delta mutant loses viability at elevated temperature,
and prolonged culture at 37 degrees C leads to loss of the mitochondrial genome.
Mutant membranes have increased phosphatidylglycerol (PG) when grown in a
nonfermentable carbon source but have almost no detectable PG in medium
containing glucose. In glucose-grown cells, maximum respiratory rate, ATPase and
cytochrome oxidase activities, and protein import are deficient in the mutant.
The ADP/ATP carrier is defective even during growth in a nonfermentable carbon
source. The mitochondrial membrane potential is decreased in mutant cells. The
decrease is more pronounced in glucose-grown cells, which lack PG, but is also
apparent in membranes containing PG (i.e. in nonfermentable carbon sources). We
propose that CL is required for maintaining the mitochondrial membrane potential
and that reduced membrane potential in the absence of CL leads to defects in
protein import and other mitochondrial functions.
PMID- 10777516
TI - HighWire press is 5 years old
PMID- 10777515
TI - Platelet-derived growth factor (PDGF) receptor-alpha activates c-Jun NH2-terminal
kinase-1 and antagonizes PDGF receptor-beta -induced phenotypic transformation.
AB - Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells.
The PDGF B-chain (c-sis proto-oncogene) homodimer (PDGF BB) and v-sis, its viral
counterpart, activate both alpha- and beta-receptor subunits (alpha-PDGFR and
beta-PDGFR) and mediate anchorage-independent growth in NIH3T3 cells. In
contrast, the PDGF A chain homodimer (PDGF AA) activates alpha-PDGFR only and
fails to induce phenotypic transformation. In the present study, we investigated
alpha- and beta-PDGFR specific signaling pathways that are responsible for the
differences between the transforming ability of PDGF AA and BB. To study PDGF BB
activation of beta-PDGFR, we established NIH3T3 clones in which alpha-PDGFR
signaling is inhibited by a dominant-negative alpha-PDGFR, or an antisense
construct of alpha-PDGFR. Here, we demonstrate that beta-PDGFR activation alone
is sufficient for PDGF BB-mediated anchorage-independent cell growth. More
importantly, inhibition of alpha-PDGFR signaling enhanced PDGF BB-mediated
phenotypic transformation, suggesting that alpha-PDGFR antagonizes beta-PDGFR
induced transformation. While both alpha- and beta-receptors effectively activate
ERKs, alpha-PDGFR, but not beta-PDGFR, activates stress-activated protein kinase
1/c-Jun NH(2)-terminal kinase-1 (JNK-1). Inhibition of JNK-1 activity using a
dominant-negative JNK-1 mutant markedly enhanced PDGF BB-mediated anchorage
independent cell growth, demonstrating an antagonistic role for JNK-1 in PDGF
induced transformation. Consistently, overexpression of wild-type JNK-1 reduced
PDGF BB-mediated transformation. Taken together, the present study showed that
alpha- and beta-PDGFRs differentially regulate Ras-mitogen-activated protein
kinase pathways critical for regulation of cell transformation, and
transformation suppressing activity of alpha-PDGFR involves JNK-1 activation.
PMID- 10777517
TI - ICln is essential for cellular and early embryonic viability.
AB - pICln is a 26-kDa protein that is ubiquitously expressed and highly conserved
from Xenopus laevis to Homo sapiens. The physiological functions of pICln remain
to be established. To address this question, we disrupted the ICln gene in
embryonic stem cells. We found that murine embryos lacking ICln die early in
gestation (between stages E3.5 and E7.5). Furthermore, we found that ICln is
essential for embryonic stem cell viability. Previously, we showed that pICln
interacts directly with a homolog of a yeast protein that binds a PAK-like kinase
and participates in the regulation of cell morphology and cell cycling. pICln
also forms a complex with several core spliceosomal proteins, and this
interaction may play a role in the regulation of spliceosomal biogenesis.
Collectively, these data strongly suggest that pICln participates in critical
cellular pathways, including regulation of the cell cycle and RNA processing.
PMID- 10777518
TI - Electron paramagnetic resonance evidence for a novel interconversion of [3Fe
4S](+) and [4Fe-4S](+) clusters with endogenous iron and sulfide in anaerobic
ribonucleotide reductase activase in vitro.
AB - We report an EPR study of the iron-sulfur enzyme, anaerobic ribonucleotide
reductase activase from Lactococcus lactis. The activase (nrdG gene) together
with S-adenosyl-L-methionine (AdoMet) give rise to a glycyl radical in the NrdD
component. A semi-reduced [4Fe-4S](+) cluster with an axially symmetric EPR
signal was produced upon photochemical reduction of the activase. Air exposure of
the reduced enzyme gave a [3Fe-4S](+) cluster. The Fe(3)S(4) cluster was
convertible to the EPR-active [4Fe-4S](+) cluster by renewed treatment with
reducing agents, demonstrating a reversible [3Fe-4S](+)- to-[4Fe-4S](+) cluster
conversion without exogenous addition of iron or sulfide. Anaerobic reduction of
the activase by a moderate concentration of dithionite also resulted in a semi
reduced [4Fe-4S](+) cluster. Prolonged reduction gave an EPR-silent fully reduced
state, which was enzymatically inactive. Both reduced states gave the [3Fe-4S](+)
EPR signal after air exposure. The iron-sulfur cluster interconversion was also
studied in the presence of AdoMet. The EPR signal of semi-reduced activase-AdoMet
had rhombic symmetry and was independent of which reductant was applied, whereas
the EPR signal of the [3Fe-4S](+) cluster after air exposure was unchanged. The
results indicate that an AdoMet-mediated [4Fe-4S](+) center is the native active
species that induces the formation of a glycyl radical in the NrdD component.
PMID- 10777519
TI - TFIIA has activator-dependent and core promoter functions in vivo.
AB - The physiological role of TFIIA was investigated by analyzing transcription in a
yeast strain that contains a TATA-binding protein (TBP) mutant (N2-1) defective
for interacting with TFIIA. In cells containing N2-1, transcription from a set of
artificial his3 promoters dependent on different activators is generally reduced
by a similar extent, indicating that TFIIA function is largely nonselective for
activators. In addition, TATA element utilization, a core promoter function, is
altered at his3 promoters dependent on weak activators. Genomic expression
analysis reveals that 3% of the genes are preferentially affected by a factor of
4 or more. Chimeras of affected promoters indicate that the sensitivity to the
TFIIA-TBP interaction can map either to the upstream or core promoter region.
Unlike wild-type TBP or TFIIA, the N2-1 derivative does not activate
transcription when artificially recruited to the promoter via a heterologous DNA
binding domain, indicating that TFIIA is important for transcription even in the
absence of an activation domain. Taken together, these results suggest that TFIIA
plays an important role in both activator-dependent and core promoter functions
in vivo. Further, they suggest that TFIIA function may not be strictly related to
the recruitment of TBP to promoters but may also involve a step after TBP
recruitment.
PMID- 10777520
TI - Isolation and functional expression of human COQ3, a gene encoding a
methyltransferase required for ubiquinone biosynthesis.
AB - The COQ3 gene in Saccharomyces cerevisiae encodes an O-methyltransferase required
for two steps in the biosynthetic pathway of ubiquinone (coenzyme Q, or Q). This
enzyme methylates an early Q intermediate, 3,4-dihydroxy-5-polyprenylbenzoic
acid, as well as the final intermediate in the pathway, converting demethyl-Q to
Q. This enzyme is also capable of methylating the distinct prokaryotic early
intermediate 2-hydroxy-6-polyprenyl phenol. A full-length cDNA encoding the human
homologue of COQ3 was isolated from a human heart cDNA library by sequence
homology to rat Coq3. The clone contained a 933-base pair open reading frame that
encoded a polypeptide with a great deal of sequence identity to a variety of
eukaryotic and prokaryotic Coq3 homologues. In the region between amino acids 89
and 255 in the human sequence, the rat and human homologues are 87% identical,
whereas human and yeast are 35% identical. When expressed in multicopy, the human
construct rescued the growth of a yeast coq3 null mutant on a nonfermentable
carbon source and restored coenzyme Q biosynthesis, although at lower levels than
that of wild type yeast. In vitro methyltransferase assays using farnesylated
analogues of intermediates in the coenzyme Q biosynthetic pathway as substrates
showed that the human enzyme is active with all three substrates tested.
PMID- 10777521
TI - Heat-inactivated proteins managed by DnaKJ-GrpE-ClpB chaperones are released as a
chaperonin-recognizable non-native form.
AB - Chaperones of Thermus thermophilus cooperate in reactivation of heat-inactivated
proteins. The protein, inactivated at a high temperature in a TDnaKJ-GrpE set,
recovered its activity during subsequent incubation with TClpB at moderate
temperature (Motohashi, K., Watanabe, Y., Yohda, M., and Yoshida, M. (1999) Proc.
Natl. Acad. Sci. U. S. A. 96, 7184-7189). Here, we report that the addition of
chaperonin (Tcpn) at moderate temperature improves the yield of the TDnaKJ-GrpE
ClpB-dependent reactivation. The trap-Tcpn, which binds substrate protein but
does not release it, inhibits reactivation severely. Maximum recovery is gained
at sub-stoichiometric amounts of each component of TDnaKJ, TGrpE, and TClpB
relative to the substrate monomer. These observations indicate that, driven by
ATP hydrolysis, TDnaKJ-GrpE-ClpB chaperones catalytically cooperate and release
heat-inactivated protein as a non-native, chaperonin-recognizable folding
intermediate.
PMID- 10777522
TI - Transcription factor S, a cleavage induction factor of the archaeal RNA
polymerase.
AB - We have analyzed the function of an archaeal protein (now called transcription
factor S (TFS)) that shows sequence similarity to eukaryotic transcription factor
IIS (TFIIS) as well as to small subunits of eukaryotic RNA polymerases I (A12.6),
II (B12.2), and III (C11). Western blot analysis with antibodies against
recombinant TFS demonstrated that this protein is not a subunit of the RNA
polymerase. In vitro transcription experiments with paused elongation complexes
at position +25 showed that TFS is able to induce cleavage activity in the
archaeal RNA polymerase in a similar manner to TFIIS. In the presence of TFS, the
cleavage activity of the RNA polymerase truncates the RNA back to position +15 by
releasing mainly dinucleotides from the 3'-end of the nascent RNA. Furthermore,
TFS reduces the amount of non-chaseable elongation complexes at position +25 as
well as position +45. These findings clearly demonstrate that this protein has a
similar function to eukaryotic TFIIS.
PMID- 10777523
TI - Site-directed mutagenesis of 2,4-dichlorophenoxyacetic acid/alpha-ketoglutarate
dioxygenase. Identification of residues involved in metallocenter formation and
substrate binding.
AB - 2,4-dichlorophenoxyacetic acid (2,4-D)/alpha-ketoglutarate (alpha-KG) dioxygenase
(TfdA) is an Fe(II)-dependent enzyme that catalyzes the first step in degradation
of the herbicide 2,4-D. The active site structures of a small number of enzymes
within the alpha-KG-dependent dioxygenase superfamily have been characterized and
shown to have a similar HXDX(50-70)HX(10)RXS arrangement of residues that make up
the binding sites for Fe(II) and alpha-KG. TfdA does not have obvious homology to
the dioxygenases containing the above motif but is related in sequence to eight
other enzymes in the superfamily that form a distinct consensus sequence
(HX(D/E)X(138-207) HX(10)R/K). Variants of TfdA were created to examine the roles
of putative metal-binding residues and the functions of the other seven
histidines in this protein. The H167A, H200A, H213A, H245A, and H262A forms of
TfdA formed inclusion bodies when overproduced in Escherichia coli DH5alpha;
however, these proteins were soluble when fused to the maltose-binding protein
(MBP). MBP-TfdA exhibited kinetic parameters similar to the native enzyme. The
H8A and H235A variants were catalytically similar to wild-type TfdA. MBP-H213A
and H216A TfdA have elevated K(m) values for 2,4-D, and the former showed a
decreased k(cat), suggesting these residues may affect substrate binding or
catalysis. The H113A, D115A, MBP-H167A, MBP-H200A, MBP-H245A and MBP-H262A
variants of TfdA were inactive. Gel filtration analysis revealed that the latter
two proteins were highly aggregated. The remaining four inactive variants were
examined in their Cu(II)-substituted forms by EPR and electron spin-echo envelope
modulation (ESEEM) spectroscopic methods. Changes in EPR spectra upon addition of
substrates indicated that copper was present at the active site in the H113A and
D115A variants. ESEEM analysis revealed that two histidines are bound
equatorially to the copper in the D115A and MBP-H167A TfdA variants. The
experimental data and sequence analysis lead us to conclude that His-113, Asp
115, and His-262 are likely metal ligands in TfdA and that His-213 may aid in
catalysis or binding of 2,4-D.
PMID- 10777524
TI - Inactivation of active thrombin-activable fibrinolysis inhibitor takes place by a
process that involves conformational instability rather than proteolytic
cleavage.
AB - Thrombin-activable fibrinolysis inhibitor (TAFI) is present in the circulation as
an inactive zymogen. Thrombin converts TAFI to a carboxypeptidase B-like enzyme
(TAFIa) by cleaving at Arg(92) in a process accelerated by the cofactor,
thrombomodulin. TAFIa attenuates fibrinolysis. TAFIa can be inactivated by both
proteolysis by thrombin and spontaneous temperature-dependent loss of activity.
The identity of the thrombin cleavage site responsible for loss of TAFIa activity
was suggested to be Arg(330), but site-directed mutagenesis of this residue did
not prevent inactivation of TAFIa by thrombin. In this study we followed TAFI
activation and TAFIa inactivation by thrombin/thrombomodulin in time and
characterized the cleavage pattern of TAFI using matrix-assisted laser desorption
ionization mass spectrometry. Mass matching of the fragments revealed that TAFIa
was cleaved at Arg(302). Studies of a mutant R302Q-TAFI confirmed identification
of this thrombin cleavage site and, furthermore, suggested that inactivation of
TAFIa is based on its conformational instability rather than proteolytic cleavage
at Arg(302).
PMID- 10777525
TI - The requirement of both extracellular regulated kinase and p38 mitogen-activated
protein kinase for stimulation of cytosolic phospholipase A(2) activity by either
FcgammaRIIA or FcgammaRIIIB in human neutrophils. A possible role for Pyk2 but
not for the Grb2-Sos-Shc complex.
AB - The signal transduction pathways initiated by opsonized zymosan (OZ) leading to
activation of cytosolic phospholipase A(2) (cPLA(2)) in human neutrophils remain
obscure. In a previous study, we showed that the activation of cPLA(2) by OZ is
tyrosine kinase-dependent. The present study demonstrates that the signals
initiated by OZ involve activation of tyrosine kinase Pyk2 but not the formation
of the adhesion protein complex, Shc-Grb2-Sos. Stimulation of cPLA(2) activity by
OZ is mediated by Fc gamma receptors (FcgammaRs) and not by complement receptors
for the C3b protein. Cross-linking of FcgammaRIIA or FcgammaRIIIB induces p38
mitogen-activated protein (MAP) kinase and extracellular regulated kinase (ERK)
phosphorylation. The kinetics of cPLA(2) activity stimulated by either of the
FcgammaRs or by both is similar to that of p38 MAP kinase and was detected as
early as 15 s after stimulation, maintained a plateau for 10 min, and decreased
thereafter. ERK activation was detected also within 15 s but decreased
significantly 5 min after stimulation. The MEK inhibitor, PD-098059, or the p38
MAP kinase inhibitor, SB-203580, caused a partial inhibition during the time
course of cPLA(2) activity, whereas their combination caused a total inhibition.
Thus, although ERK activation is significantly shorter than that of p38 MAP
kinase, it is equally required for activation and maintenance of cPLA(2) activity
by occupancy of a single receptor, FcgammaRIIA or FcgammaRIIIB.
PMID- 10777526
TI - Assembly of gamma- with alpha-globin chains to form human fetal hemoglobin in
vitro and in vivo.
AB - Soluble gamma-globin chains were expressed in bacteria and purified to assess the
mechanism of gamma- and alpha-chain assembly to form Hb F. Formation of Hb F in
vitro following incubation of equimolar mixtures of gamma and alpha chains was
about 4 x 10(5)-fold slower than assembly of alpha and beta chains to form Hb A
in vitro. Results of assembly for gamma(116Ile-->His) and gamma(112Thr-->Asp)
chains with alpha chains were similar to that of beta chains, whereas assembly of
gamma(112Thr-->Cys) and alpha chains was similar to wild type gamma chains,
indicating that amino acid differences at alpha1beta1 and alpha1gamma1
interaction sites between gamma116 Ile and beta116 His are responsible for the
different assembly rates in vitro in the formation of Hb F and Hb A. Homoassembly
in vitro of individual gamma chains as assessed by size-exclusion chromatography
shows that gamma and gamma(112Thr-->Cys) chains form stable dimers like alphabeta
and alphagamma that do not dissociate readily into monomers like beta chains. In
contrast, gamma(116Ile-->His) chains form monomers and dimers upon dilution.
These results are consistent with the slower assembly rate in vitro of gamma and
gamma(112Thr-->Cys) with alpha chains, whereas the faster rate of assembly of
gamma(116Ile-->His) and gamma(112Thr-->Asp) chains with alpha chains, like beta
chains, may be caused by dissociation to monomers. These results suggest that
dissociation of gamma(2) dimers to monomers limits formation of Hb F in vitro.
However, yields of soluble Hb F expressed in bacteria were similar to Hb A, and
no unassembled alpha and gamma chains were detected. These results indicate that
gamma chains assemble in vivo with alpha chains prior to forming stable gamma(2)
dimers, possibly binding to alpha chains as partially folded nascent gamma-globin
chains prior to release from polyribosomes.
PMID- 10777527
TI - Steady-state kinetic characterization and crystallization of a polychlorinated
biphenyl-transforming dioxygenase.
AB - The oxygenase component of biphenyl dioxygenase (BPDO) from Comamonas
testosteroni B-356 dihydroxylates biphenyl and some polychlorinated biphenyls
(PCBs), thereby initiating their degradation. Overexpressed, anaerobically
purified BPDO had a specific activity of 4.9 units/mg, and its oxygenase
component appeared to contain a full complement of Fe(2)S(2) center and catalytic
iron. Oxygenase crystals in space group R3 were obtained under anaerobic
conditions using polyethylene glycol as the precipitant. X-ray diffraction was
measured to 1.6 A. Steady-state kinetics assays demonstrated that BPDO had an
apparent k(cat)/K(m) for biphenyl of (1.2 +/- 0.1) x 10(6) M(-1) s(-1) in air
saturated buffer. Moreover, BPDO transformed dichlorobiphenyls (diClBs) in the
following order of apparent specificities: 3,3'- > 2,2'- > 4, 4'-diClB.
Strikingly, the ability of BPDO to utilize O(2) depended strongly on the biphenyl
substrate: k(cat)/K(m(O(2))) = (3.6 +/- 0. 3), (0.06 +/- 0.02), and (0.4 +/-
0.07) x 10(5) M(-1) s(-1) in the presence of biphenyl and 2,2'- and 3,3'-diClBs,
respectively. Moreover, biphenyl/O(2) consumed was 0.97, 0.44, 0.63, and 0.48 in
the presence of biphenyl and 2,2'-, 3,3'-, and 4,4'-diClBs, respectively. Within
experimental error, the balance of consumed O(2) was detected as H(2)O(2). Thus,
PCB congeners such as 2, 2'-diClB exact a high energetic cost, produce a
cytotoxic compound (H(2)O(2)), and can inhibit degradation of other congeners.
Each of these effects would be predicted to inhibit the aerobic microbial
catabolism of PCBs.
PMID- 10777528
TI - Substitution of the heme binding module in hemoglobin alpha- and beta-subunits.
Implication for different regulation mechanisms of the heme proximal structure
between hemoglobin and myoglobin.
AB - In our previous work, we demonstrated that the replacement of the "heme binding
module," a segment from F1 to G5 site, in myoglobin with that of hemoglobin alpha
subunit converted the heme proximal structure of myoglobin into the alpha-subunit
type (Inaba, K., Ishimori, K. and Morishima, I. (1998) J. Mol. Biol. 283, 311
327). To further examine the structural regulation by the heme binding module in
hemoglobin, we synthesized the betaalpha(HBM)-subunit, in which the heme binding
module (HBM) of hemoglobin beta-subunit was replaced by that of hemoglobin alpha
subunit. Based on the gel chromatography, the betaalpha(HBM)-subunit was
preferentially associated with the alpha-subunit to form a heterotetramer,
alpha(2)[betaalpha(HBM)(2)], just as is native beta-subunit. Deoxy
alpha(2)[betaalpha(HBM)(2)] tetramer exhibited the hyperfine-shifted NMR
resonance from the proximal histidyl N(delta)H proton and the resonance Raman
band from the Fe-His vibrational mode at the same positions as native hemoglobin.
Also, NMR spectra of carbonmonoxy and cyanomet alpha(2)[betaalpha(HBM)(2)]
tetramer were quite similar to those of native hemoglobin. Consequently, the heme
environmental structure of the betaalpha(HBM)-subunit in tetrameric
alpha(2)[betaalpha(HBM)(2)] was similar to that of the beta-subunit in native
tetrameric Hb A, and the structural conversion by the module substitution was not
clear in the hemoglobin subunits. The contrastive structural effects of the
module substitution on myoglobin and hemoglobin subunits strongly suggest
different regulation mechanisms of the heme proximal structure between these two
globins. Whereas the heme proximal structure of monomeric myoglobin is simply
determined by the amino acid sequence of the heme binding module, that of
tetrameric hemoglobin appears to be closely coupled to the subunit interactions.
PMID- 10777529
TI - Multiple interactions between receptor protein-tyrosine phosphatase (RPTP) alpha
and membrane-distal protein-tyrosine phosphatase domains of various RPTPs.
AB - Receptor protein-tyrosine phosphatase (RPTP) alpha belongs to the large family of
receptor protein-tyrosine phosphatases containing two tandem phosphatase domains.
Most of the catalytic activity is retained in the first, membrane-proximal domain
(RPTPalpha-D1), and little is known about the function of the second, membrane
distal domain (RPTPalpha-D2). We investigated whether proteins bound to RPTPalpha
using the two-hybrid system and found that the second domain of RPTPsigma
interacted with the juxtamembrane domain of RPTPalpha. We confirmed this
interaction by co-immunoprecipitation experiments. Furthermore, RPTPalpha not
only interacted with RPTPsigma-D2 but also with RPTPalpha-D2, LAR-D2, RPTPdelta
D2, and RPTPmu-D2, members of various RPTP subfamilies, although with different
affinities. In the yeast two-hybrid system and in glutathione S-transferase pull
down assays, we show that the RPTP-D2s interacted directly with the wedge
structure of RPTPalpha-D1 that has been demonstrated to be involved in
inactivation of the RPTPalpha-D1/RPTPalpha-D1 homodimer. The interaction was
specific because the equivalent wedge structure in LAR was unable to interact
with RPTPalpha-D2 or LAR-D2. In vivo, we show that other interaction sites exist
as well, including the C terminus of RPTPalpha-D2. The observation that
RPTPalpha, but not LAR, bound to multiple RPTP-D2s with varying affinities
suggests a specific mechanism of cross-talk between RPTPs that may regulate their
biological function.
PMID- 10777530
TI - Identification of a nuclear respiratory factor-1 binding site within the core
promoter of the human polio virus receptor/CD155 gene.
AB - In this report we describe a cis-acting element within the core promoter of the
CD155 gene specifying the polio virus receptor that is bound by the nuclear
respiratory factor-1 (NRF-1) transcription factor. DNase I footprint analysis
identified a nuclear protein binding site from -282 to -264 nucleotides upstream
of the translation initiation codon of the CD155 gene, which we have called foot
print IV (FPIV). Linker scanning mutagenesis revealed that a tandem repeat motif,
GCGCAGGCGCAG, located within FPIV was essential for the basal activity of the
CD155 core promoter. The results of the electrophoretic mobility shift assay
experiments suggested that identical FPIV binding activities were present in a
variety of nuclear extracts and that the tandem repeat was essential for binding.
A one-hybrid screen was then carried out using FPIV as bait to clone the cDNA of
the FPIV binding factor. The sequences of the cDNAs that were cloned from the
screen were identical to NRF-1, a result that was confirmed by further
electrophoretic mobility shift assay experiments. Overexpression of full-length
NRF-1 and a dominant-negative form of NRF-1 modulated reporter gene expression
driven by the core promoter. Remarkably, CD155 is the first gene shown to be
regulated by NRF-1 that possesses an expression profile during embryogenesis
correlating with this factor's proposed role in the development of the vertebrate
optic system. We propose that NRF-1, which has been shown by others to be
expressed during embryogenesis in animal systems, may be involved in regulating
the expression of CD155 at specific stages of central nervous system development.
PMID- 10777531
TI - Anion-mediated iron release from transferrins. The kinetic and mechanistic model
for N-lobe of ovotransferrin.
AB - Iron release process of ovotransferrin N-lobe (N-oTf) to anion/chelators has been
resolved using kinetic and mechanistic approach. The iron release kinetics of N
oTf were measured at the endosomal pH of 5.6 with three different anions such as
nitrilotriacetate, pyrophosphate, and sulfate using stopped flow
spectrofluorimetric method, all yielding clear biphasic progress curves. The two
observed rate constants and the corresponding amplitudes obtained from the double
exponential curve fit to the biphasic curves varied depending on the type and
concentration of anions. Several possible models for the iron release kinetic
mechanism were examined on the basis of a newly introduced quantitative equation.
Results from the curve fitting analyses were consistent with a dual pathway
mechanism that includes the competitive iron release from two different protein
states, namely, X and Y, with the respective first order rate constants of K(1)
and K(2) (X, domain closed holo N-oTf; Y, anion induced different conformer of
holo N-oTf). The reversible interconversions of X to Y and Y to X are driven by
the second order rate constant k(3) and the first order rate constant K(4),
respectively. The obtained rate constants were greatly variable for the three
anions depending on the synergistic or nonsynergistic nature. In the light of the
anion-binding sites of N-oTf located crystallographically, the compatible
mechanistic model that includes competitive anion binding to the iron
coordination sites and to a specific anion site is suggested for the dual pathway
iron release mechanism.
PMID- 10777532
TI - Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel
transcriptional corepressor molecule of activating protein-1, nuclear factor
kappaB, and serum response factor.
AB - Silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is known
to interact with Sin3 and recruit the histone deacetylases (HDACs) that lead to
hypoacetylation of histones and transrepression of target transcription factors.
Herein, we found that coexpression of SMRT significantly repressed
transactivations by activating protein-1 (AP-1), nuclear factor-kappaB
(NFkappaB), and serum response factor (SRF) in a dose-dependent manner, but not
in the presence of trichostatin A, a specific inhibitor of HDAC. Similarly,
coexpression of HDAC1 and mSin3A also showed repressive effects. Consistent with
these results, the C-terminal region of SMRT directly interacted with SRF, the AP
1 components c-Jun and c-Fos, and the NFkappaB components p50 and p65, as
demonstrated by the yeast and mammalian two hybrid tests as well as the
glutathione S-transferase pull down assays. Thus, we concluded that SMRT serves
to recruit Sin3/HDACs to SRF, NFkappaB, and AP-1 in vivo and modulate their
transactivation.
PMID- 10777533
TI - Des-Arg(10)-kallidin engagement of the B1 receptor stimulates type I collagen
synthesis via stabilization of connective tissue growth factor mRNA.
AB - Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and
fibrotic disorders; however, little is known about its role in fibrogenesis. We
examined human embryonic lung fibroblasts that constitutively express the B1
receptor and report that engagement of the B1 receptor by des-Arg(10)-kallidin
stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in
alpha1(I) collagen mRNA, and stimulated type I collagen production. These events
were not observed in B2 receptor-activated fibroblasts. In addition, B1 receptor
activation by des-Arg(10)-kallidin induced a rise in cytosolic Ca(2+) that is
consistent with B1 receptor pharmacology. Our results show that the des-Arg(10)
kallidin-stimulated increase in alpha1(I) collagen mRNA was time- and dose
dependent, with a peak response observed at 20 h with 100 nM des-Arg(10)
kallidin. The increase in CTGF mRNA was also time- and dose-dependent, with a
peak response observed at 4 h with 100 nM des-Arg(10)-kallidin. The increase in
CTGF mRNA was blocked by the B1 receptor antagonist des-Arg(10),Leu(9)-kallidin.
Inhibition of protein synthesis by cycloheximide did not block the des-Arg(10)
kallidin-induced increase in CTGF mRNA. These results suggest that engagement of
the kinin B1 receptor contributes to fibrogenesis through increased expression of
CTGF.
PMID- 10777534
TI - Characterization and regulation of the 5'-flanking region of the murine
endothelial protein C receptor gene.
AB - The protein C pathway plays a critical role in the negative regulation of blood
coagulation. The nucleotide sequence of the murine endothelial protein C receptor
(mEPCR) gene was determined for 8.8 kilobase pairs of the genomic structure and
3.4 kilobase pairs of the 5'-flanking region. RNase protection assay revealed six
major transcription start sites clustered at -100 to -109 upstream of the
translation initiation site. A series of 5'-promoter deletion fragments were
fused to a luciferase reporter gene and transiently transfected into bovine
aortic endothelium. Deletion of the sequence from -220 to -180 dramatically
reduced luciferase expression in bovine aortic endothelial cells. This region of
the murine endothelial protein C receptor gene contains one AP4 site and one SP1
site. Mutations in the core sequence of the AP4 and SP1 sites impaired both
nuclear protein binding and luciferase expression. These results suggest
important roles for AP4 and SP1 in the constitutive expression of mEPCR. A
thrombin response element (CCCACCCC) was found to mediate the induction of mEPCR
by thrombin in cell culture. Transgenic mice were developed expressing green
fluorescent protein driven by the -350 to -1 or -1080 to -1 promoter. Thrombin up
regulated mEPCR and the transgene in vivo.
PMID- 10777536
TI - Transcriptional regulation of the ATP citrate-lyase gene by sterol regulatory
element-binding proteins.
AB - In an attempt to identify unknown target genes for SREBP-1, total RNA from a
stable Chinese hamster ovary cell line (CHO-487) expressing a mature form of
human SREBP-1a (amino acids 1-487) with a LacSwitch Inducible Mammalian
Expression System was subjected to a polymerase chain reaction subtraction
method. One of the fragments was found to have 90 and 86% homology with rat and
human ATP citrate-lyase (ACL) cDNA, respectively. When Hep G2 cells are cultured
under either sterol-loaded or -depleted conditions, expression of the gene is
induced approximately 2-3-fold by sterol depletion. To investigate the direct
effect of SREBP-1a on transcription, luciferase assays using the promoter of the
human ACL gene were performed. These deletion studies indicated that a minimum
160-base pair segment contains the information required for the transcriptional
regulation brought about by enforced expression of SREBP-1a. Luciferase assays
using mutant reporter genes revealed that SREBP-dependent transcriptional
regulation is mediated by two nearby motifs, the SREBP-binding site (a TCAGGCTAG
sequence) and the NF-Y-binding site (a CCAAT box). It was confirmed by gel
mobility shift assays that recombinant SREBP-1a binds to the sequence. Data from
studies with transgenic mice and reporter assays show that the ACL gene promoter
is activated by SREBP-1a more strongly than SREBP-2 in contrast to the HMG CoA
synthase and LDL receptor gene promoters, which exhibit the same preference for
the two factors. Therefore, SREBPs transcriptionally regulates ACL enzyme
activity, which generates the cytosolic acetyl CoA required for both cholesterol
and fatty acid synthesis.
PMID- 10777537
TI - Cloning, expression, and characterization of the acyl-CoA-binding protein in
African trypanosomes.
AB - African trypanosomes are shielded from their hosts' defenses by a coat of variant
surface glycoprotein molecules, each of which is attached to the plasma membrane
by a glycosylphosphatidylinositol anchor. During the later stages of
glycosylphosphatidylinositol biosynthesis, myristic acid is incorporated into the
anchor from the donor myristoyl-CoA by a series of unique fatty acid remodeling
and exchange reactions. We have cloned and expressed a recombinant trypanosome
acyl-CoA-binding protein that has a preference for binding relatively short chain
acyl-CoAs and that has a high affinity for binding myristoyl-CoA (K(d) = 3.5 x
10(-10) M). This protein enhances fatty acid remodeling of
glycosylphosphatidylinositol precursors in the trypanosome cell-free system. We
speculate that the trypanosome acyl-CoA-binding protein plays an active role in
supplying myristoyl-CoA to the fatty acid remodeling machinery in the parasite.
PMID- 10777535
TI - Enterotoxigenic Escherichia coli secretes active heat-labile enterotoxin via
outer membrane vesicles.
AB - Escherichia coli and other Gram-negative bacteria produce outer membrane vesicles
during normal growth. Vesicles may contribute to bacterial pathogenicity by
serving as vehicles for toxins to encounter host cells. Enterotoxigenic E. coli
(ETEC) vesicles were isolated from culture supernatants and purified on velocity
gradients, thereby removing any soluble proteins and contaminants from the crude
preparation. Vesicle protein profiles were similar but not identical to outer
membranes and differed between strains. Most vesicle proteins were resistant to
dissociation, suggesting they were integral or internal. Thin layer
chromatography revealed that major outer membrane lipid components are present in
vesicles. Cytoplasmic membranes and cytosol were absent in vesicles; however,
alkaline phosphatase and AcrA, periplasmic residents, were localized to vesicles.
In addition, physiologically active heat-labile enterotoxin (LT) was associated
with ETEC vesicles. LT activity correlated directly with the gradient peak of
vesicles, suggesting specific association, but could be removed from vesicles
under dissociating conditions. Further analysis revealed that LT is enriched in
vesicles and is located both inside and on the exterior of vesicles. The distinct
protein composition of ETEC vesicles and their ability to carry toxin may
contribute to the pathogenicity of ETEC strains.
PMID- 10777538
TI - Characterization of a catalytically slow AP lyase activity in DNA polymerase
gamma and other family A DNA polymerases.
AB - Mitochondrial DNA polymerase gamma (pol gamma) is active in base excision repair
of AP (apurinic/apyrimidinic) sites in DNA. Usually AP site repair involves
cleavage on the 5' side of the deoxyribose phosphate by AP endonuclease. Previous
experiments suggested that DNA pol gamma acts to catalyze the removal of a 5'
deoxyribose phosphate (dRP) group in addition to playing the conventional role of
a DNA polymerase. We confirm that DNA pol gamma is an active dRP lyase and show
that other members of the family A of DNA polymerases including Escherichia coli
DNA pol I also possess this activity. The dRP lyase reaction proceeds by
formation of a covalent enzyme-DNA intermediate that is converted to an enzyme
dRP intermediate following elimination of the DNA. Both intermediates can be
cross-linked with NaBH(4). For both DNA pol gamma and the Klenow fragment of pol
I, the enzyme-dRP intermediate is extremely stable. This limits the overall
catalytic rate of the dRP lyase, so that family A DNA polymerases, unlike pol
beta, may only be able to act as dRP lyases in repair of AP sites when they occur
at low frequency in DNA.
PMID- 10777539
TI - Transcriptional activation by hepatocyte nuclear factor-1 requires synergism
between multiple coactivator proteins.
AB - Hepatocyte nuclear factor-1 (HNF-1) plays an important role in the regulation of
a large number of genes expressed in the liver, kidney, and pancreatic beta
cells. In exploring the molecular mechanism involved in HNF-1-dependent gene
activation in the in vivo chromatin context, we found that HNF-1 can physically
interact with the histone acetyltransferases (HATs) CREB-binding protein (CBP),
p300/CBP-associated factor (P/CAF), Src-1, and RAC3. The transcriptional
activation potential of HNF-1 on a genome integrated promoter was strictly
dependent on the synergistic action of CBP and P/CAF, which can independently
interact with the N-terminal and C-terminal domain of HNF-1, respectively.
Moreover, the HAT activity of both coactivators was important, as opposed to the
selective requirement for the HAT activity of P/CAF in activation from a
transiently transfected reporter. Interaction of CBP with the N-terminal domain
of HNF-1 greatly increased the binding affinity for P/CAF with the C-terminal
activation domain, which may represent the molecular basis for the observed
functional synergism. The results support a model that involves the combined
action of multiple coactivators recruited by HNF-1, which activate transcription
by coupling nucleosome modification and recruitment of the general transcription
machinery.
PMID- 10777540
TI - Insight into the uncoupling mechanism of sarcoplasmic reticulum ATPase using the
phosphorylating substrate UTP.
AB - Ca(2+) transport and UTP hydrolysis catalyzed by sarcoplasmic reticulum Ca(2+)
ATPase from skeletal muscle was studied. A passive Ca(2+) load inside microsomal
vesicles clearly decreased the net uptake rate and the final accumulation of
Ca(2+) but not the UTP hydrolysis rate, causing energy uncoupling. In the absence
of passive leak, the Ca(2+)/P(i) coupling ratio was 0.7-0.8. UTP hydrolysis did
not maintain a rapid component of Ca(2+) exchange between the cytoplasmic and
lumenal compartments as occurs with ATP. The uncoupling process in the presence
of UTP is associated with: (i) the absence of a steady state accumulation of ADP
insensitive phosphoenzyme; (ii) the cytoplasmic dissociation of Ca(2+) bound to
the ADP-sensitive phosphoenzyme; and (iii) the absence of enzyme inhibition by
cyclopiazonic acid. All these characteristics confirm the lack of enzyme
conformations with low Ca(2+) affinity and point to the existence of an
uncoupling mechanism mediated by a phosphorylated form of the enzyme. Suboptimal
coupling values can be explained in molecular terms by the proposed functional
model.
PMID- 10777541
TI - The murine and human cholesterol 7alpha-hydroxylase gene promoters are
differentially responsive to regulation by fatty acids mediated via peroxisome
proliferator-activated receptor alpha.
AB - We determined if fatty acids can regulate the murine Cyp7a1 and human CYP7A1 gene
promoters via peroxisome proliferator-activated receptor alpha (PPARalpha)/9-cis
retinoic acid receptor alpha (RXRalpha). In transfected cells, the murine Cyp7a1
gene promoter displayed markedly lower basal activity, but greater sensitivity to
fatty acid- or WY 14,643-activated PPARalpha/RXRalpha when compared with the
human CYP7A1 gene promoter. PPARalpha/RXRalpha can bind to a site (Site II)
located within the region at nucleotides -158 to -132 of both promoters.
Mutagenesis of the human CYP7A1 Site II element abolished the response to
activated PPARalpha/RXRalpha. The murine Cyp7a1 gene promoter contains an
additional PPARalpha/RXRalpha-binding site (Site I) located within nucleotides
72 to -57. Replacement of a single residue in human CYP7A1 Site I with that found
in the murine Cyp7a1 Site I sequence enabled PPARalpha/RXRalpha binding, and this
mutation resulted in reduced basal activity, but substantially improved the
response to activated PPARalpha/RXRalpha in transfected cells. We conclude that
fatty acids can regulate the cyp7a gene promoter via PPARalpha/RXRalpha. The
differential response of the murine Cyp7a1 and human CYP7A1 gene promoters to
PPARalpha activators is attributable to the additional PPARalpha/RXRalpha-binding
site in the murine Cyp7a1 gene promoter.
PMID- 10777542
TI - Novel inhibition of gbetagamma-activated potassium currents induced by M(2)
muscarinic receptors via a pertussis toxin-insensitive pathway.
AB - G(i) protein-coupled receptors such as the M(2) muscarinic acetylcholine receptor
(mAChR) and A(1) adenosine receptor have been shown to activate G protein
activated inwardly rectifying K(+) channels (GIRKs) via pertussis toxin-sensitive
G proteins in atrial myocytes and in many neuronal cells. Here we show that
muscarinic M(2) receptors not only activate but also reversibly inhibit these
K(+) currents when stimulated with agonist for up to 2 min. The M(2) mAChR
mediated inhibition of the channel was also observed when the channels were first
activated by inclusion of guanosine 5'-O-(thiotriphosphate) in the pipette. Under
these conditions the M(2) mAChR-induced inhibition was quasi-irreversible,
suggesting a role for G proteins in the inhibitory process. In contrast, when
GIRK currents were maximally activated by co-expressing exogenous Gbetagamma, the
extent of acetylcholine (ACh)-induced inhibition was significantly reduced,
suggesting competition between the receptor-mediated inhibition and the large
pool of available Gbetagamma subunits. The signaling pathway that led to the ACh
induced inhibition of GIRK channels was unaffected by pertussis toxin
pretreatment. Furthermore, the internalization and agonist-induced
phosphorylation of M(2) mAChR was not required because a phosphorylation- and
internalization-deficient mutant of the M(2) mAChR was as potent as the wild-type
counterpart. Pharmacological agents modulating various protein kinases or
phosphatidylinositol 3-kinase did not affect the inhibition of GIRK currents.
Furthermore, the signaling pathway that mediates GIRK current inhibition was
found to be membrane-delimited because bath application of ACh did not inhibit
GIRK channel activity in cell-attached patches. Other G protein-coupled receptors
including M(4) mAChR and alpha(1A) adrenergic receptors also caused the
inhibition, whereas other G protein-coupled receptors including A(1) and A(3)
adenosine receptors and alpha(2A) and alpha(2C) adrenergic receptors could not
induce the inhibition. The presented results suggest the existence of a novel
signaling pathway that can be activated selectively by M(2) and M(4) mAChR but
not by adenosine receptors and that involves non-pertussis toxin-sensitive G
proteins leading to an inhibition of Gbetagamma-activated GIRK currents in a
membrane-delimited fashion.
PMID- 10777543
TI - Formation of W(3)A(1) electron-transferring flavoprotein (ETF) hydroquinone in
the trimethylamine dehydrogenase x ETF protein complex.
AB - The electron-transferring flavoprotein (ETF) from Methylophilus methylotrophus
(sp. W(3)A(1)) exhibits unusual oxidation-reduction properties and can only be
reduced to the level of the semiquinone under most circumstances (including
turnover with its physiological reductant, trimethylamine dehydrogenase (TMADH),
or reaction with strong reducing reagents such as sodium dithionite). In the
present study, we demonstrate that ETF can be reduced fully to its hydroquinone
form both enzymatically and chemically when it is in complex with TMADH.
Quantitative titration of the TMADH x ETF protein complex with sodium dithionite
shows that a total of five electrons are taken up by the system, indicating that
full reduction of ETF occurs within the complex. The results indicate that the
oxidation-reduction properties of ETF are perturbed upon binding to TMADH, a
conclusion further supported by the observation of a spectral change upon
formation of the TMADH x ETF complex that is due to a change in the environment
of the FAD of ETF. The results are discussed in the context of ETF undergoing a
conformational change during formation of the TMADH x ETF electron transfer
complex, which modulates the spectral and oxidation-reduction properties of ETF
such that full reduction of the protein can take place.
PMID- 10777544
TI - Coupling of the inositol 1,4,5-trisphosphate receptor and chromogranins A and B
in secretory granules.
AB - The secretory granules of neuroendocrine cells which contain large amounts of
Ca(2+) and chromogranins have been demonstrated to release Ca(2+) in response to
inositol 1,4,5-trisphosphate (IP(3)). Moreover, chromogranin A (CGA) has been
shown to interact with several secretory granule membrane proteins, including the
IP(3) receptor (IP(3)R). To determine whether the IP(3)Rs interact directly with
chromogranins A and B (CGB), two major proteins of the secretory granules, we
have used purified IP(3)R from bovine cerebellum in the interaction study with
CGA and CGB, and have shown that chromogranins A and B directly interact with the
IP(3)R at the intravesicular pH 5.5. Immunogold cytochemical study using the
IP(3)R and CGA antibodies indicated that IP(3)R-labeled gold particles were
localized in the periphery of the secretory granules, indicating the presence of
the IP(3)Rs on the secretory granule membrane. To determine whether the IP(3)R
and chromogranins A and B are physically linked in the cells, bovine type 1
IP(3)R (IP(3)R-1) and CGA or CGB are co-transfected into COS-7 cells and co
immunoprecipitation was carried out. Immunoprecipitation of the cell extracts
demonstrated the presence of CGA-IP(3)R-1 and CGB-IP(3)R-1 complexes,
respectively, indicating the complex formation between the IP(3)R and
chromogranins A and B in native state.
PMID- 10777545
TI - Stability of the ATF2 transcription factor is regulated by phosphorylation and
dephosphorylation.
AB - Trans-activation of the activating transcription factor-2 (ATF2) in response to
cellular stress requires the N-terminal phosphorylation of ATF2 by stress
activated protein kinases (SAPK). In this study, we investigated the role of ATF2
phosphorylation in the maintenance of ATF2 stability. Activation of SAPK by
forced expression of DeltaMEKK1 increased overall ATF2 ubiquitination, presumably
because of the enhanced dimerization of ATF2. Treatment of DeltaMEKK1-expressing
cells with okadaic acid led to the increase in N-terminal phosphorylation,
protection from ubiquitination, and accumulation of exogenously expressed ATF2,
indicating the role of protein phosphatases in balancing the effects of stress
kinases. Analysis of ubiquitination and degradation of the constitutively
dimerized ATF2 mutant (ATF2(Delta150-248)) showed that activation of JNK or p38
kinase renders ATF2 resistant to ubiquitination and degradation. This effect is
mediated by JNK/p38-dependent phosphorylation of ATF2 at Thr-69 and Thr-71,
because the phosphorylation-deficient mutant (ATF2(Delta150-248-T69A,T71A)) was
not protected from ubiquitination and degradation by the activation of SAPK.
Treatment of cells with okadaic acid elevated the tumor necrosis factor alpha
induced ATF2 level and the extent of its specific N-terminal phosphorylation.
Cycloheximide, which activates SAPK, while inhibiting protein synthesis,
stabilized endogenous ATF2. However, treatment of cells with the high dose of
SB203580, which inhibits JNK and p38 kinase, resulted in efficient degradation of
ATF2 in cells exposed to cycloheximide. This degradation was abrogated by co
treatment with the proteasome inhibitor MG132. Our findings suggest that N
terminal phosphorylation of ATF2 dimers protect ATF2 from ubiquitination and
degradation. We propose the hypothesis that the balance between SAPK and protein
phosphatases affects the duration and magnitude of ATF2 transcriptional output
because of the effect on substrate recognition for ubiquitination and
degradation.
PMID- 10777546
TI - Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7
human breast cancer cell line.
AB - Estrogens can stimulate the proliferation of estrogen-responsive breast cancer
cells by increasing their proliferative response to insulin-like growth factors.
The mechanism underlying the increased proliferation could involve the induction
of components of the insulin-like growth factor signal transduction pathway by
estrogen. In this study we have examined the regulation of the expression of
insulin receptor substrate-1, a major intracellular substrate of the type I
insulin-like growth factor receptor tyrosine kinase. Estradiol increased insulin
receptor substrate-1 mRNA and protein levels at concentrations consistent with a
mechanism involving the estrogen receptor. Insulin receptor substrate-1 was not
induced significantly by the antiestrogens tamoxifen and ICI 182,780, but they
inhibited the induction of insulin receptor substrate-1 by estradiol. Analysis of
tyrosine-phosphorylated insulin receptor substrate-1 showed that the highest
levels were found in cells stimulated by estradiol and insulin-like growth factor
I, whereas low levels were found in the absence of estradiol irrespective of
whether type I insulin-like growth factor ligands were present. Insulin receptor
substrate-2, -3, and -4 were not induced by estradiol. These results suggest that
estrogens and antiestrogens may regulate cell proliferation by controlling
insulin receptor substrate-1 expression, thereby amplifying or attenuating
signaling through the insulin-like growth factor signal transduction pathway.
PMID- 10777547
TI - Simultaneous suppression of cdc2 and cdk2 activities induces neuronal
differentiation of PC12 cells.
AB - The involvement of cdc2 and cdk2 during neuronal differentiation in rat
pheochromocytoma PC12 cells was examined. When PC12 cells were cultured with
nerve growth factor (NGF), expression of cdc2 decreased significantly after day
5, while expression of cdk2 decreased gradually after day 7. Cells overexpressing
cdc2 or cdk2 were resistant to NGF-induced differentiation and growth
suppression, and maintained high cdc2 or cdk2 kinase activity, respectively,
during NGF treatment. In contrast, the NGF-treated parental cells showed a marked
decline in these kinase activities after day 3. When PC12 cells were treated with
specific inhibitors of cdc2/cdk2 (butyrolactone-I, olomoucin), they showed marked
neurite extension and up-regulation of microtubule-associated protein 2
expression. In addition, treatment with mixtures of antisense oligonucleotides
for cdc2 and cdk2 resulted in down-regulation of both cdc2 and cdk2 kinase
activities as well as significant neurite outgrowth and up-regulation of
microtubule-associated protein 2 expression. However, neurite outgrowth was not
observed in cells treated with either single antisense oligonucleotide, or
antisense cdc2 + cdk4 or cdk2 + cdk4 oligonucleotide mixtures. These results
suggest that simultaneous down-regulation of cdc2 and cdk2 activity is sufficient
and necessary for neuronal differentiation in PC12 cells.
PMID- 10777548
TI - Steady-state and transient kinetics of Escherichia coli nitric-oxide dioxygenase
(flavohemoglobin). The B10 tyrosine hydroxyl is essential for dioxygen binding
and catalysis.
AB - Escherichia coli expresses an inducible flavohemoglobin possessing robust NO
dioxygenase activity. At 37 degrees C, the enzyme shows a maximal turnover number
(V(max)) of 670 s(-1) and K(m) values for NADH, NO, and O(2) equal to 4.8, 0.28,
and approximately 100 microM, respectively. Individual reduction, ligand binding,
and NO dioxygenation reactions were examined at 20 degrees C, where V(max) is
approximately 94 s(-1). Reduction by NADH occurs in two steps. NADH reduces bound
FAD with a rate constant of approximately 15 microM(-1) s(-1), and heme iron is
reduced by FADH(2) with a rate constant of 150 s(-1). Dioxygen binds tightly to
reduced flavohemoglobin, with association and dissociation rate constants equal
to 38 microM(-1) s(-1) and 0.44 s(-1), respectively, and the oxygenated
flavohemoglobin dioxygenates NO to form nitrate. NO also binds reversibly to
reduced flavohemoglobin in competition with O(2), dissociates slowly, and
inhibits NO dioxygenase activity at [NO]/[O(2)] ratios of 1:100. Replacement of
the heme pocket B10 tyrosine with phenylalanine increases the O(2) dissociation
rate constant approximately 80-fold and reduces NO dioxygenase activity
approximately 30-fold, demonstrating the importance of the tyrosine hydroxyl for
O(2) affinity and NO scavenging activity. At 37 degrees C, V(max)/K(m)(NO) is
2,400 microM(-1) s(-1), demonstrating that the enzyme is extremely efficient at
converting toxic NO into nitrate under physiological conditions.
PMID- 10777549
TI - Identification and characterization of HAOX1, HAOX2, and HAOX3, three human
peroxisomal 2-hydroxy acid oxidases.
AB - Computer-based approaches identified three distinct human 2-hydroxy acid oxidase
genes, HAOX1, HAOX2, and HAOX3, that encode proteins with significant sequence
similarity to plant glycolate oxidase, a prototypical 2-hydroxy acid oxidase. The
products of these genes are targeted to peroxisomes and have 2-hydroxy acid
oxidase activities. Each gene displays a distinct tissue-specific pattern of
expression, and each enzyme exhibits distinct substrate preferences. HAOX1 is
expressed primarily in liver and pancreas and is most active on the two-carbon
substrate, glycolate, but is also active on 2-hydroxy fatty acids. HAOX2 is
expressed predominantly in liver and kidney and displays highest activity toward
2-hydroxypalmitate. HAOX3 expression was detected only in pancreas, and this
enzyme displayed a preference for the medium chain substrate 2-hydroxyoctanoate.
These results indicate that all three human 2-hydroxy acid oxidases are involved
in the oxidation of 2-hydroxy fatty acids and may also contribute to the general
pathway of fatty acid alpha-oxidation. Primary hyperoxaluria type 1 (PH1) is
caused by defects in peroxisomal alanine-glyoxylate aminotransferase, the enzyme
that normally eliminates intraperoxisomal glyoxylate. The presence of HAOX1 in
liver and kidney peroxisomes and the ability of HAOX1 to oxidize glyoxylate to
oxalate implicate HAOX1 as a mediator of PH1 pathophysiology.
PMID- 10777550
TI - A T4-phage deoxycytidylate deaminase mutant that no longer requires deoxycytidine
5'-triphosphate for activation.
AB - A deoxycytidylate (dCMP) deaminase encoded in T4-bacteriophage DNA that is
induced on phage infection of Escherichia coli was shown earlier (Maley, G. F.,
Duceman, B. W., Wang, A. M., Martinez, J. M., and Maley, F. (1990) J. Biol. Chem.
265, 47-51) to be similar in size, properties, and amino acid composition to the
T2-phage-induced deaminase. Neither enzyme is active in the absence of dCTP or
its natural activator, 5-hydroxymethyl-dCTP. However, on changing the arginine
(Arg) at residue 115 of the T4-deaminase to either a glutamate (R115E) or a
glutamine (R115Q), the resulting mutant enzymes were active in the absence of
dCTP, with each mutant possessing a turnover number or k(cat) that is about 15%
that of the wild-type deaminase. When compared on the basis of specific activity,
however, the mutants are about 40-50% of the wild-type (WT)-enzyme's specific
activity. Molecular weight analysis on the wild-type and mutant deaminases using
HPLC size exclusion chromatography revealed that the wild-type deaminase was
basically a hexamer, particularly in the presence of dCTP, regardless of the
extent of dilution. Under similar conditions, R115E remained a dimer, whereas
R115Q and F112A varied from hexamers to dimers particularly at concentrations
normally present in the assay solution. Activity measurements appear to support
the conclusion that the hexameric form of the enzyme is activated by dCTP, while
the dimer is not. Another feature emphasizing the difference between the WT and
mutant deaminases was observed on their denaturation-renaturation in EDTA, which
revealed the mutants to be restored to 50% of their original activities with the
WT deaminase only marginally restored.
PMID- 10777551
TI - Overproduction of Pex5p stimulates import of alcohol oxidase and dihydroxyacetone
synthase in a Hansenula polymorpha Pex14 null mutant.
AB - Hansenula polymorpha Deltapex14 cells are affected in peroxisomal matrix protein
import and lack normal peroxisomes. Instead, they contain peroxisomal membrane
remnants, which harbor a very small amount of the major peroxisomal matrix
enzymes alcohol oxidase (AO) and dihydroxyacetone synthase (DHAS). The bulk of
these proteins is, however, mislocated in the cytosol. Here, we show that in
Deltapex14 cells overproduction of the PTS1 receptor, Pex5p, leads to enhanced
import of the PTS1 proteins AO and DHAS but not of the PTS2 protein amine
oxidase. The import of the PTS1 protein catalase (CAT) was not stimulated by
Pex5p overproduction. The difference in import behavior of AO and CAT was not
related to their PTS1, since green fluorescent protein fused to the PTS1 of
either AO or CAT were both not imported in Deltapex14 cells overproducing Pex5p.
When produced in a wild type control strain, both proteins were normally imported
into peroxisomes. In Deltapex14 cells overproducing Pex5p, Pex5p had a dual
location and was localized in the cytosol and bound to the outer surface of the
peroxisomal membrane. Our results indicate that binding of Pex5p to the
peroxisomal membrane and import of certain PTS1 proteins can proceed in the
absence of Pex14p.
PMID- 10777552
TI - Induction of the fatty acid transport protein 1 and acyl-CoA synthase genes by
dimer-selective rexinoids suggests that the peroxisome proliferator-activated
receptor-retinoid X receptor heterodimer is their molecular target.
AB - The intracellular fatty acid content of insulin-sensitive target tissues
determines in part their insulin sensitivity. Uptake of fatty acids into cells is
a controlled process determined in part by a regulated import/export system that
is controlled at least by two key groups of proteins, i.e. the fatty acid
transport protein (FATP) and acyl-CoA synthetase (ACS), which facilitate,
respectively, the transport of fatty acids across the cell membrane and catalyze
their esterification to prevent their efflux. Previously it was shown that the
expression of the FATP-1 and ACS genes was controlled by insulin and by
peroxisome proliferator-activated receptor (PPAR) agonists in liver or in adipose
tissue. The aim of this investigation was to determine the effects of retinoic
acid derivatives on the expression of FATP-1 and ACS. In several cultured cell
lines, it was shown that the expression of both the FATP-1 and ACS mRNAs was
specifically induced at the transcriptional level by selective retinoid X
receptor (RXR) but not by retinoic acid receptor (RAR) ligands. This effect was
most pronounced in hepatoma cell lines. A similar induction of FATP-1 and ACS
mRNA levels was also observed in vivo in Zucker diabetic fatty rats treated with
the RXR agonist, LGD1069 (4-[1-(3,5,5,8,8-pentamethyl-5,6,7, 8-tetrahydro-2
naphthyl)ethenyl]benzoic acid). Through the use of heterodimer-selective
compounds, it was demonstrated that the modulatory effect of these rexinoids on
FATP-1 and ACS gene expression was mediated through activation of RXR in the
context of the PPAR-RXR heterodimer. The observation that both RXR and PPAR
agonists can stimulate the transcription of genes implicated in lipid metabolism,
suggest that rexinoids may also act as lipid-modifying agents and support a role
of the permissive PPAR-RXR heterodimer in the control of insulin sensitivity.
PMID- 10777553
TI - Carbachol-stimulated transactivation of epidermal growth factor receptor and
mitogen-activated protein kinase in T(84) cells is mediated by intracellular
Ca2+, PYK-2, and p60(src).
AB - Ca(2+)-dependent agonists, such as carbachol (CCh), stimulate epidermal growth
factor receptor (EGFR) transactivation and mitogen-activated protein kinase
activation in T(84) intestinal epithelial cells. This pathway constitutes an
antisecretory mechanism by which CCh-stimulated chloride secretion is limited.
Here, we investigated mechanisms underlying CCh-stimulated epidermal growth
factor receptor (EGFR) transactivation. Thapsigargin (TG, 2 microM) stimulated
EGFR and extracellular signal-regulated kinase (ERK) phosphorylation in T(84)
cells. Inhibition of either EGFR or ERK activation, with tyrphostin AG1478 (1
microM) and PD 98059 (20 microM), respectively, potentiated chloride secretory
responses to TG, as measured by changes in short-circuit current (I(sc)) across
T(84) cells. CCh (100 microM) stimulated tyrosine phosphorylation and association
of the Ca(2+)-dependent tyrosine kinase, PYK-2, with the EGFR, which was
inhibited by the Ca(2+) chelator, BAPTA (20 microM). The calmodulin inhibitor,
fluphenazine (50 microM) inhibited CCh-stimulated PYK-2 association with the EGFR
and phosphorylation of EGFR and ERK. CCh also induced tyrosine phosphorylation of
p60(src) and association of p60(src) with both PYK-2 and the EGFR. The Src family
kinase inhibitor, PP2 (20 nM-20 microM) attenuated CCh-stimulated EGFR and ERK
phosphorylation and potentiated chloride secretory responses to CCh. We conclude
that CCh-stimulated transactivation of the EGFR is mediated by a pathway
involving elevations in intracellular Ca(2+), calmodulin, PYK-2, and p60(src).
This pathway represents a mechanism that limits CCh-stimulated chloride secretion
across intestinal epithelia.
PMID- 10777554
TI - CCAAT/enhancer-binding protein-beta regulates interferon-induced transcription
through a novel element.
AB - We have described previously a novel interferon (IFN)-responsive cis-acting
enhancer element called gamma-IFN-activated transcriptional element (GATE). GATE
is distinct from the known IFN-stimulated elements and binds to novel transacting
factors. To identify the gamma-IFN-responsive transacting factors that interact
with GATE, we have screened a cDNA expression library derived from IFN-gamma
stimulated murine macrophage cell line and isolated three different cDNAs. Among
these is a gene coding for the pleiotropic transcription factor, CCAAT/enhancer
binding protein-beta (C/EBP-beta). We report here that the gene for C/EBP-beta
binds to GATE and induces gene expression. A mutant C/EBP-beta interferes with
the IFN-gamma-stimulated transcription of the ISGF3gamma (p48) promoter. Other
members of the C/EBP family do not cause these effects. Interestingly, the
expression of C/EBP-beta, not the other members of its family, is induced by IFN
gamma. These studies thus identify a novel role for C/EBP-beta in the IFN
signaling pathways.
PMID- 10777555
TI - Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in
endothelial cells induces the activation of NF-kappaB through an increased
production of intracellular reactive oxygen species.
AB - In this study we examined the effect of oxidized low density lipoprotein (ox-LDL)
on the intracellular production of reactive oxygen species (ROS) in bovine aortic
endothelial cells (BAECs) and whether this increase occurs through its binding to
the endothelial receptor lectin-like ox-LDL receptor-1 (LOX-1). Furthermore, this
study also aimed to ascertain whether the binding of ox-LDL to LOX-1 is
associated with NF-kappaB activation. ox-LDL induced a significant dose-dependent
increase in ROS production after a 30-s incubation with BAECs (p < 0.01). ROS
formation was markedly reduced in BAECs incubated with anti-LOX-1 monoclonal
antibody (p < 0.001), while control nonimmune IgG produced no effect. ox-LDL
induced a time- and dose-dependent significant increase in ROS formation only in
CHO-K1 cells stably expressing bovine LOX-1 (p < 0.001), while no increase was
present in CHO-K1 cells. The activation of the transcription factor NF-kappaB in
BAECs was evident after a 5-min incubation with ox-LDL and was attenuated by anti
LOX-1 monoclonal antibody. The conclusion is that one of the pathophysiological
consequences of ox-LDL binding to LOX-1 may be the activation of NF-kappaB
through an increased ROS production.
PMID- 10777556
TI - Purification, cloning, expression, and mechanism of action of a novel platelet
aggregation inhibitor from the salivary gland of the blood-sucking bug, Rhodnius
prolixus.
AB - Rhodnius prolixus aggregation inhibitor 1 (RPAI-1), a 19-kDa protein isolated
from the salivary gland of R. prolixus, was purified by strong cation exchange
and reverse-phase high performance liquid chromatographies. Based on 49 amino
terminal amino acid sequences of RPAI-1, primers were produced to generate probes
to screen an R. prolixus salivary gland cDNA library. A phage containing the full
length clone of RPAI-1 codes for a mature protein of 155 amino acids. RPAI-1
shows sequence homology to triabin and pallidipin, lipocalins from Triatoma
pallidipennis. The cDNA sequence was cloned in Pet17B Escherichia coli expression
vector, producing an active peptide. RPAI-1 inhibits human platelet-rich plasma
aggregation triggered by low concentrations of ADP, collagen, arachidonic acid,
thromboxane A(2) mimetics (U46619), and very low doses of thrombin and convulxin.
Here we show that ADP is the target of RPAI-1 since (i) RPAI-1 inhibits ADP
dependent large aggregation formation and secretion triggered by U46619, without
affecting Ca(2+) increase and shape change; (ii) ADP restored the inhibition of
U46619-induced platelet aggregation by RPAI-1, (iii) PGE(1)-induced increase of
cAMP (which is antagonized by U46619 in an ADP-dependent manner) was restored by
RPAI-1, (iv) RPAI-1 inhibits low concentrations of ADP-mediated responses of
indomethacin-treated platelets, and (v) RPAI-1 binds to ADP, as assessed by large
zone chromatography. RPAI-1 affects neither integrin alpha(2)beta(1)- nor
glycoprotein VI-mediated platelet responses. We conclude that RPAI-1 is the first
lipocalin described that inhibits platelet aggregation by a novel mechanism,
binding to ADP.
PMID- 10777557
TI - Mapping the agonist binding site of the nicotinic acetylcholine receptor.
Orientation requirements for activation by covalent agonist.
AB - To characterize the structural requirements for ligand orientation compatible
with activation of the Torpedo nicotinic acetylcholine receptor (nAChR), we used
Cys mutagenesis in conjunction with sulfhydryl-reactive reagents to tether
primary or quaternary amines at defined positions within the agonist binding site
of nAChRs containing mutant alpha- or gamma-subunits expressed in Xenopus
oocytes. 4-(N-Maleimido)benzyltrimethylammonium and 2
aminoethylmethanethiosulfonate acted as irreversible antagonists when tethered at
alphaY93C, alphaY198C, or gammaE57C, as well as at alphaN94C (2
aminoethylmethanethiosulfonate only). [2-(Trimethylammonium)-ethyl]
methanethiosulfonate (MTSET), which attaches thiocholine to binding site Cys,
also acted as an irreversible antagonist when tethered at alphaY93C, alphaN94C,
or gammaE57C. However, MTSET modification of alphaY198C resulted in prolonged
activation of the nAChR not reversible by washing but inhibitable by subsequent
exposure to non-competitive antagonists. Modification of alphaY198C (or any of
the other positions tested) by [(trimethylammonium)methyl]methanethiosulfonate
resulted only in irreversible inhibition, while modification of alphaY198C by [3
(trimethylammonium)propyl]methanethiosulfonate resulted in irreversible
activation of nAChR, but at lower efficacy than by MTSET. Thus changing the
length of the tethering arm by less than 1 A in either direction markedly effects
the ability of the covalent trimethylammonium to activate the nAChR, and agonist
activation depends on a very selective orientation of the quaternary ammonium
within the agonist binding site.
PMID- 10777558
TI - Distinct mechanisms of STAT phosphorylation via the interferon-alpha/beta
receptor. Selective inhibition of STAT3 and STAT5 by piceatannol.
AB - Interferon-alpha (IFNalpha) can activate several members of the signal
transducers and activator of transcription (STAT) transcription factor family, a
process that requires the tyrosine kinases Jak1 and Tyk2. Here we provide
evidence that IFNalpha-mediated activation of various STAT proteins is regulated
by distinct mechanisms. Piceatannol, previously reported as a Syk/ZAP70-specific
kinase inhibitor, selectively inhibits the tyrosine phosphorylation of STAT3 and
STAT5, but not of STAT1 and STAT2. This inhibition is paralleled by the loss of
Jak1 and IFNAR1 tyrosine phosphorylation in response to IFNalpha, whereas Tyk2
and IFNAR2 tyrosine phosphorylation is unaffected. Last, the IFNalpha-induced
serine phosphorylation of STAT1 and STAT3 is not inhibited by piceatannol but is
sensitive to the Src kinase-specific inhibitor PP2. Thus, our results not only
demonstrate that the IFNalpha/beta receptor utilizes distinct mechanisms to
trigger the tyrosine phosphorylation of specific STAT proteins, but they also
indicate a diverging pathway that leads to the serine phosphorylation of STAT1
and STAT3.
PMID- 10777559
TI - Crk activation of JNK via C3G and R-Ras.
AB - v-crk is an oncogene identified originally in CT10 chicken tumor virus. C3G, a
guanine nucleotide exchange factor (GEF) for Rap1 and R-Ras, is postulated to
transduce the oncogenic signal of v-Crk to c-Jun kinase (JNK). We have found that
R-Ras, but not Rap1, mediates JNK activation by v-Crk in 293T and NIH 3T3 cells.
Constitutively activated R-Ras, R-Ras(Val-38), but not Rap1(Val-12), activated
JNK, as did the constitutively active H-Ras(Val-12) or Rac1(Val-12). v-Crk
activation of JNK was inhibited by a dominant-negative mutant of R-Ras, R-Ras(Asn
43). JNK activation by R-Ras(Val-38) was inhibited by a dominant-negative mutant
of mixed lineage kinase 3. Among six GEFs for Ras-family G proteins, mSos1, Ras
GRF, C3G, CalDAG-GEFI, Ras-GRP/CalDAG-GEFII, and Epac/cAMP-GEFI, GEFs for either
H-Ras or R-Ras activated JNK and c-Jun-dependent transcription. CalDAG-GEFI and
Epac/cAMP-GEFI, both of which are GEFs specific for Rap1, did not activate JNK or
c-Jun-dependent transcription. These results demonstrate that R-Ras, but not
Rap1, is the downstream effector of C3G to stimulate JNK. Finally, we found that
expression of the dominant-negative R-Ras mutant induced flat reversion of NIH
3T3 cells transformed by v-Crk, suggesting that R-Ras-dependent JNK activation is
critical for the transformation by v-Crk.
PMID- 10777560
TI - Three-dimensional clustering of human RAG2 gene mutations in severe combined
immune deficiency.
AB - The V(D)J recombination, which leads to the somatic rearrangement of variable,
diversity, and joining segments, is the mechanism accountable for the diversity
of T cell receptor- and Ig-encoding genes. The products of the RAG1 and RAG2
genes are the lymphoid-specific factors responsible for the initiation of the
V(D)J recombination through the generation of a DNA double strand break. RAG1 or
RAG2 gene inactivation in the mouse leads to abortion of the V(D)J rearrangement
process, early block in both T and B cell maturation, and, ultimately, to severe
combined immune deficiency (SCID). A human SCID condition is also characterized
by an absence of mature T and B lymphocytes and is associated with mutations in
either RAG1- or RAG2-encoding genes. Based on the predicted beta-propeller three
dimensional structure model for RAG2, we found that six out of the seven
mutations described to date in T-B-SCID patients are clustered on one side of the
propeller, in regions exposed to solvent. This finding reinforces the biological
significance of this predicted model and suggests that RAG1 interacts with RAG2
on one of the side of the scaffold formed by the beta-propeller.
PMID- 10777561
TI - Superinduction of CYP1A1 gene expression. Regulation of 2,3,7, 8
tetrachlorodibenzo-p-dioxin-induced degradation of Ah receptor by cycloheximide.
AB - Cycloheximide superinduces the transcription of CYP1A1 in the presence of an
agonist for the Ah receptor (AhR). To investigate the molecular target for
"superinduction," we analyzed the agonist-induced degradation of AhR. Whereas
2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR, induces a
rapid reduction of the AhR protein, cycloheximide blocks the down-regulation of
steady state AhR. Analyses of the turnover of AhR reveal that cycloheximide
blocks the shortening of the half-life of AhR by TCDD. Blocking of the TCDD
induced AhR degradation requires inhibition of protein synthesis, because (a)
cycloheximide inhibits protein synthesis at the concentration at which it causes
superinduction and inhibition of AhR degradation; and (b) puromycin, an inhibitor
of protein synthesis by mimicking aminoacyl-tRNA, also blocks the TCDD-induced
AhR degradation. The blocking of the TCDD-induced AhR degradation correlates with
the superinduction of CYP1A1 gene expression in a time- and dose-dependent
manner. Furthermore, cycloheximide is shown to increase the accumulation of the
TCDD-activated AhR and the functional AhR x Arnt complex in nucleus.
Collectively, our results reveal a mechanism of superinduction by cycloheximide
by enhancing the stability of agonist-activated AhR. The finding that inhibition
of protein synthesis blocks the TCDD-induced AhR turnover implicates a
cycloheximide-sensitive, labile factor (designated as AhR degradation promoting
factor, or ADPF) in controlling the removal of agonist-activated AhR in nucleus.
PMID- 10777562
TI - Selective involvement of superoxide anion, but not downstream compounds hydrogen
peroxide and peroxynitrite, in tumor necrosis factor-alpha-induced apoptosis of
rat mesangial cells.
AB - Tumor necrosis factor-alpha (TNF-alpha) induces reactive oxygen species (ROS)
that serve as second messengers for intracellular signaling. Currently, precise
roles of individual ROS in the actions of TNF-alpha remain to be elucidated. In
this report, we investigated the roles of superoxide anion (O-(2)), hydrogen
peroxide (H(2)O(2)), and peroxynitrite (ONOO(-)) in TNF-alpha-triggered apoptosis
of mesangial cells. Mesangial cells stimulated by TNF-alpha produced O-(2) and
underwent apoptosis. The apoptosis was inhibited by transfection with manganese
superoxide dismutase or treatment with a pharmacological scavenger of O-(2),
Tiron. In contrast, although exogenous H(2)O(2) induced apoptosis, TNF-alpha
triggered apoptosis was not affected either by transfection with catalase cDNA or
by treatment with catalase protein or glutathione ethyl ester. Similarly,
although ONOO(-) precursor SIN-1 induced apoptosis, treatment with a scavenger of
ONOO(-), uric acid, or an inhibitor of nitric oxide synthesis, N(G)-nitro-L
argininemethyl ester hydrochloride, did not affect the TNF-alpha-triggered
apoptosis. Like TNF-alpha-induced apoptosis, treatment with a O-(2)-releasing
agent, pyrogallol, induced typical apoptosis even in the concurrent presence of
scavengers for H(2)O(2) and ONOO(-). These results suggested that, in mesangial
cells, TNF-alpha induces apoptosis through selective ROS. O-(2), but not H(2)O(2)
or ONOO(-), was identified as the crucial mediator for the TNF-alpha-initiated,
apoptotic pathway.
PMID- 10777563
TI - Hydrophobic pairwise interactions stabilize alpha-conotoxin MI in the muscle
acetylcholine receptor binding site.
AB - The present work delineates pairwise interactions underlying the nanomolar
affinity of alpha-conotoxin MI (CTx MI) for the alpha-delta site of the muscle
acetylcholine receptor (AChR). We mutated all non-cysteine residues in CTx MI,
expressed the alpha(2)betadelta(2) pentameric form of the AChR in 293 human
embryonic kidney cells, and measured binding of the mutant toxins by competition
against the initial rate of (125)I-alpha-bungarotoxin binding. The CTx MI
mutations P6G, A7V, G9S, and Y12T all decrease affinity for alpha(2)betadelta(2)
pentamers by 10,000-fold. Side chains at these four positions localize to a
restricted region of the known three-dimensional structure of CTx MI. Mutations
of the AChR reveal major contributions to CTx MI affinity by Tyr-198 in the alpha
subunit and by the selectivity determinants Ser-36, Tyr-113, and Ile-178 in the
delta subunit. By using double mutant cycles analysis, we find that Tyr-12 of CTx
MI interacts strongly with all three selectivity determinants in the delta
subunit and that deltaSer-36 and deltaIle-178 are interdependent in stabilizing
Tyr-12. We find additional strong interactions between Gly-9 and Pro-6 in CTx MI
and selectivity determinants in the delta subunit, and between Ala-7 and Pro-6
and Tyr-198 in the alpha subunit. The overall results reveal the orientation of
CTx MI when bound to the alpha-delta interface and show that primarily
hydrophobic interactions stabilize the complex.
PMID- 10777564
TI - Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled
homologs and promotes ventral cell fates in Xenopus.
AB - Wnt ligands working through Frizzled receptors have a differential ability to
stimulate release of intracellular calcium (Ca(2+)) and activation of protein
kinase C (PKC). Since targets of this Ca(2+) release could play a role in Wnt
signaling, we first tested the hypothesis that Ca(2+)/calmodulin-dependent
protein kinase II (CamKII) is activated by some Wnt and Frizzled homologs. We
report that Wnt and Frizzled homologs that activate Ca(2+) release and PKC also
activate CamKII activity in Xenopus embryos, while Wnt and Frizzled homologs that
activate beta-catenin function do not. This activation occurs within 10 min after
receptor activation in a pertussis toxin-sensitive manner, concomitant with
autophosphorylation of endogenous CamKII. Based on data that Wnt-5A and Wnt-11
are present maternally in Xenopus eggs, and activate CamKII, we then tested the
hypothesis that CamKII participates in axis formation in the early embryo.
Measurements of endogenous CamKII activity from dorsal and ventral regions of
embryos revealed elevated activity on the prospective ventral side, which was
suppressed by a dominant negative Xwnt-11. If this spatial bias in CamKII
activity were involved in promoting ventral cell fate one might predict that
elevating CamKII activity on the dorsal side would inhibit dorsal cell fates,
while reducing CamKII activity on the ventral side would promote dorsal cell
fates. Results obtained by expression of CamKII mutants were consistent with this
prediction, revealing that CamKII contributes to a ventral cell fate.
PMID- 10777565
TI - Identification of an enhancer sequence within the first intron required for
cartilage-specific transcription of the alpha2(XI) collagen gene.
AB - Type XI collagen, a heterotrimer composed of alpha1(XI), alpha2(XI) and
alpha3(XI), is primarily synthesized by chondrocytes in cartilage and is also
present in some other tissues. Type XI collagen plays a critical role in collagen
fibril formation and skeletal morphogenesis. We investigated a tissue-specific
transcriptional enhancer in the first intron of the alpha2(XI) collagen gene
(Col11a2). Transient transfection assays using reporter gene constructs revealed
that a 60-base pair (bp) segment within intron 1 increased promoter activity of
Col11a2 in rat chondrosarcoma cells but not in either BalB/3T3 cells or
undifferentiated ATDC5 cells, suggesting that it contained cell type-specific
enhancer activity. In transgenic mice, this 60-bp fragment was also able to
target beta-galactosidase expression to cartilage including the limbs and axial
skeleton, with similar localization specificity as the full-length intron 1
fragment. Competition experiments in gel shift assays using mutated
oligonucleotides showed that recombinant Sox9 bound to a 7-bp sequence, CTCAAAG,
within the 60-bp segment. Anti-Sox9 antibodies supershifted the complex of the 60
bp segment with recombinant Sox9 or with rat chondrosarcoma cell extracts,
confirming the binding of Sox9 to the enhancer. Moreover, a site-specific
mutation within the 7-bp segment resulted in essentially complete loss of the
enhancer activity in chondrosarcoma cells and transgenic mice. These results
suggest that the 7-bp sequence within intron 1 plays a critical role in the
cartilage-specific enhancer activity of Col11a2 through Sox9-mediated
transcriptional activation.
PMID- 10777566
TI - Assembly of type IV collagen. Insights from alpha3(IV) collagen-deficient mice.
AB - Type IV collagen includes six genetically distinct polypeptides named alpha1(IV)
through alpha6(IV). These isoforms are speculated to organize themselves into
unique networks providing mammalian basement membranes specificity and
inequality. Recent studies using bovine and human glomerular and testis basement
membranes have shown that unique networks of collagen comprising either alpha1
and alpha2 chains or alpha3, alpha4, and alpha5 chains can be identified. These
studies have suggested that assembly of alpha5 chain into type IV collagen
network is dependent on alpha3 expression where both chains are normally present
in the tissue. In the present study, we show that in the lens and inner ear of
normal mice, expression of alpha1, alpha2, alpha3, alpha4, and alpha5 chains of
type IV collagen can be detected using alpha chain-specific antibodies. In the
alpha3(IV) collagen-deficient mice, only the expression of alpha1, alpha2, and
alpha5 chains of type IV collagen was detectable. The non-collagenous 1 domain of
alpha5 chain was associated with alpha1 in the non-collagenous 1 domain hexamer
structure, suggesting that network incorporation of alpha5 is possible in the
absence of the alpha3 chain in these tissues. The present study proves that
expression of alpha5 is not dependent on the expression of alpha3 chain in these
tissues and that alpha5 chain can assemble into basement membranes in the absence
of alpha3 chain. These findings support the notion that type IV collagen assembly
may be regulated by tissue-specific factors.
PMID- 10777567
TI - Interaction of the N-methyl-D-aspartic acid receptor NR2D subunit with the c-Abl
tyrosine kinase.
AB - The COOH-terminal domain of the NR2D subunit of the NMDA receptor contains
proline-rich regions that show striking homology to sequences known to bind to
Src homology 3 (SH3) domains. To determine whether the proline-rich region of the
NR2D subunit interacts with specific SH3 domains, in vitro SH3 domain binding
assays were performed. A proline-rich fragment of the NR2D subunit (2D(866-1064))
bound to the Abl SH3 domain but not to the SH3 domains from Src, Fyn, Grb2, GAP,
or phospholipase C-gamma (PLCgamma). Co-immunoprecipitation of NR2D with Abl
suggests stable association of NR2D and Abl in transfected cells. The SH3 domain
plays an important role in the negative regulation of Abl kinase activity. To
determine whether the interaction of NR2D with the Abl SH3 domain alters Abl
kinase activity, Abl was expressed alone or with NR2D in 293T cells.
Autophosphorylation of Abl was readily observed when Abl was expressed alone.
However, co-expression of Abl with 2D(866-1064) or full-length NR2D inhibited
autophosphorylation. 2D(866-1064) did not inhibit DeltaSH3 Abl, indicating a
requirement for the Abl SH3 domain in the inhibitory effect. Similarly, 2D(866
1064) did not inhibit the catalytic activity of Abl-PP, which contains two point
mutations in the SH2-kinase linker domain that release the negative kinase
regulation by the SH3 domain. In contrast, the full-length NR2D subunit partially
inhibited the autokinase activity of both DeltaSH3 Abl and Abl-PP, suggesting
that NR2D and Abl may interact at multiple sites. Taken together, the data in
this report provide the first evidence for a novel inhibitory interaction between
the NR2D subunit of the NMDA receptor and the Abl tyrosine kinase.
PMID- 10777568
TI - Discovery of molecular and catalytic diversity among human diphosphoinositol
polyphosphate phosphohydrolases. An expanding Nudt family.
AB - The turnover of the "high energy" diphosphoinositol polyphosphates by Ca(2+)- and
cyclic nucleotide-modulated enzymes is considered a regulatory, molecular
switching activity. Target processes may include intracellular trafficking.
Following our earlier identification of a prototype human diphosphoinositol
polyphosphate phosphohydrolase (hDIPP1), we now describe new 21-kDa human
isoforms, hDIPP2alpha and hDIPP2beta, distinguished from each other solely by
hDIPP2beta possessing one additional amino acid (Gln(86)). Candidate DIPP2alpha
and DIPP2beta homologues in rat and mouse were also identified. The rank order
for catalytic activity is hDIPP1 > hDIPP2alpha > hDIPP2beta. Differential
expression of hDIPP isoforms may provide flexibility in response times of the
molecular switches. The 76% identity between hDIPP1 and the hDIPP2s includes
conservation of an emerging signature sequence, namely, a Nudt (MutT) motif with
a GX(2)GX(6)G carboxy extension. Northern and Western analyses indicate
expression of hDIPP2s is broad but atypically controlled; these proteins are
translated from multiple mRNAs that differ in the length of the 3'-untranslated
region because of utilization of an array of alternative (canonical and
noncanonical) polyadenylation signals. Thus, cells can recruit sophisticated
molecular processes to regulate diphosphoinositol polyphosphate turnover.
PMID- 10777569
TI - NF-kappaB inhibits apoptosis in murine mammary epithelia.
AB - The transcription factor NF-kappaB is a key modulator of apoptosis in a variety
of cell types, but to date this specific function of NF-kappaB has not been
demonstrated in epithelia. Here, we describe the activation of NF-kappaB during
post-lactational involution of the mouse mammary gland, a period of extensive
apoptosis of luminal epithelial cells. Significantly, active NF-kappaB localized
exclusively to nonapoptotic epithelial cells both in vivo and in the mammary
epithelial cell line, KIM-2, transduced with an NF-kappaB-dependent green
fluorescent protein reporter. Activation of NF-kappaB in vitro coincided with a
decrease in the cytosolic repressor, IkappaBalpha. Furthermore, induction of NF
kappaB either by extracellular ligands or, more specifically, by inhibition of
the IkappaB repressor with adenoviral constructs expressing antisense mRNA,
resulted in enhanced survival of KIM-2 cells. Therefore, although coincident with
induction of apoptosis both in vivo and in vitro, NF-kappaB appeared to exert a
selective survival function in epithelial cells. This study highlights for the
first time a role for NF-kappaB in modulating apoptosis in epithelium.
PMID- 10777570
TI - Successful targeting to rat hepatic stellate cells using albumin modified with
cyclic peptides that recognize the collagen type VI receptor.
AB - The key pathogenic event in liver fibrosis is the activation of hepatic stellate
cells (HSC). Consequently, new antifibrotic therapies are directed toward an
inhibition of HSC activities. The aim of the present study was to develop a drug
carrier to HSC, which would allow cell-specific delivery of antifibrotic drugs
thus enhancing their effectiveness in vivo. We modified human serum albumin (HSA)
with 10 cyclic peptide moieties recognizing collagen type VI receptors
(C*GRGDSPC*, in which C* denotes the cyclizing cysteine residues) yielding pCVI
HSA. In vivo experiments showed preferential distribution of pCVI-HSA to both
fibrotic and normal rat livers (respectively, 62 +/- 6 and 75 +/- 16% of the dose
at 10 min after intravenous injection). Immunohistochemical analysis demonstrated
that pCVI-HSA predominantly bound to HSC in fibrotic livers (73 +/- 14%). In
contrast, endothelial cells contributed mostly to the total liver accumulation in
normal rats. In vitro studies showed that pCVI-HSA specifically bound to rat HSC,
in particular to the activated cells, and showed internalization of pCVI-HSA by
these cells. In conclusion, pCVI-HSA may be applied as a carrier to deliver
antifibrotic agents to HSC, which may strongly enhance the effectiveness and
tissue selectivity of these drugs. This approach has the additional benefit that
such carriers may block receptors that play a putative role in the pathogenesis
of liver fibrosis.
PMID- 10777571
TI - SCAMP1 function in endocytosis.
AB - Secretory carrier membrane proteins (SCAMPs) are ubiquitous components of
recycling vesicles that shuttle between the plasma membrane, endosomes, and the
trans-Golgi complex. SCAMPs contain multiple N-terminal NPF repeats and four
highly conserved transmembrane regions. NPF repeats often interact with EH domain
proteins that function in budding of transport vesicles from the plasma membrane
or the Golgi complex. We now show that the NPF repeats of SCAMP1 bind to two EH
domain proteins, intersectin 1, which is involved in endocytic budding at the
plasma membrane, and gamma-synergin, which may mediate the budding of vesicles in
the trans-Golgi complex. Expression of SCAMP1 lacking the N-terminal NPF repeats
potently inhibited transferrin uptake by endocytosis. Our data suggest that one
of the functions of SCAMPs is to participate in endocytosis via a mechanism which
may involve the recruitment of clathrin coats to the plasma membrane and the
trans-Golgi network.
PMID- 10777572
TI - ATPase activity of a highly stable alpha(3)beta(3)gamma subcomplex of
thermophilic F(1) can be regulated by the introduced regulatory region of gamma
subunit of chloroplast F(1).
AB - A mutant F(1)-ATPase alpha(3)beta(3)gamma subcomplex from the thermophilic
Bacillus PS3 was constructed, in which 111 amino acid residues (Val(92) to
Phe(202)) from the central region of the gamma subunit were replaced by the 148
amino acid residues of the homologous region from spinach chloroplast F(1)-ATPase
gamma subunit, including the regulatory stretch, and were designated as
alpha(3)beta(3)gamma((TCT)) (Thermophilic-Chloroplast-Thermophilic). By the
insertion of this regulatory region into the gamma subunit of thermophilic F(1),
we could confer the thiol modulation property to the thermophilic
alpha(3)beta(3)gamma subcomplex. The overexpressed alpha(3)beta(3)gamma((TCT))
was easily purified in large scale, and the ATP hydrolyzing activity of the
obtained complex was shown to increase up to 3-fold upon treatment with
chloroplast thioredoxin-f and dithiothreitol. No loss of thermostability compared
with the wild type subcomplex was found, and activation by dithiothreitol was
functional at temperatures up to 80 degrees C. alpha(3)beta(3)gamma((TCT)) was
inhibited by the epsilon subunit from chloroplast F(1)-ATPase but not by the one
from the thermophilic F(1)-ATPase, indicating that the introduced amino acid
residues from chloroplast F(1)-gamma subunit are important for functional
interaction with the epsilon subunit.
PMID- 10777573
TI - Modeling and functional analysis of the interaction between von Willebrand factor
A1 domain and glycoprotein Ibalpha.
AB - Binding of the von Willebrand factor (vWF) A1 domain to the glycoprotein (GP) Ib
IX-V complex mediates platelet adhesion to reactive substrates under high shear
stress conditions, a key event in hemostasis and thrombosis. We have now used the
known three-dimensional structure of the A1 domain to model the interaction with
the GP Ibalpha sequence 271-279, which has previously been implicated in ligand
binding. Docking procedures suggested that A1 domain residues in strand beta3 and
preceding loop (residues 559-566) as well as in helix alpha3 (residues 594-603)
interact with Asp residues 272, 274, 277 and sulfated Tyr residues 278 and 279 in
GP Ibalpha. To verify this model, 14 mutant A1 domain fragments containing single
or multiple side chain substitutions were tested for their ability to mediate
platelet adhesion under flow. Each of the vWF residues Tyr(565), Glu(596), and
Lys(599) proved to be strictly required for A1 domain function, which, in
agreement with previous findings, was also dependent on Gly(561). Moreover, an
accessory functional role was apparent for a group of positively charged
residues, including Arg at positions 629, 632, 636 and Lys at positions 643 and
645, possibly acting in concert. There was, however, no evidence from the model
that these residues directly participate in forming the complex with GP Ibalpha.
These results provide a partial model of the vWF-GP Ibalpha interaction linked to
the manifestation of functional activity in platelet adhesion.
PMID- 10777574
TI - High density lipoprotein-mediated cholesterol uptake and targeting to lipid
droplets in intact L-cell fibroblasts. A single- and multiphoton fluorescence
approach.
AB - Fluorescent sterols, dehydroergosterol and NBD-cholesterol, were used to examine
high density lipoprotein-mediated cholesterol uptake and intracellular targeting
in L-cell fibroblasts. The uptake, but not esterification or targeting to lipid
droplets, of these sterols differed >100-fold, suggesting significant differences
in uptake pathways. NBD-cholesterol uptake kinetics and lipoprotein specificity
reflected high density lipoprotein-mediated sterol uptake via the scavenger
receptor B1. Fluorescence energy transfer showed an average intermolecular
distance of 26 A between the two fluorescent sterols in L-cells. Indirect
immunofluorescence revealed that both fluorescent sterols localized to L-cell
lipid droplets, the surface of which contained adipose differentiation-related
protein. This lipid droplet-specific protein specifically bound NBD-cholesterol
with high affinity (K(d) = 2 nM) at a single site. Thus, NBD-cholesterol and
dehydroergosterol were useful fluorescent probes of sterol uptake and
intracellular sterol targeting. NBD-cholesterol more selectively probed high
density lipoprotein-mediated uptake and rapid intracellular targeting of sterol
to lipid droplets. Targeting of sterol to lipid droplets was correlated with the
presence of adipose differentiation related protein, a lipid droplet-specific
protein shown for the first time to bind unesterified sterol with high affinity.
PMID- 10777575
TI - Calcium binding to the photosystem II subunit CP29.
AB - We have identified a Ca(2+)-binding site of the 29-kDa chlorophyll a/b-binding
protein CP29, a light harvesting protein of photosystem II most likely involved
in photoregulation. (45)Ca(2+) binding studies and dot blot analyses of CP29
demonstrate that CP29 is a Ca(2+)-binding protein. The primary sequence of CP29
does not exhibit an obvious Ca(2+)-binding site therefore we have used Yb(3+)
replacement to analyze this site. Near-infrared Yb(3+) vibronic side band
fluorescence spectroscopy (Roselli, C., Boussac, A., and Mattioli, T. A. (1994)
Proc. Natl. Acad. Sci. U. S. A. 91, 12897-12901) of Yb(3+)-reconstituted CP29
indicated a single population of Yb(3+)-binding sites rich in carboxylic acids,
characteristic of Ca(2+)-binding sites. A structural model of CP29 presents two
purported extra-membranar loops which are relatively rich in carboxylic acids,
one on the stromae side and one on the lumenal side. The loop on the lumenal side
is adjacent to glutamic acid 166 in helix C of CP29, which is known to be the
binding site for dicyclohexylcarbodiimide (Pesaresi, P., Sandona, D., Giuffra, E.
, and Bassi, R. (1997) FEBS Lett. 402, 151-156). Dicyclohexylcarbodiimide binding
prevented Ca(2+) binding, therefore we propose that the Ca(2+) in CP29 is bound
in the domain including the lumenal loop between helices B and C.
PMID- 10777576
TI - The functional role of basic patch, a structural element of Escherichia coli
transcript cleavage factors GreA and GreB.
AB - The transcript cleavage factors GreA and GreB of Escherichia coli are involved in
the regulation of transcription elongation. The surface charge distribution
analysis of their three-dimensional structures revealed that the N-terminal
domains of GreA and GreB contain a small and large basic "patch," respectively.
To elucidate the functional role of basic patch, mutant Gre proteins were
engineered in which the size and charge distribution of basic patch were modified
and characterized biochemically. We found that Gre mutants lacking basic patch or
carrying basic patch of decreased size bind to RNA polymerase and induce
transcript cleavage reaction in minimally backtracked ternary elongation complex
(TEC) with the same efficiency as the wild type factors. However, they exhibit
substantially lower readthrough and cleavage activities toward extensively
backtracked and arrested TECs and display decreased efficiency of photocross
linking to the RNA 3'-terminus. Unlike wild type factors, basic patch-less Gre
mutants are unable to complement the thermosensitive phenotype of GreA(-):GreB(-)
E. coli strain. The large basic patch is required but not sufficient for the
induction of GreB-type cleavage reaction and for the cleavage of arrested TECs.
Our results demonstrate that the basic patch residues are not directly involved
in the induction of transcript cleavage reaction and suggest that the primary
role of basic patch is to anchor the nascent RNA in TEC. These interactions are
essential for the readthrough and antiarrest activities of Gre factors and,
apparently, for their in vivo functions.
PMID- 10777577
TI - Alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, or alpha(2)
macroglobulin is required for vascular smooth muscle cell spreading in three
dimensional fibrin gel.
AB - It is assumed that vitronectin and other adhesion molecules induce cell
spreading. We found that vascular smooth muscle cells require unidentified plasma
components besides adhesion molecules to spread in fibrin gel, a likely
provisional matrix at wound sites. By purification, the plasma components were
found to be alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, and
alpha(2)-macroglobulin. The chemically inactivated alpha(1)-proteinase inhibitor
and alpha(2)-macroglobulin lose the spreading activity, indicating that these
proteins function as proteinase inhibitors but not as adhesion molecules. Not
only anti-integrin (alpha(v)beta(3) and alpha(5)beta(1)) antibodies but also anti
fibronectin antibodies inhibit the cell spreading. The spreading occurs without
the addition of fibronectin and integrins, suggesting that cells produce these
molecules. In the absence of the proteinase inhibitors, Western blot analysis
shows that the fibronectin is degraded in fibrin gel, while it is intact in the
presence of the inhibitors. Thus, the proteinase inhibitors prevent adhesion
molecules such as fibronectin from being degraded by a cell-derived proteinase(s)
and thus play a role in cell spreading.
PMID- 10777578
TI - Human procathepsin B interacts with the annexin II tetramer on the surface of
tumor cells.
AB - To study potential roles of plasma membrane-associated extracellular cathepsin B
in tumor cell invasion and metastasis, we used the yeast two-hybrid system to
screen for proteins that interact with human procathepsin B. The annexin II light
chain (p11), one of the two subunits of the annexin II tetramer, was one of the
proteins identified. We have confirmed that recombinant human procathepsin B
interacts with p11 as well as with the annexin II tetramer in vitro. Furthermore,
procathepsin B could interact with the annexin II tetramer in vivo as
demonstrated by coimmunoprecipitation. Cathepsin B and the annexin II tetramer
were shown by immunofluorescent staining to colocalize on the surface of human
breast carcinoma and glioma cells. Taken together, our results indicate that the
annexin II tetramer can serve as a binding protein for procathepsin B on the
surface of tumor cells, an interaction that may facilitate tumor invasion and
metastasis.
PMID- 10777579
TI - Thermodynamic consequences of grafting enhanced affinity toward the mutated
antigen onto an antibody. The case of anti-lysozyme antibody, HyHEL-10.
AB - In order to address the mechanism of enhancement of the affinity of an antibody
toward an antigen from a thermodynamic viewpoint, anti-hen lysozyme (HEL)
antibody HyHEL-10, which also recognize the mutated antigen turkey lysozyme (TEL)
with reduced affinity, was examined. Grafting high affinity toward TEL onto HyHEL
10 was performed by saturation mutagenesis into four residues (Tyr(53), Ser(54),
Ser(56), and Tyr(58)) in complementarity-determining region 2 of the heavy chain
(CDR-H2) followed by selection with affinity for TEL. Several clones enriched
have a Phe residue at site 58. Thermodynamic analyses showed that the clones
selected had experienced a greater than 3-fold affinity increase toward TEL in
comparison with wild-type Fv, originating from an increase in negative enthalpy
change. Substitution of HyHEL-10 HTyr(58) with Phe led to the increase in
negative enthalpy change and to almost identical affinity for TEL in comparison
with mutants selected, indicating that mutations at other sites decrease the
entropy loss despite little contribution to the affinity for TEL. These results
suggest that the affinity of an antibody toward the antigen is enhanced by the
increase in enthalpy change by some limited mutation, and excess entropy loss due
to the mutation is decreased by other energetically neutral mutations.
PMID- 10777580
TI - Cloning and characterization of the murine glucosamine-6-phosphate
acetyltransferase EMeg32. Differential expression and intracellular membrane
association.
AB - N-Linked glycosylation is a post-translational modification occurring in many
eukaryotic secreted and surface-bound proteins and has impact on diverse
physiological and pathological processes. Similarly important is the generation
of glycosylphosphatidylinositol linkers, which anchor membrane proteins to the
cell. Both protein modifications depend on the central nucleotide sugar UDP-N
acetylglucosamine (UDP-GlcNAc). The enzymatic reactions leading to generation of
nucleotide sugars are established, yet most of the respective genes still await
cloning. We describe the characterization of such a gene, EMeg32, which we
identified based on its differential expression in murine hematopoietic precursor
cells. We further demonstrate regulated expression during embryogenesis. EMeg32
codes for a 184-amino acid protein exhibiting glucosamine-6-phosphate
acetyltransferase activity. It thereby holds a key position in the pathway toward
de novo UDP-GlcNAc synthesis. Surprisingly, the protein associates with the
cytoplasmic side of various intracellular membranes, accumulates prior to
mitosis, and copurifies with the cdc48 homolog p97/valosin-containing protein.
PMID- 10777581
TI - The GPI-linked Ly-6 antigen E48 regulates expression levels of the FX enzyme and
of E-selectin ligands on head and neck squamous carcinoma cells.
AB - By differential display we demonstrated that antibody-mediated ligation of the
GPI-linked protein product of E48, a newly discovered human Ly-6 gene, up
regulates the expression of the FX enzyme in 3 lines of head and neck squamous
carcinoma cells. FX is responsible for the last step in the synthesis of GDP-L
fucose. The up-regulation of FX was E48 ligand-specific. 22AWT head and neck
squamous carcinoma cells expressing high levels of E48 expressed significantly
higher levels of FX than the E48 antisense transfected 22AWT cells (8-3 cells).
The former cells also expressed higher levels of two major fucosylated glycans
(the selectin ligand, Sialyl Lewis a, and VIM-2) than the E48 antisense
transfectants. Conversely, transfection of cells from the 14CWT line expressing
very low levels of E48 with E48 cDNA caused an up-regulated expression of FX and
of the two fucosylated glycans in the 14C-CMV16 transfectants. Moreover, the
expression levels of Sialyl Lewis a was significantly up-regulated on HNSCC upon
ligation of E48 by anti-E48 antibodies. The functional significance of the E48
mediated up-regulation of Sialyl Lewis a was demonstrated in rolling experiments
on E-selectin bearing surfaces under physiological conditions of shear flow and
on tumor necrosis factor alpha-activated human umbilical venous endothelial
cells. Only high E48/FX/Sialyl Lewis a expressing 14C-CMV16 cells could roll on
purified E-selectin or establish E-selectin dependent rolling on the activated
human umbilical venous endothelial cells. Low E48/FX/Sialyl Lewis a expressing
14CWT cells did not roll. These results show that E48 controls the expression of
the FX enzyme and of certain fucosylated E-selectin ligands by HNSCC. E48 may
thus function as a key regulator of the adhesiveness of these tumor cells to
inflamed vessel walls expressing E-selectin.
PMID- 10777582
TI - Identification and cloning of a new calmodulin-like protein from human epidermis.
AB - After separating by two-dimensional gel electrophoresis an extract of total
proteins from human stratum corneum, two spots were extracted and analyzed for
their peptide sequence. The resulting internal protein sequences provided
evidence for the identification of a new calcium-binding protein. Cloning of the
corresponding full-length cDNA was achieved by reverse transcriptase-polymerase
chain reaction using two keratinocyte libraries, one from proliferating cultured
keratinocytes and one from differentiated keratinocytes of reconstructed human
epidermis. The cDNA had an open reading frame encoding a new calcium-binding
protein of 146 amino acids, a member of the calmodulin family. We named this new
protein calmodulin-like skin protein (CLSP), since reverse transcriptase
polymerase chain reaction studies of CLSP expression in 10 different human
tissues revealed that this protein was particularly abundant in the epidermis
where its expression is directly related to keratinocyte differentiation.
Expression of the cloned cDNA in Escherichia coli yielded a recombinant protein
which allowed its further characterization. rCLSP is able to bind calcium, and
similarly to calmodulin, exposes thereafter hydrophobic parts which most likely
interact with target proteins. Epidermal proteins retained by CaM affinity column
are quantitatively and qualitatively distinct from those of the rCLSP column.
Sequencing of a rCLSP affinity purified protein revealed 100% identity with
transglutaminase 3, a key enzyme in terminal differentiation, indicating an
important role of CLSP in this process.
PMID- 10777583
TI - SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through
the SHP2 recruitment site of gp130.
AB - Interleukin-6 is involved in the regulation of many biological activities such as
gene expression, cell proliferation, and differentiation. The control of the
termination of cytokine signaling is as important as the regulation of initiation
of signal transduction pathways. Three families of proteins involved in the down
regulation of cytokine signaling have been described recently: (i) SH2 domain
containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine
signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have
analyzed the interplay of two inhibitors in the signal transduction pathway of
interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not
act independently but are functionally linked. The activation of one inhibitor
modulates the activity of the other; Inhibition of SHP2 activation leads to
increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a
reduction of SHP2 phosphorylation after activation of the interleukin-6 signal
transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is
essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory
activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also
interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results
suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2
and SOCS3.
PMID- 10777584
TI - Identification of a novel SCAN box-related protein that interacts with MZF1B. The
leucine-rich SCAN box mediates hetero- and homoprotein associations.
AB - The SCAN box or leucine-rich (LeR) domain is a conserved motif found within a
subfamily of C(2)H(2) zinc finger proteins. The function of a SCAN box is
unknown, but it is predicted to form alpha-helices that may be involved in
protein-protein interactions. Myeloid zinc finger gene-1B (MZF1B) is an
alternatively spliced human cDNA isoform of the zinc finger transcription factor,
MZF1. MZF1 and MZF1B contain 13 C(2)H(2) zinc finger motifs, but only MZF1B
contains an amino-terminal SCAN box. A bone marrow cDNA library was screened for
proteins interacting with the MZF1B SCAN box domain and RAZ1 (SCAN-related
protein associated with MZF1B) was identified. RAZ1 is a novel cDNA that encodes
a SCAN-related domain and arginine-rich region but no zinc finger motifs. Co
immunoprecipitation assays demonstrate that the SCAN box domain of MZF1B is
necessary for association with RAZ1. By yeast two-hybrid analysis, the carboxyl
terminus of RAZ1 is sufficient for interaction with the MZF1B SCAN box.
Furthermore, MZF1B and RAZ1 each self-associate in vitro via a SCAN box-dependent
mechanism. These data provide evidence that the SCAN box is a protein interaction
domain that mediates both hetero- and homoprotein associations.
PMID- 10777585
TI - Roles of thermal instability and proteolytic cleavage in regulation of activated
thrombin-activable fibrinolysis inhibitor.
AB - We have used site-directed mutagenesis and a recombinant expression system for
thrombin-activable fibrinolysis inhibitor (TAFI) in order to identify the
thrombin cleavage site in activated TAFI (TAFIa) and to determine the relative
contribution of proteolytic cleavage and thermal instability in regulation of
TAFIa activity in clots. Arg-330 of TAFIa had been proposed to be the thrombin
cleavage site based on studies with trypsin, but mutation of this residue to Gln
did not prevent thrombin-mediated cleavage nor did mutation to Gln of the nearby
Arg-320 residue. However, mutation of Arg-302 to Gln abolished thrombin-mediated
cleavage of TAFIa. All TAFIa variants were susceptible to plasmin cleavage.
Interestingly, all Arg to Gln substitutions decreased the thermal stability of
TAFIa. The antifibrinolytic potential of the TAFI mutants in vitro correlates
with the thermal stability of their respective TAFIa species, indicating that
this property plays a key role in regulating the activity if TAFIa. Incubation of
TAFIa under conditions that result in complete thermal inactivation of the enzyme
accelerates subsequent thrombin- and plasmin-mediated cleavage of TAFIa.
Moreover, the extent of cleavage of TAFIa by thrombin does not affect the rate of
decay of TAFIa activity. Collectively, these studies point to a role for the
thermal instability, but not for proteolytic cleavage, of TAFIa in regulation of
its activity and, thus, of its antifibrinolytic potential. Finally, we propose a
model for the thermal instability of TAFIa.
PMID- 10777586
TI - The zinc finger repressor, ZBP-89, binds to the silencer element of the human
vimentin gene and complexes with the transcriptional activator, Sp1.
AB - Vimentin is a component of the eukaryotic cytoskeleton belonging to the family of
intermediate filament proteins. It exhibits a complex pattern of tissue- and
development-specific expression. It is also a marker of the metastatic potential
of many tumor cells. Previously, the human vimentin promoter was shown to contain
several regions for the binding of positive and negative acting regulatory
factors. Until now, the silencer element, which shuts down vimentin synthesis in
selected tissues during development, was not precisely localized; nor was its
binding protein known. In vivo DMS footprinting by ligation-mediated PCR
delineated the position of guanine residues important to vimentin expression.
Transient transfection assays in HeLa cells of various vimentin 5'-end promoter
sequences and mutants thereof precisely defined two regulatory elements, a
negative element and an adjoining positive acting element. Band shift assays, UV
cross-linking, and Southwestern blot analysis confirm that the silencer element
specifically binds a protein. Several lines of evidence show that ZBP-89, a zinc
finger, Kruppel-like repressor protein is vimentin's silencer element binding
factor. Co-immunoprecipitation and DNA affinity chromatography prove that Sp1
heterodimerizes with ZBP-89 when bound to the silencer element to yield a DNA
protein complex whose mobility is indistinguishable from that displayed by HeLa
nuclear extract in band shift assays.
PMID- 10777587
TI - The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1
adipocytes.
AB - PTEN is a tumor suppressor with sequence homology to protein-tyrosine
phosphatases and the cytoskeleton protein tensin. PTEN is capable of
dephosphorylating phosphatidylinositol 3,4, 5-trisphosphate in vitro and down
regulating its levels in insulin-stimulated 293 cells. To study the role of PTEN
in insulin signaling, we overexpressed PTEN in 3T3-L1 adipocytes approximately 30
fold above uninfected or control virus (green fluorescent protein)-infected
cells, using an adenovirus gene transfer system. PTEN overexpression inhibited
insulin-induced 2-deoxy-glucose uptake by 36%, GLUT4 translocation by 35%, and
membrane ruffling by 50%, all of which are phosphatidylinositol 3-kinase
dependent processes, compared with uninfected cells or cells infected with
control virus. Microinjection of an anti-PTEN antibody increased basal and
insulin stimulated GLUT4 translocation, suggesting that inhibition of endogenous
PTEN function led to an increase in intracellular phosphatidylinositol 3,4,5
trisphosphate levels, which stimulates GLUT4 translocation. Further, insulin
induced phosphorylation of downstream targets Akt and p70S6 kinase were also
inhibited significantly by overexpression of PTEN, whereas tyrosine
phosphorylation of the insulin receptor and IRS-1 or the phosphorylation of
mitogen-activated protein kinase were not affected, suggesting that the
Ras/mitogen-activated protein kinase pathway remains fully functional. Thus, we
conclude that PTEN may regulate phosphatidylinositol 3-kinase-dependent insulin
signaling pathways in 3T3-L1 adipocytes.
PMID- 10777588
TI - The Elp2 subunit of elongator and elongating RNA polymerase II holoenzyme is a
WD40 repeat protein.
AB - A novel yeast gene, ELP2, is shown to encode the 90-kDa subunit of the Elongator
complex and elongating RNA polymerase II holoenzyme. ELP2 encodes a protein with
eight WD40 repeats, and cells lacking the gene display typical elp phenotypes,
such as temperature and salt sensitivity. Generally, different combinations of
double and triple ELP gene deletions cause the same phenotypes as single ELP1,
ELP2, or ELP3 deletion, providing genetic evidence that the ELP gene products
work together in a complex.
PMID- 10777589
TI - Selective regulation of endogenous G protein-coupled receptors by arrestins in
HEK293 cells.
AB - Arrestins play an important role in regulating desensitization and trafficking of
G protein-coupled receptors (GPCRs). However, limited insight into the
specificity of arrestin-mediated regulation of GPCRs is currently available.
Recently, we used an antisense strategy to reduce arrestin levels in HEK293 cells
and characterize the role of arrestins on endogenous G(s)-coupled receptors
(Mundell, S. J., Loudon, R. B., and Benovic, J. L. (1999) Biochemistry 38, 8723
8732). Here, we characterized GPCRs coupled to either G(q) (M(1) muscarinic
acetylcholine receptor (M(1)AchR) and P2y(1) and P2y(2) purinergic receptors) or
G(i) (somatostatin and AT1 angiotensin receptors) in wild type and arrestin
antisense HEK293 cells. The agonist-specific desensitization of the M(1)Ach and
somatostatin receptors was significantly attenuated in antisense-expressing
cells, whereas desensitization of P2y(1) and P2y(2) purinergic and AT1
angiotensin receptors was unaffected by reduced arrestin levels. To further
examine arrestin/GPCR specificity, we studied the effects of endogenous GPCR
activation on the redistribution of arrestin-2 epitope tagged with the green
fluorescent protein (arrestin-2-GFP). These studies revealed a receptor-specific
movement of arrestin-2-GFP that mirrored the arrestin-receptor specificity
observed in the antisense cells. Thus, agonist-induced activation of endogenous
beta(2)-adrenergic, prostaglandin E(2), M(1)Ach, and somatostatin receptors
induced arrestin-2-GFP redistribution to early endosomes, whereas P2y(1) and
P2y(2) purinergic and AT1 angiotensin receptor activation did not. Thus,
endogenous arrestins mediate the regulation of selective G(q)- and G(i)-coupled
receptors in HEK293 cells.
PMID- 10777590
TI - FHX, a novel fork head factor with a dual DNA binding specificity.
AB - The HNF3/fork head family includes a large number of transcription factors that
share a structurally related DNA binding domain. Fork head factors have been
shown to play important roles both during development and in the adult. We now
describe the cloning of a novel mammalian fork head factor that we have named FHX
(fork head homologous X (FHX), which is expressed in many adult tissues. In the
embryo, FHX expression showed a very early onset during the cleavage stages of
preimplantation development. Polymerase chain reaction-assisted site selection
experiments showed that FHX bound DNA with a dual sequence specificity. Sites
recognized by FHX could be classified into two different types according to their
sequences. Binding of FHX to sequences of each type appeared to occur
independently. Our data suggest that either different regions of the fork head
domain or different molecular forms of this domain could be involved in binding
of FHX to each type of site. In transfection assays, FHX was capable of
activating transcription from promoters containing FHX sites of either type.
PMID- 10777591
TI - Mechanistic studies of the effects of anti-factor H antibodies on complement
mediated lysis.
AB - We have recently reported that complement factor H, a negative regulator of
complement-mediated cytotoxicity, is produced and secreted by most bladder
cancers. This observation was exploited in the development of the BTA stat and
BTA TRAK diagnostic assays, both of which make use of two factor H-specific
monoclonal antibodies in sandwich format. Here we show that both antibodies exert
interesting effects on the biochemistry of complement activation in in vitro
systems. Antibody X13.2 competes with C3b for association with factor H and
strongly inhibits factor H/factor I-mediated cleavage of C3b, thereby evidently
inactivating a negative regulator of complement; yet, the antibody strongly
inhibits complement-mediated lysis as well. Conversely, antibody X52. 1, which
does not compete with C3b and has no effect on solution-phase cleavage of C3b, is
capable of enhancing complement-mediated lysis of various cell types, including
cancer cells, by over 10-fold. Our observations indicate that it is possible to
deconvolute the biochemical roles of factor H in complement by means of
appropriate inhibitors, a finding with potentially valuable implications for both
basic research and cancer therapy.
PMID- 10777592
TI - Reversible transdominant inhibition of a metabolic pathway. In vivo evidence of
interaction between two sequential tricarboxylic acid cycle enzymes in yeast.
AB - The enzymes of the Krebs tricarboxylic acid cycle in mitochondria are proposed to
form a supramolecular complex, in which there is channeling of intermediates
between enzyme active sites. While interactions have been demonstrated in vitro
between most of the sequential tricarboxylic acid cycle enzymes, no direct
evidence has been obtained in vivo for such interactions. We have isolated, in
the Saccharomyces cerevisiae gene encoding the tricarboxylic acid cycle enzyme
citrate synthase Cit1p, an "assembly mutation," i.e. a mutation that causes a
tricarboxylic acid cycle deficiency without affecting the citrate synthase
activity. We have shown that a 15-amino acid peptide from wild type Cit1p
encompassing the mutation point inhibits the tricarboxylic acid cycle in a
dominant manner, and that the inhibitory phenotype is overcome by a co
overexpression of Mdh1p, the mitochondrial malate dehydrogenase. These data
provide the first direct in vivo evidence of interaction between two sequential
tricarboxylic acid cycle enzymes, Cit1p and Mdh1p, and indicate that the
characterization of assembly mutations by the reversible transdominant inhibition
method may be a powerful way to study multienzyme complexes in their
physiological context.
PMID- 10777593
TI - The role of transcription factor B in transcription initiation and promoter
clearance in the archaeon Sulfolobus acidocaldarius.
AB - Mechanisms of transcription initiation appear to be remarkably conserved between
archaea and eucaryotes. For instance, there is homology between archaeal and
eucaryotic basal transcription factors. Also, the archaeal RNA polymerase (RNAP)
resembles eucaryotic nuclear RNAPs in subunit composition and at the amino acid
sequence level. Here, we examine the role of transcription factor B, the archaeal
homologue of eucaryotic transcription factor IIB, in transcription initiation. We
show that the N-terminal region of transcription factor B is required for RNAP
recruitment. Furthermore, we reveal that mutation of a conserved residue
immediately C-terminal of the N-terminal zinc ribbon motif abrogates
transcription on certain promoters. Finally, we identify the promoter sequences
responsive to this mutation and demonstrate that the effect of the mutation is to
block a late stage in transcription initiation, following formation of the
promoter open complex.
PMID- 10777594
TI - Cleavage of the serum response factor during death receptor-induced apoptosis
results in an inhibition of the c-FOS promoter transcriptional activity.
AB - The c-FOS protooncogene is rapidly induced by a wide variety of extracellular
stimuli including mitogenic signals. Regulation of c-FOS expression is tightly
dependent on the serum response element localized within its promoter. Two
transcription factors, the serum response factor (SRF) and the ternary complex
factor, bind to the serum response element and play a key role in the regulation
of the c-FOS promoter activity. In the present study, we show that two death
effectors (CH11 and TRAIL) severely impaired the transcriptional activity of the
c-FOS promoter in Jurkat T cells. This inhibition can be accounted for by the
specific cleavage by caspase 3 of the SRF both in vitro and in vivo, since acetyl
DEVD-aldehyde prevented SRF cleavage and abolished the inhibitory effect of CH11
and TRAIL on the c-FOS promoter activity. Moreover, phorbol myristate acetate, a
potent anti-apoptotic effector, was found to protect SRF completely from cleavage
by caspase 3 and also to prevent the inhibition of the c-FOS promoter activity by
death effectors. Survival factors play an essential function in the regulation of
cell growth mainly by regulating the expression of immediate early gene such as c
FOS. In this line, cleavage of SRF at the onset of apoptosis could abrogate the
ability of the cell to induce inappropriate survival pathways. All together, our
results are consistent with a role of SRF at the interface between cell survival
and death pathways.
PMID- 10777595
TI - Activating transcription factor 2 is necessary for maximal activity and serum
induction of the cyclin A promoter in chondrocytes.
AB - Endochondral bone growth is regulated through the proliferation and
differentiation of growth plate chondrocytes. Mice deficient for the activating
transcription factor 2 (ATF-2) gene show reduced proliferation of chondrocytes.
Here we demonstrate that the cyclin A gene is a target of ATF-2 in chondrocytes.
Serum stimulation of chondrogenic rat chondrosarcoma cells induces cyclin A
expression. A cyclic AMP response element (CRE) is necessary for optimal activity
and serum inducibility of the cyclin A promoter and confers regulation by ATF-2.
Phosphorylation and activity of ATF-2 are enhanced dramatically upon serum
stimulation of rat chondrosarcoma cells. Mutation of the CRE or overexpression of
dominant-negative ATF-2 inhibits serum induction of the cyclin A promoter.
Chondrocytes from ATF-2-deficient mice display reduced and delayed induction of
cyclin A upon serum stimulation. The ATF-2-related transcription factor CRE
binding protein contributes to the activity of the cyclin A CRE in chondrocytes,
whereas c-Jun and c-Fos regulate the promoter independently of the CRE. Our data
suggest that the reduction in cyclin A levels in chondrocytes from ATF-2
deficient mice contributes to their phenotype of reduced chondrocyte
proliferation and dwarfism.
PMID- 10777596
TI - Involvement of mytilins in mussel antimicrobial defense.
AB - Four cationic peptides were purified from mussel (Mytilus galloprovincialis)
hemocytes. A combination of Edman degradation and mass spectrometry of plasma
revealed (i) a previously characterized molecule, mytilin B (Charlet, M.,
Chernysh, S., Philippe, H., Hetrut, C., Hoffmann, J., and Bulet, P. (1996) J.
Biol. Chem. 271, 21808-21813) and (ii) three new isoforms, mytilin C, D, and G1.
The four molecules exhibited complementary antimicrobial properties. The cDNA
sequence coding for the mytilin B precursor was obtained from a hemocyte cDNA
library. This precursor contains a putative signal peptide of 22 residues, a
processing peptide sequence of 34 amino acids, and a C-terminal extension of 48
residues rich in acidic residues. Distribution of mytilin B mRNA and of the
corresponding peptide in various mussel tissues revealed that mytilins are
synthesized and stored in a specific hemocyte subtype. Furthermore, in an
experimental model of infection, we showed (i) a recruitment of hemocytes
containing mytilins toward the injection site within hours following bacterial
challenge, (ii) that mytilins probably play a prominent role in killing
intracellular bacteria after phagocytosis, and (ii) later an increase of mytilin
like material occurred in the plasma suggesting a secondary systemic role.
PMID- 10777597
TI - Structural determinants for post-transcriptional stabilization of lactate
dehydrogenase A mRNA by the protein kinase C signal pathway.
AB - Activation of protein kinase C (PKC) and protein kinase A (PKA) in rat C6 glioma
cells increases the half-life of short-lived lactate dehydrogenase (LDH)-A mRNA
about 5- and 8-fold, respectively. PKA and PKC act synergistically and prolong
LDH-A mRNA half-life more than 21-fold. Similar effects were observed after
transfection and transcription of a globin/lactate dehydrogenase minigene
consisting of a beta-globin expression vector in which the 3'-untranslated region
(UTR) of beta-globin had been replaced with the LDH-A 3'-UTR. Synergism was only
obtained by transcription of minigenes containing the entire 3'-UTR and did not
occur when truncated 3'-UTR fragments were analyzed. Additional mutational
analyses showed that a 20-nucleotide region, named PKC-stabilizing region (PCSR),
is responsible for mediating the stabilizing effect of PKC. Previous studies
(Tian, D., Huang, D., Short, S., Short, M. L., and Jungmann, R. A. (1998) J.
Biol. Chem. 273, 24861-24866) have demonstrated the existence of a cAMP
stabilizing region in LDH-A 3'-UTR. Sequence analysis of PCSR identified a 13
nucleotide AU-rich region that is common to both cAMP-stabilizing region and
PCSR. These studies identify a specific PKC-responsive stabilizing element and
indicate that interaction of PKA and PKC results in a potentiating effect on LDH
A mRNA stabilization.
PMID- 10777598
TI - Integrins regulate the linkage between upstream and downstream events in G
protein-coupled receptor signaling to mitogen-activated protein kinase.
AB - Receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) can both
activate mitogen-activated protein kinase (MAPK), a critical intermediate in the
transduction of proliferative signals. Numerous observations have demonstrated
that integrin-mediated cell anchorage can regulate the efficiency of signaling
from RTKs to MAPK. Recently, a relationship between integrins and GPCR signaling
has also emerged; however, little is understood concerning the mechanisms
involved. Here, we investigate integrin regulation of GPCR signaling to MAPK,
focusing on the P2Y class of GPCRs that function through activation of
phospholipase Cbeta. P2Y receptor signaling to the downstream components mitogen
activated protein kinase kinase and MAPK is highly dependent on integrin-mediated
cell anchorage. However, activation of upstream events, including inositol
phosphate production and generation of calcium transients, is completely
independent of cell anchorage. This indicates that integrins regulate the linkage
between upstream and downstream events in this GPCR pathway, just as they do in
some aspects of RTK signaling. However, the P2Y pathway does not involve cross
activation of a RTK, nor a role for Shc or c-Raf; thus, it is quite distinct from
the classical RTK-Ras-Raf-MAPK cascade. Rather, integrin-modulated P2Y receptor
stimulation of MAPK depends on calcium and on the activation of protein kinase C.
PMID- 10777599
TI - A novel activation mechanism of caspase-activated DNase from Drosophila
melanogaster.
AB - Caspase-activated DNase (CAD) is an enzyme that cleaves chromosomal DNA in
apoptotic cells. Here, we identified a DNase in Drosophila Schneider cells that
can be activated by caspase 3, and purified it as a complex of two subunits (p32
and p20). Using primers based on the amino acid sequence of the purified
proteins, a cDNA coding for Drosophila CAD (dCAD) was cloned. The polypeptide
encoded by the cDNA contained 450 amino acids with a calculated M(r) of 52,057,
and showed significant homology with human and mouse CAD (22% identity).
Mammalian CADs carry a nuclear localization signal at the C terminus. In
contrast, dCAD lacked the corresponding sequence, and the purified dCAD did not
cause DNA fragmentation in nuclei in a cell-free system. When dCAD was co
expressed in COS cells with Drosophila inhibitor of CAD (dICAD), a 52-kDa dCAD
was produced as a heterotetrameric complex with dICAD. When the complex was
treated with human caspase 3 or Drosophila caspase (drICE), the dICAD was
cleaved, and released from dCAD. In addition, dCAD was also cleaved by these
caspases, and behaved as a (p32)(2)(p20)(2) complex in gel filtration. When a
Drosophila neuronal cell line was induced to apoptosis by treatment with a kinase
inhibitor, both dCAD and dICAD were cleaved. These results indicated that unlike
mammalian CAD, Drosophila CAD must be cleaved by caspases to be activated.
PMID- 10777600
TI - Interleukin-1-mediated stabilization of mouse KC mRNA depends on sequences in
both 5'- and 3'-untranslated regions.
AB - mRNA transcribed from the mouse KC chemokine gene accumulated to significantly
higher levels in multiple cell types after treatment with interleukin 1alpha (IL
1alpha) as compared with tumor necrosis factor-alpha (TNFalpha). Although
TNFalpha and IL-1alpha both signaled the activation of nuclear factor kappaB and
enhanced transcription of the KC gene with equal potency, only IL-1alpha
treatment resulted in stabilization of KC mRNA. Nucleotide sequences that confer
sensitivity for IL-1alpha-mediated mRNA stabilization were identified within the
5'- and 3'-untranslated regions (UTRs) of KC mRNA using transient transfection of
chimeric plasmids containing specific portions of KC mRNA linked to the
chloramphenicol acetyltransferase (CAT) gene. When plasmids containing either the
3'- or 5'-UTR of KC mRNA were used, the half-life of CAT mRNA was unaltered
either in untreated or IL-1alpha-stimulated cells. In contrast, CAT mRNA
transcribed from plasmids that contained both the 5'- and 3'-UTRs of the KC mRNA
decayed more rapidly than control CAT mRNA, and this enhanced decay was prevented
in cells treated with IL-1alpha. A cluster of four overlapping AUUUA motifs
within the 3'-UTR was required, whereas the 5'-UTR region exhibited orientation
dependence. These findings indicate that cooperative function of the two
nucleotide sequences involves a distinct signaling pathway used by IL-1alpha but
not TNFalpha.
PMID- 10777601
TI - The accessibility of histone H3 tails in chromatin modulates their acetylation by
P300/CBP-associated factor.
AB - P300/CBP-associated factor (PCAF) is a transcriptional coactivator with intrinsic
histone acetylase activity. Reversible acetylation of the core histone tails in
chromatin has been linked to transcriptional regulation. Here we investigate the
mechanism whereby PCAF acetylates its target in chromatin. We demonstrate that
recombinant PACF preferentially acetylates the H3 tail in oligonucleosomes, as
compared with nucleosome core particles. The rate of acetylation is directly
related to the length of the oligonucleosomal substrate. Using a trypsin
accessibility assay, we demonstrate that the rate of acetylation is also related
to the accessibility of the H3 tail in uncondensed oligonucleosomes. We suggest
that PCAF, and perhaps other histone acetyltransferases, acetylate chromatin
templates more efficiently than core particle subunits and that this preference
arises from an increased accessibility of the H3 tail in either condensed or
uncondensed oligonucleosomes. Acetylation of the H3 tails by the native PCAF
complex is not affected by the length of the oligonucleosomal substrate. Our
results suggest that the accessibility of the H3 tail in chromatin is a major
factor affecting their rate of acetylation and that component(s) in the native
PCAF complex function to modify the organization of these tails in chromatin
thereby enhancing their accessibility to PCAF.
PMID- 10777602
TI - Structural organization of the microsomal glutathione S-transferase gene (MGST1)
on chromosome 12p13.1-13.2. Identification of the correct promoter region and
demonstration of transcriptional regulation in response to oxidative stress.
AB - The structure and regulation of the microsomal glutathione S-transferase gene
(MGST1) are considerably more complex than originally perceived to be. The MGST1
gene has two alternative first exons and is located in the 12p13.1-13.2 region.
Two other potential first exons were determined to be nonfunctional. The region
between the functional first exons cannot direct transcription. Thus, one common
promoter element directing transcription exists, and RNA splicing occurs such
that only one of the first exons (containing only untranslated mRNA) is
incorporated into each mRNA species with common downstream exons. MGST1
expression and regulation are therefore similar to those of other hepatic
xenobiotic handling enzymes, which also produce mRNA species differing only in
the 5'-untranslated regions to yield identical proteins. MGST1 was previously
considered a "housekeeping" gene, as non-oxidant inducers had little effect on
activity. However, the promoter region immediately upstream of the dominant first
exon transcriptionally responds to oxidative stress. In this respect, MGST1 is
similar to glutathione peroxidases that also transcriptionally respond to
oxidative stress. The discovery that MGST1 utilizes alternative first exon
splicing eliminates a problem with the first description of MGST1 cDNA in that it
appeared that MGST1 expression was in violation of the ribosomal scanning model.
The identification that the first exon originally noted is in fact a minor
alternative first exon far downstream of the primary first exon eliminates this
conundrum.
PMID- 10777603
TI - Steady-state levels of histone acetylation in Saccharomyces cerevisiae.
AB - The importance of control of the levels of histone acetylation for the control of
gene expression in eukaryotic chromatin is being elucidated, and the yeast
Saccharomyces cerevisiae has proven to be an important model system. The level of
histone acetylation in yeast is the highest known. However, only acetylation of
H4 has been quantified, and reports reveal loss of acetylation in histone
preparations. A chaotropic guanidine-based method for histone isolation from
intact wild-type cells or from a single-step nuclear preparation with butyrate
preserves acetylation of all core histones. Histone H4 has an average of more
than 2 acetylated lysines per molecule, distributed over 4 sites. Histones H2A,
H3, and H2B have 0. 2, approximately 2, and >2 acetylated lysines per molecule,
respectively, distributed across 2, 5, and 6 sites. Thus, yeast nucleosomes
carry, on average, 13 acetylated lysines per octamer, i. e. just above the
threshold of 10-12 deduced for transcriptionally activated chromatin of animals,
plants, and algae. Following M(r) 100,000 ultrafiltration in 2.5% acetic acid,
yeast histone H3 was purified to homogeneity by reversed-phase high pressure
liquid chromatography. Other core histones were obtained at 80-95% purity.
PMID- 10777604
TI - Human cytosolic and mitochondrial folylpolyglutamate synthetase are
electrophoretically distinct. Expression in antifolate-sensitive and -resistant
human cell lines.
AB - Folylpolyglutamate synthetase (FPGS) activity in CCRF-CEM human leukemia cells
was found in the cytosolic ( approximately 67% of total) and mitochondrial (
approximately 22%) fractions. A polyclonal antipeptide antibody (430Ab) to human
FPGS specifically recognized distinct immunoreactive bands ( approximately 60
kDa) present in each subcellular fraction. Human cytosolic FPGS (hcFPGS) migrated
more rapidly than mitochondrial FPGS (hmFPGS); their estimated difference in
molecular mass was 1 kDa. The human K562 acute nonlymphocytic leukemia and the
A253 and FaDu head and neck cancer cell lines also expressed the two FPGS
isoforms, and the ratio of hcFPGS to hmFPGS protein in each cell line was
similar. Since K562 and A253 cells are intrinsically resistant to pulse
methotrexate (MTX) exposure relative to CCRF-CEM and FaDu cells, respectively,
because of decreased MTX polyglutamate synthesis (despite having similar levels
of total FPGS activity expression), these data suggest that the natural
difference in drug sensitivity cannot be explained by compartmentalization of
FPGS activity. Higher expression of hmFPGS relative to hcFPGS was observed in
some sublines of CCRF-CEM with acquired MTX resistance suggesting that
differential expression of the hmFPGS isoform may contribute to MTX resistance
caused by decreased FPGS activity.
PMID- 10777605
TI - The efficiency and fidelity of translesion synthesis past cisplatin and
oxaliplatin GpG adducts by human DNA polymerase beta.
AB - DNA polymerase beta (pol beta) is the only mammalian DNA polymerase identified to
date that can catalyze extensive bypass of platinum-DNA adducts in vitro.
Previous studies suggest that DNA synthesis by pol beta is distributive on primed
single-stranded DNA and processive on gapped DNA. The data presented in this
paper provide an analysis of translesion synthesis past cisplatin- and
oxaliplatin-DNA adducts by pol beta functioning in both distributive and
processive modes using primer extension and steady-state kinetic experiments.
Translesion synthesis past Pt-DNA adducts was greater with gapped DNA templates
than with single-stranded DNA templates. In the processive mode pol beta did not
discriminate between cisplatin and oxaliplatin adducts, while in the distributive
mode it displayed about 2-fold increased ability for translesion synthesis past
oxaliplatin compared with cisplatin adducts. The differentiation between
cisplatin and oxaliplatin adducts resulted from a K(m)-mediated increase in the
efficiency of dCTP incorporation across from the 3'-G of oxaliplatin-GG adducts.
Rates of misincorporation across platinated guanines determined by the steady
state kinetic assay were higher in reactions with primed single-stranded
templates than with gapped DNA and a slight increase in the misincorporation of
dTTP across from the 3'-G was found for oxaliplatin compared with cisplatin
adducts.
PMID- 10777606
TI - Cyclic nucleotides suppress tumor necrosis factor alpha-mediated apoptosis by
inhibiting caspase activation and cytochrome c release in primary hepatocytes via
a mechanism independent of Akt activation.
AB - Cyclic nucleotides have been previously shown to modulate cell death processes in
many cell types; however, the mechanisms by which cyclic nucleotides regulate
apoptosis are unclear. In this study, we demonstrated that cAMP as well as cGMP
analogs suppressed tumor necrosis factor alpha (TNFalpha) plus actinomycin D
(ActD)-induced apoptosis in a dose-dependent manner in cultured primary
hepatocytes. Furthermore, forskolin, which increases intracellular cAMP levels,
also effectively suppressed TNFalpha+ActD-induced apoptosis. Activation of
multiple caspases was suppressed in cells exposed to TNFalpha+ActD in the
presence of cAMP or cGMP analogs. TNFalpha+ActD-induced cytochrome c release from
mitochondria was also inhibited by cAMP or cGMP, reinforcing our conclusion that
cyclic nucleotides interfere with the early signaling events of TNFalpha-mediated
apoptosis. We evaluated the possibility that cAMP and cGMP inhibit apoptosis by
activating the serine/threonine kinase Akt, which is known to promote cell
survival. Both cAMP- and cGMP-elevating agents led to marked increases in Akt
activation that was inhibited by the phosphatidylinositol 3'-kinase inhibitors,
LY294002 and wortmannin. However, complete inhibition of cyclic nucleotide
induced Akt activation had little effect on cyclic nucleotide-mediated cell
survival, indicating the existence of other survival pathways. Interestingly, the
specific inhibitor of protein kinase A (PKA), KT5720, blocked cGMP-mediated
protection but only partially prevented the anti-apoptotic effect of cAMP,
indicating that both PKA-dependent and -independent mechanisms are involved in
cAMP-mediated suppression of apoptosis signaling. Our data suggest that multiple
survival signaling pathways coexist in cells and that cyclic nucleotides delay
apoptosis by interfering with apoptosis signaling by both PKA-dependent and
independent mechanisms.
PMID- 10777607
TI - Ouabain-sensitive H,K-ATPase functions as Na,K-ATPase in apical membranes of rat
distal colon.
AB - Na,K-ATPase activity has been identified in the apical membrane of rat distal
colon, whereas ouabain-sensitive and ouabain-insensitive H,K-ATPase activities
are localized solely to apical membranes. This study was designed to determine
whether apical membrane Na,K-ATPase represented contamination of basolateral
membranes or an alternate mode of H,K-ATPase expression. An antibody directed
against the H, K-ATPase alpha subunit (HKcalpha) inhibited apical Na,K-ATPase
activity by 92% but did not alter basolateral membrane Na,K-ATPase activity. Two
distinct H,K-ATPase isoforms exist; one of which, the ouabain-insensitive
HKcalpha, has been cloned. Because dietary sodium depletion markedly increases
ouabain-insensitive active potassium absorption and HKcalpha mRNA and protein
expression, Na, K-ATPase and H,K-ATPase activities and protein expression were
determined in apical membranes from control and sodium-depleted rats. Sodium
depletion substantially increased ouabain-insensitive H, K-ATPase activity and
HKcalpha protein expression by 109-250% but increased ouabain-sensitive Na,K
ATPase and H,K-ATPase activities by only 30% and 42%, respectively. These studies
suggest that apical membrane Na,K-ATPase activity is an alternate mode of ouabain
sensitive H,K-ATPase and does not solely represent basolateral membrane
contamination.
PMID- 10777608
TI - Communication between the ATPase and cleavage/religation domains of human
topoisomerase IIalpha.
AB - The DNA strand passage activity of eukaryotic topoisomerase II relies on a
cascade of conformational changes triggered by ATP binding to the N-terminal
domain of the enzyme. To investigate the interdomain communication between the
ATPase and cleavage/religation domains of human topoisomerase IIalpha, we
characterized a mutant enzyme that contains a deletion at the interface between
the two domains, covering amino acids 350-407. The ATPase domain retained full
activity with a rate of ATP hydrolysis that was severalfold higher than normal,
but the ATPase activity was unaffected by DNA. The cleavage and religation
activities of the enzyme were comparable with those of the wild-type enzyme both
in the absence and presence of cancer chemotherapeutic agents. However, neither
ATP nor a nonhydrolyzable ATP analog stimulated cleavage complex formation.
Although both conserved domains retained full activity, the mutant enzyme was
unable to coordinate these activities into strand passage. Our findings suggest
that the normal conformational transitions occurring in the enzyme upon ATP
binding are hampered or lacking in the mutant enzyme. Consistent with this
hypothesis, the enzyme displayed an abnormal clamp closing activity. In summary,
the region covering amino acids 350-407 in human topoisomerase IIalpha seems to
be essential for correct interdomain communication and probably is involved in
signaling ATP binding to the rest of the enzyme.
PMID- 10777609
TI - Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate
induced pp60(c-Src) kinase activation and death of HT4 neuronal cells.
AB - HT4 hippocampal neuronal cells were studied to compare the efficacy of
tocopherols and tocotrienol to protect against glutamate-induced death.
Tocotrienols were more effective than alpha-tocopherol in preventing glutamate
induced death. Uptake of tocotrienols from the culture medium was more efficient
compared with that of alpha-tocopherol. Vitamin E molecules have potent
antioxidant properties. Results show that at low concentrations, tocotrienols may
have protected cells by an antioxidant-independent mechanism. Examination of
signal transduction pathways revealed that protein tyrosine phosphorylation
processes played a central role in the execution of death. Activation of pp60(c
Src) kinase and phosphorylation of ERK were observed in response to glutamate
treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol,
blocked glutamate-induced death by suppressing glutamate-induced early activation
of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to
glutamate-induced death. Tocotrienol treatment prevented death of Src
overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence
activity of recombinant c-Src kinase suggesting that its mechanism of action may
include regulation of SH domains. This study provides first evidence describing
the molecular basis of tocotrienol action. At a concentration 4-10-fold lower
than levels detected in plasma of supplemented humans, tocotrienol regulated
unique signal transduction processes that were not sensitive to comparable
concentrations of tocopherol.
PMID- 10777610
TI - PDZ domain-dependent suppression of NF-kappaB/p65-induced Abeta42 production by a
neuron-specific X11-like protein.
AB - It is widely believed that one of the causes of Alzheimer's disease (AD) is the
generation and secretion of beta-amyloid (Abeta) from amyloid precursor protein
in the brain. Here we report that a transcription factor, NF-kappaB/p65, induces
increased secretion of amyloidogenic Abeta42 but not Abeta40. The kappaB motif
dependent production of Abeta42 was suppressed by binding of NF-kappaB/p65 to the
PDZ domain of the X11-like protein (X11L), which a human homologue protein of LIN
10. The results suggest that the PDZ domain of X11L can control the ability of NF
kappaB/p65 to induce expression of protein(s) involved in Abeta42 production. The
amino acids 161-163 in Rel homology domain (RHD) of NF-kappaB/p65 is important in
interaction of NF-kappaB/p65 with X11L. Another subunit NF-kappaB/p50 and
heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-kappaB
and X11L may, in novel way, regulate Abeta production in neuronal cells.
Targeting X11L by specific therapy may provide the possibility to control the
progression of AD.
PMID- 10777611
TI - RNA degradation and primer selection by Moloney murine leukemia virus reverse
transcriptase contribute to the accuracy of plus strand initiation.
AB - During reverse transcription, plus strand DNA synthesis is initiated at a purine
rich RNA primer generated by the RNase H activity of reverse transcriptase (RT).
Specific initiation of plus strand synthesis from this polypurine tract (PPT) RNA
is essential for the subsequent integration of the linear viral DNA product.
Based on current models, it is predicted that priming from sites upstream of the
PPT may be tolerated by the virus, whereas efficient extension from RNA primers
located downstream from the PPT is predicted to generate dead-end products. By
using hybrid duplex substrates derived from the Moloney murine leukemia virus
long terminal repeat, we investigated the extent to which RNase H degrades the
viral RNA during time course cleavage assays, and we tested the capacity of the
polymerase activity of RT to use the resulting cleavage products as primers. We
find that the majority of the RNA fragments generated by RNase H are 2-25
nucleotides in length, and only following extensive degradation are most
fragments reduced to 10 nucleotides or smaller. Although extensive RNA
degradation by RNase H likely eliminates many potential RNA primers, based on
thermostability predictions it appears that some RNA fragments remain stably
annealed to the DNA template. RNA primers generated by RNase H within the long
terminal repeat sequence are found to have the capacity to initiate DNA synthesis
by RT; however, the priming efficiency is significantly less than that observed
with the PPT primer. We find that Moloney murine leukemia virus nucleocapsid
protein reduces RNase H degradation and slightly alters the cleavage specificity
of RT; however, nucleocapsid protein does not appear to enhance PPT primer
utilization or suppress extension from non-PPT RNA primers.
PMID- 10777612
TI - Structural and functional characterization of platelet receptor-mediated factor
VIII binding.
AB - Optimal rates of factor X (FX) activation require occupancy of receptors for
factor IXa (FIXa), factor VIII (FVIII), and FX on the activated platelet surface.
The presence of FVIII and FX increases 5-fold the affinity of FIXa for the
surface of activated platelets, and the presence of FVIII or FVIIIa generates a
high affinity, low capacity specific FX-binding site on activated platelets. We
have now examined the effects of FX and active site-inhibited FIXa (EGR-FIXa) on
the binding of both FVIII and FVIIIa to activated platelets and show the
following: (a) von Willebrand factor inhibits FVIII binding (K(i) = 0.54 nM) but
not FVIIIa binding; (b) thrombin and the thrombin receptor activation peptide
(SFLLRN amide) are the most potent agonists required for FVIII-binding site
expression, whereas ADP is inert; (c) FVa does not compete with FVIIIa or FVIII
for functional platelet-binding sites; and (d) Annexin V is a potent inhibitor of
FVIIIa binding (IC(50) = 10 nM) to activated platelets. The A2 domain of FVIII
significantly increases the affinity and stoichiometry of FVIIIa binding to
platelets and contributes to the stability of the FX-activating complex. Both
FVIII and FVIIIa binding were specific, saturable, and reversible. FVIII binds to
specific, high affinity receptors on activated platelets (n = 484 +/- 59; K(d) =
3.7 +/- 0.31 nM) and FVIIIa interacts with an additional 300-500 sites per
platelet with enhanced affinity (K(d) = 1.5 +/- 0.11 nM). FVIIIa binding to
activated platelets in the presence of FIXa and FX is closely coupled with rates
of F-X activation. The presence of EGR-FIXa and FX increases both the number and
the affinity of binding sites on activated platelets for both FVIII and FVIIIa,
emphasizing the validity of a three-receptor model in the assembly of the F-X
activating complex on the platelet surface.
PMID- 10777613
TI - An NF-Y binding site is important for basal, but not gonadotropin-releasing
hormone-stimulated, expression of the luteinizing hormone beta subunit gene.
AB - Regulated synthesis of luteinizing hormone (LH) requires coordinated
transcriptional control of the alpha and LHbeta subunits in pituitary
gonadotropes. Several cis-acting elements and trans-acting factors have been
defined for control of the LHbeta promoter through heterologous cell culture
models. In this report, we describe the identification of bipartite NF-Y
(CBF/CP1) binding sites within the proximal bovine LHbeta promoter. When
multimerized, one of these sites activates the heterologous, minimal HSV
thymidine kinase promoter in the gonadotrope-derived cell line alphaT3-1. The
functional role of the promoter-distal site in regulating the full-length bovine
LHbeta promoter was assessed in vivo using transgenic mice harboring a mutant
promoter linked to the chloramphenicol acetyltransferase reporter gene. While
this element is important for conferring high level activity of the LHbeta
promoter in pituitary, it does not appear to be essential for mediating
gonadotropin-releasing hormone (GnRH) regulation. This is the first
characterization of a cis-acting element within this GnRH-dependent promoter that
is restricted to regulating basal expression and not GnRH-induced activity.
PMID- 10777614
TI - Functional relationship between calreticulin, calnexin, and the endoplasmic
reticulum luminal domain of calnexin.
AB - Calnexin is a membrane protein of the endoplasmic reticulum (ER) that functions
as a molecular chaperone and as a component of the ER quality control machinery.
Calreticulin, a soluble analog of calnexin, is thought to possess similar
functions, but these have not been directly demonstrated in vivo. Both proteins
contain a lectin site that directs their association with newly synthesized
glycoproteins. Although many glycoproteins bind to both calnexin and
calreticulin, there are differences in the spectrum of glycoproteins that each
binds. Using a Drosophila expression system and the mouse class I
histocompatibility molecule as a model glycoprotein, we found that calreticulin
does possess apparent chaperone and quality control functions, enhancing class I
folding and subunit assembly, stabilizing subunits, and impeding export of
assembly intermediates from the ER. Indeed, the functions of calnexin and
calreticulin were largely interchangeable. We also determined that a soluble form
of calnexin (residues 1-387) can functionally replace its membrane-bound
counterpart. However, when calnexin was expressed as a soluble protein in L
cells, the pattern of associated glycoproteins changed to resemble that of
calreticulin. Conversely, membrane-anchored calreticulin bound to a similar set
of glycoproteins as calnexin. Therefore, the different topological environments
of calnexin and calreticulin are important in determining their distinct
substrate specificities.
PMID- 10777615
TI - Comparison of the functional characteristics of the nucleotide binding domains of
multidrug resistance protein 1.
AB - Multidrug Resistance Protein 1 (MRP1) transports diverse organic anionic
conjugates and confers resistance to cytotoxic xenobiotics. The protein contains
two nucleotide binding domains (NBDs) with features characteristic of members of
the ATP-binding cassette superfamily and exhibits basal ATPase activity that can
be stimulated by certain substrates. It is not known whether the two NBDs of MRP1
are functionally equivalent. To investigate this question, we have used a
baculovirus dual expression vector encoding both halves of MRP1 to reconstitute
an active transporter and have compared the ability of each NBD to be
photoaffinity-labeled with 8-azido-[(32)P]ATP and to trap 8-azido-[(32)P]ADP in
the presence of orthovanadate. We found that NBD1 was preferentially labeled with
8-azido-[(32)P]ATP, while trapping of 8-azido-[(32)P]ADP occurred predominantly
at NBD2. Although trapping at NBD2 was dependent on co-expression of both halves
of MRP1, binding of 8-azido-ATP by NBD1 remained detectable when the NH(2)
proximal half of MRP1 was expressed alone and when NBD1 was expressed as a
soluble polypeptide. Mutation of the conserved Walker A lysine 684 or creation of
an insertion mutation between Walker A and B motifs eliminated binding by NBD1
and all detectable trapping of 8-azido-ADP at NBD2. Both mutations decreased
leukotriene C(4) (LTC(4)) transport by approximately 70%. Mutation of the NBD2
Walker A lysine 1333 eliminated trapping of 8-azido-ADP by NBD2 but, in contrast
to the mutations in NBD1, essentially eliminated LTC(4) transport activity
without affecting labeling of NBD1 with 8-azido-[(32)P]ATP.
PMID- 10777616
TI - Degradation of DNA topoisomerase I by a novel trypsin-like serine protease in
proliferating human T lymphocytes.
AB - DNA topoisomerase I (Topo I) contributes to various important biological
functions, and its activity is therefore likely regulated in response to
different physiological conditions. Increases in both the synthesis and
degradation of Topo I were previously shown to accompany phytohemagglutinin
stimulation of proliferation in human peripheral T lymphocytes. The mechanism of
this degradation of Topo I has now been investigated with both in vivo and in
vitro assays. The activity of a nuclear protease that specifically degrades Topo
I was induced in proliferating T lymphocytes. The full-length Topo I protein (100
kDa) was sequentially degraded to 97- and 82-kDa fragments both in vivo and in
vitro. The initial site of proteolytic cleavage was mapped to the NH(2)-terminal
region of the enzyme. The degradation of Topo I in vitro was inhibited by
aprotinin or soybean trypsin inhibitor, suggesting that the enzyme responsible is
a trypsin-like serine protease. Furthermore, Topo I degradation by this protease
was Mg(2+)-dependent. The Topo I-specific protease activity induced during T
lymphocytes proliferation was not detected in Jurkat (human T cell leukemia)
cells and various other tested human cancer cell lines, possibly explaining why
the abundance of Topo I is increased in tumor cells.
PMID- 10777617
TI - The association of CRKII with C3G can be regulated by integrins and defines a
novel means to regulate the mitogen-activated protein kinases.
AB - In studies to define mechanisms of ERK activation in Chinese hamster ovary cells,
we have observed an inverse correlation between CRKII-C3G complex formation and
ERK activity. That is, we were able to coprecipitate the guanine nucleotide
exchange factor C3G with the adaptor protein CRKII in lysates from suspended
cells that had low ERK activity, but we could not do so or could do so less
efficiently in lysates of adherent cells with increased ERK activity. Consistent
with the presence of a functional CRKII-C3G complex, we detected more GTP-loaded
RAP1 in suspension than adherent lysates. Overexpression of cDNAs encoding B-RAF,
CRKII W109L, and PTP1B C215S activated ERK in suspension cells, the latter two
constructs also disrupting CRKII-C3G complex formation. Finally, we have also
observed that certain integrin alpha subunit cytoplasmic splice variants
differentially regulate ERK1/2 but also in a manner that correlated with levels
of a CRKII-C3G complex. Thus, these data suggest the involvement of integrins in
an ERK suppression pathway mediated by CRKII-C3G complex formation and downstream
signaling from activated RAP1.
PMID- 10777618
TI - SH2-B is required for growth hormone-induced actin reorganization.
AB - The Src homology-2 (SH2) domain-containing protein SH2-Bbeta is a substrate of
the growth hormone (GH) receptor-associated tyrosine kinase JAK2. Here we tested
whether SH2-Bbeta is involved in GH regulation of the actin cytoskeleton. Based
on cell fractionation and confocal microscopy, we find SH2-Bbeta present at the
plasma membrane and in the cytosol. SH2-Bbeta colocalized with filamentous actin
in GH and platelet-derived growth factor (PDGF)-induced membrane ruffles. To test
if SH2-Bbeta is required for actin reorganization, we transiently overexpressed
wild-type or mutant SH2-Bbeta in 3T3-F442A cells and assayed for GH- and PDGF
induced membrane ruffling and fluid phase pinocytosis. Overexpression of wild
type SH2-Bbeta enhanced ruffling and pinocytosis produced by submaximal GH but
not submaximal PDGF. Point mutant SH2-Bbeta (R555E) and truncation mutant
DeltaC555, both lacking a functional SH2 domain, inhibited membrane ruffling and
pinocytosis induced by GH and PDGF. Mutant DeltaN504, which possesses a
functional SH2 domain and enhances JAK2 kinase activity in overexpression
systems, also inhibited GH-stimulated membrane ruffling. DeltaN504 failed to
inhibit GH-induced nuclear localization of Stat5B, indicating JAK2 is active in
these cells. Taken together, these results show that SH2-Bbeta is required for GH
induced actin reorganization by a mechanism discrete from the action of SH2-Bbeta
as a stimulator of JAK2 kinase activity.
PMID- 10777619
TI - Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced
mitochondrial respiration through the induction of cytochrome c.
AB - Progression through the cell cycle requires ATP for protein synthesis,
cytoskeletal rearrangement, chromatin remodeling, and protein degradation. The
mechanisms by which mammalian cells increase respiratory capacity and ATP
production in preparation for cell division are largely unexplored. Here, we
demonstrate that serum induction of cytochrome c mRNA and processed protein in
quiescent BALB/3T3 fibroblasts is associated with a marked increase in
mitochondrial respiration. Cytochrome c was induced in the absence of any
increase in citrate synthase activity or in subunit IV of the cytochrome c
oxidase complex mRNA or protein, indicating that the enhanced respiratory rate
did not require a general increase in mitochondrial biogenesis or respiratory
chain expression. Transfections with a series of cytochrome c promoter mutants
showed that both nuclear respiratory factor 1 (NRF-1) and cAMP-response element
binding protein (CREB) binding sites contributed equally to induced expression by
serum. Moreover, CREB and NRF-1 were phosphorylated sequentially in response to
serum, and the NRF-1 phosphorylation was accompanied by an increase in its
ability to trans-activate target gene expression. The results demonstrate that
the differential transcriptional expression of cytochrome c, through sequential
transcription factor phosphorylations, leads to enhanced mitochondrial
respiratory capacity upon serum-induced entry to the cell cycle.
PMID- 10777620
TI - Role of phosphatidylinositol 3-kinase and specific protein kinase B isoforms in
the suppression of apoptosis mediated by the Abelson protein-tyrosine kinase.
AB - Leukemogenic oncogenes, such as the Abelson protein-tyrosine kinases (PTK),
disrupt the normal regulation of survival, proliferation, and differentiation in
hemopoietic progenitor cells. In the absence of cytokines, hemopoietic progenitor
cells die by apoptosis. Abl PTKs mediate suppression of this apoptotic response
leading to aberrant survival. To investigate the mechanism of Abl PTK action, we
have used an interleukin-3-dependent murine mast cell line that expresses a
temperature-sensitive form of the v-ABL PTK, which is active at the permissive
temperature of 32 degrees C and inactive at 39 degrees C. At the permissive
temperature, these cells are resistant to apoptosis induced both by the
withdrawal of the hemopoietic growth factor (interleukin-3) and the addition of
cytotoxic drugs. We demonstrate that v-Abl associates with and stimulates
activation of phosphatidylinositol 3-kinase (PI3K) and, crucially, that this
activation results in enhanced cellular levels of the mass of the second
messenger phosphatidylinositol-3,4,5-trisphosphate. Activation of PI3K leads to
enhanced activity of PKB and increased levels of the anti-apoptotic protein Bcl
X(L). Transfection of cells with a dominant negative PKB reduces both the Abl
stimulated PKB activity and the survival effect conferred by activation of this
oncogene. Thus, PI3K and PKB are required for the anti-apoptotic effects of Abl
PTK.
PMID- 10777621
TI - FKBP12 is a negative regulator of transforming growth factor-beta receptor
internalization.
AB - Transforming growth factor-beta (TGF-beta) family polypeptides regulate cell
growth and differentiation by binding to single pass serine/threonine kinases
referred to as TGF-beta type I and II receptors. Although interaction screens
have shown that the immunophilin FKBP12 interacts with TGF-beta type I receptors,
the role of FKBP12 in TGF-beta receptor action is presently unclear. Using a
chimeric TGF-beta receptor system, we have shown a specific enhancement of
internalization when FKBP12 binding to the type I receptor was prevented with
rapamycin. Moreover, although earlier studies demonstrated that type II receptor
kinase activity was required for optimal internalization in mesenchymal cells, we
found that rapamycin functioned downstream of the type II receptor kinase. Thus,
rather than modulating TGF-beta signaling, our data suggest a novel role for
FKBP12 as a negative regulator of TGF-beta receptor endocytosis.
PMID- 10777622
TI - Characterization of the roles of the 594-645 region in human endothelial nitric
oxide synthase in regulating calmodulin binding and electron transfer.
AB - It has been postulated that a segment (residues 594-645) inserted in the FMN
subdomain of human endothelial nitric-oxide synthase (eNOS) plays a crucial role
in controlling Ca(2+)-dependent CaM binding for eNOS activity. To investigate its
functions, we expressed human eNOS in a baculovirus system with deletion of a 45
residue segment from this region (residues 594-606 and 614-645, designated as
Delta45eNOS), and characterized the purified mutant enzyme. In contrast with wild
type eNOS, Delta45eNOS exhibited characteristics resembling inducible NOS (iNOS).
It contained an endogenously bound CaM, which was essential in folding and
stabilizing this mutant enzyme, and retained 60% of L-citrulline formation in 5
mM EGTA. We also produced four N-terminally truncated reductase domains with or
without the 45-residue segment, and either including or excluding the CaM-binding
sequence. Basal cytochrome c reductase activity of reductase domains without the
45-residue segment was up to 20 fold greater than that of corresponding insert
containing domains, and higher than CaM-stimulated activity of the wild-type
enzyme. A series of mutants with smaller fragment deletion in this region such as
Delta594-604, Delta605-612, Delta613-625, Delta626-634, Delta632-639, and
Delta640-645 mutants were further characterized. The crude lysate of mutants
Delta613-625 and Delta632-639 did not show activity in the presence of
Ca(2+)/CaM, while other four mutants had activity comparable to that of WTeNOS.
The purified Delta594-604 and Delta605-612 proteins had a 3-5-fold higher
affinity for Ca(2+)/CaM, but their L-citrulline forming activity was still 80%
dependent upon the addition of Ca(2+)/CaM. Both mutants exhibited a low level of
the cytochrome c and ferricyanide reductase activities, which either did not
respond to (Delta594-604) or slightly enhanced by (Delta605-612) the exogenous
CaM. In contrast, activities of Delta626-634 and Delta640-645 like those of
WTeNOS were largely Ca(2+)/CaM-dependent. Thus, our findings indicate that the N
terminal half of the 594-645 segment containing residues 594-612 plays a
significant role in regulating Ca(2+)/CaM binding.
PMID- 10777624
TI - The Catalytic Asymmetric Aldol Reaction.
AB - The construction of C-C bonds with complete control of the stereochemical course
of a reaction is of utmost importance for organic synthesis. The aldol reaction
the simple addition of an enolate donor to a carbonyl acceptor-is one of the most
powerful reactions available to the synthetic chemist. In general, control of the
relative and absolute configuration of the newly formed stereogenic centers has
been achieved through the use of chiral starting materials or chiral auxiliaries.
In recent years the search for catalytic methods that efficiently and effectively
transfer chirality information has become a major effort in synthetic organic
chemistry. Two different approaches have been taken toward the catalytic
asymmetric aldol reaction: biocatalysis and catalysis with small molecules. Both
approaches have specific advantages and limitations, and as a result are
complementary to each other. The important efforts toward both approaches are
reviewed in this article.
PMID- 10777625
TI - Ceramics and Nanostructures from Molecular Precursors.
AB - The elaboration of solids from the molecular scale by a kinetically controlled
methodology is one of the main challenges of molecular chemistry. In the long
term, this should permit the design of solids with desired properties. Here, some
examples are given which show a few methods that have been used for the
preparation of solids from molecular precursors. The one-pot synthesis of
rheologically controlled SiC is described. Access to a new kind of ceramic is
obtained by the same methodology using molecular precursors. Mixed ceramics with
interpenetrating networks are not accessible by the chemical thermodynamic route.
The chemistry of hybrid materials obtained from molecular precursors through
inorganic polymerization is presented. This class of materials offers wide
perspectives because of 1) the large possibilities opened by the organic unit, 2)
the kinetic control, which permits any kind of texture for the solid, and 3) the
aptitude of these solids to become nanostructured.
PMID- 10777626
TI - Chemistry and Biology of Plant Leaf Movements.
AB - The leaves of Mimosa pudica L. are well known for their rapid movement when
touched. Recently, we were able to isolate an excitatory substance in small
quantities from this plant, which consists of three different components
(potassium L-malate, magnesium trans-aconitate, and dimethylammonium salt). Many
plants close their leaves in the evening, as if to sleep, and open them early in
the morning (nyctinastic leaf movement). This circadian rhythm is known to be
controlled by the biological clock of such plants. Extensive studies on other
nyctinastic plants led to the isolation of a variety of leaf-opening substances
(LOSs) and leaf-closing substances (LCSs). Based on our experiments on these
bioactive substances, we found that the circadian rhythmic leaf movement of these
plants is initiated by the regulated balance of LOSs and LCSs. The balance of
concentration between the two leaf-movement factors (LMFs) is inversed during the
day. The glycoside-type LMF is hydrolyzed with beta-glucosidase, the activity of
which is regulated by the biological clock. The circadian rhythm observed in the
leaf movement is introduced by activation of beta-glucosidase regulated by the
biological clock.
PMID- 10777627
TI - Syntheses of CP-225,917 and CP-263,114.
PMID- 10777628
TI - In Spite of the Chemist's Belief: Carbonic Acid Is Surprisingly Stable.
PMID- 10777629
TI - [{Cp]
PMID- 10777630
TI - Asymmetric Catalysis with Chiral Phosphane/Phosphoramidite Ligands Derived from
Quinoline (QUINAPHOS) This work was supported by the Max Planck Society, MURST
(Rome), and the University of Messina (exchange fellowship for G.F.). We thank
Dr. C. Arena (University of Messina), Prof. G. Hanan (University of Waterloo),
and Dr. C. W. Lehmann (MPI Mulheim) for fruitful discussions.
PMID- 10777631
TI - Stereoselective Combinatorial Ugi-Multicomponent Synthesis on Solid Phase This
work was supported by the Deutsche Forschungsgemeinschaft and by the Fonds der
Chemischen Industrie.
PMID- 10777632
TI - Ring-Opening Metathesis Polymerization: Access to a New Class of Functionalized,
Monolithic Stationary Phases for Liquid Chromatography.
PMID- 10777633
TI - Optimized Two-Dimensional NLO Chromophores with a Threefold Symmetry Axis The
authors would like to thank the Volkswagenstiftung and the Fonds der Chemischen
Industrie for generous financial supports of this work.
PMID- 10777634
TI - Synthesis of the First Selective Irreversible Inhibitor of Neutral
Sphingomyelinase This work was supported by grants from the Fonds der Chemischen
Industrie. C.A. is grateful to the Land of Baden-Wurttemberg for a scholarship
from the Landesgraduiertenforderung.
PMID- 10777635
TI - Structural Characterization of a Plutonium(IV) Siderophore Complex: Single
Crystal Structure of Pu-Desferrioxamine E Support for this work is provided by
the U.S. Department of Energy (Natural and Accelerated Bioremediation Research
(NABIR) Program). We thank Professor G. Winkelmann, Universitat Tubingen, for
generously providing a sample of desferrioxamine E.
PMID- 10777636
TI - Towards Detection of a Long-lived Protonated Metal Cation: Generation of GeH(2+)
Using High-Energy Collisions This research was supported by the Deutsche
Forschungsgemeinschaft, the Volkswagen-Stiftung, and the Fonds der Chemischen
Industrie. The Konrad-Zuse-Zentrum, Berlin, is acknowledged for generous
allocation of computer time. R.S. is grateful to the Deutscher Akademischer
Austauschdienst (DAAD) for financial support, and thanks Dr. K. V. Raghavan,
Director of the Indian Institute of Chemical Technology, for his encouragement
and assistance.
PMID- 10777637
TI - The structure of IF(3) This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
PMID- 10777638
TI - Synthesis of the N-Terminal N-Myristoylated and S-Palmitoylated
Undetrigintapeptide of Endothelial NO-Synthase This research was supported by the
Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft.
PMID- 10777639
TI - 4-(N-Methylhydrazino)-7-nitro-2,1,3-benzooxadiazole (MNBDH): A Novel Fluorogenic
Peroxidase Substrate The authors would like to thank the Fonds der Chemischen
Industrie (Frankfurt/Main) for financial support.
PMID- 10777640
TI - sigma-Homoconjugation in Cyclically Preoriented N4-(Radical) Cations-N small
middle dot small middle dot small middle dotN Bond Lengths >2 A This project has
been supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
Industrie and BASF AG. We thank Dipl.-Chem. V. Peron and B. Geiser for technical
assistance.
PMID- 10777641
TI - Extremely Long, Discrete meso - meso-Coupled Porphyrin Arrays This work was
supported by Grant-in-Aids for Scientific Research (No. 11136221 and 11223205)
from the Ministry of Education, Science, Sports, and Culture of Japan and by
CREST (Core Research for Evolutional Science and Technology) from the Japan
Science and Technology Corporation (JST). The work at KRISS was supported by the
National Creative Research Initiatives of the Ministry of Science and Technology
of Korea.
PMID- 10777642
TI - Formation of Rearranged Grignard Reagents by Carbenoid-C-H Insertion This study
was supported by the Deutsche Forschungsgemeinschaft (SFB 260).
PMID- 10777643
TI - A New Biosynthetic Pathway to Alkaloids in Plants: Acetogenic Isoquinolines We
thank Dr. D. Marek and Dr. D. Moskau (Bruker AG, Fallanden, Switzerland), who
made the cryoprobe technique available to us, Prof. L. Ake Assi (Centre National
de Floristique, Abidjan Ivory Coast) for a long and fruitful collaboration on
Dioncophyllaceae and Ancistrocladaceae plants, and Dr. D. Scheutzow (Universitat
Wurzburg) for valuable advice. This work was supported by the Deutsche
Forschungsgemeinschaft (SFB 251 and Graduiertenkolleg "NMR in vivo und in
vitro"), by the Fonds der Chemischen Industrie, and by the Max-Buchner-Stiftung.
PMID- 10777644
TI - 6Li and (15)N NMR Data as a Probe for the Influence of Solvent and Intramolecular
Solvation on the Solution-State Structures of Chiral Lithium Amides The authors
are most grateful to the Swedish Natural Science Research Council and Carl
Trygger for financial support.
PMID- 10777645
TI - Low-Temperature, Catalyzed Growth of Indium Nitride Fibers from Azido-Indium
Precursors This work was supported by the U.S. National Science Foundation (Grant
CHE-9709104). We gratefully acknowledge assistance from Dr. W. R. Winchester with
GC-MS and Dr. Couture with X-ray fluorescence studies.
PMID- 10777646
TI - Oxidation - Reduction and Photochemical Reactions of Metalladecaborane Clusters:
The Interconversion of hypercloso-
PMID- 10777647
TI - Study of the Configuration Stability of the Carbon - Zinc Bond, Direct
Measurement of Enantiomeric Ratios, and Tentative Assignment of the Absolute
Configuration in Secondary Organozinc Halides We gratefully acknowledge the
financial support provided by the National Science Foundation (R.D.R.). We also
thank Dr. R. Shoemaker for his help in obtaining the NMR data.
PMID- 10777648
TI - Electrochemical Oxidation of Water to Dioxygen Catalyzed by the Oxidized Form of
the Bis(ruthenium - hydroxo) Complex in H(2)O This work was partly supported by
the Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of
Education, Science, Sports, and Culture of Japan (No. 10149259).
PMID- 10777649
TI - Designing a Helical Polymer that Reverses its Handedness at a Selected,
Continuously Variable, Temperature We would like to thank R. L. B. Selinger for
helpful discussions. The Office of Naval Research supported the work at both the
Polytechnic University and the Naval Research Laboratory. The work at the
Polytechnic University was also supported by the Chemistry and Polymers Programs
of the National Science Foundation and by the Petroleum Research Fund
administered by the American Chemical Society. We are grateful to Professor
Krzysztof Matyjaszewski of Carnegie-Mellon University for a discussion that led
to the development of this work.
PMID- 10777650
TI - Piezoelectricity in Polar Supramolecular Materials This work was partly carried
out at the University of Illinois at Urbana-Champaign and supported by grants
from the Army Research Office (DAAH04-96-1-0450) and the Office of Naval Research
(N00014-99-1-0239). S.I.S. expresses his gratitude for the support of the
Humboldt Foundation in the form of a Senior Award.
PMID- 10777651
TI - Unusual Smectic Ordering of Unlocked Copper Bis-(terpyridine) Complexes This work
was supported by the Centre National de la Recherche Scientifique (CNRS) and by
the Engineering School of Chemistry (ECPM).
PMID- 10777652
TI - An Expeditious Total Synthesis of the Natural Stereomeric Mixture of Stenusine
Following a Possible Biogenetic Pathway We are grateful to Prof. Dr. Dieter
Enders for fruitful discussions.
PMID- 10777654
TI - AlITQ-6 and TiITQ-6: Synthesis, Characterization, and Catalytic Activity We thank
the Spanish CICYT for financial support (project MAT97-1016-C02-01 and project
MAT97-1207-C03-01). U.D. and M.E.D. thank the M.E.C. and M.E.A., respectively,
for funding their doctoral fellowships.
PMID- 10777653
TI - From Large Furan-Based Calixarenes to Calixpyrroles and Calix
PMID- 10777655
TI - Ligand-Directed Structural Modification of Imidotin(II) Cubanes: The Mixed
Oxidation State Double-Cubanes
PMID- 10777657
TI - Polymeric Layers Catenated by Ribbons of Rings in a Three-Dimensional Self
Assembled Architecture: A Nanoporous Network with Spongelike Behavior.
PMID- 10777656
TI - How Important is the Inert Matrix of Supported Enantiomeric Catalysts? Reversal
of Topicity with Two Polystyrene Backbones We would like to warmly thank Prof. J.
M. J. Frechet and Dr. F. Svec for technical advice. Financial support for this
work was provided by the Spanish C.I.C.Y.T. (Project MAT96-1053) and Fundacio
Caixa Castello-Bancaixa (P1B97-10).
PMID- 10777658
TI - Asymmetric Synthesis of an Organic Compound with High Enantiomeric Excess Induced
by Inorganic Ionic Sodium Chlorate This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, Sports, and Culture.
We thank Mr. Koji Ohtake for experimental work in the early stage, Prof. Naoyuki
Koide and Dr. Takashi Mihara from the Department of Chemistry of our university
for a microscope measurement of the size of the powdered NaClO(3).
PMID- 10777659
TI - A human cDNA library for high-throughput protein expression screening.
AB - We have constructed a human fetal brain cDNA library in an Escherichia coli
expression vector for high-throughput screening of recombinant human proteins.
Using robot technology, the library was arrayed in microtiter plates and gridded
onto high-density filter membranes. Putative expression clones were detected on
the filters using an antibody against the N-terminal sequence RGS-His(6) of
fusion proteins. Positive clones were rearrayed into a new sublibrary, and 96
randomly chosen clones were analyzed. Expression products were analyzed by SDS
PAGE, affinity purification, matrix-assisted laser desorption/ionization-time-of
flight mass spectrometry, and the determined protein masses were compared to
masses predicted from DNA sequencing data. It was found that 66% of these clones
contained inserts in a correct reading frame. Sixty-four percent of the correct
reading frame clones comprised the complete coding sequence of a human protein.
High-throughput microtiter plate methods were developed for protein expression,
extraction, purification, and mass spectrometric analyses. An enzyme assay for
glyceraldehyde-3-phosphate dehydrogenase activity in native extracts was adapted
to the microtiter plate format. Our data indicate that high-throughput screening
of an arrayed protein expression library is an economical way of generating large
numbers of clones producing recombinant human proteins for structural and
functional analyses.
PMID- 10777660
TI - Determination of X-chromosome inactivation status using X-linked expressed
polymorphisms identified by database searching.
AB - The large number of redundant sequences available in nucleotide databases
provides a resource for the identification of polymorphisms. Expressed
polymorphisms in X-linked genes can be used to determine the inactivation status
of the genes, and polymorphisms in genes that are subject to inactivation can
then be used as tools to examine X-chromosome inactivation status in heterozygous
females. In this study, we have identified six new X-linked single-nucleotide
polymorphisms and determined the inactivation status of these genes by
examination of expression patterns in female cells previously demonstrated to
have skewed inactivation, as well as by analysis of somatic cell hybrids
retaining the inactive human X chromosome. Expression was seen from both alleles
in females heterozygous for the RPS4X gene, confirming the previously reported
expression from the inactive X chromosome. Expression of only a single allele was
seen in females heterozygous for polymorphisms in the BGN, TM4SF2, ATP6S1, VBP1,
and PDHA1 genes, suggesting that these genes are subject to X-chromosome
inactivation.
PMID- 10777661
TI - Identification of a new EGF-repeat-containing gene from human Xp22: a candidate
for developmental disorders.
AB - Epidermal growth factor (EGF) repeat-containing proteins constitute an expanding
family of proteins involved in several cellular activities such as blood
coagulation, fibrinolysis, cell adhesion, and neural and vertebrate development.
By using a bioinformatic approach, we have identified a new member of this family
named MAEG (MAM- and EGF-containing gene; HGMW-approved gene symbol and gene
name). Sequence analysis indicates that MAEG encodes a secreted protein
characterized by the presence of five EGF repeats, three of which display a
Ca(2+)-binding consensus sequence. In addition, a MAM domain is also present at
the C-terminus of the predicted protein product. The human and murine full-length
cDNAs were identified and mapped to human Xp22 and to the mouse syntenic region.
Northern analysis indicates that MAEG is expressed early during development.
Taken together, these data render MAEG a candidate for human and murine
developmental disorders.
PMID- 10777662
TI - Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and
RAD9p, and implications for the regulation of cell cycle progression.
AB - Schizosaccharomyces pombe hus1 promotes radioresistance and hydroxyurea
resistance, as well as S and G2 phase checkpoint control. We isolated a human
cDNA homologous to hus1, called HUS1. The major focus of this report is on a
detailed analysis of the physical interactions of the HUS1-encoded protein and
two other checkpoint control proteins, RAD1p and RAD9p, implicated in the
cellular response to DNA damage. We found that HUS1p interacts with itself and
the N-terminal region of RAD1p. In contrast, the C-terminal portion of the
checkpoint protein RAD9p is essential for interacting with HUS1p and the C
terminal region of RAD1p. Since the N-terminal portion of RAD9p was previously
demonstrated to participate in apoptosis, this protein likely has at least two
functional domains, one that regulates programmed cell death and another that
regulates cell cycle checkpoint control. Truncated versions of HUS1p are unable
to bind RAD1p, RAD9p, or another HUS1p molecule. RAD1p-RAD1p and RAD9p-RAD9p
interactions can be demonstrated by coimmunoprecipitation, but not by two-hybrid
analysis, suggesting that the proteins associate as part of a complex but do not
interact directly. Northern blot analysis indicates that HUS1 is expressed in
different tissues, but the mRNA is most predominant in testis where high levels
of RAD1 and RAD9 message have been detected. These studies suggest that HUS1p,
RAD9p, and RAD1p form a complex in human cells and may function in a meiotic
checkpoint in addition to the cell cycle delays induced by incomplete DNA
replication or DNA damage.
PMID- 10777663
TI - A clone contig of 12q24.3 encompassing the distal hereditary motor neuropathy
type II gene.
AB - We previously assigned the disease locus for autosomal dominant hereditary motor
neuropathy type II (distal HMN II) within a 13-cM interval at chromosome 12q24.3.
We constructed a physical map of the distal HMN II region based on yeast
artificial chromosomes (YACs), P1 artificial chromosomes (PACs), and bacterial
artificial chromosomes (BACs) using an STS content mapping approach. The contig
contains 26 YAC, 15 PAC, and 60 BAC clones and covers a physical distance of
approximately 5 Mb. A total of 99 STS markers, including 25 known STSs and STRs,
49 new STSs generated from clone end-fragments, 20 ESTs, and 5 known genes, were
located on the contig. This physical map provides a valuable resource for mapping
genes and markers located within the distal HMN II region and facilitates the
positional cloning of the distal HMN II gene.
PMID- 10777664
TI - Cloning and characterization of a novel human ubiquitin-specific protease, a
homologue of murine UBP43 (Usp18).
AB - The ubiquitin-specific proteases (UBP) are a family of enzymes that cleave
ubiquitin from ubiquitinated protein substrates. We have recently cloned UBP43, a
novel member of this family from AML1-ETO knock-in mice. To analyze the role of
UBP43 in hematopoiesis and leukemogenesis, we have cloned a full-length human
UBP43 cDNA by screening a human monocytic cDNA library as well as by 5'- and 3'
rapid amplification of cDNA ends analyses. This cDNA encodes a polypeptide of 372
amino acids with all of the structural motifs of a deubiquitinating enzyme. The
human UBP43 mRNA is strongly expressed in human liver and thymus. Transfection
analysis has demonstrated that UBP43 is a nuclear protein. Interestingly, the
gene encoding human UBP43 maps to chromosome 22q11.2. This region, known as
DiGeorge syndrome critical region, contains a minimal area of 2 Mb and is
consistently deleted in DiGeorge syndrome and related disorders. The syndrome is
marked by thymic aplasia or hypoplasia, parathyroid hypoplasia, or congenital
cardiac abnormalities. Taken together, our results broaden the understanding of a
new human ubiquitin-specific protease, UBP43, and suggest that this gene may also
be related to DiGeorge syndrome.
PMID- 10777665
TI - Characterization of Ngef, a novel member of the Dbl family of genes expressed
predominantly in the caudate nucleus.
AB - We have identified Ngef as a novel member of the family of Dbl genes. Many
members of this family have been shown to function as guanine nucleotide exchange
factors for the Rho-type GTPases. Ngef is predominantly expressed in brain, with
the strongest signal in the caudate nucleus, a region associated with the control
of movement. Ngef contains a translated trinucleotide repeat, a polyglutamic acid
stretch interrupted by a glycine. We have localized the Ngef gene to mouse
chromosome 1 and the human homologue of Ngef to human chromosome 2q37. We have
shown in preliminary experiments that Ngef has transforming potential in cell
culture and is able to induce tumors in nude mice.
PMID- 10777666
TI - Molecular characterization of germline NF2 gene rearrangements.
AB - Neurofibromatosis type 2 (NF2) is an autosomal dominant disease that causes a
predisposition to nervous system tumors. Deleterious point mutations have been
found in about 55% of NF2 patients, and large genomic deletions account for
approximately 33% of NF2 gene alterations. The majority of these deletions are
larger than 50 kb, with a breakpoint usually lying outside the NF2 gene. We
identified two cases of intragenic deletion with loss of 1.5 and 40 kb,
respectively. In both cases, one boundary of the deletion was located in or at
the proximity of an SVA sequence in NF2 intron 4. No sequence identity longer
than 5 bases and no signal of specific recombination have been evidenced on
either side of the deletion breakpoints. These observations are compatible with a
nonhomologous recombination being responsible for the genomic deletions. In a
third case, a paracentric inversion of chromosome 22 was found. This chromosomal
rearrangement breaks the NF2 gene in two parts and carries the first NF2 exon in
a juxta-centromeric position. The variability in position of the deletions and
the observation of a new chromosomal rearrangement in the NF2 gene underscore the
importance of FISH analysis in the molecular diagnosis of NF2.
PMID- 10777667
TI - Molecular cytogenetic evaluation in a patient with a translocation (3;21)
associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES).
AB - Blepharophimosis, ptosis, epicanthus inversus syndrome type I (BPES; OMIM 110100)
is an autosomal dominant disorder affecting craniofacial development and ovarian
function. We have identified a patient with BPES who carried a de novo reciprocal
translocation [46, XX,t(3;21)(q23;q22.1)]. Fluorescence in situ hybridization
analysis at band 3q23 using probes derived from BAC 175G20 (Research Genetics),
PACs 108L15 and 169C10 (RPCI1), and cosmids AC174D4, AC68D3, AC44F5, and AC125C5
(Lawrence Livermore National Laboratory) was performed. The patient's breakpoint
was found to lie within the overlapping region of the BAC and PACs but
centromeric to all the cosmids. However, a 10.5-kb BamHI-digested fragment,
common to the BAC and PAC clones, was shown to cross the breakpoint. The results
have placed our patient's breakpoint proximal to that of the previously reported
patient [46,XY,t(3;4)(q23;p15.2)] and within a 10.5-kb interval. This is the
second patient in which a breakpoint was refined by molecular cytogenetics. Our
findings emphasize the significance of this region for BPES.
PMID- 10777669
TI - Identification and characterization of human ZNF274 cDNA, which encodes a novel
kruppel-type zinc-finger protein having nucleolar targeting ability.
AB - A human cDNA encoding a novel zinc-finger protein, ZNF274, was identified by the
"nuclear transportation trap" method (Ueki, N., Oda, T., Kondo, M., Yano, K.,
Noguchi, T., and Muramatsu, M., 1998, Nat. Biotechnol. 16: 1338-1342). Based on
sequence analysis of the full-length cDNA, this novel gene has two alternative
splicing forms, ZNF274a and ZNF274b, which encode putative proteins of 621 and
584 amino acids, respectively. ZNF274a contains five C2H2-type zinc-finger
motifs, two KRAB-A (Kruppel-associated box) domains, and one leucine-rich domain.
ZNF274b lacks the first KRAB-A domain at the N-terminus. ZNF274 mRNA is detected
in various human tissues by Northern analysis. The ZNF274 gene is mapped distal
to marker RP S28 1 in the human chromosome 19qter region, by RH mapping. The KRAB
domains of ZNF274 exhibited transcription repressor activity when tested in GAL4
fusion protein assays. EGFP-ZNF274 fusion protein expressed in COS7 cells
predominantly localized to the nucleoli. A series of deletion constructs revealed
that a minimal domain consisting of the third and fourth zinc-fingers possesses
nucleolar targeting ability. These results suggest that ZNF274 is a ubiquitous
transcription repressor that plays a role in the nucleoli.
PMID- 10777668
TI - Cloning and expression analysis of a novel gene, RP42, mapping to an autism
susceptibility locus on 6q16.
AB - We isolated a novel mouse gene, RP42, in a systematic search for genes expressed
in proliferating neuroblasts whose human orthologs map to susceptibility loci for
autism. This gene is intronless and encodes a putative 259-amino-acid protein
that exhibits 30-36% overall sequence identity to a fission yeast and a nematode
protein (GenPept Accession Nos. CAA17006 and CAB54261). Nevertheless, no homology
to any known gene was found. RP42 has developmentally regulated expression,
particularly in proliferating neuroblasts from which neocortical neurons
originate. Its human ortholog is located in a cluster of embryonic neuronally
expressed genes on the 6q16 chromosome, making it a positional candidate
susceptibility gene for autism.
PMID- 10777670
TI - Comparative mapping of the human homologue of the rat diabetes susceptibility
gene lyp to a 1.3-Mb segment on HSA7.
AB - The rat diabetes susceptibility gene, Lyp or Lymphopenia, has been localized to
RNO4. Proximal to Lyp are the genes caspase-2 (Casp2) and pancreatic trypsin 1
(Prss1), while neuropeptide Y (Npy) is the closest distally positioned gene. In
human, the three genes are syntenic on HSA7, but they are not on a conserved
segment: CASP2 and PRSS1 are localized to 7q35, while NPY is localized to 7p15.1.
This raises the question whether the human homologue of Lyp is linked to
CASP2/PRSS1 or to NPY. We present a comparative map of the Lyp region in rat and
human, assigning the gene to a 1.3-Mb segment between RNY3 and ABP1 at 7q35.
PMID- 10777671
TI - Linkage of human narcolepsy with HLA association to chromosome 4p13-q21.
AB - Although narcolepsy is highly associated with human leukocyte antigen (HLA)
DQ6/DQB1*0602 and/or DR2/DRB1*1501, most individuals with the HLA haplotype are
free of narcolepsy. This indicates that HLA alone makes a relatively small
contribution to the development of narcolepsy and that a non-HLA gene(s) can
contribute to the genetic predisposition even in narcoleptic cases with HLA
association. We conducted a genome-wide linkage search for narcolepsy in eight
Japanese families with 21 DR2-positive patients (14 narcoleptic cases with
cataplexy and 7 cases with an incomplete form of narcolepsy). A lod score of 3.09
suggested linkage to chromosome 4p13-q21. A lod score of 1.53 was obtained at the
HLA-DRB1 locus, though this lod score may be biased since all the affected
patients and many of the family members were DR2-positive. No other loci
including hypocretin, hypocretin receptor 1, and hypocretin receptor 2 had lod
scores greater than 1.0. The present study suggests that chromosome 4p13-q21
contains a second locus for HLA-associated human narcolepsy.
PMID- 10777672
TI - Zinc increases the activity of vitamin D-dependent promoters in osteoblasts.
AB - Zinc modulates the structure and binding of the DNA binding domain of the
1alpha,25-dihydroxyvitamin D(3) receptor to specific vitamin D response element
DNA (Nature Biotechnology 16, 262-266, 1998). To determine whether zinc alters
1alpha,25-dihydroxyvitamin D(3)-regulated genes in cells, we permanently
transfected rat osteoblasts with two vitamin D-dependent promoter-reporter
systems and examined their responses to 1alpha,25-dihydroxyvitamin D(3) in the
presence of increasing amounts of extracellular zinc. When extracellular zinc
concentrations were increased in the presence of 1alpha,25-dihydroxyvitamin D(3),
there was an increase in the activity of 1alpha,25-dihydroxyvitamin D(3)
dependent promoters with increasing concentrations of zinc. The effect was
specific for zinc since metals such as copper failed to increase the activity of
1alpha,25-dihydroxyvitamin D(3)-dependent promoters. The concentration of the
vitamin D receptor within the cell and the affinity of 1alpha,25-dihydroxyvitamin
D(3) for its receptor remained unchanged with added zinc. Our results show that
zinc increases the activity of 1alpha,25-dihydroxyvitamin D(3)-dependent
promoters in osteoblasts.
PMID- 10777673
TI - Molecular cloning and genomic structure of human frizzled-3 at chromosome 8p21.
AB - WNT receptors encoded by the Frizzled genes are implicated in carcinogenesis as
well as in embryonic development. Human Frizzled-3 (FZD3) gene, encoding seven
transmembrane receptor with the N-terminal cysteine-rich domain, has been cloned
and characterized. Expression of the FZD3 mRNAs was investigated by using three
FZD3 specific probes: HF3S1, corresponding to the 5'-UTR and a part of the coding
region; HF3S2, corresponding to a part of the coding region; HF3S3, corresponding
to the 3'-UTR. HF3S1 and HF3S2 hybridized to the 14.0-, 9.0-, 4.0- and 1.8-kb
FZD3 mRNA, while HF3S3 hybridized to the 14.0-, 9.0-, and 4.0-kb FZD3 mRNA. The
14. 0-kb FZD3 mRNA was the major transcript in fetal brain and adult cerebellum,
while the 1.8-kb FZD3 mRNA was the major transcript in adult pancreas, and many
cancer cell lines examined. The 1.8-kb FZD3 mRNA, alternatively polyadenylated by
the internal AATAAA signal in the coding region, is predicted to encode the
truncated FZD3 protein lacking the region through the second extracellular loop
to the C-terminal tail, and might function as the transmembrane-type antagonist
for WNTs. The FZD3 gene consists of 8 exons, and has been mapped to human
chromosome 8p21.
PMID- 10777674
TI - Contribution of the carboxy-terminal domain of lipoprotein lipase to interaction
with heparin and lipoproteins.
AB - The C-terminal domain of lipoprotein lipase (LPL) is involved in several
important interactions. To assess its contribution to the binding ability of full
length LPL we have determined kinetic constants using biosensor technique. The
affinity of the C-terminal domain for heparin was about 500-fold lower than that
of full-length LPL (K(d) = 1.3 microM compared to 3.1 nM). Replacement of Lys403,
Arg405 and Lys407 by Ala abolished the heparin affinity, whereas replacement of
Arg420 and Lys422 had little effect. The C-terminal domain increased binding of
chylomicrons and VLDL to immobilized heparin relatively well, but was less than
10% efficient in binding of LDL compared to full-length LPL. Deletion of residues
390-393 (WSDW) did not change the affinity to heparin and only slightly decreased
the affinity to lipoproteins. We conclude that the C-terminal folding domain
contributes only moderately to the heparin affinity of full-length LPL, whereas
the domain appears important for tethering triglyceride-rich lipoproteins to
heparin-bound LPL.
PMID- 10777675
TI - Oligosaccharide trimming plays a role in the endoplasmic reticulum-associated
degradation of tyrosinase.
AB - The effect of glucosidase and mannosidase inhibitors on the ER-associated
degradation of tyrosinase was assessed in transiently transfected COS-7 cells. We
found that the glucosidase inhibitors castanospermine and deoxynojirimycin had
very little effect on tyrosinase degradation, whereas the mannosidase inhibitors
deoxymannojirimycin and kifunensine significantly delayed the rate of tyrosinase
degradation as measured by pulse-chase analysis. In addition, we show that
tyrosinase degradation is sensitive to the proteasome inhibitor lactacystin and
that tyrosinase associates with endogenous calnexin in COS-7 cells. Our data
support a model of tyrosinase degradation that involves mannose trimming,
calnexin association, and the retrograde transport of tyrosinase from the ER to
the cytosol for proteasomal degradation. The pathways of tyrosinase degradation
have important ramifications with regard to the exact types of antigenic epitopes
that are presented to the immune system.
PMID- 10777676
TI - Cloning and initial characterization of the human DPYD gene promoter.
AB - Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the
degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD
activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer
patients and with neurological abnormalities in paediatric patients. Although
variant DPYD alleles have been identified in DPD-deficient patients, they do not
adequately explain polymorphic DPD activity or associated clinical phenotypes in
vivo. DPD may be transcriptionally regulated as mRNA levels correlate with
activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking
region of the human DPYD gene was cloned and has transcriptional activity in
cultured cells. Analysis of this 5' flanking region in rhesus and cynomolgus
monkeys demonstrated conservation (>96%) between humans and primates. Putative
binding sites for ubiquitous and cell-specific factors were identified. A
polymorphism that disrupts a putative gamma-interferon response element was
identified in a cancer patient with reduced DPD activity and severe 5FU toxicity.
Further insight into regulation of DPD expression may identify new avenues for
the treatment of clinical problems associated with DPD deficiency.
PMID- 10777677
TI - Rat basophilic leukemia cells express syntaxin-3 and VAMP-7 in granule membranes.
AB - In neuronal cells, it is generally agreed that SNARE proteins underlie the
release of neurotransmitter. It is controversial, however, whether they also work
functionally in the degranulation of RBL-2H3 cells because the expression of
SNARE proteins has not been confirmed and the degranulation is not inhibited by
tetanus toxin which cleaves one of SNARE proteins, VAMP-2. We investigated the
expression and the localization of SNARE proteins including VAMP-7 which is
insensitive to tetanus toxin. RT-PCR analysis showed the existence of SNARE
proteins, including syntaxin-2, -3, -4, SNAP-23, VAMP-2, and VAMP-7. Experiments
using GFP-conjugated proteins revealed that VAMP-7 was localized only in granule
membranes, whereas syntaxin-3 was in both the plasma and granule membranes. Upon
antigen stimulation, these proteins in granule membranes moved to the cell
surface due to the fusion of granules with the plasma membrane. The results
suggest the involvement of SNARE proteins in the degranulation of RBL-2H3 cells.
PMID- 10777678
TI - The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed
in the plasma membrane.
AB - The products of the ABC gene family can be generally classified as either full
transporters of half-transporters. Full-transporters are expressed in the plasma
membrane, whereas half-transporters are usually found in intracellular membranes.
Recently, an ABC half-transporter, the ABCG2 gene product Breast
Cancer/Mitoxantrone Resistance Protein (BCRP/MXR), has been shown to cause
mitoxantrone and topotecan resistance. The purpose of this study was to determine
the expression and the intracellular localization of this protein in various drug
resistant cell lines. BCRP/MXR expression was determined by Western blot and
immunohistochemistry. This protein is highly overexpressed in several drug
resistant cell lines and localizes predominantly to the plasma membrane, instead
of to intracellular membranes as seen with all other known half-transporters.
Therefore, BCRP/MXR is unique among the ABC half-transporters by being localized
to the plasma membrane.
PMID- 10777679
TI - Interrelations between plasma homocysteine and intracellular S
adenosylhomocysteine.
AB - S-Adenosylhomocysteine, a potent intracellular methylation inhibitor, is
suggested as a potential mediator for hyperhomocysteinemia-related vascular
changes. We investigated the effect of acute and chronic hyperhomocysteinemia on
intracellular S-adenosylhomocysteine and S-adenosylmethionine in rats and humans.
Elevated plasma homocysteine in rats infused with homocysteine produced an
increase in S-adenosylhomocysteine (P < 0.001) but not S-adenosylmethionine
levels (P > 0.05) in various rat tissues. However intraerythrocyte S
adenosylhomocysteine and S-adenosylmethionine levels were not changed in
homocysteine-infused rats and human subjects with experimentally acute
hyperhomocysteinemia by methionine loading test. In contrast, erythrocyte S
adenosylhomocysteine levels were significantly higher in chronic renal failure
patients, who had chronically elevated plasma homocysteine levels, than in either
vascular disease patients or healthy controls (P < 0.05). In conclusion, acute
hyperhomocysteinemia can increase intracellular S-adenosylhomocysteine levels in
tissues actively involved in homocysteine metabolism. The findings are relevant
to homocysteine-related endothelial dysfunction since S-adenosylhomocysteine
modulates endothelial cell apoptosis.
PMID- 10777680
TI - Cry1Ac protoxin from Bacillus thuringiensis sp. kurstaki HD73 binds to surface
proteins in the mouse small intestine.
AB - Bacillus thuringiensis (Bt), considered a safe insecticide, produces insecticidal
proteins named Cry during sporulation, which possess exceptional immunological
properties. In this work using an immunohistochemical test we demonstrated that
Cry1Ac protoxin (pCry1Ac) binds to the mucosal surface of the mouse small
intestine. Ligand blot assay allowed us to detect, under denaturing conditions,
six pCry1Ac-binding polypeptides present in brush border membrane vesicles
isolated from the small intestine. Moreover, this protein induced in situ
temporal changes in the electrophysiological properties of the mouse jejunum. The
data obtained indicate a possible interaction in vivo of Cry proteins with the
animal bowel which could induce changes in the physiological status of the
intestine.
PMID- 10777681
TI - Tyrosine 50 at the subunit interface of dimeric human glutathione transferase P1
1 is a structural key residue for modulating protein stability and catalytic
function.
AB - The dimer interface in human GSTP1-1 has been altered by site-directed
mutagenesis of Tyr50. It is shown that the effects of some mutations of this
single amino acid residue are as detrimental for enzyme function as mutations of
Tyr8 in the active site. The dimeric structure is a common feature of the soluble
glutathione transferases and the structural lock-and-key motif contributing to
the subunit-subunit interface is well conserved in classes alpha, mu, and pi. The
key residue Tyr50 in GSTP1-1 was replaced with 5 different amino acids with
divergent properties and the mutant proteins expressed and characterized. Mutant
Y50F is an improved variant, with higher thermal stability and higher catalytic
efficiency than the wild-type enzyme. The other mutants studied are also dimeric
proteins, but have lower stabilities and catalytic activities that are reduced by
a factor of 10(2)-10(4) from the wild-type value. Mutants Y50L and Y50T are
characterized by a markedly increased K(M) value for GSH, while the effect is
mainly due to decreased k(cat) values for mutants Y50A and Y50R. In conclusion,
residue 50 in the interface governs both structural stability and catalytic
function.
PMID- 10777682
TI - The beta(2) subunit of soluble guanylyl cyclase contains a human-specific
frameshift and is expressed in gastric carcinoma.
AB - Soluble or nitric oxide (NO) stimulated guanylyl cyclases are obligate heme
containing heterodimers (alpha/beta). We report the full-length cDNA of the human
ortholog of the rat beta(2)-subunit from human kidney. A database search yielded
matches of the 3' non-coding sequence with previously unassigned expressed
sequence tags from kidney and stomach signet ring cell carcinoma. PCR comparison
of cDNA from stomach signet ring cell carcinoma and normal stomach tissue
demonstrated beta(2) subunit expression in cancer but not in normal tissue. On
the cDNA level a frameshift deletion of one nucleotide was present in the novel
human sequence which was confirmed on the genomic DNA level. In four closely
related nonhuman primate species the frameshift deletion was absent while
analysis of genomic DNA from different ethnic backgrounds revealed the uniform
presence of the frameshift deletion in the human population.
PMID- 10777683
TI - IgG-coated erythrocytes augment LPS-stimulated TNF-alpha secretion, TNF-alpha
mRNA levels, and TNF-alpha mRNA stability in macrophages.
AB - Previous studies have shown that IgG-coated erythrocytes (EIgG) augment the LPS
stimulated increase in serum TNF-alpha levels in animals and the LPS-stimulated
secretion of TNF-alpha by isolated macrophages. The present study evaluated the
mechanism for the effect of EIgG on LPS-stimulated TNF-alpha secretion in the
murine macrophage cell line, RAW 264.7. Incubation of the macrophages with EIgG
or IgG-coated glass beads caused a dose-dependent augmentation of LPS-stimulated
TNF-alpha secretion. The addition of EIgG increased the rate of LPS-stimulated
TNF-alpha protein secretion between 2 and 4 hr after LPS. Accordingly, EIgG
increased the levels of TNF-alpha mRNA at 2 and 3 hr after LPS. The increase in
the LPS-stimulated TNF-alpha mRNA levels caused by EIgG was associated with an
increase in TNF-alpha mRNA stability. Thus, the augmentation of LPS-stimulated
TNF-alpha secretion by EIgG was associated with an increase in TNF-alpha mRNA
levels which at least partly resulted from an increase in the stability of TNF
alpha mRNA.
PMID- 10777684
TI - Involvement of tail domains in regulation of Dictyostelium myosin II.
AB - The actin-dependent ATPase activity of Dictyostelium myosin II filaments is
regulated by phosphorylation of the regulatory light chain. Four deletion mutant
myosins which lack different parts of subfragment 2 (S2) showed phosphorylation
independent elevations in their activities. Phosphorylation-independent elevation
in the activity was also achieved by a double point mutation to replace conserved
Glu932 and Glu933 in S2 with Lys. These results suggested that inhibitory
interactions involving the head and S2 are required for efficient regulation.
Regulation of wild-type myosin was not affected by copolymerization with a S2
deletion mutant myosin in the same filaments. Furthermore, the activity linearly
correlated with the fraction of phosphorylated molecules in wild-type filaments.
These latter two results suggest that the inhibitory head-tail interactions are
primarily intramolecular.
PMID- 10777685
TI - Effect of estradiol on neuronal Swedish-mutated beta-amyloid precursor protein
metabolism: reversal by astrocytic cells.
AB - Alzheimer's disease is the most frequent neurodegenerative disorder in the aged
population and is characterized by the deposition of the 40/42-residue amyloid
beta protein (Abeta), a proteolytic fragment of the beta-amyloid precursor
protein (APP). Recently, it has been shown that physiological doses of estradiol
reduce the generation of endogenous Abeta in primary cortical neurons. Here we
investigate the influence of estrogen in amyloidogenesis and sAPPalpha secretion
in the CNS. By means of primary cortical neurons overexpressing humanized
APP(695) bearing the Swedish mutation (hAPP(695sw)), we analyzed APP maturation
in the absence or in the presence of estrogen. We show that estrogen at a 2
microM concentration increases the release of the neuroprotective sAPPalpha
fragment but does not reduce the release of Abeta in primary neurons
overexpressing the Swedish-mutated form of APP. Furthermore, neurons cocultured
with astrocytic cells or grown with astrocytes conditioned media do not exhibit
the estrogen-induced increase in sAPPalpha secretion. Altogether, our data
indicate that astrocytes interfere with estrogen in the regulation of sAPPalpha
secretion, probably via secreted factor(s).
PMID- 10777686
TI - Decreased ADP-ribosylation of the Galpha(olf) and Galpha(s) subunits by high
glucose in pancreatic B-cells.
AB - In HIT-T15 insulinoma B-cells incubated in presence of [(32)P]NAD, we identified
by autoradiography and immunoblotting ADP-ribosylation (ADP-R) of the trimeric G
protein Galpha(s) and Galpha(olf) subunits (45 kDa) induced by cholera toxin in
M1 (120,000g) and M2 (70,000g) subcellular fractions containing plasma membranes,
insulin granules, and mitochondria. This ADP-R indicates that these two fractions
contain functionally competent Galpha subunits for adenylyl cyclase activation.
Prolonged exposure of HIT-T15 cells to high glucose (25 mM instead of 6 mM)
specifically reduced the ADP-R in Galpha(s) and Galpha(olf) subunits in the M1
fraction only, despite the clear increase of their accumulation in this
compartment. A similar alteration in the ADP-R of the M1-associated Galpha(s) and
Galpha(olf) subunits was observed in pancreatic islets isolated from fasted and
fed rats. These results may explain, at least in part, the undesirable effects of
sustained hyperglycemia on the cAMP-dependent process of insulin secretion in
diabetes.
PMID- 10777687
TI - An SP1-like cis-element is the major DNA motif for differential expression
regulation of the adipocyte amino acid transporter.
AB - Adipocyte amino acid transporter (AAAT) is induced during the 3T3-L1 preadipocyte
differentiation process. In the -1819-bp 5'-upstream flanking region of the AAAT
genomic gene, six DNase I protected sites were identified by using the 3T3-L1
adipocyte nuclear extract. Results of chloramphenicol acetyltransferase (CAT)
expression from the chimeric AAAT promoter-driven CAT reporter gene indicated
that one protein binding site, from -68 to -26, was essential for the promoter
activity. However, this protein binding site does not contain recognition sites
of the transcription factors important for adipocyte differentiation, i.e., the
C/EBP or PPAR family. Further analysis revealed that the DNA sequence,
TTCAAGTCCCGCCCTCCGCT from -65 to -46, was the cis-element essential and partially
sufficient for inducible activity of the AAAT gene promoter.
PMID- 10777688
TI - Differential expression of the adipocyte amino acid transporter is transactivated
by SP1 and SP3 during the 3T3-L1 preadipocyte differentiation process.
AB - It was identified that a Sp1-like cis-element in the adipocyte amino acid
transporter gene (AAAT) promoter is the major cis-motif for its induced
expression during the 3T3-L1 preadipocyte differentiation process.
Electrophoretic mobility shift analysis of this cis DNA element showed that the
transcription factors binding to this sequence were Sp1 and Sp3. Protein analysis
of Sp1 and Sp3 in nuclear extracts from 3T3-L1 cells at various differentiation
stages indicated that these two transcription factors existed in noninduced 3T3
L1 preadipocytes, but they did not bind to the AAAT promoter element with high
affinity. They were activated after differentiation induction. It was further
demonstrated that dephosphorylation of Sp1 increased its binding affinity to this
inducible AAAT promoter element.
PMID- 10777689
TI - Direct immunization of malaria DNA vaccine into the liver by gene gun protects
against lethal challenge of Plasmodium berghei sporozoite.
AB - The liver is the first target organ for malaria parasites immediately after the
bite of an infected mosquito. We studied local immunization of malaria DNA
vaccines at the site of the liver using a gene gun as a useful tool for in vivo
transfection of foreign genes. A malaria DNA vaccine consisting of the Plasmodium
berghei circumsporozoite protein (PbCSP) gene plus the mouse IL-12 gene was
bombarded directly by a gene gun into mouse liver once or into the skin twice. A
marked protective effect was induced by gene bombardment into the liver (more
than 71%) compared with that into the skin (less than 33%). A Th1-type immune
response and high production of iNOS were observed in the hepatic lymphocytes
from mice bombarded into the liver, resulting in more effective protection
compared with those bombarded into the skin. These results provide an important
implication on the development of efficient malaria vaccine strategies.
PMID- 10777690
TI - Nestin-expressing cells in the pancreatic islets of Langerhans.
AB - The pancreatic islets of Langerhans produce several peptide hormones,
predominantly the metabolically active hormones insulin and glucagon, which are
critical for maintaining normal fuel homeostasis. Some evidence exists that
pancreatic endocrine cells turn over at a slow rate and can regenerate in certain
conditions. This could be due to the presence of pluripotent cells residing in
the pancreas. Recently the intermediate filament protein nestin has been
identified to be a marker for a multipotent stem cell in the central nervous
system. Given the similarity between the pancreatic islets and neuronal cells, we
hypothesized that stem cells expressing nestin might be present in the pancreas.
Here we present evidence that a subset of cells in the pancreatic islets express
the stem cell marker nestin. These cells might serve as precursors of
differentiated pancreatic endocrine cells.
PMID- 10777691
TI - Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1
in Japanese hereditary nonpolyposis colorectal cancer kindreds.
AB - Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal, dominantly
inherited cancer-prone syndrome. Here, we describe a novel and efficient approach
for screening mutations of two major HNPCC susceptibility genes, hMSH2 and hMLH1.
The system consists of RNA extraction from whole blood treated with the
translation inhibitor, followed by long RT-PCR of the entire coding regions
combined with direct sequencing. In analysis of 15 kindreds suspicious for HNPCC,
8 samples were subjected to analysis after puromycin treatment and 7 samples were
analyzed without puromycin treatment. Three deleterious mutations were detected
in the kindreds with puromycin treatment, while none were observed in those
without puromycin. Signals from mutated alleles were enhanced after puromycin
treatment and easily distinguished from the wild-type allele, achieved by
suppression of nonsense-mediated mRNA decay. Furthermore, 12 other mutations were
detected in 15 kindreds. The system is considered to be a reliable and useful
approach for detecting germline mutations of hMSH2 and hMLH1 in HNPCC kindreds.
PMID- 10777693
TI - Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1
receptor antagonist mRNA in rat carotid artery after balloon angioplasty.
AB - Interleukin-1beta (IL-1beta) is a pleiotropic cytokine capable of inducing smooth
muscle activation and leukocyte recruitment in restenosis and atherosclerosis.
Our present study investigated the expression of IL-1beta, IL-1 receptor
antagonist (IL-1ra), and IL-1 receptor (IL-1RI and IL-1RII) mRNA in carotid
artery after balloon angioplasty using semiquantitative reverse
transcription/polymerase chain reaction (RT/PCR) and Northern analysis. Time
course studies revealed that IL-1beta mRNA was rapidly induced at 6 h (30-fold
increase over control, P < 0.001) post balloon injury and diminished to basal
levels at 24 h. The increased expression of IL-1ra mRNA was delayed, reaching a
peak at 24 h (400-fold increase, P < 0.001) and sustained up to 14 days. The
expression of IL-1RII mRNA was remarkably similar to that of IL-1beta, whereas
the IL-1RI (the signaling receptor) mRNA expression was delayed (significantly
induced at day 1; 14.2-fold increase, P < 0.01) post balloon injury.
Immunohistochemical studies revealed a strong induction of IL-1beta in the area
with actively proliferating and migrating smooth muscle cells (i.e., in the inner
medial layer at day 1 and in neointima at day 14 after balloon injury). The
differential but concomitant expression of IL-1beta, IL-1ra, IL-1RI, and IL-1RII
mRNAs after balloon angioplasty suggests that each of these IL-1 system
components may play a distinct role in neointima formation.
PMID- 10777692
TI - In situ RT-PCR detection of CYP1A mRNA in pharyngeal epithelium and chondroid
cells from chemically untreated fish: involvement in vertebrate craniofacial
skeletal development?
AB - Knowledge about the expression sites of cytochrome P450 1A (CYP1A) mRNA is
crucial for a better understanding of the physiological function of CYP1A. We
investigated the cellular localization of CYP1A mRNA in chemically untreated fish
by use of an in situ reverse transcription-polymerase chain reaction (IS RT-PCR)
technique. The fathead minnow (Pimephales promelas) was formalin-fixed, and
paraffin-embedded. Sections (5 microm) were treated with trypsinogen. Following
reverse transcription of CYP1A mRNA, the cDNA was amplified in situ by PCR with
specific primers. Detection of the amplicons was accomplished by a second PCR
performed with digoxigenin-labeled dUTP. CYP1A mRNA expression was detected in
cytoplasm of chondroid cells surrounding hyaline cartilage in gill arches. This
result was consistent with that of immunohistochemical analysis with a CYP1A1
specific monoclonal antibody. CYP1A mRNA also was found in stratified squamous
epithelium of the pharynx and gill arches, but no staining was detected in those
cells by immunohistochemical analysis. The results indicate that IS RT-PCR is an
effective/sensitive technique for localizing low level CYP1A expression. In
addition, the sites where we identified expression of CYP1A are targets of
retinoic acid, sonic hedgehog and Hox genes, suggesting that functional CYP1A in
vertebrates could participate in craniofacial skeletal development through
involvement in the retinoic acid signaling cascade.
PMID- 10777694
TI - Human adrenoleukodystrophy protein and related peroxisomal ABC transporters
interact with the peroxisomal assembly protein PEX19p.
AB - Four ABC half transporters (ALDP, ALDRP, PMP70, and PMP69) have been identified
in the mammalian peroxisomal membrane but no function has been unambiguously
assigned to any of them. To date X-linked adrenoleukodystrophy (X-ALD) is the
only human disease known to result from a defect of one of these ABC
transporters, ALDP. Using the yeast two-hybrid system and in vitro GST pull-down
assays, we identified the peroxin PEX19p as a novel interactor of ALDP, ALDRP,
and PMP70. The cytosolic farnesylated protein PEX19p was previously shown to be
involved in an early step of the peroxisomal biogenesis. The PEX19p interaction
occurs in an internal N-terminal region of ALDP which we verified to be important
for proper peroxisomal targeting of this protein. Farnesylated wild-type PEX19p
and a farnesylation-deficient mutant PEX19p did not differ in their ability to
bind to ALDP. Our data provide evidence that PEX19p is a cytosolic acceptor
protein for the peroxisomal ABC transporters ALDP, PMP70, and ALDRP and might be
involved in the intracellular sorting and trafficking of these proteins to the
peroxisomal membrane.
PMID- 10777695
TI - XSIP1, a member of two-handed zinc finger proteins, induced anterior neural
markers in Xenopus laevis animal cap.
AB - We characterized Xenopus SIP1 (XSIP1), Smad interacting protein, from activin
treated animal caps by differential screening. The XSIP1 is very similar to mouse
SIP1 in the protein coding region including the zinc finger domain and
homeodomain. The expression pattern was analyzed by RT-PCR and whole mount in
situ hybridization. XSIP1 expression was initially restricted to the dorsal
marginal zone in the late gastrula and was subsequently expressed at the lateral
edge of neural plate and, in the tailbud stage, in the forebrain, neural tube,
and eye. Overexpression of XSIP1 at the animal caps resulted in activation of
anterior neural markers without mesodermal markers. Ectopic expression of XSIP1
induced enlargement of neural cells and disordered eye formation. In addition to
abnormal head phenotypes, many embryos were short-tailed. Our findings suggest
that XSIP1 is a transcriptional repressor, which may be involved in the activin
dependent signal pathway.
PMID- 10777696
TI - The inhibitory effects of vasoactive intestinal peptide and pituitary adenylate
cyclase-activating polypeptide on osteoclast formation are associated with
upregulation of osteoprotegerin and downregulation of RANKL and RANK.
AB - The presence of a network of peptidergic nerve fibers in the skeleton, expressing
several neuropeptides including vasoactive intestinal peptide (VIP), has been
demonstrated. This observation, together with our findings in vitro showing that
VIP can regulate the activities of osteoblasts and osteoclasts as well as the
recruitment of osteoclasts, has suggested the existence of a neuro-osteogenic
interplay in bone metabolism. In the present study, the effects of VIP and
pituitary adenylate cyclase-activating polypeptide (PACAP), two members of the
VIP/secretin/glucagon superfamily, on osteoclast formation and mRNA expression of
three key regulatory proteins involved in osteoclast formation have been
investigated. VIP, PACAP-27, and PACAP-38, at concentrations of 10(-6) M, all
significantly inhibited formation of tartrate-resistant acid phosphatase-positive
multinuclear cells (TRAP + MNC) in mouse bone marrow cultures stimulated by 1,
25(OH)(2)-vitamin D3 (D3; 10(-8) M). By using semiquantitative RT-PCR, it was
found that D3 upregulated the mRNA expressions of receptor activator of NF-kappaB
ligand (RANKL) and receptor activator of NF-kappaB (RANK), whereas the expression
of osteoprotegerin (OPG) was downregulated in mouse bone marrow cultures
stimulated by D3 for 7 days. Both VIP and PACAP-38 decreased the stimulatory
effects of D3 on RANKL and RANK expression, whereas the inhibitory effect of D3
on OPG expression was reversed by VIP and PACAP-38. These observations indicate
that the inhibitory effects of VIP and PACAP on osteoclast recruitment are due to
regulation of the expression of key proteins involved in later stages of
osteoclast differentiation.
PMID- 10777697
TI - Small heat shock protein 27 (HSP27) associates with tubulin/microtubules in HeLa
cells.
AB - One of the monoclonal antibodies raised against mitotic HeLa cells (termed as
mH3) recognized a 27-kDa protein and stained microtubules in the mitotic spindles
of HeLa cells. Immunoscreening of a HeLa cDNA library revealed that mH3 antigen
is a small heat shock protein, HSP27. Immunoprecipitation analysis using mH3
suggested that both alpha- and beta-tubulin are associated with HSP27. Further,
sucrose-cushioned ultra centrifugation revealed that HSP27 is co-sedimented with
taxol-stabilized microtubules. These results indicate that HSP27 associates with
tubulin/microtubules in HeLa cells.
PMID- 10777698
TI - Differential expression of sense and antisense transcripts of the mitochondrial
DNA region coding for ATPase 6 in fetal and adult porcine brain: identification
of novel unusually assembled mitochondrial RNAs.
AB - The mammalian mitochondrial genome is a double-stranded circular DNA molecule,
which is transcribed from both strands as polycistronic RNAs, which are further
processed to yield the mature polyadenylated mRNAs, rRNAs and tRNAs. We compared
the gene expression patterns of foetal and adult porcine brains and identified a
sequence tag from the ATPase 6 region of the mitochondrial genome which, in adult
brain, was more abundant in the sense (H-strand) form, but, in foetal brain, more
abundant in the antisense form (L-strand). By means of solution hybridisation/S1
nuclease protection assay, Northern blotting, and PCR based techniques, we
demonstrated that the ATPase 6 region of the porcine mitochondrial genome is
transcribed as co-existing, stable sense and antisense RNAs. Furthermore, we
identified sense and antisense transcripts from this region consisting of
inversely assembled fragments joined together at a direct repeat of 7
nucleotides. Our results suggest that transcription and post-transcriptional
processing of mitochondrial RNAs are much more complex than presently thought.
PMID- 10777700
TI - Silkworm hemolymph inhibits baculovirus-induced insect cell apoptosis.
AB - The effect of silkworm hemolymph on baculovirus-induced insect cell apoptosis was
investigated. The addition of silkworm hemolymph into the culture medium either
before or during the baculovirus infection increased the host cell longevity;
however, its addition after the infection was less effective. This can be
explained by the higher transfer rate of silkworm hemolymph which is caused by
endocytosis during the virus internalization step. The delayed cell death due to
silkworm hemolymph was not caused by an inhibition of the virus attachment and
internalization steps. The apoptosis was analyzed using DNA fragmentation and
TUNEL assays, and the resulting data confirm that silkworm hemolymph inhibits
baculovirus-induced insect cell apoptosis.
PMID- 10777699
TI - Monoamine oxidase B induces ERK-dependent cell mitogenesis by hydrogen peroxide
generation.
AB - The mitochondrial enzyme monoamine oxidase (MAO) A and B catalyze the oxidative
deamination of various endogenous and exogenous biogenic amines. In the present
study, we used human embryonic kidney 293 (HEK 293) cells stably transfected with
human MAO-B cDNA to investigate the potential role of hydrogen peroxide
(H(2)O(2)) produced by MAO-B isoform as an intracellular messenger involved in
regulation of cell signaling and function. The MAO substrate tyramine induced
tyrosine phosphorylation of Shc, ERK activation, and an increase in DNA synthesis
in HEK 293 expressing MAO-B, but not in wild type HEK 293 cells, which do not
express MAO. Tyramine effects were fully prevented by cell pretreatment with the
MAO inhibitor pargyline or the antioxidant N-acetylcysteine. These results show
that MAO-B induces MAPK/ERK activation and cell mitogenesis through H(2)O(2)
production.
PMID- 10777701
TI - Animal and plant members of a gene family with similarity to alkaloid
synthesizing enzymes.
AB - Here we describe novel members of a gene family which have similarity to
strictosidine synthase (SS), one of the key enzymes in the production of
monoterpene indole alkaloids. In addition to the first animal member of the
family described previously (Drosophila hemomucin), a second Drosophila member
has been identified, which appears to differ in subcellular distribution from
hemomucin. In Arabidopsis, SS-like genes form a multigene family, compatible with
a possible function as antifeedants and antibacterial compounds. In
Caenorhabditis, two members have been identified and one member each in mouse and
human. Interestingly, the human SS-like gene is strongly expressed in the brain,
the very organ many of the indole alkaloids act upon.
PMID- 10777702
TI - Decreased gene expression of adrenomedullin receptor in mouse lungs during
sepsis.
AB - Plasma concentrations of adrenomedullin (AM) are markedly increased during
sepsis, but the role of AM has not been clarified. Coexpression of calcitonin
receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 2 or
3 have been reported to form the adrenomedullin (AM) specific receptor. We
examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice
in a sepsis model induced by lipopolysaccharide (LPS). High expression of CRLR
and RAMP2 mRNA was observed in lungs of normal mice, but it was markedly
decreased in endotoxemic mice. It is suggested that the abundant binding sites of
AM in lungs are formed by CRLR and RAMP2 in healthy subjects and that their
reduction should contribute to the increase of plasma AM concentrations during
sepsis. In contrast, LPS treatment markedly increased RAMP3 gene expression in
lungs, spleen, and thymus. It is revealed that the distributions of receptor or
binding sites of AM are changed in sepsis, and it is suggested that AM plays
distinct roles in the clinical course of this syndrome.
PMID- 10777703
TI - Mechanism of regulation of HGF/SF gene expression in fibroblasts by TGF-beta1.
AB - The effect of transforming growth factor beta 1 (TGF-beta1) on levels of
hepatocyte growth factor/scatter factor (HGF/SF) gene transcripts was
investigated in the human lung embryonic fibroblast cell line, MRC-5. TGF-beta1
markedly reduced the expression of the 6. 0-kb and 3.0-kb HGF/SF mRNA, which
encode full-length HGF/SF, but it had little effect on the expression of the
alternatively spliced 1. 5-kb mRNA, which encodes NK2, a competitive HGF/SF
antagonist. Using actinomycin D to block RNA synthesis, it was observed that TGF
beta1 had little effect on the stability of the 1.5-kb NK2 mRNA but increased the
rate of degradation of the 6.0- and 3.0-kb HGF/SF mRNA transcripts by a mechanism
that was dependent on new protein synthesis. TGF-beta1 minimally increased rather
than reduced HGF/SF promoter activity in cells transiently transfected with
chloramphenicol acetyltransferase (CAT) reporter genes driven by HGF/SF gene 5'
flanking sequences. In MRC-5 cells, TGF-beta1 modulates HGF/SF gene transcripts
at the posttranscriptional level in order to favour expression of the 1.5-kb mRNA
that encodes the truncated protein NK2.
PMID- 10777704
TI - The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2
diabetes.
AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated
in adipocyte differentiation. Recently it was reported that heterozygous
deficiency of PPARgamma led to the protection from high-fat diet-induced insulin
resistance in an animal model. A Pro12Ala polymorphism has been detected in the
human PPARgamma2 gene. Since this amino acid substitution may cause a reduction
in the transcriptional activity of PPARgamma, this polymorphism may be associated
with decreased insulin resistance and decreased risk of type 2 diabetes. To
investigate this hypothesis, we performed a case-control study of the Pro12Ala
PPARgamma2 polymorphism in Japanese diabetic and non-diabetic subjects. The
frequency of Ala12 was significantly lower in the diabetic group. In an
overweight or obese group, subjects with Ala12 were more insulin sensitive than
those without. These results suggest that the PPARgamma is a thrifty gene and
that the Pro12Ala PPARgamma2 polymorphism protects against type 2 diabetes in the
Japanese.
PMID- 10777705
TI - Enhancement of S-nitrosylation in glycosylated hemoglobin.
AB - In this study, we report a novel differential nitric oxide interaction with
nonglycosylated and glycosylated hemoglobin. After in vitro incubation of
hemoglobin with S-nitroso N-acetyl penicillamine (SNAP), S-nitrosoglutathione, or
S-nitrosocysteine, S-nitrosylation was significantly higher in human glycosylated
hemoglobin purified from diabetic subjects compared to nondiabetic controls.
Inversely, spontaneous decomposition was significantly lower for S
nitrosohemoglobin obtained from glycosylated hemoglobin. Bidimensional
isoelectric focusing of hemoglobins incubated in vitro with SNAP also revealed a
greater interaction of nitric oxide with glycosylated hemoglobin. In addition, a
significantly higher level of S-nitrosohemoglobin was found in erythrocyte
lysates from streptozotocin-induced diabetic rats compared to control rats. We
suggest that highly glycosylated hemoglobin in diabetic subjects may favor S
nitrosylation, which may in turn impair vascular function, and participate in
diabetic microangiopathy.
PMID- 10777706
TI - In vivo metabolic imaging of cardiac bioenergetics in transgenic mice.
AB - Recent advances in transgenic technology have made the mouse a particularly
interesting small animal in cardiovascular research. Increasingly sophisticated
experimental methods and tools are needed for detailed characterization of
cardiovascular physiology and biochemistry in the mice. The objective of this
study was to develop a method for noninvasive evaluation of cardiac energy
metabolism in the mouse. Cardiac gated (31)P magnetic resonance spectroscopy
using Image Selected in Vivo Spectroscopy (ISIS) method was applied in old mice
overexpressing bovine growth hormone (bGH) (n = 5) and control mice (n = 5). The
localized volumes of interest were 128 and 112 microL, respectively.
Phosphocreatine-to-ATP ratio was 1.5 +/- 0.13 in the bGH mice and 2.1 +/- 0.04 in
the control group (P < 0.01). The study demonstrates the feasibility of
application of volume-selective (31)P MRS for evaluation of cardiac energy
metabolism in the mouse under maintained physiological conditions.
PMID- 10777707
TI - Chitinous materials inhibit nitric oxide production by activated RAW 264.7
macrophages.
AB - Chitinous materials have been studied in wound healing and artificial skin
substitutes for many years. Nitric oxide (NO) has been shown to contribute to
cytotoxicity in cell proliferation during inflammation of wound healing. In this
study, we examined the effect of chitin and its derivatives on NO production by
activated RAW 264.7 macrophages. Chitin and chitosan showed a significantly
inhibitory effect on NO production by the activated macrophages. Hexa-N
acetylchitohexaose and penta-N-acetylchitopentaose also inhibited NO production
but with less potency. However, N-acetylchitotetraose, -triose, -biose, and
monomer of chitin, N-acetylglucosamine and glucosamine had little effect on NO
production by the activated cells. These results suggest that the promotive
effect of chitinous material on wound healing be related, at least partly, to
inhibit NO production by the activated macrophages.
PMID- 10777708
TI - Drug-induced desensitization of insulinotropic actions of sulfonylureas.
AB - K(ATP)-channel-dependent and K(ATP)-channel-independent insulin-releasing actions
of the sulfonylurea, tolbutamide, were examined in the clonal BRIN-BD11 cell
line. Tolbutamide stimulated insulin release at both nonstimulatory (1.1 mM) and
stimulatory (16. 7 mM) glucose. Under depolarizing conditions (16.7 mM glucose
plus 30 mM KCl) tolbutamide evoked a stepwise K(ATP) channel-independent
insulinotropic response. Culture (18 h) with tolbutamide or the guanidine
derivative BTS 67 582 (100 microM) markedly reduced (P < 0. 001) subsequent
responsiveness to acute challenge with tolbutamide, glibenclamide, and BTS 67 582
but not the imidazoline drug, efaroxan. Conversely, 18 h culture with efaroxan
reduced (P < 0.001) subsequent insulinotropic effects of efaroxan but not that of
tolbutamide, glibenclamide, or BTS 67 582. Culture (18 h) with tolbutamide
reduced the K(ATP) channel-independent actions of both tolbutamide and
glibenclamide. Whereas culture with efaroxan exerted no effect on the K(ATP)
channel-independent actions of sulfonylureas, BTS 67 582 abolished the response
of tolbutamide and inhibited that of glibenclamide. These data demonstrate that
prolonged exposure to tolbutamide desensitizes both K(ATP)-channel-dependent and
independent insulin-secretory actions of sulfonylureas, indicating synergistic
pathways mediated by common sulfonylurea binding site(s).
PMID- 10777709
TI - Light chain determines the binding property of human anti-dsDNA IgG
autoantibodies.
AB - We have previously prepared human anti-double-stranded (ds) DNA IgG Fab clones
using phage-display technology. Nucleotide sequence analysis of genes of
immunoglobulin (Ig) heavy and light chain variable regions in these Fab clones
suggested that the DNA-binding activity of the clones depended on light chain
usage. To confirm the role of the light chain in antibody binding to DNA, we
constructed in the present study's new recombined Fab clones by heavy and light
chain shuffling between the original anti-dsDNA Fab clones. Clones constructed by
pairing Fdgamma fragments with the light chain from a high DNA-binding clone
showed high DNA-binding activities, whereas other constructed clones using light
chains from low DNA-binding clones showed low DNA-binding activities. Our results
indicate that light chains in anti-dsDNA antibodies can determine the DNA-binding
activity of the antibodies. Ig chain shuffling of phage-display antibodies may be
useful for investigating the molecular mechanisms for antigen-antibody binding of
human autoantibodies.
PMID- 10777710
TI - ADP modulates the dynamic behavior of the glycolytic pathway of Escherichia coli.
AB - A mathematical model that includes biochemical interactions among the PTS system,
phosphofructokinase (PFK), and pyruvate kinase (PK) is used to evaluate the
dynamic behavior of the glycolytic pathway of Escherichia coli under steady-state
conditions. The influence of ADP, phosphoenolpyruvate (PEP), and fructose-6
phosphate (F6P) on the dynamic regulation of this pathway is also analyzed. The
model shows that the dynamic behavior of the system is affected significantly
depending on whether ADP, PEP, or F6P is considered constant a steady state.
Sustained oscillations are observed only when dADP/dt not equal 0 and completely
suppressed if dADP/dt = 0 at any steady-state value. However, when PEP or F6P is
constant, the system evolves toward the formation of stable limit cycles with
periods ranging from 0.2 min to hours.
PMID- 10777711
TI - Zinc-deficient rat embryos have increased caspase 3-like activity and apoptosis.
AB - Caspase activity is a hallmark of apoptosis. Given that maternal zinc (Zn)
deficiency results in apoptosis in the rat embryo, we assessed caspase activity
in Zn-deficient embryos. Mid-gestation rat embryos were collected from dams fed
either a Zn-deficient (0.5 Zn/g) diet ad libitum, or a Zn-adequate (25 microg
Zn/g) diet ad libitum or pair fed to dams fed the Zn-deficient diet. Embryos from
dams fed the Zn-adequate diet had a normal level of cell death, while embryos
from the dams fed the Zn-deficient diet had either increased or normal levels of
cell death. Zn-deficient embryos displaying increased cell death had increased
caspase activity. Embryos with normal levels of cell death, regardless of
maternal diet, had similar caspase activities. Thus, Zn-deficiency-induced
apoptosis in vivo is associated with increased caspase activity.
PMID- 10777712
TI - The differential expression of apoptosis factors in the alveolar epithelium is
redox sensitive and requires NF-kappaB (RelA)-selective targeting.
AB - Fetal alveolar type II (fATII) epithelial cells were used to evaluate the role of
signaling factors involved in oxidative stress-induced programmed cell death
(PCD; apoptosis). Bcl-2, an antiapoptotic proto-oncogene, showed maximum
abundance in hypoxia and mild reoxygenation, but declined thereafter. The Bcl-2
counterpart, Bax, which promotes PCD, displayed an increasing logarithmic profile
with ascending DeltapO(2) regimen, such that the ratio of Bcl-2/Bax decreased as
pO(2) increased. The expression of p53, a cell cycle regulator, paralleled Bax
abundance. Pretreatment of fATII cells with l-buthionine-(S,R)-sulfoximine, an
irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting
enzyme in the biosynthesis of glutathione (GSH), enhanced Bax and p53 expression
over Bcl-2. The GSH analogue, gamma-glutamylcysteinyl-ethyl ester, down-regulated
Bax/p53 abundance but restored that of Bcl-2, thereby increasing Bcl-2/Bax. The
antioxidant and GSH precursor N-acetyl-l-cysteine favored Bcl-2 at the expense of
Bax/p53, whereas pyrrolidine dithiocarbamate induced Bax against Bcl-2, with mild
effect on p53. Sulfasalazine, a potent and specific inhibitor of NF-kappaB,
induced Bax at the expense of Bcl-2, in a p53-dependent manner. We conclude that
the differential expression of signaling factors involved in PCD in the alveolar
epithelium is redox-sensitive and mediated, at least in part, by a negative
feedback mechanism transduced by NF-kappaB.
PMID- 10777713
TI - Direct evidence for decreased sialylation and galactosylation of human serum IgA1
Fc O-glycosylated hinge peptides in IgA nephropathy by mass spectrometry.
AB - Human serum immunoglobulin IgA1 is produced in bone marrow and interacts with
specific cellular receptors that mediate biological events. In this study, we
have analyzed the detailed glycoform structure of the human serum IgA1 Fc O
glycosylated hinge region by electrospray ionization liquid mass spectrometry.
The IgA1 fragments containing the hinge glycopeptide were separated from 4 IgA
nephropathy patient (IgAN) pooled sera, 10 non-IgAN pooled sera with other
primary glomerulonephritides, and 5 healthy control subject pooled sera by
trypsin treatment and Jacalin affinity chromatography. The molecular weights of
IgA1 hinge glycopeptide were estimated using mass spectrometry, and 13 sialo and
8 asialo glycopeptide groups were identified. The results obtained clearly showed
a decrease of GalNAc, Gal, and sialic acid in IgAN compared with non-IgAN and
normal controls, and those strongly suggested the possibility that the decreased
galactosylation and sialylation of the IgA1 hinge result in its glomerular
deposition in IgAN.
PMID- 10777714
TI - Genomewide search in Canadian families with inflammatory bowel disease reveals
two novel susceptibility loci.
AB - The chronic inflammatory bowel diseases (IBDs)-Crohn disease (CD) and ulcerative
colitis (UC)-are idiopathic, inflammatory disorders of the gastrointestinal
tract. These conditions have a peak incidence in early adulthood and a combined
prevalence of approximately 100-200/100,000. Although the etiology of IBD is
multifactorial, a significant genetic contribution to disease susceptibility is
implied by epidemiological data revealing a sibling risk of approximately 35-fold
for CD and approximately 15-fold for UC. To elucidate the genetic basis for these
disorders, we undertook a genomewide scan in 158 Canadian sib-pair families and
identified three regions of suggestive linkage (3p, 5q31-33, and 6p) and one
region of significant linkage to 19p13 (LOD score 4.6). Higher-density mapping in
the 5q31-q33 region revealed a locus of genomewide significance (LOD score 3.9)
that contributes to CD susceptibility in families with early-onset disease. Both
of these genomic regions contain numerous genes that are important to the immune
and inflammatory systems and that provide good targets for future candidate-gene
studies.
PMID- 10777715
TI - Molecular cytogenetic analysis of eight inversion duplications of human
chromosome 13q that each contain a neocentromere.
AB - Neocentromeres are fully functional centromeres that have arisen in previously
noncentromeric chromosomal locations on rearranged chromosomes. The formation of
neocentromeres results in the mitotic stability of chromosomal fragments that do
not contain endogenous centromeres and that would normally be lost. Here we
describe a unique collection of eight independent patient-derived cell lines,
each of which contains a neocentromere on a supernumerary inversion duplication
of a portion of human chromosome 13q. Findings in these patients reveal insight
into the clinical manifestations associated with polysomy for portions of
chromosome 13q. The results of FISH and immunofluorescent analysis of the
neocentromeres in these chromosomes confirm the lack of alpha-satellite DNA and
the presence of CENtromere proteins (CENP)-C, -E, and hMAD2. The positions of the
inversion breakpoints in these chromosomes have been placed onto the physical map
of chromosome 13, by means of FISH mapping with cosmid probes. These cell lines
define, within chromosome 13q, at least three distinct locations where
neocentromeres have formed, with five independent neocentromeres in band 13q32,
two in band 13q21, and one in band 13q31. The results of examination of the set
of 40 neocentromere-containing chromosomes that have thus far been described,
including the 8 neocentromere-containing chromosomes from chromosome 13q that are
described in the present study, suggest that chromosome 13q has an increased
propensity for neocentromere formation, relative to some other human chromosomes.
These neocentromeres will provide the means for testing hypotheses about sequence
requirements for human centromere formation.
PMID- 10777717
TI - A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing
loss maps to 14q21-q22 in a Swiss German kindred.
AB - DFNA23, a novel locus for autosomal dominant nonsyndromic hearing loss, was
identified in a Swiss German kindred. DNA samples were obtained from 22 family
members in three generations: 10 with hearing impairment caused by the DFNA23
locus, 8 unaffected offspring, and 4 spouses of hearing-impaired pedigree
members. In this kindred, the hearing-impaired family members have prelingual
bilateral symmetrical hearing loss. All audiograms from hearing-impaired
individuals displayed sloping curves, with hearing ability ranging from normal
hearing to mild hearing loss in low frequencies, normal hearing to profound
hearing loss in mid frequencies, and moderate to profound hearing loss in high
frequencies. A conductive component existed for 50% of the hearing-impaired
family members. The majority of the hearing-impaired family members did not
display progression of hearing loss. The DFNA23 locus maps to 14q21-q22. Linkage
analysis was carried out under a fully penetrant autosomal dominant mode of
inheritance with no phenocopies. A maximum multipoint LOD score of 5.1 occurred
at Marker D14S290. The 3.0-LOD unit support interval is 9.4 cM and ranged from
marker D14S980 to marker D14S1046.
PMID- 10777716
TI - COL5A1 haploinsufficiency is a common molecular mechanism underlying the
classical form of EDS.
AB - We have identified haploinsufficiency of the COL5A1 gene that encodes the
proalpha1(V) chain of type V collagen in the classical form of the Ehlers-Danlos
syndrome (EDS), a heritable connective-tissue disorder that severely alters the
collagen-fibrillar structure of the dermis, joints, eyes, and blood vessels.
Eight of 28 probands with classical EDS who were heterozygous for expressed
polymorphisms in COL5A1 showed complete or nearly complete loss of expression of
one COL5A1 allele. Reduced levels of proalpha1(V) mRNA relative to the levels of
another type V collagen mRNA, proalpha2(V), were also observed in the cultured
fibroblasts from EDS probands. Products of the two COL5A1 alleles were
approximately equal after the addition of cycloheximide to the fibroblast
cultures. After harvesting of mRNAs from cycloheximide-treated cultured
fibroblasts, heteroduplex analysis of overlapping reverse transcriptase-PCR
segments spanning the complete proalpha1(V) cDNA showed anomalies in four of the
eight probands that led to identification of causative mutations, and, in the
remaining four probands, targeting of CGA-->TGA mutations in genomic DNA revealed
a premature stop at codon in one of them. We estimate that approximately one
third of individuals with classical EDS have mutations of COL5A1 that result in
haploinsufficiency. These findings indicate that the normal formation of the
heterotypic collagen fibrils that contain types I, III, and V collagen requires
the expression of both COL5A1 alleles.
PMID- 10777719
TI - Self-assembly in vivo.
PMID- 10777718
TI - Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta
glucosidase mutations.
AB - Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder,
results from the deficient activity of acid beta-glucosidase (GBA). Type 1
disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish
(AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in
the AJ population, (q approximately .03), whereas the 84GG insertion (q
approximately .003) occurs exclusively in the Ashkenazim. To investigate the
genetic history of these mutations in the AJ population, short tandem repeat
(STR) markers were used to map a 9.3-cM region containing the GBA locus and to
genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and
62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA
(PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and
the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common
to both populations. Of note, the presence of different divergent haplotypes
suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a
different conserved haplotype at these markers was identified on the 84GG
chromosomes, which was unique to the AJ population. On the basis of the linkage
disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had
greater haplotype diversity and less LD at the markers flanking the conserved
haplotype than did the AJ N370S chromosomes. This finding is consistent with the
presence of the N370S mutation in the non-Jewish European population prior to the
founding of the AJ population. Coalescence analyses for the N370S and 84GG
mutations estimated similar coalescence times, of 48 and 55.5 generations ago,
respectively. The results of these studies are consistent with a significant
bottleneck occurring in the AJ population during the first millennium, when the
population became established in Europe.
PMID- 10777720
TI - Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II. substrate
enzyme interactions and dynamics.
AB - Molecular dynamics simulations of protein tyrosine phosphatase 1B (PTP1B)
complexed with the phosphorylated peptide substrate DADEpYL and the free
substrate have been conducted to investigate 1) the physical forces involved in
substrate-protein interactions, 2) the importance of enzyme and substrate
flexibility for binding, 3) the electrostatic properties of the enzyme, and 4)
the contribution from solvation. The simulations were performed for 1 ns, using
explicit water molecules. The last 700 ps of the trajectories was used for
analysis determining enthalpic and entropic contributions to substrate binding.
Based on essential dynamics analysis of the PTP1B/DADEpYL trajectory, it is shown
that internal motions in the binding pocket occur in a subspace of only a few
degrees of freedom. In particular, relatively large flexibilities are observed
along several eigenvectors in the segments: Arg(24)-Ser(28), Pro(38)-Arg(47), and
Glu(115)-Gly(117). These motions are correlated to the C- and N-terminal motions
of the substrate. Relatively small fluctuations are observed in the region of the
consensus active site motif (H/V)CX(5)R(S/T) and in the region of the WPD loop,
which contains the general acid for catalysis. Analysis of the individual enzyme
substrate interaction energies revealed that mainly electrostatic forces
contribute to binding. Indeed, calculation of the electrostatic field of the
enzyme reveals that only the field surrounding the binding pocket is positive,
while the remaining protein surface is characterized by a predominantly negative
electrostatic field. This positive electrostatic field attracts negatively
charged substrates and could explain the experimentally observed preference of
PTP1B for negatively charged substrates like the DADEpYL peptide.
PMID- 10777721
TI - The probability of quantal secretion near a single calcium channel of an active
zone.
AB - A Monte Carlo analysis has been made of calcium dynamics and quantal secretion at
microdomains in which the calcium reaches very high concentrations over distances
of <50 nm from a channel and for which calcium dynamics are dominated by
diffusion. The kinetics of calcium ions in microdomains due to either the
spontaneous or evoked opening of a calcium channel, both of which are stochastic
events, are described in the presence of endogenous fixed and mobile buffers.
Fluctuations in the number of calcium ions within 50 nm of a channel are
considerable, with the standard deviation about half the mean. Within 10 nm of a
channel these numbers of ions can give rise to calcium concentrations of the
order of 100 microM. The temporal changes in free calcium and calcium bound to
different affinity indicators in the volume of an entire varicosity or bouton
following the opening of a single channel are also determined. A Monte Carlo
analysis is also presented of how the dynamics of calcium ions at active zones,
after the arrival of an action potential and the stochastic opening of a calcium
channel, determine the probability of exocytosis from docked vesicles near the
channel. The synaptic vesicles in active zones are found docked in a complex with
their calcium-sensor associated proteins and a voltage-sensitive calcium channel,
forming a secretory unit. The probability of quantal secretion from an isolated
secretory unit has been determined for different distances of an open calcium
channel from the calcium sensor within an individual unit: a threefold decrease
in the probability of secretion of a quantum occurs with a doubling of the
distance from 25 to 50 nm. The Monte Carlo analysis also shows that the
probability of secretion of a quantum is most sensitive to the size of the single
channel current compared with its sensitivity to either the binding rates of the
sites on the calcium-sensor protein or to the number of these sites that must
bind a calcium ion to trigger exocytosis of a vesicle.
PMID- 10777722
TI - The probability of quantal secretion within an array of calcium channels of an
active zone.
AB - A Monte Carlo analysis has been made of calcium dynamics in submembranous domains
of active zones in which the calcium contributed by the opening of many channels
is pooled. The kinetics of calcium ions in these domains has been determined
using simulations for channels arranged in different geometries, according to the
active zone under consideration: rectangular grids for varicosities and boutons
and lines for motor-nerve terminals. The effects of endogenous fixed and mobile
buffers on the two-dimensional distribution of free calcium ions at these active
zones are then given, together with the extent to which these are perturbed and
can be detected with different affinity calcium indicators when the calcium
channels open stochastically under an action potential. A Monte Carlo analysis of
how the dynamics of calcium ions in the submembranous domains determines the
probability of exocytosis from docked vesicles is also presented. The spatial
distribution of exocytosis from rectangular arrays of secretory units is such
that exocytosis is largely excluded from the edges of the array, due to the
effects of endogenous buffers. There is a steeper than linear increase in quantal
release with an increase in the number of secretory units in the array,
indicating that there is not just a local interaction between secretory units.
Conditioning action potentials promote an increase in quantal release by a
subsequent action potential primarily by depleting the fixed and mobile buffers
in the center of the array. In the case of two parallel lines of secretory units
exocytosis is random, and diffusion, together with the endogenous calcium
buffers, ensures that the secretory units only interact over relatively short
distances. As a consequence of this and in contrast to the case of the
rectangular array, there is a linear relationship between the extent of quantal
secretion from these zones and their length, for lengths greater than a critical
value. This Monte Carlo analysis successfully predicts the relationship between
the size and geometry of active zones and the probability of quantal secretion at
these, the existence of quantal versus multiquantal release at different active
zones, and the origins of the F1 phase of facilitation in synapses possessing
different active zone geometries.
PMID- 10777723
TI - Dynamics of fusion pores connecting membranes of different tensions.
AB - The energetics underlying the expansion of fusion pores connecting biological or
lipid bilayer membranes is elucidated. The energetics necessary to deform
membranes as the pore enlarges, in some combination with the action of the fusion
proteins, must determine pore growth. The dynamics of pore growth is considered
for the case of two homogeneous fusing membranes under different tensions. It is
rigorously shown that pore growth can be quantitatively described by treating the
pore as a quasiparticle that moves in a medium with a viscosity determined by
that of the membranes. Motion is subject to tension, bending, and viscous forces.
Pore dynamics and lipid flow through the pore were calculated using Lagrange's
equations, with dissipation caused by intra- and intermonolayer friction. These
calculations show that the energy barrier that restrains pore enlargement depends
only on the sum of the tensions; a difference in tension between the fusing
membranes is irrelevant. In contrast, lipid flux through the fusion pore depends
on the tension difference but is independent of the sum. Thus pore growth is not
affected by tension-driven lipid flux from one membrane to the other. The
calculations of the present study explain how increases in tension through
osmotic swelling of vesicles cause enlargement of pores between the vesicles and
planar bilayer membranes. In a similar fashion, swelling of secretory granules
after fusion in biological systems could promote pore enlargement during
exocytosis. The calculations also show that pore expansion can be caused by pore
lengthening; lengthening may be facilitated by fusion proteins.
PMID- 10777724
TI - Lateral diffusion of membrane proteins in the presence of static and dynamic
corrals: suggestions for appropriate observables.
AB - We consider the possibility of inferring the nature of cytoskeletal interaction
with transmembrane proteins via optical experiments such as single-particle
tracking (SPT) and near-field scanning optical microscopy (NSOM). In particular,
we demonstrate that it may be possible to differentiate between static and
dynamic barriers to diffusion by examining the time-dependent variance and higher
moments of protein population inside cytoskeletal "corrals." Simulations modeling
Band 3 diffusion on the surface of erythrocytes provide a concrete demonstration
that these statistical tools might prove useful in the study of biological
systems.
PMID- 10777725
TI - Cell property determination from the acoustic microscope generated voltage versus
frequency curves.
AB - Among the methods for the determination of mechanical properties of living cells
acoustic microscopy provides some extraordinary advantages. It is relatively
fast, of excellent spatial resolution and of minimal invasiveness. Sound velocity
is a measure of the stiffness or Young's modulus of the cell. Attenuation of
cytoplasm is a measure of supramolecular interactions. These parameters are of
crucial interest for studies of cell motility, volume regulations and to
establish the functional role of the various elements of the cytoskeleton. Using
a phase and amplitude sensitive modulation of a scanning acoustic microscope
(Hillman et al., 1994, J. Alloys Compounds. 211/212:625-627) longitudinal wave
speed, attenuation and thickness profile of a biological cell are obtained from
the voltage versus frequency or V(f) curves. A series of pictures, for instance
in the frequency range 980-1100 MHz with an increment of 20 MHz, allows the
experimental generation of V(f) curves for each pixel while keeping the lens
specimen distance unchanged. Both amplitude and phase values of the V(f) curves
are used for obtaining the cell properties and the cell thickness profile. The
theoretical analysis shows that the thin liquid layer, between the cell and the
substrate, has a strong influence on the reflection coefficient and should not be
ignored during the analysis. Cell properties, cell profile and the thickness of
the thin liquid layer are obtained from the V(f) curves by the simplex inversion
algorithm. The main advantages of this new method are that imaging can be done
near the focal plane, therefore an optimal signal to noise ratio is achieved, no
interference with Rayleigh waves occurs, and the method requires only an
approximate estimate of the material properties of the solid substratum where the
cells are growing on.
PMID- 10777726
TI - Solvent-isotope and pH effects on flagellar rotation in Escherichia coli.
AB - We studied changes in speed of the flagellar rotary motor of Escherichia coli
when tethered cells or cells carrying small latex spheres on flagellar stubs were
shifted from H(2)O to D(2)O or subjected to changes in external pH. In the high
torque, low-speed regime, solvent isotope effects were found to be small; in the
low-torque, high-speed regime, they were large. The boundaries between these
regimes were close to those found earlier in measurements of the torque-speed
relationship of the flagellar rotary motor (, Biophys. J. 65:2201-2216;, Biophys.
J., 78:1036-1041). This observation provides direct evidence that the decline in
torque at high speed is due primarily to limits in rates of proton transfer.
However, variations of speed (and torque) with shifts of external pH (from 4.7 to
8.8) were small for both regimes. Therefore, rates of proton transfer are not
very dependent on external pH.
PMID- 10777727
TI - Three-dimensional motion of the organ of Corti.
AB - The vibration of the organ of Corti, a three-dimensional micromechanical
structure that incorporates the sensory cells of the hearing organ, was measured
in three mutually orthogonal directions. This was achieved by coupling the light
of a laser Doppler vibrometer into the side arm of an epifluorescence microscope
to measure velocity along the optical axis of the microscope, called the
transversal direction. Displacements were measured in the plane orthogonal to the
transverse direction with a differential photodiode mounted on the microscope in
the focal plane. Vibration responses were measured in the fourth turn of a
temporal-bone preparation of the guinea-pig cochlea. Responses were corrected for
a "fast" wave component caused by the presence of the hole in the cochlear wall,
made to view the structures. The frequency responses of the basilar membrane and
the reticular lamina were similar, with little phase differences between the
vibration components. Their motion was rectilinear and vertical to the surface of
their membranes. The organ of Corti rotated about a point near the edge of the
inner limbus. A second vibration mode was detected in the motion of the tectorial
membrane. This vibration mode was directed parallel to the reticular lamina and
became apparent for frequencies above approximately 0.5 oct below the
characteristic frequency. This radial vibration mode presumably controls the
shearing action of the hair bundles of the outer hair cells.
PMID- 10777728
TI - A bimodal pattern of InsP(3)-evoked elementary Ca(2+) signals in pancreatic
acinar cells.
AB - InsP(3)-evoked elementary Ca(2+) release events have been postulated to play a
role in providing the building blocks of larger Ca(2+) signals. In pancreatic
acinar cells, low concentrations of acetylcholine or the injection of low
concentrations of InsP(3) elicit a train of spatially localized Ca(2+) spikes. In
this study we have quantified these responses and compared the Ca(2+) signals to
the elementary events shown in Xenopus oocytes. The results demonstrate, at the
same concentrations of InsP(3), Ca(2+) signals consisting of one population of
small transient Ca(2+) release events and a second distinct population of larger
Ca(2+) spikes. The signal mass amplitudes of both types of events are within the
range of amplitudes for the elementary events in Xenopus oocytes. However, the
bimodal Ca(2+) distribution of Ca(2+) responses we observe is not consistent with
the continuum of event sizes seen in Xenopus. We conclude that the two types of
InsP(3)-dependent events in acinar cells are both elementary Ca(2+) signals,
which are independent of one another. Our data indicate a complexity to the
organization of the Ca(2+) release apparatus in acinar cells, which might result
from the presence of multiple InsP(3) receptor isoforms, and is likely to be
important in the physiology of these cells.
PMID- 10777729
TI - Structural basis for ligand selectivity of heteromeric olfactory cyclic
nucleotide-gated channels.
AB - In vertebrate olfactory receptors, cAMP produced by odorants opens cyclic
nucleotide-gated (CNG) channels, which allow Ca(2+) entry and depolarization of
the cell. These CNG channels are composed of alpha subunits and at least two
types of beta subunits that are required for increased cAMP selectivity. We
studied the molecular basis for the altered cAMP selectivity produced by one of
the beta subunits (CNG5, CNCalpha4, OCNC2) using cloned rat olfactory CNG
channels expressed in Xenopus oocytes. Compared with alpha subunit homomultimers
(alpha channels), channels composed of alpha and beta subunits (alpha+beta
channels) were half-activated (K(1/2)) by eightfold less cAMP and fivefold less
cIMP, but similar concentrations of cGMP. The K(1/2) values for heteromultimers
of the alpha subunit and a chimeric beta subunit with the alpha subunit cyclic
nucleotide-binding region (CNBR) (alpha+beta-CNBRalpha channels) were restored to
near the values for alpha channels. Furthermore, a single residue in the CNBR
could account for the altered ligand selectivity. Mutation of the methionine
residue at position 475 in the beta subunit to a glutamic acid as in the alpha
subunit (beta-M475E) reverted the K(1/2,cAMP)/K(1/2,cGMP) and K(1/2,
cIMP)/K(1/2,cGMP) ratios of alpha+beta-M475E channels to be very similar to those
of alpha channels. In addition, comparison of alpha+beta-CNBRalpha channels with
alpha+beta-M475E channels suggests that the CNBR of the beta subunit contains
amino acid differences at positions other than 475 that produce an increase in
the apparent affinity for each ligand. Like the wild-type beta subunit, the
chimeric beta/alpha subunits conferred a shallow slope to the dose-response
curves, increased voltage dependence, and caused desensitization. In addition, as
for alpha+beta channels, block of alpha+betaCNBRalpha channels by internal Mg(2+)
was not steeply voltage-dependent (zdelta approximately 1e(-)) as compared to
block of alpha channels (zdelta 2.7e(-)). Thus, the ligand-independent effects
localize outside of the CNBR. We propose a molecular model to explain how the
beta subunit alters ligand selectivity of the heteromeric channels.
PMID- 10777730
TI - Mutating three residues in the bovine rod cyclic nucleotide-activated channel can
switch a nucleotide from inactive to active.
AB - Cyclic nucleotide-gated (CNG) channels, which were initially studied in retina
and olfactory neurons, are activated by cytoplasmic cGMP or cAMP. Detailed
comparisons of nucleotide-activated currents using nucleotide analogs and
mutagenesis revealed channel-specific residues in the nucleotide-binding domain
that regulate the binding and channel-activation properties. Of particular
interest are N(1)-oxide cAMP, which does not activate bovine rod channels, and Rp
cGMPS, which activates bovine rod, but not catfish, olfactory channels.
Previously, we showed that four residues coordinate the purine interactions in
the binding domain and that three of these residues vary in the alpha subunits of
the bovine rod, catfish, and rat olfactory channels. Here we show that both N(1)
oxide cAMP and Rp-cGMPS activate rat olfactory channels. A mutant of the bovine
rod alpha subunit, substituted with residues from the rat olfactory channel at
the three variable positions, was weakly activated by N(1)-oxide cAMP, and a
catfish olfactory-like bovine rod mutant lost activation by Rp-cGMPS. These
experiments underscore the functional importance of purine contacts with three
residues in the cyclic nucleotide-binding domain. Molecular models of nucleotide
analogs in the binding domains, constructed with AMMP, showed differences in the
purine contacts among the channels that might account for activation differences.
PMID- 10777731
TI - The kinetic and physical basis of K(ATP) channel gating: toward a unified
molecular understanding.
AB - K(ATP) channels can be formed from Kir6.2 subunits with or without SUR1. The open
state stability of K(ATP) channels can be increased or reduced by mutations
throughout the Kir6.2 subunit, and is increased by application of PIP(2) to the
cytoplasmic membrane. Increase of open-state stability is manifested as an
increase in the channel open probability in the absence of ATP (Po(zero)) and a
correlated decrease in sensitivity to inhibition by ATP. Single channel lifetime
analyses were performed on wild-type and I154C mutant channels expressed with,
and without, SUR1. Channel kinetics include a single, invariant, open duration;
an invariant, brief, closed duration; and longer closed events consisting of a
"mixture of exponentials," which are prolonged in ATP and shortened after PIP(2)
treatment. The steady-state and kinetic data cannot be accounted for by assuming
that ATP binds to the channel and causes a gate to close. Rather, we show that
they can be explained by models that assume the following regarding the gating
behavior: 1) the channel undergoes ATP-insensitive transitions from the open
state to a short closed state (C(f)) and to a longer-lived closed state (C(0));
2) the C(0) state is destabilized in the presence of SUR1; and 3) ATP can access
this C(0) state, stabilizing it and thereby inhibiting macroscopic currents. The
effect of PIP(2) and mutations that stabilize the open state is then to shift the
equilibrium of the "critical transition" from the open state to the ATP
accessible C(0) state toward the O state, reducing accessibility of the C(0)
state, and hence reducing ATP sensitivity.
PMID- 10777732
TI - Tests of continuum theories as models of ion channels. I. Poisson-Boltzmann
theory versus Brownian dynamics.
AB - Continuum theories of electrolytes are widely used to describe physical processes
in various biological systems. Although these are well-established theories in
macroscopic situations, it is not clear from the outset that they should work in
small systems whose dimensions are comparable to or smaller than the Debye
length. Here, we test the validity of the mean-field approximation in Poisson
Boltzmann theory by comparing its predictions with those of Brownian dynamics
simulations. For this purpose we use spherical and cylindrical boundaries and a
catenary shape similar to that of the acetylcholine receptor channel. The
interior region filled with electrolyte is assumed to have a high dielectric
constant, and the exterior region representing protein a low one. Comparisons of
the force on a test ion obtained with the two methods show that the shielding
effect due to counterions is overestimated in Poisson-Boltzmann theory when the
ion is within a Debye length of the boundary. As the ion gets closer to the
boundary, the discrepancy in force grows rapidly. The implication for membrane
channels, whose radii are typically smaller than the Debye length, is that
Poisson-Boltzmann theory cannot be used to obtain reliable estimates of the
electrostatic potential energy and force on an ion in the channel environment.
PMID- 10777733
TI - Tests of continuum theories as models of ion channels. II. Poisson-Nernst-Planck
theory versus brownian dynamics.
AB - We test the validity of the mean-field approximation in Poisson-Nernst-Planck
theory by contrasting its predictions with those of Brownian dynamics simulations
in schematic cylindrical channels and in a realistic potassium channel.
Equivalence of the two theories in bulk situations is demonstrated in a control
study. In simple cylindrical channels, considerable differences are found between
the two theories with regard to the concentration profiles in the channel and its
conductance properties. These differences are at a maximum in narrow channels
with a radius smaller than the Debye length and diminish with increasing radius.
Convergence occurs when the channel radius is over 2 Debye lengths. These tests
unequivocally demonstrate that the mean-field approximation in the Poisson-Nernst
Planck theory breaks down in narrow ion channels that have radii smaller than the
Debye length.
PMID- 10777734
TI - Electrostatic interaction between charybdotoxin and a tetrameric mutant of Shaker
K(+) channels.
AB - The scorpion toxin, Charybdotoxin (CTX), blocks homotetrameric, voltage-gated
K(+) channels by binding near the outer entrance to the pore in one of four
indistinguishable orientations. We have determined the pH-dependence of CTX block
of a tetrameric Shaker potassium channel with a single copy of a histidine
replacing the wild-type phenylalanine at position 425. We compared this pH
dependence with that from homotetrameric channels with four copies of the
mutation. We found that protonation of a single amino acid at position 425 had a
large effect on the affinity of the channel for CTX-much larger than expected if
only one of the four CTX binding orientations was disrupted. The pK(a) for the
H(+)-ion induced protection from CTX block indicates that the electrostatic
environment near position 425 is likely basic in nature, perhaps because of the
proximity of lysine 427. We also examined the pH-dependence of block of channels
with one and four copies of the histidine mutation by CTX containing neutralizing
mutations of four basic residues on the active face of the toxin. The results
suggested an orientation of CTX on the channel that places three of the
positively charged CTX residues very near three of the four Shaker 425 positions.
PMID- 10777735
TI - Action potential and contractility changes in [Na(+)](i) overloaded cardiac
myocytes: a simulation study.
AB - Sodium overload of cardiac cells can accompany various pathologies and induce
fatal cardiac arrhythmias. We investigate effects of elevated intracellular
sodium on the cardiac action potential (AP) and on intracellular calcium using
the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1) During
rapid pacing, AP duration (APD) shortens in two phases, a rapid phase without
Na(+) accumulation and a slower phase that depends on [Na(+)](i). 2) The rapid
APD shortening is due to incomplete deactivation (accumulation) of I(Ks). 3) The
slow phase is due to increased repolarizing currents I(NaK) and reverse-mode
I(NaCa), secondary to elevated [Na(+)](i). 4) Na(+)-overload slows the rate of AP
depolarization, allowing time for greater I(Ca(L)) activation; it also enhances
reverse-mode I(NaCa). The resulting increased Ca(2+) influx triggers a greater
[Ca(2+)](i) transient. 5) Reverse-mode I(NaCa) alone can trigger Ca(2+) release
in a voltage and [Na(+)](i)-dependent manner. 6) During I(NaK) block, Na(+) and
Ca(2+) accumulate and APD shortens due to enhanced reverse-mode I(NaCa);
contribution of I(K(Na)) to APD shortening is negligible. By slowing AP
depolarization (hence velocity) and shortening APD, Na(+)-overload acts to
enhance inducibility of reentrant arrhythmias. Shortened APD with elevated
[Ca(2+)](i) (secondary to Na(+)-overload) also predisposes the myocardium to
arrhythmogenic delayed afterdepolarizations.
PMID- 10777736
TI - Conformation and dynamics of melittin bound to magnetically oriented lipid
bilayers by solid-state (31)P and (13)C NMR spectroscopy.
AB - The conformation and dynamics of melittin bound to the
dimyristoylphosphatidylcholine (DMPC) bilayer and the magnetic orientation in the
lipid bilayer systems were investigated by solid-state (31)P and (13)C NMR
spectroscopy. Using (31)P NMR, it was found that melittin-lipid bilayers form
magnetically oriented elongated vesicles with the long axis parallel to the
magnetic field above the liquid crystalline-gel phase transition temperature
(T(m) = 24 degrees C). The conformation, orientation, and dynamics of melittin
bound to the membrane were further determined by using this magnetically oriented
lipid bilayer system. For this purpose, the (13)C NMR spectra of site
specifically (13)C-labeled melittin bound to the membrane in the static, fast
magic angle spinning (MAS) and slow MAS conditions were measured. Subsequently,
we analyzed the (13)C chemical shift tensors of carbonyl carbons in the peptide
backbone under the conditions where they form an alpha-helix and reorient rapidly
about the average helical axis. Finally, it was found that melittin adopts a
transmembrane alpha-helix whose average axis is parallel to the bilayer normal.
The kink angle between the N- and C-terminal helical rods of melittin in the
lipid bilayer is approximately 140 degrees or approximately 160 degrees, which is
larger than the value of 120 degrees determined by x-ray diffraction studies.
Pore formation was clearly observed below the T(m) in the initial stage of lysis
by microscope. This is considered to be caused by the association of melittin
molecules in the lipid bilayer.
PMID- 10777737
TI - 15N NMR study of the ionization properties of the influenza virus fusion peptide
in zwitterionic phospholipid dispersions.
AB - Influenza virus hemagglutinin (HA)-mediated membrane fusion involves insertion
into target membranes of a stretch of amino acids located at the N-terminus of
the HA(2) subunit of HA at low pH. The pK(a) of the alpha-amino group of (1)Gly
of the fusion peptide was measured using (15)N NMR. The pK(a) of this group was
found to be 8.69 in the presence of DOPC (1,2-dioleoyl-sn-glycero-3
phosphocholine). The high value of this pK(a) is indicative of stabilization of
the protonated form of the amine group through noncovalent interactions. The
shift reagent Pr(3+) had large effects on the (15)N resonance from the alpha
amino group of Gly(1) of the fusion peptide in DOPC vesicles, indicating that the
terminal amino group was exposed to the bulk solvent, even at low pH.
Furthermore, electron paramagnetic resonance studies on the fusion peptide region
of spin-labeled derivatives of a larger HA construct are consistent with the N
terminus of this peptide being at the depth of the phosphate headgroups. We
conclude that at both neutral and acidic pH, the N-terminal of the fusion peptide
is close to the aqueous phase and is protonated. Thus neither a change in the
state of ionization nor a significant increase in membrane insertion of this
group is associated with increased fusogenicity at low pH.
PMID- 10777738
TI - Solvent drag across gramicidin channels demonstrated by microelectrodes.
AB - The competition of ion and water fluxes across gramicidin channels was assessed
from the concentration distributions of both pore-impermeable and -permeable
cations that were simultaneously measured by double-barreled microelectrodes in
the immediate vicinity of a planar bilayer. Because water movement across the
membrane led to accumulation of solutes on one side of the membrane and depletion
on the other, the permeable cation was not only pushed by water across the
channel (true solvent drag); it also flowed along its concentration gradient
(pseudo-solvent drag). For the demonstration of true solvent drag, a difference
between the bulk concentrations on the hypertonic and the hypotonic sides of the
membrane was established. It was adjusted to get equal cation concentrations at
both membrane/water interfaces. From the sodium and potassium fluxes measured
along with membrane conductivity under these conditions, approximately five water
molecules were found to be transported simultaneously with one ion through the
channel. In diphytanoyl phosphatidylcholine membranes, a single-channel hydraulic
permeability coefficient of 1.6 x 10(-14) cm(3) s(-1) was obtained.
PMID- 10777739
TI - Correlation of membrane/water partition coefficients of detergents with the
critical micelle concentration.
AB - The membrane/water partition coefficients, K, of 15 electrically neutral (non
charged or zwitterionic) detergents were measured with phospholipid vesicles by
using isothermal titration calorimetry, and were compared to the corresponding
critical micellar concentrations, cmc. The detergents measured were
oligo(ethylene oxide) alkyl ethers (C(m)EO(n) with m = 10/n = 3, 7 and m = 12/n =
3.8); alkylglucosides (octyl, decyl); alkylmaltosides (octyl, decyl, dodecyl);
diheptanoylphosphatidylcholine; Tritons (X-100, X-114) and CHAPS. A linear
relation between the free energies of partitioning into the membrane and micelle
formation was found such that K. CMC approximately 1. The identity K. CMC = 1 was
used to classify detergents with respect to their membrane disruption potency.
"Strong" detergents are characterized by K. CMC < 1 and solubilize lipid
membranes at detergent-to-lipid ratios X(b) < 1 (alkylmaltosides, tritons,
heptaethylene glycol alkyl ethers). "Weak" detergents are characterized by K. CMC
> 1 and accumulate in the membrane- to detergent-to-lipid ratios X(b) > 1 before
the bilayer disintegrates (alkylglucosides, pentaethylene glycol dodecyl ether).
PMID- 10777740
TI - A (2)H NMR study of macroscopically aligned bilayer membranes containing
interfacial hydroxyl residues.
AB - The polar interface of membranes containing phosphatidylglycerol or cholesterol
was studied by (2)H nuclear magnetic resonance (NMR) as a function of membrane
hydration. The membranes were macroscopically aligned and hydrated with deuterium
oxide. Water uptake and membrane annealing was achieved under NMR control, using
a novel hydration technique. Well-resolved (2)H quadrupolar doublets were
obtained from individual hydroxyl residues and from the interlamellar water. The
response of the phosphatidylglycerol headgroup and of the cholesterol molecule to
the spontaneous evaporation of interlamellar water could be thus monitored
continuously. It is shown that the phosphatidylglycerol headgroup undergoes
changes of conformation and average orientation with respect to the membrane
surface and that the off-axis motion of the cholesterol molecule decreases. The
deuteron exchange between hydroxyl residues and surface-associated D(2)O was
determined by an inversion transfer technique. The exchange rates of the hydroxyl
residues in the phosphatidylglycerol headgroup were different and depended
strongly on the total hydration of the membrane. Significantly lower and almost
hydration-independent rates were obtained for cholesterol. These results will be
discussed with reference to earlier reports on the headgroup dynamics of
phosphatidylglycerol and on the interaction of cholesterol with the membrane
water interface.
PMID- 10777741
TI - Effect of trehalose and sucrose on the hydration and dipole potential of lipid
bilayers.
AB - The water activity in dimyristoylphosphatidylcholine (DMPC) decreases by 60% when
the lipid is dehydrated in the presence of trehalose concentrations higher than
0.02 M. In contrast, sucrose in concentrations 10 times higher produced only a
20% decrease in the water activity in the sample. Titrations of a DMPC solution
in chloroform yielded 14 water molecules per lipid when pure water was added and
seven water molecules per lipid when the titration was done with 0.025 M
trehalose. The same concentrations of sucrose produced a turbid solution, which
made it impossible to quantify the number of water molecules per lipid. Lipid
monolayers spread on an air/water interface showed a decrease from 480 mV in pure
water to 425 mV in 0.1 M trehalose. However, the same concentrations of sucrose
produced an increase of less than 100 mV. Results obtained with Fourier transform
infrared spectroscopy (FTIR) under the same conditions denoted that trehalose
binds to the carbonyl groups, while sucrose showed no specific binding. It is
concluded that per lipid molecule, 11 of 14 water molecules can be replaced by
three trehalose molecules. About four are displaced by changes in the water
activity of the bulk solution, and seven by specific interactions with the
phospholipids. In this last case, at least two of them are linked to the
carbonyls, and this appears to be the cause of the decrease in the dipole
potential of the membrane. In contrast, four sucrose molecules displace only
three water molecules per lipid, with no effect on the dipole potential or the
carbonyl groups.
PMID- 10777743
TI - Kinetics of linear rouleaux formation studied by visual monitoring of red cell
dynamic organization.
AB - Red blood cells (RBCs) in the presence of plasma proteins or other macromolecules
may form aggregates, normally in rouleaux formations, which are dispersed with
increasing blood flow. Experimental observations have suggested that the
spontaneous aggregation process involves the formation of linear rouleaux (FLR)
followed by formation of branched rouleaux networks. Theoretical models for the
spontaneous rouleaux formation were formulated, taking into consideration that
FLR may involve both "polymerization," i.e., interaction between two single RBCs
(e + e) and the addition of a single RBC to the end of an existing rouleau (e +
r), as well as "condensation" between two rouleaux by end-to-end addition (r +
r). The present study was undertaken to experimentally examine the theoretical
models and their assumptions, by visual monitoring of the spontaneous FLR (from
singly dispersed RBC) in plasma, in a narrow gap flow chamber. The results
validate the theoretical model, showing that FLR involves both polymerization and
condensation, and that the kinetic constants for the above three types of
intercellular interactions are the same, i.e., k(ee) = k(er) = k(rr) = k, and for
all tested hematocrits (0.625-6%) k < 0.13 +/- 0.03 s(-1).
PMID- 10777742
TI - Dimyristoylphosphatidylcholine/C16:0-ceramide binary liposomes studied by
differential scanning calorimetry and wide- and small-angle x-ray scattering.
AB - Ceramide has recently been established as a central messenger in the signaling
cascades controlling cell behavior. Physicochemical studies have revealed a
strong tendency of this lipid toward phase separation in mixtures with
phosphatidylcholines. The thermal phase behavior and structure of fully hydrated
binary membranes composed of dimyristoylphosphatidylcholine (DMPC) and N
palmitoyl-ceramide (C16:0-ceramide, up to a mole fraction X(cer) = 0.35) were
resolved in further detail by high-sensitivity differential scanning calorimetry
(DSC) and x-ray diffraction. Both methods reveal very strong hysteresis in the
thermal phase behavior of ceramide-containing membranes. A partial phase diagram
was constructed based on results from a combination of these two methods. DSC
heating scans show that with increased X(cer) the pretransition temperature T(p)
first increases, whereafter at X(cer) > 0.06 it can no longer be resolved. The
main transition enthalpy DeltaH remains practically unaltered while its width
increases significantly, and the upper phase boundary temperature of the mixture
shifts to approximately 63 degrees C at X(cer) = 0.30. Upon cooling, profound
phase separation is evident, and for all of the studied compositions there is an
endotherm in the region close to the T(m) for DMPC. At X(cer) >/= 0.03 a second
endotherm is evident at higher temperatures, starting at 32.1 degrees C and
reaching 54.6 degrees C at X(cer) = 0.30. X-ray small-angle reflection heating
scans reveal a lamellar phase within the temperature range of 15-60 degrees C,
regardless of composition. The pretransition is observed up to X(cer) < 0.18,
together with an increase in T(p). In the gel phase the lamellar repeat distance
d increases from approximately 61 A at X(cer) = 0. 03, to 67 A at X(cer) = 0.35.
In the fluid phase increasing X(cer) from 0.06 to 0.35 augments d from 61 A to 64
A. An L(beta')/L(alpha) (ripple/fluid) phase coexistence region is observed at
high temperatures (from 31 to 56.5 degrees C) when X(cer) > 0.03. With cooling
from temperatures above 50 degrees C we observe a slow increase in d as the
coexistence region is entered. A sudden solidification into a metastable,
modulated gel phase with high d values is observed for all compositions at
approximately 24 degrees C. The anomalous swelling for up to X(cer) = 0.30 in the
transition region is interpreted as an indication of bilayer softening and
thermally reduced bending rigidity.
PMID- 10777744
TI - The effect of peptide/lipid hydrophobic mismatch on the phase behavior of model
membranes mimicking the lipid composition in Escherichia coli membranes.
AB - The effect of hydrophobic peptides on the lipid phase behavior of an aqueous
dispersion of dioleoylphosphatidylethanolamine and dioleoylphosphatidylglycerol
(7:3 molar ratio) was studied by (31)P NMR spectroscopy. The peptides (WALPn
peptides, where n is the total number of amino acid residues) are designed as
models for transmembrane parts of integral membrane proteins and consist of a
hydrophobic sequence of alternating leucines and alanines, of variable length,
that is flanked on both ends by tryptophans. The pure lipid dispersion was shown
to undergo a lamellar-to-isotropic phase transition at approximately 60 degrees
C. Small-angle x-ray scattering showed that at a lower water content a cubic
phase belonging to the space group Pn3m is formed, suggesting also that the
isotropic phase in the lipid dispersion represents a cubic liquid crystalline
phase. It was found that the WALP peptides very efficiently promote formation of
nonlamellar phases in this lipid system. At a peptide-to-lipid (P/L) molar ratio
of 1:1000, the shortest peptide used, WALP16, lowered the lamellar-to-isotropic
phase transition by approximately 15 degrees C. This effect was less for longer
peptides. For all of the WALP peptides used, an increase in peptide concentration
led to a further lowering of the phase transition temperature. At the highest P/L
ratio (1:25) studied, WALP16 induced a reversed hexagonal liquid crystalline
(H(II)) phase, while the longer peptides still promoted the formation of an
isotropic phase. Peptides with a hydrophobic length larger than the bilayer
thickness were found to be unable to inhibit formation of the isotropic phase.
The results are discussed in terms of mismatch between the hydrophobic length of
the peptide and the hydrophobic thickness of the lipid bilayer and its
consequences for lipid-protein interactions in membranes.
PMID- 10777745
TI - A thermodynamic study of the effects of cholesterol on the interaction between
liposomes and ethanol.
AB - The association of ethanol with unilamellar dimyristoyl phosphatidylcholine
(DMPC) liposomes of varying cholesterol content has been investigated by
isothermal titration calorimetry over a wide temperature range (8-45 degrees C).
The calorimetric data show that the interaction of ethanol with the lipid
membranes is endothermic and strongly dependent on the phase behavior of the
mixed lipid bilayer, specifically whether the lipid bilayer is in the solid
ordered (so), liquid disordered (ld), or liquid ordered (lo) phase. In the low
concentration regime (<10 mol%), cholesterol enhances the affinity of ethanol for
the lipid bilayer compared to pure DMPC bilayers, whereas higher levels of
cholesterol (>10 mol%) reduce affinity of ethanol for the lipid bilayer.
Moreover, the experimental data reveal that the affinity of ethanol for the DMPC
bilayers containing small amounts of cholesterol is enhanced in the region around
the main phase transition. The results suggest the existence of a close
relationship between the physical structure of the lipid bilayer and the
association of ethanol with the bilayer. In particular, the existence of
dynamically coexisting domains of gel and fluid lipids in the transition
temperature region may play an important role for association of ethanol with the
lipid bilayers. Finally, the relation between cholesterol content and the
affinity of ethanol for the lipid bilayer provides some support for the in vivo
observation that cholesterol acts as a natural antagonist against alcohol
intoxication.
PMID- 10777746
TI - A chloride-activated Na(+)/HCO(3)(-)-coupled transport activity in corneal
endothelial membranes.
AB - Investigations of corneal endothelium were made to resolve the apparent
contradiction of the presence of sodium/bicarbonate cotransporter (NBC) in fresh
and cultured cells and NBC's reported absence in isolated plasma membrane
vesicles. Gradient-driven ion fluxes into the vesicles were measured. Short-term
incubations (0-30 s) showed the presence of a bicarbonate-dependent inward sodium
flux (BDSF), which was active when the insides of the vesicles were preloaded
with chloride ions. The BDSF was absent if chloride was present only externally
to the vesicles. Chloride at concentrations between 30 and 40 mM inside the
vesicle had its maximum effect on BDSF. Other anions (acetate, thiocyanate, or
gluconate) inside the vesicles did not mimic the chloride effect. Associated with
the net inward sodium flux was a net inward bicarbonate flux. Hill plots of
sodium influx with respect to external bicarbonate concentrations indicated that
the stoichiometry of the net transfer was 1.7 +/- 0.2 (mean +/- standard error, n
= 5) bicarbonate ions for each sodium ion transported. There was no net chloride
flux found across the membrane vesicles. The finding of a novel chloride
activated NBC activity fully resolves the apparent contradiction between whole
cell and membrane vesicle preparations.
PMID- 10777747
TI - Orientation of the infrared transition moments for an alpha-helix.
AB - Appropriate values for the orientation of the amide transition dipoles are
essential to the growing use of isotopically edited vibrational spectroscopy
generally in structural biology and to infrared dichroism measurements on
membrane-associated alpha-helices, in particular. The orientations of the
transition moments for the amide vibrations of an alpha-helix have been
determined from the ratio of intensities of the A- and E(1)-symmetry modes in the
infrared spectra of poly(gamma-methyl-L-glutamate)(x)-co-(gamma-n-octadecyl-L
glutamate)( y) oriented on silicon substrates. Samples possessing a high degree
of alignment were used to facilitate band fitting. Consistent results were
obtained from both attenuated total reflection and transmission experiments with
polarized radiation, yielding values of Theta(I) = 38 degrees, Theta(II) = 73
degrees, and Theta(A) = 29 degrees, relative to the helix axis, for the amide I,
amide II, and amide A bands, respectively. The measurements are discussed both in
the context of the somewhat divergent older determinations, and in relation to
the helix geometry and results on model amide compounds, to resolve current
uncertainties in the literature.
PMID- 10777748
TI - In vivo x-ray diffraction of indirect flight muscle from Drosophila melanogaster.
AB - Small-angle x-ray diffraction from isolated muscle preparations is commonly used
to obtain time-resolved structural information during contraction. We extended
this technique to the thoracic flight muscles of living fruit flies, at rest and
during tethered flight. Precise measurements at 1-ms time resolution indicate
that the myofilament lattice spacing does not change significantly during
oscillatory contraction. This result is consistent with the notion that a net
radial force maintains the thick filaments at an equilibrium interfilament
spacing of approximately 56 nm throughout the contractile cycle. Transgenic flies
with amino-acid substitutions in the conserved phosphorylation site of the myosin
regulatory light chain (RLC) exhibit structural abnormalities that can explain
their flight impairment. The I(20)/I(10) equatorial intensity ratio of the mutant
fly is 35% less than that of wild type, supporting the hypothesis that myosin
heads that lack phosphorylated RLC remain close to the thick filament backbone.
This new experimental system facilitates investigation of the relation between
molecular structure and muscle function in living organisms.
PMID- 10777749
TI - Thymosin-beta(4) changes the conformation and dynamics of actin monomers.
AB - Thymosin-beta(4) (Tbeta(4)) binds actin monomers stoichiometrically and maintains
the bulk of the actin monomer pool in metazoan cells. Tbeta(4) binding quenches
the fluorescence of N-iodoacetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine (AEDANS)
conjugated to Cys(374) of actin monomers. The K(d) of the actin-Tbeta(4) complex
depends on the cation and nucleotide bound to actin but is not affected by the
AEDANS probe. The different stabilities are determined primarily by the rates of
dissociation. At 25 degrees C, the free energy of Tbeta(4) binding MgATP-actin is
primarily enthalpic in origin but entropic for CaATP-actin. Binding is coupled to
the dissociation of bound water molecules, which is greater for CaATP-actin than
MgATP-actin monomers. Proteolysis of MgATP-actin, but not CaATP-actin, at Gly(46)
on subdomain 2 is >12 times faster when Tbeta(4) is bound. The C terminus of
Tbeta(4) contacts actin near this cleavage site, at His(40). By tritium exchange,
Tbeta(4) slows the exchange rate of approximately eight rapidly exchanging amide
protons on actin. We conclude that Tbeta(4) changes the conformation and
structural dynamics ("breathing") of actin monomers. The conformational change
may reflect the unique ability of Tbeta(4) to sequester actin monomers and
inhibit nucleotide exchange.
PMID- 10777750
TI - Conformational deformability of RNA: a harmonic mode analysis.
AB - The harmonic mode analysis method was used to characterize the conformational
deformability of regular Watson-Crick paired, mismatch- and bulge-containing RNA.
Good agreement between atomic Debye-Waller factors derived from x-ray
crystallography of a regular RNA oligonucleotide and calculated atomic
fluctuations was obtained. Calculated helical coordinate fluctuations showed a
small sequence dependence of up to approximately 30-50%. A negative correlation
between motions at a given base pair step and neighboring steps was found for
most helical coordinates. Only very few calculated modes contribute significantly
to global motions such as bending, twisting, and stretching of the RNA molecules.
With respect to a local helical description of the RNA helix our calculations
suggest that RNA bending is mostly due to a periodic change in the base pair step
descriptors slide and roll. The presence of single guanine:uridine or
guanine:adenine mismatches had little influence on the calculated RNA
flexibility. In contrast, for tandem guanine:adenine base pairs the harmonic mode
approach predicts a significantly reduced conformational flexibility in the case
of a sheared arrangement and slightly enhanced flexibility for a face-to-face
(imino proton) pairing relative to regular RNA. The presence of a single extra
adenine bulge nucleotide stacked between flanking sequences resulted in an
increased local atomic mobility around the bulge site (approximately 40%) and a
slightly enhanced global bending flexibility. For an adenine bulge nucleotide in
a looped-out conformation a strongly enhanced bulge nucleotide mobility but no
increased bending flexibility compared to regular RNA was found.
PMID- 10777752
TI - Sequence-dependent dynamics in duplex DNA.
AB - The submicrosecond bending dynamics of duplex DNA were measured at a single site,
using a site-specific electron paramagnetic resonance active spin probe. The
observed dynamics are interpreted in terms of the mean squared amplitude of
bending relative to the end-to-end vector defined by the weakly bending rod
model. The bending dynamics monitored at the single site varied when the length
and position of a repeated AT sequence, distant from the spin probe, were
changed. As the distance between the probe and the AT sequence was increased, the
mean squared amplitude of bending seen by the probe due to that sequence
decreased. A model for the sequence-dependent internal flexural motion of duplex
DNA, which casts the mean squared bending amplitudes in terms of sequence
dependent bending parameters, has been developed. The best fit of the data to the
model occurs when the (AT)(n) basepairs are assumed to be 20% more flexible than
the average of the basepairs within the control sequence. These findings provide
a quantitative basis for interpreting the kinetics of biological processes that
depend on duplex DNA flexibility, such as protein recognition and chromatin
packaging.
PMID- 10777751
TI - Structural changes induced by binding of the high-mobility group I protein to a
mouse satellite DNA sequence.
AB - Using spectroscopic methods, we have studied the structural changes induced in
both protein and DNA upon binding of the High-Mobility Group I (HMG-I) protein to
a 21-bp sequence derived from mouse satellite DNA. We show that these structural
changes depend on the stoichiometry of the protein/DNA complexes formed, as
determined by Job plots derived from experiments using pyrene-labeled duplexes.
Circular dichroism and melting temperature experiments extended in the far
ultraviolet range show that while native HMG-I is mainly random coiled in
solution, it adopts a beta-turn conformation upon forming a 1:1 complex in which
the protein first binds to one of two dA.dT stretches present in the duplex. HMG
I structure in the 1:1 complex is dependent on the sequence of its DNA target. A
3:1 HMG-I/DNA complex can also form and is characterized by a small increase in
the DNA natural bend and/or compaction coupled to a change in the protein
conformation, as determined from fluorescence resonance energy transfer (FRET)
experiments. In addition, a peptide corresponding to an extended DNA-binding
domain of HMG-I induces an ordered condensation of DNA duplexes. Based on the
constraints derived from pyrene excimer measurements, we present a model of these
nucleated structures. Our results illustrate an extreme case of protein structure
induced by DNA conformation that may bear on the evolutionary conservation of the
DNA-binding motifs of HMG-I. We discuss the functional relevance of the
structural flexibility of HMG-I associated with the nature of its DNA targets and
the implications of the binding stoichiometry for several aspects of chromatin
structure and gene regulation.
PMID- 10777754
TI - Aspartate 75 mutation in sensory rhodopsin II from Natronobacterium pharaonis
does not influence the production of the K-like intermediate, but strongly
affects its relaxation pathway.
AB - The early steps in the photocycle of the aspartate 75-mutated sensory rhodopsin
II from Natrobacterium pharaonis (pSRII-D75N) were studied by time-resolved laser
induced optoacoustic spectroscopy combined with quantum yield determinations by
flash photolysis with optical detection. Similar to the case of pSRII-WT,
excitation of pSRII-D75N produces in subnanosecond time a K-like intermediate.
Different to the case of K in pSRII-WT, in pSRII-D75N there are two K states.
K(E) decays into K(L) with a lifetime of 400 ns (independent of temperature in
the range 6.5-52 degrees C) which is optically silent under the experimental
conditions of our transient absorption experiments. This decay is concomitant
with an expansion of 6.5 ml/mol of produced intermediate. This indicates a
protein relaxation not affecting the chromophore absorption. For pSRII-D75N
reconstituted into polar lipids from purple membrane, the mutation of Asp-75 by
the neutral residue Asn affects neither the K(E) production yield (PhiK(e) 0.51
+/- 0.05) nor the energy stored by this intermediate (E(E)K(E) = 91 +/- 11
kJ/mol), nor the expansion upon its production (DeltaV(R,1) = 10 +/- 0.3 ml/mol).
All these values are very similar to those previously determined for K with pSRII
WT in the same medium. The millisecond transient species is attributed to K(L)
with a lifetime corresponding to that determined by electronic absorption
spectroscopy for K(565). The determined energy content of the intermediates as
well as the structural volume changes for the various steps afford the
calculation of the free energy profile of the phototransformation during the
pSRII-D75N photocycle. These data offer insights regarding the photocycle in
pSRII-WT. Detergent solubilization of pSRII-D75N affects the sample properties to
a larger extent than in the case of pSRII-WT.
PMID- 10777753
TI - Photosensitizer binding to lipid bilayers as a precondition for the
photoinactivation of membrane channels.
AB - The photodynamic activity of sulfonated aluminum phthalocyanines (AlPcS(n), 1 B850 energy transfer mechanism in bacterial LH2 complexes investigated by
B800 pigment exchange.
AB - Femtosecond transient absorption measurements were performed on native and a
series of reconstituted LH2 complexes from Rhodopseudomonas acidophila 10050 at
room temperature. The reconstituted complexes contain chemically modified
tetrapyrrole pigments in place of the native bacteriochlorophyll a-B800
molecules. The spectral characteristics of the modified pigments vary
significantly, such that within the B800 binding sites the B800 Q(y) absorption
maximum can be shifted incrementally from 800 to 670 nm. As the spectral overlap
between the B800 and B850 Q(y) bands decreases, the rate of energy transfer (as
determined by the time-dependent bleaching of the B850 absorption band) also
decreases; the measured time constants range from 0.9 ps (bacteriochlorophyll a
in the B800 sites, Q(y) absorption maximum at 800 nm) to 8.3 ps (chlorophyll a in
the B800 sites, Q(y) absorption maximum at 670 nm). This correlation between
energy transfer rate and spectral blue-shift of the B800 absorption band is in
qualitative agreement with the trend predicted from Forster spectral overlap
calculations, although the experimentally determined rates are approximately 5
times faster than those predicted by simulations. This discrepancy is attributed
to an underestimation of the electronic coupling between the B800 and B850
molecules.
PMID- 10777756
TI - Photochemical oxygen consumption sensitized by a porphyrin phosphorescent probe
in two model systems.
AB - Phosphorescence quenching of certain metalloporphyrins is used to measure tissue
and microvascular pO(2). Oxygen quenching of metalloporphyrin triplet states
creates singlet oxygen, which is highly reactive in biological systems, and these
oxygen-consuming reactions are capable of perturbing tissue oxygenation. Kinetics
of photochemical oxygen consumption were measured for a Pd-porphyrin in two model
systems in vitro over a range of irradiances (1.34-134 mW cm(-2)). For a given
irradiance, and, after correction for differing porphyrin concentrations, rates
of oxygen consumption were similar when the Pd-porphyrin was bound to bovine
serum albumin and when it was taken up by tumor cells in spheroids. At
irradiances comparable to those used in imaging superficial anatomy, rates of
oxygen consumption were sufficiently low (2.5 microM s(-1)) that tissue
oxygenation would be reduced by a maximum of 6%. An irradiance of 20 mW cm(-2),
however, initiated a rate of oxygen consumption capable of reducing tissue pO(2)
by at least 20-40%. These measured rates of consumption impose limitations on the
use of phosphorescence quenching in thick tissues. The irreversible
photobleaching of the Pd-porphyrin was also measured indirectly. The bleaching
branching ratio, 23 M(-1), is significantly lower than that of porphyrin
photodynamic agents.
PMID- 10777757
TI - Intracellular reactions in single human granulocytes upon phorbol myristate
acetate activation using confocal Raman microspectroscopy.
AB - We have obtained new evidence for the occurrence of intracellular NADPH-oxidase
activity in neutrophilic and eosinophilic granulocytes upon stimulation with
phorbol myristate acetate (PMA). PMA activation leads to a partial translocation
of cytochrome b(558) from the membranes of the specific granules to the plasma
membrane. It was suggested that NADPH-oxidase activity only takes place in the
plasma membrane, leading to an extracellular release of oxygen metabolites
because cellular self-destruction can be avoided in this way. The effects of PMA
activation were indirectly studied in recent experiments employing scavengers of
extracellular superoxide anion and hydrogen peroxide, and support for
intracellular NADPH-oxidase activity was obtained. In this paper we use Raman
microspectroscopy as a direct method to study intracellular molecular reactions
that result from cellular triggering by PMA. The molecular specificity of this
microscopic method enables us to show that intracellular reduction of both
myeloperoxidase (MPO) and cytochrome b(558) occurs in neutrophilic granulocytes.
Control measurements with cytochrome b(558)-deficient neutrophilic granulocytes
did not show a reduction of intracellular MPO. This is direct support for the
occurrence of intracellular NADPH-oxidase activity in organelles that must be in
close contact with the azurophilic granules that contain MPO. Furthermore, a
comparison was made with chemical reactions occurring in eosinophilic
granulocytes after activation with PMA. Moreover, in these cells an intracellular
reduction of eosinophil peroxidase was observed.
PMID- 10777758
TI - Restrained torsional dynamics of nuclear DNA in living proliferative mammalian
cells.
AB - Physical parameters, describing the state of chromatinized DNA in living
mammalian cells, were revealed by in situ fluorescence dynamic properties of
ethidium in its free and intercalated states. The lifetimes and anisotropy decays
of this cationic chromophore were measured within the nuclear domain, by using
the ultra-sensitive time-correlated single-photon counting technique, confocal
microscopy, and ultra-low probe concentrations. We found that, in living cells:
1) free ethidium molecules equilibrate between extracellular milieu and nucleus,
demonstrating that the cation is naturally transported into the nucleus; 2) the
intercalation of ethidium into chromatinized DNA is strongly inhibited, with
relaxation of the inhibition after mild (digitonin) cell treatment; 3)
intercalation sites are likely to be located in chromatin DNA; and 4) the
fluorescence anisotropy relaxation of intercalated molecules is very slow. The
combination of fluorescence kinetic and fluorescence anisotropy dynamics
indicates that the torsional dynamics of nuclear DNA is highly restrained in
living cells.
PMID- 10777760
TI - Observing secretory granules with a multiangle evanescent wave microscope.
AB - In total internal reflection fluorescence microscopy (TIRFM), fluorophores near a
surface can be excited with evanescent waves, which decay exponentially with
distance from the interface. Penetration depths of evanescent waves from 60 nm to
300 nm were generated by varying the angle of incidence of a laser beam. With a
novel telecentric multiangle evanescent wave microscope, we monitored and
investigated both single secretory granules and pools of granules in bovine
chromaffin cells. By measuring the fluorescence intensity as a function of
penetration depth, it is possible through a Laplace transform to obtain the
fluorophore distribution as a function of axial position. We discuss the extent
to which it is possible to determine distances and diameters of granules with
this microscopy technique by modeling the fluorescent volumes of spheres in
evanescent fields. The anisotropic near-field detection of fluorophores and the
influence of the detection point-spread function are considered. The diameters of
isolated granules between 70 nm and 300 nm have been reconstructed, which is
clearly beyond the resolution limit of a confocal microscope. Furthermore, the
paper demonstrates how evanescent waves propagate along surfaces and scatter at
objects with a higher refractive index. TIRFM will have a limited applicability
for quantitative measurements when the parameters used to define evanescent waves
are not optimally selected.
PMID- 10777759
TI - Rapid flip-flop of phospholipids in endoplasmic reticulum membranes studied by a
stopped-flow approach.
AB - The transbilayer movement of short-chain spin-labeled and fluorescent 7-nitrobenz
2-oxa-1,3-diazol-4-yl (NBD) phospholipid analogs in rat liver microsomes is
measured by stopped-flow mixing of labeled microsomes with bovine serum albumin
(BSA) solution. Extraction of analogs from the outer leaflet of microsomes to BSA
can be directly monitored in conjunction with electron paramagnetic resonance or
fluorescence spectroscopy by taking advantage of the fact that the signal of spin
labeled or fluorescent analogs bound to BSA is different from that of the analogs
inserted into membranes. From the signal kinetics, the transbilayer movement and
the distribution of analogs in microsomal membranes can be derived provided the
extraction of analogs by BSA is much faster in comparison to the transbilayer
movement of analogs. Half-times of the back-exchange for spin-labeled and
fluorescent analogs were <3.5 and <9.5 s, respectively. The unprecedented time
resolution of the assay revealed that the transbilayer movement of spin-labeled
analogs is much faster than previously reported. The half-time of the movement
was about 16 s or even less at room temperature. Transmembrane movement of NBD
labeled analogs was six- to eightfold slower than that of spin-labeled analogs.
PMID- 10777761
TI - Estimating intracellular calcium concentrations and buffering without wavelength
ratioing.
AB - We describe a method for determining intracellular free calcium concentration
([Ca(2+)]) from single-wavelength fluorescence signals. In contrast to previous
single-wavelength calibration methods, the proposed method does not require
independent estimates of resting [Ca(2+)] but relies on the measurement of
fluorescence close to indicator saturation during an experiment. Consequently, it
is well suited to [Ca(2+)] indicators for which saturation can be achieved under
physiological conditions. In addition, the method requires that the indicators
have large dynamic ranges. Popular indicators such as Calcium Green-1 or Fluo-3
fulfill these conditions. As a test of the method, we measured [Ca(2+)] in CA1
pyramidal neurons in rat hippocampal slices using Oregon Green BAPTA-1 and 2
photon laser scanning microscopy (BAPTA: 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'
tetraacetic acid). Resting [Ca(2+)] was 32-59 nM in the proximal apical dendrite.
Monitoring action potential-evoked [Ca(2+)] transients as a function of indicator
loading yielded estimates of endogenous buffering capacity (44-80) and peak
[Ca(2+)] changes at zero added buffer (178-312 nM). In young animals (postnatal
days 14-17) our results were comparable to previous estimates obtained by
ratiometric methods (, Biophys. J. 70:1069-1081), and no significant differences
were seen in older animals (P24-28). We expect our method to be widely applicable
to measurements of [Ca(2+)] and [Ca(2+)]-dependent processes in small neuronal
compartments, particularly in the many situations that do not permit wavelength
ratio imaging.
PMID- 10777762
TI - Direct probing by atomic force microscopy of the cell surface softness of a
fibrillated and nonfibrillated oral streptococcal strain.
AB - In this paper, direct measurement by atomic force microscopy (AFM) of the cell
surface softness of a fibrillated oral streptococcal strain Streptococcus
salivarius HB and of a nonfibrillated strain S. salivarius HBC12 is presented,
and the data interpretation is validated by comparison with results from
independent techniques. Upon approach of the fibrillated strain in water, the AFM
tip experienced a long-range repulsion force, starting at approximately 100 nm,
attributed to the compression of the soft layer of fibrils present at the cell
surface. In 0.1 M KCl, repulsion was only experienced when the tip was closer
than approximately 10 nm, reflecting a stiffer cell surface due to collapse of
the fibrillar mass. Force-distance curves indicated that the nonfibrillated
strain, probed both in water and in 0.1 M KCl, was much stiffer than the
fibrillated strain in water, and a repulsion force was experienced by the tip at
close approach only (20 nm in water and 10 nm in 0.1 M KCl). Differences in cell
surface softness were further supported by differences in cell surface
morphology, the fibrillated strain imaged in water being the only specimen that
showed characteristic topographical features attributable to fibrils. These
results are in excellent agreement with previous indirect measurements of cell
surface softness by dynamic light scattering and particulate microelectrophoresis
and demonstrate the potential of AFM to directly probe the softness of microbial
cell surfaces.
PMID- 10777763
TI - Hybrid scanning ion conductance and scanning near-field optical microscopy for
the study of living cells.
AB - We have developed a hybrid scanning ion conductance and scanning near-field
optical microscope for the study of living cells. The technique allows
quantitative, high-resolution characterization of the cell surface and the
simultaneous recording of topographic and optical images. A particular feature of
the method is a reliable mechanism to control the distance between the probe and
the sample in physiological buffer. We demonstrate this new method by recording
near-field images of living cells (cardiac myocytes).
PMID- 10777764
TI - Differential analysis of human leukocytes by dielectrophoretic field-flow
fractionation.
AB - The differential analysis of human leukocytes has many important biological and
medical applications. In this work, dielectrophoretic field-flow-fractionation
(DEP-FFF), a cell-separation technique that exploits the differences in the
density and dielectric properties of cells, was used to separate the mixtures of
the major human leukocyte subpopulations (T- and B-lymphocytes, monocytes, and
granulocytes). The separation was conducted in a thin chamber equipped with an
array of microfabricated interdigitated electrodes on the bottom surface, and the
separation performance was characterized by on-line flow cytometry. To
investigate optimal separation conditions for different leukocyte mixtures,
elution fractograms at various DEP field frequencies were obtained for each
leukocyte subtype. With appropriately chosen conditions, high separation
performance was achieved in separating T- (or B-) lymphocytes from monocytes, T-
(or B-) lymphocytes from granulocytes, and monocytes from granulocytes. DEP-FFF
does not involve cell-labeling or cell-modification step, and provides a new
approach to hematological analysis.
PMID- 10777765
TI - Conformational transitions in model silk peptides.
AB - Protein structural transitions and beta-sheet formation are a common problem both
in vivo and in vitro and are of critical relevance in disparate areas such as
protein processing and beta-amyloid and prion behavior. Silks provide a
"databank" of well-characterized polymorphic sequences, acting as a window onto
structural transitions. Peptides with conformationally polymorphic silk-like
sequences, expected to exhibit an intractable beta-sheet form, were characterized
using Fourier transform infrared spectroscopy, circular dichroism, and electron
diffraction. Polymorphs resembling the silk I, silk II (beta-sheet), and silk III
(threefold polyglycine II-like helix) crystal structures were identified for the
peptide fibroin C (GAGAGS repetitive sequence). Two peptides based on silk
amorphous sequences, fibroin A (GAGAGY) and fibroin V (GDVGGAGATGGS),
crystallized as silk I under most conditions. Methanol treatment of fibroin A
resulted in a gradual transition from silk I to silk II, with an intermediate
state involving a high proportion of beta-turns. Attenuated total reflectance
Fourier transform infrared spectroscopy has been used to observe conformational
changes as the peptides adsorb from solution onto a hydrophobic surface. Fibroin
C has a beta-strand structure in solution but adopts a silk I-like structure upon
adsorption, which when dried on the ZnSe crystal contains silk III crystallites.
PMID- 10777766
TI - Variable velocity liquid flow EPR applied to submillisecond protein folding.
AB - We have developed a variable velocity, rapid-mix, continuous-flow method for
observing and delineating kinetics by dielectric resonator-based electron
paramagnetic resonance (EPR). The technology opens a new facet for kinetic study
of radicals in liquid at submillisecond time resolution. The EPR system (after
Sienkiewicz, A., K. Qu, and C. P. Scholes. 1994. Rev. Sci. Instrum. 65:68-74)
accommodated a miniature quartz capillary mixer with an approximately 0.5
microliter delivery volume to the midpoint of the EPR-active zone. The flow
velocity was varied in a preprogrammed manner, giving a minimum delivery time of
approximately 150 microseconds. The mixing was efficient, and we constructed
kinetics in the 0.15-2. 1-ms time range by plotting the continuous wave EPR
signal taken during flow versus the reciprocal of flow velocity. We followed the
refolding kinetics of iso-1-cytochrome c spin-labeled at Cysteine 102. At 20
degrees C, upon dilution of guanidinium hydrochloride denaturant, a fast phase of
refolding was resolved with an exponential time constant of 0.12 ms, which was
consistent with the "burst" phase observed by optically detected flow techniques.
At 7 degrees C the kinetic refolding time of this phase increased to 0.5 ms.
PMID- 10777768
TI - Chiral discotic columnar germs of nucleosome core particles.
AB - In concentrated solution and in the presence of high concentrations of monovalent
cations, nucleosome core particles order into a discotic columnar mesophase. This
phase is limited to finite-sized hexagonal germs that further divide into six
coiled branches, following an iterative process. We show how the structure of the
germs comes from the competition between hexagonal packing and chirality with a
combination of dendritic facetting and double-twist configurations. Geometrical
considerations lead us to suspect that the chirality of the eukaryotic
chromosomes may originate from the same competition.
PMID- 10777767
TI - Motion determination in actin filament fluorescence images with a spatio-temporal
orientation analysis method.
AB - We present a novel approach of automatically measuring motion in series of
microscopic fluorescence images. As a differential method, the three-dimensional
structure tensor technique is used to calculate the displacement vector field for
every image of the sequence, from which the velocities are subsequently derived.
We have used this method for the analysis of the movement of single actin
filaments in the in vitro motility assay, where fluorescently labeled actin
filaments move over a myosin decorated surface. With its fast implementation and
subpixel accuracy, this approach is, in general, very valuable for analyzing
dynamic processes by image sequence analysis.
PMID- 10777769
TI - The extracellular signal-regulated kinase cascade is required for NMDA receptor
independent LTP in area CA1 but not area CA3 of the hippocampus.
AB - Activation of extracellular signal-regulated kinase (ERK) has been shown to be
necessary for NMDA receptor-dependent long-term potentiation (LTP). We studied
the role of ERK in three forms of NMDA receptor-independent LTP: LTP induced by
very high-frequency stimulation (200 Hz-LTP), LTP induced by the K(+) channel
blocker tetraethylammonium (TEA) (TEA-LTP), and mossy fiber (MF) LTP (MF-LTP). We
found that ERK was activated in area CA1 after the induction of both 200 Hz-LTP
and TEA-LTP and that this activation required the influx of Ca(2+) through
voltage-gated Ca(2+) channels. Inhibition of the ERK signaling cascade with
either PD 098059 or U0126 prevented the induction of both 200 Hz-LTP and TEA-LTP
in area CA1. In contrast, neither PD 098059 nor U0126 prevented MF-LTP in area
CA3 induced by either brief or long trains of high-frequency stimulation. U0126
also did not prevent forskolin-induced potentiation in area CA3. However,
incubation of slices with forskolin, an activator of the cAMP-dependent protein
kinase (PKA) cascade, did result in increases in active ERK and cAMP response
element-binding protein (CREB) phosphorylation in area CA3. The forskolin-induced
increase in active ERK was inhibited by U0126, whereas the increase in CREB
phosphorylation was not, which suggests that in area CA3 the PKA cascade is not
coupled to CREB phosphorylation via ERK. Overall, our observations indicate that
activation of the ERK signaling cascade is necessary for NMDA receptor
independent LTP in area CA1 but not in area CA3 and suggest a divergence in the
signaling cascades underlying NMDA receptor-independent LTP in these hippocampal
subregions.
PMID- 10777770
TI - Neurosteroid modulation of GABA IPSCs is phosphorylation dependent.
AB - The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone)
facilitates GABA(A) receptor-mediated ionic currents via allosteric modulation of
the GABA(A) receptor. Accordingly, allopregnanolone caused an increase in the
slow decay time constant of spontaneous GABA-mediated IPSCs in magnocellular
neurons recorded in hypothalamic slices. The allopregnanolone effect on IPSCs was
inhibited by a G-protein antagonist as well as by blocking protein kinase C and,
to a lesser extent, cAMP-dependent protein kinase activities. G-protein and
protein kinase C activation in the absence of the neurosteroid had no effect on
spontaneous IPSCs but enhanced the effect of subsequent allopregnanolone
application. These findings together suggest that the neurosteroid modulation of
GABA-mediated IPSCs requires G-protein and protein kinase activation, although
not via a separate G-protein-coupled steroid receptor.
PMID- 10777771
TI - A novel particulate form of Ca(2+)/calmodulin-dependent [correction of
Ca(2+)/CaMKII-dependent] protein kinase II in neurons.
AB - Cytoskeletal and postsynaptic density (PSD) fractions from forebrain contain
discrete spherical structures that are immunopositive for Ca(2+)/calmodulin
dependent protein kinase II (CaMKII). Spherical structures viewed by rotary
shadow electron microscopy have an average diameter of approximately 100 nm and,
in distinction to postsynaptic densities, do not immunolabel for PSD-95. These
structures were purified to near homogeneity by extraction with the detergent N
lauryl sarcosinate. Biochemical analysis revealed that CaMKII accounts for
virtually all of the protein in the purified preparation, suggesting that
spherical structures are clusters of self-associated CaMKII. Exposure of cultured
hippocampal neurons to a mitochondrial uncoupler in glucose-free medium promotes
the formation of numerous CaMKII-immunopositive structures identical in size and
shape to the CaMKII clusters observed in subcellular fractions. Clustering of
CaMKII would reduce its kinase function by preventing its access to fixed
substrates. On the other hand, clustering would not affect the ability of the
large cellular pool of CaMKII to act as a calmodulin sink, as demonstrated by the
Ca(2+)-dependent binding of gold-conjugated calmodulin to CaMKII clusters. We
propose that the observed clustering of CaMKII into spherical structures is a
protective mechanism preventing excessive protein phosphorylation upon loss of
Ca(2+) homeostasis, without compromising calmodulin regulation.
PMID- 10777772
TI - Activation of group II metabotropic glutamate receptors inhibits synaptic
excitation of the substantia Nigra pars reticulata.
AB - Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to
increased activity of glutamatergic neurons in the subthalamic nucleus (STN).
Recent studies reveal that the resultant increase in STN-induced excitation of
basal ganglia output nuclei is responsible for the disabling motor impairment
characteristic of PD. On the basis of this, it is possible that any manipulation
that reduces activity at excitatory STN synapses onto basal ganglia output nuclei
could be useful in the treatment of PD. We now report that group II metabotropic
glutamate receptors (mGluRs) are presynaptically localized on STN terminals and
that activation of these receptors inhibits excitatory transmission at STN
synapses. In agreement with the hypothesis that this could provide a therapeutic
benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal
of catalepsy in a rat model of PD. These results raise the exciting possibility
that selective agonists of group II mGluRs could provide an entirely new approach
to the treatment of PD. These novel therapeutic agents would provide a
noninvasive pharmacological treatment that does not involve the manipulation of
dopaminergic systems, thus avoiding the problems associated with current
therapies.
PMID- 10777773
TI - Evidence that G(z)-proteins couple to hypothalamic 5-HT(1A) receptors in vivo.
AB - Using in situ hybridization and immunoblot analysis, the present studies
identified G(z) mRNA and G(z)-protein in the hypothalamic paraventricular
nucleus. The role of G(z)-proteins in hypothalamic 5-HT(1A) receptor signaling
was examined in vivo. Activation of 5-HT(1A) receptors increases the secretion of
oxytocin and ACTH, but not prolactin. Intracerebroventricular infusion (3-4 d) of
G(z) antisense oligodeoxynucleotides, with different sequences and different
phosphorothioate modification patterns, reduced the levels of G(z)-protein in the
hypothalamic paraventricular nucleus, whereas missense oligodeoxynucleotides had
no effect. Neither antisense nor missense oligodeoxynucleotide treatment altered
basal plasma levels of ACTH, oxytocin, or prolactin, when compared with untreated
controls. An antisense-induced decrease in hypothalamic G(z)-protein levels was
paralleled by a significant decrease in the oxytocin and ACTH responses to the 5
HT(1A) agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT). In contrast, the
prolactin response to 8-OH-DPAT (which cannot be blocked by 5-HT(1A) antagonists)
was not inhibited by G(z) antisense oligodeoxynucleotides. G(z)-proteins are the
only members of the G(i)/G(o)-protein family that are not inactivated by
pertussis toxin. In a control experiment, pertussis toxin treatment (1
microgram/5 microliter, i.c.v.; 48 hr before the 8-OH-DPAT challenge) did not
inhibit the ACTH response, potentiated the oxytocin response, and eliminated the
prolactin response to 8-OH-DPAT. Thus, pertussis toxin-sensitive G(i)/G(o)
proteins do not mediate the 5-HT(1A) receptor-mediated increase in ACTH and
oxytocin secretion. Combined, these studies provide the first in vivo evidence
for a key role of G(z)-proteins in coupling hypothalamic 5-HT(1A) receptors to
effector mechanisms.
PMID- 10777774
TI - Involvement of retinoblastoma family members and E2F/DP complexes in the death of
neurons evoked by DNA damage.
AB - Neuronal death evoked by DNA damage requires cyclin-dependent kinase 4 (Cdk4) and
6 activity and is accompanied by elevation of cyclin D1-associated kinase
activity. Because Cdk4/6 phosphorylates retinoblastoma protein (pRb) family
members that then modulate the transcriptional activity of E2F/DP1 complexes, we
examined the involvement of these components in DNA damage-evoked neuronal death.
Camptothecin induced rapid pRb and p107 phosphorylation at a Cdk4/6
phosphorylation site followed by selective loss of Rb and p107. The CDK inhibitor
flavopiridol suppressed pRb and p107 phosphorylation and loss, implicating CDK
activity in these events. Moreover, the loss of pRb and p107 appeared to be
mediated by caspases because it was blocked by general caspase inhibitors. The
role of phosphorylation and pRb and p107 loss in the death pathway was indicated
by observations that virally mediated expression of pRb mutated at sites of
phosphorylation, including the Cdk4/6 site, inhibited death. Finally, expression
of dominant-negative versions of DP1, known to compromise E2F transcriptional
activity, protects cortical neurons from death induced by camptothecin and
sympathetic neurons from death evoked by UV treatment. Taken together, these
results implicate the CDK-pRb/E2F/DP pathway as a required element in the
neuronal death evoked by DNA damage.
PMID- 10777775
TI - Reluctant gating of single N-type calcium channels during neurotransmitter
induced inhibition in bullfrog sympathetic neurons.
AB - Whole-cell recordings have been used to extensively characterize the voltage
dependent inhibition of N-type calcium current induced by various
neurotransmitters. Results from these studies have yielded several predictions on
the effect of inhibition on N-channel gating, namely delayed channel opening and
inhibition-induced reluctant openings. Previous single N-channel studies observed
delayed channel opening but failed to find reluctant openings. However, strong
depolarizations may be necessary to see reluctant openings, but this was not
tested. We have examined N-channel gating at voltages depolarized to those used
previously and found a neurotransmitter-induced open state that has properties
predicted for the reluctant open state. The openings had lower open probability
(P(o)) and brief open times compared to the dominant gating state observed in
control (high P(o)). These reluctant events were reduced after strong
depolarizing pulses used to reverse inhibition. The threshold voltage for
activation of reluctant events was approximately 30 mV depolarized to that of the
normal gating state (high P(o)). However, an action potential will provide
sufficient depolarization to open reluctant N-channels.
PMID- 10777776
TI - Plasma membrane calcium pump isoform 1 gene expression is repressed by
corticosterone and stress in rat hippocampus.
AB - Glucocorticoids (GCs) are critical to learning and memory, in large part because
of their actions in the hippocampus. Chronic high levels of GCs have profound
effects on hippocampal structure and function and can even result in irreversible
neurodegeneration. Hippocampal GC actions are mediated by intracellular receptors
that modulate the transcription of specific target genes. In a screen for genes
repressed by GCs in rat hippocampus, we identified plasma membrane calcium pump
isoform 1 (PMCA1), a plasma membrane calcium ATPase. In Northern blots, PMCA1 was
repressed approximately 33% after a high, but not a low dose of the GC,
corticosterone (B), suggesting glucocorticoid (but not mineralocorticoid)
receptor-mediated repression. Furthermore, in situ hybridization demonstrated
that B significantly downregulated PMCA1 mRNA in all brain regions examined.
Repression of PMCA1 was also observed in cultured hippocampal neurons, but only
when the cells were in the differentiated state. Stress also repressed PMCA1
expression in hippocampus of adrenal-intact animals, and a clear inverse
correlation between B level and PMCA1 mRNA could be discerned. However, other non
B-dependent factors appeared to be involved in the response of PMCA1 to stress
because, unlike exogenous B, cold stress did not repress PMCA1 in brain regions
other than hippocampus. Moreover, in the presence of constant B (B-replaced,
adrenalectomized animals), cold stress led to increased hippocampal PMCA1
expression. These observations suggest that repression of PMCA1 represents one
molecular mechanism by which corticosteroids regulate Ca(2+) homeostasis and
hence influence neuronal activity. Moreover, other stress-related neurohumoral
factors appear to counter the repressive effects of B. Defects in the balance
between GC-mediated and non-GC-mediated effects on PMCA1 expression may have
adverse effects on neuronal function and ultimately result in irreversible
neuronal damage.
PMID- 10777777
TI - Zinc-induced cortical neuronal death: contribution of energy failure attributable
to loss of NAD(+) and inhibition of glycolysis.
AB - Excessive zinc influx may contribute to neuronal death after certain insults,
including transient global ischemia. In light of evidence that levels of
intracellular free Zn(2+) associated with neurotoxicity may be sufficient to
inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), experiments were
performed looking for reduced glycolysis and energy failure in cultured mouse
cortical neurons subjected to lethal Zn(2+) exposure. As predicted, cultures
exposed for 3-22 hr to 40 mixroM Zn(2+) developed an early increase in levels of
dihydroxy-acetone phosphate (DHAP) and fructose 1,6-bisphosphate (FBP) and a
progressive loss of ATP levels, followed by neuronal cell death; furthermore,
addition of the downstream glycolytic substrate pyruvate to the bathing medium
attenuated the fall in ATP and neuronal death. However, an alternative to direct
Zn(2+) inhibition of GAPDH was raised by the observation that Zn(2+) exposure
also induced an early decrease in nicotinamide-adenine dinucleotide (NAD(+))
levels, an event itself capable of inhibiting GAPDH. Favoring this indirect
mechanism of GAPDH inhibition, the neuroprotective effects of pyruvate addition
were associated with normalization of cellular levels of NAD(+), DHAP, and FBP.
Zn(2+)-induced neuronal death was also attenuated by addition of the energy
substrate oxaloacetate, the activator of pyruvate dehydrogenase, dichloroacetate,
or the inhibitors of NAD(+) catabolism, niacinamide or benzamide. Acetyl
carnitine, alpha-keto butyrate, lactate, and beta-hydroxy-butyrate did not
attenuate Zn(2+)-induced neurotoxicity, perhaps because they could not regenerate
NAD(+) or be used for energy production in the presence of glucose.
PMID- 10777778
TI - Slow death of postnatal hippocampal neurons by GABA(A) receptor overactivation.
AB - Neurotransmitters can have both toxic and trophic functions in addition to their
role in neural signaling. Surprisingly, chronic blockade of GABA(A) receptor
activity for 5-8 d in vitro enhanced survival of hippocampal neurons, suggesting
that GABA(A) receptor overactivation may be neurotoxic. Potentiating GABA(A)
receptor activity by chronic treatment with the endogenous neurosteroid
(3alpha,5alpha)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in
culture. Other potentiators of GABA(A) receptors, including benzodiazepines,
mimicked the cell loss, suggesting that potentiating endogenous GABA activity is
sufficient to produce neuronal death. Neurosteroid-treated neurons had lower
resting intracellular calcium levels than control cells and produced smaller
calcium rises in response to depolarizing challenges. Manipulating intracellular
calcium levels with chronic elevated extracellular potassium or with the calcium
channel agonist Bay K 8644 protected neurons. The results may have implications
for the mechanisms of programmed cell death in the developing CNS as well as
implications for the long-term consequences of chronic GABAmimetic drug use
during development.
PMID- 10777779
TI - Ethanol-associated behaviors of mice lacking norepinephrine.
AB - Although norepinephrine (NE) has been implicated in animal models of ethanol
consumption for many years, the exact nature of its influence is not clear.
Lesioning and pharmacological studies examining the role of NE in ethanol
consumption have yielded conflicting results. We took a genetic approach to
determine the effect of NE depletion on ethanol-mediated behaviors by using
dopamine beta-hydroxylase knockout (Dbh -/-) mice that specifically lack the
ability to synthesize NE. Dbh -/- males have reduced ethanol preference in a two
bottle choice paradigm and show a delay in extinguishing an ethanol-conditioned
taste aversion, suggesting that they drink less ethanol in part because they find
its effects more aversive. Both male and female Dbh -/- mice are hypersensitive
to the sedative and hypothermic effects of systemic ethanol administration, and
the sedation phenotype can be rescued pharmacologically by acute replacement of
central NE. Neither the decreased body temperature nor changes in ethanol
metabolism can explain the differences in consumption and sedation. These results
demonstrate a significant role for NE in modulating ethanol-related behaviors and
physiological responses.
PMID- 10777780
TI - Brain-derived neurotrophic factor (BDNF) induces dendritic targeting of BDNF and
tyrosine kinase B mRNAs in hippocampal neurons through a phosphatidylinositol-3
kinase-dependent pathway.
AB - This study aims to understand the mechanisms of dendritic targeting of brain
derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) mRNAs. We show
that brief depolarizations are sufficient to induce accumulation of BDNF and TrkB
mRNAs in dendrites of hippocampal neurons. Endogenous BDNF, secreted during the
KCl stimulation, contributes significantly to the dendritic accumulation of BDNF
TrkB mRNAs. In the absence of depolarization, 1 min pulses of exogenous BDNF are
sufficient to induce dendritic accumulation of BDNF-TrkB mRNAs. After binding to
TrkB, BDNF exerts this action by activating a PI-3 kinase-dependent pathway. The
accumulation of dendritic mRNA by BDNF is not mediated by BDNF-induced
neurotransmitter release. Because most hippocampal neurons coexpress BDNF and
TrkB receptors, these results show that the subcellular distribution of BDNF-TrkB
mRNAs is under the control of an autocrine-paracrine BDNF-TrkB-dependent loop.
PMID- 10777781
TI - DNA methyltransferase contributes to delayed ischemic brain injury.
AB - DNA methylation is important for controlling the profile of gene expression and
is catalyzed by DNA methyltransferase (MTase), an enzyme that is abundant in
brain. Because significant DNA damage and alterations in gene expression develop
as a consequence of cerebral ischemia, we measured MTase activity in vitro and
DNA methylation in vivo after mild focal brain ischemia. After 30 min middle
cerebral artery occlusion (MCAo) and reperfusion, MTase catalytic activity and
the 190 kDa band on immunoblot did not change over time. However, [(3)H]methyl
group incorporation into DNA increased significantly in wild-type mice after
reperfusion, but not in mutant mice heterozygous for a DNA methyltransferase gene
deletion (Dnmt(S/+)). Dnmt(S/+) mice were resistant to mild ischemic damage,
suggesting that increased DNA methylation is associated with augmented brain
injury after MCA occlusion. Consistent with this formulation, treatment with the
MTase inhibitor 5-aza-2'-deoxycytidine and the deacetylation inhibitor
trichostatin A conferred stroke protection in wild-type mice. In contrast to mild
stroke, however, DNA methylation was not enhanced, and reduced dnmt gene
expression was not protective in an ischemia model of excitotoxic/necrotic cell
death. In conclusion, our results demonstrate that MTase activity contributes to
poor tissue outcome after mild ischemic brain injury.
PMID- 10777782
TI - Glial cell line-derived neurotrophic factor is essential for postnatal survival
of midbrain dopamine neurons.
AB - Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent
trophic factors that have been identified for midbrain dopamine (DA) neurons.
Null mutations for trophic factor genes have been used frequently for studies of
the role of these important proteins in brain development. One problem with these
studies has been that often only prenatal development can be studied because many
of the knockout strains, such as those with GDNF null mutations, will die shortly
after birth. In this study, we looked at the continued fate of specific neuronal
phenotypes from trophic factor knockout mice beyond the time that these animals
die. By transplanting fetal neural tissues from GDNF -/-, GDNF +/-, and wild-type
(WT) mice into the brain of adult wild-type mice, we demonstrate that the
continued postnatal development of ventral midbrain dopamine neurons is severely
disturbed as a result of the GDNF null mutation. Ventral midbrain grafts from -/-
fetuses have markedly reduced DA neuron numbers and fiber outgrowth. Moreover, DA
neurons in such transplants can be "rescued" by immersion in GDNF before
grafting. These findings suggest that postnatal survival and/or phenotypic
expression of ventral mesencephalic DA neurons is dependent on GDNF. In addition,
we present here a strategy for studies of maturation and even aging of tissues
from trophic factor and other knockout animals that do not survive past birth.
PMID- 10777783
TI - Protein aggregation after transient cerebral ischemia.
AB - Protein aggregates containing ubiquitinated proteins are commonly present in
neurodegenerative disorders and have been considered to cause neuronal
degeneration. Here, we report that transient cerebral ischemia caused severe
protein aggregation in hippocampal CA1 neurons. By using ethanolic
phosphotungstic acid electron microscopy (EM) and ubiquitin immunogold EM, we
found that protein aggregates were accumulated in CA1 neurons destined to die 72
hr after 15 min of cerebral ischemia. Protein aggregates appeared as clumps of
electron-dense materials that stained heavily for ubiquitin and were associated
with various intracellular membranous structures. The protein aggregates appeared
at 4 hr and progressively accumulated at 24 and 48 hr of reperfusion in CA1 dying
neurons. However, they were rarely observed in dentate gyrus neurons that were
resistant to ischemia. At 4 hr of reperfusion, protein aggregates were mainly
associated with intracellular vesicles in the soma and dendrites, and the nuclear
membrane. By 24 hr of reperfusion, the aggregates were also associated with
mitochondria, the Golgi apparatus, and the dendritic plasmalemma. High-resolution
confocal microscopy further demonstrated that protein aggregates containing
ubiquitin were persistently and progressively accumulated in all CA1 dying
neurons but not in neuronal populations that survive in this model. We conclude
that proteins are severely aggregated in hippocampal neurons vulnerable to
transient brain ischemia. We hypothesize that the accumulation of protein
aggregates cause ischemic neuronal death.
PMID- 10777784
TI - Agonist- and reflex-evoked internalization of metabotropic glutamate receptor 5
in enteric neurons.
AB - We demonstrate that metabotropic glutamate receptor 5 (mGluR5) is present in the
guinea pig ileum. A punctate ring-like distribution of immunoreactivity is found
on the soma of a subset of neurons, consistent with an association of mGluR5 with
the plasma membrane. mGluR5-containing cells in the submucosal plexus are
predominantly noncholinergic and contain vasoactive intestinal peptide, a marker
of secretomotor neurons. Using immunocytochemistry in conjunction with confocal
microscopy, we show that the mGluR5 undergoes agonist- and reflex-evoked
internalization that is inhibited by the group I antagonist 1-aminoindan-1,5
dicarboxylic acid. In addition, group I mGluR antagonists reduce the distension
induced phosphorylation of cAMP-responsive element-binding protein in enteric
neurons and attenuate both glutamate- and group I agonist-induced depolarizing
responses and slow synaptic events in submucosal neurons. These findings support
the idea that mGluRs play a role in enteric reflexes and suggest that
internalization might be a major mechanism for regulation of mGluR activity.
PMID- 10777785
TI - Molecular cloning of a novel membrane glycoprotein, pal, specifically expressed
in photoreceptor cells of the retina and containing leucine-rich repeat.
AB - We have isolated a novel retina-specific gene in a screen for genes of which
expression is not apparent neonatally in rat retina but is abundant postnatally
on day 14 (P14). This gene, named Pal, encodes a putative type I transmembrane
protein containing five leucine-rich repeats (LRRs), a single C2-type Ig-like
domain, and a single fibronectin type III domain and is considered to be a new
member of the LRR and Ig superfamily. No expression of Pal was found in rat
retina at P1, but it was detected at P7 and markedly increased with subsequent
development. These expression patterns of Pal appeared to be correlated with the
development of the photoreceptor outer segments, because in the adult rat retina
it was specifically localized in these segments. Ultrastructually, Pal
immunoreactivity was distributed diffusely on the disk membrane in the lamellar
regions. On the basis of its structural features and localization pattern, Pal
may act as a receptor for a certain trophic factor or for an adhesion molecule
participating in morphogenesis. The human homolog of Pal was mapped to chromosome
10q23.2-23.3 using fluorescence in situ hybridization.
PMID- 10777786
TI - Synucleins are developmentally expressed, and alpha-synuclein regulates the size
of the presynaptic vesicular pool in primary hippocampal neurons.
AB - alpha-, beta-, and gamma-Synuclein, a novel family of neuronal proteins, has
become the focus of research interest because alpha-synuclein has been
increasingly implicated in the pathogenesis of Parkinson's and Alzheimer's
disease. However, the normal functions of the synucleins are still unknown. For
this reason, we characterized alpha-, beta-, and gamma-synuclein expression in
primary hippocampal neuronal cultures and showed that the onset of alpha- and
beta-synuclein expression was delayed after synaptic development, suggesting that
these synucleins may not be essential for synapse formation. In mature cultured
primary neurons, alpha- and beta-synuclein colocalized almost exclusively with
synaptophysin in the presynaptic terminal, whereas little gamma-synuclein was
expressed at all. To assess the function of alpha-synuclein, we suppressed
expression of this protein with antisense oligonucleotide technology.
Morphometric ultrastructural analysis of the alpha-synuclein antisense
oligonucleotide-treated cultures revealed a significant reduction in the distal
pool of synaptic vesicles. These data suggest that one function of alpha
synuclein may be to regulate the size of distinct pools of synaptic vesicles in
mature neurons.
PMID- 10777787
TI - Brain-derived neurotrophic factor differentially regulates excitatory and
inhibitory synaptic transmission in hippocampal cultures.
AB - Brain-derived neurotrophic factor (BDNF) has been postulated to be a key
signaling molecule in regulating synaptic strength and overall circuit activity.
In this context, we have found that BDNF dramatically increases the frequency of
spontaneously initiated action potentials in hippocampal neurons in dissociated
culture. Using analysis of unitary synaptic transmission and immunocytochemical
methods, we determined that chronic treatment with BDNF potentiates both
excitatory and inhibitory transmission, but that it does so via different
mechanisms. BDNF strengthens excitation primarily by augmenting the amplitude of
AMPA receptor-mediated miniature EPSCs (mEPSCs) but enhances inhibition by
increasing the frequency of mIPSC and increasing the size of GABAergic synaptic
terminals. In contrast to observations in other systems, BDNF-mediated increases
in AMPA-receptor mediated mEPSC amplitudes did not require activity, because
blocking action potentials with tetrodotoxin for the entire duration of BDNF
treatment had no effect on the magnitude of this enhancement. These forms of
synaptic regulations appear to be a selective action of BDNF because intrinsic
excitability, synapse number, and neuronal survival are not affected in these
cultures. Thus, although BDNF induces a net increase in overall circuit activity,
this results from potentiation of both excitatory and inhibitory synaptic drive
through distinct and selective physiological mechanisms.
PMID- 10777788
TI - Selective presynaptic propagation of long-term potentiation in defined neural
networks.
AB - Induction of long-term potentiation (LTP) of the synaptic connection between two
hippocampal glutamatergic neurons in a neural network formed in cell culture
resulted in a specific pattern of potentiation at other connections within the
network. We found that potentiation propagated from the site of induction
retrogradely to glutamatergic or GABAergic synapses received by the dendrites of
the presynaptic neuron and laterally to those made by its axonal collaterals onto
other glutamatergic cells. In contrast, synapses made by the same presynaptic
neuron onto GABAergic cells were not affected, and there was no postsynaptic
lateral or forward propagation to other synapses received or made by the
postsynaptic neuron. In addition, there was no secondary propagation to synapses
not directly associated with the presynaptic neuron. Both induction and
propagation of LTP required correlated spiking of the postsynaptic cell as well
as the activation of the NMDA subtype of glutamate receptors. Such selective
propagation suggests the existence of a long-range cytoplasmic signaling within
the presynaptic neuron, leading to a specific pattern of coordinated potentiation
along excitatory pathways in a neural network.
PMID- 10777789
TI - Intrinsic bias and lineage restriction in the phenotype determination of dopamine
and neuropeptide Y amacrine cells.
AB - Blastomere lineages are differentially biased to produce different
neurotransmitter subtypes of amacrine cells (Huang and Moody, 1995, 1997,). To
elucidate when this bias is acquired, we examined amacrine lineages at different
early developmental times. Our experiments demonstrate that the bias to express
dopamine and neuropeptide Y amacrine fates involves several steps before the
formation of the definitive optic cup. At cleavage stages, a retinal progenitor
that contributes large numbers of cells is already biased to produce its normal
repertoire of dopamine amacrine cells, as revealed by transplantation to a new
location, whereas the amacrine fate of a progenitor that contributes fewer cells
is modified by its new position. At neural plate stages, not all retinal
progenitors are multipotent. Nearly one-half populate only the inner nuclear
layer and are enriched in amacrine cells. During early optic vesicle stages, an
appropriate mitotic tree is required for dopamine and neuropeptide Y, but not
serotonin, amacrine cell clusters to form. Thus, the acquisition of amacrine fate
bias involves intrinsic maternal factors at cleavage, fate restriction in the
neural plate, and specified mitotic patterns in the optic vesicle. At each of
these steps only a subset of the embryonic retinal progenitors contributing to
amacrine subtypes is biased; the remaining progenitors maintain multipotency.
Thus, from the earliest embryonic stages, progenitors of the retina are a dynamic
mosaic. This is the first experimental demonstration of amacrine fate decisions
that occur during early embryonic periods in advance of the events described in
the later, committed retina.
PMID- 10777790
TI - c-Raf regulates cell survival and retinal ganglion cell morphogenesis during
neurogenesis.
AB - The signaling cascade Ras/Raf/mitogen-activated protein kinases modulates cell
proliferation, differentiation, and survival, all key cellular processes during
neural development. To better define the in vivo role of Raf during chick retinal
neurogenesis, we interfered with Raf-dependent signaling during days 4.5 to 7.5
of embryonic development by expressing a dominant negative mutant of c-Raf
(DeltaRaf), which blocks Ras-dependent Raf activation, and by overexpressing wild
type c-Raf. DeltaRaf expression induced an increase in cell death by apoptosis,
whereas it did not affect overall cell proliferation and differentiation. In
parallel, the number of Islet-1/2-positive and TUJ1-positive retinal ganglion
cells were diminished in their definitive layer, whereas there was an increase in
the number of mislocated Islet-1/2-positive cells. This disturbed morphogenesis
correlated with a disruption of the optic fiber layer. Conversely, c-Raf
overexpression caused moderate opposite effects on apoptosis. These results frame
in vivo early neurogenesis processes in which c-Raf is essential.
PMID- 10777791
TI - Laminar distribution of neurons in extrastriate areas projecting to visual areas
V1 and V4 correlates with the hierarchical rank and indicates the operation of a
distance rule.
AB - The directionality of corticocortical projections is classified as feedforward
(going from a lower to higher hierarchical levels), feedback (interconnecting
descending levels), and lateral (interconnecting equivalent levels).
Directionality is determined by the combined criteria of the laminar patterns of
the axon terminals as well as the cells of origins and has been used to construct
models of the visual system, which reveals a strict hierarchical organization
(Felleman and Van Essen, 1991; Hilgetag et al., 1996a). However, these models are
indeterminate partly because we have no indication of the distance separating
adjacent levels. Here we have attempted to determine a graded parameter
describing the anatomical relationship of interconnected areas. We have
investigated whether the precise percentage of labeled supragranular layer
neurons (SLN%) in each afferent area after injection in either visual areas V1 or
V4 determines its hierarchical position in the model. This shows that pathway
directionality in the Felleman and Van Essen model is characterized by a range of
SLN% values. The one exception is the projection of the frontal eye field to area
V4, which resembles a feedforward projection. Individual areal differences in
SLN% values are highly significant, and the number of hierarchical steps
separating a target area from a source area is found to be tightly correlated to
SLN%. The present results show that the hierarchical rank of each afferent area
is reliably indicated by SLN%, and therefore this constitutes a graded parameter
that is related to hierarchical distance.
PMID- 10777792
TI - A spatiotemporal wave of turnover and functional maturation of olfactory receptor
neurons in the spiny lobster Panulirus argus.
AB - Olfactory receptor neurons (ORNs) of crustaceans are housed in aesthetasc
sensilla that are located on the lateral flagellum of the antennule. We used
young adult spiny lobsters to examine turnover of aesthetascs and functional
maturation of their ORNs after molting. The proliferation zone for new
aesthetascs is located in the proximal part of the aesthetasc-bearing region and
progressively moves along a distoproximal axis. Older aesthetascs are lost in the
distal part of the aesthetasc-bearing region. As a result, an aesthetasc may be
shed three to six molts after it differentiates. Taurine-like immunoreactivity is
elevated in ORNs of aesthetascs that have yet to emerge on the cuticular surface
and thereafter decreases gradually and asynchronously. ORNs from the distalmost
developing aesthetascs lose taurine-like immunoreactivity immediately before
sensillar emergence, whereas ORNs from the most proximal and lateral new
aesthetascs retain taurine-like immunoreactivity throughout the intermolt stage
after sensillar emergence. Furthermore, taurine-like immunoreactivity is
inversely correlated with odor responsiveness. These results suggest that taurine
like immunoreactivity reveals immature ORNs and that their functional maturation
is not synchronized with molting and may not be completed until many weeks after
sensillar emergence. Our data suggest successive spatiotemporal waves of birth,
differentiation and functional maturation, and death of ORNs.
PMID- 10777793
TI - Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig
small intestine.
AB - The enteric nervous system contains intrinsic primary afferent neurons that allow
mucosal stimulation to initiate reflexes without CNS input. We tested the
hypothesis that submucosal primary afferent neurons are activated by 5
hydroxytryptamine (5-HT) released from the stimulated mucosa. Fast and/or slow
EPSPs were recorded in submucosal neurons after the delivery of exogenous 5-HT,
WAY100325 (a 5-HT(1P) agonist), mechanical, or electrical stimuli to the mucosa
of myenteric plexus-free preparations (+/- extrinsic denervation). These events
were responses of second-order cells to transmitters released by excited primary
afferent neurons. After all stimuli, fast and slow EPSPs were abolished by a 5
HT(1P) antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, and by
1.0 microM tropisetron, but not by 5-HT(4)-selective antagonists (SB204070 and
GR113808A) or 5-HT(3)-selective antagonists (ondansetron and 0.3 microM
tropisetron). Fast EPSPs in second-order neurons were blocked by hexamethonium,
and most slow EPSPs were blocked by an antagonist of human calcitonin gene
related peptide (hCGRP(8-37)). hCGRP(8-37) also inhibited the spread of
excitation in the submucosal plexus, assessed by measuring the uptake of FM2-10
and induction of c-fos. In summary, data are consistent with the hypothesis that
5-HT from enterochromaffin cells in response to mucosal stimuli initiates
reflexes by stimulating 5-HT(1P) receptors on submucosal primary afferent
neurons. Second-order neurons respond to these cholinergic/CGRP-containing cells
with nicotinic fast EPSPs and/or CGRP-mediated slow EPSPs. Slow EPSPs are
necessary for excitation to spread within the submucosal plexus. Because some
second-order neurons contain also CGRP, primary afferent neurons may be
multifunctional and also serve as interneurons.
PMID- 10777794
TI - Cortical regions involved in perceiving object shape.
AB - The studies described here use functional magnetic resonance imaging to test
whether common or distinct cognitive and/or neural mechanisms are involved in
extracting object structure from the different image cues defining an object's
shape, such as contours, shading, and monocular depth cues. We found overlapping
activations in the lateral and ventral occipital cortex [known as the lateral
occipital complex (LOC)] for objects defined by different visual cues (e.g.,
grayscale photographs and line drawings) when each was compared with its own
scrambled-object control. In a second experiment we found a reduced response when
objects were repeated, independent of whether they appeared in the same or a
different format (i.e., grayscale images vs line drawings). A third experiment
showed that activation in the LOC was no stronger for three-dimensional shapes
defined by contours or monocular depth cues, such as occlusion, than for two
dimensional shapes, suggesting that these regions are not selectively involved in
processing three-dimensional shape information. These results suggest that common
regions in the LOC are involved in extracting and/or representing information
about object structure from different image cues.
PMID- 10777795
TI - Cuneiform neurons activated during cholinergically induced active sleep in the
cat.
AB - In the present study, we report that the cuneiform (Cun) nucleus, a brainstem
structure that before now has not been implicated in sleep processes, exhibits a
large number of neurons that express c-fos during carbachol-induced active sleep
(AS-carbachol). Compared with control (awake) cats, during AS-carbachol, there
was a 671% increase in the number of neurons that expressed c-fos in this
structure. Within the Cun nucleus, three immunocytochemically distinct
populations of neurons were observed. One group consisted of GABAergic neurons,
which predominantly did not express c-fos during AS-carbachol. Two other
different populations expressed c-fos during this state. One of the Fos-positive
(Fos(+)) populations consisted of a distinct group of nitric oxide synthase (NOS)
NADPH-diaphorase (NADPH-d)-containing neurons; the neurotransmitter of the other
Fos(+) population remains unknown. The Cun nucleus did not contain cholinergic,
catecholaminergic, serotonergic, or glycinergic neurons. On the basis of neuronal
activation during AS-carbachol, as indicated by c-fos expression, we suggest that
the Cun nucleus is involved, in an as yet unknown manner, in the physiological
expression of active sleep. The finding of a population of NOS-NADPH-d containing
neurons, which were activated during AS-carbachol, suggests that nitrergic
modulation of their target cell groups is likely to play a role in active sleep
related physiological processes.
PMID- 10777796
TI - New insights into the hemodynamic blood oxygenation level-dependent response
through combination of functional magnetic resonance imaging and optical
recording in gerbil barrel cortex.
AB - Fast, low-angle shoot functional magnetic resonance imaging (fMRI), based on the
blood oxygenation level-dependent (BOLD) effect, was combined with optical
recording of intrinsic signals (ORIS) and 2-deoxyglucose labeling in gerbil
barrel cortex. We observed over the activated barrel a positive BOLD signal and
increased levels of deoxyhemoglobin and total hemoglobin during each period of
prolonged (30 sec) D2 vibrissal stimulation. These data show that the hemodynamic
basis of this fMRI signal is not necessarily a washout of deoxyhemoglobin, as
generally assumed. Instead, they suggest that a positive BOLD signal can also be
caused by a local increase of blood volume, even if deoxyhemoglobin levels are
persistently elevated. We also show that this alternative interpretation is
consistent with theoretical models of the BOLD signal. The changes in BOLD signal
and blood volume, which are most tightly correlated with the periodic
stimulation, peak at the site of neuronal activation. These results contribute to
the understanding of the hemodynamic mechanisms underlying the BOLD signal and
also suggest analysis methods, which improve the spatial localization of neuronal
activation with both fMRI and ORIS.
PMID- 10777797
TI - Ectopic expression of the neuropeptide pigment-dispersing factor alters
behavioral rhythms in Drosophila melanogaster.
AB - To study the function of the neuropeptide pigment-dispersing factor (PDF) in the
circadian system of Drosophila, we misexpressed the pdf gene from the grasshopper
Romalea in the CNS of Drosophila and investigated the effect of this on
behavioral rhythmicity. pdf was either ectopically expressed in different numbers
of neurons in the brain or the thoracical nervous system or overexpressed in the
pacemaker neurons alone. We found severe alterations in the activity and eclosion
rhythm of several but not all lines with ectopic pdf expression. Only ectopic pdf
expression in neurons that projected into the dorsal central brain severely
influenced activity rhythms. Therefore, we conclude that PDF acts as a
neuromodulator in the dorsal central brain that is involved in the rhythmic
control of behavior. Overexpression of pdf in the pacemaker neurons alone or in
the other neurons that express the clock genes period (per) and timeless (tim)
did not disturb the activity rhythm. Such flies still showed a rhythm in PDF
accumulation in the central brain terminals. This rhythm was absent in the
terminals of neurons that expressed PDF ectopically. Probably, PDF is
rhythmically processed, transported, or secreted in neurons expressing per and
tim, and additional PDF expression in these cells does not influence this
rhythmic process. In neurons lacking per and tim, PDF appears to be continuously
processed, leading to a constant PDF secretion at their nerve terminals. This may
lead to conflicting signals in the rhythmic output pathway and result in a
severely altered rhythmic behavior.
PMID- 10777798
TI - Novel hippocampal interneuronal subtypes identified using transgenic mice that
express green fluorescent protein in GABAergic interneurons.
AB - The chief inhibitory neurons of the mammalian brain, GABAergic neurons, are
comprised of a myriad of diverse neuronal subtypes. To facilitate the study of
these neurons, transgenic mice were generated that express enhanced green
fluorescent protein (EGFP) in subpopulations of GABAergic neurons. In one of the
resulting transgenic lines, called GIN (GFP-expressing Inhibitory Neurons), EGFP
was found to be expressed in a subpopulation of somatostatin-containing GABAergic
interneurons in the hippocampus and neocortex. In both live and fixed brain
preparations from these mice, detailed microanatomical features of EGFP
expressing interneurons were readily observed. In stratum oriens of the
hippocampus, EGFP-expressing interneurons were comprised almost exclusively of
oriens/alveus interneurons with lacunosum-moleculare axon arborization (O-LM
cells). In the neocortex, the somata of EGFP-expressing interneurons were largely
restricted to layers II-IV and upper layer V. In hippocampal area CA1, two
previously uncharacterized subtypes of interneurons were identified using the GIN
mice: stratum pyramidale interneurons with lacunosum-moleculare axon arborization
(P-LM cells) and stratum radiatum interneurons with lacunosum-moleculare axon
arborization (R-LM cells). These newly identified interneuronal subtypes appeared
to be closely related to O-LM cell, as they selectively innervate stratum
lacunosum-moleculare. Whole-cell patch-clamp recordings revealed that these cells
were fast-spiking and showed virtually no spike frequency accommodation. The
microanatomical features of these cells suggest that they function primarily as
"input-biasing" neurons, in that synaptic volleys in stratum radiatum would lead
to their activation, which in turn would result in selective suppression of
excitatory input from the entorhinal cortex onto CA1 pyramidal cells.
PMID- 10777799
TI - Classical conditioning of feeding in Aplysia: I. Behavioral analysis.
AB - A training protocol was developed to classically condition feeding behavior in
Aplysia californica using tactile stimulation of the lips as the conditional
stimulus (CS) and food as the unconditional stimulus (US). Paired training
induced a greater increase in the number of bites to the CS than unpaired
training or US-only stimulation. Memory for classical conditioning was retained
for at least 24 hr. The organization of the reinforcement pathway that supports
classical conditioning was analyzed in additional behavioral experiments. No
evidence was found for the contribution to appetitive reinforcement of US
mediating pathways originating in the lips of the animals. Bilateral lesions of
the anterior branch of the esophageal nerve, which innervates parts of the
foregut, however, were found to attenuate classical conditioning. Thus, it
appears likely that reinforcement during appetitive classical conditioning of
feeding was mediated by afferent pathways that originate in the foregut. The
companion paper () describes two neurophysiological correlates of the classical
conditioning.
PMID- 10777800
TI - Classical conditioning of feeding in Aplysia: II. Neurophysiological correlates.
AB - Feeding behavior in Aplysia californica can be classically conditioned using
tactile stimulation of the lips as conditional stimulus (CS) and food as
unconditional stimulus (US) [ (companion paper)]. Conditioning resulted in an
increase in the number of CS-evoked bites that persisted for at least 24 hr after
training. In this study, neurophysiological correlates of classical conditioning
training were identified and characterized in an in vitro preparation of the
cerebral and buccal ganglia. Stimulation of a lip nerve (AT(4)), which mediates
mechanosensory information, resulted in a greater number of buccal motor patterns
(BMPs) in ganglia isolated from animals that had received paired training than in
ganglia from control animals. The majority of the evoked BMPs were classified as
ingestion-like patterns. Intracellular recordings from pattern-initiating neuron
B31/32 revealed that stimulation of AT(4) evoked greater excitatory input in
B31/32 in preparations from animals that had received paired training than from
control animals. In contrast, excitatory input to buccal neuron B4/5 in response
to stimulation of AT(4) was not significantly increased by paired training.
Moreover, correlates of classical conditioning were specific to stimulation of
AT(4). The number of spontaneously occurring BMPs and the intrinsic properties of
two buccal neurons (B4/5 and B31/32) did not differ between groups. These results
suggest that appetitive classical conditioning of feeding resulted in the pairing
specific strengthening of the polysynaptic pathway between afferent fibers and
pattern-initiating neurons of the buccal central pattern generator.
PMID- 10777801
TI - The precision of single neuron responses in cortical area V1 during stereoscopic
depth judgments.
AB - The performance of single neurons in cortical area V1 of alert macaque monkeys
was compared against the animals' psychophysical performance during a binocular
disparity discrimination task. Performance was assessed with stimuli that
consisted of a patch of dynamic random dots, whose disparity varied from trial to
trial, surrounded by an annulus of similar dots at a fixed disparity. On each
trial, the animals indicated whether the depth of the central patch was in front
of or behind the annulus. For each disparity of the center patch, neural
performance was assessed by calculating the probability that the response of the
neuron was greater or less than the response when the center disparity was the
same as that of the annulus. Initially the animals performed the task
simultaneously with the neural recording. However, the range of disparities used,
which was appropriate for the neuronal recording, may have affected performance,
because the thresholds were substantially lower (2.6x) when the psychophysical
measurements were repeated later. Average neuronal thresholds were approximately
4x poorer than these behavioral thresholds, although the best neurons were
marginally better than the animals' behavior. Thus, the well known precision of
relative depth judgments can be supported with signals from a small number of V1
neurons. Interference with the relative depth information in the stimulus
profoundly affected behavioral thresholds, which were approximately 10x poorer
when the surround was absent or contained binocularly uncorrelated dots. In this
case, single V1 neurons consistently outperform the observer: presumably here,
psychophysical thresholds are limited by other factors (such as uncertainty about
vergence eye position).
PMID- 10777802
TI - Reversal of dopamine D(2) receptor responses by an anandamide transport
inhibitor.
AB - We characterized the pharmacological properties of the anandamide transport
inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the
effects of this drug on behavioral responses associated with activation of
dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via
a high-affinity transport mechanism that was blocked by AM404. When administered
alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was
significant 60 min after intracerebroventricular injection of the drug and was
reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no
significant catalepsy or analgesia, two typical effects of direct-acting
cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced
by systemic administration of a low dose of apomorphine, an effect that was dose
dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of
motor behaviors elicited by the selective D(2) family receptor agonist
quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously
hypertensive rats, a putative model of attention deficit hyperactivity disorder.
The results support a primary role of the endocannabinoid system in the
regulation of psychomotor activity and point to anandamide transport as a
potential target for neuropsychiatric medicines.
PMID- 10777803
TI - Coregulation of voltage-dependent kinetics of Na(+) and K(+) currents in electric
organ.
AB - The electric organ cells of Sternopygus generate action potentials whose
durations vary over a fourfold range. This variation in action potential duration
is the basis for individual variation in a communication signal. Thus, action
potential duration must be precisely regulated in these cells. We had observed
previously that the inactivation kinetics of the electrocyte Na(+) current show
systematic individual variation. In this study, using a two-electrode voltage
clamp, we found that the voltage-dependent activation and deactivation kinetics
of the delayed rectifying K(+) current in these cells covary in a graded and
predictable manner across fish. Furthermore, when Na(+) and K(+) currents were
recorded in the same cell, their voltage-dependent kinetics were highly
correlated. This finding illustrates an unprecedented degree of coregulation of
voltage-dependent properties in two molecularly distinct ionic channels. Such a
coregulation of ionic channels is uniquely observable in a cell specialized to
generate individual differences in electrical activity and in which the results
of biophysical control mechanisms are evident in behaving animals. We propose
that the precise coregulation of the voltage-dependent kinetics of multiple ionic
currents may be a general mechanism for regulation of membrane excitability.
PMID- 10777804
TI - A role for complement in the rejection of porcine ventral mesencephalic
xenografts in a rat model of Parkinson's disease.
AB - Vascularized whole organ discordant xenografts placed in the periphery are
rejected by a rapid "hyperacute" process that involves preformed antibody binding
to the xeno-antigens on the donor endothelial cells with complement activation.
In the CNS, xenografts are classically thought to be rejected more slowly by a T
cell-dependent process. We now report that xenografts of embryonic porcine
ventral mesencephalic tissue in the 6-hydroxydopamine-lesioned,
nonimmunosuppressed rat induce both a humoral and a cell-mediated response. Over
the first 10 d after implantation, the xenografts matured with identifiable TH
neurons and pig-specific neurofilament fibers extending along host white matter
tracts. During this period of time, IgM and complement binding were observed
within the graft, as well as a CD8 cellular infiltrate, leading to rejection of
the transplant over the next 25 d. These intracerebral xenografts were not
associated with an early systemic antibody response. A role for complement in
this rejection process was further investigated using cobra venom factor (CVF),
which systemically depleted the rats of complement for 7 d. CVF treatment, when
given in the period immediately before and after grafting, delayed but did not
prevent the cellular immune response induced by the graft, demonstrating that
xenografted neural tissue can activate the humoral arm of the rejection process,
in particular the complement cascade. This suggests that interventions targeting
this aspect of the immune rejection process may be of great importance for the
future development of xenotransplantation for neurodegenerative conditions.
PMID- 10777805
TI - The genetic variant Voila causes gustatory defects during Drosophila development.
AB - Voila(1), an enhancer-trap strain in Drosophila melanogaster, expresses GAL4 in
most gustatory neurons, both before and after metamorphosis. Voila(1) expression
starts at embryonic stage 10. In the periphery, it labels larval gustatory
sensilla in the antennomaxillary complex as well as in the pharynx. GAL4 is also
expressed in the CNS in a manner that prefigures expression in adult flies. Most
Voila(1/1) homozygotes die between second larval instar and early adulthood.
Moreover, escaping Voila(1/1) larvae do not show gustatory responses to NaCl and
sucrose. The simultaneous rescue of normal larval gustation together with adult
viability after removal of the transposable PGAL4 element suggests that both
these phenotypes are caused by the same inserted element.
PMID- 10777806
TI - Metaplasticity of mossy fiber synaptic transmission involves altered release
probability.
AB - Activity-dependent synaptic plasticity is a fundamental feature of CNS synapses.
Intriguingly, the capacity of synapses to express plastic changes is itself
subject to considerable activity-dependent variation, or metaplasticity. These
forms of higher order plasticity are important because they may be crucial to
maintain synapses within a dynamic functional range. In this study, we asked
whether neuronal activity induced in vivo by application of kainate can induce
lasting changes in mossy fiber short- and long-term plasticity. Several weeks
after kainate-induced status epilepticus, the mossy fiber, but not the
associational-commissural pathway, exhibits a marked loss of paired-pulse
facilitation, augmentation, and long-term potentiation (LTP). Because the
adenylyl cyclase-protein kinase A cascade is involved in mossy fiber LTP
induction, we have tested the integrity of this key pathway by pharmacological
activation of either adenylyl cyclase or protein kinase A. These treatments
resulted in LTP in control, but not in kainate-treated animals, indicating that
status-induced changes occur downstream of protein kinase A. To test whether
altered neurotransmitter release might account for these changes, we measured the
size of the releasable pool of glutamate in mossy fiber terminals. We find that
the size of the releasable pool of glutamate was significantly increased in
kainate-treated rats, indicating an increased release probability at the mossy
fiber-CA3 synapse. Therefore, we suggest that lasting changes in neurotransmitter
release probability caused by neuronal activity may be a powerful mechanism for
metaplasticity that modulates both short- and long-term plasticity in the mossy
fiber-CA3 synapse after status epilepticus.
PMID- 10777807
TI - A novel selective melanocortin-4 receptor agonist reduces food intake in rats and
mice without producing aversive consequences.
AB - Studies using nonselective agonists and antagonists of melanocortin-3 receptor
(MC3R) and MC4R point to the importance of the CNS melanocortin system in the
control of food intake. We describe here a novel compound that is highly
selective as an agonist at the MC4 receptor but has minimal activity at the MC3
receptor. When administered centrally to rats, this selective agonist increased
Fos-like immunoreactivity in the paraventricular nucleus, central nucleus of the
amygdala, nucleus of the solitary tract, and area postrema, a pattern of neuronal
activation that is similar to that induced by a nonselective MC3/4R agonist.
Additionally, it suppresses food intake when administered centrally to rats or
peripherally to db/db mice that lack functional leptin receptors via a mechanism
that is not accompanied by illness or other nonspecific effects. Conversely, a
related compound that is a selective MC4R antagonist potently increased food
intake when administered centrally in rats. These results support the hypothesis
that the brain MC4R is intimately involved in the control of food intake and body
weight and provide evidence that selective activation of MC4R causes anorexia
that is not secondary to aversive effects.
PMID- 10777808
TI - Extraretinal control of saccadic suppression.
AB - We measured the time course of saccadic suppression and tested whether
suppression results entirely from retinal image motion or has an extraretinal
source. We measured contrast thresholds for low-frequency gratings modulated
either in luminance, at 17 cd/m(2) and 0.17 cd/m(2), or color at 17 cd/m(2).
Gratings were flashed on a uniform background before, during, or after voluntary
12 degrees saccades and, additionally in the case of luminance modulated
gratings, saccades simulated by mirror motion. A 10-fold decrease in contrast
sensitivity was found for luminance-modulated gratings with saccades, but little
suppression was found with simulated saccades. Adding high-contrast noise to the
display increased the magnitude and the duration of the suppression during
simulated saccades but had little effect on suppression produced by real
saccades. Suppression anticipates saccades by 50 msec, is maximal at the moment
of saccadic onset, and outlasts saccades by approximately 50 msec. At lower
luminance, suppression is reduced, and its course is shallower than at higher
luminance. Simulated saccades produce shallower suppression over a longer time
course at both luminances. No suppression was found for chromatically modulated
gratings. Differences between real and simulated saccades in the magnitude and
time course of sensitivity loss suggest that saccadic suppression has an
extraretinal component. We model the effects of saccades by adding a signal to
the visual input, so as to saturate the nonlinear stage of visual processing and
make detection of a test stimulus more difficult.
PMID- 10777809
TI - Role of microglial-derived tumor necrosis factor in mediating CD14 transcription
and nuclear factor kappa B activity in the brain during endotoxemia.
AB - Systemic injection of the endotoxin lipopolysaccharide (LPS) upregulates the gene
encoding CD14 early in the circumventricular organs (CVOs) and later in the brain
parenchyma. The present study tested the hypothesis that the parenchymal
production of the proinflammatory cytokine tumor necrosis factor alpha (TNF
alpha) by microglial cells is responsible for triggering CD14 transcription in an
autocrine/paracrine loop-like manner. In a first set of experiments, Sprague
Dawley rats were killed 1, 3, 6, and 12 hr after an intracerebroventricular
administration of recombinant rat TNF-alpha or vehicle solution. Second, anti-rat
TNF-alpha-neutralizing antibody or vehicle solution was administrated into the
lateral ventricle 10 hr before an intraperitoneal injection of LPS. Central
administration of the cytokine caused a strong induction of IkappaBalpha, TNF
alpha, and CD14 mRNA in parenchymal microglial cells. The hybridization signal
for these transcripts was localized to the edge of the ventricles and the site of
infusion. The time-related expression of each mRNA suggested that TNF-alpha has
the ability to trigger its own production followed by the transcription of the
LPS receptor; the signal for IkappaBalpha, TNF-alpha, and CD14 peaked at 1, 3,
and 6 hr, respectively. The genes encoding TNF-alpha and mCD14 were also induced
in the CVOs and within microglial cells across the brain parenchyma in response
to intraperitoneal LPS administration. This induction in parenchymal cells of the
brain was prevented in animals that received the anti-TNF-antisera
intracerebroventricularly 10 hr before the systemic treatment with the endotoxin.
The present data provide the evidence that microglial-derived TNF-alpha is
responsible for the production of the LPS receptor CD14 during endotoxemia. This
autocrine/paracrine stimulatory loop may be of great importance in controlling
the inflammatory events that take place in the CNS during innate immune response
as well as under pathological conditions.
PMID- 10777810
TI - A site of auditory experience-dependent plasticity in the neural representation
of auditory space in the barn owl's inferior colliculus.
AB - The barn owl's optic tectum contains a map of auditory space that is based, in
part, on a map of interaural time difference (ITD). Previous studies have shown
that this ITD map is shaped by auditory experience. In this study, we
investigated whether the plasticity responsible for experience-induced changes in
ITD tuning in the tectum occurs within the tectum itself or at an earlier stage
in the auditory pathway. We altered auditory experience in young owls by
implanting an acoustic filtering device in one ear that caused frequency
dependent changes in sound timing and level. We analyzed the representation of
ITD in normal and device-reared owls in two nuclei in the ascending pathway: the
external nucleus of the inferior colliculus (ICX), the primary source of
ascending auditory input to the tectum, and the lateral shell of the central
nucleus of the inferior colliculus (ICCls), the primary source of input to the
ICX. In the ICX, device rearing caused adaptive, frequency-dependent changes in
ITD tuning, as well as changes in frequency tuning. These changes in tuning were
similar to changes that occurred in the optic tectum in the same owls. In
contrast, in the ICCls, tuning for ITD and frequency was unaffected by device
rearing. The data indicate that plasticity at the level of the ICX is largely
responsible for the adaptive adjustments in ITD tuning and frequency tuning that
are observed in the optic tecta of owls raised with abnormal auditory experience.
PMID- 10777811
TI - Activity-dependent plasticity of descending synaptic inputs to spinal motoneurons
in an in vitro turtle brainstem-spinal cord preparation.
AB - An in vitro brainstem-spinal cord preparation from adult turtles was used to test
the hypothesis that descending synaptic inputs to multifunctional spinal
motoneurons (i.e., involved in respiration and locomotion) express activity
dependent depression or potentiation. The tissue was placed in a chamber that
allowed for separate superfusion of the brainstem, spinal segments C(2)-C(4), and
C(5)-D(1). Action potential conduction between the brainstem and spinal segments
C(5)-D(1) was blocked by superfusing C(2)-C(4) with Na(+)-free solution. With
C(5)-D(1) at [K(+)] = 10 mM, electrical stimulation at C(5) every 2 min evoked
potentials in intact pectoralis (expiratory, inward rotation of shoulder) and
serratus (inspiratory, outward rotation of shoulder) nerves that were stable for
at least 2 hr. Application of conditioning stimulation (900 pulses at 1 or 10 Hz)
at C(5) decreased pectoralis evoked potential amplitudes by approximately 40%
initially and by 20% after 90 min; serratus evoked potentials were unaltered.
Conditioning stimulation (100 Hz, 900 pulses) transiently depressed pectoralis
evoked potential amplitude by <20% but produced a delayed 72% increase in
serratus evoked potential amplitude after approximately 80 min. Conditioning
stimulation (10 Hz) at C(5) also reduced the amplitude of sensory afferent evoked
potentials in pectoralis produced by stimulating ipsilateral dorsal roots at
C(8). Thus, long-lasting changes in descending synaptic inputs to multifunctional
spinal motoneurons were frequency-dependent and heterosynaptic. We hypothesize
that activity-dependent plasticity may modulate descending synaptic drive to
spinal motoneurons involved in both respiration and locomotion.
PMID- 10777812
TI - Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular
transporter-dependent GABA release from rat striatal medium spiny neurons.
AB - Given the complex interactions between dopamine D1 and glutamate NMDA receptors
in the striatum, we investigated the role of these receptors in transporter
mediated GABA release from cultured medium spiny neurons of rat striatum. Like
NMDA receptor-mediated [(3)H]-GABA release, that induced by prolonged (20 min)
dopamine D1 receptor activation was enhanced on omission of external calcium, was
action potential-independent (tetrodotoxin-insensitive), and was diminished by
the GABA transporter blocker nipecotic acid, indicating the involvement of
transporter-mediated release. Interestingly, lowering the external sodium
concentration only reduced the stimulatory effect of NMDA. Blockade of Na(+)/K(+)
ATPase by ouabain enhanced NMDA-induced but abolished dopamine-induced release.
Moreover, dopamine appeared to potentiate the effect of NMDA on [(3)H]-GABA
release. These effects of dopamine were mimicked by forskolin. mu-Opioid receptor
mediated inhibition of adenylyl cyclase by morphine reduced dopamine- and NMDA
induced release. These results confirm previous studies indicating that NMDA
receptor activation causes a slow action potential-independent efflux of GABA by
reversal of the sodium-dependent GABA transporter on sodium entry through the
NMDA receptor channel. Moreover, our data indicate that activation of G-protein
coupled dopamine D1 receptors also induces a transporter-mediated increase in
spontaneous GABA release, but through a different mechanism of action, i.e.,
through cAMP-dependent inhibition of Na(+)/K(+)-ATPase, inducing accumulation of
intracellular sodium, reversal of the GABA carrier, and potentiation of NMDA
induced release. These receptor interactions may play a crucial role in the
behavioral activating effects of psychostimulant drugs.
PMID- 10777814
TI - Cerebral asymmetry of the "top-down" allocation of attention to global and local
features.
AB - Neuropsychological and neuroimaging studies have indicated that global and local
features of a visual scene are processed differentially by the two hemispheres.
Although visual selective attention is suggested to play a role in the
hemispheric asymmetry, the precise mechanism of attentional control for the
global-local processing is not fully understood. We investigated the neural
correlates of cerebral asymmetry in directing attention to the global pattern and
local components of a hierarchical stimulus. Event-related brain potentials
(ERPs) were recorded while the subjects shifted their attention to the global or
local level of a hierarchically structured letter. The shift direction was
controlled by a preceding cue stimulus. The ERPs to the cue stimuli demonstrated
that the right temporal-parietal and left posterior temporal regions were
differentially activated during attentional allocation to the global and local
levels, respectively. These effects started 240 msec after the cue stimulus. The
late ERP components to the target stimuli also manifested the hemispheric global
local asymmetry as seen during the attentional shift. These electrophysiological
results provided an asymmetrical neural basis for the "top-down" allocation of
attention to global and local features and revealed the contribution of the
temporal-parietal cortex to this attentional mechanism.
PMID- 10777813
TI - Dual effects of D-amphetamine on dopamine neurons mediated by dopamine and
nondopamine receptors.
AB - By increasing dopamine (DA) release and activating feedback mechanisms,
amphetamine and related psychostimulants are known to inhibit DA cell firing.
Here, we report that D-amphetamine also has an excitatory effect on DA cells,
which under control conditions, is masked by the inhibitory effect of D
amphetamine and is revealed when D2-like receptors are blocked. Thus, using in
vivo single-unit recording in rats, we found that the selective D2 antagonist
raclopride not only blocked the inhibition induced by D-amphetamine but also
enabled D-amphetamine to excite DA cells. The excitation, expressed as an
increase in both firing rate and bursting, persisted when both D1- and D2-like
receptors were blocked by SCH23390 and eticlopride, suggesting that it is not
mediated by DA receptors. The norepinephrine uptake blocker nisoxetine mimicked
the effect of D-amphetamine, especially the increase in bursting, whereas the 5
HT uptake blocker fluoxetine produced no significant effect. Adrenergic alpha1
antagonists prazosin and WB4101 and the nonselective alpha antagonist
phenoxybenzamine completely blocked increase in bursting induced by D-amphetamine
and partially blocked the increase in firing rate. The alpha2 antagonist idazoxan
and the beta antagonist propranolole, however, failed to prevent D-amphetamine
from producing the excitation. Thus, revising the traditional concept, this study
suggests that D-amphetamine has two effects on DA cells, a DA-mediated inhibition
and a non-DA-mediated excitation. The latter is mediated in part through
adrenergic alpha1 receptors.
PMID- 10777815
TI - NMDA receptor activity in utero averts respiratory depression and anomalous long
term depression in newborn mice.
AB - Mutant mice lacking NMDA receptor 1 subunit (NR1) showed marked depression of
respiratory and suckling activities in vivo and overexpression of synaptic long
term depression (LTD) in a brainstem cardiorespiratory-related region (nucleus
tractus solitarius) in vitro. Pharmacological blockade of NMDA receptors in
normal newborn mice mimicked the depression in suckling activity but not
respiratory depression in vivo or brainstem LTD in vitro. Results at the
behavioral and cellular levels demonstrate that NMDA receptor deficiency during
prenatal development may unleash an anomalous form of NMDA receptor-independent
LTD along with life-threatening respiratory depression consequences in the
newborn. These findings raise the specter of cardiorespiratory dysregulation with
increased risks of morbidity and mortality in the infant as a result of premature
births or genetic or drug-induced NMDA receptor antagonism during pregnancy.
PMID- 10777816
TI - [Fungal infections in immunocompromised patients].
AB - The number of immunocompromised patients is increasing due to the intensive
therapy being administered those with cancer, organ transplant, and HIV
infection. Fungal infections are one of the important opportunistic infections in
immunocompromised patients. Early diagnosis is difficult, and the prognosis of
these patinas is usually poor. Several methods of diagnosis for fungal infections
have been developed: detection of antigens of the infected fungi from the sera is
useful for early diagnosis; polymerase chain reaction (PCR) technology may be the
most valuable method for the diagnosis of fungal infection in immunocompromised
patients, and antifungal agents are the drugs used to the fungal infections in
those patients. However, there are only five drugs available to fungal infections
in Japan. Although amphotericin B is the recommended first choice for treatment
of invasive aspergillosis, its use for immunocompromised patients is limited
because of its adverse effects. Novel antifungal agents (azoles, amphotericin B
drug deliver system, and 1,3-beta-D-glucan synthetase inhibitors) have been
developed and some of these compounds undergoing clinical trials.
PMID- 10777817
TI - [Host defense mechanisms against fungal infections].
AB - Recent advances in the research on host defense mechanisms against infections
with Candida and Aspergillus were reviewed. Modes of the defense mechanisms were
divided into three phases by thedifferent physiological circumstances surrounding
the fungi: 1, the exocrine fluid in which fungi exist on the mucosal membranes;
2, the tissues invaded by fungi with the circulating blood; and 3, the limited
lesions where fungi continue to be alive with a restricted blood flow. In each
defense mechanism, theroles of the endogenous antifungal substances such as
lactoferrin, defensins and calprotectin and leukocytes were discussed.
PMID- 10777818
TI - [A case of fixed sporotrichosis with recurred in a child following itraconazole
treatment].
AB - We report a case of fixed sporotrichosis in a 2-year-old girl who showed a
reddish nodule on her left cheek for 1 year without trauma. Fungi flora-Y
staining showed fungal elements from the exudate onthe erosion of this nodule.
Sporothrix schenckii was isolated from a culture of the fungus taken from the
biopsy specimen. Treatment with itraconazole 4.5 mg/kg/day for 16 weeks resulted
in an atrophic scar after 2.1 mg/kg/day for 8 weeks without side effects. Six
months later, her eruption recurred and wastreated with potassium iodide for 21
weeks with complete resolution. During the 1 year follow up period, there was no
recurrence. Six cases of sporotrichosis in children including ours have been
reported in Japan. Each case showed complete resolution and no recurrence.
However, careful follow-up is believed to be necessary based on our case.
PMID- 10777819
TI - [Phaeomycotic cyst caused by Phaeoacremonium parasiticum].
AB - Phaeoacremonium parasiticum was identified as the causative agent of a
phaeomycotic cyst seen just below the right knee of a 59-year-old healthy woman.
She had no history of trauma. Direct KOH examination of the pus aspirated from
the subcutaneous nodule revealed abundant mycelia, which were not too deeply
brown in color. The nodule was surgically excised, and there was no recurrence
during a half year of observation. Tissue section of the excised material
revealed rather a large cavity extending from the cutis to the subcutis. The
cavity had a thick wall composed of granulomatous tissues. Mycelial and yeast
like fungal elements were seen within the cavity and the granulomatous tissues. A
dematiaceous fungus was cultured from both pus and the excised material. The
isolates were characterized by a dark green to black colony, unbranched or
infrequently branched, brownish conidiophores bearing an aculeate monophialide
with a narrow funnel-shaped collarette, and slimy, hyaline, one-celled, ellipsoid
to allantoid conidia.
PMID- 10777820
TI - [Suppressive effects of lanoconazole on arthus phenomenon in vivo and on
production and functions of TNF in vitro].
AB - The anti-inflammatory effect of lanoconazole (LCZ) was investigated in vivo and
in vitro. The effect of LCZ was evaluated on the inflammatory reactions elicited
by intradermal injection of ovalbumin to ovalbumin-immunized rabbits, as an
Arthus phenomenon. A one or two % cream preparation of LCZ was topically applied
on the lesion daily after challenging injection until the inflamation had
diminished. By macroscopic observation and measuring the diameter of edema,
erythema, hemorrhage and necrosis, the effects of LCZ on the reactions were
compared with the reactions of the sites administered withcream vehicle as
reference agent. Two % LCZ showed an anti-hemorrhagic effect. The in vitro effect
of LCZ on production and functions of an inflammatory cytokine, TNF was also
examined. LCZ suppressed the production of TNF by murine peritoneal macrophages
at 20 micro g/ml and the adhesion of neutrophils at 100 micro g/ml. Moreover, LCZ
significantly suppressed the growth inhibitory activity of TNF against L929
fibroblasts at 0.5 micro g/ml. A very low concentration of LCZ might protect the
fibroblasts from immunological cytotoxicity in vivo. These findings suggest that
LCZ has a suppressive activity to inflammatory responses and this suppressive
action may be due to its protective activity to cells like fibroblasts.
PMID- 10777821
TI - [An autopsy case of HELLP syndrome with disseminated aspergillosis].
AB - Disseminated aspergillosis is an uncommon and unpredictable complication in
severely immunocompromised patients and poses a challenging problem in the
management and care of seriously ill patients receiving intensive care therapy.
We report an autopsied case of disseminated aspergillosis occurring ina 31-year
old female patient who was treated for HELLP (hemolysis, elevated liver enzymes,
and low platelet count) syndrome. She initially presented with edema and
proteinuria at a pregnancy check-up. At gestational age 33 weeks and 2 days, she
had right lower abdominal pain, nausea, and jaundice. The next day she delivered
a male neonate transvaginally, followed by excessive postpartum uterine bleeding.
Although an emergency hysterectomy was performed, her hemorrhagic diathesis could
not be controlled even after transcatheter embolization of the internal iliac
arteries with subsequent ligation and repeated blood transfusions totalling to
31,070 ml. She eventually died of a cerebral hemorrhage 21 days after the
parturition. Autopsy showed generalized jaundice and petechiae, as well as
extensive hemorrhage observed in the abdominal wall, peritoneal cavity, and
retroperitoneal and pelvic spaces. In addition,there were multifocal hemorrhages
found in the left temporal, right frontal and posterior lobes of the cerebrum,
and pons. Disseminated aspergillosis was found in the lungs, trachea, brain,
esophagus, stomach, heart, and thyroid gland. These findings suggest that
systemic postoperative complications, associated with massive blood transfusions
and hepatic failure, mutually contribute to the overall deterioration of host
defense mechanism, and may underlie the occurrence of devastating systemic fungal
infection.
PMID- 10777822
TI - Are giant cells conidia in Sporothrix schenckii? -Freeze-fracture electron
microscopic observation-.
AB - Sporothrix schenckii is a well-known pathogenic dimorphic fungus. In this study,
we focused on the plasma membrane ultrastructures of giant cells of S. schenckii
seen mainly on Sabouraud's dextroseagar slant medium. In the organisms grown for
1, 2, 3, 4, 6 and 8 weeks at 27 and 37 degrees C on brain heart infusion and
Sabouraud's dextrose agar slant media, the number of conidia, hyphae, brownish
and non-brownish giant cells were counted in ten separated areas under light
microscope (x100) to determine the culture conditions under which giant cells
were generated. The results showed that brownish giant cells were predominantly
seen after longer cultivation periods. Using freeze-fracture electron microscopy,
larger oval- or round shaped cells can be identified as conidia by their plasma
membrane ultrastructure characteristics, i.e, trench-like invaginations seen in
ordinary mature conidia (Maeda M et al.; Can J Microbiol 33: 40, 1987). From
these structural features seen by freeze-fracture electron microscopy, giant
cells appeared possibly be conidia and were suggested to be starved because of
their predominant existence under longer cultivation conditions.
PMID- 10777823
TI - [Protective effect of oral administration of several traditional Kampo-medicines
on lethal Candida infection in immunosuppressed mice].
AB - The protective effects of a "hozai" type of Kampo medicine, Juzen-taiho-to (Shi
quan-da-bu-tang, TJ-48), Hochu-ekki-to (Bu-zhong-yi-qi-tang, TJ-41) or Ninjin
yoei-to (Ren-shen-yang-rong-tang, TJ-108) on experimental candidiasis in
immunosuppressed mice were investigated. ICR mice, which were immunosuppressed by
injection of cyclophosphamide or prednisolone, were given these medicines orally
andchallenged intravenously with Candida albicans (day 0). Treatments with a
daily dose of 1 g/kg/day of TJ-48 or that of 1 or 2 g/kg/day of TJ-108 for 4
consecutive days from day-4 significantly prolonged the survival time of the
Candida-infected mice pretreated with cyclophosphamide. Treatments with a daily
dose of 1 g/kg/day of TJ-48 for 4 consecutive days from day 0, but not from day
4, significantly prolonged the life span of the Candida-infected mice pretreated
with prednisolone. On the basis of these results and previous findings,
characteristics of these kampo medicines as therapeutic agents against
candidiasis in immunosuppressed hosts were discussed.
PMID- 10777825
TI - What kind of controls to use in case control studies of malformed infants: recall
bias versus "teratogen nonspecificity" bias.
PMID- 10777824
TI - A case of seborrhoeic blepharitis.
AB - A fifty five-year old woman suffered from itching and scaling of the edge of her
eyelid. She had long used topical corticosteroid for this condition. Direct
examination of the scale by Parker KOH showed numerous fungal elements of spores
and hyphae of Malassezia furfur. She was treated with oral itraconazole (100 mg
daily or twice a week) for 8 weeks and was cured clinically and mycologically.
The result suggests the possibility of treatment with an anti-fungal drug for
seborrhoeic blepharitis or seborrhoeic dermatitis.
PMID- 10777826
TI - More on data from teratogen information systems (TIS)
PMID- 10777827
TI - Familial recurrence of nonsyndromic interrupted aortic arch and truncus
arteriosus with atrioventricular canal.
AB - BACKGROUND: Multifactorial inheritance is probably involved in most cases of
nonsyndromic conotruncal heart defects (CHDs), but Mendelian transmission is
often suspected. RESULTS: We report on a family with recurrence of nonsyndromic
CTHD in two double first cousins; i.e., two brothers married two sisters. One of
the cousins (case 1) had interrupted aortic arch (IAA) type B, while the other
one (case 2) had truncus arteriosus (TA) with atrioventricular canal defect
(AVCD). CONCLUSIONS: Our family further supports monogenic inheritance of CTHDs.
In addition, the presence of TA associated with AVCD in one of the patients
confirms the higher occurrence of CTHD in families with complex TA. The absence
of 22q11 microdeletion (del22q11) in our patients, as in several literature
reports of familial CTHDs, supports the existence of genes different to those
located on chromosome 22q11 which could be implicated in the pathogenesis of
CTHDs.
PMID- 10777828
TI - Effects of supplemental methionine on antiserum-induced dysmorphology in rat
embryos cultured in vitro.
AB - BACKGROUND: Heterologous antiserum to the visceral yolk sac (AVYS) is
teratogenic, inducing a spectrum of malformations in vivo and producing similar
effects in vitro. Numerous studies support the concept that AVYS-induced
malformations result from embryonic nutritional deficiency, without affecting the
maternal nutritional status. This has provided a useful model with which to
investigate the nutritional requirements of the early embryo, as well as the role
of various nutrients in the etiology of congenital defects. METHODS: In the
current investigation, we examined the effects of methionine and other nutrients
on AVYS-induced embryotoxicity in vitro. For these experiments, we cultured rat
embryos (9.5 p.c) for 48 hr with AVYS and/or methionine at several concentration
levels. RESULTS: The addition of L-methionine to AVYS-exposed cultures reduced
dysmorphology and open neural tube; this effect was concentration dependent. AVYS
induced dysmorphology was completely prevented at a concentration of L-methionine
corresponding to 50-fold the basal serum concentration. Utilization of D
methionine, L-leucine, or folic acid (5-methyltetrahydrofolate, MTHF) instead of
L-methionine had no protective effects. CONCLUSIONS: These results suggest that,
although AVYS limits the supply of all amino acids to the embryo, embryopathy
largely results from a deficiency of methionine. Furthermore, although
endocytosis and degradation of proteins by the VYS supplies most amino acids to
the embryo, free amino acids may be compensatory when this source is reduced.
These results support those of previous investigations that suggest methionine is
required for normal NT closure and that methionine is a limiting nutrient for
embryonic development.
PMID- 10777829
TI - Patterns of infant mortality caused by major congenital anomalies.
AB - BACKGROUND: We assessed the impact of recent advances in perinatal care on infant
mortality due to congenital anomaly. METHODS: Analysis of trends in congenital
anomaly-attributed infant mortality, using the 1981-1995 Statistics Canada's
birth and death records, with a total of 2,878,826 live births, 21,883 infant
deaths, and 6, 908 infant deaths due to congenital anomalies. RESULTS: Infant
mortality due to major congenital anomaly decreased from 3.11 per 1, 000 live
births in 1981 to 1.89 per 1,000 live births in 1995. Cause-specific infant
mortality rates for anencephaly, spina bifida, other central nervous system
anomalies, cardiovascular system anomalies, respiratory system anomalies,
digestive system anomalies, certain musculoskeleton anomalies, urinary system
anomalies, chromosomal anomalies, and multiple congenital anomalies were 0.20,
0.23, 0.27, 1.04, 0.24, 0.08, 0.22, 0.16, 0.22, and 0.13 per 1,000 live births,
respectively, in 1981-1983, whereas corresponding rates were 0.07, 0.07, 0.18,
0.73, 0.25, 0.03, 0.12, 0.12, 0.26, and 0.06 per 1,000 live births, respectively,
in 1993-1995. CONCLUSIONS: Recent Canadian data show that infant deaths caused by
major congenital anomalies have decreased significantly, but reductions varied
substantially according to specific forms of anomalies.
PMID- 10777830
TI - Expression of the sonic hedgehog gene in human embryos with neural tube defects.
AB - BACKGROUND: To estimate the rate of malformations observed during early human
development, a series of 38,913 first-trimester abortions were studied. Neural
tube defects (NTD) were found in 57 cases. METHODS: A histological study of
serial sections performed in 25 embryos revealed a spectrum of axial structure
abnormalities. Expression of the SHH gene was studied by in situ hybridization in
one case of CRS and in two cases of SB. RESULTS: A cervical notochord duplication
was always found in craniorachischisis (CRS, n = 8), but not in spina bifida (SB,
n = 10) or diplomyelia (split cord malformation, n = 3). In the embryo with CRS,
expression of SHH was found in both domains, corresponding to the duplicated part
of the notochord, whereas a single signal was observed in the nonduplicated part.
This expression was associated at the cervical level of the open neural tube with
a broad SHH expression domain and with two or even three domains in its lumbar
region, suggesting multiple functional floor plates. Similarly, in two embryos
with SB, two domains of SHH expression were found in the ventral neural tube.
CONCLUSIONS: Our findings suggest that notochord splitting in the cervical region
might be involved in the pathogenesis of CRS. Interestingly, similar notochord
abnormality and altered expression of the shh gene are observed in Lp mice with
NTD. This suggests that the Lp gene could be a candidate gene for human CRS.
Further studies are needed to establish the primary event responsible for the
notochord splitting and for the abnormal expression of the SHH gene in the floor
plate in embryos with CRS and SB.
PMID- 10777831
TI - Malformations in offspring of diabetic rats: morphometric analysis of neural
crest-derived organs and effects of maternal vitamin E treatment.
AB - BACKGROUND: We have previously reported on a malformation-prone Sprague-Dawley
rat substrain (U), which presents a high frequency of micrognathia in the
offspring of diabetic mothers. This malformation is related to impaired
development of the cranial neural crest cells (NCC); the defect may be prevented
by antioxidative treatment of the mother. METHODS: We have therefore investigated
whether fetuses of diabetic rats display other malformations associated with
altered cranial NCC development and whether maternal vitamin E supplementation
may affect such malformations. RESULTS: Fetuses of diabetic rats showed low-set
external ears, severely malformed Meckel's cartilage, small thyroid and thymus,
and absence of parathyroid glands. Cardiac anomalies were frequently observed,
including rightward displacement of the aorta, double outlet right ventricle
(DORV), persistent truncus arteriosus (PTA) combined with ventricular septal
defects due to a malaligned outlet septum. The malformations in the outflow tract
included abnormalities of the great arteries; right-sided aortic arch/descending
aorta, and double aortic arches. These defects tended to occur together within
individual fetuses. Maternal dietary treatment with 2% vitamin E markedly reduced
the severity of the malformations. CONCLUSIONS: The phenotypic appearance of
these defects is strikingly similar to the DiGeorge anomaly in humans, which has
been found in children of diabetic mothers together with an overrepresentation of
PTA and DORV. The malformations associated with defective NCC development in the
offspring of diabetic U rats show several morphological similarities to those in
humans; hence the teratogenic mechanisms may be similar and accessible for study.
PMID- 10777832
TI - Interrupted aortic arch: an epidemiologic study.
AB - BACKGROUND: Interruption of the aortic arch (IAA) is a rare but severe anomaly
associated with major intracardiac defects and with multisystem noncardiac
malformations, recently linked to chromosome deletion of 22q11.2. METHODS: The
Baltimore-Washington Infant Study (1981-1989), a population-based epidemiologic
study of cardiovascular malformations, evaluated 53 infants with IAA in
comparison with 3,572 controls. Risk factors for the anatomic subtypes were
evaluated in 14 cases of IAA type A and 32 cases of IAA type B, but no molecular
genetic tests were available. The distribution of associated cardiac defects was
similar for both types. RESULTS: DiGeorge syndrome (DGS) occurred more frequently
in IAA type B. Case-control comparisons demonstrated that infants in both groups
were growth retarded at birth. A family history of noncardiac defects occurred
only in IAA type B cases and included relatives with cleft lip and/or cleft
palate. Candidate risk factors were associated only in type B cases and differed
for those with (n = 10) and for those without (n = 19) DGS: a family history of
noncardiac defects (odds ratio [OR] = 7.2, 95% confidence interval [CI] = 1.5
39.2) and maternal use of aspirin during the critical period (OR = 4.8, 95% CI =
1.3-25.4) occurred with DGS, while previous stillbirth (OR = 9.4, 95% CI = 1.3
53.1), bleeding during pregnancy (OR = 3.7, 95% CI = 1.4-11.4), and maternal
exposure to arts/crafts paints (OR = 4.8, 95% CI = 1.3-17.4) were associated in
those without DGS. CONCLUSIONS: These findings confirm the heterogeneity of IAA
and of the type B subtype. Risk factors specific for cases with DGS may open a
window to further investigations of the etiology of IAA and of the associated
molecular genetic abnormalities.
PMID- 10777833
TI - Spina bifida phenotypes in infants or fetuses of obese mothers.
AB - BACKGROUND: A twofold or greater risk of neural tube defect (NTD)-affected
pregnancy has been associated with prepregnant obesity, where obesity was defined
as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina
bifida than for anencephaly. METHODS: We investigated whether finer phenotypic
classifications of spina bifida, in combination with other factors, were
associated with a BMI of >29 kg/m(2). Data were derived from a case-control study
of fetuses and infants with NTDs among 1989-1991 California births. Interviews
were conducted with mothers of 277 spina bifida cases and 517 nonmalformed
controls. RESULTS: Women with a BMI of >29 kg/m(2) compared with those 29 kg/m(2)
compared with males whose mothers were
or = 15 years, admissions data from the local hospital, women's refuge and
sobering up shelter, and police data on detentions in custody and common offences
were compared for the 12 months prior and 24 months subsequent to the
introduction of the restrictions. A random sample survey of residents aged > or =
18 years was conducted to ascertain attitudes towards the restrictions. RESULTS:
Over the two years following the introduction of the restrictions, there was a
reduction of 19.4% in annual per capita consumption of pure alcohol. This was
accompanied by declines in: hospital admissions for acute alcohol-related
diagnostic related groups; and persons taken into police custody and the
proportions of offences reported on Thursdays. A majority of survey respondents
was in favour of retaining or strengthening the existing restrictions.
CONCLUSIONS: The restrictions were effective in reducing alcohol consumption and
acute related harm and had the support of the majority of people in Tennant
Creek. On the basis of this evidence, the NT Liquor Commission made a decision to
retain them. Restrictions do not provide a simple answer to the problems
associated with excessive alcohol consumption. However, they can be an effective
part of a broad public health strategy to deal with such problems.
PMID- 10777978
TI - Liquor licensing and community action in regional and remote Australia: a review
of recent initiatives.
AB - OBJECTIVE: To review the effectiveness of community-based initiatives involving
restrictions on alcohol availability in remote and regional locations in
Australia, and to assess their implications for other communities or towns
contemplating similar measures. METHODS: Findings from evaluations of community
initiatives in Tennant Creek (NT), Derby (WA), Halls Creek (WA), Elliott (NT) and
Curtin Springs (NT) are compared with respect to impact on alcohol consumption,
and on indicators of alcohol-related harm relating to public order, health and
well-being, and economic activities. The extent of community support for these
initiatives is also examined. RESULTS: Restrictions were found to have a modest
but real impact on alcohol consumption, and a significant impact on indicators of
alcohol-related harm, especially violence. Restrictions were also found to have
widespread community support, often qualified by a belief that other measures
were also required. CONCLUSIONS: Restrictions on availability are an effective
means of reducing alcohol-related harm at a local level and, depending upon the
processes involved in their introduction, are likely to have strong community
support, provided that other measures are also pursued. IMPLICATIONS: Five issues
are identified that are likely to arise in other settings where restrictions are
contemplated. These are: the issue of representativeness ('who speaks for the
community?'); selection of particular kinds of restrictions on availability;
selection of most appropriate additional measures; universal vs. selective
restrictions; and the role of liquor licensing authorities in imposing or
facilitating restrictions.
PMID- 10777979
TI - What harms do young Australians experience in alcohol-use situations?
AB - OBJECTIVE: An insight into the alcohol-related experiences of young students in
Perth, Western Australia, with particular emphasis to alcohol-related harm.
METHOD: The sample of 2,329 students (female: n = 1,089, male: n = 1,240) is a
school-based group selected using cluster sampling, with stratification by socio
economic area and represents 11 to 12 year olds' experiences with alcohol and
alcohol-related harm. The SHAHRP survey instrument was developed and pre-tested
to measure students' knowledge, attitudes, patterns and context of use, harms
associated with the students' own alcohol consumption and harms associated with
other people's use of alcohol and incorporates the students' perceptions of
alcohol-related harm. RESULTS: Nearly two-thirds of all young people consumed
alcohol under adult supervision; nearly 40% of all young males and 34% of all
young females drink alcohol in unsupervised situations; and a fifth of young
males consumed alcohol alone. Young males start drinking younger and consumed
alcohol more regularly than young females, and consumed more alcohol per
occasion. In the past 12 months, young males experienced more than five and young
females more than three alcohol-related harms associated with their own alcohol
consumption. They experienced a similar number of harms associated with other
people's use of alcohol. Unsupervised drinkers were nearly seven times more
likely to experience alcohol-related harm than supervised drinkers and nearly 13
times more likely to experience alcohol-related harm than non-drinkers.
CONCLUSION AND IMPLICATIONS: The results can help inform the development of
alcohol education programs for young people.
PMID- 10777980
TI - Is birthweight an appropriate health-outcome measure for Torres Strait Islander
babies?
AB - BACKGROUND: Although Torres Strait Islanders (TSIs) are often combined with
Aborigines, they are a distinct group and would prefer to be considered
separately. The Queensland Perinatal Data Collection (QPDC) has been the only
population-based, perinatal collection in Australia that has distinguished
between Aboriginal and TSI mothers. It provided a unique opportunity to compare
outcome measures based on birthweight in the TSI, Aboriginal and white
populations. TSIs were of particular interest because recent research from
overseas suggests that in groups with high rates of obesity and diabetes,
birthweight is not a valid outcome measure. This is of concern because outcome
measures based on birthweight have been proposed as a way of monitoring the
neonatal health of Indigenous Australians. METHODS: Retrospective analysis of 10
years of routine data from the QPDC. RESULTS: TSIs had a birthweight distribution
similar to that of whites, but mortality rates similar to those of Aborigines.
For birthweights between 2500 g and 4000 g, TSIs had mortality rates that were
2.5 times higher than those for whites (95% CI: 1.3 to 4.2). CONCLUSIONS:
Although birthweight is widely used, it is not necessarily a valid outcome
measure in all populations. For TSIs, maternal conditions such as obesity and
diabetes might cause changes in the uterine environment that produce heavier, but
not healthier babies.
PMID- 10777981
TI - The use of conjoint analysis to elicit community preferences in public health
research: a case study of hospital services in South Australia.
AB - AIMS: To demonstrate the use of conjoint analysis (CA) in public health research
through a survey of the South Australian community about aspects of their public
hospital services. METHODS: A series of focus groups determined the most
important attributes in choice of hospital services. These were built into a CA
survey, using the discrete choice approach. The survey was posted to a
representative sample of 700 South Australians. Theoretical validity, internal
consistency and non-response bias were all investigated. RESULTS: Some 231
individuals returned the questionnaire. The attribute, 'improvement in
complication rates' was positively associated with choice of hospital. Three
attributes were found to be negatively associated with such choice: 'waiting
times for casualty', 'waiting times for elective surgery' and, anomalously,
'parking and transport facilities'. 'Travel time' and the cost attribute,
'Medicare levy' were not statistically significant. Trade-offs between the
significant attributes were estimated, as were satisfaction or utility scores for
different ways of providing hospital services. Results concerning internal
consistency and internal validity were encouraging, but some potential for non
response bias was detected. CONCLUSION: A high premium is placed on the quality
of hospital care and members of the community are prepared to choose between
hospitals largely on the basis of outcomes and length of waiting times for
elective surgery and in casualty. IMPLICATIONS: CA can yield potentially policy
relevant information about community preferences for health services.
PMID- 10777982
TI - Inequitable distribution of general practitioners in Australia: estimating need
through the Robin Hood Index.
AB - OBJECTIVE: From Census data, to document the distribution of general
practitioners in Australia and to estimate the number of general practitioners
needed to achieve an equitable distribution accounting for community health need.
METHODS: Data on location of general practitioners, population size and crude
mortality by statistical division (SD) were obtained from the Australian Bureau
of Statistics. The number of patients per general practitioner by SD was
calculated and plotted. Using crude mortality to estimate community health need,
a ratio of the number of general practitioners per person: mortality was
calculated for all Australia and for each SD (the Robin Hood Index). From this,
the number of general practitioners needed to achieve equity was calculated.
RESULTS: In all, 26,290 general practitioners were identified in 57 SDs. The mean
number of people per general practitioner is 707, ranging from 551 to 1887.
Capital city SDs have most favourable ratios. The Robin Hood Index for Australia
is 1, and ranges from 0.32 (relatively under-served) to 2.46 (relatively over
served). Twelve SDs (21%) including all capital cities and 65% of all
Australians, have a Robin Hood Index > 1. To achieve equity per capita 2489 more
general practitioners (10% of the current workforce) are needed. To achieve
equity by the Robin Hood Index 3351 (13% of the current workforce) are needed.
CONCLUSIONS: The distribution of general practitioners in Australia is skewed.
Nonmetropolitan areas are relatively underserved. Census data and the Robin Hood
Index could provide a simple means of identifying areas of need in Australia.
PMID- 10777983
TI - Outcomes of an educational activity with Victorian GPs aimed at improving
knowledge and practices in relation to sexually transmissible diseases.
AB - OBJECTIVE: To measure the effect of a simple educational strategy for general
practitioners (GPs) on their knowledge and self-reported practice in relation to
sexually transmissible disease (STD) management. METHOD: In 1995, we surveyed 520
Victorian GPs; 444 (85%) responded. A sub-sample of 242 was sent an educational
package in relation to STD management that required them to reflect on their
performance in the survey in relation to that of the sample as a whole. Two
months after they had received the package, a brief follow-up questionnaire,
using a selection of questions from the first survey, was sent to these GPs.
RESULTS: Practitioners showed statistically significant improvements in knowledge
and self-reported practice for four of the six outcomes that were examined.
CONCLUSION: A relatively simple educational package for GPs had a high
participation rate and resulted in improvements in knowledge and self-reported
practice that could contribute to increased STD case finding in the general
practice setting. IMPLICATIONS: The key to enabling GPs to make a greater
contribution to improved STD control is to encourage them to be more active in
diagnosing and treating asymptomatic disease. For asymptomatic patients, sexual
history-taking and selective screening are important skills but there are
barriers to their implementation in the general practice setting. A key objective
of GP educational programs in relation to STDs is to increase their likelihood of
taking a sexual history and the significant increase in this measure for the
whole sample was encouraging.
PMID- 10777984
TI - Reliability and validity of women's recall of mammographic screening.
AB - OBJECTIVE: To assess the reliability and validity of self-reported attendance for
mammographic screening. METHODS: To assess reliability of recall of attendance
for a screening mammogram, 100 women selected at random were interviewed twice
(approximately one week apart). To assess validity, 127 women who reported having
a mammogram within the national breast screening program (BreastScreen Australia)
consented to having their reports verified by the national program. RESULTS: Test
retest reliability for the question "Have you ever had a mammogram?" was perfect
(agreement 100%, kappa 1). Validity was also high. About one-quarter of women
(24.4%) recalled the exact date of their last mammogram and a further third
(39.4%) correctly reported the month in which the mammogram was done. Almost all
(91.3%) women reported the mammogram date accurately to within 12 months of the
recorded date. CONCLUSIONS: These data suggest that Australian women provide
reliable and valid information in relation to mammographic screening attendance.
IMPLICATIONS: Self-reported data about attendance for mammographic screening are
likely to provide reliable and valid estimates for research and health services
evaluation purposes.
PMID- 10777985
TI - Hitting up in the top end: characteristics of needle exchange clients in Darwin.
AB - OBJECTIVE: Little is known about injecting drug use (IDU) and blood-borne viral
(BBV) infection in rural Australia. METHOD: These repeat cross-sectional studies
were conducted during a two-week period in July and October-November 1998 at the
Darwin needle exchange, with 129 and 121 respondents respectively. RESULTS: The
commonest drug of choice was heroin, but the commonest drug injected was
morphine. Self-reported sharing of needles and syringes was uncommon. Self
reported serostatus for HIV was high (8% and 11.4% respectively), but seemingly
mostly associated with sexual rather than IDU risk; for hepatitis C (HCV) status,
these were 54% and 37%. Among IDUs of Aboriginal or Torres Strait Islander (ATSI)
background, who made up 14% of the first round respondents, patterns of IDU and
of BBV infection were the same as among non-ATSI respondents. CONCLUSIONS: These
surveys reveal patterns of IDU in Darwin that have both similarities and
differences with those in the major urban centres in Australia. In the absence of
a comprehensive methadone maintenance program, many participate in a more or less
informal morphine substitution program. HIV is present among these IDUs, and the
risks of further sexual transmission may be high. IMPLICATIONS: These surveys
confirm the presence among injecting drug users in Darwin of HIV, HBV and HCV,
and of the risk for further spread of these viruses. Control of blood-borne virus
transmission among IDUs requires an even greater commitment to abolishing sharing
of needles and syringes, and therefore continued support and enhancement of
needle and syringe availability.
PMID- 10777986
TI - Lipoproteins, diabeto-genicity, age and risk of diabetes mellitus death.
AB - OBJECTIVE: To examine the clinical significance of a specific relationship
between very low density lipoprotein (VLDL) and high density lipoprotein (HDL),
namely their differential, in relation to Type 2 non-insulin dependent diabetes
mellitus (NIDDM). METHODS: The study subjects were 300 female and 300 male
patients of doctors in city and rural New South Wales referred for lipid studies.
Their clinical notes suggested a relationship of VLDL-HDL to diabetes mellitus
(DM) and it was therefore hypothesised that this expression is a functional
measure of diabeto-genicity. RESULTS: By incorporation of age, a calculated
measure of risk of overt DM and consequent death can be derived. This is
confirmed by comparing the age incidence of this risk function with the age
incidence of death attributed to DM in the Australian population to give a simple
linear correlation. The principal conclusion is drawn from a mathematical model
of the population incidence of DM in terms of VLDL, HDL and age. CONCLUSION: From
this model springs the inference that NIDDM is a cumulative dyslipidaemia-over
time process. If this inference is correct, NIDDM can properly be viewed as a
societal disease of which all run a measurable risk that increases with age and
from which all will die in the long term who do not die sooner from another
cause. IMPLICATIONS: The implications for public health are the ability to
identify the individuals at raised risk before DM becomes symptomatic by
lipoprotein screening, and the ability to lower risk of DM over the whole
population by preventive measures with increased longevity for all.
PMID- 10777987
TI - Daily mortality in relation to weather and air pollution in Christchurch, New
Zealand.
AB - OBJECTIVE: To investigate the relationship between the daily number of deaths,
weather and ambient air pollution. METHOD: An ecological study. We assembled
daily data for the city of Christchurch, New Zealand (population 300,000) from
June 1988 to December 1993. We used Poisson regression models, controlling for
season using a parametric method. RESULTS: Above the third quartile (20.5 degrees
C) of maximum temperature, an increase of 1 degree C was associated with a 1%
(95% CI: 0.4 to 2.1%) increase in all-cause mortality and a 3% (0.1 to 6.0%)
increase in respiratory mortality. An increase in PM10 of 10 micrograms/m3 was
associated (after a lag of one day) with a 1% (0.5 to 2.2%) increase in all-cause
mortality and a 4% (1.5 to 5.9%) increase in respiratory mortality. We found no
evidence of interaction between the effects of temperature and particulate air
pollution. CONCLUSIONS: High temperatures and particulate air pollution are
independently associated with increased daily mortality in Christchurch. The fact
that these results are consistent with those of similar studies in other
countries strengthens the argument that the associations are likely to be causal.
IMPLICATIONS: These findings contribute to evidence of health consequences of
fuel combustion, both in the short term (from local air pollution) and in the
long term (from the global climatic effects of increased atmospheric CO2).
PMID- 10777988
TI - Anonymous linkage of New Zealand mortality and Census data.
AB - BACKGROUND: The New Zealand Census-Mortality Study (NZCMS) aims to investigate
socio-economic mortality gradients in New Zealand, by anonymously linking Census
and mortality records. OBJECTIVES: To describe the record linkage method, and to
estimate the magnitude of bias in that linkage by demographic and socio-economic
factors. METHODS: Anonymous 1991 Census records, and mortality records for
decedents aged 0-74 years on Census night and dying in the three-year period 1991
94, were probabilistically linked using Automatch. Bias in the record linkage was
determined by comparing the demographic and socio-economic profile of linked
mortality records to unlinked mortality records. RESULTS: 31,635 of 41,310
(76.6%) mortality records were linked to one of 3,373,896 Census records. The
percentage of mortality records linked to a Census record was lowest for 20-24
year old decedents (49.0%) and highest for 65-69 year old decedents (81.0%). By
ethnic group, 63.4%, 57.7%, and 78.6% of Maori, Pacific, and decedents of other
ethnic groups, respectively, were linked. Controlling for demographic factors,
decedents from the most deprived decile of small areas were 8% less likely to be
linked than decedents from the least deprived decile, and male decedents from the
lowest occupational class were 6% less likely to be linked than decedents from
the highest occupational class. CONCLUSION: The proportion and accuracy of
mortality records linked was satisfactorily high. Future estimates of the
relative risk of mortality by socio-economic status will be modestly under
estimated by 5-10%.
PMID- 10777989
TI - Use of self-report to monitor overweight and obesity in populations: some issues
for consideration.
AB - OBJECTIVE: To examine the validity of self-reported height and weight data
reported over the telephone in the 1997 NSW Health Survey, and to determine its
accuracy to monitor overweight and obesity in population surveys. METHOD: Self
reported and measured heights and weights were collected from 227 people living
in Western Sydney, who had participated in the NSW Health Survey 1997. RESULTS:
Self-reported (SR) weights and heights led to misclassification of relative
weight status. BMI, based on measured weights and heights, classified 62% of
males and 47% of females as overweight or obese, compared with 39% and 32%,
respectively, from self-report. CONCLUSIONS: Caution should be used when
interpreting SR height and weight data from surveys, because BMI derived from
these is likely to underestimate the true prevalence of overweight and obesity.
IMPLICATIONS: SR data have a place in nutrition monitoring because they are
relatively inexpensive and easy to collect. However, classifying people into
weight categories on the basis of accepted cut-points, using SR heights and
weights, yields inaccurate prevalence estimates. Periodic sub-studies of the
validity of SR heights and weights are needed to indicate the extent to which the
validity of SR is changing.
PMID- 10777990
TI - It's time: record linkage--the vision and the reality.
AB - OBJECTIVE: To examine reasons for the minimal use of Australian administrative
health data for research and evaluation. METHOD: Legislative, organisational,
social and political barriers in Australia are described. RESULTS: System changes
are identified that would support the implementation of an evaluation-oriented
health data collection system. A Universal Patient Identifier is essential.
Leadership and funding at the federal level will be required to ensure the co
ordinated introduction of a rational and integrated health data system in
Australia. CONCLUSIONS: Health data in Australia is not currently collected in a
manner that allows the assessment of health outcomes. It is time to change the
basis of health data collection from accounting to health outcomes evaluation and
to reorganise the system to support this. IMPLICATIONS: If appropriate national
health data were available, research and evaluation of services could be
undertaken and treatment outcomes and adverse events could be monitored. Such
information could provide a basis for targeted clinical trials and provide
evidence for best clinical practice.
PMID- 10777991
TI - The emperor's quality clothes: for goodness' sake, let's take the strain off the
word quality!
AB - Quality is a much used word in health care. It clearly has positive connotations.
Yet there is less than clarity in the literature as to what it means. This
article suggests that quality has to have something to do with 'goodness' and
indeed 'betterment'. It then argues that it follows that quality cannot be
defined before we have sorted out 'good' and 'better'. The author appeals for
these terms to be defined.
PMID- 10777992
TI - Tobacco taxes are no insurance against litigation.
PMID- 10777993
TI - The potential public health impact of global environmental change.
PMID- 10777994
TI - Outbreak of cryptosporidiosis in Lancashire.
PMID- 10777995
TI - Sexually transmitted diseases quarterly report: genital chlamydial infection,
ectopic pregnancy, and syphilis in England and Wales.
PMID- 10777996
TI - AIDS and HIV infection in the United Kingdom: monthly report.
PMID- 10777997
TI - Domestic violence and children: analysis and recommendations.
PMID- 10777998
TI - Prevalence and effects of child exposure to domestic violence.
AB - In recent years, researchers have focused attention on children who are exposed
to domestic violence. Although presently there are no scientifically credible
estimates of the national prevalence of children exposed to domestic violence,
existing data suggest that large numbers of American children are affected. This
article discusses the limitations of current databases and describes a promising
model for the collection of reliable and valid prevalence data, the Spousal
Assault Replication Program, which uses data collected through collaboration
between police and university researchers. Research examining the effects of
childhood exposure to domestic violence is also limited by a range of
methodological problems. Despite this, however, sufficient evidence from the body
of studies exists to conclude that such exposure has adverse effects. The
specific effects may differ depending on a host of variables, such as the
children's ages, the nature and severity of the violence, the existence of other
risk factors in the children's lives (for example, poverty, parental substance
abuse), and whether the children are also directly physically abused. In general,
childhood exposure to domestic violence can be associated with increased display
of aggressive behavior, increased emotional problems such as depression and/or
anxiety, lower levels of social competence, and poorer academic functioning. A
scientifically credible body of research on the prevalence and effects of
childhood exposure to domestic violence is necessary to promote the development
of effective interventions and to permit the proper channeling of public and
private funds. This article identifies some of the steps that can be taken to
build the research capacity necessary to obtain the needed data.
PMID- 10777999
TI - The impact of violence on children.
AB - Existing research on the effects of children's exposure to violence covers a
broad range of community, family, and media violence. This research is relevant
and useful to an examination of domestic violence in two key ways. First,
understanding how exposure to various types of violence affects children and what
best enables them to cope can point to important considerations when trying to
help children cope with exposure to domestic violence in particular. And second,
many families experiencing domestic violence are exposed to other types of
violence as well. Exposure to violence on multiple levels can affect the parents'
behavior and can compound the effects on children. This article begins with an
overview of the extent of children's exposure to various types of violence, and
then examines what is known about the effects of this exposure across the
developmental continuum. Key protective factors for children exposed to violence
are examined. Research indicates that the most important resource protecting
children from the negative effects of exposure to violence is a strong
relationship with a competent, caring, positive adult, most often a parent. Yet,
when parents are themselves witnesses to or victims of violence, they may have
difficulty fulfilling this role. In the final section, directions for future
research are discussed.
PMID- 10778000
TI - The impact of federal and state laws on children exposed to domestic violence.
AB - Until recently, few federal and state laws specifically addressed the needs of
children in families in which there is domestic violence. Yet, many laws,
particularly in the areas of domestic violence, family law, child welfare,
welfare reform, and immigration, can have profound effects on the well-being of
these children. The growing understanding by legislators and policymakers of the
potential harms of domestic violence to children has resulted in recent years in
statutory changes, particularly at the state level. However, laws that are
enacted and implemented with inadequate knowledge of the complex dynamics of
domestic violence and the unique issues battered parents and their children face
may have unintended negative consequences for the children these laws are
designed to protect. Collaboration across public and private social service
agencies and domestic violence training for court personnel are examples of
efforts that can bridge this knowledge gap and increase the likelihood that the
protective intent of the laws is carried out in practice. This article analyzes
current and proposed federal and state civil laws to better understand their
potential impact on children affected by domestic violence. A companion article
by Lemon in this journal issue examines court decisions related to these laws.
PMID- 10778001
TI - The legal system's response to children exposed to domestic violence.
AB - Historically, the legal system has not responded adequately, if at all, to cases
involving domestic violence. In the past two decades, U.S. courts and law
enforcement agencies have increasingly acknowledged the seriousness of domestic
violence and have developed responses to it. Unfortunately, the legal system has
been slower to recognize the impact of domestic violence on children. This
article highlights four key areas of case law in which the courts have begun, in
varying degrees, to examine the effects of domestic violence on children: child
custody and visitation, restraining orders, failure to protect a child from harm,
and termination of parental rights. A survey of appellate cases since 1990,
though not representative of all cases, shows an ongoing need for mandatory
judicial training on domestic violence and its effects on children, greater
clarity about how to interpret relevant laws, changes in the laws to better serve
children, and the renewal of national funding for legal aid programs. Courts and
law enforcement agencies in some locales have implemented innovative programs to
improve their interventions with children exposed to domestic violence. These
programs include coordinated court responses, child development training for
police officers, multidisciplinary team approaches, and supervised visitation
centers. However, few of these programs have been evaluated for overall
effectiveness in improving outcomes for children. Better evaluation is needed, as
is ongoing funding for the replication of successful programs nationwide. A
companion article by Matthews in this journal issue examines federal laws and
policies with regard to domestic violence and children, and reviews many of the
state statutes on which the court decisions discussed here are based.
PMID- 10778002
TI - Child protective services and domestic violence.
AB - Studies estimate that domestic violence is present in at least one-third of the
families involved in child protective services (CPS). Yet, until recently, CPS
has not directly addressed domestic violence in its handling of child abuse and
neglect cases. By the same token, domestic violence programs have historically
emphasized services for battered women, with limited understanding of the child
safety goals of CPS. Despite these historical differences, collaborative efforts
between CPS and domestic violence service programs are emerging based on a common
goal of safety from violence for all family members. Innovative strategies
include the use of domestic violence specialists in a variety of child protection
settings for case consultation and for support to the battered women, direct
referrals of battered women from domestic violence programs to family
preservation services, and cross-training of CPS workers and domestic violence
service providers. A survey of state CPS administrators and domestic violence
coalition directors conducted for this article revealed that although there is
mutual interest in greater collaboration, such efforts remain limited. New
forums, such as CPS citizen review panels and community-based CPS partnerships,
hold promise for further collaboration. Critical to successful strategies are
supportive agency leadership, greater trust and understanding across systems, a
recognition of common goals, and a willingness to change policies and practice.
PMID- 10778003
TI - Community-based domestic violence services.
AB - Community-based domestic violence services have grown significantly since their
emergence in the 1970s. Now more than 2,000 in number, domestic violence
organizations have expanded their range of programs. In addition to crisis
oriented services, such as telephone hot lines and temporary shelter, many of
these agencies provide legal, health, mental health, or vocational services or
referrals, and assistance in finding housing, relocating, and planning for
safety. Most recently, in response to increasing knowledge about the deleterious
effects of exposure to domestic violence on children, community-based service
providers have developed programs addressing children's mental health, health,
educational, and safety needs. This article describes and analyzes trends in
service delivery by these community-based organizations to children affected by
domestic violence. It concludes that, although there has been significant growth
in services, substantial segments of the target population still are not reached,
and most organizations do not yet have a sufficient range of services to meet
children's diverse needs. Challenges posed by inadequate funding, needs for
specialized staffing, and a dearth of data on the efficacy of current
intervention programs hamper domestic violence service providers' ability to meet
children's needs. However, this article highlights promising new directions in
service delivery. Community-based domestic violence organizations increasingly
are using innovative strategies to address children's service needs. These
agencies are expanding community outreach efforts and attempts to educate the
public and professionals about domestic violence and children. In addition, these
organizations are building important collaborative relationships with other
agencies concerned with children's welfare, such as child protective services,
law enforcement, schools, and health care facilities. These and related
developments suggest cautious optimism that future years will see continuing
progress in attempts by community-based organizations to address the needs of
children whose well-being is jeopardized by their exposure to domestic violence.
PMID- 10778004
TI - Health care system responses to children exposed to domestic violence.
AB - The health care system has only recently adopted protocols and training to enable
practitioners to identify and respond to victims of domestic violence. Currently,
most hospitals have domestic violence protocols in place, although training in
the use of protocols is less routine. However, because the provision of health
care focuses on the treatment of the individual, the well-being of the children
of adult domestic violence victims has received little attention in adult health
care settings. Pediatricians do not routinely receive training in domestic
violence identification and do not see responding to battered mothers as within
the purview of their practice. Innovative programs in children's hospitals in
Boston, Massachusetts, and San Diego, California, recognize that the safety of
children is integrally tied to the safety of their mothers. These programs
identify abused children whose mothers are the victims of domestic violence and
provide advocacy and support that allow mothers and children to remain together
in most instances. Little is known about the health impacts of teen dating
violence, and opportunities for screening exist in the settings where teens
receive health care. Likewise, prenatal visits provide regularized opportunities
for domestic violence screening. Integrating the health care needs of mothers and
children from violent households will require continued and expanded training,
collaboration with community institutions, and improvements in insurance
reimbursements to cover the costs of needed services.
PMID- 10778005
TI - Mental health services for children who witness domestic violence.
AB - Exposure to domestic violence has significant negative repercussions for
children's social, emotional, and academic functioning. In the past decade,
mental health professionals have developed treatment programs and approaches
aimed at mitigating these deleterious effects. Their efforts, however, are often
hampered by difficulty identifying and gaining access to the target population
because the occurrence of domestic violence remains a family secret in many
households. Clinicians and researchers have published descriptions of group and
individual therapy approaches for children who witness domestic violence. These
approaches share several goals: promoting open discussion about children's
experiences with domestic violence, helping children to deal with the emotions
and consequences that follow such exposure, reducing the problematic symptoms
children experience, strengthening children's relationships with their nonabusive
caregivers, and helping children and their families to create and maintain
relationships and living situations that are free from violence and abuse. One
limitation of the literature describing these interventions is the absence of
controlled outcome studies demonstrating the effects of these programs, in the
short and long terms. Thus, development of such evaluative components is an
important future direction for this field. Some of the other challenges that
confront clinicians include working with children's families, addressing
children's complex and intense emotional experiences, and determining whether
children have themselves been victims of abuse or neglect (and then interfacing
with child protective services).
PMID- 10778006
TI - Emerging strategies in the prevention of domestic violence.
AB - Responses to domestic violence have focused, to date, primarily on intervention
after the problem has already been identified and harm has occurred. There are,
however, new domestic violence prevention strategies emerging, and prevention
approaches from the public health field can serve as models for further
development of these strategies. This article describes two such models. The
first involves public health campaigns that identify and address the underlying
causes of a problem. Although identifying the underlying causes of domestic
violence is difficult--experts do not agree on causation, and several different
theories exist--these theories share some common beliefs that can serve as a
foundation for prevention strategies. The second public health model can be used
to identify opportunities for domestic violence prevention along a continuum of
possible harm: (1) primary prevention to reduce the incidence of the problem
before it occurs; (2) secondary prevention to decrease the prevalence after early
signs of the problem; and (3) tertiary prevention to intervene once the problem
is already clearly evident and causing harm. Examples of primary prevention
include school-based programs that teach students about domestic violence and
alternative conflict-resolution skills, and public education campaigns to
increase awareness of the harms of domestic violence and of services available to
victims. Secondary prevention programs could include home visiting for high-risk
families and community-based programs on dating violence for adolescents referred
through child protective services (CPS). Tertiary prevention includes the many
targeted intervention programs already in place (and described in other articles
in this journal issue). Early evaluations of existing prevention programs show
promise, but results are still preliminary and programs remain small, locally
based, and scattered throughout the United States and Canada. What is needed is a
broadly based, comprehensive prevention strategy that is supported by sound
research and evaluation, receives adequate public backing, and is based on a
policy of zero tolerance for domestic violence.
PMID- 10778007
TI - Domestic violence and children. A selected bibliography.
PMID- 10778008
TI - Introduction to the special section on contemporary relational psychologies and
group therapy.
PMID- 10778009
TI - From identified patient to identifiable group: the alchemy of the group as a
whole.
AB - Group-as-a-whole theory is a relational paradigm of some complexity. Despite the
growing popularity of this perspective, there is abiding confusion about the
essence of group-as-a-whole practice and whether the approach attends
sufficiently to members and part processes. The threefold aims of this article
are to (a) show how group-centered thinking differs essentially from traditional
psychodynamic theory that relies heavily on familial dynamics, interpretation,
and transference analysis; (b) present the mind-set and working principles for a
generic treatment that specifically utilizes collective forces generated in the
context of the group matrix; and (c) compare and contrast the thrust of recent
dyadic relational therapies with group therapy generally and the group-as-a-whole
approach more particularly. The relationship between the whole (group) and its
parts (members and what they bring) is detailed and demonstrated as it appears in
the context of fused, affiliated, fragmented, and differentiated groups.
PMID- 10778010
TI - Intersubjectivity and narcissism in group psychotherapy: how feedback works.
AB - In group psychotherapy, inter-subjectivity is complicated by the number and
quality of therapist-member, member-member, and member-group relations. Inter
member feedback structures the relational process. However, fears of narcissistic
injury engender resistance to this form of engagement. The nature of the
narcissistic belief system that motivates such resistance is discussed. Then, two
models of feedback are presented: the cybernetic and the inter-subjective. In the
cybernetic model, feedback is intended to inform recipients about themselves and
to change their behavior accordingly. As such, this model is consistent with
narcissistic beliefs in the power of others' perceptions to control one's being,
identity, or value. The inter-subjective model focuses, instead, on what feedback
tells recipients about their donors' worlds. This model and some of its
parameters are exemplified clinically.
PMID- 10778011
TI - The use of the self in group leadership: a relational perspective.
AB - This article, written from a relational perspective, describes a shift that is
taking place in the thinking of many psychodynamically oriented psychotherapists
regarding the practice of therapy and the implications it has for group
therapists. The shift, from one-person to two-person and multi-person theory, has
particular importance for group leaders since it recommends making the subjective
involvement of the therapist in the interactional field of the group much more a
part of the treatment process. Theory and research on the use of
countertransference, non-interpretive interventions, humor, and spontaneity by
the leader are reviewed and vignettes are presented to illustrate the application
of these ideas. Guidelines regarding the application of such ideas in group
therapy are also discussed.
PMID- 10778012
TI - Contributions of object relations theory and self psychology to relational
psychology and group psychotherapy.
AB - Object relations theory and self psychology are psychoanalytic perspectives that
are especially concerned with interpersonal relations and their mental
representations. Object relations theory began as an intrapsychic "singleton"
psychology with the work of Freud and Melanie Klein. It subsequently evolved into
a multi-person psychology with the work of Bion on groups, as well as the
clinical and theoretical contributions of Winnicott and Fairbairn. Kohutian self
psychology, which emerged later, has been interested in the relations between the
self and significant others as mirroring and idealizing "self-objects."
Stolorow's "inter-subjective perspective" emerged from self psychology as a full
fledged multi-person point of view. This article considers the significance of
contemporary object relations theory and self psychology as relational, multi
person perspectives in terms of their application to group psychotherapy,
focusing upon the group-as-a-whole, projective identification, transitional space
and object, and self/self-object relations as particularly useful constructs. A
clinical vignette is provided.
PMID- 10778013
TI - Narcissistic leadership in psychotherapy groups.
AB - Narcissistic leaders in groups are capable of impeding progress of their patients
and, at worst, can produce iatrogenic effects. Significant interferences may
occur when the therapist is unable to tolerate the expression of negative
transferences and when they need to be idealized by their patients. The rare
therapist who is a malignant narcissist is capable of inflicting severe damage by
sadistically exploiting the group to satisfy his or her own pathological needs.
Less severe interferences consist of inhibition in making transference
interpretations, reluctance to seek out training or supervision, and a difficulty
in protecting patients against being scapegoated as a result of the displacement
of negative feelings toward the therapist onto a member. The universality of
these issues among therapists is discussed and possible remediation is proposed.
PMID- 10778014
TI - Individual and group psychotherapy with infertile couples.
AB - After reviewing some of the relevant literature, the writers proceed to describe
a new development in psychotherapy for couples presenting with relatively
unexplained infertility. Several couples who had failed to achieve conception
(despite the use of assisted reproductive techniques and personal psychotherapy)
were brought together into a supportive-expressive group led by the writers, an
experienced analytic cotherapy couple. An interesting outcome is described, and
mention made of current plans for a future research project.
PMID- 10778015
TI - Response to special issue on group supervision of group psychotherapy.
PMID- 10778017
TI - New book chronicles history of medicine in Iowa
PMID- 10778016
TI - High-quality, affordable health care.
PMID- 10778018
TI - Old law, new bite mandatory abuse training.
PMID- 10778020
TI - College binge drinking in the 1990s: a continuing problem. Results of the Harvard
School of Public Health 1999 College Alcohol Study.
AB - In 1999, the Harvard School of Public Health College Alcohol Study resurveyed
colleges that participated in the 1993 and 1997 surveys. Responses to mail
questionnaires from more than 14,000 students at 119 nationally representative 4
year colleges in 39 states were compared with responses received in 1997 and
1993. Two of 5 students (44%) were binge drinkers in 1999, the same rate as in
1993. However, both abstention and frequent binge-drinking rates increased
significantly. In 1999, 19% were abstainers, and 23% were frequent binge
drinkers. As before, binge drinkers, and particularly frequent binge drinkers,
were more likely than other students to experience alcohol-related problems. At
colleges with high binge-drinking rates, students who did not binge drink
continued to be at higher risk of encountering the second-hand effects of others'
heavy drinking. The continuing high level of binge drinking is discussed in the
context of the heightened attention and increased actions at colleges. Although
it may take more time for interventions to take effect, the actions college
health providers have undertaken thus far may not be a sufficient response.
PMID- 10778019
TI - The political, social, and public health problems of binge drinking in college.
PMID- 10778021
TI - A campus-community coalition to control alcohol-related problems off campus: an
environmental management case study.
AB - The authors report on the effects of a university and community coalition in
preventing problems related to college students' off-campus drinking. The Albany,
New York, Committee on University and Community Relations used strategies based
on an environmental-management approach that focuses on changing the environment
in which individuals make decisions about alcohol consumption and related
behaviors. Committee initiatives included improving enforcement of local laws and
ordinances, creating a safety-awareness campaign for off-campus students, and
developing a comprehensive advertising and beverage-service agreement with local
tavern owners. The initiatives were associated with a decline in the number of
alcohol-related problems in the community, as indicated by decreases in the
number of off-campus noise ordinance reports filed by police and the number of
calls to a university-maintained hotline for reporting off-campus problems. An
environmental management approach, the authors suggest, has promise as an
effective means of preventing alcohol-related problems among college students.
PMID- 10778022
TI - What colleges are doing about student binge drinking. A survey of college
administrators.
AB - In 1999, the Harvard School of Public Health College Alcohol Study surveyed 734
US college administrators to learn what colleges were doing to prevent binge
drinking. Respondents rated the severity of student alcohol-abuse problems and
described prevention efforts and institutional investments in prevention
infrastructure. Prevention practices were widespread in the areas of general
education about alcohol, use of policy controls to limit access to alcohol,
restricting advertising at home-game sporting events, and allocation of living
space to alcohol-free dormitories. Programming was less prevalent for more
targeted alcohol education, outreach, and restrictions on alcohol advertising in
campus media. Nationally, most of the surveyed colleges reported having a campus
alcohol specialist, many had task forces, and about half were performing in-house
data collection. Less common were program evaluations, community agreements, or
neighborhood exchanges. Prevention practices varied with institutional
characteristics and the surveyed administrators' perceptions of the severity of
alcohol problems.
PMID- 10778023
TI - Suicide ideation among US college students. Associations with other injury risk
behaviors.
AB - Suicide, the endpoint of a continuum that begins with suicide ideation, is the
third leading cause of death among the US college-aged population. The first and
second leading causes of death among this age group, unintentional injury and
homicide, may also be linked to suicide ideation. We used data from the National
College Health Risk Behavior Survey to examine the association between suicide
ideation and injury-related behaviors among 18- to 24-year-old college students.
Students who reported suicide ideation were significantly more likely than
students who did not report considering suicide to carry a weapon, engage in a
physical fight, boat or swim after drinking alcohol, ride with a driver who had
been drinking alcohol, drive after drinking alcohol, and rarely or never used
seat belts. Given this clustering of injury-related risk behaviors, college
prevention programs should aim to reduce risks for injuries comprehensively,
rather than addressing each risk behavior separately.
PMID- 10778024
TI - In praise of feedback: an effective intervention for college students who are
heavy drinkers.
AB - The efficacy of brief motivational feedback to reduce drinking among college
students has been reported by several researchers. As an extension of this
theoretical and applied framework, the author tested the use of mailed feedback
to influence the drinking behavior of students self-identified as moderate-to
heavy drinkers in two randomized trials. A 6-week follow-up of the efforts
suggested the efficacy of the feedback intervention at reducing alcohol
consumption. The feedback mechanism used in the studies is described in detail
and possible reasons for its efficacy are explored. In light of the cost
effective nature of this intervention, it may warrant a place in larger campus
prevention programs.
PMID- 10778025
TI - Living with chronic venous leg ulcers: a descriptive study of knowledge and
functional health status.
AB - A descriptive design was used to identify the functional health status and
knowledge level of individuals living at home with chronic venous leg ulcers (N =
21). Limitations in physical function and vitality were moderate to severe,
impacting on study participants' productive activities and activities of daily
living. Severe to moderate pain was experienced by 19% of the participants. In
addition, knowledge deficits were apparent regarding the cause and treatment of
leg ulcers. Findings of this study suggest the importance of assessing these
factors in addition to the wound when caring for individuals in the community
with chronic venous leg ulcers.
PMID- 10778026
TI - Improving readability of patient education materials.
AB - Functional illiteracy contributes to negative long-term health consequences for
patients who must understand and adhere to complex health care instructions and,
therefore, is of primary importance to community health nurses. This problem is
compounded when English is the patient's second language. A process for improving
patient education materials (PEMs) through adaptation or creation of new
materials to meet the health needs of diverse groups is presented. The process
was applied to a popular health education program used with school-age children
and their parents to teach them home management of asthma. Target parents were
known to read at a 5th-grade level, and English was a second language for many of
them. Therefore, extensive revision of the existing PEMs was required. The steps
to successful revision included assessing readability and comprehensibility,
editing the materials, and evaluating the new PEMs to determine the effectiveness
of the revision measures.
PMID- 10778027
TI - End-of-life care directives among African Americans: lessons learned--a need for
community-centered discussion and education.
AB - African Americans appear to be less likely to know about advance directives and,
even if known, to complete them. This small, exploratory study used a community
centered educational group discussion to assess African Americans' knowledge,
attitudes, and utilization of end-of-life care directives before the occurrence
of a health crisis. McNemar and paired t tests were computed to detect immediate
changes in participants' initial and final perceptions about advance directives
before and after the group discussion. Findings indicated further education is
needed to clarify the terms used for advance directives. African Americans rely
on a family-centered approach to end-of-life decision making, especially in the
absence of written advance directives. They are open to community forums to
discuss end-of-life care choices if presented the opportunity. Culture plays an
essential role in this issue. There is a need for community health nurses to
develop community-based educational programs that are not a "one-size-fits-all"
approach.
PMID- 10778028
TI - Implementation and evaluation of church-based health fairs.
AB - From a comprehensive, community health-needs assessment based on the Neuman
Systems Model (Neuman, 1995), cardiovascular disease was identified as the
priority health concern in one quadrant of a small Midwestern city. The Plan, Do,
Check, Act program planning model (Dees & Garcia, 1995) was the basis for the
planning, implementation, and evaluation of a mini cardiovascular health fair
held at 3 churches. Congruence of the program planning model with the roles of
the clinical specialist in community health nursing is discussed, followed by a
discussion of the health fair goals and objectives, implementation, and formative
and summative evaluations.
PMID- 10778029
TI - Effectiveness of a cardiovascular health promotion education intervention on the
attitudes of urban African American school-age children.
AB - African American children are at risk for high rates of morbidity and mortality
associated with cardiovascular (CV) disease as they become adults, yet little is
known about the effectiveness of CV risk-reduction interventions in African
American children. This study explored the effectiveness of a concentrated CV
health promotion educational program on health-related attitudes of 76 African
American children enrolled in a mid-southern school system. The Children's
Cardiovascular Health Promotion Attitude Scale was used to examine differences in
attitude prior to and 2 weeks following a focused health education intervention.
Results demonstrate that children have preconceived attitudes regarding practice
of health behaviors and that these attitudes are modifiable with age and
developmental level specific educational interventions. Findings indicate the
need for health care providers to assume more active roles in reducing the risk
of future CV disease and death in African Americans through health promotion
education of individuals who influence the development of children's attitudes.
PMID- 10778030
TI - Relationship between breast milk feeding and atopic dermatitis in children.
AB - OBJECTIVE: To determine whether or not the breast milk feeding has a role in the
prevalence of atopic dermatitis among children. METHODS: The target population of
the study was all children participating in health check-up program for 3-year
old children in 60 municipalities locating 10 selected prefectures during
designated 2 months between October and December 1997. Using a questionnaire,
information on nutrition in infants (breast milk only, bottled milk only, or
mixed), parity, mothers' age at birth, and a history of atopic dermatitis was
obtained. Besides, data on potential confounding factors were obtained. RESULTS:
Questionnaires from 3856 children (81.6% of those who were to participate in the
programs, and 96.4% of children who participated them) were analyzed. After the
adjustment for all potential confounding factors using unconditional logistic
models, the risk of atopic dermatitis was slightly higher among children with
breast milk (odds ratio [OR] = 1.16 with 95% confidence interval [CI] 0.96-1.40).
Mothers' age at birth (OR for those who were more than 30 years or older in
comparison with those who were younger than 30 years = 1.15; 95% CI, 0.96-1.37)
and those with second or later parity orders (OR = 1.14, 95% CI; 0.95-1.35)
showed odds ratios that were higher than unity without statistical significance.
CONCLUSION: Breast milk elevates the risk of atopic dermatitis slightly without
statistical significance; the risk may be, however, higher in children in second
or later parity orders.
PMID- 10778031
TI - Prevalence of sleep disturbance and hypnotic medication use in relation to
sociodemographic factors in the general Japanese adult population.
AB - This study was the first nationwide population-based study to estimate the
prevalence rates of sleep disturbance and hypnotic medication use in the general
Japanese adult population. In 1997, 2,800 Japanese adults aged 20 years and over
were randomly selected from the 1995 Census and 1,871 were examined using the
Pittsburgh Sleep Quality Index. The respective estimated overall prevalences of
insomnia (INS), difficulty initiating sleep (DIS), difficulty maintaining sleep
(DMS), poor perceived quality of sleep (PQS) and hypnotic medication use (HMU)
were 17.3%, 8.6%, 12.9%, 17.8%, and 3.5% in males and 21.5%, 12.6%, 16.2%, 20.2%
and 5.4% in females. Among males, DIS (OR = 2.76) and PQS (OR = 2.12) were
associated with never having married. DMS was associated with being 60 years and
older (OR = 2.68) or divorced/separated (OR = 3.74). Among females, DMS was
associated with being widowed (OR = 1.65), unemployed (OR = 1.60), 40 to 59 years
old (OR = 0.57) or never having married (OR = 0.39). DIS was associated with
being widowed (OR = 1.67) or unemployed (OR = 1.58). HMU was associated with
advancing age (OR = 8.26-10.7), being widowed (OR = 2.12) or never having married
(OR = 2.84). PQS was associated with advancing age (OR = 0.63-0.50). Our study
showed sleep disturbance and hypnotic medication use were prevalent among
Japanese adults and some sociodemographic factors contributed to them.
PMID- 10778032
TI - Sleep patterns and total mortality: a 12-year follow-up study in Japan.
AB - A population-based cohort study was conducted to assess the relationship between
total mortality and self-reported sleep patterns as regards not only to sleep
duration but also subjective sleep quality. A total of 5,322 inhabitants in Gifu
Prefecture, Japan, completed a self-administered questionnaire on health status
and lifestyles including habitual sleep patterns, and were followed-up for an
average of 11.9 years. Relative risks were computed by using Cox proportional
hazards models. Both longer and shorter sleep, compared to 7-8 hour-sleep, was
related to significantly increased risk of total mortality in males (relative
risk [RR] for > or = 10 hours = 1.94, and RR for < 7 hour = 1.90), but not in
females. Females complaining of poor awakening state experienced a higher
mortality risk compared to those who woke up normally (RR: 1.97). Males who
usually fell asleep easily showed a marginally lower mortality risk compared to
those who fell asleep normally (RR: 0.70). Female users of sleeping pills were at
an elevated risk (RR: 1.89). These findings were almost unchanged after
adjustment for sleep duration and other confounders. Poor self-reported quality
of sleep seemed to be associated with an increased risk of mortality
independently of sleep duration.
PMID- 10778034
TI - Weight gain in adulthood and risk of developing glucose tolerance disturbance: a
study of a Japanese-Brazilian population. Japanese-Brazilian Diabetes Study
Group.
AB - We examined the data from 530 subjects enrolled in a survey on the prevalence of
diabetes in a Japanese-Brazilian population aged 40-79 years. Past self-reported
and current weight values were analysed. Student t test was used to compare
anthropometric measures between subjects with and without disturbance of glucose
tolerance (DGT), hypertension and dyslipidemia. Point and interval estimates of
the weight at 20 years-, age- and sex-adjusted odds ratios (OR) were obtained by
logistic regression analysis to evaluate the relationship between these diseases
and the percent weight gain. Subjects with DGT, hypertension or dyslipidemia
tended to have higher BMI during adulthood and to gain more weight in a shorter
interval of time. Also, they presented higher waist-to-hip ratio and plasma
glucose and worse lipid profile. OR were consistent with associations between
chronic diseases and percent weight gain. Trend test of OR indicated that the
risk of developing DGT alone or combined with hypertension and abdominal obesity
increased 2% and 15% by percent unit of gained weight, respectively, as compared
with those subjects with stable weight. Weight gain and the rate by which this
occurs during lifetime may confer increased risk of chronic diseases. We
suggested that preventive measures against obesity, i.e. the maintenance of
healthy body weight lifelong, are necessary to minimize the occurrence of these
diseases, also among migrant populations such as the Japanese-Brazilians.
PMID- 10778033
TI - Characteristics of receipt rate of financial aid for intractable disease patients
in Gifu Prefecture, Japan.
AB - The data on intractable disease patients who applied for official financial aid
for medical treatment in Gifu Prefecture, Japan, in fiscal year 1997 were
analyzed. In addition, to assess the nonapplied patients, a questionnaire on
intractable disease patients with disabilities needing assistance was sent to all
medical institutions in the prefecture. The results suggest that the low receipt
rate of financial aid in Gifu Prefecture results from both nonapplication by
patients and underdiagnosis at medical institutions. Percent completion of
medical treatment for intractable disease patients in a single secondary medical
service area was low. Although the percentage of patients with disabilities
authorized to receive financial aid was 4.6%, the estimated ratio of patients
with disabilities needing assistance exceeded this value. Therefore, the
dissemination of information on official services for patients and medical care
facilities must be strengthened.
PMID- 10778035
TI - Dietary patterns in a high-risk population for glucose intolerance. Japanese
Brazilian Diabetes Study Group.
AB - We evaluated dietary habits as risk factor for glucose intolerance in a high risk
population of Japanese-Brazilians enrolled in a study on the prevalence of
diabetes (DM). Based on oral glucose tolerance test and WHO criteria, 331 had
normal tolerance (NGT), 88 impaired tolerance (IGT) and 83 had type 2 DM (51 self
reported, 32 newly diagnosed diabetics). Clinical, laboratory and dietary data,
assessed by food frequency questionnaire (FFQ), were compared between the NGT
group and another composed of IGT and newly diagnosed DM (disturbed glucose
tolerance or DGT group). Associations of total energy intake and nutrient intakes
with glucose intolerance were analyzed by logistic regression. Also, subjects
with NGT and DGT entered into separate models of multiple linear regression
including BMI as the dependent variable, and total energy intake or each nutrient
as independent variables. DGT group showed higher waist-to-hip ratio, blood
pressure, plasma glucose and insulin levels and worse lipid profile. Total energy
intake, macronutrients, fibers, alcohol and saturated fat intakes did not differ
between groups; DGT was not associated with any nutrient intake in multivariate
analyses. BMI of the subjects with DGT but not with NGT was associated with
protein and cholesterol intakes in linear regression analysis. Our findings did
not support an association between nutritional factors and glucose intolerance
even in subjects who are unaware of their DGT, using FFQ to reflect current
habits. However, we suggest that protein and cholesterol intakes may be markers
of increased BMI. Despite assuming that obesity and insulin resistance precedes
DM, FFQ may not be useful in the assessment of unfavorable dietary patterns among
subjects at risk for glucose intolerance, such as Japanese-Brazilians with
elevated BMI.
PMID- 10778036
TI - Validity and reliability of the Japanese version of the selected anger expression
scale and age, sex, occupation and regional differences in anger expression among
Japanese.
AB - To examine the reliability and construct validity of the Japanese version of the
Anger Expression Scale among four Japanese communities, and to examine
distributions of anger expression scores according to sex, age, occupation, and
community, we performed a cross-sectional study among 1,802 men and 3,229 women
aged 20-70 in four geographic populations in 1995-97. We handed a self
administered questionnaire, which was selected from the Spielberger Anger
Expression Scale, to the participants in the risk factor surveys and measured
anger-in and anger-out as the anger expression scale. These scales had high
internal consistency (Cronbach's alpha coefficient was 0.97-0.98 for anger-out
and 0.77-0.86 for anger-in) and were of almost the same structure as the
original. The Pearson correlation coefficients for the anger expression scale
examined in 1995 and 1996 were 0.69 for anger-out and 0.57 for anger-in (both p <
0.001). The mean scores of both anger-out and anger-in were inversely associated
with age. The mean anger-out score was higher for men than for women (p < 0.001),
whereas the mean anger-in score did not vary significantly between the sexes.
Furthermore, the mean scores of anger-out and anger-in varied among populations
and occupational groups. The present study suggests that the Japanese version of
the selected Anger Expression Scale is an acceptable scale for evaluating anger
expression among Japanese.
PMID- 10778037
TI - Erythrocyte sedimentation rate in healthy school children of Bangladesh.
AB - The reference value of erythrocyte sedimentation rate (ESR) should be established
for a population concerned because it is influenced by many local conditions. It
has not yet been determined in healthy children of Bangladesh. This study was
done to determine the reference value of ESR in Bangladeshi children. ESR was
determined in a sample of 413 'healthy' primary school students (259 boys and 154
girls, mean age 8.7 years). Ninety-five percent of them had ESR < or = 30 mm
(Westergren 1 h). Our findings suggest that ESR value > 30 mm (Westergren 1 h)
should be considered high in Bangladeshi primary school children.
PMID- 10778038
TI - Comparison of isoflavones among dietary intake, plasma concentration and urinary
excretion for accurate estimation of phytoestrogen intake.
AB - Biological effects of dietary isoflavones, such as daidzein and genistein are of
interest in preventive medicine. We estimated the dietary intake of isoflavones
from dietary records and compared the values with the plasma concentrations and
urinary excretions in Japanese middle-aged women. The dietary intake of daidzein
and genistein was 64.6 and 111.6 mumol /day/capita (16.4 and 30.1 mg/day/capita),
respectively. The isoflavones intake was mostly attributable to tofu, natto and
miso. The median of plasma daidzein and genistein concentration was 72.46 and
206.09 nmol/L, respectively. The median of urinary excretion was 20.54 mumol /day
for daidzein, 10.79 for genistein, 15.74 for equol and 1.64 for O
desmethylangolensin (O-DMA). Equol and O-DMA were excreted by 50% and 84% of all
participants, respectively. Equol metabolizers were significantly lower the
plasma and urinary daidzein and urinary O-DMA. The dietary intake of daidzein and
genistein after the adjustment for total energy intake was significantly
correlated with the urinary excretion (r = 0.365 for daidzein and r = 0.346 for
genistein) and plasma concentration (r = 0.335 for daidzein and r = 0.429 for
genistein). The plasma concentration of isoflavones was also significantly
correlated with the urinary excretion. We conclude that in epidemiological
studies measurements of plasma concentration or urinary excretion of these
isoflavones are useful biomarkers of dietary intake and important for studies on
their relation to human health.
PMID- 10778039
TI - A managed care insurance product for the uninsured: a case study.
PMID- 10778040
TI - Exploring the role of religiosity in hypertension management among African
Americans.
AB - The role of religiosity in hypertension management among African Americans was
studied. Data were collected from in-depth, personal interviews with 20 African
Americans who had been diagnosed with hypertension for at least one year. A
majority of the participants used their religious beliefs as protective, control,
and coping mechanisms in the management of hypertension. Their personal religious
commitment enabled them to feel protected from immediate and long-term negative
consequences of hypertension, as well as find meaning in and exert control over
hypertension management. Furthermore, religious beliefs served to enhance their
ability to cope with having hypertension. These findings support the utility and
value of religiosity in the management of hypertension among African Americans.
Implications for hypertension management and educational interventions are
offered.
PMID- 10778041
TI - Barriers to health care for abused Latina and Asian immigrant women.
AB - This study identifies social, political, and cultural barriers to help seeking
from health care organizations faced by abused Latina and Asian immigrant women.
Qualitative data were collected through four semistructured ethnic-specific focus
group interviews with 28 abused Latina and Asian immigrant women. Participants
who had suffered intimate partner abuse were recruited through urban community
based organizations in San Francisco, California. Sociopolitical barriers to help
seeking and patient-provider communication included social isolation, language
barriers, and, for some, discrimination and fears of deportation. Sociocultural
barriers included dedication to the children and family unity, shame related to
the abuse, and the cultural stigma of divorce. Abused Latina and Asian immigrant
women face significant social, cultural, and political barriers to patient
provider communication and help seeking. Medical and social service providers and
policy makers may improve the quality of care for these women by understanding
and addressing these barriers.
PMID- 10778042
TI - Difficulty in reaching low-income women for screening mammography.
AB - Low-income women have a high mortality from breast cancer. Yet, they participate
in breast cancer early detection screening programs less than women in the
general population. An intervention study to improve screening mammography rates
of low-income women participating in Tennessee's TennCare program (state Medicaid
and Medicare program) revealed significant barriers to reaching these women.
Intervention methods included mail, telephone calls, and home visits. Results
indicate that only 38 percent of the women could be contacted for a baseline
survey. Reasons for noncontact included absence from home (39 percent), having
moved (22 percent), refusal to participate (17 percent), having no physical
domicile (15 percent), language barriers (4 percent), and miscellaneous other
factors (4 percent). Women with telephones tended to have a relatively higher
economic status and were more successfully reached than women without telephones.
These findings provide useful insights for future program planning and research
design.
PMID- 10778043
TI - Health status measurement performance and health status differences by age,
ethnicity, and gender: assessment in the medical outcomes study.
AB - The comparative measurement performance of self-reported health status
instruments for African American and Hispanic elderly has rarely been studied,
despite evidence of their poor health status. This study examined psychometric
performance and health status differences by age, ethnicity, and gender among
10,569 ethnically diverse patients who completed the Short-Form General Health
Survey in the Medical Outcomes Study (MOS). Hispanics and African Americans
tended to have slightly lower measurement performance than other ethnic groups.
Compared with whites, health status scores for African American and Hispanic
women were slightly but significantly lower. The small differences in health
status by ethnicity may be due to the MOS sampling strategy, which excluded low
socioeconomic status minorities with poor education and no regular medical care.
The psychometric performance of MOS health status measures should be examined in
studies of ethnically diverse, community-dwelling, elderly populations who have
poor access to care, poor education, and/or low socioeconomic status.
PMID- 10778044
TI - Determining needs and setting priorities for HIV-affected and HIV-infected
persons: northeast Ohio and San Diego.
AB - The Ryan White Comprehensive AIDS Resources Emergency (CARE) Act of 1991 requires
that communities receiving Title I funding engage in a needs assessment and
priority process to guide the allocation of those funds to various services
within the local community. This paper reports on the process and results of the
needs assessments in northeast Ohio and San Diego County for 1996-1997 and 1998.
Data from northeast Ohio's 1998 needs assessment indicated significant
differences between whites and nonwhites in the utilization of HIV specialist
care, HIV-related prescription medications such as antiretrovirals, and health
insurance. A need for additional dental care, complementary therapies, housing,
and assistance with utility payments was found in both geographic areas. Consumer
participation in San Diego's health department-based needs assessment process was
more extensive than in northeast Ohio's academic-based approach but was also
related to increased community-borne expense.
PMID- 10778045
TI - Frailty, family, and church support among urban African American elderly.
AB - A community-based survey of 507 African Americans aged 60 and older from South
Central Los Angeles was conducted to estimate the prevalence of frailty and
describe the correlation between frailty, social support from family and church,
and use of community services. Persons were considered frail if they met criteria
for any of four conditions: functional impairment, depression, urinary
incontinence, falls. Sixty-seven percent met criteria for frailty. Analyses
revealed that frail elderly were significantly less likely to report feeling very
close to family. Family contact, feeling that church was important, and receiving
church support were similar for the frail and nonfrail. Frail elderly were more
likely to use community services. These findings suggest that frail elderly in
this population may not receive more support from family and church than nonfrail
elderly. There is a need for caution when assuming families and churches in urban
African American communities are able to support the most vulnerable elderly.
PMID- 10778046
TI - The influences of race, ethnicity, and poverty on the mental health of children.
AB - Sufficient evidence demonstrates that poverty has a negative effect on the
psychological well-being of children, but most research has focused only on white
populations. The purpose of this literature review is to gain a better
understanding of the positive and negative influences of socioeconomic factors,
cultural/ethnic characteristics, and racial differences on the mental health of
children. A review of the literature on the influence of race, ethnicity, and
poverty on the mental health of children found that (1) children whose parents
are in poverty or who have experienced severe economic losses are more likely to
report or be reported to have higher rates of depression, anxiety, and antisocial
behaviors; and (2) after controlling for socioeconomic status, African Americans,
Native Americans, and Hispanics are less likely to report or be reported to have
such mental health problems. A theoretical construct for this protective effect
is related to cultural factors, such as perceived social support, deep
religiosity/spirituality, extended families, and maternal coping strategies as
buffers against psychological distress.
PMID- 10778047
TI - [Growth hormone (GH, hGH)].
PMID- 10778048
TI - [Growth hormone-releasing hormone (GHRH)].
PMID- 10778049
TI - [Somatostatin].
PMID- 10778050
TI - [Insulin like growth factor-I and II].
PMID- 10778051
TI - [Insulin-like growth factor binding protein-3 (IGFBP-3)].
PMID- 10778052
TI - [Growth hormone-binding protein].
PMID- 10778053
TI - [Luteinizing hormone (LH)].
PMID- 10778054
TI - [Follicle stimulating hormone (FSH)].
PMID- 10778055
TI - [Gonadotropin releasing hormone (GnRH)].
PMID- 10778056
TI - [Adrenocorticotropic hormone (ACTH)].
PMID- 10778057
TI - [Corticotropin-releasing hormone (CRH)].
PMID- 10778058
TI - [Lipotropins (LPH) and melanocyte-stimulating hormone (MSH)].
PMID- 10778059
TI - [Met5-enkephalin, Leu5-enkephalin].
PMID- 10778060
TI - [Beta-endorphin].
PMID- 10778061
TI - [Thyroid stimulating hormone (TSH)].
PMID- 10778062
TI - [Thyrotropin releasing hormone (TRH)].
PMID- 10778063
TI - [Prolactin (PRL)].
PMID- 10778064
TI - [Arginine vasopressin].
PMID- 10778065
TI - [Oxytocin (OT)].
PMID- 10778066
TI - [Neurophysin].
PMID- 10778067
TI - [Neurotensin].
PMID- 10778068
TI - [Total thyroxine (T4), free thyroxine (FT4)].
PMID- 10778069
TI - [Total triiodothyronine (T3), free triiodothyronine (FT3), reverse
triiodothyronine (rT3)].
PMID- 10778070
TI - [Monoiodothyronine and diiodothyronine].
PMID- 10778071
TI - [Thyroglobulin (Tg)].
PMID- 10778072
TI - [Thyroxine binding globulin (TBG)].
PMID- 10778073
TI - [Thyroxine binding capacity (TBC)].
PMID- 10778074
TI - [TSH receptor antibodies].
PMID- 10778075
TI - [Antithyroglobulin antibodies and antimicrosomal antibodies].
PMID- 10778076
TI - [Antithyroid peroxidase antibodies].
PMID- 10778077
TI - [Parathyroid hormone (PTH)].
PMID- 10778078
TI - [Parathyroid hormone-related protein (PTHrP)].
PMID- 10778079
TI - [Calcitonin (CT)].
PMID- 10778080
TI - [Calcitonin gene-related peptide (CGRP)].
PMID- 10778081
TI - [Serum cortisol, cortisone and free cortisol in urine].
PMID- 10778082
TI - [11-deoxycortisol and 21-deoxycortisol].
PMID- 10778083
TI - [18-hydroxycortisol, 18-oxocortisol, and 6 beta-hydroxycortisol].
PMID- 10778084
TI - [Corticosterone].
PMID- 10778085
TI - [11-deoxycorticosterone (DOC) and 18-OH-DOC].
PMID- 10778086
TI - [18-hydroxycorticosterone (18-OH-B)].
PMID- 10778087
TI - [Aldosterone].
PMID- 10778088
TI - [Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S)].
PMID- 10778089
TI - [Pregnenolone, pregnenolone sulfate].
PMID- 10778090
TI - [17 alpha-Hydroxypregnenolone].
PMID- 10778091
TI - [17 alpha-Hydroxyprogesterone].
PMID- 10778092
TI - [Androstenedione].
PMID- 10778093
TI - [Androsterone].
PMID- 10778094
TI - [Etiocholanolone].
PMID- 10778095
TI - [Corticosteroid-binding globulin (CBG): measurement and its clinical
implication].
PMID- 10778096
TI - [11-hydroxycorticosteroid (11-OHCS)].
PMID- 10778097
TI - [17-hydroxycorticoids (17-OHCS) and its fractions].
PMID- 10778098
TI - [Urinary 17-ketosteroids (17-KS) and 17-KS fractions].
PMID- 10778099
TI - [Urinary 17-ketogenic steroids (17-KGS) and 17-KGS fractions].
PMID- 10778100
TI - [Urinary tetrahydro-11-deoxycortisol (THS)].
PMID- 10778101
TI - [Catecholamine].
PMID- 10778102
TI - [3,4-dihydroxyphenylalanine (DOPA)].
PMID- 10778103
TI - [Dopamine].
PMID- 10778104
TI - [Dopamine-beta-hydroxylase (DBH)].
PMID- 10778105
TI - [Metanephrine (M) and normetanephrine (NM)].
PMID- 10778106
TI - [Vanillylmandelic acid (VMA) and homovanillic acid (HVA)].
PMID- 10778107
TI - [3-methoxy-4-hydroxyphenylglycol (MHPG)].
PMID- 10778108
TI - [3,4-dihydroxyphenylacetic acid (DOPAC)].
PMID- 10778109
TI - [Chromogranin A, chromogranin B, chromogranin C].
PMID- 10778110
TI - [Serotonin (5-hydroxytriptamine; 5HT)].
PMID- 10778111
TI - [5-hydroxyindole acetic acid (5HIAA)].
PMID- 10778112
TI - [Neuropeptide Y].
PMID- 10778114
TI - [Catecholestrogen].
PMID- 10778113
TI - [Estrogen: estrone (E1), estradiol (E2), estriol (E3) and estetrol (4)].
PMID- 10778115
TI - [Progesterone].
PMID- 10778116
TI - [Pregnanediol (P2), pregnanetriol (P3)].
PMID- 10778117
TI - [Total testosterone, free testosterone].
PMID- 10778118
TI - [5 alpha-Dihydrotestosterone (DHT)].
PMID- 10778119
TI - [Androstanediol, androstanediol glucuronide].
PMID- 10778120
TI - [Sex hormone-binding globulin (SHBG)].
PMID- 10778121
TI - [Human chorionic gonadotropin (hCG) and subunits].
PMID- 10778122
TI - [Human placental lactogen (hPL)].
PMID- 10778123
TI - [Inhibin and activin].
PMID- 10778124
TI - [Insulin and abnormal insulin].
PMID- 10778125
TI - [Proinsulin].
PMID- 10778126
TI - [C-peptide (CPR)].
PMID- 10778127
TI - [Pancreatic glucagon].
PMID- 10778128
TI - [Enteroglucagon (EG)].
PMID- 10778129
TI - [GLP-1 (glucagon-like peptide 1)].
PMID- 10778130
TI - [Gastrin].
PMID- 10778131
TI - [Vasoactive intestinal polypeptide (VIP)].
PMID- 10778132
TI - [Cholecystokinin.pancreozymin (CCK-PZ)].
PMID- 10778133
TI - [Substance P].
PMID- 10778134
TI - [Secretin].
PMID- 10778135
TI - [Motilin].
PMID- 10778136
TI - [Human pancreatic polypeptide (hPP)].
PMID- 10778137
TI - [Pancreatic polypeptide (PP)].
PMID- 10778138
TI - [Gastric inhibitory polypeptide (GIP)].
PMID- 10778139
TI - [Insulin antibody].
PMID- 10778140
TI - [Anti-insulin receptor antibody].
PMID- 10778141
TI - [Islet cell antibody (ICA), islet cell surface antibody (ICSA)].
PMID- 10778142
TI - [GAD antibodies, GAD65 antibody].
PMID- 10778143
TI - [Plasma renin activity (PRA) and active renin concentration (ARC)].
PMID- 10778144
TI - [Angiotensin I, angiotensin II, angiotensin III].
PMID- 10778145
TI - [Erythropoietin].
PMID- 10778146
TI - [Kallikrein, kininogen and kinin in health and disease].
PMID- 10778147
TI - [Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP)].
PMID- 10778148
TI - [Endothelin].
PMID- 10778149
TI - [Melatonin].
PMID- 10778150
TI - [Leptin].
PMID- 10778151
TI - [Cyclic AMP (cAMP)].
PMID- 10778152
TI - [Cyclic GMP (cGMP)].
PMID- 10778153
TI - [Thrombopoietin (TPO)].
PMID- 10778155
TI - [The integrin family].
PMID- 10778154
TI - [Immunoglobulin super family (ICAM, VCAM, NCAM)].
PMID- 10778156
TI - [Selectin family (E-selectin, P-selectin, L-selectin)].
PMID- 10778157
TI - [Cadherin].
PMID- 10778158
TI - [alpha-Fetoprotein (AFP)].
PMID- 10778159
TI - [Basic fetoprotein (BFP)].
PMID- 10778160
TI - [Carcinoembryonic antigen (CEA)].
PMID- 10778161
TI - [CEA (carcinoembryonic antigen) in nipple discharge].
PMID- 10778162
TI - [Pancreatic oncofetal antigen (POA), pancreatic cancer-associated antigen
(PCAA)].
PMID- 10778163
TI - [CA125].
PMID- 10778164
TI - [CA19-9].
PMID- 10778165
TI - [CA50].
PMID- 10778166
TI - [CA130].
PMID- 10778167
TI - [CA546, CA602].
PMID- 10778168
TI - [CA15-3].
PMID- 10778169
TI - [CYFRA21-1].
PMID- 10778170
TI - [Sialyl Tn antigen].
PMID- 10778171
TI - [2-->6 sialyl Lea antigen].
PMID- 10778172
TI - [BCA225].
PMID- 10778173
TI - [CA72-4 (TAG72)].
PMID- 10778174
TI - [Sialyl SSEA-1 (SLX)].
PMID- 10778175
TI - [NCC-ST-439].
PMID- 10778176
TI - [SCC antigen].
PMID- 10778177
TI - [DU-PAN-2, SPan-1].
PMID- 10778178
TI - [KMO1].
PMID- 10778179
TI - [Prostate-specific antigen (PSA) and PSA-ACT].
PMID- 10778180
TI - [Gamma-Sm].
PMID- 10778181
TI - [Prostatic acid phosphatase (PAP)].
PMID- 10778182
TI - [Tissue polypeptide antigen (TPA)].
PMID- 10778183
TI - [Immunosuppressive acidic protein (IAP)].
PMID- 10778184
TI - [PIVKA-II].
PMID- 10778185
TI - [Neuron specific enolase (NSE)].
PMID- 10778186
TI - [Elastase 1].
PMID- 10778187
TI - [5'-nucleotide phosphodiesterase isoenzyme-V (5'-NPD-V)].
PMID- 10778188
TI - [GAT (galactosyltransferase associated with tumor)].
PMID- 10778189
TI - [Small intestinal mucin antigen (SIMA)].
PMID- 10778190
TI - [Pregnancy specific beta 1 glycoprotein (SP-1)].
PMID- 10778191
TI - [Isoferritin].
PMID- 10778192
TI - [GSA-2-binding glycoprotein (GBG) and GSA-2-binding glycoprotein 2 (GBG2)].
PMID- 10778193
TI - [Pepsinogen I and II].
PMID- 10778194
TI - [Polyamine and ODC].
PMID- 10778195
TI - [Neopterin].
PMID- 10778196
TI - [Pro-gastrin-releasing peptide].
PMID- 10778197
TI - [Estrogen and progesterone receptors].
PMID- 10778198
TI - [Human chorionic gonadotropin beta-core fragment (hCG beta-cf)].
PMID- 10778199
TI - [Basic fibroblast growth factor in urine].
PMID- 10778200
TI - [Human urinary trypsin inhibitor].
PMID- 10778201
TI - [Free L-fucose (UFC) and sulfated bile acids in urine (U-SBA)].
PMID- 10778202
TI - [Urinary melanogen].
PMID- 10778203
TI - [Urinary BTA (bladder tumor antigen)].
PMID- 10778204
TI - [Urinary NMP22].
PMID- 10778205
TI - [Genetic testing as clinical tests].
PMID- 10778206
TI - [Introduction: maternal serum marker test for Down syndrome--present and
problems].
PMID- 10778207
TI - [The referral reasons of chromosome analysis and selection of samples].
PMID- 10778208
TI - [Method of chromosome analysis and karyotype description].
PMID- 10778209
TI - [Various methods of chromosome abnormality detection by DNA technology].
PMID- 10778210
TI - [Chromosome abnormalities and their clinical significance in leukemia and
lymphoma].
PMID- 10778211
TI - [Chromosome analysis of solid tumors using recent molecular-cytogenetic
techniques].
PMID- 10778212
TI - [Chromosomal analysis in congenital malformation syndromes].
PMID- 10778213
TI - [Indications of DNA diagnosis, clinical samples and storage].
PMID- 10778214
TI - [Genetic analysis--detection methods of genetic mutation].
PMID- 10778215
TI - [Methods of the detection for rearrangement of genes and its clinical relevancy].
PMID- 10778216
TI - [Significance of genetic diagnosis with oncogen and suppressor gene].
PMID- 10778217
TI - [DNA diagnosis of inborn errors of metabolism].
PMID- 10778218
TI - [Genetic analysis of malignant solid tumors].
PMID- 10778219
TI - [The genetic diagnosis of hematopoietic tumors].
PMID- 10778220
TI - [Gene diagnosis of hereditary hematological disorders].
PMID- 10778221
TI - [Molecular genetic diagnosis of muscle diseases].
PMID- 10778222
TI - [Genetic testing of triplet repeat disease].
PMID- 10778223
TI - [Genetics of neurologic disorders in children].
PMID- 10778224
TI - [Genetic diagnosis for the infectious diseases--a nonradioactive PCR-SSCP
technique].
PMID- 10778225
TI - [Genetic diagnosis of respiratory diseases].
PMID- 10778226
TI - [Molecular diagnosis of human gastrointestinal cancer].
PMID- 10778227
TI - [Hereditary assessment of cardiovascular disease].
PMID- 10778228
TI - [Genetic diagnosis of renal diseases].
PMID- 10778229
TI - [Molecular diagnosis of endocrine diseases].
PMID- 10778230
TI - [Gene mutation associated with diabetes mellitus].
PMID- 10778231
TI - [Genetic analysis of collagen diseases: rheumatic diseases].
PMID- 10778233
TI - [Nitric oxide and its related compounds].
PMID- 10778232
TI - [Analysis of atopic gene].
PMID- 10778235
TI - [NO3- in blood].
PMID- 10778234
TI - [Active oxygen].
PMID- 10778236
TI - [Allantoin].
PMID- 10778237
TI - [KL-6 antigen].
PMID- 10778238
TI - [Palmitoleic acid].
PMID- 10778239
TI - [Cholylglycine (CG)].
PMID- 10778240
TI - [Lysophospholipids].
PMID- 10778241
TI - [Serum nuclear matrix proteins (NMPs)].
PMID- 10778242
TI - Use of the MMPI-2's VRIN scale with severely disturbed populations: consistent
responding may be more problematic than inconsistent responding.
AB - The Minnesota Multiphasic Personality Inventory--Second Edition includes a new
validity scale, the VRIN scale, intended to detect random responding. High scores
are viewed as casting suspicion on the validity of the profile. For the present
study, the authors evaluated some of the complexities of the VRIN scale including
its interaction with the F scale. In particular, we tested two hypotheses. First
is that among psychotically disturbed test takers, some inconsistent responding
is an integral and expected mode of responding to a self-report measure. That is,
in an inpatient psychiatric population increased confused responding (high VRIN
score) is related in predictable ways to increased endorsement of psychotic
scales and two-point codes and to increased psychotic diagnoses. The second
hypothesis is a corollary--that the absence of inconsistency (low VRIN) in a
protocol indicating acute distress (high F) may indicate that a respondent is
being too consistent in presenting self as having severe difficulties. In this
case, the rest of the protocol may be an exaggerated description of the clinical
presentation. A sample of 521 psychiatric inpatients was used to evaluate these
hypotheses. Some support for both hypotheses is reported. Further studies are
recommended to evaluate the hypotheses.
PMID- 10778243
TI - Relationship between relaxation by guided imagery and performance of working
memory.
AB - This study tested the hypothesis that relaxation by guided imagery improves
working-memory performance of healthy participants. 30 volunteers (both sexes,
ages 17-56 years) were randomly assigned to one of three groups and administered
the WAIS-III Letter-Number Sequencing Test before and after 10-min. treatment
with guided imagery or popular music. The control group received no treatment.
Groups' test scores were not different before treatment. The mean increased after
relaxation by guided imagery but not after music or no treatment. This result
supports the hypothesis that working-memory scores on the test are enhanced by
guided imagery and implies that human information processing may be enhanced by
prior relaxation.
PMID- 10778244
TI - Program review of community residential care.
AB - This article provides an overview of the Department of Veterans Affairs Community
Residential Care Program and summarizes key literature about programs developed
in the United States. Descriptive data for 1995 and 1996 are provided to assist
program planners in comparing and contrasting client characteristics and
services. The authors conclude that, in addition to being cost effective, the
residential care program strengthens relationships between the health care
facility and the community it serves.
PMID- 10778245
TI - Vocational students' learning preferences: the interpretability of ipsative data.
AB - A number of researchers have argued that ipsative data are not suitable for
statistical procedures designed for normative data. Others have argued that the
interpretability of such analyses of ipsative data are little affected where the
number of variables and the sample size are sufficiently large. The research
reported here represents a factor analysis of the scores on the Canfield Learning
Styles Inventory for 1,252 students in vocational education. The results of the
factor analysis of these ipsative data were examined in a context of existing
theory and research on vocational students and lend support to the argument that
the factor analysis of ipsative data can provide sensibly interpretable results.
PMID- 10778247
TI - The role of aesthetic experience in changing selves.
AB - Some rapprochement between psychology and the arts may have therapeutic potential
as well as offer a basis for positive social interaction more generally. A simple
proposal is offered as a foundation.
PMID- 10778246
TI - Relationships between psychological variables relevant to asthma and patients'
quality of life.
AB - The relationships between health-related quality of life and various
psychological variables relevant to the clinical evolution of bronchial asthma
were evaluated for 101 asthma patients ages 14 to 72 years. Scores on quality of
life exhibited a significant negative correlation with perceived vulnerability,
panic-fear personality, and irritability, fatigue, airway obstruction,
hyperventilation, and panic-fear during attacks but was not significantly
correlated with preventive behaviour, attack-related behaviour, recognition, and
control of respiratory function, or quality of care. These results imply that the
effects of the former group of variables should be taken into account when
assessing asthmatic patients' quality of life.
PMID- 10778248
TI - Locus of control and attitudes toward large carnivores.
AB - It has been hypothesized tha the negative attitudes toward carnivores found among
rural groups is only one element embedded in a larger sociopolitical complex of
disputes over resource use and rural development. Negative attitudes may reflect
a protest against increased control of land use by central political authorities.
In a survey among sheep farmers, wildlife managers, and research biologists in
Norway we found that the sheep farmers expressed an external locus of control,
indicating a belief that external forces control events, relative to the two
other groups. Among sheep farmers and research biologists a positive association
was found between an external locus of control and negative attitudes toward
large carnivores.
PMID- 10778249
TI - Philosophy as a missing link between values and behavior.
AB - Despite the persistence of social scientists, evaluating the relationship between
values and behavior has not yielded clear results. Here, a model is proposed to
conceptualize and measure a person's operating philosophy. This assesses a
different level of the value structure within personality from separate values or
clusters of values; it is the evaluative structure within which a person's values
exist. Building on major philosophies, such as utilitarianism or humanism, the
model assumes that a person has a predominant Pragmatic, Intellectual, or Human
Operating Philosophy. In a sample of 801 subjects, each of these operating
philosophies had significant associations with a variety of the expected
behaviors evident in work and graduate school, such as initiative and empathy, as
well as learning styles, skills, and flexibility. Interpretation of the results
is offered as a way to understand the relationship between people's values or
beliefs and their behavior and approach to learning.
PMID- 10778250
TI - How popular is the Personality Assessment Inventory in practice and training?
AB - A review of recent survey data indicates that the Personality Assessment
Inventory ranks among the most frequently used objective personality tests in
practice and clinical training.
PMID- 10778251
TI - Moral reasoning, interpersonal skills, and cognition of rapists, child molesters,
and incest offenders.
AB - 54 inmates were subdivided into four groups and classified according to their
index offense. The groups included Rapists (n = 14), Incest Offenders (n = 9),
Child Molesters (n = 11), General Offenders (n = 20). Nonoffenders (n = 20) were
included as a control group. Psychometric tests including the Test of Nonverbal
Intelligence, the Defining Issues Test, Survey of Interpersonal Values, Porteus
Maze, and Minnesota Multiphasic Personality Inventory were administered to all
inmate and control groups. Analysis showed the rapists and child molesters scored
higher on moral reasoning on the Defining Issues Test; also rapists' scores were
more elevated on the Psychopathic Deviate and Paranoia scales of the Minnesota
Multiphasic Personality Inventory than those of other offender and control
groups. These results imply that rapists and child molesters have the ability to
understand moral issues; however, given their personality orientation, they
ignore these interpersonal social values.
PMID- 10778252
TI - Health of women: associations among life events, social support, and personality
for selected patient groups.
AB - This study examined the effects of life events, social support, personality
traits, and siblings' birth-order on the health of women. 199 middle-class
participants were included. 95 women, randomly assigned from four different
patient groups, were compared with a control group of 96 randomly selected women
without any special health problems. They completed a questionnaire which
included questions regarding family background, health, different life events,
social support, and signs of disease and a projective test, the Sivik
Psychosomatism Test. Analysis indicated that report of negative life events was
associated with more physical symptoms than positive life events and that the
patient groups reported more negative life events and less social support than
the control group.
PMID- 10778253
TI - Factor structure of the College Adjustment Scales.
AB - The present study examined the underlying structure of the College Adjustment
Scales via principal components analysis. A correlation matrix of the nine
subscales showed significant multicolinearity. A subsequent principal components
analysis demonstrated that one factor accounted for 57% of the total variance and
that the majority of subscales were moderately correlated with this single
factor. The results suggest that the College Adjustment Scales may measure the
same underlying construct and that the clinical distinctions implied by subscale
scores should be regarded with caution. Conclusions are constrained by sample
size and demographic characteristics, but the results suggest the need for
further empirical validation of the College Adjustment Scales, which may be
useful in college counseling centers.
PMID- 10778254
TI - Methodology in epidemiological studies of human neurobehavioral toxicity: a case
study with critical review.
AB - Health care professionals and government decision makers concerned with
neurotoxicity increasingly rely on neuropsychological research studies. An
example is an article relied upon by the U.S. Environmental Protection Agency
that reported effects on neurobehavioral performance in a group of factory
workers exposed to toluene by Foo, Jeyaratnam, and Koh in 1990, which is
described as lacking reliability and as having implausible contents. A critical
review can serve as an educational tool for neuropsychologists, to emphasize the
need to design and document their research and interpret findings without
speculation. For example, in the Foo, et al. study the implications of the
findings for the general population cannot be interpreted. To conclude that this
study has identified toluene as the cause of neurobehavioral deficits is a leap
of inference far exceeding the power in their study. The review underscores the
need for more critical reviews of research relied upon by decision makers and
researchers.
PMID- 10778255
TI - Students' perceptions of their self-regulatory and other-directed study
strategies: a factor analysis.
AB - Edited items on the 24-item Self-efficacy for Self-regulated Learning Scale were
combined with 7 items on external regulation developed in 1992 by Vermunt. The
inventory was administered to 244 entering freshmen enrolled in a university
orientation course. 19 students with incomplete responses were excluded from
analysis. Exploratory factor analysis with promax rotation indicated the five
factors of general organization and planning, external regulation, typical study
strategies, environmental restructuring, and recall. Coefficients alpha were .87,
.68, .74, .74, and .73, respectively.
PMID- 10778256
TI - Responses of seventh grade students to "do you have a partner with whom you would
like to have a baby?".
AB - This study investigated differences in demographic data, self-esteem, and coping
skills for 225 students in Grade 7 who reported having a partner with whom they
wanted to have a baby and 946 students who did not. Data were collected on the
Rosenberg Self-esteem Scale, the Family Crisis-oriented Personal Evaluation
Scale, and questions related to attitudes towards teen pregnancy and demographic
data. The sample included 548 (46.8%) boys and 624 (53.2%) girls whose mean age
was 13.2 yr. Students with a partner had significantly lower scores on the
curriculum questions, self-esteem, and family coping skills, combined with higher
scores in passivity. They indicated a desire to have a greater number of
children, beginning by having their first child at a younger age and believed
that having a baby improves a couple's relationship. Possible approaches may
include effective teaching methods to overcome passivity through boosting self
confidence, goal-setting, and acquiring a purpose in life besides parenting a
child.
PMID- 10778257
TI - A study of mood changes and personality during a 31-day period of chronic hypoxia
in a hypobaric chamber (Everest-Comex 97).
AB - High altitudes of more than 3,000 meters produce physiological disorders and
adverse changes in mood states. In the present study, we report analyses of mood
states and personality traits in eight experienced climbers participating in a 31
day period of confinement in hypobaric chamber and gradual decompression from sea
level to 8,848 m (Experiment 'Everest-Comex 97'). The subjects were tested at
5,500 m and 6,500 m on Day 13, 5,000 m and 6,500 m on Day 24, and 8,000 m and
8,848 m altitude on Days 27 and 31. Adverse changes in mood states, such as Vigor
and Fatigue, occurred at 8,000 m and 8,848 m, which were significantly correlated
with cerebral altitude symptomatology. In addition, a significant negative
correlation was found between Fatigue and Factor C, which is a personality
measure of emotional stability. We suggest that individuals with low emotional
stability could be more sensitive to environmental stressors than more
emotionally stable subjects who face reality.
PMID- 10778258
TI - Evaluation of a networked self-testing program.
AB - The use of a computerized, multiple-choice test bank to present practice and
assessment tests on a network was evaluated with 46 men and 119 women from a
first-year class in psychology. A correlation of .65 (p < .001) between scores on
a traditional paper-and-pencil test and scores on a computerized test provided
some validity for the computerized assessment. Regression analysis showed that
ability (previous academic performance) and motivation (number of practice tests
taken) accounted for 73% of the explained variance in computerized test scores.
Sex differences did not enter the regression equation significantly.
PMID- 10778259
TI - Sex differences in pain indices, exercise, and use of analgesics.
AB - To understand better reported sex differences in sensitivity to pain, this study
examined daily pain frequency and intensity, use of analgesics, physical
activity, and both subjective and physiological response to acute pain in 18 men
and 24 women, healthy people who provided information about their daily pain
symptoms and physical activity before completing a cold pressor task. Compared to
men, women reported more frequent and intense pain symptoms, as well as more
frequent use of analgesics and lower physical activity. Women evinced higher
physiological arousal during the cold pressor task but similar subjective pain.
The findings highlight the different ways men and women cope with pain and the
effect on their responses to acute pain.
PMID- 10778260
TI - Motivations for preventing versus assisting suicide.
AB - The motivations of those seeking to prevent and assist suicide are conceptualized
as defensive styles of repression versus sensitization adopted to deal with
personal suicidal desires.
PMID- 10778261
TI - Self-reflection and well-being: is there a healthy amount of introspection?
AB - Both extremely high and extremely low self-reflection have been considered as
risk factors for psychological maladjustment. Therefore, from an integrating
perspective medium amounts of self-reflection may constitute "healthy
introspection." To test this hypothesis, self-reflection and psychological well
being were measured with self-report tests given a pooled sample of 647 subjects.
A regressive relationship with self-reflection as a quadratic predictor of well
being was estimated using the LMS method for nonlinear structural equation
modeling. No evidence for a curvilinear effect was detected in the total sample
or in subgroups. Alternative theoretical assumptions are discussed on a
psychological and operational level.
PMID- 10778262
TI - Manic-depressive tendencies, suicidality, and perfectionism.
AB - In a sample of 82 college students, depression scores, but not manic scores, were
associated with both perfectionism and imposter scores.
PMID- 10778263
TI - Influence tactics used by subordinates: an empirical analysis of the Kipnis and
Schmidt Subscales.
AB - It was the purpose of this research to analyze the factorial and construct
validity of the Profile of Organizational Influence Strategies, Form M of Kipnis
and Schmidt, which assesses attempts to influence a manager and also attempts
when the manager has resisted doing what the employee wants. 254 German employees
from various organizations participated. The Profile of Organizational Influence
Strategies and the Blickle Inventory assessed upward influencing strategies over
2 wk. Data were analyzed with confirmatory factor analyses in a multitrait
multimethod design. All items loaded significantly on the expected factors. The
results support the factorial and convergent validity of the subscales. In
addition, the data show that initial attempts to influence and attempts after
resistance should be assessed separately.
PMID- 10778264
TI - Differentiating myoclonus from tics.
AB - A Myoclonus Versus Tic Checklist facilitates making this vexing differential
diagnosis. Although it appears to be a valuable tool for clinical, educational,
and research purposes, psychometric characterization of the Myoclonus Versus Tic
Checklist is needed.
PMID- 10778265
TI - Associations of symptoms of anxiety disorders and self-reported behavior problems
in normal children.
AB - 61 children, aged between 14 and 18 years, completed the Screen for Child Anxiety
Related Emotional Disorders, a scale of anxiety disorders symptoms, and the Youth
Self-report, a measure of internalizing, i.e., emotional, and externalizing,
i.e., behavioral, problems. Analysis showed that, with the exception of the
Social Phobia and the Specific Phobia subscales, Screen total and subscale scores
were significantly related to Internalizing problems (rs between .40 and .77).
Thus, the more frequently children reported Anxiety Disorder symptoms, the more
often they reported emotional problems. Furthermore, in particular, anxious
depressed problems as measured by the Youth Self-report were significantly
associated with scores on Screen scales. These results further support the
concurrent validity of the Screen.
PMID- 10778266
TI - Perceptions of insanity based on occupation of defendant and seriousness of
crime.
AB - The purpose was to estimate the relationship between a defendant's stated
intelligence on perceptions of his sanity and responsibility. This analog study
was a 2 (occupation of defendant) x 2 (seriousness of outcome) between-subjects
design. A scenario involving an insanity defense was read by 190 college students
who then answered a 12-item questionnaire. The hypothesis that participants would
attribute less responsibility to less intelligent defendants than to more
intelligent ones was partially supported. Belief in a Just World moderated these
evaluations. Seriousness of outcome influenced men's perceptions of the
defendant's insanity, responsibility, and sentence, but not women's. Participants
seemed to be more willing to accept the possibility that the defendant was insane
if the outcome of his crime was not serious.
PMID- 10778267
TI - Male entertainment award winners are older than female winners.
AB - It has been said that in the entertainment industry after a certain age women
have a harder time being as successful as men. Four analyses of the ages of male
and female Oscar winners, Oscar nominees, Emmy winners, and Grammy winners over
the past 25 years showed that in all four groups women were, on the average,
younger than the men. Two interpretations of these differences are delineated.
PMID- 10778268
TI - Dementia and mental retardation markers on the Rey 15-item Visual Memory Test.
AB - This study examined the qualitative errors of repetitions and confabulations on
the Rey 15-item Visual Memory Test among 500 psychiatric patients who were
divided into groups with (1) low IQ scores, (2) a diagnosis of dementia, and (3)
other psychiatric diagnoses. These groups were compared on the presence of
confabulated figures and repetitions on the Rey. The low IQ patients had the
highest rate for both confabulations (48.2%) and repetitions (43.6%). Demented
patients had the next highest rate of confabulations (39.8%) and repetitions
(39.8%). The general psychiatric patients had the lowest rates on confabulations
(16.2%) and repetitions (26.8%). Chi squared analysis showed that both
confabulations and repetitions significantly differentiated these patients of low
IQ and demented patients from general psychiatric patients. These results suggest
that clinicians who use the Rey 15-item Visual Memory Test and find either
confabulated or repeated figures should further explore the possibility that the
patient might have low intellectual functioning or dementia.
PMID- 10778269
TI - Strong commitment to traditional Protestant religious beliefs is negatively
related to beliefs in paranormal phenomena.
AB - Numerous studies have yielded small, negative correlations between measures of
paranormal and "traditional religious beliefs". This may partly reflect opinions
of Christians in the samples who take biblical sanctions against many
"paranormal" activities seriously. To test this, 391 college students (270 women
and 121 men) rated their beliefs in various paranormal phenomena and were
classified as Believers, Nominal Believers, and Nonbelievers on the strength of
their self-rated commitment to key biblical (particularly Protestant) doctrines.
As predicted, Believers were significantly less likely than Nominal Believers or
Nonbelievers to endorse reincarnation, contact with the dead, UFOs, telepathy,
prophecy, psychokinesis, or healing, while the beliefs of Nominal Believers were
similar to those of Nonbelievers. Substantial percentages of Nominal and
Nonbelievers (30-50%) indicated at least moderate acceptance of the paranormal
phenomena surveyed.
PMID- 10778270
TI - The role of police dogs as companions and working partners.
AB - Written responses to a questionnaire by 255 officers who used canines in police
work were assessed. Almost all officers frequently played with, talked to,
petted, and brushed their dogs and believed the dogs benefitted their health and
well-being. Officers whose dogs slept indoors, often in the same bedroom,
generally said they loved their dogs and they described their dogs as calm rather
than active, as indicated by a multiple correspondence analysis. These 96
officers more than the 154 officers whose dogs slept outdoors or in kennels also
planned to remain in canine work. Although departments often assumed
responsibility for purchasing the dogs, the more experienced officers usually
were involved in the final selection of dogs (logistic regression: p < .0001).
Compared with 94 officers not involved in selecting their dogs, 106 officers with
a specific role in selecting their dogs planned to stay in canine work, as shown
by a multiple correspondence analysis. They believed the dogs had saved their
lives (p < .01). Over-all, officers reported spending 4.1 hr. on-duty and 2.9 hr.
off-duty per week training their dogs, and also played with them for 6.5 hr. per
week, assuring a regular pattern of exercise for the officers. Virtually all
officers valued canine service and believed the dogs enhanced the department's
effectiveness. This study showed that both close companionship with the dog and
involvement in selecting the dog were associated both with satisfaction with the
dog and with working as a canine officer.
PMID- 10778271
TI - An examination of raters' and ratees' preferences in process and feedback in
performance appraisal.
AB - This paper examined the raters' and the ratees' preferences in Malaysia regarding
the performance appraisal process and feedback. A total of 52 managers (raters)
and 122 subordinates (ratees) participated. Analysis by t test and correlation
showed significant differences between raters and the ratees on most factors.
Ratees preferred to have more frequent appraisals than once a year and preferred
to have more frequent feedback from the managers about their performance. Ratees'
preference for the purpose of information on performance was towards salary
increase, promotion, training, and career development whereas the raters gave
more importance to training and career development.
PMID- 10778272
TI - Assessing attitudes toward gay marriage among selected Christian groups using the
lost-letter technique.
AB - 100 each envelopes were distributed to Christian church parking lots and general
public parking lots. Letters were addressed to either the "Gay Marriage
Foundation" or to a neutral organization. Significantly more neutral letters (n =
75) were returned than "Gay Marriage Foundation" letters (n = 36) from both types
of locations, but no differences were found for return rates. Gay marriage may be
a controversial topic for people in this area of California. The limitations of
the lost-letter technique prohibit fine distinctions; however, one may infer
attitudes toward gay marriage may not be more negative among Christian church
attendees than in the general public.
PMID- 10778273
TI - Workaholism and divorce.
AB - This study compared workaholism components and workaholic behaviors of managers
currently divorced or currently married. Data were collected using anonymous
questionnaires from 530 women and men. 44 divorced and 415 still-married managers
indicated similar workaholism and workaholic behaviors.
PMID- 10778274
TI - Levels of personal agency among academic majors.
AB - Action identification theory presented by Vallacher and Wegner characterizes
individual differences in identification level in terms of a personality
dimension known as "level of personal agency." Levels of personal agency, as
measured by the Behavior Identification Form, were examined in a sample of 237
college "seniors" representing eight academic majors. The mean levels of personal
agency among individuals in several of these majors were significantly different.
PMID- 10778275
TI - An outcome survey of psychology residency training program graduates of the
University of Texas Houston Medical School.
AB - A survey of 71 graduates of the psychology residency program at The University of
Texas Houston Medical School and the Texas Research Institute of Mental Science
indicated that two-thirds of the respondents were involved in private practice,
conducting primarily individual therapy, with assessment also playing a major
role in their practice. Managed care had the effect of placing limits on the
numbers of sessions available to patients, reducing income, and increasing
paperwork associated with practice. Implications for training during residency
are that individual therapy, using focused short-term approaches, and assessment
should continue to be the primary clinical experiences for trainees, and that
there should also be training in the business aspect of practice, including
marketing.
PMID- 10778276
TI - Human motor responses to simultaneous aversive stimulation and failure on a
valued task.
AB - The effects of presentation of an aversive stimulus and simultaneous failure on a
bogus intelligence test upon a subject's aggressive reactions were studied. The
subject's fist clenching was used as an indicator of aggression. Four conditions,
generated by the combinations of two kinds of stimulus delivered to the subjects
(aversive or nonaversive) and two outcomes of the task (failure or success), were
investigated. 20 female and 20 male students (ages: 17-34 years) were instructed,
upon the reception of an aversive or nonaversive acoustic signal, to press with
the right hand a device that displayed a slide. Each slide presented an item from
an intelligence test, to which the subjects were either allowed to answer
successfully (success) or not (failure). Failure increased the subject's
autonomic arousal, as measured by photoplethysmographic sensors, in all
stimulation conditions, but only the condition with aversive stimulation
increased the speed of clenching. This was interpreted as indicating subject's
tendencies to aggression. These results are discussed in relation to the effects
of frustration.
PMID- 10778277
TI - An examination of graduate students' statistical judgments: statistical and fuzzy
set approaches.
AB - The present study examined how statistical significance levels are treated and
interpreted by graduate students who use hypothesis-testing in their scientific
investigation. To test underlying psychological aspects of hypothesis-testing,
the idea of fuzzy set theory was employed to identify the uncertain points in
judgments. 34 graduate students in a psychology department made judgments about
hypothetical statistical decisions. The results indicated that (1) the majority
of these students treated significance levels on a continuum and rated them
according to the magnitude of statistical significance; (2) the subjects shifted
their decisions based on the types of hypothetical scenarios but not by the
sample sizes; instead, they interpreted a smaller sample size as being less
reliable. (3) The subjects frequently chose formally used statistical terms,
e.g., Significant and Not Significant, more than graduated verbal expressions,
e.g., Marginally Significant and Borderline Significant; and (4) the Fuzziness
(degree of confidence in decision-making) was dependent on individuals and
existed more in the critical points of transition where judgments are most
difficult. The Fuzziness Index illustrated the subtle shifts of human decision
making patterns in statistical judgments. Underlying decision uncertainties and
difficulties can be illustrated by functions generated from fuzzy set theory,
which may more closely resemble human psychological mechanism. This integrative
study of fuzzy set theory and behavioral measurements appears to provide a
technique that is more natural for examining and understanding imprecise
boundaries of human decisions.
PMID- 10778278
TI - Romantic acts and depression.
AB - The aim of the present study was to provide an examination of the relationship
between the importance individuals attach to romantic acts and depressive
symptoms. Among 140 male and 160 female English undergraduate students, the
importance individuals attach to romantic acts is significantly negatively
correlated with higher scores on the Beck Depression Inventory and the Depression
symptoms subscale of the General Health Questionnaire among the men only.
PMID- 10778279
TI - Assessing clinically significant change: application to the SCL-90-R.
AB - A Symptom Checklist (SCL-90-R) is a potentially useful measure of psychological
distress; it is frequently used in psychotherapy research and clinical practice.
The purpose of this study was to illustrate the use of the SCL-90-R for
determining statistically reliable change and clinical significance outlined by
Jacobson and Truax in 1991. This paper describes the concepts of statistical and
clinical significance of change. A proposal for obtaining and characterizing
samples is made. Then a clinician's perspective is taken. Reliable change
estimates and cut-off scores are chosen based on outcome data. Selected data from
a single psychotherapeutic process and outcome study then were used to test the
estimates of change and cut-off scores.
PMID- 10778280
TI - Personality and psychopathology of drug addicts in Puerto Rico.
AB - Drug abuse is one of the most pressing sociomedical problems of society. The
purpose of this study was to examine the personality and psychopathology of
addicts. 229 addicts in treatment programs scored high on Neuroticism and on the
Lie Scale and low on Psychoticism and Extraversion on the Eysenck Personality
Questionnaire for Puerto Rico. An Addiction Scale, based on a factor analysis,
showed a high component of Neuroticism items.
PMID- 10778281
TI - Care of elderly persons in the family: an approach based on a developmental
model.
AB - Care-giving as an act of decision-making, as a reciprocal action, and based on
sex of the care-giver, are reviewed. It is suggested that the care of elderly
parents, a long-term commitment, should be viewed from a developmental
perspective, beginning from childhood for an adult care-giver to be better
adjusted to this role and for better outcomes.
PMID- 10778282
TI - Using a small sample Q sort to identify item groups.
AB - A small sample of 40 second-year university students in Hong Kong were asked to
perform a Q sort on the 36 items of a questionnaire used to assess six dimensions
of student approaches to learning, the Learning Process Questionnaire.
Participants were instructed to sort the items into as many groups as they liked
with the only conditions being that all items within a group be as similar as
possible in perceived meaning and that no item be placed into more than one
group. By treating participants' responses as a form of multiple-choice data and
by applying optimal scaling, three solutions were obtained. A two-dimensional
plot of the optimal item scores for the first two solutions yielded 10 clearly
defined item clusters suggesting a possible ten-factor model as opposed to the
six-factor model found in studies of this questionnaire. The implications of
using this approach to identify potential competing factor models, especially
within a cross-cultural context, are discussed.
PMID- 10778283
TI - A field study of two measures of work motivation for predicting leader's
transformational behaviors.
AB - Relationships between motivation and transformational leadership were examined in
this study. 56 leaders and 234 followers from a variety of organizations were
sampled. Leaders were administered the Motivation Sources Inventory and the Job
Choice Decision-making Exercise, while followers reported leaders' behaviors
using the Multifactor Leadership Questionnaire (MLQ-rater version). Scores on the
Motivation Sources Inventory subscales subsequently correlated with the
Multifactor Leadership Questionnaire subscales of inspirational motivation,
idealized influence (behavior), and individualized consideration (range, r = .13
to .23). There were no significant correlations among any of the Job Choice
Decision-making Exercise subscales with any of the variables measured.
PMID- 10778284
TI - Internal consistency reliability and construct validity of the Dutch translation
of the Francis Scale of Attitude toward Christianity among adolescents.
AB - A sample of 1,021 young people attending Years 7, 8, 9, 10, and 11 at Catholic
secondary schools within the state-maintained sector completed the Dutch
translation of the Francis Scale of Attitude toward Christianity. The data
support its reliability and validity and commend it for further use in studies
conducted among young people in The Netherlands.
PMID- 10778285
TI - Descriptions of religious experience using trait and affect adjectives.
AB - 66 adults rated the relevance of adjectives representing dimensions of affect and
personality for describing how they felt during religious experiences.
Adjectives, representing positive affect (enthusiastic, at ease), low neuroticism
(calm, relaxed), and high agreeableness (soft-hearted, sympathetic),
conscientiousness (conscientious, reliable), and extraversion (sociable,
talkative), were rated to be descriptive of religious experiences. The failure of
openness to discriminate religious experiences is consistent with Block's
criticism (1995) of the five-factor model of personality.
PMID- 10778286
TI - FIRO-B: factors and facets.
AB - 10 FIRO-B intercorrelation matrices were factor analysed; one matrix was derived
from new FIRO-B data, all the other matrices were found in the literature. The
correlation matrices were also subjected to meta-analysis. The findings suggested
that the four FIRO-B scales associated with Inclusion and Affection are facets of
the ubiquitous interpersonal superfactor, Nurturance, but the two FIRO-B Control
scales each express an orthogonal construct both of which relate to the super
factor, Dominance.
PMID- 10778287
TI - Comparison of forced-choice and subjective probability scales measuring
behavioral intentions.
AB - Three surveys compared the accuracy of predictions based on forced-choice and
subjective probability scales. The latter produced significantly more accurate
election predictions and significantly reduced the percentage of undecided, or
"Don't Know" responses, compared to forced-choice scales in all three surveys.
Analysis indicates subjective probability scales decrease sampling error and
confirms there is an inherent source of error in traditional forced-choice
questions about voting intentions not attributable to sampling error. The results
are discussed with respect to (1) sampling and measurement errors in forced
choice and subjective probability scales measuring behavioral intentions, (2)
their practical application, and (3) cognitive theory, especially support theory.
PMID- 10778288
TI - Shyness in self-disclosure mediated by social skill.
AB - The purpose of this study was to examine the effect of Shyness and Social Skills
on Self-disclosure. Three scales, the Trait Shyness Scale, the Scale of Social
Skill, and the Self-disclosure Questionnaire were administered to 443 university
students. Scores on Shyness were highly negatively correlated with those on
Social Skills and moderately negatively correlated with Self-disclosure.
Furthermore, Self-disclosure scores correlated positively with Social Skills.
Separate factor analyses of the Shyness and Social Skills scales yielded four and
two factors, respectively. Findings suggest that shy people may have low
interpersonal skills and thus, they may hesitate to engage in self-disclosure.
PMID- 10778289
TI - Harris-Lingoes MMPI-2 Pd subscales and the assessment of law enforcement
candidates.
AB - This study analyzed the performance of 111 male law enforcement applicants on
MMPI-2 Harris-Lingoes Psychopathic Deviate (Pd) subscales. Applicants' self
descriptions derived from their scores on these subscales showed greater
confidence and resistance to authority and less social alienation and personal
unhappiness than the MMPI-2 national normative sample. A multiple regression
analysis indicated that Pd2 (Authority Problems) was the best predictor of K
corrected Pd scores for the sample of applicants.
PMID- 10778290
TI - Exposure to suggestion and creation of false auditory memories.
AB - The experiment investigated the possibility of creating false auditory memory
through exposure to suggestion. Research by Loftus and others has indicated that,
through suggestion, false memories can be created. Participants viewed a short
film and were given a 9-item questionnaire. Eight questions were used as filler
while one question asked respondents to recall a phrase one character had said.
Although the character actually said nothing, 23 of 30 respondents recalled
having heard him speak and specifically recalled his words. This statistically
significant result shows that auditory memories can also be created.
PMID- 10778291
TI - The Sexual Desire Inventory as a measure of sexual motivation in college
students.
AB - The human sexual response consists of at least two phases of behavior, the
motivational phase and the consummatory phase, which are difficult to isolate.
Sexual motivation questionnaires commonly contain items that assume sexual
intercourse or partners' experience and are often difficult to use with sexually
inexperienced persons. The Sexual Desire Inventory by Spector, Carey, and
Steinberg does not appear to be confounded with consummatory behavior. Our goal
was to check whether it can be used to measure sexual motivation. 40 men and 63
women completed the Sexual Experience Scale of sexual motivation by Frenken and
Vennix and the Sexual Desire Inventory. Scores on the two inventories were highly
correlated with this measure of sexual motivation and may be used with sexually
inexperienced individuals.
PMID- 10778292
TI - Security of medical information: the threat from within.
PMID- 10778293
TI - . . . and data for all: the NCI initiative on clinical infrastructure standards.
PMID- 10778294
TI - Biomedical computing: territorial expansion for informatics.
PMID- 10778295
TI - Positive outcomes, lower costs: using net-based IT to manage care.
PMID- 10778296
TI - Improving access to healthcare information: the Lister Hill National Center for
Biomedical Communications.
PMID- 10778298
TI - eHealthcareWorld. Changing the power structure of the industry.
PMID- 10778297
TI - Visual integration. A new technology for the thinking physician.
PMID- 10778299
TI - Wireless technology transforms healthcare delivery and tracking.
PMID- 10778300
TI - Births, marriages, divorces, and deaths: provisional data for March 1999.
PMID- 10778301
TI - PDA comments on draft guidance for industry, ANDAs: blend uniformity. Parenteral
Drug Association.
PMID- 10778302
TI - Validation of D value by different SCD culture medium manufacturer and/or
different SCD culture medium constituent.
AB - Variation in decimal reduction (D) time/value for attaining sterility assurance
was reported in terms of difference between lot to lot and/or manufacturer to
manufacturer of soybean casein digest (SCD) culture medium. The D value variation
phenomenon itself due to SCD culture medium was reported by Graham et al;
however, it was not sufficiently clarified what constituent(s) of SCD culture
medium would mainly contribute to the variation of D value. If it is not well
clarified, the reproducible sterility assurance cannot be successfully attained.
The authors studied individually the constituent of SCD broth (SCDB), SCD agar
(SCDA) and SCD broth plus 1.5% agar (SCDB/A). As a result, the culture medium
constituent causing D value variation among SCD culture medium was determined as
the difference of calcium (Ca) amount as well as the presence and the absence of
K2HPO4 in SCD culture medium. Additionally, it was clarified D value differed
significantly between SCDB and SCDA. D value using the former was around 1 min
lower than that using the latter. This phenomenon can be explained from the
formation of insoluble CaHPO4 in SCDB culture medium, resulting in insufficiency
of usable Ca to B. stearothermophilus in SCDB culture medium.
PMID- 10778303
TI - The influence of lyophilization on the polymorphic behavior of mannitol.
PMID- 10778304
TI - A note on concordance correlation coefficient.
AB - In this note, we first review some recent developments about measures of
agreement, which are often required in medicine and other sciences, with focus on
differences between these methods. In the last part, we mention five important
concerns when using a newly developed concordance correlation coefficient. Our
conclusion is that we need to be especially careful when using existing
correlation methods and a new correlation method needs to be developed in the
future.
PMID- 10778305
TI - Contamination control in HVAC systems for aseptic processing area. Part I: Case
study of the airflow velocity in a unidirectional airflow workstation with
computational fluid dynamics.
AB - A unidirectional airflow workstation for processing a sterile pharmaceutical
product is required to be "Grade A," according to EU-GMP and WHO-GMP. These
regulations have employed the wording of "laminar airflow" for unidirectional
airflow, with an unclear definition given. This seems to have allowed many
reports to describe discussion of airflow velocity only. The guidance values as
to the velocity are expressed in various words of 90 ft/min, 0.45 m/sec, 0.3
m/sec, +/- 20%, or "homogeneous air speed." It has been also little clarified how
variation in airflow velocity gives influences on contamination control of a
workstation working with varying key characteristics, such as ceiling height,
internal heat load, internal particle generation, etc. The present author has
revealed following points from a case study using Computational Fluid Dynamics:
the airflow characteristic in Grade A area shows no significant changes with
varying the velocity of supplied airflow, and the particles generated from the
operator will be exhausted outside Grade A area without contamination.
PMID- 10778306
TI - Parametric release--much ado about nothing.
PMID- 10778307
TI - Isolators and barrier devices in pharmaceutical manufacturing.
AB - The use of isolators and barrier technology in pharmaceutical manufacturing may
cause design problems, some of them unrecognised. These design problems are
highlighted in this paper and, where possible, solutions are given.
PMID- 10778308
TI - Applying a uniform layer of disinfectant by wiping.
AB - Disinfection or sterilization often requires applying a film of liquid to a
surface, frequently done by using a wiper as the applicator. The wiper must not
only hold a convenient amount of liquid, it must deposit it readily and
uniformly. Contact time is critical to disinfection efficacy. Evaporation can
limit the contact time. To lengthen the contact time, thickly applied layers are
generally preferred. The thickness of such layers can be determined by using dyes
or other tracers, as long as the tracers do not significantly affect the liquid's
surface tension and viscosity and thus do not affect the thickness of the applied
layer. Alternatively, as done here, the thickness of the layer can be inferred
from the weight loss of the wiper. Results are reported of experiments on
thickness of the layers applied under various conditions. Near saturation,
hydrophilic polyurethane foam wipers gave layers roughly 10 microns thick,
somewhat less than expected from hydrodynamic theory, but more than knitted
polyester or woven cotton. Wipers with large liquid holding capacity, refilled
often, should produce more nearly uniform layers. Higher pressures increase
saturation in the wiper, tending to thicken the layer, but higher pressures also
force liquid from the interface, tending to thin the layer, so the net result
could be thicker or thinner layers, and there is likely to be an optimal
pressure.
PMID- 10778309
TI - Steam sterilization and steam quality.
PMID- 10778310
TI - Sterilisation decision trees development and implementation.
PMID- 10778311
TI - [When should ruptured abdominal aneurysms be surgically treated?].
PMID- 10778312
TI - [Ultrasound contrast media].
PMID- 10778313
TI - [Bone lengthening. History of the development and field of applications].
AB - Leg lengthening has been performed since early in this century. The first
successful lengthening was reported in 1905. Leg lengthening evolved from forced
lengthening of the bone during anaesthesia, through use of cortical bone grafts,
plate and screws to callus distraction (callotasis). Development of external
fixators and evolution of biological concepts of bone regeneration has been
important. In 1951 Ilizarov developed his apparatus. Ilizarov pioneered the
biology of bone and soft-tissue regeneration. He performs a percutaneous
subperiosteal corticotomy and waits five to seven days prior to distraction with
a rate of 0.25 mm of length four times each day. The method has increased the
opportunities in reconstructive bone surgery. The technique is difficult with
many problems and obstacles which can be overcome.
PMID- 10778314
TI - [Surgery for ruptured abdominal aneurysm assisted by vascular unit team at the
primary receiving hospital].
AB - The objective of the study was to compare emergency operations for ruptured
abdominal aortic aneurysm (RAAA) by a mobile operation team, with operation for
RAAA carried out at our vascular unit. During a five year period (1993-1998), 18
emergency operations were carried out for abdominal aortic aneurysm (AAA) with
rupture at the primary receiving hospital with assistance from a mobile operation
team. In the same period 82 aneurysms with rupture were resected at our vascular
surgical unit. Preoperatively, patients operated at the primary receiving
hospitals had significantly lower blood pressure (P < 0.05) and an intraoperative
higher blood loss (P < 0.05). Furthermore, postoperative complications tended to
be higher among patients operated at hospitals without a vascular unit.
consequently, the mortality was 67% compared to 47% in the department. However,
1/3 of the patients operated by the mobile operation team survived. Consequently,
haemodynamically unstable non-transportable patients with an RAAA should be
considered for surgery by a mobile operation team.
PMID- 10778315
TI - [Recurrent familial intrahepatic cholestasis in the Faroe Islands].
AB - Recurrent familial intrahepatic cholestasis is an autosomal recessive disorder
characterized by episodes of severe pruritus and jaundice lasting for weeks to
months without extrahepatic bile duct obstruction. Symptom-free intervals may
last for months to years, and chronic liver damage does not develop. We recently
studied four of the five patients from the Faeroe Islands described by us 30
years ago (one had recently died), and a further five patients who were
identified after the initial report. The episodes of cholestasis were more
frequent and severe in patients with early onset, but tended to reduce in
frequency with age. The youngest patient, aged 25 years, who had had 16 episodes,
each lasting about six months, had a liver transplant after which no further
episodes were recorded (one year after surgery). Signs of chronic liver disease
were absent in all patients. The FIC1 gene was investigated for mutations in the
surviving patients. A single mutation (I661T) was found on both chromosomes in
all 9 patients, indicating that they are genetically identical for the disease
causing defect. Nevertheless, considerable differences between patients were
observed clinically.
PMID- 10778316
TI - [Injuries among 11-15 year old children].
AB - The objective is to describe the one year incidence rate of self-reported
injuries, their causes, where they happened, and their consequences within the
age group 11-15 years. Four thousand and forty-six students from a random sample
of 45 schools answered a standardized questionnaire about health and health
behaviour. This report regards injuries treated by a doctor or a nurse. During
one year, 28% were injured, 12% more than once; 12% needed medical treatment such
as a plaster cast, stitches, surgery or staying in a hospital; 16% missed at
least one full day in school. The injury incidence rate increases with age among
boys but not among girls. The proportion with more than one injury increases by
age among girls but not boys. The proportion who receive hospital treatment is
higher among boys than girls. The proportion who stay home from school because of
the injury increases with age among both girls and boys. Five percent are injured
at home, 5% at school, 9% are injured at a sport facility, and 4% in the
street/road. Ten percent report a sports injury, 4% an injury by falling, and 3%
by riding a bicycle. Most common injuries are sprain/strain/pull of a muscle
(9%), broken or dislocated bone (6%), and cuts (3%). In conclusion, the incidence
of self-reported injuries is much higher than the hospital-reported. More
research about injury-mechanisms and more preventive efforts are needed.
PMID- 10778317
TI - [Prophylactic contralateral orchiopexy in patients with testicular torsion].
AB - The aim of the study was to examine the recommendations for prophylactic
contralateral orchiopexy in patients presenting with unilateral testicular
torsion in Denmark. A questionnaire was mailed to the 61 surgical departments
treating acute urological patients. Prophylactic contralateral orchiopexy was
performed in 60 of the 61 departments. Twenty-eight departments routinely
performed a combined ipsilateral and contralateral operation. In 20 departments
the contralateral procedure was performed immediately in the case of a vital
ipsilateral testis, but delayed a median of five (3-12) weeks in the case of a
necrotic testis. In seven departments the contralateral orchiopexy was routinely
performed a median of 10 (2-12) weeks after the ipsilateral operation, and in the
remaining five departments the time of the contralateral procedure was determined
by the surgeon. In conclusion prophylactic contralateral orchiopexy was widely
used in patients with unilateral testicular torsion, but the timing of the
procedure varied.
PMID- 10778318
TI - [Acute hemolytic anemia caused by glucose-6-phosphate dehydrogenase deficiency].
AB - Glukose-6-phosphate dehydrogenase (G6PD) is essential in protecting the red cell
from oxidative damage. We report a case of acute haemolysis in a child with G6PD
deficiency. Because of the severity of the anaemia, the patient was treated with
blood transfusions and recovered fully. There are two main variants of G6PD
deficiency (the Mediterranean variant and variant A) with different clinical
profiles. Acute haemolytic attacks are induced by certain drugs, by infections
or, in the Mediterranean variant, by ingestion of fava beans (favism). Increased
awareness of this condition is necessary in Denmark because of increased
immigration.
PMID- 10778319
TI - [The UK Prospective Diabetes Study. Polypharmacy marching in?].
PMID- 10778320
TI - [Picture of the month. Rest tumors and metastases].
PMID- 10778321
TI - [Physicians and behavior of mass media--spying or attacking by the media?].
PMID- 10778322
TI - [Same day surgery--how far will we go?].
PMID- 10778323
TI - [Cochrane Colorectal Cancer Group--1998 activities].
PMID- 10778324
TI - [Somatoform disorders. What is wrong when there is "nothing" wrong?].
AB - Patients with somatoform and dissociative disorders complain of symptoms
suggesting physical disease. These patients are high utilizers of health services
but seldom receive relevant treatment. Recently empirical data have been obtained
concerning epidemiology, familiar distribution, and relation to personality in
these disorders. Somatoform patients often have comorbid depression and anxiety
disorder. These complications are often overlooked, but accessible to
psychopharmacological treatment. A number of psychotherapeutic techniques have
been developed for treatment in general practice and in hospital settings.
PMID- 10778325
TI - [Laparoscopic cholecystectomy as a same-day surgical procedure].
AB - The aim of this study was to describe the results of laparoscopic cholecystectomy
as an outpatient procedure in a prospective, consecutive, descriptive study. The
study included 50 patients selected in the period from April to December 1997,
who accepted the outpatient procedure. Preoperative complications, morbidity
during hospital stay, length of hospital stay, frequency of readmission and the
satisfaction of the patients were registered. In our investigation we found a
risk of preoperative complications of 6% (severe 0%), a morbidity during hospital
stay of 6% (severe 2%) and an incidence of readmission of 4%. A total of 74% of
the patient went home on the same day as the procedure, and 90% of all patients
had been discharged 24 hours later. The patients showed a high degree of
satisfaction. In conclusion laparoscopic cholecystectomy as an outpatient
procedure may be performed with a low risk of complications, a low incidence of
readmission, a high degree of satisfaction in patients, but with a high frequency
of primary admission (26%).
PMID- 10778326
TI - [Behavioral disorders in nursing home residents. 147 consecutive referrals to an
interdisciplinary team of consulting specialists].
AB - During a period of 22 months 147 consecutive residents with behavioural
disturbances from 80% of the Copenhagen nursing homes were referred to a visiting
team of consulting specialists. Each resident was evaluated clinically, and data
were recorded in a database. The conditions thought to represent the underlying
etiologies were dementia (79%), delirium (28%) and depression (35%). The most
commonly observed behavioural symptoms were aggressiveness, vocally disruptive
behavior and non-aggressive psychomotor symptoms. The most common interventions
suggested by the team were further diagnostic evaluations, adjustment of
pharmaceutical treatment, using the life history of the resident as a reference
for behaviour management, and psychological behavior management. There is a need
for increased focus on systematic diagnosis and treatment of behavioural
disorders, observed in nursing homes, which often have multifactorial etiology.
PMID- 10778327
TI - [Medical research and gender. An analysis of the preclinical departments at the
University of Copenhagen].
AB - The proportion of women among Danish medical graduates increased from 25% to 50%
in the years 1970 to 1996. The proportion of women among the medical scientific
staff has, however, not changed significantly over this period. At The University
of Copenhagen women comprised 16% of the preclinical faculty in 1970 and 21% in
1996, and today's lack of women cannot be explained as a legacy from previous
periods. The construction of a professional hierarchy is central in any
discussion of position and influence in scientific research. Women at the medical
faculties have in many respects a peripheral position. Relatively few have a
postgraduate medical degree, they are in general not employed in traditional
medical research areas such as physiology and anatomy, and there are
disproportionately fewer among the professors. The authors argue that the women's
position as non-doctors in low-status areas results in a lack of influence and
access to resources.
PMID- 10778328
TI - [Professional prestige and gender--clinical scientific staff in Copenhagen as an
example].
AB - At the clinical medical departments of The University of Copenhagen only 5% of
the clinical professors and 18% of the associate professors were women in 1995.
Among the other categories of the scientific staff, e.g. assistant professors,
34% were women. There was also an uneven distribution of women among the
specialties, ranging from 0% women on the scientific staff of the ear, nose and
throat specialty to 75% in geriatrics. Based on a ranking scale for the medical
specialties constructed by Album (9), the study shows that the percentage of
women within a specialty is negatively correlated to the prestige of the
specialty. On Album's scale ranging from 1 (highest) to 22 (lowest) the
specialties of the female professors had a mean ranking of 18.5 compared to 12.6
for the male professors. The mean ranking for the associate professors was 15.0
for the women compared to 8.8 for the men.
PMID- 10778329
TI - [Laparoscopic cholecystectomy as a same-day surgical procedures. Results and
patient satisfaction].
PMID- 10778330
TI - [Gastroscopic removal of penetrating gastric band].
AB - Gastric wall penetration of a gastric band after operation for morbid obesity is
a well known late complication. The treatment is usually reoperation. In this
case report we show that a band penetrating the gastric wall can be successfully
treated by gastroscopic operation. This technique is more simple than
reoperation, especially in case of morbid obesity at the time of the
complication.
PMID- 10778331
TI - [Human EGF receptor 2 and treatment of breast cancer].
PMID- 10778332
TI - [Treatment with iodine radioisotopes and thyroid-associated ophthalmopathy in
Graves' disease].
PMID- 10778334
TI - [Back pain].
PMID- 10778333
TI - [Picture of the month. Ventricular cancer].
PMID- 10778335
TI - [Is malabsorption the answer in connection with obesity?].
PMID- 10778336
TI - [Guidelines for measurement of TSH receptor antibodies in pregnant women. Results
from an evidence based symposium organized by the European Thyroid Society].
PMID- 10778337
TI - [Aerococcus urinae. A newcomer among pathogenic bacteria in clinical and
microbiological practice].
AB - A decade ago we discovered a hitherto unrecognized Aerococcus-like organism (ALO)
in urine specimens from patients with urinary tract infection. Further
microbiological and clinical investigations enabled us to classify it as a human
pathogen also causing urogenic septicaemia and endocarditis, the latter often
with lethal outcome. The organism is now designated Aerococcus urinae.
PMID- 10778339
TI - [Interobserver variation in the Red-Yellow-Black wound classification system].
AB - Communicating wound descriptions between disciplines for treatment and wound care
necessitates a simple and unequivocal classification system. The Red-Yellow-Black
(RYB) system has been suggested to comply with these demands. The reliability of
the RYB-system has, however only been investigated in small studies. The aim of
this study was to determine interobserver homogeneity (group Kappa a.m. Schouten)
of the RYB-system and further to examine whether interobserver homogeneity was
dependent on educational level. One-hundred-and-twenty photo-slides of non
healing ulcers of various etiologies were shown to 21 observers who recorded
their assessments in an entry form without discussing their assessments with the
other observers. Eighty-nine percent of the possible assessments were completed.
Observed agreement for all observers = 0.65; Kappa = 0.47. Kappa-coefficient in
subgroup of nurses = 0.49, subgroup of physicians with less than three years of
experience with wound treatment = 0.46 and for physicians with more than 10 years
of experience with wound healing = 0.48. In conclusion, we demonstrated moderate
interobserver agreement for using the RYB-characteristics. The RYB-system is
useful for communication about wound care and treatment. However, continuous
education and consensus meetings are advisable to increase agreement.
PMID- 10778338
TI - [Healing of venous leg ulcers. A randomized prospective study of a long-stretch
versus short-stretch compression bandage].
AB - The aim of the study was to compare the efficacy of two types of compression
bandage with different degrees of elasticity on healing of venous leg ulcers.
Forty-three patients with venous leg ulcers were included and blindly randomized
to treatment with one of the two types of bandage aiming at a sub-bandage
pressure in the ankle area of 40 mmHg. Forty legs were evaluated. Healed ulcers
after 12 months were observed in 71% of the long-stretch group and in 30% of the
short-stretch group (p = 0.06). Using life-table analysis the predicted healing
rate in the long-stretch group after 12 months was 81% and for the short-stretch
group 31% (p = 0.03). The mean of relative ulcer areas at 12 months was 0.25 for
the long-stretch group and 0.95 for the short-stretch group (p = 0.01). The
present study appears to indicate a positive influence of the elasticity of a
compression bandage applied with a sub-bandage pressure around 40 mmHg in the
ankle area on venous ulcer healing.
PMID- 10778340
TI - [Occurrence of carotid stenosis in patients with cerebrovascular symptoms].
AB - Stenosis of the internal carotid artery is a well known risk factor and is
estimated to be the cause of 20-30% of all strokes. As ultrasonography easily can
demonstrate arterial stenosis and causal surgical treatment is available we found
it of interest to investigate the occurrence of stenosis found among consecutive
non selected patients with focal neurological symptoms. Results of duplex
scanning from consecutive patients with various symptoms were collected.
Seventeen percent of the patients who had had transient ischaemic attacks were
found to have stenosis of 50% or greater. For the patients with persistent
central neurological symptoms (stroke) we found stenosis greater than 50% in 23%.
Only a few patients with uncharacteristic, non focal symptoms were found to have
stenoses. Carotid stenosis is found in approximately 20% of patients with focal
neurological symptoms. Hence ultrasound investigation is indicated for patients
suited for surgical treatment.
PMID- 10778341
TI - [Intravesical drug therapy in women with severe urge incontinence. Clinical
experiences from a department of gynecology].
AB - Conventional oral pharmacotherapy for urge incontinence remains problematic
because of limited efficacy and systemic side effects. In this study 27 patients
with severe urge incontinence were treated with intravesical drugs (emepron 200
mg or oxybutynin 5 mg) twice a day. They had previously on average undergone 3.3
other treatment options without satisfactory effect. The average age was 62
years, and their incontinence had on average lasted for 15 years. Seven percent
were cured and 41% were improved. Fifty-two percent had no satisfactory effect of
the treatment. The number of side effects was low, and none left the study for
this reason. Intravesical anticholinergic pharmacotherapy can be a treatment
option in women with severe urge incontinence.
PMID- 10778342
TI - [Complications after surgery for pilonidal cyst. An introduction to a new debate
on a "costly" disease].
AB - The frequency of wound complications following operation for pilonidal disease in
our department was compared with results from the literature. The case-records of
88 consecutive patients operated for 100 sinuses (12 recurrences), were evaluated
retrospectively, supplemented by a questionnaire. Wound healing problems occurred
in 69% of the sutured sinuses. Length of hospitalization was two days in
uncomplicated, five days in complicated, and eight days in open treated cases.
Convalescence (days off work) took 25 days, 41 days and 26 days, respectively.
There was no correlation between previous history of pilonidal disease, wound
healing complications, and outcome (recurrence frequency). Relapses occurred in
18%. In conclusion, the closure of pilonidal sinuses had a high frequency of
wound healing complications and recurrences.
PMID- 10778343
TI - [Eosinophilic cystitis in children].
AB - Eosinophilic cystitis is an inflammatory disorder of the urinary bladder,
characterised by irritative voiding symptoms, negative urine cultures, and
eosinophilic infiltration of the bladder wall. Since 1960 only about 20 cases
have been described in the English scientific reports, making it a rather rare
entity. In children the disease appears to be shortlived and self-limited,
requiring no specific treatment. We present a case with a 7.5-year-old boy, who
experienced spontaneous remission of all symptoms, following an acute attack of
eosinophilic cystitis.
PMID- 10778345
TI - [Language development in secretory otitis media].
PMID- 10778344
TI - [Acute pancreatitis in children caused by gallstones].
AB - A 10 year-old girl presented with acute abdominal pain. Serum-amylase was 3959
U/l. Ultrasonography showed dilatation of both the common bile duct and the
pancreatic duct and a high density area near the ampulla. Endoscopic retrograde
cholangiography (ERC) verified a stone near the ampulla, which was removed after
sphincterotomy. The girl recovered fully.
PMID- 10778346
TI - [A report on subarachnoid hemorrhage and intracranial aneurysm].
PMID- 10778347
TI - [Orlistat: medically induced malabsorption of the fat in the treatment of severe
obesity].
PMID- 10778348
TI - [In Process Citation]
PMID- 10778349
TI - [Declined semen quality?].
PMID- 10778350
TI - Shaken baby syndrome.
PMID- 10778351
TI - [Infertility due to azoospermia. Causes, examination methods and therapeutic
strategies].
AB - Azoospermia can be due to a genetic defect (abnormal karyotype, Y chromosome
micro-deletion or cystic fibroses carrier), genital tract infection or trauma.
Examination of azoospermic men includes ultrasound examination of the scrotal
contents, prostate and seminal vesicles, hormone analysis, genetic examinations
and testis biopsy. Some patients with obstructive azoospermia can be cured
surgically. If passage can not be established through the genital tract, sperm
can be obtained from the epididymis or testis for micro-insemination of oocytes
from the female partner. No increased occurrence of malformations among children
born after micro-insemination has been found, but an increased occurrence of
severe reduced semen quality may be expected, when the "ICSI boys" grow up.
Freezing of additional sperm or testis tissue is recommended.
PMID- 10778352
TI - [Assessment of nutritional risks among elderly hospitalized patients - which body
mass index and degree of weight loss should be considered?].
AB - The "Subjective Global Assessment", the "Nutrition Risk Score" and a Danish
counterpart are simple screening methods to detect patients at risk of nutrition
related complications. The cut-off points used in the screening are a body mass
index (BMI) less than 20 kg/m2 (or 18.5 kg/m2 in the Danish version) and weight
loss of more than 5% during the last month--regardless of age. This review of the
literature indicates that the optimal range of BMI for elderly people is
increasing from 18.7-25 kg/m2 to 24-29 kg/m2. It also suggests that a clinically
significant weight loss for the elderly is around 5% annually, less than in
younger age groups. Finally, there seems to be a high percentage of the old,
especially those initially malnourished, who will not benefit from nutritional
support. In conclusion, other cut-off points should be used for elderly (65+
years) patients, i.e. BMI less than 24 kg/m2 or any degree of weight loss.
PMID- 10778353
TI - [Pesticides and time to pregnancy among Danish farmers].
AB - The aim of this study was to examine time to pregnancy among farmers who used
pesticides (traditional farmers) and farmers who did not (organic farmers). A
total of 904 men, selected from the Danish Ministry of Agriculture lists of
traditional and organic farmers, participated in telephone interviews. The
participation rate was 84%. Information was collected on "time to pregnancy" for
the youngest child, exposure to pesticides and potential confounders. Using the
discrete analogue of the Cox Regression Model (including potential confounders:
male and female smoking, female age, parity and contraceptive method), the
fecundability ratio between traditional farmers using pesticides and organic
farmers was 1.03 (95% CI: 0.75-1.40). In the group of farmers who sprayed with
pesticides, none of the characteristics related to the use of pesticides could
account for the variation in time to pregnancy. No overall effect of pesticides
on male fecundability could be demonstrated in this retrospective study among
Danish farmers.
PMID- 10778354
TI - [Semen quality and fertility in a population-based follow-up study].
AB - Little is known about the importance of semen quality in male infertility. We
followed 430 first pregnancy planners with no previous reproductive experience
recruited among more than 50,000 cohabiting trade-union members. The couples were
consecutively enrolled into the study as they discontinued contraception and were
followed up for six month menstrual cycles or until a pregnancy was verified.
Each man provided a semen sample at enrollment. Women kept daily record of
vaginal bleeding and sexual activity. The probability of conception increased
with increasing sperm concentration up to 40 x 10(6)/ml, but any higher sperm
density was not associated with additional likelihood of pregnancy. The
proportion of sperm with normal morphology was strongly related to likelihood of
pregnancy, independently of sperm concentration. In conclusion, sperm
concentration and morphology are valuable biological markers of male fecundity.
Reference values for semen quality based on biological knowledge can be
established.
PMID- 10778355
TI - [Occurrence of testicular cancer in subfertile men. A case-control study].
AB - In order to evaluate the association between male subfertility and the subsequent
risk of testicular cancer, a population-based case-control study was conducted in
The Danish population. Cases were identified in the Danish Cancer Registry;
controls were randomly selected from the Danish population using the computerized
Danish Central Population Register. The men were interviewed by telephone; 514
cases and 720 controls participated. A reduced risk of testicular cancer was
associated with paternity (relative risk = 0.63; 95% confidence interval: 0.47
0.85). In men who prior to the diagnosis of testicular cancer had a lower number
of children than expected on the basis of their age, the relative risk was 1.98
(95% confidence interval: 1.43-2.75). There was no corresponding protective
effect associated with a higher number of children than expected. The
associations were similar for seminoma and non-seminoma, and were not influenced
by adjustment for potential confounding factors. These data are consistent with
the hypothesis that male subfertility and testicular cancer share important
aetiological factors.
PMID- 10778356
TI - [Topical steroids in the treatment of phimosis in children].
AB - The aim of this study was to evaluate the efficacy of steroid application in the
treatment of childhood phimosis. In a consecutive study 91 boys were treated with
application of topical betamethason 0.05% cream twice daily. The foreskin was
treated for one month, with an attempt at foreskin retraction after fourteen
days. Treatment was controlled after one month and six months. Sixty boys
achieved full retraction of the foreskin and nine had partial retraction and
relief of symptoms. Twenty-two boys had unsatisfactory response and had an
operation. Forty-five boys were controlled after six months, 13 had recurrence,
of these nine were satisfied and free of symptoms, two had a new steroid
treatment with full success, and two wanted a circumcision. A total of 74% did
not need an operation after topical steroid treatment. No side-effects or
complications were registered. Childhood phimosis can be successfully treated
with steroid application, and the treatment should be offered prior to an
operation.
PMID- 10778357
TI - [Hearing tests in a specialized practice].
AB - The purpose of the study was to evaluate the quality of examinations performed in
ENT-practice as preparation for hearing aid (HA) fitting. The material comprises
113 referrals to an audiological department from the Eastern Danish area
including an audiogram. The referrals were evaluated concerning information
relevant for HA fitting. A comparison between the pure tone air conduction
hearing thresholds measured in the ENT-practice and in the audiological
department was also performed. Only one referral contained information about all
relevant examinations. Pure tone air conduction thresholds measured in ENT
practice deviated significantly at 250 Hz-4 kHz from the hearing thresholds
measured in the audiological department, and indicated poorer hearing at all
frequencies. Only 53% of the air conduction hearing thresholds evaluated for the
average of 0.5-4 kHz corresponded with the thresholds measured in the
audiological department within the repeatability of the test (i.e. +/- 10 dB). In
conclusion, the audiometries in the referrals should only be considered as
screening.
PMID- 10778358
TI - [Respiratory depression following medication change from tramadol to morphine].
AB - Respiratory depression following change of medication from tramadol to morphine
is described in two patients. Tramadol is metabolized by cytochromoxidase CYP2D6
to O-desmethyl-tramadol with opioid agonist activity. Of the western population
7% have a mutation of the gene responsible for CYP2D6, resulting in low enzyme
activity. These persons will have little effect of tramadol. When tailoring
analgesia, the lack of response to tramadol may be interpreted as a need for
opioid dose increase. In such cases, excessive opioid doses may be prescribed
resulting in opioid side effects.
PMID- 10778359
TI - [Thrombocytopenia caused by Parvovirus B19 infection in a child with acute
lymphatic leukemia].
AB - A three-year-old boy was diagnosed with acute lymphoblastic leukemia. Two years
later, while on maintenance chemotherapy, the patient was readmitted due to
thrombocytopenia. The thrombocytopenia was caused by parvovirus B19 infection as
evidenced by the finding of specific DNA in serum and bone marrow samples.
Previous reports have highlighted the role of parvovirus B19 as a haematological
pitfall and the present case shows that this virus has the potential to mimic a
leukemic relapse.
PMID- 10778360
TI - [The Danish Infertility Cohort--a research database].
PMID- 10778361
TI - The genetically modified food fight.
PMID- 10778362
TI - Providing universal coverage under national health insurance.
PMID- 10778363
TI - Why health care is failing in a booming economy.
PMID- 10778364
TI - Utilitarianism and the perversion of the ethics of hippocrates.
PMID- 10778365
TI - Beware of bosses bearing beverages.
PMID- 10778366
TI - A baby with pink cheeks.
PMID- 10778367
TI - Biotechnology company claims to have 97% of human genes on its database.
PMID- 10778368
TI - Breast cancer researcher accused of serious scientific misconduct.
PMID- 10778369
TI - Guidelines for advertising on health web sites: who's guarding the Koop.
PMID- 10778370
TI - Growing pains of the Internet age.
PMID- 10778371
TI - Oregon's suicide video.
PMID- 10778372
TI - Outbreak of boils in an Alaskan village: a case-control study.
AB - OBJECTIVE: To determine whether taking steam baths was associated with
furunculosis and to evaluate possible risk factors for the occurrence of boils
during a large outbreak in Alaska. DESIGN: A cohort study of village residents, a
case-control study, and assessment of environmental cultures taken from steam
baths. SETTING: Village in southwestern Alaska. PARTICIPANTS: 1 adult member from
77 of the 92 households in the village was interviewed; 115 residents with at
least one boil occurring between January 1 and December 12, 1996 were considered
to be cases; 209 residents without a boil acted as the control group. All 459
village residents were included in the cohort study. MAIN OUTCOME MEASURE: Rate
of infection among all residents and residents who regularly took steam baths,
risk factors for infection, and relative risk of infection. RESULTS: 115 people
(25%) had had at least one boil. Men were more likely to have had a boil than
women (relative risk 1.5; 95% confidence interval 1.1 to 2.2). The highest rate
of infection was among people ages 25-34 years (32/76; 42%). No children younger
than 2 years had had boils. Boils were associated with using a steam bath (odds
ratio 8.1; 3.3 to 20.1). Among those who used a steam bath, the likelihood of
developing boils was reduced by routinely sitting on a towel while bathing, which
women were more likely to do, and bathing with fewer than 8 people. Of the 93
samples taken from steam baths, one Staphylococcus aureus isolate was obtained
from a bench in an outer dressing room. CONCLUSION: Using a steam bath was
associated with developing boils in this outbreak in a village in Alaska. People
should be advised to sit on towels while using steam baths.
PMID- 10778373
TI - Using towels and soap in steam baths could reduce infection.
PMID- 10778374
TI - Active management of labor: a cost analysis of a randomized controlled trial.
AB - OBJECTIVE: To compare the costs of a protocol of active management of labor with
those of traditional labor management. DESIGN: Cost analysis of a randomized
controlled trial. METHODS: From August 1992 to April 1996, we randomly allocated
405 women whose infants were delivered at the University of New Mexico Health
Sciences Center, Albuquerque, to an active management of labor protocol that had
substantially reduced the duration of labor or a control protocol. We calculated
the average cost for each delivery, using both actual costs and charges. RESULTS:
The average cost for women assigned to the active management protocol was
$2,480.79 compared with an average cost of $2,528.61 for women in the control
group (P = 0.55). For women whose infant was delivered by cesarean section, the
average cost was $4,771.54 for active management of labor and $4,468.89 for the
control protocol (P = 0.16). Spontaneous vaginal deliveries cost an average of
$27.00 more for actively managed patients compared with the cost for the control
protocol. CONCLUSIONS: The reduced duration of labor by active management did not
translate into significant cost savings. Overall, an average cost saving of only
$47.91, or 2%, was achieved for labors that were actively managed. This reduction
in cost was due to a decrease in the rate of cesarean sections in women whose
labor was actively managed and not to a decreased duration of labor.
PMID- 10778375
TI - The active management of labor: is it worth the cost?
PMID- 10778376
TI - Poor-quality studies suggest that vitamin B6 use is beneficial in premenstrual
syndrome.
PMID- 10778377
TI - A psychoeducational program increased knowledge and decreased sexual risk
behaviors in young adults with genital herpes.
PMID- 10778378
TI - A low dose of albuterol by metered-dose inhaler with a spacer was as effective as
higher doses by metered-dose inhaler or low doses by nebulizer in children with
mild acute asthma.
PMID- 10778379
TI - Severe neutropenia: a diagnostic approach.
PMID- 10778380
TI - How molecular epidemiology has changed what we know about tuberculosis.
PMID- 10778381
TI - How to treat influenza and colds.
PMID- 10778382
TI - Can exercise-induced muscle damage be avoided?
PMID- 10778383
TI - Anatomy of a medical accident.
PMID- 10778384
TI - An honest mistake, within the standard of care, will not result in a finding of
liability.
PMID- 10778385
TI - Placebo-controlled trials: good science or medical neglect?
PMID- 10778386
TI - Medical practice 2010: how we get there.
PMID- 10778387
TI - The biosphere theory of V. I. Vernadsky and the Gaia theory of James Lovelock: a
comparative analysis of the two theories and traditions.
AB - James Hutton (1726-1797) regarded Earth as a super-organism and physiology the
science to study it. A strong line of evidence for an intimate relationship of
biological and abiotic processes on Earth leads from Hutton to the Gaia theory of
J. Lovelock. A less known in the West but important approach to the biosphere as
a self-regulating system (the biosphere theory) was proposed V.I. Vernadsky (1863
1945). The main concern of this paper revolves around the question: What is the
difference between Gaia and the biosphere? To approach the problem of Earth as a
super-organism one can use also the biosphere theory of V. N. Beklemishev (1890
1962), who examined the biosphere from a morphological viewpoint.
PMID- 10778388
TI - [The mathematical modelling of population dynamics taking into account the
adaptive behavior of individuals].
AB - The general approach for modelling of abundance dynamic of biological populations
and communities is offered. The mechanisms of individual adaptation in changing
environment are considered. The approach is detailed for population models
without structure and with age structure. The property of solutions are
investigated. As examples the author studies the concrete definitions of general
models by analogy with models of Ricker and May. Theoretical analysis and
calculations shows that survival of model population in extreme situation
increases if adaptive behaviour is taking into account.
PMID- 10778389
TI - Identification of highly conserved hydrophobic amino acid motif in deduced amino
acid sequence of Elymus sibiricus L. mitochondrial S13 ribosomal protein.
AB - The nucleotide sequence of mitochondrial ribosomal protein rps13 gene from wild
perennial grass Elymus sibiricus is presented. It was determined by the method of
PCR amplification with specific oligonucleotide primers and the direct sequencing
of the amplification product. The sequence of E. sibiricus mitochondrial gene for
S13 predicts a hydrophobic ribosomal protein of 116 amino acids that shows strong
similarity to those of wheat (99.7% identity) and maize (98%). The deduced amino
acid sequence of S13 protein from E. sibiricus and homologous plant's (Zea mays,
Daucus carota, Nicotiana tabacum, Marchantia polymorpha) and nonplant's
(Escherichia coli) proteins shows the presence of hydrophobic amino acids' motif
L-X10-L-X10-M-X10-L-X10-L-. Slightly modified it can be found in many other
ribosomal proteins. This conserved motif is presumed to be particularly important
for association of the ribosomal S13 protein with other proteins in the small
subunit of the mitochondrial ribosome.
PMID- 10778390
TI - [The calcium and magnesium ion metabolic characteristics of water plants in
different taxonomic groups].
AB - Ca2+ and Mg2+ metabolism was investigated in 7 angiosperms and 3 moss species
from fresh water of different mineral content. It is considered that adaptation
in the water with low mineral content is connected with the decrease in salt
wastes of an organism. The adaptation of ion-transport system of aquatic plants
to living under conditions of low mineralization is higher in mosses than in
angiosperms. Characteristics of mosses are very low speed of salt waste in
distillate water (V0) and concentration of balance (Cb). According to suitability
of ion metabolism system to the existence in water with low mineralization
angiosperms could be divided into three groups. Some species are close to mosses,
but the majority of plants are adopted to the water with medium or high
mineralization. The difference in ion metabolism is connected with the conditions
of origin of the given groups. The authors consider that effective adaptations
were formed in the ancestor group of this taxon.
PMID- 10778391
TI - [The input of the chemical potential gradient of the water in the medium to the
energy balance of terrestrial vascular plants].
AB - One of the characteristic feature of activity of plant organism vital functions
is a speed of its inner water flow. The main source of energy providing the
transport of water is gradient of water chemical potential between soil and
atmosphere. In case of equal potentials of these surroundings, the plant organism
have additional energetic expenses to compensate the energy of external source.
Series of experiments to investigate the influence of saturation of atmosphere
with water (equilibrium of potentials) to energetic balance of plant were carried
out. The results shows that: 1) etiolate seedlings in this conditions waste 10-15
percent energy per unit of new formation more than under 70-80 percent humidity;
2) saturation of atmosphere with water above plants with well developed
transpiration surface leads to the decrease in their heat content; 3) equilibrium
of water chemical potentials of different environments increases the intensity of
intact root transpiration, i.e. intensifies "the burning" of organic matter.
Thus, gradient of water chemical potential existing in nature between
environments of different organs if sufficient source of energy for a plant.
PMID- 10778392
TI - [The mechanisms of the restriction of pollinator range in the fireweed
(Chamaenerion angustifolium) and 2 species of geranium (Geranium palustre) and G.
pratense)].
AB - Flowers of Chamaenerion angustifolium, Geranium palustre and G. pratense are
visited by more than 100 insect species. For all plants the spectrum of visitors
is similar. However the role of insects species in pollination is different and
depends on the stamen and stigma length, flexibility of pedicle and feeding
behaviour of insect inside flower. The possibility to take and to transport
pollen grains usually increase with the size of insect. The nature of this
correlation is determined by stamen and stigma length. Pollinators of G. palustre
with short stamens and stigmas are smaller than those of Ch. angustifolium and G.
pratense. On the other hand, more flexible pedicle of G. palustre prevent the
flowers from visits of big insects. Three plants studied by the authors are not
equally attractive for different insect groups. Dense in fluorescence of Ch.
angustifolium and G. pratense that usually are lifter under the grass are very
attractive for foraging social insects (honey bee, bumblebee). Flies avoid long
distance travelling and prefer single flowers located not far from each other.
For instance G. palustre is more attractive for flies not for social bees. It is
pollinated mainly by flies and solitary bees with average weight of 10-70 mg. The
main pollinators of Ch. angustifolium and G. pratense are honey bees, bumblebees
and wasps with average mass exceeding 70 mg.
PMID- 10778393
TI - [The sensitivity of the moor frog Rana arvalis Nilss. tadpoles to natural L-amino
acids and its alteration in ontogeny].
AB - The Rana arvalis tadpoles at 27-40 stages responded to solution of some L-amino
acids in concentration 10(-2) mol/l with feeding reactions. The range of
perceptible amino acids increased during development from 10 to 16. The best
feeding stimuli were aspartic and glutamic acids; amino-acids (proline and
oxyproline), methionine, leucine and isoleucine did not evoke the significant
reactions. The sensitivity to some amino acids (alanine, glutamine, lysine,
ornithine, proline and valine) was 10(-5)-10(-4) mol/l at earlier stages and
increased to 10(-6)-10(-5) mol/l during larval ontogenesis.
PMID- 10778394
TI - [The migrations of the green oak tortrix Tortrix viridana L. (Lepidoptera,
Torticidae): an analytical study].
AB - The author analyses mono-factorial theories of population dynamics of Tortrix
viridana and discusses the hypothesis of its distant and attended migrations
together with its specialized parasitoid Dirophanes invisor. Data on T. viridana
temporal-spatial distribution for the period of 1938-1995 are presented. It was
shown that the main factors caused the decrease in population numbers are intra
population mechanisms, providing the initiation long embryonic diapause for some
part of population, the decrease in the frequency of its outbreaks. Some data
indicate that large scale migrations are not important for spreading of T.
viridana outbreaks.
PMID- 10778396
TI - [Laser revascularization--a questionable method without revascularization].
PMID- 10778395
TI - Lung volume reduction surgery.
PMID- 10778397
TI - ["The best prescription may be no prescription"].
PMID- 10778398
TI - [Percutaneous myocardial laser revascularization. A new therapy technique for
patients with coronary disease and severe angina pectoris without conventional
therapy options].
AB - BACKGROUND AND OBJECTIVES: In patients with intractable angina because of end
stage coronary artery disease, transmyocardial laser revascularization (TMR)
leads to improvement of angina pectoris and increased exercise capacity. However,
surgical thoracotomy is required for TMR with considerable morbidity and
mortality. Therefore, a catheter-based laser system has been developed which
allows to create laser channels into the myocardium from the left ventricular
cavity. PATIENTS AND METHODS: 46 patients (38 m, 8 f) with refractory angina
pectoris due to severe coronary artery disease were treated with "percutaneous
myocardial laser revascularisation" (PMR). Clinical parameters (severity of
angina pectoris, use of additional nitroglycerin) and results of non-invasive
tests (exercise-ECG, echocardiography, thallium-scintigraphy) were analysed at
baseline and 3, 6 and 12 months after PMR. RESULTS: The PMR procedure was
successfully completed in all patients. In 30 patients, one region (anterior,
lateral, inferior) of the left ventricle was treated and in 16 patients, 2 or 3
regions were treated. Clinical follow-up demonstrated significant improvement of
angina pectoris (CCS-class at baseline: 3.1 +/- 0.2, 3 months after PMR: 1.8 +/-
0.7, 12 months after PMR: 1.5 +/- 0.9) (p < 0.001) and increased exercise
capacity (exercise time on standard bicycle ergometry at baseline: 383 +/- 151 s,
3 months after PMR: 494 +/- 140 s, 12 months after PMR: 480 +/- 151 s) (p <
0.05), but thallium scintigraphy failed to show improved perfusion of the laser
treated regions. CONCLUSIONS: PMR is a new safe and feasible therapeutic option
in patients with refractory angina pectoris due to end-stage coronary artery
disease. Initial results show significant improvement of clinical symptoms and an
increased exercise capacity but thallium scintigraphy failed to show improved
perfusion after PMR.
PMID- 10778399
TI - [Clinical value of scintigraphy for gastrointestinal bleeding. Experiences in a
large community hospital].
AB - BACKGROUND AND OBJECTIVE: In the majority of cases of gastrointestinal bleeding
the site and cause can be determined by gastroscope. If this is unsuccessful,
radiological and nuclear-medical tests are available. This study was undertaken
to determine the value of scintigraphy in diagnosing of the site of
gastrointestinal bleeding. PATIENTS AND METHODS: The data on 155 patients who,
between 1984 and 1988, had undergone 161 scintigraphies (with 99mTc-labelled
erythrocytes, 5 with 99mTc-Sn colloid) were retrospectively analysed. The results
were compared with other diagnostic tests that had been performed, with the
definitive diagnosis and, where applicable, the findings at surgery. RESULTS: 78
scintigrams (47%) provided positive results. The site of bleeding had been
demonstrated ca. 20 hours after the diagnostic studies had begun. In 47 of the
cases the diagnosis was confirmed by additional tests. The intestine was the most
common site of bleeding. Localization of the source of bleeding by scintigraphy
and other diagnostic tests succeeded in 34 cases, with a 82% concordance between
the tests. No bleeding was demonstrated in 88 scintigrams (53%), including all
those done with Sn-colloid. In 13 cases the final diagnosis suggested that there
had been no previous bleeding and in 43 cases the source of bleeding could not be
determined. In 32 scintigraphically negative cases the source of bleeding was
demonstrated by other tests. But only 2 of the 13 angiograms and none of the 33
double-contrast studies of the small intestine gave positive results. Among the
total number of cases in which bleeding was demonstrated, scintigraphy had a
sensitivity of 71%. CONCLUSION: Because of the long duration of observation,
scintigraphy with 99mTc-labelled erythrocytes proved superior to other diagnostic
tests in the demonstration of the bleeding. By localizing the source of bleeding
in a definite part of the gastrointestinal tract, scintigraphy points the way to
choosing other diagnostic methods or treatment. If the initial endoscopy has
failed, scintigraphy, a method of low invasiveness, should be included when
further tests are planned.
PMID- 10778400
TI - [Hepatocellular carcinoma with extension per continuitatem into the right
atrium].
AB - HISTORY AND CLINICAL FINDINGS: A 61-year-old asymptomatic patient presented with
a hepatocellular carcinoma and a history of 11 cycles of transarterial
chemoembolization. Staging investigations revealed an enlarged hepatic tumour and
a right atrial mass. INVESTIGATIONS: Computed tomography of chest and abdomen
showed a progressive tumour in both hepatic lobes with extension to the inferior
vena cava, through the diaphragma and to the right atrium. TREATMENT AND COURSE:
The patient received supportive treatment and died 3 months later. CONCLUSION:
Inspite the incidence of 1-4%, hepatocellular carcinoma with extension to the
heart has been diagnosed rarely. Although treatment is limited, early diagnosis
by abdominal echography or echocardiography is necessary for the interpretation
of cardiogenic symptoms and the prognosis.
PMID- 10778401
TI - [Hepatocyte transplantation. Possibilities for use and examples of practical
clinical application].
PMID- 10778402
TI - [Self-medication--economic, sociopharmacologic and toxicologic aspects].
PMID- 10778404
TI - [Protection against dismissal after the law for the severely disabled].
PMID- 10778403
TI - [Migraine treatment].
PMID- 10778405
TI - Is it time to address our future? Ethical and financial imperatives in HIV care.
PMID- 10778406
TI - Recent hepatitis C virus studies examined.
PMID- 10778407
TI - Best treatment of jellyfish stings?
PMID- 10778408
TI - Toxic epidermal necrolysis. A widespread, life-threatening blistering reaction.
PMID- 10778409
TI - Could your practice use a waiting room kiosk? How to turn waiting time into
learning time.
PMID- 10778410
TI - Hypertension in patients with diabetes. Strategies for drug therapy to reduce
complications.
AB - Hypertension in diabetic patients must be treated aggressively if patients are to
benefit from reduced risk of morbidity and mortality. Diabetes itself must be
diagnosed promptly, particularly in at-risk patients, so appropriate lifestyle
modifications can be made at the earliest opportunity. Although this may reduce
or delay onset of hypertension, antihypertensive drug treatment should be
initiated in the diabetic patient with even high-normal blood pressure.
Traditional approaches to management of hypertension are inappropriate for most
patients with diabetes. While ACE inhibitors, calcium antagonists, angiotensin II
receptor blockers, beta blockers, and low-dose diuretics, alone or in
combination, all currently have roles in hypertension management, the outcomes of
studies now under way may clarify some still unanswered questions about the
dangerous combination of high blood pressure and diabetes.
PMID- 10778411
TI - Infectious vaginitis. An accurate diagnosis is essential and attainable.
AB - Infectious vaginitis is a common clinical problem. Unfortunately, treatment,
including self-medication, is often instituted before an adequate evaluation has
been performed. An accurate diagnosis can usually be made in the office setting,
and effective pharmacologic treatments are readily available.
PMID- 10778412
TI - A systematic approach to laceration repair. Tricks to ensure the desired cosmetic
result.
AB - An organized, systematic approach to wound repair based on the mnemonic LACERATE
can jog the memory and ensure a successful outcome. This stepwise approach
consists of looking at the wound to assess repair options, anesthetizing and
cleaning the wound, setting up equipment, selecting the proper repair technique,
assessing results, determining the patient's tetanus immunization status, and
educating the patient about wound care.
PMID- 10778413
TI - Pleural effusions in cardiovascular disease. Pearls for correlating the evidence
with the cause.
AB - In patients with cardiomegaly and signs and symptoms compatible with CHF,
unilateral right-sided or bilateral pleural effusions of similar size are likely
to be due to left-sided CHF. Isolated right ventricular failure or chronic
pulmonary hypertension is not usually associated with pleural effusions, and
unrecognized or new-onset left ventricular dysfunction and other causes should be
considered when a patient with cor pulmonale presents with a pleural effusion.
Unilateral left-sided pleural effusions with cardiomegaly may be due to
pericardial disease. Current hypotheses do not adequately explain the laterality
of effusions in CHF or pericardial disease. Clinical and radiographic correlation
is always required; however, the associations described occur often enough to
make them useful in day-to-day clinical practice. When ascribing pleural
effusions to CHF, clinicians must be sure the clinical signs and history "fit the
picture," because pneumonia and pulmonary embolism may also cause pleural
effusions in patients with heart failure. Typical pleural effusions in patients
with uncomplicated CHF (demonstrated by small to medium-sized effusions and the
absence of fever, leukocytosis, pleuritic chest pain, or marked asymmetry in
bilateral effusions) do not require routine diagnostic thoracentesis for
evaluation. A reasonable approach in such cases is treatment of the underlying
CHF and follow-up radiography to monitor for resolution of the effusions. Prompt
diagnostic thoracentesis is indicated whenever atypical features are present and
other diagnoses are under consideration.
PMID- 10778414
TI - Corticosteroids for tuberculosis?
PMID- 10778415
TI - Primary HIV infection. Current trends in transmission, testing, and treatment.
AB - In the changing kaleidoscope of HIV disease, early detection of primary infection
has become increasingly important. Primary care physicians who recognize the
signs and symptoms are in an ideal position to diagnose the disease at an early
stage and to help stem the tide of new infections in the community. In this
article, Drs Yu and Daar discuss current strategies for early diagnosis,
including recommended testing and steps to prevent transmission of the virus, and
present the latest thinking about antiretroviral therapy during primary HIV
infection.
PMID- 10778416
TI - Practical approaches to HIV therapy. Recommendations for the year 2000.
AB - Despite advances in treatment, HIV infection continues to present a daunting
global medical challenge. Rapid development of new pharmaceutical agents has led
to significant increases in the effectiveness of therapy. However, as use of
antiretroviral drugs increases, so does our appreciation of the potential toxic
effects of these agents. In-depth knowledge of HIV pathophysiology and the
characteristics of individual drugs is mandatory for any physician caring for
patients with HIV infection. In this article, Dr Wolfe outlines a practical
approach to HIV therapy based on current consensus and his own recommendations.
PMID- 10778417
TI - HIV-associated metabolic and morphologic abnormality syndrome. Welcome therapy
may have unwelcome effects.
AB - Metabolic and morphologic complications of HAART are probably caused by several
interrelated and complex physiologic processes that are just beginning to be
understood. Whether there is validity to the current theories regarding
mitochondrial toxicity of NRTIs, lipid pathway interruptions of protease
inhibitors, or the host immune response itself as the primary culprit remains to
be seen. In the interim, physicians should use great caution and be circumspect
in their judgment with regard to "quick-fix" treatments of these complications.
Furthermore, scientifically unsupported decisions about switching antiretroviral
agents in an attempt to alleviate a particular toxic effect may place the patient
at risk for antiretroviral-therapy failure. Formal adoption of a case definition
of HAMMAS remains a priority for the scientific community, because anecdotal
observations compiled to date do not yet constitute a discrete syndrome. A clear
case definition, possibly modeled after criteria for defining rheumatic diseases,
will greatly facilitate properly designed research trials to elucidate causes and
possible treatments of this troublesome syndrome.
PMID- 10778418
TI - Designing salvage antiretroviral regimens. Some basic guidelines and use of
resistance testing.
AB - Treatment of HIV infection is rapidly changing from a hit-or-miss hodgepodge of
unknowns, in which nearly anything beneficial was acceptable, to a true science
based on reproducible principles. With this growth in complexity, HIV therapy has
become a valid field of medicine. The potency of available agents, their success
in suppressing the destructive nature of HIV infection, and the increasingly
rapid pace of technology development in this area require that HIV-seropositive
patients be treated by physicians specializing in the field. The growing but
finite number of antiretroviral therapeutic agents demands that a thoughtful,
strategic, long-term approach be formulated. The evolving science of
antiretroviral resistance testing offers great promise for better shaping this
approach, which is still less than straightforward. Potential interactions, some
good and some bad, between mutations within HIV genes will profoundly affect
therapy and are still to be defined. Declaring that a regimen has failed and
choosing a new one to replace it is a complex task, particularly when all the
factors involved are considered (e.g., rising viral load, declining CD4 count,
patient adherence, patient preferences, drug interactions, adverse effects). Care
of HIV-positive patients has always been an art, and now at last it is becoming a
science.
PMID- 10778419
TI - HIV disease in children. The many ways it differs from the disease in adults.
AB - HIV infects and affects children differently than it does adults. An
understanding of the epidemiology of pediatric HIV infection may reveal
opportunities to reduce and perhaps eliminate perinatal transmission. Knowledge
of unique diagnostic features of HIV-exposed newborns and pathogenetic
characteristics reflected in clinical manifestations helps physicians meet the
management challenges presented by children with HIV and their families.
PMID- 10778420
TI - Cancer genetics in primary care. When is genetic screening an option and when is
it the standard of care?
AB - In some families, predisposition to cancer is caused by a germline mutation in a
single gene, which produces an autosomal dominant pattern of cancer transmission.
Several hereditary cancer syndromes have been identified and for many of them,
genetic testing is clinically available. Determining which patients are at risk
for hereditary cancer begins by taking a complete family history. In particular,
a three-generation family history and pedigree can provide valuable information
for both patients and primary care physicians. When the history supports the
possibility of hereditary cancer, a qualified genetic professional can assist
with specific advice about testing and treatment options for the entire family.
If pedigree analysis substantiates a heritable form of cancer, patients should be
thoroughly informed about potential benefits, limitations, and risks of genetic
screening and offered testing as appropriate. The ultimate goal is to reduce
cancer morbidity and mortality through interventions that decrease cancer risk or
increase early detection.
PMID- 10778421
TI - How to handle myasthenic crisis. Essential steps in patient care.
AB - Myasthenic crisis, or respiratory failure requiring intubation and mechanical
ventilation, may be caused by infections, aspiration, physical and emotional
stress, and changes in medication. Although no single factor determines the need
for respiratory support, all patients with questionable respiratory status should
be admitted to the ICU. Because management of crisis includes treatment of the
underlying myasthenia gravis, a neurologist should share in any decisions
regarding care.
PMID- 10778422
TI - Lipid screening in adults. Working to prevent coronary artery disease. Institute
for Clinical Systems Improvement.
PMID- 10778423
TI - Asymptomatic 'streaks' in a healthy young man. Adolescent lumbar striae.
PMID- 10778424
TI - Foodborne and waterborne infectious diseases. Contributing factors and solutions
to new and reemerging pathogens.
AB - Demographic changes and complexities in food production, combined with
complacency about the role of infectious diseases in general and the safety of
the US food supply in particular, have brought about a resurgence in foodborne
and waterborne infectious diseases and, with it, challenges that are
unprecedented in recent times. A vigorous effort is already under way to ensure
that food and water supplies are safe. This renewed attention to food and water
safety must not be an interim response to a perceived short-term threat but,
rather, a long-term effort to protect the population from pathogenic
microorganisms whose wily adaptations will require constant vigilance.
PMID- 10778425
TI - HIV and AIDS update.
PMID- 10778426
TI - Condoms and safe sex.
PMID- 10778427
TI - [The repair processes and cell populations relationship in bone marrow of
patients with acute radiation injury: morphological study].
AB - The results of bone marrow pathomorphologic investigation in patients who died of
acute radiation sickness (3.7-13.7 Gy) after the Chernobyl accident are
presented. Stratification into three consecutive periods was performed according
to the length of postexposure survival (14-96 days) and the morphologic picture
dynamics: 1) bone marrow aplasia (2-3 weeks after exposure) with a domination of
stromal and plasma cell populations, exhibiting the morphologic characteristics
of functional activity; 2) initial repair period (3-4 weeks after exposure) was
characterized by the beginning of hematopoietic proliferation with simultaneous
occurrence of cell death via apoptosis; 3) active repair period (4 and more weeks
after exposure) was defined by increased marrow cellularity (trilineage
regeneration), accompanied by decreased number of plasma cells and occurrence of
large granular lymphocytes.
PMID- 10778428
TI - [The nature of SOS response in E. coli K-12 (uvrA) cells exposed to the different
ultraviolet doses].
AB - The kinetic and dose dependencies of the SOS-induction in E. coli (uvrA) cells
exposed to UV light were investigated. Below 2 J/m2 the rate of the SOS-induction
increased with dose. The maximal level of the SOS-response was proportional to
the UV dose. Pyrimidine dimers were necessary for the induction. In the dose
range 2-10 J/m2 the rate of the SOS-induction decreased with dose. The dose
response curve was non-linear. Pyrimidine dimers were not required for the
induction. The nature of the molecular events leading to the SOS-induction at low
and high doses was discussed.
PMID- 10778429
TI - [Methods of automated cell analysis and their application in radiation biology].
AB - The present review is concerned with the methods of automated analysis of
biological micro-objects and covers two groups into which all the systems of
automated analysis can be divided--systems of flow (flow cytometry) and scanning
(image analysis systems) type. Particular emphasis has been placed on their use
in radiobiological studies, namely, in the micronucleus test, a cytogenetic assay
for monitoring the clastogenic action of ionizing radiation commonly used at
present. It is evident that the problem is acute, with of radiobiologists'
interest in the biological action of low-dose radiation recently increasing. In
addition, the estimation of a low-level damage requires the analysis of a large
number of experimental objects. Examples of using both the methods elsewhere and
actual setups are given. The analysis of advantages and disadvantages of the
methods of automated cell analysis enables us to choose more thoroughly between
the systems of flow and scanning type to use them in particular research.
PMID- 10778430
TI - [The effect of urea, gamma- and UV-irradiation on physico-chemical
characteristics of native and immobilized inulinase].
AB - The immobilization of inulinase by ionexchange AB-26 and AB-17-2P has been made
by adsorbtion and glutaraldehyde methods. The effect of UV-radiation, carbamide
and gamma-rays on the stability of native and immobilized enzyme has been
investigated. The stability of inulinase in relation to denaturation agents has
been shown to increase with the immobilization of ionexchange. The character of
binding with the matrix affects greatly the stability of immobilized enzyme to
physical factors.
PMID- 10778431
TI - [The effect of ionizing radiation on Ca ATPase of erythrocyte membranes].
AB - Erythrocyte ghosts were irradiated with doses of 4 x 10(-3)-10(3) Gy. The
activity of Ca(2+)-ATPase, the kinetic characteristics of enzyme reaction, the
Hill's coefficient, the association constant and a number of La3+ linking centers
were determined. The structural--functional peculiarities of Ca(2+)-ATPase
changes under exposure to 4 x 10(-3) and 40 Gy of ionizing radiation have been
established.
PMID- 10778432
TI - [Autoimmune disorders in liqvidators 11 years after the Chernobyl accident].
AB - We studied long-lasting consequences of the low-doses irradiation on the immune
system of 71 clean-up workers who participated in the emergency work after the
Chernobyl Plant accident in 1986 and 25 healthy donors from Belarus. In sera of
the workers the level of autoantibodies to thyroid gland antigens (thyroglobulin
and microsomal fraction of thyroid gland) was increased in 48% of cases, the
level of autoantibodies to lens oculis antigen was increased in 44% of cases; the
level of circulating immune complexes was elevated in 55%, and the serum level of
thyroglobulin in 60% of people. Immunological disorders were found without any
definite clinical evidences of diseases and this allows us to consider the
examined contingent as a group of risk for the development of autoimmune
pathology in the future.
PMID- 10778434
TI - [The effect of acute external gamma-irradiation and thyroid glands dysfunction on
rat reproductive system and frequency of structural mutations in somatic cells of
pregnant females and their offspring].
AB - Experimental hypofunction of thyroid gland, caused by mercazolil administration,
and acute external exposure to 0.5 and 1.0 Gy of gamma-irradiation were shown to
result in disturbance of reproductive function in puberal females and of
estrogenreceptor interaction, in reduction of pregnancy probability, increase in
pre- and postimplantation lethality of fetuses as well as in rise in the
frequency of structural mutations in somatic cells of pregnant rats and their
offspring.
PMID- 10778433
TI - [Quantitative regularities for clinical manifestations of radiation injury in
large-sized laboratory animals exposed to supralethal radiation doses Gamma
neutron and electron biological effectiveness as influenced by exposure
conditions and dose distribution in the animal body].
AB - The damaging effect of gamma-neutron radiation over a wide neutron-energy range,
with average values of 0.37 and 1.2 MeV, and that of electrons with an average
electron energy of 25 MeV have been compared in dogs and two monkey species
exposed to a broad range of supralethal doses. An analysis of absorbed dose
distribution in critical organs and systems has shown the highest effect of gamma
neutron radiation with an average neutron energy of 1.2 MeV. With severity of
early clinical manifestations of damage as a criterion, electrons have appeared
the most effective. The radiosensitivity of animals grew in the order as follows:
dog-->M. fascicularis-->P. hamadryas.
PMID- 10778437
TI - [Effect of co-polymer 2-methyl-5-vinylpyridine and 2-methyl-5- vinylpyridinium-n
oxide radiation induced myelodepression in mice].
AB - On the model of cytopenia induced in mice by irradiation with a dose of 4.0 Gy it
was shown that injection of examined copolymer (400 mg/kg) 3 h after irradiation
exerts positive effect on haemopoietic system: the decrease of damage and
acceleration of repair processes.
PMID- 10778435
TI - [Relationship between electronic structure and eadioprotective activity of some
indazoles].
AB - Quantum chemical MNDO study of electronic structure for 29 indazoles has been
performed. Statistically significant quantitative relation between some
characteristics obtained and radioprotective activity was found out. Indazole
structures which data predicted for radioprotective activity (survival, %) are on
50% level or more are proposed.
PMID- 10778438
TI - [Lymphocyte subpopulation of human peripheral blood responds to the low doses of
ionizing radiation,interleukin-2 and to both factors].
AB - Increasing of 3H-thymidine incorporation in lymphocytes of human peripheral blood
which depends non-linearly on X-ray dose (3 cGy max) and interleukin-2 (IL-2)
concentration (17.5 Units/ml) is shown. However addition of IL-2 (17.5 U/ml) into
the medium of cells after irradiation (3 cGy) decreases almost to the control the
effects induced by independently shown actions. Lymphocytes subpopulation
responsible for the described phenomena are isolated during the fractionation of
lymphocytes in the density gradient and pH (V-fraction BSA). Cell fraction less
than 1-2% from the isolated lymphocytes is characterized by increasing of
spontaneous corporation of 3H-thymidine, large sizes (d > 8 mkm), decreasing
repair after UV-irradiation. It is believed that low dose irradiation and IL-2
activate this cell subpopulation of "last reaction", and higher doses of these
factors and this both actions stopping 3H-thymidine incorporation initiate
apoptosis. The relation of this sell subpopulation and before proposed
ontogenetical reserve cells is discussed.
PMID- 10778436
TI - [Radioprotective activity and toxicity of copolymer 2-methyl-5-vinyl pyridine
with 2-methyl-5-vinylpyridinium-n-oxide].
AB - In experiments in mice, hamsters and dogs therapeutic radioprotective efficiency
and toxicity of new water-soluble copolymer were studied. It was found that at
intramuscular injection of the copolymer to dogs in a dose of 5 mg/kg 24 h after
irradiation with a dose of 3.30 Gy (LD85/45) it showed pronounced therapeutic
effect (68.1%). In mice and hamsters, the effect was less pronounced: 42-21%
after irradiation with a dose of 8.0 Gy. The copolymer is low toxic substance and
according to the State standards of Russian Federation belongs to the fourth
class (harmless).
PMID- 10778439
TI - [Effect of low doses of ionizing irradiation on viability of cortical
thymocytes].
AB - The cortical thymocytes of rats in whole organism, isolated lobes of thymus and
cells suspension were exposed to ionizing radiation in a wide range of doses (0.1
200 cGy). In contrast to relatively high dose radiation (50-200 cGy), exposure to
doses of 10 cGy resulted in cell death without DNA degradation. The level of
doses lower than 10 cGy (0.5-5 cGy) induced thymocyte death which is independent
of DNA degradation, RNA and protein synthesis. With decrease in radiation dose,
the increase of latent period preceding cell death took place.
PMID- 10778440
TI - [Pharmacological approaches to study of choline- and GABA-receptor sta tes in
neuronal membranes after low doses irradiation].
AB - As a result of the study of both the acetylcholine (10(-10) M; 10(-6) M) and
gamma-aminobutyric acid (10(-9) M; 10(-5) M) effects on active K+ transport in
rat brain cortex slices using any selective antagonists of cholinoreceptors (ChR)
and GABA-receptors (GABA-R) it had been shown that after whole-body 25 cGy
irradiation (1.75 mGy/min) metabotropic muscarinic ChR and GABAB-R were involved
into processes of neurotransmitter modulation, whereas under the normal
conditions they were mediated via ionotropic nicotinic ChR and GABAA-R. Observed
changes were supposed to be an adaptive reaction. Perhaps, postirradiation
structure-functional disorders in receptors were pointed as one of the reasons
leading to essential changes in the interneuronal metabolic communication
processes in CNS.
PMID- 10778442
TI - [Sexual function of male rats exposed to the factors of the Chernobyl exclusion
zone].
AB - The influence of chronic internal and external irradiation in low doses on sexual
behavior and fertility of sexual active animals keeping within the 30-km
Chernobyl exclusion zone was studied. After the 1.5 month consumption of drinking
water containing radionuclides of natural Chernobyl spectrum the decrease in
proportion of sexual active animals and suppression of sexual motivation and
erection were observed. This deviations resulted in the reducing of the
inseminated females number. The dependence between the magnitude of total
absorbed dose and the working of the sexual behavior regulative mechanisms was
obtained. In addition, the reduction of rat fertility took place because of the
increase of preimplantation, but not post-implantation death in in irradiated
females coupled with irradiated males. The irradiation of males with total
absorbed dose on testis 0.23 cGy decreased the fertility because of sexual
behavior disturbance, and this effect was intensified by negative influence of
ionizing radiation in the range of 0.7-7.0 cGy on male gametes.
PMID- 10778441
TI - [The effect of lead on DNA repair in thymocytes of gamma-irradiated mice].
AB - The effects of Pb on the repair of DNA have been studied in the thymocytes of
gamma-irradiated mice exposed to diacetate lead in the drinking water (up to 20
mg/l) for 14-50 days. It is found that lead causes no DNA degradation by itself
and renders its genotoxic action indirectly, via inhibiting the repair of single
strand DNA breaks induced by acute gamma-irradiation of mice. Genotoxic effect of
lead is reversible that becomes evident when exposed animals are maintained on Pb
free drinking water for 1-2 weeks.
PMID- 10778443
TI - [The effect of internal exposure to 90Sr on hematopoietic stem cells in CBA
mice].
AB - After acute intake of 90Sr the changes of d-9 CFUs number in mice (CBA) bone
marrow, spleen and peripheral blood were investigated. The obtained results
indicated similar quantitative changes in bone marrow and spleen CFUs on exposure
to the 90Sr when radiation doses did not cause the decrease in life-time (1.11
kBq/g). Sarcomogeneous doses of 90Sr (29.6 kBq/g) resulted in drastic changes of
hemopoietic system: spleen haematopoiesis activation and suppression of bone
marrow functions. On the first day after 90Sr injection (29.6 kBq/g) the increase
in number of peripheral blood CFUs (circulating pool) was observed.
PMID- 10778444
TI - [Simultaneous action of UV light and hyperthermia on survival and recombination
of yeast: effect of intensity of agents on their synergistic interaction].
AB - Synergistic effects of simultaneous application of ultraviolet (UV) light and
hyperthermia on survival and recombination of diploid yeast cells were studied.
For both test-systems the dependence of the synergistic interaction on UV light
fluence rate and exposure temperature was revealed: the temperature range
synergistically increasing the action of UV light is shifted towards low
temperature values with decreasing of UV light fluence rate. For cell survival,
the dependence of the synergistic enhancement ratio on the exposure temperature
passes through a maximum. A possible qualitative interpretation of these results
is discussed.
PMID- 10778446
TI - [Modeling of different types of size-effect in accumulation of 137Cs in fish from
the cooling pond of the Chernobyl Power Plant].
AB - All known types of size-effect in accumulation of radiocesium in fish are
described on the basis of the dynamic model of distribution and migration of the
radionuclide in aquatic ecosystem. The time-dependent activity of 137Cs in
different age classes of carp and pike-perch from the Chernobyl Nuclear Power
Plant Cooling Pond is calculated. It is shown that during the first year after
the accident the activity of 137Cs in the young generations of fish was higher
(negative size-effect) owing to higher feeding rate of young fish. During the
following years the increase of activity in the older fish generations takes
place (positive size-effect). It is shown that size-dependence is more clear for
the predatory species.
PMID- 10778445
TI - [Modification of the effect of high temperature on biochemical processes by
perturbed geomagnetic field].
AB - The biochemical data on the influence of perturbed geomagnetic field on the
hormonal-mediator regulation systems are presented. The possibility of biological
effects modification under combined action of perturbed geomagnetic field and
high temperature of environment is discussed.
PMID- 10778447
TI - [The study of interaction between 134Cs and potassium in system peat soil-plant
under increasing concentration of macroelement in soil].
AB - The interaction between analogous elements K and 134Cs in the system "peat-soil
plant" was investigated. The values of some parameters of sorption model for
uptake of radionuclides by plants from soil were determined. An attempt to
interpret the processes going on in the studied system under pot experiment from
the viewpoint of soil chemistry was done. Two intervals of potassium
concentration in peat-soil were displayed, with different effect on 134Cs uptake
by plants.
PMID- 10778448
TI - [Results of the studies on radiation ecology and radiation biology at the
Institute of Biology of Komi Science Center of Ural division of Russian Academy
of Science (on 40th anniversary of the Department of Radiation Ecology)].
AB - Information about the foundation and history of the Radiation Ecology Department
and results of the researches on the effect of increased background radiation
level on plant and animal populations, migration of radionuclides in natural
biocoenosies with increased radiation level are presented.
PMID- 10778449
TI - [Nuclear medicine--therapeutic advances into new dimensions?].
PMID- 10778450
TI - [Cerebral perfusion CT: theoretical aspects, methodical implementation and
clinical experience in the diagnosis of ischemic cerebral infarction].
AB - Cerebral perfusion CT using dynamic CT after bolus injection of contrast has
recently been introduced in the clinical management of stroke patients. Based on
the indicator dilution principle various theoretical models can be formulated
which all aim at the quantitative determination of cerebral blood flow (CBF). Our
Perfusion CT approach is based on the "maximum slope" model and allows in
addition to the calculation of CBF parameter images the display of cerebral blood
volume (CBV) and "time to peak" as diagnostically meaningful parameters. This
approach allows the detection of acute ischemia of the supratentorial brain with
a sensitivity of 91% and has proven its value as a routine diagnostic tool for
acute stroke. The combination of various functional maps provides excellent
information regarding the type of ischemia. Although the direct assessment of
ischemia using absolute CBF values is severely restricted by patient dependent
systematic errors, the severity of ischemia may reliably be assessed by using
relative CBF perfusion indices.
PMID- 10778451
TI - [CT perfusion imaging in acute ischemic cerebral infarct: comparison of cerebral
perfusion maps and conventional CT findings].
AB - PURPOSE: To evaluate the findings of acute brain ischemia on different functional
maps of cerebral perfusion CT in stroke patients and to compare the results with
early ischemic changes on conventional CT. METHODS: The baseline CT scans of 45
acute stroke patients were retrospectively evaluated with respect to early CT
findings. For each patient the extent of cerebral ischemia as shown on the maps
of cerebral blood flow (CBF), cerebral blood volume (CBV), and "time to peak"
(TP) was compared and the severity of ischemia was assigned to one of three
levels based on the findings of the CBF image. RESULTS: In 75% of all patients
conventional CT was performed within 2 hours from symptom onset. 29 of 45
patients showed early signs of ischemia on conventional CT, whereas perfusion CT
revealed cerebral ischemia in all patients. Severe ischemia was found in
approximately the same rate of incidence in patients with early CT changes
(55.2%) and in those with normal findings (43.8%). If the perfusion impairment
was judged as mild or moderate the extent of the hypoperfused area was
significantly larger on the CBF and TP images than on the CBV map. This was
significantly different in patients with severe hypoperfusion where a complete
correspondence of the affected area between the three functional maps was found.
DISCUSSION: The use of conventional CT for the assessment of stroke in the
hyperacute phase is limited. Perfusion CT yields excellent information regarding
the severity and extent of ischemia. The use of various perfusion maps helps to
differentiate the core of infarction from the ischemic penumbra zone.
PMID- 10778453
TI - [Radiation exposure during spiral-CT of the paranasal sinuses].
AB - PURPOSE: Determination of the radiation doses in spiral CT of the paranasal
sinuses using a variety of mAs values and scan protocols. MATERIAL AND METHODS:
CT examinations of the paranasal sinuses were performed using an Alderson-Rando
phantom. Radiation dose was determined by LiF-TLD at the level of high risk
organs in the head and neck region for combinations of different scan parameters
(2/3, 3/3, 3/4 mm) and decreasing charges (200, 150, 100, 50, 25 mAs) on a spiral
CT. Additional measurements were performed on three other CT scanners using the
2/3 mm protocol at 50 mAs, and a single slice technique (5/5 mm) on one scanner.
RESULTS: The lowest dose values found were 1.88 mGy for the eye lenses, 1.35 mGy
for the parotid gland, 0.03 mGy for the thyroid gland and 0.1 mGy for the medulla
oblongata using 2 mm collimation and 3 mm table feed at 25 mAs. Maximal dose
values resulted using the 3/3 mm protocol at 200 mAs (31.00 mGy for the eye
lense, 0.65 mGy for the thyroid gland). There were no significant differences
found between the different CT scanners. CONCLUSIONS: Using up-to-date CT
scanners, radiation exposure may be reduced by a factor of 15-20 compared to that
of conventional CT technique. Thus, the exposure of the eye lens comes to only a
thousandth of the value supposedly inducing a cataract, as published by the ICRP.
PMID- 10778452
TI - [3D CISS, 3D MP-PAGE and 2D TSE for the preoperative MRI prior to cochlear
implantation].
AB - PURPOSE: The aim of this study was to determine the presurgical predictive value
of high resolution MRI in patients scheduled for cochlear implantation. METHOD
AND MATERIAL: The presurgical MRI (3D CISS, 3D MP-RAGE with and without i.v.
contrast medium, 2D TSE) findings of 54 patients and the intraoperative situation
reported by the surgeon were compared retrospectively. The surgical and
functional success of the cochlear implantation was evaluated. RESULTS: We found
a high degree of correlation between MRI and intraoperative findings concerning
the patency of the whole cochlea and anomalies as well as in the diagnosis of
pathology of the cochlear, vestibular and facial nerves and in anomalies of the
internal auditory canal. However, in four out of 54 patients there was a false
negative prediction regarding the patency of the cochlea. The sensitivity was 50%
(4/8), the specificity 100% (46/46). Concerning the surgical success the accuracy
was 100%. In all patients MRI gave sufficient anatomical information to the
surgeon concerning the jugular bulb and the facial nerve. CONCLUSION: A high
resolution MRI protocol consisting of coronal 2D T2w TSE, 3D T2*w transverse
CISS; plain and contrast enhanced sagittal T1w 3D MP-RAGE is recommended for the
evaluation of candidates scheduled for cochlear implantation.
PMID- 10778454
TI - [Hybrid 3D visualization and virtual endoscopy in cochlear implants].
AB - PURPOSE: The aim of this study was to demonstrate on a complex anatomical
structure the possibilities and the advantages of a superimposition of a color
coded surface and volume rendering (hybrid rendering) method with the possibility
of the performance of a virtual endoscopy. MATERIAL AND METHOD: In 6 patients
with cochlear implants a high-resolution spiral computed tomography of the
petrous bone was performed. The cochlear implants, the middle and inner ear
structures were visualized using a color-coded surface rendering method, either
shaded or as a grid. The petrous bone was visualized using a transparent volume
rendering method. RESULTS: The hybrid 3D visualization uses the advantages of
both the color-coded 3D surface and volume rendering method. In comparison to the
axial source images, the hybrid 3D visualization thus facilitates a clearer
representation and better assessment of the complex topographical relationship
without loss of diagnostic information. The virtual endoscopy facilitates an
intraluminal visualization and inspection of all color-coded 3D surface- and
volume rendered structures. CONCLUSIONS: The hybrid rendering and virtual
endoscopy make the morphological assessment of cochlear implants easier by the
simultaneous visualization of the surrounding structures and thereby support the
diagnostic imaging methods. This image processing method can be used pre
operatively for the individual planning, simulation, training and further
development of surgical procedures and interventions and post-operatively for the
control of the position and further developments of implants.
PMID- 10778455
TI - [Determination of left ventricular function parameters and myocardial mass:
comparison of MRI and EBT].
AB - PURPOSE: Comparative volumetric assessment of the left ventricle by magnetic
resonance imaging (MRI) and electron beam tomography (EBT) in patients with
ischemic and dilated cardiac disease. METHODS: Thirty-two patients underwent cine
MRI and EBT in the multislice mode. All studies were triggered to the ECG. Left
ventricular ejection fraction (EF), end-diastolic (EDV) and end-systolic volume
(ESV), and myocardial mass (MM) were determined by 3D-volumetry by MRI and EBT
and results were compared. RESULTS: The correlation between MRI and EBT for EF,
EDV, ESV, and MM were r = 0.86, r = 0.95, r = 0.95, and r = 0.93, respectively.
CONCLUSIONS: There is an excellent correlation between MRI and EBT in determining
left-ventricular parameters. Both methods are suitable for volumetric assessment
of the left ventricle.
PMID- 10778456
TI - [Effects of biphasic spiral CT, conventional and iron oxide enhanced MRI on
therapy and therapy costs in patients with focal liver lesions].
AB - PURPOSE: Evaluation of the diagnostic efficacy and cost-benefit of contrast
enhanced CT (CT) and MRI pre- and post-SPIO-particles in focal hepatic disease
with consideration of therapeutic outcome. METHODS: In 52 patients with the
suspicion of primary or secondary hepatic malignancy, biphasic spiral CT and
breath-hold gradient-echo T1- and fast spin-echo T2-weighted MRI pre- and post
iron oxide administration (1.5 T, body-phased-array coil) were compared. The
number of hepatic lesions and the related diagnoses resulting from each imaging
modality were recorded and statistically correlated to the final diagnoses
established by biopsy/OP (34/52), long term follow-up of 12 months (18/52), and a
consensus reading of all imaging modalities considering all clinical imaging
information. The most likely induced therapy resulting from each imaging test was
correlated to the final therapy. Based on data from the hospitals accountants,
the therapy-related costs were estimated without hospitalization costs. RESULTS:
In 34/52 (65.4%) of the cases the correct diagnosis was primarily stated by CT
(sensitivity [se.] 85.2%, specificity [sp.] 44.0%). In additional 10/52 of the
cases unenhanced MRI (se. 91.4%, sp. 75.0%) enabled correct diagnoses, and in
another 6 cases the diagnosis was established only by SPIO-MRI (se. 100%, sp.
86.7%). Considering the possible therapeutic recommendation arising from each
modality, CT would have induced needles therapy costs of 191,042 DM, unenhanced
MRI of 171,035 DM, and SPIO-MRI of 7,311 DM. In comparison to the real therapy
costs of 221,873 DM, this would have corresponded to an unnecessary increase of
therapy costs of 86.1%, 77.1%, and 3.3%, respectively. In two cases (1
hemangioma, 1 regenerative nodule) all modalities failed, causing unnecessary
surgery in one patient. DISCUSSION: In this problem-oriented scenario unenhanced
and SPIO-enhanced MRI proved to be superior to CT regarding diagnostic efficacy.
The cost-benefit resulted mainly due to preserving patients from unnecessary
surgical procedures.
PMID- 10778458
TI - [Low-field MRI of the ankle joint: initial experience in children and adolescents
using an open 0.2 T MR-system].
AB - PURPOSE: To evaluate the feasibility and diagnostic confidence of MRI with an
open low field System (Magnetom open, Siemens, Germany) in children with
predominantly traumatic disorders. MATERIAL AND METHODS: Conventional X-rays and
MRI examinations have been evaluated in 55 children. MRI was performed at an open
0.2 T MR-unit. The study protocol comprised coronal STIR-sequence, an angulated
T2 weighted TSE-sequence and T1 weighted SE-sequence. RESULTS: MRI showed
ligamental rupture in 33/50 (60%) cases. Injuries of the ATFL were most frequent
(27/33); osseous ligamental tears occurred in approx. 50% of all cases. Fractures
of the distal tibia and fibula were diagnosed in 28/55 children. 15/28 cases
showed an involvement of the epiphysis. We found occult fractures in 11/28
children. Fractures, diagnosed by conventional x-rays, were excluded in 6 cases.
Therapy changed in 35/55 patients on the basis of MRI-findings. CONCLUSION: Low
field MRI of the ankle joint in children and adolescents is able to show numerous
pathological conditions. We recommend low-field MRI of the ankle in children with
persistent or unclear pain of the ankle joint and inconspicuous conventional x
ray.
PMID- 10778457
TI - [Arthrography, ultrasound and MRI in rotator cuff lesions: a comparison of
methods in partial lesions and small complete ruptures].
AB - PURPOSE: To evaluate the accuracy of arthrography, ultrasound and MR imaging in
rotator cuff disease. METHODS: 40 patients suffering from subacromial impingement
syndrome for at least three months and who were selected for surgery, underwent
ultrasound, double-contrast arthrography and MR imaging. Patient preselection
focused on partial and small complete tears. RESULTS: 13/26 surgically confirmed
tears were partial tears (articular surface: 10, bursal surface: 2, intra
substance tearing: 1). Arthrography, ultrasound and MR imaging yield a
sensitivity for complete tears of 91%, 69% and 92% with a specificity of 100%,
93% and 93%. For partial tears sensitivity was 50%, 69% and 69% with a
specificity of 100%, 79% and 86%. Concerning evaluation of localisation, extent
and correct classification ultrasound was correct in 17/26 cases, MR in 21/26
cases. CONCLUSION: Arthrography is not helpful in detecting partial tears.
Ultrasound and MR imaging yield comparable accuracy. MR imaging has advantages
concerning better evaluation of extent, location and classification as well as
for the detection of associated pathologies.
PMID- 10778459
TI - [Animal experiment studies on the effectiveness of permanent occlusion of the
hepatic artery in transarterial chemoembolization].
AB - PURPOSE: To evaluate the effect of permanent occlusion of the hepatic artery on
the efficacy of transarterial chemoembolization (TACE) in an animal model.
MATERIAL AND METHODS: 12 days after inoculation of the Morris hepatoma 3924 A in
15 male ACI rats, TACE with Mitomycin C (0.25 mg/kgBW) + Lipiodol (0.2 ml/kgBW)
without (n = 5) and with permanent occlusion of the hepatic artery (n = 5) was
performed. Control group consisted of 5 rats. Tumor volume was determined by MRI
(1.0 T, T1 [TR/TE, 400/14 ms]) before and 12 days after therapy. RESULTS:
Compared to the control group, TACE without and with permanent occlusion of the
hepatic artery showed a significant reduced tumor growth after 12 days (p = 0.017
and p = 0.005). However, permanent occlusion did not improve the retarding effect
on tumor growth (p = 0.9). CONCLUSION: The effectiveness of TACE in an animal
model using a cytostatic-/lipiodol-emulsion is not improved by permanent
occlusion of the hepatic artery.
PMID- 10778460
TI - [Stent artifacts in 3D MR angiography: experimental studies].
AB - PURPOSE: The purpose of this phantom study was to evaluate the visualization of
vascular stents by using contrast-enhanced (CE) 3D MR angiography (MRA). METHODS:
The measurements were performed on a Magnetom Vision operating at 1.5 T with 25
mT/m gradients by using a head coil; a 3D FISP sequence (TR/TE/FA 4.6 ms/1.8
ms/30 degrees) was used. A phantom was designed with a length of 20 cm and
consisted of a plastic cylinder filled with hydrogel. Tubes were used to install
7 different stents (Strecker, Boston Scientific; Cragg, Mintec; Wall, Schneider;
Memotherm, Angiomed; St-Come, Trigon-MTS; Sinus, Optimed; Palmaz, Johnson &
Johnson) with different metal components. The tubes were perfused with a solution
of water and Gd-DTPA. Four radiologists evaluated the image quality. The
measurements of the endoluminal stent diameters were compared with the findings
obtained by digital subtraction angiography. The signal intensities were measured
before (inflow), within (stent) and after (outflow) the different stent types.
RESULTS: The endoluminal diameter of the Cragg stent and the strecker graft were
easily detectable. The signal loss within the lumen of the Wall stent was approx.
10% in relation to the inflow and outflow measurements. The result was an only
slightly reduced image quality. The other grafts (St-Come, Sinus, Palmaz,
Memotherm) showed significant signal losses ranging from 65% to 96%. A correct
diagnosis was not possible within these graft lumina. CONCLUSION: Contrast
enhanced MR angiography can be used to evaluate vascular stents. A prerequisite
is the application of particular commercially available grafts.
PMID- 10778461
TI - [Chloroma (granulocytic sarcoma, myeloblastoma). Clinical aspects and
radiological diagnosis].
AB - Six cases of granulocytic sarcoma are presented. A mediastinal chloroma and a
tumor of the submandibular gland were observed with two patients as single sign
of acute myeloic leukaemia. In one patient a chloroma appeared as first
manifestation of acute myeloic leukaemia. Two patients exhibited the tumor as
first symptom of a blastic crisis of chronic myelogenous leukaemia (femoral bone,
lumbar spine). The sixth patient with a myelodyplastic syndrome showed a chloroma
of the breast. Various radiological procedures were applied including plain
radiography, MRT, CT and mammography. The results are compared with literature.
Principles of therapy were supplemented.
PMID- 10778462
TI - [Radiology of gastrointestinal stromal tumors (GIST) and a case of Carney
syndrome].
AB - Gastrointestinal stromal tumors (GIST) represent an extremely rare group of
tumors, which are mostly of smooth muscle origin like leiomyomas, leiomyosarcomas
and leiomyoblastomas. With the introduction of immunohistochemical analysis an
epithelioid and an autonomic nerve variant can be distinguished. The purpose of
this review is to demonstrate the image morphological appearance of these rare
tumors together with the pathology based upon a retrospective analysis of five of
our own cases since 1997. There are no pathognomonic imaging findings for
characterizing a gastrointestinal stromal tumor; however, it should be included
in the differential diagnosis if one or multiple large, round or oval, well
delineated gastrointestinal tumors occur in combination with central necrosis.
Carney's syndrome is characterized by the syndromal association of a
gastrointestinal stromal tumor (originally: gastric leiomyosarcoma) with an extra
adrenal paraganglioma and a pulmonary chondroma. In this rare syndrome, the
radiological approach is important to diagnose or rule out the--simultaneous or
consecutive--appearance of at least two of the three tumor entities (GIST, extra
adrenal paraganglioma, pulmonary chondroma).
PMID- 10778463
TI - [Hypothenar hammer syndrome: causes, sequelae and diagnostic aspects].
AB - PURPOSE: To investigate the reasons and disease course of Hypothenar Hammer
Syndrome. INTRODUCTION: Occlusion of the ulnar artery at the level of the hamate
bone due to repetitive trauma to the hypothenar eminence is implicated as the
cause of the rarely diagnosed hypothenar hammer syndrome (HHS). The thrombotic
occlusion and the formation of an aneurysm of the ulnar artery and the
superficial palmar arch with possible peripheral embolism of the digital arteries
are a direct cause of the chronic damage to the vessel wall. Generally, HHS is
diagnosed too late for recanalization to be a viable therapeutic option. METHODS:
From 1996 to 1998 the diagnosis of an HHS was made in 8 patients at our hospital.
Etiology, clinical settings and disease course were assessed. RESULTS: Our
analysis suggests that HHS may be caused by a single severe trauma in addition to
repetitive injuries. The pathogenesis of the syndrome is dependent on the
vascular anatomy of the individual hand. Interindividual variations in the
arterial supply of the affected hand influences the clinical symptomatology with
possible masking of arterial occlusions. CONCLUSION: An exact investigation
concerning the pathogenesis of HHS is a precondition for treating the disease and
may help to establish HHS as an occupational disease. MR-angiography may be a new
approach for assessing HHS.
PMID- 10778464
TI - When and how to evaluate a patient with nephrolithiasis.
AB - Nephrolithiasis is a common disorder that afflicts up to 12% of the population
and continues to be a significant cause of patient injury. Evaluation of these
patients should include the assessment of their comorbidities and underlying
medical conditions. Patients who form stones can undergo a streamlined
evaluation. A cause can be found in more than 90% of these patients. With medical
treatment, stone-recurrence rates can be decreased by 85% for calcium oxalate
stone formation, which affects a large proportion of patients. Introduction of
nonspecific medical therapy in uncomplicated calcium stone disease may improve
the quality of life for these patients and allow utilization a simple diagnostic
protocol. This is in contrast to the previous recommendations of disease-specific
therapy. Because patients without complications represent the majority of those
who form stones, a simplified approach greatly reduces the cost of evaluation and
treatment. Underlying medical conditions, however, require disease-specific
therapy. The protocol represented here should aid physicians and patients in the
approach to management of stone disease. The fasting calcium-load test is not
required, and the entire evaluation can be performed in an ambulatory setting in
two visits. Two 24-hour urine samples should be obtained on a random and
restricted diet. Patients who form calcium stones can be subdivided into those
who form hypercalciuric and normocalciuric stones. Patients who form
normocalciuric stones are treated with conservative measures (increased fluid
intake) and potassium and magnesium citrate. Patients who form hypercalciuric
stones are treated with a combination of thiazides and potassium and magnesium
citrate.
PMID- 10778465
TI - Stone disease.
AB - Imaging studies used for the detection and characterization of urinary tract
calculi are presented in this article. Comparisons of traditional imaging studies
are made with noncontrast helical CT scanning, the most recent addition to stone
imaging. Imaging findings for noncontrast helical CT and an approach to dealing
with various combinations of CT studies are also presented.
PMID- 10778466
TI - Helical CT and ureteral colic.
AB - The advantages of nonenhanced helical CT for the diagnosis of ureteral calculi
include rapid scan time and patient throughput, safety (no contrast, less
radiation), cost-effectiveness, high accuracy, minimal invasiveness, and ability
to suggest of alternative diagnoses for flank pain--urologic and otherwise. Size
measurement and location in the ureter, the two most important determinants of
therapy, are precise with CT. It is particularly good for imaging small or
radiolucent calculi, and calculi located at the ureterovesical. Secondary signs
of obstruction and the soft-tissue rim sign are additional aids to the routine
diagnosis of ureteral calculi. CT numbers indicate the fragility and therefore
the likelihood of successful treatment of a calculus. Postprocessing options may
help guide management decisions and may help plan interventions. The authors'
experience after 30 months of using helical CT exclusively in the work-up of
ureteral colic has been extremely favorable. Without hesitation, the authors
believe that nonenhanced helical CT is the study of choice for the work-up of
ureteral calculi.
PMID- 10778467
TI - Medical therapy and new approaches to management of urolithiasis.
AB - A simple, step-by-step approach to diagnosis and medical treatment of stone
disease is described. It uses urinary stone risk profile obtained before and
after dietary modification, history, and minimum diagnostic tests. For each
abnormal stone risk factor, potential causes are discussed and treatment options
are presented. The article concludes with diagnosis and treatment of combined
disturbances.
PMID- 10778469
TI - Secondary and miscellaneous urolithiasis. Medications, urinary diversions, and
foreign bodies.
AB - Secondary stones, those with no "classic" cause, provide unusual diagnostic and
treatment challenges to the urologist. Stones related to medications, to urinary
diversions or augmentation, or to presence of foreign bodies within the urinary
tract occur rarely. Nevertheless, they represent situations that may be corrected
fully by appropriate conservative or procedural therapy, and therefore they must
be included in the differential diagnosis of many patients who present with
symptoms of urolithiasis.
PMID- 10778468
TI - Role of diet in the therapy of urolithiasis.
AB - The data reviewed in this paper indicate that there is compelling direct and
indirect evidence that certain dietary modifications can limit the risk for stone
formation. Fluid therapy should be a front-line approach for all stone formers,
because it is safe, cheap, and effective. Restricting sodium and animal-protein
consumption produces changes in the urinary environment that should benefit the
majority of stone formers, including a decrease in calcium and increase in
citrate excretion. Minimizing the intake of processed goods limits sodium
gluttony. These dietary modifications also reduce cardiovascular risks.
Indiscriminant calcium restriction should be avoided, because it could accelerate
stone formation and violate skeletal integrity. Oxalate restriction should be
considered for calcium oxalate stone formers, especially those with
hyperoxaluria. Specific recommendations for modifying the consumption of other
nutrients cannot be made at this time because of the limited available
information about the resultant effects. The aforementioned goals can be achieved
within the context of a nutritionally balanced diet providing adequate sources of
fruits and vegetables. There is a definite need for better designed studies of
the nutritional effects on stone disease. This would promote a better
understanding of the interplay between the genetic and environmental components
of this disorder.
PMID- 10778470
TI - Kidney stones as a manifestation of hypercalcemic disorders. Hyperparathyroidism
and sarcoidosis.
AB - When hypercalcemia is detected in a kidney stone formation, an intact parathyroid
hormone measurement should be made. Detection of hyperparathyroidism (HPT) is
important to prevent further stone episodes and to avoid the complications of
high serum calcium in other organ systems. Stones in patients with HPT often
contain apatite salts in addition to calcium oxalate because parathyroid excess
may create a renal tubular acidosis. The calculi seen in patients with
sarcoidosis, another hypercalcemic state that may cause stone formation, however,
are usually pure calcium oxalate. Excess generation of 1,25-dihydroxyvitamin D
results in intestinal hyperabsorption of calcium and secondary hyperoxaluria.
PMID- 10778471
TI - Genetic disorders and urolithiasis.
AB - A recent analysis of the McKusick's On-Line Mendelian Inheritance in Man (OMIM)
database revealed over 30 genetic or putatively genetic conditions in which
urolithiasis contributes to the disease pathology at least to some extent. There
is wide clinical, biochemical, and genetic heterogeneity in many of these
conditions.
PMID- 10778472
TI - Intracorporeal lithotripsy. Update on technology.
AB - The number and variety of devices currently available for endoscopic lithotripsy
reflect the reality that no single device is ideal in all situations. Although
the search for the universal lithotriptor continues, the urologist must consider
several factors if faced with the decision of which device to purchase. Perhaps
foremost among these factors is the clinical situation with which one commonly
deals. For example, although the smaller, flexible probes such as EHL or laser
demonstrate considerable utility if used ureteroscopically, the larger stone
burden associated with today's percutaneous nephrolithotripsy population often is
treated more efficiently with one of the mechanical devices employing a larger,
rigid probe, such as ultrasound or the Lithoclast. Similarly, the type and size
of endoscopic equipment at one's disposal have a significant impact on which
device to purchase or use. There are physical constraints affecting which device
may or may not be used, rigid versus flexible endoscope, working channel caliber,
and offset versus end-on-port. The skill and experience of the surgeon is also a
factor of obvious importance, particularly if one is using a modality with a
relatively narrow margin of safety such as EHL. Likewise, the training and
experience of nursing personnel is a factor, especially regarding the use of
lasers, which require certified personnel who are well versed in laser safety.
Finally, in today's environment one must carefully evaluate cost in terms of not
only initial capital outlay but also ongoing charges for disposable and
maintenance items. Thus, the decision of which device to purchase is complex and
requires careful evaluation of all of the previously noted variables. Likewise,
if one is fortunate enough to have more than one device available, the decision
of which lithotriptor to employ requires a similar decision based on sound
surgical judgment.
PMID- 10778473
TI - Extracorporeal lithotripsy. Update on technology.
AB - The development of shock-wave lithotripsy was a serendipitous event. Fortunately,
the significance of this accidental discovery was not overlooked by the engineers
at Dornier and their medical counterparts. There are many components that make up
a lithotripter, but the heart of the lithotripter is its energy source. These
machines often are categorized by the type of shock-wave generator used, and each
type of generator has its own advantages and disadvantages. Unfortunately, no
quantitative value of a shock-wave generator can be correlated to its qualitative
effect. Interestingly, each type of energy source delivers its shock-wave energy
with such distinctiveness that even the crater pattern it leaves in a stone is
unique. New technology and ideas have transformed lithotripters in form and
function so that they bear little resemblance to the original HM-1 prototype.
Ongoing research is attempting to improve ESWL in several different ways, and
advances in shock-wave generation, shock-wave measurement, and stone localization
should result in even more efficient lithotripsy. The application of the time
reversal process to lithotripsy ultimately may enable lithotripters to track
stones and electronically steer shock waves toward the target. Advances like
these herald a time when ESWL, fortunately or unfortunately, will become
automated completely.
PMID- 10778474
TI - Is there a role for open stone surgery?
AB - Modern day urinary-stone treatment involves procedures and techniques that were
not even available 20 years ago. The relatively rapid and sometimes explosive
development of ESWL, percutaneous techniques, and ureteroscopy and intracorporeal
lithotripsy has ushered in the era of minimally invasive stone management. In
many regards, open surgery has such a limited role that its performance often is
regarded as a sign of failure. To think of open stone surgery in this manner is
likely to do a disservice to a small but important segment of the urinary-stone
patient population. The critical responsibility of the urologist treating stone
disease is to be able to recognize those clinical situations in which open stone
surgery may represent at least a viable and reasonable alternative to less
invasive modalities. The duty of the surgeon is then to be able to present this
option to the patient in an unbiased fashion and to effectively perform and
implement this form of treatment if chosen. It is only with this approach that
open surgery will continue to be correctly applied on those rare occasions and
will not become a lost surgical art in the era of minimally invasive surgery.
PMID- 10778475
TI - The vesical calculus.
AB - Bladder calculi account for 5% of urinary calculi and usually occur because of
foreign bodies, obstruction, or infection. Males with prostate disease or
previous prostate surgery and women who undergo anti-incontinence surgery are at
higher risk for developing bladder calculi. Patients with SCI with indwelling
Foley catheters are at high risk for developing stones. There appears to be a
significant association between bladder calculi and the formation of malignant
bladder tumors in these patients. Transplant recipients are not at increased risk
for developing vesical calculi in the absence of intravesical suture fragments
and other foreign bodies. Patients who undergo bladder-augmentation procedures
using a vascularized gastric patch appear to be protected from vesicolithiasis,
perhaps by the acidic environment. Ileum and colon tissues, however, are
colonized by urease-producing organisms, producing an alkaline pH that promotes
stone formation. Children remain at high risk for bladder-stone development in
endemic areas. Diet, voiding dysfunction, and uncorrected anatomic abnormalities,
such as posterior urethral valves and vesicoureteral reflux, predispose them to
bladder-calculus formation. Finally, there are a number of techniques and
modalities available to remove bladder stones. Relieving obstruction, eliminating
infection, meticulous surgical technique, and accurate diagnosis are essential in
their treatment.
PMID- 10778476
TI - Management of residual stones.
AB - Stone-free status is highly dependent on selection of the appropriate surgical
technique, which should be tailored according to the individual stone and patient
parameters. Although a stone-free state is the desired outcome of surgical
intervention of urolithiasis, the authors believe that the presence of
noninfection, nonobstructive, asymptomatic postprocedural residual fragments can
be managed metabolically in order to prevent stone growth adequately. Further
surgical intervention in the case of residual fragments is warranted if the
clinical indications that prompted the original surgery persist.
PMID- 10778477
TI - Chemolysis of urinary calculi.
AB - Irrigant chemolysis was developed to collaborate with open surgery, removing the
residual fragments. With the worldwide diffusion of the procedures performed by
the endourologist in the early 1980s and the present availability of ESWL,
however, direct irrigation of stones has a reduced field of influence even as an
adjunctive measure. Urologists have applied economic analysis to their clinical
practices, and the findings related to irrigant chemolysis made this technique an
unusual procedure. The cost to the providers of medical care, the burden on the
patient in terms of suffering and loss of productivity, and the amount of time
required to liberate the patient even partially from the stones make irrigant
chemolysis an inauspicious scenario. In this era of cost containment and
decreasing length of stay, it is increasingly difficult to justify hospital
admissions for this form of therapy. Being simultaneously more expensive and less
effective than the existing alternatives, local chemolysis should be discarded,
except for special situations, such as patients at high risk for any surgical
procedure. Oral chemolysis preserves reduced indications, for example as an
adjuvant to an endourologic operation or ESWL in special situations. As long as
urinary stones continue to afflict humans, chemolysis is likely to retain a
limited but important role in their management.
PMID- 10778478
TI - Orthotopic urinary diversion in women.
AB - Orthotopic urinary diversions can be performed safely with acceptable morbidity
rates in women. Attention to detail during the surgical dissection of the bladder
neck and vagina is critical to a good outcome. With improvements in orthotopic
urinary diversions, earlier use of a cystectomy for the treatment of minimally
invasive bladder cancer may improve the survival rate in these patients.
PMID- 10778479
TI - [Epilepsy as a symptom].
AB - Epilepsy and seizures are often misinterpreted as identical phenomenon and
treatment of seizures confused with treatment of epilepsy. In this paper the
concept of both epilepsy and seizures are revised and also the more new
etiopathogenics hypothesis, stressing the importance of etiological diagnosis for
a suitable therapy and prognosis, which depends more of the etiology than the
morphology of seizures.
PMID- 10778480
TI - [Corpus callosum agenesis and epileptic seizures].
AB - INTRODUCTION: The corpus callosum is the major neopallial connection between the
two cerebral hemispheres. The corpus callosum agenesis (CCA) is found in 14% of
CNS malformations. The diagnosis is based on neuroimaging procedures
(ultrasonography, CT, MRI). The CCA is usually associated with facial dysmorphia,
developmental delay and epileptic seizures. Two casuistic are studied, one with
necropsies material and another with CCA patients alive, on which CCA was
frequently associated with other CNS malformations, in order to establish the
circumstances in which the epileptic seizures have been observed. DEVELOPMENT: It
is commonly admitted that the presenting signs or symptoms in individuals with
CCA are due to concurrent brain abnormalities and that isolated CCA is
essentially asymptomatic. The CCA is a common component in some malformative
syndromes, frequent in another, and occasional in many of them. The CCA has been
reported in many chromosomal aberrations and less frequently in inborn errors of
metabolism and neurocutaneous diseases. In the casuistic studies of 73 patients
alive, 25 (39%) have presented epileptic fits: in 24 of them the CCA was
associated to another brain abnormalities; in 17 cases, the first seizures was
recorded during the first year, in 6 cases between 1 and 3 years and in cases
after 2 years: the type of epileptic seizures is variable: neonatal convulsions
in 4 cases, infantile spasms in 5, unilateral fits in 3, and partial seizures in
1 case. In the necropsies casuistic with 26 CCA cases, 6 (23%) suffered epileptic
fits, all with another malformations of the CNS; in 3 the onset of the seizures
was during the newborn period, 2 had infantile spasms during the first years and
1 case generalized seizures during the second year. CONCLUSIONS: 1. Epileptic
seizures were observed in 23%-39% of the CCA cases studied. 2. All cases with
CCA, except for one, have also another brain abnormality. 3. In 70% of the cases,
the onset of the fits takes place during the first year. 4. The type of seizures
is variable with predominance of infantile spasms and unilateral seizures.
PMID- 10778481
TI - [Epileptic signs in alterations of neuronal migration].
AB - INTRODUCTION: A wide range of conditions are due to alterations in neurone
migration (ANM). Mental retardation, motor disorders and epilepsy are seen in all
these disorders. Anomalies included with the ANM are those produced at the time
of neuronal migration in the phase prior to neurone proliferation and during the
time following cortical organization. All these have a common characteristic,
namely an anomalous cerebral cortex (cerebral dysplasias). DEVELOPMENT: There is
a high incidence of epilepsy in ANM (60%), appearing early (10% neonatal, 42%
before 1 year old). The frequency of crises increases with age. Extended and
diffused generalized forms presents as epileptic encephalopathies (Ohtahara,
West, Lennox-Gastaut), whilst focal forms are seen as simple motor, partial
crises, complex and secondarily generalized crises with a tendency to status
epilepticus and also to continuous partial epilepsy. In diffuse, extensive forms,
the EEG is characterized by large amplitude theta-delta rhythm activity
(specific) with the presence of rapid activity (15-25 Hz) and of large amplitude
(150-300 microV) which may also be found in other processes. In localized forms
the recordings vary: localized discharges with/without crises, multifocal
discharges in more than two lobes with a defined critical area, positive
discharges, ipsilateral spike-and-wave complexes associated with focal discharges
or with normal recordings. We review different types of ANM: in the phase of
proliferation (hemimegalencephalia), the agyria-paquigyria complex; in phase of
migration: type I lissencephalias (Miller-Dieker), layered heterotopias (double
cortex), type II (cobblestone) lissencephalias and neuronal heterotopias, and in
the phase of organization of the cortex: polymicrogyria and the
esquissencephalias I and II. CONCLUSIONS: The functional prognosis in ANM depends
on the control of the crises rather than on the extent of the lesion. Surgical
treatment leads to 42% good or excellent results.
PMID- 10778482
TI - [Sleep as a method of the study of epilepsy].
AB - It has been well known from the literature that sleep and epilepsy have strong
reciprocal influences and this is true for all kinds of epilepsies. The
electroencephalographic paroxysmal activity increases in slow wave sleep and the
localization of the primary epileptogenic area is more reliable in paradoxical
sleep. The video-polygraphic recording is a mandatory methodology in the study of
the different types of epilepsies.
PMID- 10778483
TI - [Epileptic signs of metabolic origin].
AB - INTRODUCTION: It is very difficult to identify metabolic causes of epileptic
crises. This is partly because metabolic disorders are not fully understood and
partly because the complementary tests required for their identification can be
undertaken only in a few laboratories. DEVELOPMENT: We describe the
characteristics of the metabolic disorders which may most frequently lead to
epileptic crises occurring during the neonatal period, the first year of life,
between the ages of one and six years and between six and fifteen years of age.
We also emphasize the findings which may help in orientation towards diagnosis of
these metabolic disorders, and the complementary tests required for confirmation.
PMID- 10778484
TI - [Epileptic signs of neonatal hypoxia-ischemia].
AB - INTRODUCTION: Neonatal convulsions are usually symptomatic and originate mainly
from a hypoxic-ischemic (H-I) lesion. The high incidence of crises and their
serious sequelas have led us to carry out this retrospective study. PATIENTS AND
METHODS: We studied 54 histories of neonatal H-I and epileptic crises, analyzing
45 variables and evaluating their diagnostic concordance. RESULTS: In 20 children
meconium was detected during gestation and, to a lesser extent, infection and
hemorrhage. Birth was dystonic on 48 occasions, 37 at term and 12 preterm. In
most cases (27) birth weight was in accordance with gestational age. Apgar scores
were always less than 5. The crises, occasional or daily in most cases, were of
subtle semiology in 29 children, followed by generalized tonic (23), focal clonic
(13), general clonic (11), multifocal clonic (7), focal tonic and multifocal
myoclonic (6), focal myoclonic (4) and generalized myoclonic (2) crises. Only 7
EEGs were done during crises (1 normal, 3 with anomalies and 3 with slow basal
activity). Paroxystic anomalies were only found on 10 EEGs done between crises.
Cerebral echography was the method most used and most useful. Very frequently
changes were observed in other organs as the expression of a multisystemic
disorder. Most children had abnormalities on neurological examination. In most
cases, classical anti-epileptic drugs were used intravenously, and new generation
drugs were given if the crises persisted. After an average of 16-19 months of
follow-up, 13 children had died and 34 no longer had crises. However, only 20 of
the surviving children were considered to be normal, 14 had severe mental
retardation, 6 moderate and one slight retardation. CONCLUSIONS: Neonatal H-I is
the main cause of epileptic crises in the RN period, with a high percentage
mortality and severe neurological sequelas. The crises are usually well
controlled by classical anti-epileptic drugs, and are an excellent marker,
together with the Apgar score and gestational and placental changes. The
appearance of normal EEGs during periods of crises should make us doubt the
authenticity of subtle crises, perhaps corroborated by a good therapeutic
response.
PMID- 10778485
TI - [Introduction to the study of peroxisomal disorders].
AB - The peroxisome is an organelle found in all nucleated cells of mammalian. Its
name is due to H2O2 formation as result of cell respiration catalyzed by oxidases
and catalases and play and important role on myelination and neuronal migration.
Peroxisomes are formed by assembling of membrane proteins (structural, receptors
and transporters) into peroxisomal membrane. Peroxisomal proteins are encoded by
nuclear genes, synthesized on cytosol ribosomes and imported into peroxisomal
matrix, mediated by receptors and transporters membrane proteins. There are two
main categories of peroxisomal disorders: disorder of peroxisome biogenesis
exemplified by Zellweger syndrome, where multiple peroxisomal protein, functions
are deficient and disorders which involves a single peroxisomal protein,
exemplified by X-adrenoleukodystrophy, where the organelle is apparently intact.
PMID- 10778486
TI - [The peroxisome: structure, function and biogenesis].
AB - The peroxisome is the most recently identified subcellular organelle.
Understanding of its function, particularly in various aspects of lipid
metabolism and its biogenesis, has increased rapidly during the last decade. At
least 15 peroxisomal disorders have been identified, and 12 of these involve the
nervous system severely.
PMID- 10778487
TI - [The diagnosis of peroxisomal disorders in Spain during the period 1987-1997].
AB - INTRODUCTION: Peroxisomal disorders are divided into two groups: a) Those with
alterations in multiple peroxisomal functions, and b) With alterations in only
one peroxisomal function. DEVELOPMENT: During the period 1987-1997, using very
long chain fatty acids, plasmalogens and phytanic acid as diagnostic parameters,
we diagnosed 116 cases of peroxisomal disorders in Spain. The most frequent (76%)
was found to be X-linked adrenoleukodystrophy (X-ALD). Of the five phenotypes
described in this condition, the adult cerebral form is seen in a higher
percentage in the Spanish population (14%) than in other populations studied (1
3%). Defects in the assembly of peroxisomes made up 18%; the commonest phenotype
was that of Zellweger's syndrome (13 cases), followed by neonatal
adrenoleukodystrophy (5 cases) and infantile Refsum (2 cases). In the latter two
patients, study of the hepatic peroxisomes showed a mosaic distribution.
Rhizomelic punctate chondroplasia made up 3%, isolated beta-oxidation defects 2%
and defects of plasmalogen synthesis 1%. In X-ALD, diagnosis of an initial case
led to the detection of 12 presymptomatic and 70 heterozygote persons. Prenatal
diagnoses were made on 10 occasions and 7 fetuses found to be affected. The
introduction of the study of ALDP expression in the fibroblasts and the profile
of the organic acids in the urine has led to improved diagnosis of these
disorders.
PMID- 10778488
TI - [Peroxisomal disorders: classification and overview of biochemical
abnormalities].
AB - The peroxisomal disorders are subdivided into two major categories: those in
which the organelle is not formed normally (disorders of peroxisome biogenesis),
and those that are associated with defects of single peroxisomal proteins. The
Zellweger cerebrohepatorenal syndrome is the prototype of the peroxisome
biogenesis disorders. It has been shown to be due to defective import of proteins
into the organelle. Ten distinct molecular defects can lead to the failure of
import.
PMID- 10778489
TI - [Clinical symptoms of generalized peroxisomal disorders].
AB - INTRODUCTION: In generalized peroxisomal disorders, the clinical picture is not
always obvious enough to orientate the diagnosis at an early stage of the
disease. Although classic Zellweger syndrome can seldom be misdiagnosed, unless
we ignore this kind of pathology altogether, the other phenotypes (neonatal
adrenoleukodystrophy and infantile Refsum disease) are not always clearly
delineated. Above all, the diagnosis may be difficult if we expect the patient to
closely correspond to the cerebro-hepato-renal syndrome prototype. DEVELOPMENT:
Thus, we must establish a series of crucial signs and symptoms that, taken
together, make us suspect a peroxisomal disease and order the corresponding
biochemical screening. In our experience, craniofacial dysmorphia may be
misleading in the less severe phenotypes and is probably the most subjective
feature. In contrast, an infant with widely open fontanels and axial hypotonia,
in special if failure to thrive and/or hepatomegaly are associated, must be
considered suspicious enough to make us think of a peroxisomal disorder and
perform a metabolic screening. Later on in life, the neurological picture and
psychomotor delay become more and more clear, and sensorineural blindness and
deafness are virtually constant.
PMID- 10778491
TI - [Treatment of generalized peroxisomal disorders with docosahexaenoic acid ethyl
ether].
AB - INTRODUCTION: We found that patients with the Zellweger syndrome and other
generalized peroxisomal disorders have a dramatic decrease of docosahexaenoic
acid (DHA, 22:6n-3) in the blood, brain, retina and other tissues. DHA is
believed to play an important role in the brain and retina. DEVELOPMENT: Patients
with the Zellweger syndrome and its variants have severe cerebral and retinal
defects that could be related to their DHA deficiency. With this rationale, we
have been treating peroxisomal-disorder patients with a DHA derivative of a high
degree of purity (DHA ethyl ester, > 90% pure) since 1991. So far, we have
treated 13 DHA-deficient peroxisomal patients, one with the classic Zellweger
syndrome and 12 with milder variants of the disease. This paper presents the
follow-up of these DHA-treated patients. In summary, we have found important
improvements in liver function, in the plasmalogen levels and in the two ratios
26:0/22:0 y 26:1/22:0, diagnostic of the disease. We have also found clear
clinical improvements in most cases. Most significantly, magnetic resonance
imaging has shown advances in brain myelination, so far in 6 of the treated
patients. CONCLUSION: We strongly recommend treatment with DHA ethyl ester in all
DHA-deficient patients with generalized peroxisomal disorders. Logically,
treatment should be started as soon as possible, in the hope of preventing
cerebral and visual damage.
PMID- 10778490
TI - [Disorders associated with alterations in single peroxisomal proteins, including
X-linked adrenoleukodystrophy].
AB - X-linked adrenoleukodystrophy is the prototype of the disorders that involve a
single peroxisomal protein, and it is by far the most common peroxisomal
disorder. The gene that is defective in this disorder is a peroxisomal membrane
protein involved, in an as yet undefined manner, in the degradation of very long
chain fatty acids. All of the peroxisomal disorders can be identified pre- and
postnatally by non-invasive tests.
PMID- 10778493
TI - [Child neuropsychology in the next millennium].
AB - INTRODUCTION: The progress made in recent decades in neuropsychology has meant a
major advance in the recognition of sub-types of various disorders of nervous
development. DEVELOPMENT: Recognition of symptomatology by means of a fragmental
study of the components of all the different systems for obtaining information
brings to light new therapeutic options. The different neuropsychological tests
are used to study not only the final development of a particular ability but also
how this has been achieved. Study of the type of mistakes made by each child
permits recognition of the neuro-cognitive profile used. Cognitive rehabilitation
of different processes presenting in infancy and adolescence offers the
possibility of acquiring an alternative system of learning to minimize or
substitute for deficiency. This is possible in cases affecting secondary or
tertiary processing areas. CONCLUSIONS: The recognition of alternative routines,
used to overcome specific disorders of nervous system development, makes one
reflect on the way in which information is acquired, processed and produced by
the brain and the possibility of generating auxiliary strategies for processing,
even in healthy brains, so that perhaps options will be available in the case of
future lesions (aphasia, Alzheimer's disease, etc.).
PMID- 10778492
TI - [Therapeutic strategies for peroxisomal disorders].
AB - Therapies are emerging for some of these therapies, and include dietary
modification, pharmacological agents, and tissue transplants. Animal models have
been developed for several of these disorders, and will increase understanding of
disease mechanisms and facilitate the evaluation of current and new therapies,
including gene therapy.
PMID- 10778494
TI - [Children at risk for learning disorders].
AB - INTRODUCTION: To find what is meant by normal learning, it is essential to
understand learning difficulties not only from the anatomical but also from the
functional point of view. DEVELOPMENT: We review the literature concerning risk
factors for learning difficulties in order to treat them early on and attain
satisfactory long-term development. CONCLUSIONS: Learning difficulties are the
largest groups of disorders in everyday neuropaediatric practice. It should be
remembered that in most children with learning difficulties there are undiagnosed
preexisting neurological disorders, which come to light on reaching an age at
which improved academic achievement is obligatory.
PMID- 10778495
TI - [Neurocognitive and pharmacological approach to specific learning disorders].
AB - INTRODUCTION: Specific learning disorders are distinguished from general
development disorders since, in general, only a certain number of processing
mechanisms are involved whilst the remainder are unaffected. DEVELOPMENT: The
classification proposed by the DSM-IV takes a step towards clinical understanding
and use of a common nomenclature. However, neuropsychological assessment is
essential to understanding clinical subtypes. The neuro-cognitive approach, when
taking into account the processing systems affected or involved, should include
the strategies and principles of a cognitive-behavioural approach, accompanied by
computerized cognitive training. Pharmacological treatment uses drugs with
different modes of action depending on the specific neuropsychological
characteristics of each type of disorder of nerve development. We discuss the
clinical use of various drugs in view of investigations, present and past:
methylphenidate for the dys-attentional subtype of ADHD; piracetam in
developmental dyslexia of dysideatic type; citocolina in the infantile dysphasias
of sensory input predominance, thiapride in dysfluencial and combined subtype of
ADHD; pipamperona in behaviour disorders and the hyperactive-impulsive subtype of
ADHD, with or without associated and selegilina in the dysattention subtype of
ADHD and the dysgraphias of the subtype with predominance of calligraphy and
spatial disorders.
PMID- 10778496
TI - [Psychopedagogic rehabilitation of learning disorders in school children].
AB - In this paper we discuss the main contributions of the three theoretical
perspectives of psychology--conductual, cognitive and socio-historical--of
education when there are learning difficulties. Finally, we emphasize the
inefficacy of interventions and the need for implication in both the cognitive
and meta-cognitive problems, and the socio-effective and conductual problems of
these students.
PMID- 10778497
TI - [Language development: psychosocial requirements for communication].
AB - This work describes the social and psychological characteristics of attachment
adults. These features are considered as sociopsychological prerequisites for the
child language development. The focus is put on the so-called no formal
education, suitable for these attachment adults who are involved affectively and
emotionally. Some educational strategies to be practised at home are also
presented.
PMID- 10778498
TI - [Specific disorders in the language development: neurobiological basis].
AB - Studies of twins, familial aggregates and particular phenotypic conditions have
shown an inherited basis for some dysphasias or specific developmental language
impairments (SLI). This predisposition is usually multifactorial but the analysis
of some families allows to postulate an autosomal dominant transmission of
deficits in specific modular aspects of linguistic competences. Moreover,
neuroimaging studies have shown modifications of normal volumetric
interhemispheric asymmetries, and in group of SLI with receptive prominent
disorder coexist epileptiform activity in wakefulness and non-REM sleep EEG; in
some of these cases, antiepileptic drugs, specially steroids, can significantly
ameliorate the language processing. As many patients with SLI have a difficulty
for discrimination of subtle temporal indices, a hypothesis can also be made of a
dysfunction in various subcortical structures (thalamus, basal ganglia,
cerebellum) modulating the cerebral cortex in phonological processing.
PMID- 10778499
TI - [Logopedic intervention in language learning disorderss].
AB - The objective of this study is to analyze, from the conceptual point of view,
logopaedic intervention in disorders of acquisition of language. We describe the
'model of intervention at three levels': reinforcing stimulation of language,
restructuration of language and substitution of language. We analyze the concepts
of 'ambiental intervention', from the naturalist point of view, that of
functional exercises and of directed or formal exercises. We study the variables
which affect the specificity of logopaedic treatments. As a specific example we
describe intervention in auditory perception.
PMID- 10778500
TI - [Language in autistic disorders].
AB - Autism is a developmental disorder affecting social relationships, communication
and flexibility of thought. These three basic aspects of autism may present in
many different forms and degrees. Therefore autism should be considered to be a
spectrum of autistic disorders rather than a single strictly defined condition.
The spectrum of autistic disorders extends from intelligent individuals with
acceptable social integration, to severely retarded patients with scarcely any
social interaction. Language is almost always affected either in its formal
aspects or in its usage. Autistic linguistic disorders form a specific language
disorder (developmental dysphasia) and a pragmatic disorder linked both to the
primary language problem and to the social cognitive deficit. We discuss the
different linguistic syndromes observed in autistic patients with special
emphasis on the semantic-pragmatic disorder.
PMID- 10778501
TI - [Stereotypes, developmental disorders and neuroimaging studies].
AB - INTRODUCTION: We believe that it is of great interest, in neuropediatric clinic,
to value the molar behavior disorders and to accomplish the corresponding
molecular alterations in the central nervous system. PATIENTS AND METHODS: We
studied 26 patients diagnosed of serious disorders of the development, that were
presenting a typical clinic with manual stereotypes. We choose at random 5
children to practice them a study of metabolic neuroimaging through the Positron
Emission Tomography with 18Fluoro-Deoxi-Glucose (PET-FDG). RESULTS AND
CONCLUSIONS: The conclusion, more meaningful, is that the children with serious
disorders of the development present a mature failure in the neuro-function
circuits of the thalamus, as well as the cortical connection and association
areas. This clinical situation is reinforced by the results of the PET-FDG, that
presents a characteristic metabolic image of the autism children, with a
bilateral decrease of the capitation of FDG, mainly in regions as thalamus,
frontal and temporary lobes.
PMID- 10778502
TI - [Therapeutic intervention in infantile autism and generalized developmental
disorders: self-injury and self-stimulation].
AB - INTRODUCTION: In this article we present a review of the aetiology and treatment
of self-injury and self-stimulation in infantile autism and in generalized
development disorders. We summarize 20 years of study and investigation in the
treatment of these serious behaviour disorders, in a pioneer institution in
Spain: the centre for rehabilitation 'El Cau' in Castellon. DEVELOPMENT: We
describe the most frequent behaviour disorders, with particular reference to self
injury and self-stimulatory behaviour. Models explaining the aetiology and
treatment are described in a brief general review of the subject, and we consider
explicative models which integrate different treatments (in family and
institutional contexts) by means of family therapy, psychoeducational models and
social support networks.
PMID- 10778503
TI - [Psychological manifestations of epilepsy in childhood].
AB - Epilepsy in infancy, far from being a condition in which only convulsive
phenomena occur, also has important cognitive and behavioral components, which
may be more important than the epileptic seizures itself. The psychological
repercussions of epilepsy are the sum of various factors due to the epilepsy
itself, the treatment given, the side-effects of drugs given and the manner in
which the patient copes with his illness. The epilepsy itself shows the effect of
the causal lesion, lesions associated with this causal lesion and the immediate
and long-term effects of the resulting paroxystic discharges. The most
significant manifestations are: attention disorders, problems of social
relationships and problems of conduct. Treatment and diagnosis should not be
limited to treatment of the crises. In all epileptic children neuropsychological
assessment should be directed towards the detection and surveillance of the most
common problems. This has a considerable effect on the quality of life of the
epileptic patient. In cases of benign idiopathic epilepsies, which occur most
frequently in childhood, evaluation of conduct using Achenbach's questionnaire
(CBCL) may be sufficient, together with assessment of the ability to pay
attention on Continuous Performance Test (CPT) and a quantitative and qualitative
evaluation of intellectual capacity using the WISC-R or K-ABC scales.
PMID- 10778504
TI - [Epilepsy and learning: a neuropsychological approach].
AB - INTRODUCTION: The quality of life of an epileptic patient largely depends on the
interplay of the control of the convulsive crises and the degree to which higher
mental functions are affected. Some types of epilepsy lead to mental retardation
during development and with others the basic cerebral mechanisms for processing
data are damaged and this may lead to transient or permanent cogniscitive
deterioration. DEVELOPMENT: There are certain important clinical factors such as
the site of the discharge regarding the lobe, hemisphere, type of cerebral area
involved and the age of the patient. We describe the clinical features of each
type of epilepsy with respect to focal or generalized involvement. The
subclinical effects of continuous discharges affects processing in the areas
involved and therefore intellectual function, thus leading to a secondary
learning disorder. The neuropsychological tests used in investigation of higher
cerebral functions in epilepsy include, in general, tests to assess speed of
processing, attention, memory, reasoning and visuospacial ability and frontal
executive functions. CONCLUSIONS: These tests should be sufficiently sensitive so
as to detect minimal changes in the state of the illness, the time elapsed and
the medication given. Anticonvulsant drugs may themselves cause changes in mental
functions. There may often be mixed neurocognitive behaviour depending on the
drug used. There may also be transient cognitive deterioration.
PMID- 10778505
TI - [Headaches in childhood: association with sleep disorders and psychological
implications].
AB - INTRODUCTION: Infantile headache is an increasingly important cause of medical
consultation, due both to its increasing prevalence and its subsequent
repercussion on the child's life. Also, certain sleep disorders (parasomnias) are
commoner in infancy than in later life. The relationship between headache and
sleep disorders is not clear, but from the literature it would seem that there is
an association, at least in some types of headache, in adults. PATIENTS AND
METHODS: In order to determine possible alterations in patterns of sleep in
children with chronic headache (a history of headache during the previous six
months occurring more than 15/month or 180 days/year) we carried out a
comparative study on a total of 224 Valencian children aged between 3 and 15
years. Of these, 97 children had been diagnosed as having primary chronic
headache (cases) in a specialized. PAEDIATRIC NEUROLOGY CLINIC: Twenty seven
healthy children with no history of headache (controls) were found amongst the
pupils of a Valencian state school. Using a purpose-designed sleep questionnaire,
data was obtained as to the duration, hygiene, quality and incidence of
parasomnia in the two groups. RESULTS: The results showed a decrease in duration
of sleep at night, increased frequency of poor sleep hygiene, increased
prevalence of certain sleep disorders (insomnia and nocturnal wakening), of
certain parasomnias (somnambulism, somniloquy, enuresis) and of nocturnal
snoring, all of statistical significance (test chi 2 with p < 0.005). CONCLUSION:
In children there is an association between chronic headache and certain sleep
disorders.
PMID- 10778506
TI - [Disorders associated with the Gilles de la Tourette syndrome].
AB - INTRODUCTION AND OBJECTIVE: Diagnostic criteria of the Gilles de la Tourette
syndrome hasn't changed in many years. Lately, associated symptoms have became
very important. In this study, we want to stress the relationship between
precocious diagnostic criteria, proposed by us, and the associated
symptomatology, specially the obsessive-compulsive disorder. PATIENTS AND
METHODS: We have studied 30 patients with the diagnosis of Gilles de la Tourette
syndrome with associated obsessive-compulsive disorder by means of our criteria,
evaluating their fiability when confronted to the Shapiro et al and DSM III-R
criteria. CONCLUSIONS: New criteria, that we have named Munoz-Gomez, were useful
for the precocious diagnosis of this syndrome and for evaluation of the
associated symptomatology.
PMID- 10778507
TI - [Neurobiology of attention deficit-hyperactivity disorder].
AB - This is a review of current relevant evidences concerning the nature and
pathophysiological mechanisms of attention deficit hyperactivity disorder (ADHD).
From a neuropsychological point of view, clinical symptoms seem to arise from an
early dysfunction of the executive system. Patients with ADHD have deficits in
inhibitory control, cognitive flexibility, working memory and self-motivation,
and all of them account for the attentional deficit in non automatic information
processing. Decrease in prefrontal, caudate and pallidal structures, which
sustain the executive function, have been found in neuroimaging volumetry.
Cognitive evoked potentials obtained during attentional tasks have augmented
latencies and abnormal topography. A dopaminergic deficit in the structures
sustaining executive function is postulated from the results in experimental
animal models and from functional neuroimaging studies in patients, and this seem
to be the foundation of the favorable outcome with psychostimulants in correctly
diagnosed patients. Psychopedagogic interventions are necessary to help the
patient in order to get an optimal internal locus of control, which is necessary
for attention and impulsiveness inhibition, and also for compensation of
associated disorders.
PMID- 10778508
TI - [Neuropsychological subtypes of the inattention and hyperactivity syndrome].
AB - INTRODUCTION: One of the commonest neurological development disorders is the
syndrome of inattention with hyperactivity, ADHD. The complex neurobiological
network which intervenes in paying attention permits us to maintain a basal state
of alertness, to focalize and maintain attention for long periods, select the
stimulus-signal required and analyze its components, and also to simultaneously
carry out processes of input-output and performance (tutorial, controlling).
DEVELOPMENT: Damage to the various systems participating in 'paying attention'
leads to a syndrome of inattention, with or without hyperactivity. The
distinction into clinical sub-types (combined, mainly lacking attention or mainly
hyperactive and impulsive) gives a primary differentiation of the syndrome.
However, from the neuropsychological point of view, some degree of heterogeneity
within the groups which defines academic behaviour and conduct may also be
recognized. This type of study permits a more specific neuro-cognitive and
pharmacological approach. Some clinical characteristics of the syndrome of
inattention improve with different drugs, such as the state of alterness
(methylphenidate), impulsivity (pipamperone) and selective attention (tiapride).
However, this treatment is symptomatic and in most cases is useful to accompany
the ultimate biological development of the neocortical control mechanisms.
CONCLUSIONS: A neuro-cognitive approach which permits acquisition of habits of
control, functional strategies, sequential planning of activities and per- and
post-functional surveillance is fundamental. The EFE programme for training
executive functions is directed towards working with the damaged processing
mechanisms in each neuropsychological subtype.
PMID- 10778509
TI - [Studies of evoked potentials in children with the syndrome of attention deficit
and hyperactivity].
AB - INTRODUCTION: The syndrome of attention deficit and hyperactivity (SADH) is a
frequent diagnosis in school children, based on clinical criteria systematized in
the DSM-IV and the ICD-10. Nevertheless, there is no biological marker
sufficiently sensitive and specific to confirm the diagnosis and clarify the
physiopathological mechanism of this disorder of psychological development.
DEVELOPMENT: For this, endogenous evoked potentials especially the P300 wave,
related to the processes of selective attention and sensory elaboration of
discriminatory stimuli, have been used. In order to study the type of alteration
in the P300 wave of children diagnosed as having SADH, and the changes induced
after two months of treatment with methylphenidate (MF), 12 children were
studied. The paradigm of oddball type auditory stimulation was used. The latency
and wavelength of the P300 wave at the Cz electrode before (basal) and 2 hours
after taking 10 mg of MF were determined. Comparative analysis of the average
latencies before and after administration of MF showed significant differences (p
< 0.01), with a shortening of the latency following treatment. No significant
changes were seen in amplitude. In only two patients (17%) were there no
differences in the latency of response before and after treatment, and no
response at all to treatment. CONCLUSION: These results show the practical
usefulness of study of the P300 wave in children with SADH, at least for
monitoring the efficacy of pharmacological treatment.
PMID- 10778510
TI - [The evaluation of the effects of pharmacological treatment of children with
attention deficit hyperactivity disorder].
AB - In this study we approach problems related to the dosage and specific action of
methylphenidate, its effects at cognitive and social levels, possible side
effects and limitations to its usage, and methods for evaluation of the response
to treatment in the school environment. We make special mention of the importance
of both parents and teachers being familiar with these problems.
PMID- 10778511
TI - [Attention deficit hyperactivity disorders: current controversy regarding
definition, epidemiology, etiology and treatment].
AB - In this paper a review of the current literature is carried out to provide
information of consensus and divergence points from the Scientific Community,
about interesting questions in the hyperactivity disorder. The core and
traditionally debated questions are boarded, including the concept, assessment,
prognosis and etiology to finish up with the comment concerning the treatment
approaches. It's a concluded that although there aren't definitive answers, the
different approaches of conceptualization are getting closer, a better
understanding of neurobiological disorder basis, and the need of facing its
assessment and treatment from multidisciplinary and multi-methodological
assumptions is taking place.
PMID- 10778512
TI - [Tics in childhood].
AB - INTRODUCTION: Tics in infancy often cause problems in social relationships of
children and worry to their immediate family. We review some aspects of these
abnormal movements and mention Gilles de la Tourette disease, discussing the
graduation from simple tics to the more severe tics which occur in this illness.
DEVELOPMENT: Tics are the commonest abnormal movements in infancy, when
paroxystic disorders are excluded. We review the scant progress made in more than
100 years regarding their aetiology and pathogenesis. Current strategies for the
treatment of tics are considered (not only pharmacological) and choice of drug
depending on associated disorders.
PMID- 10778513
TI - [Movement disorders: dystonias which are apparently psychosomatic. Torsion
dystonias].
AB - In neuropediatric clinical practice, disorders of movement include a wide
diversity of conditions, amongst which the dystonias are uncommon in our
practice, although they have to be considered amongst the possible diagnoses in
some cases. The great variety of clinical symptoms and age of onset together with
the nonspecific, erratic clinical course make diagnosis difficult. Some clinical
pictures of genuine torsion disorders may be confused with hysterical conversion
disorders, somatizations or Munchausen's syndrome. Diagnosis requires clinical
knowledge of both conditions--torsion dystonia as opposed to hysteria or a
conversion reaction--and considerable ability and experience. Genetics and
molecular studies have helped to clarify some difficult diagnostic problems and
facilitated both diagnosis and treatment. In a diagnostic video session we show
the case of a seven year old boy who initially presented with a dystonic
disorder. There was some doubt as to the aetiology and different types of
treatment were given by different specialists. The true diagnosis was reached
after molecular genetic studies.
PMID- 10778514
TI - [Dystonia responsive to L-dopa].
AB - A comprehensive literature review is made. Clinical characteristics, differential
diagnosis, treatment with L-dopa and underlying pathological conditions are
commented.
PMID- 10778515
TI - Rationale anti-snake venom therapy: randomized controlled trials or clinical
judgment.
PMID- 10778516
TI - Randomized controlled trial on the effective dose of anti-snake venom in cases of
snake bite with systemic envenomation.
AB - Snake bite is the common cause of morbidity and mortality in India. Snake
antivenom, although very effective, is expensive, scarce, and associated with
side effects. The conventional dose may not be required in all cases and a
smaller dose may be as effective. A randomized double blind controlled trial was
conducted to compare the effect of lower versus the conventional (high) dose.
Patients presenting within 24 hours of snake bite with hematological or
neurological evidence of systemic envenomation were included in the study.
Patients were randomized either to receive high dose (2 vials over 1 hour,
followed by 2 vials over 4 hours and repeated 4 hourly until clotting parameters
normalized and then 2 vials as infusion over 24 hours) or low dose (2 vials over
1 hour, followed by 1 vial over four hours, repeated 4 hourly until clotting
parameters were normalized and then 1 vial as an infusion over 24 hours). Thirty
one patients received high dose and 29 a low dose. The mean dose of antivenom
used was significantly different in the two groups (8.9 and 4.7, respectively).
There was no mortality. The duration of stay was 4.94 and 3.48 days,
respectively. There was no difference in the transfusion, dialysis or ventilation
requirement of the two groups. Low dose regimen is more effective and required 5
vials less than the conventional dose. Each vial costs Rs. 200, so the estimated
savings is Rs. 1000 per patient.
PMID- 10778517
TI - Age at onset, gender distribution and intraarterial blood pressure changes in
atrioventricular node-dependant tachycardias.
AB - OBJECTIVE: Atrioventricular nodal reentrant tachycardia (AVNRT) and
atrioventricular reentrant tachycardia (AVRT) utilising accessory pathways
constitute the vast majority of paroxysmal supraventricular tachycardia (SVT). We
studied the age at onset, the gender distribution and the intraarterial
hemodynamics of these tachycardias. METHODS: The data of 224 patients who
underwent electrophysiology study (EPS) and radiofrequency ablation was analysed.
The age at onset of tachycardia was assessed by a careful history. The
intraarterial BP was noted during sinus rhythm (SR), immediately after
tachycardia onset (T0) and 15 seconds after the onset of tachycardia (T15).
RESULTS: The age at onset of tachycardia was a decade later for AVNRT (48 +/- 10
years) than for AVRT (37 +/- 11 years). There was no gender preponderance in the
AVNRT group (60 males, 56 females) while a male preponderance was seen in the
AVRT group (71 males, 37 females, p < 0.01). There was a marked fall in the
intraarterial systolic BP in both groups at the onset of tachycardia, from 143 +/
24 mm Hg to 108 +/- 16 mm Hg (p < 0.05) for AVNRT and from 139 +/- 25 mm Hg to
107 +/- 18 mm Hg (p < 0.05) for AVRT. There was no correlation between the rate
of tachycardia and the extent of fall of BP. CONCLUSION: Hospital-based data in
an Indian setting found a similar pattern of age of onset of AV node-dependant
tachycardia as in Western literature. However, unlike in Western studies, no
female preponderance was seen in the AVNRT group. The fall in systolic BP at the
onset of tachycardia is significant, similar in the two groups and independent of
the rate of tachycardia.
PMID- 10778518
TI - Resurgence of malaria in Mumbai--is escalating chloroquine resistance a cause?
AB - OBJECTIVES: Given the steep increase in the incidence of malaria in the city of
Mumbai in the nineties, we decided to study the causes for the same as well as
analyse the resistance pattern of P. falciparum in the city. METHODS: Smear
positive cases of acute uncomplicated P. falciparum malaria who presented to us
in 1994, 1995 and 1996 were analysed for their response to full dose chloroquine
(25 mg/kg over 3 days). Samples of those patients who satisfied criteria for in
vitro resistance testing to chloroquine and other antimalarials, were also
studied. Chloroquine level in all patients was studied on Day 3 by HPLC. In vivo
response to chloroquine was studied in 30, 71 and 78 patients while in vitro
response was studied in 17, 35 and 30 patients respectively in the above years.
RESULTS: We found in vivo chloroquine resistance figures of 36.78%, 45% and 53.8%
in the years '94, '95 and '96 and the in vitro resistance figures of 41.17%,
54.28% and 66.6% in the same years. CONCLUSIONS: Our previous studies documenting
15% chloroquine resistance in 1993 and the increasing incidence in subsequent
years suggests resistance to chloroquine as one of the causes of resurgence and
maintenance of malaria in the city. If patients of uncomplicated P. falciparum
malaria are to be treated with chloroquine, rigorous monitoring for nonresponse
and timely rescue medication is necessary. Alternative antimalarial drugs such as
mefloquine, artemisinin derivatives and sulfadoxine-pyrimethamine should be used
in patients where this is not possible.
PMID- 10778519
TI - An evaluation of oxidative stress in diabetes mellitus during uncontrolled and
controlled state and after vitamin E supplementation.
AB - OBJECTIVE: The study was conducted on 50 patients (10 insulin dependent diabetes
mellitus (IDDM) and 40 non-insulin dependent diabetes mellitus (NIDDM) of
recently diagnosed diabetes mellitus. The main objectives of the study were: 1.
To evaluate oxidative stress at uncontrolled stage. 2. To evaluate the effect of
optimal control on oxidative stress irrespective of type of drug therapy used. 3.
To further evaluate the effect of vitamin E supplementation on oxidative stress
after achieving optimal control. This was done in order to explore anti-oxidant
effect of vitamin E. METHODS: Fifty patients of uncontrolled diabetes of less
than 1 year duration and without any overt complications were studied. The
parameters of oxidative stress included malonyl-di-aldehyde (MDA), reduced
glutathione and vitamin E levels in the blood. They were done at three stages
i.e. (a) In uncontrolled stage, (b) At controlled stage and (c) After 4 weeks of
vitamin E supplementation in dosage of 400 mg daily. The parameters of control
included fasting blood sugar < or = 140 mg%, post prandial < or = 200 mg and
HbA1c < or = 7% (analysed by prepared kit). RESULTS: The significantly raised
levels of MDA and decreased levels of reduced glutathione and vitamin E during
uncontrolled stage of diabetes indicated free radical stress inducing lipid
peroxidation. The significant fall of MDA and rise in reduced glutathione and
vitamin E levels in blood after optimal control revealed its beneficial effect on
oxidative stress. The levels were not normalised but still stayed higher than
controls. After 4 weeks of vitamin E supplementation, further fall in MDA and
rise in reduced glutathione suggested beneficial effect of vitamin E over and
above the optimal control. Vitamin E estimation in blood at this stage did not
constitute parameter of oxidative stress as it was provided from outside but was
done to know the compliance of patients. Normalisation or near normalisation was
not achieved with vitamin E therapy indicating persistence of oxidative stress.
CONCLUSION: There was an evidence of oxidative stress in diabetes which decreased
with optimal control and further declined after vitamin E supplementation
indicating anti-oxidant effect of vitamin E alone. Normalisation of oxidative
stress was not achieved. A further study is desired to study the effect of
vitamin E for longer period at least 3-6 months before a definite conclusion is
drawn.
PMID- 10778521
TI - Modification of antihistaminic activity of cetirizine by nimesulide.
AB - OBJECTIVE: To study the effect of nimesulide (4-nitro-2-phenoxymethane
sulfonanilide) a non-steroidal anti-inflammatory drug, on antihistaminic activity
of cetirizine. METHOD: A randomized, double blind, cross over study was conducted
in ten healthy male volunteers. Wheal and flare responses to histamine were
measured by performing intradermal injection of histamine (2 micrograms base)
diluted in 100 microliters volume of saline on the volar surface of forearm, on
four occasions (0, 2, 4, and 6 hrs. post-dosing). Each volunteer was randomized
to receive either treatment A (cetirizine 10 mg + placebo) or treatment B
(cetirizine 100 mg + nimesulide 100 mg), with one week wash out period in between
each administration. Wheal and flare responses were measured ten minutes after
each histamine injection. RESULTS: Both cetirizine 10 mg alone and cetirizine 10
mg + nimesulide 100 mg, decreased wheal and flare responses significantly at 2
hrs. and this continued till 6 hrs. post-dosing. This decrease was highly
significant when cetirizine was given along with nimesulide. CONCLUSION: The
results suggest a synergistic effect exhibited by the combined use of cetirizine
with nimesulide.
PMID- 10778520
TI - Brucella spondylitis: an important treatable cause of low backache.
AB - OBJECTIVES: This study was undertaken to see if brucella spondylitis existed as a
cause of backache in Mumbai and to identify the clinical setting in patients of
backache where brucella serology is indicated. METHODS: In 18 months (June 1996
Dec. 1997) we performed tube agglutination test (TAT) for Brucella melitensis and
abortus on 72 patients of low backache from Orthopaedics Department of a teritary
health centre. All 72 patients satisfied the inclusion and exclusion criteria
designed to exclude radiologically detectable congenital or degenerative cause of
backache. RESULTS: Six out of 72 patients were seropositive for brucellosis. All
six patients had either history of animal contact or ingestion of raw milk or
milk product (cheese or paneer). The lumbosacral backache was severe, radiating
to the legs and straight leg raising test was significantly positive, they had
marked tenderness on spinous process of lower lumbar vertebrae. Changes of
brucella spondylitis were present on plain radiogram of lumbosacral spine in
three patients. Four patients had abnormalities on bone scintigraphy. CONCLUSION:
Low backache of brucella spondylitis closely simulates pain of prolapsed
intervertebral disc. Serologic testing for brucellosis is an important step in
management of such patients, especially when history of animal contact or raw
milk or milk product ingestion is present, as the disease can be eminantly
treated with antibiotics.
PMID- 10778522
TI - Response to exercise and ambulatory blood pressure monitoring in essential
hypertension.
AB - To evaluate the relationship of ambulatory blood pressure (ABP) recording and
blood pressure response to exercise, 58 essential hypertensive patients, not
taking any drugs, had symptom-limited treadmill stress test (TST) within 48-96
hours of ABP, TST time, blood pressure increase, decrease, mode of increase and
decrease, were independent of ABP systolic (SBP) and diastolic blood pressure
(DBP) over 24 hours, day time and night time (p = ns). SBP decrease immediately
after exercise were independent of ABP data. TST achieved heart rate was related
to both 24 hours SBP (r = -0.64, p = 0.00005) and DBP (r = -0.55, p = 0.00001) in
both day (r = -0.64, p = 0.00001 and r = -0.54, p = 0.002) and night (r = -0.52,
p = 0.0001 and r = -0.46, p = 0.003) time periods. Therefore patients with
achieved heart rate < 100% (n = 18) had higher 24 hour SBP (148 vs 132 +/- 2 mm
Hg, p = 0.0006) and DBP (92.4 +/- 6.4 vs 84 +/- 6.2 mm Hg, P = 0.006) day and
night. It is concluded that there is no overlap of diagnostic information using
blood pressure. Values in TST or ABP although achieved heart rate in exercise is
inversely related to severity of hypertension.
PMID- 10778523
TI - Mallory-Weiss syndrome: clinical features and management.
AB - OBJECTIVE: To report the clinical features, endoscopic appearance, management and
outcome of patients with upper gastrointestinal bleeding due to Mallory-Weiss
tear seen at our institution during the last seven years. METHODS: A
retrospective study of all patients with upper gastrointestinal bleeding seen
during the last seven years was performed. Patients who were bleeding from
longitudinal non-perforating tear(s) of the gastro-oesophageal mucosa were
included in the study and their clinical features, endoscopic appearance
management and outcome were recorded. RESULTS: During the study period 426
patients with upper gastrointestinal bleeding were seen. Sixty-six (15.5%) of
these were found to have bled or were bleeding from Mallory-Weiss tear(s). Twenty
seven (41%) patients with Mallory-Weiss tear had no antecedent nausea, retching,
abdominal pain or vomiting. Two patients had portal hypertension and a solitary
case bled from an iatrogenic tear induced during routine upper gastrointestinal
endoscopy. Multiple bleeding episodes were seen in 12% of cases. Twenty (30%)
patients needed endoscopic sclerotherapy. Haemostasis was achieved in all. Except
retrosternal pain, no procedure related complications were seen. CONCLUSIONS:
Mallory-Weiss tear is a common cause of upper gastrointestinal bleeding. Nearly
half of the patients have no antecedent symptoms and presented for the first time
with upper gastrointestinal bleeding. Endoscopic therapy is very effective and
safe in producing haemostasis in these patients.
PMID- 10778524
TI - Alpha tocopherol concentration in serum of critically ill patients.
AB - OBJECTIVE: Alpha tocopherol is the biologically and chemically active form of
vitamin E and is the most abundant lipid-soluble antioxidant in humans protecting
the cell membranes. Serum concentration of the antioxidant alpha tocopherol was
measured in critically ill patients in whom the excessive generation of reactive
oxygen species could compromise antioxidant defence mechanisms. METHOD: Alpha
tocopherol concentration in serum was measured spectrofluorometrically in
critically ill patients admitted in intensive care unit and age matched healthy
adults, patients with diabetes mellitus (DM) and chronic myeloid leukaemia (CML)
served as control. RESULTS: Alpha tocopherol levels were significantly lower in
critically ill patients (p < 0.001) as compared to healthy control subjects and
those in two other disease groups (DM, CML) in which reactive oxygen species are
reported to be increased. Elderly patients and patients who stayed longer than 8
days had lower plasma concentration of vitamin E. CONCLUSION: These findings
indicate that antioxidant defence could be considerably compromised in these very
sick patients and vitamin E supplementation may be beneficial in increasing their
antioxidant reserve.
PMID- 10778525
TI - Lipid peroxidation in leukaemia.
AB - OBJECTIVE: Free radicals have been implicated in the pathogenesis of leukaemias,
so the degree of lipid peroxidation was studied as a marker of disease activity
in patients of leukaemia. METHODS: Lipid peroxidation product malonyldialdehyde
(MDA) was estimated in serum from 30 patients of leukaemia by thio-barbituric
acid reaction before and after chemotherapy. There were 10 patients of acute
myeloid leukaemia (AML), 5 with acute lymphocytic leukaemia (ALL), 15 with
chronic myeloid leukaemia (CML) of which 10 were in chronic stable phase and 5 in
blast crisis. Twenty healthy age and sex matched individuals served as control.
RESULTS: There was a significant increase in MDA levels in AML and ALL patients
and serum MDA levels were higher in the active phase of disease than in
remission. We observed a direct correlation between peripheral leucocyte counts
and MDA levels. In CML, MDA levels were higher, more so in the patients who were
in blast crisis. Patients of CML blast crisis who achieved remission showed a
significant decrease in MDA levels as compared to those without remission.
CONCLUSION: We observed a significant increase in MDA levels in active phase of
acute as well as chronic leukaemia than those in remission. The proposed
mechanism for high MDA is that myeloid cells are a major source of superoxide and
other oxygen metabolites which lead to lipid peroxidation. MDA estimation in
leukaemia can be of help in detecting type of leukaemia, response of therapy, and
to predict the chances of relapse.
PMID- 10778526
TI - High altitude koilonychia.
AB - OBJECTIVE: To study the incidence of koilonychia in the residents of high
altitude. METHODS: Nails of all the patients attending the Medical Outpatient
Department (MOPD) of a multispeciality medical camp at Kaza in Himalayas (height
12,500 feet above sea level) were looked for the presence of koilonychia and were
included for the study. Those residing below 10,000 feet were excluded from the
study. A detailed history was taken and a thorough physical examination was made
in each. Routine laboratory investigations were undertaken. Serum ferritin levels
were estimated in seven. RESULTS: Koilonychia was present in 6.99% of the
patients (67 out of the 986). There were 29 males and 37 females within the age
range of 37 to 78 years. Sixty four were high landers since generations and three
were high landers from 2nd generation onward. All were right handed. Koilonychia
was in the nails of both upper and lower limbs in 14, in the nails of upper limbs
in 49 and in the nails of lower limbs in 18. In the upper limbs it was in all the
fingers in 42, in thumb, index and middle fingers of right hand in 12 and of left
hand in nine. In the lower limbs it was bilateral in the first three toes in
nine. Chronic obstructive pulmonary disease was in 29, ulcer like dyspepsia in
24, osteoarthritis of knee in 17, hypertension in 14, pulmonary tuberculosis in
eight, anxiety neurosis in five, pneumoconiosis in two and squamous cell
carcinoma of lung in one. The haemoglobin in all was normal and serum ferritin
level of the seven patients estimated was also normal. CONCLUSIONS: Koilonychia
at high altitude is present in 6.99%. It is due to retardation of nail plate
growth and is more common in upper limbs.
PMID- 10778527
TI - Infections and atherosclerosis in the Indian context.
PMID- 10778528
TI - Pictorial CME. Reiter's syndrome with keratoderma blenorrhagica.
PMID- 10778529
TI - Growth hormone therapy.
AB - Growth hormone therapy with rhGH (recombinant human growth hormone) has been
recommended for treatment of GH deficient short stature in children, repeated
hypoglycemias in infancy and early childhood due to GH deficiency, short stature
accompanying chronic renal failure prior to renal transplantation and Turner's
syndrome. It is now increasingly recommended to adults with GH deficiency
following pituitary tumour surgery or irradiation or idiopathic hypopituitarism.
There are other indications for its use where evidence for protein catabolism is
very strong such as burns injury. The end points of GH therapy in children
include achievement of desirable adult height or a growth rate velocity of < 2.5
cm/year. In adults GH deficiency, GH therapy is intended for improvement of
general well being, body composition and metabolic markers of GH function.
PMID- 10778530
TI - Building related illnesses and indoor air pollution.
AB - Building related illnesses are a common problem in developed countries and are
expected to increase rapidly in urban India. Although objective physical
abnormalities are not generally found except in a few specific diseases like
Legionnaires' disease, the symptoms can be uncomfortable and even disabling. In
this review we initially introduce the concept of indoor air pollution and
building related illnesses. Subsequently we review the sources of and exposure to
the pollutants along with their health effects and the approach to a patient of
suspected building related illness. We conclude by discussing the measures for
the control of indoor air pollution.
PMID- 10778531
TI - GLUT-4, tumour necrosis factor, essential fatty acids and daf-genes and their
role in glucose homeostasis, insulin resistance, non-insulin dependent diabetes
mellitus, and longevity.
AB - GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids
(EFAs) and their metabolites and daf-genes seem to play an important and
essential role in the maintenance of glucose homeostasis, and in the pathobiology
of obesity and non-insulin dependent diabetes mellitus (NIDDM). Daf-genes encode
for proteins which are 35% identical to the human insulin receptor, a
transforming growth factor-beta (TGF-beta) type signal and can also enhance the
expression of superoxide dismutase (SOD). On the other hand, EFAs and their
metabolites can increase the cell membrane fluidity and thus, enhance the
expression of GLUT-4 and insulin receptors. In addition, EFAs can suppress TNF
alpha production and secretion and thus, are capable of reversing insulin
resistance. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and
SOD. Hence, it is likely that there is a close interaction between GLUT-4, TNF
alpha, EFAs, daf-genes, melatonin and leptin that may have relevance to the
development of insulin resistance, obesity, NIDDM, complications due to NIDDM,
longevity and ageing.
PMID- 10778532
TI - Ion channels and channelopathy.
PMID- 10778533
TI - Angina--an Indian disease.
PMID- 10778534
TI - Epstein-Barr virus induced non-Hodgkin's lymphoma as a presenting manifestation
of acquired immune deficiency syndrome.
AB - A 30 year old, human immunodeficiency virus (HIV) positive patient presented with
fever and intra-abdominal lymphadenopathy. Cytology smears from the nodes showed
a high grade Non-Hodgkin's lymphoma (NHL) which was B cell in origin. NHL was the
acquired immune deficiency syndrome (AIDS) defining disease in this patient.
Polymerase chain reaction (PCR) studies on tumour tissue showed presence of
Epstein Barr Virus.
PMID- 10778535
TI - Myoglobinuria and transient acute renal failure in a patient revealing
hypothyroidism.
AB - Muscle involvement in hypothyroidism commonly manifests as fatigue, myalgias,
stiffness and slowed reflexes. We report a case of transient acute renal failure
related to rhabdomyolysis and myoglobinuria in a 40 year old man that revealed
the diagnosis of hypothyroidism with myopathy. The patient had proximal muscle
weakness and tenderness, markedly raised muscle enzymes and deranged renal
functions that normalised with thyroid replacement therapy. Hypothyroidism,
though rare, should be considered a definite and authentic cause of
rhabdomyolysis.
PMID- 10778536
TI - Uncommon presentations of pontine haemorrhage.
PMID- 10778537
TI - Tuberculosis of the breast.
AB - Nowadays, tuberculosis of the breast is relatively rare compared to other forms
of extrapulmonary tuberculosis. The incidence of tuberculosis of the breast has
decreased mainly due to effective antituberculous chemotherapy. We report two
cases of tuberculosis of the breast.
PMID- 10778538
TI - Brucellar spondylitis.
PMID- 10778539
TI - Parthenium hysterophorus (Congress grass) as allergen in allergic airway disease.
PMID- 10778540
TI - Sustained ventricular tachycardia in a case of aconite poisoning.
PMID- 10778541
TI - Phenytoin sodium induced diabetes insipidus.
PMID- 10778542
TI - Eosinophilic meningitis.
PMID- 10778543
TI - Liposarcoma of the mediastinum--a rare cause of haemorrhagic pleural effusion.
PMID- 10778544
TI - Myelofibrosis with myeloid metaplasia due to tuberculosis.
PMID- 10778545
TI - Topical aspirin-chloroform in the treatment of zoster associated pain.
PMID- 10778546
TI - Bioequivalence of two brands of sustained release theophylline brands.
PMID- 10778548
TI - Digital index--a new way of numerical assessment of clubbing.
PMID- 10778547
TI - Correlation between clubbing and exophthalmos and/or pretibial myxoedema in
Graves disease.
PMID- 10778549
TI - Knowledge of universal precautions among undergraduate medical students.
PMID- 10778550
TI - Hypovitaminosis D in patients attending a rheumatology clinic at a tertiary
referral clinic.
PMID- 10778551
TI - Paracetamol induced urticaria.
PMID- 10778552
TI - Neurocysticercosis: clinical and diagnostic dilemma.
PMID- 10778553
TI - Cysticercus immunoblot assay in patients with single, small enhancing lesions and
multilesional neurocysticercosis.
AB - A single, small (< 20 mm), ring or disc shaped contrast enhancing lesion located
at the cortical-subcortical junction with minimal or no surrounding edema on
computed tomography is the commonest mode of presentation of neurocysticercosis
in the Indian subcontinent. Serum samples of 37 patients with these single, small
enhancing lesions (SSEL's) and five patients with typical multilesional
parenchymal neurocysticercosis were tested by the electro-immunoblot transfer
(EITB) assay and the enzyme linked immunosorbent assay (ELISA). EITB was positive
in 18 patients (48.64%) and ELISA was positive in 21 patients (56.76%) with
SSEL's. On the other hand EITB was positive in all five patients (100%) and ELISA
was positive in four patients (80%) with multilesional neurocysticercosis. The
low sensitivity of the EITB in the SSEL's is probably linked to an insufficient
immune stimulation provided by a single cysticercus cyst.
PMID- 10778554
TI - Clinical profile of polymyositis in Kashmir valley.
AB - OBJECTIVES: The present study is a retrospective and prospective study of 24
cases of idiopathic inflammatory myopathies from Kashmir valley. The study was
conducted to depict the clinical profile of polymyositis from this part of the
world. METHODS: The diagnosis of polymyositis/dermatomyositis was established by
following the criteria of Bohan and Peter (1975). Besides relevant clinical
examination, investigations like complete blood count, ESR, muscle enzymes, LE
cell phenomenon, antinuclear antibodies and rheumatoid factor were also done.
Electrophysiological study and open muscle biopsy was performed in 21 and 24
cases respectively. RESULTS: The mean age at presentation was 34 years with 62.5%
cases presenting in fourth decade. Pelvic girdle weakness was observed in all the
24 cases. Male:Female ratio was 1:1.4. Four (16.8%) cases had associated collagen
vascular disease. No case was associated with malignancy or childhood vasculitis.
Raynauds' phenomenon was seen in seven (29.1%) cases. Creatine phosphokinase and
lactic dehydrogenase was elevated in 22 (91.6%) and 12 (50%) cases respectively.
Electromyography revealed myopathic features in 74.3% cases. Muscle biopsy
revealed features of inflammatory myopathy in 22 (91%) cases. CONCLUSIONS: The
conclusions drawn from this study are as follows: a. Younger age at presentation
b. Shorter duration of illness at presentation c. Increased frequency of
Raynaud's phenomenon as compared to other Indian series. d. No case of
polymyositis/dermatomyositis associated with malignancy or childhood vasculitis
was seen. e. Biochemical, electrophysiological and histopathological features
suggestive of shorter duration of illness were observed.
PMID- 10778555
TI - Clinical and pathological profile of 73 patients with lung carcinoma: is the
picture changing?
AB - OBJECTIVE: A prospective study was undertaken to study the clinical features and
pathological cell type of primary lung carcinoma in our institute. METHODS:
Seventy three patients were included in the study over a period of three years.
These were investigated according to a study protocol which included a detailed
history regarding the onset and progress of the disease, smoking habits, x-ray
chest, computed tomography of the chest and upper abdomen, and flexible
bronchoscopy with brushings and biopsy. RESULTS AND CONCLUSIONS: 32.85% of
patients were non-smokers. The male-female ratio was 4.2:1. Male sex, age > 50
years and history of smoking are still a risk factor for lung carcinoma. Tobacco
smoking of 20 pack-years or more is significantly associated with the incidence
of squamous cell carcinoma compared to other cell types. Adenocarcinoma (28.8%)
was the most common cell type observed. It was also the most common cell type in
central location (32.8%). Adenocarcinoma was the most common cell type diagnosis
amongst females (50%) and non-smokers (43.5%). Computed tomography done in 47
patients diagnosed additional eleven patients with rib or vertebral metastases in
addition to the three diagnosed by chest roentgenology. Computed tomography
diagnosed significant mediastinal lymphadenopathy in 16 patients in whom
mediastinal lymphadenopathy was not suspected on chest roentgenology. Computed
tomography confirmed liver metastases in four patients diagnosed by
ultrasonography and additionally in three more patients. Bronchial brushing
cytology yielded positive results in 51.72% of central tumours and 40% in
peripheral tumors. Yield of endobronchial biopsy was 59% and transbronchial
biopsy was sixty percent. At presentation 74.1% patients with non-small cell
carcinoma were inoperable and in case of small cell carcinoma 75% had extensive
disease. Fiberoptic bronchoscopy with brushings and biopsy, and computed
tomography of the chest and upper abdomen are useful investigations in the
diagnosis of lung carcinoma.
PMID- 10778556
TI - Role of radionuclide perfusion study in cold solitary thyroid nodule for
diagnosis of malignancy: a complimentary diagnostic modality to fine needle
aspiration cytology.
AB - One hundred and forty eight subjects with euthyroid solitary thyroid nodules
(STN) were taken up for radionuclide perfusion study. They were found to have a
cold STN on 99mTc thyroid static scan. All had fine needle aspiration cytology
(FNAC), and except for subjects with chronic lymphocytic thyroiditis, were
subjected to surgery for tissue diagnosis by histopathology. The diagnostic
findings in these patients of solitary thyroid nodules were correlated with the
histopathology. Radionuclide perfusion study is considered useful to
differentiate benign from malignant cold thyroid solitary nodules with high
degree of sensitivity (95%) and specificity (87.9%).
PMID- 10778557
TI - Epilepsy surgery in India: All India Institute of Medical Sciences experience.
AB - OBJECTIVES: Surgical treatment of epilepsy should be considered an important
alternative to medical therapy. The identification of a suitable candidate, pre
operative evaluation requires a multidisciplinary team. The specific diagnostic
studies required depend on the operative strategy and objective of surgical
treatment. METHODS: In twenty patients with medically intractable epilepsy, who
had clinical evaluation, electroencephalography (EEG), video-EEG monitoring using
scalp electrodes, high resolution magnetic resonance imaging (MRI),
neuropsychology, single photon emission computed tomography (SPECT) was done to
localise the seizure focus. If the investigations were concordant resective
surgery was performed. In case of frequent falls, atonic and tonic seizures, with
generalised/multifocal discharges on EEG, a callostomy was done. Surgical outcome
was assessed using Engel's 4 point scale. RESULTS: In 18 patients the seizure
focus was localised, 13 had temporal lobectomy, five extra-temporal resection,
and two had callosotomy. Fifteen patients had a follow-up of more than eight
months, mean 20.5 (range 8-35 months), 13 had outcome I (seizure free), two had
outcome II (occasional seizures), one-outcome III. Three were lost to follow-up
and one patient died. There were no major post-operative complications.
CONCLUSIONS: Surgical treatment of epilepsy is a safe, effective mode of therapy.
Suitable candidates should be identified early and referred to appropriate
centres.
PMID- 10778558
TI - The prevalence of antiphospholipid antibodies in cases of recurrent pregnancy
loss.
AB - Antiphospholipid antibodies (aPL) are a diverse family of autoantibodies reactive
against negatively charged phospholipid-protein complexes. The clinically
significant members include lupus anticoagulant (LA), anticardiolipin antibody
(aCL) and reaginic antibodies causing biological false positive (BFP) venereal
disease laboratory test (VDRL). Although detected in various clinical scenarios,
unexplained fetal loss in women of reproductive age group is the commonest
association. Fifty pregnant women of first and second trimester with a history of
two or more unexplained pregnancy losses were studied for the presence of LA, aCL
and reaginic antibodies. Thirty pregnant women of the same trimester without any
history of fetal loss were taken as control. LA was detected in nine (18%) cases
and aCL in 12 (24%) cases of the study group. The control group was negative for
any autoantibody. The prevalence of aPL in the study group found to be
statistically significant. Detection of aPL must be considered in women with
previous pregnancies complicated by unexplained fetal wastage.
PMID- 10778559
TI - Paclitaxel-epirubicin in advanced breast cancer.
AB - Breast cancer remains a major cause of morbidity and early death in women
worldwide. Despite the responsiveness of advanced breast cancer to a number of
chemotherapeutic and hormonal agents, long term outcome remains poor. The
introduction of paclitaxel with a novel mechanism of action has kindled a ray of
hope. Combination of paclitaxel with anthracyclines are being tried, with varying
degree of success. Twenty patients with metastatic or locally advanced breast
cancer were treated with Paclitaxel (175 mg/m2) and Epirubicin (80 mg/m2)
administered sequentially. Each patient received 3 to 6 such cycles at 3 weekly
intervals. A response rate of 85% (95% Confidence Interval (CI) 69%-100%) was
observed in these patients with 25% (95% CI 6%-44%) achieving complete response.
A response rate of 100% was observed in the six patients with locally advanced
disease who had not received any chemotherapy earlier. Grade III neutropenia
occurred in 5 patients and was reversible in all the cases. This combination is
well tolerated. Its efficacy is being compared in a randomised trial with CAF
regime in advanced breast cancer in our center.
PMID- 10778560
TI - Mountain desert silicosis.
AB - OBJECTIVES: To evaluate the radiological miliary shadows in the high landers of a
Himalayan desert for the presence of silicosis. METHODS: Seventeen high landers
attending the Medicine OPD of a multi-speciality medical camp at Kaza in
Himalayas (height 12,500 feet above sea level) having radiological miliary
shadows were included in the study. A detailed life time work place history was
taken. In the laboratory workup their hemogram, repeat chest skiagram, peak
expiratory flow rate, urinalysis and electrocardiogram were undertaken. Their
localities were looked for the presence of industries particularly for silicosis
prone work place. The silica contents of upper strata of soil were estimated.
RESULTS: Silicosis--chronic simple variety was present in nine males and eight
females. The youngest person was 43 years of age and oldest person was of 65
years of age. There was no silicosis prone industry in their locality. Four had
taken repeated courses of anti-tubercular treatment in adequate doses for these
miliary shadows without any change in the radiological shadows. Three had
silicosis prone work history. Seven were smokers and two had hypertension. The
miliary shadows were 2-4 mm in size and hilar lymphadenopathy was in 11 and fine
calcification of lymph nodes in two. Peak expiratory flow rate was reduced. Upper
strata of soil had a silica content of 36.8 percent. CONCLUSION: Silicosis
developed in high landers of the Himalayas even without working in silicosis
prone work place. They were exposed to silica from the non-work place silica rich
environment.
PMID- 10778561
TI - Distribution of blood viscosity values and biochemical correlates in healthy
adults.
AB - OBJECTIVE: Increase in the viscosity of blood predict clinical manifestation of
atherothrombotic vascular disease. The clinical utility of viscosity measurements
in cardiovascular risk factor requires a reference value established from a
healthy disease free population. METHODS: Blood viscosity (based on empirical
Merill's formula), fibrinogen, haematocrit and lipid profile were measured in 100
fasting healthy nonsmoking adults (50 men, 50 women). RESULTS: The mean (+/- SD)
blood viscosity values were 0.030 +/- 0.015 dyne/cm2. Men had higher viscosity
values than women. Also, men had higher triglycerides, haematocrit as well as
fibrinogen as compared to women. CONCLUSION: This study provides reference values
for the blood viscosity, fibrinogen haematocrit and lipid profile. Viscosity
measurements may improve identification and risk stratification of patients at
high risk for atherothrombotic vascular disease and its complications.
PMID- 10778563
TI - Medical profession at cross roads.
PMID- 10778562
TI - Basal ganglia calcification.
AB - Basal ganglia calcification (BGC) is now being diagnosed with increasing
frequency with widespread application of computed tomography (CT) in clinical
practice and is no more considered a rarity. During the period 1987 to 1995, 42
patients were noted to have BGC and it constituted 0.93% of all CT scan of brain
carried out during the relevant period. These patients presented with diverse
neurological and endocrine disorders i.e., epilepsy (22 patients), mental
retardation (five patients), extra-pyramidal syndromes (five patients), abnormal
behaviour (three patients), stroke (two patients), raised intracranial tension
without localizing signs (one patient), following radiotherapy (one patient), and
with hypoparathyroidism (three patients). These patients were noted to have
variable degree of calcification in different parts of brain i.e., basal ganglia
(42 cases), cerebellum (12 cases) and cerebral cortex (nine cases). Family
history of a neurological disorder was available in five patients. This study
highlights the fact that calcification of basal ganglia and other parts of the
brain is often a nonspecific finding on CT scan and it may not be possible to
establish a clinicopathological correlation.
PMID- 10778564
TI - Pictorial CME.
PMID- 10778565
TI - Imaging strategies for evaluation of carotid artery disease.
PMID- 10778566
TI - Epidemiological studies in medical practice pose practical challenges in
developing countries--a situational analysis.
PMID- 10778567
TI - Trinucleotide repeat diseases.
PMID- 10778568
TI - Retrosternal abscess caused by Aspergillus fumigatus following coronary artery
bypass surgery.
PMID- 10778569
TI - Malignancy in rheumatoid arthritis--a report of two cases.
AB - The development of malignancy in the setting of pre-existing connective tissue
disease is well known. We report two cases of rheumatoid arthritis who developed
malignancy--multiple myeloma in one of them and carcinoma cervix in the other.
Case 1 was a 62 year old man, who developed multiple myeloma three years after
the onset of rheumatoid arthritis. Case 2 was a 61 year old female with history
of rheumatoid arthritis for two years and who developed carcinoma cervix.
PMID- 10778570
TI - Fatal rabies encephalitis despite post-exposure vaccination in a diabetic
patient: a need for use of rabies immune globulin in all post-exposure cases.
PMID- 10778571
TI - Stroke like presentation of Creutzfeldt Jakob disease: an unusual variant.
AB - Creutzfeldt-Jakob disease (CJD) is a degenerative process of the brain, induced
by novel infectious agent or prion, and is usually characterized by a rapidly
progressive dementia in association with myoclonus. However different patterns of
disease presentation have been identified. The authors describe three probable
cases of CJD. None of them had positive family history or any known modes of
iatrogenic transmission. Interestingly, all the cases presented like a stroke.
This is the first series of CJD cases from this part of country.
PMID- 10778572
TI - Pulmonary hamartoma in a patient with testicular seminoma.
PMID- 10778573
TI - Ehler-Danlos syndrome type VI variant presenting with recurrent respiratory
infections and responding to high dose vitamin C.
PMID- 10778574
TI - Metaphyseal chondrodysplasia.
PMID- 10778575
TI - Megaloblastic anemia and acute subdural haematoma.
PMID- 10778576
TI - Artesunate therapy in falciparum malaria--alone or in combination.
PMID- 10778577
TI - Trials on pralidoxime.
PMID- 10778579
TI - Angiotensin converting enzyme estimation in pyrexia of unknown origin with
bilateral hilar lymphadenopathy--an essential investigation.
PMID- 10778578
TI - Uncommon iatrogenic pneumothorax.
PMID- 10778580
TI - Adrenaline precipitated intracerebral hemorrhage.
PMID- 10778581
TI - Ankle jerk in myxoedema with hemiplegia.
PMID- 10778582
TI - Antiphospholipid (Hughes) syndrome and recurrent pregnancy loss.
PMID- 10778583
TI - A preliminary study of antiphospholipid antibodies in 50 cases of bad obstetric
history.
AB - The prevalence of the antiphospholipid antibodies in certain high risk groups
like bad obstetric history is higher than previously realized. A pilot study in
50 patients of bad obstetric history, for the presence of lupus anticoagulant and
anticardiolipin antibodies was carried out to establish an association between
the presence of the antiphospholipid antibodies and recurrent fetal wastage.
Lupus anticoagulant alone was positive in six patients (12%) and anticardiolipin
antibody alone was positive in 14 patients (28%), while both lupus anticoagulant
and anticardiolipin antibodies were positive in three patients (6%). Activated
partial thromboplastin time (aPTT) and prothrombin time (PT) were not
significantly prolonged. Platelet count was normal in all the patients. We
conclude that lupus anticoagulant as based on kaolin clotting time and
anticardiolipin antibodies are important tests to detect the etiology of fetal
wastage.
PMID- 10778584
TI - Preceding infection as a risk factor of stroke in the young.
AB - INTRODUCTION: The cause of stroke in the young remains unknown in 20-50% of the
patients. Infections preceding stroke have been recently recognised to be an
independent risk factor of stroke. MATERIAL AND METHODS: Sixty consecutive
patients aged 40 years or less presenting with ischaemic completed stroke are
taken up for the study. Patients with neurological deficit of less than 24 hours,
evidence of haemorrhage on CT scan, infection occurring after the onset of stroke
were excluded. Controls consisted of age and sex matched persons residing in the
same area. Both the groups were enquired about preceding fever and infections and
were examined for evidence of infections. Serum was examined for antibodies
against measles, herpes simplex, and Japanese B encephalitis viruses. Cultures
were put up from appropriate samples and CSF examined in patients only. RESULTS:
Evidence of infection was noted in 26 (43.3%) of patients and 6 controls (p <
0.001). History of fever was elicited in 23 patients and 3 controls while 15
patients were febrile on examination at admission. Signs of local infection was
observed in 14 patients and one control. The commonest site of infection was
respiratory tract. Cultures were positive in 11 patients, commonest being beta
haemolytic streptococci in six from throat. Conventional risk factors were
identical in both groups of patients with and without evidence of preceding
infection. Smoking and alcoholism were significantly higher in patients with
preceding infection. CONCLUSION: Preceding infection is an important risk factor
of stroke in the young. Smoking and alcoholism are more frequent in patients with
preceding infection. Whether they predispose the individual for infection or
infection increases the stroke risk in them needs to be examined.
PMID- 10778585
TI - A study of lipid peroxide and alpha tocopherol in acute myocardial infarction.
AB - Thirty patients of acute myocardial infarction proven by electrocardiography
(ECG) and enzymes were included in the study. All of them received streptokinase.
A single lead showing the largest ST elevation, a proportional value for the
shift in ST segment > or = 0.5 was taken as criteria for reperfusion. ECG was
recorded at 0 hour, 3 hours and 72 hours. At the start of streptokinase and 3
hours after, marker of free radical activity malondialdehyde (MDA) and
antioxidant alpha tocopherol was measured. Mean value of serum alpha tocopherol
level at start of streptokinase (t0) 10.03 +/- 2.5 micrograms/ml and at (t3) 3
hours after streptokinase was 8.60 +/- 2.6 micrograms/ml (P < 0.001) and mean
value of serum lipid peroxidation level was 6.86 +/- 2.92 nanomol/ml at t(o) and
at t3 value was 8.4 +/- 3.88 (P < 0.012) in successfully reperfused patients. In
unsuccessful reperfusion group serum alpha tocopherol level at t(o) was 8.89 +/-
2.55 micrograms/ml and at t3 8.23 +/- 2.9 micrograms/ml (p > 0.05). Serum lipid
peroxidation level in the same group at t0 was 6.53 +/- 2.26 nanomol/ml and at t3
was 6.29 +/- 2.27 nanomol/ml (p > 0.05). The increase in free radical marker MDA
and decrease in one of the important antioxidant alpha tocopherol suggest that
free radicals are increased after coronary vessels open up. As a result
reperfused patients may be at risk of free radical mediated injury which may deny
him the full benefit of reperfusion.
PMID- 10778586
TI - Toxoplasmic encephalitis in acquired immunodeficiency syndrome.
AB - OBJECTIVES: To study the clinical course and outcome of toxoplasmic encephalitis
(TE) in patients with acquired immunodeficiency syndrome (AIDS). METHODS:
Patients infected with human immunodeficiency virus (HIV) and neurological
abnormality compatible with diagnosis of TE were enrolled in the study. These
patients were treated with combination of trimethoprim/sulfamethoxazole and
pyrimethamine. Response to therapy was assessed by clinical examination and
repeat CT/MRI scan done after three weeks of starting treatment. Those showing
response were put on prophylactic therapy. RESULTS: A total of 451 patients of
HIV infections were admitted to this centre during the study period, of these 11
patients were diagnosed to have TE. The common presenting symptoms were fever
(80%), seizures (45%), headache (45%) and altered sensorium (25%). Focal
neurological deficit was present in 80% of cases. Nine cases had ring-enhancing
lesions on CT scan while in the remaining two patient's ring lesions were seen on
MRI. These were either multiple (55%) or solitary (45%). Antitoxoplasma antibody
was detected in 10 patients. It was absent in one patient. Ten patients had
clinical and radiological improvement with trimethoprim/sulfamethoxazole and
pyrimethamine within 10 +/- 3 days of starting therapy. One patient died within
10 days of starting therapy. CONCLUSION: Toxoplasmosis is a common opportunistic
infection of the central nervous system in patients with AIDS. Majority of
patients with cerebral toxoplasmosis present with focal neurological abnormality
in presence of characteristic neuroradiological abnormality and positive
antitoxoplasma antibody titer. Response to empirical therapy helps to confirm the
diagnosis, lifelong prophylaxis there after prevents relapse of potentially fatal
and easily treatable condition.
PMID- 10778588
TI - Hypochromic anaemia in chronic renal failure--role of aluminium.
AB - BACKGROUND: Anaemia is a cardinal feature of chronic renal failure and
classically it is normochromic normocytic. Hypochromic anaemia in these patients
is often attributed to iron deficiency. AIM: This study was aimed to find the
contribution of aluminium in causation of anaemia in CRF patients. METHODS:
Dialysis dependent patients of chronic renal failure with adequate dietary intake
(> 1500 Cals/day) and no apparent source of blood loss were evaluated for type of
anaemia. (During period of this study centre didn't have reverse osmosis plant
for water treatment). Evaluation included upper GI endoscopy, complete hemogram,
serum proteins, serum iron, total iron binding capacity, and bone marrow iron
status. For aluminium evaluation serum aluminium levels were done. RESULTS: Sixty
four patients were evaluated for type of anaemia. Mean age of patients was 41.19
years (15-76 years) with male:female ratio 2.3:1. Classical normochromic picture
was seen in 28.5% while rest had hypochromic picture. On bone marrow aspiration
study two patients had zero iron stores while all others had normal/excessive
iron stores. In 10 patients with hypochromic picture, mean serum aluminium levels
were 170 micrograms/L (30-310 micrograms/L). CONCLUSIONS: This study highlights
the high prevalence of hypochromic anaemia in patients with adequate dietary
intake and aluminium overload in Indian CRF patients.
PMID- 10778587
TI - Safety and efficacy of Hartone in stable angina pectoris--an open comparative
trial.
AB - OBJECTIVES: To evaluate the safety and efficacy of 'Hartone'--a proprietary
herbal product primarily containing Terminalia arjuna in stable angina pectoris
patients. PATIENTS AND METHODS: Ten patients with stable angina pectoris were
given Hartone 2 caps twice daily for 6 weeks and 1 cap twice daily for the next 6
weeks. Haematological and biochemical investigations to assess safety were
carried out on day 0, day 42 and day 84. Serum lipid profile was done before and
after therapy. Efficacy was assessed by considering the reduction in the number
of anginal episodes and improvement in stress test. The results were compared
with 10 patients of stable angina pectoris on isosorbide mononitrate (ISMN) 20 mg
twice daily. RESULTS: Hartone afforded symptomatic relief in 80% of patients and
ISMN in 70%. The number of anginal attacks were reduced from 79/wk to 24/wk by
Hartone and from 26/wk to 7/wk by ISMN. Although patients of both groups showed
improvement in several stress test parameters compared to base line, the
difference was not statistically significant. Hartone improved BP response to
stress test in two patients and ejection fraction in one. Hartone was better
tolerated than ISMN and showed no evidence of hepatic or renal impairment. Its
effects on lipid profile was not consistent. CONCLUSION: Hartone is a safe and
effective anti-anginal agent comparable to ISMN and is better tolerated. Large
scale, randomised, double blind trials are needed to prove its efficacy.
PMID- 10778589
TI - Botulinum toxin in the treatment of writer's cramp.
AB - BACKGROUND: Writer's cramp is a task specific focal dystonia. The treatment of
writer's cramp is very disappointing. AIM: Study the effect of botulinum toxin
(BTX) in the treatment of writer's cramp. MATERIAL AND METHODS: Sixteen patients
of writer's cramp (15 men, 1 woman) with mean age of 35.75 years and mean
duration of symptoms for 3.64 years received 22 treatment sessions of botulinum
toxin-A (BTX). All patients were evaluated before, 3 and 12 weeks after BTX
therapy on a rating scale from 0-4 for ease of writing, abnormal posture and pain
(0 = normal, 4 = very severe disability). The speed of writing was also recorded
before and 3 and 12 weeks after therapy. Each patient also gave a global
subjective assessment 12 weeks after BTX therapy. RESULTS: Follow up was
available after 19 treatment sessions. Significant improvement was seen in all
the parameters studied i.e. abnormal posture (p = 0.0039), pain (p = 0.0092),
ease of writing of (p = 0.0025) and speed of writing (p = 0.0025). An improvement
of 50% or more was observed after 13 treatment sessions. Asymptomatic weakness in
the injected limb was seen in all patients but four patients complained of
weakness of fingers. The mean onset of improvement was 10.68 +/- 4.32 days and
mean duration of effect was 9.47 +/- 5.34 weeks. CONCLUSION: BTX is effective in
the treatment of writer's cramp. The draw-backs are short duration of action and
prohibitive cost.
PMID- 10778590
TI - Comparison of absorption rate and bioavailability of two brands of carbamazepine.
AB - OBJECTIVE: To assess the bioavailability of carbamazepine from two brands of
carbamazepine--Tegretol 200 and Zen-200. METHODS: A two-way randomised cross-over
bioavailability of carbamazepine was carried out in twelve healthy male
volunteers. Coded plasma samples were analysed for levels of carbamazepine by
high performance liquid chromatography (HPLC) method. Tegretol 200 and Zen-200
were tested for in-vitro dissolution profiles. RESULTS: The mean Cmax, Tmax and
t1/2a for Tegretol 200 were: 2.17 +/- 0.42 mcg/mL, 11.67 +/- 6.37 h and 2.72 +/-
1.87 h; for Zen-200 were 3.10 +/- 0.05 mcg/mL, 3.50 +/- 2.11 h and 0.76 +/- 0.76
h respectively. These values were statistically significant. However AUC (0-96 h)
value of 150.16 +/- 27.13 mcg/ml.h after Zen-200 was not statistically
significant as compared to 128.68 +/- 20.22 mcg/ml.h after Tegretol 200. The in
vitro dissolution profiles of the two formulations were dissimilar. The
fluctuations in CBZ levels after Tegretol 200 was significantly less as compared
to Zen-200. The absorption profile as judged by parameter 'A' was 50.44 +/- 10.95
for Tegretol 200 and 42.49 +/- 18.89 for Zen-200. CONCLUSION: Based on parameter
'A' and other pharmacokinetic parameters, the marketed generic carbamazepine
product, Zen-200 is not bioequivalent to Tegretol 200.
PMID- 10778591
TI - Serum vitamin E levels in patients of chronic myeloid leukaemia.
AB - OBJECTIVE: To estimate vitamin E levels in sera of patients of chronic myeloid
leukaemia (CML) before and after treatment with busulphan and hydroxyurea and to
compare the levels with those in healthy controls. METHODS: The study was carried
out in a total of 50 subjects (mean age 34 +/- 8.86 years; 25 were proved cases
of CML and 25 were healthy controls. Vitamin E level was measured by
spectrofluorometeric method. In patients of CML vitamin E level was estimated
twice i.e. once when their total leucocyte count (TLC) was raised (i.e. before
treatment) and then after treatment after bringing the TLC near normal. RESULTS:
The mean serum vitamin E level in 25 normal healthy controls was 7.19
micrograms/ml and that in 25 patients of CML at presentation (before treatment)
was 2.67 micrograms/ml. It increased to 3.61 micrograms/ml after treatment.
CONCLUSION: The results show that patients of CML have a significantly lower (p <
0.001) level of serum vitamin E as compared to normal healthy adults and that the
level of vitamin E increased significantly (p < 0.001) after treatment even
without supplementing vitamin E.
PMID- 10778593
TI - Clinical profile of ethylene Di-bromide (EDB; 1,2 dibromo ethane) poisoning.
PMID- 10778592
TI - Insulin resistance and urinary excretion of sodium in hypertensive patients with
non-insulin dependent diabetes mellitus.
AB - BACKGROUND: Hyperinsulinemia has been implicated in the pathogenesis of
hypertension both in non-diabetic and diabetic patients. A causal relationship
between renal sodium retention and hyperinsulinemia is speculated to play role in
the development of hypertension in diabetes mellitus. MATERIAL AND METHODS:
Twenty patients (12 males; 8 females) with hypertension and non-insulin dependent
diabetes mellitus (NIDDM) and twenty normotensive patients (11 males, 9 females)
with NIDDM were included in the present study. Blood samples for glucose and
immunoreactive insulin (IRI) assay were collected at 0, 30, 60 and 120 minutes
after 75 g of glucose per oral. Urinary sodium excretion in 24 hrs was estimated
by flame photometry. Insulin response to glucose and correlation between basal
insulin secretion and urinary sodium excretion were evaluated. RESULTS: Mean
fasting plasma glucose value was significantly raised in hypertensive group in
comparison with normotensive group of diabetic patients. Patients with diabetes
and hypertension and significantly higher level of serum IRI than normotensive
patients with diabetes mellitus. Urinary sodium excretion was significantly lower
in diabetic patients with hypertension than in diabetic patients without
hypertension. A negative correlation between basal insulin level and urinary Na+
excretion was observed in hypertensive patients with NIDDM. CONCLUSION: A
negative correlation between hyperinsulinemia and 24 hrs urinary Na+ excretion
was observed in patients with diabetes and hypertension. The study highlights
that patients with diabetes mellitus have tendency to retain sodium under the
influence of insulin but this needs further evaluation.
PMID- 10778594
TI - Drug-related problems and adverse drug events: negligence, litigation and
prevention.
AB - Since the inclusion of medical profession under Consumer Protection Act, Indian
doctors are facing malpractice suits. The incidence of adverse events (AEs) is
3.4-3.7, of adverse drug events (ADEs) is 2.4-6.5 and of adverse drug reactions
(ADRs) is 6.7 per 100 hospital admissions. The complications of drug-related
problems (DRPs) include therapeutic failure (TF) in 23% and new medical problems
(NMPs) in 10% and could lead to serious permanent disability and death in
majority (42%). The incidence of negligence in serious ADEs and death is 34% and
51%, respectively. Proportion of preventable ADEs is 28-50%. Errors occur most
often in prescribing (39-56%) and result in malpractice claims in 13-25% of
cases. Rational prescribing, improved therapeutic knowledge through re-training
and effective use of computers in prescribing could prevent errors and reduce
economic consequences for patients, doctors and hospitals.
PMID- 10778595
TI - Hepatitis G virus: an innocent contaminant.
PMID- 10778596
TI - Severe hyponatremia in a chronic schizophrenic patient.
PMID- 10778597
TI - Cortical blindness in acute intermittent porphyria.
PMID- 10778598
TI - Profuse variceal hemorrhage as a presenting feature of pancreatic adenocarcinoma
in a young non-icteric patient.
AB - Pancreatic adenocarcinoma can present with a vast spectrum of rare
manifestations. It usually occurs after the age of 50 years, the peak incidence
being in sixth and seventh decades. We report a previously asymptomatic subject
of pancreatic adenocarcinoma who presented for the first time with massive upper
gastrointestinal hemorrhage. Endoscopy revealed ruptured esophageal varices which
were secondary to tumour-induced thrombosis of the portal vein. Besides the
uncommon mode of presentation, the patient was unusual because of his young age.
Further, he was non-icteric at the time of presentation and remained so
throughout the clinical course despite having a large lesion in the head of the
pancreas.
PMID- 10778599
TI - Symmetric peripheral gangrene and falciparum malaria--an interesting association.
AB - Symmetric peripheral gangrene (SPG) is a rare syndrome in which disseminated
intravascular coagulation (DIC) is the most common underlying condition. We
report three cases of SPG in association with Plasmodium falciparum malaria and
DIC, an association unreported so far.
PMID- 10778600
TI - Hepatitis A and acute pancreatitis.
AB - Acute pancreatitis in association with acute viral hepatitis A in uncommon. We
present the case of a young girl with acute pancreatitis complicating acute viral
hepatitis A. The finding of IgM anti-HAV and exclusion of a vast array of other
etiologies implicates hepatitis A the cause.
PMID- 10778601
TI - Cutaneous vasculitis in a patient with primary Sjogren's syndrome.
AB - Sjogren's syndrome (SS) is an uncommonly described disorder from India. In this
report we describe a patient with SS and who developed cutaneous vasculitis.
PMID- 10778602
TI - Tuberculosis: a rare cause of splenic abscess.
AB - Splenic abscess is a rare condition associated with septicemic conditions.
Splenic abscess due to tuberculosis is still rarer, mostly diagnosed in immuno
compromised hosts. A case of tubercular splenic abscess without any underlying
disease is reported.
PMID- 10778603
TI - Percutaneous drainage of mediastinal abscess following oesophageal perforation.
PMID- 10778604
TI - Reciprocal ST segment changes in acute pancreatitis simulating acute myocardial
infarction.
PMID- 10778605
TI - Acute cerebellar ataxia following herpes zoster ophthalmicus.
PMID- 10778606
TI - Cyclosporine as a cause of unilateral gynecomastia in renal transplant recipient.
PMID- 10778607
TI - High dose cyclophosphamide in the treatment of systemic lupus erythematosus.
PMID- 10778608
TI - Clinical profile of AIDS: a study at a referral hospital.
PMID- 10778609
TI - Tuberculosis in patients with systemic lupus erythematosus.
PMID- 10778610
TI - Tuberculosis in patients with systemic lupus erythematosus.
PMID- 10778611
TI - Sparfloxacin in tuberculosis.
PMID- 10778612
TI - Sparfloxacin in mycobacterial infections.
PMID- 10778613
TI - Treatment of tuberculosis--role of sparfloxacin?
PMID- 10778614
TI - Objective Structural Clinical Examination.
PMID- 10778615
TI - Comparison of bioavailability of two brands of rifampicin.
PMID- 10778616
TI - Diet, activity and diabetes.
PMID- 10778617
TI - Influence of life style factors in development of diabetes in Indians--scope for
primary prevention.
AB - OBJECTIVE: The objective of the study was to evaluate the influence of physical
activity and stress factors on the development of diabetes mellitus (DM).
METHODS: One hundred and eighty-seven adult subjects (M:F 112:75), registered in
the primary prevention of diabetes programme for 2 or more years were studied
prospectively. The study was done only in those who had either normal glucose
tolerance (NGT) or diabetes at the time of review (tR). At entry (tE), 121
(64.7%) had normal glucose tolerance (NGT) and 66 (34.3%) had impaired glucose
tolerance (IGT) by the WHO criteria. Dietary modifications and regular exercise
programme were advised. Dietary modifications and regular exercise programme were
advised. Study subjects were reviewed during August 1997 to October 1998. At
review (TR) none had known history of diabetes. At TR, the status of glucose
tolerance was assessed by oral GTT and influence of intervention measures and
evaluation of the role of physical and psychological stress on glucose tolerance
were assessed by a questionnaire method. RESULTS: At tR, 100 (53.5%) had NGT, and
87 (46.5%) had developed diabetes (DM). Adherence to exercise and other
preventive measures was poor in the DM compared to nondiabetic group (NGT) (P <
0.0012). They showed lower dietary adherence (P = 0.042) and scores on mental
stress was higher than in NGT group (P < 0.001). After controlling for age,
gender and the initial 2 h plasma glucose, non-adherence to exercise and high
scores of psychological stress showed strong association with diabetes.
CONCLUSION: In this study, significant and independent roles of physical
inactivity and psychological stress factors are demonstrated in the development
of diabetes.
PMID- 10778618
TI - Silent myocardial ischemia and cardiac autonomic neuropathy in diabetics.
AB - OBJECTIVE: To evaluate the association of silent myocardial ischemia (SMI) with
cardiac autonomic neuropathy in asymptomatic diabetic patients. MATERIAL AND
METHODS: Two hundred asymptomatic patients of diabetes mellitus were assessed for
evidence of cardiac autonomic neuropathy. Of these, 30 (15 males, 15 females;
mean age 44.7 +/- 8.8 years) were found to have cardiac autonomic neuropathy.
Thirty (30) age and sex matched diabetic patients (mean age 42.4 +/- 7.6 years)
who had no evidence autonomic neuropathy were included in the study as control
group. Both the groups of patients were evaluated for SMI by 24 hour ambulatory
electrocardiographic (ECG) monitoring. RESULTS: Incidence of SMI was
significantly higher in patients with autonomic neuropathy 12/30 (40%) compared
to those without 3/30 (10%) p < 0.001. Duration of diabetes was more (13 +/- 1.59
years) in patients with autonomic neuropathy compared to the control group (8.66
+/- 1.55 years) p < 0.001. Serum cholesterol and triglyceride levels were
significantly higher in patients with autonomic neuropathy in comparison to
control group < 0.05 and < 0.01, respectively. There was no difference in the
pattern of SMI in the two groups (p = N.S). CONCLUSION: Cardiac autonomic
neuropathy predisposes patients with diabetes mellitus to SMI. Twenty four hour
ambulatory ECG monitoring provides useful diagnostic information in early
detection and evaluation of SMI in asymptomatic diabetic patients.
PMID- 10778619
TI - Results of allogeneic bone marrow transplant in chronic myeloid leukaemia
following conditioning with busulfan and cyclophosphamide.
AB - OBJECTIVE: To study the outcome of oral busulfan and intravenous cyclophosphamide
(BuCY 2 regimen) followed by allogeneic bone marrow transplant (BMT) in a cohort
of patients with Philadelphia chromosome (Ph+) chronic myeloid leukaemia (CML) in
a single centre. METHODS: From 1991 to March 1998, a total of 27 consecutive Ph+
CML patients received busulfan 4 mg/kg/day over 4 days and cyclophosphamide 60
mg/kg/day over 2 days followed by infusion of HLA-identical sibling
haematopoietic stem cells. All except one (who received peripheral blood stem
cells) were given donor bone marrow cells. Post-transplant graft versus host
disease (GVHD) prophylaxis included a short course of methotrexate (on days +1,
+3, +6 and +11) and cyclosporine till day +180. RESULTS: With a median follow-up
of 30.5 months (1-55+ months), 14 patients (52%) are alive free from relapse.
Early mortality was relatively high with 10 patients (37%) dying within first 100
days post-transplant. Acute GVHD developed in 14 patients (52%) inspite of GVHD
prophylaxis with methotrexate and cyclosporine; six had grade I/II and eight
grade III/IV. Chronic GVHD developed in five of 15 patients who lived beyond 70
days. CONCLUSION: Allogeneic BMT appears to result in eradication of CML and
ensure disease free survival in about half of the young patients. However,
efforts should be on to minimise early mortality.
PMID- 10778620
TI - Mortality trends in falciparum malaria--effect of gender difference and
pregnancy.
AB - Falciparum malaria in pregnancy is a significant health problem in India.
Pregnant women constitute an important high risk group for malaria infection
which may cause abortions, stillbirths, intra-uterine growth retardation (IUGR)
and premature labour. In this hospital based study on 602 admitted patients of
falciparum malaria which included 314 males, 243 non-pregnant females and 45
pregnant females, there was significantly increased mortality rate in females
(18.4%) in comparison to males (7.64%, p < 0.001). The mortality rate was highly
significant in pregnant females (37.77%) in comparison to non-pregnant females
(14.81%) and males (7.64%; p < 0.001). Severe anaemia with Hb < 5 gm% was
observed more commonly in pregnant patients (20.0%) in comparison to non-pregnant
patients (4.11%). Incidence of malaria infection was more in primi gravida and
second gravida. Pregnancy related complications in the form of preterm live
births, intra-uterine death (IUD), still births and abortions were more in primi
parous than multiparous patients. As the pregnancy is associated with increased
incidence and adverse outcome of P.falciparum malaria infection, chemoprophylaxis
should be made an integral part of antenatal care along with antianaemia therapy
to reduce the risk of serious maternal and fetal complications.
PMID- 10778621
TI - Pulmonary infections after kidney transplantation.
AB - OBJECTIVE: To retrospectively analyse the epidemiology, aetiology, temporal
profile and outcome of lung infection following kidney transplantation. METHODS:
Out of 142 consecutive renal transplant (RT) recipients who underwent live donor
transplantation from June, 1990 to May, 1998, 43 (33%) had serious infection
requiring hospitalisation of which 27 were pulmonary. All such pneumonia were
included for retrospective analysis. All had a minimum follow up of six months
(if alive) and were on triple drug immunosuppression. All had detailed and
appropriate investigations for definitive diagnosis. RESULTS: The aetiological
agents were Gram negative bacterial infection (2), Gram positive bacterial
infection (1), nocardia (2), tuberculosis (10), aspergillosis (2), mixed
bacterial and fungal infection (4), Pneumocystis (2) and unconfirmed (4). Four
patients had pneumonia because of probable nosocomial exposure. Radiologically
lobar/segmental pneumonia was observed in five, nodular lesion six,
reticulonodular lesion eight, patchy consolidation five and pleural effusion
three. Nodular pneumonias were due to aspergillosis or nocardiosis. Four patients
developed secondary cavitation. Pulmonary infections were significantly
associated with leucopenia (8/27) (p < 0.01) but not with renal dysfunction
(creat > 2 mg%), diabetes, old age or additional immunosuppression (p > 0.05).
There were 11 deaths. Mortality was related to failure to reach diagnosis (3) and
delayed institution of therapy (6 patients). Pneumonia within first six months
had a higher mortality (9/16) compared to late pneumonia (2/11). Immunomodulating
virus (CMV 4, HEP B 2) was present in six patients of whom four succumbed.
CONCLUSION: Pulmonary infection is a common and serious post-transplant infection
requiring hospitalisation, is associated with high mortality. Patients with
leucopenia are predisposed to these infections. Prophylaxis for Pneumocystis,
Nocardia and tuberculosis needs strong consideration to reduce mortality of such
infection. Nosocomial exposure risk needs careful consideration in outbreaks of
opportunistic infection.
PMID- 10778622
TI - Effect of selegiline on cognitive functions in Parkinson's disease.
AB - BACKGROUND: Selegiline hydrochloride, a selective MAO-B inhibitor is known to
improve motor functions in Parkinson's disease (PD). The present study was
undertaken to study the effect of selegiline on memory and intelligence of PD
patients. MATERIAL AND METHOD: Thirty two patients of PD were divided in two
groups: selegiline group (n = 17) received 10 mg selegiline per day and control
group (n = 15) did not receive selegiline. Patients receiving trihexyphenidyl and
selegiline were excluded. All other treatment remained unchanged. All patients
were examined at baseline and after three months for change in UPDRS score, WAIS
score, memory test and P300. RESULTS: Patients in selegiline group had less
severe disease (UPDRS score 24.11 +/- 14.07) as compared to controls (UPDRS score
40.53 +/- 18.52). There was significant improvement in UPDRS score (p < 0.05),
WAIS (p < 0.001) and memory (p < 0.001) in selegiline group. In the control group
there was a significant prolongation of P300 latency (p < 0.05). CONCLUSION: The
study suggests that selegiline improves memory functions and intelligence in PD
patients in addition to motor functions. It also prevents prolongation of P300
latency which is a marker of cognitive function.
PMID- 10778623
TI - Diagnostic significance of immunoglobulins and adenosine deaminase in pleural
effusion.
AB - OBJECTIVES: 1) To evaluate the diagnostic significance of ELISA for detection of
antibodies to antigen A60 of Mycobacterium tuberculosis and adenosine deaminase
(ADA) in patients with pleural effusion without prior history of tuberculosis, 2)
To study the importance of the above tests in patients with HIV infection and
pleural effusion. METHOD: Eighty one patients with pleural effusion were studied.
In addition to diagnostic paracentesis and pleural biopsy, pleural fluid specific
IgG, IgM, IgA against antigen A60 and fluid ADA were estimated. HIV testing
(ELISA) was done in all patients. RESULTS: Out of 81 patients, 13 were HIV
positive. IgG anti A60 had a sensitivity and specificity of 90.71% and 33.33%
respectively. The combination of IgG and IgM had a sensitivity and specificity of
96.3% and 55.55% respectively. IgA alone or in combination did not offer any
diagnostic advantage. ADA had a sensitivity and specificity of 76% and 60%
respectively. In presence of HIV infection, antibodies against A60 had a
sensitivity of 76.92% and ADA had a sensitivity of 61.54%. CONCLUSIONS: In
patients with pleural effusion, immunoglobulins against antigen A60 have a
limited diagnostic role with high false positive rates. Co infection with HIV
further reduces the value of above diagnostic tests.
PMID- 10778624
TI - Profile of extrahepatic portal venous obstruction in Mumbai.
AB - AIM OF THE STUDY: To study the clinical profile of extrahepatic portal venous
obstruction (EHPVO) in a tertiary referral centre in Mumbai. METHODOLOGY:
Retrospective analysis of records of 113 patients with EHPVO, treated between
January 1984 and May 1996. RESULTS: Thirty eight of 54 (70.4%) patients in whom
information was available were delivered at home. Eleven of the 50 (22%) had
umbilical sepsis after birth. Median disease duration was 5 years (range 4 months
31 years), with age at initial presentation 13 (range 0.5-45) years; 24 (20%)
patients presented after age 20 years. Eleven presenting initially with
splenomegaly bled after 3 (1-14) years. Number of bleeding episodes per patient
was 2.5 (1-12). 13 of 44 (29.6%) patients bled (first bleed or recurrence) after
age 20 years. Twenty five (22.3%) had ascites at some time, 17/102 (16.7%) had
hypersplenism, and hypoalbuminaemia was present in 20/103 (19.2%). Endoscopic
sclerotherapy obliterated varices in 47/52 (90.4%) in 10.5 (3-40) sessions over 7
(1-100) months. Twenty three patients underwent surgery: devascularisation in 20
(with splenectomy in seven), distal lieno-renal shunt in two, and meso-caval
shunt in one patient. Follow-up was available in 68 (60.2%) patients. Rebleeding
after sclerotherapy occurred in 27/64 (42.2%), with median one (1-5) per patient;
recurrence of varices was noted in 15/35 (42.9%) patients over 12 (3-39) months.
Varices were present in 12 patients 163 (33-305) months after surgery.
CONCLUSIONS: Home delivery and umbilical sepsis may be risk factors in the
development of EHPVO. A significant number of patients present or continue to
bleed from varices after age 20. Variceal sclerotherapy is effective for
eradication of oesophageal varices.
PMID- 10778625
TI - Antibiotics sensitivity pattern of N. gonorrhoeae with special emphasis on
norfloxacin and ciprofloxacin.
AB - The current study is carried out to find the in-vitro susceptibility of N.
gonorrhoeae to Ciprofloxacin, Norfloxacin, Gentamycin etc. in 110 isolates
obtained from acute gonococcal urethritis confirmed by smear examination. The
isolates obtained are from the patients attending the Skin and STD Clinic of a
teaching hospital, clinically diagnosed as suffering from acute gonococcal
urethritis. Antibiotic susceptibility test was done by Kirby Bauer disc diffusion
technique. Four to five similar well isolated colonies of the gonococcal strains
were picked up with a wire loop and transferred to 5 cc of sterile trypticase
soya broth (TSB). Tubes were incubated at 36 degrees C. GC agar base plates were
inoculated with suspensions using a sterile cotton swab. Antibiotic discs were
placed on these plates. The plates were incubated at 35 degrees C for 18-24 hours
in a candle jar with 5-10% CO2. The plates were then observed to note the zones
of inhibition around the discs. 87.27% of isolated strains were inhibited by
norfloxacin at an MIC of 0.06 mu gm/ml; 89.08% of the strains were inhibited by
ciprofloxacin at an MIC of 0.025 mu gm/ml. All the strains (110) were inhibited
by ciprofloxacin at a concentration of 0.2 mu gm/ml. Gentamycin sensitivity was
86.36%. Out of 110 patients, 85 were treated with norfloxacin of which 81
(95.29%) were cured. Twenty five were treated with ciprofloxacin of which 24
(96%) were cured. This study shows high sensitivity of N. gonorrhoeae to
norfloxacin and ciprofloxacin.
PMID- 10778627
TI - Pictorial CME. Complex regional pain syndrome, type I.
PMID- 10778626
TI - Mega dose intravenous methylprednisolone in bilateral simultaneous optic
neuritis.
AB - OBJECTIVES: The study was carried out to assess the efficacy of megadose
intravenous methylprednisolone in patients of bilateral simultaneous optic
neuropathy (BSON) of unknown etiology. METHODS: Fifteen consecutive patients
admitted in neurology unit were included in the study. These patients were
subjected to various investigations including MRI and CSF exam to exclude all
known causes of optic neuropathy including multiple sclerosis. All patients were
put on single dose intravenous methylprednisolone, 1 gm/day in adults and 500
mg/day in children for three days. Pre and post-treatment visual parameters
including visual evoked potentials (VEP) were carried out. RESULTS: There was a
female preponderance and the average age was 28 years. The visual acuity and P100
latences of visual evoked potentials (VEP) improved in all cases. The improvement
was statistically significant (P < 0.001). CONCLUSION: Use of intravenous
methylprednisolone is a preferred drug in bilateral simultaneous optic neuropathy
(BSON) as compared to oral or retrobulbar steroids.
PMID- 10778628
TI - Isolated cerebral hydatid cysts: a comparative study of two different types of
presentations.
AB - OBJECTIVES: To demonstrate the existence of two imaging patterns of cerebral
hydatidosis and discuss its clinical importance. MATERIAL AND METHODS: A
retrospective review of six cases of cerebral hydatidosis using various imaging
techniques including CT, MRI, angiography and cystogram. RESULTS: Clinically the
most common findings included papilloedema, headache and vomiting. Two of the
cases reported recurrence of symptoms and were reoperated. The first 4 cases
presented the classical signs of unilocular well defined cysts while the last two
cases had multilocular, often polygonal cysts with perifocal edema, calcification
and membrane detachment. CONCLUSION: Two radiologically and pathologically
distinct subtypes of hydatidosis exist. Division into groups may assist decision
over treatment protocol.
PMID- 10778629
TI - Grudgitis.
PMID- 10778630
TI - Telemedicine: applications, barriers and medico-legal aspects.
PMID- 10778631
TI - C-reactive protein--marker for atherothrombotic events.
PMID- 10778632
TI - Tracheoesophageal fistula following prolonged mechanical ventilation.
PMID- 10778633
TI - Concurrent multidrug resistant Plasmodium falciparum from northeast India.
PMID- 10778634
TI - Coexistence of anomalous pancreaticobiliary ductal union with acalculous
cholecystitis.
PMID- 10778635
TI - Polyneuritis cranialis in a case of leprosy.
PMID- 10778637
TI - Mandibulo-acral dysplasia: Indian patient with severe bony changes.
AB - We report an Indian patient with mandibulo-acral dysplasia. This patient had
absence of spinous processes of 4th and 5th cervical vertebrae and very severe
bony changes but no loss of teeth.
PMID- 10778636
TI - Fatal paraquat poisoning: report of two cases.
AB - Paraquat, a dipyridium compound is widely used as a herbicide. It is available in
India as a liquid concentrate for agricultural use and is highly toxic if
ingested. It leads to renal, hepatic, cardiac and pulmonary toxicity and also
causes burns of oral mucosa and esophagus as it is caustic in nature. We describe
two cases of paraquat poisoning who developed serious toxicity following its
ingestion and died of respiratory failure.
PMID- 10778638
TI - Insulin dependent diabetes mellitus induced by chemotherapy and granulocyte,
macrophage--colony stimulating factor.
PMID- 10778639
TI - Stiff-man syndrome--diagnostic criteria and pitfalls.
PMID- 10778640
TI - Acute renal failure and hepatitis induced by intermittent rifampicin therapy.
PMID- 10778641
TI - Acute myocardial infarction presenting as masquerading bundle branch block.
PMID- 10778642
TI - Cefoperazone induced gastrointestinal haemorrhage.
PMID- 10778643
TI - Acrocephalosyndactyly--type I (Apert's syndrome).
PMID- 10778644
TI - Tuberculin sensitivity in HIV--seropositive patients.
PMID- 10778645
TI - Haematuria caused by oral typhoid vaccine.
PMID- 10778646
TI - The role of myoglobin in early detection of acute myocardial infarction.
PMID- 10778647
TI - Serum lipoprotein(a) levels in ischaemic heart disease.
PMID- 10778648
TI - Unusual and severe forms of adverse drug reactions.
PMID- 10778649
TI - The changed clinical spectrum of malaria due to drug resistance.
PMID- 10778650
TI - Scorpion sting.
PMID- 10778651
TI - Treatment and outcome of lupus nephritis at the turn of the millennium.
PMID- 10778652
TI - Prognostic factors in diffuse proliferative lupus nephritis.
AB - BACKGROUND: Patients with diffuse proliferative lupus nephritis (DPLN) can have
variable clinical course. Identification of the predictors of outcome would help
to improve the management. We have studied the prognostic significance of
clinical, laboratory and histological parameters in patients with DPLN. METHODS:
Twenty nine patients diagnosed to be having DPLN seen between 1987 and 1991 were
followed up for over 57 months. Parameters assessed for prognostic significance
included serum creatinine, urine protein at the time of biopsy, blood pressure,
type of immunosuppression, composite scores and individual components of activity
index (AI) and chronicity index (CI). Kaplan-Meier survival curves were plotted
and the results were compared using log rank test. Fishers' exact test was used
to study the risk factors. RESULTS: End stage renal failure developed in 7/29
(24.1%) patients; 7/19 (36.8%) who had hypertension and 7/16 (43.8%) who had
nephrotic proteinuria developed renal failure, while none who had normal blood
pressure or nonnephrotic proteinuria, developed renal failure (p < 0.01). Three
patients had high activity index (> 12) and all three developed renal failure.
Other parameters such as age, gender, serum creatinine, type of
immunosuppression, CI and individual components of AI failed to predict the
outcome (p > 0.05). CONCLUSION: Hypertension, nephrotic proteinuria and high AI
were predictive of progression to end stage renal failure in patients with
diffuse proliferative lupus nephritis.
PMID- 10778653
TI - Seroprevalence of IgG antibodies to Helicobacter pylori among gastrointestinal
endoscopists, radiologists and paramedical personnel.
AB - BACKGROUND: The route of transmission of Helicobacter pylori is unknown. Since
the organism has been isolated from saliva, gastric juice and stool, medical
personnel could be at high risk for acquiring the infection during procedures
like gastrointestinal endoscopy. AIMS: To study whether endoscopy is a
professional hazard for acquisition of H. pylori. METHODS: We studied the
prevalence of IgG antibodies to H. pylori in endoscopists (n = 17), radiologists
(n = 17) and personnel from paraclinical branches (n = 35); microbiology (n =
21), pathology (n = 7) and forensic medicine (n = 7); among the paraclinical
personnel five were at high risk because they worked with cultures of H. pylori.
Subjects answered a questionnaire regarding upper gastrointestinal symptoms, and
precautions taken at the work place against infection. The serum was tested for
IgG antibodies to H. pylori using a microwell ELISA and a rapid card test.
RESULTS: H. pylori antibodies were present in five (29.4%) endoscopists, three
(17.6%) radiologists and seven (20%) paraclinical personnel; only one of the 5
high risk para medical personnel was positive. There was no correlation between
the duration of performing endoscopies and the H. pylori IgG status. CONCLUSION:
Endoscopy is not a risk factor for acquiring H. pylori infection.
PMID- 10778654
TI - Effect of protein and phosphate restricted and calcium and alphacalcidol
supplemented diet on renal and parathyroid functions and protein status in
chronic renal failure patients.
AB - OBJECTIVE: To assess the effect of low protein (0.6 g/kg/day), low phosphate (5
10 mg/kg/day) diet with calcium (600 mg/day) and alpha-D3 (0.5 microgram/day)
supplementation on renal and parathyroid functions in patients with chronic renal
failure (CRF). METHODS: The study included 20 adult patients of CRF, maintained
on diet therapy alone. The patients were followed up for renal and parathyroid
functions and protein status for 6 months at monthly interval. RESULTS: There was
symptomatic improvement in 88% patients. Blood urea and serum creatinine
decreased significantly (p < 0.001 and < 0.01, respectively) and the slope of
inverse serum creatinine against time changed to static or an upslope. Glomerular
filtration rate (GFR) improved from a basal value of 29.35 +/- 18.2 ml/min to
39.25 +/- 27 ml/min after 6 months. Serum parathyroid hormone (PTH) level of
197.65 +/- 133.7 pg/ml and post treatment level of 254.55 +/- 217.19 after 6
months were not different (p > 0.05). Serum calcium remained stationary with a
slight increase in serum phosphorus. Phosphorus had a negative correlation with
calcium and GFR, whereas calcium had a negative correlation with PTH and
phosphorus. PTH had a positive correlation with phosphorus and negative with GFR
and calcium. CONCLUSION: There was an improvement in renal functions without any
deleterious effect on the protein status of the patients of CRF. Also, there was
halting of parathyroid dysfunction especially in those patients where there was
no evidence of pre-existing hyperparathyroidism. Hence, dietry management should
be strictly enforced in CRF patients early in the course of disease.
PMID- 10778655
TI - Hypohaptoglobinaemia as a biochemical and epidemiological marker of falciparum
malaria.
AB - OBJECTIVES: The study was conducted in two parts to find out the usefulness of
hypohaptoglobinemia (Hpo) as a biochemical and epidemiological marker of malaria.
Part-I study was conducted in a Medical College Hospital to find out Hpo in
malaria and the time required for normalization of Hpo. Part-II study was
undertaken in two endemic areas of malaria to find out the prevalence of Hpo and
haptoglobin index (HI) throughout the year along with other indicators of
malaria. METHODS: In Part-I study, 172 patients of malaria constituting 58, 52
and 62 patients of cerebral malaria, uncomplicated falciparum malaria and vivax
malaria, respectively were enrolled. Along with routine haematological and
biochemical investigations, haptoglobin (Hp) estimation was done by endoplate
haptoglobin test kit on admission and at 15 days interval for 3 months. In Part
II study Hp was estimated is 305 subjects in two endemic areas of malaria. HI,
parasitic index, slide positivity rate (SPR), slide falciparum rate (SFR) were
estimated throughout the year and HI was compared with these epidemiological
markers. RESULTS: Hpo was present in 102 (92.7%) cases of falciparum malaria
which was significantly more than vivax malaria and non-malarial fever. The
normalisation of Hpo took about a month or more. The incidence of Hpo was 32.1%
is endemic and 4.7% in nonendemic area of malaria. The HI varied between 12.4 to
25.2% throughout the year and was found to be a better marker than other
classical markers of malaria. CONCLUSION: Hypohaptoglobinemia may be considered
as a useful indirect indicator of falciparum malaria. HI can be used as an
epidemiological maker which is better than classical markers of malaria used at
present.
PMID- 10778656
TI - Comparative study of platelet histamine and serotonin with their corresponding
plasma oxidases in asthmatics with normals.
AB - OBJECTIVE: Asthma is well controllable but non-curable disease. Exact
pathophysiology involved is unresolved till today. Role of allergic
hypersensitivity reaction in asthmatic on-set is well established. Present work
is an effort to elucidate some basic points of unresolved pathophysiology of
asthma taking platelets as marker. MATERIAL AND METHODS: A group of 52 normal
human subjects in the age group of 20-60 years were studied for platelet
histamine and serotonin levels and also for their plasma metabolising enzymes
diamine oxidase (DAO) and monoamine oxidase (MAO). The data was collected for 79
asthmatic patients at different stages of asthma and accordingly were studied as
four different groups of seventy nine asthmatics those were on regular treatment
and were comfortable with drugs and were free from symptomatic attack formed gr.
I; these (79) patients were followed-up during their symptomatic phase (gr. II)
and same (79) patients immediately after their recovery from symptomatic stage
studied as gr. III members. All the 79 asthmatic patients fall in gr. I, II and
III in a serial manner i.e. all (n = 79) in each group. A separate group of
thirty seven patients with known history of asthma but were symptom free and also
off drugs for last 2-4 years formed gr. IV. RESULTS: Results showed mean platelet
count in asthmatics at all four stages were in the normal range but were slightly
low in comparison with normals. Both the enzymatic levels (DAO and MAO) in gr. I,
II and III were significantly higher than normals but were same in the case of
gr. IV patients. Low levels of platelet biogenic amines were observed in
asthmatics (gr. I to gr. IV) than normals. CONCLUSIONS: Thus, study parameters
showed significant difference in asthmatics and normals. Findings of the study
have been utilized to understand unanswered hypersensitivity shown by the
asthmatics over normal individuals (non-asthmatics).
PMID- 10778657
TI - An open study to evaluate the efficacy of artemether in severe falciparum
malaria.
AB - An open clinical trial was conducted in 30 patients of severe falciparum malaria
with heavy parasitaemia (parasitized erythrocytes above 5%). Artemether (methyl
ether of dihydroartemisinin-active principle isolated from Chinese plant
Qinghaosu) was administered as 80 mg intramuscular injection twice on first day
and then single dose of 80 mg intramuscular on 2nd to 5th day. The trial could be
completed in 28 patients and two patients expired. In our observation falciparum
malaria affected the young adults in their most productive period of life i.e. 25
44 yrs. All patients became afebrile by the 4th day with fever clearance time
approximately 31.92 +/- 15.30 hr. Twenty-five patients (83.33%) became parasite
free by 5th day with mean parasite clearance time approximately 47.04 +/- 19.95
hr. Deranged liver function and renal profile was observed in 63% and 50%
patients respectively. Two patients, who died had very high degree of
parasitaemia (50% and 16%) with cerebral malaria. One died due to multiorgan
failure and other due to massive hematemesis and shock. The type of response
achieved by artemether therapy was analysed as per WHO criteria suggested for
chloroquine resistance. S response was observed in 25 patients (cure rate
83.33%). Two patients (6.66%) patients showed R II response, one patient (3.33%)
showed R III response and R I response was not observed in any patient. No
significant side effects were noted. This pilot study demonstrated that
intramuscular artemether is a useful addition to antimalarial drugs in this era
of multidrug resistant P. falciparum malaria showing high clinical potency with
virtually no side effect.
PMID- 10778659
TI - Splenectomy in sickle cell disease.
AB - INTRODUCTION: Since role of splenectomy in sickle cell disease still remains
controversial, this paper evaluates the same in 32 cases of splenectomy in sickle
disease patients observed by the author. MATERIAL AND METHODS: After proper
diagnosis by standard methods the cases were observed for 2-3 years before
deciding on splenectomy. Though acute splenic sequestration (53%) and chronic
hypersplenism (21.8%) were the main indication. Two cases of splenic abscess and
one case with frequent pain attacks were also subjected to splenectomy. There was
one immediate post-operative death. RESULTS: The cases were followed up for 1 to
> 8 years. While Acute splenic sequestration disappeared, in chronic
hypersplenism cases as well as others besides a sense of general well being,
steady state hemoglobin rose by > 2G/dl in 81% and significant increase in height
and weight was seen in 90% and 61% cases respectively. Frequency of pain attack,
fever, anaemia and need for blood transfusion improved in 79% patients.
CONCLUSION: Splenectomy in selected cases appears to be an acceptable procedure
in sickle disease.
PMID- 10778658
TI - Comparative bioavailability study of a conventional and two controlled release
oral formulations of Tegretol (carbamazepine)--200 mg.
AB - OBJECTIVES: To assess the bioquivalence of carbamazepine (CBZ) controlled release
formulation A (Tegretol CR, local) vs formulation B (Tegretol CR, Basel) and
confirm their controlled release characteristics by comparing with conventional
formulation (Tegretol). METHODS: A three-way randomized cross-over
bioavailability study was carried out using CBZ 200 mg tablets of conventional
and two controlled release formulations in twelve healthy volunteers. Coded
plasma samples were analysed for levels of CBZ by HPLC method. RESULTS: The mean
Cmax, Tmax, t1/2 and AUC for formulation A were: 1.67 +/- 0.26 mcg/mL, 24 +/- 0
hr, 47.8 +/- 9.7 hr and 136.7 +/- 25.4 mcg/ml. h; for formulation B were 1.41 +/-
0.31 mcg/mL, 25 +/- 8 hr, 46.9 +/- 7.9 and 119 +/- 32.3 mcg/ml.h and for
conventional formulation were 2.43 +/- 3.6 mcg/mL, 9.5 +/- 7.4 hr, 44.6 +/- 9.8
hr and 178.8 +/- 41.9 mcg/ml.h respectively. The fluctuation in plasma
concentration within 24 h (peak:trough) were 11.7 +/- 8.14% with conventional
formulation as compared to 0% and 1.2 +/- 3.98% with formulation A and B
respectively. The mean Tmax for both the controlled release formulations was not
statistically significant. On the basis of 90% confidence interval, mean AUC and
Cmax values obtained after controlled release formulation A, though statistically
significant (P < 0.05) lie well within the prescribed limits of 80-120% as
compared to formulation B. Thus both the controlled release formulations were
bioequivalent. In comparison to conventional formulation, both controlled release
formulations gave lower Cmax, lower AUCs, higher Tmax values, less fluctuation in
CBZ plasma concentrations, reduction in ratio of Cmax/AUC values, thus
demonstrating controlled release characteristics of the formulation. CONCLUSIONS:
Based on the above mentioned parameters both controlled release formulations are
bioequivalent and demonstrate controlled release characteristics.
PMID- 10778660
TI - Surrogate endpoints: do they really contribute in therapeutic decision making?
AB - Surrogate endpoints are substitutes for the true endpoints and measured in any
clinical research to relate in some way to the outcome of primary interest.
Inappropriate selection of surrogate markers may lead to controversies during
clinical trials or therapeutic interventions. Use of surrogate markers depends
upon thorough understanding of the pathophysiology of the disease and
pharmacology of drugs. Results obtained with surrogates should be regarded as
preliminary and necessitates definitive studies.
PMID- 10778661
TI - Pictorial CME. Pulmonary Cryptococcus neoformans infection.
PMID- 10778663
TI - Essential fatty acids in health and disease.
AB - Essential fatty acids (EFAs) form an important component of cell membranes, are
eicosanoid precursors and are therefore required for both the structure and
function of every cell in the body. EFAs can modulate the activity of protein
kinase C, T and B cell response, free radical generation and lipid peroxidation,
lymphokine secretion and cell proliferation. EFAs also have anti-mutagenic, anti
bacterial, anti-fungal and anti-viral properties. EFAs and their metabolites
lower serum cholesterol, triglycerides and blood pressure. EFAs appear to be of
benefit in atopic eczema, premenstrual syndrome, psoriasis, auto-immune disorders
especially rheumatoid arthritis and systemic lupus erythematosus, prevention of
target organ damage in diabetes mellitus, peptic ulcer disease, ulcerative
colitis, coronary heart disease and atherosclerosis. EFAs and their metabolites
can selectively kill tumor cells both in vitro and in vivo without harming normal
cells. In addition, EFAs seem to play a fundamental role in inflammation and
immune response. In view of their actions and relative safety, it is anticipated
that EFAs may be useful in the management of several diseases.
PMID- 10778664
TI - Recent advances in drug therapy for rheumatoid arthritis.
PMID- 10778662
TI - Oxygen therapy.
PMID- 10778665
TI - Postoperative endocarditis due to Candida tropicalis.
AB - In conclusion, we emphasize the importance of isolating the fungal agent from
repeated blood cultures, particularly in infective endocarditis following heart
surgeries.
PMID- 10778666
TI - Ileo-ileo-colic intussusception secondary to an ileal lipoma.
AB - Adult intussusception is extremely uncommon and constitutes approximately 5-16%
of all intussusceptions. We describe a case of ileo-ileo-colic intussusception
secondary to an ileal lipoma occurring in a 22 year old man who in addition had
autosomal dominant polycystic kidney disease. CT scan played a pivotal role in
not only demonstrating the cause of intestinal obstruction (intussusception) but
also showed that a lipoma was the lead point precipitating the intussusception.
PMID- 10778667
TI - Coronary arterial fistula in association with rheumatic heart disease.
PMID- 10778668
TI - Idiopathic hypoparathyroidism with extensive intracranial calcification
associated with kinesigenic choreoathetosis.
PMID- 10778669
TI - Post-vaccinal diffuse myelitis: magnetic resonance imaging features.
PMID- 10778670
TI - Tuberculous peritonitis: an uncommon presentation.
PMID- 10778671
TI - Cryptococcal meningitis in immunocompetent individuals.
PMID- 10778672
TI - Transient ischaemic attack caused by a small basal ganglia haematoma.
PMID- 10778673
TI - Spontaneous acute thymic hemorrhage in a patient with aplastic anemia.
PMID- 10778674
TI - Diabetes mellitus: an uncommon manifestation of pancreatic tuberculosis.
PMID- 10778675
TI - Cervical myelopathy due to fluorosis in non-endemic area of Vidarbha.
PMID- 10778676
TI - Colonic tuberculosis mimicking ulcerative colitis.
PMID- 10778677
TI - Carcinoma colon presenting as paraneoplastic syndrome neuropathy.
PMID- 10778678
TI - Benzathine penicillin.
PMID- 10778679
TI - Neuroleptic malignant syndrome.
PMID- 10778680
TI - Neuroleptic malignant syndrome.
PMID- 10778681
TI - Use of BCG as aerosol may import better immunity against tuberculosis.
PMID- 10778682
TI - Terfenadine should be withdrawn from clinical use.
PMID- 10778683
TI - Clinical relevance of reduced bioavailability of rifampicin.
PMID- 10778684
TI - Is the practice of routine sputum cultures a "sacred cow"?
PMID- 10778685
TI - Cell mediated immunity to Plasmodium vivax infection: in vitro inhibition of
parasite growth by monocyte derived macrophages.
AB - OBJECTIVE: To study the ability of soluble blood stage or cell associated
antigens of Plasmodium vivax to stimulate human peripheral blood mononuclear
cells (PBMC) and produce factors capable of causing inhibition of parasite growth
in vitro was the objective of this investigation. METHOD: A local isolate of P
vivax was either synchronized by triple sorbitol lysis for antigen preparation or
used as unsynchronized culture for parasite inhibition, employing a macrophage
inhibition assay. The soluble or cell associated antigens of P vivax were added
to human monocyte derived macrophages with P vivax parasitized red blood cells.
The percent inhibition of parasite growth was examined after 72 hrs by microscopy
of Giemsa stained smears of red blood cells from the experimental and control
groups. RESULTS: The differences in parasite inhibition were compared using
Wilcoxon rank sum test for paired differences. Unstimulated PBMC supernatants did
not inhibit parasite growth. Significant inhibition of parasite growth (90%) was
seen after incubating P vivax infected erythrocytes with PBMC supernatants
resulting from stimulation with soluble antigens (T = 3; P < 0.05). However, the
cell associated antigens of P vivax did not stimulate PBMC to activate
macrophages for parasite killing in vitro (T = 14, P < 0.05). CONCLUSION: We
conclude that the soluble blood stage antigens of P vivax can stimulate human
PBMC to produce factors capable of activating macrophages to function as effector
cells in P vivax malaria.
PMID- 10778686
TI - Cryptococcal meningitis in acquired immunodeficiency syndrome.
AB - OBJECTIVE: To study the clinical course and outcome of cryptococcal meningitis
(CM) in patients with acquired immunodeficiency syndrome (AIDS). METHOD: Patients
infected with human immunodeficiency virus (HIV) and symptoms suggestive of
meningitis were evaluated with detailed history, clinical examination and
investigations. Diagnosis of CM was based on positive India ink preparation or
positive fungal culture of CSF. All patients were treated with amphotericin those
showing response were put on oral fluconazole. RESULT: A total of 431 patients
with HIV infection were admitted to this centre during the study period, of these
15 were diagnosed to have CM. Majority of the patients had a subacute
presentation with signs of meningeal irritation seen in only seven patients.
India ink preparation and positive fungal culture on cerebrospinal fluid (CSF)
established diagnosis in all cases. All patients were treated with amphotericin B
and fluconazole. Complete response was noticed in seven patients, two patients
were lost to follow-up and six patients died during the course of therapy. Raised
intracranial tension (ICT) and disseminated disease were associated with poor
prognosis. CONCLUSION: CM is a common opportunistic fungal infection in patients
with AIDS. A high index of clinical suspicion and routine mycological
surveillance is required to diagnose this infection. Majority of patients respond
to therapy except those who have disseminated infection, altered sensorium and
features of raised ICT at presentation.
PMID- 10778687
TI - Antihypertensive efficacy and tolerability of once-daily sustained-release
diltiazem alone and in combination with ramipril in hypertension.
AB - This study assessed once-daily (OD), sustained-release (SR) diltiazem alone and
in combination with ramipril in essential hypertension. Fifty patients with
supine diastolic blood pressure (DBP) > or = 95-< or = 114 mm Hg were entered
into the active treatment phase of the study after 2 weeks of placebo run-in.
Sustained-release diltiazem 180 mg OD was administered for 2 weeks, then
optimally titrated, at 2 week intervals, to SR diltiazem 240 mg OD and then SR
diltiazem 180 mg + ramipril 2.5 mg OD to achieve supine DBP < or = 90 mm Hg.
After 4 weeks of diltiazem monotherapy (SR diltiazem 180 mg or 240 mg OD) mean
supine DBP was reduced from 102.84 +/- 3.81 mm Hg to 90.15 +/- 5.02 mm Hg (P <
0.01) and mean supine heart rate was reduced from 85.15 +/- 11.02 bpm to 77.62 +/
11.45 bpm (p < 0.01). Diltiazem monotherapy reduced supine DBP to < or = 90 mm
Hg in 35/45 (77.77%) patients. Combination therapy (SR diltiazem 180 mg +
ramipril 2.5 mg OD), received by non-responders to diltiazem monotherapy, reduced
supine DBP to < or = 90 mm Hg in 3/10 (30%) patients. Sinus bradycardia was
observed in one patient. Sustained-release diltiazem alone and in combination
with ramipril reduce blood pressure in a dose related manner and is well
tolerated.
PMID- 10778688
TI - Variable clinical severity of Hb E beta-thalassemia among Indians.
AB - OBJECTIVE: The aim of this preliminary report was to look at the effect of
genetic variations in the alpha, beta and gamma globin genes in 7 cases of
hemoglobin E/beta-thalassemia with diverse clinical expression of the disease.
METHODS: beta-thalassemia mutations were characterized by PCR and dot blot
hybridization. G gamma gene polymorphism (Xmnl) was determined by PCR followed by
restriction enzyme digestion and polyacrylamide gel electrophoresis. alpha
genotyping was done by Southern blot hybridization. RESULTS: Six cases had a
severe beta+ mutation [IVS 1 nt 5 (G-->C)] and one case had a beta zero mutation
[F/S 41/42 (-CTTT)]. Hence, the beta-thalassemia mutation does not seem to
contribute towards the clinical diversity. alpha-genotyping showed a single alpha
gene deletion of the rightward type in three of the five milder cases. The -158 G
gamma (C-->T) substitution was present at least in heterozygous state (+/-) in
all the milder cases. CONCLUSIONS: Deletional alpha thalassemia and presence of
the -158 G gamma (C->T) substitution are the two factors which appear to be more
important in decreasing the severity of the disease rather than the nature of the
beta thalassemia mutation.
PMID- 10778689
TI - Comparison of efficacy of intravenous diltiazem and esmolol in terminating
supraventricular tachycardia.
AB - OBJECTIVE: Paroxysmal supraventricular tachycardia (PSVT) can be effectively
terminated by the intravenous administration of adenosine or verapamil. However
adenosine is expensive and injectable verapamil currently is scarcely available.
While intravenous diltiazem has been shown to be useful for terminating PSVT, the
efficacy of esmolol in this regard has not been evaluated previously. Hence these
latter two drugs were studied for their efficacy in terminating PSVT. METHODS: A
prospective, randomised, crossover study was undertaken in patients presenting
with hemodynamically tolerated PSVT to the ICCU. While 50 patients had been
planned for the trial, the study had to be prematurely terminated after 32
patients had been enrolled due to the marked superiority of diltiazem. Two
sequential doses with a 5 minute interval of either drug were administered before
crossover. Diltiazem was given in a dose of 0.25 mg/kg while the esmolol dose was
0.5 mg/kg. RESULTS: Diltiazem terminated PSVT in all the 16 patients in whom it
was given as the first drug. The 12 patients who did not respond to esmolol were
also effectively treated with diltiazem. Thus totally 28/28 patients responded to
diltiazem while only 4/16 patients responded to esmolol (p < 0.001). Of the 28
patients who responded to diltiazem, in 13 patients the second bolus of diltiazem
worked after the first one had failed. No significant adverse effects were seen.
CONCLUSION: Intravenous diltiazem is highly effective and safe for terminating
PSVT. When the first bolus is ineffective, the second bolus given after 5 minutes
usually succeeds. Esmolol in the dose of 0.5 mg/kg has poor efficacy for
terminating PSVT, even when 2 boluses are administered.
PMID- 10778690
TI - Can we diagnose early Barrett's oesophagus?
AB - OBJECTIVES: The definition of Barrett's oesophagus, has been of late, is stressed
on the presence of specialised columnar epithelium with goblet cells and not on
other metaplastic epithelia, which however could be the early, immature,
undifferentiated cell types such as junctional and gastric types. Hence this
study was carried out to find out the ways of detecting the early metaplastic
cell forms before the goblet cells appear. METHODS: Among 134 cases of reflux
oesophagitis selected in the prospective study of 7 years from January 1992 to
December 1998, 31 biopsies were diagnosed as Barrett's oesophagus (BO). These
were compared with 20 age matched control biopsies from gastro-oesophageal
junction. They were studied morphologically, morphometrically and histochemically
for acid, neutral and sulphomucins using alcian blue (AB), alcian blue-periodic
acid Schiff (AB-PAS) and high iron diamine-alcin blue (HID-AB) stains. RESULTS:
Twelve of the cases were of junctional type, 16 of specialised columnar
intestinal metaplastic (IM) type (Type I = 0, Type II = 5, Type III = 11) and
three showed a combination of both junctional and Type I IM. Mucins were a
mixture of neutral mucin, sialomucin and sulphomucin while the control biopsies
showed chiefly neutral mucin. Morphometrically, the epithelial cells in BO were
taller (mean 28u in junctional types and 32u in IM) in comparison to the control
(mean 24.5 u). CONCLUSION: When the classical specialised columnar epithelium
(with goblet cells) in oesophagus is absent, presence of metaplastic junctional
type of mucosa, may, for all probabilities be considered as the initial step
towards transformation to the classical Barrett's mucosa. In such situations, it
is essential to differentiate it from the normal gastro-oesophageal junctional
epithelium and is possible with histochemical analysis of the biopsy material
aided by morphometry, especially so when the level of biopsy is not indicated.
PMID- 10778692
TI - A rational approach for the assessment of clinical competence of undergraduate
medical students.
PMID- 10778693
TI - Screening of sputum: an experience in a tertiary care hospital.
AB - In order to reduce the work load on the clinical laboratory, it has been
recommended that sputum samples, before accepting for culture, should be looked
for the presence of polymorphs and squamous epithelial cells. (An appropriate
sample should have more than 25 polymorphs per low power field and less than 10
epithelial cells per low power field; others are labelled as inappropriate). We
examined this criteria for it's suitability on 1043 samples received at the
clinical bacteriology laboratory at the All India Institute of Medical Sciences
(AIIMS) for a period of one year (September, 1996 to August, 1997). Four hundred
samples were found appropriate while 643 were inappropriate as per recommended
criteria. Amongst the 400 appropriate samples, 215 were culture positive and 185
grew normal flora. However, we found that out of 643 inappropriate samples, 195
were culture positive (p < 0.01, statistically significant). The data was further
divided into hospitalized and OPD cases. The distribution of culture positive
cases in the appropriate samples was again found to be highly significant. It is
apparent from our results that an attempt to process an inappropriate sample does
not provide useful information.
PMID- 10778691
TI - Tuberculous lymphadenitis in children--role of fine needle aspiation cytology.
AB - OBJECTIVES: Tuberculosis in children remains misdiagnosed, underdiagnosed or
paradoxically overtreated as a result of diagnostic difficulties and non-specific
manifestations such as lymphadenopathy. The aims of the study were, i) To assess
the efficiency of fine needle aspiration cytology (FNAC) in comparison to
histology to determine the prevalence of tuberculosis in lymph nodes, ii) To
compare the cytological and histopathological features of lymphadenopathy in
children to adults, iii) To analyse the clinical significance of the results in
the context of diagnosis. MATERIAL AND METHODS: The biopsies of lymph nodes
obtained during the seven year period from January 1989 to December 1995 and the
lymph nodes on which fine needle aspiration cytology was done during the period,
January 1990 to December 1995 were included for the study. Hemotoxylin and Eosin
stain was used for basic evaluation of the histopathologic features. A grading
system of 0 to 5+ was used to assess the smears to categorise them into
diagnostic groups. RESULTS: Among 1396 lymph node biopsies submitted for
evaluation of non-neoplastic conditions 54.12% (741) showed tuberculosis, in
which children constituted 9.04%. A higher incidence of 68.61% was observed on
FNAC. Both on cytology and histology, a necrotizing type of inflammation was
observed more in children, which indicated hypersensitivity. CONCLUSION: FNAC was
found to be a useful adjunct diagnostic technique especially in children, but the
need to develop a sensitive and easily available method to diagnose in
asymptomatic and high risk children still persists. Selection of patients with
lymphadenopathy for more than three weeks is important, as otherwise nonspecific
changes and acute inflammatory changes are likely to interfere with the
diagnosis.
PMID- 10778694
TI - Hereditary hemolytic disorders among the Ashram school children in Mayurbhanj
district of Orissa.
AB - Hemoglobinopathy and allied hemolytic disorders are important genetic and public
health problems in Orissa. These cause high degree of hemolytic anemia, morbidity
and mortality in the vulnerable populations. A total of 465 Ashram School
children aged 6-15 years belonging to Bathudi, Bhumiz, Kolha and Santal tribes in
six localities of Mayurbhanj district of Orissa were screened for
hemoglobinopathy, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, ABO and
Rhesus blood groups serology and any other hereditary condition. The sickle cell
trait (Hb AS) was detected in Santal (1.0%), Bathudi (1.0%) and Bhumiz (0.9%)
tribals. No case of homozygous sickle cell disease was detected among the tribes
of Mayurbhanj district. The beta-thalassemia trait was detected in Santal (8.0%),
Kolha (2.0%), Bhumiz (1.7%) and other tribal (3.8%) students. Sickle cell
hemoglobinopathy and beta-thalassemia are prevalent in this district among the
tribes, but the frequency is very low. The prevalence of G-6-PD deficiency is
considerably high (7.7-9.8%) among the tribes of Mayurbhanj district in Orissa.
Out of total 43 G-6-PD deficient subjects, there were 32 males, 9 heterozygote
females and 2 homozygous females. This shows that the antimalarial drugs should
be administered with caution as these cause hemolytic anemia, sometimes fatal
also. The distribution of ABO and Rhesus blood groups shows the preponderance of
B blood group (33.8%) over O (29.6%) and 2.1% cases of Rhesus negativity were
detected among the Bathudi tribe. This pattern is consistent with the
characteristic features of tribal populations in India.
PMID- 10778695
TI - Utility of HemoCue in estimation of hemoglobin against standard blood cell
counter method.
AB - INTRODUCTION: There are various methods which have been recommended for
haemoglobin (Hb) estimation for assessment of anaemia. Each method has it's
advantages and limitations. OBJECTIVE: The present study was conducted to assess
the utility of HemoCue, a recent method, in assessment of haemoglobin against the
standard blood cell counter (BCC) method. METHODOLOGY: Eighty five venous blood
samples were collected, Hb was assessed in each by utilising the HemoCue and BCC
methods. The results were compared utilising the standard statistical methods.
RESULTS: The HemoCue provided consistently higher value in comparison to BCC by a
margin of 0.5 g/dl. It is known that the correlation coefficient is independent
of change of origin but mean gets affected. Therefore, we can subtract 0.5 g/dl
from the Hb estimates achieved by HemoCue through which all conditions regarding
better agreement between both methods get satisfied. The two assays correlated
well. CONCLUSION: The HemoCue method was found more rapid and easy in assessment
of total hemoglobin as compared to blood cell counter method with an adjustment
of 0.5 per dl.
PMID- 10778696
TI - The enigma of the endothelium.
AB - The endothelium was earlier regarded as a relatively inert layer performing
rather simple physiological functions. However extensive research has recently
revealed that the endothelial layer performs a vast array of functions such as
maintenance of vascular tone, control over coagulation and fibrinolysis besides a
lot of chemical interactions. More recently, endothelial dysfunction has been
implicated as important in the pathogenesis of atherosclerosis, coronary artery
disease, myocardial ischemia and post-intervention restenosis. The demonstration
that endothelial dysfunction may be reversible by employing various strategies
raises the possibility of retarding the progress or even preventing the process
of atherosclerosis thereby reducing the risk of acute cardiovascular events.
PMID- 10778697
TI - Multiple cranial neuropathy: a common diagnostic problem.
AB - Syndrome of multiple cranial palsies is a common clinical problem routinely
encountered in neurological practice. Anatomical patterns of cranial nerves
involvement help in localizing the lesion. Various infections, malignant
neoplasms and autoimmune vasculitis are common disorders leading to various
syndromes of multiple cranial nerve palsies. A large number of diffuse
neurological disorders (e.g. Gullian-Barre syndrome, myopathies) may also present
with syndrome of multiple cranial nerve palsies. Despite extensive biochemical
and radiological work-up the accurate diagnosis may not be established. Few such
patients represent "idiopathic" variety of multiple cranial nerve involvement and
show good response to corticosteroids. Widespread and sequential involvements of
cranial nerves frequently suggest possibility of malignant infiltration of
meninges, however, confirmation of diagnosis may not be possible before autopsy.
PMID- 10778698
TI - Newer antimalarials.
PMID- 10778699
TI - Acute disseminated encehalomyelitis with typhoid fever.
AB - A 45 year old male came with fever, headache, altered sensorium pallor and lower
gastrointestinal bleeding. Laboratory investigations confirmed typhoid fever.
Magnetic resonance imaging (MRI) was suggestive of acute disseminated
encephalomyelitis.
PMID- 10778700
TI - Acinetobacter meningitis following head trauma.
AB - A case of acinetobacter meningitis following head injury in a patient who
developed cerebrospinal fluid otorrhea, and did not have any neurosurgical
procedure, is presented. Previously reported cases are cited, with a review of
the literature. Pefloxacin monotherapy is associated with a poor clinical
response.
PMID- 10778702
TI - Neurocysticercosis presenting as chronic meningitis.
PMID- 10778701
TI - Mycobacterium fortuitum endocarditis and meningitis after balloon mitral
valvotomy.
AB - Mycobacteria rarely cause endocardial infections. We describe the clinical course
of a patient who developed endocarditis, and meningitis with Mycobacterium
fortuitum following balloon mitral valvotomy. The patient was treated with
amikacin and clarithromycin but did not respond. She developed haemolytic anaemia
as the terminal event.
PMID- 10778703
TI - HELLP syndrome.
PMID- 10778704
TI - Acute intermittent porphyria presenting postmenopausally for the first time.
PMID- 10778705
TI - Isolated agenesis of cerebellum.
PMID- 10778706
TI - Leukemoid reaction simulating acute promyelocytic leukemia.
PMID- 10778707
TI - Role of DNA probes in characterization of pathogenic and non-pathogenic E.
histolytica.
PMID- 10778708
TI - Blood pressure measurement: application of new units educatory role of new
working groups.
PMID- 10778709
TI - Gliclazide, a better choice for type 2 diabetes.
PMID- 10778710
TI - The circadian pattern of ischaemic heart disease events in Indian population.
PMID- 10778711
TI - CPR and adrenaline in anaphylaxis.
PMID- 10778712
TI - Wide pulse pressure in acute hepatic failure.
PMID- 10778713
TI - Paracetamol poisoning--the emerging threat.
PMID- 10778714
TI - [Can a woman become pregnant after a stem cell transplantation?].
AB - Three women with chronic myelogenous leukaemia underwent stem cell
transplantation. They all were concerned about their future fertility. The first
woman underwent egg donation when she was in complete remission, and gave birth
to a healthy son. The second one underwent an IVF treatment before stem cell
transplantation: 15 embryos were frozen. The third woman asked for
cryopreservation of ovarian tissue. This procedure is not (yet) possible in our
clinic. The possibilities and complications of these three procedures are
discussed as well as the indication for the possible cryopreservation of ovarian
tissue.
PMID- 10778715
TI - [Cryopreservation of ovarian tissue open for discussion].
AB - In view of the promising developments in preclinical studies on the
cryopreservation of human ovarian tissue offering this technology as a 'fertility
insurance' to cancer patients can be justified. This commentary briefly discusses
some of the ethical issues involved, including the doctors responsibility
regarding the risk of the reintroduction of cancer, the pros and cons of both
xenotransplantation and in vitro maturation, parental responsibility in
consenting to fertility insurance for minors, and cryopreservation of ovarian
tissue of younger, healthy women who wish to postpone fertility.
PMID- 10778716
TI - [Cryopreservation of ovarian tissue; now is the time for ethical considerations].
AB - The development of ovarian tissue cryopreservation will expand the range of
clinical applications in reproductive medicine. This emerging technology may have
beneficial opportunities for patients, particularly in oncology, as well as for
the process of oocyte donation. However, it will also lead to new moral problems
requiring critical reflection concerning the criteria for tissue banking and
future clinical applications. Because cryopreservation of ovarian tissue nowadays
is the focus of experimental research, technology assessment is currently
appropriate, anticipating introduction into clinical practice. Specific
guidelines, developed by the medical profession in cooperation with ethicists and
lawyers can contribute to prudent clinical use.
PMID- 10778717
TI - [Treatment of young transsexuals in the Netherlands].
AB - For more than ten years transsexual adolescents have been diagnosed and treated
psychologically at the department of Child and Adolescent Psychiatry, University
Medical Centre in Utrecht, the Netherlands. The medical part of the treatment
takes place at the Academic Hospital of the Free University of Amsterdam.
Diagnosis is done in two phases: the first diagnostic phase and the 'real life
test'. In this second phase the ability to live in the opposite gender role is
tested. Gender dysphoric non-transsexual adolescents are offered psychological or
psychiatric interventions. For transsexual adolescents with the express wish to
undergo a sex change two types of hormones are prescribed. First, hormones which
halt the own pubertal development, then cross-sex hormones with irreversible
effects. Surgery for adolescents is not different from surgery for adults.
Although the cause of transsexuality is probably impaired sexual differentiation
at cerebral level, it appears that the risk of unjustified treatment is higher
when the treatment is administered at an early age than in adults; justified
treatment, however, has better results when it is administered at an early age.
PMID- 10778718
TI - [Cardiovascular effects of hypothyroidism].
AB - The clinical presentation of cardiac symptoms related to hypothyroidism is only
rarely observed nowadays due to early diagnosis of hypothyroidism by easily
available thyroid-stimulating hormone assays. A measurable abnormality of the
left ventricle is the lengthened duration of contraction and relaxation,
normalizing after restoration of euthyroidism. The ejection fraction and cardiac
reserve are only slightly diminished in hypothyroidism. There is reversible
diastolic disfunction. Pericardial effusion is a rare phenomenon. Diastolic
hypertension due to hypothyroidism is the most frequent cause of endocrine
hypertension. The relation between accelerated atherosclerosis and hypothyroidism
is not definitively proven. Patients below age 65 and without cardiac risk
factors can probably be treated with a full replacement dose of levothyroxin from
the beginning. There is no increased risk of percutaneous transluminal coronary
angioplasty or coronary artery bypass graft procedure in hypothyroid patients,
either during or after the intervention.
PMID- 10778719
TI - [Prevalence and treatment of hypercholesterolemia in patients with manifest
vascular disease according to practice guidelines of the current cholesterol
consensus].
AB - OBJECTIVE: To determine the prevalence of hypercholesterolaemia and the use of
lipid-lowering medication in patients with a manifest vascular disease. DESIGN:
Prospective, cross-sectional. METHODS: In patients who visited the University
Medical Centre Utrecht, the Netherlands, for the first time with a manifestation
of atherosclerosis in the period 1 September 1996-15 November 1998, we determined
by a single measurement of the cholesterol if they were eligible for lipid
lowering medication according to the cholesterol cut-off value mentioned in the
new Dutch cholesterol guidelines (1998) of the Dutch Institute for Health Care
Improvement. RESULTS: The study group comprised 737 patients: 539 (73%) males and
198 (27%) females, with a mean age of 62 year. 500 (68%) were eligible for lipid
lowering treatment. 66 patients (9%) were being treated according to the
guidelines and in 106 (14%) the aim of a cholesterol lower than 5.0 mmol/1 was
not reached despite cholesterol lowering medication. In 328 patients (45%)
hyperlipidaemia was not treated pharmacologically. CONCLUSION: Two-thirds of the
patients with manifest vascular disease had hypercholesterolaemia. Many of these
patients were not yet being treated.
PMID- 10778720
TI - [Ethanol for treatment of delirium in alcohol dependent patients on intensive
care units in the Netherlands: efficacy not proven].
AB - OBJECTIVE: To determine the use of ethanol in Dutch intensive care departments
(ICUs) for the treatment of deliriant symptoms in alcohol-dependent patients, and
to study the literature data concerning this use. DESIGN: Literature search and
questionnaire. METHOD: In Medline a search was performed from 1993 onward with
keywords 'intensive care' and 'alcohol'/'alcohol withdrawal syndrome'/'delirium'.
All Dutch ICUs received a written questionnaire (n = 247) concerning the use of
ethanol in this patient group. RESULTS: According to the literature the syndrome
is characterized by autonomous hyperactivity, resulting in tachycardia,
tachypnoea, hypertension, perspiration, fever, tremors en fear. In delirium
caused by alcohol withdrawal benzodiazepines are advised, sometimes in
combination with haloperidol. ICUs sometimes use ethanol, although the
effectiveness in preventing or treating withdrawal symptoms has never been
ascertained in scientific investigations: in a meta-analysis the conclusion is
drawn that the studies are too small and insufficiently objective to determine
the effectiveness. The response to the questionnaire was 55% (96/176). From all
ICUs, 15 (16%) used ethanol occasionally, and treated an estimated 17% of the
admitted alcohol-dependent patients. There was a tendency for large ICUs to use
ethanol in these patients more frequently. Each ICU used its own method to
calculate the required ethanol dosage. Calculation on the basis of these dosages
indicated a plasma ethanol concentration of at most 0.5 promille. CONCLUSION:
Because only a small percentage of deliriums on ICUs are caused by alcohol
withdrawal, and the effectiveness of ethanol in alcohol-dependent patients with a
delirium has never been proven, the use of ethanol in such cases is discouraged.
PMID- 10778721
TI - [Two patients with emphysematous pyelonephritis].
AB - A 55-year-old man with diabetes mellitus was sick with shivering, abdominal pain
and Escherichia coli in blood and urine cultures; a 40-year-old woman with
asthmatic bronchitis had abdominal pain and anaemia. Both had renal dysfunction
and the CT scan showed hydronephrosis with a perirenal inflammatory infiltrate
and gas in the right and left renal pelvis, respectively. The man had a difficult
recovery after treatment with antibiotics and percutaneous drainage. In the
woman, a calculus obstructed the pyelo-ureteral passage; the resected kidney
contained a squamous cell carcinoma. She was operated, received chemotherapy and
recovered. Emphysematous pyelonephritis is a rare, severe disease. Percutaneous
drainage and, if necessary, nephrectomy are paramount in the treatment. The
condition is observed mostly in patients with diabetes mellitus or obstruction of
the urinary tract.
PMID- 10778722
TI - [Respiratory syncytial virus infections and preventive options].
PMID- 10778724
TI - [Electronic medical record, confidentiality, and safeguarding of privacy].
PMID- 10778723
TI - [Creative mathematics with clopidogrel; exaggeration of the preventive effect by
the pharmaceutical company].
PMID- 10778726
TI - Brain tumor invasion rate measured in vitro does not correlate with Ki-67
expression.
AB - The need for more accurate prediction of the biological behavior of brain tumors
has lead to the use of immunohistochemical methods for assessment of
proliferating cell nuclear antigens such as Ki-67. There is a variable
association of glioma Ki-67 labeling index with patient survival. Brain invasion
by individual tumor cells also defines biological aggressiveness, and can be
assessed in vitro. Further, proliferation and migration seem to be mutually
exclusive behaviors for a given cell at a point in time. We studied the
relationship between Ki-67 labeling index and invasion rate in a group of 10
gliomas, and 2 meningiomas. Human tumor spheroids obtained from operative
specimen were co-cultured with fetal rat brain aggregates, and invasion rate was
measured by confocal microscopic observation. There was no correlation between
two measures of invasion and Ki-67 labeling. This finding supports the
dichotomous nature of glioma proliferation and invasion, and may in part explain
the limited usefulness of proliferation marker labeling.
PMID- 10778725
TI - Pediatric medulloblastoma: prognostic value of p53, bcl-2, Mib-1, and microvessel
density.
AB - The aim of this study was to retrospectively assess the prognostic value of p53
and bcl-2 protein expression, cell proliferation index (Mib-1 index), and tumor
microvessel density (factor VIII-related antigen) in pediatric medulloblastoma
patients. Tumor specimens of 55 patients (age 2-18 years) with medulloblastoma
treated with a curative intent between 1972 and 1991 were studied. Slides of
paraffin embedded tissue were stained with monoclonal antibodies (mAb) and
examined under high power light microscopy for the presence of immunoreactivity.
Microvessel density was scored both in the area of most intense staining ('Angio
max') and in 3 additional randomly selected areas. The sum of these 4 scores was
termed 'Angio-total'. 'Angio-max' and 'Angio-total' were evaluated separately by
two independent investigators to assess reproducibility. None of the parameters
studied, i.e. p53 or bcl-2 expression, Mib-1 index or microvessel density scores
were associated with patient survival. Microvessel scores between observers were
significantly but weakly correlated, with correlation coefficients (r) < 0.5 for
both 'Angio-max' and 'Angio-total'. Leptomeningeal spread at diagnosis was the
only independent factor associated with a poor survival (p = 0.003). There was no
association of leptomeningeal metastasis with any of the biological markers
tested in this study.
PMID- 10778727
TI - Vascular endothelial growth factor (VEGF) in astrocytic gliomas--a prognostic
factor?
AB - Survival in astrocytic gliomas is closely related to WHO tumor grade. Within one
tumor grade, especially in grade II and III tumors, the clinical course is
variable and can hardly be predicted by histological criteria. Neovascularization
is a neuropathological hallmark in high grade gliomas and angiogenic factors may
play an important role in malignant tumor progression. Therefore, 162 primary
astrocytic gliomas (57 astrocytomas WHO grade II, 27 astrocytomas WHO grade III
and 78 glioblastomas WHO grade IV) were investigated immunohistochemically for
expression of vascular endothelial growth factor (VEGF), which is considered to
represent the main angiogenic factor in astrocytic gliomas. Clinical data known
to influence prognosis were documented. VEGF expression was found in 21 of 57
astrocytomas WHO grade II (36.8%), in 18 of 27 astrocytomas WHO grade III (66.7%)
and in 50 of 78 glioblastomas (64.1%). A strong correlation between VEGF
expression and survival was found within the whole study group, however, within
one tumor grade no such correlation was obvious. In a multifactorial analysis
VEGF expression was not found to be an independent prognostic factor in
astrocytic gliomas.
PMID- 10778728
TI - Expression of TGFalpha in meningiomas.
AB - The objective of this study was to examine the expression of transforming growth
factor alpha (TGFalpha), a mitogen for many cell types, and its receptor in basic
subtypes of meningiomas as well as in meningiomas of varying grade. Formalin
fixed tissues from 26 meningiomas including 15 benign (5 meningothelial, 5
transitional, and 5 fibrous variants), 6 atypical, and 5 malignant examples were
immunohistochemically examined for both TGFalpha protein and EGF/TGFalpha
receptor protein. In addition, in situ hybridization (ISH) was used to detect
TGFalpha mRNA expression. Immunostaining for TGFalpha was strongest in fibrous
and atypical meningiomas, followed closely by transitional and malignant tumors.
Only weak reactivity was observed in the meningothelial variant. In all but 4
tumors (2 fibrous, 2 atypical), ISH showed TGFalpha mRNA to be present, the
signal being stronger in malignant than in conventional or atypical tumors.
Lastly, immunostaining for EGF/TGFalpha receptor was positive in all tumors
studied. Strong TGFalpha protein expression in meningiomas is commonly associated
with fibrous morphology. Although the frequent detection of both TGFalpha protein
and its mRNA, as well as of EGF/TGFalpha receptor within tumors of all type and
grades, suggests that TGFalpha serves to promote tumor growth, its possible role
in tumorigenesis or malignant progression is uncertain. In summary, demonstration
of these substances is of no utility in the classification or grading of this
common tumor because the differences in their expression among the various
meningioma subtypes were not statistically significant.
PMID- 10778729
TI - Progressive disease in children with medulloblastoma/PNET during preradiation
chemotherapy.
AB - The overall prognosis in children with medulloblastoma/PNET has not significantly
improved over the past decade. Intensive neoadjuvant chemotherapy has not yet
adequately explored. We evaluated the short-term clinical results of an intensive
chemotherapy regimen in high risk children with newly diagnosed MB/PNET, after
surgery and before radiation. Twelve previously untreated patients with high-risk
medulloblastoma/PNET, according to Chang's classification, were treated with the
following chemotherapy regimen: high dose carboplatin 600 mg/m2/day on days 1 and
2; the same course was administered 4 weeks later. One month later, high dose
cyclophosphamide 2 g/m2/day on days 1 and 2, followed by an identical course 4
weeks later. Vincristine 1, 5 mg/m2 i.v. was given on the first day of each
course. Systemic evaluation of the disease included imaging of the entire
neuraxis, including MRI of the entire spine. Out of 12 enrolled, 7 patients were
able to be evaluated for a residual disease after surgery. After two cycles of
high dose carboplatin, we noted 1 CR, 4 PR and 2 MR. After the subsequent two
cycles of high dose cyclophosphamide we observed an additional response in 4
cases. On the other hand, 4 patients clearly showed evidence of PD immediately
after the first course of cyclophosphamide (2 cases) or following the second
course. Three of the 4 patients had shown respectively 1 CR and 2 PR after the
second course of carboplatin. Whereas it was confirmed that 2 courses of high
dose carboplatin is effective in high risk MB/PNET children, we observed an
unacceptable number of PD during the subsequent high dose cyclophosphamide
therapy. A review from the literature also suggests that, in general, the longer
radiotherapy is delayed, the higher the incidence of PD. In the search for the
optimal drug combination in "sandwich chemotherapy" for children with high risk
MB/PNET, PD must be reduced to an acceptable incidence, since a high number of PD
may significantly lower the probability of long-term survival.
PMID- 10778730
TI - Pilot study of local autologous tumor infiltrating lymphocytes for the treatment
of recurrent malignant gliomas.
AB - A prospective pilot study was performed in order to assess the safety of treating
recurrent malignant gliomas (MGs) with locally infused autologous tumor
infiltrating lymphocytes (TILs) and recombinant interleukin-2 (rIL-2). Six
patients were entered between June 27, 1994 and June 2, 1995 and followed until
July 1, 1998. At surgery an Ommaya reservoir was placed for later infusion of
TILs and rIL-2. Following surgery, autologous TILs were expanded in vitro in the
presence of rIL-2 and infused on treatment days 1 and 14, with concurrent rIL-2
infusions performed three times each week for one month. Following completion of
immunotherapy all patients were offered chemotherapy. Phenotypic analysis
demonstrated TILs to be T-lymphocytes (87-99% CD3+). Of these, 4 of 6 cases (67%)
phenotyped as cytotoxic/suppressor T-lymphocytes (CD8+) and 2 of 6 cases (33%)
phenotyped as helper/inducer T-lymphocytes (CD4+). TILs demonstrated limited
selective cytotoxicity, with dose dependent cytotoxicity against autologous
tumor, allogenic tumor and long term MG cell lines. There were no significant
(Grade 3 or 4) complications. One patient developed transient low grade fevers,
and 2 developed asymptomatic hydrocephalus. All patients developed transient and
asymptomatic cerebral swelling, noted on the immediate post-treatment imaging
studies. At three and six month follow-up, 3 patients responded with partial
response, 2 demonstrated stable disease and 1 patient progressed. At long term
follow-up, 1 patient had a complete response (45 month follow-up), 2 had a
partial response (48 and 47 month follow-up) and 3 patients expired as a result
of progressive disease (at 12, 12 and 18 months following immunotherapy). A
relationship between subsequent chemotherapy or extent of resection to outcome
was not apparent but could not be excluded. This pilot study demonstrated that
locally infused autologous TILs and rIL-2 could be delivered without serious
toxicity. Further studies are indicated to determine the safety and long term
efficacy of TIL immunotherapy.
PMID- 10778731
TI - Radiation and concomitant weekly administration of paclitaxel in patients with
glioblastoma multiforme. A phase II study.
AB - The present study was conducted to evaluate the activity and toxicity profile of
radiation (RT) and concomitant chemotherapy in patients with glioblastoma
multiforme (GBM). Thirty-nine patients were treated postoperatively with RT and
concomitant administration of paclitaxel. Cranial irradiation was initiated 2-3
weeks postoperatively and was administered in 2.0 fractions, one fraction per
day, for 5 consecutive days per week, to a total of 60 Gy. Paclitaxel was
delivered at a dose of 100 mg/m2 over 3-h once weekly for 6 weeks. Thirty-three
patients received all 6 cycles of paclitaxel according to the protocol. Totally,
217 cycles were delivered all of them at full dose. The median relative dose
intensity of paclitaxel was 1 (range 0.88-1.1). Three (7.5%) patients achieved
complete and 9 (23%) partial response, while 12 (30.5%) patients demonstrated
stabilization of the disease. Side effects from combined chemoradiotherapy were
mainly mild. Grade III toxicity included infection (7.5%) and alopecia (5%).
Median time to progression was 6 (range 0.9-27) months and median survival 10.7
(range 0.9-39.5+) months. The present study has clearly shown that 100 mg/m2 of
paclitaxel in 1-h infusion weekly can be safely given concomitantly with RT in
patients with GBM with manageable toxicity. However, the efficacy of this
combined modality treatment does not appear to be superior to that of RT alone.
PMID- 10778732
TI - Post-radiotherapy myelitis observed in an AIDS patient with a meningioma: case
report and review of the literature.
AB - Radiation myelitis is an uncommon but serious complication of radiation therapy.
Although the definitive threshold to cause myelitis is unknown, it is believed
that less than 50 Gy when given in 25 or more fractions is highly unlikely to
cause myelopathy. This report describes a case of myelitis within the
radiotherapy portal in an HIV infected patient who received radiation therapy for
an atypical meningioma located in the cervical spine. A complete resolution of
the meningioma was also noted in this case. The possible contributing roles of
HIV infection and concomitant administration of antiviral drugs are discussed.
PMID- 10778733
TI - Clinical trial of intrathecal administration of 5-fluoro-2'-deoxyuridine for
treatment of meningeal dissemination of malignant tumors.
AB - Intrathecal administration of 5-fluoro-2'-deoxyuridine (FdUrd) was performed in
patients with meningeal dissemination of malignant tumors during the period from
January 1996 to September 1998, and they were followed up until February 1999.
The study population consisted of 23 patients: 12 with lung cancer, 4 with breast
cancer, 2 with colon cancer, 1 with malignant lymphoma, 2 with glioblastoma and 2
with metastatic brain tumors of unknown origin. FdUrd was administered
intrathecally through an Ommaya reservoir placed in the lateral ventricle
initially at a dose of 1 microg twice per week, and the dose was increased to 10
microg and administration schedule was also increased every day. Headache and
nuchal pain were relieved in all patients regardless of responsiveness to
intrathecal FdUrd therapy as determined from the findings in the cerebrospinal
fluid (CSF). Patients showed no side effects during the course of intrathecal
chemotherapy except for slight nausea in two patients and dull headache in one.
Sixteen of the 23 patients showed decreased cell number in the cerebrospinal
fluid (CSF). Positive cytological findings in CSF became negative in 6 of the 23
patients, and the levels of CSF tumor markers were decreased in 14.
Responsiveness to intrathecal administration of FdUrd was defined as 'response'
when both the cell number and tumor markers were decreased in both ventricular
and spinal CSF or when the cell number was decreased in cases in which the tumor
markers were not detected. Overall, 16 of the 23 patients (70%) showed complete
or partial responses to intrathecal FdUrd therapy as determined from CSF
findings. These results demonstrated the efficacy of intrathecal FdUrd
chemotherapy without apparent neurotoxicity for treatment of meningeal
dissemination of malignant tumors.
PMID- 10778734
TI - Carboplatin therapy for optic pathway tumors in children with neurofibromatosis
type-1.
AB - Symptomatic optic pathway tumors (OPT) occur in 7% of children with
neurofibromatosis type-1 (NF-1). Although tumor progression following diagnosis
is unusual in such children, specific therapy may be necessary for patients with
either severe or progressive disease. We reviewed the records of 9 children (6
girls, 3 boys) with NF-1 associated OPT who were treated with the second
generation platinum compound carboplatin. Carboplatin was given at a dose of 560
mg/mm2 every 4 weeks for a mean of 15 cycles. The mean age at presentation of the
OPT was 3.4 years. Eight children had abnormal ophthalmologic examinations at the
time of diagnosis. Only 4 patients had documented evidence of progressive disease
prior to the institution of therapy. No patient had evidence of progressive
disease following therapy. Four patients had radiologic evidence of tumor
shrinkage and 2 patients had definite improvement in vision. There was only
minimal toxicity. In conclusion, carboplatin is a safe and effective treatment
for OPT in children with NF-1. However, as disease stabilization of NF-1
associated OPT often occurs following clinical presentation, the clinician should
document tumor progression or visual deterioration prior to the institution of
therapy.
PMID- 10778735
TI - Lupine leghemoglobin I: expression in transgenic Lotus and tobacco tissues.
AB - The proximal parts of the promoters of the genes for symbiotic-type hemoglobins
are generally conserved, but the promoter of the lbI gene of lupine (LulbI) shows
some unusual structural features. It lacks typical organ-specific elements
characteristic of all the leghemoglobin gene promoters described thus far. We
have analysed its functional activity in transgenic Lotus corniculatus. A fusion
construct between the lbI promoter and the GUS reporter gene was expressed mainly
in the central zone of the root nodule, but the product was also detected in the
non-nodule root zone and in roots in tissue culture. In roots of transgenic
tobacco, the activity of the promoter was only 24% lower than in Lotus nodules.
LulbI promoter activity was also detected in tobacco leaves. Lupine hemoglobin I
has a higher sequence identity to symbiotic-type hemoglobins and thus it groups
within the "Class II" hemoglobins.
PMID- 10778736
TI - Identification of Drosophila melanogaster RECQE as a member of a new family of
RecQ homologues that is preferentially expressed in early embryos.
AB - We describe the isolation of a new type of RecQ homologue in Drosophila
melanogaster, RECQE. The Recqe gene consists of five exons and four introns, and
encodes a protein of 1058 amino acids with a predicted molecular weight of
120,000 Da. The RECQE protein has seven helicase motifs. The helicase domain
shows 42% identity overall to that of Escherichia coli RecQ DNA helicase, and is
most closely related to Homo sapiens RecQL5 and Caenorhabditis elegans E03A3.2.
The C-terminal region of RECQE protein is unique and the longest known among
members of the RecQ superfamily. We demonstrate that the RECQE protein has DNA
helicase activity and that the C-terminal region is dispensable for this
activity. The RECQE mRNA accumulates in oocytes and is expressed at high levels
in early embryos. We show for the first time that the expression of a RecQ
homologue is developmentally regulated in embryos. These data suggest that the
DNA helicase activity of RECQE might be involved in the DNA metabolism of early
embryos.
PMID- 10778737
TI - Two loci on wheat chromosome 5A regulate the differential cold-dependent
expression of the cor14b gene in frost-tolerant and frost-sensitive genotypes.
AB - Although cold acclimation in cereals involves the expression of many cold
regulated genes, genetic studies have shown that only very few chromosomal
regions carry loci that play an important role in frost tolerance. To investigate
the genetic relationship between frost tolerance and the expression of cold
regulated genes, the expression and regulation of the wheat homolog of the barley
cold-regulated gene cor14b was studied at various temperatures in frost-sensitive
and frost-tolerant wheat genotypes. At 18/15 degrees C (day/night temperatures)
frost-tolerant plants accumulated cor14b mRNAs and expressed COR14b proteins,
whereas the sensitive plants did not. This result indicates that the threshold
temperature for induction of the wheat cor14b homolog is higher in frost
resistant plants, and allowed us to use this polymorphism in a mapping approach.
Studies made with chromosome substitution lines showed that the polymorphism for
the threshold induction temperature of the wheat cor14b homolog is controlled by
a locus(i) located on chromosome 5A of wheat, while the cor14b gene was mapped in
Triticum monococcum on the long arm of chromosome 2Am. The analysis of single
chromosome recombinant lines derived from a cross between Chinese Spring/Triticum
spelta 5A and Chinese Spring/Cheyenne 5A identified two loci with additive
effects that are involved in the genetic control of cor14b mRNA accumulation. The
first locus was tightly linked to the marker psr911, while the second one was
located between the marker Xpsr2021 and Frost resistance 1 (Fr1).
PMID- 10778738
TI - Isolation and molecular characterisation of the gene encoding the cytoplasmic
ribosomal protein S28 in Prunus persica [L.]] Batsch.
AB - RT-PCR was performed on peach (Prunus persica [L.] Batsch) RNA to isolate cDNAs
corresponding to transcripts which are differentially expressed in leaves borne
on basal and apical shoots. A gene was identified which was more highly expressed
in the leaves of basal shoots, and codes for the cytoplasmic protein S28 present
in the small ribosomal subunit. The 5' leader regions of RPS28 mRNAs were found
to harbour 8-11 pyrimidine tracts, which suggested similarities to regulatory
stretches that control the translation of mRNAs for ribosomal proteins in
animals. The peach S28 is encoded by two intron-containing genes, which are both
transcribed in mitotically active tissues such as developing leaves and roots. In
situ hybridisation to shoot vegetative apices and the measurement of
nucleus/nucleolus ratios indicated that RPS28 expression was confined to areas
undergoing active cell division. The mature RPS28 mRNA was detected as a single
species in actively dividing tissues such as apical tips, developing leaves,
vegetative buds, stamens, developing fruits and roots. In contrast, accumulation
of a precursor RNA, in the presence of the mature product, was found in fully
expanded leaves and subtending stems, while only the precursor species was
detected in several late-stage tissues. This phenomenon suggested that expression
of the mature RNA is controlled at the level of splicing and turnover of the
precursor RNA. This is similar to the mode of regulation of ribosomal protein
genes in animals.
PMID- 10778739
TI - Pea chloroplast FtsZ can form multimers and correct the thermosensitive defect of
an Escherichia coli ftsZ mutant.
AB - This paper reports the isolation and characterization of a cDNA encoding the FtsZ
protein of pea. The protein is synthesised as a precursor molecule of 423 amino
acids with a molecular mass of 44 kDa. When translated in vitro, the protein is
translocated efficiently into isolated, intact pea chloroplasts, demonstrating
that the protein is localised in the chloroplast. Pea FtsZ synthesised in vitro
formed multimers in a calcium-dependent manner. The pea cDNA complemented the
thermosensitive defect of an E. coli ftsZ mutant in vivo and converted the
filamentous phenotype of the E. coli mutant into the normal wild-type morphology
at 42 degrees C. However, pea FtsZ mutants that were defective in multimerisation
in vitro failed to correct the phenotype of the E. coli ftsZ mutant in vivo. The
pea ftsZ transcripts were abundantly present in the young leaves, but barely
detectable in roots and stems and undetectable in older leaves. Light stimulated
transcription of the gene significantly in young and dark-grown leaves. This
study strongly suggests that the division mechanisms used by chloroplasts and
bacteria show considerable similarity.
PMID- 10778740
TI - Intergenic complementation truncation mutants of cyclin-dependent kinase.
AB - The Saccharomyces cerevisiae genes PHO80 and PHO85 encode, respectively, a cyclin
and cyclin-dependent kinase, which negatively regulate PHO5 gene transcription by
phosphorylating the transcription activator Pho4p. Cyclin-dependent kinases
(CDKs) are highly conserved proteins, both within and between species. It was
previously demonstrated, using reporter genes activated in yeast by Pho4p, that
hybrid proteins in which over two-thirds of Pho85p were replaced with the
homologous region from human Cdk2 retained the function of native Pho85p with
respect to promoter repression. In the present study, various truncated forms of
the hybrid human-yeast CDKs were tested for function. Surprisingly, truncations
in which significant portions of the C-terminal region of the 291-residue hybrid
CDK were deleted retained activity. Genes encoding human Cdk2 proteins which
terminated after amino acids 151, 140, 130, 120 and 90 each complement a
chromosomal pho85 gene disruption in which the HIS3 gene is inserted at codon 49.
Truncated Cdk2 proteins containing less than 60 amino acids failed to complement
the pho85::HIS3 gene disruption. Although the functional C-terminal truncations
disrupt the ATP-binding and active sites of Cdk2, reporter gene repression
mediated by these truncated proteins is apparently due to phosphorylation of
Pho4p, since a gene in which the essential lysine codon at position 33 was
converted to an arginine codon does not complement the chromosomal gene
disruption. The human Cdk2 truncations were demonstrated to function through
intergenic complementation. The intact Cdk2-Pho85 hybrid CDK complemented the
pho85 mutation in yeast strains in which the entire PHO85 coding region was
deleted from chromosome XVI. The C-terminal Cdk2 truncations, however, were non
functional in these strains and thus dependent for activity on the pho85 coding
region which remained in the mutant pho85::HIS3 chromosomal locus. These genetic
results are consistent with a model involving protein fragment complementation in
which the active site of the CDK is bisected.
PMID- 10778741
TI - A novel nuclear factor, SREB, binds to a cis-acting element, SRE, required for
inducible expression of the Aspergillus oryzae Taka-amylase A gene in A.
nidulans.
AB - The Taka-amylase A gene (taaG2) of Aspergillus oryzae is inducibly expressed in
A. nidulans upon exposure to inducing carbon sources, such as starch and maltose.
In order to identify nuclear factor(s) possibly involved in the induction of the
taaG2 gene, gel mobility shift assays and DNase I footprinting analyses were
carried out, and revealed a novel nuclear factor in A. nidulans extracts, which
specifically bound to two sites in the taaG2 promoter region, -204 to -189 and
182 to -168, which share the common sequence GGAAATT. The nuclear factor was
detected in nuclei from both induced and uninduced mycelia. Mutational analysis
within and around the binding sequences demonstrated that only the upstream
binding sequence, designated SRE (starch responsive element), was required for
the inducible expression of the taaG2 gene, and thus we designated the nuclear
factor SREB (SRE binding factor). The downstream binding site contained an
inverted SRE (ISRE) and played no role in the induction of taaG2 expression. SREB
was shown by gel retardation assays to have higher affinity for SRE than for
ISRE.
PMID- 10778742
TI - Mutational accessibility of essential genes on chromosome I(left) in
Caenorhabditis elegans.
AB - We have analyzed a region of approximately 5.4 million base pairs for mutations,
which under standard laboratory conditions result in developmental arrest,
sterility, or maternal-effect lethality in Caenorhabditis elegans. Lethal
mutations were isolated, maintained, and genetically manipulated as homozygotes
using sDp2--a duplication of the left half of chromosome I. All of the lethals
and rearrangements used in this analysis were balanced by sDp2. Relatively low
doses of mutagen, (approximately 15 mM ethylmethane sulfate; EMS), were used so
as to limit the occurrence of second-site mutations, thus increasing the
probability of recovering single nucleotide substitutions. Treatment of over
32,400 marked chromosomes resulted in 486 analyzed mutations. In this paper, we
add 133 previously unidentified let genes, isolated in the EMS screens, and one
let gene identified by a gamma-ray induced mutation, to our collection of 103
essential genes. We also recovered lethal alleles of genes for which visible
mutants already existed. In total, eight deficiencies and alleles of 237
essential genes were identified. Eighty-nine of the previously unidentified let
genes are represented by more than one lethal allele. Statistical analysis
indicates a minimum estimate of 400 essential genes in the region of chromosome I
balanced by sDp2. This region occupies approximately half of chromosome I, and
contains over 1135 protein-coding genes predicted from the genomic sequence data.
Thus, approximately one-third of the predicted genes are estimated to be
essential. Of these approximately 60% are represented by lethal alleles. Less
than 2% of the lethal-bearing strains recovered in our analysis, including the
eight genetically definable deficiencies, carried more than one lethal mutation.
Several screens were used to recover mutations for this analysis. Because all the
mutations were isolated using the same balancer, under similar screening
conditions, it was possible to compare intervals within the sDp2 region with each
other. The fraction of essential genes that present relatively large targets for
EMS was highest within the central cluster (dpy-5 to unc-13).
PMID- 10778743
TI - The protein kinases Rck1 and Rck2 inhibit meiosis in budding yeast.
AB - The genes RCK1 and RCK2 of budding yeast were initially identified as suppressors
of checkpoint mutations in fission yeast. Here, we show that homozygous diploid
rck1/rck1 mutants in standard sporulation medium enter meiosis in about half the
time required by wild-type cells. A similar, but weaker, effect is seen in
rck2/rck2 mutants, whereas double homozygous rck1/rck1 rck2/rck2 mutants display
a phenotype similar to that of the rck1/rck1 single mutants. In diploids with
mutations in either of the meiotic checkpoint genes MEC1 and RAD24,
overexpression of RCK1 or RCK2 reduces meiotic proficiency, most prominently seen
with RCK2. The rate of meiotic recombination was unaltered in rck1 and rck2
mutants. There is a transient shift in the relative abundance of the two RCK2
transcripts in meiotic cells. We propose that one function of Rck1 and Rck2 is to
inhibit meiosis.
PMID- 10778744
TI - Structure and function of a pyrimidine/purine-biased sequence from the 5'
flanking region of the basidiomycete Lentinus edodes gene priA.
AB - The priA gene of the basidiomycete Lentinus edodes possesses a pyrimidine (CT)
rich stretch (26 bp) that includes a short (6-bp) repeat, the elements of which
form a mirror repeat at and near the transcriptional initiation sites. A DNA
fragment that included this sequence was inserted into pBR322, and the resulting
plasmids were introduced into Escherichia coli. Analysis of the susceptibility of
these pBR322 derivatives to cleavage by S1 nuclease, following isolation from E.
coli, indicated the formation of an open, S1-sensitive structure within and just
downstream of the CT/AG-biased sequence. Replacement of two dTMP residues in one
of the repeat elements by dGMP resulted in the elimination of the S1-cleavable
open structure from the plasmids. To analyze the effect of the CT/AG-biased
sequence from priA in the basidiomycete Coprinus cinereus, the integrating
vectors pLC2 and pLC2mutCT were used; these contained the wild-type priA promoter
and the mutant priA promoter with the aforementioned mutation in the mirror
repeat, respectively. The Streptomyces-derived bialaphos resistance gene (bar)
was fused downstream of the promoters, and the resulting plasmids, pLC2-bar and
pLC2mutCT-bar, were introduced into C. cinereus. Transformants carrying pLC2mutCT
bar grew significantly more slowly on bialaphos-containing agar plates and
contained a noticeably lower level of the bar transcript when compared with the
transformants obtained with pLC2-bar. These results suggest that an unusual
structure induced by the CT/AG-biased sequence is required for efficient gene
expression from the priA promoter.
PMID- 10778745
TI - Foxy: an active family of short interspersed nuclear elements from Fusarium
oxysporum.
AB - A novel family of short interspersed nuclear elements (SINEs) has been identified
in Fusarium oxysporum. This family has been called Foxy. The feature that makes
Foxy unique among SINEs is the presence of 5' terminal tetranucleotide repeats.
Both the number and the sequence of these repeats vary between individual members
of the family. The genome of F. oxysporum f. sp. lycopersici contains at least
160 copies of Foxy. In a mutant obtained upon gamma irradiation of a wild-type
isolate, 13 new Foxy insertions were identified. These observations, together
with the occurrence of many Foxy-specific polymorphisms between isolates within
one vegetative incompatibility group and the presence of Foxy-specific
transcripts in the fungus, indicate that Foxy is currently active and may
contribute to the genetic variability of F. oxysporum. Since we have not been
able to detect Foxy sequences by PCR analyses in other fungi, this novel family
of SINEs seems to be confined to Fusarium species.
PMID- 10778746
TI - Cloning and characterization of oah, the gene encoding oxaloacetate hydrolase in
Aspergillus niger.
AB - The enzyme oxaloacetate hydrolase (EC 3.7.1.1), which is involved in oxalate
formation, was purified from Aspergillus niger. The native enzyme has a molecular
mass of 360-440 kDa, and the denatured enzyme has a molecular mass of 39 kDa, as
determined by gel electrophoresis. Enzyme activity is maximal at pH 7.0 and 45
degrees C. The fraction containing the enzyme activity contained at least five
proteins. The N-terminal amino acid sequences of four of these proteins were
determined. The amino acid sequences were aligned with EST sequences from A.
niger, and an EST sequence that showed 100% identity to all four sequences was
identified. Using this EST sequence the gene encoding oxaloacetate hydrolase
(oah) was cloned by inverse PCR. It consists of an ORF of 1227 bp with two
introns of 92 and 112 bp, respectively. The gene encodes a protein of 341 amino
acids with a molecular mass of 37 kDa. Under the growth conditions tested, the
highest oah expression was found for growth on acetate as carbon source. The gene
was expressed only at pH values higher than 4.0.
PMID- 10778747
TI - Telomeric silencing of a natural subtelomeric gene.
AB - The heterochromatin at telomeres can repress the expression of reporter genes
when they are transplanted into their vicinity. Although this transcriptional
silencing has been widely characterized using reporter genes, the ability of
telomeres to repress natural subtelomeric genes has remained uncertain. In a
previous report we described telomeric silencing of a yeast retrotransposon. Here
we describe the identification of a subtelomeric gene from Saccharomyces
cerevisiae that is subject to natural telomeric silencing. In addition, we show
that telomeric silencing is not a general feature of the first ORFs located
adjacent to Telomere-Associated Sequences.
PMID- 10778748
TI - Comparative analysis of the mating-type loci from Neurospora crassa and Sordaria
macrospora: identification of novel transcribed ORFs.
AB - The mating-type locus controls mating and sexual development in filamentous
ascomycetes. In the heterothallic ascomycete Neurospora crassa, the genes that
confer mating behavior comprise dissimilar DNA sequences (idiomorphs) in the mat
a and mat A mating partners. In the homothallic fungus Sordaria macrospora,
sequences corresponding to both idiomorphs are located contiguously in the mating
type locus, which contains one chimeric gene, Smt A-3, that includes sequences
which are similar to sequences found at the mat A and mat a mating-type
idiomorphs in N. crassa. In this study, we describe the comparative
transcriptional analysis of the chimeric mating-type region of S. macrospora and
the corresponding region of the N. crassa mat a idiomorph. By means of RT-PCR
experiments, we identified novel intervening sequences in the mating-type loci of
both ascomycetes and, hence, concluded that an additional ORF, encoding a
putative polypeptide of 79 amino acids, is present in the N. crassa mat a
idiomorph. Furthermore, our analysis revealed co-transcription of the novel gene
with the mat a-1 gene in N. crassa. The same mode of transcription was found in
the corresponding mating-type region of S. macrospora, where the chimeric Smt A-3
gene is co-transcribed with the mat a-specific Smt a-1 gene. Analysis of a Smt A
3 cDNA revealed optional splicing of two introns. We believe that this is the
first report of co-transcription of protein-encoding nuclear genes in filamentous
fungi. Possible functions of the novel ORFs in regulating mating-type gene
expression are discussed.
PMID- 10778749
TI - Tagging of a nitrogen pathway-specific regulator gene in Tolypocladium inflatum
by the transposon Restless.
AB - Restless is an endogenous hAT transposon found in the cyclosporin-producing
fungus Tolypocladium inflatum. This element is present in about 15 copies in a
particular strain (ATCC34921) which was used for successful gene tagging. We have
isolated a T. inflatum mutant with a defect in nitrogen metabolism. This mutant
carries a copy of the Restless element in a gene encoding a C6 zinc-finger
protein. The deduced amino acid sequence of the gene product shows a significant
similarity to the NIT4 protein of Neurospora crassa, which is a regulator of
nitrogen metabolism. The wild-type T. inflatum gene was shown to complement a nit
4 mutant of N. crassa. From these data, we conclude that the T. inflatum gene
also encodes a regulator of nitrogen metabolism, which was named tnir1
(Tolypocladium nitrogen regulator 1). To the best of our knowledge, this is the
first fungal gene to be identified by transposon-directed gene tagging. A general
method for gene tagging using an endogenous fungal transposon is presented.
PMID- 10778750
TI - Overexpression of Arabidopsis thaliana SKP1 homologues in yeast inactivates the
Mig1 repressor by destabilising the F-box protein Grr1.
AB - The timed destruction of cell cycle regulatory proteins is of key importance in
controlling cell cycle progression in eukaryotes. Recently, Skp1 from yeast
(Saccharomyces cerevisiae) was shown to play an important role in the ubiquitin
mediated proteolysis of these proteins via the Skp1-Cdc53-F-box (SCF) pathway.
Here we describe the fortuitous cloning of cDNAs for two Skp1 homologues from the
plant Arabidopsis thaliana on account of their ability to activate reporter gene
expression in yeast directed by the cyt-1 element from the promoter of the
Agrobacterium tumefaciens T-cyt gene, which is essential for expression of the
gene in plants. This element is strikingly similar in sequence to the binding
site for the yeast Migl protein, a transcriptional repressor of genes involved in
the utilisation of carbohydrates other than glucose. We report that Mig1 protein
binds to the cyt-1 element with similar specificity as a previously described
plant nuclear protein factor, and that the cyt-1 element is a target for an
unknown yeast transcriptional activator when Mig1 itself is inactivated.
Interestingly, our data further indicate that A. thaliana Skp1 inactivates Mig1
by destabilising the yeast F-box protein Grr1, which is required for cyclin
degradation and is thus involved in control of the cell cycle, and for glucose
regulated gene repression. Our results suggest that the plant counterpart of
yeast Skp1 is probably also instrumental in ubiquitin-mediated proteolysis of
specific proteins via an SCF-like pathway.
PMID- 10778751
TI - The effects of transcription and RNA processing on the initiation of chloroplast
DNA replication in Chlamydomonas reinhardtii.
AB - In Chlamydomonas reinhardtii, the origin for chloroplast DNA replication, Ori A,
overlaps the coding region for the chloroplast ribosomal protein Rpl16. In an in
vitro DNA replication system that uses cloned Ori A as template, alteration of
transcription across rpl16 affects replication activity. S1 nuclease protection
mapping of cellular RNA derived from this region revealed multiple 5' and 3'
ends, and several 3' ends were mapped within mini Ori A (224 bp), the core region
for replication initiation. We also demonstrated that the protein fraction used
in the in vitro DNA replication system contained an RNA processing activity
responsible for the generation of multiple 3' ends. The 3' ends of some of the
processed RNA species coincided with those of the cellular transcripts.
Initiation of DNA replication in the in vitro system changed the abundance of
some of the processed RNA species, and the S1 nuclease protection pattern
generated by the 3' ends now mimicked that of the in vivo transcripts. We also
monitored the pattern of 3' ends in cellular transcripts from the rpl16 region
during gametogenesis--when the chloroplast DNA is under-replicated--and detected
a change in transcript abundance that correlated with that seen in the in vitro
study. Measurements of the template activity of mutants with targeted sequences
change near the sites of processing also supported the notion that the processed
transcripts play an important role in DNA replication.
PMID- 10778752
TI - An AFLP marker that differentiates biotypes of the Asian rice gall midge
(Orseolia oryzae, Wood-Mason) is sex-linked and also linked to avirulence.
AB - In an attempt to identify a specific marker for biotype 2 of the Asian rice gall
midge (Orseolia oryzae, Wood-Mason), we used AFLP (amplified fragment length
polymorphism) fingerprinting. We identified an AFLP marker that is specifically
amplified in biotypes 1, 2 and 5 of the rice gall midge, but not in biotype 4.
Biotypes 1, 2 and 5 are avirulent to hosts bearing the Gm2 resistance gene (found
in rice variety Phalguna), whereas biotype 4 is virulent to Gm2. Based on the
sequence of this AFLP marker, SCAR (sequence characterized amplified region)
primers were designed and used in combination with previously developed SCAR
primers to distinguish effectively all five biotypes in a multiplex PCR-based
assay. The inheritance pattern of this marker in the progenies of inter-biotype
crosses between biotypes 1, 2 and 4 shows that the marker can be amplified by PCR
from all F1 females, irrespective of the biotype status of their parents.
However, the marker is present only in those male progenies whose mother was of a
Gm2 avirulent biotype. The specific amplification of this marker in the avirulent
biotypes and its pattern of inheritance show that avirulence with respect to
carriers of the Gm2 gene in rice gall midge is sex-linked.
PMID- 10778753
TI - hobo-induced rearrangements are responsible for mutation bursts at the yellow
locus in a natural population of Drosophila melanogaster.
AB - In 1981 recurrent local bursts of mutability of the yellow gene were observed in
a natural population of Drosophila melanogaster from Uman' (Ukraine). A series of
y2-like mutations in the yellow gene were recovered during the period 1982 to
1991. Most of the mutants display the y2-phenotype, i.e. mutant yellow color of
wings and body cuticle. Ninety-nine y2 mutants were shown to be generated by an
inversion that occurred between two hobo elements, one located 129 bp from the
start site of yellow transcription, and the other in the distal telomere region.
The y2 phenotype was caused by the separation of the body and wing enhancers from
the transcription unit. Many of the y2-like alleles were highly unstable and
reverted to y+, which again, gave rise to y2-like mutants. We found that the y2-
>y+-->y2 transitions were generated by repeated inversions between the two hobo
elements mentioned. The y2 and y+ alleles lost their instability after deletion
of the hobo element present at the tip of the X chromosome.
PMID- 10778754
TI - Nitric oxide reduction, the last step in denitrification by Fusarium oxysporum,
is obligatorily mediated by cytochrome P450nor.
AB - The involvement of cytochrome P450nor (P450nor) is the most striking feature of
the fungal denitrifying system, and has never been shown in bacterial systems. To
establish the physiological significance of the P450nor, we constructed and
investigated mutants of Fusarium oxysporum that lacked the gene for P450nor. We
mutated the gene by targeted integration of a disrupted gene into the chromosome
of F. oxysporum. The mutants were shown to contain neither P450nor protein nor
nitric oxide (NO) reductase (Nor) activity, implying that they are indeed
deficient in P450nor. These mutants had apparently lost the denitrifying activity
and failed to evolve nitrous oxide (N2O) upon incubation under oxygen-limiting
conditions in the presence of nitrate. Their mycelia exhibited normal levels of
dissimilatory nitrite reductase (Nir) activity and were able to evolve NO under
these conditions. The promoter region of the P450nor gene was fused to lacZ and
introduced into the wild-type strain of F. oxysporum. The transformed strain
produced beta-galactosidase under denitrifying conditions as efficiently as the
wild type does P450nor. These results represent unequivocal genetic evidence that
P450nor is essential for the reduction of NO to N2O, the last step in
denitrification by F. oxysporum.
PMID- 10778755
TI - Expression of the hemolysin operon in Escherichia coli is modulated by a nucleoid
protein complex that includes the proteins Hha and H-NS.
AB - The Escherichia coli protein Hha is a temperature- and osmolarity-dependent
modulator of the expression of the hemolysin operon. The Hha protein was purified
and its DNA-binding properties analyzed. Hha binds in a non-specific manner
throughout the upstream regulatory region of the hemolysin operon in the
recombinant hemolytic plasmid pANN202-312. A search for interacting proteins
revealed that Hha interacts with H-NS. DNA-binding studies showed that, in vitro,
Hha and H-NS together form a complex with DNA that differs from those formed with
either protein alone. These data, together with the effects of hha and hns
mutations on the expression of the hemolysin genes, suggest that in vivo H-NS and
Hha form a nucleoid-protein complex that accounts for the thermo-osmotic
regulation of the hemolysin operon in E. coli.
PMID- 10778756
TI - Diverse response of rice and maize genes encoding homologs of WPK4, an SNF1
related protein kinase from wheat, to light, nutrients, low temperature and
cytokinins.
AB - The wheat gene WPK4 encodes a 56-kDa protein kinase that belongs to group 3 of
the SNF1-related protein kinase family (SnRK3), and is up-regulated by light and
cytokinins and down-regulated by sucrose. In order to determine whether or not
this particular regulation pattern is general among plant species, we isolated
and characterized homologous genes from rice and maize. Two rice genes, OsPK4 and
OsPK7, encode proteins comprising 508 and 520 amino acids, and show,
respectively, 75% and 76% sequence similarity to WPK4. OsPK4 and OsPK7 proteins
produced in Escherichia coli were able to phosphorylate themselves and myelin
basic proteins, the reaction requiring magnesium and/or manganese ions.
Transcripts of OsPK4 were detected in all tissues tested, and amounts were
increased upon illumination, nutrient deprivation and treatment with cytokinins.
In contrast, transcripts of OsPK7 were not found in any tissues except in mature
leaves at low levels, and did not accumulate under any of the stress conditions
examined. A maize gene, ZmPK4, encodes a protein with 518 amino acids that shows
74% similarity to WPK4. Its transcripts were constitutively expressed in all
tissues, regardless of light, nutrient and cytokinin status, but were increased
upon exposure to low temperature. These results indicate that, despite the
sequence similarity between their products, genes for SnRK3 proteins are
differentially regulated in response to environmental stimuli.
PMID- 10778757
TI - A point mutation at the Miniature1 seed locus reduces levels of the encoded
protein, but not its mRNA, in maize.
AB - We report here on the molecular nature of an EMS-induced mutant, mn1-89, a leaky
semidominant allele of the Miniature1 (Mn1) seed locus that encodes a seed
specific cell wall invertase, INCW2. The mn1-89 locus specifies normal levels of
the Incw2 transcript but extremely low levels (about 6% of normal) of the protein
and enzyme activity are expressed. Sequence analysis of Incw2 clones derived from
the parental Mn1 and the mutant genotypes shows a C to T transition in the mn1-89
allele, leading to a single amino acid alteration (proline to leucine) near the C
terminus of the mutant INCW2 protein. Although this change is not in the
catalytic domain, putative N-glycosylation sites, or the beta-fructosidase motif,
it does lie in a motif that is well conserved among all plant invertases and
related fructosyltransferases. On the basis of these genetic in planta data, we
believe we have identified a proline residue in a hitherto unknown GPFG motif as
critical for the stability of such proteins. The single base change (C to T) also
leads to the elimination of a BglI restriction site in the mutant allele. Indeed,
BglI restriction digests of genomic DNAs from mn1-89 and Mn1 genotypes show one
and two fragments, respectively. Sequence analysis of RT-PCR-derived endosperm
Incw clones from mn1-1 (the reference allele) seeds predict five amino acid
substitutions relative to Mn1. Whether or not these sequences are encoded by the
mn1-1 locus or another non-allelic Incw gene in the maize genome remains to be
elucidated.
PMID- 10778758
TI - Surgical strategies in colorectal cancer metastatic to the liver.
AB - Surgical resection remains a milestone in the treatment of colorectal metastases
to the liver. There is a distinct subset of patients who benefit from surgical
resection in terms of longer survival or definitive cure. The main effort of the
surgical oncological regards the safety of the procedure and the adequacy of the
recommendation. Many studies, some of them including multivariate analysis, have
shown the presence of prognostic determinants of long-term survival and
prognostic indexes of the outcome after hepatectomy. It is now accepted that
liver resection should be done when the complete excision of all demonstrable
tumor with clear resection margins is feasible. Major contra-indication is
represented by the presence of extra-hepatic intra-abdominal disease or of
unresectable lung metastatic deposits. There is a wide literature indicating that
in very selected patients liver reresection and multiorgan synchronous or
metachronous resections are beneficial. The role of neoadjuvant chemotherapy and
especially postoperative adjuvant local (intra-hepatic) and systemic chemotherapy
is promising and supported by recent multicenter randomised clinical trials.
PMID- 10778759
TI - Validation of the modified TNM-Izumi classification for hepatocellular carcinoma.
AB - AIMS AND BACKGROUND: The clinical value of the UICC TNM classification and the
Izumi TNM modification regarding prognosis after hepatic resection was evaluated.
METHODS: Between January 1993 and December 1998, survival and disease-free
survival were analyzed in 53 cirrhotic patients (40 males, 13 females; mean age,
65 years; range, 43-81) who underwent hepatic resection for HCC. RESULTS: The 1-,
3-, and 5-year overall survivals were: 89%, 54%, and 50%, with disease-free
survivals of 70%, 38%, and 28%, respectively. The difference between stages 1 and
2 or stages 3 and 4A using the UICC TNM classification was not significant with
respect to survival or disease-free survival. Conversely, the Izumi TNM
modification showed a significant difference between each stage with respect to
survival and disease-free survival. In a multivariate analysis the lack of
micro/macro vascular invasion was predictive of long-term outcome. CONCLUSIONS:
Our results show that the UICC TNM classification for hepatocellular carcinoma is
inadequate. The Izumi modified TNM staging system is superior in assessing
prognosis for surgical HCC patients.
PMID- 10778760
TI - Factors of risk for breast cancer influencing post-menopausal long-term hormone
replacement therapy.
AB - The advantages of hormone replacement therapy (HRT) are well documented in
contrasting the symptomatology of climacterium and in reducing morbidity and
mortality associated with coronary heart disease and osteoporotic fractures of
postmenopausal age. However, growing evidence points to increased breast cancer
risk in HRT long-term users, and the adverse effect would, obviously, overwhelm
any other benefit. At present, the risk/benefit ratio of HRT is an object of hot
debate, and we feel it necessary and urgent to select women who can safely
benefit from HRT and women whose risk of breast cancer can be perilously
increased by the raised hormonal levels related to HRT. We have reviewed studies
on the breast cancer risk in HRT users and data on the interaction between
steroid hormones and breast cancer. Reasoning that the outcome of mammary cancer
can be increased by hormonal overstimulation of the breast, we have focused on
those factors of risk that could be further enhanced by the exogenous hormonal
stimulus of HRT, so as to cause a further significant increase in the risk of
breast cancer. We conclude that some biologic and clinical markers, namely
android obesity, bone density, mammographic density, androgen and estrogen
circulating levels, alcohol consumption, benign breast disease, and familiarity,
should be carefully considered before prescribing long-term HRT. Our analysis
suggests that HRT could increase the risk of breast cancer and useless in
preventing coronary heart disease and osteoporotic fractures when administered in
women with positivity for one or more of these markers.
PMID- 10778761
TI - Prognostic significance of anemia and role of erythropoietin in radiation
therapy.
AB - Anemia represents a common finding in cancer patients, especially at an advanced
stage. Anemia has an impact on the quality of life and at the same time seems to
markedly limit the disease control that can be achieved with radiotherapy. The
results of a series of clinical studies published in the last decade allow some
general observations: 1. the administration of erythropoietin, especially if
associated to ferrous sulfate is able to increase hemoglobulin levels in cancer
patients undergoing radiation therapy (combined with concomitant chemotherapy);
2. erythropoietin stimulation of hemoglobin in anemia decreases the need for
blood transfusion in cancer patients; 3. tumor response to radiation therapy
appears to be enhanced by erythropoietin-induced hemoglobulin increase. Further
clinical studies are required for assessment of indications, identification of
optimal administration modalities, cost-analysis of this promising therapy for
patients undergoing radiation therapy.
PMID- 10778762
TI - Hormonal profiles and estrogen receptors in Egyptian female breast cancer
patients.
AB - AIMS AND BACKGROUND: Hormones are considered to be an important factor in the
etiology of breast cancer. Serum hormonal profiles of premenopausal and
postmenopausal breast cancer patients as well as estrogen receptor (ER)
concentrations in breast cancer tissues were examined in an attempt to establish
a possible association between hormones and breast cancer risk and to elucidate
the biological features of the disease among Egyptian female patients. METHODS:
Levels of estradiol (E2), testosterone (T), progesterone (P), LH, FSH, prolactin,
T3, T4 and TSH were measured by highly specific radioimmunoassays in the sera of
women with breast cancer and compared to those of control subjects. ER
concentrations in breast tumor tissues were measured using 125I-radioreceptor
assay. RESULTS: Levels of T and prolactin showed a significant increase in both
premenopausal and postmenopausal patients. E2 and P levels were significantly
increased in follicular premenopausal and postmenopausal patients. Luteal E2
showed non-significant changes, whereas the luteal P level was significantly
decreased. No significant alterations were found in the levels of serum LH, FSH,
T3, T4 and TSH either in premenopausal or postmenopausal patients. Higher levels
of ER were found in the tumors of postmenopausal than in those of premenopausal
patients. A positive correlation was found between levels of ER and age of the
patients (r = 0.35), whereas a negative correlation was observed between ER and
serum E2 (r = -0.26). CONCLUSIONS: This study provides evidence of an association
between high levels of serum E2 and T and increased risk of breast cancer in
postmenopausal women. Abnormalities in serum P and prolactin are probably
associated with a breast cancer risk and ER may be considered as a biochemical
marker for breast cancer development.
PMID- 10778763
TI - Mutual predictive value of c-erbB-2 overexpression and various prognostic factors
in ductal invasive breast carcinoma.
AB - AIMS AND BACKGROUND: Breast carcinoma is a heterogeneous disease, the prognosis
of which correlates with various prognostic factors. The aim of this study was to
assess the prognostic significance of c-erbB-2 overexpression in breast carcinoma
patients in association with other known prognostic factors. METHODS & STUDY
DESIGN: The relationship between immunohistochemical expression of the c-erbB-2
oncoprotein and various established prognostic factors such as tumor size,
axillary node status, estrogen and progesterone receptor status, DNA ploidy,
proliferation index, cathepsin D expression and histological grade in invasive
ductal breast carcinoma is presented in this study. RESULTS: Of the 93 ductal
invasive carcinomas 22 (23.7%) were grade I, 51 (54.8%) grade II, and 20 (21.5%)
grade III, and the majority (78: 83.9%) were 2-5 cm in diameter. Tumor metastases
were identified in one or more lymph nodes in 55 (59.1%) patients, the remaining
38 (40.9%) patients being lymph node negative. According to the DNA histograms 40
(43.0%) tumors were aneuploid and 53 (57.0%) were diploid, and the majority of
tumors had more than 4% of cells in the S phase of the cell cycle (83.9%).
Expression of c-erbB-2 as shown by immunohistochemical intense membrane staining
was present in 49 (52.7%) tumors. Cathepsin D-positive cytoplasmic granular
staining and cathepsin D-positive stromal macrophages were found in 60 (64.5%)
and 72 (77.4%) tumors, respectively. Univariate analysis showed that overall
survival correlated significantly with axillary lymph node involvement and with
estrogen and progesterone receptor status for each of the receptors separately
and for their coexpression, and only marginally with c-erbB-2 overexpression. In
mulitivariate analysis only axillary lymph node metastases and coexpression of
estrogen and progesterone receptors were found to be independent and significant
prognostic factors. CONCLUSIONS: When patients were stratified according to c
erbB-2 expression it was shown that those with c-erbB-2 overexpression and grade
II tumors, tumor size greater than 2 cm, high content of aneuploid cells and
cathepsin D-positive stromal macrophages had a shorter long-term survival than c
erbB-2 negative patients.
PMID- 10778764
TI - A randomized open-label parallel-group study comparing ondansetron with
ondansetron plus dexamethasone in patients with metastatic breast cancer
receiving high-dose epirubicin. A Hellenic Cooperative Oncology Group study.
AB - AIMS AND BACKGROUND: The purpose of this multicenter randomized, open-label,
parallel-group study was to assess whether the addition of low-dose dexamethasone
to ondansetron results in improved control of chemotherapy-induced emesis in
patients undergoing first-line chemotherapy with high-dose epirubicin. METHODS &
STUDY DESIGN: Patients were randomized to receive either 24 mg of ondansetron or
24 mg of ondansetron plus 8 mg of dexamethasone administered as an intravenous
infusion 30 minutes prior to administration of chemotherapy. Both groups of
patients received 8 mg of ondansetron given orally from day 2 to 5 two times
daily. Fifty-three patients received ondansetron and 50 received ondansetron plus
dexamethasone. The patients recorded nausea and the number of vomits and retches
daily on diary cards. RESULTS: Significantly more patients in the ondansetron
plus dexamethasone group experienced neither vomiting nor retching during the
first day of the first course of chemotherapy compared to those receiving
ondansetron alone (79.6% vs 53.8%, P = 0.0062). Furthermore, there was a trend in
favor of ondansetron plus dexamethasone in the control of nausea. There was no
statistically significant difference between ondansetron plus dexamethasone
versus ondansetron alone in protecting patients from emesis between days 2 and 5
of the first course of chemotherapy (66.7% vs 62.7%, P = 0.68). This was probably
due to the small sample size. Ondansetron was well tolerated, with 15 patients
(15%) reporting adverse events such as headache or constipation. CONCLUSIONS: It
appears that ondansetron given intravenously in combination with dexamethasone is
more effective than ondansetron alone in the control of acute emesis in patients
undergoing their first course of chemotherapy with high-dose epirubicin. No
difference between the regimens was found with regard to nausea and delayed
emesis control.
PMID- 10778765
TI - Continuous infusion fluorouracil in the management of advanced breast cancer: a
phase II study.
AB - AIMS AND BACKGROUND: The evaluation of unconventional schedules of well-known
drugs represents a promising avenue in the search for new regimens with a better
therapeutic index in metastatic breast cancer. In particular, protracted
continuous infusion (PCI) of 5-fluorouracil (5-FU) has yielded interesting
results in gastrointestinal malignancies and in breast cancer. METHODS: From
March 1996 30 consecutive patients with heavily pretreated breast cancer were
treated with PCI 5-FU at a daily dose of 250 mg/m2 by means of disposable
elastomeric pumps until progression or toxicity. The median age was 54 years
(range, 28-71) and median performance status was 1 (range, 0-3). All patients but
four were pretreated with anthracycline-containing regimens or taxanes; the
median number of chemotherapy lines was 3 (range, 2-4). Metastatic sites were
predominantly visceral in 60% of the patient population. RESULTS: All 30 patients
were evaluable for response and toxicity. The median duration of PCI was 20 weeks
(range, 2-36 weeks). Two complete responses (7%) and eight partial remissions
(26%) were observed, giving an overall response rate of 33%. The median duration
of response was six months (range, 4-9 months). Stabilization was observed in
seven patients (23%) with a median duration of seven months (range, 3-9 months).
The main toxic effects were grade I-II mucositis and hematologic toxicity, while
grade 3 hand-foot syndrome was observed in eight patients (27%). CONCLUSIONS:
This study confirms the efficacy and safety of 5-FU at this dosage and schedule
in heavily pretreated women with advanced breast cancer. In order to improve on
these results further studies are needed in a less advanced stage of the disease
and together with other active drugs.
PMID- 10778767
TI - Cell kinetics analysis in patients affected by squamous cell carcinoma of the
head and neck treated with primary surgery and adjuvant radiotherapy.
AB - BACKGROUND: The increasing complexity of management strategies for patients with
head and neck squamous cell carcinoma (HN-SCC) calls for the investigation of new
objective prognostic parameters to subdivide patients according to the tumor's
biological aggressiveness. METHODS: We evaluated in 35 HN-SCC patients the
pretreatment cell kinetics parameters and DNA ploidy after in vivo infusion of
bromodeoxyuridine and flow cytometric analysis. Patients were treated with
radical surgery followed by conventional radiation therapy. Locoregional control
data are available for follow-up times above five years. RESULTS: We found that
the likelihood of locoregional control for patients with rapidly proliferating HN
SCC characterized by a short potential doubling time (Tpot <5 days) was
significantly smaller than for HN-SCC patients with slow tumor proliferation
(Tpot >5 days). Moreover, when patients were stratified according to DNA ploidy
and Tpot value, we found that the locoregional failure rate for rapidly
proliferating tumors was significantly higher for diploid HN-SCCs than for
aneuploid HN-SCCs. CONCLUSION: The present data suggest that patients with
resectable HN-SCC characterized by fast growth might have a worse prognosis after
surgery and adjuvant conventional radiotherapy and might benefit from more
aggressive radiotherapeutic modalities.
PMID- 10778766
TI - Tumor infiltrating lymphocytes and continuous infusion interleukin-2 after
metastasectomy in 61 patients with melanoma, colorectal and renal carcinoma.
AB - AIMS AND BACKGROUND: Adoptive immunotherapy with tumor infiltrating lymphocyte
(TIL) reinfusion plus continuous interleukin-2 (IL-2) infusion could represent an
innovative way of treating immunogenic tumors. This study therefore recruited
melanoma, colorectal and renal carcinoma patients whose metastases had been
surgically removed. STUDY DESIGN: The treatment was initially given to 22
patients with advanced disease and more recently to 39 disease-free (DF) patients
after radical metastasectomy. The latter group was selected in view of a
theoretically better lymphocyte/tumor cell ratio and with the aim to improve
disease-free and overall survival (DFS-OS) in very high risk patients. The
starting IL-2 dose was 12 MIU/day (West's schedule); doses were modulated on the
bases of toxicity parameters. Even though patients received different total
amounts of IL-2, all of them completed the treatment. RESULTS: The treatment was
offered to 22 advanced-stage cancer patients (12 melanomas, 9 colorectal
carcinomas, 1 kidney carcinoma). Few and short stabilizations were observed with
a median survival of 12 months (range, 3-29). Subsequently, another 39 patients
were treated in an adjuvant setting after radical metastasectomy (18 melanomas,
19 colorectal carcinomas, 2 kidney cancers). Eleven out of 17 DF melanoma
patients (64.7%) are still free of disease after a median of 37+ months (range,
5+ - 69+). In the group of DF colorectal cancer patients eight (44.4%) are still
DF after a median of 21+ months (range, 7+ - 67+ months). One of the two patients
with kidney cancer is still DF after 28+ months. Two patients (1 melanoma and 1
colorectal cancer) had just been treated and were therefore not evaluable. Severe
toxicity occurred in three cases but was rapidly resolved. There was a great
diversity in IL-2 doses administered; comparison of the total IL-2 dose
administered between the patients who are still DF and those who progressed
revealed no difference between the two groups of colorectal cancer patients,
whereas melanoma patients who progressed received an average IL-2 dose of 6.5
MIU/day versus 15.8 MIU/day in DF patients. No differences were observed in any
of the groups between the number of TILs reinfused and clinical response.
CONCLUSIONS: The study is still ongoing; it has been decided to focus on DF
melanoma patients after radical metastasectomy, for whom the data seem to be
encouraging. Further endpoints of the study are the role of IL-2 dosage in the
adjuvant setting, and the possibility to make correlations between biological
parameters and clinical results.
PMID- 10778768
TI - Benefit of adjuvant radiotherapy in surgically staged stage I-II endometrial
carcinoma.
AB - AIMS AND BACKGROUND: This study was performed to determine the treatment outcomes
and patterns of failure following external beam therapy in patients with
pathological stage I-II endometrial carcinoma. STUDY DESIGN: Eighty-three
patients with stage I-II endometrial carcinoma surgically staged who were found
to have high risk factors and who received postoperative radiation therapy are
the subject of this report. High risk factors were: histologic grade II-III,
depth of myometrial invasion (DMI) > or =1/2, stage II, poor prognostic histology
(clear cell, papillary serous cell) and lymphovascular invasion. RESULTS:
Recurrences were observed in six patients. The recurrences were located in the
vagina (1), lung (2), liver (1), and paraaortic lymph nodes (1). Five of the six
recurrences were stage IC and II. The overall survival (OS), cause-specific
survival (CSS) and disease-free survival (DFS) at five years were 82.9%, 85.0%
and 81.3%, respectively. DMI, grade, age and cervical stromal invasion had a
significant impact on CSS. CONCLUSION: Adjuvant radiotherapy decreases the rate
of relapse in pathologically staged high-risk stage I-II endometrial carcinoma
patients. After reviewing the other studies on this subject we conclude that
vaginal cuff brachytherapy alone could be used in stage IA grade III and stage IB
grade I-II patients because the recurrence rate is low; pelvic radiotherapy +
vaginal cuff brachytherapy should be used for stage IC-II disease. Distant
metastases occurred in five of our patients and represent a significant type of
failure.
PMID- 10778769
TI - Characterization of tumor-associated antigens on human oral squamous cell
carcinomas using monoclonal antibody 3F8E3.
AB - Tumor associated antigen (TAA) on oral squamous cell carcinoma (SCC) was
characterized using the monoclonal antibody (MAb) 3F8E3. Flow cytometric analysis
revealed a varying degree of reactivity of MAb 3F8E3 to TAA on oral tumor cells.
Pretreatment of SCC cells with pronase and trypsin annulled the reactivity of MAb
3F8E3. Sodium metaperiodate (NaIO4) and neuraminidase marginally enhanced the
binding of 3F8E3 on oral SCC cells. The studies indicate that the TAA recognized
by MAb 3F8E3 on oral tumors is a protein moiety. On Western blotting MAb 3F8E3
showed reactivity to proteins with a molecular weight of 60-66 kDa on oral tumor
lysates. MAb 3F8E3 reacted strongly to recombinant human hsp60 and 70 in ELISA.
The results suggest that MAb 3F8E3 may react to an epitope expressed on a family
of heat shock proteins.
PMID- 10778770
TI - Association between cutaneous melanoma and neurofibromatosis type 1: analysis of
three clinical cases and review of the literature.
AB - The authors report a rare association between cutaneous melanoma and Von
Recklinghausen's disease (NF-1) and analyze the possible meaning of this
occurrence. Various types of tumors have been associated with NF-1, in particular
those of neuroectodermal origin, such as malignant peripheral nerve sheath tumors
(MPNST) and phaeochromocytoma. The development of malignant melanoma in NF-1
patients is rare. Data from the literature is enable to demonstrate an increased
incidence of cutaneous melanoma in patients with neurofibromatosis but the
association of these two disorders seems reasonable in theory, as both are
abnormalities of a neural crest origin. The cases described may represent not
only a clinical report of two rarely associated disorders, but may also confirm
the biological mechanisms responsible for these infrequent diseases.
PMID- 10778771
TI - Mesenchymal chondrosarcoma of the sacrum: a case report and review of the
literature.
AB - The authors present a case of mesenchymal chondrosarcoma located in the sacrum of
a 23-year-old patient treated with radiotherapy and chemotherapy. A review of the
literature on the topic is also reported.
PMID- 10778772
TI - Chondrosarcoma of the larynx. Case report and review of the literature.
AB - Chondrosarcoma of the larynx is a rare tumor; worldwide only about 250-300 cases
have been described in the literature. We present a clinical case of laryngeal
chondrosarcoma manifesting as a swollen mass of 10 x 7 x 6 cm in the infrahyoid
and left lateral cervical region. The patient underwent total laryngectomy,
thyroidectomy and bilateral neck dissection. A review of the literature on this
disease is also reported.
PMID- 10778773
TI - Carcinosarcoma of the lung: a case report.
AB - The clinical and pathological data of a single case of carcinosarcoma of the lung
observed in the period from 1978 to 1998 were reviewed. The diagnosis was based
on immunohistochemical examination of the surgical specimen after a lower left
lobectomy. The patient was given adjuvant chemotherapy. The local recurrence
showed only sarcomatous features. The characteristics of this rare tumor are
discussed in this case report.
PMID- 10778774
TI - Rectal neurogenic sarcoma: case report and review of the literature.
AB - A neurogenic sarcoma without NF-1 was discovered in a 73-year-old woman in the
anorectal region, an unusual site for these tumors. The tumor was of high-grade
malignancy and deeply located with mesorectal infiltration; it did not originate
from a major nerve. We presume an origin from less differentiated neural crest
cells and present a review of the literature on the best treatment for these
neoplasms.
PMID- 10778775
TI - Metastatic renal cell carcinoma to the head and neck area.
AB - AIMS AND BACKGROUND: Metastases of renal cell carcinoma to the head and neck are
rare. We report on three cases with tumor spread to this area (nasal cavity,
tongue and larynx) and present a review of the literature. PATIENTS: The first
patient presented with lung and nasal cavity metastases five years after renal
tumor resection. In patient 2 the diagnosis of primary renal carcinoma and lung
and tongue metastases was concomitant. In case 3 a primary kidney tumor was not
suspected until radical resection of a tongue lesion was performed. RESULTS: The
first two patients received radiation therapy. They had been previously treated
with interleukin + interferon and vinblastine + interleukin 2 and achieved a
survival of 14 and 16 months, respectively. The third patient has not been given
any treatment to date (apart from surgery) and remains asymptomatic four years
after diagnosis. CONCLUSIONS: In patients with cell carcinoma the occurrence of
lesions in the head and neck area may suggest metastases. In some cases they may
precede the diagnosis of a renal tumor and mimic a primary head and neck tumor;
otolaryngologists should be aware of this possibility. An individualized
treatment approach is recommended. In the case of solitary metastases a surgical
excision should be performed as palliation, if not cure.
PMID- 10778776
TI - Primary carcinoid tumor of the ovary: report of an unusual case.
AB - Carcinoid tumors are endocrine malignancies that are often associated with a
characteristic syndrome, the malignant carcinoid syndrome, which is most common
in patients with small bowel tumors and liver metastases. In the rare instances
when the syndrome is present without liver metastases the primary tumor is
usually localized to the bronchus or ovary and secretes hormones directly into
the systemic circulation. About two thirds of patients with carcinoid syndrome
have evidence of carcinoid heart disease. We report on a case of a primary
ovarian carcinoid tumor with an unusual clinical presentation.
PMID- 10778777
TI - Colon cancer in pregnancy: report of a case and review of the literature.
AB - Most colon cancer cases occur in patients over 50 years of age, although about 3%
of colorectal cancer patients are younger than 40. During pregnancy the incidence
of this neoplasm is estimated to be 0.002%. To date only 32 cases of colonic
cancer arising above the peritoneal reflection during pregnancy have been
described in the literature. We report another such case, stressing the need for
constant alertness on the part of physicians in the presence of abdominal pain
and/or distension, a palpable abdominal mass, rectal bleeding and/or weight loss
during pregnancy. In fact, the reportedly poorer prognosis of this cancer in
pregnant patients is mainly due to the fact that the initial symptoms of the
malignancy are usually attributed by the patient, but also by physicians, to
normal pregnancy.
PMID- 10778779
TI - [Therapeutic strategies in oncology and quality of life: Echoes from 2 recent
congresses. IX National Congress of the Italian Society of Palliative Therapy,
Rome, 17-20 November 1999. XXV National Congress of the Tumor Italian Society
(Societa Italiana Tumori), Sorrento, 17-21 November 1999].
PMID- 10778778
TI - Lethal midline granuloma starting as granuloma laryngis.
AB - We report a case of lethal midline granuloma in a 34-year-old male patient. The
patient was referred to our hospital because of long-lasting hoarseness. He was
treated for granuloma laryngis. After two years nasal obstruction developed
followed by ulceration of the hard palate and destruction of part of the nose and
the upper lip. A biopsy demonstrated polymorphic infiltrate consisting of small
lymphocytes, plasma cells, macrophages, atypical lymphoid cells and eosinophils.
Radiotherapy was very effective and led to long-term remission. The different
etiological aspects of this syndrome are discussed.
PMID- 10778780
TI - Environmental enrichment of laboratory animals used in regulatory toxicology
studies.
AB - There is a wealth of information in the published literature which describes a
multitude of approaches to enriching the environment of laboratory animals. This
paper attempts to review the various methods of enrichment through social
contact, enhancement of the environment and diet, and improvements in husbandry.
It attempts to place the various enrichment initiatives within the context of a
laboratory which conducts regulatory toxicology, describes some of the
experiences in the author's own laboratory and attempts to highlight those ideas
which might prove practical to implement in the future. The aim is to demonstrate
that a creative approach to environmental enrichment is indeed compatible with
regulatory toxicology. It is hoped that this will encourage those responsible for
the care and welfare of animals in such a laboratory to challenge historical
practices and include environmental enrichment as a fundamental necessity of
study design.
PMID- 10778781
TI - Interference of pain control employing opioids in in vivo immunological
experiments.
AB - Pain control (PC) in laboratory animals is supported by ethical as well as
methodological considerations, aimed at preventing an interfering reduction in
food and water intake and normalizing stress hormone levels. However, little is
known about the immunomodulatory attributes of analgesics, which putatively
prevents the routine implementation of PC in immunological research. In an
established murine model of endotoxemia we investigated the immunomodulatory
properties of common clinical analgesics (the opioids fentanyl and
buprenorphine). Additionally, a literature study was conducted to investigate the
frequency of PC in laboratory animals used for immunological experimentation. In
line with various reports, we observed interactions between the opioid analgesics
and the immune system that altered the outcome of performed in vivo immunological
experiments. Of 100 evaluated publications, none mentioned the use of PC,
indicating its uncommon implementation. In conclusion, more studies on the
interactions between the immune system and analgesics are needed to establish
better criteria for adequate implementation. Finally, we propose that
methodological sections in scientific journals should clearly document whether or
not PC was employed. If PC is not used, the reason for not using it should be
stated.
PMID- 10778782
TI - The generation of monoclonal antibodies in mice: influence of adjuvants on the
immune response, fusion efficiency and distress.
AB - The objective of this study was to find a reliable alternative to Freund's
adjuvant in order to reduce the distress imposed on the animals without impairing
the fusion efficiency for immune-positive clones. For this purpose several
commercially available adjuvants and adjuvant formulations representing different
classes of molecules were compared. Humoral responses and animals' distress
evaluated by clinical assessment and histopathological examinations were
investigated and compared to fusion efficiencies. In a first set of experiments
seven adjuvants were tested essentially to determine their potential to induce
distress. Poly(A).poly(U) and GERBU were selected for further investigations due
to their low overall toxicity. They were combined with five different antigens
and compared to the classic Freund's adjuvant system (CFA/IFA) and to control
immunizations without adjuvant. The results showed that adjuvants of very low
toxicity could induce a high fusion efficiency. According to a standardized
immunization protocol, GERBU induced polyclonal titres similar to Freund's
whereas animals treated with poly(A).poly(U) did not attain titres higher than
mice immunized with antigen in saline. Poly(A).poly(U) however, exhibited the
best fusion efficiency, Freund and GERBU were slightly less efficient. Therefore
poly(A).poly(U) and GERBU may serve as valuable alternatives to Freund's adjuvant
for generating monoclonal antibodies. Furthermore, these two adjuvants are very
easy to use.
PMID- 10778783
TI - Allometric comparison of recommendations of minimum floor areas for laboratory
animals.
AB - The recommendations for minimum floor area given in the European Convention for
the Protection of Vertebrate Animals used for Experimental and other Scientific
Purposes (1986), as well as in the Publication on the Planning and Structure of
Animal Facilities for Institutes Performing Animal Experiments of the Society for
Laboratory Animal Science (GV-SOLAS 1989), are plotted in a double logarithmic
system in order to get an allometric function of recommended floor area to body
weight. Both recommendations correspond very well with the so-called metabolic
body weight seen at the allometric exponent of 0.73 and 0.70 respectively. Thus
the recommendations in general attribute the floor space according to the
metabolic body weight of the animal. Nevertheless, despite this general rule,
some species are recommended less space than others when measured on this
allometric scale. Thus it must be questioned why, for example, rabbits, chicken
and pigs are recommended less space than other species. The general allometric
measure seems at least to be a good scale for the comparison of recommended floor
space, and for the discussion of species-specific needs for more or less space.
PMID- 10778784
TI - Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent
animal model for regulatory and mechanistic toxicology studies.
AB - Six male and six female Yucatan pigs were utilized to investigate the feasibility
of this species as a non-rodent model for routine regulatory and mechanistic
toxicology studies. This study evaluated disease surveillance and computerized
electrophysiology, along with possible gross and micropathology changes. Two pigs
were used as sentinel animals to evaluate the microbiological status of the
vendor upon arrival; the other pigs were maintained as biomonitors and to provide
baseline clinical chemistry, urinalysis, pathology and electrophysiology data.
The electrophysiology tests conducted included electrocardiography (ECG),
electroretinography (ERG) and quantitative electroencephalography (qEEG), which
achieved consistent baseline values with acceptable intrasubject variation.
Tissue cholinesterase and histochemical staining were done to determine their
suitability for testing cholinesterase compounds. Evaluation of the serum
chemistry profile demonstrated increased CPK and LDH, which was likely associated
with slight haemolysis or minor subclinical muscle stress during handling. There
were no additional clinical chemistry changes or findings in haematology,
urinalysis parameters or gross pathology. Micropathology found an absence of
background lesions which would interfere with routine toxicology studies, except
for a mild rhinitis. The aetiological agent was identified by electron microscopy
as being consistent with inclusion body rhinitis of swine, previously unreported
in miniature swine. This would most notably interfere with inhalation studies.
The anatomical and physiological similarities of the Yucatan pig, along with its
ability to accept the performance of electrophysiology tests allow this species
to be considered as a suitable model for organ system testing in toxicology
studies.
PMID- 10778785
TI - Beta-adrenoceptor inhibition for induction of acute cardiac failure in pigs.
AB - For the testing of heart assist devices most animal models of acute cardiac
failure that are usually used show certain disadvantages. We therefore developed
a new method using the beta-adrenoceptor antagonist carazolol. We administered a
bolus injection of 1 mg/kg followed by a continuous infusion of 1 mg/kg/h in
adult German 'Landrasse' pigs. Blood pressure, heart rate, cardiac output and
maximum left ventricular pressure rise time showed a significant (P < 0.05)
reduction of the control value varying between 40% and 59%. The method is
suitable for the testing of surgical approaches in heart failure.
PMID- 10778786
TI - Superovulation in vesper mice, Calomys laucha--an important biomedical model for
hantavirus and arenavirus (Rodentia-Sigmodontinae).
AB - Sigmodontine rodents are poorly studied and have not received much attention as a
reproductive model. Renewed interest in the South American rodents has been
stimulated by their link to endemic diseases that are transmitted to man. Calomys
laucha acts as a reservoir of two dangerous viruses: an arenavirus named 'Junin
virus', the aetiological agent of Argentinian haemorrhagic fever, and the
hantavirus, both of which constitute serious sanitary problems. The aim of this
study was to establish suitable conditions to superovulate the vesper mouse,
Calomys laucha. We examined the hormonal doses, the time interval between
hormones, the time-course of ovulation, and the effect of female age on the
response to exogenous hormone administration. Female mice were injected with 5-5,
8-8 or 12-15 IU of PMSG/hCG, 48 h apart, at different age intervals (from 30 to >
120 days old). The best superovulation rate was obtained with 8-8 IU PMSG/hCG.
Ovulation started about 10 h post-hCG and was completed during the next 4-5 h,
and was achieved irrespectively from the oestrus cycle stage. The number of
oocytes was influenced by the age of the females. The youngest females had only a
superovulatory response. Females older than 61 days showed both ovulatory and
superovulatory responses, although 91-120-day-old females had a high ovulatory
response. Most of the oocytes (96.5%) recovered were morphologically normal. The
genus Calomys constitutes a reproductive model completely different from
conventional laboratory rodents.
PMID- 10778787
TI - Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
assay for the mouse leptin receptor (Lepr(db)) mutation.
AB - A PCR-RFLP assay for genotyping at the mouse leptin receptor (Lepr(db)) mutation
site was developed using modified primers. The first modified primer creates an
AccI restriction site in the mutant Lepr(db) allele to distinguish between the
Lepr(db) and Lepr+ alleles whereas the second modified primer creates another
AccI site in both alleles to serve as a control for restriction enzyme digestion.
The assay is robust and works efficiently on unpurified lysates of mouse tissues
and can be applied at any age of the animal. The assay may be used as a
diagnostic tool for maintenance of stocks, introgression or other types of
crosses involving the Lepr(db) mutation.
PMID- 10778788
TI - DNA detection in hair of transgenic mice--a simple technique minimizing the
distress on the animals.
AB - The breeding of transgenic animals requires that each individual offspring be
analysed for integration of transgenic deoxyribonucleic acid (DNA), unless
exclusively homozygous animals are mated. The standard protocol for
identification of transgenic animals (Hogan et al. 1994) is based on tissue
samples and preparation of chromosomal DNA including proteinase K digestion and
phenol/chloroform extraction. The procedure described here represents a much
simpler and faster method to screen offspring for the transgene DNA. It is based
on the use of hair bulbs as sample material, which can be directly used for
polymerase chain reaction (PCR) after alkaline lysis. This protocol allows large
numbers of animals to be easily screened in a minimum amount of time. A unique
advantage though, is the reduction of the distress caused to the animals. With
respect to the 3Rs (Replacement, Reduction, Refinement), and because of technical
advantages this method may replace ear or tail clipping.
PMID- 10778789
TI - Sarcocystis muris--a rare case in laboratory mice.
AB - In a lifespan transgeneration study under standard laboratory conditions using a
total of 4682 CBA/J mice, unusual intramuscular inclusions were found in the
diaphragm, heart and skeletal muscle of one mouse using light microscopy. Located
within the myocytes, they caused no visible tissue reaction. Cross-sections of
these spherical and cystic lesions showed numerous banana-shaped structures,
identified as permanent parasitic bradyzoites, which permitted these infections
to be diagnosed microscopically as sarcocystosis.
PMID- 10778791
TI - Progress in development of immunization registries--United States, 1999.
AB - Community-based and state-based immunization registries are confidential,
population-based, computerized information systems that contain data about
children's vaccinations and represent an important tool to increase and sustain
high vaccination coverage. Immunization registries consolidate vaccination
records for children from multiple providers, provide a vaccination needs
assessment for each child, generate reminder and recall vaccination notices,
produce an official vaccination record, and provide practice-specific and
community-based vaccination coverage assessments. One of the Healthy People 2010
national objectives is to increase to 95% the proportion of children aged <6
years who are enrolled in a fully operational population-based immunization
registry. To assess the status of immunization registry development, CDC analyzed
data from the 1999 Immunization Registry Annual Report (IRAR) of 64 jurisdictions
(grantees) that receive federal immunization funds under section 317d of the
Public Health Service Act. Findings from this analysis indicate that substantial
progress has been made in the United States in developing and implementing
community-based and state-based immunization registries.
PMID- 10778790
TI - Histological characteristics of the intestinal mucosa of the rat during the first
year of life.
AB - In spite of the widespread use of rats in gastrointestinal research, there is a
lack of information on the qualitative and quantitative histological
characteristics. Therefore, a study was performed in 69 male Wistar rats with
ages ranging from one day to one year old. The features studied included: height
and number of villi in the duodenum, jejunum and ileum, and depth and number of
crypts in the duodenum, jejunum, ileum, colon and rectum. Morphometric
observations were expressed in a mathematical logarithmic curve that showed a
normal, pattern of intestinal growth for each intestinal level. The number of
villi in the small intestine decreased from 1 to 35 days of age, whereas the
other intestinal parameters all increased during the same period. After 35 days
the rates of increase or decrease were lower. The quantification of these
intestinal changes provides a new complementary pattern as a reference for
research as indicators of normality or malfunction in the rat intestine.
PMID- 10778792
TI - Palmar pallor as an indicator for anthelminthic treatment among ill children aged
2-4 years--Western Kenya, 1998.
AB - Infections with the soil-transmitted intestinal helminths (i.e., Ascaris
lumbricoides, Trichuris trichiura, and hookworm), estimated to affect
approximately 1 billion persons, are among the most common and widespread human
infections. Among children aged <5 years, intestinal helminth infections cause
malnutrition and anemia, two important causes of mortality. Anthelminthic
treatment (deworming) improves nutritional status of school-aged children. The
World Health Organization and the United Nations Children's Fund (UNICEF) have
developed guidelines that include interventions for anemia and malnutrition in
the integrated management of childhood illness (IMCI) for children aged <5 years
seen at first-level health-care facilities in developing countries. Under the
IMCI guidelines, in geographic areas where hookworm or Trichuris infections are
endemic, children aged 2-4 years with palmar pallor are treated with an
anthelminthic drug. This report summarizes an investigation of the use of palmar
pallor as an indication for anthelminthic treatment among ill children aged 2-4
years seen at first-level health-care facilities in rural western Kenya; the
investigation found that palmar pallor was associated with anemia but not with
intestinal helminth infection.
PMID- 10778793
TI - Community indicators of health-related quality of life--United States, 1993-1997.
AB - It is known that persons' longevity is affected by the environmental and
population characteristics of their community. Studies that identify community
level characteristics associated with the health-related quality of life (HRQOL)
of residents could help guide local health planning. Data from the Behavioral
Risk Factor Surveillance System (BRFSS) for 1993-1997 indicate that HRQOL differs
among U.S. counties according to county population size. In addition,
socioeconomic and health status indicators, such as poverty, noncompletion of
high school, unemployment, number of persons with severe work disabilities,
mortality, and births to adolescents, also might affect county-level HRQOL
differences. This report examines initial findings on the relation between
selected community health status indicators (CHSIs) and the mean number of days
that persons aged > or =18 years reported ill health (i.e., unhealthy days), a
surveillance measure of population HRQOL. The findings suggest that CHSIs may be
useful in the public health planning process.
PMID- 10778794
TI - Influence of ankle support on joint range of motion before and after exercise: a
meta-analysis.
AB - STUDY DESIGN: Meta-analysis. OBJECTIVE: To evaluate the effects of different
types of ankle support on ankle and foot joint range of motion before and after
activity using meta-analysis procedures. BACKGROUND: The effects of ankle support
on joint range of motion before and after exercise has been extensively studied,
but the results among studies are not consistent. Obtaining knowledge from
synthesizing the available literature with a meta-analysis can provide a greater
understanding of these effects. METHODS AND MEASURES: A total of 253 cases from
19 studies were examined and included in this analysis. The treatment variables
were ankle support with 3 levels (tape, lace-up, and semirigid) and time with 2
levels (before exercise and after exercise). Standardized effect sizes were
computed for inversion, eversion, dorsiflexion, and plantar flexion range of
motion to measure the difference between control and treatment groups at each
point in time. Effect sizes were analyzed using a mixed-model factorial analysis
of variance. RESULTS: Before exercise, the semirigid condition (-2.97 +/- 0.63)
demonstrated greater restriction compared with the tape (-2.33 +/- 0.38) and lace
up conditions (-2.18 +/- 0.86) for inversion range of motion. After exercise, the
semirigid condition (-3.85 +/- 0.64) restricted inversion range of motion more
than the tape (-1.07 +/- 0.20) and lace-up (-1.56 +/- 0.29) conditions. No
differences were found between the mean effect sizes for the tape and lace-up
conditions before and after exercise. With respect to eversion range of motion,
the semirigid support (-2.69 +/- 0.43) provided greater restraint compared with
the tape (-1.00 +/- 0.21) and lace-up (-1.40 +/- 0.47) conditions. The lace-up
condition also displayed greater support compared with tape alone. For
dorsiflexion range of motion, greatest overall support was provided by the tape
condition (-0.94 +/- 0.06) compared with the lace-up condition (-0.51 +/- 0.06).
CONCLUSIONS: The greatest restriction of motion in the frontal plane was offered
by the semirigid support condition, whereas taping offered the most support for
limiting dorsiflexion range of motion. The results of this study may help
clinicians make rational decisions concerning the selection of ankle appliances
for preventing acute or chronic reinjury.
PMID- 10778795
TI - Influence of orthopaedic clinical specialist certification on clinical outcomes.
AB - STUDY DESIGN: Effect of clinical specialization was studied in a retrospective
analysis of a commercial outcomes database. OBJECTIVE: To assess effectiveness of
care as measured by changes in health status and efficiency as measured by
visits, duration of treatment episode, and net revenue between patients treated
by clinicians with and without orthopaedic clinical specialist certification
(OCS). BACKGROUND: Clinical specialization is becoming common in physical
therapy, but there are no studies to support improved efficiency or effectiveness
with advanced practitioner competencies. METHODS AND MEASURES: A total of 258
adults treated in practices participating in the Focus on Therapeutic Outcomes
process during 1996 comprised the data set. Seven physical therapists with OCS
treated 129 patients (clinical specialist group). These patients were matched to
129 patients not treated by physical therapists with OCS (comparison group)
randomly chosen from the aggregate data set. All patients completed a
standardized health status questionnaire at initial evaluation and discharge.
Standardized response means (SRMs) were calculated to measure change during
treatment. RESULTS: Therapists with OCS were more efficient than therapists
without OCS, using fewer visits (9.1 +/- 6.7 vs 11.2 +/- 7.4) for less estimated
cost ($949 +/- $736 vs $1238 +/- $1227) during the same treatment duration (35.9
+/- 48.3 vs 35.4 +/- 25.6 days) and performed fewer treatment procedures.
Overall, there was no difference in effectiveness as measured by change in health
status, that is, unit of functional improvement per episode (0.89 +/- 1.0 SRM for
clinical specialists compared with 0.88 +/- 1.0 SRM for comparison group). The
OCS group had better value (unit of functional improvement per estimated dollar)
and utilization (unit of functional improvement per visit) for the constructs of
physical functioning (value: 1.31 +/- 2.7 vs 0.78 +/- 1.8; utilization: 1.25 +/-
2.2 vs 0.76 +/- 1.6) and role physical (value: 1.26 +/- 2.9 vs 0.44 +/- 3.5;
utilization: 1.11 +/- 1.9 vs 0.51 +/- 2.3) (SRMs for OCS group vs comparison
group, respectively). CONCLUSIONS: Our data support the conclusion that physical
therapists with OCS are more efficient compared with clinicians without OCS.
Study limitations in design, small sample size, and low number of clinicians are
discussed.
PMID- 10778796
TI - Proposed practice guidelines for nonoperative anterior cruciate ligament
rehabilitation of physically active individuals.
AB - Nonoperative management of anterior cruciate ligament (ACL) rupture has not been
a successful option for those who participate in high-level physical activity.
However, there are instances when patients may want to attempt to return to
physically demanding activities with nonoperative rehabilitation for an ACL
injury. The purpose of this commentary is to describe guidelines for nonoperative
management of physically active individuals with ACL injuries who wish to return
to preinjury levels of physical activity. The guidelines are based on the results
of 2 clinical studies that improved the overall success of nonoperative
management of physically active individuals with ACL ruptures. A decision-making
process for selecting appropriate candidates for nonoperative management
(rehabilitation candidates) is described. Individuals are classified as
rehabilitation candidates if they have no concomitant ligament or mensical damage
associated with the ACL injury, have a unilateral ACL injury, and meet all 4 of
the following criteria: (1) timed hop test score of 80% or more of the uninjured
limb, (2) Knee Outcome Survey Activities of Daily Living Scale score of 80% or
more, (3) global rating of knee function of 60% or more, and (4) no more than 1
episode of giving way since the incident injury to the time of testing.
Individuals meeting the criteria of a rehabilitation candidate undergo an
intensive rehabilitation program before returning to high-level activity. The
rehabilitation program consisting of lower extremity muscle strength training,
cardiovascular endurance training, agility and sport-specific skill training, and
a training program using balance perturbations is described.
PMID- 10778797
TI - Shoulder muscle activation during aquatic and dry land exercises in nonimpaired
subjects.
AB - STUDY DESIGN: Randomized, single blind experimental design using electromyography
to measure shoulder muscle activation in nonimpaired subjects. OBJECTIVES: To
compare the muscle activation of rotator cuff and shoulder synergists during
rehabilitation exercises performed in water or on dry land. BACKGROUND: Early
motion is critical to restoration of normal shoulder function. Aquatic therapy
has been promoted as a method for increasing range of motion while minimizing
stress on the shoulder. METHODS AND MEASURES: The integrated electromyography
amplitude of 6 muscles of the shoulder girdle was examined on the nondominant
shoulders of 6 subjects (supraspinatus, infraspinatus, and subscapularis,
anterior, middle, and posterior deltoids). Each subject performed elevation (0
degree to 90 degrees) in the scapular plane with neutral rotation on land and in
water at 3 different speeds of elevation (30 degrees/s, 45 degrees/s, and 90
degrees/s). The mean percentage of the maximal voluntary contraction was
determined for each of the 3 test speeds on land and in water. Comparisons
between water and dry land were made with a repeated measures analysis of
variance. RESULTS: For all 6 muscles tested, muscle activation during the 30
degrees/s test speed and all muscles tested at the 45 degrees/s test speed was
significantly less when performed in water versus when performed on land. For
example, electromyography activation of the supraspinatus muscle was 16.68% of a
maximal voluntary contraction when elevation at was performed at 30 degrees/s on
dry land versus 3.93% when performed in water. CONCLUSION: These data suggest
that shoulder elevation in the water at slower speeds resulted in a significantly
lower activation of the rotator cuff and synergistic muscles. This decreased
muscle activation during aquatic physical therapy allows for earlier active
motion in the postoperative period without compromising patient safety.
PMID- 10778798
TI - Effects of isometric quadriceps activation on the Q-angle in women before and
after quadriceps exercise.
AB - STUDY DESIGN: Single-group test-retest design with correlation analysis.
OBJECTIVES: (1) To confirm that the Q-angle decreases with isometric quadriceps
activation (IQA), (2) to determine if the decrease in the Q-angle with IQA is
related to the magnitude of the Q-angle at rest, and (3) to determine if a
vigorous bout of exercise affects the change in the Q-angle with IQA. BACKGROUND:
The Q-angle represents an estimate of the resultant force of the quadriceps on
the patella and is a predictor of lateral movement of the patella under dynamic
conditions. METHODS AND MEASURES: Q-angles were assessed in 22 nonimpaired women
(mean +/- SD age, 22.3 +/- 4.9 years) while standing relaxed and during IQA.
Subjects then rode a cycle ergometer until a preset number of repetitions per
minute was unable to be maintained. Q-angles were again assessed while subjects
were relaxed and during IQA. RESULTS: There was a significant decrease (mean +/-
SD, 5.7 +/- 4.2 degrees) in the Q-angle with IQA compared with relaxed standing.
There was a significant relationship (r=0.72) between the Q-angle at rest and the
change with IQA. The cycle ergometer exercise resulted in a small (0.5 degrees)
but significantly greater decrease in the Q-angle with IQA compared with relaxed
standing. CONCLUSIONS: The Q-angle decreases with IQA, and the magnitude of this
decrease is dependent on the magnitude of the Q-angle at rest. Our findings
support the view that an excessive Q-angle may predispose women to greater
lateral displacement of the patella during vigorous activities and sports in
which the quadriceps muscle is stressed.
PMID- 10778799
TI - Plantar fasciitis.
PMID- 10778800
TI - Relationship between the pixel value in digital subtraction angiography and
iodine concentration: study in high iodine concentration with original phantom.
AB - Quantitative digital subtraction angiography (DSA) image analysis based on
densitometry is widely accepted and used. For the densitometoric DSA image
analysis, it is required that there is a linear relationships between the pixel
values on DSA images (DSA values) and contrast medium iodine concentration or the
thickness of the vessels or the chambers filled with contrast material. We
studied on relationship between the DSA value and iodine concentration especially
in high iodine concentration. As for the relationship between DSA values and
iodine concentration on the DSA images at low concentration, DSA phantom had a
good linear relationship. However, the relationship at the high iodine
concentration, DSA phantom sometimes lost this linear relationship. Our results
suggested that it was necessary to identify relationship between DSA values and
iodine concentration in each DSA system, especially in high iodine concentration
setting, for densitometoric DSA image analysis.
PMID- 10778801
TI - HLA-DR expression of synovium and correlation with clinical features of patients
with rheumatoid arthritis.
AB - To investigate whether the expression of human leukocyte antigen-DR (HLA-DR) in
synovial tissues obtained at synovectomy contributes to the clinical features of
patients with rheumatoid arthritis (RA), immunohistochemical analysis was
performed to determine the intensity and pattern of HLA-DR expression in synovial
tissue from 96 patients with RA. The clinical features before and 1 year after
the synovectomy were investigated. At the time of the surgery, duration of
morning stiffness was associated with the degree of HLA-DR expression in synovial
lining layer, and this synovial lining expression of HLA-DR was more frequently
observed in elbow and wrist joints than in knee joint. In patients who underwent
knee synovectomy, erythrocyte sedimentation rate and C-reactive protein level one
year after the surgery were significantly higher in the patients with intense
expression of HLA-DR in the synovial lining. Our findings showed that the
expression of HLA-DR in the synovial lining contributes to several clinical
features, and the expression in large joint such as knee may related with disease
course of patients with RA.
PMID- 10778802
TI - The prevalence of serum GB virus C/hepatitis G virus RNA and anti-E2 in Japanese
children without a history of blood transfusion.
AB - The prevalence of serum GB virus C (GBV-C)/Hepatitis G virus (HGV) RNA and anti
E2 was investigated in Japanese children younger than 16 years of age without a
history of blood transfusion and the family members of serum GBV-C/HGV RNA
positive children. The prevalences of serum GBV-C/HGV RNA and anti-E2 were 0.5%
(5/1000) and 0% (0/330), respectively. Viral RNA was also detected in the mothers
of all five GBV-C/HGV RNA-positive children and in two of their siblings.
Sequence determinations indicated the likelihood of mother-to-infant transmission
in all cases. The presence of the virus persisted for at least 10-18 months in
all 5 children, without any appearance of anti-E2.
PMID- 10778803
TI - A questionnaire survey on current surgical procedures for endometrial cancer in
Japan.
AB - The current standards for surgical procedures and lymph node dissection of
endometrial cancer in Japan were investigated using a questionnaire survey. The
estimated clinical stages used in the questionnaire were predicted from
preoperative diagnostic imaging, histopathology of endometrial biopsies and
intraoperative findings using a new classification, Federation Internationale de
Gynecologie et d'Obstetrique (FIGO) in 1988. Questionnaires were mailed to 235
institutions, and 212 institutions (90.2%) responded. As a standard surgery for
endometrial cancer, institutions performed simple total hysterectomy or
semiradical hysterectomy and bilateral adnexectomy, which accounted for 86% of
all respondents. For stage I carcinoma, simple (44%) or semi-radical (47%)
hysterectomy was carried out in 91% of institutions, while radical hysterectomy
was selected in 84% of institutions when stage II carcinoma was diagnosed
clinically. The consensus of this survey was that dissection of both the para
aortic and pelvic lymph nodes can be omitted in G1 cases showing lesions confined
to the endometrium, and that pelvic lymph nodes should be dissected, but para
aortic lymph node dissection could be omitted in G1 or G2 cases demonstrating
myometrial invasion of 1/2 or less. Moreover, findings from this survey suggest
that biopsy or dissection of the para-aortic lymph nodes was required in G3
cases, or in those patients diagnosed with myometrial invasion more than 1/2.
PMID- 10778804
TI - The absence of impairment of cliff avoidance reaction induced by subchronic
methamphetamine treatment in inbred strains of mice.
AB - Cliff avoidance reaction (CAR), an index of behavioral teratology in rodents, can
be impaired by motor, arousal, or cognitive dysfunction. We formerly reported
subchronic administration of methamphetamine (MAP) induced the CAR impairment,
which might reflect MAP-induced cognitive dysfunction, in three strains of rats.
In this study, the effects of subchronic MAP treatment on the behavioral
sensitization in stereotypy (stereotypy sensitization) and CAR were examined in
two inbred strains of male mice; C57BL/6J(C57) and DBA/2J(DBA). The animals
received 4 mg/kg/day MAP intraperitoneally for 28 days. There were apparent
strain differences in the development of stereotypy sensitization induced by
chronic MAP; DBA mice developed stereotypy sensitization quickly, but C57 did
not. Unlike rats, neither strains of mice showed the CAR impairment. These
results suggest that chronic MAP (4 mg/kg) administration did not introduce any
cognitive dysfunction measured by CAR in the two inbred mice, DBA and C57. The
discrepancy between rats and mice is still unclear. It might relate to the
species-selective effect of MAP on the CAR impairment. Further studies should to
be required.
PMID- 10778805
TI - PCR and RFLP analysis for identification and typing of Helicobacter pylori
strains isolated from gastric biopsy specimens.
AB - Helicobacter pylori (H. pylori) infection is the most common gastrointestinal
tract infection which plays an important role in the ethiopathogenesis of peptic
ulcer and gastritis. In recent years, molecular biological methods have been
presented for detection of H. pylori in addition to histopathological and
microbiological methods. Among these methods, polymerase chain reaction (PCR) and
following restriction fragment length polymorphism analyses (RFLP) are highly
sensitive methods for diagnosis and follow up of patients. In this present study
our aim was to amplify H. pylori urease A and B genes by PCR and perform RFLP
analysis. Gastric biopsy specimens from 17 female and 18 male patients were
included in the study. Amplified PCR products were subjected to RFLP analysis and
typing of the bacteria in pre and posttreatment specimens were performed. H.
pylori urease A and B gene amplification was observed in 32 pretreatment samples
and in 8 of 21 posttreatment specimens. As a result, PCR is a sensitive method to
determine the H. pylori infection. RFLP, which is another effective method in
order to demonstrate the reinfection of H. pylori.
PMID- 10778806
TI - Ceramide-induced cell death in cultured rat retinal pigment epithelial cells.
AB - We investigated whether retinal pigment epithelial (RPE) responds to ceramide, a
known second messenger of apoptosis. RPE cells were isolated by 6-8 day old Long
Evans rat eye. We used MTS assay for viability test, and used Hoechst 33552 and
propidium iodide for apoptotic cell staining. In cultured rat RPE cells, the
addition of membrane-permeable ceramide induced apoptosis-like cell death
rapidly. RPE cell death was dependent on C2-ceramide concentration. The effective
dose (ED50) of C2-ceramide was 23.64 microM. Ceramide-induced RPE cell death was
inhibited by zVAD-fmk, a CPP32-like protease inhibitor. Our findings indicated
that ceramide in RPE cell death functions upstream of CPP32-like proteases.
PMID- 10778807
TI - Telomerase activity in normal ovaries and premature ovarian failure.
AB - The average age for the onset of menopause in humans is about 51 years. On the
other hand, premature ovarian failure (POF) is generally defined as the onset of
menopause before the age of 40 years. Telomeres have been extensively examined as
a mitotic clock. Telomeric DNA is elongated by telomerase. We analyzed the
telomerase activity of 20 patients with normal ovaries and 5 patients with POF.
Telomerase activity was present in the normal ovaries, however it decreased with
age. Eight normal ovaries under 38 years of age showed significantly higher
telomerase activity among the women with a regular menstrual cycle. Two POF
patients showed high telomerase activity and 3 showed low telomerase activity.
Our findings indicate that telomerase is present in the normal human ovary and
that telomerase activity decreases with age. Patients with follicle dysfunction
showed high telomerase activity and those with follicle depletion showed very low
telomerase activity. Based on these results, we speculated that the decline of
telomerase activity in the ovary is related to primordial follicle depletion with
age and telomerase activity can be used as a marker of the ovarian functional
age.
PMID- 10778808
TI - Better health care decisions: fulfilling the promise of health services research.
PMID- 10778809
TI - Uninsured and unstably insured: the importance of continuous insurance coverage.
AB - OBJECTIVE: To examine the importance of continuous health insurance for access to
care by comparing the access and cost experiences of insured adults with a recent
time uninsured to the experiences of currently uninsured adults and experiences
of adults with no time uninsured within a reference time period (continuously
insured). DATA SOURCES: Adults ages 18-64. Data draw from three different survey
databases: the Robert Wood Johnson Foundation 1996-1997 Community Tracking
Survey, the Kaiser/Commonwealth 1997 National Survey of Health Insurance, and the
1995-1997 Kaiser/Commonwealth State Low Income Surveys. STUDY DESIGN: The study
groups individuals into three insurance categories based on respondents' reports
of insurance coverage within a reference time period: continuously insured;
insured when surveyed but with recent time uninsured; and currently uninsured. In
the two Kaiser/Commonwealth surveys the recently uninsured group included any
insured respondent with a time uninsured in the past two years. In the Community
Tracking Survey, the recently uninsured group included any insured respondent
with a time uninsured in the past year. Measures of access include foregoing
health care when needed, usual source of care, use of health care services,
difficulties paying for medical care, and satisfaction with care. DATA
COLLECTION: All three surveys were conducted primarily by telephone. The
Community Tracking Survey drew from 60 community sites, with an additional random
national sample. The Kaiser/Commonwealth National Survey was a random national
sample; the Kaiser/Commonwealth State Low Income Surveys included adults ages 18
64 with incomes at or below 250 percent of poverty in seven states: Minnesota,
Oregon, Tennessee, Florida, Texas, New York, and California. PRINCIPAL FINDINGS:
Compared to the continuously insured, those insured but with a recent time
uninsured were at high risk of going without needed care and of having problems
paying medical bills. This group was two to three times as likely as those with
continuous coverage to report access problems. Rates of access and cost problems
reported by insured adults with a recent time uninsured neared levels reported by
those who were uninsured at the time of the survey. These two groups also rated
care received more negatively than did adults with continuous insurance coverage.
In general, the access gap between persons insured and uninsured widened as a
result of distinguishing insured adults with a recent time uninsured from insured
adults with no time uninsured. CONCLUSION: Studies that focus on current
insurance status alone will underestimate the extent to which having a time
uninsured during the year contributes to access difficulties and undermines
quality of care, and will underestimate the proportion of the population at risk
because they are uninsured. Policy reforms are needed to maintain continuous
insurance coverage and avoid spells uninsured. Currently uninsured and unstably
insured adults are both at high risk.
PMID- 10778810
TI - Promises unfulfilled: implementation of expanded coverage for the elderly poor.
AB - OBJECTIVE: To examine implementation of the Qualified Medicare Beneficiary (QMB)
and Specified Low-Income Medicare Beneficiary (SLMB) programs, enacted in 1988.
The article summarizes the origin of the QMB and SLMB programs, describes what we
have learned about QMB and SLMB enrollment in state Medicaid programs and,
despite some encouraging news on the federal front, identifies policy issues that
remain in assuring access to health care for the low-income elderly. SOURCE:
Based in part on research that assessed state variations in Medicaid QMB and SLMB
enrollment of low-income Medicare beneficiaries and identified best practices
among states in administration of the QMB and SLMB programs. STUDY DESIGN:
Telephone interviews were conducted with officials in ten states to elicit
qualitative information about how state Medicaid programs have implemented
federal protections for low-income Medicare beneficiaries. PRINCIPAL FINDINGS:
The QMB and SLMB programs fail to reach a sizable proportion of potentially
eligible individuals in most states. Fragmentation of Medicare and Medicaid
benefits, complex Medicaid eligibility and income verification processes, and
rigid federal and state administrative and data systems, impede efforts to
achieve promised protection for low-income elderly persons. CONCLUSIONS: For low
income Medicare beneficiaries, obtaining financial protection against their high
out-of-pocket health care costs remains an important issue. The complexities
associated with aligning Medicare and Medicaid to deliver health benefits to low
income older persons makes improved coordination across federal and state
agencies uncertain.
PMID- 10778811
TI - Does type of health insurance affect health care use and assessments of care
among the privately insured?
AB - OBJECTIVE: To inform the debate about managed care by examining how different
types of private insurance-indemnity insurance, PPOs, open model HMOs, and closed
model HMOs-affect the use of health services and consumer assessments of care.
DATA SOURCES/DATA COLLECTION: The 1996-1997 Community Tracking Study Household
Survey, a nationally representative telephone survey of households, and the
Community Tracking Study Insurance Followback Survey, a supplement to the
Household Survey, which asks insurance organizations to match household
respondents to specific insurance products. The analysis sample includes 27,257
nonelderly individuals covered by private insurance. STUDY DESIGN: Based on
insurer reports, individuals are grouped into one of the four insurance product
types. Measures of service use include ambulatory visits, preventive care use,
hospital use, surgeries, specialist use, and whether there is a usual source of
care. Consumer assessments of care include unmet or delayed care needs,
satisfaction with health care, ratings of the last physician visit, and trust in
physicians. Estimates are adjusted to control for differences in individual
characteristics and location. PRINCIPAL FINDINGS: As one moves from indemnity
insurance to PPOs to open model HMOs to closed model HMOs, use of primary care
increases modestly but use of specialists is reduced. Few differences are
observed in other areas of service use, such as preventive care, hospital use,
and surgeries. The likelihood of having unmet or delayed care does not vary by
insurance type, but the reasons that underlie such access problems do vary:
enrollees in more managed products are less likely to cite financial barriers to
care but are more likely to perceive problems in provider access, convenience,
and organizational factors. Consumer assessments of care-including satisfaction
with care, ratings of the last physician visit, and trust in physicians-are
generally lower under more managed products, particularly closed model HMOs.
CONCLUSIONS: The type of insurance that people have-not just whether it is
managed care but the type of managed care-affects their use of services and their
assessments of the care they receive. Consumers and policymakers should be
reminded that managed care encompasses a variety of types of insurance products
that have different effects and may require different policy responses.
PMID- 10778812
TI - The effect of marginal tax rate on the probability of employment-based insurance
by risk group.
AB - RESEARCH OBJECTIVE: To evaluate the effect of the tax subsidy on participation in
employment-based health insurance for high- and low-risk individuals. The total
exclusion of employer-paid health insurance premiums from taxable income has
frequently been seen as contributing to excess insurance and hence welfare loss.
However, less attention has been paid to quantifying the extent to which the tax
subsidy mitigates the deleterious effects of adverse selection on the health
insurance market. Adverse selection reduces pooling in an insurance market, so
that high-risk individuals are either unable to obtain coverage or are forced to
pay premiums that are unaffordable to all but the wealthiest. If there is an
external benefit to society of an individual's purchase of medical care, then the
presence of adverse selection may reduce the purchase of health care below the
socially optimal level. Therefore, a mechanism for enhancing access to insurance
and ultimately to medical care for high-risk individuals may be socially
desirable. STUDY DESIGN: Data from the March 1996-March 1998 Current Population
Survey (CPS). For each observation in the sample, state and federal income tax
liability is calculated using code based on the ACIR Significant Features of
Fiscal Federalism. The probability of having employment-based coverage in either
one's own name or as a dependent is evaluated as a function of demographic
variables such as age, education, marital status and family size, family income,
type of employment, employer size, occupation, location, marginal tax rate, risk
group (determined by self-assessed health status), and an interaction between
risk group and tax rate. CPS data do not identify individuals who have declined
offered coverage. Under alternative models of employer group decision making, the
tax subsidy will have an important influence on the employer's decision to offer
coverage. If offered, high-risk individuals accept coverage, while some low-risk
individuals may decline coverage. PRINCIPAL FINDINGS: For all individuals, the
probability of having coverage is an increasing function of the marginal tax
rate. Those classified as high-risk because their own or a family member's self
assessed health status is fair or poor are less likely to have coverage than
those considered low-risk. The effect of the tax subsidy on insurance coverage is
greater for high-risk individuals than for individuals classified as low-risk.
CONCLUSIONS: These preliminary results indicate that high-risk individuals
benefit from the tax subsidy by increased access to employment-based coverage.
Therefore, welfare loss from excess levels of health insurance may be mitigated
by welfare gain through expanded access to health insurance and hence to health
care for high-risk individuals. IMPLICATIONS FOR POLICY, DELIVERY, OR PRACTICE:
Elimination or reduction of the tax exclusion of health insurance premiums may
have the unintended consequences of disproportionately reducing the probability
of obtaining coverage in the employment-based market for high-risk individuals.
PMID- 10778814
TI - Mental health parity legislation: much ado about nothing?
AB - OBJECTIVE: To determine whether state-level parity legislation has led to an
increase in utilization of mental health services. DATA SOURCES: Healthcare For
Communities (HCC), a multi-site nationally representative study sponsored by the
Robert Wood Johnson Foundation that tracks health care system changes for mental
health and substance abuse treatment. Information on state-level parity
legislation was provided by state offices of the National Alliance for the
Mentally Ill (NAMI); local and state market data come from the Area Resource
File; information on other health mandates from Blue Cross/Blue Shield. STUDY
DESIGN: Two-stage regressions are used to estimate the effect of state parity
legislation on use of any mental health services, use of specialty mental health
services, and number of specialty visits in the past year. In the first stage, we
predicted the probability that a state decides to pass parity legislation as a
function of state health care market indicators and previous legislative
activity. The fitted probability is used in the second stage to determine the
effect of this legislation on access and utilization. PRINCIPAL FINDINGS: State
parity legislation is not associated with a significant increase in any of our
measures of mental health services utilization. These results are robust to
various specifications of the models. CONCLUSIONS: Those states that are able to
pass parity legislation do not experience significant increases in the
utilization of mental health services. This may be due in part to a loss of
coverage for those people most at risk for mental health disorders. The results
could be very different, however, if strong federal legislation were passed.
PMID- 10778813
TI - Health insurance may be improving--but not for individuals with mental illness.
AB - OBJECTIVE: To explore the question of how insurance coverage has changed among
individuals with mental problems compared to the general population in the last
two years. DATA SOURCES: HealthCare for Communities, a national survey to track
health system changes. PRINCIPAL FINDINGS: The percentage of uninsured persons in
the general population has not changed very much, and more respondents believe
that health insurance coverage has improved rather than deteriorated over the
years 1996 to 1998. However, among individuals with probable mental health
disorders, more have lost insurance in those two years than have gained it and
more report decreases in health benefits. Individuals with worse mental health
consistently report a deterioration of access to care compared to individuals
with better mental health. CONCLUSIONS: Substantial activity has taken place in
state and federal legislation to increase the mental health benefits offered by
health insurance. Although this activity could have improved health insurance
especially for individuals with mental illness, such persons continue to fare
significantly worse than the general population.
PMID- 10778815
TI - Utilization of specialty mental health care among persons with severe mental
illness: the roles of demographics, need, insurance, and risk.
AB - OBJECTIVE: To examine the sociodemographic, need, risk, and insurance
characteristics of persons with severe mental illness and the importance of these
characteristics for predicting specialty mental health utilization among this
group. DATA SOURCE: The Healthcare for Communities survey, a national study that
tracks alcohol, drug, and mental health services utilization. Data come from a
telephone survey of adults from 60 communities across the United States, and from
a supplemental geographically dispersed sample. STUDY DESIGN: Respondents were
categorized as having a severe mental disorder, other mental disorder, or no
measured mental disorder. Differences among groups in sociodemographics (gender,
marital status, race, education, and income), insurance coverage, need for mental
health care (symptoms and perceived need), and risk indicators (suicide ideation,
criminal involvement, and aggressive behavior) are examined. Measures of service
use for mental health care include emergency room, inpatient, and specialty
outpatient care. The importance of sociodemographics, need, insurance status, and
risk indicators for specialty mental health care utilization are examined through
logistic regression. PRINCIPAL FINDINGS: The severely mentally ill in this study
are disproportionately African American, unmarried, male, less educated, and have
lower family incomes than those with other disorders and those with no measured
mental disorders. In a 12-month period almost three-fifths of persons with severe
mental illness did not receive specialty mental health care. One in five persons
with severe mental illness are uninsured, and Medicare or Medicaid insures 37
percent. Persons covered by these public programs are over six times more likely
to have access to specialty care than the uninsured are. Involvement in the
criminal justice system also increases the probability that a person will receive
care by a factor of about four, independent of level of need. The average number
of outpatient visits for specialty care varies little across type of disorder,
and the median number of visits (ten) is equivalent for those with a severe
mental illness and those with other disorders. CONCLUSIONS: Persons with severe
mental illness have a high level of economic and social disadvantage. Barriers to
care, including lack of insurance, are substantial and many do not receive
specialty care. Public insurance programs are the major points of leverage for
improving access, and policy interventions should be targeted to these programs.
Problems of adequate care for the severely mentally ill may be exacerbated by the
managed care trend to reductions in intensity of treatment.
PMID- 10778816
TI - Community effects on access to behavioral health care.
AB - OBJECTIVE: To explore the effects of community-level factors on access to any
behavioral health care and specialty behavioral health care. DATA: Healthcare for
Communities household survey data, merged to supplemental data from the 1990
Census Area Resource File, 1995 U.S. Census Bureau Small Area Estimates, and 1994
HMO enrollment data. STUDY DESIGN: We use a random intercept model to estimate
the influences of community-level factors on access to any outpatient care, any
behavioral health care conditional on having received outpatient care, and any
specialty behavioral health care conditional on having received behavioral health
care. DATA COLLECTION: HCC data were collected in 1997 from about 10,000
households nationwide but clustered in 60 sites. PRINCIPAL FINDINGS: Individuals
in areas with greater HMO presence have better overall access to care, which in
turn affects access to behavioral health care; individuals in poorer communities
have less access to specialty care compared to individuals in wealthier
communities. CONCLUSIONS: Our findings of lower access to specialty care among
those in poor communities raises concerns about the appropriateness and quality
of the behavioral health care they are receiving. More generally, the findings
suggest the importance of considering the current status and expected evolution
of HMO penetration and the income level in a community when devising health care
policy.
PMID- 10778817
TI - Individual income, income inequality, health, and mortality: what are the
relationships?
AB - OBJECTIVE: To examine the pathways between income inequality, self-rated health,
and mortality in the United States. DATA SOURCE: The first National Health and
Nutrition Examination Survey and Epidemiologic Follow-up Study. DESIGN: This was
a longitudinal, multilevel study. DATA COLLECTION: Baseline data were collected
on county income inequality, individual income, age, sex, self-rated health,
level of depressive symptoms, and severity of biomedical morbidity from physical
examination. Follow-up data included self-rated health assessed in 1982 through
1984 and mortality through 1987. PRINCIPAL FINDINGS: After adjustment for age and
sex, income inequality had a modest independent effect on the level of depressive
symptoms, and on baseline and follow-up self-rated health, but no independent
effect on biomedical morbidity or subsequent mortality. Individual income had a
larger effect on severity of biomedical morbidity, level of depressive symptoms,
baseline and follow-up self-rated health, and mortality. CONCLUSION: Income
inequality appears to have a small effect on self-rated health but not mortality;
the effect is mediated in part by psychological, but not biomedical pathways.
Individual income has a much larger effect on all of the health pathways.
PMID- 10778818
TI - Do quality report cards play a role in HMOs' contracting practices? Evidence from
New York State.
AB - OBJECTIVE: To answer two related questions: (1) Do managed care organizations
(MCOs) in New York State (NYS) consider quality when they choose cardiac
surgeons? (2) Do they use information about risk-adjusted mortality rates (RAMR)
provided in the New York State Cardiac Surgery Reports? DATA SOURCES: (1)
Telephone interviews with and contracting data from the majority of MCOs licensed
in NYS; (2) RAMR, quality outlier designation, and procedure volume for all
cardiac surgeons, as reported in the Cardiac Surgery Reports. STUDY DESIGN:
Interview data were analyzed in conjunction with patterns revealed by contracting
data. Null hypotheses that MCOs' contracting choices were random with respect to
the information published in the Cardiac Surgery Reports were tested. PRINCIPAL
FINDINGS: Sixty percent of MCOs ranked the quality of surgeons as most important
in their contracting considerations. Although 64 percent of MCOs indicated some
knowledge of the NYS Cardiac Surgery Reports, only 20 percent indicated that the
reports were a major factor in their contracting decision. Analyses of actual
contracting patterns show that in aggregate, the hypothesis of random choice
could be rejected with respect to high-quality outlier status and high procedure
volume but not for RAMR or poor-quality outlier status. The panel composition of
the majority of MCOs (80.2 percent) was within two standard deviations of the
expected mean under the null hypothesis. CONCLUSIONS: Despite a professed
preference for high-quality surgeons, the use of publicly available quality
reports by MCOs is currently low, and contracting practices for the majority of
MCOs do not indicate a systematic selection either for or against surgeons based
on their reported mortality scores. This study suggests that policy initiatives
to increase the effective use of report cards should be encouraged.
PMID- 10778819
TI - Associations between primary care physician satisfaction and self-reported
aspects of utilization management.
AB - OBJECTIVE: To evaluate the association between physician-reported utilization
management (UM) techniques in capitated physician groups and physician
satisfaction with capitated care. STUDY SETTING: 1,138 primary care physicians
from 89 California capitated physician groups in 1995. STUDY DESIGN: Eighty
percent of physicians (N = 910) responded to a mail survey regarding the UM
policies in their groups and their satisfaction with the care they deliver.
Physician-reported UM strategies measured included group-mandated
preauthorization (number of referrals requiring preauthorization, referral denial
rate, and referral turnaround time), group-provided explicit practice guidelines,
and group-delivered educational programs regarding capitated care. We also
measured two key dimensions of satisfaction with capitated care (multi-item
scales): (1) satisfaction with capitated care autonomy and quality, and (2)
satisfaction with administrative burden for capitated patients. EXTRACTION
METHODS: We constructed two multivariate linear regression models to examine
associations between physician-reported UM strategies and physician satisfaction,
controlling for demographic and practice characteristics and adjusting for
clustering. PRINCIPAL FINDINGS: Physician-reported denial rate and turnaround
time were significantly negatively associated with capitated care satisfaction.
Physicians who reported that their groups provided more guidelines were more
satisfied on both dimensions, while physicians who reported that their groups
sponsored more educational programs were more satisfied with administrative
burden. The number of clinical decisions requiring preauthorization was not
significantly associated with either dimension of satisfaction. CONCLUSIONS:
Physicians who reported that their groups used UM methods that directly affected
their autonomy (high denial rates and long turnaround times) were less satisfied
with care for capitated patients. However, a preauthorization policy for
referrals or tests was not, in and of itself, associated with satisfaction.
Indirect control mechanisms such as guidelines and education were positively
associated with satisfaction.
PMID- 10778820
TI - Comparing consumer-directed and agency models for providing supportive services
at home.
AB - OBJECTIVE: To examine the service experiences and outcomes of low-income Medicaid
beneficiaries with disabilities under two different models for organizing home
based personal assistance services: agency-directed and consumer-directed. DATA
SOURCE: A survey of a random sample of 1,095 clients, age 18 and over, who
receive services in California's In-Home Supportive Services (IHSS) program
funded primarily by Medicaid. Other data were obtained from the California
Management and Payrolling System (CMIPS). STUDY DESIGN: The sample was stratified
by service model (agency-directed or consumer-directed), client age (over or
under age 65), and severity. Data were collected on client demographics,
condition/functional status, and supportive service experience. Outcome measures
were developed in three areas: safety, unmet need, and service satisfaction.
Factor analysis was used to reduce multiple outcome measures to nine dimensions.
Multiple regression analysis was used to assess the effect of service model on
each outcome dimension, taking into account the client-provider relationship,
client demographics, and case mix. DATA COLLECTION: Recipients of IHSS services
as of mid-1996 were interviewed by telephone. The survey was conducted in late
1996 and early 1997. PRINCIPAL FINDINGS: On various outcomes, recipients in the
consumer-directed model report more positive outcomes than those in the agency
model, or they report no difference. Statistically significant differences emerge
on recipient safety, unmet needs, and service satisfaction. A family member
present as a paid provider is also associated with more positive reported
outcomes within the consumer-directed model, but model differences persist even
when this is taken into account. Although both models have strengths and
weaknesses, from a recipient perspective the consumer-directed model is
associated with more positive outcomes. CONCLUSIONS: Although health
professionals have expressed concerns about the capacity of consumer direction to
assure quality, particularly with respect to safety, meeting unmet needs, and
technical quality, our findings suggest that the consumer-directed service model
is a viable alternative to the agency model. Because public programs are under
growing pressure to address the long-term care needs of low-income people of all
ages with disabilities, the Medicaid personal assistance benefit needs to be
reassessed in light of these findings. Consumer-directed models may offer a less
elaborate and possibly less costly option for organizing supportive services at
home. Study limitations may limit the generalizability of these findings. This
was a natural experiment, in which only some counties offered both service models
and counties assigned recipients to a service model. The use of a telephone
survey excluded important recipient subsets, notably people with severe cognitive
impairments. A more definitive study would include direct observations as well as
survey approaches.
PMID- 10778821
TI - The Community Tracking Study analyses of market change: introduction.
AB - OBJECTIVE: To introduce two articles and describe methods that are common to
them. DATA SOURCES/STUDY SETTING: Interviews conducted in person in 1996/1997
with leaders of organizations involved in the financing and delivery of
healthcare. STUDY DESIGN: As part of the Community Tracking Study, 12
metropolitan statistical areas (MSAs) were selected randomly from MSAs with
populations over 200,000. Researchers made baseline site visits to these
communities and conducted from 36 to 60 interviews, depending on the size of the
site. The communities were compared to identify common patterns of change and
differences across communities. DATA COLLECTION/EXTRACTION METHODS: Researchers
conducted interviews with a broad cross-section of leaders in each community.
Interview modules were designed to obtain multiple perspectives on a question.
PRINCIPAL FINDINGS AND CONCLUSIONS: Fundamental changes in the way care is
actually delivered is likely to lag behind the extensive changes in
organizational relationships that are taking place.
PMID- 10778822
TI - Health plan competition in local markets.
AB - OBJECTIVE: To examine the structure of local health insurance markets and the
strategies health plans were using to respond to competitive pressures in local
markets in 1996/1997. DATA SOURCES/STUDY SETTING: Community Tracking Study site
visits conducted between May 1996 and April 1997 in 12 U.S. markets selected to
be nationally representative. STUDY DESIGN: In each site, 36 to 60 interviews on
local health system change were conducted with healthcare industry informants
representing health plans, providers, and purchasers. DATA COLLECTION/EXTRACTION
METHOD: Relevant data for this article were abstracted from standardized
protocols administered to multiple respondents in each site. PRINCIPAL FINDINGS:
Although the competitive threat from national plans was pervasive, local plans in
most sites continued to retain strong, often dominant, positions in historically
concentrated markets. In all sites, in response to purchaser pressures for stable
premiums and provider choice, and the threat of entry and to plans were using
three strategies to increase market share and market power: (1)
consolidation/geographic expansion, (2) price competition, and (3) product
line/segment diversification that focused on broad networks and open-access
products. In most markets, in response to the demand for provider choice, the
trend was away from ownership and exclusive arrangements with providers.
CONCLUSIONS: Although local plans were moving to become full-service regional
players, there was uncertainty about the abilities of all plans to sustain growth
strategies at the expense of margins and organizational stability, and to
effectively manage care with broad networks.
PMID- 10778823
TI - Organizing and managing care in a changing health system.
AB - OBJECTIVE: To examine ways in which the management and organization of medical
care is changing in response to the shifting incentives created by managed care.
DATA SOURCES: Site visits conducted in 12 randomly selected communities in 1996/
1997. STUDY DESIGN: Approximately 35-60 interviews were conducted per site with
key informants in healthcare and community organizations; about half were with
providers. DATA COLLECTION: A standardized interview protocol was implemented
across all sites, enabling cross-site comparisons. Multiple respondents were
interviewed on each issue. PRINCIPAL FINDINGS: A great deal of experimentation
and apparent duplication exist in efforts to develop programs to influence
physician practice patterns. Responsibility for managing care is being contested
by health plans, medical groups and hospitals, as each seeks to accrue the
savings that can result from the more efficient delivery of care. To manage the
financial and clinical risk, providers are aggressively consolidating and
reorganizing. Most significant was the rapid formation of intermediary
organizations, such as independent practice arrangements (IPAs), physician
hospital organizations (PHOs), or management services organizations (MSOs), for
contracting with managed care organizations. CONCLUSIONS: Managed care appears to
have only a modest effect on how healthcare organizations deliver medical care,
despite the profound effect that managed care has on how providers are organized.
Rather than improving the efficiency of healthcare organizations, provider
efforts to build large systems and become indispensable to health plans are
exacerbating problems of excess capacity. It is not clear if new organizational
arrangements will help providers manage the changing incentives they face, or if
their intent is to blunt the effects of the incentives by forming larger
organizations to improve their bargaining power and resist change.
PMID- 10778824
TI - Simulating the impact of medical savings accounts on small business.
AB - OBJECTIVE: To simulate whether allowing small businesses to offer employer-funded
medical savings accounts (MSAs) would change the amount or type of insurance
coverage. STUDY SETTING: Economic policy evaluation using a national probability
sample of nonelderly non-institutionalized Americans from the 1993 Current
Population Survey (CPS). STUDY DESIGN: We used a behavioral simulation model to
predict the effect of MSAs on the insurance choices of employees of small
businesses (and their families). The model predicts spending by each family in a
FFS plan, an HMO plan, an MSA, and no insurance. These predictions allow us to
compute community-rated premiums for each plan, but with firm-specific load fees.
Within each firm, employees then evaluate each option, and the firm decides
whether to offer insurance-and what type-based on these evaluations. If firms
offer insurance, we consider two scenarios: (1) all workers elect coverage; and
(2) workers can decline the coverage in return for a wage increase. PRINCIPAL
FINDINGS: In the long run, under simulated conditions, tax-advantaged MSAs could
attract 56 percent of all employees offered a plan by small businesses. However,
the fraction of small-business employees offered insurance increases only from 41
percent to 43 percent when MSAs become an option. Many employees now signing up
for a FFS plan would switch to MSAs if they were universally available.
CONCLUSIONS: Our simulations suggest that MSAs will provide a limited impetus to
businesses that do not currently cover insurance. However, MSAs could be
desirable to workers in firms that already offer HMOs or standard FFS plans. As a
result, expanding MSA availability could make it a major form of insurance for
covered workers in small businesses. Overall welfare would increase slightly.
PMID- 10778825
TI - The effect of Employee Assistance Programs use on healthcare utilization.
AB - OBJECTIVE: To estimate the effect of Employee Assistance Program (EAP) use on
healthcare utilization as measured by health claims. DATA SOURCES: A unique data
set that combines individual-level information on EAP utilization, demographic
information, and health insurance claims from 1991 to 1995 for all employees of a
large midwestern employer. STUDY DESIGN: Using "fixed-effect" econometric models
that control for unobserved differences between individuals' propensities to use
healthcare resources and the EAP, we perform our analyses in two steps. First,
for those employees who visited the EAP, we test whether post-EAP claims differ
from pre-EAP claims. Second, we combine claims data of individuals who went to an
EAP with those of individuals who did not use an EAP to test whether differences
in utilization exist between EAP users and nonusers. DATA COLLECTION METHODS:
From the EAP we obtained the date of first EAP contact for all employees who used
the service, and from the company's human resources department we obtained
limited demographic data on all employees. We obtained healthcare utilization
claims data on all employees and their dependents from the company's two
healthcare plans: a fee-for-service (FFS) plan and a health maintenance
organization (HMO) plan. PRINCIPAL FINDINGS: We found that going to an EAP
substantially increases both the probability of an alcohol, drug abuse, or mental
health (ADM) claim and the number of ADM claims in the same quarter as EAP
contact. The increased probability of an ADM claim persists for approximately 11
quarters after the initial contact, while the increased ADM charges persist for
approximately six quarters after the initial EAP contact. CONCLUSIONS: Our
results strongly suggest that the EAP is able to identify behavioral and other
health problems that may affect workplace performance and prompt EAP users to
access ADM and other healthcare. Consistent with the stated goals of many EAPs,
including the one examined in this study, this process should improve
individuals' health, family functioning, and workplace performance.
PMID- 10778826
TI - Impact of HMO market structure on physician-hospital strategic alliances.
AB - OBJECTIVE: To assess the impact of HMO market structure on the formation of
physician-hospital strategic alliances from 1993 through 1995. The two trends,
managed care and physician-hospital integration have been prominent in reshaping
insurance and provider markets over the past decade. STUDY DESIGN: Pooled cross
sectional data from the InterStudy HMO Census and the Annual Survey conducted by
the American Hospital Association (AHA) between 1993 and the end of 1995 to
examine the effects of HMO penetration and HMO numbers in a market on the
formation of hospital-sponsored alliances with physicians. Because prior research
has found nonlinear effects of HMOs on a variety of dependent variables, we
operationalized HMO market structure two ways: using a Taylor series expansion
and cross-classifying quartile distributions of HMO penetration and numbers into
16 dummy indicators. Alliance formation was operationalized using the presence of
any alliance model (IPA, PHO, MSO, and foundation) and the sum of the four models
present in the hospital. Because managed care and physician-hospital integration
are endogenous (e.g., some hospitals also sponsor HMOs), we used an instrumental
variables approach to model the determinants of HMO penetration and HMO numbers.
These instruments were then used with other predictors of alliance formation:
physician supply characteristics, the extent of hospital competition, hospital
level descriptors, population size and demographic characteristics, and
indicators for each year. All equations were estimated at the MSA level using
mixed linear models and first-difference models. PRINCIPAL FINDINGS: Contrary to
conventional wisdom, alliance formation is shaped by the number of HMOs in the
market rather than by HMO penetration. This confirms a growing perception that
hospital-sponsored alliances with physicians are contracting vehicles for managed
care: the greater the number of HMOs to contract with, the greater the
development of alliances. The models also show that alliance formation is low in
markets where a small number of HMOs have deeply penetrated the market. First
difference models further show that alliance formation is linked to HMO
consolidation (drop in the number of HMOs in a market) and hospital downsizing.
Alliance formation is not linked to changes in hospital costs, profitability, or
market competition with other hospitals. CONCLUSIONS: Hospitals appear to form
alliances with physicians for several reasons. Alliances serve to contract with
the growing number of HMOs, to pose a countervailing bargaining force of
providers in the face of HMO consolidation, and to accompany hospital downsizing
and restructuring efforts. IMPLICATIONS FOR POLICY, DELIVERY, OR PRACTICE:
Physician-hospital integration is often mentioned as a provider response to
increasing cost-containment pressures due to rising managed care penetration. Our
findings do not support this view. Alliances appear to serve the hospital's
interest in bargaining with managed care plans on a more even basis.
PMID- 10778827
TI - Outcomes monitoring and the testing of new psychiatric treatments: work therapy
in the treatment of chronic post-traumatic stress disorder.
AB - OBJECTIVE: To evaluate the effectiveness of a work therapy intervention, the
Department of Veterans Affairs (VA) Compensated Work Therapy program (CWT), in
the treatment of patients suffering from chronic war-related post-traumatic
stress disorder (PTSD); and to demonstrate methods for using outcomes monitoring
data to screen previously untested treatments. DATA SOURCES/STUDY SETTING:
Baseline and four-month follow-up questionnaires administered to 3,076 veterans
treated in 52 specialized VA inpatient programs for treatment of PTSD at
facilities that also had CWT programs. Altogether 78 (2.5 percent) of these
patients participated in CWT during the four months after discharge. STUDY
DESIGN: The study used a pre-post nonequivalent control group design. DATA
COLLECTION/EXTRACTION METHODS: Questionnaires documented PTSD symptoms, violent
behavior, alcohol and drug use, employment status, and medical status at the time
of program entry and four months after discharge from the hospital to the
community. Administrative databases were used to identify participants in the CWT
program. Propensity scores were used to match CWT participants and other
patients, and hierarchical linear modeling was used to evaluate differences in
outcomes between treatment groups on seven outcomes. PRINCIPAL FINDINGS: The
propensity scaling method created groups that were not significantly different on
any measure. No greater improvement was observed among CWT participants than
among other patients on any of seven outcome measures. CONCLUSIONS: Substantively
this study suggests that work therapy, as currently practiced in VA, is not an
effective intervention, at least in the short term, for chronic, war-related
PTSD. Methodologically it illustrates the use of outcomes monitoring data to
screen previously untested treatments and the use of propensity scoring and
hierarchical linear modeling to adjust for selection biases in observational
studies.
PMID- 10778829
TI - Routine preoperative testing before cataract surgery.
PMID- 10778828
TI - Illicit drug use and emergency room utilization.
AB - OBJECTIVE: To provide an empirical examination of the effect that chronic illicit
drug use has on emergency room (ER) utilization, controlling for the potential
biases introduced by correlation between unobservable determinants of chronic
illicit drug use and ER utilization. DATA SOURCES/STUDY SETTING: From the
National Household Survey on Drug Abuse 1994 (NHSDA94). STUDY DESIGN: Chronic
illicit drug use and ER utilization are analyzed for 5,384 females and 4,177
males in 1994. The study uses a two-stage estimation technique. In the first
stage, sociodemographic, drug use history, and drug use risk variables are used
to estimate the probability that the subject is a chronic illicit drug user
(CDU). In the second stage, the first-stage estimates provide information needed
to test for the possibility of bias in the estimation of ER utilization. This
bias is the result of the correlation between unobservable influences on the
probability that the person is a CDU and the probability that he or she uses an
ER. DATA COLLECTION/EXTRACTION METHODS: The data were collected through a
multistage stratified sampling design. With the use of this methodology, the
resulting data set provides the most comprehensive information on household drug
use. PRINCIPAL FINDINGS: Without a correction for the possibility of endogeneity
bias, chronic illicit drug use is a positive (for both males and females) and a
significant (for females only) determinant of the probability of using an ER for
medical treatment. After a correction for endogeneity, the influence of chronic
drug use remains positive and significant for females and becomes significant for
males. The corresponding change in probability for females is from 6 percent to
30 percent, while for males the increase is from an insignificant 0.1 percent to
a significant 36 percent change. CONCLUSIONS: We estimate that chronic drug-using
females and males, after adjustments for bias, increase the probability that they
use an ER by more than 30 percent compared to their casual or non-drug-using
counterparts. Therefore, policymakers and health services providers may consider
designing programs to bring primary care and prevention services to facilities
where drug users are more likely to seek access to care, within an ER setting.
PMID- 10778830
TI - Effects of influenza vaccination of health care workers on mortality of elderly
people.
PMID- 10778831
TI - Intubation ineffective in vigorous meconium-stained infants.
PMID- 10778832
TI - Estrogen-progestin increases breast cancer risk.
PMID- 10778833
TI - Screening mammography may not be effective at any age.
PMID- 10778834
TI - Do physicians who diagnose more mental health disorders generate lower health
care costs?
AB - BACKGROUND: Underrecognition and undertreatment of mental health disorders in
primary care have been associated with poor health outcomes and increased health
care costs, but little is known about the impact of the diagnoses of mental
health disorders on health care expenditures or outcomes. Our goal was to examine
the relationships between the proportion of mental health diagnoses by primary
care physicians and both health care expenditures and the risk of avoidable
hospitalizations. METHODS: We used cross-sectional analyses of claims data from
an independent practice association-style (IPA) managed care organization in
Rochester, New York, in 1995. The sample was made up of the 457 primary care
physicians in the IPA and the 243,000 adult patients assigned to their panels. We
looked at total expenditures per panel member per year generated by each primary
care physician and avoidable hospitalizations among their patients. RESULTS:
After adjustment for case mix, physicians who recorded a greater proportion of
mental health diagnoses generated significantly lower per panel member
expenditures. For physicians in the highest quartile of recording mental health
diagnoses, expenditures were 9% lower than those of physicians in the lowest
quartile (95% confidence interval, 5% - 13%). There was a trend (P = .051) for
patients of physicians in the highest quartile of recording mental health
diagnoses to be at lower risk for an avoidable hospitalization than those of
physicians in the lowest quartile. CONCLUSIONS: Primary care physicians with
higher proportions of recorded mental health diagnoses generate significantly
lower panel member costs, and their patients may be less likely to be admitted
for avoidable hospitalization conditions.
PMID- 10778835
TI - Mental health diagnoses and the costs of primary care.
PMID- 10778836
TI - The physician's role in educating patients. A comparison of mailed versus
physician-delivered patient education.
AB - BACKGROUND: Patients value receiving educational information during office
visits, but physicians often lack the time or training to satisfy this need. We
examined whether an increased physician role in educating patients is an
effective means of improving patient satisfaction. METHODS: Using a nonrandomized
controlled research design, we compared patient satisfaction with self-care
information provided by traditional direct-mail approaches and by physicians
during routine office visits. We also studied a control group of patients
receiving usual care. RESULTS: Patients who received a medical self-care book
from a physician were significantly more likely to be satisfied with their office
visit than those who received the book in the mail or those who experienced usual
care. The intervention group reported greater satisfaction with 11 out of 13
variables related to physician-patient communication and quality of care. There
were no significant differences between the control group and the direct-mail
group. CONCLUSIONS: The patients who received self-care information from their
physicians were significantly more satisfied with their care and their physician
patient communication experience than those in either the direct-mail group or
the control group. Our findings lend support to the growing evidence that
patients informed by their physicians are more satisfied with their care.
PMID- 10778837
TI - The organization and distribution of patient education materials in family
medicine practices.
AB - BACKGROUND: Millions of dollars are spent annually on the production and
distribution of patient education materials; however, there are no studies
describing their actual use by physicians. Using qualitative data from a large
comparative case study, our analysis evaluates how patient education materials
are organized and used in family practices. METHODS: Eighteen purposefully
selected family medicine practices were directly observed for 4 to 12 weeks each.
A total of 57 providers were shadowed by a research nurse, and detailed field
notes on 1600 patient encounters were recorded. A 3-member analysis team reviewed
the qualitative data and identified emergent patterns. RESULTS: Clinics' use of
patient education materials fell mostly into 2 distinct patterns. "Stockpilers"
were providers who relied on the clinic staff to develop and organize a common
library of patient education handouts. Providers with a "personal stash"
collected much smaller numbers of materials that they personally maintained.
Providers in the latter group had a known repertoire of a limited amount of
educational material and used it more often than providers with access to a
greater variety and number of handouts. In all practices, providers distributed
most handouts; staff and self-selection by patients played a minor role.
CONCLUSIONS: It appears that provider involvement and familiarity with patient
education materials are key to their use in clinical practice. Clinicians use
written patient education materials most efficiently by personally selecting and
maintaining a small number of handouts that address topics most relevant to their
practice.
PMID- 10778838
TI - Patient education in our offices.
PMID- 10778839
TI - Direct-to-consumer prescription drug advertising, 1989-1998. A content analysis
of conditions, targets, inducements, and appeals.
AB - BACKGROUND: We conducted a content analysis of consumer-targeted prescription
drug advertisements to explore trends in prevalence, shifts in the medical
conditions for which drugs are promoted, reliance on financial and nonmonetary
inducements, and appeals used to attract public interest. METHODS: We collected
the drug advertisements appearing in 18 consumer magazines from 1989 through
1998. Two judges independently coded each advertisement and placed it in a
category pertaining to the target audience, use of inducements, and product
benefits (mean kappa=0.93). We employed descriptive statistics, cross
tabulations, and curve estimation procedures. RESULTS: A total of 320 distinct
advertisements were identified, representing 101 brands and 14 medical
conditions. New advertisement and brand introductions increased dramatically
during this decade. Advertisements for drugs used for dermatologic, human
immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and
obstetric/gynecologic conditions were most common. Almost all of the
advertisements were aimed at the potential user of the drug, not third-party
intermediaries such as parents and spouses. Although most advertisements were
gender-neutral, women were more likely to be exclusively targeted. One eighth of
the advertisements offered a monetary incentive (eg, a rebate or money-back
guarantee), and one third made an offer of additional information in printed or
audio/video form. The most common appeals used were effectiveness, symptom
control, innovativeness, and convenience. CONCLUSIONS: Consumer-directed
prescription drug advertising has increased dramatically during the past decade.
The pharmaceutical industry is turning to this type of advertising to generate
interest in its products. Our data may be useful to physicians who want to stay
abreast of the treatments that are being directly marketed to their patients.
PMID- 10778840
TI - Which medicines do our patients want from us?
AB - BACKGROUND: The prescribing of medication, whether for infections or injuries,
has come under the scrutiny of health maintenance organizations (HMOs). Our goal
was to examine patient beliefs about the usefulness of certain classes of
medications. METHODS: We surveyed 244 consecutive adult patients who presented to
an urban private family medicine practice in Georgia. RESULTS: Regardless of who
paid for prescriptions (an HMO or the patient), most people in the survey would
be satisfied with over-the-counter medications and reassurance (84% for upper
respiratory infection, 72% for muscle strain, 56% for diarrhea). Few differences
were attributable to payment status (prepaid as opposed to fee-for-service).
African Americans are less likely than whites to accept reassurance as an
appropriate treatment. CONCLUSIONS: Patients may be more willing to accept
reassurance and over-the-counter medications than is commonly believed by
physicians.
PMID- 10778841
TI - Fibro-fatty nodules and low back pain. The back mouse masquerade.
AB - BACKGROUND: Few useful interventions exist for patients with persistent low back
pain. We suggest that a fibro-fatty nodule ("back mouse") may be an identifiable
and treatable cause of this and other types of pain. METHODS: We describe 2
patients with painful nodules in the lower back and lateral iliac crest areas. In
both cases, the signs and symptoms were unusual and presented at locations
distant from the nodule. One patient complained of severe acute lower abdominal
pain, and the other had been treated for chronic recurrent trochanteric bursitis
for several years. RESULTS: In both patients, symptoms appeared to be relieved by
multiple injection of the nodule. DISCUSSION: There is agreement that back mice
exist. Referred pain from the nodules might explain the distant symptoms and
signs in these cases. Multiple puncture may be an effective treatment because it
lessens the tension of a fibro-fatty nodule. CONCLUSIONS: Randomized trials on
this subject are needed. In the meantime, physicians should keep back mice in
mind when presented with atypical and unaccountable symptoms in the lower
abdomen, inguinal region, or legs.
PMID- 10778842
TI - Does the use of electronic medical records improve surrogate patient outcomes in
outpatient settings?
AB - BACKGROUND: We reviewed the evidence regarding the effectiveness of electronic
medical records (EMRs) as tools for improving surrogate patient outcomes in the
outpatient primary care setting. METHODS: We searched the MEDLINE database (1966
1999) to find relevant articles for inclusion in the systematic review. Reference
lists of retrieved publications were also searched for relevant citations. We
included original published reports of all prospective studies evaluating the use
of hybrid or complete EMR systems as a method of improving surrogate patient
outcomes in the outpatient primary care setting. Criteria for evaluation included
the use of a random study group assignment, appropriateness of control group,
blinded assessment of outcomes, number and reasons for withdrawal of subjects,
and attempts to minimize confounding interventions. RESULTS: Seven prospective
trials of complete EMRs and 9 prospective trials of hybrid EMRs were located.
Most evaluated the impact of EMR-generated reminders on provider and patient
compliance with health maintenance interventions. Findings were equally positive
for both complete and hybrid EMRs, and all but 1 trial reported positive results.
However, the methodologic quality of the trials was modest. Design problems
included lack of concurrent control groups, non-blinded outcome assessment, and
the presence of potentially confounding concurrent interventions. CONCLUSIONS:
Evidence from published trials suggests that utilization of either complete or
hybrid EMRs can improve some surrogate outpatient care outcomes. However,
rigorous trials that evaluate their impact on morbidity and mortality, and employ
current technologies are required before widespread adoption of EMRs can be
confidently recommended.
PMID- 10778843
TI - What to do until the POEMs arrive. An endothelial example.
AB - There is a growing trend toward evidence-based medicine, in which patient
oriented data are valued more highly than disease-oriented evidence (DOEs). In
the vernacular of evidence-based medicine, the old DOEs are slowly being replaced
by POEMs (patient-oriented evidence that matters). Unfortunately, POEMs do not
yet exist to meet every family-practice need. When there are no POEMs to
determine an appropriate therapeutic choice, another decision-making method must
be used. This method includes liberal use of DOEs combined with thoughtful use of
causal pathways to provide preliminary direction. This article applies that
method to an example from the growing basic science surrounding endothelial
functioning.
PMID- 10778844
TI - Culture confirmation of negative rapid strep test results.
PMID- 10778845
TI - Vitamin E does not prevent cardiovascular events in high-risk patients.
PMID- 10778846
TI - ACE inhibitors to prevent cardiovascular events in high-risk patients.
PMID- 10778847
TI - ERT and breast cancer.
PMID- 10778848
TI - Heights and weights in an overweight population: an UPRNet study. Upper Peninsula
Research Network.
PMID- 10778849
TI - Reversing neurodegeneration: a promise unfolds.
PMID- 10778850
TI - The ABCs of floral evolution.
PMID- 10778851
TI - Mechanisms of left-right determination in vertebrates.
PMID- 10778852
TI - Paul Sigler (1934-2000).
PMID- 10778853
TI - RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23
nucleotide intervals.
AB - Double-stranded RNA (dsRNA) directs the sequence-specific degradation of mRNA
through a process known as RNA interference (RNAi). Using a recently developed
Drosophila in vitro system, we examined the molecular mechanism underlying RNAi.
We find that RNAi is ATP dependent yet uncoupled from mRNA translation. During
the RNAi reaction, both strands of the dsRNA are processed to RNA segments 21-23
nucleotides in length. Processing of the dsRNA to the small RNA fragments does
not require the targeted mRNA. The mRNA is cleaved only within the region of
identity with the dsRNA. Cleavage occurs at sites 21-23 nucleotides apart, the
same interval observed for the dsRNA itself, suggesting that the 21-23 nucleotide
fragments from the dsRNA are guiding mRNA cleavage.
PMID- 10778854
TI - Modulation of RNA polymerase by (p)ppGpp reveals a RecG-dependent mechanism for
replication fork progression.
AB - We have discovered a correlation between the ability of Escherichia coli cells to
survive damage to DNA and their ability to modulate RNA polymerase via the
stringent response regulators, (p)ppGpp. Elevation of (p)ppGpp, or certain
mutations in the beta subunit of RNA polymerase, dramatically improve survival of
UV-irradiated strains lacking the RuvABC Holliday junction resolvase. Increased
survival depends on excision and recombination proteins and relies on the ability
of RecG helicase to form Holliday junctions from replication forks stalled at
lesions in the DNA and of PriA to initiate replication restart. The role of RecG
provides novel insights into the interplay between transcription, replication,
and recombination, and suggests a general model in which recombination underpins
genome duplication in the face of frequent obstacles to replication fork
progression.
PMID- 10778855
TI - Structural basis of collagen recognition by integrin alpha2beta1.
AB - We have determined the crystal structure of a complex between the I domain of
integrin alpha2beta1 and a triple helical collagen peptide containing a critical
GFOGER motif. Three loops on the upper surface of the I domain that coordinate a
metal ion also engage the collagen, with a collagen glutamate completing the
coordination sphere of the metal. Comparison with the unliganded I domain reveals
a change in metal coordination linked to a reorganization of the upper surface
that together create a complementary surface for binding collagen. Conformational
changes propagate from the upper surface to the opposite pole of the domain,
suggesting both a basis for affinity regulation and a pathway for signal
transduction. The structural features observed here may represent a general
mechanism for integrin-ligand recognition.
PMID- 10778856
TI - Reversal of neuropathology and motor dysfunction in a conditional model of
Huntington's disease.
AB - Neurodegenerative disorders like Huntington's disease (HD) are characterized by
progressive and putative irreversible clinical and neuropathological symptoms,
including neuronal protein aggregates. Conditional transgenic models of
neurodegenerative diseases therefore could be a powerful means to explore the
relationship between mutant protein expression and progression of the disease. We
have created a conditional model of HD by using the tet-regulatable system. Mice
expressing a mutated huntingtin fragment demonstrate neuronal inclusions,
characteristic neuropathology, and progressive motor dysfunction. Blockade of
expression in symptomatic mice leads to a disappearance of inclusions and an
amelioration of the behavioral phenotype. We thus demonstrate that a continuous
influx of the mutant protein is required to maintain inclusions and symptoms,
raising the possibility that HD may be reversible.
PMID- 10778857
TI - Molecular chaperones activate the Drosophila ecdysone receptor, an RXR
heterodimer.
AB - The steroid hormone 20-hydroxyecdysone coordinates the stages of Drosophila
development by activating a nuclear receptor heterodimer consisting of the
ecdysone receptor, EcR, and the Drosophila RXR receptor, USP. We show that
EcR/USP DNA binding activity requires activation by a chaperone heterocomplex
like that required for activation of the vertebrate steroid receptors, but not
previously shown to be required for activation of RXR heterodimers. Six proteins
normally present in the chaperone complex were individually purified and shown to
be sufficient for this activation. We also show that two of the six (Hsp90 and
Hsc70) are required in vivo for ecdysone receptor activity, and that EcR is the
primary target of the chaperone complex.
PMID- 10778858
TI - Exit from G1 and S phase of the cell cycle is regulated by repressor complexes
containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.
AB - We present evidence that Rb forms a repressor containing histone deacetylase
(HDAC) and the hSWI/SNF nucleosome remodeling complex, which inhibits
transcription of genes for cyclins E and A and arrests cells in the G1 phase of
the cell cycle. Phosphorylation of Rb by cyclin D/cdk4 disrupts association with
HDAC, relieving repression of the cyclin E gene and G1 arrest. However, the Rb
hSWI/SNF complex persists and is sufficient to maintain repression of the cyclin
A and cdc2 genes, inhibiting exit from S phase. HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF
then appear to maintain the order of cyclin E and A expression during the cell
cycle, which in turn regulates exit from G1 and from S phase, respectively.
PMID- 10778859
TI - Drosophila p53 is a structural and functional homolog of the tumor suppressor
p53.
AB - The importance of p53 in carcinogenesis stems from its central role in inducing
cell cycle arrest or apoptosis in response to cellular stresses. We have
identified a Drosophila homolog of p53 ("Dmp53"). Like mammalian p53, Dmp53 binds
specifically to human p53 binding sites, and overexpression of Dmp53 induces
apoptosis. Importantly, inhibition of Dmp53 function renders cells resistant to X
ray-induced apoptosis, suggesting that Dmp53 is required for the apoptotic
response to DNA damage. Unlike mammalian p53, Dmp53 appears unable to induce a G1
cell cycle block when overexpressed, and inhibition of Dmp53 activity does not
affect X ray-induced cell cycle arrest. These data reveal an ancestral
proapoptotic function for p53 and identify Drosophila as an ideal model system
for elucidating the p53 apoptotic pathway(s) induced by DNA damage.
PMID- 10778860
TI - Drosophila p53 binds a damage response element at the reaper locus.
AB - The tumor suppressor gene p53 regulates multiple cellular responses to DNA
damage, but the transcriptional targets that specify these responses are
incompletely understood. We describe a Drosophila p53 homolog and demonstrate
that it can activate transcription from a promoter containing binding sites for
human p53. Dominant-negative forms of Drosophila p53 inhibit both transactivation
in cultured cells and radiation-induced apoptosis in developing tissues. The cis
regulatory region of the proapoptotic gene reaper contains a radiation-inducible
enhancer that includes a consensus p53 binding site. Drosophila p53 can activate
transcription from this site in yeast and a multimer of this site is sufficient
for radiation induction in vivo. These results indicate that reaper is a direct
transcriptional target of Drosophila p53 following DNA damage.
PMID- 10778861
TI - Acute cold exposure decreases plasma leptin in women.
AB - We investigated whether cold exposure affects circulating leptin in humans. Five
women (age, 32+/-4 years; body mass index, 23.1+/-1.7 kg/m2) participated in two
separate trials. Subjects sat at room temperature ([RT] 24.8 degrees+/-0.3
degrees C) or in the cold (6.3 degrees+/-0.5 degrees C) for 90 minutes. During RT
exposure, plasma leptin and norepinephrine were unchanged over time. Cold
exposure significantly decreased plasma leptin by 14%, 17%, and 22% at 30, 60,
and 90 minutes, respectively (temperature x time interaction, P < .04). Plasma
norepinephrine increased by 400% to 500% (P < .001) and plasma glycerol increased
by 110% over baseline during cold exposure (temperature effect, P < .005). We
conclude that circulating leptin decreases during cold exposure, probably as a
result of activation of the sympathetic nervous system (SNS).
PMID- 10778862
TI - A study of human growth hormone and insulin gene regions in relation to metabolic
control of non-insulin-dependent diabetes mellitus.
AB - The possible association of human growth hormone (hGH) and insulin (INS) gene
regions with metabolic control in diabetes was investigated in 98 subjects with
non-insulin-dependent diabetes mellitus (NIDDM); 54 control subjects from the
same population were also studied. Two polymorphic restriction sites in the
region of the hGH cluster (BGLIIA and BGLIIB) show significant association with
both glycemic and hemoglobin A1c (HbA1c) levels. Mean values for plasma glucose
and HbA1c show a maximum in the BGLIIA *1/*1 genotype and a minimum in the BGLIIA
*2/*2 genotype. Mean values for plasma glucose and HbA1c show a maximum in the
BGLIIB *1/*2 genotype. The BGLIIA*2/BGLIIB*1 haplotype shows a negative
correlation with plasma glucose and HbA1c levels. Since the two markers are
located in the area surrounding the hGH-V locus, the expression of this gene in
NIDDM warrants further investigation.
PMID- 10778863
TI - Scavenging effect of nicorandil on free radicals and lipid peroxide in
streptozotocin-induced diabetic rats.
AB - Free radicals and lipid peroxide (LPO), easily formed in the diabetic state, play
an important role in the development of diabetic complications. Potentially,
nicorandil may reduce the production of free radicals and LPO in various organs.
In fact, increased LPO levels in the serum, kidney, and cardiac muscle of
diabetic (DM) rats were reduced by nicorandil treatment (N treatment). Xanthine
oxidase (XOD), which produces free radicals, was decreased in the liver and
increased in the kidney of DM rats compared with control rats, and these changes
were prevented by N treatment. The concentration of Cu, Zn-superoxide dismutase
(SOD) decreased in the cardiac muscle and increased in the kidney of DM rats, and
these changes returned to normal after N treatment. The decreased concentration
of Mn-SOD in the liver, kidney, and cardiac muscle from DM rats was also reversed
by N treatment. The changes in catalase and glutathione peroxidase (GSH-PX)
activities in DM rats were not improved effectively by N treatment. Another K
adenosine triphosphate (K-ATP) channel opener, tilisolol hydrochloride, had an
effect similar to that of nicorandil. The effects of nicorandil and tilisolol
were studied only in DM rats. These data imply that N treatment, as an
antioxidative therapy, may be beneficial in preventing diabetic complications due
to lipoperoxidation and free radicals in DM rats.
PMID- 10778864
TI - Linkage and association studies of the lipoprotein lipase gene with postheparin
plasma lipase activities, body fat, and plasma lipid and lipoprotein
concentrations: the HERITAGE Family Study.
AB - Lipoprotein lipase (LPL) is responsible for the hydrolysis of triglyceride (TG)
rich lipoproteins. The aims of the present study were (1) to test for potential
linkages (sib-pair method) between postheparin plasma lipase (lipoprotein and
hepatic lipase) activities, body fatness, plasma lipid concentrations, and LPL
polymorphisms (Ser447Ter and a tetranucleotide repeat) and microsatellite markers
flanking the LPL locus (D8S261 and D8S258); and (2) to investigate associations
between the LPL Ser447Ter (S447X) polymorphism and these phenotypes. Data on 190
parents and 312 adult offspring from 99 Caucasian families participating in the
HERITAGE Family Study were available for this study. Data were adjusted for the
effects of age within sex, and lipases, lipid variables, and abdominal visceral
fat were further adjusted for fat mass. A suggestive linkage was observed only
between the S447X polymorphism and very-low-density (VLDL)-apolipoprotein B (apo
B) (332 sib-pairs, P = .013). The S447X polymorphism was not associated with body
fat phenotypes or postheparin plasma LPL (PH-LPL) activity (men, P = .19; women,
P = .47). In contrast, the X447 allele carriers had lower plasma TG (men and
women, P = .01), VLDL-TG (men and women, P = .01), and VLDL-apo B (men and women,
P = .009). The relationships between the X447 allele and plasma TG, VLDL-TG, and
VLDL-apo B in both genders were observed in obese (body mass index [BMI] > or =
30 kg/m2) but not in normal-weight (BMI < 25 kg/m2) subjects. Thus, the S447X
polymorphism of the LPL gene is not associated with body fatness and postheparin
plasma lipase activities. However, the obese carriers of the X447 allele have
plasma TG, VLDL-TG, and plasma cholesterol/high-density lipoprotein cholesterol
(HDL-C) levels equivalent to those of normal-weight sedentary adults.
PMID- 10778865
TI - Voglibose administration before the evening meal improves nocturnal hypoglycemia
in insulin-dependent diabetic patients with intensive insulin therapy.
AB - Nocturnal hypoglycemia is one of the serious complications of intensive insulin
therapy in patients with insulin-dependent diabetes mellitus (IDDM; type 1 DM).
We assessed the effect of voglibose (alpha-glucosidase inhibitor) administration
before the evening meal on nocturnal hypoglycemia in IDDM patients with intensive
insulin therapy. Ten IDDM patients received 0.3 mg voglibose just before the
evening meal for 5 days. The diet and insulin regimen were not changed throughout
the study. Nocturnal plasma glucose levels (10 PM, 3 AM, and 7 AM) were studied
in these patients before and during voglibose administration. Blood glucose
levels were measured at 3 AM before and during voglibose treatment. The mean
plasma glucose level at 3 AM was 3.4+/-0.4 mmol/L before voglibose treatment and
7.3+/-1.0 mmol/L during treatment. Plasma glucose at 3 AM was elevated in 9 of 10
patients with voglibose. The decrease in plasma glucose from 10 PM to 3 AM was
6.5+/-0.8 mmol/L before voglibose administration but 3.2+/-0.9 mmol/L during
treatment (P < .01). The hypoglycemia rate was 52% (17 of 33 nights) before
voglibose administration but only 9.1% (3 of 33 nights) during treatment. We
conclude that voglibose administration before the evening meal improves nocturnal
hypoglycemia in IDDM patients with intensive insulin therapy.
PMID- 10778866
TI - Effect of tyrosine intake on the rate of phenylalanine hydroxylation in adult
males.
AB - This study evaluated the effect of varying levels of tyrosine intake on the
estimation of phenylalanine hydroxylation. Healthy men were fed 1 g protein kg(
1) x d(-1) for a 2-day period. On the third day, subjects consumed a formula diet
containing 1 g protein kg(-1) x d(-1) hourly over 10 hours, and primed hourly
oral doses of L-[15N]phenylalanine and L-[3,3-2H2]tyrosine for the last 6 hours.
Each subject was studied at 7 levels of tyrosine intake (3.0, 4.5, 6.0, 7.5, 9.0,
10.5, and 12.0 mg x kg(-1) x d(-1)) at a constant intake of phenylalanine (9 mg x
kg(-1) x d(-1), 4.55 micromol x kg(-1) x h(-1)). Phenylalanine hydroxylation was
estimated from the ratio of plasma amino acid isotope enrichment of
[15N]phenylalanine and [15N]tyrosine and the tyrosine flux estimated from
[2H2]tyrosine enrichment. Phenylalanine and tyrosine fluxes showed no significant
response to alterations in the intake of tyrosine. Linear regression analysis
showed a significant response such that the rate of phenylalanine hydroxylation
decreased as tyrosine intake increased (R2 = .21; P = .003). The mean rates of
phenylalanine hydroxylation were 3.89 to 8.06 micromol x kg(-1) x h(-1). Given
model uncertainties, the apparent protein breakdown observed at tyrosine intake
levels less than 10.5 mg x kg(-1) x d(-1), and the significant differences
observed between the present data and our prior data, we cannot estimate the
tyrosine requirement with any degree of certainty with the present hydroxylation
results.
PMID- 10778867
TI - Elevation of plasma fatty acids by ten-hour intralipid infusion has no effect on
basal or glucose-stimulated insulin secretion in normal man.
AB - There is controversy over the effect of free fatty acids (FFAs) on insulin
secretion. Previous studies have shown opposite effects of short- and long-term
exposure to elevated concentrations of FFAs. We studied 8 normal subjects (mean
age, 30 years; mean body mass index, 23.4 kg/m2) on 2 occasions. Each had a 10
hour overnight infusion of Intralipid 20% (Pharmacia, Milton Keynes, UK) with
simultaneous infusion of heparin (0.4 U/kg body weight/min) or a control infusion
of saline (150 mmol/L). Insulin secretion was assessed immediately after
completion of the 10-hour infusion by an intravenous glucose tolerance test.
Results were analyzed using paired ttests. Intralipid infusion caused an increase
in plasma FFAs of more than 9-fold (P < .01), with a simultaneous increase in
glycerol (P < .01) and hydroxybutyrate (P < .01). There was no difference in
blood glucose concentrations during the infusion or intravenous glucose tolerance
test. Similarly, insulin secretion was not significantly different during
Intralipid infusion or in the intravenous glucose tolerance test (peak insulin
achieved in glucose tolerance test, P = .51; total insulin secretion during
intravenous glucose tolerance test, P = .27). In conclusion, after increasing
plasma FFA concentrations over 9-fold during a 10-hour infusion of Intralipid and
heparin, we found no difference in basal or glucose-stimulated insulin secretion.
PMID- 10778868
TI - Correlation between fasting plasma glucose and two-hour plasma glucose during
oral glucose tolerance test in South Indians.
AB - The diagnostic criteria for diabetes have been recently revised and the fasting
plasma glucose (FPG) level reduced to 126 mg/dL, since the earlier cutoff of 140
mg/dL was considered to correspond to a much higher level than the 2-hour
postglucose (2 h PG) value of 200 mg/dL. However, there are few data directly
correlating FPG and 2 h PG during an oral glucose tolerance test (OGTT). This
study reports on a retrospective analysis of 5,936 OGTTs performed at a diabetes
center in South India and attempts to correlate the FPG and 2 h PG values. Using
a 2 h PG of 200 mg/dL or higher as the diagnostic criterion, 46.7% of the cohort
had diabetes. The corresponding values using the old FPG of 140 mg/dL or higher
and the new FPG of 126 mg/dL or higher were 31.7% and 39.8%, respectively. If the
FPG was further reduced to 118 mg/dL, the "diabetic yield" increased to 45.8%,
ie, it approached the figures based on a 2 h PG of > or =200 mg/dL. Various
regression equations were used to correlate FPG and 2 h PG values. When FPG was
used as the dependent variable, the semilogarithmic regression equation provided
the best fit, and using this model, the 2 h PG of 200 mg/dL corresponds to a FPG
of 118 mg/dL. When the 2 h PG was used as the dependent variable, the log-log
model provided the best fit, and using this model, a 2 h PG of 200 mg/dL
corresponds to a FPG of 118 mg/dL. Thus, a FPG of 118 mg/dL seems to correlate
with a 2 h PG of 200 mg/dL in South Indians.
PMID- 10778869
TI - Effect of venous drainage site on insulin action after pancreas transplantation
in the rat--is there insulin resistance and a risk for atherosclerosis?
AB - The aim of the present study was to determine the influence of the venous
drainage site on insulin homeostasis and the possible risk for atherosclerosis
development after pancreas transplantation. We studied inbred rats that received
pancreas transplants with either systemic (STX) or portal (PTX) venous drainage
after prior induction of diabetes with streptozotocin and sham-operated controls.
The observation period was 6 months. Fasting plasma glucose and insulin levels
were similar in all 3 groups, but fasting plasma glucagon levels were elevated in
STX (mean +/- SEM, 282+/-35 ng/L) in comparison to PTX rats (119+/-9 ng/L, P <
.05), although the difference versus the control group (191+/-31 ng/L) was
insignificant. Glucose utilization and hepatic glucose production (HGP), assessed
by a dose-response euglycemic-hyperinsulinemic clamp in combination with
tritiated glucose infusion, were similar in all 3 groups. The groups were also
similar with respect to the molar ratio of plasma C-peptide and insulin during
basal steady state and the metabolic clearance rate (MCR) of insulin during the
clamp studies, suggesting an unchanged hepatic insulin extraction (HIE) after
transplantation with either technique. Factors known to be related to
atherosclerosis, ie, blood pressure, intracellular magnesium, and fasting levels
of plasma cholesterol, triglycerides, and high-density lipoprotein (HDL) and low
density lipoprotein (LDL) cholesterol, were similar in all 3 groups. Light
microscopy of the aorta showed a slightly thicker intima in STX rats (24.3+/-0.5
microm, P < .05) versus PTX rats (21.4+/-0.7 microm) and control (21.4+/-0.6
microm); however, atherosclerosis-like lesions were absent in all 3 groups. In
conclusion, in a rat model with streptozotocin-diabetes and pancreas
transplantation but no need for immunosuppression, both systemic and portal
venous drainage avoid peripheral and hepatic insulin resistance; also, there is
no increased risk for atherosclerosis.
PMID- 10778870
TI - Intramuscular lipid content is increased in obesity and decreased by weight loss.
AB - The triglyceride content of skeletal muscle samples determined by lipid
extraction correlates with the severity of insulin-resistant glucose metabolism
in muscle. To determine whether this reflects increased triglyceride within
muscle fibers and to test the hypothesis that the lipid content in muscle fibers
is increased in obesity, the present study was undertaken using quantitative
histochemistry of Oil Red O staining of vastus lateralis muscle. A percutaneous
muscle biopsy was performed in 9 lean subjects, 15 obese subjects without type 2
diabetes mellitus (DM), and 10 obese subjects with type 2 DM (body mass index
[BMI], 23.4+/-1.0, 33.6+/-0.6, and 36.0+/-1.1 kg x m(-2) for lean, obese, and DM,
respectively). Eight obese and 7 DM subjects had a weight loss and reassessment
of muscle lipid content. Transverse muscle cryosections were examined by light
microscopy with quantitative image analysis (grayscale images obtained by analog
to digital conversion) to determine a lipid accumulation index (LAI) based on the
percentage of cross-sectional fiber area occupied by lipid droplets. Muscle fiber
lipid content was greater in obese individuals with DM than in lean individuals
(3.62%+/-0.65% v 1.42%+/-0.28%, P < .05) but was not different in obese
individuals without DM (2.53%+/-0.41%). Weight loss reduced the LAI from 3.43%+/
0.53% to 2.35%+/-0.31%. In summary, lipid accumulation within muscle fibers is
significantly increased in obesity and is reduced by weight loss. This provides
important information regarding the accumulation and distribution of skeletal
muscle triglyceride in type 2 DM and obesity.
PMID- 10778871
TI - Effect of stanol ester on postabsorptive squalene and retinyl palmitate.
AB - Stanol ester dissolved in margarine inhibits cholesterol absorption in general
and, despite increasing cholesterol synthesis, decreases serum total and low
density lipoprotein (LDL) cholesterol levels, but its effects on postprandial
lipid metabolism are unknown. We performed fat tolerance tests in 11 men at
baseline and during short-term stanol ester consumption without and with stanol
esters added to the test meal also containing retinol and squalene. Cholesterol,
triglycerides, retinyl palmitate, and squalene were analyzed in plasma,
chylomicrons, and very-low-density lipoprotein (VLDL) at baseline and 3, 4, 6, 9,
12, and 24 hours after the test meal. Serum total and LDL cholesterol only tended
to diminish after the 2-week stanol ester consumption. However, the proportion of
plasma plant sterol and cholesterol-precursor sterol to cholesterol was
significantly altered, suggesting that cholesterol absorption was diminished and
cholesterol synthesis was increased. Postprandial peak times of squalene and
retinyl palmitate in plasma, chylomicrons, and VLDL were significantly reduced by
stanol esters, but their concentrations in chylomicrons were unchanged. Stanol
esters reduced the VLDL squalene peak concentration by 23% (P < .05) and the
incremental area under the curve (AUIC) in plasma and VLDL by 22% and 32% (P <
.01 for both). Chylomicron remnant metabolism measured with triglycerides only
tended to diminish. The effects of stanol esters in the diet only and both in the
diet and with supplementation did not differ significantly. We conclude that
dietary stanol esters reduce postprandial lipoproteins measured with dietary
retinyl palmitate and especially squalene, and the reduction is observed even
though serum total and LDL cholesterol are only inconsistently decreased after
short-term stanol ester consumption.
PMID- 10778872
TI - Gemfibrozil metabolite inhibits in vitro low-density lipoprotein (LDL) oxidation
and diminishes cytotoxicity induced by oxidized LDL.
AB - We hypothesized that M1, a metabolite of gemfibrozil, may have antioxidant
properties because of its hydroxylated phenol ring, 5-(4-hydroxy-2,5-dimethyl
phenoxy)-2,2-dimethyl pentanoic acid. The susceptibility of low-density
lipoprotein (LDL) to oxidative modification was investigated by a method using
2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile [MeO-AMVN]) or Cu2+ as previously
reported. Conjugated dienes (CDs), lipid hydroperoxide (LPO), and thiobarbituric
acid-reactive substances (TBARS) were measured to evaluate the degree of LDL
oxidation. Oxidized LDL (OxLDL), which is used for cytotoxicity studies, was
prepared by the dialysis method using Cu2+ as the oxidation inducer. Cytotoxicity
induced by OxLDL was studied in J774 macrophages by colorimetric assay using 3
[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT assay). The
oxidative modification of LDL was inhibited by M1 in a dose-dependent manner. The
antioxidant effect of M1 on LDL oxidation was diminished by dialysis of the LDL
incubated with M1 against phosphate-buffered saline (PBS), suggesting that M1 is
hydrophilic rather than lipophilic. M1 diminished the cytotoxicity induced by
OxLDL, although it was milder versus probucol. These data suggest that this
gemfibrozil metabolite has an antioxidant effect on LDL, and thus M1 may
contribute to the antiatherogenic effects of gemfibrozil.
PMID- 10778873
TI - Preoperative feeding does not reverse postoperative insulin resistance in
skeletal muscle in the rat.
AB - Metabolic studies on injured and postoperative patients have shown impaired
glucose disposal in peripheral tissues after trauma. Using small-bowel resection
as a model of surgical trauma, we investigated whether substrate availability
could ameliorate the changes in muscle glucose uptake induced by trauma. We also
studied the effect of preoperative feeding on postoperative insulin-stimulated
insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3
kinase activity in both Wistar rats and genetically non-insulin-dependent
diabetic Goto-Kakazaki rats (GK rats). Serum glucose, insulin, plasma
epinephrine, lactate, and plasma nonesterified free fatty acids (NEFAs) were
measured as indicators of the metabolic state and surgical stress. Insulin
stimulated glucose transport was significantly reduced in fed traumatized Wistar
rats compared with fed nontraumatized rats (P < .05). Significant increases in in
vivo insulin-stimulated IRS-1-associated PI 3-kinase activity were found in fed
traumatized Wistar rats compared with fed nontraumatized Wistar rats and fasted
traumatized Wistar rats, as well as fed traumatized GK rats compared with fed
nontraumatized GK animals (all P < .017). Serum insulin concentrations were
significantly reduced in fed traumatized Wistar and GK rats compared with the
respective fed nontraumatized groups (both P < .01). Serum glucose levels were
significantly elevated in fed traumatized GK rats compared with fed
nontraumatized animals (P < .01). In the present study, preoperative feeding did
not prevent a postoperative reduction in insulin-stimulated glucose transport in
skeletal muscle. The finding that insulin-stimulated PI 3-kinase activity
increased after trauma in both Wistar and GK rats indicates that postoperative
insulin resistance is not caused by an impairment in the early steps of the
insulin signaling pathway. The postoperative decreases in serum insulin despite
high blood glucose suggest that trauma impairs the insulin response to
hyperglycemia.
PMID- 10778874
TI - Decreased hepatic expression of the low-density lipoprotein (LDL) receptor and
LDL receptor-related protein in aging rats is associated with delayed clearance
of chylomicrons from the circulation.
AB - Aging in both humans and rats is associated with the development of insulin
resistance and the ensuing alterations in the plasma lipoprotein profile. In this
study, young (2 months) and old (15 months) Sprague-Dawley (SD) rats were used to
investigate age-related alterations in the chylomicron clearance pathway.
Clearance from the blood of an intravenously injected bolus of 14C-labeled
cholesterol ester (CE) and 3H-labeled triacylglycerol (TAG) lymph chylomicrons
was markedly delayed in the old rats (P < .05). Hepatic expression of the two
principal receptors of chylomicron remnant removal, the low-density lipoprotein
(LDL) receptor and LDL receptor-related protein (LRP), was determined by ligand
blotting and immunoblotting. The old rats expressed 43%+/-7% of the level of LDL
receptor in the young animals (P < .05) and 45%+/-16% of the corresponding level
of LRP (P < .05). The results suggest that the delayed clearance of chylomicron
remnants in this animal model of aging and insulin resistance is due, at least in
part, to a decrease in the hepatic expression of LDL receptor and LRP.
PMID- 10778875
TI - Comparison of fasting plasma leptin concentrations in healthy subjects with high
and low plasma insulin.
AB - This study was initiated to evaluate the role of hyperinsulinemia in the
regulation of fasting plasma leptin. We measured plasma leptin and insulin
concentrations in 404 healthy nondiabetic subjects. For analytical purposes, the
population was divided into quartiles on the basis of the lowest (quartile 1) and
highest (quartile 4) plasma insulin response to oral glucose, and fasting plasma
leptin values in these 2 dichotomous groups were compared. The total plasma
integrated insulin response was 4-fold greater in quartile 4, associated with
significantly higher (P < .001) fasting plasma leptin (12.60+/-0.85 v8.53+/-0.56
ng/mL). Fasting plasma leptin concentrations remained significantly higher in the
hyperinsulinemic quartile when comparisons were made after subdividing the
population on the basis of gender, body mass index (BMI), or waist to hip ratio
(WHR). These results demonstrate that fasting plasma leptin concentrations are
significantly higher in hyperinsulinemic individuals, and this difference is
independent of either overall or central obesity.
PMID- 10778876
TI - High-fat diet feeding reduces the diurnal variation of plasma leptin
concentration in rats.
AB - To investigate the response of plasma leptin and its diurnal variation to graded
levels of dietary fat intake, adult (486.8+/-10.8 g), male rats (N = 52) were fed
diets containing 12%, 28%, 44%, and 60% fat for 4 weeks. The body weight gain and
abdominal fat pad weight were higher (P < .05) in groups fed diets containing 44%
and 60% fat compared with the two diets containing less fat. There were no
significant differences in terms of body weight or fat pad weight between animals
fed the two diets with higher fat content or between animals fed the two lower
fat diets. Twenty-four-hour energy expenditure was not different among the
dietary fat groups. After 3 days on the experimental diets, plasma leptin
increased (P < .03) in all dietary groups. The increases in leptin in animals fed
12% and 28% fat diets occurred primarily in the morning. In contrast, in groups
fed the two diets containing higher fat content, leptin levels increased mainly
in the afternoon. As a result, the daily variation in leptin increased (P < .05)
in the two groups fed lower-fat diets, but decreased (P < .04) in animals fed the
two higher-fat diets. These data demonstrate that short-term high-fat diet
feeding abolished the diurnal fluctuation of plasma leptin levels, which may
prevent proper leptin function and eventually contribute to the development of
obesity.
PMID- 10778877
TI - Effect of dietary omega-3 fatty acids and chronic ethanol consumption on reverse
cholesterol transport in rats.
AB - We previously showed that chronic ethanol feeding leads to a decrease of
apolipoprotein E (apoE) in high-density lipoprotein (HDL), whereas supplementing
this diet with 2.8% of total dietary calories as omega3-fatty acids (omega3FAs)
restores HDL-apoE to the control values. Since HDL containing apoE plays a major
role in reverse cholesterol transport (RCT), we measured the effects chronic
ethanol intake and omega3-FAs on RCT in the present study. Four groups of rats,
control normal fat (CN), alcohol-normal fat (AN), control omega3FA fat (CF), and
alcohol-omega3FA fat (AF), were fed their respective diets for 8 weeks, after
which hepatocytes and HDLs from each group were evaluated for RCT capacity
(cholesterol efflux from macrophages and uptake by liver cells). Compared with
the control diet (CN), chronic ethanol (AN) feeding inhibited the cholesterol
efflux capacity of HDL by 21% (P < .01), whereas omega3FA feeding (2.8% of total
dietary calories) stimulated this capacity by 79% (P < .01) and 25% (P < .01) in
CF and AF rats, respectively. With respect to cholesterol uptake by the liver,
there were no significant 3-way or 4-way interactions between the 4 factors, HDL
alcohol, HDL-fish oil, hepatocyte-alcohol, and hepatocyte-fish oil. The main
effects for HDL-alcohol, HDL-fish oil, and hepatocyte-alcohol were all highly
significant (P = .0001, .0001, and .007, respectively). There was a significant
HDL-alcohol and HDL-fish oil interaction (P = .0001). Hepatocyte-alcohol was not
a factor in any 2-way interactions. Our study indicates no evidence of an
interaction between the effects of omega3FAs and the effects of alcohol on
hepatocytes in terms of RCT function. Thus, feeding as little as 2.8% of the
total dietary calories as omega3FA not only restored the impaired RCT function of
HDL caused by chronic ethanol intake, but also enhanced by severalfold the
ability of HDL to promote RCT even in normal animals.
PMID- 10778878
TI - Blood lipid response to 20 weeks of supervised exercise in a large biracial
population: the HERITAGE Family Study.
AB - We studied the effects of 20 weeks of supervised cycle-ergometer exercise on
plasma lipids in 675 healthy, sedentary, normolipidemic white and black men and
women aged 17 to 65 years, participating in the HERITAGE Family Study. Fasting
plasma lipids were assessed twice at baseline and 24 and 72 hours after the last
exercise session and adjusted for plasma volume changes. No significant
differences from the mean baseline levels were observed for total, low-density
lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol and
apolipoprotein B (Apo B). A significant reduction (P < .01) from baseline levels
in plasma total and VLDL triglycerides was observed only in the 24-hour
posttraining specimens, reflecting a response to the last bout of exercise. High
density lipoprotein (HDL) cholesterol increased 3.6% for the combined group,
primarily due to an increase in HDL2, with an associated increase in Apo A-1 (P <
.001). No significant differences were noted in the HDL response by sex, race, or
age. An inverse correlation (r = -.241) was observed between the increase in HDL
cholesterol and change in body fat only in men, and the increase in HDL
cholesterol was unrelated to the change in maximal oxygen uptake (VO2max).
PMID- 10778879
TI - Tissue-specific actions of antidiabetic thiazolidinediones on the reduced fatty
acid oxidation in skeletal muscle and liver of Zucker diabetic fatty rats.
AB - Fatty acid overload has been proposed as a cause of decreased responsiveness in
the major insulin target tissues of the body such as muscle and liver tissue. We
therefore investigated fatty acid oxidation in soleus muscle and liver isolated
from Zucker diabetic fatty (ZDF) rats treated with thiazolidinediones, a new
class of antidiabetic agents. 14CO2 production from [14C]palmitic (C16:0) acid
was lower in the soleus muscle and liver of ZDF rats versus lean rats (P < .05).
When administered orally to ZDF rats for 2 weeks, the thiazolidinediones
troglitazone (300 mg/kg) and KRP-297 (10 mg/kg) increased palmitic acid oxidation
in the soleus muscle of ZDF rats (P < .05). KRP-297, but not troglitazone,
increased palmitic acid oxidation in the liver of ZDF rats (P < .05), and both
troglitazone and KRP-297 inhibited triglyceride accumulation in the skeletal
muscle of ZDF rats. Hepatic triglyceride accumulation in ZDF rats was inhibited
by KRP-297, but not by troglitazone. A reduction of fatty acid oxidation in the
liver of ZDF rats and an increase in response to KRP-297 were observed only when
C16:0 and C18:0 fatty acids, not C8:0, were used as substrates. Thus, there were
defects in fatty acid catabolic activity and triglyceride accumulation in the
soleus muscle and liver of ZDF rats. These results indicate that KRP-297 has
advantages over troglitazone in the amelioration of these lipid metabolic
abnormalities in insulin resistance associated with obesity.
PMID- 10778880
TI - Implication of insulin and nutritional factors in the regulation of intestinal
galactosyltransferase activity during postnatal development.
AB - In the rat small intestine, galactosyltransferases are the enzymes implicated in
the biosynthesis of glycoproteins of the brush-border membranes and mucins.
During postnatal development, the circulating insulin level increased at weaning
in parallel with the activities of intestinal galactosyltransferases on O-glycans
and N-glycans. This study deals with the role of insulin in the regulation of
galactosyltransferase activities during postnatal development. The treatment of
immature suckling rats with insulin induced a precocious increase in the
activities of the O-glycan and N-glycan galactosyltransferases, partly
reproducing the increase in galactosyltransferase activity normally found at
weaning, since the O-glycan galactosyltransferase activity increased more quickly
than the N-glycan galactosyltransferase activity. The sensitivity of the two
galactosyltransferase activities to insulin disappeared after weaning, a period
when drastic diet changes occur. In 22-day-old rats submitted to prolonged
nursing (high-fat diet), the activities of the O-glycan and N-glycan
galactosyltransferases were lower than those found in age-matched normally weaned
rats (high-carbohydrate diet), indicating a delay in the maturation of the
intestine of prolonged-nursing rats. The circulating insulin level of these
animals stayed lower than that of the age-matched weaned rats. When the prolonged
nursing animals were treated with insulin, the O-glycan and N-glycan
galactosyltransferase activities reached levels similar to those of the weaned
rats. These observations suggest that insulin is one of the maturation factors
for intestinal glycoprotein galactosylation and may be partly responsible for the
natural enhancement of intestinal galactosyltransferase activities observed
during postnatal development in relation to the dietary changes at weaning.
PMID- 10778881
TI - Inhibition of insulin gene expression by long-term exposure of pancreatic beta
cells to palmitate is dependent on the presence of a stimulatory glucose
concentration.
AB - Long-term exposure of pancreatic beta cells to elevated levels of fatty acids
(FAs) impairs glucose-induced insulin secretion. However, the effects of FAs on
insulin gene expression are controversial. We hypothesized that FAs adversely
affect insulin gene expression only in the presence of elevated glucose
concentrations. To test this hypothesis, isolated rat islets were cultured for up
to 1 week in the presence of 2.8 or 16.7 mmol/L glucose with or without 0.5
mmol/L palmitate. Insulin release, insulin content, and insulin mRNA levels were
determined at the end of each culture period. Palmitate increased insulin release
at each time point independently of the glucose concentration. In contrast,
insulin content was unchanged in the presence of palmitate at 2.8 mmol/L glucose,
but was markedly decreased in the presence of 0.5 mmol/L palmitate and 16.7
mmol/L glucose after 2, 3, and 7 days of culture. In the presence of a basal
concentration of glucose, insulin mRNA levels were transiently increased by
palmitate at 24 hours but were unchanged thereafter. In contrast, palmitate
significantly inhibited the stimulatory effects of 16.7 mmol/L glucose on insulin
mRNA levels after 2, 3, and 7 days. To determine whether the inhibitory effect of
palmitate on glucose-stimulated insulin mRNA levels was associated with decreased
insulin promoter activity, HIT-T15 cells were cultured for 24 hours in 11.1
mmol/L glucose in the presence or absence of palmitate, and insulin gene promoter
activity was measured in transient transfection experiments using the insulin
promoter-reporter construct INSLUC. INSLUC activity was decreased more than 2
fold after 24 hours of exposure to 0.5 mmol/L palmitate. We conclude that long
term exposure of pancreatic beta cells to palmitate decreases insulin gene
expression only in the presence of elevated glucose concentrations, in part
through inhibition of insulin gene promoter activity.
PMID- 10778882
TI - Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex
hormone receptor activity--a controlled crossover trial.
AB - Plant-derived estrogen analogs (phytoestrogens) may confer significant health
advantages including cholesterol reduction, antioxidant activity, and possibly a
reduced cancer risk. However, the concern has also been raised that
phytoestrogens may be endocrine disrupters and major health hazards. We therefore
assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens
on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic
subjects underwent two 1-month low-fat metabolic diets in a randomized crossover
study. The major differences between the test and control diets were an increase
in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000
kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were
obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the
end of each phase. Soy foods increased urinary isoflavone excretion on the test
diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet
decreased both oxidized LDL measured as conjugated dienes in the LDL fraction
(56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL
cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = .032), even in subjects already using
vitamin E supplements (400 to 800 mg/d). No significant difference was detected
in ex vivo sex hormone activity between urine samples from the test and control
periods. In conclusion, consumption of high-isoflavone foods was associated with
reduced levels of circulating oxidized LDL even in subjects taking vitamin E,
with no evidence of increased urinary estrogenic activity. Soy consumption may
reduce cardiovascular disease risk without increasing the risk for hormone
dependent cancers.
PMID- 10778883
TI - Plasma insulin concentration is more tightly linked to plasma leptin
concentration than is the body mass index.
AB - This study tested the hypothesis that the integrated plasma insulin response to
oral glucose is a more sensitive predictor of the fasting plasma leptin
concentration than the body mass index (BMI) or waist to hip ratio (WHR). For
this purpose, we determined the fasting plasma leptin concentration and plasma
insulin response to a 75-g oral glucose challenge in 76 healthy female subjects,
with a BMI of 19.1 to 36.6 kg/m2 and a WHR of 0.57 to 1.1. The results
demonstrated that fasting plasma leptin concentrations were significantly
correlated with both the BMI (r = .64, P < .001) and the plasma insulin response
to glucose (r = .61, P < .001), but not with the WHR (r = .27). Since the BMI and
the insulin response were also significantly related (r = .34, P = .003),
multivariate analysis was performed to determine if the BMI and insulin response
were independent determinants of the fasting leptin concentration. This analysis
indicated that both the BMI and insulin response were significantly related to
plasma leptin (P < .001). To pursue this issue further, the population was
divided into tertiles on the basis of the (1) plasma leptin concentration, (2)
BMI, and (3) integrated insulin response. The two variables that were most
closely linked to each other were the leptin concentration and insulin response.
In contrast, the BMI was relatively easily disassociated from the other two
variables. These results indicate that while both the plasma insulin response to
glucose and the BMI are significantly associated with the fasting plasma leptin
concentration, the plasma insulin response appears more closely associated with
the plasma leptin concentration.
PMID- 10778884
TI - Evaluation of the circadian profiles of serum dehydroepiandrosterone (DHEA),
cortisol, and cortisol/DHEA molar ratio after a single oral administration of
DHEA in elderly subjects.
AB - Aging is associated with a selective decline in circulating levels of
dehydroepiandrosterone (DHEA) and its sulfate, with no major changes in cortisol
secretion. In young subjects, serum levels of both DHEA and cortisol are
regulated according to a circadian rhythm, and an age-related attenuation of
DHEA, but not cortisol, circadian rhythmicity has been reported. Several trials
have evaluated the effects of DHEA supplementation in elderly subjects, although
the results are still controversial. However, no data are available on the 24
hour profile of DHEA circulating levels in elderly subjects with DHEA
administration. In the present study, we evaluated the circadian rhythms of DHEA,
cortisol, and the cortisol/DHEA molar ratio in old subjects treated with either
placebo (old-PL) or a single 50-mg dose of DHEA (old-D), both administered orally
at 0700 hours. For each variable, the circadian profiles were compared with those
obtained in young control subjects. The group of young subjects displayed a
circadian rhythm for both DHEA and cortisol serum concentrations but no rhythm
for the cortisol/DHEA molar ratio. In the old-PL group, the circadian rhythm of
DHEA was completely abolished, whereas significant rhythms for both cortisol and
the cortisol/DHEA molar ratio were observed. Particularly, at each time point,
the cortisol/DHEA molar ratio was significantly higher in these subjects versus
the young group. In the old-D group, the circadian rhythm of DHEA was completely
restored and was comparable to that observed in the young group. Analogous to the
observations in young subjects, the profile of the cortisol/DHEA molar ratio in
old-D subjects did not display any circadian rhythmicity, the values being almost
completely comparable to those observed in young controls. Our data demonstrate
that the circadian rhythm of DHEA is totally abolished in elderly subjects. A
single 50-mg dose of DHEA administered orally at 0700 hours restores the
circadian rhythmicity of serum DHEA and almost completely normalizes the 24-hour
profile of the cortisol/DHEA molar ratio in old subjects without affecting the
cortisol circadian rhythm.
PMID- 10778885
TI - Age-associated decrease in plasma cholesterol and changes in cholesterol
metabolism in homozygous Watanabe heritable hyperlipidemic rabbits.
AB - We examined the cholesterol metabolism of homozygous Watanabe heritable
hyperlipidemic (WHHL) rabbits, an animal model deficient in low-density
lipoprotein (LDL) receptors, to clarify the mechanism of the age-associated
decrease of plasma total cholesterol, one of the properties of WHHL rabbits. The
rabbits were examined at several ages: after weaning at 3 months, at sexual
maturation at 6 months, at 12 months, and at 24 months, equivalent to about 35
years of age in humans. Plasma total cholesterol, triglyceride, and phospholipid
levels decreased with aging by about 45%. These reductions were mainly dependent
on a decrease in the LDL fraction. In the liver microsomal fraction, although
there were no age-related changes in the cholesterol concentration and
cholesterol 7alpha-hydroxylase (C7H) activity, 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase activity increased and acyl-coenzyme A:cholesterol
acyltransferase (ACAT) activity decreased with aging. The lipolytic activity
varied with aging. The secretion rate of very-low-density lipoprotein (VLDL)
cholesterol as determined by injection of Triton WR-1339 decreased significantly
with aging, while the catabolic rate of VLDL cholesterol was about 2-fold higher
in the oldest group versus the young groups. From these results, we conclude that
the age-associated decrease in plasma cholesterol in WHHL rabbits is related not
only to a decrease in the secretion rate of VLDL cholesterol but also to an
increase in the catabolic rate.
PMID- 10778886
TI - Update on the use of auricular cartilage in laryngotracheal reconstruction.
AB - The pediatric otolaryngologist is often called upon to aid in the diagnosis and
management of subglottic stenosis. This report contains an update of our
experience using auricular cartilage in laryngotracheal reconstruction. A
retrospective review of the medical records at St Louis Children's Hospital
identified 43 children with subglottic stenosis. Thirty-one children were treated
by use of auricular cartilage with a success rate of 84%, and an overall 94%
success rate after revision surgery. Eight children in whom an anterior cricoid
split initially failed were secondarily treated with auricular cartilage with a
success rate of 75%. Two children initially treated with costochondral cartilage
underwent multiple reconstructive procedures with either auricular cartilage or
costochondral cartilage with an overall success rate of 50%. The remaining 2
children had long-segment tracheal stenosis and underwent repair with auricular
cartilage with a 50% success rate. We find that auricular cartilage grafts are
highly effective when used in a primary single-stage procedure in children with
grade I or II stenosis. We have had limited success with auricular cartilage in
patients with grade III stenosis and are reluctant to use it in grade IV
stenosis, long-segment tracheal stenosis, staged reconstruction, or revision of
an auricular or costal cartilage graft laryngotracheal reconstruction.
PMID- 10778887
TI - Effect on families and caregivers of caring for a child with laryngomalacia.
AB - We used a retrospective chart review and telephone interviews using a standard
format to 1) measure the outcome and psychosocial costs of caring for a child
with upper airway obstruction due to laryngomalacia and 2) develop an
epidemiologic instrument that measures the impact on the lives of families who
have a child with laryngomalacia. Forty-four patients had laryngomalacia
documented by endoscopy between 1993 and 1997. Complete follow-up information
through 1998 was available on 26 patients. Of the 44 patients, 37 were managed
expectantly and 7 (16%) required surgical intervention. Polysomnograms were
obtained on 11 before neonatal discharge. Twelve patients wore an apnea monitor
for at least 1 month. The quality of life analysis found that the majority of
caregivers were not substantially affected by caring for the stridorous child.
Loss of sleep and heightened anxiety were commonly reported by these caregivers.
Younger parents or parents with fewer than 3 other children were more affected by
caring for a child with laryngomalacia. There was no substantial loss of
workdays, increase in doctor visits, or difficulty in obtaining day care. Caring
for a child with laryngomalacia results in minor disruption of a family's
lifestyle.
PMID- 10778888
TI - Chemodenervation of the rat hemilarynx with phenol.
AB - In this study, the injection of phenol into the true vocal fold was evaluated on
a rat model as a possible treatment for adductor spasmodic dysphonia. A 10%
phenol solution was injected into the right true vocal fold. Quantitative
measurement of vocal fold adductory force showed reduction to 35% of the
preinjection value 3 months after injection (p < .05). Qualitative evaluation by
videolaryngoscopy demonstrated maintenance of the normal vocal fold range of
motion. Histologic studies showed a transient inflammatory infiltrate and
myolysis, while the vocal fold mucosa and the cricoarytenoid joints remained
undamaged. Further investigation into the potential use of phenol for treating
spasmodic dysphonia is warranted.
PMID- 10778889
TI - Arytenoid adduction: controlling vertical position.
AB - In flaccid laryngeal paralysis, the vocal process (VP) is displaced laterally and
superiorly. The arytenoid adduction procedure (AA) moves the VP medially and
caudally, closing the glottic gap. However, clinical evidence suggests that the
VP is more caudal after AA than in physiological phonation. The neurally intact
arytenoid is supported by tonic and phonatory activity of the posterior
cricoarytenoid muscle (PCA). We hypothesize that a posterior anchoring suture
could replace PCA support, achieving a more natural VP location. Cadaver larynges
were scanned with computed tomography at rest and after AA, alone or in
combination with a second arytenoid suture anchored to either the posterior
midline cricoid (PC) or the inferior thyroid cornu (IC). Each posterior suture
reduced caudal displacement of the VP during AA, but the glottic gap was wider
with the PC suture. In 3 patients undergoing AA for laryngeal paralysis, the IC
suture improved arytenoid posture and voice quality.
PMID- 10778890
TI - Laryngeal synkinesis revisited.
AB - First described in 1982, laryngeal synkinesis continues to play an important
diagnostic and therapeutic role following recurrent laryngeal nerve (RLN) injury.
Vocal fold motion impairment (formerly called "vocal cord paralysis"),
hyperadducted and hyperabducted vocal folds, and certain laryngeal spasmodic and
tremor disorders are often best explained by synkinesis. A closer look at these
mechanisms confirms that following RLN injury, immobile vocal folds may be nearly
normally functional (favorable), or spastic, hyperadducted, or hyperabducted
(unfavorable). This has resulted in a functional classification of laryngeal
synkinesis as follows: type I laryngeal synkinesis, with satisfactory voice and
airway (vocal fold poorly mobile, or immobile); type II synkinesis, with
spasmodic vocal folds and an unsatisfactory voice and/or airway; type III
synkinesis, with hyperadducted vocal folds and airway compromise; and type IV
synkinesis, with hyperabducted vocal folds, poor voice, and possible aspiration.
This classification facilitates the understanding of laryngeal pathophysiology
following RLN injuries and promotes a more scientific basis for management.
PMID- 10778891
TI - Surgical planning of the treatment of cholesteatoma and postoperative follow-up.
AB - There is no single surgical treatment of choice for aural cholesteatoma. The
extent of the cholesteatoma, the amount of preoperative destruction, and the size
of the mastoid pneumatization should guide the surgeon in choosing the type of
operation for a particular ear--which may range from a simple extraction of the
cholesteatoma (delivery) all the way to a radical mastoidectomy. It is the
clinical acumen that will determine the type of surgery for a given
cholesteatomatous ear, algorithms being of little use in the complex situation of
a pathological condition with infinite variables. However, even when the most
suitable surgical modality is chosen by the best of surgeons, the operated ear
will still be left with the innate cause of the cholesteatoma, namely, its
physiopathologic background and its tendency to develop a negative gas balance in
the middle ear. Because of this tendency to redevelop negative middle ear
pressure, insertion and reinsertion of ventilation tubes are often necessary to
prevent recurrent retractions and maintain aeration of the middle ear in
posterior tympanotomies and modified radical mastoidectomies. Further, when the
mastoid bowl is marsupialized, as in radical and modified radical
mastoidectomies, the mastoid bowl is often not self-cleansing, thus periodically
requiring the help of the otologist to keep it clean and dry. My study consisted
of a long-term follow-up of 368 cholesteatomatous ears, which were operated on
according to 6 different surgical modalities, ie, 112 radical mastoidectomies, 88
modified radicals, 72 posterior tympanotomies, 52 atticotomies, 36 deliveries,
and 8 obliterations. Of the 368 ears, 11% did not require any postoperative
toilet, whereas 89% required revisiting the surgeon periodically on an average of
every 5 months, for cleansing of the mastoid cavity or securing the aeration of
the middle ear by reinserting a ventilation tube.
PMID- 10778892
TI - Migraine and benign positional vertigo.
AB - Because inner ear symptoms are common in patients with migraine, we questioned
whether benign positional vertigo (BPV) is more common in patients with migraine
than in the general population. We reviewed the records of 247 patients seen in
our neurotology clinic over the past 5 years with a confirmed diagnosis of BPV.
Each patient had the typical history of BPV, and in each case the characteristic
torsional vertical positioning nystagmus was identified. All were interviewed
regarding migraine symptoms by means of standard International Headache Society
criteria. Migraine was 3 times more common in patients with BPV of unknown cause
than in those with BPV secondary to trauma or surgical procedures. Most patients
were cured with the particle repositioning maneuver, regardless of the cause.
Presumably, patients with migraine suffer recurrent damage to the inner ear (due
to vasospasm or some other mechanism) that predisposes them to recurrent bouts of
BPV.
PMID- 10778893
TI - Correlation of pure tone audiogram results and hearing benefit of tympanoplasty
for chronic suppurative otitis media.
AB - The aim of this study was to evaluate the correlation between pure tone audiogram
results and the subjective sensation of hearing benefit of patients who had
tympanoplasty for chronic suppurative otitis media. This is a prospective study
of 115 patients who had tympanoplasty between 1992 and 1994. The outcome,
including a pure tone audiogram and the subjective sensation of hearing benefit,
was evaluated at 1 year after operation. There were 63 (55%) patients with
subjective hearing benefit after the tympanoplasty. The subjective sensation of
hearing benefit correlated with the magnitude of the air conduction (AC)
threshold reduction, and increased from 39% for an AC reduction of less than or
equal to 10 dB to 100% for an AC reduction of more than 30 dB. The effect of the
interaural AC threshold difference on the subjective sensation of hearing was not
significant; improvement was felt by 92% of patients when the operated ear became
the better hearing ear, and by 73% of patients when the operated ear remained the
worse hearing ear. There was considerable discrepancy between the subjective
hearing benefit and the pure tone audiogram results. A combination of parameters,
including the air-bone gap, the AC threshold, and the subjective hearing change,
is recommended in reporting the results of tympanoplasty.
PMID- 10778894
TI - Endolaryngeal microsurgery at the anterior glottal commissure: controversies and
observations.
AB - There are a number of tenets regarding endolaryngeal microsurgical management of
disease that involves and/or encroaches upon the anterior glottal commissure
(AGC). They include avoidance of 1) bilateral epithelial incisions near the AGC,
2) removal of papillomatosis in the AGC, and 3) resection of bilateral keratosis
with atypia or carcinoma at the AGC. During the last 6 years, 115 patients
underwent microsurgical management of disease at the AGC: carcinoma in 20 (T1 in
15 and T2 in 5), keratosis in 41, papillomatosis in 20, and polypoid corditis
(Reinke's edema) in 34. No patients with polypoid corditis developed a synechia
or web. All cancers were successfully resected en bloc; 1 of the 20 patients
developed a microscopic local failure that was successfully re-resected
endoscopically. Eleven of the 20 cancers required excision of part of the
supraglottis to establish adequate exposure for the glottic cancer resection.
Eight of 15 patients with bilateral keratosis underwent staged resections.
Fourteen of 15 patients with bilateral papillomatosis required staged resections.
Twelve of the total 115 patients presented with a web secondary to prior
microsurgery, and 3 developed a new, clinically insignificant web. The
complications of management of disease in or near the AGC described by other
authors were not noted in this series. This success was primarily the result of
improved exposure in the AGC, which was achieved by use of larger and better
designed laryngoscopes and by resection of supraglottic tissue as necessary.
Positioning these prototype laryngoscopes was facilitated by the use of elevated
vector suspension and external counterpressure.
PMID- 10778895
TI - Montgomery Thyroplasty Implant for vocal fold immobility: phonatory outcomes.
AB - Forty-three patients with a diagnosis of unilateral vocal fold immobility
underwent thyroplasty type I with the Montgomery Thyroplasty Implant System.
Preoperative and postoperative evaluations were completed by means of
videostroboscopic, acoustic, and aerodynamic measures. Clinicians' perceptions of
vocal quality and patients' satisfaction with the surgery and vocal quality were
determined. Improvements after surgery were observed for glottal closure, vocal
fold amplitude, mucosal wave activity, average intensity, maximum intensity
range, maximum phonation time, glottal airflow, average sound pressure, and
subglottal pressure. Average postsurgical fundamental frequency values fell
within normal limits and did not display significant changes relative to
presurgical values. The clinicians' perceptual evaluations indicated an
improvement in voice quality for most patients. A majority of patients expressed
satisfaction with the surgery and resulting voice quality. The results of the
present study, in combination with the surgical advantages that have been
described for the Montgomery Thyroplasty Implant System, support the view that
this approach offers an attractive alternative for treating unilateral vocal fold
immobility.
PMID- 10778896
TI - Patterns of chromosomal aberrations in metastasizing and nonmetastasizing
squamous cell carcinomas of the oropharynx and hypopharynx.
AB - Although several cytogenetic events of the tumor progression cascade have been
identified in the past, the specific types of chromosomal alterations that lead
to the development of lymph node metastases are still unknown. Operative
specimens of 20 patients (10 patients with metastasizing tumors, 10 patients with
nonmetastasizing tumors) with squamous cell carcinomas of the oropharynx and
hypopharynx, along with the corresponding lymph node metastases, were
investigated by quantitative DNA measurements and comparative genomic
hybridization (CGH). Nonmetastasizing tumors (N0) displayed overrepresentations
on chromosomes 10q (8 cases); 5p (7 cases); 3q and 20q (6 cases each); 8q (5
cases); 1p and 21q (4 cases each); 7p and 20p (3 cases each); and 2p, 15q, and
19q (2 cases each). Loss of chromosomal material was found on 5q, 9p, and 14q (2
cases each). Metastasizing tumors (N+) demonstrated overrepresentations on
chromosomes 5p, 15q, and 22q (6 cases each); 3q and 11q13 (5 cases each); 20p and
21q (4 cases each); and 10q (3 cases). In 2 cases, an overrepresentation of the
chromosomal arm 3q was accompanied by a loss of chromosomal arm 3p. Less frequent
overrepresentations were observed on chromosomes 1q and 17q. Deletions were found
on chromosomes 18q (3 cases), 3p, 4q, 5q, and 19p (2 cases each); and sporadic
deletions occurred on 2q, 6q, 8p, 9p, 10p, 13q, 14q, 15q, and 16q. Whereas
overrepresentations on chromosomes 1p and 7p occurred exclusively in N0 tumors,
overrepresentations on chromosomes 1q, 11q, and 22q, along with deletions on 18q,
were only observed in N+ tumors. Quantitative DNA measurements revealed a
significantly higher percentage of aneuploid cells and a higher degree of DNA
entropy in the N+ tumors. Chromosomal overrepresentations on chromosomes 1q, 8q,
11q, 18q, and 19q occurred more frequently in the metastases than in the
corresponding primary tumors. Pairwise analysis of chromosomal alterations in the
primary tumors and associated lymph node metastases revealed a genetic
relationship, although a greater number of chromosomes on average were affected
in the lymph node metastases. Quantitative DNA measurements demonstrated greater
aneuploid values in the metastases. Recurring patterns of chromosomal alterations
in N0 and N+ tumors were demonstrated in this study. In general, metastasizing
tumors are characterized by overrepresentations on chromosomes 11q13 and 22q, and
deletions on 18q. These aberrations suggest an elevation along the tumor
progression cascade.
PMID- 10778897
TI - Pediatric lymphangiomas of the head and neck.
AB - To better define the cause, presentation, diagnosis, and staging of
lymphangiomas, we reviewed all cases of lymphangiomas of the head and neck region
in children seen at our institution between 1986 and 1996. Sixty-seven children
were identified (31 male and 36 female). Age at presentation ranged from birth to
18 years. All but 8 patients presented with an obvious mass, and 5 required
tracheotomy because of airway obstruction. The most common location was the
submandibular region (37%), followed by the parotid gland (31%). Treatment ranged
from observation to extensive and multiple resections. Thirty-one patients
underwent only 1 resection, and 2 patients received interferon as part of their
treatment. Lesions involving the lip, hypopharynx and/or larynx, the tongue, and
the floor of the mouth had high rates of recurrent or persistent disease. We
review our experience with these difficult lesions and propose a staging system
based on functional deficit, cosmetic changes, sites of involvement, and age at
diagnosis.
PMID- 10778898
TI - Slow-release 5-fluorouracil and triamcinolone reduces subglottic stenosis in a
rabbit model.
AB - A previous pilot study suggested that a sustained-release conjugate that provided
a slow release of 5-fluorouracil and triamcinolone acetonide injected into the
tracheal and paratracheal tissues of rabbits at the time of subglottic surgery
reduced the formation of subglottic stenosis. Our study was undertaken to confirm
the effect. Ten milligrams of the compound suspended in hyaluronic acid was
injected at the time of injury via a laryngofissure approach. The results showed
that the control group had a mean stenosis of 52%, whereas the treated group had
a mean stenosis of 32%. There was a significant difference between the treated
and untreated groups (p = .003). It is hoped that this co-drug ultimately can be
used in humans to reduce stenosis formation after laryngotracheal surgery and in
other forms of otorhinolaryngological surgery.
PMID- 10778899
TI - Endoscopic revision surgery for recurrent epiphora occurring after external
dacryocystorhinostomy.
AB - Recurrent epiphora after external dacryocystorhinostomy (DCR) can be a
frustrating experience for both the patient and the physician. We present the
results of a retrospective study of 18 patients with epiphora recurring after
external DCR who were operated upon to recreate lacrimal drainage through an
endoscopic endonasal approach. The procedure was successful in 83.3% of cases,
with no major complications. The results are comparable to those of an external
approach, but the cosmetic advantages are clear. It is a 1-stage procedure that
permits correction of associated intranasal disease that may be a causative
factor in the recurrence of lacrimal obstruction. The endoscopic endonasal
approach is a relatively safe and reliable option in the management of recurrent
epiphora.
PMID- 10778900
TI - Fourth branchial cyst presenting with neonatal respiratory distress.
AB - Fourth branchial cysts are quite rare. A neonate with a left lateral neck mass
and respiratory distress was found to have a fourth branchial cyst, which was
diagnosed with computed tomography and endoscopy. The characteristic computed
tomography findings included an air-containing neck cyst, which was located at
the anteromedial site of the common carotid artery with mediastinal extension.
Endoscopic examination revealed an internal opening at the apex of the pyriform
sinus, communicating with the cyst. Total excision of the cyst was performed, and
the specimen, which showed ciliated columnar epithelium with a subepithelial
lymphoid infiltrate, thyroid follicles, and thymic tissue, histologically
confirmed the diagnosis.
PMID- 10778902
TI - Chordoma of the cervical spine.
PMID- 10778901
TI - Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity.
A case report.
AB - Azithromycin, an azalide antibiotic, rarely causes ototoxicity. According to the
few reports in existence, azithromycin-induced ototoxicity occurred following
prolonged high-dose therapy in patients with acquired immunodeficiency syndrome
and resulted in a reversible sensorineural hearing loss. We present a case of
irreversible sensorineural hearing loss due to azithromycin ototoxicity in an
otherwise healthy woman following low-dose exposure to azithromycin.
PMID- 10778903
TI - The role of the clinical toxicologist in environmental toxicology.
PMID- 10778904
TI - Pyrethroid insecticides: poisoning syndromes, synergies, and therapy.
AB - BACKGROUND: Pyrethroid insecticides are widely used, but there have been
relatively few reports of systemic poisoning. These reports have, however, shown
that pharmacotherapy is difficult and that the duration of poisoning can be
unexpectedly long. Pyrethroids are ion channel toxins prolonging neuronal
excitation, but are not directly cytotoxic. Two basic poisoning syndromes are
seen. Type I pyrethroids produce reflex hyperexcitability and fine tremor. Type
II pyrethroids produce salivation, hyperexcitability, choreoathetosis, and
seizures. Both produce potent sympathetic activation. Local effects are also
seen: skin contamination producing paresthesia and ingestion producing
gastrointestinal irritation. The slow absorption of pyrethroids across the skin
usually prevents systemic poisoning, although a significant reservoir of
pyrethroid may remain bound to the epidermis. Carboxyesterase inhibitors can
enhance pyrethroid toxicity in high-dose experimental studies. Hence, the
unauthorized pyrethroid/organophosphate mixtures marketed in some developing
countries may precipitate human poisoning. Pyrethroid paresthesia can be treated
by decontamination of the skin, but systemic poisoning is difficult to control
with anticonvulsants. Pentobarbitone, however, is surprisingly effective as
therapy against systemic type II pyrethroid poisoning in rats, probably due to
its dual action as a chloride channel agonist and a membrane stabilizer.
PMID- 10778905
TI - Pyrethroid-induced paresthesia--a central or local toxic effect?
AB - BACKGROUND: Pyrethroid-induced paresthesia is frequently seen after dermal
exposure to pyrethroids. Affected individuals experience a sensation of burning,
tingling, itching, or numbness, most commonly in the face. This occurs 1-2 hours
after the beginning of exposure and resolves spontaneously. MECHANISMS:
Paresthesia occurs as a result of a direct effect on intracutaneous nerve endings
at very low pyrethroid doses. It is related to potency of the pyrethroid with
pyrethroids without an alpha-cyano group generally showing the weakest effect.
CONCLUSION: Doses sufficient to cause paresthesia are far lower than those
causing central or systemic toxicity. Paresthesia is therefore considered to be a
localized nuisance effect. The best advice to affected individuals is to prevent
paresthesia from occurring through appropriate hygiene measures and personal
protection.
PMID- 10778906
TI - Management of pyrethroid exposure.
AB - OVERVIEW: Severe pyrethroid insecticide poisoning is uncommon in the developed
world, but more common in developing countries because of its wide use in
agriculture. This short review proposes a management strategy for pyrethroid
poisoning based on the present literature. It also mentions an experimental
approach, which will require further study in animals and may have eventual
relevance for man.
PMID- 10778908
TI - Mechanisms of toxicity, clinical features, and management of diquat poisoning: a
review.
AB - USES: Diquat (1,1'-ethylene-2,2'-bipyridilium) is a nonselective bipyridyl
herbicide, related structurally to paraquat, which is used both as a contact
herbicide and a preharvest desiccant. In comparison to paraquat, diquat is used
much less widely in agriculture. MECHANISMS OF TOXICITY: Diquat is a potent redox
cycler and is readily converted to a free radical which, in reaction with
molecular oxygen, generates superoxide anions and subsequently other redox
products. These products can induce lipid peroxidation in cell membranes, and
potentially cause cell death. FEATURES: Over the period 1968-1999, only 30 cases
of diquat poisoning were reported in detail in the literature, of which 13 (43%)
were fatal. Local and systemic effects have been reported following diquat
exposure, with systemic features being invariably associated with ingestion. In
severe and usually fatal cases, gastrointestinal mucosal ulceration, paralytic
ileus, hypovolemic shock, acute renal failure, and coma have been reported.
MANAGEMENT: After rapid confirmation of the diagnosis using a qualitative urine
test, gut decontamination may be considered in patients who present within 1 hour
of a life-threatening ingestion (>6 g). Supportive measures including fluid and
electrolyte replacement should then be employed. Although hemofiltration and
hemodialysis are of proven value if renal failure supervenes, there is no
clinical evidence that hemodialysis or hemoperfusion removes toxicologically
significant amounts of diquat, thereby reducing the risk of organ failure and
preventing a fatal outcome in severe cases.
PMID- 10778907
TI - Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy
herbicide poisoning: a review.
AB - INTRODUCTION: Chlorophenoxy herbicides are used widely for the control of broad
leaved weeds. They exhibit a variety of mechanisms of toxicity including dose
dependent cell membrane damage, uncoupling of oxidative phosphorylation, and
disruption of acetylcoenzyme A metabolism. Between January 1962 and January 1999,
66 cases of chlorophenoxy herbicide poisoning following ingestion were reported
in the literature. FEATURES FOLLOWING INGESTION: Adjuvants in the formulations
may have contributed to some of the features observed. Vomiting, abdominal pain,
diarrhea, and, occasionally, gastrointestinal hemorrhage were early effects. When
present, hypotension was predominantly due to intravascular volume loss, although
vasodilation and direct myocardial toxicity may have contributed in some cases.
Neurotoxic features included coma, hypertonia, hyperreflexia, ataxia, nystagmus,
miosis, hallucinations, convulsions, fasciculation, and paralysis.
Hypoventilation occurred not infrequently, usually in association with central
nervous system depression, but respiratory muscle weakness was a factor in the
development of respiratory failure in some patients. Myopathic symptoms including
limb muscle weakness, loss of tendon reflexes, and myotonia were observed and
increased creatine kinase activity was noted in some cases. Other clinical
features reported included metabolic acidosis, rhabdomyolysis, renal failure,
increased aminotransferase activities, pyrexia, and hyperventilation. Twenty-two
of 66 patients died. FEATURES FOLLOWING DERMAL AND INHALATIONAL EXPOSURE:
Substantial dermal or inhalational 2,4-dichlorophenoxyacetic acid exposure has
occasionally led to systemic features but no such reports have been published in
the last 20 years and no fatalities have been reported at any time. Substantial
dermal exposure has been reported to cause mild gastrointestinal irritation after
a latent period followed by progressive mixed sensory-motor peripheral
neuropathy. Mild, transient gastrointestinal and peripheral neuromuscular
symptoms have also occurred after occupational inhalation exposure, with or
without dermal exposure. MANAGEMENT: In addition to supportive care, alkaline
diuresis to enhance herbicide elimination should be considered in all seriously
poisoned patients. Limited clinical data suggest that hemodialysis produces
similar herbicide clearance to alkaline diuresis without the need for urine pH
manipulation and the administration of substantial amounts of intravenous fluid
in an already compromised patient. CONCLUSIONS: While chlorophenoxy herbicide
poisoning is uncommon, ingestion of a chlorophenoxy herbicide can result in
serious and sometimes fatal sequelae. In severe cases of poisoning, alkaline
diuresis or hemodialysis to increase herbicide elimination should be considered.
PMID- 10778909
TI - Herbicide formulations.
AB - BACKGROUND: Herbicides comprise nearly half of the 5 billion pounds of pesticide
active ingredients used worldwide annually. The active ingredient must be
formulated with other ingredients to allow mixing, dilution, application, and
stability. Liquid commercial formulations for spray foliar application include
water-soluble liquids, emulsifiable concentrates, suspension concentrates or
"flowables," and gels. Dry formulations that are mixed with water for spray
application include wettable powders and water-dispersible granules. Granules are
broadcast directly out of the bag. The carrier in liquid formulations is either
water or an organic solvent or oil. The general chemical class of the carrier may
be deduced based on the solubility characteristics of the active ingredient.
Cosolvents may be necessary to optimize solubility and stability. Surfactants are
nearly universally present in herbicide formulations or added prior to
application. They aid uniform spreading of the spray droplet on the leaf and
penetration of its waxy cuticle by the active ingredient. In solvent-based
formulations, surfactants permit a stable oil-in-water emulsion to form when
diluted with water for actual use. New surfactant systems are currently of
intense competitive importance. Other formulation ingredients include pH
adjusters, buffers, milling aids, antifoaming agents, acid scavengers, dyes,
suspending agents, preservatives, dispersants, emulsifiers, densifiers,
antifreeze, and crystal promoters. In highly regulated environments, the other
formulation components in pesticides are receiving scrutiny. In the US, the EPA's
strategy has been to categorize currently used formulation ingredients into 4
lists based on their toxicology profiles. The ultimate outcome is to have all
inert ingredients on List 4, Minimal Risk. List 4 ingredients are generally
regarded as safe or have current use patterns that do not pose an unreasonable
risk of adverse effect to public health or the environment.
PMID- 10778910
TI - Chemical contamination of private drinking water supplies in the West Midlands,
United Kingdom.
AB - INTRODUCTION: In the United Kingdom, private drinking water supplies are subject
to much less stringent sampling and testing regimes than are public supplies.
Information regarding the quality of private drinking water supplies is disparate
and poorly defined. The aim of this study was to collate the data for chemical
contamination of private drinking water supplies in the West Midlands, a region
of Central England with a population of 5.3 million. METHODS: The most recent
year's data on the number of private supplies, the number of supplies sampled,
and the number and type of failures for chemical parameters were obtained from
District and Local Authorities in the West Midlands Region. RESULTS: Data covered
12-month periods during 1995-1996. Of the 6013 private supplies identified,
samples from 1297 had been tested for chemical parameters during the period of
the study. A total of 420 individual failures for chemical parameters were
reported in 386 water supplies. The majority of breaches of United Kingdom and
European Union standards were due to increased concentrations of nitrates (270),
magnesium (21), manganese (17), and iron (15). Increased turbidity was present in
27 cases. Only 6 samples breached the standard for lead and 6 for pesticides.
CONCLUSIONS: Over a quarter of the supplies tested during the period of the study
were in breach of United Kingdom and European Union legislation. Of the reported
failures, the high concentrations of nitrate and nitrite, lead, copper, and
sulfate are of concern to health and remedial action is warranted. Regular
sampling of private drinking water supplies remains necessary to prevent risk to
health from a wide variety of toxic contaminants.
PMID- 10778911
TI - Pesticides in drinking water: what should be the standard?
PMID- 10778912
TI - A case of fatal diquat poisoning: toxicokinetic data and autopsy findings.
AB - CASE REPORT: A 37-year-old man ingested in a suicide attempt 300 mL of a diquat
solution (equivalent to 60 g diquat ion). The initial diquat serum concentration
was 64 microg/mL 4 hours after poisoning. The clinical course was characterized
by a progressive anuria and by neurological disorders (coma and seizures). The
patient died 26 hours after poisoning from refractory cardiocirculatory collapse.
Extracorporeal techniques removed 1.09 g of diquat which could be considered as
significant in regard to the total amount that was likely absorbed, but they did
not influence the clinical outcome. There was marked renal tubular damage at
autopsy and the highest diquat tissue concentration was found in the kidneys.
PMID- 10778913
TI - A case of transient diabetes insipidus associated with poisoning by a herbicide
containing glufosinate.
AB - BACKGROUND: The herbicide BASTA (AgrEvo, Germany), containing glufosinate
ammonium (20%) and an anionic surfactant, polyoxyethylene alkylether sulfate
(33%), is widely used. In acute oral BASTA poisoning, patients develop a variety
of clinical signs, including disturbed consciousness, convulsions, and apnea.
These effects are suspected to be due to the effects of glufosinate on the
central nervous system. CASE REPORT: A 60-year-old man ingested 500 mL of BASTA
herbicide in a suicide attempt. He developed not only unconsciousness,
respiratory distress, and convulsions but also an increase in urine output (7885
mL/d), elevated serum sodium (167 mEq/L), elevated plasma osmolality (332
mOsm/kg), and a decrease in both urine osmolality (200 mOsm/kg) and urine
specific gravity (1.003), which suggested the development of diabetes insipidus.
The plasma level of antidiuretic hormone remained within the normal range (1.3
pg/mL), despite high plasma osmolality. The administration of desmopressin was
successful in normalizing urine volume, specific gravity, and osmolality. Serum
sodium corrected gradually within 48 hours. The possible mechanisms causing the
diabetes insipidus are discussed.
PMID- 10778914
TI - Human mast cell subsets--distinct functions in inflammation?
AB - That mast cells participate in inflammatory reactions is beyond argument. A major
question posed by mast cell biologists is whether specific functions in
inflammation are subserved by different subsets of the mast cell population. We
have investigated the two major subsets of human mast cells (MC(T) and MC(TC)),
in the chronic inflammatory processes associated with rheumatoid arthritis (RA).
Whereas normal synovium contains mainly MC(TC) mast cells, the MC(T) subset is
selectively expanded in early RA, in numbers that correlate with synoviocyte
hyperplasia and T-lymphocyte infiltration. In contrast, in RA of long duration,
MC(TC) mast cells predominate in numbers that correlate with clinical indices of
rapidity of disease progression. We suggest that MC(T) mast cells participate in
active inflammatory events, whereas MC(TC) mast cells may be more relevant in
repair or damage to connective tissues.
PMID- 10778915
TI - Induced sputum of patients with chronic obstructive pulmonary disease (COPD)
contains adhesion-promoting, therapy-sensitive factors.
AB - OBJECTIVE: The aim of this study was to investigate whether sputum of COPD
patients before and after treatment with inhaled corticosteroids (IHC) or N
acetylcysteine (NAC) exerts any effect on the adhesion of isolated
polymorphonuclear cells (PMNs) to cultured endothelial cells. METHODS: A human
endothelial cell line was grown to confluence before use in adhesion experiments.
PMNs were obtained from normal, non-smoking volunteers and preincubated (30 min,
37 degrees C) with diluted sputum sol obtained from COPD patients before the
cells were put on the endothelial cells. RESULTS: Basal adhesion of unstimulated
PMNs after 30 min at 37 degrees C in 5% CO2 was 15.9+/-1.1% (mean +/- SEM, n =
9). A significant enhancement of the adhesion to 33.0+/-1.4% (n = 11, P<0.0001)
was observed with sputum obtained from COPD patients before treatment with IHC,
and 34.6+/-1.5% (n = 10, P<0.0001) before treatment with NAC. Administration of
IHC for 8 weeks resulted in an adhesion of 27.7+/-2.4%, which is an inhibition of
31% (n = 11, P<0.05). However, treatment for 8 weeks with NAC showed no change in
the adhesion of stimulated PMNs. Long-term treatment with NAC showed a gradual
decrease of adhesion (n = 9, P<0.05), whereas long-term treatment with IHC lead
to an increase in adhesion (n = 10, P<0.02). CONCLUSIONS: These results indicate
that factors locally produced in the airways of COPD patients may promote
adhesion of neutrophils to endothelium. They further suggest that glucocorticoids
may only have a short-term transient effect on adhesion, whereas NAC showed
effects on the adhesion after administration for longer periods.
PMID- 10778916
TI - Effects of pentoxifylline and nabumetone on the serum levels of IL-1beta and
TNFalpha in rats with adjuvant arthritis.
AB - OBJECTIVE AND DESIGN: This study examined whether serum levels of cytokines, IL
1beta and TNFalpha were elevated in rats with adjuvant arthritis in relation to
disease progression, and if so, to verify the treatment effects of nabumetone (20
mg/kg, p. o.), a COX-2 inhibitor and pentoxifylline (20 mg/kg, p.o.), a type-4
phosphodiesterase (PDE4) inhibitor, alone or in combination. MATERIALS AND
METHODS: Female Wistar rats were used. Freund's complete adjuvant (FCA) was used
to induce arthritis. The increment in contralateral hind paw volume (the
secondary lesion) was determined by plethysmometry and the serum cytokines were
measured by ELISA. RESULTS: In control rats, the serum IL-1beta and TNFalpha
levels were greatly elevated on the very first day i.e. 5 h after FCA, and
thereupon a progressive decrease in IL-1beta but not TNFalpha was observed until
day 30. The secondary arthritic lesion began to increase on day 14 (125+/-26
microl), and attained its peak (330+/-79 microl) on day 21 post-adjuvant
injection. The peak arthritic lesion was significantly (p<0.001) less in rats
that received nabumetone and pentoxifylline, alone or in combination (20+/-8,
41+/-15 and 65+/-10 microL, respectively). When serum cytokine levels were
analysed on day 20 postadjuvant injection, rats treated with pentoxifylline or in
association with nabumetone, but not nabumetone alone showed significantly
lowered levels of serum TNFalpha. Unlike TNFalpha, serum IL-1beta did not vary
significantly. CONCLUSIONS: The drugs nabumetone and pentoxifylline although
appearing to produce differential effects on serum cytokine levels, seem to be
equally efficacious in attentuating the progression of FCA-induced arthritis.
Serum cytokine levels may not accurately reflect the treatment efficacy.
PMID- 10778918
TI - Alterations in protein kinase C isoforms in experimentally-induced colitis in the
rat.
AB - BACKGROUND: Although protein kinase C (PKC) isoenzymes have been implicated as
mediators for multiple physiological processes, PKC also mediates cellular and
intestinal mucosal injury. We have investigated the expression of the isoenzymes,
PKCalpha, PKCdelta, PKCepsilon and PKCzeta in colonic mucosal tissue from TNBS
treated and HLA-B27 spontaneous colitis animals. METHODS: Colonic mucosal samples
were taken at various times (2 h-14 d) after instillation of TNBS (75 mg/kg in
50% ethanol) or from HLA-B27 rats at 16-18 weeks of age. Tissues were homogenized
and separated into membrane and cytosolic fractions by centrifugation. PKC
activity was measured radioenzymatically. PKC protein for isoforms alpha, delta,
epsilon and delta was assessed by Western blot while corresponding mRNA was
analyzed by RT-PCR. RESULTS: PKC activity increased in cytosolic and membrane
fractions by 1d after TNBS and returned to normal by d3. PKCalpha protein was
translocated from cytosol to membrane by 2 h after TNBS followed by down
regulation until d3. Increases in PKCdelta, PKCepsilon and PKCzeta protein
occurred initially in membrane fractions as early as 2 h after TNBS. Increases in
cytosolic protein occurred at later times after induction of colitis. Protein
levels for all isoenzymes remained increased up to 7d after TNBS. RT-PCR revealed
that mRNA for PKCalpha decreased while PKC mRNA increased correspondingly with
their respective protein levels. In HLA-B27 rats, protein levels for all isoforms
were less than was detected in normal colonic tissue. CONCLUSIONS: The early
increase in gene expression and protein levels for PKCalpha and zeta suggest that
these isozymes may play roles in an acute model of colitis induced by TNBS. In
contrast, the increase in PKCdelta and epsilon protein was not associated with
mRNA changes suggesting that these isozymes are not similarly regulated in the
inflamed colonic mucosa. In a chronic model of experimental colonic inflammation
(HLA-B27), all of these isoforms appeared to be down-regulated.
PMID- 10778917
TI - Differential anti-inflammatory effects of immunosuppressive drugs: cyclosporin,
rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide,
cyclooxygenase-2 and PGE2 production.
AB - OBJECTIVE AND DESIGN: Cyclosporin, FK-506 and rapamycin have similar but distinct
modes of interaction with cyclophilins, calcineurins and transcription factors.
These immunosuppressive drugs have also been shown to inhibit cytotoxic and
inflammatory responses in macrophage. Therefore, we evaluated the mechanism of
action of these drugs on iNOS and COX-2 expression by macrophages, the products
of which (NO and PGE2) have cytotoxic and proinflammatory activities. MATERIALS
AND METHODS: The murine macrophage cell line RAW 264.7 was grown as monolayer
cultures. The effects of pharmacologically relevant concentrations of
cyclosporin, rapamycin and FK-506 were evaluated in the presence and absence of
lipopolysaccharide (LPS) which is a known inducer of iNOS and COX-2. Subsequently
the expression of iNOS and COX-2 were analyzed by Western and Northern analysis.
The production of NO and PGE2 were assayed by Greiss and RIA respectively.
RESULTS: Cyclosporin (1-5 microg/ml) and rapamycin (1.0-10 nM) but not FK-506 (5
10 nM) inhibited both iNOS and COX-2 expression at mRNA level which led to
significant inhibition of NO and PGE2 production. CONCLUSION: These studies
characterize differential mechanistic capacity of the immunophilin-binding
immunosuppressive drugs (comparable to hydrocortisone) to inhibit both iNOS and
COX-2 expression. Inhibition of iNOS and COX-2 mRNA accumulation by cyclosporin
and rapamycin seem to be distinct. These studies also highlight potential anti
inflammatory properties of these drugs in addition to their known
immunosuppressive activity.
PMID- 10778919
TI - Excitatory amino acid release in the locus coeruleus during naloxone-precipitated
morphine withdrawal in adjuvant arthritic rats.
AB - OBJECTIVE AND DESIGN: Excitatory amino acid levels in the locus coeruleus (LC)
and the behavioral signs during naloxone-precipitated withdrawal in arthritic
rats treated with chronic morphine were investigated by in vivo microdialysis.
METHODS: Increases in glutamate (Glu) and aspartate (Asp) were noted after
naloxone (48 nmol/5 microl, LC)-precipitated withdrawal from normal and adjuvant
arthritic rats which had been intracerebroventricularly infused for 3 days with
morphine (26 nmol/l microl/h). RESULTS: The increases in Glu and Asp levels on
morphine withdrawal in normal rats were attenuated following naloxone challenge
in the morphine-dependent arthritic rats. Moreover, behavioral signs during
morphine withdrawal were detected following the naloxone challenge in both the
morphine-dependent normal and adjuvant arthritic rats, but not in the saline
infused controls. CONCLUSIONS: These results show that the attenuation of Glu and
Asp release from the LC in the adjuvant arthritic rats might explain the anti
inflammatory and analgesic effects of mu-opioids in adjuvant arthritic rats.
PMID- 10778920
TI - Inhibitory effects of newly synthesized active center-directed trypsin-like
serine protease inhibitors on the complement system.
AB - OBJECTIVE: To obtain a synthetic anti-complement inhibitor which has stronger
activity than FUT-175 (nafamostat mesilate), as a synthetic ester derivative
containing amidino and guanidino groups. METHODS: We synthesized several modified
compounds of FUT-175. The anti-complement activities were measured using
synthetic substrates and complement-mediated hemolysis in vitro. The anti
complement activity in vivo was evaluated via Forssman systemic shock in guinea
pigs. RESULTS: FUT-175 inhibited C1r and C1s with IC50s of 1.7x10(-6) and 3.2x10(
7) M, respectively. Inhibitory activities were decreased by substitution of the
amidino group with a hydrogen atom (compound 2), but not the guanidino group with
a hydrogen atom (compound 3). Compound 6, in which the benzene ring of compound 3
was substituted with a furan ring, inhibited C1r and the complement-mediated
hemolysis in high-diluted serum with higher potency than FUT-175. The inhibitory
activity of compound 6 in hemolysis was weakened in low diluted serum. Compound 7
had a guanidino group inserted into compound 6; however, Compound 7 strongly
inhibited hemolysis even in low-diluted serum, and suppressed Forssman systemic
shock more potently than both FUT-175 and compound 6. CONCLUSIONS: These data
suggest that the 2-furylcarboxylic acid derivatives have a strong potential for
inhibiting the activities of the complement, and the guanidino group was required
to retain high inhibitory activities in vivo, and compound 7 is a hopeful anti
complement agent.
PMID- 10778921
TI - Simultaneous analysis of shikimate-derived secondary metabolites in Lithospermum
erythrorhizon cell suspension cultures by high-performance liquid chromatography.
AB - A high-performance liquid chromatography (HPLC) analysis system based on a water
acetonitrile gradient program was established for simultaneous quantification of
shikimate-derived secondary metabolites in cultured cells of Lithospermum
erythrorhizon. The cells cultured in pigment production medium (M-9) are capable
of producing five highly hydrophilic compounds such as p-hydroxybenzoic acid-O
glucoside and lithospermic acid B, as well as eleven lipophilic compounds
including echinofuran B and acetylshikonin. In addition to the wide polarities of
those compounds, many of them are unstable under light, dryness, oxygen and
heating. Thus, a new extraction procedure for all these compounds was also
established by use of ultrasonication under ice-water chilling with MeOH as the
solvent. This procedure was applied to the quantitative analyses of these
compounds in cell cultures and hairy root cultures of Lithospermum, and in the
intact plants as well.
PMID- 10778922
TI - Simultaneous determination of hydrocortisone, dexamethasone, indomethacin,
phenylbutazone and oxyphenbutazone in equine serum by high-performance liquid
chromatography.
AB - Ethyl acetate extracts of equine serum, containing 0-5 microg/ml of
hydrocortisone (HYD), dexamethasone (DEX), oxyphenbutazone (OPB), indomethacin
(IND), phenylbutazone (PB) and probenecid as internal standard, were evaporated
with nitrogen, resuspended in methanol and analyzed by HPLC, using a C-18 column
equilibrated with 51:49 acetonitrile-water, 0.1% trifluoroacetic acid, at 1
ml/min. The eluate was monitored at 254 nm. The selectivity (inter-assay
C.V.<4%), sensitivity (limits of quantitation of 0.25 microg/ml for HYD, DEX and
IND, 0.5 microg/ml for PB and 1 microg/ml for OPB, despite the occurrence of
significant degradation of OPB and PB during the analysis) and precision (intra
assay and inter-assay C.V.'s of about 3-6 and 9-15%, respectively) of the method
appeared appropriate for anti-doping control of racehorses.
PMID- 10778923
TI - Enantioselective analysis of metoprolol in plasma using high-performance liquid
chromatographic direct and indirect separations: applications in
pharmacokinetics.
AB - Direct enantioselective separation on chiral stationary phases and indirect
separation based on the formation of diastereomeric derivatives were developed
and compared for the HPLC analysis of R(+) and S(-)-metoprolol in human plasma.
Plasma samples prepared using solid-phase extraction columns or liquid-liquid
extraction were directly analyzed on a Chiralpack AD or on a Chiralcel OD-H
columns, respectively. S-(-)-menthyl choroformate was also used to yield
diastereomeric derivatives resolved on a RP-8 column. The methods were employed
to determine plasma concentrations of metoprolol enantiomers in a pharmacokinetic
study of single dose administration of racemic metoprolol to a healthy Caucasian
volunteer phenotyped as extensive metabolizer of debrisoquine. The correlation
coefficients among enantioselective metoprolol plasma concentrations (5-223
ng/ml) obtained by the three methods were equal or higher than 0.99. The direct
method that employed the chiral column Chiralpak AD may be considered the most
sensitive, although the three methods demonstrated interchangeable use in the
pharmacokinetic investigation.
PMID- 10778924
TI - Determination of mandelic acid enantiomers in urine by gas chromatography and
electron-capture or flame ionisation detection.
AB - A sensitive and stereospecific GC method was developed for the analysis of R- and
S-enantiomers of mandelic acid (MA) in urine, using a chiral CP Chirasil-Dex-CB
column. The enantiomers of MA were derivatised with isopropanol into their
corresponding isopropyl esters and determined either directly with flame
ionisation detection (FID) or after subsequent derivatisation of a hydroxy group
with pentafluoropropionic anhydride with electron-capture detection (ECD). Both
derivatisation steps proceeded with negligible inversion of enantiomers (<1%).
The limit of detection of the FID determination was 8 and 5 mg/l for R-MA and S
MA, respectively and of the ECD determination 1 mg/l for both enantiomers.
Repeatability (within-day precision) and reproducibility (day-to-day precision)
was for both enantiomers below 7.5% for the FID and below 5.8% for the ECD
analysis. The method was applied to urine of volunteers exposed to 105 and 420 mg
styrene/m3 air. In the urine of the exposed volunteers, the S-enantiomer showed
higher excretion compared to that of the R-enantiomer, with marked
interindividual differences in excretion of both enantiomers.
PMID- 10778925
TI - High-performance liquid chromatographic method with fluorescence detection for
the determination of 3-hydroxybenzo[a]pyrene and 3-hydroxybenz[a]anthracene in
the urine of polycyclic aromatic hydrocarbon-exposed workers.
AB - The described high-performance liquid chromatographic method with fluorescence
detection (HPLC-FD) permits the simultaneous determination of 3
hydroxybenzo[a]pyrene and 3-hydroxybenz[a]anthracene as the most important
metabolites of the carcinogenic polycyclic aromatic hydrocarbons (PAHs)
benzo[a]pyrene and benz[a]anthracene in human urine. After enzymatic hydrolysis,
to release the conjugated metabolites, the analytes are separated from the matrix
by means of a liquid-solid extraction step which is followed by a coupled column
HPLC procedure using an enriching precolumn consisting of silica modified with
copper phthalocyanine. This special precolumn selectively adsorbs PAHs with at
least three condensed rings and thus separates them from the urine matrix. The
quantitative analysis was carried out using a switchable fluorescence detector.
The detection limits were 6 ng/l urine (3-hydroxybenzo[a]pyrene) and 8 ng/l urine
(3-hydroxybenz[a]anthracene). The relative standard deviations of the within
series imprecision ranged between 4.0% and 9.0%. The between-day imprecision was
7.7% (3-hydroxybenz[a]anthracene) and 12.9% (3-hydroxybenzo[a]pyrene). The
recovery rates ranged between 102% and 124%. Using this analytical method we
determined PAH metabolites in post shift urine samples from 19 workers engaged in
the production of fire-proof materials. The urinary concentrations ranged from 3
to 198 ng 3-hydroxybenzo[a]pyrene per g creatinine and from 15 to 1871 ng 3
hydroxybenz[a]anthracene per g creatinine.
PMID- 10778926
TI - New and simple procedure for the determination of muramic acid in chemically
complex environments by gas chromatography-ion trap tandem mass spectrometry.
AB - A gas chromatographic-ion trap tandem mass spectrometric method was developed for
the quantification of muramic acid, a marker of bacterial peptidoglycan, in
environmental and clinical specimens. Samples (bacteria, house dust and urine)
were heated in methanolic hydrochloric acid overnight and extracted with hexane
for removal of hydrophobic compounds. The aqueous phase was evaporated and heated
in acetic anhydride and pyridine after which the product, the acetate derivative,
was washed with dilute hydrochloric acid and water. The described method is both
rapid and simple to apply, and produces a stable derivative. It should become
widely used for measuring peptidoglycan in chemically complex environments.
PMID- 10778927
TI - Enantioselective high-performance liquid chromatographic analysis of the 5-HT1A
receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Application to a
pharmacokinetic-pharmacodynamic study in rats.
AB - A rapid, sensitive and enantioselective HPLC assay for the simultaneous
determination of the reference 5-HT1A receptor agonists, R-(+)- and S-(-)-8
hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT and S-8-OH-DPAT, respectively),
in rat blood is presented. A selective extraction procedure was developed using a
preliminary sample clean-up followed by isolation of R- or S-8-OH-DPAT on mixed
mode NARC-2 solid-phase columns. Separation of the enantiomers was performed by
high-performance liquid chromatography using a Chiracel OD-R column. Detection
was obtained using an electrochemical detector set at a voltage of 0.63 V. The
mobile phase consisted of a 50 mM phosphate buffer (pH 5.5)-acetonitrile (80:20,
v/v) mixture. At a flow-rate of 1 ml min(-1), the total run time was
approximately 14 min. The limit of detection for R- and S-8-OH-DPAT was 0.5 ng
ml(-1). In the concentration range between 50 ng ml(-1) and 1000 ng ml(-1) intra-
and inter-day relative standard deviations were less than 12%. The assay was
applied to a pharmacokinetic-pharmacodynamic study in rats in which decrease of
body temperature was used as a measure of 5-HT1A receptor-mediated effect. Values
for clearance, volume of distribution at steady state and terminal elimination
rate constant were 22+/-2 ml min(-1), 1969+/-473 ml and 156+/-34 min for R-8-OH
DPAT and 16+/-1 ml min(-1), 3353+/-347 ml and 334+/-36 min for S-8-OH-DPAT,
respectively. No enantiomeric interconversion was observed in vivo from R-8-OH
DPAT to S-8-OH-DPAT or vice versa.
PMID- 10778928
TI - Concurrent quantification and pharmacokinetic analysis of cefotaxime in rat blood
and brain by microdialysis and microbore liquid chromatography.
AB - A simple but effective coupling of microdialysis and microbore liquid
chromatograph with UV detection technique was applied to the simultaneous
studying of the pharmacokinetics of cefotaxime in both the peripheral compartment
and central nervous system. The mobile phase consisted of methanol-100 mM
monosodium phosphoric acid (25:75, v/v, pH 5.5) pumped through a C18 microbore
column at a flow-rate of 0.05 ml/min. Detection of cefotaxime was set at a UV
wavelength of 254 nm. Microdialysis probes were inserted into the jugular vein
and striatum of the rat. Following stabilization of microdialysate levels, rats
received cefotaxime (20 mg/kg, i.v., n=6) via the femoral vein, and complete
concentration versus time profiles for blood and striatum were constructed. The
results indicated that cefotaxime rapidly (within 10 min) entered the
extracellular fluid of brain striatum following intravenous administration.
Noncompartmental pharmacokinetics analysis indicated that the area under the
concentration versus time ratio of cefotaxime in rat brain and blood was 6.9%,
suggesting appreciable blood-brain barrier penetration. The method was relatively
simple, imposed minimal physiological perturbance as it involved no body fluid
consumption and sampled in particular protein-unbound drugs, generally believed
to be the active fraction.
PMID- 10778929
TI - Determination of a novel thrombin inhibitor in human plasma and urine utilizing
liquid chromatography with tandem mass spectrometric and ultraviolet detection.
AB - An LC-MS-MS method and an HPLC-UV method have been developed for the assay of a
novel thrombin inhibitor in human fluids. The LC-MS-MS method is developed for
plasma, which usually requires maximum sensitivity. The HPLC-UV method is for
urine. In both methods, analytes are extracted using liquid-liquid extraction,
and analyzed by reversed-phase high-performance liquid chromatography. A tandem
mass spectrometer in the multiple reaction monitoring (MRM) mode is used for
detection of the analytes in the plasma method. UV is the detector for the urine
method. The plasma method has a lower limit of quantitation (LOQ) of 0.1 ng/ml
with a linearity range of 0.1-100 ng/ml. The urine method has an LOQ of 8.12
ng/ml (20 nM) and the linear dynamic range is 8.12-8120 ng/ml (20-20000 nM). Both
methods are fast, specific and sensitive. Various validation procedures have
proven that both methods are rugged, robust and reproducible. The research also
suggested that, while LC-MS-MS provides superior sensitivity and selectivity for
the determination of drugs and their metabolites at very low concentrations, HPLC
with a conventional detector such as UV is still useful in the analysis when the
sensitivity requirement is not crucial.
PMID- 10778930
TI - High-performance liquid chromatographic analysis of the anti-fungal agent SCH
56592 in dog serum.
AB - SCH 56592 is a novel triazole antifungal agent that is active both orally and
intravenously. This compound is in phase II-III clinical trials for the treatment
of systemic fungal infections. A high-performance liquid chromatographic (HPLC)
method was developed for the analysis of SCH 56592 in serum of dogs, a species
used for safety evaluation. The HPLC analysis involved protein precipitation with
methanol followed by separation on a C18 column and quantitation by UV absorbance
at 262 nm. The method was sensitive with a limit of quantification of 0.05
microg/ml in dog serum. The linearity was satisfactory as indicated by
correlations of >0.996, in addition to visual examination of the calibration
curves. The precision and accuracy were satisfactory as indicated by coefficients
of variation (C.V.) ranging from 2.0 to 3.8%, and bias values ranging from -6.5
to 10%. Moreover, SCH 56592 was stable in dog serum after being subjected to
three freeze-thaw cycles. The assay was shown to be sensitive, specific,
accurate, precise, and reliable for use in pharmacokinetic or toxicokinetic
studies.
PMID- 10778931
TI - Determination of isotopic enrichments of [1-13C]homocysteine, [1-13C]methionine
and [2H3-methyl-1-13C]methionine in human plasma by gas chromatography-negative
chemical ionization mass spectrometry.
AB - We describe a reliable method for the simultaneous determination of isotopic
enrichments of [1-13C]homocysteine, [1-13C]methionine and [2H3-methyl-1
13C]methionine in human plasma. Accurate [1-13C]homocysteine calibration
standards were prepared by chemical conversion via thiolactonisation of [1
13C]methionine standards. Based upon anion-exchange chromatography, (di)acetyl
3,5-bis-trifluoromethylbenzyl derivatives, preparation of accurate calibration
curves and gas chromatography-negative chemical ionization mass spectrometry,
isotopic enrichments in human plasma could be determined with TTR (%) <+/-0.2%
(N=3) for [1-13C]homocysteine (enrichment range 0-8%), [1-13C]methionine
(enrichment range 0-3%) and [2H3-methyl-1-13C]methionine (enrichment range 0
12%). The method was applied in a [2H3-methyl-1-13C]methionine tracer infusion
study in a biological model.
PMID- 10778932
TI - Studies on the metabolism and toxicological detection of the amphetamine-like
anorectic fenproporex in human urine by gas chromatography-mass spectrometry and
fluorescence polarization immunoassay.
AB - Studies on the metabolism and the toxicological analysis of fenproporex (R,S-3
[(1-phenyl-2-propyl)-amino]-propionitrile, FP) using GC-MS and fluorescence
polarization immunoassay are described. The metabolites were identified in urine
samples of volunteers by GC-MS after cleavage of conjugates, extraction and
acetylation. Besides unchanged FP, fourteen metabolites, including amphetamine,
could be identified. Two partially overlapping metabolic pathways could be
postulated: ring degradation by one- and two-fold aromatic hydroxylation followed
by methylation and side chain degradation by N-dealkylation to amphetamine (AM).
A minor pathway leads via beta-hydroxylation of AM to norephedrine. For GC-MS
detection, the systematic toxicological analysis procedure including acid
hydrolysis, extraction at pH 8-9 and acetylation was suitable (detection limits
50 ng/ml for FP and 100 ng/ml for AM). Excretion studies showed, that only AM but
neither FP nor its specific metabolites were detectable 30-60 h after ingestion
of 20 mg of FP. Therefore, misinterpretation can occur. The Abbott TDx FPIA
amphetamine/methamphetamine II gave positive results up to 58 h. All the positive
immunoassay results could be confirmed by the described GC-MS procedure.
PMID- 10778933
TI - Simultaneous determination of endogenous and 13C-labelled cortisols and
cortisones in human plasma by stable isotope dilution mass spectrometry.
AB - This study describes a capillary GC-MS method for the simultaneous determination
of endogenous cortisol and cortisone and their 13C-labelled analogues, [1,2,4,19
13C4]cortisol (cortisol-13C4) and [1,2,4,19-13C4]cortisone (cortisone-13C4), in
human plasma. [1,2,4,19-13C4,1,1,19,19,19-2H5]Cortisol (cortisol-13C4,2H5) and
[1,2,4,19-13C4,1,1,19,19,19-2H5]cortisone (cortisone-13C4,2H5) were used as
analytical internal standards. A double derivatization (bismethylenedioxy
pentafluoropropionate, BMD-PFP) with good GC behavior was employed for the GC-MS
analysis of cortisol and cortisone. Quantitation was carried out by selected-ion
monitoring of the molecular ions ([M]+*) of the BMD-PFP derivatives of cortisol
and cortisone. The sensitivity limit of the present GC-MS-SIM method was found to
be 150 pg per injection for cortisol (s/n=5.0) and 50 pg for cortisone (s/n=8.1).
The within-day reproducibility in which the amounts of unlabelled and labelled
cortisols and cortisones determined were in good agreement with the actual
amounts added, the relative errors being less than 3.07%. The inter-assay
coefficients of variation (C.V.) were less than 1.80% for unlabelled and labelled
cortisols and cortisones.
PMID- 10778934
TI - Automated quantitative determination of the new renin inhibitor CGP 60536 by high
performance liquid chromatography.
AB - A fully automated high-performance liquid chromatography method with fluorescence
detection for the determination of the renin inhibitor CGP 60536 in animal and
human plasma and urine has been developed and validated. After addition of an
internal standard, the compounds were automatically extracted from 400 microl of
plasma or urine with methyl alcohol-acetic acid (99:1, v/v) on 100-mg Bond-Elut
CN cartridges using the Gilson ASPEC system. The on-line chromatographic
separation was performed on a LiChrospher 100 RP8 5-microm particle size packed
analytical column (25x0.4 cm I.D.). The mobile phase consisted of acetonitrile
0.01 M potassium dihydrogenphosphate (65:35, v/v) at a flow-rate of 0.8 ml/min.
The analytes were detected using a fluorescence detector at excitation and
emission wavelengths of 280 and 330 nm, respectively. The limit of quantitation
was established at 4.5 ng/ml in plasma (accuracy 106% and precision 1%), and 9.0
ng/ml in urine (accuracy 101% and precision 13%). The method was applied to the
investigation of the pharmacokinetics of CGP 60536.
PMID- 10778935
TI - Rapid and highly sensitive method for the determination of verapamil,
[2H7]verapamil and metabolites in biological fluids by liquid chromatography-mass
spectrometry.
AB - A rapid and highly sensitive method for the determination of verapamil [2,8-bis
(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile+ ++] and
[2H7]verapamil and their primary metabolites D-617 [2-(3,4-dimethoxyphenyl)-5
methylamino-2-isopropylvaleronitrile], D-703 [2-(4-hydroxy-3-methoxyphenyl)-8
(3,4-dimethoxy-phenyl)-6-methyl-2-iso-p ropyl-6-azaoctanitrile], D-702 [2-(3,4
dimethoxy-phenyl)-8-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-isopr opyl-6
azaoctanitrile], norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6
azaoctanitrile] and secondary metabolites D-620 [2-(3,4-dimethoxyphenyl)-5-amino
2-isopropylvaleronitrile], D-717 [2-(4-hydroxy-3-methoxyphenyl)-5-amino-2
isopropylvaleronitrile], and D-715 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4
dimethoxy-phenyl)-2-isopropyl-6-++ +azaoctanitrile] has been developed using high
performance liquid chromatography-electrospray mass spectrometry. D-832, the
gallopamil analogue of D-617 and [2H3]norverapamil were used as internal
standards. The analytes were extracted automatically from plasma and intestinal
perfusate using end-capped CN- and C2 solid-phase extraction cartridges.
Separation of the eight analytes was achieved on a LUNA C8 analytical column
(150x2 mm I.D., 5 microm particle size) with 5 mM ammonium acetate-acetonitrile
as the mobile phase run with a gradient from 70:30 to 40:60 and run times of 15
min. With the mass spectrometer operated in the selected-ion monitoring mode, the
limits of quantification in plasma and intestinal perfusate were 1 pmol/ml for D
620, D-617, D-702, D-703, norverapamil, verapamil, and [2H7]verapamil and 2.5
pmol/ml for D-717 and D-715 using a sample size of 1 ml plasma and intestinal
perfusate. The method described was successfully applied to the determination of
verapamil, [2H7]verapamil and their metabolites in human plasma and intestinal
fluid in pharmacokinetic studies.
PMID- 10778936
TI - Chromatographic behavior of mouse serum immunoglobulin G in protein G perfusion
affinity chromatography.
AB - In this study chromatographic behavior of mouse serum immunoglobulin G (IgG) on a
protein G perfusion affinity chromatographic column was investigated
experimentally. The results indicate that the protein G column has no non
specific binding to the other proteins in mouse serum but an irreversible
adsorption to IgG under the conditions investigated. It was found that variations
of the elution solution composition, ionic strength and pH played to some extent
an essential effect on the chromatographic behavior of IgG. The influence of the
mobile phase flow-rate on the chromatographic behavior of IgG was also
researched. These results show that the dissociation of IgG from protein G
affinity packings becomes the rate-limiting step in the perfusion affinity
chromatographic separation process.
PMID- 10778937
TI - Liposomal lurtotecan (NX211): determination of total drug levels in human plasma
and urine by reversed-phase high-performance liquid chromatography.
AB - Lurtotecan (GI147211; LRT) is a semisynthetic and water-soluble analogue of the
topoisomerase I inhibitor camptothecin. To determine whether the therapeutic
efficacy of LRT in patients could be improved, the drug was encapsulated in
liposomes (NX211; Gilead Sciences). In order to allow accurate description of the
pharmacokinetic behavior of NX211 in cancer patients, we have developed sensitive
RP-HPLC assays with fluorescence detection (lambdaex=378 nm; lambdaem=420 nm) for
the determination of total LRT levels in human plasma and urine. Sample
pretreatment involved deproteinization with 10% (w/v) aqueous perchloric acid
acetonitrile (2:1, v/v), and chromatographic separations were achieved on an
Inertsil-ODS 80A analytical column. The lower limit of quantitation (LLQ) was
established at 1.00 ng/ml in plasma (200-microl sample) and at 100 ng/ml in urine
(200 microl of 40-fold diluted sample). The within-run and between-run precisions
were <7.5%. LRT concentrations in urine of <100 ng/ml were determined by a
modified procedure comprising a single solvent extraction with n-butanol-diethyl
ether (3:4, v/v). In this assay, the fluorescence signal of LRT was increased 14
fold prior to detection by post-column exposure to UV light (254 nm) in a
photochemical reaction unit. The LLQ of this assay was 0.500 ng/ml (150-microl
sample) and the within-run and between-run precisions were <10%.
PMID- 10778938
TI - Determination of 18alpha-glycyrrhizin and 18beta-glycyrrhizin in dog plasma by
high-performance liquid chromatography.
AB - A high-performance liquid chromatographic method has been developed for the
separation and determination of 18alpha-glycyrrhizin (alpha-GZ) and 18beta
glycyrrhizin (beta-GZ) in dog plasma. The two compounds were separated on a
reversed-phase column and detected by UV absorption at 254 nm. The mobile phase
was a mixture of water-methanol-60% perchloric acid (45:55:0.5, v/v) and was
adjusted to pH 8.0 with 25% ammonia solution. Indomethacin was added to the
plasma as an internal standard. Methanol was selected for the extraction of both
the compounds and internal standard. Alpha-GZ and beta-GZ could be precisely
determined in concentration of 1 mg/ml in a 0.1 ml sample.
PMID- 10778939
TI - Simple and sensitive high-performance liquid chromatographic.
AB - A rapid, selective, sensitive, and reproducible reversed-phase HPLC procedure for
the quantitative determination of mycophenolic acid (MPA)--an active plasma
metabolite of the immunosuppressant mycophenolate mofetil (MMF) in plasma is
described. The procedure involves one-step extraction of MPA and the internal
standard, standard [RS-60461-000: (E)-6-[1,3-dihydro-4-(4-carboxy-butoxy)-6
methoxy-7-methyl-3-oxo-5-is obenzo-furanyl-4-methyl-4-hexenoic acid] with
dichloromethane-dichloroethane (1:1, v/v) at acidic pH. Chromatographic
separation consisted of the mobile phase [acetonitrile-0.05% phosphate buffer, pH
3.4 (45:55, v/v)] running through the column (Techopak-10 C18) at flow-rate of
0.8 ml/min. Detection was at UV wavelength of 254 nm. The mean recoveries of MPA
and the internal standard at concentrations of 0.1 and 20 microg/ml were 89-98%,
and 90-96%, respectively. The within-day coefficients of variation for MPA were
0.3-7.8% and the day-to-day coefficients of variation were 1.1-2.0%. The minimum
detectable concentrations for both MPA and the internal standard in plasma were
0.005 microg/ml. The method was found to be suitable for use in clinical
pharmacokinetic study.
PMID- 10778940
TI - Rapid microbore liquid chromatographic analysis of biphenyldimethyl dicarboxylate
in human plasma with on-line column switching.
AB - A fully automated method including microbore liquid chromatography and column
switching was developed for the analysis of biphenyldimethyl dicarboxylate (DDB)
from human plasma samples. After direct injection of plasma samples (100 microl)
into the system, deproteinization and analyte fractionation occurred on a Capcell
Pak MF Ph-1 column (20x4 mm I.D.) and the DDB fraction was transferred from the
MF Ph-1 column to an intermediate column (35x2 mm I.D.) using 15% acetonitrile in
phosphate buffer (50 mM, pH 7.0). The main separation was performed on a
microbore C18 column (150x1.5 mm I.D.) using 45% acetonitrile in water. The
method showed excellent sensitivity (detection limit of 5 ng/ml) and good
precision (CV.< or =3.0%), and shortened total analysis time (20 min). In the
concentration range of 5-200 ng/ml, the mean recovery was 90.7+/-1.8% and the
response was linear (r2> or =0.999).
PMID- 10778941
TI - Detection of mycoloylglycerol by thin-layer chromatography as a tool for the
rapid inclusion of corynebacteria of clinical origin in the genus
Corynebacterium.
AB - A chemotaxonomic study of some corynebacteria isolated from clinical samples
revealed characteristic thin-layer chromatographic patterns for meso
diaminopimelic acid containing species included in the genera Corynebacterium,
Dermabacter and Brevibacterium. Notably, a specific compound was consistently
detected in mycolic acid containing species of the genus Corynebacterium. This
compound was composed by glycerol and mycolic acids and structural analyses
carried out by fast atom bombardment mass spectrometry in C. minutissimum
confirmed its identification as mycoloylglycerol. The chain length of mycoloyl
groups in this molecule ranged from 28 to 34 carbon atoms, being mono-, di- or
triunsaturated. Detection of mycoloylglycerol by thin-layer chromatography may be
thus useful for the rapid inclusion of a great variety of corynebacteria of
clinical origin in the genus Corynebacterium in laboratories employing
chromatographic techniques as an adjunct for the identification of these
microorganisms.
PMID- 10778942
TI - Cytochrome P-450 and other determinants of pharmacokinetics, toxicity, and
efficacy in humans.
PMID- 10778943
TI - Clinical pharmacokinetics of oxaliplatin: a critical review.
AB - Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O']
platinum; Eloxatine) is a novel platinum coordination complex used for the
treatment of metastatic colorectal carcinoma in combination with
fluoropyrimidines. The objective of this review is to integrate the key data from
multiple studies into a single, comprehensive overview of oxaliplatin disposition
in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma
ultrafiltrate after oxaliplatin administration was triphasic, characterized by a
short initial distribution phase and a long terminal elimination phase (t1/2, 252
273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2
every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient
variability in platinum exposure (area under the curve(0-48)) is moderate to low
(33 and 5% respectively). In the blood, platinum binds irreversibly to plasma
proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum
in blood cells is not considered to be clinically significant. Platinum is
rapidly cleared from plasma by covalent binding to tissues and renal elimination.
Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum
elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the
administered dose 5 days postadministration. Tissue binding and renal elimination
contribute equally to the clearance of ultrafilterable platinum from plasma.
Renal clearance of platinum significantly correlated with glomerular filtration
rate, indicating that glomerular filtration is the principal mechanism of
platinum elimination by the kidneys. Clearance of ultrafilterable platinum is
lower in patients with moderate renal impairment; however, no marked increase in
drug toxicity was reported. The effect of severe renal impairment on platinum
clearance and toxicity is currently unknown. Covariates such as age, sex, and
hepatic impairment had no significant effect on the clearance of ultrafilterable
platinum, and dose adjustment due to these variables is not required. Oxaliplatin
undergoes rapid and extensive nonenzymatic biotransformation and is not subjected
to CYP450-mediated metabolism. Up to 17 platinum-containing products have been
observed in plasma ultrafiltrate samples from patients. These include several
proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo
diaminocyclohexane platinum complexes, along with several other noncytotoxic
products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was
not displaced from plasma proteins by a variety of concomitant medications tested
in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and
irinothecan have been observed. These results indicate that the
additive/synergistic antitumor activity observed with these agents is not due to
major alterations in drug exposure, and the enhanced efficacy is likely to be
mechanistically based. Together, these PK, biotransformation, drug-drug
interaction analyses and studies in special patient populations provide a firm
scientific basis for the safe and effective use of oxaliplatin in the clinic.
These analyses also reveal that the pharmacological activity of oxaliplatin may
be attributable, at least in part, to the unique pattern of platinum disposition
observed in patients.
PMID- 10778944
TI - Universal inactivation of both p16 and p15 but not downstream components is an
essential event in the pathogenesis of T-cell acute lymphoblastic leukemia.
AB - p16/p15 regulate the cell cycle pathway by inhibiting the cyclin Ds-CDK4/6
mediated phosphorylation of pRb. We reported previously that in T-cell acute
lymphoblastic leukemia (T-ALL), p16 and p15 were frequently (approximately 70%)
inactivated at the DNA level by deletion, mutation, or hypermethylation.
Therefore, we hypothesize that inactivation of the cell cycle regulatory pathway
may be essential in the pathogenesis of T-ALL, and that the remaining T-ALL with
a wild-type p16/p15 gene likely harbor inactivation of these genes at RNA or
protein levels. Alternatively, the downstream components of the pathway including
CDK4/6, cyclin Ds, and pRb may be deregulated. In 124 primary T-ALLs, we found
inactivation of the p16 and p15 genes at the DNA level in 79 (64%) and 64 (52%)
samples, respectively. Only 9 of the 45 samples with wild-type p16 expressed p16
protein, whereas the remaining 36 lacked p16 expression at the RNA or protein
level. In the 60 samples with an intact p15 gene, only 2 expressed p15 mRNA, and
the only one analyzed lacked p15 protein. Overall, the abrogation rates for p16
and p15 at DNA/RNA/protein levels were 93% (115 of 124) and 99% (123 of 124),
respectively. Although no alterations were evident in cyclin Ds or CDK4/6, pRb
was hyperphosphorylated in the majority of samples investigated. These findings
strongly support that both p16 and p15 are specific targets in the deregulation
of the cell cycle pathway in T-ALL and that the inactivation of these genes is
most likely essential in the pathogenesis of this disease.
PMID- 10778945
TI - Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus.
AB - Cyclooxygenase-2 (COX-2) is overexpressed in various types of human malignancies
including squamous cell carcinomas (SCCs) of the esophagus, but little is known
about COX-2 expression in premalignant esophageal squamous dysplasia. To
elucidate the role of COX-2 in esophageal carcinogenesis, we examined the
expression of this enzyme in normal squamous epithelium (n = 42), squamous
dysplasia [high-grade dysplasia (HGD, n = 41; low-grade dysplasia (LGD, n = 33)];
carcinoma in situ (n = 16), mucosal invasive carcinoma (n = 18), and advanced SCC
(n = 45). Immunohistochemistry showed a significantly high COX-2 expression in
HGD compared with other lesions. The COX-2 score, an index determined by
intensity and positivity of COX-2 staining (maximum 3.0), was 0.29 +/- 0.04 in
normal esophagus, 1.75 +/- 0.11 in LGD, 2.89 +/- 0.05 in HGD, 2.17 +/-0.18 in
CIS, 1.95 +/- 0.22 in mucosal invasive carcinoma, and 1.81 +/- 0.08 in advanced
SCC. Results of reverse transcription-PCR assays confirmed those obtained by
immunohistochemistry. COX-2 expression correlated with proliferation activity
assessed by the proliferating cell nuclear antigen index in dysplastic lesions (P
= 0.001) but not in SCCs. COX-2 expression in SCC did not correlate with various
clinicopathological parameters including prognosis. Our results indicate that COX
2 is a sensitive marker for HGD and suggest that COX-2 may be involved in early
stages of squamous carcinogenesis of the esophagus.
PMID- 10778946
TI - Adenoviral expression of p53 represses telomerase activity through down
regulation of human telomerase reverse transcriptase transcription.
AB - Telomerase activation is a critical step in cellular immortality and oncogenesis.
The activity of telomerase is known to be correlated with cell proliferation, but
its regulation by cell cycle regulators is not well understood. In the present
study, we examined the effects of p53 on telomerase activity. Wild-type p53 was
introduced into SiHa cells via a recombinant adenoviral vector, Ad5CMV-p53, and
change in telomerase activity was examined by quantitative telomerase assay.
Telomerase activity in the Ad5CMV-p53-infected cells was significantly repressed
36 h after infection following down-regulation of human telomerase catalytic
subunit [human telomerase reverse transcriptase (hTERT)] mRNA expression, whereas
no change in telomerase activity was observed in the cells infected with control
vector AdSCMV-beta-gal. Interestingly, repression of telomerase activity was an
early event that preceded cell growth inhibition or apoptosis induced by p53
overexpression, suggesting that p53 directly regulates telomerase activity.
Transient expression assays using hTERT-promoter reporter constructs revealed
that overexpression of p53 significantly repressed promoter activity of hTERT. 5'
Truncation of the promoter sequences revealed that the proximal core promoter
region containing multiple binding sites for transcription factor Spl was
responsible for p53-mediated transcriptional repression. Mutations in these
binding sites for Spl led to failure of p53 to repress transcription. These
findings suggest that p53 repressed telomerase activity through down-regulation
of hTERT transcription and that interaction of p53 with Sp1 or other
transcription factors may be involved in this regulation.
PMID- 10778947
TI - Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human
glioma cells.
AB - Carboxyamido-triazole (CAI), an inhibitor of non-voltage-gated calcium channels,
has been studied in Phase I/II clinical trials following the identification of
its inhibitory effects on tumor cell invasion and motility. It has also been
reported to inhibit human endothelial cell proliferation, migration, and adhesion
to the basement membrane. In glioma, biological assays have shown CAI to be
active in inhibiting the phenotypes of invasion and angiogenesis. The exact
mechanism of action is not clearly understood, although it appears to work via
inhibition of calcium influx in several signal transduction pathways that inhibit
cell cycle progression. Recent evidence implicates apoptosis as a contributing
mechanism of chemotherapy-induced tumor cytotoxicity. Therefore, we studied the
effects of CAI on apoptosis in bovine aortic endothelial cells and a human glioma
cell line (U251N) using a variety of methods, including: (a) cell morphology; (b)
terminal deoxynucleotidyl transferase-mediated nick end labeling analysis of in
situ DNA strand breaks; (c) agarose gel electrophoresis to visualize DNA
fragmentation; and (d) flow cytometry. Here we report that the kinetics of CAI
induced apoptosis in bovine aortic endothelial cells and glioma cells was
determined to be both dose and time dependent in micromolar concentrations
achievable in brain tissue in vivo.
PMID- 10778948
TI - The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
AB - Docetaxel is a chemotherapeutic agent effective in the treatment of various solid
tumors. Patients given a standard dose of docetaxel exhibit wide interpatient
variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by
cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account
in part for differences in toxicity and CL. Twenty-one heavily pretreated
patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4
activity in each patient was measured by the [14C-N-methyl]erythromycin breath
test (ERMBT). Blood samples were taken at selected times over the next 24 h for
pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity
measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean,
2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of
docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1
liters/h/m2). The ERMBT was the best predictor of CL when compared with serum
alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic
glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient
variation in CL. Multivariate analysis showed that the natural log of ERMBT and
albumin together accounted for 72% of the interpatient variation in CL. The
greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4
activity is the strongest predictor of docetaxel CL and accounts for the majority
of interpatient differences in CL. Patients with low CYP3A4 activity are at risk
for having decreased CL and may thus experience increased toxicity from
docetaxel. Those with high activity may be receiving a suboptimal dose. By
measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses
of CYP3A4 substrates, such as docetaxel, in certain individuals.
PMID- 10778949
TI - A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231)
targeting the type I protein kinase A by two-hour infusions in patients with
refractory solid tumors.
AB - GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha
of type I protein kinase A, which plays an important role in growth and
maintenance of malignancies. Preclinically, GEM231 inhibited human cancer
xenografts either alone or synergistically with chemotherapeutic agents and has
demonstrated an improved metabolic stability and safety profile compared to the
first-generation compounds. Objectives of this study were to define the safety
profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice
weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable
for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg).
Tumor histologies included non-small cell lung cancer, renal cell cancer,
sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and
predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13
microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half
life was about 1.5 h. The only clinical toxicities were transient grade I-II
fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related
complement activation or thrombocytopenia at any dose level, except with the
first dose in one patient who had pre-existing borderline thrombocytopenia.
Transient activated partial thrombin time prolongation occurred at doses > or
=160 mg/m2. Dose-limiting toxicities included transient activated partial
thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative
reversible transaminase elevation (three of three patients at 360 mg/m2 and three
of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer
had stabilization of a previously rising carcinoembryonic antigen. Thus, in this
first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients,
high plasma concentrations of GEM231 were well tolerated without significant
acute toxicities, but prolonged treatment was associated with reversible
transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4
week treatment duration, alternative dosing schedules are being tested to
minimize the cumulative toxicity, which will be essential to extend the duration
of therapy at the highest GEM231 dose tested.
PMID- 10778950
TI - Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage
colony-stimulating factor, low-dose interleukin 2, and interferon alpha in
progressive metastatic melanoma and renal cell carcinoma.
AB - The purpose of our study was to determine the maximally tolerated dose (MTD) and
DLT of combined administration of granulocyte macrophage colony-stimulating
factor (GM-CSF), low-dose interleukin 2 (IL-2) and IFN-alpha in patients with
progressive metastatic melanoma or renal cell carcinoma (RCC). In addition, the
activation and expansion of effector cells were measured. Cohorts of three
patients were treated with increasing doses of IL-2 (1, 4, and 8 MIU/m2) and GM
CSF (2.5 and 5 microg/kg) with a constant dose of IFNalpha (5 million units) s.c.
for 12 days every 3 weeks. An additional six patients were treated at the MTD.
Immune activation was monitored during the first cycle. Response was evaluated
after two cycles. The MTD was found to be 2.5 microg/kg GM-CSF, 4 MIU/m2 IL-2,
and 5 mega units of IFNalpha. DLT was grade 4 fever, chills with hypotension,
grade 3 fatigue/malaise, and fluid retention. Dose reduction of IL-2 to 2 MIU/m2
was necessary in three of nine patients who initially received the MTD. Treatment
was initiated in the hospital but could be continued at home after 3-4 days.
Significant increases in lymphocytes, (activated) T cells (CD4+ and CD8+), NK
cells, monocyte DR expression, neutrophils, and eosinophils were found. CD8+ T
cell activation (sCD8) and NK cell expansion was mainly present in patients
receiving 2 or 4 MIU/m2 IL-2. Of eight patients with progressive metastatic RCC
after nephrectomy, three achieved a complete remission, and 1 of 7 patients with
metastatic melanoma achieved a partial remission. In our study, the MTD of
combined immunotherapy with GM-CSF, IL-2, and IFNalpha was established; DLT was:
(a) grade 4 fever with hypotension needing i.v. fluid support; and (b) grade 3
fluid retention and/or fatigue/malaise. The scheme resulted in considerable
expansion and/or activation of various effector cells. The complete responses in
RCC patients are promising but need to be confirmed in Phase II studies.
PMID- 10778951
TI - Mouse mammary tumor virus-like ENV gene sequences in human breast tumors and in a
lymphoma of a breast cancer patient.
AB - DNA sequences with very high similarity (95-98%) to the mouse mammary tumor virus
(MMTV) ENV gene have been amplified by PCR in 38.5% of human breast tumors and in
<2% of normal breast tissue (Wang et al., Cancer Res., 55: 5173-5179, 1995).
Intrigued by these findings, which suggested an exogenous viral etiology for a
certain percentage of human breast tumors, we have screened a panel of human
breast tumors and normal breast tissue for the presence of MMTV-like DNA
sequences. Using similar PCR procedures and stringent hybridization techniques,
we have detected the presence of MMTV-like ENV gene sequences in 37% of the human
breast tumors that we have analyzed. DNA sequencing has shown these sequences to
be 99% homologous to the BR6 strain of MMTV and 100% homologous to the GR and C3H
strains of MMTV. We have not detected these MMTV-like sequences in normal breast
tissue. However, we have detected these sequences by PCR and stringent
hybridization in a T-cell lymphoma of a breast cancer patient who was
simultaneously diagnosed with both diseases. Our results support the possibility
of an exogenous retroviral etiology for a certain percentage of human breast
tumors. Our results also suggest that a similar exogenous retroviral etiology may
exist for certain human T-cell lymphomas. In many inbred strains of mice, both
breast cancer and T-cell lymphoma are caused by MMTV, hence, in a certain
percentage of humans, one or both of these diseases may be caused by an MMTV-like
retroviral entity.
PMID- 10778952
TI - (F-18) fluorodeoxyglucose positron emission tomography as a predictor of
pathologic grade and other prognostic variables in bone and soft tissue sarcoma.
AB - Positron emission tomography (PET) can be used to measure tumor metabolism in
sarcomas by measuring the standard uptake value (SUV) of (F-18)
fluorodeoxyglucose (FDG). FDG-PET SUV has been shown to correlate with
histological grade. We compared FDG-PET SUV in 89 bone and soft tissue sarcomas
with histopathological features, including tumor grade, as well as with markers
of cell proliferation and cell cycle regulatory gene expression that may be
prognostically or therapeutically important. All patients had undergone PET
before biopsy. Features evaluated included grade (National Cancer Institute for
soft tissue or Mayo Clinic for bone), cellularity, and the number of mitoses per
10 400x fields. Deparaffinized, formalin-fixed sections were immunostained with
antibodies to Ki-67 (MIB-1), p53 (DO7), p21WAF1 (EA10), and mdm-2 (1B10). For Ki
67, results were estimated as a percentage of positive cells. For p53 and mdm-2,
only cases with >20% positive cells were considered to be overexpressing these
proteins. For p21WAF1, only cases with <10% positive cells were considered to
have lost normal p21WAF1 expression. Tumor S-phase percentage and ploidy were
determined by flow cytometry. FDG-PET SUV was associated with histopathological
grade, cellularity, mitotic activity, MIB labeling index, and p53 overexpression.
No association was seen with p21WAF1, mdm-2, S-phase fraction, or ploidy. Tumor
metabolism data acquired by FDG-PET may help ensure accurate grading and
prognostication in sarcoma by guiding biopsy toward the most biologically
significant regions of large masses. Further follow-up will be necessary to
determine whether FDG-PET provides independent prognostic information.
PMID- 10778953
TI - Topotecan lacks third space sequestration.
AB - The objective of this study was to determine the influence of pleural and ascitic
fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan.
Four patients with histological proof of malignant solid tumor received topotecan
(0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of
third space volumes. Serial plasma and pleural or ascitic fluid samples were
collected during each dosing and analyzed by high-performance liquid
chromatography for both the intact lactone form of topotecan and its ring-opened
carboxylate form. The apparent topotecan clearance demonstrated substantial
interpatient variability but remained unchanged within the same patient in the
presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of
pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven
courses)]. Similarly, terminal half-lives and area under the concentration-time
curve ratios of lactone:total drug in plasma were similar between courses within
each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a
mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma
concentration increased with time after dosing in all patients. The mean ratio of
third space topotecan total drug area under the concentration-time curve to that
in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be
safely administered to patients with pleural effusions or ascites and that there
is substantial penetration of topotecan into these third spaces, which may prove
beneficial for local antitumor effects.
PMID- 10778954
TI - Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and
pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced
solid tumors.
AB - Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella
auricularia with clinically promising antitumor activity documented in various in
vitro and in vivo tumor models. The objectives of this Phase I study were to
determine the maximum tolerated dose, evaluate toxic effects, and document any
antitumor activity of this novel agent. Using an electrospray ionization mass
spectroscopy system, we also characterized the clinical pharmacokinetics,
pharmacodynamics, and metabolism of DOLA-10. The maximum tolerated dose was
reached at 300 microg/m2. Granulocytopenia, the dose-limiting toxicity, was
documented in 33% of the patients treated at that dose level. There were no
episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major
nonhematological toxicity was observed. Stabilization of tumor growth was
observed in four patients, but no objective responses were seen. Whereas a two
compartment model described the DOLA-10 plasma concentration-time data reasonably
well, a three-compartment model consistently performed better. After a rapid
distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half
lives of 0.99 and 18.9 h, respectively. Significant interpatient and intrapatient
variability in DOLA-10 plasma clearances was observed. The mean area under the
concentration-time curve increased proportionally as the dose was escalated, but
there was significant overlap between dose levels. The area under the
concentration-time curve and the percentage of decline in neutrophils were
correlated. A single DOLA-10 metabolite was detected in five patients. Unlike the
in vitro studies of DOLA-10, the principal metabolite detected was an N-demethyl
derivative, confirmed by mass spectroscopy. In all five subjects, the
concentration of this metabolite never exceeded 2% of the simultaneously measured
parent drug concentration. The available preclinical, pharmacological, and
clinical data suggest that further study of escalated DOLA-10 dosing with
cytokine support is warranted.
PMID- 10778955
TI - A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated
ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory
CD19(+), CD22(+) B cell lymphoma.
AB - This study used an 8-day continuous infusion regimen of a 1:1 mixture of two
immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to
monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA;
Combotox) in a Phase I trial involving 22 patients with refractory B cell
lymphoma to determine the maximum tolerated dose, clinical pharmacology, and
toxicity profile and to characterize any clinical responses. Adult patients
received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No
intrapatient dose escalation was permitted. Patients with > or =50 circulating
tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major
toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345
ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In
contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that
included two deaths probably related to the IT. Additionally, patients exhibited
a significant potential for association between mortality and a history of either
autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and
between mortality and a history of radiation therapy (P2 = 0.036). In patients
with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent
evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37
dgA. In addition, HD37-dgA thawed at the study site tended to contain significant
particulates, which were not apparent in matched controls stored at the
originating site. This suggests that a tendency to aggregate may have resulted
from shipping, storage, and handling of the IT that occurred prior to preparation
for administration. It is not clear to what extent, if any, the aggregation of
HD37-dgA IT was related to the encountered clinical toxicities; however, the
potential to aggregate does suggest one possible basis for problems in our
clinical experience with HD37-dgA and leads us to the conclusion that non
aggregate-forming formulations for these ITs should be pursued prior to future
clinical trials.
PMID- 10778956
TI - Intravenous ifosfamide/mesna is associated with depletion of plasma thiols
without depletion of leukocyte glutathione.
AB - Depletion of cellular glutathione (GSH) enhances the efficacy of many anticancer
agents in preclinical systems. Limited published data showing depletion of GSH in
vitro and in patients by ifosfamide and/or mesna provided the rationale for a
Phase I trial. Ifosfamide and mesna were infused over 24 and 36 h, respectively,
at equal daily doses; carboplatin was given after ifosfamide to a target plasma
area under the curve of 4 mg x min x ml(-1). Plasma and peripheral WBC thiols
were quantitated by high-performance liquid chromatography. The dose of
ifosfamide was escalated from 2 to 8 g/m2; the maximum tolerated dose was 6 g/m2.
Significant depletion in plasma cysteine and homocysteine, precursors for GSH
synthesis, was observed (maximum, 95% to >99% at 8 g/m2). Plasma mesna and
cysteine/ homocysteine levels were inversely correlated; nadir levels of
cysteine/homocysteine were maintained for several hours after ifosfamide infusion
had stopped and while mesna infusion was continuing. In vitro coincubation
experiments confirmed that mesna reduces these thiols from disulfides to
sulfhydryls, which are readily cleared, as evidenced by the significantly
increased rate of excretion of cysteine in urine. In contrast, ifosfamide/mesna
treatment caused a moderate depletion of plasma GSH in only 60% of the patients,
with a nadir at 24 h and recovery immediately after the end of ifosfamide
infusion. The GSH depletion in these patients was not dose related. The profile
of GSH recovery in plasma after ifosfamide and the fact that mesna could not
reduce GSH disulfides in vitro suggest that the observed GSH depletion in plasma
in 60% of the patients may be related to direct reactions of GSH with ifosfamide
metabolites and/or mesna. Our results indicate that mesna is a modulator of GSH
precursors and that a prolonged infusion of mesna may be required to achieve GSH
precursor starvation and the consequent GSH depletion in cells.
PMID- 10778957
TI - Colorectal tumors responding to 5-fluorouracil have low gene expression levels of
dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine
phosphorylase.
AB - We had previously shown that high gene expressions (mRNA levels) of thymidylate
synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223-3229, 1997) and
thymidine phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371-2376,
1998) in pretreatment tumor biopsies could identify tumors that would be
nonresponsive to 5-fluorouracil (5-FU)-based therapy. In this study, we
investigated the association between intratumoral gene expression of the
pyrimidine catabolism enzyme dihydropyrimidine dehydrogenase (DPD) and the
response of colorectal tumors to the same 5-FU-based protocol. DPD expressions
were measured by quantitative reverse transcription-PCR in 33 pretreatment
biopsies of colorectal tumors from patients who went on to receive treatment with
5-FU and leucovorin (LV). The range of DPD gene expression in those tumors that
were nonresponsive to 5-FU was much broader than that of the responding tumors.
None of the tumors with basal-level DPD expressions above a DPD:beta-actin ratio
of 2.5 x 10(-3) (14 of 33) were responders to 5-FU/LV therapy, whereas those
tumors with DPD gene expressions below DPD: beta-actin ratio of 2.5 x 10(-3) had
a response rate of 50%. There was no correlation among DPD, TS, and TP expression
values in this set of colorectal tumors, which indicated that these gene
expressions are independent variables. All of the tumors that responded to 5-FU
therapy (11 of 33) had expression values of all three of the genes, TS, TP, and
DPD, below their respective nonresponse cutoff values, whereas, in each of the
nonresponding tumors, at least one of these gene expressions was high. The
patients with low expression of all three of the genes had significantly longer
survival than patients with a high value of any one of the gene expressions. The
results of this study show that intratumoral gene expression level of DPD is
associated with tumor response to 5-FU and that the use of more than one
independent determinant of response permits the identification of a high
percentage of responding patients.
PMID- 10778958
TI - Sequential treatment of a resistant chronic lymphocytic leukemia patient with
bryostatin 1 followed by 2-chlorodeoxyadenosine: case report.
AB - Bryostatin 1 (Bryo-1) has been shown to differentiate chronic lymphocytic
leukemia (CLL) cells to the hairy cell leukemia phenotype. The purine analogue 2
chlorodeoxyadenosine (2-CdA) exhibits enhanced activity in patients with hairy
cell leukemia compared to those with CLL. Here we present a case report of a
patient diagnosed with resistant CLL and treated sequentially with Bryo-1
followed by 2-CdA for three cycles. Molecular and biochemical parameters relative
to the sequential treatment with these agents in vivo were comparable to those
found in the WSU-CLL cell line in vitro (R. M. Mohammad et al., Clin. Cancer
Res., 4: 445-453, 1998; R. M. Mohammad et al., Biol. Chem., 379: 1253-1261,
1998). There was a significant reduction of lymphocyte count from 37.1 x
10(3)/microl before the treatment to 3.4 x 10(3)/microl after treatment, and
partial remission was achieved 2 months after the treatment. The percentage of
morphologically differentiated lymphocytes was increased from 3% before treatment
to 92% with the first cycle of Bryo-1. Similarly, expression of CD22, a marker of
differentiation, increased from 38% to 97% and was maintained at a high level for
the duration of the treatment. Analysis of the molecular markers of apoptosis in
isolated peripheral blood lymphocytes revealed an increase in the Bax:Bcl-2 ratio
after treatment with Bryo-1 in cycles 2 and 3, with associated poly(ADP-ribose)
polymerase cleavage after Bryo-1 and 2-CdA treatment. The deoxycytidine kinase:
cytosolic 5'-nucleotidase activity ratio increased modestly after Bryo-1
treatment, indicating increased sensitivity of the peripheral blood lymphocytes
to 2-CdA. In summary, we found that sequential treatment with Bryo-1 and 2-CdA
caused a significant reduction in peripheral blood lymphocytes (CLL cells) with
simultaneous induction of differentiation and the initiation of the Bax: Bcl-2
apoptotic pathway.
PMID- 10778959
TI - A multicenter phase II trial of losoxantrone (DuP-941) in hormone-refractory
metastatic prostate cancer.
AB - Our purpose in this study was to determine the efficacy and toxicity of
losoxantrone (DuP-941), an anthrapyrazole, in patients with metastatic hormone
refractory prostate cancer. Patients with metastatic prostate cancer progressing
on androgen ablation therapy without demonstrable antiandrogen withdrawal
response were treated with losoxantrone 50 mg/m2 i.v. bolus every 21 days. All of
the patients had elevated serum prostate-specific antigen (PSA) before study
entry and had no prior chemotherapy. Forty-three assessable patients were
entered. The median age was 70.6 years (range, 53.9-85.9), median Karnofsky
performance scale (KPS), 70% (50-90%), and the median serum PSA, 173 microg/liter
(12.5-11,140). The median number of courses was 4 (1-9). Five patients (25%) had
a partial response as defined by >50% decline in the serum PSA. Two of nine
patients with measurable disease had partial responses and three had minor
responses. Thirty percent of patients had improvement in KPS and 37% had an
improvement in symptoms with decrease in pain and/or decrease in analgesic
requirement. Nonhematological grade 3 and 4 toxicities were one each of grade 3
headache, grade 4 hypocalcemia, grade 3 hyperbilirubinemia, and grade 3 dyspnea.
Twenty-six patients (60%) had grade 3 or 4 absolute neutropenia. In conclusion,
losoxantrone demonstrated a partial biochemical response rate of 25%, response in
measurable disease sites in 22%, and improvement in clinical symptoms in one
third of patients. In this study, PSA increase was not necessarily associated
with lack of palliative response.
PMID- 10778960
TI - 7-monohydroxyethylrutoside protects against chronic doxorubicin-induced
cardiotoxicity when administered only once per week.
AB - Doxorubicin is a very effective antitumor agent, but its clinical use is limited
by the occurrence of a cumulative dose-related cardiotoxicity, resulting in
congestive heart failure. 7-Monohydroxyethylrutoside (monoHER), a flavonoid
belonging to the semisynthetic hydroxyethylrutoside family, has been shown to
protect against doxorubicin-induced cardiotoxicity when administered i.p. at a
dose of 500 mg/kg five times/week in combination with a weekly i.v. dose of
doxorubicin. Such a dosing schedule would be very inconvenient in clinical
practice. We therefore investigated a dosing schedule of one administration of
monoHER just before doxorubicin. The electrocardiogram was measured
telemetrically in mice after the combined treatment of doxorubicin (4 mg/kg,
i.v.) with one dose of monoHER (500 mg/kg, i.p., administered 1 h before
doxorubicin) for 6 weeks. These data were compared with the five times/week
schedule (500 mg/kg, i.p., administered 1 h before doxorubicin and every 24 h for
4 days). The increase of the ST interval was used as a measure for
cardiotoxicity. It was shown that 500 mg/kg monoHER administered only 1 h before
doxorubicin provided complete protection against the cardiotoxicity. This
protection was present for at least 10 weeks after the last treatment. Because of
the short half-life of monoHER, these results suggest that the presence of
monoHER is only necessary during the highest plasma levels of doxorubicin.
PMID- 10778961
TI - Altered pharmacokinetics and metabolism of CPT-11 in liver dysfunction: a need
for guidelines.
AB - Metabolic conversion of CPT-11 is a major route of elimination of this new
topoisomerase 1 inhibitor. Presently, recommendations for dose adjustments of CPT
11 in patients with liver dysfunction are lacking. We describe the case of a
patient with metastatic colon cancer with liver dysfunction treated with CPT-11
at two different dose levels (100 mg/m2 and 30 mg/m2, single dose, administered
as a 90-min i.v. infusion). The lactones and carboxylates of CPT-11 and SN-38
were determined by high-performance liquid chromatography. SN-38 glucuronide was
determined after deglucuronidation. The procedures allowed intrapatient
comparison of pharmacokinetics and metabolism of the drug. Severe side effects
were encountered, which could be explained by the reduced clearance of CPT-11 and
its metabolites. These included neutropenic fever with culture-proven septicemia,
thrombocytopenia, somnolence, diarrhea, and signs and symptoms of transient
hepatic failure. Our findings offer important data for the further development of
guidelines for dose reduction of CPT-11 in patients with liver dysfunction.
PMID- 10778962
TI - Delayed-type hypersensitivity response is a predictor of peripheral blood T-cell
immunity after HER-2/neu peptide immunization.
AB - Many groups that immunize cancer patients with cancer vaccines use the generation
of a delayed-type hypersensitivity (DTH) response as the primary measure of the
ability to immunize a patient to a tumor cell or specific tumor antigen. This
study examines whether the development of a tumor antigen-specific DTH response,
measured after vaccination with peptide-based vaccines, correlates to in vitro
assessment of peripheral blood antigen-specific T-cell responses. The HER-2/neu
protein was used as a model tumor antigen. Thirty-two patients who completed a
course of immunization with HER-2/neu peptide-based vaccines were analyzed. HER
2/neu peptide-specific DTH responses (n = 93) and peripheral blood T-cell
responses (n = 93) were measured 30 days after the final immunization. Size of
DTH induration was correlated with HER-2/neu-specific T-cell proliferative
responses assessed from peripheral blood lymphocytes isolated concurrently with
peptide skin test placement. HER-2/neu peptide-specific DTH responses > or =10
mm2 correlated significantly to a measurable peptide-specific peripheral blood T
cell response defined as stimulation index >2.0 (P = 0.0006). However, antigen
specific DTH responses with magnitudes between 5 and 9 mm2 were not significantly
associated with the development of systemic immunity. DTH responses between 5 and
9 mm2 carried an odds ratio of 1.3 (P = 0.61) in predicting a measurable systemic
tumor antigen response. The findings presented here demonstrate that tumor
antigen-specific DTH responses > or =10 mm2 correlate with measurable in vitro
antigen-specific lymphocytic proliferation and are, in this model system, a
reflection of systemic immunization.
PMID- 10778963
TI - Spontaneous apoptosis of CD8+ T lymphocytes in peripheral blood of patients with
advanced melanoma.
AB - Peripheral blood mononuclear cells (PBMCs) obtained from patients with advanced
melanoma but not from healthy individuals were found to undergo spontaneous ex
vivo apoptosis upon incubation in medium. PBMCs were evaluated for evidence of
apoptosis using Annexin V binding, caspase-3 activation, and DNA fragmentation
(terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). PBMCs of
patients with melanoma contained a significantly higher proportion (P = 0.0027)
of spontaneously apoptotic cells than PBMCs of controls after 24-h incubation in
medium alone. The relative proportion of activated Fas+ and tumor necrosis factor
receptor 1-positive (TNFR1+) PBMCs was significantly higher in patients with
melanoma than that observed in controls. To demonstrate that the TNF family of
receptors and ligands was involved in this type of apoptosis, PBMCs were
incubated in the presence of agonistic anti-Fas antibody (CH-11) or TNF-alpha.
The proportion of terminal deoxynucleotidyl transferase-mediated dUTP nick end
labeling-positive PBMCs undergoing spontaneous apoptosis was found to be
comparable with that induced by CH-11 antibody or TNF-alpha. Three-color flow
cytometry revealed that CD3+ Fas+ T cells were especially sensitive to apoptosis
and were preprogrammed in vivo to die. Apoptosis occurred in all subsets of PBMCs
but was significantly higher (P = 0.01) in the CD3+ CD8+ T-cell subset in
patients relative to controls. In two patients with melanoma, who responded
clinically to dendritic cell-based peptide vaccines, the proportion of apoptotic
T cells was decreased by half after therapy. In patients who were treated
previously with vaccination-based therapies, levels of T-cell apoptosis were
lower than in the other melanoma patients. The observed accelerated death of T
cells, which are activated and susceptible to apoptosis in patients with
melanoma, may contribute to a rapid turnover of immune cells, resulting in a
decreased immunocompetence.
PMID- 10778964
TI - The orally administered P-glycoprotein inhibitor R101933 does not alter the
plasma pharmacokinetics of docetaxel.
AB - This Phase I study was performed to assess the feasibility of combining docetaxel
with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting
toxicity of this combination. Fifteen patients received oral R101933 alone at a
dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating
i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and
the combination (cycle 2 and further). Dose limiting toxicity consisting of
mucositis and neutropenic fever was reached at the combination of docetaxel, 100
mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established
at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of
R101933 achieved in patients were in the same range as required in preclinical
rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of
docetaxel were not influenced by the R101933 regimen at any dose level tested, as
indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/-
4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings
indicate that the contribution of a P-glycoprotein inhibitor to the activity of
anticancer chemotherapy can now be assessed in patients for the first time
independent of its effect on drug pharmacokinetics.
PMID- 10778965
TI - Definition and refinement of chromosome 8p regions of loss of heterozygosity in
gastric cancer.
AB - Loss of heterozygosity at several chromosomal loci is a common feature of the
malignant progression of human tumors. These regions are thought to harbor one or
more putative tumor suppressor gene(s) playing a role in tumor development.
Allelic losses on the short arm of chromosome 8 (8p) have been reported as
frequent events in several cancers, and three commonly deleted regions have been
defined at 8p11.2-12, 8p21-22, and 8p23.1. To evaluate the possible involvement
of these regions in gastric cancer, we used eight microsatellite markers to
perform an extensive analysis of allele loss at 8p21-22 in 52 cases of primary
gastric adenocarcinoma. We found that 44% of tumors showed allelic loss for at
least one marker at 8p21-22. The critical region of loss was found to be between
markers LPL and D8S258, which displayed loss of heterozygosity in 39% and 33% of
cases, respectively. This region is centromeric to the LPL locus and centered on
the D8S258 locus. We conclude that 8p22 deletion is a frequent event in gastric
cancer and suggest the presence of a putative tumor suppressor gene near the
D8S258 locus. Initial steps were taken toward the identification of this gene,
which is likely to play an important role in the pathogenesis of gastric cancer
and of other tumors as well.
PMID- 10778966
TI - Thymidylate synthase expression: an independent prognostic factor for local
recurrence, distant metastasis, disease-free and overall survival in rectal
cancer.
AB - Several studies have suggested that the intratumoral level of thymidylate
synthase (TS) in colorectal tumors correlates with survival. We have studied the
correlation between TS expression in primary rectal cancer and locoregional
recurrence, distant metastases, and survival. TS enzyme levels were evaluated
immunohistochemically using the specific monoclonal antibody TS 106 in paraffin
embedded tumors from 243 patients who had undergone primary surgery for rectal
cancer during the years 1980-1993. All patients were included in prospective
randomized trials aimed at determining the clinical value of a short preoperative
course of local radiation therapy (five doses of 5 Gy each). With a median follow
up of 94 months (range, 43-202 months), it was observed by multivariate analysis
that Dukes' stage and TS expression were independent prognostic markers of
locoregional recurrence (P < 0.001 and P = 0.038, respectively) distant
metastasis (P < 0.001 and P = 0.011, respectively) disease-free survival (P <
0.001 and 0.014, respectively), and overall survival (P < 0.001 and 0.020,
respectively). By multivariate analysis, preoperative irradiation therapy showed
a borderline improvement in locoregional recurrence (P = 0.051). No other
factors, such as age, sex, differentiation of the tumor, or p53 expression, were
noted to be independent prognostic factors for clinical outcome in these
patients. We concluded that the intratumoral expression of TS in primary rectal
cancer is an independent prognostic factor for locoregional recurrence, distant
metastases, disease-free survival, and overall survival. Patients with low
intratumoral TS expression had a significantly better outcome than those with
high TS expression.
PMID- 10778967
TI - Marked increase of trypsin(ogen) in serum of linitis plastica (gastric cancer,
borrmann 4) patients.
AB - Linitis plastica, or Borrmann 4 gastric cancer, shows very poor prognosis, and
the reason has not been understood. In the present study, we examined serum
levels of trypsin(ogen) in 44 gastric cancer patients, including 17 early gastric
cancer, 18 non-Borrmann 4 advanced gastric cancer, and 9 Borrmann 4 gastric
cancer, by using the RIA gnost Trypsin kit (Hoechst Japan, Tokyo, Japan), which
was expected to detect trypsin-1, trypsin-2, trypsinogen-1, and trypsinogen-2 in
sera. The trypsin(ogen) concentration was much higher in the patients with
linitis plastica than in the other gross types of gastric cancer.
Hypertrypsinemia was identified in approximately 60% of advanced gastric cancer
cases. Lymph node involvement, liver metastasis, or poorly differentiated
adenocarcinoma is an important factor of hypertrypsinemia. The serum
trypsin(ogen) level in linitis plastica patients was 3484.4 +/- 2319.7 ng/ml
(mean +/- SD), which was significantly higher not only than that of the early
gastric cancer (384.1 +/- 92.1) but also the stage IV gastric cancer patients
(578 +/- 440.4), excluding those with linitis plastica. The elevated serum
trypsinogen level in linitis plastica patients may be related to the malignant
behavior of this type of cancer cell. Serum trypsin(ogen) of linitis plastica
shows significantly higher concentrations than do the other types of advanced
gastric cancer. Therefore, serum concentration of trypsin(ogen) might be a good
marker of gastric cancer of linitis plastica.
PMID- 10778968
TI - Concentrations of galectin-3 in the sera of normal controls and cancer patients.
AB - Galectin-3, a member of the beta-galactoside-binding animal lectins, has been
implicated in tumor invasion and metastasis. Using an immunoligand assay, we
assessed the circulating levels of galectin-3 in sera from cancer patients as
well as from healthy controls. Low serum levels of galectin-3 were detected in
healthy individuals (median, 62 ng/ml; range, 20-313 ng/ml; 95th percentile,
184.3 ng/ml). Compared with healthy individuals, galectin-3 serum levels in
patients with breast, gastrointestinal, lung, or ovarian cancer, melanoma, and
non-Hodgkin's lymphoma were significantly elevated (P = 0.014). Moreover,
galectin-3 concentrations in sera from patients with metastatic disease were
higher than in sera from patients with localized tumors. Maximum serum
concentrations of galectin-3 (median, 320 ng/ml; range, 20-950 ng/ml) were found
in patients with metastatic gastrointestinal carcinoma. These results suggest
that circulating galectin-3 may play a role in tumor progression. The possibility
of using this assay in early-stage cancer to predict metastasis should be
studied.
PMID- 10778969
TI - Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG)
lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG
level in DNA.
AB - 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively
modified lesions in DNA. Our previous study (Kondo et al, Free Radic. Biol. Med.,
27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively
stressed based on 8-OHdG determination. To elucidate 8-OHdG metabolism and its
clinical significance in colorectal carcinoma, we studied the 8-OHdG repair
system in DNA by measuring specific lyase activity and hOGG1 expression using
quantitative-competitive reverse transcription-PCR. In addition, we searched for
the presence of mutations and single nucleotide polymorphisms of the hOGG1 gene
by single-strand conformational polymorphism and sequencing analyses. It was
found that 8-OHdG-specific lyase activity and hOGG1 expression were significantly
up-regulated in carcinoma, and a proportional association between 8-OHdG levels
and either 8-OHdG lyase activity (r = 0.641, P < 0.05) or hOGG1 expression (r =
0.702, P < 0.05) was present. Whereas no difference was detected in the 8-OHdG
level between early- and advanced-stage cancer, lyase activity (1.2-fold) and
hOG1 expression (1.6-fold) were significantly increased in advanced-stage cancer.
No mutation was found in the 25 tumors examined. Three kinds of single nucleotide
polymor. phism were observed, including that of codon 326 (Ser/Cys) in exon 7.
However, there was no correlation between any of the three polymorphic patterns
and either 8-OHdG level or lyase activity. These results suggest that increased 8
OHdG levels in colorectal carcinoma are attributed to increased formation and are
maintained by induced 8-OHdG repair activity at appropriate high levels. Our
results may offer a unique approach in the development of preventive and
therapeutic interventions as well as new insights into the pathogenesis of
colorectal carcinoma.
PMID- 10778970
TI - BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute
myelogenous leukemia.
AB - Previously, we demonstrated that the level of BCL2 expression is prognostic in
acute myelogenous leukemia (AML). High levels of BCL2 correlate with an adverse
outcome when associated with favorable and intermediate prognosis cytogenetics
(FIPC), whereas low levels portend an adverse outcome when associated with
unfavorable cytogenetics (UC). Because BCL2 function can be modulated by
dimerization with family members, like BAX, or by phosphorylation by protein
kinase C alpha (PKCalpha), we hypothesize that the relative expression of these
proteins in primary leukemic cells might alter the prognostic impact of BCL2
expression. We therefore measured BAX and PKCalpha protein levels in peripheral
blood mononuclear cell lysates from 165 newly diagnosed AML patients and
correlated the expression of these proteins with BCL2 expression, patient
survival, and remission induction success. Expression levels of BAX and PKCalpha
were normalized against a control cell line, K562. BAX and PKCalpha expression
levels were heterogeneous and did not correlate with the percentage of blasts in
the sample (R2 = 0.01 and <0.01). The median expression of both was similar
across FAB groups but the range was greater for M4. A similar distribution of
expression was observed in all cytogenetic groups, except that patients with
inversion 16 demonstrated lower levels of BAX. Individually, neither PKCalpha nor
BAX expression was prognostic of response to induction therapy or survival. A
similar outcome was obtained when patients were stratified by cytogenetics into
FIPC and UC groups. However, the ratio of either BCL2:BAX (B2:BX) or
PKCalpha*B2:BX (PK*B2:BX) was highly prognostic. Patients with FIPC and a lower
ratio (less than median) of either B2:BX or PK*B2:BX had a significantly higher
remission induction rate (88 versus 69%, P = 0.04) and longer survival (median:
141 versus 80.5 weeks, P = 0.007) compared with those with ratios more than
median. For patients with UC, values of either B2:BX or PK*B2:BX below the median
had an inferior response rate to induction therapy (35 versus 78%, P = 0.0006)
and inferior survival outcomes (median survival: 11 versus 53 weeks, P =
0.00002). Interestingly, FIPC and UC patients with antiapoptotic ratios (defined
as B2:BX or PK*B2:BX more than median) had identical response rates and survival
outcomes. In multivariate analyses, the compound variables of cytogenetics and
B2:BX, or PK*B2:BX were independent predictors of survival. These results suggest
that expression levels of proteins that affect the functional status of BCL2
modify the prognostic impact of BCL2 and suggest that the role of apoptosis in
different cases of AML varies independently in the different cytogenetic
subgroups.
PMID- 10778971
TI - Allelic loss and microsatellite alterations of chromosome 3p14.2 are more
frequent in recurrent cervical dysplasias.
AB - Epidemiological studies have documented the unpredictable clinical progression or
recurrence of cervical dysplasia. Recent studies have shown several molecular
changes in cervical cancers and their associated dysplasia. We conducted
molecular analyses on a retrospectively ascertained cohort of recurrent and
nonrecurrent cervical dysplasia cases in an attempt to define molecular
biomarkers to predict progressive or recurrent disease. Cases were chosen if long
term follow-up (3-5 years after conization) and biopsy confirmation were
available. Paraffin-embedded, postconization cervical tissues from 19 recurrent
and 18 nonrecurrent dysplasias were analyzed. Human papillomavirus (HPV) was
identified by PCR for general and type-specific (HPV-16 and HPV-18) primers.
Allelotyping analysis was performed by multiplex PCR using a panel of 16
microsatellite markers targeting putative tumor suppressor gene regions on
chromosomes 3p, 5p, 6p, 9p, 11q, and 17p. The overall rate of HPV infection was
similar in both groups. In the allelotyping analysis, loss of heterozygosity at
the fragile histidine triad region in 3p14.2 was significantly higher in the
recurrent group than in the nonrecurrent group (P = 0.005). Furthermore,
microsatellite alterations (MAs) were more frequent in the recurrent group (mean
MA index, 0.254) as compared with the nonrecurrent group (mean MA index, 0.085; P
= 0.0025). These findings suggest that HPV status alone does not predict
recurrence and that loss of heterozygos. ity at the fragile histidine triad
region may represent a potential biomarker in predicting recurrence. Frequent MAs
in the recurrent group may represent an underlying genomic instability that
creates susceptibility for allelic loss, thus increasing the risk for recurrence
or progression.
PMID- 10778972
TI - Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum
drug-based chemotherapy.
AB - Preclinical studies have demonstrated a relationship between DNA mismatch repair
(MMR) status and sensitivity to cisplatin and carboplatin. MMR-deficient cells
are resistant to both drugs, and selection for cisplatin resistance in vitro is
sometimes accompanied by loss of MMR protein expression. We used
immunohistochemical staining techniques to investigate hMLH1 and hMSH2 expression
in paired ovarian tumor sections from 54 ovarian cancer patients before and after
platinum-based therapy. We sought associations between hMLH1 and hMSH2 protein
expression and clinical parameters known to be of prognostic significance as well
as response to treatment and overall survival. hMLH1 and hMSH2 staining decreased
significantly after platinum-based therapy. The percent of malignant cells that
stained positive correlated with the intensity of nuclear staining for both
proteins; staining for hMLH1 correlated well with staining for hMSH2.
Unexpectedly, expression of nuclear hMLH1 correlated negatively with response to
treatment. Expression of nuclear hMLH1 and hMSH2 was positively correlated with
pretreatment CA125 level, and expression of nuclear hMSH2 was positively
correlated with change in CA125 level after treatment. Tumor stage was associated
with expression of nuclear hMSH2, and tumor histological subtype was associated
with both hMLH1 and hMSH2 staining. No association was found between expression
of either protein and overall survival. These results indicate that the tumor is
biologically altered after chemotherapy consistent with treatment-induced
selection for cells expressing lower hMLH1 and hMSH2 levels. However,
immunohistochemical staining for either hMLH1 or hMSH2 was not highly predictive
of drug sensitivity as measured by response or survival.
PMID- 10778973
TI - A large 6q deletion is a common cytogenetic alteration in fibroadenomas, pre
malignant lesions, and carcinomas of the breast.
AB - To assess whether early breast lesions are the precursors of invasive carcinomas,
three classes of breast lesions, namely benign tumors (including fibroadenomas),
putative premalignant lesions (including cases of atypical hyperplasia), and
invasive carcinomas, were compared at the cytogenetic and molecular cytogenetic
levels. Genetic relatedness was clearly demonstrated by the sharing of several
anomalies, among which 6q deletions outnumbered all of the other alterations
detected. Indeed, deletions of the long arm of chromosome 6, most likely
occurring in epithelial cells, were present in 83.9% of benign breast tumors, 64%
of putative premalignant lesions, and 77.4% of analyzable carcinomas.
Furthermore, the interval between 6q24 and qter appeared to be the common region
of deletion in all three classes of breast lesions, whereas the minimal common
region of deletion was 6q27-qter. Interestingly, the latter region was reported
previously to be deleted in benign ovarian tumors and recently found to harbor a
gene (SEN6) that is important for SV40-mediated immortalization of human cells.
PMID- 10778974
TI - CpG island arrays: an application toward deciphering epigenetic signatures of
breast cancer.
AB - CpG island hypermethylation is a frequent epigenetic event in cancer. We have
recently developed an array-based method, called differential methylation
hybridization (DMH), allowing for a genome-wide screening of CpG island
hypermethylation in breast cancer cell lines (T. H-M. Huang et al., Hum. Mol.
Genet., 8: 459-470, 1999). In the present study, DMH was applied to screen 28
paired primary breast tumor and normal samples and to determine whether patterns
of specific epigenetic alterations correlate with pathological parameters in the
patients analyzed. Amplicons, representing a pool of methylated CpG DNA derived
from these samples, were used as hybridization probes in an array panel
containing 1104 CpG island tags. Close to 9% of these tags exhibited extensive
hypermethylation in the majority of breast tumors relative to their normal
controls, whereas others had little or no detectable changes. Pattern analysis in
a subset of CpG island tags revealed that CpG island hypermethylation is
associated with histological grades of breast tumors. Poorly differentiated
tumors appeared to exhibit more hypermethylated CpG islands than their moderately
or well-differentiated counterparts (P = 0.041). This early finding lays the
groundwork for a population-based DMH study and demonstrates the need to develop
a database for examining large-scale methylation data and for associating
specific epigenetic signatures with clinical parameters in breast cancer.
PMID- 10778975
TI - Detection of circulating tumor cells in carcinoma patients by a novel epidermal
growth factor receptor reverse transcription-PCR assay.
AB - The epidermal growth factor receptor (EGFR) is overexpressed in 50-70% of human
primary breast, lung, and colon carcinomas, whereas it is not usually expressed
in hematopoietic cells. We developed a novel reverse transcription-PCR (RT-PCR)
Southern blot assay for the detection of circulating, EGFR mRNA-expressing tumor
cells in carcinoma patients. The assay was set up by increasing the amount of
cDNA step by step in the PCR reaction. The highest sensitivity and specificity
were found when using 800 ng of cDNA in the PCR reaction. Peripheral blood
samples from 91 patients with either colon (38), lung (30), or breast (23)
carcinomas and from 38 healthy volunteers were analyzed. EGFR transcripts were
found in 44 of 75 (59%) patients with metastatic carcinoma and in 4 of 38 (10.5%)
healthy donors (P < 0.001; chi2 test). The expression of EGFR, cytokeratin 19,
and carcinoembryonic antigen mRNA in blood samples from patients with metastatic
colon carcinoma was compared. EGFR, cytokeratin 19, and carcinoembryonic antigen
transcripts were found in 8 of 11 (73%), 3 of 11 (27%), and 5 of 11 (45%)
patients, respectively. Furthermore, two of seven (29%) Dukes' B and five of nine
(55%) Dukes' C colon carcinoma patients were found to express EGFR mRNA in the
peripheral blood. All patients that expressed EGFR transcripts in the peripheral
blood were found to express the EGFR protein in the corresponding primary
carcinoma, as assessed by immunohistochemistry. These data suggest that the EGFR
assay that we developed is a highly specific and sensitive technique to detect
circulating tumor cells in patients affected by different carcinoma types.
PMID- 10778976
TI - Clinical significance of serum soluble interleukin 2 receptor-alpha in esophageal
squamous cell carcinoma.
AB - Although the serum level of soluble interleukin-2 receptor alpha (sIL-2Ralpha)
has been shown to correlate with progression and prognosis of several cancers,
data to support its clinical significance to esophageal squamous cell carcinoma
(ESCC) are limited. This study was conducted to assess the prognostic value and
source of sIL-2Ralpha in patients with ESCC. From January 1986 to June 1997, 125
patients with histopathologically confirmed ESCC were enrolled for study. Ninety
three patients underwent en bloc esophagectomy, and 32 patients with unresectable
tumor underwent palliative surgery. Four (4.3%; 4 of 93) patients died of
surgical complications. Serum levels of sIL-2Ralpha were measured by ELISA.
Expression of IL-2Ralpha, IL-2Rbeta, and IL-2Rgamma in the pathological section
was determined, respectively, by immunohistochemistry (IHC) and in situ
hybridization (ISH). Compared with the healthy control group (1020 +/-476 pg/ml,
n = 103), ESCC patients tended to have significantly higher serum sIL-2Ralpha
concentrations (1424 +/- 798 pg/ml, n = 121). The sIL-2Ralpha level was
correlated with age, Tumor-Node-Metastasis classification, tumor stage, reading
score of the IHC staining, and survival but not with the pathological grade or
lymphovascular invasion. Prognosis was worse for patients with high sIL-2Ralpha
levels (> or =1500 pg/ml) than for those with low serum sIL-2Ralpha levels (<
1500 pg/ml; P = 0.0209). It can be used as an independent prognostic factor of
ESCC. In the pathological sections, expression of IL-2Ralpha, IL-2Rbeta, and IL
2Rgamma was detected in 17 (18.1%), 83 (89.2%), and 83 (89.2%) cases,
respectively, by IHC, and the message of IL-2Ralpha was identified in tumor cells
by ISH in 30.1% (28 of 93) of the cases. Serum concentrations of sIL-2Ralpha are
frequently elevated in ESCC patients and are correlated with disease progression
and survival. These data indicate that, in addition to activated T cells, cancer
cells could be an important source of sIL-2Ralpha in ESCC patients.
PMID- 10778977
TI - A novel approach for nasopharyngeal carcinoma treatment uses phenylbutyrate as a
protein kinase C modulator: implications for radiosensitization and EBV-targeted
therapy.
AB - Sodium phenylbutyrate (NaPB) represent a new non-toxic class of compounds with
antiproliferative activities to different tumors and has been shown to modulate
many gene expressions by inhibiting histone deacetylation and DNA methylation as
the major mechanism. Butyrate and other protein kinase C (PKC) activators have
been reported to be able to activate virus enzymes. The present work investigates
whether NaPB has an antiproliferative effect or modulatory effects on EBV
associated nasopharyngeal carcinoma (NPC) and whether EBV thymidine kinase gene
can be activated to make cells susceptible to ganciclovir (GCV) therapy. NaPB
treatment displayed a dose- and time-dependent antiproliferative effect on the
NPC cell line CNE2. Cell cycle analysis revealed an inhibitory effect of NaPB on
G1-S-phase progression. Shortly after NaPB treatment, we found that PKC activity
was activated rapidly but also decreased rapidly. Down-regulation of PKC-alpha
and translocation of PKC-alpha from the cytosol to membrane were seen by Western
blot. The decrease in PKC activity by NaPB corresponds to an enhanced response to
radiation on CEN2 cells. Moreover, NaPB up-regulated EBV thymidine kinase
activity to render EBV-associated Daudi cells susceptible to killing by GCV.
Based on the observations of NaPB as a PKC modulator, the combination of NaPB,
GCV, and radiation may provide a potential novel approach for treatment of EBV
associated NPC.
PMID- 10778978
TI - High avidity melanoma-reactive cytotoxic T lymphocytes are efficiently induced
from peripheral blood lymphocytes on stimulation by peptide-pulsed melanoma
cells.
AB - To design an efficient procedure to expand high avidity melanoma reactive T cells
and to perform immunotherapies, we compared conditions of peripheral blood
lymphocyte (PBL) stimulation by Melan-A/MART-1 peptides. Avidity of induced CTLs
was evaluated by measuring their lysis and cytokine secretion to peptide-pulsed
transporter-associated protein-deficient cells and to melanoma cells. In side-by
side experiments, we show that melanoma cells, either allogeneic or autologous,
induced the growth of high avidity Melan-A-reactive CTLs from all donors, whereas
essentially low avidity T cells were induced by peptide-pulsed PBLs. We also show
that at least two cytokines, interleukin-6 and interleukin-2, were required to
promote the growth of high avidity CTLs. Once sorted by tetramer labeling or
cloning, the specificity and reactivity to tumor cells of peptide-specific T
cells induced by allogeneic melanoma cells were confirmed. We then describe a
relatively simple and efficient procedure that allowed us to obtain
systematically high amounts (in the range of billion) of high avidity Melan-A/
MART-1-specific T cells from the PBLs of HLA-A2 melanoma patients and healthy
donors in 3 months. Because this antigen is expressed by most melanoma tumors,
this procedure should be useful for checking the efficiency of adoptive
immunotherapy of melanoma tumors and using functionally well-defined Melan-A/MART
1-specific CTLs in a large group of patients.
PMID- 10778979
TI - Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2
pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine
radiosensitization in U251 human glioblastoma xenografts.
AB - In anticipation of an initial clinical Phase I trial in patients with high-grade
gliomas of p.o. administered 5-iodo2-pyrimidinone-2'-deoxyribose (IPdR) given
daily for 14 days as a prodrug for 5-iodo-2'-deoxyuridine (IUdR)-mediated tumor
radiosensitization, we determined the systemic toxicities and the percentage IUdR
DNA incorporation in normal athymic mouse tissues and a human glioblastoma
xenograft (U251) after this dosing schedule of IPdR. Using a tumor regrowth assay
of s.c. U251 xenografts, we also compared radiosensitization with this IPdR
dosing schedule to radiation therapy (XRT) alone (2 Gy/day for 4 days) or to XRT
after continuous infusion IUdR for 14 days at the maximum tolerated dose in mice
(100 mg/kg/day). Athymic mice with and without U251 s.c. xenografts tolerated 750
or 1500 mg/kg/day of p.o. IPdR (using gastric lavage) for 14 days without weight
loss or activity level changes during treatment and for a 28-day posttreatment
observation period. The percentage IUdR-DNA incorporation in U251 tumor cells was
significantly higher after p.o. IPdR (750 and 1500 mg/kg/day) for 14 days (3.1 +/
0.2% and 3.7 +/- 0.3%, respectively) than continuous infusion IUdR for 14 days
(1.4 +/- 0.1%). Compared to XRT alone, a significant sensitizer enhancement ratio
(SER) was found with the combination of p.o. IPdR (1500 mg/kg/d) + XRT (SER =
1.31; P = 0.05) but not for the combination of continuous infusion IUdR + XRT
(SER = 1.07; P = 0.57) in the U251 xenografts. The percentage IUdR-DNA
incorporation after IPdR at 1500 mg/kg/day for 14 days in normal bone marrow,
normal small intestine, and normal liver were 1.2 +/-0.2%, 3.3 +/- 0.3%, and 0.2
+/- 0.1%, respectively. We conclude that a 14-day p.o. schedule of IPdR at up to
1500 mg/kg/day results in no significant systemic toxicity in athymic mice and is
associated with significant radiosensitization using this human glioblastoma
multiforme xenograft model. Based on these data and our previously published data
using shorter IPdR dosing schedules, which also demonstrate an improved
therapeutic index for IPdR compared to IUdR, an initial clinical Phase I and
pharmacokinetic study of p.o. IPdR daily for 14 days is being designed.
PMID- 10778980
TI - Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)
PE38 (BL22) toward fresh malignant cells from patients with B-cell leukemias.
AB - Chemical conjugates of anti-CD22 monoclonal antibodies and toxins have been used
to treat CD22+ hematological malignancies. A new anti-CD22 recombinant
immunotoxin RFB4(dsFv)-PE38, composed of the Fv portion of the monoclonal
antibody RFB4 fused to a truncated form of Pseudomonas exotoxin A, is being
developed to target CD22+ tumor cells. To explore the potential clinical utility
of this recombinant toxin in treating patients with B-cell malignancies, the
fresh cells of patients were incubated ex vivo with RFB4(dsFv)-PE38. Specific
cytotoxicity was demonstrated in the malignant cells of 25 of 28 patients with a
variety of B-cell malignancies, including acute and chronic lymphocytic leukemias
and large cell, mantle cell, and follicular lymphomas. The IC50S, the
concentrations necessary for 50% inhibition of protein synthesis, were 3-10 ng/ml
in five patients and 10-50 ng/ml in seven patients. Cytotoxicity correlated with
cell death upon direct examination of the malignant cells. Significant
cytotoxicity was observed with cells containing as few as 350 CD22 sites/cell. A
more active derivative of RFB4(dsFv)-PE38, RFB4(dsFv)-PE38KDEL, was produced and
was slightly to more than 10-fold more cytotoxic toward patient cells and about
twice as toxic to mice. Thus, RFB4(dsFv)-PE38 was specifically cytotoxic toward
malignant cells from patients with B-cell leukemias. These data support the
testing of RFB4(dsFv)-PE38 in patients with CD22+ leukemias and lymphomas, which
is presently under way.
PMID- 10778981
TI - Differential cytotoxic pathways of topoisomerase I and II anticancer agents after
overexpression of the E2F-1/DP-1 transcription factor complex.
AB - The transcription factor complex E2F-1/DP-1 regulates the G1-to-S-phase
transition and has been associated with sensitivity to the S-phase-specific
anticancer agents camptothecin and etoposide, which poison DNA topoisomerase I
and II, respectively. To investigate the relationship between E2F-1 and drug
sensitivity in detail, we established human osteosarcoma U-20S-TA cells
expressing full-length E2F-1/ DP-1 under the control of a tetracycline-responsive
promoter, designated UE1DP-1 cells. Topoisomerase I levels and activity as well
as the number of camptothecin-induced DNA single- and double-strand breaks were
unchanged in UEIDP-1/tc- cells with >10-fold E2F-1/DP-1 overexpression. However,
UE1DP-1/tc- cells were hypersensitive to camptothecin in both a clonogenic assay
and four different apoptotic assays. This indicates that camptothecin-induced
toxicity in this model is due to the activation of an E2F-1/ DP-1-induced post
DNA damage pathway rather than an increase in the number of replication forks
caused by the S-phase initiation. In contrast, topoisomerase IIalpha levels (but
not topoisomerase IIbeta levels), together with topoisomerase IIalpha promoter
activity, increased 2--3-fold in UE1DP-1/tc-cells. Furthermore, the number of
etoposide-induced DNA single- and double-strand breaks increased in UE1DP-1/tc
cells together with a rise in clonogenic sensitivity to etoposide, but an equal
apoptotic sensitivity to etoposide. The increase in topoisomerase IIalpha
promoter activity in UE1DP-1/tc--cells was shown to be due to S-phase initiation
per se because it was blocked by ectopic expression of dominant negative cyclin
dependent kinase 2. In conclusion, overexpression of E2F-1/DP-1 in U-20S-TA cells
is sufficient to increase clonogenic sensitivity to both topoisomerase I- and II
targeted anticancer drugs. However, the mechanism by which this occurs appears to
be qualitatively different. The UE1DP-1 cell model may be used to elucidate post
DNA damage mechanisms of cell death induced by topoisomerase I-directed
anticancer agents.
PMID- 10778982
TI - The in vivo effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic
entry, and blood flow.
AB - Pretreatment of tumor cells with the protein kinase C (PKC) inhibitor bryostatin
1 enhances the cytotoxicity of most chemotherapeutic agents. However, in the case
of paclitaxel, this effect has been shown in vitro to be best achieved when
bryostatin-1 follows (rather than precedes) paclitaxel treatment. With
combination trials of bryostatin-1 and paclitaxel planned for clinical trials and
with only in vitro data available regarding drug sequence, we elected to
undertake an in vivo study evaluating the effect of sequential bryostatin-1 and
paclitaxel in a tumor-bearing mouse model and to correlate this effect to cell
cycle events, tumor metabolism, and tumor blood flow. At the maximum tolerated
i.p. dose, bryostatin-1 at 80 microg/kg resulted in a small but significant
increase in tumor doubling time (4.2 +/- 0.3 days) compared with control tumors
(3.0 +/- 0.3 days; P < 0.01). Mice treated with i.v. paclitaxel, administered at
a dose of 12 mg/kg every 12 h for three doses, weekly for 3 weeks, had a tumor
doubling time of 23.4 +/- 1.7 days. Mice pretreated with i.p. bryostatin-1 (80
microg/kg) followed 12 h later by i.v. paclitaxel (12 mg/kg every 12h for three
doses) weekly for 3 weeks had a tumor doubling time of 9.7 +/- 1.1 days. This was
significantly less (P < .001) than paclitaxel alone, which indicated an
inhibitory effect by bryostatin-1 on paclitaxel therapy. In comparison, tumor
bearing mice that were treated with the same dose but with the sequence of
paclitaxel followed by bryostatin-1 had a tumor doubling time of 29.6 +/- 0.6
days. This was significantly greater than the tumor doubling times for any
condition tested (P < 0.01), demonstrating the sequence dependence of this
combination. The efficacy of paclitaxel is dependent on mitotic entry, a step
that requires activation of p34cdc2 kinase activity. Treatment with paclitaxel in
vivo increased p34 cdc2 kinase activity in the mouse mammary tumors, whereas
administration of bryostatin-1 before paclitaxel prevented the p34cdc2 kinase
activation by paclitaxel. This was further evaluated in vitro by flow cytometry
in MKN-74 human gastric cancer cells. As determined by MPM-2 labeling, which
identifies cells in mitosis, pretreatment with bryostatin-1 prevented paclitaxel
treated cells from entering mitosis. Bryostatin-1 has been reported to induce
changes in muscle metabolism and to decrease muscle blood flow. These events
could impact on the interaction of bryostatin-1 with paclitaxel. Using proton
decoupled phosphorus nuclear magnetic resonance (31P-NMR) spectroscopy in vivo,
bryostatin-1 at 80 micro1g/kg induced a decrease in both intratumoral pH and high
energy phosphates. In vivo perfusion studies, using dynamic enhanced NMR imaging
with gadolinium diethylenetriamine pentaacetic acid, also demonstrated decreased
tumor blood flow. These studies suggest that the inhibition of tumor response to
paclitaxel by bryostatin-1 is multifactorial and includes such diverse factors as
inhibition of cell entry into mitosis, a decrease in pH and energy metabolism,
and a decrease in tumor blood flow. These results indicate that, as this
combination enters Phase I clinical trials, the sequence of paclitaxel followed
by bryostatin-1 will be critical in the clinical trial design.
PMID- 10778983
TI - Synergistic effect of prochlorperazine and dipyridamole on the cellular retention
and cytotoxicity of doxorubicin.
AB - Incubation of drug-resistant human tumor cells with a combination of
prochlorperazine and dipyridamole has additive/synergistic effect on the cellular
retention and cytotoxicity of doxorubicin. In patients administered a fixed dose
of doxorubicin and prochlorperazine with escalating doses of dipyridamole, mean
plasma levels of dipyridamole and prochlorperazine achieved were as high as 3.01
+/- 0.41 microm and 0.94 +/- 0.09 microm, respectively. Plasma samples from
patients were analyzed in an in vitro assay to monitor the effect on the cellular
retention of tritium-labeled daunorubicin in MDR1-transfected P388 cells. In 22
of 49 of the plasma samples analyzed, the daunorubicin in efflux blocking
activity was one-half or greater than that of cells incubated with 12.5 microM
verapamil, a well-known efflux blocker. These observations suggest that a
combination of prochlorperazine and dipyridamole may enhance cellular doxorubicin
retention by blocking efflux while reducing normal tissue toxicity and unwanted
side effects in vivo.
PMID- 10778984
TI - Requirement for the von Hippel-Lindau tumor suppressor gene for functional
epidermal growth factor receptor blockade by monoclonal antibody C225 in renal
cell carcinoma.
AB - Renal cell carcinoma (RCC) is a cytologically and histologically diverse disease
in which a spectrum of distinct molecular alterations occurs, including the
inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is
specific for the clear cell variant of RCC. The prognosis for RCC is poor, and,
to date, no effective systemic treatment is available for this cancer. In the
present study, we assessed the extent to which the transforming growth factor
alpha-epidermal growth factor receptor (EGFR) autocrine loop could be used as a
potential therapeutic target for RCC. Northern blot analysis of transforming
growth factor alpha and EGFR revealed variable but consistent expression of these
transcripts in cell lines derived from both clear cell and non-clear cell RCC
variants, indicating the potential for this autocrine loop in both tumor types.
The therapeutic utility of interruption of this feedback loop was determined by
examining growth inhibition after the exposure of these cell lines to a humanized
anti-EGFR monoclonal antibody, C225. In vitro treatment of clear cell RCC-derived
cell lines lacking VHL resulted in only a modest decrease in growth rate. In
contrast, non-clear cell RCC-derived cell lines that retained VHL responded
significantly to C225 treatment. Transfection of VHL into VHL-negative RCC cell
lines restored responsiveness to C225, indicating that this tumor suppressor gene
is required for effective EGFR blockade. Growth inhibition by C225 in VHL
positive cells was linked to a requirement for VHL to up-regulate p27 in response
to C225. These data provide compelling evidence that treatment modalities for RCC
are likely to be strongly influenced by the molecular etiology of this
phenotypically diverse cancer.
PMID- 10778985
TI - Differential antiproliferative and apoptotic response of sanguinarine for cancer
cells versus normal cells.
AB - Sanguinarine, derived from the root of Sanguinaria canadendid, has been shown to
possess antimicrobial, anti-inflammatory, and antioxidant properties. Here we
compared the antiproliferative and apoptotic potential of sanguinarine against
human epidermoid carcinoma (A431) cells and normal human epidermal keratinocytes
(NHEKs). Sanguinarine treatment was found to result in a dose-dependent decrease
in the viability of A431 cells as well as NHEKs albeit at different levels
because sanguinarine-mediated loss of viability occurred at lower doses and was
much more pronounced in the A431 carcinoma cells than in the normal
keratinocytes. DNA ladder assay demonstrated that compared to vehicle-treated
control, sanguinarine treatment of A431 cells resulted in an induction of
apoptosis at 1-, 2-, and 5-microM doses. Sanguinarine treatment did not result in
the formation of a DNA ladder in NHEKs, even at the very high dose of 10 microM.
The induction of apoptosis by sanguinarine was also evident by confocal
microscopy after labeling the cells with annexin V. This method also identified
necrotic cells, and sanguinarine treatment also resulted in the necrosis of A431
cells. The NHEKs showed exclusively necrotic staining at high doses (2 and 5
microM). We also explored the possibility of cell cycle perturbation by
sanguinarine in A431 cells. The DNA cell cycle analysis revealed that
sanguinarine treatment did not significantly affect the distribution of cells
among the different phases of the cell cycle in A431 cells. We suggest that
sanguinarine could be developed as an anticancer drug.
PMID- 10778987
TI - Apoptosis-inducing vanadocene compounds against human testicular cancer.
AB - We systematically assessed the cytotoxic effects of five metallocene dichlorides
containing vanadium (vanadocene dichloride), titanium (titanocene dichloride),
zirconium (zircodocene dichloride), molybdenum (molybdocene dichloride), and
hafnium (hafnocene dichloride) as the central metal atom and 19 other vanadocene
complexes. These compounds were tested against the human testicular cancer cell
lines Tera-2 and Ntera-2 using both 3-(4,5-dimethylthiazol-2-yl)-2,5
diphenyltetrazolium bromide assays and apoptosis assays. Notably, only the
vanadium(IV)-containing metallocenes exhibited significant cytotoxicity against
Tera-2 and Ntera-2 cells and induced apoptosis within 24 h. Vanadocenes with
dithiocyanate [VCp2(SCN)2 x 0.5 H2O] and diselenocyanate [VCp2(NCSe)2] as
ancillary ligands were identified as the most potent cytotoxic compounds.
Vanadocenes, especially the lead compound VCp2(NCSe)2, may be useful in the
treatment of testicular cancer.
PMID- 10778986
TI - Enhanced antitumor activity of 5-fluorouracil in combination with 2'-deoxyinosine
in human colorectal cell lines and human colon tumor xenografts.
AB - We investigated the effects of 2'-deoxyinosine (d-Ino), a modulator yielding
thymidine phosphorylase activity, on cellular pharmacology of 5-fluorouracil
(FUra) in various human colorectal cell lines and its antitumoral activity when
combined with FUra in human xenografts. Associating d-Ino with FUra increased by
38 up to 700 times the sensitivity of HT29 and FUra-resistant SW620 lines,
respectively, but not of CaCO2 cells, although high levels of intracellular FdUMP
and subsequent higher thymidylate synthase inhibition were observed. Cell death
studies confirmed the ability of d-Ino to enhance both early and late apoptosis
induced by FUra in HT29 and SW620 but not in CaCo2. Similarly, we showed that
associating d-Ino increased by 68 up to 101% the Fas overexpression induced by
FUra in HT29 and SW620 but not in CaCo2 cells. Anti-Fas and anti-FasL antibodies
both partly reversed this increase of cell sensitivity, thus confirming the role
Fas plays in the modulation of FUra toxicity by d-Ino. This Fas component could
explain the discrepancy between the lines because CaCO2 has been described as
insensitive to Fas-mediated apoptosis. Antitumor activity of the combination was
next investigated in nude mice transplanted with SW620. Results showed that
although FUra alone has little effect on SW620 xenografts (P > 0.05), associating
d-Ino significantly reduced the tumor growth by 57% (P < 0.05). This study
suggests that it is possible to reduce both in vitro and in vivo resistance to
FUra by modulating the way the drug is converted after cellular uptake.
PMID- 10778988
TI - Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) as a novel apoptosis
inducing anticancer agent.
AB - In a systematic effort to identify a potent anticancer agent, we synthesized 15
oxovanadium(IV) complexes and examined their cytotoxic activity against 14
different human cancer cell lines. The oxovanadium compounds included mono and
bis ancillary ligands of 1,10-phenanthroline (phen) [VO(phen), VO(phen)2, VO(Me2
phen), VO (Me2-phen)2, VO(Cl-phen), VO(Cl-phen)2, VO(NO2-phen), VO(NO2-phen)2],
2,2'-bipyridyl (bipy) [VO(bipy), VO(bipy)2, VO(Me2-bipy), VO(Me2-bipy)2], and 2
2'-bipyrimidine(bipym) [VO(bipym) and VO-(bipym)2], linked via nitrogen atoms,
and 5'-bromo-2'-hydroxyacetophenone (acph) [VO(acph)2], linked via oxygen donor
atom. The mono-chelated [VO(Me2-phen), compound 3] and bis-chelated-phen[VO(Me2
phen)2, compound 4] complexes were the most potent oxovanadium compounds and
killed target cancer cells at low micromolar concentrations. Notably, the
dimethyl substitution of the phenanthroline rings was essential for the
anticancer activity of both compound 4 [VO(Me2-phen)2] and compound 3 [VO(Me2
phen)] because unsubstituted bis-chelated and mono-chelated phen oxovanadium(IV)
complexes [VO(phen), compound 1, or VO(phen)2, compound 2] were less active.
Addition of a chloro or nitro group to the phen complexes did not significantly
improve the cytotoxic activity of the unsubstituted oxovanadium(IV) complexes.
Irrespective of the ligands, bis-chelated phenanthroline containing compounds
showed better activity than the mono-chelated phenanthroline containing
complexes. The marked differences in the cytotoxic activity of oxovanadium(IV)
complexes containing different heterocyclic ancillary ligands suggest that the
cytotoxic activity of these compounds is determined by the identity of the five
member bidentate ligands, as well as the nature of the substitutents on the
heterocyclic aromatic rings. Our results presented herein provide experimental
evidence that oxovanadium compounds induce apoptosis in human cancer cells.
Oxovanadium compounds, especially the lead compound VO(Me2-phen)2, may be useful
in the treatment of cancer.
PMID- 10778989
TI - Homocamptothecin, an E-ring-modified camptothecin, exerts more potent
antiproliferative activity than other topoisomerase I inhibitors in human colon
cancers obtained from surgery and maintained in vitro under histotypical culture
conditions.
AB - Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with
normal colon tissues. Several anti-Topo I inhibitors are already successfully
used in the clinic. We illustrate here the antiproliferative activity of a new
class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced
lactone stability (L. Lesueur-Ginot et al., Cancer Res., 59: 2939-2943, 1999).
Forty-three human colon cancers were obtained from surgical resection and
maintained under organotypical culture conditions for 48 h. Cell proliferation
was assessed in these ex vivo tumor tissue cultures by tritiated thymidine
autoradiography. As a validation of the methodology, we first analyzed in our
model the antiproliferative activity of two clinically active topoisomerase II
(Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon
cancers; and three Topo I inhibitors, camptothecin (CPT) and two clinically
active compounds (especially for colon cancers), i.e., topotecan and the active
metabolite of irinothecan, SN-38. We then compared the antiproliferative activity
of CPT, topotecan, and SN-38 against those of two investigational E-ring-modified
camptothecins, i.e., BN80245 and BN80915. Three concentrations (1, 10, and 100
nM) were studied for each compound. The results indicate that the three Topo I
inhibitors used as references, i.e., CPT, irinothecan, and SN-38, were much more
active than the two Topo II inhibitors, i.e., Adriamycin and etoposide, with SN
38 being the most efficient. The two investigational compounds BN80245 and
BN80915 exerted higher antiproliferative activity than the three anti-Topo I
reference compounds, with the highest activity observed for BN80915.
PMID- 10778990
TI - Identification of receptor-selective retinoids that are potent inhibitors of the
growth of human head and neck squamous cell carcinoma cells.
AB - Retinoids modulate the growth and differentiation of cancer cells presumably by
activating gene transcription via the nuclear retinoic acid receptor (RAR) alpha,
beta, and gamma and retinoid X receptor (RXR) alpha, beta, and gamma. We analyzed
the effects of 38 RAR-selective and RXR-selective retinoids on the proliferation
of 10 human head and neck squamous cell carcinoma (HNSCC) cell lines. All of
these cell lines expressed constitutively all of the receptor subtypes except
RARbeta, which was detected in only two of them. Most of the RAR-selective
retinoids inhibited the growth of HNSCC cells to varying degrees, whereas the RXR
selective retinoids showed very weak or no inhibitory effects. Three RAR
antagonists suppressed growth inhibition by RAR-selective agonists, as well as by
RAR/RXR panagonists such as 9-cis-retinoic acid. Combinations of RXR-selective
and RAR-selective retinoids exhibited additive growth-inhibitory effects.
Furthermore, we found that CD437, the most potent growth-inhibitory retinoid
induced apoptosis and up-regulated the expression of several apoptosis-related
genes in HNSCC cells. These results indicate that: (a) retinoid receptors are
involved in the growth-inhibitory effects of retinoids; (b) RXR-RAR heterodimers
rather than RXR-RXR homodimer are the major mediators of growth inhibition by
retinoids in HNSCC cells; and (c) induction of apoptosis can account for one
mechanism by which retinoids such as CD437 inhibit the growth of HNSCC cells.
Finally, these studies identified several synthetic retinoids, which are much
more effective than the natural RAs and can be good candidates for
chemoprevention and therapy of head and neck cancers.
PMID- 10778991
TI - The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has
activity against pancreatic human tumor xenografts.
AB - There is a great need for new therapeutic agents for patients with advanced
pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two
human pancreatic cancer xenograft models. The models used included the Panc-01
and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute
evidence that either of the in vivo models is predictive for clinical activity,
there is at least some evidence that they may be helpful in selecting agents for
clinical trials in patients with pancreatic cancer. Troxacitabine was
administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5
regimen. Gemcitabine was used as a positive control. The end points for the study
included tumor growth inhibition (TGI), final weight, and the number of partial
and complete tumor responses in the animals. Troxacitabine was highly active
against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10
and 25 mg/kg doses, respectively. The mean final tumor weights for animals given
troxacitabine were also significantly smaller (P < 0.001) compared with vehicle
controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one
complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial
tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n =
10) and, by traditional response criteria, would be considered inactive, with
TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is
that in comparison with gemcitabine, troxacitabine was more efficacious against
Panc-01 and was equally active against MiaPaCa. These in vivo results are
encouraging and support the prospect of performing Phase II and perhaps Phase III
trials with troxacitabine in patients with advanced pancreatic cancer.
PMID- 10778992
TI - Caspase activation and changes in Bcl-2 family member protein expression
associated with E2F-1-mediated apoptosis in human esophageal cancer cells.
AB - The prognosis for patients with esophageal cancer remains poor, prompting the
search for new treatment strategies. Overexpression of E2F-1 has been shown to
induce apoptosis in several cancer cell types. In the present study, the effect
of adenovirus-mediated E2F-1 overexpression on human esophageal cancer cell lines
Yes-4 and Yes-6 was evaluated. Cells were treated by mock infection, infection
with an adenoviral vector expressing beta-galactosidase (Ad5CMV-LacZ), or E2F-1
(Ad5CMVE2F-1). Western blot analysis confirmed marked overexpression of E2F-1 in
Ad5CMVE2F-1-infected cells. Overexpression of E2F-1 resulted in marked growth
inhibition and rapid loss of cell viability due to apoptosis, although Yes-6
cells were somewhat more resistant to E2F-1-mediated growth inhibition than Yes-4
cells. Cell cycle analysis revealed that overexpression of E2F-1 led to G2
arrest, followed by apoptotic cell death. p53 expression remained undetectable in
both cell lines after E2F-1 overexpression. The apoptosis inhibitor proteins of
the Bcl-2 gene family, Bcl-2, Mcl-1, and BcI-XL, decreased at 48 h after
infection in Yes-4 cells, but remained unchanged in Yes-6 cells. Levels of
retinoblastoma gene product (pRb) declined at 48 h after E2F-1 infection in Yes-4
cells, at which apoptosis predominated, whereas pRb expression remained constant
in Yes-6 cells. Expression of p14ARF did not change after E2F-1 infection in
either cell line. Involvement of caspase 3 and caspase 6 in E2F-1-mediated
apoptosis was demonstrated by cleavage of caspase 3/CPP32 and poly-ADP-ribose
polymerase, as well as fragmentation of the caspase 6 substrate, lamin B. These
results indicate that the sensitivity of esophageal cancer cells to E2F-1
mediated apoptosis may be related to differential expression of Bcl-2 family
member proteins and suggest that the adenovirus-mediated E2F-1 gene therapy may
be a promising treatment strategy for the treatment of this disease.
PMID- 10778993
TI - Energy metabolism of human LoVo colon carcinoma cells: correlation to drug
resistance and influence of lonidamine.
AB - The relationship between modification of energy metabolism and extent of drug
resistance was investigated in two sublines (LoVoDX and LoVoDX10) from human LoVo
colon carcinoma cells that exhibit different degrees of resistance to
doxorubicin. Results indicated that the extent of alteration in energy metabolism
strictly correlated with degree of resistance. In LoVoDX cells, only 14CO2
production was enhanced, whereas in the more resistant LoVoDX10 cells, both 14CO2
and aerobic lactate production were stimulated. The basal and glucose-supported
efflux rate and the amount of drug extruded by LoVoDX10 cells were significantly
higher than in the resistant LoVoDX cells. Because the expression of surface P
170 glycoprotein was similar in both cell lines, this phenomenon was attributed
to increased efflux pump activity resulting from greater ATP availability.
Inhibition of 14CO2 production, aerobic glycolysis, and clonogenic activity by
lonidamine (LND) increased with enhancement of the energy metabolism. Moreover,
LND, by affecting energy-yielding processes, reduced intracellular ATP content,
lowered the energy supply to the ATP-driven efflux pump, and inhibited, almost
completely, doxorubicin extrusion by resistant LoVo cells. These findings
strongly suggest that LND, currently used in tumor therapy, reduces drug
resistance by restoring the capacity to accumulate and retain drug of cells with
the MDR phenotype that overexpress P-170.
PMID- 10778994
TI - Correspondence re: W.M. Lin et al., loss of heterozygosity and mutational
analysis of the PTEN/MMAC1 gene in synchronous endometrial and ovarian
carcinomas. Clin. Cancer Res., 4: 2577-2583, 1998.
PMID- 10778995
TI - Correspondence re: M.S. Tockman et al., Prospective detection of preclinical lung
cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1
overexpression. Clin. Cancer Res., 3: 2237-2246, 1997.
PMID- 10778996
TI - Usefulness of carotid intima-media thickness measurement and peripheral B-mode
ultrasound scan in the clinical screening of patients with coronary artery
disease.
AB - Previous observational studies have shown a relationship between carotid intima
media thickness (IMT) and coronary artery disease (CAD). In this study the
authors evaluated the accuracy of the common carotid IMT measurement in
predicting the presence and severity of CAD and the additional information
offered by the detection of carotid, iliac, and lower limb plaques. One hundred
and fifty consecutive patients were subjected to coronary angiography and
carotid, iliac, and lower limb ultrasound scan. The mean value of six IMT
measurements of the far wall of the common carotid artery was calculated in each
patient. The mean IMT was significantly correlated to the number of stenosed
coronary vessels (r = 0.43, p<0.001), although the positive and negative
predictive value of mean IMT in identifying patients with CAD was low (81% and
46%, respectively). The combined information offered by IMT measurements and
peripheral (carotid, iliac, and lower limb) plaque detection was then used to
obtain the best multivariate regression model able to predict CAD status. The
multivariate model showed a highly significant multiple correlation coefficient
(r = 0.60, p<0.0001) and a sharp improvement in the negative predictive value
(92%) with respect to the univariable model. B-mode ultrasound scan including
common carotid IMT measurement and peripheral plaque detection may be of clinical
value in the screening of patients with CAD.
PMID- 10778997
TI - Percutaneous transluminal coronary angioplasty performed 24-48 hours after the
onset of acute myocardial infarction improves chronic-phase left ventricular
regional wall motion.
AB - The authors investigated the capacity of percutaneous transluminal coronary
angioplasty (PTCA) performed 24-48 hours after the onset of acute myocardial
infarction (AMI) to improve regional left ventricular wall motion. Twenty-four
patients were divided into two groups: a PTCA group who received successful PTCA
(14 cases) and a non-PTCA group (10 cases) who did not receive PTCA. Left
ventricular end-diastolic volume (LVEDV) increased significantly (p<0.01) from
57+/-14 mL/m2 during the acute phase to 83+/-16 mL/m2 during the chronic phase in
the non-PTCA group, whereas no significant change in LVEDV was seen in the PTCA
group (69+/-26 vs. 76+/-16 mL/m2). In addition, in patients with 99%
stenosis/thrombolysis in myocardial infarction (TIMI) grade 3 flow, increases in
regional left ventricular wall motion (delta(sd)/chord) at the infarcted site
between the acute and chronic phases were significantly greater in the PTCA group
than in the non-PTCA group (2.49+/-1.05 vs. 0.67+/-0.65, p<0.01). PTCA performed
24-48 hours after the onset of AMI improved wall motion at the infarcted site.
PMID- 10778998
TI - Antiplatelet is superior to anticoagulant treatment after coronary stenting:
fewer coronary and other events within 30 days after stenting.
AB - Stent prosthesis is a high efficacious method with low complication rates.
However, the ideal adjunctive therapy following stent implantation remains
controversial. The authors compared the effectiveness and complication rates of
aspirin-ticlopidine antiplatelet therapy vs. anticoagulant therapy with
acenocoumarol within 30 days following stent prosthesis. They prospectively
studied 404 patients following stent prosthesis while randomly receiving
anticoagulant (Group A: 201 patients) vs. antiplatelet treatment (Group B: 203
patients). Groups A and B were similar in demographic data (age, gender), stent
location, clinical presentation, indication of stenting, and type of implanted
stent. Chi-square test, t test, and Wilcoxon test for two samples were used for
statistical analysis of the results. Stent implantation was attempted in 434
cases. This was successful in 70/85 (82%) of the bailout, 122/135 (90%) of the
suboptimal, and 212/214 (99%) of the elective cases. In 201 patients
anticoagulant treatment with acenocoumarol was administered for 4 weeks (group
A), while 203 received antiplatelet treatment with ticlopidine (group B). The
need for reintervention was less and total cardiac events were fewer in group B
than in group A: three (1.5%) and nine (4.4%) vs 18 (9%) and 29 (14.4%), p<0.0008
and p<0.006 respectively. Hemorrhagic complications and total noncardiac events
were fewer in group B than in group A: six (3%) and six (3%) vs. 18 (9%) and 19
(9.5%), p<0.01 and p<0.007 respectively. The length of hospital stay was shorter
in group B than in A, p<0.0001. In conclusion, in this study of intracoronary
stenting the authors had a high success rate in 434 attempted cases. Antiplatelet
therapy was accompanied by fewer cardiac and noncardiac 1 month events when
compared with anticoagulant therapy, supporting its role as the adjunctive
treatment of choice post-stenting for the time being.
PMID- 10778999
TI - Expression of muscarinic receptor genes in the human coronary artery.
AB - The authors investigated the role of muscarinic receptors in functional control
of coronary arteries affected by intimal thickening due to arteriosclerosis. They
first examined the genetic subtypes of muscarinic receptors expressed in human
coronary arteries. Twelve samples of human coronary artery, obtained by autopsy
from eight subjects, were examined for the expression of four genetic subtypes of
muscarinic receptor, m1 to m4, by reverse transcription and polymerase chain
reaction (RT-PCR). Two subtypes, m2 and m3, were found to be expressed in the
coronary artery. The m2 gene was expressed in seven of the 12 vessels, and m3 in
eight of the 12. Expression of both m2 and m3 genes was observed in five of the
12 vessels. Neither the m1 nor m4 was expressed in these samples. These results
indicate that the m2 and m3 genes are mainly expressed in the coronary arteries
and suggest that these patterns of expression are differentially controlled to
induce the diversity of contraction/relaxation reactions induced in the coronary
arteries by acetylcholine.
PMID- 10779000
TI - Assessment of collateral perfusion: a pharmacodynamic study with buflomedil
hydrochloride.
AB - The aim of the study was to assess the influence of Buflomedil hydrochloride on
collateral function. Ten patients with isolated superficial femoral occlusions
were investigated twice by duplex sonography with measurement sites at the common
femoral artery (CF) and the popliteal artery (PA). After the second scan 200 mg
of Buflomedil hydrochloride were infused; the infusion was followed by a third
duplex examination. Endpoints assessed included the arterial diameter (D(CF),
D(PA)), the systolic peak velocity (Vmax), the mean velocity of the maximum
envelope (Vmean m.e.), the intensity weighted time average mean velocity (Vmean
i.w.), the maximum reverse flow velocity (Vrev), the end-diastolic velocity
(Venddiast), the calculated volume flow (Q), the pulsatility and the resistance
indices (PI, RI), and PI and RI based segmental damping factors (DF(PI), DF(RI)).
For the CF measurement site the infusion of Buflomedil hydrochloride resulted in
a significant reduction in Vrev and PI (p<0.05), whereas trends in the opposite
direction (increase) were observed for both measures of Vmean and for Q
(0.1150 x 109/L) and 4
(10.5%) had a platelet count between 50 and 150 x 109/L. Only two of the five
(13.2%) remaining patients who continued to have a platelet count less than 50 x
109/L had hemorrhagic manifestations necessitating intermittent therapy with
corticosteroids. CONCLUSION: Laparoscopic or open splenectomy is a safe and
effective procedure for children with chronic or refractory ITP and should be
considered when medical management fails or causes excessive toxicity.
PMID- 10779030
TI - Jaundice caused by the vanishing bile duct syndrome in a child with Hodgkin
lymphoma.
AB - The authors report a 5-year-old boy with Hodgkin disease and cholestatic jaundice
that predated the start of treatment for his lymphoma. His clinical course was
punctuated by relentless progression of jaundice, characterized by obstructive
pattern liver function tests, severe pruritus, intermittent fever, and marked
hypercholesterolemia with development of palmar xanthomata. The jaundice was
found to be attributable to vanishing bile duct syndrome (VBDS). The extent of
hepatic dysfunction precluded appropriate treatment of the lymphoma with
chemotherapy, and the boy died of liver failure. In the differential diagnosis of
jaundice in children with Hodgkin disease, VBDS should be considered.
PMID- 10779031
TI - Paraneoplastic cerebellar degeneration and Horner syndrome: association of two
uncommon findings in a child with Hodgkin disease.
AB - An 11-year-old boy admitted with a right cervical mass was found to have Hodgkin
disease. On admission, he also had right Homer syndrome and severe cerebellar
ataxia. Cranial MRI revealed marked cerebellar atrophy. He was treated with
chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine
(ABVD), in addition to radiotherapy. Three months after initiation of therapy, he
had a partial remission of tumor. Neurologic symptoms improved dramatically after
chemotherapy started. Hodgkin disease should be included in the differential
diagnosis of children with cerebellar findings and Horner syndrome.
PMID- 10779032
TI - Epstein-Barr virus--positive undifferentiated thymic carcinoma in a 12-year-old
white girl.
AB - Thymic epithelial malignant diseases are extremely rare in children. The authors
report a 12-year-old white girl admitted for a polymetastatic tumor of the
anterior mediastinum. Tumor proliferation was typical of an undifferentiated
thymic carcinoma. A close link between Epstein-Barr virus (EBV) and the tumor was
established by a high titer of anti-VCA IgA and the presence of EBV RNA and DNA
in the tumor. In addition, monoclonal viral episomes were present in tumor cells,
indicating that EBV infection was an early event in the oncogenic process. The
patient died despite resection, irradiation, and chemotherapy.
PMID- 10779034
TI - Wilms tumor in a child with trisomy 13.
AB - A 4-year-old black boy with trisomy 13, a history of frequent urinary tract
infections, and a horseshoe kidney with painless gross hematuria was examined. An
abdominal mass was detected and surgically resected. Examination of the surgical
specimen revealed a Wilms tumor. Given the concurrence of trisomy 13 and Wilms
tumor and the presence of another such case in the literature, there may be just
cause to suspect a locus on chromosome 13 that affects the probability of
developing Wilms tumor. Given the increasingly longer survival of patients with
trisomy 13, clinicians may need to be aware of the possibility of renal malignant
disease in this population of patients.
PMID- 10779033
TI - Central nervous system involvement of Epstein-Barr virus lymphoproliferative
disease in a patient with acute lymphocytic leukemia.
AB - Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) is a serious and
often fatal complication of a variety of immune-suppressed conditions. A 6-year
old boy undergoing chemotherapy for standard-risk acute lymphocytic leukemia
experienced separate episodes of EBV-LPD in different organ systems. The patient
experienced three separate episodes of EBV-LPD in the cervical lymph node, the
central nervous system (CNS), and the liver occurring, respectively, in January
1992, February 1992, and November 1993 after the completion of chemotherapy in
May 1993. The EBV presence was confirmed by in situ hybridization in the biopsy
samples from each lesion. Several different treatment modalities, including
acyclovir, intravenous gamma globulin, and surgery were used to combat the EBV
LPD. The patient has recovered completely, with normal CNS and liver function,
and for the past 6 years has experienced leukemia remission while not receiving
chemotherapy. Careful monitoring of patients and the use of new immune therapies
offer the highest chance for successful outcomes in such patients.
PMID- 10779035
TI - Long-term survival in an adolescent with widely metastatic renal cell carcinoma
with rhabdoid features.
AB - Renal cell carcinoma is rarely seen in children and adolescents. Patients with
widespread disease at diagnosis have a particularly poor survival rate.
Currently, all known chemotherapy has been ineffective in improving the median
survival in patients with advanced disease. A 13-year-old black boy with stage IV
renal cell carcinoma with rhabdoid features is a long-term disease-free survivor
after aggressive multiagent chemotherapy. After the initial evaluation and
histologic diagnosis of renal cell carcinoma, the patient received three courses
of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin,
cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor
and erythropoietin (Epogen). After an almost complete response, a radical
nephrectomy was performed and results demonstrated a solitary small nodule with
viable tumor. After surgery, he received floxuridine infusion for 14 days by
circadian schedule at 28-day intervals for a total of 1 year. The patient is well
and free of disease 5 years after initial presentation. The dramatic response to
treatment and long-term disease-free survival of this patient suggest this
chemotherapeutic approach warrants additional investigation.
PMID- 10779036
TI - Diamond-blackfan anemia and cyclosporine therapy revisited.
AB - A girl with Diamond-Blackfan anemia diagnosed in infancy started cyclosporine A
(CSA) therapy at 9 years and 8 months of age after experiencing unacceptable side
effects while receiving prednisone. Since then, she has been followed-up for more
than 4 years. She exhibited a dramatic response to CSA, with weaning and then
cessation of steroid therapy after 5 months. She has remained transfusion
independent. Attempts to discontinue CSA therapy have been unsuccessful. Relapse
of the anemia has occurred in the context of viral infections with missed CSA
doses. The major clinical problem during treatment has been recurrent oral
aphthous ulceration, which responds to topical therapy. She is currently
maintained on CSA 100 mg twice daily with a hemoglobin of 10.2 g/dL and a
reticulocyte count of 1.6%. A trial of CSA therapy should be considered in
patients with Diamond-Blackfan anemia in whom steroid therapy has failed before a
transfusion program is instituted or alternative donor stem cell transplantation
is entertained.
PMID- 10779037
TI - Multicentric Castleman disease and systemic lupus erythematosus phenotype in a
boy with Klinefelter syndrome: long-term disease stabilization with interferon
therapy.
AB - An 11-year-old boy with Klinefelter syndrome had Castleman disease (CD) of plasma
cell type develop. Nonregulated antibody production mimicked systemic lupus
erythematosus (SLE). Hepatitis C virus (HCV) infection caused significant disease
worsening. The patient was treated with a daily dosage of 2 million units/m2 of
IFN-alpha. Dramatic clinical improvement and decreasing autoimmune phenomenon
were observed. HCV RNA were cleared. Hypergammaglobulinemia did not change. The
boy has been living for 8 years with his disease. Plasma cell type CD can mimic
collagenosis. Disease worsening is caused by HCV, though it can be reversed with
IFN-alpha. Klinefelter syndrome may be a genetic susceptibility factor for CD in
some cases.
PMID- 10779038
TI - Plasma homocysteine levels in sickle cell disease and the need for folate
supplementation.
PMID- 10779039
TI - Homocysteine levels and sickle cell anemia.
PMID- 10779040
TI - Homocysteine levels and sickle cell anemia: response to Rana et al.
PMID- 10779041
TI - Aplastic crisis and acute splenic sequestration crisis.
PMID- 10779042
TI - Renal carcinoma in a patient with glycogen storage disease Ib receiving long-term
granulocyte colony-stimulating factor therapy.
PMID- 10779043
TI - Influence of ovariectomy on extracellular fluid volume in rats: assessment of
extracellular fluid volume by means of bromide.
PMID- 10779044
TI - Reactive oxygen species and endothelins in diabetic nephropathy.
PMID- 10779045
TI - Influence of ovariectomy on extracellular fluid volume in rats: assessment of
extracellular fluid volume by means of bromide.
AB - There is considerable evidence that the extracellular fluid volume (ECV) may
change in disease states or during longitudinal Intervention studies. Therefore,
the measurement of ECV is Important for studying body composition in patients and
laboratory animals. We present a modified plasma bromide (Br-, non-radioactive)
assay using anion-exchange chromatography, in which a small blood sample of 200
microL (100 microL of plasma) appeared to be enough to reproducibly measure ECV.
The inter- and intra-assay accuracy of the Br- analysis ranged from -1.6% to 0.9%
and from -0.5% to 0%, respectively. The inter- and intra-assay precision ranged
from 1.3% to 1.7% and from 0.6% to 1.2%, respectively. This modified precise and
accurate Br- analysis in a small blood sample was applied to investigate whether
the ECV changed in rats after ovariectomy. Ovariectomy significantly (P < .05)
reduced the ECV as compared with results in SHAM rats. This observation indicates
that a change in clinical condition may change ECV, which has consequences for
the determination of, for example, the fractional absorption and the relative
bioavailability of compounds principally distributed through the ECV.
PMID- 10779046
TI - Reactive oxygen species enhances endothelin-1 production of diabetic rat
glomeruli in vitro and in vivo.
AB - Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated
in the pathophysiology of diabetic nephropathy. The interrelationship between
them, however, has not been documented in this disease. To determine whether ROS
regulates ET-1 production in diabetic kidneys, we examined the in vitro and in
vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat
glomeruli. For in vitro study, the glomeruli were isolated with a sieving method
from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3
months, respectively. Superoxide was measured by a spectrophotometer, and ET-1
was measured by radioimmunoassay. The results demonstrated that the basal
production levels of superoxide and ET-1 were higher in diabetic glomeruli than
in normal glomeruli in vitro. There was a positive correlation between the
production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1
production was markedly attenuated by ROS scavengers including superoxide
dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli.
Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1
generation by both diabetic and normal glomeruli. A high glucose concentration
(500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not
diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic
glomeruli. The in vivo study demonstrated that when diabetic rats were injected
daily with superoxide dismutase or catalase after diabetes was induced, the basal
production of ET-1 was markedly attenuated after 1 week and 1 month,
respectively. These results indicate that exogenously or endogenously derived ROS
can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers
suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1
production of diabetic glomeruli may be partly caused by the effect of
hyperglycemia or insulin deficiency.
PMID- 10779047
TI - Cardiac remodeling by fibrous tissue after infarction in rats.
AB - After transmural myocardial infarction (MI), extensive myocardial remodeling by
fibrous tissue appears in both infarcted and noninfarcted myocardium, which
contributes to ventricular diastolic dysfunction. In the present study we sought
to assess the time course of collagen remodeling in the infarcted rat hearts by
detecting spatial and time-dependent cellular events related to collagen
synthesis and degradation 2 to 28 days after left coronary artery ligation. In
infarcted hearts, and compared with findings in sham-operated and unoperated rat
hearts, we found the following: (1) macrophages infiltrated into sites of MI and
visceral pericardium on day 2 and gradually disappeared after day 14; (2)
myofibroblasts (MyoFb) first appeared at these sites of repair on day 3 and
remained abundant thereafter at all time points examined; (3) transforming growth
factor-beta1 (TGF-beta1) mRNA was enhanced in infarcted and noninfarcted
myocardium on day 2 and remained throughout 28 days; (4) type I and III collagen
mRNAs began to increase at and remote to MI on day 3 and remained elevated
thereafter; (5) matrix metalloproteinase-1 mRNA was significantly increased at
and remote to MI on day 3, declined to the control level on day 7, and remained
low thereafter; (6) tissue inhibitor of matrix metalloproteinase (TIMP)-I, -II,
and -III mRNAs were markedly elevated at sites of repair on day 3 and sustained
throughout 28 days; (7) fibrillar collagen accumulation that was evident at and
remote to MI on day 7 continued to accumulate thereafter at each site over 4
weeks. When compared with findings in unoperated rat heart, pericardial fibrosis
was evident in both infarcted and noninfarcted heart, and the temporal response
of collagen generation/ degradation in pericardium was similar to that in
infarcted myocardium. Thus collagen synthesis is activated in both infarcted and
noninfarcted rat myocardium after transmural anterior infarction and is
persistent throughout the 28-day period of study, whereas early collagen
degradation is short lived and inactivated in the fibrogenic phase. Activated TGF
beta1 mRNA expression is accompanied by the appearance of MyoFb and the
expression of fibrillar collagens and TIMPs, suggesting that this fibrogenic
cytokine may contribute to collagen remodeling in the rat heart after MI.
PMID- 10779048
TI - Up-regulation of the proteasome subunit LMP7 in tissues of endotoxemic rats.
AB - The proteasome has been implicated in systemic responses to infection or
inflammatory stimuli including catabolism of skeletal muscle. Cytokines including
tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are
known to be elevated systemically and locally under these conditions. They are
also known to be potent inducers of three peptide subunits of the proteasome,
including LMP7, that replace constitutively expressed subunits and change
enzymatic properties. To determine whether endotoxemia alters the expression of
inducible proteasome subunits, we examined the levels of LMP7 in tissues from
rats 3 days after the injection of lipopolysaccharide (LPS) or normal saline
solution (NS). By both immunoblotting and immunohistochemistry, significant
increases in levels of LMP7 were observed in the heart, kidney, and lung of
animals given LPS as compared with results in NS-treated animals, whereas
immunoblotting revealed no changes in LMP7 levels in skeletal muscle or brain.
Increased expression of LMP7 was limited to certain subpopulations of cells and
was further localized at the subcellular level. Decreases in organ weight were
also documented for organs in which the expression of LMP7 was up-regulated.
Systemic or local release of cytokines or other proinflammatory mediators is
suggested as the most likely mechanism for changes in LMP7 expression during
endotoxemia. Changes in LMP7 expression may have functional consequences that
contribute to organ dysfunction during systemic responses to infection and
inflammatory stimuli.
PMID- 10779049
TI - Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects
and patients with diffuse parenchymal lung disease.
AB - Vascular endothelial growth factor (VEGF) is a potent angiogenic agent that is
expressed by epithelial cells in the mature lung of various animal species. We
hypothesized that VEGF levels in lower respiratory tract secretions may vary with
age or with lung inflammation in human beings. We measured VEGF165 in
bronchoalveolar lavage fluid (BALF) from normal volunteers (NVs) of varying age
and from patients with cystic fibrosis (CF), sarcoidosis, or idiopathic pulmonary
fibrosis (IPF). A considerable gradient in VEGF levels was found with relatively
high VEGF concentrations in BALF as compared with serum VEGF. VEGF levels were
303 +/- 34 pg/mL (mean +/- SEM) in serum samples from patients with CF (N = 9)
versus 122 +/- 16 pg/mL for the comparable, youngest group of NVs (P < .01). BALF
VEGF concentrations were 165 +/- 17 pg/mL for CF upper lobe BALF (N = 9), 140 +/-
17 pg/mL for CF lower lobe BALF (N = 9), and 235 +/- 24 pg/mL for young adult NVs
(N = 29). Serum VEGF levels did not differ significantly between NVs and patients
with interstitial lung disease, but mean BALF VEGF levels declined significantly
with advancing age in NVs and were significantly depressed in patients with IPF
(32 +/- 6 pg/mL) as compared with all other groups, including the oldest group of
NVs (134 +/- 13 pg/mL, P < .0001). We conclude that a considerable gradient in
VEGF concentration exists from epithelial bronchoalveolar surface fluid to serum.
Concentrations of VEGF in lower respiratory tract secretions vary with age and
are significantly depressed in IPF.
PMID- 10779050
TI - Animal models for studies on cold-induced platelet activation in human beings.
AB - When human platelets are chilled below about 20 degrees C, they spontaneously
activate, a phenomenon that limits their storage lifetime. We have previously
shown that this activation in chilled human platelets is associated with passage
through a lipid phase transition. Because animal models are necessary for
Investigating methods for cold storage of platelets, it is essential to determine
whether such phase transitions and chilling-induced activation are found in these
models. In this study we examined platelets from some commonly used animal models
pigs, rhesus monkeys, mice, dogs, and rabbits. Using Fourier transform infrared
spectroscopy (FTIR), we detected the thermotropic membrane phase transition in
Intact platelets and assessed the morphologic response of the platelets to
chilling. Statistical analysis of both FTIR and shape change show that of the
animal models tested, pig platelets are most similar to human platelets. These
studies suggest that pigs and pig platelets are the models of choice for the
study of cold-induced platelet activation in human beings.
PMID- 10779051
TI - Influence of parathyroid hormone, calcitonin, 1,25(OH)2 cholecalciferol, calcium,
and the calcium ionophore A23187 on erythrocyte morphology and blood viscosity.
AB - Parathyroid hormone and calcitonin, both endocrine modulators of calcium
homeostasis, may influence blood rheology. Parathyroid hormone is known to reduce
erythrocyte survival, leading to anemia. Calcitonin has been found to have some
vascular effects. We have analyzed the Influence of parathyroid hormone (10(-7)
to 10(-10) mol/L), calcitonin (10(-6) to 10(-12) mol/L), 1,25(OH)2
cholecalciferol (10(-7) to 10(-10) mol/L), additional calcium in plasma (+1 and 2
mmol/L), and the calcium lonophore A23187 (50 micromol/L) on erythrocyte
morphology and blood viscosity at high shear rate (94 s(-1)) and low shear rate
(0.1 s(-1)) in vitro. The loading of erythrocytes with calcium by the ionophore
A23187 produced a marked echinocytic shape transformation, an increased blood
viscosity at high shear rate caused by decreased deformability of these cells,
and a decreased viscosity at low shear rate caused by decreased aggregation of
echinocytes. In contrast, increasing plasma calcium concentrations, parathyroid
hormone, calcitonin, and 1,25(OH)2 vitamin D3 had no effect on erythrocyte
morphology and blood viscosity. We conclude that an increase in intraerythrocytic
calcium leads to severe echinocytosis and altered blood viscosity. The endocrine
modulators of calcium homeostasis--namely, parathyroid hormone, calcitonin, and
1,25(OH)2 vitamin D3--apparently do not influence intraerythrocytic calcium to a
significant degree and have, therefore, no influence on cell morphology and blood
viscosity.
PMID- 10779052
TI - Angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke
prone spontaneously hypertensive rats.
AB - Angiotensin-converting enzyme inhibitors (ACEIs) cause regression of hypertensive
left ventricular hypertrophy (LVH) by reducing angiotensin II, increasing
bradykinin, or both. The mechanisms of these cardioprotective effects remain
controversial. The aims of this study were to determine whether the
cardioprotective effects of ACEIs are mediated by reducing angiotensin II and
whether ACEIs ameliorate the morphologic, physiologic, and biochemical changes in
the hearts of stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs
were treated with hydralazine, captopril, or candesartan, an angiotensin II type
1 receptor (AT1R) antagonist, from age 12 to 24 weeks. We measured systolic blood
pressure (SBP), left ventricular weight (LVW), left ventricular (LV) myocyte
cross-sectional area (myocyte size), LV Interstitial collagen volume fraction
(ICVF), perivascular collagen area/luminal area ratio (PVCA/LA), the medial area
to luminal area ratio (MA/LA), the relative amount of V3 myosin heavy chain
(MHCV3), and coronary reserve maximum (coronary flow max/ventricular weight
(CFmax/VW)). These parameters were compared with those of untreated SHRSPs and
Wistar-Kyoto rats (WKYs). SHRSPs exhibited decreased coronary reserve and LVH
with an increase in myocyte size, PVCA/LA, MA/LA, and MHCV3 at 12 weeks of age.
In addition to these changes, 24-week-old SHRSPs showed an increase in ICVF. The
LVW, coronary reserve, myocyte size, PVCA/LA, ICVF, and MHCV3 of SHRSPs treated
with captopril or candesartan all approached control values. In contrast,
hydralazine decreased only ICVF. These results suggest that ACEIs regress LVH and
normalize coronary reserve by modulating the effects of angiotensin II via AT1R
on the induction of cardiomyocyte hypertrophy, perivascular fibrosis, and medial
thickening of intramyocardial coronary arteries in SHRSPs. We concluded that
these effects, in addition to the reduction of SBP, are important in causing the
regression of LVH.
PMID- 10779053
TI - Minimally invasive surgery for primary hyperparathyroidism: a systematic review.
AB - BACKGROUND: The aim of the present paper was to systematically review the
literature regarding the safety and efficacy of minimally invasive
parathyroidectomy techniques in patients with primary hyperparathyroidism.
Studies using unilateral or endoscopic exploration following imaging were
compared with bilateral open neck exploration. METHODS: Studies on minimally
invasive parathyroid surgery were identified using MEDLINE (1984 to August 1998),
EMBASE (1974 to August 1998) and Current Contents (1993 to week 34, 1998). The
search terms were ((endoscop* or (minimal* and invasive) or unilateral) and
parathyroid). The Cochrane Library was searched from 1966 to issue 3 1998, using
the search terms 'parathyroidectomy or parathyroid resection'. Human studies of
patients with primary hyperparathyroidism using unilateral or endoscopic
exploration were included. Animal studies describing minimally invasive technique
development were also included. A surgeon and researcher independently assessed
the retrieved articles for their inclusion in the review. Studies directly
comparing the unilateral method with bilateral open neck exploration were used to
analyse outcomes. RESULTS: Analysis of data using odds ratios and 95% confidence
intervals (CI) indicated a tendency to favour the unilateral technique. These
individual studies generally had large CI, however; therefore preference to the
unilateral procedure cannot be espoused with certainty. There is also a selection
bias due to the strict enrollment criteria for unilateral surgery. CONCLUSIONS:
The proposed role of minimally invasive parathyroid surgery is for patients with
primary hyperparathyroidism who have unilateral parathyroid pathology. To assess
the safety and efficacy of minimally invasive techniques it is suggested that
their introduction be monitored as part of a trial in Australia, from which data
should be accrued to a register.
PMID- 10779054
TI - Zuckerkandl's tubercle of the thyroid gland in association with pressure
symptoms: a coincidence or consequence?
AB - BACKGROUND: The Zuckerkandl's tubercle (ZT) of the thyroid gland is a well
described anatomical landmark, but few studies have clearly defined its
association with pressure symptoms. METHODS: Sixty-six consecutive patients who
had primary thyroid surgery were prospectively included in the present study
between late January and early August 1998. RESULTS: A total of 96 capsular
dissections were performed at thyroid surgery. Grades two and three ZT were
recognized in 77 (80.2%) dissections. In general 49 (63.6%) of them were
associated with significant pressure symptoms. In 43 (87.8%) of the dissections
with pressure symptoms, grade 3 ZT was observed (mean weight of goitre: 154.8 g).
Interestingly in this group, 16 (37.2%) patients with pressure symptoms had a
goitre that was < 100 g and in one patient it was only 21 g. CONCLUSIONS: The
pressure symptom of the thyroid gland does not always appear to be due to the
large size of the goitre. In a relatively small-size goitre the ZT may cause
significant pressure symptoms. Observations in the present study supported a
strong association of enlarged ZT with pressure symptoms. We believe this is
unlikely to be simply a coincidence but rather a consequence of the enlarged
tubercle. Nonetheless a prospective randomized study is called for to allow
meaningful and objective evidence to be drawn.
PMID- 10779055
TI - Gastric resection in the aged (> or = 80 years) with gastric carcinoma: a
multivariate analysis of prognostic factors.
AB - BACKGROUND: The incidence of gastric neoplasm is increasing in the elderly
population. Therefore, a rational method of treatment for gastric cancer in the
elderly should be constituted to improve the survival. The purpose of the present
study was to clarify whether the patient's age is an independent prognostic
factor and to determine clinicopathological characteristics in the elderly.
METHODS: Curative resection of gastric cancer was carried out on 601 patients who
were 40 years or older. They were divided into the following two groups: younger
patients (between 40 and 79 years old) and elderly patients (80 years or older).
The clinicopathologic features of these patients were reviewed retrospectively
and multivariate analysis was carried out. RESULTS: The distinguishing features
of gastric cancer in the elderly patients were intestinal and mixed types of
cancer, distal third stomach dominance in the tumour location, advanced stage of
disease, and a low rate of extensive lymph node dissection (D3 or more).
Regarding the recurrence site, the liver was the dominant site in the elderly
group (25.3% in the younger group vs 54.5% in the elderly group). The 10-year
disease-free survival rate of the elderly group was 53.2%, which was
significantly worse than that (79.9%) of the younger patients (P = 0.0004). In
multivariate analysis, an age of > or = 80 years is an independent prognostic
factor, as well as stage, depth of tumour invasion, lymph node metastasis,
scirrhous carcinoma, and blood transfusion. CONCLUSIONS: Results indicate that
gastric cancer in elderly patients has a poorer prognosis than that in younger
patients.
PMID- 10779056
TI - Large bowel volvulus in childhood.
AB - BACKGROUND: Large bowel volvulus is extremely uncommon in children. The probable
pathogenesis, predisposing factors and management of large bowel volvulus in
children are debatable. METHODS: Seven consecutive cases of large bowel volvulus
occurring over a 6-year period are reported. RESULTS: Two patients with caecal
volvulus, one with transverse and subsequent sigmoid volvulus, one with
transverse colon volvulus and three children with sigmoid volvulus are reported.
Four girls and one boy with cerebral palsy, one female with Moya Moya disease and
spastic paraplegia and an otherwise healthy boy presented at a mean age of 8.3
years (range: 3-15 years). The common presentation was abdominal distension (n =
6), tenderness (n = 6), constipation (n = 7) and bloody mucoid discharge per
rectum (n = 6). Plain abdominal X-ray and barium enema were diagnostic. Resection
with primary ileocolic, colocolic or colorectal anastomosis was performed in all
cases. The mean follow-up was 3.4 years (range: 1-6 years) and there was no
mortality. CONCLUSIONS: Large bowel volvulus in children may be due to congenital
anomalous or absent ligamentous fixation of the large bowel, and abnormal
mesocolon or a common ileocolo-mesentery. Large bowel obstruction due to volvulus
must be considered in the differential diagnosis in a child presenting with
constipation associated with bloody mucoid discharge per rectum. Resection of the
involved segment and primary anastomosis is the definitive treatment for large
bowel volvulus in children.
PMID- 10779057
TI - Neck dissection and ipsilateral radiotherapy in the management of cervical
metastatic carcinoma from an unknown primary.
AB - BACKGROUND: In a small proportion of patients presenting with metastases to
cervical lymph nodes the primary cancer remains occult despite thorough
evaluation. The present report examines patterns of failure and outcome following
an initial treatment strategy directed principally at the clinically involved
side of the neck. METHODS: From a prospectively compiled computerized database 38
patients were identified with metastatic squamous cell carcinoma from an occult
primary site. These patients were evaluated with respect to initial treatment,
subsequent detection of a primary tumour, neck recurrence and survival
characteristics. RESULTS: Thirty-seven of 38 patients were treated with curative
intent and all had neck dissection. Adjuvant radiotherapy was given to 34 of the
37 (90%; 32 postoperatively and two pre-operatively). Radiotherapy was directed
at the ipsilateral neck alone in 24 patients while 10 received comprehensive
treatment to both sides of the neck and potential occult primary sites. The rate
of control of disease in the ipsilateral neck was 91% while the failure rate in
the contralateral neck was 16% (six patients). A primary cancer was ultimately
identified in five patients (13%). Disease-specific survival was 63% at 4 years.
Clinical N3 stage, extracapsular tumour extension and involved surgical margins
predicted for poorer survival on univariate analysis. Analysis using multiple
risk factors found that only involved surgical margins predicted for treatment
failure. CONCLUSIONS: Despite generally advanced disease at presentation,
patients presenting with cervical metastasis from an unknown primary carcinoma
have a reasonable survival expectation and aggressive treatment is warranted, but
approximately half will develop recurrent disease. Careful follow-up is required
if effective salvage treatment is to be instituted.
PMID- 10779058
TI - Rectal cancer in the Kingdom of Saudi Arabia: the King Faisal Specialist Hospital
experience.
AB - BACKGROUND: No survival data have yet been published from the Kingdom of Saudi
Arabia for patients with rectal cancer. The present paper reports experience with
these patients over an 8-year period. METHODS: All patients referred to the King
Faisal Specialist Hospital (KFSH) between March 1990 and February 1998 for the
primary management of rectal cancer were entered into a computerized database.
Prior to 1993 patients did not receive adjuvant therapy. Kaplan-Meier survival
curves and the log-rank test were used to compare outcome data. RESULTS: There
were 70 men (average age: 55.6 years) and 75 women (average age: 52.8 years).
Twelve per cent of patients admitted a family history of colorectal carcinoma
(CRC). Twenty-seven per cent of tumours were circumferential. Most tumours were
larger than 4 cm and the lowest edge of the majority of tumours was less than 6
cm from the anal verge. Fifty-four per cent of tumours were fixed; 69% of
patients received either pre-operative or postoperative radiotherapy. A total of
106 patients underwent 'curative' surgery. Equal numbers of patients had abdomino
perineal resection (APR) and anterior resection (AR) of the rectum. Thirty-five
patients received blood peri-operatively (APR, 34%; AR, 12%). Major anastomotic
leakage following AR occurred in two patients. Two patients died within 30 days
of surgery. Ten patients were lost to follow-up. Following curative AR, eight
patients had a distal resection margin of < 2 cm and two patients (Dukes' C)
developed local recurrence (25%); 37 patients had a margin > 2 cm and seven
developed local recurrence (18.9%). A total of 48 patients underwent curative
APR, and four patients developed local recurrence (8.3%). Overall local
recurrence was tumour stage-dependent (Dukes' B, 8.8%; Dukes' C, 29.3%).
Recurrence was local in 13 patients. Pre-operative radiotherapy seemed to reduce
average tumour size (3.6 vs 4.3 cm). The crude overall 5-year survival rate was
39%. The 5-year survival rate for patients with Dukes' stage C cancers following
'curative' surgery was 25%. CONCLUSION: Curative surgery can be performed with a
relatively low requirement for blood transfusion, a low mortality and morbidity,
and comparable outcomes to Western studies in spite of the large, low and often
advanced stage of the tumours managed. Local recurrence rates following curative
resection and re-anastomosis for low rectal cancers may be reduced by resisting
patient pressure to avoid stomata.
PMID- 10779059
TI - Eighteen-year experience with femoro-femoral bypass.
AB - BACKGROUND: The role of femoro-femoral bypass in the management of aorto-iliac
occlusive disease has evolved during the past two decades. The aim of the present
study was to evaluate the early and long-term outcomes of femoro-femoral bypass
grafts performed at the University of Hong Kong Medical Centre during an 18-year
period. METHODS: From 1981 to 1998, a retrospective analysis of 61 patients who
underwent femoro-femoral bypass at the University of Hong Kong Medical Centre was
undertaken. Data on demographic features and results of surgical intervention
were reviewed. Early outcomes (morbidity, mortality and improvement of clinical
category) and long-term outcomes (graft patency, patient survival and limb
salvage rates) were analysed. RESULTS: The postoperative morbidity and mortality
rates were 16% and 7%, respectively. Clinical success was achieved in 48 patients
(79%) after operation. The primary patency of femoro-femoral bypass was 86%, 79%
and 71% at 1, 3 and 5 years, respectively. The limb salvage rate was 85% at 3
years. The cumulative survival rate of the study population was 89%, 82% and 73%
at 1, 3 and 5 years, respectively. CONCLUSIONS: Femoro-femoral bypass was
successful in relieving ischaemic pain and limb salvage in approximately 80% of
patients. A 5-year patency rate of 71% was achieved. Femoro-femoral bypass
remains a valuable surgical procedure for limb salvage in poor-risk patients with
unilateral iliac artery occlusion.
PMID- 10779060
TI - Study populations and casemix: influence on analysis of postoperative outcomes.
AB - BACKGROUND: The importance of patient casemix as a determinant of surgical
outcome is now being recognized. The present study was undertaken in order to
compare the presentation and outcomes in colorectal patients managed surgically
by the same surgeon, in the same way, in different settings. METHODS: Colorectal
outcome data from the University Department of Surgery in Wellington and the King
Faisal Specialist Hospital in Riyadh were analysed in order to determine casemix
differences between the two hospitals. Data relating to the type of surgery, the
surgeon, the patient's disease, the operation performed and the postoperative
complications were compared. Specific colorectal clinical indicators were
compared for two commonly performed operations for rectal cancer: anterior
resection and abdomino-perineal resection of the rectum. RESULTS: Wellington
patients were slightly older and there were more females. Emergency surgery was
more frequent in Wellington. Left hemicolectomy, sigmoid colectomy, abscess
drainage and pilonidal surgery were more common in Wellington whereas abdomino
perineal resection and anterior resection of the rectum, stoma closure, fistula
surgery, seton insertion, restorative proctocolectomy and ileostomy were
undertaken more frequently in Riyadh. More complex anal fistulas were managed in
Riyadh. Condylomata accuminata, pilonidal abscess, anorectal abscess, rectal
prolapse and diverticular disease were rarely seen in Riyadh. There were more
postoperative pulmonary and cardiac complications in Wellington. Patients having
anterior resection of the rectum were younger in Riyadh and there were
proportionally more females. There were some obvious numerical outcome
differences in postoperative atelectasis, wound infection, anastomotic leak and
deep vein thrombosis rates but none of these reached statistical significance
except atelectasis. In Riyadh the usual male-to-female ratio of patients
undergoing abdomino-perineal resection was reversed but, again, none of the
numerical outcome differences observed reached statistical significance except
postoperative atelectasis and intraabdominal abscess. CONCLUSION: Although not
statistically significant, the results of the present study suggest that when the
same surgeon operates using the same technique in different communities, the
outcomes may be different. Care should thus be taken when comparing different
populations with different casemixes before definitive conclusions are made in
comparative studies.
PMID- 10779062
TI - Management of the axilla in early breast cancer: is it time to change tack?
AB - The standard surgical treatment of the axilla in patients with early breast
cancer is about to undergo a radical change. Although axillary dissection is an
excellent procedure for both staging and local control, particularly in the
clinically positive axilla, it has considerable morbidity and may understage a
significant proportion of patients, because it will usually miss micrometastases
that can occur in approximately 10% of 'node negative' patients. An increasing
number of patients whose tumours are either non-invasive (ductal carcinoma in
situ; DCIS), micro-invasive, tubular cancers or low-grade T1a tumours without
lymphovascular invasion may be spared axillary surgery because the risk of
axillary disease is 0-3%. Many studies, both prospective trials and large
retrospective series, show that axillary radiotherapy alone provides similar
local control rates to axillary dissection in patients with clinically negative
axillas. Primary treatment of the axilla with radiotherapy alone, however, does
not allow appropriate staging. Sentinel lymph node biopsy is being increasingly
used in patients with breast cancer to provide this information. When a sentinel
node is identified it is equal to or better than axillary dissection for staging
the axilla and, if the node is positive, it will help select patients who should
then proceed to further axillary surgery or axillary radiotherapy. Although
sentinel lymph node biopsy is being rapidly adopted in many centres worldwide,
the results of randomized controlled trials are needed before it can be
recommended as the standard of care.
PMID- 10779061
TI - Thyroid pathology associated with primary hyperparathyroidism.
AB - BACKGROUND: Thyroid carcinoma and benign thyroid disease associated with primary
hyperparathyroidism (PHPT) have been well described. With the developing trend
toward minimally invasive parathyroidectomy without intra-operative thyroid gland
palpation, thyroid pathology may be missed. The authors consider it timely to
revisit the issue of thyroid pathology found at neck exploration for PHPT.
METHODS: A retrospective review of all cases of neck exploration for PHPT between
1993 and 1998 at Liverpool Hospital was undertaken. RESULTS: There were 65
patients in the study group (44 women, 21 men; mean age: 59 years). The most
common indication for surgery was asymptomatic hypercalcaemia. The mean pre
operative calcium level was 2.9 mmol/L and the mean parathyroid hormone (PTH)
level was 17 pmol/L. There were 26 cases (40%) of coexistent thyroid pathology.
Ten cases (15%) were of mild multinodular change, seven cases (11%) were of
severe multinodular change requiring thyroidectomy, three cases (4%) were nodules
secondary to Hashimoto's thyroiditis and six cases (10%) were suspicious nodules
that proved to be either adenomas (n = 3) or carcinomas (n = 3) following
excision. There were four papillary carcinomas detected in the present series
with a mean metastases, age, completeness of excision, invasion size (MACIS)
score of 4.92. CONCLUSION: A 25% association of significant thyroid pathology
with PHPT is reported. Despite pre-operative tests there were two cases (4%) of
thyroid carcinoma where the decision to resect the thyroid gland was made
following intra-operative thyroid gland palpation. One of these two papillary
carcinoma patients would have fulfilled criteria for minimally invasive
parathyroid surgery. When evaluating results of minimally invasive parathyroid
surgery one must be aware of the potential for missed thyroid pathology.
PMID- 10779063
TI - Grantsmanship: achieving success in research funding.
AB - High-quality research is seldom feasible without skillful grantsmanship. Like
most skills it is learnt and then improved by practice. Fortunately, there is a
consistent formula to constructing a research grant, provided certain guidelines
are followed. The grant application need not be a significant barrier between a
good idea and its realization in improvements to patient care. This paper
outlines the essential principles in the construction of the successful research
grant application.
PMID- 10779064
TI - Progress of surgical training in Papua New Guinea to the end of the 20th century.
AB - BACKGROUND: Health care in Papua New Guinea (PNG) throughout the 20th century has
been characterized by a significant shortage of medical practitioners and
surgical expertise. A number of initiatives within the country and from outside
have sought to address these deficiencies of numbers and quality. The present
paper seeks to review the development of surgery and surgical training in PNG.
METHODS: Review of the surgical literature, reports and records in the Division
of Surgery at the University of Papua New Guinea (UPNG), and personal
observations are used to look critically at the content and productivity of the
various training initiatives. RESULTS: For the first half of the century, PNG
relied on national medical assistants who were trained, supervised and directed
by expatriate doctors. Medical training of PNG doctors began in 1951 and by 1999
more than 600 doctors had graduated. Expatriate specialist surgeons arrived in
1950 and were the only surgeons until the postgraduate Master of Medicine
(surgical) programme produced its first graduates in 1978. This programme has now
produced 37 surgeons who are reasonably well distributed throughout the country.
Higher surgical diplomas were introduced in 1994 for more specialized training of
some of the general surgeons. These training developments have been supported by
AusAid as well as by Australian surgeons. CONCLUSIONS: Surgical expertise has
progressively improved throughout the 20th century with the most major advances
being achieved in the last decade. Training programmes have provided an expanding
core of expertise of considerable quality, but the numbers of doctors and
surgeons remain well below requirements.
PMID- 10779065
TI - Intussusception in coeliac disease: a little-known association.
PMID- 10779066
TI - Urethral carcinoma: an unusual cause of peri-urethral abscess.
PMID- 10779067
TI - Metastatic malignant fibrous histiocytoma: a rare cause of small bowel
intussusception.
PMID- 10779068
TI - The role of liposomes in drug delivery and diagnostic imaging: a review.
AB - This manuscript is not intended as a comprehensive overview of the large filed of
liposome technology and all its applications. However, our intent was to present
current data, which are active, cutting-edge research. Because of their unique
properties liposomes will continue to be investigated in drug delivery and
imaging systems, and very likely will be incorporated into our discipline of
veterinary medicine as the clinical applications of liposomes continue to expand.
PMID- 10779069
TI - Use of radiography, computed tomography and magnetic resonance imaging for
evaluation of navicular syndrome in the horse.
AB - Radiographic evaluation of navicular syndrome is problematic because of its
inconsistent correlation with clinical signs. Scintigraphy often yields false
positive and false negative results and diagnostic ultrasound is of limited
value. Therefore, we assessed the use of computed tomography and magnetic
resonance imaging in a horse with clinical and radiographic signs of navicular
syndrome. Cadaver specimens were examined with spiral computed tomographic and
high-field magnetic resonance scanners and images were correlated with pathologic
findings. Radiographic changes consisted of bony remodeling, which included
altered synovial fossae, increased medullary opacity, cyst formation and shape
change. These osseous changes were more striking and more numerous on computed
tomographic and magnetic resonance images. They were most clearly defined with
computed tomography. Many osseous changes seen with computed tomography and
magnetic resonance imaging were not radiographically evident. Histologically
confirmed soft tissue alterations of the deep digital flexor tendon, impar
ligament and marrow were identified with magnetic resonance imaging, but not with
conventional radiography. Because of their multiplanar capability and tomographic
nature, computed tomography and magnetic resonance imaging surpass conventional
radiography for navicular imaging, facilitating earlier, more accurate diagnosis.
Current advances in imaging technology should make these imaging modalities
available to equine practitioners in the future.
PMID- 10779070
TI - Distinguishing rhinitis and nasal neoplasia by radiography.
AB - To compare the incidence of radiographic signs in dogs with rhinitis and primary
nasal neoplasia and to assess the performance of observers for distinguishing
these conditions, the nasal radiographs of 72 dogs with either rhinitis (n = 42)
or primary nasal neoplasia (n = 30) were examined by two independent observers
using custom-designed forms to record their interpretations. Rhinitis was
associated with a higher incidence of focal or multifocal lesions, localised soft
tissue opacities, lucent foci, and a lack of frontal sinus involvement. Neoplasia
was associated with soft tissue opacities and loss of turbinate detail that
affected the entire ipsilateral nasal cavity, signs of invasion of the bones
surrounding the nasal cavity, and soft tissue/fluid opacities within the
ipsilateral frontal sinus. The signs with the highest positive predictive value
(PPV) for rhinitis were absence of frontal sinus lesions and lucent foci in nasal
cavity (PPV of each 82%), and invasion of surrounding bones for neoplasia (PPV
88%). There were no significant differences in the position of the lesion within
the nasal cavity, incidence of unilateral versus bilateral lesions, calcified
lesions, or absence of teeth. There was moderate agreement between observers
about the diagnosis (kappa 0.59). Areas (SE) under ROC curves were 0.94 (0.03)
and 0.96 (0.03) for observers A and B, respectively (not significantly different;
P = 0.68). These results indicate a high accuracy for radiologists examining dogs
with nasal diseases. Differentiation of rhinitis and nasal neoplasia should be
based on finding combinations of radiologic signs that together have a high PPV.
Differences in interpretation between experienced observers in this study suggest
that certain signs are potential sources of error.
PMID- 10779071
TI - Computed tomographic findings of dogs with cubital joint lameness.
AB - The purpose of this study was to identify the incidence of abnormal computed
tomography (CT) findings in dogs with lameness of one or both elbows. CT
examinations of 102 elbows in 51 dogs were reviewed individually and by group
consensus by 3 examiners and graded for various abnormalities. Frequently
encountered abnormalities included abnormal shape and sclerosis of the medial
coronoid process of the ulna, irregularity of the radial incisure of the ulna,
and ulnar trochlear notch sclerosis. Other abnormalities included
distinct/separate or fissure/in situ fragmentation of the medial coronoid;
lucency of the radial incisure; ununited anconeal process; sclerosis, lucency, or
flattening of the medial aspect of the humeral condyle; osteophyte formation; and
joint incongruity. In conclusion, CT of the canine cubital joint is useful in
identification of various lesions beyond simple fragmentation of the medial
coronoid process of the ulna.
PMID- 10779072
TI - Low-field magnetic resonance imaging of the equine tarsus: normal anatomy.
AB - The objective of this study was to define the normal gross anatomic appearance of
the adult equine tarsus on a low-field magnetic resonance (MR) image. Six
radiographically normal, adult, equine tarsal cadavers were utilized. Using a
scanner with a 0.064 Tesla magnet, images were acquired in the sagittal,
transverse and dorsal planes for T1-weighted and the sagittal plane for T2
weighted imaging sequences. Anatomic structures on the MR images were identified
and compared with cryosections of the imaged limbs. Optimal image planes were
identified for the evaluation of articular cartilage, subchondral bone, flexor
and extensor tendons, tarsal ligaments, and synovial structures. MR images
provide a thorough evaluation of the anatomic relationships of the structures of
the equine tarsus.
PMID- 10779073
TI - Magnetic resonance, computed tomographic and radiologic findings in a dog with
discospondylitis.
AB - Magnetic resonance (MR), computed tomographic and radiographic imaging were
conducted in a dog with discospondylitis. The MR findings were increased T2 and
decreased T1 signal intensity of the soft tissues ventral to vertebral bodies,
the end plates of the same vertebral bodies and the intervertebral disc, and are
similar to those described in human with discospondylitis.
PMID- 10779074
TI - Radiographic diagnosis--engorged ticks appearing as distinct radiographic
opacities.
PMID- 10779075
TI - Incomplete ossification of the humeral condyle in Vietnamese pot-bellied pigs.
AB - The purpose of this study was to evaluate the occurrence of humeral condylar
fractures in Vietnamese pot-bellied pigs and to postulate a possible predisposing
cause for these fractures. Thirteen Vietnamese pot-bellied pigs (Group A) were
evaluated over an eight year period (1990-1998), each with a history of either a
unilateral or bilateral forelimb lameness. The cause of lameness was localized to
the elbow region. Of the thirteen pigs, twenty-one elbows were evaluated
radiographically. Pigs ranged in age from six months to four years old. All pigs
over the age of seven months showed radiographic evidence of elbow degenerative
joint disease. Fractures involving the medial aspect of the humeral condyle were
identified in 8/21 studies (38%). A well-defined linear intracondylar articular
lucency was identified in 7/21 studies (33%) on the craniocaudal projection. The
site of this lucency corresponded to the location of the articular component of
the fractures seen involving the humeral condyle. The elbows of five pot-bellied
pigs with no known history of forelimb lameness or trauma (Group B) were
evaluated radiographically following euthanasia. All five pigs were of unknown
age and gender. An intracondylar vertical linear lucency was identified
bilaterally in three pigs (60%). Concurrent degenerative joint disease was
present in all instances. The remaining two pigs were radiographically normal.
Computed tomography of the elbows was performed in one affected pig from Group B.
The radiographic findings in this pig were verified. Histopathology of the right
elbow of this affected pig was diagnostic for incomplete endochondral
ossification of the humeral condyle. A similar condition involving the humeral
condyle has been previously described in Cocker and Brittany Spaniels. These
canine breeds also have a high incidence of humeral condylar fractures. It is
postulated that Vietnamese pot-bellied pigs are similarly prone to humeral
condylar fractures, even in the absence of known trauma, due to incomplete
ossification of the humeral condyle.
PMID- 10779076
TI - Non-cardiac thoracic ultrasound in 75 feline and canine patients.
AB - The purpose of this study was to describe the ultrasonographic appearance of non
cardiac diseases of the small animal thorax. Ultrasound images from a total of 75
animals (26 cats and 49 dogs) were compared to cytologic, histopathologic, and
necropsy findings. Clinical diagnoses included neoplasia of the mediastinum,
pleura, or lungs (43); idiopathic mediastinal cyst (3); diaphragmatic or
peritoneopericardial hernia (4); lung lobe torsion (1); pulmonary eosinophilic
infiltrates (1); and idiopathic, chylous, congestive heart failure, or
lymphangiectasia associated pleural effusion (14). In the remaining 9 patients, a
definitive diagnosis was not obtained. Ultrasound-guided fine needle aspirate was
performed in 56 patients; 1 of these also had an ultrasound-guided tissue core
biopsy. Of the fine needle aspirates, 51 (91%) were diagnostic. Ultrasound
examination, particularly when accompanied by guided tissue sampling, can be a
valuable tool in the diagnosis of non-cardiac intrathoracic lesions.
PMID- 10779077
TI - Most dogs with medullary rim sign on ultrasonography have no demonstrable renal
dysfunction.
AB - The medullary rim sign is a distinct hyperechoic line in the renal medulla
parallel to the corticomedullary junction that has been reported in dogs with a
variety of renal diseases. To examine the association between medullary rim sign
and renal disease, the medical records of thirty-two dogs that had medullary rim
sign were reviewed retrospectively. Eighteen dogs (56%) had no evidence of renal
dysfunction; 14 (44%) had clinicopathological evidence of renal disease,
including 6 (19%) that had hypercalcemic nephropathy. Most dogs (72%) in which
medullary rim sign was the only ultrasonographic finding affecting the kidneys
had no evidence of renal dysfunction. In contrast, 78% dogs that had medullary
rim sign and other renal signs (reduced size, increased medullary echogenicity,
and pyelectasia) had renal disease. On the basis of this study, the medullary rim
sign appears to be a non-specific ultrasonographic sign; however, the possibility
cannot be excluded that is a sentinel sign of subclinical renal disease.
PMID- 10779078
TI - Duplex-ultrasonographic evaluation of the common carotid artery in the resting,
sedated and anesthetized horse.
AB - The aim of this study was to determine the blood flow in the carotid artery
during halothane anaesthesia by means of duplex-sonography. Seventeen warm blood
horses were evaluated in dorsal and lateral recumbency and the results were
compared with the values of the same horses resting and under sedation. The cross
sectional area of the vessels, the time-averaged maximal blood velocity, time
averaged maximal blood flow and the resistance index were determined and the flow
profile was evaluated. During halothane anesthesia the total blood flow shows a
significant increase which is not dependent on the positioning of the horse. Mean
blood velocity is decreased by sedation and significantly increased during
anesthesia. Reduced peripheral resistance is expressed by a decline of the
resistance index. After sedation and during recumbency there is an increase in
diameter of the carotid artery.
PMID- 10779079
TI - Non-invasive diagnosis of ischemic brain damage after cardiopulmonary
resuscitation in dogs by using transcranial Doppler ultrasonography.
AB - We have attempted to identify whether it is possible to utilize transcranial
Doppler ultrasonography to evaluate the brain damage that occurs after
resuscitation from 3 min (control group) and 12 min (damage group) of cardiac
arrest in dogs. In this study we used transcranial Doppler ultrasonography to
follow the basilar arterial flow and middle cerebral arterial flow for 180 min
following the induction of cardiac arrests. Two abnormal waveform patterns (the
"to-and-fro" and "diastolic no-flow" patterns) were found in all dogs in the
damage group whereas abnormal waveforms were not detected in the control group.
Pathological diagnosis revealed that, compared with the control group, the damage
group recognized ischemic alteration at the level of the hippocampus and caudate
nucleus. In conclusion, this study shows that the basilar arterial flow of
observed with transcranial Doppler ultrasonography may be use for the prediction
of outcome and the diagnosis of brain damage in the dog.
PMID- 10779080
TI - Measuring sphere-like structures using transrectal ultrasonography.
AB - Sphere-like structures are commonly measured for clinical or research purposes.
We measured two diameters, the circumference (perimeter) and cross sectional area
of 113 equine ovarian follicles in a water bath then determined the relationships
between those measurements and the actual volume of fluid in the follicles. Cross
sectional area, diameter3 and area2/3 were all highly correlated with the volume
of the structures and superior (p < 0.05) to diameter or perimeter as predictors
of volume. As predictors of volume, there was no significant difference (p >
0.05) between cross-sectional area, diameter3, and area2/3. Because of the ease
of measuring diameter, we suggest that diameter3 be used to estimate the actual
size of sphere-like structures by ultrasonographic measurement. A table was
generated for clinical use to show how much the largest diameter of a fluid
filled structure (follicle, cyst, hematoma, etc.) would have to increase or
decrease to indicate a significant change in the volume of the structure.
PMID- 10779081
TI - Scintigraphic characterization of distal radial physeal closure in young
Standardbred racehorses.
AB - A longitudinal scintigraphic and radiographic study of distal radial physeal
activity in 14 Standardbred trotters was conducted to quantify and visually
evaluate physeal uptake around the time of physeal closure. Initial intense 99mTc
HDP uptake was seen, followed by a rapid decrease of activity starting at a mean
age of 20 months. Mean physeal to distal diaphyseal ROI and line profile ratios
compared to ratios of mature horses decreased from 2.8 to 1.4 at the time of
radiographic closure at 24-32 months. Ratios then gradually decreased until
values of mature horses were reached at the end of the study (mean age 42
months). Visually discernible distal radial physeal activity was present with
declining frequency throughout the study. This study indicates that, in the
normal Standardbred trotter, there is mild distal radial physeal uptake present
after radiographic evidence of physeal closure. This uptake is not likely to
confound evaluation of pathologic conditions of the physeal or carpal regions.
PMID- 10779082
TI - Dr. W. Harker Rhodes: Recipient of the ACVR Distinguished Service Award. American
College of Veterinary Radiology.
PMID- 10779083
TI - Targeting of the renin-angiotensin system by antisense gene therapy: a possible
strategy for the long-term control of hypertension.
AB - Traditional pharmacological agents have been successfully used for the treatment
of hypertension for a number of decades. However, this therapeutic regimen has
reached a conceptual plateau and a cure for the disease is far from appearing on
the horizon. With this in mind, and recent advances in state of the art gene
delivery system coupled with the anticipated completion of the human genome
project, it is timely to think about the possibility of treating and/or curing
hypertension using genetic means. In this review, we discuss the role of renin
angiotensin system (RAS) in hypertension; the current gene delivery/gene transfer
systems and the RAS as a target for gene therapy to treat hypertension; the
successful use of retroviral vectors to deliver antisense to the AT1 receptor
(AT1-AS) to prevent the development of hypertension and cardiovascular
pathophysiology; the potential use of the viral vectors for the reversal of
hypertension; and the future of antisense gene therapy and potential advantages
and limitations of this regimen in the treatment and/or control of hypertension.
PMID- 10779084
TI - Impaired endothelial function in arterial hypertension and hypercholesterolemia:
potential mechanisms and differences.
AB - This review focuses on the role of impaired endothelial function for the
development of atherosclerosis in human arterial hypertension and
hypercholesterolemia in vivo. Potential mechanisms underlying impaired
endothelial function and decreased bioavailability of nitric oxide under these
clinical conditions are discussed and potential differences in these mechanisms
between arterial hypertension and hypercholesterolemia are outlined. It further
addresses therapeutic strategies aiming to improve the bioavailability of nitric
oxide in these patients. The overall conclusion is that the bioavailability of
nitric oxide is probably impaired not by a single defect, but by various
mechanisms affecting nitric oxide synthesis as well as nitric oxide breakdown. In
both diseases, increased superoxide anion production and oxidative stress
represents a major mechanism. However, potential differences in the underlying
mechanisms of superoxide production or nitric oxide synthesis are evident between
arterial hypertension and hypercholesterolemia. Decreased bioavailability of
nitric oxide does not only impair endothelium-dependent vasodilation, but also
activates other mechanisms that play an important role in the pathogenesis of
atherosclerosis. Thus, therapeutic strategies should aim to restore
bioavailability of nitric oxide, which has been demonstrated for lipid-lowering
therapy in hypercholesterolemia. The mechanisms by which nitric oxide
bioavailability can be improved by any drug therapy remain to be elucidated and
may provide further insights into the mechanisms that are involved in impaired
endothelial function and atherogenesis.
PMID- 10779085
TI - The debate on the amplifier hypothesis' - some comments.
PMID- 10779086
TI - Direct and surrogate measures of the white-coat effect: methodological aspects
and clinical relevance.
PMID- 10779087
TI - Difference between office and ambulatory blood pressure or real white coat
effect: does it matter in terms of prognosis?
AB - OBJECTIVE: The blood pressure (BP) response to the doctor's visit, generally
referred as the white coat (WC) response, is usually estimated by the difference
between office BP (OBP) and ambulatory BP (ABP). The purpose of this study was to
determine the validity of this estimation. To that end, we compared the real WC
effect and the estimated WC effect (OBP-ABP) in terms of magnitude and
consequences on target organs. DESIGN: The study comprised 88 patients referred
for hypertension. The real WC effect was measured using a Finapres device and
expressed as the maximal WC effect (Max WC) or the average WC effect (Aver WC).
For the estimation of target organ damages, the whole hypertensive group was
separated into two groups according to the medians of the Aver WC, the Max WC,
and the estimated WC effects, successively. Left ventricular mass index, E to A
mitral wave ratio and pulse wave velocity were compared between groups as were
serum creatinine, cholesterol and glucose levels. RESULTS: The estimated WC
effect proved to be a bad index of the real response to the doctor's visit as
assessed by their difference of magnitude between the two (20 +/- 17, 12 +/- 12
and 30 +/- 14 mmHg as estimated WC, Aver WC and Max WC effects, respectively),
their loose correlations (r=0.31, P=0.004 between estimated WC and Aver WC
effects; r=0.27, P=0.01 between estimated WC and Max WC effects), and finally by
the fact that they were in agreement in less than two-thirds of the patients for
the categorization of the WC response. Concerning target organ damages, no
difference in terms of cardiac mass, diastolic function, arterial distensibility,
renal function and cardiovascular risk profile could be discerned between the
groups with a high and a low WC effect, either real or estimated, when age and
ABP were taken into account. CONCLUSION: The present work supports the view that
the true WC effect and its estimation are not equivalent. However, the way in
which the WC response is defined does not alter its effect on target organs or
cardiovascular risk profile.
PMID- 10779088
TI - Comparison of nurse- and physician-determined clinic blood pressure levels in
patients referred to a hypertension clinic: implications for subsequent
management.
AB - BACKGROUND: When measuring BP, the physician induces a transient pressor response
triggered by an alarm reaction. This 'white-coat effect' can influence
therapeutic decisions. Whether it depends on the characteristics of the physician
has not been evaluated. OBJECTIVE: To assess the 'white-coat effect' induced by
several physicians in a large sample of patients, using the blood pressure
measured by trained nurses as a reference. SETTING: Referral hypertension clinic.
METHODS: Patients were selected for the study if they had been referred for the
first time to the clinic and if they had had their supine systolic/diastolic
blood pressure measured by a trained nurse (mean of the last two of three
measurements taken every 1 min by an oscillometric device) and a physician
(auscultatory method using a standard mercury sphygmomanometer). Physicians were
included in the study provided they had seen at least 25 patients during the
study period. The between-physician difference was assessed using linear
regression analysis. Physician blood pressure was the dependent and nurse blood
pressure was the independent variable. RESULTS: From 1 January 1997 to 15
September 1997, 1062 patients (50% male, aged 52 +/- 14 years), seen by 10
physicians (26-187 patients per physician) and one nurse were included for
analysis. The mean systolic/diastolic blood pressure for physicians was 162 +/-
27/ 97 +/- 15 mmHg and that for the nurse was 155 +/- 24/ 88 +/- 14 mmHg. The
nurse-physician differences were -6 mmHg (range -67 to +66) for systolic and -8
mmHg (-44 to +31) for diastolic blood pressures. Major differences were observed
between individual physicians. Intercepts of the physician blood pressure versus
nurse blood pressure relationship ranged from 0.1 -60.7 mmHg for systolic and
from 13.3-55.3 mmHg for diastolic pressures. The slopes of this relationship
differed less between physicians for systolic (0.72-1) than for diastolic
pressures (0.56-0.97). There was no difference between the patients seen by
physicians in patients' age, sex, tobacco consumption, anti-hypertensive
treatment or target-organ damage. CONCLUSION: Large between-physician differences
exist in the magnitude of the white-coat effect that cannot be explained by
patient characteristics. Physicians should therefore not make any decisions based
on blood pressure measured manually during a first encounter.
PMID- 10779089
TI - Increased blood pressure response to the cold pressor test in pregnant women
developing pre-eclampsia.
AB - OBJECTIVES: Recent data indicate an increased vascular reactivity due to an
overactivity of the sympathetic nervous system in women with pre-eclampsia. We
therefore evaluated whether this increased vascular reactivity can be detected
prior to the clinical manifestation of preeclampsia by the use of a physiological
stimulus. DESIGN: Prospective data collection. SETTING: Clinic of Obstetrics and
Gynecology in a 2000 bed tertiary care hospital. PARTICIPANTS: One hundred and
twenty-three pregnant women between the 16th to 20th week of gestation.
INTERVENTIONS: A cold pressor test was performed by positioning an ice-bag on the
forehead of the woman for 3 min. Blood pressure and heart rate were monitored by
a continuous, noninvasive blood pressure measurement device during the stimulus
and after removal of the icebag. A clinical follow-up was carried out by review
of the charts after delivery to identify those women who have developed pre
eclampsia. RESULTS: Ten (8%) out of 123 pregnant women developed pre-eclampsia.
During the cold pressor test systolic as well as diastolic blood pressure
increased significantly and was more pronounced in women developing pre-eclampsia
compared with healthy pregnant women (systolic blood pressure: 14.2 +/- 5.5
versus 8.5 +/- 7.2 mmHg, P= 0.02; diastolic blood pressure: 7.3 +/- 4.9 versus
3.9 +/- 4.7 mmHg, P=0.03). The change in heart rate was similar between both
groups (8 +/- 2.6 versus 10.4 +/- 6.4 beats/min, not significant). CONCLUSIONS:
An increased vasoconstrictive response to a physiological stimulus is present in
women with pre-eclampsia as a sign of an increased vascular reactivity prior to
clinical manifestation of the disease. The cold pressor test may be a suitable
diagnostic tool to identify women, who will develop pre-eclampsia. However,
future studies in larger cohorts are required to establish the final value of
this test.
PMID- 10779090
TI - Physical activity level is an independent predictor of the diurnal variation in
blood pressure.
AB - OBJECTIVE: The aim of this study was to define the relationship between physical
activity and the magnitude of the percentage fall in blood pressure at night
(nocturnal dip). METHODS: We simultaneously monitored 24-h ambulatory blood
pressure and measured physical activity by actigraphy in 434 patients. Blood
pressure was measured every 20 min; the actigraph integrated an activity score
every 10 s. Mean daytime and night-time activity were calculated from mean scores
for the 15 min preceding each blood pressure measurement. Nocturnal dip in
systolic and diastolic blood pressure (SBP and DBP) were regressed on mean (log
transformed) daytime activity. Mean night-time activity, age, gender, smoking
status, body mass index (BMI) and clinic blood pressure were added into a
multiple linear regression. RESULTS: The patient group was heterogeneous in age,
gender and mean 24-h blood pressure. Mean daytime activity level was
significantly and positively associated with the magnitude of the nocturnal dip
in both SBP and DBP. Increased night-time activity was significantly associated
with a smaller nocturnal dip. Older patients had a smaller nocturnal dip per log
unit daytime activity. Nocturnal dip in SBP was greater in males, and smaller in
those taking antihypertensive medications. Smoking, BMI and clinical blood
pressure level were not associated with the extent of the nocturnal dip after
adjustment for other factors. CONCLUSIONS: Daytime and night-time physical
activity levels are independently and significantly predictive of the magnitude
of the nocturnal dip in blood pressure. Variation in activity may confound
interpretation of 24-h ambulatory blood pressure monitoring, and contribute to
the poor reproducibility of dipper status.
PMID- 10779091
TI - Effect of vitamin C on ambulatory blood pressure and plasma lipids in older
persons.
AB - OBJECTIVES: To determine the effect of oral vitamin C supplements on ambulatory
blood pressure and plasma lipids. DESIGN: A 6-month double-blind randomized
placebo-controlled cross-over study with a 1 -week washout between cross-over
periods. METHODS: Vitamin C 500 mg daily or matching placebo was given to 40 men
and women aged between 60 and 80 years for 3 months each in a cross-over fashion.
Clinic and 24-h ambulatory blood pressure, plasma ascorbate and lipids were
measured at baseline and at the end of each cross-over phase. RESULTS: Clinic
blood pressure did not change between placebo and vitamin C phases. Daytime
ambulatory blood pressure showed a small but significant fall in systolic blood
pressure (2.0 +/- 5.2 mmHg; 95% confidence interval 0-3.9 mmHg) but not in
diastolic blood pressure. Regression analysis showed that with increasing
baseline daytime blood pressure the fall in blood pressure with vitamin C
supplementation increased. Regression analysis of the change in high-density
lipoprotein (HDL) cholesterol showed a significant effect of sex on the change in
HDL cholesterol. In women, but not men, HDL cholesterol increased significantly
by 0.08 +/- 0.11 mmol/l, P=0.007. There was no change in low-density lipoprotein
cholesterol between treatment periods. CONCLUSION: In older adults high intakes
of ascorbic acid have modest effects on lowering high systolic blood pressure,
which could contribute to the reported association between higher vitamin C
intake and lower risk of cardiovascular disease and stroke.
PMID- 10779092
TI - Excess mortality associated with increased pulse pressure among middle-aged men
and women is explained by high systolic blood pressure.
AB - OBJECTIVE: To assess the risk of death from coronary heart disease, stroke, all
cardiovascular diseases and all-cause mortality associated with pulse pressure
among the middle-aged population. METHODS AND DESIGN: A prospective 15-year
follow-up cohort study was conducted of two independent cross-sectional random
samples of the population who participated in baseline surveys in 1972 or 1977.
Each survey included a self-administered questionnaire with questions on smoking
and antihypertensive drug treatment, measurements of height, weight and blood
pressure and the determination of the serum cholesterol concentration.
Multivariate analyses were performed by using Cox proportional hazard models.
SETTING: The provinces of North Karelia and Kuopio in eastern Finland
PARTICIPANTS: Men and women aged 45-64 years with no history of myocardial
infarction or stroke at the time of the baseline survey were selected. In total
4333 men and 5270 women took part in this follow-up study. RESULTS: The relative
risk of coronary heart disease, stroke, cardiovascular disease and all-cause
mortality increased with the increasing pulse pressure in individuals aged 45-64
years independent of the diastolic blood pressure level. Only in women with
diastolic blood pressure > or = 95 mmHg was the relative risk of fatal stroke not
statistically significant. After adjustment for systolic blood pressure, the
positive association between mortality and increasing pulse pressure disappeared.
CONCLUSION: Increasing pulse pressure is a predictor of death from coronary heart
disease, stroke, cardiovascular disease and all causes in men and women aged 45
64 years, but the increase in risk is entirely associated with the increase in
systolic blood pressure.
PMID- 10779093
TI - High-normal serum homocysteine concentrations are associated with an increased
risk of early atherosclerotic carotid artery wall lesions in healthy subjects.
AB - OBJECTIVE: Moderate hyperhomocysteinaemia is common in the general population and
has been linked with systemic atherosclerotic vascular disease. We studied the
relation of sonographically determined carotid intima-media wall thickness to
serum homocysteine concentrations in asymptomatic, healthy subjects. METHODS AND
RESULTS: Seventy-five male and female untreated subjects (mean age 49 years,
range 22-75) with normal serum folate concentrations were included. High
resolution duplex sonography was used to determine intima-media thickness of the
common carotid artery. Serum homocysteine concentration was measured by high
performance liquid chromotography with fluorescence detection. Mean intima-media
thickness (+/- SD) was 0.78 +/- 0.19 mm (range 0.5-1.35) and mean serum
homocysteine concentration was 10.5 +/- 2.81 micromol/l (range 5.7-19.6). In
stepwise regression models, statistically significant predictors of intima-media
thickness included age, body mass index, LDL cholesterol and homocysteine (R2 =
0.51). Homocysteine concentration was independently associated with intima-media
thickness after adjustment for the other variables (P < 0.001) and explained an
additional 18% of the variation of intima-media thickness. CONCLUSIONS: In
healthy subjects, high-normal serum homocysteine concentrations are associated
with an increased prevalence of carotid artery wall thickening. The significance
of the contribution of homocysteine to the variation of carotid intima-media
thickness, even at concentrations previously believed to be normal, suggests a
role for homocysteine as an independent risk factor for early carotid artery
atherosclerosis in the asymptomatic subjects.
PMID- 10779094
TI - Association between the apolipoprotein E polymorphism and arterial wall thickness
in asymptomatic adults.
AB - OBJECTIVES: The polymorphism of the apolipoprotein E gene (epsilon2, epsilon3,
epsilon4) affects plasma cholesterol but the relationship with artery wall
thickness has indicated contradictory results. This study investigated the
relationship between apolipoprotein E polymorphism and vascular phenotypes of the
carotid and radial arteries, two arterial sites differently affected by
atherosclerosis. METHODS: We studied a cohort of 320 Caucasian subjects (age 49
+/- 12 years) without evidence of cardiovascular disease. Structural (internal
diameter and wall thickness) and functional phenotypes (compliance,
distensibility) were evaluated for the common carotid and the radial arteries
using high resolution echo-tracking devices. Genotypes of apolipoprotein E were
determined by allele-specific oligonucleotides hybridization. Because of the
relative low frequency of some apolipoprotein E genotypes, they were designated
as E2 (epsilon2/epsilon2, epsilon2/epsilon3), E3 (epsilon3/epsilon3), and E4
(epsilon4/epsilon4, epsilon3/epsilon4). RESULTS: Apolipoprotein E allele
frequencies were epsilon2 = 0.08, epsilon3 = 0.79, epsilon4 = 0.13. Subjects with
epsilon4 allele had the highest levels of total serum cholesterol and low density
lipoprotein cholesterol; subjects with epsilon2 allele had the lowest levels (P <
0.001). Considering carotid hypertrophy as intima-media thickness > 660 microm,
and radial hypertrophy as intima-media thickness > 260 microm, a logistic
regression model testing determinants of arterial hypertrophy (age, gender,
weight, systolic blood pressure, smoking habits, and total serum cholesterol)
observed a significant and positive association between carotid hypertrophy and
epsilon2 allele carriers (P= 0.03). In contrast, no association was found between
hypertrophy and apolipoprotein E genotypes for the radial artery. No association
was observed between the apolipoprotein E genotypes and functional artery
parameters. CONCLUSIONS: In subjects without any evidence of cardiovascular
disease, the presence of the epsilon2 allele is related to wall hypertrophy in
carotid artery despite favourable effect on the lipid profile.
PMID- 10779095
TI - Headache in patients with mild to moderate hypertension is generally not
associated with simultaneous blood pressure elevation.
AB - OBJECTIVE: Although headache is regarded a symptom of hypertension, its relation
to blood pressure, especially in mild and moderate hypertension, is not clear.
Thus, the aim of the study was to investigate whether headache in patients with
mild to moderate hypertension may be attributed to simultaneous elevations in
blood pressure. DESIGN AND METHODS: Ambulatory blood pressure monitoring (ABPM)
was performed in patients (mean age 48 +/- 10 years, n = 150, 92 men, 58 women)
classified, according to their office blood pressure, as stage 1 -2 hypertensives
(JNC VI). Headache periods were recorded in patients' diaries. RESULTS: Headaches
were generally not directly associated with blood pressure elevations in the
studied group of stage 1-2 hypertensive patients because (i) blood pressure
values from headache periods were not significantly higher than those from
headache-free periods; (ii) blood pressure values directly preceding the pain
were not significantly different from values at the beginning of headache; and
(iii) in the vast majority of hypertensives, their maximal blood pressure values
were recorded during headache-free periods. Moreover, in some instances, patients
who showed maximal ABPM values during headache had relatively high blood
pressure, i.e. > or = 180/110 mmHg. CONCLUSIONS: Our results did not support the
opinion that headache experienced by stage 1-2 hypertensives was generally caused
by simultaneous elevation in blood pressure. The direct mechanisms of headache in
hypertension, as well as the relation between increments in blood pressure above
180/110 mmHg and headache, need further investigations.
PMID- 10779096
TI - Cardiac hypertrophy depends upon sleep blood pressure: a study in rats.
AB - OBJECTIVE: The objective of this study was to determine whether cardiac
hypertrophy in hypertensive rats could be reduced and normalized by intermittent
reduction of blood pressure, and to determine whether left ventricular
hypertrophy was related to 24 h workload or peak blood pressure responses.
METHODS: Hypertension was created by the application of a 0.20 mm clip to the
left renal artery. Blood pressure response was monitored using a telemetry system
(Data Science International). Blood pressure was reduced for varying periods of
the day by giving different doses of captopril in the drinking water or by intra
peritoneal administration. Cardiac size was measured by weighing the ventricles
and factoring by the body weight to obtain a cardiac index. RESULTS: Captopril 75
mg/kg per day and 25 mg/kg per day in the drinking water administered between
1800 and 2000 h lowered the 24 h blood pressure more than captopril 15 mg/kg per
day or 5 mg/kg per day intra-peritoneally given at 0800 h. Captopril 75 mg/kg per
day and captopril 15 mg/kg per day (intra-peritoneal) caused regression of
cardiac hypertrophy whereas the other doses had no effect The best predictor of
the cardiac hypertrophy response was the blood pressure between 0800 and 1200 h
(i.e. the sleeping blood pressure). Twenty-four hour cardiac work did not
correlate with the response. CONCLUSION: Cardiac hypertrophy can be reduced by
intermittent treatment of elevated blood pressure. It is also caused by
intermittent elevation of blood pressure. It appears that the crucial factor is
when these alterations in blood pressure take place. An elevated blood pressure
during the sleeping hours causes left ventricular hypertrophy, whereas a normal
blood pressure during the sleeping hours allows reduction. It is suggested that
acute wall stress is the signal to initiate the events that lead to cardiac
hypertrophy but this only occurs if the hormonal milieu is appropriate.
PMID- 10779097
TI - Early impairment of coronary flow reserve and increase in minimum coronary
resistance in borderline hypertensive patients.
AB - OBJECTIVE: To evaluate relations between coronary flow velocity and myocardial
oxygen demand at rest, as well as coronary vasodilator capacity and flow reserve,
in asymptomatic subjects with borderline hypertension as compared to normotensive
controls and patients with sustained high blood pressure (HBP) and without left
ventricular hypertrophy (LVH). SUBJECTS AND METHODS: Forty-two asymptomatic males
were studied: 13 healthy normotensive volunteers; 12 subjects with borderline HBP
and 17 asymptomatic subjects with sustained systemic hypertension. Coronary flow
velocity in left anterior descending artery and coronary flow reserve were
assessed by transesophageal echo-doppler at baseline and during intravenous
adenosine infusion. Left ventricular mass, peak systolic wall stress (PSWS; Pa),
and midwall fractional shortening (MFS; %) were obtained from M-mode images of
the left ventricle in transthoracic long-axis view and in transesophageal
transgastric view. RESULTS: Coronary flow velocity at baseline was not
significantly different in the three groups, despite significantly higher rate
pressure product (RPP) in the hypertensive groups as compared with controls. Only
in control subjects, was resting coronary flow velocity significantly correlated
with RPP (y = 4279 + 200x, r = + 0.58, P < 0.05) and PSWS (y = 17.2 + 5.1 x, r =
+ 0.62, P < 0.05). Coronary reserve was 3.5 +/- 0.65 in controls and
significantly lower (P < 0.05) in borderline hypertensive (2.87 +/- 0.46) and in
sustained hypertensive subjects (2.66 +/- 0.56). Minimum coronary resistance was
significantly increased in both hypertensive groups (1.30 +/- 0.29 and 1.39 +/-
0.48 mmHg/s per cm) as compared to normotensive controls (0.93 +/- 0.20 mmHg/s
per cm, P < 0.01). CONCLUSIONS: In asymptomatic subjects with borderline
hypertension and without LVH, a significant reduction in coronary flow reserve is
already detectable and appears almost entirely related to an impaired coronary
vasodilator capacity rather than to an increased myocardial oxygen demand.
PMID- 10779098
TI - QT dispersion and hypertensive heart disease in the elderly.
AB - AIM: To determine the predictors and risk of increased QT dispersion in the
elderly hypertensive patients. METHODS: A 12-lead electrocardiogram (ECG), M-mode
echocardiography and ambulatory blood pressure as well as Holter monitoring were
performed for 67 patients over 60 years of age with essential hypertension (I and
II(o) WHO). The presence of ischaemic changes on ECG was evaluated based on the
Minnesota Code. QT intervals were corrected with Bazett's formulae and QT
dispersion was determined as the difference between maximal and minimal QTc
intervals. Interventricular septal thickness (IVSTd), left ventricular internal
diameter (LVDd) and posterior wall thickness (PWTd) were measured and left
ventricular mass index (LVMI) was calculated. Subjects were divided according to
the median of QTc dispersion (0.10 s). The differences between groups were
assessed using chi-squared and Student's t-test. RESULTS: Subjects with increased
QTc dispersion did not differ from those with low QTc dispersion when age, gender
and body mass index were analysed. Similarly, the average systolic blood
pressure, diastolic blood pressure and blood pressure variability were comparable
in both groups. The mean QTc interval was similar in both groups. In patients
with increased QT dispersion, left ventricular hypertrophy (LVH) and ischaemic
changes on ECG were more frequently recognized (respectively 41.2 versus 18.2%, P
< 0.001; 47.1 versus 21.2%, P < 0.05). Moreover, these subjects presented a
significantly greater number of premature ventricular beats (317.1 +/- 665.6
versus 64.88 +/- 188.6, P < 0.05) and higher classes of Lown's arrhythmia scale
(classes III-IV, 23.35% versus 9.1%). LVMI was insignificantly higher in the
group with greater QTc dispersion (165.82 +/- 54.5 versus 145.07 +/- 36.47 g/
m2). Other echocardiographic indices of LVH were similar in both groups. On the
other hand, the analysis of regression indicated positive correlation between the
dispersion of QTc interval and thickness of left ventricle walls (for IVSd - r =
0.37; for PWd - r = 0.31), relative wall thickness (r = 0.28) and LVMI (r =
0.28). CONCLUSIONS: QTc dispersion is increased in the elderly hypertensive
individuals, with the presence of LVH and myocardial ischaemia on ECG. These
patients are more likely to demonstrate severe ventricular dysrhythmias.
PMID- 10779099
TI - Insulin-stimulated cardiac glucose uptake is impaired in spontaneously
hypertensive rats: role of early steps of insulin signalling.
AB - OBJECTIVE: Although the heart is one of the target organs of insulin, it is still
unknown whether the effect of insulin on cardiac muscle is preserved in essential
hypertension, where insulin resistance has been observed in skeletal muscle.
METHODS: We evaluated cardiac glucose uptake and the early steps of insulin
signalling in spontaneously hypertensive (SHR, 10-12 weeks old) and in age
matched normotensive Wistar-Kyoto (WKY) rats. Cardiac glucose uptake
(micromol/100 g per min) was assessed by 2-[14C]deoxyglucose method. After an
overnight fast, 16 WKY rats and 17 SHR underwent a hyperinsulinemic euglycemic
clamp. In particular, 2-h intravenous (i.v.) infusion of insulin (10 mU/kg per
min) or saline (NaCl 0.9%) was administered, followed by an i.v. bolus injection
of 2-[14C]deoxyglucose (100 microCi/kg) to measure cardiac glucose uptake.
RESULTS: During saline infusion, cardiac glucose uptake was significantly higher
in SHR compared to WKY rats (85 +/- 18 versus 8 +/- 3 mg/kg per min, P < 0.01).
Furthermore, insulin was able to markedly increase cardiac glucose uptake in WKY
rats whereas this insulin action was entirely abolished in SHR; thus, the cardiac
glucose uptake became similar in the two rat strains (76 +/- 16 versus 82 +/- 16
mg/kg per min, not significant). More importantly, during saline infusion SHR
showed a significantly higher phosphorylation of insulin receptor substance-1
(IRS-1) coupled to enhanced association of the p85 subunit of
phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and to an increased PI 3
kinase activity compared to WKY rats. As expected, insulin exposure evoked an
activation of its signalling cascade in WKY rats. In contrast, in SHR, the
hormone failed to activate post-receptor molecular events. CONCLUSIONS: Our data
indicate that the heart of SHR shows an overactivity of the proximal steps of
insulin signalling which cannot be further increased by the exposure to the
hormone. This abnormality may account for the marked increase of basal cardiac
glucose uptake and the loss of insulin-stimulated glucose uptake observed in SHR.
PMID- 10779100
TI - Endothelin-1 inactivating peptidase in the human kidney and urine.
AB - OBJECTIVE: Recently, an apparently novel, specific endothelin-1 inactivating
metalloendopeptidase (ET-1 peptidase) has been isolated from the rat kidney. In
this study we attempted to determine whether the same or a similar peptidase is
present in the human kidney, and whether the enzyme is excreted into the urine.
The urinary ET-1 peptidase could serve as an indirect index of the renal
endothelin system, both in physiology and pathophysiology. METHODS: Kidney
specimens were obtained from part of nephrectomized kidneys unaffected by any
neoplastic process from six adult patients. The enzyme was purified using
differential centrifugation, detergent solubilization of the membrane proteins,
ultrafiltration and nondenaturing gel electrophoresis. The enzyme activity assays
were performed at pH 5.5 and 37 degrees C in the presence of increasing
concentrations of unlabelled peptides and inhibitors using a fixed amount of
[125I]ET-1 as substrate. The degradation extent was quantified with
trichloroacetic acid precipitation and high performance liquid chromatography.
The degrading activity of ET-1 was determined in urine samples from adult
patients with hypertension, children with chronic renal failure and those with
stable renal allograft RESULTS: ET-1 peptidase from the human kidney displays
characteristics close to that of the rat ET-1 peptidase we have recently
described (J. Hypertens 1994; 12:1155-1162). The enzyme, a membrane-bound
metalloendopeptidase, exhibits low electro- phoretical mobility on nondenaturing
gel (Rf 0.08); it is an apparently heterologous structure comprising three
enzymatically inactive subunits, it has a pH optimum at 5.5, a nanomolar range
affinity to the ET-1 (KM 180 nmol/l) that is hydrolysed to two main degradation
products, and a 10-100-fold lower affinity to big ET-1 (KM 11.5 micromol/l),
endothelin 11 21 fragment (KM 15.3 micromol/l), endothelin antagonist Trp-Leu-Asp
Ile-Ile-Trp (KM 3.1 micromol/I), gastrin (KM 2.2 micromol/l) and cholecystokinin
(KM 4.0 micromol/l). Substance P, neuropeptide Y, atrial natriuretic peptide,
bradykinin, angiotensin II and enkephalin were poor substrates for the enzyme.
The most powerful inhibitors of the ET-1 peptidase included thiorphan (IC50 0.28
nmol/l), phosphoramidon (IC50 0.55 nmol/l), phenanthroline (IC50 11.5
micromol/l), cyclosporin (IC50 400 micromol/l), phosphate (IC50 1.2 mmol/l),
citrate (IC50 0.6 mmol/l) and aniline naphthalene sulphonic acid (IC50 0.25
mmol/l). Our data suggest that three ET-1 degrading peptidases with optimal
activity at pH 4.5, 5.5 and 7.0, respectively, are excreted into the urine. The
enzyme with a pH optimum 4.5 is of lysosomal origin whereas the two other enzymes
correspond by their pH optima to the renal ET-1 peptidase and neutral
endopeptidase. We have found statistically significant increases (P < 0.001) in
the activity of both lysosomal and ET-1 peptidase in the urine in patients with
hypertension and in children with chronic renal failure compared with healthy
subjects or children with stable renal allograft CONCLUSIONS: Human kidney
contains an acidic, highly specific endothelin-1 inactivating
metalloendopeptidase that may have a key role in the regulation of concentrations
of renal and circulating endothelins. The enzyme is excreted into the urine where
its activity seems to be increased in patients with hypertension and chronic
renal failure; it may potentially serve as an indirect index of the renal
endothelin system.
PMID- 10779101
TI - Ambulatory blood pressure 16-26 years after the first urinary tract infection in
childhood.
AB - OBJECTIVE: To evaluate blood pressure in a population-based cohort with
urographic renal scarring after childhood urinary tract infection. DESIGN: Follow
up investigation 16-26 years after the first recognized urinary tract infection.
SETTING: University out-patient clinic for children with urinary infections
serving the local area. PATIENTS: From the original cohort of 1221 consecutive
children with first urinary tract infection diagnosed during 1970-1979, 57 of 68
with non-obstructive renal scarring participated as well as 51 matched subjects
without scarring. MAIN OUTCOME MEASURE: 24 h ambulatory blood pressure. RESULTS:
Acceptable blood pressure monitorings were obtained from 53 individuals with and
47 without scarring. There were no significant differences between the two groups
even when only patients with the most extensive scarring (individual kidney
clearance < 30 ml/min per 1.73 m2) or patients with bilateral scarring were
compared with the non-scarring group. Mean systolic or diastolic blood pressure
above +2 SD were found in 5/53 (9%) and 3/47 (6%) in the scarring and non
scarring group, respectively. Plasma renin activity, angiotensin II and
aldosterone concentrations were not significantly different, but atrial
natriuretic protein was significantly higher in the scarring group (P = 0.004).
CONCLUSION: This study demonstrates a low risk of hypertension two decades after
childhood urinary tract infection. It should be stressed that the patients with
renal scarring were under close supervision throughout childhood. Those with
scarring had higher concentrations of atrial natriuretic protein which might
indicate a counter-regulation mechanism.
PMID- 10779102
TI - Multimicroelectrode stimulation within the cat L6 spinal cord: influences of
electrode combinations and stimulus interleave time on knee joint extension
torque.
AB - During multimicroelectrode stimulation within the cat L6 spinal cord, the number
of electrodes activated, their separation distance, and the stimulus interleave
time all influenced isometric knee joint extension torque. The torque evoked by
stimulation with a three electrode combination could be enhanced or suppressed
when compared with that evoked by single or paired electrode stimulation. A
similar difference was noted when comparing two electrode combination versus
single electrode stimulation. Relative fatigue was not improved significantly by
interleaving the stimuli from two or three microelectrodes. Compared with the
extension torque response evoked by noninterleaved stimulation, torque evoked by
interleaved stimulation with the two microelectrode combination was decreased
when the electrode distance was 2.0 mm or less and increased when the electrode
distance was 3.0 mm. Designing an optimal stimulation strategy for
multimicroelectrode spinal cord stimulation will be challenging and complex if a
suppression effect among these electrodes is to be avoided. To reduce muscle
fatigue, an asynchronous, interleaved strategy of stimulation may be required.
PMID- 10779103
TI - Selective activation of muscle groups in the feline hindlimb through electrical
microstimulation of the ventral lumbo-sacral spinal cord.
AB - Selective activation of muscle groups in the feline hindlimb by electrical
stimulation of the ventral lumbo-sacral spinal cord was investigated. Spinal cord
segments L5 to S1 were mapped using a penetrating tungsten needle electrode.
Locations that produced isolated contraction of quadriceps, tibialis anterior or
triceps surae/plantaris muscles when stimulated with a current of 40 microA or
less, and in which spread of activity to other muscles was not detected after
increasing the stimulus to at least twice the threshold level, were defined as
belonging to the target muscle's "activation pool." The quadriceps activation
pool was found to extend from the beginning of L5 to the middle of L6. The
tibialis anterior activation pool extended from the beginning of L6 to the middle
of L7, and the triceps surae/plantaris activation pool extended from the caudal
end of L6 to the beginning of S1. The three activation pools were located in
Rexed motor lamina IX and their spatial organization was found to correspond well
with that of the anatomically defined motor pools innervating the same muscles.
The spatial and functional segregation of motor pools manifested at the spinal
cord level can have direct applications in the areas of functional electrical
stimulation and motor control.
PMID- 10779104
TI - Muscle recruitment through electrical stimulation of the lumbo-sacral spinal
cord.
AB - The goal of this study was to determine the feasibility of producing graded
muscle contraction in individual muscles or muscle groups by electrically
stimulating motor neurons in the lumbo-sacral spinal cord. Recruitment curves
were obtained for quadriceps, tibialis anterior and triceps surae/plantaris by
stimulating their activation pools in the ventral horn of the feline spinal cord.
Mean twitch times-to-peak for quadriceps, tibialis anterior and triceps
surae/plantaris were 33.0, 41.0, and 36.0 ms, respectively. Twitch duration as a
function of stimulus strength demonstrated a mixed motor unit recruitment order,
distinctively different from the inverse recruitment order exhibited by
conventional methods of electrical stimulation of peripheral nerve. The
recruitment curve slopes (expressed as a percentage of maximum force per
nanocurrent of delivered charge) were shallow: 7.9 for quadriceps, 2.6 for
tibialis anterior and 8.5 for triceps surae/plantaris. These results show that
graded control of force in individual muscles or muscle groups can be obtained
through spinal cord stimulation, and suggest that spinal cord stimulation could
be used for functional neuromuscular stimulation applications.
PMID- 10779105
TI - Functional electrical stimulation of abdominal muscles to augment tidal volume in
spinal cord injury.
AB - Functional electrical stimulation (FES) of abdominal muscles as a method of
enhancing ventilation was explored in six neurologically intact subjects and five
subjects with spinal cord injury (SCI) who had levels of injury between C4 and
C7. Pulmonary ventilation was augmented in both groups predominantly due to an
increase in tidal volume. The average increase in tidal volume during FES for the
neurologically intact group was 350 ml, while in the SCI group it was 220 ml. The
FES caused active volume decreases in both the lower thorax and upper abdomen,
which together appear to be the mechanism behind the increases seen in tidal
volume. Therefore, the proposed method might be useful in future clinical
practice. The results indicate that FES of abdominal muscles should be more
thoroughly explored as a potential technique of ventilatory support in SCI. The
results also point to the necessity for further studies of maintaining the
condition of the chest wall in the pulmonary rehabilitation of individuals with
tetraplegia.
PMID- 10779106
TI - Measurement of external pressures generated by nerve cuff electrodes.
AB - When external pressures are applied to a peripheral nerve, tissue damage can
occur via compression and blood flow occlusion, resulting in degeneration and
demyelination of axons. Although many types of nerve electrodes have been
designed to avoid or minimize this pressure during stimulation of the nerve or
recording of its activity, the measurement of the pressure exerted by these cuffs
has not been reported. Currently, only theoretical models are used to predict
nerve cuff electrode pressures. We have developed a nerve cuff electrode pressure
sensor to measure external pressures exerted by peripheral nerve cuff electrodes.
The sensor has a high sensitivity, linear response with little hysteresis and
reproducible output. Pressure measurements have been obtained for split-ring and
spiral cuff electrodes. The measurements obtained are in agreement with
theoretical predictions. Moreover, they indicate that the pressures exerted by
cuffs currently used for stimulation generate only a small amount of pressure,
which is below the pressure required to occlude blood flow in nerves. The results
also suggest that this new sensor can provide reliable measurement of external
pressures exerted by nerve electrodes and would be an important tool for
comparing various nerve cuff electrode designs.
PMID- 10779107
TI - Adaptive neural network control of cyclic movements using functional
neuromuscular stimulation.
AB - In this study, we evaluated the performance of an adaptive feedforward controller
and its ability to automatically develop and customize stimulation patterns for
use in functional neuromuscular stimulation (FNS) systems. Results from previous
experiments using the pattern generator/pattern shaper (PG/PS) controller to
generate isometric contractions demonstrated its ability to adjust stimulation
patterns to account for recruitment nonlinearities and muscle dynamics. In this
study, the PG/PS controller was tested under isotonic conditions. This evaluation
required the PG/PS controller to account for muscle length-tension and force
velocity properties as well as limb dynamics. The performance of the adaptive
controller was also compared with that of a proportional-derivative (PD) feedback
controller. The PG/PS controller is composed of a neural network system that
adaptively filters a periodic signal to produce a muscle stimulation pattern for
generating cyclic movements. We used computer-simulated models to determine
controller parameters for the PG/PS and PD controller that perform well across a
variety of musculoskeletal systems. The controllers were then experimentally
evaluated on both legs of two subjects with spinal cord injury. Results indicated
that the PG/PS controller was able to achieve and maintain better tracking
performance than the PD controller. This study indicates that the PG/PS control
system may provide an effective mechanism for automatically customizing
stimulation patterns for individuals using FNS systems.
PMID- 10779108
TI - Tremor suppression through impedance control.
AB - This paper presents a method for designing tremor suppression systems that
achieve a specified reduction in pathological tremor power through controlling
the impedance of the human-machine interface. Position, rate, and acceleration
feedback are examined and two techniques for the selection of feedback
coefficients are discussed. Both techniques seek a desired closed-loop human
machine frequency response and require the development of open-loop human-machine
models through system identification. The design techniques were used to develop
a tremor suppression system that was subsequently evaluated using human subjects.
It is concluded that nonadaptive tremor suppression systems that utilize
impedance control to achieve a specified reduction in tremor power can be
successfully designed when accurate open-loop human-machine models are available.
PMID- 10779109
TI - Analysis of arm trajectories of everyday tasks for the development of an upper
limb orthosis.
AB - Spatiotemporal arm and body movements of able-bodied subjects performing nine
everyday tasks were recorded for the purpose of guiding the development of an
upper-limb orthosis. To provide a user the opportunity to carry out these tasks
with natural movements, the orthosis should allow replication of the measured
trajectories. We outline the orthosis architecture, which supports the user's
upper arm and forearm, and analyze the movement data to obtain orthosis design
specifications. Trajectories were obtained using six-degree-of-freedom magnetic
position sensors affixed to the wrist, elbow, shoulder, trunk and head. Elbow
trajectory data were decomposed into ranges along the principle Cartesian axes to
provide a generally useful envelope measure. The smallest Cartesian parallel
piped that contained the elbow trajectories for most tasks was approximately 30
cm front/back, 15 cm side/side, and 17 cm up/down. A rough lower bound estimate
obtained by asking subjects to repeat the tasks while minimizing elbow movement
substantially reduced movement in the up/down and side/side dimensions. Elbow
angles were generally in the range 50 degrees-150 degrees, and the angle of the
forearm with respect to vertical was 10 degrees-110 degrees. Raw trajectory data
may be downloaded from www://asel.udel.edu/robotics/orthosis/range.h tml.
PMID- 10779110
TI - Feedback error learning neural network for trans-femoral prosthesis.
AB - Feedback-error learning (FEL) neural network was developed for control of a
powered trans-femoral prosthesis. Nonlinearities and time-variations of the
dynamics of the plant, in addition to redundancy and dynamic uncertainty during
the double support phase of walking, makes conventional control methods very
difficult to use. Rule-based control, which uses a knowledge base determined by
machine learning and finite automata method is limited since it does not respond
well to perturbations and environmental changes. FEL can be regarded as a hybrid
control, because it combines nonparametric identification with parametric
modeling and control. This paper presents simulation of a powered trans-femoral
prosthesis controlled by a FEL neural network. Results suggest that FEL can be
used to identify inverse dynamics of an arbitrary trans-femoral prosthesis during
simple single joint movements (e.g., sinusoidal oscillations). The identified
inverse dynamics then allows the tracking of an arbitrary trajectory such as a
desired walking pattern within a multijoint structure. Simulation shows that the
identified controller responds correctly when the leg motion is exposed to a
perturbation such as a frequent change of the ground reaction force or the hip
joint torque generated by the user. FEL eliminates the need for precise, tedious,
and complex identification of model parameters.
PMID- 10779111
TI - Practical low-cost visual communication using binary images for deaf sign
language.
AB - Deaf sign language transmitted by video requires a temporal resolution of 8 to 10
frames/s for effective communication. Conventional videoconferencing
applications, when operated over low bandwidth telephone lines, provide very low
temporal resolution of pictures, of the order of less than a frame per second,
resulting in jerky movement of objects. This paper presents a practical solution
for sign language communication, offering adequate temporal resolution of images
using moving binary sketches or cartoons, implemented on standard personal
computer hardware with low-cost cameras and communicating over telephone lines.
To extract cartoon points an efficient feature extraction algorithm adaptive to
the global statistics of the image is proposed. To improve the subjective quality
of the binary images, irreversible preprocessing techniques, such as isolated
point removal and predictive filtering, are used. A simple, efficient and fast
recursive temporal prefiltering scheme, using histograms of successive frames,
reduces the additive and multiplicative noise from low-cost cameras. An efficient
three-dimensional (3-D) compression scheme codes the binary sketches. Subjective
tests performed on the system confirm that it can be used for sign language
communication over telephone lines.
PMID- 10779112
TI - A novel speech controller for radio amateurs with a vision impairment.
AB - This paper describes a portable speech controller system for persons with a
vision impairment to adjust the channel frequency of a radio set via speech
commands. The speech commands are recognized on a general-purpose digital signal
processor using a hidden Markov model (HMM), and are used to remotely control
radio channel changes.
PMID- 10779113
TI - Design and evaluation of a software prototype for participatory planning of
environmental adaptations.
AB - A software prototype to support the planning process for adapting home and work
environments for people with physical disabilities was designed and later
evaluated. The prototype exploits low-cost three-dimensional (3-D) graphics
products in the home computer market. The essential features of the prototype
are: interactive rendering with optional hardware acceleration, interactive walk
throughs, direct manipulation tools for moving objects and measuring distances,
and import of 3-D-objects from a library. A usability study was conducted,
consisting of two test sessions (three weeks apart) and a final interview. The
prototype was then tested and evaluated by representatives of future users: five
occupational therapist students, and four persons with physical disability, with
no previous experience of the prototype. Emphasis in the usability study was
placed on the prototype's efficiency and learnability. We found that it is
possible to realise a planning tool for environmental adaptations, both regarding
usability and technical efficiency. The usability evaluation confirms our
findings from previous case studies, regarding the relevance and positive
attitude towards this kind of planning tool. Although the prototype was found to
be satisfactorily efficient for the basic tasks, the paper presents several
suggestions for improvement of future prototype versions.
PMID- 10779114
TI - Controlling mouse pointer position using an infrared head-operated joystick.
AB - This paper describes the motivation for and the design considerations of a low
cost head-operated joystick. The paper briefly summarizes the requirements of
head-operated mouse pointer control for people with disabilities before
discussing a set of technological approaches that can be used to satisfy these
requirements. The paper focuses on the design of a head-operated joystick that
uses infrared light emitting diodes (LED's) and photodetectors to determine head
position, which is subsequently converted into signals that emulate a Microsoft
mouse. There are two significant findings. The first is that, while nonideal
device characteristics might appear to make the joystick difficult to use, users
naturally compensate for nonlinearities, in a transparent manner, because of
visual feedback of mouse pointer position. The second finding, from relatively
informal, independent trials, indicates that disabled users prefer a head
operated device that has the characteristics of a joystick (a relative pointing
device) to those of a mouse (an absolute pointing device).
PMID- 10779115
TI - Evaluation of an isometric and a position joystick in a target acquisition task
for individuals with cerebral palsy.
AB - Individuals with cerebral palsy (CP) with upper limb disability have difficulty
operating standard computer input devices such as, a mouse and a keyboard. The
present study evaluated the performance of unimpaired individuals and those with
CP in the use of a zero-order spring-centered position joystick and a zero-order
isometric joystick when interacting with the computer. We hypothesize that the
isometric device due to its stiff resistance would provide better control on
cursor movement than the position joystick. The subjects acquired differently
sized targets at different distances by positioning a cursor on the target.
Performance with the position joystick was superior to that of the isometric
joystick. The time to acquire the target was directly proportional to the cursor
target distance A, and indirectly proportional to the target size W. Subjects
chose to move more slowly toward the smaller and closer targets and they
increased speed for larger and more distant targets. The phase-plane diagram that
plots values of the velocity profile of the cursor over its displacement revealed
the presence of one large amplitude movement that accounts for the peak velocity
of the cursor, and several submovements. Fitts' index of difficulty, log(e)(2W/A)
was found to be a good predictor of the movement time in a cursor positioning
task for both, unimpaired individuals and those with CP.
PMID- 10779116
TI - Development of a wheelchair occupant injury risk assessment method and its
application in the investigation of wheelchair securement point influence on
frontal crash safety.
AB - To promote proper wheelchair securement in transportation, the proposed
ANSI/RESNA Standard on Wheelchairs Used as Seats in Motor Vehicles will require
that all transit wheelchairs be equipped with four securement points compatible
with strap-type tiedowns. Through computer simulations, the location of these
securement points has been found to influence wheelchair user response to a
frontal crash. This study develops and employs an injury risk assessment method
to compare the crashworthiness of various securement point configurations. The
comparative injury risk assessment method is designed to predict the risk
associated with internalized crash forces, as well as risk associated with
secondary occupant impact with the vehicle interior. Injury criteria established
by Federal Motor Vehicle Safety Standards and General Motors, along with
excursion limitations set by the Society of Automotive Engineers (SAE) J2249
Wheelchair Tiedowns and Occupant Restraint Systems (WTORS) Standard were used as
benchmarks for the risk assessment method. The simulation model subjected a
secured commercial powerbase wheelchair with a seated 50th percentile male Hybrid
III test dummy to a 20 g/30 mph crash. The occupant was restrained using pelvic
and shoulder belts, and the wheelchair was secured with four strap-type tiedowns.
Results indicated that securement points located 1.5 in to 2.5 in above the
evaluated wheelchair's center of gravity provide the most effective occupant
protection.
PMID- 10779117
TI - Biomechanical analysis of legrest support of occupied wheelchairs: comparison
between a conventional and a compensatory legrest.
AB - This study was undertaken to investigate the effects of elevating legrest on
posture and pressure distribution in a group of ten able-bodied subjects sitting
in a manual wheelchair. Two types of legrest were tested: a conventional
elevating legrest with a fixed axis of rotation, and a compensatory elevating
legrest with a moving axis of rotation. A three-dimensional (3-D) kinematics
analysis was carried out to assess body posture simultaneously with pressure
measurement data collected at the back, seat, calf and foot supports. The
compensatory legrest enables to lengthen foot support as the legrest proclines.
This compensation at the knee joint level has a beneficial effect in minimizing
pelvic and thigh motion as well as in reducing pressure distribution under seat
and foot supports. In contrast, the use of a conventional legrest modifies
significantly the subject's posture and induces a substantial increase of 40% on
pressure data under ischial tuberosities in procline position. These findings are
important for disabled and elderly people who need to elevate their lower leg
frequently.
PMID- 10779118
TI - A mechanical arthrometer to measure knee joint contracture in rats.
AB - Animal models for joint diseases are necessary for in vivo studies. Joint
contractures are characterized by lack of the normal range of motion of a joint
most often due to increased soft tissue stiffness. Biological and biochemical
data have been obtained but biomechanical data on small animals are rare. An
instrument was developed to measure rat knee angular displacement at various soft
tissue loads in normal and pathological circumstances. This article describes the
instrument and reports its reproducibility and accuracy. The reproducibility and
accuracy of this instrument was found to be acceptable thereby validating its use
for research purposes with adult rat knees.
PMID- 10779119
TI - Biomechanical evaluation of a prototype foot/ankle prosthesis.
AB - In this paper, we report on our pilot evaluation of a prototype foot/ankle
prosthesis. This prototype has been designed and fabricated with the intention of
providing decreased ankle joint stiffness during the middle portion of the stance
phase of gait, and increased (i.e., more normal) knee range of motion during
stance. Our evaluation involved fitting the existing prototype foot/ankle
prosthesis, as well as a traditional solid ankle cushioned heel (SACH) foot, to
an otherwise healthy volunteer with a below-knee (BK) amputation. We measured
this individual's lower extremity joint kinematics and kinetics during walking
using a video motion analysis system and force platform. These measurements
permitted direct comparison of prosthetic ankle joint stiffness and involved side
knee joint motion, as well as prosthetic ankle joint moment and power.
PMID- 10779120
TI - Nitric oxide as a metabolic regulator during exercise: effects of training in
health and disease.
AB - 1. Accumulating animal and human data suggest that nitric oxide (NO) is important
for both coronary and peripheral haemodynamic control and metabolic regulation
during performance of exercise. 2. While still controversial, NO of endothelial
origin is thought to potentiate exercise-induced hyperaemia, both in the
peripheral and coronary circulations. The mechanism of release may include both
acetylcholine derived from the neuromuscular junction and vascular shear stress.
3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmicro,
incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In
addition to being a potential modulator of blood flow, skeletal muscle-derived NO
is an important regulator of muscle contraction and metabolism. In particular,
recent human data indicate that NO modulates muscle glucose uptake during
exercise, independently of blood flow. 4. Exercise training in healthy
individuals promotes adaptations in the various NO systems, which can increase NO
bioavailability through a variety of mechanisms, including increased NOS enzyme
expression and activity. Such adaptations likely contribute to increased exercise
capacity and protection from cardiovascular events. 5. Cardiovascular risk
factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as
well as established disease, are associated with impairment of the various NO
systems. Given that NO is an important signalling mechanism during exercise, such
impairment may contribute to limitations in exercise capacity through inadequate
coronary or peripheral blood delivery and via metabolic effects. 6. Exercise
training in individuals with elevated cardiovascular risk or established disease
can increase NO bioavailability and may represent an important mechanism by which
exercise training provides benefit in the setting of secondary prevention.
PMID- 10779121
TI - Congenic rats for hypertension: how useful are they for the hunting of
hypertension genes?
AB - 1. Linkage studies have revealed quantitative trait loci (QTL) for blood pressure
in the rat genome using genetic hypertensive rat models. To identify the genes
responsible for hypertension, the construction of congenic rats is essential. 2.
To date, several congenic strains have been obtained from spontaneously
hypertensive or Dahl salt-sensitive rats. The results of these studies should be
interpreted according to whether the rats carry the whole QTL region or not. 3.
After establishing congenic strains, three strategies are possible: (i) an
orthodox positional cloning in which, using subcongenic strains, the QTL region
is cut down to smaller fragments suitable for physical mapping; (ii) a positional
candidate strategy in which candidate genes in the QTL regions are studied; or
(iii) physiological studies in which intermediate phenotypes directly associated
with the hypertension gene are explored. Several other experimental strategies
are also available using congenic strains as new animal models for hypertension.
4. To make the most of advances in DNA technology, the precise evaluation of the
phenotypic difference between congenic strains carrying different QTL or between
a congenic and parental strain is critical.
PMID- 10779123
TI - Cardiac and vascular responses in deoxycorticosterone acetate-salt hypertensive
rats.
AB - 1. Hypertension leads to ventricular hypertrophy and, eventually, to heart
failure. The present study has investigated the functional consequences of
deoxycorticosterone acetate (DOCA)-salt hypertension in rats by defining the
inotropic, chronotropic and vascular responses to noradrenaline (NA; beta1
adrenoceptor agonist), forskolin (adenylate cyclase activator) and theophylline
(phosphodiesterase inhibitor). 2. Administration of DOCA (25 mg, s.c., every 4th
day) and excess salt (1% NaCl in drinking water) to uninephrectomized rats
increased left ventricular wet weight by 35 and 71% after 4 and 8 weeks,
respectively. Addition of KCl (0.4%) or CaCl2 (1%) in the drinking water for 4
weeks attenuated blood pressure increases, but not ventricular weight increases
(46 and 28%, respectively). 3. Positive inotropic responses in papillary muscles
from uninephrectomized rats to NA (-log EC50 6.73+/-0.38; n = 7), forskolin (-log
EC50 6.15+/-0.31; n = 7) and CaCl2 (-log EC50 2.40+/-0.02; n = 14) were unchanged
in hypertrophied left ventricles of DOCA and DOCA-CaCl2 rats, although maximal
responses to NA were decreased in DOCA-KCI rats (1.2+/-0.6 mN, n = 8; DOCA-salt
2.9+/-0.5 mN, n = 6); theophylline was less potent in DOCA-salt rats. Positive
chronotropic responses to NA, forskolin and theophylline in right atria and
negative inotropic responses to carbachol in papillary muscles were unchanged. 4.
Maximal vasoconstrictor responses to NA in thoracic aortic rings were reduced in
DOCA-KCI rats to 2.4+/-0.9 mN (n = 5), but were increased in DOCA-CaCl2 rats to
26.6+/-2.2 mN (n = 7; DOCA-salt 7.8+/-2.2 mN, n = 9). Vasorelaxant responses to
forskolin and theophylline were unchanged. 5. These results show that cardiac
responses are only minimally affected during the development of DOCA-salt
hypertension-induced hypertrophy, despite the reported decreases in adenylate
cyclase activity, in these rats. This is in contrast with the decreased responses
reported in other rat models of cardiac hypertrophy and in the failing human
heart. Thus, hypertrophy in hearts of DOCA-salt hypertensive rats does not
produce similar changes to the failing human heart.
PMID- 10779122
TI - Pretreatment with ramiprilat induces cardioprotection against free radical injury
in guinea-pig isolated heart: involvement of bradykinin, protein kinase C and
prostaglandins.
AB - 1. Pretreatment with ramiprilat, an angiotensin-converting enzyme (ACE)
inhibitor, induced cardioprotection and its possible mechanism of action was
investigated in guinea-pig Langendorff perfused heart. 2. Superoxide anion (*O2
), produced by hypoxanthine and xanthine oxidase, and the 1,1-diphenyl-2-picryl
hydrazyl (DPPH) free radical were used for triggering free radical injury in
cardiac tissue. 3. 1,1-Diphenyl-2-picryl-hydrazyl and *O2- significantly reduced
left ventricular developed pressure (LVDP), +/-dP/dt(max), heart rate and
coronary flow. Left ventricular end-diastolic pressure (LVEDP) was elevated and
lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid
reactive substances (TBARS) formation were significantly increased. 4.
Pretreatment with ramiprilat induced cardioprotection against DPPH and *O2- free
radical injury. Cardiac functions (LVDP, LVEDP and +/-dP/dt(max)) were
significantly improved. Both LDH and TBARS were reduced. 5. HOE 140 (a selective
bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC)
inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) all abolished the
cardiac protective effect of ramiprilat. However, N(G)-nitro-L-arginine methyl
ester, a nitric oxide synthase inhibitor, had no effect. 6. In conclusion,
ramiprilat pretreatment induces cardioprotection against either DPPH or *O2- free
radical injury. The protective effect depends on activation of B2 receptors and
PKC. Prostaglandin synthesis is also involved.
PMID- 10779125
TI - Ginkgo biloba extract attenuates the development of hypertension in
deoxycorticosterone acetate-salt hypertensive rats.
AB - 1. We examined the effects of Ginkgo biloba extract (GBE) on the development of
hypertension, platelet activation and renal dysfunction in deoxycorticosterone
acetate (DOCA)-salt hypertensive rats. Both DOCA-salt hypertensive rats and
normotensive rats were fed a 2% GBE diet for 20 days. Blood pressure (BP) was
measured by two methods, namely by the tail-cuff and telemetry methods. 2.
Development of hypertension was attenuated in rats fed a 2% GBE diet. In
addition, an increase in heart weight, an indicator of sustained high BP, was
inhibited significantly by feeding of the GBE diet. 3. Decreases in 5
hydroxytryptamine content in platelets, a marker of platelet activation in vivo
associated with hypertension, were also prevented by feeding of the GBE diet.
Ginkgo biloba extract itself did not inhibit ADP- and collagen-induced platelet
aggregation examined in vitro. Feeding of the GBE diet tended to inhibit
increases in plasma urea nitrogen due to hypertension. 4. The telemetry study
demonstrated that BP and heart rate (HR) showed a clear circadian rhythm and the
antihypertensive effect of GBE was prominent in the daytime, a resting period for
rats. This anti-hypertensive effect of GBE was not detected in normotensive rats.
In contrast, the inhibitory effect of GBE on HR was independent of time and was
observed in both normotensive and hypertensive rats. 5. These results indicate
that GBE has an anti-hypertensive and bradycardiac action, which are time
dependent and independent, respectively. Thus, it appears that the
chronopharmacological action of GBE may be ascribed not to pharmacokinetic
factors, but rather to a circadian susceptibility rhythm to GBE in DOCA-salt
hypertensive rats.
PMID- 10779126
TI - Tissue distribution of alpha-tocopherol in nephrotic rats.
AB - 1. Reactive oxygen species are involved in the pathogenesis of puromycin
aminonucleoside (PAN) nephrosis and alpha-tocopherol is one of the major anti
oxidants in the body. 2. In the present study, we measured the levels of alpha
tocopherol by high-performance liquid chromatography in the plasma and in nine
tissues of control and nephrotic rats obtained 10 days after either 0.9% saline
solution or PAN injection, respectively. 3. In nephrotic rats, alpha-tocopherol
levels increased four-fold in plasma; however, the molar ratio of alpha
tocopherol/ cholesterol remained unchanged, suggesting that the increase in alpha
tocopherol content was attributable to an increase in plasma lipid concentration.
4. In nephrotic rats, the alpha-tocopherol/cholesterol ratio increased 1.33-fold
in adrenal glands and 1.34-fold in the testis, but remained unchanged in heart,
spleen, liver, kidney lung, brain and muscle. 5. These data suggest that, in PAN
nephrotic rats, there are alterations in the distribution of alpha-tocopherol and
there is no deficiency of alpha-tocopherol in plasma or tissues.
PMID- 10779127
TI - KRN2391: dual action on rat pulmonary artery and no loss of potency in pulmonary
hypertension.
AB - 1. The pulmonary vasorelaxant properties of KRN2391 (N-cyano-N'-(2-nitroxyethyl)
3-pyridinecarboximidamide) were examined in isolated ring preparations of main
(MPA) and intralobar (IPA) pulmonary artery from control and pulmonary
hypertensive rats (exposure to hypoxia, 10% oxygen, for 1 week). 2. On both MPA
and IPA, pulmonary vasorelaxant responses were inhibited by methylene blue (10
micromol/L) or glibenclamide (1 or 10 micromol/L). Thus, KRN2391 has the
properties of both a nitric oxide (NO) donor and a K(ATP) channel opener on rat
pulmonary arteries. 3. KRN2391 was more potent and gave a greater maximum
relaxation on MPA (-log EC(50) 6.47; maximum 92% reversal of induced contraction)
than on IPA (-log EC(50) 6.09; maximum 58% reversal of induced contraction).
Comparable differences between MPA and IPA were seen for SIN-1 (NO donor) and
levcromakalim (K(ATP) channel opener). 4. KRN2391 was equipotent in MPA from
control and pulmonary hypertensive rats but, when glibenclamide (10 micromol/L)
was present, KRN2391 was six-fold less potent in preparations from pulmonary
hypertensive than control rats. An eight-fold reduction in potency was seen for
SIN-1 (no glibenclamide) in arteries from pulmonary hypertensive rats, confirming
previous findings with other NO donors. 5. It is concluded that the dual
mechanism of action of KRN2391 accounts for the finding that this drug is equally
potent in pulmonary arteries from pulmonary hypertensive and control rats. In the
context of pulmonary hypertension, this property of the drug could give it an
advantage over drugs that act solely as NO donors because these decline in
potency, at least in animal models of this disease.
PMID- 10779124
TI - KRH-594, a new angiotensin AT1 receptor antagonist, ameliorates nephropathy and
hyperlipidaemia in diabetic spontaneously hypertensive rats.
AB - 1. We examined whether KRH-594, a new angiotensin AT1 receptor antagonist,
ameliorates the progression of diabetic nephropathy and hyperlipidaemia in
streptozotocin (STZ)-induced diabetic unilateral nephrectomized spontaneously
hypertensive rats (DM-1K-SHR) or not. 2. The oral administration of KRH-594 (3
and 10 mg/kg per day) and candesartan cilexetil (1 mg/kg per day) for 16 weeks
significantly reduced systolic blood pressure, urinary albumin and urinary total
protein in DM-1K-SHR. 3. In a histological study, KRH-594 (3 and 10mg/kg per day)
and candesartan cilexetil (0.3 and 1 mg/kg per day) dose-dependently improved
glomerulosclerosis and the hyalin cast of tubules in DM-1K-SHR kidneys. Both KRH
594 (10 mg/kg per day) and candesartan cilexetil (0.3 and 1 mg/kg per day) dose
dependently inhibited cardiac hypertrophy. 4. KRH-594 (3 and 10 mg/kg per day),
but not candesartan cilexetil, dose-dependently reduced the levels of
triglyceride, total cholesterol and phospholipids in DM-1K-SHR. 5. These results
suggest that KRH-594 improves diabetic complications, such as nephropathy and
hyperlipidaemia, with hypertension.
PMID- 10779128
TI - Treatment of joint pain in Crohn's patients with budesonide controlled ileal
release.
AB - 1. Joint pain is a frequent manifestation of Crohn's disease. Budesonide
controlled ileal release (CIR) is a predominantly topically acting
glucocorticosteroid, which is effective in treating active ileal or ileocaecal
Crohn's disease. 2. Therefore, it was of interest to study the effect of this
predominantly topically acting therapy on the treatment of an extraintestinal
symptom of Crohn's disease by analysing data collected from budesonide CIR
(Entocort; Astra Draco AB, Lund, Sweden) trials. 3. Three large studies of
budesonide CIR treatment in active Crohn's disease provided a reliable source of
clinical data. Of the 611 patients treated in the prospective double-blind
controlled trials, 291 had joint pain (arthritis/arthralgia) at entry, which was
recorded as part of the Crohn's Disease Activity Index. Statistical analysis was
based on all patients treated, provided that the patient had joint pain at the
start of treatment. 4. Daily oral budesonide CIR (9mg) resulted in clinical
remission of joint pain in 74% (95% confidence intervals (CI) 67-82%) of
patients. This outcome was nearly twice as good as placebo (41%; 95% CI 34-57%)
and as good as the outcome effected by daily oral prednisolone (40mg; 72%; 95% CI
60-84%). The favourable response to budesonide CIR (9 mg) did not correlate with
glucocorticosteroid-associated side effects or with adrenal suppression, which
were half those in the prednisolone (40 mg/day) group. 5. The favourable outcome
may relate to restitution of normal intestinal immune function.
PMID- 10779129
TI - Effect of experimental diabetes on GABA-mediated inhibition of neurally induced
contractions in rat isolated trachea.
AB - 1. In the present study, we investigated the effect of GABA and selective GABA
agonists and antagonists on neurally induced tracheal contractions in
streptozotocin (STZ) diabetic rats. 2. Contractile responses to electrical field
stimulation (EFS) in rat tracheal rings were completely abolished by atropine and
tetrodotoxin, but were unaffected by the ganglion blocker hexamethonium,
indicating that they were mediated via neuronal release of acetylcholine (ACh).
3. Contractions induced by EFS, but not by exogenous ACh, were inhibited by GABA
and the selective GABA(B) receptor agonist baclofen, but not by the selective
GABA(A) receptor agonist 3-aminopropane sulphonic acid. The inhibitory effects of
GABA or baclofen were not affected by the GABA(A) antagonist bicuculline, but
were significantly reversed by the GABA(B) antagonist phaclofen. 4. The
inhibitory effects of both GABA and baclofen were found to be significantly
greater in trachea from control rats compared with tissues from diabetic rats. 5.
Non-adrenergic, non-cholinergic relaxation responses elicited by EFS in
precontracted tracheal rings from diabetic and control rats were similar in
magnitude and were unaffected by GABA or GABA analogues. 6. These results suggest
that GABA decreases the response to EFS by directly inhibiting the evoked release
of ACh through GABA(B) receptors in rat trachea and that STZ-induced diabetes
causes an impairment in the inhibitory effect of GABA on neurally induced
contractions in this tissue.
PMID- 10779131
TI - A short history of nitroglycerine and nitric oxide in pharmacology and
physiology.
AB - 1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin,
following work with Theophile-Jules Pelouze. Sobrero first noted the 'violent
headache' produced by minute quantities of NG on the tongue. 2. Constantin
Hering, in 1849, tested NG in healthy volunteers, observing that headache was
caused with 'such precision'. Hering pursued NG ('glonoine') as a homeopathic
remedy for headache, believing that its use fell within the doctrine of 'like
cures like'. 3. Alfred Nobel joined Pelouze in 1851 and recognized the potential
of NG. He began manufacturing NG in Sweden, overcoming handling problems with his
patent detonator. Nobel suffered acutely from angina and was later to refuse NG
as a treatment. 4. During the mid-19th century, scientists in Britain took an
interest in the newly discovered amyl nitrite, recognized as a powerful
vasodilator. Lauder Brunton, the father of modern pharmacology, used the compound
to relieve angina in 1867, noting the pharmacological resistance to repeated
doses. 5. William Murrell first used NG for angina in 1876, although NG entered
the British Pharmacopoeia as a remedy for hypertension. William Martindale, the
pharmaceutical chemist, prepared '...a more stable and portable preparation':
1/100th of a grain in chocolate. 6. In the early 20th century, scientists worked
on in vitro actions of nitrate-containing compounds although little progress was
made towards understanding the cellular mode of action. 7. The NG industry
flourished from 1900, exposing workers to high levels of organic nitrites; the
phenomena of nitrate tolerance was recognized by the onset of 'Monday disease'
and of nitrate-withdrawal/overcompensation by 'Sunday Heart Attacks'. 8. Ferid
Murad discovered the release of nitric oxide (NO) from NG and its action on
vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized
the importance of the endothelium in acetylcholine-induced vasorelaxation (in
1980) and Louis Ignarro and Salvador Moncada identified endothelial-derived
relaxing factor (EDRF) as NO (in 1987). 9. Glycerol trinitrate remains the
treatment of choice for relieving angina; other organic esters and inorganic
nitrates are also used, but the rapid action of NG and its established efficacy
make it the mainstay of angina pectoris relief.
PMID- 10779130
TI - Importance of histamine, glutathione and oxyradicals in modulating gastric
haemorrhagic ulcer in septic rats.
AB - 1. The ulcerogenesis of gastric haemorrhagic damage during sepsis is unclear. The
present study first proposes that gastric haemorrhagic ulcer is modulated by
mucosal glutathione, histamine and oxyradicals in lipopolysaccharide (LPS)
induced sepsis in rats. The protective effects of several drugs on the
ulcerogenic parameters also were evaluated. 2. Male specific pyrogen-free Wistar
rats were deprived of food for 24 h. For the induction of sepsis, intravenous LPS
(0, 1, 3 or 10 mg/kg in 1 mL sterilized normal saline) was challenged to rats 12
h after withdrawal of food. Rat stomachs were vagotomized, followed by irrigation
for 3 h with normal saline or a physiological acid solution containing 100 mmol/L
HCI and 54 mmol/L NaCl. 3. The aggravation of gastric ulcerogenic parameters,
such as gastric acid back-diffusion, luminal haemoglobin content, mucosal lipid
peroxide production, histamine concentration, as well as lowered concentrations
of defensive substances, including mucosal glutathione, were dependent on the
doses of LPS used for challenge. A high correlation was observed between mucosal
histamine release and lipid peroxide production in LPS rats. 4. The ulcerogenic
parameters obtained in LPS (3 mg/kg, i.v.) rats were potently attenuated by
diamine oxidase, ketotifen and zinc sulphate. 5. Several oxyradical scavengers,
including glutathione, dimethylsulphoxide and allopurinol, also were effective in
inhibiting haemorrhagic ulcer. 6. In conclusion, gastric mucosal histamine
release and oxyradical generation play pivotal roles in the formation of
haemorrhagic ulcers in septic rats.
PMID- 10779133
TI - Teaching about thyroid in our schools.
PMID- 10779132
TI - Glycopyrrolate treatment of drooling in an adult male patient with cerebral
palsy.
AB - 1. The aim of the study was to assess the effect of glycopyrrolate on drooling in
an adult male patient with cerebral palsy. 2. After a thorough medical
examination and consent in writing by the responsible guardian, a baseline sum
score for frequency and seriousness of drooling was established over a 2 week
period in addition to data on shifts of handkerchiefs, urination, defecation and
observation of behaviour. Glycopyrrolate (1 mg) tablets were then administered,
starting with one tablet daily the third week and increasing the daily dose by
one tablet per week until a maximum of four tablets during week six and 4 days of
week seven when the daily dose was reduced to two tablets for 3 days. For the
four weeks 8-11 three tablets were given daily. In week 12 the dose was reduced
to two tablets and for the weeks 13-15 no tablets of glycopyrrolate were given.
3. For as long as the patient received three to four tablets of glycopyrrolate
daily, drooling was markedly reduced and handkerchiefs were not necessary on some
days. After the tablets were withdrawn drooling increased to approximately the
same level as it was before treatment. No adverse medical, psychological, or
social effects were observed. 4. For shorter periods, glycopyrrolate can be given
in controlled doses provided that an adequate medical assessment has been
undertaken.
PMID- 10779134
TI - The rat hepatic lectin-1 subunit of the asialoglycoprotein receptor is
upregulated by thyrotropin and downregulated by neoplastic transformation of
thyroid cells.
AB - We have recently shown that the rat hepatic lectin (RHL)-1 subunit of the
asialoglycoprotein receptor (ASGPr) is expressed in the PC C13 differentiated
thyroid cell line. To investigate in vivo the expression of RHL-1 and the ability
of thyrotropin (TSH) to modulate its expression, reverse-transcriptase polymerase
chain reaction (RT-PCR) and Western blot assays have been performed on thyroid
extracts from rats treated with thyroxine (T4) or propylthiouracil (PTU), each of
which modulates TSH levels. It is shown that RHL-1 expression is down-regulated
by T4 (which decreases serum TSH) and upregulated by PTU (which increases serum
TSH), at both mRNA and protein levels. The sensitivity of RHL-1 to neoplastic
transformation of thyroid cells has been investigated. The RHL-1 expression
pattern has been studied in PC C13 thyroid cells transformed by several oncogenes
that induce different degrees of malignancy and dedifferentiation. RT-PCR and
Western blot assays show that RHL-1 expression progressively decreases as PC C13
cells acquire a more transformed phenotype. Expression of glyceraldehyde-3
phosphate dehydrogenase (GAPDH) mRNA, a housekeeping gene used as internal
control to normalize RHL-1 mRNA content, exhibits no variations in the different
PC C13 cell lines used. In addition, we show that both native and asialo
thyroglobulin (Tg) bind RHL-1 in vitro, and native Tg binds RHL-1 on the surface
of PC C13 cells. After thyroid cells transformation, the surface expression of
RHL-1 is inhibited in a measure that correlates with the mRNA and protein levels.
Therefore, the RHL-1 inhibition at the mRNA, protein and plasma membrane
expression follows a gradient that parallels the progressive acquisition of the
fully transformed phenotype in the PC C13 system. The results reported in the
present article, together with our previous data, suggest that RHL-1 expression
could be regulated, at least in part, by the same transcription factors involved
in the expression of the other molecules characteristic of the thyroid
differentiated state.
PMID- 10779135
TI - Expressions of human sodium iodide symporter mRNA in primary and metastatic
papillary thyroid carcinomas.
AB - The sodium iodide symporter (NIS) is a plasma membrane protein that is
responsible for iodide transport into thyroid cells. To understand the regulation
and expression of human NIS (hNIS) in papillary thyroid carcinomas, we evaluated
the expression levels of hNIS mRNA in primary and lymph node metastatic papillary
carcinoma tissues. The correlation of mRNA levels between hNIS and thyroid
specific genes, thyrotropin (TSH) receptor, and thyroglobulin (Tg), were also
investigated. Twenty-three cases of papillary carcinoma and 7 pairs of primary
and lymph node metastastic tissues were included in this study. We measured the
expression levels of hNIS, TSH receptor, and Tg mRNAs by semiquantitative reverse
transcription-polymerase chain reaction (RT-PCR) and RNase protection assay
(RPA). The levels of hNIS mRNA in lymph node metastatic tissues were evaluated by
RT-PCR. By semiquantitative RT-PCR, 87% of papillary carcinoma (20/23) expressed
hNIS mRNA, but the degrees of expression were variable and were lower than those
of normal thyroid tissues. The decreased expression of hNIS mRNA in papillary
carcinoma compared to normal thyroid tissue was also noticed by RPA. All 23
papillary carcinomas in this study showed the expression of TSH receptor and Tg
mRNAs. The levels of TSH receptor mRNA were again lower in papillary thyroid
carcinomas than in normal controls. The level of hNIS mRNA was correlated with
the levels of TSH receptor (r = 0.449, p < 0.05), but not with Tg mRNA. In
addition, significant correlation of mRNA level was observed between TSH receptor
and Tg (r = 0.706, p < 0.01). Two of six lymph node metastatic tissues did not
show hNIS mRNA even with significant hNIS expressions in papillary carcinoma
tissues in thyroid. The levels of hNIS expression of the remaining four lymph
node metastatic tissues were lower than those of corresponding primary tissues.
Interestingly, one case showed no hNIS expression in primary tissue, but
significant hNIS expression in lymph node metastatic tissue. No correlation was
found in hNIS mRNA expression between primary and lymph node metastatic tissues.
Our results suggest that the measurements of hNIS mRNA level in primary tissues
may not predict the therapeutic response to radioactive iodine.
PMID- 10779136
TI - Thyrotropin regulation of cyclic adenosine monophosphate production in human
coronary artery smooth muscle cells.
AB - Thyroid disease has been associated with the occurrence of pathophysiologic
changes in the vasculature that may result in part from altered serum thyroid
hormone and serum lipid levels. Thyrotropin (TSH) levels are also altered in
thyroid disease, but a direct effect of TSH on vascular smooth muscle has not
previously been considered. In the present study, human coronary artery smooth
muscle cells (CASMC) were induced into two morphologically distinct forms by
culturing in either (1) growth factor supplemented, 0.5% serum medium (SmGM-3) or
(2) basal medium (SmBM) plus 10% fetal bovine serum (FBS). Intracellular cyclic
adenosine monophosphate (cAMP) accumulation was determined by radioimmunoassay
after exposure to increasing doses of bovine TSH. Cells grown in SmBM/10% FBS for
3 days exhibited a dose-dependent increase in intracellular cAMP that reached a
level 10 times higher than baseline at the highest dose examined (100 mIU/mL). In
contrast, cells grown in SmGM-3 medium exhibited no change in intracellular cAMP
on exposure to increasing TSII. Low serum (0.5% FBS) reduced the ability of TSH
to stimulate cAMP above the control value in CASMC. Pretreatment of CASMC with
either transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor
alpha (TNF-alpha) lowered basal levels of cAMP production, but did not inhibit
the ability of TSH to stimulate cAMP production. Human, but not rat aortic smooth
muscle cells in culture also responded to TSH with a significant increase in
cAMP. The results of this study suggest that TSH may exert direct effects on
vascular smooth muscle mediated by adenylate cyclase activation that could
conceivably affect the progression of vascular disease associated with thyroid
dysfunction.
PMID- 10779137
TI - Maturation of human hypothalamic-pituitary-thyroid function and control.
AB - Measurements of serum thyrotropin (TSH) and free thyroxine (T4) concentrations
were conducted in infants, children, and adults to assess maturation of the
hypothalamic-pituitary-thyroid (HPT) feedback control axis. Serum free T4 and TSH
concentration data were collated for cord blood of the midgestation fetus, for
premature and term infants, and for peripheral blood from newborn infants,
children, and adults. Mean values were plotted on a nomogram developed to
characterize the reference ranges of the normal axis quantitatively based on data
from 522 healthy subjects, 2 weeks to 54 years of age; 83 untreated hypothyroid
patients; and 116 untreated hyperthyroid patients. Samples for 75 patients with
thyroid hormone resistance were also plotted. The characterized pattern of HPT
maturation included a progressive decrease in the TSH/free T4 ratio with age,
from 15 in the midterm fetus, to 4.7 in term infants, and 0.97 in adults.
Maturation plotted on the nomogram was complex, suggesting increasing
hypothalamic-pituitary T4 resistance during fetal development, probably secondary
to increasing thyrotropin-releasing hormone (TRH) secretion, the marked, cold
stimulated TRH-TSH surge at birth with reequilibration by 2-20 weeks, and a final
maturation phase characterized by a decreasing serum TSH with minimal change in
free T4 concentration during childhood and adolescence. The postnatal maturative
phase during childhood and adolescence correlates with the progressive decrease
in thyroxine secretion rate (on a microg/kg per day basis) and metabolic rate and
probably reflects decreasing TRH secretion.
PMID- 10779138
TI - The use of fine-needle aspiration biopsy under ultrasound guidance to assess the
risk of malignancy in patients with a multinodular goiter.
AB - PURPOSE: Fine-needle aspiration biopsy (FNAB) is a commonly performed procedure
used in the evaluation of solitary thyroid nodules, in which the risk of
malignancy is approximately 5% in most patients. Recently, the use of ultrasound
(US) guidance in FNAB has been shown to enhance the diagnostic efficacy of this
procedure. However, the risk of malignancy in thyroid nodules occurring within a
multinodular goiter (MNG) has not been completely clarified, nor has the optimal
means of investigating such nodules using FNAB. SUBJECTS AND METHODS: We
performed a retrospective study of all patients seen over a 4-year period with a
MNG that had one or more nodules who underwent FNAB under US guidance. The
results from the history and physical examination, thyroid function and antibody
tests, radionuclide studies, thyroid sonogram, cytology of aspirated nodules, and
surgical pathology were recorded and analyzed. RESULTS: A total of 93 nodules
were aspirated in 61 patients with MNG. Adequate material was obtained in 96% of
aspirates on the first attempt. Sixty-seven aspirates in 44 patients yielded
benign cytology and 22 aspirates in 15 patients yielded suspicious cytology. All
patients with suspicious cytology underwent thyroid surgery. Thyroid cancer was
found in 5 of these nodules, including 4 cases of papillary cancer and 1 case of
Hurthle cell cancer, and 1 additional patient had occult papillary cancer
discovered. The overall malignancy rate in thyroid nodules among the patients
with MNG was approximately 5%. CONCLUSIONS: FNAB under US guidance is a useful
diagnostic modality in the evaluation of thyroid nodules in selected patients
with MNG. Because the risk of thyroid malignancy in these nodules is comparable
to that which exists in solitary thyroid nodules, the possibility of thyroid
malignancy should be considered in all patients with MNG.
PMID- 10779139
TI - Neuropsychological follow-up in early-treated congenital hypothyroidism: a
problem-oriented approach.
AB - Screening programs for congenital hypothyroidism (CH) dramatically improved the
neuropsychological prognosis in affected children. However, mild impairments in
cognitive performances, poorer motor skills, defective language abilities, and
learning problems have been reported in some studies of early-treated CH
children. The occurrence of these defects makes neuropsychological follow-up
mandatory. The aim of the present study was to identify those neuropsychological
functions that are more frequently affected in early-treated CH children and that
might require prompt rehabilitation treatment to prevent permanent defects. The
study group involved 24 CH children. Levothyroxine (LT4) treatment (initial dose
8-10 microg/kg per day) was started at mean age of 28 days (range 15-45) and was
then adjusted with the goal to keep thyrotropin (TSH) and free thyroid hormone
levels in the normal range. Cognitive evaluation was performed at 3, 5, and 7
years of age and did not significantly differ from that of controls. Mean
neurological scores were lower in children 5 years of age than in controls.
Children with severe neonatal hypothyroidism (serum thyroxine [T4] < 2 microg/dL)
had significantly lower neurological scores compared to less affected CH children
and normal controls. The most affected functions were balance, extremity
coordination, fine motricity, quality of movements, associated movements, and
head movements. Language disorders were observed in half of CH children at 3 and
5 years of age, but moderately severe defects were restricted to those with
severe neonatal hypothyroidism. In conclusion, a problem-oriented, simplified
neuropsychological follow-up of early-treated children with CH should not
systematically include the frequent repetition of time-consuming and expensive
psychometric tests because individual IQ scores are in the normal range of tests
in almost all CH children and can be differentiated from those of normal controls
only on a population-statistic basis. Selected tests of motor proficiency are
indicated at 3 and 5 years of age to detect those defects in motor skills that
appear to be more specifically affected in CH children. Language performances are
at particular risk in CH children, and should be always checked at 3 and 5 years
of age. Children with even mild language disorders or delayed language
achievements should be regularly reevaluated at 6-month intervals and, if no
spontaneous improvement is observed, they should receive specific rehabilitation
treatment. No further motor and language evaluation is warranted in CH children
with normal tests at age 5 years.
PMID- 10779140
TI - The value of ultrasonography in predicting autoimmune thyroid disease.
AB - Ultrasonography (US) may demonstrate a diffuse reduction in thyroid echogenicity
(low-amplitude echoes) in autoimmune thyroid disease (AITD), which includes
chronic lymphocytic thyroiditis and Graves' disease, as well as in subacute
thyroiditis. The reported occurrence of this finding in AITD varies from 19% to
95%. To assess the validity of diffuse reduction in thyroid echogenicity as a
predictor of AITD, 3,077 patients referred for US of the thyroid were examined
prospectively with regard to reduced versus normal thyroid echogenicity. The most
frequent reasons for referral were goiter, thyroid dysfunction, neck discomfort,
and/or difficulty in swallowing. Ultrasonography demonstrated diffuse reduction
in thyroid echogenicity in 485 patients. Of these, 452 patients had available
records of fine-needle aspiration biopsy (FNAB), and were included in the study.
From the remaining patients, with normal thyroid echogenicity, 100 consecutive
patients were selected as controls. In 411 of the 452 study patients (90.9%)
there was at least one laboratory finding consistent with possible AITD: cytology
indicating lymphocytic thyroiditis, 287 of 363 patients (79.1%) with diagnostic
specimens; elevated levels of peroxidase antibodies (TPOAb), 225 of 337 (66.8%);
elevated thyrotropin (TSH) levels, 290 of 450 (64.4%); or low TSH levels, 79 of
450 (17.6%). The final diagnosis was: chronic autoimmune (Hashimoto's)
thyroiditis in 352 patients; Graves' disease in 47 patients; subacute
(granulomatous) thyroiditis in 7 patients; toxic nodular goiter in 3 patients;
and toxic adenoma in 2 patients. In the remaining 41 patients, those without
laboratory results consistent with AITD, the final diagnosis was colloid goiter
in 37 and thyroid cancer in 4 patients. In the 100 controls, laboratory results
were consistent with possible AITD in 14 patients: elevated TPOAb levels in 5 of
49 patients with retrieved antibody results; lymphocytic thyroiditis in 2
patients; elevated TSH levels in 2 patients; and low TSH levels in 2 patients. In
these controls, the final diagnosis was: chronic autoimmune thyroiditis in 7;
toxic nodular goiter in 6 patients, and toxic adenoma in 1 patient. The
corresponding positive and negative predictive values of reduced thyroid
echogenicity as an indicator of AITD were 399 of 452 (88.3% [95% CI, 85% to
91%]), and 93 of 100 (93.0% [95% CI, 88% to 98%]), respectively. Thus, diffuse
reduction in thyroid echogenicity was a valid predictor of AITD.
PMID- 10779141
TI - Bone metastases from thyroid carcinoma: clinical characteristics and prognostic
variables in one hundred forty-six patients.
AB - To describe the clinical characteristics and define the indicators that best
predict survival in patients with bone metastases from thyroid carcinomas. We
collected data from medical records of 146 patients with documented bone
metastases from thyroid carcinoma seen at our medical center over a 38-year
period. Univariate and multivariate analyses of prognostic indicators for
survival were performed. Bone metastases were present at the initial diagnosis in
47% of patients. Vertebrae (29%), pelvis (22%), ribs (17%), and femur (11%) were
the most common sites of metastases. Multiple lesions were present in 53% of the
cases. The overall 10-year survival rate from the time of diagnosis of thyroid
cancer was 35%, and from diagnosis of initial bone metastasis was 13%. By
univariate analysis from the time of the initial bone metastasis, radioiodine
uptake by skeletal metastases, the absence of nonosseous metastases and treatment
with radioiodine were significant prognostic factors. By multivariate analysis,
radioiodine uptake by skeletal metastases and the absence of nonosseous
metastases were independent favorable prognostic variables for survival. In a
subgroup of patients in which histologic specimens were available and were
reviewed, Hurthle cell carcinoma was the most favorable histologic subtype for
survival with the undifferentiated subtype being the worst. The spread of thyroid
carcinoma to bone is more common in patients over 45 years of age, is usually
symptomatic, and is often multicentric. Overall survival is best in those whose
lesions concentrate radioactive iodine and those who have no nonosseous
metastases.
PMID- 10779142
TI - A clear cell variant of follicular carcinoma presenting as an autonomously
functioning thyroid nodule.
AB - We report a case of an autonomously functioning thyroid nodule (AFTN) that proved
to be almost exclusively a clear cell variant of follicular carcinoma. AFTNs are
generally felt to be benign lesions with exceptions forming the basis of case
reports. Likewise, clear cell tumors of the thyroid are rare. To our knowledge,
this combination of two unusual thyroid conditions has not been previously
reported. The initial scans of this patient were so characteristic for a
degenerating AFTN that attention was first directed toward a very large
contralateral lobe. While it is debatable whether all AFTNs should be biopsied,
on the basis of this and other cases, it is recommended that AFTNs that contain a
central photopenic area on scan be biopsied to be sure that cystic degeneration,
a commonly seen phenomenon in larger AFTNs, is indeed present rather than a
malignancy.
PMID- 10779143
TI - A case of sarcoidosis and sarcoid granuloma, papillary carcinoma, and Graves'
disease in the thyroid gland.
AB - Sarcoidosis is a systemic chronic granulomatous disease of unknown etiology most
commonly affecting young females. The disease was first described in the thyroid
gland in 1938. Our patient, a 27-year-old male with known sarcoidosis, was
referred to the National University Hospital for acute symptoms of thyrotoxicosis
(weight loss of 6 kg, tremor, thyroid enlargement, and tachycardia). Laboratory
findings showed suppressed serum thyrotropin (TSH, <0.03 mU/L [0.5-4.20]),
increased total thyroxine (T4) (223 nmol/L, [60-140]), and triiodothyronine (T3)
(8.5 nmol/L, [1.5-2.7]). Furthermore, Tc-99m pertechnetate scintigraphy disclosed
diffuse accumulation of the isotope confirming the diagnosis of Graves' disease.
During the next 18 months of antithyroid treatment (thiamazole, Thycapzol)
hyperthyroidism was difficult to control, the thyroid gland gradually enlarged,
and surgery was recommended. Initially, the patient declined surgery but after an
additional 18 months, he accepted surgery. During the 36-month period of
antithyroid drug treatment TSH was suppressed (<0.01 mU/L) and T3 often elevated
despite high doses of thiamazole. Total thyroidectomy was performed, and
histologic examination of the removed thyroid tissue confirmed the diagnosis of
Graves' disease and also the presence of sarcoid granuloma and metastatic
papillary adenocarcinoma with spread to neck lymph nodes. Four months later, a
modified radical neck dissection was performed with removal of neck lymph nodes
followed by external radiation therapy (2 Gy x 32 fractions to the neck). The
concomitant presence of sarcoidosis, papillary carcinoma, and Graves' disease in
a thyroid gland, to our knowledge, has not previously been described in the
literature.
PMID- 10779145
TI - Images in thyroidology. Medullary thyroid cancer.
PMID- 10779144
TI - Should you always trust FNA interpretations?
PMID- 10779146
TI - Inducible nitric oxide synthase (iNOS) expression in liver and splenic T
lymphocyte rise are associated with liver histological damage during experimental
hepatitis A virus (HAV) infection in Callithrix jacchus.
AB - Callithrix jacchus is considered a reliable animal model for hepatitis A virus
(HAV) infection. All three HAV orally inoculated marmosets developed hepatitis -
the infection was monitored by continuous virus shedding, high levels of serum
enzyme alanine aminotransferase, specific antibody and seroconversion 3-6 weeks
after HAV inoculation. HAV antigen was detected in liver by immunofluorescence 4
days post inoculation (PI) and onwards. To gain insight into the biological role
of inducible nitric oxide synthase (iNOS) during immune-related acute liver
injury the enzyme was searched in frozen biopsies: immunofluorescent labeling was
found in the cytoplasm of liver cells mainly Kupffer's cells and spleen
macrophages (CD68+) starting 11 days PI with maximum intensity on the fifth to
sixth week PI. Necroinflammatory liver lesions characteristic of viral hepatitis
were also observed at 10 days PI with maximum severity at 4 to 6 weeks PI.
Furthermore, T lymphocytes (CD2+) were raised at this time point. No difference
was evident in the frequency of B lymphocytes (CD20+). Therefore, iNOS expression
preceded necroinflammatory liver lesion and maximal immunofluorescence reaction
was coincident with tissue injury, supporting the hypothesis that NO contributes
to hepatic cytotoxic mechanism but also to virus clearance. The concomitant rise
in T-lymphocyte population may suggest a role for these cells in this and/or
other independent HAV-induced pathological changes.
PMID- 10779147
TI - Effects of dietary fat on benz-a-pyrene-induced forestomach tumorigenesis in mice
chronically exposed to arsenic.
AB - The modulating effect of As (As2O3) in drinking water plus dietary fatty acids on
benzo-a-pyrene (BP) induced forestomach tumorigenesis was assayed in mice fed
with corn oil (CO), Olein (O), palmstearin (PS) and cod liver oil (CLO) enriched
formulae, and a mixed-fat (S-stock) diet during 28 weeks. Neither pre-or
neoplastic lesions were recorded in esophagus or forestomach of mice treated with
As alone. CLO diet showed a protective effect. Indeed, multiple epidermal
hyperplasia were significantly reduced compared to S group and a reduction in
papillomas multiplicity with respect to S, CO and O groups was also observed.
Mice fed on PS formula showed minor papillomas per mouse with respect to CO and
O. These results indicate that As plus BP did not exhibit any synergistic effect
on the development of epidermoid tumor lesions, whereas CLO diet exerted
antipromoting activity . In spite of their common essential fatty acid deficiency
(EFAD) condition, PS and O lots showed contradictory results. Hence, the dietary
enrichment in 18:1 n-9 (O diet) per se, and not the EFAD state, may play a
deleterious role. Corn diet showed no promoting activity on the epidermoid tumor
development in this model.
PMID- 10779148
TI - Retinoblastoma protein in microphthalmic mice.
AB - A microphthalmic strain of mice was used to study immunoresponse of the
retinoblastoma protein. Comparing wild-type, heterozygote and homozygote
microphthalmic eyes, we found an increasing labelling of phosphorylated
retinoblastoma protein (pRb) in the retinal pigment epithelium. Additionally,
microphthalmic eyes expressed pRb in the neuroepithelium. Especially rosettes
were strongly labelled.
PMID- 10779149
TI - Neuronal and inducible nitric oxide synthase distribution in retinas of
microphthalmic mice.
AB - A study about the distribution of neuronal nitric oxide synthase (n-NOS) and
inducible NOS (i-NOS) was performed in microphthalmic retinas at postnatal day
(pd) 2 and pd 7. Neither n-NOS nor i-NOS immunoresponse could be detected at pd
2. At pd 7, i-NOS activity was revealed in the retinas of mi/mi littermates but
not in those of heterozygotes or wild-type littermates. The expression of n-NOS
corresponded to the postnatal retinal development. Retinal rosettes were strongly
labelled.
PMID- 10779150
TI - Lipoxygenase inhibitor FLM 5011, an effective protectant of myocardial
microvessels against ischemia-reperfusion injury? An ultrastructural-morphometric
study.
AB - The lipoxygenase inhibitor FLM 5011 was used for protection of the coronary
microcirculation against ischemia/ reperfusion injury after ligation of the left
coronary artery in dogs. Epimyocardial biopsies from ischemic and non-ischemic
areas of protected and unprotected areas taken before and after ischemia of 90
min duration and after 180 min reperfusion were analysed by means of electron
microscopic morphometry. The ischemic injury consisted in endothelial swelling,
luminal blebbing, and formation of irregular protrusions, partly occurrence of
pericapillary edema and cellular debris. Plasmalemmal vesicles seemed to decrease
in frequency, mitochondria showed focal or generalized degeneration of cristae
and matrix. Reperfusion partly deteriorated the damage, partly restoration of
ultrastructural parameters was to be observed. There were no significant
differences between the infarcted and not infarcted areas. FLM 5011 treatment
reduced the endothelial edema, blebbing and occurrence of pericapillary debris
and stabilized the number of vesicles. The protection of the mitochondrial
cristae and matrix was statistically significant. The results indicate that FLM
5011, under the condition of the experiment, effectively protects the
ultrastructure of essential endothelial structures of myocardial
microcirculation, explained by the blocking of the noxious leucotrienes and
peptidoleucotrienes liberated by the 5-lipoxygenase pathway of the free
arachidonic acid and by scavenging of oxygen free radicals. The results must be
confirmed by further experiments including biochemical and functional parameters.
PMID- 10779151
TI - Hypovolemia in rats increases mortality rates following endotoxin administration.
AB - The aim of the present study was to examine whether acute or chronic hypovolemia
increase the mortality rates of rats following endotoxin injection. Another aim
of this study was to examine whether this increase in sensitivity can be
explained by increased leakage of endotoxin from the digestive tract to the blood
stream. Chronic hypovolemia was caused by water deprivation for 8 days. Acute
hypovolemia was caused by injection of sucrose (300mg/100g) or by hemorrhage of a
volume of up to 2.1 ml/100g. The hypovolemia was examined by measuring the plasma
volume using Evans Blue (EB). Endotoxin at various doses was injected to the
hypovolemic rats and the lethality of the various treatments was examined. Acute
and chronic hypovolemia caused a significant increase inthe mortality rates of
rats injected IP with a dose of 1-1.5 mg/100g endotoxin. Endotoxin administration
(6mg/100g) by drinking to hypovolemic rats did not cause death at all. In
contradistinction, injection of galactoseamine to rats that underwent similar
treatments caused 100% mortality. Endotoxin tolerance reduced the mortality rates
following galactoseamine injection to the control level of administration of
endotoxin without hypovolemia (p < 0.001). Injection of the antibiotic polymixin
B following the galactoseamine injection also decreased mortality rates to 40% (p
< 0.05). Examination of plasma endotoxin concentration exhibited a significant
increase following administration of endotoxin by drinking to hypovolemic rats (p
< 0.001) compared to rats that received the same amount of endotoxin but without
hypovolemia. These results indicate that one possible explanation for the
increased mortality rate of the hypovolemic rats after endotoxin injection is due
to leakage of endotoxin from the digestive tract.
PMID- 10779152
TI - Influence of ochratoxin A and an extract of artichoke on the vaccinal immunity
and health in broiler chicks.
AB - The combined effect of ochratoxin A (at diet levels of 130, 305 and 790 ppb) and
penicillic acid was studied in 100 broiler chicks. Serological investigations
revealed significantly lower haemagglutination inhibiting antibody titers in the
experimental chicks immunized with vaccine against Newcastle disease. A
statistically significant decrease of the body weight and the relative weight of
lymphoid organs as well as a significant increase of the relative weight of
kidneys and liver were seen. The main degenerative changes were observed in the
proximal convoluted tubules in kidneys and slight degenerative changes were found
in the hepatocytes. Degenerative changes and depletion of lymphoid cells were
observed in the bursa Fabricii, thymus, spleen and Peyer's patches of intestinal
mucosa. Serum analyses revealed significant decreases of the total protein and
cholesterol, and significant increases of the uric acid and glucose.
Haematological analyses showed a slight anaemia, leucocytosis and slightly
decompensated metabolic acidosis. A statistically significant protective effect
of 5% total water extract of artichoke on humoral immune response (increase of
haemaglutination inhibiting antibody titer), relative organ weight as well as on
pathomorphological, haematological and biochemical changes induced by ochratoxin
A, was established.
PMID- 10779153
TI - Immunopathological study on the development of swine serum-induced bile duct
lesions in BALB/c and DBA/2 mice.
AB - To compare the difference in the development of swine serum (SS)-induced bile
duct lesion (BDL) between high responder BALB/c and low responder DBA/2 mice, the
mice of both strains injected with SS twice a week for up to 4 weeks were killed
and examined immunopathologically after the 2nd, 4th, 6th and 8th SS-injection,
respectively. In BALB/c mice, BDL developed rapidly following the SS-injections,
and a slight enlargement of common bile ducts accompanied with infiltration of T
helper cells and eosinophils was detected after the 2nd SS-injection. From the
4th injection on, BDL was characterized by proliferation of mucous glands,
hyperplasia and hypertrophy of biliary and glandular epithelial cells, periductal
fibrosis, infiltration of eosinophils, plasma cells and T helper cells, and
increase of mast cells, resulting in more apparent enlargement of common bile
ducts. Several hypertrophied biliary and glandular epithelial cells were positive
for mouse immunoglobulins and SS. BDL subsided after cessation of the SS
treatment. On the other hand, in DBA/2 mice, immune response and inflammatory
reaction were very weak, and only slight BDL were detected.
PMID- 10779154
TI - New animal model of diphtheritic myocarditis.
AB - A new rabbit experimental model was developed in order to study the role of the
lymph system in the pathogenesis of diphtheritic myocarditis. We injected the
diphtheritic toxin into the connective tissue (tela cellularis) of the anterior
mediastinum. (It inevitably drains from there to the lymph vessels of the heart.)
As a result, typical Diphtheritic Myocarditis along with the severe lesion of the
regional lymph nodes of the heart was induced.
PMID- 10779155
TI - Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative
activity and apoptosis in colon mucosa and colon tumors induced by 1,2
dimethylhydrazine in rats.
AB - Forty-eight two-month-old outbred female LIO rats were injected weekly with a
single dose of 1,2-dimethylhydrazine (DMH; 21 mg/kg of body weight) administered
s.c. for 15 consecutive weeks. From the day of the 1st injection of the
carcinogen the part of rats were given five days a week during the night time
(from 18.00 h to 08.00 h) melatonin dissolved in tap water, 20 mg/l. 10 rats were
treated similarly with solvents and served as control. The experiment was
terminated 6 months after the first injection of the carcinogen. Colon tumors
(mainly adenocarcinomas) developed in a hundred percent of rats exposed both to
DMH or to DMH plus melatonin. However, descending colon carcinomas were observed
in 65 % of rats exposed to DMH plus melatonin against 100% in those exposed to
DMH alone (p < 0.01). The multiplicity of colon tumors was also reduced in rats
under the influence of melatonin. This effect is correlated with the significant
inhibitory effect of the pineal hormone on mitotic index and with stimulating
effect of melatonin on the relative number of apoptotic cells (TUNEL-method) in
colon tumors. Long-term treatment with melatonin was followed also by the
decrease in the area of lymphoid infiltrates in the colon mucosa of tumor-bearing
rats.
PMID- 10779156
TI - Alterations in rat's brain capillaries in a model of focal cerebral necrosis.
AB - Focal brain compression causes cerebral tissue damage. In this study we followed
alterations in capillary ultrastructure in the rat cortex and neurohypophysis
caused by 40 mm Hg compression for 15 minutes. One day after experiment we
observed clogging of capillaries, accumulation of collagen fibrills under the
basement membrane and necrosis or apoptosis of endothelial cells. Four days after
it the basement membrane was multiplicated, blurred and thickened. In the
neurohypophysis the formation of vessels lined with the atypical continuous
endothelium was seen. There was also evidence for the migration of pericytes
through the blurred basement membrane and the differentiation of pericytes into
endothelial cells. Thus, vascular injury in the compressed brain is followed by a
highly ordered sequence of processes in the basement membrane and perivascular
cells leading to capillary repair.
PMID- 10779157
TI - Gene-modified dendritic cells for use in tumor vaccines.
AB - Dendritic cells (DCs) are potent antigen-presenting cells capable of priming
activation of naive T cells. Because of their immunostimulatory capacity,
immunization with DCs presenting tumor antigens has been proposed as a treatment
regimen for cancer. The results from translational research studies and early
clinical trials point to the need for improvement of DC-based tumor vaccines
before they become a more broadly applicable treatment modality. In this regard,
studies suggest that genetic modification of DCs to express tumor antigens and/or
immunomodulatory proteins may improve their capacity to promote an antitumor
response. Because the DC phenotype is relatively unstable, nonperturbing methods
of gene transfer must be employed that do not compromise viability or
immunostimulatory capacity. DCs expressing transgenes encoding tumor antigens
have been shown to be more potent primers of antitumor immunity both in vitro and
in animal models of disease; in some measures of immune priming, gene-modified
DCs exceeded their soluble antigen-pulsed counterparts. Cytokine gene
modification of DCs has improved their capacity to prime tumor antigen-specific T
cell responses and promote antitumor immunity in vivo. Here, we review the
current status of gene-modified DCs in both human and murine studies. Although
successful results have been obtained to date in experimental systems, we discuss
potential problems that have already arisen and may yet be encountered before
gene-modified DCs are more widely applicable for use in human clinical trials.
PMID- 10779158
TI - Combination gene therapy: synergistic inhibition of human immunodeficiency virus
Tat and Rev functions by a single RNA molecule.
AB - Current drug combinations can achieve long-term suppression of HIV replication in
infected individuals. Unfortunately, complicated dosing schedules and high
toxicity make long-term compliance with drug regimens difficult for most
patients. Gene therapy may provide a permanent solution for HIV disease by
generating cells genetically resistant to virus replication. As with the highly
active antiretroviral therapies, genetic drugs must have strong antiviral potency
and the ability to prevent the emergence of escape mutants. We have constructed
antiviral genes containing unique combinations of Tat- and Rev-binding decoys.
The new antiviral molecules are chimeric TAR-RRE RNAs that are expressed only in
HIV infected cells in a Tat-regulated manner. One RNA molecule competes for both
Tat and Rev binding, and thus blocks the activation and the expression of all
viral genes. The two functional Tat- and Rev-binding domains exhibit the highest
synergy at the lowest concentration. Conservative quantitative estimates of this
synergistic effect were I = 0.24 at 50% inhibition, in terms of the Berenbaum
"interaction index," indicating that the combined construct was approximately
fourfold more potent than would be predicted on the basis of additive effects.
The possibility of HIV escape from this inhibition is unlikely, because it
requires simultaneous mutation of TAR and RRE in a manner in which both Tat and
Rev preserve their respective functions. TAR-RRE combination decoys represent the
first example of mathematically proven synergistic antiviral activity between two
domains of the same molecule.
PMID- 10779159
TI - A hyperfusogenic gibbon ape leukemia envelope glycoprotein: targeting of a
cytotoxic gene by ligand display.
AB - An important goal in cancer gene therapy is the development of novel targeted
cytotoxic genes. The observation that transfection of a GaLV envelope
glycoprotein lacking an R peptide into human cells results in considerable cell
cell fusion and subsequent cell death prompted us to explore the potential for
using this fusogenic membrane glycoprotein (FMG) as a targeted cytotoxic gene. As
proof of principle, we therefore displayed epidermal growth factor (EGF) on the N
terminus of GaLV envelope glycoproteins both with and without an R peptide (GaLV
R+ and GaLV R-). Transfection of the GaLVR+ envelope expression plasmids did not
cause cell-cell fusion. The GaLV R+ envelopes were incorporated into retroviral
vectors whose infectivity was investigated on EGF receptor-positive and -negative
cells. The vector incorporating an N-terminally unmodified envelope was able to
infect all human cell lines tested. Infectivity of the vector incorporating an
envelope on which EGF was displayed was restricted on EGF receptor-positive cells
(but not on EGF receptor-negative cells) and could be restored by protease
cleavage of the displayed domain or competition with exogenous ligand. The cell
cell fusion capacity of the GaLV R- envelope glycoproteins (N-terminally
unmodified and with N-terminal display of both EGF and insulin-like growth factor
I [IGF-I]) was investigated by plasmid DNA transfection. While the N-terminally
unmodified GaLV R- fused all human cell types tested, fusogenicity of GaLV R- on
which EGF or IGF-I was displayed was considerably restricted on receptor-positive
cells. "Reciprocal" competition experiments showed that fusogenicity could be
restored by competition only with the relevant exogenous ligand. Thus the
specificity of cell-cell fusion by a hyperfusogenic GaLV envelope glycoprotein
can be regulated by N-terminal display of growth factor ligands. There is
therefore significant potential for further development of the targeting of the
cell-killing capability of this fusogenic viral glycoprotein by using strategies
similar to those we have developed for the targeting of retroviral vectors.
PMID- 10779160
TI - Immune responses against replication-deficient adenovirus inhibit ovalbumin
specific allergic reactions in mice.
AB - Replication-deficient adenovirus vector (Ad) is one of the most efficient gene
transfer vehicles for human gene therapy. However, Ad is antigenic, known to
evoke prominent inflammatory responses in vivo, and there are concerns that using
Ad in patients with immune-mediated disorders (allergy and autoimmune diseases)
may affect the status of the diseases. To evaluate this concept in a manner close
to clinical scenarios, a mouse model of airway eosinophilic inflammation was
developed by administering intraperitoneal injections and inhalations of chicken
ovalbumin (OA), with Ad administered intranasally 5 days after the OA
sensitization. The administration of Ad resulted in a significant suppression of
eosinophil counts in peripheral blood as well as in the bronchoalveolar lavage
fluid (BALF), and a decrease in OA-specific IgE. The decrease in the number of
eosinophils in BALF was associated with a marked upregulation of interferon gamma
(IFN-gamma) expression. In contrast, the Ad-specific, delayed-type
hypersensitivity response and efficacy of reporter gene expression mediated by Ad
were only marginally affected in animals sensitized with OA. Together, these data
support the idea that Ad administration in patients with Th2-mediated immune
disorders does not exacerbate the parameters of ongoing inflammations or gene
transfer efficiency, and with its ability to induce prominent type 1 immune
response to the antigen in vivo, Ad could potentially be used as an efficient
adjuvant to control immune disorders where Th2 cell-mediated mechanisms are
involved.
PMID- 10779161
TI - Immunogenetic therapy of human melanoma utilizing autologous tumor cells
transduced to secrete granulocyte-macrophage colony-stimulating factor.
AB - We performed a clinical study of five patients with melanoma to evaluate the
immunobiological effects of retrovirally transduced autologous tumor cells given
as a vaccine to prime draining lymph nodes. Patients were inoculated with both
wild-type (WT) and GM-CSF gene-transduced tumor cells in different extremities.
Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were removed.
There was an increased infiltration of dendritic cells (DCs) in the GM-CSF
secreting vaccine sites compared with the WT vaccine sites. This resulted in a
greater number of cells harvested from the GM-CSF-VPLNs compared with the WT
VPLNs at a time when serum levels of GM-CSF were not detectable. Four of five
patients proceeded to have the adoptive transfer of GM-CSF-VPLN cells secondarily
activated and expanded ex vivo with anti-CD3 MAb and IL-2. One patient had a
durable complete remission of metastatic tumor. Utilizing cytokine (IFN-gamma, GM
CSF, IL-10) release assays, GM-CSF-VPLN T cells manifested diverse responses when
exposed to tumor antigen in vitro. In two of two patients, GM-CSF-VPLN T cell
responses were different from those of matched WT-VPLN cells. This study
documents measurable immunobiologic differences of GM-CSF-transduced tumor cells
given as a vaccine compared with WT tumor cells. The complete tumor remission in
one patient provides a rationale to pursue this approach further.
PMID- 10779162
TI - Antigen-specific induction of peripheral T cell tolerance in vivo by codelivery
of DNA vectors encoding antigen and Fas ligand.
AB - Fas ligand (FasL, CD95L) induces apoptosis in activated T cells with upregulated
Fas (CD95) expression through the process termed activation-induced cell death
(AICD). We postulated that coexpression of antigen and FasL within individual
antigen-presenting cells would lead to antigen-specific activation of T cells and
to their consequent deletion by FasL-mediated AICD. A DNA-gelatin coacervate
containing transferrin cell ligand, calcium, and the lysosomatropic agent
chloroquine, a formulation previously shown to achieve high-level transfection of
immune and muscle cells in vivo, was used to codeliver plasmids encoding FasL and
antigen. Mice developed a strong cytolytic T cell response to beta-Gal when
injected with DNA encoding beta-galactosidase (LacZ) model antigen, either as
naked DNA or DNA nanoparticles, but failed to respond when there was concomitant
injection of nanoparticles containing both the LacZ and murine FasL DNA vectors.
This loss of T cell response was systemic, specific for beta-Gal, complete when
nanoparticles were administered before antigen challenge, and decreased the T
cell response from prior immunization with LacZ DNA. In effect, this
"tolerization" injection induced antigen-specific peripheral tolerance in study
mice, and represents a possible approach to the treatment of autoimmune diseases
and transplantation rejection.
PMID- 10779163
TI - Prolonged expression and effective readministration of erythropoietin delivered
with a fully deleted adenoviral vector.
AB - Helper-dependent (HD) adenoviral (Ad) vectors, in which all viral coding
sequences are deleted, have been generated. We show here that intravenous
delivery of a mouse EPO (mEPO) expression cassette cloned in an HD vector in
immunocompetent mice is effective and long lasting, but not permanent. A precise
dose-response relationship between the dose of injected virus and stable EPO
serum levels was observed, together with a 100-fold increase in gene expression
per infectious particle when compared with a first-generation Ad vector bearing
the same cassette. As a direct consequence, therapeutic increases in hematocrit
that lasted more than 6 months were achieved with minute amounts of virus, which
caused no detectable production of neutralizing antibodies. Intravenous
readministration of the HD-mEPO vector in the same mice was as effective as in
naive animals without any need for prior immunosuppression. Finally, HD-mEPO
injection in subtotally nephrectomized rats improved the anemic status induced by
surgery. HD Ad vectors are thus excellent tools for EPO gene therapy.
PMID- 10779164
TI - Photochemical transfection: a new technology for light-induced, site-directed
gene delivery.
AB - The development of methods for specific delivery of therapeutic genes into target
tissues is an important issue for the further progress of in vivo gene therapy.
In this article we report on a novel technology, named photochemical
transfection, to use light to direct a precise delivery of therapeutic genes to a
desired location. The technology makes use of photosensitizing compounds that
localize mainly in the membranes of endosomes and lysosomes. On illumination
these membrane structures will be destroyed, releasing endocytosed DNA into the
cell cytosol. Using a green fluorescent protein gene as a model we show that
illumination of photosensitizer-treated cells induces a substantial increase in
the efficiency of transfection by DNA-poly-L-lysine complexes. Thus, in a human
melanoma cell line the light treatment can increase the transfection efficiency
more than 20-fold, reaching transfection levels of about 50% of the surviving
cells. In this article various parameters of importance for the use of this
technology are examined, and the potential use of the technology in gene therapy
is discussed.
PMID- 10779165
TI - Partial correction of murine hemophilia A with neo-antigenic murine factor VIII.
AB - We have previously reported a factor VIII knockout (FVIII KO) mouse model for
hemophilia A. Here we demonstrate the presence of nonfunctional heavy chain
factor VIII protein in the mouse, making it an excellent model for cross-reacting
material (CRM)-positive hemophilia A patients, who express normal levels of a
dysfunctional FVIII protein. We attempted to correct these mice phenotypically by
transduction of wild-type mouse factor VIII cDNA delivered in an E1/E3-deleted
adenoviral vector by tail vein injection. All treated mice displayed initial high
level FVIII expression that diminished after 1 month. Ten of 12 mice administered
between 6 x 10(9) and 1 x 10(11) particles/mouse along with anti-CD4 antibody
showed long-term FVIII activity (0.03-0.05 IU/ml, equivalent to 3-5% of normal
FVIII) that corrected the phenotype. Wild-type murine FVIII was a neo-antigen to
the KO mice, generating both cytotoxic and humoral immune responses. Immune
suppression with anti-CD4 antibody abrogated these immune responses. These data
demonstrate that despite the presence of endogenous FVIII protein the immune
system still recognizes a species-specific transgene protein as a neo-antigen,
eliciting a cytotoxic T cell response. This phenomenon may exist in the treatment
of other genetic disorders by gene therapy.
PMID- 10779166
TI - Modified human immunodeficiency virus-based lentiviral vectors display decreased
sensitivity to trans-dominant Rev.
AB - As a first step toward the development of HIV-based conditionally replicating
defective interfering particles expressing trans-dominant Rev (TdRev), we studied
whether mutation of the splicing signals and replacement of the RRE by the SRV-1
CTE would render these vectors less sensitive to TdRev. Vectors with mutations in
the splicing signals (SD-/RRE+) yielded high titers (5 X 10(6) CFU/ml) and showed
higher levels of cytoplasmic unspliced mRNA than the corresponding SD+/RRE+
vectors either in the absence of Rev, in the presence of TdRev, or in the
presence of both TdRev and Rev. Proviral copies of SD-/RRE+ vectors were rescued
more efficiently than SD+/RRE+ vectors when TdRev was expressed. Vectors with the
SRV-1 CTE (SD+/CTE+ and SD-/CTE+) expressed high levels of cytoplasmic unspliced
mRNA in the absence of Rev expression. Titers obtained with the SD-/CTE+ vectors
(10(6) CFU/ml) were higher than the titers obtained with SD+/CTE+ vectors. We
also tested the effect of other structural modifications such as the orientation
of the expression cassette and the presence of the central polypurine tract
(cPPT/CTS). We show that an expression cassette cloned in the reverse orientation
with respect to the LTRs or elimination of the cPPT/CTS element severely affected
vector titers. We also demonstrated that these vectors can be efficiently
mobilized from their proviral state by HIV trans-complementing functions, and
transduced into secondary target cells without suffering any genomic
rearrangement.
PMID- 10779167
TI - Muscle transfection by electroporation with high-voltage and short-pulse currents
provides high-level and long-lasting gene expression.
AB - Gene transfer into muscle by electroporation with low-voltage and long-pulse
(LV/LP, 100 V/50 msec) currents was shown to be more efficient than simple
intramuscular DNA injection. Nevertheless, transgene expression declined from day
7 and only reached 10% of the maximum 3 weeks after electroporation. We have
optimized electroporation conditions including voltage, pulse number, and the
amount of injected luciferase-encoding plasmid DNA in the tibialis anterior
muscle. Using high-voltage and short-pulse (HV/SP, 900 V/100 microsec) currents,
we observed an average 500-fold increase in luciferase expression, in comparison
with nonelectroporated muscle. Moreover, sustained and long-lasting gene
expression was observed for at least 6 months. When we compared HV/SP currents
with LV/LP currents, luciferase expression was similar 24 hr after
electroporation. One month later, whereas luciferase expression was stable in
muscle electroporated with HV/SP currents, it decreased 600-fold in muscle
electroporated with LV/LP currents. In conclusion, electroporation with high
voltage and short-pulse currents provides high-level and long-lasting gene
expression in muscle.
PMID- 10779168
TI - Human gene marker/therapy clinical protocols.
PMID- 10779169
TI - Structural organization of nicotinic acetylcholine receptors.
AB - Nicotinic acetylcholine receptor of the electric ray Torpedo is the most
comprehensively characterized neurotransmitter receptor. It consists of five
subunits (alpha2beta gammadelta) amino acid sequences of which were determined by
cDNA cloning and sequencing. The shape and size of the receptor were determined
by electron cryomicroscopy. It has two agonist/competitive antagonist binding
sites which are located between subunits near the membrane surface. The receptor
ion channel is formed by five transmembrane helices (M2) of all five subunits.
The position of the binding site for noncompetitive ion channel blockers was
found by photoaffinity labelling and site-directed mutagenesis. The intrinsic
feature of the receptor structure is the position of the agonist/competitive
antagonist binding sites in close vicinity to the ion channel spanning the
bilayer membrane. This peculiarity may substantially enhance allosteric
transitions transforming the ligand binding into the channel opening and
physiological response. Muscle nicotinic acetylcholine receptors from birds and
mammals are also pentaoligomers consisting of four different subunits (alpha2beta
gammadelta or alpha2beta epsilondelta) with high homology to the Torpedo
receptor. Apparently, the pentaoligomeric structure is the main feature of all
nicotinic, both muscle and neuronal, receptors. However, the neuronal receptors
are formed only by two subunit types (alpha and beta) or are even pentahomomers
(alpha7 neuronal receptors). All nicotinic receptors are ligand-gated ion
channel, the properties of the channels being essentially determined by amino
acid residues forming M2 transmembrane fragments.
PMID- 10779170
TI - Structure and mechanisms of function of visual system proteins.
AB - Recent progress in understanding visual signal transduction in retinal cells is
summarized. The roles of particular proteins in activation, amplification and
termination of the photoresponse are described. Detailed information on the
structure and function of the photoreceptor protein rhodopsin is presented. The
latest data on visual pigment sequences, rhodopsin mutations in the autosomal
dominant retinitis pigmentosa, and the results of site-directed mutagenesis of
the rhodopsin molecule are summarized.
PMID- 10779171
TI - Phototransduction and calcium.
AB - In the early 1970s it became clear that an unknown intracellular messenger
participated in signal transduction in retinal rod cells. Ca2+ and cGMP had been
considered as candidates for such a messenger until 1985 when the cGMP-gated
conductance of the plasma membrane was discovered. However, for the last several
years, Ca2+ has taken revenge as a signal molecule which contributed to the
processes underlying the photoreceptor cell recovery. This review describes the
overall picture of phototransduction molecular mechanisms with special emphasis
on participation of Ca2+ in visual cell signalling.
PMID- 10779172
TI - Integrins: structure and functions.
AB - Integrins are cell surface transmembrane glycoproteins which perform receptor
functions in cell interactions with the extracellular matrix and cell-cell
contacts. Another function of integrins is transduction of signals which mediate
the effects of the matrix on the physiological activity of cells (motility,
proliferation, differentiation, etc.). Contemporary views on the molecular
structure of integrins and their involvement in the organization of the
cytoskeleton and control of gene activity are presented. Biochemical mechanisms,
by which the signal functions of integrins are realized, are discussed. The data
on the participation of integrins in oncogenic cell transformation, metastasis,
and apoptosis are analyzed.
PMID- 10779173
TI - A new level of hormonal signal transduction: primary nuclear action of protein
and peptide hormones.
AB - Contemporary data on the possibility of primary nuclear action of protein and
peptide hormones are analyzed and summarized. Experimental data on the nuclear
accumulation of protein and peptide hormones and their receptors, ligand
dependence of nuclear translocation of membrane receptors, intranuclear
distribution of membrane receptors, and dependence of nuclear accumulation of
membrane receptors on the cell type are discussed. Evidence and hypothesis on the
possible mechanisms of intracellular and transnuclear transport of protein and
peptide hormones and their receptors, and association of nuclear translocation
with cell proliferation are presented. Putative mechanisms of realization of the
signal functions of protein and peptide hormones in the nucleus, including
activation of autonomous nuclear signal cascades and phosphorylation of nuclear
proteins, and the possibility of direct interaction of the nuclear pool of
membrane receptors with transcription factors and DNA are analyzed. A possible
biological role of primary nuclear action of protein and peptide hormones is
discussed.
PMID- 10779174
TI - Membrane receptors and intracellular calcium.
AB - The mechanisms of Ca2+ level regulation in the cytoplasm by neurotransmitters,
hormones, and growth factors and described. The role of G-proteins, second
messengers and protein kinases in the regulation of activity of Ca2+ channels and
pumps is discussed. The contributions of the endoplasmic reticulum, plasma
membrane, nucleus, mitochondria and other intercellular compartments to the
increase in the cytoplasmic Ca2+ concentration are estimated. The data concerning
the relationships between the activities of systems of active and passive Ca2+
transport across the membrane are reviewed. The general mechanisms of
intracellular Ca2+ oscillation are summarized, and a possible role of this
process in the neuroendocrine signal transduction is discussed.
PMID- 10779175
TI - Molecular mechanisms of action of prostaglandin E2 in the regulation of water
osmotic permeability.
AB - The functional role and molecular mechanisms of action of prostaglandin E2 (PGE2)
in the regulation of water osmotic permeability in osmoregulatory epithelia
(mammalian collecting tubules and amphibian urinary bladder) are considered. The
paper describes the modern classification of PGE2 receptors, their distribution
along a nephron and receptor-coupled intracellular second messenger systems. The
mechanism of the inhibitory action of PGE2 on the antidiuretic hormone-induced
enhancement of water osmotic permeability is analyzed. Special attention is given
to the role of PGE2 as an auto- or paracrine regulator of water osmotic
permeability in the phenomenon of ADH-independent increase of water permeability
observed in an isolated amphibian urinary bladder in replacements of the
surrounding serous solution. It is concluded that the osmoregulatory epithelium
is not only a place of the maximum level of PGE2 synthesis in the kidney but is
also characterized by a great diversity of PGE2 receptor subtypes: EP1, EP2, EP3
and EP4 have been revealed in the mammalian collecting tubules. Such a diversity
of PGE2 receptors is in a good agreement with different functional effects of
PGE2 in the osmoregulatory epithelium. The data considered suggest that PGE2 is
not less important in the regulation of water and ion transport in the
osmoregulatory epithelium than antidiuretic hormone.
PMID- 10779176
TI - The role of sphingomyelin cycle metabolites in transduction of signals of cell
proliferation, differentiation and death.
AB - Sphingomyelin cycle metabolites ceramide, sphingosine and sphingosine 1-phosphate
play an important role in cell proliferation, differentiation, reception,
oncogenesis and apoptosis. Ceramide is an intracellular second messenger for
apoptosis activating proteases and specific phosphatases. Sphingosine is an
endogenous inhibitor of protein kinase C and has an inhibitory effect on many
cell functions depending on the activity of this enzyme. On the other hand,
sphingosine can activate other kinases depending on the concentration, cell type
and nature of a stimulus and release Ca2+ from intracellular stores thereby
regulating cell proliferation. Sphingosine induces apoptosis and its level is
increased in cells as a result of action of apoptotic inducers. A phosphorylated
product of sphingosine, sphingosine 1-phosphate, mediates the mitogenic signal,
induces Ca2+ mobilization and protects cells from apoptosis resulting from
elevation of ceramide. The quantitative levels of sphingomyelin metabolites in
the cell determine the dynamic balance between the apoptotic and mitogenic
signals.
PMID- 10779177
TI - Regulation of the conductance and resting potential by extracellular K+ in frog
taste receptor cells.
AB - The effect of extracellular K+ on membrane currents was investigated by the patch
clamp and fast perfusion techniques in frog (Rana temporaria) taste receptor
cells (TRCs). When added to the bath, K+ increased the TRC conductance. The
integral current and current fluctuations depended on the K+ concentration (2.5
90 mM) in the manner which suggested extracellular K+ to serve as a ligand
activating ionic channels (potassium-activated (PA) channels). The influence of
different ions on the PA current reversal potential indicated that the
responsible channels are mainly permeable to K+ and H+. Relative permeabilities
were estimated as P(H):P(K) = 3600:1. With 110 mM KCl in the patch pipette and
110 mM NaCl in the bath, isolated TRCs exhibited the resting potentials from -75
to -65 mV. When raised from 2.5 to 110 mM, extracellular K+ intensively
depolarized TRCs. Membrane potential vs. K+ concentration displayed a slope of
about 41 mV per logarithmic unit. This indicates that the K+ permeability of the
TRC membrane dominates the other in setting the potential. With 10 mM K+ in the
bath, the PA channels were the major contributor to setting the TRC resting
potential. External K+ markedly increased the sensitivity of isolated TRCs to
bath solution pH due to the activation of the PA channels suggesting their role
in sour transduction.
PMID- 10779178
TI - Genetic patterning of embryonic inner ear development.
AB - The commitment of the otocyst to form balance (pars superior) and hearing (pars
inferior) receptors is under the control of patterning genes. Intersecting
patterns of gene expression has been proposed to explain the regionalization of
inner ear sensory receptor development. Insights into the roles of patterning
genes is being acquired from the analysis of inner ear development of null
mutation mice. An example of the consequences of the loss of expression of a
single patterning gene is the effect of a null mutation of paired-box gene 2
(Pax2) on formation of the cochlea. Pax2 transcripts are expressed in the pars
inferior of the otocyst and null mutant inner ears show agenesis of the cochlea.
This is an example of the profound effect that loss of a single patterning gene
can have on inner ear development. However, more typically there is redundancy of
gene action during inner ear development as exemplified by the overlapping
pattern of expression of two closely related homeobox-containing genes (i.e. Hmx2
and Hmx3) in the pars superior of the otocyst. Hmx2 and Hmx3 genes are both
expressed early in otic development with Hmx3 transcripts present in the placode.
However, null mutation of the Hmx3 patterning gene produced only a limited
vestibular defect, and did not result in the agenesis of the vestibule. This
result suggests that there is redundancy in genes that have similar patterns of
regional expression in the otic anlagen.
PMID- 10779179
TI - Effect of carbon dioxide on cochlear blood flow in guinea pigs.
AB - The influence of carbon dioxide (CO2) on cochlear blood flow (CBF), blood
pressure (SBP) and skin blood flow (SBF) was studied in anaesthetized guinea
pigs. A transient acute respiratory acidosis was produced by inhalation of CO2
and oxygen (O2) gas mixtures. The blood flows were measured by laser Doppler
flowmetry (LDF). High CO2 increased CBF and SBP, and decreased SBF in a dose
dependent manner. The responses of CBF, SBP and SBF to high CO2 were reversible.
Our results indicate that high CO2 (and low pH) dilates the smooth muscle of the
blood vessels, resulting in an increase in CBF. CO2 also activates the
sympathetic nervous system in the whole body, producing an increase in SBP. The
distribution of alpha-adrenergic fibres receptors is abundant in skin and scarce
in the cochlea. The constrictive effect on blood vessels is much greater in the
skin than in the cochlea, thus our results showed a decrease in SBF during
stimulation with higher CO2.
PMID- 10779180
TI - Intense noise-induced apoptosis in hair cells of guinea pig cochleae.
AB - Cells can die by two distinct pathways: apoptosis and necrosis. To explore
whether intense noise can induce hair cell (HC) death via the apoptotic pathway,
we systematically examined morphological changes in guinea pig cochlear HC nuclei
stained with Hoechst 33342, a fluorescent dye specifically labelling the nuclear
DNA. A narrow band noise centred at 4 kHz with levels at 110 dB, 115 dB or 120 dB
(SPL) was applied for 4 h and the exposed cochleae were collected at various
intervals (3 h, 3 or 14 days) after the noise exposure. Auditory function was
monitored by measuring thresholds of auditory brain stem responses. In the noise
damaged cochleae, there were two major types of nuclear changes, nuclear
condensation appeared as karyorrhexis or karyopyknosis and nuclear swelling.
Karyorrhexis and karyopyknosis predominately appeared in the severely damaged
cochlear region in the animals exposed to 120 dB noise and examined 3 h after the
noise exposure. In contrast, swelling of nuclei occurred in all of the noise
exposed cochleae, and was the feature change in the animals exposed to 110 and
115 dB noise. This pathological change persisted at least for 14 days after the
noise exposure. The typical changes of karyorrhexis and karyopyknosis noted in
the animals exposed to 120 dB noise were morphologically similar to those nuclear
changes described in previous studies for apoptosis, suggesting that the
apoptotic process may be involved in intense noise-induced HC death.
PMID- 10779181
TI - Effects of betahistine metabolites on frog ampullar receptors.
AB - Previous studies have demonstrated that betahistine, an histamine-like substance
used widely as an anti-vertigo drug, can decrease ampullar receptor resting
discharge without affecting their mechanically evoked responses. Pharmacokinetic
studies have shown that this drug is transformed, mainly at the hepatic level,
into aminoethylpyridine (M1), hydroxyethylpyridine (M2), then excreted with the
urine as pyridylacetic acid (M3). The goal of the present study was to
investigate whether betahistine metabolites are also able to affect vestibular
receptor activity. Results demonstrated that, in the range tested (10(-7)-10(-2)
M), M2 and M3 exerted no effect, whereas M1, at concentrations higher than 10(-6)
M, was able to reduce the resting discharge of ampullar receptors without
affecting the evoked responses. M1 therefore exerts effects similar to those of
betahistine on ampullar receptors. This might be of some clinical interest. On
the basis of our data, the hypothesis may be put forward that the anti-vertigo
action of betahistine is at first achieved by betahistine itself and then
sustained by M1.
PMID- 10779182
TI - Localization of soluble guanylate cyclase activity in the guinea pig inner ear.
AB - The aim of this study was to characterize the nitric oxide (NO) receptor soluble
guanylate cyclase (sGC), to determine the cells targeted by NO and to elucidate
the function of the NO/cGMP pathway in the inner ear. sGC activity in the inner
ear was localized by immunohistochemical detection of NO-stimulated cGMP. Soluble
guanylate cyclase activity in the cochlea was detected in the nerve endings
underneath the outer and inner hair cells, supporting cells, stria vascularis and
vessels. In the vestibular organs, sGC activity was detected in the cytoplasm of
sensory cells, nerve fibres, dark cells and transitional cells and vessels. These
findings suggest that the NO/cGMP pathway may be involved in regulatory processes
in neurotransmission, blood flow and inner ear fluid homeostasis.
PMID- 10779183
TI - Direct evidence of nitric oxide production in guinea pig vestibular sensory
cells.
AB - Production of nitric oxide (NO) in the vestibular organ of the guinea pig was
investigated using the new fluorescence indicator, DAF-2DA, for direct detection
of NO. The utricular maculae and isolated vestibular sensory cells were examined
to locate NO production sites. The fluorescence intensity of the sensory cells
was augmented by stimulation with L-arginine, and significantly increased after
inoculation with LPS. This is the first direct evidence of NO production in the
vestibular end organs. NO may play an important role for the vestibular
physiology and also be involved in disease of the inner ear.
PMID- 10779184
TI - Paraspinal muscle response to electrical vestibular stimulation.
AB - Galvanic (electrical) vestibular stimulation (GVS) has been used to study the
role of the vestibular system in postural control by inducing postural sway in
standing subjects. The purpose of this study was to determine the timing and
pattern of activation in the paraspinal muscles in response to GVS and to compare
these responses with those in the muscles of the lower leg. Binaural-bipolar GVS
was applied to the skin overlying the mastoid processes of 10 subjects while they
stood on a force plate with their eyes closed. The stimulus consisted of a 0.6 mA
5-pulse sequence. Each pulse lasted for 2 s, followed by 4 s of rest. The centre
of pressure (COP) vs. time for each trial was calculated from the reaction forces
and moments. Surface electromyographic (EMG) signals from the paraspinal and
gastrocnemius muscles were recorded bilaterally. The EMG signals were rectified
and integrated (iEMG). The iEMG from the muscles on the cathodal side of the body
were then subtracted from the iEMG of the anodal side muscles, to yield a
differential EMG (dEMG). Both the paraspinal and gastrocnemius muscles became
activated in response to the stimulus. The pattern of activation was consistent
with the changes observed in the centre of pressure. The primary response in both
muscles acted to move the body toward the anode. This primary response began at
74 +/- 20 ms in the paraspinal muscles and at 118 +/- 18 ms in the gastrocnemius.
A second component of the response began at 232 +/- 27 ms in the paraspinal
muscles and 262 +/- 54 ms in the gastrocnemius muscles. This second phase of the
response was opposite in direction to the primary response and was responsible
for decelerating the body and maintaining the deviated position of the centre of
mass over the base of support. Following the termination of the stimulus, the
opposite pattern of muscle activation in both the paraspinal and the
gastrocnemius muscles was observed. The results of this study suggest that the
paraspinal muscles may play a significant role in the frontal plane response to
vestibular stimulation during stance in humans.
PMID- 10779185
TI - Auditory cortical responses in patients with Bell's palsy.
AB - We recorded auditory evoked magnetic responses with a whole-scalp 122-channel
SQUID neuromagnetometer in 14 patients with Bell's palsy (9 with left-sided and 5
with right-sided) and in 10 controls. The stimuli were 50-ms 1-kHz tone bursts,
delivered first to the left and then to the right ear at interstimulus intervals
(ISIs) of 1, 2 and 4 s. In patients, the N100m, the 100-ms response originating
in the auditory cortices peaked, on average, 8 ms earlier and the response
strengths were, on average, 7 nAm stronger over the contralateral than
ipsilateral hemisphere. The response latencies and strengths did not differ
significantly from those of controls and there were no significant differences in
response latencies and strengths between the stimulation of the affected and
healthy side. On average, the response latencies and strengths increased as a
function of ISI over both hemispheres both in patients and in controls. These
findings suggest that Bell's palsy is an isolated peripheral neuropathy that does
not affect the function of the auditory pathways.
PMID- 10779186
TI - Audiometric characterization of a family with digenic autosomal, dominant,
progressive sensorineural hearing loss.
AB - In this study, a non-syndromic progressive bilateral high frequency hearing loss
is described in a family with 141 identified members. Recent genetic analyses
indicated a digenic inheritance with linkage to the gene loci DFNA2 and DFNA12.
The affected family members who shared haplotypes at both loci (type I) showed an
early postlingual onset and a more rapid rate of progress compared with those
with one either of the two disease associated haplotypes (type II). The
audiometric pattern was cochlear without a vestibular involvement. Auditory
brainstem response audiometry and magnetic resonance imaging indicated normal
retrocochlear features. The otoacoustic emissions were affected for both type I
and type II, whereas the acoustic stapedius reflex thresholds were normal in most
cases. It is concluded that both types had an outer hair cell/micro-mechanical
abnormality, but that the DFNA 2 type might have an additional dysfunction at the
level of the inner hair cells. It is furthermore pointed out that the application
of refined audiometric techniques as well as a further development of new
techniques is needed in order to characterize the phenotypes of the rapidly
expanding number of genetically defined inner ear abnormalities.
PMID- 10779187
TI - Expression of human beta-defensin 1 mRNA in human nasal mucosa.
AB - Antimicrobial peptides are cationic proteins that are found in a wide range of
organisms. Recent reports suggested that human beta-defensin 1 (hBD-1), a
prominent group of antimicrobial peptides, is an important component of the
innate immune response, particularly at mucosal surfaces that are vulnerable to
colonization by potential pathogens. Therefore, hBD-1 may participate in
providing intrinsic nasal mucosal defence against microbial infections. The
present study aimed to look for hBD-1 mRNA in human nasal mucosa without obvious
signs of inflammation. Total RNA was isolated from human inferior turbinate
mucosa and hBD-1 mRNA was detected in these tissues by using reverse
transcription and polymerase chain reaction (RT-PCR). By in situ hybridization,
hBD-1 mRNA was predominantly localized in superficial epithelial cells and
submucosal glandular epithelium of human inferior turbinate mucosa. These data
suggest that nasal epithelia and submucosal glands may secrete hBD-1,
contributing to the mucosal defences of the nose.
PMID- 10779188
TI - Effect of intranasal treatment with capsaicin on the recurrence of polyps after
polypectomy and ethmoidectomy.
AB - The aim of this study was to evaluate the influence of five intranasal
applications of capsaicin, performed after endoscopic polypectomy associated with
partial middle turbinectomy and anterior ethmoidectomy, on the recurrence of
nasal polyps and the intensity of nasal obstruction and rhinorrhea. Fifty-one
patients (19 females, 32 males, mean age 43 years) suffering from nasal polyposis
for more than 1 year were included in this double blind, randomized, placebo
controlled study. During post-surgical controls, local anaesthesia and
vasoconstriction of the middle meatus area were performed in all patients with a
cotton pellet soaked with lidocain and adrenaline. In 29 patients, the same type
of cotton pellet soaked with capsaicin (3 x 10(-6) mol. dissolved in 70% ethanol)
was left into the middle meatus of both nostrils for 20 min. As a control group,
22 patients, matched for age and sex, were treated with the capsaicin vehicle
alone (70% ethanol). All patients studied received the intranasal treatment once
a week for 5 weeks. Subjective evaluations of nasal airway resistance (NAR) and
rhinorrhea were recorded by means of a visual analogue scale. Clinical staging of
the nasal polyposis (graded from stage 0 = absence of polyp to stage 3 = polyps
occupying the entire nasal cavity) was evaluated by the same ENT specialist (ZW)
using a 0 degrees endoscope. All parameters were recorded for each patient 1 week
before surgery, then once a month for 9 months. Patients treated by endoscopic
surgery followed by intranasal capsaicin application, reported a marked reduction
in their NAR compared with the pretreatment evaluation (p<0.001). In contrast,
patients treated with the vehicle alone did not have any significant improvement
of their subjective NAR. Subjective rhinorrhea was not modified by either
treatment. Patients treated with capsaicin showed a significant smaller staging
of their nasal polyposis compared with the control group (p<0.001). These
observations suggest that endoscopic surgery followed by intranasal capsaicin
application reduces polyps and nasal obstruction recurrence and could be an
alternative treatment to expensive corticosteroids in developing countries.
PMID- 10779189
TI - Nasal histamine reactivity; relationships to skin-test responses, allergen
provocation and symptom severity in patients with long-continuing allergic
rhinitis.
AB - It has been reported that skin-test reactivity and rhinitis symptom severity
weaken in the course of time. A corresponding weakening might also be seen in non
specific nasal hyper-reactivity, but the relationships of these responses are
poorly understood. Our aim was to measure nasal responsiveness to histamine in a
series of patients with long-continuing allergic rhinitis and to compare these
measurements with skin test responses, allergen provocation and changes in
severity of allergic rhinitis symptoms. A total of 73 patients in whom allergic
rhinitis had been verified over 20 years earlier were re-interviewed and re
investigated. Skin prick tests with common allergens were performed and the
presence of nasal allergy was confirmed by allergen provocation. Non-specific
nasal hyper-reactivity was determined with nasal histamine challenge using four
concentrations of histamine phosphate. The response was registered by counting
sneezes, recording changes in nasal discharge and mucosal swelling and measuring
nasal airway resistance. Sneezing and discharge scores showed that milder non
specific nasal hyper-reactivity was associated with lack of reactivity in skin
prick tests and nasal allergen challenge. No association was observed between
allergy test results and changes in nasal airway resistance during the histamine
provocation. In most patients the symptoms of rhinitis had become milder or
disappeared during the follow-up, but the results of the histamine challenge
showed no relationship with the changes in symptom severity. In patients with
allergic rhinitis, reactivity to histamine is associated with a concomitant
change in skin and nasal mucosal reactivity to allergens.
PMID- 10779190
TI - Evaluation of methods for endoscopic staging of nasal polyposis.
AB - Endoscopy is needed for reliable evaluation of the treatment of nasal polyposis.
In this study, we compared the reproducibility of various score systems for
staging nasal polyposis and the inter-individual variations between
investigators. The mass of the polyps was assessed by five methods, three new
techniques (numbers 1, 2 and 3) and two established ones (numbers 4 and 5). These
were: 1, lateral imaging projecting the extension of the polyps by drawing on a
schematic picture of the lateral wall of each nasal cavity; 2, assessment of
polyp obstruction estimating the proportion of the total nasal cavity volume
occupied by polyps; 3, nasal airway patency--determining the relationship between
the patient's patent airway lumen and an imaginary maximal nasal airway lumen; 4,
a score system with four steps ad modum Lildholdt et al.--determining their
relationship to fixed anatomical landmarks; and 5, a score system with three
steps ad modum Lund and Mackay--determining their relationship to the middle
meatus. High correlations were found between the first and the second assessments
by a given investigator with all five methods used to score nasal polyposis. High
correlations were also shown between the various methods. When three
investigators examined a given patient, there were no significant differences
between the investigators using score systems 1, 3 and 4. However, with score
systems 2 and 5, there was insufficient agreement between the investigators. The
patient's symptom of nasal blockage was not a good indicator of the size of the
polyps, especially as regards small polyps. Two of the best methods tested (1 and
4) were selected for further clinical studies regarding evaluation of the
sensitivity of score systems to detect changes in polyp size during treatment.
PMID- 10779191
TI - Postnatal presence of paraseptal cartilages in humans: a description of
morphology and size.
AB - Paraseptal cartilages (PCs) have been the subject of controversy, in that some
authors believe them to be absent or rarely present, while others have described
them to exist at predictable locations in adult human tissue specimens. This
study seeks to determine the presence or absence of PCs in humans and describe
their morphology and size. Nasal septal tissue from 19 adults and 1 child were
paraffin embedded, coronally sectioned, placed on slides, and stained for
microscopic observation. For all specimens, PCs were identified and lengths were
calculated. Selected PCs were also digitized in order to calculate volume.
Results demonstrated that PCs were present in all 20 tissue specimens and assumed
a common morphology. In each, PCs were found to begin as hyaline cartilage lobes
that extend projections in a superolateral direction as an anteroposterior course
is followed. The projections were found to rotate inferiorly until each PC was
found to assume a position that extended below the nasal septum. Length measures
in adults ranged from 8,725 to 19,000 microm (x = 14,188.9 microm) and volumes
ranged from 7.7 to 24.2 (x = 13.2) x 10(-3) ml. A quantitative comparison to
foetal data from a previous study suggests prenatal and/or postnatal growth of
PCs. Results from this study support the presence of PCs in adult humans as well
as prenatal/postnatal growth of PCs.
PMID- 10779192
TI - Effects of a pressure surround on the regional taste detection threshold for
sodium chloride.
AB - The question as to whether tactile stimulation alters proximal taste function in
humans has never been answered, despite the suggestion of anatomical and
physiological associations between somatosensory and gustatory function in a
number of species. In this study, we established NaCl detection thresholds for a
25 mm2 anterior tongue region on four test occasions in each of 12 men and 12
women. Testing was performed using the Regional Automated Taste Testing System
(RATTS), a device that allows for accurate temporal and spatial presentation of
tastants to the lingual surface. On each test occasion, a different negative
pressure (vacuum suction) was applied around the stimulus presentation field of
the glass stimulation device (i.e. 40, 50, 60 and 70 mmHg). The order of
presentation of the vacua was systematically counterbalanced among subjects
across sessions using 4 x 4 Latin square sequences. Neither the vacua nor their
order of presentation meaningfully altered the taste threshold values, even
though the higher vacua produced persistent discernible discomfort in most
subjects. On average, taste thresholds tended to be marginally lower in women
than in men. These data indicate that static vacuum-induced tactile stimulation
around a discrete anterior taste field has no meaningful influence on NaCl
detection threshold sensitivity.
PMID- 10779193
TI - Dissection plane of the human vocal fold lamina propria and elastin fibre
concentration.
AB - To determine whether a natural plane of dissection occurs in the normal human
vocal fold, semi-blunt instruments (Bouchayer laryngeal dissectors) were used to
dissect the lamina propria. The depth of the plane of dissection was correlated
with the elastin fibre concentration to determine whether the plane occurred at a
predictable point in the elastin concentration as it increased between the
superficial and middle layers. Eight human larynges were dissected using an
operative microscope. The dissection plane consistently occurred between 23-50%
depth into the lamina propria. No consistent correlation was found with the
elastin fibre concentration. The depth of the plane of dissection has an
interesting association with age: dissection planes occurred more superficially
in older specimens.
PMID- 10779194
TI - Biofilm formation on voice prostheses: influence of dairy products in vitro.
AB - Laryngectomized patients use silicone rubber voice prostheses to regain their
speech, however, the lifetime of these devices is limited due to biofilm
formation. Following anecdotal evidence, the influence of various dairy products
on biofilm formation on voice prostheses was studied, using the artificial throat
model. Biofilms were grown on Groningen and Provox2 voice prostheses by
inoculating two artificial throats with the total microflora isolated from an
explanted Groningen voice prosthesis. After 3 days, one throat was perfused three
times daily with 650 ml dairy product; the other was perfused with phosphate
buffered saline, used as a control. After 12 days the microflora on each voice
prosthesis was determined. Perfusion of the artificial throat with buttermilk
three times daily for 9 days reduced the amount of bacteria and yeasts in the
biofilm on Groningen voice prostheses to 3% and 15% of the control, respectively.
These effects were not observed with a pasteurized conservable buttermilk
product. Yakult fermented milk drink, Mona mild yoghurt, Mona vifit yoghurt, semi
skimmed milk and low-fat yoghurt reduced the amount of bacteria by various
degrees, ranging from 12% (Yakult) to 88% (Mona mild) of the control, but these
products did not inhibit, and sometimes even stimulated, yeast growth. A
combination of buttermilk and Yakult did not show a synergistic effect, as
expected. Effects for the Provox2 voice prosthesis were less pronounced. These in
vitro experiments in the artificial throat demonstrated that the formation of the
biofilm on voice prostheses can be lessened by the daily use of certain dairy
products, of which buttermilk had the strongest inhibitory effect, followed by
Yakult.
PMID- 10779195
TI - Proper use of serum antibody titres against Epstein-Barr virus in nasopharyngeal
carcinoma: IgA/virus capsid antigen for diagnosis and EBV-related nuclear antigen
2 for follow-up.
AB - Sera from patients with nasopharyngeal carcinoma (NPC) show high titres of IgA
antibodies to Epstein-Barr viral capsid antigen (IgA/VCA). We reported previously
that the serum titres for Epstein-Barr virus-related nuclear antigen-2 (EBNA2)
correlated with NPC patients' prognosis. To investigate which is better for
diagnosing NPC and predicting patient prognosis, the titration of serum IgA/VCA
or EBNA2, we examined the same serum titres. Sixteen cases of NPC in which serum
EBNA2 antibody titres had been tested, were investigated for the serum IgA/VCA
antibody titres before and after radiation treatment. All NPC cases showed
positive reactions with indirect immunofluorescence staining, and the median
titre was 252. Twelve normal controls, 5 mesopharyngeal carcinoma patients, 4
hypopharyngeal carcinoma patients, 4 laryngeal carcinoma patients and 6 malignant
lymphoma were also examined, but they showed negative or relatively low titres. A
follow-up study revealed that IgA/VCA titres remained mostly stable. These
results indicate a close relationship between IgA/VCA and NPC, however, prognosis
correlated better with EBNA2 titres than with IgA/VCA titres.
PMID- 10779196
TI - Vascular endothelial growth factor expression correlates with p53 mutation and
angiogenesis in squamous cell carcinoma of the head and neck.
AB - Vascular endothelial growth factor (VEGF) has potent angiogenic activity and has
been identified in a wide variety of malignancies, including head and neck
squamous cell carcinoma (HNSCC). The tumour-suppressor gene p53 has been thought
to regulate VEGF. Cryostat sections of 33 head and neck squamous cell carcinomas
(HNSCC) were immunostained for VEGF using a standard streptavidin-biotin complex
procedure. To evaluate angiogenesis, microvascular density was counted by
staining endothelial cells immunohistochemically using anti-vWF monoclonal
antibody. The p53 gene status was analysed using a PCR-SSCP analysis and direct
sequencing. VEGF positive staining was detected in 18 (55%) out of 33 tumours.
VEGF immunoreactivity did not correlate with the main clinicopathological
characteristics of the patients (localization, T-stage, N-status, histological
grading). Statistical analysis gave a clear correlation between the tumour
vascularity and the VEGF protein expression (p = 0.0036). VEGF negative tumours
showed a lower mean number of microvessels per microscopic field (60.3 +/- 15.5)
than VEGF positive tumours (79.6 +/- 22.9). P53 mutations were identified in 12
(36.4%) of 33 tumours. The association of p53 mutations and VEGF expression level
was significant (0.027). The higher microvessel density in VEGF positive tumours
supports the importance of VEGF for tumour angiogenesis in HNSCC. Our results
support the hypothesis of a p53 regulation on the angiogenic process through a
VEGF up-regulation.
PMID- 10779197
TI - Vestibular evoked myogenic potentials in humans.
PMID- 10779198
TI - Epidemiological surveillance of infectious diseases in France.
AB - Epidemiological surveillance, namely the continuous monitoring of diseases and
health determinants in a population, has developed over the past fifteen years,
in the sphere of human health as well as in animal health. All epidemiological
surveillance networks include the following four stages: data collection, data
transmission, data processing and dissemination of information. However, despite
this basic similarity, the very many networks existing in France are extremely
varied in nature. At the national level, the bodies involved in epidemiological
surveillance for infectious animal diseases are the Direction generale de
l'alimentation, the Agence francaise de securite sanitaire des aliments and, to a
lesser degree, the Institut francais de recherche pour l'exploitation de la mer.
In the field, the networks rely on the Direction des services veterinaires,
veterinary practitioners, laboratories in each departement, and livestock
producers' groups (especially animal health protection groups). Some twenty
French networks currently in operation are presented in this article according to
a classification based on published criteria. In the case of human infectious
diseases, epidemiological surveillance is carried out almost entirely by the
Direction generale de la sante and the Directions departementales d'action
sanitaire et sociale, the Institut de veille sanitaire and the various Centres
nationaux de reference (CNRs). Most human infectious diseases are monitored by
one or more of the following broad categories of networks: reporting of
notifiable diseases, the CNRs, the network of sentinel doctors, the network of
hospital laboratories and departments, and medical causes of death. An example
where surveillance is covered by several networks is also presented, namely
surveillance for salmonellosis and Salmonella. Lastly, methods for evaluating
networks are discussed.
PMID- 10779199
TI - Proinflammatory cytokines and viral respiratory disease in pigs.
AB - Swine influenza virus (SIV), porcine respiratory coronavirus (PRCV) and porcine
reproductive and respiratory syndrome virus (PRRSV) are enzootic viruses causing
pulmonary infections in pigs. The first part of this review concentrates on known
clinical and pathogenetic features of these infections. SIV is a primary
respiratory pathogen; PRCV and PRRSV, on the contrary, tend to cause subclinical
infections if uncomplicated but they appear to be important contributors to
multifactorial respiratory diseases. The exact mechanisms whereby these viruses
cause symptoms and pathology, however, remain unresolved. Classical studies of
pathogenesis have revealed different lung cell tropisms and replication kinetics
for each of these viruses and they suggest the involvement of different lung
inflammatory responses or mediators. The proinflammatory cytokines interferon
alpha (IFN-alpha), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL
1) have been shown to play key roles in several respiratory disease conditions.
The biological effects of these cytokines and their involvement in human viral
respiratory disease are discussed in the second part of this review. The third
part summarises studies that were recently undertaken in the authors' laboratory
to investigate the relationship between respiratory disease in pigs and bioactive
lung lavage levels of IFN-alpha, TNF-alpha and IL-1 during single and combined
infections with the above viruses. In single SIV infections, typical signs of
swine "flu" were tightly correlated with an excessive and coordinate production
of the 3 cytokines examined. PRCV or PRRSV infections, in contrast, were
subclinical and did not induce production of all 3 cytokines. Combined infections
with these 2 subclinical respiratory viruses failed to potentiate disease or
cytokine production. After combined inoculation with PRCV followed by bacterial
lipopolysaccharide, both clinical respiratory disease and TNF-alpha/IL-1
production were markedly more severe than those associated with the respective
single inoculations. Taken together, these data are the first to demonstrate that
proinflammatory cytokines can be important mediators of viral respiratory
diseases in pigs.
PMID- 10779200
TI - Clinical response and immunomodulation following experimental challenge of calves
with type 2 noncytopathogenic bovine viral diarrhea virus.
AB - Eight calves between 16 and 18 weeks of age that were seronegative to bovine
viral diarrhea virus (BVDV), bovine leucosis virus and bovine immunodeficiency
like virus were infected (day 0) intranasally with the type 2 noncytopathogenic
Canadian 24515 field isolate of BVDV in order to evaluate the effect of BVDV
infection on certain clinical, hematological and immunological parameters. All
virus-exposed animals developed fever and showed a significant (P < 0.05, 0.01 or
0.001) drop in the number of circulating leucocytes (neutrophils, lymphocytes and
monocytes) by day 3 or 5 post-exposure (PE), which continued to the end of the
experiment at day 12 PE. BVDV was consistently isolated from the peripheral blood
buffy coat cells from day 5 PE, and also from selected tissues (spleen, thymus,
mesenteric and submaxillary lymph nodes, small intestine, lungs and thyroid
gland) that were collected at the time of euthanasia of the animals at day 12 PE.
Diminished significant (P < 0.05) percentages of peripheral blood mononuclear
cells (PBMCs) expressing at their surface either B7 and MHC II molecules were
observed in virus-exposed calves at days 7, 10 and/or 12 PE, when compared to
virus-nonexposed control calves (n = 5). However, no changes in the percentages
of PBMCs expressing either B4 or MHC I molecules were observed throughout the
experiment. Finally, a significant (P < 0.05 or 0.01) enhanced phagocytic
capability of the PBMCs, as analyzed by flow cytometry, was observed in virus
exposed animals at days 3, 5, 7, 10 and 12 PE, when compared to control calves.
These results demonstrated the virulence of the 24515 isolate of BVDV in 4 to 4.5
month-old calves, and suggest that type 2 BVDV infection in calves is associated
with dysregulation of certain immunological functions.
PMID- 10779201
TI - Purification and characterisation of bovine WC1+ gammadelta T lymphocytes from
peripheral blood.
AB - In order to isolate and characterise resting WC1+ gammadelta T cells from cattle,
we developed a protocol for purifying these cells by negative selection from
peripheral blood. The purification method included five steps: separation of
mononuclear cells on lymphoprep, depletion of monocytes by adherence to plasma
coated gelatin, enriching T cells on a nylon wool column, depleting CD2+ T cells
by sheep red blood cells (SRBC), and finally depleting CD4+ and CD8+ T cells by
the magnetic cell sorting technique (MACS). This procedure proved efficient and
reproducible, and the purity of the isolated WC1+ gammadelta T cells was more
than 97% as analysed by flow cytometry (FACS). Cytokines and costimulatory
molecules mRNA expression was assessed by the reverse transcriptase polymerase
chain reaction (RT-PCR) technique in freshly isolated resting WC1+ T cells. We
found that purified uncultured WC1+ T cells express TNF-alpha, CD28, CTLA-4 and
IL-2R alpha mRNA transcripts but do not express those for IL-2, IL-4, IL-6, IL-10
and IFN-gamma. The expression of CD28 and CTLA-4 transcripts on bovine WC1+ T
cells indicates that these genes are evolutionarily conserved.
PMID- 10779202
TI - Bovine respiratory syncytial virus: first serological evidence in Uruguay.
AB - Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease
in calves resulting in a substantial economic loss for the cattle industry
worldwide. In order to determine the presence of BRSV in Uruguay, an
immunoenzymatic test was set up, using a recombinant BRSV nucleocapsid (N)
protein as the antigen. The N protein was produced in Sf9 insect cells by a
recombinant baculovirus expressing the N protein. Serum samples collected from
one hundred cattle from four different geographic regions of Uruguay were
analyzed. Antibodies against the N protein of BRSV were detected in 95% of the
serum samples analyzed. These results show for the first time the presence of
BRSV antibodies and suggest a widespread BRSV infection in the cattle population
of Uruguay.
PMID- 10779203
TI - The effect of two levels of dietary protein on resistance and resilience of dairy
goats experimentally infected with Trichostrongylus colubriformis: comparison
between high and low producers.
AB - Numerous studies have examined the interactions between protein nutrition and the
response to nematode parasitism in sheep, but very few in goats. Compared with
other ruminants, goats are less resistant to nematode infection. In addition, in
dairy goats, high producing animals have been shown to be less resistant and less
resilient to infection compared to low producing ones. The objective of the
present study was to examine the consequences of protein supplementation on both
resistance and resilience of dairy goats to nematode trickle infection, taking
into account the initial level of milk production of the animals. During a 14
week period, 40 milking goats received a high protein (HP) diet supplying 130% of
the protein requirements, and 38 goats were fed a intermediate protein (IP) diet
(120% of the protein requirements). In addition, half of each group was given a
weekly trickle infection with Trichostrongylus colubriformis larvae, the other
part of the flock remained non-infected. Faecal egg counts (FEC), eosinophil
counts and pathophysiological data (urea, albumin and inorganic phosphate
concentrations in the serum) were measured twice a month. Milk production data
(milk yield, protein and fat contents) were also recorded every 15 days. The
results showed that FECs were lower (p < 0.05) and eosinophil counts higher (p <
0.05) in the animals receiving the HP diet suggesting that resistance was
enhanced by protein supplementation. Meanwhile, milk parameters (related to
resilience) were not affected by the level of protein in the diet when
considering the whole groups. In contrast, in the high producing goats, the milk
production and milk composition parameters were improved with the HP diet. To
conclude, we have seen that the expression of both resistance and resilience did
not appear when the coverage of the protein requirements was insufficient.
Because the milk production is dependent on the protein supply, we suggest that
there is a competition in the use of the protein between the development of
resistance and the milk production.
PMID- 10779204
TI - Effect of strategic gastrointestinal nematode control on faecal egg count in
traditional West African cattle.
AB - This paper reports on the effect of strategic anthelmintic treatments and other
determinants on faecal egg counts (FEC) of Trichostrongyles in N'Dama cattle of a
west African village. Initially, 527 animals from 13 private N'Dama cattle herds
were monitored in a longitudinal study from October 1989 to December 1994. Each
herd was stratified by age and animals were sequentially allocated to two groups
with similar age distributions. One group received a single anthelmintic
treatment of fenbendazole (7.5 mg/kg BW), in October 1989 (n = 250), whereas the
other group remained untreated (n = 277) throughout the study. In the next rainy
season (June to October), the treated animals were treated twice (in July and
September). The same treatment schedule was used in the subsequent rainy seasons
until December 1994. Biannual anthelmintic treatments decreased the level of FEC
between 31% (late dry season) and 57% (rainy season), when compared to untreated
controls. The highest levels of FEC were found during the rainy season from June
to October. FEC levels decreased until 4 years of age, after which they remained
on a constant low level. The variability of returns to anthelmintic treatments
between herds did not seem to be influenced by FEC at the herd level. The
financial evaluation of anthelmintic interventions cannot be predicted from FEC
and must necessarily rely on the direct monitoring of livestock productivity
parameters.
PMID- 10779205
TI - In vitro inhibitory effect of SR 27417, a potent platelet-activating factor (PAF)
receptor antagonist, on the PAF-induced bovine platelet aggregation.
AB - The in vitro inhibitory effect of SR 27417, an antagonist of the platelet
activating factor (PAF) receptor, on PAF-induced platelet aggregation was studied
in blood collected from seven healthy Friesien calves. Inhibitory effects of SR
27417 were determined at thirteen different concentrations (0.1-400 nM) by using
the dose-response curves of PAF on calf platelet aggregation. In the presence of
SR 27417, the maximal slopes of aggregation (%/min) induced by low and high
concentrations of PAF were significantly different from the control values
obtained without an antagonist at p < or = 0.05 and p < or = 0.01 respectively.
In vitro PAF-induced calf platelet aggregation was dose-dependently inhibited by
SR 27417. The drug inhibited PAF-induced platelet aggregation in a competitive
reversible manner (pA2 = 10.46 +/- 2.36 mol x L(-1)). In conclusion, the results
of our study showed that addition of SR 27417 to bovine platelet in vitro
inhibits PAF-induced platelet aggregation.
PMID- 10779206
TI - From food to nutritional support to specific nutraceuticals: a journey across
time in the treatment of disease.
AB - Hospitalized patients who are unable to eat or cannot eat enough to meet their
metabolic needs are given parenteral or enteral nutritional support. This form of
therapy is now also given to patients at home. Nutritional support is a recent
development, prior to which the value of food was recognized for its medicinal
benefits as nutraceuticals. The value of such "alternative" therapy is now being
rediscovered by many patients who enhance their dietary intake with these
traditional remedies. In Western culture, conventional medicine until recently
has largely rejected the use of such "alternative" therapeutic intervention.
Based on an increasing database, though, insight has been gained concerning the
scientific validity of many previously termed established nutraceuticals. We
focus here on the effects of honey, green tea, ginseng, and vitamin
supplementation on the immune system. Honey has proven antimicrobial activity.
Green tea enhances humoral and cell-mediated immunity while decreasing the risk
of certain cancers and the risk of cardiovascular disease. Ginseng enhances
production of macrophages, B and T cells, natural killer cells, and colony
forming activity of bone marrow. Vitamin supplementation is associated with
increased antibody titer response to both hepatitis B and tetanus vaccines as a
result of macrophage and T cell stimulation. Because of these findings,
nutraceuticals are becoming more widely accepted as an adjunct to conventional
therapies for enhancing general well-being.
PMID- 10779207
TI - Nutritional treatment with branched-chain amino acids in advanced liver
cirrhosis.
AB - During the last 20 years there has been much interest in nutritional treatment
for patients with advanced cirrhosis. Most studies have measured the potential
benefit of nutritional supplements of dietary proteins, generic protein
hydrolysates, or specific branched-chain amino acid (BCAA)-enriched formulas in
regard to nutritional parameters and hepatic encephalopathy. The issue is not
definitively settled; data are conflicting and meta-analyses have failed to
produce unequivocal results. A consensus review, recently produced under the
auspices of the European Society for Parenteral and Enteral Nutrition, concluded
that: (1) patients with cirrhosis tend to be hypermetabolic, and a higher-than
normal supply of dietary proteins is needed to achieve nitrogen balance; (2) most
patients tolerate a normal or even increased dietary protein intake, without risk
of hepatic encephalopathy; (3) a modified eating pattern, based on several meals
and a late evening snack, is useful; (4) in severely malnourished patients, amino
acid supplements may be considered to provide the necessary amount of proteins to
meet protein requirements; (5) in a few patients intolerant to the required
protein intake, BCAA supplements may be considered to provide the necessary
nitrogen intake without detrimental effects on the mental state, perhaps even
improving it. Future studies are needed to quantify the advantage of nutritional
support with amino acids or BCAA supplements on overall well-being,
complications, and ultimately survival with a long-lasting disease where self
perceived health-related quality of life is a major outcome.
PMID- 10779208
TI - Nutritional pharmacotherapy of chronic liver disease: from support of liver
failure to prevention of liver cancer.
AB - Many patients with liver cirrhosis are in a state of protein and energy
malnutrition and require careful nutritional support. Our research has revealed
that approximately 30% of the patients have protein-energy malnutrition, 40%
protein malnutrition, and 10% energy malnutrition; 20% are in a normal
nutritional state. Supplementation with branched-chain amino acids alleviates
chronic liver failure, improves the protein nutritional state, and subsequently
prolongs survival. In contrast, therapeutic modalities for energy malnutrition
have not yet been fully elucidated and await further studies. Improved survival
of the cirrhotic patients essentially brings a higher incidence of hepatocellular
carcinoma (HCC). A synthetic analogue of vitamin A (acyclic retinoid or 4,5
dehydrogeranyl geranoic acid) prevents at least the development of second primary
tumors after curative treatment of preceding HCC. The mechanism of this cancer
chemo-prevention is clonal deletion of premalignant and latent malignant cells by
the retinoid. We describe our clinical experiences with these two nutritional
pharmacotherapies of chronic liver diseases and review their basic mechanisms.
PMID- 10779209
TI - Nutrition and Crohn's disease.
PMID- 10779210
TI - Therapeutic efficacy of elemental enteral alimentation in Crohn's disease.
PMID- 10779211
TI - Role of arginine in immunonutrition.
AB - Arginine plays an important role in many physiologic and biologic processes
beyond its role as a protein-incorporated amino acid. Dietary supplementation of
arginine can enhance wound healing, regulate endocrine activity and potentiate
immune activity. Under normal unstressed conditions the arginine requirement of
adult humans is fulfilled by endogenous sources, however this is compromised
during times of stress, especially in critical illness. These finding have led to
use of arginine supplementation as part of an immune-enhancing dietary regimen to
help combat the immune suppression seen in such patients. Though the results from
studies examining the use of this type of immunonutrition in critically ill
patients are far from definitive, they are promising that this mode of therapy
may be of some advantage. A better understanding of the in vivo biology of
arginine and its metabolism is necessary to truly define a benefit from arginine
supplementation.
PMID- 10779212
TI - N-3 polyunsaturated fatty acids in pharmaconutrition and immunonutrition.
PMID- 10779213
TI - Effect of administration of nucleosides and nucleotides on protein turnover and
the hypoxic myocardium.
AB - Nucleotides and nucleosides have effects on improving energy metabolism and
enhancing immune function. Under a surgical stress, requirement of nucleotides
are increased as well as nitrogen. A well-balanced nucleoside solution (OG-VI)
was developed for parenteral administration and its effect was examined in
animals. The OG-VI solution contained 3.11% of nucleosides which was composed of
inosine, guanosine monophosphate, cytidine, uridine and thymidine of 4:4:4:3:1 in
molar ratio. The whole body protein turnover increased significantly in rats
received total parenteral nutrition (TPN) with OG-VI after 70% hepatectomy and
enhanced the fractional protein synthesis rates of the muscle and liver. Also
myocardial contractility (%segment shortening, %SS) in dogs after occlusion of
left anterior descending artery (LAD) was recovered to 70% after reperfusion in
the OG-VI group. The creatine phosphate (PCr) / inorganic phosphate (Pi) was
maintained the baseline level and did not decrease after hypoxia in the OG-VI
group while PCr/ Pi was decreased after hypoxia in normal rat. These data
suggested that the nucleoside-nucleotide (OG-VI) improved nitrogen metabolism and
might stimulate synthesis of high-energy phosphate in recovery after severe
surgical stress.
PMID- 10779214
TI - Helicobacter pylori-negative peptic ulcers: frequency and implications for
management.
AB - Most patients with peptic ulcers are infected with Helicobacter pylori, but the
infection may not be responsible for the ulcer. It is increasingly recognized
that different causes of ulcers coexist in a given patient, confounding
determination of the exact cause of the ulcer. For example, in infected patients
with ulcers who also are using nonsteroidal anti-inflammatory drugs (NSAIDs), it
is not possible to establish the ulcer's cause. Moreover, recent studies in the
United States in infected patients with duodenal ulcers who were treated with
various regimens to prove their efficacy in eradicating H. pylori and preventing
ulcer recurrence found that approximately 20% of patients suffered an ulcer
recurrence despite successful H. pylori eradication. The infection clearly did
not cause their ulcers but was originally thought to have done so. Thus, as many
as one-fifth of patients with ulcers may have the cause falsely attributed to H.
pylori infection. When this number is added to that of ulcer patients who are H.
pylori-negative upon original presentation--at least 20% in other recent U.S.
studies--it is evident that the proportion of non-H. pylori ulcer patients is
larger than originally believed. This proportion is likely to increase with the
declining incidence of H. pylori infection. Other causes of ulcers include the
use of aspirin and NSAIDs (which may be surreptitious), hypersecretory states,
Crohn's disease, and patients with "idiopathic" ulcers. Patients with
"idiopathic" ulcers are characterized by postprandial hypersecretion of acid and
hypergastrinemia with accelerated gastric emptying. H. pylori ulcers may be
difficult to manage because antisecretory drugs are less effective in inhibiting
gastric acidity in the absence of H. pylori infection.
PMID- 10779215
TI - Helicobacter pylori-negative peptic ulcer in Japan: which contributes most to
peptic ulcer development, Helicobacter pylori, NSAIDS or stress?
AB - Of 302 patients with peptic ulcer, 11 (3.6%) proved negative for Helicobacter
pylori: 9 with gastric ulcer (GU) and 2 with duodenal ulcer (DU). Among these 11
H. pylori-negative patients with ulcers, two with GU were using non-steroidal
anti-inflammatory drugs (NSAIDs) and one with GU was using a corticosteroid. The
Hanshin-Awaji earthquake induced life-event stress that not only triggered but
exacerbated GU, particularly in the elderly, resulting in a higher GU/DU ratio
than the corresponding period of the previous year (3.07 vs. 1.88) in the
devastated area. Furthermore, the seroprevalence of the infection and the odds
ratio from the case-control study were similar to or even higher than that
reported previously in patients with GUs unrelated to the earthquake. H. pylori
and the use of NSAIDs are the major independent risk factors for peptic ulcers,
although, H. pylori infection plays some role in the development of peptic ulcers
under stressful conditions.
PMID- 10779216
TI - Non-Helicobacter pylori ulcer disease in rheumatoid arthritis patients receiving
long-term NSAID therapy.
AB - Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are
considered the major causes of peptic ulcer. If ulcers are not attributable to H.
pylori, most are thought to be attributable to NSAIDs. We have previously
reported that rheumatoid arthritis (RA) patients taking NSAIDs long term (NSAIDs
group) are more likely to develop gastric ulcers, which commonly occur in the
gastric antrum. In addition, the morphology of gastric ulcers in the NSAIDs group
differs from that in the non-NSAIDs group (control group), in whom NSAIDs are not
involved in the occurrence of gastric ulcers. In this study, we compared gastric
ulcers in the NSAIDs group with those in the control group in terms of H. pylori
infection. The positive rate of H. pylori in gastric ulcers was significantly
lower in the NSAIDs group than in control group (53.6% vs 91.5%). At the ulcer
site they were seen significantly less often in the antrum than in either the
angle or body of the stomach (35% vs 100%) in the NSAIDs group. On the other
hand, the H. pylori-positive rate for ulcers in the antrum did not differ
significantly from that in the angle and body of the stomach (81.8% vs 93.8%) in
the control group. These findings suggest that H. pylori plays little role in
antral ulcers in those taking NSAIDs.
PMID- 10779217
TI - Helicobacter pylori: criminal or innocent bystander?
AB - Most patients with peptic ulcer disease are infected with Helicobacter pylori.
However, the infection may not be always causative for the disease. The
prevalence of H. pylori infection is about 50% in general. Therefore, half of the
patients with peptic ulcer could be infected with this microorganism just by
chance. In such cases, H. pylori may do nothing for the ulcer, although it causes
chronic active gastritis. This could be the reason for the existence of both H.
pylori-positive nonrecurring ulcers and ulcers that recur even after cure of H.
pylori infection. H. pylori-positive non-recurring ulcers should be included in
non-H. pylori ulcer disease in addition to H. pylori-negative ulcers. NSAIDs are
the major cause of H. pylori-negative ulcers, especially H. pylori-negative
gastric ulcers. However, more than 10% of ulcers recurred even after cure of H.
pylori infection in nonusers of NSAIDs in a 7-year follow-up study. In the same
study, 46% of ulcers did not recur in patients in whom eradication of H. pylori
failed. There are few (<5%) H. pylori-negative ulcers; about 10% of ulcers recur
after cure of H. pylori infection, and about 40% of H. pylori-positive ulcers do
not recur. These are all non-H. pylori ulcers, and they represent 30% of all
ulcers, which is the general prevalence rate for nonulcer subjects. Therefore, H.
pylori may be an innocent bystander in approximately one third of all ulcer
patients.
PMID- 10779218
TI - Helicobacter pylori-negative ulcer disease.
AB - The proportion of ulcer patients without evidence of Helicobacter pylori
infection varies considerably in different parts of the world, which may be
explained by the different prevalence of H. pylori infection in the background
population. In any ulcer patient with an H. pylori-negative test, it is important
to consider that the test may be falsely negative due to treatment with
antibiotics, bismuth preparations, or potent acid inhibitory therapy. The
commonest cause of true H. pylori-negative ulcers is usage of nonsteroidal anti
inflammatory drugs, so patients should be carefully questioned about such
therapy. Rarer causes of H. pylori-negative duodenal ulcers include
gastroduodenal Crohn's disease and Zollinger-Ellison syndrome. About 50% of H.
pylori-negative duodenal ulcer patients have no apparent explanation for the
ulcer disease. A proportion of these patients have increased gastric acid
secretion and increased duodenal acid load, which is likely to be of pathogenic
significance. H. pylori-negative ulcers are more difficult to control with
antisecretory drugs.
PMID- 10779219
TI - Reg protein: a possible mediator of gastrin-induced mucosal cell growth.
PMID- 10779220
TI - Molecular mechanisms for the growth factor action of gastrin.
PMID- 10779221
TI - Epithelial-mesenchymal interaction in gastric mucosal restoration.
AB - In this review article we discuss the role of growth factors in gastric ulcer
healing using an in vitro wound repair model with gastric epithelial and
mesenchymal cells. Several growth factors accelerate gastric epithelial and
mesenchymal wound healing in vitro with acceleration of cell migration and
proliferation. Epidermal growth factor, transforming growth factor-alpha
(TGFalpha), hepatocyte growth factor, and insulin accelerate predominantly
gastric epithelial wound healing; and TGFbeta and basic fibroblast growth factor
predominantly accelerate gastric mesenchymal wound healing. Platelet-derived
growth factor-betabeta and insulin-like growth factor-1 (IGF-1) accelerate both
significantly. Among these growth factors, IGF-1 produced from fibroblasts plays
a key role in the gastric epithelial-mesenchymal interaction during the process
of gastric wound healing.
PMID- 10779222
TI - Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil
peptides.
AB - The trefoil peptide family is comprised of three small peptides (designated pS2,
SP, and ITF) exhibiting a unique motif of three intrachain loops formed by
disulfide bonds. These highly protease-resistant peptides are secreted onto the
mucosal surface by goblet cells or their equivalents. Most importantly, these
factors protect epithelium from injury and promote repair through restitution
after injury has occurred. Targeted deletion of the gene encoding ITF results in
exquisite sensitivity to colonic injury by standard agents (e.g., dextran sodium
sulfate) due to an inability to repair the epithelium. Studies have led to
insight into the intracellular responses to trefoil peptides, including ras
dependent MAP kinase activation and activation of epidermal growth factor
receptor. Among other effects, activation of these pathways is associated with
redistribution of E-cadherin from the cell surface to intracellular domains,
where it is complexed with catenins, and phosphorylation of akt, inactivating
this kinase associated with apoptosis. In addition, trefoil peptides appear to
block both p53 dependent and p53 independent apoptosis through pathways
associated with activation of EGFR and P13 kinase. These observations suggest
that trefoil peptides elicit a coordinated cellular response enabling cell
migration without triggering the programmed cell death response usually
precipitated by cell detachment from a stationary anchored state.
PMID- 10779223
TI - Effects of loss-of-function and gain-of-function mutations of c-kit on the
gastrointestinal tract.
AB - Protooncogene c-kit encodes a receptor tyrosine kinase, KIT. Interstitial cells
of Cajal (ICCs) that are important for the autonomous movement of the
gastrointestinal tract essentially require the normal function of the KIT for
their development. Therefore, germline loss-of-function mutations of the c-kit
gene cause deficiency of ICCs that results in disturbed gastrointestinal
movement. On the other hand, somatic gain-of-function mutations of the c-kit gene
induce gastrointestinal stromal tumors (GIST) that are considered to originate
from ICCs. Moreover, germline gain-of-function mutations of the c-kit gene are a
cause of familial development of multiple GISTs.
PMID- 10779224
TI - Regulation of collagen alpha1(I) expression in hepatic stellate cells.
AB - The regulation of collagen alpha1(I) expression in hepatic stellate cells (HSCs)
occurs in a complex fashion that is just beginning to be determined. The presence
of regulatory sequences in both the 5' and 3' regions of the mRNA appear to be
critical to its regulation in HSCs and are involved in the increased expression
of collagen in activated HSCs. The 3' UTR contains a C-rich site that binds
alphaCP, a known RNA-binding protein that is responsible for the increased
stability of the mRNA in activated HSCs. Given that alphaCP is present in both
activated and quiescent HSCs, there must be a mechanism for modifying alpha(CP to
bind to the RNA in activated but not quiescent HSCs. The 5' region contains an
evolutionary conserved stem-loop region that encompasses the translation
initiation codon. This stem-loop can bind protein(s) in activated HSCs in an RNA
cap-dependent manner. Such binding, together with the binding of alphaCP to the
3' UTR, can facilitate translation of collagen alpha1(I) mRNA, resulting in
increased mRNA steady-state levels and collagen synthesis. A role of alphaCP in
activating translation initiation has also been demonstrated. These two
mechanisms work together to upregulate collagen alpha1(I) production in activated
but not quiescent HSCs.
PMID- 10779225
TI - Epidemiology of gastric cancer: an evaluation of available evidence.
AB - Despite a dramatic reduction in incidence and mortality rates, gastric cancer
(GC) is still one of the most common malignant neoplasias worldwide. Surgical and
medical treatments have not substantially improved during the last decades, and
large-scale early diagnosis programs have proven feasible in only one high-risk
country, Japan. A large number of studies have indicated that salted, smoked,
pickled, and preserved foods (rich in salt, nitrite, and preformed N-nitroso
compounds) are associated with an increased risk of GC. In contrast, strong
evidence has been provided that high consumption of fresh fruit and raw
vegetables and a high intake of antioxidants are associated with a reduced risk
of GC. Domestic refrigeration and reduced salt consumption are considered to play
a role in explaining the decreasing temporal trend and the geographical patterns
of GC. Familial factors have been suspected to play a role in GC susceptibility,
and recently germ line mutations in the E-cadherin gene were identified in a few
families. Evidence of a positive association between Helicobacter pylori
infection and GC risk has been provided by most prospective studies that overall
suggest a two- to threefold increase in risk. Randomized intervention studies on
H. pylori eradication and its effects on GC predisposing conditions (atrophic
gastritis and intestinal metaplasia) are in progress and represent a priority for
epidemiological research in view of the potential preventive applications.
Overall, it is evident that several factors (including diet, individual
susceptibility and H. pylori infection) interact in a complex multifactorial
process, leading over a long period of time to GC.
PMID- 10779226
TI - Helicobacter pylori infection is the primary cause of gastric cancer.
AB - Helicobacter pylori causes gastric cancer in human and in experimental animals.
The link between gastritis and H. pylori is causal. Differences in the incidence
of gastric cancer in populations with similar high prevalence of H. pylori
infection can be related to the differences in the age of acquisition of chronic
atrophic gastritis, which in turn is related to an interaction between
environmental factors, especially diet, and H. pylori infection. The low odds
ratios reported in epidemiology studies evaluating the relation between gastric
cancer and H. pylori infection reflect the high overall prevalence of H. pylori
in the population and do not accurately reflect the strength of the association.
It is time to stop doing serologic studies to confirm the association of gastric
cancer with H. pylori and instead expend our efforts on eliminating the infection
and investigating the mechanism(s) and interactions.
PMID- 10779227
TI - Helicobacter pylori gastritis of the gastric carcinoma phenotype: is histology
capable of identifying high-risk gastritis?
AB - Several studies have shown that Helicobacter pylori infection implies an
increased risk for developing gastric carcinoma. However, it has to be considered
that only a few among those infected with H. pylori develop gastric cancer. It is
therefore desirable to identify risk indicators of H. pylori gastritis in the
presence of which gastric carcinoma is most likely to occur. In our view, the
risk indicators intestinal metaplasia and atrophy, frequently cited in the
literature, are not suitable, as they are focal changes whose detection at the
routine diagnostic workup may be confounded by sampling error and because early
carcinoma (in particular of the diffuse type) is often not associated with
intestinal metaplasia or atrophy. For this reason we investigated the diffuse
gastritis parameters "grade of gastritis" and "activity of gastritis" for their
suitability as risk indicators. We found that H. pylori gastritis, particularly
in the corpus, is significantly more pronounced in gastric carcinoma patients or
individuals with a family history of gastric cancer than in matched controls.
Hence, a simple comparison of the grade of gastritis and activity of gastritis in
the antrum and corpus might help identify patients with H. pylori gastritis with
an increased cancer risk. Currently. we are testing this hypothesis in an ongoing
gastric cancer prevention study in Germany, Austria, and Czechia.
PMID- 10779228
TI - International comparability of the pathological diagnosis for early cancer of the
digestive tract: Munich meeting.
AB - Large differences have been found between Western and Japanese pathologists'
diagnosis of adenoma/dysplasia versus early carcinoma for gastric, esophageal.
and colorectal epithelial neoplastic lesions. In this study we examined whether
differences in experience in gastrointestinal pathology can to some extent
explain these differences in diagnostic practice. Three Japanese, one British,
and two German pathologists with much experience and one North American
pathologist with less experience in routine diagnostic work reviewed 52
microscopic slides: 16 gastric, 24 esophageal, and 12 colorectal biopsy and
resection specimens obtained from patients with lesions ranging from early
carcinoma to adenoma, dysplasia, and regenerative epithelium. The extent of
agreement between the diagnoses of the four individual Western pathologists and
the most common Japanese diagnoses was assessed by kappa statistics. For the 16
gastric lesions, a diagnosis of suspected or definite carcinoma was made by the
Japanese pathologists in 69%-75% of the slides, by three experienced Western
pathologists in 56%-63% (high kappa values: 0.61, 0.64, 0.65), and by the less
experienced Western pathologist in only 31% of the slides (low kappa value:
0.10). For the 24 specimens of esophageal squamous lesions, carcinoma in situ and
suspected or definite carcinoma were diagnosed by the Japanese in 96%-100% and by
the Western pathologists in 63%-88% of the slides (low kappa values: 0.17, 0.25,
0.25, 0.27). For the 12 colorectal lesions, the Japanese diagnosed suspected or
definite carcinoma in 58%-83%, whereas all Western pathologists followed the
World Health Organization definition of colorectal carcinoma and diagnosed
suspected or definite carcinoma in only 0-42% of the slides (kappa values: 0.04,
0.10,0.12, 0.49). In conclusion, there were few differences in diagnoses between
experienced Western and Japanese pathologists for gastric lesions but
considerable differences for esophageal and colorectal lesions. The differences
in the diagnosis of adenoma/dysplasia versus early carcinoma between Western and
Japanese pathologists found in previous studies may in large part be attributable
to differences in experience with regard to gastric neoplasia and to differences
in interpretation and nomenclature with regard to esophageal and colorectal
neoplasia.
PMID- 10779229
TI - Genetic and epigenetic alterations in multistep carcinogenesis of the stomach.
AB - An accumulation of multiple genetic and epigenetic alterations of oncogenes,
tumor suppressor genes, DNA repair genes, cell cycle regulators, cell adhesion
molecules, and the growth factor/receptor system is involved in the course of
multistep conversion of normal epithelial cells to clinical gastric cancer. Some
of them differ depending on the histological type, well-differentiated
(intestinal) and poorly differentiated (diffuse) types, suggesting the presence
of two distinct genetic pathways. Genetic instability, chromosomal instability
(telomere reduction), and immortality (activation of telomerase and expression of
telomerase reverse transcriptase: TERT) participate in the initial step of
stomach carcinogenesis. Because TERT protein expression precedes the telomerase
activities in precancerous lesions, TERT expression may be a prerequisite for
telomerase activation. The cyclin E gene is amplified in 15%-20% of gastric
cancer. Reduced expression of a cyclin-dependent kinase (CDK) inhibitor, p27Kip1,
is frequently found in gastric cancer associated with high grade malignancy. E2F
1, an important downstream target of cyclins/CDKs, is overexpressed in about 40%
of gastric carcinomas, whereas gene amplification of E2F-1 rarely occurs. Loss of
heterozygosity (LOH) of p73, the p53-related new tumor suppressor gene,
preferentially occurs in well-differentiated adenocarcinomas of foveolar type
expressing pS2, a gastric-specific trefoil factor, indicating the importance of
p73 LOH in the genesis.
PMID- 10779230
TI - What is reasonable treatment for gastric adenocarcinoma?
AB - From its pattern of metastasis and recurrence, gastric carcinoma can be
recognized as a slow-growing malignancy whose local control is still the most
important part of treatment. With application of asymptomatic population
screening and awareness of the high risk of this disease among the general
population in Japan, many early lesions and even noninvasive cancers have been
detected. For such tumors as noninvasive ductal carcinoma of the breast, local
resection has become the popular treatment, and endoscopic mucosal resection is
used for many early lesions. For advanced cancers, extended lymph node dissection
has been applied in Japan and some other countries. The treatment results have
improved remarkably in these countries. There are several reasonable explanations
for the effectiveness of extended nodal dissection, but it is still controversial
because of reported excessive postoperative morbidity and mortality and lack of
proof in a randomized controlled trial. The Dutch Gastric Cancer Trial could not
prove the benefit of extended lymph node dissection, although some data suggest
its benefit over limited dissection. Further clinical trials seem necessary to
evaluate its value in Western countries, but such trials should be carried out in
limited specialist centers to exclude technical bias of two types of operation.
PMID- 10779231
TI - Detailed colonoscopy for detecting early superficial carcinoma: recent
developments.
AB - Early superficial colorectal carcinoma (CRC) has been commonly detected by
routine colonoscopic examination in Japan. A series of 769 early CRCs and 4821
adenomas were diagnosed by colonoscopy at Hiroshima University Medical Hospital
between 1991 and 1998. Of early CRCs, macroscopically superficial early CRCs
accounted for 209 lesions (28%). Among 5590 lesions of adenomas and carcinomas,
depressed-type lesions showed a significantly higher malignant potential for
cancerous and submucosal invasion than elevated lesions (polypoid, IIa-type
lesions, and G-LST). As one of the quantitative examinations for early CRC, pit
pattern observed by magnifying video-colonoscopy was useful. We performed
magnifying observations for 265 lesions of colorectal neoplasias using Kudo's pit
pattern classification for 2 years. Depressed-type lesions characterized the Ills
and V pit patterns, and elevated lesions characterized the III(L) pit pattern.
The incidence of cancer was significantly higher in lesions with IIIs and V pit
patterns. Furthermore, the V(N) pit pattern was considered a significant
indicator of submucosal invasion. These results indicated that superficial early
CRC could be considered to constitute about one-third of all early CRCs. Of them,
the depressed-type lesions showed a significantly higher malignant potential than
elevated lesions. Pit pattern observation by magnifying videocolonoscopy is
useful for predicting the histology/invasion depth of early CRC.
PMID- 10779232
TI - How does surgical technique affect outcomes in rectal cancer?
PMID- 10779233
TI - Significance and limit of lymph node dissection: efficacy of combined modalities.
PMID- 10779234
TI - Recent advances in colorectal chemotherapy: oral fluorinated pyrimidines,
oxaliplatin and irinotecan.
PMID- 10779235
TI - New drugs for colorectal cancer based on Japanese experience.
PMID- 10779237
TI - Contraceptive use in Canada: 1984-1995.
AB - CONTEXT: In every country, contraceptive behavior has important implications for
fertility and the prevalence of sexually transmitted diseases (STDs). There has
been relatively little attention to contraceptive practices in Canada, however,
particularly how patterns of method use may have changed. METHODS: Data on
contraceptive use were collected from 5,315 women in the 1984 Canadian Fertility
Survey, and from 3,220 women and 3,449 men in the 1995 General Social Survey.
RESULTS: Among Canadian women aged 15-49, current contraceptive use declined from
69% to 60% between 1984 and 1995. Pill use dropped from 19% to 17%, and IUD use
declined from 6% to 3%. However, during the same period, condom use increased
from 6% to 10%; tubal ligation declined from 24% to 17%, while vasectomy
increased. In addition, the proportion of women sterilized for reasons other than
contraception rose between 1984 and 1995. Men were less likely to rely on
sterilization than were women (31 % vs. 40%). Men reported higher levels of
condom use (22%), but lower levels of pill use among their partners (9%), than
did women (10% and 17%, respectively). CONCLUSIONS: Contraceptive behavior in
Canada is unique: The decline in contraceptive use over the last decade has left
Canada's overall contraceptive prevalence among the lowest in the industrialized
world, and the rate of sterilization among the highest These changes in
contraceptive behavior complicate efforts to plan for social and health needs,
particularly policy decisions focusing on reducing infections with STDs.
PMID- 10779236
TI - Psychosocial factors and the timing of prenatal care among women in New Jersey's
HealthStart program.
AB - CONTEXT: Helping high-risk pregnant women obtain prenatal care early is the main
policy goal of most U.S. publicly funded programs aimed at reducing the incidence
of low birth weight and infant mortality It is therefore crucial to understand
the factors that influence when women initiate prenatal care. METHODS: The
effects of psychosocial and demographic risk factors on the timing of entry into
prenatal care were estimated using data on roughly 90,000 Medicaid recipients who
participated in New Jersey's HealthStart prenatal care program. RESULTS: Overall,
37% of women began prenatal care in the first trimester. Multivariate logistic
regression indicated that women who lived in poor housing conditions and those
who smoked, drank or used hard drugs had a reduced likelihood of entering care
early (odds ratios, 0.8-0.9), while those who had clinical depression or who
experienced domestic violence or abuse had elevated odds of early entry (1.1
1.2). The risk factor with the greatest impact on the timing of prenatal care was
the wantedness of the pregnancy; women whose pregnancy was unwanted had
dramatically reduced odds of entering care early (0.4). Separate analyses of
women of varying racial and ethnic backgrounds demonstrated the differential
effects of risk factors, the importance of including ethnicity with race and the
universal impact of wantedness across racial and ethnic groups. CONCLUSIONS:
Entry into prenatal care for at-risk women is affected by factors from multiple
domains. It is important for prenatal programs to recognize the complexity of the
issue as well as the barriers that different subgroups of women face.
PMID- 10779238
TI - Are there unmet family planning needs in Europe?
AB - CONTEXT: The measurement of unmet need for family planning--the discrepancy
between individuals' sexual and contraceptive behavior and their stated fertility
preferences--has generally focused on developing countries. There has so far been
little effort to measure how low unmet family planning needs can go in more
developed countries, where contraceptive practice is supposedly (nearly) perfect.
METHODS: Data were taken from Fertility and Family Surveys (FFS) conducted in
recent years in selected member states of the United Nations Economic Commission
for Europe, and minimum and maximum estimates of unmet need were calculated for
10 countries with the requisite data. RESULTS: The proportion of individuals with
an unmet need for family planning (i.e., who have a current unwanted pregnancy or
who are fecund, are sexually active, want no more births but are not using
contraceptives) is as low as 3% in two European countries and below 10% in most.
However, levels of unmet need in countries with economies in transition (13% in
Latvia and Lithuania and 23% in Bulgaria) surpass some of the lowest levels
observed for developing countries. Considerable within-country variations are
seen. For instance, unmet need is more prominent among men than among women in
seven of the nine countries for which there are data. Moreover, unmet need
increases with family size and with age, suggesting an unmet need for limiting
rather than for spacing births. In all of the countries except Hungary, unmet
need is higher among those in marital unions than among those in less formal
relationships. Level of education is another important dimension of unmet need,
with less-educated respondents having the highest level of unmet need in nine of
the 10 countries. Multivariate analyses confirm most of these results. Moreover,
there is a clear association between unmet need and abortion ratios: Where levels
of unmet need are high, the number of abortions per 100 live births is also
relatively high. CONCLUSIONS: Data on unmet need, supplemented with information
on induced abortion and related issues, could provide countries in Europe with
useful inputs for formulating and implementing responsive reproductive health
policies and programs.
PMID- 10779240
TI - The pill at 40--a new look at a familiar method. Whose pill is it, anyway?
PMID- 10779241
TI - The pill at 40--a new look at a familiar method. The pill and men's involvement
in contraception.
PMID- 10779239
TI - Relationship dynamics, ethnicity and condom use among low-income women.
AB - CONTEXT: Women's protection against HIV and sexually transmitted diseases (STDs)
depends upon their ability to negotiate safer sex. It is important to know how
cultural norms and gender roles, which vary by ethnicity, may either constrain or
encourage negotiation of condom use. METHODS: Questionnaires were completed by
393 low-income non-Hispanic black, Hispanic and non-Hispanic white women who were
sexually active and attending family planning and STD clinics and other public
health and social service centers in Miami in 1994 and 1995. Multivariate logit
techniques were used to identify ethnic differences in relationship dynamics and
to determine couple- and individual-level factors associated with consistent use,
occasional use or nonuse of condoms. RESULTS: Black and Hispanic women reported
higher levels of consistent condom use (15-17%) than did white women (4%). Nearly
all black and white women (90-95%) said that they were extremely or somewhat
comfortable talking about condoms with their partner, whereas 76% of Hispanic
women did so. A larger proportion of Hispanic women (55%) reported joint
contraceptive decision-making than did black women (26%) or white women (31%).
Among women who reported that their partner made contraceptive decisions, 28%
used condoms consistently or occasionally, compared with 24% among women who made
the decision themselves. When the couple made the decision jointly, 41% of them
were condom users. Hispanic women scored the lowest on a scale of condom-related
self-efficacy, yet also reported the highest levels of confidence in their condom
negotiating skills. Multivariate analysis indicated that, compared with white
women, black and Hispanic women were more likely to be consistent condom users
than nonusers (odds ratios, 10.2 and 18.9, respectively). Women who shared
financial decision-making with their partner were almost 80% less likely to be a
consistent condom user, and women who did not participate in financial decisions
were more than 90% less likely to do so, than were women who made monetary
decisions independently. CONCLUSIONS: HIV prevention and intervention programs
should emphasize birth control discussion between partners and the development of
condom-related self-efficacy and negotiation skills, and these programs also
should customize prevention messages according to ethnicity and social context.
PMID- 10779242
TI - The pill at 40--a new look at a familiar method. Mothers, daughters and the pill.
PMID- 10779243
TI - The pill at 40--a new look at a familiar method. Black women and the pill.
PMID- 10779245
TI - Evidence-based preventive care: a timely matter.
PMID- 10779244
TI - The pill at 40--a new look at a familiar method. Will the pill become obsolete in
this century?
PMID- 10779246
TI - Tympanocentesis: to tap or not to tap.
PMID- 10779247
TI - Nightmares and disorders of dreaming.
AB - Dreams occur during all stages of sleep. Nightmares are common. They can be
associated with poor sleep and diminished daytime performance. Frequent
nightmares are not related to underlying psychopathology in most children and in
some "creative" adults. However, recurrent nightmares are the most defining
symptom of post-traumatic stress disorder and may be associated with other
psychiatric illnesses. Night terrors are arousal disorders that occur most often
in children and usually occur early in the sleep period. Patients with rapid-eye
movement behavior disorder often present with nocturnal injury resulting from the
acting out of dreams. Dream disorders may respond to medication, but behavioral
treatment approaches have shown excellent results, particularly in patients with
post-traumatic stress disorder and recurrent nightmares.
PMID- 10779248
TI - Acute otitis media: Part I. Improving diagnostic accuracy.
AB - Acute otitis media is overdiagnosed. Symptoms are neither sensitive nor specific
for the diagnosis of otitis media; fever and ear pain are present in only one
half of patients. Undue reliance on one feature--redness of the tympanic membrane
-and failure to assess tympanic membrane mobility with pneumatic otoscopy
contribute to inaccurate diagnoses. Adequate visualization of the tympanic
membrane is often impaired by low light output from old otoscope bulbs and
blockage of the ear canal by cerumen. Distinguishing acute otitis media from
otitis media with effusion is clinically important because antibiotics are seldom
indicated for the latter condition. A key differentiating feature is the position
of the tympanic membrane: it is usually bulging in acute otitis media and in a
neutral position or a retracted position in otitis media with effusion.
Tympanometry and acoustic reflectometry can be useful adjunctive tools to confirm
the presence of fluid in the middle ear. Selective use of tympanocentesis in
cases of refractory or recurrent middle ear disease can help guide appropriate
therapy and avoid unnecessary medical or surgical interventions.
PMID- 10779249
TI - Management of giant cell arteritis and polymyalgia rheumatica.
AB - Giant cell arteritis and polymyalgia rheumatica are closely related disorders
that affect persons more than 50 years of age and cause substantial morbidity.
Patients with giant cell arteritis typically have a localized headache,
nonspecific systemic symptoms, temporal artery tenderness and a high erythrocyte
sedimentation rate (ESR). The diagnosis is confirmed by characteristic pathologic
findings on temporal artery biopsy. Patients with polymyalgia rheumatica usually
have similar nonspecific systemic symptoms, proximal muscle pain and stiffness,
and an elevated ESR. The diagnosis is based on the clinical findings. Both
disorders are treated with corticosteroids: high dosages for giant cell arteritis
(prednisone in a dosage of 40 to 60 mg per day) and lower dosages for polymyalgia
rheumatica (prednisone in a dosage of 10 to 20 mg per day). Symptom relief in
response to treatment is rapid and reinforces the diagnosis. After normalization
of the ESR, the corticosteroid is tapered, with the patient monitored closely for
symptom recurrence. Most patients require corticosteroid therapy for two to three
years and experience one or more treatment complications.
PMID- 10779250
TI - Acute renal failure.
AB - Acute renal failure occurs in 5 percent of hospitalized patients. Etiologically,
this common condition can be categorized as prerenal, intrinsic or postrenal.
Most patients have prerenal acute renal failure or acute tubular necrosis (a type
of intrinsic acute renal failure that is usually caused by ischemia or toxins).
Using a systematic approach, physicians can determine the cause of acute renal
failure in most patients. This approach includes a thorough history and physical
examination, blood tests, urine studies and a renal ultrasound examination. In
certain situations, such as when a patient has glomerular disease, microvascular
disease or obstructive disease, rapid diagnosis and treatment are necessary to
prevent permanent renal damage. By maintaining euvolemia, recognizing patients
who are at increased risk and minimizing exposure to nephrotoxins, physicians can
decrease the incidence of acute renal failure. Once acute renal failure develops,
supportive therapy is critical to maintain fluid and electrolyte balances,
minimize nitrogenous waste production and sustain nutrition. Death is most often
caused by infection or cardiorespiratory complications.
PMID- 10779251
TI - Promoting and supporting breast-feeding.
AB - The family physician can significantly influence a mother's decision to breast
feed. Prenatal support, hospital management and subsequent pediatric and maternal
visits are all-important components of breast-feeding promotion. Prenatal
encouragement increases breast-feeding rates and identifies potential problem
areas. Hospital practices should focus on rooming-in, early and frequent breast
feeding, skilled support and avoidance of artificial nipples, pacifiers and
formula. Infant follow-up should be two to four days postdischarge, with liberal
use of referral and support groups, including lactation consultants and peer
counselors.
PMID- 10779252
TI - Hip pain in athletes.
AB - Hip pain in athletes involves a wide differential diagnosis. Adolescents and
young adults are at particular risk for various apophyseal and epiphyseal
injuries due to lack of ossification of these cartilaginous growth plates. Older
athletes are more likely to present with tendinitis in these areas because their
growth plates have closed. Several bursae in the hip area are prone to
inflammation. The trochanteric bursa is the most commonly injured, and the lesion
is easily identified by palpation of the area. Iliotibial band syndrome presents
with similar lateral hip pain and may be identified by provocative testing
(Ober's test). A methodical physical examination that specifically tests the
various muscle groups that move the hip joint can help determine a more specific
diagnosis for the often vague complaint of hip pain. A number of hip conditions
are more prevalent in athletes of certain ages. Transient synovitis is a common
diagnosis in the very young, Legg-Calve-Perthes disease causes bony disruption of
the femoral head in prepubescents, and slipped capital femoral epiphysis is seen
most commonly in obese adolescent males. Femoral neck stress fractures are seen
in adult athletes, especially those involved in endurance sports, and can
progress to necrosis of the femoral head if not found early. Older athletes may
be limited by degenerative joint disease but nonetheless should be encouraged to
stay active.
PMID- 10779253
TI - Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives.
AB - Benzodiazepines are widely prescribed for a variety of conditions, particularly
anxiety and insomnia. They are relatively safe and, with overdose, rarely result
in death. However, used chronically, benzodiazepines can be addicting. These
agents are often taken in combination with other drugs of abuse by patients with
addiction disorders. In such patients, alternatives to benzodiazepines may be
preferable and may include antidepressants, anticonvulsants, buspirone,
antihypertensive agents and the newer neuroleptic medications. Caution must be
used when prescribing benzodiazepines to patients with a current or remote
history of substance abuse.
PMID- 10779254
TI - Drug therapy for obesity.
AB - Obesity is a common health problem in the United States, and effective treatment
is challenging. Obesity is associated with an increased mortality rate and risk
factors such as hypertension, hyperlipidemia and diabetes mellitus. Numerous
treatments are available for obesity. Behavioral therapy, surgery and
pharmacologic treatment have been used with varying degrees of success. Older
anorectic agents have significant side effects and limited benefit, and some have
even been withdrawn from the U.S. market because of a possible association with
cardiovascular complications. The safety of newer agents must be extensively
evaluated before widespread use is recommended. Therefore, behavioral therapy,
including regular exercise and the development of healthy eating habits,
continues to be the best treatment for long-term weight loss.
PMID- 10779255
TI - Recognition of common childhood malignancies.
AB - Although cancer has an annual incidence of only about 150 new cases per 1 million
U.S. children, it is the second leading cause of childhood deaths. Early
detection and prompt therapy have the potential to reduce mortality. Leukemias,
lymphomas and central nervous system tumors account for more than one half of new
cancer cases in children. Early in the disease, leukemia may cause nonspecific
symptoms similar to those of a viral infection. Leukemia should be suspected if
persistent vague symptoms are accompanied by evidence of abnormal bleeding, bone
pain, lymphadenopathy or hepatosplenomegaly. The presenting symptoms of a brain
tumor may include elevated intracranial pressure, nerve abnormalities and
seizures. A spinal tumor often presents with signs and symptoms of spinal cord
compression. In children, lymphoma may present as one or more painless masses,
often in the neck, accompanied by signs and symptoms resulting from local
compression, as well as signs and symptoms of systemic disturbances, such as
fever and weight loss. A neuroblastoma may arise from sympathetic nervous tissue
anywhere in the body, but this tumor most often develops in the abdomen. The
presentation depends on the local effects of the solid tumor and any metastases.
An abdominal mass in a child may also be due to Wilms' tumor. This neoplasm may
present with renal signs and symptoms, such as hypertension, hematuria and
abdominal pain. A tumor of the musculoskeletal system is often first detected
when trauma appears to cause pain and dysfunction out of proportion to the
injury. Primary care physicians should be alert for possible presenting signs and
symptoms of childhood malignancy, particularly in patients with Down syndrome or
other congenital and familial conditions associated with an increased risk of
cancer.
PMID- 10779256
TI - Falls in the elderly.
AB - Falls are the leading cause of injury-related visits to emergency departments in
the United States and the primary etiology of accidental deaths in persons over
the age of 65 years. The mortality rate for falls increases dramatically with age
in both sexes and in all racial and ethnic groups, with falls accounting for 70
percent of accidental deaths in persons 75 years of age and older. Falls can be
markers of poor health and declining function, and they are often associated with
significant morbidity. More than 90 percent of hip fractures occur as a result of
falls, with most of these fractures occurring in persons over 70 years of age.
One third of community-dwelling elderly persons and 60 percent of nursing home
residents fall each year. Risk factors for falls in the elderly include
increasing age, medication use, cognitive impairment and sensory deficits.
Outpatient evaluation of a patient who has fallen includes a focused history with
an emphasis on medications, a directed physical examination and simple tests of
postural control and overall physical function. Treatment is directed at the
underlying cause of the fall and can return the patient to baseline function.
PMID- 10779257
TI - Just a scar?
PMID- 10779258
TI - A potentially violent patient?
PMID- 10779259
TI - Adult immunization--pneumococcal vaccine.
PMID- 10779260
TI - ACIP recommendations for the prevention of hepatitis A through immunization.
Advisory Committee on Immunization Practices.
PMID- 10779261
TI - The Antiretroviral Pregnancy Registry Interim Report.
PMID- 10779262
TI - Management of essential infantile esotropia with botulinum toxin A: review and
recommendations.
PMID- 10779263
TI - The feasibility of introducing a visual screening test for children during
vaccination campaigns.
AB - PURPOSE: A visual screening test for children was prepared for the use of
paramedics during vaccination campaigns. This test was used in a vaccination
campaign in Taquaritinga, Sao Paulo, Brazil. METHODS: The campaign was carried
out by two paramedics trained by ophthalmologists. The first 130 children
vaccinated whose families showed interest in participating in the visual
screening program were chosen. The program consisted of demographic information
and eight questions, a visual screening test for children >4 years, and an
external eye examination. After studying the data collected, the paramedic
decided if the child needed a more thorough ophthalmologic examination. RESULTS:
Of the 4505 children vaccinated, 130 children participated in the screening test.
One (76.9%) hundred of the 130 children were reexamined by ophthalmologists. Of
these, 38 (29.2%) were initially considered to have visual disorders.
Ophthalmologic disorders were confirmed in 22 (57.9%) children; of these, 3 were
already under ophthalmologic care. The paramedics correctly screened a total of
77 (77%) children. CONCLUSION: Visual screening during vaccination campaigns is
simple and rapid, and provides the opportunity to identify children with visual
disorders during the critical stage of visual development without the need of
ophthalmologists.
PMID- 10779264
TI - Abnormal function of the parvocellular visual system in anisometropic amblyopia.
AB - PURPOSE: To study the function of the parvocellular (P) and the magnocellular (M)
visual systems with steady-state visual evoked potentials (VEPs) in anisometropic
amblyopes. METHODS: A matrix of isolated checks was superimposed on a steady
background with different check sizes and temporal frequencies to form specific
stimuli to preferentially activate the P or the M visual system. The amplitude of
the VEP fundamental frequency was analyzed at the electrode Oz of 5 anisometropic
amblyopes and 22 normal subjects. The normal subjects were tested at two visual
acuity (VA) levels, 20/20 and 20/40, modified by lenses, to match with the VA
levels of the fellow eyes and the amblyopic eyes of the amblyopes, respectively.
RESULTS: No significant amplitude difference was found between the dominant eyes
and nondominant eyes of the normal subjects for either P or M stimuli at both
20/20 and 20/40 VA levels (P>.05). No significant amplitude difference was found
between the fellow eyes of the amblyopes and the dominant eyes of normals for
either P or M stimuli at 20/20 VA level (P>.05). A significant amplitude
difference was found between the amblyopic eyes and the nondominant eyes of the
normals for P stimuli (P<.05) but not for M stimuli (P>.05) at 20/40 VA level.
CONCLUSIONS: The amplitude of the VEP fundamental frequency was selectively
reduced for P stimuli in anisometropic amblyopic eyes. This clinical
electrophysiologic finding confirms that only the function of the P visual system
is abnormal in anisometropic amblyopic eyes.
PMID- 10779265
TI - Relationship between serum inositol concentration and development of retinopathy
of prematurity: a prospective study.
AB - PURPOSE: To examine the relationship between the intake of sugar inositol, serum
inositol levels, and ROP in three groups of low birthweight infants receiving
feedings containing various concentrations of inositol. METHODS: Infants with a
birthweight <1500 g, with severe lung disease, were eligible for the study when
they began enteral feedings. Infant formulas contained three different inositol
concentrations: 2500, 710, and 242 micromol/L. Serum inositol concentrations were
averaged over specific time intervals. A logistic regression model was used to
investigate the confounding effect of duration of mechanical ventilation and
oxygen therapy, birthweight, Apgar score, and serum inositol concentration on
development of ROP. RESULTS: Infants receiving high inositol formula and with
higher serum inositol concentrations at birth and after 30 days had a
statistically significant lower incidence of severe ROP than those receiving the
lower inositol formula and with lower serum concentrations (P<.05). The effective
serum inositol concentration (EC90) associated with lesser disease was >215
micromol/L. By logistic regression, the odds of developing severe ROP were
greater among infants with low serum inositol concentration (odds ratio=4.7, 95%
confidence interval 0.90-24.8, P=.017). CONCLUSION: Inositol supplementation may
help prevent the most severe form of ROP.
PMID- 10779266
TI - Incidence and survival characteristics of retinoblastoma in Singapore from 1968
1995.
AB - PURPOSE: To describe the incidence and survival of 69 Singapore residents with
retinoblastoma in all Singapore hospitals from 1968-1995. METHODS: Data of all
Singapore residents diagnosed with retinoblastoma from 1968-1995 were collected
by the Singapore Cancer Registry based on notifications from physicians,
pathology records, hospital discharge records, and death certificates. The
medical records of 46 patients were traced, and information on laterality of
tumor, spread of tumor, mode of treatment, and family history of retinoblastoma
was obtained. Time trends and survival characteristics of the cohort were
described. RESULTS: The incidence rate of retinoblastoma was 2.4 per 1 million
for children <9 years and 11.1 per 1 million for children <5 years. The incidence
of retinoblastoma has been almost uniform over time from 1968-1995, except for an
apparent increase in 1988-1992. The 3-year survival rate for retinoblastoma was
83%. Survival rates were higher in children <2 years because children who present
at a younger age may have tumors diagnosed at earlier stages of the disease.
There was no difference in survival rates for sex, race, laterality, family
history of retinoblastoma, treatment, or year of diagnosis. CONCLUSION:
Retinoblastoma is the most common eye cancer in children that may cause blindness
or death. The incidence rates of retinoblastoma in Singapore have remained fairly
stable over 28 years, and the survival rate is higher in younger children. This
study will be helpful in monitoring future disease patterns in Asian populations.
PMID- 10779268
TI - Nasolacrimal duct obstruction.
PMID- 10779267
TI - Evaluation of hemodynamic changes in the ophthalmic artery with color Doppler
ultrasonography after strabismus surgery.
AB - PURPOSE: To investigate the blood flow changes in ophthalmic artery with color
Doppler ultrasonography after strabismus surgery. METHODS: Twenty eyes of 19
patients who underwent recession or resection surgery on two horizontal rectus
muscles in 1 eye were examined using color Doppler ultrasonography preoperatively
and 1 week and 1 month postoperatively. Measurements from both eyes of 16 age-
and sex-matched normal subjects served as control data. The systolic maximum
velocity, mean velocity, end-diastolic velocity, pulsatility index, and
resistance index of the ophthalmic artery were determined. The Mann-Whitney U
test was performed for comparison of the control and study group preoperatively
for any hemodynamic parameter. Statistical comparison of the preoperative and
postoperative measures in the study group was performed with Friedman's two-way
analysis of variance. RESULTS: No difference (P>.05) was observed preoperatively
between the study and control groups for any hemodynamic parameter in the
ophthalmic artery. Although the ophthalmic artery showed a slight increase in
systolic maximum velocity 1 month postoperatively, there were no statistically
significant differences (P>.05) in velocities or resistance in the ophthalmic
artery at any interval. CONCLUSION: Two horizontal rectus muscle operations in a
previously unoperated eye do not cause significant hemodynamic changes in the
ophthalmic artery. However, further studies are needed to obtain more information
about the effect of multiple vertical rectus muscle operations on the blood flow
parameters of the ophthalmic artery.
PMID- 10779269
TI - 10-year-old boy with Duane syndrome OS.
PMID- 10779270
TI - Cataract as an additional sign in CHARGE syndrome.
PMID- 10779271
TI - Retinoblastoma in a patient with Lowe's syndrome.
PMID- 10779272
TI - Traumatic vitreous hemorrhage from a persistent hyaloid artery.
PMID- 10779273
TI - Atypical chorioretinitis as an early presentation of subacute sclerosing
panencephalitis.
PMID- 10779274
TI - Kawasaki disease presenting as orbital cellulitis.
PMID- 10779275
TI - The effect of gender on the prevalence of atopy and asthma.
PMID- 10779276
TI - Bronchial hyperresponsiveness and its relationship to asthma in childhood.
PMID- 10779277
TI - Comparison of mechanisms of IL-3 induced histamine release and IL-3 priming
effect on human basophils.
AB - We have investigated the mechanisms by which interleukin-3 (IL-3) induces
histamine release and primes basophils for increased histamine release in
response to anti-IgE- and N-formyl-methionyl-leucyl-phenylalanine (fMLP). The
responsiveness of basophils from atopic donors was variable, only 5/11 subjects
showing release of > 10%, to IL-3 in the range 0.1-100 ng/ml. IL-3-induced
histamine release required both extracellular Ca2+ and cell membrane IgE, removal
of membrane IgE by lactate stripping or desensitization of basophils by
incubation with anti-IgE in a Ca2+-free medium blocking IL-3-induced histamine
release. IL-3 also primed basophils for histamine release by anti-IgE and fMLP in
the same concentration range as it evoked histamine release. When IL-3 and either
anti-IgE or fMLP were combined, the result was additive or supra-additive
depending on the basophil donor. Unlike IL-3-evoked histamine release, IL-3
priming of basophils for fMLP-induced histamine release was shown to be
independent of the presence of both cell surface IgE and of extracellular
calcium. The protein kinase C (PKC) inhibitor, staurosporine (10 nM), inhibited
anti-IgE induced histamine release, but neither IL-3 induced histamine release
nor IL-3 priming of IgE- and fMLP-induced histamine release. Pertussis toxin (1.0
microg/ml) inhibited fMLP-induced histamine release but not anti-IgE-induced
histamine release, IL-3-evoked histamine release or IL-3 priming. These results
indicate that IL-3 modulates mediator release from human basophils by two
mechanisms; a direct release of histamine which involves cell surface IgE and the
influx of extracellular calcium but which is unlikely to proceed by the same
mechanism as cross-linkage of IgE, and a priming effect which is independent of
IgE and extracellular Ca2+ and which enhances the secretory effects of a wide
range of unrelated secretagogues.
PMID- 10779278
TI - Annual variations in grass pollen seasons in London 1961-1990: trends and
forecast models.
AB - The record of daily average grass pollen concentrations monitored at St Mary's
Hospital, Paddington, London, U.K. since 1961 is the longest duration pollen data
set in Europe. Analysis of the results identifies the trends and characteristics
of grass pollen seasons over three decades. During this time seasonal allergic
rhinitis has increased significantly in Britain. The annual start dates, length
of season and severity are examined in relation to the main meteorological
variables of cumulated temperatures above 5.5 degrees C and precipitation
measured at one site within London and two in the surrounding rural areas. Land
use changes are also considered. Significant decreases have taken place in both
the duration and severity of the seasons, particularly between the 1960s and the
early 1970s but also through the last 20 yr. This is largely a result of a
decrease in pollen abundance in the region. The decline in pollen counts has
slowed in recent years due to the increase in flowering grasses caused by the set
aside policy and by uncut verges. Grass pollen seasons have tended to start later
over the last two decades, despite an increase in the cumulated temperature
profiles during late winter and spring. Empirical models have been developed
using multiple regressions to incorporate meteorological and pollen data for the
last 20 yr in order to forecast the start dates, duration and severity of the
grass pollen seasons. These models were applied successfully using the data for
1991 and 1992. Predictions of the main characteristics of the pollen seasons can
be obtained relatively early in the year through the use of these models by
employing the monthly weather forecasts in conjunction with long-term average
weather profiles.
PMID- 10779279
TI - Identification of basophils by immunohistochemistry in the airways of post-mortem
cases of fatal asthma.
AB - There is increasing evidence for the role of basophils in the pathogenesis of
bronchial asthma. To examine the presence of basophils in the airways of patients
with fatal asthma by immunohistochemistry, we stained lung tissues from four post
mortem cases who had died from severe asthmatic attacks and four controls with a
monoclonal antibody raised against tryptase (AA-1) and anti-IgE. Mast cells and
basophils were identified in the bronchioles as AA-1- and anti-IgE-positive
cells, and anti-IgE-positive cells, respectively. Airway mast cells were found
beneath the basement membrane, near blood vessels in the submucosa, and adjacent
to the submucosal glands, and scattered throughout the muscle bundles. There was
a significant increase of mast cells in the asthma group compared with the
control group (203.5+/-84.6/mm2, mean+/-s.d. vs 37.7+/-8.7/mm2, P<0.05, n=4). In
contrast, basophils were observed in the airway lumen, in the bronchial
epithelium and in the submucosa. The number of basophils in the bronchioles was
81.8+/-55.5/mm2 (n = 4); however, basophils were not found at all in the airways
of the control group. Although eosinophils, B lymphocytes and macrophages bear
low affinity IgE receptors and could react with anti-IgE, the location of these
cells in the close sections did not correspond closely with basophils. The
presence of basophils in lung tissues obtained from fatal asthma patients
supports the view that basophils play a role in the pathogenesis of bronchial
asthma.
PMID- 10779280
TI - Expression of CD35 (CR1) and CD11b (CR3) on circulating neutrophils and
eosinophils from allergic asthmatic children.
AB - Complement receptors on neutrophils and eosinophils play a role in activation and
adhesion. During asthmatic reactions these receptors have been found elevated on
circulating granulocytes. In the present study we compared the expression of CD35
(complement receptor type 1) and CD11b (complement receptor type 3) on
neutrophils and eosinophils from asthmatic and non-asthmatic children. This was
done in whole blood samples using depolarized light scattering for the
discrimination of neutrophils and eosinophils. The non-stimulated expression as
well as the upregulated expression of receptors by the chemotactic peptide N
formylmethionyl-leucyl-phenyl-alanine (fMLP) were studied. The results showed
that without prior stimulation only the expression of CD35 on neutrophils was
significantly elevated in children with asthma (P<0.05). After up-regulation with
fMLP, the CD11b expression on neutrophils (P<0.005, fMLP: 0.002 microM) and
eosinophils (P<0.05, fMLP: 0.02 microM) was significantly higher in asthmatic
children than in the controls. These results indicate that the inducible
expression of CD11b on neutrophils and eosinophils from allergic asthmatic
children is primed in vivo.
PMID- 10779281
TI - Molecular cloning of a house dust mite allergen with common antibody binding
specificities with multiple components in mite extracts.
AB - Plaque radio-immuno assay has been used to isolate an IgE-binding clone from a
lambda gt11 library of Dermatophagoides pteronyssinus cDNA. The clone HD6
contained DNA encoding a 215 residue protein which contained a predicted 17 amino
acid residue leader sequence, no cysteines and a single N-glycosylation site. The
198 residue mature protein would have a predicted MW of 22,177 D. No homologues
were found in searches of the data banks. Sera from 14/38 allergic children
reacted strongly with the polypeptide produced by the clone (37%). Skin tests
showed reactivity in 16/30 (53%) allergic patients and 0/10 of controls. Affinity
purification of rabbit antibodies with the clone showed that antibodies to the
polypeptide had specificities to multiple products in mite extracts corresponding
to components of Mr 29, 27 and 24 K by Western blotting. Absorption studies of
IgE in allergic serum indicated further entities at 13 and 11.5 kD. It is
proposed to name this allergen Der p VII.
PMID- 10779282
TI - Atopy in childhood. I. Gender and allergen related risks for development of hay
fever and asthma.
AB - Reasons for the gender differences in prevalence rates for asthma remain unclear.
We have examined the relationships between allergen skin-test reactions and
diagnoses of hay fever and asthma in New Zealand boys and girls examined at the
age of 13 years. Information on current and past wheezing, diagnosed asthma, and
hay fever was obtained for 662 subjects (341 boys) of a birth cohort followed
longitudinally to the age of 13 years, using a physician-administered
questionnaire. Atopic status was determined by skin-prick tests to 11 common
allergens. The proportion of 13-year-old boys with current asthma was 1.6 times
higher and of ever-diagnosed asthma 1.4 times higher than in girls, but the
prevalence of recurrent wheeze (> or = three episodes per year) not diagnosed as
asthma, or of hay fever, was not significantly different between the sexes. The
prevalence of diagnosed asthma increased with increasing numbers of positive skin
tests, but hay fever without asthma was little affected above one positive skin
test. Boys had a greater prevalence of any positive skin-test (50.1% vs 37.1%),
two or more positive tests (29.3% vs 21.8%), and responses to house dust mite
(34.0% vs 23.1%) and cat (14.7% vs 11.2%). Gender differences for asthma became
insignificant when adjusted for skin-test responsiveness to house dust mite
and/or cat. The proportion of children with diagnosed asthma increased with
increasing size of weals to house dust mite and cat dander. Gender differences in
allergen sensitivities partly explain the gender differences in diagnosed asthma
in children. In both sexes, risk of asthma was primarily associated with
sensitization to indoor allergens (house dust mite and cat), and was related to
the magnitude of the skin-test response, while the risk of hay fever was
primarily associated with grass pollen sensitivity.
PMID- 10779283
TI - Atopy in childhood. II. Relationship to airway responsiveness, hay fever and
asthma.
AB - While airway hyperresponsiveness is usually associated with a diagnosis of asthma
or symptoms of wheezing, some individuals with rhinitis show airway
hyperresponsiveness as do some with no symptoms whatsoever. We have studied the
correlations between symptoms, airway hyperresponsiveness and atopy as determined
by skin-prick tests in a cohort of New Zealand children. A total of 662 members
of a birth cohort were studied at age 13 years using a respiratory questionnaire,
skin-prick tests to 11 common allergens, and an abbreviated validated
methacholine challenge test to determine airway responsiveness. Airway
hyperresponsiveness (methacholine PC20 FEV1 < or = 8 mg/ml) was strongly
correlated with reported asthma and current wheezing (P<0.0001) and also with
atopy, especially to house dust mite and cat (P<0.0001). As weal size for both
house dust mite and cat increased, so did the proportion of children with airway
hyperresponsiveness. All children with diagnosed asthma and airway
hyperresponsiveness were atopic. Skin-test reactions to house dust mite and cat
were strongly correlated with any degree of measurable airway responsiveness
(PC20 FEV1 < or = 25 mg/ml) in children with rhinitis (P<0.00001), and remained
significantly correlated even in children without current asthma, without asthma
ever and without rhinitis (P<0.001). Atopy is a major determinant of airway
hyperresponsiveness in children, not only in those with reported histories of
asthma and wheezing, but also in the absence of any history suggesting asthma and
rhinitis.
PMID- 10779284
TI - Atopy in childhood. III. Relationship with pulmonary function and airway
responsiveness.
AB - The relationship between atopy and pulmonary function in children, and how these
relate directly or indirectly to airway hyperresponsiveness, is uncertain. We
have examined these relationships in a sample of 13-year-old children. A
questionnaire on respiratory symptoms, skin-prick tests to 11 common allergens,
spirometry and an abbreviated methacholine challenge test were completed by 662
members (341 boys) of a birth cohort of New Zealand children followed
longitudinally to age 13. There was a significant relationship between the
presence and degree of atopy, and baseline pulmonary function. Low FEV1/VC ratios
were associated with a greater likelihood of airway responsiveness, not only in
subjects with diagnosed asthma, but also in the full cohort and in the sub-group
of 426 children who denied asthma or current wheeze. The relationships between
baseline FEV1/VC and airway responsiveness were stronger in atopic than in non
atopic children, with the strongest relationships in children sensitive to house
dust mite and/or cat dander. In the presence of atopy, progressively lower levels
of lung function were strongly associated with a higher prevalence of airway
responsiveness (P<0.001). In non-atopic subjects, only those with the most
impaired lung function (FEV1/VC < 75%) showed any substantive prevalence of
airway responsiveness. The relationship between the degree of atopy and the
FEV1/VC ratio, although significant in univariate analysis, became completely non
significant after accounting for airway responsiveness. In 13-year-old children,
atopy, especially to house dust mite and cat dander, was correlated with
pulmonary function expressed as FEV1/VC ratio. Airway responsiveness likewise
correlated with impaired baseline lung function. The apparent relationship of
lung function to atopy occurred primarily as a result of the relationship between
atopy and airway responsiveness. Atopy and impaired lung function were additive
factors predicting airway responsiveness.
PMID- 10779285
TI - Allergic and inflammatory eye disease--report on the BSACI (Ophthalmic section)
satellite meeting held at the International Conference Centre, Birmingham, 1993.
PMID- 10779286
TI - Food intolerance and the scientific trap.
PMID- 10779287
TI - Asthma and altitude.
PMID- 10779288
TI - Testing for inhalant allergy in asthma.
PMID- 10779289
TI - Histamine-free diet: treatment of choice for histamine-induced food intolerance
and supporting treatment for chronic headaches.
AB - Histamine-induced food intolerance is not IgE-mediated. Skin-prick testing and
specific IgE to food allergens are typically negative. Food rich in histamine or
red wine may cause allergy-like symptoms such as sneezing, flush, skin itching,
diarrhoea and even shortness of breath. The suspected reason is a diminished
histamine degradation based on a deficiency of diamine oxidase. As diamine
oxidase cannot be supplemented, a histamine-free diet was implemented to reduce
histamine intake. Forty-five patients with a history of suffering from
intolerance to food or wine (n = 17) and chronic headache (n = 28) were put on
the diet over months to years. Fish, cheese, hard cured sausages, pickled cabbage
and alcoholic beverages had to be avoided. Complaint intensity and drug-use per
week prior to and 4 weeks after a histamine-free diet were compared. After 4
weeks on the diet 33/45 patients improved considerably (P < 0.01), eight of them
had total remission. In 12/45 patients, however, no changes in symptoms were
observed. Symptoms of food or wine intolerance significantly decreased (P < 0.02;
treatment of choice), headaches decreased in frequency (P < 0.001), duration and
intensity. After eating histamine-rich food symptoms were reproducible and could
be eliminated by anti-histamines in most patients. These data indicate the role
of histamine in food and wine intolerance and that histamine-rich food causes a
worsening of symptoms in patients suffering from chronic headaches. Results
obtained support the hypothesis of a deficiency of diamine oxidase in patients
with intolerance to food or wine.
PMID- 10779290
TI - Effect of beclomethasone dipropionate nasal aerosol on serum markers of bone
metabolism in children with seasonal allergic rhinitis.
AB - Thirty-nine children with grass pollen hay fever were randomly treated with nasal
inhaled beclomethasone dipropionate (BDP) 200 or 400 microg/day or sodium
cromoglycate (SCG) 30 mg/day for 2 months during the pollen season. Serum
osteocalcin (OC), parathyroid hormone (PTH), total alkaline phosphatase (AP),
bone alkaline phosphatase (BAP) and type I collagen telopeptide (ICTP) were
measured immediately before, 1 and 2 months after treatment and 1 week after
stopping the therapy. No significant changes in OC, PTH, AP, BAP and ICTP serum
level occurred within each group. Minor and probably clinically insignificant
between group differences were occasionally found. Our study shows that BDP nasal
spray has no significant effect on common markers of bone metabolism.
PMID- 10779291
TI - Spontaneous histamine release in whole blood in patients before and after 4
months of specific immunotherapy.
AB - Spontaneous histamine release (SHR) in whole blood was assessed before and after
4 months of specific immunotherapy (SIT) for allergic rhinoconjunctivitis in 32
patients. Spontaneous histamine release was significantly enhanced (P < 0.05) in
patients prior to immunotherapy compared with 20 controls. Spontaneous histamine
release decreased significantly in patients after 4 months of specific
immunotherapy (P < 0.04) and almost reached the same values as spontaneous
histamine release in controls. Clinical success of treatment after 4 months was
seen in 15 patients (improvement > or =50%), 10 of whom showed a significant
decrease in spontaneous histamine release. Decrease of spontaneous histamine
release after 4 months indicates the efficacy of specific immunotherapy already
at an early stage of treatment. Assessment of spontaneous histamine release
appears to be a useful and easily performable method for monitoring success of
treatment of patients during specific immunotherapy.
PMID- 10779292
TI - Pistachio nut hypersensitivity: identification of pistachio nut allergens.
AB - Type I hypersensitivity to pistachio nut antigens was demonstrated in three
patients by means of immediate skin-test reactivity, specific IgE determination
by a fluoroimmunoassay (CAP), CAP-inhibition and leucocyte histamine release.
Sensitization to other dried fruits and pollens was observed in the patients. The
CAP-inhibition studies revealed significant crossreactivity between pistachio and
cashew nut belonging to the Anacardiaceae family, and between pistachio nut and
other dried fruits belonging to taxonomically unrelated botanical families. No
relevant crossallergenicity was observed between pistachio nut and Lolium and
Olea pollens. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS
PAGE) of a pistachio nut extract followed by immunoblotting analysis identified
four IgE-binding bands with molecular weights of 34, 41, 52 and 60 kD.
PMID- 10779293
TI - Effects of the platelet activating factor antagonists BN 52021 and BN 50730 on
antigen-induced bronchial hyperresponsiveness and eosinophil infiltration in lung
from sensitized guinea-pigs.
AB - The involvement of platelet activating factor (PAF) in antigen-induced bronchial
hyperresponsiveness was investigated by the use of the PAF antagonists BN 52021
and BN 50730, in a guinea-pig model where sensitization and challenge were
performed by aerosol. Male Hartley guinea-pigs were sensitized by two aerosol
exposures at 48 hr intervals to a 0.9% NaCl solution (saline) containing 2 mg/ml
ovalbumin for 30 min. Fifteen to 20 days later, guinea-pigs were challenged by
exposure to five successive aerosols of increasing concentrations of ovalbumin
(OA) or respectively, 10 microg/ml, 100 microg/ml, 1 mg/ml, 5 mg/ml and 10 mg/ml
for 15 min each, or saline alone. Three to four hr and 18-24 hr after the aerosol
challenge the guinea-pigs were prepared for recording of bronchopulmonary
response and aerosol administrations were then generated with an ultrasonic
nebulizer. The bronchopulmonary responses induced by successive 1-min aerosol
bursts of acetylcholine (ACh) was assessed. As compared with saline-challenged
guinea-pigs, an enhanced bronchopulmonary response to aerosol administration of
cumulative doses of ACh was observed, 3-4 hr and 18-24 hr post-ovalbumin
challenge. When the sensitized guinea-pigs were pretreated 1 hr before ovalbumin
exposure with BN 52021 or BN 50730 (25 mg/kg, per os), a significant inhibition
of the increase in the bronchopulmonary response to ACh was observed, both at 3-4
hr and 18-24 hr. Furthermore, when guinea-pigs were treated 3-4 hr after the
ovalbumin exposure with BN 52021 or BN 50730, a significant inhibition of the
hyperresponsiveness to ACh was recorded at 18-24 hr. A marked accumulation of
eosinophils in the peribronchial regions was observed on histological
preparations of lung specimens collected 4 hr or 24 hr after ovalbumin exposure.
Pretreatment of the guinea-pigs by BN 50730 or BN 52021 did not modify the
eosinophil accumulation in the peribronchial area. No significant difference in
the number of eosinophils collected in the bronchoalveolar lavage fluid is
observed, 24 hr post-ovalbumin challenge, under the pretreatment with BN 52021 or
BN 50730. Pretreatment of guinea-pigs by BN 50730 or BN 52021 significantly
reduced the PAF-induced (100 microg/ml) increase in eosinophil number in the
peribronchial area. By contrast, they did not inhibit the eosinophilia induced by
aerosol administration of LTB4 (5 microg/ml). These results suggest that the
bronchial hyperresponsiveness observed in this study is associated with
eosinophil accumulation in the lung. The potent inhibition of the bronchial
hyperresponsiveness by the two unrelated antagonists of PAF suggests that the
lipid mediator is involved in its triggering and duration, but not in the
eosinophil infiltration.
PMID- 10779294
TI - Three cases of occupational asthma and rhinitis caused by garlic.
PMID- 10779295
TI - Abnormalities in histamine pharmacodynamics in chronic urticaria.
AB - Histamine plays a key role in the pathogenesis of chronic urticaria (CU). The
authors of this paper have studied the effects of ingested histamine in 25
patients with CU. A 120 mg dose of histamine, well-tolerated in the healthy
subject, was instillated into the duodenum. Concomitantly, plasma histamine (H)
levels and plasma and urinary methylhistamine (MH) levels were measured.
Intraduodenal administration of histamine was responsible for the development of
an attack of urticaria in 64% of patients, while control subjects were
asymptomatic. Plasma histamine levels were significantly higher after digestive
histamine challenge (DHC) in patients with CU compared with controls. An abnormal
increase in plasma histamine was observed in 72% of them. Plasma MH exhibited the
same kinetic behaviour with a usually delayed time-pattern. Urinary MH
concentration was higher in patients presenting with early-onset urticaria during
the first hour than in those with the late-onset type between 1 and 12 hr after
DHC. The coefficient of methylation (plasma MH/MH+H) was not significantly
different in patients presenting with an attack of urticaria following DHC and in
other subjects. Urinary excretion of MH and urinary flow increased significantly
in patients presenting with an attack of urticaria following DHC which
corresponds to increased absorption of histamine during the 5-hr period following
DHC and its role on excretion by the kidney via vasodilation which it induces.
This study demonstrates the abnormal frequency of disturbances in the metabolism
of exogenous histamine in patients with CU. Increased plasma H accounts for the
abnormal passage of H across the intestinal barrier which can result either from
intestinal hyperpermeability and/or a deficit in the enzymatic catabolism of
histamine. The systems of methylation and urinary clearance of MH appear to be
effective. It is thus postulated that there is a deficit in diamine oxidase (DAO)
in the enterocyte. The lack of correlation between the kinetic behaviour of
plasma H and the onset of urticaria draws attention to the extent of individual
variability in skin reactivity to histamine.
PMID- 10779296
TI - Influence of allergen avoidance at high altitude on serum markers of eosinophil
activation in children with allergic asthma.
AB - A cohort of 12 asthmatic children was followed over several months, during which
they moved back and forth from an allergen-free to an allergen-rich environment
at high and low altitude, respectively. The children were treated with non
steroidal anti-asthmatic drugs as clinically needed. Histamine PC20-FEV1 was
unaltered during the study period, whereas serum levels of eosinophil cationic
protein (ECP) and eosinophil protein X (EPX) showed significant changes when the
children were exposed to the offending allergens. The total IgE significantly
increased during exposure. The serum levels of myeloperoxidase (MPO) as well as
of chemotactic factors for both neutrophils and eosinophils were unaltered during
allergen exposure. We conclude that the serum markers of eosinophil activity ECP
and EPX are sensitive indices of allergen exposure in asthmatic atopic children.
PMID- 10779297
TI - Interleukin-8 is a chemo-attractant for eosinophils purified from subjects with a
blood eosinophilia but not from normal healthy subjects.
AB - Interleukin-8 (IL-8), a pro-inflammatory cytokine with potent neutrophil
chemotactic activity, was studied for its effect on eosinophil migration
responses, in vitro. Normal density eosinophils were isolated from healthy, non
atopic subjects (<0.35 x 10(9) eosinophils/l) and individuals with various
diseases associated with a blood eosinophilia (range 0.56 x 10(9)-12.2 x 10(9)
eosinophils/l). IL-8 produced a dose-dependent migrational response for
eosinophils from subjects with an eosinophilia, optimal at 10(-8) M (P < 0.01)
and the major component of the migrational response was chemokinesis. On a molar
basis, IL-8 (EC50 approximately 10(10) M) was 100-fold more potent than platelet
activating factor (PAF), although a comparison of the migrational responses
showed that at optimal concentrations IL-8 (10(-8) M) produced only 30% maximal
responses stimulated by PAF (10(-6) M). In contrast, IL-8 tested over a wide
concentration range had a negligible effect on eosinophils from normal subjects.
A direct correlation between the total blood eosinophil counts for all subjects
and the absolute magnitude of the migrational response to IL-8 (r = 0.727, P <
0.01 at 10(-8) M), PAF (r = 0.551, P < 0.03 at 10(-6) M) and N-formyl-methionyl
leucyl-phenylalanine (fMLP) (r = 0.689, P < 0.02 at 10(-8) M), suggested that
heightened eosinophil migrational responses to inflammatory mediators may arise
as a consequence of in vivo priming mechanism(s) associated with the development
of an eosinophilia. In this regard, eosinophils derived from human cord blood
mononuclear cells cultured in the presence of eosinophilopoietic cytokines IL-3
and IL-5, produced migrational responses to IL-8 and PAF, that were comparable
with that of eosinophils from eosinophilic subjects. Furthermore, incubation of
eosinophils from normal donors with IL-5 (optimal concentration 10(-9) M),
significantly enhanced the subsequent migrational responses to both IL-8 (10(-8)
M, P < 0.01) and PAF (10(-8) M, P < 0.05). Therefore, the increased
responsiveness of eosinophils from eosinophilic subjects may reflect in vivo
priming by IL-5 and this phenomenon may contribute partly to the mechanism(s) by
which eosinophils preferentially accumulate at sites of allergic inflammation.
PMID- 10779298
TI - The effectiveness of a peripatetic allergy nurse practitioner service in managing
atopic allergy in general practice--a pilot study.
AB - The effectiveness of an allergy nurse practitioner service operating within
community health care was evaluated in terms of symptom improvement and reduction
in allergy related general practitioner consultations and prescribed medication.
A postal questionnaire survey of 53 allergy patients, identified from three
general practices in the Norwich area during a pilot scheme, was carried out
concurrently with a survey of the patients' case records at the surgeries. The
questionnaire included questions concerning allergy status, general practitioner
visits and the number of prescribed medications supplied. The main outcome
measures were the number of general practitioner consultations and prescribed
medications before and after the allergy nurse practitioner consultation and the
patient's reported level of symptoms. The results showed that the intervention of
an allergy nurse practitioner consultation produced significant reductions in the
outcome measures. The number requiring a general practitioner consultation fell
by 40% (from 133 to 80, P < 0.001) and the number of prescribed medications fell
by 42% (from 153 to 89, P < 0.001). Twenty-seven (69%) of the 39 patients who
responded to the questionnaire reported an improvement in symptoms, whilst 26% (n
= 10) remained the same and 5% (n = 2) were worse. An additional study of 23 of
the +ve skin-tested patients, over an extended period, showed greater reductions
in general practitioner consultations and prescribed medication (71%, P < 0.001
and 59%, P < 0.004 respectively). In conclusion, it is apparent that the
application of developed skills and expertise in allergy assessment by a nurse
coupled with time can lead to improvement in symptom level in allergy patients.
Such a service also has the possibility of providing savings within the National
Health Service. Simply prescribing drugs without a system of self-management and
avoidance measures is unlikely to improve the care available to allergy patients.
PMID- 10779299
TI - Longitudinal changes in skin-prick test reactivity.
PMID- 10779300
TI - Signal transduction mechanisms in human eosinophils.
PMID- 10779301
TI - The circulating renin-angiotensin system and the response to hypotension.
PMID- 10779302
TI - Crustacea allergy.
PMID- 10779303
TI - The aerodynamic characteristics of cat allergen.
AB - To further characterize airborne cat allergen and a newly established cat
challenge facility, airborne Fel d I levels and particle size distributions were
studied in both the cat challenge room and home environments under different
conditions of ventilation and physical activity. In the cat room, there has been
a dramatic and continued rise in the concentration of airborne Fel d I since the
room was established. No differences in total airborne Fel d I levels or particle
size distribution were detected under widely differing rates of ventilation (40
air changes per hour vs 8 ac/hr vs < 1 ac/hr). Likewise, altering ventilation had
little effect on the clearance of airborne antigen after disturbance. Significant
increases in allergen levels were detected, however, after simply allowing the
cats to leave their holding cage and move about the room. Fel d I levels in homes
ranged from 2-468.5 ng/m3, similar to the levels seen in the cat room without
disturbance. Fel d I particle size distribution was very consistent in both homes
and the cat room with the majority of airborne Fel d I being detected on
particles > 17 microm. Although very little allergen (< 15%) was detected on
particles < 4 microm, this important fraction was present under all conditions.
We conclude that airborne cat allergen resides primarily on relatively large
particles, that a small but consistent fraction is found on very small particles,
and that neither allergen levels or particles size distribution are significantly
influenced by ventilation.
PMID- 10779304
TI - Exposure to house dust mite allergen of children admitted to hospital with
asthma.
AB - Eighty-two children admitted to hospital with exacerbations of asthma were
studied to determine how many were exposed to house dust mites at the time of
admission and displayed immediate hypersensitivity to house dust mites. The
concentration of house dust mite allergen (Der p I) was measured in dust obtained
from the child's mattress, bedroom floor and living room floor. Sixty-two (75%)
children admitted had been exposed to > 10 microg Der p I/g. Sixty-seven (82%)
children were sensitive to house dust mite (RAST > or = 1 +, or weal > or = 3
mm): 49 (60%) children were both exposed and sensitive. In contrast in a control
group of 44 children, 31 (70%) (n.s.) were exposed to > 10 microg Der p I/g, 10
(23%) (P<0.001) were sensitive to house dust mite, and 7 (16%) (P<0.001) were
both exposed and sensitive. Seventy-three homes were revisited 6 months after the
child's initial admission. During the preceding month 14 children had been
readmitted, 12 were fully investigated; of these 10 were both sensitive to house
dust mite and still exposed to > 10 microg Der p I/g. In contrast, of the
remaining 62 children who were not readmitted, only 19 were both sensitive and
still exposed to > 10 microg Der p I/g (P<0.001). In conclusion, the majority of
children admitted to hospital with exacerbations of asthma were exposed to house
dust mite allergen and were house dust mite sensitive. Further the results
suggest that continued exposure to higher concentrations of mite allergen may be
associated with the risk of readmission.
PMID- 10779305
TI - Monoclonal antibody immunoassay for quantitative analysis of group V allergens in
grass pollen extracts.
AB - A two-site monoclonal antibody (MoAb) ELISA has been developed for the
quantification of the Phleum pratense major allergen, Phl p V. The assay is based
on two MoAbs which recognize different non-overlapping epitopes on the Phl p V
molecule; one antibody (1D11) was immobilized on the solid phase and the other
(3B2) was biotinylated. An affinity-purified Phl p V preparation (purity of 95%)
was used as standard. The assay has a sensitivity of 10 ng/ml of allergen and is
suitable for the detection of group V allergen in aqueous grass extracts. The
specificity of the assay was investigated with 14 grass pollen and five non-grass
pollen extracts. Different levels of group V allergen were detected in extracts
of grasses, but not in non-grasses. The assay gives a good correspondence with
allergenic activity of extracts as determined by ELISA inhibition using serum
pool of allergic patients. The results indicate that the two-site MoAb ELISA
could be very useful in the standardization of allergenic extracts from grass
pollen.
PMID- 10779306
TI - Allergens from birch pollen and pollen of the European chestnut share common
epitopes.
AB - Type I allergy to pollen of the European chestnut (Castanea sativa) represents a
major cause of pollinosis in (sub) Mediterranean areas. Using sera from 14
patients with established allergy to pollen of the European chestnut, 13/14 sera
(92%) showed IgE-binding to a 22 kD protein, 2/14 (14%) displayed additional
binding to a 14 kD protein and 1/14 (7%) bound only to the 14 kD protein of
European chestnut pollen extract. Two monoclonal mouse antibodies, BIP 1 and BIP
4, directed against different epitopes of Bet v I (the major birch pollen
allergen), and a rabbit antibody to recombinant birch profilin (rBet v II) were
used to characterize the proteins of the European chestnut pollen. The
recombinant birch pollen allergens, rBet v I and rBet v II (profilin) were
employed to show common allergenic structures on proteins from both birch and
European chestnut pollen by IgE-inhibition experiments. Despite the fact that the
22 kD protein displayed a higher molecular weight in comparison to the 17 kD
major birch pollen allergen, Bet v I, we could demonstrate reactivity of both
monoclonal antibodies, BIP 1 and BIP 4, with this protein. A complete inhibiton
of IgE-binding to this 22 kD protein was shown by pre-incubating sera with
purified recombinant Bet v I. In addition, the 14 kD protein could be identified
by IgE-inhibition studies with recombinant Bet v II and by using a rabbit anti
profilin antibody as the profilin from pollen of the European chestnut.
PMID- 10779307
TI - The renin angiotensin system and hymenoptera venom anaphylaxis.
AB - Components of the renin angiotensin system, namely renin, angiotensinogen,
angiotensin I and II and aldosterone were measured in plasma of patients with
hymenoptera venom anaphylaxis (n = 50) and healthy non-allergic controls (n =
25). Patients with a history of anaphylactic reactions to hymenoptera venom who
did not undergo immunotherapy showed significantly reduced renin,
angiotensinogen, angiotensin I and angiotensin II in plasma as compared with
controls (P < 0.05). There was no difference in the aldosterone concentration
between patients and controls. Angiotensin I, angiotensin II, renin and
angiotensinogen levels were the same in male and female patients. There was also
no difference in the angiotensin I, II, renin or angiotensinogen levels between
young and older patients. A significant inverse correlation between the severity
of clinical symptoms and the plasma levels of renin (r = -0.382, P < 0.001),
angiotensinogen (r = -0.567, P < 0.0001), angiotensin I (r = -0.656, P < 0.0001)
and angiotensin II (r = 0.0762, P < 0.0001) was found: the lower the levels the
more severe the clinical symptoms. No correlation was found for aldosterone.
Hymenoptera venom allergic patients with repeated anaphylactic reactions during
hyposensitization did not tolerate the sting of a living insect (n = 6). In these
patients, renin, angiotensinogen, angiotensin I and II remained significantly
lower than in healthy non-allergic controls. Patients with successful
immunotherapy (n = 27) who tolerated the sting of a living insect had renin,
angiotensin I and II significantly higher than patients without immunotherapy.
These findings suggest a possible role of the renin angiotensin system in
hymenoptera venom anaphylaxis.
PMID- 10779308
TI - Formation of phosphatidylinositol-4-phosphate in human peripheral blood
eosinophils.
AB - To evaluate the presence of phosphatidylinositol-4-phosphate in peripheral blood
eosinophils, venous blood was drawn from normal healthy volunteers. The
eosinophils were isolated on a Percoll gradient and were incubated with
[gamma32P]ATP in the presence of Mg2+. After stopping the reaction, lipid
extraction was performed with acidic medium and phospholipids were separated by
thin-layer chromatography on 1% (w/v) oxalic acid- and potassium oxalate
impregnated silica gel plates. Considerable amounts of radioactivity were found
to be incorporated into phosphatidylinositol-4-phosphate on both plates. This
reaction requires ATP and Mg2+, and maximal response is seen at 10 microM ATP and
20 mM Mg2+. The reaction is dependent upon the time and temperature of the assay
system. No significant superoxide anion generation from the eosinophils incubated
with ATP at the concentrations used in the study was observed. These results
suggest the possible presence of phosphatidylinositol kinase which catalyses the
formation of phosphatidylinositol-4-phosphate from endogenous
phosphatidylinositol in human peripheral blood eosinophils.
PMID- 10779309
TI - Trypsin-like protease of mites: purification and characterization of trypsin-like
protease from mite faecal extract Dermatophagoides farinae. Relationship between
trypsin-like protease and Der f III.
AB - A serine protease from mite faecal extract, Dermatophagoides farinae, was
purified using DEAE-Sephacel anion exchange chromatography and Superdex 75 pg gel
chromatography. The molecular weight of this protease was 34 kD on SDS-PAGE under
reducing conditions. The optimal pH and temperature of the protease were 8.0 and
47 degrees C, respectively. In addition, this protease cleaved arginyl or lysyl
residue containing substrates selectively and was only inhibited by aprotinin,
FUT-175, and soy bean trypsin inhibitor and not by chymostatin, E-64 and
iodoacetic acid. These results show that our purified serine protease belongs to
the trypsin-type. Purified trypsin-like protease was shown to be allergenic by
enzyme-linked immunosorbent assay. Antigenicity of trypsin-like protease was
completely different from those of Der f I and Der f II. Both, 20 N-terminal
amino acid sequence and amino acid compositions of the purified protease were
very similar to those of Der f III. Good similarities were found between trypsin
like protease and Der f III concerning physicochemical properties such as
molecular weight on SDS-PAGE and ammonium sulphate solubility. Summarizing the
above data, it can be concluded that a trypsin-like protease from mite faecal
extract is actually the Der f III allergen and that it may be involved in the
digestive process of the mite as it was found not in mite body but in mite
faeces.
PMID- 10779310
TI - Treatment of steroid-dependent asthma with recombinant interferon-gamma.
AB - We have recently reported that treatment of patients with severe atopic
dermatitis with recombinant interferon-gamma (rIFN-gamma) resulted in clinical
improvement as well as a reduction of circulating eosinophils. Since IgE
dependent late phase allergic reactions and eosinophilic infiltration are thought
to play an important role in the pathogenesis of asthma, we conducted a two
centre randomized double-blind placebo-controlled trial of rIFN-gamma in the
treatment of steroid-dependent asthma. Patients were treated with daily
subcutaneous injections of either 0.05 mg/m2 rIFN-gamma (n = 9) or placebo (n =
11) for 90 days. All patients completed the study without significant drug
toxicity noted. Oral prednisone dose, forced expiratory volume in 1 second
(FEV1), peak expiratory flow rates (PEFR) and circulating eosinophil counts were
monitored throughout the trial. There was no significant difference between the
two treatment groups in per cent reduction from baseline of daily prednisone (P =
0.51). There was also no significant difference between the two treatment groups
in per cent change from baseline in FEV1 (P = 0.54) or in PEFR (P = 0.75). Total
circulating eosinophil counts decreased by 31% in the rIFN-gamma group and
increased by 8.5% in the placebo group (P = 0.09). We conclude that this
treatment regimen was not effective in patients with steroid-dependent asthma.
PMID- 10779311
TI - Rapid onset of action of levocabastine eye-drops in histamine-induced
conjunctivitis.
AB - Levocabastine is a recently developed, potent H1-receptor blocker intended for
topical application. Seventeen healthy non-atopic volunteers participated in this
randomized, double-blind, placebo-controlled study undertaken to investigate the
speed of onset of action, efficacy and tolerability of levocabastine eye-drops
after a histamine challenge. The degree of histamine-induced ocular inflammation
was found to be significantly less after administration of levocabastine compared
with placebo. Furthermore, levocabastine was shown to be rapidly effective with
an onset of action within 10 min. Levocabastine eye-drops were well-tolerated and
no adverse reactions to the study drug were reported. Levocabastine eye-drops
appear to be a valuable therapeutic approach for the treatment of histamine
mediated ocular allergies.
PMID- 10779312
TI - Extracellular HCO(3)(-) dependence of electrogenic Na/HCO(3) cotransporters
cloned from salamander and rat kidney.
AB - We studied the extracellular [HCOabstract (3) (-)] dependence of two renal clones
of the electrogenic Na/HCO(3) cotransporter (NBC) heterologously expressed in
Xenopus oocytes. We used microelectrodes to measure the change in membrane
potential (DeltaV(m)) elicited by the NBC cloned from the kidney of the
salamander Ambystoma tigrinum (akNBC) and by the NBC cloned from the kidney of
rat (rkNBC). We used a two-electrode voltage clamp to measure the change in
current (DeltaI) elicited by rkNBC. Briefly exposing an NBC-expressing oocyte to
HCOabstract (3 )(-)/CO(2) (0.33-99 mM HCOabstract (3)(-), pH(o) 7.5) elicited an
immediate, DIDS (4, 4-diisothiocyanatostilbene-2,2-disulfonic acid)-sensitive and
Na(+)-dependent hyperpolarization (or outward current). In DeltaV(m) experiments,
the apparent K(m ) for HCOabstract (3)(-) of akNBC (10. 6 mM) and rkNBC (10.8 mM)
were similar. However, under voltage-clamp conditions, the apparent K(m) for
HCOabstract (3)(-) of rkNBC was less (6.5 mM). Because it has been reported that
SOabstract (3)(=)/HSO abstract (3)(-) stimulates Na/HCO(3 ) cotransport in renal
membrane vesicles (a result that supports the existence of a COabstract (3)(=)
binding site with which SOabstract (3)(=) interacts), we examined the effect of
SOabstract (3)(=)/HSO abstract (3)(-) on rkNBC. In voltage-clamp studies, we
found that neither 33 mM SOabstract (4)(=) nor 33 mM SOabstract (3)
(=)/HSOabstract (3)(-) substantially affects the apparent K(m) for HCO abstract
(3)(-). We also used microelectrodes to monitor intracellular pH (pH(i)) while
exposing rkNBC-expressing oocytes to 3.3 mM HCOabstract (3 )(-)/0.5% CO(2). We
found that SO abstract (3)(=)/HSOabstract (3 )(-) did not significantly affect
the DIDS-sensitive component of the pH(i) recovery from the initial CO(2 )
induced acidification. We also monitored the rkNBC current while simultaneously
varying [CO(2)](o), pH(o), and [COabstract (3)(=)](o) at a fixed [HCOabstract
(3)(-)](o) of 33 mM. A Michaelis-Menten equation poorly fitted the data expressed
as current versus [COabstract (3)(=)](o ). However, a pH titration curve nicely
fitted the data expressed as current versus pH(o). Thus, rkNBC expressed in
Xenopus oocytes does not appear to interact with SOabstract (3 )(=), HSOabstract
(3)(-), or COabstract (3)(=).
PMID- 10779314
TI - Specific and nonspecific effects of protein kinase C on the epithelial Na (+)
channel.
AB - The Xenopus oocyte expression system was used to explore the mechanisms of
inhibition of the cloned rat epithelial Na(+) channel (rENaC) by PKC (Awayda,
M.S., I.I. Ismailov, B.K. Berdiev, C.M. Fuller, and D.J. Benos. 1996. J. Gen.
Physiol. 108:49-65) and to determine whether human ENaC exhibits similar
regulation. Effects of PKC activation on membrane and/or channel trafficking were
determined using impedance analysis as an indirect measure of membrane area.
hENaC-expressing oocytes exhibited an appreciable activation by hyperpolarizing
voltages. This activation could be fit with a single exponential, described by a
time constant (tau) and a magnitude (DeltaI (V)). A similar but smaller magnitude
of activation was also observed in oocytes expressing rENaC. This activation
likely corresponds to the previously described effect of hyperpolarizing voltage
on gating of the native Na(+) channel (Palmer, L.G., and G. Frindt. 1996. J. Gen.
Physiol. 107:35-45). Stimulation of PKC with 100 nM PMA decreased DeltaI(V) in
hENaC-expressing oocytes to a plateau at 57.1 +/- 4.9% (n = 6) of baseline values
at 20 min. Similar effects were observed in rENaC-expressing oocytes. PMA
decreased the amiloride-sensitive hENaC slope conductance (g(Na)) to 21.7 +/-
7.2% (n = 6) of baseline values at 30 min. This decrease was similar to that
previously reported for rENaC. This decrease of g (Na) was attributed to a
decrease of membrane capacitance (C (m)), as well as the specific conductance
(g(m)/C(m )). The effects on g(m)/C(m) reached a plateau within 15 min, at
approximately 60% of baseline values. This decrease is likely due to the specific
ability of PKC to inhibit ENaC. On the other hand, the decrease of C(m) was
unrelated to ENaC and is likely an effect of PKC on membrane trafficking, as it
was observed in ENaC-expressing as well as control oocytes. At lower PMA
concentrations (0.5 nM), smaller changes of C(m) were observed in rENaC- and
hENaC-expressing oocytes, and were preceded by larger changes of g(m ) and by
changes of g(m)/C(m), indicating specific effects on ENaC. These findings
indicate that PKC exhibits multiple and specific effects on ENaC, as well as
nonspecific effects on membrane trafficking. Moreover, these findings provide the
electrophysiological basis for assessing channel-specific effects of PKC in the
Xenopus oocyte expression system.
PMID- 10779313
TI - Heterologous facilitation of G protein-activated K(+) channels by beta-adrenergic
stimulation via cAMP-dependent protein kinase.
AB - To investigate possible effects of adrenergic stimulation on G protein-activated
inwardly rectifying K(+) channels (GIRK), acetylcholine (ACh)-evoked K(+)
current, I(KACh), was recorded from adult rat atrial cardiomyocytes using the
whole cell patch clamp method and a fast perfusion system. The rise time of
I(KACh ) was 0. 4 +/- 0.1 s. When isoproterenol (Iso) was applied simultaneously
with ACh, an additional slow component (11.4 +/- 3.0 s) appeared, and the
amplitude of the elicited I(KACh) was increased by 22.9 +/- 5.4%. Both the slow
component of activation and the current increase caused by Iso were abolished by
preincubation in 50 microM H89 (N-[2-((p -bromocinnamyl)amino)ethyl]-5
isoquinolinesulfonamide, a potent inhibitor of PKA). This heterologous
facilitation of GIRK current by beta-adrenergic stimulation was further studied
in Xenopus laevis oocytes coexpressing beta(2)-adrenergic receptors, m(2 )
receptors, and GIRK1/GIRK4 subunits. Both Iso and ACh elicited GIRK currents in
these oocytes. Furthermore, Iso facilitated ACh currents in a way, similar to
atrial cells. Cytosolic injection of 30-60 pmol cAMP, but not of Rp-cAMPS (a cAMP
analogue that is inhibitory to PKA) mimicked the beta(2)-adrenergic effect. The
possibility that the potentiation of GIRK currents was a result of the
phosphorylation of the beta-adrenergic receptor (beta(2)AR) by PKA was excluded
by using a mutant beta(2)AR in which the residues for PKA-mediated modulation
were mutated. Overexpression of the alpha subunit of G proteins (Galpha(s)) led
to an increase in basal as well as agonist-induced GIRK1/GIRK4 currents
(inhibited by H89). At higher levels of expressed Galpha(s), GIRK currents were
inhibited, presumably due to sequestration of the beta/gamma subunit dimer of G
protein. GIRK1/GIRK5, GIRK1/GIRK2, and homomeric GIRK2 channels were also
regulated by cAMP injections. Mutant GIRK1/GIRK4 channels in which the 40 COOH
terminal amino acids (which contain a strong PKA phosphorylation consensus site)
were deleted were also modulated by cAMP injections. Hence, the structural
determinant responsible is not located within this region. We conclude that, both
in atrial myocytes and in Xenopus oocytes, beta-adrenergic stimulation
potentiates the ACh-evoked GIRK channels via a pathway that involves PKA
catalyzed phosphorylation downstream from beta(2)AR.
PMID- 10779315
TI - Annexins V and XII alter the properties of planar lipid bilayers seen by
conductance probes.
AB - Annexins are proteins that bind lipids in the presence of calcium. Though
multiple functions have been proposed for annexins, there is no general agreement
on what annexins do or how they do it. We have used the well-studied conductance
probes nonactin, alamethicin, and tetraphenylborate to investigate how annexins
alter the functional properties of planar lipid bilayers. We found that annexin
XII reduces the nonactin-induced conductance to approximately 30% of its original
value. Both negative lipid and approximately 30 microM Ca(2+) are required for
the conductance reduction. The mutant annexin XIIs, E105K and E105K/K68A, do not
reduce the nonactin conductance even though both bind to the membrane just as
wild-type does. Thus, subtle changes in the interaction of annexins with the
membrane seem to be important. Annexin V also reduces nonactin conductance in
nearly the same manner as annexin XII. Pronase in the absence of annexin had no
effect on the nonactin conductance. But when added to the side of the bilayer
opposite that to which annexin was added, pronase increased the nonactin-induced
conductance toward its pre-annexin value. Annexins also dramatically alter the
conductance induced by a radically different probe, alamethicin. When added to
the same side of the bilayer as alamethicin, annexin has virtually no effect, but
when added trans to the alamethicin, annexin dramatically reduces the asymmetry
of the I-V curve and greatly slows the kinetics of one branch of the curve
without altering those of the other. Annexin also reduces the rate at which the
hydrophobic anion, tetraphenylborate, crosses the bilayer. These results suggest
that annexin greatly reduces the ability of small molecules to cross the membrane
without altering the surface potential and that at least some fraction of the
active annexin is accessible to pronase digestion from the opposite side of the
membrane.
PMID- 10779316
TI - Identification of a peptide toxin from Grammostola spatulata spider venom that
blocks cation-selective stretch-activated channels.
AB - We have identified a 35 amino acid peptide toxin of the inhibitor cysteine knot
family that blocks cationic stretch-activated ion channels. The toxin, denoted
GsMTx-4, was isolated from the venom of the spider Grammostola spatulata and has
<50% homology to other neuroactive peptides. It was isolated by fractionating
whole venom using reverse phase HPLC, and then assaying fractions on stretch
activated channels (SACs) in outside-out patches from adult rat astrocytes.
Although the channel gating kinetics were different between cell-attached and
outside-out patches, the properties associated with the channel pore, such as
selectivity for alkali cations, conductance ( approximately 45 pS at -100 mV) and
a mild rectification were unaffected by outside-out formation. GsMTx-4 produced a
complete block of SACs in outside-out patches and appeared specific since it had
no effect on whole-cell voltage-sensitive currents. The equilibrium dissociation
constant of approximately 630 nM was calculated from the ratio of association and
dissociation rate constants. In hypotonically swollen astrocytes, GsMTx-4
produces approximately 40% reduction in swelling-activated whole-cell current.
Similarly, in isolated ventricular cells from a rabbit dilated cardiomyopathy
model, GsMTx-4 produced a near complete block of the volume-sensitive cation
selective current, but did not affect the anion current. In the myopathic heart
cells, where the swell-induced current is tonically active, GsMTx-4 also reduced
the cell size. This is the first report of a peptide toxin that specifically
blocks stretch-activated currents. The toxin affect on swelling-activated whole
cell currents implicates SACs in volume regulation.
PMID- 10779317
TI - Polarization of Na(+)/H(+) and Cl(-)/HCO (3)(-) exchangers in migrating renal
epithelial cells.
AB - Cell migration is crucial for processes such as immune defense, wound healing, or
the formation of tumor metastases. Typically, migrating cells are polarized
within the plane of movement with lamellipodium and cell body representing the
front and rear of the cell, respectively. Here, we address the question of
whether this polarization also extends to the distribution of ion transporters
such as Na(+)/H(+) exchanger (NHE) and anion exchanger in the plasma membrane of
migrating cells. Both transporters are required for locomotion of renal
epithelial (Madin-Darby canine kidney, MDCK-F) cells and human melanoma cells
since their blockade reduces the rate of migration in a dose-dependent manner.
Inhibition of migration of MDCK-F cells by NHE blockers is accompanied by a
decrease of pH(i). However, when cells are acidified with weak organic acids,
migration of MDCK-F cells is normal despite an even more pronounced decrease of
pH(i). Under these conditions, NHE activity is increased so that cells are
swelling due to the accumulation of organic anions and Na(+). When exclusively
applied to the lamellipodium, blockers of NHE or anion exchange inhibit migration
of MDCK-F cells as effectively as when applied to the entire cell surface. When
they are directed to the cell body, migration is not affected. These data are
confirmed immunocytochemically in that the anion exchanger AE2 is concentrated at
the front of MDCK-F cells. Our findings show that NHE and anion exchanger are
distributed in a polarized way in migrating cells. They are consistent with
important contributions of both transporters to protrusion of the lamellipodium
via solute uptake and consequent volume increase at the front of migrating cells.
PMID- 10779318
TI - The role of the putative inactivation lid in sodium channel gating current
immobilization.
AB - We investigated the contribution of the putative inactivation lid in voltage
gated sodium channels to gating charge immobilization (i.e., the slow return of
gating charge during repolarization) by studying a lid-modified mutant of the
human heart sodium channel (hH1a) that had the phenylalanine at position 1485 in
the isoleucine, phenylalanine, and methionine (IFM) region of the domain III-IV
linker mutated to a cysteine (ICM-hH1a). Residual fast inactivation of ICM-hH1a
in fused tsA201 cells was abolished by intracellular perfusion with 2.5 mM 2
(trimethylammonium)ethyl methanethiosulfonate (MTSET). The time constants of
gating current relaxations in response to step depolarizations and gating charge
voltage relationships were not different between wild-type hH1a and ICM
hH1a(MTSET). The time constant of the development of charge immobilization
assayed at -180 mV after depolarization to 0 mV was similar to the time constant
of inactivation of I(Na) at 0 mV for hH1a. By 44 ms, 53% of the gating charge
during repolarization returned slowly; i.e., became immobilized. In ICM
hH1a(MTSET), immobilization occurred with a similar time course, although only
31% of gating charge upon repolarization (OFF charge) immobilized. After
modification of hH1a and ICM-hH1a(MTSET) with Anthopleurin-A toxin, a site-3
peptide toxin that inhibits movement of the domain IV-S4, charge immobilization
did not occur for conditioning durations up to 44 ms. OFF charge for both hH1a
and ICM-hH1a(MTSET) modified with Anthopleurin-A toxin were similar in time
course and in magnitude to the fast component of OFF charge in ICM-hH1a(MTSET) in
control. We conclude that movement of domain IV-S4 is the rate-limiting step
during repolarization, and it contributes to charge immobilization regardless of
whether the inactivation lid is bound. Taken together with previous reports,
these data also suggest that S4 in domain III contributes to charge
immobilization only after binding of the inactivation lid.
PMID- 10779319
TI - Kinetic, mechanistic, and structural aspects of unliganded gating of
acetylcholine receptor channels: a single-channel study of second transmembrane
segment 12' mutants.
AB - The spontaneous activity of adult mouse muscle acetylcholine receptor channels,
transiently expressed in HEK-293 cells, was studied with the patch-clamp
technique. To increase the frequency of unliganded openings, mutations at the 12'
position of the second transmembrane segment were engineered. Our results
indicate that: (a) in both wild type and mutants, a C <--> O kinetic scheme
provides a good description of spontaneous gating. In the case of some mutant
constructs, however, additional states were needed to improve the fit to the
data. Similar additional states were also needed in one of six patches containing
wild-type acetylcholine receptor channels; (b) the delta12' residue makes a more
pronounced contribution to unliganded gating than the homologous residues of the
alpha, beta, and straightepsilon subunits; (c) combinations of second
transmembrane segment 12' mutations in the four different subunits appear to have
cumulative effects; (d) the volume of the side chain at delta12' is relevant
because residues larger than the wild-type Ser increase spontaneous gating; (e)
the voltage dependence of the unliganded gating equilibrium constant is the same
as that of diliganded gating, but the voltage dependences of the opening and
closing rate constants are opposite (this indicates that the reaction pathway
connecting the closed and open states of the receptor changes upon ligation); (f)
engineering binding-site mutations that decrease diliganded gating (alphaY93F,
alphaY190W, and alphaD200N) reduces spontaneous activity as well (this suggests
that even in the absence of ligand the opening of the channel is accompanied by a
conformational change at the binding sites); and (g) the diliganded gating
equilibrium constant is also increased by the 12' mutations. Such increase is
independent of the particular ligand used as the agonist, which suggests that
these mutations affect mostly the isomerization step, having little, if any,
effect on the ligand-affinity ratio.
PMID- 10779321
TI - Calcium-induced calcium release in smooth muscle: loose coupling between the
action potential and calcium release.
AB - Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as
elementary calcium release events (calcium sparks) associated with the opening of
L-type Ca(2+) channels. In heart cells, a tight coupling between the gating of
single L-type Ca(2+) channels and ryanodine receptors (RYRs) underlies calcium
release. Here we demonstrate that L-type Ca(2+) channels activate RYRs to produce
CICR in smooth muscle cells in the form of Ca(2+) sparks and propagated Ca(2+)
waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly
linked to the gating of L-type Ca(2+) channels. L-type Ca(2+) channels can open
without triggering Ca(2+) sparks and triggered Ca(2+) sparks are often observed
after channel closure. CICR is a function of the net flux of Ca(2+) ions into the
cytosol, rather than the single channel amplitude of L-type Ca(2+) channels.
Moreover, unlike CICR in striated muscle, calcium release is completely
eliminated by cytosolic calcium buffering. Thus, L-type Ca(2+) channels are
loosely coupled to RYR through an increase in global [Ca(2+)] due to an increase
in the effective distance between L-type Ca(2+) channels and RYR, resulting in an
uncoupling of the obligate relationship that exists in striated muscle between
the action potential and calcium release.
PMID- 10779320
TI - Asymmetric and independent contribution of the second transmembrane segment 12'
residues to diliganded gating of acetylcholine receptor channels: a single
channel study with choline as the agonist.
AB - Mutagenesis studies have suggested that the second transmembrane segment (M2)
plays a critical role during acetylcholine receptor liganded gating. An adequate
description of the relationship between gating and structure of the M2 domain,
however, has been hampered by the fact that many M2 mutations increase the
opening rate constant to levels that, in the presence of acetylcholine, are
unresolvably fast. Here, we show that the use of saturating concentrations of
choline, a low-efficacy agonist, is a convenient tool to circumvent this problem.
In the presence of 20 mM choline: (a) single-channel currents occur in clusters;
(b) fast blockade by choline itself reduces the single-channel conductance by
approximately 50%, yet the excess open-channel noise is only moderate; (c) the
kinetics of gating are fitted best by a single-step, C <--> O model; and (d)
opening and closing rate constants are within a well resolvable range.
Application of this method to a series of recombinant adult mouse muscle M2 12'
mutants revealed that: (a) the five homologous M2 12' positions make independent
and asymmetric contributions to diliganded gating, the delta subunit being the
most sensitive to mutation; (b) mutations at delta12' increase the diliganded
gating equilibrium constant in a manner that is consistent with the sensitivity
of the transition state to mutation being approximately 30% like that of the open
state and approximately 70% like that of the closed state; (c) the relationship
between delta12' amino acid residue volume, hydrophobicity or alpha-helical
tendency, and the gating equilibrium constant of the corresponding mutants is not
straightforward; however, (d) rate and equilibrium constants for the mutant
series are linearly correlated (on log-log plots), which suggests that the
conformational rearrangements upon mutation are mostly local and that the
position of the transition state along the gating reaction coordinate is
unaffected by these mutations.
PMID- 10779322
TI - Nicotinic receptor fourth transmembrane domain: hydrogen bonding by conserved
threonine contributes to channel gating kinetics.
AB - The fourth transmembrane domain (M4) of the nicotinic acetylcholine receptor
(AChR) contributes to the kinetics of activation, yet its close association with
the lipid bilayer makes it the outermost of the transmembrane domains. To
investigate mechanistic and structural contributions of M4 to AChR activation, we
systematically mutated alphaT422, a conserved residue that has been labeled by
hydrophobic probes, and evaluated changes in rate constants underlying ACh
binding and channel gating steps. Aromatic and nonpolar mutations of alphaT422
selectively affect the channel gating step, slowing the rate of opening two- to
sevenfold, and speeding the rate of closing four- to ninefold. Additionally,
kinetic modeling shows a second doubly liganded open state for aromatic and
nonpolar mutations. In contrast, serine and asparagine mutations of alphaT422
largely preserve the kinetics of the wild-type AChR. Thus, rapid and efficient
gating of the AChR channel depends on a hydrogen bond involving the side chain at
position 422 of the M4 transmembrane domain.
PMID- 10779323
TI - Role of the cyclic AMP response element binding complex and activation of mitogen
activated protein kinases in synergistic activation of the glycoprotein hormone
alpha subunit gene by epidermal growth factor and forskolin.
AB - The aim of these studies was to elucidate a role for epidermal growth factor
(EGF) signaling in the transcriptional regulation of the glycoprotein hormone
alpha subunit gene, a subunit of chorionic gonadotropin. Studies examined the
effects of EGF and the adenylate cyclase activator forskolin on the expression of
a transfected alpha subunit reporter gene in a human choriocarcinoma cell line
(JEG3). At maximal doses, administration of EGF resulted in a 50% increase in a
subunit reporter activity; forskolin administration induced a fivefold
activation; the combined actions of EGF and forskolin resulted in synergistic
activation (greater than eightfold) of the alpha subunit reporter. Mutagenesis
studies revealed that the cyclic AMP response elements (CRE) were required and
sufficient to mediate EGF-forskolin-induced synergistic activation. The combined
actions of EGF and forskolin resulted in potentiated activation of extracellular
signal-regulated kinase (ERK) enzyme activity compared with EGF alone. Specific
blockade of ERK activation was sufficient to block EGF-forskolin-induced
synergistic activation of the alpha subunit reporter. Pretreatment of JEG3 cells
with a p38 mitogen-activated protein kinase inhibitor did not influence
activation of the alpha reporter. However, overexpression of c-Jun N-terminal
kinase (JNK)-interacting protein 1 as a dominant interfering molecule abolished
the synergistic effects of EGF and forskolin on the alpha subunit reporter. CRE
binding studies suggested that the CRE complex consisted of CRE binding protein
and EGF-ERK-dependent recruitment of c-Jun-c-Fos (AP-1) to the CRE. A dominant
negative form of c-Fos (A-Fos) that specifically disrupts c-Jun-c-Fos DNA binding
inhibited synergistic activation of the alpha subunit. Thus, synergistic
activation of the alpha subunit gene induced by EGF-forskolin requires the ERK
and JNK cascades and the recruitment of AP-1 to the CRE binding complex.
PMID- 10779324
TI - TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine
proteins.
AB - The translocation liposarcoma (TLS) gene is fused to the ETS-related gene (ERG)
in human myeloid leukemia, resulting in the generation of a TLS-ERG protein. We
demonstrate that both TLS and the TLS-ERG leukemia fusion protein bind to RNA
polymerase II through the TLS N-terminal domain, which is retained in the fusion
protein; however, TLS recruits members of the serine-arginine (SR) family of
splicing factors through its C-terminal domain, whereas the TLS-ERG fusion
protein lacks the ability to recruit SR proteins due to replacement of the C
terminal domain by the fusion partner ERG. In transient-transfection assays, the
TLS-ERG fusion protein inhibits E1A pre-mRNA splicing mediated by these TLS
associated SR proteins (TASR), and stable expression of the TLS-ERG fusion
protein in K562 cells alters the splicing profile of CD44 mRNA. These results
suggest that TLS fusion proteins may lead to cellular abnormalities by
interfering with the splicing of important cellular regulators.
PMID- 10779325
TI - On the mechanism by which alkaline pH prevents expression of an acid-expressed
gene.
AB - Previous work has shown that zinc finger transcription factor PacC mediates the
regulation of gene expression by ambient pH in the fungus Aspergillus nidulans.
This regulation ensures that the syntheses of molecules functioning in the
external environment, such as permeases, secreted enzymes, and exported
metabolites, are tailored to the pH of the growth environment. A direct role for
PacC in activating the expression of an alkaline-expressed gene has previously
been demonstrated, but the mechanism by which alkaline ambient pH prevents the
expression of any eukaryotic acid-expressed gene has never been reported. Here we
show that a double PacC binding site in the promoter of the acid-expressed gabA
gene, encoding gamma-aminobutyrate (GABA) permease, overlaps the binding site for
the transcriptional activator IntA, which mediates omega-amino acid induction.
Using bacterially expressed fusion proteins, we have shown that PacC competes
with IntA for DNA binding in vitro at this site. Thus, PacC repression of GABA
permease synthesis is direct and occurs by blocking induction. A swap of IntA
sites between promoters for gabA and amdS, a gene not subject to pH regulation,
makes gabA expression pH independent and amdS acid expressed.
PMID- 10779326
TI - A functionally essential domain of RFX5 mediates activation of major
histocompatibility complex class II promoters by promoting cooperative binding
between RFX and NF-Y.
AB - Major histocompatibility complex class II (MHC-II) molecules occupy a pivotal
position in the adaptive immune system, and correct regulation of their
expression is therefore of critical importance for the control of the immune
response. Several regulatory factors essential for the transcription of MHC-II
genes have been identified by elucidation of the molecular defects responsible
for MHC-II deficiency, a hereditary immunodeficiency disease characterized by
regulatory defects abrogating MHC-II expression. Three of these factors, RFX5,
RFXAP, and RFXANK, combine to form the RFX complex, a regulatory protein that
binds to the X box DNA sequence present in all MHC-II promoters. In this study we
have undertaken a dissection of the structure and function of RFX5, the largest
subunit of the RFX complex. The results define two distinct domains serving two
different essential functions. A highly conserved N-terminal region of RFX5 is
required for its association with RFXANK and RFXAP, for assembly of the RFX
complex in vivo and in vitro, and for binding of this complex to its X box target
site in the MHC-II promoter. This N-terminal region is, however, not sufficient
for activation of MHC-II expression. This requires an additional domain within
the C-terminal region of RFX5. This C-terminal domain mediates cooperative
binding between the RFX complex and NF-Y, a transcription factor binding to the Y
box sequence of MHC-II promoters. This provides direct evidence that RFX5
mediated cooperative binding between RFX and NF-Y plays an essential role in the
transcriptional activation of MHC-II genes.
PMID- 10779327
TI - Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires
activation of the NF-kappaB pathway and is dependent on p53 phosphorylation.
AB - p53 plays a key role in guarding cells against DNA damage and transformation. We
previously demonstrated that the human T-cell lymphotropic virus type 1 (HTLV-1)
Tax can inactivate p53 transactivation function in lymphocytes. The present study
demonstrates that in T cells, Tax-induced p53 inactivation is dependent upon NF
kappaB activation. Analysis of Tax mutants demonstrated that Tax inactivation of
p53 function correlates with the ability of Tax to induce NF-kappaB but not p300
binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome
by overexpression of a dominant IkappaB mutant. Tax-NF-kappaB-induced p53
inactivation is not due to p300 squelching, since overexpression of p300 does not
recover p53 activity in the presence of Tax. Further, using wild-type and p65
knockout mouse embryo fibroblasts (MEFs), we demonstrate that the p65 subunit of
NF-kappaB is critical for Tax-induced p53 inactivation. While Tax can inactivate
endogenous p53 function in wild-type MEFs, it fails to inactivate p53 function in
p65 knockout MEFs. Importantly, Tax-induced p53 inactivation can be restored by
expression of p65 in the knockout MEFs. Finally, we present evidence that
phosphorylation of serines 15 and 392 correlates with inactivation of p53 by Tax
in T cells. This study provides evidence that the divergent NF-kappaB
proliferative and p53 cell cycle arrest pathways may be cross-regulated at
several levels, including posttranslational modification of p53.
PMID- 10779328
TI - Regulation of the Jak2 tyrosine kinase by its pseudokinase domain.
AB - Activation of Jak tyrosine kinases through hematopoietic cytokine receptors
occurs as a consequence of ligand-induced aggregation of receptor-associated Jaks
and their subsequent autophosphorylation. Jak kinases consist of a C-terminal
tyrosine kinase domain, a pseudokinase domain of unknown function, and Jak
homology (JH) domains 3 to 7, implicated in receptor-Jak interaction. We analyzed
the functional roles of the different protein domains in activation of Jak2.
Deletion analysis of Jak2 showed that the pseudokinase domain but not JH domains
3 to 7 negatively regulated the catalytic activity of Jak2 as well as Jak2
mediated activation of Stat5. Phosphorylation of Stat5 by wild-type Jak2 was
dependent on the SH2 domain of Stat5; however, this requirement was lost upon
deletion of the pseudokinase domain of Jak2. Investigation of the mechanisms of
the pseudokinase domain-mediated inhibition of Jak2 suggested that this
regulation did not involve protein tyrosine phosphatases. Instead, analysis of
interactions between the tyrosine kinase domain and Jak2 suggested that the
pseudokinase domain interacted with the kinase domain. Furthermore, coexpression
of the pseudokinase domain inhibited the activity of the single tyrosine kinase
domain. Finally, deletion of the pseudokinase domain of Jak2 deregulated signal
transduction through the gamma interferon receptor by significantly increasing
ligand-independent activation of Stat transcription factors. These results
indicate that the pseudokinase domain negatively regulates the activity of Jak2,
probably through an interaction with the kinase domain, and this regulation is
required to keep Jak2 inactive in the absence of ligand stimulation. Furthermore,
the pseudokinase domain may have a role in regulation of Jak2-substrate
interactions.
PMID- 10779329
TI - Slap negatively regulates Src mitogenic function but does not revert Src-induced
cell morphology changes.
AB - Src-like adapter protein (Slap) is a recently identified protein that negatively
regulates mitogenesis in murine fibroblasts (S. Roche, G. Alonso, A. Kazlausakas,
V. M. Dixit, S. A. Courtneidge, and A. Pandey, Curr. Biol. 8:975-978, 1998) and
comprises an SH3 and SH2 domain with striking identity to the corresponding Src
domains. In light of this, we sought to investigate whether Slap could be an
antagonist of all Src functions. Like Src, Slap was found to be myristylated in
vivo and largely colocalized with Src when coexpressed in Cos7 cells.
Microinjection of a Slap-expressing construct into quiescent NIH 3T3 cells
inhibited platelet-derived growth factor (PDGF)-induced DNA synthesis, and the
inhibition was rescued by the transcription factor c-Myc but not by c-Jun/c-Fos
expression. Fyn (or Src) overexpression overrides the G(1)/S block induced by
both SrcK- and a Slap mutant with a deletion of its C terminus (SlapDeltaC), but
not the block induced by Slap or SlapDeltaSH3, implying that the C terminus is a
noncompetitive inhibitor of Src mitogenic function. Furthermore, a chimeric
adapter comprising SrcDeltaK fused to the Slap C terminus (Src/SlapC) also
inhibited Src function during the PDGF response in a noncompetitive manner, as
Src coexpression could not rescue PDGF signaling. Slap, however, did not reverse
deregulated Src-induced cell transformation, as it was unable to inhibit
depolymerization of actin stress fibers while still being able to inhibit
SrcY527F-induced DNA synthesis. This was attributed to a distinct Slap SH3
binding specificity, since the chimeric Slap/SrcSH3 molecule, in which the Slap
SH3 was replaced by the Src SH3 sequence, substantially restored stress fiber
formation. Indeed, three amino acids important for ligand binding in Src SH3 were
replaced in the Slap SH3 sequence; Slap SH3 did not bind to the Src SH3 partners
p85alpha, Shc, and Sam68 in vitro, and the chimeric tyrosine kinase Slap/SrcK,
composed of SlapDeltaC fused to the SH2 linker kinase sequence of Src, was not
regulated in vivo. Furthermore, the Src SH3 domain is required for signaling
during mitogenesis and since Slap/SrcK behaved as a dominant negative in the PDGF
mitogenic response when microinjected into quiescent fibroblasts. We conclude
that Slap is a negative regulator of Src during mitogenesis involving both the
SH2 and the C terminus domains in a noncompetitive manner, but it does not
regulate all Src function due to specific SH3 binding substrates.
PMID- 10779330
TI - Bcl-3 expression promotes cell survival following interleukin-4 deprivation and
is controlled by AP1 and AP1-like transcription factors.
AB - We have analyzed the interleukin-4 (IL-4)-triggered mechanisms implicated in cell
survival and show here that IL-4 deprivation induces apoptotic cell death but
does not modulate Bcl-2 or Bcl-x expression. Since Bcl-x expression is
insufficient to ensure cell survival in the absence of IL-4, we speculate that
additional molecules replace the antiapoptotic role of Bcl-2 and Bcl-x in an
alternative IL-4-triggered pathway. Cell death is associated with Bcl-3
downregulation and Bcl-3 expression blocks IL-4 deprivation-induced apoptosis,
suggesting that Bcl-3 acts as a survival factor in the absence of growth factor.
To characterize the IL-4-induced regulation of murine Bcl-3 expression, we cloned
the promoter of this gene. Sequencing of the promoter showed no TATA box element
but did reveal binding sites for AP1, AP1-like, and SP1 transcription factors.
Retardation gels showed that IL-4 specifically induces AP1 and AP1-like binding
activity and that mutation of these binding sites abolishes the IL-4-induced Bcl
3 promoter activity, suggesting that these transcription factors are important in
Bcl-3 promoter transactivation. IL-4 deprivation induces downregulation of Jun
expression and upregulation of Fos expression, both of which are proteins
involved in the formation of AP1 and AP1-like transcription factors.
Overexpression of Jun family proteins transactivates the promoter and restores
Bcl-3 expression in the absence of IL-4 stimulation. Taken together, these data
describe a new biological role for Bcl-3 and define the regulatory pathway
implicated in Bcl-3 expression.
PMID- 10779331
TI - E2F4 and E2F1 have similar proliferative properties but different apoptotic and
oncogenic properties in vivo.
AB - Loss of retinoblastoma (Rb) tumor suppressor function, as occurs in many cancers,
leads to uncontrolled proliferation, an increased propensity to undergo
apoptosis, and tumorigenesis. Rb negatively regulates multiple E2F transcription
factors, but the role of the different E2F family members in manifesting the
cellular response to Rb inactivation is unclear. To study the effect of
deregulated E2F4 activity on cell growth control and tumorigenesis, transgenic
mouse lines expressing the E2F4 gene under the control of a keratin 5 (K5)
promoter were developed, and their phenotypes were compared to those of
previously generated K5 E2F1 transgenic mice. In contrast to what has been
observed in vitro, ectopically expressed E2F4 was found to localize to the
nucleus and induce proliferation to an extent similar to that induced by E2F1 in
transgenic tissue. Unlike E2F1, E2F4 does not induce apoptosis, and this
correlates with the differential abilities of these two E2F species to stimulate
p19(ARF) expression in vivo. To examine the role of E2F4 in tumor development,
the mouse skin two-stage carcinogenesis model was utilized. Unlike E2F1
transgenic mice, E2F4 transgenic mice developed skin tumors with a decreased
latency and increased incidence compared to those characteristics in wild-type
controls. These findings demonstrate that while the effects of E2F1 and E2F4 on
cell proliferation in vivo are similar, their apoptotic and oncogenic properties
are quite different.
PMID- 10779333
TI - SINE retroposons can be used in vivo as nucleation centers for de novo
methylation.
AB - SINEs (short interspersed elements) are an abundant class of transposable
elements found in a wide variety of eukaryotes. Using the genomic sequencing
technique, we observed that plant S1 SINE retroposons mainly integrate in
hypomethylated DNA regions and are targeted by methylases. Methylation can then
spread from the SINE into flanking genomic sequences, creating distal epigenetic
modifications. This methylation spreading is vectorially directed upstream or
downstream of the S1 element, suggesting that it could be facilitated when a
potentially good methylatable sequence is single stranded during DNA replication,
particularly when located on the lagging strand. Replication of a short
methylated DNA region could thus lead to the de novo methylation of upstream or
downstream adjacent sequences.
PMID- 10779332
TI - Repair of intermediate structures produced at DNA interstrand cross-links in
Saccharomyces cerevisiae.
AB - Bifunctional alkylating agents and other drugs which produce DNA interstrand
cross-links (ICLs) are among the most effective antitumor agents in clinical use.
In contrast to agents which produce bulky adducts on only one strand of the DNA,
the cellular mechanisms which act to eliminate DNA ICLs are still poorly
understood, although nucleotide excision repair is known to play a crucial role
in an early repair step. Using haploid Saccharomyces cerevisiae strains disrupted
for genes central to the recombination, nonhomologous end-joining (NHEJ), and
mutagenesis pathways, all these activities were found to be involved in the
repair of nitrogen mustard (mechlorethamine)- and cisplatin-induced DNA ICLs, but
the particular pathway employed is cell cycle dependent. Examination of whole
chromosomes from treated cells using contour-clamped homogenous electric field
electrophoresis revealed the intermediate in the repair of ICLs in dividing
cells, which are mostly in S phase, to be double-strand breaks (DSBs). The origin
of these breaks is not clear since they were still efficiently induced in
nucleotide excision and base excision repair-deficient, mismatch repair
defective, rad27 and mre11 disruptant strains. In replicating cells, RAD52
dependent recombination and NHEJ both act to repair the DSBs. In contrast, few
DSBs were observed in quiescent cells, and recombination therefore seems
dispensable for repair. The activity of the Rev3 protein (DNA polymerase zeta) is
apparently more important for the processing of intermediates in stationary-phase
cells, since rev3 disruptants were more sensitive in this phase than in the
exponential growth phase.
PMID- 10779334
TI - Deficient gene expression in protein kinase inhibitor alpha Null mutant mice.
AB - Protein kinase inhibitor (PKI) is a potent endogenous inhibitor of the cyclic AMP
(cAMP)-dependent protein kinase (PKA). It functions by binding the free catalytic
(C) subunit with a high affinity and is also known to export nuclear C subunit to
the cytoplasm. The significance of these actions with respect to PKI's
physiological role is not well understood. To address this, we have generated by
homologous recombination mutant mice that are deficient in PKIalpha, one of the
three isoforms of PKI. The mice completely lack PKI activity in skeletal muscle
and, surprisingly, show decreased basal and isoproterenol-induced gene expression
in muscle. Further examination revealed reduced levels of the phosphorylated
(active) form of the transcription factor CREB (cAMP response element binding
protein) in the knockouts. This phenomenon stems, at least in part, from lower
basal PKA activity levels in the mutants, arising from a compensatory increase in
the level of the RIalpha subunit of PKA. The deficit in gene induction, however,
is not easily explained by current models of PKI function and suggests that PKI
may play an as yet undescribed role in PKA signaling.
PMID- 10779335
TI - Long palindromic sequences induce double-strand breaks during meiosis in yeast.
AB - Inverted-repeated or palindromic sequences have been found to occur in both
prokaryotic and eukaryotic genomes. Such repeated sequences are usually short and
present at several functionally important regions in the genome. However, long
palindromic sequences are rare and are a major source of genomic instability. The
palindrome-mediated genomic instability is believed to be due to cruciform or
hairpin formation and subsequent cleavage of this structure by structure-specific
nucleases. Here we present both genetic and physical evidence that long
palindromic sequences (>50 bp) generate double-strand breaks (DSBs) at a high
frequency during meiosis in the yeast Saccharomyces cerevisiae. The palindrome
mediated DSB formation depends on the primary sequence of the inverted repeat and
the location and length of the repeated units. The DSB formation at the
palindrome requires all of the gene products that are known to be responsible for
DSB formation at the normal meiosis-specific sites. Since DSBs are initiators of
nearly all meiotic recombination events, most of the palindrome-induced breaks
appear to be repaired by homologous recombination. Our results suggest that short
palindromic sequences are highly stable in vivo. In contrast, long palindromic
sequences make the genome unstable by inducing DSBs and such sequences are
usually removed from the genome by homologous recombination events.
PMID- 10779336
TI - Fission yeast Eso1p is required for establishing sister chromatid cohesion during
S phase.
AB - Sister chromatid cohesion is essential for cell viability. We have isolated a
novel temperature-sensitive lethal mutant named eso1-H17 that displays spindle
assembly checkpoint-dependent mitotic delay and abnormal chromosome segregation.
At the permissive temperature, the eso1-H17 mutant shows mild sensitivity to UV
irradiation and DNA-damaging chemicals. At the nonpermissive temperature, the
mutant is arrested in M phase with a viability loss due to a failure to establish
sister chromatid cohesion during S phase. The lethal M-phase arrest phenotype,
however, is suppressed by inactivation of a spindle checkpoint. The eso1(+) gene
is not essential for the onset and progression of DNA replication but has
remarkable genetic interactions with those genes regulating the G(1)-S transition
and DNA replication. The N-terminal two-thirds of Eso1p is highly homologous to
DNA polymerase eta of budding yeast and humans, and the C-terminal one-third is
homologous to budding yeast Eco1p (also called Ctf7p), which is required for the
establishment of sister chromatid cohesion. Deletion analysis and determination
of the mutation site reveal that the function of the Eco1p/Ctf7p-homologous
domain is necessary and sufficient for sister chromatid cohesion. On the other
hand, deletion of the DNA polymerase eta domain in Eso1p increases sensitivity to
UV irradiation. These results indicate that Eso1p plays a dual role during DNA
replication. The C-terminal region acts to establish sister chromatid cohesion,
and the N-terminal region presumably catalyzes translesion DNA synthesis when
template DNA contains lesions that block regular DNA replication.
PMID- 10779338
TI - Enhanced transformation by a plasma membrane-associated met oncoprotein:
activation of a phosphoinositide 3'-kinase-dependent autocrine loop involving
hyaluronic acid and CD44.
AB - A Met-hepatocyte growth factor receptor oncoprotein, Tpr-Met, generated by
chromosomal rearrangement, fuses a protein dimerization motif with the
cytoplasmic domain of the Met receptor, producing a cytosolic, constitutively
activated tyrosine kinase. Although both the Met receptor and the Tpr-Met
oncoprotein associate with the same substrates, activating mutations of the Met
receptor in hereditary papillary renal carcinomas have different signaling
requirements for transformation than Tpr-Met. This suggests differential
activation of membrane-localized pathways by oncogenic forms of the membrane
bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To establish
which pathways might be differentially regulated, we have localized the
constitutively activated Tpr-Met oncoprotein to the membrane using the c-src
myristoylation signal. Membrane localization enhances cellular transformation,
focus formation, and anchorage-independent growth and induces tumors with a
distinct myxoid phenotype. This correlates with the induction of hyaluronic acid
(HA) and the presence of a distinct form of its receptor, CD44. A pharmacological
inhibitor of phosphoinositide 3' kinase (PI3'K), inhibits the production of HA,
and conversely, an activated, plasma membrane-targeted form of PI3'K is
sufficient to enhance HA production. Furthermore, the multisubstrate adapter
protein Gab-1, which couples the Met receptor with PI3'K, enhances Met receptor
dependent HA synthesis in a PI3'K-dependent manner. These results provide a
positive link to a role for HA and CD44 in Met receptor-mediated oncogenesis and
implicate PI3'K in these events.
PMID- 10779337
TI - Molecular interactions involved in the transactivation of the human T-cell
leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4).
AB - The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral
transcription through three 21-bp repeats located in the U3 region of the HTLV-1
long terminal repeat and called Tax-responsive elements (TxREs). Each TxRE
contains nucleotide sequences corresponding to imperfect cyclic AMP response
elements (CRE). In this study, we demonstrate that the bZIP transcriptional
factor CREB-2 is able to bind in vitro to the TxREs and that CREB-2 binding to
each of the 21-bp motifs is enhanced by Tax. We also demonstrate that Tax can
weakly interact with CREB-2 bound to a cellular palindromic CRE motif such as
that found in the somatostatin promoter. Mutagenesis of Tax and CREB-2
demonstrates that both N- and C-terminal domains of Tax and the C-terminal region
of CREB-2 are required for direct interaction between the two proteins. In
addition, the Tax mutant M47, defective for HTLV-1 activation, is unable to form
in vitro a ternary complex with CREB-2 and TxRE. In agreement with recent results
suggesting that Tax can recruit the coactivator CREB-binding protein (CBP) on the
HTLV-1 promoter, we provide evidence that Tax, CREB-2, and CBP are capable of
cooperating to stimulate viral transcription. Taken together, our data highlight
the major role played by CREB-2 in Tax-mediated transactivation.
PMID- 10779339
TI - Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the
pRb/E2F pathway.
AB - The retinoblastoma protein (pRb)/E2F pathway regulates commitment of mammalian
cells to replicate DNA. On the other hand, mitogen-stimulated cells deprived of
E2F activity can still maintain physiologically relevant levels of cyclin E
dependent kinase activity and gradually enter S phase, suggesting the existence
of a DNA synthesis-inducing mechanism parallel to the pRb/E2F axis. Here we show
that regulatable ectopic expression of cyclin E or transcriptionally active Myc
can rapidly induce DNA synthesis in U2OS-derived cell lines whose E2F activity is
blocked by a constitutively active pRb (pRbDeltacdk) mutant. The effect of Myc is
associated with Cdc25A phosphatase and cyclin E-CDK2 kinase activation and
abolished by antagonizing Myc activity with the dominant-negative (dn) MadMyc
chimera. Moreover, while abrogation of either endogenous E2F or Myc activity only
delays and lowers DNA synthesis in synchronized U2OS cells or rat diploid
fibroblasts, concomitant neutralization of both abolishes it. Whereas ectopic Myc
and E2F1 rescue the G(1)/S delay caused by pRbDeltacdk (or dnDP1) and MadMyc,
respectively, cyclin E or Cdc25A can restore DNA replication even in cells
concomitantly exposed to pRbDeltacdk and MadMyc. However, coexpression of dnCDK2
neutralizes all of these rescuing effects. Finally, proper transcription of
cyclin E and Cdc25A at the G(1)/S transition requires both Myc and E2F
activities, and subthreshold levels of ectopic cyclin E and Cdc25A
synergistically restore DNA synthesis in cells with silenced Myc and E2F
activities. These results suggest that Myc controls a G(1)/S-promoting mechanism
regulating cyclin E-CDK2 in parallel to the "classical" pRb/E2F pathway.
PMID- 10779340
TI - Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1.
AB - The Ran binding protein RanBP1 is localized to the cytosol of interphase cells. A
leucine-rich nuclear export signal (NES) near the C terminus of RanBP1 is
essential to maintain this distribution. We now show that RanBP1 accumulates in
nuclei of cells treated with the export inhibitor, leptomycin B, and collapse of
the nucleocytoplasmic Ran:GTP gradient leads to equilibration of RanBP1 across
the nuclear envelope. Low temperature prevents nuclear accumulation of RanBP1,
suggesting that import does not occur via simple diffusion. Glutathione S
transferase (GST)-RanBP1(1-161), which lacks the NES, accumulates in the nucleus
after cytoplasmic microinjection. In permeabilized cells, nuclear accumulation of
GST-RanBP1(1-161) requires nuclear Ran:GTP but is not inhibited by a dominant
interfering G19V mutant of Ran. Nuclear accumulation is enhanced by addition of
exogenous karyopherins/importins or RCC1, both of which also enhance nuclear Ran
accumulation. Import correlates with Ran concentration. Remarkably, an E37K
mutant of RanBP1 does not import into the nuclei under any conditions tested
despite the fact that it can form a ternary complex with Ran and importin beta.
These data indicate that RanBP1 translocates through the pores by an active,
nonclassical mechanism and requires Ran:GTP for nuclear accumulation. Shuttling
of RanBP1 may function to clear nuclear pores of Ran:GTP, to prevent premature
release of import cargo from transport receptors.
PMID- 10779341
TI - Evidence for the involvement of nucleotide excision repair in the removal of
abasic sites in yeast.
AB - In eukaryotes, DNA damage induced by ultraviolet light and other agents which
distort the helix is removed by nucleotide excision repair (NER) in a fragment
approximately 25 to 30 nucleotides long. In humans, a deficiency in NER causes
xeroderma pigmentosum (XP), characterized by extreme sensitivity to sunlight and
a high incidence of skin cancers. Abasic (AP) sites are formed in DNA as a result
of spontaneous base loss and from the action of DNA glycosylases involved in base
excision repair. In Saccharomyces cerevisiae, AP sites are removed via the action
of two class II AP endonucleases, Apn1 and Apn2. Here, we provide evidence for
the involvement of NER in the removal of AP sites and show that NER competes with
Apn1 and Apn2 in this repair process. Inactivation of NER in the apn1Delta or
apn1Delta apn2Delta strain enhances sensitivity to the monofunctional alkylating
agent methyl methanesulfonate and leads to further impairment in the cellular
ability to remove AP sites. A deficiency in the repair of AP sites may contribute
to the internal cancers and progressive neurodegeneration that occur in XP
patients.
PMID- 10779342
TI - Retinoblastoma protein enhances the fidelity of chromosome segregation mediated
by hsHec1p.
AB - Retinoblastoma protein (Rb) plays important roles in cell cycle progression and
cellular differentiation. It may also participate in M phase events, although
heretofore only circumstantial evidence has suggested such involvement. Here we
show that Rb interacts, through an IxCxE motif and specifically during G(2)/M
phase, with hsHec1p, a protein essential for proper chromosome segregation. The
interaction between Rb and hsHec1p was reconstituted in a yeast strain in which
human hsHEC1 rescues the null mutation of scHEC1. Expression of Rb reduced
chromosome segregation errors fivefold in yeast cells sustained by a temperature
sensitive (ts) hshec1-113 allele and enhanced the ability of wild-type hsHec1p to
suppress lethality caused by a ts smc1 mutation. The interaction between Hec1p
and Smc1p was important for the specific DNA-binding activity of Smc1p.
Expression of Rb restored part of the inactivated function of hshec1-113p and
thereby increased the DNA-binding activity of Smc1p. Rb thus increased the
fidelity of chromosome segregation mediated by hsHec1p in a heterologous yeast
system.
PMID- 10779343
TI - Deletion of the PAT1 gene affects translation initiation and suppresses a PAB1
gene deletion in yeast.
AB - The yeast poly(A) binding protein Pab1p mediates the interactions between the 5'
cap structure and the 3' poly(A) tail of mRNA, whose structures synergistically
activate translation in vivo and in vitro. We found that deletion of the PAT1
(YCR077c) gene suppresses a PAB1 gene deletion and that Pat1p is required for the
normal initiation of translation. A fraction of Pat1p cosediments with free 40S
ribosomal subunits on sucrose gradients. The PAT1 gene is not essential for
viability, although disruption of the gene severely impairs translation
initiation in vivo, resulting in the accumulation of 80S ribosomes and in a large
decrease in the amounts of heavier polysomes. Pat1p contributes to the efficiency
of translation in a yeast cell-free system. However, the synergy between the cap
structure and the poly(A) tail is maintained in vitro in the absence of Pat1p.
Analysis of translation initiation intermediates on gradients indicates that
Pat1p acts at a step before or during the recruitment of the 40S ribosomal
subunit by the mRNA, a step which may be independent of that involving Pab1p. We
conclude that Pat1p is a new factor involved in protein synthesis and that Pat1p
might be required for promoting the formation or the stabilization of the
preinitiation translation complexes.
PMID- 10779344
TI - Binding of equine infectious anemia virus rev to an exon splicing enhancer
mediates alternative splicing and nuclear export of viral mRNAs.
AB - In addition to facilitating the nuclear export of incompletely spliced viral
mRNAs, equine infectious anemia virus (EIAV) Rev regulates alternative splicing
of the third exon of the tat/rev mRNA. In the presence of Rev, this exon of the
bicistronic RNA is skipped in a fraction of the spliced mRNAs. In this report,
the cis-acting requirements for exon 3 usage were correlated with sequences
necessary for Rev binding and transport of incompletely spliced RNA. The presence
of a purine-rich exon splicing enhancer (ESE) was required for exon 3
recognition, and the addition of Rev inhibited exon 3 splicing. Glutathione-S
transferase (GST)-Rev bound to probes containing the ESE, and mutation of GAA
repeats to GCA within the ESE inhibited both exon 3 recognition in RNA splicing
experiments and GST-Rev binding in vitro. These results suggest that Rev
regulates alternative splicing by binding at or near the ESE to block SR protein
ESE interactions. A 57-nucleotide sequence containing the ESE was sufficient to
mediate Rev-dependent nuclear export of incompletely spliced RNAs. Rev export
activity was significantly inhibited by mutation of the ESE or by trans
complementation with SF2/ASF. These results indicate that the ESE functions as a
Rev-responsive element and demonstrate that EIAV Rev mediates exon 3 exclusion
through protein-RNA interactions required for efficient export of incompletely
spliced viral RNAs.
PMID- 10779345
TI - Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that
govern translational repression.
AB - Control of the translational repressor, PHAS-I, was investigated by expressing
proteins with Ser/Thr --> Ala mutations in the five (S/T)P phosphorylation sites.
Results of experiments with HEK293 cells reveal at least three levels of control.
At one extreme is nonregulated phosphorylation, exemplified by constitutive
phosphorylation of Ser82. At an intermediate level, amino acids and insulin
stimulate the phosphorylation of Thr36, Thr45, and Thr69 via mTOR-dependent
processes that function independently of other sites in PHAS-I. At the third
level, the extent of phosphorylation of one site modulates the phosphorylation of
another. This control is represented by Ser64 phosphorylation, which depends on
the phosphorylation of all three TP sites. The five sites have different
influences on the electrophoretic properties of PHAS-I and on the affinity of
PHAS-I for eukaryotic initiation factor 4E (eIF4E). Phosphorylation of Thr45 or
Ser64 results in the most dramatic decreases in eIF4E binding in vitro. However,
each of the sites influences mRNA translation, either directly by modulating the
binding affinity of PHAS-I and eIF4E or indirectly by affecting the
phosphorylation of other sites.
PMID- 10779346
TI - A novel 50-kilodalton fragment of host cell factor 1 (C1) in G(0) cells.
AB - Host cell factor 1 (HCF-1; also called C1) is a 230-kDa protein which is cleaved
posttranslationally into separate but associated N- and C-terminal polypeptides.
These polypeptides are components of the C1 complex, along with Oct-1 and the
viral protein VP16. The C1 complex is formed when herpes simplex virus (HSV)
infects a cell and is responsible for transcription of the HSV immediate-early
genes. A temperature-sensitive mutation in the N-terminal kelch domain of HCF-1
reversibly arrests cells in a G(0)-like state when grown at the nonpermissive
temperature, and the same domain interacts with VP16 in the formation of the C1
complex. The form of HCF-1 in primary G(0) cells was investigated by using
peripheral blood mononucleocytes and serum-arrested human primary fibroblasts. A
novel 50-kDa N-terminal fragment of HCF-1 encompassing the kelch domain was
identified in the cytoplasm of these cells. This fragment arises by proteolysis
of the full-length HCF-1 protein and is able to associate with VP16.
PMID- 10779347
TI - Essential role for the C-terminal noncatalytic region of SHIP in FcgammaRIIB1
mediated inhibitory signaling.
AB - The inositol phosphatase SHIP binds to the FcgammaRIIB1 receptor and plays a
critical role in FcgammaRIIB1-mediated inhibition of B-cell proliferation and
immunoglobulin synthesis. The molecular details of SHIP function are not fully
understood. While point mutations of the signature motifs in the inositol
phosphatase domain abolish SHIP's ability to inhibit calcium flux in B cells,
little is known about the function of the evolutionarily conserved, putative
noncatalytic regions of SHIP in vivo. In this study, through a systematic
mutagenesis approach, we identified the inositol phosphatase domain of SHIP
between amino acids 400 and 866. Through reconstitution of a SHIP-deficient B
cell line with wild-type and mutant forms of SHIP, we demonstrate that the
catalytic domain alone is not sufficient to mediate FcgammaRIIB1/SHIP-dependent
inhibition of B-cell receptor signaling. Expression of a truncation mutant of
SHIP that has intact phosphatase activity but lacks the last 190 amino acids
showed that the noncatalytic region in the C terminus is essential for inhibitory
signaling. Mutation of two tyrosines within this C-terminal region, previously
identified as important in binding to Shc, showed a reduced inhibition of calcium
flux. However, studies with an Shc-deficient B-cell line indicated that Shc-SHIP
complex formation is not required and that other proteins that bind these
tyrosines may be important in FcgammaRIIB1/SHIP-mediated calcium inhibition.
Interestingly, membrane targeting of SHIP lacking the C terminus is able to
restore this inhibition, suggesting a role for the C terminus in localization or
stabilization of SHIP interaction at the membrane. Taken together, these data
suggest that the noncatalytic carboxyl-terminal 190 amino acids of SHIP play a
critical role in SHIP function in B cells and may play a similar role in several
other receptor systems where SHIP functions as a negative regulator.
PMID- 10779348
TI - Role of oxidative phosphorylation in Bax toxicity.
AB - The Bcl-2-related protein Bax is toxic when expressed either in yeast or in
mammalian cells. Although the mechanism of this toxicity is unknown, it appears
to be similar in both cell types and dependent on the localization of Bax to the
outer mitochondrial membrane. To investigate the role of mitochondrial
respiration in Bax-mediated toxicity, a series of yeast mutant strains was
created, each carrying a disruption in either a component of the mitochondrial
electron transport chain, a component of the mitochondrial ATP synthesis
machinery, or a protein involved in mitochondrial adenine nucleotide exchange.
Bax toxicity was reduced in strains lacking the ability to perform oxidative
phosphorylation. In contrast, a respiratory-competent strain that lacked the
outer mitochondrial membrane Por1 protein showed increased sensitivity to Bax
expression. Deficiencies in other mitochondrial proteins did not affect Bax
toxicity as long as the ability to perform oxidative phosphorylation was
maintained. Characterization of Bax-induced toxicity in wild-type yeast
demonstrated a growth inhibition that preceded cell death. This growth inhibition
was associated with a decreased ability to carry out oxidative phosphorylation
following Bax induction. Furthermore, cells recovered following Bax-induced
growth arrest were enriched for a petite phenotype and were no longer able to
grow on a nonfermentable carbon source. These results suggest that Bax expression
leads to an impairment of mitochondrial respiration, inducing toxicity in cells
dependent on oxidative phosphorylation for survival. Furthermore, Bax toxicity is
enhanced in yeast deficient in the ability to exchange metabolites across the
outer mitochondrial membrane.
PMID- 10779349
TI - Phospholipase C is involved in kinetochore function in Saccharomyces cerevisiae.
AB - The budding yeast PLC1 gene encodes a homolog of the delta isoform of mammalian
phosphoinositide-specific phospholipase C. Here, we present evidence that Plc1p
associates with the kinetochore complex CBF3. This association is mediated
through interactions with two established kinetochore proteins, Ndc10p and Cep3p.
We show by chromatin immunoprecipitation experiments that Plc1p resides at
centromeric loci in vivo. Deletion of PLC1, as well as plc1 mutations which
abrogate the interaction of Plc1p with the CBF3 complex, results in a higher
frequency of minichromosome loss, nocodazole sensitivity, and mitotic delay.
Overexpression of Ndc10p suppresses the nocodazole sensitivity of plc1 mutants,
implying that the association of Plc1p with CBF3 is important for optimal
kinetochore function. Chromatin extracts from plc1Delta cells exhibit reduced
microtubule binding to minichromosomes. These results suggest that Plc1p
associates with kinetochores and regulates some aspect of kinetochore function
and demonstrate an intranuclear function of phospholipase C in eukaryotic cells.
PMID- 10779350
TI - Roles for non-TATA core promoter sequences in transcription and factor binding.
AB - Sequence blocks within the core region were swapped among RNA polymerase II
promoters to explore effects on transcription in vitro. The pair of blocks
flanking TATA strongly influenced general transcription, with an additional
effect on promoter activation. These flanking elements induced a change in the
ratio of activated to basal transcription, whereas swapping TATA and initiator
sequences only altered general transcription levels. Swapping the flanking blocks
influenced binding by general transcription factors TBP and TFIIB. The results
suggest that the architecture of the extended core sequence is important in
determining promoter-specific effects on both general transcription levels and
the tightness of regulation.
PMID- 10779352
TI - Identification of a novel E2F3 product suggests a mechanism for determining
specificity of repression by Rb proteins.
AB - The tumor suppressor function of Rb is intimately related to its ability to
interact with E2F and repress the transcription of E2F target genes. Here we
describe a novel E2F product that specifically interacts with Rb in quiescent
cells. This novel E2F, which we term E2F3b, is encoded by a unique mRNA
transcribed from an intronic promoter within the E2F3 locus. The E2F3b RNA
differs from the previously characterized E2F3 RNA, which we now term E2F3a, by
the utilization of a unique coding exon. In contrast to the E2F3a product that is
tightly regulated by cell growth, the E2F3b product is expressed equivalently in
quiescent and proliferating cells. But, unlike the E2F4 and E2F5 proteins, which
are also expressed in quiescent cells and form complexes with the p130 protein,
the E2F3b protein associates with Rb and represents the predominant E2F-Rb
complex in quiescent cells. Thus, the previously described specificity of Rb
function as a transcriptional repressor in quiescent cells coincides with the
association of Rb with this novel E2F product.
PMID- 10779351
TI - UV-Induced stabilization of c-fos and other short-lived mRNAs.
AB - Irradiation of cells with short-wavelength ultraviolet light (UVC) changes the
program of gene expression, in part within less than 15 min. As one of the
immediate-early genes in response to UV, expression of the oncogene c-fos is
upregulated. This immediate induction is regulated at the transcriptional level
and is transient in character, due to the autocatalyzed shutoff of transcription
and the rapid turnover of c-fos mRNA. In an experiment analyzing the kinetics of
c-fos mRNA expression in murine fibroblasts irradiated with UVC, we found that,
in addition to the initial transient induction, c-fos mRNA accumulated in a
second wave starting at 4 to 5 h after irradiation, reaching a maximum at 8 h,
and persisting for several more hours. It was accompanied by an increase in Fos
protein synthesis. The second peak of c-fos RNA was caused by an UV dose
dependent increase in mRNA half-life from about 10 to 60 min. With similar
kinetics, the mRNAs of other UV target genes (i.e., the Kin17 gene, c-jun,
IkappaB, and c-myc) were stabilized (e.g., Kin17 RNA from 80 min to more than 8
h). The delayed response was not due to autocrine cytokine secretion with
subsequent autostimulation of the secreting cells or to UV-induced growth factor
receptor activation. Cells unable to repair UVC-induced DNA damage responded to
lower doses of UVC with an even greater accumulation of c-fos and Kin17 mRNAs
than repair-proficient wild-type cells, suggesting that a process in which a
repair protein is involved regulates mRNA stability. Although resembling the
induction of p53, a DNA damage-dependent increase in p53 was not a necessary
intermediate in the stabilization reaction, since cells derived from p53 knockout
mice showed the same pattern of c-fos and Kin17 mRNA accumulation as wild-type
cells. The data indicate that the signal flow induced by UV radiation addresses
not only protein stability (p53) and transcription but also RNA stability, a
hitherto-unrecognized level of UV-induced regulation.
PMID- 10779353
TI - Complex transcriptional regulatory mechanisms control expression of the E2F3
locus.
AB - E2F transcription activity has been shown to play a critical role in cell growth
control, regulating the expression of a variety of genes that encode proteins
important for the initiation of DNA replication and cell cycle regulation. We
have shown that the E2F3 locus encodes two protein products: the E2F3a product,
which is tightly regulated by cell growth, and the E2F3b product, which is
constitutively expressed throughout the cell cycle. To further explore the
mechanism controlling the expression of the two E2F3 gene products, we analyzed
the genomic sequences flanking the 5' region of E2F3a and E2F3b. We find that a
series of E2F binding sites confer negative control on the E2F3a promoter in
quiescent cells, similar to the control of the E2F1 and E2F2 promoters. In
addition, a group of E-box elements, which are Myc binding sites, confer
responsiveness to Myc and are necessary for full activation of the E2F3a promoter
in response to growth stimulation. Based on these results and past experiments,
it appears that the E2F1, E2F2, and E2F3a genes are similarly regulated by growth
stimulation, involving a combination of E2F-dependent negative control and Myc
mediated positive control. In contrast, the constitutive expression of the E2F3b
gene more closely reflects the control of expression of the E2F4 and E2F5 genes.
PMID- 10779355
TI - IkappaB kinase alpha (IKKalpha) regulation of IKKbeta kinase activity.
AB - Two related kinases, IkappaB kinase alpha (IKKalpha) and IKKbeta, phosphorylate
the IkappaB proteins, leading to their degradation and the subsequent activation
of gene expression by NF-kappaB. IKKbeta has a much higher level of kinase
activity for the IkappaB proteins than does IKKalpha and is more critical than
IKKalpha in modulating tumor necrosis factor alpha activation of the NF-kappaB
pathway. These results indicate an important role for IKKbeta in activating the
NF-kappaB pathway but leave open the question of the role of IKKalpha in
regulating this pathway. In the current study, we demonstrate that IKKalpha
directly phosphorylates IKKbeta. Moreover, IKKalpha either directly or indirectly
enhances IKKbeta kinase activity for IkappaBalpha. Finally, transfection studies
to analyze NF-kappaB-directed gene expression suggest that IKKalpha is upstream
of IKKbeta in activating the NF-kappaB pathway. These results indicate that
IKKalpha, in addition to its previously described ability to phosphorylate
IkappaBalpha, can increase the ability of IKKbeta to phosphorylate IkappaBalpha.
PMID- 10779354
TI - Overlapping expression of early B-cell factor and basic helix-loop-helix proteins
as a mechanism to dictate B-lineage-specific activity of the lambda5 promoter.
AB - The basic helix-loop-helix (bHLH) transcription factors are a large group of
proteins suggested to control key events in the development of B lymphocytes as
well as of other cellular lineages. To examine how bHLH proteins activate a B
lineage-specific promoter, I investigated the ability of E47, E12, Heb, E2-2, and
MyoD to activate the lambda5 surrogate light chain promoter. Comparison of the
functional capacity of the E2A-encoded E47 and E12 proteins indicated that even
though both were able to activate the lambda5 promoter and act in synergy with
early B-cell factor (EBF), E47 displayed a higher functional activity than E12.
An ability to act in synergy with EBF was also observed for Heb, E2-2, and MyoD,
suggesting that these factors were functionally redundant in this regard. Mapping
of functional domains in EBF and E47 revealed that the dimerization and DNA
binding domains mediated the synergistic activity. Electrophoretic mobility shift
assay analysis using the 5' part of the lambda5 promoter revealed formation of
template-dependent heteromeric complexes between EBF and E47, suggesting that the
synergistic mechanism involves cooperative binding to DNA. These findings propose
a unique molecular function for E47 and provide overlapping expression with EBF
as a molecular mechanism to direct B-cell-specific target gene activation by bHLH
proteins.
PMID- 10779356
TI - Distinct phosphoisoforms of the Xenopus Mcm4 protein regulate the function of the
Mcm complex.
AB - Initiation of DNA replication in eukaryotes requires the assembly of
prereplication complexes (pre-Rcs) at the origins of replication. The assembly
and function of the pre-Rcs appear to be controlled by phosphorylation events. In
this study we report the detailed characterization of the cell cycle
phosphorylation of one component of the Xenopus pre-Rcs, the Mcm protein complex.
We show that individual Mcm subunits are differentially phosphorylated during the
cell cycle. During mitosis, the Mcm4 subunit is hyperphosphorylated, while the
other subunits are not actively phosphorylated. The mitotic phosphorylation of
Mcm4 requires Cdc2-cyclin B and other unknown kinases. Following exit from
mitosis, the Mcm4 subunit of the cytosolic interphase complex undergoes
dephosphorylation, and the Mcm2, Mcm3, or Mcm6 subunits are then actively
phosphorylated by kinase(s) other than cyclin-dependent kinases (Cdks) or Cdc7.
The association of the Mcm complex with the pre-Rcs correlates with the formation
of a transient interphase complex. This complex contains an intermediately
phosphorylated Mcm4 subunit and is produced by partial dephosphorylation of the
mitotic hyperphosphorylated Mcm4 protein. Complete dephosphorylation of the Mcm4
subunit inactivates the Mcm complex and prevents its binding to the chromatin.
Once the Mcm complex is assembled on the chromatin the Mcm4 and the Mcm2 proteins
are the only subunits phosphorylated during the activation of the pre-Rcs. These
chromatin-associated phosphorylations require nuclear transport and are
independent of Cdk2-cyclin E. These results suggest that the changes in Mcm4
phosphorylation regulate pre-Rc assembly and the function of the pre-Rcs on the
chromatin.
PMID- 10779357
TI - Role of the mitochondrial Hsp70s, Ssc1 and Ssq1, in the maturation of Yfh1.
AB - The mitochondrial matrix of the yeast Saccharomyces cerevisiae contains two
molecular chaperones of the Hsp70 class, Ssc1 and Ssq1. We report that Ssc1 and
Ssq1 play sequential roles in the import and maturation of the yeast frataxin
homologue (Yfh1). In vitro, radiolabeled Yfh1 was not imported into ssc1-3 mutant
mitochondria, remaining in a protease-sensitive precursor form. As reported
earlier, the Yfh1 intermediate form was only slowly processed to the mature form
in Deltassq1 mitochondria (S. A. B. Knight, N. B. V. Sepuri, D. Pain, and A.
Dancis, J. Biol. Chem. 273:18389-18393, 1998). However, the intermediate form in
both wild-type and Deltassq1 mitochondria was entirely within the inner membrane,
as it was resistant to digestion with protease after disruption of the outer
membrane. Therefore, we conclude that Ssc1, which is present in mitochondria in
approximately a 1,000-fold excess over Ssq1, is required for Yfh1 import into the
matrix, while Ssq1 is necessary for the efficient processing of the intermediate
to the mature form in isolated mitochondria. However, the steady-state level of
mature Yfh1 in Deltassq1 mitochondria is approximately 75% of that found in wild
type mitochondria, indicating that this retardation in processing does not
dramatically affect cellular concentrations. Therefore, Ssq1 likely has roles in
addition to facilitating the processing of Yfh1. Twofold overexpression of Ssc1
partially suppresses the cold-sensitive growth phenotype of Deltassq1 cells, as
well as the accumulation of mitochondrial iron and the defects in Fe/S enzyme
activities normally found in Deltassq1 mitochondria. Deltassq1 mitochondria
containing twofold-more Ssc1 efficiently converted the intermediate form of Yfh1
to the mature form. This correlation between the observed processing defect and
suppression of in vivo phenotypes suggests that Ssc1 is able to carry out the
functions of Ssq1, but only when present in approximately a 2,000-fold excess
over normal levels of Ssq1.
PMID- 10779358
TI - ADP-ribosylation factor 6 regulates actin cytoskeleton remodeling in coordination
with Rac1 and RhoA.
AB - In this study, we have documented an essential role for ADP-ribosylation factor 6
(ARF6) in cell surface remodeling in response to physiological stimulus and in
the down regulation of stress fiber formation. We demonstrate that the G-protein
coupled receptor agonist bombesin triggers the redistribution of ARF6- and Rac1
containing endosomal vesicles to the cell surface. This membrane redistribution
was accompanied by cortical actin rearrangements and was inhibited by dominant
negative ARF6, implying that bombesin is a physiological trigger of ARF6
activation. Furthermore, these studies provide a new model for bombesin-induced
Rac1 activation that involves ARF6-regulated endosomal recycling. The bombesin
elicited translocation of vesicular ARF6 was mimicked by activated Galphaq and
was partially inhibited by expression of RGS2, which down regulates Gq function.
This suggests that Gq functions as an upstream regulator of ARF6 activation. The
ARF6-induced peripheral cytoskeletal rearrangements were accompanied by a
depletion of stress fibers. Moreover, cells expressing activated ARF6 resisted
the formation of stress fibers induced by lysophosphatidic acid. We show that the
ARF6-dependent inhibition of stress fiber formation was due to an inhibition of
RhoA activation and was overcome by expression of a constitutively active RhoA
mutant. The latter observations demonstrate that activation of ARF6 down
regulates Rho signaling. Our findings underscore the potential roles of ARF6,
Rac1, and RhoA in the coordinated regulation of cytoskeletal remodeling.
PMID- 10779359
TI - Role of Gab1 in heart, placenta, and skin development and growth factor- and
cytokine-induced extracellular signal-regulated kinase mitogen-activated protein
kinase activation.
AB - Gab1 is a member of the Gab/DOS (Daughter of Sevenless) family of adapter
molecules, which contain a pleckstrin homology (PH) domain and potential binding
sites for SH2 and SH3 domains. Gab1 is tyrosine phosphorylated upon stimulation
of various cytokines, growth factors, and antigen receptors in cell lines and
interacts with signaling molecules, such as SHP-2 and phosphatidylinositol 3
kinase, although its biological roles have not yet been established. To reveal
the functions of Gab1 in vivo, we generated mice lacking Gab1 by gene targeting.
Gab1-deficient embryos died in utero and displayed developmental defects in the
heart, placenta, and skin, which were similar to phenotypes observed in mice
lacking signals of the hepatocyte growth factor/scatter factor, platelet-derived
growth factor, and epidermal growth factor pathways. Consistent with these
observations, extracellular signal-regulated kinase mitogen-activated protein
(ERK MAP) kinases were activated at much lower levels in cells from Gab1
deficient embryos in response to these growth factors or to stimulation of the
cytokine receptor gp130. These results indicate that Gab1 is a common player in a
broad range of growth factor and cytokine signaling pathways linking ERK MAP
kinase activation.
PMID- 10779360
TI - p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking
p53, p21, and/or gadd45 genes.
AB - Human cells lacking functional p53 exhibit a partial deficiency in nucleotide
excision repair (NER), the pathway for repair of UV-induced DNA damage. The
global genomic repair (GGR) subpathway of NER, but not transcription-coupled
repair (TCR), is mainly affected by p53 loss or inactivation. We have utilized
mouse embryo fibroblasts (MEFs) lacking p53 genes or downstream effector genes of
the p53 pathway, gadd45 (Gadd45a) or p21 (Cdkn1a), as well as MEFs lacking both
gadd45 and p21 genes to address the potential contribution of these downstream
effectors to p53-associated DNA repair. Loss of p53 or gadd45 had a pronounced
effect on GGR, while p21 loss had only a marginal effect, determined by
measurements of repair synthesis (unscheduled DNA synthesis), by immunoassays to
detect removal of UV photoproducts from genomic DNA, and by assays determining
strand-specific removal of CPDs from the mouse dhfr gene. Taken together, the
evidence suggests a role for Gadd45, but relatively little role for p21, in DNA
repair responses to UV radiation. Recent evidence suggests that Gadd45 binds to
UV-damaged chromatin and may affect lesion accessibility. MEFs lacking p53 or
gadd45 genes exhibited decreased colony-forming ability after UV radiation and
cisplatin compared to wild-type MEFs, indicating their sensitivity to DNA damage.
We provide evidence that Gadd45 affects chromatin remodelling of templates
concurrent with DNA repair, thus indicating that Gadd45 may participate in the
coupling between chromatin assembly and DNA repair.
PMID- 10779361
TI - Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are
separable from binding to viral oncoproteins.
AB - The pocket domain of pRB is required for pRB to arrest the cell cycle. This
domain was originally defined as the region of the protein that is necessary and
sufficient for pRB's interaction with adenovirus E1A and simian virus s40 large T
antigen. These oncoproteins, and other pRB-binding proteins that are encoded by a
variety of plant and animal viruses, use a conserved LXCXE motif to interact with
pRB. Similar sequences have been identified in multiple cellular pRB-binding
proteins, suggesting that the viruses have evolved to target a highly conserved
binding site of pRB that is critical for its function. Here we have constructed a
panel of pRB mutants in which conserved amino acids that are predicted to make
close contacts with an LXCXE peptide were altered. Despite the conservation of
the LXCXE binding site throughout evolution, pRB mutants that lack this site are
able to induce a cell cycle arrest in a pRB-deficient tumor cell line. This G(1)
arrest is overcome by cyclin D-cdk4 complexes but is resistant to inactivation by
E7. Consequently, mutants lacking the LXCXE binding site were able to induce a
G(1) arrest in HeLa cells despite the expression of HPV-18 E7. pRB mutants
lacking the LXCXE binding site are defective in binding to adenovirus E1A and
human papillomavirus type 16 E7 protein but exhibit wild-type binding to E2F or
DP, and they retain the ability to interact with CtIP and HDAC1, two
transcriptional corepressors that contain LXCXE-like sequences. Consistent with
these observations, the pRB mutants are able to actively repress transcription.
These observations suggest that viral oncoproteins depend on the LXCXE-binding
site of pRB for interaction to a far greater extent than cellular proteins that
are critical for cell cycle arrest or transcriptional repression. Mutation of
this binding site allows pRB to function as a cell cycle regulator while being
resistant to inactivation by viral oncoproteins.
PMID- 10779363
TI - Characterization of growth-differentiation factor 15, a transforming growth
factor beta superfamily member induced following liver injury.
AB - We have identified a new murine transforming growth factor beta superfamily
member, growth-differentiation factor 15 (Gdf15), that is expressed at highest
levels in adult liver. As determined by Northern analysis, the expression of
Gdf15 in liver was rapidly and dramatically up-regulated following various
surgical and chemical treatments that cause acute liver injury and regeneration.
In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA
localization that appeared to reflect the known patterns of hepatocyte injury in
each experimental treatment. In addition, treatment of two hepatocyte-like cell
lines with either carbon tetrachloride or heat shock induced Gdf15 mRNA
expression, indicating that direct cellular injury can induce Gdf15 expression in
the absence of other cell types, such as inflammatory cells. In order to
investigate the potential functions of Gdf15, we created Gdf15 null mice by gene
targeting. Homozygous null mice were viable and fertile. Despite the dramatic
regulation of Gdf15 expression observed in the partial-hepatectomy and carbon
tetrachloride injury models, we found no differences in the injury responses
between homozygous null mutants and wild-type mice. Our findings suggest either
that Gdf15 does not have a regulatory role in liver injury and regeneration or
that Gdf15 function within the liver is redundant with that of other signaling
molecules.
PMID- 10779362
TI - Structure-function analysis of SUV39H1 reveals a dominant role in heterochromatin
organization, chromosome segregation, and mitotic progression.
AB - SUV39H1, a human homologue of the Drosophila position effect variegation modifier
Su(var)3-9 and of the Schizosaccharomyces pombe silencing factor clr4, encodes a
novel heterochromatic protein that transiently accumulates at centromeric
positions during mitosis. Using a detailed structure-function analysis of SUV39H1
mutant proteins in transfected cells, we now show that deregulated SUV39H1
interferes at multiple levels with mammalian higher-order chromatin organization.
First, forced expression of full-length SUV39H1 (412 amino acids) redistributes
endogenous M31 (HP1beta) and induces abundant associations with inter- and
metaphase chromatin. These properties depend on the C-terminal SET domain,
although the major portion of the SUV39H1 protein (amino acids 89 to 412) does
not display affinity for nuclear chromatin. By contrast, the M31 interaction
surface, which was mapped to the first 44 N-terminal amino acids, together with
the immediately adjacent chromo domain, directs specific accumulation at
heterochromatin. Second, cells overexpressing full-length SUV39H1 display severe
defects in mitotic progression and chromosome segregation. Surprisingly, whereas
localization of centromere proteins is unaltered, the focal, G(2)-specific
distribution of phosphorylated histone H3 at serine 10 (phosH3) is dispersed in
these cells. This phosH3 shift is not observed with C-terminally truncated mutant
SUV39H1 proteins or with deregulated M31. Together, our data reveal a dominant
role(s) for the SET domain of SUV39H1 in the distribution of prominent
heterochromatic proteins and suggest a possible link between a chromosomal
SU(VAR) protein and histone H3.
PMID- 10779364
TI - Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4
antagonists.
AB - The bicyclams represent a new entity of low-molecular weight molecules that
inhibit human immunodeficiency virus (HIV) infection through a specific blockade
of CXCR4 (fusin), the receptor for the CXC chemokine SDF-1 (soluble-derived
factor), which is also used as coreceptor by T-lymphotropic HIV strains to enter
their target cells. The bicyclam AMD3100 or 1,1'-[1,4-phenylenebis(methylene)]
bis-1,4, 8,11-tetraazacyclotetradecane octahydrochloride dihydrate, is able to
block the CXCR4 receptor and to inhibit HIV replication at nanomolar
concentrations while not being toxic to the host cells at 100,000-fold higher
concentrations. It is the most specific and most potent CXCR4 antagonist that has
been described to date.
PMID- 10779365
TI - The guanine nucleotide exchange factor RasGRP is a high -affinity target for
diacylglycerol and phorbol esters.
AB - RasGRP is a recently described guanine nucleotide exchange factor (GEF) that
possesses a single C1 domain homologous to that of protein kinase C (PKC). The
phorbol ester [(3)H]phorbol 12, 13-dibutyrate ([(3)H]PDBu) bound to this C1
domain (C1-RasGRP) with a dissociation constant of 0.58 +/- 0.08 nM, similar to
that observed previously for PKC. Likewise, the potent PKC activator bryostatin
1, a compound currently in clinical trials, showed high affinity binding for C1
RasGRP. Structure activity analysis using several phorbol ester analogs showed
both similarities and differences in ligand selectivity compared with PKC; the
differences were comparable in magnitude to those between different PKC isoforms.
Similarly, the potency of the PKC inhibitor calphostin C to inhibit [(3)H]PDBu
binding to C1-RasGRP was similar to that observed for PKC. In contrast to the
relative similarities in ligand recognition, the lipid cofactor requirements
differed between RasGRP and PKC. The C1 domain plus the EF-hand motif of RasGRP
(C1EF-RasGRP) was markedly less dependent on acidic phospholipids than was
PKCalpha. The differences in lipid requirements were reflected in differential
ligand selectivity under conditions of limiting lipid. Despite the presence of
twin EF-hand like motifs, calcium did not affect the binding of [(3)H]PDBu to
C1EF-RasGRP. We conclude that RasGRP is a high affinity receptor for phorbol
esters and diacylglycerol. RasGRP thus provides a direct link between
diacylglycerol generation or phorbol ester/bryostatin treatment and Ras
activation.
PMID- 10779366
TI - Regulation of recombinant gamma-aminobutyric acid (GABA)(A) and GABA(C) receptors
by protein kinase C.
AB - Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate induced a
continuous decrease in the gamma-aminobutyric acid (GABA)-activated current
amplitude from recombinant GABA receptors (formed by rho1 or alphabetagamma
subunits) expressed in Xenopus oocytes. This decline was due to internalization
of receptors from the plasma membrane as confirmed by a decrease in surface
fluorescence with green fluorescence protein-tagged receptors as well as a
concomitant decrease in surface [(3)H]GABA binding. PMA specifically caused
internalization of GABA receptors, but not neuronal acetylcholine receptors
(alpha(7) or alpha(4)beta(2)), indicating the internalization was not a general,
nonspecific phenomenon. Mutation of rho1 PKC phosphorylation sites, identified by
in vitro phosphorylation, did not prevent GABA receptor internalization, nor did
coexpression of the rho1 M3-M4 intracellular loop along with rho1 GABA receptors.
It is likely that PKC-mediated phosphorylation of other proteins, rather than
rho1 itself, was required for the internalization. Both rho1 and alphabetagamma
receptors did not degrade after phorbol 12-myristate 13-acetate-induced
internalization, but returned to the membrane surface within 24 h. These data
suggest internalized receptors can exist in an intracellular compartment that can
be delivered back to the plasma membrane. Thus, by regulating GABA receptor
surface expression, PKC may play a key role in the regulation of GABA-mediated
inhibition.
PMID- 10779367
TI - Up-regulation of airway smooth muscle histamine H(1) receptor mRNA, protein, and
function by beta(2)-adrenoceptor activation.
AB - Histamine, released from activated mast cells, causes bronchoconstriction
mediated by H(1) receptors, whereas beta(2)-agonists are widely used for the
relief of bronchoconstriction. In this study, we examined the effects of the
beta(2)-adrenoceptor agonist, fenoterol, on the expression of H(1) receptors at
the mRNA and protein levels, and functional responses. Incubation of bovine
tracheal smooth muscle with fenoterol (10(-7) M) for 2 h increased H(1) receptor
mRNA (maximum approximately 190%). The number of H(1) receptors was increased
after 12 and 18 h without any change in binding affinity. In the contraction
experiments, the concentration-response curves for histamine-induced contraction
were shifted significantly to the left after 18-h exposure to fenoterol,
consistent with the increase in receptor number. The fenoterol-induced increase
in H(1) receptor mRNA was concentration-dependent and was abolished by
propranolol and ICI 118551, but not by CGP 20712A, indicating that fenoterol acts
via beta(2)-adrenoceptors. These effects were mimicked by other cAMP-elevating
agents forskolin and prostaglandin E(2), and by the stable cAMP analog 8-bromo
cAMP. Cycloheximide alone produced superinduction of H(1) receptor mRNA and
augmented the fenoterol-induced increase in H(1) receptor mRNA. Fenoterol
increased both the stability and the transcription rate of H(1) receptor mRNA.
Pretreatment with dexamethasone did not prevent fenoterol-induced up-regulation
of H(1) receptor mRNA. Thus, fenoterol increases the expression of airway smooth
muscle H(1) receptors via activation of the cAMP system through increased gene
transcription and mRNA stability. This mechanism may be involved in the adverse
responses encountered with the clinical use of short-acting beta(2)-agonists.
PMID- 10779368
TI - Stimulatory effects of delta-hexachlorocyclohexane on Ca(2+)-activated K(+)
currents in GH(3) lactotrophs.
AB - delta-Hexachlorocyclohexane (delta-HCH), a lipophilic neurodepressant agent, has
been shown to inhibit neurotransmitter release and stimulate ryanodine-sensitive
Ca(2+) channels. However, the effect of delta-HCH on neuronal activity remains
unclear, although it may enhance the gamma-aminobutyric acid-induced current. Its
effects on ionic currents were investigated in rat pituitary GH(3) cells and
human neuroblastoma IMR-32 cells. In GH(3) cells, delta-HCH increased the
amplitude of Ca(2+)-activated K(+) current (I(K(Ca))). delta-HCH (100 microM)
slightly inhibited the amplitude of voltage-dependent K(+) current. delta-HCH (30
microM) suppressed voltage-dependent L-type Ca(2+) current (I(Ca, L)), whereas
gamma-HCH (30 microM) had no effect on I(Ca, L). In the inside-out configuration,
delta-HCH applied intracellularly did not change the single channel conductance
of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels; however, it did
increase the channel activity. The delta-HCH-mediated increase in the channel
activity is mainly mediated by its increase in the number of long-lived openings.
delta-HCH reversibly increased the activity of BK(Ca) channels in a concentration
dependent manner with an EC(50) value of 20 microM. delta-HCH also caused a left
shift in the midpoint for the voltage-dependent opening. In contrast, gamma-HCH
(30 microM) suppressed the activity of BK(Ca) channels. Under the current-clamp
mode, delta-HCH (30 microM) reduced the firing rate of spontaneous action
potentials; however, gamma-HCH (30 microM) increased it. In neuroblastoma IMR-32
cells, delta-HCH also increased the amplitude of I(K(Ca)) and stimulated the
activity of intermediate-conductance K(Ca) channels. This study provides evidence
that delta-HCH is an opener of K(Ca) channels. The effects of delta-HCH on these
channels may partially, if not entirely, be responsible for the underlying
cellular mechanisms by which delta-HCH affects neuronal or neuroendocrine
function.
PMID- 10779369
TI - Mutating the highly conserved second membrane-spanning region 9' leucine residue
in the alpha(1) or beta(1) subunit produces subunit-specific changes in the
function of human alpha(1)beta(1) gamma-aminobutyric Acid(A) receptors.
AB - The properties of the human alpha(1)beta(1) gamma-aminobutyric acid (GABA)(A)
receptors were investigated after mutation of a highly conserved leucine residue
at the 9' position in the second membrane-spanning region (TM2). The role of this
residue in alpha(1) and beta(1) subunits was examined by mutating the 9' leucine
to phenylalanine, tyrosine, or alanine. The mutations were in either the alpha(1)
subunit (alpha*beta), the beta(1) subunit (alphabeta*), or in both subunits
(alpha*beta*), and the receptors were expressed in Sf9 cells. Our results show
that the rate of desensitization is increased as the size and hydrophobicity of
the 9' residue in the alpha(1) subunit is increased: Y, F > L > A, T. Mutation of
L9' in only the beta(1) subunit (alphabeta*) to either phenylalanine or tyrosine
increased the EC(50) value for GABA at least 100 times, but the EC(50) was
unchanged in alphabeta* alanine mutants. In the 9' alpha(1) mutants (alpha*beta,
alpha*beta*) the GABA EC(50) was minimally affected. In alpha*beta and
alpha*beta*, but not alphabeta*, the peak currents evoked by millimolar
concentrations of GABA were greatly reduced. The reduction in currents could only
be partially accounted for by decreased expression of the receptors These
findings suggest different roles for the two types of subunits in GABA activation
and later desensitization of alpha(1)beta(1) receptors. In addition, an increase
in the resting membrane conductance was recorded in alanine but not in
phenylalanine and tyrosine mutants, indicating that the side chain size at the 9'
position is a major determinant of current flow in the closed conformation.
PMID- 10779370
TI - Importance of valine at position 152 for the substrate transport and 2beta
carbomethoxy-3beta-(4-fluorophenyl)tropane binding of dopamine transporter.
AB - Human and bovine dopamine transporters (DAT) demonstrate discrete functional
differences in dopamine (DA), 1-methyl-4-phenylpyridium (MPP(+)) transport, and
cocaine analog binding. In a previous study, the functional analyses on the
chimeras of human and bovine DAT have revealed that the region from residues 133
through 186 (encompassing the third transmembrane domain) is responsible for the
substrate transport and cocaine analog binding. The present study has been
carried out to determine the specific amino acid(s) conferring DAT functions by
interchanging the amino acid residues in the corresponding region between human
and bovine DAT. As described previously, the DA, MPP(+) transport, and 2beta
carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding almost disappeared in
chimera hb3 in which the region from residues 133 through 186 of bovine DAT was
substituted into human DAT. Replacement of isoleucine, residue 152 of chimera hb3
(bovine DAT sequence), with valine, the human DAT residue at the identical
position, remarkably restored the substrate transport and CFT binding to 76% to
98% of the human DAT values. Similarly, substitution of isoleucine for valine at
position 152 in the human DAT reduced the substrate transport and CFT binding by
57% to 97%. Among other amino acids tested at position 152 of the chimera hb3,
only alanine resulted in small but significant increases in the DAT functions
ranging from 16 to 34%. Thus, valine at position 152 plays a crucial role for
molecular mechanisms underlying the interactions of DA, MPP(+), and CFT with
human DAT.
PMID- 10779371
TI - The effect of mutations in the DRY motif on the constitutive activity and
structural instability of the histamine H(2) receptor.
AB - In previous studies we showed that the wild-type histamine H(2) receptor stably
expressed in Chinese hamster ovary cells is constitutively active. Because
constitutive activity of the H(2) receptor is already found at low expression
levels (300 fmol/mg protein) this receptor is a relatively unique member of the G
protein-coupled receptor (GPCR) family and a useful tool for studying GPCR
activation. In this study the role of the highly conserved DRY motif in
activation of the H(2) receptor was investigated. Mutation of the aspartate 115
residue in this motif resulted in H(2) receptors with high constitutive activity,
increased agonist affinity, and increased signaling properties. In addition, the
mutant receptors were shown to be highly structurally instable. Mutation of the
arginine 116 residue in the DRY motif resulted also in a highly structurally
instable receptor; expression of the receptor could only be detected after
stabilization with either an agonist or inverse agonist. Moreover, the agonist
affinity at the Arg-116 mutant receptors was increased, whereas the signal
transduction properties of these receptors were decreased. We conclude that the
Arg-116 mutant receptors can adopt an active conformation but have a decreased
ability to couple to or activate the G(s)-protein. This study examines the
pivotal role of the aspartate and arginine residues of the DRY motif in GPCR
function. Disruption of receptor stabilizing constraints by mutation in the DRY
motif leads to the formation of active GPCR conformations, but concomitantly to
GPCR instability.
PMID- 10779372
TI - Mechanism-based inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2
bromovinyl)uracil in the presence of NADPH.
AB - Purified recombinant human dihydropyrimidine dehydrogenase (hDPD) was incubated
with (14)C-labeled (E)-5-(2-bromovinyl)uracil ([(14)C]BVU) in the presence of
NADPH to investigate a possible mechanism in the 18 patient deaths caused by
interactions of 5-fluorouracil prodrugs with the new oral antiviral drug,
sorivudine. BVU is formed from sorivudine by gut flora and absorbed through
intestinal membrane. hDPD, a rate-limiting enzyme for the catabolism of 5
fluorouracil and endogenous pyrimidines in the human, was NADPH dependently
radiolabeled and inactivated by [(14)C]BVU. Two radioactive tryptic fragments, I
and II, isolated from radiolabeled hDPD were found by complete amino acid
sequencing to originate from a common regional amino acid sequence located at
positions 656 (Lys) to 678 (Arg) for I and positions 657 (Ser) to 678 (Arg) for
II. However, only Cys(671), which should be present in the peptides, was not
identified by amino acid sequencing. Mass spectrometric analysis of the tryptic
fragments indicated that the sulfhydryl group of Cys(671) in the hDPD was
modified with 5, 6-dihydro-5-(2-bromoethylydenyl)uracil (BEDU), a putative allyl
bromide type of reactive molecule, to form a sulfide bond with loss of hydrogen
bromide. The Cys(671) sulfide bearing the debrominated BEDU had a 5,6
dihydrouracil ring highly strained by the exocyclic double bond at the 5
position, so that it underwent facile hydrolytic ring fission with alkali and
heated acid treatments. A new proposal is also made for the amino acid sequence
of the pyrimidine-binding domain, including Cys(671), of DPD in the human and
other species.
PMID- 10779373
TI - The neuroprotective agent riluzole activates the two P domain K(+) channels TREK
1 and TRAAK.
AB - Riluzole (RP 54274) is a potent neuroprotective agent with anticonvulsant,
sedative, and anti-ischemic properties. It is currently used in the treatment of
amyotrophic lateral sclerosis. This article reports that riluzole is an activator
of TREK-1 and TRAAK, two important members of a new structural family of
mammalian background K(+) channels with four transmembrane domains and two pore
regions. Whereas riluzole activation of TRAAK is sustained, activation of TREK-1
is transient and is followed by an inhibition. The inhibitory process is
attributable to an increase of the intracellular cAMP concentration by riluzole
that produces a protein kinase A-dependent inhibition of TREK-1. Mutants of TREK
1 lacking the Ser residue where the kinase A phosphorylation takes place are
activated in a sustained manner by riluzole. TRAAK is permanently activated by
riluzole because, unlike TREK-1, it lacks the negative regulation by cAMP.
PMID- 10779374
TI - 125I-alpha-conotoxin MII identifies a novel nicotinic acetylcholine receptor
population in mouse brain.
AB - alpha-Conotoxin MII (CtxMII), a peptide toxin from the venom of the predatory
cone snail Conus magus, displays an unusual nicotinic pharmacology. Specific
binding of a radioiodinated derivative ((125)I-alpha-CtxMII) was identified in
brain region homogenates and tissue sections. Quantitative autoradiography
indicated that (125)I-alpha-CtxMII binding sites have an unique pharmacological
profile and distribution in mouse brain, being largely confined to the
superficial layers of the superior colliculus, nigrostriatal pathway, optic
tract, olivary pretectal, and mediolateral and dorsolateral geniculate nuclei.
Expression of alpha-CtxMII binding sites in the nigrostriatal pathway, combined
with evidence for alpha-CtxMII-sensitivity of nicotine-induced [(3)H]dopamine
release in rodent striatal preparations indicates that (125)I-alpha-CtxMII
binding nicotinic acetylcholine receptors are likely to be physiologically
important. Unlabeled alpha-CtxMII potently (K(i) < 3 nM) competed for a subset of
[(3)H]epibatidine binding sites in mouse brain homogenates, but weakly (IC(50) >
10 microM) interacted with (125)I-alpha-bungarotoxin and (-)-[(3)H]nicotine
binding sites, confirming this compound's novel nicotinic pharmacology.
Quantitative autoradiography revealed that alpha-CtxMII binds with high affinity
at a subset of [(3)H]epibatidine binding sites with relatively low cytisine
affinity ("cytisine-resistant" sites), resolving [(3)H]epibatidine binding into
three different populations, each probably corresponding to a receptor subtype.
The majority population seems to correspond to that which binds nicotine and
cytisine with high affinity ("cytisine-sensitive" sites). Comparison of the
cytisine-resistant population's distribution with that of alpha3 subunit mRNA
expression suggests that the fractions both more and less sensitive to alpha
CtxMII probably contain the alpha3 subunit, perhaps in combination with different
beta subunits.
PMID- 10779375
TI - ATP, an agonist at the rat P2Y(4) receptor, is an antagonist at the human P2Y(4)
receptor.
AB - The nucleotide selectivities of the human P2Y(4) (hP2Y(4)) and rat P2Y(4)
(rP2Y(4)) receptor stably expressed in 1321N1 human astrocytoma cells were
determined by measuring increases in intracellular [Ca(2+)] under conditions that
minimized metabolism, bioconversion, and endogenous nucleotide release. In cells
expressing the hP2Y(4) receptor, UTP, GTP, and ITP all increased intracellular
[Ca(2+)] with a rank order of potency of UTP (0.55) > GTP (6.59) = ITP (7.38),
(EC(50), microM). ATP, CTP, xanthine 5'-triphosphate (XTP), and diadenosine
5',5"'-P(1), P(4)-tetraphosphate (Ap(4)A), all at 100 microM, were inactive at
the hP2Y(4) receptor. In cells expressing the rP2Y(4) receptor, all seven
nucleotides increased intracellular [Ca(2+)] with similar maximal effects and a
rank order of potency of UTP (0.20) > ATP (0. 51) > Ap(4)A (1.24) approximately
ITP (1.82) approximately GTP (2. 28) > CTP (7.24) > XTP (22.9). Because ATP is
inactive at the hP2Y(4) receptor, we assessed whether ATP displayed antagonist
activity. When coapplied, ATP shifted the concentration-response curve to UTP
rightward in a concentration-dependent manner, with no change in the maximal
response. A Schild plot derived from these data gave a pA(2) value of 6.15 (K(B)
= 708 nM) and a slope near unity. Additionally, CTP and Ap(4)A (each at 100
microM) inhibited the response to an EC(50) concentration of UTP by approximately
40 and approximately 50%, respectively, whereas XTP had no effect. The inhibitory
effects of ATP, CTP, and Ap(4)A were reversible on washout. Thus, ATP is a potent
agonist at the rP2Y(4) receptor but is a competitive antagonist with moderate
potency at the hP2Y(4) receptor.
PMID- 10779376
TI - Identification of benzodiazepine binding site residues in the gamma2 subunit of
the gamma-aminobutyric acid(A) receptor.
AB - gamma-Aminobutyric acid(A) receptor gamma-subunits are important for
benzodiazepine (BZD) binding and modulation of the gamma-aminobutyric acid
mediated Cl(-) current. Previously, by using gamma2/alpha1 chimeric subunits, we
identified two domains of the gamma2-subunit, Lys-41-Trp-82 and Arg-114-Asp-161,
that are, in conjunction, necessary and sufficient for high-affinity BZD binding.
In this study, we generated additional gamma2/alpha1 chimeric subunits and gamma2
point mutants to identify specific residues within the gamma2 Lys-41-Trp-82
region that contribute to BZD binding. Mutant gamma2 and gamma2/alpha1 chimeric
subunits were expressed with wild-type alpha1 and beta2 subunits in HEK 293
cells, and the binding of several BZDs was measured. We present evidence that the
gamma2 region Met-57-Ile-62 is important for flunitrazepam binding and that, in
particular, gamma2 Met-57 and gamma2 Tyr-58 are essential determinants for
conferring high-affinity binding. Furthermore, we identify an additional residue,
gamma2 Ala-79, that not only is important for high-affinity binding by
flunitrazepam (a strong positive modulator) but also plays a crucial role in the
binding of the imidazobenzodiazepines Ro15-1788 (a zero modulator) and Ro15-4513
(a weak negative modulator) in the BZD binding pocket. Results from site-directed
mutagenesis of gamma2 Ala-79 suggest that this residue may be part of a
microdomain within the BZD binding site that is important for binding
imidazobenzodiazepines. This separation of drug-specific microdomains for
competitive BZD ligands lends insight into the structural determinants governing
the divergent effects of these compounds.
PMID- 10779377
TI - Octamer transcription factor-1 enhances hepatic nuclear factor-1alpha-mediated
activation of the human UDP glucuronosyltransferase 2B7 promoter.
AB - The human UDP glucuronosyltransferase, UGT2B7, is expressed in the liver and
gastrointestinal tract, where it catalyzes the glucuronidation of steroids and
bile acids. In this study, the UGT2B7 gene was isolated and its proximal promoter
was analyzed. The UGT2B7 gene consists of 6 exons and extends over 16 kilobases
(kb). It does not contain a canonical TATA box but has a region (-2 to -40)
adjacent to the transcription start site that binds nuclear proteins. This region
contains a consensus hepatic nuclear factor-1alpha (HNF1alpha)-binding site and
an overlapping AT-rich segment. Varying lengths of the UGT2B7 gene promoter, with
and without these sites, were fused to the firefly luciferase reporter gene and
transfected into HepG2 cells. UGT2B7 promoter activity with the HNF1/AT-rich
element was stimulated by cotransfection with HNF1alpha. Additional activation
was observed when HNF1alpha and octamer transcription factor-1 (Oct-1) were
cotransfected simultaneously. However, Oct-1 alone did not stimulate promoter
activity and did not bind to the promoter in the absence of HNF1alpha. Deletion
of the HNF1/AT-rich region, or mutations in this region, abolished UGT2B7 gene
promoter activity and prevented HNF1alpha-mediated increases in promoter
activity. The presence of HNF1alpha and octamer transcription factor-1 (Oct-1) in
the protein complex that bound to the HNF1/AT-rich region was demonstrated by gel
shift analyses with antibodies specific to HNF1alpha and Oct-1 protein. These
results strongly suggest that the liver-enriched factor HNF1alpha binds to, and
activates, the UGT2B7 gene promoter and that the ubiquitous transcription factor,
Oct-1, enhances this activation by directly interacting with HNF1alpha. This
interaction between HNF1alpha and Oct-1 may fine-tune UGT2B7 expression.
PMID- 10779378
TI - The mechanism of phosphorylation of anti-HIV D4T by nucleoside diphosphate
kinase.
AB - The last step in the intracellular activation of antiviral nucleoside analogs is
the addition of the third phosphate by nucleoside diphosphate (NDP) kinase
resulting in the synthesis of the viral reverse transcriptase substrates. We have
previously shown that dideoxynucleotide analogs and 3'-deoxy-3'-azidothymidine
(AZT) as di- or triphosphate are poor substrates for NDP kinase. By use of
protein fluorescence, we monitor the phosphotransfer between the enzyme and the
nucleotide analog. Here, we have studied the reactivity of D4T (2',3'-dideoxy
2',3'-didehydrothymidine; stavudine) as di- (DP) or triphosphate (TP) at the pre
steady state. The catalytic efficiency of D4T-DP or -TP is increased by a factor
of 10 compared with AZT-DP or -TP, respectively. We use an inactive mutant of NDP
kinase to monitor the binding of a TP derivative, and show that the affinity for
D4T-TP is in the same range as for the natural substrate deoxythymidine
triphosphate, but is 30 times higher than for AZT-TP. Our results indicate that
D4T should be efficiently phosphorylated after intracellular maturation of a
prodrug into D4T-monophosphate.
PMID- 10779379
TI - Mutational analysis of trp-229 of human immunodeficiency virus type 1 reverse
transcriptase (RT) identifies this amino acid residue as a prime target for the
rational design of new non-nucleoside RT inhibitors.
AB - Trp-229 is part of the non-nucleoside reverse transcriptase inhibitor (NNRTI)
binding pocket of HIV type 1 (HIV-1) reverse transcriptase (RT), and is also part
of the "primer grip" of HIV-1 RT. Using site-directed mutagenesis, seven RT
mutants were constructed bearing the mutations 229Phe, 229Tyr, 229Ile, 229His,
229Lys, 229Cys, and 229Gln. We found that all of the mutants showed severely
compromised RNA- and DNA-dependent DNA polymerase activities (<2% of wild-type
activity). The recombinant 229Phe and 229Tyr RT enzymes were among the mutant
enzymes with the highest activity (0.7 and 1.1% of wild-type activity,
respectively) and we evaluated these for resistance against several NNRTIs. No
resistance was found for the 229Phe RT, but the 229Tyr RT showed a approximately
20-fold resistance against UC-781 and lower resistance against emivirine and
nevirapine. Attempts to make recombinant virus strains bearing the single 229Phe
or 229Tyr RT mutation failed. Experiments in which we varied the pentenyl ether
substituent of the thiocarboxanilide UC-781 revealed that Trp-229 can be
specifically targeted by NNRTIs and that an alkenyloxy group length of five atoms
assures an optimal interaction of the thiocarboxanilides with Trp-229. Our
findings indicate that Trp-229, when combined with other crucial immutable amino
acids (i.e., Tyr-318), is an appropriate candidate for the targeted design of new
NNRTIs.
PMID- 10779380
TI - Activation of signal transducers and activators of transcription by alpha(1A)
adrenergic receptor stimulation in PC12 cells.
AB - In PC12 cells stably expressing alpha(1A)-adrenergic receptors (ARs),
norepinephrine (NE) activates several mitogen-activated protein kinase pathways
and causes differentiation (). Using retroviral luciferase reporters, we found
that NE also activated both signal transducers and activators of transcription
(Stat) and gamma-interferon-activated sequence-mediated transcriptional
responses, with maximal effects similar to those caused by interleukin-6 (IL-6).
UTP and epidermal growth factor had no effect, whereas nerve growth factor caused
a small Stat activation. Responses to NE were blocked by prazosin and depended on
receptor density. Responses to NE were not blocked by inhibitors of mitogen
activated protein kinase kinase (PD98059), protein kinase C (GFX203290), Src
(PP2), Jak2 (AG490), or the calcium chelator 1, 2-bis(2-aminophenoxy)ethane
N,N,N',N'-tetraacetic acid. The p38 mitogen-activated protein kinase inhibitors
SB202190 and SB203580 blocked Stat activation by NE, the epidermal growth factor
receptor inhibitor AG1478 caused a small inhibition, but the phosphoinositide 3
kinase inhibitor LY294002 potentiated both responses. Gel shifts confirmed
formation of nuclear factors binding to both Stat and gamma-interferon-activated
sequence consensus sequences in response to NE and IL-6. Immunoprecipitation
experiments showed that IL-6 increased tyrosine phosphorylation of Stat1 and
Stat3 in PC12 cells, whereas NE caused a sustained increase in tyrosine
phosphorylation of Stat1. These results suggest that alpha(1A)-AR stimulation
causes Stat-mediated transcriptional responses in PC12 cells that are not
downstream of known second messenger or tyrosine kinase pathways.
PMID- 10779381
TI - [(3)H]MRE 3008F20: a novel antagonist radioligand for the pharmacological and
biochemical characterization of human A(3) adenosine receptors.
AB - The lack of a radiolabeled selective A(3) adenosine receptor antagonist is a
major drawback for an adequate characterization of this receptor subtype. This
paper describes the pharmacological and biochemical characterization of the
tritiated form of a new potent A(3) adenosine receptor antagonist, the pyrazolo
triazolo pyrimidine derivative [(3)H]5N-(4-methoxyphenylcarbamoyl)amino-8-propyl
2-(2-furyl )pyrazolo [4,3-e] -1,2,4- triazolo[1,5-c]pyrimidine ([(3)H]MRE
3008F20). [(3)H]MRE 3008F20 bound specifically to the human adenosine A(3)
receptor expressed in CHO cells (hA(3)CHO), and saturation analysis revealed a
single high affinity binding site, K(D) = 0.80 +/- 0.06 nM, with a B(max) = 300
+/- 33 fmol/mg protein. This new ligand displayed high selectivity (1294-, 165-,
and 2471-fold) in binding assay to human A(3) versus A(1), A(2A), and A(2B)
receptors, respectively, and binds to the rat A(3) receptors with a K(i) > 10
microM. The pharmacological profile of [(3)H]MRE 3008F20 binding to hA(3)CHO
cells was evaluated using known adenosine receptor agonists and antagonists with
a rank order of potency consistent with that typically found for interactions
with the A(3) adenosine receptors. In the adenylyl cyclase assay the same
compounds exhibited a rank order of potency identical with that observed in
binding experiments. Thermodynamic data indicated that [(3)H]MRE 3008F20 binding
to hA(3)CHO is entropy- and enthalpy-driven in agreement with the typical
behavior of other adenosine antagonists to A(1) and A(2A) receptors. These
results show that [(3)H]MRE 3008F20 is the first antagonist radioligand with high
affinity and selectivity for the human A(3) adenosine receptor and may be used to
investigate the physiopathological role of A(3) adenosine receptors.
PMID- 10779382
TI - Pharmacological properties of Y-27632, a specific inhibitor of rho-associated
kinases.
AB - Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide++ +
dihydrochloride] is widely used as a specific inhibitor of the Rho-associated
coiled-coil forming protein serine/threonine kinase (ROCK) family of protein
kinases. This study examined the inhibition mechanism and profile of actions of Y
27632 and a related compound, Y-30141 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(1H
pyrrolo[2, 3-b]pyridin-4-yl)cyclohexan-ecarboxamide dihydrochloride]. Y-27632 and
Y-30141 inhibited the kinase activity of both ROCK-I and ROCK-II in vitro, and
this inhibition was reversed by ATP in a competitive manner. This suggests that
these compounds inhibit the kinases by binding to the catalytic site. Their
affinities for ROCK kinases as determined by K(i) values were at least 20 to 30
times higher than those for two other Rho effector kinases, citron kinase and
protein kinase PKN. [(3)H]Y-30141 was taken up by cells in a temperature- and
time-dependent and saturable manner, and this uptake was competed with unlabeled
Y-27632. No concentrated accumulation was found, suggesting that the uptake is a
carrier-mediated facilitated diffusion. Y-27632 abolished stress fibers in Swiss
3T3 cells at 10 microM, but the G(1)-S phase transition of the cell cycle and
cytokinesis were little affected at this concentration. Y-30141 was 10 times more
potent than Y-27632 in inhibiting the kinase activity and stress fiber formation,
and it caused significant delay in the G(1)-S transition and inhibition of
cytokinesis at 10 microM.
PMID- 10779383
TI - Role for early growth response-1 protein in alpha(1)-adrenergic stimulation of
fibroblast growth factor-2 promoter activity in cardiac myocytes.
AB - Fibroblast growth factor-2 (FGF-2), a mitogenic, angiogenic, and cardioprotective
agent, is released from the postnatal heart by a mechanism of transient
remodelling of the sarcolemma during contraction. Both release of FGF-2 and its
synthesis can be increased with adrenergic stimulation. We reported previously
that FGF-2 synthesis can be regulated at the transcriptional level by alpha
adrenergic stimulation of cultured neonatal rat cardiac myocytes as well as in
the adult mouse heart. Examination of the proximal promoter region of both human
and rat FGF-2 gene sequences revealed binding sites for the early growth response
1 (Egr-1) protein. Using gel mobility shift assays, we observed a transient
increase in a complex between nuclear extracts from neonatal rat cardiac myocytes
treated with inducers of Egr-1, including the alpha-adrenergic agonist
phenylephrine, angiotensin II, and phorbol ester, and a consensus Egr-1 DNA
element. A similar complex was seen with the FGF-2 promoter region -7/+42 as the
DNA probe, but not when the Egr-1 element at nucleotides +3/+31 was disrupted.
Participation of Egr-1 protein in the complex was confirmed by competition with
Egr-1 DNA elements and antibodies. With deletion analysis and transfection of
neonatal rat cardiac myocytes, the alpha-adrenergic response was localized to
nucleotides -110/+42 of the FGF-2 gene in the context of a hybrid FGF
2/luciferase reporter gene, -110FGFp.luc. Overexpression of Egr-1 increased
110FGFp.luc gene expression, whereas mutation of its Egr-1 element at nucleotides
+3/+31 abolished alpha-adrenergic responsiveness. These data indicate that Egr-1
is involved in the alpha-adrenergic stimulation of the FGF-2 promoter region in
neonatal cardiac myocytes.
PMID- 10779384
TI - Analysis of a mutation in phosphodiesterase type 4 that alters both inhibitor
activity and nucleotide selectivity.
AB - Cyclic nucleotide phosphodiesterase type 4 (PDE4) is a cAMP-specific
phosphodiesterase that is found as four distinct genes in the mammalian genome
(PDE4A, 4B, 4C, and 4D). Mutation analysis was done to identify the amino acids
involved in activity and inhibitor selectivity. Mutations at Asp333 were made in
HSPDE4D3 based on mutations that affect rolipram sensitivity in RNPDE4B1. The
PDE4D3 Asp-Asn mutant was resistant to inhibition by rolipram as well as several
other PDE4 inhibitors tested. These results suggest that this residue is near the
inhibitor binding pocket in PDE4D3. Sequence comparison of PDE4 with cGMP
specific PDE proteins shows a conserved aspartic acid at position 333 in PDE4D3
and a conserved asparagine at this position in PDE enzymes that hydrolyze cGMP.
Therefore, cGMP hydrolysis by PDE4D3 Asp-Asn was measured. PDE4D3 Asp-Asn
hydrolyzes cGMP with kinetic constants similar to those observed for this protein
with cAMP (K(m) approximately 20 microM, V(max) approximately 2 micromol
AMP/min/mg recombinant protein). Under identical conditions, the K(m) value for
cAMP hydrolysis by wild-type PDE4D3 is 3 microM and the V(max) value is 1
micromol AMP/min/mg recombinant protein. In addition, the PDE4D3 Asp-Ala mutant
protein could hydrolyze cGMP. Finally, the analogous mutation in HSPDE4B1
(Asp413Asn) also allows hydrolysis of cGMP. These results show that this aspartic
acid residue is important in inhibitor binding and nucleotide discrimination and
suggest this residue is in the active site of PDE4.
PMID- 10779385
TI - Activation of cannabinoid receptors in rat brain by WIN 55212-2 produces coupling
to multiple G protein alpha-subunits with different potencies.
AB - Previous studies had shown that the amplification factors for cannabinoid
receptors, defined as the number of total G proteins activated per occupied
receptor, differs between several rat brain regions. In this study, we sought to
determine which specific Gi/Go(alpha) subunits were activated by CB1 receptors in
several rat brain regions and if this coupling might explain the regional
differences in receptor/G protein amplification factors. Furthermore, we examined
whether cannabinoid agonists might activate different subtypes of G(alpha)
subunits with varying degrees of efficacy and/or potency. Activation of specific
G proteins by cannabinoid receptors was evaluated by the ability of the agonist
WIN 55212-2 to stimulate incorporation of [alpha-(32)P]azidoanilido-GTP into
G(alpha) subunits in membranes. Photolabeled G proteins were either directly
resolved using urea/SDS-polyacrylamide gel electrophoresis or first
immunoprecipitated with specific antisera for different G(alpha) subunits before
electrophoresis. Individual G(alpha) subunits were separated into distinct bands
on a single gel and the amount of agonist-induced increase in radioactivity was
quantified by densitometry. Stimulation of CB1 receptors by WIN 55212-2 resulted
in the activation of a distinct pattern of at least five different
G(ialpha)/G(oalpha) subunits in several brain regions. Furthermore, although the
pattern of G proteins activated by WIN 55212-2 appeared to be similar across
brain regions, slight differences were observed in both the percentage of
increase and the amount of the individual G(alpha) subunits activated. Most
importantly, the amount of WIN 55212-2 required to half-maximally activate
individual G proteins in the cerebellum varied over a 30-fold range for different
G(alpha) subunits. These results suggest that cannabinoid receptors activate
multiple G proteins simultaneously in several brain regions and both the efficacy
and potency of cannabinoid agonists to activate individual G(alpha) subunits may
vary considerably.
PMID- 10779386
TI - Increased CYP2J expression and epoxyeicosatrienoic acid formation in
spontaneously hypertensive rat kidney.
AB - Epoxyeicosatrienoic acids (EETs) are major products of cytochrome P450 (CYP)
catalyzed metabolism of arachidonic acid in the kidney. The potent effect of EETs
on renal vascular tone and tubular ion and water transport implicates their role
in the regulation of renal function and blood pressure. The present study was
designed to test the hypothesis that CYP-catalyzed EET formation was altered in
the spontaneously hypertensive rat (SHR) kidney. The formation of 14,15- and
11,12-EET was approximately 2-fold higher in incubations of arachidonic acid with
SHR renal cortical microsomes relative to microsomes from normotensive Wistar
Kyoto (WKY) rats. This was consistent with increased expression of a CYP2J2
immunoreactive protein in the SHR cortex and outer medulla. In contrast, there
was no significant difference in the levels of the CYP2E and CYP2C epoxygenases
in SHR and WKY kidneys. Protein and RNA analysis suggests that the CYP2J2
immunoreactive protein that is overexpressed in the SHR kidney is distinct from
the known rat CYP2J isoforms. EET formation also was documented in vivo from
measurements of urinary EET excretion. Importantly, the excretion rates of 14,15
, and 11,12-EETs were 2.5- and 1.8-fold higher, respectively, in SHR than WKY
kidney. These studies provide both in vitro and in vivo evidence for increased
EET formation in the SHR kidney and identify a novel CYP2J2 immunoreactive
protein that is differentially expressed in the hypertensive kidney. In light of
the known biological properties of the EETs, these findings may be important in
elucidating the mechanisms that control renal vascular tone and tubular ion
transport in the SHR.
PMID- 10779387
TI - Inhibition of aquaporin-1 water permeability by tetraethylammonium: involvement
of the loop E pore region.
AB - Previously, the only known blockers of water permeability through aquaporin-1
(AQP1) water channels were mercurial reagents such as HgCl(2). For AQP1,
inhibition by mercury has been attributed to the formation of a mercaptide bond
with cysteine residue 189 found in the putative pore-forming region loop E. Here
we show that the nonmercurial compound, tetraethylammonium (TEA) chloride,
reduces the water permeability of human AQP1 channels expressed in Xenopus
oocytes. After preincubation of the oocytes for 15 min with 100 microM TEA, AQP1
water permeability was reduced by 20 to 40%, a degree of partial block similar to
that obtained with 15 min of incubation in 100 microM HgCl(2). The reduction of
water permeability was dose-dependent for tested concentrations up to 10 mM TEA.
TEA blocks the Shaker potassium channel by interacting with a tyrosine residue in
the outer pore region. We tested whether an analogous tyrosine residue in loop E
of AQP1 could be involved in the binding of TEA. Using polymerase chain reaction,
tyrosine 186 in AQP1, selected for its proximity to the mercury-binding site, was
mutated to phenylalanine (Y186F), alanine (Y186A), or asparagine (Y186N). Oocyte
expression of the mutant AQP1 channels showed that the water permeability of
Y186F was equivalent to that of wild-type AQP1; the other mutant channels did not
conduct water. However, in contrast to wild-type AQP1, the water permeability of
Y186F was not reduced with 100 microM TEA. These results suggest that TEA reduces
AQP1 water permeability by interacting with loop E.
PMID- 10779388
TI - Lysophosphatidic acid modulates alpha(1b)-adrenoceptor phosphorylation and
function: roles of Gi and phosphoinositide 3-kinase.
AB - The effect of lysophosphatidic acid on the phosphorylation and function of
alpha(1b)-adrenoceptors transfected into rat-1 fibroblasts was studied. This
phospholipid mitogen increased in a concentration-dependent fashion (EC(50)
approximately 50 nM) the phosphorylation of these adrenoceptors. Lysophosphatidic
acid-induced alpha(1b)-adrenoceptor phosphorylation was relatively rapid (t(1/2)
approximately 1 min), intense (2.5-fold), and sustained for at least 60 min. The
effect of lysophosphatidic acid was blocked by pretreatment with pertussis toxin.
The alpha(1b)-adrenoceptor phosphorylation induced by lysophosphatidic acid was
not blocked by genistein, a tyrosine kinase inhibitor, but it was inhibited by
inhibitors of protein kinase C (bisindolylmaleimide I, staurosporine, and Ro 31
8220) and phosphoinositide 3-kinase (wortmannin and LY 294002). The ability of
norepinephrine to increase cytosol calcium concentration was markedly decreased
in cells previously challenged with lysophosphatidic acid. Norepinephrine-induced
[(35)S]GTPgammaS binding in membrane preparations was used as an index of the
functional coupling of the alpha(1b)-adrenoceptors and G proteins. Norepinephrine
stimulated [(35)S]GTPgammaS binding was markedly decreased in membranes from
cells pretreated with lysophosphatidic acid. This effect of lysophosphatidic acid
was blocked by pretreatment with wortmannin or staurosporine. Our data indicate
that: 1) activation of lysophosphatidic acid receptors induce phosphorylation of
alpha(1b)-adrenoceptors; 2) this effect is mediated through pertussis toxin
sensitive G proteins, phosphatidylinositol 3-kinase, and protein kinase C; and 3)
the phosphorylation of alpha(1b)-adrenoceptors induced by the lipid mitogen is
associated to adrenoceptor desensitization.
PMID- 10779389
TI - Human 5-hydroxytryptamine(5A) receptors activate coexpressed G(i) and G(o)
proteins in Spodoptera frugiperda 9 cells.
AB - The ability of the human 5-hydroxytryptamine serotonin type 5A (h5-ht(5A))
receptor to couple to G proteins from distinct families was investigated through
the simultaneous infection of Spodoptera frugiperda 9 insect cells with
recombinant baculoviruses encoding the various proteins. Expression of G proteins
was demonstrated in immunoblots. Receptor-G protein coupling was monitored by
high-affinity agonist binding and agonist-induced stimulation of [(35)S]guanosine
5'-O-(3-thio) triphosphate binding to membranes. Receptors expressed alone
displayed low-affinity agonist binding, and endogenous G proteins were only
poorly stimulated on the addition of 5-hydroxytryptamine. When receptors were
coexpressed with mammalian G(i)/G(o) proteins (Galpha(i) or Galpha(o) plus
Gbeta(1)gamma(2)), the coupled phenotype was achieved: agonists bound with high
affinity in a guanosine-5'-(beta, gamma-imido)triphosphate-sensitive manner and
stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding to high levels.
These effects were not observed on coexpression with G(z)/G(s)/G(q/11/16) or
G(12/13). Various ligands were evaluated for their agonistic, antagonistic, or
inverse agonistic behavior in both receptor binding and activation assays.
Although G(o) displayed different receptor coupling characteristics than G(i)
proteins, no clear coupling preference was evident. Coexpression of receptors and
Galpha(i) subunits without Gbeta(1)gamma(2) produced increases in both agonist
affinity and maximum G protein activation that were smaller than those in the
presence of Gbeta(1)gamma(2), suggesting that Gbeta(1)gamma(2) coexpression
improves receptor-G protein coupling. Similarly, coexpression of receptors with
Gbeta(1)gamma(2) alone resulted in an improved interaction with endogenous G
proteins. Our results demonstrate that h5-ht(5A) receptors expressed in
Spodoptera frugiperda 9 cells selectively and functionally couple to coexpressed
mammalian G(i) and G(o) proteins.
PMID- 10779390
TI - Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2
cannabinoid receptor: antagonism by anandamide.
AB - The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) bind to G
protein-coupled central and peripheral cannabinoid receptors CB1 and CB2,
respectively. Due to the relatively high expression of the CB2 isotype on
peripheral immune cells, it has been hypothesized that this receptor mediates the
immunosuppressive effects of cannabinoids. Unfortunately, there was a dearth of
pharmacological studies with the endocannabinoids and human CB2 (hCB2). These
studies compare and contrast the potency and efficacy of anandamide, 2-AG, and
the synthetic cannabinoid HU210 at hCB2. Using [(35)S]guanosine-5'-O-(3
thio)triphosphate (GTPgammaS) and radioligand bindings in insect Sf9-hCB2
membranes, we showed that both endocannabinoids bound hCB2 with similar affinity
and that the cannabinoids acted as full agonists in stimulating [(35)S]GTPgammaS
exchange, although 2-AG was 3-fold more potent than anandamide (EC(50) = 38.9 +/-
3.1 and 121 +/- 29 nM, respectively). In a mammalian expression system (Chinese
hamster ovary-hCB2 cells), HU210 and 2-AG maximally inhibited forskolin
stimulated cAMP synthesis (IC(50) = 1.61 +/- 0.42 nM and 1.30 +/- 0.37 microM,
respectively) although anandamide was ineffective. In Chinese hamster ovary-hCB2
membranes, HU210 and 2-AG were also full agonists in stimulating [(35)S]GTPgammaS
binding (EC(50) = 1.96 +/- 0.35 and 122 +/- 17 nM, respectively), but anandamide
was a weak partial agonist (EC(50) = 261 +/- 91 nM; 34 +/- 4% of maximum). Due to
its low intrinsic activity, coincubation with anandamide effectively attenuated
the functional activity of 2-AG at hCB2. Collectively, the data showed that both
endocannabinoids bound hCB2 with similar affinity, but only 2-AG functioned as a
full agonist. Moreover, the agonistic activity of 2-AG was attenuated by
anandamide.
PMID- 10779391
TI - Excision of beta-D- and beta-L-nucleotide analogs from DNA by the human cytosolic
3'-to-5' exonuclease.
AB - The cytosolic 3'-to-5' exonuclease from chronic lymphocytic leukemia cells was
highly purified, and its ability to remove beta-D- and beta-L-nucleotide analogs
from the 3'-end of DNA was determined. The relative rate of excision of beta-D
ddCMP, beta-L-ddCMP, beta-L-FddCMP, beta-L-SddCMP, beta-L-Fd4CMP, and beta-L
OddCMP from the 3'-end of a single-stranded oligonucleotide primer or a primer
annealed with complementary DNA and/or RNA templates was assessed. The rate of
excision of beta-D-nucleotides from the 3'-end of DNA was higher than that of
beta-L-nucleotides, which could be partly attributable to the affinity of the
enzyme to beta-D-nucleotide-terminated DNA being 5-fold higher compared with that
of beta-L-nucleotide-terminated DNA. The rate of removal of beta-L-Fd4CMP and
beta-L-OddCMP from the 3'-end of DNA was at least 8 to 10 times lower compared
with that of beta-L-SddCMP. HIV reverse transcriptase could elongate DNA primers
after the removal of chain terminators by the cytosolic exonuclease.
Concentrations of nucleoside 5'-monophosphate analogs that inhibit the cytosolic
exonuclease by 50% were estimated. Among the nucleoside 5'-monophosphate analogs
examined, beta-L-Fd4CMP appeared to be the most effective inhibitor of the
cytosolic exonuclease, with an ID(50) value of 38 microM.
PMID- 10779392
TI - Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null
embryo fibroblast.
AB - The aryl hydrocarbon receptor (AHR) is known to mediate the toxic and
carcinogenic effects of polycyclic aromatic hydrocarbons and dioxins. High
affinity AHR ligands, such as 2,3,7, 8-tetrachlorodibenzeno-p-dioxin, have been
shown to modify cell proliferation and differentiation. However, the mechanisms
by which AHR affects cell proliferation and differentiation are not fully
understood. To investigate the role of AHR in cell proliferation, mouse embryonic
fibroblasts (MEFs) derived from AHR-null mice were obtained and characterized.
Compared with wild-type MEFs, AHR-null cells exhibited a lower proliferation rate
with an accumulation of 4N DNA content and increased apoptosis. The expression
levels of Cdc2 and Plk, two kinases important for G(2)/M phase of cell cycle,
were down-regulated in AHR-null MEFs. In contrast, transforming growth factor
beta (TGF-beta), a proliferation inhibitor in several cell lines, was present at
high levels in conditioned medium from AHR-null MEFs. Concomitant with G(2)/M
cell accumulation, treatment of wild-type MEFs with TGF-beta3 also resulted in
down-regulation of both Cdc2 and Plk. Thus, overproduction of TGF-beta in AHR
deficient cells appears to be the primary factor that causes low proliferation
rates and increased apoptosis. Taken together, these results suggest that AHR
influences TGF-beta production, leading to an alteration in cell cycle control.
PMID- 10779393
TI - Involvement of regions in domain I in the opioid receptor sensitivity of alpha1B
Ca(2+) channels.
AB - The structural basis of Ca(2+) channel inhibition by G proteins has received
considerable attention recently, and multiple regions on Ca(2+) channels that
interact with G protein subunits have been identified. We have demonstrated
previously that a region extending from the N terminus to the I/II loop of the
Ca(2+) channel is involved in determining the differences between alpha1B and
alpha1E Ca(2+) channels with respect to inhibition by G proteins. Here we explore
this region of the channel in greater detail in an effort to further define the
regions involved in determining inhibition. Chimeric Ca(2+) channels constructed
from alpha1B and alpha1E Ca(2+) channels revealed that the N terminus, the I/II
loop, and domain I all play an important role in determining inhibition. We
identified a 70-amino acid fragment from domain I that mediates the effects of
domain I, and a 50-amino acid fragment from the I/II loop that mediates the
effects of the I/II loop. When these regions from alpha1B were exchanged into
alpha1E, inhibition identical with that of alpha1B was observed. The differences
between alpha1B and alpha1E in the identified region of domain I involve residues
that are predicted to be almost exclusively extracellular. Mutations to some of
the high-affinity G protein binding regions of alpha1B (alpha interaction domain,
CC14, and a C-terminal Galpha binding site) caused relatively little change in
inhibition, which suggests that these sites are not necessary individually for G
protein-mediated inhibition and may help to explain the small effects of
exchanging these regions in isolation.
PMID- 10779394
TI - Selective enhancement of beta-adrenergic receptor signaling by overexpression of
adenylyl cyclase type 6: colocalization of receptor and adenylyl cyclase in
caveolae of cardiac myocytes.
AB - We investigated the effect of adenovirally mediated overexpression of adenylyl
cyclase type 6 (AC6), a major form of AC expressed in mammalian heart, on G
protein-coupled receptor regulation of cAMP production in neonatal rat
ventricular myocytes. Following gene transfer of AC6, isoproterenol- and
forskolin-stimulated increases in cAMP were markedly enhanced, whereas basal
levels of cAMP and responses to several other agonists that stimulate cAMP
formation, e. g., prostaglandin E(2) (PGE(2)), H(2) agonist, glucagon, and A(2)
agonist were not increased. Studies to test whether the selective enhancement in
beta-adrenergic receptor (AR) response might result from inhibition of AC6 by
Galpha(i) and Gbetagamma indicated that pertussis toxin-sensitive inhibition by
the muscarinic cholinergic agonist carbachol was unaltered in myocytes
overexpressing AC6. Pertussis toxin treatment failed to reveal an enhancement by
AC6 overexpression of basal or PGE(2)-stimulated cAMP. Immunoblot analysis of
membrane fractions indicated that beta(1)-AR and AC6 are expressed in fractions
enriched in caveolin-3 and morphologic caveolae. The data suggest that loss of
G(i)-mediated inhibition is not the mechanism for enhancement of beta-AR
stimulated cAMP formation and that key components of beta-AR-mediated activation
of AC exist in caveolae of cardiac myocytes, providing a means by which beta-AR
response is selectively enhanced by increasing AC6 expression.
PMID- 10779395
TI - Understanding circadian rhythmicity in Neurospora crassa: from behavior to genes
and back again.
AB - Circadian clocks have been described in organisms ranging in complexity from
unicells to mammals, in which they function to control daily rhythms in cellular
activities and behavior. The significance of a detailed understanding of the
clock can be appreciated by its ubiquity and its established involvement in human
physiology, including endocrine function, sleep/wake cycles, psychiatric illness,
and drug tolerances and effectiveness. Because the clock in all organisms is
assembled within the cell and clock mechanisms are evolutionarily conserved,
simple eukaryotes provide appropriate experimental systems for dissecting the
clock. Significant progress has been made in deciphering the circadian system in
Neurospora crassa using both genetic and molecular approaches, and Neurospora has
contributed greatly to our understanding of (1) the feedback cycle that comprises
a circadian oscillator, (2) the mechanisms by which the clock is kept in
synchrony with the environment, and (3) the genes that reside in rhythmic output
pathways. Importantly, the lessons learned in Neurospora are relevant to our
understanding of clocks in higher eukaryotes.
PMID- 10779396
TI - The complete DNA sequence of the nuclear ribosomal RNA gene complex of
Verticillium dahliae: intraspecific heterogeneity within the intergenic spacer
region.
AB - The complete DNA sequence of the nuclear ribosomal RNA gene complex of
Verticillium dahliae: Intraspecific heterogeneity within the intergenic spacer
region. Fungal Genetics and Biology 29, 19-27. The complete sequence of the
nuclear ribosomal DNA gene complex of the phytopathogenic fungus Verticillium
dahliae has been determined. The tandemly repeated unit was 7216 bp long and
appears to be the shortest rDNA cluster described so far among filamentous fungi.
Primer pairs were designed for amplification of the region spanning half of the
28S subunit, the intergenic spacer (IGS), and the 5' end of 18S subunit of a
number of Verticillium strains, isolated from various hosts and geographic
origins. Great heterogeneity was detected in the amplified products of the IGS
region resulting in fragments varying from 1.6 to 2.0 kb. The majority of
Verticillium isolates were classified into two groups with 1.6- and 1.7-kb
amplified products, respectively. The former group included 31 V. dahliae, 7 V.
longisporum, and 1 V. albo-atrum isolates, whereas the latter included 10 V.
dahliae and 1 V. albo-atrum isolates. Sequence analysis of representative PCR
products of the above groups identified a "hot-spot" region harboring most of
larger insertions, whereas most of the small changes were due to transitions and
transversions. One V. longisporum isolate with a 2.0-kb PCR product contained 13
perfectly conserved tandem repeats of 39 bp long. The presence of similar
incomplete sequences in the corresponding regions of V. dahliae, V. longisporum,
and V. albo-atrum isolates revealed a particular standard motif of insertions in
the IGS region of the genus and is discussed.
PMID- 10779397
TI - Using DNA-tagged mutagenesis to improve heterologous protein production in
Aspergillus oryzae.
AB - Using DNA-tagged mutagenesis to improve heterologous protein production in
Aspergillus oryzae. Fungal Genetics and Biology 29, 28-37. Restriction enzyme
mediated integration (REMI) has been employed as a mutagen to generate two
insertion libraries in an Aspergillus oryzae strain expressing a Thermomyces
lanuginosus lipase. The REMI libraries were created using linearized plasmid
containing the A. oryzae pyrG and either BamHI or EcoRI enzyme. The libraries
were screened for lipase production, and mutants with increased production were
isolated. The genomic DNA flanking the integration event was cloned from one of
the mutants with increased lipase titers (DEBY10.3). Nucleotide sequence of the
flanking DNA revealed similarity to the Aspergillus nidulans palB gene.
Disruption of the palB gene in a strain producing lipase resulted in increased
lipase expression. Additionally, complementation of the palB phenotype of
DEBY10.3 led to a decrease in lipase production. These lines of evidence
demonstrate that the increase in lipase yield in DEBY10.3 is linked to the palB
phenotype generated by the integration of the pyrG gene into the palB gene. The
results also demonstrated that tagged mutagenesis with REMI can be used to
identify genes that influence expression of heterologous proteins.
PMID- 10779398
TI - Gene disruption by biolistic transformation in serotype D strains of Cryptococcus
neoformans.
AB - Gene disruption by biolistic transformation in serotype D strains of Cryptococcus
neoformans. Fungal Genetics and Biology 29, 38-48. Cryptococcus neoformans is an
opportunistic fungal pathogen with a defined sexual cycle and well-developed
genetic and molecular approaches. Two different transformation systems have been
developed, and a number of genes have been disrupted by homologous recombination.
However, the frequency of homologous recombination achieved by these approaches
has differed dramatically between strains of the A and D serotypes.
Transformation by electroporation in serotype D strains results in homologous
recombination at frequencies of 1/1000 to 1/100,000, whereas transformation by
the biolistic method has resulted in gene disruption at frequencies between 2 and
50% in serotype A strains. We find that gene disruption by homologous
recombination can be achieved in the congenic serotype D strain series by
biolistic transformation with frequencies of approximately 1 to 4%. By this
approach, we have readily disrupted the genes encoding a MAPK homolog (CPK1), the
calcineurin A catalytic subunit (CNA1), and a G protein alpha subunit (GPA1). By
physical and genetic methods, we show that these mutations result from targeted
recombination events without ectopic integrations. Because genetic approaches can
be applied in the congenic serotype D strains, our observations represent a
significant advance in molecular approaches to understand the physiology and
virulence of this important human pathogen.
PMID- 10779399
TI - A mutation in the eln2 gene encoding a cytochrome P450 of Coprinus cinereus
affects mushroom morphogenesis.
AB - A dominant mutation of the elongationless2 (eln2) gene of the mushroom Coprinus
cinereus (eln2-1) affects pattern formation in the development of fruit body
primordia, causing dumpy primordia which culminate in mature fruit bodies with
short stipes. Phenotypic analyses revealed disturbance of tissue organization and
cell morphogenesis in the primordial shaft and suggested that the defects in the
primordial shaft interfere with differentiation of the stipe tissue in the mutant
primordia. The eln2 locus was assigned to chromosome XII and the eln2-1 mutant
gene was cloned from a chromosome XII-specific cosmid library as a genomic
fragment that brings about the dominant mutant phenotype. The eln2 gene encodes a
novel type of microsomal cytochrome P450 enzyme (CYP502) and is constitutively
expressed. The eln2-1 mutation is a 4-bp deletion in the 3'-terminal region of
the gene, leading to truncation of C-terminal 18 amino acids. We suggest that the
truncation affects the activity of the CYP502 enzyme.
PMID- 10779400
TI - Insights into HIV-specific immune function: implications for therapy and
prevention in the new millennium.
PMID- 10779401
TI - Pulmonary alveolar proteinosis is a disease of decreased availability of GM-CSF
rather than an intrinsic cellular defect.
AB - Granulocyte-macrophage colony stimulating factor (GM-CSF) deficient mice develop
a pulmonary alveolar proteinosis (PAP) syndrome which is corrected by the
administration/expression of GM-CSF. These observations implicate GM-CSF in the
pathogenesis of human PAP. We hypothesized that human PAP may involve an
intrinsic cellular defect in monocytes/macrophages with an inability to produce
GM-CSF and/or respond to GM-CSF. Thus, we investigated the cytokine responses to
GM-CSF and LPS from peripheral blood monocytes and alveolar macrophages from
patients with idiopathic PAP and healthy controls. Macrophage inflammatory
protein-1-alpha (MIP) was measured from GM-CSF-stimulated cells and GM-CSF was
measured from LPS-stimulated cells by ELISA. The MIP and GM-CSF production by
monocytes and alveolar macrophages did not differ between PAP patients and
healthy controls. Growth of the GM-CSF-dependent human myeloid cell line TF-1 was
inhibited by serum from all patients studied (n = 10) and all patients had anti
GM-CSF antibody in their serum. The BAL from PAP patients had less detectable GM
CSF by ELISA than healthy controls (P = 0.05); in contrast, the inhibitory
cytokine, interleukin-10 (IL-10), was increased in PAP compared to controls (P =
0.04). IL-10 is a potent inhibitor of LPS-stimulated GM-CSF production from
healthy control alveolar macrophages. These studies are the first to demonstrate
that circulating monocytes and alveolar macrophages from PAP patients are able to
synthesize GM-CSF and respond to GM-CSF, suggesting no intrinsic abnormalities in
GM-CSF signaling. In addition, these observations suggest that PAP in a subset of
patients is the result of decreased availability of GM-CSF due to GM-CSF blocking
activity and reduced GM-CSF production by IL-10.
PMID- 10779402
TI - The microbial product lipopolysaccharide confers diabetogenic potential on the T
cell repertoire of BDC2.5/NOD mice: implications for the etiology of autoimmune
diabetes.
AB - Both genetic predisposition and environmental factors participate in the etiology
of Type-1 diabetes. To test the role of the microbial product lipopolysaccharide
(LPS) as an environmental trigger of autoimmune diabetes, we employed transgenic
(tg) BDC2.5/NOD mice that bear an islet-specific CD4(+) T cell repertoire (>95%),
but do not develop the spontaneous diabetes that typifies the NOD (nonobese
diabetic) strain. LPS administration provoked diabetes in BDC2.5/NOD mice by
their 16th week of age. However, LPS administration in NOD mice did not
accelerate their diabetes. This finding indicates that the frequency of islet
specific T cells influences LPS-mediated diabetes. Furthermore, in vitro LPS
cultured splenocytes from BDC2. 5/NOD and BDC2.5-microMT (B-cell-deficient) mice
effectively transferred diabetes into immunodeficient NOD-scid/scid mice but not
immunosufficient NOD mice. Therefore, B lymphocytes are not required for LPS
provoked autoimmune diabetes. Flow cytometric analysis then revealed that LPS
stimulation in vitro induced the expression of an IL-2 receptor (CD25) on CD4 T
cells; this indicates that the activation of islet-specific T cells is a
prerequisite to eliciting diabetes in this situation. Overall, these results
point to microbial LPS as an etiopathogenic agent of autoimmune diabetes.
PMID- 10779403
TI - Evaluation of assays for the detection of autoantibodies to the ribosomal P
proteins.
AB - Sera from systemic lupus erythematosus patients that had antibodies to the
ribosomal P proteins were compared in several different assays. The enzyme-linked
immunosorbent assay (ELISA) method was compared to the Western immunoblotting
method using either affinity purified human or bovine ribosomal P proteins. All
30 normal sera had no significant reactivity with these antigens. The most
sensitive test was the ELISA using the human P protein, where 31/32 patients were
positive (97%). The assay with bovine proteins in ELISA yielded 28/32 (88%)
positive results. Immunoblotting with either bovine or human P protein was
equally effective with 30/32 (94%) positive. An ELISA incorporating human P
proteins is a more sensitive assay for clinical diagnosis than an ELISA with the
bovine protein. Immunoblotting is a sensitive method, but is less convenient and
is not quantitative. The ELISA with the human protein appears to be the method of
choice.
PMID- 10779404
TI - Intratracheal administration to the lung enhances therapeutic benefit of an MBP
peptide in the treatment of murine experimental autoimmune encephalomyelitis.
AB - The treatment of autoimmune diseases by targeted down-regulation of autoantigen
specific cells has been accomplished by the administration of high doses of
autoantigen. We performed direct comparisons between injection of myelin basic
protein peptide and administration by several nonparenteral routes to determine
whether route impacted benefit in the treatment of murine allergic
encephalomyelitis, a model for multiple sclerosis. The range of effective peptide
doses spanned over 1000-fold, and route of delivery played a major role in
determining optimal dose. The oral route of administration was the least
effective, requiring at least 50- to 100-fold more antigen than subcutaneous
injection, which in turn required at least 10-fold more antigen than delivery of
peptide to the lung using an intratracheal instillation. Intratracheal delivery
was also considerably more effective than inhalation of peptide, and, unlike
inhalation, resulted in obvious penetration of delivered material deep into the
lung. The increase in therapeutic efficacy did not appear to result from slower
systemic delivery of antigen. Accumulation of peptide on antigen presenting cells
in the spleen and in the brain was less efficient using the intratracheal route
of administration compared to subcutaneous injection, implicating a special role
for the lung microenvironment in the induction of immune nonresponsiveness.
PMID- 10779406
TI - Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin
in systemic lupus erythematosus T cells.
AB - Previous experiments in our laboratory indicated that calcineurin expression and
PP2B phosphatase activity increased when estrogen was cultured with SLE T cells
but not with T cells from normal women. In this report we extended our findings
to show that estrogen receptor (ER) antagonism by ICI 182,780 inhibited the
estrogen-dependent increase in calcineurin mRNA and phosphatase PP2B activity
indicating that estrogen action was mediated through the ER. Inhibition of de
novo protein synthesis with cycloheximide suggested that the estrogen-dependent
increase in T cell calcineurin mRNA was a direct effect of the ER and new protein
synthesis was not required. Estrogen increased calcineurin mRNA in systemic lupus
erythematosus (SLE) T cells at 6 h after the start of culture correlating with
increased phosphatase activity at this same time. Phosphatase activity increased
significantly (P < 0.02) in lupus T cells cultured for 8 h in estradiol
containing medium. Reverse transcription and polymerase chain amplification
revealed that ER-beta and ER-alpha were expressed in female and male T cells from
SLE patients and normal controls. However, calcineurin steady-state mRNA levels
were unaffected by estradiol in cultured T cells from male SLE patients and
normal male and female controls. These data indicate that estrogen, bound to the
ER, evokes a direct increase in calcineurin expression in T cells from female
lupus patients. This gender-specific response suggests that ER function is
altered in women with the female predominant autoimmune disease, SLE.
PMID- 10779405
TI - The induction of EAE is only partially dependent on TNF receptor signaling but
requires the IL-1 type I receptor.
AB - Experimental autoimmune encephalomyelitis develops in mice immunized with CNS
antigens. To elucidate the role that specific proinflammatory cytokines play in
the induction of this process we examined the development of EAE in mice with
targeted disruptions of the TNF p55 or p75 or the IL-1 p80 receptors. EAE
developed in mice with either one or both TNF receptors deleted although the
onset of disease in mice with the p55 receptor deleted was delayed. However, mice
with a deletion of the IL-1 p80 receptor failed to develop any inflammatory
lesions in the CNS or evidence of clinical EAE. Thus we conclude that TNF or its
receptors contribute to, but are not necessary for, the induction of EAE while
the IL-1 p80 receptor is absolutely required. The p55 TNF receptor plays a role
in determining the onset of disease and its severity.
PMID- 10779407
TI - Immunochemical characterization of purified human oxidized low-density
lipoprotein antibodies.
AB - The goal of this study was to characterize the isotypes and reactivity of human
autoantibodies to copper oxidized LDL (oxLDL). Forty-six purified oxLDL
antibodies contained immunoglobulins of the three major isotypes, with a
predominance of IgG, subclasses 1 and 3. These IgG isotypes are known to interact
with FcRgammaI and to activate the complement system and thus are potentially
able to activate macrophages and cause foam cell formation. The same purified
antibodies were tested for cross-reactivity with malondialdehyde (MDA)-, glycated
(Glyc)-, and native (n)LDL and cardiolipin. Absorption with oxLDL resulted in a
decrease of reactivity of 77.2 +/- 4.7%. Absorption with MDA-LDL resulted in a
wider range of reduction of reactivity values, ranging from 50 to 87%, possibly
reflecting differences in the degree of MDA modification. Absorption with Glyc-
and nLDL caused a minor decrease in the reactivity of antibodies to oxLDL (5.9 +/
7.1 and 6.8 +/- 6. 4%, respectively), comparable to the reduction of reactivity
(2.1 +/- 4.0%) measured after absorption with transferrin, an irrelevant protein
used as a negative control. These results suggest that oxLDL antibodies recognize
primarily MDA epitopes. To determine whether purified oxLDL antibodies also
recognize other epitopes known to be generated during copper oxidation of LDL,
such as 4-hydroxynonenal (HNE)- and N(epsilon)(carboxymethyl)-lysine (CML), two
additional sets of experiments were carried out. First, we monitored the
formation of CML-, MDA-lysine, and HNE-lysine at different times during copper
oxidation of two LDL pools. Both pools showed simultaneous increases in protein
modification, as indicated by increasing fluorescence emission at 430 nm, and in
immunoreactivity with oxLDL antibodies, coinciding closely with MDA modification
of lysine groups. Second, we assessed whether the reactivity of oxLDL antibodies
could be blocked by absorption with CML- or HNE-LDL. HNE-LDL did not react with
isolated oxLDL antibodies. Highly modified CML-LDL (>90% of lysine residues
modified) reduced the reactivity of oxLDL antibodies, but only by 25.5%. Finally,
we investigated the possible cross-reactivity of oxLDL antibodies with
cardiolipin. Seventeen purified oxLDL antibodies were used in this study, which
showed that absorption with oxLDL or nLDL did not affect their reactivity with
immobilized cardiolipin.
PMID- 10779408
TI - Glycyrrhizin improves the resistance of MAIDS mice to opportunistic infection of
Candida albicans through the modulation of MAIDS-associated type 2 T cell
responses.
AB - Compared with normal mice, MAIDS mice (mice infected with LP-BM5 murine leukemia
virus) exhibited an increase up to 100 times greater in susceptibility to
infection with Candida albicans. The impaired resistance of MAIDS mice to the
infection was recovered to levels observed in normal mice by the administration
of glycyrrhizin (GR), an active component of licorice roots. MAIDS mice
inoculated with CD4(+) T cells from GR-treated mice were also resistant to C.
albicans infection. Normal mice inoculated with CD4(+) T helper type 2 cells (Th2
cells) from MAIDS mice were susceptible to C. albicans infection at the same
levels shown in MAIDS mice. The susceptibility of normal mice inoculated with
type 2 T cells was reversible by (i) administration of GR and (ii) inoculation of
CD4(+) T cells from GR-treated mice and injection of a mixture of mAbs targeted
against type 2 cytokines (IL-4 and IL-10). Type 2 cytokines were not detected in
sera of MAIDS mice inoculated with CD4(+) T cells from GR-treated mice, while
they were present in sera of MAIDS mice treated with saline. These results
suggest that, by inducing CD4(+) T cells which suppress type 2 cytokine
production by MAIDS-associated Th2 cells, GR improves the resistance of MAIDS
mice to C. albicans infection.
PMID- 10779409
TI - Role for interferon-gamma in rat strains with different susceptibility to
experimental autoimmune myasthenia gravis.
AB - Experimental autoimmune myasthenia gravis (EAMG) is caused by autoantibodies
against the nicotinic acetylcholine receptor (AChR) at the neuromuscular
postsynaptic membrane and represents an animal model of myasthenia gravis in
human. Recent studies highlighted the roles of TH1 cytokines (IFN-gamma, IL-12),
rather than TH2 cytokines (IL-4), in the pathogenesis of EAMG by using homozygous
(-/-) knockout mice with an EAMG-susceptible genetic background. To further
evaluate a role for IFN-gamma, we injected recombinant rat IFN-gamma (rrIFN
gamma) at the time of immunization with AChR in complete Freund's adjuvant to
EAMG-susceptible Lewis rats and EAMG-resistant Wistar Furth (WF) rats. RrIFN
gamma enhanced Lewis rat EAMG. The exacerbated muscular weakness was associated
with higher levels of anti-AChR IgG and enhanced TNF-alpha responses. Anti-AChR
IgG antibody levels were augmented to a similar extent as in Lewis rats, however,
the identical immunization and IFN-gamma injection induced only mild and
transient EAMG in WF rats due to the default TH3 phenotype development and
inherent low TH1 responses. We conclude that IFN-gamma plays a major role in the
pathogenesis of EAMG in the Lewis rat, but fails to break disease resistance in
the WF rat.
PMID- 10779410
TI - Urine levels of CD46 (membrane cofactor protein) are increased in patients with
glomerular diseases.
AB - Soluble membrane cofactor protein (MCP, CD46) has not been detected by
conventional ELISA in human urine. Here, we established a highly sensitive assay
method for determination of urinary MCP (uMCP) using monoclonal antibody-coated
paramagnetic beads. This method enabled us to detect less than 0.05 ng/ml of
purified membrane and recombinant soluble MCP, a sensitivity 10-fold higher than
that of conventional ELISA. In normal subjects, the levels of uMCP were <0. 05
ng/ml. The levels of uMCP were elevated in patients with IgA nephropathy and more
prominently in patients with rapidly progressive glomerulonephritis. The levels
of uMCP were correlated significantly with those of serum MCP (sMCP) and N-acetyl
beta-glucosaminidase and nonsignificantly with those of beta(2)-microglobulin,
total urine protein, or serum creatinine. The properties of uMCP were
inconsistent with those of the reported sMCP, since uMCP showed three bands on
SDS-PAGE/immunoblotting with molecular mass profiles different from those of
sMCP. uMCP exhibited factor I cofactor activity for cleavage of C3b comparable to
that of sMCP. The origin of uMCP, however, remains to be determined. These
results, taken together with the parameter correlation profiles, suggested that
uMCP is secreted or produced secondary to tubular or glomerular damage. The
physiological role and clinical significance of uMCP are now within the scope of
our investigation by establishment of this assay.
PMID- 10779411
TI - Structural basis for selectivity of a small molecule, S1-binding, submicromolar
inhibitor of urokinase-type plasminogen activator.
AB - BACKGROUND: Urokinase-type plasminogen activator (uPA) is a protease associated
with tumor metastasis and invasion. Inhibitors of uPA may have potential as drugs
for prostate, breast and other cancers. Therapeutically useful inhibitors must be
selective for uPA and not appreciably inhibit the related, and structurally and
functionally similar enzyme, tissue-type plasminogen activator (tPA), involved in
the vital blood-clotting cascade. RESULTS: We produced mutagenically
deglycosylated low molecular weight uPA and determined the crystal structure of
its complex with 4-iodobenzo[b]thiophene 2-carboxamidine (K(i) = 0.21 +/- 0.02
microM). To probe the structural determinants of the affinity and selectivity of
this inhibitor for uPA we also determined the structures of its trypsin and
thrombin complexes, of apo-trypsin, apo-thrombin and apo-factor Xa, and of uPA,
trypsin and thrombin bound by compounds that are less effective uPA inhibitors,
benzo[b]thiophene-2-carboxamidine, thieno[2,3-b]-pyridine-2-carboxamidine and
benzamidine. The K(i) values of each inhibitor toward uPA, tPA, trypsin,
tryptase, thrombin and factor Xa were determined and compared. One selectivity
determinant of the benzo[b]thiophene-2-carboxamidines for uPA involves a hydrogen
bond at the S1 site to Ogamma(Ser190) that is absent in the Ala190 proteases,
tPA, thrombin and factor Xa. Other subtle differences in the architecture of the
S1 site also influence inhibitor affinity and enzyme-bound structure.
CONCLUSIONS: Subtle structural differences in the S1 site of uPA compared with
that of related proteases, which result in part from the presence of a serine
residue at position 190, account for the selectivity of small thiophene-2
carboxamidines for uPA, and afford a framework for structure-based design of
small, potent, selective uPA inhibitors.
PMID- 10779412
TI - Antagonists of protein-protein interactions.
AB - Protein-protein interactions are often attractive, but not straightforward,
targets for disease therapy. Two strategies for identifying inhibitors of these
interactions, peptide phage display and high-throughput screening, have recently
shown new promise.
PMID- 10779413
TI - The advantages of ambiguous orientation.
AB - Recent studies have revealed that although it is possible for certain
transcription factors to bind in an orientated fashion on DNA, they have not
evolved to do so. Rather, they rely on contacts with other proteins to precisely
define their mode of binding.
PMID- 10779414
TI - Potentiation of CD3-induced expression of the linker for activation of T cells
(LAT) by the calcineurin inhibitors cyclosporin A and FK506.
AB - The activation of blood cells, including T cells, triggers intracellular signals
that control the expression of critical molecules, including cytokines and
cytokine receptors. We show that T-cell receptor (TCR) ligation increases the
cellular level of the protein linker for activation of T cells (LAT), a molecule
critical for T-cell development and function. T-cell activation increased LAT
messenger RNA, as determined by reverse transcription-polymerase chain reaction
and by Northern blotting. The TCR-induced increase in LAT expression involved the
activation of the serine/threonine kinases PKC and MEK, because inhibitors of
these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol
myristate acetate up-regulated LAT expression. Strikingly, the calcineurin
inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT
expression, suggesting that the activation of calcineurin following TCR ligation
negatively regulates LAT expression. Accordingly, Ca(++ )ionophores, which can
activate calcineurin by increasing intracellular Ca(++), blocked the TCR-induced
increase in cellular LAT. CsA and FK506 blocked the Ca(++ )ionophores' inhibitory
effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR
induced LAT expression; under the same conditions, these compounds did not
increase the expression of 14 other molecules that previously had been implicated
in T-cell activation. These data show that TCR-induced LAT expression involves
the activation of the PKC-Erk pathway and is negatively regulated by the
activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT
expression by CsA and FK506 suggests that the action of these agents involves up
regulating the cellular level of critical signaling molecules. These findings may
have important therapeutic implications. (Blood. 2000;95:2733-2741)
PMID- 10779415
TI - Specific and rapid induction of the proapoptotic protein Hrk after growth factor
withdrawal in hematopoietic progenitor cells.
AB - Hrk is a newly described proapoptotic member of the Bcl-2 family that is mainly
expressed in hematopoietic tissues and cultured neurons. In this study we have
examined the expression and activity of Hrk in hematopoietic progenitors. To
address these issues, we used 3 growth factor-dependent murine hematopoietic cell
lines, HCD-57, FDCP-Mix, and FL5.12. The expression of Hrk was undetectable in
cells cultured with growth factors, but it was rapidly up-regulated on growth
factor withdrawal. In contrast, the expression of Bcl-x(L) decreased and that of
proapoptotic Bax, Bad, and Bak was unchanged or down-regulated after removal of
growth factors. This pattern of expression correlated with the induction of
apoptosis. Hrk was also up-regulated in human cell lines and in bone marrow
derived CD34(+) cells cultured in the absence of growth factors. In addition, the
levels of Hrk were up-regulated after treatment with the chemotherapeutic drug
etoposide. Expression of prosurvival Bcl-x(L) or Bcl-2 proteins blocked the
induction of Hrk. Hrk was induced in FDCP-Mix cells treated with ionomicin in the
presence of IL-3, suggesting that cytosolic calcium may regulate the expression
of this proapoptotic protein. Furthermore, ectopic expression of Hrk induced cell
death of hematopoietic progenitors in the presence of IL-3. Thus, Hrk is
specifically and rapidly induced in hematopoietic progenitors after growth factor
deprivation or treatment with chemotherapeutic drugs, and this may be sufficient
to induce apoptosis in these cells. (Blood. 2000;95:2742-2747)
PMID- 10779416
TI - Role of SUMO-1-modified PML in nuclear body formation.
AB - The tumor-suppressive promyelocytic leukemia (PML) protein of acute promyelocytic
leukemia (APL) has served as one of the defining components of a class of
distinctive nuclear bodies (NBs). PML is delocalized from NBs in APL cells and is
degraded in cells infected by several viruses. In these cells, NBs are disrupted,
leading to the aberrant localization of NB proteins. These results have suggested
a critical role for the NB in immune response and tumor suppression and raised
the question of whether PML is crucial for the formation or stability of NB. In
addition, PML is, among other proteins, covalently modified by SUMO-1. However,
the functional relevance of this modification is unclear. Here, we show in
primary PML(-/-) cells of various histologic origins, that in the absence of PML,
several NB proteins such as Sp100, CBP, ISG20, Daxx, and SUMO-1 fail to
accumulate in the NB and acquire aberrant localization patterns. Transfection of
PML in PML(-/-) cells causes the relocalization of NB proteins. By contrast, a
PML mutant that can no longer be modified by SUMO-1 fails to do so and displays
an aberrant nuclear localization pattern. Therefore, PML is required for the
proper formation of the NB. Conjugation to SUMO-1 is a prerequisite for PML to
exert this function. These data shed new light on both the mechanisms underlying
the formation of the NBs and the pathogenesis of APL. (Blood. 2000;95:2748-2752)
PMID- 10779417
TI - The primacy of the gastrointestinal tract as a target organ of acute graft-versus
host disease: rationale for the use of cytokine shields in allogeneic bone marrow
transplantation.
AB - Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone
marrow transplantation (BMT), limits the application of this curative but toxic
therapy. Studies of inflammatory pathways involved in GVHD in animals have shown
that the gastrointestinal (GI) tract plays a major role in the amplification of
systemic disease. Damage to the GI tract increases the translocation of
inflammatory stimuli such as endotoxin, which promotes further inflammation and
additional GI tract damage. The GI tract is therefore critical to the propagation
of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to
the prevention of GVHD include reducing the damage to the GI tract by
fortification of the GI mucosal barrier through novel "cytokine shields" such as
IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while
preserving a graft-versus-leukemia effect in animal models, and they now deserve
formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)
PMID- 10779418
TI - HTLV-II down-regulates HIV-1 replication in IL-2-stimulated primary PBMC of
coinfected individuals through expression of MIP-1alpha.
AB - The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in
individuals also infected with HIV-1 is poorly understood. To evaluate the
reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood
mononuclear cell (PBMC) cultures from coinfected individuals were established in
the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II
replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1
production were inversely correlated to the HTLV-II proviral load in vivo and its
replication ex vivo. These observations suggested a potential interaction between
the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis
factor-alpha (TNF-alpha) were measured in the same coinfected PBMC cultures.
Endogenous IL-2 was not produced, whereas IL-6 and TNF-alpha were secreted at
levels compatible with their known ability to up-regulate HIV-1 expression. The
HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1alpha (MIP
1alpha), and MIP-1beta were also determined in IL-2-stimulated PBMC cultures. Of
interest, their kinetics and concentrations were inversely related to those of
HIV-1 replication. Experiments were performed in which CD8(+) T cells or PBMCs
from HTLV-II monoinfected individuals were cocultivated with CD4(+) T cells from
HIV-1 monoinfected individuals separated by a semipermeable membrane in the
presence or absence of antichemokine neutralizing antibodies. The results
indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up
regulating viral suppressive CC-chemokines and, in particular, MIP-1alpha. This
study is the first report indicating that HTLV-II can influence HIV replication,
at least in vitro, via up-regulation of HIV-suppressive chemokines. (Blood.
2000;95:2760-2769)
PMID- 10779419
TI - Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute
lymphoblastic leukemia in childhood: significantly lower risk without cranial
radiotherapy.
AB - Secondary neoplasms (SNs) represent serious late complications after successful
treatment of malignant diseases. To evaluate the rate and type of SNs after
Berlin-Frankfurt-Munster (BFM) treatment in children with acute lymphoblastic
leukemia (ALL), we analyzed the data from the BFM database and the German
Childhood Cancer Registry (GCCR). Between April 1979 and April 1995, 5006
children with B-precursor or T-ALL were enrolled in 5 ALL-BFM multicenter trials.
The median follow-up time from diagnosis was 5.7 years (range 1.5-18 years). By
December 1997, 52 SNs were documented, including 16 acute myeloid leukemias
(AMLs), 13 neoplasms of the central nervous system (CNS), and 23 other neoplasms.
Compared with the expected numbers estimated from incidence rates derived from
the GCCR, this represented a 14-fold increase for all cancers and a 19-fold
increase for CNS tumors. SNs developed 0.9 to 15 years (median: 6 years) after
the diagnosis of ALL; 46 patients were in first complete remission (CR). The
overall cumulative risk of SNs at 15 years was 3.3% (95% confidence interval
[CI]: 1.6%-5.1%) and 2.9% (95% CI: 1.6%-4.2%) in first CR. The risk was 3.5% (95%
CI: 1.5%-5. 5%) after treatment, including cranial irradiation and significantly
lower in nonirradiated patients: 1.2% (95% CI: 0.2%-2.3%; P =.048). The
development of secondary AML was not associated with the use of any specific
cytotoxic agent. Considering the high-survival rate of this large unselected ALL
cohort, the risk of SN is relatively low, though higher, especially after cranial
irradiation, than in the general population. Long-term follow-up is mandatory,
and further SNs with longer latency periods are to be expected. (Blood.
2000;95:2770-2775)
PMID- 10779420
TI - Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult
patients with iron overload.
AB - We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus
injection of deferoxamine and after 12 hours of subcutaneous continuous infusion
of the drug in 27 patients with iron overload (mean age, 55.7 years). In most
patients, the iron overload was due to multiple transfusions administered during
chemotherapy or as part of supportive care for a hematologic or oncologic
disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis
and spherocytosis. Similar urinary iron excretion was observed with the 2 methods
of administration; mean +/- SD values were 6935.3 +/- 3832.3 microg/48 hours with
subcutaneous bolus injection and 6630.4 +/- 3606.9 microg/48 hours with
subcutaneous continuous infusion (P =.3). Twenty-six patients (96.3%) chose to
continue therapy with bolus injection. The long-term efficacy of bolus injection
was evaluated by measuring the serum ferritin concentration at regular intervals
for a follow-up time of 20.1 +/- 4.5 months. Ferritin concentration decreased to
below 1000 microg/L in 73% of the patients and to below 500 microg/L in 42% and
became normal in 26%. Best results were obtained in patients who were no longer
receiving blood transfusions when chelation therapy was initiated. Three of 26
patients (11.5%) had mild, transient side effects after bolus injection. Larger
prospective, randomized studies must be conducted before deferoxamine bolus
injection can be routinely recommended for patients with iron overload. (Blood.
2000;95:2776-2779)
PMID- 10779421
TI - Linkage analysis demonstrates that the prothrombin G20210A mutation jointly
influences plasma prothrombin levels and risk of thrombosis.
AB - Association studies suggest that the G20210A mutation (G to A substitution at
nucleotide position 20210) in the prothrombin gene (PT) is associated with
increased plasma prothrombin activity and with increased risk for venous
thromboembolism. To test directly for linkage between this PT variant and plasma
prothrombin activity we performed a family-based study. The G20210A genotypes and
plasma prothrombin activity levels were determined in 435 individuals belonging
to 22 extended Spanish families. The sample was composed of 388 homozygous (G/G)
normal individuals and 43 heterozygote (G/A) and 4 homozygote (A/A) carriers for
the G20210A mutation. The results of variance-component linkage analysis yielded
a highly significant lod score of 3.6 (P = 2.4 x 10(-5)) between this mutation
and a quantitative trait locus (QTL) that influences prothrombin activity.
Importantly, a conditional linkage analysis that simultaneously accounted for
association with the G20210A variant completely eliminated the linkage signal,
which indicates that this mutation affects the function of the prothrombin gene.
Additionally, a bivariate linkage analysis of plasma prothrombin activity and
thrombosis significantly improved the linkage signal for prothrombin activity
(lod score = 4.7; P = 1.5 x 10(-6)) and provided strong evidence that this QTL
has a pleiotropic effect on the risk of thrombosis (lod score = 2.43; P =.0004).
These results represent the first direct genetic evidence that a QTL in the PT
gene influences prothrombin activity levels and susceptibility to thrombosis and
strongly support the conclusion that G20210A is a functional polymorphism.
(Blood. 2000;95:2780-2785)
PMID- 10779423
TI - Improvement of erythropoiesis in beta-thalassemic mice by continuous
erythropoietin delivery from muscle.
AB - beta-Thalassemias are highly prevalent genetic disorders that can cause severe
hemolytic anemia. The main pathophysiologic feature of beta-thalassemia is the
accumulation of unpaired alpha-globin chains in erythrocyte precursors and red
blood cells (RBCs). This accumulation alters cell membrane function and results
in early cell destruction and ineffective erythropoiesis. Correction of globin
chain imbalance through the induction of fetal hemoglobin (HbF) synthesis is a
tentative therapeutic approach for this class of diseases. In short-term in vitro
or in vivo assays, recombinant human erythropoietin increases the frequency of
erythroid precursors programmed to HbF in humans and to beta-minor globin in
mice. In contrast, long-term treatment of beta-thalassemic patients did not
induce HbF significantly. We took advantage of highly efficient adeno-associated
virus-mediated (AAV-mediated) gene transfer into mouse muscle to induce a robust
and sustained secretion of mouse erythropoietin in beta-thalassemic mice, which
represent a suitable model for human beta-thalassemia intermedia. A 1-year follow
up of 12 treated animals showed a stable correction of anemia associated with
improved RBC morphology, increased beta-minor globin synthesis, and decreased
amounts of alpha-globin chains bound to erythrocyte membranes. More effective
erythropoiesis probably accounted for a reduction of erythroid cell
proliferation, as shown by decreased proportions of circulating reticulocytes and
by reduced iron 59 ((59)Fe) incorporation into erythroid tissues. This study
indicates that the continuous delivery of high amounts of autologous
erythropoietin induced a sustained stimulation of beta-minor globin synthesis and
a stable improvement of erythropoiesis in the beta-thalassemic mouse model.
(Blood. 2000;95:2793-2798)
PMID- 10779422
TI - Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical,
therapeutic, and prognostic features.
AB - Fifty-two cases of autoimmune hemolytic anemia (AHA) were observed within a
series of 1203 patients (4.3%) with chronic lymphocytic leukemia (CLL) followed
at a single institution. Nineteen were observed at the time of CLL diagnosis and
33 during the clinical follow-up. Ninety percent of the patients with CLL/AHA
showed active CLL and 25% had been treated previously. The antierythrocyte
autoantibody (AeAb) was an IgG in 87% of cases and an IgM in 13%. A lymphocyte
count more than 60 x 10(9)/L (P <.00001), age above 65 years (P <.01), and male
gender (P <.01) emerged as independent parameters that correlated significantly
with an increased rate of AHA at CLL diagnosis. Patients previously treated with
chlorambucil (CB) plus prednisone (PDN) and with fludarabine plus PDN showed a
similar rate of AHA (1.8% and 2.5%, respectively). After steroid therapy
associated with CB in case of active CLL, 70% of patients achieved the complete
disappearance of the AeAb. The actuarial AHA relapse-free survival probability
was 54% at 5 years and the median survival probability after AHA was 41 months.
Infections represented the main cause of morbidity and mortality. IgG AHA and the
occurrence of AHA at the same time of CLL diagnosis emerged as independent
factors significantly correlated with a better survival probability of AHA/CLL
patients. Taken together, this study indicates that in CLL, AHA is a rare event
with no independent effect on survival for which steroids, associated with CB if
required, and a careful management of infections may successfully control the 2
conditions. Cooperative studies are needed to better define the optimal steroid
schedule and the therapeutic role of other immunosuppressive agents and
splenectomy. (Blood. 2000;95:2786-2792)
PMID- 10779424
TI - Correction of the coagulation defect in hemophilia A mice through factor VIII
expression in skin.
AB - To test the hypothesis that factor VIII expressed in the epidermis can correct
hemophilia A, we generated transgenic mice in a factor VIII-deficient background
that express human factor VIII under control of the involucrin promoter. Mice
from 5 transgenic lines had both phenotypic correction and plasma factor VIII
activity. In addition to the skin, however, some factor VIII expression was
detected in other tissues that have stratified squamous epithelia. To determine
whether an exclusively cutaneous source of factor VIII could correct factor VIII
deficiency, we grafted skin explants from transgenic mice onto mice that are
double knockouts for the factor VIII and RAG-1 genes. Two graft recipients had
plasma factor VIII activity of 4% to 20% of normal and improved whole blood
clotting compared with factor VIII-deficient mice. Thus, expression of factor
VIII from the epidermis can correct hemophilia A mice, thereby supporting the
feasibility of cutaneous gene therapy for systemic disease. (Blood. 2000;95:2799
2805)
PMID- 10779426
TI - Isolation and characterization of human CD34(-)Lin(-) and CD34(+)Lin(-)
hematopoietic stem cells using cell surface markers AC133 and CD7.
AB - Recent evidence indicates that human hematopoietic stem cell properties can be
found among cells lacking CD34 and lineage commitment markers (CD34(-)Lin(-)). A
major barrier in the further characterization of human CD34(-) stem cells is the
inability to detect this population using in vitro assays because these cells
only demonstrate hematopoietic activity in vivo. Using cell surface markers AC133
and CD7, subfractions were isolated within CD34(-)CD38(-)Lin(-) and CD34(+)CD38(
)Lin(-) cells derived from human cord blood. Although the majority of CD34(
)CD38(-)Lin(-) cells lack AC133 and express CD7, an extremely rare population of
AC133(+)CD7(-) cells was identified at a frequency of 0.2%. Surprisingly, these
AC133(+)CD7(-) cells were highly enriched for progenitor activity at a frequency
equivalent to purified fractions of CD34(+) stem cells, and they were the only
subset among the CD34(-)CD38(-)Lin(-) population capable of giving rise to
CD34(+) cells in defined liquid cultures. Human cells were detected in the bone
marrow of non-obese/severe combined immunodeficiency (NOD/SCID) mice 8 weeks
after transplantation of ex vivo-cultured AC133(+)CD7(-) cells isolated from the
CD34(-)CD38(-)Lin(-) population, whereas 400-fold greater numbers of the AC133(
)CD7(-) subset had no engraftment ability. These studies provide novel insights
into the hierarchical relationship of the human stem cell compartment by
identifying a rare population of primitive human CD34(-) cells that are
detectable after transplantation in vivo, enriched for in vitro clonogenic
capacity, and capable of differentiation into CD34(+) cells. (Blood. 2000;95:2813
2820)
PMID- 10779425
TI - Generation of T cells from adult human hematopoietic stem cells and progenitors
in a fetal thymic organ culture system: stimulation by tumor necrosis factor
alpha.
AB - To investigate the T-lymphopoietic capacity of human adult bone marrow (ABM)
hematopoietic progenitor cells, CD34+Lin-, CD34+CD38+, and CD34++CD38- cells were
cultured in a severe combined immunodeficient (SCID) mouse fetal thymic organ
culture (FTOC). Direct seeding of these progenitors resulted in a moderate to
severe cell loss, particularly for the CD34++CD38- cell fraction, and T cells
could only be generated from the CD34+Lin- fraction. Preincubation for 36 hours
with interleukin-3 (IL-3) and stem cell factor (SCF) led to an improved cell
survival and proliferation, although T-cell development was seen only in the
CD34+Lin- fraction. Addition of tumor necrosis factor (TNF)-alpha to IL-3 + SCF
supplemented preincubation medium resulted in optimal cell survival, cell
proliferation. and T-cell generation of all 3 cell fractions. The TNF-alpha
effect resulted in an up-regulation of CD127 (ie, the IL-7 receptor alpha-chain)
in a small subset of the CD34+ cells. No evidence could be generated to support
the possibility that TNF-alpha inhibits a cell population that suppresses T-cell
differentiation. A quantitatively different T-cell generation potency was still
seen between the 3 subpopulations: CD34+Lin- (100% success rate) > CD34+CD38+
(66%) > CD34++CD38- (25%). These data contrast with our previous findings using
fetal liver and cord blood progenitors, which readily differentiate into T
lymphocytes in FTOC, even without prestimulation with cytokines. Our results
demonstrate that adult CD34++CD38- cells, known to contain hematopoietic stem
cells, can differentiate into T-lymphocytes and that a significant difference
exists in T-lymphopoietic activity of stem cells derived from ontogenetically
different sources. (Blood. 2000;95:2806-2812)
PMID- 10779427
TI - Retinoic acid is a negative regulator for the differentiation of cord blood
derived human mast cell progenitors.
AB - We examined the effects of retinoids on the human mast cell development using a
serum-deprived culture system. When 10-week cultured mast cells derived from
CD34(+) cord blood cells were used as target cells, both all-trans retinoic acid
(ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem
cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF
plus RA at 10(-7) mol/L was one tenth of the value obtained by SCF alone). The
early steps in mast cell development appear to be less sensitive to RA according
to the single CD34(+)c-kit(+) cord blood cell culture study. The optimal
concentration of RAs also reduced the histamine concentration in the cultured
mast cells (3.00 +/- 0.47 pg per cell in SCF alone, 1.44 +/- 0.18 pg per cell in
SCF+ATRA, and 1.41 +/- 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed
the expression of RARalpha, RARbeta, RXRalpha, and RXRbeta messenger ribonucleic
acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective
agonist at 10(-10) mol/L to 10(-7) mol/L decreased the number of mast cells grown
in SCF, whereas an RXR-selective agonist at up to 10(-8) mol/L was inactive.
Among RAR subtype selective retinoids used at 10(-9) mol/L to 10(-7) mol/L, only
the RARalpha agonist was equivalent to ATRA at 10(-7) mol/L in its ability to
inhibit mast cell growth. Conversely, the addition of excess concentrations of a
RARalpha antagonist profoundly counteracted the retinoid-mediated suppressive
effects. These results suggest that RA inhibits SCF-dependent differentiation of
human mast cell progenitors through a specific receptor. (Blood. 2000;95:2821
2828)
PMID- 10779428
TI - Effects of cell cycle activation on the short-term engraftment properties of ex
vivo expanded murine hematopoietic cells.
AB - Loss of long-term hematopoietic stem cell function in vitro is associated with
cell cycle progression. To determine whether cytokine-induced proliferation also
limits the rate of short-term engraftment and potential clinical utility of ex
vivo expanded hematopoietic cells, murine Sca-1(+)c-kit(+)Lin(-) cells were
cultured in interleukin-6 (IL-6), IL-11, granulocyte colony-stimulating factor (G
CSF), stem cell factor, flk-2 ligand, and thrombopoietin for 7 days. Cells
amplified 2000-fold were then stained with Hoechst 33342, separated into
G(0)/G(1) (72% +/- 3%) or S/G(2)/M (27% +/- 3%) fractions by flow sorting, and
injected into lethally irradiated mice. Although long-term (more than 6 months)
engraftment of lymphoid and myeloid lineages was greater in primary and secondary
recipients of expanded cells residing in G(0)/G(1) at the time of
transplantation, there were no noted differences in the short-term (less than 6
weeks) recovery kinetics of circulating blood cells. When hematopoietic cells
were expanded in cultures containing the tetrapeptide stem cell inhibitor N
Acetyl-Ser-Asp-Lys-Pro (AcSDKP) to reduce progenitor cycling prior to
transplantation, again there were no differences observed in short-term
reconstitution by inhibited or uninhibited cells. Interestingly, AcSDKP
significantly accelerated engraftment by expanded hematopoietic cells when
administered in vivo at the time of transplantation. Leukocytes recovered to 20%
of normal levels approximately 1 week faster, and thrombocytopenia was largely
abrogated in AcSDKP-treated versus untreated mice. Therefore, while AcSDKP can
accelerate the engraftment of ex vivo expanded hematopoietic progenitors, which
suggests a relatively simple approach to improve their clinical utility, its
effects appear unrelated to cell cycle arrest. (Blood. 2000;95:2829-2837)
PMID- 10779429
TI - REDK, a novel human regulatory erythroid kinase.
AB - We have identified a novel regulatory erythroid kinase (REDK) that is homologous
to a family of dual-specificity kinases. The yeast homolog of REDK negatively
regulates cell division, suggesting a similar function for REDK, which is
primarily localized in the nucleus. REDK is present in hematopoietic tissues,
such as bone marrow and fetal liver, but the RNA is expressed at significant
levels only in erythroid or erythropoietin (EPO)-responsive cells. Two novel
forms of cDNA (long and short) for REDK have been isolated that appear to be
alternative splice products and imply the presence of polypeptides with differing
amino termini. The ratio of short-to-long forms of REDK increases dramatically in
CD34(+) cells cultured with EPO, suggesting differing regulation and function for
each form. REDK is predominantly found in nuclear, rather than cytoplasmic,
protein extracts, and immunoprecipitated REDK is active in phosphorylating
histones H2b, H3, myelin basic protein, and other coimmunoprecipitated proteins.
Antisense REDK oligonucleotides promote erythroid colony formation by human bone
marrow cells, without affecting colony-forming unit (CFU)-GM, CFU-G, or CFU-GEMM
numbers. Maximal numbers of CFU-E and burst-forming unit-erythroid were
increased, and CFU-E displayed increased sensitivity to suboptimal EPO
concentrations. The data indicate that REDK acts as a brake to retard
erythropoiesis. (Blood. 2000;95:2838-2846)
PMID- 10779430
TI - Monocytes express high amounts of Notch and undergo cytokine specific apoptosis
following interaction with the Notch ligand, Delta-1.
AB - Notch signaling has been shown to play a key role in cell fate decisions in
numerous developmental systems. Using a reverse transcriptase-polymerase chain
reaction (RT-PCR) assay, we reported the expression of human Notch-1 in CD34+
progenitors. In this study, we evaluated the expression of human Notch-1 and
Notch-2 protein by hematopoietic cells. In immunofluoresence study, we detected
low amounts of Notch-1 and Notch-2 protein in both CD34+ and CD34+Lin- cells,
high amounts in CD14+ monocytes as well as B and T cells, but no expression in
CD15+ granulocytes. We further found that an immobilized truncated form of the
Notch ligand, Delta-1, induced apoptosis in monocytes in the presence of
macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage
colony-stimulating factor (GM-CSF). The widespread expressions of Notch proteins
suggest multiple functions for this receptor during hematopoiesis. These studies
further indicate a novel role for Notch in regulating monocyte survival. (Blood.
2000;95:2847-2854)
PMID- 10779431
TI - Thrombin activatable fibrinolysis inhibitor and the risk for deep vein
thrombosis.
AB - Thrombin activatable fibrinolysis inhibitor (TAFI, or procarboxypeptidase B) is
the precursor of a recently described carboxypeptidase that potently attenuates
fibrinolysis. Therefore, we hypothesized that elevated plasma TAFI levels induce
a hypofibrinolytic state associated with an increased risk for venous thrombosis.
To evaluate this hypothesis, we developed an electroimmunoassay for TAFI antigen
and used this assay to measure TAFI levels in the Leiden Thrombophilia Study, a
case-control study of venous thrombosis in 474 patients with a first deep vein
thrombosis and 474 age- and sex-matched control subjects. In 474 healthy control
subjects, an increase of TAFI with age was observed in women but not in men. Oral
contraceptive use also increased the TAFI concentration. TAFI levels above the
90th percentile of the controls (> 122 U/dL) increased the risk for thrombosis
nearly 2-fold compared with TAFI levels below the 90th percentile (odds ratio,
1.7; 95% confidence interval, 1.1-2.5). Adjustment for various possible
confounders did not materially affect this estimate. These results indicate that
elevated TAFI levels form a mild risk factor for venous thrombosis. Such levels
were found in 9% of healthy controls and in 14% of patients with a first deep
vein thrombosis. Elevated TAFI levels did not enhance the thrombotic risk
associated with factor V Leiden but may interact with high factor VIII levels.
(Blood. 2000;95:2855-2859)
PMID- 10779432
TI - Shortage of circulating naive CD8(+) T cells provides new insights on
immunodeficiency in aging.
AB - Clinical observations indicate that elderly people are prone to severe, often
lethal infectious diseases induced by novel pathogens. Since the ability to mount
primary immune responses relies on the availability of naive T cells, the
circulating naive T-cell reservoir was evaluated throughout the human life span.
Naive T cells were identified as CD95(-) T lymphocytes for their phenotypic and
functional features. Indeed, the lack of CD95 marker is sufficient to identify a
population of naive T cells, as defined by coincidence with previously
characterized CD45RA(+) CD62L(+) T cells. Naive CD95(-) T cells, as expected,
require a costimulatory signal, such as CD28, to optimally proliferate after anti
CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120
healthy subjects ranging in age from 18 to 105 years revealed that naive T cells
decreased sharply with age. The younger subjects had a naive T-lymphocyte count
of 825 +/- 48 cells/microL, and the centenarians had a naive T-lymphocyte count
of 177 +/- 28 cells/microL. Surprisingly, the naive T-cell count was lower in
CD8(+) than in CD4(+) subsets at any age, and the oldest individuals were almost
completely depleted of circulating naive CD8(+) T cells (13 +/- 4 cells/microL).
Concomitantly, a progressive expansion of CD28(-) T cells occurs with age, which
can be interpreted as a compensatory mechanism. These data provide new insights
into age-related T-cell-mediated immunodeficiency and reveal some analogies of T
cell dynamics between advanced aging and human immunodeficiency virus (HIV)
infection. In conclusion, the exhaustion of the naive CD8(+) T-cell reservoir,
which has never been reported before, suggests that this T-cell pool is a major
target of the aging process and may define a parameter possibly related to the
life span of humans. (Blood. 2000;95:2860-2868)
PMID- 10779433
TI - Role of IL-16 in delayed-type hypersensitivity reaction.
AB - Interleukin (IL)-16 is a chemoattractant cytokine for CD4(+) leukocytes. Because
delayed-type hypersensitivity (DTH) reaction is mediated by T helper 1 (Th1)
cells and CD4(+) T cells can be chemoattracted by IL-16, we have investigated the
involvement of IL-16 in the DTH reaction. Immunohistochemical analysis revealed
the IL-16 expression in infiltrating cells and epithelial cells in the DTH
footpads. The IL-16 expression was also detected intracellularly in the
infiltrating cells. In addition, markedly increased production of IL-16 was
detected in the DTH footpad extracts, but not in the control footpad extracts, by
an enzyme-linked immunosorbent assay and also by Western blot analysis. The DTH
footpad extracts exhibited a strong chemoattractant activity toward splenic T
cells, which was significantly inhibited by the inclusion of neutralizing
monoclonal antibody (mAb) against IL-16 in the migration assay. Furthermore,
treatment of sensitized mice in vivo with the anti-IL-16 neutralizing mAb
significantly suppressed the footpad swelling induced by an antigen challenge,
together with decreased infiltration of leukocytes including not only CD4(+) T
cells but also CD8(+) T cells and macrophages into the DTH footpads. Decreased
production of macrophage inflammatory protein 1alpha was also observed in the DTH
footpad extracts by the mAb treatment. These results suggest that IL-16 plays an
important role in the recruitment of leukocytes-presumably including antigen
specific Th1 cells, which secrete cytokines and chemokines mediating the
following hypersensitivity reaction after activation by the interaction with
Langerhans cells carrying the antigen-for the elicitation of DTH response.
(Blood. 2000;95:2869-2874)
PMID- 10779434
TI - Nonsteroidal anti-estrogens inhibit the functional differentiation of human
monocyte-derived dendritic cells.
AB - Dendritic cells (DC) are professional antigen-presenting cells with a unique
capacity to initiate and regulate immune responses. Immature CD1a(+) DC can be
cultured from CD14(+) monocytes in the presence of interleukin (IL)-4 and
granulocyte macrophage colony-stimulating factor in vitro. Results of this study
show that the nonsteroidal anti-estrogens toremifene and tamoxifen inhibit this
differentiation. In the presence of anti-estrogens the cells lose CD14
expression, but remain CD1a(-) and clearly have less dendritic processes than
immature DC. Functionally, anti-estrogen-treated cells are inferior to immature
DC in inducing proliferation of allogeneic T cells and in producing IL-12 p70
protein after CD40 ligation. The expression of the costimulatory molecules CD80
and CD86 is differentially regulated by anti-estrogens during DC differentiation.
Furthermore, anti-estrogens are also able to inhibit the terminal maturation of
DC. By inhibiting the functional differentiation of DC, anti-estrogens may have a
role in the treatment and prevention of autoimmune diseases. (Blood. 2000;95:2875
2882)
PMID- 10779435
TI - Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor
specific T lymphocytes infiltrating renal cell carcinomas.
AB - In this study, we showed that renal tumors contain substantial subsets of CD8(+)
p58(+) T cells. From 1 of these tumors, T cells were amplified in mixed
lymphocytes-tumor cell cultures and p58(+) T cells were selected immunologically.
After expansion, phenotypic and functional features of p58(+) and p58(-) T cells
were examined. The p58(+) T cells expressed p58.2 receptor and corresponded to
CD3(+), CD8(+), T-cell receptor (TCR) alpha/beta(+) T cells that were CD56(+) and
CD28(-). Functionally, p58(+) T cells showed a low level of lytic activity
against autologous tumor cells that was dramatically and specifically increased
by anti-p58.2 monoclonal antibody. On the other hand, p58(-) CD8(+) T cells did
not lyse autologous tumor cells and had non-major histocompatibility complex
restricted cytotoxicity against K562 and Daudi cells. A p58(+) cytotoxic T
lymphocyte (CTL) clone (4C7) with the same characteristics as the p58(+) T-cell
line was derived. This CTL clone did not lyse autologous normal B cells but lysed
several HLA-A1(+) renal tumor cell lines. Analysis of TCR repertoire diversity
showed that the p58(+) T-cell line contained 3 TCR rearrangements, whereas the
TCR repertoire of p58(-) T cells was polyclonal. Interestingly, TCR transcripts
of p58(+) T cells and of CTL clone 4C7 were detected as prominent ex vivo in
tumor cells but not in peripheral blood mononuclear cells, suggesting that these
cells are antigen specific and amplified at the tumor site. (Blood. 2000;95:2883
2889)
PMID- 10779436
TI - Defensins are dominant HLA-DR-associated self-peptides from CD34(-) peripheral
blood mononuclear cells of different tumor patients (plasmacytoma, chronic
myeloid leukemia).
AB - The HLA-DR-associated peptides from peripheral blood mononuclear cells of 2
patients with plasmacytoma and 1 with chronic myeloid leukemia were isolated,
identified, and compared. Several were identified as derivatives of the defensin
family. Defensins (or human neutrophil peptides [HNP]) are antimicrobial,
cationic peptides of 29 to 35 amino acids in length and are the major
constituents of the azurophilic granules of human neutrophils. Using peripheral
blood cells from leukapheresis, containing about 90% of polymorphonuclear cells,
we could identify HNP-1, -2, and -4 and propeptides of up to 49 amino acids in
length, eluted from HLA class II molecules. Binding of isolated and synthetic
defensin peptides to various HLA-DR alleles using an in vitro binding/competition
assay based on size exclusion chromatography revealed that defensin may bind into
the peptide-binding groove. In a T-cell competition assay, defensins were able to
reduce the proliferation of an HLA-DR-restricted T-cell line after preincubation
of stimulating cells (CHO-DRB1*0401 transfectants) with defensin. Therefore,
binding of defensins might prevent T-cell recognition of HLA class II molecules
expressed on different blood precursor cells (all of which are "nonprofessional"
antigen-presenting cells) by blocking the HLA peptide-binding groove or,
alternatively, might protect defensin-expressing cells from self-destruction.
(Blood. 2000;95:2890-2896)
PMID- 10779437
TI - P-glycoprotein plays a drug-efflux-independent role in augmenting cell survival
in acute myeloblastic leukemia and is associated with modulation of a
sphingomyelin-ceramide apoptotic pathway.
AB - P-glycoprotein (pgp), which is the product of the MDR1 (multidrug resistance-1)
gene, has an established role as a mediator of cytotoxic drug resistance in acute
myeloid leukemia (AML). To study the role of pgp in mediating apoptosis
resistance in AML cells deprived of serum and growth factors, apoptosis was
quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7
AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a
significant increase in apoptosis in the presence of the pgp-specific antibody
UIC2 (mean increase: 58%; range: 11%-95%; P <. 05). Likewise, apoptosis in growth
factor-deprived TF1 cells cultured for 30 hours increased 2.5-fold in the
presence of 25 microg/mL UIC2. The pgp reversal agent PSC-833 (1 micromol/L)
augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to
a comparable degree in 6 pgp-ve samples. To determine whether the sphingomyelin
ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to
cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific
IC(30) (the concentration of daunorubicin that caused apoptotic cell death in 30%
of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which
inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment
apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was
significantly more effective at augmenting apoptosis in pgp-ve patient blasts
(median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples
(median: 7%; range: 0%-27%; P =.028). Cellular accumulation of exogenous SM was
associated with apoptosis and also occurred in nonapoptotic patient cells treated
with PSC-833. However, this effect was not seen following treatment with the UIC2
antibody. These results indicate that pgp is able to exert a protective effect on
AML cell viability and that this is associated with a reduced effect of exogenous
SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp
independent mechanism to alter SM distribution and to augment apoptosis induced
in AML cells by serum and growth factor withdrawal. (Blood. 2000;95:2897-2904)
PMID- 10779438
TI - Autocrine nerve growth factor is essential for cell survival and viral maturation
in HHV-8-infected primary effusion lymphoma cells.
AB - High levels of nerve growth factor (NGF) are found in sera from individuals
infected with human herpesvirus 8 (HHV-8). BC-1 and BCBL-1 cells are primary
effusion lymphoma-derived B-cell lines; BC-1 cells are infected by HHV-8 and the
Epstein-Barr virus (EBV), and BCBL-1 cells are infected only by HHV-8. Both cells
express NGF receptors and produce NGF, whereas RAMOS cells (a B-cell line that is
negative for HHV-8 and EBV) express NGF receptors but do not produce detectable
NGF. Neutralization of endogenous NGF results in cell growth inhibition and
apoptosis in BCBL-1 cells and, to a minor extent, in BC-1 cells. When the HHV-8
lytic cycle is induced in BCBL-1 cells by tetradecanoyl phorbol acetate (TPA), an
initial reduction of endogenous NGF production is observed, and many cells
undergo apoptosis. However, at 48 hours, TPA-treated cells produce significantly
more NGF than untreated controls, and a subsequent recovery of cell viability is
observed. Consistent with this finding, the addition of exogenous NGF or anti-NGF
antibodies to TPA-treated cells reduces or increases, respectively, the rate of
apoptosis in response to TPA. Finally, electron microscopy of TPA-treated BCBL-1
cells shows that the addition of exogenous NGF increases the number of cells
producing and releasing complete virions as compared with the controls (25%
versus 5%). On the contrary, NGF neutralization leads to the production of
defective viral progeny in about 2% of cells. These data indicate that NGF is
essential for both cell survival and virus maturation in HHV-8-infected cell
lines. (Blood. 2000;95:2905-2912)
PMID- 10779439
TI - Analysis of the biologic properties of p230 Bcr-Abl reveals unique and
overlapping properties with the oncogenic p185 and p210 Bcr-Abl tyrosine kinases.
AB - The reciprocal translocation between chromosomes 9 and 22 that fuses coding
sequences of the Bcr and Abl genes is responsible for a remarkably diverse group
of hematologic malignancies. A newly described 230-kd form of Bcr-Abl has been
associated with an indolent myeloproliferative syndrome referred to as chronic
neutrophilic leukemia. We have cloned the corresponding gene and examined the
biologic and biochemical properties of p230 Bcr-Abl after retroviral-mediated
gene transfer into hematopoietic cell lines and primary bone marrow cells. p230
Bcr-Abl-expressing 32D myeloid cells were fully growth factor-independent and
activated similar signal transduction pathways as the well-characterized p210 and
p185 forms of Bcr-Abl. In contrast, primary mouse bone marrow cells expressing
p230 required exogenous hematopoietic growth factors for optimal growth, whereas
p185- and p210-expressing cells were independent of growth factors. The 3 Bcr-Abl
proteins exerted different effects on differentiation of bone marrow cells. p185
induced outgrowth of lymphoid precursors capable of tumor formation in
immunodeficient mice. In contrast, p210- and p230-expressing bone marrow cells
caused limited outgrowth of lymphoid precursors that failed to form tumors in
immunodeficient mice. Removal of cytokines and autologous stroma from Bcr-Abl
expressing bone marrow cultures produced the expansion of distinct lineages by
the various Bcr-Abl proteins. p185 drove expansion of cytokine-independent
lymphoid progenitors, while p210 and p230 generated cytokine-independent
monocyte/myeloid cells. These findings suggest that the different Bcr-Abl fusion
proteins drive the expansion of different hematopoietic populations, which may
explain the association of the various Bcr-Abl oncoproteins with different
spectra of human leukemias. (Blood. 2000;95:2913-2921)
PMID- 10779440
TI - Variable heavy chain gene analysis of follicular lymphomas: correlation between
heavy chain isotype expression and somatic mutation load.
AB - The expansion of follicular lymphomas (FLs) resembles, both morphologically and
functionally, normal germinal center B-cell growth. The tumor cells proliferate
in networks of follicular dendritic cells and are believed to be capable of
somatic hypermutation and isotype switching. To investigate the relation between
somatic mutation and heavy chain isotype expression, we analyzed the variable
heavy (V(H)) chain genes of 30 FL samples of different isotypes. The V(H) genes
of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype
switched lymphomas contained more somatic mutations than immunoglobulin M
positive lymphomas (33.8 mutations per V(H) gene versus 23.0, respectively). In
all but one of the FLs, the ratios of replacement versus silent mutations in the
framework regions were low, independent of the absolute number of somatic
mutations and the level of intraclonal variation. Analysis of relapse samples of
4 FLs showed no obvious increase in somatic mutation load in most FLs and a
decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence
for selection of certain subclones, rather than clonal evolution. Our findings
question if intraclonal variation is always a reflection of ongoing somatic
hypermutation. This may have implications for the concept of antigen-driven
lymphomagenesis. (Blood. 2000;95:2922-2929)
PMID- 10779441
TI - MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an
extranodal lymphoma.
AB - Cytogenetic abnormalities at chromosome 1q21 are among the most common lesions in
diffuse large-cell lymphoma and have been associated with a poor prognosis. A
novel cell line, SKI-DLCL-1, was established from ascitic fluid that carries a
t(1;14)(q21;q32) chromosomal translocation. Using pulsed-field gel
electrophoresis, the breakpoint on the IgH locus mapped to a gamma locus between
Calpha(1) and Calpha(2). A cosmid library was prepared from SKI-DLCL-1, and
Cgamma-positive clones spanning the breakpoint were identified by screening with
fluorescence in situ hybridization. The breakpoint occurs 860 bp downstream of
the 3' UTR of the MUC1 gene. The break appears to be a staggered double-strand
break consistent with an error in immunoglobulin class switching. The MUC1 gene
is highly transcribed and translated, and the protein is highly glycosylated. It
is postulated that MUC1 expression is brought under the control of the 3'Ealpha
enhancer. MUC1 lies in a region of chromosome 1 characterized by an unusually
high density of genes, with 7 known genes in a region of approximately 85 kb. To
determine whether there was a pleiotropic effect of the expression of genes in
the region as a consequence of the translocation, the expression of 6 additional
genes was assessed. None of the other genes in this region (CLK2, propin, COTE1,
GBA, metaxin, and thrombospondin 3) are overexpressed in SKI-DLCL-1. Thus, the
translocation t(1;14)(q21;q32) seen in both the primary tumor and the derived
cell line results in the marked overexpression of MUC1 without affecting the
expression of other genes in the region. (Blood. 2000;95:2930-2936)
PMID- 10779442
TI - Loss of heterozygosity on 10q and microsatellite instability in advanced stages
of primary cutaneous T-cell lymphoma and possible association with homozygous
deletion of PTEN.
AB - Previous cytogenetic studies of primary cutaneous T-cell lymphoma (CTCL) were
based on limited numbers of patients and seldom showed consistent nonrandom
chromosomal abnormalities. In this study, 54 tumor DNA samples from patients with
CTCL were analyzed for loss of heterozygosity on 10q. Allelic loss was identified
in 10 samples, all of which were from the 44 patients with mycosis fungoides
(10/44 patients; 23%). Of the patients with allelic loss, 3 were among the 29
patients with early-stage myosis fungoides (T(1) or T(2)) (3/29 patients; 10%),
whereas the other 7 were among the 15 patients with advanced cutaneous disease
(T(3) or T(4)) (7/15 patients; 47%). The overlapping region of deletion was
between 10q23 and 10q24. In addition, microsatellite instability (MSI) was
present in 13 of the 54 samples (24%), 12 from patients with mycosis fungoides
and 1 from a patient with Sezary syndrome. There was also an association between
MSI and disease progression in patients with mycosis fungoides, with 6 of 15
(40%) patients with MSI having advanced cutaneous disease and only 6 of 29 (21%)
having early-stage disease. Samples with allelic loss on 10q were analyzed for
abnormalities of the tumor suppressor gene PTEN (10q23.3). No tumor-specific
mutations were detected, but homozygous deletion was found in 2 patients. Thus,
we found loss of heterozygosity on 10q and MSI in advanced cutaneous stages of
mycosis fungoides. These findings indicate that a tumor suppressor gene or genes
in this region may be associated with disease progression. Furthermore,
abnormalities of PTEN may be important in the pathogenesis of mycosis fungoides,
but our data imply that this gene is rarely inactivated by small deletions or
point mutations. (Blood. 2000;95:2937-2942)
PMID- 10779443
TI - Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated
phagocytosis.
AB - Interactions between the Wiskott-Aldrich (WAS) protein (WASp), small GTPases, and
the cytoskeletal organizing complex Arp2/3 appear to be critical for the
transduction of signals from the cell membrane to the actin cytoskeleton in
hematopoietic cells. This study shows that Fcgamma-receptor (FcgammaR)-mediated
phagocytosis is impaired in WASp-deficient peripheral blood monocytes, and that
in macrophages, formation of the actin cup and local recruitment of tyrosine
phosphorylated proteins is markedly attenuated. Results also show that, in normal
macrophages, WASp itself is actively recruited to the cup, suggesting that
assembly of this specialized cytoskeletal structure is dependent on its
expression. (Blood. 2000;95:2943-2946)
PMID- 10779444
TI - Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI
and RhoGDI) in neutrophils from patients with severe congenital neutropenia.
AB - Severe congenital neutropenia (SCN) or Kostmann syndrome is a disorder of
myelopoiesis characterized by a maturation arrest at the stage of promyelocytes
or myelocytes in bone marrow and absolute neutrophil counts less than 200/microL
in peripheral blood. Treatment of these patients with granulocyte colony
stimulating factor (G-CSF) leads to a significant increase in circulating
neutrophils and a reduction in infection-related events in more than 95% of the
patients. To date, little is known regarding the underlying pathomechanism of
SCN. G-CSF-induced neutrophils of patients with SCN are functionally defective
(eg, chemotaxis, superoxide anion generation, Ca(++ )mobilization). Two guanosine
triphosphatases (GTPases), Rac2 and RhoA, were described to be involved in many
neutrophil functions. The expression of these GTPases and their regulation in
patients' neutrophils were of interest. This study determined that the guanosine
diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed at the protein
level in patients' neutrophils and that overexpression is a result of G-CSF
treatment. RhoA and LyGDI are expressed at similar levels, whereas Rac2 shows a
decreased expression. In addition, association of Rac2 and RhoGDI or LyGDI is
abrogated or not detectable based on the low Rac2 expression in patients'
neutrophils. (Blood. 2000;95:2947-2953)
PMID- 10779445
TI - Importance of L-selectin-dependent leukocyte-leukocyte interactions in human
whole blood.
AB - The objective of this study was to investigate whether leukocytes could be
recruited by rolling leukocytes in a human whole blood model system. In all
experiments, either neutrophils, whole blood, or diluted blood was perfused over
immobilized E-selectin. With isolated neutrophils (2 x 10(5)/mL), the free
flowing neutrophils were captured by attached neutrophils to form secondary
interactions that resulted in lines of rolling leukocytes. These secondary
tethers accounted for 50% to 60% of all interactions and were eliminated by an L
selectin antibody, which also eliminated the lines of rolling leukocytes.
Perfusion of whole blood or diluted blood revealed no lines of rolling
leukocytes. The addition of red blood cells to isolated neutrophils either in a
1000:1 or a 10:1 ratio also inhibited lines of rolling leukocytes. Leukocytes
were fluorescently labeled with rhodamine-6G so that leukocyte-leukocyte
interactions could be studied in whole blood. A small number of secondary tethers
(less than 20%) occurred and could be reduced by more than 80% with an L-selectin
antibody. However, the overall impact on leukocyte recruitment was negligible.
Similar experiments were performed using murine whole blood or isolated murine
leukocytes. In the absence of red blood cells, murine leukocytes also formed
lines of rolling leukocytes on E-selectin, and secondary tethers accounted for
50% of total interactions. However, when murine blood (diluted 1:5 with buffer)
was perfused over E-selectin, secondary tethers accounted for only 13% of total
interactions. These interactions were completely absent when blood was used from
L-selectin-deficient mice. These data demonstrate for the first time that the
importance of L-selectin-dependent leukocyte-leukocyte interactions is greatly
reduced in whole blood and does not enhance overall recruitment of leukocytes in
this physiologic milieu. (Blood. 2000;95:2954-2959)
PMID- 10779446
TI - Intracellular iron status as a hallmark of mammalian cell susceptibility to
oxidative stress: a study of L5178Y mouse lymphoma cell lines differentially
sensitive to H(2)O(2).
AB - The redox properties of iron make this metal a key participant in oxygen-mediated
toxicity. Accordingly, L5178Y (LY) mouse lymphoma cell lines, which display a
unique inverse cross-sensitivity to ionizing radiation (IR) and hydrogen peroxide
(H(2)O(2)), are a suitable model for the study of possible differences in the
constitutive control of intracellular iron availability. We report here that the
level of iron in the cytosolic labile iron pool (LIP), ie, potentially active in
the Fenton reaction, is more than 3-fold higher in IR-resistant, H(2)O(2)
sensitive (LY-R) cells than in IR-sensitive, H(2)O(2)-resistant (LY-S) cells.
This difference is associated with markedly greater content of ferritin H
subunits (H-Ft) in LY-S than in LY-R cells. Our results show that different
expression of H-Ft in LY cells is a consequence of an up-regulation of H-Ft mRNA
in the LY-S mutant cell line. In contrast, posttranscriptional control of iron
metabolism mediated by iron-responsive element-iron regulatory proteins (IRPs)
interaction is similar in the 2 cell lines, although IRP1 protein levels in iron
rich LY-R cells are twice those in iron-deficient LY-S cells. In showing that LY
cell lines exhibit 2 different patterns of intracellular iron regulation, our
results highlight both the role of high LIP in the establishment of pro-oxidant
status in mammalian cells and the antioxidant role of ferritin. (Blood.
2000;95:2960-2966)
PMID- 10779447
TI - Selectively increased growth of fetal hemoglobin-expressing adult erythroid
progenitors after brief treatment of early progenitors with transforming growth
factor beta.
AB - We have studied the effect of transforming growth factor beta (TGFbeta) on
erythropoiesis in cultures from adult peripheral blood, using flow cytometric
enumeration of fetal hemoglobin (HbF)-containing cells. TGFbeta caused a dramatic
increase in the proportions of cells that accumulated HbF together with adult
hemoglobin (HbA) (F+A+ cells). This highly significant (P <.0001) increase in F+
cell proportion was achieved by TGFbeta treatment during the first 4 days of
culture and was sustained during further culture expansion in the absence of
TGFbeta. The increase in F+ cell proportions did not depend on the cytokine
combination (EPO+SCF+IL3, EPO+SCF, EPO+IL3, SCF+IL3) used during the phase of
TGFbeta treatment. Increased F+ cell proportions were paralleled by an increased
molecular ratio of HbF/ HbF+ HbA, measured by cation exchange high-performance
liquid chromatography (HPLC). In addition to the effect on F+ cell proportions,
TGFbeta caused a dramatic increase in overall cell division potential. By the
time cultures reached terminal growth arrest (12-14 days in controls and 18-26
days after TGFbeta), the overall numbers of F+ cells produced per initially
seeded clonogenic cell was approximately 10 times higher in the TGFbeta-treated
cultures than in the controls. We propose to investigate whether the TGFbeta
induced increase in relative and absolute numbers of nucleated F+ cells, as
demonstrated in vitro, can be translated into increased F+ erythrocytes in vivo,
allowing therapeutic application for some beta-hemoglobinopathies. (Blood.
2000;95:2967-2974)
PMID- 10779448
TI - The assessment of serum nontransferrin-bound iron in chelation therapy and iron
supplementation.
AB - Nontransferrin-bound iron (NTBI) appears in the serum of individuals with iron
overload and in a variety of other pathologic conditions. Because NTBI
constitutes a labile form of iron, it might underlie some of the biologic damage
associated with iron overload. We have developed a simple method for NTBI
determination, which operates in a 96-well enzyme-linked immunosorbent assay
format with sensitivity comparable to that of previous assays. A weak ligand,
oxalic acid, mobilizes the NTBI and mediates its transfer to the iron chelator
deferoxamine (DFO) immobilized on the plate. The amount of DFO-bound iron,
originating from NTBI, is quantitatively revealed in a fluorescence plate reader
by the fluorescent metallosensor calcein. No NTBI is found in normal sera because
transferrin-bound iron is not detected in the assay. Thalassemic sera contained
NTBI in 80% of the cases (range, 0.9-12.8 micromol/L). In patients given
intravenous infusions of DFO, NTBI initially became undetectable due to the
presence of DFO in the sera, but reappeared in 55% of the cases within an hour of
cessation of the DFO infusion. This apparent rebound was attributable to the loss
of DFO from the circulation and the possibility that a major portion of NTBI was
not mobilized by DFO. NTBI was also found in patients with end-stage renal
disease who were treated for anemia with intravenous iron supplements and in
patients with hereditary hemochromatosis, at respective frequencies of 22% and
69%. The availability of a simple assay for monitoring NTBI could provide a
useful index of iron status during chelation and supplementation treatments.
(Blood. 2000;95:2975-2982)
PMID- 10779449
TI - Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans.
AB - A recent study in dogs suggested that erythropoietin (EPO) not only promotes the
synthesis of increased numbers of reticulated platelets but that these newly
produced platelets are hyperreactive compared with controls. Because of the
increasing use of EPO in the perioperative setting, we characterized the effects
of EPO on platelet reactivity in healthy human volunteers. In a randomized,
controlled trial, we studied the effects of EPO on platelet reactivity,
thrombopoiesis, and endothelial activation in circumstances similar to those of
autologous blood donation. Thirty healthy male volunteers received placebo or EPO
(100 or 500 U/kg of body weight given intravenously) three times a week for 2
weeks and underwent phlebotomy on days 8 and 15. Thrombin receptor-activating
peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during
EPO treatment. The enhanced platelet reactivity was also reflected by a 50%
increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a
dose-dependent fashion by more than 100% during EPO treatment, indicating
substantial activation of endothelial cells. A 10% to 20% increase in platelet
counts was observed in both EPO groups on day 5. In the placebo group, platelets
increased only several days after the first phlebotomy. The increase in platelet
counts was not reflected by changes in the amounts of reticulated platelets or
circulating progenitor cells. In summary, we found that EPO markedly enhances
endothelial activation and platelet reactivity, which may adversely affect
patients at cardiovascular risk. However, the increased platelet reactivity could
be exploited in patients with platelet dysfunction. (Blood. 2000;95:2983-2989)
PMID- 10779451
TI - Circulation online only : april 25, 2000
PMID- 10779450
TI - Quantitative measure of c-abl and p15 methylation in chronic myelogenous
leukemia: biological implications.
AB - We used a sensitive, quantitative bisulfite PCR assay, methylation sensitive
single nucleotide primer extension (Ms-SNuPE), to measure methylation of the 5'
CpG islands of c-abl and p15 in chronic myelogenous leukemia (CML) patients
during progression. We found that the Pa promoter of c-abl was methylated in 81%
(17/21) of the white blood cells (WBCs) of CML patients, which correlates with
previous reports. In contrast, WBCs from healthy donors, acute myelogenous
leukemias, acute lymphocytic leukemias, and myelodysplastic syndromes were
unmethylated at the c-abl Pa promoter locus. We also observed p15
hypermethylation in 24% (8/34) of CML cases. Methylation of the p15 but not c-abl
Pa promoters was associated with CML progression (P = 0.047 vs 0.46), and the two
events were independently acquired. We conclude that de novo methylation of c-abl
and p15 both occur in CML, and analysis of DNA methylation changes using the
bisulfite-based MS-SNuPE assay allows both a sensitive and quantitative
assessment of these molecular events compared to other methods currently
utilized. (Blood. 2000;95:2990-2992)
PMID- 10779452
TI - Severe aortic stenosis with low systolic gradient:the good and bad news.
PMID- 10779453
TI - Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis.
AB - BACKGROUND: Intracoronary gamma-radiation therapy reduces recurrent in-stent
restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent
restenosis Trial) was designed to examine the efficacy and safety of the beta
emitter 90-yttrium for the prevention of recurrent ISR. METHODS AND RESULTS: A
total of 50 consecutive patients with ISR in native coronaries underwent
percutaneous transluminal coronary angioplasty, laser angioplasty, rotational
atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter
was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire
that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon
surface. In 17 patients, manual stepping of the radiation catheter was necessary
for lesions >25 mm in length. The radiation was delivered successfully to all
patients, with a mean dwell time of 3.0+/-0.4 minutes. Fractionation of the dose
due to ischemia was required in 11 patients. At 6 months, the binary angiographic
restenosis rate was 22%, the target lesion revascularization rate was 26%, and
the target vessel revascularization rate was 34%; all rates were significantly
lower than those of the placebo group of gamma-WRIST. CONCLUSIONS: beta-Radiation
with a 90-yttrium source used as adjunct therapy for patients with ISR results in
a lower-than-expected rate of angiographic and clinical restenosis.
PMID- 10779454
TI - Prognostic impact of coronary vasodilator dysfunction on adverse long-term
outcome of coronary heart disease.
AB - BACKGROUND: Endothelial vasodilator dysfunction is a characteristic feature of
patients at risk for coronary atherosclerosis. Therefore, we prospectively
investigated whether coronary endothelial dysfunction predicts disease
progression and cardiovascular event rates. METHODS AND RESULTS: Coronary
vasoreactivity was assessed in 147 patients using the endothelium-dependent
dilator acetylcholine, sympathetic activation by cold pressor testing, dilator
responses to increased blood flow, and dilation in response to nitroglycerin.
Cardiovascular events (cardiovascular death, unstable angina, myocardial
infarction, percutaneous transluminal coronary angioplasty, coronary bypass
grafting, ischemic stroke, or peripheral artery revascularization) served as
outcome variables over a median follow-up period of 7.7 years. Patients suffering
from cardiovascular events during follow-up (n=16) had significantly increased
vasoconstrictor responses to acetylcholine infusion (P=0. 009) and cold pressor
testing (P=0.002), as well as significantly blunted vasodilator responses to
increased blood flow (P<0.001) and the intracoronary injection of nitroglycerin
(P=0.001). Impaired endothelial and endothelium-independent coronary
vasoreactivity were associated with a significantly higher incidence of
cardiovascular events by Kaplan-Meier analysis. By multivariate analysis, all
tests of coronary vasoreactivity were significant, independent predictors of a
poor prognosis, even after adjustment for traditional cardiovascular risk factors
or the presence of atherosclerosis itself. CONCLUSIONS: Coronary endothelial
vasodilator dysfunction predicts long-term atherosclerotic disease progression
and cardiovascular event rates. Thus, the assessment of coronary endothelial
vasoreactivity can provide pivotal information as both a diagnostic and
prognostic tool in patients at risk for coronary heart disease.
PMID- 10779455
TI - Elevated HDL cholesterol is a risk factor for ischemic heart disease in white
women when caused by a common mutation in the cholesteryl ester transfer protein
gene.
AB - BACKGROUND: The level of HDL cholesterol is inversely related to the risk of
ischemic heart disease. METHODS AND RESULTS: In 9168 women and men from a general
population and 946 women and men with ischemic heart disease (all white), we
tested the hypothesis that the Ile405Val mutation in the cholesteryl ester
transfer protein gene (CETP) affects HDL cholesterol levels and the risk of
ischemic heart disease. The relative frequencies of Ile/Ile, Ile/Val, and Val/Val
carriers were 0.46, 0.43, and 0.11 for both women and men. Women with these 3
genotypes had mean HDL cholesterol levels of 1.68, 1.75, and 1.82 mmol/L,
respectively (P<0.001, ANOVA), as well as a significant decrease in the ratio of
total to HDL cholesterol (P=0. 002, ANOVA). On multiple logistic regression
analysis, women not treated with hormone replacement therapy who were
heterozygous or homozygous for Val405 had a 1.4-fold (95% CI 1.0 to 1.9) to 2.1
fold (95% CI 1.3 to 3.4) increase in the risk of ischemic heart disease. No
significant associations were found in men. CONCLUSIONS: Increased HDL
cholesterol levels caused by mutations in CETP are associated with an increased
risk of ischemic heart disease in white women.
PMID- 10779456
TI - Relationship of socioeconomic status to the incidence and prehospital, 28-day,
and 1-year mortality rates of acute coronary events in the FINMONICA myocardial
infarction register study.
AB - BACKGROUND: Low socioeconomic status (SES) is associated with increased coronary
heart disease mortality rates. There are, however, very little data on the
relation of SES to the incidence, recurrence, and prognosis of myocardial
infarction (MI) events. METHODS AND RESULTS: The FINMONICA MI Register recorded
detailed information on all MI events among men and women aged 35 to 64 years in
3 areas of Finland during the period of 1983 to 1992. We carried out a record
linkage of the MI register data with files of Statistics Finland to obtain
information on indicators of SES, such as taxable income and education, for each
individual who is registered. In the analyses, income was grouped into 3
categories (low, middle, and high), and education was grouped into 2 categories
(basic and secondary or higher). Among men with their first MI event (n=6485),
the adjusted incidence rate ratios were 1.67 (95% CI 1.57 to 1.78) and 1.84 (95%
CI 1.73 to 1.95) in the low- and middle-income categories compared with the high
income category. For 28-day mortality rates, the corresponding rate ratios were
3.18 (95% CI 2.82 to 3.58) and 2.33 (95% CI 2.03 to 2.68). Significant
differentials were observed for prehospital mortality rates, and they remained
similar up to 1 year after the MI. Findings among the women were consistent with
those among the men. CONCLUSIONS: The excess coronary heart disease mortality and
morbidity rates among persons with low SES are considerable in Finland. To bring
the mortality rates of low- and middle-SES groups down to the level of that of
the high-SES group constitutes a major public health challenge.
PMID- 10779457
TI - Social support, depression, and mortality during the first year after myocardial
infarction.
AB - BACKGROUND: We previously reported that depression after myocardial infarction
(MI) increases the long-term risk of cardiac mortality. Other research suggests
that social support may also influence prognosis. This article examines the
interrelationships between baseline depression and social support in terms of
cardiac prognosis and changes in depression symptoms over the first post-MI year.
METHODS AND RESULTS: For this study, 887 patients completed the Beck Depression
Inventory (BDI) and the Perceived Social Support Scale (PSSS) at about 7 days
after MI. Some 32% had BDIs > or =10, indicating mild to moderate depression. One
year survival status was determined for all patients. Follow-up interviews,
including the BDI, were conducted with 89% of survivors. There were 39 deaths (35
cardiac). Elevated BDI scores were related to cardiac mortality (P=0.0006), but
PSSS scores and other measures of social support were not. There was a
significant interaction between depression and the PSSS (P=0. 016). The
relationship between depression and cardiac mortality decreased with increasing
support. Furthermore, residual change score analysis revealed that among 1-year
survivors who had been depressed at baseline, higher baseline social support was
related to more improvement in depression symptoms than expected. CONCLUSIONS:
Post-MI depression is a predictor of 1-year cardiac mortality, but social support
is not directly related to survival. However, very high levels of support appear
to buffer the impact of depression on mortality. Furthermore, high levels of
support predict improvements in depression symptoms over the first post-MI year
in depressed patients. High levels of support may protect patients from the
negative prognostic consequences of depression because of improvements in
depression symptoms.
PMID- 10779458
TI - Nitric oxide spares myocardial oxygen consumption through attenuation of
contractile response to beta-adrenergic stimulation in patients with idiopathic
dilated cardiomyopathy.
AB - BACKGROUND: The results of recent studies suggest that NO synthase may increase
in the failing myocardium and that NO modulates the myocardial contractile
response to beta-adrenergic stimulation. However, there are few data regarding
the physiological role of NO in patients with heart failure. The aim of the
present study was to address the role of NO in left ventricular (LV) contractile
response to beta-adrenergic stimulation and corresponding oxygen expenditure in
human heart failure. METHODS AND RESULTS: We studied 15 patients with heart
failure due to idiopathic dilated cardiomyopathy (mean ejection fraction 0.33).
We examined LV contractility (E(max), the slope of end-systolic pressure-volume
relation), LV external work (EW), myocardial oxygen consumption (MVO(2)), and
mechanical efficiency (measured as EW/MVO(2)) with the use of conductance and
coronary sinus thermodilution catheters before and during dobutamine (DOB)
infusion via a peripheral vein (4. 8+/-0.3 microg. kg(-1). min(-1) IV). Heart
rate was kept constant with atrial pacing. We carried out a similar protocol
during the intracoronary infusion of the NO synthase inhibitor N(G)-monomethyl-L
arginine (L-NMMA; 200 micromol). DOB increased E(max), EW, and MVO(2) (by 77+/
17%, 39+/-5%, and 21+/-5%, respectively), leading to an increase in mechanical
efficiency (25.4+/-3.1% to 29.6+/-4.1%). L-NMMA alone did not significantly
change these variables. Although the concurrent infusion of DOB with L-NMMA
increased E(max), EW, and MVO(2) (by 140+/-21%, 64+/-9%, and 35+/-5%,
respectively) more than DOB alone, mechanical efficiency did not increase further
(24.3+/-3.3% to 29.5+/-4.5%) because EW and MVO(2) increased in parallel.
Conclusions-These data suggest that in patients with idiopathic dilated
cardiomyopathy, endogenous NO spares MVO(2) through attenuation of LV contractile
response to beta-adrenergic stimulation while maintaining LV energy-converting
efficiency.
PMID- 10779459
TI - Frequency and clinical implications of fluid dynamically significant diffuse
coronary artery disease manifest as graded, longitudinal, base-to-apex myocardial
perfusion abnormalities by noninvasive positron emission tomography.
AB - BACKGROUND: Diffuse coronary atherosclerosis is the substrate for plaque rupture
and coronary events. Therefore, in patients with mild arteriographic coronary
artery disease without significant segmental dipyridamole-induced myocardial
perfusion defects, we tested the hypothesis that fluid dynamically significant
diffuse coronary artery narrowing is frequently manifest as a graded,
longitudinal, base-to-apex myocardial perfusion abnormality by noninvasive PET.
METHODS AND RESULTS: In this study, 1001 patients with documented coronary artery
disease by coronary arteriography showing any visible coronary artery narrowing
underwent rest-dipyridamole PET perfusion imaging. Quantitative severity of
dipyridamole-induced, circumscribed, segmental PET perfusion defects was
objectively measured by automated software as the minimum quadrant average
relative activity indicating localized flow limiting stenoses. Quantitative
severity of the graded, longitudinal, base-to-apex myocardial perfusion gradient
indicating fluid dynamic effects of diffuse coronary artery narrowing was
objectively measured by automated software as the spatial slope of relative
activity along the cardiac longitudinal axis. CONCLUSIONS: In patients with mild
arteriographic disease without statistically significant dipyridamole-induced
segmental myocardial perfusion defects caused by flow-limiting stenoses compared
with normal control subjects, there was a graded, longitudinal, base-to-apex
myocardial perfusion gradient significantly different from normal control
subjects (P=0. 001) that was also observed for moderate to severe dipyridamole
induced segmental perfusion defects (P=0.0001), indicating diffuse disease
underlying segmental perfusion defects; 43% of patients with or without segmental
perfusion defects demonstrated graded, longitudinal, base-to-apex perfusion
abnormalities beyond +/-2 SD of normal control subjects, indicating diffuse
coronary arterial narrowing by noninvasive PET perfusion imaging.
PMID- 10779460
TI - Severe aortic stenosis with low transvalvular gradient and severe left
ventricular dysfunction:result of aortic valve replacement in 52 patients.
AB - BACKGROUND: The outcome of aortic valve replacement in patients with severe
aortic stenosis, low transvalvular gradient, and severe left ventricular
dysfunction is not well known. METHODS AND RESULTS: Between 1985 and 1995, 52
patients with left ventricular ejection fraction (EF) < or =35% and aortic
stenosis with transvalvular mean gradient <30 mm Hg underwent aortic valve
replacement. The mean (+/-SD) preoperative characteristics included EF, 26+/-8%;
aortic valve mean gradient, 23+/-4 mm Hg; aortic valve area, 0.7+/-0.2 cm(2); and
cardiac output, 3.7+/-1.2 L/min. Simultaneous coronary artery bypass graft
surgery was performed in 32 patients (62%). Perioperative (30-day) mortality was
21% (11 of 52 patients). Ten additional patients died during follow-up. Advanced
age (P=0.048) and small aortic prosthesis size (P=0.03) were significant
predictors of hospital mortality by univariate analysis. By multivariate
analysis, the only predictor of surgical mortality was smaller prosthesis size.
The only predictor of postoperative survival was improvement in postoperative
functional class (P=0.04). Postoperative functional improvement occurred in most
patients. Postoperative EF was assessed in 93% of survivors; 74% demonstrated
improvement. Positive change in EF was related to smaller preoperative aortic
valve area and female sex. CONCLUSIONS: Despite severe left ventricular
dysfunction, low transvalvular mean gradient, and increased operative mortality,
aortic valve replacement was associated with improved functional status.
Postoperative survival was related to younger patient age and larger aortic
prosthesis size, and medium-term survival was related to improved postoperative
functional class.
PMID- 10779461
TI - Rate of change in aortic valve area during a cardiac cycle can predict the rate
of hemodynamic progression of aortic stenosis.
AB - BACKGROUND: The ability to predict the rate of hemodynamic progression in an
individual patient with valvular aortic stenosis has been elusive. The purpose of
the present study was to evaluate whether the rate of change in aortic valve area
(AVA) measured during the ejection phase of a cardiac cycle predicts the rate of
hemodynamic progression in patients with asymptomatic aortic stenosis. METHODS
AND RESULTS: In 84 adults with initially asymptomatic aortic stenosis and a
baseline AVA of > or =0.9 cm(2), annual echocardiographic data were obtained
prospectively (mean follow-up 2.8+/-1.3 years). With the initial echocardiogram,
the ratio of AVA measured at mid-acceleration and mid-deceleration to the AVA at
peak velocity was calculated. The primary outcome variable was the annual rate of
change in AVA (rate of progression), with rate of progression classified as rapid
(a reduction in AVA of > or =0.2 cm(2)/y) or slow (<0.2 cm(2)/y). Rapid
progression was significantly associated with an AVA ratio of > or =1.25
(P=0.004, risk ratio 3.1, 95% CI 1.2 to 7.9). The sensitivity, specificity, and
positive predictive value of AVA ratio of > or =1.25 for the prediction o rapid
progression of valvar aortic stenosis was 64%, 72%, and 80% respectively. The
decrease in ejection fraction measured from the initial to final echocardiogram
was small but greater for patients with an AVA ratio of > or =1.25 (-4+/-7%
versus +2+/-7%, P<0.001). CONCLUSIONS: A flow-dependent change in AVA can be
measured during a routine transthoracic echocardiographic study. The rate of
change in AVA is an additional measure of disease severity and may be used to
predict an individual's risk for subsequent rapid disease progression.
PMID- 10779462
TI - A method for determining the reference effective flow areas for mechanical heart
valve prostheses: in vitro validation studies.
AB - BACKGROUND: The anatomic opening area (AOA) is usually reported as the primary
index of mechanical heart valve function. Because flow contracts immediately
distal to an orifice as a result of the vena contracta effect, AOA may not be a
good measure of true effective flow area. METHODS AND RESULTS: Laser flow imaging
was used to visualize the contraction in the jet flow stream as it passed through
bileaflet mechanical valves under steady and pulsatile conditions. Such
visualization allowed clear measurement of the individual vena contracta areas
(VCAs) of the 3 valve orifices. VCAs for side orifices were larger (94+/-2% of
AOA) than those through the central orifice (34+/-8%). Formation of large radial
vortices around the leaflet tips constricted the central orifice flow stream and
appeared to be the main reason for smaller central VCA. Total VCA remained
constant until approximately 0.5 orifice diameters ( approximately 1.0 cm)
downstream, beyond which cross-sectional area increased as a result of
entrainment of receiving chamber flow. Total VCA was larger for steady flow
(89.6+/-2.7% of AOA) than for pulsatile flow (76.3+/-5.0% of AOA). CONCLUSIONS:
This study further clarifies flow dynamics through bileaflet mechanical valves
and provides previously unavailable reference information on VCAs for these
valves. Such information should aid clinicians in explaining Doppler-derived and
catheter-measured pressure discrepancies, validating clinical techniques for
quantifying effective flow areas, and optimizing valve size for implantation. The
method should also be useful for comparative studies of different valve designs.
PMID- 10779463
TI - Relationship between regional cardiac hyperinnervation and ventricular
arrhythmia.
AB - BACKGROUND: Sympathetic nerve activity is known to be important in ventricular
arrhythmogenesis, but there is little information on the relation between the
distribution of cardiac sympathetic nerves and the occurrence of spontaneous
ventricular arrhythmias in humans. METHODS AND RESULTS: We studied 53 native
hearts of transplant recipients, 5 hearts obtained at autopsy of patients who
died of noncardiac causes, and 7 ventricular tissues that had been surgically
resected from the origin of ventricular tachycardia. The history was reviewed to
determine the presence (group 1A) or absence (group 1B) of spontaneous
ventricular arrhythmias. Immunocytochemical staining for S100 protein,
neurofilament protein, tyrosine hydroxylase, and protein gene product 9.5 was
performed to study the distribution and the density of sympathetic nerves. The
average left ventricular ejection fraction was 0.22+/-0.07. A total of 30
patients had documented ventricular arrhythmias, including ventricular
tachycardia and sudden cardiac death. A regional increase in sympathetic nerves
was observed around the diseased myocardium and blood vessels in all 30 hearts.
The density of nerve fibers as determined morphometrically was significantly
higher in group 1A patients (total nerve number 19.6+/-11.2/mm(2), total nerve
length 3.3+/-3.0 mm/mm(2)) than in group 1B patients (total nerve number 13.5+/
6.1/mm(2), total nerve length 2.0+/-1.1 mm/mm(2), P<0. 05 and P<0.01,
respectively). CONCLUSIONS: There is an association between a history of
spontaneous ventricular arrhythmia and an increased density of sympathetic nerves
in patients with severe heart failure. These findings suggest that abnormally
increased postinjury sympathetic nerve density may be in part responsible for the
occurrence of ventricular arrhythmia and sudden cardiac death in these patients.
PMID- 10779464
TI - Endovascular irradiation from beta-particle-emitting gold stents results in
increased neointima formation in a porcine restenosis model.
AB - BACKGROUND: Recent studies have shown that ionizing radiation reduces neointima
formation after balloon angioplasty and stent implantation in experimental models
of restenosis and first clinical trials. The objective of this study was to
determine the dose distribution of a new beta-particle-emitting radioactive gold
stent and to evaluate the dose-dependent vascular response in the coronary
overstretch pig model. METHODS AND RESULTS: Sixteen Gottinger minipigs underwent
placement of 11 nonradioactive and 36 beta-particle-emitting stents with activity
levels of 10.4+/-0.6, 14.9+/-2.4, 22.8+/-1.3, 35.8+/-2. 8, and 55.4+/-5.3 microCi
of (198)Au. Three months after implantation, the percent area stenosis,
neointimal thickness, neointimal area, and vessel injury were analyzed by
quantitative histomorphometry. The lifetime radiation doses at a depth of 1 mm
were 3.3+/-0.2, 4.7+/-0.5, 7.2+/-0.4, 11.4+/-0.9, and 17.6+/-1.7 Gy for the
different activity groups. No dose-response relationship was observed in the
radioactive stents with respect to percent area stenosis (P=0.297), mean
neointimal thickness (P=0.82), or mean neointimal area (P=0.65). Significantly
lower neointima formation and less luminal narrowing was seen in the control
group than in the beta-particle-emitting stents (P<0.001). Multilinear regression
analysis revealed that only radioactivity made a significant independent
contribution to the degree of percent area stenosis (P<0. 001). CONCLUSIONS:
Neointima formation in pigs is markedly increased by beta-particle-emitting
stents with (198)Au as the radioisotope. This study provides evidence that
dosages of 3 to 18 Gy of low-dose-rate beta-particle irradiation via endovascular
stents cause pronounced luminal narrowing in the animal model at 3 months.
PMID- 10779465
TI - Modulation of functionally active endothelin-converting enzyme by chronic neutral
endopeptidase inhibition in experimental atherosclerosis.
AB - BACKGROUND: Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET
1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2
isoforms (ECE-1alpha and ECE-1beta), the result of alternative splicing of a
common gene. Neutral endopeptidase (NEP) is a genetically distinct
metallopeptidase that degrades the natriuretic peptides. These peptides mediate
antiproliferative and vasodilating actions. We sought to demonstrate the
distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to
determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular
wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with
atheroma formation. Our hypothesis was that chronic NEP-I, in association with
augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus
reducing tissue ET-1 concentrations and associated atheroma formation. METHODS
AND RESULTS: Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet)
and NEP-I-treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30
mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1alpha and
ECE-1beta immunoreactivity was present in the aortas of both groups. Compared
with control values, plasma cGMP concentrations were increased (2.8+/-0.6 versus
8.4+/-1.2 pmol/mL, P<0.05), ECE-1 activity was attenuated (68+/-3% versus 32+/
8%, P<0. 05), aortic tissue ET-1 concentrations were reduced (4.6+/-0.5 versus
3.2+/-0.3 pg/mg protein, P<0.05), and atheroma formation was attenuated (62+/-6%
versus 34+/-5%, P<0.01) by NEP-I. CONCLUSIONS: These studies suggest that ECE-1
is present and functionally active in the vascular wall in atherosclerosis.
Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the
endothelin system in this cardiovascular disease state.
PMID- 10779467
TI - Application of cDNA microarrays in determining molecular phenotype in cardiac
growth, development, and response to injury.
AB - BACKGROUND: Normal myocardial development and the tissue response to cardiac
stress are accompanied by marked changes in gene expression; however, the extent
of these changes and their significance remain to be fully explored. We used cDNA
microarrays for gene expression profiling in rat cardiac tissue samples to study
developmental transitions and the response to myocardial infarction (MI). METHODS
AND RESULTS: Microarrays with rat cDNAs for 86 known genes and 989 anonymous
cDNAs obtained by molecular subtraction (representational difference analysis) of
mRNA from sham-operated and 6-week post-MI samples were used in 2-color
hybridization experiments. Twelve known genes previously associated with
myocardial development were identified together with 10 uncharacterized expressed
sequence tags and 36 genes not previously associated with cardiac development.
After MI, genes associated with myocardial stress and wound healing exhibited
differences in magnitude and expression kinetics, and 14 genes not previously
associated with MI were identified. In situ hybridization revealed mRNA
localization characteristic of wound healing and vascular and cardiomyocyte
reactivity. CONCLUSIONS: Tissue analysis of gene expression with cDNA microarrays
provides a measure of transcriptional or posttranscriptional regulation and
cellular recruitment. Our results demonstrate the complexity of gene regulation
in the developing myocardium and show that cDNA microarrays can be used to
monitor the evolution of the cardiac stress-inducible phenotype.
PMID- 10779466
TI - Nitric oxide modulates expression of cell cycle regulatory proteins: a cytostatic
strategy for inhibition of human vascular smooth muscle cell proliferation.
AB - BACKGROUND: We examined the effect of NO on the proliferation and cell cycle
regulation of human aortic vascular smooth muscle cells (VSMCs). METHODS AND
RESULTS: The NO donor diethylenetriamineNONOate (10(-5) to 10(-3) mol/L)
inhibited proliferation in response to 10% fetal calf serum (FCS) and 100 ng/mL
platelet-derived growth factor-BB in a concentration-dependent manner. This
effect was not observed with disintegrated diethylenetriamineNONOate or with the
parent compound, diethylenetriamine. Adenoviral transfection of endothelial NO
synthase (NOS) inhibited proliferation in response to FCS, which was prevented
with N(G)-nitro-L-arginine methyl ester. NOS overexpression did not inhibit
proliferation in response to platelet-derived growth factor, although the
transfection efficiency and protein expression were similar to those of FCS
stimulated cells. Nitrate release was selectively enhanced from FCS-treated
cells, indicating that NOS was activated by FCS only. NO caused G(1) cell cycle
arrest. Cytotoxicity was determined with trypan blue exclusion, and apoptosis was
assessed with DNA fragmentation. Cyclin-dependent kinase 2 expression level,
threonine phosphorylation, and kinase activity were inhibited. Cyclin A
expression was blunted, whereas cyclin E remained unchanged. p21 expression was
induced, and p27 remained unaltered. The effect on cyclin A and p21 started
within 6 hours and preceded the changes in cell cycle distribution. Proliferation
in response to 10% FCS was barely inhibited with 8-bromo-cGMP (10(-3) mol/L) but
was blunted with both forskolin and 8-bromo-cAMP. Proliferation in response to 2%
FCS was inhibited with 8-bromo-cGMP, but it did not mimic the cell cycle effects
of NO. CONCLUSIONS: NO inhibits VSMC proliferation by specifically changing the
expression and activity of cell cycle regulatory proteins, which may occur
independent of cGMP. Adenoviral overexpression of endothelial NOS represents a
cytostatic strategy for gene therapy of vascular disease.
PMID- 10779468
TI - Basic fibroblast growth factor increases tissue factor expression in circulating
monocytes and in vascular wall.
AB - BACKGROUND: Basic fibroblast growth factor (bFGF) promotes vascular repair and
angiogenesis and can induce in vitro tissue factor (TF), a potent agent
initiating thrombogenesis, which probably plays a role in angiogenesis. We
investigated whether bFGF administration induced TF expression by monocytes and
vascular cells. METHODS AND RESULTS: We studied TF expression in normally fed
(n=16) and cholesterol-fed (2% for 6 weeks, n=16) rabbits. Animals were then
randomized to receive intravenous bFGF (2.5 microg twice weekly for 3 weeks) or
saline injections. TF expression was evaluated in mononuclear cells from arterial
blood and in aortic sections by an immunohistochemical assay using a monoclonal
anti-rabbit TF antibody (activator protein 1). Monocyte TF expression was
increased by bFGF administration in both normal and hypercholesterolemic rabbits
(129+/-45 versus 19+/-3 mU TF/1000 monocytes, P<0.05, and 31+/-12 versus 7+/-1 mU
TF/1000 monocytes, P<0.005, respectively) and was further increased by
stimulation of monocytes by endotoxin in vitro. TF expression was lower in
hypercholesterolemic rabbits than in normal rabbits. In the media of the vascular
wall, bFGF induced strong TF expression in normal rabbits and only weak TF
expression in hypercholesterolemic ones. CONCLUSIONS: This study demonstrates
that systemic administration of bFGF induces an impressive increase of TF
expression in circulating monocytes and in the vascular wall in normal and to a
lower extent in hypercholesterolemic rabbits. The significance of this
observation in terms of inducing thrombosis in vivo needs clarification.
PMID- 10779469
TI - Short-term effects of rapid pacing on mRNA level of voltage-dependent K(+)
channels in rat atrium: electrical remodeling in paroxysmal atrial tachycardia.
AB - BACKGROUND: Atrial fibrillation causes electrophysiological changes of the
atrium, thereby facilitating its maintenance. Although the expression of ion
channels is modulated in chronic atrial fibrillation, it is yet unknown whether
paroxysmal atrial fibrillation can also lead to electrical remodeling by
affecting gene expression. METHODS AND RESULTS: To examine the short-term effects
of rapid pacing on the mRNA level of voltage-dependent K(+) channels, high-rate
atrial pacing was performed in Sprague-Dawley rat hearts. Total RNA was prepared
from the atrial appendages from 0 to 8 hours after the onset of pacing, and mRNA
levels of Kv1.2, Kv1. 4, Kv1.5, Kv2.1, Kv4.2, Kv4.3, erg, KvLQT1, and minK were
determined by RNase protection assay. Among these 9 genes, the mRNA level of the
Kv1.5 channel immediately and transiently increased, with bimodal peaks at 0.5
and 2 hours after the onset of pacing. Conversely, the pacing gradually and
progressively decreased the mRNA levels of the Kv4.2 and Kv4.3 channels. The
increase of Kv1.5 and the decrease of Kv4.2 and Kv4.3 mRNA levels were both rate
dependent. In correspondence with the changes in the mRNA level, Kv1. 5 channel
protein transiently increased in the membrane fraction of the atrium during a 2-
to 8-hour pacing period. Electrophysiological findings that the shortening of the
action potential produced by 4-hour pacing was almost abolished by a low
concentration of 4-aminopyridine implied that the increased Kv1.5 protein was
functioning. CONCLUSIONS: Even short-term high-rate atrial excitation could
differentially alter the mRNA levels of Kv1.5, Kv4.2, and Kv4.3 in a rate
dependent manner. In particular, increased Kv1.5 gene expression, having a
transient nature, implied the possible biochemical electrical remodeling unique
to paroxysmal tachycardia.
PMID- 10779471
TI - Images in cardiovascular medicine. Differential color imaging technique of
helical CT angiography in the diagnosis of total anomalous pulmonary venous
drainage.
PMID- 10779470
TI - The US healthcare system 2010: problems, principles, and potential solutions.
PMID- 10779472
TI - Cardiac fibroma resulting in fatal ventricular arrhythmia.
PMID- 10779473
TI - Hyperhomocysteinemia, MTHFR, and risk of vascular disease.
PMID- 10779474
TI - Methylenetetrahydrofolate reductase gene and coronary artery disease.
PMID- 10779475
TI - Repeated administration of vasopressin but not epinephrine maintains coronary
perfusion pressure after early and late administration during prolonged
cardiopulmonary resuscitation in pigs.
PMID- 10779476
TI - Right bundle-branch block, ST-segment elevation, and sudden death.
PMID- 10779477
TI - Psychological factors and ischemic heart disease.
PMID- 10779478
TI - A biologist's view of the Drosophila genome annotation assessment project.
PMID- 10779479
TI - Gene-finding approaches for eukaryotes.
PMID- 10779480
TI - Powers and pitfalls in sequence analysis: the 70% hurdle.
PMID- 10779481
TI - Evolution and variation of the yeast (Saccharomyces) genome.
AB - In this review we describe the role of the yeast Saccharomyces in the development
of human societies including the use of this organism in the making of wine,
bread, beer, and distilled beverages. We also discuss the tremendous diversity of
yeast found in natural (i.e., noninoculated) wine fermentations and the
scientific uses of yeast over the past 60 years. In conclusion, we present ideas
on the model of "genome renewal" and the use of this model to explain the mode by
which yeast has evolved and how diversity can be generated.
PMID- 10779482
TI - Frequent human genomic DNA transduction driven by LINE-1 retrotransposition.
AB - Human L1 retrotransposons can produce DNA transduction events in which unique DNA
segments downstream of L1 elements are mobilized as part of aberrant
retrotransposition events. That L1s are capable of carrying out such a reaction
in tissue culture cells was elegantly demonstrated. Using bioinformatic
approaches to analyze the structures of L1 element target site duplications and
flanking sequence features, we provide evidence suggesting that approximately 15%
of full-length L1 elements bear evidence of flanking DNA segment transduction.
Extrapolating these findings to the 600,000 copies of L1 in the genome, we
predict that the amount of DNA transduced by L1 represents approximately 1% of
the genome, a fraction comparable with that occupied by exons.
PMID- 10779483
TI - Large-scale comparison of fungal sequence information: mechanisms of innovation
in Neurospora crassa and gene loss in Saccharomyces cerevisiae.
AB - We report a large-scale comparison of sequence data from the filamentous fungus
Neurospora crassa with the complete genome sequence of Saccharomyces cerevisiae.
N. crassa is considerably more morphologically and developmentally complex than
S. cerevisiae. We found that N. crassa has a much higher proportion of "orphan"
genes than S. cerevisiae, suggesting that its morphological complexity reflects
the acquisition or maintenance of novel genes, consistent with its larger genome.
Our results also indicate the loss of specific genes from S. cerevisiae.
Surprisingly, some of the genes lost from S. cerevisiae are involved in basic
cellular processes, including translation and ion (especially calcium)
homeostasis. Horizontal gene transfer from prokaryotes appears to have played a
relatively modest role in the evolution of the N. crassa genome. Differences in
the overall rate of molecular evolution between N. crassa and S. cerevisiae were
not detected. Our results indicate that the current public sequence databases
have fairly complete samples of gene families with ancient conserved regions,
suggesting that further sequencing will not substantially change the proportion
of genes with homologs among distantly related groups. Models of the evolution of
fungal genomes compatible with these results, and their functional implications,
are discussed.
PMID- 10779484
TI - Systematic management and analysis of yeast gene expression data.
AB - We report steps toward the systematic management, standardization, and analysis
of functional genomics data. We developed the ExpressDB database for yeast RNA
expression data and loaded it with approximately 17.5 million pieces of data
reported by 11 studies with three different kinds of high-throughput RNA assays.
A web-based tool supports queries across the data from these studies. We examined
comparability of data by converting data from 9 studies (217 conditions) into
mRNA relative abundance estimates (ERAs) and by clustering of conditions by ERAs.
We report on generation of ERAs and condition clustering for non-microarray data
(5 studies, 63 conditions) and describe initial attempts to generate microarray
based ERAs (4 studies, 154 conditions), which exhibit increased error, on our web
site http://arep.med.harvard. edu/ExpressDB. We recommend standards for data
reporting, suggest research into improving comparability of microarray data
through quantifying and standardizing control condition RNA populations, and also
suggest research into the calibration of different RNA assays. We introduce a
model for a database that integrates different kinds of functional genomics data,
Biomolecule Interaction, Growth and Expression Database (BIGED).
PMID- 10779485
TI - Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse
chromosome 3: identification of a candidate segment of ancestral DNA by haplotype
mapping.
AB - Type 1 diabetes in the nonobese diabetic (NOD) mouse arises as a consequence of T
cell-mediated destruction of the insulin-producing beta cells of the pancreas.
Although little is known of the events that initiate and subsequently drive beta
cell destruction it is clear that the entire process is under complex genetic
control. At present 19 loci have been mapped that influence the development of
diabetes either at the level of initiation of insulitis or at the level of
progression from insulitis to overt diabetes, or both. Previously, we have mapped
one of these loci, Idd3, to a 0.35-cM interval on proximal mouse chromosome 3. In
the present study we have narrowed the map position of this locus to an interval
of 0.15 cM by a combination of novel congenic strains and an ancestral haplotype
analysis approach. We have constructed a physical contig in bacterial artificial
chromosome (BAC) clones across the minimal interval. Restriction mapping of the
BAC contig placed the maximum size of the Idd3 interval at 780 kb between the
markers D3Nds36 and D3Nds76. To refine further the Idd3 interval we developed a
series of novel single nucleotide polymorphisms (SNPs) and carried out haplotype
analysis on DNA from mouse strains known to carry either Idd3 susceptibility or
protective alleles. This haplotype analysis identified a 145-kb segment of
ancestral DNA between the microsatellite marker D3Nds6 and the SNP 81.3. One
haplotype of this ancestral segment of DNA is found in mouse strains carrying an
Idd3 susceptibility allele and another is found in mouse strains carrying an Idd3
protective allelle. Within the 780-kb congenically defined interval this 145-kb
segment represents the most likely location for Idd3. The Il2 gene, which encodes
the cytokine interleukin 2 (IL2), maps to this interval and is a strong candidate
for Idd3. To investigate whether sequence variation exists in the promoter region
of the Il2 gene, which might alter its expression, we sequenced the promoter
region of the Il2 gene from mouse strains carrying either an Idd3 susceptibility
or resistance allele. Two sequence variants were identified, neither of which
fell in known regulatory elements within the Il2 promoter. In agreement with this
observation steady-state Il2 mRNA levels showed no variation between susceptible
and resistant mouse strains. These data suggest that the profound protection from
diabetes seen in congenic mice carrying an Idd3 protective allele is unlikely to
be due to differences in the level of expression of the Il2 gene. Instead, all of
the current data support our hypothesis that Idd3 corresponds to amino acid
variation at the amino terminus of Il2.
PMID- 10779486
TI - Construction of a high-resolution 2.5-Mb transcript map of the human 6p21.2
6p21.3 region immediately centromeric of the major histocompatibility complex.
AB - We have constructed a 2.5-Mb physical and transcription map that spans the human
6p21.2-6p21.3 region and includes the centromeric end of the MHC, using a
combination of techniques. In total 88 transcription units including exons,
cDNAs, and cDNA contigs were characterized and 60 were confidently positioned on
the physical map. These include a number of genes encoding nuclear and splicing
factors (Ndr kinase, HSU09564, HSRP20); cell cycle, DNA packaging, and apoptosis
related [p21, HMGI(Y), BAK]; immune response (CSBP, SAPK4); transcription
activators and zinc finger-containing genes (TEF-5, ZNF76); embryogenesis related
(Csa-19); cell signaling (DIPP); structural (HSET), and other genes (TULP1,
HSPRARD, DEF-6, EO6811, cyclophilin), as well as a number of RP genes and
pseudogenes (RPS10, RPS12-like, RPL12-like, RPL35-like). Furthermore, several
novel genes (a Br140-like, a G2S-like, a FBN2-like, a ZNF-like, and B1/KIAA0229)
have been identified, as well as cDNAs and cDNA contigs. The detailed map of the
gene content of this chromosomal segment provides a number of candidate genes,
which may be involved in several biological processes that have been associated
with this region, such as spermatogenesis, development, embryogenesis, and
neoplasia. The data provide useful tools for synteny studies between mice and
humans, for genome structure analysis, gene density comparisons, and studies of
nucleotide composition, of different isochores and Giemsa light and Giemsa dark
bands.
PMID- 10779487
TI - New target regions for human hypertension via comparative genomics.
AB - Models of human disease have long been used to understand the basic
pathophysiology of disease and to facilitate the discovery of new therapeutics.
However, as long as models have been used there have been debates about the
utility of these models and their ability to mimic clinical disease at the
phenotypic level. The application of genetic studies to both humans and model
systems allows for a new paradigm, whereby a novel comparative genomics strategy
combined with phenotypic correlates can be used to bridge between clinical
relevance and model utility. This study presents a comparative genomic map for
"candidate hypertension loci in humans" based on translating QTLs between rat and
human, predicting 26 chromosomal regions in the human genome that are very likely
to harbor hypertension genes. The predictive power appears robust, as several of
these regions have also been implicated in mouse, suggesting that these regions
represent primary targets for the development of SNPs for linkage disequilibrium
testing in humans and/or provide a means to select specific models for additional
functional studies and the development of new therapeutics.
PMID- 10779488
TI - Genome annotation assessment in Drosophila melanogaster.
AB - Computational methods for automated genome annotation are critical to our
community's ability to make full use of the large volume of genomic sequence
being generated and released. To explore the accuracy of these automated feature
prediction tools in the genomes of higher organisms, we evaluated their
performance on a large, well-characterized sequence contig from the Adh region of
Drosophila melanogaster. This experiment, known as the Genome Annotation
Assessment Project (GASP), was launched in May 1999. Twelve groups, applying
state-of-the-art tools, contributed predictions for features including gene
structure, protein homologies, promoter sites, and repeat elements. We evaluated
these predictions using two standards, one based on previously unreleased high
quality full-length cDNA sequences and a second based on the set of annotations
generated as part of an in-depth study of the region by a group of Drosophila
experts. Although these standard sets only approximate the unknown distribution
of features in this region, we believe that when taken in context the results of
an evaluation based on them are meaningful. The results were presented as a
tutorial at the conference on Intelligent Systems in Molecular Biology (ISMB-99)
in August 1999. Over 95% of the coding nucleotides in the region were correctly
identified by the majority of the gene finders, and the correct intron/exon
structures were predicted for >40% of the genes. Homology-based annotation
techniques recognized and associated functions with almost half of the genes in
the region; the remainder were only identified by the ab initio techniques. This
experiment also presents the first assessment of promoter prediction techniques
for a significant number of genes in a large contiguous region. We discovered
that the promoter predictors' high false-positive rates make their predictions
difficult to use. Integrating gene finding and cDNA/EST alignments with promoter
predictions decreases the number of false-positive classifications but discovers
less than one-third of the promoters in the region. We believe that by
establishing standards for evaluating genomic annotations and by assessing the
performance of existing automated genome annotation tools, this experiment
establishes a baseline that contributes to the value of ongoing large-scale
annotation projects and should guide further research in genome informatics.
PMID- 10779489
TI - MAGPIE/EGRET annotation of the 2.9-Mb Drosophila melanogaster Adh region.
AB - Our challenge in annotating the 2.91-Mb Adh region of the Drosophila melanogaster
genome was to identify genetic and genomic features automatically, completely,
and precisely within a 6-week period. To do so, we augmented the MAGPIE microbial
genome annotation system to handle eukaryotic genomic sequence data. The new
configuration required the integration of eukaryotic gene-finding tools and DNA
repeat tools into the automatic data collection module. It also required us to
define in MAGPIE new strategies to combine data about eukaryotic exon predictions
with functional data to refine the exon predictions. At the heart of the
resulting new eukaryotic genome annotation system is a reverse comparison of
public protein and complementary DNA sequences against the input genome to
identify missing exons and to refine exon boundaries. The software modules that
add eukaryotic genome annotation capability to MAGPIE are available as EGRET
(Eukaryotic Genome Rapid Evaluation Tool).
PMID- 10779490
TI - GeneID in Drosophila.
AB - GeneID is a program to predict genes in anonymous genomic sequences designed with
a hierarchical structure. In the first step, splice sites, and start and stop
codons are predicted and scored along the sequence using position weight matrices
(PWMs). In the second step, exons are built from the sites. Exons are scored as
the sum of the scores of the defining sites, plus the log-likelihood ratio of a
Markov model for coding DNA. In the last step, from the set of predicted exons,
the gene structure is assembled, maximizing the sum of the scores of the
assembled exons. In this paper we describe the obtention of PWMs for sites, and
the Markov model of coding DNA in Drosophila melanogaster. We also compare other
models of coding DNA with the Markov model. Finally, we present and discuss the
results obtained when GeneID is used to predict genes in the Adh region. These
results show that the accuracy of GeneID predictions compares currently with that
of other existing tools but that GeneID is likely to be more efficient in terms
of speed and memory usage.
PMID- 10779491
TI - Ab initio gene finding in Drosophila genomic DNA.
AB - Ab initio gene identification in the genomic sequence of Drosophila melanogaster
was obtained using (human gene predictor) and Fgenesh programs that have organism
specific parameters for human, Drosophila, plants, yeast, and nematode. We did
not use information about cDNA/EST in most predictions to model a real situation
for finding new genes because information about complete cDNA is often absent or
based on very small partial fragments. We investigated the accuracy of gene
prediction on different levels and designed several schemes to predict an
unambiguous set of genes (annotation CGG1), a set of reliable exons (annotation
CGG2), and the most complete set of exons (annotation CGG3). For 49 genes,
protein products of which have clear homologs in protein databases, predictions
were recomputed by Fgenesh+ program. The first annotation serves as the optimal
computational description of new sequence to be presented in a database. Reliable
exons from the second annotation serve as good candidates for selecting the PCR
primers for experimental work for gene structure verification. Our results shows
that we can identify approximately 90% of coding nucleotides with 20% false
positives. At the exon level we accurately predicted 65% of exons and 89%
including overlapping exons with 49% false positives. Optimizing accuracy of
prediction, we designed a gene identification scheme using Fgenesh, which
provided sensitivity (Sn) = 98% and specificity (Sp) = 86% at the base level, Sn
= 81% (97% including overlapping exons) and Sp = 58% at the exon level and Sn =
72% and Sp = 39% at the gene level (estimating sensitivity on std1 set and
specificity on std3 set). In general, these results showed that computational
gene prediction can be a reliable tool for annotating new genomic sequences,
giving accurate information on 90% of coding sequences with 14% false positives.
However, exact gene prediction (especially at the gene level) needs additional
improvement using gene prediction algorithms. The program was also tested for
predicting genes of human Chromosome 22 (the last variant of Fgenesh can analyze
the whole chromosome sequence). This analysis has demonstrated that the 88% of
manually annotated exons in Chromosome 22 were among the ab initio predicted
exons. The suite of gene identification programs is available through the WWW
server of Computational Genomics Group at http://genomic.sanger.ac.uk/gf. html.
PMID- 10779492
TI - Using database matches with for HMMGene for automated gene detection in
Drosophila.
AB - The application of the gene finder HMMGene to the Adh region of the Drosophila
melanogaster is described, and the prediction results are analyzed. HMMGene is
based on a probabilistic model called a hidden Markov model, and the
probabilistic framework facilitates the inclusion of database matches of varying
degrees of certainty. It is shown that database matches clearly improve the
performance of the gene finder. For instance, the sensitivity for coding exons
predicted with both ends correct grows from 62% to 70% on a high-quality test
set, when matches to proteins, cDNAs, repeats, and transposons are included. The
specificity drops more than the sensitivity increases when ESTs are used. This is
due to the high noise level in EST matches, and it is discussed in more detail
why this is and how it might be improved.
PMID- 10779493
TI - Genie--gene finding in Drosophila melanogaster.
AB - A hidden Markov model-based gene-finding system called Genie was applied to the
genomic Adh region in Drosophila melanogaster as a part of the Genome Annotation
Assessment Project (GASP). Predictions from three versions of the Genie gene
finding system were submitted, one based on statistical properties of coding
genes, a second included EST alignment information, and a third that integrated
protein sequence homology information. All three programs were trained on the
provided Drosophila training data. In addition, promoter assignments from an
integrated neural network were submitted. The gene assignments overlapped >90% of
the 222 annotated genes and 26 possibly novel genes were predicted, of which some
might be overpredictions. The system correctly identified the exon boundaries of
70% of the exons in cDNA-confirmed genes and 77% of the exons with the addition
of EST sequence alignments. The best of the three Genie submissions predicted 19
of the annotated 43 gene structures entirely correct (44%). In the promoter
category, only 30% of the transcription start sites could be detected, but by
integrating this program as a sensor into Genie the false-positive rate could be
dropped to 1/16,786 (0.006%). The results of the experiment on the long
contiguous genomic sequence revealed some problems concerning gene assembly in
Genie. The results were used to improve the system. We show that Genie is a
robust hidden Markov model system that allows for a generalized integration of
information from different sources such as signal sensors (splice sites, start
codon, etc.), content sensors (exons, introns, intergenic) and alignments of
mRNA, EST, and peptide sequences. The assessment showed that Genie could
effectively be used for the annotation of complete genomes from higher organisms.
PMID- 10779494
TI - Promoter prediction on a genomic scale--the Adh experience.
AB - We describe our statistical system for promoter recognition in genomic DNA with
which we took part in the Genome Annotation Assessment Project (GASP1). We
applied two versions of the system: the first uses a region-based approach toward
transcription start site identification, namely, interpolated Markov chains; the
second was a hybrid approach combining regions and signals within a stochastic
segment model. We compare the results of both versions with each other and
examine how well the application on a genomic scale compares with the results we
previously obtained on smaller data sets.
PMID- 10779495
TI - Drosophila genomic sequence annotation using the BLOCKS+ database.
AB - A simple and general homology-based method for gene finding was applied to the
2.9-Mb Drosophila melanogaster Adh region, the target sequence of the Genome
Annotation Assessment Project (GASP). Each strand of the entire sequence was used
as query of the BLOCKS+ database of conserved regions of proteins. This led to
functional assignments for more than one-third of the genes and two-thirds of the
transposons. Considering the enormous size of the query, the fact that only two
false-positive matches were reported emphasizes the high selectivity of protein
family-based methods for gene finding. We used the search results to improve
BLOCKS+ by identifying compositionally biased blocks. Our results confirm that
protein family databases can be used effectively in automated sequence annotation
efforts.
PMID- 10779496
TI - Using GeneWise in the Drosophila annotation experiment.
AB - The GeneWise method for combining gene prediction and homology searches was
applied to the 2.9-Mb region from Drosophila melanogaster. The results from the
Genome Annotation Assessment Project (GASP) showed that GeneWise provided
reasonably accurate gene predictions. Further investigation indicates that many
of the incorrect gene predictions from GeneWise were due to transposons with
valid protein-coding genes and the remaining cases are pseudogenes or possible
annotation oversights.
PMID- 10779497
TI - A microsphere-based assay for multiplexed single nucleotide polymorphism analysis
using single base chain extension.
AB - A rapid, high throughput readout for single-nucleotide polymorphism (SNP)
analysis was developed employing single base chain extension and cytometric
analysis of an array of fluorescent microspheres. An array of fluorescent
microspheres was coupled with uniquely identifying sequences, termed
complementary ZipCodes (cZipCodes), which allowed for multiplexing possibilities.
For a given assay, querying a polymorphic base involved extending an
oligonucleotide containing both a ZipCode and a SNP-specific sequence with a DNA
polymerase and a pair of fluoresceinated dideoxynucleotides. To capture the
reaction products for analysis, the ZipCode portion of the oligonucleotide was
hybridized with its cZipCodes on the microsphere. Flow cytometry was used for
microsphere decoding and SNP typing by detecting the fluorescein label captured
on the microspheres. In addition to multiplexing capability, the ZipCode system
allows multiple sets of SNPs to be analyzed by a limited set of cZipCode-attached
microspheres. A standard set of non-cross reactive ZipCodes was established
experimentally and the accuracy of the system was validated by comparison with
genotypes determined by other technologies. From a total of 58 SNPs, 55 SNPs were
successfully analyzed in the first pass using this assay format and all 181
genotypes across the 55 SNPs were correct. These data demonstrate that the
microsphere-based single base chain extension (SBCE) method is a sensitive and
reliable assay. It can be readily adapted to an automated, high-throughput
genotyping system. [Primer sequences used in this study are available as online
supplementary materials at www.genome.org.]
PMID- 10779498
TI - Genetic linkage mapping of zebrafish genes and ESTs.
AB - Genetic screens in zebrafish (Danio rerio) have isolated mutations in hundreds of
genes essential for vertebrate development, physiology, and behavior. We have
constructed a genetic linkage map that will facilitate the identification of
candidate genes for these mutations and allow comparisons among the genomes of
zebrafish and other vertebrates. On this map, we have localized 771 zebrafish
genes and expressed sequence tags (ESTs) by scoring single-stranded
conformational polymorphisms (SSCPs) in a meiotic mapping panel. Of these
sequences, 642 represent previously unmapped genes and ESTs. The mapping panel
was comprised of 42 homozygous diploid individuals produced by heat shock
treatment of haploid embryos at the one-cell stage (HS diploids). This "doubled
haploid" strategy combines the advantages of mapping in haploid and standard
diploid systems, because heat shock diploid individuals have only one allele at
each locus and can survive to adulthood, enabling a relatively large quantity of
genomic DNA to be prepared from each individual in the mapping panel. To
integrate this map with others, we also scored 593 previously mapped simple
sequence length polymorphisms (SSLPs) in the mapping panel. This map will
accelerate the molecular analysis of zebrafish mutations and facilitate
comparative analysis of vertebrate genomes.
PMID- 10779499
TI - Global properties of the metabolic map of Escherichia coli.
AB - The EcoCyc database characterizes the known network of Escherichia coli small
molecule metabolism. Here we present a computational analysis of the global
properties of that network, which consists of 744 reactions that are catalyzed by
607 enzymes. The reactions are organized into 131 pathways. Of the metabolic
enzymes, 100 are multifunctional, and 68 of the reactions are catalyzed by >1
enzyme. The network contains 791 chemical substrates. Other properties considered
by the analysis include the distribution of enzyme subunit organization, and the
distribution of modulators of enzyme activity and of enzyme cofactors. The
dimensions chosen for this analysis can be employed for comparative functional
analysis of complete genomes.
PMID- 10779500
TI - PipMaker--a web server for aligning two genomic DNA sequences.
AB - PipMaker (http://bio.cse.psu.edu) is a World-Wide Web site for comparing two long
DNA sequences to identify conserved segments and for producing informative, high
resolution displays of the resulting alignments. One display is a percent
identity plot (pip), which shows both the position in one sequence and the degree
of similarity for each aligning segment between the two sequences in a compact
and easily understandable form. Positions along the horizontal axis can be
labeled with features such as exons of genes and repetitive elements, and colors
can be used to clarify and enhance the display. The web site also provides a plot
of the locations of those segments in both species (similar to a dot plot).
PipMaker is appropriate for comparing genomic sequences from any two related
species, although the types of information that can be inferred (e.g., protein
coding regions and cis-regulatory elements) depend on the level of conservation
and the time and divergence rate since the separation of the species. Gene
regulatory elements are often detectable as similar, noncoding sequences in
species that diverged as much as 100-300 million years ago, such as humans and
mice, Caenorhabditis elegans and C. briggsae, or Escherichia coli and Salmonella
spp. PipMaker supports analysis of unfinished or "working draft" sequences by
permitting one of the two sequences to be in unoriented and unordered contigs.
PMID- 10779501
TI - Agkistin, a snake venom-derived glycoprotein Ib antagonist, disrupts von
Willebrand factor-endothelial cell interaction and inhibits angiogenesis.
AB - Glycoprotein (GP) Ib, an adhesion receptor expressed on both platelets and
endothelial cells, mediates the binding of von Willebrand factor (vWF). Platelet
GPIb plays an important role in platelet adhesion and activation, whereas the
interaction of vWF and endothelial GPIb is not fully understood. We report here
that agkistin, a snake venom protein, selectively blocks the interaction of vWF
with human endothelial GPIb and inhibits angiogenesis in vivo. Agkistin
specifically blocked human umbilical vein endothelial cell (HUVEC) adhesion to
immobilized vWF in a concentration-dependent manner. Fluorescein isothiocyanate
(FITC)-conjugated agkistin bound to HUVECs in a saturable manner. AP1, a
monoclonal antibody (mAb) raised against GPIb, specifically inhibited the binding
of FITC-conjugated agkistin to HUVECs in a dose-dependent manner, but other anti
integrin mAbs raised against alpha(v)beta(3), alpha(2)beta(1), and
alpha(5)beta(1) did not affect this binding reaction. However, neither agkistin
(2 microgram/ml) nor AP1 (40 microgram/ml) apparently reduced HUVEC viability.
Both agkistin and AP1 exhibited a profound anti-angiogenic effect in vivo when
assayed by using the 10-day-old embryo chick chorioallantoic membrane model.
These results suggest endothelial GPIb plays a role in spontaneous angiogenesis
in vivo, and the anti-angiogenic effect of agkistin may be because of disruption
of the interaction of endogenous vWF with endothelial GPIb.
PMID- 10779502
TI - Reaction of human myoglobin and H2O2. Involvement of a thiyl radical produced at
cysteine 110.
AB - The human myoglobin (Mb) sequence is similar to other mammalian Mb sequences,
except for a unique cysteine at position 110. Reaction of wild-type recombinant
human Mb, the C110A variant of human Mb, or horse heart Mb with H(2)O(2)
(protein/H(2)O(2) = 1:1.2 mol/mol) resulted in formation of tryptophan peroxyl
(Trp-OO( small middle dot)) and tyrosine phenoxyl radicals as detected by EPR
spectroscopy at 77 K. For wild-type human Mb, a second radical (g approximately
2. 036) was detected after decay of Trp-OO( small middle dot) that was not
observed for the C110A variant or horse heart Mb. When the spin trap 5,5-dimethyl
1-pyrroline N-oxide (DMPO) was included in the reaction mixture at protein/DMPO
ratios /=1:25 mol/mol,
DMPO-tyrosyl radical adducts were detected. Mass spectrometry of wild-type human
Mb following reaction with H(2)O(2) demonstrated the formation of a homodimer
(mass of 34,107 +/- 5 atomic mass units) sensitive to reducing conditions. The
human Mb C110A variant afforded no dimer under identical conditions. Together,
these data indicate that reaction of wild-type human Mb and H(2)O(2) differs from
the corresponding reaction of other myoglobin species by formation of thiyl
radicals that lead to a homodimer through intermolecular disulfide bond
formation.
PMID- 10779503
TI - Probing the active center gorge of acetylcholinesterase by fluorophores linked to
substituted cysteines.
AB - To examine the influence of individual side chains in governing rates of ligand
entry into the active center gorge of acetylcholinesterase and to characterize
the dynamics and immediate environment of these residues, we have conjugated
reactive groups with selected charge and fluorescence characteristics to
cysteines substituted by mutagenesis at specific positions on the enzyme.
Insertion of side chains larger than in the native tyrosine at position 124 near
the constriction point of the active site gorge confers steric hindrance to
affect maximum catalytic throughput (k(cat)/K(m)) and rates of diffusional entry
of trifluoroketones to the active center. Smaller groups appear not to present
steric constraints to entry; however, cationic side chains selectively and
markedly reduce cation ligand entry through electrostatic repulsion in the gorge.
The influence of side chain modification on ligand kinetics has been correlated
with spectroscopic characteristics of fluorescent side chains and their capacity
to influence the binding of a peptide, fasciculin, which inhibits catalysis
peripherally by sealing the mouth of the gorge. Acrylodan conjugated to cysteine
was substituted for tyrosine at position 124 within the gorge, for histidine 287
on the surface adjacent to the gorge and for alanine 262 on a mobile loop distal
to the gorge. The 124 position reveals the most hydrophobic environment and the
largest hypsochromic shift of the emission maximum with fasciculin binding. This
finding likely reflects a sandwiching of the acrylodan in the complex with the
tip of fasciculin loop II. An intermediate spectral shift is found for the 287
position, consistent with partial occlusion by loops II and III of fasciculin in
the complex. Spectroscopic properties of the acrylodan at the 262 position are
unaltered by fasciculin addition. Hence, combined spectroscopic and kinetic
analyses reveal distinguishing characteristics in various regions of
acetylcholinesterase that influence ligand association.
PMID- 10779504
TI - p300 and p300/cAMP-response element-binding protein-associated factor acetylate
the androgen receptor at sites governing hormone-dependent transactivation.
AB - The androgen receptor (AR) is a sequence-specific DNA-binding protein that plays
a key role in prostate cancer cellular proliferation by dihydrotestosterone and
the induction of secondary sexual characteristics. In this study we demonstrate
that the AR can be modified by acetylation in vitro and in vivo. p300 and
p300/cAMP-response element-binding protein acetylated the AR at a highly
conserved lysine-rich motif carboxyl-terminal to the zinc finger DNA-binding
domain. [(14)C]acetate-labeling experiments demonstrated that AR acetylation by
p300 in cultured cells requires the same residues identified in vitro. Point
mutation of the AR acetylation site (K632A/K633A) abrogated dihydrotestosterone
dependent transactivation of the AR in cultured cells. Mutation of the p300 CH3
region or the p300/cAMP-response element-binding protein histone acetylase domain
reduced ligand-dependent AR function. The identification of the AR as a direct
target of histone acetyltransferase co-activators has important implications for
targeting inhibitors of AR function.
PMID- 10779505
TI - Inhibition of papain by S-nitrosothiols. Formation of mixed disulfides.
AB - S-Nitrosylation of protein thiols is one of the cellular regulatory mechanisms
induced by NO. The cysteine protease papain has a critical thiol residue
(Cys(25)). It has been demonstrated that NO or NO donors such as sodium
nitroprusside and N-nitrosoaniline derivatives can reversibly inhibit this enzyme
by S-NO bond formation in its active site. In this study, a different regulated
mechanism of inactivation was reported using S-nitrosothiols as the NO donor.
Five S-nitroso compounds, S-nitroso-N-acetyl-dl-penicillamine, S
nitrosoglutathione, S-nitrosocaptopril, glucose-S-nitroso-N-acetyl-dl
penicillamine-2, and the S-nitroso tripeptide acetyl-Phe-Gly-S
nitrosopenicillamine, exhibited different inhibitory activities toward the enzyme
in a time- and concentration-dependent manner with second-order rate constants
(k(i)/K(I)) ranging from 8.9 to 17.2 m(-1) s(-1). The inhibition of papain by S
nitrosothiol was rapidly reversed by dithiothreitol, but not by ascorbate, which
could reverse the inhibition of papain by NOBF(4). Incubation of the enzyme with
a fluorescent S-nitroso probe (S-nitroso-5-dimethylaminonaphthalene-1-sulfonyl)
resulted in the appearance of fluorescence of the protein, indicating the
formation of a thiol adduct. Moreover, S-transnitrosylation in the incubation of
S-nitroso inactivators with papain was excluded. These results suggest that
inactivation of papain by S-nitrosothiols is due to a direct attack of the highly
reactive thiolate (Cys(25)) in the enzyme active site on the sulfur of S
nitrosothiols to form a mixed disulfide between the inactivator and papain.
PMID- 10779506
TI - The gene encoding the mitogen-responsive phosphoprotein Dab2 is differentially
regulated by GATA-6 and GATA-4 in the visceral endoderm.
AB - Gene targeting studies have demonstrated that the zinc finger transcription
factor GATA-6 lies upstream in a transcriptional cascade that controls
differentiation of the visceral endoderm. To understand the function of GATA-6 in
the visceral endoderm and to identify genes regulated by GATA-6 in this tissue,
subtractive hybridization was performed using template cDNAs derived from
differentiated wild-type embryonic stem (ES) cells and GATA-6(-/-) ES cells,
respectively. These analyses revealed that the gene encoding Dab2, a mitogen
responsive phosphoprotein, is differentially expressed in wild-type and GATA-6
deficient ES cells. Consistent with these findings, Dab2 is expressed in the
visceral endoderm of wild-type embryos but not in the visceral endoderm of GATA-6
deficient embryos. Cotransfection experiments demonstrate that the human Dab2
promoter can be transactivated by forced expression of GATA-6 in NIH-3T3 cells.
In contrast, forced expression of GATA-4 does not transactivate the human Dab2
promoter and Dab2 is expressed in the visceral endoderm of GATA-4 null embryos.
Surprisingly, the specificity of GATA-6-induced transactivation of the Dab2
promoter is not mediated through its zinc finger DNA-binding domain. Taken
together, these data demonstrate that the mitogen-responsive phosphoprotein Dab2
is a downstream target of GATA-6 in the visceral endoderm. Moreover, these data
demonstrate that molecular mechanisms have evolved that direct, and distinguish,
the functional specificity of GATA family members when they are developmentally
coexpressed.
PMID- 10779507
TI - Localization and genomic organization of a new hepatocellular organic anion
transporting polypeptide.
AB - Based on sequence homology to the human organic anion transporting polypeptide 2
(OATP2; SLC21A6), we cloned a new member of the SLC21A superfamily of solute
carriers, termed OATP8 (SLC21A8). The protein of 702 amino acids showed an amino
acid identity of 80% with human OATP2. Based on Northern blotting, the expression
of OATP8 was restricted to human liver. Cosmid clones containing the genes
encoding human OATP1 (SLC21A3), OATP2 (SLC21A6), and OATP8 (SLC21A8) served to
establish their genomic organization. All three genes contained 14 exons with 13
identical splice sites when transferred to the amino acid sequence. An antibody
raised against the carboxyl terminus localized OATP8 to the basolateral membrane
of human hepatocytes and the recombinant glycoprotein, expressed in MDCKII cells,
to the lateral membrane. Transport properties of OATP8 were studied in stably
transfected MDCKII and HEK293 cells. Organic anions transported by human OATP8
included sulfobromophthalein, with a K(m) of 3.3 microm, and 17beta-glucuronosyl
estradiol, with a K(m) of 5.4 microm. Several bile salts were not substrates.
Thus, human OATP8 is a new uptake transporter in the basolateral hepatocyte
membrane with an overlapping but distinct substrate specificity as compared with
OATP2, which is localized to the same membrane domain.
PMID- 10779508
TI - Estrogen receptor-related receptor alpha 1 interacts with coactivator and
constitutively activates the estrogen response elements of the human lactoferrin
gene.
AB - The human estrogen receptor-related receptor (ERRalpha1, NR3B1a) was shown to
bind a steroidogenic factor binding element (SFRE), TCAAGGTCATC, 26 base pairs
upstream from the estrogen response element (ERE) of the human lactoferrin gene
promoter. A mutation made at SFRE significantly reduced estrogen-dependent
transcription from the lactoferrin ERE in human endometrial cells. In this study,
we demonstrated that ERRalpha1 binds both SFRE and ERE elements and
constitutively transactivates the lactoferrin gene promoter. In DNase I
footprinting protection analysis, both SFRE and ERE regions were protected by
glutathione S-transferase-ERRalpha1 fusion protein. The receptor formed two
protein-DNA complexes with either SFRE or ERE in electrophoresis mobility shift
assay. Homodimerization of ERRalpha1 was confirmed with the mammalian two-hybrid
system. ERRalpha1 activates reporter constructs containing various types of
estrogen response elements in endometrial and non-endometrial cells in transient
transfection experiments. Overexpressing the coactivator, SRC1a or GRIP1, further
enhances ERRalpha1-induced transcriptional activity. We demonstrated that the AF2
domain of ERRalpha1 is essential for the transactivation function and that
deletion or mutation at this region abrogates the activation capability. Protein
protein interaction between the SRC1a and ERRalpha1 C terminus was confirmed with
a GST glutathione S-transferase "pull-down" assay. When comparing ERRalpha1 and
the estrogen receptor alpha (ERalpha) in many of the experiments, we found that
ERalpha can also bind SFRE of the lactoferrin gene and transactivate the promoter
activity in a ligand-dependent manner. The present study demonstrated that
ERRalpha1 binds similar DNA elements as ERalpha and confers its transactivation
function constitutively. Therefore, ERRalpha1 may actively modulate the estrogen
response of lactoferrin gene as well as other estrogen-responsive genes.
PMID- 10779509
TI - Coreceptor function of mutant human CD4 molecules without affinity to gp120 of
human immunodeficiency virus.
AB - Despite extensive mutational studies on the human CD4 molecule and its affinity
to human immunodeficiency virus (HIV) envelope glycoprotein gp120, coreceptor
functions of such mutant molecules have only been examined by indirect
measurement of their affinity to class II major histocompatibility complex (MHC)
molecules. In this report, coreceptor functions of mutant human CD4 molecules,
which have no or reduced affinity to an HIV envelope protein, gp120, were
assessed in a murine T cell receptor/class II MHC recognition system. The
substitution of human C" beta strand with the murine homologous segment resulted
in the loss of the coreceptor function as well as in the complete loss of gp120
binding capacity, corroborating the consensus that Phe-43 in C" beta strand plays
crucial roles in both situations. However, simultaneous replacement of the C'-C"
loop along with the C" beta strand by homologous murine segments rescued the
coreceptor function, whereas gp120 binding capacity remained negative. Further
analysis indicated that insertion of lysine between Gly-41 and Ser-42 can
partially compensate for the coreceptor function lost by the Phe-43 --> Val
mutation. Although the coreceptor function of these mutant CD4 molecules in a
human T cell recognition system is yet to be determined, these observations
necessitate a re-evaluation of the role played by Phe-43 in coreceptor function.
Examination of the sensitivities of the mutant CD4 molecules expressed on HeLa
cells to infection by a T cell-tropic HIV-1 strain indicated that only those
mutants that had completely lost gp120 binding capacity were resistant to the
infection. All mutants having whole C" substitution, irrespective of additional
substitutions or their coreceptor functions, were resistant to the infection.
PMID- 10779510
TI - Limits of protein folding inside GroE complexes.
AB - The GroE chaperones of Escherichia coli promote the folding of other proteins
under conditions where no spontaneous folding occurs. One requirement for this
reaction is the trapping of the nonnative protein inside the chaperone complex.
Encapsulation may be important to prevent unfavorable intermolecular interactions
during folding. We show here that, especially for oligomeric proteins, the timing
of encapsulation and release is of critical importance. If this cycle is
decelerated, misfolding is observed inside functional chaperone complexes.
PMID- 10779511
TI - Structural and functional studies with antibodies to the integrin beta 2 subunit.
A model for the I-like domain.
AB - To establish a structure and function map of the beta2 integrin subunit, we
mapped the epitopes of a panel of beta2 monoclonal antibodies including function
blocking, nonblocking, and activating antibodies using human/mouse beta2 subunit
chimeras. Activating antibodies recognize the C-terminal half of the cysteine
rich region, residues 522-612. Antibodies that do not affect ligand binding map
to residues 1-98 and residues 344-521. Monoclonal antibodies to epitopes within a
predicted I-like domain (residues 104-341) strongly inhibit LFA-1-dependent
adhesion. These function-blocking monoclonal antibodies were mapped to specific
residues with human --> mouse knock-out or mouse --> human knock-in mutations.
Combinatorial epitopes involving residues distant in the sequence provide support
for a specific alignment between the beta-subunit and I domains that was used to
construct a three-dimensional model. Antigenic residues 133, 332, and 339 are on
the first and last predicted alpha-helices of the I-like domain, which are
adjacent on its "front." Other antigenic residues in beta2 and in other integrin
beta subunits are present on the front. No antigenic residues are present on the
"back" of the domain, which is predicted to be in an interface with other
domains, such as the alpha subunit beta-propeller domain. Most mutations in the
beta2 subunit in leukocyte adhesion deficiency are predicted to be buried in the
beta2 subunit I-like domain. Two long insertions are present relative to alpha
subunit I-domains. One is tied down to the back of the I-like domain by a
disulfide bond. The other corresponds to the "specificity-determining loop"
defined in beta1 and beta3 integrins and contains the antigenic residue Glu(175)
in a disulfide-bonded loop located near the "top" of the domain.
PMID- 10779512
TI - Identification and purification of vitamin K-dependent proteins and peptides with
monoclonal antibodies specific for gamma -carboxyglutamyl (Gla) residues.
AB - Novel monoclonal antibodies that specifically recognize gamma-carboxyglutamyl
(Gla) residues in proteins and peptides have been produced. As demonstrated by
Western blot and time-resolved immunofluorescence assays the antibodies are pan
specific for most or all of the Gla-containing proteins tested (factors VII, IX,
and X, prothrombin, protein C, protein S, growth arrest-specific protein 6, bone
Gla protein, conantokin G from a cone snail, and factor Xa-like proteins from
snake venom). Only the Gla-containing light chain of the two-chain proteins was
bound. Decarboxylation destroyed the epitope(s) on prothrombin fragment 1, and
Ca(2+) strongly inhibited binding to prothrombin. In Western blot,
immunofluorescence, and surface plasmon resonance assays the antibodies bound
peptides conjugated to bovine serum albumin that contained either a single Gla or
a tandem pair of Gla residues. Binding was maintained when the sequence
surrounding the Gla residue(s) was altered. Replacement of Gla with glutamic acid
resulted in a complete loss of the epitope. The utility of the antibodies was
demonstrated in immunochemical methods for detecting Gla-containing proteins and
in the immunopurification of a factor Xa-like protein from tiger snake venom. The
amino acid sequences of the Gla domain and portions of the heavy chain of the
snake protein were determined.
PMID- 10779513
TI - A carboxylate triad is essential for the polymerase activity of Escherichia coli
DNA polymerase I (Klenow fragment). Presence of two functional triads at the
catalytic center.
AB - The catalytic roles of two essential active-site aspartates at positions 705 and
882 of Escherichia coli DNA polymerase I have been well established (Steitz, T.
A. (1998) Nature 391, 231-232). We now demonstrate that the participation of at
least one additional carboxylate, a glutamate at position 710 or 883, is
obligatory for catalysis. This conclusion has been drawn from our investigation
of the properties of single (E710D, E710A, E883D, and E883A) and double
(E710D/E883D and E710A/E883A) substitutions of residues Glu(710) and Glu(883).
While single substitutions of either of the glutamates resulted in some reduction
in polymerase activity, the mutant enzyme with simultaneous substitution of both
glutamates with alanine exhibited a nearly complete loss of activity.
Interestingly, substitution with two aspartates in place of the glutamates
resulted in an enzyme species that catalyzed DNA synthesis in a strictly
distributive mode. Pyrophosphorolytic activity of the mutant enzymes reflected
their polymerase activity profiles, with markedly reduced pyrophosphorolysis by
the double mutant enzymes. Moreover, an evaluation of Mg(2+) and salt optima for
all mutant enzymes of Glu(710) and Glu(883) revealed significant deviations from
that for the wild type, implying a possible role of these glutamates in metal
coordination as well as in maintaining the structural integrity of the active
site.
PMID- 10779514
TI - Suppressor mutations in the chloroplast-encoded large subunit improve the thermal
stability of wild-type ribulose-1,5-bisphosphate carboxylase/oxygenase.
AB - A temperature-conditional, photosynthesis-deficient mutant of the green alga
Chlamydomonas reinhardtii, previously recovered by genetic screening, results
from a leucine 290 to phenylalanine (L290F) substitution in the chloroplast
encoded large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase
(Rubisco, EC ). Rubisco purified from mutant cells grown at 25 degrees C has a
reduction in CO(2)/O(2) specificity and is inactivated at lower temperatures than
those that inactivate the wild-type enzyme. Second-site alanine 222 to threonine
(A222T) or valine 262 to leucine (V262L) substitutions were previously isolated
via genetic selection for photosynthetic ability at the 35 degrees C restrictive
temperature. These intragenic suppressors improve the CO(2)/O(2) specificity and
thermal stability of L290F Rubisco in vivo and in vitro. In the present study,
directed mutagenesis and chloroplast transformation were used to create the A222T
and V262L substitutions in an otherwise wild-type enzyme. Although neither
substitution improves the CO(2)/O(2) specificity above the wild-type value, both
improve the thermal stability of wild-type Rubisco in vitro. Based on the x-ray
crystal structure of spinach Rubisco, large subunit residues 222, 262, and 290
are far from the active site. They surround a loop of residues in the nuclear
encoded small subunit. Interactions at this subunit interface may substantially
contribute to the thermal stability of the Rubisco holoenzyme.
PMID- 10779515
TI - Structure of a C-type carbohydrate recognition domain from the macrophage mannose
receptor.
AB - The mannose receptor of macrophages and liver endothelium mediates clearance of
pathogenic organisms and potentially harmful glycoconjugates. The extracellular
portion of the receptor includes eight C-type carbohydrate recognition domains
(CRDs), of which one, CRD-4, shows detectable binding to monosaccharide ligands.
We have determined the crystal structure of CRD-4. Although the basic C-type
lectin fold is preserved, a loop extends away from the core of the domain to form
a domain-swapped dimer in the crystal. Of the two Ca(2+) sites, only the
principal site known to mediate carbohydrate binding in other C-type lectins is
occupied. This site is altered in a way that makes sugar binding impossible in
the mode observed in other C-type lectins. The structure is likely to represent
an endosomal form of the domain formed when Ca(2+) is lost from the auxiliary
calcium site. The structure suggests a mechanism for endosomal ligand release in
which the auxiliary calcium site serves as a pH sensor. Acid pH-induced removal
of this Ca(2+) results in conformational rearrangements of the receptor,
rendering it unable to bind carbohydrate ligands.
PMID- 10779516
TI - Functional delineation of three groups of the ATP-dependent family of chromatin
remodeling enzymes.
AB - ATP-dependent chromatin remodeling enzymes antagonize the inhibitory effects of
chromatin. We compare six different remodeling complexes: ySWI/SNF, yRSC,
hSWI/SNF, xMi-2, dCHRAC, and dNURF. We find that each complex uses similar
amounts of ATP to remodel nucleosomal arrays at nearly identical rates. We also
perform assays with arrays reconstituted with hyperacetylated or trypsinized
histones and isolated histone (H3/H4)(2) tetramers. The results define three
groups of the ATP-dependent family of remodeling enzymes. In addition we
investigate the ability of an acidic activator to recruit remodeling complexes to
nucleosomal arrays. We propose that ATP-dependent chromatin remodeling enzymes
share a common reaction mechanism and that a key distinction between complexes is
in their mode of regulation or recruitment.
PMID- 10779517
TI - Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend
on specific amino acid residues in a consensus calmodulin-binding motif in
the(alpha)1C subunit.
AB - L-type Ca(2+) channels are unusual in displaying two opposing forms of
autoregulatory feedback, Ca(2+)-dependent inactivation and facilitation. Previous
studies suggest that both involve direct interactions between calmodulin (CaM)
and a consensus CaM-binding sequence (IQ motif) in the C terminus of the
channel's alpha(1C) subunit. Here we report the functional effects of an
extensive series of modifications of the IQ motif aimed at dissecting the
structural determinants of the different forms of modulation. Although the
combined substitution by alanine at five key positions (Ile(1624), Gln(1625),
Phe(1628), Arg(1629), and Lys(1630)) abolished all Ca(2+) dependence,
corresponding single alanine replacements behaved similarly to the wild-type
channel (77wt) in four of five cases. The mutant I1624A stood out in displaying
little or no Ca(2+)-dependent inactivation, but clear Ca(2+)- and frequency
dependent facilitation. An even more pronounced tilt in favor of facilitation was
seen with the double mutant I1624A/Q1625A: overt facilitation was observed even
during a single depolarizing pulse, as confirmed by two-pulse experiments.
Replacement of Ile(1624) by 13 other amino acids produced graded and distinct
patterns of change in the two forms of modulation. The extent of Ca(2+)-dependent
facilitation was monotonically correlated with the affinity of CaM for the mutant
IQ motif, determined in peptide binding experiments in vitro. Ca(2+)-dependent
inactivation also depended on strong CaM binding to the IQ motif, but showed an
additional requirement for a bulky, hydrophobic side chain at position 1624.
Abolition of Ca(2+)-dependent modulation by IQ motif modifications mimicked and
occluded the effects of overexpressing a dominant-negative CaM mutant.
PMID- 10779518
TI - Developmental regulation of collagenase-3 mRNA in normal, differentiating
osteoblasts through the activator protein-1 and the runt domain binding sites.
AB - Collagenase-3 mRNA is initially detectable when osteoblasts cease proliferation,
increasing during differentiation and mineralization. We showed that this
developmental expression is due to an increase in collagenase-3 gene
transcription. Mutation of either the activator protein-1 or the runt domain
binding site decreased collagenase-3 promoter activity, demonstrating that these
sites are responsible for collagenase-3 gene transcription. The activator protein
1 and runt domain binding sites bind members of the activator protein-1 and core
binding factor family of transcription factors, respectively. We identified core
binding factor a1 binding to the runt domain binding site and JunD in addition to
a Fos-related antigen binding to the activator protein-1 site. Overexpression of
both c-Fos and c-Jun in osteoblasts or core-binding factor a1 increased
collagenase-3 promoter activity. Furthermore, overexpression of c-Fos, c-Jun, and
core-binding factor a1 synergistically increased collagenase-3 promoter activity.
Mutation of either the activator protein-1 or the runt domain binding site
resulted in the inability of c-Fos and c-Jun or core-binding factor a1 to
increase collagenase-3 promoter activity, suggesting that there is cooperative
interaction between the sites and the proteins. Overexpression of Fra-2 and JunD
repressed core-binding factor a1-induced collagenase-3 promoter activity. Our
results suggest that members of the activator protein-1 and core-binding factor
families, binding to the activator protein-1 and runt domain binding sites are
responsible for the developmental regulation of collagenase-3 gene expression in
osteoblasts.
PMID- 10779519
TI - Bicarbonate binding activity of the CmpA protein of the cyanobacterium
Synechococcus sp. strain PCC 7942 involved in active transport of bicarbonate.
AB - The cmpABCD operon of the cyanobacterium Synechococcus sp. strain PCC 7942
encodes an ATP-binding cassette transporter involved in HCO(3)(-) uptake. The
three genes, cmpBCD, encode membrane components of an ATP-binding cassette
transporter, whereas cmpA encodes a 42-kDa cytoplasmic membrane protein, which is
46.5% identical to the membrane-anchored substrate-binding protein of the
nitrate/nitrite transporter. Equilibrium dialysis analysis using H(14)CO(3)(-)
showed that a truncated CmpA protein lacking the N-terminal 31 amino acids,
expressed in Escherichia coli cells as a histidine-tagged soluble protein,
specifically binds inorganic carbon (CO(2) or HCO(3)(-)). The addition of the
recombinant CmpA protein to a buffer caused a decrease in the concentration of
dissolved CO(2) because of the binding of inorganic carbon to the protein. The
decrease in CO(2) concentration was accelerated by the addition of carbonic
anhydrase, indicating that HCO(3)(-), but not CO(2), binds to the protein. Mass
spectrometric measurements of the amounts of unbound and bound HCO(3)(-) in CmpA
solutions containing low concentrations of inorganic carbon revealed that CmpA
binds HCO(3)(-) with high affinity (K(d) = 5 microm). A similar dissociation
constant was obtained by analysis of the competitive inhibition of the CmpA
protein on the carboxylation of phosphoenolpyruvate by phosphoenolpyruvate
carboxylase at limiting concentrations of HCO(3)(-). These findings showed that
the cmpA gene encodes the substrate-binding protein of the HCO(3)(-) transporter.
PMID- 10779520
TI - Interferon-alpha induces nmi-IFP35 heterodimeric complex formation that is
affected by the phosphorylation of IFP35.
AB - Nmi and IFP35 are interferon (IFN)-induced proteins. In cells treated with IFN
gamma, Nmi enhances the association of transcription co-activator CBP/p300 with
signal transducer and activator of transcription proteins, and IFP35 forms a high
molecular weight cytosolic complex of unknown constituents. Here we show that Nmi
and IFP35 co-immunoprecipitate with an anti-keratin 19 antibody, which is due to
cross-reaction of the antibody with Nmi, and suggests an Nmi-IFP35 physical
association. In support of this, Nmi and IFP35 co-immunoprecipitate using anti
Nmi and anti-IFP35 antibodies, manifest enhanced colocalization as determined by
immunofluorescence staining of IFN-treated cells, and form heterodimers as
determined by chemical cross-linking. Nmi and IFP35 are primarily cytosolic
proteins, and their interaction is increased after IFN-alpha treatment of cells
as early as 1 h after exposure. Sucrose gradient sedimentation and size
fractionation showed a shift of Nmi-IFP35 heterodimers toward a heavier fraction
(100-200 kDa) in IFN-alpha-treated cells. This dynamic complex formation is
reversed by pretreatment with okadaic acid. Two-dimensional gel analysis
indicates that the IFN-induced complex formation correlates with IFP35
dephosphorylation. Our data demonstrate Nmi-IFP35 cytosolic localization and
heterodimerization, and an IFN-alpha-regulated molecular event in which Nmi and
IFP35 participate, reversibly and by a dephosphorylation dependent fashion, in a
100-200-kDa molecular complex formation.
PMID- 10779521
TI - Vascular endothelial junction-associated molecule, a novel member of the
immunoglobulin superfamily, is localized to intercellular boundaries of
endothelial cells.
AB - During the process of lymphocyte homing to secondary lymphoid organs, such as
lymph nodes and tonsils, lymphocytes interact with and cross a specialized
microvasculature, known as high endothelial venules. There is a great deal of
information available about the first steps in the homing cascade, but molecular
understanding of lymphocyte transmigration through the intercellular junctions of
high endothelial venules is lacking. In analyzing expressed sequence tags from a
cDNA library prepared from human tonsillar high endothelial cells, we have
identified a cDNA encoding a novel member of the immunoglobulin superfamily. The
protein, which we have termed VE-JAM ("vascular endothelial junction-associated
molecule"), contains two extracellular immunoglobulin-like domains, a
transmembrane domain, and a relatively short cytoplasmic tail. VE-JAM is
prominently expressed on high endothelial venules but is also present on the
endothelia of other vessels. Strikingly, it is highly localized to the
intercellular boundaries of high endothelial cells. VE-JAM is most homologous to
a recently identified molecule known as Junctional Adhesion Molecule, which is
concentrated at the intercellular boundaries of both epithelial and endothelial
cells. Because the Junctional Adhesion Molecule has been strongly implicated in
the processes of neutrophil and monocyte transendothelial migration, an analogous
function of VE-JAM during lymphocyte homing is plausible.
PMID- 10779522
TI - A distinct sequence (ATAAA)n separates methylated and unmethylated domains at the
5'-end of the GSTP1 CpG island.
AB - What defines the boundaries between methylated and unmethylated domains in the
genome is unclear. In this study we used bisulfite genomic sequencing to map the
boundaries of methylation that flank the 5'- and 3'-ends of the CpG island
spanning the promoter region of the glutathione S-transferase (GSTP1) gene. We
show that GSTP1 is expressed in a wide range of tissues including brain, lung,
skeletal muscle, spleen, pancreas, bone marrow, prostate, heart, and blood and
that this expression is associated with the CpG island being unmethylated. In
these normal tissues a marked boundary was found to separate the methylated and
unmethylated regions of the gene at the 5'-flank of the CpG island, and this
boundary correlated with an (ATAAA)(19-24) repeated sequence. In contrast, the 3'
end of the CpG island was not marked by a sharp transition in methylation but by
a gradual change in methylation density over about 500 base pairs. In normal
tissue the sequences on either side of the 5'-boundary appear to lie in separate
domains in which CpG methylation is independently controlled. These separate
methylation domains are lost in all prostate cancer where GSTP1 expression is
silenced and methylation extends throughout the island and spans across both the
5'- and 3'-boundary regions.
PMID- 10779523
TI - Macrophage-enriched myristoylated alanine-rich C kinase substrate and its
phosphorylation is required for the phorbol ester-stimulated diffusion of beta 2
integrin molecules.
AB - An early event of beta(2) integrin activation is the increased diffusion rate of
this molecule on the cell surface, thereby providing integrin molecules with a
better chance to meet the ligands. The activation of protein kinase C (PKC)
stimulates integrin diffusion by releasing the cytoskeletal constraint on
integrin molecules. We report here that macrophage-enriched myristoylated alanine
rich C kinase substrate (MacMARCKS), a membrane-associated PKC substrate involved
in integrin activation, is required for this PKC-stimulated diffusion of integrin
molecules. Using the single-particle tracking technique, we observed that the
activation of PKC stimulated an 11-fold increase in the diffusion rate of beta(2)
integrins in wild type J774 macrophage cells but not in those expressing mutant
MacMARCKS. Further evidence is provided from a MacMARCKS-deficient cell line in
which phorbol esters failed to stimulate the diffusion of integrin. Transfection
of wild type MacMARCKS into these cells restored the rapid diffusion rate of the
beta(2) integrins. The phosphorylation of MacMARCKS is important because
transfection of a nonphosphorylatable MacMARCKS mutant or the addition of
staurosporine eliminates the rapid diffusion rate of integrin. Furthermore,
adding cytochalasin D bypasses the MacMARCKS deficiency and stimulates beta(2)
integrin diffusion, suggesting that MacMARCKS's involvement in integrin
activation is prior or at the site of cytoskeleton. Therefore, we conclude that
MacMARCKS is required for releasing the cytoskeletal constraint on integrin
molecules during PKC-mediated integrin activation.
PMID- 10779524
TI - Identification of a novel, dendritic cell-associated molecule, dectin-1, by
subtractive cDNA cloning.
AB - Dendritic cells (DC) are special subsets of antigen presenting cells
characterized by their potent capacity to activate immunologically naive T cells.
By subtracting the mRNAs expressed by the mouse epidermus-derived DC line XS52
with the mRNAs expressed by the J774 macrophage line, we identified five novel
genes that were expressed selectively by this DC line. One of these genes encoded
a type II membrane-integrated polypeptide of 244 amino acids containing a
putative carbohydrate recognition domain motif at the COOH-terminal end. This
molecule, termed "dectin-1," was expressed abundantly at both mRNA and protein
levels by the XS52 DC line, but not by non-DC lines (including the J774
macrophage line). Dectin-1 mRNA was detected predominantly in spleen and thymus
(by Northern blotting) and in skin-resident DC, i.e. Langerhans cells (by reverse
transcription-polymerase chain reaction). Affinity-purified antibody against
dectin-1 identified a 43-kDa glycoprotein in membrane fractions isolated from the
XS52 DC line and from the dectin-1 cDNA-transfected COS-1 cells. His-tagged
recombinant proteins containing the extracellular domains of dectin-1 showed
marked and specific binding to the surface of T cells and promoted their
proliferation in the presence of anti-CD3 monoclonal antibody at suboptimal
concentrations. These in vitro results suggest that dectin-1 on DC may bind to as
yet undefined ligand(s) on T cells, thereby delivering T cell co-stimulatory
signals. Not only do these results document the efficacy of subtractive cDNA
cloning for the identification of unique genes expressed by DC, they also provide
a framework for studying the physiological function of dectin-1.
PMID- 10779525
TI - Stimulation of NFkappa B activity by multiple signaling pathways requires PAK1.
AB - The p21-activated kinase (PAK1) is a serine-threonine protein kinase that is
activated by binding to the Rho family small G proteins Rac and Cdc42hs. Both Rac
and Cdc42hs have been shown to regulate the activity of the transcription factor
NFkappaB. Here we show that expression of active Ras, Raf-1, or Rac1 in
fibroblasts stimulates NFkappaB in a PAK1-dependent manner and that expression of
active PAK1 can stimulate NFkappaB on its own. Similarly, in macrophages
activation of NFkappaB as well as transcription from the tumor necrosis factor
alpha promoter depends on PAK1. In these cells lipopolysaccharide is a potent
activator of PAK1 kinase activity. We also demonstrate that expression of active
PAK1 stimulates the nuclear translocation of the p65 subunit of NFkappaB but does
not activate the inhibitor of kappaB kinases alpha or beta. These data
demonstrate that PAK1 is a crucial signaling molecule involved in NFkappaB
activation by multiple stimuli.
PMID- 10779526
TI - Ion channel clustering by membrane-associated guanylate kinases. Differential
regulation by N-terminal lipid and metal binding motifs.
AB - The postsynaptic density protein PSD-95 and related membrane-associated guanylate
kinase (MAGUK) proteins assemble signal transduction complexes at sites of cell
cell contact including synapses. Whereas PSD-95 and PSD-93 occur only at
postsynaptic sites in hippocampal neurons, SAP-102 also occurs in axons. In
heterologous cells, PSD-95 and PSD-93 mediate cell surface ion channel
clustering, but SAP-102 and SAP-97 do not. This selective ion channel clustering
activity by MAGUKs is explained by differential palmitoylation, as PSD-93 and PSD
95 are palmitoylated though SAP-97, and SAP-102 are not. Rather than being
palmitoylated, we find that N-terminal cysteines from SAP-102 tightly bind to
zinc. And, appending the N terminus of SAP-102 to PSD-95 results in localization
of the chimera to both axons and dendrites. These data suggest that lipid
modifications and heavy metal associations with the N termini of MAGUKs mediate
differential functions and subcellular localizations of these synaptic scaffolds.
PMID- 10779527
TI - Structure-function analysis of protease-activated receptor 4 tethered ligand
peptides. Determinants of specificity and utility in assays of receptor function.
AB - Thrombin activates protease-activated receptors (PARs) by specific cleavage of
their amino-terminal exodomains to unmask a tethered ligand that binds
intramolecularly to the body of the receptor to effect transmembrane signaling.
Peptides that mimic such ligands are valuable as agonists for probing PAR
function, but the tethered ligand peptide for PAR4, GYPGKF, lacks potency and is
of limited utility. In a structure-activity analysis of PAR4 peptides, AYPGKF was
approximately 10-fold more potent than GYPGKF and, unlike GYPGKF, elicited PAR4
mediated responses comparable in magnitude to those elicited by thrombin. AYPGKF
was relatively specific for PAR4 in part due to the tyrosine at position 2;
substitution of phenylalanine or p-fluorophenylalanine at this position produced
peptides that activated both PAR1 and PAR4. Because human platelets express both
PAR1 and PAR4, it might be desirable to inhibit both receptors. Identifying a
single agonist for both receptors raises the possibility that a single antagonist
for both receptors might be developed. The AYPGKF peptide is a useful new tool
for probing PAR4 function. For example, AYPGKF activated and desensitized PAR4 in
platelets and, like thrombin, triggered phosphoinositide hydrolysis but not
inhibition of adenylyl cyclase in PAR4-expressing cells. The latter shows that,
unlike PAR1, PAR4 couples to G(q) and not G(i).
PMID- 10779528
TI - Paralogy and orthology of tyrosine kinases that can extend the life span of
Caenorhabditis elegans.
AB - Modification of any one of three transmembrane protein tyrosine kinase (PTK)
genes, old-1, old-2 (formerly tkr-1 and tkr-2, respectively), and daf-2 can
extend the mean and maximum life span of the nematode Caenorhabditis elegans. To
identify paralogs and orthologs, we delineated relationships between these three
PTKs and all known transmembrane PTKs and all known mammalian nontransmembrane
PTKs using molecular phylogenetics. The tree includes a number of invertebrate
receptor PTKs and a novel mammalian receptor PTK (inferred from the expressed
sequence tag database) that have not previously been analyzed. old-1 and old-2
were found to be members of a surprisingly large C. elegans PTK family having 16
members. Interestingly, only four members of this transmembrane family appeared
to have receptor domains (immunoglobulin-like in each case). The C-terminal
domain of this family was found to have a unique sequence motif that could be
important for downstream signaling. Among mammalian PTKs, the old-1/old-2 family
appeared to be most closely related to the Pdgfr, Fgfr, Ret, and Tie/Tek
families. However, these families appeared to have split too early from the old
1/old-2 family to be orthologs, suggesting that a mammalian ortholog could yet be
discovered. An extensive search of the expressed-sequence tag database suggested
no additional candidate orthologs. In contrast to old-1 and old-2, daf-2 had no
C. elegans paralogs. Although daf-2 was most closely related to the mammalian
insulin receptor family, a hydra insulin receptor-like sequence suggested that
daf-2 might not be an ortholog of the insulin receptor family. Among PTKs, the
old-1/old-2 family and daf-2 were not particularly closely related, raising the
possibility that other PTK families might extend life span. On a more general
note, our survey of the expressed-sequence tag database suggested that few, if
any, additional mammalian PTK families are likely to be discovered. The one novel
family that was discovered could represent a novel oncogene family, given the
prevalence of oncogenes among PTKs. Finally, the PTK tree was consistent with
nematodes and fruit flies being as divergent as nematodes and mammals, suggesting
that life extension mechanisms shared by nematodes and fruit flies would be
reasonable candidates for extending mammalian life spans.
PMID- 10779529
TI - Molecular evolution of the wingless gene and its implications for the
phylogenetic placement of the butterfly family Riodinidae (Lepidoptera:
papilionoidea).
AB - The sequence evolution of the nuclear gene wingless was investigated among 34
representatives of three lepidopteran families (Riodinidae, Lycaenidae, and
Nymphalidae) and four outgroups, and its utility for inferring phylogenetic
relationships among these taxa was assessed. Parsimony analysis yielded a well
resolved topology supporting the monophyly of the Riodinidae and Lycaenidae,
respectively, and indicating that these two groups are sister lineages, with
strong nodal support based on bootstrap and decay indices. Although wingless
provides robust support for relationships within and between the riodinids and
the lycaenids, it is less informative about nymphalid relationships. Wingless
does not consistently recover nymphalid monophyly or traditional subfamilial
relationships within the nymphalids, and nodal support for all but the most
recent branches in this family is low. Much of the phylogenetic information in
this data set is derived from first- and second-position substitutions. However,
third positions, despite showing uncorrected pairwise divergences up to 78%, also
contain consistent signal at deep nodes within the family Riodinidae and at the
node defining the sister relationship between the riodinids and lycaenids.
Several hypotheses about how third-position signal has been retained in deep
nodes are discussed. These include among-site rate variation, identified as a
significant factor by maximum likelihood analyses, and nucleotide bias, a
prominent feature of third positions in this data set. Understanding the
mechanisms which underlie third-position signal is a first step in applying
appropriate models to accommodate the specific evolutionary processes involved in
each lineage.
PMID- 10779530
TI - Molecular evolution of two paralogous tandemly repeated heterochromatic gene
clusters linked to the X and Y chromosomes of Drosophila melanogaster.
AB - Here we report the peculiarities of molecular evolution and divergence of
paralogous heterochromatic clusters of the testis- expressed X-linked Stellate
and Y-linked Su(Ste) tandem repeats. It was suggested that Stellate and Su(Ste)
clusters affecting male fertility are the amplified derivatives of the unique
euchromatic gene betaCK2tes encoding the putative testis-specific beta-subunit of
protein kinase CK2. The putative Su(Ste)-like evolutionary intermediate was
detected on the Y chromosome as an orphon outside of the Su(Ste) cluster. The
orphon shows extensive homology to the Su(Ste) repeat, but contains several
Stellate-like diagnostic nucleotide substitutions, as well as a 10-bp insertion
and a 3' splice site of the first intron typical of the Stellate unit. The orphon
looks like a pseudogene carrying a drastically damaged Su(Ste) open reading frame
(ORF). The putative Su(Ste) ORF, as compared with the Stellate one, carries
numerous synonymous substitutions leading to the major codon preference. We
conclude that Su(Ste) ORFs evolved on the Y chromosome under the pressure of
translational selection. Direct sequencing shows that the efficiency of concerted
evolution between adjacent repeats is 5-10 times as high in the Stellate
heterochromatic cluster on the X chromosome as that in the Y-linked Su(Ste)
cluster, judging by the frequencies of nucleotide substitutions and single
nucleotide deletions.
PMID- 10779531
TI - Contrasting patterns of molecular evolution of the genes on the new and old sex
chromosomes of Drosophila miranda.
AB - In organisms with chromosomal sex determination, sex is determined by a set of
dimorphic sex chromosomes that are thought to have evolved from a set of
originally homologous chromosomes. The chromosome inherited only through the
heterogametic sex (the Y chromosome in the case of male heterogamety) often
exhibits loss of genetic activity for most of the genes carried on its homolog
and is hence referred to as degenerate. The process by which the proto-Y
chromosome loses its genetic activity has long been the subject of much
speculation. We present a DNA sequence variation analysis of marker genes on the
evolving sex chromosomes (neo-sex chromosomes) of Drosophila miranda. Due to its
relatively recent origin, the neo-Y chromosome of this species is presumed to be
still experiencing the forces responsible for the loss of its genetic activity.
Indeed, several previous studies have confirmed the presence of some active loci
on this chromosome. The genes on the neo-Y chromosome surveyed in the current
study show generally lower levels of variation compared with their counterparts
on the neo-X chromosome or an X-linked gene. This is in accord with a reduced
effective population size of the neo-Y chromosome. Interestingly, the rate of
replacement nucleotide substitutions for the neo-Y linked genes is significantly
higher than that for the neo-X linked genes. This is not expected under a model
where the faster evolution of the X chromosome is postulated to be the main force
driving the degeneration of the Y chromosome.
PMID- 10779532
TI - Phylogenetic analyses indicate that the 19'Hexanoyloxy-fucoxanthin-containing
dinoflagellates have tertiary plastids of haptophyte origin.
AB - The three anomalously pigmented dinoflagellates Gymnodinium galatheanum,
Gyrodinium aureolum, and Gymnodinium breve have plastids possessing 19'
hexanoyloxy-fucoxanthin as the major carotenoid rather than peridinin, which is
characteristic of the majority of the dinoflagellates. Analyses of SSU rDNA from
the plastid and the nuclear genome of these dinoflagellate species indicate that
they have acquired their plastids via endosymbiosis of a haptophyte. The
dinoflagellate plastid sequences appear to have undergone rapid sequence
evolution, and there is considerable divergence between the three species.
However, distance, parsimony, and maximum-likelihood phylogenetic analyses of
plastid SSU rRNA gene sequences place the three species within the haptophyte
clade. Pavlova gyrans is the most basal branching haptophyte and is the outgroup
to a clade comprising the dinoflagellate sequences and those of other
haptophytes. The haptophytes themselves are thought to have plastids of a
secondary origin; hence, these dinoflagellates appear to have tertiary plastids.
Both molecular and morphological data divide the plastids into two groups, where
G. aureolum and G. breve have similar plastid morphology and G. galatheanum has
plastids with distinctive features.
PMID- 10779533
TI - Evidence that a family of miniature inverted-repeat transposable elements (MITEs)
from the Arabidopsis thaliana genome has arisen from a pogo-like DNA transposon.
AB - Sequence similarities exist between terminal inverted repeats (TIRs) of some
miniature inverted-repeat transposable element (MITE) families isolated from a
wide range of organisms, including plants, insects, and humans, and TIRs of DNA
transposons from the pogo family. We present here evidence that one of these MITE
families, previously described for Arabidopsis thaliana, is derived from a larger
element encoding a putative transposase. We have named this novel class II
transposon Lemi1. We show that its putative product is related to transposases of
the Tc1/mariner superfamily, being closer to the pogo family. A similar truncated
element was found in a tomato DNA sequence, indicating an ancient origin and/or
horizontal transfer for this family of elements. These results are reminiscent of
those recently reported for the human genome, where other members of the pogo
family, named Tiggers, are believed to be responsible for the generation of
abundant MITE-like elements in an early primate ancestor. These results further
suggest that some MITE families, which are highly reiterated in plant, insect,
and human genomes, could have arisen from a similar mechanism, implicating pogo
like elements.
PMID- 10779534
TI - Expansion and molecular evolution of the interferon-induced 2'-5' oligoadenylate
synthetase gene family.
AB - The mammalian 2'-5' oligoadenylate synthetases (2'-5'OASs) are enzymes that are
crucial in the interferon-induced antiviral response. They catalyze the
polymerization of ATP into 2'-5'-linked oligoadenylates which activate a
constitutively expressed latent endonuclease, RNaseL, to block viral replication
at the level of mRNA degradation. A molecular evolutionary analysis of available
OAS sequences suggests that the vertebrate genes are members of a multigene
family with its roots in the early history of tetrapods. The modern mammalian 2'
5'OAS genes underwent successive gene duplication events resulting in three size
classes of enzymes, containing one, two, or three homologous domains. Expansion
of the OAS gene family occurred by whole-gene duplications to increase gene
content and by domain couplings to produce the multidomain genes. Evolutionary
analyses show that the 2'-5'OAS genes in rodents underwent gene duplications as
recently as 11 MYA and predict the existence of additional undiscovered OAS genes
in mammals.
PMID- 10779535
TI - Terminal-sequence conservation identifies spliceosomal introns in ascomycete 18S
RNA genes.
AB - Twenty-four new insertions were obtained from seven different locations in the
nuclear 18S rDNA for seven species of the lichen-forming fungal genus PHYSCONIA:
They were analyzed allowing for terminal sequence conservation by adopting a
flexible approach to exact insertion site position, and they were compared with
12 previously reported small insertion sequences from the 18S ribosomal RNA gene.
Such insertions have previously been proposed to be degenerate self-splicing
group I introns; however, the methodology used here identified consensus terminal
sequences characteristic of spliceosomal introns. This finding is the first
suggestion that multiple spliceosomal introns occur in ribosomal genes.
PMID- 10779536
TI - Human population expansion and microsatellite variation.
AB - Polymorphisms at di-, tri-, and tetranucleotide microsatellite loci have been
analyzed in 14 worldwide populations. A statistical index of population
expansion, denoted S(k), is introduced to detect historical changes in population
size using the variation at the microsatellites. The index takes the value 0 at
equilibrium with constant population size and is positive or negative according
to whether the population is expanding or contracting, respectively. The use of
S(k) requires estimation of properties of the mutation distribution for which we
use both family data of Dib et al. for dinucleotide loci and our population data
on tri- and tetranucleotide loci. Statistical estimates of the expansion index,
as well as their confidence intervals from bootstrap resampling, are provided. In
addition, a dynamical analysis of S(k) is presented under various assumptions on
population growth or decline. The studied populations are classified as having
high, intermediate, or low values of S(k) and genetic variation, and we use these
to interpret the data in terms of possible population dynamics. Observed values
of S(k) for samples of di-, tri-, and tetranucleotide data are compatible with
population expansion earlier than 60,000 years ago in Africa, Asia, and Europe if
the initial population size before the expansion was on the order of 500. Larger
initial population sizes force the lower bound for the time since expansion to be
much earlier. We find it unlikely that bottlenecks occurred in Central African,
East Asian, or European populations, and the estimated expansion times are rather
similar for all of these populations. This analysis presented here suggests that
modern human populations departed from Africa long before they began to expand in
size. Subsequently, the major groups (the African, East Asian, and European
groups) started to grow at approximately same time. Populations of South America
and Oceania show almost no growth. The Mbuti population from Zaire appears to
have experienced a bottleneck during its expansion.
PMID- 10779537
TI - Evolutionary lineages of RT1.Ba in the Australian Rattus.
AB - In this study, the evolutionary history of the variable second exon of RT1.Ba and
its adjoining intron b are compared across a number of species and subspecies of
the Australian RATTUS: Three lineages are identified in the second intron across
a range of Rattus species. Two of these lineages, separated by the insertion of a
probable rodent short interspersed nucleotide element and by point mutations
outside the indel region, are both found in each of the major clades of the
endemic Australian RATTUS: This pattern of ancestral polymorphism is reflected in
the adjoining exon 2 sequences, although phylogenetic constraints confirm that
the clustering is not identical to that of the associated intron sequences. In
addition, the coding sequences show evidence of the retention of ancestral
polymorphism, with identical exon sequences found in two divergent species, and
some indication of gene conversion detected for the exon sequences.
PMID- 10779538
TI - Phylogeny and divergence times in Pinaceae: evidence from three genomes.
AB - In Pinaceae, the chloroplast, mitochondrial, and nuclear genomes are paternally,
maternally, and biparentally inherited, respectively. Examining congruence and
incongruence of gene phylogenies among the three genomes should provide insights
into phylogenetic relationships within the family. Here we studied intergeneric
relationships of Pinaceae using sequences of the chloroplast matK gene, the
mitochondrial nad5 gene, and the low-copy nuclear gene 4CL. The 4CL gene may
exist as a single copy in some species of Pinaceae, but it constitutes a small
gene family with two or three members in others. Duplication and deletion of the
4CL gene occurred at a tempo such that paralogous loci are maintained within but
not between genera. Exons of the 4CL gene have diverged approximately twice as
fast as the matK gene and five times more rapidly than the nad5 gene. The
partition-homogeneity test indicates that the three data sets are homogeneous. A
combined analysis of the three gene sequences generated a well-resolved and
strongly supported phylogeny. The combined phylogeny, which is topologically
congruent with the three individual gene trees based on the Templeton test, is
likely to represent the organismal phylogeny of Pinaceae. This phylogeny agrees
to a certain extent with previous phylogenetic hypotheses based on morphological,
anatomical, and immunological data. Disagreement between the previous hypotheses
and the three-genome phylogeny suggests that morphology of both vegetative and
reproductive organs has undergone convergent evolution within the pine family.
The strongly supported monophyly of Nothotsuga longibracteata, Tsuga mertensiana,
and Tsuga canadensis on all three gene phylogenies provides evidence against
previous hypotheses of intergeneric hybrid origins of N. longibracteata and T.
mertensiana. Divergence times of the genera were estimated based on sequence
divergence of the matK gene, and they correspond well with the fossil record.
PMID- 10779539
TI - Error, bias, and long-branch attraction in data for two chloroplast photosystem
genes in seed plants.
AB - Sequences of two chloroplast photosystem genes, psaA and psbB, together
comprising about 3,500 bp, were obtained for all five major groups of extant seed
plants and several outgroups among other vascular plants. Strongly supported, but
significantly conflicting, phylogenetic signals were obtained in parsimony
analyses from partitions of the data into first and second codon positions versus
third positions. In the former, both genes agreed on a monophyletic gymnosperms,
with Gnetales closely related to certain conifers. In the latter, Gnetales are
inferred to be the sister group of all other seed plants, with gymnosperms
paraphyletic. None of the data supported the modern "anthophyte hypothesis,"
which places Gnetales as the sister group of flowering plants. A series of
simulation studies were undertaken to examine the error rate for parsimony
inference. Three kinds of errors were examined: random error, systematic bias
(both properties of finite data sets), and statistical inconsistency owing to
long-branch attraction (an asymptotic property). Parsimony reconstructions were
extremely biased for third-position data for psbB. Regardless of the true
underlying tree, a tree in which Gnetales are sister to all other seed plants was
likely to be reconstructed for these data. None of the combinations of genes or
partitions permits the anthophyte tree to be reconstructed with high probability.
Simulations of progressively larger data sets indicate the existence of long
branch attraction (statistical inconsistency) for third-position psbB data if
either the anthophyte tree or the gymnosperm tree is correct. This is also true
for the anthophyte tree using either psaA third positions or psbB first and
second positions. A factor contributing to bias and inconsistency is extremely
short branches at the base of the seed plant radiation, coupled with extremely
high rates in Gnetales and nonseed plant outgroups.
PMID- 10779540
TI - Appropriate likelihood ratio tests and marginal distributions for evolutionary
tree models with constraints on parameters.
AB - We show how to make appropriate likelihood ratio tests for evolutionary tree
models when parameters such as edge (internodes or branches) lengths have
nonnegativity constraints. In such cases, under the null model of an edge length
being zero, the marginal distribution of this parameter is proven to be a "half
normal", that is, 50% zero values and 50% the positive half of a normal
distribution. Other constrained parameters, such as the proportion of invariant
sites, give similar results. To make likelihood ratio tests between nested
models, e.g., H(0): homogeneous site rates, and H(1): site rates follow a gamma
distribution with variance 1/k, then asymptotically as sequence length increases,
the distribution under H(0) becomes a mixture of chi distributions, in this case
50% chi(0), and 50% chi(1) (where the subscript denotes degrees of freedom, i.e.
, not the usually assumed 100% chi(1); which leads to a conservative test). Such
mixtures are sometimes called distributions. Simulations show that even with
sequences as short as 125 sites, some parameters, including the proportion of
invariant sites, fit asymptotic distributions closely.
PMID- 10779541
TI - Sex chromosomal transposable element accumulation and male-driven substitutional
evolution in humans.
AB - We sequenced the genomic region containing the human Y-linked zinc finger gene
(ZFY). Comparison of ZFY to the related region on the X chromosome (ZFX) and to
autosomal sequences reveals a significant accumulation of transposable elements
on the sex chromosomes. In addition, five times as many retroviruslike elements
(RLEs) are present in the ZFY region as in the ZFX region. Thus, transposable
elements accumulate more rapidly on the sex chromosomes, and the insertion of
RLEs may occur more frequently in the male than in the female germ line. When the
accumulation of substitutions in Alu elements was analyzed, it was found that the
Alu elements at the Y-chromosomal locus diverged significantly faster than those
at the X-chromosomal locus, whereas the divergence of autosomal Alu elements was
intermediate. The male-to-female mutation rate ratio was estimated to be 2.5.
PMID- 10779542
TI - The complete mitochondrial DNA sequence of the horseshoe crab Limulus polyphemus.
AB - We determined the complete 14,985-nt sequence of the mitochondrial DNA of the
horseshoe crab Limulus polyphemus (Arthropoda: Xiphosura). This mtDNA encodes the
13 protein, 2 rRNA, and 22 tRNA genes typical for metazoans. The arrangement of
these genes and about half of the sequence was reported previously; however, the
sequence contained a large number of errors, which are corrected here. The two
strands of Limulus mtDNA have significantly different nucleotide compositions.
The strand encoding most mitochondrial proteins has 1. 25 times as many A's as
T's and 2.33 times as many C's as G's. This nucleotide bias correlates with the
biases in amino acid content and synonymous codon usage in proteins encoded by
different strands and with the number of non-Watson-Crick base pairs in the stem
regions of encoded tRNAs. The sizes of most mitochondrial protein genes in
Limulus are either identical to or slightly smaller than those of their
Drosophila counterparts. The usage of the initiation and termination codons in
these genes seems to follow patterns that are conserved among most arthropod and
some other metazoan mitochondrial genomes. The noncoding region of Limulus mtDNA
contains a potential stem-loop structure, and we found a similar structure in the
noncoding region of the published mtDNA of the prostriate tick Ixodes hexagonus.
A simulation study was designed to evaluate the significance of these secondary
structures; it revealed that they are statistically significant. No significant,
comparable structure can be identified for the metastriate ticks Rhipicephalus
sanguineus and Boophilus microplus. The latter two animals also share a
mitochondrial gene rearrangement and an unusual structure of mt-tRNA(C) that is
exactly the same association of changes as previously reported for a group of
lizards. This suggests that the changes observed are not independent and that the
stem-loop structure found in the noncoding regions of Limulus and Ixodes mtDNA
may play the same role as that between trnN and trnC in vertebrates, i.e., the
role of lagging strand origin of replication.
PMID- 10779543
TI - Patterns of diversity among SINE elements isolated from three Y-chromosome genes
in carnivores.
PMID- 10779544
TI - How molecules evolve in eubacteria.
PMID- 10779545
TI - 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases.
AB - 5-lipoxygenase (5-LO) catalyzes the initial steps in the formation of
leukotrienes, a group of inflammatory mediators derived from arachidonic acid
(AA). Here we describe that activation of p38 mitogen-activated protein kinase in
human polymorphonuclear leukocytes and in Mono Mac 6 cells leads to activation of
downstream kinases, which can subsequently phosphorylate 5-LO in vitro. Different
agents activated the 5-LO kinase activities, including stimuli for cellular
leukotriene biosynthesis (A23187, thapsigargin, N-formyl-leucyl-phenylalanine),
compounds that up-regulate the capacity for leukotriene biosynthesis (phorbol 12
myristate 13-acetate, tumor necrosis factor alpha, granulocyte/macrophage colony
stimulating factor), and well known p38 stimuli as sodium arsenite and sorbitol.
For all stimuli, 5-LO kinase activation was counteracted by SB203580 (3 microM or
less), an inhibitor of p38 kinase. At least two p38-dependent 5-LO kinase
activities were found. Based on migration properties in in-gel kinase assays and
immunoreactivity, one of these was identified as mitogen-activated protein kinase
activated protein kinase 2 (MAPKAP kinase 2). The other appeared to be MAPKAP
kinase 3; however, it could not be excluded that also other p38-dependent kinases
contributed. When polymorphonuclear leukocytes were incubated with sodium
arsenite (strong activator of 5-LO kinases), platelet-activating factor and
exogenous AA, there was a 4-fold increase in 5-LO activity as compared with
incubations with only platelet-activating factor and AA. This indicates that 5-LO
phosphorylation can be one factor determining cellular 5-LO activity.
PMID- 10779546
TI - Endogenous tumor necrosis factor protects the adult cardiac myocyte against
ischemic-induced apoptosis in a murine model of acute myocardial infarction.
AB - Previous studies have shown that proinflammatory cytokines, such as tumor
necrosis factor (TNF), are expressed after acute hemodynamic overloading and
myocardial ischemia/infarction. To define the role of TNF in the setting of
ischemia/infarction, we performed a series of acute coronary artery occlusions in
mice lacking one or both TNF receptors. Left ventricular infarct size was
assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride
(TTC) staining in wild-type (both TNF receptors present) and mice lacking either
the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left
ventricular infarct size as assessed by TTC staining was significantly greater (P
< 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with
either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or
TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in
wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated
no significant difference between groups; however, the peak frequency and extent
of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared
with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient
mice did not appear to be secondary to a selective up-regulation of the Fas
ligand/receptor system in these mice. These data suggest that TNF signaling gives
rise to one or more cytoprotective signals that prevent and/or delay the
development of cardiac myocyte apoptosis after acute ischemic injury.
PMID- 10779547
TI - Inhibition of calcium/calmodulin kinase II alpha subunit expression results in
epileptiform activity in cultured hippocampal neurons.
AB - Several models that develop epileptiform discharges and epilepsy have been
associated with a decrease in the activity of calmodulin-dependent kinase II.
However, none of these studies has demonstrated a causal relationship between a
decrease in calcium/calmodulin kinase II activity and the development of seizure
activity. The present study was conducted to determine the effect of directly
reducing calcium/calmodulin-dependent kinase activity on the development of
epileptiform discharges in hippocampal neurons in culture. Complimentary
oligonucleotides specific for the alpha subunit of the calcium/calmodulin kinase
were used to decrease the expression of the enzyme. Reduction in kinase
expression was confirmed by Western analysis, immunocytochemistry, and exogenous
substrate phosphorylation. Increased neuronal excitability and frank epileptiform
discharges were observed after a significant reduction in calmodulin kinase II
expression. The epileptiform activity was a synchronous event and was not caused
by random neuronal firing. Furthermore, the magnitude of decreased kinase
expression correlated with the increased neuronal excitability. The data suggest
that decreased calmodulin kinase II activity may play a role in epileptogenesis
and the long-term plasticity changes associated with the development of
pathological seizure activity and epilepsy.
PMID- 10779548
TI - In vitro evolution of a T cell receptor with high affinity for peptide/MHC.
AB - T cell receptors (TCRs) exhibit genetic and structural diversity similar to
antibodies, but they have binding affinities that are several orders of magnitude
lower. It has been suggested that TCRs undergo selection in vivo to maintain
lower affinities. Here, we show that there is not an inherent genetic or
structural limitation on higher affinity. Higher-affinity TCR variants were
generated in the absence of in vivo selective pressures by using yeast display
and selection from a library of Valpha CDR3 mutants. Selected mutants had greater
than 100-fold higher affinity (K(D) approximately 9 nM) for the peptide/MHC
ligand while retaining a high degree of peptide specificity. Among the high
affinity TCR mutants, a strong preference was found for CDR3alpha that contained
Pro or Gly residues. Finally, unlike the wild-type TCR, a soluble monomeric form
of a high-affinity TCR was capable of directly detecting peptide/MHC complexes on
antigen-presenting cells. These findings prove that affinity maturation of TCRs
is possible and suggest a strategy for engineering TCRs that can be used in
targeting specific peptide/MHC complexes for diagnostic and therapeutic purposes.
PMID- 10779549
TI - Increased IGF-II protein affects p57kip2 expression in vivo and in vitro:
implications for Beckwith-Wiedemann syndrome.
AB - In both human and mouse, the Igf2 gene, localized on chromosomes 11 and 7,
respectively, is expressed from the paternally inherited chromosome in the
majority of tissues. Insulin-like growth factor-II (IGF-II) plays an important
role in embryonic growth, and aberrant IGF2 expression has been documented in
several human pathologies, such as Beckwith-Wiedemann syndrome (BWS), and a wide
variety of tumors. Human and mouse genetic data strongly implicate another gene,
CDKN1C (p57(kip2)), located in the same imprinted gene cluster on human
chromosome II, in BWS. p57(KIP2) is a cyclin-dependent kinase inhibitor and is
required for normal mouse embryonic development. Mutations in CDKN1C (p57(kip2))
have been identified in a small proportion of patients with BWS, and removal of
the gene from mice by targeted mutagenesis produces a phenotype with elements in
common with this overgrowth syndrome. Patients with BWS with biallelic expression
of IGF2 or with a CDKN1C (p57(kip2)) mutation, as well as overlapping phenotypes
observed in two types of mutant mice, the p57(kip2) knockout and IGF-II
overexpressing mice, strongly suggest that the genes may act in a common pathway
of growth control in situations where Igf2 expression is abnormal. Herein, we
show that p57(kip2) expression is reduced on IGF-II treatment of primary embryo
fibroblasts in a dose-dependent manner. In addition, p57(kip2) expression is down
regulated in mice with high serum levels of IGF-II. These data suggest that the
effects of increased IGF-II in BWS may, in part, be mediated through a decrease
in p57(kip2) gene expression.
PMID- 10779550
TI - The role of members of the pertussis toxin-sensitive family of G proteins in
coupling receptors to the activation of the G protein-gated inwardly rectifying
potassium channel.
AB - Inwardly rectifying potassium (K(+)) channels gated by G proteins (Kir3.x family)
are widely distributed in neuronal, atrial, and endocrine tissues and play key
roles in generating late inhibitory postsynaptic potentials, slowing the heart
rate and modulating hormone release. They are directly activated by G(betagamma)
subunits released from G protein heterotrimers of the G(i/o) family upon
appropriate receptor stimulation. Here we examine the role of isoforms of
pertussis toxin (PTx)-sensitive G protein alpha subunits (G(ialpha1-3) and
G(oalphaA)) in mediating coupling between various receptor systems (A(1),
alpha(2A), D(2S), M(4), GABA(B)1a+2, and GABA(B)1b+2) and the cloned counterpart
of the neuronal channel (Kir3.1+3.2A). The expression of mutant PTx-resistant
G(i/oalpha) subunits in PTx-treated HEK293 cells stably expressing Kir3.1+3.2A
allows us to selectively investigate that coupling. We find that, for those
receptors (A(1), alpha(2A)) known to interact with all isoforms, G(ialpha1-3) and
G(oalphaA) can all support a significant degree of coupling to Kir3.1+3.2A. The
M(4) receptor appears to preferentially couple to G(ialpha2) while another group
of receptors (D(2S), GABA(B)1a+2, GABA(B)1b+2) activates the channel
predominantly through G(betagamma) liberated from G(oA) heterotrimers.
Interestingly, we have also found a distinct difference in G protein coupling
between the two splice variants of GABA(B)1. Our data reveal selective pathways
of receptor activation through different G(i/oalpha) isoforms for stimulation of
the G protein-gated inwardly rectifying K(+) channel.
PMID- 10779551
TI - Xenopus kielin: A dorsalizing factor containing multiple chordin-type repeats
secreted from the embryonic midline.
AB - The midline tissues are important inductive centers of early vertebrate embryos.
By signal peptide selection screening, we isolated a secreted factor, Kielin,
which contains multiple cys-rich repeats similar to those in chordin (Chd).
Expression of Kielin starts at midgastrula stages in the notochord and is
detected in the floor plate of neurula embryos. Kielin is induced in mesoderm and
in ectoderm by nodal-related genes. Chd is sufficient to activate Kielin
expression in mesoderm whereas Shh or HNF-3beta in addition to Chd is required
for induction in ectoderm. Kielin has a distinct biological activity from that of
Chd. Injection of Kielin mRNA causes dorsalization of ventral marginal zone
explants and expansion of MyoD expression in neurula embryos. Unlike Chd, Kielin
does not efficiently induce neural differentiation of animal cap ectoderm,
suggesting that the activity of Kielin is not simply caused by BMP4 blockade.
Kielin is a signaling molecule that mediates inductive activities of the
embryonic midline.
PMID- 10779552
TI - Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and
synapses.
AB - Voltage-gated sodium channels perform critical roles for electrical signaling in
the nervous system by generating action potentials in axons and in dendrites. At
least 10 genes encode sodium channels in mammals, but specific physiological
roles that distinguish each of these isoforms are not known. One possibility is
that each isoform is expressed in a restricted set of cell types or is targeted
to a specific domain of a neuron or muscle cell. Using affinity-purified isoform
specific antibodies, we find that Na(v)1.6 is highly concentrated at nodes of
Ranvier of both sensory and motor axons in the peripheral nervous system and at
nodes in the central nervous system. The specificity of this antibody was also
demonstrated with the Na(v)1.6-deficient mouse mutant strain med, whose nodes
were negative for Na(v)1.6 immunostaining. Both the intensity of labeling and the
failure of other isoform-specific antibodies to label nodes suggest that Na(v)1.6
is the predominant channel type in this structure. In the central nervous system,
Na(v)1.6 is localized in unmyelinated axons in the retina and cerebellum and is
strongly expressed in dendrites of cortical pyramidal cells and cerebellar
Purkinje cells. Ultrastructural studies indicate that labeling in dendrites is
both intracellular and on dendritic shaft membranes. Remarkably, Na(v)1.6
labeling was observed at both presynaptic and postsynaptic membranes in the
cortex and cerebellum. Thus, a single sodium channel isoform is targeted to
different neuronal domains and can influence both axonal conduction and synaptic
responses.
PMID- 10779553
TI - Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in
human hepatocarcinomas.
AB - Genomic imprinting is a reversible condition that causes parental-specific
silencing of maternally or paternally inherited genes. Analysis of DNA and RNA
from 52 human hepatocarcinoma samples revealed abnormal imprinting of genes
located at chromosome 11p15 in 51% of 37 informative samples. The most frequently
detected abnormality was gain of imprinting, which led to loss of expression of
genes present on the maternal chromosome. As compared with matched normal liver
tissue, hepatocellular carcinomas showed extinction or significant reduction of
expression of one of the alleles of the CDKN1C, SLC22A1L, and IGF2 genes. Loss of
maternal-specific methylation at the KvDMR1 locus in hepatocarcinoma correlated
with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as
a long-range imprinting center active in adult tissues. These results point to
the role of epigenetic mechanisms leading to loss of expression of imprinted
genes at chromosome region 11p15 in human tumors.
PMID- 10779554
TI - Preservation of myocardial beta-adrenergic receptor signaling delays the
development of heart failure after myocardial infarction.
AB - When the heart fails, there is often a constellation of biochemical alterations
of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of
cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are
mediated through enhanced activity of the betaAR kinase (betaARK1), the
expression of which is increased in ischemic and failing myocardium. These
changes are widely viewed as representing an adaptive mechanism, which protects
the heart against chronic activation. In this study, we demonstrate, using in
vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of
betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs
seen in the failing heart may actually be maladaptive. In a rabbit model of heart
failure induced by myocardial infarction, which recapitulates the biochemical
betaAR abnormalities seen in human heart failure, delivery of the betaARKct
transgene at the time of myocardial infarction prevents the rise in betaARK1
activity and expression and thereby maintains betaAR density and signaling at
normal levels. Rather than leading to deleterious effects, cardiac function is
improved, and the development of heart failure is delayed. These results appear
to challenge the notion that dampening of betaAR signaling in the failing heart
is protective, and they may lead to novel therapeutic strategies to treat heart
disease via inhibition of betaARK1 and preservation of myocardial betaAR
function.
PMID- 10779555
TI - Uncompensated polyuria in a mouse model of Bartter's syndrome.
AB - We have used homologous recombination to disrupt the mouse gene coding for the
NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick
ascending limb and macula densa. This gene is one of several that when mutated
causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria
and electrolyte imbalance. Homozygous NKCC2-/- pups were born in expected numbers
and appeared normal. However, by day 1 they showed signs of extracellular volume
depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By
day 7, they were small and markedly dehydrated and exhibited renal insufficiency,
high plasma potassium, metabolic acidosis, hydronephrosis of varying severity,
and high plasma renin concentrations. None survived to weaning. Treatment of -/-
pups with indomethacin from day 1 prevented growth retardation and 10% treated
for 3 weeks survived, although as adults they exhibited severe polyuria (10
ml/day), extreme hydronephrosis, low plasma potassium, high blood pH,
hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an
inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin
rescued -/- adults except that hydronephrosis was mild. The polyuria,
hypercalciuria, and proteinuria of the -/- adults and furosemide-treated wild
type mice were unresponsive to inhibitors of the renin angiotensin system,
vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes
polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant
animals should be valuable for uncovering new pathophysiologic and therapeutic
aspects of genetic disturbances in water and electrolyte recovery by the kidney.
PMID- 10779556
TI - An autologous oral DNA vaccine protects against murine melanoma.
AB - We demonstrated that peripheral T cell tolerance toward murine melanoma self
antigens gp100 and TRP-2 can be broken by an autologous oral DNA vaccine
containing the murine ubiquitin gene fused to minigenes encoding peptide epitopes
gp100(25-33) and TRP-2(181-188). These epitopes contain dominant anchor residues
for MHC class I antigen alleles H-2D(b) and H-2K(b), respectively. The DNA
vaccine was delivered by oral gavage by using an attenuated strain of Salmonella
typhimurium as carrier. Tumor-protective immunity was mediated by MHC class I
antigen-restricted CD8(+) T cells that secreted T(H)1 cytokine IFN-gamma and
induced tumor rejection and growth suppression after a lethal challenge with
B16G3. 26 murine melanoma cells. Importantly, the protective immunity induced by
this autologous DNA vaccine against murine melanoma cells was at least equal to
that achieved through xenoimmunization with the human gp100(25-33) peptide, which
differs in its three NH(2)-terminal amino acid residues from its murine
counterpart and was previously reported to be clearly superior to an autologous
vaccine in inducing protective immunity. The presence of ubiquitin upstream of
the minigene proved to be essential for achieving this tumor-protective immunity,
suggesting that effective antigen processing and presentation may make it
possible to break peripheral T cell tolerance to a self-antigen. This vaccine
design might prove useful for future rational designs of other recombinant DNA
vaccines targeting tissue differentiation antigens expressed by tumors.
PMID- 10779557
TI - Characterization of PDZ-binding kinase, a mitotic kinase.
AB - hDlg, the human homologue of the Drosophila Discs-large (Dlg) tumor suppressor
protein, is known to interact with the tumor suppressor protein APC and the human
papillomavirus E6 transforming protein. In a two-hybrid screen, we identified a
322-aa serine/threonine kinase that binds to the PDZ2 domain of hDlg. The mRNA
for this PDZ-binding kinase, or PBK, is most abundant in placenta and absent from
adult brain tissue. The protein sequence of PBK has all the characteristic
protein kinase subdomains and a C-terminal PDZ-binding T/SXV motif. In vitro, PBK
binds specifically to PDZ2 of hDlg through its C-terminal T/SXV motif. PBK and
hDlg are phosphorylated at mitosis in HeLa cells, and the mitotic phosphorylation
of PBK is required for its kinase activity. In vitro, cdc2/cyclin B
phosphorylates PBK. This evidence shows how PBK could link hDlg or other PDZ
containing proteins to signal transduction pathways regulating the cell cycle or
cellular proliferation.
PMID- 10779558
TI - The Gcd10p/Gcd14p complex is the essential two-subunit tRNA(1-methyladenosine)
methyltransferase of Saccharomyces cerevisiae.
AB - The modified nucleoside 1-methyladenosine (m(1)A) is found at position 58 in the
TPsiC loop of many eukaryotic tRNAs. The absence of m(1)A from all tRNAs in
Saccharomyces cerevisiae mutants lacking Gcd10p elicits severe defects in
processing and stability of initiator methionine tRNA (tRNA(i)(Met)). Gcd10p is
found in a complex with Gcd14p, which contains conserved motifs for binding S
adenosylmethionine (AdoMet). These facts, plus our demonstration that gcd14Delta
cells lacked m(1)A, strongly suggested that Gcd10p/Gcd14p complex is the yeast
tRNA(m(1)A)methyltransferase [(m(1)A)MTase]. Supporting this prediction, affinity
purified Gcd10p/Gcd14p complexes used AdoMet as a methyl donor to synthesize
m(1)A in either total tRNA or purified tRNA(i)(Met) lacking only this
modification. Kinetic analysis of the purified complex revealed K(M) values for
AdoMet or tRNA(i)(Met) of 5.0 microM and 2.5 nM, respectively. Mutations in the
predicted AdoMet-binding domain destroyed GCD14 function in vivo and (m(1)A)MTase
activity in vitro. Purified Flag-tagged Gcd14p alone had no enzymatic activity
and was severely impaired for tRNA-binding compared with the wild-type complex,
suggesting that Gcd10p is required for tight binding of the tRNA substrate. Our
results provide a demonstration of a two-component tRNA MTase and suggest that
binding of AdoMet and tRNA substrates depends on different subunits of the
complex.
PMID- 10779559
TI - Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus
of the rat.
AB - The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism
of action is unknown. We have demonstrated previously that exogenous and
endogenous IL-1 acts specifically in the rat striatum to dramatically enhance
ischemic and excitotoxic brain damage and cause extensive cortical injury. Here
we tested the hypothesis that this distant effect of IL-1 is mediated through
polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL
1beta injected into the rat striatum with the excitotoxin alpha-amino-3-hydroxy-5
methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1beta
(mRNA and protein) mainly in the cortex where maximum injury occurs. Marked
increases in IL-1beta mRNA and protein were also observed in the hypothalamus. S
AMPA, injected alone into the striatum, caused only localized damage, but
administration of IL-1beta into either the striatum or the lateral hypothalamus
immediately after striatal S-AMPA resulted in widespread cell loss throughout the
ipsilateral cortex. Finally we showed that the cortical cell death produced by
striatal coinjection of S-AMPA and IL-1beta was significantly reduced by
administration of the IL-1 receptor antagonist into the lateral hypothalamus.
These data suggest that IL-1beta can act in the hypothalamus to modify cell
viability in the cortex. We conclude that IL-1-dependent pathways project from
the striatum to the cortex via the hypothalamus and lead to cortical injury, and
that these may contribute to a number of human neurological conditions including
stroke and head trauma.
PMID- 10779560
TI - Nuclear structure in normal and Bloom syndrome cells.
AB - Bloom syndrome (BS) is a rare cancer-predisposing disorder in which the cells of
affected persons have a high frequency of somatic mutation and genomic
instability. BLM, the protein altered in BS, is a RecQ DNA helicase. This report
shows that BLM is found in the nucleus of normal human cells in the nuclear
domain 10 or promyelocytic leukemia nuclear bodies. These structures are punctate
depots of proteins disrupted upon viral infection and in certain human
malignancies. BLM is found primarily in nuclear domain 10 except during S phase
when it colocalizes with the Werner syndrome gene product, WRN, in the nucleolus.
BLM colocalizes with a select subset of telomeres in normal cells and with large
telomeric clusters seen in simian virus 40-transformed normal fibroblasts. During
S phase, BS cells expel micronuclei containing sites of DNA synthesis. BLM is
likely to be part of a DNA surveillance mechanism operating during S phase.
PMID- 10779561
TI - The fourth chromosome of Drosophila melanogaster: interspersed euchromatic and
heterochromatic domains.
AB - The small fourth chromosome of Drosophila melanogaster (3.5% of the genome)
presents a puzzle. Cytological analysis suggests that the bulk of the fourth,
including the portion that appears banded in the polytene chromosomes, is
heterochromatic; the banded region includes blocks of middle repetitious DNA
associated with heterochromatin protein 1 (HP1). However, genetic screens
indicate 50-75 genes in this region, a density similar to that in other
euchromatic portions of the genome. Using a P element containing an hsp70-white
gene and a copy of hsp26 (marked with a fragment of plant DNA designated pt), we
have identified domains that allow for full expression of the white marker (R
domains), and others that induce a variegating phenotype (V domains). In the
former case, the hsp26-pt gene shows an accessibility and heat-shock-inducible
activity similar to that seen in euchromatin, whereas in the latter case,
accessibility and inducible expression are reduced to levels typical of
heterochromatin. Mapping by in situ hybridization and by hybridization of
flanking DNA sequences to a collection of cosmid and bacterial artificial
chromosome clones shows that the R domains (euchromatin-like) and V domains
(heterochromatin-like) are interspersed. Examination of the effect of genetic
modifiers on the variegating transgenes shows some differences among these
domains. The results suggest that heterochromatic and euchromatic domains are
interspersed and closely associated within this 1.2-megabase region of the
genome.
PMID- 10779562
TI - The phylogeny of closely related species as revealed by the genealogy of a
speciation gene, Odysseus.
AB - Molecular differentiation between races or closely related species is often
incongruent with the reproductive divergence of the taxa of interest. Shared
ancient polymorphism and/or introgression during secondary contact may be
responsible for the incongruence. At loci contributing to speciation, these two
complications should be minimized (1, 2); hence, their variation may more
faithfully reflect the history of the species' reproductive differentiation. In
this study, we analyzed DNA polymorphism at the Odysseus (OdsH) locus of hybrid
sterility between Drosophila mauritiana and Drosophila simulans and were able to
verify such a prediction. Interestingly, DNA variation only a short distance away
(1.8 kb) appears not to be influenced by the forces that shape the recent
evolution of the OdsH coding region. This locus thus may represent a test case of
inferring phylogeny of very closely related species.
PMID- 10779563
TI - Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function
and predisposition to inflammation.
AB - We have investigated whether exposure to Gram-negative bacterial endotoxin in
early neonatal life can alter neuroendocrine and immune regulation in adult
animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long
term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated
mean plasma corticosterone concentrations that resulted from increased
corticosterone pulse frequency and pulse amplitude. In addition to this marked
effect on the development of the HPA axis, neonatal endotoxin exposure had long
lasting effects on immune regulation, including increased sensitivity of
lymphocytes to stress-induced suppression of proliferation and a remarkable
protection from adjuvant-induced arthritis. These findings demonstrate a potent
and long-term effect of neonatal exposure to inflammatory stimuli that can
program major changes in the development of both neuroendocrine and immunological
regulatory mechanisms.
PMID- 10779564
TI - Growth of new brainstem connections in adult monkeys with massive sensory loss.
AB - Somatotopic maps in the cortex and the thalamus of adult monkeys and humans
reorganize in response to altered inputs. After loss of the sensory afferents
from the forelimb in monkeys because of transection of the dorsal columns of the
spinal cord, therapeutic amputation of an arm or transection of the dorsal roots
of the peripheral nerves, the deprived portions of the hand and arm
representations in primary somatosensory cortex (area 3b), become responsive to
inputs from the face and any remaining afferents from the arm. Cortical and
subcortical mechanisms that underlie this reorganization are uncertain and appear
to be manifold. Here we show that the face afferents from the trigeminal nucleus
of the brainstem sprout and grow into the cuneate nucleus in adult monkeys after
lesions of the dorsal columns of the spinal cord or therapeutic amputation of an
arm. This growth may underlie the large-scale expansion of the face
representation into the hand region of somatosensory cortex that follows such
deafferentations.
PMID- 10779566
TI - 5-methylcytosine-DNA glycosylase activity is present in a cloned G/T mismatch DNA
glycosylase associated with the chicken embryo DNA demethylation complex.
AB - We previously have shown that DNA demethylation by chicken embryo 5
methylcytosine DNA glycosylase (5-MCDG) needs both RNA and proteins. One of these
proteins is a RNA helicase. Further peptides were sequenced, and three of them
are identical to the mammalian G/T mismatch DNA glycosylase. A 3,233-bp cDNA
coding for the chicken homologue of human G/T mismatch DNA glycosylase was
isolated and sequenced. The derived amino acid sequence (408 aa) shows 80%
identity with the human G/T mismatch DNA glycosylase, and both the C and N
terminal parts have about 50% identity. As for the highly purified chicken embryo
DNA demethylation complex the recombinant protein expressed in Escherichia coli
has both G/T mismatch and 5-MCDG activities. The recombinant protein has the same
substrate specificity as the chicken embryo 5-MCDG where hemimethylated DNA is a
better substrate than symmetrically methylated CpGs. The activity ratio of G/T
mismatch and 5-MCDG is about 30:1 for the recombinant protein expressed in E.
coli and 3:1 for the purified enzyme from chicken embryos. The incubation of a
recombinant CpG-rich RNA isolated from the purified DNA demethylation complex
with the recombinant enzyme strongly inhibits G/T mismatch glycosylase while
slightly stimulating the activity of 5-MCDG. Deletion mutations indicate that G/T
mismatch and 5-MCDG activities share the same areas of the N- and C-terminal
parts of the protein. In reconstitution experiments RNA helicase in the presence
of recombinant RNA and ATP potentiates the activity of 5-MCDG.
PMID- 10779567
TI - National security and scientific communication.
PMID- 10779568
TI - Purification and characterisation of a novel cysteine conjugate beta-lyase from
the tapeworm Moniezia expansa.
AB - The paper presents the first report of the purification of an invertebrate
cysteine conjugate beta-lyase (CCBL). CCBL activity was shown to predominate
within the cytosolic fraction of tissue from the tapeworm Moniezia expansa. The
monomeric cytosolic enzyme was isolated with a M(r) of 72 kDa and co-purified
with transaminase activity towards L-aspartate. The substrate profile for M.
expansa CCBL is different from that of mammalian CCBLs. Exploiting the
differences in mammalian and parasite substrate profiles will facilitate the
development of helminth targeted conjugates which will not be activated by host
(mammalian) CCBLs.
PMID- 10779565
TI - A binding pocket for a small molecule inhibitor of HIV-1 entry within the
transmembrane helices of CCR5.
AB - HIV-1 entry into CD4(+) cells requires the sequential interactions of the viral
envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors
CCR5 and CXCR4. A plausible approach to blocking this process is to use small
molecule antagonists of coreceptor function. One such inhibitor has been
described for CCR5: the TAK-779 molecule. To facilitate the further development
of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to
prevent HIV-1 infection, and we have mapped its site of interaction with CCR5. We
find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by
blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We
could identify no amino acid substitutions within the extracellular domain of
CCR5 that affected the antiviral action of TAK-779. However, alanine scanning
mutagenesis of the transmembrane domains revealed that the binding site for TAK
779 on CCR5 is located near the extracellular surface of the receptor, within a
cavity formed between transmembrane helices 1, 2, 3, and 7.
PMID- 10779569
TI - Allopatric combination of Fasciola hepatica and Lymnaea truncatula is more
efficient than sympatric ones.
AB - Parasites are capable of rapid evolutionary changes relative to their hosts, due
to short life cycle, short generation time, and high fecundity. The direction of
the evolution of parasite virulence can be studied in cross-transfer experiments,
combining hosts and parasites from different localities, and comparing the
outcome of established (sympatric and potentially locally adapted) and novel
(allopatric) combinations of hosts and parasites. We aimed to compare the
compatibility with snails hosts, the infectivity of metacercariae in rabbits and
rats, and the fitness among different combinations (French-FF and Spanish-SS
sympatries and allopatry-FS). The first isolate of Fasciola hepatica and its
corresponding intermediate host, Lymnaea truncatula originated from Lugo's
northwestern Spain. The second isolate of parasite and snail was collected in the
Limoges area in central France. The Spanish snails were more susceptible to their
sympatric trematode than the French snails. The Spanish flukes were more
infective to intermediate hosts (snails) than the French flukes, but subsequent
definitive hosts (rats or rabbits) infections remained similar. The estimated
fitness was low in sympatric infections and highly similar (from 4.7 to 5.3). The
fitness similarity corresponds, however, to different variations in life-history
traits that could represent different strategies among the host-parasite local
combinations. The infection rate in snails, metacercarial productivity,
metacercarial infectivity, and the estimated fitness were better for allopatric
combination (FS). The susceptibility data showed a higher efficiency of flukes in
the allopatric snail population than in their local snail population. However,
our results were obtained after one generation and from a single isolate and it
remains to be determined if all allopatric fluke-snail isolates may present a
better fitness. Nevertheless our results indicate that introduction of liver
fluke-infected cattle should be monitored carefully, as it could result in the
introduction of more efficient parasites.
PMID- 10779570
TI - Oceanic barriers as indicated by scombrid fishes and their parasites.
AB - Four genera of scombrid fishes (26 species) and their copepod (32 species) and
monogenean ectoparasites (25 species) were used to test the hypothesis that the
East Pacific Barrier is responsible for the most pronounced break in the circum
tropical warm water fauna of the continental shelves, and not the New World
Barrier. Analysis at the species level showed that there is a primary centre of
diversity in the West Pacific, and a secondary centre in the West Atlantic. The
former, almost entirely, shares its species of the largely coastal Scomberomorus
and Grammatorcynus and their parasites with seas located to the west. Only four
parasites (all copepods) are shared by the East and West Pacific, and they are
circum-tropical. In contrast, the West Pacific shares species of the more pelagic
Scomber and their parasites with seas both to the east and west, although at the
genus level, only two circum-tropical monogenean genera are shared by the E and W
Pacific. We conclude that the East Pacific Barrier has been a 100% or almost 100%
effective barrier to dispersal of species of Scomberomorus, Grammatorcynus and
their parasites, whereas for species of Scomber and their parasites, the East
Pacific has been a less effective barrier.
PMID- 10779571
TI - Purification and properties of an acid phosphatase from Entamoeba histolytica HM
1:IMSS.
AB - Entamoeba histolytica contains and secretes acid phosphatase, which has been
proposed as a virulence factor in some pathogenic microorganisms. In this work,
we purified and characterised a membrane-bound acid phosphatase (MAP) from E.
histolytica HM-1:IMSS and studied the effect of different chemical compounds on
the secreted acid phosphatase and MAP activities. MAP purification was
accomplished by detergent solubilisation, and affinity and ion exchange
chromatographies. The enzyme showed a pI of 5.5-6.2, an optimum pH of 5.5, and a
Km value of 1.14 mM with p-nitrophenyl phosphate.
PMID- 10779572
TI - Trypanosoma cruzi: parasitaemia produced in mice does not seem to be related to
in vitro parasite-cell interaction.
AB - The interaction of Trypanosoma cruzi strains producing subpatent or high
parasitaemia in mice with mouse macrophages, Vero and L929 cells was evaluated
using tissue culture trypomastigotes. Macrophages were the cells most readily
infected while Vero cells presented the highest parasite intracellular
multiplication rates. Subpatent strains were equal or more infective than the
high parasitaemia. Due to the small number of strains, no correlation could be
established between the zymodemes and parasitaemia or parasite-cell interaction
in vitro. However parasitaemia in mice does not seem to be related to in vitro
parasite-cell interaction.
PMID- 10779573
TI - Identification of a 30 kDa antigen from leishmania (L.) chagasi amastigotes
implicated in protective cellular reponses in a murine model.
AB - An antigen of apparent molecular mass of 30 kDa, termed p30, was purified from
Leishmania (L.) chagasi amastigotes after separation of parasite extracts by
sodium dodecyl sulfate-polyacrylamide gel eletroctrophoresis followed by
electroelution. The use of the purified antigen in lymphocyte cultures from
BALB/c mice previously immunised with L. (L.) chagasi amastigotes led to high
levels of proliferation. Animal immunisation with p30 plus complete Freund's
adjuvant either by subcutaneous or intraperitoneal route led to comparable
antigenic stimulation. Similar stimulation indices induced by p30 were also
obtained when animals were immunised with Corynebacterium parvum as adjuvant by
the intraperitoneal route. Detection of IL-2 and IFN-gamma in the supernatants
from lymphocytes stimulated by p30 and inhibition of the production of these
lymphokines in the presence of anti-CD4 strongly indicated the involvement of the
Th1 subset in the responses elicited by p30 antigen. Immunisation of BALB/c mice
with p30 provided partial protection against challenge with L. (L.) chagasi
amastigotes, indicating a protective role for p30 and that Th1 can be related to
accquired resistance to visceral leishmaniasis in a murine model. Further
characterisation studies were performed by the use of a monoclonal antibody
directed to a cysteine proteinase of 30 kDa from L. (L.) amazonensis amastigotes.
Despite the cross-reactivity presented by p30 from both Leishmania species, the
p30 from L. (L.) chagasi amastigotes lacks proteolytic activity.
PMID- 10779574
TI - Isolation of antigen from the circulating immune complex in mice infected with
Plasmodium berghei.
AB - Circulating immune complex (CIC) is known to play a role in pathological
glomerular alterations in malaria. However, the nature of the antigens comprising
the CIC is still not fully understood. We report here the isolation of the
antigen in CIC and its localisation in mice infected with Plasmodium berghei
NK65. The antigen was successfully isolated from CIC extracted from the blood of
mice infected with P. berghei, by using C1q-coated microplates. The molecular
mass of the antigen separated from CIC bound to C1q was found to be 78 kDa.
Furthermore, localisation of the antigen was examined by the fluorescent antibody
technique and immunoelectron microscopy. The antigen was detected in the
parasitised erythrocyte and the mesangial matrix by both methods. These results
suggest that the 78 kDa protein might be associated with the glomerular
alterations in malaria infection.
PMID- 10779575
TI - Biological characterisation of Sarcocystis neurona isolated from a Southern sea
otter (Enhydra lutris nereis).
AB - Sarcocystis neurona was isolated from the brain of a juvenile, male southern sea
otter (Enhydra lutris nereis) suffering from CNS disease. Schizonts and
merozoites in tissue sections of the otter's brain reacted with anti-S. neurona
antiserum immunohistochemically. Development in cell culture was by endopolyogeny
and mature schizonts were first observed at 3 days postinoculation. PCR of
merozoite DNA using primer pairs JNB33/JNB54 and restriction enzyme digestion of
the 1100 bp product with Dra I indicated the organism was S. neurona. Four of
four interferon-gamma gene knockout mice inoculated with merozoites developed S.
neurona-associated encephalitis. Antibodies to S. neurona but not Sarcocystis
falcatula, Toxoplasma gondii, or Neospora caninum were present in the serum of
inoculated mice. This is the first isolation of S. neurona from the brain of a
non-equine host.
PMID- 10779576
TI - Induction cues for tegument formation during the transformation of Schistosoma
mansoni cercariae.
AB - Adult schistosomes are parasitic blood flukes that have a continuous double lipid
bilayered membrane surrounding the entire worm. This tegumental membrane is
synthesised during invasion of the vertebrate host by free-swimming infectious
forms called cercariae. As cercariae invade their final hosts they lose their
tails and encounter a changing environment that includes altered temperature,
sugar concentration and osmolarity. We have identified a glucose transporter
protein designated SGTP4 that is found exclusively in the outer adult tegument
and on membranous vesicles within the tegumental cytoplasm. By using
immunofluorescence analysis to monitor the appearance and distribution of SGTP4
we can track the process of new tegumental membrane formation and examine the
cues that trigger this developmental pathway. Cercariae in water do not transform
their tegument while those incubated in rich medium do so rapidly. We have
examined which of the many constituents of rich medium are responsible for
triggering this transformation. Incubation in a solution of moderate osmolarity
(120 mOsM PBS) is sufficient by itself to trigger tegument transformation, albeit
at a slower rate relative to incubation in rich medium. Adding either glucose (to
100 mM) to the solution or increasing the temperature of incubation (from 22
degrees C to 37 degrees C) further increased the rate of tegument biogenesis. The
introduction of glucose together with an increase in the incubation temperature
further accelerated the process, suggesting that these factors act
synergistically to promote transformation rates. The critical nature of
osmolarity in inducing the process is highlighted by the fact that transformation
proceeds as efficiently in 360 mOsM alone as it does in rich medium. While the
fatty acids linolenic acid (cis-9, cis-12, cis-15-octadecatrienoic acid at 1 mM)
and capric acid (Decanoic acid, at 0.1 mM) have both been proposed to stimulate
tegumental transformation, we show that neither promotes the morphogenesis of a
normal schistosomulum tegument. The schistosomicide praziquantel (to 1 mM) has no
detectable effect on new tegument formation.
PMID- 10779577
TI - Detection of Babesia caballi infection by enzyme-linked immunosorbent assay using
recombinant 48-kDa merozoite rhoptry protein.
AB - The 48-kDa Babesia caballi merozoite rhoptry protein was expressed using a pGEX4T
expression vector in Escherichia coli as glutathione S-transferase fusion protein
(GST-BC48), and the expressed GST-BC48 was used in an ELISA to detect specific
antibodies in serum samples. No cross-reaction was observed with sera from horses
experimentally infected with Babesia equi. GST-BC48 ELISA was a highly sensitive
and specific test when compared with the CFT. A total of 209 horse sera obtained
from Central Mongolia were examined with the GST-BC48 ELISA and 46.4% (97/209)
were found to be seropositive for B. caballi, suggesting that the GST-BC48 ELISA
can be successfully used for both quarantine and epidemiological studies.
PMID- 10779578
TI - Molecular typing of Toxoplasma gondii strains by GRA6 gene sequence analysis.
AB - The utility of sequence polymorphisms in the dense granule antigen GRA6 gene as
typing markers for Toxoplasma gondii was investigated. The coding region of GRA6
was amplified, sequenced and compared for 30 Toxoplasma strains from eight
different zymodemes (Z1-Z8). Sequence alignment identified nucleotide
polymorphisms at 24 positions out of 690 bp, which correlated with murine
virulence. Types I, II, and III could be distinguished from each other on the
basis of three, 10, and six variable positions, respectively. Two deletions of 15
bp and 3 bp existed in the avirulent (type II) strains. With one exception, all
polymorphic positions resulted in amino acid substitutions, and the two gaps of
15 bp and 3 bp caused the deletion of six amino acids in type II strains. Intra
specific polymorphisms were also found in the virulent group. A high degree of
sequence polymorphism correlating with the phenotypes of T. gondii strains points
to the GRA6 gene being a good marker for strain characterisation and typing of
the isolates of this apicomplexan. The large variety of amino acid changes
supports the view that the GRA6 protein plays an important role in the
antigenicity and pathogenicity of T. gondii. The existence of polymorphic
restriction sites for endonuclease MseI was used to develop a PCR-RFLP method
which could simply differentiate the three different groups (types I, II, III) of
T. gondii.
PMID- 10779579
TI - Transcriptional and post-transcriptional in organello labelling of Trypanosoma
brucei mitochondrial RNA.
AB - In organello labelling of Trypanosoma brucei mitochondrial (mt) RNA was
characterised with respect to nucleotide requirements and drug sensitivity.
Mitochondrial transcriptional activity is maximal in the presence of all
ribonucleoside-triphosphate NTPs, and can be inhibited by UTP depletion.
Mitochondrial transcription can also be partially inhibited by actinomycin D
(actD) or ethidium bromide (EtBr). Post-transcriptional UTP incorporation is
insensitive to actinomycin D or ethidium bromide. Proteins were identified that
interact with transcriptional and post-transcriptionally labelled RNAs, and
confirm the in vitro RNA-binding properties discovered for a number of T. brucei
mt proteins. These experiments reveal new strategies for studying mt
transcription and processing in T. brucei mitochondria.
PMID- 10779580
TI - Optimisation of flow cytometric measurement of parasitaemia in plasmodium
infected mice.
AB - Mouse malaria is often used as a model for drug testing. The results of drug
trials are monitored by tedious (and consequently, sometimes inaccurate)
microscopic counting of blood smears, or by flow cytometry. We suggest an
improved, accurate and time-saving flow cytometric method for determination of
parasitaemias in mice infected with Plasmodium vinckei petteri or Plasmodium
berghei. The method involves collection of drops of blood from the tail vein,
fixation, storage, permeabilisation, staining and analysis with a visible range
flow cytometer. Three nucleic acid dyes, YOYO-1, propidium iodide and acridine
orange were compared. YOYO-1 was found to be the best stain for the
discrimination of parasitised erythrocytes from non-infected ones. A good direct
correlation was obtained between parasitaemia determined by conventional
microscopy and parasitaemia measured by flow cytometry. Drug effects could be
assessed by the cytometric method. For the detection of low level of parasitemia,
parasitised cells were treated with RNAse to completely cancel RNA-derived
signals originating from host reticulocytes. This procedure also revealed
discrete peaks arising from red cells infected with multiple parasites or from
parasites with different numbers of nuclei.
PMID- 10779581
TI - DNA evidence that Ostertagia gruehneri and Ostertagia arctica (Nematoda:
ostertagiinae) in reindeer from Norway and Svalbard are conspecific.
AB - DNA sequences of ITS-1 and ITS-2 of rDNA were determined for 16 individual adult
males each of Ostertagia gruehneri and Ostertagia arctica from Svalbard reindeer
(Rangifer tarandus platyrhynchus) and Eurasian tundra reindeer (R. t. tarandus).
Each ITS was virtually identical in O. gruehneri and O. arctica and the three
mixed bases detected were shared by both species. Our results strongly suggest
that O. gruehneri and O. arctica are dimorphic males of the same species.
PMID- 10779582
TI - Phylogenetic position of the monogeneans Sundanonchus, Thaparocleidus, and
Cichlidogyrus inferred from 28S rDNA sequences.
AB - A molecular phylogeny was inferred from newly obtained partial 28S rRNA gene
sequences of Sundanonchus micropeltis (Sundanonchidae), Thaparocleidus siamensis
and Cichlidogyrus sp. (Ancyrocephalidae), and other already available sequences.
Although sequences are lacking for several families, the following phylogenetic
relationships could be inferred. The Diplectanidae were the sister-group to a
clade including Sundanonchus and the Ancyrocephalidae; Sundanonchus was the
sister-group to the Ancyrocephalidae, therefore suggesting validity of the
Sundanonchidae, which include this single genus; within the Ancyrocephalidae,
Thaparocleidus (Ancylodiscoidinae) was the sister-group to the four other taxa,
though with relatively low support, suggesting that the Ancylodiscoidinae are the
sister-group to the Ancyrocephalinae.
PMID- 10779583
TI - Molecular investigation of African isolates of Trichinella reveals genetic
polymorphism in Trichinella nelsoni.
AB - Molecular genetic studies were carried out on three isolates of Trichinella
nelsoni (from Kenya, Tanzania and South Africa) and three isolates of Trichinella
T8 (from South Africa and Namibia) from sylvatic carnivores and from a sylvatic
swine. A probe (pT7.3) specific for T. nelsoni was obtained by screening a pUC18
genomic library. The pT7.3 sequence was 346 bp in length with an AT content of
70%. The sequence is present approximately 200 times per haploid genome. Southern
blot analysis of Hind III digested DNAs of the three isolates of T. nelsoni
revealed that the hybridisation patterns of the isolates from Kenya and Tanzania
were identical and that they differed from that of the isolate from South Africa,
indicating the presence of polymorphism in this species. A pUC18 genomic library
of Trichinella T8 was also screened, and one clone (pT8.3) was found to be
specific for homologous DNA by dot blot, but Southern blot analysis of DNA
samples from eight genotypes showed different hybridisation signals for both
Trichinella T8 and Trichinella britovi DNAs. No differences in the nucleotide
sequences of the expansion segment V were observed for the T. nelsoni isolates.
However, they differed from those of Trichinella T8. The presence of Trichinella
T8 in Africa south of the Sahara and its genetic relationship with T. britovi
remain unclear and warrant detailed investigations.
PMID- 10779584
TI - Parasites and host life-history traits: implications for community ecology and
species co-existence.
AB - Most of the evidence for a key role of parasites in structuring communities is
based on the idea of a differential susceptibility of host species to infection
and its consequences. Recent advances in community ecology suggest that life
history traits of free-living species can be an important determinant of their co
existence within communities. On the other hand, parasites have the potential to
indirectly alter the life-history traits of their hosts, such as developmental
time or dispersal. We discuss the idea that these indirect effects could
influence the structure of free-living and parasite communities. We explore this
idea in relation to related concepts including 'parasitic arbitration' and
engineering processes.
PMID- 10779586
TI - The short forms of HLA-G are unlikely to play a role in pregnancy because they
are not expressed at the cell surface.
AB - HLA-G is a nonclassical class I MHC molecule of unknown function expressed on
human invasive trophoblast. In trophoblast cells, HLA-G mRNA is alternatively
spliced into a variety of forms which are predicted to encode a full length
membrane-bound form, three short membrane-bound isoforms and two soluble
isoforms. The aim of this study was to determine which of these protein isoforms
are translated, which are expressed on the cell surface and which are secreted.
Artificial cDNAs encoding the isoforms were generated by PCR mutagenesis, ligated
to an epitope tag and transfected into a human cell line capable of expressing
MHC class I. Protein products of appropriate sizes were detected in cells
transfected with cDNAs encoding all membrane-bound forms, but surface
biotinylation studies indicated that only full length membrane-bound HLA-G was
present at the cell surface. Full length HLA-G was also detected by surface
antibody binding and flow cytometry. Soluble HLA-G1 was detected in cells
transfected with the appropriate cDNA only after treatment with monensin, which
inhibits transport of glycoproteins through the Golgi apparatus. These results
suggest that full length HLA-G, but not short HLA-G isoforms can be expressed on
the surface of human cells and that soluble HLA-G is rapidly secreted. Thus, it
is likely that the full length membrane-bound and soluble forms of HLA-G are the
only biologically active forms to which the mother is exposed.
PMID- 10779587
TI - Hypothalamo-pituitary control of the cell-mediated immunity in rat embryos: role
of LHRH in regulation of lymphocyte proliferation.
AB - The role of the neuroendocrine system in the development of cell-mediated
immunity has been studied in fetal rats. The spontaneous and mitogen-induced
proliferation of liver lymphocytes and thymocytes was evaluated in vitro in rats
at the 22nd prenatal day following surgical ablation of the forebrain
(encephalectomy) or of the entire brain and pituitary (decapitation) in rat
fetuses in utero at the 18th day. Non-operated and sham-operated fetuses served
as controls. The ablation of the entire brain and pituitary in rat fetuses
resulted in an increase (40-60%) of spontaneous proliferation of liver and thymic
cells in comparison with sham-operated fetuses. The ablation of the forebrain
including the hypothalamus caused a decrease in the mitogenic proliferative
response of thymocytes and liver lymphocytes for 40 and 20%, respectively. The
ablation of the entire brain including the hypothalamus and pituitary resulted in
a 80% decrease of the proliferative response of thymocytes and in the full
suppression of proliferation of liver lymphocytes. The immune proliferative
response was restored by the LHRH administration either systemically to operated
fetuses (0.2 microg/fetus) or to the cell culture (10(-9) and 10(-7) M). It was
concluded that the central nervous system was important for maturation of the
immune system in rats during the prenatal period. In particular, neuroendocrine
system are likely to play a major role as LHRH treatment in vitro and in vivo
appeared to contribute to this regulation.
PMID- 10779588
TI - Inhibitory effects of human seminal plasma on an ELISA used to detect anti-sperm
antibodies: implications for the determination of sperm quality.
AB - The in vitro inhibitory effect of human seminal plasma on an ELISA used to detect
anti-sperm antibodies have been observed. The mean inhibition rate of seminal
plasma samples from 75 men was 61.5+/-23.1%. The inhibition rate of 29 samples
from normal sperm group was 71. 14+/-18.25%, while that of 46 samples from the
abnormal sperm group was 55.43+/-23.98%. The results show that human seminal
plasma from semen with high quality sperms possesses a high inhibitory rate to
anti-sperm antibody reactions, suggesting its efficiency for immunosuppression of
humoral immune reactions. Its possible implications are discussed.
PMID- 10779589
TI - A null mutation in HLA-G is not associated with preeclampsia or intrauterine
growth retardation.
AB - Modulation of the expression of genes of the major histocompatibility complex
(MHC) in tissues at the maternal-fetal interface almost certainly plays a role in
successful development of the semi-allogeneic fetus. While expression of the
classical class I genes (HLA-A, B, C) is low to non-existent at this site, the
non-classical molecule, HLA-G, is expressed uniquely in fetal cells at the
maternal-fetal interface. The recent demonstration that homozygotes for a
deletion mutation in exon 3 (1597DeltaC) of HLA-G do not express the full-length
HLA-G1 isoforms indicates a potential reduction in expression of this isoform in
heterozygotes. If the full-length isoform of HLA-G (i.e. HLA-G1) contributes to
proper invasion of maternal spiral arteries by extravillous cytotrophoblast, then
1597DeltaC heterozygotes could be at increased risk for disorders of trophoblast
invasion. Two populations, infants with intrauterine growth retardation (IUGR)
and infants of preeclamptic (PE) mothers, were genotyped for the 1597DeltaC
polymorphism. The frequency of 1597DeltaC in these samples was not significantly
different from healthy controls, suggesting that heterozygotes for this deletion
mutation are not at significantly increased risk for PE or IUGR (P = 0.727 and
0.803, respectively).
PMID- 10779590
TI - Tumor necrosis factor-alpha soluble receptor p55 (sTNFp55) and risk of
preeclampsia in Peruvian women.
AB - We conducted a large case-control study to assess the risk of preeclampsia with
elevated sTNFp55 concentrations (markers of excessive TNF-alpha release) in
Peruvian women. A total of 125 women with preeclampsia and 179 normotensive women
were included in a study conducted during the period, June 1997 through January
1998. Antepartum (third-trimester) plasma sTNFp55 was measured by enzyme linked
immunosorbent assay. Mean plasma sTNFp55 concentrations were 32.4% higher among
preeclampsia cases (920.1+/-30.4 pg/ml) as compared with controls (694.8+/-15.0
pg/ml, Student's t-test P<0.001). There was a strong linear increase in risk of
preeclampsia with increasing concentrations of sTNFp55 (linear trend P-value <0.
001). After adjusting for confounding factors, women in the highest quartile
experienced a 10-fold increased risk of preeclampsia as compared with women in
the lowest quartile (adjusted odds ratio, 10.3; 95% confidence interval, 4.1
25.9). Compared with women in the highest quartile, women in the second and third
quartiles experienced a 3-fold or greater increased risk of preeclampsia
(adjusted odds ratios were 3.1 and 3.8, respectively). Excessive TNF-alpha
release (as measured by the detection of the soluble receptor sTNFp55 in maternal
plasma collected before delivery) is increased in pregnancies complicated by
preeclampsia as compared with normotensive pregnancies. These findings are
consistent with most previous studies.
PMID- 10779591
TI - IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during
labour and complicated pregnancies.
AB - Serum interleukin-18 (IL-18) levels were measured in women in different
trimesters of pregnancy, in labour, puerperium and in various complicated
pregnancies. There was a significant elevation of IL-18 levels in pregnant sera
from the first trimester until the onset of labour. Once labour began, IL-18
levels increased further and remained until at least the third day of puerperium.
The high levels of IL-18 in sera were also observed in various complicated
pregnancies, such as premature rupture of membranes (PROM), acute fatty liver of
pregnancy and fetal growth restriction. IL-18 is likely to play a role in
pregnancy.
PMID- 10779592
TI - Characterization of domains of the phosphoriboprotein P0 of Plasmodium
falciparum.
AB - Antibodies against the amino-terminal domain of the Plasmodium falciparum P0
phosphoriboprotein were detected extensively in immune people living in malaria
endemic areas of India. It has been shown earlier that specific antibodies raised
against the PfP0N domain (17-61 amino acid) of the PfP0 protein inhibit P.
falciparum growth in vitro. To study the properties of the rest of the protein,
the remaining 61-316 amino acids on the carboxy-side of the PfP0 protein were
expressed as a glutathione-S-transferase fusion protein (PfP0C). Antibodies
raised against PfP0C identified the 38 kDa P0 protein on a parasite Western blot
analysis. An ELISA assay using both the PfP0N and PfP0C fusion proteins showed no
reactivity with malaria patient sera samples, but showed extensive reactions with
the immune sera. Antibodies against both the PfP0C and PfP0N domains were raised
in rabbits and different inbred strains of mice. T-cells from immunized mice
showed lymphoproliferation when presented with PfP0 protein domains. IgG from
both anti-PfP0N and anti-PfP0C sera inhibited the growth of P. falciparum in
vitro in a concentration dependent manner. The IgG did not show any significant
effect on the growth of intraerythrocytic stages, but specifically inhibited re
invasion of red cells. Merozoites and sexual stages showed surface reactivity to
both anti-PfP0N and anti-PfP0C antibodies in immunofluorescence assays. These
properties strongly indicate PfP0 as a possible target for invasion-blocking
antibodies.
PMID- 10779594
TI - Deletion of the parasite-specific insertions and mutation of the catalytic triad
in glutathione reductase from chloroquine-sensitive Plasmodium falciparum 3D7.
AB - The flavoenzyme glutathione reductase (GR; NADPH+glutathione disulphide+H(+)-
>NADP(+)+2 glutathione-SH) of Plasmodium falciparum is a promising drug target
against tropical malaria. As P. falciparum genes are assumed to be highly
polymorphic we have cloned and expressed the GR cDNA of the chloroquine-sensitive
strain 3D7. In comparison to the known GR of the chloroquine-resistant K1 strain
there are three base exchanges all of them leading to amino acid substitutions
(residues 281, 285 and 335). The catalytic efficiency k(cat)/K(m) of the 3D7
enzyme is 5-fold lower than for the K1 enzyme. In contrast, vis-a-vis the drugs
carmustine, methylene blue and fluorophenyliso-alloxazine the two enzyme species
exhibited identical inhibition kinetics. Two structural motifs which are specific
for P. falciparum GR were studied by mutational deletion analysis of 3D7 GR. Loop
126-138 appears to be important for folding and stability of the enzyme, whereas
the subdomain 318-350 was found to be involved in FAD-binding. The subdomain has
no major influence on the known functions of the catalytic triad Cys-40, Cys-45
and His-485'. Flavin absorption spectroscopy of inactive point mutants showed
that Cys-45 forms a thiolate charge transfer complex and Cys-40 is the
interchange thiol, which reduces glutathione disulphide. The mutant His-485-->Gln
had a normal K(m) for glutathione disulphide reduction but only 0.8% residual
catalytic activity when compared with wild-type GR, which confirms its function
as an acid/base catalyst. The parasite-specific domains in combination with the
reactive catalytic residues appear to be a suitable target matrix for inhibiting
GR in vivo.
PMID- 10779593
TI - Characterization of the heat-shock protein 60 chaperonin from Onchocerca
volvulus.
AB - Chaperonin 60 (cpn60) belongs to the group of ubiquitous molecular chaperones
that comprise the heat shock proteins, nucleoplasmins and chaperonins. Antibodies
to recombinant CPN60 from humans was used to screen a cDNA library of Onchocerca
volvulus and antigen-positive clones were selected. Sequencing of the DNA inserts
confirmed their identity as cpn60 transcripts. These are distinct from a cpn60
sequence recorded previously from O. volvulus (GenBank accession number Y09416)
that appears to be of endobacterial origin, rather than derived from the parasite
itself. The full-length sequence of the cDNA (designated Ov-cpn60) codes for a
protein of 64.3kDa (598 amino acid residues) and shares significant identity with
homologous gene products from Caenorhabditis elegans (72%), humans (69%), yeast
(53%) and Escherichia coli (50%). The endobacterial and parasite sequences are
41% conserved. Ov-CPN60 migrates with an apparent molecular mass of 65kDa on SDS
PAGE and is present in all life-cycle stages, as determined by immunoblotting
with rabbit antibodies raised against the recombinant protein. Immunogold
electron microscopy identified the protein within mitochondria, as expected, but
also in extra-mitochondrial sites, including inclusion bodies of the glandular
oesophagus (in infective larvae), the uterine wall, cytosol of developing
spermatids, and the hypodermis and cuticle. Endobacteria were also labelled,
indicating cross-reactivity between CPN60 from the parasite and its intracellular
symbiont. In human infections, serum antibodies to Ov-CPN60 were present in only
11% of cases from Ecuador, but in 81-89% of subjects in three separate foci from
West Africa. There was no relationship between antibody levels and age, sex, or
infection intensity, and no consistent association between the serological
response and immune status. An evaluation of antibody specificities in individual
sera revealed a mixture of parasite-specific and host crossreactive anti-CPN60
antibodies, the ratio of which varied amongst geographic areas. It is concluded
that antibody responses to Ov-CPN60 are unlikely to contribute either to host
protection or pathology in onchocerciasis.
PMID- 10779595
TI - Identification of mariner-like elements from the root-knot nematode Meloidogyne
spp.
AB - The Meloidogyne species are agriculturally important pests widespread in the
world. These polyphagous endoparasitic nematodes possess an astonishing ability
to bypass the plant resistance genes in few generations. However, the genes and
mechanisms involved in this molecular determinism are not yet known. Except
cytogenetic and cytotaxonomic studies, few data are available concerning their
genome. There is therefore an important need of molecular tools for genetic
investigation of their virulence character and other aspects of host-pathogen
interactions. In that respect, the presence of mariner-like-elements (MLEs) was
assessed in these endoparasitic nematodes by a polymerase chain reaction (PCR)
assay using degenerate primers designed from two conserved regions of the mariner
transposase open reading frame (ORF). Four Meloidogyne species of the five tested
revealed the presence of MLEs in their genome. Southern blot analysis indicated
that sequences hybridizing to the mariner transposase-like PCR clones occur at a
moderate to low copy number in the different Meloidogyne spp. genomes. The
phylogenetic analysis show that the Meloidogyne MLEs may form new subfamilies of
mariner. Moreover, five PCR clones were shown to possess a continuous ORF
suggesting the presence of putative transposase-like coding regions.
PMID- 10779596
TI - Succinate dehydrogenase in Plasmodium falciparum mitochondria: molecular
characterization of the SDHA and SDHB genes for the catalytic subunits, the
flavoprotein (Fp) and iron-sulfur (Ip) subunits.
AB - Mitochondria of malaria parasites generate a membrane potential through an
electron transport system that is a possible target of primaquine and a new anti
malarial drug, atovaquone. However, little information is available for
conclusive understanding of the respiratory chain in Plasmodium mitochondria. In
the present study, we cloned and characterized from Plasmodium falciparum the
genes for the catalytic subunits, SDHA for the flavoprotein (Fp) and SDHB for
iron-sulfur protein (Ip), of succinate-ubiquinone oxidoreductase (complex II),
which is a marker enzyme for mitochondria and links the TCA cycle and respiratory
chain directly. Each of the two genes contains a single open reading frame (ORF),
which are located on different chromosomes, 1860 nucleotides on chromosome 10 for
SDHA and 963 nucleotides on chromosome 12 for SDHB. The expression of these genes
in asynchronous erythrocytic stage cells was confirmed by observation of 3.3 and
2.4 kb transcripts from the SDHA and SDHB genes, respectively. The SDHA and SDHB
genes encode proteins of 620 (Fp) and 321 (Ip) amino acids with molecular masses
of 69.2 and 37.8 kDa, respectively. A mitochondrial presequence essential for the
import of mitochondrial proteins encoded by nuclear DNA, as well as almost all
the conserved amino acids indispensable for substrate binding and the catalytic
reaction were found in these peptides, indicating the functional importance of
this enzyme in the parasite. Interestingly, a P. falciparum-specific insertion
and a unicellular organism-specific deletion were found in the amino acid
sequence of Fp. This is the first report of the primary structure of the
protozoan succinate dehydrogenase.
PMID- 10779597
TI - Larvae-induced plasma membrane wounds and glycoprotein deposition are
insufficient for Trichinella spiralis invasion of epithelial cells.
AB - Trichinella spiralis L1 larvae infect susceptible hosts by invading epithelial
cells that line the small intestine. Invasion also occurs in vitro when larvae
are inoculated into cultures of epithelial cells from several different animal
species. To further investigate the mechanism of invasion, we studied the
interaction of larvae with the rat epithelial cell line IEC-6. Larvae did not
invade IEC-6 cells, but did cause the cells to take up parasite glycoproteins.
Glycoprotein bearing cells remained viable and were detectable in monolayers for
as long as 24 h, suggesting that the glycoproteins were not toxic for cells.
Immunofluorescence revealed that parasite glycoproteins localized in the nuclei,
mitochondria and cytoplasm and we found evidence for selection of certain
molecules between nuclear and cytoplasmic compartments. Using fluorescent
dextrans as fluid phase markers we found 17-38% of the cells in inoculated
monolayers were engorged with dextran and that dextran was free in the cytoplasm.
Increased dextran uptake was not lethal, required the presence of activated
larvae, and was often associated with uptake of parasite glycoproteins. These
observations suggest that larvae caused plasma membrane wounds. Our results
showed that neither delivery of glycoproteins nor mechanical wounding is
sufficient to allow entry of the parasite into resistant epithelial cells.
Because both invasion-resistant and susceptible epithelial cells undergo non
lethal wounding, we propose that larvae-induced injury to epithelial cells may
result in release of cell-specific mediators that signal larva to invade a
particular cell line or, alternatively, to ignore it.
PMID- 10779598
TI - Cloning, characterization and functional expression of a cyclophilin of Entamoeba
histolytica.
AB - Full-length Entamoeba histolytica cyclophilin gene (EhCyp) was isolated,
characterized and recombinantly expressed in bacterial cells. The deduced amino
acid sequence of EhCyp shows 60-70% identity with cyclophilins from other
organisms and has conserved the cyclophilin signature motifs and residues
involved in cyclosporin A binding. Upstream of the 501 bp open reading frame of
EhCyp, sequences resembling the putative consensus E. histolytica CE1, CE2 and
CE3 regulatory elements were found. Northern blot assays revealed a single
transcript of 0.63 kb. The transcription start was determined by primer extension
at position -13 relative to the initial ATG codon. Cyclosporin A binding and
peptidyl-proplyl cis-trans isomerase activities characteristic of cyclophilin
were detected in soluble extracts of E. histolytica trophozoites and in the
recombinant protein. In both cases, the isomerase activity was inhibited by
nanomolar concentrations of cyclosporin A. Treatment of cultured trophozoites
with cyclosporin A decreased their proliferation with a 50% inhibition value of 1
microg/ml and was lethal in doses over 50 microg/ml.
PMID- 10779599
TI - Plasmodium falciparum phosphoenolpyruvate carboxykinase is developmentally
regulated in gametocytes.
AB - Plasmodium species have the capacity to fix carbon dioxide during intracellular
development. This process contributes to the pool of free amino acids and
metabolites, which are the end products of glucose metabolism in the malaria
parasite. A gene encoding phosphoenolpyruvate carboxykinase (PEPCK), an enzyme
known to catalyze CO(2) fixation was identified in the genome of the human
parasite Plasmodium falciparum by DNA microarray analysis experiments and was
cloned and characterized. PfPEPCK is a 66.2 kDa, ATP-dependent enzyme which is
closely related to PEPCK from plants and yeast but markedly different from the
host enzyme human PEPCK. PfPEPCK transcript and active enzyme levels are
upregulated in the transmissible and zygote stages of parasite development
relative to the asexual blood stages. Elevated expression of PfPEPCK during the
extracellular zygote phase of P. falciparum development within the
microenvironment of the mosquito midgut may reflect a glucose-rare medium and
suggests a possible switch in carbohydrate metabolism to a gluconeogenesis
pathway.
PMID- 10779600
TI - Molecular cloning, sequencing and expression of a serine proteinase inhibitor
gene from Toxoplasma gondii.
AB - A cDNA clone from a Toxoplasma gondii tachyzoite cDNA library encoding a serine
proteinase inhibitor (serpin) was isolated. The 1376 bp cDNA sequence encodes a
294 amino acid protein with a putative signal peptide of 23 amino acids resulting
in a mature protein with a predicted mass of 30,190 Da and a pI of 4.86. This
protein has internal sequence similarity of residues 30-66, 114-150, 181-217 and
247-283 indicating a four-domain structure. The four domains exhibit high
identity to serine proteinase inhibitors belonging to the non-classical Kazal
type family. The gene is single copy in the tachyzoite haploid genome of RH
strain and was amplified by polymerase chain reaction (PCR). Several introns were
identified. The sequence encoding the mature protein was amplified by PCR, cloned
into the pQE30 vector and expressed in Escherichia coli. Specific antiserum
generated against the recombinant protein was used in immunoblot assay and two
bands of 38 and 42 kDa were detected in a whole parasite homogenate. The
recombinant protein showed trypsin-inhibitory activity, one of the two potential
specificities. We discuss the possible roles that T. gondii serpin(s) may play in
the survival of the tachyzoites in the host.
PMID- 10779601
TI - Targeted integration into a rRNA locus results in uniform and high level
expression of transgenes in Leishmania amastigotes.
AB - This report describes the construction of a DNA cassette for integration into a
genomic small sub-unit rRNA locus of Leishmania mexicana by homologous
recombination. Reporter genes encoding beta-galactosidase or green fluorescent
protein and the gene conferring hygromycin resistance were integrated downstream
of a RNA polymerase I-driven rRNA promoter. To ensure high expression of the
marker proteins in the intracellular, amastigote stage, transgene coding
sequences were followed by the intergenic region of the L. mexicana cysteine
proteinase B 2.8 gene which provides processing signals required for high level
expression in this life-cycle stage. Integration of the DNA cassette was also
efficiently obtained in L. major. We show that either beta-galactosidase or the
green fluorescent protein were abundantly, stably and uniformly expressed in
promastigotes and amastigotes of both Leishmania sp. The transgenic lines allow
parasite detection at high sensitivity in the tissues of infected mice and will
be useful to follow infections in macrophages in culture and in animal hosts.
PMID- 10779602
TI - Molecular cloning and characterization of an IgE-reactive protein from Anisakis
simplex: Ani s 1.
AB - Ingestion of the parasitic nematode Anisakis simplex in undercooked fish can
cause severe allergic reactions in some individuals. Using pooled human sera from
sensitized patients we have probed an expression library for A. simplex antigens.
One positive clone was found to encode a full length 21 kDa protein with strong
homology to nematode troponins. The recombinant protein was expressed as a GST
fusion protein and found by immunoblot analysis to react with sera from 20% of
allergic patients. The presence of functional EF-hand Ca(2+) binding motifs was
demonstrated by gel-shift analysis.
PMID- 10779603
TI - Structure and sequence variation of the trypanosome spliced leader transcript.
AB - We have assessed the potential of using the spliced leader (SL) or mini-exon gene
as a marker for molecular phylogenetic analysis of genus Trypanosoma. A total of
27 trypanosome sequences were compared, 18 of these being newly reported. In
contrast to genus Leishmania, we found the non-transcribed spacer region of the
SL locus in trypanosomes to be far too variable for informative comparison of all
but the most closely related species. At the other extreme, the short (39 nt) SL
exon was usually completely conserved and hence uninformative. The SL RNA showed
variation in both length (97-152 nt) and sequence among different trypanosome
species, with most variation occurring in stem-loop II. Consequently, this region
could not be aligned with confidence in multiple sequence alignment, severely
reducing the number of phylogenetically informative nucleotide positions. In
computer simulation, most of the SL RNAs readily folded into the 3 stem-loop
secondary structure predicted previously, but again stem-loop II was highly
variable. No obvious correlation could be seen between the length of this stem
loop and trypanosome biology. We conclude that the SL repeat is not an
informative phylogenetic marker for long range evolutionary studies of genus
Trypanosoma.
PMID- 10779604
TI - Molecular cloning of a putative alpha3-fucosyltransferase from Schistosoma
mansoni.
AB - Alpha 3-fucosylation of protein or lipid substrates is an important component of
the host/parasite interactions during schistosomiasis. In this process, alpha3
fucosyltransferases (alpha3-FucTs) are considered as key enzymes ensuring both
parasite survival and adaptation in their (in)vertebrate hosts. In this paper, we
report the molecular cloning of a putative alpha3-FucT from Schistosoma mansoni
that we termed SmFucTA. The full-length SmFucTA encodes a typical transmembrane
type II protein with a short cytoplasmic domain, a transmembrane segment and a
long C-terminal catalytic domain. In this region, the GDP-fucose binding site is
well conserved whereas the putative acceptor site displays sequence divergence
compared to the corresponding region from vertebrate and invertebrate alpha3
FucTs. Southern blot analysis suggested that SmFucTA is present as several copies
or has highly related counterparts in the S. mansoni genome. Northern blot
revealed a single SmFucTA transcript at 2 kb in adult worms. Affinity purified
antibodies directed against recombinant SmFucTA identified a 50 kDa native
protein that localizes to the subtegumental and parenchymal regions of adult
worms.
PMID- 10779606
TI - Cloning and characterization of beta-tubulin genes from Echinococcus
multilocularis.
PMID- 10779605
TI - Identification and predicted structure of a leucine-rich repeat motif shared by
Leishmania major proteophosphoglycan and Parasite Surface Antigen 2.
PMID- 10779607
TI - Experimental DNA melting behavior of the three major Schistosoma species.
PMID- 10779608
TI - Molecular characterisation of a Theileria lestoquardi gene encoding a candidate
sporozoite vaccine antigen.
PMID- 10779609
TI - Analysis of antisense and double stranded RNA downregulation of A2 protein
expression in Leishmania donovani.
PMID- 10779610
TI - Trafficking of cysteine proteinase to Leishmania lysosomes: lack of involvement
of glycosylation.
PMID- 10779613
TI - Corrigendum to "Intra and inter-specific microsatellite variation in the
leishmania subgenus Viannia".
PMID- 10779614
TI - Microbial reductive dehalogenation of polychlorinated biphenyls.
AB - Under anaerobic conditions, microbial reductive dechlorination of polychlorinated
biphenyls (PCBs) occurs in soils and aquatic sediments. In contrast to
dechlorination of supplemented single congeners for which frequently ortho
dechlorination has been observed, reductive dechlorination mainly attacks meta
and/or para chlorines of PCB mixtures in contaminated sediments, although in a
few instances ortho dechlorination of PCBs has been observed. Different
microorganisms appear to be responsible for different dechlorination activities
and the occurrence of various dehalogenation routes. No axenic cultures of an
anaerobic microorganism have been obtained so far. Most probable number
determinations indicate that the addition of PCB congeners, as potential electron
acceptors, stimulates the growth of PCB-dechlorinating microorganisms. A few PCB
dechlorinating enrichment cultures have been obtained and partially
characterized. Temperature, pH, availability of naturally occurring or of
supplemented carbon sources, and the presence or absence of H(2) or other
electron donors and competing electron acceptors influence the dechlorination
rate, extent and route of PCB dechlorination. We conclude from the sum of the
experimental data that these factors influence apparently the composition of the
active microbial community and thus the routes, the rates and the extent of the
dehalogenation. The observed effects are due to the specificity of the
dehalogenating bacteria which become active as well as changing interactions
between the dehalogenating and non-dehalogenating bacteria. Important
interactions include the induced changes in the formation and utilization of H(2)
by non-dechlorinating and dechlorinating bacteria, competition for substrates and
other electron donors and acceptors, and changes in the formation of acidic
fermentation products by heterotrophic and autotrophic acidogenic bacteria
leading to changes in the pH of the sediments.
PMID- 10779615
TI - Hexadecane mineralization and denitrification in two diesel fuel-contaminated
soils.
AB - The effect of nitrate, ammonium and urea on the mineralization of
[(14)C]hexadecane (C(16)H(34)) and on denitrification was evaluated in two soils
contaminated with diesel fuel. In soil A, addition of N fertilizers did not
stimulate or inhibit background hexadecane mineralization (4.3 mg C(16)H(34) kg(
1) day(-1)). In soil B, only NaNO(3) stimulated hexadecane mineralization (0.91
mg C(16)H(34) kg(-1) day(-1)) compared to soil not supplemented with any nitrogen
nutrient (0.17 mg C(16)H(34) kg(-1) day(-1)). Hexadecane mineralization was not
stimulated in this soil by NH(4)NO(3) (0.13 mg C(16)H(34) kg(-1) day(-1)), but
the addition of NH(4)Cl or urea suppressed hexadecane mineralization (0.015 mg
C(16)H(34) kg(-1) day(-1)). Addition of 2 kPa C(2)H(2) did not inhibit the
mineralization process in either soil. Denitrification occurred in both soils
studied when supplemented with NaNO(3) and NH(4)NO(3), but was not detected with
other N sources. Denitrification started after a longer lag in soil A (10 days)
than in soil B (4 days). In soil A microcosms supplemented with NaNO(3) or
NH(4)NO(3), rates of denitrification were 20.6 and 13.6 mg NO(3)(-) kg(-1) day(
1), respectively, and in soil B, they were 18.5 and 12.5 mg NO(3)(-) kg(-1) day(
1), respectively. We conclude that denitrification may lead to a substantial loss
of nitrate, making it unavailable to the mineralizing bacterial population.
Nitrous oxide was an important end-product accounting for 30-100% of total
denitrification. These results indicate the need for preliminary treatability
studies before implementing full-scale treatment processes incorporating
commercial fertilizers.
PMID- 10779616
TI - Comparison of pure cultures and natural assemblages of planktonic photosynthetic
sulfur bacteria by low molecular mass RNA fingerprinting.
AB - Pure cultures of phototrophic sulfur bacteria were compared to natural
populations that bloom in karstic lakes by electrophoretic analysis of low
molecular mass RNA molecules (lmwRNA) and microscopy. Similarities between
dominant community members, field isolates and reference strains were established
by comparing the lmwRNA band patterns through dendrograms produced with Euclidean
distances and the average linkage clustering method, by a single, quick, one-step
method. The fingerprinting analysis had three objectives: (i) to compare
microbial assemblages from different geographical locations, (ii) to compare
those organisms which grow in pure culture to those forming planktonic blooms and
(iii) to give a preliminary view of the identity of the predominant community
members. The lmwRNA analysis yielded a number of clusters consistent with the
microscopic observations and allowed rapid comparison of the microbial
communities without the need to isolate their individual components. The
fingerprints of natural communities were different from most of the laboratory
strains tested. Purple sulfur bacteria responsible for the blooms analyzed in
karstic lakes were more closely related to the Thiocystis group than to the
classical strains extensively studied in the laboratory.
PMID- 10779617
TI - Effect of 2-bromo-ethane sulfonate, molybdate and chloroform on acetate
consumption by methanogenic and sulfate-reducing populations in freshwater
sediment.
AB - The relative importance of methanogenesis and sulfate reduction in freshwater
sediment supplemented with acetate was investigated. Addition of acetate
stimulated both methane formation and sulfate reduction, indicating that an
active aceticlastic population of methanogens and sulfate reducers was present in
the sediment. Sulfate reducers were most important in the consumption of acetate.
However, when sulfate reducers were inhibited, acetate was metabolised at a
similar rate by methanogens. Acetate, propionate and valerate accumulated only
when both processes were inhibited by the combined addition of 2-bromo-ethane
sulfonate and molybdate. The relative amounts of acetate, propionate and valerate
were 93, 6 and 1 mol%, respectively. These results demonstrate the role of
acetate as a key intermediate in the terminal step of organic matter
mineralisation in the sediment. Addition of chloroform inhibited both
methanogenesis and sulfate reduction. We studied the inhibitory effect of CHCl(3)
on homoacetogenic bacteria, sulfate-reducing bacteria and methanogens. The
results showed that inhibition by CHCl(3) correlates with microorganisms, which
operate the acetyl-CoA cleavage pathway. We propose that chloroform can be used
to elucidate the role of different metabolic types of sulfate reducers to sulfate
reduction in natural environments.
PMID- 10779618
TI - Effect of Cd-containing wood ash on the microflora of coniferous forest humus.
AB - The use of wood ash in forestry has been questioned because the cadmium (Cd)
concentration of ash, which varies between 1 and 20 mg kg(-1) ash, exceeds the
level allowed for fertilizers (3 mg kg(-1)) used in agriculture. To investigate
the combined and separated effects of Cd and ash on the forest humus microflora,
pumice or wood ash, spiked with a water-soluble (CdCl(2)) or -insoluble (CdO)
form of Cd at three levels (0, 400 and 1000 mg kg(-1)), were applied at a
fertilization level of 5000 kg ha(-1) in a laboratory microcosm study. The trial
consisted of 60 microcosms (five replications per treatment), which were
incubated in darkness at +20 degrees C and a constant relative air humidity of
60%. After two months the humus in the microcosms was sampled. Analyses of CO(2)
evolution to measure the overall microbial activity and of phospholipid fatty
acid (PLFA) pattern to measure microbial community structure were performed. The
substrate-use patterns of Biolog EcoPlates were analyzed as a measure of
bacterial functionality. Finally the bacterial (3)H-thymidine incorporation in
the presence of different concentrations of Cd and the number of colony forming
units (cfu) of bacteria on nutrient agar in the presence of 0, 5 and 20 mg Cd l(
1) agar were applied to measure Cd tolerance. The use of pumice (pH of humus
under the pumice 4.0) did not induce any changes in the above variables compared
to two untreated microcosms (humus pH 3.9). Pumice was therefore used to
distribute the Cd evenly over the humus surface in order to estimate the possible
effect of Cd without ash (pH of humus under the ash 7.0). The application of ash
increased the microbial activity, changed the PLFA and substrate-use patterns and
increased cfu compared to the humus under pumice. The form and level of Cd in the
ash had no further effect on this result. In the humus under pumice the level,
but not the form of Cd decreased the microbial activity and changed the PLFA
pattern compared to the unspiked pumice. None of the treatments induced bacterial
tolerance to Cd. Ash thus protected the humus microflora from the harmful effects
of Cd.
PMID- 10779619
TI - Characterization of 3-chlorobenzoate degrading aerobic bacteria isolated under
various environmental conditions.
AB - The rates of bacterial growth in nature are often restricted by low
concentrations of oxygen or carbon substrates. In the present study the metabolic
properties of 24 isolates that had been isolated using various concentrations of
3-chlorobenzoate, benzoate and oxygen as well as using continuous culture at high
and low growth rates were determined to investigate the effects of these
parameters on the metabolism of monoaromatic compounds. Bacteria were enriched
from different sampling sites and subsequently isolated. In batch culture this
was done both under low oxygen (2% O(2)) and air-saturated concentrations.
Chemostat enrichments were performed under either oxygen or 3-chlorobenzoate
limiting conditions. Bacteria metabolizing aromatics with gentisate or
protocatechuate as intermediates (gp bacteria) as well as bacteria metabolizing
aromatic compounds via catechols (cat bacteria) were isolated from batch cultures
when either benzoate or 3CBA were used as C sources, regardless of the enrichment
conditions applied. In contrast, enrichments performed in chemostats at low
dilution rates resulted in gp-type organisms only, whereas at high dilution rates
cat-type organisms were enriched, irrespective of the oxygen and 3-chlorobenzoate
concentration used during enrichment. It is noteworthy that the gp-type of
bacteria possessed relatively low u(max) values on 3CBA and benzoate along with
relatively high substrate and oxygen affinities for these compounds. This is in
contrast with cat-type of bacteria, which seemed to be characterized by high
maximum specific growth rates on the aromatic substrates and relatively high
apparent half saturation constants. In contrast, bacteria degrading
chlorobenzoate via gentisate or protocatechuate may possibly be better adapted to
conditions leading to growth at reduced rates such as low oxygen and low
substrate concentrations.
PMID- 10779620
TI - Reduction in denitrification activity in field soils exposed to long term
contamination by 2,4,6-trinitrotoluene (TNT).
AB - Terrestrial sites contaminated with 2,4,6-trinitrotoluene (TNT) are a widespread
and persistent problem and often contain non-vegetated areas with TNT
concentrations well in excess of 1000 mg kg(-1). In this study, we examined the
effect of TNT on denitrification activity in field soils, and compared the
sensitivity of denitrifying enzymes to TNT. DNA probes assessed the prevalence of
nirS, nirK and nosZ (encoding cd(1) or copper nitrite reductase and nitrous oxide
reductase, respectively), denitrifying genotypes in the culturable and total
microbial community. The nitrate (NaR), nitrite (NiR) and nitrous oxide (N(2)OR)
reductase activities in field soil and in isolates were assessed by gas
chromatography. The relative occurrence of the nirK, nirS or nosZ genotypes
increased in the cultured community and in total uncultured community DNA as
nitroaromatic concentrations increased. However, denitrifying activity decreased
in response to increasing TNT concentrations, with an IC(50) for NaR+NiR+nitric
oxide reductase (NOR) of 400 mg TNT kg(-1) soil and for N(2)OR of 26 mg TNT kg(
1) soil. The denitrifying activity of four soil isolates also decreased in
response to TNT, with N(2)OR activity being three times more sensitive to TNT
than NaR+NiR+NOR activity. Interestingly, there were 118 times more nirK isolates
than nirS isolates in uncontaminated soil but only 1.5 times more in soil
containing 17400 mg kg(-1) TNT. The results from this study indicated that TNT
reduced denitrification activity in field soils, and N(2)OR was much more
sensitive to TNT than NaR+NiR+NOR.
PMID- 10779621
TI - Characterization of bacterial strains able to grow on high molecular mass
residues from crude oil processing.
AB - Oil residues containing high molecular mass hydrocarbons, rich in polyaromatic
compounds, are frequent end-products of crude oil processing and are poorly
biodegradable. Their disposal poses an environmental problem. Through batch
enrichments from contaminated soils we have isolated and characterized seven
bacterial strains that can use a residue from crude oil processing as a source of
carbon and energy. The residue was a complex mixture of high molecular mass
compounds, including saturated, aromatic and polycyclic aromatic hydrocarbons
(PAHs). Analysis of the metabolic profiles of the strains isolated showed that
they could all metabolize long-chain-length alkanes efficiently, but not PAHs.
Strains degrading naphthalene, a simple PAH, did exist in the soil inocula used,
but could be isolated only when enrichments were performed using pure naphthalene
as the sole carbon source. All strains tested emulsified the oil residue and
their ability to produce surfactants was studied.
PMID- 10779622
TI - PCR typing of tetracycline resistance determinants (Tet A-E) in Salmonella
enterica serotype Hadar and in the microbial community of activated sludges from
hospital and urban wastewater treatment facilities in Belgium.
AB - The distribution of tetracycline resistance determinants Tet A-E was studied by
PCR in 40 tetracycline-resistant Salmonella enterica serotype Hadar (S. hadar)
isolates collected from human patients in 1996 and 1997, as well as in the
microbial community originating from activated sludges of hospital and urban
wastewater treatment facilities. A fast DNA extraction and purification method
from activated sludges was used to provide amplifiable DNA. The method is based
on the direct lysis of bacteria improved by bead-beating followed by DNA
purification on polyvinylpolypyrrolidone spin columns to remove PCR inhibitors.
The purified DNAs from salmonellae and activated sludges were characterized for
the presence of tetracycline determinants with specific primer pairs designed on
the basis of published sequences. The Tet A determinant was present in all
clinical isolates and DNAs extracted from the bacterial community of the selected
activated sludges. The Tet C determinant was identified in only one of the 40
clinical isolates and in six of the seven environmental samples. No signal was
detected for Tet B, D and E determinants. This study revealed a high and stable
prevalence of the Tet A determinant in both salmonellae clinical isolates and the
microbial community of activated sludges from hospital and urban wastewater
treatment facilities over a 2-year period.
PMID- 10779623
TI - Green tea polyphenols and tannic acid act as potent inhibitors of phorbol ester
induced nitric oxide generation in rat hepatocytes independent of their
antioxidant properties.
AB - The deleterious effects of excessive release of nitric oxide (NO) have been
implicated in the tissue damage and inflammation. In this study, the effect of
various flavonoids and other oxidant scavenging chemical agents have been studied
for their ability to inhibit 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced
NO generation in rat hepatocyte. Hepatocytes activated with TPA (25-200 nM)
released NO in a concentration- and time-dependent manner. Green tea polyphenols
(GTP) and tannic acid (TA) were most effective in inhibiting TPA-induced NO
generation (90%). These agents were also effective in inhibiting NO formation
when added 2 h following TPA addition. The other oxidant scavengers, such as L
histidine, sodium azide, vitamin E and sodium benzoate, were not found to be
effective even up to 1.0 mM concentration. These results suggest that TA and GTP
are potent inhibitors of NOS activity and the inhibition of TPA-induced NO
generation by these polyphenols is independent of their antioxidant activity. It
is tempting to speculate that these agents could be utilized in the
pharmacological manipulations of NO-dependent pathophysiological responses.
PMID- 10779624
TI - Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma.
AB - We examined plasma levels of vascular endothelial growth factor (VEGF) and basic
fibroblast growth factor (bFGF) in 54 patients with gastric carcinoma.
Postoperative survival was significantly poorer in patients with plasma VEGF
levels more than 10.0 pg/ml at the time of surgery. By an univariate analysis of
the factors affecting survival, serosal invasion, lymph node metastasis,
peritoneal dissemination, lymphatic vessel invasion, curability, and VEGF
proteins were significant. By a multivariate analysis only VEGF levels and
curability remained significant. Patients with recurrent disease, including liver
metastasis, had significantly higher plasma VEGF concentrations than those with
resectable primary tumors. VEGF, not bFGF, may serve as an independent
prognosticator and a sensitive indicator for liver recurrence in patients with
gastric carcinoma.
PMID- 10779625
TI - Effects of neoplastic transformation and teniposide (VM26) on protein kinase C
isoform expression in rodent fibroblasts.
AB - This study examined changes in protein kinase C (PKC) isoforms in rodent
fibroblasts (rat F111 and mouse NIH3T3), transformed by the polyoma virus middle
T antigen (mT) and undergoing apoptosis in response to teniposide (VM26). The mT
transformed cells up-regulated PKC delta and down-regulated both PKC epsilon and
PKC lambda expression, and were more sensitive to the drug than their non
transformed counterparts. The drug treatment further lowered the expression of
PKC epsilon, triggered nuclear translocation of PKC delta and its site-specific
proteolysis, consistent with the notion that changes in specific PKC isoforms
play a role not only in the neoplastic transformation of fibroblasts, but also in
their apoptotic response.
PMID- 10779626
TI - Development of a novel (32)P-postlabeling method for the analysis of 3'-azido-3'
deoxythymidine.
AB - 3'-Azido-3'-deoxythymidine (AZT) was the first anti-retroviral nucleoside analog
to be used in the treatment and prevention of acquired immunodeficiency syndrome
(AIDS). A novel (32)P-postlabeling assay, based upon thymidine kinase (TK)
instead of the conventional T(4) polynucleotide kinase, has been developed for
the detection of the levels of AZT incorporated into DNA. After enzymatic
digestion of DNA to deoxynucleoside 3'-monophosphates, AZT was isolated by ethyl
acetate extraction. The ethyl acetate was evaporated and the AZT was postlabeled
by 5'-phosphorylation with [gamma-(32)P]ATP and TK. AZT was detected at a level
of 51.5+/-6.3 (mean+/-SD; n=4) AZT molecules/10(5) nucleotides following in vitro
incorporation of the drug into high-molecular-weight rat-liver DNA. The (32)P
postlabeling method was further validated by the detection of AZT in lung and
liver DNA from neonatal mice treated with AZT. The levels of AZT in lung and
liver DNA were proportional to the dose, with the levels in lung DNA being two
fold higher than those for liver DNA. The limit of detection for the assay was 8
AZT molecules/10(7) nucleotides using 10 microg of DNA.
PMID- 10779627
TI - Potentiation of benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis in
mice by D,L-buthionine-S,R-sulfoximine-mediated tissue glutathione depletion.
AB - In vitro studies have suggested that the glutathione (GSH) S-transferase (GST)
catalyzed GSH conjugation is an important mechanism for the detoxification of (+)
anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE],
which is the activated form of the widespread environmental pollutant
benzo[a]pyrene (BP). However, in vivo experimental evidence for the importance of
GSH/GST system in defense against carcinogenic effects of BP is lacking. We
hypothesized that if GSH/GST were to play an important role in the detoxification
of (+)-anti-BPDE, the tumorigenic activity of BP would be increased by depleting
the levels of GSH, which is the required nucleophilic substrate for GST-catalyzed
conjugation reactions. In the present study, we have tested the above hypothesis
by determining the effect of D, L-buthionine-S,R-sulfoximine (BSO)-mediated
tissue GSH depletion on BP-induced tumorigenesis of the lung and forestomach in
female A/J mice. Treatment of mice with three i.p. injections of 2.5 mmol BSO/kg
(12 h apart) plus 20 mM BSO in drinking water, resulted in a statistically
significant reduction in hepatic, pulmonary and forestomach GSH levels. At the
same time, BSO-administration caused a statistically significant increase in BP
induced pulmonary and forestomach tumor multiplicity. To the best of our
knowledge, the present study is the first report that provides in vivo
experimental evidence for the importance of GSH/GST system in cellular protection
against carcinogenic effects of BP.
PMID- 10779628
TI - Expression of cyclin E and p27(KIP1) in cervical carcinoma.
AB - Carcinogenesis is characterized by deregulation of the cell cycle. Although p53
is still the most important cell-cycle regulator in human malignancies, there is
an increased body of evidence indicating that the aberrant expression of cyclins
and cyclin-dependent kinase (CDK) inhibitors is considered as one of the most
important events in malignant transformation of various human cancers. Among
these cell-cycle regulators, the role of cyclin E and p27(KIP1) in the
tumorigenesis of the uterine cervix has been poorly defined. Using formalin
fixed, paraffin-embedded cervical tissues, we investigated the expression of
cyclin E and p27(KIP1) by immunohistochemistry, and human papillomavirus (HPV)
types 16 and 18 by nested polymerase chain reaction (PCR) in 22 control cases, 23
cases with cervical intraepithelial neoplasia (CIN), and 45 patients with
invasive cervical carcinoma (ICC). The p27 index (P27I) was significantly lower
in patients with ICC and CIN compared to those with a normal cervix. Patients
with either invasive cancer or CIN were found to have a significantly higher
cyclin E index (CEI) than the controls (P<0.05). Our results were consistent with
the concept that the deregulated expression of cyclin E and p27(KIP1) may play an
important role in the neoplastic transformation of cervical carcinoma.
PMID- 10779629
TI - Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral
cancer cells.
AB - As part of our previous search for new compounds with improved biological
activities including antibiotic, antiviral, anti-inflammatory, and tumor growth
inhibition activities, we synthesized some caffeic acid phenethyl ester (CAPE)
like compounds from commercially available caffeic acid. Nine chemicals were
tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay
on the growth of buccal mucosal fibroblast (BF), oral submucosus fibroblast
(OSF), neck metastasis of Gingiva carcinoma (GNM), and tongue squamous cell
carcinoma (TSCCa) cells. CAPE and its ethyl analogue show significant
cytotoxicity on OSF, GNM, and TSCCa cells, but not on BF cells. The results
suggest that CAPE-like compounds may be potential chemotherapy agents against
oral cancer.
PMID- 10779630
TI - Absence of hSNF5/INI1 mutation in human lung cancer.
AB - Frequent occurrence of chromosome 22q deletions in lung cancer indicates the
presence of a tumor suppressor gene on this chromosome arm. The hSNF5/INI1 gene
at chromosome 22q11.2 has recently been shown to act as a tumor suppressor in
rhabdoid tumors. To investigate whether the hSNF5/INI1 gene located on chromosome
22q is involved in lung carcinogenesis, mutation analysis of the hSNF5/INI1 gene
was performed using 50 lung cancer cell lines. No mutations causing amino acid
substitutions or frameshifts were found by PCR-SSCP analysis of the entire coding
region. The results indicated that the hSNF5/INI1 gene is not inactivated in lung
cancers and suggested the presence of another tumor suppressor gene on chromosome
22q. Thus, further studies are necessary to identify the target lung tumor
suppressor gene(s) on chromosome 22q.
PMID- 10779631
TI - Tumor formation suppressed in gammadeltaT knock-out mice.
AB - Tumor formation was examined in mice in which the beta-chain gene of alphabetaT
was knocked out (alphabetaT-KO mice) or the delta-chain gene of gammadeltaT was
knocked out (gammadeltaT-KO mice). Development of Hepa 1-6 cell hepatoma was
observed in six of six alphabetaT-KO mice, in four of six wild-type mice, and in
only one of six gammadeltaT-KO mice. These results imply that gammadeltaT cells
play a role in suppression of killer cell activity in tumor-bearing mice.
PMID- 10779632
TI - Loss of IGF-II imprinting in endometrial tumors: overexpression in
carcinosarcoma.
AB - The genomic imprinting of the maternal allele defines the monoallelic expression
of the IGF-II gene in most human tissues. The loss of imprinting (LOI) leading to
biallelic overexpression of IGF-II has been reported in several human
malignancies, including uterine leiomyosarcoma. To ascertain if LOI occurs in
endometrial malignancies, the allelic expression of the IGF-II gene was examined
in samples of normal human endometrium (n=22) and endometrial tumors (n=12) by
assessing the ApaI polymorphism in cDNA segments amplified by RT-PCR. The
biallelic overexpression of IGF-II mRNA, involving activation of all four (P1-P4)
promoters, was detected in one normal endometrium and in one endometrial
carcinosarcoma. Low level biallelic expression of IGF-II was also detected in two
samples of hormone-unresponsive/Type II endometrial carcinomas. The level of IGF
I mRNA in these four samples was low. The IGF-IR mRNA was overexpressed in all
endometrial cancers including the carcinosarcoma sample, but not in normal
endometrium. These data suggest that LOI associated with overexpression of IGF-II
and concomitant overexpression of IGF-IR may play a role in the rare
carcinosarcoma of the endometrium.
PMID- 10779633
TI - Effects of tetracyclines on angiogenesis in vitro.
AB - Most tumors kill their hosts by the process of metastasis rather than by local
growth of the primary mass. A significant factor contributing to the distant
invasion of cancer cells is the ability of tumors to produce large numbers of new
blood vessels in their midst, known as angiogenesis. This both provides access to
nourishment for the primary cancer and enables the cells to escape from the tumor
and enter the bloodstream. We have been examining agents that appear to inhibit
metastasis and, in particular, angiogenesis. We now report on the ability of the
synthetic tetracycline, doxycycline, and the chemically-modified tetracycline,
COL-3, to inhibit angiogenesis in a quantitative in vitro assay of angiogenesis,
using human umbilical vascular endothelial cells (HUVECs) attached to
microcarrier beads.
PMID- 10779634
TI - Induction of KAI-1 expression in metastatic cancer cells by phorbol esters.
AB - KAI-1 is a tumor suppressor gene whose down-regulation has been shown to be
associated with the development of metastases of cancer cells. Here, we
demonstrated that KAI-1 expression was induced by activating protein kinase C
even in metastatic prostate cancer cell lines in which its expression was
significantly down-regulated. KAI-1 expression was enhanced in a dose-dependent
manner by PMA, and its induction is at least in part due to transcriptional
activation. Pretreatment with calphostin C abrogated its induction by PMA. Our
findings may provide useful information for developing a novel drug capable of
inducing KAI-1 expression and thereby inhibiting metastasis.
PMID- 10779635
TI - Salvia miltiorrhiza inhibits cell growth and induces apoptosis in human hepatoma
HepG(2) cells.
AB - Salvia miltiorrhiza (SM) is a traditional Chinese herbal medicine, commonly used
to treat liver diseases in China for centuries. Several earlier studies have
indicated that SM exhibits anti-tumor properties, but its mechanism remains to be
elucidated. In this study, we evaluated the molecular mechanism of SM in a human
hepatoma cell line, HepG(2). Our results show that SM exerted clear cytotoxic
effects, and strongly inhibited the proliferation of HepG(2) cells. It was also
observed that SM treatment caused apoptotic cell death as evaluated by: (a),
morphological changes by using acridine orange/ethidium bromide staining; (b),
DNA fragmentation by TdT-mediated dUTP nick end labeling (TUNEL); and (c), sub
G(1) cell analysis. Furthermore, depletion of intracellular glutathione (GSH) and
reduction of mitochondrial membrane potential were found to be involved in the
initiation of apoptosis by SM.
PMID- 10779636
TI - Expression of mediated P-glycoprotein multidrug resistance related to Tc-99m MIBI
scintimammography results.
AB - We prospectively studied a total of 24 patients with breast cancer to evaluate
the relationship between the degree of accumulation of technetium-99m sestamibi
(Tc-99m MIBI) and p-glycoprotein (Pgp) expression in tumor tissues. All 24
patients underwent Tc-99m MIBI scintimammography before surgery or biopsy.
Immunohistochemical studies were performed on multiple non-consecutive sections
of the same tumor using a Pgp specific monoclonal antibody, JSB-1. Planar images
were started 10 min after injection of Tc-99m MIBI. Tumor to background (T/B)
ratios calculated from the planar images were correlated with Pgp expression as
determined by immunohistochemical studies. The T/B ratios were significantly
lower for tumors in eight patients with positive Pgp expression (Group 1) than in
16 patients with negative expression (Group 2) (1.40+/-0.11 and 2.76+/-0.60, P<0.
05). Our data confirmed that Tc-99m MIBI scintimammography is useful for
determination of the presence of multidrug resistance due to Pgp expression in
patients with breast cancer.
PMID- 10779637
TI - Morphological change, loss of deltapsi(m) and activation of caspases upon
apoptosis of colorectal adenocarcinoma induced by 5-FU.
AB - Apoptosis is clearly distinguished from necrosis, morphologically and chemically.
Morphologically, apoptosis is characterized by a condensed nucleus and the
disappearance of microvilli without disruption of the cytoplasm. In this report,
we demonstrate that 5-fluorouracil (5-FU)-induced early apoptotic cells are
characterized by (i) ultracondensed mitochondria, (ii) no change in the
microvilli or nucleus, (iii) a high mitochondrial transmembrane potential
(Deltapsi(m)), and (iv) being annexin V(negative). The early apoptotic cells also
show the active forms of caspase 8 and caspase 9. They rapidly lose Deltapsi(m)
after further incubation. Therefore, we conclude that the ultracondensation of
mitochondria precedes the loss of Deltapsi(m) and the exposure of
phosphatidylserine to the outer leaflet of the cell membrane.
PMID- 10779638
TI - Prevention of cross-contamination during sampling procedure in molecular
detection for cancer micrometastasis.
AB - Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques have been
widely employed as an ultra-sensitive method for detection of micrometastases in
patients with various types of malignancies. Messenger RNA of a specific marker
gene is a target for RT-PCR amplification to examine the presence of
micrometastases in body fluids or tissues obtained from human. We developed the
RT-PCR assay specific for rat beta-actin mRNA, which cannot detect human
counterpart and assessed how much contamination of rat tissues can influence the
result of RT-PCR assay and how to avoid the influence of the contamination in RT
PCR assay.
PMID- 10779639
TI - Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and
breast cancer susceptibility.
AB - The glutathione S-transferase (GST) family of enzymes function in the body to
detoxify carcinogenic compounds. Several genes that code for these enzymes are
polymorphic, with particular genotypes previously shown to confer an increased
cancer risk. In this study, we investigated the role of three GST genes (GSTM1,
GSTP1 and GSTT1) in the development of sporadic breast cancer. Genotypes were
determined in 129 breast cancer affected and 129 age and sex matched control
individuals. Results did not support an involvement of these specific GST gene
polymorphisms, either independently or in combination, in susceptibility to
sporadic breast cancer in the tested Australian Caucasian population.
PMID- 10779640
TI - Nitrotyrosine in esophageal squamous cell carcinoma and relevance to p53
expression.
AB - We have examined the expression of nitrotyrosine, a marker of peroxynitrite
formation, in 55 esophageal cancers by immunohistochemistry. Nitrotyrosine was
detected in 21 of 55 (38.2%) esophageal cancers. Comparison of nitrotyrosine
expression and the pathological findings showed that there was a significant
association between the expression of nitrotyrosine and each of the depth of
tumor invasion (P<0.01), occurrence of metastasis (P<0.05), pathological stage
(P<0.01), smoking status (P<0.05) and alcohol intake (P<0.05). The survival rate
of patients with nitrotyrosine-negative cancer was significantly higher than that
of patients with nitrotyrosine-positive cancer (log-rank test, P<0.01). p53 was
detected in 29 of 55 (52.7%) esophageal cancers, however, p53 expression did not
correlate with nitrotyrosine expression. In conclusion, nitrotyrosine, a product
of nitrogen species, is expressed in esophageal squamous cell carcinoma, which
suggests that exogenous risk factors, such as tobacco and alcohol, through NO,
are associated with carcinogenesis and progression of esophageal squamous cell
carcinoma.
PMID- 10779641
TI - Loss of p16 and p27 is associated with progression of human gastric cancer.
AB - We performed the immunohistochemical staining for six G1 check point cell cycle
proteins to study their expression patterns and roles in the gastric
carcinogenesis. We studied 76 cases of paraffin blocks that included the sections
of 18 tubular adenomas (TA), 38 early gastric carcinomas (EGC) (20 cases of
mucosal type, nine cases of submucosal type with no nodal metastasis, nine cases
of submucosal type with nodal metastasis), 20 advanced gastric carcinomas (AGC)
(ten cases with no nodal metastasis, ten cases with nodal metastasis). We found
that abnormal expression of p16 and p27 increased with the progression of tubular
adenomas to advanced gastric cancers. Inverse relationship between pRb and p16
proteins was found in a small portion of the gastric tumors. Expressions of pRb
and cdk4 were consistently high in benign and malignant gastric tumors.
Expression of cyclin D1 and cyclin E rather decreased with the tumor progression.
In conclusion, losses of p16 and p27 seem to play a significant role during the
gastric carcinogenesis, and the G1 checkpoint cell cycle proteins such as pRb,
cdk4, cyclin D1, and cyclin E variably participate in the gastric carcinogenesis
and metastasis by the mechanisms which are yet unknown; thus, further studies
need to be performed to elucidate the mechanisms.
PMID- 10779642
TI - Possible role of hepatocyte growth factor/scatter factor and activin A produced
by the target organ in liver metastasis.
AB - The molecular mechanism of organ-specific metastasis to the liver remains largely
unknown. However, it is conceivable that paracrine growth factors produced by a
target organ induce migration and proliferation of malignant cells to that organ,
and this is the cause of organ-specific metastasis. In this study, we
investigated the effect of hepatocyte growth factor/scatter factor (HGF/SF) and
activin A, which are known to be produced by the liver, on the motility and
growth of liver-metastatic cell line FBJ-LL. HGF/SF and activin A induced
motility synergistically, but they did not affect the proliferation of FBJ-LL
cells. Expression of the HGF/SF receptor, the c-met gene, and the activin
receptor type IA, type IB, and type IIA genes in FBJ-LL cells was detected by
reverse transcription polymerase chain reaction. These findings suggest that both
HGF/SF and activin A promote organ-specific metastasis to the liver by induction
of migration through their specific receptors on liver-metastatic cells.
PMID- 10779643
TI - Frequency and markov chain analysis of amino-acid sequences of human tumour
necrosis factor.
AB - The amino-acid sequence of human tumour necrosis factor was measured according to
two- and three-amino-acid sequences. The measured frequency and probability were
compared with predicted frequency and probability. Of 232 two-amino-acid
sequences in human tumour necrosis factor, 64 (27.586%) and 24 (10.345%)
sequences can be explained by the predicted frequency and the predicted
probability according to a purely random mechanism. Of 243 non-appeared two-amino
acid sequences in human tumour necrosis factor, 176 (72. 428%) and 42 (17.284%)
sequences can be explained by the predicted frequency and the predicted
probability according to a purely random mechanism. No measured Markov transition
probability matches the predicted conditional probability. No more-than-two-amino
acid sequences can be explained by a purely random mechanism.
PMID- 10779644
TI - Different kinases phosphorylate nucleophosmin/B23 at different sites during G(2)
and M phases of the cell cycle.
AB - The recombinant GST-nucleophosmin/B23 and the truncated mutants were tested for
phosphorylation in cell-free extracts of G(2) and M phases or by purified
kinases. Our results indicated that a threonine residue at amino acids (a.a.) 185
240 was phosphorylated by cdc2 kinase during the entry of mitosis while the
serine phosphorylation site at the middle acidic portion of the molecule (a. a.
83-152) was phosphorylated by casein kinase II during G(2) phase. Our results
also showed that there was possibly another serine phosphorylation at site other
than the middle portion of nucleophosmin/B23 (a.a. 83-152) during the entry of
cells into mitosis. The demonstration of the characteristic changes in
phosphorylation of nucleophosmin/B23 during the cell cycle implicates important
role of nucleophosmin/B23 in the control of the fate of nucleoli and cell growth.
PMID- 10779645
TI - Expression of the 37-kDa laminin binding protein in murine lung tumor cell
correlates with tumor angiogenesis.
AB - Expression of the 37-kDa laminin binding protein (37LBP), a precursor protein of
the 67-kDa laminin receptor, correlates well with the biological aggressiveness
of cancer cells. Previously, we have established murine lung cancer cell lines
T11 and T15, in which 37LBP expression was remarkably diminished, and reported
that the mean survival time of the T11 and the T15-recipients was significantly
prolonged compared with that of the control cell lines (P29 and T42). In the
present study, immunohistochemical findings of the tumors demonstrated that the
microvessel density in the T11 (28. 1+/-7.2/mm(2)) and in the T15 tumor (29.7+/
6.5/mm(2)) were significantly lower than that observed in P29 (46.3+/-8.7/mm(2))
or in T42 (50.5+/-4.4/mm(2)). Expression of vascular endothelial growth factor
(VEGF) was repressed in T11 and T15 compared with its expression in P29 and T42.
It was also shown that conditioned media of T11 and T15 cells exhibited
significantly reduced proliferation and migration of the capillary endothelial
cells. These results suggest that decreased expression of 37LBP in antisense-RNA
transfectant may relate to its low tumorigenicity, and that this effect may be
partly caused by the diminished tumor angiogenesis of murine lung cancer.
PMID- 10779646
TI - Mutational analysis of the p27(kip1) gene in hepatocellular carcinoma.
AB - p27(Kip1) is an inhibitor of cyclin-dependent kinase. It has been reported that
reduced p27(Kip1) expression is present in human hepatocellular carcinoma. To
determine the role of p27(Kip1) in hepatocarcinogenesis, 46 cases with
hepatocellular carcinomas were studied. p27(Kip1) mutation was first screened by
single strand conformation polymorphism, and direct DNA sequencing was then
performed on those cases with mobility shifts. Two polymorphism sites were found.
One is a previously described polymorphism at codon 109 (GTC-->GGC) which was
found in two cases. The second polymorphism was identified at codon 55 (GCG-
>GCA) in six of the 46 cases. However, the polymorphism at codon 55 was also
present in seven of 93 healthy controls (7.5%), indicating that it is not
associated with a predisposition for development of hepatocellular carcinoma
(Fisher's exact test, 0.05). These results show that p27(Kip1) mutation is not a
frequent event in human hepatocellular carcinoma, and suggest that it may be
inactivated predominantly by transcriptional and/or posttranscriptional
regulation rather than genomic aberrations.
PMID- 10779647
TI - Lack of mutation at p16INK4A gene but expression of aberrant p16INK4A RNA
transcripts in human ovarian carcinoma.
AB - Alterations of the p16INK4A gene are frequent in various human cancers. We
investigated p16INK4A gene status in 20 ovarian carcinomas by PCR (polymerase
chain reaction), PCR-SSCP (polymerase chain reaction-single strand conformation
polymorphism) and sequencing techniques. None of the primary tumors showed any
mutational or deletional events. However, 19 out of 20 tumors displayed both a
methylated and an unmethylated p16INK4A promoter. In some of these samples, we
detected aberrant p16INK4A transcripts, with partial deletions of both exons 1
and 2, which could not encode a functional p16INK4A protein. The sequences of the
aberrant mRNA revealed common 4-7 nucleotide sequences before and after the
deleted region, which might cause abnormal splicing of mRNA transcripts. These
results suggest that both promoter methylation and aberrant mRNA processing may
interfere with p16INK4A expression in ovarian tumors.
PMID- 10779648
TI - Low levels of NPM gene expression in UV-sensitive human cell lines.
AB - Nucleophosmin (NPM) is a major nuclear matrix protein associated with neoplastic
growth in various cell types. We recently suggested that expression of the NPM
gene is involved in an increased resistance to UV irradiation in human cells
against the cell-killing effects of UV (mainly 254nm wavelength far-ultraviolet
ray) [Y. Higuchi, K. Kita, H. Nakanishi, X-L. Wang, S. Sugaya, H. Tanzawa, H.
Yamamori, K. Sugita, A. Yamaura, N. Suzuki, Biochem. Biophys. Res. Commun. 248
(1998) 597-602]. In the present study, expression levels of the NPM gene were
examined in human cell lines with a high sensitivity to UV cell-killing. Cockayne
syndrome patient-derived cell lines, CSAI and CSBI, and the Xeroderma pigmentosum
patient-derived cell line, XP2OS(SV), XP13KY, XP3KA, XP6BE(SV), XP101OS and
XP3BR(SV), have been investigated for their NPM mRNA expression with Northern
blotting analysis. All of these UV-sensitive cells demonstrated lower expression
levels compared with those of normal fibroblast cells, FF, or an UV-resistant
cell line, UH(r)-10; quite a lower level of expression in XP205(SV) cells after
UV irradiation in contrast to a distinguishable increase in the expression in
UV(r)- cells. These results confirmed an intimate correlation between degree of
UV sensitivity and expression levels of the NPM gene in human cells.
PMID- 10779649
TI - Clinical significance of lymph node micrometastasis of pN0 esophageal squamous
cell carcinoma.
AB - The lymph nodes of 59 patients with pN0 esophageal squamous cell carcinomas were
examined immunohistochemically using cytokeratin (CK) antibody. Primary tumors
were immunostained with cyclin D1 (CD1) and E-cadherin (E-cad) antibody. Lymph
node micrometastasis (MM) was found in 39 (55.5%) patients. Tumor recurrence was
found in 17 patients and all but one of them had MM. The 5-year survival rate was
significantly poorer in patients with MM than in those without MM. Almost all
patients with positive CD1 and negative E-cad expression had MM. The examination
of CD1 and E-cad expression in primary tumors may be useful for predicting MM.
PMID- 10779650
TI - Carcinogen dose-dependent variation in the transgene mutation spectrum in
urethane-induced lung tumors in transgenic mice carrying the human prototype c-Ha
ras gene.
AB - Urethane-induced lung tumors and their genetic changes were investigated in
transgenic (Tg) mice carrying a human prototype c-Ha-ras gene (rasH2 mice). Male
and female rasH2 mice and non-transgenic (non-Tg) littermates were injected
intraperitoneally with 1000 mg/kg of urethane once or three times at 2-day
intervals. Hyperplasias and adenomas of the lung were observed in all animals of
each group from week 10, and carcinomas were observed in male and female rasH2
mice of the triple injection group from week 10 and female non-Tg mice of the
single injection group at 15/20 weeks. The multiplicities of lung proliferative
lesions including hyperplasias, adenomas and carcinomas, in treated rasH2 mice
were significantly higher than those in treated non-Tg mice. CAG to CTG
transversions were observed in the c-Ha-ras gene in these lung proliferative
lesions of rasH2 mice of the single injection group at high incidence (male:
58.3%, female: 62.5%), but no mutations of the mouse c-Ki-ras gene were evident
in either rasH2 or non-Tg mice. In the triple injection group, transgene
mutations were detected at a relatively low incidence, and mouse c-Ki-ras gene
mutations(CAA to CGA) were observed in both rasH2 and non-Tg mice. These results
suggest that the variation of the lesions induced by different doses of urethane
was not the cause of the variation of the mutation spectrum and mutations of both
transgene and mouse c-K-ras gene are not principal genetic events in urethane
induced lung proliferative lesions in rasH2 mice.
PMID- 10779651
TI - Organ-dependent modifying effects of oltipraz on N-nitrosobis(2-oxopropyl)amine
(BOP)-initiation of tumorigenesis in hamsters.
AB - 5-(2-Pyrazinyl)-4-methyl-1,2-dithiole-thione (oltipraz), a substituted 1,2
dithiole-3-thione, is known to inhibit tumorigenesis induced by variety of
carcinogens in several animal model systems. In the present experiment, the
modifying effects of dietary oltipraz, given during N-nitrosobis(2
oxopropyl)amine (BOP) initiation of carcinogenesis, were investigated in Syrian
hamsters. A total of 120 six-week-old females were divided into six groups.
Groups 1-3 (30 animals each) were thrice given subcutaneous injections of BOP (10
mg/kg, body weight) at 1 week intervals and fed diets supplemented with 400 or
200 ppm of oltipraz or basal diet alone, starting 1 week prior and finishing 1
week after the carcinogen exposure. Groups 4-6 (10 animals each) were similarly
treated without application of BOP. At the end of the 52nd experimental week, all
surviving animals were autopsied and examined histopathologically for
proliferative lesions of the major target organs for BOP tumorigenicity,
including pancreas, liver, kidney, and lung. The incidences and multiplicity of
adenocarcinomas of the pancreas were higher in groups 1 and 2 than in group 3
although without statistical significance. The incidence of pancreatic duct
dysplasias was significantly (P<0.05) increased in group 2 (62.0%) but not in
group 1 (50.0%) as compared with group 3 (46.6%). While the incidences of
alveolar adenomas and carcinomas were significantly (P<0.05) decreased by the
high dose, the multiplicities of hepatocellular adenomas, cholagiocellular
carcinomas and gall bladder adenomas were elevated in the BOP/oltipraz groups
(P<0.05). The results of the present study suggest that oltipraz exerts organ
dependent modifying effects on BOP-induced carcinogenesis in hamsters when given
in the initiation stage.
PMID- 10779652
TI - Prognostic significance of p53 mutations in non-small cell lung cancer: a meta
analysis of 829 cases from eight published studies.
AB - Mutation of the p53 tumor suppressor gene is considered a possible marker of poor
survival among patients with non-small cell lung cancer (NSCLC). This report
presents the results of a meta-analysis of the available data addressing this
issue. Using previously described methods, a protocol was developed for a meta
analysis examining the prognostic significance of p53 mutations in NSCLC. Two
year survival data derived from 829 patients in eight published studies were
analyzed using a general variance-based method employing confidence intervals
described by Greenland (Epidemiol. Rev. 9 (1986) 1-30). The outcome of interest
was a summary relative risk (RRs) reflecting the risk of death at 2 years
associated with p53 mutation positive versus p53 negative disease. Prior to
calculation of a RRs, an analysis for homogeneity (Q) showed Q to equal 22.3.
With 8 degrees of freedom, this yielded a P value corresponding to P<0.005. This
indicated substantial heterogeneity across studies in terms of their estimate of
effect. Although a RRs of 1.52 was found when all eight studies were combined
(favoring a negative prognostic role for p53 mutation), the validity of this
estimate is questionable since the existing heterogeneity indicates that factors
other than p53 mutation account for the variability in RRs across studies.
Sensitivity analyses suggested that selection bias might represent an important
source of variability in that p53 mutations may differ in their effects on
biological behavior of NSCL tumors. Other possible confounders include smoking
history, race, geographic location of study and socio-economic status. The
available data do not support a clear role for p53 mutation as a prognostic
marker in NSCLC. It appears that multiple sources of bias may contribute to
spurious association of p53 mutation status and survival. Future analyses must
control for possible confounders in order to determine whether certain p53
mutations are truly associated with poor clinical outcome.
PMID- 10779653
TI - Perils in the pursuit of mechanisms.
PMID- 10779654
TI - Vulvodynia: an introduction and critical review of a chronic pain condition.
AB - Vulvodynia, or chronic vulvar discomfort, has become an increasingly recognized
complaint in the medical literature. However, classification, assessment, and
treatment for vulvodynia have not been universally established. There is a
serious need for greater understanding of this disorder since evidence suggests,
although not life-threatening, vulvodynia appears to have a significant impact on
quality of life. This article reviews the medical and psychological literature on
vulvodynia published since 1983, the first year vulvodynia was recognized as a
diagnosis in the medical literature. The purpose of this article is to provide a
review of the literature on diagnostic issues, treatment options, and
psychosocial sequelae with the aim of highlighting areas in need of future
research. Finally, suggestions are made for considering vulvodynia from a
multidimensional, chronic pain perspective.
PMID- 10779655
TI - Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT
in rats.
AB - The present study was designed to investigate which subtypes of spinal 5-HT
receptors are involved in 5-HT-induced antinociception using the mechanical pain
test. Serotonin and various selective antagonists or agonists for 5-HT receptor
subtypes (5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3) and 5-HT(4)) were
administered intrathecally (i.t.) in rats. The i.t. injection of 5-HT (1 microg)
produced significant antinociceptive effects using the paw pressure test.
Pretreatment with the 5-HT(2C) receptor antagonist mesulergine (1 and 10 microg)
and the 5-HT(3) receptor antagonist tropisetron (1 and 10 microg) reversed
totally the antinociception induced by 5-HT. Furthermore, at a dose of 10 microg,
both the 5-HT(2A) receptor antagonist ketanserin and the 5-HT(1B) receptor
antagonist penbutolol, but neither the 5-HT(1A) receptor antagonist WAY 100635
nor the 5-HT(4) receptor antagonist GR113808, attenuated the antinociceptive
effect induced by 5-HT. In addition, an i.t. injection of the 5-HT(3) agonist
mCPBG induced significant antinociceptive effects whereas the 5-HT(2) agonist DOI
did not produce analgesia. These results suggest that although the precise degree
of the involvement of spinal serotonergic 5-HT(3) receptors remains to be
elucidated due to some differences in the effect of agonists or antagonists,
these receptors seem to play a role in the antinociceptive effect of 5-HT against
a mechanical acute noxious stimulus. The involvement of 5-HT(2C) is more
questionable due to the observed discrepancies between the effects of the used
agonist and antagonist. 5-HT(1A) and 5-HT(4) receptors do not seem to be
involved. In addition, a possible functional interaction between spinal
serotonergic receptors may exist.
PMID- 10779656
TI - Effect of preoperative oral dextromethorphan on immediate and late postoperative
pain and hyperalgesia after total abdominal hysterectomy.
AB - Dextromethorphan is a noncompetitive N-methyl-D-aspartate (NMDA) receptor
antagonist known to inhibit wind-up and NMDA-mediated nociceptive responses of
dorsal horn neurons. Experimental and clinical studies indicate that NMDA
receptor antagonists may potentiate the effect of analgesics such as morphine,
local anesthetics and NSAIDs. Results from previous clinical studies of
dextromethorphan in postoperative pain are conflicting, possibly related to
administration of insufficient doses of the drug. Fifty patients scheduled for
non-malignant elective abdominal hysterectomy in general anesthesia were
randomized to receive oral dextromethorphan 150 mg, or placebo 1 h before
surgery. The patients received patient-controlled analgesia with morphine for 24
h postoperatively as the only analgesic. Patient-controlled analgesia (PCA)
morphine consumption was reduced with 30% from 0-4 h after operation in patients
receiving dextromethorphan compared with placebo (P=0.02); no differences were
observed from 5-24 h postoperatively. There were no significant differences
between groups for visual analogue scale scores at rest, during cough, or during
mobilization, pressure pain detection thresholds, von Frey hair pain detection
thresholds, or peak flow. At 24 h after operation, hyperalgesia to von Frey hair
stimulation proximal to the surgical wound was easily detected in 23 of 25
patients receiving dextromethorphan, and in 22 of 25 patients receiving placebo,
with no significant difference between groups. Pooled data from both groups
showed a weak but significant correlation between the extent of hyperalgesia at
24 h after operation, and total 24 h postoperative PCA morphine consumption
(Rs=0.28, P=0.05). Three months postoperatively, hyperalgesia was still
detectable in 18 of 22 examined patients in the dextromethorphan group, and in 16
of 23 patients in the placebo group, without statistical differences between
groups. There were no significant differences in side-effects (nausea, vomiting,
sedation). In conclusion, oral dextromethorphan 150 mg reduced PCA morphine
consumption immediately (0-4 h) after hysterectomy, without prolonged effects on
pain or wound hyperalgesia. A positive correlation between the magnitude of wound
hyperalgesia at 24 h after operation, and total 24 h postoperative PCA morphine
consumption was demonstrated.
PMID- 10779657
TI - Depletion of macrophages reduces axonal degeneration and hyperalgesia following
nerve injury.
AB - Inflammatory mechanisms are believed to play an important role in hyperalgesia
resulting from nerve injury. Hyperalgesia following nerve injury is temporally
linked with Wallerian degeneration and macrophage recruitment, and is reduced in
WLD mice, in which Wallerian degeneration is delayed. We sought more direct
evidence that macrophages contribute to hyperalgesia and Wallerian degeneration
by depleting macrophages with liposomes loaded with dichloromethylene
diphosphonate (clodronate, Cl(2)MDP). Rats were subjected to partial ligation of
the sciatic nerve. Intravenous injection of liposome-encapsulated clodronate
reduced the number of macrophages in the injured nerve, alleviated thermal
hyperalgesia and protected both myelinated and unmyelinated fibres against
degeneration. The results confirm the role of circulating monocytes/macrophages
in the development of neuropathic hyperalgesia and Wallerian degeneration due to
partial nerve injury. Macrophage depletion immediately after nerve injury could
have some clinical potential in prevention of neuropathic pain.
PMID- 10779658
TI - Spatial mapping of the zone of secondary hyperalgesia reveals a gradual decline
of pain with distance but sharp borders.
AB - The purpose of this study was to examine how pain to punctate mechanical stimuli
varies with position within the zone of secondary hyperalgesia. Secondary
hyperalgesia was produced by an intradermal injection of capsaicin (50 microg)
into the volar forearm of human volunteers (n=9). Before and at 20, 60 and 100
min after the capsaicin injection, a computer-controlled electromechanical
stimulator was used to deliver controlled-force stimuli to the skin via a 12-mm
wide, 100-microm thick blade probe. Three forces (16, 32 and 64 g; 1 s) were each
applied in a random order to 10 sites spaced in 1-cm increments along a line
starting 1 cm from the injection site and ending near the wrist. At 40 and 80 min
after capsaicin injection the 'zone of hyperalgesia' was determined with use of a
hand-held 20-g von Frey probe. Whereas, before capsaicin, the blade probe
produced little or no pain, after capsaicin the 32-g and 64-g stimuli evoked pain
consistently within but not outside the border of secondary hyperalgesia
determined with the von Frey probe. Within the zone of hyperalgesia the average
pain ratings to the 64-g stimulus decreased exponentially with distance from the
injection site. Surprisingly, the space constant for this exponential decay was
large (about 18 cm), and thus the decrease in pain ratings from the center to the
edge of the secondary zone was small (37%). However, pain ratings dropped
precipitously just outside the zone of secondary hyperalgesia. This finding
unlikely reflects a ceiling effect because pain ratings within the zone of
secondary hyperalgesia increased linearly with force. The relatively uniform pain
ratings to the blade stimuli within the zone of secondary hyperalgesia and the
sharp border that delimits the zone of hyperalgesia indicate that this sensory
disturbance approaches being an 'all-or-nothing' phenomenon. Thus, a two-state
model for central plasticity is needed to explain secondary hyperalgesia.
PMID- 10779659
TI - Painful neuropathy decreases membrane calcium current in mammalian primary
afferent neurons.
AB - Hyperexcitability of the primary afferent neuron leads to neuropathic pain
following injury to peripheral axons. Changes in calcium channel function of
sensory neurons following injury have not been directly examined at the channel
level, even though calcium is a primary second messenger-regulating neuronal
function. We compared calcium currents (I(Ca)) in 101 acutely isolated dorsal
root ganglion neurons from 31 rats with neuropathic pain following chronic
constriction injury (CCI) of the sciatic nerve, to cells from 25 rats with normal
sensory function following sham surgery. Cells projecting to the sciatic nerve
were identified with a fluorescent label applied at the CCI site. Membrane
function was determined using patch-clamp techniques in current clamp mode, and
in voltage-clamp mode using solutions and conditions designed to isolate I(Ca).
Somata of peripheral sensory neurons from hyperalgesic rats demonstrated
decreased I(Ca). Peak calcium channel current density was diminished by injury
from 3.06+/-0.30 pS/pF to 2. 22+/-0.26 pS/pF in medium neurons, and from 3.93+/
0.38 pS/pF to 2. 99+/-0.40 pS/pF in large neurons. Under these voltage and
pharmacologic conditions, medium-sized neuropathic cells lacked obvious T-type
calcium currents which were present in 25% of medium-sized cells from control
animals. Altered Ca(2+) signalling in injured sensory neurons may contribute to
hyperexcitability leading to neuropathic pain.
PMID- 10779660
TI - Intrathecally administered spermine produces the scratching, biting and licking
behaviour in mice.
AB - Intrathecal (i.t.) administration of spermine (0.1-10000 fmol), an endogenous
polyamine, produced the behavioural response mainly consisting of biting and/or
licking of the hindpaw along with a slight hindlimb scratching directed toward
the flank in mice, which peaked at 5-15 min and almost disappeared at 30 min
after an injection. The behaviour induced by spermine (10 pmol) was dose
dependently inhibited by intraperitoneal injection of morphine (0.125-0.5 mg/kg).
The characteristic behaviour was also inhibited dose-dependently by i.t. co
administration of ifenprodil (62.5-4000 pmol), a competitive antagonist of the
polyamine recognition site on N-methyl-D-aspartate (NMDA) receptor ion-channel
complex, and D(-)-2-amino-5-phosphonovaleric acid (D-APV) (0.5-2 nmol) and 3-((+/
)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (7. 8-500 pmol), the
competitive NMDA receptor antagonists, and (5R, 10S)-(+)-5-methyl-10,11-dihydro
5H-dibenzo[a,b]cycloheptene-5, 10-imine hydrogen maleate (MK-801) (0.5-4 nmol),
an NMDA ion-channel blocker, but not by 6-cyano-7-nitroquinoxaline-2,3-dione
(CNQX), a non-NMDA receptor antagonist. Both (2S, 3S)-[cis-2-(diphenylmethyl)-N
[(2-methoxyphenyl)-methyl]-1-azabicy clo [2.2.2]octane-3-amine] (CP-96,345), a
non-peptidic neurokinin-1 (NK-1) receptor antagonist, and CP-96,344, its inactive
2R,3R enantiomer, inhibited spermine-induced behavioural response in a dose
dependent manner. However, [Tyr(6), D-Phe(7), D-His(9)]-substance P(6-11)
(sendide) and [D-Phe(7), D-His(9)]-substance P(6-11), the selective antagonists
for NK-1 receptors, were without affecting spermine-induced behaviour. These
results indicate that spermine-induced behaviour is mediated through the
polyamine recognition site on NMDA receptor ion-channel complex without the
involvement of substance P system in the mouse spinal cord.
PMID- 10779661
TI - Spinal interleukin-1beta reduces inflammatory pain.
AB - Inflammation or injury often lead to chronic pain states such as hyperalgesia
where the perception of a normally painful stimulus is significantly exaggerated.
Interleukin-1beta (IL-1beta) is a cytokine that is an important mediator of the
inflammatory response. In addition, IL-1beta has been implicated in the
modulation of pain transmission in both the peripheral and central nervous
systems. We evaluated the spinal effect of this cytokine in the presence and
absence of a peripheral carrageenan inflammation in rats since the spinal cord is
a major region of the central nervous system in which nociceptive input is
processed and modulated. Our results indicate that intrathecal IL-1beta has no
effect on the latency of paw withdrawal in response to a noxious thermal
stimuluation in normal rats. In contrast, we have observed that IL-1beta produces
significant antinociception when administered intrathecally in rats with
peripheral inflammation (carrageenan model). The IL-1beta effect appears to be
selective as it is reversed when IL-1beta is administered in the presence of an
IL-1beta neutralizing antibody. We evaluated some putative mechanisms of this IL
1beta-mediated antinociception and found it to be non-opioid-dependent.
Collectively, these data indicate that intrathecal IL-1beta has no effect on the
processing of thermal nociceptive information in the absence of a peripheral
inflammation. Therefore, the response to acute pain remains normal in these rats.
In contrast, IL-1beta is antinociceptive when applied spinally during
inflammation. These results indicate that IL-1beta reduces inflammatory
hyperalgesia while sparing the protective functions of acute pain. This study
offers new insights into the role of IL-1beta and nociceptive processing at the
level of the spinal cord and suggests that development of IL-1beta agonists may
be an alternative to opiate based therapies in the treatment of inflammatory
pain.
PMID- 10779663
TI - Heme oxygenase type 2 plays a role in formalin-induced nociception.
AB - Although much attention has been focused in recent years on nitric oxide synthase
(NOS) as an enzyme intimately involved in many types of nociceptive signaling,
the enzyme heme oxygenase (HO) has received little attention. Yet, HO produces
gaseous second messenger molecule CO which, like NO, has proven to be an
important neurotransmitter in the CNS. In these studies we provide detailed
evidence that HO activity is critical to formalin-induced licking behavior in
mice. The HO inhibitor tin protoporphyrin (Sn-P) dose-dependently reduced
formalin-stimulated licking behavior in both phases of the formalin assay. This
apparent analgesic effect was unlikely due to the non-specific effects of this
agent as Sn-P did not alter rotarod performance, and the blood-brain barrier
impermeant HO inhibitor zinc protoporphyrin (Zn-P) had little effect on licking
times. We also hypothesized that heme oxygenase type 2 (HO-2) was the specific
isoform of HO involved in nociception. Mice with a targeted disruption of the HO
2 gene were found to have greatly reduced licking times. Furthermore, Sn-P did
not further reduce licking times when administered to HO-2 knockout animals.
Taken together our evidence indicates that HO plays an important role in
nociceptive signaling related to inflammatory-type pain, and that HO-2 is the
isozyme mediating this nociception.
PMID- 10779662
TI - Amino acid release into the knee joint: key role in nociception and inflammation.
AB - This study examined the release of several amino acids after induction of knee
joint inflammation in rats using kaolin and carrageenan. During the initial 10
min collection after knee joint injection with the irritants, the concentration
of glutamate and the nitric oxide metabolites, arginine and citrulline, doubled.
This increase persisted for at least two hours. During the same time period
aspartate concentrations remained unchanged. Direct knee joint administration of
lidocaine prevented the increases in amino acid concentration measurable by
microdialysis probe inserted into the joint. These data suggest the possibility
that glutamate may be released by neuronal endings in the joint.
PMID- 10779664
TI - Low intensity vagal nerve stimulation lowers human thermal pain thresholds.
AB - The effect of vagal nerve stimulation (VNS) on thermal pain sensation was studied
in eight subjects who had vagal nerve stimulators surgically implanted for
purposes of seizure control. Prior to their involvement in the study, all
subjects had the intensity of their VNS (30 Hz, 0.5 ms, 1.0-2.75 mA) adjusted
upwards until achieving their desired clinical effect of reduced seizures.
Thermal pain thresholds were determined using a Medoc TSA-2001 with a thermode
applied to the skin of the forearm. During VNS at settings 100% of those used
clinically to control their seizures, subjects showed a statistically significant
decrease in their thermal pain threshold of 1.1+/-0.4 degrees C. Acute effects of
graded VNS on thermal pain thresholds were determined in seven of the subjects
after cessation of chronic VNS. Two thermal threshold measurements were obtained
while the subject received sham stimulation (0 mA intensity), during tactile
control stimulation and during 30 s of VNS at intensities approximately 33, 66
and 100% of the settings utilized to control their seizures. Tactile control
stimulation was provided by electrical stimulation of the skin of the ankle with
the intensity adjusted by the patient to match the intensity of any sensations
felt in the neck during VNS. Subjects were not aware of the settings employed.
Their stimulator was adjusted with each trial and an ascending/descending
ordering of intensity was utilized with an inter-trial interval of 2 min. Thermal
pain thresholds were significantly decreased in relation to tactile control
stimulation at all intensities of VNS tested with the greatest effect occurring
at the 66% level. Subjects were also monitored non-invasively and hemodynamic
responses to VNS were determined. No significant alterations in hemodynamic
variables were observed. The findings of this human study are consistent with
experiments in non-human animals which demonstrate a pro-nociceptive effect of
low intensity VNS.
PMID- 10779665
TI - Sex-dependent effects of reported familial pain history on recent pain complaints
and experimental pain responses.
AB - Previous research has demonstrated that both sex and familial pain history can
influence clinical pain, and sex is known to affect experimental pain responses.
However, the potential interactive effects of sex and family history on pain
related symptoms and experimental pain have not been investigated. This
experiment examined recent pain complaints and laboratory pain responses as a
function of sex and reported family history of pain in 212 (122 female, 90 male)
young adults. All subjects completed questionnaires regarding family history of
pain, recent pain experiences, and psychological measures of hypervigilance.
Then, warmth detection thresholds, heat pain thresholds and heat pain tolerances
were determined. Results revealed sex-dependent influences of familial pain
history on recent pain complaints and experimental pain responses. Specifically,
a positive family history of pain was associated with increased reports of pain
over the previous month and poorer general health as well as enhanced sensitivity
to thermal stimuli among females but not males. Higher levels of hypervigilance
accounted for some of the family history effects on recent pain complaints but
not experimental pain measures. Potential mechanisms underlying these effects of
family history among females are discussed.
PMID- 10779666
TI - Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in
mice.
AB - Human subjects infected with herpes or varicella-zoster viruses complain of pain,
such as allodynia, in or near the region with vesicles. However, the mechanisms
of the pain are unclear. We show for the first time that infection with herpes
simplex virus type-1 (HSV-1) induces allodynia and hyperalgesia in mice. When HSV
1 was inoculated on the hind paw of the mouse, eruption appeared on the back on
day 5 post-inoculation, and zosteriform skin lesions were developed on the
inoculated side. Allodynia and hyperalgesia became apparent in the hind paw on
the inoculated side on day 5 and persisted until at least day 8. HSV-1 DNA was
detected in the dorsal root ganglia from days 2 to 8 post-inoculation, with a
peak effect on day 5. The application of heat-inactivated HSV-1 induced no
allodynia, hyperalgesia and skin lesion. When started from days 0 or 2, repeated
treatment with acyclovir, anti-HSV-1 agent, inhibited the appearance of
allodynia, hyperalgesia, eruption and the viral proliferation in the dorsal root
ganglia. In contrast, when started from days 5 or 6, acyclovir treatment slightly
inhibited the development of skin lesions and the viral proliferation, but not
allodynia and hyperalgesia. These results suggest that the propagation of HSV-1
in the dorsal root ganglia produces allodynia and hyperalgesia as a result of
functional abnormality of the sensory neurons in mice. This may be a useful model
for studying the mechanisms of herpetic pain.
PMID- 10779667
TI - Transient changes in the synthesis of nitric oxide result in long-term as well as
short-term changes in acetic acid-induced writhing in mice.
AB - A single injection of nitric oxide (NO) synthase (NOS) inhibitors prevents the
development of persistent hyperalgesia induced by various manipulations,
suggesting that NO precipitates long-term changes in nociception. We examined the
possibility that inhibition of NOS may also be sufficient to produce long-term
decreases in nociceptive assays, such as writhing, that are known to be sensitive
to the short-term effects of NOS inhibitors. We characterized short- and long
term effects of NOS inhibitors, N(omega)-nitro-L-arginine (L-NAME) or 7-nitro
indazole (7-NI) injected intrathecally (i.t.) in mice on acetic acid-induced
writhing. Doses of L-NAME that had no effect on hot plate or tail flick latencies
inhibited writhing (0. 01-30 nmol) as well as spinal nNOS activity (5 and 100
nmol) when injected i.t. 60-90 min before testing. Anti-nociception was not
mimicked by D-NAME but was prevented by co-administration with the NO precursor,
L-arginine. Injection i.t. of 7-NI (30 min), a selective inhibitor of neuronal
NOS (nNOS), inhibited NOS activity in the spinal cord and produced anti
nociception, confirming that writhing is sensitive to inhibition of nNOS.
Although the acute action of both NOS inhibitors dissipated completely by 3-6 h,
a delayed and prolonged inhibition of writhing was again observed 24 h after L
NAME (5-100 nmol), a time when spinal NOS activity was no longer inhibited by L
NAME (5 and 100 nmol) or 7-NI (25 nmol). This novel effect appears to be
initiated by the transient inhibition of nNOS as delayed anti-nociception was
mimicked by 7-NI at doses (10-100 nmol) that no longer inhibited spinal nNOS (25
nmol) at 24 h. Co-administration with L-arginine prevented the delayed (24 h)
anti-nociceptive effects of L-NAME (30 nmol). L-Arginine (30 and 100 nmol) was
without effect on nociception when administered alone 60 min or 24 h prior to
testing. Together these data indicate that brief changes in the activity of nNOS
induce both long- as well as short-term changes in nociception.
PMID- 10779668
TI - Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)
epibatidine and ABT-594 in models of persistent inflammatory and neuropathic
pain.
AB - The anti-nociceptive and locomotor effects of the nicotinic acetylcholine
receptor (nAChR) agonists (+)-epibatidine and ABT-594 were compared in the rat.
Acute thermal nociception was measured using the tail flick test. Mechanical
hyperalgesia was measured as paw withdrawal threshold (PWT) in response to a
mechanical stimulus in two animal models of persistent pain; (1) 24 h following
subplantar injections of Freund's complete adjuvant (FCA) into the left hind paw
or (2) 11-15 days following a partial ligation of the left sciatic nerve.
Disruption of locomotor function was assessed using an accelerating rotarod
device. In all tests, (+)-epibatidine was significantly more potent than ABT-594.
Both (+)-epibatidine and ABT-594 dose-dependently increased tail flick latencies
but only at doses that also disrupted performance in the rotarod test. On the
other hand, (+)-epibatidine and ABT-594 dose-dependently reversed inflammatory
and neuropathic hyperalgesia at significantly lower doses than that needed to
disrupt performance in the rotarod test. In summary, ABT-594 is less potent than
(+)-epibatidine in assays of acute and persistent pain and in the rotarod assay.
However, ABT-594 displayed a clearer separation between its motor and anti
hyperalgesic effects. This shows that nicotinic agonists with improved
selectivity between the nicotinic receptor subtypes could provide strong
analgesic effects with a much improved therapeutic window.
PMID- 10779669
TI - Teasing apart quality and validity in systematic reviews: an example from
acupuncture trials in chronic neck and back pain.
AB - The objectives of the study were (1) to carry out a systematic review to assess
the analgesic efficacy and the adverse effects of acupuncture compared with
placebo for back and neck pain and (2) to develop a new tool, the Oxford Pain
Validity Scale (OPVS), to measure validity of findings from randomized controlled
trials (RCTs), and to enable ranking of trial findings according to validity
within qualitative reviews. Published RCTs (of acupuncture at both traditional
and non-traditional points) were identified from systematic searching of
bibliographic databases (e.g. MEDLINE) and reference lists of retrieved reports.
Pain outcome data were extracted with preference given to standardized outcomes
such as pain intensity. Information on adverse effects was also extracted. All
included trials were scored using a five-item 0-16 point validity scale (OPVS).
The individual RCTs were ranked according to their OPVS score to enable more
weight to be placed on the trials of greater validity when drawing an overall
conclusion about the efficacy of acupuncture for relieving neck and back pain.
Statistical analyses were carried out on the OPVS scores to assess the
relationship between trial finding (positive or negative) and validity. Thirteen
RCTs met the inclusion criteria. Five trials concluded that acupuncture was
effective, and eight concluded that it was not effective for relieving back or
neck pain. There was no obvious difference between the findings of trials using
traditional and non-traditional points. Using the new OPVS scale, the validity
scores of the included trials ranged from 4 to 14. There was no significant
relationship between OPVS score and trial finding (positive versus negative).
Authors' conclusions did not always agree with their data. We drew our own
conclusions (positive/negative) based on the data presented in the reports. Re
analysis using our conclusions showed a significant relationship between OPVS
score and trial finding, with higher validity scores associated with negative
findings. OPVS is a useful tool for assessing the validity of trials in
qualitative reviews. With acupuncture for chronic back and neck pain, we found
that the most valid trials tended to be negative. There is no convincing evidence
for the analgesic efficacy of acupuncture for back or neck pain.
PMID- 10779670
TI - Evidence for increased plasma levels of calcitonin gene-related peptide in
migraine outside of attacks.
AB - Although calcitonin gene-related peptide (CGRP) has been shown to be elevated in
jugular venous blood of adult migraineurs during acute migraine attacks, it
remains unknown whether CGRP is increased outside of attacks in jugular or
cubital venous blood. The aim of the present study was to compare interictal
plasma levels of CGRP in adult migraine patients and in healthy controls. Twenty
patients with a diagnosis of migraine with or without aura and 20 healthy
controls were included. In blood from the cubital vein, CGRP levels were
significantly higher in patients (75+/-8 pmol/l (mean+/-SEM)) than in controls
(49+/-3 pmol/l) (P=0.005). The subgroup of patients suffering exclusively from
migraine without aura (n=14) also had significantly higher levels of CGRP (82+/
10 pmol/l) than controls (n=20; 49+/-3 pmol/l) (P=0.001). The findings could not
be explained by confounding factors such as age, sex or use of contraceptive
pills. We therefore conclude that CGRP is increased in cubital venous blood of
migraineurs outside of attack. It is hypothesized that this finding may reflect a
long-lasting or permanent abnormal neurogenic vascular control in patients with
migraine.
PMID- 10779671
TI - Towards an objective quantitative assessment of daily functioning in migraine: a
feasibility study.
AB - Migraine is a chronic disabling disorder, with migraine episodes significantly
reducing quality of life and leading to impaired functioning (physically,
socially, emotionally) both at home and at work. We explored whether ambulatory
accelerometry can be used as an objective method to quantify the behavioral
aspects of migraine-related disability. Four body mounted uni-axial piezo
resistive accelerometers were used to quantify the time spent in different body
postures (lying, sitting, standing), physical activities (walking, cycling) and a
general index of body motility during eight migraine attacks and subsequent
recovery periods of six patients in their habitual environment. The migraine
attacks and recovery periods could be monitored after about 1 h, which was the
time required for the investigator to travel to the patient and for the sensors
to be attached. In order to quantify the influence of a migraine episode on daily
activities, we also performed measurements during a headache-free baseline period
of the same patients. Overall, the procedures functioned well, indicating that
ambulatory accelerometry measurements before, during and after a migraine attack
are feasible to perform. Furthermore, our quantitative data revealed that
migraine always influenced behavior by reducing overall body motility and that,
dependent upon the severity of the attack, the effectiveness of acute treatment
and the time of day, the time spent in various body positions, dynamic
activities, and the number of postural transitions were affected. This
feasibility study showed that ambulatory accelerometry can provide the objective
behavioral effect parameters for the evaluation of migraine and its treatment on
daily functioning in the habitual environment of migraine patients.
PMID- 10779672
TI - Experimental muscle pain produces central modulation of proprioceptive signals
arising from jaw muscle spindles.
AB - The aim of the present study was to investigate the effects of intramuscular
injection with hypertonic saline, a well-established experimental model for
muscle pain, on central processing of proprioceptive input from jaw muscle
spindle afferents. Fifty-seven cells were recorded from the medial edge of the
subnucleus interpolaris (Vi) and the adjacent parvicellular reticular formation
from 11 adult cats. These cells were characterized as central units receiving jaw
muscle spindle input based on their responses to electrical stimulation of the
masseter nerve, muscle palpation and jaw stretch. Forty-five cells, which were
successfully tested with 5% hypertonic saline, were categorized as either dynamic
static (DS) (n=25) or static (S) (n=20) neurons based on their responses to
different speeds and amplitudes of jaw movement. Seventy-six percent of the cells
tested with an ipsilateral injection of hypertonic saline showed a significant
modulation of mean firing rates (MFRs) during opening and/or holding phases. The
most remarkable saline-induced change was a significant reduction of MFR during
the hold phase in S units (100%, 18/18 modulated). Sixty-nine percent of the DS
units (11/16 modulated) also showed significant changes in MFRs limited to the
hold phase. However, in the DS neurons, the MFRs increased in seven units and
decreased in four units. Finally, five DS neurons showed significant changes of
MFRs during both opening and holding phases. Injections of isotonic saline into
the ipsilateral masseter muscle had little effect, but hypertonic saline
injections made into the contralateral masseter muscle produced similar results
to ipsilateral injections with hypertonic saline. These results unequivocally
demonstrate that intramuscular injection with an algesic substance, sufficient to
produce muscle pain, produces significant changes in the proprioceptive
properties of the jaw movement-related neurons. Potential mechanisms involved in
saline-induced changes in the proprioceptive signals and functional implications
of the changes are discussed.
PMID- 10779673
TI - Alleviation of mechanical and thermal allodynia by CGRP(8-37) in a rodent model
of chronic central pain.
AB - CGRP(8-37) is a truncated version of calcitonin gene-related peptide (CGRP) that
binds to the CGRP receptor with similar affinity but does not activate the
receptor and is a highly selective CGRP receptor antagonist. CGRP and activation
of its receptor appear to play a role in peripheral inflammatory and neuropathic
models of pain although there is considerable controversy. The aim of this study
was to examine possible anti-nociceptive effects of CGRP(8-37) on a model of
chronic central neuropathic pain known to develop weeks after spinal hemisection.
Adult male Sprague-Dawley rats were given a spinal hemisection (N=34) or a sham
surgery (N=10) at the T13 spinal segment. An externally accessible PE-10
intrathecal catheter that terminated at T13 was used for drug delivery. Animals
were allowed to recover for 4 weeks at which time the hemisected animals
displayed mechanical and thermal allodynia bilaterally, in both forelimbs and
hindlimbs. CGRP(8-37) was delivered just prior to a testing session in 1, 5, 10,
or 50 nM doses in artificial cerebral spinal fluid in 10 microl volumes. CGRP(8
37) was effective in alleviating mechanical and thermal allodynia in a dose
dependent manner (P<0.05). The 50 nM dose was most efficacious for both forelimb
and hindlimb responses (P<0.05). The period of efficacy was 10 min to onset for a
duration of 20 min. Post-drug washout responses were not statistically
significant compared to pre-drug responses. The sham control groups demonstrated
no statistically significant difference at any dose of CGRP(8-37) when compared
to pre-surgical baseline values. In conclusion, CGRP(8-37) is effective in
abolishing mechanical and thermal allodynia produced by spinal hemisection.
Consequently, the CGRP receptor may play a role in chronic central neuropathic
pain and offers a novel therapeutic approach to managing chronic central pain.
PMID- 10779674
TI - Zinc in the extracellular area of the central nervous system is necessary for the
development of kainic acid-induced persistent hyperalgesia in mice.
AB - Kainic acid produces a persistent hyperalgesia when injected intraperitoneally
(i.p.) in the rat or mouse. At higher doses than those needed to influence
nociception, kainic acid induces seizures and translocation of histologically
reactive zinc in the hippocampus. We tested the hypothesis that zinc, localized
in a population of small diameter primary afferent neurons, plays a role in
kainic acid-induced hyperalgesia similar to that in the hippocampus where zinc
translocation accompanies kainic acid-induced seizures. The importance of zinc in
the extracellular area was assessed by the influence of compounds that chelate
divalent cations (disodium calcium ethylene diaminetetraacetate (CaEDTA)) or zinc
(dipicolinic acid (DPA)) on kainic acid-induced hyperalgesia. When measured using
the tail flick assay, thermal hyperalgesia was blocked by pretreatment
intrathecally (i.t.) with either 10 nmol of NaCaEDTA or 1 nmol of DPA, drugs
whose distribution is limited to the extracellular area. Injection of 10 ng zinc
chloride i.t. had no long-term effect on nociception or on kainic acid-induced
hyperalgesia. Whether zinc is translocated in response to a hyperalgesic dose of
kainic acid was determined using the zinc-selective dye, N-(6-methoxy-8-quinolyl)
para-toluenensulfonamide (TSQ), which produces a delicate stain in the neuropil
of the mouse spinal cord as well as a dense stain in the hippocampus. Injection
of a hyperalgesic dose of kainic acid failed to alter TSQ fluorescence in either
the spinal cord or hippocampus, in contrast to the distinct bleaching of TSQ in
the hippocampus 24 h after a convulsant dose of kainic acid. Together these data
suggest that, while not translocated, zinc in the extracellular area is necessary
but not sufficient for the development of kainic acid-induced hyperalgesia.
PMID- 10779675
TI - Extraterritorial neuropathic pain correlates with multisegmental elevation of
spinal dynorphin in nerve-injured rats.
AB - Neuropathic pain is often associated with the appearance of pain in regions not
related to the injured nerve. One mechanism that may underlie neuropathic pain is
abnormal, spontaneous afferent drive which may contribute to NMDA-mediated
central sensitization by the actions of glutamate and by the non-opioid actions
of spinal dynorphin. In the present study, injuries to lumbar or sacral spinal
nerves elicited elevation in spinal dynorphin content which correlated temporally
and spatially with signs of neuropathic pain. The increase in spinal dynorphin
content was coincident with the onset of tactile allodynia and thermal
hyperalgesia. Injury to the lumbar (L(5)/L(6)) spinal nerves produced elevated
spinal dynorphin content in the ipsilateral dorsal spinal quadrant at the L(5)
and L(6) spinal segments and in the segments immediately adjacent. Lumbar nerve
injury elicited ipsilateral tactile allodynia and thermal hyperalgesia of the
hindpaw. In contrast, S(2) spinal nerve ligation elicited elevated dynorphin
content in sacral spinal segments and bilaterally in the caudal lumbar spinal
cord. The behavioral consequences of S(2) spinal nerve ligation were also
bilateral, with tactile allodynia and thermal hyperalgesia seen in both hindpaws.
Application of lidocaine to the site of S(2) ligation blocked thermal
hyperalgesia and tactile allodynia of the hindpaws suggesting that afferent drive
was critical to maintenance of the pain state. Spinal injection of antiserum to
dynorphin A((1-17)) and of MK-801 both blocked thermal hyperalgesia, but not
tactile allodynia, of the hindpaw after S(2) ligation. These data suggest that
the elevated spinal dynorphin content consequent to peripheral nerve injury may
drive sensitization of the spinal cord, in part through dynorphin acting directly
or indirectly on the NMDA receptor complex. Furthermore, extrasegmental increases
in spinal dynorphin content may partly underlie the development of
extraterritorial neuropathic pain.
PMID- 10779677
TI - Dynamics of ethanol translocation in Saccharomyces cerevisiae as detected by
(13)C-NMR.
AB - (13)C-NMR has yielded to the dynamics study of ethanol as carbon and energy
source in the metabolic oscillation of Saccharomyces cerevisiae. Three ethanol
fractions such as media, cytoplasm and mitochondria were observed and
characterised by different longitudinal relaxation times and chemical shifts.
PMID- 10779676
TI - Lumbar transplant of neurons genetically modified to secrete brain-derived
neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve
constriction.
AB - Chronic delivery of anti-nociceptive molecules by means of cell grafts near the
pain processing centers of the spinal cord is a newly developing technique for
the treatment of neuropathic pain. The rat neuronal cell line, RN33B, derived
from E13 rat brainstem raphe and immortalized with the SV40 temperature-sensitive
allele of large T antigen (tsTag), was transfected with rat brain-derived
neurotrophic factor cDNA (BDNF), and the BDNF-synthesizing cell line, 33BDNF.4,
was isolated. The 33BDNF.4 cells synthesized mature BDNF protein at permissive
temperature (33 degrees C), when the cells were proliferating, and during
differentiation at non-permissive temperature (39 degrees C) in vitro. The bio
active BDNF protein was also secreted by the cells during both growth conditions,
as measured by ELISA analysis of BDNF content and secretion. The bio-activity of
the BDNF in 33BDNF.4 cell conditioned media was assessed by neurite outgrowth
from E15 dorsal root ganglion (DRG) cultures. A control cell line, 33V1,
transfected with the vector alone, did not synthesize or secrete any significant
BDNF at either growth condition. Both cell lines were used as grafts in a model
of chronic neuropathic pain induced by unilateral chronic constriction injury
(CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile
allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the
affected hindpaw. When 33BDNF.4 and 33V1 cells were transplanted in the lumbar
subarachnoid space of the spinal cord 1 week after CCI, they survived greater
than 7 weeks on the pia mater around the spinal cord and the 33BDNF.4 cells
continued to synthesize BDNF in vivo. Furthermore, the tactile and cold allodynia
and tactile and thermal hyperalgesia induced by CCI was significantly reduced
during the 2-7 week period after grafts of 33BDNF.4 cells. The maximal effect on
chronic pain behaviors with the BDNF grafts occurred 2-3 weeks after transplant
and the anti-nociceptive effects of the BDNF cell grafts was permanent.
Transplants of the control 33V1 cells had no effect on the allodynia and
hyperalgesia induced by CCI and these cells did not synthesize BDNF in vivo.
These data suggest that a chronically applied, low local dose of BDNF supplied by
transplanted cells near the spinal dorsal horn was able to reverse the
development of chronic neuropathic pain following CCI. The use of neural cell
lines that are able to deliver anti-nociceptive molecules, such as BDNF, in a
model of chronic pain offers a novel approach to pain management and such
'biologic minipumps' can be developed for safe use in humans.
PMID- 10779678
TI - A new Chinese hamster ovary cell line expressing alpha2,6-sialyltransferase used
as universal host for the production of human-like sialylated recombinant
glycoproteins.
AB - Chinese hamster ovary (CHO) cells are widely employed to produce glycosylated
recombinant proteins. Our group as well as others have demonstrated that the
sialylation defect of CHO cells can be corrected by transfecting the alpha2,6
sialyltransferase (alpha2,6-ST) cDNA. Glycoproteins produced by such CHO cells
display both alpha2,6- and alpha2,3-linked terminal sialic acid residues, similar
to human glycoproteins. Here, we have established a CHO cell line stably
expressing alpha2,6-ST, providing a universal host for further transfections of
human genes. Several relevant parameters of the universal host cell line were
studied, demonstrating that the alpha2,6-ST transgene was stably integrated into
the CHO cell genome, that transgene expression was stable in the absence of
selective pressure, that the recombinant sialyltransferase was correctly
localized in the Golgi and, finally, that the bioreactor growth parameters of the
universal host were comparable to those of the parental cell line. A second step
consisted in the stable transfection into the universal host of cDNAs for human
glycoproteins of therapeutic interest, i.e. interferon-gamma and the tissue
inhibitor of metalloproteinases-1. Interferon-gamma purified from the universal
host carried 40.4% alpha2,6- and 59.6% alpha2,3-sialic acid residues and showed
improved pharmacokinetics in clearance studies when compared to interferon-gamma
produced by normal CHO cells.
PMID- 10779679
TI - The presence of an extractable substance in the CSF of humans with cerebral
vasospasm after subarachnoid haemorrhage that correlates with phosphatase
inhibition.
AB - The cellular events leading to cerebral vasospasm after subarachnoid haemorrhage
are poorly understood, although an increase in smooth muscle myosin light chain
phosphorylation has been observed. This study set out to determine if phosphatase
inhibition may be involved in the pathological maintenance of tension observed
during vasospasm. We found that 1 nM okadaic acid, a type 2A protein phosphatase
inhibitor, elicited an increase in rate of O(2) consumption in the porcine
carotid artery similar to that by cerebrospinal fluid (CSF) from vasospastic
patients (CSF(V), n=5) (control 0.23+/-0.03, CSF(V) 0.84+/-0.16 and okadaic acid
0.85+/-0.02 micromol min(-1) g dwt(-1)). It was also observed that phosphatase
inhibition with 1 nM okadaic acid significantly slowed relaxation after a stretch
in a similar fashion to CSF(V) haemorrhage. CSF from vasospastic subarachnoid
haemorrhage patients, but not from those without vasospasm, contains an
extractable substance which modulates myosin light chain phosphorylation in
vitro. A phosphatase preparation obtained from the porcine carotid artery
dephosphorylated 63+/-2% of the phosphorylated (MLC(20)) substrate in vitro, and
non-vasospastic CSF treated enzyme dephosphorylated 60+/-2.6%. Okadaic acid
inhibited phosphatase dephosphorylated only 7.5+/-1% of the substrate where
CSF(V) treated enzyme dephosphorylated 22+/-2.8% of the substrate. We conclude
that inhibition of smooth muscle phosphatase may be involved in the mechanisms
associated with cerebral vasospasm after subarachnoid haemorrhage.
PMID- 10779681
TI - A lectin from an edible mushroom Pleurotus ostreatus as a food intake-suppressing
substance.
AB - In an experiment in which rats were allowed free access to food and water, the
rats did not eat the diet containing a mushroom Pleurotus ostreatus even if they
were emaciated. A P. ostreatus lectin (POL) was isolated from the mushroom as the
food intake-suppression principle. In hemagglutination inhibition assays, Me
alphaGalNAc was the most potent inhibitor among the monosaccharides tested. Among
all the sugars tested, 2'-fucosyllactose (Fucalpha1-->2Galbeta1-->4Glc) was the
strongest inhibitor and its inhibitory potency was five times greater than that
of Me-alphaGalNAc. POL exhibited a binding ability to bovine submaxillary mucin
(BSM) and asialo-BSM and the other glycoproteins were inert to the binding. The
food intake-suppressing activity of POL was dependent on the dose. The diet
containing 0.1% POL caused a 50% decrease in the food intake of rats against the
control.
PMID- 10779680
TI - Transport of 1,5-anhydro-D-glucitol into insulinoma cells by a glucose-sensitive
transport system.
AB - The uptake of 1,5-anhydro-D-glucitol (1,5-AG) occurs by passive mechanisms in
cells or tissues that have passive glucose transporters. It is known that serum
1,5-AG concentrations are reduced in patients with diabetes mellitus. To
elucidate the metabolism of this substance and its physiological role in
pancreatic beta-cells, we assayed 1,5-AG transport in the insulinoma-derived cell
lines, RINr and MIN6. Both cell lines showed an insulin-insensitive,
concentration-dependent uptake of 1,5-AG with a saturation time of approximately
120 min, and most of the 1,5-AG in the cytoplasm was in the free form. A biphasic
saturation curve was obtained using a wide range of 1,5-AG concentrations,
suggesting that accumulation was mediated by a high affinity and a low affinity
transporter. The high affinity transporter had a K(m) of 10.4 in RINr cells and
13.0 mM in MIN6 cells, and the low affinity transporter had a K(m)100 times,
being much higher than the physiological concentrations of 1,5-AG. These results
indicate that the 1,5-AG carrier system in insulinoma cells is distinct from that
in either the somatic cells or renal tubular cells. These findings also suggest
that a unique 1,5-AG transport system is present in pancreatic beta-cells.
PMID- 10779682
TI - Isolation and characterization of DM40 and DM43, two snake venom
metalloproteinase inhibitors from Didelphis marsupialis serum.
AB - From Didelphis marsupialis serum, two antihemorrhagic proteins were isolated by
DEAE-Sephacel, Phenyl-Sepharose and Superdex 200 and characterized. Their masses
by mass spectrometry were 40318 AMU for DM40 and 42373 and 43010 AMU for DM43,
indicating the presence of isoforms for the last. Molecular masses of 44.8 and
47.3 were obtained by SDS-PAGE, respectively for DM40 and DM43. Both inhibitors
showed isoelectric points lower than 3.5 and glycosylation percentages varying
from 20.5 to 29.0%, as estimated by chemical deglycosylation and amino acid
analysis. N-terminal sequences of the first 17 residues of DM40 and DM43 were
identical except for the exchange of R9 for P9. Both were homologous to oprin, a
similar inhibitor from Didelphis virginiana serum. No evidence of complex
formation between DM40 and DM43 was observed either by native PAGE or gel
filtration chromatography. In addition to the antihemorrhagic activity, DM40 and
DM43 inhibited the hydrolysis of casein, fibrinogen and fibronectin by Bothrops
jararaca venom. DM43 also showed antilethal, antiedematogenic and
antihyperalgesic activities. None of the inhibitors showed enzymatic activity on
casein. Both proteins formed stable complexes with jararhagin and inhibited its
hemorrhagic effect as well as the enzymatic activity of this toxin on fluorogenic
substrate.
PMID- 10779683
TI - NADH-dependent decavanadate reductase, an alternative activity of NADP-specific
isocitrate dehydrogenase protein.
AB - The well known NADP-specific isocitrate dehydrogenase (IDH) obtained from pig
heart was found to oxidize NADH with accompanying consumption of oxygen
(NADH:O(2)=1:1) in presence of polyvanadate. This activity of the soluble IDH
protein has the following features common with the previously described membrane
enzymes: heat-sensitive, active only with NADH but not NADPH, increased rates in
acidic pH, dependence on concentrations of the enzyme, NADH, decavanadate and
metavanadate (the two constituents of polyvanadate), and sensitivity to SOD and
EDTA. Utilizing NADH as the electron source the IDH protein was able to reduce
decavanadate but not metavanadate. This reduced form of vanadyl (V(IV)) was
similar in its eight-band electron spin resonance spectrum to vanadyl sulfate but
had a 20-fold higher absorbance at its 700 nm peak. This decavanadate reductase
activity of the protein was sensitive to heat and was not inhibited by SOD and
EDTA. The IDH protein has the additional enzymic activity of NADH-dependent
decavanadate reductase and is an example of "one protein--many functions".
PMID- 10779684
TI - Enhancement of AA-amyloid formation in mice by transthyretin amyloid fragments
and polyethylene glycol.
AB - The mechanism behind amyloid formation is unknown in all types of amyloidosis.
Several substances can enhance amyloid formation in animal experiments. To induce
secondary systemic amyloid (AA-type amyloid) formation, we injected silver
nitrate into mice together with either amyloid fibrils obtained from patients
with familial polyneuropathy (FAP) type I or polyethylene glycol (PEG). Mice
injected with silver nitrate only served as controls. Amyloid deposits were
detectable at day 3 in animals injected with amyloid fibrils and in those
injected with PEG, whereas in control mice, deposits were not noted before day
12. Our results indicate that amyloid fibrils from FAP patients and even a non
sulfate containing polysaccharide (PEG) have the potential to act as amyloid
enhancing factors.
PMID- 10779685
TI - Spatiotemporal dynamics of fibrin formation and spreading of active thrombin
entering non-recalcified plasma by diffusion.
AB - The spatiotemporal dynamics of clot growth was studied in non-stirred non
recalcified plasma where thrombin entered by diffusion. Under these conditions,
the clot rapidly grew for 30-45 min and then stopped growing on reaching 0.4-0.5
mm in size. The dynamics of clot growth and its size almost did not depend on the
thrombin concentration in the range from 50 to 400 nM. FITC-thrombin was shown to
permeate the growing clot. The clot size in antithrombin-deficient plasma
increases with decreasing antithrombin concentration, being 1.5 mm in the plasma
depleted of antithrombin to 5% of its initial level. The data on the spatial
distribution of amidolytic activity in the growth zone of the clot suggested that
thrombin was not the sole source of this activity. Analysis showed that this
additional activity arising during thrombin diffusion into plasma was largely
accounted for by thrombin-alpha(2)-macroglobulin complex.
PMID- 10779686
TI - Modulation of glucan-binding protein activity in streptococci by fluoride.
AB - Glucan-binding lectin (GBL) activity of Streptococcus sobrinus was significantly
reduced by fluoride in the growth medium. Approximately 1.5 mM fluoride was
required for a 50% reduction in GBL activity. In addition to the GBL, several
other glucan-binding proteins were reduced when the bacteria were grown in
subinhibitory fluoride. Fluoride had no effect on glucosyltransferases (GTFs),
enzymes capable of converting sucrose into alpha-1,6-glucans. All the proteins
were detected by use of enhanced chemiluminescence (ECL of fluorescein-labeled
dextran) and Western blotting of renatured SDS-PAGE gels. The effects of fluoride
on the bacteria were abrogated when the manganous ion was included in the growth
medium. It thus appears that one mechanism of action of fluoridated water is its
effects on glucan-binding proteins. The fluoride may be reducing metabolism of
the mangano aquo ion, essential for expression of the glucan-binding proteins.
PMID- 10779687
TI - Importance of association between permeabilization and electrophoretic forces for
intramuscular DNA electrotransfer.
AB - Gene transfer using electrical pulses is a rapidly expanding field. Many studies
have been performed in vitro to elucidate the mechanism of DNA electrotransfer.
In vivo, the use of efficient procedures for DNA electrotransfer in tissues is
recent, and the question of the implied mechanisms is largely open. We have
evaluated the effects of various combinations of square wave electric pulses of
variable field strength and duration, on cell permeabilization and on DNA
transfection in the skeletal muscle in vivo. One high voltage pulse of 800 V/cm,
0.1 ms duration (short high pulse) or a series of four low voltage pulses of 80
V/cm, 83 ms duration (long low pulses) slightly amplified transfection efficacy,
while no significant permeabilization was detected using the (51)Cr-EDTA uptake
test. By contrast, the combination of one short high pulse followed by four long
low pulses led to optimal gene transfer efficiency, while inducing muscle fibers
permeabilization. These results are consistent with additive effects of
electropermeabilization and DNA electrophoresis on electrotransfer efficiency.
Finally, the described new combination, as compared to the previously reported
use of repeated identical pulses of intermediate voltage, leads to similar gene
transfer efficiency, while causing less permeabilization and thus being likely
less deleterious. Thus, combination of pulses of various strengths and durations
is a new procedure for skeletal muscle gene transfer that may represents a clear
improvement in view of further clinical development.
PMID- 10779688
TI - Inverting character of alpha-glucuronidase A from Aspergillus tubingensis.
AB - Alpha-glucuronidase A from Aspergillus tubingensis was found to be capable of
liberating 4-O-methyl-D-glucuronic acid (MeGlcA) only from those beechwood
glucuronoxylan fragments in which the acid is attached to the non-reducing
terminal xylopyranosyl residue. Reduced aldotetrauronic acid, 4-O-methyl-D
glucuronosyl-alpha-1,2-D-xylopyranosyl-beta-1,4-xylopyranosyl-beta-1,4-xylitol,
was found to be a suitable substrate to follow the stereochemical course of the
hydrolytic reaction catalyzed by the purified enzyme. The configuration of the
liberated MeGlcA was followed in a D(2)O reaction mixture by (1)H-NMR
spectroscopy. It was unambiguously established that MeGlcA was released from the
substrate as its beta-anomer from which the alpha-anomer was formed on
mutarotation. This result represents the first experimental evidence for the
inverting character of a microbial alpha-glucuronidase, a member of glycosyl
hydrolase family 67 (EC 3.1.1.139).
PMID- 10779689
TI - Redox properties of iron-dithiocarbamates and their nitrosyl derivatives:
implications for their use as traps of nitric oxide in biological systems.
AB - While the Fe(2+)-dithiocarbamate complexes have been commonly used as NO traps to
estimate NO production in biological systems, these complexes can undergo complex
redox chemistry. Characterization of this redox chemistry is of critical
importance for the use of this method as a quantitative assay of NO generation.
We observe that the commonly used Fe(2+) complexes of N-methyl-D-glucamine
dithiocarbamate (MGD) or diethyldithiocarbamate (DETC) are rapidly oxidized under
aerobic conditions to form Fe(3+) complexes. Following exposure to NO,
diamagnetic NO-Fe(3+) complexes are formed as demonstrated by the optical,
electron paramagnetic resonance and gamma-resonance spectroscopy,
chemiluminescence and electrochemical methods. Under anaerobic conditions the
aqueous NO-Fe(3+)-MGD and lipid soluble NO-Fe(2+)-DETC complexes gradually self
transform by reductive nitrosylation into paramagnetic NO-Fe(2+)-MGD complexes
with yield of up to 50% and the balance is converted to Fe(3+)-MGD and nitrite.
In dimethylsulfoxide this process is greatly accelerated. More efficient
transformation of NO-Fe(3+)-MGD into NO-Fe(2+)-MGD (60-90% levels) was observed
after addition of reducing equivalents such as ascorbate, hydroquinone or
cysteine or with addition of excess Fe(2+)-MGD. With isotope labeling of the NO
Fe(3+)-MGD with (57)Fe, it was shown that these complexes donate NO to Fe(2+)
MGD. NO-Fe(3+)-MGD complexes were also formed by reversible oxidation of NO
Fe(2+)-MGD in air. The stability of NO-Fe(3+)-MGD and NO-Fe(2+)-MGD complexes
increased with increasing the ratio of MGD to Fe. Thus, the iron-dithiocarbamate
complexes and their NO derivatives exhibit complex redox chemistry that should be
considered in their application for detection of NO in biological systems.
PMID- 10779690
TI - Copper-catalyzed autoxidations of GSH and L-ascorbic acid: mutual inhibition of
the respective oxidations by their coexistence.
AB - Glutathione (GSH) is known to inhibit copper-catalyzed autoxidation of L-ascorbic
acid (AA); in this study, AA was found to conversely inhibit copper-catalyzed
autoxidation of GSH. To elucidate the mechanism of the mutual inhibition of the
autoxidations of these two reducing substances in their coexistence, we have
kinetically investigated these phenomena. The study of the former phenomenon
revealed that GSH forms a 1:1 chelate with Cu(+) and thereby prevents the
autoxidation of AA. By the analysis of the latter phenomenon, it was postulated
that the inhibition of GSH oxidation by AA is due to rapid reduction of thiyl
radical of GSH by AA rather than competition of AA with GSH in the reduction of
Cu(2+). The effect of GSH on the formation of hydroxyl radical by the copper
catalyzed autoxidation of AA was also studied and it was found that the hydroxyl
radical formation was delayed dose-dependently by GSH with time lags comparable
to those of the oxidation of AA. Because there are several lines of evidence that
redox-active copper ions are released from tissues under pathological conditions,
it is possible that such copper ions coexist with AA and GSH in vivo, and in such
a situation, GSH may exert an inhibitory effect on the hydroxyl radical formation
caused by the autoxidation of AA.
PMID- 10779691
TI - Fast repair of dAMP radical anions by phenylpropanoid glycosides and their
analogs.
AB - Repair effect on 2'-deoxyadenosine-5'-monophosphate (dAMP) radical anions by
phenylpropanoid glycosides (PPGs) and their analogs, isolated from Chinese folk
medicinal herb, was studied using pulse radiolysis technique. The radical anion
of dAMP was formed by the reaction of hydrated electron with dAMP. On pulse
irradiation of nitrogen-saturated dAMP aqueous solution containing 0.2 M t-BuOH
and one of PPGs or their analogs, the transient absorption spectrum of the
radical anion of dAMP decayed with the formation of that of the radical anion of
PPGs or their analogs within several decades of microseconds after electron pulse
irradiation. The results indicated that dAMP radical anions can be repaired by
PPGs or their analogs. The rate constants of the repair reactions were deduced to
be 1.6-4.5 x 10(8) M(-1) s(-1).
PMID- 10779692
TI - Synthesis and secretion of selenoprotein P by cultured rat astrocytes.
AB - Selenoprotein P is an extracellular protein that has been postulated to have an
oxidant defense function. It has survival-promoting properties for cultured
neurons and its mRNA is present in the brain. This study sought to determine the
primary structure of rat brain selenoprotein P and to assess its production by
cultured brain cells. The cDNA of selenoprotein P was isolated from a rat brain
cDNA library and was found to encode the same peptide sequence as rat liver cDNA.
Thus the primary structure of brain selenoprotein P is the same as selenoprotein
P from liver. Astrocytes and a cerebellar granule cell preparation (CGC) were
obtained from rat brains and established in culture. The CGC was estimated to
contain up to 5% glial cells. Both preparations were shown to contain
selenoprotein P mRNA. During incubation with (75)Se-labeled selenite, both cell
preparations secreted a (75)Se-labeled protein into the medium that corresponded
in size to selenoprotein P. Also, the (75)Se-labeled protein could be
precipitated from both media with an antiserum to selenoprotein P. This shows
that astrocytes and the CGC secrete selenoprotein P. Selenoprotein P is made in
the brain and may have an oxidant defense function there.
PMID- 10779693
TI - Presence and inducibility of peroxisomes in a human glioblastoma cell line.
AB - We investigated the effect of the peroxisomal proliferator (PP) perfluorodecanoic
acid (PFDA), alone or in combination with 9-cis-retinoic acid (RX) on the human
glioblastoma cell line Lipari (LI). Cell proliferation, apoptotic rate,
peroxisome morphology and morphometry, peroxisomal enzyme activities and the
presence of peroxisome proliferator-activated receptors (PPARs) were examined. We
show that PFDA alone produces pleiotropic effects on LI cells and that RX
enhances some of these effects. Peroxisomal number and relative volume, as well
as palmitoyl-CoA oxidase activity and protein, are increased by PFDA treatment,
with a synergistic effect by RX. The latter, alone or in association with PFDA,
induces catalase activity and protein, increases apoptosis and decreases cell
proliferation. PPAR isotypes alpha and gamma were detected in LI cells. While the
former is apparently unaffected by either treatment, the latter increases in
response to PFDA, independent of the presence of RX. The results of this study
are discussed in terms of PPARalpha activation and PPARgamma induction by PFDA,
by either a direct or an indirect mechanism.
PMID- 10779694
TI - MUC-6 mucin is a major component of "blood group substance" from human ovarian
cyst fluid.
AB - Ovarian cyst fluid has been a valuable source of the mucins (traditionally termed
"blood group substances") that were used for the elucidation of the structures of
the ABO Lewis blood group determinants, but the identity of the mucin peptide
core(s) carrying these carbohydrate specificities is not known. An ovarian cyst
fluid mucin was purified, deglycosylated with HF and digested with trypsin or
chymotrypsin to yield a number of peptides. Amino acid sequencing of these
peptides yielded five different sequences which showed complete or partial
homology to the MUC-6 apomucin deduced from DNA sequencing. As no other sequences
were identified, it is concluded that MUC-6 is the major mucin core structure of
ovarian cyst fluid mucin.
PMID- 10779695
TI - The blood-nerve barrier: enzymes, transporters and receptors--a comparison with
the blood-brain barrier.
AB - The blood-brain barrier (BBB) has been much more extensively investigated than
the blood-nerve barrier (BNB). Nevertheless it is clear that there are both
similarities and differences in the molecular and morphophysiological
characteristics of the two barrier systems. A number of enzymes, transporters and
receptors have been investigated at both the BNB and BBB, as well as in the
perineurium of peripheral nerves, which is also a metabolically active diffusion
barrier. While there have been few systematic comparisons of the distribution of
these molecules in both the BNB and BBB, it is apparent from the data available,
reviewed in this article, that their distribution also supports the concept of
the BNB and BBB having some features in common but also showing distinct
identities. These similarities and differences cannot simply be accounted for by
the presence of the inductive influences of astrocytes at the BBB and absence at
the BNB. Whether the Schwann cell also has the capacity to induce some BNB
properties remains to be determined.
PMID- 10779696
TI - Long-term theophylline treatment changes the effects of angiotensin II and
adenosinergic agents on the seizure threshold.
AB - The effects of angiotensin II (ANG II), sarmesin, losartan, PD 123319, and
adenosine A (1) receptor agonist N(6)-cyclopentyladenosine (CPA) administered
i.c.v. in untreated and in theophylline-treated male mice (50 mg/kg i.p. twice
daily for 14 days) were studied on the pentylenetetrazol (PTZ) seizure threshold.
The threshold was increased after long-term theophylline treatment. ANG II,
sarmesin, and CPA increased the threshold in theophylline-untreated mice, whereas
it decreased the threshold in theophylline-treated animals. Losartan did not
change the threshold in theophylline-untreated mice but decreased it in
theophylline-treated animals. PD 123319 did not change the seizure threshold both
in theophylline-untreated and -treated mice. Taken together, the data
demonstrated that repeated exposure to theophylline selectively changes the
effects of ANG II and adenosinergic agents on the PTZ seizure threshold. The
results indicate that both angiotensin AT(1) and adenosine A(1) receptor subtypes
could possess interactive mechanisms of adaptation to chronic theophylline
treatment.
PMID- 10779698
TI - Clomethiazole protects against hemineglect in a primate model of stroke.
AB - Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in
the marmoset, a New World species of monkey, produces unilateral functional
deficits, including motor neglect with the contralesional arm and contralesional
spatial hemineglect. In this study we examined whether clomethiazole, a drug
which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of
the hemineglect and other deficits in this primate model of stroke. Nine monkeys
received pMCAO; 1 h later four of the nine were administered clomethiazole by
intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps,
which released clomethiazole for 48 h. The monkeys had been trained and tested on
a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks
later. Three weeks after pMCAO, monkeys treated with clomethiazole had a
significantly reduced degree of spatial neglect compared to untreated controls.
Clomethiazole was not effective against the severe contralesional motor
impairment in the current study, although it ameliorated a somewhat less severe
motor deficit in a previous study in which the more distal, M2 segment of the
middle cerebral artery had been occluded. Postmortem analysis of the brains
showed that clomethiazole treatment had significantly reduced the area of damage
in part of the parietal cortex. These data suggest that clomethiazole may reduce
the neglect that can be a debilitating consequence of right-sided stroke in man.
PMID- 10779697
TI - kappa-opioid agonist stimulated regional distribution of [(35)S]GTPgammas binding
in butorphanol continuously infused rat.
AB - Butorphanol is a mixed agonist/antagonist opioid analgesic agent, which exerts
its effects mainly by interaction with the kappa-opioid receptor. Opioid
receptors are coupled to G proteins of G(i)/G(o) family, and recently a decrease
in micro-opioid activation of G proteins has been reported in specific brainstem
nuclei after chronic morphine administration. The influence of centrally
administered butorphanol on agonist-stimulated G protein coupling was examined in
the rat brain, using in situ guanylyl-5'-O-(gamma-[(35)S]thio)-triphosphate
(GTPgammaS) binding autoradiography. Rats were treated with butorphanol (26
nmol/microl/h) by intracerebroventricular infusion via osmotic minipumps for 3
days. The distribution of [(35)S]GTPgammaS binding in the brain 7 h after the
termination of butorphanol infusion was measured in the presence or absence of
the selective kappa-opioid agonist, U-50,488. This agonist significantly
increased [(35)S]GTPgammaS binding in the parietal cortex, caudate putamen,
thalamus, and central gray of control rats, but not in those regions of the
butorphanol-infused animals. These results suggest that chronic administration of
butorphanol developed tolerance and abolished U-50,488 activation of G proteins
in these brain areas.
PMID- 10779699
TI - Peripheral NMDA and non-NMDA receptors contribute to nociception: an
electrophysiological study.
AB - The present study investigated the effects of peripheral administration of N
methy-D-aspartate (NMDA) and non-NMDA receptor antagonists on C-fiber evoked
responses of the spinal dorsal horn neurons in the spinalized rats. When DL-2
amino-5-phosphonovaleric acid (AP5) (10 mM, 1 mM, 0.1 mM, 20 microl) or 6, 7
dinitroquinoxaline-2, 3-dione (DNQX) (1 mM, 0.1 mM, 0.01 mM, 20 microl) was
subcutaneously injected into the receptive field on the hindplantar region, C
fiber evoked responses of the dorsal horn neurons were profoundly inhibited in a
dose-dependent manner. Three hours after subcutaneous injection of carrageenan
into the ipsilateral hindpaw, NMDA and non-NMDA antagonist-induced inhibition of
C-fiber evoked responses was more potent than that in the normal rat (Student's t
test, p < 0.05). In the carragenan-treated rats, DNQX-induced inhibition was
stronger than AP-5-induced one (Student's t-test, p < 0.05). The results suggest
that peripheral NMDA and non-NMDA receptors are involved in mediating excitation
of nociceptors.
PMID- 10779700
TI - Diminished central fatigue by inhibition of the L-system transporter for the
uptake of tryptophan.
AB - Nagase genetically analbuminemic rats (NAR) were run to fatigue. Administration
of branched chain amino acids (BCAA) before exhaustive exercise, resulted in a
post-fatigue decreased tryptophan uptake (-22%, p < 0.05) and 5-hydroxytryptophan
(5-HTP) uptake (-29%, p < 0.01) into the synaptosomes isolated from the striatum
when compared with saline administration. At the same time, NAR who received
either BCAA or 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH, a specific
inhibitor for the L-system transporter) had a considerably prolonged run time to
exhaustion (by twofold), compared to those who received either saline or albumin
treatments. When classified by run time, it was of interest that, when the data
for BCAA and BCH treatments for the longer run time NAR (Group B) was combined,
it gave rise to a significant decrease in synaptosomal tryptophan and 5-HTP of a
similar magnitude to that observed with BCAA alone. These levels were lower than
those observed in NAR in the shorter run time group (Group A) for all treatments.
These results support the view that an activated serotonergic function may be
involved in central fatigue, which can be diminished by inhibition of the L
system transporter.
PMID- 10779701
TI - Deramciclane inhibits N-methyl-D-aspartate receptor function.
AB - Effects of the novel anxiolytic drug deramciclane on excitatory amino acid
release and transmembrane Ca(2+) ion flux processes were compared in rat
cerebrocortical homogenates containing resealed plasmalemma fragments and nerve
endings. Deramciclane (10 microM) significantly inhibited [(3)H]D-aspartate
release and transmembrane Ca(2+) flux to N-methyl-D-aspartate in the absence of
Mg(2+). By contrast, inhibition of [(3)H]D-aspartate release and transmembrane
Ca(2+) flux evoked by 0.1 mM (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionate in the presence of Mg(2+) and 10 microM cyclothiazide by 10 microM
deramciclane was not significant. In the presence of N-methyl-D-aspartate
receptor antagonists, deramciclane (10 microM) did not inhibit [(3)H]D-aspartate
release to N-methyl-D-aspartate. These results suggest an involvement of the
inhibition of a presynaptic N-methyl-D-aspartate receptor in the anxiolytic
properties of deramciclane.
PMID- 10779702
TI - Effects of the anion channel blocker DIDS on ouabain- and high K(+)-induced
release of amino acids from the rat cerebral cortex.
AB - Amino acid release from the rat cerebral cortex was analyzed using an in vivo
cortical cup perfusion model. Topical applications of ouabain or high
extracellular K(+) were used to mimic two dimensions of ischemic conditions which
promote cell swelling and amino acid release. Ouabain (30 microM) induced
significant releases of taurine, gamma-aminobutyric acid (GABA), aspartate,
glutamate and phosphoethanolamine. The anion channel blocker, 4, 4'
diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS; 1 mM), inhibited ouabain
induced release of all these amino acids except for glutamate. Exposure to high
extracellular K(+) (75 mM) induced a delayed rise in the levels of taurine in the
superfusates and an immediate increase in GABA levels. There were no significant
releases of other amino acids. The release of taurine and GABA was sensitive to
the blocking of anion channels with DIDS. Both ouabain- and high K(+)-induced
taurine release is likely to be mediated by DIDS sensitive anion channels. The
extracellular accumulation of the other amino acids, where insensitive to DIDS,
may be mediated by mechanisms other than swelling-induced anion channels.
PMID- 10779703
TI - Mice transgenic for the human Huntington's disease mutation have reduced
sensitivity to kainic acid toxicity.
AB - The mechanism underlying the pathology of Huntington's disease (HD) is unknown,
although there is substantial evidence supporting a role for excitotoxicity. The
discovery of abnormal aggregations of protein in the brains of patients with HD,
as well as in the brains of transgenic mice modeling this disease, has led to the
suggestion that these "inclusions" have a pathogenic role. However, the
relationship between inclusion formation and the progressive neurodegeneration in
HD remains unclear. Here, we used mice transgenic for the first exon of the HD
gene and an expanded CAG repeat (R6/2 line) to examine the role of neuronal
intranuclear inclusions in kainic acid (KA) excitotoxicity. Unexpectedly, we
found that the toxicity of KA was markedly attenuated in R6/2 mice compared with
wild-type mice. In particular, the number and severity of KA-induced seizures in
R6/2 mice was significantly reduced. When seizures occurred in 3-week-old R6/2
mice, we found lesions in the CA3 region of the hippocampus. However, neuronal
intranuclear inclusions were not induced by KA in 3-week-old mice. Further, in
older mice (9 weeks), the pre-existence of inclusions in CA3 neurons did not
increase the vulnerability of neurons to KA, since no lesions were seen in 9-week
R6/2 mouse brain. Our results suggest that an increased susceptibility to
excitotoxic stimuli does not underlie the early phase of the neurological
phenotype in R6/2 mice, although a role in later stages is not excluded by our
findings. The significance of these findings is discussed in the context of the
R6/2 mouse as a model for HD.
PMID- 10779704
TI - Interferon-gamma-responsive neuronal sites in the normal rat brain: receptor
protein distribution and cell activation revealed by Fos induction.
AB - Constitutive expression of the interferon-gamma receptor protein (IFN-gammaR),
and the distribution of cells in which Fos, a marker of cell activation, is
induced by intracerebroventricular administration of IFN-gamma, were studied in
the rat brain by immunohistochemistry. IFN-gammaR immunopositivity was found in
neuronal elements, which exhibited a selective distribution being concentrated in
the piriform and entorhinal cortex, midline thalamus and medial hypothalamic
structures, brainstem nociceptive relays (including the periaqueductal gray, the
parabrachial nuclei and the caudal part of the spinal trigeminal nuclei), and
circumventricular organs such as the median eminence and area postrema. IFN-gamma
induced Fos expression mostly corresponded to neuronal sites of receptor
distribution. Because of its topographical distribution, it is suggested that
activation of the IFN-gammaR in neurons may play a role to limit spread of
infections in the brain and, in concert with other proinflammatory cytokines, to
modulate adaptive responses to an antigen challenge mediated by the central
nervous system.
PMID- 10779705
TI - The biology of enhancer-dependent transcriptional regulation in bacteria:
insights from genome sequences.
AB - The bacterial transcription factor sigma(N) (sigma-N, sigma-54, RpoN) confers
upon RNA polymerase (RNAP) properties distinct from those of the major house
keeping form of RNAP, which contains sigma(70) (sigma-70, RpoD). Transcription by
RNAP containing sigma(N) is subject to enhancer-dependent regulation. Far from
being an 'oddity' or 'exception to the rule', the occurrence of sigma(N) in the
genome sequences of such diverse bacteria as Aquifex aeolicus, Bacillus subtilis,
Chlamydia spp. and Borrelia burgdorferi argues for its biological importance. The
availability of complete genome sequences of several (eu)bacteria offers an
opportunity to extend our understanding of this special form of transcriptional
regulation. By scanning their genome sequences, new functions have been predicted
for enhancer-dependent transcription in A. aeolicus, Chlamydia trachomatis,
Escherichia coli, Treponema pallidum and B. burgdorferi.
PMID- 10779706
TI - Osmoregulated periplasmic glucans in Proteobacteria.
AB - Large amounts of osmoregulated periplasmic glucans (OPGs) are found in the
periplasmic space of Proteobacteria. Four families of OPGs are described on the
basis of structural features of the polyglucose backbone. Depending on the
species considered, OPGs can be modified to various extent by a variety of
substituents. Genes governing the backbone synthesis are identified in a limited
number of species. They belong to three unrelated families. OPG synthesis is
subject to osmoregulation and feedback control. Osmoregulation can occur at the
level of gene expression and/or at the level of enzyme activity. Mutants
defective in OPG synthesis have a highly pleiotropic phenotype, indicative of an
overall alteration of their envelope properties. Mutants of this kind were
obtained as attenuated or avirulent derivatives of plant or animals pathogen.
Thus, OPGs appear to be important intrinsic components of the Gram-negative
bacterial envelope, which can be essential in extreme conditions found in nature,
and especially when bacteria must interact with an eukaryotic host.
PMID- 10779708
TI - Biodegradation of diethyl phthalate in soil by a novel pathway.
AB - Biodegradation of diethyl phthalate (DEP) has been shown to occur as a series of
sequential steps common to the degradation of all phthalates. Primary degradation
of DEP to phthalic acid (PA) has been reported to involve the hydrolysis of each
of the two diethyl chains of the phthalate to produce the monoester monoethyl
phthalate (MEP) and then PA. However, in soil co-contaminated with DEP and MeOH,
biodegradation of the phthalate to PA resulted in the formation of three
compounds, in addition to MEP. These were characterised by gas chromatography
electron ionisation mass spectrometry and nuclear magnetic resonance as ethyl
methyl phthalate, dimethyl phthalate and monomethyl phthalate, and indicated the
existence of an alternative pathway for the degradation of DEP in soil co
contaminated with MeOH. Transesterification or demethylation were proposed as the
mechanisms for the formation of the three compounds, although the 7:1 ratio of
H(2)O to MeOH means that transesterification is unlikely.
PMID- 10779707
TI - Isolation and characterization of alkane-utilizing Nocardioides sp. strain CF8.
AB - A butane-utilizing bacterial strain CF8 was isolated and identified as a member
of the genus Nocardioides from chemotaxonomic and 16S rDNA sequence analysis.
Strain CF8 grew on alkanes ranging from C(2) to C(16) in addition to butane and
various other substrates including primary alcohols, carboxylic acids, and
phenol. Butane degradation by strain CF8 was inactivated by light, a specific
inactivator of copper-containing monooxygenases. The unique thermal aggregation
phenomenon of acetylene-binding polypeptides was also observed for strain CF8.
These results suggest that butane monooxygenase in strain CF8 is a third example
of the copper-containing monooxygenases previously described in ammonia oxidizers
and methanotrophs.
PMID- 10779709
TI - Specific binding of recombinant Listeria monocytogenes p60 protein to Caco-2
cells.
AB - The Listeria monocytogenes p60 is a major extracellular protein, which is
believed to be involved in the invasion of these bacteria into their host cells.
So far the mechanism by which p60 participates in the internalization or
penetration of L. monocytogenes is still veiled. To determine the possibility of
a direct interaction of p60 with the host cell surface, the iap gene was
recombinantly expressed in Escherichia coli and used for binding studies with the
enterocyte-like Caco-2 cells. Fluorescence activated flow cytometry and confocal
laser scanning microscopy revealed a cell membrane specific staining with p60,
which implications in Listeria virulence are discussed.
PMID- 10779710
TI - Characterization of the desulforubidin operons from Desulfobacter vibrioformis
and Desulfobulbus rhabdoformis.
AB - The genes encoding the desulforubidin type of dissimilatory sulfite reductase
(Dsr) from the sulfate-reducing bacteria Desulfobacter vibrioformis and
Desulfobulbus rhabdoformis were cloned and sequenced. Similar to the genes for
dissimilatory sulfite reductase from the genera Archaeoglobus, Desulfovibrio and
Desulfotomaculum the dsr genes were found to form an operon, dsrABD, where dsrA
and dsrB encode the structural subunits, alpha and beta, of Dsr, respectively.
dsrD encodes a conserved unknown protein apparently restricted to sulfate
reducing species. In Desulfobacter vibrioformis a fourth gene, designated dsrN,
was found downstream of dsrD forming a contiguous operon, dsrABDN. DsrN showed
significant sequence homology to cobyrinic a,c-diamide synthase, which is
involved in the biosynthesis of vitamin B12. A function for DsrN in amidation of
siroheme is likely. Analysis of the dsrAB-encoded proteins confirmed that the
high conservation observed for other types of dissimilatory sulfite reductase is
also found in desulforubidin. The use of Dsr sequences in unravelling the
phylogeny of sulfate-reducing bacteria is discussed.
PMID- 10779711
TI - Identification of a putative LPS-associated cation exporter from Rhizobium
leguminosarum bv. viciae.
AB - A gene, cpaA, with similarity to calcium proton antiporters has been identified
adjacent to lpcAB in Rhizobium leguminosarum. LpcA is a galactosyl transferase
while LpcB is a 2-keto-3-deoxyoctonate transferase, both of which are required to
form the lipopolysaccharide (LPS) core in R. leguminosarum. Mutations in lpcAB
result in a rough LPS phenotype with a requirement for elevated calcium
concentrations to allow growth, suggesting that truncation of the LPS core
exposes a highly negatively charged molecule. This is consistent with the LPS
core being one of the main sites for binding calcium in the Gram-negative outer
membrane. Strain RU1109 (cpaA::Tn5-lacZ) has a normal LPS layer, as measured by
silver staining and Western blotting. This indicates that cpaA mutants are not
grossly affected in their LPS layer. LacZ fusion analysis indicates that cpaA is
constitutively expressed and is not directly regulated by the calcium
concentration. Over-expression of cpaA increased the concentration of calcium
required for growth, consistent with CpaA mediating calcium export from the
cytosol. The location of lpcA, lpcB and cpaA as well as the phenotype of lpcB
mutants suggests that CpaA might provide a specific export pathway for calcium to
the LPS core.
PMID- 10779712
TI - Transposon targeting determined by resolvase.
AB - The Mu-related transposon Tn5090, also called Tn402, was observed to be highly
selective for targets clustered in or close to recombination sites of serine-type
recombinases in plasmids R388 and RP1. Transposition to the par area of RP1
responded strongly to a deletion in the gene of resolvase ParA. A search in
sequence databanks revealed further insertions of Tn5090/Tn402 close to different
genes of resolvases. These results imply that the target selection of Tn5090
depends on a property that is shared among several serine recombinases.
PMID- 10779713
TI - Insertional inactivation of mtrX and mtrY genes from the mithramycin gene cluster
affects production and growth of the producer organism Streptomyces argillaceus.
AB - Mithramycin is an antitumor aromatic polyketide synthesized by Streptomyces
argillaceus. Two genes (mtrX and mtrY) of the mithramycin gene cluster were
inactivated by gene replacement. Inactivation of mtrX, that encodes an ABC
excision nuclease system for DNA repair, produced a mutant that was affected in
the normal rate of growth. Expression of mtrX in Streptomyces albus in a
multicopy plasmid vector conferred a low increase in resistance to mithramycin.
Inactivation of mtrY, that encodes a protein of unknown function, produced a 50%
decrease in mithramycin biosynthesis. When mtrY was expressed in the wild-type S.
argillaceus in a multicopy plasmid, this caused about 47% increase in the levels
of mithramycin production. It is proposed that mtrX and mtrY could code for a
secondary defense mechanism and a mithramycin regulatory element, respectively.
PMID- 10779714
TI - Cloning and expression of an alpha-amylase encoding gene from the
hyperthermophilic archaebacterium Thermococcus hydrothermalis and biochemical
characterisation of the recombinant enzyme.
AB - An alpha-amylase encoding gene from the extremely thermophilic Archaea
Thermococcus hydrothermalis was cloned and expressed in Escherichia coli. The
encoded alpha-amylase possesses molecular characteristics specific to the
Archaea, especially from Pyrococcus species, with biochemical characteristics of
the alpha-amylases from Thermococcus. The gene is 1374 bp long and encodes a
protein of 457 amino acids composed of a 22 amino acid putative signal peptide
and a 435 amino acid mature protein (calculated molecular mass 49236 Da). The T.
hydrothermalis recombinant alpha-amylase is optimally active at 75-85 degrees C
and at pH 5.0-5.5.
PMID- 10779715
TI - FnrP interactions with the Pasteurella haemolytica leukotoxin promoter.
AB - Pasteurella haemolytica FnrP is homologous to Fnr, the global transcriptional
regulator of anaerobic respiration in Escherichia coli. To investigate the role
of O(2) in the expression of P. haemolytica leukotoxin, we tested a lktC::lacZ
fusion constructed in E. coli for a FnrP-mediated regulatory effect under aerobic
and anaerobic growth conditions. Both E. coli Fnr and FnrP suppressed leukotoxin
transcription under aerobic conditions. Under anaerobic conditions, Fnr
suppressed transcription, while FnrP increased transcription. These results were
confirmed using FnrP*, a mutant form of FnrP that activates anaerobically
inducible genes under aerobic conditions. In mobility shift assays, partially
purified FnrP bound to a potential regulatory site in a P. haemolytica lktC
promoter fragment.
PMID- 10779716
TI - A sensitive microsphere coagulation ELISA for Escherichia coli O157:H7 using
Russell's viper venom.
AB - A microsphere coagulation enzyme-linked immunosorbent assay (MC-ELISA) using
Russell's viper venom factor X activator (RVV-XA) is described for the detection
of Escherichia coli O157:H7. This microtitre plate assay comprises a standard
sandwich immunoassay incorporating RVV-XA as the enzyme label. Coagulation
substrate together with polystyrene microspheres are added to the wells of the
microtitre plate. RVV-XA initiates the coagulation cascade causing formation of
an artificial clot of polystyrene microspheres bound together with fibrin. As few
as 10(2) E. coli O157 in a well (10(3) per ml) can be detected within 3 h. The
assay is two orders of magnitude more sensitive than a standard ELISA and is a
generic technique with the potential for widespread use in sandwich immunoassays.
PMID- 10779717
TI - Interactions between type III secretion apparatus components from Yersinia pestis
detected using the yeast two-hybrid system.
AB - Interactions among the Yersinia secretion (Ysc) proteins of Yersinia pestis were
explored using the yeast two-hybrid system. Various pairwise combinations of the
yscEFGHIKLN and Q genes fused to the DNA-binding or activation domain of the
yeast GAL4 gene were introduced into yeast, and expression of a reporter gene
encoding beta-galactosidase was detected. Combinations of yscN and yscL, yscL and
yscQ, and yscQ and yscK resulted in high levels of reporter gene activation.
These results suggest that YscL interacts with both YscN and YscQ, and that YscQ
interacts with both YscL and YscK. Three-hybrid analyses using plasmid pDELA to
target a third hybrid protein to the yeast nucleus was used to detect the
formation of ternary protein complexes. Using the three-hybrid system, YscQ
expressed from plasmid pDELA was able to bring together the YscK and YscL fusion
proteins. In a similar manner, YscL expressed from plasmid pDELA was able to
bring together the YscN and YscQ fusion proteins. Together, these results suggest
that a complex composed of YscN, YscQ, YscK and YscL is involved in the assembly
and/or function of the Y. pestis type III secretion apparatus.
PMID- 10779718
TI - Enhancement of in vitro growth and resistance to gray mould of Vitis vinifera co
cultured with plant growth-promoting rhizobacteria.
AB - The potential of a plant growth-promoting rhizobacterium, Pseudomonas sp. (strain
PsJN), to stimulate the growth and enhancement of the resistance of grapevine
(Vitis vinifera L.) transplants to gray mould caused by Botrytis cinerea has been
investigated. In vitro inoculation of grapevine plantlets induced a significant
plant growth promotion which made them more hardy and vigorous when compared to
non-inoculated plantlets. This ability increased upon transplanting. When grown
together with B. cinerea, the causal agent of gray mould, significant differences
of aggressiveness were observed between the inoculated and non-inoculated plants.
The presence of bacteria was accompanied by an induction of plant resistance to
the pathogen. The beneficial effect from this plant-microbe association is being
postulated.
PMID- 10779719
TI - Cloning, functional expression and partial characterization of the glucose kinase
from Renibacterium salmoninarum.
AB - The complete glcK gene from the fish pathogen Renibacterium salmoninarum,
encoding a glucose kinase, was analyzed and expressed. The partial
characterization of the recombinant enzyme confirmed that it belongs to a group
of glucose kinases involved in carbon catabolite repression. Multiple sequence
alignments were used to deduce a new consensus sequence for this family of
bacterial proteins, characterized by several conserved Cys residues. This
sequence was more specific and allowed the detection of the first eukaryotic
protein of this family. The recombinant enzyme was inhibited by N-ethylmaleimide
and the substrates protected the enzyme from this inhibition, suggesting the
presence of Cys residues in or close to the active site.
PMID- 10779720
TI - Characterisation of the activator effect of glycogen on amylosucrase from
Neisseria polysaccharea.
AB - Amylosucrase produces an insoluble alpha-1,4-linked glucan from sucrose,
releasing fructose. In addition to polymerisation, in the presence of sucrose as
sole substrate, amylosucrase catalyses sucrose hydrolysis and oligosaccharide
synthesis in significant proportions. The effects of both glycogen acceptor and
sucrose concentrations on the reactions catalysed by the highly purified
amylosucrase from Neisseria polysaccharea were investigated. Sucrose hydrolysis
decreased strongly with the increase of the concentration of glycogen, as did
oligosaccharide synthesis, by glucose transfer onto glucose and fructose. The
glucosyl units consumed were then preferentially used for elongation of glycogen
chains. The study of the kinetic behaviour of amylosucrase revealed a strong,
sucrose concentration dependent activator effect of glycogen. This activation was
decreased at high sucrose concentration. The optimal sucrose concentrations
increased with glycogen concentration, suggesting competition between sucrose and
glycogen, and the presence of a second non-catalytic acceptor binding site which
could bind various acceptors (glucose, maltose, glycogen) and also sucrose.
PMID- 10779721
TI - Identification of intermediates of in vivo trichloroethylene oxidation by the
membrane-associated methane monooxygenase.
AB - The rate and products of trichloroethylene (TCE) oxidation by Methylomicrobium
album BG8 expressing membrane-associated methane monooxygenase (pMMO) were
determined using 14C radiotracer techniques. [(14)C]TCE was degraded at a rate of
1.24 nmol (min mg protein)(-1) with the initial production of glyoxylate and then
formate. Radiolabeled CO(2) was also found after incubating M. album BG8 for 5 h
with [(14)C]TCE. Experiments with purified pMMO from Methylococcus capsulatus
Bath showed that TCE could be mineralized to CO(2) by pMMO. Oxygen uptake studies
verified that M. album BG8 could oxidize glyoxylate and that pMMO was responsible
for the oxidation based on acetylene inactivation studies. Here we propose a
pathway of TCE oxidation by pMMO-expressing cells in which TCE is first converted
to TCE-epoxide. The epoxide then spontaneously undergoes HCl elimination to form
glyoxylate which can be further oxidized by pMMO to formate and CO(2).
PMID- 10779722
TI - Resuscitation of viable but nonculturable cells of Vibrio parahaemolyticus
induced at low temperature under starvation.
AB - Vibrio parahaemolyticus is known to exist in a viable but nonculturable state
when incubated at low temperature under starvation. It has long been debated
whether the culturable cells which appear after temperature upshift are the
result of true resuscitation or regrowth of a few residual culturable cells.
Starved V. parahaemolyticus cells at 4 degrees C reached the nonculturable stage
in about 12 days. The true resuscitation of nonculturable cells of V.
parahaemolyticus occurred after spreading them onto an agar medium supplemented
with H(2)O(2)-degrading compounds such as catalase or sodium pyruvate. The
proposed method may be applicable to detecting the enteropathogen from
environmental samples.
PMID- 10779723
TI - Reduced host resistance and Th1 response to Cryptococcus neoformans in
interleukin-18 deficient mice.
AB - Using interleukin (IL)-18 deficient (IL-18(-/-)) mice, we examined the role of IL
18 in the host resistance and Th1 response against infection with Cryptococcus
neoformans. Fungal clearance in the lung was reduced in IL-18(-/-) mice, although
there was no significant change in the level of dissemination to the brain. The
DTH response, as determined by footpad swelling, was also diminished in IL-18(-/
) mice compared to control wild-type (WT) mice. The levels of IL-12 and
interferon (IFN)-gamma in the sera were significantly lower in IL-18(-/-) mice
than in WT mice. Spleen cells from infected WT mice produced a high level of IFN
gamma upon stimulation with the microbe, while only a low level of IFN-gamma
production was detected in spleen cells from infected IL-18(-/-) mice.
Administration of IL-18 almost completely restored the reduced response in IL-18(
/-) mice, while IL-12 showed a marginal effect. These results demonstrated the
important role of IL-18 in the resistance and Th1 response of mice to C.
neoformans by potentiating the production of IFN-gamma.
PMID- 10779724
TI - Physiology and continuous culture of the hyperthermophilic deep-sea vent archaeon
Pyrococcus abyssi ST549.
AB - The deep-sea vent archaeon Pyrococcus abyssi strain ST549 was grown in batch
cultures in closed bottles and by continuous culture in a gas-lift bioreactor,
both in the presence and in the absence of elemental sulfur. Growth on
carbohydrates, proteinaceous substrates and amino acids was investigated. The
disaccharides maltose and cellobiose were shown not to be able to enhance growth
suggesting that P. abyssi ST549 is unable to use them as carbon sources. By
contrast, proteinaceous substrates such as peptone and brain heart infusion were
shown to be very good substrates for the growth of P. abyssi ST549 and allowed
growth at high steady-state cell densities in continuous culture. Growth on brain
heart infusion was shown to require additional nutrients when sulfur was not
present in the culture medium. Growth on amino acids only took place in the
presence of sulfur. These results indicate that sulfur plays an important role in
the metabolism and energetics of P. abyssi ST549.
PMID- 10779726
TI - Who determines our trajectory beyond the year 2000 - you do
PMID- 10779725
TI - A consensus Porphyromonas gingivalis promoter sequence.
AB - We have determined the transcription start points (tsp) for recently identified
Porphyromonas gingivalis W50 genes, kgp, rgpA, rgpB (formerly designated prtK,
prtR, and prtRII respectively), fetB and the mcmAB operon. Alignment of the DNA
upstream of these tsp and those from the literature has enabled us to identify
consensus sequences that may represent a P. gingivalis promoter. There is a
potential -10 hexamer sequence, 5'-TATATT-3' centred on average at -10/11 nt
which is repeated at -19/20 nt and an upstream consensus, 5'-CAGAT(A/G)-3' which
is centred at -39/40 nt.
PMID- 10779728
TI - The physiological state of captive and migrating Great White Pelicans (Pelecanus
onocrotalus) revealed by their blood chemistry.
AB - The Great White Pelican Pelecanus onocrotalus is an endangered migratory bird,
threatened by diminishing natural feeding sites and by persecution by fishermen.
The majority of the migrating White Pelican (71000) stop-over in Israel during
their autumn migration to Africa. As part of a larger study, aimed to assess the
necessity of feeding during the stop-over in Israel, we examined the blood
chemistry of captive and migrating White Pelicans. Blood was sampled from captive
birds maintained on a fish diet, after food deprivation for 48 h and from wild
birds brought from the field during migration. Food deprivation resulted in
increased plasma levels of triglycerides and in lower levels of urea, potassium
and calcium. In migrating birds, increased plasma levels of urea and CPK and
lower levels of creatinine were revealed. In general, the coefficient of
variation in the blood chemistry of migrating pelicans was higher than in the
captive birds, that is to say, that these birds were in a variable physiological
condition. The blood profile of migrating and wintering pelicans did not indicate
a state of dehydration but did indicate energy deficiency. The less extreme
changes in blood chemistry of the 48 h food-deprived compared to migrating
pelicans suggest that the former did not reach a state of starvation. We conclude
that for White Pelicans the stop-over in Israel is a must in order to rest and
replenish their fuel reserves for completion of their autumn migration to Africa.
PMID- 10779727
TI - Dietary modulation of intestinal enzymes of the house sparrow (Passer
domesticus): testing an adaptive hypothesis.
AB - Insectivorous/frugivorous passerine species studied so far lack the ability to
modulate intestinal maltase activity, in contrast to galliformes. We tested for
dietary modulation of small intestine (SI) enzymes including maltase in house
sparrows to understand whether the difference between the galliformes on the one
hand, and the passerines on the other, reflects a phylogenetic pattern (maltase
modulated in galliformes but not passerines), a dietary pattern (maltase
modulated in granivores but not insectivore/frugivores), some other pattern, or
chance. We also tested the prediction that intestinal peptidase activity would be
increased on a high protein (HP) diet. Birds were fed three diets high in starch,
protein, or lipid for 10 days. For birds on the HP diet (60.3% protein) we
observed the predicted upward modulation of aminopeptidase-N activity, as
compared with the lower-protein, high starch (HS) (12.8% protein) diet. In
contrast, birds eating the HS diet had similar maltase and sucrase activities,
and only slightly higher isomaltase activity, compared with birds eating the high
protein (HP), starch-free diet. Birds eating high lipid (HL) diet had low
activities of both carbohydrases and peptidase. Considering that the statistical
power of our tests was adequate, we conclude that house sparrows show little or
no increase in carbohydrases in response to elevated dietary carbohydrate. We
cannot reject the hypothesis that maltase lability among avian species has a
phylogenetic component, or that high dietary fat has a depressing effect on both
carbohydrase and peptidase activities.
PMID- 10779729
TI - Gizzard myoglobin contents and feeding habits in avian species.
AB - In an attempt to consider physiological function of myoglobin (Mb), we determined
Mb contents of gizzard smooth muscles with special reference to feeding habits in
85 avian species of 19 orders. The Mb content in 44 species of herbivorous birds
was 7.52+/-3.81 mg/g wet muscle, which was significantly higher than the value of
2.34+/-1.74 mg/g in 41 species of carnivorous ones (P<0.001). Buffering capacity,
as determined by in vitro titration method, was 37.3+/-5.5 slykes/g in gizzard
smooth muscles of 75 species and 60.7+/-10.5 slykes in breast skeletal muscles of
77 species (P<0.001), which suggests a significantly higher dependence, almost
comparable to cardiac muscles, of the gizzard muscular function on aerobic
metabolism. Together with the fact that blood circulation in the gizzard is very
low at resting, and might be further limited during activity, we conclude that
the higher Mb content in gizzards of herbivorous birds is an adaptation, to allow
storage and/or facilitated diffusion of oxygen, during process of high mechanical
work required to grind down hard and fibrous vegetable food under the conditions
of limited circulatory supply.
PMID- 10779730
TI - Developmental changes in organic osmolytes in prenatal and postnatal rat tissues.
AB - At high osmotic pressures, mammalian kidney medulla, heart, lens, and brain
utilize organic osmolytes to regulate cell volume. However the types and
proportions of these solutes vary among tissues in patterns and for non-osmotic
roles not fully elucidated. To clarify these, we analyzed osmolyte-type solute
contents in rat tissues at 7 and 2 days prenatal and at 0, 7, 14, 21 (weaning),
35 (juvenile) and 77 (adult) days postnatal. Placentas were dominated by betaine,
taurine, and creatine, which decreased between the prenatal times. Fetuses were
dominated by glutamate and taurine, which increased between the times. In
cerebrum, hindbrain and diencephalon, taurine dominated at early stages, but
dropped after postnatal day 7, while myo-inositol, glutamine, creatine and
glutamate increased after birth, with the latter two dominating in adults. In
olfactory bulb, taurine content declined gradually with age and was equal to
glutamate in adults. In all brain regions, glycerophosphorylcholine (GPC) reached
a peak in juveniles. In postnatal renal medulla, urea, sodium, GPC, betaine, and
taurine increased sharply at day 21. Thereafter, most increased, but taurine
decreased. In heart, taurine dominated, and increased with age along with
creatine and glutamine, while glutamate decreased after postnatal day 7. In lens,
taurine dominated and declined in adults. These patterns are discussed in light
of hypotheses on non-osmotic and pathological roles of these solutes.
PMID- 10779731
TI - Regional hypoxia elicits regional changes in chorioallantoic membrane vascular
density in alligator but not chicken embryos.
AB - Hypoxic incubation increases vascularization in the chick chorioallantoic
membrane (CAM). The effect of regional hypoxia on the vascular density of
American alligator (Alligator mississippiensis) and chicken (Gallus gallus) CAMs
was studied to determine if hypoxic proliferation of blood vessels is localized
or global across the CAM. Eggs were incubated under normoxic conditions with a
portion of the eggshell covered with non-toxic beeswax to induce external
regional hypoxia. CAMs were examined under a microscope with a 'bulls eye'
coverslip and a vascular density index (VDI) was determined. The hypoxic portions
of the alligator CAMs were more vascular than the normoxic portions (VDI = 200.9
versus 157. 8, respectively). Presumably this response is maladaptive by causing
increased blood flow to the poorly oxygenated portions, i.e. increased 'shunt'.
Thus, we hypothesize increased vascularity due to hypoxic incubation is due to
local release and subsequent rapid local breakdown or uptake of angiogenic
factors. In contrast, the hypoxic and normoxic portions of the chick CAMs
exhibited virtually no difference in VDI (VDI= 211.5 versus 217.9, respectively).
We suggest the air cell and air space of the chicken eggs allows for circulation
of gas in ovo, eliminating the possibility of regional internal hypoxia.
PMID- 10779732
TI - The role of beta-adrenergic receptors in the cutaneous water evaporation
mechanism in the heat-acclimated pigeon (Columba livia).
AB - The effects of selective and non-selective beta-adrenergic agents on cutaneous
water evaporation (CWE) were studied in hand-reared rock pigeons (Columba livia).
CWE was measured by the vapor diffusive resistance method, using a transient
porometer. Intramuscular and subcutaneous injections of a non-selective beta
adrenergic antagonist (propranolol) or a selective beta(2)-adrenergic antagonist
(ICI-118551) to heat-acclimated (HAc) pigeons at ambient temperature (T(a)) of 24
degrees C resulted in intensive CWE. The CWE values that were triggered by
propranolol and ICI-118551 (18.59+/-0.73 and 16.48+/-0.70 mg cm(-2) h(-1),
respectively) were close to those induced by heat exposure (17.62+/-1.40 mg cm(
2) h(-1)). Subcutaneous administration of propranolol produced local response.
Intramuscular injection of salbutamol (selective beta(2)-adrenergic agonist) to
HAc pigeons drastically diminished CWE induced by either propranolol, metoprolol
or heat exposure. Such manipulations also enhanced panting at relatively low
T(a)s (42 degrees C). The inhibition of beta(1)-adrenergic receptors by
metoprolol increased CWE, while inhibition by atenolol produced no change from
basal values. This difference may be attributed to their distinctive nature in
penetrating the blood-brain barrier. Our findings indicate a regulatory pathway
for CWE consisting of both beta(1)- and beta(2)-adrenergic receptors. We suggest
that the beta(1)-adrenergic effect is restricted mainly to the CNS, while the
beta(2)-adrenergic effect takes place at the effector level. We postulate this
level to be either the cutaneous microvasculature or the epidermal layer.
PMID- 10779733
TI - Spectral imaging of red blood cells in experimental anemia of Cyprinus carpio.
AB - In the present work we have studied the effect of experimental anemia induced at
both low and optimal temperatures on erythropoiesis in Cyprinus carpio. The
results showed that hemoglobin concentration per cell was similar in both
temperature conditions, however, red blood cell (RBC) concentration was higher at
the optimal temperature. Induced anemia caused an abrupt decrease in RBC
concentration, while the hemoglobin concentration per cell remained unchanged.
Recovery, as shown by electron microscopy, was characterized by the release of
differentiating young and intermediate cells to the peripheral blood. It was
revealed that with the progression of differentiation the nucleus/cytoplasm ratio
decreases, the chromatin condenses and the shape of the nucleus changes from
round to elliptical. Spectral imaging revealed an increase in the optical density
of chromatin with the maturation of the cells. The chromatin that was dispersed
over the nuclear volume in the young cells becomes highly ordered in the mature
cells. Spectral similarity mapping revealed the formation of a novel structure of
high symmetry, representing chromatin rearrangement during the process of
cellular differentiation.
PMID- 10779734
TI - The effect of short term confinement stress on binding characteristics of sex
steroid binding protein (SBP) in female black bream (Acanthopagrus butcheri) and
rainbow trout (Oncorhynchus mykiss).
AB - The effect of short term confinement stress on sex steroid binding protein (SBP)
binding characteristics was examined in female black bream (Acanthopagrus
butcheri), and rainbow trout (Oncorhynchus mykiss). Black bream were sampled
immediately after capture from the wild and again after 1, 6 or 24 h confinement.
Rainbow trout were sampled before and after 5 h confinement. Confinement of black
bream for 6 h after capture significantly reduced the binding capacity of SBP.
Binding affinity also tended to be lower after confinement. There were no
differences in binding affinity or capacity of black bream SBP after 1 or 24 h
confinement, or rainbow trout SBP after 5 h confinement. Plasma from rainbow
trout at 3 and 6 h after treatment with cortisol was compared to plasma from
saline-injected controls. No significant differences in binding characteristics
were detected, but there was a trend of decreased binding capacity in cortisol
injected fish compared to controls at 6 h post-injection. Relative binding
studies indicated that plasma cortisol at concentrations 100x or more greater
than plasma estradiol (E(2)) may displace E(2) from SBP in black bream, and act
to reduce circulating levels of E(2) through increased clearance of free steroid.
Physiological levels of cortisol did not displace E(2) from SBP in trout. The
observed changes in SBP and the competition of physiological concentrations of
cortisol for SBP binding sites may generate a component of the stress-induced
falls in plasma levels of E(2) reported across a range of species.
PMID- 10779735
TI - Purification and characterization of epidermis-origin hemolymph protein in
Galleria mellonella.
AB - Epidermis-origin hemolymph protein (EOHP) was identified and purified from the
last instar larval hemolymph of Galleria mellonella by anion exchange
chromatography, chromatofocusing chromatography, and Sephadex G-100. The EOHP has
a native molecular mass of 47 kDa and is composed of one subunit. The isoelectric
point of the EOHP was determined to be 5.3. The amino acid composition of the
EOHP was rich in aspartic acid, glutamic acid and lysine, but poor in tyrosine,
methionine, and tryptophan. EOHP is present in hemolymph over the period from the
4th instar larvae to the adult stage examined. Concentration of EOHP is high
during the larval stage but gradually decreased during the developmental stage
from pupal to adult stage. EOHP is present in the cuticle, fat bodies and trachea
but not in hemocytes, fore gut, mid gut and hind gut.
PMID- 10779736
TI - Carotenoid and retinoid--two pigments in a gecko eye lens.
AB - The eye lenses of the Moroccan day gecko Quedenfeldtia trachyblepharus contain
two different pigments: a retinoid (minor pigment) and a carotenoid (major
pigment). The retinoid, all-trans 3, 4-didehydroretinol, is bound to iota
crystallin, which comprises only 2% of the total amount of crystallins. The
carotenoid is associated to gammas-crystallin - comprising about 10% of total
amount of crystallins--and causes the dark yellow colour of the lens. The
absorption spectrum of the isolated carotenoid shows a major, triple-peaked band
at 372, 392, and 416 nm and two minor peaks at 284 and 294 nm. This spectrum
reminds of that of galloxanthin, a carotenoid found in oil droplets of some avian
retinae. The absorption spectrum of the carotenoid-gammas-crystallin complex is
shifted 6-8 nm bathochromically. In the lens, this complex absorbs ultraviolet
and shortwave blue radiation, supposedly improving the optical quality of the
dioptric apparatus and protecting the retina against photodamage. Both the
retinoid and the carotenoid are present in eye cups. The lenticular carotenoid of
Quedenfeldtia is the first example of a carotenoid in the lens of a terrestrial
vertebrate with a sufficiently high concentration to be physiologically effective
as a UV-filter. Additionally, it is unique in being the first example of a
carotenoid associated with gammas-crystallin.
PMID- 10779737
TI - Coagulation and fibrinolysis in capybara (Hydrochaeris hydrochaeris), a close
relative of the guinea-pig (Cavia porcellus).
AB - Fibrinolytic and coagulation properties of capybara (Hydrochaeris hydrochaeris,
LINNAEUS, 1766) plasma were analysed and the results compared to the guinea-pig
(Cavia porcellus), a close relative. Capybara fibrinogen was isolated and
fibrinolysis of its plasma was carried out in a homologous system and with bovine
fibrin. Undiluted plasma did not have fibrinolytic activity on fibrin plates;
euglobulins gave a dose-related response. Zymography of capybara and guinea-pig
plasma gave the same patterns of activity as human or bovine plasma. Human
urokinase (UK) and tissue plasminogen activator (t-PA) produced lysis in capybara
fibrin plates. Streptokinase (SK) (500 IU/ml) did not activate capybara or guinea
pig plasma. In this system, human plasma was extensively activated. Coagulation
tests for both species of rodent were prolonged. The capybara showed values for
prothrombin time (PT) shorter than activated thromboplastin time (APTT). The
guinea-pig, as already shown, had longer PT values. Factors X and VII were very
low for capybara and guinea-pig when tested using reference curves and diagnostic
kits for human plasma. It is suggested that the capybara could be a valuable
laboratory animal considering its size and closeness to the guinea-pig, and this
could allow for the provision of materials from one single animal when convenient
or necessary.
PMID- 10779738
TI - Glucose metabolism in crossbred Holstein cattle feeding on two types of roughage
at different stages of lactation.
AB - An experiment was performed to study the glucose kinetics of crossbred Holstein
cattle feeding on either hay or 5% urea-treated rice straw during early lactation
(30 days post partum), mid-lactation (120 days post partum) and late lactation
(210 days post partum). Two breeds: Holstein FriesianxRed Sindhi (50:50 = 50% HF)
and Holstein FriesianxRed Sindhi (87.5:12.5 = 87.5% HF) were used. In early
lactating 87.5% HF animals feeding on either hay or urea-treated rice straw, the
high milk yields and lactose secretion were related to glucose uptake by the
udder and udder blood flow as compared with those of 50% HF animals. Marked
decreases in udder blood flow, glucose uptake, lactose secretion and milk yield
were apparent in mid- and late lactation of both groups of 87.5% HF animals. In
contrast, both groups of 50% HF animals showed no significant changes in udder
blood flow, udder glucose uptake, lactose secretion and milk yields throughout
the course of lactation. Total glucose entry rate using 3-[3H] glucose infusion,
recycling of glucose carbon and plasma glucose clearance significantly increased
during late lactation for 50 and 87.5% HF animals feeding on urea-treated rice
straw. The utilization rates of glucose using [U-(14)C] glucose infusion were not
significantly different among groups of animals and periods of lactation. It can
be concluded that 87.5% HF animals have the genetic potential for a higher milk
yield, but a shorter peak yield and poorer persistence in comparison with 50% HF
animals. Changes in the utilization of glucose by the mammary gland for milk
production in both groups of crossbred animals during feeding on either hay or
urea-treated rice straw would be dependent on intramammary changes.
PMID- 10779739
TI - Mitochondria-rich cells in anuran amphibia: chloride conductance and regional
distribution over the body surface.
AB - The distribution and density (D(mrc)) of mitochondria-rich cells (MR cells) in
skin epithelium, were determined over the whole body surface in nine species of
anuran Amphibia that live in a variety of habitats. It was found that the more
terrestrial species (beginning with Hyla arborea) have a higher density of MR
cells in their pelvic region. In the skin of aquatic (Xenopus laevis) or
fossorial (Pelobates syriacus) species, D(mrc) is evenly distributed over the
whole body surface. In dorsal skin pieces of H. arborea that lack detectable MR
cells, transepithelial voltage activation did not induce Cl(-) conductance as it
did in ventral pieces. Skins from Bufo viridis and X. laevis, both have MR cells
in their skin, differ markedly in their biophysical properties: a Cl(-) specific
current conductance is predominant in the skin epithelium of B. viridis, and is
absent in X. laevis. In the latter, anionic conductance is due to glandular
secretion. The biophysical properties cannot therefore be related solely to the
presence or density of MR cells. Mitochondria-rich cells are sites of Cl(-)
conductance across the skin of those amphibians that show this property, but must
have different function(s) in other species. It is suggested that the specific
zonal distribution of MR cells in the species that were examined in this study
could be due to ion exchange activity and water conservation in more terrestrial
environments.
PMID- 10779740
TI - Thermoregulation and the effect of body temperature on call temporal parameters
in the cicada Diceroprocta olympusa (Homoptera: Cicadidae).
AB - We investigated the thermoregulatory behavior, thermal responses (minimum flight,
maximum voluntary tolerance and heat torpor temperatures) and the effect of body
temperature (T(b)) on call parameters in the cicada Diceroprocta olympusa
(Walker). Regression of T(b) as a function of ambient (T(a)) or perch
temperatures (T(p)) suggests thermoregulation is occurring. Thermoregulation
occurs through behavioral changes that alter the uptake of solar radiation. T(p)
is a better predictor of T(b) than is T(a). Thermal responses (minimum flight
temperature 20.4 degrees C, maximum voluntary tolerance temperature 37 degrees C,
and heat torpor temperature 46.7 degrees C) may be related to the humid,
grassland habitat of the species. In contrast to other acoustic insects, no
significant relationship was found between the temporal parameters of the calling
song and T(b) within the population of D. olympusa.
PMID- 10779741
TI - Cutting edge: CD4 is not required for the functional activity of IL-16.
AB - IL-16 functions as a chemoattractant factor, inhibitor of HIV replication, and
inducer of proinflammatory cytokine production. Previous studies have suggested
that CD4 is the receptor for IL-16, because only CD4+ cells respond to IL-16 and
both the anti-CD4 Ab OKT4 and soluble CD4 can block IL-16 function. However,
these are only indirect evidence of a requirement for CD4, and to date a direct
interaction between IL-16 and CD4 has not been shown. In this paper, we report
that cells from CD4 knockout mice are as responsive to IL-16 as their CD4 wild
type equivalents in both assays testing for IL-16 function (chemotaxis and
production of proinflammatory cytokines). In addition, the inhibitory effect of
soluble CD4 on IL-16 function observed using CD4 wild type murine cells was not
observed using CD4 knockout cells. These data demonstrate that CD4 is not
required for IL-16 function and suggest that another molecule acts as the major
receptor.
PMID- 10779742
TI - Blockade of T cell activation using a surface-linked single-chain antibody to
CTLA-4 (CD152).
AB - CTLA-4 (CD152) engagement can down-regulate T cell activation and promote the
induction of immune tolerance. However, the strategy of attenuating T cell
activation by engaging CTLA-4 has been limited by sharing of its natural ligands
with the costimulatory protein CD28. In the present study, a CTLA-4-specific
single-chain Ab (scFv) was developed and expressed on the cell surface to promote
selective engagement of this regulatory molecule. Transfectants expressing anti
CTLA-4 scFv at their surface bound soluble CTLA-4 but not soluble CD28.
Coexpression of anti-CTLA-4 scFv with anti-CD3epsilon and anti-CD28 scFvs on
artificial APCs reduced the proliferation and IL-2 production by resting and
preactivated bulk T cells as well as CD4+ and CD8+ T cell subsets. Importantly,
expression of anti-CTLA-4 scFv on the same cell surface as the TCR ligand was
essential for the inhibitory effects of CTLA-4-specific ligation. CTLA-4-mediated
inhibition of tyrosine phosphorylation of components of the proximal TCR
signaling apparatus was similarly dependent on coexpression of TCR and CTLA-4
ligands on the same surface. These findings support a predominant role for CTLA-4
function in the modification of the proximal TCR signal. Using T cells from
DO11.10 and 2C TCR transgenic mice, negative regulatory effects of selective CTLA
4 ligation were also demonstrated during the stimulation of Ag-specific CD4+ and
CD8+ T cells by MHC/peptide complexes. Together these studies demonstrate that
selective ligation of CTLA-4 using a membrane-bound scFv results in attenuated T
cell responses only when coengaged with the TCR during T cell/APC interaction and
define an approach to harnessing the immunomodulatory potential of CTLA-4
specific ligation.
PMID- 10779743
TI - Vitamin D3 affects differentiation, maturation, and function of human monocyte
derived dendritic cells.
AB - We studied the effects of 1alpha,25-dihydroxyvitamin D3 (1alpha, 25-(OH)2D3) on
differentiation, maturation, and functions of dendritic cells (DC) differentiated
from human monocytes in vitro in the presence of GM-CSF and IL-4 for 7 days.
Recovery and morphology were not affected by 1alpha,25-(OH)2D3 up to 100 nM. DC
differentiated in the presence of 10 nM 1alpha,25-(OH)2D3 (D3-DC) showed a marked
decrease in the expression of CD1a, while CD14 remained elevated. Mannose
receptor and CD32 were significantly increased, and this correlated with an
enhancement of endocytic activity. Costimulatory molecules such as CD40 and CD86
were slightly decreased or nonsignificantly affected (CD80 and MHC II). However,
after induction of DC maturation with LPS or incubation with CD40 ligand
transfected cells, D3-DC showed marginal increases in MHC I, MHC II, CD80, CD86,
CD40, and CD83. The accessory cell function of D3-DC in classical MLR was also
inhibited. Moreover, allogeneic T cells stimulated with D3-DC were poor
responders in a second MLR to untreated DC from the same or an unrelated donor,
thus indicating the onset of a nonspecific hyporesponsivity. In conclusion, our
data suggest that 1alpha,25-(OH)2D3 may modulate the immune system, acting at the
very first step of the immune response through the inhibition of DC
differentiation and maturation into potent APC.
PMID- 10779744
TI - Donor MHC class II antigen is essential for induction of transplantation
tolerance by bone marrow cells.
AB - Posttransplant infusion of donor bone marrow cells (BMC) induces tolerance to
allografts in adult mice, dogs, nonhuman primates, and probably humans. Here we
used a mouse skin allograft model and an allogeneic radiation chimera model to
examine the role of MHC Ags in tolerance induction. Infusion of MHC class II Ag
deficient (CIID) BMC failed to prolong C57BL/6 (B6) skin grafts in ALS- and
rapamycin-treated B10.A mice, whereas wild-type B6 or MHC class I Ag-deficient
BMC induced prolongation. Removal of class II Ag-bearing cells from donor BMC
markedly reduced the tolerogenic effect compared with untreated BMC, although
graft survival was significantly longer in mice given depleted BMC than that in
control mice given no BMC. Infusion of CIID BMC into irradiated syngeneic B6 or
allogeneic B10.A mice produced normal lymphoid cell reconstitution including CD4+
T cells except for the absence of class II Ag-positive cells. However, irradiated
B10.A mice reconstituted with CIID BMC rejected all B6 and a majority of CIID
skin grafts despite continued maintenance of high degree chimerism. B10.A mice
reconstituted with B6 BMC maintained chimerism and accepted both B6 and CIID skin
grafts. Thus, expression of MHC class II Ag on BMC is essential for allograft
tolerance induction and peripheral chimerism with cells deficient in class II Ag
does not guarantee allograft acceptance.
PMID- 10779745
TI - Analysis of human V alpha 24+ CD4+ NKT cells activated by alpha-glycosylceramide
pulsed monocyte-derived dendritic cells.
AB - Human V alpha 24+ NKT cells with an invariant TCR (V alpha 24-J alpha Q) have
been shown to be specifically activated by synthetic glycolipids such as alpha
galactosylceramide and alpha-glucosylceramide in a CD1d-restricted and V alpha 24
TCR-mediated manner. We recently characterized V alpha 24+ CD4- CD8- double
negative (DN) NKT cells using alpha-galactosylceramide-pulsed monocyte-derived
dendritic cells. Here, we compare V alpha 24+ CD4+ NKT cells with human V alpha
24+ DN NKT cells from the same donor using alpha-galactosylceramide-pulsed
monocyte-derived dendritic cells. Human V alpha 24+ CD4+ NKT cells were
phenotypically and functionally similar to the human V alpha 24+ DN NKT cells
characterized previously. Both of them use V alpha 24-J alpha Q-V beta 11 TCR and
express CD161 (NKR-P1A), but not the other NK receptors tested so far. They also
produce cytokines such as IL-4 and IFN-gamma, and, in regard to IL-4 production,
V alpha 24+ CD4+ NKT cells produce more IL-4 than V alpha 24+ DN NKT cells. The
cells exhibit marked cytotoxic activity against the U937 tumor cell line, but not
against the NK target cell line, K562. Although at least some of the factors
responsible for the stimulation of V alpha 24+ NKT cells have been clarified,
little is known regarding the killing phase of these cells. Here we show that the
cytotoxic activity of V alpha 24+ NKT cells against U937 cells is mediated mainly
through the perforin pathway and that ICAM-1/LFA-1 as well as CD44/hyaluronic
acid interactions are important for the effector phase of V alpha 24+ NKT cell
mediated cytotoxicity against U937 cells.
PMID- 10779746
TI - The roles of CD28 and CD40 ligand in T cell activation and tolerance.
AB - Costimulation of T cell activation involves both the B7:CD28 as well as the CD40
ligand (CD40L):CD40 pathway. To determine the importance of these pathways to in
vitro and in vivo T cell activation, a direct comparison was made of the
responses of TCR transgenic T cells lacking either CD28 or CD40L. In vitro, CD28
/- T cells showed a greater reduction in proliferative responses to Ag than did
CD40L-/- T cells. The absence of CD28 resulted in defective Th2 responses,
whereas CD40L-/- T cells were defective in Th1 development. In vivo, CD28-/- T
cells failed to expand upon immunization, whereas CD40L-/- T cells could not
sustain a response. These results suggest that CD28 is critical for initiating T
cell responses, whereas CD40L is required for sustained Th1 responses. The
different functional roles of these costimulatory pathways may explain why
blocking B7:CD28 and CD40L:CD40 interactions has an additive effect in inhibiting
T cell responses.
PMID- 10779747
TI - The regulation of CD95 (Fas) ligand expression in primary T cells: induction of
promoter activation in CD95LP-Luc transgenic mice.
AB - The interaction between CD95 (Fas) and CD95L (Fas ligand) initiates apoptosis in
a variety of cell types. Although the regulation of CD95L expression on activated
T cells is an area of intense study, knowledge related to the induction of CD95L
promoter activity in primary T cells is lacking. In this report we describe the
generation of a novel transgenic mouse strain, CD95LP-Luc, in which murine CD95L
promoter sequence controls the expression of a luciferase reporter gene. We use
these mice to illustrate several important findings related to transcriptional
regulation of CD95L in primary T cells. We demonstrate that maximal CD95L
promoter activity occurs only after prolonged T cell stimulation and requires
costimulation through CD28. We provide evidence that thymocytes express
CD95L/luciferase after strong TCR ligation and that inducible CD95L promoter
activation is present, but unequal, in both Th1 and Th2 effector cells. We also
illustrate that while agonist peptide presentation by APCs generates robust
proliferation during a primary T cell response, the same stimulus induces only
modest CD95L promoter activity. These results suggest alternate explanations for
the well-characterized delay in CD95-mediated activation-induced cell death
following initial ligation of the TCR.
PMID- 10779748
TI - Astrocyte-targeted expression of IL-12 induces active cellular immune responses
in the central nervous system and modulates experimental allergic
encephalomyelitis.
AB - The role of IL-12 in the evolution of immunoinflammatory responses at a localized
tissue level was investigated. Transgenic mice were developed with expression of
either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes
targeted to astrocytes in the mouse CNS. Glial fibrillary acidic protein (GF)-IL
12 mice, bigenic for the p35 and p40 genes, developed neurologic disease which
correlated with the levels and sites of transgene-encoded IL-12 expression. In
these mice, the brain contained numerous perivascular and parenchymal
inflammatory lesions consisting of predominantly CD4+ and CD8+ T cells as well as
NK cells. The majority of the infiltrating T cells had an activated phenotype
(CD44high, CD45Rblow, CD62Llow, CD69high, VLA-4 high, and CD25+). Functional
activation of the cellular immune response was also evident with marked cerebral
expression of the IFN-gamma, TNF, and IL-1alphabeta genes. Concomitant with
leukocyte infiltration, the CNS expression of immune accessory molecules was
induced or up-regulated, including ICAM-1, VCAM-1, and MHC class II and B7-2.
Glial fibrillary acidic protein-p40 mice with expression of IL-12 p40 alone
remained asymptomatic, with no inflammation evident at any age studied. The
effect of local CNS production of IL-12 in the development of experimental
autoimmune encephalomyelitis was studied. After immunization with myelin
oligodendrocyte glycoprotein-peptides, GF-IL-12 mice had an earlier onset and
higher incidence but not more severe disease. We conclude that localized
expression of IL-12 by astrocytes can 1) promote the spontaneous development of
activated type 1 T cell and NK cellular immunity and cytokine responses in the
CNS, and 2) promote more effective Ag-specific T cell dynamics but not activity
in experimental autoimmune encephalomyelitis.
PMID- 10779749
TI - Delayed and separate costimulation in vitro supports the evidence of a transient
"excited" state of CD8+ T cells during activation.
AB - Although the two-signal model for T cell activation states that a signal-1
through the TCR and a costimulatory signal-2 are required for optimal
stimulation, it is now clear that the requirement for costimulation can be
bypassed under certain conditions. We previously reported that this is the case
for naive CD8+ T cells in vitro. In the present study we tested the effect of
signal-2 when delivered after signal-1 has been disrupted. Naive CD8+ T cells
from TCR transgenic mice were stimulated in vitro by using immobilized
recombinant single-chain MHC molecules alone as signal-1. This signal was then
stopped after different lengths of time, and anti-CD28 mAb as signal-2 was given
either immediately or after a time lag. We found that signal-2 can potentiate a
short signal-1 when added sequentially. Moreover, a time lag between the two
signals does not abolish this potentiation. If the strength of signal-1, but not
its duration, is increased, then the time lag between the delivery of signals 1
and 2 can be lengthen without loss of potentiation. Together, our results
indicate that the two signals do not need to be delivered concomitantly to get
optimal T cell activation. We suggest that the CD8+ T cells can reach a transient
"excited" state after being stimulated with signal-1 alone, characterized by the
cell's ability to respond to separate and delayed signal-2.
PMID- 10779750
TI - MHC class I antigen processing of an adenovirus CTL epitope is linked to the
levels of immunoproteasomes in infected cells.
AB - Proteasomes are the major source for the generation of peptides bound by MHC
class I molecules. To study the functional relevance of the IFN-gamma-inducible
proteasome subunits low molecular mass protein 2 (LMP2), LMP7, and mouse
embryonal cell (MEC) ligand 1 in Ag processing and concomitantly that of
immunoproteasomes, we established the tetracycline-regulated mouse cell line
MEC217, allowing the titrable formation of immunoproteasomes. Infection of MEC217
cells with Adenovirus type 5 (Ad5) and analysis of Ag presentation with Ad5
specific CTL showed that cells containing immunoproteasomes processed the viral
early 1B protein (E1B)-derived epitope E1B192-200 with increased efficiency, thus
allowing a faster detection of viral entry in induced cells. Importantly, optimal
CTL activation was already achieved at submaximal immunosubunit expression. In
contrast, digestion of E1B-polypeptide with purified proteasomes in vitro yielded
E1B192-200 at quantities that were proportional to the relative contents of
immunosubunits. Our data provide evidence that the IFN-gamma-inducible proteasome
subunits, when present at relatively low levels as at initial stages of
infection, already increase the efficiency of antigenic peptide generation and
thereby enhance MHC class I Ag processing in infected cells.
PMID- 10779751
TI - Development of Th1-inducing capacity in myeloid dendritic cells requires
environmental instruction.
AB - Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC
can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1
promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an
intrinsic attribute of human myeloid DC, but both depend on environmental
instruction. Uncommitted immature DC require exposure to IFN-gamma, at the moment
of induction of their maturation or shortly thereafter, to develop the capacity
to produce high levels of IL-12p70 upon subsequent contact with naive Th cells.
This effect is specific for IFN-gamma and is not shared by other IL-12-inducing
factors. Type 1-polarized effector DC, matured in the presence of IFN-gamma,
induce Th1 responses, in contrast to type 2-polarized DC matured in the presence
of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to
further modulation, which may facilitate their potential use in immunotherapy.
PMID- 10779752
TI - Evidence of selective processing of immunodominant epitopes in virally infected
cells.
AB - Recent advances in clarifying the molecular mechanisms involved in Ag processing
and presentation have relied heavily on the use of somatic cell mutants deficient
in proteasome subunits, TAP transporter, and cell surface expression of MHC class
I molecules. Of particular interest currently are those mutants that lack
specific protease activity involved in the generation of antigenic peptides. It
is theoretically possible that deficiencies of this nature could selectively
prevent the cleavage of certain peptide bonds and thus generate only a subset of
antigenic peptides. Gro29/Kb cell line is derived from the wild-type murine Ltk-
cell line. This cell line is one example of a mutant that lacks specific protease
activities. This deficiency manifests itself in an inability to generate a subset
of immunodominant peptide epitopes derived from vesicular stomatitis virus and
herpes simplex virus. This in turn leads to a general inability to present these
viral epitopes to cytotoxic T lymphocytes (CTL). These studies describe a unique
Ag processing deficiency and provide new insight into the role of proteasome
independent proteases in MHC class I-restricted peptide generation.
PMID- 10779753
TI - Humoral immune responses in Cr2-/- mice: enhanced affinity maturation but
impaired antibody persistence.
AB - Deficiency in CD21/CD35 by disruption of the Cr2 loci leads to impaired humoral
immune responses. In this study, we detail the role of CD21/CD35 on Ab responses
to the hapten (4-hydroxy-3-nitrophenyl)acetyl conjugated to chicken gamma
globulin. Surprisingly, Cr2-/- mice generate significant Ab responses and
germinal center (GC) reactions to low doses of this Ag in alum, although the
magnitude of their responses is much reduced in comparison with those of Cr2+/-
and C57BL/6 controls. Increasing Ag dose partially corrected this deficit. In
situ study of the somatic genetics of GC B cells demonstrated that VDJ
hypermutation does not require CD21/CD35, and Cr2-/- mice exhibited enhanced
affinity maturation of serum Ab in the post-GC phase of the primary response. On
the other hand, Cr2-/- mice displayed accelerated loss of serum Ab and long-lived
Ab-forming cells. These observations suggest that B cell activation/survival
signals mediated by CD21 and/or the retention of Ag by CD21/CD35 play important
roles in the generation, quality, and maintenance of serum Ab.
PMID- 10779754
TI - Crry/p65, a membrane complement regulatory protein, has costimulatory properties
on mouse T cells.
AB - It is known that certain type I membrane molecules (complement receptors type 1
and 2) belonging to the regulators of complement activation (RCA) family are
involved in the regulation of B lymphocyte activation. In contrast, only GPI
anchored RCA molecules (CD55) have been described to be involved in T lymphocyte
activation. In this study, we describe a novel function for the mouse RCA type I
membrane protein Crry/p65 as a costimulatory molecule in CD4+ T cell activation.
This is shown by increased anti-CD3-induced proliferation of CD4+ spleen T
lymphocytes in the presence of the Crry/p65-specific mAb P3D2. Furthermore, Ab
induced coligation of Crry/p65 and CD3 favors IL-4 rather than IFN-gamma
secretion in these cells. Crry/p65 signaling was also observed regardless of
additional Ca2+, protein kinase C, or CD28-mediated costimuli. Analysis of
intracellular intermediaries shows that Crry/p65-CD3 coligation enhances certain
TCR/CD3-mediated signals, producing increased early tyrosine phosphorylation of
many substrates and enhanced activation of the mitogen-activated protein kinase,
extracellular signal-related kinase. These data fit well with the association of
Crry/p65 with the tyrosine kinase Lck found in T cell lysates. The epitope
recognized by the mAb P3D2 interferes with the protective role of Crry/p65 on C3
deposition. The relationship between protective function and costimulation by
Crry/p65 is discussed. Our results support a multifunctional role for Crry/p65 in
T cells and suggest new links between the natural and adaptive immune responses.
PMID- 10779755
TI - In vivo behavior of peptide-specific T cells during mucosal tolerance induction:
antigen introduced through the mucosa of the conjunctiva elicits prolonged
antigen-specific T cell priming followed by anergy.
AB - The mucosa of the conjunctiva is an important site of entry for environmental Ags
as well as Ags emanating from the eye itself. However, very little is known about
T cell recognition of Ag introduced through this important mucosal site. We have
characterized the in vivo process of CD4 T cell recognition of Ag delivered via
the conjunctival mucosa. Application of soluble OVA to the conjunctiva of BALB/c
mice induced potent T cell tolerance. APC-presenting OVA peptide in vivo was only
found in the submandibular lymph node and not in other lymph nodes, spleen, or
nasal-associated lymphoid tissue. Similarly, in TCR transgenic DO11. 10 adoptive
transfer mice, OVA-specific CD4+ T cell clonal expansion was only observed in the
submandibular lymph node following conjunctival application of peptide. These
experiments thus define a highly specific lymphatic drainage pathway from the
conjunctiva. OVA-specific T cell clonal expansion peaked at day 3 following
initiation of daily OVA administration and gradually declined during the 10-day
treatment period, but remained elevated compared with nontreated adoptive
transfer mice. During this period, the T cells expressed activation markers, and
proliferated and secreted IL-2 in vitro in response to OVA stimulation. In
contrast, these cells were unable to clonally expand in vivo, or proliferate in
vitro following a subsequent OVA/CFA immunization. These results suggest that Ag
applied to a mucosal site can be efficiently presented in a local draining lymph
node, resulting in initial T cell priming and clonal expansion, followed by T
cell anergy.
PMID- 10779756
TI - Antigen-experienced CD4 T cells display a reduced capacity for clonal expansion
in vivo that is imposed by factors present in the immune host.
AB - It is thought that protective immunity is mediated in part by Ag-experienced T
cells that respond more quickly and vigorously than naive T cells. Using adoptive
transfer of OVA-specific CD4 T cells from TCR transgenic mice as a model system,
we show that Ag-experienced CD4 T cells accumulate in lymph nodes more rapidly
than naive T cells after in vivo challenge with Ag. However, the magnitude of
clonal expansion by Ag-experienced T cells was much less than that of naive T
cells, particularly at early times after primary immunization. Ag-experienced CD4
T cells quickly reverted to the slower but more robust clonal expansion behavior
of naive T cells after transfer into a naive environment. Conversely, the
capacity for rapid clonal expansion was acquired by naive CD4 T cells after
transfer into passively immunized recipients. These results indicate that rapid
in vivo response by Ag-experienced T cells is facilitated by Ag-specific Abs,
whereas the limited capacity for clonal expansion is imposed by some other factor
in the immune environment, perhaps residual Ag.
PMID- 10779758
TI - CD28-specific antibody prevents graft-versus-host disease in mice.
AB - The costimulatory molecules B7-1 and B7-2 regulate T cell activation by
delivering activation signals through CD28 and inhibitory signals through CTLA4.
Graft-vs-host disease (GVHD) is caused by activated donor T cells. Previously, we
showed that CD28-deficient donor T cells induced less-severe GVHD than wild-type
donor T cells, suggesting that CD28 signals exacerbate GVHD. In this paper we
demonstrate that CTLA4 signals attenuate the severity of GVHD. Targeting the CD28
receptor with a specific mAb modulates the receptor in vivo, inhibits donor T
cell expansion, and prevents GVHD. CTLA4 signaling was necessary for this effect
because treatment with a soluble ligand that blocks binding of B7 to both CD28
and CTLA4 did not prevent GVHD as effectively as anti-CD28 mAb. These results
support the current model of T cell costimulation in which CD28 signals amplify
GVHD while CTLA4 signals inhibit GVHD, providing evidence that selective
targeting of CD28 might be a better therapeutic strategy for inducing
immunological tolerance than blocking the ligands for both CD28 and CTLA4.
PMID- 10779757
TI - Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses
in vivo.
AB - Secondary lymphoid tissue chemokine (SLC, also referred to as Exodus 2 or 6Ckine)
is a recently identified high endothelial-derived CC chemokine. The ability of
SLC to chemoattract both Th1 lymphocytes and dendritic cells formed the rationale
to evaluate this chemokine in cancer immunotherapy. Intratumoral injection of
recombinant SLC evidenced potent antitumor responses and led to complete tumor
eradication in 40% of treated mice. SLC-mediated antitumor responses were
lymphocyte dependent as evidenced by the fact that this therapy did not alter
tumor growth in SCID mice. Studies performed in CD4 and CD8 knockout mice also
revealed a requirement for both CD4 and CD8 lymphocyte subsets for SLC-mediated
tumor regression. In immunocompetent mice, intratumoral SLC injection led to a
significant increase in CD4 and CD8 T lymphocytes and dendritic cells,
infiltrating both the tumor and the draining lymph nodes. These cell infiltrates
were accompanied by the enhanced elaboration of Th1 cytokines and chemokines
monokine induced by IFN-gamma and IFN-gamma-inducible protein 10 but a
concomitant decrease in immunosuppressive cytokines at the tumor site. In
response to irradiated autologous tumor, splenic and lymph node-derived cells
from SLC-treated tumor-bearing mice secreted significantly more IFN-gamma, GM
CSF, and IL-12 and reduced levels of IL-10 than did diluent-treated tumor-bearing
mice. After stimulation with irradiated autologous tumor, lymph node-derived
lymphocytes from SLC-treated tumor-bearing mice demonstrated enhanced cytolytic
capacity, suggesting the generation of systemic immune responses. These findings
provide a strong rationale for further evaluation of SLC in tumor immunity and
its use in cancer immunotherapy.
PMID- 10779759
TI - Faithful expression of the human 5q31 cytokine cluster in transgenic mice.
AB - Interleukins -4, -5, and -13, cardinal cytokines produced by Th2 cells, are
coordinately expressed and clustered in 150-kb syntenic regions on mouse
chromosome 11 and human chromosome 5q31. We analyzed two sets of human yeast
artificial chromosome transgenic mice that contained the 5q31 cytokines to assess
whether conserved sequences required for their coordinate and cell-specific
regulation are contained within the cytokine cluster itself. Human IL-4, IL-13,
and IL-5 were expressed under Th2, but not Th1, conditions in vitro. Each of
these cytokines was produced during infection with Nippostrongylus brasiliensis,
a Th2-inducing stimulus, and human IL-4 was generated after activation of NK T
cells in vivo. Consistently fewer cells produced the endogenous mouse cytokines
in transgenic than in control mice, suggesting competition for stable expression
between the mouse and human genes. These data imply the existence of both
conserved trans-activating factors and cis-regulatory elements that underlie the
coordinate expression and lineage specificity of the type 2 cytokine genes in
lymphocytes.
PMID- 10779760
TI - IL-2 signaling in human monocytes involves the phosphorylation and activation of
p59hck.
AB - The activating properties of IL-2 and the structure of the IL-2R on human
monocytes are well characterized. However, relatively little is known about the
biochemical mechanisms involved in IL-2 signal transduction in these cells. We
investigated the role of protein tyrosine kinases (PTKs) in the activation of
monocytes by IL-2. Incubation of monocytes with the PTK inhibitor herbimycin A
(HA) resulted in the dose-dependent suppression of IL-2-induced monocyte
tumoricidal activity. This inhibition was rather potent, as a concentration of HA
as low as 0.5 microM caused a complete abrogation of cytolytic activity.
Furthermore, HA markedly suppressed the ability of IL-2 to induce IL-1 beta, TNF
alpha, IL-6, and IL-8 mRNA expression and protein secretion by monocytes. Anti
phosphotyrosine immunoblotting demonstrated that IL-2 induced a rapid and time
dependent increase in tyrosine phosphorylation of several cellular proteins of
molecular masses ranging from 35 to 180 kDa. Interestingly, IL-2 caused a
significant up-regulation of the constitutive levels of hck PTK mRNA and protein
relative to medium-treated cells as well as an increase in p59hck tyrosine
phosphorylation. Finally, we demonstrated by in vitro kinase assay that the
specific activity of p59hck PTK was also induced by IL-2 in monocytes. Thus,
these data show that the activation of PTKs is required for the triggering of
monocyte effector and secretory functions by IL-2 and strongly suggest that
p59hck is a key participant in IL-2 signaling in human monocytes.
PMID- 10779761
TI - A VH11V kappa 9 B cell antigen receptor drives generation of CD5+ B cells both in
vivo and in vitro.
AB - B lymphocytes can be divided into different subpopulations, some with distinctive
activation requirements and probably mediating specialized functions, based on
surface phenotype and/or anatomical location, but the origins of most of these
populations remain poorly understood. B cells constrained by transgenesis to
produce an Ag receptor derived from a conventional (B-2) type cell develop a B-2
phenotype, whereas cells from mice carrying a B-1-derived receptor acquire the B
1 phenotype. In this study transgenic enforced expression of a B cell receptor
(mu/kappa) originally isolated from a CD5+ (B-1a) B cell generates B-1 phenotype
cells in bone marrow cultures that show a distinctive B-1 function, survival in
culture. Despite their autoreactivity, we find no evidence for receptor editing
or that the paucity of B-2 cells is the result of tolerance-induced selection.
Finally, Ca2+ mobilization studies reveal a difference between transgenic B-1
cells in spleen and peritoneal cavity, with cells in spleen much more responsive
to anti-B cell receptor cross-linking. We discuss these results in terms of
specificity vs lineage models for generation of distinctive B cell
subpopulations.
PMID- 10779763
TI - A physiological ligand of positive selection is seen with high specificity.
AB - Positive selection is a process that ensures that peripheral T cells express TCR
that are restricted to self-MHC molecules. This process requires both self-MHC
and self-peptides. We have recently established a TCR transgenic mouse model
(C10.4 TCRtrans+) in which the transgenic TCR was selected on the nonclassical
MHC class Ib molecule H2-M3 in conjunction with a physiologically occurring
peptide derived from the mitochondrial NADH-dehydrogenase subunit 1 gene (9-mer
peptide). Here, the specificity of positive selection of C10.4 TCRtrans+ T cells
was examined using a fetal thymic organ culture system. We demonstrated that at
low peptide concentrations, shortening the NADH-dehydrogenase subunit 1 gene 9
mer peptide or mutating its surface-exposed side chains severely impaired its
ability to induce positive selection. We concluded that under physiological
conditions positive selection of C10.4 TCRtrans+ T cells was highly specific and
occurred at low epitope densities.
PMID- 10779762
TI - Breakdown of tolerance to a neo-self antigen in double transgenic mice in which B
cells present the antigen.
AB - Transgenic (Tg) mice expressing a foreign Ag, hen egg lysozyme (HEL), under
control of the alphaA-crystallin promoter ("HEL-Tg" mice) develop immunotolerance
to HEL attributed to the expression of HEL in their thymus. In this paper we
analyzed the immune response in double (Dbl)-Tg mice generated by mating the HEL
Tg mice with Tg mice that express HEL Abs on their B cells ("Ig-Tg" mice). The B
cell compartment of the Dbl-Tg mice was unaffected by the HEL presence and was
essentially identical to that of the Ig-Tg mice. A partial breakdown of tolerance
was seen in the T cell response to HEL of the Dbl-Tg mice, i.e., their lymphocyte
proliferative response against HEL was remarkably higher than that of the HEL-Tg
mice. T-lymphocytes of both Dbl-Tg and Ig-Tg mice responded to HEL at
concentrations drastically lower than those found stimulatory to lymphocytes of
the wild-type controls. Cell mixing experiments demonstrated that 1) the
lymphocyte response against low concentrations of HEL is due to the exceedingly
efficient Ag presenting capacity of the Ab expressing B cells and 2) breakdown of
tolerance in Dbl-Tg mice can also be attributed to the APC capacity of B cells,
that sensitize in vivo and stimulate in vitro populations of T cells with low
affinity toward HEL, assumed to be escapees of thymic deletion. These results
thus indicate that T cell tolerance can be partially overcome by the highly
potent Ag presenting capacity of Ab expressing B cells.
PMID- 10779764
TI - Stat3-dependent induction of p19INK4D by IL-10 contributes to inhibition of
macrophage proliferation.
AB - We have previously reported that IL-10 inhibits proliferation of normal bone
marrow-derived macrophages and of the monocyte/macrophage cell line J774.
Activation of Stat3 was shown to be necessary and sufficient to mediate
inhibition of proliferation. To investigate further the mechanism of growth
arrest, we examined the effect of IL-10 on expression of cell cycle inhibitors.
We found that IL-10 treatment increases expression of the cyclin-dependent kinase
inhibitors p19INK4D and p21CIP1 in macrophages. IL-10 cannot induce p19INK4D
expression or block proliferation when Stat3 signaling is blocked by a dominant
negative Stat3 or a mutant IL-10Ralpha which does not recruit Stat3 in J774
cells, whereas p21CIP1 induction is not affected. An inducibly active Stat3
(coumermycin-dimerizable Stat3-Gyrase B), which suppresses J774 cell
proliferation, also induced p19INK4D expression. Sequencing of the murine
p19INK4D promoter revealed two candidate Stat3 binding sites, and IL-10 treatment
activated a reporter gene controlled by this promoter. These data suggest that
Stat3-dependent induction of p19INK4D mediates inhibition of proliferation.
Enforced expression of murine p19INK4D cDNA J774 cells significantly reduced
their proliferation. Use of antisense p19INK4D and analysis of p19INK4D-deficient
macrophages confirmed that p19INK4D is required for optimal inhibition of
proliferation by IL-10, and indicated that additional IL-10 signaling events
contribute to this response. These data indicate that Stat3-dependent induction
of p19INK4D and Stat3-independent induction of p21CIP1 are important components
of the mechanism by which IL-10 blocks proliferation in macrophages.
PMID- 10779765
TI - The linker phosphorylation site Tyr292 mediates the negative regulatory effect of
Cbl on ZAP-70 in T cells.
AB - The protooncogene product Cbl has emerged as a negative regulator of tyrosine
kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal
tyrosine kinase binding (TKB) domain. In this study, we demonstrate that
overexpression of Cbl in Jurkat T cells decreases the TCR-induced phosphorylation
of ZAP-70 and other cellular phosphoproteins. Coexpression of Cbl with ZAP-70 in
COS cells reproduced the Cbl-induced reduction in the level of phosphorylated ZAP
70. The effect of Cbl was eliminated by the TKB-inactivating G306E mutation in
Cbl as well as by a phenylalanine mutation of Tyr292 within the TKB domain
binding site on ZAP-70. Notably, the oncogenic Cbl-70Z/3 mutant associated with
ZAP-70, but did not reduce the levels of phosphorylated ZAP-70. Overexpression of
Cbl, but not Cbl-G306E, in Jurkat T cells led to a decrease in the TCR-induced NF
AT luciferase reporter activity. Overexpression of the TKB domain itself, but not
its G306E mutant, functioned in a dominant-negative manner and led to an increase
in NF-AT reporter activity. Cbl-70Z/3-overexpressing cells exhibited an increase
in both basal and TCR-induced NF-AT luciferase reporter activity, and this trend
was reversed by the G306E mutation. Finally, by reconstituting a ZAP-70-deficient
Jurkat T cell line, p116, we demonstrate that wild-type ZAP-70 is susceptible to
the negative regulatory effect of Cbl, whereas the ZAP-70-Y292F mutant is
resistant. Together, our results establish that the linker phosphorylation site
Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.
PMID- 10779766
TI - Functional and phenotypic evidence for presentation of E alpha 52-68 structurally
related self-peptide(s) in I-E alpha-deficient mice.
AB - The Y-Ae mAb and the 1H3.1 TCR-alpha beta (V alpha 1/V beta 6) are two immune
receptors specific for I-Ab MHC class II molecules complexed to the 52-68
fragment of the alpha-chain of I-E class II molecules (the E alpha 52-68
peptide). A profound intrathymic negative selection occurs in 1H3.1 TCR
transgenic mice in the presence of an I-E alpha transgene. The administration of
mAbs to 1H3.1/I-E alpha double-transgenic newborn mice reveals that Y-Ae, but not
the isotype-matched anti-I-E Y17 mAb, rescues a significant number of mature (V
beta 6highCD4+CD8-) thymocytes and allows the detection of E alpha 52-68-reactive
T cells in the periphery. These observations indicate that deletion of
autoreactive T cells can be specifically inhibited in vivo by an mAb specific for
the deleting self-peptide:self-MHC class II complex. Similar inhibition
experiments indicate that C57BL/6 (I-Ab+/I-E alpha-) mice constitutively express
an E alpha-independent, Y-Ae-recognizable epitope(s). This finding is confirmed
by the phenotypic analysis of mature (MHC class II high) C57BL/6 bone marrow
derived dendritic cells. Collectively, these observations further illustrate the
peptide specificity of negative selection and demonstrate that MHC class II
positive cells from unmanipulated C57BL/6 mice that lack a functional I-E alpha
gene can assemble one or more self-peptide:I-Ab complexes recognizable by the E
alpha 52-68:I-Ab complex-specific Y-Ae mAb.
PMID- 10779767
TI - Increased DNA vaccine delivery and immunogenicity by electroporation in vivo.
AB - DNA vaccines have been demonstrated to be potent in small animals but are less
effective in primates. One limiting factor may be inefficient uptake of DNA by
cells in situ. In this study, we evaluated whether cellular uptake of DNA was a
significant barrier to efficient transfection in vivo and subsequent induction of
immune responses. For this purpose, we used the technique of electroporation to
facilitate DNA delivery in vivo. This technology was shown to substantially
increase delivery of DNA to cells, resulting in increased expression and elevated
immune responses. The potency of a weakly immunogenic hepatitis B surface Ag DNA
vaccine was increased in mice, as seen by a more rapid onset and higher magnitude
of anti-hepatitis B Abs. In addition, the immunogenicity of a potent HIV gag DNA
vaccine was increased in mice, as seen by higher Ab titers, a substantial
reduction in the dose of DNA required to induce an Ab response, and an increase
in CD8+ T cell responses. Finally, Ab responses were enhanced by electroporation
against both components of a combination HIV gag and env DNA vaccine in guinea
pigs and rabbits. Therefore, cellular uptake of DNA is a significant barrier to
transfection in vivo, and electroporation appears able to overcome this barrier.
PMID- 10779768
TI - Cell death-associated translocation of plasma membrane components induced by CTL.
AB - In the very early stages of target cell apoptosis induced by CTL, we found that
fluorescence of labeling probes of the target plasma membrane, such as N-(3
triethylammoniumpropyl)-4-(p-dibutylaminostyryl)pyridin ium dibromide (FM1-43),
was translocated into intracellular membrane structures including nuclear
envelope and mitochondria. This translocation was associated with the execution
of CTL-mediated killing, because neither the CTL-target conjugation alone nor the
binding of noncytotoxic Th2 clone with target cell was sufficient to provoke the
process. Although FM1-43 translocation was observed in perforin-mediated
cytotoxicity, examinations with several other dyes failed to detect the evidence
for membrane damages that may cause influx of the dye. Moreover, the
translocation was also observed in Fas-dependent apoptosis. These data indicate
that the translocation precedes the damage of plasma membrane and intracellular
organella in the course of apoptotic cell death and may represent the existence
of a membrane trafficking that mediates the translocation of plasma membrane
components in the early onset of apoptotic cell death.
PMID- 10779769
TI - Thymic dendritic cells express inducible nitric oxide synthase and generate
nitric oxide in response to self- and alloantigens.
AB - Thymocytes maturing in the thymus undergo clonal deletion/apoptosis when they
encounter self- or allo-Ags presented by dendritic cells (DCs). How this occurs
is a matter of debate, but NO may play a role given its ability of inducing
apoptosis of these cells. APC (a mixed population of macrophages (Mphi) and DCs)
from rat thymus expressed high levels of inducible NO synthase (iNOS) and
produced large amounts of NO in basal conditions whereas iNOS expression and NO
production were very low in thymocytes. Analysis by FACS and by double labeling
of cytocentrifuged preparations showed that DCs and MPhi both express iNOS within
APC. Analysis of a purified preparation of DCs confirmed that these cells express
high levels of iNOS and produce large amounts of NO in basal conditions. The
capacity of DCs to generate NO was enhanced by exposure to rat albumin, a self
protein, and required a fully expressed process of Ag internalization,
processing, and presentation. Peptides derived from portions of class II MHC
molecules up-regulate iNOS expression and NO production by DCs as well, both in
self and allogeneic combinations, suggesting a role of NO in both self and
acquired tolerance. We also found that NO induced apoptosis of rat double
positive thymocytes, the effect being more evident in anti-CD3-stimulated cells.
Altogether, the present findings might suggest that DC-derived NO is at least one
of the soluble factors regulating events, in the thymus, that follow recognition
of self- and allo-Ags.
PMID- 10779770
TI - Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and
macrophages at sites of Th1-mediated inflammation.
AB - Stat4 is a key transcription factor involved in promoting cell-mediated immunity,
whose expression in mature cells has been reported to be restricted to T and NK
cells. We demonstrate here, however, that Stat4 expression is not restricted to
lymphoid cells. In their basal state, monocytes do not express Stat4. Upon
activation, however, IFN-gamma- and LPS-treated monocytes and dendritic cells
express high levels of Stat4. Monocyte-expressed Stat4 in humans is
phosphorylated in response to IFN-alpha, but not IL-12. In contrast, the Th2
cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in
activated monocytes, while having little effect on Stat6 expression. Moreover,
macrophages in synovial tissue obtained from patients with rheumatoid arthritis
express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated
human disease. IFN-alpha-induced Stat4 activation in human monocytes represents a
previously unrecognized signaling pathway at sites of Th1 inflammation.
PMID- 10779771
TI - Cytoprotection of human umbilical vein endothelial cells against apoptosis and
CTL-mediated lysis provided by caspase-resistant Bcl-2 without alterations in
growth or activation responses.
AB - Graft endothelial cells are primary targets of host CTL-mediated injury in acute
allograft rejection. As an in vitro trial of gene therapy to reduce CTL-mediated
endothelial injury, we stably transduced early passage HUVEC with a caspase
resistant mutant form (D34A) of the anti-apoptotic gene Bcl-2. Bcl-2
transductants were compared with HUVEC transduced in parallel with an enhanced
green fluorescent protein (EGFP) gene. Both transduced HUVEC have equivalent
growth rates in complete medium and both show contact inhibition of growth.
However, compared with EGFP-transduced HUVEC, the Bcl-2-transduced cells are
resistant to the apoptotic effects of serum and growth factor withdrawal and are
also resistant to the induction of apoptosis by staurosporine or by ceramide,
with or without TNF. Transduced Bcl-2 did not reduce TNF-mediated NF-kappaB
activation or constitutive expression of class I MHC molecules. HUVEC expressing
D34A Bcl-2 were significantly more resistant to lysis by either class I
restricted alloreactive or PHA-redirected CTL than were HUVEC expressing EGFP. We
conclude that transduction of graft endothelial cells with D34A Bcl-2 is a
possible approach for reducing allograft rejection.
PMID- 10779772
TI - IL-6 receptor independent stimulation of human gp130 by viral IL-6.
AB - The genome of human herpes virus 8, which is associated with Kaposi's sarcoma,
encodes proteins with similarities to cytokines and chemokines including a
homologue of IL-6. Although the function of these viral proteins is unclear, they
might have the potential to modulate the immune system. For viral IL-6 (vIL-6),
it has been demonstrated that it stimulates IL-6-dependent cells, indicating that
the IL-6R system is used. IL-6 binds to IL-6R, and the IL-6/IL-6R complex
associates with gp130 which dimerizes and initiates intracellular signaling.
Cells that only express gp130 but no IL-6R cannot be stimulated by IL-6 unless a
soluble form of the IL-6R is present. This type of signaling has been shown for
hematopoietic progenitor cells, endothelial cells, and smooth muscle cells. In
this paper we show that purified recombinant vIL-6 binds to gp130 and stimulates
primary human smooth muscle cells. IL-6R fails to bind vIL-6 and is not involved
in its signaling. A Fc fusion protein of gp130 turned out to be a potent
inhibitor of vIL-6. Our data demonstrate that vIL-6 is the first cytokine which
directly binds and activates gp130. This property points to a possible role of
this viral cytokine in the pathophysiology of human herpes virus 8.
PMID- 10779773
TI - Cyclic nucleotide phosphodiesterase 3B is a downstream target of protein kinase B
and may be involved in regulation of effects of protein kinase B on thymidine
incorporation in FDCP2 cells.
AB - Wild-type (F/B), constitutively active (F/B*), and three kinase-inactive (F/Ba-,
F/Bb-, F/Bc-) forms of Akt/protein kinase B (PKB) were permanently overexpressed
in FDCP2 cells. In the absence of insulin-like growth factor-1 (IGF-1),
activities of PKB, cyclic nucleotide phosphodiesterase 3B (PDE3B), and PDE4 were
similar in nontransfected FDCP2 cells, mock-transfected (F/V) cells, and F/B and
F/B- cells. In F/V cells, IGF-1 increased PKB, PDE3B, and PDE4 activities
approximately 2-fold. In F/B cells, IGF-1, in a wortmannin-sensitive manner,
increased PKB activity approximately 10-fold and PDE3B phosphorylation and
activity ( approximately 4-fold), but increased PDE4 to the same extent as in F/V
cells. In F/B* cells, in the absence of IGF-1, PKB activity was markedly
increased ( approximately 10-fold) and PDE3B was phosphorylated and activated (3-
to 4-fold); wortmannin inhibited these effects. In F/B* cells, IGF-1 had little
further effect on PKB and activation/phosphorylation of PDE3B. In F/B- cells, IGF
1 activated PDE4, not PDE3B, suggesting that kinase-inactive PKB behaved as a
dominant negative with respect to PDE3B activation. Thymidine incorporation was
greater in F/B* cells than in F/V cells and was inhibited to a greater extent by
PDE3 inhibitors than by rolipram, a PDE4 inhibitor. In F/B cells, IGF-1-induced
phosphorylation of the apoptotic protein BAD was inhibited by the PDE3 inhibitor
cilostamide. Activated PKB phosphorylated and activated rPDE3B in vitro. These
results suggest that PDE3B, not PDE4, is a target of PKB and that activated PDE3B
may regulate cAMP pools that modulate effects of PKB on thymidine incorporation
and BAD phosphorylation in FDCP2 cells.
PMID- 10779774
TI - Characterization of human inducible costimulator ligand expression and function.
AB - The inducible costimulator (ICOS) is the newest member of the CD28/CD152 receptor
family involved in regulating T cell activation. We constructed a soluble-Ig
fusion protein of the extracellular domain of human ICOS and used it as a probe
to characterize expression patterns of the ICOS ligand (ICOSL). ICOSIg did not
bind to CD80- or CD86-transfected Chinese hamster ovary cell lines, demonstrating
that ICOSL is distinct from those ligands identified for CD28/CD152. ICOSIg
showed selective binding to monocytic and B cell lines, whereas binding was
undetectable on unstimulated monocytes and peripheral blood T and B cells.
Expression of ICOSL was induced on monocytes after integrin-dependent plastic
adhesion. Pretreatment of monocytes with mAb to the beta2-integrin subunit CD18
decreased adhesion and abolished ICOSL up-regulation but had no effect on CD80/86
(CD152 ligand (CD152L)) expression. Both ICOSL and CD152L were up-regulated on
monocytes by IFN-gamma but by distinct signaling pathways. Unlike CD152L
expression, ICOSL expression did not change when monocytes were differentiated
into dendritic cells (DCs) or after DCs were induced to mature by LPS, TNF-alpha,
or CD40 ligation. Addition of ICOSIg to allogeneic MLRs between DCs and T cells
reduced T cell proliferative responses but did so less efficiently than CTLA4Ig
(CD152Ig) did. Similarly, ICOSIg also blocked Ag-specific T cell proliferation to
tetanus toxoid. Thus, ICOSL, like CD80/86, is expressed on activated monocytes
and dendritic cells but is regulated differently and delivers distinct signals to
T cells that can be specifically inhibited by ICOSIg.
PMID- 10779776
TI - DO11.10 and OT-II T cells recognize a C-terminal ovalbumin 323-339 epitope.
AB - The OVA323-339 epitope recognized by DO11.10 (H-2d) and OT-II (H-2b) T cells was
investigated using amino- and carboxy-terminal truncations to locate the
approximate ends of the epitopes and single amino acid substitutions of OVA323
339 to identify critical TCR contact residues of the OVA323-339 peptide. DO11.10
and OT-II T cells are both specific for a C-terminal epitope whose core
encompasses amino acids 329-337. Amino acid 333 was identified as the primary TCR
contact residue for both cells, and amino acid 331 was found to be an important
secondary TCR contact residue; however, the importance of other secondary TCR
contact residues and peptide flanking residues differ between the cells.
Additional OVA323-339-specific clones were generated that recognized epitopes
found in the N-terminal end or in the center of the peptide. These findings
indicate that OVA323-339 can be presented by I-Ad in at least three binding
registers. This study highlights some of the complexities of peptide Ags such as
OVA323-339, which contain a nested set of overlapping T cell epitopes and MHC
binding registers.
PMID- 10779775
TI - MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T
cell epitopes for autoantibody production in murine systemic lupus erythematosus.
AB - The systemic lupus erythematosus-like syndrome in MRL/lpr mice involves high
titered IgG autoantibodies, particularly antinuclear Abs that target histones,
DNA, and RNA particles. Although T cell help is required for the generation of
antinuclear Abs, the epitopes recognized by such helper T cells are unknown. To
address this question, we isolated and sequenced self peptides bound by MHC class
II molecules from MRL/lpr mice. We identified a number of peptides that are not
seen in similar preparations from nonautoimmune C3H animals. The "abnormal"
peptide donors include histone, a protein component of a small nuclear
ribonucleoprotein, ribosomal proteins, and RNA processing enzymes. We postulate
that the peptides from these donors are T cell epitopes required for the
generation of the most frequent antinuclear Abs specificities seen in MRL/lpr
mice.
PMID- 10779777
TI - Accelerated proteasomal degradation of membrane Ig heavy chains.
AB - Membrane IgG H chains turn over considerably more rapidly than secretory Ig H
chains in the 18-81 A2 pre-B cell line. This rapid degradation occurs in
proteasomes. N-Glycosylated membrane Ig H chains accumulate in the endoplasmic
reticulum in the presence of proteasomal inhibitors, suggesting that
retrotranslocation and proteasomal degradation of membrane Ig H chains may be
closely coupled processes. Accelerated proteasomal degradation of membrane Ig H
chains was also observed in transfected nonlymphoid cells. At steady state, the
membrane form of the H chain associates more readily with Bip and calnexin than
its secretory counterpart. The preferential recognition of membrane, as opposed
to secretory, Ig H chains by some endoplasmic reticulum chaperones, may provide
an explanation for the accelerated proteasomal degradation of the former.
PMID- 10779778
TI - RGS molecule expression in murine B lymphocytes and ability to down-regulate
chemotaxis to lymphoid chemokines.
AB - Ag-mediated changes in B lymphocyte migration are important for normal immune
function, yet the mechanisms by which these changes occur are poorly defined.
Because chemokines direct many lymphocyte movements, molecules that regulate
signaling by G protein-coupled chemokine receptors are likely to participate in
Ag receptor-induced changes in cell migration. In this study, we have
investigated the expression pattern and activity in murine B cells of members of
the regulators of G protein signaling (RGS) family of molecules. We present the
sequence of mouse RGS1 and describe a novel short isoform of RGS3 that we term
RGS3s. Following in vivo activation by Ag, B cells rapidly up-regulate expression
of RGS1 and RGS2 while simultaneously decreasing expression of RGS3 and RGS14.
Anergic hen egg lysozyme autoantigen-binding B cells are also shown to have
slightly elevated RGS1 and RGS2 expression. CD40 signaling, by contrast, fails to
cause rapid up-regulation of RGS1 or RGS2. Using a transient transfection
approach in a mature B cell line, 2PK3, we demonstrate that RGS1 and RGS3s are
effective inhibitors of chemotaxis toward the lymphoid tissue chemokines stromal
cell-derived factor-1, B lymphocyte chemoattractant, and EBV-induced molecule 1
ligand chemokine, whereas RGS2 has a minimal effect on migration to these
chemokines. Together these findings support the conclusion that Ag-mediated
changes in RGS molecule expression are part of the mechanism by which Ag receptor
signaling regulates B cell migration within lymphoid tissues. The findings also
suggest important roles for additional G protein-mediated events in B cell
activation and tolerance.
PMID- 10779779
TI - Characterization of superantigen-induced clonal deletion with a novel clan III
restricted avian monoclonal antibody: exploiting evolutionary distance to create
antibodies specific for a conserved VH region surface.
AB - Evolution of the Ab system has yielded three clans of VH region genes that are
represented in almost every known higher species with an adaptive immune system.
These clans are defined by sequence homologies primarily in highly conserved
framework (FR) subdomains, which serve a scaffolding function maintaining the
conformation of loops responsible for Ag binding. Structural analyses indicate
that the VH FR1 and FR3 form a conserved composite exposed surface, which has
been implicated in interactions with B cell superantigens. To directly
investigate the expression of clan-defined supraclonal sets, we exploited the
evolutionary distance of the chicken immune system and the selection power of
phage display, to derive Abs diagnostic for clan III Ig. Using a specially
tailored immunization and selection strategy, we created recombinant avian single
chain Fv Abs specific for the clan III products, including those from the human
VH3 family, and the analogous murine 7183, S107, J606, X24, and DNA4 families,
and binding was competitive with natural B cell superantigens. The archetype, LJ
26, was demonstrated to recognize a clan-specific surface expressed in diverse
mammalian, and also the Xenopus and chicken, immune systems. In flow-cytometric
studies with LJ-26, we found that treatment of heterozygous T15i transgenic mice
with a model B cell superantigen induced a clan III-restricted clonal deletion.
These studies demonstrate the utility of a novel recombinant serologic reagent to
study the composition of the B cell compartment and also the consequences of B
cell superantigen exposure.
PMID- 10779780
TI - Molecular mechanisms of target recognition in an innate immune system:
interactions among factor H, C3b, and target in the alternative pathway of human
complement.
AB - In the alternative pathway of complement (APC) factor H is the primary control
factor involved in discrimination between potential pathogens. The APC deposits
C3b on possible Ags, and the interaction with factor H determines whether the
initial C3b activates the APC. Factor H is composed of a linear array of 20
homologous short consensus repeats (SCR) domains with many functional sites.
Three of these sites are involved in binding C3b and regulating complement
activation; others bind to sialic acid and/or heparin and are responsible for
host recognition. Using site-directed mutations we have examined the
contributions of each of these sites to target discrimination and to functional
activities of factor H. Decay acceleration by SCR1-4 of C3/C5 convertases bound
to nonactivators was strongly dependent on SCR domains 11-15 and 16-20. Loss of
these regions caused a 97% loss of activity, with SCR16-20 being the most
critical (>90% loss). On APC activators the pattern of site usage was different
and unique on each. On yeast, deletion of the 10 C-terminal domains (SCR11-20)
had no effect on specific activity. On rabbit erythrocytes, this deletion caused
loss of 75% of the specific activity. An examination of binding affinity to C3b
on the four cell types demonstrated that factor H exhibits a unique pattern of
SCR involvement on each cell. The results reveal a complex molecular mechanism of
discrimination between microbes and host in this ancient innate defense system
and help explain the different rates and intensities of APC activation on
different biological particles.
PMID- 10779781
TI - Biosynthesis and posttranslational regulation of human IL-12.
AB - IL-12 is a heterodimeric proinflammatory cytokine consisting of a light alpha
chain, formerly defined as p35, disulfide-linked to a heavier beta-chain,
formerly defined as p40. The beta-chain is also produced in large excess in a
free form, and disulfide-linked beta-chain homodimers with anti-inflammatory
effects are produced in the mouse. We analyzed the biosynthesis and glycosylation
of IL-12 in human monocytes, and in a cell line stably transfected with IL-12
alpha and beta genes (P5-0.1). The IL-12 heterodimer and free beta-chain were
immunoprecipitated from supernatants and cell lysates of metabolically labeled
cells and resolved in SDS-PAGE. Whereas the beta-chain showed similar pI pattern
whether in the free form or associated in the heterodimer, either in the secreted
or intracellular form, the alpha-chain in the secreted heterodimer was much more
acidic than that present in the intracellular heterodimer. Deglycosylation
experiments with neuraminidase and Endo-F combined with two-dimensional PAGE of
single bands of the intracellular vs extracellular IL-12 heterodimer revealed
that the alpha-chain was extensively modified with sialic acid adducts to N
linked oligosaccharides before secretion. N-glycosylation inhibition by
tunicamycin (TM) did not alter free beta-chain secretion, while preventing the IL
12 heterodimer assembling and secretion. Pulse-chase experiments indicated that
IL-12 persists intracellularly for a long period as an immature heterodimer, and
that glycosylation is the regulatory step that determines its secretion. beta
chain disulfide-linked homodimers were observed in TM-treated P5-0.1 cells, but
in neither TM-treated nor untreated monocytes.
PMID- 10779782
TI - A switch in distinct I kappa B alpha degradation mechanisms mediates constitutive
NF-kappa B activation in mature B cells.
AB - Inducible activation of cytoplasmic NF-kappa B/Rel transcription factors occurs
via proteasome-dependent degradation of an associated inhibitor, termed I kappa B
alpha. Mature B lymphocytes constitutively express nuclear NF-kappa B, which is
important for their long-term survival. The intrinsic mechanisms by which B cells
constitutively activate NF-kappa B are unknown. In this paper we demonstrate that
maintenance of NF-kappa B activity in primary B cells is mediated by a novel
calcium-dependent, but proteasome-independent, mechanism. Moreover, we show that
differentiation of conditionally transformed pre-B cells is accompanied by a
switch from proteasome-dependent to proteasome-independent degradation of I kappa
B alpha. Our findings indicate that I kappa B alpha degradation mechanisms are
dynamic during B cell development, and ultimately establish constitutive NF-kappa
B activity in mature B lymphocytes.
PMID- 10779783
TI - Neutralization of maternal IL-4 modulates congenital protozoal transmission:
comparison of innate versus acquired immune responses.
AB - IL-4 levels were modulated in mice to test the hypothesis that induction of a
maternal type 1 response would decrease the frequency of congenital Neospora
caninum transmission. This hypothesis tested the relationship between IL-4 and
both innate and adaptive immunity utilizing two basic experimental designs. In
the first, maternal IL-4 was neutralized with mAb during pregnancy in naive mice
concomitant with initial, virulent infection. In the second, maternal IL-4 was
neutralized before pregnancy concomitant with a priming inoculation consisting of
live, avirulent N. caninum tachyzoites followed by virulent challenge during
subsequent gestation. In mice that were naive before pregnancy, neutralization of
IL-4 during gestational challenge did not result in decreased congenital
transmission as measured by PCR performed on 1-day-old neonatal mice. In mice
that were primed and modulated before pregnancy, congenital transmission from
gestational challenge was significantly decreased compared with control mice.
Reduction in transmission constituted a decrease in the numbers of mice
transmitting N. caninum and a lower frequency of transmission by individual dams
(p < 0.05). Decreased congenital transmission was associated with significantly
lower levels of maternal splenocyte IL-4 secretion, lower IL-4 mRNA levels, and
higher levels of IFN-gamma secretion. Protected mice had significantly decreased
Neospora-specific IgG1 compared with nonmodulated mice. These studies define a
relationship between maternal Ag-specific immunity and the frequency of
congenital transmission and demonstrate that modulation of type 2 cytokine
responses can change the frequency of congenital protozoal transmission.
PMID- 10779784
TI - Human cytomegalovirus strain-dependent changes in NK cell recognition of infected
fibroblasts.
AB - NK cells play a key role in the control of CMV infection in mice, but the
mechanism by which NK cells can recognize and kill CMV-infected cells is unclear.
In this study, the modulation of NK cell susceptibility of human CMV (hCMV)
infected cells was examined. We used a human lung and a human foreskin fibroblast
cell line infected with clinical isolates (4636, 13B, or 109B) or with laboratory
strains (AD169, Towne). The results indicate that all three hCMV clinical
isolates confer a strong NK resistance, whereas only marginal or variable effects
in the NK recognition were found when the laboratory strains were used. The same
results were obtained regardless of the conditions of infection, effector cell
activation status, cell culture conditions, and/or donor-target cell
combinations. The NK cell inhibition did not correlate with HLA class I
expression levels on the surface of the target cell and was independent of the
leukocyte Ig-like receptor-1, as evaluated in Ab blocking experiments. No
relevant changes were detected in the adhesion molecules ICAM-I and LFA-3
expressed on the cell surface of cells infected with hCMV clinical and laboratory
strains. We conclude that hCMV possesses other mechanisms, related neither to
target cell expression of HLA-I or adhesion molecules nor to NK cell expression
of leukocyte Ig-like receptor-1, that confer resistance to NK cell recognition.
Such mechanisms may be lost during in vitro passage of the virus. These results
emphasize the differences between clinical hCMV isolates compared with laboratory
strains.
PMID- 10779785
TI - Requirement of endogenous stem cell factor and granulocyte-colony-stimulating
factor for IL-17-mediated granulopoiesis.
AB - IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulates
hematopoiesis and causes neutrophilia consisting of mature granulocytes. In this
study, we show that IL-17-mediated granulopoiesis requires G-CSF release and the
presence or induction of the transmembrane form of stem cell factor (SCF) for
optimal granulopoiesis. However, IL-17 also protects mice from G-CSF
neutralization-induced neutropenia. G-CSF neutralization completely reversed IL
17-induced BM progenitor expansion, whereas splenic CFU-GM/CFU-granulocyte
erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sld and
littermate control mice. Thus, there remained a significant SCF/G-CSF-independent
effect of IL-17 on splenic granulopoiesis, resulting in a preservation of mature
circulating granulocytes. IL-17 is a cytokine that potentially interconnects
lymphocytic and myeloid host defense and may have potential for therapeutic
development.
PMID- 10779786
TI - Evidence for human CD4+ T cells in the CD1-restricted repertoire: derivation of
mycobacteria-reactive T cells from leprosy lesions.
AB - Both the CD4-CD8- (double negative) and CD4-CD8+ T cell lineages have been shown
to contain T cells which recognize microbial lipid and glycolipid Ags in the
context of human CD1 molecules. To determine whether T cells expressing the CD4
coreceptor could recognize Ag in the context of CD1, we derived CD4+ T cell lines
from the lesions of leprosy patients. We identified three CD4+ Mycobacterium
leprae-reactive, CD1-restricted T cell lines: two CD1b restricted and one CD1c
restricted. These T cell lines recognize mycobacterial Ags, one of which has not
been previously described for CD1-restricted T cells. The response of CD4+ CD1
restricted T cells, unlike MHC class II-restricted T cells, was not inhibited by
anti-CD4 mAb, suggesting that the CD4 coreceptor does not impact positive or
negative selection of CD1-restricted T cells. The CD4+ CD1-restricted T cell
lines produced IFN-gamma and GM-CSF, the Th1 pattern of cytokines required for
cell-mediated immunity against intracellular pathogens, but no detectable IL-4.
The existence of CD4+ CD1-restricted T cells that produce a Th1 cytokine pattern
suggests a contributory role in immunity to mycobacterial infection.
PMID- 10779787
TI - Linkage of foreign carrier protein to a self-tumor antigen enhances the
immunogenicity of a pulsed dendritic cell vaccine.
AB - The unique Ag-presenting capabilities of dendritic cells (DCs) make them
attractive vehicles for the delivery of therapeutic cancer vaccines. While tumor
Ag-pulsed DC vaccination has shown promising results in a variety of murine tumor
models and early clinical trials, the optimal form of tumor Ag for use in DC
pulsing has not been determined. We have studied DC vaccination using alternative
forms of a soluble protein tumor Ag, the tumor-specific Ig idiotype (Id)
expressed by a murine B cell lymphoma. Vaccination of mice with Id-pulsed DCs was
able to induce anti-Id Abs only when the Id was modified to constitute a hapten
carrier system. DCs pulsed with Id proteins modified to include foreign constant
regions, foreign constant regions plus GM-CSF, or linkage to keyhole limpet
hemocyanin (KLH) carrier protein were increasingly potent in their ability to
elicit anti-Id Abs. Vaccination with Id-KLH-pulsed DCs induced tumor-protective
immunity superior to that obtained with Id-KLH plus a chemical adjuvant, and
protection was not dependent upon effector T cells. Rather, protection was
associated with the induction of high titers of anti-Id Abs of the IgG2a
subclass, characteristic of a Th1 response. These findings have implications for
the design of therapeutic Ag-pulsed DC vaccines for cancer immunotherapy in
humans.
PMID- 10779788
TI - Synthetic endotoxin-binding peptides block endotoxin-triggered TNF-alpha
production by macrophages in vitro and in vivo and prevent endotoxin-mediated
toxic shock.
AB - Lipid A, the conserved portion of endotoxin, is the major mediator of septic
shock; therefore, endotoxin-neutralizing molecules could have important clinical
applications. Here we show that peptides derived from Limulus anti-LPS factor
(LALF), bactericidal/permeability increasing protein (BPI) and endotoxin-binding
protein, bind to lipid A and block the recombinant LALF/lipid A interaction in
vitro. Because their neutralizing capacity in vitro as well as in vivo has been
limited, we created hybrid peptides comprising two endotoxin-binding domains. The
hybrid molecule LL-10-H-14, containing endotoxin-binding domains from LALF and
endotoxin-binding protein, turned out to be the most active peptide within the
series of peptides tested here to inhibit the CD14/lipid A interaction and is
able in vitro to block the endotoxin-induced TNF-alpha release of murine
macrophages up to 90%. Furthermore, LL-10-H-14 not only reduced peak serum levels
of TNF-alpha of mice when preinjected but also reduced TNF-alpha levels when
given 15 min after the endotoxin challenge. As compared with other peptides, only
LL-10-H-14 is able to strongly decrease endotoxin-stimulated TNF-alpha release by
human macrophage cell lines as well as by PBMC. Furthermore, the hybrid peptide
is protective against endotoxin-provoked lethal shock. As such, LL-10-H-14 could
have prophylactic and/or therapeutic properties in humans for the management of
septic shock.
PMID- 10779789
TI - Regulation and role of IFN-gamma in the innate resistance to infection with
Chlamydia pneumoniae.
AB - By using mice genomically lacking IFN-gammaR, IL-12, perforin, and recombination
activating gene-1 (RAG-1), we analyzed the regulation and importance of IFN-gamma
in the control of infection with Chlamydia pneumoniae. IL-12 participates in
resistance of mice to C. pneumoniae, probably by regulating the protective levels
of IFN-gamma mRNA. In turn, IFN-gamma is necessary for the increased IL-12p40
mRNA accumulation that occurs in lungs during infection with C. pneumoniae,
suggesting a positive feedback regulation between these two cytokines. In
experiments including RAG-1-/-/IFN-gammaR-/- mice we showed that IFN-gamma
produced by innate cells controls the bacterial load and is necessary for the
increased accumulation of transcripts for enzymes controlling high output NO
release (inducible NO synthase), superoxide production (gp-91 NADPH oxidase), and
catalysis of tryptophan (indoleamine 2, 3-dioxygenase (IDO)), mechanisms probably
related to bacterial killing. Adaptive immune responses diminish the levels of
IFN-gamma and IL-12 mRNA and thereby the levels of inducible NO synthase, IDO,
and gp91 NADPH oxidase transcripts. By using RAG-1-/-/perforin-/- mice, we
excluded the overt participation of NK cell cytotoxicity in the control of C.
pneumoniae. However, NK cells and probably other innate immune cells release IFN
gamma during the bacterial infection.
PMID- 10779790
TI - In BALB/c mice, IL-4 production during the initial phase of infection with
Leishmania major is necessary and sufficient to instruct Th2 cell development
resulting in progressive disease.
AB - In contrast to intact BALB/c mice, BALB/c mice rendered deficient in Vbeta4+ CD4+
T cells develop a Th1 response to infection with Leishmania major and are
resistant. Vbeta4-deficient BALB/c mice are unable to generate the early IL-4
transcription occurring in Vbeta4 Valpha8 CD4+ T cells of BALB/c mice within 1
day of infection. Here we demonstrate that treatment of Vbeta4-deficient BALB/c
mice with IL-4 during the first 64 h after infection instructs Th2 cell
development and susceptibility to infection. The demonstrated inability of IL-4
to reverse the resistant phenotype of BALB/c mice treated with anti-CD4 mAb the
day before infection suggest that these effects of IL-4 require its interaction
with CD4+ T cells. In contrast to draining lymph node cells from BALB/c mice,
cells from Vbeta4-deficient BALB/c mice remain responsive to IL-12 following
infection. Strikingly, administration of IL-4 to Vbeta4-deficient BALB/c mice
renders their lymph node cells unresponsive to IL-12 by down-regulating IL-12R
beta2-chain expression. This study directly demonstrates that in BALB/c mice IL-4
is necessary and sufficient to initiate the molecular events steering Th2 cell
maturation and susceptibility to L. major.
PMID- 10779791
TI - Phenotype and functions of brain dendritic cells emerging during chronic
infection of mice with Toxoplasma gondii.
AB - During chronic infection of mice with Toxoplasma gondii, gene message for IL
12p40, CD86, and the potassium channel Kv1.3 was detected in brain mononuclear
cells, suggesting the presence of dendritic cells (DC) in the CNS. Consistently,
cells bearing the DC markers CD11c and 33D1 were localized at inflammatory sites
in the infected brain. The number of isolated CD11c+ brain cells increased until
peak inflammation. The cells exhibited the surface phenotype of myeloid DC by
coexpressing 33D1 and F4/80, little DEC-205, and no CD8alpha. These brain DC were
mature, as indicated by high-level expression of MHC class II, CD40, CD54, CD80,
and CD86. They triggered Ag-specific and primary allogeneic T cell responses at
very low APC/T cell ratios. Among mononuclear cells from encephalitic brain, DC
were the main producers of IL-12. Evidence for a parasite-dependent development
of DC from CNS progenitors was obtained in vitro: after inoculation of primary
brain cell culture with T. gondii, IL-12-secreting dendriform cells emerged, and
DC marker genes were expressed. Different stimuli elicited the generation and
maturation of brain DC: neutralization of parasite-induced GM-CSF prevented
outgrowth of dendriform cells and concomitant release of IL-12. IL-12 production
was up-regulated by external IFN-gamma but was stopped by inhibiting parasite
replication. Consistently, DC isolated from GM-CSF-treated brain cell culture
were activated to secrete IL-12 by exposure to parasite lysate. In sum, these
results demonstrate T. gondii-induced expansion and functional maturation of DC
in the CNS and, thus, highlight a mechanism that may contribute to the chronicity
of the host response.
PMID- 10779792
TI - Biological correlates of capsular (quellung) reactions of Cryptococcus
neoformans.
AB - The capsular swelling or quellung reaction was reported almost 100 years ago and
described the effect of Abs on the appearance of microbial capsules. Despite
widespread use to assess Ab binding to capsules, relatively little is known as to
the mechanism of this effect or its biological consequences. The fungus
Cryptococcus neoformans is an attractive system to study capsule reactions
because it has a large polysaccharide capsule that is readily visible by light
microscopy. When viewed by differential interference contrast microscopy, binding
of mAb to C. neoformans cells produced two distinct capsular reactions that
depended on the Ab epitope specificity and the yeast serotype. In the first
pattern, termed "rim," the capsule appears transparent with a highly refractive
outer edge. In the second pattern, termed "puffy," the capsule appears opaque and
lacks a highly refractive outer rim. mAbs that bind with a rim pattern suppress
the overall rate of C3 deposition on the yeast via the classical and alternative
complement pathways. In contrast, mAbs that bind with a puffy pattern do not
affect C3 deposition. Protective and nonprotective IgM mAbs produce rim and puffy
patterns, respectively. These results indicate that: 1) capsule reactions are a
consequence of Ab-induced changes in capsular refractive index; 2) the type of
capsule reaction depends on the Ab specificity; and 3) Ab-induced changes in
refractive index correlate with biological activities important for host defense
against C. neoformans. Our results provide the first evidence associating
distinct capsule reaction patterns with Ab biological activity.
PMID- 10779793
TI - Intersection of group I CD1 molecules and mycobacteria in different intracellular
compartments of dendritic cells.
AB - Human CD1a, CD1b, and CD1c molecules can present mycobacterial glycolipids to T
cells. Because phagosomes containing viable mycobacteria represent early
endosomal compartments, we studied where mycobacterial glycolipids intersect with
CD1 molecules in infected APC. CD1b and CD1c, but not CD1a, localized to late
endosomes/lysosomes. CD1a and CD1c were predominantly expressed on the cell
surface and in mycobacterial phagosomes of the early endosomal stage. In
contrast, CD1b was present in a subset of mycobacterial phagosomes representing
mature phagolysosomes. Released mycobacterial glycolipids including
lipoarabinomannan and phosphatidylinositol mannosides were transported from the
phagosome into late endosomes/lysosomes and to uninfected bystander cells. The
macrophage mannose receptor, which has been implicated in glycolipid uptake by
APC for CD1b-mediated presentation, was absent from mycobacterial phagosomes and
may therefore not be involved in trafficking of glycolipids between phagosomes
and late endosomes/lysosomes. In conclusion, all three CD1 molecules have access
to mycobacteria and glycolipids thereof, but at different intracellular sites.
This allows sampling by CD1a, CD1b, and CD1c of mycobacterial glycolipids from
different intracellular sites of the infected cell, which has important
implications for processing and presentation of such Ags during mycobacterial
infections.
PMID- 10779794
TI - Up-regulation of VCAM-1 and differential expansion of beta integrin-expressing T
lymphocytes are associated with immunity to pulmonary Mycobacterium tuberculosis
infection.
AB - Immune responses rely on an intricate system of adhesion molecules to coordinate
the homing and retention of lymphocytes in both secondary lymphoid tissues and at
sites of infection. To define the events associated with pulmonary immune
responses, the expression of endothelial addressins and integrins on T cells was
analyzed during Mycobacterium tuberculosis infection. In infected lung,
expression of endothelial VCAM-1, but not mucosal addressin cell adhesion
molecule-1, was up-regulated from 4 wk postinfection and persisted to at least 12
wk. Subsequent analysis of the corresponding integrins expressed on lung CD4+ and
CD8+ T cells revealed an accumulation of beta1high/beta7-/low, and to a lesser
extent beta7high, integrin-expressing T cells during infection. Examination of
integrin heterodimers showed that while alpha4 integrin was predominantly
expressed on beta1high/beta7-/low cells, alphaE integrin was primarily associated
with beta7high. The majority of activated/memory T cells recruited during
infection expressed high levels of beta1 integrin and undetectable or low levels
of beta7 integrin. These T cells were capable of producing IFN-gamma, a cytokine
crucial for controlling M. tuberculosis infection. Rapid expansion of beta1high,
beta7-, and beta7high T cell populations in the lung upon secondary mycobacterial
infection indicates the participation of these populations in the acquired immune
response to the infection. Furthermore, treatment of infected mice with mAb to
alpha4 or alpha4beta7 integrin led to a reduction in lymphocytes and increase in
granulocytes in the pulmonary infiltrate. These results reveal a crucial role for
adhesion molecules in the generation of an effective pulmonary immune response to
M. tuberculosis infection.
PMID- 10779795
TI - Apoptotic thymocyte clearance in scavenger receptor class A-deficient mice is
apparently normal.
AB - Studies of apoptotic cell uptake by phagocytes in vitro have implicated a number
of different receptors capable of mediating ingestion. However, there is
currently little evidence for involvement of any of these candidate receptors in
vivo. Previously, we have shown by the use of a blocking mAb against the class A
scavenger receptor (SR-A) and thymic macrophages prepared from SR-A null mice,
that this receptor is responsible for approximately 50% of the uptake of
apoptotic thymocytes in vitro. In this study we have investigated the frequency
of dying cells in the thymus of mice lacking SR-A. Our inability to demonstrate
increased frequencies of nonphagocytosed Annexin V+, TUNEL+, or propidium iodide+
apoptotic thymocytes suggests there is no deficiency in apoptotic thymocyte
clearance in these mice. Even when the rate of thymocyte apoptosis was increased
by exposure of receptor-deficient mice to gamma irradiation, we did not detect a
difference in the numbers of dying cells compared with similarly treated wild
type animals. This provides the first direct evidence of redundancy in apoptotic
cell clearance mechanisms in vivo.
PMID- 10779796
TI - Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator.
AB - Endothelial cells (ECs) are key participants in angiogenic processes that
characterize tumor growth, wound repair, and inflammatory diseases, such as human
rheumatoid arthritis (RA). We and others have shown that EC molecules, such as
soluble E-selectin, mediate angiogenesis. Here we describe an EC molecule, Lewisy
6/H-5-2 glycoconjugate (Ley/H), that shares some structural features with the
soluble E-selectin ligand, sialyl Lewisx (sialyl Lex). One of the main previously
recognized functions of Lewisy is as a blood group glycoconjugate. Here we show
that Ley/H is rapidly cytokine inducible, up-regulated in RA synovial tissue,
where it is cell-bound, and up-regulated in the soluble form in angiogenic RA
compared with nonangiogenic osteoarthritic joint fluid. Soluble Ley/H also has a
novel function, for it is a potent angiogenic mediator in both in vitro and in
vivo bioassays. These results suggest a novel paradigm of soluble blood group Ags
as mediators of angiogenic responses and suggest new targets for therapy of
diseases, such as RA, that are characterized by persistent neovascularization.
PMID- 10779797
TI - IL-6 is required for the development of Th1 cell-mediated murine colitis.
AB - Proinflammatory cytokines have been demonstrated to play a crucial role in the
pathogenesis of Crohn's disease. Among those cytokines, strong expression of IL-6
has been repeatedly demonstrated. To examine the role for IL-6 in the
pathogenesis of Crohn's disease, we introduced anti-IL-6R mAb to a murine model
of colitis. Colitis was induced in C.B-17-scid mice transferred with CD45RBhigh
CD4+ T cells from BALB/c mice. Anti-IL-6R mAb or rat IgG was administered weekly
after T cell transfer. ICAM-1 and VCAM-1 expression were analyzed by
immunohistochemistry. Colonic cytokine expression was determined by RT-PCR. Mice
treated with mAb showed normal growth, whereas controls lost weight. The average
colitis score was 0.64 for mAb-treated mice and 1.80 for controls. T cell
expansion in treated mice was less remarkable than in the controls. Colonic ICAM
1 and VCAM-1 expression were markedly suppressed by mAb. IFN-gamma, TNF-alpha,
and IL-1beta mRNA were reduced by the treatment. The results presented here show
a crucial role for IL-6 in the pathogenesis of murine colitis and suggest a
therapeutic potential of anti-IL-6R mAb for treatment of human Crohn's disease.
PMID- 10779798
TI - Long-term survival of hamster hearts in presensitized rats.
AB - We transplanted hamster hearts into rats that had been sensitized to hamster
cardiac grafts 5 days earlier as a model for discordant xenotransplantation.
Sensitized rats had high serum levels of elicited anti-donor IgM and IgG that
caused hyperacute rejection. Transient complement inhibition with cobra venom
factor (CVF) plus daily and continuing cyclosporin A (CyA) prevented hyperacute
rejection. However, grafts underwent delayed xenograft rejection (DXR). DXR
involved IgG and associated Ab-dependent cell-mediated rejection, because
depletion of IgG or Ab-dependent cell-mediated rejection-associated effector
cells prolonged graft survival and the serum-mediated Ab-dependent cell-mediated
cytotoxicity in vitro. Blood exchange in combination with CVF/CyA treatment
dramatically decreased the level of preexisting Abs, but DXR still occurred in
association with the return of Abs. Splenectomy and cyclophosphamide acted
synergistically to delay Ab return, and when combined with blood exchange/CVF/CyA
facilitated long-term survival of grafts. These grafts survived in the presence
of anti-donor IgM, IgG, and complement that precipitated rejection of naive
hearts, indicating that accommodation (survival in the presence of anti-graft Abs
and complement) had occurred. We attribute the long-term survival to the removal
of preexisting anti-donor Abs and therapy that attenuated the rate of Ab return.
Under such conditions, the surviving hearts showed expression in endothelial
cells and smooth muscle cells of protective genes and an intragraft Th2 immune
response. Th2 responses and protective genes are associated with resistance to
IgM- and IgG-mediated, complement-dependent and -independent forms of rejection.
PMID- 10779799
TI - Kinetics and mechanism of ATP-dependent IL-1 beta release from microglial cells.
AB - Endotoxin-dependent release of IL-1 beta from mouse microglial cells is a very
inefficient process, as it is slow and leads to accumulation of a modest amount
of extracellular cytokine. Furthermore, secreted IL-1 beta is mostly in the
procytokine unprocessed form. Addition of extracellular ATP to LPS-primed
microglia caused a burst of release of a large amount of processed IL-1 beta. ATP
had no effect on the accumulation of intracellular pro-IL-1 beta in the absence
of LPS. In LPS-treated cells, ATP slightly increased the synthesis of pro-IL-1
beta. Optimal ATP concentration for IL-1 beta secretion was between 3 and 5 mM,
but significant release could be observed at concentrations as low as 1 mM. At
all ATP concentrations IL-1 beta release could be inhibited by increasing the
extracellular K+ concentration. ATP-dependent IL-1 beta release was also
inhibited by 90 and 60% by the caspase inhibitors YVAD and DEVD, respectively.
Accordingly, in ATP-stimulated microglia, the p20 proteolytic fragment derived
from activation of the IL-1-beta-converting enzyme could be detected by
immunoblot analysis. These experiments show that in mouse microglial cells
extracellular ATP triggers fast maturation and release of intracellularly
accumulated IL-beta by activating the IL-1-beta-converting enzyme/caspase 1.
PMID- 10779800
TI - Genetic factors determine the contribution of leukotrienes to acute inflammatory
responses.
AB - Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase
pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad
spectrum of inflammatory processes. To investigate the influence of genetic
factors on the contribution of LT to acute inflammation, we generated congenic 5
lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical
application of AA evoked a vigorous inflammatory response in 129 and DBA mice,
whereas only a modest response was seen in B6 animals. The response to AA in 129
and DBA strains is LT dependent. In contrast, LT make little contribution to this
response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent,
since this response was substantially reduced by treating B6 mice with a
cyclooxygenase inhibitor. These data suggest that prostanoids are essential for
AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators
of this response in 129 and DBA strains. In contrast, the response to AA in the
peritoneal cavity is robust in the 129 and B6 strains, but was significantly
blunted in DBA mice, showing that strain differences in the response to AA are
tissue specific. Variations in these and other experimental models of
inflammation appear to correlate directly with the ability of a particular mouse
strain and a specific tissue to respond to LT, specifically LTC4. Taken together,
these findings indicate that the relative contribution of prostanoids and LT to
inflammatory responses is variable not only between strains but also between
different tissues within these inbred mouse lines.
PMID- 10779801
TI - Secretory phospholipases A2 induce beta-glucuronidase release and IL-6 production
from human lung macrophages.
AB - Secretory phospholipases A2 (sPLA2s) are a group of extracellular enzymes that
release fatty acids at the sn-2 position of phospholipids. Group IIA sPLA2 has
been detected in inflammatory fluids, and its plasma level is increased in
inflammatory diseases. To investigate a potential mechanism of sPLA2-induced
inflammation we studied the effect of group IA (from cobra venom) and group IIA
(human synovial) sPLA2s on human macrophages. Both sPLA2s induced a concentration
and Ca2+-dependent, noncytotoxic release of beta-glucuronidase (16.2 +/- 2.4%
and 13.1 +/- 1.5% of the total content with groups IA and IIA, respectively).
Both sPLA2s also increased the rate of secretion of IL-6 and enhanced the
expression of IL-6 mRNA. Preincubation of macrophages with inhibitors of the
hydrolytic activity of sPLA2 or cytosolic PLA2 did not influence the release of
beta-glucuronidase. Incubation of macrophages with p-aminophenyl-mannopyranoside
BSA (mp-BSA), a ligand of the mannose receptor, also resulted in beta
glucuronidase release. However, while preincubation of macrophages with mp-BSA
had no effect on beta-glucuronidase release induced by group IIA sPLA2, it
enhanced that induced by group IA sPLA2. A blocking Ab anti-mannose receptor
inhibited both mp-BSA- and group IIA-induced beta-glucuronidase release. Taken
together, these data indicate that group IA and IIA sPLA2s activate macrophages
with a mechanism independent from their enzymatic activities and probably related
to the activation of the mannose receptor or sPLA2-specific receptors. The
secretion of enzymes and cytokines induced by sPLA2s from human macrophages may
play an important role in inflammation and tissue damage associated with the
release of sPLA2s.
PMID- 10779802
TI - IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein
S100A8.
AB - The murine calcium-binding protein S100A8 is a potent chemoattractant for
neutrophils and monocytes in vivo and in vitro but may also play a protective
role. We show that the kinetics of induction of S100A8 mRNA in elicited murine
macrophages (Mac) by LPS, IFN-gamma, and TNF were distinct from the C-C
chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage-inflammatory
protein-1alpha (MIP-1alpha), and RANTES. Monomeric S100A8 was predominantly
secreted. IFN substantially increased S100A8 mRNA levels after 1 h with optimal
induction after 12 h; induction by TNF was slower and more sustained. TNF did not
up-regulate MCP-1 and MIP-1alpha mRNA in these cells. Luciferase reporter assays
confirmed that LPS and IFN induce S100A8 gene transcription and mRNA in LPS
treated Mac showed little decay over 16 h, whereas transcripts induced by IFN and
TNF were markedly less stable. Newly synthesized proteins may be required for
mRNA transcription and stabilization in response to LPS. S100A9 associates with
A8 in neutrophils, but was not coinduced with S100A8. S100A8 gene induction in
Mac stimulated with LPS and IFN may be modulated by mobilization of intracellular
Ca2+ concentration from distinct intracellular stores and/or the extracellular
compartment and by distinct pathways involving protein kinase C and leading to
activation of mitogen-activated protein kinase.
PMID- 10779803
TI - The T cell repertoire selected in vitro against EBV: diversity, specificity, and
improved purification through early IL-2 receptor alpha-chain (CD25)-positive
selection.
AB - Polyclonal T cell lines specific for EBV proteins have proved efficient in
preventing EBV-related immunoblastic lymphoma after allogeneic bone marrow
transplantation. To gain insight into the composition of the EBV-specific T cell
repertoire that ensured patient protection, we performed for the first time an
extensive characterization of eight cytotoxic T cell lines selected in vitro
against EBV-transformed autologous lymphoblastoid cell lines (BLCL). These T cell
lines consist of 50-100 distinct T cell clones, of which 32-96% are specific for
autologous BLCL. Moreover, we demonstrate that reactivities against only five EBV
proteins (BZLF1, BMLF1, EBNA-3A, EBNA-3C, and LMP2) cover 86% (32/37) of the
specificities detected. In addition, we describe an improved method of T cell
harvesting using a CD25 selection procedure which reduces the time required to
obtain specific T cells and improves the purity of EBV-specific T cells, thus
showing promise for use in adoptive transfer protocols.
PMID- 10779804
TI - Baseline airway hyperreactivity in A/J mice is not mediated by cells of the
adaptive immune system.
AB - Human asthma is characterized by increased airway hyperreactivity to a variety of
bronchoconstricting agents. Aberrant type 2 immune responses in the lung have
been associated with airway hyperreactivity in both human asthma and in murine
models of allergic airways disease. Despite their intrinsically elevated basal
airway reactivity to smooth muscle constricting agents, A/J mice demonstrated no
inherent inflammatory cell infiltration nor elevation of type 2 cytokines in the
lung. Crossed bone marrow reconstitution experiments between A/J and MHC congenic
B10.A mice revealed enhanced airway reactivity only in A/J recipients,
irrespective of whether they had been reconstituted with A/J or B10. A
hemopoietic cells. Further, A/J-derived bone marrow cells did not affect the
reactivity of B10.A recipients. Although mice on RAG-deficient and IL-4-deficient
backgrounds demonstrate substantial abrogation of allergen-induced airway
hyperreactivity, these gene deletions had no impact on the elevated baseline
reactivity when backcrossed onto A/J mice. Thus, in these mice, basal airway
hyperreactivity is maintained independently of type 2 immunity induced by
allergens.
PMID- 10779805
TI - Differential role of Fas/Fas ligand interactions in cytolysis of primary and
metastatic colon carcinoma cell lines by human antigen-specific CD8+ CTL.
AB - We have previously identified mutated ras peptides reflecting the glycine to
valine substitution at position 12 as HLA-A2-restricted, CD8+ CTL neo-epitopes.
CTL lines produced against these peptide epitopes lysed the HLA-A2+ Ag-bearing
SW480 primary colon adenocarcinoma cell line, although IFN-gamma treatment of the
targets was necessary to achieve efficient cytotoxicity. Here, we compared the
lytic phenotype of the SW480 cell line to its metastatic derivative, SW620, as an
in vitro paradigm to further characterize the nature of a HLA class I-restricted,
Ag-specific CTL response against neoplastic cell lines of primary and metastatic
origin. Although both colon carcinoma cell lines were lysed by these Ag-specific
CTL following IFN-gamma pretreatment, the mechanisms of lysis were distinct,
which reflected differential levels of sensitivity to the Fas pathway. Whereas
IFN-gamma pretreatment rendered SW480 cells sensitive to both Fas-dependent and
independent (perforin) pathways, SW620 cells displayed lytic susceptibility to
Fas-independent mechanisms only. Moreover, pretreatment of SW480 cells with the
anti-colon cancer agent, 5-fluorouracil (5-FU), led to enhanced Fas and ICAM-1
expression and triggered Ag-specific CTL-mediated lysis via Fas- and perforin
based pathways. In contrast, these phenotypic and functional responses were not
observed with SW620 cells. Overall, these data suggested that 1) IFN-gamma and 5
FU may enhance the lytic sensitivity of responsive colon carcinoma cells to
immune effector mechanisms, including Fas-induced lysis; 2) the malignant
phenotype may associate with resistance to Fas-mediated lysis in response to Ag
specific T cell attack; and 3) if Ag-specific CTL possess diverse lytic
capabilities, this may overcome, to some extent, the potential "escape" of Fas
resistant carcinoma cells.
PMID- 10779806
TI - Macrophage colony-stimulating factor antagonists inhibit replication of HIV-1 in
human macrophages.
AB - Macrophages infected with HIV-1 produce high levels of M-CSF and macrophage
inflammatory protein-1alpha (MIP-1alpha). M-CSF facilitates the growth and
differentiation of macrophages, while the chemotactic properties of MIP-1alpha
attract both T lymphocytes and macrophages to the site of HIV infection. Studies
described in this work indicate M-CSF may function in an autocrine/paracrine
manner to sustain HIV replication, and data suggest possible therapeutic
strategies for decreasing viral load following HIV infection. We show that
macrophage infection with measles virus or respiratory syncytial virus, in
contrast to HIV-1, results in production of MIP-1alpha, but not M-CSF. Thus, M
CSF appears to be specifically produced upon infection of macrophages with HIV-1.
Furthermore, addition of M-CSF antagonists to HIV-1-infected macrophages,
including anti-M-CSF monoclonal or polyclonal Abs or soluble M-CSF receptors,
dramatically inhibited HIV-1 replication and reduced production of MIP-1alpha.
Our results suggest that biologic antagonists for M-CSF may represent novel
strategies for inhibiting the spread of HIV-1 by 1) blocking virus replication in
macrophages, 2) reducing recruitment of HIV-susceptible T cells and macrophages
by MIP-1alpha, and 3) preventing the establishment and maintenance of infected
macrophages as a reservoir for HIV.
PMID- 10779807
TI - T cell activity after dendritic cell vaccination is dependent on both the type of
antigen and the mode of delivery.
AB - Previous work in both human and animal models has shown that CTL responses can be
generated against proteins derived from tumors using either peptide-pulsed
dendritic cells (DCs) or nucleic acids from the tumor transfected into autologous
DCs. Despite the efficacy of this approach for vaccine therapy, many questions
remain regarding whether the route of administration, the frequency of
administration, or the type of Ag is critical to generating T cell responses to
these Ags. We have investigated methods to enhance CTL responses to a peptide
derived from the human proto-oncogene HER-2/neu using mice containing a chimeric
HLA A2 and H2Kb allele. Changes in amino acids in the anchor positions of the
peptide enhanced the binding of the peptide to HLA-A2 in vitro, but did not
enhance the immunogenicity of the peptide in vivo. In contrast, when autologous
DCs presented peptides, significant CTL activity was induced with the altered,
but not the wild-type, peptide. We found that the route of administration
affected the anatomic site and the time to onset of CTL activity, but did not
impact on the magnitude of the response. To our surprise, we observed that weekly
administration of peptide-pulsed DCs led to diminishing CTL activity after 6 wk
of treatment. This was not found in animals injected with DCs every 3 wk for six
treatments or in animals initially given DCs weekly and then injected weekly with
peptide-pulsed C1R-A2 transfectants.
PMID- 10779809
TI - Fiche n 33 : BCR
PMID- 10779808
TI - Induction of AIDS virus-specific CTL activity in fresh, unstimulated peripheral
blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified
vaccinia virus Ankara boost regimen.
AB - The observed role of CTL in the containment of AIDS virus replication suggests
that an effective HIV vaccine will be required to generate strong CTL responses.
Because epitope-based vaccines offer several potential advantages for inducing
strong, multispecific CTL responses, we tested the ability of an epitope-based
DNA prime/modified vaccinia virus Ankara (MVA) boost vaccine to induce CTL
responses against a single SIVgag CTL epitope. As assessed using both 51Cr
release assays and tetramer staining of in vitro stimulated PBMC, DNA
vaccinations administered to the skin with the gene gun induced and progressively
increased p11C, C-->M (CTPYDINQM)-specific CD8+ T lymphocyte responses in six of
six Mamu-A*01+ rhesus macaques. Tetramer staining of fresh, unstimulated PBMC
from two of the DNA-vaccinated animals indicated that as much as 0.4% of all
CD3+/CD8alpha+ T lymphocytes were specific for the SIVgag CTL epitope.
Administration of MVA expressing the SIVgag CTL epitope further boosted these
responses, such that 0.8-20.0% of CD3+/CD8alpha+ T lymphocytes in fresh,
unstimulated PBMC were now Ag specific. Enzyme-linked immunospot assays confirmed
this high frequency of Ag-specific cells, and intracellular IFN-gamma staining
demonstrated that the majority of these cells produced IFN-gamma after peptide
stimulation. Moreover, direct ex vivo SIV-specific cytotoxic activity could be
detected in PBMC from five of the six DNA/MVA-vaccinated animals, indicating that
this epitope-based DNA prime/MVA boost regimen represents a potent method for
inducing high levels of functionally active, Ag-specific CD8+ T lymphocytes in
non-human primates.
PMID- 10779810
TI - [LGD1069: an antagonist to the X retinoid receptor].
PMID- 10779811
TI - [Screening for cancer: what's new?].
AB - Setting up of screening programmes for cancers has been the result of evaluation
studies but even more of the existence (or non existence) of national policies
for cancer control. We know for sure that mammographic screening can reduce
breast cancer mortality in women from age 50 onwards, smear screening has a
favourable impact on cervical cancer mortality and incidence, and faecal blood
testing in stools may reduce colon cancer mortality. Other questions, considered
for a long time as settled, are coming back, either because new data are
available, such as in screening for breast cancer before age 50, or because new
screening methods are being proposed, such as for lung cancer. Finally, the
recognition of populations at very high genetic risk makes necessary the search
for answers for example for familial breast and/or ovarian cancer. Last but not
least is the methodological challenge: how can we rapidly provide answers, which
implies the need for new approaches, in addition to randomized controlled trials?
PMID- 10779812
TI - [Abnormal cervical smear: what to do? National Agency for Accreditation and
Evaluation in Health].
PMID- 10779813
TI - [Phase II study of docetaxel in inoperable advanced non small cell lung cancer].
AB - The purpose is to determine the response to, and toxicity of docetaxel (Taxotere)
in patients with inoperable non small cell lung cancer (NSCLC), previously
untreated. Seventy patients with stage IIIB or IV NSCLC were treated by 100
mg/m2/ 3 weeks of docetaxel until tumor progression or severe toxicity.
Premedication with diosmine and prednisolone was given in all patients: 66/70
were eligible and 55/70 were assessable for antitumoral activity. Median age: 63
years, WHO performans status 0-1: 83%, stage IV: 96%. For eligible patients,
17/66 (26%) achieved an objective response: 1 complete response and 16 partial
response (IC 95% = 15-36). With a median follow-up of 23.4 months (range 14.9
28.7), for evaluable patients, the median response duration was 8 months, the
median time to progression 4 months, and the median survival time 10 months. The
median number of administered cycles is 5 (range 1-12). The estimate one year
survival rate was 47%. Seventy-six patients presented neutropenia (grade 3-4);
febrile neutropenia was observed in 7% of cycles. Non haematological toxicities
are: fluid retention related to docetaxel (2.9%), diarrhea (6%), nausea-vomiting
(4%), asthenia (3%), nail changes (6%). Docetaxel (Taxotere) administered at 100
mg/m2/3 weeks has relevant clinical activity in previously untreated NSCLC with a
acceptable toxicity.
PMID- 10779814
TI - [Oral granisetron solution as prophylaxis for chemotherapy-induced emesis in
children: double-blind study of 2 doses].
AB - This multicentric double-blind, dose-ranging study was to compare efficacy and
safety of two oral doses of granisetron solution in the prevention of
chemotherapy-induced emesis in children with malignant diseases : 294 children,
aged 1 to 16, treated with a moderately or highly emetogenic chemotherapy were
randomly assigned to receive oral granisetron either 20 microg/kg (n = 143) or 40
microg/kg (n = 151) before and 6 to 12 hours after the start of chemotherapy.
Fifty-one percent of patients treated with 20 microg/kg bd of oral granisetron
solution achieved a complete response (no vomiting, no worse than mild nausea, no
rescue therapy and no withdrawal during the specified period) and 59% achieved a
major response (no more than one episode of vomiting, no worse than mild nausea,
no rescue therapy and no withdrawal during the specified period). There was no
difference between the two oral doses of granisetron. Treatment was rated as good
or very good by investigators in 70% of cases. In conclusion, oral granisetron
suspension either at 20 microg/kg bd or at 40 microg/kg bd showed good efficacy
and safety in the prevention of chemotherapy-induced emesis in children with
malignant diseases. Oral granisetron solution can be used as prophylaxis of
emesis in children receiving moderately or highly emetogenic chemotherapy.
PMID- 10779815
TI - [Predictive value of preoperative abdominopelvic CT for optimal cytoreduction
surgery in ovarian carcinoma].
AB - Some patients underwent laparoscopy without optimal debulking surgery as initial
treatment for advanced ovarian carcinoma. The amount of residual tumor following
primary surgery was an important prognosis factor. Neoadjuvant chemotherapy is a
new therapeutic approach. Secondary, optimal surgery could be done in better
conditions. The purpose was to access the ability of preoperative abdominopelvic
CT to predict success of debulking surgery for ovarian carcinoma: less than 1 cm
of residual tumor size after initial surgery. We reviewed 39 patients (2 stages
Ic, 1 stage IIc, 22 stages III and 14 stages IV) operated on for ovarian
carcinoma between January 1992 and December 1997. Surgical criteria of inability
to perform optimal surgical cytoreduction were compared with abdominopelvic CT
done the month before. CT scans were prospectively assessed by radiologist A and
retrospectively (3 months to 6 years delay) rewiewed separately by radiologists A
and B without surgical data. Nineteen patients underwent optimal debulking
surgery: 13 no residual tumor and 6 with residual lesions under 1 cm. The
interreader (0.73) and intrareader (0.9) agreement, worked out by Kappa
coefficient, was juged good to very good. The sensitivity of CT was 91% with a
specificity of 95%. These results allowed us to determine wich CT criteria were
accurate and reproducible to be a helpfull for therapeutic choice and to avoid
laparotomy without optimal surgery.
PMID- 10779816
TI - Rectangular flaps technique for treatment of congenital hand syndactyly.
AB - The authors analysed a series of 22 patients undergoing surgical correction of
congenital hand syndactyly by the rectangular flap technique. Using our
evaluation method, we found that good functional and aesthetic results were
obtained in 77.3% of the patients, with a complication rate of 13.6%. We
concluded that the rectangular flap technique has a simple design, is easily
reproducible by in-training staff, has good results, and can be applied on the
majority of the syndactyly cases.
PMID- 10779817
TI - Influence of physical exercise and sodium intake on arterial pressure and cardiac
hypertrophy in rats.
AB - Evidence shows that cardiac hypertrophy (CH) is a risk factor for many
cardiovascular diseases. Several stimuli may cause CH-like manifestations and
promote volume or pressure overload. Exercise-induced cardiac hypertrophy is an
expected adaptation to regular exercise training. Salt intake has been shown to
be the most important determinant of blood pressure in different populations. The
purpose of the present work was to verify the influence of physical exercise and
sodium intake on the blood pressure and myocardium. The study was performed on 36
rats divided into six groups: Group I (diet without salt overload), Group II
(diet without salt overload and swimming), Group III (diet with 2.5% NaCl
solution and swimming), Group IV (diet with 5% NaCl solution and swimming), Group
V (diet with 2.5% NaCl solution without exercise), Group VI (diet with 5% NaCl
solution without exercise). The arterial pressure was significantly lower in
Group I when compared with Group IV. The ratio of cardiac mass/body mass was
increased in Groups III and IV. In conclusion, there was evidence that exercise
training and NaCl intake promotes arterial hypertension and cardiac hypertrophy.
PMID- 10779818
TI - Fatal pulmonary thromboembolism in gastrectomy intraoperative procedures by
gastric adenocarcinoma: case report.
AB - The case of a patient with gastric adenocarcinoma with indication for gastrectomy
is reported. The surgery took place without complications. A palliative, subtotal
gastrectomy was performed after para-aortic lymph nodes compromised by neoplasm
were found, which was confirmed by pathological exam of frozen sections carried
out during the intervention. At the end of the gastroenteroanastomosis procedure,
the patient began to show intense bradycardia: 38 beats per minute (bpm),
arterial hypotension, changes in the electrocardiogram's waveform (upper
unlevelling of segment ST), and cardiac arrest. Resuscitation maneuvers were
performed with temporary success. Subsequently, the patient had another
circulatory breakdown and again was recovered. Finally, the third cardiac arrest
proved to be irreversible, and the intra-operative death occurred. Necropsy
showed massive pulmonary embolism. The medical literature has recommended
heparinization of patients, in an attempt to avoid pulmonary thromboembolism
following major surgical interventions. However, in the present case,
heparinization would have been insufficient to prevent death. This case indicates
that it is necessary to develop preoperative propedeutics for diagnosing the
presence of venous thrombi with potential to migrate, causing pulmonary
thromboembolism (PTE). If such thrombi could be detected, preventative measures,
such as filter installation in the Cava vein could be undertaken.
PMID- 10779819
TI - Relationship between plasma creatinine concentration and glomerular filtration in
preterm newborn infants.
AB - Fluid management and dosage regimens of drugs in preterm infants should be based
on the glomerular filtration rate. The current methods to determine glomerular
filtration rate are invasive, time-consuming, and expensive. In contrast,
creatinine clearance can be easy obtained and quickly determined. The purpose of
this study was to compare plasma creatinine on the third and seventh day of life
in preterm newborn infants, to evaluate the influence of maternal creatinine, and
to demonstrate creatinine clearance can be used as a reliable indicator of
glomerular filtration rate. We developed a prospective study (1994) including 40
preterm newborns (gestational age < 37 weeks), average = 34 weeks; birth weight
(average) = 1840 g, in the first week of life. Inclusion criteria consisted of:
absence of renal and urinary tract anomalies; O2 saturation >/= 92%; adequate
urine output (>1ml/kg/hr); normal blood pressure; absence of infections and no
sympathomimetic amines in use. A blood sample was collected to determine plasma
creatinine (enzymatic method) on the third and seventh day of life and creatinine
clearance (CrCl) was obtained using the following equation: [formula: see text],
k = 0.33 in preterm infant All plasma creatinine determinations showed normal
values [third day: 0.78 mg/dl +/- 0.24 (mean +/- SD)and seventh day: 0.67 mg/dl
+/- 0.31 - (p>0.05)]. Also all creatinine clearance at third and seventh day of
life were normal [third day: 19.5 ml/min +/- 5.2 (mean +/- SD) and seventh day:
23.8 ml/min +/- 7.3 - (p>0,05)]. All preterm infants developed adequate renal
function for their respective gestational age. In summary, our results indicate
that, for clinical practice, the creatinine clearance, using newborn length, can
be used to estimate glomerular filtration rate in preterm newborn infants.
PMID- 10779820
TI - Radiographic aspects and angioarchitectural arrangements in corrosion casts of
the blood supply to the human sternocleidomastoid muscle by the
sternocleidomastoid branch of the occipital artery.
AB - The contribution of the sternocleidomastoid branch of the occipital artery
(superior arterial pedicle-SAP) to the irrigation of the sternocleidomastoid
muscle (SCM) was evaluated in fresh human cadavers by injecting radiological dye
and a resin for microvasculature corrosion casts. From its insertion in the
mastoid process of the temporal bone, the SCM was divided into superior, medium,
and inferior thirds. In most of the SCM, The SAP are formed by two longitudinal
parallel branches. In all specimens, the radiological dye injected into the SAP
reached or trespassed the middle part of the studied SCM. The SAP was poorly
distributed in the lowermost region of the inferior third of the SCM, suggesting
the contribution of other arteries or pedicles. The corrosion casts of the
microvasculature showed a profuse network of microscopic vessels in those levels
where the SAP was detected.
PMID- 10779821
TI - Double pylorus: case report and review of the literature.
AB - Double pylorus is an unusual condition in which a double communication between
the gastric antrum and the duodenal bulb occurs. It may be congenital, or it may
be acquired complication of peptic ulcer disease. We present a case of double
pylorus in a gentleman with epigastric pain and previous history of peptic ulcer
disease. The relationship between Helicobacter pylori and this disease was
assessed. A review of the literature, the role of associated diseases and the
role of H. pylori are discussed.
PMID- 10779822
TI - Low blood glucose levels and other complications during growth hormone
supplementation in sepsis.
AB - Blood glucose levels in the high normal range or even moderate hyperglycemia is
the expected profile in septic postoperative patients receiving high-calorie
enteral alimentation. The addition of growth hormone as an anabolic agent should
additionally reinforce this tendency. In a cancer patient undergoing partial
gastrectomy with lymphadenectomy and suffering from postoperative subphrenic
abscess and prolonged sepsis, tube feeding (38.3 kcal/kg/day) and growth hormone
(0.17 IU/kg/day) were simultaneously administered for 25 days. Blood glucose
levels were in the lower limits of the normal range before growth hormone
introduction, and continued with a similar tendency during most of the
therapeutic period. Two additional complications, namely heart arrest and
peripheral edema, were documented during the same period. It is concluded that
sepsis was the most likely mechanism for low glucose values, and that high
calorie enteral diet and growth hormone supplementation did not prevent that
result. It is uncertain whether heart arrest was due to the drug, but its
association with peripheral edema is well documented in clinical series.
PMID- 10779824
TI - Oxygen deficit is related to the exercise time to exhaustion at maximal aerobic
speed in middle distance runners.
AB - The purpose of this study was to show the relationship between oxygen deficit and
the time to exhaustion (tlim) at maximal aerobic speed (MAS). The minimum speed
that elicits VO(2max) was assumed to be the maximal aerobic speed (MAS). Fourteen
subelite male runners (mean (SD: age = 27 +/- 5 yrs: VO(2max) = 68.9 +/- 4.6 ml
kg (-1). min ( -1); MAS = 21.5 +/- 1 km h (-1) ) participated in the study. Each
subject performed an incremental test to determine and MAS. The subjects ran to
exhaustion at velocities corresponding to 100 and 120 % MAS. Oxygen deficit was
measured during the period exercise to exhaustion at 120% of MAS and was
calculated from the difference between O(2) demand and the accumulated O 2
uptake. The tlim values at 100% MAS were correlated with the values of tlim at
120% MAS (r = 0.52). The results reveal that the oxygen deficit was related to
the time to exhaustion at MAS and indicate that the greater the oxygen deficit,
the greater the time to exhaustion at MAS. It was also noted that the adjustment
of oxygen consumption is related to the oxygen deficit. In other words, the
subjects who have an important anaerobic capacity are the most efficient during
an exercise time to exhaustion at MAS. The time limit values can be expressed by
a linear regression making intervene MAS and anaerobic capacity. This conclusion
could be of great interest in the training of middle distance runners.
PMID- 10779823
TI - The influence of hypo- and hyperthyreosis on insulin receptors and metabolism.
AB - Changes in thyroid status affect metabolism not only directly, but influence it
also by alterations in insulin secretion and action. Despite several
investigations, these effects are, however, poorly characterised or even
controversial. The aim of the studies was to investigate the effect of
hyperthyreosis (HT) and hypothyreosis (HPT) on insulin binding by rat liver
membranes. Some metabolic parameters reflecting insulin and thyroid hormones
action were also determined. HT and HPT were developed by daily administration
for 3 weeks of thyroxine (T (4) ) and thiouracil (TU), respectively. Experimental
hyperthyreosis and hypothyreosis caused deep changes in metabolism. The greatest
alterations were observed in body and thyroid glands weight, blood
triiodothyronine (T (3) ), T (4), glucose, and insulin levels, liver glycogen
amount and number of insulin receptors. HT reflected in rats in slower rate of
growth and in smaller thyroid glands weight. In comparison to controls, T (4)
concentration in HT was almost doubled and it was reduced by about 30% in HPT.
Also, T(3), insulin and glucose levels in HT were heightened. Simultaneously,
binding of insulin to liver membranes was elevated in HT and reduced in HPT. In
HT the number of high affinity insulin receptors (HAIRs) and low affinity insulin
receptors (LAIRs) was increased, whereas in HPT the amount of HAIRs was
diminished. HT caused a drastic reduction of glycogen concentration in liver, but
no changes were observed for muscle glycogen. Considering lipid metabolism, only
free fatty acids (FFA) level in blood was changed (in HPT), but no differences
were observed in serum concentration of triglycerides and cholesterol. Several
metabolic changes observed in HT and HPT seem to be the dire ct consequence of
alterations of thyroid hormone concentrations. These disturbances, together with
the direct effect of HT or HPT on insulin secretion, binding and action lead, in
turn, to changes in the other metabolic parameters. As a result of these
disturbances the adaptive mechanisms appear. One of them is change in the number
of insulin membrane receptors taking place even against the well known "down
regulation" theory.
PMID- 10779825
TI - Luteinizing hormone releasing hormone increases proliferation of meningioma cells
in vitro.
AB - The fact that meningioma shows at least a 2:1 predilection for women over men is
considered to be due to endocrinological and paracrine regulation of the
development of this tumour. The presence of receptors for the luteinizing hormone
releasing hormone (LHRH) in gynaecological cancer permits the use of LHRH
agonistic or antagonistic analogues with a direct effect or by the gonado
pituitary axis suppression in the treatment of these tumours. Therefore, the
effect of LHRH on meningioma cells is tested in this study. Meningioma cells from
three female patients were cultured and LHRH (50 ng/ml) was added to the growth
medium daily, for fourteen days. At the end of this period the cells were counted
by means of a Coulter Counter. The stimulating effects of LHRH on the increase of
the amount of cells in the meningioma monolayer culture were 146% (p < 0.01),
134% (p < 0.05) and 141% (p < 0.05) of the control, respectively, for the three
patients.
PMID- 10779826
TI - Muscular force transmission: a unified, dual or multiple system? A review and
some explorative experimental results.
AB - Structures contributing to force transmission in muscle are reviewed combining
some historical and relatively recently published experimental data. Also,
effects of aponeurotomy and tenotomy are reviewed shortly as well as some new
experimental results regarding these interventions that reinforce the concept of
myofascial force transmission. The review is also illustrated by some new images
of single muscle fibres from Xenopus Laevis indicative of such transmission and
some data about locations of insertion of human gluteus maximus muscle. From this
review and the new material, emerges a line of thought indicating that mechanical
connections between muscle fibres and intramuscular connective tissue play an
important role in force transmission. New experimental observations are presented
for non-spanning muscle (i.c., rat biceps femoris muscle), regarding the great
variety of types of intramuscular connections that exist i n addition to myo
tendinous junctions at the perimuscular ends of muscle fibres. Such connections
are classified as (1) tapered end connections, (2) Myo-myonal junctions, (3) myo
epimysial junctions and (3) Myo-endomysial junctions. This line of thought is
followed up by consideration of a possible role of connections of intra- and
extramuscular connective tissue in force transmission out of the muscle.
Experimental results of an explorative nature, regarding the interactions of
extensor digitorum longus (EDL), tibialis anterior (TA) and hallucis longus (HAL)
muscles within a relatively intact dorsal flexor compartment of the rat hind leg,
indicate that: (1) length force properties of EDL are influenced by TA activity
in a length dependent fashion. Depending on TA length, force exerted by EDL, kept
at constant origin insertion distance, is variable and the effect is influenced
by EDL length itself as well; (2) Force is transmitted from muscle to
extramuscular connective tissue and vice versa. As a consequence force exerted at
proximal and distal tendons of a muscle are not always equal. The difference
being transmitted by extramuscular connective tissue and may appear at the
tendons of other muscles or may be transmitted via connective tissue directly to
bone. It is concluded that the system of force transmission from skeletal muscle
should be considered as a multiple system.
PMID- 10779828
TI - Intracerebroventricular infusion of hypertonic NaCl increases urinary CGMP in
healthy and cirrhotic rats.
AB - Implication of serum atrial natriuretic peptide (ANP) and endothelin-1 (ET1) in
the central nervous system (CNS)-induced natriuresis and hypertension
respectively, was investigated in healthy and cirrhotic rats. Both healthy and
nonascitic CCl(4)-induced cirrhotic rats under pentobarbital anesthesia received
either normotonic (140 mmol/L) or hypertonic (320 mmol/L) NaCl artificial
cerebrospinal fluid into the CNS lateral ventricle at a rate of 8.3 microl/min
for 120 min. A sham operated group, but not centrally infused, served as matched
control. Hypertonic NaCl solution significantly increased mean arterial pressure
(MAP) similarly in both healthy (n = 5) ((MAP: 16 mm Hg, 13%) and cirrhotic rats
(n = 6) ((MAP: 20 mm Hg, 15%) (ANOVA, p <.001) although the latter showed a
slower increment. Under hypertonic NaCl infusion, natriuresis was also
significantly increased in a similar manner in both healthy (U (Na) V: baseline:
0.38 +/- 0.22 micromol/min x 100 g; experiment: 2.36 +/- 0.90 micromol/min x 100
g; mean +/- SD) and cirrhotic rats (0.69 +/- 0.48 vs. 3.16 +/- 0.87; p <.001). By
contrast, central hypertonic NaCl solutions did not show a significant
modification of serum ANP in neither healthy (62 +/- 18 fmol/ml vs. 51 +/- 17
fmol/ml) nor cirrhotic rats (126 +/- 61 vs. 115 +/- 30). Likewise, ET-1 was not
significantly modified under central hypertonic NaCl infusion in neither healthy
(352 +/- 46 pg/ml vs. 344 +/- 39 pg/ml) nor cirrhotic rats (287 +/- 58 vs. 277 +/
61). Despite no modification in serum ANP, there was a significant increment in
urinary excretion of cGMP under central hypertonic NaCl infusions in bo th
healthy (6.8 +/- 4.1 pmol/min x 100 g vs. 13.0 +/- 6.5 pmol/min x 100 g; p <.05)
and cirrhotic rats (8.6 +/- 1.7 vs. 11.1 +/- 1.3; p <.05). Our data indicate the
preservation of the mechanisms of central natriuresis in a model of non-ascitic
CCl(4 )-induced cirrhosis in rats. An increment in urinary cGMP could potentially
be implicated in the natriuretic response obtained by intracerebroventricular
hypertonic NaCl stimulus in both healthy and cirrhotic rats. The lack of
modification of serum ANP and ET-1 does not appear to support a systemic
implication of these peptides in the natriuretic and hypertensive responses
respectively induced by this manoeuvre.
PMID- 10779827
TI - Routing, processing and export of rat pituitary prolactin: identification of a 36
kDa disulphide-bridged oligomeric preprolactin.
AB - To gain an insight in the routing, processing and export of rat prolactin, rat
pituitary cells were cultured in serum-free medium in the presence of
cycloheximide, carbonyl cyanide m-chlorophenylhydrazone, Brefeldin A and
monensin. The potential influence of these perturbants, whose well documented
effects are the altering of protein synthesis and transport, was studied on rat
prolactin molecular size isoforms appearing in cellular extracts and in culture
medium. The outcome of the culture experiments as recorded in vertical SDS-PAGE,
thiol gradient electrophoresis and sequential SDS-PAGE followed by prolactin
specific immunoblotting and densitometry, was as follows: (1) at the cellular
level we were able to characterize a novel 36 kDa protein as a disulphide-bridged
oligomeric precursor prolactin, which is presumably rapidly transformed in the
cis/medial Golgi; to designate monomeric rat prolactin as an early Golgi protein
and t o advance evidence that the main processing of the glycosylated rat
prolactin is a cis/medial Golgi event; (2) in release none of the perturbants
disturbed the relative distribution of monomeric and glycosylated rat prolactin,
the main molecular size isoforms currently secreted by untreated pituitary cells,
or induced the appearance of transformed molecular size isoforms; (3) the
secretion mode indicates that rat prolactin is released via the regulated pathway
in the presence of the perturbants used.
PMID- 10779829
TI - The effect of myo-inositol on ethanol-induced metabolic changes and insulin
concentration in the rat.
AB - Myo-inositol was found to possess several beneficial effects on the organism. The
effect of myo-inositol on ethanol-induced metabolic changes and insulin
concentration was investigated in growing rats. The increase in liver
triglycerides induced by ethanol drinking (10% ethanol solution as the only
drinking fluid for 10 days) was completely abolished by simultaneous treatment
with myo-inositol (0. 1 g/100 g b.w., every day given intragastrically). The
ethanol-evoked decrease in blood insulin and the increase in liver glycogen were
also partially prevented by myo-inositol. Myo-inositol did not cause any
undesirable metabolic changes in the rats. The results indicate that myo-inositol
may be useful in the treatment of some metabolic consequences of alcohol
drinking.
PMID- 10779830
TI - Mechanoreceptors in the glabrous skin of the human hand.
AB - Since the first systematic analysis concerning the functional properties of
mechanoreceptors in the glabrous skin of the human hand was made in 1970, the
amount of available data has grown tremendously. Whereas the first research in
the seventies was aimed at achieving a standard functional description of the
mechanoreceptors, research of the last two decades mostly has been directed
towards developing a more detailed and extended model of these receptors. For
example, recent investigations attempted to examine the role of populations of
mechanoreceptors with respect to the recognition of texture and shape of an
object touched by the human hand. Knowledge of the behaviour of the
mechanoreceptive units in the glabrous skin of the human hand is especially
relevant to people with a diminished or lost vision who depend on their tactile
system to perceive objects they cannot hear or smell. This essay tries to give a
brief overview of the development of this field from the first experiments on
human beings to the state of knowledge that has been gained today.
PMID- 10779831
TI - Humans with traumatic brain injuries show place-learning deficits in computer
generated virtual space.
AB - Spatial learning and memory has been linked to the hippocampus and temporal lobes
and though these areas are often damaged in traumatic brain injury (TBI), spatial
learning deficits after TBI have not received much attention. In the present
study, a virtual environment was used to challenge people with TBI to solve a
task comparable to the Morris water maze, which in turn has been shown to be
highly sensitive to hippocampal and frontal lobe dysfunction in laboratory
animals. A regular computer monitor was used to present 12 participants with TBI
and 12 age- and sex-matched comparison participants with a computer-generated,
three-dimensional "virtual arena maze," consisting of a large round arena within
a very large square room. Participants were required to learn the place of an
invisible target on the floor of the room based solely on distal cues on the
walls of the room. Eight of the 12 participants with moderate to severe TBI
showed substantial place-learning deficits in comparison to the uninjured
participants. Performance in the virtual environment correlated with self
reported frequency of wayfinding problems in everyday life and with scores on a
test of episodic memory, the Rivermead Behavioural Memory Task. These data
confirm that deficits in spatial learning and memory follow TBI, and suggest that
the virtual arena maze may provide a new method for objectively assessing them.
PMID- 10779832
TI - Differential demands on working memory for guiding a simple action sequence:
evidence from closed-head-injured subjects.
AB - In the present study, a working memory paradigm was used to assess coordinative
abilities required for the flexible control of a sequence of actions. Subjects
had to maintain and recall a list of digits that functioned as an ensemble of
activity cues used for guiding a sequence of forced-choice responses. In three
task conditions, the demand on the selection of the activity cues was varied
parametrically to manipulate the requirement of coordinating maintenance and
processing operations of working memory for guiding the response sequences. A
comparison between subjects suffering from severe closed head injury (CHI) and
matched controls in a blocked presentation of task conditions revealed that
patients, in contrast to controls, did not preplan the sequence by rearranging
the ensemble of activity cues prior to execution of the action sequence.
Patients' performance was more comparable to controls tested in a random
presentation in which preplanning was not possible. Our results further suggest
that patients are less efficient in selecting activity cues from working memory,
especially in more demanding situations when activity cues have to be completely
reordered for guiding a sequence of actions. These results point to an executive
dysfunction in CHI subjects that may contribute to the deficits known as
inflexible and rigid behavior.
PMID- 10779833
TI - Evaluation of a WMS-R malingering index in a non-litigating clinical sample.
AB - The purpose of this study was to examine the prevalence of a Wechsler Memory
Scale-Revised "malingering index" in a large sample of non-litigating individuals
from an inpatient substance abuse program. Past research has demonstrated that
experimental-malingerers often obtain substantially lower scores on the
Attention/Concentration Index than on the General Memory Index. In the present
study, only a small percentage of patients showed large General Memory -
Attention/Concentration difference scores. These results provide further support
for the validity of this difference score as a marker for non-optimal effort.
PMID- 10779834
TI - Role of perceptual and organizational factors in amnesics' recall of the Rey
Osterrieth complex figure: a comparison of three amnesic groups.
AB - To examine the contribution of visual-perceptual and visual-organizational
factors to visual memory in amnesia, Korsakoff, medial temporal, and anterior
communicating artery (ACoA) aneurysm amnesics' copy, organization, and recall
performance on the Rey-Osterrieth Complex Figure was assessed. Korsakoff patients
were matched to medial temporal patients in terms of severity of amnesia, while
the ACoA group, which was less severely amnesic, was matched to the Korsakoff
patients on performance on executive tasks. Results indicated that while both the
ACoA and Korsakoff groups had poorer copy accuracy and organization than
controls, only the Korsakoff patients' copy accuracy was worse than the other two
amnesic groups. While the Korsakoff patient's visuoperceptual deficits could
partially explain this group's poor performance at immediate recall, the
Korsakoff group's comparatively worse performance at delayed recall could not be
accounted for by poor copy accuracy, reduced visual organization, or even the
combined influence of these two factors.
PMID- 10779835
TI - Estimated premorbid intelligence mediates neurobehavioral change in individuals
infected with HIV across 12 months.
AB - This study tested whether estimated premorbid intelligence moderates worsening
neurobehavioral dysfunction in HIV infection. 155 homosexual men (54 controls, 49
HIV+ asymptomatic, 24 HIV+ symptomatic, 28 AIDS) with stable disease status were
tested on measures of executive function at baseline and 12-month follow-up.
Premorbid intelligence was estimated on the basis of a demographically-based
regression equation (Hamsher, 1984), and participants were classified as average
or above-average intelligence. Regardless of disease status, participants with
above-average IQ showed no declines on measures of executive function across
time. In contrast, among those with average IQ, symptomatic groups showed
declines, whereas the asymptomatic group did not. The findings support the
hypothesis that estimated premorbid intelligence mediates declines in
neuropsychological function in patients with stable HIV status. These findings
are consistent with theoretical models of cognitive reserve capacity.
PMID- 10779837
TI - Parkinsonian motor characteristics in unipolar major depression.
AB - Clinical observation points to similarities between psychomotor retardation in
major depression and bradykinesia in Parkinson's disease (PD). While common
elements of neuropathology have been proposed to account for this, experimental
investigations of this possible link have been few and inconclusive. The present
study attempts to determine whether patients with depression display the
characteristically Parkinsonian reliance on external cues; and if so, whether
this is common to both melancholic and non-melancholic patients. Twenty three
patients with unipolar major depression (11 melancholic and 12 non-melancholic)
and 24 age-matched healthy controls performed a serial choice reaction time task
known to be sensitive to Parkinsonian movement deficits. The melancholic patients
showed a Parkinsonian pattern of impairment on the task, exhibiting a particular
difficulty when initiating movements in the absence of external cues. This was
largely alleviated when a moderate amount of external cueing was provided. At a
high level of advance information, melancholic patients were again slow relative
to controls. A base-line measure of bradykinesia and a derived measure of
dependence upon external cues both correlated significantly with CORE (measure of
psychomotor disturbance) ratings. The non-melancholic patients did not show any
measurable motor impairment. This cue-dependent deficit may be due to an
underlying basal ganglia dysfunction similar to that involved in PD, i.e. a
failure of internal cueing. Difficulty with a high level of external cueing might
reflect bradyphrenia or a prefrontal motor deficit of ability to plan multiple
upcoming movements simultaneously. The results suggest that depression subtypes
involve differing patterns of fronto-striatal impairment.
PMID- 10779836
TI - Effects of preferred hand and sex on the perception of tactile simultaneity.
AB - The effects of handedness, sex and the influence of hand placement in
extrapersonal space on temporal information processing was investigated by
measuring thresholds for perceiving the simultaneity of pairs of tactile stimuli.
Simultaneity thresholds of preferred right handed and left handed university
students with left hemisphere speech representation were compared using unimanual
and bimanual stimulation at three hand placements (midline, lateral and crossed).
In unimanual conditions two fingers of one hand were stimulated (single
hemisphere), whereas in the bimanual conditions one finger of each hand was
stimulated (cross hemispheres). Bimanual minus unimanual thresholds provided an
estimate of interhemisphere transmission time (IHTT) regardless of hand
placement. The effects of hemispace varied with the type of stimulation. With
unimanual stimulation, overall thresholds were longer at the midline placement,
however, with bimanual stimulation, thresholds were longer when the hands were
spatially separated (crossed and/or uncrossed). Left handers' IHTTs were 8 ms
faster than those of right handers. IHTTs in males were faster than females with
hands placed in lateral (by 10.8 ms) or crossed (by 9.8 ms) but not midline
positions. It was concluded that the cerebral hemispheres are equally capable of
discriminating temporal intervals, but that the left hemisphere predominates when
there is uncertainty about location of stimulation.
PMID- 10779838
TI - Card sorting performance and ADHD symptomatology in children and adolescents with
tourette syndrome.
AB - Children and adolescents with Tourette Syndrome (TS) do not have a characteristic
neuropsychological profile. Performance on complex cognitive tasks, particularly
those associated with executive functioning (EF), has been variable and sometimes
contradictory. The high rate of comorbidity of TS with disorders, especially
Attention Deficit Hyperactivity Disorder (ADHD), may account for such
variability. A group of 57 individuals with TS, aged 8 - 16, was examined on a
component of executive functioning in relation to comorbid symptomatology of
ADHD. Each participant was evaluated using two EF measures, the Wisconsin Card
Sorting Test (WCST) and the California Card Sorting Test (CCST). Using factor
analytic procedures for purposes of data reduction, WCST and CCST measures loaded
on different factors. Individuals with TS who had a high rate of ADHD
symptomatology did not differ from those with a lower rate of ADHD symptomatology
on any measure of card sorting performance.
PMID- 10779839
TI - Preliminary study of working memory in children with stroke related to sickle
cell disease.
AB - The verbal working memory abilities of children with stroke related to sickle
cell disease (SCD) (n = 20) were compared to those of control children with SCD
who had no history of stroke (n = 11). Memory span for one-, two-, and three
syllable words was assessed. For children with anterior infarcts, overall span
was comparable to that of controls, but the typical effect of word length on span
was reduced. For children with diffuse infarcts, overall span was reduced in
comparison to that of controls, but the typical effect of word length on span was
observed. For children with posterior infarcts, overall span was comparable to
that of controls and the typical effect of word length on span was observed.
These results provide preliminary evidence that patterns of working memory
performance may vary across children with infarcts affecting different regions of
the brain.
PMID- 10779840
TI - Three words three shapes: A clinical test of memory.
AB - Three Words - Three Shapes was designed as an easy "bedside" test for elderly
patients that assesses verbal and nonverbal memory within the same modality. In
the present study, it was administered to patients with probable Alzheimer's
disease (PRAD), a control group of non-demented older subjects (NC) and a group
of patients with Korsakoff's amnesia (KA). Incidental recall and several other
measures of learning, retention and recognition differentiated control from PRAD
and KA subjects. PRAD and KA subjects' performance was similar, but there were
some material-specific interactions. This test is relatively easy and some of the
derived measures could prove useful in staging amnesia progression beyond the
earliest stages of PRAD when more difficult tests yield floor effects.
PMID- 10779841
TI - Development of two spanish versions of the verbal selective reminding test.
AB - The Selective Reminding procedure has become a widely used test for evaluating
verbal learning and memory. However, since this test was mainly devised for use
in English speaking individuals, disadvantages could appear when translations of
the test are applied to Spanish speaking patients. To overcome these
difficulties, two Spanish versions of the Verbal Selective Reminding Test were
devised and administered to 48 healthy individuals, 19-31 years in age, in two
separate sessions. We found that performances on the two forms were comparable,
except for one measure. All the variables on both forms yielded significant
positive correlations. We also examined test-retest reliability separately for
both possible orders, with Order 2 (Form 2 administered first) being more
reliable than Order 1 (Form 1 administered first).
PMID- 10779842
TI - Edouard Claparede and the auditory verbal learning test.
AB - This paper describes the role of the Swiss psychologist Edouard Claparede (1873
1940) in developing the Test de memoire des mots (Test of Memory for Words), a
test consisting of one free-recall trial of a 15-word list that is the antecedent
of the auditory verbal learning tests (AVLT) of Rey and others. The fact that
Claparede's test has survived in modified form for 80 years makes it one of the
oldest mental tests in continuous use. In addition to developing the AVLT,
Claparede's pioneering contributions to neuropsychology include forensic
assessment of cognitive deficits and research on implicit learning in amnesia.
PMID- 10779843
TI - Familial occurrence of artefactual ocular hypertension from thick corneas and of
primary open angle glaucoma in a French Canadian kindred.
AB - We describe the coexistence of artefactual ocular hypertension due to increased
central corneal thickness (CCT>585 microm), with primary open angle glaucoma
(POAG) in a French Canadian kindred. Seventeen members of the family were
examined and classified as to their glaucoma status. The mean CCT for our
glaucoma patients (580 microm; n=5) and that for normals (552 microm; n=6) were
within two standard deviations of the mean value provided in the literature (531
microm +/- SD=29 microm). The mean CCT of 611 microm for the suspect group (n=6)
was considerably higher than for the glaucoma and normal groups. All but one of
the suspects were classified as ocular hypertensives on the basis of high
intraocular pressures (IOPs). When the IOPs for these patients (mean 22.6 mmHg)
were corrected for their CCTs, all had pressures of <21 mmHg (mean 16.4 mmHg).
Ten of the seventeen family members had thick CCTs, and transmission of thick
corneas was seen in two generations. A number of individuals in this family had
optic nerve head drusen (9/17) and the mean CCT of these individuals (601 microm)
was higher than the mean CCT (560 microm) of the group without drusen (P=0.020 by
t test). Artefactual ocular hypertension and POAG can be present in different
members of the same family. The presence of a thick cornea appears to be an
inherited trait and may be associated with the presence of optic nerve drusen.
This association suggests a developmental relationship between thick corneas and
optic nerve head drusen which needs to be studied further.
PMID- 10779844
TI - Microfibril abnormalities of the lens capsule in patients with Marfan syndrome
and ectopia lentis.
AB - PURPOSE: To determine the distribution and structure of fibrillin microfibrils in
the three fibrillin-rich lens capsule zones of subjects with the Marfan syndrome.
METHODS: Capsules were dissected from nine lenses extracted intracapsularly from
Marfan syndrome patients. The capsules were divided and mounted flat on gelatin
coated glass slides. ABC immunoperoxidase staining with monoclonal anti-fibrillin
antibody was used to visualize and localize fibrillin in these specimens. The
staining patterns and microscopic structure of microfibrils were compared to
those of normal controls. RESULTS: There were no bundles of fibrillin fibers in
Zone I - a 0.75-mm wide peripheral ring of the anterior capsule that normally
contains radial bunches of fibrillin fibers; instead, fine disorganized fibrillin
positive fragments were dispersed in this region. The size and shape of the
fragments varied among patients. In contrast to normal lenses, there was only
light staining for fibrillin in Zone II - a 1-mm wide meshwork of normally
fibrillin-rich fibers that encircles the equator and serves as an insertion
platform for most zonular fibers. The radial periodic bands of Zone III - a 0.1
mm wide ring on the most peripheral part of the normal posterior capsule - were
identifiable in some samples, but stained only faintly for fibrillin. CONCLUSION:
Fibrillin microfibrils are disrupted and fragmented in the lens capsule of
patients with the Marfan syndrome. The qualitative, quantitative, and structural
abnormalities of fibrillin deposition in the lens capsule of these patients
support a causal relationship to lens abnormalities in this disease.
PMID- 10779845
TI - Corneal transplantation in a patient with mucopolysaccharidosis type VII (Sly
disease).
AB - PURPOSE: To illustrate a good visual outcome following penetrating keratoplasty
in a patient with Sly disease, a rare mucopolysaccharidosis (MPS) caused by a
deficiency of beta-glucuronidase. METHODS: A 15-year-old male with progressive
bilateral corneal opacification had a complete medical, genetic, and ophthalmic
evaluation followed by a penetrating keratoplasty. RESULTS: The cornea has
remained clear for two years following surgery. Histopathology of the corneal
button demonstrated vacuoles and granular inclusions consistent with this
lysosomal storage disease. CONCLUSION: While research is ongoing in the fields of
enzyme replacement and bone marrow transplantation, these treatments may not
alleviate or reverse the corneal clouding. This case illustrates that cornea
transplantation may be a valuable treatment option for visually rehabilitating
such patients.
PMID- 10779846
TI - Morning glory disk anomaly, choroidal coloboma, and congenital constrictive
malformations of the internal carotid arteries (moyamoya disease).
AB - PURPOSE: To report a patient with congenital constrictive malformations of the
internal carotid arteries and a morning glory disc anomaly (MGDA). METHODS:
Descriptive case report. RESULTS: A 14-year-old girl underwent serial
ophthalmologic examinations since the age of seven years because of blurred
vision and floaters. A right optic disk anomaly was present that was most
compatible with an MGDA accompanied by an inferior choroidal coloboma. Because of
the association of such disc malformations with moyamoya disease, the patient
underwent cerebral MRI and MRA that showed narrowing of both internal carotid
arteries, a finding consistent with early-stage moyamoya disease. CONCLUSION:
This case illustrates the importance of recognizing the association of MGDA with
moyamoya disease, a treatable condition that may have devastating neurological
consequences.
PMID- 10779847
TI - Identification of a novel mutation in the paired domain of PAX3 in an Iranian
family with waardenburg syndrome type I.
AB - Waardenburg syndrome Type I (WS1) is an autosomal dominant disorder that has
previously been associated with mutations in the PAX3 gene on the 2q35 region. In
this study, we used an Iranian WS1 family with seven affected individuals in
three generations. The phenotypic characteristics of the family include
sensorineural deafness, dystopia canthorum, hypopigmented skin patches of the
upper limbs, congenital white forelock, confluent white eyebrows, nonpigmented
iris, poliosis, and hypopigmentation of the retina. Herein, we report a
previously unidentified single-base substitution in exon II (C-->T at position
218) that results in a change of serine to leucine (S73L) in this family. This
change was not observed in 100 chromosomes of healthy unrelated individuals. This
mutation is within the PAX3 paired domain region, a structure that is highly
conserved and implicated in DNA binding. This is the first identification of a
PAX3 mutation for this phenotype in the Iranian population. This also provides
additional confirmation for the involvement of this gene in the etiology of WS1.
PMID- 10779848
TI - Summary of heritable ocular disorders and selected systemic conditions with eye
findings.
AB - A previously published table of ocular genetic disorders and inherited systemic
conditions with eye findings has been updated with a comprehensive review of
world literature. This tabulation of conditions is designed to provide a useful
desk reference for practitioners and medical scientists. The summary will serve
again as a benchmark of the significant advances that have occurred in the past
few years.
PMID- 10779849
TI - Kabuki syndrome - report of six cases and review of the literature with emphasis
on ocular features.
AB - Six cases of Kabuki syndrome (KS) with ocular anomalies are reported and the
variety of ocular features reported in the literature for this syndrome is
described. Routine ocular examinations are recommended for every patient with KS
because of the high proportion of ocular anomalies found in these patients, the
presence of which can hamper development if not adequately addressed.
PMID- 10779850
TI - Dietary sodium chloride (salt), other dietary components and blood pressure:
paradigm expansion, not paradigm shift.
PMID- 10779851
TI - A non-invasive cardiovascular index for the quantification of arterial load.
AB - OBJECTIVE: Our aim is to quantify steady and pulsatile components of arterial
load in a concise and sensitive way by means of a new non-invasive cardiovascular
index (NICI). METHODS AND RESULTS: NICI is based on non-invasively measured
pressure (sphygmomanometer), stroke volume index and cardiac index (Doppler
echocardiography and ECG) and yields a numerical value (in mm Hg). It expresses
the difference between the actual arterial load and reference loading conditions
as determined in a control group (29 M/35 F, age 34 +/- 13 yr.) of healthy
subjects, with blood pressure 116/61 mm Hg (systolic/diastolic), stroke volume
index (SVI) 34 +/- 18 ml.m-2 and cardiac index (CI) 2.1 +/- 0.5 l.min-1.m-2. NICI
was calculated in the control group and in 23 borderline hypertensive subjects
(10 M/13 F, age 65 +/- 12 yr.) with blood pressure 156/79 mm Hg, SVI 36 +/- 10
ml.m-2 and CI 2.4 +/- 0.6 l.min-1.m-2. NICI was higher in borderline
hypertensives (33 +/- 51 vs. 0 +/- 34 mm Hg; P < 0.001) and was strongly
correlated with total peripheral resistance index (r = 0.89; P < 0.001) and with
the ratio of SVI and pulse pressure (r = -0.89; P < 0.001), expressing the
combined effect of both known determinants of cardiac load. NICI was also
correlated with effective arterial elastance index (r = 0.89; P < 0.001).
CONCLUSIONS: NICI quantifies, within a logical biomechanical framework, the
arterial load as seen by the ejecting ventricle. It combines steady and pulsatile
components of arterial load and has a single control value of zero mm Hg.
PMID- 10779852
TI - Long-term time-related predictivity of coronary events as a function of a single
measurement of serum cholesterol and systolic blood pressure.
AB - OBJECTIVE: To study the time-related association of a single measurement of serum
cholesterol and systolic blood pressure with the occurrence of a first coronary
event in a population sample of middle-aged men. METHODS AND RESULTS: A single
measurement of serum total cholesterol and systolic blood pressure (along with
age, cigarette consumption, physical activity at work and body mass index as
possible confounders) was made in 1,605 coronary disease-free men aged 40-59
belonging to the Italian rural cohorts of the Seven Countries Study. During 25
years of follow-up 353 men developed a first event, that is a coronary death
(sudden or not), and definite or possible myocardial infarction. Twenty-five
partitioned proportional hazards models were solved, one for each independent
year of follow-up, to predict the risk of incident events. Single-year hazard
functions, separately for serum cholesterol and systolic blood pressure, were
cumulated and smoothed. The resulting curves showed a regularly increasing risk
for coronary events. They fit straight lines, with large correlation coefficients
for both serum total cholesterol (r = 0.99) and systolic blood pressure (r =
0.99). These slopes were similar to the coefficients estimated by a single
proportional hazards model solved for all events during 25 years. CONCLUSION: A
single measurement of serum total cholesterol and systolic blood pressure in
middle aged-men maintains a regular and monotonic relationship with occurrence of
a first coronary event during 25 years of follow-up.
PMID- 10779853
TI - Postpericardiotomy syndrome during intensive immunosuppression after cardiac
transplantation.
AB - A 15-year-old man with end-stage heart failure due to dilated cardiomyopathy,
underwent heart transplantation. In the second postoperative week, while being
treated with monoclonal antibodies (OKT3), cyclosporine and azathioprine, he
developed a postpericardiotomy syndrome and cardiac tamponade, which necessitated
emergency pericardiocentesis. Corticosteroids, administered according to the
immunosuppression protocol, resulted in the prompt subsidence of the syndrome.
This is the first report of a large pericardial effusion and cardiac tamponade
due to a postpericardiotomy syndrome in an adult cardiac recipient.
PMID- 10779854
TI - Early presentation of a giant true left ventricular aneurysm.
PMID- 10779855
TI - Left circumflex coronary artery arising as a terminal extension of the right
coronary artery.
PMID- 10779856
TI - COMT inhibition in Parkinson's disease: rationale and clinical relevance.
PMID- 10779857
TI - The potential and limitations of transcranial Doppler in clinical practice.
AB - The aim of this review is to bring the clinical relevance of transcranial Doppler
(TCD) to light with all of its possibilities and limitations. Indeed, TCD, a non
invasive ultrasound technique, allows instantaneous evaluation of the cerebral
blood flow, adding physiological information to the anatomical images. Although
TCD is frequently used in some places, in other regions TCD remains relatively
unknown. However, TCD can help the neurologist not only in the management of
cerebrovascular disease, but also in a wide variety of central nervous system
disorders. TCD monitoring with multichannel and multigate probes can assess
vascular reactivity by following various parameters, such as CO2 or arterial
blood pressure. Despite the need for more work, emboli detection seems to offer
great potential in the future diagnosis, treatment, and prevention of stroke.
PMID- 10779858
TI - Magnetic resonance imaging in psychiatry.
AB - Recent technical advances in MR imaging have led to several new applications in
psychiatric imaging. There is a renewed interest in the further elucidation of
the etiopathogenesis of some psychiatric disorders and clinical-radiological
correlations are increasingly reported. Volume measurements are frequently used
and in the near future, functional MR imaging carries high expectations. A brief
survey is given of the recent applications of these new techniques in
schizophrenia, affective disorders, dementia, anorexia nervosa, and other less
common disorders.
PMID- 10779859
TI - [Generation of isolated words in normal subjects].
AB - This study aims at analyzing the performance according to age, sex, and
educational level in 112 French normal subjects on word generation tests, i.e.,
time-limited production of a noun or a verb semantically linked to a target
"noun" or "verb". The nature of hits (exclusively production of nouns) has
moreover been analyzed according to different features of the targets: noun vs
verb, names of natural objects vs handmade objects, transitive vs intransitive
verbs. Results show 1) a significant effect of age and educational level on
performance, 2) a degree of difficulty, the verb/verb production test being
significantly more difficult than the three other tests, 3) a convergency effect
according to the natural vs handmade dichotomy, as subjects tend to produce,
without specific instruction, an item belonging to the same category as that of
the stimulus, and 4) object nouns tend to be produced in response to transitive
verbs whereas subject nouns are not predominantly produced in response to
intransitive verbs.
PMID- 10779860
TI - Adult-onset nemaline myopathy and monoclonal gammopathy: a case report.
AB - A 47-year-old female developed proximal limb weakness after hysterectomy for
uterine fibromatosis. Muscle strength slowly improved, but relapse occurred at
age 52. She presented with progressive gait difficulty, proximal limb weakness,
and painful calves. Family history was not contributory. Cranial nerves, deep
tendon reflexes, and sensation were normal. Serum creatine kinase was normal. An
IgG kappa monoclonal protein was found. Nerve conduction studies were normal, but
EMG showed brief small polyphasic motor unit action potentials with early
recruitment in proximal muscles. Muscle biopsy showed abundant rods, atrophic
muscle fibres, and type 1 fibre predominance. The sarcolemma was immunoreactive
for IgG kappa. Plasmapheresis was unsuccessful, but methylprednisolone and
azathioprine led to moderate improvement of muscle strength, associated with
reduced monoclonal protein levels. This is the third case report, describing the
association of monoclonal gammopathy and late-onset nemaline myopathy. Presence
of a monoclonal protein at the sarcolemma and responsiveness to immunosuppressive
treatment are suggestive of a dys-immune origin.
PMID- 10779861
TI - Serum levels of alpha-carotene, beta-carotene, and retinol in patients with
multiple sclerosis.
PMID- 10779862
TI - Hypnagogic hallucinations and REM-sleep: an alternative pathophysiology.
PMID- 10779863
TI - Tuberculous cerebellar abscess.
PMID- 10779864
TI - Stroke and pseudoxanthoma elasticum.
PMID- 10779865
TI - Characterization of a major envelope protein from the rumen anaerobe Selenomonas
ruminantium OB268.
AB - Cell envelopes from the Gram-negative staining but phylogenetically Gram-positive
rumen anaerobe Selenomonas ruminantium OB268 contained a major 42 kDa heat
modifiable protein. A similarly sized protein was present in the envelopes of
Selenomonas ruminantium D1 and Selenomonas infelix. Sodium dodecyl sulfate
polyacrylamide gel electrophoresis of Triton X-100 extracted cell envelopes from
S. ruminantium OB268 showed that they consisted primarily of the 42 kDa protein.
Polyclonal antisera produced against these envelopes cross-reacted only with the
42 kDa major envelope proteins in both S. ruminantium D1 and S. infelix,
indicating a conservation of antigenic structure among each of the major envelope
proteins. The N-terminus of the 42 kDa S. ruminantium OB268 envelope protein
shared significant homology with the S-layer (surface) protein from Thermus
thermophilus, as well as additional envelope proteins containing the cell surface
binding region known as a surface layer-like homologous (SLH) domain. Thin
section analysis of Triton X-100 extracted envelopes demonstrated the presence of
an outer bilayer over-laying the cell wall, and a regularly ordered array was
visible following freeze-fracture etching through this bilayer. These findings
suggest that the regularly ordered array may be composed of the 42 kDa major
envelope protein. The 42 kDa protein has similarities with regularly ordered
outer membrane proteins (rOMP) reported in certain Gram-negative and ancient
eubacteria.
PMID- 10779866
TI - Factors affecting the freeze-fracture morphology of in vivo polyhydroxyalkanoate
granules.
AB - Interesting morphologies were observed when Comamonas acidovorans containing
polyhydroxyalkanoates (PHA) of various compositions was freeze-fractured at
temperatures far below the glass transition temperatures of PHA. In vivo granules
of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) comparatively showed the most
ductility, and could be stretched extensively. Contrary to the uniform needle
type deformation shown by the poly(3-hydroxybutyrate) homopolymer when fractured
at -110 degrees C, copolymers containing 3-hydroxyvalerate units showed various
deformation structures. Similar observations were made when in vivo granules of
poly(3-hydroxybutyrate-co-4-hydroxybutyrate) were freeze-fractured, although the
ductility of the latter was much reduced. In addition, it was found that
fracturing at -160 degrees C resulted in decreased ductility of the PHA granules
with the concomitant increase in the number of mushroom-type deformation
structures. Our results suggest that PHA granules with higher resistance to
freeze-fracture deformation show less ductility, and therefore produce the
mushroom-type morphology. This is the first report on the freeze-fracture
morphology of PHA copolymers containing short-chain-length monomers.
PMID- 10779867
TI - Ca2+ fluxes in developing Trichoderma viride mycelium.
AB - The properties of both Ca2+ influx and efflux in the mycelium during the life
cycle of Trichoderma viride were studied by means of 45Ca2+ and by X-ray
fluorescence spectroscopy measurements. The properties of the 45Ca2+ influx and
effluxes indicate that they are mediated by different transport systems. The Ca2+
influx could be mediated by an electrogenic Ca2+/nH+ antiport, or by an Ca2+
uniport system. Both Ca2+ influx and efflux were stimulated by the uncouplers
(and the treatment leading to the suppression of energy metabolism) and by
azalomycin F, an antifungal agent. Salicylate stimulated the Ca2+ efflux, but
inhibited the Ca2+ influx. In the isolated preparation of crude
vacuolar/mitochondrial fraction, salicylate induced the Ca2+ release, as did
A23187. Azalomycin F moderately released Ca2+ from the microsomal fraction. On
the other hand, uncouplers did not release Ca2+ from the isolated organelles, but
inhibited to a different extent the ATP-dependent and -independent Ca2+ influx.
The results could be explained in terms of the capacitative Ca2+ influx
mechanism. The rate of 45Ca2+ influx, or of the 40Ca2+ content, was maximal after
about 30 h of submerged cultivation, and then decreased. The results show that
loading of internal Ca2+ stores occurs in the early stages of the development of
mycelium only, and the Ca2+ influx mechanism is developmentally down-regulated,
being almost nonexistent during its later stages. In older mycelium, growth seems
to be autonomous of the extracellular Ca2+ until the onset of conidiation.
PMID- 10779868
TI - Detection of the Na(+)-translocating NADH-quinone reductase in marine bacteria
using a PCR technique.
AB - To examine the distribution of the Na(+)-translocating NADH-quinone reductase
(Na(+)-NQR) among marine bacteria, we developed a simple screening method for the
detection of this enzyme. By reference to the homologous sequences of the Na(+)
NQR operons from Vibrio alginolyticus and Haemophilus influenzae, a pair of
primers was designed for amplification of a part of the sixth ORF (nqr6) of the
Na(+)-NQR operon. When PCR was performed using genomic DNA from 13 marine
bacteria, a 0.9-kbp fragment corresponding to nqr6 was amplified in 10 strains.
Although there were three PCR-negative strains phylogenetically, based on the
sequence of the 16S rRNA, these were placed far from the PCR-positive strains. No
product was observed in the case of nonmarine bacteria. The nucleotide and
predicted amino acid sequences of nqr6 were highly conserved among the PCR
positive marine bacteria. A phylogenetic analysis of marine bacteria, based on
nqr6 sequencing, was performed.
PMID- 10779870
TI - Characterization of high density monolayers of the biofilm bacterium Caulobacter
crescentus: evaluating prospects for developing immobilized cell bioreactors.
AB - Caulobacters are biofilm-forming members of the natural flora of soil and aquatic
environments, which exhibit several characteristics that make them attractive for
development of high surface area microbial bioreactors or biosensors. Although
caulobacters are well characterized genetically, little is known about their
biofilm-forming characteristics as a monoculture, or their tolerance of
bioreactor-like conditions. Here we investigated the ability of caulobacters to
spontaneously form high-density monolayers on artificial surfaces under a variety
of environmental conditions, using phase contrast image analysis to assess
biofilm density, and epifluorescence with the vital stain DiBAC to assess
viability. With adequate nutrition, extremely dense monolayers formed within 24
48 h, and maintained near 100% viability in experiments ranging up to 22 days.
When areas were abraded to remove cells, repopulation occurred rapidly with
characteristics similar to the population of a clean surface. When established
monolayers were starved for nutrients, a significant fraction of the cells
detached from the surface, and cells remaining on the surface no longer tested as
viable. Within 4-6 h of nutrient restoration, however, cells in the monolayer
again appeared normal and tested as 100% viable. This is the first demonstration
that Caulobacter crescentus is stable and amenable to high density monolayer
growth and resists starvation, though some cells may express a programmed
response to detach from the surface under severe nutrient limitation.
PMID- 10779869
TI - Shuttle vectors for genetic manipulations in Ustilago maydis.
AB - Shuttle vectors with new or improved features were constructed to enable facile
genetic manipulations in the plant pathogen Ustilago maydis. Sets of plasmids
selectable in media containing geneticin, carboxin, nourseothricin, or
hygromycin, able to replicate autonomously, to transform U. maydis by
integration, and to express foreign genes under control of the homologous
glyceraldehyde-3-phosphate dehydrogenase promoter, were built upon a common pUC19
vector backbone. This permits a large number of choices for a cloning site,
blue/white screening for recombinant plasmids, rapid transfer of a cloned DNA
fragment between plasmids, and choice of several dominant drug-resistance markers
for selection in U. maydis.
PMID- 10779871
TI - Development of a xylitol biosensor composed of xylitol dehydrogenase and
diaphorase.
AB - In preparation for the development of a xylitol biosensor, the xylitol
dehydrogenase of Candida tropicalis IFO 0618 was partially purified and
characterized. The optimal pH and temperature of the xylitol dehydrogenase were
pH 8.0 and 50 degrees C, respectively. Of the various alcohols tested, xylitol
was the most rapidly oxidized, with sorbitol and ribitol being reduced at 65% and
58% of the xylitol rate. The enzyme was completely inactive on arabitol, xylose,
glucose, glycerol, and ethanol. The enzyme's xylitol oxidation favored the use of
NAD+ (7.9 U/mg) over NADP+ (0.2 U/mg) as electron acceptor, while the reverse
reaction, D-xylulose reduction, favored NADPH (7.7 U/mg) over NADH (0.2 U/mg) as
electron donor. The K(m) values for xylitol and NAD+ were 49.8 mM and 38.2
microM, respectively. For the generation of the xylitol biosensor, the above
xylitol dehydrogenase and a diaphorase were immobilized on bromocyan-activated
sephallose. The gel was then attached on a dissolved oxygen electrode. In the
presence of vitamin K3, NAD+ and phosphate buffer, the biosensor recorded a
linear response to xylitol concentration up to 3 mM. The reaction was stable
after 15 min. When the biosensor was applied to a flow injection system, optimal
operation pH and temperature were 8.0 and 30 degrees C, respectively. The
strengths and limitations of the xylitol biosensor are its high affinity for
NAD+, slow reaction time, narrow linear range of detection, and moderate affinity
for xylitol.
PMID- 10779872
TI - Comparative evaluation of conjugate vaccines in the Haemophilus influenzae
infection model.
AB - We used a murine model of Haemophilus influenzae type b (Hib) infection to
analyze the immunologic response to two commercially available PRP conjugate
vaccines (HbOC, PRP-T). The mortality rate in mice infected with a large dose of
the bacteria after vaccination with HbOC or PRP-T at two and three doses was
significantly lower than in non-vaccinated mice and mice vaccinated by one dose.
Furthermore, for infections caused by a small bacterial dose, the mortality rate
in mice vaccinated with one, two, or three doses was significantly lower than in
non-vaccinated mice. The induction level of anti-PRP antibodies, especially IgG,
in serum of mice vaccinated by two or three doses was higher than in those
vaccinated with a single dose. Our results indicate that the dose of vaccine
influences its efficacy in protecting against Hib infection. Our results also
showed a lack of difference between two different PRP conjugate vaccines.
PMID- 10779874
TI - Characterization of chitinases excreted by Bacillus cereus CH.
AB - Bacillus cereus CH was shown to excrete chitinases into the culture supernatant
when cultivated in a medium containing 0.2% colloidal chitin, whereas the removal
of colloidal chitin resulted in a low activity. After concentration of the
culture supernatant by precipitation with ammonium sulfate, the induced
chitinases were purified by sequential chromatography. Four different chitinases,
A, B1, B2, and B3 with molecular masses of 35, 47, 58, and 64 kDa, respectively,
were separated. All chitinases showed similarities in their kinetic parameters
when observed with colloidal chitin, including an optimal pH of 5.0-7.5, and an
optimal temperature between 50-60 degrees C. Chitinase A hydrolyzed glycol chitin
and p-nitrophenyl-di-N-acetyl-beta-chitobioside at similar rates to that of
colloidal chitin, whereas group B chitinases hydrolyzed both substrates in much
lower rates. From analyses of the reaction products, it is most likely that
chitinase A and all group B chitinases hydrolyze the substrates tested in an endo
fashion. However, group B chitinases were distinct from chitinase A in possessing
high transglycosylation activity. From amino terminal sequencing, chitinases B1,
B2, and B3 were shown to have almost identical sequences, which differed from
that of chitinase A. The similarities in the reaction modes and amino terminal
sequences among chitinases B1, B2, and B3 suggest that these chitinases may be
derived from a presumptive precursor protein through C-terminal processing.
PMID- 10779873
TI - Introduction of the Serratia marcescens chiA gene into an endophytic Pseudomonas
fluorescens for the biocontrol of phytopathogenic fungi.
AB - An endophytic strain of Pseudomonas fluorescens was isolated from micropropagated
apple plantlets and introduced into beans (Phaseolus vulgaris) via their root
tips. It was shown to be present as an endophyte in the roots at a level of 1.2 x
10(5) CFU/g fresh weight. The gene coding for the major chitinase of Serratia
marcescens, chiA, was cloned under the control of the tac promoter into the broad
host-range plasmid pKT240 and the integration vector pJFF350. Pseudomonas
fluorescens carrying tacchiA either on the plasmid or integrated into the
chromosome is an effective biocontrol agent of the phytopathogenic fungus
Rhizoctonia solani on bean seedlings under plant growth chamber conditions.
PMID- 10779875
TI - Differential transport properties of D-leucine and L-leucine in the archaeon,
Halobacterium salinarum.
AB - The transport of D-leucine was compared with that of L-leucine in Halobacterium
salinarum. When a high-outside/low-inside Na+ gradient was imposed, D-leucine as
well as L-leucine accumulated in envelope vesicles, supporting the hypothesis
that D-leucine is transported via a symport system along with Na+. Kinetic
analyses, including inhibition experiments, indicated that both enantiomers are
transported via a common carrier. However, a Hill plot indicated a single binding
site for Na+ during L-leucine transport, but dual binding sites for Na+ during D
leucine transport. Furthermore, D-leucine transport was dependent on electrical
membrane potential, suggesting that a transporter bound with D-leucine is
positively charged. L-leucine transport was slightly, if at all, dependent on
membrane potential, suggesting that a transporter bound with L-leucine is
electrically neutral. These results indicate that the leucine carrier in
Halobacterium salinarum translocates two moles of Na+ per mole of D-leucine, and
one mole of Na+ per mole of L-leucine.
PMID- 10779876
TI - Inactivation of maltose permease and maltase in sporulating Saccharomyces
cerevisiae.
AB - Maltose transport and maltase activities were inactivated during sporulation of a
MAL constitutive yeast strain harboring different MAL loci. Both activities were
reduced to almost zero after 5 h of incubation in sporulation medium. The
inactivation of maltase and maltose permease seems to be related to optimal
sporulation conditions such as a suitable supply of oxygen and cell concentration
in the sporulating cultures, and occurs in the fully derepressed conditions of
incubation in the sporulation acetate medium. The inactivation of maltase and
maltose permease under sporulation conditions in MAL constitutive strains
suggests an alternative mechanism for the regulation of the MAL gene expression
during the sporulation process.
PMID- 10779877
TI - Effects of non-ionic surfactants on the uptake and hydrolysis of
fluoresceindiacetate by alkane-oxidizing bacteria.
AB - Biological effects of non-ionic surfactants on alkane-oxidizing bacteria were
studied by assessing their influence on the uptake of prefluorochrome
fluoresceindiacetate (FDA) and its intracellular hydrolysis to fluorescein. Both
decreasing and increasing rates of hydrolysis as a consequence of the presence of
surfactants were observed. The surfactants influenced the uptake of FDA, but not
its intracellular hydrolysis. The effects of the surfactants on the uptake rate
depended strongly on the structure and physico-chemical properties of the
surfactants. There was no qualitative or significant quantitative difference in
surfactant susceptibility between induced (alkane grown) and non-induced bacteria
(acetate grown), even though the induced cells possess greater cell surface
hydrophobicity.
PMID- 10779878
TI - Localization of phytase in Selenomonas ruminantium and Mitsuokella multiacidus by
transmission electron microscopy.
AB - The localization of phytase (myo-inositol-hexaphosphate phosphohydrolase) in the
ruminal bacteria, Selenomonas ruminantium JY35 and Mitsuokella multiacidus
46/5(2), was determined with transmission electron microscopy. Phosphate produced
from the enzymatic dephosphorylation of the calcium salt of phytic acid is
precipitated as calcium phosphate. The calcium is then replaced with lead to
produce electron-dense lead phosphate. This deposition of lead phosphate
localized phytase in S. ruminantium JY35 and M. multiacidus 46/5(2) to the outer
membrane, and confirmed intracellular expression of the enzyme in Escherichia
coli pSrP.2, the recombinant clone which possesses the gene (phyA) encoding
phytase (phyA) in S. ruminantium.
PMID- 10779879
TI - Schizophrenia: building and fixing scientific models.
PMID- 10779880
TI - Are animal studies of antipsychotics appropriately dosed? Lessons from the
bedside to the bench.
AB - Animal models are crucial for understanding the mechanism of action of
antipsychotics. However, the dose of an antipsychotic in animal studies is often
arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard.
Recent clinical positron emission tomography (PET) studies in patients show all
antipsychotics to block dopamine D2 receptors, and most are effective at doses
that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence
of side effects rises sharply. To use this "bedside" information to inform the
"bench," we measured D2 occupancy in rats using a method similar in principle to
the [11C]-raclopride PET method in humans. We found that: 1) as in humans,
haloperidol is effective in animal models of antipsychotic action when D2
occupancy > 70% and leads to effects in models of extrapyramidal side effects
when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2
occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give
little D2 occupancy after 24 hours due to the very short half-life of haloperidol
in rats (2.5 hours versus 24 hours in humans). We conclude that most previous
animal studies of antipsychotics have used doses giving rise to inappropriately
high acute D2 occupancy and inappropriately low D2 occupancy between doses. We
exemplify how this dosing confounder could lead to inappropriate conclusions.
Data from the bedside translated to the bench--using D2 occupancy as a mediating
variable--will lead to more valid animal models.
PMID- 10779881
TI - Dual cytoarchitectonic trends: an evolutionary model of frontal lobe functioning
and its application to psychopathology.
AB - OBJECTIVE: To introduce and discuss an evolutionary model of frontal lobe
functioning (the dual cytoarchitectonic trends theory [DTT]) and its application
to understanding the neurobiology of schizophrenia and anxiety disorders. METHOD:
An introduction to the DTT with respect to neural architecture, connectivity, and
function is presented. In addition, neurobiologic, neuropathologic, clinical, and
cognitive research supporting the application of this model to schizophrenia and
anxiety disorders is reviewed. RESULTS: Traditional neuropsychologic models of
acquired brain damage have been limited in their ability to explain frontal lobe
dysfunction and its consequences in relation to psychopathology. The DTT offers
an appropriately general neural-systems framework that may be better able to
account for the diversity of symptoms, widespread neuropathology, and
developmental abnormalities that are associated with most forms of
psychopathology. CONCLUSIONS: Research investigating the neurobiology of
psychopathology would benefit from adopting models of brain dysfunction that are
consistent with neurodevelopmental pathology and evolution. Such efforts would
likely lead to a greater understanding of neurobiologic mechanisms and,
ultimately, better treatment strategies.
PMID- 10779882
TI - On the pharmacotherapy of obsessive-compulsive disorder: is a consensus possible?
AB - OBJECTIVE: To examine the efficacy and tolerability of clomipramine compared with
the selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive
compulsive disorder (OCD), bearing in mind the recent Expert Consensus Guidelines
recommendation to use clomipramine after 2 to 3 failed SSRI trials. METHOD: The
literature on the pharmacotherapy of OCD was critically examined. RESULTS: The
available research evidence is not conclusive but suggests that clomipramine
possesses greater anti-obsessional efficacy than do the SSRIs. In addition, when
clomipramine is presented to patients in a positive way, and properly used in
small initial doses with gradual increases, it seems to be tolerated as well as
the SSRIs. CONCLUSION: Recently expressed opinions that clomipramine should be
used to treat OCD after 2 to 3 failed SSRI trials are not supported by research
evidence. Both clomipramine and the SSRIs may be used as first-line treatments
for OCD.
PMID- 10779883
TI - Perceptions of parental bonding and symptom severity in adults with depression:
mediation by personality dimensions.
AB - OBJECTIVE: An association between anomalous parental bonding experiences (lack of
parental care, overprotection, or both) and depression during adulthood has been
observed in several studies. The objective of the present study was to evaluate
several different personality dimensions as possible mediators of the
relationship between perceptions of parental bonding and depressive symptoms in
adulthood. METHODS: Outpatients with depression (n = 138) completed the Parental
Bonding Instrument (PBI), the Beck Depression Inventory (BDI), and several
measures of proposed personality vulnerabilities to depression. The conceptual
and methodological criteria of Baron and Kenny (1986) were used to assess
possible mediating effects of personality variables. RESULTS: In men,
overprotection by their fathers was significantly associated with depression;
neuroticism, socially prescribed perfectionism, and concern over mistakes acted
as mediators of this relationship. In women, lack of care by their mothers was
significantly associated with depression; self-criticism, socially prescribed
perfectionism, and concern over mistakes mediated this relationship. CONCLUSIONS:
The present study provides evidence that personality factors may mediate the
observed relationship between parental rearing style and depression. These
potential causal mechanisms warrant longitudinal evaluation.
PMID- 10779884
TI - Predictors of service use and social conditions in patients with psychotic
disorders.
AB - OBJECTIVE: To determine independent predictors of outcome on 3 separate
dimensions--namely, relapse and service use, employment, and living conditions-
in patients with psychotic disorders. METHOD: One hundred and thirty-four
patients, most with a diagnosis of schizophrenia or schizoaffective disorder
(94%), were treated and followed up in a comprehensive treatment program with
inpatient and community treatment components. Complete data on several predictor
and outcome variables were available on 93 patients. Relationships between
predictor variables and each dimension of outcome were analyzed using Spearman
correlation and multiple regression analysis. RESULTS: Results showed that the
use of inpatient resources (days in hospital) during the follow-up period was
predicted by days in hospital prior to entry into the program, as was employment
status. Although substance abuse was related to employment status, it did not
have any predictive value. Better living conditions were predicted by being
female and having a later age of onset. CONCLUSIONS: Use of inpatient resources
and social dimensions of outcome in schizophrenia may be predicted by different
patient- or illness-related variables. These relationships are likely to be
modified by the nature and content of treatment received.
PMID- 10779885
TI - Comorbidity in juvenile obsessive-compulsive disorder: a report from India.
AB - OBJECTIVE: Using minimal exclusion criteria, to assess systematically the
psychiatric comorbidity in children and adolescents with obsessive-compulsive
disorder (OCD) and compare the findings with those of previous studies. METHOD:
Fifty-four children and adolescents who satisfied DSM-III-R criteria for OCD were
assessed using a structured interview schedule, the Children's version of the
Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and the questionnaire for tic
disorders. All 54 subjects were recruited from the Child and Adolescent
Psychiatry (CAP) services of the National Institute of Mental Health and Neuro
Sciences (NIMHANS), Bangalore, South India. Diagnoses were determined
consensually after a review of all the available data. RESULTS: Comorbidity was
found in 69% of the sample: 22% were diagnosed with disruptive disorders; 20% met
criteria for mood disorders; 19% had anxiety disorders; and 17% had tic
disorders. Only 1 subject had bipolar disorder, and none had psychosis. The rates
for individual diagnoses--in particular, the rates for disruptive disorders,
bipolar disorder, and psychosis--were considerably lower than those reported in
previous studies. CONCLUSIONS: Patterns of comorbidity in this study differed
from those previously reported. Novel patterns of comorbidity with disruptive
disorders, bipolar disorder, and psychosis reported in a few recent studies were
not replicated in this study. These differences are probably due to different
ascertainment methods. Comorbidity needs to be assessed in large epidemiological
samples before definite associations can be made between certain comorbid
disorders and juvenile OCD.
PMID- 10779886
TI - Measuring depression in Canada's elderly Chinese population: use of a community
screening instrument.
AB - OBJECTIVE: To assess the reliability and validity of a 15-item Chinese Geriatric
Depression Scale (GDS) to measure depression in Canada's elderly Chinese
population. METHOD: A random sample of 96 elderly Chinese in a Canadian city was
surveyed by telephone. The measure of depression used was the 15-item Chinese
version of the GDS. In addition, the physical and mental health of the
respondents was assessed by a Chinese version of the SF-12, questions on self
perceived general health, and questions on self-reported illnesses and health
concerns. RESULTS: The prevalence rate of depression in the elderly Chinese who
participated in this study is approximately 20%, which is much lower than that of
elderly Chinese in the United States (US). Cronbach's alpha and split-half
reliability coefficients were 0.88 and 0.89 respectively. GDS scores are
significantly correlated with the mental health component (r = -0.74) of the SF
12, indicating a strong convergent validity. GDS scores are also correlated with
the physical health component of the SF-12 (r = -0.41), self-perceived general
health (r = -0.26), and illnesses (r = 0.52), demonstrating concurrent validity.
CONCLUSIONS: The 15-item Chinese GDS has good internal consistency and both
convergent and concurrent validity. It can help to identify depression among the
elderly Chinese, allowing early identification and prevention of this problem.
Further research is required to support its use in clinical settings.
PMID- 10779887
TI - The use of selective serotonin reuptake inhibitors during pregnancy and
lactation: current knowledge.
AB - This article reviews the effects of the selective serotonin reuptake inhibitor
(SSRI) class of antidepressants in pregnant and lactating women for the treatment
of depression and anxiety disorders. An examination of the literature was
conducted using Medline (1966 to present). Despite methodological concerns and
the scarcity of data on this important subject, the majority of recent
investigations demonstrate safety of the fetus exposed to SSRIs during pregnancy.
All of the SSRIs reported in the studies are excreted into breast milk, and low
levels have been found in infant serum. The implications of this for practice
include identifying the effects of treatment versus nontreatment on the mother
infant dyad. Further research must examine long-term neurobehavioural
teratogenicity in exposed infants.
PMID- 10779889
TI - Antidepressants increase gene expression of a neuroprotective enzyme.
PMID- 10779888
TI - Estrogen receptor activation and tardive dyskinesia.
AB - OBJECTIVE: To undertake a selective review of the epidemiology, etiology, and
treatment of tardive dyskinesia (TD), with emphasis on the potential influence of
estrogen in its expression. METHOD: Both Medline and Psycinfo databases were used
to search for articles with the following key words: tardive dyskinesia, humans,
animals, dopamine, estrogen, estrogen replacement therapy, antioxidants and
oxidative stress. RESULTS: The studies reviewed here suggest that estrogen
modulates dopamine-mediated behaviours and that it protects against oxidative
stress-induced cell damage caused by long-term exposure to antipsychotic
medication. CONCLUSIONS: Estrogen's multimodal role in the central nervous system
may prove useful for the amelioration or prevention of TD. All the evidence
suggests that a placebo-controlled, randomized trial with safer forms of estrogen
should be conducted in postmenopausal women with TD.
PMID- 10779890
TI - Bilateral pulmonary embolism in a patient on clozapine therapy.
PMID- 10779891
TI - The Internet, suicide, and human mental functions.
PMID- 10779892
TI - Continuing medical education.
PMID- 10779893
TI - Re: The effects of hypnosis on dissociative identity disorder.
PMID- 10779894
TI - Quetiapine associated with acute mental status changes.
PMID- 10779895
TI - Capgras syndrome during the wake and dream state.
PMID- 10779896
TI - Trichotillomania: a challenge to research and practice.
AB - This review explores several aspects of trichotillomania relevant to clinical
theory and practice. It is concluded that research outlining the phenomenology
and patterns of comorbidity of trichotillomania have been advanced significantly
in recent years. However, no current diagnostic category appropriately classifies
trichotillomania. Research with nonclinical populations suggests that
trichotillomania is more common than previously believed and that additional
epidemiological research is warranted. Continued elaboration of existing
etiological models incorporating varying theoretical perspectives is also
encouraged. Assessment of trichotillomania could also be improved by the
continued development of reliable and valid standardized measures. This article
reviews both pharmacological and psychological treatments for trichotillomania,
with an emphasis on habit-reversal training. Though some interventions appear
effective in the short-term, reported relapse rates are high and future research
on treatment for trichotillomania should focus on improving long-term outcomes.
It is clear that despite a recent flux of research centering on trichotillomania,
significant challenges for understanding and treating this psychological disorder
still exist for researchers and clinicians. Based on this review of the
literature, and on our clinical experience with trichotillomania, we propose
directions for future research with this underserved psychiatric group.
PMID- 10779897
TI - Psychosocial adjustment of adult children of alcoholics: a review of the recent
empirical literature.
AB - This review examines controlled studies of the psychosocial adjustment of adult
children of alcoholics (ACOAs) published since 1988. ACOAs appear at increased
risk for a variety of negative outcomes, including substance abuse, antisocial or
under-controlled behaviors, depressive symptoms, anxiety disorders, low self
esteem, difficulties in family relationships, and generalized distress and
maladjustment. However, none of these outcomes are uniformly observed in ACOAs
and none are specific to ACOAs. Comorbid parental pathology, childhood abuse,
family dysfunction, and other childhood stressors may contribute to or produce
similar outcomes. There is little empirical support for "ACOA syndromes"
described in the clinical literature.
PMID- 10779898
TI - The impact of comorbid mood and personality disorders in the cognitive-behavioral
treatment of panic disorder.
AB - The present review examined the effect of comorbid major depressive disorder and
personality disorder on the outcome of cognitive-behavioral interventions for
panic disorder. Panic disorder patients often present with these comorbid
conditions, but for the most part, treatment studies have paid little attention
to them. Most studies on the effects of comorbidity on treatment outcome address
pharmacological treatment. However, there is a growing literature on the effect
of additional disorders on the outcome of cognitive-behavioral interventions for
panic disorder. Findings from the studies of comorbidity with depression are
equivocal, possibly reflecting inconsistencies in measurement methodology across
studies. However, personality psychopathology was found to exert a detrimental
effect on the outcome of cognitive-behavioral treatment for panic disorder.
Further research is necessary to elucidate the impact of these concurrent
conditions on cognitive-behavioral treatment for panic disorder. It is suggested
that studies utilizing cognitive-behavioral treatment routinely examine the
influence of comorbid conditions on treatment outcome.
PMID- 10779899
TI - Attention-deficit hyperactivity disorder and posttraumatic stress disorder:
differential diagnosis in childhood sexual abuse.
AB - Attention-deficit hyperactivity disorders (ADHD) and posttraumatic stress
disorder (PTSD) are the most commonly diagnosed disorders in sexually abused
children (SAC). There is a high degree of symptom overlap and comorbidity between
these disorders, and differential diagnosis can be confusing. Current diagnostic
criteria do not include PTSD as a differential diagnosis for ADHD, nor do
existing assessment guidelines address these diagnostic similarities. This may
have serious implications for SAC. This literature review describes the
psychological impact of child sexual abuse and possible consequences for
misdiagnosing ADHD in SAC. A comparison of criteria from the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition (American Psychiatric
Association, 1994) criteria for ADHD and PTSD is presented, and commonalities are
discussed. On the basis of this comparison, recommendations are made for
improving clinical decision-making and for facilitating differential diagnosis.
Routine inquiry about traumatic experiences in children presenting with ADHD
symptoms is suggested to increase accuracy in differential diagnosis.
PMID- 10779900
TI - Social skills deficits associated with depression.
AB - This article reviews the empirical evidence of impaired social skills associated
with depression. Conceptualizations of social skills are examined followed by
evidence from self-report, observer-rating, and behavioral assessments of
depressed people's social skills. Evidence of social skills deficits in children
with depression and in people with bipolar disorder is also examined. The
effectiveness of social skills training as a treatment of depression is
evaluated. Three different theoretical relationships between disrupted social
skills and depression are described and evaluated, including poor social skills
as a cause of depression, depression as a cause of poor social skills, and poor
social skills as a vulnerability factor in the development of depression.
Currently, there is some evidence to support each of these conceptualizations, as
the relationship between poor social skills and depression can take a variety of
forms.
PMID- 10779901
TI - Treatment of maladaptive behavior in acquired brain injury: remedial approaches
in postacute settings.
AB - This article describes remedial behavior therapy approaches for the treatment of
maladaptive behavioral sequelae to an acquired brain injury (ABI). Remedial
approaches are sophisticated and nonintrusive treatment strategies that involve
teaching the individual skills or capacities to manage difficult life
circumstances. Functional equivalence is one major category of remedial
intervention and involves the determination of the behavioral function of the
problem behavior and the teaching of an adaptive alternative response or skill
cluster that provides the individual with efficient access to that function.
Errorless remediation is a second category and entails teaching the individual to
tolerate situations associated with problem behavior through hierarchical
exposure to increasingly difficult conditions and reinforcement for successful
management of those conditions.
PMID- 10779903
TI - [Transformation of Mycoplasma hominis by plasmid pAM120 using electroporation].
AB - Mycoplasma hominis was transformed by electroporation with plasmid pAM120
containing the transposon Tn916 that carried the tetM gene responsible for the
resistance to tetracycline. The frequency of transformation was 10(-7)-10(-8)
colony-forming units (CFU) per 10 micrograms of plasmid DNA. The PCR analysis of
transformed DNA confirmed the transposon integration into the mycoplasma genome.
PMID- 10779902
TI - Update on home visiting for pregnant women and parents of young children.
PMID- 10779904
TI - [Genomic organization of the murine neuro-d4 gene].
AB - As the first step toward obtaining the null mutation or knock out of the neuro-d4
gene, we isolated phages containing fragments of the gene from a mouse genomic
library. The nucleotide sequence of a region of the gene more than 10 kb in size
was determined.
PMID- 10779905
TI - [Effect of a null mutation in the priA gene on radioresistance of Escherichia
coli].
AB - According to Kogoma's model of DNA recombination by replication, the PriA protein
is involved in the RecBCD pathway of double-strand break (DSB) repair, which is
associated with extensive DNA degradation, at the stage of primosome assembly in
D-loops (intermediates of strand exchange at the ends of DSB) for the subsequent
switch to DSB-induced DNA resynthesis. Comparable data on possible involvement of
the PriA protein in the repair of gamma-ray-induced lethal lesions in cells of
the wild-type strain of Escherichia coli (strain AB1157) and in two radiation
resistant mutants Gamr445 and Gamr444 were obtained. In all the three strains
examined, the null priA2::kan mutation in the structural priA gene was shown to
markedly enhance the radiation sensitivity, causing a two- to threefold increase
in the slopes of linear dose-survival curves. In the AB1157 strain, the
inactivation of PriA is manifested most clearly in the range of low doses (up to
0.15 kGy) when the priA2::kan mutation had only a slight effect on the radiation
resistance of Gamr mutants. It can be assumed that, in these mutants with a
decreased level of postradiation DNA degradation, the PriA-dependent RecBCD
pathway of DSB repair associated with extensive DNA resynthesis is not essential
for the repair of lethal lesions at low doses. However, this pathway becomes
crucial at higher doses (> 0.5 kGy) even for radiation-resistant strains,
especially for the most resistant Gamr444 mutant.
PMID- 10779906
TI - [Cloning and expression of the lux-operon of Photorhabdus luminescens, strain
Zm1: nucleotide sequence of luxAB genes and basic properties of luciferase].
AB - A chromosomal fragment of bacteria Photorhabdus luminescence Zm1, which contains
the lux operon, was cloned into the vector pUC18. The hybrid clone containing
plasmid pXen7 with the EcoRI fragment approximately 7-kb was shown to manifest a
high level of bioluminescence. By subcloning and restriction analysis of the
EcoRI fragment, the location of luxCDABE genes relative to restriction sites was
determined. The nucleotide sequence of the DNA fragment containing the luxA and
luxB genes encoding alpha- and beta-subunits of luciferase was determined. A
comparison with the nucleotide sequences of luxAB genes in Hm and Hw strains of
Ph. luminescence revealed 94.5 and 89.7% homology, respectively. The
enterobacterial repetitive intergenic sequence (ERIC) of 126 bp typical for Hw
strains was identified in the spacer between the luxD and luxA genes. The lux
operon of Zm1 is assumed to emerge through recombination between Hm and Hw
strains. Luciferase of Ph. luminescence was shown to possess a high thermal
stability: its activity decreased by a factor of 10 at 44 degrees C for 30 min,
whereas luciferases of marine bacteria Vibrio fischeri and Vibrio harveyi were
inactivated by one order of magnitude at 44 degrees C for 1 and 6 min,
respectively. The lux genes of Ph. luminescence are suggested for use in gene
engineering and biotechnology.
PMID- 10779907
TI - [Age-related changes in crossing over in Drosophila resemble the picture of
interchromosomal effect of chromosome rearrangement on crossing over].
AB - Crossing over in the left arm of chromosome 2 (2L) was studied in successive
broods of Drosophila melanogaster females carrying intact chromosomes (+/+),
inversion Muller-5 in the X chromosome (M-5/+), and insertion of the Y-chromosome
material into region 34A (Is(2L)/+). The regions net-dp, dp-b, b-pr and pr-cn
were examined in 14 two-day-old broods of females +/+ and M-5/+ and in 10 broods
of females Is(2L)/+. In all lines, the highest level of crossing over was in the
first three broods (eggs laid during the first 6 days of oviposition) and the
lowest level in the broods 7-8 (eggs laid at days 14-16). A high rate of crossing
over in the first broods of females +/+ and M-5/+ was due to an increment of
exchanges in the proximal euchromatin regions (b-pr and pr-cn) and to an increase
in the number of tetrads with double exchanges. These changes are similar to a
pattern of the interchromosomal effect on crossing over (IEC) in structurally
normal chromosomes. In Is(2L)/+ females, a high level of crossing over was due to
extensive exchanges in the interstitial regions net-dp and dp and an increase in
the number of tetrads with single exchanges. These changes resembled the IEC in
rearranged chromosomes (in this case, in chromosomes bearing an insertion). Thus,
the age changes of crossing over are similar to the consequences of the presence
or absence of IEC. Age changes in crossing over in a chromosome depended both on
the local rearrangements in this chromosome (the local effect on crossing over,
LEC) and on rearrangements in nonhomologous chromosomes (IEC). In the first
broods, both LEC and IEC decreased with an increase in the level of crossing
over. In subsequent broods, the reduced level of crossing over was accompanied by
an increase in both LEC and IEC. This suggests that the mechanisms responsible
for the age changes in crossing over and IEC may have common steps. The contact
model of crossing over may explain the similarity between the age changes in
crossing-over and IEC. It is suggested that both phenomena result from delayed
determination of crossing over in a meiotic cell. This may occur due to the
retarded formation of the local contacts in one of the homologous chromosome
pairs or because a higher number of local contacts is required to trigger
crossing over in a meiotic cell (of early age).
PMID- 10779908
TI - [Divergence of karyofunds in sibling species of the plumosus group (Diptera:
Chironomidae)].
AB - Cytogenetic differentiation of eight sibling species of the plumosus group was
examined. The karyofunds of these sibling species were shown to diverge
incompletely. In each species karyofund, the banding sequences homologous to
those of the remaining species of this group were revealed. The number of banding
sequences that displayed interspecific homology varied from 3 to 13 per species
karyofund. In a species karyotype, the homologous sequences were localized to
chromosome arms 1-6. Both similar and contrasting frequencies of homologous
banding sequences were observed in karyofunds of different sibling species. The
average cytogenetic distance between sibling species of the plumosus group was
2.618 +/- 0.400. The presence of species-specific banding sequences, the absence
of homologous banding sequences in some chromosome arms of the karyotype, and
different frequencies of the homologous banding sequences determined the
cytogenetic divergence of the sibling species.
PMID- 10779909
TI - [Phases of the effect of the homeotic Walker mutation in the development of
Drosophila melanogaster].
AB - In this work, critical ontogenetic stages for wing traits affected by temperature
sensitive mutation Walker (Wk) were determined. The interaction between the Wk
gene and some genes responsible for the cell-cycle control was studied. At
various ontogenetic stages, the mutants were exposed to 17 degrees C for 12 h,
and, at the beginning of oviposition, the fly age was registered. Nine types of
wing abnormalities were classified. The temperature treatment during three
developmental stages (12-24, 48-60, and 96-108 h) resulted in a decrease in
normal wing number and a substantial increase in wing abnormalities. Different
morphological types of imaginal disks were revealed: nondifferentiated disks,
those lacking the notum region, and those with duplications of wing-forming
regions. The allele-specific interaction between Wk and allele v27 of the Klp61F
gene was also revealed. We suggest that gene Wk is a high-ranking gene in the
system of genetic control of ontogeny, because the Wk mutation is manifested in
numerous phenotypic variants both in the control and in the experiment and a
complete set of these variants was observed at each developmental stage upon
temperature treatment. The pleiotropic effect of the Wk gene on the formation of
some Drosophila organs, including eyes and halters which are beyond the scope of
this report, is in agreement with this suggestion.
PMID- 10779911
TI - [Karyotype and divergence of stream Dolly Varden from the Southern Sakhalin].
AB - The karyotype of stream Dolly Varden inhabiting a tributary of the Belaya River
(the basin of Naiba River, southern Sakhalin) was determined (2n = 82 and NF = 98
+ 2). According to the main characteristics (chromosome number and arm number,
the presence of a pair of marker submeta-subtelocentric chromosomes with
nucleolus organizer regions (NORs), one pair of large acrocentric chromosomes,
and one pair of subtelocentric chromosomes), this karyotype is identical to the
karyotype of anadromous southern Dolly Varden from Salvelinus malma
krasheninnikovi of Primorye and Japan. However, in most stream Dolly Varden
individuals, additional active nucleolus organizer regions (NORs) located in
telomeric and paracentric regions of two to three pairs of acrocentric
chromosomes were revealed. It is suggested that the stream and anadromous
southern forms of Dolly Varden are evolutionarily related NORs that are silent in
the anadromous souther form are active in the stream form. Possible causes of
these differences in NOR activity are discussed.
PMID- 10779910
TI - [RAPD-markers linked to the locus for resistance to the race 4 pathogen for black
rot, Xanthomonas campestris pv. campestris (Pamm.) Dow., in Brassica rapa L].
AB - Association between the RAPD markers and the resistance to race 4 of the black
rot causative agent was studied in Brassica rapa L. Experiments were carried out
using doubled haploid lines, obtained via crosses between the race 4-susceptible
fodder turnip and resistant pak-choi, and the F2 progeny of the crosses between
the doubled haploid lines with contrasting resistance. The WE(22)980 RAPD marker
inherited from the pak-choi and associated with the clubroot susceptibility was
also linked to the locus responsible for the resistance to race 4 of Xanthomonas
campestris pv. campestris. The two other RAPD markers were linked to
susceptibility to black rot. Simultaneous association of the same DNA markers
with the resistance/susceptibility to two different obligate pathogens favored
the hypothesis on cluster organization of the resistance genes in plants. The
markers described can be used in plant breeding and in further investigation of
the genetic bases of resistance in plants.
PMID- 10779913
TI - [Distribution of a deletion-insertion polymorphism in intergenic region V of
mitochondrial DNA among the aboriginal population of Tuva].
AB - Mitochondrial DNA region V deletion-insertion polymorphism was examined in three
Tuvinian populations inhabiting western, northeastern, and southeastern parts of
the republic. The 9-bp deletion was characterized by nonrandom distribution
across the Tuva territory: its frequency in the western population (13.37%) was
statistically significantly higher than that in the northeastern (4.62%), and
southeastern populations, as well as in Mongols, who are territorially and
ethnically close to Tuvinians. The insertion mutation in the region V was
detected with a frequency of about 3% in two out of the three populations tested.
PMID- 10779912
TI - [Polymorphism T174M of the angiotensinogen gene in Siberian populations].
AB - The level of T174M polymorphism of the angiotensinogen gene (AGT) was studied for
the first time in Siberian populations. The frequency of allele M was found to be
7% in Russians, 6% in Tuvinians, and 4% in Buryats. In the Mongoloid population
of Siberia (Tuvinians and Buryats), the genotypic frequencies deviated from Hardy
Weinberg equilibrium (P < 0.05). The studied polymorphism of the AGT gene
determined in Siberian populations was compared with that of other ethnic groups
in the world population, and genetic distinctions were estimated. Only the Buryat
population was found to differ significantly from the French, English, and
Chinese in the frequency of allele M. No association between the T174M
polymorphism of the AGT gene and pathological pregnancy (gestosis) was revealed
in Buryat women.
PMID- 10779914
TI - [Microsatellite haplotypes of the Y-chromosome demonstrate the absence of
subdivisions and presence of several components in the Tuvinian male gene pool].
AB - The haplotype analysis of seven Y-chromosome microsatellites in three regional
populations of Tuvinians revealed high intrapopulation variation in the male gene
pool of the modern population of the Tuva Republic. In total, 49 haplotypes were
found in 111 individuals; only four haplotypes occurred at a frequency higher
than 5%. High genetic diversity (H = 0.935) suggested a high power of
discrimination for the Y-chromosome haplotypes. The analysis of molecular
variance (AMOVA) and other data did not reveal subdivision of the Tuvinian
population with respect to Y-chromosome haplotypes. Most haplotypes found in
Tuvinians formed two lines. Line A included approximately 64% of the haplotypes
found, line B, approximately 24%. A putative ancestral haplotype of line B was
similar to a haplotype most common in modern Caucasoids (Md = 3), whereas a
putative ancestral haplotype of line A proved to be distant from the ancestral
haplotype of line A and haplotypes common for Caucasoids and Mongoloids.
Estimates of the age of the Y-chromosome lines showed that the male gene pool of
modern Tuvinians originated in the late Paleolithic or Neolithic period. With two
methods, the age of line A was estimated at 3500 or 18,000 years and the age of
line B was approximately at 5500 or 15,000 years. Considering the less
conservative estimates to be more reliable, line B was assumed to originate from
the ancient Caucasoid population of the Tuva region. The more widespread and
evolutionarily younger line A was associated with the peopling region by ancient
Mongoloid tribes of the Turkic language group in the Hun-Sarmatian period.
PMID- 10779915
TI - [Effect of inactivating the p33ING1 tumor suppressor on the function of cell
cycle "checkpoints" and genome stability].
AB - Novel candidate tumor suppressor p33ING1 is known to regulate activity of the p53
protein. The effect of p33ING1 inactivation on the functioning of the cell cycle
"checkpoints" and the frequency of chromosomal aberrations was examined.
Transduction of the p33-GSEas genetic suppressor element, known to reduce the p53
activity, into p53-positive rat and human cells resulted in: (1) partial
abolishment of ethylmetansulphonate- or colcemid-induced arrest of the G1-to-S
transition in the G0-synchronized cultures; (2) abolishment of the block in the S
phase by the DNA synthesis inhibitor, N-phosphonacetil-L-aspartate (PALA); (3) an
increase of the number of spontaneous chromosomal breaks and sister-chromatid
exchanges; (4) increased frequency of colchicine-induced polyploidy. Similar
effects were observed upon transduction of the p53-GSE22 genetic suppressor
element, known to reduce p53 transcriptional activity. Presumably, the effect of
p33ING1 inactivation on the cell cycle checkpoints and genetic stability is
associated with a decrease in p53 activity.
PMID- 10779916
TI - [A defense mechanism of human cells in the radioadaptive response and
antimutagenic activity of interferon has common paths].
AB - The radioadaptive response was assessed by the chromosome aberration test in
lymphocytes of humans with hereditary diseases of connective tissue, which were
earlier characterized as repair-deficient: Marfan syndrome (SM), Elers-Danlos
syndrome (E-D), and homocystinurea (HCU). The radioadaptive response was observed
in cells of patients with Marfan syndrome and Elers-Danlos syndrome but not in
cells of patients with homocystinurea. Parameters of cell protection against
gamma-irradiation at radioadaptive response were similar to those obtained in
cells pretreated with interferon. These data indicate, first, the possibility
that repair pathways and the radioadaptive response are independent and second,
that there are common pathways of protection upon radioadaptive response and the
antimutagenic action of interferon.
PMID- 10779917
TI - [Computer system for simulating population dynamic patterns of polygenes and
mobile genetic elements upon truncation selection for a quantitative trait].
AB - A computer system was developed for simulation of population dynamics of
interacting polygene patterns and mobile genetic elements (MGEs) under selection
for a quantitative trait. The system is stochastic (Monte Carlo) and takes into
account the main sources of random change in the patterns (recombinations,
transpositions, excisions), genetic drift, and determined trends of selection and
other genetic processes in a finite population. Using this model, it is possible
to analyze the dynamics of many population parameters that cannot be
experimentally estimated: frequencies of polygenic alleles, proportions of
adaptive and random fixations, average heterozygosities of polygenes and MGEs,
coefficient of inbreeding, heritability, etc. In addition, the model can be used
to test various hypotheses on polygene-MGE interaction.
PMID- 10779918
TI - [Truncation family selection and nonsystematic inbreeding leads to a rapid
fixation of a pattern of mobile genetic elements in a computer model].
AB - A computer simulation model of the population dynamics of a polygenic system and
a pattern of mobile genetic elements (MGEs) under directional truncation
selection for a quantitative trait was developed. Modifier MGEs were shown to be
rapidly and adaptively fixed (or lost) together with the modified polygenes.
Marker MGEs and independent MGE copies were fixed and lost just as rapidly but in
a random manner. Using specific marking of initial haploid genomes and direct
computing of the mean proportion of identical encounters at each locus in each
generation, it was shown that the mean nonselective inbreeding coefficient F(n)
dramatically increases in the course of selection, reaching values 0.7-0.9 in 15
20 generations. As a result, adaptive homozygotization of polygenes and modifier
MGEs and random homozygotization of marker MGEs, independent MGE copies, and all
other genes of the genome occurs. These results confirm the hypothesis on the
"champion" polygene pattern advanced earlier to explain the data of selection
experiments.
PMID- 10779919
TI - [Possibilities of selection with an increase in frequency of meiotic
recombination (simulation and experiment)].
AB - Polymorphism of rec genes, modifier genes of recombination frequency (rf), was
analyzed. Genetic population analysis was used to estimate the efficiency of some
schemes of direct and indirect selection for higher rf in a marked chromosomal
region. A new modification of the cyclic selection scheme, based on selection of
double recombinant marker genotypes in the offspring of self-fertilized plants,
was found to be most effective in many cases. This indirect selection scheme was
studied in more detail using deterministic and stochastic computer simulation.
Effects of various factors on the efficiency of the modified scheme were
analyzed. These factors were different degrees of cross-fertilization,
differential adaptation of recombinant and non-recombinant gametes and zygotes,
linkage between marker genes and rec genes, and environmental variation of rf.
Sample sizes and the number of crosses required for a stable rf increase in
experiment were estimated. Statistical properties of two new modified tests for
comparison of rf values were studied. An experiment with marker forms of tomato
were conducted taking into account the recommendations following from the results
of simulation.
PMID- 10779920
TI - [Analysis of polymorphism of the D11S2008 locus of the catalase gene in patients
with hypertension and ischemic heart disease in non-insulin-dependent diabetes
mellitus in the Muscovite population].
AB - The allele and genotype frequency distributions of the D11S2008 tetranucleotide
microsatellite linked with the catalase (CAT) gene were compared between patients
with insulin-dependent diabetes mellitus (IDDM) with (N = 72) and without (N =
82) coronary heart disease (CHD), and between IDDM patients with normal arterial
tension (N = 82) and with arterial hypertension (N = 42). In total, eight alleles
were found. The alleles varied in length from 120 to 148 bp and included from 15
to 22 tetranucleotide repeats. The groups did not differ in D11S2008 allele and
genotype frequencies; the only exception was that the frequency of genotype 18/19
in patients with CHD (31.9%) was significantly higher than in the controls
(18.3%). Thus, the D11S2008 polymorphic locus located in proximity to the
catalase gene proved to be weakly associated with CHD, but not associated with
arterial hypertension, in IDDM patients. Genotype 18/19 was associated with a
higher risk of CHD.
PMID- 10779921
TI - [Stability of expressing the nptII gene in transgenic tobacco plants (nicotiana
tabacum L.) with multiple T-DNA insertions].
AB - The stability of nptII gene expression was assessed in transgenic tobacco plants
with multiple T-DNA insertions. The plants were obtained by self-pollination in
the first (T1) and second (T2) generations and also in F1 from crossing T1
plants. The multiple copies showed stable Mendelian inheritance.
PMID- 10779922
TI - Life expectancy.
PMID- 10779923
TI - Health status of children.
PMID- 10779924
TI - Health in mid-life.
PMID- 10779925
TI - Health among older adults.
PMID- 10779926
TI - Psychological health--depression.
PMID- 10779927
TI - Income inequality and mortality among working-age people in Canada and the US.
PMID- 10779928
TI - Personal health practices: smoking, drinking, physical activity and weight.
PMID- 10779929
TI - Health care services--recent trends.
PMID- 10779930
TI - Collaborative, individualized assessment.
AB - Collaborative, individualized assessment is an approach to psychological
assessment in which the assessor and the client work together to develop
productive understandings. Collaboration is a means of individualizing the
assessment--its process, resulting suggestions, and written accounts. In this
approach, life events are regarded as primary data. Test scores, categories, and
related research are used as bridges into a particular life and as tools for then
exploring that life. This article, an invited Master Lecture presented at the
1999 Society for Personality Assessment (SPA) meeting, presents examples of
contextualizing, intervening, describing in life-world terms, and writing
individualized reports with suggestions. Historical struggles to promote
individualized assessment and current openness to its practices, especially
within SPA, are mentioned. A hermeneutic approach to impression formation is
described.
PMID- 10779931
TI - Interobserver agreement, intraobserver reliability, and the Rorschach
Comprehensive System.
AB - Interrater agreement and reliability for the Rorschach have recently come under
increasing scrutiny. This is the second report examining methods of Comprehensive
System reliability using principles derived from observational methodology and
applied behavioral analysis. This study examined a previous nonpatient sample of
20 protocols (N = 412 responses) and also examined a new clinical sample of 20
protocols (N = 374 responses) diagnosed with Research Diagnostic Criteria.
Reliability was analyzed at multiple levels of Comprehensive System data,
including response-level individual codes and coding decisions and ratios,
percentages, and derivations from the Structural Summary. With a number of
exceptions, most Comprehensive System codes, coding decisions, and summary scores
yield acceptable, and in many instances excellent, levels of reliability.
Limitations arising from the nature of Rorschach data and Comprehensive System
coding criteria are discussed.
PMID- 10779932
TI - Responses of Japanese and American university students to the STAI items that
assess the presence or absence of anxiety.
AB - Symptom endorsements and item response patterns on the anxiety-present and
anxiety-absent items of the State-Trait Anxiety Inventory Form Y (Spielberger,
1983) for 149 Japanese (99 living in Japan and 50 studying in the United States)
and 76 American university students were compared. Although mean scores for the
state and trait anxiety-absent items were comparable for Japanese students living
in Japan and Japanese international students studying in the United States, the
scores of both Japanese groups were significantly higher than those of American
students. These differences were attributable to much higher scores of Japanese
students on anxiety-absent items that corresponded to a lack of positive
feelings. Japanese students had a tendency to inhibit positive (anxiety-absent)
feelings, resulting in higher anxiety scores. Responses to anxiety-present and
anxiety-absent items should be considered independently in scoring anxiety
scales.
PMID- 10779934
TI - Origin and history of an early TAT card: picture C.
AB - The origin and history of Picture C is reviewed, and the role that David Ricks
played in preserving many original TAT materials is presented. I suggest that a
process similar to that employed with Picture C may have been used in the
development of the other "old standbys." The unusual directions for the use of
Picture C may possibly suggest awareness by C. D. Morgan and Murray of Schwartz's
earlier work with the picture-story technique.
PMID- 10779933
TI - Coping, mood, and aspects of personality in Spanish translation and evidence of
convergence with English versions.
AB - Research on stress and its influence on health and well-being has flourished for
several decades, examining as predictors such psychosocial variables as
personality and coping. This work now often targets multiethnic samples. Because
many potential participants lack facility in English, a need exists for
translations of measures into other languages. We translated 6 instruments into
Spanish and studied their characteristics. Of these, 3 were measures of
personality qualities: the Life Orientation Test--Revised (Scheier, Carver, &
Bridges, 1994), the Behavioral Inhibition/Behavioral Activation Scales (Carver &
White, 1994), and the Measure of Body Apperception (Carver et al., 1998). The
others were the Brief COPE (Carver, 1997), the Center for Epidemiological Studies
-Depression Scale (Radloff, 1977), and an abbreviated version of the Profile of
Mood States (McNair, Lorr, & Droppelman, 1971). Correlations between English and
Spanish versions in bilingual samples were all above. 72, except for the COPE's
Behavioral Disengagement scale. Alpha reliabilities of the Spanish versions were
comparable to those of the English versions. Correlations among measures in a
sample of cancer patients were similar across languages.
PMID- 10779935
TI - The MMPI-2 in Peru: a normative study.
AB - In this study, we compared a Peruvian normative group to the standard Minnesota
Multiphasic Personality Inventory-2 (MMPI-2; Butcher, Dahlstrom, Graham,
Tellegen, & Kaemmer, 1989b) U.S. normative sample. The MMPI-2 Hispanic Version
was administered under standardized conditions to participants with a wide range
of age, educational, occupational, and socioeconomic levels. Between the 2
samples, there was a high degree of similarity across most basic and
supplementary scales. Elevations (Ts = 60-65) were found on Scale F for men and
women and Scales Mf and MDS for women only. For both men and women, small
elevations (Ts = 55-60) were found on several other scales. The differences were
consistent with those found in other Latin American populations. The results of
this study suggest that the adaptation of the MMPI-2 with the U.S. norms is
appropriate for use in Peru.
PMID- 10779936
TI - Exploring the factor structure of the Mood and Anxiety Symptom Questionnaire
(MASQ).
AB - L. A. Clark and Watson (1991) proposed a tripartite model of anxiety and
depression defined in terms of common symptoms relating to general distress,
anxiety-specific symptoms of hyperarousal, and depression-specific symptoms of
low positive affect and loss of interest. To aid the measurement of and
discrimination between anxiety and depression they developed the Mood and Anxiety
Symptom Questionnaire (MASQ). Although potentially useful, the MASQ is still in
an early stage of development, and there is an indication that a discrepancy
exists between items and scales. Therefore, the aim of this study was to explore
the items and factors of the MASQ and determine whether a pattern similar to that
suggested by L. A. Clark and Watson would emerge. Factor analysis of the MASQ
revealed 3 factors relating to general distress, positive affect, and anxious
arousal. Inspection of the individual items indicated that some refinements are
required.
PMID- 10779937
TI - Assessing achievement, affiliation, and power motives all at once: the Multi
Motive Grid (MMG).
AB - In this article, we introduce the Multi-Motive Grid (MMG), a new diagnostic tool
to measure motives with respect to their hope and fear components. The MMG
combines features of the Thematic Apperception Test (TAT) with features of self
report questionnaires. Similar to the TAT, a set of 14 pictures representing a
balanced set of achievement-arousing, affiliation-arousing, and power-arousing
situations is presented together with a set of statements representing important
motivational states. Six motive scores can be calculated: hope of success (HS)
and fear of failure (FF) for the achievement motive, hope of affiliation (HA) and
fear of rejection (FR) for the affiliation motive, and hope of power (HP) and
fear of power (FP) for the power motive. Results of factor analyses suggest a 3
factor solution, with a general fear factor (FF, FR, FP), a factor combining the
hope components of achievement and power (HS and HP), and a third factor
representing HA, but the 6 a priori factors also reflect a sound structural
model. Reliability data show that the internal consistency and retest reliability
of the MMG scales satisfy traditional standards. External validity of the MMG has
been established in all 3 motive domains. Three separate studies document that
(a) individuals high in resultant achievement motivation perform better and
report more flow experience, (b) individuals high in resultant power motivation
profit more from a leadership training program, and (c) individuals high in
resultant affiliation motivation recollect more highly memorable affiliative
themes.
PMID- 10779938
TI - Predicting parenting behaviors from Antisocial Practices content scale scores of
the MMPI-2 administered during pregnancy.
AB - This article examines the relation between scores on the Antisocial Practices
(ASP) content scale of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2;
Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) and parenting behaviors in
a sample of low-income women. During pregnancy, 141 women were administered the
MMPI-2 and then placed into 1 of 3 groups: an antisocial, nonclinical, or
clinical control group. When their children were 13 and 24 months old, antisocial
mothers were observed to be less understanding and more hostile and harsh in
their parenting styles than mothers in the other groups. The nonclinical and
clinical control groups did not differ on any measures. Other MMPI-2 measures of
antisocial behavior were not predictive of harsh parenting styles. These findings
support the predictive and construct validity of the ASP content scale of the
MMPI-2.
PMID- 10779940
TI - Implementing Orlando's nursing theory: a pilot study.
AB - 1. Implementing Orlando's Nursing Theory results in positive, patient-centered
outcomes. 2. Orlando's Nursing Theory provides a "road map" for nursing staff to
use when approaching patients. 3. Patients' levels of immediate distress decrease
significantly when Orlando's Nursing Theory is used.
PMID- 10779939
TI - Psychiatric hospitalization and process description: what will nursing add?
AB - 1. Inpatient treatment programs operating in the managed care environment must
clearly articulate their treatment outcomes and the processes of care that are
connected to these outcomes. 2. The work of inpatient psychiatric nurses can be
organized and articulated through the therapeutic processes of the Four S Model:
Safety, Structure, Support, and Symptom Management. 3. Nurses are vital
contributors to the inpatient treatment process, but will be marginalized if they
are unable to articulate how their interventions contribute to the positive
treatment outcomes.
PMID- 10779941
TI - Psychopathology and behavioral problems in mental retardation.
AB - 1. The lack of psychiatric services for the mentally retarded is of particular
concern for advanced practice nurses in psychiatry. 2. Prevalence of
psychopathology and behavioral problems in the mentally retarded appears to be
significant. 3. For purposes of diagnostic clarity, a thorough mental status and
neurological examination specifically devised for the mentally retarded
population must be utilized.
PMID- 10779942
TI - Continuous quality improvement to an electroconvulsive therapy delivery system.
AB - 1. ECT is known to be highly effective in relieving severe depression; however,
there are few published articles focusing on nursing care of patients receiving
ECT. 2. Education is an important component of nursing care. Lack of information
about ECT can cause a high level of anxiety and reluctance to consent to ECT. 3.
Using the Continuous Quality Improvement Model, nurses can improve the quality of
a whole system of care delivery.
PMID- 10779943
TI - [Internal ribosome entry sites in viral and cellular RNA].
PMID- 10779944
TI - [Bacterial toxins and their use].
PMID- 10779945
TI - ["Translesion synthesis", or molecular "steeplechase"].
PMID- 10779946
TI - [An edited segment of the kinetoplast gene MURF4 (ATPase 6) in leishmania has a
similar structure].
PMID- 10779947
TI - [Point mutations in region 663-666 of intron 6 or the tryptophan oxygenase gene,
connected with a series of mental disorders, disrupts the transcription factor
YY1 binding site].
PMID- 10779948
TI - [Analysis of foreign epitopes inserted in HBcAG. Possible routes for solving the
problem of chimeric core particle self assembly].
PMID- 10779949
TI - [Prediction of the exon-intron structure by comparing nucleotide sequences from
various genomes].
PMID- 10779950
TI - [Mutual effect of oligonucleotides and fluorescent probes on the effectiveness of
hybridization with oligonucleotides, immobilized on biological microchips].
PMID- 10779951
TI - [Statistical analysis of complete bacterial genomes: palindromes and systems of
restriction-modification].
PMID- 10779952
TI - [Software for analyzing bacterial genomes].
PMID- 10779953
TI - [Genomic organization of the suppressor gene for tumor growth ING1].
PMID- 10779954
TI - [Environment of the 5'-terminal nucleotide of the mRNA codon at P and E-sites of
the human ribosome: crosslinking with pUUUGUU derivatives, bearing a
photoactivated group on the uracil residue or on 5'-phosphate].
PMID- 10779955
TI - [Specific endonuclease activity of integrase encoded by MDG4 (gypsy)
retrotransposon].
PMID- 10779956
TI - [Proteins, tightly bound with a transcribed segment of rDNA in chromatin from
isolated nuclei, nucleoids and nucleoproteins of human lymphocytes. Isolation and
partial characteristics of candidate proteins].
PMID- 10779957
TI - [Analysis of genes, coding for DNA gyrase from the mycoplasma Acholeplasma
laidlawii PG-8B].
PMID- 10779958
TI - [Local duplication of genes with insertion of a complex microsatellite].
PMID- 10779959
TI - [Optical properties of fluorochromes, promising for use in biological
microchips].
PMID- 10779960
TI - [Ethidium bromide binding with native and denatured poly(dA)poly(dT)].
PMID- 10779961
TI - [Mutation of p53 is necessary for stable transformation of REF52 cells by myc+ras
oncogenes].
PMID- 10779962
TI - [Properties of envelope protein of the K1 Kazakh strain of tobacco mosaic virus].
PMID- 10779963
TI - [Detection and characteristics of defective interfering RNA associated with
cocksfoot mottle sobemovirus].
PMID- 10779964
TI - [Analysis of genomic variability of planted Panax ginseng by RAPD].
PMID- 10779965
TI - Working and buying at home.
PMID- 10779966
TI - How's that about incentives and comp?
PMID- 10779967
TI - Facility design, substance abuse also factors in forklift incidents.
PMID- 10779968
TI - Developing a customer-first attitude.
PMID- 10779969
TI - Applying OH&S standards and guidelines.
PMID- 10779970
TI - Online telecommuting resources.
PMID- 10779971
TI - Braced for the fall.
PMID- 10779972
TI - Sky-high security.
PMID- 10779973
TI - Tie-back triumph.
PMID- 10779974
TI - Say no to noise.
PMID- 10779975
TI - A new generation.
PMID- 10779976
TI - Basics of head and face protection.
PMID- 10779977
TI - Eyewear saves a welder's sight.
PMID- 10779978
TI - Safety beyond OSHA requirements.
PMID- 10779979
TI - Get moving--and fast.
PMID- 10779980
TI - Taking control.
PMID- 10779981
TI - Updating sharps safety.
PMID- 10779982
TI - Auditing OSHA's proposed self-auditing policy.
PMID- 10779983
TI - Expanding campus safety objectives.
PMID- 10779984
TI - Pain: above all, do no harm, or make sure the result is worthy of the suffering.
PMID- 10779985
TI - IGF1 and leukemia.
PMID- 10779986
TI - Cardiotoxicity in children after bone marrow transplantation.
PMID- 10779987
TI - Pain variations during cancer treatment in children: a descriptive survey.
AB - Structural interviews were conducted with 66 children and their families to
investigate how the experience of pain varied during cancer treatment. At
diagnosis, 49% experienced cancer-related pain. Intense pain was more common at
the beginning of treatment when it was often believed that pain treatment could
be better. Procedure- and treatment-related pain were the major problems
initially. Procedural pain gradually decreased, but treatment-related pain was
constant and dominating. For some procedures pain was rated highest initially,
lower during the second period, and higher again during the final part of
treatment. Pain intensity measurement was seldom performed, and parents
increasingly considered themselves better judges of their child's pain than
professionals. Increased knowledge about pain and pain treatment in children with
cancer, where most pain is iatrogenic, will help us to meet the needs and demands
of children and parents, and to reduce pain to a minimum.
PMID- 10779988
TI - Paternal employment in agriculture and childhood kidney cancer.
AB - This paper explores the hypothesis that there is an association between risk of
childhood kidney cancer and paternal employment in occupations that have
potential for exposure to herbicides and/or pesticides. In contrast to a previous
study using paternal occupations at the time of the child's death, no significant
association was found between such potential paternal exposures (using paternal
occupations at the time of the child's birth) and the risk of cancer of the
kidney in childhood (OR 0.88, 95% CI 0.20-3.84). In addition, this paper
quantifies the extent to which paternal occupational information on death
certificates can be used as a proxy for paternal occupation at birth and how such
misclassification could affect risk estimates. An example is given showing how a
recently reported association between kidney cancer and paternal agricultural
employment may have been overestimated as a result of the use of death
certificate information.
PMID- 10779989
TI - Obesity in leukemia survivors: the familial contribution.
AB - A high prevalence of obesity in survivors of acute lymphoblastic leukemia (ALL)
has been described, but genetic and social influence in obesity has not been
analyzed in this group of patients. The authors studied a population of 33 long
term (25 females, 8 males) in first remission who had reached their final height.
All patients received cranial irradiation as part of their central nervous system
(CNS)-directed therapy and no patient received growth hormone. The body mass
index (BMI: weight/height2) of patients and their biological parents was
calculated and submitted to statistical analysis. Obesity was defined as BMI
greater than the 85th centile. No excessive obesity was found among the males at
final height. Fifty-six percent of the females were obese. In this group of 14
obese female survivors 59% had obese mother, but only 14% had obese fathers. The
results indicate a significant maternal predisposition to obesity.
PMID- 10779990
TI - Male gonadal function in survivors of childhood Hodgkin and non-Hodgkin lymphoma.
AB - The aim of this study was to investigate the impact of therapy on long-term
gonadal function of young people cured of childhood lymphomas and to assess
whether a prepubertal state during the treatment protects the gonads from
chemotherapy and/or radiotherapy late effects. Clinical evaluation, semen
analysis, and endocrine status were studied in 20 survivors of childhood
lymphomas. Five patients received Inverted Y radiotherapy, 2320 cGy (1550-4000);
all 20 received chemotherapy as follows: MOPP/ABVD protocol, 9 patients; COMP
protocol, 5 patients; MOPP protocol, 3 patients; other protocols, 3 patients.
Semen analysis results were as follows: normal values, 4/20 patients;
oligospermia, 8/20 patients; azoospermia, 8/20 patients; FSH above normal level,
10/20 patients; 4/5 who received Inverted Y irradiation were azoospermic and 1
was severely oligospermic. Treatment damage to the testis involves tubular
germinal elements. Radiotherapy and chemotherapy combinations that included
nitrogen mustard or cyclophosphamide were associated with high rates of
oligospermia and azoospermia. MOPP/ABVD combination did not have a significant
better outcome of sperm counts compared to MOPP alone. Age at chemotherapy did
not correlate with the sperm count; hence a prepubertal state did not protect the
gonad from the late effects of treatment.
PMID- 10779991
TI - Clinical presentations of infection by the human herpesvirus-7 (HHV-7).
AB - Reports on the clinical picture of primary infection with the human herpesvirus-7
(HHV-7) are scarce. A heterogenous population of 478 patients (1 month-14 years)
was examined for the presence of an acute HHV-7 infection. A variety of clinical
pictures can be observed during primary infection with HHV-7, such as exanthema
subitum and mononucleosis-like syndrome. The authors describe in two children,
for the first time, the presentation of HHV-7-infection as an acute exacerbation
or relapse of a patient's chronic disease. The hematological changes for the
respective clinical presentations during HHV-7 infection are reported.
PMID- 10779992
TI - Decreased insulin-like growth factor-I receptor sites on circulating mononuclear
cells from children with acute leukemia.
AB - Insulin-like growth factor-I (IGF-I) is a known mitogen for various cell types,
including those of the hematopoietic cell system. To study the role of IGF-I in
the neoplastic process of leukemia in children, the authors have determined the
number of IGF-I binding sites on circulating mononuclear cells of children with
acute leukemia as compared to normal children, using binding assays. The IGF-I
binding sites per cell on peripheral mononuclear cells of children with leukemia
decreased compared to those of the control group (411 +/- 73 and 1334 +/- 227,
respectively, p < .001), while their affinity increased (Kd = 0.14 +/- 0.04 and
0.43 +/- 0.16, respectively, p = .05). Furthermore, in the patients, the number
of the IGF-I binding sites was significantly lower in the subgroup of the
peripheral mononuclear cells, which included lymphocytes and monocytes, as
compared to their number in the peripheral blast cells (254 +/- 43.6 and 536 +/-
98.6, respectively, p = .02). A significant reduction was found in serum GHBP
levels in the patients as compared to the controls (28.21 +/- 1.93 and 35.83 +/-
2.90, respectively, p = .02), while serum IGF-I and growth hormone levels were
similar in patient and control groups. These results suggest a possible
involvement of IGF-I in childhood acute leukemia, but further studies are needed
to establish whether IGF-I plays a role in this disease.
PMID- 10779993
TI - Lymphohistiocytic anaplastic large cell lymphoma stage I: long-term survival
after resection alone.
AB - A 17-year-old female presented with axillary lymphoadenopathy, which, on biopsy,
demonstrated an anaplastic large cell lymphoma of the lymphohistiocytic type
(ALCL-LH). The tumor cells expressed the CD30 antigen and reacted with the ALK1
antibody, suggesting the presence of the nucleophosmin-anaplastic large cell
lymphoma kinase (NPM/ALK) fusion protein. No other adenopathy was found.
Following a wide excision of the lymph node and without postoperative treatment,
the patient remains free of disease 5 years later. This case demonstrates the
potential curability of patients with early stages of ALCL by local treatment.
PMID- 10779994
TI - A case of malignant lymphoma in a patient with high levels of CA125 and CA19-9.
AB - The authors encountered a case of malignant lymphoma in a patient who had high
levels of CA125 and CA19-9. These tumor markers showed almost identical changes
during the clinical course of the disease. To date, there has been no
investigation of these markers as they relate to malignant lymphoma.
Unfortunately, the normal values of CA125 and CA19-9 in children were not known
and thus this case could not be compared with disease-free children. This study
shows CA125 and CA19-9 levels of the children that do not have the malignant
diseases, and reports on one case of malignant lymphoma in a patient who
presented with high levels of these markers.
PMID- 10779995
TI - Secondary leukemia in a child with neuroblastoma while on oral etoposide: what is
the cause?
AB - To date little has been reported about the risk of therapy-related leukaemia (t
AML) in children receiving oral etoposide therapy. The authors present a case of
t-AML that developed in a child with metastatic neuroblastoma 18 months after he
received oral etoposide, given for palliation purpose. The leukemic blasts were
examined by morphological, immunohistochemical, cytogenetic, and molecular
genetic analyses. Although the t-AML developed following oral etoposide therapy,
the child had previously received high-dose, multiagent chemotherapy, and
rearrangement of the MLL gene was not demonstrated. The use of modern multiagent
therapy often makes it difficult to appropriately apportion blame for causation
of specific side effects. Moreover, the etiology of t-AML and mechanism of
leukemogenesis are likely to be multifactorial and complex. Further studies on
the precise association with different therapies are thus needed. Oral etoposide
remains an effective palliative agent and its usage should not be excluded
without most careful consideration of the risks.
PMID- 10779996
TI - [ATP and polyphosphate-dependent bacterial NAD+-kinases].
AB - Measurable levels of activity of NAD+ kinases of actinomycetes Micrococcus luteus
and Corynebacterium ammoniagenes were observed after substituting inorganic
tripolyphosphate for ATP, whereas the enzyme from the eubacterium Escherichia
coli was not active with this substrate. Gradient PAGE found two molecular
isoforms of NAD+ kinase in C. ammoniagenes and E. coli; four forms were found in
M. luteus. All isoforms of this enzyme found in C. ammoniagenes and M. luteus
displayed a NADP-synthesizing activity in the presence of either ATP or
tripolyphosphate. Because of its capability of utilizing inorganic
tripolyphosphate, M. luteus is the most promising NADP producer organism.
PMID- 10779997
TI - [Enzymatic hydrolysis of willow treated with a steam burst without preliminary
water extraction with a high concentration of substrate].
AB - A laboratory reactor equipped with a screw press was used for hydrolysis of steam
SO2 exploded willow Salix caprea by a composition of Trichoderma reesei and
Aspergillus foetidus enzyme preparations at high substrate concentrations.
Optimal conditions providing the maximal volume of hydrolysis syrup with maximal
sugar concentrations were determined. Two different hydrolysis procedures were
developed in order to exclude initial washing of steam-pretreated plant raw
material by large volumes of water, which is necessary to eliminate the
inhibitory effect of explosion by-products on enzymatic hydrolysis. The first
procedure included a one-hour-long enzymatic prehydrolysis of the substrate, then
separation of sugar syrup containing 40-60 g/l of glucose, 20-25 g/l of xylose,
and up to 10% of disaccharides, as well as up to 35% of the initial enzymatic
activity, then addition of a diluted acetate buffer (pH 4.5), and subsequent
hydrolysis of the substrate by the adsorbed enzymes leading to the final
accumulation of up to 140 g/l glucose and up to 15 g/l xylose. In the second
scenario, the exploded willow was initially adjusted by alkali to pH 4.5 and then
hydrolyzed directly by added enzymes for 24 hours. This procedure resulted in a
nearly total polysaccharide hydrolysis and accumulation of up to 170 g/l glucose
and 20 g/l xylose. The reasons of inhibition of enzymatic hydrolysis are
discussed.
PMID- 10779998
TI - [Isolation and purification of acetolactate synthase and acetolactate
decarboxylase from a Lactococcus lactis culture].
AB - Enzymes catalyzing the synthesis and subsequent transformation of alpha
acetolactate (AcL)--acetolactate synthase (AcLS) and acetolactate decarboxylase
(AcLDC)--were isolated and partially purified from the cells of lactic acid
bacteria Lactococcus lactis ssp. lactis biovar. diacetylactis strain 4. The
preparation of AcLS, purified 560-fold, had a specific activity of 358,300 U/mg
protein (9% yield). The preparation of AcLDC, purified 4828-fold, had a specific
activity of 140 U/mg protein (4.8% yield). The enzymes exhibited optimum activity
at pH 6.5 and 6.0, respectively (medium, phosphate buffer). The values of
apparent Km, determined for AcLS and AcLDC with pyruvate and AcL, respectively,
were equal to 70 mM and 20 mM. AcLS appeared as an allosteric enzyme with low
affinity for the substrate and a sigmoid dependence of the activity on the
substrate concentration. In the case of AcLDC, this dependence was hyperbolic,
and the affinity of the enzyme for its substrate was high (Km = 20 mM). Leucine,
valine, and isoleucine were shown to be activators of AcDLC.
PMID- 10779999
TI - [Comparative study of soluble and immobilized phenol oxidase from the fungus
Mycelia sterilia IBR 35219/2].
AB - Phenol oxidase (EC 1.14.18.1) from the microscopic fungus Mycelia sterilia IBR
35219/2 was immobilized using glutaraldehyde on macroporous silica carriers. The
enzyme immobilized on amino-Silochrome SKh-2 or aminopropyl-Silochrome 350/80
exhibited maximum activity. Soluble and immobilized phenol oxidases were
compared. Compared to the soluble enzyme, the activity of which was optimum at pH
5.5, immobilized phenol oxidase exhibited optimum activity under slightly more
acidic conditions (pH 5.2). Immobilization considerably increased the enzyme
stability. Both soluble and immobilized forms of phenol oxidase from M. sterilia
IBR 35219/2 catalyze oxidative conversion of phenolic compounds of the green tea
extract.
PMID- 10780000
TI - [Determining role of media in peroxide oxidation of aromatic type antioxidants
with participation of methemalbumins].
AB - Participation of the complexes of hemin and albumins (or delipidated albumins) in
peroxidation of aromatic free radical scavengers and antioxidants was studied at
varying hemin/albumin ratios. The radical-scavenging amines included o
phenylenediamine (OPD) and tetramethylbenzidine (TMB); the antioxidants, gallic
acid (GA) and GA polydisulfide (GAPD). Peroxidation reactions were carried out in
buffered physiological saline (BPS) supplemented with 2% dimethylsulfoxide(DMSO),
pH 7.4 (medium A), or in 40% aqueous dimethylformamide (DMF), pH 7.4 (medium B).
In all systems involving methemalbumins, kinetic constants (kcat), Michaelis
constants (kM), and the ratios thereof (kcat/kM) were determined for OPD
oxidation in medium A and TMB oxidation in medium B. Oxidation of OPD, GA, and
GAPD in medium A was characterized by a decrease in the catalytic activity of
hemin after the formation of hemin-albumin complexes. Conversely, oxidation of
TMB and OPD in medium B was distinguished by pronounced activation of hemin
present within methemalbumins.
PMID- 10780001
TI - [Melanin pigments of the fungi Paecilomyces variotii and Aspergillus
carbonarius].
AB - Pigments synthesized by micromycetes Paecilomyces variotii and Aspergillus
carbonarius are true melanins. Copper ions and bicyclic phenolic compounds
stimulated melaninogenesis, whereas benzotriazole inhibited this process.
Precursors of melanin pigments were obtained and identified. p-Hydroxybenzoic
acid was shown to be the main product of melanin degradation. Melanins of these
fungi are concluded to belong to the dihydronaphthalene group.
PMID- 10780003
TI - [Furane compounds formed upon heating highly-sugared fermented media].
AB - 5-Methylfurfural diethyl acetal, 5-methylfuran acid ester, and 4-hydroxypentanoic
acid ethyl ester were first identified in high-sacchariferous corn media
subjected to alcoholic fermentation by Mucor X-I culture and in aged sweet wines
by means of GLC, GLC-MS, and TLC, as well as by UV and IR spectroscopic
examinations. These substances are products of enzymatic esterification of sugars
followed by their dehydration by heat treatment or long seasoning of grape wines.
PMID- 10780002
TI - [Inactivation of polygalacturonase in the process of growth of the yeast
Saccharomyces pastorianus].
AB - The effect of exogenous glucose addition on polygalacturonase (EC 3.2.1.15)
activity in the culture medium of Saccharomyces pastorianus was studied. An rapid
but transient decrease in the enzyme activity was observed after 9-12 h after
adding glucose to the culture medium. This effect was not associated with protein
degradation or modification in the spectrum of secreted proteins. Ethyl acetate
appeared in the culture medium during this period.
PMID- 10780004
TI - [Transformation of lignins from grape solids during alcoholic fermentation].
AB - Conversion of lignins contained in solid parts of Rkatsiteli grapes (crests,
seeds, and skin) during alcoholic fermentation by wine yeast in Reader's medium
was studied. Various species of wine yeast were used: Saccharomyces oviformis, S.
vini Kakhuri 42, S. chodati Teliani 79, and S. uvarum Tsinandali 77. We found
that lignins from solid parts of grapes are partially decomposed during alcoholic
fermentation, which releases low-molecular-weight aromatic compounds into the
medium. A peculiar feature of lignin decomposition during alcoholic fermentation
is the formation of reduction products.
PMID- 10780005
TI - [Extracellular proteinases and chitinases, produced by a Streptomyces kurssanovii
culture].
AB - Extracellular enzymes--a chitinase and a protease with molecular weights 22 and
32 kDa, respectively--were isolated from Streptomyces kurssanovii cells. After
purification on modified regenerated chitin, the enzymes were virtually
homogeneous according to denaturing PAGE. Both enzymes were found to degrade
chitosan.
PMID- 10780006
TI - [Microbial degradation of components of waste water from phenol-producing
industry].
AB - Processes of aerobic biodegradation of components of phenol production sewage
(phenol, acetophenone, dimethylphenylcarbinol, cumene hydroperoxide, alpha
methylstyrene, benzoate, and p-hydroxybenzoate) by bacterial strains obtained
from the collection of Saratov Institute of Biocatalysis were studied. The
metabolic reactions were shown to be oxidative and have a common catabolic
sequence (cumene hydroperoxide-dimethylphenyl-carbinol alpha-methylstyrene
acetophenone-phenyl acetate-phenol-pyrocatechol-aromatic ring breakage). Benzoate
and p-hydroxybenzoate were degraded through the formation of pyrocatechol and
protocatechuate, respectively. Metabolic pathways were similar in model mixtures
of components and sewage samples.
PMID- 10780007
TI - [Study of microbial degradation of nonionic surface-active agents in designing
technologies for purifying waste water].
AB - Studies of degradation of non-ionic surfactants (NISA) in a model purification
plant of an original design demonstrated an high rate and depth of degradation
processes compared with periodic cultivation of free or immobilized degrading
strains. A virtually complete primary degradation (99-99.5%), with destruction of
the oxyethyl moiety of the molecule, was observed. In addition, NISA molecules
were degraded to a greater extent, including considerable degradation of the
hydrocarbon radical, partial degradation of aromatic structures in Neonol, and
utilization of biologically "unyielding" fractions of commercial NISA
preparations: polyethylene glycol (PEG) and long-chain fractions of polymer
homologues.
PMID- 10780008
TI - [Effect of gas phase composition on formation of hydrocarbons by Desulfovibrio
desulfuricans].
AB - Changes in the synthesis of extracellular metabolic products generated by sulfate
reducing bacteria Desulfovibrio desulfuricans grown on a lactate-containing
mineral medium in the presence of H2 and CO2 at various volume ratios in the
gaseous phase were studied. An increase in the amount of extracellular products
synthesized by the bacteria was observed at an H2/CO2 ratio of 3:1. High
concentrations of molecular hydrogen (80-95%) in the presence of 5-20% CO2
facilitated the synthesis of hydrocarbons (alkanes) whose highest concentrations
were produced at an H2/CO2 ratio of 9:1. An increase in the initial CO2
concentration in the gaseous phase above 20% increased the amount of oxygenated
compounds in the culture.
PMID- 10780009
TI - [Effect of conditions of culturing Penicillium funiculosum G-15 on production of
extracellular glucose oxidase].
AB - Effects of conditions of Penicillium funiculosum G-15 cultivation on the
production of extracellular glucose oxidase were studied. The data showed that
surface and submerged methods of cultivation can be used for obtaining a glucose
oxidizing enzyme. The optimum conditions for submerged cultivation (25 degrees C,
initial pH 5.0, and aeration of 3 l/l per min) and surface cultivation
(temperature 25 degrees C and initial pH 4.0) providing the maximum levels of
glucose oxidase synthesis were determined.
PMID- 10780010
TI - [Effect of conditions of culturing Pseudomonas rathonis T on characteristics of a
biosensor for determining anionic surface-active agents].
AB - The dependence of the sensitivity of a microbial biosensor of anionic surfactants
(AS) on the growth phase of Pseudomonas rathonis T, a strain capable of degrading
surfactants, was studied. Correlations were found between the optimum values of
temperature and pH of microbial growth, substrate utilization, and functional
performance of the microbial biosensor. These results allow the process of AS
detection to be optimized.
PMID- 10780011
TI - [Ochratoxin A: study of grain contamination].
AB - Ochratoxin A was quantitatively monitored in grain extracts by indirect solid
phase enzyme immunoassay with the use of an immobilized conjugate of the toxin
with gelatin and polyclonal rabbit antibodies raised against the ochratoxin A-BSA
conjugate. This monitoring found that 1.7 to 18.5% of the samples were
contaminated with the toxin at a concentration of 25.9-291.7 micrograms/kg. An
analysis of forage grain found ochratoxin A at concentrations of 440-3250
micrograms/kg.
PMID- 10780013
TI - [Preparation and immunochemical properties of monoclonal antibodies to potato
ring rot pathogen Corynebacterium sepedonicum].
AB - Five stable hybridoma lines producing monoclonal antibodies to Corynebacterium
sepedonicum were obtained. The specificity of monoclonal antibodies obtained was
characterized. Interactions of the antibodies with native cells and antigenic
preparations from bacterial cell extracts were studied. The epitope specificity
of these antibodies to their recognized antigens and the use of the antibodies in
advanced immunodiagnostic assays are discussed.
PMID- 10780012
TI - [Effect of methyljasmononate on induction of late-blight resistance of potatoes
using arachidonic acid].
AB - Methyl ester of jasmonic acid (Me-JA) influences the induced resistance of potato
tubers to late blight caused by Phytophthora infestans. Treatment of potato tuber
disk surface with Me-JA solution or exposure to an atmosphere containing Me-JA
vapors (10(-6)-10(-5) M) increased the rate of rishitin biosynthesis induced by
arachidonic acid or P. infestans. Methyl jasmonate increased the sensitivity of
potato tissue to arachidonic acid. As a result, in the presence of Me-JA, the
protective properties of arachidonic acid were observed at lower concentrations
than in the absence of Me-JA. In addition, Me-JA reduced the adverse effects of
lipoxygenase inhibitors (salicylhydroxamic acid and esculetin) on the induced
resistance of potato tubers to late blight. Therefore, the synergistic
interaction of Me-JA and biogenic elicitors can be regarded as part of a
mechanism of potato defense against diseases.
PMID- 10780014
TI - [Activity of a proteinaceous polygalacturonase inhibitor in potato plants].
AB - The activity of a protein inhibitor of polygalacturonase (PIPG) was studied in
potato tubers during storage and in potato leaves and stems during vegetation.
The activity of PIPG in tubers varied from between seasons. The activity of PIPG
during dormancy changed depending on the storage stage and temperature. As a
rule, it was higher in etiolated sprouts than in the tubers. The activity of PIPG
was slightly higher in leaves of adult vegetating plants than in stems and
decreased by the end of vegetation. These changes in the activity of PIPG are
suggested to be associated with changes in the growth rate.
PMID- 10780016
TI - [Effect of exogenous quercetin on the level of carbohydrates and amino acids in
Lycopersicon esculentum fruit].
AB - Low doses of the exogenous flavonoid quercetin increased in contents of sugars in
tomato fruits of various cultivars. The content of glucose in tomato fruits of
cv. Ukrainskii teplichnyi increased from 3.62 to 11.24% per unit dry weight.
Increases in the content of glucose were found in all tomato cultivars examined.
An analysis of qualitative and quantitative compositions of amino acids showed
that their levels were markedly decreased in fruits of quercetin-treated plants.
Our studies and data found in the literature suggest that this effect is due to
the synthesis of sugars from amino acids by gluconeogenesis. The reverse process
of sugar hydrolysis does not occur because exogenous quercetin inhibits the
activity of pyruvate kinase.
PMID- 10780015
TI - [The effect of the substance exin on development of microbial infections and
isolation of ethylene in plants].
AB - Effects of Exin on infection of tomato, potato, and cabbage plants with
Pseudomonas solanacearum and Erwinia carotovora and a fungus Sclerotium rolfsii
were studied. The treatment of infected plants with Exin caused no significant
effect on the development of the disease. Treatment with streptomycin as a
standard for comparison completely inhibited the growth of these microorganisms.
Pretreatment with Exin one to eight days before infecting inhibited the
development of diseases. The numbers of tomato and potato plants damaged among
those infected with P. solanacearum were lower by 10 and 35% respectively. In
field experiments (350 plants per variant), treatment with Exin decreased the
development of wilt caused by S. rolfsii and P. solanacearum and rot caused by E.
carotovora. Treatment with Exin activated the release of ethylene for not less
than 30 days. Possible mechanisms of the effects of Exin are discussed.
PMID- 10780017
TI - [Preparation of agar and agarose from the red algae Ahnfeltia tobuchiensis].
AB - A simple and inexpensive procedure of agar and agarose production from the red
alga Ahnfeltia tobuchiensis was developed, which needs no additional
chromatographic purification.
PMID- 10780018
TI - Explicitly modeling the effects of aging on response time.
AB - Research into the effects of aging on response time has focused on Brinley plots.
Brinley plots are constructed by plotting mean response times for older subjects
against those for young subjects for a set of experimental conditions. The
typical result is a straight line with a slope greater than 1 and a negative
intercept. This linear function has been interpreted as showing that aging leads
to a general slowing of cognitive processes. In this article, we show that the
slope of the Brinley plot is actually a measure of the relative standard
deviations of older versus young subjects' response times; it is not a measure of
general slowing. We examine current models of the effects of aging on mean
response time and show how they might be reinterpreted. We also show how a more
comprehensive model, Ratcliff's diffusion model (1978), can account for Brinley
plot regularities and, at the same time, provide an account of accuracy rates,
the shapes of response time distributions, and the relative speeds of error and
correct response times, aspects of the data about which models designed to
account for Brinley plots are mute. We conclude by endorsing a research approach
that applies explicit models to response time data in aging in order to use the
parameters of the model to interpret the effects of aging.
PMID- 10780019
TI - Accounts of the confidence-accuracy relation in recognition memory.
AB - Confidence and accuracy, while often considered to tap the same memory
representation, are often found to be only weakly correlated (e.g., Bothwell,
Deffenbacher, & Brigham, 1987; Deffenbacher, 1980). There are at least two
possible (nonexclusive) reasons for this weak relation. First, it may be simply
due to noise of one sort or another; that is, it may come about because of both
within- and between-subjects statistical variations that are partially
uncorrelated for confidence measures on the one hand and accuracy measures on the
other. Second, confidence and accuracy may be uncorrelated because they are
based, at least in part, on different memory representations that are affected in
different ways by different independent variables. We propose a general theory
that is designed to encompass both of these possibilities and, within the context
of this theory, we evaluate effects of four variables--degree of rehearsal, study
duration, study luminance, and test luminance--in three face recognition
experiments. In conjunction with our theory, the results allow us to begin to
identify the circumstances under which confidence and accuracy are based on the
same versus different sources of information in memory. The results demonstrate
the conditions under which subjects are quite poor at monitoring their memory
performance, and are used to extend cue utilization theories to the domain of
face recognition.
PMID- 10780020
TI - Meaning resolution processes for words: a parallel independent model.
AB - Lexical ambiguity research over the last two decades is reviewed, with a focus on
how that literature applies to understanding the resolution of meaning for words.
Early models of ambiguity processing dealt almost exclusively with the time
course of the effects of context on lexical access, in order to address the issue
of modularity of lexical access. Newer models of ambiguity processing accommodate
recent findings of early context effects that are contingent on both strength of
context and meaning frequency. The most important contribution of these newer
models of ambiguity processing is not to the modularity debate, but to
investigation of the range of parameters affecting the entire meaning resolution
process, including meaning access as well as the integration of meanings into
context. As an example of this approach, we describe a simple quantitative model
of meaning resolution that subsumes many other models as parametric variations.
PMID- 10780022
TI - "Work ethic" in pigeons: reward value is directly related to the effort or time
required to obtain the reward.
AB - Stimuli associated with less effort or with shorter delays to reinforcement are
generally preferred over those associated with greater effort or longer delays to
reinforcement. However, the opposite appears to be true of stimuli that follow
greater effort or longer delays. In training, a simple simultaneous
discrimination followed a single peck to an initial stimulus (S+FR1 S-FR1) and a
different simple simultaneous discrimination followed 20 pecks to the initial
stimulus (S+FR20 S-FR20). On test trials, pigeons preferred S+FR20 over S+FR1 and
S-FR20 over S-FR1. These data support the view that the state of the animal
immediately prior to presentation of the discrimination affects the value of the
reinforcement that follows it. This contrast effect is analogous to effects that
when they occur in humans have been attributed to more complex cognitive and
social factors.
PMID- 10780021
TI - In defense of abstractionist theories of repetition priming and word
identification.
AB - There is a great deal of interest in characterizing the representations and
processes that support visual word priming and written word identification more
generally. On one view, these phenomena are supported by abstract orthographic
representations that map together visually dissimilar exemplars of letters and
words (e.g., the letters A/a map onto a common abstract letter code a*). On a
second view, orthographic codes consist in a collection of episodic
representations of words that interact in such a way that it sometimes looks as
if there are abstract codes. Tenpenny (1995) contrasted these general approaches
and concluded by endorsing the episodic account, arguing that no evidence demands
that we posit abstract orthographic representations. This review reconsiders the
evidence and argues that a variety of priming and nonpriming research strongly
supports the conclusion that abstract orthographic codes exist and support
priming and word identification. On this account, episodic representations are
represented separately from abstract orthographic knowledge and contribute
minimally to these functions.
PMID- 10780023
TI - Don't look! Don't touch! Inhibitory control of eye and hand movements.
AB - Inhibitory control of eye and hand movements was compared in the stop-signal
task. Subjects moved their eyes to the right or left or pressed keys on the right
or left in response to visual stimuli. The stimuli were either central (angle
brackets pointing left or right) or peripheral (plus signs turning into Xs left
or right of fixation), and the task was either pro (respond on the same side as
the stimulus) or anti (respond on the opposite side). Occasionally, a stop signal
was presented, which instructed subjects to inhibit their responses to the go
stimulus. Stop-signal reaction times (SSRTs) were faster overall for eye
movements than for hand movements, and they were affected differently by stimulus
conditions (central vs. peripheral) and task (pro vs. anti), suggesting that the
eyes and hands are inhibited by different processes operating under similar
principles (i.e., a race between stop and go processes).
PMID- 10780024
TI - Age and individual differences in visuospatial processing speed: testing the
magnification hypothesis.
AB - Forty young adults and 40 older adults performed seven visuospatial information
processing tasks. Factor analyses of the response times (RTs) yielded a single
principal component with a similar composition in both age samples. For both
samples, regressing the mean RTs of fast and slow subgroups for the seven tasks
(18 conditions) on the corresponding mean RTs for their age group accounted for
99% of the variance. Taken together, these findings suggest that individual
differences in processing time were largely task independent. The magnification
hypothesis, a simple mathematical model of the interaction between age and
ability, is presented. This model correctly predicts the finding that in both the
young and the older adult groups, individual differences increased systematically
with task difficulty. The magnification hypothesis also explains the regression
parameters describing individual differences among young adults and predicts
correctly that equivalent parameters describe individual differences among older
adults. According to the magnification hypothesis, the RTs of slower individuals
are more affected by aging than those of faster individuals, and slower
individuals may be more at risk with respect to other biological insults (e.g.,
changes in health status) as well.
PMID- 10780025
TI - The reverse Stroop effect.
AB - In classic Stroop interference, manual or oral identification of sensory colors
presented as incongruent color words is delayed relative to simple color naming.
In the experiment reported here, this effect was shown to all but disappear when
the response was simply to point to a matching patch of color. Conversely, strong
reverse Stroop interference occurred with the pointing task. That is, when the
sensory color of a color word was incongruent with that word, responses to color
words were delayed by an average of 69 msec relative to a word presented in gray.
Thus, incongruently colored words interfere strongly with pointing to a color
patch named by the words, but little interference from incongruent color words is
found when the goal is to match the color of the word. These results suggest that
Stroop effects arise from response compatibility of irrelevant information rather
than automatic processing or habit strength.
PMID- 10780026
TI - Conceptual activation of distractors during selection is not sufficient to
produce negative priming.
AB - Negative priming (NP) occurs when responses are slower because the targets were
distractors on the preceding trial. Word-naming NP occurs only with words that
have been presented repeatedly as targets; novel words do not show NP. The
activation-inhibition explanation is that representations of repeated-word
distractors are activated already and must be inhibited; the inhibition carries
over to the next trial. If this explanation is correct, novel-word NP should
occur if the word is semantically primed (thus activating its representation)
before it occurs as a distractor. In two experiments, there was NP for words from
a repeated set, and the magnitude of NP increased when the same word could occur
as a target on consecutive trials. There was positive, rather than negative,
priming for novel-word targets that had been semantically primed as distractors.
Either the activation from semantic priming was not sufficiently strong to
require inhibition, or the activation-inhibition hypothesis does not refer to
activation of conceptual representations.
PMID- 10780027
TI - The left-to-right nature of the masked onset priming effect in naming.
AB - Two experiments were performed to investigate the nature of the masked onset
priming effect in naming, that is, the facilitation in naming latency that is
observed when a target shares the initial grapheme/phoneme with a masked prime.
Experiment 1 showed that the effect is not due to position-independent letter
priming, since the naming of nonword targets preceded by masked primes was
facilitated only if the prime shared the initial letter with the target (e.g.,
suf-SIB) and not if the prime shared the final letter (e.g., mub-SIB). Experiment
2 showed that the effect reflects the sharing of onsets rather than the initial
letter, since facilitation due to an overlap of the initial letter was observed
only for the simple onset target (e.g., penny-PASTE) for which the letter
corresponded to the onset, and not for complex onset targets (e.g., bingo-BLISS).
It is argued that the serial nature of the masked onset priming effect is best
interpreted as the planning of articulation, rather than as the computation of
phonology from orthography.
PMID- 10780028
TI - Reading aloud polysyllabic words and nonwords: the syllabic length effect
reexamined.
AB - Two experiments were run in order to reinvestigate the role of the number of
syllables in naming. Experiment 1 (word naming) showed that effects of number of
syllables on naming latency were observed for very low-frequency words but not
for high-frequency words (thus replicating Jared & Seidenberg's, 1990, finding).
In Experiment 2 (nonword naming), syllabic length effects were also obtained for
nonwords. Control experiments found no effect on the latency of delayed naming of
the same words and nonwords. These results suggest that naming does require
syllabic decomposition, at least for very low-frequency words and nonwords in
French. In particular, these data are compatible with any model of reading that
postulates that reading aloud depends on the activity of two procedures: (1) a
procedure that operates in parallel across a letter string (and does not generate
a strong syllabic length effect) and that is the predominant process in
generating responses to high-frequency words, and (2) another procedure that
operates serially across a letter string (and generates a strong syllabic length
effect) and that is the predominant process in generating responses to very low
frequency words and nonwords. These results are discussed in the context of the
multiple-trace memory model for polysyllabic word naming (Ans, Carbonnel, &
Valdois, 1998).
PMID- 10780029
TI - Implicit word activation during prerecognition processing: false recognition and
remember/know judgments.
AB - Recognition memory for spoken words is influenced by phonetic resemblance between
test words and items presented during study. Presentation of derived nonwords
(e.g., /d/ransparent or transparen/d/) on a study list produces a higher than
normal false recognition rate to base words (e.g., transparent). Test words that
share beginning phonemes with studied nonwords have more false recognitions than
do those that share ending phonemes. The latter difference has been attributed to
familiarity resulting from prerecognition processing of spoken stimuli. As a
listener hears/traens/, "transparent" may be activated as a potential solution.
In the present experiments, we minimized contributions of postrecognition
processing to this phenomenon by presenting a semantically unrelated test word
(transportation) that was also expected to be activated during prerecognition
stages of processing. The results indicated that false recognition was increased
for words presumed to be activated only during prerecognition processing.
Remember (R) and know (K) judgments revealed that the majority of studied words
were R, and the majority of false recognitions were K. The lowest proportion of R
judgments occurred for test words that were not activated during postrecognition
processing (e.g., transportation and control words).
PMID- 10780030
TI - The effects of a levels-of-processing manipulation on false recall.
AB - The present study attempted to determine the effect of a levels-of-processing
manipulation on the incidence of false recall. In Experiment 1, participants
engaged in either a vowel counting task or a concrete/abstract rating task; in
Experiment 2, participants engaged in either a vowel counting task or a category
sorting task. Results of both experiments demonstrated that participants who
engaged in a deeper level of processing (i.e., concrete/abstract ratings or
category sorting) recalled significantly more list items and critical lures. The
present findings thus lend support to theories that attribute false memories to
activation-based factors.
PMID- 10780031
TI - Much ado about mirrors.
AB - Takano (1998) has suggested four different kinds of reversal to explain why
mirrors reverse left and right and not up and down or back and front. In fact,
mirrors perform only one kind of reversal: They simply reverse about their own
planes, and reflection about one plane is equivalent to reflection about any
other, plus a translocation and rotation. The reflection of an object is termed
its enantiomorph. Perception of the enantiomorphic relation normally requires an
act, either physical or mental, of alignment. In deciding whether two objects are
enantiomorphs, there is a tendency to align them so that the reversal is about
the axis of least asymmetry. But in deciding whether a single object is one of
two possible enantiomorphic forms, people generally rotate it to some canonical
orientation. In the case of objects with defined top-bottom, back-front, and left
right axes, the canonical orientation is determined by the top-bottom and back
front axes, leaving the left-right axis to carry the reversal. The main reason
for this, I suggest, is that the top-bottom and back-front axes have functional
priority, and the left-right axis cannot be defined until top-bottom and back
front are established. This means that the latter two axes have priority in
establishing the canonical orientation. The left-right axis is usually, but not
always, the axis of least asymmetry.
PMID- 10780033
TI - Conflict of interest and respiratory care.
PMID- 10780032
TI - Mirror reversal simply explained without recourse to psychological processes.
AB - This paper proposes a simple and definitive solution to the mirror reversal
problem, "Why does a mirror reverse left and right but not up and down?" The
solution is given by combining the inversion caused by the optical process of
mirroring and the definition of the left-right axis. Thus the left-right reversal
of mirror images essentially does not involve psychological processes, in
contrast to the multiprocess hypothesis recently proposed by Takano.
PMID- 10780034
TI - Effects of respiratory impedance on the performance of bi-level pressure
ventilators.
AB - BACKGROUND: Noninvasive positive pressure ventilation (NPPV) has been studied in
several settings and shown to reduce patient morbidity associated with
endotracheal intubation. Intolerance to NPPV has been estimated at 25-33%, a
substantial proportion of attempts to ventilate noninvasively. Bi-level pressure
ventilators (BPVs) have been designed for NPPV, yet their response to changes in
respiratory impedance has not been extensively evaluated. To determine responses
of BPVs to changing impedance conditions, we tested 4 BPVs to evaluate the
potential for intolerance. We also developed a mathematical model for BPV
performance that accounted for impedance conditions, leak, pressure settings, and
inspiratory flow cutoff level. METHODS: Four BPV models at the same settings were
challenged to ventilate a triggered test lung under a range of impedance
conditions while measuring tidal volume (VT) and intrinsic positive end
expiratory pressure (auto-PEEP). The model was used to predict VT and auto-PEEP
under normal, restrictive, and obstructive conditions. RESULTS: The BPV models
tested delivered VT in a similar manner. VT decreased with decreased compliance
and increased resistance. Auto-PEEP developed with increased resistance and
compliance. The model predicted a VT delivery dependent on inspiratory flow
cutoff level. For the obstructive condition, the model predicts an optimal VT
delivery within a specific inspiratory flow cutoff range that becomes narrower
with increasing resistance. CONCLUSIONS: VT delivery and auto-PEEP generated by
BPVs are highly dependent on the prevailing impedance condition. Though there are
differences between BPV models, generally, performance was similar between the
models tested. This report suggests that knowledge of both respiratory system
impedance and the performance of the BPV in use are required to attend to
inadequate VT delivery and auto-PEEP generation. Furthermore, the model predicts
a relatively narrow range for inspiratory flow cutoff that provides adequate
ventilatory support without causing hyperinflation in patients with obstructive
conditions.
PMID- 10780035
TI - Reevaluation of continuous oxygen therapy after initial prescription in patients
with chronic obstructive pulmonary disease.
AB - BACKGROUND: Long-term oxygen therapy improves survival and quality of life in
hypoxemic patients with chronic obstructive pulmonary disease (COPD). The need
for long-term oxygen therapy should be determined when patients are medically
stable. The Third Oxygen Consensus Conference recommended reevaluating patients 1
3 months after continuous oxygen therapy (COT) is initiated, if initiated when
the patient is medically unstable. METHODS: A cross-sectional study was performed
to examine how often orders for COT are reevaluated pursuant to the guidelines
promulgated by the Third Oxygen Therapy Consensus Conference, and to assess the
impact that following these guidelines would have on the cost of COT. RESULTS: Of
226 patients prescribed home oxygen therapy, 92 had COPD as a primary diagnosis
and 57 were prescribed COT. Only 19 (35%) of 55 patients who returned to the
clinics were appropriately reevaluated. The rate of appropriate reevaluation was
significantly higher among pulmonary physicians than among primary care
physicians (65% vs 17%; odds ratio: 9.0; 95% confidence interval: 2.5-32). Of 19
patients who were appropriately reevaluated, 11 (58%) were discontinued from COT.
The patients who were discontinued from COT had a significantly higher percent of
predicted forced expiratory volume in the first second than those who were not
(34 +/- 8.6% vs 25 +/- 8.8%; p = 0.04). CONCLUSIONS: In our study, most patients
were clinically unstable when COT was prescribed, and a significant number of
patients remained on COT without reevaluation. Up to 60% of those patients could
potentially be discontinued from COT if appropriately reevaluated. Referring a
patient initiated on COT to a pulmonary specialist for the proper use of oxygen
is strongly recommended. Reevaluating such patients in a timely fashion and
discontinuing unnecessary oxygen concentrators could possibly save $106-153
million per year in the United States.
PMID- 10780036
TI - Spirometry in normal subjects in sitting, prone, and supine positions.
AB - OBJECTIVE: Determine whether pulmonary function testing is affected by patient
positioning. METHODS: In a descriptive study with measurements made in a
sequential but randomized order at a university-based pulmonary function
laboratory, 20 healthy men, ages 18-50 years, were evaluated with spirometric
assessment of forced vital capacity (FVC), forced expiratory volume in the first
second (FEV1), and maximum voluntary ventilation (MVV) in the sitting, supine,
and prone positions. Subjects were excluded for body mass index (BMI) > 30 kg/m2
or abnormal baseline spirometry. RESULTS: Comparing sitting to supine and prone
positions, there was a statistically significant decline in the spirometry values
(reported as percent of predicted normal +/- standard error of the mean). FVC was
102% +/- 4% while sitting, 95% +/- 4% while supine, and 94% +/- 4% while prone.
FEV1 was 104% +/- 3% while sitting, 96% +/- 3% while supine, and 94% +/- 3% while
prone. MVV was 115% +/- 4% while sitting, 102% +/- 4% while supine, and 97% +/-
3% prone. CONCLUSION: In healthy men with BMI < 30 kg/m2, changing from the
sitting to supine or prone position results in statistically significant change
in respiratory pattern. However, all spirometry values in each position were
normal by American Thoracic Society definitions.
PMID- 10780037
TI - Persistent left superior vena cava: case report and literature review.
AB - A persistent left superior vena cava (PLSVC) is the most common thoracic venous
anomaly. It is a persistent remnant of a vessel that is present as a counterpart
of normal right-sided superior vena cava (SVC) in early embryological development
but normally disappears later. Although it can be easily diagnosed by the
characteristic chest radiographic appearance of a pulmonary artery catheter (PAC)
passed through it after being inserted into the left subclavian or jugular vein,
its diagnosis is usually missed by the presence of normal (right) SVC and the
passage of the catheter on the right side. Its diagnosis can be confirmed by many
noninvasive and invasive tests, or it is incidentally diagnosed at thoracic
surgery or autopsy. If it is not associated with other congenital cardiac
anomalies, it is usually asymptomatic and hemodynamically insignificant. However,
PLSVC has important clinical implications in certain situations. In this article,
we describe a patient with bilateral SVC (a normal right SVC and a PLSVC)
identified by a PAC in the PLSVC and the pacemaker wires in the right SVC. In
addition, we review the literature on prevalence, embryological development,
diagnosis, and clinical implications of PLSVC.
PMID- 10780039
TI - Are digital distance learners learning or just distant?
PMID- 10780038
TI - 1999 Donald F Egan Scientific Lecture. Weaning from mechanical ventilation: what
have we learned?
PMID- 10780040
TI - Guidelines for nasal provocations with aspects on nasal patency, airflow, and
airflow resistance. International Committee on Objective Assessment of the Nasal
Airways, International Rhinologic Society.
AB - Under the auspices of the International Rhinologic Society (IRS) there is an
'International Committee on Objective Assessment of the Nasal Airways'. In 1984
Rhinology published the Committee's recommendations regarding rhinomanometry
(Clement, 1984). During the last Congresses of the European Rhinologic Society
(ERS) a subcommittee within that committee has discussed nasal provocations and
the value of measuring nasal patency, airflow and airflow resistance to evaluate
such provocations. The following is an effort to a consensus of indications and
techniques for nasal provocation and to a critical analysis of methods to measure
the effects. Only the most known methods will be discussed, i.e. acoustic
rhinometry, rhinostereometry, nasal peak airflow and rhinomanometry with its
different techniques. For graded responses after provocations the use of such
methods is of clinical value only in combination with scores from symptoms such
as sneezes and secretion, as allergic rhinitis symptoms consist of obstruction,
sneezing, itching and concomitant symptoms of the neighbouring organs. For
research all methods can be recommended to be used and their respective value is
depending on the specific scientific purposes.
PMID- 10780041
TI - The nasal valves: changes in anatomy and physiology in normal subjects.
AB - There is confusion in the literature concerning the physiology and pathology of
the nasal valve, and some debate as to whether there is one valve or two. In an
attempt to clarify these uncertainties we have measured nasal function by
assessing nasal minimum cross-sectional area, inspiratory resistance and peak
inspiratory flow under baseline conditions and after the application of a topical
vasoconstrictor. These measurements were then repeated following the application
of external and internal nasal splints. Whatever test was employed the results
showed that vasoconstriction tended to be the most potent stimulus which changed
nasal function producing significant expansion of the minimum cross-sectional
area, a decrease in inspiratory resistance and an increase in peak inspiratory
flow. External splints also increased the minimal cross sectional area but they
had no effect on inspiratory resistance or on the tendency of the vestibular rim
to collapse at high inspiratory flow rates. The tendency for lower lateral
cartilage collapse was, however, prevented by internal splintage using alar
dilators. The results of this study suggest that there is an internal valve at
the nasal isthmus where the principal alterations in airway patency follow
changes in mucosal congestion, and a mobile external valve where airflow is
limited by the tendency of the alar cartilages to collapse. These should be
considered as separate entities with differing pathophysiology and these
differences should be taken into account when treating patients with airway
obstruction due to pathology at these sites.
PMID- 10780042
TI - A new method for endoscopic evaluation in rhinology: videocapture.
AB - The aim of the study is to analyze a new method for the elaboration of endoscopic
images of the nasal cavity called "videocapture" and to compare the data from
this technique with the ones obtained with anterior active rhinomanometry.
Videocapture is based on a software program able to process endoscopic images, to
file them and to measure perimeter and area of the structures inside the images
recorded. We enrolled 27 patients with inferior turbinate hypertrophy and we
performed, before and after nasal decongestion test, anterior active
rhinomanometry, acoustic rhinometry, videocapture to compare the results obtained
with these different techniques. The results we got confirm in a statistically
significant way, the reliability of videocapture and its easy way of application.
PMID- 10780043
TI - Value of radiologic imaging and computer assisted surgery in surgical decisions
of the anterior skull base lesions.
AB - The role of radiologic imaging in surgical decision making of anterior skull base
lesions has been found to be critical in the endoscopic surgical management of
these lesions. The non-invasive radiologic imaging may include the use of CT
scans, MRI scans, MRA scans and their subtraction technique. The imaging offers
an understanding of the vascularity of the lesion, the relationship to the nearby
neurovascular structures and the type of tissue density of these lesions. The
addition of image guided applications offers one a sagittal reconstruction and a
3-D imaging capacity which has immensely improved the accuracy and precision in
endoscopic surgical applications in these areas.
PMID- 10780044
TI - Eosinophil count in nasal secretions of subjects with and without nasal symptoms.
AB - The aim of this paper, based on a cross-sectional study of 129 patients with
nonallergic chronic nasal symptoms and 40 healthy controls, was to examine the
leucocyte differential count in nasal secretions as a diagnostic test. Nasal
secretions were collected using preweighed suction glass canulas under controlled
conditions (-100Pa, 30 sec). Leucocyte and differential counts were performed
using a Thoma hemocytometer and on cytospin slides after May-Grunwald-Giemsa
staining. The percentage of eosinophils (Eo) was significantly higher in patients
(mean +/- SEM: 15.1 +/- 2.3%) than in controls (5 +/- 2.6%) (p < 0.04).
Comparison of the frequency distribution of the percentage of Eo in patients and
controls clearly showed a subgroup of patients presenting with nasal secretion
hypereosinophilia, and allowed us to set the positivity criterion at Eo = 20%.
Diurnal variations in Eo count in 11 controls and 8 patients confirmed the value
of the cutoff point. In 28 patients with nasal polyposis who underwent surgery, a
correlation was found between secretion and tissue eosinophelia (r = 0.58, p =
0.001). Patients with nasal secretion hypereosinophilia had no more leucocytes in
their secretions than healthy controls, the increase in eosinophils being
balanced by a decrease in neutrophils. In patients without hypereosinophilia, the
number of leucocytes per milligram of secretion was four times higher (8672 +/-
2521) than in the controls (2020 +/- 823) (p = 0.06) (cut-off point = 2500
leu/mg). These data show that the nasal cytogram can be modified either in
qualitative or quantitative way, probably depending on the underlying
inflammatory process.
PMID- 10780045
TI - The prevalence and significance of incidental paranasal sinus abnormalities on
MRI.
AB - Morphological changes in the paranasal sinuses are regularly noted on MRI, but
little is known about the incidence and significance of these changes in the
general population. The purpose of this study was 1) to classify the
morphological changes in the paranasal sinuses seen on MRI 2) to investigate the
prevalence, site and type of paranasal abnormalities and 3) to evaluate the
significance of the findings by relating them to the presence of sinusitis
symptoms, allergy, smoking habits and seasonal variations. In a one-year period,
404 patients referred to MRI for suspected intracranial neurological pathology
were prospectively investigated. Before undergoing the scan the patients
completed a questionnaire. The observed morphological conditions were classified
so that mucous thickening < 5 mm was recorded as normal; > or = 5 mm, total sinus
opacification or fluid and polyps as pathological. According to this
classification 31.7% of the patients had pathological findings in the sinuses. A
significantly higher incidence was found in the winter period and in patients
with symptoms associated to sinusitis. "Blocked nose" was the only symptom
occurring significantly more often in patients with pathological changes. There
was no significant relationship between paranasal sinus abnormalities and sex,
age, allergy, smoking habits, previous events of sinusitis or frequent events of
colds. Criteria for pathological MRI findings in the paranasal sinuses are
desirable and might improve the basis for a decision on the correct medical or
surgical treatment.
PMID- 10780046
TI - Congenital nasal pyriform aperture stenosis in newborn: report on three cases.
AB - Congenital nasal pyriform aperture stenosis (CNPAS) is recognized as a cause of
nasal airway obstruction in the newborn. The nasal pyriform aperture is narrowed
by a bony overgrowth of the nasal process of the maxilla. The CNPAS may occur as
an isolated congenital defect or in combination with other abnormalities. Three
cases of CNPAS are reported with special attention to the clinical presentation
and to the management recommendation prior to surgery. Surgical repair was
performed for all these three highly symptomatic patients using a sublabial
approach for drilling the nasal process in order to obtain a wider nasal
vestibular patency. All of them were equipped with bilateral nasal stenting.
PMID- 10780047
TI - Unilateral blindness in a child with acute sinusitis.
AB - Orbital infection in association with sinusitis is an emergency. It may cause
visual disturbances, and in rare cases even permanent blindness by affecting the
optic nerve. We report an unusual case of acute sinusitis that was complicated by
irreversible visual loss in a young patient. As there is increasing evidence that
respiratory viruses play an important role in the pathogenesis of acute community
acquired sinusitis and spontaneous healing with only symptomatic treatment is
common, the use of antibiotics in the treatment of acute sinusitis may not be
needed in all cases. If the general policy to use antibiotics in acute sinusitis
will be changed to more restrained and expectant, we have to be even more aware
of these nowadays rare complications.
PMID- 10780048
TI - Chondrosarcoma of the nasal septum.
AB - Chondrosarcoma of the nasal septum is a rather uncommon tumour. Therefore, only
limited numbers of cases have been described in the literature. This paper
reveals one more case observed at the ORL department of Dicle University. In the
present case, by using a transnasal and transpalatal approach, total resection of
the tumour was performed in conjunction with postoperative radiotherapy.
PMID- 10780049
TI - Short- and long-term effects of a 12-week intensive functional restoration
programme in individuals work-disabled by chronic spinal pain.
AB - The short- and long-term effects of a 12-week intensive functional restoration
programme for 153 participants with chronic spinal pain are reported. The average
patient sick leave before the programme started was about one year. At the 2-year
follow-up, 69% of the participants reported in telephone interviews that they
were working either part time or full time. Aerobic fitness, trunk muscle
strength and lifting capacity increased during the programme. In the non-working
groups, pain was rated higher and quality of life lower than in the working
groups at the 1- and 2-year follow-ups. For the women's return to job, the best
predictors were the time since the original pain onset and the achieved capacity
to lift from waist to shoulder level. For the men's return to job, the best
predictors were the initial work situation, the time since the original pain
onset, the oxygen uptake and the lumbar lifting capacity at the end of the
programme. The results of this non-controlled rehabilitation programme, both
short- and long-term, support earlier findings that intensive rehabilitation can
increase physical capacity and general well-being.
PMID- 10780050
TI - Professional phagocytes: predators and prey of microorganisms.
AB - Phagocytosis is an ancient cellular function. However, professional phagocytes
have evolved only in higher organisms, where they play an important role in host
defence. Professional phagocytes are capable of engulfing relatively large
microorganisms and killing them with a combination of various microbicidal
systems. Crucial killing mechanisms of phagocytes include superoxide generation
by phagocyte NADPH oxidase and release of microbicidal proteins through
exocytosis of performed granules. Phagocytes are also able to interfere with
microbial growth through alteration of the phagosomal ionic environment
(acidification, iron depletion). While the microbicidal mechanisms of phagocytes
are extremely efficient and capable of killing most microorganisms, pathogenic
microorganisms have developed mechanisms to resist phagocytes. Microorganisms
capable of surviving within phagocytes are rare, but represent very successful
pathogens, such as Mycobacterium tuberculosis. Other pathogens, such as S.
aureus, have developed strategies to evade phagocytosis. How microorganisms are
phagocytosed and killed, and why certain pathogens resist these mechanisms, are
crucial questions for an understanding of the pathogenesis of infectious diseases
and the development of innovative treatment approaches.
PMID- 10780051
TI - Antiviral therapy: current options and challenges.
AB - This article reviews current options and concepts for drug treatment of viral
infections with the exception of human immunodeficiency virus infection. Advances
in antiviral drug development and in rapid diagnostic methods have resulted in
efficient management strategies, particularly for infections due to herpes
simplex virus, varicella-zoster virus, cytomegalovirus, influenza A and B
viruses, and chronic hepatitis B and C. Newer antiviral agents, such as
valaciclovir and famciclovir, have a high oral bioavailability which permits less
frequent intake and avoidance of intravenous therapy in many cases. As an
alternative to subcutaneous interferon-alpha (IFN-alpha) treatment, oral
lamivudine is now approved for therapy of chronic hepatitis B. The addition of
oral ribavirin to IFN-alpha treatment has been shown to be superior to IFN-alpha
alone for therapy of chronic hepatitis C. By contrast to amantadine,
neuraminidase inhibitors such as zanamivir or oseltamivir (GS4104) have activity
against both influenza A and B viruses and are well tolerated. First results of
controlled trials with these agents are discussed. The emergence of herpes virus
resistance to antiviral drugs is of concern, and validation of alternative
treatment for patients with documented resistance is required. Future
investigations may also help to clarify the therapeutic role of novel antiviral
drugs and formulations, such as the oral prodrug of cidofovir, valganciclovir,
compounds 1263W94 and Bay 38-4766, and pleconaril.
PMID- 10780052
TI - News in autoimmune disease.
AB - The diversity of strategies reflects as much the lack of ideal treatments as it
does the imagination of the investigators. Many aspects such as manipulation of
apoptosis and extracorporeal removal of autoantibodies have been omitted due to
space restrictions. Although most successful treatment strategies have been based
on proven basic research principles, most require well performed, prospective,
randomised clinical trials before optimistic anecdotes translate to clinical
practice. We must not forget the aim of improving quality of life for our
patients, and not just improvement of immunological laboratory parameters.
PMID- 10780053
TI - Does infection control control infections?
AB - Compelling data exist for the return on investment of infection control
activities. Such information is important in the era of managed care where cost
containment and accountability are mandated.
PMID- 10780054
TI - [The hospitalized patient with fever and mental status changes].
AB - The case is discussed of a 74-year-old patient hospitalised with acute colitis,
who newly developed headache, fever, and mental status changes on the 14th day
after admission. The course of the disease was characterised by rapid progression
with loss of consciousness and the development of extensive brain oedema, despite
broad-spectrum antibiotic therapy. The patient died on the 17th of
hospitalisation.
PMID- 10780055
TI - [Pruritus with unusual cutaneous lesions].
PMID- 10780056
TI - [Single and double high-dose chemotherapy with autologous stem cell
transplantation in children with advanced solid tumors: first experiences].
AB - The disease-free survival of children with malignant disorders has increased
impressively over the last three decades due to better understanding of tumour
biology and the resultant improvement in diagnosis and therapy. Children with
advanced and relapsed solid tumours, such as brain tumour, alveolar
rhabdomyosarcoma, Ewing's sarcoma, or neuroblastoma, have not benefited from this
progress. The concept of myeloablative high-dose chemotherapy (HDT) is based on
the observation that certain cytostatic drugs have a steep linear dose-response
curve, and thus escalating the dose may increase the tumour cell kill. The
interest in HDT intensified when autologous stem cells mobilised from the
peripheral blood became available, in view of the possibility of increasing the
cell dose, which correlates directly with the time period of haematopoietic
recovery and thus reduces therapy-associated toxicity. The aim of the study was
to evaluate the feasibility of single or double HDT by autologous peripheral
blood stem cell transplantation (PBSCT) after each cycle in children, and to
obtain pilot data for future prospective clinical trials. 11 children aged
between 2.8 and 17.2 years with brain tumours, soft tissue sarcomas, germ-cell
tumours and neuroblastomas were analysed over a 2-year-period. 7 of the 11
children are in complete remission 2+ and 24+ months after HDT, 3 died of
progressive disease and one child died of therapy-associated complications. The
median hospital stay was 29.5 (22-104) days. An absolute neutrophil granulocyte
count of 0.5 x 10(9)/l was achieved after a median stay of 11 days and a platelet
count of > 20 x 10(9)/l independent of platelet transfusions was achieved after
11 days. Painful stomatitis leading to total parenteral nutrition (9 children)
and intravenous morphine therapy (6 children) was the most serious toxicity.
Single or double HDT with autologous PBSCT after each cycle is feasible in
children and offers basic data for conducting phase III paediatric clinical
studies.
PMID- 10780057
TI - [Quality of dispensation of prescription medication from the patients' point of
view].
AB - A cross-sectional survey investigated quality relevant aspects of the most common
distribution channels (pharmacies, self-dispensing physicians) for prescription
drugs in Switzerland. A self-administered questionnaire focusing on consumers'
behaviour, perception and priorities regarding the process of dispensation of
prescriptive medication was mailed to a random sample of 3000 patients, aged 18
years or older, with regular intake of prescriptive medication. Chi-square
analysis was performed on 1058 responses. 60% of the respondents received their
medication mainly or exclusively from pharmacies and 40% from self-dispensing
physicians. In German-speaking Switzerland 53% of participants received their
prescription drugs exclusively or mainly from self-dispensing physicians,
compared to only 10% in the French-speaking area (p = 0.00). This distribution
confirms the existing differences in regulation of self-dispensation in these
regions. Most of the patients took 2-4 prescriptive drugs a day. The French Swiss
received slightly more prescriptive medication than the German Swiss (p = 0.05).
45% of the participants, especially women and people using a pharmacy, reported
additional, usually occasional over-the-counter medication. Provision of
technical information (41%), friendliness (19%), and the availability of drugs
(19%) were valued most important when receiving prescription drugs and 96% of the
participants were satisfied with the service. In consequence, the participants
were strongly bound to their source of drug supply. Some 80% received
instructions for use there. However, only half were informed about the purpose of
the medication, drugs' side effects, or possible drug interactions. Physicians
provided such information more often than pharmacy staff. This observation may be
attributable to the double role played by the self-dispensers, who provide
medical care and at the same time hand out the drug. In conclusion, patients'
satisfaction is achieved equally by both medication channels. However, there is a
need to improve counselling to ensure excellence in the supply of drugs.
PMID- 10780058
TI - [Mechanisms of neuroinvasion by prions: molecular principles and present state of
research].
AB - The prion was defined by Stanley Prusiner as the infectious agent that causes
transmissible spongiform encephalopathies and equated with the prion protein
PrPSc. Its cognate gene, Prnp, was identified by Charles Weissmann in Zurich, and
shown to encode the host protein PrPC. Since the latter discovery, transgenic
mice have contributed many important insights to the field of prion biology,
including an understanding of the molecular basis of the species barrier for
prions. By disrupting the Prnp gene, it was shown that an organism that lacks
PrPC is resistant to infection by prions. Introduction of mutant PrP genes into
PrP-deficient mice was used to investigate the structure-activity relationship of
the PrP gene with regard to scrapie susceptibility. Ectopic expression of PrP in
Prnp-knockout mice provided a useful strategy for the identification of host
cells competent for prion replication. Finally, the availability of Prnp-knockout
mice and transgenic mice overexpressing PrP allows selective reconstitution
experiments aimed at expressing PrP in neurografts or in specific populations of
hemato- and lymphopoietic cells. The latter studies have allowed us to clarify
some of the mechanisms of prion spread and disease pathogenesis.
PMID- 10780059
TI - [Allergy to house dust mites].
AB - The prevalence of atopic disease in Switzerland is 15-20%. About 30% of these
patients have perennial symptoms and a substantial proportion are allergic to
house-dust mite proteins. If absolute air humidity is lower than 7.0 g water per
kg air, house-dust mites will not proliferate. This is why the occurrence of
house-dust mites varies between different regions. About half of the patients
with allergy to house-dust mites complain of rhinitis, a quarter of asthma and a
quarter of asthma and rhinitis. The diagnosis is usually by history, skin prick
tests and if necessary provocation. Therapy includes allergen avoidance
(reduction of air humidity in dwellings by ventilation, encasing of mattresses
and bedding), medication (mainly topical corticosteroids) and specific
immunotherapy.
PMID- 10780060
TI - [Abdominal tumor].
PMID- 10780061
TI - [Value of positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) in
early detection of residual tumor in oro-pharyngeal-laryngeal carcinoma].
AB - OBJECTIVE: To evaluate and compare the performances of FDG-PET imaging, MRI and
clinical examination in the detection of residual tumour 3 months after treatment
of patients with head and neck squamous cell carcinoma. PATIENTS: A consecutive
sample of 50 patients with squamous cell carcinoma of the oral cavity,
oropharynx, hypopharynx or larynx, or a cervical lymph node metastasis from an
unknown primary site excluding T1 lip and T1 vocal cord tumours. METHODS:
Treatment outcome was assessed after 3 months by clinical examination, MRI, and
FDG-PET scan. Sensitivity, specificity and accuracy were calculated relative to
proven biopsy of residual tumour or a clinical follow-up of 4 months. RESULTS:
Residual cancer was confirmed in 8 patients (16%), while the clinical follow-up
was unsuspicious in the remaining 42 patients. PET-FDG had a sensitivity of 100%
as compared to MRI (88%) and clinical examination (63%). Specificity was higher
for clinical examination (90%), intermediate for MRI (83%) and lowest for PET-FDG
(74%). CONCLUSIONS: This study finds very high sensitivity for PET-FDG in the
detection of residual tumour. However, its lower specificity, lack of anatomical
resolution, and high cost, require further studies to determine its role in
routine screening.
PMID- 10780062
TI - [Follow-up after histologically verified radical resection of early cancers of
the mouth cavity: results of a prospective multicenter study].
AB - INTRODUCTION: Early stage oral cavity carcinoma is curable in most cases. This
study follows the course of early stage squamous cell carcinoma of the oral
cavity after radical surgical resection, in order to assess the necessity of
further treatment modalities. MATERIAL AND METHODS: In a prospective multicentric
study, 110 patients with T1-T2 and N0-N1 (without capsular invasion) squamous
cell carcinoma of the oral cavity were enrolled. All patients were treated
exclusively by surgical resection with histopathologically proven negative
margins. RESULTS: Among 96 patients (14 excluded because of positive margins),
followed-up for 3 years, 18 presented a local or regional recurrence. In 12 of
these 18 loco-regional control was reestablished by second treatment. Overall,
the 4-year disease-specific survival probability was 94%. Patients treated
initially by selective neck dissection had significantly lower recurrence rates
than those without neck surgery. CONCLUSION: Early (T1-2, N0-1) squamous cell
carcinoma of the oral cavity is adequately treated by surgery alone. The surgical
procedure should include margin-free resection of the primary combined with
selective neck dissection. Systematic postoperative radiotherapy does not appear
necessary. Neck dissection is advocated in N0 patients as well.
PMID- 10780063
TI - [Value of panendoscopy in assessment of mouth cavity, pharyngeal and laryngeal
cancers].
AB - The concept of multiple squamous cell carcinoma in the region of the upper
aerodigestive tract was first described over 100 years ago by Billroth. The aim
of our study was to assess the incidence of synchronous and metachronous second
primary tumours and refine the role of panendoscopy in diagnosing them. The
charts of 358 patients presenting for initial treatment of primary squamous cell
carcinoma of the upper aerodigestive tract between January 1990 and December 1995
were reviewed. The incidence of second primary tumours was 16.2%, 6.4% being
synchronous and 9.8% metachronous. In only 3.1% of all patients was a synchronous
tumour clinically silent and only revealed by panendoscopy. Synchronous tumours
were most likely to be located in the oral cavity, pharynx or larynx (61%),
whereas metachronous second primary tumours were most likely to be located in the
lung (57%). Though the incidence of synchronous second primary tumours revealed
by routine panendoscopy is low (3%), we still recommend this investigation
because it is often necessary for exact assessment of the first primary tumour.
Further, it is ideal for training in the use of rigid endoscopy. In our opinion
panendoscopy involves minimal time, cost and morbidity.
PMID- 10780064
TI - [Treatment of laryngeal cancer: cordectomy or crico-hyoido-epiglottopexy versus
radiotherapy].
AB - INTRODUCTION: Both radiotherapy and endoscopic or open functional surgery are
recognised treatments for laryngeal cancer stage I and II. A comparison between
two groups of patients treated with either modality may clarify the indications
for both treatments. METHODS: Over a period of 13 years two separate series of
patients were treated for laryngeal cancer (stage I and II) by either surgery (n
= 72) or radiotherapy (n = 81). We have analysed and compared the two groups.
RESULTS: Statistical analyses show a better local control among patients treated
with surgery, when the anterior commissure was involved (p < 0.01) or with
extension of the tumour (T2). However, long-term survivals were not significantly
different in the two groups. As postradiation recurrence was diagnosed at an
early stage, salvage (requiring total laryngectomy in many cases) was efficient
but contributed to an appreciable difference in the long-term laryngeal
preservation rate between the two groups (91% after radiotherapy and 99% after
surgery). CONCLUSION: The treatment of laryngeal cancer must always compromise
between oncological efficiency and functional preservation. With anterior
commissure involvement (T1b) or more extensive disease (T2), surgery appears to
be better. Therefore, preservation of perfect laryngeal function should be
subordinate to oncological safety.
PMID- 10780065
TI - [When is laryngectomy indicated in hypopharyngeal carcinoma?].
AB - INTRODUCTION: We studied the histories of 121 patients with hypopharyngeal
carcinoma treated at our clinic from 1990-1998. From 1990-1993 all patients with
curable hypopharyngeal carcinoma were treated by surgery. Radiotherapy was used
for those in whom surgery was impossible or who refused laryngectomy. In 1994 we
changed our therapy and only patients in whom the voice could be preserved were
treated surgically. All others received radiotherapy as primary treatment. The
goal of this study was to ascertain whether and how this shift in therapy was
influenced by T and N stage. METHODS: From 1990-1993, 57 patients with
hypopharyngeal carcinoma were registered at our clinic. Surgery was performed in
32, 16 received radiotherapy and 9 only palliative treatment. During this time
there was no difference in diseased specific survival between the radiotherapy
and surgical groups. Therapy was therefore changed in 1994 to preserve voice
function. From 1994-1998, 64 patients were diagnosed. Only 10 were treated
surgically. 40 received radiotherapy and 14 no curative therapy. Age, N and T
stage were comparable in both groups. To show differences we performed Kaplan
Meier survival rates for both groups and for the N and T stage of patients
undergoing surgery or radiotherapy respectively. RESULTS: 3-year survival was 68%
in patients treated from 1990-1993 and 38% from 1994-1998. The difference was
statistically significant (p-value 0.02). Survival for nodal stages 0 and 1 was
much better in patients undergoing surgery than those receiving radiotherapy.
Multivariant analysis was highly significant. T-category showed no tendency for
either treatment modality. DISCUSSION: After a switch in the treatment of
hypopharyngeal carcinoma in 1994 there was a significant change in survival. For
patients with nodal stage 0 and 1 surgery brought much better survival. We
conclude that surgery should be the primary treatment for all patients in these
small nodal stages, even if total laryngectomy is necessary.
PMID- 10780066
TI - [Salvage surgery in laryngeal and hypopharyngeal carcinoma].
AB - INTRODUCTION: The aim of this study was to analyse survival and complications in
patients undergoing surgery for squamous cell carcinoma of the larynx and
hypopharynx as a salvage procedure for recurrent tumours after radiotherapy.
METHODS: Between January 1990 and December 1998, 166 patients with previously
untreated squamous cell carcinoma of the larynx and hypopharynx were primarily
treated by radiotherapy. Local failure occurred in 77 patients (46%). 57 (34%)
underwent salvage surgery. RESULTS: 5-year survival for the 42 patients with
carcinoma of the larynx was 60% and for the 15 patients with carcinoma of the
hypopharynx 20%. The overall rate of postsurgical complications was 33% in
patients with laryngeal and 47% in patients with hypopharyngeal cancer.
DISCUSSION: There are few data in the literature regarding the clinical outcome
in patients whose tumours are not controlled by initial radiotherapy. Our results
indicate that only in carefully selected cases is salvage surgery successful in
treating radiation failure in hypopharyngeal cancer. In patients with carcinoma
of the larynx salvage surgery is successful and the rate of postoperative
complications acceptable.
PMID- 10780067
TI - [Quality of life after treatment of laryngeal carcinoma: surgery versus
radiotherapy].
AB - Radiotherapy and surgery for laryngeal cancer achieve comparable results in
patient survival. Therefore, the expected quality of life is increasingly
influencing the choice of treatment. The aim of this study was to compare the
quality of life of patients after surgery or radiotherapy for laryngeal
carcinoma. To evaluate quality of life, we used the validated European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire
Core 30 (EORTC QLQ-C30) and the EORTC Head and Neck module (EORTC QLQ-H&N35). 65
patients who were treated with either radiotherapy or surgery for laryngeal
cancer between January 1990 and December 1995, and who were alive and free of
tumour in January 1999, were included in this study. In the first group with
small tumours (T1/T2), 40 patients were treated by CO2-laser surgery and 16 by
primary radiotherapy. In the second group with more advanced tumours (T3/T4), 5
patients underwent total laryngectomy and 4 primary radiotherapy. In the first
group there was good global quality of life with no significant difference
between the two treatment modalities. Surgically treated patients scored
significantly better than the irradiated patients in questions about swallowing
of solid food, xerostomia and dental problems. No other significant differences
were found: hoarseness in particular was rated equally after both treatments. In
the second group there was also good global quality of life with no significant
difference between the two treatment modalities. The laryngectomized patients
scored equally on questions about voice function, talking on the phone and social
behaviour. As far as quality of life is concerned we can recommend both treatment
modalities for patients with laryngeal cancer of all stages.
PMID- 10780068
TI - [Skin and mucous membrane reactions during and after radiotherapy].
AB - The temporary acute reactions during radiotherapy are a burden for the patient.
These reactions are due to a depletion of stem cells and depend on the single
dose, the total dose and the irradiated volume. The WHO describes the acute
changes in a graded scale from 0 to IV. A knowledge of the course of these events
helps the otolaryngologist to inform patients competently, calm their fears and
give support during treatment. Efficacious measures to alleviate symptoms are
presented.
PMID- 10780069
TI - [Reconstruction of the anterior mouth floor by surgical flap microanastomosis:
oncologic and functional results].
AB - INTRODUCTION: The purpose of this retrospective study was to evaluate oncological
and functional results after reconstruction of the anterior floor of the mouth
using free flaps. METHODS: From 1992 to 1998, 30 patients with squamous cell
carcinoma of the anterior floor of the mouth underwent surgical excision and
primary reconstruction with either free forearm- or bone-composed flaps.
Functional assessment included evaluation by the Karnofsky scale, Performance
Status Scale for Head and Neck Cancer (PSS-HNC), articulation test and
videofluoroscopic examination. RESULTS: 16 patients underwent reconstruction with
a free forearm flap, 13 with an iliac crest flap and 1 with a fibula flap. The
most serious local complication was partial flap necrosis in two cases. Local
control was 90% at 24 months and the specific survival rate was 92% at five
years. Functional evaluation was performed on 19 patients: PSS-HNC median score
for diet was 70 (range 50-100), the score for speech was 70 (range 50-100) and
the score for "eating in public" was 65 (range 25-100). Patients with a major
mobile tongue resection had a lower score compared to patients with minor or no
mobile tongue resection. Videofluoroscopy showed swallowing alterations following
large resections of soft tissues. DISCUSSION: Our study confirms that wide
resection of mobile tongue is associated decreased rehabilitation quality.
Mandibulectomy does not influence rehabilitation.
PMID- 10780070
TI - [Impact of diagnosis and treatment of early stage secondary tumors on outcome for
the oncologic ORL patient].
AB - OBJECTIVE: To study the incidence, location and stage of second primary tumours
in patients with head and neck cancer and analyse the survival and outcome of
patients with early-stage second primary tumours. METHODS: Retrospective chart
review of patients treated for head and neck cancer from 1989 to 1993. Survival
analyses and statistical comparisons with the Kaplan-Meier method and log-rank
test. RESULTS: 99 of the 311 patients had second primary tumours. 45 patients had
synchronous second primary tumours and 54 metachronous second primary tumours,
diagnosed at an early stage (stage 0 or I) in 78 and 63% of cases respectively.
Patients with second primary tumours had a significantly (p = 0.03) lower
survival rate than patients with single tumour. However, for patients with early
stage second primary tumours survival was not significantly decreased (p = 0.3).
DISCUSSION: This study confirms the high incidence of second primary tumours and
their negative impact on the outcome of patients with head and neck cancer. Early
diagnosis and treatment of second primary tumours results in a survival rate very
similar to that of patients with a single head and neck cancer. This provides
indirect evidence that in patients with curable initial head and neck cancer
intensive screening for second primary tumours may result in an improved overall
outcome.
PMID- 10780071
TI - [Value of fine needle aspiration biopsy in diagnosis of cervical masses].
AB - Fine needle aspiration is a widely used diagnostic tool. Its use for the
evaluation of head and neck masses remains somewhat controversial. This
retrospective study analyses all patients presenting with neck masses
investigated by fine needle aspiration in our institution from January 1997 to
December 1998. 372 fine needle aspirations were performed. Cytological diagnosis
was possible in 91%. Sensitivity was found to be 100%, specificity 99% and
accuracy 99.7%. When including indeterminants in the false-negatives, overall
sensitivity is 73%, overall specificity 100% and overall accuracy 90%. There were
no complications, and in particular no suprainfection and no tumoural spread at
the puncture site. We conclude that fine needle aspiration is a sensitive and
specific modality which is very helpful in the diagnostic work-up of a neck mass.
PMID- 10780072
TI - [Hypothyroidism after combined surgical and radiotherapy treatment of cancer of
the ORL area].
AB - INTRODUCTION: Hypothyroidism is a well described complication of head and neck
cancer treatment, but routine testing of thyroid function is generally not done.
The combination of surgery and radiotherapy seems to increase the risk of thyroid
hypofunction. METHODS: Thyroid function was measured in 82 patients treated for
head and neck cancer (different types of surgical resection combined with pre- or
postoperative radiotherapy). The treatment was undertaken 1 to 220 months before
measurement of THS and T4. RESULTS: 43 out of the 82 patients (52%) had abnormal
thyroid tests. Hormonal replacement was necessary in 20/43 cases (24%). More than
85% of patients treated by total laryngectomy or pharyngo-laryngectomy,
associated with hemithyroidectomy or not, had hypothyroidism and replacement
therapy was necessary in more than half of these patients. For the other types of
surgery the incidence of hypothyroidism was 32% with 10% of patients needing
substitution. DISCUSSION: A high percentage of patients treated by surgery and
radiotherapy develop hypothyroidism. In our experience, routine thyroid function
testing is necessary in this group.
PMID- 10780073
TI - [Thyroid surgery: traps and preventing complications].
AB - A retrospective analysis was conducted of all thyroid operations performed at the
ENT department in St. Gallen, Switzerland, between 1995 and 1997. The
complications and technique of this surgery are outlined. In 79 patients 111
thyroid lobe resections were performed. No injury occurred to the superior
laryngeal nerve. One recurrent laryngeal nerve injury and one permanent
hypocalcaemia were observed. No revision operations were required for haematoma
or infection. The different steps in the operative procedure, such as skin
incision, handling of the strap muscles and identification of the parathyroid
gland and superior laryngeal nerve, as well as the monitoring of the recurrent
laryngeal nerve, are discussed.
PMID- 10780074
TI - [Cervicofacial necrotizing fasciitis].
AB - INTRODUCTION: Necrotising fasciitis is still a severe disease whose outcome is
occasionally fatal. METHODS: Between August 1994 and August 1998, 6 patients with
necrotising fasciitis, 5 in the neck area and one in the facial area, were
treated. The source of the infection was odontogenic in 3 cases, pharyngeal in 2
and an insect sting in the left upper eyelid in one case. RESULTS: Following
evaluation by CT scan, immediate surgical exploration with debridement and
drainage was performed. Revision proved necessary in most cases. One patient
suffered severe complications. Median stay in the intensive care unit was 7 days
and in hospital 20 days. DISCUSSION: Deep and extensive neck infections require
investigation by CT scan. All affected areas must be explored and drained
immediately, including thoracotomy if mediastinitis is present. Apart from
appropriate antibiotic therapy, the further course of the disease should be
carefully monitored to detect further spread of the infection as well as
complications.
PMID- 10780075
TI - [Surgical therapy concept in primary hyperparathyroidism].
AB - INTRODUCTION: Primary hyperparathyroidism is a relatively rare disease caused in
80-85% of cases by solitary adenoma of the parathyroid glands. The laboratory
findings are hypersecretion of PTH and hypercalcaemia. We distinguish between
asymptomatic and symptomatic primary hyperparathyroidism. 25 patients of our
clinic who underwent surgery in 1996 and 1997 are presented to illustrate our
surgical concept of therapy. METHODS: 7 patients were asymptomatic and 18
symptomatic with regard to primary hyperparathyroidism. Preoperative localisation
was facilitated by ultrasonography of the neck, which was used in all cases.
Bilateral exploration of the neck under general anaesthesia similarly to
thyroidectomy was the gold standard. Monitoring the inferior laryngeal nerve
helped to protect it. In 6 cases intraoperative parathyroid hormone monitoring
(rapid PTH assay) was applied. RESULTS: More than a third of the symptomatic
group of patients had neurological or psychiatric diseases, followed by symptoms
of the musculoskeletal and urological systems. Possible reasons for surgical
intervention were persistent hypercalcaemia, age over 50, radiological findings
of kidney stones or decreased kidney function. In 17 patients the preoperative
ultrasonographic localisation was consistent with the intraoperative clinical
findings. The sensitivity of this method was 68%. Intraoperative pathology showed
17 patients with a solitary adenoma, 4 ectopic, 2 cases had double adenoma, and 2
others hyperplasia with enlargement of all glands. After resection of the
pathological parathyroid glands there was a decrease of parathyroid hormone in
intraoperative hormone monitoring of approximately 60%. The preoperative
hypercalcaemia (mean 2.99 mmol/l) usually normalised 4 hours postoperatively.
There was no severe intraoperative bleeding and the inferior laryngeal nerve was
preserved in all cases. All patients were monitored at 3-month intervals for
parathyroid hormone and serum calcium during the first year after operation. One
patient had persistently elevated parathyroid hormone without clinical findings.
DISCUSSION: Parathyroidectomy is an efficient and safe operation with excellent
normalisation of serum calcium and parathyroid hormone and a high rate of patient
satisfaction. In this study assessment of ultrasonography was the preferred
method of locating enlarged parathyroid glands before operation. However, this
method is not based on unilateral exploration of the glands. Therefore, we prefer
to locate all four glands, an approach based on the literature [1, 2].
Intraoperative monitoring of parathyroid hormone facilitates assessment of the
operative result [3]. Normalisation of calcium in serum and the effectiveness and
safety of the surgical method are confirmed in other publications [4-8]. In 24 of
our patients normocalcaemia resulted within 12 hours after operation and in one
patient within 4 days. One year after operation and endocrinological checkup all
25 patients were asymptomatic and normocalcaemic, while one patient had
persistently high parathyroid hormone of unknown origin.
PMID- 10780076
TI - [Incidental ultrasound detection of thyroid nodule: what next?].
AB - INTRODUCTION: The routine use of ultrasonography in ENT to investigate the
lymphatic system of the neck leads to a number of incidentally found thyroid
nodules. METHODS: After reevaluating our patients from 7/95 to 12/98 we searched
the relevant literature for a reasonable diagnostic pathway for these findings.
RESULTS: 67 patients had one or more incidentally found thyroid nodules. 23 were
followed sonographically. 8 patients had fine needle biopsy as a first diagnostic
step. One nodule was cytologically suspect for papillary carcinoma, which was
confirmed later histologically after resection. DISCUSSION: Autopsy studies
showed a 5% malignancy rate in the occult thyroid nodules. Most of these occult
growths are papillary carcinomas with a relatively good prognosis, especially
when they measure less than one centimeter. We recommend performing a fine needle
biopsy in any patient with a thyroid nodule > 1 cm, with a history of prior
irradiation of the neck or with medullary carcinoma in the family. Clinical and
sonographic follow-up should be done after 6 to 12 months in the rest of the
cases.
PMID- 10780077
TI - [Liposarcoma in the area of the head-neck].
AB - Liposarcoma is the second most common soft tissue sarcoma occurring in adults,
though it rarely involves the head and neck region. Fewer than 100 such cases
have been described in the literature. We present two additional cases and a
review of the literature. Prognosis is mainly determined by histologic grade. A
high incidence of local recurrence is typical of all subtypes. Complete surgical
excision is the most effective treatment. In the head and neck region the extent
of the excision is limited by the proximity of neurovascular structures. The
benefits of adjuvant radiotherapy in head and neck liposarcoma remain uncertain.
Studies on liposarcoma at other sites indicate that addition of radiotherapy to
surgery may result in longer local recurrence-free survival, though without
improvement of overall survival.
PMID- 10780078
TI - [Endonasal dacryocystorhinostomy: technique and results].
AB - BACKGROUND: Endonasal dacryocystorhinostomy has recently become an important
alternative to the classical external Toti procedure. OBJECTIVE: To analyse the
outcome after endonasal dacryocystorhinostomy. METHODS: For this purpose 28 of 34
patients treated by endonasal dacryocystorhinostomy between May 1994 and November
1998 were investigated. RESULTS: After an average follow-up of 28 months, 23 of
the 28 patients (82%) are free of symptoms. Two additional patients became
symptom-free after revision surgery. The total success rate is 89%. The only
complications seen were 2 cases of asymptomatic synechiae and one case of mild
hyposmia. CONCLUSIONS: Endonasal dacryocystorhinostomy is a rapid, safe, and
elegant method for the treatment of post-saccal nasolacrimal duct obstructions.
PMID- 10780079
TI - [Results of voice rehabilitation with Provox prostheses].
AB - From 1992 to 1998, 105 patients of the Department of Otorhinolaryngology, Head
and Neck Surgery in Berne underwent laryngectomy with primary implantation of a
Provox prosthesis. These patients were followed up in an open prospective study
and evaluated by the HRS scale, based on speaking ability and quality as well as
on prosthesis care. 46 patients (44%) attained successful rehabilitation of the
voice, defined as 12-15 points according to the HRS scale. Age, tumour stage and
postoperative irradiation did not influence the results. Compared to the patient
group with less than 12 HRS points, frequent replacements or short in situ
lifetime of the prosthesis improve the results of rehabilitation. Patient
compliance is an important factor in achieving success with the Provox
prosthesis.
PMID- 10780080
TI - [Infectious mononucleosis: when is tonsillectomy indicated?].
AB - INTRODUCTION: Infectious mononucleosis is usually a benign, self-limited disorder
of the lymphopoietic system. Tonsillopharyngitis is a common presentation of the
disease. Occasionally upper airway obstruction or a prolonged swallowing disorder
require surgical intervention. METHODS: We conducted a retrospective analysis of
all infectious mononucleosis cases seen at the ENT clinic in St. Gallen,
Switzerland, between 1994 and 1998. RESULTS: 21 records were analysed, among
which 19 patients needed hospital care. 11 cases required tonsillectomy. The
average duration of fever of the patients undergoing surgery was markedly lower
(9 days) than the conservatively managed cases (14.2). DISCUSSION: Tonsillectomy
is well tolerated, eliminates airway obstruction and rapidly improves swallowing.
PMID- 10780081
TI - [A new self-retaining titanium-gold stapes prosthesis].
AB - Various aspects of stapes surgery have been improved since its introduction in
1958 by Shea. However, fixation of the prosthesis on the long process of the
incus remains difficult. Furthermore, the functional result of crimping cannot be
predicted. Necrosis of the lenticular process still occurs. A new stapes
prosthesis has been developed with the Kurz Co. The use of titanium allowed an
innovative design: titanium has a shape memory, and a clip was constructed which
uses this memory for fixation on the incus. Two new instruments were also
developed to facilitate application of the prosthesis: a prosthesis inserter and
a prosthesis crimper. The clip does not strangulate the incus; it is attached
only to the superior and inferior surface of the incus, which are the crucial
locations for mechanical transmission of the piston-like movements of the
ossicular chain. Avoidance of circumferential attachment should reduce the risk
of incus necrosis. Once the clip is pushed onto the incus no further crimping is
necessary. The piston is of pure gold, as in this company's gold piston which has
been in use for many years. In future the prosthesis may be all-titanium.
PMID- 10780082
TI - [EBV infection as etiology of otomastoiditis with peripheral facial paralysis in
the child].
AB - Case report on a 15-month-old girl with acute bilateral otomastoiditis with
facial nerve palsy in the course of an EBV infection. Although the initial
mononucleosis blood test was negative the diagnosis was established by the
presence of blastic transformed lymphocytes with immunoreaction for the latent
membrane protein of EBV, and the presence of EBV-mRNA in the majority of
lymphocytes in the biopsy specimen. The occurrence of facial nerve palsy in the
course of an EBV infection is relatively rare but well known. The present case
involved a viral otomastoiditis with a typical course, which was complicated by
facial nerve palsy after a few days of illness. A case of this kind has only once
been described in an adult patient and has never been reported in a child.
PMID- 10780083
TI - [Otitis and sinusitis: research on associated pathology of the middle ear in the
adult].
AB - The author looked for associated pathologies in adult otitis media. In 31 cases
collected during 11 months of private practice as en ENT specialist he observed
radiological anomalies of the sinus cavities in 19 cases (61%), concomitant ENT
ailments in 9 (29%) and serious deterioration of general condition in 3 (10%). He
concludes that adult otitis media is not an isolated phenomenon and that its
management must take other associated pathologies into account.
PMID- 10780084
TI - [Evolution of sudden deafness without treatment].
AB - Spontaneous recovery of hearing following sudden deafness is evaluated. Between
1983 and 1997, 59 patients presenting with sudden hearing loss deliberately
declined treatment. Recovery is similar for low and high frequency hearing
losses, 40% of cases recovering hearing with an interaural threshold difference
below 20 dB. These results are similar to those of several studies using
different treatments. Therefore, sudden deafness need not be treated at all
costs.
PMID- 10780085
TI - [Stapes surgery in anomalies of the course of the facial nerve].
AB - In 548 stapes operations performed in Berne during the period 1994-1998, an
anomaly of the course of the facial nerve was observed in 37 cases. 29 exhibited
partial prolapse of the nerve over the oval window, with or without dehiscence of
the bony canal, while 5 showed total prolapse of the nerve over the oval window.
In one case the nerve was duplicated round the oval window and in a further
instance the facial nerve was situated over the promontory and also over the oval
window. In one other case the nerve was spread widely over the oval window.
Concomitant anomalies of the stapes were frequently observed. The following
surgical techniques were employed: in the case of partial prolapse of the nerve,
a small piston was placed in the lower part of or in the oval window, which was
widened towards the promontory. In cases of total prolapse of the facial nerve
the prosthesis was drilled straight into the promontory. Where the nerve was
duplicated the prosthesis was placed in the footplate between the nerve branches,
and where the nerve ran over the promontory and over the oval window the
prosthesis was placed above the oval window. In the case where the nerve was
spread widely over the oval window, no prosthesis was inserted. 78% of patients
had a residual air-bone gap of 20 dB or less; in only three cases did hearing
fail to improve. One patient with Crouzon disease involving a complex anomaly had
a hearing impairment of 22 dB. There was no deafness, facial paralysis or vertigo
with nystagmus.
PMID- 10780086
TI - [Normal and pathological facial mimicry: objective analysis].
AB - INTRODUCTION: Objective evaluation methods for facial nerve function are yet to
be standardised. Unresolved issues include what should be measured for different
facial movements and how these measurements should be performed. METHODS: 5
facial mimics were analysed in normal subjects and in patients with facial
paralysis. For each mimic the best measurement was determined and two global
indexes derived. RESULTS: The best measurements were of surfaces close to the
moving facial zone. These measurements and the global indexes correlated well
with gradings by the House-Brackmann scale.
PMID- 10780087
TI - [Correlation between objective criteria and subjective evaluation of symptoms in
chronic rhinosinusitis].
AB - INTRODUCTION: We evaluated the possible correlations between the extent of
inflammatory infiltration of the nasal mucosa caused by mechanical irritation
(septal deviation and hypertrophy of the middle turbinate) and nasal airway
resistance measured by rhinomanometry and acoustic rhinometry. Subjective
evaluation of the nasal obstruction, rhinorrhoea and headache was done by visual
analogic scale and compared with the inflammation. PATIENTS AND METHODS: 40
patients with a more than 18 months' history of chronic rhinosinusitis associated
with septal deviation and/or hypertrophy of the middle turbinate were included in
the study. The density of inflammatory cells (graded from + to +3, where + means
few and +3 abundant inflammatory cells) in the mucosa of the middle turbinate was
evaluated histopathologically. RESULTS: We found a significant correlation
between subjective intensity of nasal obstruction and inflammation (mainly
lymphocytes) of the middle turbinate mucosa and the value of nasal airway
resistance measured by rhinomanometry. No correlation was found between the other
parameters studied. CONCLUSION: Mechanical stimulation at the level of
turbinoseptal contact causes inflammation in the mucosa which correlates with
both subjective nasal airway resistance and rhinomanometry values.
PMID- 10780088
TI - [Atypical pneumatization of the paranasal sinus system].
AB - 200 CT scans of adult patients with paranasal sinus problems seen in the ENT
Department either in the University Hospital in Berne, Switzerland, or in the
University Hospital in Munich, Germany, were analysed. Among these we found 9
striking abnormalities of paranasal sinus anatomy. We found abnormalities which
caused clinical symptoms, such as an infected concha bullosa, a fine-septated
infected maxillary sinus, a pneumosinus dilatans of the frontal sinus with
aesthetic problems, and a cellula orbito-ethmoidalis with sinusitis. Some of
these abnormalities were found by coincidence, such as a cellula orbito
sphenoidalis and an extreme pneumatisation of the sinus sphenoidalis with a
pneumatised processus pterygoideus. 2 cases show the importance of preoperative
evaluation of a possible abnormal sinus to avoid operative complications: a sinus
sphenoidalis with a pneumatisated clivus and an intraluminal a. carotis interna.
The other case involved an optic nerve running free through the sphenoidal sinus.
In conclusion we stress the importance of preoperative CT examination and the
choice of a coronary or axial CT scan, which reveals any abnormal anatomy of the
paranasal sinus pneumatisation and thus increases the safety and efficiency of
paranasal sinus surgery.
PMID- 10780089
TI - [Significance of human papillomaviruses (HPV) in sinonasal papillomas].
AB - The present study comprises 43 patients with sinonasal papillomas operated on
between 1990 and 1997 at the ENT Department, University Hospital of Zurich.
Histology showed 5 cases of exophytic papilloma (EP) (12%), 34 cases of inverted
papilloma (IP) (79%) including 4 cases of associated carcinoma (9%), and 4 cases
of columnar cell papilloma (CCP) (9%). Recurrence developed in 6 of 41 patients
(2 EP, 4 IP) (15%). HPV was detected in 4 of 37 specimens (11%) both by in situ
hybridization (ISH) and polymerase chain reaction (PCR). HPV-11 was found in 3
lesions (2 EP, 1 IP), whereas HPV-6b was detected only in one lesion (1 EP).
Altogether 3 of 5 EP (60%), one of 29 IP (3%) and one of 6 recurrent papillomas
(1 EP) (17%) tested positive for HPV. Our findings suggest a possible role for
HPV in the pathogenesis of exophytic papilloma. As no correlation was found with
associated malignancy and recurrence of disease, screening for HPV seems not to
be useful as a prognostic parameter.
PMID- 10780090
TI - [Partial inferior turbinectomy with security (T.I.P.S.) in chronic nasal
obstruction: personal surgical technique and outcome].
AB - Partial inferior turbinectomy with security (PITS) was performed in 224 patients.
In 206 cases (92%) surgery was bilateral and 76 patients (34%) had no other
associated intervention. The follow-up period ranged in the whole group from 12
to 64 months (mean 31 months). In the group of 76 patients the follow-up period
ranged from 12 to 55 months (mean 28 months). The nasal obstruction was
significantly reduced in 204 cases (91% of all patients operated on). The group
of 76 cases including 9 children underwent isolated bilateral turbinectomy with
90% successful results. The principal interest of this publication is a detailed
description of this new personal technique for a safe, rapid, non-haemorrhagic
and inexpensive method which can be easily performed even in children and also in
one-day surgery.
PMID- 10780091
TI - [Predictive value of nocturnal pulse oximetry in sleep apnea screening].
AB - The monitoring of overnight oxygen saturation is widely used for sleep apnoea
screening. The point of this screening has been questioned as a wide range of
sensitivity has been reported in the literature. In a prospective study 70
subjects presenting with a possible sleep apnoea-hypopnoea syndrome had overnight
oximetry followed by polysomnography 2 to 4 months later. Compared to
polysomnography, the sensitivity of oximetry for sleep apnoea-hypopnoea was
85.2%, the specificity 77.8% and the predictive value positive 96.3%. When short,
non-significant, repetitive desaturations have been declared pathologic,
sensitivity increased to 91.8%. In the hands of an expert user, oximetry
represents an excellent instrument for detecting patients with sleep apnoea
hypopnoea. Patients with pathological nocturnal oximetry are candidates for nCPAP
treatment and therefore should undergo a sleep laboratory investigation.
PMID- 10780092
TI - [Madelung disease and obstructive sleep apnea syndrome: apropos of a case].
AB - Madelung's disease, or benign symmetric lipomatosis, is an uncommon disease. It
is an unencapsulated fatty infiltration which in rare cases extends into the
perilaryngeal space and mediastinum. The authors present a case complicated by an
obstructive syndrome and sleep apnoea syndrome, which was successfully treated by
continuous positive airway pressure. The literature is reviewed.
PMID- 10780093
TI - The Mediterranean diet and endothelial function: why some dietary fats may be
healthy.
AB - Evidence from both diet and physiologic studies suggests that some dietary fats-
but not others--impair endothelial function in the short term, possibly by a
mechanism of oxidative stress. This insight may affect our advice to patients
about heart-healthy eating.
PMID- 10780094
TI - Who should receive the Lyme disease vaccine?
PMID- 10780096
TI - Avoiding tick bites
PMID- 10780095
TI - Tick trouble: overview of tick-borne diseases.
AB - Tick-borne diseases can be severe or even fatal, but when identified early, most
can be easily treated. Tick-borne diseases often present with nonspecific
symptoms. Therefore it is important for the primary care physician to be familiar
with the epidemiology of these diseases and their presentations. Although Lyme
disease is the most common and well-known of the many tick-borne diseases, Rocky
Mountain spotted fever, ehrlichiosis, and babesiosis are also threats throughout
the United States.
PMID- 10780097
TI - An elderly man with intermittent right arm numbness and polycythemia.
PMID- 10780098
TI - Angioplasty and stenting in acute coronary syndromes: who, when, how, and why.
AB - PTCA and stenting now form an integral part of therapy for acute coronary
syndromes and are important in achieving the optimal clinical outcome.
PMID- 10780099
TI - Raloxifene: a new choice for treating and preventing osteoporosis.
AB - Selective estrogen receptor modulators (SERMs) are a new class of drugs that
provide a new option for addressing the health challenges of postmenopausal
women. This review discusses the proposed mechanism of action of SERMs and
describes clinical findings on raloxifene, a SERM now available for treating and
preventing osteoporosis.
PMID- 10780100
TI - Pancreas transplantation in type 1 diabetes: hope vs reality.
AB - Pancreas transplantation can improve quality of life for patients with type 1
diabetes by eliminating hypoglycemic and hyperglycemic episodes, the need for
insulin injections, frequent self-monitoring of blood glucose levels, and dietary
restrictions. Increasing evidence suggests that it may slow the progression of
long-term diabetic complications. On the other hand, patients risk the adverse
effects of lifelong immunosuppression.
PMID- 10780101
TI - The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not.
AB - The Heart Outcomes Prevention Evaluation (HOPE) study found that the ACE
inhibitor ramipril can lower the risk of atherosclerotic disease events and death
in patients without heart failure but with known atherosclerosis or with diabetes
plus at least one cardiovascular risk factor. This benefit was independent of
ramipril's effect on blood pressure. Additional benefits were a reduced risk of
diabetic nephropathy in diabetic patients, and a lower likelihood of newly
diagnosed diabetes. On the other hand, vitamin E in the doses and duration
studied (400 IU/day for 4.5 years) did not lower risk significantly.
PMID- 10780102
TI - The genetics, screening, and treatment of epithelial ovarian cancer: an update.
AB - Recent genetic findings are shedding light on who is at risk for epithelial
ovarian cancer, by far the most common of ovarian malignancies. Current screening
tests are inadequate, but a serum test of lysophosphatidic acid shows promise.
Clinical trials show that cisplatin or carboplatin plus paclitaxel increases
progression-free and overall survival times vs regimens that do not contain
paclitaxel, and that a carboplatin-paclitaxel regimen is less toxic than
cisplatin-paclitaxel and can be given on an outpatient basis. The development of
newer cytotoxic drugs and alternative routes of administering chemotherapy offers
hope of improved survival for women with advanced ovarian cancer.
PMID- 10780103
TI - It's time medicine stopped burying its mistakes.
PMID- 10780104
TI - [Evolutionary chromosomes and sex dimorphism].
AB - In order to understand the phenomenon of sex, it is not enough to know about its
reproductive role and role in recombination. In addition, knowledge of its
evolutionary role is required. Sexual differentiation allows us to test
evolutionary innovations in the male genome before they are transmitted to the
female genome. This is possible in the framework of dichronous evolution, when
the evolution of the male sex goes faster than the evolution of the female sex.
This implies that there clearly should be male genes, which are already present
in the male genome, but are not yet in the female genome; and vice versa, there
should exist female genes, which have already been lost by the male sex, but
still remain in females. Dichronicity results from different reaction norm of the
sexes. This interpretation implies (1) the nomadic behavior of genes in the
genome (2) the existence of evolutionary sexual dimorphism, which begins in the
form of modificational changes in the female sex followed by selection-derived
changes in the male sex; (3) the discovery of evolutionary roles of chromosomes
and the proposition of a new concept, according to which the Y-chromosome
represents a "gateway" for environment-related information coming to the genome,
i.e., place of "birth" and testing of new genes, which comprise the basis of
evolutionary sexual dimorphism--its initiator, accelerator, and regulator. The X
chromosome is the "transport" chromosome that transfers new genes from the Y
chromosomes into autosomes and therefore serves as a stabilizer, relaxer, and
liquidator of evolutionary sexual dimorphism; it also serves as repository of the
outgoing genes that await elimination. This concept provides for a new
interpretation of the appearance, localization, and movement of genes along
chromosomes and between them, and it sheds new light on the phenomena of
chromosomal inactivation, mobile genes, association of Y-chromosome with stress,
viruses, etc.
PMID- 10780106
TI - [Structure-physiological activity correlation for picolinic acid derivatives
based on quantum chemical data].
AB - Correlation between structure and properties for picolinic acid derivatives with
and without bimodal effect was evaluated by quantum chemical calculations.
Comparative data obtained by SCF MO method in the 3-21G/6-31G* basis indicate
lower ionization potential in picolinic acid derivatives with bimodal effect as
compared to those lacking this effect. This validates our previous assumption
that physiological bimodal effect is defined by the electron structure of the
molecules. Quantum chemical calculations allowed us to predict bimodal
physiological activity in amino-substituted derivatives of picolinic acid.
PMID- 10780105
TI - [Polyclonal antibodies, labeling radial nerve cells of the starfish Asterias
amurensis].
AB - The results of preliminary studies suggest that the cytoskeletal fraction of the
radial nerve of the starfish Asterias amurensis contained a 32 kDa protein, which
is tissue specific. This protein was isolated from the radial nerve by
preparative electrophoresis and used as an antigen for raising polyclonal
antibodies. When testing these antibodies on sections of the starfish tissues, it
was shown that they interact only with the proteins present in the radial nerve
cells. A conclusion was drawn that the raised antibodies may be used as a cell
marker when studying regeneration of the nervous system in starfish.
PMID- 10780107
TI - [Morpho-biochemical study of the liver and serum albumins during
tetrachloromethane intoxication and administration of antihypoxants,
antioxidants, and actoprotectors].
AB - Organism intoxication with tetrachloromethane induces a complex of
transformations in the liver and serum albumins system manifested in the liver as
necroses in the central lobe, dilatation of sinus capillaries and blood stasis in
them, increased content of total water, and changed magneto-relaxation properties
indicating decreased structurization of water. The system of serum albumins shows
decreased total concentration of albumins in the serum, decreased constant of 1
(phenylamino)-8-sulfonaphthalene probe binding, increased mean number of probe
binding per albumin molecule, and increased accessibility of probe in the protein
probe complex for the quencher indicating changed type of interaction between the
protein and fluorescent probe. Introduction of a antihypoxant, antioxidant, or
actoprotector has a positive effect on the condition of the liver and serum
albumins system: The studied indices are nearly completely normalized.
PMID- 10780108
TI - [Changes in the activity of superoxide dismutase, glutathione peroxidase,
microsomal lipid peroxidation, and content of trace elements in organs and
tissues following copper introduction].
AB - Chronic application of various copper concentrations on the skin decreases
endogenous levels of iron, zinc, and copper in the serum. Single introduction of
disperse copper positively correlates with the level of the oxidation products
and Fe/Zn ratio in the liver. Single introduction of ionic and electron-neutral
copper induces phased changes in superoxide dismutase and glutathione peroxidase
activities. Positive correlation between activities of these enzymes points to
efficient control of O2-radicals, dismutation products, and hydroperoxides level
by the antioxidant enzymes in animal tissues treated with copper.
PMID- 10780109
TI - [Indoleacetic acid levels in the potato organs during various stages of
ontogenesis and the role their dynamics in the tuber growth regulation].
AB - During ontogenesis of the potato (Solanum tuberosum L.), the content of
indoleacetic acid (IAA) in different organs was determined. The dynamics of IAA
in the leaves corresponded to changes in photosynthetic activity. The treatment
with IAA increased the intensity of photosynthesis. It was shown that the IAA
content increased in the leaves and that IAA ascended to the stem basal part in
the second half of vegetation. The accumulation of IAA in the stem basal part
gave rise to a positive gradient of sugar in the stem, differentiation of stolons
and transport of assimilate in the grown tubers. A correlation was found between
the content of IAA in tubers and the rate of its growth.
PMID- 10780110
TI - [Modeling of the plant community: individual oriented approach. II. A model of a
community].
AB - The individual-based approach to modeling of the plant cover dynamics is
discussed. This approach takes into account that the cover consists of individual
interacting plants, i.e., is a community. According to the principle of "minimal
angle of viewing", this approach can be considered as approaching the object
earlier considered from the energy standpoint (Monsi and Saeki, 1953; Khil'rni,
1957). An element of the model of community, balance model of plant dynamics, was
considered in part I of the article. The community model is 2-D, i.e., it
considers the growth and dying of plants in relation to their mutual geometrical
arrangement in the community. Mechanisms of division and re-division of the
territory among the plants of community are important elements of the community
model. These mechanisms use the Voronoi mosaic. Some results of the development
and analysis of the model of community are considered, such as the possibility of
non-monotonous competition in homogeneous communities and -3/2 rule considered as
"one of the most general principles of plant population biology" (White, 1980).
The 2-D individual-based approach to modeling can be an effective tool for
analysis of the influence of many "microscopic" features of the community
structure on its macroscopic behavior.
PMID- 10780111
TI - ['Conditioning factor' in plant cell cultures of various taxa].
AB - The activity of the "conditioning factor" from the cultures of plant cells of
various taxa was assayed in biotests with the tobacco and wheat cell cultures.
The conditioned media of crops did not activate the growth of a diluted (400
fold) culture of tobacco cells. Conditioned media from the cultures of cells of
other monocotyledonous plants, such as asparagus or spiderwort, stimulated the
tobacco culture growth like those from the cultures of cells of dicotyledonous
and gymnospermous plants. The growth of a diluted (2000-fold) culture of wheat
cells was activated by the conditioned media from all cell cultures used in these
experiments. We can propose that conditioning factors of monocotyledonous,
dicotyledonous and gymnospermous plants do not differ from each other in the
character of biological action and may have a similar chemical nature. The nil or
weak activity of conditioned media from the cultures of crop cells may be related
to the presence, in addition to the conditioning factors, of inhibitors of cell
culture growth.
PMID- 10780112
TI - [A boundary between palearctic and afrotropical faunistic kingdoms (based on the
lizard distribution (Reptilia, Sauria))].
AB - In order to define the limit between Palearctic and Afrotropical kingdoms, we
studied the apparent transition zone between them which we limited by the North
range boundary of Agama agama--the northernmost representative of a typical
Afrotropical genus--and by the South range boundary of the southernmost
representatives of Palearctic genera Acanthodactylus, Chalcides, Stenodactylus,
and Tarentola. We also considered fauna of Southwest Arabian lizards including a
representative of Afrotropical genus (Latastia longicaudata). Similarity of range
and origin allowed us to class all species living within these boundaries into
nine groups: Palearctic, Afrotropical, widespread, Afroarabian, zone endemics of
Palearctic genera, zone endemics of Afrotropical genera, zone endemics of
Afroarabian genera, zone endemics of tropical genera, and zone endemics at the
generic level. Range superposition allowed us to map species abundance of each
group. Predominance (over 50%) of Palearctic or Afrotropical species on the
studied territory allowed us to assign it to the corresponding faunistic kingdom.
The regions where neither of these groups exceeded 50% were assigned to the
transition zones.
PMID- 10780113
TI - [Breeding biology of the whiskered auklet (Aethia pygmaea): incubation, chick
growth, and feather ontogenesis].
AB - This is the second publication on the results of studies of the whiskered auklet
breeding biology on Buldir Island. In 1993, according to the time of chick
hatching the egg-laying period began in late April-early May. The single egg was
incubated by both parents, which relieved each other once a day, usually at early
night. Among the chicks under observation, the first hatched on June 11; the
median of hatching was on June 17. After hatching, the egg shell usually remained
in the nest. The chick was continuously brooded by one of parents for the first
several days but since the age of 7-9 days, it stayed in the nest by itself
during the daytime. Each parent fed the chick once a day, at early night,
although occasional feedings were recorded also during daytime and at dawn. A
newly hatched chick was covered by typical embryonal (natal) down. The remiges,
rectrices, their coverts, and large feathers on pteryla humeralis had a mesoptile
stage during their growth (the second down generation). The juvenile plumage
consisted of semiplumes of types I and II and contour feathers of type I and,
possibly, type II. In fledglings, the ornamental feathers were underdeveloped:
the crest was absent and facial plumes only began growing. By reaching 100 g, the
chicks left their nests at the age of about 37 days. A longer nesting period than
in other Aethia auklets appears to be related to a low feeding rate due to the
nocturnal activity in the colony.
PMID- 10780114
TI - [The morphological variability coordinated with the population cycle of the
widely distributed (the water vole Arvicola terrestris L.) and mountain (the big
eared vole Alticola macrotis Radde) vole species].
AB - This paper presents an analysis of variation of skull size and shape in the
course of population cycles of two ecologically different vole species: water
vole and high-mountain vole. We have found consistent changes of the direction,
rate, and balance of morphogenesis during population cycles. We discuss the role
of intra-populational factors and inter-populational variation during the
territorial expansion of the species.
PMID- 10780115
TI - [Reactivity of blood vessels: the role of mechanical stimulation and initial
tone].
AB - We have studied hemodynamic and some other correlates of the myogenic and
endothelium-dependent control of vessel tone and reactivity in experiments with
anesthetized cats and rats, as well as in vitro experiments with isolated
segments of the mesenteric and tail artery of the rats. We present evidence for
the important role of mechanical stimulation of endotheliocytes in the formation
of vasodilation in skeletal muscles in response to increased amplitude of the
pulse pressure, as well as in response to their active or passive contractions.
Interference between mechanical, neurohumoral, and metabolic effects on vascular
tone were studied. In spontaneously hypertensive rats, endothelium-dependent
vasodilation initiated by increased oscillations of pulse pressure is diminished.
We also describe relationships between systemic hemodynamic responses and the
initial arterial tone.
PMID- 10780116
TI - [Study of the photodynamic effect of new photosensitizers on the single neuron].
AB - We studied reactions of isolated crayfish mechanoreceptor neurons to photodynamic
effects of various photosensitizers: methylene blue, chlorins e6 and p6, sulfated
allumophthalocyanin Photosens, Janus green B, protoporphyrin IX, and two
derivatives of hematoporphyrin IX, Photoheme and Photosan-3. The neurons were
irradiated by a helium-neon laser (632.8 nm, 0.3 Wt/cm3) after 30-min
photosensitization. They proved to be very sensitive to the photodynamic effect:
When the cells stained by photosensitizers at nanomolar concentrations were
irradiated, their firing activity underwent irreversible changes and they died.
The dynamics of the firing activity of the neurons depended on the
photosensitizer type and concentration. Photosens, Photoheme and chlorin p6
proved to be the most efficient.
PMID- 10780117
TI - [Geoinformational model of the carbon reserve of the Russian tundra zone].
AB - We present a summary of our own gas measurement data on biogenic fluxes of CO2 in
various ecosystems of the Russian tundra zone, using seasonal and geographical
extrapolations based on mathematical simulation modeling. The model follows
construction principles of geoinformational systems and consists of (1) a
computer map of tundra landscape boundaries; (2) a meterological database; (3) a
model of changes of the phytomass; and (4) the actual model of carbon fluxes. The
model, which uses a 10-day step, allows estimates of regional and landscape
associated macroscopic carbon fluxes and predicts the response of the tundras to
climatic changes. The data obtained are in good agreement with independently
obtained estimates of the major characteristics of tundra carbon balance.
PMID- 10780118
TI - [Study of the new settler Beroe ovata in the Black sea].
AB - Primary data on population, size, and distribution of a new settler--comb jelly
Beroe ovata--in the Black Sea are presented. We studied certain aspects of its
nutrition, consumed organisms, and digestion time. Comb jellies Mnemiopsis leidyi
and Pleurobachia pileus were established as the nutritional targets of B. ovata.
Mnemiopsis proved to be more accessible and assimilable. Preliminary data on
metabolic level and threshold oxygen content in B. ovata were obtained;
proportions of dry and wet weight of B. ovata were determined. Population changes
of new settler Mnemiopsis and other jellylike animals in the Northeast part of
the sea induced by B. ovata were analyzed. We observed sharp decrease in
population of Mnemiopsis, a species that induced degradation of the Black Sea
ecosystem within the last decade.
PMID- 10780119
TI - Adolescent and family predictors of physical aggression, communication, and
satisfaction in young adult couples: a prospective analysis.
AB - This study tested a model wherein the family conflict, depression, and antisocial
behavior of 254 adolescents (mean age = 17 years; 63% female) are prospectively
related to functioning within a marital (51%) or dating relationship in young
adulthood (mean age = 23 years). Family aversive communication in adolescence and
adolescent antisocial behavior predicted couple physical aggression. Family
aversive communication predicted dyadic satisfaction and aversive couple
communication for married women and dating men. Among those with partners who
reported little antisocial behavior, adolescent antisocial behavior inversely
predicted couple satisfaction and facilitative behavior. Partner antisocial
behavior did not mediate the relation between adolescent characteristics and
couple functioning. Findings emphasize the importance of the early family
environment and psychopathology of the adolescent in the development of adaptive
couple relationships.
PMID- 10780120
TI - Family, peer, and individual correlates of depressive symptomatology among U.S.
and Chinese adolescents.
AB - This study examined the correlates of symptoms of depressed mood among
adolescents in 2 dramatically different cultures (n = 502 in Tianjin, People's
Republic of China; n = 201 in greater Los Angeles). Gender, stressful life
events, perceived parental warmth, and conflict with parents were associated in
the expected direction with depressive symptoms in each cultural setting. As
predicted, regression analyses showed that the quality of family relationships
and grades in school had significantly stronger associations with depressive
symptoms among Chinese youths than among U.S. youths, whereas gender differences
in depressive symptoms were greater among the U.S. youths. Peer warmth moderated
the effects of particular risk factors for depressive symptoms in each cultural
setting.
PMID- 10780121
TI - Predictors of work adjustment in bipolar I patients: a naturalistic longitudinal
follow-up.
AB - This study explored the clinical and psychosocial predictors of work adjustment
in 52 Bipolar I patients over a 2-year longitudinal period and examined
associations between work functioning and social relationships, personality
features, stressful life events, and clinical variables. Analyses indicated that
psychosocial variables (personality disorder symptoms and social functioning)
added significantly to prediction of work functioning after clinical variables
were entered. Stressful life events were not associated with work adjustment.
Overall, presence of a good quality supportive relationship was the strongest
unique predictor of work. The results highlight the need to study functional
outcomes in patients, especially because they appear only modestly associated
with clinical status.
PMID- 10780122
TI - Long-term posttreatment functioning among patients with unipolar depression: an
integrative model.
AB - This study tested an integrative structural equation model of posttreatment
functioning among 165 depressed patients followed for an average of 9 years after
the end of an episode of treatment. The model examined (a) the link between life
change and psychosocial resource change and (b) the role of resource change in
mediating the relationship between life change and change in depression. An
increase in the preponderance of negative over positive life events was
associated with a decline in resources and an increase in depressive symptoms. A
decline in resources was associated with an increase in depressive symptoms. The
association between changes in events and depressive symptoms was completely
mediated through resource change. These findings indicate that life stressors
contribute to posttreatment depression through an erosion of personal and social
resources.
PMID- 10780123
TI - Effects of transdermal nicotine patches on abstinence-induced and cue-elicited
craving in cigarette smokers.
AB - The impact of a transdermal nicotine patch on smokers' craving for cigarettes and
reactivity to smoking cues was investigated. Sixty-one smokers were assessed
during 2 sessions separated by 6 hr. Cue reactivity to imaginal and in vivo
smoking and nonsmoking stimuli was evaluated during both sessions. During the
interval between sessions, participants were abstinent from cigarettes and wore
either a nicotine transdermal (21 mg) or placebo patch. In both sessions,
exposure to in vivo and imaginal smoking stimuli elicited cue-specific increases
in craving, negative affect, vividness, heart rate, and skin conductance. The
nicotine patch attenuated craving and other effects induced by abstinence from
cigarettes but had no selective impact on craving or any other reaction elicited
by smoking cues. These results are discussed in terms of models of craving and
clinical implications of transdermal nicotine for craving reduction.
PMID- 10780124
TI - Treatment of spit tobacco users with transdermal nicotine system and mint snuff.
AB - The purpose of this study was to examine the effects of nicotine patch and mint
snuff (a nonnicotine product) on craving, withdrawal symptoms, and treatment
outcome. This study involved a 2 x 2 factorial design, with Active Nicotine
Versus Placebo Patch as one of the factors and Mint Snuff Versus No Mint Snuff as
the other factor. Spit tobacco users (N = 402, n = 100-101 in each condition)
were randomly assigned to 1 of the 4 treatment conditions for a period of 10
weeks. Treatment outcome was measured up to 62 weeks. The results showed that the
nicotine patch was effective in increasing short-term abstinence over the placebo
patch and in reducing craving and withdrawal signs and symptoms from spit
tobacco. Although mint snuff was not effective in enhancing treatment outcome, it
reduced craving and withdrawal symptoms. No interaction effects were observed. At
this time, the use of the nicotine patch and mint snuff should be primarily
considered for the reduction of craving and withdrawal symptoms.
PMID- 10780125
TI - Give them prizes, and they will come: contingency management for treatment of
alcohol dependence.
AB - This study evaluated the efficacy of a contingency management (CM) procedure that
provided opportunities to win prizes as reinforcers. At intake to outpatient
treatment, 42 alcohol-dependent veterans were randomly assigned to receive
standard treatment or standard treatment plus CM, in which they earned the chance
to win prizes for submitting negative Breathalyzer samples and completing steps
toward treatment goals. Eighty-four percent of the CM participants were retained
in treatment for an 8-week period compared with 22% of the standard treatment
participants (p < .001). By the end of the treatment period, 69% of those
receiving CM were still abstinent, but 61% of those receiving standard treatment
had used alcohol (p < .05). These results support the efficacy of this CM
procedure. Participants earned an average of $200 in prizes. This CM procedure
may be suitable for use in standard treatment settings because prizes can be
solicited from the community.
PMID- 10780126
TI - Predictors and outcomes of posttraumatic stress disorder in World War II veterans
exposed to mustard gas.
AB - Current posttraumatic stress disorder (PTSD) associated with participation in
secret military tests of mustard gas during World War II was assessed in 363 male
military veterans who were randomly sampled from a registry developed by the
Department of Veterans Affairs. Current prevalence was 32% for full PTSD and 10%
for partial PTSD. Prevalence of PTSD varied as a function of risk and protective
factors, including volunteering, physical symptoms during the tests, and
prohibited disclosure. Prediction of partial PTSD was weaker than prediction of
full PTSD. Veterans with full PTSD reported poorer physical health, a higher
likelihood of several chronic illnesses and health-related disability, greater
functional impairment, and higher likelihood of health care use than those with
no PTSD. Veterans with partial PTSD also had poorer outcomes than did veterans
with no PTSD in a subset of these domains. There is discussion of the traumatic
elements of experimental mustard gas exposure, vulnerability to PTSD, and the
relevance of these findings to understanding the broad range of outcomes
associated with PTSD.
PMID- 10780127
TI - Ambulatory cardiovascular activity in Vietnam combat veterans with and without
posttraumatic stress disorder.
AB - The present study investigated the relationship between daily diary affect
ratings and ambulatory cardiovascular activity in 117 male Vietnam combat
veterans (61 with posttraumatic stress disorder [PTSD] and 56 without PTSD).
Participants completed 12-14 hr of ambulatory monitoring and daily diary affect
ratings. Compared with veterans without PTSD, veterans with PTSD reported higher
negative affect and lower positive affect in daily diary ratings. No differences
were detected for mean laboratory initial recordings or mean ambulatory heart
rate (HR), systolic blood pressure (SBP), or diastolic blood pressure (DBP).
However, compared with veterans without PTSD, veterans with PTSD demonstrated
higher SBP and DBP variability and a higher proportion of HR activity (compared
with initial recording values) during daily activity. There was a significant
Time of Day x Group interaction for mean HR, with a trend for PTSD participants
to maintain HR levels during evening hours.
PMID- 10780128
TI - Treatment settings for persons with alcoholism: evidence for matching clients to
inpatient versus outpatient care.
AB - This study compared inpatient, intensive outpatient, and standard outpatient
treatment settings for persons with alcoholism and tested a priori hypotheses
about the interaction of setting with client alcohol involvement and social
network support for drinking. Participants (N = 192) were assigned randomly in
cohorts to 1 of the 3 settings. The settings did not differ in posttreatment
primary drinking outcomes, although inpatients had significantly fewer jail and
residential treatment days combined than outpatients. Clients high in alcohol
involvement benefited more from inpatient than outpatient care; the opposite was
true at low alcohol involvement levels. Network drinking support did not moderate
setting effects. Clients low in cognitive functioning also appeared to benefit
more from inpatient than outpatient care. Improved outcomes might be achieved by
matching degree of alcohol involvement and cognitive functioning to level of
care.
PMID- 10780129
TI - Similarity of prior trauma exposure as a determinant of chronic stress responding
to an airline disaster.
AB - The cumulative effects of trauma were examined in 108 workers at the site of a
major air disaster at 4 time points over a year following the crash. The
influence of trauma history on chronic distress and physiological arousal
associated with the crash were examined. Stress levels were expected to differ on
the basis of the similarity of prior trauma exposure to work at the crash site.
Prior traumatic exposure that was "dissimilar" to this type of work was
associated with greater vulnerability to crash-related stress, that is, more
distress and crash-related intrusions during the year following the crash.
Accumulation of a variety of different traumatic experiences appeared to
sensitize workers to the new stressor and to perpetuate chronic stress.
Understanding the role of trauma history is important for improving intervention
efforts aimed at alleviating stress following a trauma.
PMID- 10780130
TI - Detecting and describing preventive intervention effects in a universal school
based randomized trial targeting delinquent and violent behavior.
AB - This study examined theoretical, methodological, and statistical problems
involved in evaluating the outcome of aggression on the playground for a
universal preventive intervention for conduct disorder. Moderately aggressive
children were hypothesized most likely to benefit. Aggression was measured on the
playground using observers blind to the group status of the children. Behavior
was micro-coded in real time to minimize potential expectancy biases. The
effectiveness of the intervention was strongly related to initial levels of
aggressiveness. The most aggressive children improved the most. Models that
incorporated corrections for low reliability (the ratio of variance due to true
time-stable individual differences to total variance) and censoring (a floor
effect in the rate data due to short periods of observation) obtained effect
sizes 5 times larger than models without such corrections with respect to
children who were initially 2 SDs above the mean on aggressiveness.
PMID- 10780131
TI - The effect of systematic variation in retrospective conduct disorder reports on
antisocial personality disorder diagnoses.
AB - A diagnosis of antisocial personality disorder (ASPD) requires a conduct disorder
(CD) diagnosis. A CD diagnosis is often obtained retrospectively. This study
tested the influence of current behavior on CD recall and the association between
recent behavior change and inconsistencies in contemporaneous and retrospective
CD reports. Five hundred young adults reported ASPD; retrospective CD; current
problem behavior; and, at ages 12 to 15 years, contemporaneous CD. True-positive,
true-negative, false-positive, and false-negative CD and ASPD groups were
identified. The results supported the hypotheses. Participants whose current
behavior agreed with past behavior provided reliable retrospective CD reports.
Inaccurate diagnoses occurred among participants whose current behavior was
inconsistent with past behavior, either becoming more problematic (CD and ASPD
false positives) or less problematic (CD and ASPD false negatives) over time.
PMID- 10780132
TI - Self-regulation of affect in attention deficit-hyperactivity disorder (ADHD) and
non-ADHD boys: differences in empathic responding.
AB - This study examined differences in empathy and other emotions between boys with
and without attention deficit-hyperactivity disorder (ADHD). Empathy was measured
by an empathy response task (ERT) and through self- and parent reports of
emotion. On the ERT, children responded verbally to 8 fictitious stories. Results
from the ERT revealed that boys with ADHD were less empathic than boys without
ADHD. Boys with ADHD less frequently matched the emotion they identified in the
character with the one identified in themselves and gave fewer character-centered
interpretations in their descriptions of the character's emotion. Parent-report
data revealed that boys with ADHD exhibited more behavioral manifestations of
sadness, anger, and guilt than did boys without ADHD. No differences were found,
however, on measures of emotional intensity or emotional reactions to external
contingencies. The results are discussed with respect to current theories of
ADHD.
PMID- 10780133
TI - The presence of security blankets or mothers (or both) affects distress during
pediatric examinations.
AB - Because of parental interference, some pediatricians prefer examining children
without parents nearby. Can inanimate, noninterfering attachment agents placate
children during medical evaluations? Accompanied through random assignment by
their mother, blanket, mother plus blanket, or no supportive agent, 64 blanket
attached or blanket-nonattached 3-year-olds underwent 4 routine medical
procedures. Behavioral and physiological measures showed that mothers and
blankets (for children attached to them) equally mitigated distress compared with
no supportive agents. However, simultaneously presenting 2 attachment agents did
not produce additive soothing effects. For comforting blanket-attached children
during moderately upsetting medical procedures, blankets can function as
appropriate maternal substitutes. Distress evidenced by children with no
attachment agent demonstrates the undesirability of conducting medical
examinations without supportive agents.
PMID- 10780134
TI - A national survey of practicing psychologists' attitudes toward psychotherapy
treatment manuals.
AB - There has been considerable debate and little empirical data on the role of
psychotherapy treatment manuals in clinical practice. Attitudes toward treatment
manuals are a potentially important determinant of how likely practitioners are
to use manual-based treatments in clinical practice. A total of 891 practicing
psychologists nationwide were surveyed about their attitudes toward treatment
manuals and their ideas about the content of manuals. Practitioners held widely
varying attitudes toward treatment manuals, and ideas about what constitutes a
manual were associated with attitudes in a predictable way. Recommendations are
made for how to gather more useful information about practitioners' attitudes
toward the many changes affecting current models of clinical practice.
PMID- 10780135
TI - Therapeutic alliance: predicting continuance and success in group treatment for
spouse abuse.
AB - This study examined the role of the therapeutic alliance between client and
therapist on group treatment outcome in 70 husband-to-wife violent couples.
Strength of husbands' alliance assessed at Session 1 was positively associated
with treatment outcome, as measured by decreased husband-to-wife mild and severe
psychological and physical aggression. Strength of wives' alliance was unrelated
to treatment outcome. Finally, although alliance was related to treatment
outcome, it was unrelated to treatment completion.
PMID- 10780136
TI - Effectiveness of an Internet-based program for reducing risk factors for eating
disorders.
AB - This study evaluated an Internet-delivered computer-assisted health education
(CAHE) program designed to improve body satisfaction and reduce weight/shape
concerns--concerns that have been shown to be risk factors for the development of
eating disorders in young women. Participants were 60 women at a public
university randomly assigned to either an intervention or control condition.
Intervention participants completed the CAHE program Student Bodies. Measures of
body image and disordered eating attitudes were assessed at baseline,
postintervention, and 3-month follow-up. At follow-up, intervention participants,
compared with controls, reported a significant improvement in body image and a
decrease in drive for thinness. This program provides evidence for the
feasibility and effectiveness of providing health education by means of the
Internet.
PMID- 10780137
TI - Integrative behavioral couple therapy: an acceptance-based, promising new
treatment for couple discord.
AB - Although traditional behavioral couple therapy (TBCT) has garnered the most
empirical support of any marital treatment, concerns have been raised about both
its durability and clinical significance. Integrative behavioral couple therapy
(IBCT) was designed to address some of these limitations by combining strategies
for fostering emotional acceptance with the change-oriented strategies of TBCT.
Results of a preliminary clinical trial, in which 21 couples were randomly
assigned to TBCT or IBCT, indicated that therapists could keep the 2 treatments
distinct, that both husbands and wives receiving IBCT evidenced greater increases
in marital satisfaction than couples receiving TBCT, and that IBCT resulted in a
greater percentage of couples who either improved or recovered on the basis of
clinical significance data. Although preliminary, these findings suggest that
IBCT is a promising new treatment for couple discord.
PMID- 10780138
TI - Telephone-administered cognitive-behavioral therapy for the treatment of
depressive symptoms in multiple sclerosis.
AB - This study examined the efficacy of an 8-week telephone-administered cognitive
behavioral therapy (CBT) for the treatment of depressive symptomatology in
multiple sclerosis (MS) patients. The treatment, Coping with MS (CMS), included a
patient workbook designed to structure the treatment, provide visual aids, and
help with homework assignments. Thirty-two patients with MS, who scored at least
15 on the Profile of Mood States Depression-Dejection scale, were randomly
assigned to either the telephone CMS or to a usual-care control (UCC) condition.
Depressive symptomatology decreased significantly in the CMS condition compared
with the UCC condition. Furthermore, adherence to interferon beta-1a, a disease
modifying medication for the treatment of MS, was significantly better at the 4
month follow-up among patients who received CMS as compared with those in the UCC
condition.
PMID- 10780139
TI - Children's perceptions of peers with somatic symptoms: the impact of gender,
stress, and illness.
AB - OBJECTIVE: To investigate how illness characteristics influence children's
responses to ill peers. METHODS: A sample of 363 4th and 5th graders responded to
a vignette describing a peer with abdominal pain. In a 2 x 2 x 2 x 2 design,
conditions varied by (a) evidence for organic disease, (b) presence of stress,
(c) sex of vignette character, and (d) sex of respondent. Children rated symptom
severity, liking for the peer, and whether the peer should be excused from normal
responsibilities. RESULTS: Same sex preferences significantly influenced
children's liking for a peer. Children viewed symptoms with an organic etiology
as more severe than those without one. Under certain conditions, symptom severity
judgments mediated the relation between the presence of organic disease and (a)
liking and (b) granting relief from responsibility. The presence of stress had
little effect on ratings of symptom severity, liking, or relief from
responsibility. CONCLUSIONS: Gender and evidence of organic disease influence
children's perceptions of and responses to symptomatic peers.
PMID- 10780140
TI - Children's attitudes and behavioral intentions toward a peer presented as obese:
does a medical explanation for the obesity make a difference?
AB - OBJECTIVE: To examine the effect of information on children's attitudes and
behavioral intentions toward a peer presented as obese. METHODS: Children (N =
184) were randomly assigned to observe a video of a boy or girl in one of three
conditions: average-weight, obese, obese with medical information explaining the
obesity. They rated stereotypical attitudes on the Adjective Checklist and
behavioral intentions on the Shared Activities Questionnaire (SAQ-B). RESULTS:
Ratings were generally more favorable for the average-weight than for the obese
condition. However, provision of medical information had a positive effect on
attitudes toward the obese peer only for younger children and a negative effect
on willingness of older children to share academic activities with the peer. Boys
and girls showed more positive behavioral intentions toward the same-sex target
child regardless of obesity condition. CONCLUSIONS: Information explaining
obesity has a minimal positive effect on children's attitudes and behavioral
intentions toward a peer presented as obese.
PMID- 10780141
TI - Children with pediatric conditions: can peers' impressions be managed? And what
about their friends?
PMID- 10780142
TI - A reexamination of a childhood cancer stereotype.
AB - OBJECTIVE: To examine whether young adults have stereotypical beliefs toward
children who have been treated for cancer. METHODS: Undergraduate participants
read a vignette describing a child labeled either healthy (HL), in remission from
cancer and no longer undergoing treatment (RCL), or in remission and still
undergoing treatment (RCTL) and rated the child on the Ratings of the Child
Questionnaire (ROCQ). Univariate and multivariate analyses of variance were
conducted. RESULTS: Participants rated the HL child more positively than the RCL
or RCTL child; the RCL and RCTL child ratings did not differ. Females evaluated
the child more positively than did males. CONCLUSIONS: These results support
previous findings of a childhood cancer stereotype. However, effect sizes were
small, which may indicate a weak stereotype with these specific participants.
PMID- 10780143
TI - Beyond mothers and children: finding the family in pediatric psychology.
PMID- 10780144
TI - Response to hypo- and hyperglycemia in adolescents with type I diabetes.
AB - OBJECTIVE: To assess the appropriateness of adolescents' responses to hypo- and
hyperglycemia and to examine the relationship of patient age, gender, diabetes
duration, diabetes knowledge, parental supervision, and glycemic control to
response appropriateness. METHODS: We assessed 125 adolescents' responses to
daily episodes of hypo- and hyperglycemia by 24-hour recall interviews; responses
were coded for type and appropriateness. RESULTS: Adolescents responded
inappropriately to 38% of hypoglycemic and 29% of hyperglycemic episodes.
Parental supervision of blood glucose testing did not increase the likelihood of
an appropriate response; in the case of hyperglycemic episodes, it appeared to be
counterproductive. Adolescents who responded inappropriately to hyperglycemia
were also older but not different from those who responded appropriately by
gender, disease duration, diabetes knowledge, or glycemic control. CONCLUSIONS:
Health providers and family members may underestimate adolescents' difficulty
managing hypo- and hyperglycemia appropriately. The presence of parental
supervision does not ensure an appropriate response; parents may be particularly
misinformed about the management of hyperglycemia.
PMID- 10780145
TI - Brief report: cautions against using the Stanford-Binet-IV to classify high-risk
preschoolers.
AB - OBJECTIVE: To explore concurrent and predictive validity of the Stanford-Binet:
Fourth Edition (SB-IV) by comparing scores on the SB-IV with scores from the
Battelle Developmental Inventory (BDI) and later achievement scores in
preschoolers at risk due to very low birthweight, and/or intraventricular
hemorrhage (IVH) and other medical complications. METHODS: At ages 3,4, and 5, 92
preschoolers were tested with the SB-IV and BDI as part of an 8-year early
intervention follow-up. RESULTS: The SB-IV and BDI concurrent correlations at
ages 3, 4, and 5 were statistically significant (r = .73-.78, p < .0001), as were
predictive correlations (r = .58-.85, p < .0001). However, the BDI and SB-IV
failed to place the children in the same categories for intervention services.
With the BDI as the comparison measure, SB-IV failed to detect 87% of the
children who were "delayed" (by BDI) at age 3 and 50% of the "delayed" children
at age 5. CONCLUSIONS: Caution is recommended when using the SB-IV to assess high
risk for early intervention eligibility.
PMID- 10780146
TI - Cognitive and psychomotor development of infants with orofacial clefts.
AB - OBJECTIVE: To compare at ages 3, 12, and 24 months the cognitive and psychomotor
development of 29 infants with cleft lip and palate (CLP), 28 infants with cleft
palate only (CPO), and a demographically matched comparison (COMP) group of 69
infants; to examine predictors of cognitive status at age 24 months in the cleft
group. METHODS: Infants were administered the Bayley Scales of Infant Development
(BSID), mother-infant interactions were observed, and medical records were
reviewed. RESULTS: CLP and CPO groups scored lower than the COMP group on the
BSID, but did not differ from one another. Cleft group infants scored lower than
COMP group infants on BSID items assessing nonverbal and expressive language
skills. Quality of maternal interaction predicted the 2-year Mental Development
Index (MDI) scores of infants with clefts. CONCLUSIONS: Infants with clefts show
relative deficits in cognitive and psychomotor development. Cognitive deficits
are apparent in nonverbal as well as verbal areas of performance.
PMID- 10780147
TI - The autopsy in the 21st century: time for reconsideration.
AB - In recent years, the autopsy rate has dramatically declined. Using three cases,
we attempt to explore the current questions concerning the value of the autopsy.
The discussion centers around the importance of the autopsy to medicine and
family members of the deceased, the impact of technological advances on the
autopsy, and discordant pre- and post-mortem diagnoses. We conclude that the
decrease in autopsy rates is secondary to underutilization of the autopsy as a
diagnostic and educational tool.
PMID- 10780148
TI - Noninvasive estimation of pulmonary capillary wedge pressure from computed
radiography.
AB - PURPOSE: This study was undertaken to see if computed radiography (CR) could be
used to estimate pulmonary capillary wedge pressure (PCWP). METHODS: Radiographic
measurements of pulmonary artery-bronchus ratios (ABR), cardiomegaly,
interstitial edema, alveolar edema, and pleural effusion, obtained from portable
CR images of patients admitted to an intensive care unit, were compared to
hemodynamic measurements of PCWP. We prospectively predicted a normal PCWP when
ABR was < or = 1.0, and an elevated PCWP when ABR was > or = 1.1. RESULTS: There
was a significant difference between mean ABR in those with normal PCWP (1.014 +/
0.259) and those with elevated PCWP (1.422 +/- 0.234) (p < 0.0001). There was a
positive correlation between PCWP and ABR (r = 0.38, r2 = 0.147, p = 0.0001). ABR
was 95% sensitive, 86% specific, and 93% accurate in predicting PCWP (p =
0.0001). Cardiomegaly, interstitial edema, alveolar edema, and pleural effusion
were not as useful. CONCLUSIONS: Measurements of ABR from portable CR images can
be used to estimate PCWP.
PMID- 10780149
TI - The medico/legal year in review--1999.
PMID- 10780150
TI - Procuring for profit ... a fetal dilemma.
PMID- 10780151
TI - [Classical themes].
PMID- 10780152
TI - [Psychotherapy of posttraumatic stress disorders].
AB - Since the diagnosis of posttraumatic stress disorder (PTSD) was introduced in DSM
III in 1980, a variety of psychotherapeutic approaches have been developed to
address the specific problems and needs of traumatized patients. Successful
treatment of PTSD requires a well thought-out therapeutic attitude. The therapist
must find a well-balanced position between over-identification and turning away
out of helplessness. A sensation-seeking attitude should be avoided as should the
danger of vicarious traumatisation. In many instances, PTSD can not be treated
sufficiently by psychotherapy alone: a comprehensive, multi-modal treatment plan
may include pharmacotherapeutic, physical, social, legal, and other
interventions. Early psychotherapeutic interventions in the immediate aftermath
of a traumatic event follow the rules of crisis intervention (immediacy, focus on
the current problems, time limitation). Special attention should be paid to the
issues of developing a trusting therapeutic relationship, creating an atmosphere
of safety, helping the patient to regain control over and/or distance himself
from intrusive recollections. Eye Movement Desensitization and Reprocessing
(EMDR) and other "power therapies" can offer quick relief from symptoms. After
collective traumatization, psychological debriefings are widely used although the
evidence for their usefulness in preventing PTSD is questionable. In patients
with chronic PTSD, the psychotherapist should not work exclusively on the
traumatic event and its sequelae: treatment should be oriented towards the future
rather than the past. Instead of exploring, the therapist should try to activate
the patients' resources and help them to find new meaning in their future life.
PMID- 10780153
TI - [ "Weight phobia". A discussion of the problem of "atypical" and "not otherwise
specified" eating and weight disorders].
AB - A number of authors have stated that the problem of classifying patients whose
diagnosis does not meet all the criteria of anorexia and bulimia nervosa has not
been satisfactorily solved. The question has been asked if it is justified to
regard characteristics like "weight phobia" or body image disturbance as valid
diagnostic criteria. In the present study the differences observed in three
groups of patients with eating and weight disorders (anorexia: n = 42; bulimia: n
= 29; atypical group without "weight phobia": n = 14) were compared using the
Giessen-Test. The atypical group was shown to be significantly more "tractable"
on scale 2 than the main groups, which achieved a higher score on "dominance".
Significant differences between the atypical group and the "uncontrolled" group
of patients with bulimia were noted for scale 3, with the atypical group showing
comparable results to those recorded in the anorexic group on "compulsiveness".
The authors discuss the significance of the results under an epistemological
aspect. The description and classification of clinical phenomena which is based
on the clinical manifestation of the disorder independently of theoretical
concepts is therefore indispensible for realising a uniform basis for
communication by researchers worldwide. Equally indispensible is the
differentiation or "extension" of the classification to allow a more detailed
systematic categorisation guided along specific theoretical concepts. This
requires the operational definition of psychopathological and psychodynamic
criteria as, e.g. "the struggle for identy" or the "relentless pursuit of
thinness". The experiences with the OPD (Operationalized Psychodynamic Diagnosis;
1996) have shown this to be a difficult but viable approach.
PMID- 10780155
TI - [The effectiveness of the initial interview at a psychosomatic- psychotherapeutic
outpatient unit].
AB - In a cross sectional study of 1945 consecutive patients seen at a psychosomatic
psychotherapeutic outpatient unit between 1993 and 1995, we investigated how the
therapists assessed the effectiveness of their work and what correlations there
were with patient characteristics and with the way the therapists conducted the
initial session. The therapists' ratings indicated that about two thirds of the
patients benefited from the consultation. In the multivariate analysis of the
data the most important determinants of effectiveness were found to be the
patient's motivation, the ICD diagnosis, the patient's level of personality
organisation and the reason for the consultation. In addition, we did a one-year
follow-up of 260 patients to analyse the determinants that help patients to agree
to the proposed treatment plan. Of the 235 patients for whom treatment was
recommended, 174 (74%) actually began a treatment program. Our results show that
a patient is more likely to accept the treatment recommendation if the therapist
conducts the session in a certain way (e.g. provides detailed information) and
helps the patient to find an appropriate therapist.
PMID- 10780154
TI - [Long-term changes in borderline symptoms of patients after client-centered group
psychotherapy].
AB - In a follow-up study the long-term changes of borderline symptomatic of 14
patients with the diagnosis borderline personality disorder (criteria by Kernberg
and Rorschach test) are compared with 13 patients with diagnosis schizophrenia
and 16 patients with diagnosis depression (each case according to ICD-9
criteria). The Diagnostic Interview for Borderline Patients (DIB) is evaluated to
comprehend the structure and kinds of borderline symptoms before and 4 years
after treatment. Borderline patients are treated in a setting of client-centred
group psychotherapy (twice a week, approximately 100 sessions). The treatment of
the patients joining the control group is based on clinical standard. As a result
all patients reduced the borderline-like symptoms. However, the most significant
changes can be seen in the borderline group. 2 out of 14 borderline patients
still fulfill the DIB Criteria of borderline personality disorder. Nevertheless,
there are differences in the reduction of specific categories of borderline
symptoms. The greatest changes are in the categories "loss of impulse control"
and "psychotic episodes", whereas there are only slight improvements in the
category "interpersonal relationships".
PMID- 10780156
TI - [Do patients with rheumatoid arthritis suppress anger and aggression?].
AB - Given the contradictory findings on aggression in patients with rheumatoid
arthritis (RA), this topic was examined again in two studies. In both studies RA
patients and patients with arthrosis were compared (in-patients in study I, n =
28 in each sample; out-patients in study II, each sample comprising 22 subjects).
Two aggression/anger inventories (Fragebogen zur Erfassung von
Aggressivitatsfaktoren = FAF and State-Trait-Anger-Expression Inventory = STAXI)
with a total of 10 scales were used for comparison. Samples were matched for
gender and age; duration and severity of illness were used as covariates. No
replicable differences between groups were found in any variable. Our results do
not support aggression theories of rheumatoid arthritis.
PMID- 10780159
TI - [Self concept and parental images in patients with affective disorders--a
clinical study with the Giessen Test].
AB - The relationship between self, ideal self and normative self was studied in a
sample of 139 patients with affective disorders and 73 patients with orthopaedic
complaints. The depressive patients showed significant-asymmetric relationships
between self and ideal self even after recovery from the clinical depression.
Neurotic depressive patients could be distinguished from unipolar depressive
patients in this regard. The self-concept of the depressive patients was
characterised by means of the bipolar Giessen-test dimensions "insufficiency of
performance", "lack of social adjustment" and "lack of social contact" and by
means of the GT-dimensions "negative social resonance" and "depressive mood".
There were no specific relationships between self-image and parental images in
the depressive sample. The results underline the necessity of therapeutic
interventions in depressive patients during the so-called symptom-free interval.
PMID- 10780157
TI - [Comorbidity of diabetes mellitus and eating disorders. A comparison of
psychological features of eating disordered and non-eating disordered patients
with diabetes mellitus].
AB - As part of a multicentre study on the comorbidity of diabetes mellitus and eating
disorders, the following paper compares the psychological features of diabetic
patients with and without an eating disorder. In a sample of 663 diabetic
patients (type 1: n = 341 type 2: n = 322), eating disorder related variables,
self-esteem, body acceptance and emotional distress, especially depression in
diabetic patients with and without an eating disorder, were compared. A possible
relationship to diabetic control was investigated. Type 2 diabetics revealed more
pronounced psychopathology in comparison to type 1 diabetics. According to our
assumption, diabetic patients with an eating disorder and diabetic patients who
deliberately reduced insulin in order to loose weight (insulin purging) revealed
a much more severe psychopathology compared to diabetics without an eating
disorder. The type of diabetes was of no importance. With the exception of the
variable body and figure satisfaction in the sample of type 1 diabetes and the
variable self-acceptance in the sample of type 2 diabetes, no relationship to
diabetic control could be found.
PMID- 10780158
TI - [What are the physical complaints without pathological clinical signs in patients
with diabetes mellitus?].
AB - In previous research it was found that patients with diabetes mellitus suffer
from multiple physical symptoms even early in their disease course. Such
complaints may relate to blood glucose levels or can be understood as a sign of
distress in respect to the diagnosis of a chronic disease. PURPOSE: This study
was performed to evaluate in a cross-sectional analysis all the symptoms that
patients may complain of and to relate these symptoms to a possible dysfunction
of the autonomic nervous system. METHOD: We assessed the complaints of 66
patients with diabetes mellitus and compared these variables with those of
patients with psychological disturbances (n = 794) or somatic disease (n = 162).
The symptoms were recorded by means of several questionnaires such as the
"Giessener Beschwerdebogen" (GBB), "the Freiburger Personlichkeitsinventar"
(FPI), the German version of the State Trait Anxiety Inventory (STAI) and the
German version of the State Trait Anger Expression Inventory (STAXI). The
autonomic nervous system was assessed using resting and mental stress conditions
in a subset of patients with diabetes mellitus (n = 29) and psychological
disturbances (n = 44). RESULTS: Patients suffering from diabetes mellitus and
psychological disturbances showed a tendency to higher scores in GBB, STAI and
STAXI. As far as psychological disturbances are concerned, the complaints
experienced by patients with diabetes mellitus were found to be similar to those
with somatic diseases. Both groups, however, rate clearly below those with
psychological disturbances. The results of autonomic testing showed a significant
disturbance in patients with diabetes mellitus with reduced sensitivity of the
baroreceptor indicating autonomic neuropathy. CONCLUSION: Some of the physical
complaints of patients with diabetes mellitus can be understood in connection
with autonomic dysfunction. Moreover, an explicitly psychological view of these
complaints may not be correct.
PMID- 10780160
TI - [Religiosity and subjective well-being].
AB - More than 200 studies showed correlations between religiosity and mental health,
which are predominantly positive, but also negative and neutral. A model is
proposed, which refers not only to clinical perspectives, but also to the
sociological research concerning the relationships between religiosity and
subjective well-being (life satisfaction, happiness etc.). This model
conceptualizes subjective well-being as a protective counterpart to mental health
deficits. More specifically, this model describes important processes of
religiously motivated social interaction and intrapsychic regulation of emotions,
and interprets them as interactions between religiosity and subjective well
being.
PMID- 10780161
TI - [Emotional experience, expression and communication in musical improvization. A
qualitative-quantitative single case study].
AB - In this study the theory-conducted empirical procedure for analyzing active
improvisatory music therapy of a single case will be described. The
operationalization and tests for validation will be described. According to the
aim of the study, the results show that the used method is appropriate to
describe different and repetitive (emotional) patterns of improvisatory playing,
which reflect the personal (emotional) and interpersonal pathology and healthy
parts of the examined patient. With the aid of several tests the results of
validating the macro-process will be discussed.
PMID- 10780169
TI - Porcine reproductive and respiratory syndrome virus (PRRSV): kinetics of
infection in lymphatic organs and lung.
AB - Pigs were infected by the oronasal route with European isolates of the porcine
reproductive and respiratory syndrome virus (PRRSV; I10 and Cobbelsdorf). The
kinetics of infection in lymphatic organs and the lung were analysed by
immunofluorescence detection of virus antigen, re-isolation of the virus and
reverse transcription--polymerase chain reaction (RT-PCR) for PRRSV-specific RNA.
The kinetics of PRRSV infection proceeded in three phases, irrespective of the
varying infestation of lymphatic organs within the first days post-infection
(p.i.). First, an early acute infection of lymphatic organs developed within the
first week and was characterized by a high number of antigen-positive
macrophages. Second, a delayed acute infection of the lung was observed, which
was most pronounced during the second and third week p.i. when a high number of
infected alveolar macrophages was observed. The acute infection of lymphatic
organs had resolved at this time. Infected cells in the lung were predominantly
located in pneumonic lesions. Third, a persistent infection was demonstrated by
RT-PCR and immunohistology when the experiments were terminated at day 49 p.i.
The virus persisted in lymphatic organs, especially in the tonsils, and in the
lung. At this stage, indications for a re-occurrence of acute infection were
observed in restricted areas of the lung.
PMID- 10780168
TI - The in vitro secretion of acetylcholinesterase by adult stages of Heligmosomoides
polygyrus: the effects of broad-spectrum anthelmintics.
AB - The secretion of acetylcholinesterase (AChE) by female and male Heligmosomoides
polygyrus was studied in different in vitro culture media. AChE secretion was
increased in the presence of fetal calf serum or bovine serum albumin (BSA). In
the absence of crowding effects, specific AChE activity in excretion/secretion
products was higher for male (2.41 +/- 0.07 mumol min-1 l-1 mg-1) than for female
(0.56 +/- 0.04 mumol min-1 mg-1) worms but on a per nematode basis both sexes
showed comparable rates of secretion. Acetylthiocholine iodide was the favoured
substrate of the enzyme. When the nematodes were incubated in vitro with
albendazole (ABZ), ricobendazole (RBZ), mebendazole (MBZ), levamisole (LVM),
morantel (MRT) or ivermectin (IVM), at concentrations from 1 mM to 10 nM, in RPMI
medium for 2 or 6 h and then transferred to a drug-free medium (RPMI medium
supplemented with 0.5% BSA) for 24 h or continuously exposed to the drugs in
supplement-free medium (24 h), the concentration- and time-dependent inhibitory
effects on AChE secretion were observed. The continued exposure to the drugs for
all incubation periods (with a single exception for LVM 1 mM) produced the
highest levels of inhibition. Under these conditions, the concentrations
inhibiting the secretion of AChE by 50% (IC50) relative to drug-free controls
were estimated. The IC50 values ranged from 0.012 microM (IVM) to 2.96 microM
(MRT). The potential of this bioassay for the selective primary evaluation of new
compounds with broad-spectrum anti-nematodal activity is discussed.
PMID- 10780170
TI - Use of an alkaline phosphatase-labelled probe for the detection of Mycoplasma
synoviae in chickens.
AB - Short nucleotides directly labelled to alkaline phosphatase (SNAP probes) are an
interesting alternative to digoxigenin-labelled probes (DIG probes), because they
reduce the number of steps necessary in dot blots for the detection of DNA or
amplificate. This study examined the questions whether a SNAP probe might not
only save time, but also increase the sensitivity of another PCR-based DNA probe
test using a digoxigenin probe. Amplificates obtained by multispecies polymerase
chain reaction (PCR), with either purified genomic DNA or DNA extracted from
tracheal swabs taken in chicken flocks, were detected by both methods. The
results for the clinical specimens were compared to culture. Under stringent
conditions, the specificity and sensitivity obtained with the SNAP probe were
comparable to the results obtained with the DIG probe. The quantities 10 fg (SNAP
probe) and 100 fg (DIG probe) of purified Mycoplasma synoviae DNA were detected
after amplification, but more positive clinical specimens were detected with the
DIG probe. Under non-stringent conditions sensitivity with purified DNA did no
change, but the coloration of the dots improved markedly, and more positive
specimens could be detected with the SNAP probe than with the DIG probe, truly
positives as confirmed by culture. Because cross-reaction with Mycoplasma
gallisepticum and Mycoplasma imitans, two species with DNA that was also
recognized by the multispecies primers, occurred under non-stringent conditions,
it was concluded that, to take the full advantage of SNAP probes, their use in
combination with species-specific primer pairs is recommended. PCR as a method
for mycoplasma detection is however, always accompanied with serological and
cultural methods. When a M. synoviae mono-infection is likely by serological
results, non-stringent dot blot conditions and use of the SNAP probe will ease
and improve the detection of mycoplasma.
PMID- 10780171
TI - Airborne gram-negative bacterial flora in animal houses.
AB - The concentration and the species composition of airborne gram-negative bacteria
were studied in four cattle houses, one pig house and one poultry barn. On
average only between 0.02 and 5.2% of the total number of culturable aerobic
bacteria were identified as gram-negative bacteria. Obligate anaerobic gram
negative bacteria were not isolated at all. In the airborne gram-negative
bacterial flora the following bacterial families dominated: the
Enterobacteriaceae, the Pseudomonadaceae and the Neisseriaceae. Within the family
of the Enterobacteriaceae the species Escherichia coli and Enterobacter
agglomerans were predominant. In animal houses using straw as bedding material
Ent. agglomerans was most frequent, whereas in animal houses without litter E.
coli was mainly found. Airborne Neisseriaceae were isolated very frequently in
cow barns with Acinetobacter lowffii as the primary species. Airborne
Pseudomonadaceae were found in high concentrations during periods of high air
humidity. The results presented may also give some indications on the origin and
sources of airborne endotoxins in animal housing.
PMID- 10780172
TI - Neospora caninum infection in a clinically healthy calf: parasitological study
and serological follow-up.
AB - In this study a case of congenital infection in a clinically healthy calf is
reported. The mother showed high antibody levels (IFAT) at 230 days of gestation
(IgG titres > or = 1:1600, IgM titres > or = 1:320) and the parasite was isolated
from placental cotyledonary villi at calving. The IgM values are indicative of a
recent infection in the third trimester of gestation. The calf was monitored
serologically for IgM and IgG from birth until slaughtering, at 8 months of age.
IgM titre showed a peak at birth, while IgG peak was observed at 40-60 days of
age. Parasitic isolation was obtained by biological tests using Swiss mice or
VERO cell cultures inoculated with brain and spinal cord tissues. The parasitic
presence in the calf was also evidenced in the myocardium with
immunohistochemical method. The results are very important because they
demonstrate that the period of gestation in which the cow becomes infected is an
important factor in the pathogenesis of N. caninum induced abortion: in fact, the
acquisition of infection in the third trimester of gestation allowed the foetus
to develop a sufficient grade of immunocompetency to limit parasite
multiplication with the result of a calf born clinically healthy.
PMID- 10780173
TI - Abscess disease, caseous lymphadenitis, and pulmonary adenomatosis in imported
sheep.
AB - The occurrence of abscess disease, caseous lymphadenitis, and pulmonary
adenomatosis in sheep in Denmark is reported for the first time. Subcutaneous
abscesses were observed in imported 4- to 5-month-old lambs of the Lacaune breed
10 days after arrival in Denmark. Abscesses were mostly located in the head, neck
and shoulder regions close to the regional lymph nodes. Bacteriological
examinations revealed growth of Staphylococcus aureus ssp. anaerobius in all
animals with subcutaneously located abscesses containing a viscous white-yellow
odourless mass. In addition, Corynebacterium pseudotuberculosis was isolated from
abscesses in one animal and lesions consistent with pulmonary adenomatosis were
found in four animals.
PMID- 10780174
TI - Isolation of Mycoplasma meleagridis from free-ranging birds of prey in Germany.
AB - In this study tracheal swabs and air sac biopsies of 68 raptors of different
species that were found injured or debilitated in Germany were investigated for
the occurrence of mycoplasmas. Mycoplasma meleagridis, Mycoplasma falconis,
Mycoplasma buteonis, Mycoplasma gypis and five mycoplasma isolates not identified
so far could be isolated from 32 (47%) birds. Mycoplasma meleagridis could be
detected in five birds. These birds did not show clinical signs or
histopathological alterations in air sac biopsies related to the infection.
PMID- 10780175
TI - Inactivation of bovine herpesvirus 1 in semen using a hyperimmune egg yolk semen
extender.
AB - Hyperimmune egg yolk semen extender was used for the inactivation of bovine
herpesvirus (BHV-1) in experimentally infected bovine semen. As much as 5 x 10(4)
TCID50/ml of virus was inactivated in semen as assayed by tissue culture.
Moreover the hyperimmune egg yolk semen extender did not produce any adverse
effect on the quality of the semen after being frozen/thawed in comparison with
normal egg yolk semen extender (P > 0.05). The hyperimmune egg yolk semen
extender is considered an important tool for containing the spread of BHV-1 from
infected semen.
PMID- 10780176
TI - [Results of molecular screening of anti-cancer agents. 8. Results of screening of
possible anti-cancer agents in Japan].
PMID- 10780177
TI - [Results of the evaluation of anti-cancer agents by using human cancer cell
panels: details of interpretation].
PMID- 10780178
TI - Prescribing influenza vaccine: for whom?
PMID- 10780180
TI - A skin lesion found by serendipity.
AB - A 77-year-old retired postal worker presented with symptoms of recurrent
aspiration pneumonia, for which he had last been seen one month earlier.
Oropharyngeal dysfunction, presumably caused by previous strokes, was
demonstrated by video-esophagoscopy, and a percutaneous gastrostomy tube was
placed at that time.
PMID- 10780179
TI - Abnormal ECG after a head injury.
PMID- 10780181
TI - Inhaled corticosteroids: 1. Local toxicity.
PMID- 10780182
TI - Making meetings work.
PMID- 10780183
TI - Severe back pain and a history of tuberculosis.
PMID- 10780184
TI - Advances in the approach to acute coronary syndromes.
AB - Acute coronary syndromes is a new term that encompasses the many permutations of
acute ischemic heart disease. Management guidelines can help steer clinicians
through diagnosis and facilitate rational selection of therapy from the myriad of
available treatments.
PMID- 10780185
TI - Treatment of latent and tertiary syphilis.
AB - Although the efficacy of penicillin treatment for syphilis has been amply
demonstrated, the optimal, curative dosage is still undefined. Some patients
experience a third stage of the disease long after secondary-stage symptoms have
resolved. Treatment differs in early and late latency and with the specific
manifestations of tertiary-stage disease.
PMID- 10780186
TI - Controlling cancer pain.
AB - More than a third of patients undergoing therapy for cancer and 60% to 90% of
those with advanced malignancy report significant pain. Effective analgesic
therapy is available, yet large segments of this population--in particular,
elderly patients in nursing homes, minorities, and women--receive inadequate
palliative therapy.
PMID- 10780187
TI - Improving communication with patients.
AB - Aspects of patients' emotional or mental states--such as anger or unspoken
assumptions about health and illness--can complicate management of their physical
illness. Proper communication techniques can help the physician break through
those barriers to medical care and strengthen the therapeutic relationship.
PMID- 10780188
TI - Addressing the dramatic rise in multiple pregnancies.
AB - Practitioners of reproductive medicine have come under scrutiny and criticism
because of the sharp increase in multi-fetal gestations during the past two
decades. Several factors contribute to the problem. However, the negative
consequences of multiple pregnancy are now generally acknowledged, and active
efforts toward a solution are underway.
PMID- 10780190
TI - [Malignant lymphoma. Epidemiologic review of 150 cases].
AB - In the present paper the incidence of lymphomatous disease in Messina and its
province, with growing urbanization and rural limiting areas, is discussed: by
analysing 150 cases of malignant lymphoma observed at our Institute from 1990 to
1995. The method proposed, based on data obtained from the medical files of these
patients, took into consideration various parameters such as age, sex, residence,
profession, clinical and bioptic diagnosis, LDH and disease presentation. The
final results showed an increase of the risk for NHL in the rural province where
the main profession is agriculture or handicraft (ceramics, forged iron,
glasswork, refinery), in subjects above 60 years of age; for the HL instead, over
the years, a minor incidence of risk has been observed. The data obtained were
partially similar to those reported in the international literature. The most
present form in NHL was the lymphocytic and the centrocytic follicular form,
while for HL it was the mixed cells form. The relationship between the two sexes
was higher in males with HL and almost equal in NHL. The age range mostly
affected by HL was between 25 and 65 years of age.
PMID- 10780189
TI - [Elevated levels of lipoprotein(a) are present in subjects with early ischemic
cardiopathy and with a familial history of ischemic cardiopathy].
AB - BACKGROUND: Elevated levels of lipoprotein(a) are associated with a greater risk
of atherothrombotic cardiovascular diseases. Since the Lp(a) levels are
genetically determined and fairly stable in the course of life and a family
history appears to be an independent risk factor of cardiovascular diseases, we
evaluated the behavior of Lp(a) levels in patients with early events of coronary
heart disease (CHD) and also in subjects with positive family history of ischemic
heart diseases. METHODS: The levels of lipoprotein (a) [Lp(a)] were measured in
254 subjects, 138 males and 116 females with an average age of 48.6 +/- 13.8
years (range 20-76 years). Diabetic subjects, females submitted to oestrogen
treatment and those already in treatment with hypolipidaemic drugs were excluded
from the study. Forty of the 254 patients (15.7%), 27 males and 13 females, had
CHD (29 a previous myocardial infarction and 11 a stable angina). A positive
family history for CHD was considered present (102 of the 254 patients) if one or
more first degree relatives had angina or myocardial infarction before the age of
60 years in men and 65 in women. RESULTS: The levels of Lp(a) were higher (p <
0.01) in women (25.1 +/- 28.3 mg/dl) compared to men (17.6 +/- 18.4 mg/dl),
without differences in relation to age. The Lp(a) plasmatic levels were not
correlated with age, body mass index, total cholesterol, LDL and HDL,
triglycerides, apo B, apo AI, fibrinogen and there were no differences in Lp(a)
levels in presence or absence of other known cardiovascular risk factors such as
hypertension and smoking. The Lp(a) levels were not different between subjects
with CHD (28.15 +/- 31.7 mg/dl) and controls (20.3 +/- 22.8 mg/dl). The subjects
with CHD were older and had higher levels of fibrinogen and a significantly
greater prevalence of hypertension and family history of CHD. Fifteen of the 40
subjects with CHD had an early onset of CHD (before 50 years of age) and only in
such patients the Lp(a) levels were significantly greater compared to controls
(35.8 +/- 33.2 mg/dl vs 20.3 +/- 22.8 of the controls, p < 0.01), independently
of other variables (age, BMI, smoking, hypertension, cholesterol, triglycerides,
HDL-c, LDL-c, fibrinogen). Furthermore the Lp(a) plasmatic levels were higher in
subjects with a family history of CHD (28.3 +/- 27.6 mg/dl vs 16.3 +/- 18.6 mg/dl
of the subjects without a family history of CHD, p < 0.01) even if they had or
not had a previous coronary ischemic event. CONCLUSIONS: Such data confirm the
importance of high levels of Lp(a) above all for the early events of CHD and for
the subjects with a family history of CHD, which could be expression of a greater
predisposition for cardiovascular events.
PMID- 10780191
TI - [Indices of disease activity in systemic lupus erythematosus. Review of the
literature].
AB - Systemic lupus erythematosus is a multisystem autoimmune disease characterized by
the production of autoantibodies reacting with many different self antigens. The
analysis of clinical expression and evolution of this disease is a milestone in
the definition of therapeutic strategies. A parameter universally accepted as
gold standard is lacking so far. About 60 indices for defining and measuring the
activity of this disease have been proposed in the last 20 years. The most
important of these are discussed in this review, focusing both on their role in
the evaluation and outcome of patients and on the main studies assessing their
validity and reliability.
PMID- 10780192
TI - A man with worsening weakness.
AB - The contemporary presence of organomegaly, skin manifestations, polyneuropathy,
endocrinopathy and monoclonal component characterises the POEMS syndrome, often
associated with osteosclerotic myeloma and Castelman's disease and more frequent
in the Japanese. Clinical manifestations seem to be related to the production of
many interleukins, mainly IL-1, IL-6 and TNF. Several endocrinopathies have been
described, the most frequent being diabetes. Only one previous case of
hypoparathyroidism associated with the syndrome has been described in medical
reviews. Polyneuropathy is often sensitivo-motory and skin disease accounts for
Raynaud phenomenon, skin pigmentation, hypertricosis and others. We describe the
case of a 74-year-old man who underwent clinical examination for weakness mainly
in the legs. Clinical and instrumental data showed rhabdomyolysis due to
hypoparathyroidism. The contemporary presence of a monoclonal band of light
chains on proteic electrophoresis, organomegaly and distal leg neuropathy allowed
us to make a diagnosis of POEMS syndrome.
PMID- 10780193
TI - [Mirizzi syndrome].
AB - Mirizzi's syndrome is a rare, but well described cause of obstructive jaundice
which occurs in less than 1% of patients presenting for cholecystectomy. The
syndrome is due to a stone impacted in the cystic duct or in the neck of
gallbladder, causing compression or obstruction of the common emphatic duct. The
clinic, physiopathologic, diagnostic and therapeutic aspects of this disease are
described. The patient observed, arrived in emergency with obstructive jaundice
and hyperpyrexia. Echography showed a remarkable dilatation of the biliary ducts,
whereas endoscopic retrograde cholangiography (ERCP) showed an obstruction of the
hepatic common duct of undefinable nature (stone, neoplasia). The surgical
operation performed in emergency made clear the diagnostic doubt. Since
inflammation impacted biliary duct and gallbladder, an incision of the
gallbladder at its fundus was performed. In this way it was possible to extract
about 40 stones of dimensions less than 1 cm, and one of 3 x 1 cm, impacted in
the cystic duct, compressing the common hepatic duct. A partial cholecystectomy
was performed and no connection between gallbladder and common emphatic duct
(fistula) was found. The surgical operation led to complete resolution of the
symptomatology. Therefore, the conclusions is drawn that Mirizzi's syndrome a
rare but non infrequent pathology, finds its definition and complete resolution
with surgical operation. Mirizzi's syndrome or obstructive jaundice due to
extrinsic compression of principal biliary duct by a stone impacted in the cystic
duct, is an uncommon complication of cholecystic lithiasis. Although this
syndrome is rare (1%), it causes obstructive jaundice, sometimes dangerous, and
serious complications as recurrent cholangitis.
PMID- 10780194
TI - [Changes caused by mineral water on gastrointestinal motility in patients with
chronic idiopathic dyspepsia].
AB - BACKGROUND: The antidyspeptic property of mineral waters has been based for ages
on empirical data. In the present paper the effects of one of them (Tettuccio,
Montecatini) on gastrointestinal motility of patients with dyspepsia has been
evaluated. METHODS: The study was carried out on 24 patients with idiopathic
dyspepsia and delayed gastric emptying at scintigraphy and 18 healthy subjects
with normal gastric emptying. The gastric emptying of this mineral water was
studied with a scintigraphic method in comparison with tap water, while its
effects on gastroduodenal contractions were evaluated by of manometry. RESULTS:
The gastric emptying of this mineral water was significantly faster than that of
tap water, both in dyspeptic patients and in normals. Manometric examination
showed that the administration of mineral water induced a brief decrease of
phasic motor activity, followed by a progressive increase, which in some cases
ended in an activity front of the Migrating Motor Complex. CONCLUSIONS: This
mineral water has a stimulating effect on both gastric emptying and
interdigestive cyclic motor activity of the gastroduodenal tract. Both these
effects could be useful in the treatment of chronic idiopathic dyspepsia and
impaired gut clearing.
PMID- 10780195
TI - [Acquired angioneurotic edema. Clinical and biological characteristics in 9
patients].
AB - OBJECTIVE: Angioneurotic edema (AE) is a rare but severe disease. Hereditary AE
is the more well-known form. The acquired form is exceptional: the symptoms are
the same but there are some biologic and treatment differences. We investigated
the clinical and biochemical features in nine patients with acquired
angioneurotic edema (AAE). PATIENTS AND METHODS: Four of the patients with type I
AAE presented an accelerated metabolism of C1Inh, associated with a hematology
disease. Their C4, C1q and C1Inh plasma levels were low. Four patients had type
II AAE associated with an autoantibody to C1Inh. Their C1Inh plasma levels were
normal or low but the functional levels were low in all four. One patient had AAE
induced by oral contraceptives. The C1Inh plasma level was normal but the
functional level was very low; there were no autoantibodies. Symptoms resolved
when oral contraceptives were withdrawn and the C1Inh level returned to normal.
DISCUSSION: Treatment of AAE is a difficult matter. For type I AAE, it consists
in treating the associated disease. For type II AAE, the treatment goal is to
lower the autoantibody level. Management of these diseases requires close
collaboration between clinicians and biologists.
PMID- 10780197
TI - [Drug hypersensitivity syndrome to valproic acid].
AB - BACKGROUND: Drug-induced hypersensitivity syndrome is an uncommon but potentially
life-threatening idiosyncratic drug reaction. It is usually due to aromatic anti
convulsants. We report the second case induced by sodium valproate, a non
aromatic anticonvulsant. CASE REPORT: A 28-year-old woman was treated with sodium
valproate for 5 weeks. She suddenly developed a generalized maculo-papulous
eruption with fever, node enlargement, hypereosinophilia and altered liver
function. DISCUSSION: Drug-induced hypersensitivity is rarely induced by valproic
acid. The time-course and positive patch tests using the diluted drug establish
the diagnosis.
PMID- 10780196
TI - [Bepridil: importance of serum level in treatment surveillance].
AB - OBJECTIVE: Despite precise recommendations for prescription and monitoring,
tosades de pointes is still observed with bepridil. The purpose of this study was
to demonstrate the contribution of bepridil serum assay in therapeutic
supervision. PATIENTS AND METHODS: Seventy-five patients over 70 years of age
were included. Prolongation of the QT interval was observed in 23 patients.
RESULTS: The potential prognostic factors for increased QT interval as
demonstrated by univariate logistic regression were hypokaliemia, bradycardia,
renal failure and bepridil serum level. After multivariate logistic regression,
the persisting causal factors for increased QT interval were hypokaliemia,
bradycardia and bepridil serum level. CONCLUSION: Prolongation of the QT interval
remains dependent on several variables. Bepridil determination during treatment
is insufficient alone.
PMID- 10780198
TI - [Leiomyosarcoma of Meckel's diverticulum in cystic form].
AB - BACKGROUND: Leiomyosarcoma is an uncommon small bowel tumor. About 60 cases of a
Meckel's diverticulum localization have been reported. We present a very rare
form of leiomyosarcoma arising in a Meckel's diverticulum, mimicking a very large
abdominal cyst. CASE REPORT: Abdominal ultrasound evidenced a voluminous cystic
mass in the abdomen of a 37-year-old man consulting for abdominal discomfort.
Computed tomography visualized a tissular component with contrast uptake.
Laparotomy was performed with resection of a 4 liter cyst on the Meckel's
diverticulum. Histology reported leiomyosarcoma. DISCUSSION: Leiomyosarcoma of
the small bowel mainly develops in an extraluminal localization. Necrotic
remodeling explains the cyst formation. Computed tomography with contrast
injection can be most helpful for diagnosis. Surgery provides the only possible
cure in still localized forms. Other treatments have failed to demonstrate any
benefit. Prognosis is mainly related to the histological grading according to the
mitotic index.
PMID- 10780199
TI - [Hydatid cyst of the gluteal muscle. Apropos of a case].
PMID- 10780200
TI - [Auriculo-ventricular arrhythmia due to carboplatin].
PMID- 10780201
TI - [Recurrent facial nerve paralysis in hereditary neuropathy with liability to
pressure palsy].
PMID- 10780202
TI - [Peritoneal infections: preventive effect of perioperative supplemental oxygen
administration].
PMID- 10780203
TI - [Frequency and costs of hospital stays for hypoglycemia in France in 1995].
AB - OBJECTIVES: Diabetes is a highly prevalent chronic disease causing serious
complications. Hypoglycemia is the most frequent, the most serious, and the most
feared by patients and families. Hospitalization may be necessary and can be
costly. The main objective of this study was to determine the number of cases of
hypoglycemia cared for annually in France in an inpatient setting and to estimate
the annual financial impact of hospitalizations. PATIENTS AND METHODS: The number
of hypoglycemias seen annually by physician s in France and the frequencies of
hospitalizations for hypoglycemia were determined from a literature search.
Complementary data on costs were obtained from the national PMSI mission. Our
sample included 817 hospital stays between 1994 and 1995. RESULTS: In 1992,
physicians in France cared for 40,000 episodes of hypoglycemia. There were 10,800
hospitalizations. In 9 out of 10 cases, the hospital stay lasted several days
and, despite hospitalization, 1.9% of the patients died. Mean total medical cost
of a hospital stay for hypoglycemia was 14,000 FF ($2,100) (median 10,000 FF,
range 1,200-120,000 FF). Mean length of stay was 6.6 days. DISCUSSION: Mean unit
cost for hospital stays for hypoglycemia is high. Based on the 1993 SESI survey,
the probable annual cost for the society for hospital care of patients with
hypoglycemia was an estimated 108 to 151 million FF ($16-22 million) in 1995.
This figure only takes into account the visible cost of caring for hypoglycemia
patients. Ambulatory care was not taken into consideration. Education, for the
patient and family, is fundamental for the prevention and treatment of
hypoglycemia. CONCLUSION: It is important to have this estimation due to the
absence of a medicoeconomic study on ambulatory and hospital care for
hypoglycemia. Complementary studies should be conducted to estimate the total
annual cost of hypoglycemia in France.
PMID- 10780204
TI - [Hypocalcemia of hypomagnesemia: parathyroid deficiency rather tha parathyroid
resistance].
PMID- 10780205
TI - [Apropos of rubella in pregnancy].
PMID- 10780206
TI - [Fetal pain].
AB - IN UTERO CARE: The definition of pain proposed by the International Association
for the Study of Pain is not adapted to the newborn or to the fetus because it
assumes recognition and verbal expression of an unpleasant experience.
Neonatologists have however demonstrated that full term and highly premature
infants experience pain. In addition, the health of these infants improves with
proper management. Such an approach is indispensable, not only from an obvious
humane point of view, but also because treatment of pain in utero could have a
beneficial effect for the fetus. PRENATAL PAIN AND ITS CONSEQUENCES: As it is
impossible to resolve the question of conscious perception of pain by the fetus,
we use experimental or clinical arguments favoring sensitivity to pain to assess
pain during fetal life. We have also investigated the deleterious consequences of
antenatal pain and how to evaluate them clinically in order to propose
therapeutic care. It can be accepted that the fetus is able to perceive pain as
early as 26 weeks gestation, possibly from 20 weeks. In the short-term, fetal
pain causes changes in behavior, hemodynamics and hormonal functions but the long
term consequences remain unknown. ANTENATAL ANALGESIA: As no validated data on
assessment of pain in the fetus are available, prevention becomes primordial in
all at risk situations (pregnancy termination beyond 24 weeks gestation, in utero
interventions). Morphine derivatives (sufentanil) would be the analgesic of
choice for antenatal pain.
PMID- 10780207
TI - [Causal interactions of estrogens and alcohol in cancer of the breast].
AB - BACKGROUND: The majority of studies and meta-analyses tend to show a very slight
increase of risk of beast cancer in post-menopausal women receiving hormone
replacement therapy (HRT). Such results must however be interpreted in light of
biases including intensive follow-up in women taking HRT and unknown or new
parameters. DATA: Several publications have demonstrated an increased relative
risk of breast cancer in women consuming alcohol. This increase rises linearly
with the level of alcohol intake. To date, this parameter has been neglected in
post-menopausal women taking HRT. Two studies have demonstrated a rise in breast
cancer in women taking HRT who drink alcohol. No particular explanation is put
forward. INTERPRETATION: Based on an experimental human study, E. Ginsburg has
shown that there is a considerable and long-duration increase in estradiolemia in
women on HRT who also drink alcohol. This hyperestradiolemia could exceed the
promotion threshold of breast carcinogenesis. This new parameter must be taken
into consideration as effective preventive measures can be implemented:
convincing women taking HRT to limit their alcohol intake.
PMID- 10780208
TI - [The role of drugs in falls in the elderly. Epidemiologic aspects].
AB - FALLS AND POST-FALL SYNDROME: Falls are a major health problem among the elderly
because of the resulting psychological sequelae (sometimes termed "post-fall
syndrome") and in a few cases serious injury, particularly hip fractures. DRUGS
AND FALLS: The scientific literature on the link between medications and falls
and fractures suggests that psychotropic drugs used in about 50% of residents of
nursing homes and in 20% in the community cause around 30% of falls in nursing
homes and 20% of falls in the community. PSYCHOTROPS: The relative effect of
selective serotonin reuptake inhibitors and tricyclic antidepressors and the
relative effect of short/long acting or sedative/hypnotic benzodiazepines are not
well established. CARDIOVASCULAR DRUGS: Appropriate use of cardiovascular
medications and analgesics does not increase the risk of falls. PREVENTION: These
data reinforce the concept that reducing the use of psychotrops, especially
benzodiazepines, is probably one of the most effective means of reducing serious
falls in older people.
PMID- 10780209
TI - [What possible treatments for liver cirrhosis patients with a small
hepatocellular carcinoma?].
AB - UNDERLYING LIVER DISEASE: Most cases of hepatocellular carcinoma (HCC) develop in
subjects with an underlying chronic liver disease, primarily hepatitis C
infection. The underlying liver disease greatly limits treatment possibilities
due to the restrictions on surgery or the risk of recurrence even when surgical
resection, chemoembolization or alcoholization appears to be successful. IN CASE
OF NORMAL LIVER FUNCTION: Percutaneous destruction of the tumor with
alcoholization or radiofrequency techniques can be effective against HCC tumors
measuring less than 3 cm. Access is however sometimes limited, leading to partial
destruction and risk of local recurrence. When the patient's liver functions are
compatible with surgery, resection of the tumor and its adjacent portal segment
has been found to be effective against tumors measuring 3 to 5 cm.
TRANSPLANTATION: Liver transplantation is by far the most effective treatment for
HCC, treating both the carcinoma and the underlying liver disease. Indications
are however limited to patients with at most 3 tumors measuring less than 3 cm
with no portal involvement and who can be expected to tolerate the major surgery.
In addition, the absence of tumoral extension while waiting for transplantation
is an important factor.
PMID- 10780210
TI - [Fractal geometry: its possible applications to radiologic imaging].
PMID- 10780211
TI - [Dentascan computed tomography of the mandibular incisive canal. Its radiologic
anatomy and the therapeutic implications].
AB - PURPOSE: To stress the importance of CT depiction of the mandibular incisive
canal. This anatomical structure contains a major neurovascular bundle and is
thus very important in the planning of mandibular implants in the canine-incisive
area. MATERIALS AND METHODS: January through December 1998, sixty patients
unselected by age and gender were submitted to mandibular CT. Axial slices were
acquired with 1-1.5 mm thickness and 1 mm table feed, and the images were then
reformatted with a dedicated dental software. Both the conventional and the
Helical techniques were used. RESULTS: The incisive canal appears on Dentascan
transverse reconstructions as a round low-density area within mandibular
trabecular bone, which is surrounded by a higher-density rim representing the
canal walls. This anatomical structure originates from the mental foramen and
continues mesially to the mental symphysis. The mandibular canal was visualized
in 95% of cases bilaterally (57/60); the incisive canal was depicted on the left
side in 41.6% of cases (25/60) and on the right side in 51.6% (31/60).
CONCLUSIONS: The importance of careful assessment of the mandibular canal course
before implantology is now widely recognized. The same holds true for the canine
incisive region in the jaw, to detect the incisive canal if present and prevent
any complications from its accidental damage. CT with a dedicated software showed
the incisive canal in a large number of patients, which calls for precise
reporting of its presence, course, and relationships with teeth.
PMID- 10780212
TI - [Breast carcinoma diagnosed in mammographic screening incidentally. Research on
the radiologic signs in prior mammograms].
AB - PURPOSE: To determine how many cancers screen-detected at subsequent rounds were
already visible on previous screening mammograms, and to study their radiological
features. MATERIALS AND METHODS: The previous screening mammograms of 100 women
who had cancers screen-detected at subsequent rounds (group A), and the negative
screening mammograms of 200 women (group B) who had a further negative screening
test two years later, were mixed for a new reading. The two groups were similar
for age and year of examination. These films were blindly reviewed by 5
radiologists. Then, mammograms were reviewed retrospectively, with knowledge of
subsequent diagnostic results. Finally the A group findings were classified as:
1) true negative: no radiological signs; 2) minimal sign: a nonspecific
abnormality is retrospectively visible at the site of subsequent cancer; 3) false
negative: "she should have been recalled"; 4) misdiagnosis at assessment: the
woman had been recalled, but the cancer was missed after the assessment
procedures. RESULTS: 60% of cases were true negatives, 29% were minimal signs, 9%
were false negative and 2% were misdiagnosed at assessment. The most common
radiological sign found among false negative cases was an architectural
distortion: opacities and calcifications were more frequent among minimal signs.
Only 10 of 40 cancers retrospectively visible on previous mammograms had reached
stage II at diagnosis. At blinded review, the radiologists found false
abnormalities in a considerable number of healthy women (average: 29%).
DISCUSSION AND CONCLUSIONS: Our study shows that mammography sensitivity can be
improved. Cancer radiological signs may go undetected due to difficult
interpretation (opacities, calcifications) or perception (architectural
distortions). The use of a low threshold of suspicion (as in a reading test) in
real screening might permit to detect more cancers (most of them, however, would
not reach advanced stages at subsequent rounds), but might also lead to many
unnecessary assessments and, probably, to some benign biopsies in healthy women.
In conclusion, an attempt at improving mammography sensitivity by lowering the
threshold of suspicion can not be directly recommended due to the considerable
negative effects related to a loss in specificity. A reading test similar to the
one presented in our study would be a useful training procedure for radiologists
who are involved in a screening program.
PMID- 10780213
TI - [Breast calcifications. The usefulness of a standardized system for the
description and assessment of the mammographic findings to improve the positive
predictive value].
AB - PURPOSE: To investigate the usefulness of a standardized reporting and data
system in improving the positive predictive value of mammography in breast
calcifications. MATERIALS AND METHODS: Using the Breast Imaging Reporting and
Data System lexicon developed by the American College of Radiology, we defined 5
descriptive categories of breast calcifications and classified diagnostic
suspicion of malignancy on a 3-grade scale (low, intermediate and high). Two
radiologists reviewed 117 mammographic studies selected from those of the
patients submitted to surgical biopsy for mammographically detected
calcifications from January 1993 to December 1997, and classified them according
to the above criteria. The positive predictive value was calculated for all
examinations and for the stratified groups. RESULTS: Thirty-five of 36 cases
classified as low-grade suspicion at mammography were benign at histology, while
the extant one was a microinvasive lobular carcinoma in situ. Of 44 cases of
intermediate-grade suspicion, 21 were benign while 23 were malignant lesions. All
the 37 cases graded as highly suspicious were actually carcinomas. The positive
predictive value was 0.52 for the whole series, 0.02 in the low suspicion group,
0.52 in the intermediate suspicion group and finally 1.0 in the high suspicion
group. If the low suspicion cases had not undergone surgical biopsy, the positive
predictive value would have been 0.74, with a single false-negative. DISCUSSION
AND CONCLUSION: Defining a standardized system for assessing and describing
breast calcifications helps improve the diagnostic accuracy of mammography in
clinical practice.
PMID- 10780214
TI - [The prognostic significance of 99mTc-MDP breast scintigraphy. A comparison with
histological and molecular parameters].
AB - INTRODUCTION: Breast scintigraphy (BS) with the bone-seeking agent 99mTc
medronate (MDP) can be usefully combined with mammography to diagnose and
characterize questionable breast lumps. However this radiotracer does not seem to
provide any further prognostic information about breast cancer. Therefore we
investigated the prognostic yield of MDP-BS searching for correlations between
scintigraphic findings and the major biological and histologic parameters.
MATERIALS AND METHODS: We retrospectively analyzed a series of 44 primary breast
cancers. All patients had undergone 99mTc-MDP bone scan for preoperative staging,
as well as conventional breast imaging. We statistically compared the
cancer/background ratio (c/b index) with lesion histotype, diameter, grading, and
the tissue concentrations of steroid receptors, cathepsine D, type 1 timidine
kinase, pS2 and p53 proteins. RESULTS: MDP-BS failed to depict 11 of 44 lesions
(O 0.5-2 cm), detected 7 of 16 mammographically questionable lesions and
correctly visualized the two multifocal cases. Also, MDP-BS depicted no
metastatic axillary lymph nodes. We found no statistically significant
correlation between the c/b index and the prognostic markers. DISCUSSION AND
CONCLUSIONS: Differently from BS with 99mTc-MIBI, 201T1, 18F-FDG, 111In-OCT and
radiolabeled estrogens and despite its good overall accuracy, MDP-BS appears to
have no prognostic role. In fact, despite the well-known capability of soft
tissue lesions to take up the tracer, MDP tumor trapping seems to depend mainly
on the increased permeability of neovessels and on interstitial space
enlargement. Few reports are available in the literature on the correlation
between in vivo MDP uptake by the breast cancer and prognostic parameters. Thus,
we tested possible correlations between the amount of MDP taken up by the breast
cancer, histologic features and cell concentrations of some major biomarkers. The
lack of any statistical significance is in agreement with the theory, and
confirms the little prognostic value of MDP-BS. Nevertheless, further trials are
warranted on larger series of cases to validate our personal findings.
PMID- 10780215
TI - [The role of computed tomography in gunshot lesions of the chest. The authors'
personal experience].
AB - PURPOSE: CT is a valuable tool in assessing thoracic gunshot wounds. CT is also
the method of choice in emergency, because it permits rapid depiction of bullet
damage to the chest and to other body districts. This in turn permits correct
assessment of the main thoracic injuries, plus adequate and prompt planning of
surgical treatment or support intensive care. We report on the role of CT in
diagnosing the complex pleuropulmonary, cardiovascular and thoracic wall injuries
caused by gunshot wounds, with their specific and acute signs which differ
greatly from those of other types of chest trauma. MATERIAL AND METHODS: In the
last 4 years, we observed 76 cases of gunshot injury, twenty-six of them involved
the chest. The patients, 25 men and 1 woman (mean age: 32 years, range: 17-48),
were all submitted to emergency CT with i.v. contrast agent injection and the CT
angiography technique. The reanimator was always present to monitor the patients'
vital functions and shock state. CT of the chest was integrated with CT of the
abdomen and pelvis in 4 cases and with CT of the skull in 3 cases, to detect
associated bullet wounds if any. RESULTS: The most frequent CT finding was lung
parenchyma tear and bruise (25 cases), followed by hemothorax (18 cases) and
subcutaneous chest wall emphysema (9 cases). Pneumothorax was seen in 5 cases,
associated with hemothorax in 6; rib injuries were found in 7 cases;
pneumomediastinum was found in 4 cases and areas of pulmonary atelectasis in 3;
the diaphragm was ruptured in 4 cases. CT showed spinal involvement in 11
patients, with injury of D3 and D5 in 4 and 3 cases, respectively; signs of
interrupted spinal marrow were found in 7 cases. Damage from gunshot wounds was
detected in the liver, spleen, skull and limbs in 3, 2, 3 and 10 cases,
respectively. DISCUSSION AND CONCLUSIONS: Chest radiography shows major gunshot
wound damage to the chest and lungs, except for heart injuries and minimal
pneumothorax. When abdominal and skull injuries are associated, CT should be the
method of choice because it permits prompt and panoramic assessment of the
severity of pulmonary and extrathoracic damage. This results in prompt and
targeted treatment, avoiding unnecessary delays which may damage the patient
further.
PMID- 10780216
TI - [3-dimensional magnetic resonance angiography in apnea with the rapid infusion of
a paramagnetic contrast medium in studying the thoracic aorta].
AB - INTRODUCTION: We investigated the diagnostic accuracy of gadolinium-enhanced 3D
MRA in the assessment of thoracic aortic diseases. MATERIAL AND METHODS: Thirty
eight patients with diagnosed or suspected conditions of thoracic aorta were
examined with contrast-enhanced MRA. All the examinations were performed with a
1.5 T superconductive magnet acquiring breath-hold 3D fast Gradient-Echo (GE)
sequences (TR = 5.9 ms; TE = 1.2 ms; FA = 45 degrees; FOV = 48 cm; thickness = 2
2.5 mm; locs = 30-32; TA = 22-24 s; MA = 512) on the coronal plane. The contrast
agent was injected bolus after a bolus-test to evaluate circulation time.
RESULTS: Three-dimensional gadolinium-enhanced MRA permitted to correctly
diagnose aneurysm in 18 patients, dissection in 13 patients and coarctation in 3
patients. In the former the size and extent of the aneurysmal lumen and its
relationship to aortic side branches was demonstrated. As for dissections we
evaluated the following parameters: 1) type; 2) presence of intimal flap; 3)
thrombosis of the false lumen; 4) dilatation of the aorta; 5) assessment of great
vessel origins. MRA data were correlated with those of biplane transesophageal
esophageal echocardiography, conventional MRI and spiral CT. In the three
patients with aortic coarctation the site of coarctation was correctly
identified, the degree of aortic narrowing evaluated and the collateral vessels
demonstrated. CONCLUSIONS: In our opinion contrast-enhanced three-dimensional MR
angiography should be the screening technique of choice in the evaluation of
thoracic aorta thanks to its low invasiveness, short acquisition time, large
field of view and morphologic resolution. ECG gating is not needed. Limitations
are found in the study of wall and periaortic region which are better evaluated
with conventional MR imaging.
PMID- 10780217
TI - [Defecography by spiral computed tomography].
AB - PURPOSE: We investigated the possible role of helical CT defecography in pelvic
floor disorders by comparing our results with those of conventional defecography.
MATERIAL AND METHODS: Our series consisted of 90 patients, namely 62 women and 28
men, ranging in age 24-82 years. They were all submitted to conventional
defecography, and 18 questionable cases were also studied with helical CT
defecography. The conventional examination was performed during the 4 standard
phases of resting, squeezing, Valsalva and straining; we used a remote-control
unit. The parameters for helical CT defecography were: 5 mm beam collimation,
pitch 2, 120 KV, 250 mAs and 18-20 degrees gantry inclination to acquire coronal
images of the pelvic floor. The rectal ampulla was distended with a bolus of 300
mL nonionic iodinated contrast agent (dilution: 3 g/cc). The patient wore a
napkin and was seated on the table, except for those who could not hold the
position and were thus examined supine. Twenty-second helical scans were
performed at rest and during evacuation; multiplanar reconstructions were
obtained especially on the sagittal plane for comparison with conventional
defecographic images. RESULTS: An unquestionable diagnosis could be made in all
the 18 patients submitted to helical CT defecography. The diagnosis was in
agreement with proctology results and added new information in all cases. Sixteen
patients had constipation and 2 fecal incontinence--one from rectal prolapse and
the other from a rectovaginal fistula. In this latter case helical CT
defecography permitted to confirm the fistula and suggest its course. One patient
had a previously undetected ovarian cancer metastatic to the anterior rectal
wall. DISCUSSION AND CONCLUSIONS: Coronal helical CT defecography images
permitted to map the perineal floor muscles, while sagittal reconstructions
provided information on the ampulla and the levator ani. To conclude, helical CT
defecography performed well in the study of pelvic floor disorders and can follow
conventional defecography especially in questionable cases.
PMID- 10780218
TI - [The assessment of chronic pancreatitis by magnetic resonance and MR
cholangiopancreatography. II. The semeiotics and results].
PMID- 10780219
TI - [Endovascular treatment in diseases of the thoracic aorta].
AB - PURPOSE: To determine whether endovascular treatment of thoracic aorta conditions
can be an effective alternative approach to surgical repair. MATERIAL AND
METHODS: July 1997 to February 1999, eighteen patients (16 men and 2 women; 58.6
+/- 14.8 years) presenting with different kinds of descending aorta conditions
were selected for the endovascular treatment. All patients exhibited severe
comorbid pulmonary and/or cardiovascular medical conditions which increased
surgical risk. All implants were performed in the operating room under
fluoroscopic and TEE guidance. Clinical and imaging follow-up was performed 1, 3,
6 and 12 months later. RESULTS: The endovascular treatment was successful in 17
cases. No deaths or major complications occurred. No leakage was evident at post
procedure angiography. The patients were discharged after 6 +/- 4 days. MRI or CT
study performed before hospital discharge showed aneurysms exclusion in 16
patients. In the four cases of dissection, thrombosis of the false lumen was
evident since the first follow-up study. In the group of patients (11 cases) with
6 months follow-up, the diameters of stented aortic segments decreased. No late
leakage was observed and thrombosis was complete in all cases. DISCUSSION: The
natural history of aortic aneurysms and dissection is progressive toward dilation
and aortic rupture. Surgery of descending thoracic aorta is burdened with a
mortality of 8-12% in elective cases and over 50% in emergency cases or aortic
dissection. The endovascular treatment of aortic conditions was introduced in
clinical practice in 1991 and literature data show that it is effective, with
lower mortality and morbidity rates than surgical treatment. CONCLUSION: Our
results stress the feasibility and effectiveness of endovascular procedure in the
treatment of complex thoracic aorta conditions even in high risk patients. Thus,
endovascular treatment of thoracic aorta can be considered an effective
alternative approach to conventional surgery.
PMID- 10780220
TI - [Echo-guided percutaneous treatment of chronic calcific tendinitis of the
shoulder].
AB - PURPOSE: We report on our personal technique and the results of US-guided
percutaneous treatment of chronic calcific tendinitis. MATERIAL AND METHODS:
January 1997 to March 1999, seventy patients with known chronic calcific
supraspinatus tendinitis were submitted to the US-guided treatment. All patients
had undergone plain radiography, US, and physical and psychiatric examination.
Plain radiography and aspiration biopsy demonstrated hard and radiopaque
calcification in 59 patients and soft and faintly milky calcification in 11
cases; calcification diameter ranged 6-30 mm. US showed tendon thickening, with
bulging of the outer tendon surface; 10 patients also had moderate dilatation of
the subacromial bursa. Psychiatric examination revealed chronic pain exacerbated
at night, which was always associated with motion impairment. The selection
criteria for treatment were calcification diameter > 6 mm, integrity of the
tendon, and chronic pain. After superficial planes were anesthetized, a 16 G
needle was positioned inside the calcification under US guidance and the calcific
deposits were fragmented and aspirated. Then, 0.5-1 mL triamcinolone acetonide
(40 mg) was injected in the soft tissues or subacromial bursa. RESULTS: Pain
resolution and recovery of the full range of motion were seen in 42 patients
(60%), and mild functional impairment was seen in 7 cases (10%), while 2 patients
(2%) were unchanged. Post-treatment plain radiography showed calcification
disappearance in 41 patients (58.5%) and debulking in 29 (41.5%); the
calcifications were significantly debulked (> 60%) in 27 patients (38.5%).
However, calcification diameter was substantially unchanged in 2 patients (3%)
and there remained tendon bulging; in these patients clinical symptoms did not
improve. No rotator cuff tears or new tendon calcifications were found in any of
our patients even at 19-28 months' follow-up. DISCUSSION: The US-guided technique
always allowed easy location of calcific deposits and complete aspiration of all
soft calcifications. Splintering of hard calcifications helped migration of
residual deposits to vascularized soft tissues, which accelerated the--frequently
complete--resorption process. We privileged extensive and prolonged fragmentation
of the calcifications using a single needle, versus the technique using a second
needle, saline lavage and aspiration of residual deposits. CONCLUSION: US-guided
percutaneous treatment with aspiration and splintering of chronic calcific
supraspinatus tendinitis is a conservative, simple, well-tolerated procedure
which can be considered the method of choice after the failure of medical
treatment.
PMID- 10780221
TI - [The percutaneous drainage of prostatic abscesses in the dog].
AB - INTRODUCTION: Prostatic abscesses are an uncommon finding in the dog; they are
most frequently seen in dogs over six years old, often in association with benign
hyperplasia. Ultrasonography (US) is an essential technique to study prostatic
conditions in the dog, because the particular anatomical site of this gland in
the dog makes rectal palpation insufficient to assess even macroscopic changes.
Presently, US-guided drainage makes a particularly efficient tool for treatment
of this condition in these patients. We report on our personal technique of
percutaneous drainage of prostatic abscesses in the dog. MATERIAL AND METHODS:
Forty-five dogs of different breeds and age were examined. Some of them were
given short anesthesia or mild sedation for restraining purposes, although this
procedure is painless and could be performed under local anesthesia like in human
patients. In man, the approach is perineal, but in the dog it is best to use an
abdominal approach with right or left inguinal positions. US is necessary for
correct drainage of the abscess and for monitoring throughout the procedure.
DISCUSSION AND CONCLUSION: US-guided percutaneous drainage of prostatic abscesses
in the dog proved to be a safe and quick tool providing excellent results. No
patients exhibited any postoperative complication and we had as little as 10%
relapses at 30 days. The following drainage with alcoholization of the abscessual
cavity resolved the conditions definitively. This technique was particularly
interesting for both its success rate and the lack of postoperative
complications, which are usually quite common after conventional surgery.
PMID- 10780222
TI - [The relationships between the general practitioner and the oncological
radiotherapist. A preliminary study by telephone interviews].
AB - PURPOSE: We addressed the issue of the relationship between the general
practitioner (GP) and the radiotherapist to improve the quality of care of cancer
patients. MATERIAL AND METHODS: The study consisted in evaluating medical
requests and phone interviews, with a questionnaire with yes/no and multiple
choice answers to the following 5 questions: 1) Do you think a cancer diagnosis
is always a hopeless death sentence? 2) Is it professionally rewarding to cure a
cancer patient? 3) Are you satisfied with your relationship, as a general
practitioner, with oncologic reference centers? 4) Is it more wearing for a
general practitioner to manage a cancer than a noncancer patient? 5) Would you
answer a questionnaire about the relationship between the general practitioner,
the cancer patient and the oncologist? We evaluated 1590 medical requests and
made 401 phone interviews; 255 colleagues (70%) answered the questionnaire.
RESULTS: Medical requests were correctly and completely formulated by GPs in 45%
of cases. A cancer diagnosis was not considered a hopeless death sentence in
90.9% of cases and 76% of GPs considered it professionally rewarding to cure a
cancer patient. 75.6% of GPs considered it more wearing to manage a cancer than a
noncancer patient, and female GPs felt this more strongly than their male
counterparts. Irrespective of gender, GPs over 50 years of age tend to consider
cancer a hopeless and fatal disease. The relationship with oncologic centers was
considered satisfactory in 86.2% of cases. However, since cancer patients need
greater medical care, GPs would like a closer cooperation with oncologists.
DISCUSSION AND CONCLUSIONS: The great interest GPs took in this study encourages
further investigation through a more in depth questionnaire designed with the
help of GPs themselves and interested statisticians.
PMID- 10780223
TI - [A neonatal sacrococcygeal teratoma studied by spiral computed tomography. A case
report].
PMID- 10780224
TI - [The Poland syndrome. A case study with magnetic resonance, radiology, echography
and color Doppler].
PMID- 10780225
TI - [Mazabraud's syndrome. A case report].
PMID- 10780226
TI - [The Noonan syndrome and malformation of the inner ear. A case study by the
steady-state MR technic].
PMID- 10780227
TI - [Langerhans-cell histiocytosis of the otomastoid area. A case report].
PMID- 10780228
TI - [Cerebrotendinous xanthogranulomatosis. Apropos a case].
PMID- 10780229
TI - [Central pontine myelinolysis. Apropos a case].
PMID- 10780230
TI - [Schistosomiasis of the spinal cord. The MR aspects in a case].
PMID- 10780231
TI - [A ruptured aneurysm of the bronchial artery. A report of a case studied by
spiral computed tomography and a review of the literature].
PMID- 10780232
TI - [Idiopathic intestinal pseudo-obstruction of the colon. A case report].
PMID- 10780233
TI - [A case of a teratocarcinoma with retroperitoneal location].
PMID- 10780234
TI - [Hydrospermatocyst with ectopic insertion of the ureter associated with
homolateral renal agenesis. A magnetic resonance case study].
PMID- 10780235
TI - [Adrenal hydatidosis. The computed tomographic picture in a case].
PMID- 10780236
TI - [Crazy paving].
PMID- 10780237
TI - [Pulling ears].
PMID- 10780238
TI - [Cannibalism or pedantry?].
PMID- 10780240
TI - The effects of morphine on clocked fixed-interval performance: stimulus function
or strength of stimulus control?
AB - The present experiment was conducted to determine whether the modification of the
effects of morphine by food deprivation would occur under conditions of strong
stimulus control. Four pigeons pecked response keys under a multiple fixed
interval (FI) 5-min and clocked fixed-interval (CFI) 5-min schedule of food
presentation. During the FI component, the key was lit green and the house light
was on throughout. During the CFI component, the key light and house light
settings changed in a regular manner as the interval elapsed. In all conditions,
pigeons received a range of doses of morphine (1.0-10.0 mg/kg) and saline. In the
first condition, pigeons were maintained at 80% of their free-feeding weights.
When calculated over entire 5-min intervals, morphine produced dose-dependent
decreases in the index of curvature (a measure of temporal patterning) during the
FI component, but did not affect the index of curvature during the CFI component.
A more detailed analysis revealed that the index of curvature during the last
stimulus in the CFI sequence was reduced in a dose-dependent manner, similar to
the effects obtained for the entire FI component. When the pigeons were
maintained at 70% and 90% of their free-feeding weights, measures of the effects
of morphine on temporal patterning did not differ as a function of body weight.
The effects of morphine on rates of key-pecking, however, were related to body
weight. For three of four pigeons, rates of key-pecking were not suppressed until
higher doses, and increases in rates of key-pecking were more common at lower
doses, when the pigeons were maintained at 70% of their free-feeding weights,
than when they were maintained at 90% of their free-feeding weights. It is
suggested that the effects of morphine on CFI performance can be understood in
terms of the function of the stimuli that comprise the schedule, rather than the
strength of the stimulus control engendered.
PMID- 10780239
TI - Differential expression of response-disruptive and somatic indices of opiate
withdrawal during the initiation and development of opiate dependence.
AB - The current study examined the conditions that are necessary and sufficient for
the initiation and progression of acute morphine dependence using two indices of
opiate withdrawal: suppression of operant response rates and a somatic withdrawal
rating scale. Separate groups of rats were pretreated with morphine (5 mg/kg,
s.c.) a total of three times at intervals of 24 h, 1, 3, or 6 weeks. Rats
received a single dose of naloxone 4 h after each morphine pretreatment. Naloxone
induced suppression of operant responding (0.33 mg/kg, s.c.) was significantly
potentiated with repeated exposure to morphine even at the 6-week inter-treatment
interval (ITI). At 24-h, 1-week and 3-week ITIs, rats treated with naloxone only
after the third and final morphine pretreatment showed similar suppression of
operant responding following naloxone to rats treated with naloxone after all
three morphine pretreatments. However, at the 6-week ITI, the response-disruptive
effects of naloxone administered for the first time after the third morphine
pretreatment were no greater than the effects of naloxone administered after a
single morphine pretreatment. In contrast to results seen with suppression of
operant responding as the withdrawal index, potentiation of somatic signs of
withdrawal was observed only at the 24-h ITI. These results indicate that a
neuroadaptive state resembling opiate dependence can be initiated after just one
injection of morphine, and that the response-disruptive effects of naloxone
appear to be a particularly sensitive index of the initiation and progression of
acute opiate dependence.
PMID- 10780241
TI - Individual differences in behavioral tolerance to amphetamine and the economic
context of reinforcement loss.
AB - The economic context (i.e. an enriched vs impoverished environment) affects many
drug-induced phenomena. The present study examined whether the 'experienced'
economic context of operant responding was associated with the degree of
tolerance to the behavioral effects of amphetamine. Eight rats lever pressed for
food reinforcement under a multiple schedule consisting of several variable
interval schedules (8, 17, 55, 150, and 250 s). Amphetamine was first
administered acutely (0.2, 0.8, 1.6, and 3.2 mg/kg), then chronically (dose
tailored for each subject) over 30 consecutive sessions. Baseline saline
injections were also administered during the acute regimen. Herrnstein's single
alternative matching equation described the rats' response rate data well under
all conditions. A parameter in Herrnstein's equation (re), which has been shown
to vary with experimentally-arranged contextual reinforcement, was used as the
index of the experienced economic context for each subject under baseline
conditions. Differences in the value of re predicted individual differences in
the degree of tolerance. Under most variable-interval (VI) schedules, and when
all schedules were aggregated, less tolerance accrued if the baseline context was
experienced as enriched, and more tolerance accrued if the baseline context was
experienced as impoverished. In terms of the reinforcement loss hypothesis, the
results suggest that tolerance was not determined by reinforcement loss per se,
but by how much the animal lost relative to the economic context in which the
operant task was embedded.
PMID- 10780242
TI - Subjective and behavioral effects of repeated d-amphetamine in humans.
AB - Behavioral sensitization is thought to be an important determinant of drug-taking
and drug-seeking behaviors. Although there is abundant research characterizing
behavioral sensitization in animals, there is little evidence for this phenomenon
in humans. The aim of the present study was to determine if repeated oral d
amphetamine administration enhances self-reported mood and other behavioral
indices of d-amphetamine effects in humans. Sixteen healthy volunteers, with no
prior stimulant use, received two doses of d-amphetamine (20 mg) and two doses of
placebo, in alternating order, on 4 consecutive days, under double-blind
conditions. Mood and behavioral effects were measured using standard self-report
questionnaires. Heart rate, blood pressure, psychomotor performance, and tapping
speed were also monitored. d-Amphetamine elicited prototypical increases on
several measures including self-reported drug effects, mood, and physiological
responses. However, except for a slight reduction in 'feel drug' scores during
the first hour of the second d-amphetamine session, the majority of effects were
not altered on the second session. These results indicate that the subjective
effects of d-amphetamine display only an apparent mild tolerance after a single
exposure 48 h earlier.
PMID- 10780243
TI - Individual differences in subjective responses to ethanol and triazolam.
AB - This study evaluated the relationship between sedative-like subjective responses
to ethanol and triazolam in normal, healthy volunteers. It was hypothesized that
subjects' responses to the two drugs would be correlated, because of the common
mechanism of action of the drugs at the GABAA receptor complex. Twenty-seven
volunteers (14 male, 13 female), aged 21-35 years, received beverages or capsules
containing ethanol (0.2, 0.4 or 0.8 g/kg), triazolam (0.125, 0.25 or 0.5 mg) or
placebo (two sessions) on eight separate sessions in a random order. Various self
reported and objective drug effects were measured, including measures of sedative
like subjective effects, as indexed by the ARCI PCAG scale. PCAG scores of
individual subjects across the three active doses of each drug were fitted with a
straight line function (y = a + bx), and the correlation of the slopes from the
fitted curves for ethanol and triazolam was examined. Among the participants who
reported any sedative-like responses to ethanol, the sedative-like effects of
ethanol and triazolam were positively correlated. That is, subjects who exhibited
the steepest dose-related effects on measures of subjective sedation after
ethanol also exhibited the steepest slopes after triazolam. These findings
provide partial support for the idea that ethanol and triazolam produce their
sedative-like effects through the same mechanism.
PMID- 10780244
TI - An investigation of endogenous neuroactive steroid-induced modulation of
ethanol's discriminative stimulus effects.
AB - Neuroactive steroids exhibit rapid non-genomic central nervous system activity,
including modulation of GABAA and NMDA receptors, two receptors known to mediate
the effects of methanol. Neuroactive steroids that modulate GABAA receptors in a
manner similar to ethanol were expected to potentiate the discriminative stimulus
and/or rate-suppressing effects of ethanol. In contrast, neuroactive steroids
that modulate GABAA or NMDA receptors in a manner opposite to ethanol were
hypothesized to attenuate the effects of ethanol. Adult male rats were trained to
discriminate 1.0 or 2.0 g/kg ethanol (i.g.) from water (i.g.). Animals were
pretreated with subthreshold doses (i.p.) of ethanol and neuroactive steroids and
exposed to an acute stressor (n = 5), prior to conducting ethanol cumulative
dosing (i.p.) tests. Only ethanol and 3 beta, 5 beta-P pretreatments potentiated
the discriminative stimulus effects of ethanol. None of the six neuroactive
steroid manipulations attenuated the effects of ethanol. These results
demonstrate that a neuroactive steroid, endogenous in humans, can enhance the
interoceptive effects of ethanol.
PMID- 10780245
TI - Further characterization of the quinine taste discrimination stimulus in rhesus
monkeys: effects of inter-trial interval, number and distribution of test
stimuli.
AB - The purpose of the current investigation was to characterize further the taste
discriminative stimulus properties of quinine. Using a food-maintained two-choice
(quinine and water) discrimination paradigm, the effects of varying inter-trial
intervals, and the number and distribution of test stimuli were examined in
rhesus monkeys (Macaca mulatta). Monkeys were trained to respond under a chain
schedule of reinforcement (FR5B-fluid, FR30B-food) with a 60-s inter-trial
interval. Interestingly, the quinine discrimination remained invariant across all
the conditions tested: alterations in inter-trial interval (0, 15, 30, 45, 60 s),
alterations in the number of test stimuli (six at quarter-log unit increments
[0.1-1 mg/ml] versus 10 at quarter-log unit increments [0.01-1 mg/ml]), and
alterations in the distribution of the test stimuli (quarter-log unit increments
[0.1-0.1 mg/ml] versus half-log unit increments [0.01-1 mg/ml]) failed to alter
the quinine discriminative stimulus (ED50s ranged from 0.18-0.29 mg/ml).
Furthermore, incorrect lever selections were very rare (less than 12% of all test
sessions), independent of test stimuli order (i.e. quinine followed by water
trials, water followed by quinine trials), and independent of the progress
through the test session (i.e. incorrect lever selections were consistent-
approximately one error for every 10 trials--within early, middle and late
portions of the session). These results demonstrate the reliability and
robustness of the quinine taste discriminative stimulus in rhesus monkeys and
provide further validation for the experimental paradigm.
PMID- 10780246
TI - Effects of the group II metabotropic glutamate receptor agonist, LY354740 on
schedule-controlled behaviour in rats.
AB - The present study examined the effect of the novel, systemically active Group II
metabotropic glutamate (mGlu) receptor agonist, LY354740, on schedule-controlled
behaviour in rats. Responding for food reward was maintained by three different
operant procedures; the first, a three-component conflict schedule; the second, a
multiple fixed-interval 60 s/fixed-ratio 10 (FI60/FR10) schedule and the third, a
differential reinforcement of low rates of responding 10 s (DRL10) schedule. In
the first procedure, rats were trained to respond for food on a schedule
comprising of variable-interval 30 s (food, VI30) and fixed-ratio 10 (food +
shock, FR10) components separated by time-out (TO). LY354740 (1.25-5 mg/kg, i.p.)
produced a dose-related reduction in responding during the VI component and
increased responding during the TO component, while having no effect on
responding during the punished FR10 phase. In the FI60/FR10 schedule, LY354740
produced a dose-related reduction in the high rates of responding observed during
the FR10 component of the schedule. Although LY354740 (0.6-10 mg/kg, i.p.) had no
effect on the overall response rates produced by the FI60 component, there was a
shift in the temporal distribution of responding as measured by the quarter-life.
LY354740 (10 mg/kg, i.p.) increased the low rates towards the start of the
interval, while decreasing the rates of responding towards the end of the FI60
period. In the DRL10 s schedule, LY354740 (5-20 mg/kg, i.p.) had no effect on the
total number of responses but produced a significant reduction in the total
number of rewards, suggesting that the temporal control of responding had been
disrupted. The changes in operant responding occurred at doses that decreased
exploratory behaviour. In summary, LY354740 modified responding maintained by all
three operant schedules at doses which suppressed spontaneous activity. These
data demonstrate that stimulation of Group II mGlu receptors can produce changes
in responding which are dependent on the base-line rate of responding, suggesting
that mGlu 2/3 receptors may be involved in the stimulus and temporal control of
behaviour.
PMID- 10780247
TI - SR 141716A, a cannabinoid receptor antagonist, reverses the behavioural effects
of anandamide-treated rats.
AB - We employed the CB1 cannabinoid receptor antagonist SR 141716A (3 mg/kg, i.p.) to
investigate whether behavioural effects induced in rats by anandamide, an
endogenous cannabinoid (20 mg/kg, i.p.), were mediated by the cannabinoid CB1
receptor. Anandamide reduced ambulatory (67%) and non-ambulatory activities
(rearing and grooming, 84% and 90% respectively), with a strong cataleptic
effect, produced hypothermia (about -1 degree C) and hindlimb splaying, and
reduced defecation (79%). It did not significantly increase either the tail-flick
or hot-plate latencies. Except for the decreased defecation, these responses were
all blocked by SR 141716A. Although only single doses of the agonist and
antagonist were used, the findings indicate that these behavioural effects are
probably mediated by an interaction with cannabinoid CB1 receptors.
PMID- 10780248
TI - Effects of nicotine on spatial learning in C57BL mice.
AB - In the present study, the effects of nicotine on spatial memory in C57BL/6J mice
was evaluated. Mice were trained in a water maze during four daily sessions of
three trials each. In the first experiment, nicotine (0.7 and 0.35 mg/kg) or
saline was administered once daily for 4 days, 15 min before the start of daily
training: an impairment of performance of the water maze was observed in the
group treated with 0.7 mg/kg of nicotine. In the second experiment, nicotine (0.7
and 0.35 mg/kg) or saline was administered from the 5 days prior to the beginning
of the task and during the 4 days of acquisition. The results indicated an
improvement in the rate of learning in the 9-day nicotine treated groups. The
comparison between 4-day and 9-day treated groups revealed that the group
receiving 0.35 mg/kg of nicotine for 9 days displayed significantly shorter
latencies than all the other groups, while the group receiving 0.7 mg/kg of
nicotine for 4 days performed significantly worse than all the other groups. The
most noteworthy result is that nicotine was more effective after a more prolonged
administration than when administered only during the training days.
PMID- 10780249
TI - Anxiety in a transgenic mouse model of cortical-limbic neuro-potentiated
compulsive behavior.
AB - Anxiety and amygdalar stimulation may induce or exacerbate compulsions triggered
by cortical-limbic hyperactivity, as in human obsessive-compulsive disorder
(OCD). We previously created transgenic mice that exhibit OCD-like biting,
movement and behavioral perseverance abnormalities. These behaviors are caused by
expression of a neuro-potentiating cholera toxin (CT) transgene in dopamine D1
receptor-expressing (D1+) neurons within the amygdalar intercalated nucleus (ICN)
and within cortical areas that project to orbitofrontal cortex and striatum. Here
we tested whether anxiety and increased amygdalar stimulation may play a role in
eliciting or exacerbating such behaviors. D1CT mice exhibited increased
thigmotaxis (tendency of mice to remain along the perimeter of open areas) in the
open field assay, and increased latency to first transit and reduced transit
number in the light-dark assay. These studies indicate that the D1CT mice exhibit
a significant increase in behavioral indicators of anxiety. Furthermore,
yohimbine, a drug that induces both amygdalar stimulation and behavioral
indicators of anxiety, exacerbated abnormal leaping in D1CT mice but failed to
exacerbate their abnormal behavioral perseverance. These data suggest that
chronic potentiation of D1+ neurons in the amygdalar ICN increases anxiety and
facilitates particular compulsive behaviors.
PMID- 10780250
TI - Assessing memory in mice using habituation of nose-poke responding.
AB - The present experiments investigated the validity and utility of measuring the
habituation of a nose-poke response to assess memory in mice. Mice were placed in
an operant chamber equipped with two holes in one wall. Nose-poke responses were
recorded by the interruption of a photo-beam across the openings of the holes.
Responding produced no consequences. Nose-poke responding was recorded over 20
min for one-four daily sessions. Habituation, as defined by a decrease in the
number of nose-pokes over time, was observed during sessions as well as between
daily sessions. When the inter-session interval was increased from 1 to 8 days,
habituation decayed in a time-dependent manner indicating memory was involved in
the habituation phenomenon. CD-1, C57/BL and Swiss Webster X DBA mouse strains
all displayed robust time-dependent habituation. Scopolamine, in CD-1 mice, dose
dependently disrupted habituation in an anterograde (0.1-1 mg/kg) and retrograde
(1-10 mg/kg) procedure. The present procedure provides a rapid and novel method
to assess habituation in a variety of strains of mice and may be a useful
addition to existing procedures for measuring memory function in mice.
PMID- 10780251
TI - Strain-dependent effects of anandamide on memory consolidation in mice are
antagonized by naltrexone.
AB - Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently
impaired retention of an inhibitory avoidance response in DBA/2 mice, while
improving it in C57BL/6 mice. The effects on retention performance induced by the
drug appear to be due to an effect on memory consolidation. They were observed
when drug was given at short, but not long, periods of time after training, i.e.
when the memory trace was susceptible to modulation. These effects of anandamide
parallel those of opioid agonists, as previously reported. Moreover, the opioid
antagonist naltrexone improved retention in DBA/2 mice, while impairing it in
C57BL/6 mice. Pre-treatment with the opioid antagonist at a non-effective dose
(0.1 mg/kg) antagonized the effects of anandamide on memory consolidation in both
strains. These results strongly suggest that endogenous cannabinoids affect
memory processes through opioid systems. The possible involvement of other
neurotransmitter systems, such as dopamine, in strain-dependent effects of
anandamide in memory consolidation is discussed.
PMID- 10780252
TI - Daily injections of cyanamide enhance both ethanol-induced locomotion and brain
catalase activity.
AB - A role for brain catalase in the mediation of some psychopharmacological effects
of ethanol has been proposed. In the present study, we investigated the effects
of repeated cyanamide injections on the activity of brain catalase, as well as on
the ethanol-induced locomotion of mice. Male Swiss mice were pre-treated with
cyanamide (10 mg/kg; three times per day, 5 days) or saline. At different times
(2, 3, 6 or 9 days) following this treatment, animals were injected with ethanol.
Immediately following this ethanol challenge, animals were placed in the open
field chambers and locomotor activity was assessed for 10 min. Results indicated
an increase in ethanol-induced locomotion of mice pre-treated with cyanamide 2, 3
or 6 days before the ethanol challenge. Brain catalase activity showed an
enhancement at the same time period and the two variables showed a significant
correlation. No differences between pre-treatment groups on ethanol blood levels
were observed at time of testing. In a second study, the effects of these
cyanamide treatment conditions on d-amphetamine-induced locomotor activity were
assessed. Results indicated no differences between pre-treatment groups in d
amphetamine-induced locomotion. Thus, these data suggest that repeated daily
injections of cyanamide can simultaneously induce both brain catalase and
locomotor activity, and that these effects may be strongly related. Furthermore,
the present study provides further support for the notion that brain catalase
activity may be a factor mediating some of the psychopharmacological effects of
ethanol.
PMID- 10780253
TI - Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch
Nyhan syndrome.
AB - Rats were treated as neonates with either 6-hydroxydopamine (6-OHDA) 100
micrograms or vehicle intracisternally. Upon maturation, animals receiving 6-OHDA
were assigned to four groups, with two of the four groups receiving
intraventricular 5,7-dihydroxytryptamine (5,7-DHT) 75 micrograms bilaterally. At
94 days of age, animals were injected with either SKF-38393 (3.0 mg/kg,
intraperitoneally (i.p.)), a dopamine D1 agonist, or m-chlorophenylpiperazine (m
CPP) (3.0 mg/kg, i.p.), a 5-HT2C agonist, in an attempt to evoke behaviors such
as stereotypical chewing, head-nodding, self-biting and self-mutilation. Both SKF
38393 and m-CPP induced the target behaviors in animals receiving 6-OHDA alone.
Animals receiving additional 5,7-DHT treatment did not show any of the target
behaviors in response to SKF-38393, but exhibited a much higher sensitivity to m
CPP. Pre-treatment with SCH-23390 in animals receiving 6-OHDA alone was effective
in preventing SKF-38393-induced target behaviors, but not those induced by m-CPP.
Pre-treatment with mianserin partially antagonized the effects of both SKF-38393
and m-CPP in these same animals. In groups receiving both neonatal 6-OHDA and
adult 5,7-DHT, mianserin was effective in reducing m-CPP-induced behaviors, while
SCH-23390 was largely ineffective. These data provide evidence of a serial
relationship between the D1 and 5-HT2C receptor systems in the neostriatum of
animals receiving neonatal 6-OHDA lesions.
PMID- 10780254
TI - Rapid recovery of self-stimulation responding from depression by clozapine is
prevented by the alpha 2-adrenoceptor agonist, clonidine.
AB - Typical and atypical antipsychotic agents were tested on rats responding for
variable-interval electrical stimulation of the ventral tegmental area (VTA). The
typical neuroleptics, chlorpromazine and haloperidol, led to prolonged depression
of responding lasting at least 4 h, whereas response rates after similarly
effective doses of the atypical agents, clozapine and risperidone, recovered to
control levels in the same period. The role of alpha 2-adrenoceptors in producing
these differences was investigated by administering clozapine together with an
alpha 2-adrenoceptor agonist, clonidine, and chlorpromazine together with an
alpha 2-adrenoceptor antagonist, idazoxan. The addition of clonidine extended the
response-depressant activity of clozapine, resulting in prolonged depression
comparable to that produced by chlorpromazine or haloperidol. Conversely, the
addition of idazoxan to chlorpromazine shortened the duration of chlorpromazine's
suppressant action to a level comparable to that of clozapine or risperidone.
These results suggest that the brevity of clozapine's effects on operant
behaviour (a feature which may be related to its reduced liability to
extrapyramidal side-effects) may be a consequence of its alpha 2-adrenoceptor
antagonist properties.
PMID- 10780255
TI - Comparison of the pharmacological properties of classical and novel BZ-omega
receptor ligands.
AB - The experiments in this study compared the pharmacological properties of several
BZ-omega receptor ligands, including the imidazobenzodiazepine imidazenil, the
beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido [1,2
a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative SX-3228,
with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro
experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [3H]flumazenil
binding non-selectively in membranes from rat cerebellum and spinal cord, two
brain areas enriched in the BZ-omega 1 and BZ-omega 2 receptor subtypes,
respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in
displacing [3H]flumazenil binding to membranes from rat cerebellum than from
spinal cord or hippocampus, indicating selectivity for the BZ-omega 1 receptor
subtype. The in vivo experiments showed that all compounds increased the latency
to clonic seizures produced by isoniazid. However, the maximal increase in
latency induced by diazepam, clobazam, abecarnil, RWJ 46771 and SX-3228 was
greater than that of bretazenil, imidazenil and Y-23684, thereby indicating that
these latter compounds have low intrinsic efficacy. In the punished drinking, the
punished lever pressing and the elevated plus-maze tests in rats, three models of
anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects
but at doses which were close to those producing hypolocomotion, ataxia and
myorelaxation as measured in activity cages, the rotarod and the loaded grid
tests, respectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like
activity at much lower doses than those which impaired motor performances. The
magnitude of the positive effects of Y-23684 was similar to that of the reference
BZs, suggesting that it may become a valuable alternative to currently used
agents for the treatment of anxiety disorders. Abecarnil, RWJ 46771 and SX-3228
produced weaker or non-specific anxiolytic-like effects as they decreased anxiety
related behaviours at doses similar or close to those impairing motor
performance. However, unlike the other compounds they induced myorelaxation at
doses which were 3-10 times higher than those needed to produce decrease in
exploratory activity. It is suggested that the behavioural profiles of abecarnil,
RWJ 46771 and SX-3228 may be attributed to their selectivity for the BZ-omega 1
receptor subtype which may account for their sedative activity, thereby masking
other effects including anxiolytic-like activity. This suggests that BZ receptor
modulation of anxiety may involve BZ receptor subtypes other than BZ-omega 1.
PMID- 10780256
TI - Cannabinoid ligands and their effects on learning and performance in rhesus
monkeys.
AB - To characterize the role of CB1 receptors in mediating the acquisition of new
behavior or learning, delta 9-THC (delta 9-tetrahydrocannabinol), WIN 55,212-2 (R
(+)-(2,3-dihydro-5-methyl-3-[(4-morpho-linyl)methyl]pyrol - (1,2,3-de]-1,4
benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate), SR141716A (N
(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlor- phenyl)-4-methyl-1H-pyrazole
3-carboxamide hydrochloride) and cannabidiol were administered to monkeys
responding under a multiple schedule of repeated acquisition and performance of
conditional discriminations. SR141716A, a putative antagonist at CB1 receptors,
was also administered in combination with delta 9-THC. In one component of the
multiple schedule, subjects acquired a different complex discrimination each
session (acquisition component), whereas in the other component the
discrimination remained the same each session (performance component). Correct
responding in each component was maintained by food presentation under a variable
ratio (VR) schedule, whereas incorrect responding (errors) produced a time-out.
Administered prior to the start of the session, delta 9-THC and WIN 55,212-2 dose
dependently decreased overall response rate in both the acquisition and
performance components. Both drugs also selectively increased the percentage
errors in the acquisition component, but only at higher doses. SR141716A and
cannabidiol also dose-dependently decreased overall response rate in both
schedule components, but neither drug increased the percentage of errors.
Decreases in response rate were also observed 24 hours after administration of
SR141716A at doses greater than 1 mg/kg. When lower doses of SR141716A (0.1-1
mg/kg) were administered in combination with delta 9-THC, there was a dose
dependent antagonism of the rate-decreasing and error-increasing effects of delta
9-THC (i.e. the dose-effect curves for delta 9-THC-induced disruptions in
responding were shifted rightward). In summary, CB1-receptor agonists such as
delta 9-THC and WIN 55,212-2 were more disruptive to the rate and accuracy of
learning in old-world monkeys than the CB1-receptor antagonist SR141716A or
cannabidiol.
PMID- 10780257
TI - Predicting relapse to cocaine-seeking behavior: a multiple regression approach.
AB - Recovery of previously extinguished responding to stimuli paired with the
administration of drugs of abuse is becoming a widely utilized animal model of
relapse to drug-seeking behaviors. While this approach is useful for identifying
factors such as conditioned stimuli that are associated with drug-seeking, it has
not directly identified behaviors that might predict susceptibility to relapse.
In this study, rats were initially screened for locomotor activity in response to
a novel environment. Rats were then trained to self-administer cocaine. A
stimulus light and tone were paired with each infusion of cocaine. After 14 days
of self-administration (maintenance) rats underwent 7 days of extinction trials
(extinction phase 1), in which responding yielded neither cocaine nor the
presentation of the conditioned stimulus. After extinction phase 1, rats
responded for presentations of the compound stimulus in the absence of cocaine
(test day 1). Rats then underwent 3 more days of extinction (extinction phase 2).
After extinction phase 2, rats were once again allowed to self-administer cocaine
(test day 2) and received presentations of the compound stimulus. Hierarchical
regression equations, utilizing data from locomotor screening and the average
responding during maintenance and extinction phases 1 and 2, were then
constructed in order to predict the magnitude of responding on test days 1 and 2.
A model utilizing locomotor activity, maintenance responding and extinction phase
1 responding accounted for over 76% of the variance associated with responding on
test day 1, with extinction phase 1 as best predictor. A further model indicated
that locomotor activity was the best predictor of propensity to self-administer
cocaine on test day 2. These regression models provide a novel approach to
determining factors that may predict relapse to drug-seeking behaviors.
PMID- 10780258
TI - Blockade of cocaine-induced increases in adrenocorticotrophic hormone and
cortisol does not attenuate the subjective effects of smoked cocaine in humans.
AB - Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA)
axis reduces the discriminative stimulus and reinforcing effects of cocaine in
laboratory rodents. We have recently reported that attenuation of cocaine-induced
increases in cortisol does not modulate the subjective effects of smoked cocaine
in humans. To examine whether attenuation of HPA function at the pituitary level
reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre
treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h
before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were
administered in counterbalanced order under each pre-treatment condition.
Dexamethasone alone increased heart rate and blood pressure, and completely
abolished cocaine-induced adrenocorticotrophic hormone and cortisol release.
Maximal heart rate following cocaine administration was significantly increased
by dexamethasone. However, the subjective effects of cocaine were not affected by
dexamethasone pre-treatment. These results extend our earlier findings with
humans, indicating that the role of the HPA axis in mediating the effects of
cocaine is limited. These data are concordant with findings in non-human
primates, but contrast with findings in laboratory rodents, thus underscoring the
importance of validation of rodent models with laboratory studies in humans.
PMID- 10780259
TI - Low-dose oral cocaine in humans: acquisition of discrimination and time-course of
effects.
AB - Seven cocaine-abusing volunteers were trained to discriminate 50 mg oral cocaine
vs placebo across 50 2-h sessions. Discriminative, subjective and autonomic
effects were assessed with a procedure developed for precise characterization of
their acute time-course. Subjective effects of oral cocaine began 10-15 min post
drug, peaked at 40-50 min and took up to 100 min post-drug to return nearly to
baseline. Autonomic effects also began 10-15 min post-drug, peaked at 40-50 min
and typically returned to baseline by 120 min post-drug; for most participants,
peak heart rate and blood pressure remained within the range seen with placebo.
Six out of seven participants acquired the discrimination (although this
typically required 15-30 sessions, and there were some intriguing dissociations
between the ability to discriminate oral cocaine from placebo and the ability to
identify it as a stimulant). In most participants, oral cocaine produced
increases in ratings of 'liking', 'alertness' and 'good effects', and in motor
performance. Overall, the results support the sensitivity of the behavioral
testing procedure used, and show that 50 mg oral cocaine can serve as a
discriminative stimulus in adult humans.
PMID- 10780260
TI - Daily mirfentanil induces (cross-) tolerance to the rate-decreasing effects of
morphine and not mirfentanil.
AB - The fentanyl derivative mirfentanil has a novel set of behavioral effects in non
humans including low-efficacy opioid actions and non-opioid antinociceptive
actions. This study evaluated the rate-decreasing effects of mirfentanil,
morphine, naltrexone and ketamine in pigeons both prior to and during a period of
chronic treatment with mirfentanil (3.2-17.8 mg/kg/day). Daily treatment with
mirfentanil did not modify the rate-decreasing effects of mirfentanil or
ketamine; however, daily treatment decreased sensitivity to the rate-decreasing
effects of morphine and increased sensitivity to naltrexone. These results
demonstrate a lack of tolerance to an apparently non-opioid action (rate
decreasing effect) of mirfentanil, which might predict a lack of tolerance to the
non-opioid antinociceptive actions of this compound. These results further
indicate that cross-tolerance (to morphine) and dependence (increased sensitivity
to naltrexone) can occur in the absence of tolerance (to mirfentanil).
PMID- 10780261
TI - Memory restoring and neuroprotective effects of the proline-containing dipeptide,
GVS-111, in a photochemical stroke model.
AB - Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by
combination of the intravenous photosensitive dye Rose Bengal administration with
focused high-intensity illumination of the frontal bone, was shown to provoke a
pronounced deficit in step-through passive avoidance performance in rats without
concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS
111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1
h after ischaemic lesion and then for 9 post-operative days, with the last
administration 15 min before testing, attenuated the deficit. This treatment
significantly diminished the volume of the infarcted area. Thus, post-ischaemic
injection of GVS-111 demonstrated both cognition-restoring and neuroprotective
properties. The cognition-restoring effect is probably based on an increase in
neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS
111 combine antioxidant activity with the ability to attenuate glutamate-provoked
neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates
the main metabolic shifts involved in pathogenesis of brain ischaemia.
PMID- 10780262
TI - Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and
recommended nomenclature based on divergent evolution and chromosomal mapping.
AB - As currently being performed with an increasing number of superfamilies, a
standardized gene nomenclature system is proposed here, based on divergent
evolution, using multiple alignment analysis of all 86 eukaryotic aldehyde
dehydrogenase (ALDH) amino-acid sequences known at this time. The ALDHs represent
a superfamily of NAD(P)(+)-dependent enzymes having similar primary structures
that oxidize a wide spectrum of endogenous and exogenous aliphatic and aromatic
aldehydes. To date, a total of 54 animal, 15 plant, 14 yeast, and three fungal
ALDH genes or cDNAs have been sequenced. These ALDHs can be divided into a total
of 18 families (comprising 37 subfamilies), and all nonhuman ALDH genes are named
here after the established human ALDH genes, when possible. An ALDH protein from
one gene family is defined as having approximately < or = 40% amino-acid identity
to that from another family. Two members of the same subfamily exhibit
approximately > or = 60% amino-acid identity and are expected to be located at
the same subchromosomal site. For naming each gene, it is proposed that the root
symbol 'ALDH' denoting 'aldehyde dehydrogenase' be followed by an Arabic number
representing the family and, when needed, a letter designating the subfamily and
an Arabic number denoting the individual gene within the subfamily; all letters
are capitalized in all mammals except mouse and fruit fly, e.g. 'human ALDH3A1
(mouse, Drosophila Aldh3a1).' It is suggested that the Human Gene Nomenclature
Guidelines (http://++www.gene.ucl.ac.uk/nomenclature/guidelines.h tml) be used
for all species other than mouse and Drosophila. Following these guidelines, the
gene is italicized, whereas the corresponding cDNA, mRNA, protein or enzyme
activity is written with upper-case letters and without italics, e.g. 'human,
mouse or Drosophila ALDH3A1 cDNA, mRNA, or activity'. If an orthologous gene
between species cannot be identified with certainty, sequential naming of these
genes will be carried out in chronological order as they are reported to us. In
addition, 20 human ALDH variant alleles that have been reported to date are
listed herein and are recommended to be given numbers (or a number plus a capital
letter) following an asterisk (e.g. 'ALDH3A2*2, ALDH2*4C'). It is anticipated
that this eukaryotic ALDH gene nomenclature system will be extended to include
bacterial genes within the next 2 years and that this nomenclature system will
require updating on a regular basis; an ALDH Web site has been established for
this purpose (http://++www.uchsc.edu/sp./sp./alcdbase/a ldhcov.html) and will
serve as a medium for interaction amongst colleagues in this field.
PMID- 10780263
TI - Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of
the antidepressant agent venlafaxine in humans.
AB - According to in-vitro studies with microsomes from human livers and from yeast
expression systems with high CYP2D6 activity, the major oxidation pathway of
venlafaxine is catalysed by CYP2D6. In this study, we investigated the role of
the CYP2D6 polymorphism and the effects of low-dose quinidine, a selective
inhibitor of, CYP2D6, on the disposition of venlafaxine. Fourteen healthy men,
eight with the extensive metabolizer and six with the poor metabolizer phenotype
were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h
on two occasions (1 week apart); once alone and once during the concomitant
administration of quinidine sulfate 100 mg every 12 h. Blood and urine samples
were collected under steady-state conditions over one dosing interval (12 h).
When venlafaxine was administered alone, the oral clearance of venlafaxine was
more than fourfold less in poor metabolizers compared to extensive metabolizers
(P < 0.05). This was mainly due to a decreased capability of poor metabolizers to
form O-desmethylated metabolites at the position 4 of the aromatic moiety. In
extensive metabolizers, quinidine decreased venlafaxine oral clearance from 100
+/- 62 l/h to 17 +/- 5 l/h (mean +/- SD; P < 0.05) without any effects on renal
clearance (4 +/- 1 l/h during venlafaxine alone and 4 +/- 1 l/h during
venlafaxine plus quinidine). In these individuals, the sequential metabolism of
venlafaxine to O-desmethylvenlafaxine and to N,O-didesmethylvenlafaxine was
inhibited by quinidine coadministration so that metabolic clearances to O
desmethylated metabolites decreased from 43 +/- 32 l/h to 2 +/- 1 l/h (P < 0.05).
In poor metabolizers, coadministration of quinidine did not cause significant
changes in oral clearance and partial metabolic clearances of venlafaxine to its
various metabolites. Decreased CYP2D6 activity could also be associated with
cardiovascular toxicity as observed in four patients during treatment with the
drug. Thus, genetically determined or pharmacologically altered CYP2D6 activity
represents a major determinant of venlafaxine disposition in humans.
PMID- 10780264
TI - Genetic polymorphisms influence variability in benzene metabolism in humans.
AB - The role of genetic polymorphism in modulating urinary excretion of two benzene
metabolites, i.e. trans,trans-muconic acid (t,t-MA) and S-phenylmercapturic acid
(PMA), has been investigated in 59 non-smoking city bus drivers, professionally
exposed to benzene via vehicle exhausts. Exposure to benzene was determined by
personal passive samplers (mean +/- SD = 82.2 +/- 25.6 micrograms/m3), while
internal dose and metabolic rate were evaluated by measuring urinary excretion of
unmodified benzene (mean +/- SD = 361 +/- 246 ng/l), t,t-MA (mean +/- SD = 602 +/
625 micrograms/g creatinine), and PMA (mean +/- SD = 5.88 +/- 4.76 micrograms/g
creatinine). Genetic polymorphism at six loci encoding cytochrome-P450-dependent
monooxygenases (CYP2E1 and CYP2D6), glutathione-S-transferases (GSTT1, GSTP1 and
GSTM1) and NAD(P)H:quinone oxidoreductase (NQOR) was determined by polymerase
chain reaction-based methods. No evidence emerged for a possible role of CYP2E1,
GSTM1 and GSTP1 polymorphisms in determining the wide differences observed in the
rate of benzene biotransformation. Conversely, a significantly higher t,t-MA
urinary excretion was found to be correlated to, GSTT1 null genotype, and a
significantly lower PMA excretion was detected in the subjects lacking NQOR
activity and in the CYP2D6 extensive-metabolizers. Many biological (i.e. age and
body burden) or lifestyle factors (i.e. rural or urban residence, use of paints
and solvents, medication, alcohol and coffee intake), also taken into account as
potential confounders, did not influence the correlations found. These findings
suggest that CYP2D6, GSTT1 and NQOR polymorphisms contribute in explaining the
metabolic variability observed in our sample. Therefore, these polymorphisms
should be regarded as potential risk factors for benzene-induced adverse health
effects.
PMID- 10780265
TI - Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity.
AB - We evaluated the utility of the 3-methoxymorphinan/dextromethorphan (3MM/DM)
urinary ratio to reflect baseline CYP3A activity, and its ability to discriminate
moderate CYP3A inhibition during fluvoxamine therapy. For 4 months, oral
dextromethorphan 30 mg and intravenous midazolam 0.025 mg/kg were administered to
nine men every 14 days, and to 10 premenopausal women during the follicular and
luteal phases of their menstrual cycles. Phenotyping during the first 3 months or
cycles established baseline CYP3A activity. During the fourth month, individuals
were given fluvoxamine 150 mg/day. CYP3A activity was expressed as both the
urinary 3MM/DM molar ratio and midazolam plasma clearance (MDZ CL). 3MM/DM ratios
were independent of dextromethorphan CYP2D6 phenotype (r = 0.13, P = 0.6).
Intraindividual variability in baseline CYP3A activity (median, 25-75th
percentile), as determined by coefficients of variation, was 48.3% (36.8-68.8%)
for 3MM/DM and 10.3% (8.3-11.8%) for MDZ CL. No significant correlation between
3MM/DM and MDZ CL either at baseline (r = -0.22, P = 0.4) or during fluvoxamine
therapy (r = -0.15, P = 0.6) was noted. With fluvoxamine 150 mg/day, median
percentage change in the 3MM/DM ratios was -50.0% (-105.6-6.0%; P = 0.7), and
median percentage change in MDZ CL was -33.7% (-27.0-39.3%; P < 0.0001). Only MDZ
CL consistently indicated moderate inhibition of hepatic CYP3A activity. In
addition, there was a lack of correlation between the magnitudes of fluvoxamine
induced change in 3MM/DM and MDZ CL (r = 0.41, P = 0.1). The large
intraindividual variability of the 3MM/DM urinary ratio, as well as the inability
to discriminate moderate CYP3A inhibition, makes this a suboptimal method for
accurately assessing CYP3A activity.
PMID- 10780266
TI - Involvement of acetaldehyde for full protection against alcoholism by
homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene
in Asians.
AB - There is a functional polymorphism of the mitochondrial aldehyde dehydrogenase
(ALDH2) gene with the variant allele (ALDH2*2) encoding a protein subunit that
confers low activity to the tetrameric enzyme. Genetic epidemiologic studies have
strongly suggested that homozygosity for the allele ALDH2*2 is sufficient in
completely inhibiting the development of alcoholism in Asians. To study the
pathophysiology of this unique pharmacogenetic effect, we recruited a total of
eighteen adult Han Chinese men, matched by age, body-mass index, nutritional
state and homozygosity at the alcohol dehydrogenase gene loci from a population
base of 273 men. Six individuals were chosen for each of the three ALDH2
allelotypes: homozygous ALDH2*2/*2, heterozygous ALDH2*1/*2, and homozygous
ALDH2*1/*1. Following a low dose of ethanol (0.2 g/kg body weight), blood
ethanol/acetaldehyde concentrations, cardiac and extracranial/intracranial
arterial hemodynamic parameters, as well as self-rated subjective sensations,
were measured for 130 min. Homozygous ALDH2*2 individuals were found to be
strikingly responsive to the small amount of alcohol, as evidenced by the
pronounced cardiovascular hemodynamic effects as well as subjective perception of
general discomfort for as long as 2 h following ingestion. This low-dose alcohol
hypersensitivity, accompanied by a prolonged and large accumulation of
acetaldehyde in blood, provides an explanation for the strong protection against
heavy drinking and alcoholism in individuals homozygous for the ALDH2*2 gene
allele.
PMID- 10780267
TI - Three and four dimensional-quantitative structure activity relationship (3D/4D
QSAR) analyses of CYP2D6 inhibitors.
AB - Three- and four-dimensional quantitative structure activity relationship (3D/4D
QSAR) pharmacophore models of competitive inhibitors of CYP2D6 were constructed
using data from our laboratory or the literature. The 3D-QSAR pharmacophore
models of the common structural features of CYP2D6 inhibitors were built using
the program Catalyst (Molecular Simulations, San Diego, CA, USA). These 3D-QSAR
models were compared with 3D and 4D-QSAR partial least squares (PLS) models which
were constructed using molecular surface-weighted holistic invariant molecular
(MS-WHIM) descriptors of size and shape of inhibitors. The first Catalyst model
was generated from multiple conformers of competitive inhibitors (n = 20) of
CYP2D6 mediated bufurolol 1'-hydroxylation. This model demonstrated a correlation
of observed and predicted Ki (apparent) values of r = 0.75. A second Catalyst
model was constructed from literature derived Ki (apparent) values (n = 31) for
the inhibition of CYP2D6. This model provided a correlation of observed and
predicted inhibition for CYP2D6 of r = 0.91. Both Catalyst Ki pharmacophores were
then validated by predicting the Ki (apparent) of a test set of known CYP2D6
inhibitors (n = 15). Ten out of 15 of these Ki (apparent) values were predicted
to be within one log residual of the observed value using our CYP2D6 inhibitor
model, while the literature model predicted nine out of 15 values. Similarly, 3D-
and 4D-QSARs derived from PLS MS-WHIM for our dataset yielded predictable models
as assessed using cross-validation. The corresponding cross-validated PLS MS-WHIM
model for the literature dataset yielded a comparable 3D-QSAR and improved 4D
QSAR value. Such computational models will aid in future prediction of drug-drug
interactions.
PMID- 10780268
TI - Tentative association of the serotonin transporter with schizophrenia and
unipolar depression but not with bipolar disorder in Han Chinese.
AB - The serotonin transporter gene (SERT) plays an important role in the serotonin
uptake into neurons. Recently, several polymorphisms including a variable-number
tandem-repeat (VNTR) in the second intron and an insertion/deletion polymorphism
(5-HTT linked polymorphic region, 5-HTTLPR) were identified and reported to be
associated with a variety of mental illnesses, including major depression,
bipolar disorder, anxiety-related traits, and autism. In our study, we performed
an association study between the SERT VNTR polymorphism and schizophrenia (n =
260), bipolar disorder (n = 137), and unipolar depression (n = 33) in the Han
Chinese. A large group of ethnically matched control individuals (n = 362) were
also genotyped. Allele 12 of the VNTR polymorphism was associated with
schizophrenia (P = 0.007) and unipolar depression (P = 0.011). Bipolar disorder
was not associated with the VNTR (P = 0.93). Thus, we conclude that the SERT VNTR
polymorphism may be a risk factor for both schizophrenia and unipolar depression,
but not for bipolar disorder, in the Han Chinese.
PMID- 10780269
TI - Association between glutathione S-transferase pi genetic polymorphisms and oral
cancer risk.
AB - Polymorphisms in the gene encoding the glutathione S-transferase (GST) pi
metabolizing enzyme have previously been associated with susceptibility to
various cancers. In this study, the importance of GSTP1 genotypes as determinants
of risk for oral cancer was assessed by examining the prevalence of GSTP1 alleles
in 157 incident oral cancer cases and 260 non-cancer control individuals
frequency-matched by race, sex, and age at diagnosis (+/- 5 years). The GSTP1*A,
GSTP1*B, GSTP1*C, and GSTP1*D alleles were elucidated by polymerase chain
reaction-restriction fragment length polymorphism analysis of polymorphisms
present in codons 105 (isoleucine:valine) and 114 (alanine:valine) of the GSTP1
gene. Increased risk for oral cancer was observed in individuals who were
homozygous for any combination of GSTP1 polymorphic alleles (i.e. *B, *C, and/or
*D alleles; odds ratio = 2.4, 95% confidence interval = 1.2-4.8). Similar risk
was observed in both Caucasians (odds ratio = 2.6, 95% confidence interval = 1.1
6.2) and African-Americans (odds ratio = 2.3, 95% CI = 0.68-7.5). A greater risk
was observed in individuals with the GSTP1 (Var/Var) genotype who were exposed to
low levels of smoking (i.e. < or = 20 pack-years [py], odds ratio = 3.4, 95%
confidence interval = 1.1-11) than among heavier smokers (i.e. > 20 pack-years
[py], odds ratio = 1.4, 95% confidence interval = 0.48-4.0). These results
suggest that GSTP1 genotype may play a role in risk for oral cancer particularly
among lighter smokers.
PMID- 10780270
TI - The dopamine D2 receptor 5'-flanking variant, -141C Ins/Del, is not associated
with reduced dopamine D2 receptor density in vivo.
AB - The Del allele of the -141C (Ins/Del) polymorphism located in the immediate 5'
flanking region of the human dopamine D2 receptor gene has been reported to be
associated with reduced promoter activity in vitro. However, genetic association
studies of the -141C (Ins/Del) polymorphism with schizophrenia and alcoholism
have yielded conflicting results. In this report, we explored the effect of the
Del allele on the D2 receptor binding characteristics in vivo in healthy
volunteers using positron emission tomography and D2 receptor antagonist,
[11C]raclopride. No difference in D2 receptor density was observed between the
Del allele carriers compared to the individuals with the Ins/Ins genotype,
indicating that the genetic variation at the -141C (Ins/Del) site does not affect
D2 receptor expression level in vivo.
PMID- 10780271
TI - Frequency of functionally important beta-2 adrenoceptor polymorphisms varies
markedly among African-American, Caucasian and Chinese individuals.
AB - There are ethnic differences in the prevalence and severity of hypertension and
asthma and in beta-2 adrenergic receptor (BAR2)-mediated vascular responses. Two
common polymorphisms of the human BAR2, Arg16 to Gly and Gln27 to Glu, are
associated with alterations in BAR2 response, both in vitro and in vivo. Ethnic
differences in disease manifestations and responses to treatment may be explained
by the altered frequency of BAR2 polymorphisms. To determine the relative
frequencies of the Arg16 to Gly and Gln27 to Glu BAR2 polymorphisms in different
ethnic groups we studied 415 (123 African-American, 188 Caucasian-American and
104 Chinese) healthy individuals. There was a marked interethnic difference in
the frequency of the BAR2 polymorphisms among the ethnic groups. The Glu27 allele
was more frequent in Caucasian-American (34.8%) than in African-American
individuals (20.7%) (P = 0.0001) and much less frequent in Chinese individuals
(7.2%) (P = 0.0001 versus African-American or Caucasian-American). The homozygous
Glu27 genotype was more frequent in Caucasian-American (15.4%) than African
American individuals (4.9%) (P = 0.003) and was not observed in Chinese. The
Gly16 allele (54.3% versus 41.3%) and homozygous genotype (35.1% versus 18.3%)
were more common in Caucasian-American than Chinese individuals (P = 0.003 for
both). There is a marked ethnic difference in the frequency of these two common
BAR2 polymorphisms among African-American, Caucasian-American and Chinese
individuals, with a markedly reduced frequency of the Glu27 polymorphism, the
polymorphism associated with resistance to desensitization and increased BAR2
responses, in African-American and Chinese individuals. Such ethnic genotypic
differences may explain previously observed alterations in the response to the
BAR agonists in different ethnic groups.
PMID- 10780272
TI - Genomic structure and sequence analysis of a human inositol polyphosphate 1
phosphatase gene (INPP1).
AB - Lithium remains the most widely used long-term treatment for bipolar affective
disorder, but the molecular mechanisms underlying its therapeutic efficacy have
not been fully elucidated. Two enzymes involved in the phospholipase C signalling
system, namely the myo-inositol monophosphatase (IMPase) and the inositol
polyphosphate 1-phosphatase (IPPase), have been postulated as targets for the
therapeutic action of lithium in manic-depressive illness. Intriguingly,
Drosophila mutants lacking IPPase activity display a defect in synaptic
transmission, and this alteration could be phenocopied by lithium exposure. We
recently demonstrated the presence of several polymorphisms in the IPPase
encoding inositol polyphosphate 1-phosphatase gene (INPP1) cDNA and suggested
that polymorphic variants of the human IPPase might be associated with the
striking difference in lithium response among bipolar patients. We report the
genomic structure and organization of the INPP1 gene on chromosome 2q32. Based on
DNA sequencing of the entire genomic region containing INPP1, we found that the
gene consists of six exons and spans more than 25 kb. Expression analysis showed
that INPP1 is present as a 1.9 kb mRNA transcript in all organs and tissues
examined, including the central nervous system. The level of expression varies,
with at least a fourfold higher transcript level in testis compared with other
tissues with high expression. A highly polymorphic dinucleotide repeat, (CA)18
25, with an observed heterozygosity of 0.86 was detected immediately downstream
of the gene. The present sequence information will be used to further investigate
the possible role of the INPP1 gene in lithium-treated bipolar illness.
PMID- 10780273
TI - Rapid high-performance liquid chromatographic method for determination of
debrisoquine and 4-hydroxy-debrisoquine in urine for CYP2D6 phenotyping.
PMID- 10780275
TI - Capitation and risk adjustment in health care.
AB - Capitation and risk adjustment have become the chosen policy instruments to seek
cost containment and equity of access for many developed health care systems.
Increasingly, this entails the prospective setting of global budgets for the
health care expenditures incurred by health care plans on behalf of their
members. Methods of deriving such budgets are diverse and tailored to the
specific circumstances of the health care system they seek to serve. This special
issue presents a collection of papers devoted to issues surrounding the
rationale, derivation, and implementation of capitation and risk adjustment
methods of financing health care. These are discussed within the context of
health care systems in eight countries, illustrating the range of interest in the
topic. Undoubtedly, capitation and risk adjustment will become increasingly
significant elements of virtually all systems of health care and we hope the
collection of papers will help to stimulate further debate and research in this
important and interesting area of health care financing.
PMID- 10780274
TI - Role of arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) genotypes in
susceptibility to oral/pharyngeal and laryngeal cancers.
PMID- 10780276
TI - Capitation funding in Australia: imperatives and impediments.
AB - Health service funding mechanisms are pivotal in the pursuit of health system
objectives, as they provide strong financial incentives for actors in the system
to achieve policy goals. Underpinning funding mechanisms is a set of key economic
principles, or objectives, that should guide their design and use: efficiency,
equity, and accountability. The Australian health system has historically
performed relatively poorly in relation to these objectives, with evidence of
inefficiencies, inequities, and poor accountability in many areas of health
services. The primary cause of these shortcomings may lie in the complex set of
funding and delivery arrangements at the State and Federal levels of government.
Potentially significant improvements in the performance of the health system
would be available from the integration of the funding and delivery of services
within a single tier of government, coupled with the development of a national
weighted capitation approach to funding. To develop a national capitation funding
model a number of unique factors require consideration, including the current
fragmentation of services, the role of the private sector, the needs of
indigenous populations, and the effects of rurality. The data available to
develop a capitation model is of a level of detail and quality not readily found
elsewhere. If policy statements promoting efficiency, accountability, and
particularly equity are to be actively pursued, a national capitation model based
on robust methods should become a cornerstone of Australian health system reform.
PMID- 10780278
TI - Risk adjusting capitation: applications in employed and disabled populations.
AB - Risk adjustment may be a sensible strategy to reduce selection bias because it
links managed care payment directly to the costs of providing services. In this
paper we compare risk adjustment models in two populations (public employees and
their dependents, and publicly-insured low income individuals with disabilities)
in Washington State using two statistical approaches and three health status
measures. We conclude that a two-part logistic/GLM statistical model performs
better in populations with large numbers of individuals who do not use health
services. This model was successfully implemented in the employed population, but
the managed care program for the publicly insured population was terminated
before risk adjustment could be applied. The choice of the most appropriate
health status measure depends on purchasers' principles and desired outcomes.
PMID- 10780279
TI - Growing importance of capitation in Switzerland.
AB - Since its liberalization the Swiss health insurance market has shown risk
selection activities of the insurance funds, which call for risk adjustment.
Because risk selection continues to be profitable under the current risk
adjustment formula, fast growing HMO and PPO plans are (mis)used to attract good
risks rather than to contain costs. For fear of being replaced by one centralised
fund, social health insurers are themselves proposing improvements of the risk
adjustment formula, to be applied to funds. The revised formula proposed in this
paper, applicable among funds for risk adjustment and to gate-keeping models to
calculate fair capitation, explains 12.4% of the variance of health care
expenditure, halves profits from risk selection, and uses only the (few) data
that are available in Switzerland.
PMID- 10780277
TI - Needs-based primary medical care capitation: development and evaluation of
alternative approaches.
AB - OBJECTIVE: To develop and evaluate alternative methods of adjusting primary
medical care capitation payments for variations in relative need for health care
among enrolled practice populations. METHODS: We developed alternative needs
based capitation formulae and applied them to a sample of capitation-funded
primary care practices to assess each formula's performance against a reference
standard of capitation payments based on age, sex and self-assessed health status
of the enrolled populations. The alternative formulae were based on: (1) age and
sex; (2) age, sex and individually-measured socioeconomic characteristics; (3)
age, sex and socioeconomic characteristics imputed from census data for
enrollees' neighbourhood of residence; (4) age, sex and standardized mortality
ratio for enrollees' neighbourhood of residence. RESULTS: Age/sex-adjusted
capitation payments for the six practices studied ranged from 10% higher to 18%
lower than the reference standard payments. Capitation formulae based on
socioeconomic and mortality data did not perform consistently better than the
current age/sex-based formula. CONCLUSIONS: Primary medical care capitation
payments adjusted only for age and sex do not reflect the relative health care
needs of enrolled practice populations. Our alternative formulae based on
socioeconomic and mortality data also failed to reflect relative needs. Methods
that use other approaches to adjusting for differences in relative need among
enrolled populations should be investigated.
PMID- 10780280
TI - Risk adjustment and the fear of markets: the case of Belgium.
AB - In Belgium the management and administration of the compulsory and universal
health insurance is left to a limited number of non-governmental non-profit
sickness funds. Since 1995 these sickness funds are partially financed in a
prospective way. The risk adjustment scheme is based on a regression model to
explain medical expenditures for different social groups. Medical supply is taken
out of the formula to construct risk-adjusted capitation payments. The risk
adjustment formula still leaves scope for risk selection. At the same time, the
sickness funds were not given the instruments to exert a real influence on
expenditures and the health insurance market has not been opened for new
entrants. As a consequence, Belgium runs the danger of ending up in a situation
with little incentives for efficiency and considerable profits from cream
skimming.
PMID- 10780281
TI - Ignoring small predictable profits and losses: a new approach for measuring
incentives for cream skimming.
AB - Under inadequate capitation formulae competing health insurers have an incentive
for cream skimming, i.e., the selection of enrollees whom the insurer expects to
be profitable. When evaluating different capitation formulae, previous studies
used various indicators of incentives for cream skimming. These conventional
indicators are based on all actual profits and losses or on all predictable
profits and losses. For the latter type of indicators, this paper proposes, as a
new approach, to ignore the small predictable profits and losses. We assume that
this new approach provides a better indication of the size of the cream skimming
problem than the conventional one, because an insurer has to take into account
its costs of cream skimming and the (statistical) uncertainties about the net
benefits of cream skimming. Both approaches are applied in theoretical and
empirical analyses. The results show that, if our assumption is right, the
problem of cream skimming is overestimated by the conventional ways of measuring
incentives for cream skimming, especially in the case of relatively good
capitation formulae.
PMID- 10780282
TI - Modelling of resource allocation to health care authorities in Stockholm county.
AB - Since the Stockholm County Council introduced a system of purchasers and
providers there has been a quest for population-based resource allocation models
to allocate monies to purchasers of health care. In contrast to models used in
Britain, Swedish models have been based on individual level data. This paper
presents recent developments in the model used in Stockholm for all care except
primary care, testing new statistical methods for compression and clustering of
the matrices used and the effect of introducing diagnostic information in
addition to the demographic and socio-economic information used before. We also
show the effect of using more current data sources by replacing existing census
variables with data from annually updated registers. Since the aim is to use the
resource allocation models for prospective budgeting we test and evaluate the
predictive power of the models one to two years ahead. Moreover, two calibration
methods are compared: Cross-sectional modelling, based on data for one year only,
versus prospective modelling, using population characteristics for one year and
registered health-care costs for a following year. While models including
diagnostic information are deemed valuable, the prospective models yield little
improvement. Further, although it takes a combination of new variables to replace
the census based model, the resulting model now implemented by Stockholm County
Council has fewer estimated parameters.
PMID- 10780283
TI - Contract design for primary care physicians: physician location and practice
behaviour in small communities.
AB - Most western countries employ a combination of fee-for-service, fixed salary and
per capita subsidies to finance the services of general practitioners. Based on
Norwegian data, the authors demonstrate that these financial schemes have been
used in different types of municipalities. The authors argue that the fee-for
service and per capita components should be allowed to vary between primary
physicians and municipalities: (a) If the patient population per primary
physician is low and patient supply is unstable, the per capita subsidy or work
free income should be differentiated to ensure recruitment of physicians. (b)
Physicians in municipalities with low physician coverage should be allotted a low
basic grant, whilst per capita subsidy and fee-for-service payments should be
used to stimulate service production. The opposite situation exists where there
is a potential of supplier inducement due to high physician coverage. (c) The
responsibility for designing contracts should be assigned to local rather than
national authorities. These suggestions go against important elements in the
reform of primary physician services in Norway.
PMID- 10780284
TI - Risk adjustment of capitation payments to behavioral health care carve-outs: how
well do existing methodologies account for psychiatric disability?
AB - This study used 1994-1995 administrative data from a large public employer to
examine the viability of commercial risk adjustment systems for setting
capitation payments to competing behavioral health care "carve-outs". The ability
of Hierarchical Condition Categories and Adjusted Diagnostic Groups to predict
psychiatric expenditures was improved by controlling separately for psychiatric
disability. However, even the best models underpredicted expenditures of patients
with psychiatric disability by 15%. Relative to full capitation, "mixed" payment
systems and soft capitation reduce the ability of carve-outs to earn
disproportionate profits by enrolling healthy patients and avoiding sick ones,
yet also diminish incentives for cost containment.
PMID- 10780285
TI - Differential involvement of dopamine in mediating the discriminative stimulus
effects of low and high doses of caffeine in rats.
AB - The hypothesis that low and high doses of caffeine produce effects that are
differentially mediated by dopamine (DA) receptor mechanisms was investigated in
rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats
trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an
average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine
required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the
DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50
75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced
predominantly saline-appropriate responding (< 40%) in rats trained to
discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus
generalization was no greater than it was when either agonist was tested alone.
The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline
appropriate responding in both groups of rats. Neither the DA D1 receptors
antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists
eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56
mg/kg of caffeine. When administered in combination with caffeine, both the DA D1
and DA D2 antagonists antagonized completely the discriminative stimulus effects
of the low training dose of caffeine, but did not alter the discriminative
stimulus effects of the high training dose. These results suggest that the
discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of
caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.
PMID- 10780286
TI - Assessment of D3 versus D2 receptor modulation of the discriminative stimulus
effects of (+)-7-OH-DPAT in rats.
AB - Although there are presently no highly selective agonists for the D3 dopamine
receptor, a number of compounds reported to bind with moderate selectivity to D3
receptors are currently employed to investigate the importance of D3 receptors in
the behavioral effects of psychostimulant drugs. For example, 7-hydroxy-N,N-di-n
propyl-2-aminotetralin (7-OH-DPAT) has been used extensively to investigate the
role of D3 receptors in the reinforcing and discriminative stimulus properties of
cocaine and d-amphetamine. However, recent investigations with a relatively
selective D3 antagonist, PNU-99194A, have led us to question the importance of D3
receptors in the discriminative stimulus effects of 7-OH-DPAT. In the present
study, 16 male Sprague-Dawley rats were trained to discriminate (+)-7-OH-DPAT
(0.03 mg/kg, subcutaneously (s.c.)) from saline in a two-choice operant procedure
using a fixed-ratio 20 schedule of water reinforcement. Consistent with previous
findings, PNU-99194A appeared to attenuate only partially (+)-7-OH-DPAT
discrimination at a dose that disrupted responding in most subjects. Moreover, a
highly selective D2 agonist, PNU-91356A, substituted completely and in a dose
dependent manner for (+)-7-OH-DPAT, while d-amphetamine produced only partial
substitution for the training drug. These data indicate that D2 receptor actions
appear to be more important than D3 receptor actions in exerting the
discriminative stimulus effects of (+)-7-OH-DPAT. Continued efforts to determine
the relative importance of D2 vs D3 receptor actions in the modulation of the
discriminative stimulus effects of (+)-7-OH-DPAT are discussed.
PMID- 10780287
TI - Effects of post-training infusions of a mitogen-activated protein kinase kinase
inhibitor into the hippocampus or entorhinal cortex on short- and long-term
retention of inhibitory avoidance.
AB - We recently demonstrated the time-dependent impairment of long-term retention of
a step-down inhibitory avoidance task in rats induced by post-training infusion
of the specific MAPKK (mitogen-activated protein kinase kinase) inhibitor PD
098059 into the hippocampus (HIP), amygdala (AMY), entorhinal cortex (EC) and
posterior parietal cortex (PPC). Here we investigate the role of the MAPK cascade
in the HIP and the EC on both short- and long-term retention of inhibitory
avoidance in rats, using three different doses of the MAPKK inhibitor PD 098059.
Adult male Wistar rats were trained and tested in inhibitory avoidance and given
an infusion of PD 098059 (0.5, 5.0 or 50.0 microM) at 0, 30, 90, 120, 180, 270 or
360 min after training. A retention test session was carried out at 90, 180 or
270 min after training (short-term memory, STM) and/ or 24 h after training (long
term memory, LTM). When infused into the HIP at 0 min, but not at 30, 90, 120 or
180 min after training, PD 098059 impaired STM. Intrahippocampal PD 098059
impaired LTM when infused at 180 min, but not at 0, 30, 90, 120 or 270 min after
training. When infused into the EC, PD 098059 enhanced STM when given at 0 min
after training and had no effect when given at 30, 90, 120 or 180 min after
training. In this structure, PD 098059 impaired LTM when given at 180 or 270 min,
but not at 30, 90, 120 or 360 min after training. All effects were dose
dependent. These findings indicate that the MAPK cascade in the HIP and EC is
differentially involved in short- and long-term retention of inhibitory avoidance
in rats.
PMID- 10780288
TI - Effects of sildenafil on long-term retention of an inhibitory avoidance response
in mice.
AB - Sildenafil (1, 3, 10, and 30mg/kg, intraperitoneally (i.p.)), a cyclic guanosine
monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor,
facilitated retention performance of a one-trial step-through inhibitor avoidance
task, when administered to male Swiss mice immediately after training, as
indicated by performance on a retention test 48 h later. The dose-response curve
was an inverted U in this dose range, although only the dose of 3 mg/kg of
sildenafil produced significant effects. Sildenafil did not affect response
latencies in mice not given the footshock on the training trial, indicating that
the actions of sildenafil on retention were not due to non-specific proactive
effects on retention performance. The effects of sildenafil (3 mg/kg, i.p.) were
time-dependent, and the administration of sildenafil (3 mg/kg, i.p.) 30 min prior
to the retention test did not affect retention in mice given post-training
injections of vehicle or sildenafil (3 mg/kg, i.p.). However, the administration
of sildenafil (3mg/kg, i.p.) 30 min before training also enhanced retention
performace. Further, when mice were trained and received immediate post-training
sildenafil (3 mg/kg) and were tested for retention either 1 week or 1 month
later, at each retention interval the performance was comparable to that found
with a 48-h retention interval. Finally, an enhancement of retention was also
observed in female Swiss mice that received sildenafil (3 mg/kg, i.p.)
immediately, but not 180min, after training. These findings could indicate that
the actions of sildenafil on retention are not sex-dependent. The results suggest
that sildenafil influences retention by modulating time-dependent mechanisms
involved in memory storage and that the effects are long lasting. A possible
participation of the nitric oxide (NO)-guanylyl cyclase-cGMP system also is
suggested.
PMID- 10780289
TI - Dose-dependent effects but not sensitization of DRL 45-s performance by oral d
amphetamine with cumulative- and repeated-dosing regimens.
AB - The effects of d-amphetamine (AMPH) on a food-reinforced DRL 45-s schedule were
evaluated using both cumulative- and repeated-dosing drug regimens. These two
dosing regimens were designed to evaluate sensitization as a shift in the dose
response relationship, inasmuch as a range of doses was imposed within each
dosing session. Daily 190-min sessions were composed of five 35-min subsessions
separated by 3-min time-out periods. For selected sessions, five cumulative or
repeated oral doses of AMPH were administered across the session, with a dose
given during each of the time-out periods prior to the start of each subsession.
Drug sessions were separated by intervals of 7-l0 days of non-drug sessions. Four
cumulative dose-effect functions for AMPH were determined: for each dose-effect
determination session, increasing doses (0.5, 1, 2, 4, 8 mg/kg gavage) were
successively administered prior to each subsession. Four dose-effect functions
were then determined in which a 0.5 mg/kg AMPH dose was repeated for each
subsession (repetitive-dose regimen) rather than escalating subsession dose size.
Then, four additional functions were determined using a larger repetitive dose of
1 mg/kg AMPH. Cumulative doses resulted in a leftward shift in the inter-response
times (IRT) distribution accompanied by dose-dependent increases in subcriterion
responses (< 45 s) and decreases in reinforced responses. The repeated doses of
0.5 or 1 mg/kg AMPH also resulted in progressive intrasession increases in
subcriterion responses and decreases in reinforced responses. Although
intrasession, accumulating dose effects were evident and statistically
significant, there was no statistical significance or trend supporting
sensitization of differential reinforcement of low-rate (DRL) responding with
either cumulative- or repeated-dosing regimens across drugging sessions, unlike a
previous, similar study in which oral cocaine resulted in robust sensitization.
PMID- 10780290
TI - Regulation of emotional behaviour by day length in mice: implication of
melatonin.
AB - Pineal melatonin secretion occurs at night in all vertebrates and the duration of
its secretion is negatively correlated with day length. As short-day exposure was
previously shown to decrease emotional behaviour of mice toward an unfamiliar
environment, the present study was designed to determine whether such behavioural
changes could be mediated by melatonin. In a first experiment, the effects of a 3
week exposure to various day lengths (18h-6h, 12h-12h and 6h-18h light-dark
conditions) on neophobic behaviour (free-exploratory paradigm) were examined in
both BALB/c mice, which exhibit a very transitory melatonin peak of low amplitude
in a 12h light-12h dark cycle, and C3H/He mice, which present a clear melatonin
rise during the night-time. A second experiment was designed to determine if the
decrease of emotional reactivity induced by a short-day exposure (6h-18h light
dark cycle during 3 weeks) in C3H/He mice could be counteracted by a daily
treatment with a melatonin antagonist, S 22153 (1, 5 and 25 mg/kg/day). The short
day exposure was found to decrease neophobic reactions in both C3H/He and BALB/c
mice. In contrast, the long-day exposure enhanced neophobia in C3H/He mice only.
S 22153 was found to counteract, in a dose-dependent manner, the anxiolytic-like
effects induced by the short-day exposure in C3H/He mice. The present results
provide evidence that the modulation of circulating melatonin could be involved
in the emotional changes related to day-length variations. Further studies are
needed to investigate whether pinealectomy could counteract the photoperiod
related changes in anxiety.
PMID- 10780291
TI - Behavioural consequences of repeated social defeat in the mouse: preliminary
evaluation of a potential animal model of depression.
AB - The behavioural consequences of repeated social defeat, coupled with the stress
of continuously living opposite a dominant animal, were assessed in male NMRI
mice. The method adopted here differed from the previously published techniques
in that the physical element of the social defeat procedure was reduced to a
minimum. The subordinate animals consistently weighed less than control animals,
and displayed a reduced number of visits to the partition compared to the
dominant animals, which has previously been used as a marker of social behaviour.
The subordinate animals did not show any differences in the amount of ethanol
solution consumed compared to controls, and did not display an increase in
immobility time measured in the forced swimming test. The subordinate animals
did, however, display anxiogenic-like behaviour as indicated by an increased
aversion of the light section of the black/white test box, which was partially
reversed by chronic treatment (3weeks; 20mg/kg/day) with the antidepressant,
citalopram. Decreased exploration by the subordinate animals in the black/white
test box was also observed, which was reversed by chronic citalopram treatment.
It is suggested that, whilst the model requires further validation, it may be a
useful approach for the study of antidepressant compounds.
PMID- 10780292
TI - Effects of drugs on responding under concurrent fixed-interval schedules and
concurrent fixed-ratio schedules.
AB - Pigeons were trained to respond under concurrent fixed-interval fixed-interval
(concurrent FI FI) schedules with Fl values (in seconds) of 30/300, 60/240,
60/60, 240/60 and 300/30. A second group was trained to respond under concurrent
fixed-ratio fixed-ratio (concurrent FR FR) with FR values of 10/40, 10/20, 20/20,
20/10 and 40/10. Under the concurrent Fl Fl schedules, pigeons responded much
less often on the key with the higher reinforcement density than would be
predicted basing on a perfect matching of the ratio of responses made to the
ratio of reinforcers delivered, and the pigeons also showed a bias towards
responding on the left key. Pentobarbital, methamphetamine, morphine and
phencyclidine had little effect on bias, but high doses of methamphetamine,
morphine and phencyclidine decreased undermatching. Under the concurrent FR FR
schedules, pigeons responded almost entirely on the key with the higher
reinforcement density. Only pentobarbital consistently disrupted this pattern of
responding.
PMID- 10780293
TI - Effects of phentermine on responding maintained by progressive-ratio schedules of
cocaine and food delivery in rhesus monkeys.
AB - Previous reports indicate that intravenous pretreatment with phentermine can
decrease cocaine-maintained responding without affecting food-reinforced
responding under fixed-ratio schedules. The present experiments were designed to
explore the generality of this effect using progressive-ratio schedules of
reinforcement and different routes of phentermine administration. Unit doses of
cocaine and food-pellet magnitudes were identified that maintained similar
breaking points, and the effects of acute exposure to phentermine were assessed.
In Experiment 1, a 'conventional' (one-trial) progressive-ratio schedule was
used, in which response requirements increased after each reinforcer delivery; in
Experiment 2, a 'modified' (five-trial) progressive-ratio schedule was used, in
which response requirements increased after every five reinforcer deliveries. In
one group of monkeys, responding was maintained by food; in another, cocaine
infusions maintained responding. Phentermine (0.1-5.6mg/kg, intramuscularly
(i.m.)) dose-dependently decreased breakpoints on both progressive-ratio
schedules. There were no differences in phentermine's effects on cocaine- and
food-maintained behavior. In Experiment 3, intravenous administration of
phentermine had largely similar effects. Taken together with results from
previous reports, these data suggest that the effects of phentermine pretreatment
are influenced by the behavioral procedure used to maintain responding and/or by
the efficacy of the food and cocaine reinforcers.
PMID- 10780295
TI - The calcium channel antagonist, nimodipine, decreases operant self-administration
of low concentrations of ethanol.
AB - This study examined effects of the dihydropyridine calcium channel antagonist,
nimodipine, on operant self-administration of ethanol, under a progressive-ratio
schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists
have been reported to decrease the ethanol withdrawal syndrome, the development
of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site
density in the central nervous system (CNS) is increased by chronic alcohol
treatment. In addition, these drugs decrease reinforcing effects of
psychostimulants. In the present studies, nimodipine was administered, once
weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg,
nimodipine decreased the break point, and number of reinforcers obtained, for
ethanol concentrations of 5, 10 and 15%. At 50mg/kg, nimodipine only decreased
the break point, and number of reinforcers, for 5% ethanol. Responding for higher
concentrations of ethanol was unaffected by nimodipine, as was responding when
ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or
0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect
on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor
activity, but 10 mg/kg nimodipine only slightly decreased static activity counts.
The results suggest that nimodipine, at the lower dose tested, decreased the
reinforcing properties of low concentrations of ethanol.
PMID- 10780294
TI - Influence of light cycle on response to 5-HT1A ligands in punished responding in
rats.
AB - Since the introduction of buspirone, the 5-HT1A receptor has been a focal point
for serotonergic research into the treatment of anxiety. Two of the more commonly
used methodologies for evaluating potential anxiolytics are the Geller-Seifter
model and the elevated plus maze. In the Geller-Seifter model, administration of
5-HT1A agonists produce an anxiolytic-like profile consisting of an increase in
the number of responses made during the punished component. An anxiolytic-like
response in the elevated plus maze consists of an increase in the number of
entries and/or time spent in the open arms of the maze. Recently, there have been
reports of differential drug effects with 5-HT1A ligands in the elevated plus
maze depending on when in the diurnal cycle the 5-HT1A agents were administered.
The purpose of the current study was to characterize the response to 5-HT1A
compounds in normal and reverse light cycle animals in the Geller-Seifter model.
8-OH-DPAT [(+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene] produced
a decrease in unpunished responding and an increase in punished responding during
both the light and dark phase. The administration of WAY 100,635 [N-?2-[4-(2
methoxyphenyl)-1-piperazinyl] ethyl?-N-(2-pyridinyl)cyclohexanecarboxamide
trihydrochloridel alone was without effect in both the light and dark phase.
Furthermore, pre-treatment with WAY 100,635 completely antagonized both the rate
decreasing effects in the unpunished component and the increase in punished
responding observed with 8-OH-DPAT during both the light and dark phase. The
results of the current study diverge from previous findings of sensitivity to the
diurnal cycle in other models reflective of modulation of the 5-HT1A receptor.
The robustness of the response, in this case punished lever pressing, may be less
sensitive than other more naturalistic or ethological methods (i.e. elevated plus
maze) in detecting the subtle changes in receptor function due to the diurnal
cycle.
PMID- 10780296
TI - Establishing preference for lidocaine solution to water: comparison between a
fading and an abrupt-removal procedure for withdrawing a compound vehicle.
AB - Rats were exposed to daily, 3-h, fixed-time 1-min food-pellet delivery sessions,
which is a procedure that produces overdrinking (schedule-induced polydipsia). In
previous polydipsia studies, rats came to prefer solutions of drug or non-drug
agents to concurrently presented water if the agents had first been offered in a
glucose-saccharin vehicle that was slowly eliminated (faded), leaving a choice
between a substance in water vehicle vs water. In the first experiment, a more
rapid vehicle-fading procedure was used to produce a preference for 0.19mg/ml
lidocaine to water. In the second experiment, the vehicle was abruptly changed to
water, which also resulted in a strong preference for lidocaine solution,
although the lidocaine solution volumes ingested for the final sessions were
significantly less than in the first experiment. The results are consistent with
a conditioned flavor/nutrient preference interpretation for the institution of
the lidocaine preference in both experiments. Although flavor/nutrient
conditioning can be a sufficient condition for generating a substance preference,
a previous experiment showed that it was not a necessary condition.
PMID- 10780297
TI - Lack of difference between HAD and LAD rats in the stimulus generalization of
ethanol to nicotine.
AB - High alcohol drinking (HAD) and low alcohol drinking (LAD) rats were trained to
discriminate 0.5 g/kg ethanol from saline. HAD and LAD rats learned the
discrimination at the same rate and to the same level of asymptotic performance.
In substitution tests, increasing doses of ethanol produced increased responding
on the ethanol lever with dose-effect curves that were very similar in HAD and
LAD rats. There was no generalization from ethanol to nicotine, or d-amphetamine,
in either HAD or LAD rats. These data may be contrasted with data obtained with
alcohol preferring rats (P rats) and alcohol non-preferring rats (NP rats), where
the ethanol discrimination was learned more rapidly, asymptotic performance was
better in P than in NP rats, and ethanol discriminative stimulus generalized to
nicotine and partially to d-amphetamine in P, but not in NP rats. These data
suggest that the differences in ethanol consumption reported previously by P and
HAD rats relative to NP and LAD rats is not necessarily related to strain
differences in ethanol discrimination as the differences in ethanol
discrimination previously observed between P and NP rats do not occur in HAD and
LAD rats.
PMID- 10780298
TI - Naltrexone and morphine alter the discrimination and plasma levels of ethanol.
AB - The opioid antagonist, naltrexone, reduces intake of, and operant responding for,
ethanol, but reports of how the opioid agonist morphine alters these effects are
conflicting. We examined the discrimination and plasma levels of ethanol with
naltrexone and morphine pretreatments. Rats were trained to discriminate ethanol
(1.5 g/kg; i.g.) from water, under a two-lever, food-reinforced procedure.
Ethanol and pentobarbital, but not amphetamine, substituted for ethanol in a dose
related manner. Naltrexone reduced ethanol-induced, ethanol-appropriate
responding to about 35%, but the peripherally-acting antagonist, naltrexone
methobromide, was without effect. Morphine neither substituted for nor enhanced
ethanol-appropriate responding. Rather, ethanol-induced, ethanol-appropriate
responding was attenuated in a dose-related manner by morphine administration.
Neither naltrexone nor morphine altered ethanol-appropriate responding to the
substitution with pentobarbital. In another group of rats, both naltrexone and
morphine decreased plasma ethanol levels, and delayed the time of peak
concentrations, suggesting that opiates alter the behavioral effects of ethanol
through both pharmacokinetic and pharmacodynamic mechanisms. The similarities
between an opioid agonist and an antagonist suggest that either naltrexone has
opioid agonist-like effects, or that these effects occur through non-opioidergic
mechanisms.
PMID- 10780299
TI - Sensitization of operant behavior to oral cocaine with increasing- and repetitive
dose regimens.
AB - This study evaluated whether operant behavior was subject to sensitization upon
repeated exposure to cocaine. The behavior of eight rats was reinforced by food
pellet delivery under a differential reinforcement of low-rate (DRL) 45-s
schedule, in daily sessions of 190 min. Each session was composed of five 35-min
subsessions, with each subsession preceded by a 3-min time out period (TO). For
selected sessions, a cumulative dose-effect relation for cocaine, using
increasing doses, was first determined by oral gavage administration of a dose
during each subsession. Three such cycles were given, separated by between seven
and ten sessions. Later, four further cycles were given, using a repetitive 10
mg/kg cocaine per os (p.o.) dose, rather than an increasing dose. Under both
dosing procedures, within a cocaine cycle (session), shorter (<45 s) inter
response times (IRT) progressively increased with doses, and reinforced responses
decreased. As cycles were repeated, the shorter IRT increases became
progressively more marked, indicating the development of sensitization to the
effect of cocaine. With the second procedure (repetitive 10 mg/kg doses),
reinforcement rate decreases became more marked as cycles were repeated, but this
change did not occur using the increasing-dose procedure. Upon later exposure to
repetitive 5 mg/kg dosing cycles, none of these rate changes occurred, and
performances were equivalent to those occurring under saline cycles. Exposure to
cumulative dose regimens of oral cocaine can result in the sensitization of
operant behavior to the effects of cocaine.
PMID- 10780300
TI - Establishing oral preference for quinine, phencyclidine and caffeine solutions in
rats.
AB - Rats were given fixed-time, 1-min food-pellet delivery sessions, for 3 h every
day, which resulted in over drinking (schedule-induced polydipsia). In previous
research, groups of animals came to prefer solutions of cocaine or lidocaine to
concurrently presented water, if the drugs were first offered in a
glucose/saccharin vehicle, which was then gradually eliminated, so that the
choice became a drug solution in water vehicle versus water. In the present
experiment, the same procedure produced a preference for 0.025 mg/ml quinine
solution to water, indicating that a bitter solution that was not a topical
anesthetic agent could come to be preferred. After establishing preference for
quinine solution, it was possible to gradually remove quinine while increasing
phencyclidine (PCP) concentration to produce preference for 0.075 mg/ml PCP
solution, and similarly to produce subsequent preference for 0.1 mg/ml caffeine
solution, although not for all animals. For additional groups, drinking either
0.15 mg/ml PCP or 0.1 mg/ml caffeine, while gradually reducing the
glucose/saccharin vehicle to water vehicle was a less successful procedure for
establishing the respective drug preferences. The latter result suggests that
first instituting a preference for quinine solution to water facilitated the
later establishment of preferences for PCP and caffeine solutions.
PMID- 10780301
TI - Discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys.
AB - The present study characterized the discriminative-stimulus effects of triazolam
and midazolam in rhesus monkeys. Six monkeys discriminated 0.1 mg/kg of triazolam
from vehicle under a fixed-ratio 5 (FR 5) schedule of stimulus-shock termination
(SST). Four monkeys subsequently discriminated 0.56 mg/kg of midazolam from
vehicle under the same schedule of reinforcement. Benzodiazepine (BDZ) agonists
midazolam and diazepam, and the barbiturate pentobarbital, substituted for
triazolam, and the non-competitive N-methyl-D-aspartate (NMDA) antagonist
ketamine did not. Triazolam, diazepam, lorazepam, flunitrazepam, as well as the
barbiturates amobarbital and pentobarbital, substituted for midazolam, and
ketamine did not. The BDZ antagonist flumazenil antagonized both the triazolam
and midazolam discriminative stimuli. Bretazenil, a low-efficacy BDZ agonist, did
not substitute for the midazolam discriminative stimulus in three of the monkeys
and shifted the midazolam dose-effect curve to the right; in a fourth monkey,
bretazenil substituted for midazolam and shifted the midazolam dose-effect curve
to the left. Schild analyses with flumazenil or bretazenil, in combination with
midazolam, yielded slopes that deviated significantly from unity. While clearly
supporting the notion that BDZ agonists produce stimulus effects by acting at the
gamma-aminobutyric acidA (GABA(A)) receptor complex, these data also suggest that
the discriminative-stimulus effects of midazolam might be mediated by more than
one BDZ receptor subtype.
PMID- 10780302
TI - Prepulse inhibition of the startle reflex in rats: effects of compounds acting at
various sites on the NMDA receptor complex.
AB - Prepulse inhibition (PPI) of the startle reflex in rats is disrupted by N-methyl
D-aspartate (NMDA) receptor non-competitive antagonists (phencyclidine-like
compounds). In order to explore more thoroughly the control exerted by NMDA
receptors on PPI, we assessed the effects of i.p. administration, in Sprague
Dawley rats, of compounds acting as antagonists or agonists at the five binding
sites of the NMDA receptor complex. The non-competitive NMDA receptor antagonists
phencyclidine (1-6 mg/kg) and MK-801 (dizocilpine: 0.05-0.2 mg/kg) robustly and
dose-dependently disrupted PPI. A similar effect was obtained with the
competitive NMDA receptor antagonists CGS 19755 (1-20 mg/kg) and CPP (3-20
mg/kg), but not with the cation Mg2+ (100 and 200 mg/kg), the glycine/NMDA
binding site antagonist L-701,324 (1-10 mg/kg), or the polyamine/NMDA binding
site antagonist eliprodil (3-20 mg/kg). Potentiation of glutamatergic
neurotransmission by NMDA (10-50 mg/kg), and the glycine/NMDA site partial
agonist d-cycloserine (1-30 mg/kg) also failed to modify PPI, though d
cycloserine diminished PPI at higher doses (50-200 mg/kg). Co-administration of
sub-threshold doses of CPP (3 mg/kg) and phencyclidine (2 mg/kg) resulted in an
additive effect, disrupting PPI. In contrast, co-administration of L-701,324 (6
mg/kg) with phencyclidine (2 mg/kg), eliprodil (20 mg/kg), or CPP (3 mg/kg), did
not disrupt PPI. These results demonstrate that PPI-disrupting effects can only
be obtained with phencyclidine-like compounds and NMDA receptor competitive
antagonists. Treatment with compounds that potentially augment glutamatergic tone
were without effect. Finally, despite the permissive control of the glycine/NMDA
binding site on glutamatergic neurotransmission, the glycine/NMDA binding site
antagonist L-701,324 did not produce synergistic activity when combined with
antagonists at the glutamate, polyamine/NMDA or phencyclidine-like compound
binding sites.
PMID- 10780303
TI - The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic
function.
AB - Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes
caused by the administration of the 5HT2A receptor against DOI, and by the 5HT
precursor (-)5HTP, were significantly increased by pretreatment with the non
competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine
administration also significantly increased the locomotor activity induced by the
serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased
only the head shakes induced by DOI, but did not alter the behavior elicited by 8
OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the
agonists used. The dizocilpine-induced potentiation of head shakes elicited by
DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not
modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (
)sulpiride. The dopamine receptor antagonists did, however, counteract the
dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the
locomotor response to all the serotonergic agonists. The results indicate that,
unlike competitive NMDA receptor antagonists, the non-competitive antagonists
enhanced the expression of serotonergic stimulation, and suggest that a glutamate
deficiency could contribute to the pathogenesis of schizophrenia, not only
through dopaminergic, but also through serotonergic, hyperactivity.
PMID- 10780304
TI - The effects of melatonin on the behavioural disturbances induced by chronic mild
stress in C3H/He mice.
AB - In rodents, exposure to chronic mild stress (CMS) is known to induce
unresponsiveness to environmental stimuli, as well as sleep disturbances,
suggesting some analogies between this syndrome and human depression.
Furthermore, numerous studies reported a decrease in nocturnal melatonin
concentration in depressed patients, compared with controls. The present study
was conducted to test a possible preventative action of daily treatment with
melatonin on behavioural alterations induced in C3H/He mice by CMS exposure. In
addition to daily spontaneous locomotor activity and preference for sucrose
solution, the emotional behaviour of mice was examined in a stressful situation
(light/dark choice test), as well as in a situation devoid of constraining
components (free-exploratory paradigm), after three weeks of CMS. The results
showed that the behaviour of C3H/He mice was disrupted after CMS. Stressed mice
exhibited blunted emotional reactivity in both the light/dark choice test and the
free-exploratory situation. While unstressed mice presented no variation in their
preference for a sucrose solution, stressed mice presented a decrease in such
preference towards the end of the CMS exposure. Furthermore, daily spontaneous
locomotor activity of the mice was reduced after CMS. Daily treatment of stressed
mice with melatonin was able to prevent several CMS-induced disturbances, except
in the light/dark choice test, where melatonin was ineffective. Compared to the
effects of 10 mg/kg of fluoxetine, which completely prevented CMS-induced
dysregulation of behaviour, melatonin was less effective. The present results
support the idea that melatonin may be implicated in an homeostatic system which
protects animals from disruptions induced by chronic stress.
PMID- 10780305
TI - Modifications of the behavioral profile of non-competitive NMDA receptor
antagonists, memantine, amantadine and (+)MK-801 after chronic administration.
AB - Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists show
antiparkinsonian-like activity in animal models, and possess neuroprotective
properties. However they also induce a number of behavioral side effects in
rodents at higher doses; these include learning impairment, hyperlocomotion, and
ataxia. The present study focused on the possible development of tolerance, or
sensitization, to any of these effects after sustained administration, either by
repeated injection or continuous infusion. When memantine or (+)MK-801 (20 and
0.31 mg/kg/day respectively) were either infused or repeatedly injected for 14
days, tolerance was observed to their learning impairing effect at high doses, in
a passive avoidance test. Tolerance to their ataxic effect developed after
repeated administration ((+)MK-801 and memantine), or after infusion (memantine).
Sensitization to the locomotor stimulation was seen following repetitive
injections of memantine for 14 days, but not seen with (+)MK-801. In animals with
an unilateral 6-OHDA lesion of the nigrostriatal system, acute administration of
memantine caused ipsilateral rotations, which were augmented following 14 days of
infusion. The potency of amantadine to antagonize neuroleptic-induced catalepsy
was unchanged following either infusion or repeated injections. The various acute
effects of non-competitive NMDA receptor antagonists were modified differently by
sustained treatment (i.e. tolerance to learning impairment and ataxia;
sensitization to memantine's locomotor stimulation). The anti-cataleptic activity
of amantadine remained unaltered. However, differences between drugs and the two
treatment regimens (i.e. repetitive versus continuous treatments) were apparent.
PMID- 10780306
TI - Intra-hippocampal KN-62 hinders the memory of habituation acquired alone, but not
simultaneously with a water-finding task.
AB - Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal
hippocampus. After recovery from surgery, they were submitted to a water-finding
task, which required detecting a water tube in an open field, and then
remembering its location under conditions of thirst. This task was acquired
simultaneously with habituation to the open field. Training and test sessions
lasted 2 min, in addition to the time spent at the water tube. The training-test
interval was 24 h, during which the animals were deprived of water. Immediate
post-training intra-hippocampal administration of the calcium/calmodulin
dependent protein kinase II (CaMKII) inhibitor KN-62 (3.6 ng/side) attenuated
memory of the water-finding task, but not that of the habituation acquired
concomitantly. However, when the habituation was carried out alone in the absence
of the water-finding task, its retention was inhibited by KN-62. Thus, depending
on circumstances, habituation can be memorized with or without hippocampal CaMKII
activity. In the post-training period, CA1 neurones appear to 'choose' which task
will be processed by a metabolic pathway that includes CaMKII.
PMID- 10780307
TI - Haloperidol-induced within-session response decrement patterns and catalepsy in
rats: behavioural dissociation.
AB - The typical antipsychotic haloperidol is known to induce extra-pyramidal side
effects (EPS). Catalepsy in rats is generally regarded as a valid model for
detecting the EPS liability of compounds in humans. Together with its
antipsychotic and cataleptogenic actions, haloperidol causes an attenuation of
instrumental responding which becomes larger in the course of a session: a within
session response decrement. The present study compared the time-course of
haloperidol-induced catalepsy, measured by a bar test, to the haloperidol-induced
within-session response decrements, measured by operant behaviour under a fixed
ratio 10 schedule of reinforcement. Rats were trained to press a lever on a Fixed
Ratio 10 schedule of food reinforcement during sessions of 15 min. When
responding was stable, saline or haloperidol in 0.03 mg/kg, 0.1 mg/kg, or 0.3
mg/kg was administered intra-peritoneally either 30, 90 or 180 min prior to
behavioural testing. The number of lever presses, food tray visits and latency to
press the lever and to visit the food tray were analysed in five successive
blocks of 3 min. Catalepsy was tested 30, 60, 90, 120, and 180 min. after
injection, by placing a rat with its forepaws on a horizontal bar. The latency to
remove both forepaws from the bar was scored. Within-session response decrements
were present at 0.1 mg/kg and at 0.3 mg/kg, from 30 min after administration
onward. At these doses, latency to press the lever was increased after 30 and 90
min, but not significantly after 180 min. Latency to visit the tray was affected
only after 30 min, at 0.3 mg/kg. Haloperidol induced a dose-dependent increase in
catalepsy from 60 min onwards, with maximal effect after 120 min. A dissociation
between the time-course of occurrence of within-session response decrement and
the cataleptogenic action of haloperidol, as well as between the latter and both
latency measures, was found. Consequently, the present data suggest that within
session response decrements are not obviously caused by catalepsy-related
impairments.
PMID- 10780308
TI - Post-session intra-perifornical region quinpirole infusions retard the
consolidation of an appetitive differential conditioning task.
AB - We have shown previously that post-session infusions of the D2/D3 dopamine
receptor antagonist sulpiride within the perifornical region of the lateral
hypothalamus (PFH) greatly facilitated the acquisition of an appetitive
differential conditioning task. Here, we have examined the effects of the D2/D3
dopamine receptor agonist quinpirole on acquisition of this task. Conditioning
sessions consisted of an initially neutral stimulus (CS+) preceding availability
of a 10% sucrose reward (US), and a control stimulus (CS-), never associated with
the US, were presented, followed by bilateral intra-PFH infusions of quinpirole
(0, 0.1, 10 nmol). The acquisition of a conditioned approach response during the
CS+ period was impaired by quinpirole administration in a dose-dependent manner.
No other behavioural measure was affected. All groups subsequently acquired the
conditioned approach response, following cessation of the post-session infusion
procedure. The present data extends previous findings, suggesting that the level
of activation of dopamine receptors in the vicinity of the PFH significantly
influences the consolidation of appetitive Pavlovian associations.
PMID- 10780309
TI - A new paradigm for blood coagulation research.
PMID- 10780310
TI - A comparative double-blind, randomised trial of a new second generation LMWH
(bemiparin) and UFH in the prevention of post-operative venous thromboembolism.
The Bemiparin Assessment group.
AB - A randomised, prospective, double-blind trial was performed, to compare the
safety and efficacy of a new low-molecular-weight heparin (LMWH) Bemiparin and
standard unfractionated heparin (UFH), for the prophylaxis of postoperative
venous thromboembolism. 300 patients scheduled to undergo elective hip
arthroplasty were included. The principal outcome measures were the incidence of
thromboembolic events and bleeding complications. 149 patients received 3,500
anti-Xa IU of bemiparin plus a placebo injection daily and 149 patients received
5,000 IU of UFH twice a day. The two groups were similar with respect to factors
likely to affect the risk of developing post-operative venous thromboembolism
(VTE) and risk of bleeding events. During the post-operative period, 34 patients
developed VTE complications; 9 (7.2%) in the bemiparin group and 25 (18.7%) in
the UFH group. VTE in the two groups was statistically significant (OR of 2.96;
95% CI 1.32-6.62 and p = 0.01). There were no significant differences in the
frequency of bleeding complications: major bleeding requiring discontinuation of
prophylaxis, (OR 1.21; 95% CI 0.36-4.05; p = 1.00), the measured median operative
blood loss (p = 0.77) or the median postoperative drain loss (p = 0.97), and the
number of patients who developed wound haematoma (OR 0.87; 95% CI 0.31-2.46; p =
1.00). A comparison of coagulation parameters on the preoperative day with post
operative day 2 +/- 1, day 6 +/- 1 and day of discharge showed a significantly
higher AT concentration, anti-factor Xa activity and TFPI levels in the bemiparin
group when compared with UFH. This study demonstrates that bemiparin, in a single
daily subcutaneous dose of 3,500 anti-Xa IU in high risk patients undergoing hip
arthroplasty is more effective than UFH administered twice daily at a dose of
5,000 IU in the prevention of postoperative VTE. Both agents are equally safe.
PMID- 10780312
TI - Recurrent venous thrombosis and markers of inflammation.
AB - Inflammatory processes may play a key role in venous thrombosis, by inducing a
procoagulant state through the action of cytokines and chemokines on monocytes
and endothelial cells. Plasma concentrations of three inflammatory mediators,
interleukin 6 (IL-6), interleukin 8 (IL-8) and monocyte chemotactic protein 1
(MCP-1), that mediate the cross-talk between inflammation and coagulation, were
measured in 182 subjects with recurrent venous thrombosis and 350 healthy
subjects recruited through a general practice. Elevated levels of IL-6 (>90th
percentile of the control group) were detected in 25.8% of the patients with
venous thrombosis in comparison with 10% (by definition) of the controls [odds
ratio 2.4 (95%CI 1.5-3.8)]. In 21.5% of the patients elevated plasma levels of IL
8 (>90th percentile) were determined [odds ratio 2.0 (95%CI 1.2-3.5)]. Elevated
levels of MCP-1 (>90th percentile) were detected in 24.1% of the patients [odds
ratio 1.9 (95%CI 1.2-3.2)]. This is the first large clinical study showing that
an increase in inflammatory mediators is associated with venous thrombosis.
Future prospective studies are necessary to clarify the causal nature of the
inflammatory process with respect to venous thrombosis.
PMID- 10780311
TI - Thrombotic variables and risk of idiopathic venous thromboembolism in women aged
45-64 years. Relationships to hormone replacement therapy.
AB - Hormone replacement therapy (HRT) has been shown to increase the relative risk of
idiopathic venous thromboembolism (VTE) about threefold in several observational
studies and one randomised controlled trial. Whether or not this relative risk is
higher in women with underlying thrombophilia phenotypes, such as activated
protein C (APC) resistance, is unknown. We therefore restudied the participants
in a case-control study of the relationship between the use of HRT and the
occurrence of idiopathic VTE in women aged 45-64 years. After protocol
exclusions, 66 of the cases in the original study and 163 of the controls were
studied. Twenty haematological variables relevant to risk of VTE were analysed,
including thrombotic states defined from the literature. The relative risk of VTE
showed significant associations with APC resistance (OR 4.06; 95% CI 1.62,
10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and
high coagulation factor IX (2.34; 1.26, 4.35), or fibrin D-dimer (3.84; 1.99,
7.42). HRT use increased the risk of VTE in women without any of these thrombotic
states (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative
risk of VTE was also found in women with prothrombotic states. Thus for example,
the combination of HRT use and APC resistance increased the risk of VTE about 13
fold compared with women of similar age without either APC resistance or HRT use
(OR 13.27; 95% CI 4.30, 40.97). We conclude that the combination of HRT use and
thrombophilias (especially if multiple) increases the relative risk of VTE
substantially; hence women known to have thrombophilias (especially if multiple)
should be counselled about this increased risk prior to prescription of HRT.
However, HRT increases the risk of VTE about fourfold even in women without any
thrombotic abnormalities: possible causes are discussed.
PMID- 10780313
TI - Use of the PFA-100 apparatus to assess platelet function in patients undergoing
PTCA during and after infusion of c7E3 Fab in the presence of other antiplatelet
agents.
AB - The PFA-100 (Dade) is a new functional whole blood analyzer, the accuracy and
reliability of which have been evaluated in von Willebrand disease and during
acetyl salicylate acid therapy. This new test has the advantages of rapidity and
simplicity. It may be useful to monitor new antiplatelet agents, such as
GPIIb/IIIa receptor antagonists. The objective of this study was to assess the
PFA-100 in comparison with aggregometry and with the percentage of blockaded
receptors GPIIb/IIIa during and after c7E3 Fab infusion in fifteen patients
undergoing PTCA. Our results showed a change of closure time values from normal
to abnormal within a small margin of flow cytometric values (60-75% of blockaded
receptors), and moreover a variable platelet response to long-term low dose
aspirin treatment in agreement with aggregometry. No influence with heparin was
observed. In conclusion, this study shows that PFA-100 may be helpful in the
decision making for additional antiaggregant therapy before PTCA or in monitoring
long-term GPIIb/IIIa receptor antagonist treatment.
PMID- 10780314
TI - Regional variation in plasminogen activator inhibitor-1 expression in adipose
tissue from obese individuals.
AB - High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent
finding in obesity and adipose tissue has recently been suggested to be a source
of circulating PAI-1 in humans. In the present study, differences in adipose
tissue gene expression and protein secretion rate of PAI-1 between subcutaneous
and visceral adipose tissue was analysed in specimens obtained from 22 obese
individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous
adipose tissue than in visceral adipose tissue (292 +/- 50 vs 138 +/- 24 ng PAI
1/10(7) cells, P <0.05). In accordance with the secretion data, subcutaneous
adipose tissue contained about three-fold higher levels of PAI-1 mRNA than
visceral adipose tissue (2.43 +/- 0.37 vs 0.81 +/- 0.12 attomole PAI-1
mRNA/microg total RNA, P <0.00 ). PAI-1 secretion from subcutaneous but not from
visceral adipose tissue correlated significantly with cell size (r = 0.43,
P<0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI
1 and had a higher PAI-1 gene expression than visceral adipose tissue from the
same obese individuals. Bearing in mind that subcutaneous adipose tissue is the
largest fat depot these finding may be important for the coagulation
abnormalities associated with obesity.
PMID- 10780315
TI - Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t
plasminogen activator inhibitor and C reactive protein levels in coronary artery
disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and
in Combination Treatment.
AB - AIM OF THE STUDY: We studied the effects of fluvastatin and bezafibrate in
monotherapy and in combination on plasma fibrinogen, t-plasminogen activator
inhibitor (PAI-1) and C reactive protein (CRP) in patients with coronary artery
disease (CAD) and mixed hyperlipidaemia. DESIGN: In this randomised, double
blind, multicentre trial 333 patients with stable angina pectoris or previous
myocardial infarction or coronary revascularisation and mixed hyperlipidaemia
(LDL-cholesterol 135-250 mg/dl and triglycerides (TG) 180-400 mg/dl) were
randomised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg +
bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24
weeks. RESULTS: Plasma fibrinogen significantly decreased after treatment with
the combinations fluvastatin+bezafibrate (-14 and -16%) and with bezafibrate
monotherapy (-9%). No significant reduction was observed after fluvastatin
monotherapy (-4%). No significant changes were observed in PAI-1 and CRP plasma
levels. Combination therapy significantly decreased both LDL-C and TG, and
significantly increased HDL-C. CONCLUSIONS: The combined effects on fibrinogen
and plasma lipids achieved by fluvastatin and bezafibrate combination treatment
might be more useful than the simple reduction of cholesterol in preventing
ischaemic cardiovascular disease.
PMID- 10780316
TI - Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic
determinants.
AB - Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. In
search of genetic factors causing elevated levels of total homocysteine in plasma
(tHcy), we investigated a cohort of consecutively identified, unrelated
thrombosis patients (n = 28) having intermediate or severe hyperhomocysteinemia
(30 micromol/l 100 micromol/l,
respectively). The methylene-tetrahydrofolate reductase (MTHFR) 677C-->T
genotype, and the complete cystathionine beta-synthase (CBS) genotype was
determined in all patients. We found that the MTHFR T/T genotype was strongly
correlated with intermediate hyperhomocysteinemia, being present in 73.9% of
those cases (17 of 23). In three of five patients with severe
hyperhomocysteinemia, compound heterozygosity for CBS mutations was detected.
Among the mutations, two novel missense mutations: 1265C-->T (S422L) and 1397C-
>T (S466L) were detected. The phenotype in those patients was quite mild,
thromboembolism apart. This indicates that a search for CBS mutations in patients
with severe hyperhomocysteinemia is important to ensure the detection of a
possible CBS deficiency, thus enabling treatment. Co-existence of the MTHFR T/T
genotype and the common CBS 844ins68 variant was significantly higher among
patients (10.7%) as compared to controls (1.2%), indicating that this genotype
combination is a thrombotic risk factor (P <0.05). In a few patients,
hyperhomocysteinemia could not be explained by this genetic approach, suggesting
that other genetic risk factors were implicated.
PMID- 10780317
TI - HPA-1 and HPA-3 polymorphisms of the platelet fibrinogen receptor and coronary
artery disease and myocardial infarction.
AB - Platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa) plays a fundamental
role in atherothrombosis. The human platelet antigen (HPA) -1 and the HPA-3 are
the most extensively studied polymorphisms of GPIIIa and GPIIb, respectively.
This study was designed to test, in a large population, the hypothesis that these
polymorphisms represent a risk factor for the occurrence of coronary artery
disease (CAD) and myocardial infarction (MI). Consecutive, angiographically
examined patients with significant coronary stenoses but without symptoms or
signs of old or acute MI constituted the group with CAD (CAD, n = 998) and those
with old or acute MI constituted the group with MI (MI, n = 793). As controls
served subjects, matched with patients for age and sex, with neither angiographic
CAD nor symptoms or signs of MI (matched controls [MC], n = 340) as well as a
group of blood donors without cardiac symptoms or signs of CAD (BD, n = 104).
Genotype distribution was similar across the groups; HPA-1a/a: HPA-1a/b: HPA-1b/b
was 75.0%: 22.1%: 2.9% in BD, 72.6%: 24.7%: 2.6% in MC, 70.5%: 26.8%: 2.7% in
CAD, and 70.7%: 26.4%: 2.9% in MI; HPA-3a/a: HPA-3a/b: HPA-3b/b was 39.4%: 40.4%:
20.2% in BD, 33.5%: 50.0%: 16.5% in MC, 35.0%: 46.4%: 17.0% in CAD, and 37.1%:
48.0%: 16.5% in MI. There was no interaction between these polymorphisms, nor
between each of these polymorphisms and other risk factors. Thus, the HPA-1 and
HPA-3 polymorphisms are neither separately nor in concert associated with any
measurable increase of the risk for CAD or MI in angiographically evaluated
subjects.
PMID- 10780318
TI - The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with
the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR)
gene. A case-control study of patients with early-onset thrombotic events.
AB - Total fasting plasma homocysteine (tHcy), homozygosity for the C677T mutation of
the methylenetetrahydrofolate reductase (MTHFR) gene and for the A2756G mutation
of the methionine synthase (MS) gene, vitamin B12 and folate plasma levels were
evaluated in 170 consecutive patients (89 M, 81 F; mean age 41 +/- 12 yrs) with
documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at
first episode 36 +/- 11 yrs), and in 182 age- and sex-matched healthy control
subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 microM in men and >15
microM in women) was detected in 45 patients (26.5%) and in 18 controls (9.9%,
Mantel-Haenszel OR and 95% C.I. after stratification for arterial or venous
thrombosis: 3.25, 1.78-5.91). The 677TT MTHFR genotype was not significantly more
prevalent in patients (27.6%) than in controls (21.4%, RR = 1.42: 0.84-2.41), and
markedly contributed to HHcy (Mantel-Haenszel RR after stratification for
case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype, observed in 4
patients (2.4%) and 8 controls (4.4%), was not associated to HHcy. tHcy was
negatively correlated to folate and vitamin B12 levels, with better correlation
found in subjects with the 677TT mutation (r = -0.42 and -0.25) than with the
677CC or CT MTHFR genotype (r = 0).37 and -0.11). However, folate was similar in
patients and controls and vitamin B12 was higher in patients (460 +/- 206 vs. 408
+/-185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variation in
tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype,
gender, and by the interaction of the MTHFR genotype with folate (p < or =0.028);
the interactions of vitamin B12 with the MTHFR genotype, gender and
patient/control status also significantly contributed to the variation in tHcy
levels (p < or =0.028). A 4-week administration of 5-methyltetrahydrofolate (15
mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype,
but the response to treatment correlated with vitamin B,2 levels (p = 0.023).
Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12
requirements irrespective of the A2756G polymorphism of the MS gene. Yet
unidentified abnormalities of MS or of any of the enzymes participating in the
synthesis of methylated vitamin B12 may play an important role in the phenotypic
expression of moderate hyperhomocysteinemia.
PMID- 10780319
TI - Exclusion of known protease-activated receptors in factor VIIa-induced signal
transduction.
AB - The protease activity is mandatory for intracellular activities induced by
coagulation factor VIIa (FVIIa), and in this way it resembles signal transduction
induced by thrombin and trypsin caused by specific, proteolytic cleavage of
protease activated receptors (PARs). The mechanism for FVIIa-induced signal
transduction is, however, not known although a mechanism involving PAR cleavage
has been deduced from studies of cytosolic Ca2+ release and p44/p42 mitogen
activated protein kinase (MAPK) activation. In the present work we have examined
the possibilities that i) FVIIa-induced signal transduction involves the
activation of one of the four known PARs, or ii) exposure of cells to FVIIa
releases a soluble ligand that is responsible for MAPK activation. For this
purpose, we evaluated the effects of FVIIa, thrombin, FXa, trypsin and PAR
agonist peptides on the Ca2+ release and MAPK activation in tissue factor-(TF)
transfected baby hamster kidney (BHK[+TF]) cells and Madin-Darby canine kidney
(MDCK) cells. FVIIa induced a significant MAPK signal in BHK(+TF) cells and in
MDCK-I and -II cells whereas no MAPK activation was observed with thrombin, FXa
or PAR agonist peptides. Thrombin, trypsin, PAR-1 and PAR-2 agonist peptides
induced a prominent Ca2+ response in both cell types. In contrast the cells did
not respond with a detectable Ca2+ signal when treated with FVIIa. These results
suggest that the intracellular activity induced by FVIIa is distinctly different
from that induced by trypsin, thrombin and FXa not involving any of the known
PARs. Conditioned medium from BHK(+TF) cells treated with FVIIa failed to induce
a MAPK response in untreated BHK(+TF) cells when FVIIa was removed by
immunoadsorption from the medium prior to its transfer to the untreated BHK(+TF)
cells. Although it is not possible entirely to exclude a transient response close
to the cell surface, the data suggest that the intracellular response was not
induced by an autocrine release of a soluble mediator to the medium.
PMID- 10780320
TI - The HR2 haplotype of factor V: effects on factor V levels, normalized activated
protein C sensitivity ratios and the risk of venous thrombosis.
AB - We studied the HR2 haplotype of the factor V gene in a case-control study for
venous thrombosis including 474 patients with a first deep-vein thrombosis and
474 age- and sex-matched healthy controls (Leiden Thrombophilia Study, LETS). We
investigated both the original His1299Arg (A4070G) polymorphism and the Met385Thr
(T1328C) polymorphism. This latter polymorphism, located in exon 8 (heavy chain),
is always present in the HR2 haplotype, but also occurs on its own in a His1299
(wt) background. The HR2 haplotype was not associated with an increased risk of
venous thrombosis (OR = 1.2, 95% confidence interval: 0.8-2.0). We did not find
an association between the HR2 haplotype and a reduced sensitivity for activated
protein C (APC) in non-carriers of factor V Leiden (FVL). However, in compound
heterozygous FVL/HR2 carriers the sensitivity for APC was reduced. The HR2
haplotype was also associated with reduced factor V antigen levels in both
patients and controls. Sequence analysis of the promoter region of factor V in
HR2 homozygotes did not reveal any sequence variations that could explain the
reduced FV levels. Our results show that the HR2 haplotype is not associated with
an increased risk of venous thrombosis or with a reduced sensitivity for APC in
non-FVL carriers. However, the HR2 haplotype is associated with a reduced
sensitivity for APC in carriers of FVL and with reduced factor V antigen levels.
PMID- 10780322
TI - The thrombogram: monitoring thrombin generation in platelet-rich plasma.
AB - A method is described in which thrombin activity in clotting plasma can be
monitored through the continuous measurement of the fluorescent split-product of
the substrate Z-Gly-Gly-Arg-AMC. The signal is not impaired by turbidity;
therefore proper measurement is not disturbed by the occurrence of a clot or the
presence of platelets and direct measurement in platelet rich plasma is possible.
PMID- 10780321
TI - Analysis of prothrombotic effects of two human monoclonal IgG antiphospholipid
antibodies of apparently similar specificity.
AB - Two human monoclonal antiphospholipid antibodies (APA) of the IgG type, HL-5B and
RR-7F have been generated from a patient with primary antiphospholipid syndrome
and recurrent cerebral microemboli (H.L.) and from a patient with SLE without
evidence of recurrent thrombosis (R.R.). Both monoclonal APA have similar
characteristics in ELISA tests. To further analyse the prothrombotic potential,
their effect on human monocytes and platelets, and bovine aortic endothelial
cells (BAEC) was investigated. Monocytes were isolated from buffy coats by
standard techniques. They were incubated either with the respective monoclonal
APA in different concentrations, or a control monoclonal IgG of the same subtype,
or plasma of the patients, from whom the antibodies were isolated. Incubation
with LPS served as positive control. BAEC were grown to confluence, and then
incubated with the appropriate agonists. Procoagulant activity (PCA) was
determined by a single stage clotting assay. PCA expression after incubation is
given as the ratio of the coagulation times observed with media only divided by
that observed with the agonist. A PCA ratio >1 indicates the induction of PCA by
the agonist. At 1 microg/ml HL-5B yielded a PCA ratio of 1.63 +/- 0.16 while RR
7F induced no significant rise to 1.06 +/- 0.18. Dose response curves showed that
RR-7F can induce PCA at higher concentrations. However, its effect is approx.
1/50 of HL-5B based on equimolar antibody concentration. Further analysis
indicates that the majority of the PCA induced by monoclonal APA can be inhibited
by a specific tissue factor antibody. Neither monoclonal antibody induced PCA in
BAEC. Sera from both patients were able to induce PCA in monocytes. However, the
PCA ratio of serum from H.L. was higher (1.78) than that of R.R. (1.44). Neither
monoclonal APA had an effect on platelets as determined by flow cytometric
analysis of CD62P, CD41, CD42b expression and fibrinogen binding with and without
previous activation with 5 microM ADP or 15 microM TRAP-6. Similarly, there were
no differences in platelet aggregation to different stimuli including submaximal
activation. In summary, these data provide further evidence that induction of
tissue factor in monocytes is one of the procoagulant effects of APA.
Furthermore, the binding specificity of APA is perhaps not suited to predict the
biological effects of the antibodies.
PMID- 10780323
TI - A functional assay suggests that heterodimers exist in two C-terminal gamma-chain
dysfibrinogens: Matsumoto I and Vlissingen/Frankfurt IV.
AB - Because it contains three pairs of polypeptides, fibrinogen isolated from
heterozygous individuals is expected to be a mixture of homodimers and
heterodimers. Nevertheless, heterozygous individuals with only homodimers have
been identified. We synthesized two recombinant fibrinogens with the mutations
from fibrinogen Vlissingen/ Frankfurt IV (gamma(delta)319, 320) and Matsumoto I
(gammaD364H), both identified in heterozygous individuals. We found that
polymerization of these fibrinogens was undetectable in 30 min; polymerization of
a 1:1 mixture of variant and normal fibrinogen was the same as polymerization of
a 1:1 mixture of buffer and normal fibrinogen; polymerization of either plasma
fibrinogen was markedly impaired when compared to the 1:1 mixture of the
respective variant and normal fibrinogens. We conclude that each plasma
fibrinogen is a mix of homodimers and heterodimers, such that the incorporation
of heterodimers into the fibrin clot impairs polymerization. We suggest that
incorporation of heterodimers can induce clinical symptoms.
PMID- 10780324
TI - TNF 41-62 and TNF 78-96 have distinct effects on LPS-induced tissue factor
activity and the production of cytokines in human blood cells.
AB - Biological activities of peptides representing two different regions in the TNF
molecule were investigated. We have earlier reported that one of the peptides
studied, TNF 36-62, induced chemotaxis in granulocytes and monocytes. TNF 41-62,
a shorter analog of TNF 36-62, possessed similar chemotactic effects. Both
peptides caused a weak enhancement of LPS -induced IL-6 production and tissue
factor activity by monocytes in whole blood. The third peptide studied, TNF 78
96, was selected from a region located on the opposite side of the beta-sheet
sandwich structure of the TNF molecule, and includes the loop 84-88 that has been
shown to be involved in TNF receptor interaction. TNF 78-96 possessed properties
quite different from TNF 36-62 and TNF 41-62. It amplified several fold PMA
induced secretion of elastase, and enhanced significantly PMA-induced secretion
of cathepsin G from the neutrophils, activities which were effectively abolished
by an anti-human TNF antibody. The TNF 78-96 peptide also inhibited LPS-induced
TF activity in monocytes of whole blood, and it abolished the TNF enhancing
effect of LPS-induced TF activity in a dose dependent manner. This suggests that
the TNF 78-96 peptide may bind to the TNF receptor(s), without potentiating the
same signals as native TNF. It may thereby prevent binding of the native TNF and
the resultant activation effect of TNF. It also, at high concentrations,
inhibited LPS-induced IL-6 production whereas it caused a doubling of LPS-induced
IL-8 in monocytes and granulocytes in whole blood. These results clearly show
that distinct TNF activities can be induced by peptide sequences taken from
different regions of TNF. The TNF 78-96 peptide might be useful in downregulation
of LPS-induced monocyte activations in vivo.
PMID- 10780325
TI - Lack of tPA significantly affects antithrombotic therapy by a GPIIb/IIIa
antagonist, but not by a thrombin inhibitor in mice.
AB - The interaction of fibrinolytic components with platelets or coagulation factors
after endothelial injury, was investigated in mouse deficient in tissue type
plasminogen activator (tPA -/-), or urokinase (uPA -/-) and in their wild type
control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery
using the photochemical reaction. Blood flow was continuously monitored and the
time needed before the vessel became completely obstructed was within 11 min in
all types of mice. When GR144053, a platelet glycoprotein IIb/IIIa antagonist, or
argatroban, a thrombin inhibitor, was applied, the time required to occlusion was
prolonged in a dose-dependent manner in all types of mice. However, when GR144053
was injected in tPA -/- mice, the most significant changes were observed: that is
the estimated ED50 was 14.8 times higher than the one in tPA +/+ mice. On the
other hand, when argatroban was injected in tPA -/- mice, the estimated ED50 was
not changed. Platelet aggregation, haemostasis tests and bleeding times were not
significantly different among the different types of mice. In conclusion, the
antithrombotic effect of platelet inhibition by a GPIIb/IIIa antagonist, is
severely affected by the absence or presence of tPA-production. Thus, the lack of
tPA significantly reduces the antithrombotic efficacy.
PMID- 10780327
TI - Identification of a novel 33-kDa Ser/Thr kinase that phosphorylates the
cytoplasmic tail of protease-activated receptor 1 (thrombin receptor) in human
platelets.
AB - Stimulation of human platelets with thrombin or thrombin receptor agonist peptide
(TRAP/ Ser-Phe-Leu-Leu-Arg-Asn) resulted in phosphorylation of the protease
activated receptor 1 (PAR1). However, protein kinase(s), capable of
phosphorylating PAR1 upon activation of this receptor, has not been as yet
identified in human platelets. The present study was undertaken to assess the
presence of protein kinase(s) that may interact with PAR1 using a procedure based
on the ability of protein kinase to undergo renaturation and phosphorylate a
protein substrate fixed in a gel. We employed a fusion protein that was prepared
using a glutathione S-transferase (GST) and the cytoplasmic tail of PARI (Pro368
Thr425)(GST-PAR1) or a reverse sequenced peptide of this domain (GST-rPAR1). The
results showed that treatment of platelets with thrombin induced about 10-fold
increase in the activity of the 33-kDa Ser/Thr protein kinase, which was also
activated by TRAP, but not by hirudin-treated thrombin or
diisopropylfluorophosphate-inactivated thrombin, suggesting that it is activated
through PAR1. Furthermore, treatment of platelets with thromboxane A1 analog,
STA2, led to an activation of this protein kinase and phosphorylation of PAR1. In
conclusion, the present study provides evidence of homologous and heterologous
activation of a novel 33-kDa Ser/Thr kinase that phosphorylates the cytoplasmic
tail of PAR1.
PMID- 10780326
TI - Thrombopoietin increases platelet sensitivity to alpha-thrombin via activation of
the ERK2-cPLA2 pathway.
AB - Thrombopoietin (TPO) regulates stem cell proliferation and maturation of
megakaryocytes by activating the c-Mp1-receptor, a member of the hematopoietic
cytokine family. As human platelets possess c-Mp1-receptors and
supraphysiological concentrations of TPO trigger platelet aggregation and
secretion, we searched for the signalling pathways through which the c-Mp1
receptor might activate platelets. A physiological concentration of TPO (20
ng/mL) did not trigger platelet functions, but increased their sensitivity to
alpha-thrombin resulting in a 4-fold faster dense granule secretion. The effect
of TPO was abolished by indomethacin and caused by synergism with signal
generation by alpha-thrombin at the level of the cytosolic phospholipase A2
(cPLA2) pathway resulting in more arachidonate release, cPLA2 phosphorylation and
thromboxane A2 formation. A similar synergism was seen at the level of
extracellular signal-regulated kinase 2 (ERK2 or p42-MAPK). These data suggest,
that TPO increases the sensitivity of platelets to alpha-thrombin by enhancing
cPLA2 activation via the ERK2-cPLA2 pathway.
PMID- 10780328
TI - Intimal tissue factor activity is released from the arterial wall after injury.
AB - Tissue factor (TF), the initiator of coagulation, has been implicated as a
critical mediator of arterial thrombosis. Previous studies have demonstrated that
TF is rapidly induced in the normal rodent arterial wall by balloon injury, but
is not associated with fibrin deposition. A second injury, however, performed 10
14 days after the first, is followed by small platelet-fibrin microthrombi. This
study was undertaken to better localize active TF in balloon-injured rat arteries
and to explore possible mechanisms underlying the apparent discrepancy between
injury-induced TF expression and the lack of large platelet-fibrin thrombi. By
immunohistochemistry, TF antigen was first detected in the media 24 h after
injury to rat aortas, and subsequently accumulated in the neointima. Using an ex
vivo flow chamber, no TF activity (Factor Xa generation) was found on the luminal
surface of normal or injured aortas. Wiping the luminal surface with a cotton
swab exposed TF activity in all vessels; levels were increased approximately 3
fold in arteries containing a neointima. The exposed TF activity was rapidly
washed into the perfusate, rendering the luminal surface inactive. The loss of
luminal TF into the circulation may attenuate thrombosis at sites of arterial
injury.
PMID- 10780329
TI - No evidence for the CD31 C/G gene polymorphism as an independent risk factor of
coronary heart disease.
PMID- 10780330
TI - ABO blood group and risk of venous thrombosis in heterozygous carriers of factor
V Leiden.
PMID- 10780331
TI - Circulating endothelial cells in Behcet's disease with cerebral thrombophlebitis.
PMID- 10780332
TI - Does peroral administration of factor VIII induce oral tolerance in patients with
acquired haemophilia A?
PMID- 10780333
TI - Continuous infusion of recombinant factor VIIa (NovoSeven) in the treatment of a
patient with type III von Willebrand's disease and alloantibodies against von
Willebrand factor.
PMID- 10780334
TI - Recombinant factor VIIa for bleeding in refractory thrombocytopenia.
PMID- 10780335
TI - Factor VIII inhibitor associated with esophageal carcinoma.
PMID- 10780336
TI - Lipoprotein profiles, not anthropometric measures, correlate with serum
lipoprotein(a) values in children: the Taipei children heart study.
AB - OBJECTIVE: Plasma lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular
disease. The purpose of this study is to evaluate the correlation of
anthropometric measures, lipids and lipoprotein profiles and serum Lp(a) values
among children in Taiwan. We will attempt to find parameters that will be able to
predict Lp(a) levels in children. DESIGN AND METHODS: After a probability
proportional-to size, multi-stages sampling procedure, we randomly sampled 1500
schoolchildren from 10 schools in Taipei city. Anthropometric measures including
body weight, body height, waist and hip circumference and skinfolds were
measured. We used standard methods to measure serum total cholesterol (CHOL),
triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), apolipoprotein
A1 and B (ApoA1 and ApoB) and Lp(a) levels. We also calculated low density
lipoprotein-cholesterol (LDL-C) and CHOL HDL-C ratio (TCHR) by formula. RESULTS:
We sampled 1283 children (635 boys and 648 girls) with a mean age of 13.3 years
(from 12 to 16 years) in this study. The mean and medium serum Lp(a) levels were
16.8 and 8.8 mg/dl among boys and 20.8 and 11.9 mg/dl among girls. Children in
the highest quintile of Lp(a) (mean = 49.6 and 58.6 mg/dl for boys and girls,
respectively) had higher CHOL, LDL-C, ApoB levels and TCHR than children in the
lowest quintile (mean = 3.1 and 3.7 mg/dl for boys and girls, respectively).
Lipids and lipoprotein profiles, such as CHOL, LDL-C, Apo-B and TCHR were
positively correlated with Lp(a) levels in both genders. Furthermore, the
children with Lp(a) levels greater than or equal to 30 mg/dl had higher CHOL, LDL
C and Apo-B levels when compared to children with Lp(a) levels less than 30
mg/dl. After adjusting for age, cigarette smoking, alcohol drinking, puberty
development and heart rates, LDL-C and ApoB levels were significantly positively
associated with Lp(a) levels while ApoA1 was negatively associated among boys.
Among girls, only Apo-B was significantly positively associated with Lp(a) and TG
was negatively associated with Lp(a) levels. Most importantly, none of the
anthropometric measures were significantly correlated with Lp(a) levels.
CONCLUSIONS: From this study, we found that lipids and lipoproteins profiles,
rather than degree of adiposity as reflected by anthropometric measures, are
significantly associated with serum Lp(a) levels among school children.
PMID- 10780337
TI - Relationship between hyperuricemia and other cardiovascular disease risk factors
among adult males in Taiwan.
AB - Hyperuricemia is associated with cardiovascular disease risk factors such as
obesity, impaired glucose tolerance, hypertension, and hyperlipidemia. However,
this relationship between serum uric acid (SUA) concentrations and cardiovascular
disease (CVD) is a controversial one, especially among males. The purpose of this
study is to evaluate the association between SUA concentrations and other CVD
risk factors among adult males in Taiwan. After multi-stage sampling procedures,
we randomly selected 1743 Taiwanese males with a mean age of 35 years (from 22 to
54) in this study. Anthropometric, blood pressure and biochemical variables,
including serum uric acid, glucose, total cholesterol and triglyceride
concentrations, were measured. Among the study population, the mean SUA
concentration was 6.5 +/-1.5 mg/dl. There were 290 (16.6%) subjects with SUA
concentrations > or = 8.0 mg/dl (defined as hyperuricemia). Compared to
normouricemic subjects, hyperuricemic subjects had significantly greater age
adjusted body weight (75.3 vs. 69.2 kg, p < 0.001), body mass index (BMI, 25.5
vs. 23.6 kg/m2, p < 0.001), higher blood pressure (BP, 120.2 vs. 115.2 mmHg for
systolic BP and 78.5 vs. 75.3 mmHg for diastolic BP, both p < 0.001) and blood
lipid concentrations (193.8 vs. 182.1 mg/dl for total cholesterol and 123.7 vs.
94.4 mg/dl for triglycerides, both p < 0.001). SUA concentration was positively
correlated with body weight, BMI, BP and serum lipid concentrations (all p <
0.001). In multivariate regression analyses, after adjusting for potential
confounders, SUA concentration was significantly positively associated with
diastolic BP, serum total cholesterol and triglyceride concentrations. An
increase of 1 mg/dl of SUA was associated with a 2.1 mg/dl elevation in serum
total cholesterol (p < 0.001) and a 5.4 mg/dl increase in triglyceride (p <
0.001). From this study, we found that hyperuricemia in subjects is associated
with being overweight, and having high blood pressure and hyperlipidemia. There
is a significantly positive association between SUA concentration and other CVD
risk factors among adult males in Taiwan.
PMID- 10780338
TI - Sociodemographic factors related to self-medication in Spain.
AB - To identify the sociodemographic factors associated to self-medication (i.e. use
of non-prescription medicines) and undesirable self-medication, a cross-sectional
study was carried out using a sample (n = 20,311) representative of the
population of adults of 16 years of age and older in Spain. Multivariate Cox's
regression was used. The prevalence of self-medication in the sample was 12.7%
during the two weeks preceding the interview. Self-medication is more prevalent
among women, persons who live alone, and persons who live in large cities. For
persons who reported acute disorders, self-medication prevalence was higher among
those with higher educational levels. The prevalence of undesirable self
medication in the sample was 2.5% during the two weeks previous to the interview.
Undesirable self-medication is twice as common among persons older than 40 years,
as compared to persons younger than 27 years. Undesirable self-medication
prevalence is 53.0% higher among those who live alone as compared to those who
live with their partner (95% confidence interval (CI): 15.2-103.2) and 36.8%
higher among students as compared to full-time workers (95% CI: 1.9-83.5). People
over 40 years of age, people living alone, and students should be the priority
target populations for public health education programs aimed at improving the
quality of self-medication behavior.
PMID- 10780339
TI - Changes in the alcohol consumption pattern among schoolchildren in Barcelona.
AB - Alcohol consumption is a major health problem in most developed countries. In
Mediterranean countries, experimentation with alcoholic beverages typically
occurs during the early adolescent years within the family context. In this study
we analysed alcohol consumption and its determinants in a survey of a sample of
schoolchildren in 1994. The results were compared to those obtained in a previous
study in 1987. In 1994 a random, stratified sample of all 8th grade classrooms of
a city, public, private or subsidised school was, obtained. Some 759 13 and 14
year old pupils responded to a self-administered questionnaire on health-related
habits. Overall, there was a high awareness of alcohol in the environment, as
20.7% of the pupils reported their father was a regular or occasional drinker and
41.6% declared some of their friends were drinking. Compared with the results of
the 1987 survey, there was a marked decline in the proportion of schoolchildren
reporting alcohol consumption by their father or their siblings. Regarding the
pupils' consumption, 66.7% of them had tried drinking alcohol in 1994, 54.7%
declared they were allowed to drink in family celebrations, and 17.2% had
experienced being drunk. Most of these indicators showed a significant decrease
compared with the 1987 data, with the exception of drunken episodes where there
appears to be no changes. The results suggest that there are some changes in the
Spanish context, where regular drinking among adolescents may be declining.
PMID- 10780341
TI - Prevalence of hypothyroidism and diabetes mellitus in elderly kibbutz members.
AB - The aim of this study was to determine the prevalence of hypothyroidism and
diabetes mellitus (DM) in elderly (aged 65-92 years) kibbutz members in Northern
Israel. METHOD: The medical records of 1096 elderly (642 females and 454 males)
residing in 11 kibbutzim were reviewed for data regarding thyroid function tests
(TSH and FT4) and fasting blood glucose. Fasting blood glucose levels above 7.8
mmol/l was considered diagnostic for diabetes mellitus. RESULTS: The prevalence
of hypothyroidism was 14% (9.7% in males and 18.2% in females) and that of DM was
11.5% (12.1% in males and 11.1% in females). In 74% of the diabetics the
diagnosis was made after the age of 60 years. Distribution of treatment
modalities in diabetics was as follows: diet only 42%. oral hypoglycemic agents
52% and Insulin 6%. Subclinical hypothyroidism (serum TSH levels above 4.5 mU/L
with normal FT4 levels) was detected in 38% of all the hypothyroid subjects.
CONCLUSION: The data suggest that diabetes mellitus and primary hypothyroidism
are common disorders in elderly subjects. DM in the elderly can usually be
handled with diet and oral hypoglycemic drugs. Since the clinical features of
hypothyroidism in the elderly are often atypical, we suggest that elderly
subjects should be screened for hypothyroidism.
PMID- 10780340
TI - Associations of family environment and individual factors with tobacco, alcohol,
and illicit drug use in adolescents.
AB - Despite abundant literature the respective roles of psychosomatic status,
personality, health perception, family environment, and sport activity in
tobacco, alcohol and illicit drug use have not been well known. To assess their
roles, an epidemiological cross-sectional study was conducted in 3294 middle and
high school adolescents, 2396 (73%) of whom agreed to participate. The
standardized questionnaire was filled out by the teenagers under the supervision
of the teachers. Strong associations were found between tobacco, alcohol, and
illicit drug use. The prevalence of alcohol use and illicit drug use were
respectively 7 and 10 times higher in smokers than in non-smokers. On the whole,
the potential risk factors for tobacco, alcohol, and illicit drug use were age,
psychosomatic status and psychotropic drug consumption, boring family atmosphere,
not living with both father and mother, and health perception. Mother being a
housewife was a protective factor. No marked role was noted for the head of
family's socio-occupational category. Personality would be indicators of self
control ability. Indeed, some self-reported personalities (serious, attentive,
calm, organized) had protection roles whereas some others (easily irritable,
aggressive, worried, clumsy, careless, solitary, etc.) were risk factors (risk
taking or deviant behaviors). Some sports activities were found to be negatively
related, but some others related positively with drug use, possibly due to
repetitive meetings between the adolescents at risk. Preventive measures may be
targeted at these risk factors.
PMID- 10780342
TI - Hospitalizations due to falls in Jewish and Arab children in northern Israel.
AB - In Israel, there are no epidemiological data regarding nonfatal childhood falls.
A retrospective survey was conducted in order to find epidemiological
characteristics of childhood falls among the different populations of northern
Israel. During the years 1993 through 1995, 3082 children were hospitalized in
Rambam Medical Center (RMC) due to injury. The children were subdivided into the
four main populations: Jewish and Arab residents of Haifa region (the main
metropolitan area) and Jewish and Arab residents of the Galilee region (the rural
region). All of the children who suffered injury that required mechanical
ventilation and careful assessment were admitted to the PICU. The charts of the
children admitted to the PICU were then further studied. The demographic
characteristics of all the cases of falls were statistically analyzed and the
annual admission rates due to falls were calculated using the national
statistical registrations of children in Israel. Falls were responsible for 1049
admissions due to injury, one third of the total number of children who were
admitted due to an injury. Most of the children were five years of age or
younger. Two thirds of the total childhood falls were of Arabs. The majority of
the admissions were of two major sub-populations of northern Israel: Arab
residents of Galilee region (66%) and Jewish residents of Haifa region (34%).
Higher admission rate was found among Arab children of the Western Galilee
district in comparison with Jewish children of the Haifa district. Most of the
children who were admitted to the PICU were Arabs: nearly all of these children
were from the rural region. More Arab than Jewish children who fell were admitted
to the PICU and the majority of these cases were falls from buildings (private
houses). Arab children of the rural region were responsible for 95% of the cases.
These falls were mainly in staircases (46%) and from balconies (21%), roofs (11%)
and windows (11%). The findings of the present study suggest that young Arab
rural children in northern Israel are at high risk to a severe injury due to
fall. Possible causes are discussed and a preventative intervention is suggested.
PMID- 10780343
TI - Physical abuse--physicians knowledge and reporting attitude in Israel.
AB - The objective of this study was to assess knowledge and attitudes towards
physical child abuse among pediatricians and family physicians in northern
Israel. METHODS: An interview consisting of multiple choice questions and
vignettes were employed. A stratified sample of 107 physicians from hospitals and
community clinics and of different disciplines and educational cultural
backgrounds was surveyed. RESULTS: Child abuse diagnosis was considered
infrequently or not at all by 43% of the participants and a proportion of them
were hesitant in their reporting intentions. A low consistency in the approach to
diagnosis and management was found. Medical discipline, sex and age of the
physician as well as level of knowledge and the family's socioeconomic status
were not significantly related to reporting behaviors. A significant effect of
medical training/cultural background (p = 0.01) and medical discipline (p = 0.04)
on knowledge of child abuse were found. No relationship between knowledge and
reporting behaviour was found. CONCLUSION: The results of this study are a reason
for concern. A more active role of medical schools and health administrations in
abuse-oriented education and training effort is required, particularly in
societies in transition.
PMID- 10780344
TI - Comparison between research data and routinely collected register data for
studying childhood health.
AB - Cohort studies are usually based on detailed information gathered on a limited
number of individuals. Increasing collection of administrative registers offers
an alternative method to gather health data. In the first study health
information from birth until the age of seven years on 8708 children born in the
two most northern provinces of Finland in 1985-86 was gathered through
questionnaires, medical record reviews, medical examinations and some register
data. In the second study, similar information on 8222 children born in the same
provinces in 1987 was gathered using administrative registers. Both data
collection methods gave equal results for mortality, long-term medication. and
cumulative incidence of diabetes and intellectual disabilities. The register data
identified more children with delayed development, but less children with long
term illness (77% of the level identified by the research data), with asthma
(74%), and with epilepsy (40%). The register data was unsuitable for
investigating hearing and vision disorders. The administrative data gave a gender
ratio similar to that of the research data for two of the variables with poor
coverage (asthma and epilepsy), but identified more boys with long-term illness
in general than the research data. Administrative registers are useful for
studying many long-term health problems, e.g. those resulting in hospital care or
social benefits or those registered in vital statistics. Specific cohort studies
with separate data collection is still needed to study for example outpatient
care, self-assessed health, growth and development.
PMID- 10780345
TI - Confidential enquiry into avoidable vehicle accident deaths in the province of
Modena, Italy.
AB - The authors describe the methods and results of a kind of study confidential
enquiries into avoidable deaths very rarely performed in the Mediterranean area.
After assessing some quali/ quantitative evaluation criteria, an independent
expert panel investigated the quality of each step in emergency health care.
Information was collected by clinical and forensic reports (clinical method). Of
102 cases, 4 were avoidable deaths and 18 probably avoidable. These results,
which are comparable with other similar ones found in Italy (autoptic method) and
abroad, have been useful in highlighting some health care errors: in particular,
in on-site care and in emergency department diagnosis and treatment. Other
avoidable factors emerging were the inappropriateness of transporting severe
trauma cases to a small hospital lacking proper equipment and trained staff, and
the importance of staff training in first emergency care of severe trauma on
ambulance. This situation had been highlighted previously and led to
implementation of trauma centres. The methods implemented turned out to be quite
statistically reproducible and have been used in local health care planning,
especially in the rearrangement of ambulance deployment and emergency staff
training.
PMID- 10780346
TI - Gastrointestinal infection due to Anisakis simplex in southern Italy.
AB - The authors present four cases of infection due to Anisakis in an area where
people are prone to infectious diseases transmitted by raw fish, but in which the
presence of this parasite has never been reported. Three of four cases were
discovered accidently during surgical procedures for co-existing abdominal
pathologies. Raw fish was apparently not involved in all patients.
Characteristics of the patients are discussed.
PMID- 10780347
TI - Epidemiological trend of human leptospirosis in Italy between 1994 and 1996.
AB - In the three-year period 1994 1996, 222 reports on human cases of leptospirosis
were received by the Italian Ministry of Health. The average annual number of
reports was 29.2% lower than in the preceding eight years. In all cases but two
the infections were thought to have been acquired in Italy. As in previous years,
the majority of cases was observed in the northern regions of the country
(83.8%), mostly in males (88.9%). Cases occurred in all age groups, but were more
common in the working-age population (15-64 years). There was no common-source
outbreaks. The typical leptospiral seasonal course, with a peak in August, was
observed. During 1994, leptospirosis was the reported cause of death in 19
patients. Mortality was higher among males than females. The overall fatality
rate was 22.6%. During the study period, a total of 126 cases of leptospirosis
were confirmed by the National Centre for Leptospirosis or one of the 12 Regional
Leptospira Laboratories. Of the 103 patients for whom information on place of
residence, contact with animals, occupational and recreational activities was
available, 98 (95.1%) were people who live in rural areas or devote themselves to
occupational or recreational activities at risk. The likely source of infection
and the mode of exposure were known for 55 patients. Forty-five patients (81.8%)
were likely infected by contaminating water (43 cases) or soil (2 cases), ten
(18.2%) by direct contact with animals or animal urine. Both running (51.2%) and
stagnant water (27.9%) have been reported as a source of infection. Rodents were
implicated in 50.0% of the 10 cases involving animals. In comparison with the
preceding eight-year period, the risk of contracting leptospirosis was found to
have increased for recreational activities (from 34.7 to 38.2%) and decreased for
occupational activities (from 45.8 to 32.7%). A large number of infections,
however, was ascribed to accidental events (25.5%). As in the previous period,
besides fever, the involvement of the liver was the most frequent clinical
manifestation (70.8%). Influenza-like symptoms were the only signs of illness in
15.1% of cases. Infections by 9 different serogroups were detected. The most
frequent antibodies were those against serovars icterohaemorrhagiae, poi,
copenhageni and brattislava. The presence of co-agglutinins against serovars
belonging to different serogroups prevented the identification of the presumptive
infecting serogroup in 19.8% of subjects.
PMID- 10780348
TI - Hepatitis C virus, hepatitis B virus and human immunodeficiency virus infection
in pregnant women in North-East Italy: a seroepidemiological study.
AB - BACKGROUND: Pregnant women can be considered a sentinel population, because they
are a relatively unselected population whose prevalence data may be extended to
the general population. METHODS: A seroepidemiological study was carried out in
Padua (North-East Italy) to assess the epidemiological aspects of HCV. HBV and
HIV infection in 2059 pregnant women consecutively seen at the Department of
Obstetrics and Gynaecology during 1996. Out of them, 1804 (87.2%) were indigenous
and 255 (12.8%) immigrants. Sociodemographical and sanitary data were collected
for each woman. RESULTS: The overall prevalence of anti-HCV was 1.9% (42.5% with
detectable HCV-RNA); HBsAg was found in 1.0%: the prevalence of anti-HIV was
0.3%. Findings are substantially consistent with the epidemiological picture of
such infections in the general population of our geographic area. A parenteral
risk factor for HCV infection was found in 19 subjects (47.5%): 18 were
intravenous drug users and 1 a blood transfusion recipient. HBsAg seroprevalence
was higher in immigrants than in autochthonous (3.1% vs. 0.7% respectively, p <
0.01). One of the 6 anti-HIV positive women was intravenous drug user. Logistic
regression analysis was carried out for each viral agent to determine which
characteristics were independently associated with infection: anti-HCV prevalence
resulted independently associated to Italian origin (OR: 3.7), unmarried status
(OR: 2.7), unemployed condition (OR: 6.1) and history of previous abortion (OR:
2.8). HBsAg prevalence was independently associated to unemployed condition (OR:
10.8), whereas HIV positivity was significantly related to the unmarried status
(OR: 18.5). CONCLUSION: Our study pinpoints the need of screening all pregnant
women for HCV and HIV infection, in addition to the HBsAg screening which is
compulsory in Italy.
PMID- 10780350
TI - A new method for the synthesis of N3-alkylated analogs of 5-fluorouracil.
AB - 5-Fluorouracil (5-FU) is converted to the adducts 1a,b then subjected to
Mitsunobu reaction with the secondary alcohols to give the condensates 2a,b.
Hydrogenation of 2a,b with Pd/C affords N3-alkyl-5-fluorouracil 3a,b.
PMID- 10780349
TI - Synthesis of 3'alpha-carbo-substituted 2',3'-dideoxyribonucleosides from
naturally occurring nucleosides.
AB - Naturally occurring ribonucleosides, uridine and adenosine, were converted to
their 3'alpha-CH2CO2Me and 3'alpha-CH2PO(OPh)2 2',3'-dideoxy analogues. The
present reaction sequence starts with oxidative cleavage of the 2',3'-cis-diol
system, and involves radical-mediated reconstruction of furanose ring as the key
step.
PMID- 10780351
TI - Synthesis and biological activity of unusual nucleosides having 3,4
bis(hydroxymethyl) thietane ring as a sugar moiety.
AB - The enantiomerically pure synthesis of 9-[(2'S, 3'S)-bis(hydroxymethyl)thietan-1'
yl]adenine 2,3'-thio analog of oxetanocin A, was achieved via coupling of
silylated 6-chloropurine and sulfoxide 16 under Pummerer reaction conditions.
PMID- 10780352
TI - Reactivity of 2'-deoxyoxanosine, a novel DNA lesion.
AB - 2'-Deoxyoxanosine (dOxo) is a novel DNA lesion produced from 2'-deoxyguanosine by
the reaction with nitrous acid or nitric oxide. We found that dOxo reacted with
glycine under physiological conditions. The product was identified by
spectrometric data as an adduct between the six membered ring of dOxo and an
amino group of glycine. The adduct was more stable than dOxo under physiological
conditions. The incubation of an oligodeoxynucleotide containing dOxo with
glycine gave also rise to the adduct. These results suggest that dOxo formed in
DNA reacts with amino groups of various compounds around DNA in vivo resulting in
the adduct.
PMID- 10780353
TI - New procedure of the Mitsunobu reaction as the key step in peptide nucleic acid
(PNA) monomers synthesis.
AB - PNAs are relatively novel DNA analogues, intensively studied due to their
potential as gene-targeted drugs with antigene and antisense properties. In 1996
we elaborated a new method of synthesis of PNA monomer backbones based on the
Mitsunobu reaction with N-tosyl-protected (Tos) amino acid esters as acidic
components of the reaction. Since the method used for the Tos group removal
requires conditions incompatible with various functional groups, here we modified
the procedure by replacing the tosyl group with o-nitrobenzenesulfonyl (o-NBS)
group. Using the new procedure we obtained protected PNA monomer backbones with
various amino acid side chains. The pseudodipeptide secondary amine groups were
then deprotected by thiolysis, and after standard work-up acylated with thymin-1
ylacetic acid, to give the protected monomers. Since the deprotection of the
secondary amine group occurs under mild conditions, the procedure is of general
applicability and allows various modifications of PNA structure by using diverse
beta-amino alcohols and alpha-amino acid esters.
PMID- 10780354
TI - Synthetic study on carbocyclic analogs of cyclic ADP-ribose, a novel second
messenger: an efficient synthesis of cyclic IDP-carbocyclic-ribose.
AB - An efficient synthesis of cyclic IDP-carbocyclic-ribose, as a stable mimic for
cyclic ADP-ribose, was achieved. 8-Bromo-N1-carbocyclic-ribosylinosine derivative
10, prepared from N1-(2,4-dinitrophenyl)inosine derivative 5 and an optically
active carbocyclic amine 6, was converted to 8-bromo-N1-carbocyclic
ribosylinosine bisphosphate derivative 15. Treatment of 15 with I2 in the
presence of molecular sieves in pyridine gave the desired cyclic product 16
quantitatively, which was deprotected and reductively debrominated to give the
target cyclic IDP-carbocyclic-ribose (3).
PMID- 10780355
TI - Synthesis and structure-activity relationships of novel nikkomycin analogs:
inhibitors of the fungal cell wall biosynthesis enzyme chitin synthase.
AB - A series of novel nikkomycin analogs, which inhibited chitin synthase, the fungal
cell wall biosynthesis enzyme, has been synthesized and evaluated their
inhibitory activities.
PMID- 10780356
TI - Synthesis of nucleotide antibiotics having N-acyl phosphoramidate linkages.
AB - This paper reports the synthesis of nucleotide antibiotics having N-acyl
phosphoramidate linkages. The key reaction, the construction of the N-acyl
phosphoramidate linkage was achieved by the reaction of nucleoside 5'
phosphoramidite derivatives with carboxamide derivatives in the presence of 5
(3,5-dinitrophenyl)-1H-tetrazole as a very effective activator. By use of this
activator, Phosmidosine was synthesized by condensation of an appropriately
protected 8-oxoadenosine 5'-O-phosphoramidite derivative with an N-protected
prolinamide derivative. In the case of Agrocin 84, the two P-N bonds were
constructed progressively. The N-acyl phosphoramidate linkage at the 5'-position
of the ribose moiety was similarly synthesized. After phosphorylation of the
amino group of the adenine moiety, a fully protected Agrocin 84 derivative, which
would be converted to Agrocin 84, was successfully synthesized.
PMID- 10780357
TI - Nucleic acid synthesis for investigations of gene functions.
AB - The chemical syntheses of genes encoding human c-Ha-ras and T4 endonuclease V are
described. These genes have been used for studies of mutagenesis by damaged bases
and recognition of nucleic acids by proteins. The modes of interaction of photo
damaged DNA and cognate antibodies have also been investigated by biochemical and
physicochemical approaches.
PMID- 10780358
TI - Synthesis and anti-HIV activity of unusual nucleoside oxanosine derivatives.
AB - A series of the oxanosine and carbocyclic oxanosine derivatives were synthesized
to evaluate for their anti-HIV activity. Compound 1, 7 and 9 showed weak anti-HIV
activities.
PMID- 10780359
TI - The first synthesis of herbicidin B, a tricyclic-sugar adenine nucleoside
antibiotic, using samarium diiodide-promoted aldol-type C-glycosidation reaction
as a key-step.
AB - A first total synthesis of the nucleoside antibiotic herbicidin B (1) was
achieved in which a novel aldol-type C-glycosidation reaction promoted by
samarium diiodide (SmI2) was used as a key step. Construction of the desired
stereochemistry of the tricyclic-sugar moiety was successfully achieved by
conformational restriction strategy based on repulsion between adjacent bulky
protecting groups on the pyranose ring.
PMID- 10780360
TI - Synthesis of carbocyclic nucleosides bearing a cyclopropane ring.
AB - A carbocyclic cyclopropane fused nucleoside, 9-(c-4
hydroxymethylbicyclo[3.1.0]hex-r-2-yl)-9H-adenine, has been efficiently
synthesized from 2-azabicyclo-[2.2.1]hex-5-en-3-one (ABH) in 6 steps, namely
cyclopropanation, -reductive amide cleavage (RAC) reaction and adenine ring
construction.
PMID- 10780361
TI - Synthesis of S-adenosyl-L-homocysteine hydrolase inhibitors and their biological
activities.
AB - Several nucleosides have been prepared as a possible inhibitor of human S
adenosyl-L-homocysteine (SAH) hydrolase for the development of anti-viral agents.
Recently, SAH hydrolase has been considered as an attractive target for parasite
chemotherapy for malaria. We report synthesis of several nucleosides including
carbocyclic nucleosides and their inhibitory activities against recombinant
malaria and human SAH hydrolases.
PMID- 10780362
TI - Synthesis of novel nucleotide analogues possessing a difluoromethylenephosphonato
group. Evaluation of the inhibitory activity for purine nucleoside phosphorylase.
AB - Novel nucleotide analogues 1-6 were prepared as "multi-substrate" analogue
inhibitors for purine nucleoside phosphorylases (PNPs). The cyclopropane and the
tetrahydrofuran moieties of the alkyl spacer connecting a nucleobase and
difluoromethylene phosphonic acid were found to be effective for good inhibition
of PNPs.
PMID- 10780363
TI - Synthesis and characterization of new chiral peptide nucleic acid (PNA) monomers.
AB - PNAs are DNA analogues in which the nucleic acid's backbone is replaced by a
chiral or achiral pseudopeptide backbone and nucleobases are attached to the
backbone by methylene carbonyl linkers. The easy to modify PNA structure gives
the possibility to obtain monomers, and subsequently oligomers, with improved
properties. We have synthesised several new PNA monomers, starting from a series
of 2'-substituted methyl N-(2-Boc-aminoethyl)glycinates. The pseudodipeptides
were obtained using modified Kosynkina's method, based on the reductive amination
of N-Boc-protected alpha-amino aldehydes [glycinal, isoleucinal, valinal,
tryptophanal, serinal(Bzl), prolinal] with methyl glycinate. The compounds were
then acylated with nucleic acid base derivatives by simplified procedure, and the
purification was limited to the last step of the synthesis. The applied procedure
is useful in synthesis of various chiral PNA monomers.
PMID- 10780364
TI - Synthesis of oxy-peptide nucleic acids with mixed sequences.
AB - Syntheses of N-Fmoc delta-amino acids with an ether linkage in the main chain and
six different nucleobases on the side chain, Fmoc-NH-C*H(CH2-CH2-B)-CH2-O-CH2
COOH (B = N6-benzoyladenine, thymine, uracil, N-benzoylcytosine, guanine, and N2
isobutyrylguanine) are described. The delta-amino acids were prepared through 8
12 step synthesis starting from L-homoserine and could be linked together to form
novel peptide nucleic acids (oxy-PNAs = OPNAs) by solid-phase peptide synthesis.
PMID- 10780365
TI - Synthesis of oligonucleotides containing the oxidatively modified kappaB site:
unique binding affinity to the NFkappaB p50 homodimer.
AB - Synthesis of oligonucleotide 26-mers including single 5-formyl-2'-deoxyuridine
(1) or 5-formyl-2'-O-methyluridine (2) in place of thymidine at the kappaB site
has been accomplished. One of the 26-mers with 1 was critically discriminated by
the NFkappaB p50 homodimer in binding.
PMID- 10780366
TI - Further studies of KMnO4 oxidation of synthetic DNAs containing oxidatively
damaged bases.
AB - Recently we found that KMnO4 oxidation of DNA oligomers containing a 7,8-dihydro
8-oxoguanine (8-oxo-G) residue induces damage to the neighboring base residues;
other modified bases, 7,8-dihydro-8-oxoadenine (8-oxo-A) and 5-hydroxyuracil (5
oh-U), show similar behavior in DNA. The present study indicated that the ability
to induce damage, which could also occur by the oxidation of a 5-oh-C residue,
was low as in the case of 5-oh-U. On the other hand, in order to examine the
pathways and the intermediates for the oxidative degradation of 8-oxo-A, we have
carried out the KMnO4 oxidation using an 8-oxo-2'-deoxyadenosine derivative as a
model and have determined the structures of the three major products.
PMID- 10780367
TI - Chemical synthesis and properties of (6-4) photoproduct and its analogs.
AB - We report the preparation of a deoxyribooligonucleotide containing a new thymine
(6-4) photoproduct analog. The (6-4) photoproduct is one of the major forms of
DNA lesions, and leads to mutation in DNA. An antibody (64M5) that binds the (6
4) photoproduct has been described. To investigate the interaction of the
photoproduct with the 64M5 antibody, we prepared a (6-4) photoproduct analog in
which the two thymines were connected with a formacetal linkage. With UV
irradiation, the thymine dimer with the formacetal linkage reacted to the (6-4)
photoproduct faster than the phosphodiesterified dimer, and the yields of the
analog was higher than those of the natural thymine dimer. The 64M5 antibody
exhibited sufficient binding to a tetranucleotide containing the (6-4)
photoproduct analog with a formacetal linkage, although the association constant
was slightly lower than that for the natural lesion. This (6-4) photoproduct
analog may be useful for investigation of other proteins that recognize the (6-4)
photoproduct.
PMID- 10780368
TI - Reversible photoligation of DNA via 5-vinyldeoxyuridine.
AB - We report a novel non-enzymatic template-directed reversible photoligation of
oligodeoxyribonucleotides (ODNs). In this photoligation system, a modified ODN
containing 5-vinyldeoxyuridine at 5'-end reacts by photoirradiation at 366 nm
with cytosine and thymine at the 3'-end of another ODN in the presence of a
complementary template to yield a ligated ODN quantitatively. The ligated ODN can
be split site-selectively to regenerate the parent ODN by photoirradiation at 302
nm.
PMID- 10780369
TI - Cleavage of parallel-stranded DNA duplex by peplomycin metal complexes.
AB - Peplomycin-mediated degradation of parallel-stranded (ps) duplex was
investigated. It was found that Co- and Fe-peplomycins degraded ps DNA duplex by
4'-hydrogen abstraction at 5'-GPy (pyrimidine) site in a similar manner to that
of antiparallel B-DNA. While the orientation of two strands of ps and B-form DNA
duplexes are reversed, peplomycin metal complex can bind to ps DNA duplex to
cause oxidative DNA damage. These results indicate that peplomycin metal complex
mainly interacts with one strand which is damaged.
PMID- 10780370
TI - Efficient cross-linking to cytidine by functional nucleobases capable of in situ
activation.
AB - We have previously demonstrated that the ODNs with 2-amino-6-(2
phenylsulfoxyethyl)purine nucleoside derivative were capable of efficient
interstrand cross-linking with cytidine selectively. In this new strategy, less
reactive precursor was auto-activated within a duplex to generate 2-amino-6
vinylpurine derivative. However, it turned out that 2-amino-6-(2-phenylsulfinyl)
ethylpurine nucleoside was not applicable as the precursor for the synthesis of
DNA oligomers with G-rich sequences. In this report, 2-amino-6-(2
methylsulfinylethyl)purine nucleoside has been proven to be more suitable as a
precursor for DNA synthesis. In addition, the ODNs incorporating either 2-amino-6
(2-phenylsulfoxy ethyl)purine or 2-amino-6-vinylpurine showed high reactivity
toward the cytidine at the target site but quite less reactivity was observed for
it at non-target site, demonstrating high site-selectivity.
PMID- 10780371
TI - Synthesis and properties of oligonucleotides containing carbocyclic L-nucleoside
analogues with a restricted glycosyl conformation.
AB - To construct nuclease-resistant oligonucleotides, we designed novel carbocyclic L
nucleoside analogues (1-4) whose glycosyl conformation is fixed at chi = 180
degrees by an oxygen-bridge between the base and the cyclopentane ring. We have
already achieved the racemic synthesis of these analogues. In this study, we
succeeded in synthesizing an optically active form of these analogues. The
properties of oligonucleotides containing them will be shown.
PMID- 10780372
TI - Synthesis of oligodeoxyribonucleotides bearing a functional group at 2'-position
by post-synthetic modification.
AB - A novel 2'-thio-2'-deoxyuridine derivative bearing a reactive ester at 2'
position was synthesized and incorporated into oligodeoxyribonucleotides (ODNs)
for the post-synthetic modification of ODNs. This ODNs was reacted with several
amines to give ODNs having a functional group at 2'-position.
PMID- 10780373
TI - X-ray analysis of a DNA dodecamer containing 2'-deoxy-N4-methoxycytidine.
AB - The crystal structure of DNA dodecamer with the sequence of d(CGCAAATTXGCG),
where X is 2'-deoxy-N4-methoxycytidine, has been determined by X-ray analysis.
The dodecamers form a double helix with B-form conformation. The electron density
indicates that the two modified cytosine bases respectively make a pair with the
adenine bases on the opposite strand in a manner of Watson-Crick geometry and
that the methoxy groups are in anti conformation to the N3 atom.
PMID- 10780374
TI - Homogeneous detection of a target nucleic acid sequence by combination of the
intercalation activating fluorescence DNA probe and the isothermal sequence
amplification.
AB - We demonstrated the homogeneous real-time detection of RNA produced during
isothermal TRC amplification by INAF probe.
PMID- 10780375
TI - The interaction of benzimidazole compounds with DNA: intercalation and groove
binding modes.
AB - Benzimidazole compounds (Fig. 1) have been synthesized to study their DNA-binding
properties. Results obtained with spectroscopy and viscosity measurements
indicate that the binding mode varies from intercalation to groove-binding,
depending on the number of benzimidazole rings (conformation and size of
compounds).
PMID- 10780376
TI - Affinity separation of messenger RNA by thermo-responsive polymer carrying
oligo(dT).
AB - The conjugate between oligo(dT)16 and thermo-responsive polymer, poly(N
isopropylacrylamide), was prepared for isolation of poly(A)+ RNA from total RNA.
The hybridization reaction between the conjugate and poly(A) (average length: 320
base) was equilibrated in 10 min, and all the poly(A) (16 nmol base for 24 nmol
base of conjugate) was precipitated when raising the solution temperature to 35
degrees C. The precipitate was dissolved in water, and poly(A) was dissociated
from the conjugate by heating to 65 degrees C. This separation system was
successfully applied to the isolation of poly(A)+ RNA from total RNA.
PMID- 10780377
TI - DNA analysis by microfabricated capillary electrophoresis device.
AB - The LIGA (Lithographie Galvanoformung Abformung) process using synchrotron
radiation lithography is applied to the microfabrication of capillary array
electrophoresis (CAE) device. Laser-induced fluorescence detection system for the
CAE device has been constructed by the modification of laser confocal
fluorescence microscopy. DNA molecules were detected during migrating in the
microchannels filled with polymer separation matrices under electric field to
optimize the separation conditions for DNA analysis. Based on this observation,
we demonstrated that microfabricated CAE device is realized the fast separation
of DNA.
PMID- 10780378
TI - Rapid detection of the gene of Legionella pneumophila using the fluorescence
polarization with the asymmetric PCR.
AB - We attempted the rapid detection method of Legionella pneumophila by the
asymmetric PCR and the fluorescence polarization. Eleven extracted DNAs from L.
pneumophila serogroup 1 to approximately 6, L. bozemanii, L. dumoffii, L.
gormanii, L. micdadei, and Pseudomonas aeruginosa were amplified by asymmetric
PCR, and the polarization of those products were measured. Only the polarization
of L. pneumophila serogroup 1 to approximately 6 rose within a few minutes after
the beginning of measurement. The sensitivity to L. pneumophila using this method
was 10(3) cells.
PMID- 10780379
TI - Folding transition of long duplex DNA from mammalian cells.
AB - Conformational change in individual giant DNAs from pig liver is studied by use
of fluorescence microscopy. With the addition of spermidine (a trivalent amine),
each DNA chains undergo abrupt transition from an elongated coiled state into a
folded compact state. It is found that the all-or-none characteristics in the
folding transition for the mammalian DNA is similar to that in phage DNAs.
PMID- 10780380
TI - Quantification analysis of splice signal sequences: mutation of 3'-splice signal
sequence and mechanism of unsplicing in a beta-thalassemia pre-mRNA.
AB - Strength of splice signal sequence plays an important role in mammalian pre-mRNA
splicings. In the splicing of human beta-globin thalassemia pre-mRNA, a 25
nucleotide deletion covering the signal sequence at 3'-splice site of intron 1
causes unsplicing of intron 1, while splicing of intron 2 occurs normally. This
gives abnormal mRNA and beta-thalassemia disease. If 3'-splice site of intron 1
is inactivated, two 5'-splice signals of introns 1 and 2 compete with each other
for the 3'-splice site of intron 2. Our quantification analysis revealed that the
5'-splice signal of intron 2 is stronger than that of intron 1, explaining the
mechanism for unsplicing of intron 1.
PMID- 10780381
TI - Statistical analysis of DNA sequencing data (1): accuracy test of DNA data by
partial re-sequencing.
AB - To qualify DNA data, we have developed a statistical method of deciding whether
the DNA data has an acceptable accuracy in sequencing process. The method is to
test the probability of sequencing errors, based on partial re-sequencing. The
method was successfully applied to a yeast mitochondrial DNA which is previously
sequenced (1). The analysis indicates that the entire sequence is very accurate
although we found one base change error on the ND1 gene sequence data by a
partial re-sampling. This method is applicable to any DNA data.
PMID- 10780382
TI - Genome structure of Ri plasmid (2). Sequencing analysis of T-DNA and its flanking
regions of pRi1724 in Japanese Agrobacterium rhizogenes.
AB - We sequenced 42.6 kb including T-DNA and its flanking regions which corresponds
to about 1/5 of entire length of a mikimopine-type Ri plasmid, pRi1724 in A.
rhizogenes. We identified 37 ORFs (Open Reading Frames) including genes in total.
Among them, 20 ORFs are probably new genes. Those ORFs have similarity with those
in Agrobacterium and 9 ORFs of them was newly found on Ri plasmids.
PMID- 10780383
TI - Isolation of cDNAs that cover the entire coding region of a novel human protein
D40.
AB - Previously, we have reported a novel protein, D40, that specifically binds to a
nuclear factor GCF by two-hybrid system. Northern analysis on tumor cell lines
revealed that mRNA of D40 is about 5 kb. To get cDNA clones that cover the total
coding region of D40 protein, approximately 5 x 10(5) clones of a human cDNA
library were screened, and then several positive clones were obtained. RACE was
performed to get the 5' end of the cDNA. DNA sequencing revealed an open reading
frame that encodes a protein with 887 amino acids. in vitro transcription and
translation analysis of D40 revealed that the molecular weight of the protein is
110 to approximately 130 kda.
PMID- 10780384
TI - Chromosomal assignment of a novel human gene D40.
AB - We have previously reported an identification of a novel human cellular factor,
D40. Here, we report the chromosomal localization of the gene that encodes D40.
Fluorescent in situ hybridization (FISH) was performed to determine the
chromosomal region that D40 gene resides. The chromosomes that derived from
normal adult male lymphocytes were hybridized with a mixture of cDNA probes that
cover the entire coding region of D40. D40 gene mapped to the long arm of
chromosome 15q14-15.
PMID- 10780385
TI - Transcriptional regulation of cruxrhodopsin gene from extremely halophilic
archaeon Haloarcula japonica strain TR-1.
AB - Transcription of the cruxrhodopsin (cR) gene in extremely halophilic archaeon
Haloarcula japonica strain TR-1 was investigated using Northern analysis to
quantify message level. In the cell cultures growing in the dark, cR transcript
level remained very low. In contrast, exposure of the cell cultures to light
stimulated transcription of the cR gene. In addition, cR gene transcription was
also induced when Ha. japonica was grown under high oxygen tension and then
shifted to low oxygen tension in the dark. These results suggested that
transcription of the cR gene is regulated by high light intensity and low oxygen
tension.
PMID- 10780386
TI - Molecular cloning of A1-ATPase gene from extremely halophilic archaeon Haloarcula
japonica strain TR-1.
AB - The genes encoding A1-ATPase A- and B-subunits were cloned from Haloarcula
japonica strain TR-1. Nucleotide sequencing analysis of the A1-ATPase gene
revealed that the A- and B-subunits consisted of 586 and 473 amino acids,
respectively. The deduced amino acid sequences of the A- and B-subunits of Ha.
japonica showed high identities with those of Halobacterium salinarum and
Haloferax volcanii. The consensus ATP-binding motif was found in the A-subunit.
PMID- 10780387
TI - Nucleotide sequences of animal mitochondrial tRNAs(Met) possibly recognizing both
AUG and AUA codons.
AB - To elucidate the role of modified nucleosides of tRNA in mitochondrial
translation systems, especially with regard to their codon recognition, we
purified mitochondrial tRNAs(Met) isolated from liver of frog, chicken and rat,
and determined their nucleotide sequences. All of these tRNAs(Met) were found to
possess 5-formylcytidine in the first letter of the anticodon, which is known to
be prerequisite for bovine mt tRNA(Met) to decode AUA codon as well as AUG codon.
These tRNA possesses two pseudeuridines in similar positions, and only chicken
tRNA(Met) had ribothymidine at the first position of the T-loop, which is always
found in the usual tRNAs. Considering that AUA codon is used as five times
frequently as AUG codon in these animal mitochondrial genomes, it is deduced that
5-formylcytidine at the wobble position is essential for the recognition of both
AUA and AUG codons.
PMID- 10780388
TI - Incorporation of two nonnatural amino acids into proteins through extension of
the genetic code.
AB - A novel method of the in vitro incorporation of two nonnatural amino acids into
proteins through extension of the genetic code was developed. The streptavidin
mRNA containing AGGU and CGGG, and chemically aminoacylated tRNA(ACCU) and
tRNA(CCCG) were prepared, then they were added into E. coli in vitro protein
synthesizing system. As a result, two nonnatural amino acids were successfully
incorporated into desired sites of streptavidin.
PMID- 10780389
TI - Correlation between mRNA structure of the coding region and translational pauses.
AB - Discontinuous translational elongation of polypeptides is observed during spider
dragline silk fibroin synthesis (1,2). The repeating segment of one of the two
subunit proteins constituting spider major ampullate (dragline) silk of Nephila
clavipes, Spidroin 2, consists of alternate alanine-rich and proline-rich regions
(3). It was found that the calculated free energy of the secondary structure of
Spidroin 2 mRNA per nucleotide for the alanine-rich region is about the same as
that for the successive proline-rich region. The small stability changes of local
mRNA secondary structures along the mRNA chain suggest that the translational
pauses observed for dragline silk fibroin synthesis may not be correlated with
Spidroin 2 mRNA structure, in contrast to Spidroin 1 mRNA structure which may
explain the translational pauses (4).
PMID- 10780390
TI - Preparation of DNA containing 7-methylguanine as unique lesions.
AB - The predominant adduct produced by both endogenous and exogenous methylating
agents is 7-methylguanine(m7G). Most studies on the repair of m7G reported so far
used methylated DNA as substrates which contained other unintended lesions. In
the presented study, DNA substrates containing m7G as unique lesions were
prepared by DNA polymerase reactions. Using these substrates, damage recognition
of E. coli 3-methyladenine DNA glycosylase II (AlkA) was analyzed. The obtained
results suggested that the repair rate of m7G by AlkA was affected by the
flanking sequence context of the lesion.
PMID- 10780391
TI - MTHFR gene variant is not associated with diabetic nephropathy in Japanese.
AB - Genetic predisposition has been implicated in diabetic nephropathy. The C677T
variant of the MTHFR gene has been suggested to play a role in the development of
not only vascular diseases but also diabetic microangiopathies. By using
polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method using
Hinf I, we investigated whether this variant is associated with diabetic
nephropathy in Japanese. By analysing 274 unrelated Japanese patients with type
II DM with or without nephropathy, there was no significant difference in the
genotype distribution of this variant. The distribution of the three genotypes
were not different among patients with micro- or macroalbuminuria and those
without nephropathy. Although previous reports suggest a role of this variant
with diabetic microangiopathies, our observations suggest that this variant is
does not play an important role in the pathogenesis of diabetic nephropathy in
Japanese.
PMID- 10780392
TI - A possible function of DNA curvature in a vector system that allows efficient
expression of heterologous proteins in CHO cells.
AB - A cis-acting element derived from the nontranscribed spacer region of murine rDNA
allows efficient expression of heterologous proteins in transformed Chinese
hamster ovary (CHO) cells. Analysis of the structural conformation of this cis
acting element revealed that it has a DNA curvature. Whether the DNA curvature
plays any roles in regulating expression of heterologous proteins or not has been
studied.
PMID- 10780393
TI - Antisense oligodeoxynucleotides: useful tool for search and assessment of new
targets for anti-malarial drugs.
AB - We investigated about targeting for new antimalarial drugs using antisense (AS)
oligodeoxynucleotides (ODNs). Synthetic nuclease-resistant ODNs (phosphorothioate
(PS) ODNs and ODNs containing 4'alpha-C-(2-aminoethyl)thymidines (4'-amino ODNs))
which target mitochondrial succinate dehydrogenase (SDH) iron-sulfur subunit
(IP), had antimalarial activity (EC50; about 1.0 microM). Furthermore we showed
that intra-parasitic SDH IP mRNA levels, which were detected using quantitative
RT-PCR assay, were decreased 13% of control after the 24 h expose to SDH IP AS.
From the results, we conclude that SDH has potential as the target for novel
antimalarials, and AS ODNs is effective for search and assessment of targets for
new antimalarial drugs.
PMID- 10780394
TI - Fluorescent probe and permeability to cells of isopoly (S-carboxymethyl-L
cysteine) derivative of nucleic acid bases.
AB - Isopoly(S-carboxymethyl-L-cysteine) derivatives of nucleic acid bases were found
to form stable complex with oligo-DNA in vitro. Fluorescent probed isopoly(S
carboxymethyl cysteine) derivatives of nucleic acid bases were prepared as
antisense oligomers. The transfection of the oligomer into cells was carried out
by HVJ-liposome method. Fluorescence was observed from the cells treated with HVJ
liposome including fluorescent probed oligomers.
PMID- 10780395
TI - Comparison of thermodynamic stabilities between PNA (peptide nucleic acid)/DNA
hybrid duplexes and DNA/DNA duplexes.
AB - We have examined quantitatively stabilities of PNA/DNA hybrid duplexes with
identical nearest-neighbor base pairs and compared stabilities between PNA/DNA
and DNA/DNA. The average difference of stabilization energy of the short PNA/DNA
was 0.9 kcal mol(-1), which suggests that the stability of the hybrids with
identical nearest-neighbor base pairs can be predicted with the nearest-neighbor
model as well as those of nucleic acid duplexes.
PMID- 10780396
TI - Positional effect of single bulge nucleotide on PNA(peptide nucleic acid)/DNA
hybrid stability.
AB - We report positional effect of bulge nucleotide on PNA/DNA hybrid stability. CD
spectra showed that PNA/DNA hybrids required at least seven base pairings at a
stem region to form a bulged structure. On the other hand, DNA/DNA could form
bulged structure when there are only four base pairings adjacent to the bulge
nucleotide. We discuss why PNA requests such a many base pairings to form bulged
structure from a nearest neighbor standpoint.
PMID- 10780398
TI - Direct laser trapping of single globular DNA molecules.
AB - We show herein that a single T4 phage DNA molecule which was transformed from
coiled to globular state, was trapped directly by Nd:YAG laser (1064 nm). We also
estimated trapping force of globular DNA molecules.
PMID- 10780397
TI - Preparation and evaluation of ODN conjugates with polycation comb-type copolymer.
AB - Oligodeoxynucleotide (ODN) conjugates with the polylysine comb-type copolymer
having an ability to promote and stabilize duplex and triplex DNA formation were
prepared. 5'-Aminated ODN was succinylated with succinic anhydride. The resulting
ODNs having carboxyl terminus were coupled with epsilon-amino groups of the comb
type copolymer using water soluble carbodiimide. The conjugate free from
unconjugated ODNs was obtained by gel permeation chromatography. The resulting
conjugate maintains ability to form duplex and triplex DNA as estimated by
melting curve analysis. Both specificity and stability of the triplex DNA
formation were increased by employing the ODN-copolymer conjugates compared to
those with their mixture.
PMID- 10780399
TI - Rapid and inexpensive recovery method of DNA fragments from agarose and
polyacrylamide gels by a cotton-wool column tube.
AB - We developed a rapid, convenient, simple, and inexpensive method for isolating
pure DNA from agarose and polyacrylamide gels using cotton wool tubes. DNA
fragments ranging in size from 193-23,130 bp can be easily recovered within 2
hours by centrifugation through cotton wool from gel slices. The recovery rate of
this method is 35% to 50%, when estimated for isolation of lambda DNA-HindIII
fragments. We have also recovered 700-bp polymerase chain reaction (PCR) products
using cotton wool tubes from electrophoresis on both a 0.8% agarose gel and a 6%
polyacrylamide gel, in which satisfactory yields of more than 50% were obtained.
The DNA thus recovered in this way is biologically active and can be used as a
substrate for further experimental procedures without additional purification
steps.
PMID- 10780400
TI - Immobilization of DNA by UV irradiation and its utilization as functional
materials.
AB - The water-insoluble DNA film was successfully prepared by UV irradiation. The DNA
film was stable in water. It could effectively accumulated the DNA-binding
intercalating materials, such as ethidium bromide, dibenzo-p-dioxin and
benzo[a]pyrene, in their aqueous solutions. On the other hand, DNA was
immobilized onto nonwoven cellulose fabrics, also by the UV irradiation. The DNA
immobilized cloth was found to bind silver ions. The DNA-cloth containing silver
ion showed antibacterial activity. The water-insoluble DNA prepared by UV
irradiation has a potential ability to serve as biomaterials for medical,
engineering and environmental objects.
PMID- 10780401
TI - A facile synthesis of DNA oligomers with modified backbones via the
phosphoramidite method without nucleoside base protection.
AB - A convenient synthesis of DNA oligomers with modified back bones including
phosphorothioates and phosphotriesters has been developed on the basis of the
phosphoramidite strategy without nucleoside base protection. In this synthesis, a
new, convenient method for the preparation of N-free-5'-O-dimethoxytrityl-2'
deoxyribonucleoside by the direct O-selective dimethoxytritylation of the parent
nucleosides has also been disclosed.
PMID- 10780402
TI - Trityl mass-tags for encoding in combinatorial oligonucleotide synthesis.
AB - Combinatorial libraries of oligonucleotides on beads were synthesised by a split
and-mix strategy using 5'-DMTr- or 5'-Fmoc- nucleoside phosphoramidites. Trityl
moieties with different masses were used to encode for the bases coupled at each
step in the synthesis of oligonucleotides selected by hybridisation from the
libraries. Tags orthogonal to the nucleotides added were produced by coupling
amines of different MW to an activated carboxyl group(s) on the trityl moiety.
Tags can be released from the support by laser irradiation and measured directly
by TOF without matrix. Alternatively, they may be released by an acidic treatment
and then analysed by (MA)LDI-TOF.
PMID- 10780403
TI - Toward artificial ribonucleases: design and synthesis of 2'-O
methyloligonucleotides with a terpyridine-copper(II) complex.
AB - In order to construct an antisense 2'-O-methyloligonucleotide with an internal
terpyridine-Cu(II) complex, a novel synthon was synthesized. This synthon was a
2'-deoxy-uridine-3'-phosphoramidite derivative with a terpyridine group at the 5'
O and a dimethoxytritylated hydroxypropyl group at the C-5. The antisense agent
cleaved the RNA site-specifically and in a moderate yield.
PMID- 10780404
TI - Artificial DNAs with metal-assisted base pairs.
AB - Two types of artificial beta-C-nucleosides, 2 and 3, were newly synthesized,
which possess a metal chelating site (2-aminophenol and catechol, respectively)
at the nucleobase moiety. These nucleosides are expected to form metal-assisted
base pairs in oligonucleotides and thereby to control high-order structures and
functions of DNAs.
PMID- 10780405
TI - Synthesis and properties of oligonucleotides containing 2'-pyrenylalkyluridine.
AB - The synthesis, binding and fluorescence properties of oligonucleotides containing
the uridine modified at the 2'-position by a pyrene group using different length
of linker arm have been described. It is demonstrated that the oligonucleotides
possessing a C3-amide group at the 2'-position display an enhanced signal of the
pyrene monomer fluorescence upon binding to DNA segments.
PMID- 10780407
TI - Does 29-mer RNA hairpin of the HIV-1 TAR RNA sequence bind magnesium? 19F-NMR and
modelling studies.
AB - 5-Fluorouridine residues have been introduced into functionally important bulge
and loop regions of 29-mer HIV-1 TAR RNA hairpins I and II to study Mg2+ and Ca2+
binding using 19F-NMR spectroscopy. There was no substantial binding detected up
to 20-molar excess in case of both cations, whereas association of argininamide,
used as a reference ligand, could be detected at less than 1-molar excess. The
deltadelta 19F value of 1.93 ppm observed for (F)U23 upon argininamide binding is
in agreement with former NMR studies of TAR RNA/argininamide complex. However,
obtained results do not confirm U38 x A27 x U23 base-triple formation. The
unmodified HIV-1 TAR RNA hairpin resulted from 600 ps in aqua molecular dynamics
simulation was subjected to a molecular mechanics modelling of Mg+ binding.
PMID- 10780406
TI - Study on RNA structure by pyrene-labeled 2'-O-methyloligoribonucleotides.
AB - Properties of 2'-O-methyloligoribonucleotides containing 2'-O-(1
pyrenylmethyl)uridine were investigated as the fluorescent probe to search the
single strand regions on RNA secondary and tertiary structure. The pyrene-labeled
2'-O-methyloligoribonucleotide (OMUpy) showed remarkable increase of fluorescence
intensity to 333-fold at 375 nm when hybridized with the complementary
oligoribonucleotide. When OMUpy, complementary to loop or stem regions, was
applied to E. coli 5S-rRNA, the fluorescence intensities were increased in a
sequence specific manner. The difference of the fluorescence intensities
corresponds to the higher-order structure of 5S-rRNA, suggesting that pyrene
labled 2'-O-methyloligoribonucleotide can be applicable to search single strand
regions of RNA.
PMID- 10780408
TI - DNA HOMO as a new landmark for nucleic acid properties. ab initio calculations
and experimental mapping.
AB - Of the non-covalent binding forces in DNA-drug or DNA-protein interaction,
electrostatic interaction, stacking interaction, hydrogen bonds and hydrophobic
effect have been well established. However, only a few HOMO-LUMO interaction in
DNA have been reported. We examined the ab initio calculations of B-DNA duplex 5
mers. Based on the calculated results, we investigated the mapping of HOMO
experimentally and found that DNA cleavage patterns with Co(II) and BPO (Benzoyl
peroxide) were in good agreement with the ab initio calculation results.
PMID- 10780409
TI - N6-methoxyadenine in damaged DNA has two faces in property of Watson-Crick base
pairing.
AB - In order to investigate mutation mechanism with oxyamine, two DNA dodecamers
containing 2'-deoxy-N6-methoxyadenosine have been synthesized and their crystal
structures have been determined. The dodecamers are associated in B form
duplexes. The methoxy groups attached to the adenine bases do not affect the DNA
conformation significantly. Electron densities clearly show that N6
methoxyadenine moiety forms Watson-Crick type pairing with both, thymine and
cytosine bases. Such two faces in pairing are the origin of pyrimidine transition
mutation.
PMID- 10780410
TI - Preparation of 2'-deoxyribonucleosides with an identically 2H/13C-labeled sugar
residue.
AB - Thymidine with the stereoselectively 2H/13C-Labeled sugar moiety, (2'R)(5'S)
[1',2',3',4',5'-(13)C5;2',5'-(2)H2]-thymidine, was synthesized from uniformly 13C
labeled glucose, via the selectively deuterated ribose derivative prepared by the
stereo-controlled deuteride transfer reactions. The labeled sugar moiety of the
thymidine was then transferred to 2'-deoxyadenosine, 2'-deoxyguanosine, and 2'
deoxyuridine, by the enzymatic transglycosylation reactions by purine and
pyrimidine nucleoside phosphorylases, in good yields. Labeled 2'-deoxyuridine was
chemically converted to 2'-deoxycytidine. Consequently, all of the 2'
deoxynucleosides prepared by this method has the identically labeled sugar
moiety. By using DNA oligomers containing the identically labeled sugar residue
for NMR studies, any possible complexity in NMR data analyses expected to be
observed for DNA oligomers containing variously labeled nucleosides can be
minimized.
PMID- 10780411
TI - Chemical synthesis of novel base pairs and their enzymatic incorporation into
DNA.
AB - A novel base pair, 2-amino-6-(N,N-dimethylamino)purine (denoted x) and the
counter part, pyridin-2-one (denoted y) were designed. The bulky 6-dimethylamino
group of x is expected to eliminate base pairing with all natural bases. The
phosphoramidite of x for DNA templates and the 2'-deoxyribonucleoside
triphosphate of y (dyTP) for a substrate were synthesized, and the selectivity of
the enzymatic incorporation of dyTP opposite x in the templates was examined.
dyTP was preferentially incorporated opposite x than canonical dNTPs by Klenow
fragment of Escherichia coli DNA polymerase I. While dyTP was also incorporated
opposite A and G, the misincorporation was suppressed in the presence of dTTP and
dCTP, respectively.
PMID- 10780412
TI - Synthesis of 4'-substituted nucleosides and their biological evaluation.
AB - 4'-C-Ethynyl-beta-D-arabino- and 4'-C-ethynyl-beta-D-2'-deoxy-ribo-pentofuranosyl
pyrimidines were synthesized. Most of these 4'-ethynyl nucleosides showed
interesting biological activities.
PMID- 10780413
TI - Interaction of a novel antitumor agent TAS-103 with DNA.
AB - Interaction of a novel antitumor agent TAS-103 with DNA has been studied by a
variety of methods including thermal melting study, UV-Visible spectroscopy, 1H-
and 31P-NMR spectroscopy. Thermal melting study indicated that TAS-103 stabilizes
the double stranded form of DNA and the relative binding strength of TAS-103 is
equal to that of ethidium bromide (EtBr). UV-Visible spectroscopy demonstrated
that titration curves are nearly identical with all DNA oligomers producing a
hypochromic and hypsochromic effect. A hypsochromic effect of TAS-103 is differ
from typical intercalators such as EtBr and Actinomycin D that exhibit a
bathochromic effect. 1H- and 31P-NMR spectroscopy revealed that TAS-103 has
mainly two binding modes. Major binding mode is outside binding and minor binding
mode is intercalation.
PMID- 10780414
TI - Disturbance of genetic information by a ribonucleotide analogue.
AB - The synthetic base analogue, 6H,8H-3,4-dihydropyrimido[4,5-c][1,2]oxazin-7-one
(P), can efficiently base pair with A and G. We have previously demonstrated that
the deoxyribonucleoside of P (dP) is highly mutagenic and that this is due to the
ambiguous base pairing ability of P. In this work, we have shown that the
ribonucleoside triphosphate of P (rPTP) induces C to U mutation on an in vitro
model of retroviral genomic RNA replication pathway. This mutation induction by
rPTP may be specific to retroviruses, since host genomic DNA should not be
affected by such a ribonucleotide analogue, although temporary transcription
translation errors may occur.
PMID- 10780415
TI - Cytotoxic mechanism of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd).
AB - The molecular mechanism of cell death induced by 1-(3-C-ethynyl-beta-D-ribo
pentofuranosyl)cytosine (ECyd: Figure 1), a potent inhibitor of RNA synthesis,
was performed using mouse mammary tumor FM3A cells and human fibrosarcoma HT1080
cells. ECyd induced the characteristics of apoptosis on these cells, such as
morphological changes, DNA fragmentations (Figure 2), and caspase-3-like protease
activation. General caspases inhibitor (Z-Asp-CH2-DCB) inhibited these changes
and cell death. We also found that ECyd induced DNA and 28S ribosomal RNA (rRNA)
fragmentations. Though the mechanisms of rRNA fragmentations haven't revealed, it
suggests that translational function of the treated cells should be disturbed.
These results indicate that antitumor mechanism of ECyd are characteristics of
apoptosis on the cells and rRNA fragmentations is one of the death events
resulted inhibition of RNA synthesis.
PMID- 10780416
TI - Photo-regulated duplex- and triplex-formation of the modified DNA carrying
azobenzene.
AB - The duplex- and triplex- forming activity of oligonucleotide was photo-regulated
by using the isomerization of azobenzene in the side chain. When the azobenzene
was isomerized from the trans-form to the cis-form by photo-irradiation, the
melting temperatures of the duplex and triplex between the oligonucleotide and
its complementary counterpart were significantly lowered.
PMID- 10780417
TI - Promotion mechanism of triplex DNA formation by comb-type polycations:
thermodynamic analyses of sequence specificity and ionic strength dependence.
AB - We have previously reported that in the presence of poly (L-lysine)-graft-Dextran
(PLL-g-Dex) copolymer, the binding constant of the pyrimidine-motif triplex
formation at neutral pH is about 100-times higher than that observed without any
triplex stabilizer. Here, to explore the mechanism of the promotion effect of the
PLL-g-Dex copolymer at neutral pH, the sequence specificity and the ionic
strength dependence of the pyrimidine-motif triplex formation was examined in the
absence or presence of the copolymer. The sequence specificity of the pyrimidine
motif triplex formation at neutral pH in the presence of copolymer was almost
similar to that at acidic pH without the copolymer. As the concentration of
magnesium cation increased, the binding constant of the pyrimidine-motif triplex
formation without the copolymer increased. On the other hand, the binding
constant of the pyrimidine-motif triplex formation in the presence of the
copolymer decreased upon the increase in the concentration of magnesium cation.
Considering these results in light of counterion condensation (CC) theory, we
conclude that the copolymer does not hinder the sequence specificity of the
triplex formation, and isolates the triplex formation from the CC effect, which
may lead to a net increase in entropy change upon the triplex formation,
providing a favorable component to binding constant of the triplex formation.
PMID- 10780418
TI - Acceleration of DNA strand exchange by polycation comb-type copolymer.
AB - Polycation comb-type copolymers which are composed of poly(L-lysine) backbone and
dextran graft chain (PLL-graft-Dex) accelerated DNA duplex and triplex formation
and stabilized under physiologically relevant condition remarkably. In this
study, we have examined the ability of polycation copolymer in promoting strand
exchange between duplex DNA and its complementary single-stranded DNA. It was
demonstrated that the strand exchange rate was considerably accelerated by the
polycation comb-type copolymer.
PMID- 10780419
TI - Strand invasion by DNA-peptide conjugates and peptide nucleic acids.
AB - Peptide nucleic acids (PNAs) and conjugates between oligonucleotides and cationic
peptides possess superior potential for strand invasion at complementary
sequences. We discovered that oligonucleotide-peptide conjugates and PNAs fall
into three classes based on their hybridization efficiency; i) those
complementary to inverted repeats within AT-rich region hybridize with highest
efficiency; ii) those complementary to areas adjacent to inverted repeats or near
AT-rich regions hybridize with moderate efficiency; and iii) those complementary
to other regions do not detectably hybridize. The correlations between oligomer
chemistry, DNA target sequence, and hybridization efficiency that we report here
have important implications for the recognition of duplex DNA.
PMID- 10780420
TI - Isopoly(S-carboxymethyl-L-cysteine) derivatives of nucleic acid bases: effects of
D-cysteine derivatives on the interaction with DNA.
AB - Isopoly(S-carboxymethyl-D-cysteine) derivatives of nucleic acid bases were
prepared to study the effect of chirality on the complex formation with oligo
DNA. The D-cysteine unit in the L-cysteine oligomer caused decrease of Tm for the
complex with DNA.
PMID- 10780422
TI - Quantitative detection of a DNA ligase reaction on a quartz-crystal microbalance.
AB - We report here kinetic analyses of DNA ligation by using a DNA-immobilized quartz
crystal microbalance (QCM), which enables in situ real-time monitoring of both
the binding of ligase and ligation reaction on DNA strands, as mass changes.
PMID- 10780421
TI - Recognition control of the nucleic acid model through conformational switching of
nucleobase induced by borate ester formation of cis-2',3'-diol.
AB - A novel nucleic acid model that possessed 5'-amino-5'-deoxyuridine at alpha- and
gamma-position of L-glutamic acid through amide linkage using 5'-amino group was
synthesized and the conformation and the hybridization properties were studied.
The complex of alpha-PRNA with complementary DNA/RNA was more stable than the
corresponding natural duplex in the absence of borate. Its recognition ability
was however lost when borax was added to the solution.
PMID- 10780423
TI - DNA coated with cationic fullerene derivative. A possible microwire in water.
AB - Fullerene derivative 2 carrying pyridinium cation bound to sonicated calf thymus
DNA in water. The binding ratio was 1 fullerene unit to 1 phosphate residue,
giving the complex where DNA strand is seemingly coated with electron-conducting
fullerenes. Cyclic voltammetry shows three-step redox couples in the complex, and
the current peaks were broadened and shifted to positive side as compared to
uncomplexed 2. Binding of 2 onto grooves of DNA double helix was suggested.
PMID- 10780424
TI - Ultra-high resolution DNA structures.
AB - This paper describes the progress in our efforts at producing ultra-high
resolution (< 0.8 A) DNA structures using advanced cryo-crystallography and
synchrotron. Our work is aimed at providing reliable geometric (bond length and
bond angle), electronic and motional information of DNA molecules in different
conformational contexts. These highly-reliable, new structures will be the basis
for constructing better DNA force-field parameters, which will benefit the
structural refinement of DNA, protein-DNA complexes, and ligand-DNA complexes.
PMID- 10780425
TI - Comparison of the efficiency of various coupling systems in the acylation of
model secondary amines with thymin-1-ylacetic acid.
AB - Peptide nucleic acids (PNAs) make a promising group of DNA analogues. The
backbone of typical PNA oligomers is composed of N-(2-aminoethyl)glycine units,
linked by the peptide bonds. The backbone secondary amine groups are acylated
with carboxyalkyl derivatives of nucleobases. One of the PNA synthesis step
causing some problems is the acylation of the monomer backbone with the
nucleobase derivatives. The aim of the study was to compare the efficiency of
various coupling systems in the acylation. Simple model compounds (piperidine and
proline) were used, as well as equimolar amounts of the coupling reagents.
Selected systems based on carbodiimides, aminium or phosphonium salts, mixed
anhydride, and active esters were tested.
PMID- 10780426
TI - Formation of 8-nitroguanine from 2'-deoxyguanosine by NO/O2 system.
AB - We investigated the reaction of 2'-deoxyguanosine (dGuo) with NO/O2 gas mixture
under physiological condition and detected 8-nitroguanine, which is known as a
novel DNA lesion caused by peroxynitrite (ONOO-). The yield increased with
increase in the ratio of O2 and pH. The reaction mechanism is discussed.
PMID- 10780427
TI - The relationship between metal-metal distance of two metal ions chelated complex
and RNA cleavage activity.
AB - We prepared a series of ligands possessing two binding sites for metal
coordination: in each ligand molecule, two binding sites with the same
functionality (2,2'-dipicolylamino group) were placed at the of various methyl
arenes. Thus, the distances between the metal binding sites were different from
ligand to ligand. We examined the rate of the hydrolysis of RNA dimer catalyzed
by La3+ ion binuclear complexes of the ligands. The catalytic activity of the
binuclear complexes increased as the distance between the metal binding sites was
decreased.
PMID- 10780428
TI - An efficient method for the synthesis of [2-(15)N]guanosine and 2'-deoxy[2
(15)N]guanosine derivatives.
AB - Nucleophilic substitution reaction of 6-chloro-2-fluoro-9-beta-D-ribofuranosyl-9H
purine derivative, prepared from guanosine, with potassium [15N]phthalimide at 40
degrees C for 9 h in DMF, followed by hydrolysis, afforded [2-(15)N]guanosine
derivative efficiently. The corresponding 2'-deoxy derivative was also
synthesized through a similar procedure.
PMID- 10780429
TI - Synthesis and properties of oligonucleotides containing 2'-O-methyl-2
thiouridine.
AB - New methods to synthesize 2'-O-methyl-2-thiouridine and its phosphoramidite
building block for incorporation into oligonucleotides were developed.
Oligonucleotides containing 2'-O-methyl-2-thiouridine were expected to be
favorable as antisense agents in several respects, i.e., nuclease resistance,
stable RNA duplex formation, and exact base recognition. Therefore, to make them
clear, we synthesized oligonucleotides having 2'-O-methyl-2-thiouridine and
analyzed their properties in detail.
PMID- 10780430
TI - Synthesis and properties of novel antisense oligonucleotides bearing an
anthraquinone moiety at an internucleotide linkage.
AB - Antisense oligonucleotides bearing an anthraquinone moiety at an internucleotide
linkage were synthesized utilizing the stereoisomers of anthraquinone
incorporated T-C dimer phosphoramidite derivatives. Some physicochemical
properties of the anthraquinon bearing oligomers were investigated.
PMID- 10780431
TI - Synthesis of telomere-mimic carbocyclic 5'-nor oligodeoxynucleotides.
AB - Telomere-mimic S-ODNs have been synthesized and examined their effects on the
proliferation of human tumor cell lines by XTT assay. Furthermore, the guanosine
derivatives of carbocyclic 5'-nor nucleoside were synthesized.
PMID- 10780432
TI - Interaction of cationic alpha-helical peptide with phosphorothioate DNA hybrid.
AB - Synthetic amphiphilic alpha-helix peptides were found to bind to stabilize double
or triple stranded DNA. The stabilization effect was significant for cationic
alpha-helix peptides which indicated the importance of electrostatic interaction
of positive charge of peptide and negative charge of DNA. It should be also
pointed out that hybrid double or triple helical complexes containing
phosphorothioate oligonucleotide were stabilized to a larger extent respect to
phosphodiester oligonucleotides. Since it was shown that cationic amphiphilic
alpha-helix peptide accelerate membrane permeability of DNA, the present study
can provide a solution for the problems of antisense or triplex oligonucleotide
in their practical application.
PMID- 10780433
TI - Interaction of amphiphilic cyclic peptide with double and triple stranded DNA.
AB - It was found that Gramicidin S (GS) with intramolecular antiparallel beta-sheet
structure could bind to and thermally stabilize double and triple stranded DNA.
UV melting study revealed that GS stabilized mixed sequence dsDNA in the presence
of Mg2+ (deltaTm = +6.0) but it stabilized dsDNA with homosequence only in the
absence of Mg2+. It should be pointed out that GS specifically stabilized the
third strand (Hoogsteen base pair) but not double strand (Watson-Crick base pair)
in triple helix DNA.
PMID- 10780434
TI - Photoreactivity of 5-iodouracil-containing DNA-Sso7d complex.
AB - X-ray structure of DNA-Sso7d complex indicated that binding of this protein
causes sharp DNA bending. In order to examine whether this protein also causes
DNA bending in solution, photoreactions of 1U-substituted DNA in the presence and
the absence of Sso7d protein were investigated. It was found that the unusual
intrastrand hydrogen abstraction at methyl of adjacent thymine occurred
efficiently at the observed bending site of crystal structure.
PMID- 10780435
TI - DNA binding affinity of pentapeptides selected from combinatorial library.
AB - The combinatorial method has been applied to determine peptide ligands to the
duplex DNA by using the solid-state pentapeptide library and the target-DNA
conjugated magnetic beads. Seventy-one sequences were determined as ligands for
AT duplex. Interestingly, hydrophobic amino acids such as Phe, Ile and Gly were
most frequently determined. Relative binding affinity of the selected
pentapeptides with the various DNA sequences was estimated by ethidium
displacement assay in 10 mM SHE buffer. FQGII constituted of amino acids that
were most frequently determined in the random screening showed highest binding
affinity to the duplex DNA.
PMID- 10780436
TI - Construction of nonnatural DNA library.
AB - Nonnatural DNA polymerase substrates which contain many kinds of modified
functional groups are synthesized. The C-5 position of dUTP was modified by amino
acid, saccharide. These compounds were incorporated on a DNA double strand using
E. Coli DNA polymerase. This nonnatural DNA library contains a larger diversity
than native DNA or RNA and has a higher chemical stability than RNA. This library
will be useful for in vitro selection study, combinatorial chemistry, and the
preparation of supramolecular structures.
PMID- 10780437
TI - Extended in vitro selection for synthesis of novel molecular recognition
oligonucleotide derivatives.
AB - In vitro selection of RNA aptamer containing biotin-carrying nucleotide was
carried out used for development of a new type of molecular sensor. Cytidine 5'
triphosphate (CTP) carrying biotinyl group at the N6-position was used in this
technique. A pool of biotin-containing RNAs, which binds specifically to
adenosine 5'-triphosphate (ATP), was obtained and used for competitive binding
assay of ATP. The selected nonnatural RNA possesses many biotinyl groups to
render it a high sensitivity toward ATP.
PMID- 10780438
TI - Combinatorial approach to development of peptides that recognize DNA tetraloops.
AB - We report recognition system for DNA tetraloops (dA1G2G3C4T5T6C7G8G9C10C11T12
(core) and dAGGCTTCGGCCT (AP2); X = abasic nucleotide) by peptides selected with
combinatorial chemistry. As a result, peptides with Thr/Glu/His and Gln/Asp were
obtained in binding of DNA core and AP2, respectively.
PMID- 10780439
TI - DNA hybridization sensor utilizing [Os(5,6-dmphen)3]2+ by square wave
voltammetry.
AB - DNA hybridization detection utilizing [Os(5,6-dmphen)3]2+ (tris(5,6-dimethyl
phenanthroline) osmium(II/III)) as hybridization indicator was studied, because
[Os(5,6-dmphen)3]2+ has the most largest association constant (K2+) and high
current density in osmium methyl substituted phenanthroline complexes. As the
result, target DNA could be detected selectively ranging from 6.9 x 10(-10) to
6.9 x 10(-5) g/mL using square wave voltammetry.
PMID- 10780440
TI - Metal ion-directed DNA recognition by chelating DNA ligands.
AB - Novel DNA ligand bearing oxine and pyridinium group has been synthesized. The DNA
binding of this ligand was regulated by coexisting Cu2+ over the range of more
than three orders in magnitude of binding constant. This should be due to the
metal-mediated dimerization of the ligand and concomitant emergence of cationic
charges. There were definite two DNA binding modes for the ligand dimer depending
on the P/L ratio.
PMID- 10780441
TI - Highly sensitive detection of target gene by electrochemical method.
AB - A highly sensitive DNA sensing method was developed using electrochemically
active ligand. This method is based on the detection of electric current
generated by electrochemically active ligand concentrated on the electrode.
Electrochemically active, intercalating ligand can bind to the double stranded
DNA of target gene sequence on the electrode, where the complementary single
strand is immobilized as a probe. We succeeded in the detection of 0.1 amol
target gene. The technique was applicable to the detection of 0.1-10 amol gene.
PMID- 10780442
TI - Structural analysis of the complex of a distamycin analogue with the Dickerson
dodecamer 13C labeled at 5'-carbons using NMR spectroscopy.
AB - Structural analysis of the complex of a distamycin analogue (Tallimustine) with
the Dickerson dodecamer d(C*G*C*G*A*A*T*T*C*G*C*G) [N*:[5'-(13)C]nucleotide] was
performed by NMR spectroscopy and the results will be described in detail.
PMID- 10780443
TI - Conformational classification of functional nucleic acids.
AB - The kink parameters would provide the tolerant aspect for irregular helical
structure of nucleic acid. Using these kink parameters, the classification of
conformation space was carried for the functional nucleic acid molecules. The
kink parameters could afford us the simple structural aspects about the
constructive parts of functional molecules. Local elastic kink phenomena can be
classified by rod like models with the combination of kink parameters. The
constructive parts, such as the stable tetra nucleotides loop, U-turn
conformation and adenosine platform, were selected and the statistical analyses
were carried on the parameters calculated by program BIOCON.
PMID- 10780444
TI - The guanosine binding mechanism of the Tetrahymena group I intron.
AB - The Tetrahymena group I intron catalyzes self-splicing through two consecutive
transesterification reactions, using a single guanosine-binding site (GBS). In
this study, we constructed a model RNA that contains the GBS and a conserved
guanosine nucleotide at the 3'-terminus of the intron (omegaG). We determined by
NMR the solution structure of this model RNA, and revealed the guanosine binding
mechanism of the group I intron. The G22 residue, corresponding to omegaG,
participates in a base triple, G22 xx G3 x C12, hydrogen-bonding to the major
groove edge of the Watson-Crick G3 x C12 pair. The G22 residue also interacts
with A2, which is semi-conserved in all sequenced group I introns.
PMID- 10780445
TI - In situ monitoring of peptide-bound dsDNA selection on a GCN4-bZIP-immobilized
quartz-crystal microbalance.
AB - A highly sensitive 27 MHz quartz-crystal microbalance (QCM) was applied as a
device of dsDNA in vitro selection. When GCN4-bZIP peptides were immobilized on
the small Au electrode of the QCM, dsDNAs having TGACTCA sequences could be
mainly selected from DNA library having a 15-bp random region, which was
consistent with the sequence observed by X-ray crystallography.
PMID- 10780447
TI - Recognition and cleavage of double-stranded DNA by yeast VMA1-derived
endonuclease.
AB - DNA endonuclease derived from the yeast VMA1-gene product recognizes and cleaves
31 base-pairs of double-stranded DNA (dsDNA). Mixtures of the endonuclease (VDE)
with a full DNA substrate consisting of 34 base-pairs, with nicked substrates
each having a nick in either DNA chain, and with cleaved substrates each having a
cleaved-off chain are prepared. Molecular weights (MWs) of eluted peaks from gel
filtration columns were estimated from elution profiles in the presence of Mg2+
ions. Each mixture exhibited an elute peak at about 63k MW, larger than the MW of
VDE unbound to dsDNA. This indicates that VDE and dsDNA substrates form stable
complexes. The mixture of VDE either with the full substrate or with the nicked
substrate having a nick in the anti-sense chain eluted an additional 25k-MW peak,
which presumably corresponds to a cleaved product. The complex of VDE with the
full substrate was eluted at 62k-MW location in the absence of Mg2+ ions and
yielded a single crystal. Stable complexes of VDE either with the dsDNA
substrates or with the cleaved products are obtainable.
PMID- 10780446
TI - Abasic site recognition mechanism by the Escherichia coli exonuclease III.
AB - In order to elucidate the mechanism of AP site recognition by Echerichia coli
exonuclease III (exoIII), site-directed mutagenesis of the Tyr109, the Trp212,
and the Phe213 residues, which were conserved in the type II AP endonuclease from
various organisms and located in the vicinity of the catalytic site, was
performed. The exoIII-W212S mutant lacked any detectable AP endonuclease activity
and binding ability to the duplex DNA containing an AP site, while the exoIII
Y109S and exoIII-F213W mutants retained a low level of activities (13% and 83%,
respectively, compared with wild-type exoIII). This study suggests that the
Trp212 is an important component for abasic site recognition by the E. coli
exonuclease III.
PMID- 10780448
TI - The functional analysis of 4.5S RNA in ribosomal translocation.
AB - 4.5S RNA is a stable 114-nucleotide RNA of the bacterium Escherichia coli (E.
coli). We found that 4.5S RNA have the ability of binding EF-G using gel mobility
shift assay. Increasing in the concentration of GDP increase the binding activity
of 4.5S RNA to EF-G. Based on these data, we propose that 4.5S RNA release EF-G
from ribosome.
PMID- 10780449
TI - A role of the C-terminal region adjacent to the zinc-fingers in the DNA binding
ability of Rme1p, a regulator of meiosis in S. cerevisiae.
AB - Rme1p is a zinc-finger protein and has a pivotal role in control of meiosis in
Saccharomyces cerevisiae. The DNA binding domain of Rme1p consists of three zinc
finger segments and the C-terminal 16 amino acid residues (called C-TR). To
examine the role of C-TR, a series of mutant Rme1p fused with maltose binding
protein (MBP) were constructed, purified, and characterized, in terms of the DNA
binding ability. The basic amino acid residues R287 and K290, and the hydrophobic
residues F288, L292, 1295, and L296 play an important role for DNA binding,
suggesting that the C-TR forms an amphipathic alpha-helix. Also, it was shown
that the mutations in the basic amino acid residues abolish the repression and
inhibition of spore formation by Rme1p in vivo. Hence, the C-TR is important for
in vivo function of Rme1p.
PMID- 10780450
TI - NMR signal assignment of the polyuridine tract of the single-stranded RNA
complexed with Sxl RBD1-RBD2 by using residue selective [5-(2)H]uridine
substitutions.
AB - Using [5-(2)H]uridine phosphoramidite, we synthesized a series of 2H-labeled
Drosophila Sex-lethal (Sxl) target RNAs, in which all the uridine residues except
one were specifically replaced by [5-(2)H]uridine. By observing the H5-H6 cross
peaks of RNA in the TOCSY spectra, we unambiguously assigned all the base proton
resonances of the target RNA in a Sxl x RNA complex. Furthermore, it was shown
that Sxl differently recognizes A and G in a position prior to the polyuridine
tract.
PMID- 10780451
TI - Inhibitory effects of of L-2'-deoxyguanosine 5'-triphosphate (L-dGTP) and L-2'
deoxythymidine 5'-triphosphate (L-dTTP) on human telomerase.
AB - Telomerase, which synthesizes telomeric DNA in eukaryotic cells, is classified as
a reverse transcriptase. To clarify the recognition of 2'-deoxyribonucleoside 5'
triphosphate (dNTP) chirality by telomerase, we studied the inhibitory effects of
L-dGTP on HeLa cell telomerase activity using a quantitative 'stretch PCR' assay.
L-dGTP had a weakly inhibitory effect (IC50 = 200 microM) in the presence of 10
microM dGTP. This effect was less obvious when the concentration of dGTP was
higher. L-dTTP had a similar inhibitory effect. These findings suggest that
telomerase may bind to L-dGTP and L-dTTP, and that the ability of telomerase to
bind to dGTP or dTTP is changed.
PMID- 10780452
TI - Ubiquitination of the transcriptional coactivator p300 during retinic acid
induced differentiation.
AB - Transcriptional coactivator p300 plays an important role in differentiation
processes of various cell lines. In this report, we examined levels of p300
protein and the related protein, CREB binding protein (CBP), during the retinoic
acid (RA)-induced differentiation of F9 cell. As a result, the level of p300
protein began to decrease at 36 h after treatment with RA dramatically, however,
the level of CBP protein did not alter. Moreover, ubiquitinated p300 protein was
only detected in differentiated F9 cells. These results suggest that p300 protein
is possibly degraded via the ubiquitin-dependent pathway during the RA-induced
differentiation of F9 cells.
PMID- 10780453
TI - Search for a selenocysteine tRNA in Bacillus subtilis.
AB - Activity to convert serine to selenocysteine in B. subtilis was studied but no
activity was detected. In addition, although we tried to find its selenocysteine
tRNA (tRNA(SeCys)) gene from a total genome sequence (1) by the computer search
with FASTA against E. coli selC (2), no convincing candidate was found. These
results suggest that in B. subtilis, selenium-related system is considerably
different from known one like E. coli.
PMID- 10780454
TI - Relationship of the CCA sequence of tRNA with the early evolutional aspect of
aminoacyl-tRNA synthetases.
AB - The CCA sequence is common to the 3'-ends of all tRNAs. We investigated the
requirement of the CCA sequence in aminoacylation with the cognate aminoacyl-tRNA
synthetases (aaRSs) and several interesting conclusions could be drawn. In tRNAs
belonging to the class I aaRSs, decreased aminoacylation activities resulted from
the substitution of A76 with a pyrimidine, whereas in tRNAs belonging to the
class II aaRSs, decreased aminoacylation activities resulted from the
substitution with guanine. The results suggest that aminoacylation of proto-tRNA
might have started through the direct hydrophobic (or stacking) interaction
between the large, hydrophobic amino acid residue (now utilizing a class I aaRS)
of aminoacyl-AMP and the 3'-terminal adenine. The shorter distance between the
adenine and the 2'-OH position than the 3'-OH position, and the bulkiness and
hydrophobicity of amino acids may be important reasons why class I aaRSs select
the 2'-OH position in aminoacylation. Molecular mechanics-based conformation
modeling also indicated that the resulting positioning of the adenine and the
amino acid residue of 2'-aminoacyl-adenosine for large amino acid is in the
vicinity. In contrast, in the case of small amino acids (with class II aaRSs)
which would not be able to use the hydrophobic interaction, a protein enzyme
might have participated in the aminoacylation reaction from an early stage. The
active-site folds of aaRSs belonging to each class reflect the history of
evolution: typical nucleotide-binding fold (Rossman fold) in the case of class I
aaRSs, and primitive fold which is found also among the family of nonribosomal
peptide synthetases in the case of class II aaRSs.
PMID- 10780455
TI - In vivo selection of RNA-binding peptides from combinatorial libraries.
AB - We have used a two step procedure to identify peptides that bind strongly to the
Rev-response element (RRE) of HIV. In the first step, RRE-binding peptides were
screened from a combinatorial peptide library generated by "randomization" using
a small subset of the 20 amino acids. In the second step, one such RRE-binding
peptide, RSG-1, was "evolved" into an even stronger RRE-binding peptide using a
codon-based mutagenesis procedure. After 2 rounds of evolution, RSG-1.2 bound the
RRE with 7-fold higher affinity than wild-type Rev peptide.
PMID- 10780456
TI - Specific RNA protease inhibitors from in vitro selection.
AB - RNA aptamers that bind to and inhibit the proteolytic activity of subtilisin BPN'
are selected in vitro from pools of random RNA. The RNAs in vitro transcribed
from the isolated clones show highly specific inhibition toward the microbial
serine proteases. From the sequences of the isolated clones, a C/A-rich sequence
was obtained. The kinetic features of the common C/A-rich sequence will be
discussed.
PMID- 10780458
TI - Probing of the secondary structure of maxizymes.
AB - The protein encoded by chimeric BCR-ABL mRNA causes chronic myelogenous leukemia
(CML). We showed previously that a novel allosterically controllable ribozyme, of
the type known as a maxizyme, can cleave this mRNA, with high specificity and
high-level activity in vivo. In order to probe the putative conformational
changes, we used a weakly alkaline solution to hydrolyze differentially
phosphodiester bonds that were located in different environments. As indicated by
earlier data obtained in vivo, our results demonstrated that the active
conformation was achieved only in the presence of the junction within the
chimeric BCR-ABL mRNA.
PMID- 10780457
TI - Comparative study of two ribozymes and DNA-enzyme against the same RNA target.
AB - Two ribozymes, hammerhead ribozyme and hairpin ribozyme, and a DNA-enzyme were
designed to cleave a same RNA target, the same site of the rat complement
regulatory factor 512 antigen mRNA. The kinetic properties of these RNA-cleaving
enzymes were measured and compared under the same conditions, using multiple
turnover kinetics and competition kinetics. The catalytic efficiencies of these
enzymes, and also the order of these enzymes will be discussed.
PMID- 10780459
TI - Design and NMR analysis of HDV ribozymes for structural investigation.
AB - Three variants of minimized hepatitis delta virus (HDV) RNA ribozyme systems (Rz
1 to approximately Rz-3) (Fig. 1) were designed on the basis of the "pseudoknot"
structure model and synthesized. Rz-1 is a cis-acting ribozyme system (a cleaved
form, 56-mer) in which stem IV is deleted from the active domain of genomic HDV
RNA. Rz-1 was uniformly labeled with stable isotopes, 13C and 15N. The 2D-NOESY
and 2D-HSQC data for Rz-1 suggest that Rz-1 forms the pseudoknot structure and
G38 which is opposite to the cleavage site makes a base-pair. Rz-2 is a trans
acting ribozyme system which consists of three RNA oligomer strands (substrate: 8
mer, the cytidine residue at the cleavage site is replaced by 2'-O
methylcytidine; enzyme: 16-mer plus 35-mer). Rz-3 is a ribozyme in which the
three RNA strands of Rz-2 are connected. It turns out that Rz-3 forms an inactive
structure with low cleavage activity (k(obs) = 0.009) and final cleavage yield
(6%). Rz-3 has the highest cleavage activity at pH 5.5. The optimal activity at
acidic pH is similar to that of the wild type ribozyme. We also synthesized and
examined the activity and structure of Rz-4 (designed by Perrotta and Been) which
consists of two RNA strands (1).
PMID- 10780460
TI - Photodynamic antisense regulation using psoralen-conjugated oligo(nucleoside
phosphorothioate)s (I). Growth regulation of cervical carcinoma cells.
AB - To increase the antisense regulatory effect of oligo(nucleoside
phosphorothioate)s (S-Oligo), a photo-crosslinking reagent, 4, 5', 8
trimethylpsoralen, was used in this study. Psoralen-conjugated oligo(nucleoside
phosphorothioate) (Ps-S-Oligo) complementary to the human papillomavirus type 18
(HPV18) mRNA drastically inhibited the cellular proliferation of cervical cancer
cells only upon UVA-irradiation. In contrast, Ps-S-Oligos with mismatched
sequences and scrambled one showed lesser inhibitory effects than that with
matched one. These results suggest that psoralen-conjugated antisense S-Oligo has
significant potential to regulate gene expression upon UVA-irradiation.
PMID- 10780461
TI - Properties of circular dumbbell RNA/DNA chimeric oligonucleotides containing
antisense phosphodiester oligonucleotides.
AB - We have designed a new class of oligonucleotides, "dumbbell RNA/DNA chimeric
phosphodiesters", containing two alkyl loop structures with RNA/DNA base pairs
(sense (RNA) and antisense (DNA) in the double helical stem. The reaction of
nicked (NDRDON) and circular (CDRDON) dumbbell RNA/DNA chimeric oligonucleotides
with RNaseH gave the corresponding antisense phosphodiester oligonucleotide
together with the sense RNA cleavage products. The liberated antisense
phosphodiester oligodeoxynucleotide was bound to the target 35mer RNA, which gave
35mer RNA cleavage products by treatment with RNaseH. The circular dumbbell
RNA/DNA chimeric oligonucleotide showed more nuclease resistance than the linear
antisense phosphodiester oligodeoxynucleotide(anti-ODN) and the nicked dumbbell
RNA/DNA chimeric oligonucleotide.
PMID- 10780462
TI - Phosphorothioate G3T4G3 motifs inhibits the early stage of HIV-1 infection.
AB - It is well known that G-rich phosphorothioate oligonucleotides (G-rich PS) bind
to the V3 loop of HIV-1 gp120 and inhibit HIV-1 infection. In this study, we
investigated the inhibitory mechanism of a new type of G-rich PS (PS-G3T4G3) on
the replication cycle of HIV-1. PS-G3T4G3 inhibits both cell to cell and cell
free infections. Binding and entry assays revealed that the inhibitory step of PS
G3T4G3 occurs at the early stage of HIV-1 infection. V3 loop-specific mAb test
showed that PS-G3T4G3 binds to the V3 loop and prevents its interaction with
chemokine receptors. These results suggest that PS-G3T4G3 may be a novel
candidate for an HIV-1 inhibitor.
PMID- 10780463
TI - Synthesis and properties of oligodeoxynucleotides containing a C-2 polyamine
bearing deoxyguanosine residue as artificial ribonuclease.
AB - Oligodeoxynucleotides containing a 2-fluoro-2'-deoxyinosine residue substituting
normal 2'-deoxyguanosine residue were synthesized. Upon treating with ethanol
solution of polyamine, the fluorine atom in the oligomers were readily
substituted with the polyamine. The thermal stabilities of the duplexes consisted
of the polyamine-bearing oligomers and their cDNAs as well as their RNA cleaving
activity were investigated.
PMID- 10780464
TI - Improvement of efficiency of the Ce(IV)-induced DNA scission--relationship
between the kinetic parameters (k(cat) and Km) and the DNA structure.
AB - The Michaelis constant (Km) for double-stranded DNA, single-stranded DNA, and
dinucleotide hydrolysis by Ce(IV) ion are 4.4, 15, and more than 40 mM,
respectively. The order of the k(cat), however, is dinucleotide >>
oligonucleotides. Not only the improvement of k(cat) but also that of Km is
important for the design of an efficient artificial nuclease.
PMID- 10780465
TI - Development of a system to classify 3D structural character of RNA.
AB - We are developing a computational system to extract structural character of RNA.
We made a program that classifies conformers by recognizing the hydrogen bonding
patterns. The program was applied to a set of 279 conformers and they were
classified into about 40 groups. The system is expected to be useful for
searching structural motifs of RNA and classifying large number of generated
conformers in structural modeling process.
PMID- 10780466
TI - Imaging the RecA-DNA complex by atomic force microscopy.
AB - Atomic force microscopy (AFM) was applied to study the RecA protein and its
complexes with DNA in air and in aqueous solution. RecA and DNA were reacted
under several conditions, and deposited onto a mica substrate pre-treated in
various ways. We found that the structure of the RecA and RecA-DNA complexes,
especially the height of the molecules, was affected by the sample preparation
method such as gel filtration, and environment during imaging.
PMID- 10780467
TI - In vitro selection of deoxyribozymes with DNA capping activity.
AB - In vitro selection was used to isolate a series of deoxyribozymes from a pool of
random-sequence DNAs that catalyze an ATP-dependent self-capping reaction. Each
deoxyribozyme catalyzes the transfer of the nucleoside and alpha-phosphate
moieties of ATP to the phosphate group located at its 5' terminus, thereby
creating a 5',5'-pyrophosphate cap. This same pyrophosphate cap structure is
formed by T4 DNA ligase during the classical process of DNA ligation. These DNA
capping enzymes representative of a collection of self-processing deoxyribozymes
that can be used for the directed modification of DNA.
PMID- 10780468
TI - Rapid and specific detection of RNA base sequence using fluorescence
polarization.
AB - Rapid and specific determination of the RNA gene of hepatitis C virus (HCV),
which had been multiplied by NASBA, was performed using a fluorescence
polarization assay. The polarization of the probe DNA in the presence of HCV
positive sample, amplified by NASBA, was obviously different from those in the
presence of negative control samples. The total time for the gene amplification
and detection was about 90 min, while the polarization detection was completed
within 10 min. The slight increase of polarization was also confirmed with the
hybridization between probe oligo-DNA 25-mers and the synthesized complementary
oligo-RNA 25-mers. The polarization of positive and negative samples showed
excellent agreement with the results obtained from electrophoresis and dot-blot
hybridization.
PMID- 10780469
TI - Efficiency enhancement of long-range energy transfer by sequential multistep FRET
using fluorescence labeled DNA.
AB - The efficiency of long-range (ca. 80 A) fluorescence energy transfer was enhanced
about 1.5 times by a third chromophore located midway between two chromophores. A
third chromophore should act like a relay station in sequential multistep energy
transfer.
PMID- 10780470
TI - Single large DNA molecule analysis using fluorescence microscopy.
AB - A large DNA analysis method which enable to obtain spatial information of
positions of specific sequences along DNA molecule has been developed. Making use
of the phenomenon that large DNA molecule is elongated stably under alternative
current field in a concentrated linear polymer solution, direct observation of
elongated individual lambda DNA molecules with fluorescence probes was carried
out using fluorescence microscopy. Then, the spatial positions of the
fluorescence spot of the probe on the DNA molecule were determined by image
analysis.
PMID- 10780472
TI - Synthesis and DNA-binding of acridine-netropsin hybrid molecules.
AB - We have designed and synthesized acridine-netropsin hybrid molecules.
Spectroscopic (absorption, CD, flow dichroism and fluorescence) measurements
reveal that hybrid molecules interact with DNA by both intercalation and minor
groove binding and shows enhanced preference for AT-rich sites.
PMID- 10780471
TI - Direct measurement of DNA by means of AFM.
AB - We have demonstrated that the electrostatic stretch-and-positioning method is
useful for the analysis of a long DNA molecule by means of atomic force
microscopy (AFM). DNA molecules were stretched parallel to the field line, and
immobilized onto the aluminum electrodes patterned on a glass plate. Through AFM
observation, we confirmed the immobilization of individual DNA molecules, not
aggregate.
PMID- 10780473
TI - Synthesis of pyrrole-imidazole-duocarmycin polyamide and its sequence selective
DNA alkylation.
AB - The new solid phase synthesis of sequence-specific DNA alkylating polyamides
containing segment A of Du86 (Duo), N-methylimidazole (Im) and N-methylpyrrole
(Py) amino acids is described. New monomer building block N-carboxylmethyl Py
(Pyc) was synthesized from 2-methylpyrrolecarboxylate by eight steps. After
normal coupling of FMOC-protected-Im and -Py monomer, the deprotection of silyl
group generates free carboxylic acid. Introduction of various types of functional
groups on solid support will be presented.
PMID- 10780474
TI - Novel DNA-binding ligands with sequence selectivity based on hydrophobic
structure.
AB - We have developed diamino-bistetrahydrofuran compounds (diamino-bisTHF) as new
DNA binding molecules. Diamino-bisTHF (3:RR8) stabilized GC-rich duplex DNA with
sequence specificity. DNA binding affinity increased as the alkyl chain was
lengthened, indicating that the hydrophobic interaction is essential for DNA
binding. It was also found that DNA binding affinity of the ligands depends on
the stereochemistry of the amino group. In thermodynamic evaluation, diamino
bisTHF (3:RR8) showed a high affinity to the 12 bp duplex at a molar ratio of
1:1.
PMID- 10780476
TI - Novel GG-specific DNA photocleavers: p-cyanobenzamide-terthiazole derivatives.
AB - We have synthesized novel GG-selective photocleavers containing the p
cyanobenzamide group which exerts DNA cleaving activity via a thiazole based
multistep electron transfer.
PMID- 10780475
TI - Amplification of bleomycin-induced DNA cleavage by pyrrole triamide.
AB - We investigated the amplification of bleomycin-induced DNA cleavage by synthetic
pyrrole triamide (PyPyPy) using 32P-labeled DNA fragments obtained from human
genes. Peplomycin, a kind of bleomycins, plus Fe(II) caused DNA cleavage at the
5'-GC-3' and 5'-GT-3' sequences (damaged bases are underlined). The addition of
PyPyPy enhanced the cleavage at cytosine and thymine residues 3' to consecutive
guanines, particularly at the 5'-GGGGC-3' and 5'-GGGGT-3' sequences. These
results suggest that PyPyPy binds to DNA to induce its conformational change,
resulting in alteration of the site specificity and amplification of DNA
cleavage. The present study on amplifiers of antitumor drugs would show a novel
approach to the establishment of more effective chemotherapy.
PMID- 10780477
TI - Mechanism of ribosome RNA apurinic site specific lyase.
AB - A new enzyme, which we named ribosome RNA apurinic site specific lyase (RALyase),
has been characterized. The enzyme specifically cleaves a phosphodiester bond at
the apurinic site in the sarcin/ricin domain of 28S rRNA in ribosomes. The cut
ends of wheat 28S rRNA were determined as 5'---GUACG-alpha-hydroxy-alpha, beta
unsaturated aldehyde and pGAGGA---3' for the 3' fragment, demonstrating that the
enzyme catalyzes the beta-elimination reaction.
PMID- 10780478
TI - Drosophila tRNAs hyperprocessed in vitro by ribonuclease P.
AB - In transposon copia-related retrovirus-like particles of Drosophila, a 5' half
fragment produced by the cleavage of mature initiator methionine tRNA is used as
the primer for minus-strand reverse transcription. This cleavage is called
hyperprocessing. We have previously reported that the catalytic RNA subunit of
RNase P catalyzes this hyperprocessing in vitro and that this cleavage is
dependent on the occurrence of an altered conformation of the tRNA substrate.
Here, we found that other mature tRNAs of Drosophila were also hyperprocessed by
M1 RNA in vitro and that some of such tRNAs were probably alanine and histidine
tRNAs. Here we report these two tRNAs can also adopt their alternative
conformations very similar to that of initiator methionine tRNA.
PMID- 10780479
TI - Molecular cloning and characterization of a nuclear gene encoding a putative
subunit of tRNA splicing endonuclease from Arabidopsis thaliana.
AB - tRNA splicing endonuclease is required to produce mature tRNAs from intron
containing tRNA precursors. To characterize the structural features of plant
endonuclease, we have isolated a cDNA and a corresponding genomic DNA clone from
libraries of Arabidopsis thaliana which encode a putative subunit of the
endonuclease. The gene product has an apparent mass of 27 kDa and contains a
homologous domain of approximately 130 amino acids at the C-terminal region
commonly found in other eucaryal and archaeal counterparts. Southern
hybridization analysis of Arabidopsis genomic DNA utilizing the cDNA clone as
probe indicates the presence of at least two related genes.
PMID- 10780480
TI - Functional analysis of the transcriptional coactivators p300 and CBP using
ribozyme.
AB - p300 and CERB binding protein (CBP) are transcriptional coactivator which
participate many signal transduction pathways via interaction with DNA binding
proteins. In this study, we investigated functions of p300 and CBP during the
retinoic acid (RA) induced F9 cell differentiation using hammerhead ribozymes. In
wild type F9 cells, induction of c-jun gene was observed at 18 h after treatment
with RA. Interestingly, RA-dependent expression of c-jun gene was not induced in
cells expressing the p300-directed ribozyme. By contrast, the CBP-directed
ribozyme did not affect expression of the c-jun gene. These results suggest that
p300 is critical for the induction of c-jun gene during RA-induced
differentiation.
PMID- 10780481
TI - DNA structures recognized by the human UV-DDB protein.
AB - DNA recognition by the human UV-damaged DNA-binding (UV-DDB) protein was
characterized. By circular permutation analyses, DNA duplexes containing the (6
4) photoproduct and the abasic site analog were found to be bent at angles of 54
degrees and 57 degrees, respectively, when they formed a complex with this
protein. Although kinked NMR structures have been reported, fluorescence
resonance energy transfer experiments revealed that these duplexes had no
intrinsic bend. These results suggest that the UV-DDB protein binds DNA that can
be bent easily at the above angle.
PMID- 10780482
TI - Crystal structures of the 64M-2 and 64M-3 antibody Fabs complexed with DNA (6-4)
photoproducts.
AB - Crystal structures of the 64M-2 antibody Fab fragment complexed with DNA
photoproducts of dT(6-4)T and dTT(6-4)TT, and of the 64M-3 Fab fragment complexed
with dT(6-4)T were determined. The 5'-thymine base of the bound dT(6-4)T ligand
is in a half-chair conformation, and its base plane is nearly perpendicular to
the planar 3'-pyrimidone base. The 64M-2 and 64M-3 Fabs have a common structure
suitable for accommodating the dT(6-4)T ligand. In each of the antigen binding
sites of the 64M-2 and 64M-3 Fabs, basic residues of His 35H and Arg 95H are
located at the bottom of the binding pocket, and are hydrogen-bonded to the base
moieties of dT(6-4)T. Two water molecules are involved in the interactions that
intervene between the base moieties and the binding site. Aromatic residues of
Trp 33H and Tyr 100iH form a side-wall of the pocket and are in van der Waals
interactions with the base moieties. The Trp 33H side-chain is placed in parallel
to the 3'-pyrimidone base, and the Tyr 100iH side-chain is nearly perpendicular
to the 5'-thymine base. His 27dL, Tyr 32L, Leu 93L, and Ser 58H forming another
side-wall are located in the vicinity of the sugar-phosphate backbone. In the 64M
2 Fab complex with dTT(6-4)TT, 5'- and 3'-side phosphate groups are also involved
in interaction with Fab residues.
PMID- 10780483
TI - Structural study of an RNA aptamer for a Tat protein complexed with ligands.
AB - An RNA aptamer for an HIV Tat protein has been isolated by the in vitro SELEX
method. The RNA aptamer binds to the Tat protein 50-100 times more strongly than
native TAR RNA does. Here, we have investigated the structure of the RNA aptamer
complexed with ligands, partial peptide fragments of the Tat protein or
argininamide, by multidimensional 1H/13C/15N NMR. It is strongly suggested that
two U:A:U base triples are formed in the RNA aptamer upon binding of ligands.
Specific hydrogen bonds between arginine side chains of ligands and guanine bases
located adjacent to the base triples are identified. On the basis of many
intramolecular and intermolecular NOEs, a structural model of the complex has
been constructed.
PMID- 10780484
TI - Design of artificial pepetides that recognize the HIV RRE IIB RNA.
AB - Peptide nucleic acid (PNA) conjugated peptides, derived from HIV-1 Rev, were
designed and synthesized in order to construct molecules that recognize HIV RRE
IIB RNA. The competitive binding analyses using fluorescent Rev peptide revealed
that the PNA unit on the peptide affected the RNA binding.
PMID- 10780485
TI - The harpin ribozyme: the roles of ions in RNA cleavage.
AB - The cleavage reaction of the hairpin ribozyme is facilitated by divalent metal
ions, such as Mg2+, or by non-metallic polycations, such as the polyamine
spermine. We show substantial enhancement of cleavage with combinations of
metallic and non-metallic ions. In addition we elucidate the locations of some
ion binding sites by Fenton chemistry.
PMID- 10780486
TI - Allosteric ribozymes sensitive to the second messengers cAMP and cGMP.
AB - We have engineered allosteric ribozymes by combining modular rational design with
combinatorial strategies. This new procedure was used to create allosteric
ribozymes that are activated by specific nucleoside 3',5'-cyclic monophosphates
(cNMPs). A random-sequence domain was attached to stem II of hammerhead ribozymes
via a communication module that serves as an interface between ribozyme and the
effector binding site. Subjecting this initial random pool to in vitro selection
methods produced populations that respond, or cleave, only in the presence of
specific effector molecules. From generation 18, 20 and 23, cGMP, cCMP and cAMP
specific responsive ribozymes, respectively, were isolated and characterized.
These methods show great promise for engineering allosteric ribozymes and for
creating new ligand-specific aptamers.
PMID- 10780487
TI - Extended in vitro selection for synthesis of novel catalytic oligonucleotide
derivatives.
AB - A new catalyst, which is composed of nonnatural ribonucleotides, was synthesized
by the in vitro selection method. Nonnatural RNAs that bound to N
methylmesoporphyrin were selected from a pool of random-sequence RNAs containing
2'-amino cytidine 5'-triphosphate (2'-amino CTP) instead of CTP. The selected
RNAs not only bound to the ligand, N-methylmesoporphyrin (NMM), but also
catalyzed metalation reaction of porphyrin.
PMID- 10780488
TI - Induction of ribozyme activity by anti-ribozyme oligonucleotides.
AB - A new type of hammerhead ribozyme, with cleavage activity enhanced by
oligonucleotides, was constructed. Stem II of the ribozyme was substituted with a
non complementary loop (loop II). The modified ribozyme exhibited negligible
cleavage of a target RNA; however, it was converted to an active molecule in the
presence of oligonucleotides which were complementary to loop II. The
oligonucleotide compensated for the disabled stem II by binding with the
ribozyme. The induction of the cleavage activity was sequence-specific and the
oligonucleotides containing a purine base as the 3'-dangling end were able to
induce the cleavage activity of the ribozyme most efficiently. A photo
crosslinking experiment proved that a pseudo-half-knot structure was formed in
the active molecule. The cleavage of two kinds of substrate RNAs with different
sequences was controlled by the corresponding ribozymes activated by specific
oligonucleotides.
PMID- 10780489
TI - Development of a short Ca2+-dependent deoxyribozyme with RNA cleavage activity.
AB - We developed a short Ca2+-dependent deoxyribozyme with 11 mer catalytic loop
domain (dGGCTACAACGA) that catalyzed site-specific RNA cleavage reaction between
rA and rU. The second-order rate constant of this short deoxyribozyme is 1.7 x
10(7) M(-1) min(-1) at 37 degrees C, and this value is very similar to that of
the deoxyribozyme (dGGCTAGCTACAACGA) in the presence of Ca2+.
PMID- 10780490
TI - Action of metal ions directly involved in the cleavage reaction of hammerhead
ribozymes.
AB - Recently, hammerhead ribozyme-mediated cleavage was analyzed as a function of the
concentration of La3+ ions in the presence of a fixed concentration of Mg2+ ions
so that the role could be monitored of metal ions that are directly involved in
the cleavage reaction. The resultant bell-shaped curve for activation of cleavage
was used to support the proposed double-metal-ion mechanism of catalysis.
However, other studies demonstrated that binding of a metal ion to the pro-Rp
oxygen (P9 oxygen) of the phosphate moiety of nucleotide A9 and N7 of nucleotide
G10.1 is critical for efficient catalysis. In order to clarify the effect of this
metal ion, we chemically synthesized hammerhead ribozyme (7-deaza-R34) that
included a minimal modification, namely, an N7-deazaguanine residue in place of
G10.1.
PMID- 10780491
TI - Selection of intracellularly active ribozymes in mammalian cells.
AB - Ribozymes are expected to be useful as antiviral agents and powerful tools of
functional analysis of unknown gene products in vivo. For use of ribozymes in
vivo, they must be fully functional in the intracellular environment. Not all
ribozymes selected in vitro would be expected to work in vivo, whereas ribozymes
selected in the intracellular environment should retain their function in vivo.
With the eventual aim of using ribozymes as antiviral agents or biological tools
in mammalian cells, we then devised a novel selection system in mammalian cells
of active ribozymes by targeting at a gene for the cyclin dependent kinase
inhibitor (CDKI), p16INK4a. In this system, we found that p16INK4a-knockdown
cells became malignant and they formed foci. In the mammalian system, we
confirmed that the selected cells harbored the active ribozyme, indicating that
our positive selection systems in vivo were operational.
PMID- 10780492
TI - Importance of short pseudoknot base pairs between two single-stranded regions of
HDV ribozyme.
AB - Human hepatitis delta virus (HDV) ribozyme can catalyze self-cleavage reaction in
the presence of Mg2+ ions, yielding products with 2',3'-cyclic phosphate and 5'
OH termini as do hammerhead and hairpin ribozymes. Recently, the tertiary
structure of 3'-cleaved product of genomic HDV ribozyme was solved by X-ray
crystallographic analysis. In this structure three single-stranded regions (SSrA,
-B and -C) interacts intricately with hydrogen bonds between bases, phosphate
oxygens and 2'-OHs to form nested double pseudoknot structure. Especially two
Watson-Crick base pairs, 726G-710C and 727G-709C, between SSrA and SSrC, seems to
be important for compact folding. To characterize the necessity of the two base
pairs, we performed in vitro selection of active ribozymes using random RNA pool
which mutated at 709, 710, 726 and 727. The result indicates that basically one G
C base pair is necessary for the activity.
PMID- 10780493
TI - Measurement of the rate of RNA hydrolysis in aqueous solution at elevated
temperatures using a new monitoring method for hydrothermal reactions.
AB - A new monitoring method for hydrothermal reactions, which is capable to monitor
reactions in aqueous solution at 100-300 degrees C in 0.003-140 s, has been
applied for the measurements of the rate of hydrolysis of oligonucleotides
containing ribonucleic phosphodiester linkage. The hydrolyses of several types of
oligonucleotides were monitored using the method at over 100 degrees C.
PMID- 10780494
TI - Cellular repair mechanism of 5-formyluracil.
AB - 5-Formyluracil (fU) is an oxidative DNA base damage. This damage has been
suggested to be mutagenic and but enzymatic repair of the damage is little known.
In this study, repair enzymes that recognize fU have been studied. Kinetic
analysis of the repair activity of E. coli 3-methyladenine DNA glycosylase II
(AlkA) showed that fU was removed by AlkA with the efficiency comparable to 7
methylguanine. We also examined the participation of the methyl-directed mismatch
repair system. The affinity of MutS to the fU:G mispair was essentially similar
to that of the T:G mispair that was most efficiently recognized by the MutSLH
system. These results suggest two distinct repair pathways of fU in E. coli.
PMID- 10780495
TI - Nuclear localization of transcription factor Sp1.
AB - Transcription factor Sp1 is importantly related to expression of many cellular
genes. In order to identify the nuclear localization signal of Sp1, various
truncated regions of Sp1 were fused to green fluorescent protein (GFP) and were
expressed in HeLa cell. The C-terminal region are required to localize Sp1 in the
nucleus of HeLa cell.
PMID- 10780496
TI - Development of an HIV-1-dependent expression vector with the Cre/loxP system.
AB - Previously, we used the human methionine tRNA promoter as an expression cassette
for hammerhead ribozymes. The tRNA promoter driven ribozyme was targeted against
the LTR portion of the HIV-1 NL4-3 strain. We constructed VSV-G-pseudotyped MuLV
based vectors expressing the ribozyme. The ribozyme expressing retrovirus vector
strongly suppressed gag p24 antigen production in freshly HIV-1 infected MT-4
cells. In this study, the potential of such a molecular genetic intervention was
examined by using the Cre-loxP recombination system. Site-specific excision of
HIV-1 was achieved by using this model system with an acute infection. These
studies represent one step toward the development of a novel antiviral strategy
for the treatment of AIDS.
PMID- 10780497
TI - Inter-species consistency in the behavioural pharmacology of nicotine dependence.
AB - Studies on the dependence-related behavioural effects of nicotine in animals and
humans have been compared to assess the extent of inter-species consistency in
relation to the face, construct and predictive validity of the animal models. The
major areas covered in this selective review are neuroadaptations occurring as a
consequence of repeated exposures to nicotine (i.e. tolerance, sensitization and
withdrawal) and the stimulus properties of nicotine (positively reinforcing,
discriminative stimulus and aversive stimulus effects). Most of these phenomena
were demonstrated first in animal subjects, often many years before comparable
data for humans became available, although this was not invariably the case. It
is argued that the overall pattern of results for the neuroadaptations is very
similar across species. More specifically, it is proposed that repeated exposure
to nicotine produces a change from a relatively aversive initial overall profile
to one in which tolerance has developed to the aversive effects and the positive
effects on mood have been enhanced or sensitized; at the same time a withdrawal
syndrome develops that can now be assessed by a variety of measures in animal and
human subjects. With regard to stimulus properties, the nicotine discriminative
stimulus in animal and human subjects shows a particularly close correspondence,
which may reflect the functional equivalence of the procedures in the different
species. The self-administration of pure nicotine, as contrasted with tobacco
smoke, has been firmly established in animal subjects for some time but there are
only a small number of strictly comparable studies in humans. Both differences
and similarities in findings across species may be seen; however, care must be
taken to identify the possible confounding influence of procedural variation
between species, rather than the species per se, as the determining factor.
Overall, the animal studies in this area have shown remarkably good predictive
validity, coupled with rather more variable levels of face and construct
validity.
PMID- 10780498
TI - Implications for tobacco regulation and public health. Commentary on Stolerman's
Inter-species consistency in the behavioural pharmacology of nicotine dependence.
PMID- 10780499
TI - An anthology of behavioural pharmacology. Commentary on Stolerman's Inter-species
consistency in the behavioural pharmacology of nicotine dependence.
PMID- 10780500
TI - Molecular mechanisms of the positive reinforcing effect of nicotine.
AB - Animal models of nicotine dependence are fundamental experimental tools for the
understanding of the neurobiological and molecular processes underlying smoking
behaviour. Substance use is controlled by four main processes: positive
reinforcing effects, aversive effects, discriminative effects and stimulus
conditioned effects of the drug. In this article, the molecular and neural bases
of the positive reinforcing effects of nicotine are summarized, focusing on data
obtained in experiments including unambiguous and objective measurements of the
reinforcing properties of nicotine. Operant behaviour paradigms, in particular
intravenous nicotine self-administration, offer such a possibility within a solid
theoretical framework. Nicotine self-administration produces changes in the
mesocorticolimbic DA system, a key component of the reward system, as do other
addictive drugs. The role of the mesocorticolimbic DA system as the main
substrate of the reinforcing properties of nicotine is supported by converging
experiments, including the evidence that nicotine self-administration is
attenuated in mutant mice lacking the beta2 subunit of neural acetylcholine
nicotinic receptor. The long-term adaptive molecular changes in the target
neurons of the terminal fields of the mesocorticolimbic DA system, including
transcriptional regulation mediated by c-fos family gene products on other genes,
suggest that the mesolimbic DA projection to the nucleus accumbens is mainly
involved in the stimulus-reward learning process. These data represent an initial
set of information only, which may help to develop a more complete and reliable
model of the molecular dynamics underlying the reinforcing effects of nicotine.
PMID- 10780501
TI - Baseline-dependency of nicotine effects: a review.
AB - 'Rate-dependency', a founding observation of behavioral pharmacology, generally
indicates that effects of drugs will be inversely related to the rate of operant
responding under control conditions (i.e. decrease in high-rate behaviors and
increase in low-rate behaviors). 'Baseline-dependency' encompasses rate
dependency and extends this notion to other drug effects, including those
assessed by means other than 'rate' (such as subjective mood self-reports).
Although little human research has specifically investigated the effects of
nicotine as a function of baseline level of responding, a number of studies
suggest baseline-dependent differences in the influence of nicotine on behavioral
and cognitive task performance and on subjective mood responses. Results of many
animal studies also are very consistent with these observations. Baseline
dependency, perhaps, is most clearly demonstrated in comparisons between groups
selected on the basis of specific characteristics (e.g. high vs low 'trait
hostility'), or within subjects as a result of acute environmental manipulations
(e.g. high vs low 'stress' task). Moreover, baseline-dependency of the effects of
nicotine may have broader applicability in explaining individual differences in
vulnerability to nicotine dependence, particularly among those with psychiatric
disorders (e.g. depression). While individual differences in responses to
nicotine may be due to differences in pharmacological sensitivity to nicotine, as
commonly assumed, they also may be due partly to individual and situationally
determined differences in baseline level of responding on the measure of
interest. Consideration of the conditions under which baseline-dependent effects
of nicotine are observed may clarify both individual difference and situational
influences on responses to nicotine.
PMID- 10780502
TI - Do the origins of behavior matter? Commentary on Perkins' Baseline-dependency of
nicotine effects: a review.
PMID- 10780503
TI - The Questionnaire of Smoking Urges is sensitive to abstinence and exposure to
smoking-related cues.
AB - The Questionnaire of Smoking Urges (QSU) was designed to measure cravings
elicited by abstinence from cigarette smoking. In the present study, the
sensitivity of the QSU both to brief periods of abstinence and to exposure to
smoking-related cues was investigated. A progressive ratio (PR) operant procedure
was also employed, in which behaviour was maintained either by primary
reinforcement (puffs on a cigarette) or by secondary reinforcement (tokens
exchanged later for puffs on a cigarette) in separate experiments. Dependent
smokers, who were not abstinent or who were abstinent for either 2 or 4 h, were
tested in both a cue-rich and a no-cue environment. The results indicated that
the QSU was sensitive both to brief periods of abstinence and to exposure to
smoking-related cues, but the effect of smoking-related cues on QSU scores was
maximal in non-abstinent smokers. In contrast, neither abstinence nor exposure to
smoking-related cues significantly influenced the number of reinforcers earned,
or the number of responses made, in either PR task. However, there was a
significant interaction between gender and degree of abstinence on PR performance
under primary reinforcement, and correlations between PR and QSU measures that
were dependent on a complex interaction between the presence/absence of smoking
related cues and the type of reinforcer used. These results suggest that the QSU
is sensitive to subtle influences on subjective urges to smoke in dependent
smokers and, although PR measures are relatively insensitive to these influences,
there is some evidence that PR performance is related to subjective measures of
the urge to smoke.
PMID- 10780504
TI - A comparison of measures of relative reinforcing efficacy and behavioral
economics: cigarettes and money in smokers.
AB - In this experiment, we compared behavioral economic measures and measures of the
relative reinforcing efficacy of cigarettes and money between-participants. The
experiment proceeded in two phases. In the first phase, money and cigarettes were
available on separate progressive ratio (PR) schedules when they were solely
available. The response requirement for the PR schedule increased across
sessions, rather than within a session. In the second phase, money and cigarettes
were made concurrently available at some of the response requirements employed
during the PR schedule. Measures of (1) PR breakpoint, (2) peak response rate,
(3) preference, (4) elasticity and (5) Pmax (the price at which the greatest
amount of responding occurs) were compared within participant. Across the PR- and
concurrent-schedule conditions, the three measures of reinforcing efficacy
(breakpoint, response rate and preference) yielded an inconsistent assessment of
the relative reinforcing efficacy of money and cigarettes. The reinforcer that
resulted in greater peak response rates varied across subjects, while PR
breakpoint was higher for cigarettes in all participants. Further, in concurrent
schedules, preferences for cigarettes or money reversed across the response
requirements. Behavioral economic analyses suggest that Pmax and elasticity are
related to PR breakpoint, and that preference can be predicted from a comparison
of the demand curves under single-schedule conditions. Implications for the
concept of reinforcing efficacy are discussed.
PMID- 10780505
TI - Daily uplifts, hassles, stresses and cognitive failures: in cigarette smokers,
abstaining smokers, and non-smokers.
AB - Cigarette smokers (n = 25), temporarily abstaining smokers (n = 25) and non
smokers (n = 25), self-rated their feelings of stress, arousal and pleasure,
every 3 h over a normal day. Then, later in the evening, they rated the hassles,
uplifts, stresses and cognitive failures they had experienced during the day. The
abstaining smokers reported significantly worse psychological states on every
assessment measure, in comparison with both non-smokers and non-deprived smokers.
Abstinence thus led to greater stress, lower arousal, less pleasure, more
cognitive failures, more hassles and less uplifts. The non-deprived smokers did
not differ from the non-smokers on any dependent variable. These findings support
the Deprivation Reversal Model, which states that the apparent benefits of
smoking only represent the reversal of unpleasant abstinence effects. These data
provide no evidence to support the Nicotine Resource Model, which suggests that
tobacco smoking can relieve stress and improve cognitive functions. The
repetitive use of nicotine by cigarette smokers does not seem to generate any
real psychobiological gains or advantages. Instead, dependent smokers need
regular hits of nicotine just to remain feeling normal.
PMID- 10780506
TI - Asymmetric generalization between the discriminative stimulus effects of nicotine
and cocaine.
AB - The discriminative stimulus effects of nicotine and cocaine were studied, alone
and in combination, in rats. Two sets of rats were trained to press one lever
when injected intraperitoneally (i.p.) with either nicotine (0.1 mg/kg = 0.6
micromol/kg, Set 1) or cocaine (8.9 mg/kg base = 29.4 micromol/kg, Set 2), and
another lever when injected with saline. Rats learned to discriminate drug from
saline, and maintained discriminative control throughout the study (at > 85% drug
appropriate responding). In accordance with most previous findings, cocaine only
partially substituted for nicotine (maximum = 41% nicotine-lever responding). The
nicotinic agonist, nornicotine, produced dose-related, near-full substitution for
nicotine (maximum = 76% nicotine-lever responding), whereas the peripherally
acting nicotinic agonist, methylcarbamylcholine, did not substitute for nicotine.
The muscarinic receptor agonist pilocarpine also failed to substitute for
nicotine. However, in the cocaine-trained rats, nicotine substituted fully for
cocaine in a dose-dependent manner, demonstrating that cross-generalization
between the two drugs is not symmetrical. Finally, administration of each drug as
a pre-treatment to the other yielded inconsistent increases in each drug's
discriminative stimulus effects. The results are congruent with the view that the
discriminative stimulus effects of nicotine and cocaine share common features,
but the asymmetric pattern of cross-generalization and the interactions revealed
in the combination tests also suggest that there are important differences
between them.
PMID- 10780507
TI - Influencing the specificity of drug mixture discriminations by varying the
training procedure.
AB - Studies of the discriminative stimulus effects of drug mixtures provide an
approach to polydrug abuse and to studies on single drugs with multiple effects.
The experiments described here investigated whether the use of the AND-OR
procedure increases the specificity of drug mixture discriminations. Rats were
trained to discriminate a mixture of nicotine (0.4 mg/ kg) plus midazolam (0.2
mg/kg) from saline (AND-discrimination, n = 10) or to discriminate the same
mixture from its component drugs alone (AND-OR discrimination, n = 10). The
studies used two-lever operant procedures with a tandem variable interval 1 min
fixed ratio 10 (FR 10) schedule of food reinforcement. Under AND-discrimination
conditions, there was partial generalization to amphetamine and pentobarbitone
when each drug was administered singly. With the AND-OR-discrimination, there was
no generalization to amphetamine and partial generalization to pentobarbitone. In
'single substitution' tests, pentobarbitone or amphetamine was co-administered
with the training doses of nicotine and midazolam, respectively; there was full
generalization in the AND-discrimination and no generalization under AND-OR
conditions. In 'dual substitution' tests, mixtures of amphetamine plus
pentobarbitone produced full generalization under AND-discrimination conditions,
and partial generalization in the AND-OR procedure. Wherever comparisons were
made, generalization was less under AND-OR- than under the AND-discrimination
procedure, confirming that the AND-OR procedure can increase the specificity of
discriminations based on drug mixtures. The similarity with findings reported
previously for training with mixtures of amphetamine plus pentobarbitone suggests
that this may reflect a general principle rather than a phenomenon restricted to
particular training drugs.
PMID- 10780508
TI - The effect of repeated nicotine administration on the performance of drug-naive
rats in a five-choice serial reaction time task.
AB - Nicotine improves cognitive performance both in animals and in humans,
particularly in tests involving attentional processes. The five-choice serial
reaction time task (5-CSRTT) is widely used as a model of attentional performance
in rats, and previous studies have demonstrated effects of nicotine in this task
on measures such as improved reaction time. Using a modified version of this task
(in which rats were required to respond to the disappearance of one of five
stimulus lights), we evaluated the effects of repeated nicotine administration
(0.3 mg/kg, intraperitoneally, on three occasions over 7 days) in drug-naive
rats. After the first administration, nicotine increased accuracy and reduced
inappropriate responding (anticipatory responses and responses during time-out)
compared to performance following vehicle administration on the preceding day.
However, with repeated administration the improvement in accuracy disappeared,
and other effects became apparent. Thus, after the third administration the main
effects of nicotine were to increase inappropriate responding and to reduce
reaction times. A fourth administration 1-2 weeks later produced similar results
to the third administration, suggesting that the effects of nicotine were now
constant. Despite the general increase in inappropriate responding, there was no
impairment in accuracy. In contrast to the response to repeated nicotine, the
performance of the rats on the 3 vehicle days remained constant. These data
demonstrate that the administration of nicotine to drug-naive subjects improves
performance in the 5-CSRTT but that with repeated administration this effect
disappears and is replaced by a profile in which inappropriate and impulsive
responding predominate.
PMID- 10780509
TI - AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats.
AB - Nicotinic acetylcholine systems have been found to be important for learning and
memory function. The prototypic nicotinic agonist nicotine has been shown in a
variety of studies to improve aspects of cognitive function. The specific
involvement of nicotinic receptor subtypes is now being investigated. The
involvement of alpha7 nicotinic receptors was assessed in this project using a
novel alpha7 nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous
injection 20 min before testing) of the racemic mixture AR-R 13489 and its active
isomer AR-R 17779 were assessed in adult female Sprague-Dawley rats using the
eight-arm radial maze. AR-R 13489 (2 mg/kg) caused a significant improvement of
long-term win-shift acquisition after 3 weeks of training (n = 10 per group). The
same dose of AR-R 17779 also caused a significant improvement in repeated
acquisition within each daily session in the radial-arm maze. In another study,
the active isomer AR-R 17779 significantly improved radial-arm maze working
memory function in rats with lesions to the septohippocampal projection. Fimbria
fornix lesions significantly impaired working memory performance and AR-R 17779
significantly reversed that impairment. These studies showed that alpha7
nicotinic agonist treatment improved learning in two radial-arm maze tasks and
reversed working memory impairment caused by fimbria-fornix sections, providing
evidence for alpha7 involvement in learning and memory, and the potential
therapeutic use of AR-R 17779.
PMID- 10780510
TI - Differential improvement in memory-related task performance with nicotine by aged
male and female rhesus monkeys.
AB - Central nicotinc acetylcholine receptors have been targeted for the development
of novel treatments for memory deficits in Alzheimer's disease (AD) and other
neurodegenerative disorders. Nicotine itself has been shown to improve memory
related task performance in aged animals and in AD patients. Administration of
nicotinic receptor agonists to laboratory animals, and the effects of cigarette
smoking in humans attributed to nicotine, have in many instances been shown to
exert sexually dimorphic actions. Low doses (2.5-20 microg/kg, intramuscularly)
of nicotine have been shown to improve the performance of an automated delayed
matching-to-sample (DMTS) task in aged rhesus monkeys. The purpose of this study
was to determine whether aged females receive the same level of benefit to the
positive mnemonic action of nicotine as do males. In this study six male (21.7+/
1.2 years) and seven female (22.5+/-0.9 years) rhesus monkeys each received an
ascending series of four doses of nicotine over 5 weeks. Most control parameters
were similar between the two sexes, although task latencies were longer and more
variable in the female subjects. The males maintained a significant improvement
in task performance over the entire nicotine dose range. This level of
improvement extended to 24 h after nicotine administration. Task accuracy by
females appeared to improve only after they received the two higher doses of
nicotine, and their responses exhibited considerable variability over the entire
dose range. However, in calculating an individualized 'Best Dose', males and
females exhibited a similar level of task improvement (15-30% above baseline).
Therefore, aged female subjects may require a greater level of individualized
treatment and perhaps higher doses of nicotinic agonists to achieve the maximal
mnemonic benefit.
PMID- 10780511
TI - Time-course of changes in the social interaction test of anxiety following acute
and chronic administration of nicotine.
AB - The purpose of these experiments was to explore the hypothesis that the effects
of nicotine on anxiety depend on the time since administration and the duration
of treatment. In the social interaction test of anxiety, acute nicotine
administration (0.1 mg/kg, subcutaneously) decreased social interaction when rats
were tested 5 min after injection, but increased it when they were tested 30 min
after injection. Social interaction was also decreased 1 h post-injection, but
levels returned to baseline between 3 and 30 h. As these changes were independent
of any changes in locomotor activity, nicotine seemed to be having both
anxiogenic and anxiolytic effects at different times after injection. An
anxiolytic effect was also observed 30 min after the second nicotine injection,
and the anxiogenic effect observed 5 min after injection remained after 4 days of
nicotine administration. However, after 7 days of nicotine treatment, tolerance
was observed to both these effects. When rats were tested 72 h after the last of
7 or 14 days of nicotine treatment, an anxiogenic withdrawal response was
observed. Thus, an oppositional mechanism may underlie tolerance to the
anxiolytic effects, whereas there is as yet no evidence for this type of
mechanism mediating tolerance to the anxiogenic effects.
PMID- 10780512
TI - Locomotor behavioral effects of prenatal and postnatal nicotine exposure in rat
offspring.
AB - The purpose of this study was to determine if prenatal/postnatal nicotine
exposure results in hyperactive offspring. Rat offspring were exposed to
nicotine, through implantation of osmotic minipumps in dams, at levels of 0.75,
1.5 and 3.0 mg/kg/day, for 19 days prenatally and 16 days postnatally. Offspring
were measured for gestation length, body weight, litter size, sex difference and
locomotor activity. No significant effects were shown for gestation length,
litter size or male to female pup ratio. However, higher percentage of pup deaths
resulted from nicotine-exposed dams than from control dams. Significantly less
litter body weight was shown in nicotine-exposed offspring on postnatal day 1
when compared to controls. However, these offspring surpassed the control groups
in litter body weight on postnatal day 14 and 21. Hyperactivity was shown in
offspring exposed to prenatal/postnatal nicotine at levels of 0.75 and 3.0
mg/kg/day on postnatal day 14, but not on postnatal day 21 or at the 1.5
mg/kg/day condition. Results are consistent with the hypothesis that rat
offspring are susceptible to the neurochemical and neurobehavioral effects of
prenatal/postnatal nicotine exposure.
PMID- 10780513
TI - Chemotherapy for high-grade gliomas.
PMID- 10780514
TI - Bisphosphonates in the adjuvant treatment of cancer: experimental evidence and
first clinical results. International Bone and Cancer Study Group (IBCG).
AB - Several animal models, as well as a number of cell culture experiments, indicate
a prophylactic effect of bisphosphonates in respect of subsequent bone
metastasis. Moreover, in preliminary clinical trials involving patients with
advanced breast cancer and local or remote metastases, biophosphonates produced a
reduction in new skeletal metastases. This overview summarizes and discusses the
results of the latest investigations. It opens with a section on the
pathophysiology of bone metastasis, which is followed by a report on animal
models and first studies of bisphosphonate treatment as a new approach in
systemic adjuvant therapy.
PMID- 10780515
TI - Treatment, long-term outcome and prognostic variables in 214 unselected AML
patients in Sweden.
AB - With the aim of describing an unselected series of acute myeloid leukaemias (AML)
in adults, patients diagnosed 1987-1992 in the Orebro region of central Sweden
were reviewed by investigating hospital records. By utilizing: (1) The Swedish
Cancer Registry, (2) The Cause of Death Registry, (3) listings of pathology bone
marrow reports and (4) listings of inpatient discharge diagnoses, we attempted to
find all patients. Among secondary AML, only blast-crises of CML were excluded. A
total of 214 cases of AML with a median age of 69.5 years were verified
corresponding to a mean yearly incidence in adults of 5.4/100 000. Of all
patients, 56% had received 'high-dose' induction treatment, 28% 'low-dose'
treatment and 16% no cytostatic treatment. Median survival for all patients was
5.8 months and the probability of survival at 5 years was 9.3%. The 120 'high
dose' treated patients had a total CR rate of 67%, median CR duration 10.1 months
and median survival 11.4 months. Age, LDH and kidney function were found to be
independent prognostic variables for survival. The inclusion of patients
unreferred from district hospitals makes this study unique as an example of
unselected AML.
PMID- 10780516
TI - Treatment of persistent trophoblastic disease later than 6 months after diagnosis
of molar pregnancy.
AB - Of 4257 patients with gestational trophoblastic disease (GTD) registered between
1986 and 1996 with the Trophoblastic Screening and Treatment Centre, Sheffield,
231 women required chemotherapy; 28 were treated 24 weeks or more after the
initial evacuation of products of conception. In 18 patients late treatment was a
result of a predetermined watch and wait policy on the part of the Centre; these
patients formed the study group. Patients were identified from the Centre's
computer database. The time interval from first evacuation (diagnosis) to start
of chemotherapy was calculated for each patient. Hospital records were reviewed
when the interval of observation was 24 weeks or greater to determine patient
characteristics, treatment and outcome. Eighteen women were treated 'late'
(according to Centre policy), with a median age of 30 years (range 21-57 years).
The interval from diagnosis to treatment ranged from 24 to, in one case, 56 weeks
(median 33 weeks). Fourteen of 18 women had complete moles, 3/18 had partial
moles and one had unclassified disease. All women had low-risk disease and were
treated with single-agent methotrexate; 17 were cured with this regimen, one also
required salvage chemotherapy. In conclusion, where a successful surveillance
programme is in operation for GTD, a wait and watch policy can be adopted without
compromising patients whose definitive treatment is commenced more than 6 months
after the initial diagnosis.
PMID- 10780518
TI - Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients.
AB - Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease
characterized by hamartomatous gastrointestinal polyps and mucocutaneous
pigmentation, with an increased risk for various neoplasms, including
gastrointestinal cancer. Recently, the PJS gene encoding the serine/threonine
kinase STK11 (also named LKB1) was mapped to chromosome 19p13.3, and germline
mutations were identified in PJS patients. We screened a total of ten Korean PJS
patients (nine sporadic cases and one familial case including two patients) to
investigate the germline mutations of the STK11 gene. By polymerase chain
reaction-single-strand conformation polymorphism and DNA sequencing analysis,
three kinds of mis-sense mutation and a frame-shift mutation were identified:
codon 232 (TCC to CCC) in exon 5, codon 256 (GAA to GCA) in exon 6, codon 324
(CCG to CTG) in exon 8, and a guanine insertion at codon 342 resulting in a
premature stop codon in exon 8. These mis-sense variants were not detected in 100
control DNA samples. Furthermore, we found an intronic mutation at the
dinucleotide sequence of a splice-acceptor site: a one base substitution from AG
to CG in intron 1, which may cause aberrant splicing. Most reported germline
mutations of the STK11 gene in PJS patients were frame-shift or non-sense
mutations resulting in truncated proteins. Together, these findings indicate that
germline mis-sense mutations of the STK11 gene are found in PJS patients in
addition to truncating mutations. The effects of these mutations on protein
function require further examination. In summary, we found germline mutations of
the STK11 gene in five out of ten Korean PJS patients.
PMID- 10780517
TI - Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B
NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002
protocol.
AB - From July 1990 to March 1996, 112 children with stage III or IV B-cell non
Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone
marrow without central nervous system (CNS) disease were treated on the United
Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the
French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls.
According to the extent of the primary disease, patients were sub-staged into
three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with
abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary
lymphoma often presenting as pleural effusion (n = 16). Univariate and
multivariate analyses were carried out to evaluate the prognostic significance of
lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to
achieve complete remission (CR). With a median follow up of 48 months (range 12
92), the overall and event free survival (EFS) is 87% (95% confidence interval
(CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%)
never achieved CR, of whom one is alive following high-dose therapy. Eight
patients (7.1%) relapsed after achieving CR, three are alive after second-line
therapy. There were three early toxic deaths (2.7%), mainly from infection, and
one late death from a second cancer. There was no significant difference in EFS
according to LDH level at diagnosis, the sub-stage or the time to CR. This study
confirms the overall good prognosis and low rate of toxic deaths in patients with
advanced B-NHL treated with this intensive regimen. No significant difference in
EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis
making it difficult to identify a group that should not receive intensive
therapy.
PMID- 10780519
TI - Interphase cytogenetics of multicentric renal cell tumours confirm associations
of specific aberrations with defined cytomorphologies.
AB - To demonstrate associations of certain chromosomal aberrations with defined renal
cell tumour (RCT) subtypes, we analysed 239 tumour nephrectomy cases for
specimens with multicentric tumours. Chromosomal in situ hybridization was then
performed on 15 cases with 34 foci (16 conventional renal cell carcinomas (RCCs),
and 18 papillary RCTs (11 carcinomas and seven adenomas) for specific chromosomal
aberrations, using alpha-satellite probes for chromosomes 3, 7 or 17. Particular
preference was given to cases which had separate foci with different
cytomorphologies. Furthermore, we compared aberrations in relation to tumour
size, stage, grade and between different foci in a specimen. Thirty-four cases
had multiple tumours. Forty-seven per cent of the multicentric tumours were
conventional RCCs and 53% papillary RCTs (against 83% solitary conventional RCCs
and 5% solitary papillary RCTs). Three conventional RCCs sized 8 mm (G3), 13 cm
(pT2, G2) and 15 cm (pT3b, G3), respectively, revealed monosomy 3, and 13 were
disomic. Seventeen papillary RCTs (11 carcinomas and six adenomas) displayed
trisomy 17, irrespective of size or grade. Four papillary carcinomas and six
papillary adenomas had trisomy 7, and the rest (seven papillary carcinomas and
one papillary adenoma) revealed disomy 7. In conclusion, papillary RCTs were
tendentially multicentric. Although specific for conventional RCCs heedless of
size, monosomy 3 was only observed in high-grade and/or advanced tumours. Trisomy
17 was only detectable in papillary RCTs irrespective of tumour state, showing
increased copies with tumour growth. Papillary RCTs also appeared to lose some
copies of chromosome 7 with tumour progress, possibly reflecting malignancy.
PMID- 10780520
TI - Presence of activin signal transduction in normal ovarian cells and epithelial
ovarian carcinoma.
AB - In this study, we have investigated the expression of inhibin subunits and
activin receptors (ActRs) in normal and malignant ovarian cells. Each product of
the inhibin subunits (alpha, betaa, betab) and activin receptors (ActRs)
amplified by reverse transcription polymerase chain reaction were detected as a
single band in human granulosa cells, surface epithelial cells (OSE), and the
ovarian cancer cell lines OVCAR 3 and SKOV 3. Western blot analysis was performed
using polyclonal antibodies against ActR IIa or IIb peptides based on 13 COOH
terminal amino acids; cultured human granulosa cells were used as a positive
control. Using ActR IIa antibody, one major band corresponding to approximately
80 kDa and one minor band corresponding to 105 kDa were observed in the samples.
One single band at approximately 60 kDa was detected in OVCAR 3 and a 50 kDa band
was detected with ActR IIb antibody in cultured granulosa cell, OSE and SKOV 3.
Although no detectable change was induced in Smad 4 mRNA in OVCAR 3, Smad 2 mRNA
levels were increased during 48 h treatment with activin A (50 ng ml(-1)). These
data provide a better understanding as the first step in the mechanism of action
of the activin in the epithelial ovarian carcinoma.
PMID- 10780521
TI - A simplified and reliable HPV testing of archival Papanicolaou-stained cervical
smears: application to cervical smears from cancer patients starting with
cytologically normal smears.
AB - The efficacy of four methods to recover DNA from Papanicolaou (Pap)-stained
archival cervical smears for optimal detection of human papillomavirus (HPV) DNA
by GP5+/bioGP6+ polymerase chain reaction (PCR) was investigated. Two of the
methods were based on proteinase K treatment and two based on treatment with
guanidinium thiocyanate (GTC). The quality of the DNA as measured by PCR assays
amplifying different sizes of the beta-globin gene appeared to be superior for
the GTC-based assays. Using competitive beta-globin PCR assays, one of the GTC
based, assays, provisionally named High Pure PCR Template Preparation (HPPTP)
assay, yielded by far the highest quantity of amplifiable DNA. It allowed the
recovery of 2.2 x 10(5) to 3 x 10(5) genome equivalents in smears containing 5 x
10(5) to 20 x 10(5) nucleated cells, indicating a mean efficiency of 26% (range
of 15-44%). In contrast, the other methods revealed markedly lower efficiencies
varying from 1% to 10%. The use of the HPPTP assay as a reliable processing
procedure was validated by demonstrating a complete agreement in HPV detection
and 93% agreement in HPV typing between 39 archival Pap-stained and paired fresh
frozen cervical smears. This method was applied to 40 archival smears from ten
cervical cancer patients (selected from a group of 200 patients) which had a
history of 3-6 smears with the first smear being Pap 1 or 2 taken at least 5
years before cancer was diagnosed. The average time period between the first Pap
1/2 smear that contained the same HPV type as in the corresponding carcinoma and
diagnosis of cervical cancer was 12.0 +/- 2.9 years. All subsequent smears were
invariably positive for the same HPV type which was also found in the cervical
cancer biopsy. In conclusion, the HPPTP assay provides a reliable and efficient
means to extract DNA from Pap-stained archival cervical smears for the detection
of HPV DNA by PCR and would be the method of choice for future HPV analysis of
archival Pap-stained cervical smears.
PMID- 10780522
TI - Vascular endothelial growth factor, platelet-derived endothelial cell growth
factor and angiogenesis in non-small-cell lung cancer.
AB - High microvessel density, an indirect measure of angiogenesis, has been shown to
correlate with increased tumour size, lymph node involvement and poor prognosis
in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth
factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)
expression correlate with angiogenesis and a poor outcome in this disease. In a
retrospective study VEGF and PD-ECGF expression and microvessel density were
evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2)
from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal
antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and
PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade
tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed
a weak positive correlation between VEGF and PD-ECGF expression in cancer cells
(r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a
higher microvessel density than VEGF or PD-ECGF only expressing tumours.
Furthermore a proportion of high vascular grade tumours expressed neither growth
factor. Univariate analysis revealed tumour size, nodal status, microvessel
density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour
size (P < 0.02) and microvessel density (P < 0.04) remained significant on
multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic
growth factors and have prognostic significance in NSCLC. Furthermore the study
underlines the prognostic significance of microvessel density in operable NSCLC.
PMID- 10780523
TI - Expression of alpha(v)beta6 integrin in oral leukoplakia.
AB - The distribution of alpha(v)beta6 integrin was examined in oral leukoplakia,
lichen planus and squamous cell carcinomas using immunohistochemistry. Controls
included oral mucosal wounds, chronically inflamed and normal oral mucosa.
Integrins beta1, beta3, beta4, beta5, fibronectin and tenascin were also studied.
The integrin alpha(v)beta6 was highly expressed throughout the whole lesion of
90% of the squamous cell carcinomas but was not present in any of the normal
specimens. alpha(v)beta6 integrin was also expressed in 41% of the leukoplakia
specimens, and 85% of the lichen planus samples, but in none of the tissues with
inflammatory hyperplasia or chronic inflammation. The expression of beta1
integrins was localized in the basal layer, and that of the beta4 at the cell
surface facing the basement membrane of all specimens. The integrins beta3 and
beta5 were absent from all normal and leukoplakia specimens. Fibronectin and
tenascin were present in the connective tissue underneath the epithelium of all
the sections, and their expression was similar in both alpha(v)beta6-positive and
alpha(v)beta6-negative tissues. A group of 28 leukoplakia patients were followed
1-4 years after first diagnosis. In this group, initially alpha(v)beta6 integrin
positive leukoplakia specimens had high tendency for disease progression while
alpha(v)beta6-negative specimens did not progress. These results suggest that the
expression of alpha(v)beta6 integrin could be associated in the malignant
transformation of oral leukoplakias.
PMID- 10780524
TI - Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas:
relationship to tumour behaviour.
AB - The prediction of pituitary tumour behaviour, in terms of response to treatment
from which can be derived optimal management strategies, is a challenge that has
been approached using several different means. Angiogenesis in other tumour types
has been shown to be correlated with poor response to treatment and tumour
recurrence. The aim of this paper is to assess the role of measurements of cell
proliferation and angiogenesis in predicting pituitary tumour behaviour. The
proliferative capacity of the tumour was assessed using the Ki-67 labelling index
(LI) while bcl-2 expression was used to assess anti-apoptotic pathways. The
microvessel density (MVD) was assessed using antibodies to CD31 and factor VIII
related antigen, and with biotinylated ulex europaeus agglutinin I. There was no
difference between Ki-67 LI and MVD of functionless tumours that recurred and
those that did not, but bcl-2 expression was significantly lower in tumours that
subsequently regrew. Macroprolactinomas had significantly higher LI than
microprolactinomas and than all other tumours. Cell proliferation and
angiogenesis were not related, showing that both processes are under different
control mechanisms in pituitary tumours. In contrast there was a positive
relationship between markers of angiogenesis and bcl-2 expression in
prolactinomas, GH-secreting tumours and non-recurrent functionless tumours with
higher levels of bcl-2 expression being found in the more vascular tumours. These
findings may suggest that angiogenesis is related to the ability of tumour cells
to survive rather than their proliferative activity.
PMID- 10780525
TI - Expressions of Fas ligand and other apoptosis-related genes and their prognostic
significance in epithelial ovarian neoplasms.
AB - Expression of apoptosis-related proteins, bcl-2, Bax, Fas and Fas ligand (L), in
ovarian epithelial neoplasms together with its clinical relevance was examined by
immunohistochemistry. They included 36 cases with adenoma, 33 with low potential
malignancy (LPM) and 63 with carcinomas. bcl-2 expression was observed in 14 of
36 cases (39%) with adenoma, five of 33 (15%) with LPM (P< 0.05) and 12 of 63
(19%) with carcinoma (P < 0.05). Cases with bcl-2 expression showed more
favourable prognosis than those without, but the difference was not statistically
significant. There was no difference in frequency of Bax and Fas expression
between each histologic category. Fas L expression was observed in one of 36
cases (3%) with adenoma, but in 12 of 33 (36%) with LPM (P < 0.001) and 42 of 63
(67%) with carcinoma (P < 0.0001). In carcinomas, cases expressing Fas L showed a
less favourable prognosis than those without (P = 0.02). Density of CD8+
lymphocytes, possibly cytotoxic T-cells, was higher in serous carcinoma with
negative Fas L expression than those with positive Fas L expression. These
findings suggest that Fas L expressing carcinomas induce apoptosis in
infiltrating CTL with Fas expression, and escape from immune surveillance.
PMID- 10780526
TI - Expression of SCF splice variants in human melanocytes and melanoma cell lines:
potential prognostic implications.
AB - Stem cell factor (SCF), the ligand for c-Kit, is known to regulate developmental
and functional processes of haematopoietic stem cells, mast cells and
melanocytes. Two different splice variants form predominantly soluble (sSCF or
SCF-1) and in addition some membrane-bound SCF (mSCF or SCF-2). In order to
explore the prognostic significance of these molecules in melanoma, total SCF,
SCF splice variants and c-Kit expression were studied in normal skin melanocytes
and in 11 different melanoma cell lines, using reverse transcription polymerase
chain reaction, immunocytochemistry and enzyme-linked immunosorbent assay. Nine
of the 11 melanoma cell lines expressed SCF-1 mRNA, only two of them SCF-2, and
these two also SCF-1. Coexpression of both SCF-1 and c-Kit was noted in five cell
lines, and only one cell line as well as normal melanocytes expressed both SCF-1
and SCF-2 as well as c-Kit. Corresponding results were obtained on
immunocytochemical staining. Of three exemplary melanoma cell lines studied, two
expressing SCF mRNA also released SCF spontaneously and on stimulation, whereas
the line lacking SCF and c-kit mRNA (SK-Mel-23) failed to do so. These data
demonstrate thus that melanoma cell lines, particularly those known to
metastasize in vivo, lose the ability to express SCF-2 mRNA, suggesting that this
molecule may serve, next to c-Kit, as a prognostic marker for malignant melanoma.
PMID- 10780527
TI - Bisphosphonates induce apoptosis in human breast cancer cell lines.
AB - Breast cancer has a prodigious capacity to metastasize to bone. In women with
advanced breast cancer and bone metastases, bisphosphonates reduce the incidence
of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that
some bisphosphonates reduce the tumour burden in bone with a consequent increase
in survival, raising the possibility that bisphosphonates may have a direct
effect on breast cancer cells. We have investigated the in vitro effects of
bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth,
viability and induction of apoptosis in three human breast cancer cell lines (MDA
MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye
assay, and cell viability was quantitated by MTS dye reduction. Induction of
apoptosis was determined by identification of morphological features of apoptosis
using time-lapse videomicroscopy, identifying morphological changes in nucleis
using Hoechst staining, quantitation of DNA fragmentation, level of expression of
bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly
(ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced
cell viability in all three cell lines. Zoledronate was the most potent
bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB
231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35
and 25 microM, whereas clodronate and EB 1053 were more than two orders of
magnitude less potent. An increase in the proportion of cells having
morphological features characteristic of apoptosis, characteristic apoptotic
changes in the nucleus, time-dependent increase in the percentage of fragmented
chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of
PARP, all indicate that bisphosphonates have direct anti-tumour effects on human
breast cancer cells.
PMID- 10780528
TI - Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive
drugs AQ4N and tirapazamine.
AB - The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti
tumour effect of cyclophosphamide was assessed in three murine tumour models. In
male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50-150 mg kg(
1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect
equivalent to a single 200 mg kg 1 dose of cyclophosphamide. Tirapazamine (25 mg
kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect
equivalent to a single 150 mg kg(-1) dose of cyclophosphamide. In C3H mice
implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing
was found with both drugs in combination with cyclophosphamide (50-200 mg kg(
1)); AQ4N (50-200 mg kg(-1)) produced a more effective combination than
tirapazamine (12.5-50 mg kg(-1)). Unlike tirapazamine, which showed a significant
increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg(
1)) 6 h prior to cyclophosphamide (100 mg k(-1)) resulted in no additional
toxicity towards bone marrow cells compared to that caused by cyclophosphamide
alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to
tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg(
1)).
PMID- 10780529
TI - Characterization of antigen-presenting properties of tumour cells using virus
specific cytotoxic T lymphocytes.
AB - Immunotherapy of tumours by induction of tumour-specific cytotoxic T-lymphocytes
(CTLs) will only be effective for tumours with a functional antigen processing
and presentation machinery. However, many tumours are known to down-regulate
expression of major histocompatibility complex (MHC) class I molecules and/or to
impair antigen processing. It is therefore desirable to evaluate the ability of a
given tumour to present antigenic epitopes before developing an immunotherapy
protocol. In this study we have used influenza virus as a tool to determine the
antigen-presenting capacities of the murine neuroblastoma C1300 cell line NB41A3,
a frequently used model for human neuroblastoma. Immunofluorescence analyses
revealed low and moderate expression of MHC class I molecules Dd and Kk
respectively. Nevertheless, infected NB41 A3 cells were lysed efficiently by
influenza-specific CTLs. These results demonstrate that all steps of the antigen
processing pathway function properly in the NB tumour cells, and that the limited
MHC class I expression suffices for efficient recognition by CTLs. In addition,
lysis of the NB tumour cells shows that the cells are susceptible to CTL-induced
apoptosis, a pathway that is often impaired in tumour cells. These
characteristics make neuroblastoma a suitable target for immunotherapy. The
presented assay allows evaluation of various immunological properties of tumour
cells and, thus, represents a valuable tool to assess whether a given tumour will
be susceptible to immunotherapy or not.
PMID- 10780530
TI - Suppression of proline-directed protein kinase F(A) expression inhibits the
growth of human chronic myeloid leukaemia cells.
AB - Initial studies revealed that proline-directed protein kinase F(A) (PDPK F(A))
was overexpressed in various cancerous tissues relative to normal controls.
However, the functional role of overexpressed PDPK F(A) in cancer remains to be
established. In this report, we explore the potential role of PDPK F(A) in
leukaemia cell growth by investigating the effects of partial inhibition of this
kinase on the malignant phenotype of human chronic myeloid leukaemia cells
(K562). Cloning of PDPK F(A) cDNA and its recombinant antisense expression vector
and PDPK F(A)-specific antibody were successfully developed. Two stable antisense
clones of K562 cells were subcloned which expressed 70% and 45% of PDPK F(A)
respectively, compared with control-transfected clone in both immunoprecipitate
activity assay and immunoblot analysis. In sharp contrast, these two antisense
clones expressed no significant suppression of any other related PDPK family
members, indicating the specificity of these two antisense clones. Moreover,
these antisense clones proportionally and potentially exhibited cell growth
retardation, poor clonogenic growth in soft agar and loss of serum independence.
The results demonstrate that specific antisense suppression of PDPK F(A) is
sufficient to interfere with the growth of K562 cells, indicating that PDPK F(A)
is essential for human chronic myeloid leukaemia cell growth.
PMID- 10780532
TI - The "crowding effect" in tapeworm infections. 1950.
PMID- 10780531
TI - Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy
by localized treatment with G-CSF.
AB - Photofrin-based photodynamic therapy (PDT) has recently been approved for
palliative and curative purposes in cancer patients. It has been demonstrated
that neutrophils are indispensable for its anti-tumour effectiveness. We decided
to evaluate the extent of the anti-tumour effectiveness of PDT combined with
administration of granulocyte colony-stimulating factor (G-CSF) as well as the
influence of Photofrin and G-CSF on the myelopoiesis and functional activity of
neutrophils in mice. An intensive treatment with G-CSF significantly potentiated
anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of
tumour growth and prolongation of the survival time of mice bearing two different
tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice
were completely cured of their tumours after combined therapy and developed a
specific and long-lasting immunity. The tumours treated with both agents
contained more infiltrating neutrophils and apoptotic cells then tumours treated
with either G-CSF or PDT only. Importantly, simultaneous administration of
Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted
in an increased number of neutrophils demonstrating functional characteristics of
activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with
G-CSF observed in two murine tumour models suggest that clinical trials using
this tumour therapy protocol would be worth pursuing.
PMID- 10780533
TI - The crowding effect revisited. 1951.
PMID- 10780534
TI - The ecology of "crowding".
PMID- 10780535
TI - Attachment-inducing capacities of fish tissue extracts on oncomiracidia of
Neobenedenia girellae (Monogenea, Capsalidae).
AB - When oncomiracidia of Neobenedenia girellae (Monogenea, Capsalidae) were
incubated in wells with lyophilized extracts of fish skin epithelia on the
bottom, some attached to the well bottom with the haptor unfolded and shed the
ciliated epidermal cells. Based on these morphological changes in oncomiracidia,
we developed a new assay method to examine the attachment-inducing capacities of
various fish extracts for oncomiracidia. Attachment-inducing capacities were
found only in extracts of fish skin epithelium and not in other fish extracts. No
significant difference in capacities was observed among extracts of skin
epithelia of 4 fish species. Wheat germ lectin and concanavalin A suppressed
capacities in extracts of skin epithelia of Japanese flounder and yellowtail,
respectively. Suppressed capacities were recovered by adding sugars that bound
specifically to these lectins. These results indicate that some sugar-related
chemical substances that exist specifically in fish epithelium induce the
attachment of N. girellae oncomiracidia.
PMID- 10780536
TI - Proteinase activities in total extracts and in medium conditioned by Acanthamoeba
polyphaga trophozoites.
AB - Acanthamoeba species can cause granulomatous encephalitis and keratitis in man.
The mechanisms that underlie tissue damage and invasion by the amoebae are poorly
understood, but involvement of as yet uncharacterized proteinases has been
suggested. Here, we employed gelatin-containing gels and azocasein assays to
examine proteinase activities in cell lysates and in medium conditioned by
Acanthamoeba polyphaga trophozoites. Azocasein hydrolysis by cell lysates was
optimally detected at pH 4.0-5.0 and was predominantly associated with the
activity of cysteine proteinases. Compatible with enzyme activation during
secretion, culture supernatants additionally contained a prominent azocasein
hydrolyzing activity attributable to serine proteinases; these enzymes were
better detected at pH 6.0 and above, and resolved at 47, 60, 75, 100, and >110
kDa in overlay gelatin gels. Although a similar banding profile was observed in
gels of trophozoite lysates, intracellular serine proteinases were shown to be
activated during electrophoresis and to split the substrate during migration in
sodium dodecyl sulfate gels. Blockage of serine proteinases with
phenylmethylsulfonylfluoride prior to electrophoresis permitted the detection of
43-, 59-, 70-, and 100-130-kDa acidic cysteine proteinases in cell lysates, and
of 3 (43, 70, and 130 kDa) apparently equivalent enzymes in culture supernatants.
Under the conditions employed, no band associated with a metalloproteinase
activity could be depicted in substrate gels, although the discrete inhibition of
supernatants' azocaseinolytic activity by 1,10-phenanthroline suggested secretion
of some metalloproteinase.
PMID- 10780538
TI - Relationship between structure and stability of a Halipegus occidualis component
population in green frogs: a test of selective treatment.
AB - The aggregated nature of helminth parasite populations has led to the suggestion
that selectively treating heavily infected hosts can efficiently reduce parasite
abundance and morbidity within a host population. Moreover, it has been
postulated that a selective treatment protocol might have long-term effects on
parasite transmission by disrupting the stability attributed to aggregated
parasite population distributions by theoretical models. Long-term investigation
has demonstrated year-to-year consistency in the population dynamics of Halipegus
occidualis in green frogs from Charlie's Pond, North Carolina. In 1996, removal
of all but 1 worm from each frog with > or =15 worms reduced the estimated
component worm population by 45%, thereby decreasing mean intensity and
aggregation (variance-to-mean ratio) of H. occidualis in the frogs by 85% and
63%, respectively. The following year, mean intensity, aggregation, and host
colonization trends returned to pretreatment levels, indicating no effect of worm
removal and demonstrating the stability of this host-parasite system. Although
this result might be attributable to inefficient treatment or the presence of
infection reservoirs, it is suggested that parasite population stability in this
system might be governed by prevalence rather than intensity of adult worms.
Therefore, repeated selective treatment might effectively modify intensity
dependent morbidity in similar host-parasite systems but should not affect
further parasite transmission.
PMID- 10780537
TI - Quantifying parasites in samples of hosts.
AB - Whereas terminological recommendations require authors to use mean intensity or
mean abundance to quantify parasites in a sample of hosts, awkward statistical
limitations also force them to use either the median or the geometric mean of
these measures when making comparisons across different samples. Here, we propose
to reconsider this inconsistent practice by giving priority to biological realism
in the interpretation of different statistical descriptors and choosing the
statistical tools appropriate to our decisions. Prevalence, mean intensity, and
indices of parasite distribution (such as median intensity) are suitable
descriptors to quantify parasites in a sample of hosts. These measures have
different biological interpretations and need different statistical methods to be
compared between samples.
PMID- 10780539
TI - Margolisius abditus n. gen., n. sP. (Copepoda: Lernaeopodidae) from gill lamellae
of a remora (Remora remora) collected in the Gulf of California.
AB - Margolisius abditus n. gen., n. sp. (Copepoda: Lernaeopodidae) is described from
female specimens collected from gill lamellae of a remora, Remora remora (L.),
captured in the Gulf of California near Punta Arena, Baja California. Comparison
of this species with 13 lernaeopodid genera with which it shares (a) absence of
posterior trunk processes; (b) presence of a relatively long cylindrical
cephalothorax, usually reflected along the dorsal surface of the trunk; and (c) a
marine habitat showed that it cannot be placed in any of them, thus necessitating
establishment of a new genus. Margolisius abditus n. sp. is the smallest known
lernaeopodid species, its ovigerous females measuring about 0.5 mm in total
length.
PMID- 10780540
TI - Dionchus postoncomiracidia (Monogenea: Dionchidae) from the skin of blacktip
sharks, Carcharhinus limbatus (Carcharhinidae).
AB - Postoncomiracidia of Dionchus sp. are described from specimens collected from the
skin of 2 blacktip sharks Carcharhinus limbatus, captured in the northern Gulf of
Mexico. The parasites resemble nonciliated oncomiracidia hatched from eggs laid
by Dionchus sp. on gills of a cobia Rachycentron canadum and adults of Dionchus
remorae that were collected from gills of a common sharksucker Echeneis
naucrates, captured in association with a third blacktip shark. The hamuli of the
postoncomiracidia were morphologically similar to those of adult D. remorae. This
is the first report of dionchids from an elasmobranch and from a location other
than the gills. These findings support the idea that some dionchid oncomiracidia
colonize the skin of sharks or other aquatic vertebrates that sponsor remoras,
prior to transferring to other remoras and maturing.
PMID- 10780541
TI - Tick infestations of birds in coastal Georgia and Alabama.
AB - Mist-netted birds were examined for ticks on Jekyll Island, Glynn Co., Georgia
(32 bird species) in 1996-1998, and at Fort Morgan, Baldwin Co., Alabama (36
species) in 1998 during fall migration. Sixty-two (14.7%) of 423 birds from
Jekyll Island and 22 (13.3%) of 165 birds from Fort Morgan were infested with
ticks. The mean number of ticks per infested bird was 2.0 on Jekyll Island and
6.3 at Fort Morgan. Ten species of birds were infested with ticks on Jekyl1
Island where 87% of all ticks were recovered from 3 species: the common
yellowthroat (Geothlypis trichas), gray catbird (Dumetella carolinensis), and
northern waterthrush (Seiurus noveboracensis). Eight species of birds were
infested with ticks at Fort Morgan where 83% of all ticks were recovered from 3
species: the brown thrasher (Toxostoma rufum), swamp sparrow (Melospiza
georgiana), and common yellowthroat. Six species of ticks (Amblyomma americanum,
Amblyomma maculatum, Haemaphysalis leporispalustris, Ixodes brunneus, Ixodes
minor, and Ixodes scapularis) were recovered from the Georgia birds, whereas 3
species (A. maculatum, H. leporispalustris, and Ixodes dentatus) were recovered
from the Alabama birds. Attempts to isolate Borrelia burgdorferi sensu stricto,
the etiologic agent of Lyme borreliosis, from Ixodes spp. ticks recovered from
birds were unsuccessful.
PMID- 10780543
TI - Effect of the digenean parasite Proterometra macrostoma on host morphology in the
freshwater snail Elimia livescens.
AB - Parasitism can affect size in gastropods by altering the host's growth rate, but
other morphological effects of parasitism have rarely been examined. In this
study, the relationship between variation in host morphology and parasitism was
examined in a population of the freshwater snail Elimia livescens. Differences
were found in the morphology of snails infected with the digenean Proterometra
macrostoma and uninfected snails. In order to differentiate between 2 hypotheses
to explain these differences in morphology, snails were experimentally infected
in the laboratory and several morphological traits were measured after 180 days.
One hypothesis suggests that parasite-induced changes in shell development
explain differences in morphology between infected and uninfected snails. The
other hypothesis suggests that selective mortality of infected hosts explains the
difference. In the experiment, differences were found between infected snails and
uninfected snails in overall size but not in any measurements of shape. The short
duration of the experiment relative to the duration of most infections may
account for why field-infected snails differed in shape but experimentally
infected snails did not. Parasite-induced changes in growth rate are the most
likely explanation for the larger size of infected snails relative to uninfected
snails.
PMID- 10780542
TI - Argentophilic structures of miracidia and cercariae of Philophthalmus lucipetus
(Philophthalmidae: Trematoda) from Israel.
AB - Argentophilic structures of Philophthalmus lucipetus miracidia and cercariae from
Israel are described. Eighty-four of 87 miracidia examined displayed an epidermal
plate arrangement of 6:8:4:2 = 20, similar to other Philophthalmus species.
Twenty papilla-like structures are arranged on the terebratorium in 3 groups,
along 1 axis. Sixteen body papillae are located at the bases of epidermal plates
of row 1. Eyespots are mediodorsal, between rows 1 and 2. Excretory pores are
lateral, between rows 2 and 3. Features common to Israeli and Bulgarian isolates,
differentiating them from other species, include the presence of 16 body papillae
as opposed to 10 in other species, and a maximum of 20 papillae on the
terebratorium as opposed to 19 in the others. About 3% of the miracidia displayed
different plate arrangements. Among the argentophilic structures of P. lucipetus
cercariae, the Israeli and Bulgarian P. lucipetus show a common pattern of 2-4
excretory pores in the tail, but arrangement of cephalic CI3 and CI5 papillae in
the 2 isolates is insufficiently unequivocal for species determination. The data
presented show that miracidial characteristics, rather than those of cercariae,
aid in determining the species of philophthalmids. They also support former
evidence attesting to the identity of the Bulgarian and Israeli species.
PMID- 10780544
TI - Ultrastructural analyses of the Caenorhabditis elegans sqt-1(sc13) left roller
mutant.
AB - The sqt-1 gene is 1 of the several loci in Caenorhabditis elegans that primarily
affects organismal morphology. Certain mutations in the sqt-1 gene can produce
left roller animals, i.e., they rotate around their long axis and move in
circular paths. We describe the morphological alterations seen in the cuticle of
the left roller sqt-1(sc13). Deep-etched replica analyses showed that the fibrous
layer is composed of a unique strand of parallel fibers, instead of the 2 meeting
at an angle of 60 degrees as observed in the wild-type strain. In addition,
honeycomb elements, fibers organized in a pentagonal fashion above the fibrous
layer, completely fill the intermediate layer that is empty spaces in the wild
type. These morphological alterations are likely to be involved in generating the
helical twist of the sqt-1(sc13) left roller mutant.
PMID- 10780545
TI - Presence of double-stranded RNAs in human and calf isolates of Cryptosporidium
parvum.
AB - We examined the occurrence of 2 virus-like double-stranded (ds)RNAs in human and
calf isolates of Cryptosporidium parvum senso latu and other microorganisms,
including 7 other members of the genus. A total of 32 isolates of C. parium, 16
from humans (5 from acquired immune deficiency syndrome patients) and 16 from
calves, were analyzed. Ethidium bromide staining, or Northern blot analysis, or
reverse transcription/polymerase chain reaction, or all 3 methods, revealed that
both genotype 1 and genotype 2 isolates of C. parvum possessed these dsRNAs. No
other Cryptosporidium spp. or other organisms examined possessed these dsRNAs.
Comparison analysis of partial cDNA sequences of dsRNAs from human and calf
isolates revealed a high degree of similarity (>92% and >93% identical
nucleotides for large and small dsRNAs, respectively). Slight, consistent
differences in nucleotide sequences could be seen at select sites and were
associated with an isolate being either genotype 1 or 2. Because of the
widespread distribution of the dsRNAs, the similarity of these molecules between
isolates, and high host specificity, these nucleic acids may prove to represent
species-specific molecular markers for C. parvum. Evidence also suggests that the
dsRNA can be utilized for molecular genotyping of C. parvum.
PMID- 10780546
TI - Evolutionary relationships among the Schistosomatidae (Platyhelminthes:Digenea)
and an Asian origin for Schistosoma.
AB - Schistosome blood flukes parasitize birds, mammals, and crocodilians and are
responsible for causing one of the great neglected diseases of humanity,
schistosomiasis. A phylogenetic study of 10 schistosome genera using
approximately 1,100 bases of the large subunit of the nuclear ribosomal gene
complex revealed 2 major clades. One clade is entirely mammalian and includes the
genera Schistosoma and Orientobilharzia. A close examination of relationships in
this group suggests that the medically important Schistosoma arose in Asia and
not in Africa as generally presumed and is paraphyletic. The second clade is
primarily avian, consisting of 6 genera of exclusively avian parasites and 2
genera of North American mammal flukes. These results indicate a secondary host
capture of mammals on the North American continent. This study provides little
evidence concerning the ancestral molluscan or vertebrate schistosome host but
does demonstrate that host switching has been an important feature of schistosome
evolution. Evidence also indicates that the reduced sexual dimorphism
characteristic of some avian schistosomes is derived evolutionarily.
PMID- 10780547
TI - Antigenic analysis of gamonts of Hepatozoon canis purified from leukocytes.
AB - Hepatozoon canis is a tick-borne apicomplexan parasite of dogs that infects
neutrophils and parenchymal tissues. To study the antigenic characteristics of
this parasite, a technique was devised for the purification of gamonts from
peripheral blood neutrophils. White blood cells were separated on Ficoll-Hypaque
density gradients and the gamonts were released from the host neutrophils by
nitrogen cavitation. The blood used for purification originated from dogs with
natural or experimental infections of H. canis with a parasitemia of 1.4-33%. The
number of parasites collected ranged from 1.5 X 10(6) to 4.2 X 10(7). Portions of
purified gamonts were separated and examined under phase and scanning electron
microscopy, and the remaining purified parasites were then used as a source of
antigens to characterize the humoral immune response by western blot analysis.
Serum antibodies from infected dogs recognized more than 15 gamont antigens, and
the antigenic patterns observed with sera from naturally and experimentally
infected dogs were nearly similar. Four immunodominant protein bands of relative
molecular weights of 107, 88, 63, and 28 kDa were recognized by all of the sera
examined. The technique applied here for the isolation of host cell-free gamonts
will facilitate studies on antigenic composition and immune responses against H.
canis and on antigenic relationships between Hepatozoon from different host
species and geographic regions.
PMID- 10780548
TI - Interferon- or interleukin-10 production is induced by related Trypanosoma cruzi
antigens.
AB - The purpose of this study was to evaluate the effects of a crude Trypanosoma
cruzi antigen (TCA) and its partially purified subfractions TCF1, TCF2 on
peripheral blood mononuclear cells (PBMC) of normal donors and chagasic patients.
TCFI and TCF2 stimulated cells from normal donors and chagasic patients in
association with a significant production of interleukin (IL)-10. Only PBMC from
chagasic patients multiplied after incubation with TCA and released mainly
interferon-y but also IL-10. Neither the production of IL-2 and IL-4 nor CD4/CD8
ratios were changed after culture with antigens. These data suggest that some
antigens active during the acute phase of T. cruzi infection would stimulate the
production of cytokines that promote progression of infection, and the immune
system can produce a desired cytokine(s) once the appropriate antigenic stimulus
is used.
PMID- 10780549
TI - Cytokine expression and specific lymphocyte proliferation in two strains of
Cryptosporidium parvum-infected gamma-interferon knockout mice.
AB - Differences in the immune response between 2 strains of interferon-gamma knockout
mice (BALB/c-GKO and C57BL/6-GKO) infected with Cryptosporidium parvum were
examined because the course of infection among these 2 strains is markedly
different. Infection of the BALB/c-GKO with C. parvum (2 X 10(6) oocysts/mouse)
resulted in slight weight loss, oocyst shedding, and recovery from infection by 2
wk postinfection (PI). Infection with 100 oocysts in the C57BL/6-GKO mice
resulted in significant weight loss, oocyst shedding, and death by day 10 PI.
Splenocytes from infected mice were able to proliferate in a dose-dependent
manner to soluble C. parvum-sporozoite antigen (SAg). In vitro stimulation with
SAg resulted in an increase in interleukin (IL)-2, IL-4, IL-5, and tumor necrosis
factor-alpha mRNA cytokine expression from splenocytes of infected BALB/cGKO
mice. In contrast, only IL-5 mRNA expression was increased in the splenocytes
from C. parvum-infected C57BL/6-GKO mice. Phenotypic analysis indicated no
significant differences in the splenic cell populations. Previous studies
indicated that susceptibility to C. parvum is dependent on CD4+ T cells and
interferon-gamma production. The present study indicates that although both of
these strains of knockout mice become infected with C. parvum, resolution of
infection may be in part dependent on the expression of Th2 cytokines.
PMID- 10780550
TI - Rescue of sporocysts of Schistosoma mansoni in nonsusceptible Biomphalaria by
head-foot transplantation into susceptible snails.
AB - To measure the longevity of sporocysts of Schistosoma mansoni in nonsusceptible
snails (13-16-R1 and Salvador strains of Biomphalaria glabrata, and Biomphalaria
obstructa), the head-foot (HF) of miracidia-exposed snails was transplanted into
the hemocoel of a susceptible NIH albino recipient at 1-36 days postexposure
(DPE). Recipient snails which were not exposed to miracidia then were monitored
for infection transferred by the implant, and infection prevalences in recipients
of HF transplants from nonsusceptible donors were compared to those in snails
implanted with an HF from NIH albino donors. Transplants from NIH albino snails
between 1 to 15 DPE infected 98% of recipients. Similarly, at 1 DPE, 69-85% of
transplants from nonsusceptible snails contained viable sporocysts, as shown by
resulting patent infections in the recipients. Recipient infection prevalence,
and presumably numbers of transplants containing viable sporocysts, declined as a
function of DPE, and by 5-9 DPE this decrease was significant for all 3 types of
nonsusceptible donors. However, viable sporocysts still occurred in B. obstructa
and 13-16-R1 B. glabrata as late as 19 and 20 DPE, respectively, and in Salvador
B. glabrata as late as 33 DPE. Thus, sporocysts persist in nonsusceptible snails
considerably longer than suggested by results of previous histological studies.
PMID- 10780551
TI - Morphology and life history of Petasiger variospinosus (trematoda:
echinostomatidae) in the Free State, South Africa.
AB - Specimens of the freshwater snail Bulinus tropicus (Krauss, 1848) collected in
the Free State, South Africa shed cercariae with an oral collar bearing 27
spines. Tadpoles of the African clawed toad Xenopus laevis laevis Daudin, 1802
collected from the same waters harbored metacercariae with a similar collar of
spines. Adults were obtained after feeding infected tadpoles to laboratory-reared
reed cormorants, Phalacrocorax africanus (Gmelin, 1789). The parasite was
identified as Petasiger variospinosus (Odhner, 1910), the life cycle was
experimentally completed, and stages described by the use of light and scanning
electron microscopy.
PMID- 10780552
TI - Natural transfer of helminths of marine origin to freshwater fishes with
observations on the development of Diphyllobothrium alascense.
AB - Infective stages of helminths of 5 species that occur as adults in marine mammals
were found in burbot, Lota lota (L.) (Gadidae), from the lower Kuskokwim River
(southwestern Alaska): Diphyllobothrium alascense Rausch et Williamson, 1958;
Pyramicocephalus phocarum (Fabricius, 1780); Corynosoma strumosum (Rudolphi,
1801); Corynosoma semerme (Forsell, 1904); and Pseudoterranova decipiens (Krabbe,
1878). Some larval stages were obtained also from smelt, Osmerus mordax dentex
Steindachner, an anadromous fish important as prey of burbot. Burbot, which are
freshwater fish, could become paratenic hosts of those helminths by means of at
least 3 interactions: by consuming marine fishes in brackish waters at river
mouths, by feeding on marine fishes that enter lower reaches of rivers, or by
preying on anadromous fishes as they migrate up rivers. Consumption of burbot by
people may result in infection by helminths of marine origin; of those recorded,
only P. decipiens may be significantly pathogenic. Attempts to rear P. phocarum
in dogs were unsuccessful. Plerocercoids of D. alascense, of very small size and
found only in the gastric lumen of burbot, readily infected dogs. For study of
their development, strobilae were obtained at intervals of 48 hr to 32 days
postinfection. In heavy infections, some strobilae developed slowly, while others
underwent rapid development.
PMID- 10780553
TI - Tritrichomonas foetus extracellular cysteine proteinase cleavage of bovine IgG2
allotypes.
AB - Bovine trichomoniasis is a sexually transmitted disease associated with
reproductive failure. Systemic immunization results in protective IgG antibodies
in uterine and vaginal secretions. Because bovine IgG2 is a better opsonin than
IgG1, it is potentially important in defense. Yet, Tritrichomonas foetus
extracellular cysteine proteinase (TFECP) cleaves bovine IgG2, evading protective
IgG2 responses. Variations in resistance of the 2 IgG2 allotypes to digestion may
explain inherited differences in protection. To address this hypothesis, TFECP
was incubated with both IgG2 allotypes at different concentrations and times. The
digestion products were separated by sodium dodecyl sulfate polyacrylamide gel
electrophoresis, stained, and quantitated by image analysis. IgG2a was digested
faster by TFECP than IgG2b. Differences in the sizes and numbers of digestion
products were observed, but the presence of bands the size of Fc and Fd fragments
indicated that both allotypes were cleaved at the hinge. Cysteine in the
digestion mixture reduced the antibody molecules and increased the rate of
digestion, but IgG2a was still more susceptible to cleavage than IgG2b in the
absence of cysteine. Thus, not only reduced H chains can be cleaved by cysteine
proteinase secreted by T. foetus but also intact functional antibody molecules.
Because parasites may evade protective antibody responses by cleaving IgG2,
animals with the more resistant IgG2b allotype may be better protected by
immunization than animals with the more readily digested IgG2a allotype.
PMID- 10780554
TI - Cloning and expression of a cysteine proteinase gene from Paragonimus westermani
adult worms.
AB - A gene encoding a cysteine proteinase from Paragonimus westermani has been cloned
and expressed in Escherichia coli. The cysteine proteinase cDNA fragment was
amplified by reverse transcription-polymerase chain reaction (RT-PCR) using
degenerate oligonucleotide primers derived from the conserved active site of the
cysteine proteinase. The 5' and 3' regions of the gene were amplified using a PCR
technique for the rapid amplification of cDNA ends. The cloned gene has an open
reading frame of 687 bp and deduced amino acid sequence of 229. Sequence analysis
and alignment showed significant homologies with the eukaryotic cysteine
proteinases and conservation of the Cys, His, and Asp residues that form a
catalytic triad. Analysis of the expressed protein on sodium dodecyl sulfate
polyacrylamide gel electrophoresis showed that the molecular weight of the
protein was approximately 28.5 kDa. The expressed protein reacted with the sera
of patients with paragonimiasis but not with the sera of fascioliasis and
clonorchiasis. These results suggest that the expressed protein may be valuable
as a specific diagnostic material for the immunodiagnosis of paragonimiasis.
PMID- 10780555
TI - A new Eimeria sP. from the plumbeous Central American caecilian, Dermophis
mexicanus (amphibia: gymnophiona) from Volcan Tajumulco, Department of San
Marcos, Guatemala.
AB - Fresh fecal samples from 5 caecilians (Dermophis mexicanus) were collected and
examined for coccidia in the summer of 1998. The caecilians were collected in the
Department of San Marcos, Guatemala. Two of the 5 (40%) specimens of caecilians
contained an Eimeria species that is described here as new. This represents the
first coccidia described from a gymnophionian host. Sporulated oocysts are
spheroidal to subspheroidal, 19.5 X 17.7 (16-23 x 15-21) microm, micropyle and
oocyst residuum are absent, and 3 (or more) polar granules are always present.
Sporocysts are ovoidal, 11.0 X 7.2 (10-12 x 6-9); a Stieda body and sporocyst
residuum are present.
PMID- 10780556
TI - Falcaustra kutcheri n. sP. (nematoda: kathlaniidae) from Geoemyda yuwonoi
(testudines: emydidae) from Sulawesi, Indonesia.
AB - Falcaustra kutcheri n. sp. (Nematoda: Kathlaniidae) from feces of the turtle
Geoemyda yuwonoi is described and illustrated. Falcaustra kutcheri n. sp.
represents the 68th species to be assigned to this genus and is distinguished
from other oriental species by the distribution pattern of caudal papillae of the
male: 10 pairs of sessile caudal papillae, 4 pairs precloacal, 1 pair adcloacal,
5 pairs postcloacal.
PMID- 10780557
TI - Molecular systematics of Mesocestoides sPP (cestoda: mesocestoididae) from
domestic dogs (Canis familiaris) and coyotes (Canis latrans).
AB - The genus Mesocestoides Vaillant, 1863 includes tapeworms of uncertain
phylogenetic affinities and with poorly defined life histories. We previously
documented 11 cases of peritoneal cestodiasis in dogs (Canis familiaris L.) in
western North America caused by metacestodes of Mesocestoides spp. In the current
study, DNA sequences were obtained from metacestodes collected from these dogs (n
= 10), as well as proglottids from dogs (n = 3) and coyotes (Canis latrans Say,
1823 [n = 2]), and tetrathyridia representing laboratory isolates of M. corti (n
= 3), and these data were analyzed phylogenetically. Two nuclear genetic markers,
18S ribosomal DNA and the second internal-transcribed spacer (ITS 2), were
sequenced. Phylogenetic analysis of the 18S rDNA data recovered a monophyletic
group composed of all samples of Mesocestoides spp., distinct from closely
related outgroup taxa (Amurotaenia Akhmerov, 1941 and Tetrabothrius Rudolphi,
1819). Initial analysis of the ITS 2 data resolved 3 clades within Mesocestoides.
Two proglottids from dogs formed a basal clade, a second clade was represented by
tetrathyridial isolates, and a third clade included all other samples.
Interpretation of these data from an apomorphy-based perspective identified 6
evolutionary lineages. We also assessed whether metacestodes from dogs (n = 4)
are capable of asexual proliferation in laboratory mice. One tetrathyridial and 2
acephalic isolates from dogs proliferated asexually. Further investigation is
warranted to determine which of the lineages represent distinct species and to
determine the life history strategies of Mesocestoides spp.
PMID- 10780558
TI - Description of Gordionus porosus n. sP. and redescription of Gordionus ondulatus
(Nematomorpha, parachordodinae) with scanning electron microscopy.
AB - Two hairworms from Argentina, Gordionus porosus n. sp. and Gordionus ondulatus
(Nematomorpha, Gordioidea), are described and illustrated. The cuticle of both
species shows only 1 areolar type. Areoles of G. porosus are polygonal and
surrounded by minute bristles and the interareolar groove is wide and with large
pores. Gordionus ondulatus is characterized by rectangular or irregular areoles
from which margins cuticular elongations project as finger-like structures,
giving an undulated appearance. Comparing these species to the remaining American
species of Gordionus, G. porosus is close to Gordionus violaceus by virtue of the
large number of small bristles surrounding the areoles and can be distinguished
by the shape of these bristles and by the arrangement and shape of the areoles.
Gordionus ondulatus differs from the other species of the genus by its undulating
margins. Giordinus lineatus and Giordinus violaceus have been reported in North
America, Giordinus platycephalus in North and Central America, Giordinus
capitosulcatus in Central America, and Giordinus prismaticus, G. ondulatus, and
G. porosus only in South America.
PMID- 10780559
TI - Phylogenetic relationships of Hepatozoon (Apicomplexa: Adeleorina) based on
molecular, morphologic, and life-cycle characters.
AB - To evaluate higher-level affinities of Hepatozoon species within Apicomplexa, we
sequenced the 18S rRNA gene from 2 parasites (Hepatozoon americanum and
Hepatozoon canis) of dogs and 1 (Hepatozoon catesbianae) of bullfrogs. Sequences
from other apicomplexans among the Sarcocystiidae, Eimeriidae, Theileriidae,
Plasmodiidae, Cryptosporiidae, and Babesiidae, a Perkinsus species and 2
dinoflagellates were obtained from GenBank. Phylogenetic analysis indicated that
Plasmodium, Cryptosporidium, and Hepatozoon form a monophyletic group distinct
from representatives of other apicomplexan families. Although equivocal, our
analysis indicated that Plasmodium and Cryptosporidium are sister taxa and that
Hepatozoon is basal to them. To evaluate phylogenetic affinities among H.
americanum, H. canis, and other species of Hepatozoon, we examined 18 morphologic
and life-cycle features of 13 species currently assigned to Hepatozoon. This
analysis indicates paraphyly of Hepatozoon (as currently arranged) because
Hepatozoon lygosomarum was found most closely related to Hemolivia mauritanicum.
These results, combined with results of previous studies, support elevating
Hepatozoon to familial level (Hepatozoidae) as originally suggested by Wenyon in
1926. Both DNA sequence data and morphologic and life-cycle characters support a
sister-group relationship between H. americanum and H. canis.
PMID- 10780560
TI - Six new species of coccidia (Apicomplexa: Eimeriidae) from East African
chameleons (Sauria: Chamaeleonidae).
AB - Coprological examination of 83 East African chameleon specimens revealed 32.5%
prevalence of coccidian parasites. Six species are described as new: Eimeria
tilburyi n. sp. from Chamaeleo jacksonii has cylindrical oocysts, 28.9 (26-33) x
16.0 (14-18) microm and occasionally a small polar granule. Sporocysts are oval
to ellipsoidal, 10.6 (9-12) x 7.2 (6-8) microm, without Stieda and substieda
bodies; endogenous stages were found in the gall bladder. Oocysts of Eimeria
largeni n. sp. from Chamaeleo gracilis are broadly cylindrical, 31.2 (29.5-34) x
19.3 (18.5-20) microm, with 1-3 polar granules. Sporocysts are oval, 10.2 (10-11)
x 7.6 (7-8.5) microm, without Stieda and substieda bodies. Eimeria bohemii n. sp.
from Chamaeleo melleri has cylindrical oocysts, 25.0 (24-26) x 14.0 (13-15)
microm, without a polar granule. Sporocysts are broadly oval, 9.4 (9-10) x 6.5 (6
7) microm, without Stieda and substieda bodies. Isospora wildi n. sp. from
Chamaeleo dilepis has subspherical to broadly oval oocysts, 25 (22-28) x 21.4 (18
24) microm, with a smooth wall 1 microm thick. Sporocysts are broadly oval to
ellipsoidal, 12.3 (12-13) x 9.7 (9-10) microm, with Stieda and substieda bodies.
Oocysts of Isospora necasi n. sp. from C. melleri are subspherical to broadly
oval, 26.6 (21-30) x 24.3 (20-27) microm, with a velvetlike wall 2 microm thick.
Sporocysts are broadly ellipsoidal, 12.8 (12-14) x 9.8 (9-10) microm, with
slightly pointed end and with Stieda and substieda bodies. Oocysts of Isospora
munriyu n. sp. from C. jacksonii are spherical to subspherical, 23.6 (21.5-25) x
21.9 (21-23) microm, with a finely granulated wall 1.5 microm thick. Sporocysts
are broadly ellipsoidal, 12.4 (12-13) X 8.7 (8-10) microm, with Stieda and
substieda bodies.
PMID- 10780561
TI - Phylogeny of the Ascaridoidea (Nematoda: Ascaridida) based on three genes and
morphology: hypotheses of structural and sequence evolution.
AB - Ascaridoid nematodes parasitize the gastrointestinal tract of vertebrate
definitive hosts and are represented by more than 50 described genera. We used
582 nucleotides (83% of the coding sequence) of the mitochondrial gene cytochrome
oxidase subunit 2, in combination with published small- and large-subunit nuclear
rDNA sequences (2,557 characters) and morphological data (20 characters), to
produce a phylogenetic hypothesis for representatives of this superfamily. This
combined evidence phylogeny strongly supported clades that, with 1 exception,
were consistent with Fagerholm's 1991 classification. Parsimony mapping of
character states on the combined evidence tree was used to develop hypotheses for
the evolution of morphological, life history, and amino acid characters. This
analysis of character evolution revealed that certain key features that have been
used by previous workers for developing taxonomic and evolutionary hypotheses
represent plesiomorphic states. Cytochrome oxidase subunit 2 nucleotides show a
strong compositional bias to A+T and a substitution bias to thymine. These biases
are most apparent at third positions of codons and 4-fold degenerate sites, which
is consistent with the nonrandom substitution pattern of A+T pressure. Despite
nucleotide bias, cytochrome oxidase amino acid sequences show conservation and
retention of critical functional residues, as inferred from comparisons to other
organisms.
PMID- 10780562
TI - Two malaria parasites (Apicomplexa: Plasmodiidae) of the Australian skink Egernia
stokesii.
AB - The Australian skink Egernia stokesii is parasitized uncommonly by Plasmodium
circularis n. sp. and by Plasmodium mackerrasae. Plasmodium circularis is
distinguished from all other plasmodiids by immature schizonts that encircle host
cell nuclei, forming an unbroken ring from apparent fusion of the attenuated
ends. Mature schizonts contract into halteridial or dumbbell-shaped forms 15.6 x
4.3 microm, LW 66.2 microm2, with 19-52 nuclei. Rounded or oval gametocytes are
9.0 x 7.3 microm, LW 66.9 microm2, and L/W 1.24. Gametocyte LW is 2.63 x host
erythrocyte nucleus size and 1.79X uninfected erythrocyte nuclei. Plasmodium
mackerrasae occurs in high prevalence and often massive parasitemia in E.
stokesii. Schizonts, often oblong, elongate, or oval, are 5.1 x 3.7 microm, LW
19.8 microm2, with 7.2 merozoites. Immature gametocytes, elongate with terminal
nucleus, may produce multiple infections of 6 or more parasites. Mature
gametocytes, usually rounded, are 5.8 x 4.6 microm, LW 26.7 microm2, and L/W
1.29. Gametocyte size is 0.98 x host erythrocyte nucleus size and 1.03 x
uninfected erythrocyte nuclei. Phanerozoites, in endothelium or connective tissue
of most organs, may appear in large numbers in circulating blood as seemingly
intact bodies of regular form, similar to or larger than phanerozoites seen in
sections. Previously unreported phenomena for hemosporidian parasites include
extremely large, highly irregular exoerythrocytic schizonts, in circulating
blood, perhaps torn from endothelial lining of blood vessels and sinuses, and a
visible flooding of free merozoites into the blood stream.
PMID- 10780563
TI - The sesquiterpene lactone dehydroleucodine (DhL) affects the growth of cultured
epimastigotes of Trypanosoma cruzi.
AB - Here, we report an inhibitory effect of a sesquiterpene lactone dehydroleucodine
(DhL) on the growth of Trypanosoma cruzi in culture. At concentrations of the
drug between 5 and 10 microg/ml in the medium,the parasites remained alive for at
least 4 days. Higher concentrations of DhL were lethal for the parasites within a
few hours. The effect of DhL is irreversible. Morphological changes induced by
DhL were also observed in the parasites. The effect of DhL was blocked by the
presence of reducing substrates such as glutathione or dithiothreitol, but these
agents were not able to reverse the effect of DhL if added 2 days after the start
of drug exposure.
PMID- 10780564
TI - Cryptosporidium serpentis oocysts and microsporidian spores in feces of captive
snakes.
AB - Fecal smears of 90 snakes, 29 lizards, and 8 turtles and tortoises were tested
for Cryptosporidium spp. oocysts and microsporidian spores. Microsporidian spores
measured mean = 3.7 microm in length and mean = 2.3 microm in width and were
present in feces of 19 snakes and 1 lizard (16%); 13 of these snakes also shed
Cryptosporidium serpentis oocysts. The oocysts were numerous in all positive
samples, whereas microsporidian spores were always sparse, irrespective if
whether fecal samples contained the oocysts. Retrospective examination of reptile
clinical records revealed that all animals shedding microsporidian spores died
naturally due to diseases, pathologic conditions, and clinical problems or were
killed due to severe cryptosporidiosis. The present study indicates that
microsporidian infections in reptiles have the features of an opportunistic
infection.
PMID- 10780565
TI - Survival and distribution of Echinostoma caproni in the small intestine of ICR
mice up to 36 hours after the death of the host.
AB - This study examined survival and distribution of Echinostoma caproni in the small
intestine of ICR mice at various times up to 36 hr following the death of the
host. Adult worms were obtained at 2-wk postinfection of 21 ICR mice each
infected with 50 metacercarial cysts. Mice were killed with light ether
anesthetization and cervical dislocation and maintained at room temperature (22
+/- 1C) until examination at 0 (controls), 2, 4, 6, 12, 24, and 36 hr postmortem.
Survival was based on worm activity and distribution was assessed on the basis of
worm location in 1 of 5 equal intestinal segments numbered from the pylorus to
the ileocecal valve. Worms were alive up to 36 hr post-mortem and were
distributed mainly in segments 3 and 4 at all times postmortem. Histochemical Oil
Red O studies on whole control and experimental worms showed neutral lipids
localized in the protone-phridial tubules and the excretory bladder. Eggs from
experimental worms at all times produced miracidia that infected Biomphlaria
glabrata snails.
PMID- 10780566
TI - Host death: a necessary condition for the transmission of Aphalloides coelomicola
Dollfus, Chabaud, and Golvan, 1957 (Digenea, Cryptogonimidae)?
AB - Eggs of the trematode Aphalloides coelomicola were observed free in the abdominal
cavity of Pomatoschistus microps from March 1993 to October 1995 (Pisces,
Gobiidae) in the Vaccares lagoon (delta du Rhone, France). The eggs were
contained in a fine membrane of parasitic origin as no immunological reaction of
the fish was noted. The alternatively high prevalence of adults and low
prevalence of free eggs, and vice versa, suggest that P. microps is both the
second intermediate and final hosts of the trematode Aphalloides coelomicola and
that the mechanism of transfer to the first intermediate host is through death of
the definitive host.
PMID- 10780567
TI - The palearctic oystercatcher Haematopus ostralegus, a natural definitive host for
Gymnophalloides seoi.
AB - In order to verify the role of migrating birds as natural definitive hosts for
Gymnophalloides seoi (Gymnophallidae), Palearctic oystercatchers, Haematopus
ostralegus, were caught from several western coastal areas in the Republic of
Korea and examined for intestinal flukes. Five (71.4%) of 7 oystercatchers were
infected with 302-1,660 (mean 892) adult G. seoi. In intestinal sections of the
host, worms were found in the intervillous space of the mucosal layer. We
conclude that the oystercatcher is a natural definitive host for G. seoi.
PMID- 10780568
TI - Defining GERD.
AB - "It is not the death of GERD that I seek, but that it turns from its evil ways
and follows the path of righteousness." The reflux world is fully aware of what
GERD is and what GERD does. What the world does not know, however, is the answer
to the most important yet least asked question surrounding GERD's raison-d'etre:
Why is GERD here and why do we have it? What GERD is: abnormal gastric reflux
into the esophagus that causes any type of mischief. What GERD does: causes
discomfort and/or pain with or without destroying the mucosa; causes stricture or
stenosis, preventing food from being swallowed; sets the stage for the
development of esophageal adenocarcinoma; invades the surrounding lands to harass
the peaceful oropharyngeal, laryngeal and broncho-pulmonary territories; reminds
us that we are not only human, but that we are dust and ashes. Why GERD is here:
We propose three separate and distinct etiologies of GERD, and we offer the
following three hypotheses to explain why, after 1.5 million years of standing
erect, we have evolved into a species (specifically Homosapiens sapiens) that is
destined to live with the scourge of GERD. Hypothesis 1: congenital. The
antireflux barrier, comprising the smooth-muscled lower esophageal sphincter, the
skeletal-muscled right crural diaphragm and the phreno-esophageal ligament does
not completely develop due to a developmental anomaly or incomplete gestation.
Hypothesis 2: acute trauma: The antireflux barrier in adults suffering acute
traumatic injury to the abdomen or chest is permanently disrupted by unexpected
forces, such as motor vehicle accidents (with steering wheel crush impact), blows
to the abdomen (from activities such as boxing, etc.), heavy lifting or moving
(e.g., pianos, refrigerators) or stress positions (e.g., hand stands on parallel
gym bars). The trauma creates a hiatal hernia that renders the antireflux
mechanism useless and incapable of preventing GERD. Hypothesis 3: chronic trauma:
The antireflux barrier in children and adults is gradually weakened over time as
a result of chronic straining to defecate and straining in an unphysiologic
position, both of which stem from our modern day habits of eating a low-fiber
diet and living on the high-seated toilet. We suggest that the chronic traumatic
hiatal hernia is (a) the cause of more than 90 percent of the GERD that stalks
the Western world; (b) is a direct result of abandoning the popular and worldwide
practice of squatting to socialize, eat and defecate; and (c) is our just reward
for adopting the "civilized" high sitting position on chairs and modern toilets.
PMID- 10780569
TI - Clinical epidemiology and natural history of gastroesophageal reflux disease.
AB - In the MUSE classification of gastroesophageal reflux disease (GERD), esophagitis
is assessed by the presence of metaplasia, ulcer, stricture, or erosion, each
being graded as absent, mild or severe. Daily reflux symptoms affect about 4 to 7
percent of the population; erosive esophagitis occurs in about 2 percent; the
prevalence rate of Barrett's metaplasia is 0.4 percent; and esophageal
adenocarcinoma leads to two deaths per million living population. In persons with
GERD symptoms, about 20 percent are found to have erosive esophagitis, while
ulcers or strictures are found in less than 5 percent of all patients with
erosive esophagitis. No clear-cut temporal progression exists between successive
grades of disease severity, as the most severe grade of GERD is reached at the
onset of the disease. Mild forms of GERD tend to be more common in women than
men, while severe GERD characterized by erosive esophagitis, esophageal ulcer,
stricture or Barrett's metaplasia are far more common in men than women. All
forms of GERD affect Caucasians more often than African Americans or Native
Americans. The prevalence of GERD is high among developed countries in North
America and Europe and relatively low in developing countries in Africa and Asia.
During the past three decades, hospital discharges and mortality rates of gastric
cancer, gastric ulcer and duodenal ulcer have declined, while those of esophageal
adenocarcinoma and GERD have markedly risen. These opposing time trends suggest
that corpus gastritis secondary to Helicobacter pylori infection protects against
GERD. This hypothesis is consistent with the geographic and ethnic distributions
of GERD. Case-control studies also indicate that cases with erosive esophagitis
are less likely to harbor active or chronic corpus gastritis than controls
without esophagitis.
PMID- 10780570
TI - Endoscopic evaluation of gastro-esophageal reflux disease.
AB - Endoscopy is, currently, the initial investigation of choice for the
investigation of gastroesophageal reflux disease (GERD) in clinical practice and
clinical research. Erosion severity is predictive of a patient's response to
therapy and of the likelihood of relapse after therapy. It is, therefore,
important to grade the severity of erosive reflux esophagitis, particularly in
the context of clinical trials. The Savary-Miller endoscopic classification
system is used widely but usage and interpretation are very variable. The "MUSE"
(metaplasia [M], ulceration [U], stricturing [S] and erosions [E]) classification
provides clear definitions of the relevant endoscopic features, and it is based
on a standardized report form, which allows the endoscopist to make a clear
record of esophagitis severity. Recent studies confirm that endoscopists can
identify erosions or mucosal breaks, ulcers, strictures, and metaplasia
reproducibly. The "L.A." (Los Angeles) classification describes four grades of
esophagitis severity (A to D), based on the extent of esophageal lesions known as
"mucosal breaks," but it does not record the presence or severity of other GERD
lesions. Thus, for patients with "complicated" reflux disease, the "MUSE"
classification offers a more comprehensive description of esophagitis severity.
Endoscopy is not universally applicable: 40 to 60 percent of patients with
typical reflux symptoms do not have esophageal erosions and are now considered to
have "endoscopy negative reflux disease" (ENRD). Thus, endoscopy is not the final
arbiter as to a diagnosis of reflux disease, and it is not, therefore, a
necessary prerequisite to therapy. Endoscopy is indicated at first presentation
for patients with alarm symptoms referable to the upper gastrointestinal tract.
It has also been proposed that all patients with chronic GERD should have a "once
in-a-lifetime" endoscopy; in the absence of Barrett's esophagus or other
complications, no follow-up is required unless the patient's symptoms change
significantly. A surveillance program with multiple biopsies should be instituted
if there is evidence of Barrett's esophagus. Endoscopic evaluation should
document the presence and extent of esophageal erosions using the L.A. or MUSE
classification systems; complications should also be documented and may be
recorded using the MUSE classification. Non-erosive changes such as erythema may
be ignored on the basis of present evidence, and there are no clear data to
support the use of endoscopic biopsies for the diagnosis of GERD.
PMID- 10780571
TI - The role of hiatus hernia in GERD.
AB - Increased esophageal acid exposure in gastroesophageal reflux disease has several
potential causes, some related primarily to physiological dysfunction of the LES
and others related to anatomic distortion of the gastroesophageal junction as
occurs with hiatus hernia. One attractive feature of implicating hiatal hernias
in the pathogenesis of reflux disease is that, like reflux disease, axial hernias
become more common with age and obesity. However, the importance of hiatus hernia
is obscured by imprecise definition and an all-or-none conceptualization that has
led to wide variation in estimates of prevalence among normal or diseased
populations. There are at least three potentially significant radiographic
features of a hiatus hernia: axial length during distention, axial length at
rest, and competence of the diaphragmatic hiatus. Although any or all of these
features may be abnormal in a particular instance of hiatus hernia, each is of
different functional significance. Grouping all abnormalities of the
gastroesophageal junction as "hiatus hernia" without detailing the specifics of
each case defies logic. Mechanistically, the gastroesophageal junction must
protect against reflux both in static and dynamic conditions. During abrupt
increases in intra-abdominal pressure, the crural diaphragm normally serves as a
"second sphincter," and this mechanism is substantially impaired in individuals
with a gaping hiatus. Large, non-reducing hernias also impair the process of
esophageal emptying, thereby prolonging acid clearance time following a reflux
event (especially while in the supine posture). These anatomically-determined
functional impairments of the gastroesophageal junction lead to increased
esophageal acid exposure. Thus, although hiatus hernia may or may not be an
initiating factor at the inception of reflux disease, it clearly can act as a
sustaining factor accounting for the frequently observed chronicity of the
disease.
PMID- 10780573
TI - Epithelial lineage and transformation.
PMID- 10780572
TI - Rab11 in dysplasia of Barrett's epithelia.
AB - Barrett's esophagus predisposes affected patients to the development of
esophageal adenocarcinoma. The development of adenocarcinoma proceeds along a
progression through low- and high-grade dysplasia. Surveillance of Barrett's
patients requires serial endoscopic investigations and grading mucosal biopsies.
Unfortunately, grading of biopsies by conventional hematoxylin and eosin staining
is fraught with significant interobserver variations. We have found in both
biopsy and resection specimens that immunostaining for the small GTP binding
protein Rab11 is increased in low-grade dysplastic cells. This staining is lost
in high-grade dysplastic cells. These results suggest that low-grade dysplastic
cells undergo an apical trafficking blockade, which is released as cells progress
to the less differentiated phenotype of high-grade dysplasia and adenocarcinoma.
Examination of the SKGT-4 esophageal adenocarcinoma cell line demonstrated
prominent mRNA and protein expression for Rab11. Rab11 immunostaining was present
in SKGT-4 cells as a perinuclear nidus of punctate staining along with a more
diffuse punctate pattern. Thus, Rab11 expression was present in a esophageal
adenocarcinoma cells in culture. Markers of vesicle trafficking may be critical
factors for grading of mucosal dysplastic transitions leading to adenocarcinoma.
PMID- 10780574
TI - Acid and the esophagus.
PMID- 10780575
TI - Pepsin and the esophagus.
AB - Esophagitis results from excessive exposure of the esophagus to gastric juice
through an ineffective or dysfunctional lower esophageal sphincter mechanism. A
possible role of pepsin in damaging the esophageal mucosa with consequent
esophagitis may be examined directly by testing pepsin under various conditions
in experimental models of esophagitis. Since gastric juice contains both acid and
pepsin, all experiments examine separately effects of perfusion of the esophagus
by acid without and with pepsin in various combinations. Acid perfusion alone at
concentrations represented by pH 1.3 or above does not produce esophagitis. The
addition of pepsin to acid between pH 1 and 3.5 causes considerable acute
esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5,
pepsin does not damage the esophagus. The damage caused by acidified pepsin may
be made much worse by the further addition of aspirin or other NSAIDs, presumably
by further breaking down mucosal barriers.
PMID- 10780576
TI - Helicobacter pylori and dyspepsia.
AB - It is clear that non-ulcer (or functional) dyspepsia is a heterogeneous syndrome
that includes a subset of patients with unrecognized gastroesophageal reflux.
Patient heterogeneity combined with inadequate study methodology has led to
enormous confusion in interpreting the relationship between Helicobacter pylori
and non-ulcer dyspepsia. The possibility that H. pylori is associated with
gastroesophageal reflux disease may explain, in part, the difficulty in
establishing a link between non-ulcer dyspepsia and H. pylori infection. It is
unclear whether the prevalence of H. pylori is increased in non-ulcer dyspepsia
over and above the background population. H. pylori does not appear to be linked
to heartburn or other specific upper gastrointestinal tract symptoms. The results
of eradication trials in H. pylori-infected patients with non-ulcer dyspepsia
have been equivocal and generally flawed. There is no doubt that H. pylori is not
a sufficient cause of non-ulcer dyspepsia, because it is well documented in the
literature that dyspepsia can occur in the absence of infection and infection can
occur in the absence of symptoms. At this stage, there is insufficient evidence
to support the hypothesis that H. pylori is etiologically linked to non-ulcer
dyspepsia, but data from well designed large randomized controlled trials of
eradication therapy, are awaited with great interest.
PMID- 10780578
TI - Drugs, bugs, and esophageal pH profiles.
AB - Until relatively recently, gastroesophageal reflux disease (GERD) was thought to
be a relatively trivial problem, and pharmaceutical companies initially had
remarkably little interest in clinical trials for GERD. Over the last ten years,
GERD therapy has become the subject of intense interest, since reflux disease is
now recognized as a major market for antisecretory and prokinetic drugs. Even low
technology antacids are now known to effectively neutralize esophageal acid
prevent acid reflux for up to 90 minutes. Esophageal pH profiling is known to be
an excellent surrogate for clinical efficacy of GERD drugs, particularly in
erosive esophagitis. Years ago, famotidine normalized esophageal mucosal exposure
to pH < 4.0 only when administered in doses of 40 mg twice a day. Subsequent
studies confirmed that multiple daily dosing of histamine-2 receptor antagonists
(H2RAs) was mandatory for GERD treatment, with clear dose-response relationships
for each agent. Proton pump inhibitors (PPIs) have each been carefully assessed
in terms esophageal and gastric pH profiles. Omeprazole has a particularly flat
dose response curve, making it difficult to differentiate pH or clinical effects
of 20 vs. 40 mg doses. Improved rapidity of onset and/or enhanced potency is
demonstrable in pH data obtained with lansoprazole, rabeprazole and pantoprazole.
Such differences will translate to improved clinical efficacy, based on the meta
analyses of Richard Hunt and his group in Canada that correlate pH effects and
symptom relief/healing. PPI's have dependably surpassed H2RAs and prokinetic
drugs in management of the more severe grades of esophagitis. Helicobacter pylori
has a peculiar relationship to GERD. There has been some concern that PPIs given
to patients with H. pylori might accelerate development of severe atrophic
gastritis. It is also now known that eradication of H. pylori may increase
symptomatic GERD (possibly as a result of increased gastric acid secretion once
the bacteria have been eliminated). New data confirm nocturnal breakthrough of
acid secretion and esophageal acid exposure in three-fourths of patients on
omeprazole 20 mg twice daily. This nocturnal acidity can be controlled more
effectively with a nighttime dose of an H2RA than with a third dose of
omeprazole. Control of acid secretion and improved gastric and esophageal pH
profiles are goals of modern GERD therapy, and the product that most cost
effectively normalizes esophageal acid exposure will have a substantial advantage
in the ever-growing GERD marketplace.
PMID- 10780577
TI - Signal transduction in esophageal and LES circular muscle contraction.
AB - Contraction of normal esophageal circular muscle (ESO) in response to
acetylcholine (ACh) is linked to M2 muscarinic receptors activating at least
three intracellular phospholipases, i.e., phosphatidylcholine-specific
phospholipase C (PC-PLC), phospholipase D (PLD), and the high molecular weight
(85 kDa) cytosolic phospholipase A2 (cPLA2) to induce phosphatidylcholine (PC)
metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA),
resulting in activation of a protein kinase C (PKC)-dependent pathway. In
contrast, lower esophageal sphincter (LES) contraction induced by maximally
effective doses of ACh is mediated by muscarinic M3 receptors, linked to
pertussis toxin-insensitive GTP-binding proteins of the G(q/11) type. They
activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate
(PIP2), producing inositol 1,4,5-trisphosphate (IP3) and DAG. IP3 causes release
of intracellular Ca++ and formation of a Ca++-calmodulin complex, resulting in
activation of myosin light chain kinase and contraction through a calmodulin
dependent pathway. Signal transduction pathways responsible for maintenance of
LES tone are quite distinct from those activated during contraction in response
to maximally effective doses of agonists (e.g., ACh). Resting LES tone is
associated with activity of a low molecular weight (approximately 14 kDa)
pancreatic-like (group 1) secreted phospholipase A2 (sPLA2) and production of
arachidonic acid (AA), which is metabolized to prostaglandins and thromboxanes.
These AA metabolites act on receptors linked to G-proteins to induce activation
of PI- and PC-specific phospholipases, and production of second messengers.
Resting LES tone is associated with submaximal PI hydrolysis resulting in
submaximal levels of inositol trisphosphate (IP3-induced Ca++ release, and
interaction with DAG to activate PKC. In an animal model of acute esophagitis,
acid-induced inflammation alters the contractile pathway of ESO and LES. In LES
circular muscle, after induction of experimental esophagitis, basal levels of PI
hydrolysis are substantially reduced and intracellular Ca++ stores are
functionally damaged, resulting in a reduction of resting tone. The reduction in
intracellular Ca++ release causes a switch in the signal transduction pathway
mediating contraction in response to ACh. In the normal LES, ACh causes release
of Ca++ from intracellular stores and activation of a calmodulin-dependent
pathway. After esophagitis, ACh-induced contraction depends on influx of
extracellular Ca++, which is insufficient to activate calmodulin, and contraction
is mediated by a PKC-dependent pathway. These changes are reproduced in normal
LES cells by thapsigargin-induced depletion of Ca++ stores, suggesting that the
amount of Ca++ available for release from intracellular stores defines the signal
transduction pathway activated by a maximally effective dose of ACh.
PMID- 10780579
TI - Pharmacologic modulation of motility.
AB - Etiologically, gastroesophageal reflux disease (GERD) can be regarded as motility
disorder: Although blocking acid is effective in the treatment of GERD, it does
not overcome the underlying pathologic factors that allow acid, pepsin, and bile
to reflux into the esophagus. Prokinetic agents address the upper
gastrointestinal motility disturbances contributing to GERD and, thus, have an
important role in the short- and long-term medical management of reflux
esophagitis. This paper discusses the rationale for the effectiveness of
pharmacologic modulation by reviewing current concepts and postulated theories
about the mechanisms underlying the neuromuscular abnormalities. The
multifactorial aspects of GERD are addressed and the potential for tailoring
medical therapy also emphasized.
PMID- 10780581
TI - Helicobacter pylori modulation of gastric acid.
AB - Helicobacter pylori plays major causative roles in peptic ulcer disease and
gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs)
contributes to duodenal injury, and diminished acid secretion in patients with
gastric cancer allows carcinogen-producing bacteria to colonize the stomach.
Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU
patients and hypo-secreting relatives of gastric cancer patients. Therefore, we
and others have asked how H. pylori causes these disparate changes in acid
secretion. H. pylori gastritis more or less restricted to the gastric antrum in
DU patients is associated with increased acid secretion. This is probably because
gastritis increases release of the antral acid-stimulating hormone gastrin and
diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial
products and inflammatory cytokines including TNFalpha may cause these changes in
endocrine function. Gastritis involving the gastric corpus tends to diminish acid
secretion, probably because bacterial products and cytokines including IL-1
inhibit parietal cells. Pharmacological inhibition of acid secretion increases
corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric
hypo-secretion of any cause might become self-perpetuating. H. pylori-associated
mucosal atrophy will also contribute to acid hypo-secretion and is more likely in
when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric
acid secretion in patients with esophagitis are limited but suggest that acid
secretion is normal or slightly diminished. Nevertheless, H. pylori infection may
be relevant to the management of esophagitis because: (i) H. pylori infection
increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump
inhibitors may increase the tendency of H. pylori to cause atrophic gastritis;
and (iii) successful eradication of H. pylori is reported to increase the
likelihood of esophagitis developing in patients who had DU disease. Points (ii)
and (iii) remain controversial and more work is clearly required to elucidate the
relationship between H. pylori, acid secretion, gastric mucosa atrophy and
esophagitis.
PMID- 10780582
TI - Management of gastroesophageal reflux disease: the primary care strategy.
AB - Gastroesophageal reflux disease (GERD) is a common problem in the community and
in general practice. General practitioners and family physicians need to
understand patients' reasons for consultation and also be aware of alarm symptoms
suggestive of serious disease. A primary care management strategy for GERD is
proposed, in which the place of endoscopic and other investigations is defined,
the role of lifestyle modification discussed, and recommendations for longer-term
therapy and management are made.
PMID- 10780580
TI - pH, healing rate, and symptom relief in patients with GERD.
AB - Gastroesophageal reflux symptoms are common and occur in all of us from time to
time. In others, reflux may be associated with ulcerative esophagitis. The
symptoms may be aggravated by large meals, coffee, smoking and position.
Physiological and pathological reflux can be separated by the frequency and
duration of the exposure of the lower esophagus to acid. Pathological reflux
results in symptoms and also esophagitis and ulceration in some patients.
Although gastroesophageal reflux disease (GERD) is considered to result from a
disorder of motility in the esophagus, gastric acid and peptic activity are
deemed pivotal to the initiation and continuation of the esophageal damage and
the development of symptoms. Acid exposure in the esophagus is normally less than
4 percent of the 24 hours with a pH below 4. An increase over 4 percent of the
time with a pH less than 4 is considered pathological. Hence, antisecretory drugs
have become the principle approach to the treatment of reflux symptoms and
esophagitis since they reduce the acidity, of gastric juice and the activity of
pepsin. Importantly, they also reduce the volume of gastric juice available for
reflux into the esophagus. There is a clear relationship between the degree and
duration of acid suppression and the relief of heartburn and healing of
esophagitis. Pharmacodynamic studies with different dose regimens of the H2
receptor antagonists and the proton pump inhibitors show a difference in the
degree and duration of the antisecretory effect, and this correlates closely with
the results of clinical trials with respect to the healing of esophagitis and the
relief of symptoms. Proton pump inhibitors achieve healing rates by week four,
which are not achieved by H2-receptor antagonists even after 12 weeks of
treatment. The advantage of proton pump inhibitors over H2-receptor antagonists
is due to the greater degree, longer duration of effect and more complete
inhibition of acid secretion that maintains intragastric pH above 4 for a maximal
duration. Although there is no significant difference between proton pump
inhibitors with respect to healing of esophagitis, symptom relief occurs earlier
with lansoprazole than omeprazole, and this is probably due to the greater oral
bioavailability and faster onset of action of lansoprazole when compared to
omeprazole.
PMID- 10780583
TI - Helicobacter pylori, proton pump inhibitors and gastroesophageal reflux disease.
AB - Proton pump inhibitors have become of pivotal importance for the treatment of
GERD. The purpose of this paper is to review the interaction between Helicobacter
pylori and PPIs in the treatment of GERD. H. pylori exaggerates the acid
suppressive effects of PPIs. During treatment with these drugs, H. pylori
positive subjects thus have a higher intragastric pH than H. pylori-negative
subjects. The mechanism for this phenomenon remains to be elucidated. We
hypothesize that it is related to H. pylori-induced corpus gastritis, which
impairs parietal cell function. The available evidence suggests that this
phenomenon has no clinical relevance for the treatment of GERD. The 24-hr
esophageal pH during PPI treatment does not depend on the H. pylori status, nor
does the medication dose needed for maintenance therapy or the number of clinical
relapses during such therapy depend on the H. pylori status. PPIs, on the other
hand, also affect H. pylori. During treatment with these drugs, the pattern of
bacterial colonization and associated gastritis shifts proximally. The increased
gastritis of the body mucosa is associated with a more rapid development of
atrophic gastritis, a condition characterized by a loss of gastric glands and
associated with an increased cancer risk. For these reasons, one has to consider
H. pylori eradication in infected GERD patients in need of PPI maintenance
therapy.
PMID- 10780584
TI - Medical therapy of gastroesophageal reflux disease in secondary and tertiary care
settings.
AB - Gastroesophageal reflux disease (GERD) is common. Many patients with recurring or
troublesome symptoms are referred for endoscopic examination. Patients seen in
secondary care usually have failed OTC or primary care anti-reflux therapy. Acid
suppression is the mainstay of healing and maintenance therapy. Increasingly
proton pump inhibitors (PPIs) are preferred above H2 receptor antagonists
(H2RAs), not only for the more severe end of the GERD spectrum but also for
patients with mild degrees of esophagitis. Not all patients respond
symptomatically to acid suppression, not even with high dose PPI. Prokinetics are
mainly useful in the milder degrees of GERD. It is still not clear whether a
particular symptom cluster can be recognized for which prokinetics are especially
useful. The concept of "step-up versus step-down" approach remains in need for
proper validation. Switching from PPIs to cisapride for "step-down" maintenance
appears inadequate in practice. All current therapies have shortcomings; H2RAs
insufficiently block meal-stimulated acid secretion; long-term strong acid
suppression worsens Helicobacter pylori-associated inflammation in the corpus and
may accelerate development of atrophy; PPI-potency is substantially weaker in non
H. pylori infected individuals. Optimization of individualized therapy will
require more potent and more precisely targeted motility modulating drugs and
superior acid/peptic inhibiting pharmaceuticals.
PMID- 10780585
TI - Acid inhibition and gastroesophageal reflux disease.
PMID- 10780586
TI - The effect of surgery on pressure and motility.
PMID- 10780587
TI - Elderly injury: a profile of trauma experience in the Sunshine (Retirement)
State.
AB - OBJECTIVE: By using mandatory discharge data from a state agency, the records of
116,687 patients hospitalized for treatment of injury were evaluated to develop
an epidemiologic and demographic profile of this population and to compare
outcomes of patients treated in state-designated trauma centers (TC) with those
treated in nontrauma centers (NTC). METHODS: Injury severity was calculated by
using the International Classification Injury Severity Score methodology to
compute individual diagnosis survival risk ratios from 698,187 reported
diagnoses, and then by using these survival risk ratios to determine probability
of survival for every patient. The population was then categorized by age, injury
type, treatment facility designation, injury severity as indicated by probability
of survival, and discharge disposition. Incidence of potentially preventable
death was compared between TC and NTC, as was the effect on outcome of noninjury
comorbidity. RESULTS: The average age of this population was 58 +/- 26 years with
significant skew toward the elderly in NTC (mean age, 62 +/- 26 years). The most
commonly encountered injuries likewise reflected the elderly nature of this
population. Although 71.3% received care in NTC, the majority of severely injured
were treated in TC. Potentially preventable mortality (>0.5) was significantly
lower in TC. The effect of noninjury comorbidity on outcome was better managed by
TC, both in terms of decreased mortality and in proportion of patients discharged
home. CONCLUSION: These data demonstrate the unique characteristics of injury
victims treated in the state of Florida and indicate that the developing trauma
system is demonstrating productivity in terms of avoidance of preventable death,
efficient management of noninjury comorbid problems, and more complete recovery
as indicated by proportion of patients discharged to home.
PMID- 10780588
TI - Factors affecting prognosis with penetrating wounds of the heart.
AB - OBJECTIVE: To determine factors affecting prognosis for patients with penetrating
wounds of the heart. METHODS: A retrospective review of 302 patients with
penetrating heart wounds undergoing emergency thoracotomy (August of 1980 through
June of 1997) in a Level I trauma center. RESULTS: There were 148 patients with
gunshot wounds (GSW) and 154 patients with stab wounds with 23% and 58% survival
rates, respectively. Of 43 patients having no signs of life at the scene, 5
patients (12%) achieved some cardiac activity and were brought to the operating
room (OR), but none survived. Of 67 patients "arresting" in the ambulance, 23 got
to the OR, but only 3 patients (4%) survived. Of 27 patients "arresting" in the
emergency department (ED), 18 patients reached the OR, but only 5 patients (19%)
survived. Of 15 patients having an ED thoracotomy because of rapid deterioration
there, 4 patients (27%) survived. Thus, of the 152 patients with an ED
thoracotomy, 93 patients had gunshot wounds and none survived; of the 59 with
stab wounds, 12 (20%) survived (p < 0.001). Of 150 patients having an OR
thoracotomy, 111 (74%) survived. Single-chamber injuries had a survival rate of
51% (112 of 219 patients), but multiple chamber and/or intrapericardial great
vessel injuries had only a 13% survival rate (11 of 83 patients) (p < 0.001).
Intrapericardial aortic injuries were uniformly fatal in 15 patients. In patients
with stab wounds, pericardial tamponade was associated with a higher survival
rate (66%; 56 of 84 patients) than in those without tamponade (47%; 33 of 70
patients). CONCLUSION: The physiologic status of the patient at presentation,
mechanism of injury, and presence of a tamponade were significant prognostic
factors in this series of penetrating cardiac injuries. Multiple-chamber
injuries, especially with great vessel involvement, were associated with a high
mortality rate. ED thoracotomies for gunshot wounds of the heart were uniformly
fatal.
PMID- 10780589
TI - Major trauma enhances store-operated calcium influx in human neutrophils.
AB - PURPOSE: Chemotaxins from inflammatory sites prime or activate neutrophils (PMN)
by using cytosolic calcium ([Ca2+]i) fluxes as second messengers. [Ca2+]i can be
mobilized rapidly by receptor-mediated entry or store-release, or more slowly by
store-operated calcium influx (SOCI). We studied [Ca2+]i mobilization by
chemotaxins and how trauma impacts the calcium entry mechanisms used by
chemotaxins. METHODS: [Ca2+]i flux was studied by spectrofluorometry. The
contributions of early and late [Ca2+]i currents to net calcium flux were
compared after stimulation by more potent (fMLP, C5a, PAF) or less potent (IL-8,
GRO-alpha, and LTB4) agonists. Store operated [Ca2+]i mobilization was reflected
by the ratio of area under the [Ca2+]i efflux curve to peak [Ca2+]i (efflux
curve). PMN from trauma patients (ISS > 25) and pair-matched volunteer (n = 7
pairs) were then primed and stimulated with thapsigargin to compare cell calcium
stores and SOCI. RESULTS: Late [Ca2+]i mobilization made more important
contributions to fMLP, PAF, and C5a signals than to IL-8, GRO-alpha, or LTB4 (p <
0.01 all comparisons). Calcium stores and store release were only marginally
lower after injury (p = not significant), but trauma PMN showed far higher
[Ca2+]i influx after thapsigargin (p = 0.007), and greater net SOCI (p = 0.034).
CONCLUSIONS: SOCI may play an important role in PMN activation, and trauma
increases PMN SOCI. Prolonged elevations of [Ca2+]i due to enhanced SOCI may
alter stimulus-response coupling to chemotaxins and contribute to PMN dysfunction
after injury.
PMID- 10780590
TI - Inhibition of neutrophil apoptosis after severe trauma is NFkappabeta dependent.
AB - BACKGROUND: Systemic inflammation may inhibit neutrophil (PMN) apoptosis and
promote multiple organ dysfunction syndrome. We hypothesize that severe trauma
causes dysregulation of PMN apoptosis. METHODS: Neutrophils were isolated from
trauma patients (24-72 hours after injury; n = 16) and controls (healthy
volunteers) and incubated for 18 hours. In separate experiments, control cells
were treated +/- the nuclear factor kappa beta (NFkappabeta) inhibitor
pyrrolidinithiocarbamate then incubated with 25% patient or control plasma.
Apoptosis was quantified by enzyme-linked immunosorbent assay for histone
associated DNA and annexin V fluorescence-activated cell sorter. NFkappabeta
activation was determined by Western blot for phosphorylated I kappabeta.
RESULTS: Apoptosis was inhibited in trauma patient PMN. Neutrophil apoptosis
correlated with multiple organ dysfunction syndrome score, Acute Physiology and
Chronic Health Evaluation II, and platelet count. Patient plasma inhibited
apoptosis and induced phosphorylation of I kappabeta in control cells. Inhibition
of PMN apoptosis by patient plasma was blocked by pretreatment with
pyrrolidinithiocarbamate. CONCLUSION: NFkappabeta-dependent inhibition of
neutrophil apoptosis occurs after trauma. Early inhibition of PMN apoptosis is
dependent on the magnitude of injury.
PMID- 10780591
TI - Age should not be a consideration for nonoperative management of blunt splenic
injury.
AB - BACKGROUND: Operative management of blunt splenic injury is recommended for
adults > or = 55 years. Because this is not our practice, we did a retrospective
review to compare outcomes of patients > or = 55 years old versus patients < 55
years old. METHODS: During a 5-year period ending in July of 1998, 461 patients
(3%) admitted to our Level I trauma center had a blunt splenic injury. Eighty-six
patients (19%) died within 24 hours of massive injuries, leaving 375 patients for
evaluation. Data were obtained from our trauma registry and medical records.
RESULTS: A total of 29 patients (8%) were > or = 55 years old (mean age, 67 +/- 2
years; mean injury severity score [ISS] 25 +/- 2). Of these, 18 patients (62%)
underwent nonoperative management (NOM). A total of 346 patients (92%) were < 55
years old (mean age, 28 +/- 0.6; mean ISS, 20 +/- 1). Of these, 198 patients
(57%) underwent NOM. The failure rate was not different between the two age
groups (17% vs. 14%). However, the ISS and mortality rate were significantly
higher in the older age group that failed (ISS, 29.3 +/- 2.6 vs. 19.5 +/- 2.1;
mortality: 67% vs. 4%). None of the deaths could be attributed to splenic injury.
CONCLUSION: Adults > or = 55 years old with blunt splenic injury are successfully
treated by NOM. Although older adults had significantly greater injuries, they
had similar failure rates of NOM when compared with younger adults. Older adults
had significantly higher mortality, but this was not a result of their splenic
injury. Therefore, age should not be a criteria for NOM of blunt splenic injury.
PMID- 10780592
TI - External fixation as a bridge to intramedullary nailing for patients with
multiple injuries and with femur fractures: damage control orthopedics.
AB - BACKGROUND: The advantages of early fracture fixation in patients with multiple
injuries have been challenged recently, particularly in patients with head
injury. External fixation (EF) has been used to stabilize pelvic fractures after
multiple injury. It potentially offers similar benefits to intramedullary nail
(IMN) in long-bone fractures and may obviate some of the risks. We report on the
use of EF as a temporary fracture fixation in a group of patients with multiple
injuries and with femoral shaft fractures. METHODS: Retrospective review of
charts and registry data of patients admitted to our Level 1 trauma center July
of 1995 to June of 1998. Forty-three patients initially treated with EF of the
femur were compared to 284 patients treated with primary IMN of the femur.
RESULTS: Patients treated with EF had more severe injuries with significantly
higher Injury Severity Scores (26.8 vs. 16.8) and required significantly more
fluid (11.9 vs. 6.2 liters) and blood (1.5 vs. 1.0 liters) in the initial 24
hours. Glasgow Coma Scale score was lower (p < 0.01) in those treated with EF (11
vs. 14.2). Twelve patients (28%) had head injuries severe enough to require
intracranial pressure monitoring. All 12 required therapy for intracranial
pressure control with mannitol (100%), barbiturates (75%), and/or
hyperventilation (75%). Most patients had more than one contraindication to IMN,
including head injury in 46% of cases, hemodynamic instability in 65%,
thoracoabdominal injuries in 51%, and/or other serious injuries in 46%, most
often multiple orthopedic injuries. Median operating room time for EF was 35
minutes with estimated blood loss of 90 mL. IMN was performed in 35 of 43
patients at a mean of 4.8 days after EF. Median operating room time for IMN was
135 minutes with an estimated blood loss of 400 mL. One patient died before IMN.
One other patient with a mangled extremity was treated with amputation after EF.
There was one complication of EF, i.e., bleeding around a pin site, which was
self-limited. Four patients in the EF group died, three from head injuries and
one from acute organ failure. No death was secondary to the fracture treatment
selected. One patient who had EF followed by IMN had bone infection and another
had acute hardware failure. CONCLUSION: EF is a viable alternative to attain
temporary rigid stabilization in patients with multiple injuries. It is rapid,
causes negligible blood loss, and can be followed by IMN when the patient is
stabilized. There were minimal orthopedic complications.
PMID- 10780593
TI - NISS predicts postinjury multiple organ failure better than the ISS.
AB - BACKGROUND: The Injury Severity Score (ISS) has been observed consistently to be
a robust predictor of postinjury multiple organ failure (MOF). However, the ISS
fails to account for multiple injuries to the same body region. Recently, the
"new" ISS (NISS) has been proposed to address this shortcoming. Preliminary
studies suggest the NISS is superior to the ISS in predicting trauma mortality.
Our purpose was to determine whether the NISS is a better predictor of postinjury
MOF than the ISS. METHODS: A total of 558 patients admitted to our Level I trauma
center with ISS > 15, age > 15 years, and survival > 48 hours were prospectively
identified; 101 (18%) developed postinjury MOF. Data characterizing postinjury
MOF were collected, and the NISS was calculated retrospectively. The ISS and NISS
were compared as univariate predictors of MOF. Multivariate analysis was used to
determine whether substitution of NISS for ISS resulted in a superior predictive
model. RESULTS: In 295 patients (53%), the NISS was greater than the ISS. This
subgroup of patients experienced a greater frequency of MOF (26.7% vs. 8.3%, p <
0.0001), a higher mortality (12.8% vs. 4.9%, p < 0.001), and a higher early
transfusion requirement (6.7 U vs. 3.6 U, p < 0.0001) compared with the group in
which NISS equaled ISS. Moreover, the NISS yielded better separation between
patients with and without MOF reflected by the greater difference in median NISS
scores compared with ISS scores. The multivariate predictive model, including
NISS, showed a better goodness of fit compared with the same model that included
ISS. CONCLUSIONS: The NISS is superior to the ISS in the prediction of postinjury
MOF. This measure of tissue injury severity should replace the ISS in trauma
research.
PMID- 10780594
TI - Using Trauma and Injury Severity Score (TRISS)-based analysis in the development
of regional risk adjustment tools to trend quality in a voluntary trauma system:
the experience of the Trauma Foundation of Northeast Ohio.
AB - BACKGROUND: Presently, no trauma system exists in Ohio. Since 1993, all hospitals
in Cuyahoga County (CUY), northeast Ohio (n = 22) provide data to a trauma
registry. In return, each received hospital-specific data, comparison data by
trauma care level and a county-wide aggregate summary. This report describes the
results of this approach in our region. METHODS: All cases were entered by paper
abstract or electronic download. Interrater reliability audits and z score
analysis was performed by using the Major Trauma Outcome Study and the CUY 1994
baseline groups. Risk adjustment of mortality data was performed using
statistical modeling and logistic regression (Trauma and Injury Severity Score,
Major Trauma Outcome Study, CUY). Trauma severity measures were defined. RESULTS:
In 1995, 3,375 patients were entered. Two hundred ninety-one died (8.6%).
Severity measures differed by level of trauma care, indicating differences in
case mix. Probability of survival was lowest in the Level I centers, highest in
the acute care hospitals. Outcomes z scores demonstrated survival differences for
all levels. CONCLUSIONS: In a functioning trauma system, the most severely
injured patients should be cared for at the trauma centers. A low volume at acute
care hospitals is desirable. By using Trauma and Injury Severity Score with
community-specific constants, NE Ohio is accomplishing these goals. The Level I
performance data are an interesting finding compared with the data from the Level
II centers in the region
PMID- 10780595
TI - Tissue hemoglobin O2 saturation during resuscitation of traumatic shock monitored
using near infrared spectrometry.
AB - BACKGROUND: Near infrared (NIR) spectrometry offers a noninvasive monitor of
tissue hemoglobin O2 saturation and has been developed to report a quantitative
clinical variable, StO2 [= HbO2/(HbO2 + Hb)]. In this study, a prototype NIR
oximeter was used to investigate the hypothesis that changes in systemic O2
delivery index (D(O2)I) would be reflected by changes in StO2 in skeletal muscle,
subcutaneous tissue, or both, as reperfusion occurs during shock resuscitation.
StO2 was also compared with other indices of severity of shock or adequacy of
resuscitation, including arterial base deficit, lactate, gastric mucosal P(CO2)
(PgCO2), and mixed venous hemoglobin O2 saturation (S(VO2)). METHODS: Skeletal
muscle and subcutaneous tissue StO2 were monitored simultaneously in eight
severely injured trauma patients (88% blunt mechanism; age, 42 +/- 6 years;
Injury Severity Score, 27 +/- 3) during standardized shock resuscitation in the
intensive care unit with the primary goal of D(O2)I > or = 600 mL O2/min/m2 for
24 hours, and for an additional 12 hours during transition from resuscitation to
standard intensive care unit care. RESULTS: Skeletal muscle StO2 increased
significantly from 15 +/- 2% (mean +/- SEM) at the start of resuscitation to 49
+/- 14% at 24 hours, and to approximately 55% from 25 to 36 hours. Subcutaneous
tissue StO2 approximately 82% and was significantly greater than skeletal muscle
StO2 throughout. D(O2)I increased significantly from 372 +/- 54 to 718 +/- 47 mL
O2/min/m2 during resuscitation. Over 36 hours, mean D(O2)I and skeletal muscle
StO2 were highly correlated (r = 0.95). Neither D(O2)I-PgCO2 nor D(O2)I-S(VO2)
were significantly correlated; neither S(VO2) nor subcutaneous tissue StO2
changed significantly. CONCLUSION: Hemoglobin O2 saturation was monitored
noninvasively and simultaneously in skeletal muscle and subcutaneous tissues as
StO2 (%) by using a prototype NIR oximeter. Skeletal muscle StO2 tracked systemic
O2 delivery during and after resuscitation. As a rapidly deployable, noninvasive
monitor of peripheral tissue oxygenation and O2 delivery, skeletal muscle StO2
obtained using NIR spectrometry would be useful to guide resuscitation in the
intensive care unit, to monitor resuscitation status in the operating room, and,
potentially, in combination with indicators such as base deficit and lactate, to
detect shock during initial assessment of the severe trauma patient in the
emergency department.
PMID- 10780597
TI - Effects of trauma cases on the care of patients who have chest pain in an
emergency department.
AB - BACKGROUND: Trauma victims sometimes take priority over other patients because
their injuries require immediate treatment. We examined whether such demands
might compromise the care of patients with acute chest pain in an emergency
department. METHODS: Case patients were patients with chest pain who arrived
immediately after a major trauma victim. Control patients were patients with
chest pain who arrived on a preceding day when no trauma patient was in the
emergency department. RESULTS: Case and control patients were similar in mean age
(60 vs. 60 years, p = not significant), percentage male (47 vs. 53%, p = not
significant) and percentage ultimately diagnosed as cardiac (29 vs. 33%, p = not
significant). Case patients spent an average of 81 minutes longer in the
emergency department (297 vs. 216 minutes, p = 0.009). Similar delays were
observed in the subgroup of patients ultimately diagnosed as cardiac (309 vs. 217
minutes, p = 0.029). Case patients had generally worse scores on the American
College of Emergency Physicians Quality Assurance Index (75.6 vs. 84.4, p =
0.027), particularly those ultimately diagnosed as cardiac (60.3 vs. 85.1, p =
0.002). The common failures were failure to administer aspirin, undertreatment of
ongoing pain, and failure to provide instructions regarding treatment and need to
return. CONCLUSION: Trauma victims can decrease the timeliness and quality of
care for other patients who have potentially life-threatening conditions in an
emergency department.
PMID- 10780596
TI - Effect of prehospital advanced life support on outcomes of major trauma patients.
AB - OBJECTIVE: Determine whether prehospital advanced life support (ALS) improves the
survival of major trauma patients and whether it is associated with longer on
scene times. METHODS: A 36-month retrospective study of all major trauma patients
who received either prehospital bag-valve-mask (BVM) or endotracheal intubation
(ETI) and were transported by paramedics to our Level I trauma center. Logistic
regression analysis determined the association of prehospital ALS with patient
survival. RESULTS: Of 9,451 major trauma patients, 496 (5.3%) had either BVM or
ETI. Eighty-one percent received BVM, with a mean Injury Severity Score of 29 and
a mortality rate of 67%; 93 patients (19%) underwent successful ETI, with a mean
Injury Severity Score of 35 and a mortality rate of 93%. Adjusted survival for
patients who had BVM was 5.3 times more likely than for patients who had ETI (95%
confidence interval, 2.3-14.2, p = 0.00). Survival among patients who received
intravenous fluids was 3.9 times more likely than those who did not (p = not
significant). Average on-scene times for patients who had ETI or intravenous
fluids were not significantly longer than those who had BVM or no intravenous
fluids. CONCLUSION: ALS procedures can be performed by paramedics on major trauma
patients without prolonging on-scene time, but they do not seem to improve
survival.
PMID- 10780598
TI - Alterations of preliminary readings on radiographic examinations minimally affect
outcomes of trauma patients discharged from the emergency department.
AB - BACKGROUND: We hypothesized that trauma patients could be discharged safely from
the emergency department (ED) before the availability of official readings for
their radiologic examinations. We also sought to determine whether trauma
patients were more prone to alterations of preliminary interpretations than other
ED patients. METHODS: Alterations of preliminary readings (PR) for patients
discharged from the ED were reviewed. If the official readings conflicted with
the PR used for the patient's disposition, attempts were made to contact the
patient and provide the appropriate follow-up. Data recorded included the type of
radiographic examination, the presence of a missed injury, and the follow-up. By
using institutional data, the incidence of inaccurate PR were compared for trauma
patients and other ED patients (chi2 test, Fisher exact test, p < 0.05). RESULTS:
Between January of 1998 and December of 1998, 102 of 38,260 discharged ED
patients had official readings differing from PR. Forty-three of the changed
readings involved 42 of the 1,073 discharged trauma patients, who were more
likely to harbor inaccurate PR (<0.0001) than other discharged ED patients.
Twenty-eight altered readings involved plain films and 15 involved computed
tomographic scans. The most common altered readings involved computed tomographic
scans of the head and face (n = 13). Twelve missed injuries were detected, most
commonly related to a missed injury of the extremity (7 cases). Nine other cases
involved the detection of incidental pathologic conditions. Eight patients
required repeat ED visits for clinical and radiographic evaluation, and one
patient required subsequent hospital admission. CONCLUSION: Discharged trauma
patients are more likely to harbor alterations of preliminary interpretations
than other ED patients. Although the official readings for these trauma patients
will occasionally reveal previously undetected pathologic conditions, the
majority of such cases can be managed with outpatient follow-up.
PMID- 10780599
TI - Training residents using simulation technology: experience with ultrasound for
trauma.
AB - BACKGROUND: The need for surgeons to become proficient in performing and
interpreting ultrasound examinations has been well recognized in recent years,
but providing standardized training remains a significant challenge. The UltraSim
(MedSim, Ft. Lauderdale, Fla) ultrasound simulator is a modified ultrasound
machine that stores patient data in three-dimensional images. By scanning on the
UltraSim mannequin, the student can reconstruct these images in real-time,
eliminating the need for finding normal and abnormal models, while providing an
objective method of both teaching and testing. The objective of this study was to
compare the posttest results between residents trained on a real-time ultrasound
simulator versus those trained in a traditional hands-on patient format. We
hypothesized that both methods of teaching would yield similar results as judged
by performance on the interpretive portion of a standardized posttest. It is
designed as a prospective, cohort study from two university trauma centers
involving residents at the beginning of their first or second postgraduate year
of training. The main outcome measure was performance on a standardized posttest,
which included interpretation of ultrasound cases recorded on videotape. METHODS:
Students first took a written pretest to evaluate their baseline knowledge of
ultrasound physics as well as their ability to interpret basic ultrasound images.
The didactic portion of the course used the same teaching materials for all
residents and included lectures on ultrasound physics, ultrasound use in
trauma/critical care, and a series of instructional videos. This didactic session
was followed by 1 hour for each student of hands-on training on medical
models/medical patients (group I) or by training on the ultrasound simulator
(group II). The pretest was repeated at the completion of the course (posttest).
Data were stratified by postgraduate year, i.e., PG1 or PG2. RESULTS: A total of
74 residents were trained and tested in this study (PG1 = 48, PG2 = 26). All
residents showed significant improvement in their pretest and posttest scores (p
= 0.00) in both their knowledge of ultrasound physics and in their interpretation
of ultrasound images. Importantly, we could not demonstrate any significant
difference between groups trained on models/patients (group I) versus those
trained on the simulator (group II) when comparing their posttest interpretation
of ultrasound images presented on videotapes (PG1, group I mean score 6.9 +/- 1.4
vs. PG1, group II mean score 6.5 +/- 1.6, p = 0.32; PG2, group I mean score 7.7
+/- 1.4 vs. PG2, group II mean score 7.9 +/- 1.2, p = 0.70). CONCLUSION: The use
of a simulator is a convenient and objective method of introducing ultrasound to
surgery residents and compares favorably with the experience gained with
traditional hands-on patient models.
PMID- 10780600
TI - The April 8, 1998 tornado: assessment of the trauma system response and the
resulting injuries.
AB - BACKGROUND: On April 8, 1998, an F5 tornado touched down in two counties of
Alabama producing a wide path of destruction. The presence of a regional trauma
system in this area presents an opportunity to evaluate the effectiveness of the
system in responding to the victims of this natural disaster. METHODS: Emergency
room logs and the regional trauma system database were searched for all patients
treated for injuries sustained from the tornado, and medical records were
reviewed for demographic information, mode of transportation to hospital,
injuries, treatment, and outcome. Fatalities were identified by means of the
coroner's office. RESULTS: A total of 224 patients were evaluated at nine area
hospitals, of whom 63 (28%) required admission. There were 32 deaths: 30 persons
were dead at the scene, and 2 patients subsequently died at Level I trauma
centers. Among patients with nonfatal injuries, 39% were managed at Level I
facilities, 46% at Level III facilities, and 15% at nontrauma facilities. Forty
patients (55%) seen at Level I facilities required admission compared with 15
patients (17%) at Level III facilities and 8 patients (29%) at nontrauma
facilities; Level I facilities also had the highest Injury Severity Score. Of
patients requiring admission, 83% were transported by emergency medical services;
these patients also had the highest Injury Severity Score. CONCLUSION: The
regional trauma system facilitated appropriate and efficient triage to system
hospitals, routing the most severely injured patients to the Level I centers
without overwhelming them with the more numerous, less severely injured patients.
PMID- 10780601
TI - Thoracic aortic injury: how predictive is mechanism and is chest computed
tomography a reliable screening tool? A prospective study of 1,561 patients.
AB - BACKGROUND: Thoracic aortic injury (TAI) is a devastating condition in which
prompt recognition can obviate morbidity and mortality. It is a long-held belief
that TAI is more likely when there is a "major mechanism of injury." The purposes
of this prospective study were to determine mechanism characteristics that are
predictive of TAI and to evaluate chest computed tomography (CT) as a screening
tool for TAI. METHODS: Over a 5 1/2 year period, blunt chest trauma patients at
two Level I trauma centers were evaluated for potential TAI. Patients were
assigned mechanism and radiograph scores from 1 (low suspicion for TAI) to 5
(very high suspicion for TAI). Immediate aortography was obtained when suspicion
for TAI was very high. The remaining patients were evaluated with contrast
enhanced chest CT. Confirmatory aortography was obtained on all positive chest CT
scans and on all patients with mechanism scores of 4 or 5 even if the CT was
negative. Mechanism and radiographic data were correlated with the results of
aortic imaging. RESULTS: Of the 1,561 patients evaluated for TAI, 30 aortic
injuries were found. The assessment of mechanism was imperfect with a reliance on
often incomplete and subjective data. The subjective mechanism score proved to be
the most useful predictor of TAI. Radiographic scores were useful but insensitive
for intimal injuries. Computed tomography was found to have 100% and 100% NPV for
TAI. CONCLUSION: Considering the inherent difficulties in identifying patients at
risk for TAI and the effectiveness of chest CT as a screening tool for aortic
injury, we recommend liberal use of chest CT in blunt chest trauma. Guidelines
for determining the need for aortic imaging are outlined.
PMID- 10780602
TI - Is routine roentgenography needed after closed tube thoracostomy removal?
AB - BACKGROUND: Efficacy of chest radiograph protocol after tube thoracostomy tube
(CT) removal. METHODS: Retrospective review (July of 1995 to July of 1996) of 141
patients with CT followed throughout their hospitalization. Excluded patients
died (23 patients) or had thoracotomy (13 patients) before CT removal. RESULTS: A
total of 105 patients had 113 CT removed (mean age, 36.9 years; Injury Severity
Score = 23.4; CT duration, 5.0 days). Protocol chest radiographs were performed
on average at 7.9 and 22.1 hours. Recurrent pneumothorax (RHPTX = new
interpleural air) occurring in 12 patients (11%) and persistent pneumothorax
(PHPTX = same volume of interpleural air) occurring in 13 patients (12%) caused
no clinical problems and were treated without tube replacement. Three patients
had symptoms after removal; none had RHPTX. Two patients had clinical signs; one
reaccumulated a hemothorax requiring CT replacement, the other improved without
replacement. CONCLUSIONS: Clinically significant RHPTX/PHPTX after CT removal is
infrequent. Signs not symptoms detect CT removal complications. At our
institution, chest radiographs are obtained in a delayed manner from protocol and
offer no benefit over clinical assessment.
PMID- 10780604
TI - Treatment of humeral shaft delayed unions and nonunions with humeral locked
nails.
AB - OBJECTIVE: To report experience with use of humeral locked nails in treating
humeral delayed unions and nonunions. The following techniques yielded
encouragingly good results: static locking, short-to-long segment nailing, bone
grafting, fracture compression, and minimal surgical trauma. DESIGN AND METHODS:
A total of 41 consecutive patients with 13 delayed unions and 28 nonunions were
treated with humeral locked nails. Delay from trauma to surgery averaged 4.2
months for delayed union and 15.5 months for nonunion. The average age of
patients was 50.2 years; average follow-up time was 23.2 months. There were 7
proximal-third fractures, 21 middle-third fractures, and 13 distal-third
fractures. The antegrade approach was used for 13 fractures and retrograde for
28. Open nailing was performed in 39 fractures and closed nailing in 2. If the
fracture motion was still present after nail insertion, axial compression of the
fracture site was specially applied. Bone grafting was performed in the fractures
with open nailing. Thirty-four fractures were nailed with 8-mm nails, and 7
fractures were nailed with 7-mm nails. RESULTS: With a single operation, all but
two patients achieved osseous union in, on average, 5.6 months. One of these two
patients eventually gained union after another surgery with fracture compression
along the original nail and concurrent bone grafting. The second patient,
undergoing hemodialysis for chronic renal failure, had persistent nonunion. At
follow-up, for patients with antegrade nailing, all but four patients had less
than 20 degrees limitation of shoulder abduction. For patients with retrograde
nailing, all but two had less than 10 degrees limitation of elbow motion. Only
the patient with persistent nonunion had continual pain and significant
impairment of arm function. CONCLUSIONS: Humeral locked nailing seems to be
effective for humeral delayed unions or nonunions. It may be an acceptable
alternative for fractures unsuited for plate fixation, such as those with
comminution, osteoporosis, or a severely adhered radial nerve.
PMID- 10780603
TI - Effects of timing of diatrizoate (water-soluble contrast medium) administration
on pancreatic microcirculatory derangement in cerulein pancreatitis in rats.
AB - OBJECTIVE: We investigated whether the timing of administration of contrast
medium after onset of acute pancreatitis is critical in determining the magnitude
of microcirculatory derangement. METHODS: An acute pancreatitis model in male
Sprague-Dawley rats (225-275 g) was established by continuous infusion of
cerulein (15 mg/kg per hour). The mean arterial pressure was monitored
continuously by means of a femoral artery catheter. Diatrizoate (Hypaque-76), a
water-soluble contrast medium, was delivered through a femoral vein catheter at
doses corresponding to those given to humans, either 1, 2, or 3 hours after
pancreatitis induction. In vivo microscopy and laser-Doppler flowmetry were used
to investigate microcirculatory derangement. The water contents of the pancreas
and lung, the malondialdehyde levels of the pancreas, and the trypsinogen
activation peptide levels in the serum were measured at the end of the experiment
(8 hours after infusion of cerulein). RESULTS: Early administration of contrast
medium (1 hour after pancreatitis induction) resulted in significantly greater
changes in microcirculation and mean arterial pressure than did late
administration (2 or 3 hours after pancreatitis induction). Rats given contrast
medium 1 hour after induction also had highest pancreas and lung water contents,
the highest pancreas malondialdehyde levels, and the highest serum trypsinogen
activation peptide levels. CONCLUSION: These results show that a water soluble
contrast medium that is often used for computed tomographic imaging of the
pancreas can adversely affect the pancreatic microcirculatory parameters, such as
tissue perfusion and leukocyte sticking, and hemodynamics in a cerulein-induced
model of acute pancreatitis. Early administration seems to cause more severe
derangement of the pancreatic microcirculation.
PMID- 10780605
TI - Central hemodynamics during reamed intramedullary nailing of unilateral tibial
fractures.
AB - BACKGROUND: Intramedullary nailing of a long-bone fracture results in
intravasation of bone marrow contents into the right atrium and pulmonary
vascular bed and, therefore, may alter cardiac and pulmonary hemodynamics.
METHODS: Central hemodynamic changes were recorded in 12 healthy adults with a
unilateral simple tibial fracture undergoing intramedullary nailing. The patients
were cannulated with a pulmonary artery catheter. Reamed intramedullary nailing
was performed during general anesthesia. Preoperative and immediate postoperative
hemodynamic variables were compared and intraoperative changes studied. RESULTS:
During the operation, the right ventricular preload as represented by central
venous pressure and the right ventricular afterload as presented by mean
pulmonary arterial pressure increased significantly. Preoperative and
postoperative arterial oxygen tension values demonstrated hypoxia. Abnormal
pulmonary shunting and increased oxygen consumption were observed as well.
CONCLUSION: Changes in cardiac and pulmonary hemodynamics are already present
after the trauma and before the reamed intramedullary nailing procedure.
PMID- 10780606
TI - Analysis of pulmonary fat embolism in blunt force fatalities.
AB - OBJECTIVE: To investigate the incidence, severity, and origin of pulmonary fat
embolism (PFE) in persons dying from blunt force trauma within 24 hours of
injury. METHODS: The study population consisted of blunt force fatalities.
Controls were subjects dying from natural causes or nonblunt force injury. Tissue
was removed from lung lobes and prepared for histologic examination using osmium
tetroxide to stain for fat. Lung sections were graded for PFE on a scale of 0 (no
emboli) to 4 (five or more emboli in a majority of fields). RESULTS: The blunt
force group consisted of 56 decedents. Mortality was 93% within 4 hours.
Fractures were present in 54 (96%) of decedents, and soft tissue injury was
universal. Thirty eight (68%) of decedents were positive for PFE vs. 3 of 20
(15%) in controls. Mean score for PFE was 2.94 +/- 1.15 and 1.01 +/- 0.94,
respectively (p < 0.005). Bone marrow emboli were not observed in any of the
sections. Severity of PFE was positively associated with survival time. Analysis
of PFE against sex, age, height, weight, number of injuries, and number of
fractures showed no significant correlations. CONCLUSIONS: A significant degree
of PFE develops rapidly in a majority of persons dying of blunt force trauma.
Although the source of fat for embolization has been suggested to be bone marrow,
no evidence of myeloid tissue was found in any of the lung sections. Nor was
there a correlation of PFE and number of fractures. Soft tissue injury is
considered the primary cause of PFE.
PMID- 10780607
TI - Isolated acute knee injuries in the general population.
AB - OBJECTIVE: Knee injuries are common in the general population, yet most studies
have concentrated on special populations. The purpose of this study was to
describe the types of injuries, injury events, age, and sex distributions in a
community population. METHODS: The medical records of all residents of Olmsted
County, Minnesota, 17 years of age or older who had a first visit for an isolated
acute knee (acute was defined as occurring within 60 days of the physician visit)
injury between January 1, 1993, and January 1, 1996, were abstracted. RESULTS: A
total of 664 patients (4/1,000 community adults, 46% women and 54% men) presented
to a physician for evaluation and treatment of an isolated acute knee injury.
Injured men were on average younger than women and more likely to have an injury
during a sports activity, whereas women's injuries were more likely to be the
result of non-sports-related falls. Knee sprain or strain was the most common
final diagnosis (36%). Approximately half (49%) of the patients had a single
visit. The likelihood of orthopedic surgeon's care (37% overall) increased with
injury severity and age of the patient. Overall, 12% of subjects had surgical
treatment recommended. CONCLUSION: Knee injuries are common, often result in a
single visit, seldom receive surgical intervention, and the majority are cared
for entirely by generalist physicians.
PMID- 10780608
TI - Nonskeletal cervical spine injuries: epidemiology and diagnostic pitfalls.
AB - BACKGROUND: Cervical spine injuries are the most commonly missed severe injuries
with serious implications for the patient and physician. The diagnosis of
subluxations or spinal cord injuries in the absence of vertebral fractures,
especially in unevaluable patients, poses a major challenge. The objective of
this study was to study the incidence and type of cervical spine trauma according
to mechanism of injury; identify problems and pitfalls in the diagnosis of
nonskeletal cervical spine injuries. METHODS: Retrospective study of all C-spine
injuries caused by traffic accidents or falls admitted over a 5-year period at a
large Level I trauma center. Data were obtained from the trauma registry, review
of patient charts, and radiology reports. RESULTS: During the study period, there
were 14,755 admissions due to traffic injuries or falls who met trauma center
criteria. There were 292 patients with C-spine injuries, for an overall incidence
of 2.0% (3.4% in car occupants, 2.8% for pedestrians, 1.9% for motorcycle riders,
and 0.9% for falls). The incidence of C-spine injuries in patients with a Glasgow
Coma Scale score of 13 to 15 was 1.4%, 9 to 12 was 6.8%, and in < or =8 was 10.2%
(p < 0.05). Of C-spine injuries, 85.6% (250 patients) were a vertebral fracture,
10.6% of the injuries (31 patients) were subluxation without fractures, and 3.8%
(11 patients) were an isolated spinal cord injury without fracture or
subluxation. Of the 31 patients with isolated subluxations, one-third required an
early endotracheal intubation before clinical evaluation of the spine, because of
associated severe head injury or hypotension. Adequate lateral C-spine films
diagnosed or suspected 30 of the 31 subluxations (96.8%). The combination of
plain films and computed tomographic (CT) scan diagnosed or suspected all
injuries. Of the 11 patients with isolated cord injury, 27.3% required early
intubation before clinical evaluation of the spine. The diagnosis of cord injury
was made on admission in only five patients (45.5%). In three patients, the
neurologic examination on admission was normal and neurologic deficits appeared a
few hours later. In the remaining three patients (two intubated, one
intoxicated), the diagnosis was missed clinically and radiologically.
CONCLUSIONS: Isolated nonskeletal C-spine injuries are rare but potentially
catastrophic because of the high incidence of neurologic deficits and missed
diagnosis. In subluxations, the combination of an adequate lateral film and CT
scan was reliable in diagnosing or highly suspecting the injury. A large
prospective study is needed to confirm these findings, before a recommendation is
made to remove the cervical collar if the findings of these investigations are
normal. However, in isolated cord injuries, the diagnosis was often missed
because of associated severe head trauma and the low sensitivity of the plain
films and CT scans.
PMID- 10780609
TI - Intrathoracic blood volume as an end point in resuscitation of the severely
burned: an observational study of 24 patients.
AB - BACKGROUND: Treatment of burn shock according to empirical resuscitation formulas
is still considered the gold standard, and the burn community does not advocate
the use of invasive cardiorespiratory monitoring in general. As a consequence,
data dealing with early postburn hemodynamics are sparse, and only few studies
have paid attention to the topic of end-point burn shock resuscitation. However,
recent studies have suggested that burn survival may be improved when invasive
monitoring is used to guide fluid therapy during the shock phase. MATERIALS AND
METHODS: In an observational study of 24 patients with severe burns, the
transpulmonary double indicator dilution technique was used for semi-invasive
hemodynamic monitoring. The clinical utility of the intrathoracic blood volume
(ITBV) as an end-point variable for fluid resuscitation was evaluated, comparing
correlation of filling pressure obtained by a pulmonary artery catheter and
intrathoracic blood volume to cardiac index and oxygen delivery. In addition
fluid volume predicted by the Parkland burn formula was compared with the actual
fluid volume given when ITBV was used as end point for resuscitation. RESULTS:
ITBV-guided resuscitation was associated with restoration of preload and
peripheral delivery of oxygen within 24 hours in the majority of patients.
Augmentation of ITBV was significantly correlated with changes in cardiac index
and oxygen transport rate. No such correlation could be demonstrated for the
conventional preload parameters such as central venous pressure and pulmonary
capillary wedge pressure. Thus, ITBV seemed in burned, hypovolemic patients a
better indicator of the preload component of the cardiac output than the
conventional preload parameters obtained with the pulmonary artery catheter.
Significantly larger volumes of crystalloids than predicted by the Parkland
formula were administered when ITBV was used as end point for resuscitation. The
extravascular lung water remained normal during this extraordinary high volume
load. CONCLUSION: ITBV may be a reliable preload indicator to guide volume
therapy in life-threatening burns, and end-point-fixed resuscitation to this
parameter seems to be associated with significantly higher fluid administration
than calculated compared with traditional burn formulas. The effects of burn
resuscitation to fixed end points on survival and multiple organ failure should
be evaluated in future randomly assigned trials.
PMID- 10780610
TI - Civilian landmine injuries in Sri Lanka.
AB - OBJECTIVES: The purpose of this study was to describe the injuries sustained by
displaced people returning home after a military conflict when landmines were not
removed. METHOD: This study describes the landmine injuries to patients at the
Jaffna Teaching Hospital in northern Sri Lanka over a 20-month period, from May
1, 1996, to December 31, 1997. RESULTS: There were definite and identifiable
landmine injury patterns. Patients were most often wounded in the lower
extremities, had multiple wounds, and were injured together in groups. Victims
were most often male, but there were unusually high numbers of women, children,
and elderly injured. Mortality rates and amputation rates were high. Deaths
occurred early after injury. Higher incidences of mine injuries could be
associated with two important activities: returning home and agriculture.
CONCLUSIONS: Civilians returning home after armed conflicts are at risk of injury
when landmines are not removed. No one is spared. This problem is preventable.
PMID- 10780611
TI - Mechanisms and patterns of injuries related to large animals.
AB - BACKGROUND: Injuries from encounters with large animals represent a significant
health risk for rural communities. We evaluated our regional trauma centers'
experience with large-animal injuries to determine whether certain mechanisms and
patterns of injury predicted either major head/craniofacial or torso
(chest/abdomen/pelvis) trauma. METHODS: The hospital courses of 145 patients with
injuries related to large animals were reviewed retrospectively to determine
patterns of injury, specific injury mechanisms, species-specific injuries, and
predictors of multiple body region trauma. RESULTS: Seventy-nine patients (55%)
were injured by horses, 47 patients (32%) by bulls, 16 patients (11%) by cows,
and 3 patients (2%) by wild animal attacks. The predominant species-specific
mechanisms of injury were falls (horses), tramplings (bulls), and kicks (cows).
Brain/craniofacial injuries were most common from horse-related encounters (32%),
whereas bull and cow encounters usually resulted in torso injuries (45% and 56%,
respectively). Multiple body region injuries occurred in 32% of patients.
Fractures of the upper extremities were more often associated with torso and
head/craniofacial injuries (48%) than lower extremity injuries (17%) (p = 0.02).
CONCLUSION: Large animal injuries frequently involve multiple body regions with
species-specific mechanisms. Upper extremity injuries are associated with a
significantly higher percentage of torso and head/craniofacial injuries, which
may have implications for field triage.
PMID- 10780612
TI - Pancreatographic classification of pancreatic ductal injuries caused by blunt
injury to the pancreas.
AB - BACKGROUND: In the treatment of patients with pancreatic injury, the focus of
attention is usually on main ductal injuries. METHODS: To develop a
classification system for pancreatic ductal injuries, we retrospectively analyzed
blunt pancreatic injuries in 40 patients. We assessed the relationships between
findings on pancreatography (36 endoscopic retrograde procedures and 4
transduodenal procedures), the treatment modality, and the clinical course.
RESULTS: Patients with class 1 injuries (radiographically normal ducts, n = 13)
could be treated nonsurgically without major complications. Patients with class 2
injuries (branch injuries, n = 7), in whom contrast medium from ductal branches
did not leak from the pancreatic parenchyma (class 2a, n = 3), could be treated
nonsurgically. Patients with leaks into the retroperitoneal space (class 2b, n =
4) required at least a drainage laparotomy. Patients with class 3 injuries (main
duct injuries, n = 20), including two patients in whom conservative treatment
resulted in severe complications, required laparotomy. CONCLUSION: This
classification system for pancreatic ductal injuries may facilitate the selection
of appropriate therapeutic modalities for patients with blunt pancreatic injury.
PMID- 10780613
TI - Practice Management Guidelines for Prophylactic Antibiotic Use in Tube
Thoracostomy for Traumatic Hemopneumothorax: the EAST Practice Management
Guidelines Work Group. Eastern Association for Trauma.
AB - Multiple factors contribute to the development of posttraumatic empyema. These
factors include the conditions under which the tube is inserted (emergent or
urgent), the mechanism of injury, retained hemothorax, and ventilator care. The
incidence of empyema in placebo groups ranges between 0 and 18%. The
administration of antibiotics for longer than 24 hours did not seem to
significantly reduce this risk compared with a shorter duration, although the
numbers in each series were small. Most reports found a significant reduction in
pneumonitis when patients received prolonged prophylactic antibiotics. This use
of antibiotics might possibly be better described as presumptive therapy rather
than prophylactic.
PMID- 10780614
TI - The EAST Practice Management Guidelines for Prophylactic Antibiotic Use in Tube
Thoracostomy for Traumatic Hemopneumothorax: a commentary. Eastern Association
for Trauma.
PMID- 10780615
TI - Scandinavian guidelines for initial management of minimal, mild, and moderate
head injuries. The Scandinavian Neurotrauma Committee.
AB - BACKGROUND: The Scandinavian Neurotrauma Committee was initiated by the
Scandinavian Neurosurgical Society to develop evidence-based guidelines for
improved care of neurotrauma patients. METHODS: A MEDLINE search identified 475
papers dealing with the management of minimal, mild, and moderate head injuries.
Forty-two studies presenting class II evidence on the initial management of such
injuries were reviewed and management guidelines were developed. RESULTS:
Implementation of the Head Injury Severity Scale is advocated. Patients with
minimal injuries (no loss of consciousness, Glasgow Coma Scale score of 15) can
be safely discharged. Routine early computed tomographic scan is recommended in
cases with mild injuries (history of loss of consciousness, Glasgow Coma Scale
score = 14-15) and patients with normal scans may be discharged. Computed
tomographic scan and admission is mandatory in moderate injuries (Glasgow Coma
Scale score = 13). All patients harboring additional risk factors should be
scanned and admitted. A flow-chart for clinical decision making and a Head Injury
Instruction card is introduced. CONCLUSIONS: The Scandinavian Neurotrauma
Committee suggests guidelines that should be safe and cost-effective for the
initial management of minimal, mild, and moderate head injuries.
PMID- 10780616
TI - Osteocutaneous pedicle flap of the foot for salvage of below-knee amputation
level after lower extremity injury.
PMID- 10780617
TI - "Flow-through" type free flap for revascularization and simultaneous coverage of
a nearly complete amputation of the foot: case report and literature review.
PMID- 10780618
TI - Unilateral transverse acetabular fracture with medial displacement of the femoral
head after an epileptic seizure.
PMID- 10780619
TI - Massive extraperitoneal hemorrhage after soft tissue trauma to the pubic branch
of the inferior epigastric artery.
PMID- 10780620
TI - Postinjury torso ultrasound: FAST should be SLOH.
PMID- 10780621
TI - Vancomycin-dependent enterococcal strains: case report and review.
AB - We report, to our knowledge, the first isolation of VDE from a burn unit. Our
experience was similar to earlier reports, in that continuous administration of
vancomycin and previous VRE isolation preceded the recovery of VDE. Given the
increasing prevalence of VRE as a nosocomial pathogen, intensive care units must
now be attuned to the emergence of VDE as serious pathogen.
PMID- 10780622
TI - Eye injuries from airbags with seamless module covers.
AB - BACKGROUND: A recent trend in automotive interior design has the airbag placed
behind a seamless module cover. Airbag deployment through these seamless module
covers may release foam particles at high velocities that could result in eye
injuries. METHODS: Twenty-one tests (n = 21) were performed in which foam
particles, similar to those observed from airbag deployments, were impacted onto
porcine eyes. Injury analysis was performed by using fluorescein dye, ophthalmic
ultrasound, and necropsy. RESULTS: As seen in case reports of airbag-induced eye
injuries, corneal abrasions were the most recorded injuries in the porcine eye
impact tests. A logistic regression analysis demonstrated that kinetic energy was
the most significant contributor to injury (p = 0.0023), whereas foam type was a
poor contributor to the model (p = 0.45). An injury risk curve was generated
based on kinetic energy that gave a 50% risk of corneal abrasion at 0.183 J.
CONCLUSION: If the production of foam particles during airbag deployment is
unavoidable, the injury risk function presented for the kinetic energy of the
particles offers a design guide to minimize corneal abrasions.
PMID- 10780623
TI - Pediatric aortic pseudoaneurysm associated with a gunshot wound to the chest.
PMID- 10780624
TI - Descending aortic cannulation during emergent thoracotomy for a trauma victim.
PMID- 10780625
TI - Eye movement abnormalities during reading in patients with Alzheimer disease.
AB - OBJECTIVE: This goal of this study was to evaluate reading ability by assessing
eye movements during reading among patients with Alzheimer disease (AD) compared
with normal elderly controls. BACKGROUND: Reading is disturbed in patients with
AD. These patients may have changes in reading ability early in the course of
their disease before clinical alexia or abnormalities are apparent on standard
reading tasks. METHOD: Reading competence was evaluated by recording eye
movements during reading in 14 patients with mild to moderate clinically probable
AD and 14 age- and education-matched controls. RESULTS: All patients with AD
could recognize letters and words and could understand written material of
similar difficulty. Despite successful reading comprehension among the patients
with AD, their oculographs showed slowed reading and irregular eye movements.
Compared with controls, the patients with AD did not differ in saccadic duration;
however, they had significantly longer fixation times, more forward saccades per
line of text, and more saccadic regressions. In addition, increased reading
difficulty significantly correlated with a scale of dementia severity in the
patients with AD. CONCLUSIONS: This pattern of eye movements corresponds to
increased text difficulty and probably represents difficulty with lexical
semantic access in AD. These results suggest that disordered eye movements can
signal difficulties in reading ability in AD even before complaints of reading
difficulty or abnormalities on reading tests and may be a means of identifying
linguistic impairment early in this disorder.
PMID- 10780626
TI - Impaired insight in Alzheimer disease: association with cognitive deficits,
psychiatric symptoms, and behavioral disturbances.
AB - OBJECTIVE: The purpose of this study was to evaluate symptoms associated with
impaired insight in patients with Alzheimer disease (AD). BACKGROUND: Although
unawareness of deficits is common in AD, the relation of awareness to psychiatric
and behavioral disturbances has not been extensively studied. METHOD: We
conducted a cross-sectional investigation of 91 patients with probable AD
according to the criteria of the National Institute of Neurological and
Communicative Disorders and Stroke and the Alzheimer's Disease and Related
Disorders Association. Awareness of cognitive and functional deficits was
measured with the Inaccurate Insight item from the Neurobehavioral Rating Scale.
Psychiatric and behavioral symptoms were measured using factor scores and
individual items from the Neurobehavioral Rating Scale. Global cognitive deficits
were measured using the Mini-Mental State Examination (MMSE). RESULTS: Stepwise
regression analysis showed that insight was associated with MMSE score,
depression/anxiety factor score, and agitation/disinhibition factor score.
Variables not associated with awareness of deficits included patient age,
behavioral retardation factor score, verbal output disturbance factor score, and
psychosis factor score. Post hoc analyses showed a positive relation (i.e.,
greater insight, more symptomatology) between deficit awareness and symptoms of
depressed mood and anxiety. There was a negative relation (i.e., greater insight,
less symptomatology) between insight and symptoms of hostility, agitation,
inattention, and tension. In a follow-up stepwise regression analysis, increased
deficit awareness was associated with a higher MMSE score, greater depressed
mood, and decreased agitation. CONCLUSIONS: These findings suggest that patients
with AD may experience symptoms of depressed mood in relation to increased
awareness of decrements in functioning. The data also indicate that patients with
poor insight demonstrate greater agitated behavior. Consistent with previous
research, impaired insight was higher in the later stages of the illness.
PMID- 10780627
TI - Right body side performance decrement in congenitally dyslexic children and left
body side performance decrement in congenitally hyperactive children.
AB - OBJECTIVE: Simple and complex visuomotor performance of the right and left sides
of the body was investigated in 37 children with left hemisphere lesions, 35
children with right hemisphere lesions, 53 developmentally dyslexic children, 29
developmentally hyperactive children, and 35 "normal" children who had endured a
very mild head injury with no sequelae. BACKGROUND: Lateralized soft signs, EEG
topography, metabolic brain imaging, and neuropsychological test profiles suggest
a predominance of left hemisphere dysfunction in dyslexia and right hemisphere
dysfunction in hyperactivity. METHOD: Nine measures of lateralized performance
were drawn from the Purdue pegboard, Letter cancellation, Rey complex figure,
Wechsler Intelligence Scale for Children (WISC) Mazes, and WISC Picture
completion tests. RESULTS: The children with left hemisphere lesions manifested
significantly weaker performance on test components involving the right body
side, relative to the normal controls, on the Purdue pegboard, Rey complex figure
(delayed recall condition), and WISC Picture completion tests, and the dyslexic
children on the former two. The children with right hemisphere lesions manifested
significantly weaker performance on test components involving the left body side,
relative to the normal controls, on the WISC Mazes test, as did the hyperactive
children. CONCLUSIONS: We propose that (1) contralateral performance decrement
results from a unilateral cortical lesion in children, and (2) developmental
dyslexia may comprise a slight predominance of left hemisphere dysfunction and
developmental hyperactivity of right hemisphere dysfunction.
PMID- 10780628
TI - Radiotherapeutic effects on brain function: double dissociation of memory
systems.
AB - OBJECTIVE: The neurocognitive sequelae of therapeutic cranial irradiation are not
well characterized in adults with primary brain tumors. To address this problem,
we prospectively examined neuropsychological findings during two phases of
radiation effects. BACKGROUND: Investigations of radiation effects have revealed
variable outcomes that range from no radiation-associated morbidity to severe
cognitive impairment, but have relied on case reports or retrospective studies of
late-delayed changes in white matter or in cognition. No reliable radiographic or
neurocognitive tools exist to describe the multiple phases of radiation effects.
METHOD: Twenty adult patients (median age, 39 years) from a university hospital
were treated with radiotherapy (RT) for low-grade primary brain tumors.
Prospective longitudinal neuropsychological studies were compared at baseline
(after surgery and before irradiation) and at 3, 6, and 12 months after RT to
examine early-delayed effects, including verbal memory changes in 20 patients and
visual memory changes in 11 patients. We also examined cognitive changes during
the late-delayed phase for up to 3 years after RT and determined whether early
delayed memory deficit predicted late-delayed memory deficit in a small subset of
patients. A comprehensive neuropsychological battery was used, including verbal
and visual memory tests designed to compare learning, storage, and retrieval.
RESULTS: Patients demonstrated normal verbal memory at baseline, decrement, and
then rebound in verbal retrieval. Deficit at baseline and recovery up to 1 year
after RT defined visual memory. Together, these observations constitute a double
dissociation of memory functions. No changes over time were observed in other
neurocognitive tests or in fatigue or mood measures. Time-dependent patterns of
each long-term memory test were examined in relation to lesion site in individual
patients. CONCLUSIONS: The double dissociation of memory functions after RT may
provide markers for the damaging and facilitative early-delayed effects of RT.
Late-delayed effects were not predicted based on early-delayed changes in a small
sample.
PMID- 10780629
TI - A neuropsychological study of the postpolio syndrome: support for depression
without neuropsychological impairment.
AB - OBJECTIVE: This study aimed to examine cognitive functioning in postpolio
syndrome (PPS) after controlling for the effects of depression and illness
behavior. BACKGROUND: Few studies have investigated the possible cognitive
sequelae of PPS, despite widespread documented subjective complaints of "mental
fatigue." METHOD: A total of 23 PPS sufferers, 20 polio survivors without PPS,
and 22 matched controls were compared using the Beck Depression Inventory-II; the
Illness Behaviour Questionnaire; a chronic fatigue syndrome symptom checklist;
and several measures of memory, attention, and concentration, including the Brown
Petersen Task, Stroop Test, Austin Maze, California Verbal Learning Test, Trail
Making Test, Controlled Oral Word Association Test, and Symbol-Digit Modalities
Test. RESULTS: In those participants with a medically confirmed diagnosis of PPS,
there was a significantly higher level of depressive and hypochondriacal
symptomatology as compared with the other two groups. Nevertheless, no
significant differences existed between the three groups on neuropsychological
measures. CONCLUSIONS: These results indicate that the attention and memory
difficulties reported by PPS sufferers may be linked to the physical or
psychological manifestations of the illness rather than to objective decrements
in cognitive performance.
PMID- 10780630
TI - Cognitive effects of 1- and 20-hertz repetitive transcranial magnetic stimulation
in depression: preliminary report.
AB - OBJECTIVE: To determine the cognitive effects of daily repetitive transcranial
magnetic stimulation (rTMS) administered under the conditions of a treatment
trial for major depression. BACKGROUND: Although daily left dorsal prefrontal
rTMS has improved mood in some patients with treatment-refractory depression,
potential cognitive side effects of extended daily treatment have not been
systematically studied. METHOD: In a randomized double-blind treatment study, 10
subjects (mean age, 42 +/- 15 years) with an episode of major depression received
either 2 weeks of low-frequency (1 Hz) or high-frequency (20 Hz) rTMS (800
pulses, 20 trains over 20 minutes, 80% of motor threshold, 5 days per week) to
the left dorsolateral prefrontal cortex and then were crossed over to the other
treatment condition. Patients received cognitive testing at baseline and after
the first and second weeks of low- or high-frequency rTMS, which was examined by
repeated-measures ANOVA. RESULTS: Of 16 cognitive measures tested after 1 or 2
weeks of rTMS compared with baseline status, none showed deterioration, and the
only significant main treatment effect indicated improvement on a list-recall
test from pre- to post-rTMS after 1 week (p <0.05). CONCLUSIONS: These
preliminary data suggest no gross deleterious cognitive effects of 2 weeks of 1-
or 20-Hz rTMS at 80% of motor threshold over the left prefrontal cortex. Further
cognitive studies of the effects of rTMS at other parameters used in clinical
trials for mood disorders remain to be undertaken.
PMID- 10780631
TI - The motor vehicle collision injury syndrome.
AB - OBJECTIVE: The objective of this study was to examine the central nervous system
changes that may occur after acceleration/deceleration injuries in motor vehicle
accidents. BACKGROUND: Occupants of motor vehicles involved in a collision often
develop a disabling syndrome consisting of head, neck, and back pain; impaired
short-term memory and concentration; fatigue and a loss of stamina; poor balance;
and a change in personality. Injury victims experience a loss of motivation,
emotional lability, and a decrease in libido. The major features of this injury
syndrome are subjective, and there usually are few objective findings on physical
examination. The pathogenesis of this syndrome is poorly understood, but it is
hypothesized that the collision impact produces an inertial strain injury to the
anterior regions of the brain which depresses the functions of the frontotemporal
lobes, at the same time, sensitizing somatosensory neural afferent systems.
Damage to the orbital surfaces of the frontotemporal lobes, in particular,
impairs the gating mechanisms that normally limit sensory input to the brain and
further promotes central sensitization. The psychiatric disorders that emerge in
the wake of these injuries are likely grounded in these pathologic events.
METHOD: The current literature on the biomechanics of head injury and the
associated brain imaging findings in minor head injury are reviewed. A summary of
some of the biochemical sequelae of strain injury to the brain is also provided,
with an emphasis on the changes in energy metabolism and excitatory amino acid
release. CONCLUSIONS: Early intervention to arrest the injury-induced metabolic
cascade, and treatment with agents that activate cerebral metabolism may mitigate
the symptoms of this injury syndrome.
PMID- 10780632
TI - Significance of abnormal brain perfusion in catatonia: a case report.
AB - OBJECTIVE: In this case study, the significance of perfusion abnormalities in
catatonia is examined. BACKGROUND: Recurrent catatonic symptoms are frequently
observed in psychiatric disorders, but the predictors of relapse of the catatonic
symptoms remain unknown. Perfusion abnormalities have been reported during
catatonic states; however, little is known about brain functioning of catatonic
patients during remission. METHOD: A catatonic patient was evaluated by clinical
interview, behavioral examination, and functional neuroimaging (single photon
emission computed tomography) to determine diagnosis and brain perfusion.
RESULTS: The patient exhibited persistent hypoperfusion of the basal ganglia even
after achieving symptomatic remission. CONCLUSIONS: These findings predict a
secondary cause and may predict a chronic course.
PMID- 10780633
TI - Kleine-Levin syndrome and psychosis: observation from an unusual case.
AB - OBJECTIVE: This study evaluated the possible pathologic relation between Kleine
Levin syndrome (KLS) and mood disorders. BACKGROUND: A 28-year-old man with a
remote history of KLS had the sudden onset of a manic episode with psychotic
features after the end of hypersomnolence. METHOD: The patient received an
extensive laboratory examination, including single photon emission computed
tomography and magnetic resonance imaging. RESULTS: Single photon emission
computed tomography showed decreased tracer perfusion in the basal ganglion,
hypothalamus, and right frontotemporal region. Magnetic resonance imaging
revealed a cystic lesion in the pineal region. CONCLUSIONS: Hypothalamic
dysfunction has been described in KLS and mood disorders, but pineal gland
dysfunction has been mentioned only rarely. The clinical and neuroimaging
findings suggest the need for further study of KLS.
PMID- 10780634
TI - Neuropsychological and magnetic resonance imaging abnormalities associated with a
plasmacytoma of the frontal dura: a case report.
AB - OBJECTIVE: The goal of this investigation was to describe the neuropsychological
and magnetic resonance imaging (MRI) findings in a patient with an extramedullary
plasmacytoma that extensively infiltrated the cerebral dura, especially over the
frontal region. BACKGROUND: Extramedullary plasmacytomas are rare tumors that
have been reported to involve the dura matter in only a small number of cases. In
most of the reported occurrences, the dura plasmacytomas were successfully
treated with a combination of surgery and irradiation, without prominent
cognitive sequelae. METHOD: MRI of the brain and neuropsychological tests were
conducted approximately 13 months after the patient underwent radiotherapy. In
addition, measures of frontal lobe personality characteristics were obtained
before and after radiotherapy. RESULTS: MRI findings revealed extensive
enhancement around the anterior frontal lobes and prominent involvement of the
anterior longitudinal fissure. Results from neuropsychological testing indicated
mild to moderately impaired performance on tests of working memory, complex
attention, and cognitive flexibility. Further, the patient reported experiencing
personality changes consistent with frontal lobe dysfunction as part of the
initial symptoms of the disease, which remained unchanged after treatment.
CONCLUSIONS: Our findings are the first to describe cognitive sequelae of dural
plasmacytomas. In addition, results from this case study reveal that
plasmacytomas of the frontal dura produce personality changes similar to those
observed in patients with significant frontal lobe injury. Finally, plasmacytomas
that significantly infiltrate the frontal lobes may be insensitive to
radiotherapy and result in residual cognitive and personality abnormalities.
PMID- 10780635
TI - Hallucinatory experiences at high altitude.
PMID- 10780636
TI - Genetics of growth and reproduction in the turkey. 14. Changes in genetic
parameters over thirty generations of selection for increased body weight.
AB - A line (F) of turkeys was selected over 30 generations for increased 16-wk BW.
The base population for the F line was a randombred control population (RBC2)
that was maintained without conscious selection and used to remove yearly
environmental variation in the F line. Selection was effective in increasing 16
wk BW in the F line. Selection differentials based on the mean of selected
parents minus mean of entire population (intended) and intended selection
differentials weighted for number of offspring produced (actual) did not
consistently differ, indicating that natural selection was not significantly
opposing artificial selection. The realized heritability (h2) of 16-wk BW in the
F line, based on the linear regression of the selection response on accumulated
actual selection differentials, declined with selection; the decline appeared to
be slightly different for males than females. For both sexes combined, the
realized h2 was 0.309+/-0.022 (SE), 0.268+/-0.033, 0.242+/-0.026, and 0.254+/
0.007, respectively, for Generations 1 to 10, 11 to 20, 21 to 30, and 1 to 30.
Genetic increases in 16-wk BW in the F line were positively associated with BW at
other ages (8, 20, and 24 wk of age and at 50% production), days from stimulatory
lighting to production of the first egg, and egg weight. Genetic increases were
negatively associated with egg production, intensity of lay (maximum and average
clutch length and rate of lay), and hatch of fertile eggs. There was no
significant relationship between 16-wk BW and total days lost from broodiness or
fertility. The genetic changes in some correlated traits were not consistent in
all generation intervals studied, indicating that the genetic correlation between
the selected trait (16 wk BW) and the correlated trait changed with selection.
PMID- 10780637
TI - Relationships between bilateral asymmetry and tonic immobility reaction or
heterophil to lymphocyte ratio in five breeds of chickens.
AB - Bilateral asymmetry of several morphological traits, tonic immobility reaction,
and leucocyte ratio were studied in hens and cocks from four Spanish breeds of
chickens (Castellana, Buff Prat, Red Villafranquina, and Barred Red Vasca) and an
F2 cross between Castellana and Buff Prat (C x BP - F2). Any two or all three
types of bilateral asymmetry (fluctuating asymmetry, directional asymmetry, and
antisymmetry) occurred together for the same trait in the different breeds. There
was a significant difference in relative asymmetry among breeds (P < 0.05) for
feather and spur lengths in males, and considerable negative heterosis for
relative asymmetry of leg and wing lengths in C x BP - F2 males (-38 and -12%,
respectively). The degree of relative asymmetry varied among traits and was
between 3 and 12 times greater for spur length in males and for wing bay area in
Villafranquina males. There were significant differences among breeds (P < 0.05)
for tonic immobility duration. The duration of tonic immobility was positively
associated with the mean relative asymmetry of all traits in females from the
Villafranquina breed (r = 0.32; P < 0.05), but this finding was not consistent
across the different breeds. No significant difference was found among breeds in
terms of heterophil to lymphocyte ratio. Although there was no significant
association between mean relative asymmetry of all traits and heterophil to
lymphocyte ratio, males from the Villafranquina breed had a positive and
significant relationship between relative asymmetry for wing bay area and
leucocyte ratio (r = 0.34; P < 0.05). These results suggest that relative
asymmetry measures did not provide a general tool to assess fear or stress
susceptibility.
PMID- 10780638
TI - Comparative performance, blood chemistry, and carcass composition of two lines of
Pekin ducks reared mixed or separated by sex.
AB - Male and female Pekin ducks selected (F2 generation) for greater breast muscle
thickness (MT) and an unselected control (C) were used in this study under mixed-
or separated-sex rearing. Ducks in the separated-sex program had significantly
higher body weights than the birds in the mixed-sex program. The ducks selected
for greater breast muscle thickness exhibited superior (P < 0.05) body weight up
to 42 d of age. Males from the MT line reached market weight at 6 wk, but the
breast muscle thickness, measured by ultrasound scanning, improved significantly
from 6 to 7 wk of age. Males had greater (P < 0.05) breast muscle thickness than
females. At both ages and for both sexes, the MT line had greater (P < 0.05)
breast muscle thickness than the C line. The MT ducks consumed more (P < 0.05)
feed up to 6 wk, but no significant difference was found in cumulative feed
consumption at 7 wk, and the lines did not differ (P > 0.05) in feed:gain ratio.
Males had significantly higher cumulative feed consumption at 6 wk but had a more
desirable (P < 0.05) feed:gain ratio than females at 7 wk. Compared with females
from the C line, MT females had significantly higher carcass yield, higher body
protein, and lower fat. The MT females had higher plasma glucose and lower uric
acid than the C females, but no significant difference was found between the MT
and C lines for plasma triglycerides and total cholesterol. The results of this
study support the utility of ultrasound scanning in duck selection, the separated
rearing of ducklings, and the possibility of reducing the slaughter age of lean
males.
PMID- 10780640
TI - Laying hen behavior. 1. Effects of cage type and startle stimuli.
AB - The well-being of commercial laying hens plays an important role in egg
production. Behaviors such as pacing, displaced preening, increased aggression,
and redirected activities have been associated with stress in poultry. This study
was conducted to determine whether two strains of commercial layers, reported to
differ in level of excitability, behave differently in two types of commercial
cages. DeKalb Delta and Hy-Line W36 hens, 40 to 45 wk of age, were housed six to
eight per cage in open or solid-sided cages, at an equal density between cages.
For each strain, there were six cages per cage type for a total of 24 cages. In
the first five experiments, behavioral data were obtained at a distance of 1 m by
instantaneous or scan sampling. These experiments included hen behavior in both
types of cages with and without the presence of frustrating or startle
conditions. Some significant differences in behavior existed within experiments
but not consistently among all experiments. Sampling method did not affect
reliability of data collection. Two trials were then conducted to determine
whether the length of time to return to normal activity after a startle stimulus
is influenced by the cage type or strain. In the first startle experiment, DeKalb
hens returned to normal activity more quickly than did Hy-Line hens (P = 0.07);
this strain difference was not found when the experiment was repeated. Cage type
did not appear to affect the behavior of birds adversely, although neither cage
type appeared to confer an advantage. No clear differences were found in behavior
by strain or by strain within cage.
PMID- 10780639
TI - Vitamin E and immune responses of broiler pureline chickens.
AB - Immunological responses of cockerels fed diets containing either 10 or 300 mg/kg
of vitamin E were measured in three commercial broiler nuclear lines designated
as A, B, and C. All cockerels were fed the 10 mg/kg diet to 91 d of age, at which
time half were continued on that diet and the other half were fed a diet
supplemented to contain 300 mg/kg of vitamin E. Sixteen days after feeding the
diets, cutaneous basophil hypersensitivity (CBH), which is an in vivo, cell
mediated immune response, was determined as the increase in toe-web skin
thickness 24 h after an injection with phytohemagglutinin-P (PHA-P). Twenty-two
days after feeding the diets, heterophils and lymphocytes were enumerated. At
this time cockerels were also inoculated intravenously with 0.1 mL of 0.25% SRBC.
The injection with SRBC was repeated 27 d later. Six and 20 d after each
injection, antibody titers were determined. Mercaptoethanol-resistant (IgG) and
mercaptoethanol-sensitive (IgM) antibodies were also measured in the secondary
titers. The ratio of heterophils to lymphocytes increased, and CBH response was
depressed by feeding the higher vitamin E diet. For cockerels of Lines A and B,
the higher level of vitamin E maintained primary and secondary SRBC antibody
levels, whereas for Line C, levels were depressed. The effect of the higher
vitamin E diet on IgG and IgM was also stock-dependent. The enhanced
heterophil:lymphocyte ratio from feeding vitamin E suggests an improved
phagocytic ability of the immune system. Relative asymmetries for toe-web skin
thickness and shank length were similar for the three lines.
PMID- 10780641
TI - Laying hen behavior 2. Cage type preference and heterophil to lymphocyte ratios.
AB - Studies were conducted to determine hen preference for and stress response to
cage type. By using a plywood (1.25 cm) test apparatus with open- and solid-sided
compartments and a plexiglass divider at the entrance for controlling passage,
birds (n = 20) were evaluated as to their choice of compartment after training
and acclimation. For each test, after training, an individual bird was placed in
the start box and given 1 min to acclimate before making a choice. The experiment
was repeated after rotating the apparatus 180 degrees. In Experiment 1, the open
sided compartment was chosen by 45% of the hens, and the solid-sided compartment
by 25% (P = 0.02); 30% chose neither. In Experiment 2, the compartment with open
sides was chosen by 70% of the hens, and that with solid sides was chosen by 15%
(P = 0.004); 15% chose neither. The length of time required to choose one
compartment over the other did not differ in either experiment (P = 0.29; P =
0.76). In Experiment 3, tests were videotaped from 0830 h to 1330 h, and tapes
were scored for time spent in each compartment. Birds were observed to spend more
time in open- compared with solid-sided compartments (P = 0.02). To assess stress
level of birds exposed to each type of enclosure, blood was collected from 24
commercial Hy-Line W36 hens housed long-term in either open (n = 12) or solid (n
= 12) cages, and heterophil:lymphocyte (H:L) ratios were determined. Birds in
solid cages had higher H:L ratios than did birds in open cages (P = 0.02),
indicating a greater stress response. These data would suggest that hens may
prefer greater visual access to their surroundings afforded by open cages.
PMID- 10780642
TI - Physical, chemical, and microbiological changes in the ceca of broiler chickens
subjected to incremental feed withdrawal.
AB - Trials were conducted to determine the effect of feed withdrawal on the weight,
pH, native bacterial flora, and the persistence of Salmonella typhimurium in the
ceca of market-age broilers. Broilers were provided medicated or unmedicated feed
and then were subjected to feed withdrawal for 0 to 24 h in transportation crates
or on litter. After feed withdrawal, broilers were stunned, bled, scalded, and
picked. One cecum from each bird was aseptically removed and weighed. The cecum
was then blended in 20 mL of distilled water, and the pH of the blended
suspension was measured. The number of total aerobes, Enterobacteriaceae, S.
typhimurium, and lactic acid bacteria in the suspension were enumerated on the
appropriate bacteriological media. Results indicated that up to 24 h of feed
withdrawal produced no significant change in cecal weight and that cecal pH
varied by up to 0.3 units during feed withdrawal. There were significant
increases in the population of Enterobacteriaceae during feed withdrawal in
Trials 2 and 3, and there was a significant increase in the population of cecal
aerobes in Trial 3. Feed withdrawal produced significant decreases in the
population of lactic acid bacteria in all trials, but no significant change in
the population of S. typhimurium occurred during feed withdrawal. There were no
significant differences in cecal weight, pH, native bacteria populations, or S.
typhimurium populations between broilers that were subjected to feed withdrawal
on litter or in crates. Findings indicate that feed withdrawal does not always
effectively evacuate the contents of the ceca and that the ceca of broilers
subjected to feed withdrawal can remain a source of foodborne bacterial
pathogens.
PMID- 10780643
TI - Effects of nutritionally balanced and stabilized flaxmeal-based diets on Eimeria
tenella infections in chickens.
AB - Twenty Sex Sal cockerels were randomly assigned to each of eight groups; each of
four nutritionally balanced diets were fed to two groups from 1 d through 4 wk of
age. These diets contained 0, 2, 5, or 10% stabilized flaxseed meal that provided
a calculated 0, 0.45, 1.11, or 2.22% n-3 fatty acids, primarily linolenic acid.
At 3 wk of age, one group of chickens from each diet treatment was infected with
Eimeria tenella and was housed in separate but similar conditions to uninfected
control chickens. At 6 d postinfection, chickens were weighed, bled, killed, and
scored for lesions. No level of dietary flaxmeal tested provided protection
against weight gain depression, increased feed conversion ratios, or lesions. We
concluded that these diets did not protect against E. tenella infection because
levels of linolenic acid were not high enough, and the oxidative potentials were
well suppressed by vitamin E and other stabilizers present.
PMID- 10780644
TI - The use of instructional technology in poultry science curricula in the United
States and Canada: 1. Demographics of technology and software use.
AB - This paper describes a study conducted in recognition of the increasingly
widespread use of computers and the importance of exposure to instructional
technologies in all aspects of poultry science curriculum. The study consisted of
the distribution and analyses of two cross-sectional surveys to gather detailed
information on the use of instructional technology (IT) in poultry science
curricula in the US and Canada. One survey was sent to departments to obtain
profiles of poultry science degree programs and the availability of IT and
general support for its use. A second survey was designed to obtain individual
profiles of faculty use of IT and attitudes toward the use of such technologies.
Information presented in this paper includes basic demographics, estimates of
survey validity, and a cross-section of instructional technologies used in
poultry science education. The survey found that poultry science faculty reported
higher levels of use for some instructional technologies than was expected from
recent reports in the literature for higher education in general. Traditional
technologies were widely used for instruction, but computers and the Internet
were almost as popular. Reasons for the high levels of use may be due to an
increasing user-friendliness of equipment and software applications, as well as
the rapid acceptance over the past 2 yr of computers and Internet technologies
among the general public. Involvement with IT projects appears to be changing
from passive to active, consistent with faculty reports of high interest levels
and active experimentation with technology and software.
PMID- 10780645
TI - The use of instructional technology in poultry science curricula in the United
States and Canada: 2. Factors contributing to the use of instructional
technology.
AB - This paper describes a study conducted in recognition of the increasingly
widespread use of computers and the importance of exposure to instructional
technology (IT) in all aspects of the poultry science curriculum. The study
consisted of the distribution and analysis of two cross-sectional surveys. One
survey was sent to departments to obtain profiles of poultry science degree
programs and the availability of IT and general support for its use. The second
survey was sent to faculty to obtain individual profiles of IT use and of factors
which may influence IT use. Herein are reported the results and analysis of those
factors that are thought to contribute to or limit the diffusion of these media
among poultry science faculty. Analysis consisted of descriptive statistics and
contingency table comparisons using Likelihood Ratio chi-square. Factors that
appear to be most important to faculty use of IT are availability of desired IT
equipment, access to adequate expert assistance, availability of knowledgeable
peers willing to share their experience and expertise, and exposure to concrete
examples and ideas of how to use IT. All of these factors contribute to another
important factor in participation and adoption: making it as easy as possible for
faculty to learn and to use advanced IT methods.
PMID- 10780646
TI - The effects of long-term caging and molt of Single Comb White Leghorn hens on
heterophil to lymphocyte ratios, corticosterone and thyroid hormones.
AB - Two commercial strains of 18-wk-old Single Comb White Leghorn (SCWL) hens, HyLine
W-36 and DeKalb XL, were housed six hens per cage in layer cages at two densities
(361 and 482 cm2 per bird) with two replications each per strain and density
combination. The high density treatment contained 24 hens per replication, and
the low density treatment contained 18 hens per replication. Egg production was
measured during the first egg production cycle, a molt (fast) period, and the
first 4 wk of the second lay cycle (20 to 68 wk of age). Blood samples were
obtained from six hens from each replicate in each strain and density combination
(total of 48) at 20, 26, 34, 43, 51, 62, 64, and 68 wk of age. In addition, blood
samples were obtained in a random order from hens in each cage, and the sequence
of sampling was recorded (1 to 6). Blood smears were made, from which heterophil
to lymphocyte ratios (H:L) were determined. Radioimmunoassays were conducted to
determine levels of plasma corticosterone (CS), 3,5,3'-triiodothyronine (T3), and
thyroxine (T4). The results indicated that strain did not affect percentage hen
day egg production (%HDP). Strain and cage density did not affect H:L, T3, T4, or
CS. However, these parameters were affected by bird age, which was related to the
egg production cycle. Plasma CS significantly (P < or = 0.001) increased during
peak %HDP at 26 wk and 64 wk during the molt (fast), and H:L significantly (P <
or = 0.001) increased during the molt (fast) at 64 wk. The sequence in which
blood samples were obtained, from hens within a cage in sampling order, also
increased plasma CS. The CS was significantly (P < or = 0.001) elevated in the
third, fifth, and sixth hens from which blood samples were drawn. Plasma T3 and
T4 changed during the production cycle. The T3 was significantly (P < or =
0.0001) depressed during peak egg production at 26 wk and during the molt (fast)
at 64 wk when compared with the other time periods. Plasma T4 was depressed (P <
or = 0.0001) at 51 wk and was elevated (P < or = 0.0001) at 64 wk during the molt
(fast). The physiological and metabolic parameters of the different hen strains
and cage densities were similar during egg production. However, CS, T3, T4, and
H:L changed with age in relation to the egg production cycle. In addition, the
physiological demands of peak egg production and molt (fast) appeared to be
similar.
PMID- 10780647
TI - Influence of genetic selection for antibody production against sheep blood cells
on energy metabolism in laying hens.
AB - Genetic selection in chickens has been utilized to enhance immune responses that
may influence resistance to diseases. It is important, however, to investigate
the effects of this selection on other physiological processes. Therefore, this
study was conducted to determine whether selection for antibody (Ab) production
against SRBC has an effect on energy metabolism. Laying hens from three lines
were used in this study, two of which were selected for 15 generations for Ab
response against SRBC, and the third was nonselected and randombred. The hens
used were from four different groups. The first two groups were from the lines
that were selected for either high (SH) or low (SL) Ab production. The second two
groups were control birds (nonselected) that had either high (CH) or low (CL) Ab
titers that were similar to those in the SH and SL lines, respectively. The birds
were housed in climate-respiration chambers. Body weights and energy metabolism
were measured. Body weights of SL hens were significantly (P < 0.05) higher than
those of SH hens. However, the BW for the two nonselected groups were similar but
significantly less than the SL group. Energy partitioning was similar in all
groups; however, ME for maintenance for the selected groups (119 kcal x kg(-0.75
x d(-1)) was numerically, but not significantly (P < 0.09), higher than that of
the nonselected groups (112 kcal x kg(-0.75) x d(-1)). These results suggest that
divergent selection for Ab may result in an increase in the requirements of
energy for maintenance, which is not directly related to the amount of Ab
produced. Furthermore, these results support previous findings of the presence of
a negative correlation between BW and the levels of Ab in selected lines.
PMID- 10780648
TI - Protein and energy evaluation of soybean meals processed from genetically
modified high-protein soybeans.
AB - A conventional and two genetically modified soybean samples were processed to
dehulled soybean meal (SBM) at a pilot plant and were compared with SBM from a
commercial processing plant. Crude protein levels (%) of the experimental SBM
samples were M700, 52.5; M702, 53.4; and M703, 62.7. The commercial SBM sample
(UI) contained 47.5% protein. Amino acid, gross energy, lipid, and fiber analyses
were carried out, and true metabolizable energy and true amino acid digestibility
were determined with adult cecectomized cockerels. Digestible Lys, Met, Cys, Thr,
and Val, and also TMEn, were higher (P < 0.05) and NDF, fat, and phospholipids
were lower in M703 than in the other SBM samples. The results of this study
indicate that M703 has considerable advantages over conventional SBM as a feed
ingredient for broiler chickens.
PMID- 10780649
TI - Nutritional value of enzyme- or sodium hydroxide-treated feathers from dead hens.
AB - Two feather digestion processes to remove the feathers from the carcasses of dead
hens were evaluated for their impact on the nutritional quality of the resulting
feather meal. There were three treatments: control (untreated feathers), a
feather-digesting enzyme, and NaOH treatment. Both enzyme- and NaOH-treated
feathers were easily separated from the hen carcasses. The CP level of enzyme
treated feathers after autoclaving (49.90%) was significantly less than the
control and NaOH-treated feathers (94.48 and 87.31%, respectively) because of
elevated ether extract levels resulting from skin and abdominal fat release
during the 12-h enzyme incubation. Before autoclaving, pepsin digestibilities of
enzyme- and NaOH-treated feathers were significantly higher than the control.
However, after autoclaving, no significant difference was found in pepsin
digestibility between the control and enzyme treatments or control and NaOH
treatments. The typical limiting amino acids, methionine, lysine, and histidine,
in feathers were present at greater levels in the resulting enzyme-feather meal
(E-FM) compared with the NaOH-feather meal (N-FM) or control-feather meal (C-FM)
on a percentage of CP basis. Cystine levels, however, were significantly lower in
the E-FM and N-FM compared with that of the C-FM. In chick bioassays, no
significant differences were found in protein efficiency ratio (PER) and net
protein ratio (NPR) among C-FM, E-FM, and N-FM. The AMEn of E-FM (4.52 kcal/g)
was significantly higher than the C-FM (3.58) or N-FM (2.79). These findings
indicated that although enzyme treatment could improve the nutritional quality of
feathers from dead hens, NaOH treatment was a more rapid means of separating
feathers from the carcass.
PMID- 10780650
TI - The effects of various dietary levels of phytase and available phosphorus on
performance of laying hens.
AB - Data previously obtained from our laboratory indicated that addition of 300 U of
phytase/kg diet supported optimal long-term performance of laying hens (20 to 70
wk) fed a corn-soybean meal (SBM) diet containing 0.10% available phosphorus
(AP). Our primary objective was to determine if a phytase level lower than 300
units/kg is adequate for a commercial strain of Single Comb White Leghorn laying
hens (n = 504) fed a corn-SBM diet containing no supplemental P (0.10% AP).
Dietary treatments consisted of the corn-SBM basal diet (0.10% AP, 3.8% Ca, and
17% CP) supplemented with 0, 100, 200, 250, or 300 U of phytase/kg, 0.05%
inorganic P (0.15% AP), and a positive control diet containing 0.45% AP. Each of
the seven dietary treatments was fed to six replicate groups of 12 hens from 20
to 60 wk of age. No significant differences in performance were observed among
treatments during the first 8 wk of the experiment. By 28 wk of age, the 0.10% AP
diet, with no supplemental phytase or P, resulted in significantly lower (P <
0.05) egg production and body weight compared with all other dietary treatments.
Feed consumption, feed efficiency, and egg yield were subsequently depressed by
32 wk of age in hens fed the 0.10% AP diet. No other significant differences
among treatments were observed for performance averaged over the entire 40-wk
experimental period. The mean daily AP intake of hens fed the 0.15% AP, 0.45% AP,
and 0.10% AP + phytase diets was 155, 474, and 103 mg, respectively. The results
of this study indicate that phytase improves the utilization of P in corn-SBM
diets for laying hens and that corn-SBM diets containing 0.10% AP + 100 units of
phytase/kg diet or 0.15% AP supported egg production performance that was not
significantly different (P > 0.05) from that of hens fed a corn-SBM diet
containing 0.45% AP.
PMID- 10780651
TI - Effects of dietary vitamin E on the quality of table eggs enriched with n-3 long
chain fatty acids.
AB - Because of the proposed cardioprotective benefits of n-3 fatty acids and vitamin
E, a trial was carried out to investigate the possibility of enriching eggs with
n-3 fatty acid and vitamin E added to the hen's diet. One hundred ninety-two Hy
Line Brown hens, 39-wk-old, were divided into eight groups: four groups received
the basal diet supplemented with 3% lard and four doses of dl-alpha-tocopheryl
acetate (0, 50, 100, and 200 ppm), whereas the diets of the other groups were
supplemented with 3% of fish oil and the same doses of vitamin E. The
performances of the hens and egg weights were not affected either by the type of
lipid supplement or by the vitamin level. The treatment with fish oil caused a
dramatic increase (P < 0.01) of all n-3 fatty acids of the yolk, particularly EPA
(19.53 vs. 0.74 mg/egg) and DHA (143.70 vs. 43.66 mg/egg), and an appreciable
decrease of arachidonic acid (25.54 vs. 67.72 mg/egg). The different levels of
dietary vitamin E slightly affected the fatty acid composition of the yolk. Yolk
alpha-tocopherol increased linearly as dietary dl-alpha-tocopheryl acetate
increased (P < 0.01) from the control level of 90.93 microg/g of yolk to 313.84
microg/g of yolk when 200 ppm were added to the hen diets. Twenty-eight days of
storage at room temperature (20 to 25 C) did not alter the yolk fatty acid
profile, and, moreover, the levels of vitamin E remained still very close to
those observed in fresh egg.
PMID- 10780652
TI - Body composition and development measured repeatedly by computer tomography
during growth in two types of turkeys.
AB - Distribution and development of fat, muscles, and bone were studied repeatedly by
computer tomography from 4 to 17 wk of age in two commercial strains of turkeys
(BUT-9 and Nicholas) of both sexes. Generally, the proportion of total fat and
meat increased and bone decreased significantly throughout the experimental
period for both strains and sexes. When compared at the same age or body weight,
BUT-9 tended to have a higher percentage of meat than did Nicholas (0 to 3
percentage units). From 8 to 17 wk of age, Nicholas showed higher fat percentage
and lower bone percentage than BUT-9. Based on this study, regardless of weight
at slaughtering, BUT-9 should be preferred. Because males had a significantly
higher body weight gain and higher percentage of meat from 8 wk of age, males
should be used in production to fit the market for high slaughter weights with
large pieces of meat. Because females had a higher meat percentage at young ages
compared with males, but showed an earlier fattening and lower weight gain,
females should preferably be slaughtered at lower live weights. Computer
tomography can be considered an appropriate but expensive method to study body
composition and development in turkeys.
PMID- 10780653
TI - The characterization and incidence of pale, soft, exudative turkey meat in a
commercial plant.
AB - Pale, soft, exudative (PSE) turkey meat is a growing problem for industry and has
been associated with rapid postmortem pH decline and loss of protein
functionality, similar to PSE pork. This study was designed to estimate the
incidence of PSE meat in a commercial plant and use response surface methodology
to characterize the relationship between pH, lightness (L* value), and water
holding capacity (WHC). One hundred thirty-four turkey breast fillets were
selected from the processing line so that 67 had normal color (lightness), and
the other 67 were more pale than normal. Fillets were analyzed at time of
deboning (1.5 h postmortem) and at 24 h postmortem for color (L* value), pH, drip
loss, expressible moisture, and temperature. Additionally, L* values were
measured on 2,995 turkey breasts from the processing line to determine the
commercial incidence of PSE meat based on color. The pale fillets had
significantly lower pH, greater L* value, and less WHC but equal temperature when
compared with the fillets with normal color. The L* value and pH were correlated
with WHC as measured by expressible moisture, but L* value seems to have more
predictive value. By using the L* value range (>53) from the pale-selected
fillets as an indication of paleness, approximately 40% of the 2,995 fillets
would exhibit poor WHC. These results suggest that PSE meat can represent a
significant portion of commercially processed turkey breast meat and that the L*
value measurement could be used to sort turkey meat so that PSE type meat could
be used in specialized formulations.
PMID- 10780654
TI - Influence of the level and location of contamination on the multiplication of
Salmonella enteritidis at different storage temperatures in experimentally
inoculated eggs.
AB - Prompt refrigeration to temperatures capable of restricting microbial growth has
been recommended as an approach to reducing the likelihood that contaminated eggs
will transmit Salmonella enteritidis to humans. By using experimentally
contaminated egg components, the present study determined the extent to which
small numbers of S. enteritidis could grow to more dangerous levels at different
temperatures over a period up to 3 d. This model was intended to simulate the
potential opportunities for S. enteritidis multiplication following oviposition
and prior to the achievement of internal temperatures able to prevent further
microbial growth in eggs. At a relatively warmer incubation temperature (25 C)
and with higher inoculum doses (150 cells), rapid and substantial S. enteritidis
multiplication often occurred, especially when the bacteria had an opportunity
for access to yolk nutrients and when contaminated eggs were incubated for 2 or 3
d before sampling. Extensive multiplication of S. enteritidis was less frequently
observed at lower inoculum doses (15 cells), shorter storage times (1 d), and
lower temperatures (10 to 17.5 C) and when contaminants were introduced into the
albumen.
PMID- 10780655
TI - Plasma 17beta-estradiol levels and ovarian interstitial cell structure in
embryonic Japanese quail.
AB - Plasma concentrations of 17beta-estradiol (E2) and left ovarian histology were
investigated by light and electron microscopy in female Japanese quail from Day
10 of embryonic development through Day 7, posthatch. Plasma E2 levels remained
relatively constant (102 to 140 pg/mL) in the embryo followed by a sharp decrease
posthatch (47 to 70 pg/mL). Beginning on Day 10 of incubation, cells in the
medullary portion (medullary cell; MC) of the left ovaries exhibited
ultrastructural evidence of steroidogenic capability. The MC had numerous lipid
droplets in close proximity to the smooth endoplasmic reticulum (SER).
Mitochondria were also observed in the vicinity of the lipid droplets and SER. On
Days 10 and 12, the cristae of the inner mitochondrial membranes were of a
lamellar configuration; the cristae of some mitochondria in MC had a tubular
appearance by Day 14. These data document relative ontogenic changes in ovarian
morphology and plasma E2 levels during the early developmental period in female
Japanese quail. These data further support the role of this steroid in sexual
differentiation.
PMID- 10780656
TI - Identification of epididymal stones in diverse rooster populations.
AB - The epididymal region of the male reproductive tract is essential for sperm
maturation, and dysfunction of this region results in infertility. Adult roosters
have been observed to develop epididymal stones and consequently have reduced
fertility. Efferent ductule cysts were first observed in White Leghorn roosters
ages 18 to 26 wk. By 26 wk of age, the cysts had become solid, irregularly
shaped, yellow-green stones primarily containing calcium (48%). The number and
size of stones (9 to 160 microm, largest diameter) increased with age in affected
males. Incidence ranged from 0 to 94% within rooster flocks surveyed. Stones have
also been observed in broiler breeder roosters. Histological analysis of Leghorn
and broiler breeder reproductive tracts revealed chronic inflammation with
abundant interstitial mononuclear cell infiltrates. The normal, highly folded
structure of efferent ductules was replaced by a thin, eroded epithelial layer
with few luminal sperm. Abnormal areas were found interspersed with normal areas
of epithelium. Broiler breeder male fertility trials demonstrated that birds with
stones compared with normal males had reduced fertility following both natural
mating (24.8+/-10.5% vs. 66.1+/-7.2%) and artificial insemination (47.8+/-16% vs.
82.0+/-6%). At 62 wk of age, testis weight (14.2+/-1.4 g vs. 20.5+/-1.2 g), daily
sperm production (8.1+/-1.3 x 10(8) vs. 12.3+/-0.8 x 10(8) sperm per testis per
day), and circulating testosterone concentrations (0.9+/-0.3 vs. 2.6+/-0.4 ng/mL)
were all significantly reduced in males with stones. In conclusion, we are
reporting a new dysfunction of the rooster reproductive tract that affects
diverse bird populations and decreases fertility.
PMID- 10780657
TI - Parathyroid hormone receptor binding property in the shell gland of oviduct of
the guineafowl during an oviposition cycle.
AB - Parathyroid hormone (PTH) receptor binding property in the membrane fraction of
the endometrium of the shell gland (uterus) of the guineafowl was analyzed by the
use of [125I]PTH-related peptide (PTHrP) binding assays. Specificity,
reversibility, and saturation of binding were demonstrated. Scatchard plots
revealed a single class of binding sites. The equilibrium dissociation constant
(Kd) was 0.50 to 1.15 nM in laying birds and 1.07 to 1.16 nM in nonlaying birds.
The maximum binding capacity (Bmax) per milligram of membrane protein was 65.2 to
110.9 femtomoles (fmol) in laying birds and 105.8 to 120.6 fmol in nonlaying
birds. Both Kd and Bmax values changed within the above range during an
oviposition cycle in laying birds, showing a decrease during the period of
eggshell formation. No change was found in nonlaying birds. The results suggest
that PTH/PTHrP receptors are present in the shell gland of the guineafowl, and
their binding may be related to eggshell formation.
PMID- 10780658
TI - Extraction and quantification by ELISA of eggshell organic matrix proteins
(ovocleidin-17, ovalbumin, ovotransferrin) in shell from young and old hens.
AB - The eggshell matrix is mainly composed of proteins that are thought to influence
shell formation and calcification and, thus, modify the resulting properties of
the shell. We investigated the potential of some of these proteins as biomarkers
of eggshell quality by developing a competitive indirect ELISA for quantifying
ovotransferrin, ovalbumin, and ovocleidin-17 in eggshell extract. Eggshell
fragments were demineralized in acetic acid (20%) and freeze-dried. The micro
extraction yield was markedly increased (>50%) when Tween 20 was added to the
subsequent extraction and dialysis milieus. Microplates were coated with
ovotransferrin and ovalbumin in a 0.1M carbonate-bicarbonate buffer, but
ovocleidin-17 was fixed with acetone (-20 C, 20 min). Optimal dilutions of the
monoclonal (ovotransferrin) and polyclonal (ovalbumin and ovocleidin-17)
antibodies were 1/3,000, 1/25,000 and 1/4,000, respectively. The inhibition
curves were optimized by preincubating the antibodies and proteins overnight. The
intraassay coefficient (<5%), parallelism of the standards and samples curves,
and recovery (101%) were satisfactory for ovotransferrin. Measurements of
ovalbumin were less precise because of higher interassay variation and
differences between the slopes of standard and sample inhibition curves.
Ovocleidin-17 assays showed similar slopes for standard and eggshell extracts.
Although the total protein in soluble matrix extracts was not affected by age,
the concentrations of these proteins were higher in eggshell extracts from older
hens compared with those from young hens: 1.98x for ovotransferrin, 1.86x for
ovalbumin, and 1.58x for ovocleidin-17. The quantification of specific eggshell
matrix proteins in shell of differing quality is, therefore, a promising tool for
analyzing the origin of eggshell faults and may provide useful information for
breeding programs.
PMID- 10780659
TI - Identification of some components of basal lamina of avian ovarian follicle.
AB - Experiments were conducted to identify components of the basal lamina of the
ovarian follicle. Pure and intact basal lamina was isolated from preovulatory
follicles of the chicken ovary. Some components of the basal lamina could be
solubilized with guanidine-HCl (designated Fraction 1) and remaining components
with beta-mercaptomethanol containing guanidine-HCl (designated Fraction 2). With
Western blot analysis, monoclonal and polyclonal antibodies raised against avian,
mammalian, and human proteins recognized proteins in Fractions 1 and 2 of
solubilized basal lamina. Thus, antibodies raised against extracellular matrix
proteins, laminin, fibronectin, entactin or nidogen, tenascin, heparan sulfate
proteoglycan, osteonectin, and Type IV collagen reacted positively with basal
lamina proteins. Antibodies raised against the growth factors; epidermal growth
factor; acidic and basic fibroblast growth factors; platelet-derived growth
factor-AA; transforming growth factor-alpha; transforming growth factor-beta1,
beta2, -beta3, and -beta5; and insulin-like growth factor-I and -II cross-reacted
with basal lamina proteins. Similarly, antibodies raised against insulin-like
growth factor-binding proteins-2, -3, -4, -5, -6, and -7 cross-reacted with basal
lamina proteins. In addition, antibodies generated against matrix
metalloproteinases-1, -2, -3, -4, -8, -9, and -13 reacted positively with basal
lamina proteins. Furthermore, antibodies produced against tissue inhibitors of
matrix metalloproteinases-1, -2, -3, and -4 also reacted positively with basal
lamina proteins. Moreover, interleukin-3, granulocyte macrophage-colony
stimulating factor, interferon-gamma antibodies recognized proteins in basal
lamina. These observations are consistent with the view that the basal lamina of
avian ovarian follicle is a store or source of biologically active molecules,
namely growth factors, growth factor-binding proteins, cytokines, matrix
metalloproteinases, and their tissue inhibitors. The growth factors could exert
major effects on ovarian cell behavior and function, and the enzymes could
participate in tissue remodeling during follicular development.
PMID- 10780660
TI - Morphometric and mechanical properties of femora in young adult male turkeys with
and without femoral fractures.
AB - Morphologic and torsional mechanical properties of femora were evaluated in three
groups of turkeys to determine whether turkeys that incurred femoral fracture
have different radiographic, morphologic, and torsional mechanical properties
than do turkeys without femoral fracture, and if body weight was a factor
differentiating affected and nonaffected turkeys. Nine turkeys with unilateral
femoral fractures and nine turkeys without fractures from Farm A were compared
with a group of nine age and genetically matched turkeys from Farm B. Turkeys
from Farm A were 10 to 25% heavier (26.2+/-0.9 kg) and turkeys from Farm B were
10% lighter (18.2+/-0.9 kg) than expected breed standards. Femoral length,
cortical thickness, medullary diameter, and diaphyseal curvature were measured
from craniocaudal and lateromedial radiographs. One intact femur from each of
five turkeys with a contralateral femoral fracture (Farm A), nine unaffected
turkeys from Farm A, and nine turkeys from Farm B were subjected to failure in a
torsion test. Geometric and mechanical results were compared. Turkeys from Farm A
had a thicker cortex and a smaller medullary diameter than turkeys from Farm B.
Turkeys from Farm A had significantly lower torsional stiffness and failure
torque values compared with turkeys from Farm B, when differences in body weight
were accounted for (analysis of covariance, P < 0.05). Mechanical failure torque
calculated from geometric values suggests that organic or inorganic material
arrangement and composition may be responsible, in part, for differences between
groups. Femoral fractures may be associated with insufficient skeletal adaptation
to heavy body weight.
PMID- 10780661
TI - Release and complex formation of soluble VEGFR-1 from endothelial cells and
biological fluids.
AB - One of the key molecules promoting angiogenesis is the endothelial cell-specific
mitogen, vascular endothelial growth factor (VEGF or VEGF-A), which acts through
two high-affinity receptor tyrosine kinases (VEGFR), VEGFR-1 (or Flt-1) and VEGFR
2 (or KDR/Flk-1). It was shown before that a soluble variant of VEGFR-1 (sVEGFR
1) can be generated by differential splicing of the flt-1 mRNA. This soluble
receptor is an antagonist to VEGF action, reducing the level of free, active VEGF
A, and therefore, plays a pivotal role in the generation of vascular diseases
like pre-eclampsia or intra-uterine growth retardation. Here we show that sVEGFR
1 is produced by cultured human microvascular and macrovascular endothelial cells
and a human melanoma cell line. The soluble receptor is mainly complexed with
ligands; only 5-10% remains detectable as free, uncomplexed receptor protein.
Furthermore, we show the time course of total and free sVEGFR-1 release together
with its putative ligands, VEGF-A and placenta growth factor (PIGF), from
macrovascular endothelial cells. The release of sVEGFR-1 was quantitatively
measured in two different ELISA types. The release of sVEGFR-1 was strongly
enhanced by phorbol-ester (PMA); the cells produced up to 22 ng/ml of sVEGFR-1
after 48 hours. The expression of VEGF-A and PIGF was moderately influenced by
PMA. We also show a hypoxia-induced increase of sVEGFR-1 expression in cells
cultured from placenta, a tissue that has a high flt-1 gene expression. Moreover,
we demonstrate that sVEGFR-1 in amniotic fluids acts as a sink for exogenous
VEGF165 and PIGF-2. Here, for the first time, to what extent recombinant ligands
have to be added to compensate for the sink function of amniotic fluids was
analyzed. In conclusion, human endothelial cells produce high levels of sVEGFR-1,
which influences the availability of VEGF-A or related ligands. Therefore, sVEGFR
1 may reduce the ligand binding to transmembrane receptors and interfere with
their signal transduction.
PMID- 10780662
TI - Association of plectin with Z-discs is a prerequisite for the formation of the
intermyofibrillar desmin cytoskeleton.
AB - Plectin is a high-molecular mass protein (approximately 500 kd) that binds actin,
intermediate filaments, and microtubules. Mutations of the plectin gene cause a
generalized blistering skin disorder and muscular dystrophy. In adult muscle,
plectin is colocalized with desmin at structures forming the intermyofibrillar
scaffold and beneath the plasma membrane. To study the involvement of plectin in
myofibrillogenesis, we analyzed the spatial and temporal expression patterns of
plectin in cultured differentiating human skeletal muscle cells and its
relationship to desmin intermediate filaments during this process. Northern and
Western blot analyses demonstrated that at least two different plectin isoforms
are expressed at all developmental stages from proliferating myoblasts to mature
myotubes. Using immunocytochemistry, we show that the localization of plectin
dramatically changes from a network-like distribution into a cross-striated
distribution during maturation of myocytes. Double immunofluorescence experiments
revealed that desmin and plectin are colocalized in premyofibrillar stages and in
mature myotubes. Interestingly, plectin was often found to localize to the
periphery of Z-discs during the actual alignment of neighboring myofibrils, and
an obvious cross-striated plectin staining pattern was observed before desmin was
localized in the Z-disc region. We conclude that the association of plectin with
Z-discs is an early event in the lateral alignment of myofibrils that precedes
the formation of the intermyofibrillar desmin cytoskeleton.
PMID- 10780663
TI - In vivo detection of ultraviolet photoproducts and their repair in purkinje
cells.
AB - We previously developed a highly sensitive method to assess in situ repair
kinetics of ultraviolet (UV)-induced DNA photoproducts in epidermal cells using
monoclonal antibodies specific for cyclobutane pyrimidine dimers (CPDs) and
pyrimidine-pyrimidone (6-4) photoproducts (64PPs) by immunohistochemistry. In
order to determine whether nucleotide excision repair capacity is operative in
postmitotic mature neurons, brain surfaces of adult mice were exposed to UVB, and
induction and removal of CPDs and 64PPs in Purkinje cell DNA were assessed
immunohistochemically. UVB penetrated brain tissue to a depth sufficient to allow
quantitative study. CPDs but not 64PPs were clearly detectable in the nuclei of
Purkinje cells at doses >500 J/m2, in a dose-dependent manner. A time course
experiment showed a statistically significant decrease of CPDs with time after
irradiation. Although there was no apparent removal on Day 1, about half of CPDs
were removed within 5 days, and the repair was essentially completed by Day 10.
We conclude that non-dividing cerebellar neuronal cells can indeed repair UV
induced DNA damage, but with relatively low efficiency as compared with dividing
epidermal cells.
PMID- 10780664
TI - CD4+ T cell-mediated cytotoxicity toward thyrocytes: the importance of Fas/Fas
ligand interaction inducing apoptosis of thyrocytes and the inhibitory effect of
thyroid-stimulating hormone.
AB - The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular
interactions between thyrocytes and CD4+ T cells have been determined in thyroid
gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction
between antigen-presenting cells and T cells regulates the apoptosis of the
former cells triggered by the latter cells. The inhibition of Fas-mediated
apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of
thyrocytes in patients with Graves' disease. We investigated the potential role
of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of
Fas-mediated apoptosis of the former cells induced by the latter cells. The
presence of only a few specific T cells responsive to a putative autoantigen has
hampered the investigation of specific T cell activation toward antigen
presenting cells (APCs). Therefore, we used a superantigen, staphylococcal
enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in
vitro since it stimulates a large proportion of T cells with particular Vbeta
elements. Spontaneous apoptosis of thyrocytes in culture was not found even in
the presence of various kinds of cytokines. In contrast, a clear induction of Fas
mediated apoptosis by anti-Fas IgM was determined in interferon-gamma (IFN-gamma)
stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T
cells toward IFN-gamma-stimulated thyrocytes in the presence of SEB was induced,
and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade
of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T
cells cocultured with IFN-gamma-stimulated thyrocytes in the presence of SEB was
clearly induced. Furthermore, the addition of mAbs against CD54 and CD58
inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity
of CD4+ T cells toward IFN-gamma-stimulated, SEB-pulsed thyrocytes was markedly
inhibited when we used thyrocytes cultured with IFN-gamma in the presence of
thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1)
CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an
SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T
cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on
activated CD4+ T cells. The presence of costimulating molecules such as CD54 and
CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells.
3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are
similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to
the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by
activated CD4+ T cells.
PMID- 10780665
TI - DMBA-induced mammary pathologies are angiogenic in vivo and in vitro.
AB - We have previously shown that human pre-invasive diseases of the breast are
angiogenic. In addition, normal epithelium from women with coincident or
subsequent invasive breast cancer is more vascular than normal epithelium from
women with no breast cancer. To develop a model in which to study the regulation
of angiogenesis in pre-invasive mammary pathologies, we examined 7,12
dimethylbenz[a]anthracene (DMBA)-induced rat mammary tissues for the presence of
neovascularization in pre-invasive histopathologies. These studies included
morphometric analysis of tissue vascularity in pre-invasive lesions. In addition,
we isolated fresh tumors and histologically normal epithelium (organoids) from
DMBA or vehicle-treated control rats to test their ability to induce endothelial
cell tubule formation in vitro. Finally, we examined tumors for their ability to
produce vascular endothelial cell growth factor. The morphometric studies
documented that with epithelial progression, the ability of individual cells to
elicit angiogenesis increases. The in vitro studies showed that isolated tumors
from these animals stimulate angiogenesis. Furthermore, normal epithelium from
DMBA-treated rats is more angiogenic than epithelium from control animals.
Finally, DMBA-induced tumors produce vascular endothelial growth factor (VEGF)
mRNA, therefore, DMBA-induced mammary tumorigenesis is one model in which to test
the dependency of progression on angiogenesis.
PMID- 10780666
TI - Mutations of the p53 gene in nasal NK/T-cell lymphoma.
AB - Mutations of the p53 tumor suppressor gene are reported in various kinds of
malignancies including lymphomas. However, p53 gene mutations in nasal NK/T-cell
lymphoma have not been reported because most parts of tumors are necrotic and a
small amount of living tumor tissues is available for the molecular study.
Expression and mutations of the p53 gene were examined in the paraffin-embedded
specimens of the nasal lesions from 42 Chinese (Beijing and Chengdu) and Japanese
(Okinawa and Osaka) patients with nasal NK/T-cell lymphoma by the
immunohistochemistry and single strand conformation polymorphism (SSCP) analysis
of polymerase chain reaction (PCR) amplified products followed by direct
sequencing. Thirty single-nucleotide substitution mutations were observed in 20
of 42 cases (47.6%). Among the 30 mutations, 18 were missense (mainly G:C to A:T
transitions), 9 were silent, and 1 was a nonsense mutation. The remaining 2
mutations involved intron 5 and exon 5 terminal points. Abnormal expression of
the p53 protein was also observed in 19 of 42 (45.2%) cases. The incidence was
significantly (4-fold) higher in the cases of Osaka than those in other areas,
although the incidence of p53 mutations in the cases of Osaka was one-half to one
third of those in the other three areas. The results may suggest some racial,
environmental, or lifestyle differences in the cause of nasal tumorigenesis.
PMID- 10780667
TI - An in vitro model for the study of human bone marrow angiogenesis: role of
hematopoietic cytokines.
AB - This study describes a human bone marrow endothelial cell culture in which
endothelial cells are organized into capillary tubes. These endothelial cells
were positive for von Willebrand Factor, expressed CD34, CD31, and L-fucose
residues, took up acetylated low-density lipoproteins, contained Weibel-Palade
bodies, and were ensheathed in a basal lamina (which included laminin beta1, EDa+
and EDb+ fibronectin, and collagen type iv). Pericytes expressing alpha-smooth
muscle (alpha-SM) actin were spatially associated with the capillary tubes and
there was a highly significant correlation between the number of capillary tubes
and pericytes. In this model, basal angiogenesis was found to be vascular
endothelial growth factor (VEGF)-dependent, because neutralization of endogenous
VEGF induced a dramatic regression in the number of tubes. However, the presence
of alpha-SM actin-expressing pericytes in the linings of endothelial tubes
partially prevented the VEGF-neutralized tube regression. We also observed that
nitric oxide production contributed to basal angiogenesis and that upregulation
of nitric oxide increased the number of tubes. Tube numbers also decreased when
antibodies neutralizing the integrin alphavbeta5 were applied to the cultures.
Moreover, addition of any of the hematopoietic cytokines, erythropoietin, stem
cell factor, granulocytic colony stimulating factor, or granulomonocytic colony
stimulating factor induced a highly significant increase in tube formation. When
erythropoietin and granulocytic colony stimulating factor were added, this
increase was larger than the maximum increase observed with VEGF. Thus, we have
described an in vitro model for human bone marrow angiogenesis in which pericytes
and basal lamina matrix were associated with endothelial cells and formed fully
organized capillary tubes. In this model, cytokines known to regulate
hematopoiesis also seemed to be mediators of angiogenesis. This culture system
may therefore prove to be a valuable tool for the study of hematopoietic
cytokines on angiogenesis.
PMID- 10780669
TI - Ras signaling is involved in the expression of Fas-L in glioma.
AB - Fas-L expresses on a variety of tumors and is suspected to modify the dialog
between tumor and the immune system. However, the cellular abnormality in tumor
cells leading to an aberrant expression of Fas-L is unclear. In this study, we
demonstrate the involvement of Ras signaling in the Fas-L expression in several
ways. First, the activated Ha-rasval12 gene enhanced the Fas-L expression of
primary human glial cells. Second, blocking the Ras signal pathway in glioma
cells by lovastatin or the Ha-rasAsn17 dominant-negative mutant gene resulted in
reduced Fas-L expression. Transfection of the Ha-rasAsn17 into glioma cells also
inhibited the activation of NFKB, which is a downstream component of Ras
signaling. Accordingly, the membrane-permeable NFKB competitor suppressed the Fas
L expression. Furthermore, the Fas-L expression coincided with the Ras activity
in the murine 212 cells, in which the Ras activity could be induced by isopropyl
3-D-thiogalactoside. In summary, these results suggest that the enhanced Ras
signaling with consequential NFKB activation, which is a frequent defect found in
tumors, could mediate the Fas-L expression of tumors.
PMID- 10780668
TI - Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II-
dependent.
AB - To determine whether myocyte death and angiotensin II (AT II) formation are
implicated in the development of diabetic cardiomyopathy, rats were injected with
streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days.
Expression of the components of the renin-angiotensin system (RAS) and AT II
levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the
number and distribution of AT II sites in myocytes were measured at 3 and 10
days. The effects of AT1 blockade on local RAS and cell death were examined at 3
days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and
decreased at 10 and 28 days, in spite of high concentrations of blood glucose.
Cell necrosis was absent throughout. Angiotensinogen, renin, and AT1 receptor
increased in myocytes from diabetic rat hearts, while angiotensin-converting
enzyme and AT2 remained constant. AT II quantity increased severalfold, as did
the fraction of AT II positive cells and the number of AT II sites per myocyte.
However, AT II labeling decreased at 10 days, which paralleled the reduction in
myocyte death. AT1 antagonist inhibited upregulation of this receptor and
angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks
with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of
viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy
may be viewed as an AT II-dependent process in which that peptide plays a
critical role in myocyte death and hypertrophy.
PMID- 10780670
TI - Evidence for keratinocyte immortalization in high-grade squamous intraepithelial
lesions of the cervix infected with high-risk human papillomaviruses.
AB - In this study, we demonstrate that expression of cyclin B protein is up-regulated
and persists into the upper epithelial layers in parallel with cyclin A
expression in high-grade squamous intraepithelial lesions (SIL) infected with
human papillomaviruses 16, 31, 33, 51, 58, 66, and 67 (n = 33). In contrast, low
grade SIL infected with human papillomaviruses 16, 18, 31, 33, 39, 51, 52, 56,
58, and 66 (n = 27) show weaker cyclin B expression confined to basal and
parabasal cells despite extension of cyclin A and Ki67 expression into
superficial cells. Moreover, aneusomy is present in 20% of the high-grade lesions
but in none of the low-grade lesions. The persistent expression of cyclin B in
high-grade SIL, and the restriction of aneusomy to high-grade SIL suggest that
there is cell cycle progression. In combination with in vitro studies, this
provides evidence that high-grade SIL lesions have undergone immortalization.
PMID- 10780671
TI - Regulation of vascular growth and regression by matrix metalloproteinases in the
rat aorta model of angiogenesis.
AB - Matrix metalloproteinases (MMPs) have been implicated in the formation of
microvessels during angiogenesis, but their role in vascular regression is poorly
understood. The rat aorta model of angiogenesis was used to study the function of
MMPs at different stages of the angiogenic process. Gelatin zymography and
Western analysis demonstrated production of MMP-2 and MMP-9 by aortic outgrowths
in serum-free collagen gel culture. MMP-2 was found in both culture medium and
collagen gel, whereas MMP-9 was predominantly associated with the gel. MMP
expression increased gradually during the angiogenic growth phase and stayed high
when vessels regressed and collagen lysed around the aortic rings. The MMP
inhibitors, batimastat and marimastat, blocked formation of microvessels when
added to the culture medium at the beginning of the experiment. They, however,
stabilized the microvessels and prevented vascular regression after the
angiogenic growth phase. This effect was observed also under conditions of
angiogenic stimulation by basic fibroblast growth factor. MMP inhibitor-mediated
stabilization of microvessels was associated with inhibition of collagen lysis
and accumulation of collagen fibrils in the subendothelial space. This study
demonstrates that MMPs promote microvessel formation during the early stages of
angiogenesis, but also contribute to the reabsorption of the neovasculature in
the later stages of this process. The time-dependent divergent effects of MMPs on
microvessel growth and survival may influence the in vivo activity of MMP
inhibitors used to treat angiogenesis-dependent disorders.
PMID- 10780672
TI - Development of intermediate-grade (mantle cell) and low-grade (small lymphocytic
and marginal zone) human non-Hodgkin's lymphomas xenotransplanted in severe
combined immunodeficiency mouse models.
AB - We have used severe combined immunodeficiency (SCID) (c.b.-17, ICR/SCID) mice to
develop xenotransplantation (XT) models for human intermediate-and-low-grade non
Hodgkin's lymphomas (NHL). In the past, SCID mice have provided a variety of
useful XT models for human hematopoietic neoplasms that primarily involve the
acute leukemias and some nonhematopoietic tumors, but only rare reports exist on
use of the SCID mouse model in the study of primary tumor cells from NHL.
Intermediate-grade and low-grade NHL are the most common lymphomas seen in
adults. There is no effective therapy for those types of NHL, and they have not
been established in an animal model to date. The lack of an animal model has
hampered studies that can evaluate the disease process in vivo as well as the
definition of therapeutic parameters involved in treatment. We report in this
study that primary patient samples of NHL ( intermediate grade and low grade)
have been successfully established in SCID mice after XT. NHL include
intermediate-grade (mantle cell lymphoma) and low-grade (eg, small lymphocytic
lymphoma/chronic lymphocytic lymphoma and marginal zone lymphoma) forms. Studies
have been directed toward creating appropriate conditions for the optimal
grafting of these NHL in SCID mice so that the disease process in humans could be
accurately simulated. These studies indicate that development of XT-human
lymphoma cells in SCID mice appear to be linked to their biologic and/or clinical
behavior, transplanted lymphoma cell number, and age, as well as to the natural
killer cell status of the SCID mouse recipients. Evidence has also shown that NHL
cells can exhibit homing or trafficking patterns in SCID recipients that resemble
those observed in patients with gastrointestinal lymphomatous involvement
(particularly that of mantle cell lymphoma). Our studies also indicate that
artefactual influences, such as the outgrowth of Epstein-Barr virus-associated
lymphoblastoid lesions, are rare occurrences in the human NHL/SCID models that we
have established.
PMID- 10780673
TI - Two different types of sialoadenitis in the NOD- and MRL/lpr mouse models for
Sjogren's syndrome: a differential role for dendritic cells in the initiation of
sialoadenitis?
AB - Sjogren's syndrome is an autoimmune disease that primarily affects the salivary
and lacrimal glands. In these glands, focal lymphocytic infiltrates develop.
Little is known about the initiation of this autoimmune disease. Antigen
presenting cells (APC) such as dendritic cells (DC) can play a role in the
initiation of autoimmunity. To date, no data on the presence of DC in Sjogren's
syndrome are available. Several mouse strains, the nonobese diabetic (NOD) and
the MRL/Ipr mouse, can be used as models for Sjogren's syndrome. We compared the
development of sialoadenitis in the submandibular glands (SMG) of NOD and MRL/Ipr
mice with particular focus on the presence of APC. DC, macrophages, T cells, and
B cells in the SMG were studied by means of immunohistochemistry, after which
positively stained cells were quantified. NOD-severe combined immunodeficiency
(SCID) mice were used to study the presence of APC in the SMG in the absence of
lymphocytes. Before lymphocytic infiltration, increased numbers of DC were
detected in the SMG of NOD mice compared with those numbers in control mice and
MRL/Ipr mice, which suggests that DC play a role in the initiation of
sialoadenitis in NOD mice. In the SMG of NOD mice, lymphocytic infiltrates
organized in time. In MRL/Ipr mice, however, lymphocytic infiltrates were already
organized at the time of appearance. This organization was lost over time. In
conclusion, two types of sialoadenitis are described in two mouse models for
Sjogren's syndrome. Differences exist with regard to early events that may lead
to the development of sialoadenitis and to the composition and organization of
inflammatory infiltrates. It is possible that different types of sialoadenitis
also exist in humans and that the pathogenetic process in both the early and late
phases of the autoimmune reaction differs among patients.
PMID- 10780674
TI - AAC-11 overexpression induces invasion and protects cervical cancer cells from
apoptosis.
AB - To identify the genes involved in cervical carcinogenesis, we applied the mRNA
differential display (DD) method to analyze normal cervical tissue, cervical
cancer, metastatic lymph node, and cervical cancer cell line. We cloned a 491-bp
cDNA fragment, CC231, which was present in metastatic tissue and cervical cancer
cell line, but absent in normal cervical and cervical cancer tissues. The 491 bp
cDNA fragment has 98% homology to the previously published sequence, AAC-11
(antiapoptosis clone 11). The levels of AAC-11 mRNA expressions in nine normal
cervical and nine primary cervical cancer tissues were low. Its expression was
higher in three metastatic tissues and five cervical cancer cell lines (HeLa,
CaSki, SiHa, CUMC-3, and CUMC-6). Invasion of matrigel and adhesion to laminin by
AAC-11 transfected CUMC-6 cells were increased by approximately 2-fold and 4
fold, respectively. Northern blot analysis showed that matrix metalloproteinase
(MMP)-2 and membrane type 1 MMP (MT1-MMP) genes were found to be expressed in
high levels in AAC-11-transfected cancer cells. But MMP-2 and MT1-MMP were not
expressed in cells transfected with vector alone or wild-type cells. AAC-11
transfected cells expressed an elevated level of MMP-2 protein as assessed by
immunoblotting. On the contrary, tissue inhibitor of MMP (TIMP-2) expression was
detectable in cells transfected with vector alone or wild-type cells,
respectively. Its expression was undetectable in AAC-11 transfected cells. In
cervical cancer cells transfected with AAC-11, the expression of beta-catenin was
up-regulated. These suggest that overexpressions of MMP-2 and MT1-MMP, loss of
TIMP-2 expression, and up-regulation of beta-catenin by AAC-11 transfection may
contribute to the development of cervical cancer invasion. AAC-11 gene
transfection increased cervical cancer cell colonization. The effect of AAC-11 on
cultured cervical cancer cells was associated with antiapoptotic process.
Approximately 50% of the AAC-11 transfected cells in serum-free medium died after
2 weeks, compared to 1 week for vector alone or wild-type cells. These results
suggest that AAC-11 may serve as a candidate metastasis-related and apoptosis
inhibiting gene in human cervical cancer.
PMID- 10780675
TI - Interleukin-8 overexpression is present in pyoderma gangrenosum ulcers and leads
to ulcer formation in human skin xenografts.
AB - Interleukin-8 (IL-8) is a potent chemotactic polypeptide for neutrophils.
However, the role of this cytokine during inflammation remains unclear. Skin
specimens from patients with pyoderma gangrenosum demonstrated IL-8
overexpression in skin ulcers, which suggests a role for IL-8 in the development
of the disease. We therefore constructed a recombinant adenovirus expressing the
complementary deoxyribonucleic acid encoding human IL-8 (IL-8/Ad5) that induces a
2000-fold increase in IL-8 expression of infected human fibroblasts in vitro.
Human skin engrafted to severe combined immunodeficiency mice and then injected
with the recombinant virus demonstrated erythema, an intense perivascular
infiltration of neutrophils, and extravasation of erythrocytes after 8 hours. By
12 hours after injection, neutrophils had accumulated beneath the epidermis,
which then necrotized, and one or more ulcers that remained for approximately 2
weeks were observed. Clinically and histologically, the ulcers resembled pyoderma
gangrenosum. These clinical and experimental findings suggest an etiologic role
of IL-8 in the pathogenesis of pyoderma gangrenosum.
PMID- 10780676
TI - Human dendritic cells in the severe combined immunodeficiency mouse model: their
potentiating role in the allergic reaction.
AB - Dendritic cells (DCs) are present in the lungs and airways of healthy and
allergic subjects where they are exposed to inhaled antigens. After the uptake of
antigens, DCs migrate to lymphoid organs where T cells initiate and control the
immune response. The migratory properties of DCs are an essential component of
their function but remain unclear in the situation of allergic diseases. To
better understand the role of DCs in response to allergens, we first investigated
their presence in an original experimental model of allergic asthma: the
humanized severe combined immunodeficiency (SCID) mouse reconstituted with
peripheral blood mononuclear cells from patients sensitive to Dermatophagoides
pteronyssinus (Dpt). Human DCs were detected in lungs of mice developing an
inflammatory pulmonary infiltrate and appeared to be mainly located in the
alveolar spaces. In a second step, human DCs were generated in vitro from
monocytes and injected into naive SCID mice exposed or not exposed to Dpt
aerosols. Their migratory behavior was explored, as well as their potential role
in modulating the IgE production after exposure to Dpt. After exposure to Dpt,
the number of DCs present in airways decreased, while it increased into the
spleen and thymus of the mice. The IgE production increased in the presence of
DCs as compared with mice not injected with DCs. These results suggest that DCs
may play a role in the pulmonary allergic reaction developed in response to Dpt
in SCID mice.
PMID- 10780677
TI - Three-dimensional organisation of mitochondrial clusters in regenerating dorsal
root ganglion (DRG) neurons from neonatal rats: evidence for mobile mitochondrial
pools.
AB - We report for the first time the rearrangement of mitochondrial arrays in
developing dorsal root ganglion (DRG) neurons isolated from neonatal rats in
culture. Neurons were loaded with the mitochondria-specific fluorescent dye JC-1,
and three-dimensional (3D) reconstruction of mitochondrial fluorescence was
performed by confocal laser sectioning in fresh neurons and neurons kept in
culture up to a week. We found that after 24 hours the mitochondria become
reorganised to form clusters in the axonal hillocks. Axonal extension and
neuronal network formation coincided with a redistribution of the mitochondrial
clusters. In the extended axons the mitochondria become spaced along the axonal
length; however, they formed clusters in the branch points and growth cones. We
conclude that the initial clusters of mitochondria may be storage pools of mobile
mitochondria able to be mobilised to provide energy for axonal transport during
neuronal regeneration and neuronal outgrowth. These findings may have relevance
to the rate of axonal regeneration and axonal transport in adult DRG neurons, and
neuronal polarisation and axonal outgrowth regulation in developing DRG neurons.
PMID- 10780679
TI - Variation in rat sciatic nerve anatomy: implications for a rat model of
neuropathic pain.
AB - We discovered a variation of rat sciatic nerve anatomy as an incidental finding
during the anatomical exploration of the nerve lesion site in a rat neuropathic
pain model. To confirm the composition and distribution of rat sciatic nerve,
macroscopic anatomical investigation was performed in both left and right sides
in 24 adult Sprague-Dawley rats. In all rats, the L4 and L5 spinal nerves were
fused tightly to form the sciatic nerve. However, the L6 spinal nerve did not
fuse with this nerve completely as a part of the sciatic nerve, but rather sent a
thin branch to it in 13 rats (54%), whereas in the remaining 11 rats (46%), L6
ran separately along with the sciatic nerve. Also, the L3 spinal nerve sent a
thin branch to the L4 spinal nerve or sciatic nerve in 6 rats (25%). We conclude
that the components of sciatic nerve in Sprague-Dawley rats vary from L3 to L6;
however, the major components are L4 and L5 macroscopically. This finding is in
contrast to the standard textbooks of rat anatomy which describe the sciatic
nerve as having major contributions from L4, L5, and L6.
PMID- 10780678
TI - Gene expression of antioxidant enzymes in experimental diabetic neuropathy.
AB - Chronic hyperglycemia results in a large deficit in nerve blood flow. Both
autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant
peripheral sensory neuropathy in streptozotocin-induced diabetes in the rat. Free
radical defenses, especially involving antioxidant enzymes, have been suggested
to be reduced, but scant information is available on chronic hyperglycemia. We
evaluated the gene expression of glutathione peroxidase, catalase, and superoxide
dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG)
and superior cervical ganglion, as well as enzyme activity of glutathione
peroxidase in DRG and sciatic nerve in experimental diabetic neuropathy of 3
months and 12 months durations. We also evaluated nerve electrophysiology of
caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen
in all nerves in experimental diabetic neuropathy at both 3 and 12 months. Gene
expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase,
and manganese superoxide dismutase were not reduced in experimental diabetic
neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in
experimental diabetic neuropathy at 12 months. Glutathione peroxidase enzyme
activity was normal in sciatic nerve. We conclude that gene expression is not
reduced in peripheral nerve tissues in very chronic experimental diabetic
neuropathy. Changes in enzyme activity may be related to duration of diabetes or
due to post-translational modifications.
PMID- 10780680
TI - Effect of ischemia and cooling on the response to high frequency stimulation in
rat tail nerves.
AB - In normal rat tail nerves the effect of temperature and ischemia on the response
to long-term high frequency stimulation (HFS) (143 Hz) was studied. The effect of
temperature was studied in two consecutive tests at 14 degrees C and 35 degrees
C. Prior to the HFS the peak-to-peak amplitude (PP-amp) of the compound nerve
action potential was 139 +/- 20 microV (mean +/- SD) and 127 +/- 37 microV at 35
degrees C and 14 degrees C, respectively (NS). After 15 min of HFS the PP-amp was
reduced to 45.3 +/- 20.5% of baseline level at 14 degrees C as compared with 80.8
+/- 10.2% at 35 degrees C (p < 0.001). Applying ischemia to the rat tail, an
additional fall of the PP-amp was seen after 15-20 min of HFS at both low (20 Hz)
and high (143 Hz) stimulation frequencies. In conclusion, ischemia and cooling
result in an impaired ability to transmit high frequency impulses.
PMID- 10780681
TI - Guillain-Barre syndrome occurring in two women after ketoacidosic comatose state
disclosing an insulin-dependent diabetes mellitus.
AB - We report two women who presented with a Guillain-Barre syndrome just after a
ketoacidosic comatose state disclosing an insulin-dependent diabetes mellitus.
One had characteristic clinical signs and the other had major motor involvement.
At neurophysiologic investigations, one had typical demyelinating neuropathy
whereas the second had mainly axonal degeneration. At ultrastructural examination
of a peripheral nerve biopsy, features of macrophage-associated demyelination
were present in both nerve specimens, thus confirming the diagnosis of acute
inflammatory demyelinating polyneuropathy, i.e., Guillain-Barre syndrome.
Prominent axonal involvement was also present in the motor nerves of the second
patient. Insulin therapy had to be permanently continued and these two cases are
quite different from the transient diabetes sometimes observed in certain cases
of Guillain-Barre syndrome. Both the latter and insulin-dependent diabetes
mellitus probably have auto-immune mechanisms. It is likely that in our two
patients both auto-immune diseases were triggered by a common event. Such cases
of Guillain-Barre syndrome have to be distinguished from other acute diabetic
neuropathies.
PMID- 10780682
TI - Pre-, intra-, and postoperative three-dimensional evaluation of adolescent
idiopathic scoliosis.
AB - The authors measured and compared the pre-, intra-, and postoperative three
dimensional shape of the spine during corrective surgery to quantify the specific
contribution of positioning, anesthesia, surgical exposure, surgical
instrumentation, and postural adaptation of the thoracic and lumbar spine. In 58
adolescent girls with idiopathic scoliosis undergoing corrective surgery by a
posterior approach, the three-dimensional geometry of the thoracic and lumbar
spine was documented in the standing position before and after surgery using a
three-dimensional reconstruction technique based on multiplanar radiography, and
the intraoperative three-dimensional geometry was measured using a three
dimensional magnetic digitizer before and after installation of the first rod.
Prone positioning, anesthesia, and surgical exposure are responsible for a
considerable decrease in all curves in the frontal and sagittal plane.
Instrumentation with the first rod produces additional substantial and favorable
three-dimensional changes with partial restoration of the normal sagittal curves
and sagittal shift of the plane of maximum deformity. Although no loss of
correction was observed in the frontal plane when patients resumed their standing
position, a "spring-back" effect on the spine was noted in the sagittal plane and
a loss of three-dimensional correction was seen in the orientation of the plane
of maximum deformity. Surgeons can use the knowledge of these various changes to
achieve better results by more careful attention to the preoperative positioning
of patients and to curve correction in the sagittal plane when instrumentation is
applied to the spine.
PMID- 10780683
TI - A preliminary report on the effect of measured strength training in adolescent
idiopathic scoliosis.
AB - The authors studied 12 adolescent patients with scoliosis (10 girls and 2 boys)
who were 11 to 16 years old and had curvatures ranging from 20 degrees to 60
degrees. Seven were right thoracic curves and five were thoracolumbar with double
curves. When tested on the MedX Torso Rotation Machine, both sides were unequal
in their torso rotation strength all patients. Myoelectric activity was
asymmetric in both sides and in abdominal and paraspinal muscles of all patients.
These asymmetries were corrected completely with torso rotation, which was
associated with significant strength gains. Strength gains ranged from 12% to
40%. A 16-year-old girl with a 60 degree lumbar curve progressed and had surgery.
None of the remaining patients progressed, and 4 of the 12 had decreases in their
curvatures from 20 degrees to 28 degrees. None of the patients used braces during
this study.
PMID- 10780684
TI - Three-dimensional rotations of the thoracic spine after distraction with and
without rib resection: a kinematic evaluation of the apical vertebra in rabbits
with induced scoliosis.
AB - An experimental model of induced scoliosis in New Zealand rabbits was studied to
evaluate the effects of rib resection on the apical vertebra during distraction
for scoliosis surgery. After concave distraction, three-dimensional rotations of
the apical vertebra were measured using a motion analysis system, which included
three cameras and six reflective markers. Distraction with rib resection on the
convexity produced minimal rotations in the coronal plane (0.77 degrees),
sagittal plane (0.96 degrees), and transverse plane (0.61 degrees) compared with
no rib resection. The distraction maneuver with rib resection has no significant
effect on derotation of the apical vertebra in the coronal and transverse plane,
but slightly greater forward rotation was apparent in the sagittal plane (p <
0.05). Resection of three convex ribs directly corrects the rib prominence and
does not seem to improve derotation.
PMID- 10780685
TI - Correlative analysis of the sagittal profile of the spine in patients with beta
thalassemia and in healthy persons.
AB - This prospective study compares several roentgenographic parameters of the
thoracic and lumbar spine in patients with beta-thalassemia and in healthy
persons who served as controls. Eighty-four patients with beta-thalassemia and 84
age- and gender-matched healthy persons were examined clinically and
radiologically (thoracic kyphosis, lumbar lordosis, and vertebral and sacral
inclination). Although there was a significant difference in the vertebral
inclination from T6 to L1, L4, and L5 between patients and controls, thoracic
kyphosis and lumbar lordosis did not differ in the two groups. The apical
vertebra of the thoracic kyphosis in patients and controls was T7 and T6,
respectively, whereas L4 was the apical vertebra of the lumbar lordosis in both
groups. There were no age- or gender-related differences in the magnitude of
sacral inclination, thoracic kyphosis, or lumbar lordosis in the patients with
beta-thalassemia compared with controls. Lumbar lordosis was significantly
correlated with sacral inclination in both patients with beta-thalassemia and
controls. Beta-thalassemia does not affect sagittal profile of the thoracic and
lumbar spine but it is associated by structural changes on the frontal plane of
the spine that are expressed as a high prevalence of scoliosis.
PMID- 10780686
TI - A method for dynamic measurement of lumbar lordosis.
AB - Trunk flexion-extension is accomplished with pelvic and thoracic rotation in the
sagittal plane and a smooth coordination of lumbar vertebral translation and
rotation. Several systems exist that measure gross trunk movements, but they
typically do not track changes in lumbar arc length or curvature. A method for
dynamic measurement of changes in lumbar arc length that uses a lordosimeter is
presented. A static validation study of postures showed that the measurements are
repeatable and compare favorably with a standard measure of lumbar curvature. In
a dynamic validation study of a lifting task with a 23-kg load, the measurement
method was highly correlated with thoracic and pelvic angular displacement. A
discussion of the utility of this measure in biomechanical modeling is presented.
A clinical or field version of the lordosimeter is also described.
PMID- 10780687
TI - Clinical outcome scales for use in a rabbit model of cervical myelopathy.
AB - This study determined the ability of an upper extremity Tarlov scale, a lower
extremity Tarlov scale, and the Durham scale to predict the development of
myelopathy and the likelihood of survival in a rabbit model of surgical
treatments for cervical spondylotic myelopathy. Forty-eight rabbits were
evaluated using the scales after cervical spinal surgery. Logistic regression
analysis revealed that all three scales could predict the occurrence of
myelopathy. However, only the Durham and lower extremity Tarlov scales also
predicted the likelihood of survival. The Durham scale is offered as a useful
predictor of myelopathy and survival in an animal model of surgical treatments
for cervical spondylotic myelopathy. The lower extremity Tarlov scale is also a
useful predictor of outcome; however, the upper extremity Tarlov scale is not
recommended.
PMID- 10780689
TI - Retroperitoneal laparoscopic lateral approach to the lumbar spine: a new
approach, technique, and clinical trial.
AB - A retroperitoneal laparoscopic (retroperitoneoscopic) lateral approach to achieve
decompression for a far lateral disk lesion in the lumbar spine or to remove a
paravertebral neurinoma without disrupting the facet is described. The operating
space is maintained using a powered mechanical lift and a flat inflatable
retractor mainly to make a longitudinal separation between the psoas major and
the quadratus lumborum. This technique has been performed successfully in 22
cases using retroperitoneoscopy. The best indications of this new procedure are
lateral disk herniation at the L5-S1 level or around the conus medullaris at the
L1-L2 level. The described procedure provides adequate exposure necessary for
extraforaminal exploration, discectomy, and nerve root decompression, and it is
sufficient for treating extreme lateral lumbar herniation localized to the L1-S1
level and spinal nerve root tumors.
PMID- 10780688
TI - Factors influencing the outcome of degenerative lumbar spinal stenosis.
AB - The objective of this study was to evaluate the influence of decreased dural sac
cross-sectional area and baseline clinical parameters on the outcome of patients
treated surgically or conservatively for lumbar spinal stenosis. Computed
tomography or magnetic resonance imaging scans of 37 patients were digitized and
the dural sac cross-sectional area was calculated. This parameter and baseline
clinical, socioeconomic, and anthropometric data of the patients were correlated
with 1-year and 2-year follow-up data. The decrease in dural sac cross-sectional
area negatively affected walking capacity on follow-up controls in patients
treated conservatively, whereas such a relation was not observed among surgically
treated patients. Female sex was the main parameter that worsened the global
outcome of degenerative lumbar spinal stenosis, particularly after surgical
treatment.
PMID- 10780690
TI - Use of the anterior interbody fresh-frozen femoral head allograft in
circumferential lumbar fusions.
AB - Many studies in the literature have documented the outcome of circumferential
lumbar fusions. However, no study has specifically evaluated the performance of
the anterior fresh-frozen femoral head allograft as a structural interbody graft
material. All office and hospital records, including charts and radiographs, were
reviewed to obtain pertinent clinical and radiographic information. The cases
included 23 single-level fusions, 22 two-level fusions, and 5 fusions of three or
more levels. In all, 88 fusion levels were analyzed radiographically. The mean
follow-up time was 28 months (range, 24 to 36 months). All procedures were
performed in a single stage. At the latest follow-up, clinical outcome was graded
good to excellent in 39 (78%) cases, fair in 8 (16%) cases, and poor in 3 (6%)
cases. The average time to anterior radiographic fusion was 6 months (range, 4 to
8 months). The overall fusion rate was 98%. The average preoperative anterior
disk space height was 10 mm, 14 mm immediately after operation, and 13 mm at
follow-up. The posterior disk space height averaged 5 mm before operation, 7 mm
immediately after operation, and 6 mm at follow-up. The average segmental
lordosis was 7 degrees before operation, 10 degrees immediately after operation,
and 10 degrees at follow-up. Late postoperative disk space collapse of 3 mm or
more was noted in 17% of the fused disk spaces examined. Seventy-eight percent of
the disk spaces maintained a disk space height greater than that of their
preoperative value at the latest follow-up. Segmental lordosis did not change
significantly at follow-up. The occurrence of collapse did not correlate with the
clinical result, smoking history, or surgical indication (p < 0.05).
Perioperative complications included one pleural effusion, two urinary tract
infections, and one deep wound infection. Late complications included five
painful graft sites and two patients with pseudarthrosis. Fresh-frozen femoral
head allograft fulfills its desired function as an anterior structural graft in
combination with rigid posterior transpedicular fixation, maintaining the disk
space height achieved at surgery while reliably allowing remodeling and
incorporation into a solid anterior fusion.
PMID- 10780691
TI - Biomechanical effect of anterior grafting devices on the rotational stability of
spinal constructs.
AB - In the thoracolumbar spine, frequently strut grafting is used to restore the
anterior and middle column defects. Biomechanical stability of the surgical
construct may be altered significantly depending on the type of anterior grafting
devices. In this study, a biomechanical flexibility test was conducted to compare
the stabilizing role of various types of anterior grafting devices, such as a
polymethylmethacrylate block, tricortical iliac crest bone graft, one large Harms
cage, and two small Harms cages using a calf lumbar corpectomy model. The Harms
cage, especially one large cage, improved the axial rotational stability
significantly in both anterior and posterior fixation groups as compared with the
iliac bone or polymethylmethacrylate. No significant difference in the
stabilizing role was found among different grafting devices in lateral bending,
flexion, and extension. These results suggest that a more rigid spinal construct
can be obtained by using a metal cage with improved friction at the cage-bone
interface.
PMID- 10780692
TI - An experimental approach to spinal fusion using sintered bovine bone in a pig
model.
AB - Sintered bovine bone is a biomaterial based on calcium phosphate, an organized
crystal of bone mineral that possesses a natural trabecular structure. The
authors considered whether sintered bovine bone can integrate with recipient bone
and adjust to the strength of recipient bone for anterior spinal fusion in an
animal model. Either autologous iliac bone or sintered bovine bone was implanted
for a spinal body fusion. Some pigs underwent exposure of the spinal bodies
without implantation. Based on radiographic evaluation, manual palpation,
biomechanical testing, and histologic examination, spinal fusion with sintered
bovine bone resulted in a composition and structure similar to that of the
autograft (or of no implantation). The sintered bovine bone with its moderate
strength tended to adjust to the bone stiffness of the host bone in the specimens
as new bone grew.
PMID- 10780693
TI - The durability of small-diameter rods in lumbar spinal fusion.
AB - The use of a small-diameter rod in lumbar fusion offers a lower hardware profile
and reduced implant bulk. Concern has been raised, however, about the ability of
smaller rods to withstand the cyclic loads placed on them until fusion is
achieved. This study is a retrospective radiographic review designed to evaluate
the durability of a 4.75-mm diameter rod in the early postoperative period before
fusion healing. Examination of postoperative radiographs revealed two instances
of rod failure that occurred more than 24 months after operation among 85 cases
of pedicle screw instrumentation followed for an average of 32 months. Based on
these preliminary data, the benefits of a small-diameter rod can be obtained
without an increased incidence of rod failure during the initial healing period.
PMID- 10780694
TI - Reoperation for spinal restenosis in achondroplasia.
AB - The characteristics of spinal restenosis in achondroplasia and its treatment are
evaluated in this study. Radiologic and surgical findings were correlated to
establish the causes of achondroplastic spinal restenosis and the benefits of its
therapy. Eight patients (five men, three women) with spinal restenotic
complications of achondroplasia were studied. The most common neurological sign
of recurrent stenosis was impaired motor function. The mean interval between the
most recent surgeries was 8.2 years (9.5 years for surgeries at the same levels).
The most common causes of recurrent stenosis were facet hypertrophy and disk
disease. The complications were a dural tear and cerebellar hemorrhage in one
patient and transient neurological deterioration in another. One patient died
after operation. Restenosis can occur many years after original decompression in
the achondroplastic spine, and repeated operation can successfully lessen pain
and neurological symptoms in most patients.
PMID- 10780695
TI - Eccentric compression of the spinal canal causing dominantly contralateral-side
symptoms.
AB - In this retrospective study, five patients are described in whom the dural sac at
the thoracic and lumbar spine was compressed by a herniated disk or stenosis,
located eccentrically in the spinal canal. In all of them, the symptoms or
neurologic findings were dominantly in the limb contralateral to the side of
compression. All five patients were operated on and the compressing disk or
lamina was removed, resulting in immediate improvement of symptoms. In only one
of the patients was the compression at the common level of L4-L5. In the
remaining four patients, compression was at the low thoracic or upper lumbar
spine. With the exception of one patient, the area of canal compression was
greater than 50%.
PMID- 10780696
TI - Prevention of positional brachial plexopathy during surgical correction of
scoliosis.
AB - Continuous intraoperative monitoring of spinal cord function using somatosensory
evoked potentials (SSEP) has gained nearly universal acceptance as a reliable and
sensitive method for detecting and possibly preventing neurologic injury during
surgical correction of spinal deformities. In several reports, spinal cord injury
was identified successfully based on changes in SSEP response characteristics,
specifically amplitude and latency. Less well documented and used, however, is
monitoring of peripheral nerve function with SSEPs to identify and prevent the
neurologic sequelae of prolonged prone positioning on a spinal frame. The authors
describe a patient who underwent surgical removal of spinal instrumentation but
was not monitored. A brachial plexopathy developed in this patient from pressure
on the axilla exerted by a Relton-Hall positioning frame during spinal surgery.
In addition, data are presented from 15 of 500 consecutive pediatric patients who
underwent surgical correction of scoliosis between 1993 and 1997 with whom
intermittent monitoring of ulnar nerve SSEPs was used successfully to identify
impending brachial plexopathy, a complication of prone positioning. A
statistically significant reduction in ulnar nerve SSEP amplitude was observed in
18 limbs of the 500 patients (3.6%) reviewed. Repositioning the arm(s) or
shoulders resulted in nearly immediate improvement of SSEP amplitude, and all
awoke without signs of brachial plexopathy. This complication can be avoided by
monitoring SSEPs to ulnar nerve stimulation for patients placed in the prone
position during spinal surgery.
PMID- 10780697
TI - Chromosome identification and assignment of DNA clones in the dog using a red fox
and dog comparative map.
AB - We have developed a novel method for identifying dog chromosomes and
unambiguously mapping specific clones onto canine chromosomes. This method uses a
previously established red fox/dog comparative chromosome map to guide the FISH
mapping of cloned canine DNA. Mixing metaphase preparations of the red fox and
dog enabled a single hybridization to be performed on both species. We used this
approach to map the chromosomal locations of twenty-six canine cosmids. Each
cosmid contains highly polymorphic microsatellite markers currently used by the
DogMap project to compile the canine linkage map. All but two cosmids were
successfully assigned to subchromosomal regions on red fox and dog chromosomes.
For eight cosmids previously mapped on dog chromosomes, we confirmed and refined
the canine chromosomal assignments of seven cosmids and corrected an erroneous
assignment regarding cosmid CanBern1. These results demonstrate that the red fox
and dog comparative chromosome map can greatly improve the accuracy and
efficiency of chromosomal assignments of canine genetic markers by FISH.
PMID- 10780698
TI - Maternally inherited X chromosome is not inactivated in mouse blastocysts due to
parental imprinting.
AB - Mouse embryos having an additional maternally inherited X chromosome (X(M))
invariably die before midgestation with the deficient extraembryonic ectoderm of
the polar trophectoderm lineage, whereas postnatal mice having an additional
paternally inherited X chromosome (X(P)) survive beyond parturition. A
cytogenetic study led us to hypothesize that abnormal development of such embryos
disomic for X(M) (DsX(M)) is attributable to two doses of active X(M) chromosome
in extraembryonic tissues. To test the validity of this hypothesis, we examined
the initial X chromosome inactivation pattern in embryos at the blastocyst stage
by means of replication banding method as well as RNA FISH detecting Xist
transcripts. X(P) was the only asynchronously replicating X chromosome, if any,
in X(M)X(M)X(P) blastocysts, and no such allocyclic X chromosome was ever
detected in X(M)X(M)Y blastocysts. In agreement with these findings, only one
Xist paint signal was detected in 79% of X(M)X(M)X(P) cells, whereas no such
signal was found in X(M)X(M)Y embryos. Thus, the present study supports the
hypothesis that two X chromosomes remaining active in the extraembryonic cell
lineages due to the maternal imprinting explain the underdevelopment of
extraembryonic structures and hence early postimplantation death of DsX(M)
embryos.
PMID- 10780699
TI - An XX/XY sex chromosome system in a fish species, Hoplias malabaricus, with a
polymorphic NOR-bearing X chromosome.
AB - Cytogenetic studies were carried out in the fish, Hoplias malabaricus, from the
Parque Florestal do Rio Doce (Brazil). This population is characterized by 2n =
42 chromosomes for both males and females and an XX/XY sex chromosome system,
confirmed through several banding methods. Females show 24 metacentric, 16
submetacentric and 2 subtelocentric chromosomes. Males show 24 metacentric, 17
submetacentric and 1 subtelocentric chromosomes. While the X chromosome is easily
recognized (the only subtelocentric element), the Y chromosome is somewhat
difficult to identify but appears to correspond to the smallest submetacentric in
the male karyotype. In-situ hybridization with an 18S rDNA probe showed 10 well
labeled chromosomes, including the X chromosome. The 5S rDNA is interstitially
located in a single metacentric pair independent of the 18S rDNA sites. The NOR
on the X chromosome is always active and occurs adjacent to a heterochromatic
distal segment on the long arm. Variations in size of the NORs and/or
heterochromatic segment correspond to a polymorphic size condition observed in
the X chromosome. The present results confirm the XX/XY sex chromosome system in
the population analyzed as well as a new cytotype in the Hoplias malabaricus
group.
PMID- 10780700
TI - Introgression of Lilium rubellum Baker chromosomes into L. longiflorum Thunb.: a
genome painting study of the F1 hybrid, BC1 and BC2 progenies.
AB - Interspecific hybrids between Lilium longiflorum (L, 2n = 2x = 24) and Lilium
rubellum (R, 2n = 2x = 24) were produced with the aim of transferring desirable
horticultural traits from L. rubellum to L. longiflorum. All F1 hybrids (LR, 2n =
2x = 24) and BC1 individuals (LLR, 2n = 3x = 36) were phenotypically uniform for
plant height, flowering time, leaf shape and flower colour. The BC1 plants were,
in spite of their triploid nature, fertile and could be used as a female parent
in backcrossings with autotetraploid L. longiflorum (LLLL, 2n = 4x = 48). Twelve
BC2 individuals were obtained and three of them were selected for further
chromosome analysis. As L. longiflorum and L. rubellum chromosomes were
indistinguishable in the hybrids, genomic in-situ hybridization (GISH) was
applied to establish the parentage of the chromosomes of the F1 hybrids and the
BC1 and BC2 progenies. GISH confirmed the LLRR constitution of the doubled
amphimonoploid (allodiploid), and the LLR constitution of all BC1 plants. The
three selected BC2 plants were, as expected, aneuploid, containing three complete
sets of L. longiflorum chromosomes and six, seven or eight L. rubellum
chromosomes, respectively. However, L/R translocation or recombinant chromosomes
could not be demonstrated in the mitotic metaphase complements of the F1, BC1 and
BC2 plants. In spite of the high frequencies of homoeologous recombination in the
F1 hybrids (LR) pollen was found to be sterile in all cases. At metaphase I of
the pollen mother cells of the BC1 plants, genome painting did not reveal any
cases of homoeologous pairing and recombination between L and R chromosomes. This
lack of exchange between homoeologous chromosome segments indicates complete
preferential pairing of the L and R chromosomes in the F1 (amphidiploid) and BC1
plants. It seems that the preferential pairing in the F1 and BC1 hybrids hinder
the introgression of the chromosome segments or species-specific genes into the
recipient for breeding purposes.
PMID- 10780701
TI - Evaluation of 24-color multifluor-fluorescence in-situ hybridization (M-FISH)
karyotyping by comparison with reverse chromosome painting of the human breast
cancer cell line T-47D.
AB - Multifluor-fluorescence in-situ hybridization (M-FISH) chromosome paints for all
the chromosomes in the human complement labeled with different combinations of
fluorochromes is a recent technological development enabling assignment of
chromosomal material to rearranged chromosomes. Little data is available on the
accuracy and limitations of the approach to the analysis of complex karyotypes,
which are characteristic of many malignant diseases. Here we compare M-FISH
analysis of the breast-cancer-derived cell line T-47D with a previous analysis by
reverse chromosome painting analysis of flow-sorted chromosomes from the same
material. This demonstrated a high degree of concordance. It also illustrated the
limitations of M-FISH analysis, including difficulties identifying small regions
of chromosomal material and intrachromosomal rearrangements. Confirmation of
selected aberrations using less-complex mixtures of painting probes and further
definition of abnormalities using single copy markers may be required. The
detailed karyotype description possible by M-FISH analysis contrasts with the
definition in the original G-banding analysis. This and the level of concordance
with reverse FISH painting supports the utility of the approach in the definition
of complex karyotypes.
PMID- 10780702
TI - Fate of multicentric and ring chromosomes induced by a new gametocidal factor
located on chromosome 4Mg of Aegilops geniculata.
AB - A new gametocidal (Gc) factor was identified on chromosome 4Mg of Aegilops
geniculata Roth. When transferred to Chinese Spring wheat, monosomic and disomic
Triticum aestivum-Ae. geniculata chromosome 4Mg addition plants undergo regular
first and second meiotic divisions. Male gametogenesis in disomic 4Mg addition
plants also is normal. However, chromosome breakage and anaphase bridges were
observed at ana/telophase of the first (29%) and second (11%) pollen mitosis in
monosomic 4Mg addition plants. Gc-induced multicentric and ring chromosomes can
be transmitted to the offspring and initiate breakage fusion bridge (BFB) cycles
in dividing root tip meristem cells of the derived sporophytes. The fate of
multicentric and ring chromosomes was analyzed in root meristems at different
time intervals after seed germination. The majority of the BFB cycles ceased
about 32 days after germination. Broken chromosome ends were healed either by the
fusion of a centric and an acentric fragment forming terminal translocation
chromosomes or as deficiencies or telocentric chromosomes. Lack of cytologically
detectable telomeric repeats at the stabilized newly broken termini suggests that
chromosome healing by addition of telomeric repeats may be a gradual process.
PMID- 10780703
TI - Replication asynchrony increases in women at risk for aneuploid offspring.
AB - We attempted to demonstrate a relation between a loss of replication control,
centromere dysfunction, and predisposition to non-disjunction. Couples with a
Down syndrome offspring were the high-risk probands. One-color FISH (fluorescent
in-situ hybridization) was applied to interphase nuclei (lymphocytes).
Replication pattern of two pairs of alleles, RB-1 and 21q22, were studied, and
the rate of aneuploidy was estimated using two alpha-satellite probes of
chromosomes 8 and 18. Our results suggest the existence of an association between
replication timing and the rate of non-disjunction. A higher rate of allele
asynchrony and aneuploidy was found in older women and in mothers of a Down
syndrome offspring. These findings may reflect a predisposition for meiotic non
disjunction in these women.
PMID- 10780704
TI - Evidence that kinetochore fibre microtubules shorten predominantly at the pole in
anaphase flea-beetle spermatocytes.
AB - Kinetochore spindle fibres in flea-beetle metaphase primary spermatocytes have
two regions with distinct morphologies. As seen after staining with antibodies
against tubulin, the kinetochore microtubules are tightly bundled in the 5 microm
closest to the kinetochore but they splay out in the region closest to the pole.
This morphology persists throughout anaphase. This distinct morphology allows one
to deduce the site where kinetochore microtubules depolymerise during anaphase.
During poleward movement of the autosomes in anaphase, the bundled region
shortens by about 0.25 microm for each 1 microm the chromosome moves poleward;
this suggests that, during anaphase, 75% of the kinetochore microtubule
shortening occurs at the pole end. Sex chromosomes in metaphase cells are
separated from the autosomes and do not move poleward at the same time as the
autosomes: they are reported to move poleward when the autosomes are in
metaphase, to stop part way to the poles, and to move poleward again as the
autosomes do (Virkki 1970). Kinetochore microtubules of the sex chromosomes also
have bundled and splayed regions; measurements of those regions suggest that
these chromosomes may move poleward before the autosomes enter anaphase, but not
afterwards.
PMID- 10780705
TI - The consequences of a non-uniform tension across kinetochores: lessons from
segregation of chromosomes in the permanent translocation heterozygote Oenothera.
AB - The alternate (zigzag) configuration of the chromosome ring in oenotheras
fulfills the requirement of high tension across kinetochores for stability of the
configuration and the progression to anaphase. However, also semialternate
configurations (two pairs of adjacent kinetochores interspaced among the zigzag)
fulfill the requirement of high tension across kinetochores. If only the
magnitude of tensile force acting on a kinetochore pair governs the stability of
microtubule attachments, the probability of occurrence of the semialternate
configurations would be higher than that of fully alternate configurations. Yet
the percentage of irregularity in the zigzag configuration is surprisingly low,
which means that the semialternate configurations are corrected. The only
difference which distinguishes the fully alternate and the semialternate
configurations with respect to the tension across kinetochores is that the
tension across a kinetochore alternating with its neighbors is rather uniformly
distributed over the kinetochore, while there is a gradient of the tension in the
kinetochore having a non-alternating neighbor, with low tension on the side of
this neighbor. Apparently, a low tension across a part of a kinetochore brings
about correction of its attachment to microtubules. This hypothesis fits with the
repeat subunit model of the kinetochore; apparently, each subunit can function
autonomously in the tension-governed mechanisms, stabilizing its attachment and
controlling the metaphase-to-anaphase transition.
PMID- 10780706
TI - Chromosomal mapping of adenosine receptor genes in chicken suggests clustering of
two members of the gene family.
PMID- 10780707
TI - Mariner-like transposable elements are interspersed within the rDNA-associated
heterochromatin of the pufferfish Tetraodon fluviatilis (Osteichthyes).
PMID- 10780708
TI - Association of antiretroviral therapy with detection of HIV-1 RNA and DNA in the
anorectal mucosa of homosexual men.
AB - OBJECTIVE: To determine whether combination antiretroviral therapy is associated
with reduced detection of HIV-1 RNA and DNA in the anorectal mucosa of men who
have sex with men (MSM). DESIGN: Cross-sectional study of 233 MSM recruited from
community and clinic sites in Seattle, Washington between July 1996 and December
1997. METHODS: HIV-1 RNA and HIV-1 DNA were detected in anorectal swab specimens
by polymerase chain reaction amplification assays. RESULTS: HIV-1 RNA was
detected significantly less often in anorectal specimens from users of
combination antiretroviral therapies, whether a protease inhibitor was received
(15/89; 17%) or not (16/53; 30%), than in men not receiving therapy (43/88; 49%)
(P < 0.001, P = 0.03, respectively). In contrast, HIV-1 DNA was detected only
slightly less frequently in anorectal specimens obtained from men receiving
protease inhibitors (35/81; 43%) or reverse transcriptase inhibitors alone
(22/48; 46%) than in specimens from men not receiving therapy (45/78; 58%) (P =
0.07, P = 0.20, respectively). Among men with < 50 copies HIV-1 RNA/ml plasma,
detection of HIV-1 RNA in anorectal specimens was rare (1/54; 2%) but detection
of HIV-1 DNA was common (14/50; 28%). CONCLUSIONS: Combination antiretroviral
therapy is associated with reductions in HIV-1 RNA, but HIV-1 DNA remains
detectable in the anorectal canal of almost half of MSM receiving such therapy.
Condom use during anal intercourse should be encouraged, regardless of plasma
viral load response to potent antiretroviral therapy.
PMID- 10780709
TI - HIV-1 Tat increases endothelial solute permeability through tyrosine kinase and
mitogen-activated protein kinase-dependent pathways.
AB - OBJECTIVE: HIV-1 infection is associated with alterations of several vascular
endothelial functions including adhesion molecule expression, growth, and
vascular permeability. The bases of these errors are not known, but might involve
secretion of the HIV-1 derived transcription factor 'Tat-1'. This study
investigated Tat-1 mediated endothelial barrier changes and second message
regulation of this phenomenon. METHODS: We exposed human umbilical vein
endothelial cell monolayers to Tat-1 (0-150 ng/ml) for up to 48 h and measured
resulting changes in monolayer permeability. We also investigated the role of
tyrosine and mitogen activated protein (MAP) kinases, and protein kinase G using
the pharmacological blockers genistein, PD98059 and KT5823 respectively. RESULTS:
Tat-1 significantly reduced monolayer barrier and increased albumin permeability
within 24 h. Tat-1 also stimulated tyrosine phosphorylation of multiple
endothelial proteins, disorganized junctional phosphotyrosine staining and
increased the number of these immunostaining structures. The increased
permeability produced by Tat-1 was blocked by genistein and PD98059, but not by
KT5823. Genistein and PD98059 pretreatment also prevented the changes in
phosphotyrosine immunostaining produced by Tat-1 and blocked phosphorylation of
several proteins including MAP kinase. CONCLUSION: These results suggest that HIV
may dysregulate endothelial barrier through the effects of Tat-1. These blocker
experiments suggest that the effects of Tat are transcription/translation
dependent. These data demonstrate that Tat increases endothelial albumin
permeability in vitro through tyrosine kinase and MAP kinase, but not protein
kinase G pathways.
PMID- 10780710
TI - Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective
haplotype.
AB - OBJECTIVES: Several natural polymorphisms in the genes for the human CC-chemokine
receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic
variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change
at position 64] is in strong linkage disequilibrium with a mutation within the
CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are
not resistant to sexual transmission of HIV-1, but progress significantly more
slowly to HIV-1 disease. It is therefore important to determine the global
distributions of CCR2-64I and CCR5-59653T genetic variants and define the degree
of linkage between them. DESIGN AND METHODS: We have developed molecular beacon
based, real-time PCR allele discrimination assays for all three chemokine
receptor mutations, and used these spectral genotyping assays to genotype 3923
individuals from a globally distributed set of 53 populations. RESULTS: CCR2-64I
and CCR5-59653T genetic variants are found in almost all populations studied:
their allele frequencies are greatest (approximately 35%) in Africa and Asia but
decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage
disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for
both CCR2-64I and CCR5-59653T polymorphisms). CONCLUSIONS: The greater
geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with
that of CCR5-delta32 suggests that it is a much older mutation whose origin
predates the dispersal of modern humans.
PMID- 10780711
TI - Factors associated with the successful modification of antiretroviral therapy.
HIV Outpatient Study Investigators.
AB - OBJECTIVES: To assess the characteristics of medication regimen modification and
the influence of a commercial genotypic resistance assay on the short-term (3-12
weeks) viral load response (> or = 0.5 log reduction) in HIV-1-infected patients
extensively treated with antiretroviral therapy (ART). METHODS: A nested cohort
study was performed in two clinics from the HIV Outpatient Study of 96 persons
with a HIV-1 viral load of 10(4) log copies/ml or greater taking at least two
antiretroviral medications. RESULTS: Successful modification was associated with
adding at least two new medications [relative risk (RR), 1.5; 95% confidence
interval (CI), 1.1-2.2], adding a drug from a previously unused class of agents
(RR, 2.0; CI, 1.4-2.9), the initiation of a non-nucleoside reverse transcriptase
inhibitor (NNRTI) (RR, 1.7; CI, 1.2-2.4), but not substituting a protease
inhibitor or the use of a commercial genotypic resistance assay. CONCLUSION:
Incorporating a drug from a previously unused class or changing at least two new
medications, but, within the confines of this study, not using a commercial
genotypic resistance assay, was associated with the successful modification of
ART as measured by a reduction in viral load.
PMID- 10780713
TI - Oral zidovudine during labor to prevent perinatal HIV transmission, Bangkok:
tolerance and zidovudine concentration in cord blood. Bangkok Collaborative
Perinatal HIV Transmission Study Group.
AB - OBJECTIVES: To evaluate tolerance for the oral administration of zidovudine (ZDV)
during labor and measure the resulting ZDV concentrations in umbilical cord
blood. DESIGN: A cross-sectional study of women in a placebo-controlled trial of
short-course ZDV (twice a day from 36 weeks' gestation until labor and every 3 h
during labor) to prevent perinatal HIV transmission in Bangkok. METHODS:
Umbilical cord blood was collected. Sixty control specimens and specimens from
372 women (182 in the ZDV group, 190 in the placebo group) were tested for ZDV by
radioimmunoassay (lower detection limit < 1 ng/ml). RESULTS: All women in the ZDV
group took one or more labor dose, 170 (93%) took their last dose within 3 h of
delivery, and only five (3%) experienced nausea or vomiting, a proportion similar
to the placebo group. The median concentration of ZDV in the cord blood in the
ZDV group was 252 ng/ml (range, < 1-1133 ng/ml); 31 (17%) specimens were less
than 130 ng/ml (0.5 microM), the concentration thought to be active against HIV
in vitro. Median concentrations were 189 ng/ml in specimens from women taking one
or two labor doses, 290 ng/ml in those taking three or four doses, and 293 ng/ml
in those taking more than four doses (P < 0.01). The ZDV concentration was not
associated with time since the last dose, body weight, or perinatal transmission.
CONCLUSION: Oral intrapartum ZDV was feasible and well tolerated. Most ZDV
concentrations in the cord blood after oral dosing during labor were at
therapeutic concentrations but were lower than those reported after continuous
intravenous administration. Although concentrations were not associated with
perinatal transmission, these data do not exclude the possibility that
intrapartum and neonatal chemoprophylaxis is effective.
PMID- 10780712
TI - Insights into the reasons for discontinuation of the first highly active
antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive
patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients.
AB - OBJECTIVE: To evaluate the frequency of discontinuation of the first highly
active antiretroviral regimen (HAART) and the factors predictive of discontinuing
for toxicity and failure in a population-based cohort of HIV-positive individuals
in Italy, naive from antiretrovirals at enrolment. METHODS: The study population
consisted of individuals who initiated HAART and had at least one follow-up
visit. The primary end-points were discontinuation of any component of HAART for
drug toxicity and discontinuation for failure. Survival analyses were performed
to identify predictive factors for reaching the two end-points. RESULTS: Eight
hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this
consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one
protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients
(36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%)
due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95%
confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-1 0.3)
due to failure. Independent factors associated with discontinuation for toxicity
were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus
women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10
3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard
gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for
each additional month). Discontinuation due to failure was independently
associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10
copies/ml higher), and with type of treatment (indinavir-containing regimens, RH
= 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI,
0.04-1.26 versus hard-gell saquinavir). CONCLUSIONS: If the current HAART regimen
caused no toxicity, less than 10% of naive patients discontinue their first HAART
regimen because of failure after 1 year from starting therapy.
PMID- 10780714
TI - Induction and maintenance therapy of cytomegalovirus central nervous system
infection in HIV-infected patients.
AB - OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir
combination in induction therapy (IT) and maintenance therapy (MT) for
cytomegalovirus (CMV) central neurological disorders in HIV-infected patients.
DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one
patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n =
14) during the era before highly active antiretroviral therapy (HAART) received
intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day
followed by MT. The primary endpoint was clinical efficacy, assessed at the end
of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT
resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization.
Eight patients did not respond clinically. Side-effects leading to drug
discontinuation occurred in 10 patients during IT. Among the 23 patients who
qualified for the maintenance phase, CMV disease progressed in 10, with a median
time to the first relapse of 126 days (range 64-264 days). Overall, the median
survival time was 3 months [95% confidence interval (CI), 2-4 months].
CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for
CMV central nervous system (CNS) infection, with an improvement or stabilization
in 74% of patients. Life-long MT with this combination is recommended as long as
the immune system is profoundly impaired.
PMID- 10780715
TI - Predictors of tuberculosis transmission in prisons: an analysis using
conventional and molecular methods.
AB - OBJECTIVE: To determine the tuberculosis (TB) transmission patterns within the
prison system in Catalonia, conventional epidemiological techniques were combined
with DNA fingerprinting of Mycobacterium tuberculosis. METHODS: IS6110- and
polymorphic GC-rich repeat sequence (PGRS)-based restriction fragment length
polymorphism (RFLP) were combined with epidemiological studies to assess the
relatedness of isolates from all patients with confirmed TB at five prisons in
the province of Barcelona (Catalonia, Spain), between 1 July 1994 and 31 December
1996. Risk factors for transmission were analysed to a logistic regression. The
extent of drug-resistant TB was also assessed. RESULTS: The incidence of TB
during the study period was 2775 cases per 100,000 inmate years. Of the 247
culture-positive cases, 126 (51%) appeared to have active TB as a result of
recent transmission. Using conventional epidemiological methods, 14 active chains
of transmission were identified in prison involving 65 isolates (52% of clustered
patients). A lengthy history of imprisonment [odds ratio (OR) 2.8, 95% confidence
interval (CI) 1.52-5.11] and pulmonary TB (OR 2.36, 95% CI 1.17-4.75) were
independently associated with clustering. Low rates of both initial (2.9%) and
acquired drug resistance (5.8%) were identified and there was no evidence of the
transmission of drug-resistant TB. CONCLUSION: In the prison system studied, the
recent transmission of TB contributes substantially to the overall incidence of
the disease. Both lengthy incarcerations and delays in identifying inmates with
pulmonary symptoms play a key role in this recent transmission. Directly observed
therapy (DOT) is a critical control strategy for reducing the emergence of drug
resistance and for avoiding the transmission of resistant organisms.
PMID- 10780716
TI - Partner type and condom use.
AB - OBJECTIVES: To examine the association between type of sexual partnership and
condom use consistency. DESIGN: A prospective follow-up study of women attending
two urban clinics for sexually transmitted diseases (STD). METHODS: Sexual
diaries recording barrier method, partner initials and partner type for each act
of intercourse were kept by 869 women. Condom use by partner type was evaluated
in three ways in the entire group: among women who encountered multiple partners,
during months in which women encountered multiple partners, and within sexual
partnerships that changed status during the study. RESULTS: Consistency of condom
use was higher with new and casual partners than with regular partners in the
entire group and among women who encountered multiple partners. In months in
which partners of different types were encountered, condom-use consistency was
higher with new and casual partners than with regular partners. Consistent condom
use decreased in partnerships that changed status from new to regular. The female
condom was used more often with regular partners than with new or casual partners
in the entire study group, among women who encountered multiple partners, and
during months in which a woman achieved consistent use with her regular partner.
CONCLUSIONS: This study provides strong evidence that condom use behavior is
modified by partner type. Observations about condom use and partner type made in
cross-sectional or retrospective surveys also hold in the present longitudinal
analyses of individual women and of partnerships that change status. The female
condom may be an important option for achieving consistent protection within
stable partnerships.
PMID- 10780717
TI - Repeat HIV testing: high-risk behaviour or risk reduction strategy?
AB - OBJECTIVE: To examine the characteristics of repeat and first-time HIV testers
and consider their implications for HIV test counselling. METHODS: An anonymous
questionnaire was completed by nearly 1500 people seeking an HIV test between
September 1997 and July 1998 at a same-day HIV testing clinic in London, United
Kingdom. Repeat testers were those people who had previously tested HIV negative
and were returning for another test. Information was collected on self-reported
unprotected penetrative sex (UPS) in the previous 3 months and reasons for
seeking the present test. RESULTS: Overall, 50.6% (721/1446) of all clinic
attenders were repeat testers: gay men 71.7% (337/470), heterosexual men 42.1%
(208/494) and heterosexual women 38.6% (186/482). No significant differences were
found between repeat and first time testers in the frequency of UPS (P > or =
0.06). However, gay men (but not heterosexual men and women) reporting three or
more previous HIV tests were significantly more likely to report higher-risk UPS
(i.e. with a partner whose HIV status was either positive or unknown) (42.2%)
than those who had had one-two or no previous tests (25.3 and 25.4%,
respectively; P = 0.002). Over half the heterosexual men and women, and one third
of gay men said they were seeking the current HIV test in preparation for a new
relationship; these proportions did not differ significantly between repeat and
first-time testers (P > 0.1). CONCLUSION: In this London HIV testing clinic, no
significant differences were found in the frequency of UPS between repeat and
first-time testers with the exception of gay men with a history of three or more
previous HIV tests, who reported elevated levels of high-risk sexual behaviour.
For many people, repeat HIV testing has become part of a risk reduction strategy
to establish seroconcordance with a regular partner. HIV test counselling
provides the opportunity both to address high-risk behaviour and to reinforce
personal risk-reduction strategies.
PMID- 10780718
TI - Cancer risk among men with, or at risk of, HIV infection in southern Europe.
AB - OBJECTIVE: To evaluate the cancer risk in southern European men with, or at risk
of, HIV infection. DESIGN: An analysis of longitudinal data to assess time
dependent rare events. METHODS: Data from a cohort of HIV seroconverters, and
from two hospital-based HIV seroprevalent cohorts were combined and analysed. The
number of cancer cases observed was compared with the expected number, obtained
from cancer incidence rates among men in the general population. Age-standardized
incidence ratios (SIR) and their 95% confidence intervals (CI) were computed.
RESULTS: A total of 19,609 person-years of observation were accumulated among HIV
positive men, and 7957 person-years among HIV-negative men. Among HIV-positive
men, statistically significant increased SIR were seen for Hodgkin's disease (HD)
(SIR = 8.7), liver cancer (SIR = 11.0), and cancer of the salivary glands (SIR =
33.6). An excess of lung cancer was seen among intravenous drug users (IDU), but
not among homosexual men. When the risk of all non-AIDS-defining cancers was
considered, HIV-positive men had a nearly twofold excess (95% CI: 1.2-2.8). A
risk of similar magnitude emerged among HIV-negative IDU (95% CI: 1.0-4.5),
largely attributable to lung cancer and HD. CONCLUSION: These findings confirm
that HIV infection increases the risk of HD, whereas they suggest that the risk
of hepatocellular carcinoma may also be enhanced by HIV infection. The
observation of an elevated risk of lung cancer in both HIV-positive and HIV
negative IDU points to personal behaviours unrelated to HIV infection.
PMID- 10780719
TI - Ten-year trends in CD4 cell counts at HIV and AIDS diagnosis in a London HIV
clinic.
AB - OBJECTIVE: To examine temporal trends (1986-1996) in the CD4 cell count at first
HIV-1 positive test and initial AIDS diagnosis, and the influence of selected
patient characteristics and treatment factors on these trends. DESIGN: A
retrospective clinic-based study. SETTING: Three hospital-based clinics in West
London. PATIENTS: A group of 5921 adult HIV-1-seropositive persons and 2835
reported patients with AIDS over a 10-year period from 1 January 1986 to 1
October 1996. METHODS: The CD4 cell count at HIV diagnosis (CD4HIV) was defined
as the nearest CD4 cell count to within 2 months of HIV diagnosis; and the CD4
cell count at AIDS diagnosis (CD4AIDS) as the last CD4 cell count in the two
months prior to the development of AIDS. Simple and multiple linear regression
analysis were used to examine the influence of selected covariates on CD4HIV and
CD4AIDS. RESULTS: The percentage of patients with an available CD4HIV and CD4AIDS
increased from less than 5% in 1987 to 53% and 40%, respectively, in 1990, and
79% and 48%, respectively, in 1996. Patients with a missing CD4HIV or CD4AIDS
were younger and less likely to have received antiretroviral therapy or
prophylaxis for Pneumocystis carinii pneumonia (PCP). There was no significant
change in CD4HIV over a 10-year period (median 334 x 10(6) cells/l), but a lower
CD4HIV was associated with older age at presentation and injecting drug use.
There was a delay in the onset of clinical AIDS, with a fall in the median
CD4AIDS value from 99 x 10(6) cells/l prior to 1987, to 58 x 10(6) cells/l in
1990, 68 x 10(6) cells/l in 1994 and 60 x 10(6) cells/l in 1996; this decline in
onset was seen for PCP as well as for cytomegalovirus and atypical mycobacterial
infections. At all time periods, a lower CD4AIDS was associated with combined use
of antiretroviral therapy and PCP prophylaxis. After adjustment for use of
antiretroviral therapy and PCP prophylaxis prior to AIDS diagnosis, year of
diagnosis was no longer associated with CD4AIDS. There was a significant trend
towards an improved survival following AIDS diagnosis from 20.1 months prior to
1988, to 20.3 months (1989-1990), 21.0 months (1991-1992) and 22.1 (1993-1994) (P
< 0.0005). CONCLUSIONS: The observed decline in CD4AIDS value was related to the
introduction of antiretroviral therapy in 1988, and PCP prophylaxis in 1989.
Temporal changes in the CD4 cell count at HIV and AIDS diagnosis among different
demographic groups can provide insights into the changing natural history of the
HIV epidemic and access to medical care. We recommend monitoring of the CD4 cell
count at new HIV and AIDS diagnosis and at initiation of antiretroviral therapy
as additional measures in national HIV/AIDS surveillance.
PMID- 10780720
TI - Model-based evaluation of single-round mass treatment of sexually transmitted
diseases for HIV control in a rural African population.
AB - OBJECTIVES: To compare the impact of single-round mass treatment of sexually
transmitted diseases (STD), sustained syndromic treatment and their combination
on the incidence of HIV in rural Africa. METHODS: We studied the effects of STD
interventions by stochastic simulation using the model STDSIM. Parameters were
fitted using data from a trial of improved STD treatment services in Mwanza,
Tanzania. Effectiveness was assessed by comparing the prevalences of gonorrhoea,
chlamydia, syphilis and chancroid, and the incidence of HIV, in the general adult
population in simulations with and without intervention. RESULTS: Single-round
mass treatment was projected to achieve an immediate, substantial reduction in
STD prevalences, which would return to baseline levels over 5-10 years. The
effect on syphilis was somewhat larger if participants cured of latent syphilis
were not immediately susceptible to re-infection. At 80% coverage, the model
projected a reduction in cumulative HIV incidence over 2 years of 36%. A similar
impact was achieved if treatment of syphilis was excluded from the intervention
or confined to those in the infectious stages. In comparison with sustained
syndromic treatment, single-round mass treatment had a greater short-term impact
on HIV (36 versus 30% over 2 years), but a smaller long-term impact (24 versus
62% over 10 years). Mass treatment combined with improved treatment services led
to a rapid and sustained fall in HIV incidence (57% over 2 years; 70% over 10
years). CONCLUSIONS: In populations in which STD control can reduce HIV
incidence, mass treatment may, in the short run, have an impact comparable to
sustained syndromic treatment. Mass treatment combined with sustained syndromic
treatment may be particularly effective.
PMID- 10780721
TI - Sexually transmitted infections in European HIV-infected women: incidence in
relation to time from infection. European Study on the Natural History of HIV
Infection in Women.
AB - OBJECTIVES: To investigate the prevalence and incidence of sexually transmitted
infections (STI) in HIV-infected women in relation to time from infection and
sexual behaviour. DESIGN: The European study on the natural history of HIV
infection in women is a prospective cohort study of 487 HIV-infected women with a
known interval of seroconversion from 12 European countries. METHODS: Incidence
was measured with person-time methods. Generalized estimating equations analysis
was used to determine risk factors for STI. RESULTS: At entry, 15% of the women
were diagnosed with at least one acute STI (chlamydial infection, trichomoniasis
or gonorrhoea), 10% with at least one other STI (genital warts or genital
ulcerations) and 13% with vaginal candidiasis. Although frequently diagnosed
during follow-up, the occurrence of acute STI and vaginal candidiasis decreased,
whereas the occurrence of other STI increased with ongoing time from HIV
infection. Furthermore, women with a history of prostitution [relative risk (RR),
2.00; 95% confidence interval (95% CI), 1.20-3.33] and women with irregular
condom use (RR, 7.74; 95% CI, 3.52-17.0) were at higher risk for an acute STI.
CONCLUSIONS: Although STI diagnoses were frequent, the occurrence of acute STI
declined with time from infection which might be explained by changed sexual
behaviour over time. The occurrence of other STI increased with time from HIV
infection, presumably due to reactivation as a result of immunosuppression.
PMID- 10780722
TI - The effect of syringe exchange use on high-risk injection drug users: a cohort
study.
AB - OBJECTIVE: To determine whether syringe exchange program use is associated with
cessation of syringe sharing among high-risk injection drug users. DESIGN AND
METHODS: Between 1992 and 1996, street-recruited injection drug users were
interviewed and received HIV testing and counseling semi-annually, as part of a
dynamic cohort study. We examined a cohort of 340 high-risk injection drug users
for whom two observations, 6-months apart, were available and who reported
syringe sharing at the first interview. Multivariate logistic regression analysis
was performed to determine the relationship between syringe exchange program use
and cessation of syringe sharing, while controlling for confounding factors.
RESULTS: At follow-up interview, 60% (204 of 340) reported quitting syringe
sharing. High-risk injection drug users who began using the syringe exchange
program were more likely to quit sharing syringes [adjusted odds ratio (AOR),
2.68; 95% confidence interval (CI), 1.35-5.33], as were those who continued using
the syringe exchange program (AOR,1.98; 95% CI, 1.05-3.75) in comparison with non
syringe exchange program users, while controlling for confounding factors.
CONCLUSIONS: The initiation and continuation of syringe exchange program use
among high-risk injection drug users is independently associated with cessation
of syringe sharing. Syringe exchange program use can be an important component in
reducing the spread of blood-borne infectious diseases among high-risk injection
drug users.
PMID- 10780723
TI - Opposite effects of IFN-gamma on CCR5 and CXCR4 expression and on entry of M- and
T-tropic HIV in epithelial cells.
PMID- 10780724
TI - Increased incidence of peripheral neuropathy with co-administration of stavudine
and isoniazid in HIV-infected individuals.
PMID- 10780725
TI - The costs of antiretroviral drug wastage.
PMID- 10780726
TI - Immune recovery inflammatory folliculitis.
PMID- 10780727
TI - Pharmacokinetics of efavirenz in a patient on maintenance haemodialysis.
PMID- 10780728
TI - Effects of hydroxyurea on T cell count changes during primary HIV infection.
PMID- 10780729
TI - Cidofovir ocular toxicity is related to previous ocular history.
PMID- 10780730
TI - Detection of maternal DNA in cord blood at birth after elective caesarean section
or vaginal delivery.
PMID- 10780731
TI - HIV/sexually transmitted disease education and prevention in US bathhouse and sex
club environments.
PMID- 10780732
TI - Phenotypic resistance to protease inhibitors in patients who fail on highly
active antiretroviral therapy predicts the outcome at 48 weeks of a five-drug
combination including ritonavir, saquinavir and efavirenz.
PMID- 10780734
TI - Life-cycle of Isospora mehlhornii sp. nov. (Apicomplexa : Eimeriidae), parasite
of the Egyptian swallow Hirundo rubicola savignii.
AB - Fifty-seven Hirundo rubicola savignii swallows were collected from Damietta,
Tanta, Dakahlyia and Sharkia Provinces, Egypt. They were examined for coccidian
parasites. The percentage of infection with Isospora stages was 12.3%. After
diagnosis it was noted that the parasites belong to a new species. The
unsporulated oocysts were spherical, measuring 25.7-31.9 microm in diameter with
a mean of 28.3 microm. A micropyle, polar granule and oocyst residuum were
absent. Sporocysts appeared lemon-shaped and measured 19.6-24.5 microm x 12.5
17.5 microm with a mean of 22.9 x 14.4 microm. Stieda body and the sporocyst's
residual body were clearly visible. Sporozoites measured 11-14.2 x 4.4-5.1 microm
with a mean of 11.4 x 4.7 microm. Sporulation time was 72 h at room temperature
(25 degrees C). Endogenous stages including schizogony and gamogony were detected
in epithelial cells of the duodenum, jejunum and ileum of the host. Schizogony
consisted of two generations. Mature first generation schizonts reached up to 11
microm in diameter and produced merozoites measuring 3.5 x 1.7 microm. Mature
second generation schizonts measured 17.2 x 12.3 microm and produced merozoites
measuring 11.8 x 2.2 microm. Gamogonic stages were differentiated into
microgamonts and macrogamonts. Mature microgamonts were spherical and measured
23.2 microm in diameter, producing curved microgametes measuring 4.5 x 0.7
microm. The ovoid macrogametes measured 19.6 x 14.7 microm and were characterized
by a large nucleus and nucleolus. Early, more or less spherical, oocysts were
detected inside the intestinal epithelial cells and in the intestinal lumen. They
measured 19.6 microm in diameter. The sporont measured 17.2 microm in diameter.
Cytochemical studies on schizogony, gamogony and oocysts were accomplished and
showed distribution of polysaccharides and composition of the oocyst wall.
PMID- 10780733
TI - Expression of SAG-1 of Toxoplasma gondii in transgenic mice.
AB - We describe the expression of SAG-1 cDNA in B6C3F1 mice by microinjecting a 3.3
kbp DNA fragment, consisting of the cytomegalovirus enhancer-chicken beta-actin
hybrid promoter and SAG-1 into the pronucleus of a fertilized egg at the one-cell
stage. Offspring derived from this microinjection were analyzed for the
integration and functional expression of the SAG-1 transgene. Steady-state
expressions of both the mRNA for SAG-1 and SAG-1 protein product were detected in
the brain, thymus, spleen and liver. Approximately 50% of F1 and F2 progeny
inherited the SAG-1 transgene from SAG-1 transgenic mice in Mendelian fashion.
These results indicated that SAG-1 transgenic lines were established. Transgenic
mice harboring the SAG-1 gene will contribute a critical tool of defining the
molecular mechanisms of SAG-1 in pathogenesis and host immune response.
PMID- 10780735
TI - A cDNA encoding the highly immunodominant antigen of Strongyloides stercoralis:
gamma-subunit of isocitrate dehydrogenase (NAD+).
AB - A full length cDNA encoding the highly immunodominant 41 kDa antigen of
Strongyloides stercoralis (P5), recognized by 83% of human patients [Siddiqui et
al. (1997) Parasitol Res 83:655-658], is obtained. A clone containing a 1371 bp
insert was selected following screening of the S. stercoralis cDNA library with
antibodies specific to antigen P5. The nucleotide sequence of this insert
identified a cDNA coding for the gamma-subunit of isocitrate dehydrogenase
(NAD+), GenBank Accession Number AF176568. The conceptually translated amino acid
sequence of the open reading frame for the gamma-subunit of S. stercoralis
isocitrate dehydrogenase (NAD+) encodes a 388 amino acid residue protein with an
apparent molecular weight of 43 kDa and a predicted pI of 7.15. The sequence is
71% A/T, reflecting the characteristic A/T codon bias of S. stercoralis. The
amino acid sequence of the S. stercoralis gamma-subunit of isocitrate
dehydrogenase (NAD+) is compared with those of Caenorhabditis elegans, rat and
human NAD(+)-ICDH. The diagnostic potential of the S. stercoralis gamma-subunit
of isocitrate dehydrogenase (NAD+) is also discussed.
PMID- 10780736
TI - Survival of destrobilated adults of Taenia crassiceps in T-cell-depleted
Mongolian gerbils.
AB - In Mongolian gerbils (Meriones unguiculatus), prednisolone treatment induces the
survival of strobilated Taenia crassiceps to sexual maturity followed by fecal
release of gravid proglottides. The mechanism underlying the effects of
prednisolone has not been elucidated in this taeniid/rodent model. Using a novel
murine monoclonal antibody specific to a cell-surface determinant of gerbil T
cells (HUSM-M.g.15 of IgG2b isotype) for in vivo depletion of the cells, we
examined the T-cell dependence of the following two phenomena: (1) elimination of
strobilated T. crassiceps from the intestine of naive gerbils, and (2) depressed
egg formation by the cestode in prednisolone-treated gerbils. In T-cell-depleted
gerbils, only destrobilated adults were recovered from the intestine, although
the recovery rate was comparable with that observed in prednisolone-treated
animals. Egg formation by the cestode in T-cell-depleted, prednisone-treated
gerbils did not differ from that seen in gerbils treated with prednisolone alone.
We conclude that one of main effects of prednisolone can be ascribed to the
suppression of T-cell functions that work to eliminate strobilated T. crassiceps
from gerbils.
PMID- 10780737
TI - Pseudocapillaria (Ichthyocapillaria) ophisterni sp. n. (Nematoda : Capillariidae)
from the swamp-eel Ophisternon aenigmaticum (Pisces) in Mexico.
AB - A new nematode species, Pseudocapillaria ophisterni sp. n., is described from the
intestine and rarely from the stomach of the swamp-eel, Ophisternon aenigmaticum
Rosen et Greenwood, from Catemaco Lake, Veracruz, Mexico. In having both caudal
lobes in the male interconnected by a distinct dorsal membrane, it belongs to the
subgenus Ichthyocapillaria. It differs from the three species in this subgenus
mainly in possessing either a distinctly longer spicule or a smaller length of
oesophagus relative to body length. It also differs in host type and geographical
distribution. P. ophisterni is the first capillariid species reported from
synbranchiform fishes.
PMID- 10780738
TI - Intracellular calcium and pH conditions of cultured cells infected with Eimeria
bovis or E. separata.
AB - Loading of Eimeria bovis-infected Vero cells with membrane-permeant acetoxymethyl
esters (AM-esters) of ion-sensitive dyes provided us with a noninvasive method
for investigation of the permeability of the parasitophorous vacuole membrane
(PVM) and simultaneous measurement of Ca2+ and H+ concentrations in different
compartments of the infected cells. The distribution patterns of the cleaved
membrane-impermeant dyes argue against the existence of nonselective pores in the
PVM. There is also no indication of a parasitophorous duct connecting the
vacuolar space with extracellular media. The pH inside the parasitophorous
vacuole (PV) was lower than that in the cytoplasm of the host cell or the
parasite, whereas the [Ca2+] in these compartments did not differ significantly.
In HT29 cells infected with E. separata for 24 h the Ca2+ response to
extracellular adenosine triphosphate (ATP) was significantly reduced, indicating
influences on the host cell's intracellular signaling.
PMID- 10780739
TI - Ultrastructure of spermiogenesis and the spermatozoon of Opecoeloides furcatus
(Trematoda, Digenea, Opecoelidae), a parasite of Mullus barbatus (Pisces,
Teleostei).
AB - Spermiogenesis and mature spermatozoa of Opecoeloides furcatus (Digenea,
Opecoelidae) are described by means of transmission electron microscopy.
Spermiogenesis in this fluke matches the general pattern of digenetic trematodes.
Striated rootlets associated with the two centrioles and an intercentriolar body
are present in the differentiation zone. Flagellar rotation of two flagella and
their proximodistal fusion with a median cytoplasmic process also characterize
the spermiogenesis of O. furcatus. Nevertheless, asynchronicity is reported for
the proximodistal fusion of the two flagella. Mature spermatozoa of O. furcatus
are filiform, tapering at both ends and they present all the characteristic
features found in the Digenea gamete: two flagella, mitochondrion, nucleus and
two bundles of parallel cortical microtubules. Nevertheless several peculiarities
distinguish the mature spermatozoon of O. furcatus from the gamete of other
digenetic trematodes.
PMID- 10780740
TI - In vitro leucocyte proliferative responses and lymphocyte sub-types in guinea
pigs with genetically determined high- and low-level responsiveness to
Trichostrongylus colubriformis.
AB - In vitro leucocyte proliferative responses to parasite antigens and to mitogens
as well as lymphocyte sub-types were compared in guinea pigs with genetically
determined differences in their ability to express protective immunity against
Trichostronylus colubriformis infection. Proliferative responses to parasite
antigens were greatest in high-responder (HR) animals, but cells from low
responder (LR) animals were generally more responsive to mitogens. However, HR
circulating leucocytes were more responsive to the T-cell-dependent B-cell
mitogen pokeweed mitogen (PWM), and the response of HR, but not LR, cells
increased during primary infection with T. colubriformis. Flow cytometry revealed
significantly greater numbers of circulating B-cells in HR animals and, as
observed for responsiveness to PWM, the number of circulating B-cells increased
in HR, but not LR, animals during primary infection with this parasite. These
findings suggest a larger and more labile population of B-cells in HR guinea
pigs.
PMID- 10780741
TI - Further report on Cryptosporidium in Barcelona zoo mammals.
AB - The prevalence of fecal shedding of Cryptosporidium in 36 primates (21 species
and subspecies) and 62 herbivores (36 species and subspecies) housed at the
Barcelona zoo was studied. Cryptosporidial oocysts were found in stool samples of
14 Primate, 18 Artiodactyla, 2 Perissodactyla, and 1 Proboscidea species. None of
them showed symptoms related to the parasite. Neither the sex nor the group
condition (alone or in a group) of the animals studied appeared to be correlated
with parasitic prevalence. The results extend the host species range of the
protozoan to 18 new animals (6 Primate, 10 Artiodactyla, 1 Perissodactyla, and 1
Proboscidea species) and confirm the endemic status of Cryptosporidium at the
Barcelona zoo. We conclude that maintenance of the parasitic endemic status is
probably due to the presence of animal carriers as well as to the physical
features of some facilities where oocysts could remain viable and infectious.
PMID- 10780743
TI - Scanning electron microscopy of Chilomastix mesnili (Wenyon 1910) Alexieieff,
1912.
AB - Scanning electron microscopy of Chilomastix mesnili shows that the cysts are
lemon-shaped with one end broadly rounded and the other conical. The trophozoite
has five flagella coming out of the anterior end. Four of these are free and the
fifth is attached to the body by an undulating membrane. The undulating membrane
extends along the whole length of the body of the parasite with the exception of
the tail. The tail is an elongated structure almost equal in length to the main
body of the parasite.
PMID- 10780742
TI - Development of Fasciolopsis buski (Trematoda : Fasciolidae) in Hippeutis
umbilicalis and Segmentina trochoideus (Gastropoda : Pulmonata).
AB - Sequential development and histopathologic effects of Fasciolopsis buski larvae
were examined in two species of pulmonate snail, Hippeutis umbilicalis and
Segmentina trochoideus. Miracidial attachment and penetration began 5 min post
exposure (PE). On day 2 PE, the sporocysts rapidly increased in size and over
days 3-7 PE, they transformed into mother rediae which migrated to the ovotestis
on day 10 PE. In both species of snail, daughter rediae were initially observed
on day 17 PE, the first cercariae emerged on day 21 PE, and from that day onward
daughter rediae were the dominant larval form occupying the ovotestis.
Histopathologic changes were confined exclusively to the ovotestis and included
lytic lesions due to mechanical damage, and disappearance of all cellular
elements. No inflammatory responses were observed in the ovotestis, and no
degenerated larvae of any kind were observed in the snails. Infected snails did
not produce egg masses and lived no longer than 35 days. The lack of differences
in miracidial recognition and penetration, and in the temporal, sequential, and
spatial development of F. buski larvae in H. umbilicalis and S. trochoideus
indicate that both these snail species are equally susceptible to F. buski.
PMID- 10780744
TI - Cloning and characterization of Entamoeba histolytica antigens recognized by
human secretory IgA antibodies.
AB - To identify the Entamoeba histolytica antigens capable of inducing secretory IgA
(sIgA) responses in humans, a cDNA library from the strain HM1:IMSS was immuno
screened with saliva from patients with intestinal amebiasis or amebic liver
abscess. Clones isolated with sIgA antibodies from patients with intestinal
amebiasis corresponded to the known serine-rich protein isoform, a 29 kDa
cysteine-rich protein and 1-alpha elongation factor. Clones corresponding to
enolase, cyclophilin, ribosomal protein L23a, and an Hsp70 family protein were
isolated with sIgA from a patient with amebic liver abscess. A glutamic acid-rich
peptide (EhGARP) positive with sIgA from a patient with amebic liver abscess was
also isolated; for EhGARP, no homologs were found in the protein databases. The
antigens isolated are potentially useful in the development of an oral vaccine or
new diagnostic tools for amebiasis.
PMID- 10780745
TI - Presence of Phlebotomus (Transphlebotomus) mascittii Grassi, 1908 (Diptera :
Psychodidae) in Germany.
AB - During an entomology survey in July 1999, one male and three female Phlebotomus
(Transphlebotomus) mascittii were caught in southwestern Baden Wurttemberg. This
is the first record of phlebotomine sandflies in Germany.
PMID- 10780746
TI - Prevalence of Haplometra cylindracea infection in three species of Lymnaea snails
in central France.
AB - Field investigations were performed over a 2- or 3-year period at five sites in
central France to determine the prevalence of Haplometra cylindracea infection in
three species of adult Lymnaea, and to compare it with that of Fasciola hepatica
infection recorded in the same snails. L. glabra, L. palustris, and L. truncatula
harboured Haplometra larval forms but the prevalence of this infection varied
according to the site and snail species studied. The prevalences in May ranged
over 0-66.9% in L. glabra, 3-7.7% in L. palustris, and 0-31.5% in L. truncatula.
The mean intensity of H. cylindracea infection in May did not show any
significant variation, whatever the site and species studied. The prevalence of
F. hepatica infection was significantly lower in snails collected in sites known
for H. cylindracea infection than in those originating from nearby meadows (0-1%
instead of 1-5%). H. cylindracea could develop in some Lymnaea species and its
occurrence had an impact in snails by decreasing the prevalence of F. hepatica
infection.
PMID- 10780747
TI - Helminth fauna of snakes (Reptilia, Serpentes) in Belorussian Polesye.
PMID- 10780748
TI - Findings of Fasciola hepatica Linnaeus 1758, in wild animals in Belorussian
Polesye.
PMID- 10780749
TI - Helminth fauna of lizards (Reptilia, Sauria) in the southern part of Belarus.
PMID- 10780750
TI - Postpneumonectomy pulmonary oedema revisited.
PMID- 10780751
TI - Do long-acting beta2-adrenergic agonists deserve a different place in guidelines
for the treatment of asthma and COPD?
PMID- 10780752
TI - Development of severe hypoxaemia in chronic obstructive pulmonary disease
patients at 2,438 m (8,000 ft) altitude.
AB - The arterial oxygen tensions (Pa,02) in chronic obstructive pulmonary disease
(COPD) patients travelling by air, should, according to two different guidelines,
not be lower than 7.3 kPa (55 mmHg) and 6.7 kPa (50 mmHg), respectively, at a
cabin pressure altitude of 2,438 m (8,000 ft). These minimum in-flight Pa,O2
values are claimed to correspond to a minimum Pa,O2 of 9.3 kPa (70 mmHg) at sea
level. The authors have tested whether this limit is a safe criterion for
predicting severe in-flight hypoxaemia. The authors measured arterial blood gases
at sea-level, at 2,438 m and at 3,048 m (10,000 ft) in an altitude chamber at
rest and during light exercise in 15 COPD patients with forced expiratory volume
in one second (FEV1) <50% of predicted, and with sea-level Pa,O2 >9.3 kPa.
Resting Pa,O2 decreased below 7.3 kPa and 6.7 kPa in 53% and 33% of the patients,
respectively, at 2,438 m, and in 86% and 66% of the patients at 3,048 m. During
light exercise, Pa,O2 dropped below 6.7 kPa in 86% of the patients at 2,438 m,
and in 100% of the patients at 3,048 m. There was no correlation between Pa,O2 at
2,438 m and pre-flight values of Pa,O2, FEV1 or transfer factor of the lung for
carbon monoxide. In contrast to current medical guidelines, it has been found
that resting arterial oxygen tension >9.3 kPa at sea-level does not exclude
development of severe hypoxaemia in chronic obstructive pulmonary disease
patients travelling by air. Light exercise, equivalent to slow walking along the
aisle, may provoke a pronounced aggravation of the hypoxaemia.
PMID- 10780753
TI - Endothelin mediates pulmonary vascular remodelling in a canine model of chronic
embolic pulmonary hypertension.
AB - It is well known that endothelin (ET)-1 mediates vascular remodelling in various
kinds of clinical and experimental pulmonary hypertension. The aim of this study
was to investigate whether ET-1 is associated with the development of pulmonary
vascular remodelling in a canine model of chronic embolic pulmonary hypertension.
Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization
with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor
antagonist, was administered throughout the study. Haemodynamic measurements and
plasma ET-1 assays were performed every 2 months. Eight months after initial
embolization, computer-assisted morphometry and immunohistochemistry were
performed on the lung tissue including that from three control dogs. Pulmonary
arterial pressure and pulmonary vascular resistance were increased in all
embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1
concentration and pulmonary arterial wall thickness were increased compared to
control animals, and ET-1 immunoreactivity was detected in thickened pulmonary
arteries. In bosentan treated dogs, pulmonary arterial walls were not
significantly thickened. Pulmonary vascular remodelling, associated with elevated
plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung
tissue is attenuated by the endothelin receptor antagonist, bosentan. These
findings suggest that endothelin mediates pulmonary vascular remodelling in a
canine model of chronic embolic pulmonary hypertension.
PMID- 10780754
TI - Respiratory muscle activity in patients with COPD walking to exhaustion with and
without pressure support.
AB - The function of the diaphragm and other respiratory muscles during exercise in
chronic obstructive pulmonary disease (COPD) remains controversial and few data
exist regarding respiratory muscle pressure generation in this situation. The
inspiratory pressure/time products of the oesophageal and transdiaphragmatic
pressure, and the expiratory gastric pressure/time product during exhaustive
treadmill walking in 12 patients with severe COPD are reported. The effect of
noninvasive positive pressure ventilation during treadmill exercise was also
examined in a subgroup of patients (n=6). During free walking, the inspiratory
pressure/time products rose early in the walk and then remained level until the
patients were forced to stop because of intolerable dyspnoea. In contrast, the
expiratory gastric pressure/time product increased progressively throughout the
walk. When patients walked the same distance assisted by noninvasive positive
pressure ventilation, a substantial reduction was observed in the inspiratory and
expiratory pressure/time products throughout the walk. When patients walked with
positive pressure ventilation for as long as they could, the pressure/time
products observed at exercise cessation were lower than those observed during
exercise cessation after free walking. It is concluded that, in severe chronic
obstructive pulmonary disease, inspiratory muscle pressure generation does not
increase to meet the demands imposed by exhaustive exercise, whereas expiratory
muscle pressure generation rises progressively. Inspiratory pressure support was
shown to substantially unload all components of the respiratory muscle pump.
PMID- 10780755
TI - Predictors of weaning outcome in chronic obstructive pulmonary disease patients.
AB - Several threshold values for predicting weaning outcome from mechanical
ventilation have been proposed. These values, however, have been obtained in
nonhomogeneous patient populations. The aim of the present study was to determine
the threshold values in chronic obstructive pulmonary disease (COPD) patients and
compare them to those reported for nonhomogeneous patient populations. The
initial weaning trial included 81 COPD patients. Fifty-three of them underwent a
successful weaning trial, whereas 28 failed it. The latter were enrolled into the
present investigation, and were restudied during a subsequent successful trial.
The weaning indices used were those reported in the literature. The threshold
values obtained were within 10% of those reported for a nonhomogeneous patients
population only for tidal volume and effective compliance. The classification
error was <20% for maximal inspiratory pressure (MIP), occluded inspiratory
pressure swing (deltaPI)/MIP, rapid and shallow breathing (respiratory
frequency/tidal volume), and compliance, rate, oxygenation, pressure index
(CROP), whereas the area under the receiver operating characteristic curves was
>0.9 only for deltaPI/MIP and CROP. In conclusion, the threshold values obtained
in chronic obstructive pulmonary disease patients who failed the first weaning
attempt differed from those previously reported. Although a gold standard weaning
index is not available for chronic obstructive pulmonary disease patients, the
occluded inspiratory pressure swing/ maximal inspiratory pressure and compliance,
rate, oxygenation, pressure index may be candidates for such a role.
PMID- 10780756
TI - Comparison of the safety of drug delivery via HFA- and CFC-metered dose inhalers
in CAO.
AB - The objective of this study was to compare the long-term safety of a fixed
combination of fenoterol hydrobromide (50 microg) and ipratropium bromide (20
microg) delivered using a metered dose inhaler (MDI) formulated with a non
chlorinated propellant, hydrofluoroalkanel34a (HFA-MDI), with delivery using the
conventional chlorofluorocarbon propellant (CFC-MDI, Berodual/Bronchodual). The
study was designed according to Safety Assessment of Marketed Medicines (SAMM)
guidelines, to reflect as far as possible the use of MDls under normal
prescribing conditions. Two thousand and twenty-seven patients with chronic
airways obstruction (CAO) were enrolled from 99 centres in France, 95 centres in
Germany and 24 centres in Italy. Following a 2-week run-in period, patients were
randomized on a 2:1 basis (1,348 patients to HFA-MDI, 679 patients to CFC-MDI) to
receive a flexible dose regimen of the combination (2 puffs, 2-4 times a day, as
prescribed by the investigator) during a 12-week open label phase. The overall
incidence of adverse events was comparable between both groups. In addition, the
incidence of respiratory side effects was also similar, with CAO exacerbations or
bronchitis the most frequently recorded events. The safety profile of the HFA
formulation was comparable to those of the marketed CFC-MDIs used in Germany and
France/Italy. No clinically significant differences were detected between HFA134a
or CFC driven inhalers on the switch from CFC- to HFA-MDI (2 weeks before
randomisation versus 2 weeks after randomization). There was a trend for taste
complaints to be reported more frequently by patients in the HFA-MDI group (0.7%
before randomization versus 3.4% after randomization). This, however, was an
expected finding as the HFA134a formulation does have a different taste to the
CFC formulation. No difference between formulations was observed in the
incidences of coughing or paradoxical bronchospasm. The incidence of falls in
FEV1 >15% within 15 min following inhalation at each of the clinic visits was
1.2% for both CFC- and HFA-MDIs. In conclusion, administration of a
fenoterol/ipratropium bromide combination via hydrofluoroalkane-metered dose
inhaler is as safe as delivery by the currently available chlorofluorocarbon
metered dose inhaler, in an extended population of patients with CAO under normal
prescribing conditions.
PMID- 10780757
TI - Split-night versus full-night studies for sleep apnoea/hypopnoea syndrome.
AB - Investigation and treatment of sleep apnoea/hypopnoea syndrome (SAHS) is placing
increasing demands on healthcare resources. This workload may be reduced by using
split-night studies instead of the standard full-nights of diagnostic
polysomnography and continuous positive airway pressure (CPAP) titration. Split
night studies involve polysomnography in the first half of the night followed, if
there is an abnormal frequency of apnoeas and hypopneas, by CPAP titration for
the remainder of the night. The authors' database of all patients prescribed a
CPAP trial 1991-1997 was used to compare long-term outcomes in all 49 (46
accepting CPAP) patients prescribed split-night studies with those in full-night
patients, matched 1:2 using an apnoea/ hypopnoea index (AHI) of +/-15% and
Epworth score of +/-3 units. Classical symptoms of SAHS were the main reason for
the split-night studies (n=27). There were no differences between the groups in
long-term CPAP use, median nightly CPAP use (split-night 6.0 h x night-1,
interquartile range (IQR) 3.8-7.4, full-night; 6.2 h x night-1, IQR 3.7-7.0,
p=0.9), post-treatment Epworth scores and frequency of nursing
interventions/clinic visits required. The median time from referral to treatment
was less for the split-night patients (13 months, IQR 11-20 months) than for full
night patients (22 months, IQR 12-34 months; p=0.003). Split-night studies, in
selected patients, result in equivalent long-term continuous positive airway
pressure use to full-night studies with shorter treatment times and less
healthcare utilization.
PMID- 10780758
TI - Long-term effects of CPAP on daytime functioning in patients with sleep apnoea
syndrome.
AB - Daytime sleepiness, impaired cognitive performance and dysphoric mood are often
present in patients with obstructive sleep apnoea syndrome (SAS). This
prospective controlled study evaluates the effects of treatment with continuous
positive airway pressure (CPAP) during 1 yr on daytime functioning in a large
group of patients with SAS. The authors studied 80 patients (mean+/-sem 49+/-1
yrs) with SAS with a mean apnoea-hypopnoea index of 60+/-2 h-1, and 80 healthy
control subjects matched for sex and age (46+/-1 yrs.). Measurements were
obtained at the beginning of the study and 12+/-1 months later, and included:
daytime sleepiness (Epworth scale), depression and anxiety (Beck tests),
vigilance (Steer-Clear) and reaction time (Psychometer Vigilance Test 192). Drug,
coffee and alcohol intake, as well as the sleep schedule, were also recorded.
Results showed that, before treatment, patients were more somnolent (p<0.001),
anxious (p<0.01) and depressed (p<0.001) than control subjects. Also, they had a
longer reaction time (p<0.05) and poorer vigilance (p<0.01). The use of CPAP
improved significantly the levels of somnolence (p<0.0001) and vigilance
(p<0.01), but failed to modify anxiety and depression. Reaction time changes were
minor. Variables with a potential confounding effect did not change during the
study. These results provide firm evidence to substantiate the use of continuous
positive airway pressure in patients with sleep apnoea syndrome.
PMID- 10780759
TI - Airway inflammation, airway responsiveness and cough before and after inhaled
budesonide in patients with eosinophilic bronchitis.
AB - Eosinophilic bronchitis is a common cause of chronic cough, characterized by
sputum eosinophilia similar to that seen in asthma, but unlike asthma the
patients have no objective evidence of variable airflow obstruction or airway
hyperresponsiveness. The reason for the different functional associations is
unclear. The authors have tested the hypothesis that in eosinophilic bronchitis
the inflammation is mainly localized in the upper airway. In an open study the
authors measured the lower (provocative concentration causing a 20% fall in
forced expiratory volume in one second (PC20)) and upper (PC25 MIF50) airway
responsiveness to histamine, lower and upper airway inflammation using induced
sputum and nasal lavage, in II patients with eosinophilic bronchitis. The authors
assessed changes in these measures and in cough reflex sensitivity to capsaicin
and cough severity after 400 microg of inhaled budesonide for 4 weeks. A nasal
eosinophilia was present in only three patients with one having upper airway
hyperresponsiveness. Following treatment with inhaled corticosteroids the
geometric mean sputum eosinophil count decreased from 12.8% to 2.9% (mean
difference 4.4-fold, 95% confidence interval (CI) 2.14-10.02), the mean +/- sem
cough visual analogue score on a 100 mm scale decreased from 27.2 +/- 6.6 mm to
12.6 +/- 5.7 mm (mean difference 14.6, 95% CI 9.1-20.1) and the cough sensitivity
assessed as the capsaicin concentration required to cause two coughs (C2) and
five coughs (C5) improved (C2 mean difference 0.75 doubling concentrations, 95%
CI 0.36-1.1; C5 mean difference 1.3 doubling concentration, 95% CI 0.6-2.1).
There was a significant positive correlation between the fold change in sputum
eosinophil count and doubling dose change in C5 after inhaled budesonide
(r=0.61). It is concluded that upper airway inflammation is not prominent in
eosinophilic bronchitis and that inhaled budesonide improves the sputum
eosinophilia, cough severity and sensitivity suggesting a causal link between the
inflammation and cough.
PMID- 10780760
TI - Effects of inhaled steroids on methacholine-induced bronchoconstriction and gas
trapping in mild asthma.
AB - According to a recent hypothesis, airway smooth muscle regulates airway calibre
mostly at high lung volume, whereas the mucosa and adventitia dimensions dominate
at low lung volumes. It was thought that if inhaled steroids decrease the
thickness of airway wall in asthma, then forced vital capacity (FVC), which
reflects the functional changes at low lung volume, should decrease less during
induced bronchoconstriction than flow at high volume. The study was conducted in
31 mild asthmatics under control conditions and during a methacholine challenge
before and after 4-weeks treatment with inhaled fluticasone dipropionate (1.5 mg
daily, 16 patients) or placebo (15 patients). After fluticasone dipropionate
treatment, control forced expiratory volume in one second (FEV1), and maximal
flow at 50% of control FVC during forced expiration after a maximal (V'max,50)
and a partial inspiration (V'p,50) significantly increased. During methacholine
challenge, FVC decreased less than did FEV1 or V'max,50, and so did inspiratory
vital capacity compared to V'p,50. Both the provocative dose of methacholine
causing a 20% fall in FEV1 and the bronchodilator effect of deep inhalation
significantly increased. The latter was assessed by means of the regression
coefficient of all V'max,50 plotted against V'p,50. No significant changes in
these parameters occurred after placebo. These data show that inhaled steroids
remarkably blunt the occurrence of gas trapping during induced
bronchoconstriction in mild bronchial asthma, possibly due to their effect on
airway wall remodelling.
PMID- 10780761
TI - Efficacy and duration of action of the antileukotriene zafirlukast on cold air
induced bronchoconstriction.
AB - The objectives of the study were to assess the magnitude of the effect of the
leukotriene receptor antagonist, zafirlukast, against cold air-induced
bronchoconstriction following the first dose and to assess magnitude and duration
after 5 days of dosing. Nineteen patients with asthma were included. In a
randomized cross-over design, either zafirlukast 20 mg or 80 mg b.d. or placebo
were given over 5 days. Challenges were performed 3 h post first dose and 3, 8,
12 and 24 h post last dose. The authors assessed the provocative ventilation rate
necessary to achieve a 10% (PV10) and 20% (PV20) fall in forced expiratory volume
in one second. The median PV20 3 h post first dose was 69.1 L x min-1 for
zafirlukast 80 mg compared to 40 L x min-1 for placebo (p=0.004). The
corresponding median value for zafirlukast 20 mg was 59.9 L x min-1 (p=0.06). At
steady state the differences in PV20, between zafirlukast 80 mg and placebo were
significant at 8 h and 12 h post last dose. The corresponding difference for
zafirlukast 20 mg was statistically significant at 8 h post last dose. The
analysis of PV10 yielded compatible results. There was no significant protection
24 h after last dose. This study has demonstrated that zafirlukast offers
significant protection against cold air-induced bronchoconstriction in asthma.
The degree and duration of protection were dose-dependent. However, there was a
large interindividual variability for the protective effect of this leukotriene
receptor antagonist.
PMID- 10780762
TI - Acute effects of air pollution on respiratory health of 50-70 yr old adults.
AB - The aim of this study was to investigate the association between daily changes in
respiratory health and air pollution in 489 adults, aged 50-70 yrs, with and
without chronic respiratory symptoms, living in urban and nonurban areas in the
Netherlands. Subjects were selected from the general population with a screening
questionnaire. During three consecutive winters starting in 1992/1993, peak
expiratory flow (PEF) and respiratory symptoms were registered in a daily diary.
Daily measurements of particles with a 50% cut-off aerodynamic diameter of 10
microm (PM10), black smoke (BS), sulphate, sulphur dioxide (SO2) and nitrogen
dioxide (NO2) were conducted. The difference in PM10, BS and sulphate
concentrations between urban and nonurban areas was small, but there was more
contrast in the concentrations of SO2 and NO2. In symptomatic subjects from urban
areas, PM10, BS, sulphate and SO2 concentrations were associated with the
prevalence of large decrements in morning PEF (>20% below the median). BS in
particular was also associated with upper respiratory symptoms (URS). The
magnitude of the effect estimates was in the order of an 80% increase in PEF
decrements and a 20% increase in URS for a 40 microg x m-3 increase of the same
day BS concentration. In symptomatic subjects from nonurban areas, no consistent
associations between air pollution and health indicators were observed. However,
the differences in effect estimates between urban and nonurban symptomatic panels
were small and nonsignificant. In nonsymptomatic adults from both areas, no
consistent pattern of associations with air pollution was found. In conclusion,
air pollution effects were only found in symptomatic adults in the urban areas.
PMID- 10780763
TI - Risk factors for bronchial hyperresponsiveness in workers exposed to acid
anhydrides.
AB - Risk factors for bronchial hyperresponsiveness have previously been established
in the general community. In settings where occupational asthma is a risk, it has
not been established whether occupational sensitization or measures of exposure
are important. Bronchial responsiveness to histamine was measured in a cohort of
506 workers exposed to acid anhydrides. Skin-prick tests were performed with
conjugates of phthalic, maleic and trimellitic anhydride with human serum albumin
and with common inhalant allergens. Employment and smoking histories were
recorded. Occupational exposure was measured using personal air samplers and
estimates of past exposure made by retrospective exposure assessment. Three
hundred and seventy workers (73%) had bronchial responsiveness measured (median
age 39 yrs, range 18-77) and 46 (12%) of these were hyperresponsive (provocative
dose causing a 20% fall in forced expiratory volume in one second (FEV1; PD20) <
or = 8 micromol). Twelve (3%) of these responsive workers had a skin-prick test
reaction to an acid anhydride conjugate, 124 (34%) to a common inhalant allergen,
and 148 (40%) were current smokers. Multivariate analysis showed that
occupational sensitization, sensitization to a common inhalant allergen, age, and
pack-years of smoking were independent risk factors for bronchial
hyperresponsiveness. Of these only occupational sensitization was completely
independent of baseline FEV1. It is concluded that sensitization to acid
anhydrides is a significant risk factor for bronchial hyperresponsiveness.
However, measures of personal acid anhydride exposure were not associated with
bronchial hyperresponsiveness.
PMID- 10780765
TI - Prevalence of asthma in 13-14 yr-old schoolchildren across Israel.
AB - There is evidence that the incidence and severity of asthma are increasing
worldwide, but there are limited data on asthma in Israel. The aim of this study
was to investigate the prevalence and severity of asthma and asthma symptoms in
13-14 yr-old schoolchildren in Israel. The self-completed questionnaire used was
a modified version of that developed by the International Study of Asthma and
Allergies in Childhood (ISAAC), and was administered to a national sample of
12,918 children. The prevalence of asthma ever, wheezing ever and wheezing in the
last 12 months were 13.7, 23.8 and 17.9% respectively. Significantly higher rates
of a history of asthma and asthma symptoms were observed in Jews compared with
Arabs. Although asthma ever was more prevalent in males than in females, asthma
symptoms were significantly more common in females. The type of area of residence
had no effect on the prevalence of wheezing. The ethnic differences in the
prevalence of asthma persisted after controlling for sex, district of residence
and level of urbanization. The prevalence of both asthma and asthma symptoms in
Israel are slightly above the mean reported from 10 other countries in Europe and
the Far-East.
PMID- 10780764
TI - Short-term exposure to air pollution in a road tunnel enhances the asthmatic
response to allergen.
AB - The aim of this study was to assess whether air pollution in road tunnels would
promote asthmatic reactions in persons with mild allergic asthma. Twenty
volunteers with mild allergic asthma were exposed, inside a car, for 30 min in a
Stockholm city road tunnel. As a control, the subjects were exposed to much lower
pollution levels in a suburban area. Four hours after the exposure, the subjects
inhaled a low dose of allergen. Asthmatic reaction during the early phase was
measured as the increase in specific airway resistance 15 min after allergen
inhalation and during the late phase as the decrease in lung function forced
expiratory volume in one second 3-10 h after allergen inhalation. Asthma symptoms
and drug use were monitored up to 18 h after allergen inhalation. The median
nitrogen dioxide level during exposure was 313 microg x m-3 (range 203-462). The
median levels of particles with 50% cut-off aerodynamic diameters of 10 (PM10)
and 2.5 microm (PM2.5) were 170 (range 103-613) and 95 (range 61-218) micro x m
3, respectively. Subjective symptoms during tunnel exposure were not pronounced.
However, subjects exposed to tunnel N02 levels of > or = 300 microg x m-3 had a
significantly greater early reaction, following allergen exposure, as well as
lower lung function and more asthma symptoms during the late phase, compared to
control. Also, subjects with PM2.5 exposure > or = 100 microg x m-3 had a
slightly increased early reaction compared to control. In conclusion, exposure to
air pollution in road tunnels may significantly enhance asthmatic reactions to
subsequently inhaled allergens.
PMID- 10780766
TI - Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect
of flunisolide.
AB - Inhaled corticosteroids are capable of reducing the level of exhaled nitric oxide
(expiratory nitric oxide fraction (FE,NO)) in asthmatic patients in a dose
dependent fashion. The aim of this study was to evaluate whether or not treatment
with an inhaled steroid can prevent changes in FE,NO after the exposure to
relevant allergens, following avoidance, in asthmatic children allergic to house
dust mite. Thirty-two house dust mite-allergy asthmatic children were randomly
allocated to treatment with inhaled flunisolide (500 microg b.i.d) or placebo and
evaluated before and 2 weeks after a period of natural exposure to mite antigens.
Lung function and FE,NO were evaluated. FE,NO was increased in the placebo
treated group after antigen exposure. Treatment with inhaled flunisolide
prevented such increase in FE,NO (p<0.001). No change was observed in lung
function parameters. Inhaled flunisolide is effective in preventing the increase
in airway inflammation observed in allergic asthmatic children re-exposed to
allergens.
PMID- 10780767
TI - Cartilaginous airway wall dimensions and airway resistance in cystic fibrosis
lungs.
AB - It is not clear how airway pathology relates to the severity of airflow
obstruction and increased bronchial responsiveness in cystic fibrosis (CF)
patients. The aim of this study was to measure the airway dimensions of CF
patients and to estimate the importance of these dimensions to airway resistance
using a computational model. Airway dimensions were measured in lungs obtained
from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1),
or autopsy (n=4). These dimensions were compared to those of airways from
lobectomy specimens from 72 patients with various degrees of chronic obstructive
pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were
introduced into a computational model to study their effect on airway resistance.
The inner wall and smooth muscle areas of peripheral CF airways were increased
3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium
was 53% greater in height in peripheral CF airways. The sensitivity and maximal
plateau resistance of the computed dose/response curves were substantially
increased in the CF patients compared to COPD patients. The changes in airway
dimensions of cystic fibrosis patients probably contribute to the severe airflow
obstruction, and to increased bronchial responsiveness, in these patients.
PMID- 10780768
TI - Endothelin-1 production is associated with eosinophilic rather than neutrophilic
airway inflammation.
AB - Endothelin-1 (ET-1) is a strong bronchoconstrictor which possesses pro
inflammatory properties and is claimed to be an important mediator in bronchial
asthma. The present study was undertaken to investigate whether ET-1 synthesis,
in an inflammation dominated by neutrophilic granulocytes, is as pronounced as
previously demonstrated in an airway inflammation dominated by eosinophils.
Moreover, the authors compared the production of ET-1 and tumour necrosis factor
(TNF)-alpha in rat lungs following intratracheal instillation of either
lipopolysaccharide (LPS) (neutrophilic inflammation) or Sephadex (SDX)
(eosinophilic). The lung tissue ET-1 messenger ribonucleic acid (mRNA) expression
was not increased in LPS treated animals whereas a six-fold increase was measured
after 30 min in the SDX group (p<0.05). TNF-alpha mRNA signals increased early
following LPS instillation, peaking at 2 h, whereas elevated TNF-alpha mRNA in
the SDX model was observed at 24 h. The ET-1 concentrations in bronchoalveolar
lavage fluid (BALF) rose slightly, but significantly, 3 h after both LPS and SDX
exposure. At 24 h no further rise in ET-1 levels was observed in the LPS model,
while a substantial increase in the ET-1 concentration was measured in the SDX
group (p<0.05). The TNF-alpha concentrations in BALF rose considerably at 3 h in
the LPS group, but was nearly abolished at 24 h. In SDX challenged animals
however, an increase in BALF-TNF-alpha did not occur until 24 h postchallenge. In
conclusion, intratracheal instillation of lipopolysaccharide, leading to a purely
neutrophilic lung inflammation, does not induce synthesis of endothelin-1. This
is in contrast to observations during an eosinophilic airway inflammation,
indicating a specific role of endothelin-1 in lung inflammations dominated by
eosinophils. In contrast to in vitro experiments, no evidence for induction of
endothelin-1 synthesis was observed by high levels of tumour necrosis factor
alpha in vivo.
PMID- 10780770
TI - Epidemiology of community-acquired pneumonia in adults: a population-based study.
AB - In this prospective study, the authors assessed the incidence, aetiology, and
outcome of patients with community-acquired pneumonia in the general population.
From December 1993 to November 1995, a study was performed in a mixed residential
industrial urban population of the "Maresme" region in Barcelona, Spain. All
subjects > or =14 yrs of age (annual average population size 74,368 inhabitants)
with clinically suspected community-acquired pneumonia were registered. All cases
were re-evaluated by chest radiographs on the 5th day of illness and at monthly
intervals until complete recovery. Urine and blood samples were obtained for
culture and antigen detection. When lower respiratory tract secretions were
obtained, these were also cultured. There were 241 patients with community
acquired pneumonia, with an annual incidence rate of 1.62 cases (95% confidence
interval, 1.42-1.82) per 1,000 inhabitants. Incidence rates increased by age
groups and were higher in males than in females. Of 232 patients with
aetiological data, 104 had an identifiable aetiology. A total of 114 pathogens
were found (single pathogen 94, two pathogens 10). There were 81 episodes of
bacterial infection and 33 of viral infection. The most common pathogens were
Streptococcus pneumoniae, Chlamydia pneumoniae, and influenza A and B viruses. No
case of Hantavirus infection was found. The rate of hospital admission was 61.4%
with a mean+/-SD length of 11.7+/-10.1 days, a mean period of 23.0+/-14.3 days
inactivity, and an overall mortality rate of 5%. The high rate of hospital
admission, prolonged stay in hospital, and long period of inactivity all continue
to constitute a social and health care burden of community-acquired pneumonia.
PMID- 10780769
TI - Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and
smooth muscle cells.
AB - Cyclo-oxygenase (COX) inhibitors may have a role in reducing inflammation in
asthma and other pulmonary diseases. COX inhibitors have different selectivities
for the two COX isoenzymes (COX 1 and COX 2) which vary between purified enzyme
and intact cell preparations. The relative selectivity of COX inhibitors has not
been studied in human airway cells. A number of COX inhibitors in cultured human
airway cells were compared which exclusively express either COX 1 (primary degree
cultured human airway smooth muscle (HASM) cells) or COX 2 (A549 pulmonary
epithelial cell-line) as measured by Western blotting. COX activity was assayed
by prostaglandin (PG)E2 production following 30 min incubation with 5 mM
arachidonic acid. COX activity in both cell types was similar; HASM cells 92.2+/
12.1 ng PGE2 x mg-1 protein, A549 cells 87.7+/-24.4 ng PGE2 mg-1 protein. In HASM
cells the median inhibitory concentration (IC50) was >10-5 M for nimesulide, 3.2
x 10-6 M for N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulphonamide (NS398), 1.8 x
10-8 M for flurbiprofen, 6.7 x 10-9 M for indomethacin and >10-5 M for aspirin.
In A549 cells the IC50 was 1.8 x 10-9M for nimesulide, 4.1 x 10-9 M for NS398,6.2
x 10-10 M for flurbiprofen, 1.3 x 10-8 M for indomethacin and >10-5 M for
aspirin. Sodium valerate had no effect in either HASM or A549 cells. The COX
2:COX 1 selectivity ratio (COX 2 IC50/COX I IC50) was <0.0001 for nimesulide,
0.001 for NS398, 0.03 for flurbiprofen and 1.9 for indomethacin. In conclusion
the present study has shown that cyclo-oxygenase inhibitors have a range of
selectivities for cyclo-oxygenase 1 and cyclo-oxygenase 2 in intact human airway
cells. The relative cyclo-oxygenase 2 selectivity of N-(2-cyclohexyloxy-4
nitrophenyl)-methanesulphonamide and nimesulide may have implications for the
treatment of asthma and other inflammatory pulmonary diseases.
PMID- 10780771
TI - Tumour necrosis factor-alpha production in human alveolar macrophages: modulation
by inhaled corticosteroid.
AB - Using an ex vivo alveolar macrophage model, the hypothesis that inhaled
preparations of corticosteroids might have important anti-inflammatory effects on
cells of the peripheral airway was tested. The tumour necrosis factor (TNF)-alpha
inducing potential of three glycolipid preparations from nonpathogenic
(arabinofuranasyl lipoarabinomannan (LAM (Ara-LAM)) and virulent (mannase LAM
(ManLAM)) mycobacteria and Gram-negative bacteria (lipopolysaccharide (LPS)), in
primary alveolar macrophage preparations was investigated. A novel inhaled
chlorofluorocarbon (CFC)-free preparation of beclomethasone dipropionate
(hydrofluoroalkane 134a (HFA)-BDP) with increased peripheral lung deposition was
investigated for its ability to modulate glycolipidinduced TNF-alpha production
by human alveolar macrophages, in comparison with a CFC-containing preparation
and placebo. Compared to the basal TNF-alpha bioactivity of 0.72 ng x mL-1
(geometric mean), the TNF-alpha bioactivity in the macrophage preparation
increased following incubation with LPS (138 ng x mL-1, p<0.001), AraLAM (12.6 ng
mL-1, p<0.001) and ManLAM (1.42 ng x mL-1, p=0.02). HFA-BDP, administered in
vivo, significantly reduced LPS- and ManLAM-induced TNF-alpha production by
alveolar macrophages cultured ex vivo. No change in glycolipid-induced TNF-alpha
production was observed following in vivo administration of CFC-BDP or HFA
placebo. This is the first demonstration of an immunomodulatory effect on
alveolar cells of corticosteroid delivered via metered dose inhaler. The present
findings suggest that alveolar deposition of beclomethasone dipropionate is
capable of modulating the inflammatory potential of the alveolar macrophage
population.
PMID- 10780772
TI - Restoration by vacuum inflation of original alveolar dimensions in small human
lung specimens.
AB - Resection of lung specimens results in deflated and distorted lung structures. If
no major airway is present (as in the case of small lung specimens from
biopsies), lung dimensions cannot be restored by inflation under 25 cmH20. This
impedes morphological analysis of the tissue. This report describes a simple and
easy procedure to restore alveolar dimensions in deflated small lung specimens.
Small human lung samples were inflated using moderate vacuum conditions which are
provided by a common water stream-driven vacuum device. Restoration of alveolar
dimensions and morphology was evaluated for paraffin-embedded as well as frozen
tissue, using morphometric and immunohistological analysis. Vacuum inflation
results in restoration of original lung dimensions as judged by light and
scanning electron microscopy, and by analysis of the mean linear intercept, and
the average length, width, perimeter and surface area. It also results in
markedly improved cutting characteristics, allowing reliable sectioning of 2
microm cryosections and achieving high resolution images in immunofluorescence.
Vacuum inflation is a simple and easy procedure to restore lung architecture of
small human lung specimens/biopsies with a concomitant improvement of cutting
characteristics. It allows for correct histological analysis of small specimens
which cannot be inflated otherwise.
PMID- 10780773
TI - Validation of assays for inflammatory mediators in sputum.
AB - Commercially available immune assays are being used with increasing frequency in
the study of lung inflammation. However, their performance in complex biological
fluids is rarely assessed. The authors wished to assess their reliability to
determine whether the results obtained in sputum samples can be easily
interpreted. The reproducibility of several such assays was therefore determined
together with their ability to recover known amounts of pure reagent. Sputum sol
phase was obtained from several patients with chronic lung disease and used
together with the reagents in a series of "spiking" and dilutional experiments.
Results confirmed that the enzyme assay for myeloperoxidase and the immune assays
for interleukin-8, leukotriene B4 and secretory leukoproteinase inhibitor were
all reproducible (intra-assay coefficient of variation 3.8-7.7%). Furthermore,
each of these assays gave >85% recovery of a "spike" with pure reagent. However,
the immune assay for myeloperoxidase (although reproducible) gave poor recovery
and was dependent on the degree of sample dilution and elastase content. These
studies confirm that the reliabilities of fluid phase measurements should be
assessed before being widely applied to complex biological samples.
PMID- 10780774
TI - Airway smooth muscle in health and disease; methods of measurement and relation
to function.
AB - Smooth muscle is present and probably functional in the airways in utero and
increases in absolute area during growth with little further change during
adulthood. It encircles the entire airway below the level of the main bronchus,
in a roughly circular orientation, except at high lung volumes. It occupies
relatively more of the airway wall in the peripheral airways, reaching a maximum
in the membranous bronchioles. Measurement of smooth muscle area in the airway
wall is confounded by clinical classification of cases, methods of tissue
retrieval and preparation, staining and orientation of sections, magnification,
image analysis and statistical methods of comparison between groups. Airway
smooth muscle area is pathologically increased in inflammatory conditions of the
airways such as chronic obstructive pulmonary disease, in relation to airways
obstruction, and asthma, in relation to severity and airway size (between 25 and
250% compared with control cases). It is increased in sudden infant death
syndrome, but there are few studies in other conditions such as bronchiectasis.
In asthma, smooth muscle must shorten (not necessarily to an abnormal degree) for
the structural abnormalities of the airway to manifest as excessive airway
narrowing. Not surprisingly there is renewed interest in the relationships
between the mechanical and contractile properties of smooth muscle, parenchymal
properties and lung volume and how these interact to determine smooth muscle
length. The relative importance of smooth muscle area and mechanical properties,
altered airway structure and airway inflammation in disease are yet to be
determined.
PMID- 10780776
TI - Endobronchial tuberculosis with expectoration of tracheal cartilages.
AB - A case of endotracheal tuberculosis with expectorations of the lateral one-third
of the multiple tracheal cartilages is reported. Fibreoptic bronchoscopy revealed
caseous materials and loosening of the tracheal cartilages. The patient
expectorated cartilaginous material several times before and after fibreoptic
bronchoscopy. In spite of the loss of tracheal cartilages, tracheal lumen was
maintained with a mild airflow limitation. The remaining two-thirds of the
tracheal cartilage rings seemed to be strong enough to support the tracheal lumen
opening during the respiratory cycle. Although rare, expectoration of bronchial
cartilage can be one of the clinical features of endobronchial tuberculosis.
PMID- 10780775
TI - The pathogenesis of lung injury following pulmonary resection.
AB - Postpneumonectomy pulmonary oedema (PPO) develops in approximately 5% of patients
undergoing pneumonectomy or lobectomy, and has a high associated mortality
(>50%). In its extreme form, PPO follows a clinical and histopathological course
indistinguishable from acute respiratory distress syndrome. Perioperative fluid
overload, impaired lymphatic drainage following node dissection and trauma caused
by surgical manipulation have been implicated in the pathogenesis of PPO.
However, PPO more probably represents the pulmonary manifestation of a
panendothelial injury consequent upon inflammatory processes induced by the
surgical procedure, which involves collapse and re-expansion of the operative
lung to permit hilar dissection and pulmonary resection. High inspired oxygen
concentrations are required to overcome the effects of shunt. Animal studies have
shown that pulmonary ischaemia/reperfusion can result in oedema formation,
possibly due to the generation of pro-oxidant forces. Moreover, plasma taken from
patients undergoing lobectomy or pneumonectomy (but not lesser resections) shows
evidence of oxidative damage. Such evidence suggests either that the high
inspired oxygen concentrations associated with one-lung ventilation, or
ischaemia/reperfusion injury, may modulate post-pneumonectomy pulmonary oedema.
Mechanisms by which redox imbalance may result in tissue damage and
postpneumonectomy pulmonary oedema are discussed.
PMID- 10780777
TI - Chronic interstitial lung disease due to Epstein-Barr virus infection in two
infants.
AB - This case study reports on two infants, 5 and 6 months of age, respectively, with
chronic interstitial lung disease who presented with failure to thrive,
tachypnoea, rales and mild hypoxaemia. Epstein-Barr virus (EBV) was detected by
in situ hybridization in lung biopsy specimens and by EBV-deoxyribonucleic acid
polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) fluid in one
patient and by in situ hybridization and PCR analysis in BAL fluid in the second
patient. There was serological evidence of immunoglobulin G antibodies to EBV
capsid antigen by indirect immunofluorescence in both patients. After 7 months of
respiratory symptoms one patient was successfully treated with a 10 day course of
intravenous ganciclovir followed by oral acyclovir for 20 days. The other patient
became symptom free after 3.5 months of respiratory symptoms, without any
specific antiviral medication. During a follow-up of 2 and 1.5 yrs, respectively,
both infants remained symptom free and showed normal physical development.
PMID- 10780778
TI - "The skeletal muscle in chronic respiratory diseases", summary of the ERS
research seminar in Rome, Italy, February 11-12 1999.
PMID- 10780779
TI - FRAXE mutation in a mentally retarded subject and in his phenotypically normal
twin brother.
AB - The FRAXE fragile site, 600 kb distal to the more common FRAXA, has been reported
to be expressed in subjects with mild non-syndromal mental retardation (MR).
Amplification of more than 200 GCC repeats, associated with methylation of the
adjacent CpG island at Xq28, leads to the expression of the fragile site. In 1996
a large gene, FMR2, transcribed distally from the CpG island and downregulated by
repeat expansion and methylation, was identified. Among 232 mentally retarded
patients, tested FRAXA negative, we identified an Italian family segregating a
hypermethylated expansion at the FRAXE locus in two dizygotic twin brothers,
their sister and their mother. The index case was referred at 23 years of age
with severe MR, epilepsy, a dysmorphic face with a high arched palate, marfanoid
habitus and hyperreflexia of the lower limbs. His brother was referred to as
normal and psychometric tests confirmed he is not mentally retarded. All members
of the family underwent FRAXE molecular analysis, after cytogenetic expression of
the fraX site and negative FRAXA test. Interestingly, an expansion and a
hypermethylation at the FRAXE locus were found in all of them. Fibroblasts from
the clinically normal brother were assayed for FMR2 expression and the
transcription of the gene was found to be silenced. The presence of a
phenotypically normal male with absent FMR2 expression in fibroblasts suggests
that the relationship between the FRAXE mutation, FMR2 expression and MR needs to
be further investigated.
PMID- 10780780
TI - Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion
as a candidate for autosomal recessive polycystic kidney disease.
AB - The locus PKHD1 (polycystic kidney and hepatic disease 1) has been linked to all
typical forms of the autosomal recessive polycystic kidney disease (ARPKD) and
maps to chromosome 6p21.1-p12. We previously defined its genetic interval by the
flanking markers D6S1714 and D6S1024. In our current work, we have fine-mapped
the gene for the human P1 protein (MCM3), thought to be involved in the DNA
replication process, to this critical region. We have also established its
genomic structure. Mutation analyses using SSCP were performed in ARPKD patients'
cDNA samples, leading to the exclusion of this gene as a candidate for this
disorder. We also identified two intragenic polymorphisms that allowed families
with critical recombination events to be evaluated. Although neither marker was
informative in these individuals, they are the closest yet described for PKHD1
and may help to refine the candidate region.
PMID- 10780781
TI - FISH mapping of the sex-reversal region on human chromosome 9p in two XY females
and in primates.
AB - Accumulating evidence suggests that haploinsufficiency of a dosage-sensitive
gene(s) in human chromosome 9p24.3 is responsible for the failure of testicular
development and feminisation in XY patients with monosomy for 9p. We have used
molecular cytogenetic methods to characterise the sex-reversing 9p deletions in
two XY females. Fluorescence in situ hybridisation (FISH) with YACs from the
critical 9p region containing an evolutionarily conserved sex-determining gene,
DMRT1, is a very fast and reliable assay for patient screening. Comparative YAC
mapping on great ape and Old and New World monkey chromosomes demonstrated that
the critical region was moved from an interstitial position on the ancestral
primate chromosome to a very subtelomeric position in chimpanzee and humans by a
pericentric inversion(s). Pathological 9p rearrangements may be the consequence
of an evolutionary chromosome breakpoint in close proximity to the sex-reversal
region.
PMID- 10780782
TI - The human EZH2 gene: genomic organisation and revised mapping in 7q35 within the
critical region for malignant myeloid disorders.
AB - The EZH2 gene is a homolog of the Drosophila Polycomb group (PcG) gene enhancer
of zest, a crucial regulator of homeotic gene expression. Several lines of
evidence suggest a critical role for the EZH2 protein during normal and perturbed
development of the haematopoietic and central nervous systems. Indeed, the EZH2
protein has been shown to associate with the Vav proto-oncoprotein and with the
XNP protein, the product of a mental retardation gene. The EZH2 gene was
previously reported to be located on chromosome 21q22 and was proposed as a
candidate gene for some characteristics of the Down syndrome phenotype. We report
here the genomic structure and fine mapping of the EZH2 gene. We demonstrate that
the functional gene actually maps to chromosome 7q35 and that the sequence
previously isolated from a chromosome 21 cosmid corresponds to a pseudogene.
Finally, the nature of the EZH2 protein and its mapping to the critical region
for malignant myeloid disorders lead us to propose the EZH2 gene is involved in
the pathogenesis of 7q35-q36 aberrations in myeloid leukaemia.
PMID- 10780783
TI - Accuracy of family history of cancer: clinical genetic implications.
AB - Family medical history is the cornerstone of clinical genetic diagnosis and
management in cases of familial cancer. The soundness of medical decisions can be
compromised if reports by the family on affected relatives are inaccurate.
Although very time consuming, family medical histories are therefore routinely
verified. To investigate whether such verification is clinically justified, we
retrospectively analysed the accuracy of a consecutive series of 383 tumour
reports from counsellees on 120 families in our clinic. We evaluated these
families for the impact of verification on clinical genetic diagnosis and
management. Accuracy according to cancer type showed marked variation, ranging
from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42%
and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy
was related to the degree of kinship of the affected relative, but not to age and
gender of the counsellee, nor to the reason for referral or personal history of
cancer. Age at diagnosis and multiple primary tumours were reported accurately in
97% and 94% of cases, respectively. In six out of 120 families verification data
changed clinical genetic management, in five of these the genetic risk was
reduced. Although verification of all reported cancer cases in a family remains
the 'gold standard' for clinical as well as research purposes, verification of
reports on breast cancer can be limited without seriously compromising medical
decision making. In cases where verification is impossible because medical
records are unavailable, findings from studies such as ours may help in
interpreting family histories.
PMID- 10780784
TI - Potential relationship between genotype and clinical outcome in propionic
acidaemia patients.
AB - Propionic acidaemia (PA) is an autosomal recessive disorder caused by mutations
in either of the PCCA or PCCB genes which encode the alpha and beta subunits,
respectively, of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). In
this work we have examined the biochemical findings and clinical outcome of 37
Spanish PA patients in relation to the mutations found in both PCCA and PCCB
genes. We have detected 27 early-onset and 101 late-onset cases, showing
remarkably similar biochemical features without relation to either the age of
onset of the disease or the defective gene they have. Twenty-one of the patients
have so far survived and three of them, now adolescents, present normal
development. Different biochemical procedures allowed us to identify the
defective gene in 9 PCCA deficient and 28 PCCB deficient patients. Nine putative
disease-causing mutations accounting for 77.7% of mutant alleles were identified
among PCCA deficient patients, each one carrying a unique genotypic combination.
Of PCCB mutant alleles 98% were characterised. Four common mutations (ins/del,
E168K, 1170insT and A497V) were found in 38/52 mutant chromosomes investigated,
whereas the remainder of the alleles harbour 12 other different mutations. By
examining the mutations identified both in PCCA and PCCB genes and the clinical
evolution of patients, we have found a good correlation between certain mutations
which can be considered as null with a severe phenotype, while certain missense
mutations tend to be related to the late and mild forms of the disease.
Expression studies, particularly of the missense mutations identified are
necessary but other genetic and environmental factors probably contribute to the
phenotypic variability observed in PA.
PMID- 10780785
TI - Characterization of a novel mitochondrial DNA deletion in a patient with a
variant of the Pearson marrow-pancreas syndrome.
AB - We have recently diagnosed a patient with anaemia, severe tubulopathy, and
diabetes mellitus. As the clinical characteristics resembled Pearson marrow
pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas
in this patient, we have performed DNA analysis to seek for deletions in mtDNA.
DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length,
with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle.
No deletion could be detected in mtDNA of leukocytes from her mother and young
brother, indicating the sporadic occurrence of this deletion. During culture,
skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a
selection against the deletion in proliferating cells. We estimate that per cell
division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in
situ hybridisation (FISH) and mitochondria-mediated transformation of rho(o)
cells we could show inter- as well as intracellular variation in the distribution
of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore,
we studied the mitochondrial translation capacity in cybrid cells containing
various proportions of deleted mtDNA. This result revealed a sharp threshold,
around 80%, in the proportion of deleted mtDNA, above which there was strong
depression of overall mitochondrial translation, and below which there was
complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic
loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.
PMID- 10780786
TI - Physicians' attitudes towards mammography and prophylactic surgery for hereditary
breast/ovarian cancer risk and subsequently published guidelines.
AB - After a BRCA mutation has been identified in the context of hereditary
breast/ovarian cancer (HBOC), mammographic screening and prophylactic surgery are
two of the main options available to those responsible for the clinical
management of healthy women. The aim of this study was to describe the attitudes
of specialists towards the clinical management of women with an HBOC risk: this
information was collected prior to the publication of the recent French
guidelines. A random national sample of 1169 French surgeons, gynaecologists and
obstetricians was surveyed using a mailed questionnaire, to which 700 of these
physicians (60%) responded. When dealing with a BRCA mutated woman, 88.6% of the
respondents said they would recommend mammographic screening, but only 27.1%
would recommend that it should be carried out annually from the age of 30 years
onwards, as recommended in the French guidelines; 10.9% would find it acceptable
to propose prophylactic mastectomy from the age of 30 years, and 22.9% would find
it acceptable to propose prophylactic oophorectomy from the age of 35 years. The
specialists who agreed with recommending breast/ovarian cancer genetic testing
also had more positive attitudes towards prophylactic mastectomy (adj OR = 3.4,
95% CI = 1.4-8.2), as did those who had previously recommended prophylactic
mastectomy when gene testing was not yet available (adj OR = 2.06, 95% CI = 1.23
3.44). The respondents' attitudes towards prophylactic oophorectomy and
mastectomy were significantly associated (adj OR = 3.9; 95% CI = 2.3-6.5).
Previous recommendation of prophylactic mastectomy was associated (P < 0.01) with
a higher level of knowledge of breast/ovarian cancer genetics and with medical
practice in this field. French physicians' attitudes towards mammographic
screening and prophylactic surgery were not in complete agreement with the
subsequently published French guidelines, the impact of which has now to be
considered. Constantly evolving knowledge about the efficacy of preventive
intervention will give practitioners new elements to integrate into their
counselling.
PMID- 10780787
TI - Mechanism of spreading of the highly related neurofibromatosis type 1 (NF1)
pseudogenes on chromosomes 2, 14 and 22.
AB - Neurofibromatosis type 1 (NF1) is a frequent hereditary disorder that involves
tissues derived from the embryonic neural crest. Besides the functional gene on
chromosome arm 17q, NF1-related sequences (pseudogenes) are present on a number
of chromosomes including 2, 12, 14, 15, 18, 21, and 22. We elucidated the
complete nucleotide sequence of the NF1 pseudogene on chromosome 22. Only the
middle part of the functional gene but not exons 21-27a, encoding the
functionally important GAP-related domain of the NF1 protein, is presented in
this pseudogene. In addition to the two known NF1 pseudogenes on chromosome 14 we
identified two novel variants. A phylogenetic tree was constructed, from which we
concluded that the NF1 pseudogenes on chromosomes 2, 14, and 22 are closely
related to each other. Clones containing one of these pseudogenes cross
hybridised with the other pseudogenes in this subset, but did not reveal any in
situ hybridisation with the functional NF1 gene or with NF1 pseudogenes on other
chromosomes. This suggests that their hybridisation specificity is mainly
determined by homologous sequences flanking the pseudogenes. Strong support for
this concept was obtained by sequence analysis of the flanking regions, which
revealed more than 95% homology. We hypothesise that during evolution this subset
of NF1 pseudogenes initially arose by duplication and transposition of the middle
part of the functional NF1 gene to chromosome 2. Subsequently, a much larger
fragment, including flanking sequences, was duplicated and gave rise to the
current NF1 pseudogene copies on chromosomes 14 and 22.
PMID- 10780788
TI - WBSCR14, a putative transcription factor gene deleted in Williams-Beuren
syndrome: complete characterisation of the human gene and the mouse ortholog.
AB - Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting several
systems caused by a heterozygous deletion in the chromosomal region 7q11.23. A
common interval that includes up to 17 genes reported so far is deleted in the
great majority of patients. Elastin haploinsufficiency is responsible for the
cardiovascular features, but the specific contribution of other deleted genes to
the WBS phenotype remains unknown. We have fully characterised a gene commonly
deleted in WBS, WBSCR14, previously reported in a truncated form as WS-bHLH. The
WBSCR14 cDNA encodes an 852amino acid protein with a basic helix-loop-helix
leucine-zipper motif (bHLHZip) and a bipartite nuclear localisation signal
(BNLS), suggesting a function as a transcription factor. WBSCR14 is expressed as
a 4.2kb transcript predominantly in adult liver and at late stages of foetal
development. The WBSCR14 locus encompasses 33 kb of genomic DNA with 17 exons.
Two intragenic polymorphic dinucleotide repeats have been identified and used to
verify hemizygosity in WBS patients. We have also cloned the mouse ortholog and
mapped its locus to mouse chromosome 5, in a region of conserved synteny with
human 7q11.23. Given that other bHLHZip proteins are dosage sensitive and based
on the putative function of WBSCR14 as a transcription factor, hemizygosity at
this locus could be involved in some features of WBS.
PMID- 10780789
TI - Examination of trisomy 13, 18 and 21 foetal tissues at different gestational ages
using FISH.
AB - In man high levels of aneuploidy are seen in spontaneous abortions. Very few
autosomal trisomies survive to birth, the three most common being those for
chromosome 13, 18 and 21 giving rise to the syndromes named Patau, Edwards and
Down respectively. Since the majority of these spontaneously abort, what makes
the survivors different from the aborters? Could it be that they have tissue
specific mosaicism with the additional normal cell line supporting survival? In
this study fluorescence in situ hybridisation was used as a convenient way to
detect trisomy in interphase cells. To study the level of mosaicism across
gestation, different tissues from 21 trisomic foetuses were analysed using probes
for chromosome 13, 18, 21, X and Y. Two trisomy 18 foetuses exhibited mosaicism.
Two others, one trisomy 13 and one trisomy 18 had mosaic placentas. There was no
clear association between the limited mosaicism seen and severity of the
phenotype. We conclude that at least for this sample set, tissue-specific
mosaicism was not likely to be responsible for potential survival to birth.
PMID- 10780790
TI - Prenatal detection of a 17p11.2 duplication resulting from a rare recombination
event and novel PCR-based strategy for molecular identification of Charcot-Marie
Tooth disease type 1A.
AB - Charcot-Marie-Tooth disease, type 1A (CMT1A) is caused in most cases by a 1.5 Mb
duplication on chromosome 17p11.2 arising after unequal crossing-over between
repeated sequences called CMT1A-REPs, flanking the 1.5 Mb unit. A 3.2 kb
recombination hot spot has been defined, resulting in a junction fragment between
EcoRI (distal CMT1A-REP) and SacI (proximal CMT1A-REP). This was further reduced
to a 1.7kb EcoRI-NsiI fragment, and recently to a 731 bp hot spot region within
this fragment. We describe the CMT1A-REPs-based PCR method used to identify CMT1A
duplications and report on a family case in which a 29-year-old pregnant woman
requested prenatal diagnosis for two successive pregnancies because her husband
was affected with CMT1A. Our method enabled us to characterise the duplication in
both foetuses and demonstrate that it arose from a rare recombination event
taking place outside the 1.7 kb region. Since our approach is simple and enables
the entire set of duplications occurring after recombination in the enlarged
3.2kb region including the hot spot to be detected, we suggest it might be
considered for use in primary screening for pre- and postnatal diagnosis of
CMT1A.
PMID- 10780791
TI - DNA arrays: methods and applications: report on HUGO Meeting, Tartu, Estonia, 23
26 May, 1999.
PMID- 10780792
TI - Air pollution and allergy.
AB - Epidemiological studies have found a recent increase in the prevalence of
allergic diseases, especially in industrialized countries. A change in
environmental factors may be considered as one of the causes of this increase. It
has been reported that the prevalence of allergic diseases is higher in polluted
areas than in unpolluted ones. Therefore, we focused on the effect of one air
pollutant, suspended particulate matter (SPM), on allergic responses. We showed
that SPM had an enhancing effect on the IgE antibody production in mice. In
Japan, the number of cars with diesel engines has increased rapidly, and it has
been calculated that 35-80% of SPM in large cities consists of diesel exhaust
particulates (DEP). We demonstrated that DEP had an adjuvant effect on the IgE
antibody production in mice when administered intraperitoneally or intranasally.
In humans, it has been shown that nasal challenge with DEP enhanced total IgE and
specific IgE production in nasal lavages. Furthermore, it has been demonstrated
that DEP had an enhancing effect on Th2-type cytokine synthesis in both mice and
humans. It cannot be excluded that DEP may be related to the increase in
prevalence of allergic diseases through the effect on the IgE antibody production
and Th2-cytokine synthesis.
PMID- 10780793
TI - Eosinophils are neither migrated nor activated in the skin lesions of atopic
dermatitis in infants.
AB - Eosinophils and eosinophil cationic protein (ECP) were examined in the skin
lesions of 10 infants with atopic dermatitis (aged 4 months to 7 years). In all
10 patients, neutrophils and eosinophils were rarely seen in these lesions.
Moreover, in the immunohistochemical study, ECP was scarcely detected in any of
them. Our results suggest that eosinophils are neither migrated nor activated in
the skin in atopic dermatitis in infants.
PMID- 10780794
TI - Effects of allergen immunotherapy on the nasal mucosa in patients with allergic
rhinitis.
AB - Despite the varied immunological changes occurring after allergen immunotherapy,
the precise mechanism, or the mechanisms responsible for clinical effectiveness
of allergen immunotherapy have not been clearly determined. Postulated
immunomodulatory mechanisms include a decrease in cellular responsiveness, a
production of blocking antibodies, a reduction in the number of mast cells, and
activation of T-cell suppressor mechanisms. Nineteen allergic rhinitis patients
(study group) with house dust mite sensitivity and 10 nonallergic control
subjects were studied. In the study group, the nasal mucosal biopsies were
obtained prior to immunotherapy and were repeated after 1 year, and specimens
were evaluated by light and electron microscopy. After the third month of
immunotherapy, nasal symptom scores were reduced significantly and disappeared in
the sixth month (p <0.01). No significant changes were observed in the levels of
immunoglobulins, IgG subclasses and complement levels (p <0.05), except IgG4/IgG1
ratio (p <0.05). A comparison of histopathological findings of nasal mucosa in
each case revealed an improvement in epithelial loss, inflammation, thickening of
basal membrane and fibrosis (p <0.05). A significant correlation was observed
between epithelial loss and mast cell accumulation with symptom score (p <0.001).
These results suggest that the improvement of nasal epithelial cells and
reduction of mast cell accumulation in nasal mucosa may be one of the mechanisms
that could explain the improvement of nasal allergy symptoms following
immunotherapy.
PMID- 10780795
TI - Double-blind study of cetirizine and loratadine versus placebo in patients with
allergic rhinitis.
AB - The aim of this double-blind study was to evaluate the effectiveness of
cetirizine and loratadine versus placebo in patients with allergic rhinitis. The
study included a total of 90 patients suffering from moderate to severe allergic
rhinitis as determined by a symptom score, with hypersensitivity to house mites
and with high IgE. The study lasted 7 weeks, including 1 for pretreatment, 4 for
treatment and 2 posttreatment (washout). During the study, each patient received
either one tablet of placebo, 10 mg of cetirizine or 10 mg of loratadine daily.
The evaluation was carried out by rhinomanometry to analyze the symptoms on days
1, 15, 29 and 43. The nasal cytology was analyzed on days 1 and 29. For
statistical analysis we used the Mantel-Haenszel method and chi-square test. We
found that antihistamines showed good effectiveness in improving the
symptomatology in patients with allergic rhinitis. The improvement by
rhinomanometry and by symptom score versus placebo was good. It was concluded
that both antihistamines were significantly superior to placebo and that
cetirizine performed better in comparison to loratadine versus placebo, although
not as statistically significant.
PMID- 10780796
TI - Immune complexes IgE/IgG in airborne allergy: increase during pollen season.
AB - In the present study we addressed the question of IgE/IgG immune complex serum
level in 92 patients with respiratory allergy in relation to their clinical
status. Twenty patients with allergy to insect stings and 22 healthy volunteers
were also investigated. IgE/IgG immune complexes and IgG anti-IgE antibodies were
estimated using double antibody solid-phase immunoassays in IgG serum fractions
isolated by protein A affinity chromatography or in fractions obtained by
Sephacryl S-300 gel filtration. Three people (14%) from the control group, two
patients (10%) with insect allergy and 41 patients (45%) from the group with
airborne allergy exhibited an increased serum level of IgE/IgG immune complexes
(chi2, p <0.05). IgG anti-IgE serum level was also significantly higher in the
examined group of patients with airborne allergy than in the control group. None
of the factors analyzed, including the kind of allergic disease, the type of
inhalant allergen (pollen or house dust antigens), the severity of allergy judged
from the frequency and intensity of symptoms for 1 year preceding blood sampling
and the symptoms exhibited during blood sampling, showed a statistically
significant relation to the level of IgE/IgG immune complexes or IgG anti-IgE,
when the whole group of patients with respiratory allergy was analyzed. A
distinct difference between patients investigated during and outside of the
pollen season was found in patients with isolated pollen allergy. The latter
exhibited an increase of IgE/IgG immune complexes (57% vs. 29%) significantly
more often, which indicates the possible involvement of IgE/IgG immune complexes
in the pathogenesis of pollen allergy.
PMID- 10780798
TI - Immunoblot analysis for laboratory diagnosis of ataxia-telangiectasia: use of
Epstein-Barr virus-transformed or phytohemagglutinin-stimulated lymphoblasts for
detection of ATM protein.
AB - Ataxia-telangiectasia (A-T) is a genetic disorder characterized by a progressive
ataxia, immunodeficiency, neurological abnormalities, hypersensitivity to
ionizing radiation, and predisposition to cancer. The gene responsible for A-T
(ATM) has been cloned and shown to code for a 350 kDa polypeptide containing
3,056 amino acid residues. Detection of ATM mutations for laboratory diagnosis of
A-T is laborious and not practical, unless there are common mutations in a
population. We describe here immunoblot analysis for the detection of ATM in
seven Japanese A-T patients from five families and in controls using ATM3BA
antibody. ATM protein was routinely and clearly detected in Epstein-Barr virus
(EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from
controls. However, it could not be detected consistently in unstimulated
peripheral blood mononuclear cells (PBMCs) from controls. We also detected ATM
protein in control fibroblasts, but the background was relatively higher than in
control lymphoblasts. ATM protein was not detected or dramatically decreased in
EBV-transformed lymphoblasts from all seven patients tested and in fibroblasts
from one patient. Immunoblot analysis using EBV-transformed or PHA-stimulated
lymphoblasts represents a useful approach for laboratory diagnosis for A-T. The
latter is especially preferable since it takes only 3 days to obtain sufficient
cells for analysis.
PMID- 10780799
TI - Schnitzler syndrome: a case study.
AB - Schnitzler syndrome is a clinical entity of unknown etiopathogenesis and is an
unusual cause of chronic urticaria. It is characterized by the presentation of a
monoclonal band, especially IgM, as well as fever, asthenia and arthralgia. We
present the case of a 48-year-old man with 5 years of recurrent urticarial
lesions, slight itching, as well as lip, face and occasional pharyngeal edema.
The patient had also suffered from fever and right hip and left knee arthralgia.
The protein electrophoresis and the immunoelectrophoresis presented an IgG band
and a slight lambda band, which is suggestive of a monoclonal gammopathy. The
bone marrow examination showed a slight increase in the lymphoplasmatic cells.
The marrow biopsy was negative. In order to rule out tumorous, infectious and
rheumatic processes as well as collagen diseases, other complementary
examinations were performed with negative results. The diagnosis of Schnitzler
syndrome as a cause of chronic urticaria requires a thorough study in order to
rule out other systemic processes provoking the same symptoms.
PMID- 10780797
TI - Latex allergy among operating room personnel in Turkey.
AB - This study was performed to evaluate the prevalence of latex allergy among health
care workers in Turkey, as well as to compare the medical histories with the skin
test results and investigate the risk factors. Using a 1/100 weight/volume
commercial skin prick test (SPT), we investigated latex sensitization in 206
health care workers who regularly use latex products. One hundred atopic and 100
nonatopic patients without occupational latex exposure were also examined as
control groups. Latex SPTs were positive in 10 health care workers (9.22%),
whereas none of the control patients was found to have positive SPT to latex.
Health care workers were divided into two groups based on the latex SPT results.
There was no significant difference between the latex SPT-positive and -negative
health care worker groups according to age, sex and total exposure time to latex.
In the latex SPT positive group, daily exposure time and daily glove use were
significantly higher (p <0.05). The symptoms related to latex products were
limited to hands and itching was present in all, however, erythema was found in
68.4%, and contact urticaria in 52.6% in the latex SPT positive group. These
symptoms in the latex SPT negative health care group were 21.4%, 14.4%, and 1.6%,
respectively (p <0.0001). History of allergic rhinitis, bronchial asthma and
conjunctivitis were also higher in the SPT-positive group (p <0.05).
Additionally, we found sensitivity to house dust mites and/or grass pollens in
seven cases of latex allergy. Patch tests with rubber additives were positive in
five out of 42 medical care workers. Two surgeons were found to have both type-I
hypersensitivity to latex and type-IV hypersensitivity to rubber additives. Our
results suggest that the frequency of latex allergy is higher in the atopic
health care workers with a high exposure to latex, and that SPT is a sensitive,
safe, cheap and easy method of testing the diagnosis of latex hypersensitivity.
PMID- 10780800
TI - Anaphylaxis to pine nuts and immunological cross-reactivity with pine pollen
proteins.
AB - Despite the wide use of pine nuts, the fruit of Pinus pinea, only a few reports
of allergic reactions to them have been published. We present herein a case of
food allergy to pine nuts in a patient who showed no clinical symptoms to pine
pollen despite the presence in her serum of specific IgE antibodies. In order to
verify whether the reaction against pine nuts was IgE mediated, specific IgE
against pine nuts and pollen were evaluated by skin-prick test, prick by prick
and RAST. Immunoblotting and immunoblotting-inhibition were used to evaluate the
allergenic components of both extracts and their cross-reactivity. Prick by prick
with fresh pine nuts and RAST with pine nut and pine pollen extracts showed that
the patient had high levels of specific IgE against both extracts. Immunoblotting
experiments showed the presence in serum of IgE antibodies against several
components in pine nuts and pollen. Immunoblotting-inhibition experiments
demonstrated the presence of some cross-reacting components. These data confirm
the existence of food allergy induced by pine nuts. This sensitization to pine
nuts developed with no symptoms of pine pollinosis. Development of pollinosis may
require a longer time of exposure to allergens. Based on the cross-reactivity
between pine nut and pine pollen extracts, cosensitization to these two allergens
could be possible.
PMID- 10780801
TI - Erythropoietic protoporphyria with antinuclear antibody positivity: avoiding
misdiagnosis of systemic lupus erythematosus.
AB - A young eunuchoid man was referred to our hospital with suspected erythropoietic
protoporphyria. Serum antinuclear antibody (ANA) was found to be positive
immediately after the porphyria attack and disappeared 30 days later. Many
authors have mentioned the coexistence of systemic lupus erythematosus (SLE) and
porphyria. As these two disorders have similar clinical features, the clinician
must be alert and use strict diagnostic criteria in determining the presence of
SLE with porphyria. In the past, elevation of ANA was reported in the cases of
acute intermittent porphyria. However, there have been no reports in the cases of
erythropoietic protoporphyria. In addition, the patient was found to have
hypogonadotropic hypogonadism consistent with Kallmann's syndrome. To our
knowledge, this report is the first case showing the coexistence of Kallmann's
syndrome and erythropoietic protoporphyria. As yet, the clinical importance of
this association remains unknown.
PMID- 10780802
TI - The effects of morphine on responding under variable-interval schedules: rate
related effects, behavioral mechanisms and Herrnstein's hyperbola.
AB - The study was designed to integrate rate-related principles and Herrnstein's
hyperbolic matching equation (1970) as they apply to drug effects. It was also
designed to assess the validity of an interpretation of Herrnstein's equation
used to account for the behavioral mechanisms of drug action. Eight rats were
trained to press a lever under a range of variable-interval (VI) schedules of
reinforcement using sucrose solution (0.1 M) as a reinforcer. After 90 baseline
sessions the effect of morphine sulfate, 3, 6, 12 and 17 mg/kg, on responding was
tested. Response rates were suppressed in a dose-dependent manner after morphine
administration. Herrnstein's equation, which states that responding is a function
of relative reinforcement rate, provided a good description of the relationship
between responding and reinforcement under most conditions. Therefore, the
traditional variable used to predict the drug effect in rate-dependency
functions, baseline response rate, was compared to a new variable, baseline
relative reinforcement rate. Relative reinforcement rate performed as well as
response rate in predicting the drug effect. In order to test if Herrnstein's
hyperbola can identify the behavioral mechanisms of the action of morphine, the
concentration of the sucrose solution was increased (0.32 M). The y-asymptote of
Herrnstein's equation, k, increased as sucrose concentration increased. This
calls into question one common interpretation of Herrnstein's equation used to
identify the behavioral mechanisms of drug action.
PMID- 10780803
TI - Effects of lithium dose (UCS) on the acquisition and extinction of a
discriminated morphine aversion: tests with morphine and delta9-THC.
AB - The effects of varying the lithium dose (unconditioned stimulus [UCS]; LiCl range
30-180 mg/kg) on the acquisition and extinction of stimulus control by 5.6 mg/kg
of morphine in a discriminated taste aversion (DTA) procedure were examined in
rats. In addition, pharmacological specificity was examined by substituting (-)
delta-9-tetrahydrocannabinol (delta9-THC) for morphine during a test phase
intervening between acquisition and extinction. DTA acquisition was more rapid at
higher LiCl doses. The lowest dose of LiCl, 30 mg/kg, did not robustly maintain a
DTA. Two groups treated with 60 mg/kg LiCl, differing only in the type of
drinking nozzle used (ball-bearing vs standard non-ball-bearing), behaved
similarly. Suppression of drinking was related to the morphine dose, in an
orderly manner (dose range 0.3-10 mg/kg), in rats for which morphine was followed
by LiCl. No significant decline in drinking occurred for rats for which morphine
was followed by saline, except perhaps at the 10 mg/kg test dose of morphine. The
control of drinking was pharmacologically specific; both experimental and control
animals were equally affected in tests with delta9-THC (0.3-10 mg/kg). Low doses
of delta9-THC increased water consumption; this did not occur with morphine.
During extinction the reinstitution of drinking was similar across groups that
had been effectively conditioned, i.e. there was no apparent effect of lithium
dose on extinction. After extinction, a much attenuated reaction occurred to
morphine in tests with 3 and 10 mg/kg. These doses of morphine had significantly
suppressed drinking before the extinction phase. Collectively, these data add to
the formal similarities between sensory and drug discriminative stimuli.
PMID- 10780804
TI - Behavioural effects of glutamate receptor agonists in morphine-dependent rats.
AB - Glutamate receptors are implicated in the development and expression of drug
dependence. Substantial experimental evidence suggests that antagonists acting at
the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors attenuate the
severity of opioid withdrawal. However, it is less clear whether opioid
withdrawal can be potentiated by agonists of glutamate receptors. The present
study evaluated the behavioural effects of various agonists of glutamate
receptors, as well as a nitric oxide (NO) donor, in morphine-dependent rats
trained to discriminate 0.1 mg/kg of naloxone from saline. None of the following
drugs produced appreciable levels of naloxone-like responding (substitution
tests) or potentiated the discriminative stimulus effects of naloxone: NMDA (3-56
mg/kg), glycine (100-1000 mg/kg), glutamate (1000-3000 mg/kg), kainate (0.3-3
mg/kg), isosorbide dinitrate (30-300 mg/kg). Nevertheless, expression of some
morphine withdrawal-like somatic and behavioural signs ('wet-dog'-like shaking,
scream on touch, ptosis, tremor, chewing, weight loss) was facilitated by NMDA,
glycine, and isosorbide dinitrate. These results suggest that, compared to
somatic symptoms, subjective effects of opioid withdrawal (as reflected by
discriminative stimulus effects) are not mimicked by direct activation of
glutamate receptors.
PMID- 10780805
TI - Sensitization to apomorphine in pigeons is due to conditioning, subject to
generalization but resistant to extinction.
AB - Apomorphine (Apo) administration induces a persistent bout of pecking in pigeons
and other birds. Repeated injections of Apo in pigeons lead to sensitization,
i.e. the pecking response to a particular dose increases up to a dose-dependent
asymptotic level. It is also known that Apo-induced pecking can be classically
conditioned to the cage environment where the animals experience the effect of
the drug. Here we address the question of whether, and to what extent, the
sensitization effect arises as a consequence of a conditioning or of a
pharmacological process. An extinction experiment demonstrated that an extinction
procedure supposed to be effective in inhibiting the conditioned pecking response
was not effective in suppressing the sensitization to Apo, thus casting
provisional doubt on the conditioning hypothesis. However, a conditioning
experiment demonstrated that the sensitization effect undoubtedly involved an
important component of conditioning to an experimental cage environment, but also
suggested that there was an additional component possibly not due to learning. A
generalization experiment, however, showed that this second component was very
probably due to a stimulus generalization effect deriving from conditioning to
the home cage, suggesting that learning can account for most, if not all, of the
increase in Apo-induced pecking and that an exclusively pharmacological
sensitization process plays, at best, a minor role. The apparent contrast between
the results of the first experiment, indicating that the sensitization is not
affected by inhibitory conditioning, and the results of the last two experiments,
suggesting that the sensitization is due to excitatory conditioning, can be
resolved by assuming that Apo induces a drug-state-dependent conditioning. These
results are related to findings and arguments concerning the sensitization to
psychostimulant drugs in mammals.
PMID- 10780806
TI - Prenatal protein restriction increases sensitization to cocaine-induced
stereotypy.
AB - The present study characterized the total amount of stereotyped behavior
following acute and repeated administration of cocaine in male and female
prenatally protein malnourished rats. Adult offspring of female Sprague-Dawley
rats fed either a low (6% casein) or adequate (25% casein) protein diet 5 weeks
prior to mating and throughout their pregnancy were studied. Once every 3 days
(for a total of six injections), half the rats from each nutritional treatment
group (repeated exposure) were injected with cocaine (30 mg/kg, i.p.) and their
total amount of stereotypy (rearing, forepaw treading, compulsive sniffing and
head bobbing) monitored. The remaining rats received five saline injections
followed by a cocaine injection on the last injection day (acute exposure group)
and their behavioral response was also measured. Despite being slightly less
sensitive to cocaine following their first injection, by the sixth injection,
prenatally protein malnourished animals in the repeated-exposure group exhibited
significantly greater sensitization to the psychomotor stimulant effects of
cocaine than well-nourished controls. In the acute exposure groups, however,
prenatally malnourished males, but not females, exhibited significantly more
stereotypy than well-nourished subjects following a single cocaine injection.
These findings have implications for characterizing addiction potential in the
previously malnourished rats, as well as providing additional information
regarding factors which can influence sensitization.
PMID- 10780807
TI - Effects of training history on drug discrimination under concurrent fixed
interval schedules.
AB - Pigeons with previous pentobarbital-discrimination training under concurrent VI
60 VI 240 and concurrent FI 60 FI 240 schedules were trained to respond under a
concurrent FI 15 FI 285 schedule of food presentation. A second group of pigeons
was trained only under the concurrent FI 15 FI 285 schedule. When responding
stabilized during training sessions, both groups made 75-85% of their responses
on the key where responses produced the reinforcer under the FI 15 component of
the concurrent schedule. When the schedule was changed to concurrent FI 150 FI
150, the presence or absence of pentobarbital continued to control responding for
the group with the extensive training history, but responding by the other group
was rapidly controlled by the new reinforcement schedule. These data suggest that
the behavioral history of the subject can be an important determinant of stimulus
control by drugs. Despite these effects of training history on drug
discrimination responding, during the first minute of the session, the dose
response curves for pentobarbital, chlordiazepoxide, ethanol, phencyclidine and
methamphetamine were similar in both groups of pigeons.
PMID- 10780808
TI - Naltrexone does not attenuate the acute behavioral effects of ethanol or
pentobarbital in humans.
AB - The aim of the present study was to determine whether naltrexone, an opioid
antagonist, attenuates the acute subject-rated, performance-impairing and
physiological effects of ethanol or pentobarbital. To accomplish this aim, two
separate experiments were conducted. In Experiment 1, eight volunteers (one
female, seven males) received ethanol (0, 0.5 and 1.0 g/kg) alone and in
combination with naltrexone (0, 50 and 100 mg). In Experiment 2, eight different
volunteers (five females, three males) received pentobarbital (0, 150 and 300
mg), alone and in combination with naltrexone (0, 50 and 100 mg). Subjects
received one of the nine possible drug-naltrexone combinations under double-blind
conditions during each of nine experimental sessions. Order of drug
administration was mixed, and at least 48 h separated all sessions. In Experiment
1, subjects orally ingested ethanol 1 h after naltrexone. In Experiment 2,
subjects ingested naltrexone 1 h after pentobarbital. The timing of drug
administration was arranged so that the peak behavioral effects of ethanol or
pentobarbital occurred so that across peak plasma levels of naltrexone. Drug
effects were assessed before drug administration and periodically afterwards for
5 h using a battery of subject-rated drug-effect questionnaires and performance
measures previously shown to be sensitive to the acute effects of ethanol.
Ethanol and pentobarbital produced prototypical subject-rated drug effects (e.g.
increased subject ratings of Drunk, Drug Liking, Elated and Good Effects) and
impaired performance. Naltrexone did not produce significant effects on these
measures. In other words, naltrexone did not attenuate the acute subject-rated
and performance-impairing effects of ethanol or pentobarbital. The mechanism by
which naltrexone exerts its clinical effect in the treatment of alcohol
abuse/dependence remains unclear.
PMID- 10780809
TI - Evaluation of limited and unlimited food intake during withdrawal in triazolam
dependent baboons.
AB - Chronic administration of benzodiazepine (BZ) agonists in baboons typically
increases food intake, in a dose-dependent manner, during drug administration and
suppresses food intake after termination of drug dosing. To determine if
suppressed food intake after termination of chronic BZ administration (i.e.
withdrawal) was related to increased food consumption during drug administration,
the effects of chronic triazolam (1.0 mg/kg/day, intragastrically, for 30-34
days) and subsequent triazolam withdrawal on food intake was studied under two
conditions in each of four baboons: (1) when the number of pellets was unlimited;
and (2) when the number of pellets was limited so that pellet intake could not
increase above the mean number of pellets per day obtained during a preceding
vehicle condition. Pellets were available during daily 20-h sessions under a
fixed-ratio 10 schedule of reinforcement. All baboons completed both pellet
conditions, and the order of exposure was counterbalanced across subjects. During
the unlimited pellet condition, pellets per day were increased during triazolam
administration and then were suppressed in a time-limited manner when triazolam
was discontinued in all four baboons. When pellet intake was limited during
triazolam administration, pellet intake after triazolam discontinuation was
suppressed in three of four baboons, and the magnitude and duration of
suppression was generally less than during the unlimited pellet condition. Other
behavioral signs of withdrawal (e.g., tremor/jerk, vomit/retch) were observed in
all four baboons under both pellet conditions. These data suggest that the
hyperphagic effects of triazolam appear to contribute to the subsequent
suppression of food intake during triazolam withdrawal. However, these
hyperphagic effects do not account for the entire phenomenon of suppressed food
intake during BZ withdrawal.
PMID- 10780810
TI - Spatial learning deficit after NMDA receptor blockade and state-dependency.
AB - The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine
(MK-801) (0.08 and 0.12 mg/kg, i.p.) was used to examine whether spatial memory
is learned state-dependently. Rats pre-treated with drug or saline were trained
for 9 days in an eight-arm radial maze, in which four arms were baited. On the
tenth day MK-801-treated rats were injected with saline and one group of saline
treated rats were injected with MK-801 (0.12 mg/kg) while another received
saline. Performance of spatial memory was analysed for state-dependency. Neither
rats treated with 0.08 mg/kg nor 0.12 mg/kg of MK-801 for 9 days were impaired in
recall of spatial memory under saline. However, MK-801 impaired acquisition of
spatial memory, with deficits in working memory and less marked deficits in
reference memory. Motor activity (speed) was enhanced at both doses. Thus,
learning under NMDA receptor blockade does not necessarily produce a condition
that impedes the expression of the learning task under a different condition.
PMID- 10780812
TI - The effects of feeding and housing on the behaviour of the laboratory rabbit.
AB - The effects of housing, feeding time and diet composition on the behaviour of the
laboratory rabbit were examined. The animals were caged individually in single or
double metal cages with perforated metal floors, metal walls, and bars in the
front, or kept as a group in floor pens. The light/dark cycle was 12/12 h with
light from 04:00 to 16:00 h and 30 min twilight. One experiment compared feeding
equal energy levels of a high energy diet (10.1 MJ/kg) and with a low energy diet
(7.0 MJ/kg) at 08:00 h. The second experiment compared feeding the high energy
diet at 08:00 h and at 14:00 h. In both studies the behaviour of the rabbits was
recorded between 08:00 and 14:00 h and between 16:00 and 22:00 h. Feeding the
animals at 14:00 h reduced abnormal behaviour during the dark period compared to
feeding at 08:00 h, whereas no difference in behaviour could be detected between
feeding a high-energy and a low-energy diet at 08:00 h. Animals in floor pens
generally showed less abnormal behaviour than caged animals. The results indicate
that the welfare for caged rabbits can be improved by feeding the animals in the
afternoon rather than in the morning.
PMID- 10780811
TI - SR 141716A, a CB1 cannabinoid receptor antagonist, potentiates the locomotor
stimulant effects of amphetamine and apomorphine.
AB - The intraperitoneal (i.p.) injection of apomorphine or d-amphetamine
significantly increased locomotor activity in Sprague-Dawley rats. Prior
administration of the cannabinoid receptor antagonist, SR 141716A, significantly
enhanced the stimulant effect of both d-amphetamine and apomorphine in a dose
dependent manner. Administration of SR 141716A alone had no effect on locomotor
activity. These data indicate that endogenous cannabinoids exert an inhibitory
action on the increase in locomotor activity produced by amphetamine and
apomorphine.
PMID- 10780813
TI - Aspen wood-wool is preferred as a resting place, but does not affect intracage
fighting of male BALB/c and C57BL/6J mice.
AB - Aspen wood-wool, provided as nesting material, was evaluated as a possible
improvement of cage environment for 10-14-week-old inbred male mice maintained in
groups of six (BALB/c n = 72 and C57BL/6J n = 36). The daily behaviour of mice
was video recorded and their body weight, food consumption, weights of some
organs and serum corticosterone concentrations were measured. Aggressive
interactions between cage mates and against a strange intruder as well as the
number of wounds on the back of the animals was monitored in order to evaluate
the effect of nesting material on intermale aggression. Nesting material did not
affect the daily active/passive behaviour patterns of mice, although animals
clearly preferred it as a resting place. BALB/c mice given nesting material
showed less weight gain and smaller brown adipose tissue weights than animals
without nesting material. The other characteristics measured were not affected by
the presence of nesting material in either strain. The presence of nesting
material had no effect on fighting in cages. C57BL/6J mice were more aggressive
than BALB/c mice according to the number of wounded animals in a cage. Wounded
BALB/c mice had enlarged spleens and decreased epididymal adipose tissue weights.
In conclusion, the nesting material used in this study did not adversely affect
the animals. On the other hand, the material was clearly preferred to
conventional bedding as a resting place. These findings suggest that nesting
material may improve the cage environment of laboratory mice. Furthermore, there
was an indication of strain differences in aggressive behaviour. It could be
suggested that C57BL/6J mice are less tolerant towards intruders and housing six
mice per cage is not suitable for this strain.
PMID- 10780814
TI - Nesting material and number of females per cage: effects on mouse productivity in
BALB/c, C57BL/6J, DBA/2 and NIH/S mice.
AB - Two different materials-aspen wood-wool and paper towel-were compared as nesting
material for three inbred mouse strains (BALB/c, C57BL/6J and DBA/2) housed in
barrier conditions. In addition, the effect of varying the number of females per
cage (one to three per cage) of these three strains and with NIH/S outbred mouse
stock was studied. The number of litters, litter size and neonatal mortality were
determined, as well as age, sex and weight of weanlings. The type of nesting
material did not affect the characteristics monitored. In all strains, the number
of weanlings per female was greatest in singly-housed females. In terms of the
number of weanlings per cage, two females per cage gave the best result. In DBA/2
mice, neonatal mortality increased when several females were caged together.
PMID- 10780815
TI - Non-surgical catheterization of the jugular vein in young pigs.
AB - Current methods utilized for serial blood collection in the young pig are limited
due to the stress and/or discomfort to which the pig is exposed. Thus, we have
developed a non-surgical, minimally invasive cannulation technique which allows
jugular vein catheter placement in the young pig without causing extended
discomfort or stress. The procedure described is rapid (approximately 8 min/pig)
and relatively simple, requiring only minimal anaesthesia for immobilization of
the pig during the procedure. Routinely, 2-week-old piglets are standing in their
pens within 15-20 min from initiation of the procedure. Piglets recover rapidly
from the procedure and display no clinical indications of pain or discomfort.
Serum concentrations of cortisol, a standard indicator of stress and/or
discomfort, are asymptomatic within 2 h of completing the procedure (k = 26.14+/
3.03 ng/ml). Stress is limited to the initial immobilization of the piglets. With
this technique of cannulation, we routinely maintain catheter patency for 2 days,
and often for as long as 5 days.
PMID- 10780816
TI - A new porcine model of reperfusion injury after lung transplantation.
AB - Rodent models have been described to investigate lung preservation and
reperfusion injury but have significant disadvantages. In large animals single
lung transplant studies are probably optimal but problems remain over the ability
to rigorously separate the lungs for assessment while promoting medium to long
term animal survival for meaningful investigation. Our aim was to develop a novel
and refined large animal model to assess reperfusion injury in the transplanted
lung, overcoming the difficulties associated with existing models. Specifically,
small animal models of lung transplantation usually have short perfusion times
(often one hour) and include extracorporeal circuits while larger animal models
often require the contralateral lung to be excluded after transplantation-an
unphysiological situation under which to evaluate the graft. A porcine model of
left lung allotransplantation was developed in which native and donor lungs are
individually ventilated. Sampling catheters placed within the graft lung allowed
specimen withdrawal without mixing of blood from the contralateral lung after
reimplantation. The model permits a variety of clinical scenarios to be simulated
with the native lung supporting the animal irrespective of function in the graft.
This model has been used in over 60 transplant procedures with a postoperative
survival time of 12 h being readily achieved. The mean operating time was 2.6 h.
The mortality rate is 4% in our series. We have found the model to be reliable,
reproducible and flexible. We propose this model as an adaptable investigation
for evaluating lung reperfusion injury and preservation.
PMID- 10780817
TI - Bacterial counts in canine duodenal fluid after exposure to saline, sodium
bicarbonate and hypertonic dextrose solutions used to maintain patency of
chronically implanted catheters.
AB - Flushing of intestinal vascular access ports (VAPs) is commonly performed to
prevent the problems of blockage and infection, and in this study four different
flushing solutions were compared. The growth of bacteria from canine duodenal
contents was compared in: 0.9% saline, 50% dextrose, 8.4% sodium bicarbonate
(NaHCO3) and 0.01 M phosphate buffered saline (PBS). Duodenal contents from three
laboratory beagles were serially diluted in these four solutions, spread plated
onto agar at 24 h periods for 7 days and bacterial counts were performed.
Immediately after the duodenal juices were added, no significant differences
could be seen in bacterial counts with any of the solutions. Over the 7 day
period, bacterial numbers greatly increased in saline and phosphate buffered
saline, but greatly decreased in dextrose and sodium bicarbonate solutions.
Dextrose and sodium bicarbonate appeared to be the most promising flushing
solutions tested to minimize infections of associated intestinal VAPs.
PMID- 10780818
TI - The telomerase activities in several organs and strains of rats with ageing.
AB - Telomerase activity is known to be implicated both in cell immortalization and
carcinogenesis. Telomerase activity has not been detected in most human somatic
tissues. However, we previously confirmed that the activity is present both in
methylazoxymethanol acetate-induced rat colonic adenocarcinoma and non-treated
colonic mucosa, presumably indicating the tissue-specific activity of the enzyme
in rats. To determine the standard activity of rat telomerase in various organs
in relation to differences in sex, age and strain, we examined the activity by
using the telomeric repeat amplification protocol (TRAP) assay. The testis,
liver, and colon mucosa showed the activity. The brain had very low or negative
activity in 5-week-old male rats of the F344, SD, Wistar, Donryu or ACI strains.
Age (5-week-old and 9-month-old) or sex difference for the activity was not
apparent in rats of these strains. In general, telomerase activity in the fetal
brain, liver and kidney was stronger than in the adult organ. The telomerase
activity of each organ was different from that of human. This difference may
indicate that the rat has a specific mechanism for maintaining the telomeric
repeats of the chromosome even in somatic tissues. The basic information
resulting from this study may be useful for the study of the role of telomerase
in tumorigenesis in animal experiment models.
PMID- 10780819
TI - Is carbon dioxide (CO2) a useful short acting anaesthetic for small laboratory
animals?
AB - The anaesthetic effect of carbon dioxide (CO2) was investigated under
predetermined exposure times in rats, mice and guinea pigs with admixture of 20%
of oxygen (O2), and with 20% of ambient air in rats. In rats first symptoms
(median) were detectable between 7 and 9.5 s, the induction time (median) varied
between 16 and 20.5 s and the surgical tolerance (median) was 40 s (after 60 s of
exposure) and 53.5 s (after 120 s of exposure) to 80% CO2/20% O2. When O2 was
replaced by ambient air, a surgical tolerance of 53.5 s (after 60 s of exposure)
and 77 s (after 120 s of exposure) was measured. In mice the induction time to
80% CO2/20% O2 was 10 s and the surgical tolerance 19.5 s (after 120 s of
exposure). Guinea pigs showed an induction period of 20 s and a surgical
tolerance of 50 s (after 30 s of exposure) to 80% CO2/O2. Recovery was short and
smooth in all species. This method of general anaesthesia seems to be suitable
for short and painful interventions, mainly in rats, but also in guinea pigs.
PMID- 10780820
TI - Short duration anaesthesia with medetomidine and ketamine in cynomolgus monkeys.
AB - Cynomolgus monkeys were anaesthetized with either intramuscular ketamine (10
mg/kg or intramuscular ketamine 2 mg/kg and medetomidine 50 microg/kg. Various
physiological measurements were made once the animals were safe to handle and
again 10 min later. Cardiovascular and respiratory function were well maintained
with both regimens but the heart rate was lower and arterial-alveolar carbon
dioxide gradient was higher in the animals that received medetomidine. In those
animals that received medetomidine, atipamezole was given to reverse the
medetomidine but there was no difference in recovery times between the two
regimens. Anaesthesia was not entirely reliable with medetomidine/ketamine and we
recommend caution when using this mixture.
PMID- 10780821
TI - Use of oral buprenorphine ('buprenorphine jello') for postoperative analgesia in
rats--a clinical trial.
AB - Buprenorphine (0.1, 0.2, 0.3 or 0.4 mg/kg) in a flavoured gelatin base was
administered preoperatively to rats undergoing a flank laparotomy. A control
group of animals underwent surgery and received only flavoured gelatin. Body
weight loss was significantly greater in the group which received no analgesia
than in any of the analgesic-treated groups (P < 0.01). Food consumption was
reduced significantly in all groups except in those animals which received 0.3
mg/kg buprenorphine. Water consumption was significantly reduced in the control
(no analgesia) group (P < 0.001), but was not significantly depressed in the
analgesic-treated groups (P > 0.05). Between-group comparisons did not show any
significant difference between the different dose rates of analgesia used on
either the change in body weight or the reduction in food or water consumption.
The results of this study support the use of buprenorphine jelly for post
surgical analgesia in rats. This route of delivery is easy to use, and causes a
minimum of stress to the rats.
PMID- 10780822
TI - The VX2 carcinoma in the rabbit auricle as an experimental model for intra
arterial embolization of head and neck squamous cell carcinoma with dextran
microspheres.
AB - A head and neck cancer model is developed using the VX2 carcinoma cell line
injected s.c. in both ears of New Zealand White (NZW) rabbits. The study is
focused on the effects of intraarterial embolization of the carcinomas with a new
type of dextran hydrogel microspheres. During the phase of exponential growth the
tumour-surface doubling-time was 7.1+/-2.0 days. Standard deviation in growth of
the tumours was significantly larger between separate animals than between
tumours growing in the left and right auricle of each individual animal (2.0
versus 0.65 days). A fresh cell suspension containing at least 10 x 10(6) vital
tumour cells was necessary to yield a tumour-take of 85%. The caudal auricular
artery perfuses the caudal half of the external ear and is very suitable for
macroscopic cannulation. Histological evaluation shows, that the use of dextran
hydrogel microspheres of at least 25 microm in combination with ligation of non
tumour perfusing branches of the central auricular artery yields diffuse
embolization of the VX2 carcinoma. This tumour model can be of use in further
studies to optimize particle size and dosage for embolization as well as to
evaluate the effect of different anti-neoplastic drugs, slowly released by
controlled degradation of dextran microspheres.
PMID- 10780823
TI - Adaptation of corticosterone-but not beta-endorphin-secretion to repeated blood
sampling in rats.
AB - Effects of short-term repeated blood sampling on the secretion of corticosterone
(CORT) and beta-endorphin (beta-END) were evaluated in male Wistar rats. Blood
was drawn from the tail vein of conscious rats four times within 2 h both at the
peak and trough period of the diurnal corticosterone secretion cycle. All rats
were well accustomed to the procedure. The main findings were: (1) At both
sampling intervals, CORT increased significantly in response to the first
sampling and declined to baseline values in successive samples. (2) beta-END also
increased significantly in response to the first sampling but remained elevated
in successive samples. (3) Intensities of initial CORT and beta-END responses
correlated positively with each other and with the baseline beta-END values.
Feedback inhibition of CORT secretion with sustained elevation of beta-END titres
suggests a moderate stress intensity of the repeated blood sampling procedures.
In general, due to lack of short-term feedback inhibition, beta-END seems to
reflect the effects of repeated administration of moderate intense stressors more
closely than CORT.
PMID- 10780824
TI - Tribromoethanol (Avertin) as an anaesthetic in mice.
PMID- 10780825
TI - Chronobiotic effects of gepirone, a potential antidepressant with 5HT1A receptor
partial agonist properties.
AB - Abnormal timing in the circadian system is reported in endogenous depression.
Gepirone, a 5HT1A receptor partial agonist, has anxiolytic and antidepressant
properties. We determined whether gepirone was able to modify the functioning of
the circadian system. Single i.p. injections of gepirone in hamsters induced
phase-advances in the circadian activity rhythm when administered during the
subjective day, but had no effect when given during the subjective night. Single
i.p. gepirone injections also blocked the phase-shifting effects of a light
pulse, at a time when gepirone by itself had no effect on the activity rhythm.
Chronic gepirone treatment in hamsters kept under a 14/10 light-dark cycle
induced a phase-advance in the activity rhythm, modifying the phase-relationship
between this rhythm and the light-dark cycle. After transfer to constant
darkness, gepirone-treated hamsters showed a shortened free-running period of
activity, compared to controls. Both acute and chronic gepirone treatment thus
have major effects on the circadian rhythm of locomotor activity in rodents. In
view of the hypothesized role for disturbed circadian rhythms in the
pathophysiology of depression, and the use of 5HT-related drugs for its
treatment, the results provide further support for the possibility that some of
the therapeutic effects of these compounds may be due to their effects on
temporal organization.
PMID- 10780826
TI - Effects of GABA-transporter (GAT) inhibitors on rat behaviour in open-field and
elevated plus-maze.
AB - The behavioural consequences of inhibition of gamma-aminobutyric acid (GABA)
uptake were studied. Two GABA uptake inhibitors, tiagabine and SKF 89976-A, were
administered to rats, and behaviour was analysed 30 min later in a standard open
field, an enriched open field, and an elevated plus-maze. Eight groups of animals
received either saline (0.9%), tiagabine, or SKF 89976-A. At a dose of 18.5
mg/kg, tiagabine, an established antiseizure drug, impaired motor coordination,
enhanced exploratory activity and reduced anxiety related behaviour. SKF 89976-A
exhibited minimal effects over the dose range tested. These results indicate that
inhibition of GABA uptake might be a pharmacological strategy to treat not only
epilepsy, but also anxiety disorders.
PMID- 10780827
TI - Isolation rearing-induced disruption of prepulse inhibition: further evidence for
fragility of the response.
AB - The present study investigated isolation-induced disruptions of prepulse
inhibition (PPI), and effects on locomotor activity as a function of home caging
condition (sawdust vs grid-floor) in the Wistar rat. Isolates reared in grid
floor cages did not show a disruption of PPI. However, when isolates were reared
in sawdust cages, a PPI deficit was evident. In an open field environment,
isolates demonstrated significantly increased spontaneous locomotor activity
compared to their group-housed counterparts, irrespective of the caging condition
employed. Grouped animals reared in grid-floor cages, however, showed reduced
activity compared to grouped animals reared in sawdust cages. Although d
amphetamine treatment appeared to enhance locomotor activity selectively in
isolates, particularly in those reared in grid-floor cages, this result could be
explained by the existing pre-drug activity levels. With respect to PPI, not only
were isolation-induced deficits in the Wistar rat difficult to detect in a
variable prepulse intensity PPI procedure, but when apparent, the deficits were
of a fragile nature. The findings suggest that caging condition may be a critical
methodological factor in experiments investigating isolation-induced PPI
deficits. Indeed, our results may indicate that rearing animals in grid-floor
cages represents a form of chronic mild stress, which can interfere with normal
sensorimotor gating mechanisms, in addition to other behaviours.
PMID- 10780828
TI - Alcohol and the appetizer effect.
AB - In order to evaluate the effects of alcohol on appetite, 12 unrestrained and 10
restrained men ate lunch 20 min after consuming preloads consisting of water, an
alcoholic fruit juice (alcohol) and a non-alcoholic fruit juice (juice). The
unrestrained men ate significantly less after the juice preload, and ate most
after alcohol. Intake was not altered significantly in the restrained men.
However, both the alcohol and juice preloads reduced rated hunger and increased
fullness, relative to the water control, in both restrained and unrestrained men.
When the relationship between rated appetite and intake within the test meal was
modelled mathematically, it was found that hunger increased more during the
initial stages of the test meal in the unrestrained men who had consumed alcohol
than in any other condition. No such effects were seen in the restrained
subjects. Overall, these results suggest that alcohol has a complex action on
appetite, which includes some form of appetite stimulation, and this may explain
the excess energy intake reported previously in moderate alcohol consumers.
PMID- 10780829
TI - The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of
Parkinson's disease: a detailed behavioural analysis of the therapeutic and
undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.
AB - The goal of this study was to evaluate the validity of the pretreated,
unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD).
For that purpose, a detailed ethogram was developed and assessed in four male
rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery
contralateral to the dominant limb. Subsequently, the behavioural effects of the
dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were
studied. The ethogram was found to allow a clear-cut and objective separation of
drug-induced behaviours into therapeutic and undesired effects in the MPTP
treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal
directed fore-limb movements, and distinct types of ipsilaterally directed
rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as
body displacement, contralateral fore-limb movements and contralateral rotational
behaviours, assessment of the new detailed ethogram revealed that this increase
was completely due to the activation of abnormal, non-goal-directed behaviours,
such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new
ethogram made clear that the drug treatments induced not only dyskinesia and
dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In
summary, the detailed behavioural analysis showed that this model does not
adequately predict the clinical effects of the D2 agonist. It is concluded that
the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict
the therapeutic and undesired effects of dopaminergic drugs in humans.
PMID- 10780830
TI - The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a
model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.
AB - The aim of this study was twofold: (1) to study the predictive validity of the
drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's
disease (PD), and (2) to investigate the therapeutic and undesired effects of the
D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA
pretreated monkeys. A detailed ethogram was used, allowing the separation of
therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP
administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L
DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered
intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA
group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4,
pretreated). All drug treatments increased the parameters used classically to
evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia.
However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had
therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF
82958, but not L-DOPA, induced additional undesired effects; including epileptoid
behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA
unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as
undesired effects. Although the effects of SKF 82958 on fore-limb movements,
rotational behaviours and body displacement were comparable in the naive and
pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA
pretreated group from day one. It is concluded that the bilaterally MPTP-treated
monkey is an animal model with predictive validity for PD: it adequately predicts
the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is
concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD,
because it did not induce therapeutic effects, but instead elicited several
undesired effects.
PMID- 10780831
TI - RU-24969 disrupts d-amphetamine self-administration and responding for
conditioned reward via stimulation of 5-HT1B receptors.
AB - Behavioural and neurochemical evidence indicates a facilitatory effect of 5
hydroxytryptamine (5-HT), acting via 5-HT1B receptors, on dopamine (DA) systems.
To explore this interaction further, these experiments examined the effects of
the 5-HT1A/1B agonist RU-24969 on behaviours known to involve the mesolimbic DA
system. These behaviours were locomotor activity, intravenous self-administration
of d-amphetamine, responding for a conditioned reward (CR), and the response
potentiating effects of amphetamine on CR responding. Locomotor activity was
enhanced by 1 and 3 mg/kg RU 24969, and both doses also reduced responding for d
amphetamine (60 microg/kg/infusion). Changing the unit dose produced a
characteristic U-shaped dose-response curve. This dose-response relationship was
not apparent following injection of RU-24969. Across all unit infusion doses of
amphetamine, the level of responding was fairly constant. In the CR experiments,
rats responded for a conditioned stimulus that was previously paired with water.
RU-24969 completely disrupted responding for CR, and also abolished CR responding
in rats injected with 3 microg d-amphetamine in the nucleus accumbens. RU-24969
also markedly suppressed responding for water. The suppressant actions of RU
24969 on amphetamine self-administration and CR responding involve stimulation of
5-HT1B receptors, since they were reversed by the 5-HT1B/1D antagonist GR 127935
(3 mg/kg), but not by the 5-HT1A antagonist WAY-100635 (1 mg/kg). None of the
behavioural effects of RU-24969 are consistent with a selective action to enhance
mesolimbic DA function. Rather, global activation of 5-HT1B receptors appear to
exert a general disruptive effect on operant responding.
PMID- 10780832
TI - Disruption of the discriminative stimulus effects of S(+)-3,4
methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by
fluoxetine.
AB - This study utilized drug discrimination procedures to assess the functional
consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin
depletion, and to determine whether concomitant injections of fluoxetine averted
these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)
MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant
procedure. After dose generalization tests were completed, training was
suspended, and subjects were administered saline injections twice daily for four
days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline,
to ascertain that discriminative stimulus control was maintained in the absence
of training over a two-week period. All subjects received two additional weeks of
training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily
for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline
(SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were
conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections,
S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA
generalization tests, and rose from 2.78% to 22.14% during SAL generalization
tests. This disruption did not occur, however, in rats administered the
combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished
discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated
rats. Postmortem neurochemical assays indicated that 5-HT levels were
significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL,
compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5
HIAA levels were significantly lower in the prefrontal cortices of both (+/-)
MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control.
These results support previous findings that fluoxetine protects against (+/-)
MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug
discrimination is a sensitive assay in which to examine behavioral correlates of
(+/-)-MDMA-induced serotonergic deficits, and the protection against these
deficits by fluoxetine.
PMID- 10780833
TI - A comparison of two behavioral measures of psychomotor activation following
intravenous amphetamine or cocaine: dose- and sensitization-dependent changes.
AB - This paper presents data concerning the dose-effect relationships of
intravenously administered amphetamine and cocaine on two widely used measures of
psychomotor activation: locomotor crossover activity in neurologically intact
rats, and rotational behavior in rats with a unilateral 6-hydroxydopamine lesion.
There were marked differences in dose-effect relationships, both as a function of
drug and of behavioral measure. Amphetamine produced a linear increase in
rotational behavior over a wide range of doses (the highest effective dose was
76.8 times the lowest), but a linear increase in locomotor crossover activity
over only a narrow dose range (the highest effective dose was only four times the
lowest). In contrast, for cocaine, the dose-effect relationships for the two
behaviors were very similar, but for both behaviors the effective dose range was
quite narrow, the highest effective dose being only between two and four times
the lowest. The data highlight the advantages and disadvantages of these measures
as indices of the psychomotor activating effects of psychostimulant drugs.
PMID- 10780834
TI - Effect of nitric oxide synthesis inhibition on c-Fos expression in hippocampus
and cerebral cortex following two forms of learning in rats: an
immunohistochemistry study.
AB - This study investigated the effect of NO on c-Fos expression using
immunocytochemical techniques, following training in the one-trial passive
avoidance response and Morris water maze tasks. Fos-like immunoreactive (FLI)
neurons were examined in the hippocampus and cerebral cortex of rats in which
intracerebroventricular (i.c.v.) injection of Nomega-nitro-L-arginine (NAME) was
given 30 min before training in the experimental groups. The results showed that:
(1) when compared with untreated rats or rats receiving i.c.v. saline injection,
fos-like immunoreactive neurons were significantly increased in both brain
regions following training in either task, and (2) preceding i.c.v. injections of
NAME blocked both the formation of memory and the increased expression of c-Fos
in both brain regions subjected to training on the two models. These results
suggest that NO production may be a critical factor for the formation of memory
and the enhanced c-Fos expression, and so might contribute to the long-term
plasticity of synaptic organization in the two brain regions.
PMID- 10780835
TI - Intrahippocampal infusion of an inhibitor of protein kinase A separates short-
from long-term memory.
AB - Rats implanted bilaterally with cannulae in the CA1 region of the dorsal
hippocampus were trained in one-trial step-down inhibitory (passive) avoidance,
and tested for short- and long-term memory of this task at 1.5-3.0 and at 24 h
from training, respectively. At various times after training (0, 22, 45, 90, 135
or 175 min) they received a 0.5 microl infusion of the protein kinase A (PKA)
inhibitor, KT5720 (0.1 or 0.5 microg), or of its vehicle (20% dimethylsulfoxide
in saline). At the higher dose, KT5720 inhibited PKA activity by 90%. KT5720
blocked long-term memory (LTM) when given either 0 or 175 min posttraining, and
short-term memory (STM) when given 0, 22, 45 or 90 min post-training. Therefore,
PKA plays a different role in the process of formation of the two types of
memory. Its role in LTM may be related to the peak of PKA activity, and to the
levels of its substrate, nuclear P-CREB, that have been described in a previous
paper to occur at 0 and again at 3 h after training. The role of PKA in STM may
well involve other substrates of the enzyme. This finding points to a cleavage
between the mechanisms of STM and LTM formation.
PMID- 10780836
TI - Ethanol state dependence involving a lever press response requirement in rats.
AB - Previous studies have found that the timely completion of an FR10 schedule of
food-rewarded lever pressing in rats demonstrates state dependence in drug-to
saline state changes with benzodiazepines and NMDA antagonists, but not with
ethanol. We report here that, using sweetened condensed milk rather than food
pellets as a reward, ethanol nonetheless produces a symmetrical state dependence
with the lever press response requirement at doses that also impair acquisition.
Extensive parametric studies are needed to unravel the apparently subtle
conditions that govern the occurrence and features of the state dependence
produced by various CNS compounds.
PMID- 10780837
TI - Techniques of embryo transfer and facility decontamination used to improve the
health and welfare of transgenic mice.
AB - 'Reduction' and 'Refinement' can be achieved in transgenic mouse studies by re
deriving transgenic mouse lines and subsequently maintaining them under high
standards of husbandry in a unit with restricted access. This report describes
the initial steps of a project to improve the health and welfare of transgenic
mice at the European Molecular Biology Laboratory (EMBL), by re-deriving
transgenic lines as microbiologically defined animals to be maintained in a
barrier unit in a newly constructed animal facility. A pilot study showed that it
was possible to transfer embryos obtained from contaminated donor mice in the old
facility to specific pathogen free recipients housed in a ventilated cabinet in
the new unit, without concomitant carry over of disease. The offspring born
following embryo transfer were of high health status and did not show any
evidence of contamination with any of the pathogens present in the mice in the
old animal unit. Antibodies to various murine viruses (mouse hepatitis virus
(MHV), rota virus, reo-3 virus, Theilers encephalomyelitis virus, adenovirus) and
parasites were present in sentinel animals from the old animal house whereas the
re-derived animals were found to be free of virus antibodies and parasites.
Therefore the methods used were considered to be successful in terms of disease
prevention and enhancement of welfare. The barrier unit was sterilized without
the use of formaldehyde or related substances, to minimize the risks to personnel
and to the environment from using potentially dangerous substances. From the
results of in vitro and in vivo screening, the protocol for sterilization
described here was found to be effective in achieving microbiological sterility
of the barrier unit and was cost effective.
PMID- 10780838
TI - Home cage presentation of complex discrimination tasks to marmosets and rhesus
monkeys.
AB - The study reported here demonstrates the feasibility of presenting cognitive
tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to
either marmosets or rhesus monkeys in their home cages. This location of testing
offers opportunities for the measurement of additional indices, for example
spontaneous behaviour (Prowse et al. 1995) and electrophysiology (Pearce et al.
1998) as well as facilitating repeated test presentation. Results from 12
marmosets and 4 rhesus monkeys which have completed several sequences of an eight
stage discrimination task involving simple discriminations, compound
discriminations and reversals are reported. The paradigm developed has
application in long-term studies. Tests from CANTAB have been used extensively in
normal humans (Robbins et al. 1994) as well as a range of patient groups (Owen et
al. 1992, Elliott et al. 1995) and to assess drug effects (Coull et al. 1996).
Additionally some of these tests have been presented to marmosets (Roberts et al.
1988) to examine neuropsychological functioning. This comparative approach
facilitates meaningful cross species comparison, particularly in the study of the
effects of pharmacological intervention.
PMID- 10780839
TI - Monitoring of piglets' open field activity and choice behaviour during the replay
of maternal vocalization: a comparison between Observer and PID technique.
AB - The paper presents a new system for the automatic monitoring of open field
activity and choice behaviour of medium-sized animals. Passive infrared motion
detectors (PID) were linked on-line via a digital I/O interface to a personal
computer provided with self-developed analysis software based on LabVIEW (PID
technique). The set up was used for testing 18 one-week-old piglets (Sus scrofa)
for their approach to their mother's nursing vocalization replayed through
loudspeakers. The results were validated by comparison with a conventional
Observer technique, a computer-aided direct observation. In most of the cases, no
differences were seen between the Observer and PID technique regarding the
percentage of stay in previously defined open field segments, the locomotor open
field activity, and the choice behaviour. The results revealed that piglets are
clearly attracted by their mother's nursing vocalization. The monitoring system
presented in this study is thus suitable for detailed behavioural investigations
of individual acoustic recognition. In general, the PID technique is a useful
tool for research into the behaviour of individual animals in a restricted open
field which does not rely on subjective analysis by a human observer.
PMID- 10780840
TI - The effect of cage size and enrichment on core temperature and febrile response
of the golden hamster.
AB - The aim of this study is to determine the effect of cage size and cage
enrichment. Golden hamsters were individually housed in standard cages of four
different sizes and in enriched cages of three different sizes since 3 weeks of
age. Each of the seven housing groups consisted of 12 hamsters. After 14 weeks of
housing in their respective environments the measurements started. The mean
baseline rectal temperature was significantly higher in hamsters housed in small
cages than in hamsters housed in large cages. After the injection of fever
inducing lipopolysaccharide rectal temperature increased by 1 to 2 degrees C. The
increase of rectal temperature and the fever index were the highest in animals
housed in large cages and the smallest in animals housed in small cages. Through
cage enrichment and increasing cage size the mean febrile response increased
while the mean baseline rectal temperature decreased. Cage size and cage
enrichment had no effect on the dispersion of the measured values. The
differences in microclimate between large and small cages were too small to have
an effect on thermoregulation. The results indicate that housing in small cages
induce chronic stress which obviously affects thermoregulation. The findings
demonstrate that the results of some physiological experiments are significantly
influenced by the pre-experimental housing conditions.
PMID- 10780841
TI - Housing conditions affect susceptibility to mercury in the golden hamster.
AB - Individually-housed and group-housed golden hamsters (Mesocricetus auratus), aged
8 weeks, were studied with regard to their susceptibility to a single gavage of
mercuric chloride (10 mg/kg body weight). Body weight and food consumption were
measured for 10 days (day -9 to day 0) in a pre-application period and for 13
days (day 1 to day 13) in a post-application period. Mercuric chloride
administration significantly reduced body weight gain in both isolated and
grouped hamsters at day 1 compared to vehicle controls. While the individually
housed treated hamsters recovered during the post-application period, the group
housed treated hamsters showed a reduced body weight gain over the whole post
application period. Results are discussed in relation to elevated susceptibility
to intoxication in group-housed hamsters triggered by high social stress. This
study highlights the need to carefully consider the housing conditions which can
influence the results of teratological experiments.
PMID- 10780842
TI - The influence of pre-anaesthetic administration of buprenorphine on the
anaesthetic effects of ketamine/medetomidine and pentobarbitone in rats and the
consequences of repeated anaesthesia.
AB - Rats received pentobarbitone (60, 48 and 36 mg/kg i.p.) or ketamine/medetomidine
(75/100, 60/80 and 45/60 mg/microg/kg i.p.) alone, or one hour following
buprenorphine (0.5 mg/kg s.c.). Animals were anaesthetized once per week for 6
weeks with one of three anaesthetic doses according to a randomized block design.
In the pentobarbitone group, animals which received buprenorphine had longer
sleep times (236 +/- 22 cf. 204 +/- 21 min) and longer durations of surgical
anaesthesia (83 +/- 14 cf. 27 +/- 8 min) (P<0.01), these effects being
potentiated with increasing anaesthetic doses (P<0.01). A greater degree of
respiratory depression was found in animals that received buprenorphine (P<0.01)
although this was judged clinically acceptable in all cases. Unexpectedly high
mortality and a high incidence of anaesthetic complications (nine of 16 animals)
in the ketamine/medetomidine group made statistical analysis of these data
impossible. We conclude that for pentobarbitone, pre-anaesthetic administration
of buprenorphine reduces the dose of anaesthetic required to produce surgical
anaesthesia, in addition to the presumed benefits of pre-emptive analgesia. In
view of the high mortality encountered, we advise caution when considering pre
anaesthetic use of opioids in combination with ketamine/medetomidine in rats.
PMID- 10780843
TI - Comparison of the effects of four anaesthetic agents on somatosensory evoked
potentials in the rat.
AB - Electrophysiological techniques provide an objective and non-invasive measure of
neurological function. In order to undertake detailed evoked potential studies in
rats on repeated occasions, it is necessary to find an appropriate anaesthetic
agent which has minimal and reproducible effects on the parameters to be studied
and also has a minimal effect on the general welfare of the animals. In this
study we compared the effects of four common anaesthetic agents (ketamine
xylazine, medetomidine, isoflurane and fentanyl/fluanisone-midazolam) on
somatosensory evoked potentials (SEPs) in rats following electrical stimulation
of the fore- and hind-paw. Fentanyl/fluanisone-midazolam was found to be well
tolerated by the animals and to have, in general, the least deleterious effect on
SEPs. For example, the response recorded at the level of the somatosensory cortex
(P1), following forelimb stimulation, appeared on average 1.80 ms earlier with
fentanyl/fluanisone-midazolam than with the other agents and the peak-to-peak
amplitude (CI to CII) of the response recorded at the cervical (C3) level was on
average 5.86 microV greater with fentanyl/fluanisone-midazolam.
Fentanyl/fluanisone-midazolam is, therefore, recommended as the anaesthetic of
choice for longitudinal studies of SEPs in the rat.
PMID- 10780845
TI - A rapid and non-surgical procedure for jugular catheterization of pigs.
AB - A rapid and non-surgical method for jugular catheterization in pigs was set up in
30 piglets of 6.2 kg, 23 pigs of 46 kg and 84 kg and two lactating multiparous
sows. The animal was restrained on a V-shaped table (piglets) or with a rope
around the mandible (slaughter pigs and sows). The vein was located with the
Vacutainer system and a wire guide was inserted into the Vacutainer needle up to
the vein lumen. When the needle was removed, the catheter was inserted over the
wire guide and advanced until it penetrated the skin and thereafter, the vein
wall. The catheter was fixed outside by a large tape and coiled inside a patch
just behind the ears. The technique utilizes readily available material and is no
more risky for the animal than a single blood sampling. Moreover, it can be
performed within 15 to 20 min (including animal restraint) within pens. This new
approach might have important implications not only for research purposes by
facilitating repeated blood samplings but also for projects which require a rapid
and easy method for testing of any kind of pharmaceutical or other type of
products under husbandry conditions.
PMID- 10780844
TI - The effect of buprenorphine on the course of disease in laboratory rabbits
infected with myxoma virus.
AB - The only method of assessing the virulence of myxoma virus is to record survival
times of rabbits inoculated with the virus. This raises ethical concerns about
using animals in experiments where death is the end point. We investigated
whether or not the opioid analgesic buprenorphine could be used in rabbits
without compromising the myxoma virus virulence assay and on the presumption that
animals may suffer pain during the course of the disease. Thirty, 5-month-old New
Zealand White rabbits were divided into two groups stratified for weight and
gender, and inoculated intradermally with 100 pfu of the Standard Laboratory
Strain (SLS) of myxoma virus. At day 6 post infection (p.i.), when eyelid
swelling was first seen, each animal in one group was treated with 0.03 mg/kg
buprenorphine, subcutaneously, morning and evening until death. Animals in the
other group were untreated. Animals were weighed daily and rectal temperatures
taken morning and evening. Intake of food and water was assessed as was general
demeanor including respiratory effort. There was no significant difference in
mean survival time, weight change, or demeanor between the two groups. Increased
respiratory effort was seen from day 10 p.i. in animals surviving up to and
beyond that time but again there was no difference between groups. Animals
treated with buprenorphine refused food and water a day earlier than untreated
animals, and had lower temperatures immediately prior to death. It was concluded
that the opiate analgesic buprenorphine can be used without compromising the
current virulence assay for the SLS of myxoma virus in New Zealand White rabbits
but that the clinical signs of myxomatosis that could be attributed to pain were
not abrogated.
PMID- 10780846
TI - Effects of coprophagy on serum urea and the weight of the gastrointestinal tract
of fed or fasted rats.
AB - Coprophagy can be minimized by fitting rat cages with metal grids which allow
faecal pellets to pass through to the floor of the cage. When bedding was omitted
overnight, the extent of coprophagy could be estimated from the weight of the
droppings on the cage floor or the weight of the gastrointestinal (GI) tract
removed from rats housed with or without grids. The effect of coprophagy was also
demonstrated by the elevation of serum urea nitrogen in rats that consumed
faeces. Therefore, precautions against coprophagy, or their absence, should be
specified in all experimental protocols and reports.
PMID- 10780847
TI - Evaluation of hypothalamo-pituitary-adrenal activity in the tree shrew (Tupaia
belangeri) via salivary cortisol measurement.
AB - Saliva sampling is frequently used in humans for adrenal glucocorticoid hormone
analysis because of advantages such as non-invasiveness, the ease of collection,
and storing of the samples. To transfer this advantageous method to laboratory
mammals, potentially confounding factors such as stressful handling procedures
have to be excluded. In the present study we established a method for collecting
saliva for cortisol measurement in freely moving adult male tree shrews (Tupaia
belangeri). The practicability of the procedure was demonstrated (i) by stress
induced changes in cortisol levels revealing a significant increase during the
stress phase (control = 0.91 nmol/l vs stress = 1.71 nmol/l), and (ii) by
reporting no significant differences in salivary cortisol levels before and after
performance of a learning task. The present study emphasizes the use of salivary
cortisol analysis especially for monitoring acute changes in the hypothalamo
pituitary-adrenal axis activity in male tree shrews.
PMID- 10780848
TI - Haematology and serum chemistry parameters of the pregnant rat.
AB - This study describes the baseline haematology and serum chemistry values found in
non-pregnant, pregnant (gestational days [GD] 2-21) and lactating (postnatal days
1-9) Sprague Dawley rats (n = 3-10/day) from the NCTR breeding colony of Crl:COBS
CD(SD)BR strain. Maternal body weights on GD0 ranged from 250 to 300 g. Multiple
analytes were measured in both whole blood and serum of dams. Amniotic fluid,
fetal serum, and postnatal pup serum analyte values were also acquired. Maternal
blood was collected from the heart under subterminal carbon dioxide (CO2)
anaesthesia. Most pregnant dam blood values were not appreciably different from
values for non-pregnant dams until near term; near-term values for some analytes
(red blood cells, haemoglobin, haematocrit, mean corpuscular haemoglobin
concentration, alkaline phosphatase, albumin, total protein, glucose, total
bilirubin, sodium, and chloride) decreased but returned to near-normal values
soon after delivery. The most dramatic change was a three-fold elevation of serum
triglyceride levels near term with a subsequent decrease at birth. Most serum
chemistry analytes measured in progeny increased after birth except for alkaline
phosphatase, calcium and potassium levels which decreased.
PMID- 10780849
TI - Immunohistological characterization of leukocytes in the lungs of healthy mice
and after bacterial intratracheal infection.
AB - Leukocytes in the peripheral lung parenchyma of mice have not been characterized
histologically during bacterial infection. The aim of this study was to
investigate (a) the immunohistological characteristics of healthy murine lungs
and (b) the cell kinetics during acute inflammation. BALB/c and MF1 mice were
examined; as well as transgenic mice with the gene defect of cystic fibrosis (CF)
in the airways as an animal model for this disease. MF1 mice served as controls
for the transgenic animals. Lavaged and perfused lungs were snap frozen. B and T
lymphocytes, CD4+ and CD8+ cells, dendritic cells, neutrophils and a subset of
macrophages were enumerated on cryostat lung sections. The lung tissue and
bronchoalveolar lavage (BAL) of BALB/c mice, infected intratracheally with
Haemophilus influenzae type b (Hib), were studied at different time points after
infection. In the lungs of healthy mice, including CF mice, the largest
population was that of T cells, CD4+ cells being always more frequent than CD8+
cells. During acute inflammation the number of neutrophils in the lung parenchyma
and BAL increased strongly within the first hours after bacterial instillation
and reached baseline levels within one week. This study provides a semi
quantitative analysis of immunocompetent cells in normal and infected murine lung
tissue. Differences in cell numbers are found between different strains.
Moreover, the cellular reaction during Hib infection in mouse lungs is dominated
by neutrophils, as expected in a primary immune response. In uninfected CF mice
the numbers and distribution of immune cells in the lung tissue are normal,
indicating that the cellular defense is adequate.
PMID- 10780850
TI - The ethical acceptability of animal experiments: a proposal for a system to
support decision-making.
AB - We describe a system to support decision-making on the ethical acceptability of
animal experiments for scientific researchers and others responsible for ethical
decision-making in animal experiments. The system consists of eight steps. Each
step contains a number of substantive questions or a computational rule, leading
to a well-articulated moral judgment on specific animal experiments. The system
comprises a number of moral assumptions and pre-emptive norms, but leaves enough
room for moral discretion and personal responsibility. The general ethical ideas
behind the moral choices and assumptions are sketched and potential objections to
the overall approach are discussed.
PMID- 10780851
TI - Mousepox: a threat to mouse colonies.
PMID- 10780852
TI - Suppressed bone turnover by bisphosphonates increases microdamage accumulation
and reduces some biomechanical properties in dog rib.
AB - It has been hypothesized that suppression of bone remodeling allows microdamage
to accumulate, leading to increased bone fragility. This study evaluated the
effects of reduced bone turnover produced by bisphosphonates on microdamage
accumulation and biomechanical properties of cortical bone in the dog rib. Thirty
six female beagles, 1-2 years old, were divided into three groups. The control
group (CNT) was treated daily for 12 months with saline vehicle. The remaining
two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per
day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right
ninth rib was assigned to cortical histomorphometry or microdamage analysis. The
left ninth rib was tested to failure in three-point bending. Total cross
sectional bone area was significantly increased in both RIS and ALN compared with
CNT, whereas cortical area did not differ significantly among groups. One-year
treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS,
53%; ALN, 68%) without impairment of mineralization and significantly increased
microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT.
Although bone strength and stiffness were not significantly affected by the
treatments, bone toughness declined significantly in ALN (20%). Regression
analysis showed a significant nonlinear relationship between suppressed
intracortical bone remodeling and microdamage accumulation as well as a
significant linear relationship between microdamage accumulation and reduced
toughness. This study showed that suppression of bone turnover by high doses of
bisphosphonates is associated with microdamage accumulation and reduced some
mechanical properties of bone.
PMID- 10780853
TI - True strength.
PMID- 10780854
TI - Chromosomal mapping of osteopenia-associated quantitative trait loci using
closely related mouse strains.
AB - Peak bone mineral density (BMD) is a highly heritable trait in humans and is
currently the best predictor of skeletal fragility underlying osteoporosis. The
SAMP6 mouse strain displays unusually low BMD at maturity, and age-dependent
osteopenia associated with defective osteoblastogenesis. To identify quantitative
trait loci (QTLs) influencing bone density, we constructed crosses between SAMP6
and either AKR/J or SAMP6, two related mouse strains of higher peak BMD. Due to
common ancestry of these strains, intercross parents differed at only 39-40% of
227 highly-polymorphic genotyping markers, thus restricting our search to this
informative portion of the genome and reducing the number of mice required for
QTL significance. Using dual energy X-ray absorptiometry (DEXA), we measured
spinal BMD in F2 cross progeny at 4 months of age, and selectively genotyped
those in the highest and lowest quartiles for BMD. Based on linear regression of
bone density on genotype, including Composite Interval Mapping to enhance mapping
precision while adjusting for effects of distal markers, we identified multiple
QTLs significantly affecting spinal BMD; these were mapped to regions of
chromosomes 2 (two sites, one confirmed in both crosses), 7, 11, 13 and 16. One
of these loci had been previously identified as a significant bone-density QTL,
while 3 substantiate QTLs suggested by a low-power study of 24 recombinant-inbred
mouse lines. Such recurrent appearance of QTLs, especially in crosses involving
distantly-related strains, implies that polymorphism at these loci may be favored
by evolution and might underlie variation in peak bone density among humans.
PMID- 10780855
TI - Transforming growth factor-beta1 gene polymorphism, bone turnover, and bone mass
in Italian postmenopausal women.
AB - Transforming growth factor beta1 (TGF-beta1) is abundant in bone and is an
important regulator of the osteoclastic-osteoblastic interaction (coupling). The
sequence variation, 713-8delC in the TGF-beta1 gene has previously been found to
be associated with very low bone mass in osteoporotic women and with increased
bone turnover in both osteoporotic and normal women. The possible association of
this polymorphism with bone mass and bone turnover has now been investigated in
256 postmenopausal Italian women. A significant association of TGF-beta1 with
bone mass was detected in the populations. Subjects carrying the sequence
variation 713-8delC (Tt) genotype showed a significantly lower bone mineral
density (BMD) at the hip than those without sequence variation in the genotype
(TT). Individuals carrying the tt genotype have a more severe osteoporosis
(P=0.0001 vs. TT and Tt genotypes). The frequency of the fragility fractures was
significantly lower in individuals with TT genotype than in those with the Tt and
tt genotypes (X2=21.9; P=0.006). Furthermore a significant association was found
between 713-8delC and bone turnover. The results suggest a strong evidence for an
association among the 713-8delC allele of the TGF-beta1 gene and the femoral BMD,
the prevalence of osteoporotic fractures, and finally a high bone turnover in a
sample of Italian postmenopausal women.
PMID- 10780856
TI - Expression of osteoclast differentiation signals by stromal elements of giant
cell tumors.
AB - The mechanisms by which primary tumors of the bone cause bone destruction have
not been elucidated. Unlike most other lytic bone tumors, osteoclastomas,
otherwise known as giant cell tumors (GCT), contain osteoclast-like cells within
the tumor stroma. A new member of the TNF-ligand superfamily member, osteoclast
differentiation factor (ODF/OPGL/RANKL/TRANCE), was recently identified. ODF was
shown to directly stimulate osteoclastogenesis, in the presence of M-CSF. In this
study, the expression of ODF was examined in a number of tumor samples associated
with bone lysis in vivo. In addition, we investigated expression of the ODF
receptor on osteoclast precursors, RANK, as well as the ODF inhibitor
osteoprotegerin (OPG), and another TNF-ligand superfamily member, TRAIL,
previously shown to abrogate the inhibitory effects of OPG. We report here the
novel finding that GCT stromal cells contain abundant ODF mRNA, whereas the giant
cell population exclusively expresses RANK mRNA. These results are consistent
with the osteoclast-mediated bone destruction by these tumors. We also report the
expression of OPG and TRAIL mRNA in GCT samples. A comparison with other lytic
and nonlytic tumors of bone showed that GCT express more ODF and TRAIL mRNA
relative to OPG mRNA. In addition, GCT were found to express a number of
cytokines previously reported to play central roles in osteoclastogenesis,
namely, IL-1, -6, -11, -17, as well as TNF-alpha. Importantly, GCT were also
found to express high levels of M-CSF mRNA, a cytokine shown to be an essential
cofactor of ODF, and a survival factor for mature and developing osteoclasts.
Furthermore, expression of these molecules by stromal cells isolated from GCT
continued in vitro. Thus GCT constitutively express all of the signals that are
currently understood to be necessary for the differentiation of osteoclasts from
precursor cells.
PMID- 10780857
TI - Compactin suppresses bone resorption by inhibiting the fusion of prefusion
osteoclasts and disrupting the actin ring in osteoclasts.
AB - Compactin (mevastatin), which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG
CoA) reductase, and thus biosynthesis of cholesterol and the prenylation of
proteins, inhibits osteoclastic bone resorption. Although it has been suggested
that compactin inhibits bone resorption by inducing apoptosis of osteoclasts, the
pathway by which compactin inhibits resorption has not been established. We
investigated the effect of compactin on the differentiation of osteoclasts and
the relationship between the morphological changes elicited by compactin and its
inhibitory effect on bone resorption. Compactin inhibited the differentiation of
osteoclasts, interfering with the fusion process by which prefusion osteoclasts
(pOCs) develop into multinucleated osteoclast-like cells (OCLs), and also
disrupted the actin ring of OCLs. The potency of compactin to inhibit fusion of
pOCs and to disrupt the actin ring of OCLs corresponded to that of compactin to
inhibit bone resorption. The effects of compactin were prevented by the addition
of MVA lactone or its downstream products farnesylpyrophosphate (FPP) and
geranylgeranyl-pyrophosphate (GGPP) but not by squalene. Apoptosis of OCLs was
not induced by the concentration of compactin that inhibited fusion of pOCs and
disrupted the actin ring. The normal process of pOC fusion and the integrity of
the actin ring were restored by the withdrawal of compactin from the cultures
after they had been treated with compactin for 24 h, but they were not restored
by the addition of zVAD-fmk, a caspase inhibitor. Compactin also reversibly
inhibited interleukin-1beta (IL-1beta)-, 1alpha,25-dihydroxyvitamin D3 (1
alpha,25(OH)2D3)-, and parathyroid hormone (PTH)-stimulated 45Ca release in bone
organ cultures. Our results indicate that the inhibitory effects of compactin on
bone resorption result from the inhibition of fusion of pOCs into OCLs and
disruption of actin ring in OCLs and that apoptosis of OCLs is not necessary for
these inhibitory effects of compactin. These effects of compactin are likely to
be a consequence of the inhibition of prenylation of proteins that play an
important role in the fusion of pOCs and in maintaining actin ring integrity in
OCLs.
PMID- 10780858
TI - Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in
murine bone marrow cultures from adult mice: antagonism by noggin.
AB - Bone morphogenetic proteins (BMPs) have been heretofore implicated in the
induction of osteoblast differentiation from uncommitted progenitors during
embryonic skeletogenesis and fracture healing. We have tested the hypothesis that
BMPs are also involved in the osteoblastogenesis that takes place in the bone
marrow in postnatal life. To do this, we took advantage of the properties of
noggin, a recently discovered protein that binds BMP-2 and -4 and blocks their
action. Addition of human recombinant noggin to bone marrow cell cultures from
normal adult mice inhibited both osteoblast and osteoclast formation; these
effects were reversed by exogenous BMP-2. Consistent with these findings, BMP-2
and -4 and BMP-2/4 receptor transcripts and proteins were detected in these
primary cultures, in a bone marrow-derived stromal/osteoblastic cell line, as
well as in murine adult whole bone; noggin expression was also documented in all
these preparations. Moreover, addition of antinoggin antibody caused an increase
in osteoblast progenitor formation. These findings suggest that BMP-2 and -4 are
expressed in the bone marrow in postnatal life and serve to maintain the
continuous supply of osteoblasts and osteoclasts; and that, in fact, BMP-2/4
induced commitment to the osteoblastic lineage is a prerequisite for osteoclast
development. Hence, BMPs, perhaps in balance with noggin and possibly other
antagonists, may provide the tonic baseline control of the rate of bone
remodeling on which other inputs (e.g., hormonal, biomechanical, etc.) operate.
PMID- 10780860
TI - Protein undernutrition-induced bone loss is associated with decreased IGF-I
levels and estrogen deficiency.
AB - Protein undernutrition is a known factor in the pathogenesis of osteoporotic
fracture in the elderly, but the mechanisms of bone loss resulting from this
deficiency are still poorly understood. We investigated the effects of four
isocaloric diets with varying levels of protein content (15, 7.5, 5, and 2.5%
casein) on areal bone mineral density (BMD), bone ultimate strength,
histomorphometry, biochemical markers of bone remodeling, plasma IGF-I, and sex
hormone status in adult female rats. After 16 weeks on a 2.5% casein diet, BMD
was significantly decreased at skeletal sites containing trabecular or cortical
bone. Plasma IGF-I was decreased by 29-34% and no estrus sign in vaginal smear
was observed. To investigate the roles of estrogen deficiency and protein
undernutrition, the same protocol was used in ovariectomized (OVX) or sham
operated (SHAM) rats, pair-fed isocaloric diets containing either 15 or 2.5%
casein. Trabecular BMD was decreased by either manipulation, with effects
appearing to be additive. Cortical BMD was decreased only in rats on a low
protein diet. This was accompanied by an increased urinary deoxypyridinoline
excretion without any change in osteocalcin levels, suggesting an uncoupling
between resorption and formation. Isocaloric protein undernutrition decreased
bone mineral mass and strength. This effect might be related to decreased plasma
IGF-I and/or estrogen deficiency with a consequent imbalance in bone remodeling.
PMID- 10780859
TI - A novel synthetic triazolotriazepine derivative JTT-606 inhibits bone resorption
by down-regulation of action and production of bone resorptive factors.
AB - In the search for a new class of bone-sparing agents, we have conducted random
screening of the domestic chemical library using 45Ca release assay from
prelabeled cultured neonatal mouse calvariae and identified a novel synthetic
triazolotriazepine JTT-606 as a candidate for a potent inhibitor of bone
resorption. JTT-606 inhibited 45Ca release dose dependently not only in the
control calvarial culture but also in the stimulated cultures by interleukin
1alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), and parathyroid hormone
(PTH). JTT-606 also inhibited both basal and stimulated osteoclast-like (OCL)
cell formation in the coculture of mouse osteoblastic cells and bone marrow cells
dose dependently, indicating its inhibitory effect on osteoclast differentiation.
Ex vivo OCL cell formation by cultured bone marrow cells collected from
ovariectomized (OVX) mice also was decreased dose dependently by in vivo
application of JTT-606 to a level similar to that from sham-operated mice.
Furthermore, JTT-606 inhibited resorbed pit formation by isolated mature
osteoclasts as well as by unfractionated bone cells derived from rabbit long
bones in the control and FGF-2-stimulated cultures dose dependently, indicating
both the direct and the indirect actions of JTT-606 on mature osteoclast
function. In addition, JTT-606 reduced production of IL-1alpha, tumor necrosis
factor alpha (TNF-alpha), IL-6, and granulocyte-macrophage colony-stimulating
factor (GM-CSF) in the human peripheral blood mononuclear cell culture. In vivo
analyses of mature OVX rats revealed that the application of JTT-606 for 12 weeks
increased the BMD of the lumbar spine and decreased the levels of serum
osteocalcin and urine deoxypyridinoline to levels similar to those of 17beta
estradiol-treated OVX rats. We propose that JTT-606 may inhibit both osteoclast
differentiation and function by down-regulating both the action and the
production of bone resorptive factors. It is speculated that JTT-606 could be a
potent agent for the treatment of osteopenic disorders with elevated osteoclastic
bone resorption.
PMID- 10780861
TI - Fractal dimension of trabecular bone projection texture is related to three
dimensional microarchitecture.
AB - The purpose of this work was to understand how fractal dimension of two
dimensional (2D) trabecular bone projection images could be related to three
dimensional (3D) trabecular bone properties such as porosity or connectivity. Two
alteration processes were applied to trabecular bone images obtained by magnetic
resonance imaging: a trabeculae dilation process and a trabeculae removal
process. The trabeculae dilation process was applied from the 3D skeleton graph
to the 3D initial structure with constant connectivity. The trabeculae removal
process was applied from the initial structure to an altered structure having 99%
of porosity, in which both porosity and connectivity were modified during this
second process. Gray-level projection images of each of the altered structures
were simply obtained by summation of voxels, and fractal dimension (Df) was
calculated. Porosity (phi) and connectivity per unit volume (Cv) were calculated
from the 3D structure. Significant relationships were found between Df, phi, and
Cv. Df values increased when porosity increased (dilation and removal processes)
and when connectivity decreased (only removal process). These variations were in
accordance with all previous clinical studies, suggesting that fractal evaluation
of trabecular bone projection has real meaning in terms of porosity and
connectivity of the 3D architecture. Furthermore, there was a statistically
significant linear dependence between Df and Cv when phi remained constant.
Porosity is directly related to bone mineral density and fractal dimension can be
easily evaluated in clinical routine. These two parameters could be associated to
evaluate the connectivity of the structure.
PMID- 10780862
TI - Changes in cortical bone mineralization in the developing mandible: a three
dimensional quantitative computed tomography study.
AB - Quantitative computed tomography (QCT) was completed in 34 subjects between the
ages of 9 and 33 years with symmetrical mandibles in order to investigate the
three-dimensional cortical bone mineral density (BMD) distribution in the
mandible. The number and distribution of the pixels were determined at three
levels: (1) representing the entire mandibular bone; (2) the cortical bone at 60%
above the baseline defined as the segmentation level (around 1050 mg/cm3) and
representative of only cortical bone; and (3) the highest mineralized cortical
bone (>1250 mg/cm3). The geometrical distribution of the highest mineralized
areas was evaluated by three-dimensional reconstruction of the images. The total
number of pixels for the entire mandible increased significantly at each time
point represented at four increasing ages groups (9-11 years of age, 12-14 years
of age, 15-17 years of age, and >18 years of age). The male and female subjects
had a similar total number of pixels for the entire mandible before the age of
11, but the male subjects showed a significantly larger total number of
mandibular pixels after that age. Comparison of the number of pixels for pure
cortical bone (60% segmentation level) and the highest mineralized cortical bone
indicated a significant increase with maturation with the greatest change
occurring between the 13-year and 16-year age groups. However, the ratio of
cortical bone/total bone increased at a more rapid rate in the male subjects and
reached a plateau by the 16-year age group, showing distinct differences in
mineralization of the mandible between the sexes.
PMID- 10780863
TI - Risk factors for longitudinal bone loss in elderly men and women: the Framingham
Osteoporosis Study.
AB - Few studies have evaluated risk factors for bone loss in elderly women and men.
Thus, we examined risk factors for 4-year longitudinal change in bone mineral
density (BMD) at the hip, radius, and spine in elders. Eight hundred elderly
women and men from the population-based Framingham Osteoporosis Study had BMD
assessed in 1988-1989 and again in 1992-1993. BMD was measured at femoral neck,
trochanter, Ward's area, radial shaft, ultradistal radius, and lumbar spine using
Lunar densitometers. We examined the relation of the following factors at
baseline to percent BMD loss: age, weight, change in weight, height, smoking,
caffeine, alcohol use, physical activity, serum 25-OH vitamin D, calcium intake,
and current estrogen replacement in women. Multivariate regression analyses were
conducted with simultaneous adjustment for all variables. Mean age at baseline
was 74 years +/-4.5 years (range, 67-90 years). Average 4-year BMD loss for women
(range, 3.4-4.8%) was greater than the loss for men (range, 0.2-3.6%) at all
sites; however, BMD fell with age in both elderly women and elderly men. For
women, lower baseline weight, weight loss in interim, and greater alcohol use
were associated with BMD loss. Women who gained weight during the interim gained
BMD or had little change in BMD. For women, current estrogen users had less bone
loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD. For
men, lower baseline weight and weight loss also were associated with BMD loss.
Men who smoked cigarettes at baseline lost more BMD at the trochanter site.
Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25
OH vitamin D, or calcium intake. Risk factors consistently associated with bone
loss in elders include female sex, thinness, and weight loss, while weight gain
appears to protect against bone loss for both men and women. This population
based study suggests that current estrogen use may help to maintain bone in
women, whereas current smoking was associated with bone loss in men. Even in the
elderly years, potentially modifiable risk factors, such as weight, estrogen use,
and cigarette smoking are important components of bone health.
PMID- 10780864
TI - Patients with prior fractures have an increased risk of future fractures: a
summary of the literature and statistical synthesis.
AB - Numerous studies have reported increased risks of hip, spine, and other fractures
among people who had previous clinically diagnosed fractures, or who have
radiographic evidence of vertebral fractures. However, there is some variability
in the magnitudes of associations among studies. We summarized the literature and
performed a statistical synthesis of the risk of future fracture, given a history
of prior fracture. The strongest associations were observed between prior and
subsequent vertebral fractures; women with preexisting vertebral fractures
(identified at baseline by vertebral morphometry) had approximately 4 times
greater risk of subsequent vertebral fractures than those without prior
fractures. This risk increases with the number of prior vertebral fractures. Most
studies reported relative risks of approximately 2 for other combinations of
prior and future fracture sites (hip, spine, wrist, or any site). The confidence
profile method was used to derive a single pooled estimate from the studies that
provided sufficient data for other combinations of prior and subsequent fracture
sites. Studies of peri- and postmenopausal women with prior fractures had 2.0 (95
% CI = 1.8, 2.1) times the risk of subsequent fracture compared with women
without prior fractures. For other studies (including men and women of all ages),
the risk was increased by 2.2 (1.9, 2.6) times. We conclude that history of prior
fracture at any site is an important risk factor for future fractures. Patients
with a history of prior fracture, therefore, should receive further evaluation
for osteoporosis and fracture risk.
PMID- 10780865
TI - Skeletal effects of parathyroid hormone infusion in ovariectomized rats with or
without estrogen repletion.
AB - We employed skeletally matured rats to study changes in biochemical markers of
bone turnover, bone mineral density (BMD), and bone biomechanics produced by
continuous elevation of parathyroid hormone (PTH) in estrogen-deplete and
replete rodents. Ninety-six 7-month-old virgin female rats were divided randomly
into 12 groups (n = 8) and treated as follows. One group was killed on the day of
surgery. The remaining groups were either bilaterally ovariectomized (Ovx) or
sham-operated and left untreated for 8 weeks, at which point, two groups, one
sham and one Ovx, were killed. The remaining nine groups were treated for 2 weeks
or 4 weeks. One sham and two Ovx groups received subcutaneous implants of Alzet
miniosmotic pumps with vehicle for PTH. Two Ovx groups were given pumps with
vehicle as well as a subcutaneous implant of 17beta-estradiol, which delivered 10
microg/kg per day. Two Ovx groups were implanted with rat PTH(1-34) in Alzet
miniosmotic pumps, which delivered 30 microg PTH/kg per day. Two Ovx groups were
implanted with both estradiol pellets and PTH-loaded pumps. One group of Ovx
animals from each treatment was killed after 2 weeks and the other after 4 weeks.
Biochemical markers of bone turnover, serum osteocalcin and urinary free
pyridinoline, BMD, and mechanical strength of excised bones were measured. As
expected, there was a significant increase in N-terminal PTH and serum calcium
levels in all PTH infusion groups. Both serum osteocalcin and urinary
pyridinoline showed a rapid increase within the first 2 weeks of the PTH infusion
and remained elevated at week 4. In estrogen-replete groups, osteocalcin
increased by week 2 of PTH infusion but pyridinoline did not increase until week
4. BMD of the distal and proximal femur showed the expected decrease 8 weeks
after ovariectomy but did not exhibit any further changes during the 4 weeks of
treatment with vehicle. Four weeks of PTH infusion in Ovx animals resulted in BMD
loss at the midshaft, distal, and proximal regions of the femur. Estrogen
repletion by itself, beginning 8 weeks after ovariectomy, produced no change in
BMD at any site when compared with from Ovx vehicle-treated rats. Estrogen
repletion in PTH-infused Ovx animals resulted in significant improvements of BMD
comparable with sham-operated animals at all three femoral regions. The
indentation test at the cancellous bone of the distal femur, three-point bending
test at the midshaft femur, and cantilever bending test at the femoral neck
showed that the changes in mechanical strength in these sites were consistent to
the changes found in BMD. Our results showed that (1) continuously elevated
levels of PTH induced additional loss of BMD in estrogen-deficient animals beyond
the rapid bone loss phase associated with ovariectomy, (2) estrogen repletion,
given by implant, to PTH-infused Ovx animals, reversed these BMD changes
increasing BMD to levels comparable with estrogen-sufficient rats, and (3) these
changes were reflected in the mechanical strength determined at these sites.
These results lend experimental support that hormone replacement therapy may
benefit bone health in postmenopausal women with primary hyperparathyroidism
(PHPT). In addition, it raises the possibility that a continuous elevation of PTH
could exert anabolic effects on skeletal tissue if its catabolic component can be
minimized.
PMID- 10780866
TI - Long-term corticosteroid therapy induces mild changes in trabecular bone texture.
AB - The relative roles of bone mineral density (BMD) decrease and of
microarchitectural changes in corticosteroid-induced osteoporosis (CIOP) are
debated. Our objective has been to evaluate both bone microarchitecture (by a
fractal analysis of texture on radiographs) and BMD in corticosteroid (CS)
treated patients. In this study, 60 patients from a rheumatology unit with a mean
age of 60.6+/-14.8 years taking CS therapy for more than 6 months and a
cumulative dose of prednisone over 1 g and 57 controls among age-matched patients
and hospital staff were recruited. Bone diseases and bone-modifying drugs (except
calcium, vitamin D, and hormonal replacement therapy [HRT]) were considered as
exclusion criteria. A fractal analysis of trabecular bone texture was performed
on calcaneus radiographs after an oriented analysis in 18 directions. The fractal
analysis was based on the fractional Brownian motion model. Results were
expressed by H parameter (H = 2 - fractal dimension) in each direction, Hmean
being the average of 18 directions, Hmini the minimum, and Hmaxi the maximum. BMD
was measured by double-energy X-ray absorptiometry (DEXA) at the femoral neck
(FN) and lumbar spine (LS). The odds ratios (OR) were calculated for a variation
of 1 SD. The mean duration and dose of CS therapy was 5.6+/-6.6 years and 16.9+/
19.7 g. CS therapy was significantly correlated to a decrease in FN or LSBMD: OR
= 1.95, 95% confidence interval (CI, 1.29-2.97) and OR = 3.19 (CI, 1.80-5.66),
respectively. The Hmean and Hmaxi were significantly lower in the cases than in
the controls: P = 0.03 and P = 0.02; OR = 1.67 (CI, 1.10-2.54) and OR = 1.75 (CI,
1.05-2.37). A similar trend was observed with Hmini but the difference did not
reach the level of statistical significance: P = 0.06, OR = 1.57 (CI, 1.05-2.37).
This study was repeated among cases and controls who had never taken HRT
(respectively, n = 40 and n = 39). The results were similar. Among patients
taking CS therapy, the presence of nontraumatic fractures was inversely related
to BMD values but not to texture parameters. These data have shown that long-term
CS therapy induces both BMD decrease and trabecular bone texture changes. The
effect of CS therapy was much stronger on BMD than on the fractal H parameter.
These results are in accordance with previous studies showing a lower effect of
CS therapy on bone microarchitecture than on bone mass. These results can be
contrasted with those observed in women with postmenopausal osteoporosis and
vertebral crush fractures in which the variations in the fractal parameters are
more significant than the BMD variations.
PMID- 10780867
TI - Effects of alendronate on bone quality and remodeling in glucocorticoid-induced
osteoporosis: a histomorphometric analysis of transiliac biopsies.
AB - Effects of alendronate (ALN) on bone quality and turnover were assessed in 88
patients (52 women and 36 men aged 22-75 years) who received long-term oral
glucocorticoid exposure. Patients were randomized to receive oral placebo or
alendronate 2.5, 5, or 10 mg/day for 1 year and stratified according to the
duration of their prior glucocorticoid treatment. Transiliac bone biopsies were
obtained for qualitative and quantitative analysis after tetracycline double
labeling at the end of 1 year of treatment. As previously reported in
glucocorticoid-induced osteoporosis, low cancellous bone volume and wall
thickness were noted in the placebo group as compared with normal values.
Alendronate treatment was not associated with any qualitative abnormalities.
Quantitative comparisons among the four treatment groups were performed after
adjustment for age, gender, and steroid exposure. Alendronate did not impair
mineralization at any dose as assessed by mineralization rate. Osteoid thickness
(O.Th) and volume (OV/BV) were significantly lower in alendronate-treated
patients, irrespective of the dose (P = 0.0003 and 0.01, respectively, for O.Th
and OV/BV); however, mineral apposition rate was not altered. As anticipated,
significant decreases of mineralizing surfaces (76% pooled alendronate group; P =
0.006), activation frequency (-72%; P = 0.004), and bone formation rate (-71%; P
= 0.005) were also noted with alendronate treatment. No significant difference
was noted between the changes observed with each dose. Absence of tetracycline
label in trabecular bone was noted in approximately 4% of biopsies in placebo and
alendronate-treated groups. Trabecular bone volume, parameters of
microarchitecture, and resorption did not differ significantly between groups. In
conclusion, alendronate treatment in patients on glucocorticoids decreased the
rate of bone turnover, but did not completely suppress bone remodeling and
maintained normal mineralization at all alendronate doses studied. Alendronate
treatment did not influence the osteoblastic activity, which is already low in
glucocorticoid-induced osteoporosis.
PMID- 10780868
TI - Differences in skeletal kinetics between vertebral and humeral bone measured by
18F-fluoride positron emission tomography in postmenopausal women.
AB - We have sought to investigate regional differences in skeletal kinetics between
lumbar vertebrae and the humerus of postmenopausal women with 18F-fluoride
positron emission tomography (PET). Twenty-six women, mean age 62 years, had
dynamic PET scans of the lumbar spine and lower humerus after the injection of
180 MBq 18F-fluoride ion. Plasma arterial input functions (IFs) were calculated
from a mean IF measured arterially from 10 women and scaled according to late
individual venous activity. Vertebral and humeral time activity curves were
measured by placing regions of interest (ROI) over lumbar vertebrae and the
humeral shaft. Using a three-compartmental model and nonlinear regression
analysis the macroconstant Ki, representing plasma clearance of fluoride to bone
mineral, and the individual rate constants K1 (related to regional skeletal blood
flow) and k2 to k4 describing transport between plasma, an extracellular fluid
compartment and a bone mineral compartment, were measured. Mean vertebral Ki
(3.47x10(-2) ml x min(-1) x ml(-1)) and K1 (1.08x10(-1) ml x min(-1) x ml(-1))
were found to be significantly greater than humeral Ki (1.64x10(-2) ml min(-1)
ml(-1); P<0.0001) and K1 (3.90x10(-2) ml x min(-1) x ml(-1); P<0.0001) but no
significant differences were found in k2, k3, and k4. These findings confirm
differences in regional skeletal kinetics between lumbar vertebrae and the lower
humerus. These observations may help increase our understanding of the regional
differences in pathophysiology and response to treatment that have been observed
in sites consisting predominantly of either trabecular or cortical bone. 18F
fluoride PET may prove to be a valuable technique in the noninvasive measurement
of regional skeletal metabolism.
PMID- 10780869
TI - Alfacalcidol inhibits bone resorption and stimulates formation in an
ovariectomized rat model of osteoporosis: distinct actions from estrogen.
AB - Although alfacalcidol has been widely used for the treatment of osteoporosis in
certain countries, its mechanism of action in bone, especially in the vitamin D
replete state, remains unclear. Here we provide histomorphometric as well as
biochemical evidence that alfacalcidol suppresses osteoclastic bone resorption in
an ovariectomized rat model of osteoporosis. Furthermore, when compared with
17beta-estradiol, a representative antiresorptive drug, it is evident that
alfacalcidol causes a dose-dependent suppression of bone resorption, and yet
maintains or even stimulates bone formation, as reflected in increases in serum
osteocalcin levels and bone formation rate at both trabecular and cortical sites.
17beta-Estradiol, which suppresses bone resorption to the same extent as
alfacalcidol, causes a parallel reduction in the biochemical and
histomorphometric markers of bone formation. As a final outcome, treatment with
alfacalcidol increases bone mineral density and improves mechanical strength more
effectively than 17beta-estradiol, with a more pronounced difference in cortical
bone. We conclude that estrogens depress bone turnover primarily by suppressing
bone resorption and, as a consequence, bone formation as well, whereas
alfacalcidol "supercouples" these processes, in that it suppresses bone
resorption while maintaining or stimulating bone formation.
PMID- 10780870
TI - Premenopausal smoking and bone density in 2015 perimenopausal women.
AB - The importance of cigarette smoking in relation to bone mass remains uncertain,
especially in younger women. In a recent meta-analysis including 10 studies in
premenopausal women no effect was seen in this age group. We used baseline data
from a large national cohort study (Danish Osteoporosis Prevention Study [DOPS])
to study the cumulated effect of pre- and perimenopausal smoking on bone mineral
density (BMD) measured shortly after the cessation of cyclic bleedings. Baseline
observations on 2015 recently menopausal women were available. Eight hundred
thirty-two women were current smokers and 285 were exsmokers. Significant
negative associations of cigarette smoking coded as current, ex-, or never
smoking were seen on bone mass in the lumbar spine (P = 0.012), femoral neck
(P<0.001), and total body (P<0.001). Quantitatively, the differences between
current smokers and never smokers were limited to 1.6, 2.9, and 1.9%,
respectively. A statistical interaction was found between smoking and fat mass,
indicating that women in the highest tertile of fat mass were unaffected by
cigarette smoking. Serum vitamin D levels and osteocalcin were inversely related
to the number of cigarettes smoked per day (r = 0.11 and P<0.001; r = 0.17 and P
= 0.04), respectively. Bone alkaline phosphatase (BALP) and urinary
hydroxyproline (U-OHP) were unaffected by current smoking. The average cumulated
effect of premenopausal smoking on bone is small but biologically significant.
Reduced body mass in smokers explains part of the negative effect on the skeleton
and a complex interaction between smoking and fat mass on the skeleton is
indicated. Serum levels of 25-hydroxyvitamin D (25-OHD) and osteocalcin are lower
in smokers, which may effect rate of bone loss.
PMID- 10780871
TI - Garlic and onions: their effect on eicosanoid metabolism and its clinical
relevance.
AB - Garlic (Allium sativum) and onion (Allium cepa) are among the oldest of all
cultivated plants. Additionally, both plants have been used as medicinal agents
for thousands of years. Both garlic and onion have been shown to have
applications as antimicrobial, antithrombotic, antitumor, hypolipidaemic,
antiarthritic and hypoglycemic agents. In recent years, extensive research has
focussed on the beneficial and medicinal properties of garlic and onions. In
particular, the use of these agents in the treatment and prevention of
cardiovascular disease and cancer is an area of considerable investigation and
interest.
PMID- 10780872
TI - Fumonisin B1 influenced the effects of arachidonic acid, prostaglandins E2 and A2
on cell cycle progression, apoptosis induction, tyrosine- and CDC2-kinase
activity in oesophageal cancer cells.
AB - In a previous study, we showed that, of a group of lipids including arachidonic
acid (AA), prostaglandins E2 (PGE2) and A2 (PGA2), PGA2 had the most marked
effect on the inhibition of cell growth, activation of tyrosine kinase activity,
lowering of the number of G1-phase cells, and induction of p53 levels in
oesophageal carcinoma (WHCO3) cells. No significant effects by the three lipids
were seen in normal monkey kidney cells. In the present study, the effects of the
inhibitor of ceramide synthesis, fumonisin B1 (FB1), a metabolite of Fusarium
verticillioides (= F. moniliforme) which is implicated in the high incidence of
oesophageal cancer, were determined on AA, PGE2 and PGA2 WHCO3 treated cells. In
the presence of FB1, the lipid-enhanced tyrosine kinase activity was lowered.
Flow cytometric and morphological studies showed that FB1 lowered the marked
apoptosis induced by especially PGA2. FB1, however, in combination with AA, PGE2
or PGA2 increased the number of G2/M cells. AA>PGE2>PGA2 alone decreased CDC2
kinase activity, but, in the presence of FB1, CDC2-kinase activity was
significantly increased. The PGA2- and AA-induced p53 levels were lowered in the
presence of FB1. We concluded that FB1 diminished the cytotoxic effects of the
lipids on oesophageal tumour cells.
PMID- 10780874
TI - A simple and efficient method for hemoglobin removal from mammalian tissue
cytosol by zinc sulfate and its application to the study of lipoxygenase.
AB - A simple and efficient method is described to remove hemoglobin (Hb) from human
term placental cytosol to study dioxygenase and co-oxidase activities of
lipoxygenase. In the untreated samples, 70%-80% of the linoleic acid-dependent
dioxygenase and co-oxidase activities were found to be associated with the pseudo
lipoxygenase activity of Hb. Zinc sulfate (0.5 mM) precipitated >97% of the Hb
present in the cytosol. The dioxygenase activity of the ZnSO4 treated cytosol
exhibited a Vmax value of 313 nmoles linoleic acid hydroperoxide formed/min/mg
protein and a K(M) of 1.4 mM for linoleic acid. The ZnSO4 treated cytosol
displayed co-oxidase activity toward benzidine, dimethoxybenzidine, guaiacol,
pyrogallol, tetramethylbenzidine and tetramethyl-p-phenylenediamine.
Nordihydroguaiaretic acid, 5,8,11-eicosatriynoic acid, butylated hydroxyanisole,
butylated hydroxytoluene and gossypol caused concentration dependent inhibition
of dioxygenase and co-oxidase activities. These results suggest ZnSO4
precipitation of Hb from cytosol does not alter the functional characteristics of
the human term placental lipoxygenase.
PMID- 10780873
TI - Effect of polyunsaturated fatty acids on dexamethasone-induced gastric mucosal
damage.
AB - BACKGROUND: Increased dietary intake of polyunsaturated fatty acids (PUFAs) is
known to be associated with a decrease in the incidence of peptic ulcer disease
possibly due to increase in the synthesis of prostaglandins. But, it is also
likely that conversion of PUFAs to PGs may not always be required for gastric
mucosal protection. Present study was designed to study the role of PUFAs in
pathobiology of steroid induce gastric damage in rats. METHODS: Wistar rats were
treated with 5 mg/kg bodyweight of dexamethasone to induce gastric mucosal
ulcers. Effects of PUFAs was studied by supplementation of Fish oil (rich in n-3
EPA and DHA) and AA rich oil. Famotidine was used as a positive control.
Generation of lipid peroxides, nitric oxide and the activity of anti-oxidant
enzymes were also studied. RESULTS: Dexamethasone induced ulceration was
associated with changes in the phospholipid fatty acid profile, levels of lipid
peroxidation products, nitric oxide and activity of anti-oxidant enzymes. The
fatty acid profile showed an increase in LA and a decrease in other PUFAs like
GLA, AA, EPA and DHA. When PUFAs were supplemented in the form of Fish oil and AA
rich oil or when the animals were treated with H2-blocker, famotidine, there was
a decrease in the incidence of ulceration in the animals associated with near
normalization of changes in the phospholipid fatty acid profile. The levels of
lipid peroxides, nitric oxide, and anti-oxidant activity also reverted to control
values. CONCLUSIONS: Dexamethasone induced gastric ulceration was prevented by
PUFAs. This is supported by the results of our earlier study where in it was
noted that in patients with DU plasma lipid peroxides, nitric oxide and
phospholipid fatty acid pattern and red cell antioxidant activity were altered
similar to those seen in dexamethasone treated group of the present study. These
abnormalities, similar to the PUFA treated groups of the present study, reverted
to normalcy following treatment of the patients with lansoprazole, a proton pump
inhibitor. Further, PUFAs are known to inhibit the growth of Helicobacter pylori
in vitro. Hence, it is concluded that PUFAs, free radicals, nitric oxide and anti
oxidants play a significant role in the pathobiology of peptic ulcer.
PMID- 10780875
TI - Antioxidant activity of selected Indian spices.
AB - Spices and vegetables possess antioxidant activity that can be applied for
preservation of lipids and reduce lipid peroxidation in biological systems. The
potential antioxidant activities of selected spices extracts (water and alcohol
1:1) were investigated on enzymatic lipid peroxidation. Water and alcoholic
extract (1:1) of commonly used spices (garlic, ginger, onion, mint, cloves,
cinnamon and pepper) dose-dependently inhibited oxidation of fatty acid, linoleic
acid in presence of soybean lipoxygenase. Among the spices tested, cloves
exhibited highest while onion showed least antioxidant activity. The relative
antioxidant activities decreased in the order of cloves, cinnamon, pepper,
ginger, garlic, mint and onion. Spice mix namely ginger, onion and garlic; onion
and ginger; ginger and garlic showed cumulative inhibition of lipid peroxidation
thus exhibiting their synergistic antioxidant activity. The antioxidant activity
of spice extracts were retained even after boiling for 30 min at 100 degrees C,
indicating that the spice constituents were resistant to thermal denaturation.
The antioxidant activity of these dietary spices suggest that in addition to
imparting flavor to the food, they possess potential health benefits by
inhibiting the lipid peroxidation.
PMID- 10780876
TI - Renal synthesis of prostacyclin and thromboxane in healthy women: differential
effects of a short-term saline loading.
AB - It is accepted that the urinary excretions of the stable metabolites of
prostaglandin (PG)I2 and thromboxane(Tx) A2, 6-keto-PGF1alpha (6KPGF) and TxB2
respectively, provide an accurate estimate of both basal and stimulated renal
synthesis of their precursors. The excretory profile of these metabolites has
been evaluated in healthy women submitted to a short-term expansion in
extracellular fluid volume. Salt retention (SR group, n=6) was induced by
physiological saline (0.9% NaCl) i.v. infusions (2 L per day) over a period of 2
days. On the third day the increase in body weight was 0.92 +/- 0.27 kg (P<0.05).
The results of the study have been compared to those previously obtained in
normal balance of sodium and potassium (N group, n=20) and in induced salt
depletion (SD group, n=14). A common study protocol was used. Basal values of
plasma renin activity (PRA) and urinary aldosterone excretion were determined.
Renal functional exploration [clearance (cl.) method] was performed during
hypotonic polyuria (induced by oral water load) and subsequent moderate
antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue).
Urinary 6KPGF and TxB2 concentrations were estimated by RIA method and their
urinary excretions were determined at both high and low urinary flow rates. The
linear regressions of the urinary metabolite excretions vs. urinary flow rate
were estimated by using the data obtained in both hypotonic polyuria and
antidiuresis. Salt retention (SR vs. N group) was effective in decreasing the
basal values of plasma renin activity and urinary aldosterone excretion.
Moreover, during hypotonic polyuria it was effective in increasing the absolute
and fractional excretions of sodium and chloride, in the absence of significant
variations in mean arterial pressure and creatinine cl. Regarding urinary
prostanoid excretions the following results were obtained. 1. Comparative data
for hypotonic polyuria. In the SR vs. N group, the urinary excretion of 6KPGF was
significantly higher, whereas that of TxB2 was not significantly different. In
the SR vs. SD group, the urinary excretion of 6KPGF was not significantly
different, whereas that of TxB2 was significantly lower. 2. Comparative data for
the regression lines of the urinary prostanoid excretions vs. diuresis. In the SR
vs. N group, the regression line slope for 6KPGF excretion was significantly
higher, whereas that for TxB2 excretion was not significantly different. In the
SR vs. SD group, the regression line slope for 6KPGF excretion was not
significantly different, whereas that for TxB2 excretion was significantly lower.
3. Correlative data in the SR group during hypotonic polyuria. The plasma
chloride concentration was positively correlated with urinary flow rate, absolute
and fractional chloride excretions, and 6KPGF excretion but not with TxB2
excretion. In conclusion, functionally effective salt retention in healthy women
induces a selective stimulation of renal synthesis of prostacyclin, unlike salt
depletion, in which the synthesis of both PGI2 and TxA2 is upregulated.
PMID- 10780877
TI - Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action
of gamma linolenic acid in breast cancer cells.
AB - Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces
cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism
of these actions is not clear. We have shown that GLA acts via peroxisome
proliferator activated receptors (PPARs), by stimulating their phosphorylation
and translocation to the nucleus. Removing PPAR gamma with antisense oligos
abolished the effect of GLA on the expression of adhesion molecules and tumour
suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from
patients with breast cancer showed a reduction of expression of both PPARs in
cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor
for GLA in the regulation of gene expression in breast cancer cells.
PMID- 10780878
TI - Gamma-linolenic acid provides additional protection against ventricular
fibrillation in aged rats fed linoleic acid rich diets.
AB - Ligation of the coronary artery in rats produces severe ventricular fibrillation
(VF) and malignant cardiac arrhythmia. Mortality increases with the age of the
animal. Diets rich in saturated fatty acids (SF) but low in linoleic acid (LA)
increase, but diets high in LA and low in SF decrease the severity of VF and
mortality in older animals. The effects of an LA enriched diet can be blocked by
inhibition of cyclooxygenase suggesting that conversion of LA to eicosanoids is
central to the development of VF. Conversion of LA to gamma-linolenic acid (GLA)
via delta-6 desaturase is the first step in the process. The activity of delta-6
desaturase declines with age. Thus inclusion of GLA in the diet of older animals
may provide an additional benefit over LA alone. Dietary supplements of evening
primrose oil (EPO) to one year old rats reduced ischaemic VF more than a
supplement of sunflower seed oil (SSO) without GLA. Substitution of borage oil
(more GLA than EPO but less LA than either EPO or SSO) was without additional
benefit.
PMID- 10780879
TI - Soft tissue sarcomas and p53 mutations.
PMID- 10780880
TI - Curcumin is an in vivo inhibitor of angiogenesis.
AB - BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from
the commonly used spice turmeric. In animal models, curcumin and its derivatives
have been shown to inhibit the progression of chemically induced colon and skin
cancers. The genetic changes in carcinogenesis in these organs involve different
genes, but curcumin is effective in preventing carcinogenesis in both organs. A
possible explanation for this finding is that curcumin may inhibit angiogenesis.
MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the
proliferation of primary endothelial cells in the presence and absence of basic
fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation
of an immortalized endothelial cell line. Curcumin and its derivatives were
subsequently tested for their ability to inhibit bFGF-induced corneal
neovascularization in the mouse cornea. Finally, curcumin was tested for its
ability to inhibit phorbol ester-stimulated vascular endothelial growth factor
(VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell
proliferation in a dose-dependent manner. Curcumin and its derivatives
demonstrated significant inhibition of bFGF-mediated corneal neovascularization
in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production.
CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic
activity in vitro and in vivo. The activity of curcumin in inhibiting
carcinogenesis in diverse organs such as the skin and colon may be mediated in
part through angiogenesis inhibition.
PMID- 10780881
TI - Specific killing of HIV-infected lymphocytes by a recombinant immunotoxin
directed against the HIV-1 envelope glycoprotein.
AB - BACKGROUND: 3B3 is a high-affinity anti-gp120 antibody that neutralizes a wide
range of primary and laboratory isolates of HIV-1. The parental antibody was
isolated from a combinatorial phage display library constructed from bone marrow
RNA of an HIV-infected individual. We have generated a highly active immunotoxin
using the 3B3 single-chain Fv (scFv) which can specifically kill lymphocytes
infected by HIV-1. MATERIALS AND METHODS: We used recombinant DNA technology to
clone the Fv fragment of 3B3 and produce a single-chain Fv (scFv). 3B3 scFv was
then fused to a truncated version of Pseudomonas exotoxin A (PE38), giving rise
to a recombinant immunotoxin 3B3(Fv)-PE38 that was expressed in E. coli and
purified to near homogeneity. RESULTS: 3B3(Fv)-PE38 binds with the same affinity
as the parental Fab antibody to the MN strain of gp120. The immunotoxin
specifically kills a gp120-expressing transfected cell line and a chronically HIV
infected lymphocytic cell line. The immunotoxin is very stable at 37 degrees C,
retaining 80% of its original activity after 24 hr. CONCLUSIONS: Potent
immunotoxins such as 3B3(Fv)-PE38 could be utilized in combination with multidrug
cocktails that limit viral replication to help reduce viral reservoirs in
patients with AIDS.
PMID- 10780882
TI - Expression pattern of the Ets-related transcription factor Elf-1.
AB - Members of the Ets family of winged helix-loop-helix transcription factors play
important roles in the development and function of multiple mammalian cell
lineages. Elf-1 is an Ets-related transcription factor that is expressed at high
levels in T cells and is known to regulate the expression of several T cell
genes, including the granulocyte-macrophage colony stimulating factor (GM-CSF)
gene, the interleukin-2 receptor alpha subunit (IL-2Ralpha) gene, and the CD4
gene. In the studies described in this report, we have characterized the pattern
of expression of Elf-1 in the developing mouse embryo and in adult mouse tissues
as well as in multiple immortalized human and murine cell lines. Elf-1 is
expressed at high levels throughout thymocyte development, with equivalent levels
of Elf-1 expression seen in all subsets of maturing thymocytes and T cells.
Somewhat surprisingly, however, Elf-1 is also expressed at high levels in
epithelial cells lining the oral cavity, the lung, the CNS, and the
gastrointestinal and urinary tracts as well as in the skin of the developing
mouse embryo and at lower levels in the adult mouse testis and liver. Western
blot analyses of a large number of immortalized cell lines demonstrated high
level Elf-1 expression in T and B lymphocyte and macrophage cell lines as well as
in two prostate carcinoma cell lines. Low-level expression was observed in
fibroblasts, embryonic stem cells, and myoblasts. Taken together, our data
suggest that in addition to its role in regulating T cell development and
function, Elf-1 may regulate gene expression in the B cell and myelomonocytic
lineages, as well as in multiple epithelial cell types during murine embryonic
development.
PMID- 10780883
TI - Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor
confers resistance to the antiproliferative effect of interferon-alpha.
AB - BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 442 amino
acid polypeptide-designated viral interferon regulatory factor (vIRF) that
displays homology to members of the interferon regulatory factor (IRF) family
that bind to consensus interferon sequences and transactivate cellular genes that
can modulate growth inhibition. Studies were conducted to determine whether vIRF
affects the growth suppression mediated by interferon-alpha (IFN-alpha) in a
human B lymphocyte cell line. MATERIALS AND METHODS: The human B lymphocyte cell
line Daudi, which is sensitive to the antiproliferative effects of IFN-alpha, was
stably transfected to express vIRF, and the proliferative response of vIRF
expressing cells to IFN-alpha was compared with controls. The effect of vIRF on
IRF- 1 transactivation was analyzed by co-transfection of an IFN-alpha-responsive
chloramphenicol acetyltransferase reporter and expression plasmids encoding IRF-1
and vIRF. Electrophoretic mobility shift assays were conducted to determine
whether vIRF interferes with the DNA binding activity of IRF-1. RESULTS: Daudi
human B lymphocyte cells expressing vIRF were resistant to the antiproliferative
effects of IFN-alpha, whereas wild-type Daudi or Daudi cells transformed with
vector DNA were growth inhibited by IFN-alpha. The activation of an interferon
responsive reporter by IFN-alpha or IRF-1 was repressed by expression of vIRF.
IRF-1 DNA binding activity was unaffected by vIRF, and vIRF alone did not bind to
the interferon consensus sequence. CONCLUSIONS: These studies revealed that vIRF
functions to inhibit interferon-mediated growth control of a human B lymphocyte
cell line by targeting IRF-1 transactivation of interferon-inducible genes. Since
KSHV is a B lymphotropic herpesvirus associated with two forms of B lymphocyte
neoplasms, these effects of vIRF likely contribute to B cell oncogenesis
associated with KSHV infection.
PMID- 10780884
TI - Reversal of established rat crescentic glomerulonephritis by blockade of
macrophage migration inhibitory factor (MIF): potential role of MIF in regulating
glucocorticoid production.
AB - Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory
cytokine that also counter-regulates glucocorticoid action. We investigated
whether immunoneutralization of MIF could reverse established experimental
crescentic glomerulonephritis and if this treatment could modulate endogenous
glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six
littermate pairs of rats. Once crescentic disease was established on day 7, one
animal in each pair was given a daily injection of neutralizing anti-MIF antibody
(Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In
addition, a group of 6 animals was killed on day 7 of disease without any
treatment. Animals receiving the control Ab exhibited a rapidly progressive
glomerulonephritis with severe renal injury (proteinuria), loss of renal function
(creatinine clearance), anemia, and marked histologic damage (including
glomerular crescent formation), compared with animals killed on day 7 without
treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by
restoring normal renal function and reducing histological damage compared with
untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab
treatment also prevented severe anemia (p < 0.05). Reversal of disease was
associated with a significant reduction in leukocyte infiltration and activation
and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment
caused a significant increase in endogenous serum corticosterone levels, which
correlated with the reversal of disease parameters. In conclusion, this study has
demonstrated that blocking MIF activity can partially reverse established
crescentic glomerulonephritis and suggests that MIF operates by both enhancing
the cellular immune response and suppressing the endogenous anti-inflammatory
glucocorticoid response.
PMID- 10780885
TI - Moulds, mites and childhood asthma.
PMID- 10780886
TI - Beta-adrenoceptor agonists in bronchial asthma: role of k+-channel opening in
mediating their bronchodilator effects.
PMID- 10780887
TI - Importance of house dust mite and Alternaria allergens in childhood asthma: an
epidemiological study in two climatic regions of Australia.
AB - The relation of house dust mite allergen levels to asthma and allergy was
examined in two population samples of children aged 8-11 years in northern New
South Wales. We studied 805 children in Lismore (a hot, humid, coastal region)
and 770 in Moree/Narrabri (a hot, dry inland region). Respiratory symptoms were
measured by questionnaire, bronchial hyperresponsiveness (BHR) by histamine
inhalation test, and allergy by skin-prick tests. Current asthma was defined as
the presence of both wheeze in last 12 months and BHR. Der p I levels were
measured in dust from the bed and floors in the homes of 57 randomly selected
children in the coastal region and of 74 inland children. Der p I levels were
significantly higher by the coast (83.0 vs 11.2 microg/g, P < 0.001). House dust
mite sensitivity was of similar prevalence in both regions (28.6 vs 26.4%, n.s.)
but Alternaria sensitivity was higher inland (4.0 vs 15.2% P<0.001). Bronchial
responsiveness was more severe in coastal children sensitized to house dust mites
and in inland children who were sensitized to Alternaria. The adjusted odds
ratios for current asthma in children sensitized to house dust mites were 21.3
(95% CI 10.5, 43.2) by the coast and 2.7 (95% CI 1.3, 5.4) inland, and in
children sensitized to Alternaria were 3.4 (95% CI 1.3, 9.1) in the coastal
region and 5.6 (95% CI 3.1, 10.1 inland. These studies suggest that high house
dust mite allergen levels in a humid, subtropical region act to significantly
increase bronchial responsiveness in sensitized children, and that Alternaria
allergens have a similar but less potent action in a dry, rural region.
PMID- 10780889
TI - Familial occurrence of atopic disease: genetic versus environmental factors.
AB - Cumulative life prevalence of atopic disease (any of reported symptoms of
asthma/wheezy bronchitis, allergic rhinitis, eczema and urticaria) was studied by
means of a questionnaire in 19814 (7-, 10- and 14-year-old) Swedish school
children and their parents. Maternal history was found to be twice as common as
paternal history. The children of affected mothers contracted atopic disease in
the same proportion as the children of affected fathers yielding twice as many
affected children with affected mothers than with affected fathers. The strongest
parental influence on childhood disease was seen for multiple symptoms and for
congruent symptoms with both parents. The number of children with both parents
affected was 1.6 times larger than expected. A possible dose-response effect in
polygenic inheritance is discussed as well as assumed impact of environmental
factors with a tendency to familial clustering.
PMID- 10780888
TI - Early neutrophil but not eosinophil or platelet recruitment to the lungs of
allergic horses following antigen exposure.
AB - Previous studies have shown that bronchoalveolar lavage fluid from horses with
allergic respiratory disease and showing clinical symptoms contains increased
numbers of neutrophils. In some cases, the eosinophil count is also increased. In
this study the time course of changes in lung function and the accumulation of
radiolabelled leucocytes and platelets in the lungs of allergic and normal horses
has been examined during a 7 hr allergen exposure. Antigen challenge had no
effect on pleural pressure or the distribution of radiolabelled neutrophils,
eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses,
there was an increase in pleural pressure and neutrophil accumulation in the
lungs, both of which were evident after 4-5 hr. However, during the 7 hr
challenge period radiolabelled eosinophils were detected in the lungs of only 1/6
horses exhibiting an increase in pleural pressure and in 1/7 horses that failed
to show a change in airway function despite a clinical history of allergic
respiratory disease. Antigen challenge did not alter the distribution of
radiolabelled platelets in the five allergic horses tested. These results
demonstrate that increased pleural pressure is not accompanied by eosinophil or
platelet accumulation in the lungs of horses with allergic respiratory disease
following exposure to antigen. However, changes in airway function can be
associated with neutrophil accumulation but can also take place in the absence of
this cell recruitment. This raises the possibility that the presence of
neutrophils in the lung is not a prerequisite for changes in lung function.
PMID- 10780890
TI - Optimized preparation of Aspergillus fumigatus extracts for allergy diagnosis.
AB - Extracts of Aspergillus fumigatus are required for the measurement of specific
antibodies that are important indices in the diagnosis of allergic
bronchopulmonary aspergillosis (ABPA). This study investigated the effect of
different culture conditions on the production and release of antigenic and
allergenic proteins of A. fumigatus. Increasing the incubation temperature from
25 degrees C to 37 degrees C altered the production of proteins by the mycelium
which resulted in the release of a greater number of proteins that reacted with
precipitating antibodies. Static sporulating cultures produced a much wider
antigenic spectrum than shake cultures although the number of precipitating
proteins (5 and 3 respectively) and major IgE binding proteins (5 and 3
respectively) was not greatly altered. The widest range of proteins bound by
precipitating antibody or IgE from ABPA serum were released into the culture
filtrate during 28 day static incubation at 37 degrees C. The resultant extract
proved useful for screening patients for specific IgE and will provide a starting
material for the identification of individual antigens or allergens.
PMID- 10780891
TI - Inhibition of bronchial hyperresponsiveness to histamine induced by intravenous
administration of leukotriene C4 by novel thromboxane A2 receptor antagonists ONO
NT-126 and ONO-8809 in guinea-pigs.
AB - We studied the effect of intravenous administration of leukotriene (LT) C4 on
bronchial responsiveness to histamine and airway wall thickening in guinea-pigs.
Guinea-pigs were killed and the lungs were fixed in formalin. Slides from
paraffin-embedded sections of the lungs were stained and the airways that were
cut in transverse sections were measured by tracing enlarged images using a
digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary
mechanics analyser and we calculated two indices, an index of airway wall
thickening and the one of airway hyperresponsiveness to histamine, from changes
of baseline-Raw and peak-Raw following intravenous administration of histamine
before and after the intravenous administration of LTC4. Intravenous
administration of 3 microg/kg LTC4 for 1 hr induced an increase of the relative
thickness of the airway wall in peripheral bronchi by the histological
examination. In analysis of airway function, intravenous administration of 3
microg/kg LTC4 for 1 hr induced airway hyperresponsiveness to histamine with
airway wall thickening. Thromboxane A2 receptor antagonists ONO-NT-126 and ONO
8809 inhibited the LTC4-induced airway hyperresponsiveness to histamine in a dose
dependent manner, but not the airway wall thickening induced by LTC4, suggesting
that the effect of LTC4 on bronchial hyperresponsiveness is likely to be mediated
through TXA2.
PMID- 10780892
TI - IgG and IgA subclass antibodies against Aspergillus umbrosus in farmer's lung
disease.
AB - Fifty patients with farmer's lung disease (FL), 20 asymptomatic exposed farmers,
and 18 healthy controls were investigated for total IgG and total IgA, as well as
subclass antibody levels against Aspergillus umbrosus, the most common fungus to
which FL patients in Finland have been exposed. Enzyme-linked immunosorbent assay
(ELISA) revealed significantly elevated levels of specific total IgG and IgA
antibodies in the sera of patients during the acute phase of the disease. Both
IgG1 and IgG2 subclass antibodies and both IgA1 and IgA2 subclass antibodies were
significantly associated with the disease. The antibody levels decreased during
the first 3 months, when mould exposure was avoided and when an oral 6-week
steroid treatment was administered. During the next 12 month follow-up, the mean
antibody levels continued to decrease, even though re-exposure might have
occurred. The results (with sensitivity 94% and specificity 95%) imply that in
addition to the measurement of A. umbrosus-specific IgG, determination of both A.
umbrosus-specific IgG1 and IgA might also be useful in the serodiagnosis of acute
stage of FL.
PMID- 10780893
TI - A retrospective study on the safety of immunotherapy in pregnancy.
AB - Eighty-one Indian patients received immunotherapy for allergic diseases during
109 pregnancies. Their allergy clinic records were analysed retrospectively and
this revealed an incidence similar to or less than the general population with
regard to abortion, perinatal mortality, prematurity, toxaemia and congenital
malformation. A control group of 60 contemporary Indian patients (82 pregnancies)
who refused immunotherapy were also analysed retrospectively and this revealed a
higher incidence of abortion, prematurity and toxaemia as compared with those
treated with immunotherapy. It is concluded that immunotherapy for allergic
diseases is safe in pregnancy. Immunotherapy is safe even when it is initiated
for the first time in a pregnant patient, an aspect not reported in any study
until now.
PMID- 10780894
TI - Lack of role for mononuclear cell-derived histamine releasing factors in
occupational asthma due to western red cedar.
AB - Occupational asthma due to Western Red Cedar (WRCA) is attributed to
sensitization to plicatic acid (PA), but does not appear to be dependent on PA
specific IgE antibodies. Exposure to PA induces histamine release in vivo and in
vitro, so if IgE is not important, other mechanisms of histamine release must
presumably operate in WRCA. To explore the possible role of histamine-releasing
factors in WRCA, peripheral blood mononuclear cells were obtained and cultured
with PA, PA-albumin conjugate plicatic acid-human serum albumin (PA-HSA), grass
pollen or Concanavalin A using a standard histamine releasing factor (HRF)
generation protocol. Supernatants were dialysed to remove endogenous histamine
and then assayed for histamine releasing activity using human basophils as
targets and a Con A-induced bulk supernatant as an internal HRF standard. In
contrast to some previous reports, spontaneous HRF release from the peripheral
blood mononuclear cells (PBMC) of WRCA patients (n=9) and atopic asthmatic
subjects (n=5) was not elevated compared with the non-asthmatic controls (n=11;
five atopic and six non-atopic). Both PA and PA-HSA induced the production of
small amounts of HRF by PBMC of WRCA patients, but a similar degree of HRF
generation was also observed in PBMC from the atopic asthmatic, atopic
nonasthmatic, and non-atopic subjects. In contrast, grass pollen induced the
production of HRF by PBMC from the subjects with positive skin tests to grass
pollen but not by PBMC of non-atopic subjects, confirming that our methods and
assay were capable of detecting antigen-specific HRF production. Since neither PA
nor PA-HSA induced significantly elevated HRF production from PBMC of WRCA
patients, it seems unlikely that PA-induced HRFs play a substantial role in the
pathogenesis of WRCA.
PMID- 10780895
TI - Study of eosinophil-endothelial adhesion, production of oxygen radicals and
release of eosinophil cationic protein by peripheral blood eosinophils of
patients with rheumatoid arthritis.
AB - Beside lymphocytes and neutrophils, eosinophils are also involved in the
inflammatory reaction in rheumatoid arthritis (RA). In this study, adhesion
characteristics of peripheral blood eosinophils were studied in 43 RA patients
and 19 controls, together with the expression of the beta2-integrin Mac-1
(CD11b/CD18). In addition, the production of oxygen radicals of isolated
peripheral blood eosinophils and serum levels of eosinophil cationic protein
(ECP) were measured in order to evaluate eosinophil activation. Adhesion of
eosinophils to unstimulated human vascular endothelium was significantly higher
in RA patients with active disease (n = 4) compared with controls (n = 14) (P <
0.005) and compared with patients with less active RA (n = 16) (P < 0.05).
Nevertheless, the expression of the adhesion molecule Mac-1 (CD11b/CD18) was not
increased in RA patients. ECP levels were higher in RA patients with active
disease (P < 0.01). Release of oxygen radicals in response to phorbol stimulation
was significantly elevated in active RA compared with controls (P < 0.05) and to
less active RA (P < 0.05). We conclude that eosinophils of RA patients,
especially those with active disease, are activated or at least primed and are
involved in the inflammatory process in RA, analogous to the inflammation in
asthma. The higher adhesion to inflamed endothelium is indicative of a higher
infiltration in the joints, where tissue damage can be caused by toxic oxygen
radicals and by granular proteins, such as ECP.
PMID- 10780896
TI - Genetic polymorphism of the beta-2 adrenergic receptor in atopic and non-atopic
subjects.
AB - To investigate a possible genetic basis for reported differences in beta-2
receptor expression in atopic subjects, DNA from 42 atopic children (22
asthmatics and 22 with allergic rhinitis) and 30 non-atopic subjects was Southern
blotted and Ban-1 restriction fragment polymorphisms (RFLPS) were studied using a
2.6 kb probe of the human beta-2 receptor gene. Two alleles 3.1 kb and 2.9 kb
were identified. Homozygotes and heterozygotes for the two alleles were found
with equal frequency in the atopic patients who had asthma and in those who had
allergic rhinitis only. The gene frequencies for the upper and lower alleles were
0.45 and 0.55 respectively. Our studies do not provide evidence for an
association between a particular polymorphic form of the human beta-2 receptor
gene and atopy.
PMID- 10780897
TI - Occupational allergy to bumble bee venom.
PMID- 10780898
TI - Cutaneous late-phase response in food-allergic children and adolescents with
atopic dermatitis.
PMID- 10780899
TI - GABA-Activated ligand gated ion channels: medicinal chemistry and molecular
biology.
PMID- 10780900
TI - A study of the relationship between biological activity and prolyl amide isomer
geometry in oxytocin using 5-tert-butylproline to augment the Cys(6)-Pro(7) amide
cis-isomer population.
AB - Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5
tert-butylproline for proline in oxytocin, [Mpa(1)]oxytocin, and
[dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t
BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor;
however, both peptides maintained the pharmacophore characteristics responsible
for signal transfer evoking the same maximal response as oxytocin in the single
dose procedure and exhibiting partial agonistic activity in the cumulative dose
response procedure. Although [dPen(1)]oxytocin exhibited inhibitory as well as
partial agonistic activity, [dPen(1),5-t-BuPro(7)]oxytocin exhibited only
inhibitory potency with a similar in vitro pA(2) value of 7.50 in the absence of
magnesium. In the presence of magnesium, [dPen(1), 5-t-BuPro(7)]oxytocin
exhibited stronger inhibitory potency than [dPen(1)]oxytocin and no partial
agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis-
and trans-isomers by two-dimensional NMR experiments in water indicated that the
Cys(6)-Pro(7) peptide bond cis-isomer population was augmented relative to the
prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert
butylproline(7) analogues of oxytocin, [Mpa(1)]oxytocin and [dPen(1)]oxytocin.
Although caution must be taken when relating the increase in cis-isomer
population with an influence on biological activity in [5-t-BuPro(7)]oxytocin
analogues, the synthesis and evaluation of analogues 1-3 have provided additional
evidence that can be used to support the hypothesis that the prolyl amide cis
isomer may favor antagonism and the trans-isomer is necessary for agonist
activity.
PMID- 10780901
TI - 3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related
to diazoxide and pinacidil as potassium channel openers acting on vascular smooth
muscle cells: design, synthesis, and pharmacological evaluation.
AB - A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides
structurally related to diazoxide and pinacidil were synthesized and tested as
possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well
as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to
previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1
dioxides, most of the new compounds were found to be poorly active on B-cells but
exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H
pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2
butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds
bearing the alkyl side chain of pinacidil, were found to be the most active
representatives of their respective series on rat aorta rings. 3
Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4
thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically
stimulated guinea pig ileum and on oxytocin-induced contractions of the rat
uterus. Further biological investigations ((86)Rb efflux measurements,
vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and
presence of glibenclamide) revealed that compounds 4d and 5d, but not compound
5f, expressed the pharmacological profile of classical K(ATP) channel openers. In
conclusion, by changing the position of the nitrogen atom in the pyridine ring,
we now have obtained a family of drugs expressing an opposite tissue selectivity.
Taken as a whole, the present findings also suggest that 3-alkylamino-4H
pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be
considered as new examples of K(ATP) channel openers expressing a pharmacological
profile similar to that of pinacidil and diazoxide.
PMID- 10780902
TI - Improving the oral bioavailability of the iron chelator HBED by breaking the
symmetry of the intramolecular H-bond network.
AB - Physicochemical analysis and Monte Carlo simulations were used to identify
structural features which prevent oral absorption of HBED, a potent iron
chelator. In water the dominant conformations of HBED involve the hydrophobic
collapse of the two aromatic rings. These conformations are favored in polar
media because they expose the polar phenolic hydroxy groups to the solvent and
partially shield the nonpolar aromatic rings. In a less polar solvent such as
chloroform, a symmetrical H-bond network between the carboxylates and the amines
dominates the conformational space. This leads to the exposure of the phenolic
hydroxy groups to the solvent, which is unfavorable for solvation. The low
solubility of HBED in nonpolar solvents was confirmed experimentally by
determination of the partition coefficients in octanol, chloroform, and
cyclohexane and may explain the poor membrane permeability of this compound. The
high conformational stability which disfavors partitioning into phospholipids is
mainly due to the symmetrical H-bond network. Potentiometric titrations of a
monoester of HBED in MeOH/water indicate that the protonation sequence was
changed compared to that of the parent compound, suggesting that the symmetrical
H-bond network was disrupted. Conformational analysis in chloroform confirmed
that, in contrast to HBED, no symmetric interaction between the carboxylate and
the nitrogen amines is possible in the half-ester and a variety of conformations
which allow partial shielding of the polar phenolic OH groups are energetically
possible. This theoretical model predicting a better solubility of the half
esters in nonpolar solvents was supported by the large increase in the partition
coefficients in octanol, chloroform, and cyclohexane measured experimentally. The
high absorbability predicted by physicochemical and computer simulation methods
was corroborated by in vivo experiments in marmoset monkeys where the monoethyl
ester derivative of HBED was well-absorbed orally while the parent compound was
nearly ineffective in the same model.
PMID- 10780903
TI - Study on selectin blocker. 8. Lead discovery of a non-sugar antagonist using a 3D
pharmacophore model.
AB - We have developed a pharmacophore model of a ligand/E-selectin complex to screen
drug candidates for selectin blockers. In a series of sugar mimetic studies of
the E-selectin ligand, sialyl Lewis X (sLe(x)), we have already found a potent
compound, a sulfated Le(x) analogue (1), and also have proposed how compound 1
binds to E-selectin (Tsujishita, H.; Hiramatsu, Y.; Kondo, N.; Ohmoto, H.; Kondo,
H.; Kiso, M.; Hasegawa, A. J. Med. Chem. 1997, 40, 362-369). To find drug
candidates that fit into the binding pocket of E-selectin, we constructed an
original 3D-pharmacophore model from structural information of a compound 1/E
selectin complex model and screened lead compounds for selectin blockers using a
commercially available database ACD-3D. As a result, we discovered a lead
compound (2) containing good selectin inhibitory activity, and in addition, we
succeeded to preliminarily optimize it to a more active lead compound (3) with
micromolar IC(50) values, based on the 3D-pharmacophore model investigation. This
methodology using the 3D-pharmacophore model could be applicable as a pre-screen
system for selectin blockers.
PMID- 10780904
TI - Synthesis and evaluation of several new (2-chloroethyl)nitrosocarbamates as
potential anticancer agents.
AB - Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential
anticancer alkylating agents. These compounds were designed with carrier moieties
that would either act as prodrugs or confer water solubility. All compounds were
screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD
1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents
showed good activity with IC(50) values in the range of 1-10 microg/mL against at
least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso
4-acetoxybenzyl ester (3), was selected for further study in vivo against
intraperitoneally implanted P388 murine leukemia. In addition to the
aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl
ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4, 6-tetra-O-acetyl-1
alpha,beta-D-glucopyranose ester (24) were evaluated against subcutaneously
implanted M5076 murine sarcoma in mice. None of these compounds were active in
vivo.
PMID- 10780905
TI - Synthesis and in vitro evaluation of novel morpholinyl- and
methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy-2-naphthyl)propionic acid
(Naproxen) for topical drug delivery.
AB - Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters
of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro
for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f
were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the
morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of
dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and
quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen in human serum.
Compounds 3c-f showed higher aqueous solubility and similar lipophilicity,
determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0
when compared to naproxen. At pH 7.4 they were significantly more lipophilic than
naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin
permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present
study indicates using a methylpiperazinyl group yields prodrugs that are
partially un-ionized under neutral and slightly acidic conditions, and thus, a
desirable combination is achieved in terms of aqueous solubility and
lipophilicity. Moreover, the resulting combination of biphasic solubility and
fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave
improved topical delivery of naproxen.
PMID- 10780906
TI - AMP deaminase inhibitors. 2. Initial discovery of a non-nucleotide transition
state inhibitor series.
AB - A series of N3-substituted coformycin aglycon analogues are described that
inhibit adenosine 5'-monophosphate deaminase (AMPDA) or adenosine deaminase
(ADA). The key steps involved in the preparation of these compounds are (1)
treating the sodium salt of 6, 7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4)
with an alkyl bromide or an alkyl mesylate to generate the N3-alkylated compound
5 and (2) reducing 5 with NaBH(4). Selective inhibition of AMPDA was realized
when the N3-substituent contained a carboxylic acid moiety. For example, compound
7b which has a hexanoic acid side chain inhibited AMPDA with a K(i) = 4.2 microM
and ADA with a K(i) = 280 microM. Substitution of large lipophilic groups alpha
to the carboxylate provided a moderate potency increase with maintained
selectivity as exemplified by the alpha-benzyl analogue 7j (AMPDA K(i) = 0.41
microM and ADA K(i) > 1000 microM). These compounds, as well as others described
in this series of papers, are the first compounds suitable for testing whether
selective inhibition of AMPDA can protect tissue from ischemic damage by
increasing local adenosine concentrations at the site of injury and/or by
minimizing adenylate loss.
PMID- 10780907
TI - AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon
analogues.
AB - N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA)
inhibitory potency are described. Replacement of the 5-carboxypentyl substituent
in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8-tetrahydroimidazo[4,5
d][1, 3]diazepin-8-ol (2) described in the previous article with various
carboxyarylalkyl groups resulted in compounds with 10-100-fold improved AMPDA
inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two
carbon alkyl tether. For example, 3-[2-(3-carboxy-5-ethylphenyl)ethyl]-3,6,7,8
tetrahydroimidazo[4, 5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a
K(i) = 0. 06 microM. The compounds within the series also exhibited >1000-fold
specificity for AMPDA relative to adenosine deaminase.
PMID- 10780908
TI - AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues:
N3-alkylmalonates as ribose 5'-monophosphate mimetics.
AB - AMP deaminase (AMPDA) inhibitors increase the levels of extracellular adenosine
and preserve intracellular adenylate pools in cellular models of ATP depletion
and therefore represent a potential new class of antiischemic drugs. Recently we
reported that replacement of the ribose 5'-monophosphate component of the very
potent transition-state analogue AMPDA inhibitor coformycin monophosphate (1)
with a simple alkylcarboxy group resulted in potent, selective, and cell
penetrating AMPDA inhibitors. Here we report that replacement of this
alkylcarboxy group with an alpha-substituted alkylmalonic acid resulted in
enhanced inhibitor potency. The lead compound, 3-(5, 5-dicarboxy-6-(3
(trifluoromethyl)phenyl)-n-hexyl)coformycin aglycon (21), exhibited an AMPDA K(i)
of 0.029 microM which is (3 x 10(5))-fold lower than the K(M) for the natural
substrate AMP. A comparison of inhibitory potencies shows that the diacid
analogues with alpha-benzyl substituents are 2-10-fold more inhibitory than
similar monoacid-monoester, monoester-monoamide, or diester derivatives. Finally,
these diacid analogues are 2-40-fold more potent inhibitors than the
corresponding monocarboxylates.
PMID- 10780909
TI - Soft drugs. 12. Design, synthesis, and evaluation of soft bufuralol analogues.
AB - In the search for more potent but still short-acting beta-blockers (BB), the
methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 2-(1-adamantyl)ethyl, and
methylthiomethyl esters of the acidic inactive metabolite of bufuralol were
synthesized based on the "inactive metabolite" approach. The cleavage of the
ester bond by blood and tissue esterases rapidly deactivates these compounds,
resulting in an ultrashort duration of action. The beta-antagonist potencies and
time courses of actions of the new "soft" BBs were characterized by recording ECG
and intra-arterial blood pressure (BP) in rats. In the isoproterenol-induced
tachycardia model, while bufuralol at an iv dose of 1 mg/kg (3.8 micromol/kg)
diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted
for only 10-30 min at equimolar dose. The inactive metabolite did not decrease HR
significantly. The first four members of this series of compounds showed the
highest beta-blocking potencies, ranging between 25% and 50% of that of
bufuralol. Next, the effects of these most active compounds on resting HR and BP
were evaluated in comparison to esmolol. Infused for 10 min at a rate of 20
micromol/kg/min, esmolol decreased HR and mean arterial pressure (MAP) by 40% and
60%, respectively. The soft drugs at doses ranging only between 2 and 4
micromol/kg/min resulted in a 20-40% decrease in HR and a 30-50% reduction in
MAP. However, the time courses of both the bradycardic and hypotensive effects of
the soft drugs were superimposable to that of esmolol, diminishing within 60 min
after the discontinuation of the infusions.
PMID- 10780910
TI - Structure-activity relationships and binding mode of styrylquinolines as potent
inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture.
AB - Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1
integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at
nontoxic concentrations. To explore the mechanism of action of these inhibitors,
various novel styrylquinoline derivatives were synthesized and tested against HIV
1 IN and in cell-based assays. Regarding the in vitro experiments, the structural
requirements for biological activity are a carboxyl group at C-7, a hydroxyl
group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the
in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the
introduction of various substituents or its replacement by heteroatomic nuclei.
Regarding the ex vivo assays, the structural requirements for activity are more
stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid
group in the quinoline, the presence of one ortho pair of substituents at C-3'
and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is
imperatively required for inhibitory potency. Starting from literature data and
the SARs developed in this work, a putative binding mode of styrylquinoline
inhibitors to HIV-1 IN was derived.
PMID- 10780911
TI - Synthesis and preliminary biological evaluations of CC-1065 analogues: effects of
different linkers and terminal amides on biological activity.
AB - CC-1065 analogues possessing a biologically active CBI functional group and amide
substituted indole and benzofuran were synthesized. The IC(50) values of
compounds 26, bearing two indoles, and 25, bearing only one indole, are 0.4 and 3
nM, respectively, against U937 leukemia cells in vitro. The IC(50) values of
compounds 28, bearing a butyramino group, and 27, bearing an acetamino group, are
0.008 and 0.4 nM, respectively, against U937 leukemia cells in vitro. Compound
29, bearing a double-bond linker, is about 4-fold more potent than 25, bearing no
double-bond linker. Compound 26 is highly potent against all cell lines tested in
the NCI in vitro screening with IC(50) values in the 0.1-5 nM range for most cell
lines. Compounds 26 and 30 are highly active against L1210 leukemia in mice.
Compound 26 is also active against B16BL6 melanoma in mice. Most importantly, 26
and 30 are not myelosuppressive at therapeutically effective doses. The mechanism
of tumor cell death is through induction of apoptosis, and is accompanied by DNA
fragmentation.
PMID- 10780912
TI - Structural studies on bioactive compounds. 32. Oxidation of tyrphostin protein
tyrosine kinase inhibitors with hypervalent iodine reagents.
AB - Hydroxylated styrenes (tyrphostins) undergo oxidation by hypervalent iodine
oxidants such as [(diacetoxy)iodo]benzene (DAIB) to give a range of products
depending on the structure of the phenolic substrate, the solvent, the oxidant
stoichiometry, and the purification strategy. Conditions have been developed to
modify the phenolic component of the tyrphostin without affecting the appended
substituted-vinyl moiety. Novel products include: unstable 2-acyloxy-2-methoxy-4
(substituted-vinyl)cyclohexadienones and their rearrangement products 2-acyloxy-4
hydroxy-3-methoxy-1-(substituted-vinyl)benzenes; phenyliodoniophenolates and
their rearrangement products iodophenoxytyrphostins; and 3,3'-dialkoxy-2,2'
dihydroxy-5, 5'-di(substituted-vinyl)biphenyls. None of these oxidation products
displayed enhanced activity in vitro in the NCI 60-cell line panel or in a panel
of human breast cancer cell lines, compared to their tyrphostin precursors. The
inhibitory activity of three representative tyrphostins (3e,n, 28) was not
modulated by aerobic/anaerobic conditions in MCF-7 and MDA 468 cells and was
independent of EGFR status in clones of ZR75B cells transfected with this
receptor. Basal growth of MCF-7 cells was unaffected by co-administration of the
growth factors EGF, TGF-alpha, IGF-I, and IGF-II, and the new agents did not
inhibit EGFR and c-erbB2 autophosphorylation in cell lysates from MDA 468 or
SkBr3 cells, respectively, suggesting that receptor tyrosine kinases are not
targets for these compounds. Growth stimulation by the tyrphostin 3n in the ER(+)
breast cell lines MCF-7, T47D, and ZR75-1 was abolished by 1 microM tamoxifen,
suggesting that this compound has estrogen agonist activity.
PMID- 10780913
TI - Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA
affinic tetra- and pentacyclic acridines.
AB - New synthetic routes to a series of tetra- and pentacyclic acridines related in
structure to marine natural products are reported. The novel water-soluble agent
dihydroindolizino[7,6,5-kl]acridinium chloride 14 has inhibitory activity in a
panel of non-small-cell lung and breast tumor cell lines exceeding that of m
AMSA. The salt inhibited the release of minicircle products of kDNA confirming
that disorganization of topoisomerase II partly underlies the activity of the
compound. COMPARE analysis of the NCI mean graph profile of compound 14 at the
GI(50) level corroborates this conclusion with Pearson correlation coefficients
(>0.6) to clinical agents of the topoisomerase II class: however, this
correlation was not seen at the LC(50) level. The inhibitory action of 14 on
Saccharomyces cerevisiae transfected with human topoisomerase II isoforms showed
a 3-fold selectivity against the IIalpha isoform over the IIbeta isoform. Unlike
m-AMSA, 14 is not susceptible to P-glycoprotein-mediated drug efflux and retains
activity in lung cells with derived resistance to the topoisomerase II inhibitor
etoposide.
PMID- 10780914
TI - Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and
kappa opioid receptors: molecular recognition loci for the pharmacophore and
address components of kappa antagonists.
AB - Molecular modifications of both the kappa opioid antagonist norbinaltorphimine
(norBNI, 1) and the kappa receptor have provided evidence that the selectivity of
this ligand is conferred through ionic interaction if its N17' protonated amine
group (an "address") with a nonconserved acidic residue (Glu297) on the kappa
receptor. In the present study, we have examined the effect of structural
modifications on the affinity of norBNI analogues for wild-type and mutant kappa
and mu opioid receptors expressed in COS-7 cells. Compounds 2, 3, and 7, which
have an antagonist pharmacophore and basic N17' group in common with norBNI,
retained high affinity for the wild-type kappa but exhibited greatly reduced
affinity for mutant kappa receptors (E297K and E297A). Modification of the
phenolic or N-substituent groups of the antagonist pharmacophore (4 and 5) or
removal of basicity at the address N17' center (6) led to greatly reduced
affinity for the wild-type and mutant receptors. The reduced affinity upon
modification of the kappa receptor is consistent with the ionic interaction of
the protonated N17' group of kappa antagonists (1-3, 7) with the carboxylate
group of E297 at the top of TM6. This was supported by the greatly enhanced
affinity of compounds 1-3 for the mutant mu receptor (K303E), as compared to the
wild-type mu receptor, given that residue K303 occupies a position equivalent to
that of E297 in the kappa receptor. In view of the high degree of homology of the
seven TM domains of the kappa and mu opioid receptors, it is suggested that the
antagonist pharmacophore is bound within this highly conserved region of the
kappa or mutant mu receptor and that an anionic residue at the top of TM6 (E297
or K303E, respectively) provides additional binding affinity.
PMID- 10780915
TI - Synthesis and evaluation of tryprostatin B and demethoxyfumitremorgin C
analogues.
AB - Tryprostatin B and demethoxyfumitremorgin C are fungal inhibitors of mammalian
cell cycle progression at the G(2)/M transition. N-Alkyl derivatives of the L-Trp
L-Pro diketopiperazine were prepared as analogues of tryprostatin B, and two of
these were more active than the natural product. A second series of cis- and
trans-tetrahydro-beta-carbolines annulated to a diketopiperazine were prepared as
analogues of demethoxyfumitremorgin C. The nature of the alkyl substituent, as
well as its cis or trans relationship in the tetrahydro-beta-carboline ring, was
found to have a significant effect on cytotoxic activity. Small cis-alkyl
substituents fall into the demethoxyfumitremorgin C family, whereas bulky benzyl
trans compounds appear to act via a different mechanism of action.
PMID- 10780916
TI - Structure-activity studies for a novel series of tricyclic substituted
hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents
for the symptomatic treatment of benign prostatic hyperplasia (BPH).
AB - In search of a uroselective agent that exhibits a high level of selectivity for
the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles
was synthesized. A generic pharmacophoric model was developed requiring the
presence of a basic amine core and a fused heterocyclic side chain separated by
an alkyl chain. It was shown that the 6-OMe substitution with R, R
stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon
spacer chain were optimal. In contrast to the highly specific requirements for
the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused
heterocyclic attachments were tolerated with retention of potency and
selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes
were used to further characterize these compounds, and in vivo models of vascular
vs prostatic tone were used to assess uroselectivity.
PMID- 10780917
TI - Synthesis, spectroscopy, and cytotoxicity of glycosylated acetogenin derivatives
as promising molecules for cancer therapy.
AB - Several glycosyl derivatives of squamocin (1) have been synthesized by
glycosylation under Lewis acid catalysis with two different 1-O-acetyl sugars.
Separation of these compounds has been achieved by HPLC and centrifugal partition
chromatography (CPC). A detailed NMR, ESIMS, and LSIMS study allowed complete
structural elucidations. The cytotoxic activity of the glycosyl derivatives was
investigated and compared with that of squamocin and dihydrosquamocin against
human epidermoid carcinoma cells (KB), African green monkey (Cercopithecus
aethiops) kidney epithelial cells (VERO), and mouse lymphocytic leukemia cells
(L1210). The antiproliferative effects of some derivatives were studied on cell
cycles in mouse lymphocytic leukemia cells (L1210).
PMID- 10780918
TI - Syntheses of (R)- and (S)-2- and 6-fluoronorepinephrine and (R)- and (S)-2- and 6
fluoroepinephrine: effect of stereochemistry on fluorine-induced adrenergic
selectivities.
AB - Several routes to the enantiomers of fluoronorepinephrines (1) and
fluoroepinephrines (2) were explored. A catalytic enantioselective
oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric
synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining
steps of two respective routes. Binding studies of the catecholamines with
alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined.
The assays confirmed that fluorine substitution had marked effects on the
affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors,
depending on the position of substitution. Thus, a fluoro substituent at the 2
position of (R)-norepinephrine and (R)-epinephrine reduced activity at both
alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)
receptors, while fluorination at the 6-position reduced activity at the beta(1)-
and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were
less predictable.
PMID- 10780919
TI - Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4
deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in
the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro
antitumor activity.
AB - Seven N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-o rnithine (2,
PT523) analogues were synthesized by modifications of the literature synthesis of
the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell
growth. In growth assays against cultured CCRF-CEM human leukemic cells exposed
to drug for 72 h, the IC(50) values of analogues in which N(10) was replaced by
CH(2) and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus
these analogues are more potent than 1 (IC(50) = 4.4 +/- 1.0 nM) or 2 (IC(50) =
1.5 +/- 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC(50) = 1.2 +/- 0.25 nM)
was not statistically different from 2 but was more potent than edatrexate, the
10-ethyl-10-deaza analogue of 1, which had an IC(50) of 3.3 +/- 0.36 nM. In
contrast, the analogue of 2 with both an ethyl and a CO(2)Me group at the 10
position had an IC(50) of 54 +/- 4.9 nM, showing this modification to be
unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC(50) of 1.2 +/-
0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety
does not diminish cytotoxicity. The analogues in which the (CH(2))(3) side chain
was replaced by slightly longer CH(2)SCH(2) and (CH(2))(2)SCH(2) groups gave
IC(50) values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less
potent than the parent molecule. However the analogues in which the aromatic COOH
group was at the meta and para positions of the phthaloyl ring had IC(50) values
of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously
observed with these compounds against other cell lines. Overall, the results in
this study support the conclusion that, while the position of the phthaloyl COOH
group and the length of the amino acid side chain in 2 are important determinants
of cytotoxic potency, changes in the pABA region and 9, 10-bridge are well
tolerated and can even increase potency.
PMID- 10780920
TI - Synthesis and antimalarial activity of artemisinin derivatives containing an
amino group.
AB - In search of water-soluble artemisinin derivatives that are more stable than
sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5)
were synthesized and tested in mice. All products tested (except 5a and 5b) are
the beta isomers. These basic compounds combined with organic acids (oxalic acid,
maleic acid, etc. ) to yield the corresponding salts. Generally, the maleates
have better solubility in water than the corresponding oxalates. The aqueous
solutions of these salts can be kept at room temperature for several weeks
without any discernible decomposition. Compounds 3f, 3h, and 3r are much more
active against P. berghei than artesunic acid by oral administration and
therefore were further tested in monkeys. However, their oral efficacies are
poorer than that of artesunic acid against P. knowlesi in rhesus monkeys. It is
interesting to note that 3f, 3h, and 3r showed much lower efficacies against P.
berghei when they were administered subcutaneously than orally.
PMID- 10780921
TI - A minimalist approach to gene mapping: locating the gene for acheiropodia, by
homozygosity analysis.
AB - Acheiropodia is an autosomal recessive disease that results in hemimelia (lack of
formation of the distal extremities). We performed a complete genome screen of
seven members of an extended pedigree that included three siblings with
acheiropodia. Homozygosity mapping was used to identify regions most likely to
harbor the gene for acheiropodia in this pedigree. In these two key regions (14p
and 7q), further genotyping of one additional affected member of this pedigree
plus seven additional unaffected siblings provided evidence, through linkage
analysis, that the 7q36 region contains the acheiropodia gene. In this region, a
maximum two-point LOD score of 3.81 (4.2 with multipoint analysis) was achieved,
and a homozygous haplotype spanning a region of 11.7 cM was seen in all affected
in this pedigree. Finally, genotypic analysis of two additional cases of
acheiropodia with no known relation to the other samples revealed homozygous
sharing of a portion of the same haplotype on 7q36, which reduces the chromosomal
location of the acheiropodia gene to an 8.6-cM region. Localization of this gene,
at the screening level, by use of data from only three affected subjects,
provides an example of how certain genes may be mapped by use of a minimal number
of affected cases.
PMID- 10780923
TI - A cytochrome c variant resistant to heme degradation by hydrogen peroxide.
AB - BACKGROUND: Cytochrome c has peroxidase-like activity and can catalyze the
oxidation of a variety of organic substrates, including aromatic, organosulfur
and lipid compounds. Like peroxidases, cytochrome c is inactivated by hydrogen
peroxide. During this inactivation the heme prosthetic group is destroyed.
RESULTS: Variants of the iso-1-cytochrome c were constructed by site-directed
mutagenesis and were found to be more stable in the presence of hydrogen peroxide
than the wild type. No heme destruction was detected in a triple variant (Tyr67-
>Phe/Asn52-->Ile/Cys102-->Thr) with the catalytic hydrogen peroxide concentration
of 1 mM, even following the loss of catalytic activity, whereas both double
variants Tyr67-->Phe/Cys102-->Thr and Asn52-->Ile/Cys102-->Thr showed a greater
rate of peroxide-induced heme destruction than observed with the wild-type
protein. CONCLUSIONS: Heme destruction and catalytic inactivation are two
independent processes. An internal water molecule (Wat166) is shown to be
important in the heme destruction process. The absence of a protein radical in
the resistant variant suggests that the protein radical is necessary in the heme
destruction process, but presumably is not involved in the reactions leading up
to the protein inactivation.
PMID- 10780922
TI - Familial juvenile hyperuricemic nephropathy: localization of the gene on
chromosome 16p11.2-and evidence for genetic heterogeneity.
AB - Familial juvenile hyperuricemic nephropathy (FJHN), is an autosomal dominant
renal disease characterized by juvenile onset of hyperuricemia, gouty arthritis,
and progressive renal failure at an early age. Using a genomewide linkage
analysis in three Czech affected families, we have identified, on chromosome
16p11.2, a locus for FJHN and have found evidence for genetic heterogeneity and
reduced penetrance of the disease. The maximum two-point LOD score calculated
with allowance for heterogeneity (HLOD) was 4.70, obtained at recombination
fraction 0, with marker D16S3036; multipoint linkage analysis yielded a maximum
HLOD score of 4.76 at the same location. Haplotype analysis defined a 10-cM
candidate region between flanking markers D16S501 and D16S3113, exhibiting
crossover events with the disease locus. The candidate interval contains several
genes expressed in the kidney, two of which-uromodulin and NADP-regulated thyroid
hormone-binding protein-represent promising candidates for further analysis.
PMID- 10780924
TI - Construction and in vitro analysis of a new bi-modular polypeptide synthetase for
synthesis of N-methylated acyl peptides.
AB - BACKGROUND: Many active peptides are synthesized by nonribosomal peptide
synthetases (NRPSs), large multimodular enzymes. Each module incorporates one
amino acid, and is composed of two domains: an activation domain that activates
the substrate amino acid and a condensation domain for peptide-bond formation.
Activation domains sometimes contain additional activities (e.g. N-methylation or
epimerization). Novel peptides can be generated by swapping domains. Exchange of
domains containing N-methylation activity has not been reported, however.
RESULTS: The actinomycin NRPS was used to investigate domain swapping. The first
two amino acids of actinomycin are threonine and valine. We replaced the valine
activation domain of module 2 with an N-methyl valine (MeVal) activation domain.
The recombinant NRPS (AcmTmVe) catalyzes the formation of threonyl-valine. In the
presence of S-adenosyl-methionine, valine was converted to MeVal but subsequent
dipeptide formation was blocked. When acyl-threonine (the natural intermediate)
was present at module 1, formation of acyl-threonine-MeVal occurred. The
epimerization domain of AcmTmVe was impaired. CONCLUSIONS: A simple activation
domain can be replaced by one with N-methylation activity. The same condensation
domain can catalyze peptide-bond formation between N-methyl and nonmethylated
amino acids. Modification of the upstream amino acid (i.e. acylation of
threonine), however, was required for condensation with MeVal. Steric hindrance
reduces chemical reactivity of N-methyl amino acids - perfect substrate
positioning may only be achieved with acylated threonine. Loss of the epimerase
activity of AcmTmVe suggests N-methyltransferase and epimerase domains, not found
together naturally, are incompatible.
PMID- 10780925
TI - Generation of a dual-labeled fluorescence biosensor for Crk-II phosphorylation
using solid-phase expressed protein ligation.
AB - BACKGROUND: The site-specific chemical modification of proteins has proved to be
extremely powerful for generating tools for the investigation of biological
processes. Although a few elegant methods exist for engineering a recombinant
protein at a unique position, these techniques cannot be easily extended to allow
several different chemical probes to be specifically introduced into a target
sequence. As such multiply labeled proteins could be used to study many
biological processes, and in particular biomolecular interactions, we decided to
investigate whether such protein reagents could be generated using an extension
of the semisynthesis technique known as expressed protein ligation. RESULTS: A
solid-phase expressed protein ligation (SPPL) technology is described that
enables large semisynthetic proteins to be assembled on a solid support by the
controlled sequential ligation of a series of recombinant and synthetic
polypeptide building blocks. This modular approach allows multiple, different
chemical modifications to be introduced site-specifically into a target protein.
This process, which is analogous to solid-phase peptide synthesis, was used to
dual-label the amino and carboxyl termini of the Crk-II adapter protein with the
fluorescence resonance energy transfer pair tetramethylrhodamine and fluorescein,
respectively. The resulting construct reports (through a fluorescence change) the
phosphorylation of Crk-II by the nonreceptor protein tyrosine kinase, c-Abl, and
was used to probe the protein-protein interactions that regulate this important
post-translational process. CONCLUSIONS: SPPL provides a powerful method for
specifically modifying proteins at multiple sites, as was demonstrated by
generating a protein-based biosensor for Crk-II phosphorylation. Such protein
derivatives are extremely useful for investigating protein function in vitro and
potentially in vivo. This modular approach should be applicable to many different
protein systems.
PMID- 10780926
TI - Biosynthetic phage display: a novel protein engineering tool combining chemical
and genetic diversity.
AB - BACKGROUND: Molecular diversity in nature is developed through a combination of
genetic and chemical elements. We have developed a method that permits selective
manipulation of both these elements in one protein engineering tool. It combines
the ability to introduce non-natural amino acids into a protein using native
chemical ligation with exhaustive targeted mutagenesis of the protein via phage
display mutagenesis. RESULTS: A fully functional biosynthetic version of the
protease inhibitor eglin c was constructed. The amino-terminal fragment (residues
8-40) was chemically synthesized with a non-natural amino acid at position 25.
The remaining carboxy-terminal fragment was expressed as a 30-residue peptide
extension of gIIIp or gVIIIp on filamentous phage in a phage-display mutagenesis
format. Native chemical ligation was used to couple the two fragments and
produced a protein that refolded to its active form. To facilitate the packing of
the introduced non-natural amino acid, residues 52 and 54 in the carboxy-terminal
fragment were fully randomized by phage-display mutagenesis. Although the
majority of the observed solutions for residues 52 and 54 were hydrophobic -
complementing the stereochemistry of the introduced non-natural amino acid - a
significant number of residues (unexpected because of stereochemical and charge
criteria) were observed in these positions. CONCLUSIONS: Peptide synthesis and
phage-display mutagenesis can be combined to produce a very powerful protein
engineering tool. The physical properties of the environment surrounding the
introduced non-natural residue can be selected for by evaluating all possible
combinations of amino acid types at a targeted set of sites using phage-display
mutagenesis.
PMID- 10780928
TI - Rapid identification of key amino-acid-DNA contacts through combinatorial peptide
synthesis.
AB - BACKGROUND: Basic helix-loop-helix (bHLH) transcription factors are characterized
by a conserved four-helix bundle that recognizes a specific hexanucleotide DNA
sequence in the major groove. Previous studies have shown that amino acids in the
basic region make base-specific contacts, whereas the HLH region is responsible
for dimerization. Structural data suggest that portions of the loop region may be
proximal to the DNA; however, the role of the loop in DNA-binding affinity and
specificity has not been investigated. RESULTS: Protein-DNA recognition by the
Drosophila bHLH transcription factor Deadpan was probed using combinatorial solid
phase peptide synthesis methods. A series of bHLH peptide libraries that modulate
amino acid content and length in the loop region was screened with DNA and
peptide affinity columns, and analyzed using matrix-assisted laser desorption
ionization mass spectrometry (MALDI-MS). A functional bHLH peptide with reduced
loop length was found, and Lys80 was unambiguously identified as the sole loop
residue critical for DNA binding. Unnatural amino acids were substituted at this
position to assess contributions of the terminal amino group and the alkyl chain
length to DNA-binding affinity and specificity. CONCLUSIONS: Using combinatorial
solid-phase peptide synthesis methods and MALDI-MS, we were able to rapidly
identify a key amino acid involved in DNA binding by a bHLH protein. Our approach
provides a powerful alternative to current recombinant DNA methods to identify
and probe the energetics of protein-DNA interactions.
PMID- 10780929
TI - Publishing in the journals of the APS: why are authors charged fees?
PMID- 10780927
TI - Dissecting cellular processes using small molecules: identification of colchicine
like, taxol-like and other small molecules that perturb mitosis.
AB - BACKGROUND: Understanding the molecular mechanisms of complex cellular processes
requires unbiased means to identify and to alter conditionally gene products that
function in a pathway of interest. Although random mutagenesis and screening
(forward genetics) provide a useful means to this end, the complexity of the
genome, long generation time and redundancy of gene function have limited their
use with mammalian systems. We sought to develop an analogous process using small
molecules to modulate conditionally the function of proteins. We hoped to
identify simultaneously small molecules that may serve as leads for the
development of therapeutically useful agents. RESULTS: We report the results of a
high-throughput, phenotype-based screen for identifying cell-permeable small
molecules that affect mitosis of mammalian cells. The predominant class of
compounds that emerged directly alters the stability of microtubules in the
mitotic spindle. Although many of these compounds show the colchicine-like
property of destabilizing microtubules, one member shows the taxol-like property
of stabilizing microtubules. Another class of compounds alters chromosome
segregation by novel mechanisms that do not involve direct interactions with
microtubules. CONCLUSIONS: The identification of structurally diverse small
molecules that affect the mammalian mitotic machinery from a large library of
synthetic compounds illustrates the use of chemical genetics in dissecting an
essential cellular pathway. This screen identified five compounds that affect
mitosis without directly targeting microtubules. Understanding the mechanism of
action of these compounds, along with future screening efforts, promises to help
elucidate the molecular mechanisms involved in chromosome segregation during
mitosis.
PMID- 10780930
TI - Role of C-peptide in human physiology.
AB - The C-peptide of proinsulin is important for the biosynthesis of insulin but has
for a long time been considered to be biologically inert. Data now indicate that
C-peptide in the nanomolar concentration range binds specifically to cell
surfaces, probably to a G protein-coupled surface receptor, with subsequent
activation of Ca(2+)-dependent intracellular signaling pathways. The association
rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular
cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is
stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin
growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)
ATPase and endothelial nitric oxide synthase activities. Data also indicate that
C-peptide administration is accompanied by augmented blood flow in skeletal
muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin
excretion, and improved nerve function, all in patients with type 1 diabetes who
lack C-peptide, but not in healthy subjects. The possibility exists that C
peptide replacement, together with insulin administration, may prevent the
development or retard the progression of long-term complications in type 1
diabetes.
PMID- 10780931
TI - Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein
expression in rat brown adipocytes.
AB - Uncoupling protein (UCP), the mitochondrial protein specific to brown adipose
tissue, is activated transcriptionally in response to cold and adrenergic agents.
We studied the role of triiodothyronine (T(3)) on the adrenergic stimulation of
UCP mRNA expression by use of primary cultures of rat brown adipocytes. Basal UCP
mRNA levels are undetectable. Norepinephrine (NE) increases UCP mRNA during
differentiation, not during proliferation. In hypothyroid conditions, UCP mRNA
response to NE is almost absent. The presence of T(3) (0.2-20 nM) greatly
increases the adrenergic response (30-fold). The sensitivity of UCP mRNA
responses to NE is potentiated approximately 100-fold by the presence of T(3).
The effect is proportional to the dose and time of preexposure to T(3). The
increases obtained with NE and T(3) are prevented by actinomycin and
cycloheximide. T(3) greatly stabilizes UCP mRNA transcripts. The effects of
thyroxine and retinoic acid are weaker than those of T(3). In conclusion, in
cultured rat brown adipocytes, T(3) is required and both synergizes with NE to
increase UCP mRNA and stabilizes its mRNA transcripts.
PMID- 10780932
TI - Endurance training increases FFA oxidation and reduces triacylglycerol
utilization in contracting rat soleus.
AB - We examined the effects of 8 wk of intense endurance training on free fatty acid
(FFA) transporters and metabolism in resting and contracting soleus muscle using
pulse-chase procedures. Endurance training increased maximal citrate synthase
activity in red muscles (+54 to +91%; P 84%
maximum O(2) uptake, starting 3 h after a 412-kcal mixed meal. The meal induced a
small rise in glycemia with sustained insulin and glucagon increases. Preexercise
glucose total R(a) and utilization (R(d)) were equal and approximately 130% of
the PA level. Exercise hyperglycemia in PP was delayed and diminished and, in
early recovery, was of shorter duration and lesser magnitude (P = 0.042). Peak
catecholamine (12- to 16-fold increase) and R(a) (PP: 11.5 +/- 1.4, PA: 13.8 +/-
1.4 mg. kg(-1). min(-1)) responses did not differ, and their responses during
exercise were significantly correlated. Exercise glucagon, insulin, and glucagon
to-insulin responses were small or not significant. R(d) reached the same peak
(PP: 8.0 +/- 0.6, PA: 9.3 +/- 0.8 mg. kg(-1). min(-1)) but was greater at 20-120
min of recovery in PP (P = 0.001). Therefore, the total R(a) response to IE is
preserved despite the possibility of prior PP suppression of endogenous R(a) and
is consistent with catecholamine mediation. Post-IE hyperglycemia is reduced in
the postprandial state.
PMID- 10780934
TI - Dose-response characteristics of insulin action on glucose metabolism: a non
steady-state approach.
AB - The traditional methods for the assessment of insulin sensitivity yield only a
single index, not the whole dose-response curve information. This curve is
typically characterized by a maximally insulin-stimulated glucose clearance
(Cl(max)) and an insulin concentration at half-maximal response (EC(50)). We
developed an approach for estimating the whole dose-response curve with a single
in vivo test, based on the use of tracer glucose and exogenous insulin
administration (two steps of 20 and 200 mU x min(-1) x m(-2), 100 min each). The
effect of insulin on plasma glucose clearance was calculated from non-steady
state data by use of a circulatory model of glucose kinetics and a model of
insulin action in which glucose clearance is represented as a Michaelis-Menten
function of insulin concentration with a delay (t(1/2)). In seven nondiabetic
subjects, the model predicted adequately the tracer concentration: the model
residuals were unbiased, and their coefficient of variation was similar to the
expected measurement error (approximately 3%), indicating that the model did not
introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects
had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min)
and maximal responses (Cl(max) = 705 +/- 46 vs. 668 +/- 259 ml x min(-1) x m(-2),
respectively), whereas EC(50) was 240 +/- 84 microU/ml in the lean vs. 364 +/-
229 microU/ml in the obese (P < 0.04). EC(50) and the insulin sensitivity index
(ISI, initial slope of the dose-response curve), but not Cl(max), were related to
body adiposity and fat distribution with r of 0.6-0.8 (P < 0.05). Thus, despite
the small number of study subjects, we were able to reproduce information
consistent with the literature. In addition, among the lean individuals, t(1/2)
was positively related to the ISI (r = 0.72, P < 0.02). We conclude that the test
here presented, based on a more elaborate representation of glucose kinetics and
insulin action, allows a reliable quantitation of the insulin dose-response curve
for whole body glucose utilization in a single session of relatively short
duration.
PMID- 10780935
TI - Utilization of very low density lipoprotein by rat heart: the effect of
endotoxin.
AB - The effect of endotoxin on myocardial utilization of very low density lipoprotein
(VLDL) triacylglycerol (TAG) was studied. VLDL was prepared by rat liver
perfusion and tested as substrate in the isolated working rat heart. Both liver
and heart donor rats were pretreated in vivo with endotoxin or vehicle (control).
VLDL-TAG synthesized by endotoxin-pretreated livers was assimilated and oxidized
at an increased rate by hearts compared with control VLDL-TAG, regardless of the
cardiac endotoxic status, with increased cardiac mechanical performance (cardiac
output, hydraulic work). There was no change in incorporation of labeled VLDL
lipids into myocardial tissue lipids. Lipoprotein lipase (LPL) activity was
increased in endotoxin-pretreated hearts, and after perfusion with "endotoxic"
VLDL, there was a tendency for translocation of LPL from tissue-residual to
heparin-releasable compartments, but these changes were modest. Analysis of the
VLDL composition showed that endotoxin-pretreated livers produced apolipoprotein
(apo)-B48 VLDL with decreased particle size (and hence TAG content), but apo-B100
VLDL was unchanged. Oleate content of VLDL was increased, but there was no
difference in apo-C or apo-E content. These results suggest that VLDL-TAG
produced during sepsis/endotoxinemia may be destined for utilization by the heart
as energy substrate. However, the mechanism for its increased efficacy is
uncertain.
PMID- 10780936
TI - Hyperbaric oxygen treatment attenuates cytokine induction after massive
hemorrhage.
AB - We investigated the effect of hyperbaric oxygen treatment (HBO) on cytokine
induction after hemorrhage, because hypoxia induces cytokines in vitro.
Chronically cannulated conscious rats were subjected to 40 ml/kg of hemorrhage
and resuscitated with the shed blood and twice the volume of saline either under
room air (room air group) or under 100% oxygen at 3 atmospheres absolute
(hyperbaric group). Rats exposed to HBO with no hemorrhage served as controls.
Time course changes in plasma endotoxin level, arterial ketone body ratio (AKBR),
serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and their hepatic mRNA
were detected in the three groups. Plasma endotoxin levels increased
significantly after hemorrhage, and there were no significant differences between
the room air group and the hyperbaric group. In the room air group, AKBR dropped
rapidly after hemorrhage and became minimal at hour 1, which was associated with
significant increases in TNF-alpha and IL-6 at both mRNA and circulating levels.
HBO significantly attenuated decreases in AKBR after hemorrhage with a
significant reduction of mortality and cytokine induction. These results indicate
that HBO attenuated the cytokine induction after hemorrhage by improving liver
ischemia, and they suggest that tissue hypoxia may be responsible, at least in
part, for cytokine induction after massive hemorrhage.
PMID- 10780937
TI - Effect of enteral glutamine on leucine, phenylalanine and glutamine metabolism in
hypercortisolemic subjects.
AB - The effect of enteral Gln on protein and Gln metabolism was investigated during
experimental hypercortisolemia. Four groups of subjects that had received
corticosteroids and either enteral Gln (0.5 g x kg(-1) x day(-1) for 2 days) or
isonitrogenous Ala-Gly were studied in a fasted or in a fed state. In either
state, enteral Gln, compared with Ala-Gly, induced no statistically significant
change in the endogenous rate of Leu appearance, an index of proteolysis, Leu
oxidation, and nonoxidative Leu disposal, an index of protein synthesis, as
studied by kinetics of [1-(13)C]Leu. Similar data were obtained from kinetics of
[(2)H(5)]Phe, resulting in an unchanged protein balance in both cases. In
contrast, enteral Gln significantly decreased the endogenous rate of Gln
appearance and Gln de novo synthesis in the fed state (P < 0.05) as estimated by
the kinetics of [(15)N]Gln. This decrease in Gln de novo synthesis induced by Gln
could contribute to spare amino acids in hypercatabolic patients.
PMID- 10780938
TI - Functional comparison of the role of dynamin 2 splice variants on GLUT-4
endocytosis in 3T3L1 adipocytes.
AB - Previously, we reported that expression of a dominant-interfering neuronal
specific dynamin 1 (K44A/dynamin 1) inhibited the plasma membrane internalization
of GLUT-4 in 3T3L1 adipocytes (15). To investigate the role of the ubiquitously
expressed isoform of dynamin, dynamin 2, on adipocyte GLUT-4 internalization, and
to determine whether dynamin splice variants have functional specificity, we
expressed each of the four dynamin 2 isoforms (aa, ab, ba, and bb) as either wild
type proteins or GTPase-defective mutants. When expressed as enhanced green
fluorescent protein (EGFP) fusions, these isoforms were found to have overlapping
subcellular distributions being localized throughout the cell cytoplasm, on
punctate vesicles and in a perinuclear compartment. This distribution was
qualitatively similar to that of endogenous dynamin 2 and overlapped with GLUT-4
in the basal state. Expression of wild-type dynamin 2 isoforms had no effect on
the basal or insulin-stimulated distribution of GLUT-4; however, expression of
the dominant-interfering dynamin 2 mutants inhibited GLUT-4 endocytosis. These
data demonstrate that dynamin 2 is required for GLUT-4 endocytosis in 3T3L1
adipocytes and suggest that, relative to GLUT-4 trafficking, the dynamin 2 splice
variants have overlapping functions and are probably not responsible for
mediating distinct GLUT-4 budding events.
PMID- 10780939
TI - Osteoblast-like cells of the hypophysectomized rat: a model of aberrant
osteoblast development.
AB - In a previous work, we demonstrated that the osteoprogenitors derived from the
marrow stroma of the hypophysectomized (HX) rat demonstrate enhanced
proliferative and differentiation capacities when placed in an optimal
microenvironment. In this study, we sought to investigate the potential of the
trabecular osteoblast-like cells of the HX rat. These cells represent a more
mature pool of osteoblasts than the progenitors derived from the marrow stroma.
We examined all three stages of osteoblast development using trabecular
osteoblast-like cells derived from age-matched intact rats as a control. Using
thymidine incorporation and cell number as indicators of proliferation, we found
that these cells, like the osteoprogenitors derived from the HX rat, demonstrate
augmented proliferation when placed in culture. Additionally, type I collagen
expression remained at significant levels past the end stages of proliferation,
at which point it is expected to be downregulated. Matrix maturation markers,
such as alkaline phosphatase activity and bone sialoprotein expression, however,
were significantly lower than in the controls. Mineralization potential, as
measured by mineralized nodule formation, Ca(2+) content, and OPN and OCN
expression, was also significantly reduced. Our results have uncovered an
aberrant model of osteoblast development in which proliferation is deregulated,
resulting in a minimal capacity of these cells to develop into fully
differentiated mineralizing osteoblasts.
PMID- 10780940
TI - Effect of dexamethasone on fetal hepatic glutamine-glutamate exchange.
AB - Intravenous infusion of dexamethasone (Dex) in the fetal lamb causes a two- to
threefold increase in plasma glutamine and other glucogenic amino acids and a
decrease of plasma glutamate to approximately one-third of normal. To explore the
underlying mechanisms, hepatic amino acid uptake and conversion of L-[1
(13)C]glutamine to L-[1-(13)C]glutamate and (13)CO(2) were measured in six sheep
fetuses before and in the last 2 h of a 26-h Dex infusion. Dex decreased hepatic
glutamine and alanine uptakes (P < 0.01) and hepatic glutamate output (P <
0.001). Hepatic outputs of the glutamate (R(Glu,Gln)) and CO(2) formed from
plasma glutamine decreased to 21 (P < 0.001) and 53% (P = 0.009) of control,
respectively. R(Glu,Gln), expressed as a fraction of both outputs, decreased (P <
0.001) from 0.36 +/- 0.02 to 0.18 +/- 0.04. Hepatic glucose output remained
virtually zero throughout the experiment. We conclude that Dex decreases fetal
hepatic glutamate output by increasing the routing of glutamate carbon into the
citric acid cycle and by decreasing the hepatic uptake of glucogenic amino acids.
PMID- 10780941
TI - Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis.
AB - Cytosolic citrate is proposed to play a crucial role in substrate fuel selection
in the heart. However, little is known about factors regulating the transfer of
citrate from the mitochondria, where it is synthesized, to the cytosol. Further
to our observation that rat hearts perfused under normoxia release citrate whose
(13)C labeling pattern reflects that of mitochondrial citrate (B. Comte, G.
Vincent, B. Bouchard, and C. Des Rosiers. J. Biol. Chem. 272: 26117-26124, 1997),
we report here data indicating that this citrate release is a specific process
reflecting the mitochondrial efflux of citrate, a process referred to as
cataplerosis. Indeed, measured rates of citrate release, which vary between 2 and
21 nmol/min, are modulated by the nature and concentration of exogenous
substrates feeding acetyl-CoA (fatty acid) and oxaloacetate (lactate plus
pyruvate) for the mitochondrial citrate synthase reaction. Such release rates
that represent at most 2% of the citric acid cycle flux are in agreement with the
activity of the mitochondrial tricarboxylate transporter whose participation is
also substantiated by 1) parallel variations in citrate release rates and tissue
levels of citrate plus malate, the antiporter, and 2) a lowering of the citrate
release rate by 1,2, 3-benzenetricarboxylic acid, a specific inhibitor of the
transporter. Taken together, the results from the present study indicate that
citrate cataplerosis is modulated by substrate supply, in agreement with the role
of cytosolic citrate in fuel partitioning, and occurs, at least in part, through
the mitochondrial tricarboxylate transporter.
PMID- 10780942
TI - Inverse relationship between protein intake and plasma free amino acids in
healthy men at physical exercise.
AB - The effect of a "normal" (n = 8) and "high" (n = 6) protein intake (1 and 2.5 g x
kg(-1) x day(-1), respectively) and of exercise on plasma amino acid (AA)
concentrations, insulin, and glucagon concentrations was followed throughout a
continuous 24-h period in adult male subjects at energy balance after six days on
a standardized diet and exercise program. Subjects were fasting from 2100 on day
6 to 1200 on day 7 and then fed 10 identical meals hourly until 2100. Physical
exercise was performed (46% maximal oxygen uptake) between 0830 and 1000
(fasting) and in a fed state (1600-1730) on each day. The normal-protein group
showed fasting plasma AA concentrations that were higher (P < 0.05) than those
for the high-protein group, except for leucine, methionine, and tyrosine.
Glutamine, glycine, alanine, taurine, and threonine concentrations were
distinctly higher ( approximately 30% or greater) throughout the 24-h period in
subjects consuming the normal- vs. the high-protein diets. Exercise appeared to
increase, although not profoundly, the plasma concentrations of amino acids
except for glutamate, histidine, ornithine, and tryptophan. The profound diet
related differences in plasma AA concentrations are only partially explained by
differences in the renal clearance of the amino acids. We speculate on the
possible metabolic basis for these findings.
PMID- 10780943
TI - Oxoproline kinetics and oxoproline urinary excretion during glycine- or sulfur
amino acid-free diets in humans.
AB - L-5-oxoproline (L-5-OP) is an intermediate in glutathione synthesis, possibly
limited by cysteine availability. Urinary 5-OP excretion has been proposed as a
measure of glycine availability. We investigated whether 5 days of dietary sulfur
amino acid (SAA-free) or glycine (Gly-free) restriction affects plasma kinetics
of 5-OP and urinary excretion of L- and D-5-OP in 6 healthy men. On day 6, L-5-[1
(13)C]oxoproline and [3,3-(2)H(2)]cysteine were infused intravenously for 8 h (3
h fast/5 h fed). In a control study (adequate amino acid mixture), plasma
oxoproline fluxes were 37.8 +/- 13.8 (SD) and 38.4 +/- 14.8 micromol x kg(-1) x
h(-1); oxidation accounted for 85% of flux. Cysteine flux was 47.9 +/- 8.5 and
43.2 +/- 8.5 micromol x kg(-1) x h(-1) for fast and fed phases, respectively.
Urinary excretion of L- and D-5-OP was 70 +/- 34 and 31.1 +/- 13.3 micromol/mmol
creatinine, respectively, during days 3-5, and 46.4 +/- 13.9 and 22.4 +/- 8.3
micromol/mmol over the 8-h tracer study. The 5-OP flux for the Gly-free diet was
higher (P = 0. 018) and tended to be higher for the SAA-free diet (P = 0.057)
when compared with the control diet. Oxidation rates were higher on the Gly-free
(P = 0.005) and SAA-free (P = 0.03) diets. Cysteine fluxes were lower on the the
Gly-free (P = 0.01) and the SAA-free diets (P = 0.001) compared with the control
diet. Rates of L-5-OP excretion were unchanged by withdrawal of SAA or Gly for 5
days but increased on day 6 (P = 0.005 and P = 0.019, respectively). Thus acute
changes in the dietary availability of SAA and Gly alter oxoproline kinetics and
urinary 5-OP excretion.
PMID- 10780944
TI - Threonine dehydrogenase is a minor degradative pathway of threonine catabolism in
adult humans.
AB - The threonine dehydrogenase (TDG) pathway is a significant route of threonine
degradation, yielding glycine in experimental animals, but has not been
accurately quantitated in humans. Therefore, the effect of a large excess of
dietary threonine, given either as free amino acid (+Thr) or as a constituent of
protein (+P-Thr), on threonine catabolism to CO(2) and to glycine was studied in
six healthy adult males using a 4-h constant infusion of L-[1-(13)C]threonine and
[(15)N]glycine. Gas chromatography-combustion isotope ratio mass spectrometry was
used to determine [(13)C]glycine produced from labeled threonine. Threonine
intakes were higher on +Thr and +P-Thr diets compared with control (126, 126, and
50 micromol x kg(-1) x h(-1), SD 8, P < 0.0001). Threonine oxidation to CO(2)
increased threefold in subjects on +Thr and +P-Thr vs. control (49, 45, and 15
micromol x kg(-1) x h(-1), SD 6, P < 0.0001). Threonine conversion to glycine
tended to be higher on +Thr and +P-Thr vs. control (3.5, 3.4, and 1.6 micromol x
kg(-1) x h(-1), SD 1.3, P = 0.06). The TDG pathway accounted for only 7-11% of
total threonine catabolism and therefore is a minor pathway in the human adult.
PMID- 10780945
TI - Induction of growth hormone (GH) mRNA by pulsatile GH-releasing hormone in rats
is pattern specific.
AB - Growth hormone-releasing hormone (GHRH) is a main inducer of growth hormone (GH)
pulses in most species studied to date. There is no information regarding the
pattern of GHRH secretion as a regulator of GH gene expression. We investigated
the roles of the parameters of exogenous GHRH administration (frequency,
amplitude, and total amount) upon induction of pituitary GH mRNA, GH content, and
somatic growth in the female rat. Continuous GHRH infusions were ineffective in
altering GH mRNA levels, GH stores, or weight gain. Changing GHRH pulse amplitude
between 4, 8, and 16 microg/kg at a constant frequency (Q3.0 h) was only
moderately effective in augmenting GH mRNA levels, whereas the 8 microg/kg and 16
microg/kg dosages stimulated weight gain by as much as 60%. When given at a 1.5-h
frequency, GHRH doubled the amount of GH mRNA, elevated pituitary GH stores, and
stimulated body weight gain. In the rat model, pulsatile but not continuous GHRH
administration is effective in inducing pituitary GH mRNA and GH content as well
as somatic growth. These studies suggest that the greater growth rate, pituitary
mRNA levels, and GH stores seen in male compared with female rats are likely
mediated, in part, by the endogenous episodic GHRH secretory pattern present in
males.
PMID- 10780946
TI - Dual regulation of leptin secretion: intracellular energy and calcium dependence
of regulated pathway.
AB - Rodent leptin is secreted by adipocytes and acutely regulates appetite and
chronically regulates body weight. Mechanisms for leptin secretion in cultured
adipocytes were investigated. Acutely, energy-producing substrates stimulated
leptin secretion about twofold. Biologically inert carbohydrates failed to
stimulate leptin secretion, and depletion of intracellular energy inhibited
leptin release. There appears to be a correlation between intracellular ATP
concentration and the rate of leptin secretion. Insulin increased leptin
secretion by an additional 25%. Acute leptin secretion is calcium dependent. When
incubated in the absence of calcium or in the presence of intracellular calcium
chelators, glucose plus insulin failed to stimulate leptin secretion. In
contrast, basal leptin secretion is secreted spontaneously and is calcium
independent. Adipocytes from fatter animals secrete more leptin, even in the
absence of calcium, compared with cells from thinner animals. Acute stimulus
secretion coupling mechanisms were then investigated. The potassium channel
activator diazoxide and the nonspecific calcium channel blockers nickel and
cadmium inhibited acute leptin secretion. These studies demonstrate that
intracellular energy production is important for acute leptin secretion and that
potassium and calcium flux may play roles in coupling intracellular energy
production to leptin secretion.
PMID- 10780947
TI - Protein turnover modifications induced by the protein feeding pattern still
persist after the end of the diets.
AB - This study was undertaken to determine whether the protein feeding pattern could
induce chronic adaptation of protein turnover. After a 15-day adaptive period,
elderly (68 yr) and young (26 yr) women received, for 14 days, a diet providing
200 KJ x kg fat-free mass (FFM)(-1) x day(-1), where the daily protein intake
(1.7 g protein x kg FFM(-1) x day(-1)) was either spread over 4 meals in the
spread pattern or mainly (80%) consumed at noon in the pulse pattern. One day
after the end of the dietary treatment, whole body leucine kinetics were measured
by use of a continuous [(13)C]leucine infusion, both in the postabsorptive state
and in the same fed state. The pulse pattern was able to induce, in young as in
elderly women, a lower postabsorptive leucine oxidation and endogenous leucine
flux than the spread pattern and improved the responsiveness of nonoxidative
leucine disposal during 4-h oral feeding. Thus the pulse pattern was able to
induce chronic regulation of protein metabolism in young as in elderly women.
PMID- 10780948
TI - Direct evidence of fiber type-dependent GLUT-4 expression in human skeletal
muscle.
AB - GLUT-4 expression in individual fibers of human skeletal muscles in younger and
older adults was studied. Furthermore, the dependency of insulin-stimulated
glucose uptake on fiber type distribution was investigated. Fiber type
distribution was determined in cryosections of muscle biopsies from 8 younger (29
yr) and 8 older (64 yr) healthy subjects, and estimates of GLUT-4 expression in
individual fibers were obtained by combining immunohistochemistry and stereology.
GLUT-4 was more abundantly expressed in slow compared with fast muscle fibers in
both younger (P < 0.007) and older (P < 0. 001) subjects. A 25% reduction of GLUT
4 density in fast fibers (P < 0.001) and an unchanged GLUT-4 density in slow
fibers were demonstrated in older compared with younger subjects. Insulin
stimulated glucose uptake rates measured by hyperinsulinemic, euglycemic clamp
were not correlated with the fraction of slow fibers in the young (r = -0.45, P >
0.25) or in the elderly (r = 0. 11, P > 0.75) subjects. In conclusion, in human
skeletal muscle, GLUT-4 expression is fiber type dependent and decreases with
age, particularly in fast muscle fibers.
PMID- 10780949
TI - Decreased cardiac output at the onset of diabetes: renal mechanisms and
peripheral vasoconstriction.
AB - Recently we reported that hindquarter blood flow, measured 24 h/day, decreased
progressively over the first 6 days of type 1 diabetes in rats. That response,
coupled with the tendency of mean arterial pressure to increase, suggested a
vasoconstrictor response. The purpose of this study was to measure the changes in
cardiac output together with the renal hemodynamic and excretory responses to
allow integrative determination of whether vasoconstriction likely accompanies
the onset of type 1 diabetes. Rats were instrumented with a Transonic flow probe
on the ascending aorta and with artery and vein catheters, and cardiac output and
mean arterial pressure were measured continuously, 24 h/day, throughout the
study. The induction of diabetes, by withdrawing intravenous insulin-replacement
therapy in streptozotocin-treated rats, caused a progressive decrease in cardiac
output that was 85 +/- 5% of control levels by day 7. This was associated with
significant increases in glomerular filtration rate, renal blood flow, and
microalbuminuria as well as urinary fluid and sodium losses, with a negative
cumulative sodium balance averaging 15.7 +/- 1.6 meq by day 7. Restoring insulin
replacement therapy reversed the renal excretory responses but did not correct
the negative sodium balance, yet cardiac output returned rapidly to control
values. Increasing sodium intake during the diabetic and recovery periods also
did not significantly affect the cardiac output response during any period. These
results indicate that cardiac output decreases significantly at the onset of type
1 diabetes without glycemic control, and although volume loss may contribute to
this response, there also is a component that is not volume or sodium dependent.
We suggest this may be due to vasoconstriction, but to what extent local blood
flow autoregulation or active vasoconstriction may have mediated that response is
not known.
PMID- 10780950
TI - Functional alteration of dihydropyridine-sensitive Ca(2+) channels in the adrenal
glomerulosa of pregnant rats.
AB - Our previous work on aldosterone secretion suggested that dihydropyridine
sensitive calcium channels, one type of voltage-dependent calcium channels
(VDCC), are functionally impaired in adrenal capsule preparations from the
pregnant rat. The aim of this study was to determine whether, during pregnancy,
the density and/or activity of these channels is altered in the adrenal zona
glomerulosa. These VDCC measured with [(3)H]nitrendipine binding were not
different between membrane preparations of nonpregnant and pregnant rats. Western
blots were performed using two different antibodies, a polyclonal (PcAb) directed
against the alpha(1)-subunit of VDCC and a monoclonal (McAb) that recognizes an
intracellular domain of that protein. McAb immunoreactivity showed a significant
decrease in preparations from pregnant rats, whereas no difference was observed
with PcAb. VDCC activity was estimated by (45)Ca(2+) uptake in isolated adrenal
cortex and by intracellular calcium concentration ([Ca(2+)](i)) in adrenal
glomerulosa cells with the Ca(2+) probe fura PE3. These measurements revealed
that KCl stimulation produced greater Ca(2+) influx in nonpregnant than in
pregnant rats. Nifedipine (a blocker of VDCC) inhibited this stimulation only in
nonpregnant rats, whereas BAY K 8644 (an activator of VDCC) increased Ca(2+)
influx in pregnant rats only. These data suggest that, during pregnancy, the
altered regulation of calcium homeostasis in adrenal glomerulosa is linked to a
conformational alteration of VDCC.
PMID- 10780951
TI - Single exposure to testosterone in adulthood rapidly induces regularity in the
growth hormone release process.
AB - The neonatal gonadal steroid milieu is known to be important in imprinting the
striking sexual dimorphism of growth hormone (GH) secretion; however, the
influence of the sex steroids on GH control in adult life and their
mechanism/site of action are largely unknown. In the present study, we tested the
hypothesis that testosterone (T) subserves the gender-specific regularity of the
GH release process in adulthood. The approximate entropy statistic (ApEn) was
used to quantify the degree of regularity of GH release patterns over time.
Eighteen hours after a single subcutaneous injection of 1 mg T, both sham
operated and ovariectomized (OVX) female adult rats displayed plasma GH profiles
that were strikingly similar to the regular male-like ultradian rhythm of GH
secretion. The highest ApEn values, denoting greater disorderliness of GH
secretion, were observed in the ovary-intact group, and T injection significantly
(P < 0.001) reduced this irregularity whether or not the ovaries were present.
Serial intravenous injections of GH-releasing hormone (GHRH) caused a similar
increase in plasma GH levels in sham-operated females independently of time of
administration. In contrast, female rats administered T exhibited a male-like
intermittent pattern of GH responsiveness to GHRH, the latter known to be due to
the cyclic release of endogenous somatostatin. These results demonstrate that
acute exposure to T during adult life can rapidly and profoundly "masculinize" GH
pulse-generating circuits in the female rat. Our findings suggest that the
enhanced orderliness characteristic of the GH release process in males, compared
with females, is regulated by T. We postulate that this T-induced regularity is
mediated at the level of the hypothalamus by inducing regularity in somatostatin
secretion, which in turn governs overall GH periodicity.
PMID- 10780952
TI - Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance.
AB - Whereas truncal (central) adiposity is strongly associated with the insulin
resistant metabolic syndrome, it is uncertain whether this is accounted for
principally by visceral adiposity (VAT). Several recent studies find as strong or
stronger association between subcutaneous abdominal adiposity (SAT) and insulin
resistance. To reexamine the issue of truncal adipose tissue depots, we performed
cross-sectional abdominal computed tomography, and we undertook the novel
approach of partitioning SAT into the plane superficial to the fascia within
subcutaneous adipose tissue (superficial SAT) and that below this fascia (deep
SAT), as well as measurement of VAT. Among 47 lean and obese glucose-tolerant men
and women, insulin-stimulated glucose utilization, measured by euglycemic clamp,
was strongly correlated with both VAT and deep SAT (r = -0.61 and -0.64,
respectively; both P < 0.001), but not with superficial SAT (r = -0.29, not
significant). Also, VAT and deep SAT followed a highly congruent pattern of
associations with glucose and insulin area under the curve (75-g oral glucose
tolerance test), mean arterial blood pressure, apoprotein-B, high-density
lipoprotein cholesterol, and triglyceride. Superficial SAT had markedly weaker
association with all these parameters and instead followed the pattern observed
for thigh subcutaneous adiposity. We conclude that there are two functionally
distinct compartments of adipose tissue within abdominal subcutaneous fat and
that the deep SAT has a strong relation to insulin resistance.
PMID- 10780953
TI - Epinephrine infusion during moderate intensity exercise increases glucose
production and uptake.
AB - The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake
(VO(2 max))] comprises a marked increment in glucose production (R(a)) and a
lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a)
correlates with plasma catecholamines but not with the glucagon-to-insulin
(IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able
to markedly stimulate R(a), this would support an important role for the
catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass
index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40
min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without
[control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))]
from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a)
increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(
1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) =
0.923, P 10-fold in control cell lines, and this
activation was markedly reduced in GLUT-1-overexpressing cell lines. A
catalytically inactive mutant of MEKK1, an upstream kinase in the JNK pathway,
reduced hypoxia-induced apoptosis by 39%. These findings show that GLUT-1
overexpression prevents hypoxia-induced apoptosis possibly via inhibition of
stress-activated protein kinase pathway activation.
PMID- 10780955
TI - Upregulation of bradykinin B1-receptor expression after myocardial infarction.
AB - To determine the influence of the myocardial infarction (MI) on bradykinin B1
receptor (B1R) regulation, we studied its expression in the left ventricle (LV)
after MI. Rats were submitted to a permanent occlusion of the left coronary
artery. Six hours, 24 h and 6 days after MI or after sham operation, left
ventricular pressure (LVP) and dP/dt(max) were measured. LV-total RNA was
extracted and B1R expression was analysed by a RNase-protection assay (each group
n = 6). LVP and dP/dt(max) were impaired at all time points after MI. Basal B1R
expression was not detectable in controls. Six hours after MI, the B1R expression
was upregulated and reached a maximum 24 h after MI (4 fold vs. 6 h). Six days
post-MI, B1R expression returned to levels found 6 h after MI. These data are the
first demonstration for an induced myocardial B1R expression in an in vivo model
of MI.
PMID- 10780956
TI - Peroxynitrite-mediated release of arachidonic acid from PC12 cells.
AB - A short term exposure of PC12 cells to a concentration of tert-butylhydroperoxide
(tB-OOH) causing peroxynitrite-dependent DNA damage and cytotoxiticity promoted a
release of arachidonic acid (AA) that was sensitive to phospholipase A(2)
(PLA(2)) inhibitors and insensitive to phospholipase C or diacylglycerol lipase
inhibitors. The extent of AA release was also mitigated by nitric oxide synthase
(NOS) inhibitors and peroxynitrite scavengers. Low levels (10 microM) of
authentic peroxynitrite restored the release of AA mediated by tB-OOH in NOS
inhibited cells whereas concentrations of peroxynitrite of 20 microM, or higher,
effectively stimulated a PLA(2) inhibitor-sensitive release of AA also in the
absence of additional treatments. These results are consistent with the
possibility that endogenous as well as exogenous peroxynitrite promotes
activation of PLA(2).
PMID- 10780957
TI - Upregulation by glucocorticoids of responses to eosinopoietic cytokines in bone
marrow from normal and allergic mice.
AB - Since the production of eosinopoietic cytokines (GM-CSF, IL-3, IL-5) is inhibited
by glucocorticoids, while responsiveness to these cytokines is enhanced in bone
marrow of allergic mice, we studied the ability of glucocorticoids to modulate
murine bone-marrow eosinopoiesis. Progenitor (semi-solid) and/or precursor
(liquid) cultures were established from bone-marrow of: (a) normal mice; (b)
ovalbumin-sensitized and challenged mice or (c) dexamethasone (1-5 mg kg(-1))
injected mice. Cultures were established with GM-CSF (2 ng ml(-1)) or IL-5 (1 ng
ml(-1)), respectively, alone or associated with dexamethasone, hydrocortisone or
corticosterone. Total myeloid colony numbers, frequency and size of eosinophil
colonies, and numbers of eosinophil-peroxidase-positive cells were determined at
day 7. In BALB/c mice, dexamethasone (10(-7) M) increased GM-CSF-stimulated
myeloid colony formation (P = 0.01), as well as the frequency (P=0.01) and size
(P<0.01) of eosinophil colonies. Dexamethasone (10(-7) M) alone had no effect.
Dexamethasone (10(-7)-10(-10) M) increased (P<0.002) eosinophil precursor
responses to IL-5. Potentiation by dexamethasone was still detectable: (a) on low
density, immature, nonadherent BALB/c bone-marrow cells, (b) on bone-marrow from
other strains, and (c) on cells from allergic mice. Hydrocortisone and
corticosterone had similar effects. Dexamethasone administered in vivo, 24 h
before bone-marrow harvest, increased subsequent progenitor responses to GM-CSF
(P = 0.001) and precursor responses to IL-5 (P<0.001). These effects were blocked
by RU 486 (20 mg kg(-1), orally, 2 h before dexamethasone, or added in vitro at
10 microM, P<0.001). Glucocorticoids, acting in vivo or in vitro, through
glucocorticoid receptors, enhance bone-marrow eosinopoiesis in naive and allergic
mice.
PMID- 10780958
TI - Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in
RAW 264.7 cells by andrographolide.
AB - Andrographolide, an active component found in leaves of Andrographis paniculata,
has been reported to exhibit nitric oxide (NO) inhibitory property in endotoxin
stimulated macrophages, however, the detailed mechanisms remain unclear. In the
present study we investigated the effect of andrographolide on the expression of
inducible NO synthase (iNOS) mRNA, protein, and enzyme activity in RAW 264.7
macrophages stimulated with lipopolysaccharide (LPS) plus interferon-gamma (IFN
gamma). RAW 264.7 cells stimulated with LPS/IFN-gamma activated NO production; in
this condition andrographolide (1-100 microM) inhibited NO production in a dose
dependent manner with an IC(50) value of 17.4+/-1.1 microM. Andrographolide also
reduces the expression of iNOS protein level but without a significant effect on
iNOS mRNA. The reduction of iNOS activity is thought to be caused by decreased
expression of iNOS protein. In a protein stability assay, andrographolide
moderately but significantly reduced the amount of iNOS protein as suggested by
accelerating degradation. Furthermore, andrographolide also inhibited total
protein de novo synthesis as demonstrated by [(35)S]-methionine incorporation. As
a whole, these data suggest that andrographolide inhibits NO synthesis in RAW
264.7 cells by reducing the expression of iNOS protein and the reduction could
occur through two additional mechanisms: prevention of the de novo protein
synthesis and decreasing the protein stability via a post-transcriptional
mechanism. It is also possible that inhibition of iNOS protein expression and NO
production under immune stimulation and/or bacteria infection may explain, in
part, the beneficial effects of andrographolide as an anti-inflammatory agent.
PMID- 10780959
TI - Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine
on isolated smooth muscle from the rat and guinea-pig.
AB - Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to
possess antiaddictive properties in several models of drug dependence. We have
examined their effect at mu-opioid receptors regulating neurogenic contractions
of several smooth muscle preparations and also against spontaneous contractions
of the rat isolated portal vein. Ibogaine (pIC(50) 5.28) and 18
methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of
cholinergic contractions of the guinea-pig ileum which was not affected by the
opioid receptor antagonist naloxone (1 microM). In the rat isolated vas deferens
ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement
of purinergic contractions. Both agents (30 microM) caused a 3 - 5 fold rightward
displacement of DAMGO-induced inhibition of purinergic contractions, but similar
effects were observed for ibogaine against alpha(2)-adrenoceptor-mediated
inhibition of neurogenic responses. In the guinea-pig isolated bladder both
ibogaine (10 microM) and 18-methoxycoronaridine (10 microM) caused a 2 fold
increase in the purinergic component of neurogenic contractions without
significantly altering cholinergic contractions or responses to exogenous ATP. In
contrast, ibogaine (1 - 30 microM), but not 18-methoxycoronaridine, caused a
concentration-dependent enhancement of spontaneous contractions of the rat
isolated portal vein. In summary, while ibogaine and 18-methoxycoronaridine
modulated electrically-evoked contractions in the three preparations examined, we
have no evidence for a selective interaction with pre-junctional mu-opioid
receptors. The pronounced enhancement of purinergic contractions produced by both
agents is a novel finding and worthy of further investigation.
PMID- 10780960
TI - Splice isoforms of alpha(1a)-adrenoceptor in rabbit.
AB - Two splice isoforms of rabbit alpha(1a)-adrenergic receptor (AR), (named
alpha(1a)-OCU.2-AR and alpha(1a)-OCU.3-AR) have been isolated from the liver cDNA
library in addition to the previously reported isoform (alpha(1a)-OCU.1-AR).
Although they have the identical splice position with human alpha(1a)-AR
isoforms, the C-terminal sequences are distinct from those of human isoforms.
Among these rabbit alpha(1a)-AR isoforms, there are no significant differences in
pharmacological properties: high affinity for prazosin, WB4101, KMD-3213 and
YM617 and low affinity for BMY7378, using COS-7 cells expressing each isoform by
radioligand binding assay. Competitive reverse transcription-polymerase chain
reaction (RT - PCR) analysis revealed that mRNA of alpha(1a)-ARs was expressed in
liver, thoracic aorta, brain stem and thalamus of rabbit. The splice isoforms
exhibited a distinct distribution pattern in rabbit; alpha(1a)-OCU. 1-AR was
expressed most abundantly in those tissues. CHO clones, stably expressing each
isoforms with receptor density 740 fmol mg(-1) protein in alpha(1a)-OCU.1-AR,
1200 fmol mg(-1) in alpha(1a)-OCU.2-AR and 570 fmol mg(-1) in alpha(1a)-OCU.3-AR,
respectively, showed a noradrenaline-induced increase in inositol trisphosphate
which was suppressed by prazosin. Noradrenaline elicited a concentration
dependent increase in extracellular acidification rate (EAR) in the CHO clones
with pEC(50) values of 6. 19 for alpha(1a)-OCU.1-AR, 6.49 for alpha(1a)-OCU.2-AR
and 6.58 for alpha(1a)-OCU.3-AR, respectively. Noradrenaline caused a
concentration-dependent increase in intracellular Ca(2+) concentration
([Ca(2+)]i) in the CHO clones with pEC(50) values of 6. 14 for alpha(1a)-OCU.1
AR, 7.25 for alpha(1a)-OCU.2-AR and 7.70 for alpha(1a)-OCU.3-AR, respectively. In
conclusion, the present study shows the occurrence of three splice isoforms of
rabbit alpha(1a)-AR, which are unique in C-terminal sequence and in tissue
distribution. They show similar pharmacological profiles in binding studies but
alpha(1a)-OCU.3-AR had the highest potency of noradrenaline in functional studies
in spite of the lowest receptor density. These findings suggest that the
structure of C-terminus of alpha(1a)-ARs may give the characteristic functional
profile.
PMID- 10780961
TI - O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive
properties.
AB - Cannabinoids have low water solubility, necessitating the use of a solubilizing
agent. In this paper we investigated whether a novel water-soluble cannabinoid, 3
(5'-cyano-1', 1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)-Delta(8)-
tetrahydroca nnabinol hydrochloride (O-1057), would interact with cannabinoid
receptors when water or saline were used as the only vehicle. O-1057 displaced
[(3)H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell
membranes expressing CB(1) or CB(2) cannabinoid receptors, with pK(i) values of
8.36 and 7.95 respectively. It also displaced [(3)H]-CP55940 from specific
binding sites on rat brain membranes (pK(i) = 7.86). O-1057 inhibited forskolin
stimulated cyclic AMP production by both CB(1)- and CB(2)-transfected CHO cells
(pEC(50) = 9.16 and 9.72 respectively), its potency matching that of CP55940 and
exceeding that of Delta(9)-tetrahydrocannabinol. In the mouse isolated vas
deferens, O-1057 inhibited electrically-evoked contractions with pEC(50) and
E(max) values of 9.73 and 76.84% respectively. It was antagonized by 100 nM
SR141716A, the pK(B) of SR141716A against O-1057 (8.90) approximating to that
against CP55940 (8.97). O-1057 also behaved as a CB(1) receptor agonist in vivo,
reducing mouse spontaneous activity and rectal temperature when injected
intravenously and inducing antinociception in the mouse tail flick test when
given intravenously (ED(50) = 0.02 mg kg(-1)), intrathecally,
intracerebroventricularly or by gavage. In all these assays, O-1057 was more
potent than Delta(9)-tetrahydrocannabinol and, at 0.1 mg kg(-1) i.v., was
antagonized by SR141716A (3 mg kg(-1) i.v.). These data demonstrate the ability
of the water-soluble cannabinoid, O-1057, to act as a potent agonist at CB(1) and
CB(2) receptors and warrant investigation of the clinical potential of O-1057 as
an analgesic.
PMID- 10780962
TI - Effect of heparin on antigen-induced airway responses and pulmonary leukocyte
accumulation in neonatally immunized rabbits.
AB - The effect of single administrations of aerosolized heparin, low molecular weight
heparin (LMWH) and the linear polyanionic molecule, polyglutamic acid (PGA) were
examined on antigen-induced airway hyperresponsiveness and leukocyte accumulation
in neonatally immunized rabbits. Adult litter-matched NZW rabbits immunized
within 24 h of birth with Alternaria tenuis antigen were treated with heparin,
LMWH or PGA prior to or following antigen challenge (Alternaria tenuis). For each
drug-treated group, a parallel group of rabbits were treated with the appropriate
vehicle. In all groups, airway responsiveness to inhaled histamine and
bronchoalveolar lavage (BAL) was performed 24 h prior to and following antigen
challenge. Basal lung function in terms of resistance (R(L)) and dynamic
compliance (C(dyn)) and acute bronchoconstriction was unaltered by pre-treatment
with heparin, LMWH or PGA compared to their respective vehicles 24 h prior to or
following antigen challenge. In vehicle-treated animals, airway
hyperresponsiveness to inhaled histamine was indicated by an increase in the
maximal responses of the cumulative concentration-effect curves to histamine and
reductions in R(L)PC(50) and C(dyn)PC(35) values 24 h following antigen
challenge. Heparin and LMWH given prior to antigen challenge significantly
inhibited the development of airway hyperresponsiveness, whereas PGA did not.
When given following antigen challenge, all three drugs failed to inhibit the
development of airway hyperresponsiveness. Eosinophil and neutrophil cell numbers
in BAL fluid increased significantly 24 h following antigen challenge. Heparin,
LMWH and PGA failed to inhibit the increase in cell numbers following antigen
challenge whether given prior to or following antigen challenge.
PMID- 10780963
TI - Histamine H(3)-receptor antagonists inhibit gastroprotection by (R)-alpha
methylhistamine in the rat.
AB - (R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, is
capable of protecting the gastric mucosa against differently acting damaging
agents. The objective of the present study was to determine whether H(3)
receptors mediate its protective action in the rat. Gastric mucosal lesions were
induced intragastrically (i.g.) by 0.6 N HCl, 1 ml rat(-1). (R)-alpha
methylhistamine, 100 mg kg(-1) i.g., substantially reduced the severity of
macroscopically and histologically assessed damage caused by concentrated acid.
Prior treatment with highly selective H(3)-receptor antagonists, ciproxifan (0.3,
1 and 3 mg kg(-1) i.g.) and clobenpropit (3, 10 and 30 mg kg(-1) i.g.), dose
dependently inhibited the protection exerted by (R)-alpha-methylhistamine up to a
complete reversal. When given alone at high doses, both antagonists tended to
worsen the HCl-induced histologic damage. During basal conditions, (R)-alpha
methylhistamine, 100 mg kg(-1) i. g., caused a significant increase in titratable
acidity of the gastric juice. Prior treatment with ciproxifan (3 mg kg(-1) i.g.)
and clobenpropit (30 mg kg(-1) i.g.) did not alter the secretory response to (R)
alpha-methylhistamine. Clobenpropit alone, but not ciproxifan, increased the
volume of gastric juice, and both compounds alone had no effect on titratable
acid. Present findings support evidence that H(3) receptors are actively involved
in the maintenance of gastric mucosal integrity, with no apparent role in the
regulation of basal gastric acid secretion.
PMID- 10780964
TI - An improved in vitro bioassay for the study of 5-HT(4) receptors in the human
isolated large intestinal circular muscle.
AB - Recently, it was demonstrated that 5-HT induces relaxation of human colon
circular muscle through activation of 5-HT(4) receptors and 5-HT(7) receptors.
The aim of the current study was to develop a new in vitro bioassay of human
colon that would facilitate the pharmacological analysis of 5-HT responses
mediated solely by 5-HT(4) receptors. Contracting circular muscle strips with KCl
(80 mM) yielded a stable contractile tension and, in contrast to muscarinic
cholinoceptor agonists and histamine, a profound reduction of spontaneous
contractility. This allowed the establishment of reproducible, fully-defined,
agonist concentration-response curves by cumulative dosing. Under these
conditions, 5-HT induced a concentration-dependent relaxation (pEC(50) 7.31, Hill
slope 0.91). Neither methysergide (10 microM) nor granisetron (1 microM) affected
the 5-HT-induced relaxation, suggesting that 5-HT(1), 5-HT(2), 5-HT(3), 5-ht(5),
5-HT(6) or 5-HT(7) receptors are not involved. The lack of effect of tetrodotoxin
(0.3 microM) indicated a direct effect of 5-HT on the smooth muscle. The
selective 5-HT(4) receptor antagonists GR 113808, GR 125487 and RS 39604
competitively antagonized the 5-HT-induced relaxation (pK(B) 9.43, 10.12 and
8.53, respectively). SB 204070 (1 nM) produced a rightward shift (pA(2) 10.34)
and depression of the 5-HT curve. These affinity estimates are similar to those
previously reported for 5-HT(4) receptors. The selective 5-HT(4) receptor
agonists, prucalopride and R076186, induced relaxations (pEC(50) 7.50 and 7.57,
respectively), that were blocked by GR 113808 (3 nM), yielding pA(2) estimates of
9.31 and 9.21, respectively. To summarise, in KCl (80 mM)-contracted muscle
strips, 5-HT induces relaxation through activation of a homogeneous smooth muscle
5-HT(4) receptor population. This new bioassay allows the focused,
pharmacological characterization of human colonic 5-HT(4) receptors in vitro.
PMID- 10780965
TI - Pharmacokinetic-pharmacodynamic modelling of the convulsant interaction between
norfloxacin and biphenyl acetic acid in rats.
AB - Fluoroquinolones (FQs) are associated with a low incidence of central nervous
system (CNS) side effects, possibly leading to convulsions, especially when co
administered with nonsteroidal anti-inflammatory drugs (NSAIDS). Although the in
vivo pro-convulsant activity of NSAIDS is essentially unknown, the convulsant
potential of FQs is traditionally evaluated by in vitro gamma-aminobutyric acid
(GABA) binding experiments in the presence of 4-biphenyl acetic acid (BPAA), the
active metabolite of fenbufen. The aim of this study was therefore to investigate
the BPAA-norfloxacin convulsant interaction in vivo. Male Sprague-Dawley rats (n
= 27) were given BPAA orally, at various doses 1 h before norfloxacin infusion,
which was maintained until the onset of maximal seizures, when cerebrospinal
fluid (CSF) and plasma samples were collected for analysis. An inhibitory E(max)
effect model with a baseline effect parameter was fitted to the norfloxacin
versus BPAA concentrations in the CSF, previously shown to be part of the
biophase. This model includes three parameters: the concentrations of norfloxacin
in the absence of BPAA (C(CSF0, Nor)), and when BPAA concentration tends toward
infinity (C(CSFbase, Nor)), and the BPAA concentration for which half of the
maximal effect is observed (C(CSF50, BPAA)). The maximal proconvulsant effect of
BPAA is given by the C(CSF0, Nor) / C(CSFbase, Nor) ratio, estimated to
approximately 6 in this study. Derived models were developed in plasma to account
for the non-linear CSF diffusion of norfloxacin and protein binding of BPAA. In
conclusion this study has shown that the convulsant interaction between
norfloxacin and BPAA in rats, can be adequately characterized by modelling of the
CSF concentrations of the two drugs at the onset of activity, following their
administration in various proportions.
PMID- 10780966
TI - Selective block of late Na(+) current by local anaesthetics in rat large sensory
neurones.
AB - The actions of lignocaine and benzocaine on transient and late Na(+) current
generated by large diameter (> or =50 microm) adult rat dorsal root ganglion
neurones, were studied using patch-clamp techniques. Both drugs blocked whole
cell late Na(+) current in a concentration-dependent manner. At 200 ms following
the onset of a clamp step from -110 to -40 mV, the apparent K for block of late
Na(+) current by lignocaine was 57.8+/-15 microM (mean+/-s.e.mean, n = 4). The
value for benzocaine was 24.9+/-3.3 microM, (mean+/-s.e. mean, n = 3). The effect
of lignocaine on transient current, in randomly selected neurones, appeared
variable (n = 8, half-block from approximately 50 to 400 microM). Half-block by
benzocaine was not attained, but both whole-cell (n = 11) and patch data
suggested a high apparent K,>250 microM. Transient current always remained after
late current was blocked. The voltage-dependence of residual late current steady
state inactivation was not shifted by 20 microM benzocaine (n = 3), whereas 200
microM benzocaine shifted the voltage-dependence of transient current steady
state inactivation by -18.7+/-5.9 mV (mean+/-s.e.mean, n = 4). In current-clamp,
benzocaine (250 microM) could block subthreshold, voltage-dependent inward
current, increasing the threshold for eliciting action potentials, without
preventing their generation (n = 2). Block of late Na(+) current by systemic
local anaesthetic may play a part in preventing ectopic impulse generation in
sensory neurones.
PMID- 10780967
TI - Central and peripheral cannabinoid modulation of gastrointestinal transit in
physiological states or during the diarrhoea induced by croton oil.
AB - We have evaluated the effect of cannabinoid drugs, administered intraperitoneally
(i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in
control and in croton oil-treated mice. The cannabinoid agonists, WIN 55,212-2 (2
239 nmol mouse(-1)) and cannabinol (24-4027 nmol mouse(-1)), decreased while the
CB(1) antagonist SR141716A (2-539 nmol mouse(-1)) increased transit in control
mice. WIN 55,212-2, cannabinol and SR141716A had lower ED(50) values when
administered i.c.v., than when administered i.p. The CB(2) antagonist SR144528
(52 nmol mouse(-1), i.p.) was without effect. During croton oil (0.01 ml mouse(
1), p.o.)-induced diarrhoea, the ED(50) values of i.p. -injected WIN 55,212-2 and
cannabinol (but not SR141716A) were significantly decreased (compared to control
mice). However, the ED(50) values of WIN 55,212-2 were similar after i.p. or
i.c.v. administration. The inhibitory effects of WIN 55,212-2 and cannabinol were
counteracted by SR141716A (16 nmol mouse(-1), i.p.) but not by SR144528 (52 nmol
mouse(-1), i.p.) both in control and croton-oil treated mice. Ganglionic blockade
with hexamethonium (69 nmol mouse(-1), i.p.) did not modify the inhibitory effect
of i.p. -injected cannabinoid agonists either in control or in croton-oil treated
mice. The lower ED(50) values of cannabinoid drugs after i.c.v. administration
suggest a central (CB(1)) site of action. However, a peripheral site of action is
suggested by the lack of effect of hexamethonium. In addition, croton oil-induced
diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.
PMID- 10780968
TI - Loss of muscarinic antinociception by antisense inhibition of M(1) receptors.
AB - The effect on cholinergic analgesia of inactivation of the M(1) gene by an
antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse hot plate
test. Mice received a single intracerebroventricular (i.c.v.) injection of anti
M(1) aODN (0.3, 1. 0 or 2.0 nmol per injection), degenerate ODN (dODN) or vehicle
on days 1, 4 and 7. A dose-dependent inhibition of the antinociception induced by
the muscarinic agonists oxotremorine (0.1 mg kg(-1) s.c.) and McN-A-343 (30
microg per mouse i.c.v.) and the cholinesterase inhibitor physostigmine (0.2 mg
kg(-1) s.c.) was observed 24 h after the last i.c.v. injection of aODN. Time
course experiments revealed that, after the end of the aODN treatment,
sensitivity to analgesic drugs progressively appeared reaching the normal range
at 96 h. The anti-M(1) aODN was selective against muscarinic antinociception
since the enhancement of pain threshold produced by morphine and baclofen were
not affected by the above-mentioned treatment. dODN, used as control, did not
affect muscarinic antinociception. Binding studies evidenced a selective
reduction of M(1) receptor levels in the hippocampus of aODN-treated mice.
Neither aODN, dODN nor vehicle produced any behavioural impairment of mice as
revealed by the rota-rod and Animex experiments. These results indicate that
activation of M(1) muscarinic receptor subtype is fundamental to induce central
cholinergic analgesia in mice.
PMID- 10780969
TI - In vitro and in vivo effects of kinin B(1) and B(2) receptor agonists and
antagonists in inbred control and cardiomyopathic hamsters.
AB - The aims of this study were to examine the possible alterations occurring in the
effects of kinins on isolated aortae of inbred control (CHF 148) and
cardiomyopathic (CHF 146) hamsters of 150 - 175 and 350 - 375 days of age.
Bradykinin (BK) and desArg(9)BK contracted isolated aortae (with or without
endothelium) of hamsters of both strains and ages. After tissue equilibration (90
min), responses elicited by both kinin agonists were stable over the time of
experiments. The patterns of isometric contractions of BK and desArg(9)BK were
however found to be different; desArg(9)BK had a slower onset and a longer
duration of action than BK. Potencies (pEC(50) values) of BK in all groups of
hamsters were significantly increased by preincubating the tissues with captopril
(10(-5) M). No differences in the pEC(50) values and the E(max) values for BK or
desArg(9)BK were seen between isolated vessels from inbred control and
cardiomyopathic hamsters. The myotropic effect of BK was inhibited by the
selective non peptide antagonist, FR 173657 (pIC(50) 7.25+/-0.12 at the
bradykinin B(2) receptor subtype (B(2) receptor)). Those of desArg(9)BK, at the
bradykinin B(1) receptor subtype (B(1) receptor) were abolished by either R 715
(pIC(50) of 7. 55+/-0.05; alpha(E) = 0), Lys[Leu(8)]desArg(9)BK (pIC(50) of
7.21+/-0. 01; alpha(E) = 0.22) or [Leu(8)]desArg(9)BK (pIC(50) of 7.25+/-0.02;
alpha(E) = 0.18). FR 173657 had no agonistic activity, exerted a non competitive
type of antagonism and was poorly reversible (lasting more than 5 h) from B(2)
receptor. In vivo, FR 173657 (given per os at 1 and 5 mg kg(-1), 1 h before the
experiment) antagonized the acute hypotensive effect of BK in anaesthetized
hamsters. It is concluded that aging and/or the presence of a congenital
cardiovascular disorder in hamsters are not associated with changes in the in
vitro aortic responses to either BK or desArg(9)BK.
PMID- 10780970
TI - Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through
CCK(A) receptors.
AB - It has been proposed that the vagus nerve plays a role in mediating
cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying
and gastric acid secretion. To examine the contribution of the efferent pathways
in realizing these effects, efferent mass activity in the ventral gastric vagal
nerve in Sprague-Dawley rats was recorded. Intravenous infusion of CCK-8 (0.1-1
nmol) suppressed the efferent activity. The effect of CCK-8 was significantly
reduced in animals with total subdiaphragmatic vagotomy in comparison to those
with partial vagotomy. Intravenous infusion of CCK(A) receptor antagonist L
364,718 (1-100x10(-6) g) blocked the response of vagal efferent activity to 0.1
nmol CCK-8, but the CCK(B) receptor antagonist L-365,260 (1-100x10(-6) g) did not
in the conditions of either partial or total vagotomy. Intracisternal infusion of
L-364,718 (1x10(-6) g) blocked the response of vagal efferent activity to 0.1
nmol CCK-8 i.v. Infusion of exogenous CCK-8 did not affect the activity of
supradiaphragmatic vagal afferents. The results suggest that the effect of
systemically administered CCK-8 on vagal efferent activity is mediated by both
peripherally (subdiaphragmatically) and centrally localized CCK(A) receptors.
PMID- 10780971
TI - Identification of the cytochrome P450 enzymes involved in the metabolism of
cisapride: in vitro studies of potential co-medication interactions.
AB - Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal
tract motility. Structurally, cisapride is a substituted piperidinyl benzamide
that interacts with 5-hydroxytryptamine-4 receptors and which is largely without
central depressant or antidopaminergic side-effects. The aims of this study were
to investigate the metabolism of cisapride in human liver microsomes and to
determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride
biotransformation. Additionally, the effects of various drugs on the metabolism
of cisapride were investigated. The major in vitro metabolite of cisapride was
formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the
production of norcisapride. By using competitive inhibition data, correlation
studies and heterologous expression systems, it was demonstrated that CYP3A4 was
the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride,
albeit to a much lesser extent. The mean apparent K(m) against cisapride was
8.6+/-3.5 microM (n = 3). The peak plasma levels of cisapride under normal
clinical practice are approximately 0.17 microM; therefore it is unlikely that
cisapride would inhibit the metabolism of co-administered drugs. In this in vitro
study the inhibitory effects of 44 drugs were tested for any effect on cisapride
biotransformation. In conclusion, 34 of the drugs are unlikely to have a
clinically relevant interaction; however, the antidepressant nefazodone, the
macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and
indinavir and the calcium channel blocker mibefradil inhibited the metabolism of
cisapride and these interactions are likely to be of clinical relevance.
Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole,
itraconazole and fluconazole, when administered orally or intravenously, would
inhibit cisapride metabolism.
PMID- 10780972
TI - Antihyperalgesic effects of delta opioid agonists in a rat model of chronic
inflammation.
AB - Opioid receptors in the brain activate descending pain pathways to inhibit the
nociceptive response to acute noxious stimuli. The aim of the present study was
to clarify the role of supraspinal opioid receptors in modulating the nociceptive
response to persistent inflammation in rats. Subcutaneous administration of 50
microl of complete Freund's Adjuvant (CFA) into the plantar surface of the
hindpaw induced a significant decrease in paw withdrawal latency to thermal
stimuli (P<0.01) at 24 h post-injection. Intracerebroventricular (i.c.v.)
administration of the mu opioid receptor agonists, DAMGO and morphine, and the
delta opioid receptor agonists, deltorphin II and SNC80, significantly reversed
the hyperalgesic response associated with peripheral inflammation in a dose
dependent manner (P<0.0001). The mu and delta agonists also significantly
attenuated the antinociceptive response to acute thermal stimulation in rats
(P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of
SNC80 less efficacious, in modulating the response to acute thermal nociception
in comparison to hyperalgesia associated with persistent inflammation. These
results indicate that mu and delta opioid receptors in the brain modulate
descending pain pathways to attenuate the nociceptive response to acute thermal
stimuli in both normal and inflamed tissues. The heightened response to delta
agonists in the hyperalgesia model suggests that delta opioid receptors in the
brain are promising targets for the treatment of pain arising from chronic
inflammation.
PMID- 10780974
TI - Characterization of the ATPase released during sympathetic nerve stimulation of
the guinea-pig isolated vas deferens.
AB - The release of ATPase activity evoked by electrical field stimulation (EFS) (8
Hz, 25 s) was investigated in several tissues in which adenosine 5'-triphosphate
(ATP) acts as a neurotransmitter. Superfusate collected during EFS of sympathetic
nerves of the guinea-pig, rat and mouse isolated vas deferens and parasympathetic
nerves of the guinea-pig isolated urinary bladder contained ATPase activity. ATP
breakdown was fastest in superfusate collected from the guinea-pig isolated vas
deferens. However, EFS of the enteric nerves of the guinea-pig isolated taenia
coli did not release any detectable ATPase. The ATPase released from the guinea
pig isolated vas deferens metabolized ATP at similar rates at incubation
temperatures of 37 degrees C and 20 degrees C. Lineweaver-Burke analysis of the
initial rates of ATP hydrolysis gave a K(M) of 39 microM and a V(max) of 1039
pmol ATP metabolized min(-1) ml(-1) superfusate. 6-N,N-diethyl-D-beta,gamma
dibromomethyleneATP (ARL 67156), pyridoxalphosphate-6-azophenyl-2',4'-disulphonic
acid (PPADS) and pyridoxal-5'-phosphate (P-5-P) all inhibited the ATPase activity
in a concentration-dependent manner with a potency order of ARL 67156 = PPADS>P-5
P. In conclusion, EFS of several tissues in which ATP is a neurotransmitter
causes the release of an ATPase and activity is greatest in the guinea-pig vas
deferens. The enzyme has pharmacological and kinetic characteristics that are
similar to ectonucleoside triphosphate diphosphohydrolases.
PMID- 10780973
TI - Suppression of apoptosis by glucocorticoids in glomerular endothelial cells:
effects on proapoptotic pathways.
AB - Tumour necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced
apoptosis of bovine glomerular endothelial cells is now recognized as an
important part in the pathogenesis of glomerulonephritis characterized by early
mitochondrial cytochrome c release, mitochondrial permeability transition, Bak
protein upregulation, Bcl-X(L) protein downregulation and caspase-3 activation.
Co-treatment of cells with 10 nM dexamethasone and TNF-alpha or LPS blocked
roughly 90% of apoptotic cell death in glomerular endothelial cells. The action
of glucocorticoids could be documented in that they prevented all apoptotic
markers such as DNA laddering, DNA fragmentation measured by the diphenylamine
assay as well as morphological alterations. To mechanistically elucidate the
action of glucocorticoids we evaluated whether glucocorticoids elicit a time
dependent effect. For dexamethasone, to maximally inhibit DNA fragmentation a
preincubation period was not required. Even if dexamethasone was supplemented 6 h
following TNF-alpha or LPS we observed a maximal inhibitory effect. Concerning
its influence on TNF-alpha and LPS signal transduction, we found that
dexamethasone only partially prevented cytochrome-c-release as a first sign of
apoptotic cell death but efficiently blocked mitochondrial permeability
transition. Moreover, TNF-alpha- and LPS-induced Bak upregulation, Bcl-X(L)
downregulation, and the activation of caspase-3-like proteases, measured
fluorometrically using DEVD-AMC and PARP cleavage, were efficiently blocked by
dexamethasone. We postulate that glucocorticoids exert their inhibitory action
upstream of the terminal death pathways but downstream of primary receptor
mediated signals by blocking pro-apoptotic signals pre- and/or post cytochrome c
release and mitochondrial signalling.
PMID- 10780975
TI - Neuropeptide Y regulates intracellular calcium through different signalling
pathways linked to a Y(1)-receptor in rat mesenteric small arteries.
AB - Simultaneous measurements of intracellular calcium concentration ([Ca(2+)](i))
and tension were performed to clarify whether the mechanisms which cause the
neuropeptide Y (NPY)-elicited contraction and potentiation of noradrenaline
contractions, and the NPY inhibition of forskolin responses are linked to a
single or different NPY receptor(s) in rat mesenteric small arteries. In resting
arteries, NPY moderately elevated [Ca(2+)](i) and tension. These effects were
antagonized by the selective Y(1) receptor antagonist, (R)-N(2)-(diphenacetyl)-N
[(4-hydroxyphenyl)methyl]-D-argininea mide (BIBP 3226) (apparent pK(B) values of
8.54+/-0.25 and 8.27+/-0.17, respectively). NPY (0.1 microM) caused a near 3 fold
increase in sensitivity to noradrenaline but did not significantly modify the
tension-[Ca(2+)](i) relationship for this agonist. BIBP 3226 competitively
antagonized the contractile response to NPY in arteries submaximally
preconstricted with noradrenaline (pA(2) 7.87+/-0.20). In arteries activated by
vasopressin, the adenylyl cyclase activator forskolin (3 microM) induced a
maximum relaxation and a return of [Ca(2+)](i) to resting levels. NPY completely
inhibited these effects. The contractile responses to NPY in arteries maximally
relaxed with either sodium nitroprusside (SNP) or nifedipine were not
significantly higher than those evoked by the peptide at resting tension, in
contrast to the contractions to NPY in forskolin-relaxed arteries. BIBP 3226
competitively antagonized the contraction to NPY in forskolin-relaxed arteries
with a pA(2) of 7.92+/-0.29. Electrical field stimulation (EFS) at 8-32 Hz caused
large contractions in arteries relaxed with either forskolin or noradrenaline in
the presence of phentolamine. These responses to EFS were inhibited by BIBP 3226.
Similar EFS in resting, non-activated arteries did not produce any response. The
present results suggest that different intracellular pathways are linked to a
single NPY Y(1) receptor in intact rat mesenteric small arteries, and provide
little support for involvement of other postjunctional NPY receptors in the
contractile responses to NPY. Neurally released NPY also seems to act through
Y(1) receptors, and may serve primarily as an inhibitor of vasodilatation.
PMID- 10780976
TI - Characterization of a novel nonpeptide vasopressin V(2)-agonist, OPC-51803, in
cells transfected human vasopressin receptor subtypes.
AB - We discovered the first nonpeptide arginine-vasopressin (AVP) V(2)-receptor
agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using
HeLa cells expressing human AVP receptor subtypes (V(2), V(1a) and V(1b)) and
compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide
V(2)-receptor agonist. OPC-51803 and dDAVP displaced [(3)H]-AVP binding to human
V(2)- and V(1a)-receptors with K(i) values of 91.9+/-10.8 nM (n = 6) and 3.12+/
0.38 nM (n = 6) for V(2)-receptors, and 819+/-39 nM (n = 6) and 41.5+/-9.9 nM (n
= 6) for V(1a)-receptors, indicating that OPC-51803 was about nine times more
selective for V(2)-receptors, similar to the selectivity of dDAVP. OPC-51803
scarcely displaced [(3)H]-AVP binding to human V(1b)-receptors even at 10(-4) M,
while dDAVP showed potent affinity to human V(1b)-receptors with the K(i) value
of 13.7+/-3.2 nM (n = 4). OPC-51803 concentration-dependently increased cyclic
adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing
human V(2)-receptors with an EC(50) value of 189+/-14 nM (n = 6). The
concentration-response curve for cyclic AMP production induced by OPC-51803 was
shifted to the right in the presence of a V(2)-antagonist, OPC-31260. At 10(-5)
M, OPC-51803 did not increase the intracellular Ca(2+) concentration
([Ca(2+)](i)) in HeLa cells expressing human V(1a)-receptors. On the other hand,
dDAVP increased [Ca(2+)](i) in HeLa cells expressing human V(1a)- and V(1b)
receptors in a concentration-dependent fashion. From these results, OPC-51803 has
been confirmed to be the first nonpeptide agonist for human AVP V(2)-receptors
without agonistic activities for V(1a)- and V(1b)-receptors. OPC-51803 may be
useful for the treatment of AVP-deficient pathophysiological states and as a tool
for AVP researches.
PMID- 10780978
TI - Inhibition by various antipsychotic drugs of the G-protein-activated inwardly
rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
AB - To investigate the effects of various chemical classes of antipsychotic drugs:
haloperidol, thioridazine, pimozide and clozapine, on the G-protein-activated
inwardly rectifying K(+) (GIRK) channels, we carried out Xenopus oocyte
functional assays with GIRK1 and GIRK2 mRNAs or GIRK1 and GIRK4 mRNAs. In oocytes
co-injected with GIRK1 and GIRK2 mRNAs, application of each of the various
antipsychotic drugs immediately caused a reduction of inward currents through the
basally active GIRK channels. These responses were not observed in the presence
of 3 mM Ba(2+), which blocks the GIRK channels. In addition, in uninjected
oocytes, none of the drugs tested produced any significant current response.
These results indicate that all the antipsychotic drugs tested inhibited the
brain-type GIRK1/2 heteromultimeric channels. Furthermore, similar results were
obtained in oocytes co-injected with GIRK1 and GIRK4 mRNAs, indicating that the
antipsychotic drugs also inhibited the cardiac-type GIRK1/4 heteromultimeric
channels. All the drugs tested inhibited, in a concentration-dependent manner,
both types of GIRK channels with varying degrees of potency and effectiveness at
micromolar concentrations. Only pimozide caused slight inhibition of these
channels at nanomolar concentrations. We conclude that the various antipsychotic
drugs acted as inhibitors at the brain-type and cardiac-type GIRK channels. Our
results suggest that inhibition of both types of GIRK channels by these drugs
underlies some of the side effects, in particular seizures and sinus tachycardia,
observed in clinical practice.
PMID- 10780977
TI - Effects of cannabinoid receptor agonists on neuronally-evoked contractions of
urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human.
AB - This study investigated the cannabinoid receptor, known to inhibit neuronally
evoked contractions of the mouse isolated urinary bladder, in bladder sections
isolated from mouse, rat, dog, pig non-human primate or human. The CB(1)-like
pharmacology of the cannabinoid receptor in mouse isolated bladder observed
previously was confirmed in this study by the rank order of agonist potencies: CP
55940>/=WIN 55212-2>HU 210>JWH 015>anandamide, the high affinity of the CB(1)
selective antagonist, SR 141716A (apparent pK(B) 8.7), and the low affinity of
the CB(2) antagonist, SR 144528 (apparent pK(B)<6.5). In these studies, SR
141716A (10-100 nM) significantly potentiated electrically-evoked contractions in
this tissue by an undetermined mechanism. A similar rank order of agonist
potencies was determined in rat isolated bladder sections (CP 55, 940> or =WIN
55212-2>JWH 015). In this tissue, the maximal inhibitory effect of all agonists
was lower than in the mouse bladder. Indeed, the effects of both HU 210 and
anandamide were too modest to quantify potency accurately. In the rat isolated
bladder, SR 141716A (30 nM) or SR 144528 (100 nM), reversed the inhibitory effect
of WIN 55212-2 (apparent pK(B) = 8.4 and 8.0, respectively) or JWH 015 (apparent
pK(B) = 8.2 and 7.4, respectively). These findings may demonstrate
pharmacological differences between the rat and mouse orthologues of the CB(1)
receptor. Alternatively, they may be attributed to a mixed population of CB(1)
and CB(2) receptors that jointly influence neurogenic contraction of the rat
bladder, but cannot be differentiated without more selective ligands. WIN 55212-2
had no effect on electrically-evoked contractions of bladder sections isolated
from dog, pig, cynomolgus monkey and human. These findings suggest that the
effect of cannabinoid agonists to inhibit neurogenic contraction of the mouse and
rat bladder is not conserved across all mammalian species.
PMID- 10780979
TI - FP-receptor mediated trophic effects of prostanoids in rat ventricular
cardiomyocytes.
AB - The aim of this study was to characterize the receptor subtype involved in
cardiac effects of prostanoids. For this purpose we determined in neonatal and
adult rat cardiomyocytes effects of prostanoids on inositol phosphate (InsP)
formation (assessed as accumulation of total [(3)H]-InsP's in myo-[(3)H]-inositol
pre-labelled cells) and on rate of protein synthesis (assessed as [(3)H]
phenylalanine incorporation), and on contractile force in left ventricular strips
of the rat heart. For comparison, effects of prostanoids on InsP-formation and
contractile force were determined in rat thoracic aorta, a classical TP-receptor
containing tissue. Prostanoid increased InsP-formation and rate of protein
synthesis in neonatal as well as adult rat cardiomyocytes; the order of potency
was in neonatal (PGF(2alpha)>PGD(2)> or =PGE(2)> or =U 46619>PGE(1)) and adult
(PGF(2alpha)>PGD(2)> or =PGE(2)>U 46619) rat cardiomyocytes well comparable.
Moreover, in electrically driven left ventricular strips PGF(2alpha) caused
positive inotropic effects (pD(2) 7.5) whereas U 46619 (up to 1 microM) was
uneffective. In contrast, in rat thoracic aorta U 46619 was about 100 times more
potent than PGF(2alpha) in increasing InsP-formation and contractile force. The
TP-receptor antagonist SQ 29548 only weakly antagonized prostanoid-induced
increases in rate of protein synthesis (pK(B) about 6) in rat cardiomyocytes but
was very potent (pK(B) about 8-9) in antagonizing prostanoid-induced increases in
InsP-formation and contractile force in rat aorta. We conclude that, in
cardiomyocytes of neonatal and adult rats, the prostanoid-receptor mediating
increases in InsP-formation and rate of protein synthesis is a FP-receptor.
Moreover, stimulation of these cardiac FP-receptors can mediate increases in
contractile force.
PMID- 10780980
TI - Contribution of B(2) receptors for bradykinin in arthus reaction-induced plasma
extravasation in wild-type or B(2) transgenic knockout mice.
AB - The aim of the present study was to investigate the contribution of bradykinin
(BK) B(1) and B(2) receptors in a model of type III hypersensitivity, the reverse
passive Arthus reaction (RPA), in wild-type mice and transgenic B(2) knockout
littermates. BK (10 microg mouse(-1)) or bovine serum albumin (0.5 mg mouse(-1))
induced a sustained Evans blue extravasation for more than 80 min in naive or
rabbit anti-bovine serum albumin-treated mice (RPA model), respectively. The
response to the two stimuli was prevented by the B(2) receptor antagonist, HOE
140, but not by [Leu(8)]desArg(9)-BK (B(1) receptor antagonist). In contrast to
the wild-type littermates, RPA and bradykinin were unable to trigger an increase
in plasma extravasation in B(2) knockout mice. Furthermore, endothelin-1 (5
microg mouse(-1)) and a selective NK-1 receptor agonist [Sar(9),Met (O(2))(11)]
SP (20 microg mouse(-1)), triggered a significant increase in peritoneal plasma
extravasation in both wild-type and B(2) knockout animals. A pretreatment with
indomethacin (200 microg mouse(-1)) significantly reduced the RPA-induced but not
the BK-induced increase in Evans blue extravasation. Furthermore, RPA, but not
BK, triggered a significant indomethacin-sensitive increase in peritoneal
prostaglandin E(2) content. Our results suggest a pivotal role for B(2) receptors
in the mechanism of plasma extravasation which occurs during the reverse passive
Arthus reaction in the mouse. Moreover, our results suggest an important
contribution of prostanoids in the plasma leakage mechanisms triggered by RPA but
not by bradykinin.
PMID- 10780981
TI - Enhanced relaxation of porcine coronary arteries after acute exposure to a
physiological level of 17beta-estradiol involves non-genomic mechanisms and the
cyclic AMP cascade.
AB - The present study extends our previous finding that the endothelium-independent
relaxation in porcine coronary artery rings is enhanced after short-term (20 min)
exposure to a physiological concentration (1 nM) of 17beta-estradiol and
demonstrates that this effect may be attributable to activation of the cyclic AMP
pathway. Isometric tension was recorded in isolated rings of porcine coronary
arteries. Relaxation by levcromakalim and sodium nitroprusside, but not
bradykinin and calcium ionophore A23187, were significantly potentiated following
20 min treatment with 1 nM 17beta-estradiol. This enhancing effect was
insensitive to the transcriptional and translational inhibitors, actinomycin D
and cycloheximide respectively and absent following repeated washing of the rings
prior to construction of relaxation-response curves. The potentiating actions of
1 nM 17beta-estradiol on endothelium-independent relaxation were mimicked by the
cyclic AMP analogue 8-Bromo-cyclic AMP and the protein kinase A activator Sp
cyclic AMPS but not by the cyclic GMP analogue 8-Bromo-cyclic GMP. The modulatory
effect of 17beta-estradiol was increased in the presence of the phosphodiesterase
inhibitor 3-isobutyl-1-methylxanthine. The cyclic AMP-dependent protein kinase A
inhibitor Rp-cyclic AMPS, but not the cyclic GMP antagonist Rp-8-Bromo-cyclic
GMPS, effectively inhibited the enhancing effects 1 M 17beta-estradiol had on the
relaxation responses of levcromakalim and sodium nitroprusside. These data
support our earlier findings that physiologically relevant concentrations of
17beta-estradiol can acutely modify vasorelaxation in vitro. Furthermore, we
report that this short-term effect of 17beta-estradiol on vasorelaxation appears
to be mediated via non-genomic pathways and involves the cyclic AMP cascade.
PMID- 10780982
TI - Comparison of the activity and disposition of the novel cholesterol absorption
inhibitor, SCH58235, and its glucuronide, SCH60663.
AB - Previous studies described the metabolism-based discovery of a potent, selective
inhibitor of intestinal absorption of cholesterol, SCH58235 (Ezetimibe). Here we
demonstrate that the phenolic glucuronide (SCH60663) of SCH58235, was more potent
at inhibiting cholesterol absorption in rats than SCH58235, when administered by
the intraduodenal route. To understand the increased potency of the glucuronide,
the metabolism and distribution of SCH58235 and SCH60663 were studied in bile
duct-cannulated rats. One minute after intraduodenal delivery of SCH58235,
significant levels of compound were detected in portal plasma; >95% was
glucuronidated, indicating that the intestine was metabolizing SCH58235 to its
glucuronide. When intraduodenally delivered as SCH58235, the compound was
glucuronidated, moved through the intestinal wall, into portal plasma, through
the liver, and into bile. However, when delivered as SCH60663, >95% of the
compound remained in the intestinal lumen and wall, which may explain its
increased potency. Significant inhibition of cholesterol absorption and
glucuronidation of SCH58235 occurred when SCH58235 was intravenously injected
into bile duct-cannulated rats. Autoradiographic analysis demonstrated that drug
related material was located throughout the intestinal villi, but concentrated in
the villus tip. These data indicate that (a) SCH58235 is rapidly metabolized in
the intestine to its glucuronide; (b) once glucuronidated, the dose is excreted
in the bile, thereby delivering drug related material back to the site of action
and (c) the glucuronide is more potent than the parent possibly because it
localizes to the intestine. Taken together, these data may explain the potency of
SCH58235 in the rat (ID(50) = 0.0015 mg kg(-1)) and rhesus monkey (ID(50) =
0.0005 mg kg(-1)).
PMID- 10780983
TI - Investigations into pharmacological antagonism of general anaesthesia.
AB - The effects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were
examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone
and propofol in mice. The aim was to investigate the possibility of selective
antagonism, which, if seen, would provide information about the mechanism of the
anaesthesia. The general anaesthetic effects of ketamine were unaffected by
bicuculline; antagonism was seen with 4-aminopyridine and significant
potentiation with 300 mg kg(-1) NMDLA (N-methyl-DL-aspartate). The calcium
agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and
antagonism of such anaesthesia was seen with TRH. A small, but significant,
antagonism of the general anaesthesia produced by ethanol was seen with
bicuculline, and a small, significant, potentiation with 4-aminopyridine. There
was an antagonist effect of TRH, but no effect of NMDLA. Potentiation of the
anaesthetic effects of pentobarbitone was seen with NMDLA and with 4
aminopyridine and the lower dose of bicuculline (2.7 mg kg(-1)) also caused
potentiation. There was no significant change in the ED(50) value for
pentobarbitone anaesthesia with TRH. Bicuculline did not alter the anaesthetic
actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine.
TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg(
1) significantly potentiated the anaesthesia. These results suggest that
potentiation of GABA(A) transmission or inhibition of NMDA receptor-mediated
transmission do not appear to play a major role in the production of general
anaesthesia by the agents used.
PMID- 10780984
TI - Role of kynurenines in the neurotoxic actions of kainic acid.
AB - The neurotoxic actions of kainic acid can be partly suppressed by antagonists
acting at N-methyl-D-aspartate (NMDA) receptors. The present study examined the
possible role of endogenous components of the kynurenine pathway to this
phenomenon. Administration of kainate (2 nmols) into the hippocampus of
anaesthetized rats produced damage in the CA1 and CA3 regions. The involvement of
NMDA receptors was confirmed by the ability of dizocilpine (1 mg kg(-1)) to
reduce cell loss in the CA1 region from 92 to 42%. The co-administration of m
nitrobenzoylalanine (20 nmols into the hippocampus), an inhibitor of kynurenine
hydroxylase and kynureninase, together with a systemic injection of the compound
(100 mg kg(-1), i.p.), afforded some protection against kainate, reducing cell
loss from 91 to 48%. Protection was not exerted against damage by quinolinic acid
or NMDA, excluding a direct interaction between m-nitrobenzoylalanine and NMDA
receptors. The protective effect of m-nitrobenzoylalanine was not prevented by
glycine, which would be expected to reverse protection caused by an elevation in
the levels of endogenous kynurenic acid, arguing against a major role for
increased levels of kynurenic acid. The results indicate that inhibition of the
kynurenine pathway offers protection against kainate-induced damage. One possible
mechanism for the protection is that an increased production of quinolinic acid
in the brain, possibly from glial cells and macrophages activated by the initial
kainate insult, normally contributes to the local activation of NMDA receptors
and thus to kainate-induced cerebral insults. This generation of endogenous
quinolinic acid would be suppressed by m-nitrobenzoylalanine.
PMID- 10780985
TI - Antagonism of nicotinic receptors of rat chromaffin cells by N,N, N-trimethyl-1
(4-trans-stilbenoxy)-2-propylammonium iodide: a patch clamp and ligand binding
study.
AB - The effect of the oxystilbene derivative F3 was tested on nAChRs of whole-cell
patch-clamped rat chromaffin cells in vitro and of rat adrenal gland membranes
using (125)I-epibatidine. F3 (30 nM) rapidly and reversibly blocked inward
currents generated by pulse applications of nicotine, shifting the dose-response
curve to the right in a parallel fashion without changing the maximum response.
The action of F3 was voltage insensitive and not due to altered current reversal
potential. The R isomer of F3 was more potent (IC(50) = 350+/-30 nM) than its S
enantiomer (IC(50) = 1.5+/-0.3 microM). Nicotine-evoked currents were insensitive
to 10 microM alpha-bungarotoxin. Equi-amplitude currents evoked by nicotine or
epibatidine were similarly antagonized by R-F3 in a reversible fashion.
Epibatidine-evoked currents readily produced receptor desensitization. Adrenal
membranes specifically bound (125)I-epibatidine with a single population of
binding sites endowed with high affinity (K(D) = 159 pM) and B(max) of 6.5+/-1.3
fmol mg(-1) of protein. (125)I-epibatidine binding was specifically displaced by
cytisine (K(i) = 68 nM) or ACh (K(i) = 348 nM). F3 specifically displaced (125)I
epibatidine binding although with lower affinity (K(i) = 29.6 microM) than in
electrophysiological experiments. (125)I-epibatidine binding to rat adrenal
tissue was insensitive to alpha-bungarotoxin which readily antagonized (125)I
epibatidine binding to bovine adrenal tissue. The present results suggest that F3
is a relatively potent and apparently competitive antagonist of nAChRs on rat
chromaffin cells. Since previous studies have indicated that F3 targets different
subtypes on chick neuronal tissue, it appears that nAChRs display interspecies
differences to be considered for drug development studies.
PMID- 10780986
TI - Release of dopamine from human neocortex nerve terminals evoked by different
stimuli involving extra- and intraterminal calcium.
AB - The release of [(3)H]-dopamine ([(3)H]-DA) from human neocortex nerve terminals
was studied in synaptosomes prepared from brain specimens removed in neurosurgery
and exposed during superfusion to different releasing stimuli. Treatment with 15
mM KCl, 100 microM 4-aminopyridine, 1 microM ionomycin or 30 mM caffeine elicited
almost identical overflows of tritium. Removal of external Ca(2+) ions abolished
the overflow evoked by K(+) or ionomycin and largely prevented that caused by 4
aminopyridine; the overflow evoked by caffeine was completely independent of
external Ca(2+). Exposure of synaptosomes to 25 microM of the broad spectrum
calcium channel blocker CdCl(2) strongly inhibited the 4-aminopyridine-induced
tritium overflow while that evoked by ionomycin remained unaffected. The Ca(2+)
chelator, 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA),
reduced significantly the K(+)- and the caffeine-induced tritium overflow. The
effect of caffeine was attenuated by exposure to the ryanodine receptor blocker
dantrolene or when the membrane-impermeant inositol trisphosphate receptor
antagonist, heparin, was entrapped into synaptosomes; the combined treatment with
dantrolene and heparin abolished the release elicited by caffeine. Tetanus toxin,
entrapped into human neocortex synaptosomes to avoid prolonged incubation,
inhibited in a concentration-dependent manner the K(+)- or the 4-aminopyridine
evoked tritium overflow; in contrast, the release stimulated by ionomycin and by
caffeine were both totally insensitive to the same concentrations of tetanus
toxin. Western blot analysis showed about 50% reduction of the content of the
vesicular protein, synaptobrevin, in synaptosomes poisoned with tetanus toxin. In
conclusion, the release of dopamine from human neocortex nerve terminals can be
triggered by Ca(2+) ions originating from various sources. It seems that stimuli
not leading to activation of voltage-sensitive Ca(2+) channels elicit Ca(2+)
dependent, probably exocytotic, release that is insensitive to tetanus toxin.
PMID- 10780987
TI - Characterization and distribution of prolactin releasing peptide (PrRP) binding
sites in the rat--evidence for a novel binding site subtype in cardiac and
skeletal muscle.
AB - Prolactin releasing peptide (PrRP) was recently purified from bovine hypothalamus
and binds to the orphan receptor, UHR-1. We examined the distribution and
kinetics of (125)I-PrRP binding in rat tissues together with molecular
characterization by chemical cross-linking and Northern blotting. In this study
(125)I-PrRP binding showed specificity and rapid association and dissociation.
Specific binding was found in membranes from rat tissues including brain
(hypothalamus, medulla oblongata and cerebellum), pituitary, heart, soleus
muscle, adipose tissue, kidney, adrenal gland, testis and small intestine. In
hypothalamus, pituitary, heart and soleus competition analysis indicated only one
class of binding site in each tissue. Binding affinity for PrRP (IC(50)) and
binding site density (B(max)) respectively were 5.2+/-0.9 nM and 674+/-97 fmol mg
protein(-1) in hypothalamus (n = 5), 1.4+/-0.6 nM and 541+/-126 fmol mg protein(
1) in pituitary (n = 3), 6.6+/-0.7 nM and 628+/-74 fmol mg protein(-1) in heart
(n = 4) and 9.8+/-0.9 nM and 677+/-121 fmol mg protein(-1) in soleus muscle (n =
4). Analysis of (125)I-PrRP-binding site complexes by chemical cross-linking
showed a binding site M(r) of 69,000 in hypothalamus and 41,000 in heart and
soleus. Northern analysis of polyA(+) RNA from hypothalamus showed a 4.2 kb band
as expected for UHR-1, but heart and soleus showed a 4.8 kb band. Taken together
these results indicate that there may be different subtypes of PrRP binding sites
in rat tissues which may differ from UHR-1.
PMID- 10780988
TI - Allosteric modulators affect the efficacy of partial agonists for recombinant
GABA(A) receptors.
AB - Different alpha subunits of human gamma-aminobutyric acid type A (GABA(A))
receptors were transiently expressed together with beta(3) and gamma(2) subunits
in Xenopus oocytes to examine the interactions of various GABA(A) agonists and
representative allosteric modulators. Chloride currents elicited by agonists were
measured using two electrode voltage clamp electrophysiology. Where compounds
behaved as full agonists, i.e. GABA on all subtypes and 4,5,6, 7
tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP) on alpha2beta(3)gamma(2) GABA(A)
receptors, agonist concentration-response curves were shifted to the left by the
benzodiazepine full agonist chlordiazepoxide and the anticonvulsant loreclezole,
or to the right by the inverse agonist 6, 7-dimethoxy-4-ethyl-beta-carboline-3
carboxylic acid methyl ester (DMCM), with no effect on the maximal currents
(I(max)). In contrast, maximal responses for different partial GABA(A) agonists
on all benzodiazepine-sensitive alpha(x)beta(3)gamma(2) GABA(A) receptors were
enhanced by chlordiazepoxide. I(max) values for piperidine-4-sulphonic acid (P4S)
on alpha(1)beta(3)gamma(2), THIP on alpha(3)beta(3)gamma(2), and 5-(4
piperidyl)isothiazol-3-ol (thio-4-PIOL) on alpha(2)beta(3)gamma(2) and
alpha(5)beta(3)gamma(2) GABA(A) receptors were increased by chlordiazepoxide,
while that for P4S on alpha(1)beta(3)gamma(2) receptors was decreased by DMCM.
The I(max) values for partial agonists were also enhanced by pentobarbitone, the
neurosteroid allopregnanolone and loreclezole irrespective of receptor subtype or
the nature of the partial agonist. In the light of models of ligand-gated ion
channel receptor activation we suggest two possible mechanisms of action for the
effects of allosteric modulators on partial agonist receptor activation: either
selective modulation of agonist affinity for the open/closed state, or direct
modulation of the gating process itself.
PMID- 10780989
TI - Mepyramine but not cimetidine or clobenpropit blocks pertussis toxin-induced
histamine sensitization in rats.
AB - The effects of pertussis toxin (PT) and the role of histaminergic H(1), H(2) and
H(3) receptor blockade on the actions of histamine on blood pressure, heart rate,
blood gas values, and mortality were studied in anaesthetized rats. Four days
after treatment with PT, histamine dose-dependently decreased mean arterial blood
pressure (MAP) and PT enhanced the histamine-induced decrease in MAP. In the PT
but not in the inactivated PT (IPT) or saline treated group three out of six
animals died after the highest dose of histamine (300 mg kg(-1), i.v.) In order
to determine the type of histamine receptor that mediates HS, 4 days after PT the
selective antagonists mepyramine (H(1)), cimetidine (H(2)) and clobenpropit
(H(3)) were administered 20 min before the challenge with histamine. Mepyramine
completely inhibited both the enhanced histamine-induced decrease in MAP and
mortality brought about by PT. Cimetidine and clobenpropit had no protective
effects, but rather enhanced the histamine-induced mortality elicited by PT. The
present study shows that PT caused HS in rats which is primarily mediated via
H(1) and secondarily via H(2) and H(3) receptors. These results are considered to
be a first step in the elucidation of the mechanism(s) of the HS test used in the
quality control of acellular pertussis vaccine.
PMID- 10780990
TI - Proteinase-activated receptor-2 (PAR-2): regulation of salivary and pancreatic
exocrine secretion in vivo in rats and mice.
AB - Proteinase-activated receptor-2 (PAR-2) is expressed throughout the
gastrointestinal tract including the pancreas, and may be involved in digestive
functions. The aim of our study was to evaluate a potential role for PAR-2 in
regulating salivary and pancreatic exocrine secretion in vivo. PAR-2-activating
peptides (PAR-2-APs), but not selective PAR-1-APs, administered intravenously,
increased salivary secretion in the mouse or rat; this effect of the PAR-2-APs
was unaffected by atropine, phentolamine, propranolol or indomethacin. Secretion
(amylase) by rat parotid gland slices in vitro was also stimulated by PAR-2-APs
and trypsin, but not by activation of other PARs. PAR-2-APs, administered to rats
in vivo, caused a prompt effect on pancreatic exocrine secretion. PAR-2 mRNA,
known to be present in pancreatic tissue, was also detected in parotid tissue.
Our results indicate that in addition to a potential role in regulating
cardiovascular and respiratory functions, PAR-2 may also play a general role in
vivo for the direct regulation of glandular exocrine secretion.
PMID- 10780991
TI - Inverse agonism at G protein-coupled receptors: (patho)physiological relevance
and implications for drug discovery.
PMID- 10780993
TI - In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal
cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate
and aspartate.
AB - Although the 5-HT(6) receptor subtype was identified some 5 years ago, very
little is known about its function within the brain. Here we demonstrate, for the
first time, the neurochemical effects of a selective 5-HT(6) receptor ligand.
Using in vivo microdialysis in the freely moving rat, we evaluated the effects of
the selective 5-HT(6) receptor antagonist SB-271046 by simultaneous measurement
of 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NA), glutamate and
aspartate from the striatum and frontal cortex. SB-271046 did not alter basal
levels of 5-HT, DA and NA in either brain region. Similarly, there was no change
basal levels of either of the excitatory amino acids within the striatum. In
contrast, administration of SB-271046 (10 mg kg(-1) s.c.) produced a significant
(P<0.05), tetrodotoxin-dependent, increase in extracellular levels of both
glutamate and aspartate within the frontal cortex, reaching maximum values of
375.4+/-82.3 and 215. 3+/-62.1% of preinjection values, respectively.
PMID- 10780992
TI - The muscarinic M(5) receptor: a silent or emerging subtype?
PMID- 10780994
TI - Involvement of sensory nerves in vasodilator responses to acetylcholine and
potassium ions in rat hepatic artery.
AB - In the presence of ouabain (1 mM), acetylcholine and KCl (5 mM) evoked
endothelium-independent relaxations in rat hepatic arteries. Treatment with
capsaicin (10 microM), scopolamine (1 microM) or CGRP(8 - 37) (3 microM)
prevented these relaxations. Acetylcholine-induced relaxations in intact arterial
segments in the presence of indomethacin (10 microM) and N(G)-nitro-L-arginine
(0.3 mM) were only partially inhibited by ouabain plus BaCl(2) (30 microM).
However, ouabain plus BaCl(2) almost abolished such relaxations in capsaicin-pre
treated preparations. In arteries without endothelium, the neurosecretagogue
alpha-latrotoxin (1 nM) induced complete relaxations, which were abolished by
CGRP(8 - 37) or pre-treatment with capsaicin. alpha-Latrotoxin also induced a
smooth muscle hyperpolarization (12+/-2 mV), which was abolished by CGRP(8 - 37).
The ability of ouabain to disclose a CGRP-mediated neurogenic relaxation must be
considered when this agent is used as a pharmacological tool. The results further
suggest that CGRP is a nerve-derived hyperpolarizing factor in the rat hepatic
artery.
PMID- 10780995
TI - Neuroleptics ameliorate phencyclidine-induced impairments of short-term memory.
AB - 1. Phencyclidine (PCP), a non-competitive NMDA-receptor antagonist, is able to
induce schizophrenia-like symptoms in animals and in humans. It is known that
schizophrenic patients have deficits in memory processes. 2. Therefore, it was
investigated whether subchronic pulsatile or continuous application of 5.0 mg kg(
1) PCP over 5 days induce short-term memory deficits in holeboard learning and
the action of two different neuroleptics on this behavioural test. 3. First, an
impairment in the holeboard task was described when the animals were tested 24 h
after the last application but not after 15 min or 1 h after the last injection.
Secondly, the influence of haloperidol and risperidone on the PCP-induced short
term memory changes was tested. 4. The combined application of PCP and
risperidone led to a complete antagonism of the short-term deficits, but the
combined treatment with haloperidol was accompanied by a partial abolishment of
the PCP-induced deficits. 5. PCP led to an upregulation of the glutamate binding
sites in striatum and nucleus accumbens whereas the D(2) binding sites were
reduced in striatum. The D(1) binding sites seem to be unchanged. The receptor
protein expression of glutamate receptors mGluR1, GluR2, GluR5/7 and NMDAR1 were
not modified in response to PCP treatment. 6. The determination of a
subpopulation of GABAergic interneurons shows a decrease of the cells within the
CA3 of the hippocampal formation. 7. These findings indicate that PCP induced
impairments in short term memory can be detected by holeboard learning and may
provide an interesting tool for the search of new neuroleptics.
PMID- 10780996
TI - Central injection of nitric oxide synthase inhibitors increases peripheral
interleukin-6 and serum amyloid A: involvement of adrenaline from adrenal
medulla.
AB - 1. Accumulating evidence suggests that plasma levels of interleukin-6 (IL-6), a
major cytokine stimulating the synthesis of acute phase proteins, are intimately
regulated by the central nervous system (CNS). 2. In the present study, effects
of intracerebroventricular (i.c. v) injection of N(G)-nitro-L-arginine methyl
ester (L-NAME) or 7-nitroindazole, nitric oxide synthase (NOS) inhibitors, on
plasma IL-6 levels and peripheral IL-6 mRNA expression were examined in mice. 3.
L-NAME (0.1 - 2 microg per mouse i.c.v.) and 7-nitroindazole (0.2 - 2 microg per
mouse i.c.v.) induced a dose-dependent increase in plasma IL-6 levels and a
subsequent increase in circulating serum amyloid A, a liver acute-phase protein.
In contrast, an intraperitoneal (i.p.) injection of L-NAME up to the dose of 25
microg per mouse had no effect. 4. Pretreatment with yohimbine (alpha(2)
adrenergic antagonist; 1 mg kg(-1) i.p.), or ICI-118,551 (beta(2)-adrenergic
antagonist; 2 mg kg(-1) i.p.), but not with prazosin (alpha(1)-adrenergic
antagonist; 1 mg kg(-1) i.p.), nor betaxolol (beta(1)-adrenergic antagonist; 2 mg
kg(-1) i.p.), significantly inhibited the central L-NAME-induced plasma IL-6
levels. 5. I.c.v. (50 microg per mouse) or i.p. (100 mg kg(-1)) pretreatment with
6-hydroxydopamine had no effect on central L-NAME-induced plasma IL-6 levels.
However, intrathecal (i.t.) pretreatment with 6-hydroxydopamine (20 microg per
mouse) markedly inhibited central L-NAME-induced plasma IL-6 levels. Both
yohimbine (1.5 microg per mouse i.t.) and ICI-118,551 (1.5 microg per mouse i.
t.) were effective in inhibition of central L-NAME-induced plasma IL-6 levels. 6.
There was an elevation of base-line plasma IL-6 levels in adrenalectomized
animals. The adrenalectomy-enhanced levels were not further increased by central
L-NAME. 7. L-NAME (2 microg per mouse i.c.v.) induced an increase in IL-6 mRNA
expression in liver, spleen, and lymph node. 8. These results suggest that NOS
activity in the brain tonically down-regulates peripheral IL-6 by inhibiting
adrenaline release from the adrenal medulla.
PMID- 10780997
TI - Neurokinin B- and specific tachykinin NK(3) receptor agonists-induced airway
hyperresponsiveness in the guinea-pig.
AB - 1. The aim of this study was to determine whether neurokinin B (NKB) or specific
agonists of tachykinin NK(3) receptors, [MePhe(7)]NKB and senktide, were able to
induce airway hyperresponsiveness in guinea-pigs. The effects of these compounds
were compared to those of substance P (SP), neurokinin A (NKA) and the
preferential tachykinin NK(1) ([Sar(9), Met(0(2))(11)]SP) or NK(2)
([betaAla(8)]NKA (4-10)) receptor agonists. 2. In guinea-pigs pretreated with
phosphoramidon (10(-4) M aerosol for 10 min) and salbutamol (8.7x10(-3) M for 10
min), all tachykinins administrated by aerosol (3x10(-7) to 10(-4) M) induced
airway hyperresponsiveness 24 h later, displayed by an exaggerated response to
the bronchoconstrictor effect of acetylcholine (i.v.). The rank order of potency
was: [betaAla(8)]NKA (4
10)>NKA=NKB=senktide=[MePhe(7)]NKB=[Sar(9),Met(0(2))(11)]SP>SP. 3. Airway
hyperresponsiveness induced by [MePhe(7)]NKB was prevented by the tachykinin
NK(3) (SR 142801) and NK(2) (SR 48968) receptor antagonists. 4.
Bronchoconstriction induced by tachykinins administered by aerosol was also
determined. SP, NKA, NKB and the tachykinin NK(1) and NK(2) receptor agonist
induced bronchoconstriction. The rank order of potency was: NKA=[betaAla(8)]NKA
(4-10)>NKB=SP=[Sar(9), Met(0(2))(11)]SP. Under similar conditions, and for
concentrations which induce airway hyperresponsiveness, senktide and
[MePhe(7)]NKB failed to induce bronchoconstriction. 5. It is concluded that
tachykinin NK(3)-receptor stimulation can induce airway hyperresponsiveness and
that this effect is not related to the ability of tachykinins to induce
bronchoconstriction.
PMID- 10780998
TI - Enhanced expression of haem oxygenase-1 by nitric oxide and antiinflammatory
drugs in NIH 3T3 fibroblasts.
AB - 1. Haem oxygenase-1 (HO-1) can exert protective effects against oxidative stress
and inflammation. Fibroblasts participate in inflammatory responses where they
produce high levels of prostaglandins (PGs) and nitric oxide (NO). However,
little is known of the presence of HO-1 in these cells and the possible
interactions among these pathways. Incubation of cells with NO donors, spermine
nonoate (SPNO) and S-nitroso-N-acetylpenicillamine (SNAP), induced a dose- and
time-dependent expression of HO-1 protein. 2. NO donors increased basal PGE(2)
release although they reduced PGE(2) accumulated in the medium and cyclo
oxygenase (COX) activity when cells were stimulated with lipopolysaccharide
(LPS). COX-2 protein was weakly induced by SPNO in basal conditions and in the
presence of LPS a synergy for HO-1 and COX-2 protein expression was observed. 3.
Our results indicate that reactive oxygen species participate in the inductive
effect of NO donors or LPS on HO-1 expression, whereas endogenous NO production
may play a role in the mechanism of the synergy exhibited by SPNO and LPS on HO-1
and COX-2 expression. In this system, zinc protoporphyrin IX did not affect
nitrite levels but reduced COX activity. 4. The selective COX-2 inhibitors
SC58125 and NS398 as well as the non-selective COX inhibitor, indomethacin,
strongly reduced PGE(2) synthesis and showed a synergy with NO donors in HO-1 and
COX-2 induction. Addition of PGE(2) had no effect, suggesting a mechanism
independent of PGs formation. 5. In inflammatory conditions a number of factors
could cooperate to induce HO-1 and COX-2, with a positive regulation by COX
inhibitors.
PMID- 10780999
TI - Characterization of the binding of two novel glycine site antagonists to cloned
NMDA receptors: evidence for two pharmacological classes of antagonists.
AB - The potency of two novel glycine site antagonists, GV150,526A and GV196,771A, was
assessed by their ability to inhibit the binding of [(3)H]-MDL105,519 to cell
homogenates prepared from mammalian cells transfected with either NR1-1a, NR1-2a,
NR1-1a/NR2A, NR1-1a/NR2B, NR1-1a/NR2C or NR1-1a/NR2D NMDA receptor clones. The
inhibition constants (K(i)s) for GV150,526A displacement of [(3)H]-MDL105,519
binding to either NR1-1a or NR1-2a expressed alone were not significantly
different and were best fit by a one-site binding model. GV150,526A inhibition to
NR1-1a/NR2 combinations was best fit by a two-site model with the NR1-1a/NR2C
having an approximate 2 - 4 fold lower affinity compared to other NR1-1a/NR2
receptors. The K(i)s for GV196,771A displacement of [(3)H]-MDL105,519 binding to
NR1-1a, NR1-2a and all NR1-1a/NR2 combinations was best fit by a two-site binding
model. There was no significant difference between the K(i)s for the binding to
NR1-1a and NR1-2a; NR1-1a/NR2A receptors had an approximate 4 fold lower affinity
for GV196,771A compared to other NR1-1a/NR2 combinations. The K(i)s for both
GV150, 526A and GV196,771A for the inhibition of [(3)H]-MDL105,519 binding to
membranes prepared from adult rat forebrain were determined and compared to the
values obtained for binding to cloned NMDA receptors. The K(i)s for a series of
glycine site ligands with diverse chemical structures were also determined for
the inhibition of [(3)H]-MDL105,519 binding to NR1-1a/NR2A receptors. L689,560
displayed similar binding characteristics to GV150,526A. It is suggested that
glycine site antagonists may be divided into two classes based on their ability
to distinguish between NR1 and NR1/NR2 receptors with respect to binding curve
characteristics.
PMID- 10781000
TI - Evidence for a M(1) muscarinic receptor on the endothelium of human pulmonary
veins.
AB - 1. To characterize the muscarinic receptors on human pulmonary veins associated
with the acetylcholine (ACh)-induced relaxation, isolated venous and arterial
preparations were pre-contracted with noradrenaline (10 microM) and were
subsequently challenged with ACh in the absence or presence of selective
muscarinic antagonists. 2. ACh relaxed venous preparations derived from human
lung with a pD(2) value of 5.82+/-0.09 (n=16). In venous preparations where the
endothelium had been removed, the ACh relaxations were abolished (n=4). ACh
relaxed arterial preparations with a pD(2) value of 7. 06+/-0.14 (n=5). 3.
Atropine (1 microM), the non selective antagonist for muscarinic receptors,
inhibited ACh-induced relaxations in human pulmonary veins. The affinity value
(pK(B) value) for atropine was: 8.64+/-0.10 (n=5). The selective muscarinic
antagonists (darifenacin (M(3)), himbacine (M(2),M(4)), methoctramine (M(2)) and
pFHHSiD (M(1),M(3))) also inhibited ACh-induced relaxations in venous
preparations. The pK(B) values obtained for these antagonists were not those
predicted for the involvement of M(2 - 5) receptors in the ACh-induced relaxation
in human pulmonary veins. 4. The pK(B) value for darifenacin (1 microM) was
significantly greater in human pulmonary arterial (8.63+/-0.14) than in venous
(7.41+/-0.20) preparations derived from three lung samples. 5. In human pulmonary
veins, the pK(B) values for pirenzepine (0.5 and 1 microM), a selective
antagonist for M(1) receptors, were: 7.89+/-0.24 (n=7) and 8.18+/-0.22 (n=5),
respectively. In the venous preparations, the pK(B) values derived from the
functional studies with all the different muscarinic antagonists used were
correlated (r=0.89; P=0.04; slope=0.78) with the affinity values (pK(i) values)
previously published for human cloned m1 receptors in CHO cells. 6. These results
suggest that the relaxations induced by ACh are due to the activation of M(1)
receptors on endothelial cells in isolated human pulmonary veins.
PMID- 10781001
TI - Smooth muscle layer-dependent distribution of 5-hydroxytryptamine(7) receptor in
the porcine myometrium.
AB - 1. To analyse the mechanisms of muscle layer-dependent inhibition of porcine
myometrial contractility by 5-hydroxytryptamine (5-HT), the effects of 5-HT, 5
carboxamidotryptamine(5-CT), 5-methoxytryptamine (5-MeOT), forskolin and cyclic
adenosine 3', 5'-monophosphate (cyclic AMP) analogues on spontaneous and
stimulant-induced contractions were examined in longitudinal (LM) and circular
muscles (CM). In addition, accumulation of cyclic AMP by 5-HT and distribution of
5-HT(7) receptors in LM and CM layers were compared using biochemical and
molecular approaches. 2. 5-HT receptor agonists inhibited the spontaneous
contractions of LM and CM (5-CT>5-HT>5-MeOT), but CM was more sensitive than was
LM. The inhibition by the agonists was antagonized by methiothepin (100 nM). 3.
Carbachol-, high-K(+)-, histamine- and Ca(2+)-induced contractions were inhibited
by 5-HT with different responses (CM>LM). Even in the presence of 3-isobutyl-1
methylxanthine (IBMX), the inhibition by 5-HT in the CM was still more
conspicuous than that in the LM. 4. Compared with the CM, the inhibition of
spontaneous contraction by forskolin, dibutyryl-cyclic AMP and 8-bromo-cyclic AMP
was marked in the LM. 5. 5-HT (1 nM - 1 microM) increased the cyclic AMP in both
muscle layers, but the increment in the CM was higher than that in the LM whether
IBMX was present or not. 6. LM and CM layers contained a single class of [(3)H]-5
CT binding sites with a similar K(d) value (0.21 - 0.24 nM). However, B(max) (5
HT(7) receptor concentration) in the CM (120.6 fmol mg(-1) protein) was higher
than that in the LM (30.4 fmol mg(-1) protein). 7. The molecular study (reverse
transcription polymerase chain reaction) demonstrated the expression of 5-HT(7)
receptor mRNA in the CM was higher than that in the LM. 8. These results suggest
that the muscle layer-dependent difference in inhibition by 5-HT is not
restricted to spontaneous contraction but applies to various contractions in the
porcine myometrium. Different inhibition of the contractility by 5-HT is caused
by muscle layer-related accumulation of cyclic AMP (CM>LM), due to smooth muscle
layer dependent distribution (CM>LM) of 5-HT(7) receptors.
PMID- 10781002
TI - Evaluation of iNOS-dependent and independent mechanisms of the microvascular
permeability change induced by lipopolysaccharide.
AB - 1. Subcutaneous injection of lipopolysaccharide (LPS) increases plasma leakage in
mouse skin. Pretreatment with LPS conditions mice tolerant to the LPS-induced
plasma leakage. Nitric oxide (NO) has been suggested to be involved in these LPS
effects. A specific role of inducible NO synthase (iNOS) was investigated in the
LPS-induced plasma leakage using iNOS deficient mice. 2. Plasma leakage in mouse
skin was measured by the local accumulation of Pontamine sky blue at the site of
subcutaneous injection of LPS (Sal. typhimurium). LPS (100 - 400 microg site(-1))
produced a dose-related increase in dye leakage in both iNOS deficient and wild
type mice with about 40% less dye leakage in iNOS deficient mice. 3. Indomethacin
(5 mg kg(-1)), N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide (NS-398) (1
mg kg(-1)), diphenhydramine (10 mg kg(-1)) and anti-TNF-alpha antibody (dilution
1 : 400, 10 ml kg(-1)) inhibited the LPS-induced dye leakage in both iNOS
deficient and wild-type mice, whereas N(G)-nitro-L-arginine methyl ester (L-NAME)
(10 mg kg(-1)) or aminoguanidine (10 mg kg(-1)) inhibited that in wild-type but
not in iNOS deficient mice. 4. Pretreatment with LPS (0.15 mg kg(-1) i.p.) 4 h
before decreased the LPS-induced dye leakage in wild-type but not in iNOS
deficient mice. LPS pretreatment increased serum corticosterone levels in both
mice, while it increased the serum nitrate/nitrite levels in wild-type but not in
iNOS deficient mice. 5. These studies indicate that an increase in vascular
permeability induced by LPS is mediated by NO produced by iNOS, eicosanoids,
histamine and TNF-alpha. The tolerance against LPS-induced vascular permeability
change may be mediated by iNOS induction but not by an increased release of
endogenous corticosteroids.
PMID- 10781003
TI - Correlation of leukocyte adhesiveness, adhesion molecule expression and leukocyte
induced contraction following balloon angioplasty.
AB - 1. The aim of this study was to examine the changes in leukocyte adhesion and
leukocyte-induced contraction in balloon-injured rabbit subclavian artery and to
correlate these changes with vessel morphology and expression of adhesion
molecules on the injured arteries. 2. Rabbits were anaesthetized and their left
subclavian arteries were injured by balloon inflation and withdrawal followed by
sacrifice at 2, 24, 48 h or 8 days after injury. The left and right subclavian
arteries were removed and leukocytes were isolated from autologous rabbit blood.
Leukocyte-induced contraction was measured in 5-HT precontracted artery rings and
leukocyte adhesion was measured using (51)Cr-labelled leukocytes.
Immunocytochemistry using paraffin-embedded tissue was employed to detect changes
in the expression of adhesion molecules on injured arteries. 3. Autologous
leukocytes caused a contraction of rabbit subclavian artery rings, which was
prevented by L-NAME (10(-3) M). Balloon-induced injury abolished the contractile
response to leukocytes, which correlated with loss of carbachol-induced
relaxation 4. Balloon injury markedly enhanced the adhesiveness of the subclavian
artery for leukocytes, most notably at 24 and 48 h after injury (1.7 and 1.8 fold
respectively). Increased leukocyte adhesion at these two time points correlated
with an upregulation of E-selectin, P-selectin and VCAM-1 expression on the
remaining endothelium of the injured artery. 5. Vessel morphology revealed that
balloon inflation had induced an infiltration of inflammatory cells into the
vessel wall, the greatest increase being seen at 24 h after injury. 6. It is
concluded that an increase in the expression of E-selectin, P-selectin and VCAM-1
following balloon-induced injury leads to enhanced leukocyte adhesion and
migration into the injured vessel.
PMID- 10781004
TI - Identification of the adenylyl cyclase-activating 5-hydroxytryptamine receptor
subtypes expressed in the rat submandibular gland.
AB - 1. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to increase cyclic AMP
production in dispersed cell aggregates from the major salivary glands of the
rat. The goal of the present study was to identify the 5-HT receptor subtypes
that mediate these effects in rat submandibular glands (SMG). 2. Among the 5-HT
receptor subtypes identified in the rat, 5-HT(4(a,b)), 5-HT(6) and 5-HT(7(a,b,c))
activate adenylyl cyclase (AC). We used subtype specific primers to screen rat
SMG by reverse transcription-PCR. Results indicate the presence of mRNA for 5
HT(4(b)) and 5-HT(7(a)) but not for 5-HT(4(a)), 5-HT(6) and 5-HT(7(b,c)). 3. In
dispersed SMG cells, 5-carboxyamidotryptamine (5-CT), a 5-HT(7) receptor agonist,
stimulated cyclic AMP synthesis with higher potency (EC(50)=27+/-5 nM) but lower
efficacy than 5-HT, suggesting a 5-HT(7) component and an additional component in
the response to 5-HT. The 5-HT(7) contribution was further supported by
antagonism of the 5-CT effect by metergoline, a 5-HT(7) antagonist, which
exhibited an affinity (K(i)=50 nM) similar to that obtained at the cloned 5-HT(7)
receptor. 4. In the presence of a maximally effective concentration of 5-CT, 5-HT
produced an additional increase in cyclic AMP production that was inhibited by
the 5-HT(4) receptor antagonist, GR113808, suggesting that the second component
of cyclic AMP production is mediated by 5-HT(4) receptors. 5. These findings
indicate the presence in rat SMG of both 5-HT(4(b)) and 5-HT(7(a)) receptors
positively coupled to AC.
PMID- 10781005
TI - The role of nitric oxide in the responses of the ovine digital artery to
vasoactive agents and modification of these responses by endotoxin and cytokines.
AB - 1. Laminitis, an important cause of lameness in domestic ungulates, occurs as a
result of altered digital perfusion. Endotoxin and cytokines may mediate the
vascular derangements observed through alterations in nitric oxide production. In
this study, the vascular responses of the isolated ovine digital artery were
examined and the influence of endotoxin and cytokines investigated. 2. Neither
removal of the endothelium nor incubation with N(G)-nitro-L-arginine methyl ester
(L-NAME, 300 microM) altered the response to phenylephrine (PE, 1 nM to 300
microM). Indomethacin (10 microM) decreased PE log EC(50) from -6.22+/-0.08 to
6.55+/-0.07. Acetylcholine (1 nM to 1 mM) and bradykinin (BK, 100 pM to 3 microM)
induced endothelium-dependent relaxation. Bradykinin-induced relaxation was
reduced by L-NAME, E(max) falling from -61.7+/-7.4 to -34.0+/-2.1%. Addition of
indomethacin further reduced BK E(max) to -9.6+/-2.8%. Sodium nitroprusside (1 nM
to 300 microM) produced endothelium-independent relaxation that was unaffected by
L-NAME or indomethacin. 3. Following a 6 h incubation with endotoxin (3 microml(
1)), arterial responses to PE and BK did not differ from polymyxin B-treated
controls (10 microg ml(-1)). Arteries incubated for 6 h with interferon-gamma
(IFN-gamma, 10 ng ml(-1)) and tumour necrosis factor-alpha (TNF-alpha, 5 ng ml(
1)) exhibited greater relaxation to BK (E(max)-50.0+/-5.1%) than polymyxin B
treated controls (E(max)-33.1+/-4.0%), but did not differ in their response to
PE. 4. Prolonged incubation (16 h) with endotoxin (3 microg ml(-1)) did not alter
the response to PE, however incubation with IFN-gamma (10 ng ml(-1)), TNF-alpha
(5 ng ml(-1)) and interleukin-1beta (20 ng ml(-1)) for 16 h increased PE log
EC(50) from -6.44+/-0.09 to -6. 10+/-0.11. 5. Nitric oxide is an important
mediator of endothelium-dependent relaxation in ovine digital arteries but does
not modulate PE-induced vasoconstriction. Incubation with cytokines decreased the
sensitivity of digital arteries to PE.
PMID- 10781006
TI - Impaired vascular sensitivity to nitric oxide in the coronary microvasculature
after endotoxaemia.
AB - 1. The effects of endotoxaemia on coronary vasodilator responses to bradykinin
(BK), sodium nitroprusside (SNP) and nicardipine were investigated in the rat
isolated heart perfused at constant flow ex vivo. 2. Dose-dependent reductions in
coronary perfusion pressure reaching a maximum of 56+/-3 and 57+/-5 mmHg were
observed for BK and SNP respectively. The BK response was biphasic, consisting of
a rapid dilator response that was insensitive to N(G)nitro-L-arginine methyl
ester (L-NAME, 0.1 mM) and a second slower component whose duration was
attenuated by L-NAME. 3. Hearts obtained from rats treated with endotoxin (2.5 mg
kg(-1), i.p.) for 2 or 6 h had increased basal coronary perfusion pressure and
reduced vasodilator responses to BK or SNP. Dilator responses to nicardipine were
not affected by endotoxin treatment. In vitro perfusion of hearts from endotoxin
treated rats with L-NAME (0.1 mM) restored SNP responses to control values. 4.
Treatment with dexamethasone (1 mg kg(-1)), 1 h before endotoxin did not alter
the endotoxin-induced impairment of dilator responses to BK or SNP. 5. These
results show that coronary microvascular responses are altered following
endotoxin exposure. Endotoxin results in increased coronary microvascular tone
despite induction of NO synthase and inhibits the dilator response to BK and SNP,
vasodilators that act via the release of NO. Responses to SNP in endotoxin
treated hearts were restored to control values in the presence of L-NAME
suggesting that enhanced endogenous NO synthesis might saturate guanylate cyclase
resulting in reduced response to NO donors. The reduced response to vasodilators
and increased coronary resistance might be important in determining the response
of the coronary circulation to systemic inflammation and infection.
PMID- 10781007
TI - Evidence for the involvement of peroxynitrite in ischaemic preconditioning in rat
isolated hearts.
AB - 1. The aim of this study was to investigate the involvement of peroxynitrite,
reactive metabolite originating from nitric oxide and superoxide, in
preconditioning of the ischaemic myocardium in rat isolated hearts. 2. Isolated
hearts perfused with Krebs-Henseleit solution were preconditioned either by 3 min
of coronary artery occlusion (CAO) or by peroxynitrite administration at three
different concentrations (0.1, 1, 10 microM) for 3 min, followed by 10 min
reperfusion and 30 min of CAO. Peroxynitrite, at 1 microM concentration,
decreased the incidence of VT from 100% (n=14) to 62% (n=13) and abolished the
occurrence of VF (50% in the control group). 3. N-2-mercaptopropionylglycine
(MPG, 1 microM - 10 mM) produced a concentration-dependent inhibition of
peroxynitrite signals in luminol chemiluminescence and 67+/-1% inhibition was
observed at 100 microM (n=7). MPG (at 300 microM, n=7) added to the perfusate 10
min prior to ischaemic preconditioning or peroxynitrite infusion and maintained
until CAO, significantly reversed the beneficial effects of the ischaemic and
peroxynitrite-treated groups. MPG administration in the peroxynitrite-treated
group increased the incidence of VT from 62% (n=13) to 100% (n=10) and total VF
from 0% (n=0) to 67% (n=10). Similarly, MPG elevated the incidence of VT from 50%
(n=10) to 100% (n=8) in the ischaemic preconditioned group. On its own, MPG did
not affect the severity of cardiac arrhythmias. 4. These results suggest that
endogenously produced peroxynitrite plays a significant role in the
antiarrhythmic effect of ischaemic preconditioning in the rat isolated hearts.
PMID- 10781008
TI - Cisplatin-induced early and delayed emesis in the pigeon.
AB - 1. Intravenously injected cisplatin at a dose of 4 mg kg(-1) induced early and
delayed emesis in all pigeons without occurrence of lethality during a 72 h
observation period. The early emetic response occurred with a latency of 81.3+/
8.0 min (n=15) and reached a peak at 2 - 3 h, and decreased gradually within 8 h
after injection. Then the delayed emetic response, whose peak was found between
10 to 23 h, lasted up to 48 h. The emetic response markedly declined after 48 h.
2. Reserpine markedly reduced monoamine levels in both brain and intestine and
completely abolished the early and delayed emesis. Dexamethasone markedly reduced
not only the early but also the delayed emetic responses. p-Chlorophenylalanine
decreased the level of serotonin in brain and intestine without affecting
noradrenaline and dopamine and partly reduced the early emetic response, but did
not affect delayed emesis. 3. Bilateral vagotomy prolonged the latency time to
the onset of early emesis, and reduced the emetic responses in both the early and
delayed phases. 4. The above results suggest that the cisplatin-induced early
emesis in the pigeon is partially mediated via the vagal nerve and reserpine
sensitive monoaminergic systems including the serotonergic system; the delayed
emesis is associated with monoaminergic but not the serotonergic systems.
PMID- 10781009
TI - Ecto-nucleotide pyrophosphatase modulates the purinoceptor-mediated signal
transduction and is inhibited by purinoceptor antagonists.
AB - 1. The effect of ecto-nucleotide pyrophosphatase (ecto-NPPase; EC 3.6.1. 9) on
the ATP- and ADP-mediated receptor activation was studied in rat C6 glioma cells.
The P2-purinoceptor antagonists pyridoxalphosphate-6-azophenyl-2',4'-disulphonic
acid (PPADS) and reactive blue (RB2) are potent inhibitors (IC(50)=12+/-3 microM)
of the latter enzyme. 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid (DIDS),
5'-phosphoadenosine 3'-phosphate (PAP) and suramin were less potent inhibitors
with an IC(50) of 22+/-4, 36+/-7 and 72+/-11 microM respectively. 2. P1
purinoceptor antagonists CGS 15943, cyclo-pentyl theophylline (CTP) and
theophylline did not affect the activity of the ecto-NPPase. 3. ATP- and ADP
mediated P2Y(1)-like receptor activation inhibited the (-)-isoproterenol-induced
increase of intracellular cyclic AMP concentration. PPADS, an ineffective P2Y
antagonist in C6, potentiated the ATP and ADP effect approximately 3 fold due to
inhibition of nucleotide hydrolysis by the ecto-NPPase. 4. We conclude that ecto
NPPase has a modulator effect on purinoceptor-mediated signalling in C6 glioma
cell cultures.
PMID- 10781011
TI - Behavioural and physiological effects induced by an infusion of antisense to
alpha(2D)-adrenoceptors in the rat.
AB - 1. The aim of this study was to investigate the behavioural and physiological
effects of an i.c.v. infusion of antisense oligonucleotide to the alpha(2D)
adrenoceptor subtype. Behavioural and physiological parameters were monitored for
2 days before the infusion, throughout the 3-day infusion period and for 3 days
following the end of the infusion. 2. The antisense infusion resulted in a
significant increase in behavioural activity characterized by increased
locomotion and grooming scores. Behavioural activity scores of rats treated with
antisense to alpha(2D)-adrenoceptors were significantly higher than those of rats
treated with vehicle (H(2)O) or the mismatch toxicity control on day 4 and day 5
and, significantly higher than vehicle controls on day 6. 3. Body weight gain was
significantly reduced in the antisense-treated rats at the end of the study
compared to the vehicle (34%) and mismatch groups (30%), although daily food and
water intakes were not significantly different at any time point. 4. Pupil
diameters of rats infused with antisense to alpha(2D)-adrenoceptors were
significantly greater than those of animals treated either with vehicle or
mismatch oligonucleotide on day 5 of the study. On day 6, the pupil diameters of
these animals were still significantly greater than the mismatch group. 5. In
conclusion, an i.c.v. infusion of antisense to the alpha(2D)-adrenoceptor induced
behavioural activation in rats, increased pupil diameter and reduced total weight
gain. These effects were specific to the antisense-treated group and were fully
reversed post-infusion.
PMID- 10781010
TI - Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia
in mice: a model to detect agonist and antagonist activities at these receptors.
AB - This work investigates the receptor acted upon by imidazoline compounds in the
modulation of morphine analgesia. The effects of highly selective imidazoline
ligands on the supraspinal antinociception induced by morphine in mice were
determined. 2. Intracerebroventricular (i.c.v.) or subcutaneous (s.c.)
administration of ligands selective for the I(2)-imidazoline receptor, 2-BFI, LSL
60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased
morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed
I(1)-imidazoline and alpha(2)-adrenoceptor agonist, RX821002, a potent alpha(2)
adrenoceptor antagonist that displays low affinity at I(2)-imidazoline receptors,
nor the selective non-imidazoline alpha(2)-adrenoceptor antagonist RS-15385-197,
modified the analgesic responses to morphine. 3. Administration of pertussis
toxin (0.25 microg per mouse, i.c.v.) 6 days before the analgesic test blocked
the ability of the I(2)-imidazoline ligands to potentiate morphine
antinociception. 4. The increased effect of morphine induced by I(2)-imidazoline
ligands (agonists) was completely reversed by idazoxan and BU 224. Identical
results were obtained with IBI, which alkylates I(2)-imidazoline binding sites.
Thus, both agonist and antagonist properties of imidazoline ligands at the I(2)
imidazoline receptors were observed. 5. Pre-treatment (30 min) with deprenyl, an
irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of
morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30 min before
morphine did not alter the effect of the opioid. At longer intervals (24 h) a
single dose of either clorgyline or deprenyl reduced the density of I(2)
imidazoline receptors and prevented the I(2)-mediated potentiation of morphine
analgesia. 6. These results demonstrate functional interaction between I(2)
imidazoline and opioid receptors. The involvement of G(i)-G(o) transducer
proteins in this modulatory effect is also suggested.
PMID- 10781012
TI - Role of uptake inhibition and autoreceptor activation in the control of 5-HT
release in the frontal cortex and dorsal hippocampus of the rat.
AB - 1. Using brain microdialysis, we compared the relative role of 5
hydroxytryptamine (5-HT; serotonin) blockade and somatodendritic 5-HT(1A) and/or
terminal 5-HT(1B) autoreceptor activation in the control of 5-HT output. 2.
Fluoxetine (10 mg kg(-1) i.p.) doubled the 5-HT output in frontal cortex and
dorsal hippocampus. The 5-HT(1A) receptor antagonist WAY 100635, (0.3 mg kg(-1)
s.c.) potentiated the effect of fluoxetine only in frontal cortex (to
approximately 500 % of baseline). 3. Methiothepin (10 mg kg(-1) s.c.) further
enhanced the 5-HT rise induced by fluoxetine+WAY 100635, to 835+/-179% in frontal
cortex and 456+/-24% in dorsal hippocampus. Locally applied, methiothepin
potentiated the fluoxetine-induced 5-HT rise more in the former area. 4. The
selective 5-HT(1B) receptor antagonist SB-224289 (4 mg kg(-1) i.p.) enhanced the
effect of fluoxetine (10 mg kg(-1) i.p.) in both areas. As with methiothepin, SB
224289 (4 mg kg(-1) i.p.) further enhanced the 5-HT increase produced by
fluoxetine+WAY 100635 more in frontal cortex (613+/-134%) than in dorsal
hippocampus (353+/-59%). 5. Locally applied, fluoxetine (10 - 300 microM;
EC(50)=28 - 29 microM) and citalopram (1 - 30 microM; EC(50)=1.0 - 1.4 microM)
increased the 5-HT output two to three times more in frontal cortex than in
dorsal hippocampus. These data suggest that the comparable 5-HT increase produced
by systemic fluoxetine in frontal cortex and dorsal hippocampus results from a
greater effect of reuptake blockade in frontal cortex that is offset by a greater
autoreceptor-mediated inhibition of 5-HT release. As a result, 5-HT autoreceptor
antagonists preferentially potentiate the effect of fluoxetine in frontal cortex.
PMID- 10781013
TI - Apparent species differences in the kinetic properties of P2X(7) receptors.
AB - 1. Apparent species differences in the responses of recombinant P2X(7) receptors
to repeated application of 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) have been
investigated. 2. Repeated application of 100 microM BzATP resulted in a
progressive increase in current magnitude (current growth) at mouse and human,
but not rat P2X(7) receptors. 3. Current growth was thought to reflect
progressive dilation of the P2X(7) ion-channel to a pore permeable to large
molecules (MW<900), suggesting that channel dilation was not occurring at the rat
P2X(7) receptor. However, 100 microM BzATP produced a rapid influx of YO-PRO-1
(MW375) in cells expressing rat or human P2X(7) receptors. 4. There were,
however, species differences in agonist potency such that 100 microM BzATP was a
supra-maximal concentration at rat, but not human or mouse, P2X(7) receptors.
Importantly, when sub-maximal concentrations of BzATP or ATP were examined,
current growth occurred at rat P2X(7) receptors. 5. The rate of current growth
and YO-PRO-1 accumulation increased with agonist concentration and appeared more
rapid at rat and human, than at mouse P2X(7) receptors. 6. The potency of BzATP
and ATP was 1.5 - 10 fold lower in naive cells than in cells repeatedly exposed
to ATP. 7. This study demonstrates that current growth occurs at mouse, rat and
human P2X(7) receptors but only when using sub-maximal concentrations of agonist.
Previously, current growth was thought to reflect the progressive increase in
pore diameter of the P2X(7) receptor ion channel, however, the results of this
study suggest a progressive increase in agonist potency may also contribute.
PMID- 10781014
TI - Involvement of the cyclic AMP system in the switch from tolerance into
supersensitivity to the antinociceptive effect of the opioid sufentanil.
AB - 1. We have previously demonstrated that chronic and simultaneous treatment of
rats with the mu-opioid receptor agonist sufentanil and the Ca(2+) channel
blocker nimodipine, not only prevented tolerance development, but the animals
became supersensitive to the antinociceptive effect of the opioid. The focus of
the present work was to determine the possible involvement of cross interactions
between the adenylyl cyclase pathway and L-type voltage-sensitive Ca(2+)
channels, in modulating the switch from opioid tolerance into supersensitivity.
2. The modulatory effect of sufentanil on adenylyl cyclase activity was
determined by measuring cyclic AMP production in slices from the cortex of rats
rendered tolerant or supersensitive to the antinociceptive effect of the opioid.
Tolerance was induced by chronic infusion of sufentanil, at a rate of 2 microg h(
1), for 7 days. Supersensitivity was induced by concurrent infusion of sufentanil
(2 microg h(-1)) and nimodipine (1 microg h(-1)) for 7 days. Antinociception was
evaluated by the tail-flick test. 3. Tolerance to the analgesic effect of
sufentanil was associated with a significant reduction in the response of
adenylyl cyclase to forskolin. Furthermore, the effect of the opioid on forskolin
induced cyclic AMP accumulation was abolished. On the other hand,
supersensitivity to the analgesic effect of the opioid was associated with an
increase in both, the adenylyl cyclase response to forskolin, and the opioid
inhibition of cyclic AMP production. 4. We suggest that sustained L-type Ca(2+)
channel blockade may result in changes in the adenylyl cyclase effector system
triggered by mu-opioid receptor activation, leading to the switch from opioid
tolerance into supersensitivity.
PMID- 10781015
TI - Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and
peptide activators of protease-activated receptor-1 in porcine isolated coronary
artery.
AB - 1. Mechanisms of protease-activated receptor-1 (PAR1)- and PAR2-induced
relaxation were investigated in pre-contracted porcine coronary artery ring
preparations. 2. Thrombin (0.01 - 0.3 u ml(-1)) and the PAR1-activating peptide
SFLLRN (0.1 - 10 microM) caused concentration- and endothelium-dependent
relaxation. pEC(50)s (-log u ml(-1) for enzymes, -log M for peptides) and maximum
relaxations (R(max), %) for thrombin were 1.8+/-0.1 and 93.5+/-2.8% respectively,
and for SFLLRN 6.8+/-0.1 and 90.8+/-1.3%. Similar concentration- and endothelium
dependent relaxations occurred with trypsin (pEC(50) 2.3+/-0.2; R(max) 94.1+/
1.9%) and the PAR2-activating peptide SLIGRL (pEC(50) 6.5+/-0.2; R(max) 92.4+/
1.6%). 3. Relaxations to thrombin, SFLLRN, trypsin and SLIGRL were significantly
inhibited (P<0.05) to similar extents by the nitric oxide (NO) synthase inhibitor
N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the NO scavenger oxyhaemoglobin
(20 microM), both separately and in combination. 4. In the presence of the L-type
voltage-operated calcium channel (L-VOCC) inhibitor nifedipine (0.3 microM), K(+)
(67 mM) abolished the L-NOARG-resistant relaxations to thrombin, SFLLRN, trypsin
and SLIGRL. However, nifedipine alone significantly (P<0.05) reduced the pEC(50)
(1.5+/-0.1) and R(max) (77.5+/-7.0%) for thrombin but had no effect on
relaxations to SFLLRN, trypsin or SLIGRL. Furthermore, L-NOARG-resistant
relaxations to thrombin were abolished by nifedipine, whereas relaxations to
SFLLRN, trypsin or SLIGRL were not further inhibited by combined treatment with
nifedipine and L-NOARG, than they were with L-NOARG treatment alone. 5. Similar
selective inhibition of the L-NOARG-resistant relaxation to thrombin, but not
SFLLRN, occurred with verapamil (1 microM) and diltiazem (3 microM). 6. Our
results suggest heterogeneous mechanisms in the NO-independent relaxation to
thrombin and peptide activators of PAR1 in the porcine coronary artery.
PMID- 10781017
TI - Geoffrey H. Gold (1949-2000)
PMID- 10781016
TI - CGRP and adrenomedullin binding correlates with transcript levels for calcitonin
receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) in
rat tissues.
AB - 1. Putative receptors for CGRP and adrenomedullin have been investigated in the
rat. Calcitonin Receptor-Like Receptor (CRLR), in combination with Receptor
Activity Modifying Proteins (RAMPs) is hypothesized to bind either CGRP or
adrenomedullin. The receptors known as RDC1 and L1 have also been shown to bind
CGRP and adrenomedullin respectively. 2. In this study it is shown that rat CRLR
cDNA specifies a CGRP receptor when co-transfected with RAMP-1 cDNA and an
adrenomedullin receptor when co-transfected with either RAMP-2 or RAMP-3 cDNA in
human embryonic kidney 293 cells. 3. CRLR, RAMP, RCD1 and L1 mRNA levels and CGRP
and adrenomedullin receptor densities have been measured and correlated with each
other in eight rat tissues selected for their distinctive patterns of CGRP and
adrenomedullin binding. 4. The data are consistent with the predictions of the
CRLR/RAMP model. CGRP binding correlates well with RAMP-1 mRNA levels (R=1.0,
P=0.007), adrenomedullin binding shows a tendency to vary with RAMP-2 mRNA levels
(R=0.85, P=0.14) and total binding is correlated with CRLR mRNA levels (R=0.94,
P=0.03). The data do not support the hypothesis that RDC1 and L1 account for the
majority of CGRP and adrenomedullin binding respectively.
PMID- 10781018
TI - Sexually dimorphic and isomorphic glomeruli in the antennal lobes of the sphinx
moth Manduca sexta.
AB - Antennal lobes of adult male and female Manduca sexta were compared in order to
investigate the nature and extent of sexual dimorphism of the primary olfactory
center of this lepidopteran species. Complete identification of the glomeruli led
to the conclusion that all female glomeruli have homologous male counterparts.
Thus, there is no sex-specific glomerulus present in one sex and absent in the
other. Sexual dimorphism (i.e. glomeruli present but morphologically different in
males and females), however, does occur in the three glomeruli composing the male
macroglomerular complex. The female homologs of this complex consist of two
previously identified 'large female glomeruli' and one newly identified normal
sized glomerulus. The lateral and medial large female glomeruli are interpreted
to be homologous to the first two macroglomerular-complex glomeruli-the cumulus
and toroid 1. The third male component, the toroid 2, was tentatively identified
with a normal-sized spheroidal glomerulus of the female, called here the 'small
female glomerulus'. The 60 'ordinary' glomeruli that make up the rest of the
glomerular neuropil were found to be homologous in males and females, with the
exception of two anomalous (or uncertain) glomeruli. Some variations in relative
position and size observed among those glomeruli suggest a diffuse, quantitative
kind of sexual dimorphism.
PMID- 10781019
TI - Synergism among ternary mixtures of fourteen sweeteners.
AB - The purpose of the present study was to determine the degree of synergism of
sweet taste among ternary mixtures of 14 sweeteners. A trained panel evaluated
ternary mixtures of 14 sweeteners varying in chemical structure and type. The
ternary mixtures that were tested were limited to those in which the compounds
comprising the mixture were synergistic in binary combinations, according to an
earlier study. All sweeteners in the ternary mixtures were isointense with 2%
sucrose, according to a previously developed formulae. Each self-mixture was also
tested (e.g. 2% sucrose + 2% sucrose + 2% sucrose). The triad with the highest
mean sweetness intensity rating was alitame-neohesperidin dihydrochalcone
rebaudioside-A (10.8). This represents an increase of 99.4% when compared with
the average of the self-mixtures. While this is greater than the maximum of 74%
increase found for binary mixtures, more dyadic combinations of sweeteners tested
previously exhibited synergism than ternary combinations tested here. However,
most ternary mixtures were synergistic (significantly greater than the average of
the three self-mixtures) to some degree.
PMID- 10781020
TI - The plant sesquiterpene germacrene D specifically activates a major type of
antennal receptor neuron of the tobacco budworm moth Heliothis virescens.
AB - Plants release hundreds of volatiles that are important in interactions with
insects or other organisms. However, knowledge is scarce as to which of the
compounds are detected by the organism's olfactory receptor neurons. In the
present study, single receptor neurons on the antennae of the tobacco budworm
moth, Heliothis virescens, were screened for their sensitivities to naturally
produced plant volatiles by the use of gas chromatography linked to
electrophysiological recordings from single cells (GC-SCR). Plant volatiles,
collected by aeration of host and non-host plants, were tested on each receptor
neuron via parallel GC-columns. Thus, simultaneous recordings of the gas
chromatogram and the neuron responses to each component were obtained. One type
of receptor neuron, appearing in 80% of all experiments, responded with high
sensitivity and selectivity to one particular component, present in host as well
as non-host mixtures. The component, identified as a sesquiterpene hydrocarbon by
linked gas chromatography-mass spectrometry, was isolated from a sesquiterpene
fraction of cubebe oil and identified by NMR as germacrene D. The purified
compound was then re-tested via gas chromatography on the same receptor neuron
type, verifying the identification. A weaker response to another sesquiterpene
hydrocarbon was also recorded.
PMID- 10781021
TI - Effects of various taste stimuli on heart rate in humans.
AB - Relationships between taste stimuli and heart rate were evaluated in 29 healthy
university students. The test solutions were sucrose, NaCl, citric acid, quinine
HCl and monosodium glutamate (MSG). Heart rate increased by 7.1-13.6% for all the
taste stimuli after use as compared with pre-stimuli values. The maximum
increases in heart rate came approximately 25 s after the taste stimuli. After
the increases, heart rate returned to pre-stimuli levels after between 80 and 100
s. Heart rate reached its maximum with citric acid. Recovery from the heart-rate
increase was more delayed for quinine-HCl and MSG than for the other stimuli.
Except for sucrose, increases in heart rate and the hedonic scale values of the
taste solutions showed significant negative correlation. These findings show that
the taste stimuli solutions increased the heart rate and that the increase
differed with the concentration and taste solution used.
PMID- 10781022
TI - Analysis of the molecular basis for octanal interactions in the expressed rat 17
olfactory receptor.
AB - Expression studies have shown that the rat I7 olfactory receptor (OR-I7) responds
preferentially to the aldehyde n-octanal. We wished to predict which residues in
OR-I7 bind octanal and how the biophysical properties of these residues determine
the receptor's odor selectivity. Building on our previous work on aldehyde
interactions in olfactory receptors, we constructed a molecular model of OR-I7
based on the 7.5 A resolution three-dimensional map of rhodopsin. Octanal was
automatically docked in the model. The results predicted an odor-binding pocket
approximately 10 A from the extracellular surface, in a location similar to the
epinephrine-binding pocket of the beta-adrenergic receptor and the odor-binding
pocket of a previous olfactory receptor model. A lysine on TM4 and an aspartate
on TM5 interacted with the aldehyde moiety of octanal. Hydrophobic residues
formed Van der Waals contacts with the hydrocarbon portion of octanal. We docked
related odor compounds and found that the predicted affinities compared favorably
with experimental results. We also tested a number of amino acid substitutions in
order to predict their effects on octanal affinity and provide leads for future
experimental work.
PMID- 10781023
TI - Effects of anion substitution on hydration behavior and water uptake of the red
spotted toad, Bufo punctatus: is there an anion paradox in amphibian skin?
AB - Amphibians absorb water osmotically across their skins and rely on chemosensory
information from the skin to assess the suitability of hydration sources. The
time spent with skin in contact with a moist surface provides a quantitative
measure of their ability to perceive the ionic and osmotic properties of aqueous
solutions. Dehydrated toads given hyperosmotic (250 mM) solutions of NaCl or Na
gluconate showed significantly longer periods of hydration behavior on the
gluconate solution, but they lost water osmotically when immersed in either
solution. Similarly, dehydrated toads given 250 mM solutions of NaCl, Na-acetate,
Na-phosphate or Na-gluconate showed a progressively greater length of hydration
time on solutions with the larger mol. wt anions. These results are consistent
with the chemosensory phenomenon previously described in mammalian tongue as
'anion paradox'. On dilute (50 mM) solutions of NaCl or Na-gluconate, the
hydration time was not different between anions, despite toads gaining water more
rapidly when immersed in dilute NaCl than in Na-gluconate solutions. The
differing behavioral results with hyperosmotic and hypoosmotic salt solutions
suggest that chemosensory transduction through toad skin involves both
transcellular and paracellular pathways.
PMID- 10781024
TI - Suppression of S-methylglutathione-induced tentacle ball formation by peptides
and nullification of the suppression by TGF-beta in Hydra.
AB - Tentacle ball formation (TBF) in Hydra elicited by S-methylglutathione (GSM) was
modulated by a number of biologically active peptides. Hydra fed on Artemia,
which had been hatched in a common salt solution supplemented with LiCl and
ZnCl(2), easily induced TBF in response to GSM after pretreatment with trypsin.
After Hydra were treated with 100 pg/ml trypsin for 10 min, the response to GSM
(TBF) was sensitively suppressed by acidic fibroblast growth factor and other
biologically active peptides for >10 h. Various peptides, but not transforming
growth factor beta (TGF-beta), suppressed GSM-induced TBF in a specific pattern
for each peptide. However, TGF-beta was unique in that it did not suppress the
response to GSM, but nullified the suppressive effect of other peptides. Only
active TGF-beta nullified the suppressive effect of the peptides, and the latent
form of TGF-beta neither suppressed GSM-induced TBF nor nullified the suppressive
effect of other peptides. Members of the TGF-beta family suppressed GSM-induced
TBF. These results indicate that all peptides examined, except for TGF-beta
suppressed the response to GSM in a manner specific to each peptide. This assay
system would be useful in identification of biologically active peptides.
PMID- 10781025
TI - Selective removal of a target stimulus localized by taste in humans.
AB - Recent studies have shown that people can localize a punctate gustatory stimulus
on the lingual epithelium in the absence of discriminative tactile cues. The
present studies examined the human ability to localize taste sensations on the
tongue and to use this information to remove selectively a target stimulus (a
flavored, 1 cm(3) gelatin cube) from the mouth when presented with non-target
distractors that vary in number and taste. Findings indicate that humans are
capable of localizing and removing either an aversive or an appetitive gustatory
target from a field of tactile distractors via taste sensations alone, although
this ability diminishes as the number of distractors increases (implicating
serial searches, rather than parallel). In addition, humans can localize and
selectively remove a target taste in the presence of distractors of another
distinct taste quality. Under these conditions performance is either unaffected
or reduced, which indicates that contrast with the distinct taste of the
distractors does not enhance performance. Humans also are capable of removing a
nearly tasteless cube from a field of flavored distractors, but this is clearly a
more difficult task, suggesting that 'tactile capture' of taste occurs for the
tasteless target cube and interferes with the localization of taste. Finally,
perceived suprathreshold stimulus intensity did not seem to be related to the
ability to localize and remove a target stimulus via taste sensations and failed
to account for variations in performance across individuals.
PMID- 10781026
TI - Olfactory discrimination ability for aliphatic odorants as a function of oxygen
moiety.
AB - We tested the ability of human subjects to distinguish between aliphatic odorants
sharing the same number of carbon atoms but differing in their functional groups.
1-Alcohols, n-aldehydes, 2-ketones and n-carboxylic acids of four, six and eight
carbon atoms, respectively, were employed. In a forced-choice triangular test
procedure 20 subjects were repeatedly presented with 18 odor pairs and asked to
identify the bottle containing the odd stimulus. We found (i) that as a group,
the subjects performed significantly above chance level in all tasks and thus
were clearly able to discriminate between all odor pairs presented; (ii) marked
interindividual differences in discrimination performance, ranging from subjects
who were able to significantly distinguish between all 18 odor pairs to subjects
who failed to do so with 1/3 of the tasks; (iii) a lack of significant
differences in performance between male and female, and between Japanese and
German subjects; (iv) that odor pairs that involved 2-ketones and/or n-carboxylic
acids were significantly easier to discriminate compared to odor pairs that
involved 1-alcohols and/or n-aldehydes, and thus a clear dependence of
discriminability on type of functional group; and (v) that aliphatic odorants
with eight carbon atoms (irrespective of their oxygen moiety) were significantly
more difficult to discriminate from each other compared to substances with four
or six carbon atoms. The results suggest that functional groups may be an
important determinant of the interaction between stimulus molecule and olfactory
receptor in aliphatic substances, and thus may be a molecular property affecting
odor quality in a substance class-specific manner.
PMID- 10781028
TI - The 33rd annual meeting of the japanese association for the study of taste and
smell (JASTS XXXIII)
PMID- 10781027
TI - Rewiring the olfactory bulb: changes in odor maps following recovery from nerve
transection.
AB - Recent studies have shown that axons from olfactory receptor subtypes converge
onto glomeruli in fixed positions within the olfactory bulb. Different receptor
subtypes project to different glomeruli, forming a spatial distribution of odor
information or 'odor maps'. Olfactory receptor neurons are continuously replaced
throughout the life span of an animal, yet they preserve this highly localized
mapping of receptor subtypes. In this study we used a transgenic mouse (P2-IRES
tau-lacZ) to map axons from a single receptor subtype (P2 receptors) in order to
determine if regenerating axons were able to re-establish the P2 receptor map
following nerve transection. Results confirm that P2 receptor axons retain their
capacity to grow back to the olfactory bulb and converge onto glomeruli following
nerve transection. However, the location and number of convergence sites was
significantly altered compared to the control map. This change in the spatial
distribution of axons alters the topography of odor mapping and has important
implications for the processing of olfactory information. Findings from this
study may explain why animals recovering from nerve injury require odor training
before odor discrimination is restored. Future studies of olfactory receptor
mapping could prove helpful in planning strategies to rewire connections in the
brain and to restore function following injury or neurological disease.
PMID- 10781029
TI - Serine/Threonine kinases 3pK and MAPK-activated protein kinase 2 interact with
the basic helix-loop-helix transcription factor E47 and repress its
transcriptional activity.
AB - In the search for physiological substrates of MAPK-activated protein (MAPKAP)
kinases, we identified the basic helix-loop-helix (bHLH) transcription factor E47
as an interaction partner of chromosome 3p kinase (3pK) and MAPKAP-K2 (MK2). The
E2A protein E47 is known to be involved in the regulation of tissue-specific gene
expression and cell differentiation. E47 is a phosphoprotein, and we identified
3pK and MK2 as E47 kinases in vitro. Furthermore, the expression of either kinase
results in a repression of the transcriptional activity of E47 on an E-box
containing promoter. In summary, the MAPK-activated protein kinases 3pK and MK2
were identified to form an assembly with the bHLH protein E47 suggesting that
these kinases are regulators of E47 activity and E47-dependent gene expression.
PMID- 10781030
TI - Dietary flavonoids and the MLL gene: A pathway to infant leukemia?
PMID- 10781031
TI - Brain growth and the cognitive map.
PMID- 10781032
TI - Absinthe and gamma-aminobutyric acid receptors.
PMID- 10781033
TI - Allosteric activation of the CaR by L-amino acids.
PMID- 10781034
TI - Polyamines in spermiogenesis: not now, darling.
PMID- 10781035
TI - Introduction. The evolution of evo-devo biology.
PMID- 10781036
TI - The Cambrian "explosion": slow-fuse or megatonnage?
AB - Clearly, the fossil record from the Cambrian period is an invaluable tool for
deciphering animal evolution. Less clear, however, is how to integrate the
paleontological information with molecular phylogeny and developmental biology
data. Equally challenging is answering why the Cambrian period provided such a
rich interval for the redeployment of genes that led to more complex body plans.
PMID- 10781038
TI - Evolution of the bilaterian body plan: what have we learned from annelids?
AB - Annelids, unlike their vertebrate or fruit fly cousins, are a bilaterian taxon
often overlooked when addressing the question of body plan evolution. However,
recent data suggest that annelids offer unique insights on the early evolution of
spiral cleavage, anteroposterior axis formation, body axis segmentation, and head
versus trunk distinction.
PMID- 10781037
TI - Regulatory evolution and the origin of the bilaterians.
AB - The adult body plan of bilaterians is achieved by imposing regional
specifications on pluripotential cells. The establishment of spatial domains is
governed in part by regulating expression of transcription factors. The key to
understanding bilaterian evolution is contingent on our understanding of how the
regulation of these transcription factors influenced bilaterian stem-group
evolution.
PMID- 10781040
TI - It's a bug's life.
AB - Although the mechanisms of anterior-posterior axis formation are well understood
in Drosophila, both embryological and molecular studies suggest significant
variation in the mechanisms generating this axis within the Insecta class as a
whole.
PMID- 10781039
TI - Arthropods: developmental diversity within a (super) phylum.
AB - The expression patterns of developmental genes provide new markers that address
the homology of body parts and provide clues as to how body plans have evolved.
Such markers support the idea that insect wings evolved from limbs but refute the
idea that insect and crustacean jaws are fundamentally different in structure.
They also confirm that arthropod tagmosis reflects underlying patterns of Hox
gene regulation but they do not yet resolve to what extent Hox expression domains
may serve to define segment homologies.
PMID- 10781041
TI - Inversion of the chordate body axis: are there alternatives?
AB - One major morphological difference between chordates and annelids or arthropods
is the opposite orientation of the nerve cord and heart. A long-standing proposal
is that the chordate axis evolved by inverting the body of an ancestor with the
annelid/arthropod orientation. However, the data can also be explained by a
common ancestor with diffuse dorsoventral organization, followed by oppositely
directed condensation of the nerve cord and relocation of the heart in the two
lines.
PMID- 10781042
TI - Vertebrate innovations.
AB - Vertebrate innovations include neural crest cells and their derivatives,
neurogenic placodes, an elaborate segmented brain, endoskeleton, and an increase
in the number of genes in the genome. Comparative molecular and developmental
data give new insights into the evolutionary origins of these characteristics and
the complexity of the vertebrate body.
PMID- 10781043
TI - The new animal phylogeny: reliability and implications.
AB - DNA sequence analysis dictates new interpretation of phylogenic trees. Taxa that
were once thought to represent successive grades of complexity at the base of the
metazoan tree are being displaced to much higher positions inside the tree. This
leaves no evolutionary "intermediates" and forces us to rethink the genesis of
bilaterian complexity.
PMID- 10781045
TI - Evolution of biological complexity.
AB - To make a case for or against a trend in the evolution of complexity in
biological evolution, complexity needs to be both rigorously defined and
measurable. A recent information-theoretic (but intuitively evident) definition
identifies genomic complexity with the amount of information a sequence stores
about its environment. We investigate the evolution of genomic complexity in
populations of digital organisms and monitor in detail the evolutionary
transitions that increase complexity. We show that, because natural selection
forces genomes to behave as a natural "Maxwell Demon," within a fixed
environment, genomic complexity is forced to increase.
PMID- 10781044
TI - Precambrian animal diversity: putative phosphatized embryos from the Doushantuo
Formation of China.
AB - Putative fossil embryos and larvae from the Precambrian phosphorite rocks of the
Doushantuo Formation in Southwest China have been examined in thin section by
bright field and polarized light microscopy. Although we cannot completely
exclude a nonbiological or nonmetazoan origin, we identified what appear to be
modern cnidarian developmental stages, including both anthozoan planula larvae
and hydrozoan embryos. Most importantly, the sections contain a variety of small
(/= 5 that occurred within 20 km of our stations during the observation
period. Changes were also detected at greater epicentral distances (up to 75 km)
before two other EQs, including one EQ of magnitude 4.7, which was preceded by a
signal simultaneously recorded at three widely separated stations. These
geoelectric potential changes have been distinguished through the following
criteria from a multitude of other changes, which were noise of various origins.
(i) The selected changes were proportional in amplitude to the length of the
recording station's short ( approximately 100 m) dipoles and were simultaneously
detected also on long (1-10 km) dipoles when the latter were in operation. (ii)
No such changes occurred during the observation period that were not followed by
EQs. Although the EQ precursory nature of these geoelectric potential changes is
admittedly unproven, it seems that the present results warrant continued serious
research into the occurrence, generation, and transmission of these signals and
their possible causal relationship to EQs.
PMID- 10781061
TI - Uncovering the [2Fe2S] domain movement in cytochrome bc1 and its implications for
energy conversion.
AB - In crystals of the key respiratory and photosynthetic electron transfer protein
called ubihydroquinone:cytochrome (cyt) c oxidoreductase or cyt bc(1), the
extrinsic [2Fe2S] cluster domain of its Fe-S subunit assumes several
conformations, suggesting that it may move during catalysis. Herein, using
Rhodobacter capsulatus mutants that have modifications in the hinge region of
this subunit, we were able to reveal this motion kinetically. Thus, the bc(1)
complex (and possibly the homologous b(6)f complex in chloroplasts) employs the
[2Fe2S] cluster domain as a device to shuttle electrons from ubihydroquinone to
cyt c(1) (or cyt f). We demonstrate that this domain movement is essential for
cyt bc(1) function, because a mutant enzyme with a nonmoving Fe-S subunit has no
catalytic activity, and one with a slower movement has lower activity. This
motion is apparently designed with a natural frequency slow enough to assure
productive Q(o) site charge separation but fast enough not to be rate limiting.
These findings add the unprecedented function of intracomplex electron shuttling
to large-scale domain motions in proteins and may well provide a target for cyt
bc(1) antibiotics.
PMID- 10781062
TI - The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis
of infantile neuronal ceroid lipofuscinosis.
AB - Mutations in palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme that
removes fatty acyl groups from cysteine residues in modified proteins, cause the
fatal inherited neurodegenerative disorder infantile neuronal ceroid
lipofuscinosis. The accumulation of undigested substrates leads to the formation
of neuronal storage bodies that are associated with the clinical symptoms. Less
severe forms of PPT1 deficiency have been found recently that are caused by a
distinct set of PPT1 mutations, some of which retain a small amount of
thioesterase activity. We have determined the crystal structure of PPT1 with and
without bound palmitate by using multiwavelength anomalous diffraction phasing.
The structure reveals an alpha/beta-hydrolase fold with a catalytic triad
composed of Ser115-His289-Asp233 and provides insights into the structural basis
for the phenotypes associated with PPT1 mutations.
PMID- 10781063
TI - A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by
ubiquitination.
AB - Temporal control of p27(Kip1) (p27) degradation imposes periodicity in its
activity during cell cycle progression and its accumulation during cell cycle
exit. Degradation of p27 is initiated by phosphorylation of p27 at Thr-187, which
marks the protein for ubiquitination by SCF(Skp2) and subsequent proteolysis by
the 26S proteasome. Here we show that the p27 ubiquitination activity in cell
extracts depends on the presence of the ubiquitin-like protein Nedd8 and enzymes
that catalyze Nedd8 conjugation to proteins. Moreover, we show that
reconstitution of the p27 ubiquitination activity of recombinant SCF(Skp2) also
requires Nedd8 conjugation pathway components. Inactivation of the Nedd8
conjugation pathway by a dominant negative mutant of the Nedd8-conjugating enzyme
Nce1/Ubc12 blocks the ubiquitination and degradation of p27 in cell extracts.
Consistent with a role in cell-cycle progression, Nedd8 is expressed in
proliferating cells and is itself down-regulated upon cellular differentiation.
These results suggest that the Nedd8 conjugation pathway may regulate the
turnover of p27(Kip1), independently of p27 phosphorylation, and further
establishes the identity of protein components involved in p27 ubiquitination.
Finally, these findings provide a direct demonstration of a function for Nedd8 in
a biological process.
PMID- 10781064
TI - The in vitro and in vivo phosphotyrosine map of activated MuSK.
AB - The muscle-specific receptor tyrosine kinase MuSK plays a crucial role in
neuromuscular synapse formation. Activation of MuSK is induced by agrin leading
to clustering of several proteins, including acetylcholine receptors, at synaptic
sites. In a first step to elucidate the signal transduction cascade following
MuSK activation and leading to clustering of synaptic proteins, we sought to
identify the tyrosine residues that are phosphorylated in activated MuSK. We
mapped the tyrosine residues that are phosphorylated in vitro and in vivo using
methods that provide high sensitivity and do not require radioactive tracers. We
expressed MuSK in insect cells by using a baculovirus expression vector and
mapped the tyrosines that are phosphorylated in MuSK in an in vitro kinase assay
using matrix-assisted laser desorption ionization MS to sequence tryptic peptides
fractionated by HPLC. In addition, we isolated MuSK from Torpedo electric organ
and used nanoelectrospray tandem mass spectrometry and parent ion scanning to
identify the tyrosine residues that are phosphorylated in activated, endogenous
MuSK in vivo. We found that six of the nineteen intracellular tyrosine residues
in MuSK are phosphorylated in activated MuSK: the juxtamembrane tyrosine (Y553),
the tyrosines within the activation loop (Y750, Y754, and Y755), a tyrosine near
the beginning of the kinase domain (Y576), and a tyrosine (Y812) within the C
terminal lobe of the kinase domain. Our biochemical data are consistent with
results from functional experiments and establish a good correlation between
tyrosine residues that are phosphorylated in activated MuSK and tyrosines that
are required for MuSK signaling.
PMID- 10781065
TI - Selecting rRNA binding sites for the ribosomal proteins L4 and L6 from randomly
fragmented rRNA: application of a method called SERF.
AB - Two-thirds of the 54 proteins of the Escherichia coli ribosome interact directly
with the rRNAs, but the rRNA binding sites of only a very few proteins are known.
We present a method (selection of random RNA fragments; SERF) that can identify
the minimal binding region for proteins within ribonucleo-protein complexes such
as the ribosome. The power of the method is exemplified with the ribosomal
proteins L4 and L6. Binding sequences are identified for both proteins and
characterized by phosphorothioate footprinting. Surprisingly, the binding region
of L4, a 53-nt rRNA fragment of domain I of 23S rRNA, can simultaneously and
independently bind L24, one of the two assembly initiator proteins of the large
subunit.
PMID- 10781067
TI - Association of Escherichia coli ribosomes with the inner membrane requires the
signal recognition particle receptor but is independent of the signal recognition
particle.
AB - In mammalian cells, as well as Escherichia coli, ribosomes translating membrane
proteins interact cotranslationally with translocons in the membrane, and this
interaction is essential for proper insertion of nascent polypeptides into the
membrane. Both the signal recognition particle (SRP) and its receptor (SR) are
required for functional association of ribosomes translating integral membrane
proteins with the translocon. Herein, we confirm that membrane targeting of E.
coli ribosomes requires the prokaryotic SRalpha homolog FtsY in vivo.
Surprisingly, however, depletion of the E. coli SRP54 homolog (Ffh) has no
significant effect on binding of ribosomes to the membrane, although Ffh
depletion is detrimental to growth. These and other observations suggest that, in
E. coli, SRP may operate downstream of SR-mediated targeting of ribosomes to the
plasma membrane.
PMID- 10781066
TI - Functional interaction between the Werner Syndrome protein and DNA polymerase
delta.
AB - Werner Syndrome (WS) is an inherited disease characterized by premature onset of
aging, increased cancer incidence, and genomic instability. The WS gene encodes a
1,432-amino acid polypeptide (WRN) with a central domain homologous to the RecQ
family of DNA helicases. Purified WRN unwinds DNA with 3'-->5' polarity, and also
possesses 3'-->5' exonuclease activity. Elucidation of the physiologic
function(s) of WRN may be aided by the identification of WRN-interacting
proteins. We show here that WRN functionally interacts with DNA polymerase delta
(pol delta), a eukaryotic polymerase required for DNA replication and DNA repair.
WRN increases the rate of nucleotide incorporation by pol delta in the absence of
proliferating cell nuclear antigen (PCNA) but does not stimulate the activity of
eukaryotic DNA polymerases alpha or epsilon, or a variety of other DNA
polymerases. Moreover, we show that functional interaction with WRN is mediated
through the third subunit of pol delta: i.e., Pol32p of Saccharomyces cerevisae,
corresponding to the recently identified p66 subunit of human pol delta. Absence
of the third subunit abrogates stimulation by WRN, and stimulation is restored by
reconstituting the three-subunit enzyme. Our findings suggest that WRN may
facilitate pol delta-mediated DNA replication and/or DNA repair and that
disruption of WRN-pol delta interaction in WS cells may contribute to the
previously observed S-phase defects and/or the unusual sensitivity to a limited
number of DNA damaging agents.
PMID- 10781068
TI - A biological function for cadmium in marine diatoms.
AB - The oceanic distribution of cadmium follows closely that of major algal nutrients
such as phosphate. The reasons for this "nutrient-like" distribution are unclear,
however, because cadmium is not generally believed to have a biological function.
Herein, we provide evidence of a biological role for Cd in the marine diatom
Thalassiosira weissflogii under conditions of low zinc, typical of the marine
environment. Addition of Cd to Zn-limited cultures enhances the growth rate of T.
weissflogii, particularly at low pCO(2). This increase in growth rate is
reflected in increased levels of cellular carbonic anhydrase (CA) activity,
although the levels of TWCA1, the major intracellular Zn-requiring isoform of CA
in T. weissflogii, remain low. (109)Cd label comigrates with a protein band that
shows CA activity and is distinct from TWCA1 on native PAGE of radiolabeled T.
weissflogii cell lysates. The levels of the Cd protein are modulated by CO(2) in
a manner that is consistent with a role for this enzyme in carbon acquisition.
Purification of the CA-active fraction leads to the isolation of a Cd-containing
protein of 43 kDa. It is now clear that T. weissflogii expresses a Cd-specific
CA, which, particularly under conditions of Zn limitation, can replace the Zn
enzyme TWCA1 in its carbon-concentrating mechanism.
PMID- 10781069
TI - Single-electron reduction of the oxidized state is coupled to proton uptake via
the K pathway in Paracoccus denitrificans cytochrome c oxidase.
AB - The reductive part of the catalytic cycle of cytochrome c oxidase from Paracoccus
denitrificans was examined by using time-resolved potential measurements on black
lipid membranes. Proteoliposomes were adsorbed to the black lipid membranes and
Ru(II)(2, 2'-bipyridyl)(3)(2+) was used as photoreductant to measure flash
induced membrane potential generation. Single-electron reduction of the oxidized
wild-type cytochrome c oxidase reveals two phases of membrane potential
generation (tau(1) approximately 20 micros and tau(2) approximately 175 micros)
at pH 7.4. The fast phase is not sensitive to cyanide and is assigned to electron
transfer from Cu(A) to heme a. The slower phase is inhibited completely by
cyanide and shows a kinetic deuterium isotope effect by a factor of 2-3. Although
two enzyme variants mutated in the so-called D pathway of proton transfer (D124N
and E278Q) show the same time constants and relative amplitudes as the wild-type
enzyme, in the K pathway variant K354M, tau(2) is increased to 900 micros. This
result suggests uptake of a proton through the K pathway during the transition
from the oxidized to the one-electron reduced state. After the second laser flash
under anaerobic conditions, a third electrogenic phase with a time constant of
approximately 1 ms appears. The amplitude of this phase grows with increasing
flash number. We explain this growth by injection of a second electron into the
single-electron reduced enzyme. On multiple flashes, both D pathway mutants
behave differently compared with the wild type and two additional slow phases of
tau(3) approximately 2 ms and tau(4) approximately 15 ms are observed. These
results suggest that the D pathway is involved in proton transfer coupled to the
uptake of the second electron.
PMID- 10781070
TI - Robust perfect adaptation in bacterial chemotaxis through integral feedback
control.
AB - Integral feedback control is a basic engineering strategy for ensuring that the
output of a system robustly tracks its desired value independent of noise or
variations in system parameters. In biological systems, it is common for the
response to an extracellular stimulus to return to its prestimulus value even in
the continued presence of the signal-a process termed adaptation or
desensitization. Barkai, Alon, Surette, and Leibler have provided both
theoretical and experimental evidence that the precision of adaptation in
bacterial chemotaxis is robust to dramatic changes in the levels and kinetic rate
constants of the constituent proteins in this signaling network [Alon, U.,
Surette, M. G., Barkai, N. & Leibler, S. (1998) Nature (London) 397, 168-171].
Here we propose that the robustness of perfect adaptation is the result of this
system possessing the property of integral feedback control. Using techniques
from control and dynamical systems theory, we demonstrate that integral control
is structurally inherent in the Barkai-Leibler model and identify and
characterize the key assumptions of the model. Most importantly, we argue that
integral control in some form is necessary for a robust implementation of perfect
adaptation. More generally, integral control may underlie the robustness of many
homeostatic mechanisms.
PMID- 10781071
TI - mRNA splicing-mediated C-terminal replacement of transcription factor Hac1p is
required for efficient activation of the unfolded protein response.
AB - Eukaryotic cells control the levels of molecular chaperones and folding enzymes
in the endoplasmic reticulum (ER) by a transcriptional induction process termed
the unfolded protein response (UPR) according to the needs within the ER. In
Saccharomyces cerevisiae, expression of the UPR-specific transcription factor
Hac1p is tightly regulated at the level of mRNA splicing that depends on an
unconventional system. Thus, HAC1 precursor mRNA is constitutively expressed but
not translated. A sensor molecule Ire1p/Ern1p-mediated signaling from the ER
specifically removes an intron of 252 nucleotides from the precursor mRNA, and
the resulting mature mRNA is translated to produce Hac1p. Because the 5' splice
site is located near the C-terminal end of the Hac1p-coding region, this splicing
replaces the last 10 codons of the ORF with an exon encoding 18 aa without
affecting the N-terminal 220-aa region which contains the DNA-binding domain.
Here, we found that this C-terminal 18-aa segment functions as a potent
activation domain. Therefore, the splicing event joins the HAC1 DNA-binding
domain to its activation domain, allowing rapid posttranscriptional generation of
a potent transcriptional activator (238-aa Hac1p) that activates the UPR
efficiently. This suggests that the UPR is hardly activated by Hac1p produced
without splicing (230-aa Hac1p) which may occur in the absence of Ire1p/Ern1p
mediated signaling from the ER. Based on these and other results, we propose that
the control of expression and activity of Hac1p meets the requirements of the ER.
PMID- 10781072
TI - Outer mitochondrial membrane permeability can regulate coupled respiration and
cell survival.
AB - Coupled cellular respiration requires that ATP and ADP be efficiently exchanged
between the cytosol and the mitochondrial matrix. When growth factors are
withdrawn from dependent cells, metabolism is disrupted by a defect in ATP/ADP
exchange across the mitochondrial membranes. Unexpectedly, we find that this
defect results from loss of outer mitochondrial membrane permeability to
metabolic anions. This decrease in anion permeability correlates with the changes
in conductance properties that accompany closure of the voltage-dependent anion
channel (also known as mitochondrial porin). Loss of outer membrane permeability
(i) results in the accumulation of stored metabolic energy within the
intermembrane space in the form of creatine phosphate, (ii) is prevented by the
outer mitochondrial membrane proteins Bcl-x(L) and Bcl-2, and (iii) can be
reversed by growth factor readdition. If outer membrane impermeability persists,
the disruption of mitochondrial homeostasis culminates in loss of outer
mitochondrial membrane integrity, cytochrome c redistribution, and apoptosis. The
recognition that outer membrane permeability is regulated under physiological
conditions has important implications for the understanding of bioenergetics and
cell survival.
PMID- 10781073
TI - The human papillomavirus type 16 negative regulatory RNA element interacts with
three proteins that act at different posttranscriptional levels.
AB - In human papillomaviruses, expression of the late genes L1 and L2, encoding the
capsid proteins, is restricted to the upper layers of the infected epithelium. A
79-nt GU-rich negative regulatory element (NRE) located at the 3' untranslated
region of the human papillomavirus 16 L1 gene was identified previously as key to
the posttranscriptional control of late gene expression. Here, we demonstrate
that in epithelial cells, the NRE can directly bind the U2 auxiliary splicing
factor 65-kDa subunit, the cleavage stimulation factor 64-kDa subunit, and the
Elav-like HuR protein. On induction of epithelial cell differentiation, levels of
the U2 auxiliary splicing factor 65-kDa subunit decrease, levels of the cleavage
stimulation factor 64-kDa subunit increase, and the levels of HuR remain
unchanged, although redistribution of the HuR from the nucleus to the cytoplasm
is observed. Late gene transcripts, which appear to be fully processed, are
detected in undifferentiated W12 cells, but are confined in the nucleus. We
propose that repression of late gene expression in basal epithelial cells may be
caused by nuclear retention or cytoplasmic instability of NRE-containing late
gene transcripts.
PMID- 10781074
TI - Abnormal spermatogenesis and reduced fertility in transition nuclear protein 1
deficient mice.
AB - Transition nuclear proteins (TPs), the major proteins found in chromatin of
condensing spermatids, are believed to be important for histone displacement and
chromatin condensation during mammalian spermatogenesis. We generated mice
lacking the major TP, TP1, by targeted deletion of the Tnp1 gene in mouse
embryonic stem cells. Surprisingly, testis weights and sperm production were
normal in the mutant mice, and only subtle abnormalities were observed in sperm
morphology. Electron microscopy revealed large rod-like structures in the
chromatin of mutant step 13 spermatids, in contrast to the fine chromatin fibrils
observed in wild type. Steps 12-13 spermatid nuclei from the testis of Tnp1-null
mice contained, in place of TP1, elevated levels of TP2 and some protamine 2 (P2)
precursor. Most of the precursor was processed to mature P2, but high levels of
incompletely processed forms remained in epididymal spermatozoa. Sperm motility
was reduced severely, and approximately 60% of Tnp1-null males were infertile. We
concluded that TP1 is not essential for histone displacement or chromatin
condensation. The absence of TP1 may partially be compensated for by TP2 and P2
precursor, but this dysregulation of nucleoprotein replacement results in an
abnormal pattern of chromatin condensation and in reduced fertility.
PMID- 10781076
TI - Primitive synteny of vertebrate major histocompatibility complex class I and
class II genes.
AB - Major histocompatibility complex (MHC) class I and class II molecules bind to and
display peptidic antigens acquired from pathogens that are recognized by
lymphocytes coordinating and executing adaptive immune responses. The two classes
of MHC proteins have nearly identical tertiary structures and were derived from a
common ancestor that probably existed not long before the emergence of the
cartilaginous fish. Class I and class II genes are genetically linked in
tetrapods but are not syntenic in teleost fish, a phylogenetic taxon derived from
the oldest vertebrate ancestor examined to date. Cartilaginous fish (sharks,
skates, and rays) are in the oldest taxon of extant jawed vertebrates; we have
carried out segregation analyses in two families of nurse sharks and one family
of the banded houndshark that revealed a close linkage of class IIalpha and beta
genes both with each other and with the classical class I (class Ia) gene. These
results strongly suggest that the primordial duplication giving rise to classical
class I and class II occurred in cis, and the close linkage between these two
classes of genes has been maintained for at least 460 million years in
representatives of most vertebrate taxa.
PMID- 10781077
TI - A recombination hotspot delimits a wild-species quantitative trait locus for
tomato sugar content to 484 bp within an invertase gene.
AB - In nature, genetic variation usually takes the form of a continuous phenotypic
range rather than discrete classes. The genetic variation underlying quantitative
traits results from the segregation of numerous interacting quantitative trait
loci (QTLs), whose expression is modified by the environment. To uncover the
molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived
from the green-fruited tomato species Lycopersicon pennellii. The wild-species
allele increased glucose and fructose contents in cultivated tomato fruits in
various genetic backgrounds and environments. Using nearly isogenic lines for the
QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide
polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron
of a fruit-specific apoplastic invertase. We suggest that the differences between
the Brix9-2-5 alleles of the two species are associated with a polymorphic
intronic element that modulates sink strength of tomato fruits. Our results
demonstrate a link between naturally occurring DNA variation and a Mendelian
determinant of a complex phenotype for a yield-associated trait.
PMID- 10781075
TI - Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L
proteases.
AB - Ovulation is a precisely timed process by which a mature oocyte is released from
an ovarian follicle. This process is initiated by the pituitary surge of
luteinizing hormone (LH), is temporally associated with transcriptional
regulation of numerous genes, and is presumed to involve the synthesis and/or
activation of specific proteases that degrade the follicle wall. The progesterone
receptor (PR), a nuclear receptor transcription factor, is induced in granulosa
cells of preovulatory follicles in response to the LH surge and has been shown to
be essential for ovulation, because mice lacking PR fail to ovulate and are
infertile. Using these mice as a model in which to elucidate PR-regulated genes
in the ovulation process, we show that the matrix metalloproteinases MMP-2 and
MMP-9 are not targets of PR during ovulation. In contrast, two other proteases,
ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs)
and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of
PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of
preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa
cells of growing follicles by follicle-stimulating hormone, but the highest
levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a
PR-dependent manner. The identification of two regulated proteases in the ovary,
together with their abnormal expression in anovulatory PR knockout mice, suggests
that each plays a critical role in follicular rupture and represents a major
advance in our understanding of the proteolytic events that control ovulation.
PMID- 10781078
TI - A mutant hunt for defects in membrane protein assembly yields mutations affecting
the bacterial signal recognition particle and Sec machinery.
AB - We describe an Escherichia coli genetic screen that yields mutations affecting
two different cellular processes: disulfide bond formation and membrane protein
assembly. The mutants defective in disulfide bond formation include additional
classes of dsbA and dsbB mutations. The membrane protein assembly defective
mutants contain a mutation in the secA operon and three mutations in the ffs
gene, which encodes 4.5S RNA. These latter mutations are the only ones to be
isolated in a gene encoding a component of the bacterial signal recognition
particle by screening in vivo for defects in membrane protein insertion. A
sensitive method for examining membrane protein localization shows that the ffs
and secA locus mutations affect membrane assembly of the polytopic membrane
protein, MalF. The ffs mutations also affect the membrane insertion of the FtsQ
and the AcrB proteins. Although both the ffs and the secA locus mutations
interfere with membrane protein assembly, only the latter also reduces export of
a protein containing a cleavable signal sequence.
PMID- 10781079
TI - Prolyl 4-hydroxylase is required for viability and morphogenesis in
Caenorhabditis elegans.
AB - The genome of Caenorhabditis elegans possesses two genes, dpy-18 and phy-2, that
encode alpha subunits of the enzyme prolyl 4-hydroxylase. We have generated
deletions within each gene to eliminate prolyl 4-hydroxylase activity from the
animal. The dpy-18 mutant has an aberrant body morphology, consistent with a role
of prolyl 4-hydroxylase in formation of the body cuticle. The phy-2 mutant is
phenotypically wild type. However, the dpy-18; phy-2 double mutant is not viable,
suggesting an essential role for prolyl 4-hydroxylase that is normally
accomplished by either dpy-18 or phy-2. The effects of the double mutation were
mimicked by small-molecule inhibitors of prolyl 4-hydroxylase, validating the
genetic results and suggesting that C. elegans can serve as a model system for
the discovery of new inhibitors.
PMID- 10781080
TI - Attention deficit/hyperactivity disorder children with a 7-repeat allele of the
dopamine receptor D4 gene have extreme behavior but normal performance on
critical neuropsychological tests of attention.
AB - An association of the dopamine receptor D4 (DRD4) gene located on chromosome
11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated
and replicated by multiple investigators. A specific allele [the 7-repeat of a 48
bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an
etiological factor in attentional deficits manifested in some children diagnosed
with this disorder. In the current study, we evaluated ADHD subgroups defined by
the presence or absence of the 7-repeat allele of the DRD4 gene, using
neuropsychological tests with reaction time measures designed to probe
attentional networks with neuroanatomical foci in D4-rich brain regions. Despite
the same severity of symptoms on parent and teacher ratings for the ADHD
subgroups, the average reaction times of the 7-present subgroup showed normal
speed and variability of response whereas the average reaction times of the 7
absent subgroup showed the expected abnormalities (slow and variable responses).
This was opposite the primary prediction of the study. The 7-present subgroup
seemed to be free of some of the neuropsychological abnormalities thought to
characterize ADHD.
PMID- 10781081
TI - Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular
immune responses.
AB - NY-ESO-1, a member of the cancer-testis family of antigens, is expressed in a
subset of a broad range of different human tumor types. Patients with advanced NY
ESO-1-expressing tumors frequently develop humoral immunity to NY-ESO-1, and
three HLA A2-restricted peptides were defined previously as targets for cytotoxic
CD8(+) T cells in a melanoma patient with NY-ESO-1 antibody. The objectives of
the present study were (i) to develop enzyme-linked immunospot (ELISPOT) and
tetramer assays to measure CD8(+) T cell responses to NY-ESO-1, (ii) to determine
the frequency of CD8(+) T cell responses to NY-ESO-1 in a series of HLA-A2
patients with NY-ESO-1 expressing tumors, (iii) to determine the relation between
CD8(+) T cell and humoral immune responses to NY-ESO-1, and (iv) to compare
results of NY-ESO-1 ELISPOT assays performed independently in two laboratories
with T cells from the same patients. NY-ESO-1 ELISPOT and tetramer assays with
excellent sensitivity, specificity, and reproducibility have been developed and
found to correlate with cytotoxicity assays. CD8(+) T cell responses to HLA-A2
restricted NY-ESO-1 peptides were detected in 10 of 11 patients with NY-ESO-1
antibody, but not in patients lacking antibody or in patients with NY-ESO-1
negative tumors. The results of ELISPOT assays were concordant in the two
laboratories, providing the basis for standardized monitoring of T cell responses
in patients receiving NY-ESO-1 vaccines.
PMID- 10781082
TI - CD4+ T cells derived from B cell-deficient mice inhibit the establishment of
peripheral B cell pools.
AB - We demonstrate that adoptive transfer of peritoneal cavity B cells fails to
replenish the peripheral B-1 cells in adult B cell-deficient (mu(-/-)) mice but
does replenish adult RAG-1(-/-) mice. We show that this lack of self
replenishment in mu(-/-) mice is mediated by strongly inhibitory, radiation
sensitive CD4(+) T cells that also function in cotransfer studies to block the
reconstitution of B-1 cells and inhibit accumulation of bone marrow-derived B-2
cells in the periphery in irradiated recipients. CD8(+) T cells from mu(-/-) do
not mediate this inhibition. The inhibitory CD4(+) T cells develop early in life,
because B-1 cell replenishment occurs normally when B-1 cells are transferred
into mu(-/-) neonates. Thus, we conclude that the presence of B cells in the
neonate conditions the CD4(+) T-cell population to permit the establishment and
maintenance of normal B cell pools throughout life.
PMID- 10781083
TI - Lsh, an SNF2/helicase family member, is required for proliferation of mature T
lymphocytes.
AB - Lsh (Hells) is closely related to SNF2/helicase family members that remodel
chromatin and thus regulate gene transcription. In the adult mouse Lsh is
expressed primarily in lymphoid tissue, showing the highest level in thymocytes.
Lsh gene expression can be induced in thymic pro-T cells by pre-T cell receptor
crosslinking and in mature T cells by T cell receptor crosslinking together with
costimulation via CD28. The time course of Lsh gene and protein expression
correlated closely with the onset of S phase of the cell cycle. To explore the
function of Lsh during lymphoid development or activation, we deleted the Lsh
gene by homologous recombination in ES cells. Fetal liver cells from Lsh-/- were
used as a source of hematopoietic precursors to reconstitute lymphoid development
in Rag2-/- mice. Lsh-/- (compared to Lsh+/+ or +/-) chimeras showed a modest
reduction in thymocyte numbers due to a partial arrest at the transition from the
CD4(-)CD8(-) stage to the CD4(+)CD8(+) stage of T cell development. Mature
peripheral lymphocytes were reduced in number to approximately 60% for T cells
and 40% for B cells; however, V(D)J recombination of the immune receptor genes
was normal. Although polyclonal activation of Lsh-/- T cells induced normal
levels of cytokines, cell proliferation was severely suppressed and cells
underwent apoptosis. Several genes involved in the regulation of apoptosis were
expressed normally with the exception of Bcl-2 that was actually elevated. These
findings demonstrate that Lsh is not obligatory for normal lymphoid development
but is essential for normal proliferation of peripheral T lymphocytes.
PMID- 10781084
TI - Plasticity in the organization and sequences of human KIR/ILT gene families.
AB - The approximately 1-Mb leukocyte receptor complex at 19q13.4 is a key polymorphic
immunoregion containing all of the natural killer-receptor KIR and related ILT
genes. When the organization of the leukocyte receptor complex was compared from
two haplotypes, the gene content in the KIR region varied dramatically, with
framework loci flanking regions of widely variable gene content. The ILT genes
were more stable in number except for ILT6, which was present only in one
haplotype. Analysis of Alu repeats and comparison of KIR gene sequences, which
are over 90% identical, are consistent with a recent origin. KIR genesis was
followed by extensive duplication/deletion as well as intergenic sequence
exchange, reminiscent of MHC class I genes, which provide KIR ligands.
PMID- 10781085
TI - Discovery of a spermatogenesis stage-specific ornithine decarboxylase antizyme:
antizyme 3.
AB - Previous studies with mice overproducing ornithine decarboxylase have
demonstrated the importance of polyamine homeostasis for normal mammalian
spermatogenesis. The present study introduces a likely key player in the
maintenance of proper polyamine homeostasis during spermatogenesis. Antizyme 3 is
a paralog of mammalian ornithine decarboxylase antizymes. Like its previously
described counterparts, antizymes 1 and 2, it inhibits ornithine decarboxylase,
which catalyzes the synthesis of putrescine. Earlier work has shown that the
coding sequences for antizymes 1 and 2 are in two different, partially
overlapping reading frames. Ribosomes translate the first reading frame, and just
before the stop codon for that frame, they shift to the second reading frame to
synthesize a trans-frame product. The efficiency of this frameshifting depends on
polyamine concentration, creating an autoregulatory circuit. Antizyme 3 cDNA has
the same arrangement of reading frames and a potential shift site with definite,
although limited, homology to its evolutionarily distant antizyme 1 and 2
counterparts. In contrast to antizymes 1 and 2, which are widely expressed
throughout the body, antizyme 3 transcription is restricted to testis germ cells.
Expression starts early in spermiogenesis and finishes in the late spermatid
phase. The potential significance of antizyme 3 expression during spermatogenesis
is discussed in this paper.
PMID- 10781086
TI - L-amino acid sensing by the extracellular Ca2+-sensing receptor.
AB - The extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) recognizes and
responds to (i.e., "senses") Ca(2+)(o) as its principal physiological ligand. In
the present studies, we document that the CaR is activated not only by
extracellular calcium ions but also by amino acids, establishing its capacity to
sense nutrients of two totally different classes. l-Amino acids, especially
aromatic amino acids, including l-phenylalanine and l-tryptophan,
stereoselectively mobilized Ca(2+) ions in the presence of the CaR agonists,
Ca(2+)(o), gadolinium (Gd(3+)(o)), and spermine in fura-2-loaded human embryonic
kidney (HEK-293) cells stably transfected with the human CaR. l-amino acid
dependent effects were observed above, but not below, a threshold level of
Ca(2+)(o) of approximately 1.0 mM. l-Amino acids, particularly aromatic amino
acids, also stereoselectively enhanced the sensitivity of the CaR to its
agonists, Ca(2+)(o) and spermine. Branched-chain amino acids were almost
inactive, and charged amino acids, including arginine and lysine, were much less
effective than aromatic and other amino acids. l-amino acid mixtures emulating
the amino acid composition of fasting human plasma reproduced the effects of high
concentrations of individual l-amino acids on Ca(2+) mobilization and enhanced
the sensitivity of the CaR to Ca(2+)(o). The data presented herein identify the
CaR as a molecular target for aromatic and other l-amino acids. Thus, the CaR can
integrate signals arising from distinct classes of nutrients: mineral ions and
amino acids. The actions of l-amino acids on the CaR may provide explanations for
several long recognized but poorly understood actions of dietary protein on
calcium metabolism.
PMID- 10781087
TI - Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth
factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway.
AB - Biological signals for transforming growth factor beta (TGF-beta) are transduced
through transmembrane serine/threonine kinase receptors that signal to a family
of intracellular mediators known as Smads. Smad2 and Smad4 are important for
transcriptional and antiproliferative responses to TGF-beta, and their
inactivation in human cancers indicates that they are tumor suppressors. A
missense mutation at a conserved arginine residue in the amino-terminal MH1
domain of both Smad2 and Smad4 has been identified in tumors from patients with
colorectal and pancreatic cancers, respectively. However, the mechanism whereby
this mutation interferes with Smad activity is uncertain. Here we show that these
mutations do not disrupt activation of Smads, including receptor-mediated
phosphorylation of Smad2, Smad2/Smad4 heteromeric complex formation, and Smad
nuclear translocation. In contrast, we demonstrate that the mutant Smads are
degraded rapidly in comparison with their wild-type counterparts. We show that
this decrease in Smad protein stability occurs through induction of Smad
ubiquitination by pathways involving the UbcH5 family of ubiquitin ligases. These
studies thus reveal a mechanism for tumorigenesis whereby genetic defects in
Smads induce their degradation through the ubiquitin-mediated pathway.
PMID- 10781088
TI - Conditional expression of a Gi-coupled receptor causes ventricular conduction
delay and a lethal cardiomyopathy.
AB - Cardiomyopathy is a major cause of morbidity and mortality. Ventricular
conduction delay, as shown by prolonged deflections in the electrocardiogram
caused by delayed ventricular contraction (wide QRS complex), is a common feature
of cardiomyopathy and is associated with a poor prognosis. Although the G(i)
signaling pathway is up-regulated in certain cardiomyopathies, previous studies
suggested this up-regulation was compensatory rather than a potential cause of
the disease. Using the tetracycline transactivator system and a modified G(i)
coupled receptor (Ro1), we provide evidence that increased G(i) signaling in mice
can result in a lethal cardiomyopathy associated with a wide QRS complex
arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality
rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice
from further mortality and allowed partial improvement in systolic function.
Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are
consistent with hyperactive G(i) signaling. DNA-array analysis also identified
known markers of cardiomyopathy and hundreds of previously unknown potential
diagnostic markers and therapeutic targets for this syndrome. Our system allows
cardiomyopathy to be induced and reversed in adult mice, providing an
unprecedented opportunity to dissect the role of G(i) signaling in causing
cardiac pathology.
PMID- 10781089
TI - Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997):
analysis of seroconversions to ORF65 and ORF73.
AB - We have shown previously that human herpesvirus 8 (HHV8) seroconversion for
antibodies to the latency-associated nuclear antigen encoded by ORF73 and/or the
lytic capsid antigen (vp19) encoded by ORF65 is associated with orogenital
contact and is strongly linked to the development of Kaposi's sarcoma among HIV
infected individuals in the Amsterdam Cohort Studies. Here, we investigate the
relationship between seroconversion to these antigens and primary HHV8 infection.
Between 1984 and 1997, 215 HHV8 seroconversions to ORF73 (106 cases or 49%)
and/or to ORF65 (159 cases or 74%) were recorded in the cohort of homosexual men.
The HHV8 seroconversion rate among HIV-infected homosexual men (6.2 per 100
person years) was consistently higher than among HIV-uninfected men (2.6 per 100
person years). In HIV-infected but not in uninfected individuals, seroconversion
to ORF73/latency-associated nuclear antigen precedes that to ORF65/vp19. Antibody
levels to both ORF65- and ORF73-encoded antigens were higher in HIV-infected than
in HIV-uninfected men, and among HIV-seropositives, antibody levels to ORF65/vp19
rise even higher with declining CD4 cell counts and peak with Kaposi's sarcoma
development, suggesting continuing and increasing viral replication. In 10.3% of
HHV8 seroconversions, transient serum viremia could be demonstrated before or at
seroconversion. Together with the previously reported link between unprotected
orogenital sex and HHV8 seroconversion, our observations suggest that HHV8
seroconversions result from primary infections.
PMID- 10781090
TI - 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B
signaling pathway.
AB - Prostaglandin J(2) (PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy
Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of
prostaglandin D(2) that have been suggested to exert antiinflammatory effects in
vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator
activated receptor gamma (PPARgamma) and has been demonstrated to inhibit the
induction of inflammatory response genes, including inducible NO synthase and
tumor necrosis factor alpha, in a PPARgamma-dependent manner. We report here that
15d-PGJ(2) potently inhibits NF-kappaB-dependent transcription by two additional
PPARgamma-independent mechanisms. Several lines of evidence suggest that 15d
PGJ(2) directly inhibits NF-kappaB-dependent gene expression through covalent
modifications of critical cysteine residues in IkappaB kinase and the DNA-binding
domains of NF-kappaB subunits. These mechanisms act in combination to inhibit
transactivation of the NF-kappaB target gene cyclooxygenase 2. Direct inhibition
of NF-kappaB signaling by 15d-PGJ(2) may contribute to negative regulation of
prostaglandin biosynthesis and inflammation, suggesting additional approaches to
the development of antiinflammatory drugs.
PMID- 10781091
TI - Development of an extrachromosomal cloning vector system for use in Borrelia
burgdorferi.
AB - Molecular genetic analysis of Borrelia burgdorferi, the cause of Lyme disease,
has been hampered by the absence of any means of efficient generation,
identification, and complementation of chromosomal and plasmid null gene mutants.
The similarity of borrelial G + C content to that of Gram-positive organisms
suggested that a wide-host-range plasmid active in Gram-positive bacteria might
also be recognized by borrelial DNA replication machinery. One such plasmid,
pGK12, is able to propagate in both Gram-positive and Gram-negative bacteria and
carries erythromycin and chloramphenicol resistance markers. pGK12 propagated
extrachromosomally in B. burgdorferi B31 after electroporation but conferred only
erythromycin resistance. pGK12 was used to express enhanced green fluorescent
protein in B31 under the control of the flaB promoter. Escherichia coli
transformed with pGK12 DNA extracted from B31 expressing only erythromycin
resistance developed both erythromycin and chloramphenicol resistance, and
plasmid DNA isolated from these transformed E. coli had a restriction pattern
similar to the original pGK12. Our data indicate that the replicons of pGK12 can
provide the basis to continue developing efficient genetic systems for B.
burgdorferi together with the erythromycin resistance and reporter egfp genes.
PMID- 10781092
TI - The Pseudomonas syringae Hrp pathogenicity island has a tripartite mosaic
structure composed of a cluster of type III secretion genes bounded by
exchangeable effector and conserved effector loci that contribute to parasitic
fitness and pathogenicity in plants.
AB - The plant pathogenic bacterium Pseudomonas syringae is divided into pathovars
differing in host specificity, with P. syringae pv. syringae (Psy) and P.
syringae pv. tomato (Pto) representing particularly divergent pathovars. P.
syringae hrp/hrc genes encode a type III protein secretion system that appears to
translocate Avr and Hop effector proteins into plant cells. DNA sequence analysis
of the hrp/hrc regions in Psy 61, Psy B728a, and Pto DC3000 has revealed a Hrp
pathogenicity island (Pai) with a tripartite mosaic structure. The hrp/hrc gene
cluster is conserved in all three strains and is flanked by a unique exchangeable
effector locus (EEL) and a conserved effector locus (CEL). The EELs begin 3 nt
downstream of the stop codon of hrpK and end, after 2.5-7.3 kb of dissimilar
intervening DNA with tRNA(Leu)-queA-tgt sequences that are also found in
Pseudomonas aeruginosa but without linkage to any Hrp Pai sequences. The EELs
encode diverse putative effectors, including HopPsyA (HrmA) in Psy 61 and
proteins similar to AvrPphE and the AvrB/AvrC/AvrPphC and AvrBsT/AvrRxv/YopJ
protein families in Psy B728a. The EELs also contain mobile genetic element
sequences and have a G + C content significantly lower than the rest of the Hrp
Pai or the P. syringae genome. The CEL carries at least seven ORFs that are
conserved between Psy B728a and Pto DC3000. Deletion of the Pto DC3000 EEL
slightly reduces bacterial growth in tomato, whereas deletion of a large portion
of the CEL strongly reduces growth and abolishes pathogenicity in tomato.
PMID- 10781093
TI - The murine homolog of human Nectin1delta serves as a species nonspecific mediator
for entry of human and animal alpha herpesviruses in a pathway independent of a
detectable binding to gD.
AB - The full-length cDNA of the murine homolog of human nectin1delta (mNectin1delta),
also known as human poliovirus receptor related 1 (PRR1) or herpesvirus entry
mediator C, was cloned and showed a >90% identity with its human counterpart.
mNectin1delta is expressed in some murine cell lines, exemplified by NIH 3T3 and
L cells, and in murine tissues. It mediates entry of an extended range of herpes
simplex virus (HSV) strains, porcine pseudorabies virus (PrV), and bovine
herpesvirus 1. A soluble form of the mediator blocked infectivity in
mNectin1delta and human nectin1delta (hNectin1delta)-expressing cells, suggesting
a physical interaction of the mediator with virions. The higher concentrations of
soluble mNectin1 required to block infectivity relative to soluble hNectin1
suggest that the target of the two molecules is not identical. Entry of HSV, but
not PrV, was blocked by soluble mNectin1delta in NIH 3T3 and L cells. Two
features were unexpected. First, soluble mNectin1delta failed to physically
interact with HSV glycoprotein D (gD) at a detectable level, although it
interacted physically with virions. Second, coexpression of mNectin1delta and HSV
gD did not restrict HSV or PrV infection, whereas coexpression of hNectin and gD
did restrict infection, suggesting that mNectin1delta fails to be sequestered by
HSV gD. We conclude that mNectin1delta serves as a species-nonspecific mediator
for entry of the human and animal alphaherpesviruses. This activity, at least for
HSV, is independent of a detectable binding to gD.
PMID- 10781094
TI - A self-recombining bacterial artificial chromosome and its application for
analysis of herpesvirus pathogenesis.
AB - A self-recombining bacterial artificial chromosome (BAC) containing the 142-kb
pseudorabies virus genome was constructed such that the viral genome is rapidly
excised from the BAC vector backbone on delivery into mammalian cells. The
recombination is mediated by loxP sites in the plasmid and Cre recombinase
encoded within the BAC vector. A synthetic intron inserted in the middle of the
cre ORF completely inhibits recombination in Escherichia coli, but is spliced out
after delivery of the plasmid into mammalian cells. Recombination is efficient,
and pure virus lacking the BAC vector backbone is immediately isolated from
transfected mammalian cells without the need of serial passage or plaque
purification.
PMID- 10781095
TI - Genome-wide analysis of vaccinia virus protein-protein interactions.
AB - To detect interactions between proteins of vaccinia virus, we carried out a
comprehensive two-hybrid analysis to assay every pairwise combination. We
constructed an array of yeast transformants that contained each of the 266
predicted viral ORFs as Gal4 activation domain hybrid proteins. The array was
individually mated to transformants containing each ORF as a Gal4-DNA-binding
domain hybrid, and diploids expressing the two-hybrid reporter gene were
identified. Of the approximately 70,000 combinations, we found 37 protein-protein
interactions, including 28 that were previously unknown. In some cases, e.g.,
late transcription factors, both proteins were known to have related roles
although there was no prior evidence of physical associations. For some other
interactions, neither protein had a known role. In the majority of cases,
however, one of the interacting proteins was known to be involved in DNA
replication, transcription, virion structure, or host evasion, thereby providing
a clue to the role of the other uncharacterized protein in a specific process.
PMID- 10781096
TI - Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross
beta conformation.
AB - Filamentous inclusions made of alpha-synuclein constitute the defining
neuropathological characteristic of Parkinson's disease, dementia with Lewy
bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease
are associated with mutations A53T and A30P in alpha-synuclein. We report here
the assembly properties and secondary structure characteristics of recombinant
alpha-synuclein. Carboxy-terminally truncated human alpha-synuclein (1-87) and (1
120) showed the fastest rates of assembly, followed by human A53T alpha
synuclein, and rat and zebra finch alpha-synuclein. Wild-type human alpha
synuclein and the A30P mutant showed slower rates of assembly. Upon shaking,
filaments formed within 48 h at 37 degrees C. The related proteins beta- and
gamma-synuclein only assembled after several weeks of incubation. Synthetic human
alpha-synuclein filaments were decorated by an antibody directed against the
carboxy-terminal 10 amino acids of alpha-synuclein, as were filaments extracted
from dementia with Lewy bodies and multiple system atrophy brains. Circular
dichroism spectroscopy indicated that alpha-synuclein undergoes a conformational
change from random coil to beta-sheet structure during assembly. X-ray
diffraction and electron diffraction of the alpha-synuclein assemblies showed a
cross-beta conformation characteristic of amyloid.
PMID- 10781097
TI - Prostaglandin D synthase gene is involved in the regulation of non-rapid eye
movement sleep.
AB - To examine the function of prostaglandin (PG) D synthase (PGDS) gene, as well as
endogenously produced PGD(2) in sleep regulation in vivo, we generated transgenic
(TG) mice that overexpress human PGDS gene to study their sleep behavior.
Although no difference was observed in the sleep/wake patterns between wild-type
and TG mice, a striking time-dependent increase in non-rapid eye movement (NREM),
but not in rapid eye movement (REM), sleep was observed in two independent lines
of TG mice after stimulation by tail clipping. Concomitantly, the spontaneous
locomotor activity of TG animals was drastically decreased in response to the
tail clip. Induction of NREM sleep in TG mice was positively correlated with the
PGD(2) production in the brain. Sleep, locomotion, and PGD(2) content were
essentially unchanged in wild-type mice after tail clipping. The results with TG
mice demonstrate the involvement of the PGDS gene in the regulation of NREM
sleep.
PMID- 10781098
TI - Colocalization and coassembly of two human brain M-type potassium channel
subunits that are mutated in epilepsy.
AB - Acetylcholine excites many central and autonomic neurons through inhibition of M
channels, slowly activating, noninactivating voltage-gated potassium channels. We
here provide information regarding the in vivo distribution and biochemical
characteristics of human brain KCNQ2 and KCNQ3, two channel subunits that form M
channels when expressed in vitro, and, when mutated, cause the dominantly
inherited epileptic syndrome, benign neonatal familial convulsions. KCNQ2 and
KCNQ3 proteins are colocalized in a somatodendritic pattern on pyramidal and
polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for
KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a
presynaptic role for a distinct subgroup of M-channels in the regulation of
action potential propagation and neurotransmitter release. KCNQ2 and KCNQ3 can be
coimmunoprecipitated from brain lysates. Further, KCNQ2 and KCNQ3 are
coassociated with tubulin and protein kinase A within a Triton X-100-insoluble
protein complex. This complex is not associated with low-density membrane rafts
or with N-methyl-d-aspartate receptors, PSD-95 scaffolding proteins, or other
potassium channels tested. Our studies thus provide a view of a signaling complex
that may be important for cognitive function as well as epilepsy. Analysis of
this complex may shed light on the unknown transduction pathway linking
muscarinic acetylcholine receptor activation to M-channel inhibition.
PMID- 10781099
TI - A decamer duplication in the 3' region of the BRI gene originates an amyloid
peptide that is associated with dementia in a Danish kindred.
AB - Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto
encephalica, is an autosomal dominant disorder characterized by cataracts,
deafness, progressive ataxia, and dementia. Neuropathological findings include
severe widespread cerebral amyloid angiopathy, hippocampal plaques, and
neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence
analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri,
the peptide originated by a point mutation at the stop codon of gene BRI in
familial British dementia. Molecular genetic analysis of the BRI gene in the
Danish kindred showed a different defect, namely the presence of a 10-nt
duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before
the normal stop codon 267. The decamer duplication mutation produces a frame
shift in the BRI sequence generating a larger-than-normal precursor protein, of
which the amyloid subunit (designated ADan) comprises the last 34 C-terminal
amino acids. This de novo-created amyloidogenic peptide, associated with a
genetic defect in the Danish kindred, stresses the importance of amyloid
formation as a causative factor in neurodegeneration and dementia.
PMID- 10781100
TI - D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate
receptor.
AB - Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both
glutamate binding and the binding of an endogenous coagonist that has been
presumed to be glycine, although D-serine is a more potent agonist. Localizations
of D-serine and it biosynthetic enzyme serine racemase approximate the
distribution of NMDA receptors more closely than glycine. We now show that
selective degradation of d-serine with D-amino acid oxidase greatly attenuates
NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch
clamp recordings or indirectly by using biochemical assays of the sequelae of
NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are
fully reversed by exogenously applied D-serine, which by itself did not
potentiate NMDA receptor-mediated synaptic responses. Thus, D-serine is an
endogenous modulator of the glycine site of NMDA receptors and fully occupies
this site at some functional synapses.
PMID- 10781101
TI - Brain size does not predict general cognitive ability within families.
AB - Hominid brain size increased dramatically in the face of apparently severe
associated evolutionary costs. This suggests that increasing brain size must have
provided some sort of counterbalancing adaptive benefit. Several recent studies
using magnetic resonance imaging (MRI) have indicated that a substantial
correlation (mean r = approximately 0.4) exists between brain size and general
cognitive performance, consistent with the hypothesis that the payoff for
increasing brain size was greater general cognitive ability. However, these
studies confound between-family environmental influences with direct
genetic/biological influences. To address this problem, within-family (WF)
sibling differences for several neuroanatomical measures were correlated to WF
scores on a diverse battery of cognitive tests in a sample of 36 sibling pairs.
WF correlations between neuroanatomy and general cognitive ability were
essentially zero, although moderate correlations were found between prefrontal
volumes and the Stroop test (known to involve prefrontal cortex). These findings
suggest that nongenetic influences play a role in brain volume/cognitive ability
associations. Actual direct genetic/biological associations may be quite small,
and yet still may be strong enough to account for hominid brain evolution.
PMID- 10781102
TI - Potent blockade of sodium channels and protection of brain tissue from ischemia
by BIII 890 CL.
AB - We have synthesized a new benzomorphan derivative, 2R-[2alpha,3(S*), 6alpha]
1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-3-[2-(phenylmethoxy)propyl]-2, 6-methano
3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced
[(3)H]batrachotoxinin A-20alpha-benzoate from neurotoxin receptor site 2 of the
Na(+) channel in rat brain synaptosomes (IC(50) = 49 nM), but exhibited only low
affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na(+)
channels in cells transfected with type IIA Na(+) channel alpha subunits and
shifted steady-state inactivation curves to more negative potentials. The IC(50)
value for the inactivated Na(+) channel was much lower (77 nM) than for Na(+)
channels in the resting state (18 microM). Point mutations F1764A and Y1771A in
transmembrane segment S6 in domain IV of the alpha subunit reduced the voltage-
and frequency-dependent block, findings which suggest that BIII 890 CL binds to
the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine
induced glutamate release in brain slices, as well as glutamate release and
neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg/kg s.c.) reduced
lesion size in mice and rats when administered 5 min after permanent focal
cerebral ischemia at doses that did not impair motor coordination. In contrast to
many other agents, BIII 890 CL was neuroprotective in both cortical and
subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is
a potent, selective, and highly use-dependent Na(+) channel blocker that protects
brain tissue from the deleterious effects of focal cerebral ischemia in rodents.
PMID- 10781103
TI - Elevated subsarcolemmal Ca2+ in mdx mouse skeletal muscle fibers detected with
Ca2+-activated K+ channels.
AB - Duchenne muscular dystrophy results from the lack of dystrophin, a cytoskeletal
protein associated with the inner surface membrane, in skeletal muscle. The
cellular mechanisms responsible for the progressive skeletal muscle degeneration
that characterizes the disease are still debated. One hypothesis suggests that
the resting sarcolemmal permeability for Ca(2+) is increased in dystrophic
muscle, leading to Ca(2+) accumulation in the cytosol and eventually to protein
degradation. However, more recently, this hypothesis was challenged seriously by
several groups that did not find any significant increase in the global
intracellular Ca(2+) in muscle from mdx mice, an animal model of the human
disease. In the present study, using plasma membrane Ca(2+)-activated K(+)
channels as subsarcolemmal Ca(2+) probe, we tested the possibility of a Ca(2+)
accumulation at the restricted subsarcolemmal level in mdx skeletal muscle
fibers. Using the cell-attached configuration of the patch-clamp technique, we
demonstrated that the voltage threshold for activation of high conductance Ca(2+)
activated K(+) channels is significantly lower in mdx than in control muscle,
suggesting a higher subsarcolemmal [Ca(2+)]. In inside-out patches, we showed
that this shift in the voltage threshold for high conductance Ca(2+)-activated
K(+) channel activation could correspond to a approximately 3-fold increase in
the subsarcolemmal Ca(2+) concentration in mdx muscle. These data favor the
hypothesis according to which an increased calcium entry is associated with the
absence of dystrophin in mdx skeletal muscle, leading to Ca(2+) overload at the
subsarcolemmal level.
PMID- 10781104
TI - The molecular physiology of heavy metal transport in the Zn/Cd hyperaccumulator
Thlaspi caerulescens.
AB - An integrated molecular and physiological investigation of the fundamental
mechanisms of heavy metal accumulation was conducted in Thlaspi caerulescens, a
Zn/Cd-hyperaccumulating plant species. A heavy metal transporter cDNA, ZNT1, was
cloned from T. caerulescens through functional complementation in yeast and was
shown to mediate high-affinity Zn(2+) uptake as well as low-affinity Cd(2+)
uptake. It was found that this transporter is expressed at very high levels in
roots and shoots of the hyperaccumulator. A study of ZNT1 expression and high
affinity Zn(2+) uptake in roots of T. caerulescens and in a related
nonaccumulator, Thlaspi arvense, showed that alteration in the regulation of ZNT1
gene expression by plant Zn status results in the overexpression of this
transporter and in increased Zn influx in roots of the hyperaccumulating Thlaspi
species. These findings yield insights into the molecular regulation and control
of plant heavy metal and micronutrient accumulation and homeostasis, as well as
provide information that will contribute to the advancement of phytoremediation
by the future engineering of plants with improved heavy metal uptake and
tolerance.
PMID- 10781105
TI - A longevity assurance gene homolog of tomato mediates resistance to Alternaria
alternata f. sp. lycopersici toxins and fumonisin B1.
AB - The phytopathogenic fungus Alternaria alternata f. sp. lycopersici (AAL) produces
toxins that are essential for pathogenicity of the fungus on tomato (Lycopersicon
esculentum). AAL toxins and fumonisins of the unrelated fungus Fusarium
moniliforme are sphinganine-analog mycotoxins (SAMs), which cause inhibition of
sphingolipid biosynthesis in vitro and are toxic for some plant species and
mammalian cell lines. Sphingolipids can be determinants in the proliferation or
death of cells. We investigated the tomato Alternaria stem canker (Asc) locus,
which mediates resistance to SAM-induced apoptosis. Until now, mycotoxin
resistance of plants has been associated with detoxification and altered affinity
or absence of the toxin targets. Here we show that SAM resistance of tomato is
determined by Asc-1, a gene homologous to the yeast longevity assurance gene LAG1
and that susceptibility is associated with a mutant Asc-1. Because both
sphingolipid synthesis and LAG1 facilitate endocytosis of
glycosylphosphatidylinositol-anchored proteins in yeast, we propose a role for
Asc-1 in a salvage mechanism of sphingolipid-depleted plant cells.
PMID- 10781106
TI - Ca2+ channels at the plasma membrane of stomatal guard cells are activated by
hyperpolarization and abscisic acid.
AB - In stomatal guard cells of higher-plant leaves, abscisic acid (ABA) evokes
increases in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) by means of Ca(2+)
entry from outside and release from intracellular stores. The mechanism(s) for
Ca(2+) flux across the plasma membrane is poorly understood. Because [Ca(2+)](i)
increases are voltage-sensitive, we suspected a Ca(2+) channel at the guard cell
plasma membrane that activates on hyperpolarization and is regulated by ABA. We
recorded single-channel currents across the Vicia guard cell plasma membrane
using Ba(2+) as a charge-carrying ion. Both cell-attached and excised-patch
measurements uncovered single-channel events with a maximum conductance of 12.8
+/- 0.4 pS and a high selectivity for Ba(2+) (and Ca(2+)) over K(+) and Cl(-).
Unlike other Ca(2+) channels characterized to date, these channels rectified
strongly toward negative voltages with an open probability (P(o)) that increased
with [Ba(2+)] outside and decreased roughly 10-fold when [Ca(2+)](i) was raised
from 200 nM to 2 microM. Adding 20 microM ABA increased P(o), initially by 63- to
260-fold; in both cell-attached and excised patches, it shifted the voltage
sensitivity for channel activation, and evoked damped oscillations in P(o) with
periods near 50 s. A similar, but delayed response was observed in 0.1 microM
ABA. These results identify a Ca(2+)-selective channel that can account for
Ca(2+) influx and increases in [Ca(2+)](i) triggered by voltage and ABA, and they
imply a close physical coupling at the plasma membrane between ABA perception and
Ca(2+) channel control.
PMID- 10781107
TI - Toc34 is a preprotein receptor regulated by GTP and phosphorylation.
AB - Most proteins present in chloroplasts are synthesized in the cytosol and are
posttranslationally translocated into the organelle. A multicomponent
translocation machinery located in both the outer and the inner envelope of
chloroplasts was identified, but the mode of action of many subunits remains
unclear. Here, we describe the regulation of an early step of translocation
occurring at the outer envelope. The outer envelope translocon subunit Toc34 can
be phosphorylated, and GTP binding is regulated by phosphorylation. In vitro,
Toc34 acts as a receptor for proteins containing a chloroplast-targeting signal.
Interaction of Toc34 with the transit peptide is highly regulated and depends on
GTP binding to Toc34 and on phosphorylation of the transit peptide of the
preprotein.
PMID- 10781108
TI - Conserved plant genes with similarity to mammalian de novo DNA
methyltransferases.
AB - DNA methylation plays a critical role in controlling states of gene activity in
most eukaryotic organisms, and it is essential for proper growth and development.
Patterns of methylation are established by de novo methyltransferases and
maintained by maintenance methyltransferase activities. The Dnmt3 family of de
novo DNA methyltransferases has recently been characterized in animals. Here we
describe DNA methyltransferase genes from both Arabidopsis and maize that show a
high level of sequence similarity to Dnmt3, suggesting that they encode plant de
novo methyltransferases. Relative to all known eukaryotic methyltransferases,
these plant proteins contain a novel arrangement of the motifs required for DNA
methyltransferase catalytic activity. The N termini of these methyltransferases
contain a series of ubiquitin-associated (UBA) domains. UBA domains are found in
several ubiquitin pathway proteins and in DNA repair enzymes such as Rad23, and
they may be involved in ubiquitin binding. The presence of UBA domains provides a
possible link between DNA methylation and ubiquitin/proteasome pathways.
PMID- 10781110
TI - Cadmium and iron transport by members of a plant metal transporter family in
Arabidopsis with homology to Nramp genes.
AB - Metal cation homeostasis is essential for plant nutrition and resistance to toxic
heavy metals. Many plant metal transporters remain to be identified at the
molecular level. In the present study, we have isolated AtNramp cDNAs from
Arabidopsis and show that these genes complement the phenotype of a metal uptake
deficient yeast strain, smf1. AtNramps show homology to the Nramp gene family in
bacteria, yeast, plants, and animals. Expression of AtNramp cDNAs increases
Cd(2+) sensitivity and Cd(2+) accumulation in yeast. Furthermore, AtNramp3 and
AtNramp4 complement an iron uptake mutant in yeast. This suggests possible roles
in iron transport in plants and reveals heterogeneity in the functional
properties of Nramp transporters. In Arabidopsis, AtNramps are expressed in both
roots and aerial parts under metal replete conditions. Interestingly, AtNramp3
and AtNramp4 are induced by iron starvation. Disruption of the AtNramp3 gene
leads to slightly enhanced cadmium resistance of root growth. Furthermore,
overexpression of AtNramp3 results in cadmium hypersensitivity of Arabidopsis
root growth and increased accumulation of Fe, on Cd(2+) treatment. Our results
show that Nramp genes in plants encode metal transporters and that AtNramps
transport both the metal nutrient Fe and the toxic metal cadmium.
PMID- 10781109
TI - Specific and heritable genetic interference by double-stranded RNA in Arabidopsis
thaliana.
AB - We investigated the potential of double-stranded RNA interference (RNAi) with
gene activity in Arabidopsis thaliana. To construct transformation vectors that
produce RNAs capable of duplex formation, gene-specific sequences in the sense
and antisense orientations were linked and placed under the control of a strong
viral promoter. When introduced into the genome of A. thaliana by Agrobacterium
mediated transformation, double-stranded RNA-expressing constructs corresponding
to four genes, AGAMOUS (AG), CLAVATA3, APETALA1, and PERIANTHIA, caused specific
and heritable genetic interference. The severity of phenotypes varied between
transgenic lines. In situ hybridization revealed a correlation between a
declining AG mRNA accumulation and increasingly severe phenotypes in AG (RNAi)
mutants, suggesting that endogenous mRNA is the target of double-stranded RNA
mediated genetic interference. The ability to generate stably heritable RNAi and
the resultant specific phenotypes allows us to selectively reduce gene function
in A. thaliana.
PMID- 10781111
TI - Some transformations of color information from lateral geniculate nucleus to
striate cortex.
AB - We have recorded the responses of single cells in the lateral geniculate nucleus
(LGN) and striate cortex of the macaque monkey. The response characteristics of
neurons at these successive visual processing levels were examined with
isoluminant gratings, cone-isolating gratings, and luminance-varying gratings.
The main findings were: (i) Whereas almost all parvo- and konio-cellular LGN
cells are of just two opponent-cell types, either differencing the L and M cones
(L(o) and M(o) cells), or the S vs. L + M cones (S(o) cells), relatively few
striate cortex simple cells show chromatic responses along these two cardinal LGN
axes. Rather, most are shifted away from these LGN chromatic axes as a result of
combining the outputs (or the transformed outputs) of S(o) with those of L(o)
and/or M(o) cells. (ii) LGN cells on average process color information linearly,
exhibiting sinusoidal changes in firing rate to isoluminant stimuli that vary
sinusoidally in cone contrast as a function of color angle. Some striate cortex
simple cells also give linear responses, but most show an expansive response
nonlinearity, resulting in narrower chromatic tuning on average at this level.
(iii) There are many more +S(o) than -S(o) LGN cells, but at the striate cortex
level -S(o) input to simple cells is as common as +S(o) input. (iv) Overall, the
contribution of the S-opponent path is doubled at the level of the striate
cortex, relative to that at the LGN.
PMID- 10781112
TI - How reliable are human phylogenetic hypotheses?
AB - Cladistic analysis of cranial and dental evidence has been widely used to
generate phylogenetic hypotheses about humans and their fossil relatives.
However, the reliability of these hypotheses has never been subjected to external
validation. To rectify this, we applied identical methods to equivalent evidence
from two groups of extant higher primates for whom reliable molecular phylogenies
are available, the hominoids and papionins. We found that the phylogenetic
hypotheses based on the craniodental data were incompatible with the molecular
phylogenies for the groups. Given the robustness of the molecular phylogenies,
these results indicate that little confidence can be placed in phylogenies
generated solely from higher primate craniodental evidence. The corollary of this
is that existing phylogenetic hypotheses about human evolution are unlikely to be
reliable. Accordingly, new approaches are required to address the problem of
hominin phylogeny.
PMID- 10781113
TI - Shared cognitive representations of perceptual and semantic structures of basic
colors in Chinese and English.
AB - Two perceptual structures (based on colors) and one semantic structure (based on
names) of eight basic chromatic colors were obtained from three judged similarity
tasks for 41 Mandarin Chinese-speaking females in Taiwan and 35 English-speaking
females in the United States. Major findings include the following: (i) there are
robust and reliable individual differences among individuals, (ii) the structures
for Chinese and English speakers are similar, and (iii) the semantic structure of
color names is similar to the perceptual structures of colors. The results place
strong constraints on theories relating to individual differences, linguistic
relativity, and the relation of perceptual and semantic structures for colors.
PMID- 10781114
TI - Recent advances in understanding the actions and toxicity of nitrous oxide.
PMID- 10781116
TI - Randomised double-blind comparison of fentanyl, mivacurium or placebo to
facilitate laryngeal mask airway insertion.
AB - In a double-blind randomised study, we compared conditions during insertion of
the laryngeal mask airway in 150 patients who received either fentanyl 1
microg.kg-1, mivacurium 0.04 mg.kg-1 or normal saline, before induction of
anaesthesia with propofol 2 mg.kg-1. Insertion conditions, including mouth
opening, swallowing, gagging or coughing, head or limb movement and ease of
insertion, were each graded using a three-point scale. The median (interquartile
range) summed insertion scores were more favourable with the use of fentanyl [8.0
(7.0-9.0)] and mivacurium [7.5 (6.8-8.3)] than with normal saline [9.0 (7.8
10.3); p < 0.01]. Fentanyl and mivacurium decreased swallowing and head or limb
movement, and mivacurium improved mouth opening. Insertion conditions were
similar between fentanyl and mivacurium, while both prolonged apnoea. Fentanyl
and mivacurium are equally effective in facilitating insertion of the laryngeal
mask airway following anaesthetic induction with propofol.
PMID- 10781115
TI - Postoperative pain control following remifentanil-based anaesthesia for major
abdominal surgery.
AB - Eighty patients undergoing major abdominal surgery using remifentanil-based
anaesthesia were randomly allocated in a double-blind manner to receive an
intravenous bolus of fentanyl, buprenorphine, morphine or piritramide 20 min
before the end of surgery. A reduced dose was administered postoperatively when
patients reported moderate pain. Subsequent analgesia was provided by patient
controlled analgesia (PCA). The mean time from the end of anaesthesia to
spontaneous respiration was 9 +/- 5 min. At first pain assessment, 63% of
patients reported no or mild pain; 80% of patients required the second opioid
bolus, those receiving piritramide needed the bolus significantly later than
patients receiving buprenorphine or fentanyl. First PCA requirement also occurred
significantly later in the piritramide group. This technique provided effective
postoperative pain relief and transition to routine PCA and did not compromise
recovery.
PMID- 10781117
TI - A prospective randomised controlled study of patient-controlled propofol sedation
in phobic dental patients.
AB - The safety and effectiveness of patient-controlled propofol sedation was
prospectively assessed in 18 healthy, phobic dental patients. Using a randomised,
crossover design each patient received two sessions of equivalent dental
treatment under patient-controlled or clinician-controlled propofol sedation. The
patient-controlled technique used 29.8% less drug (time-weighted dose) than the
clinician-controlled method (p = 0.011). There was a high correlation between
number of demands and number of doses actually infused during the patient
controlled technique (r = 0.99, p < 0. 001). Clinically, the level of sedation
was lighter and the degree of operator satisfaction was higher with patient
controlled sedation. Blood pressure and arterial oxygen saturation showed minimal
changes and remained within normal ranges during both techniques. Patient
controlled sedation produced a greater reduction in dental and general anxiety
compared with clinician-controlled sedation, but the difference did not reach
statistical significance. Three times the number of patients expressed a
preference for the patient-controlled, compared with the clinician-controlled,
technique. Patient-controlled sedation provides safe and acceptable intra
operative anxiolysis for phobic dental patients, but with reduced propofol
dosage.
PMID- 10781118
TI - Use of diclofenac in children with asthma.
AB - This study investigated the effect of diclofenac on the lung function of 70
children aged 6-15 years with a diagnosis of asthma, recruited from a hospital
respiratory clinic. Peak flow and a forced expiratory flow-volume loop were
measured and the patients were then given 1-1.5 mg.kg-1 effervescent diclofenac
orally. Spirometry was repeated at 10, 20 and 30 min, a 15% decrease in results
being considered a significant reduction in lung function. No patient
demonstrated a consistent reduction in lung function of > 15% during the study
and there were no reports of wheezing or increased bronchodilator use after
completion of the spirometry. In conclusion, we studied a group of genuine
asthmatics and found no clinically significant incidence of bronchospasm with the
use of a single therapeutic dose of diclofenac.
PMID- 10781119
TI - Emergence characteristics and postoperative laryngopharyngeal morbidity with the
laryngeal mask airway: a comparison of high versus low initial cuff volume.
AB - In this study we tested the hypothesis that the initial cuff volume of the
laryngeal mask airway influences emergence characteristics and postoperative
laryngopharyngeal morbidity. One hundred and sixty adult patients undergoing
minor surgery were randomly assigned for airway management with the laryngeal
mask airway with either a fully inflated cuff (LMA-High) or a semi-inflated cuff
(LMA-Low). Anaesthesia was with propofol, nitrous oxide, oxygen and isoflurane.
Following insertion, the cuff was inflated with either 15 or 30 ml for the size 4
(females) and 20 or 40 ml for the size 5 (males). At the end of surgery, a
blinded observer documented the presence or absence of adverse airway events
(hypoxia, hypercapnea, coughing, retching, regurgitation/vomiting, airway
obstruction, hypoventilation, hiccupping, biting, body movement or shivering)
during every 1 min epoch and cardiorespiratory variables (heart rate, mean blood
pressure, arterial oxygen saturation, end-tidal carbon dioxide and respiratory
rate) every 5 min until the patient was awake and the laryngeal mask airway
removed. Patients were interviewed about pharyngolaryngeal morbidity (sore
throat, dysphonia and dysphagia) immediately before leaving the postanaesthesia
care unit and 18-24 h following surgery. Analysis by epoch showed more partial
airway obstruction in the LMA-High group, but analysis by patient numbers
revealed no difference. Heart rate was slightly higher in the LMA-High group upon
arrival in the postanaesthesia care unit, but otherwise there were no differences
in cardiorespiratory responses. Sore throat and dysphagia were more common in the
LMA-High group. We conclude that, in general, emergence characteristics with the
laryngeal mask airway are not influenced by the volume of air used to inflate the
cuff, but that postoperative sore throat and dysphagia are more likely at high
initial cuff volumes.
PMID- 10781120
TI - The implications of HIV for the anaesthetist and the intensivist.
AB - The acquired immune deficiency syndrome has reached pandemic proportions.
Anaesthetists should be aware of the implications of dealing with increasing
numbers of both diagnosed and undiagnosed, symptomatic and asymptomatic, human
immunodeficiency virus-infected patients in the fields of intensive therapy,
operating theatre anaesthesia, obstetrics and pain management. With recent
advances, important insights have been gained into the pathogenesis of human
immunodeficiency virus. Molecular techniques allow quantification of viral
burden, and together with CD4 T-lymphocyte count, prognosis and response to
therapy can be evaluated. New drugs and therapeutic regimens have improved
prognosis for those who are infected with the virus and vertical transmission of
infection from mother to infant can be minimised. Should accidental occupational
exposure to the virus occur, a prophylactic regimen of antiretroviral drugs can
be administered in an attempt to prevent subsequent human immunodeficiency virus
infection.
PMID- 10781121
TI - Alteration in flow delivery with antisyphon devices.
AB - The aim of this study was to determine whether infusion sets containing
antisyphon devices increased the time to initial flow from syringe drivers. The
antisyphon devices assessed were those manufactured by B Braun, Wescott and
Vygon. Each device was placed between a 50-ml syringe and a spiral extension set
and primed with saline. A fourth syringe and spiral extension set acted as a
control. The infusion sets were placed in four identical syringe drivers and
started simultaneously. The time from pressing the start button until the initial
flow for each infusion set (start-up time) was recorded. The test was conducted
15 times each at 2 ml.h-1, 10 ml. h-1 and 50 ml.h-1. At 2 ml.h-1 the start-up
time was significantly longer with all the antisyphon sets compared with the
control (p < 0. 0001). At higher infusion rates the differences between the
antisyphon sets and the control were less pronounced. Clinicians who use syringe
driver infusions should be aware of this delay between the activation of the
infusion pump and the onset of flow and take steps to prevent it.
PMID- 10781122
TI - A comparison of the intubating laryngeal mask tracheal tube with a standard
tracheal tube for fibreoptic intubation.
AB - We conducted a prospective randomised study to compare the intubating laryngeal
mask tracheal tube with a standard tube, for ease of tracheal intubation over a
fibrescope. Thirty-six patients were investigated, using a sequential analysis
technique. Ease of intubation was improved when the intubating laryngeal mask
tracheal tube was used compared with the standard tube (p = 0.0009). Median
(interquartile range [range]) intubation times (time from the tube's tip being
level with the patient's teeth to successful placement) were 1.5 (1-2.3 [1-3]) s
when the intubating laryngeal mask tracheal tube was used and 5 (3-7.3 [3-13]) s
when the standard tube was used (p < 0.0001).
PMID- 10781123
TI - Laser surgery in a patient with Romano-Ward (long QT) syndrome and an automatic
implantable cardioverter defibrillator.
AB - A 48-year-old woman with Romano-Ward syndrome (a hereditary long QT syndrome),
asthma and an automatic implantable cardioverter defibrillator presented for
laser surgery for debulking of a massive nasopharyngeal tumour prior to
radiotherapy. Automatic implantable cardioverter defibrillators have only
relatively recently been used to treat patients with the long QT syndrome and are
indicated for the high-risk individual when conventional treatment has failed or
when beta-blockers are contraindicated. If surgery requires the use of surgical
diathermy, a cardiac technician must be present to deactivate the defibrillator
and external pacing electrodes are sited on the chest until the defibrillator can
be reactivated. Radiotherapy requires both deactivation and shielding of the
device.
PMID- 10781124
TI - Upper airway reflex sensitivity following general anaesthesia for day-case
surgery.
AB - We have studied changes in upper airway reflex sensitivity following general
anaesthesia using dilute ammonia vapour as a chemical stimulant in 16 patients
undergoing elective laparoscopic gynaecological surgery. We measured the
threshold concentration of ammonia vapour required to elicit a transient
reduction of inspiratory flow caused by glottic closure, defined as a glottic
stop. Measurements of upper airway reflex sensitivity and auditory reaction time
were obtained before surgery, and at 60 and 120 min after recovery. Auditory
reaction time was depressed significantly at 60 min but was similar to baseline
values 120 min after recovery. Upper airway reflex sensitivity remained
significantly reduced at 60 and 120 min despite the return of auditory reaction
time to normal. The lack of correlation between upper airway reflex sensitivity
and auditory reaction time suggests that central nervous system depression alone
does not explain the delayed recovery in airway reactivity.
PMID- 10781125
TI - The efficacy of surgically placed epidural catheters for analgesia after
posterior spinal surgery.
AB - Posterior spinal fusion for correction of scoliosis is a major procedure for
which the provision of satisfactory, safe postoperative analgesia is often a
problem. One possible solution involves the placement of epidural catheters under
direct vision by the surgeon at the end of the procedure, followed by an epidural
infusion of local anaesthetic with or without an opioid. Despite its simplicity,
this technique has not been reported as being consistently successful. We report
an observational study of the analgesia achieved with surgically placed epidural
catheters and of the reasons for the failure of the technique. Fourteen
consecutive patients undergoing posterior spinal fusion had epidural catheters
placed by the surgeon and had radio-opaque dye injected down the catheter 15 min
before their routine postoperative chest X-ray. Analgesia was assessed at 0, 6,
12 and 24 h after surgery using visual analogue scores. Five patients had
inadequate pain control; none of these patients had dye visible in the epidural
space. Seven patients had dye visible in the epidural space; all of these cases
had satisfactory analgesia. In two cases, dye was observed in the paravertebral
gutters; both of these patients had satisfactory postoperative analgesia. This
small pilot study suggests that correctly placed 'surgical' epidural catheters
are capable of providing good analgesia after posterior spinal fusion and that
misplaced catheters, seen in a large proportion of patients, are associated with
inadequate analgesia.
PMID- 10781126
TI - An independent assessment of a supraregional pain management programme and
comparison of patients' and general practitioners' perceptions of the effects.
AB - This study was designed to evaluate the therapeutic response, as perceived by
patients and their general practitioners, to a supraregional residential pain
management programme (INPUT). Twenty patients who completed the INPUT programme
and their general practitioners, were sent locally designed questionnaires.
Eighteen patients and 16 general practitioners responded. Patients were assessed
for the effects of the programme on a wide variety of treatment targets
reflecting quality of life. General practitioners were questioned about changes
in dependence upon healthcare services. The mean time from attending INPUT to
assessment was 11.4 (5.7) months. Thirteen patients indicated a moderate or
maximal improvement in quality of life. General practitioners reported a reduced
use of healthcare services and improvement in quality of life. The majority of
our patients attending INPUT gained benefits that improved their quality of life.
Healthcare services appeared to benefit from the patients' greater independence
in managing their symptoms.
PMID- 10781127
TI - Intra-ocular pressure and haemodynamic changes after tracheal intubation and
extubation: a comparative study in glaucomatous and nonglaucomatous children.
AB - This prospective, controlled study was conducted to compare the effects of
tracheal intubation and extubation on intra-ocular pressure changes and
haemodynamic parameters in paediatric patients with and without glaucoma. The
children were scheduled for intra-ocular surgery. Twenty children with normal
intra-ocular pressure and 15 with glaucoma were studied. A standardised general
anaesthetic was administered to both groups. After 5 min of anaesthesia, intra
ocular pressure, heart rate and noninvasive blood pressure were measured. These
measurements were repeated 30 s and 2 min after tracheal intubation. Further
measurements were taken before, and 30 s and 2 min after extubation. The increase
in intra-ocular pressure after intubation was greater in the glaucomatous group
than in the normal group. The increase in intra-ocular pressure was greater after
extubation than intubation in both groups, but was similar in the two groups.
However, because of the already increased intra-ocular pressure in glaucomatous
children, they may be at an increased risk of visual damage after intubation and
extubation.
PMID- 10781128
TI - The relationship between change in blood pressure, blood pressure and time.
AB - Physiological homeostatic mechanisms and interventions by anaesthetists attempt
to moderate excessive change in many biological variables during anaesthesia.
These mechanisms may have fast or slow response times. This study describes how
mean arterial blood pressure changes with time and how the change is dependent
upon the pre-existing blood pressure. The results demonstrate the 'regression
towards the mean' concept; low arterial blood pressures increase and high
pressures decrease. The data are the result of all interactions and have been
used to produce an 'envelope' into which 80% of all changes fall. Alarm systems
using this envelope could warn of excessive changes that occur within short time
intervals.
PMID- 10781129
TI - Visible and occult blood contamination of laryngeal mask airways and tracheal
tubes used in adult anaesthesia.
AB - The purpose of this study was to compare visible and occult blood contamination
of 50 laryngeal mask airways and 50 tracheal tubes following routine anaesthesia
for procedures not involving the oropharyngeal or nasal cavities. All airway
devices were examined visually for the presence of blood before washing in 100 ml
of water. A semiquantitative dipstick was used to test for the presence of blood
in the washings. Laryngeal mask airways were examined visually by both authors to
test agreement. The results show that occult blood contamination occurred in 78%
of tracheal tubes and 76% of laryngeal mask airways, while visible blood
contamination was 16% and 12%, respectively. Other studies reporting visible
blood contamination of airway devices probably underestimate the true incidence
of blood contamination. Oral secretions following the use of these devices should
be considered as high risk for transmission of blood-born viruses. Anaesthetic
and recovery staff should be protected against the risks of occupational exposure
to oral secretions following the use of airway devices.
PMID- 10781130
TI - The role of anaesthetists as peri-operative physicians.
PMID- 10781131
TI - Early detection of patients at risk (PART)
PMID- 10781132
TI - Temporary occlusion of a persistent tracheocutaneous fistula during anaesthesia.
PMID- 10781133
TI - Upper airway obstruction secondary to a lingual tonsil.
PMID- 10781134
TI - Percutaneous dilational trachestomy in the morbidly obese.
PMID- 10781135
TI - A novel approach to inspiratory vocal cord dysfunction.
PMID- 10781136
TI - The role of the Combitube in airway management.
PMID- 10781137
TI - The tracheal tube 'pull-back' test.
PMID- 10781138
TI - Right- or left-handed laryngoscopy?
PMID- 10781139
TI - Delayed extubation facilitated with the use of a laryngeal mask airway (LMA) on
the intensive care unit (ICU)
PMID- 10781140
TI - Posture and ventilator associated pneumonia.
PMID- 10781142
TI - Haemodynamic instability with iodinated contrast agents.
PMID- 10781143
TI - Hyperkalaemia and rapid blood transfusion.
PMID- 10781144
TI - Use of a pleurogram to identify the position of a misplaced subclavian catheter.
PMID- 10781145
TI - Accidental intraperitoneal insertion of femoral haemodialysis catheter in tense
ascites and anasarca.
PMID- 10781146
TI - Control of tracheal cuff pressure.
PMID- 10781149
TI - Anaesthetic machines vs. draw-over apparatus.
PMID- 10781150
TI - Emergency drugs.
PMID- 10781151
TI - FW-537-1 fluid warmer.
PMID- 10781153
TI - Presentation of 0.167% bupivacaine in 500-ml bags.
PMID- 10781155
TI - Poor interlock safety with datum sevoflurane vaporisers.
PMID- 10781157
TI - Simple apparatus for continuous nebulisation of prostacyclin.
PMID- 10781158
TI - Anaesthetic preassessment clinics.
PMID- 10781159
TI - Inadequate training? Perhaps not!
PMID- 10781160
TI - Caesarean section in a patient with Engelmann's disease.
PMID- 10781162
TI - Clinical efficacy of anti-emetics following surgery.
PMID- 10781164
TI - Cerebrospinal fluid filtration for treating Guillain-Barre syndrome: is there any
pathological background?
PMID- 10781165
TI - Remifentanil infusions for cardiac and vascular anaesthesia.
PMID- 10781166
TI - Faking unconsciousness.
PMID- 10781167
TI - Pain relief post craniotomy: a balanced approach?
PMID- 10781168
TI - Pain relief in children after neurosurgery.
PMID- 10781169
TI - The 'Sevophone' for induction of children.
PMID- 10781170
TI - New method for assessing sensory blockade.
PMID- 10781171
TI - Avoiding air emboli during pressure infusion.
PMID- 10781172
TI - More painful spikes.
PMID- 10781173
TI - Syringe labels using an empty drug ampoule.
PMID- 10781174
TI - Dystrophia myotonica.
PMID- 10781175
TI - Hypoxia caused by body piercing.
PMID- 10781176
TI - Nip - ple.
PMID- 10781177
TI - Wonderful wonderful Copenhagen?
PMID- 10781178
TI - Facts and future lines of research in lower urinary tract symptoms in men and
women: an overview of the role of alpha1-adrenoreceptor antagonists.
PMID- 10781179
TI - alpha1-adrenergic receptors in the lower urinary tract and vascular bed:
potential role for the alpha1d subtype in filling symptoms and effects of ageing
on vascular expression.
PMID- 10781180
TI - Mode of action of alpha1-adrenoreceptor antagonists in the treatment of lower
urinary tract symptoms.
PMID- 10781181
TI - A detailed description, by age, of lower urinary tract symptoms in a group of
community-dwelling women.
PMID- 10781183
TI - New developments in the pharmacological management of prostate cancer.
PMID- 10781182
TI - Current view and status of the treatment of lower urinary tract symptoms and
neurogenic lower urinary tract dysfunction.
PMID- 10781184
TI - Target sites for manipulating apoptosis in prostate cancer.
PMID- 10781185
TI - The role of endothelin-1 and endothelin receptor antagonists in prostate cancer.
PMID- 10781187
TI - The world federation of hemophilia
PMID- 10781186
TI - Facts and future lines of research in prostate cancer: concluding remarks.
PMID- 10781188
TI - Hemophilia 2000 in Montreal; bringing the global haemophilia community together
PMID- 10781189
TI - Controlling acute bleeding episodes with recombinant factor VIIa in haemophiliacs
with inhibitor: continuous infusion and bolus injection.
AB - The efficacy of recombinant activated factor VII (rFVIIa, NovoSeven) in five
Haemophiliacs (four Haemophilia A, one Haemophilia B), with high inhibitors
ranging from 70 to 1900 Bethesda units, was evaluated. The treatment regimen was
divided into two groups: group I, continuous infusion of 16.5 microg h-1 kg-1
body weight (bw) after the initial bolus of 90 microg kg-1 bw in three episodes
of severe bleeding and group II, bolus injection 80-150 microg kg-1 bw every 3
hours for a maximum of four doses in six haemarthroses. The bleeding was
effectively controlled within 1 to 48 h in five of nine bleeding episodes. One
patient in group I, who had active arterial bleeding requiring sutures, had an
ineffective response and three patients in group II had partially effective
responses because the rFVIIa was given after the onset of bleeding at 36, 44 and
72 h, respectively. The prothrombin time was shortened and the FVII:C levels were
successfully achieved at approximately 10 U mL-1. The continuous infusion reduced
the total dose of rFVIIa by 50%. Recurrent bleeding episodes were found in three
patients; two occurred at the same site after ceasing rFVIIa for 51 h and while
receiving rFVIIa at 144 h and one occurred at a new site after ceasing rFVIIa for
12 h. Our experience would suggest that rFVIIa is effective in controlling acute
bleeding episodes in Haemophiliacs with high inhibitors either by continuous
infusion or bolus injection.
PMID- 10781190
TI - The use of central venous catheters (portacaths) in children with haemophilia.
AB - The experience with central venous implantable devices (portacaths) has been
reviewed in children attending the Auckland Hospital Haemophilia Centre. Fourteen
children had 23 portacaths inserted. Thirteen had severe Haemophilia A, of whom
five had high responding inhibitors to factor VIII. All the children were HIV
negative. Ages ranged from 4 months to 13 years at the time of initial placement
and 12 were under 5 years. Indications for portacath placement included primary
and secondary prophylaxis, induction of immune tolerance, prophylactic therapy
post intracranial haemorrhage and poor venous access. Catheter-related infections
occurred in 48% of cases. Staphylococcal species were the most common organisms
isolated followed by gram-negative bacilli. 63% of the infections were
successfully cleared with antibiotics. Haematoma formation occurred in 17% of
catheters, primarily in patients who had high factor VIII inhibitor levels.
Mechanical problems including blockage, leakage and extrusion of the portacath
occurred less frequently (13%). The significant rate of infection in this
immunocompetent population is consistent with other reports. Despite the obvious
benefits of portacaths this complication is potentially serious and causes
appreciable morbidity. In contrast, bleeding complication rates were relatively
low.
PMID- 10781191
TI - Optimising local therapy during oral surgery in patients with von Willebrand
disease: effective results from a retrospective analysis of 63 cases.
AB - Bleeding after dental extractions is very frequent in patients with von
Willebrand disease (vWD) and in the past often necessitated transfusions with
factor VIII/von Willebrand factor concentrates (vWFc). To evaluate the benefits
of a standard local therapy on bleeding complications during oral surgery, 63
consecutive patients with vWD were analysed retrospectively. All types of vWD
were included: type 1 (n=31), type 2 (n=22) and type 3 (n=10). All the patients
had dental extractions or periodontal surgery at the same hospital by the same
oral surgeons. All cases had been given tranexamic acid (TA) before and for 7
days after surgery. As additional local therapy fibrin glue (FG) was used during
surgery in several patients. Additional systemic therapies were: desmopressin
(DDAVP, 0.3 microg kg-1) and fVIII/vWF concentrates (vWFc, 40 U kg-1) given as a
single dose before surgery. The 29 subjects (46%) treated locally did not bleed.
Among the remaining cases, 24 (38%) were given DDAVP as additional systemic
therapy and 6 (9.5%) received vWFc. There was bleeding after surgery in only two
cases who had been given local FG (type 2 B) or systemic vWFc (type 3), but
bleeding was stopped with an additional local application of FG. Our data suggest
that a standard local therapy with TA and FG with DDAVP can prevent bleeding
complications during oral surgery in the majority of patients (84%) with vWD and
reduce the need for concentrates, with all their possible complications and high
costs.
PMID- 10781193
TI - Cardiac surgery and catheterization in patients with haemophilia.
AB - The present study summarizes the results of 12 cardiac surgical procedures
performed in a carrier of Haemophilia B and in six patients with Haemophilia A at
a single centre from 1979 to 1998. The median age of the patients at the time of
intervention was 56 years ranging from 18 years to 73 years. The six patients
with Haemophilia A ranged in severity from moderately to mildly affected. Three
patients were hepatitis C antibody positive. No patients were HIV antibody or
hepatitis B surface antigen positive. The cardiac procedures included cardiac
catheterization (n=4), coronary artery bypass surgery (n=2), percutaneous
transluminal coronary angioplasty (n=1), cardiac valve replacement (AVR n=1 and
AVR/MVR n=2), and closure of an atrial septal defect and subsequent drainage of a
pericardial effusion (n=1). No patients had demonstrable inhibitors at the time
of surgery. Haemostasis was achieved with AHF in 10/11 procedures and high purity
factor IX (Immunine) in one procedure. The initial procedures involved
intermittent bolus factor therapy while more recently, AHF was administered by
continuous intravenous infusion. All patients demonstrated excellent intra- and
post-operative haemostasis. These results, although from a small and varied group
of patients, demonstrate that cardiac surgical procedures can be performed safely
in patients with Haemophilia.
PMID- 10781192
TI - Acquired haemophilia - a study of ten cases.
AB - Clinico-haematological features in 10 patients with acquired Haemophilia are
presented. Three patients had FVIII inhibitors following pregnancy while in six
the cause for development of inhibitors could not be determined. One patient had
acquired von Willebrand's disease. Lupus anticoagulant coexisted with Factor VIII
inhibitors in three patients. All patients presented with sudden onset of
bleeding without any past or family history of a bleeding disorder. Factor VIII
inhibitor levels ranged from 8 to 512 Bethesda units in the nine patients.
Immunosuppressive therapy was given to 8 patients, consisting of CVP regimen or
corticosteroids with endoxan or cyclosporin. Seven patients had clinical and
laboratory responses and one patient did not respond. One patient had severe
postpartum bleeding with acute shock which was controlled with FEIBA. Diagnosis
and management of idiopathic acquired Haemophilia, thus, continues to be a major
challenge, and among acquired Haemophilia, postpartum Haemophilia has good
prognosis.
PMID- 10781194
TI - Loss of factor VIII activity during storage in PVC containers due to adsorption.
AB - Recombinant factor VIII concentrates are stable when administered in a
reconstituted form according to the manufacturer's specifications, and undiluted
via infusion with syringe mini-pumps. However many Haemophilia centres administer
recombinant factor VIII further diluted in intravenous fluids for greater ease of
administration. To investigate the stability of recombinant factor VIII during
administration as a diluted infusion, reconstituted factor VIII was stored in
polyvinylchloride (PVC) mini-bags undiluted (146 IU mL-1) and at factor VIII
concentrations of 10 IU mL-1 and 2 IU mL-1. After 48 h of storage at room
temperature in PVC mini-bags, the recoveries of factor VIII activity were 41.9%
of the initial activity for the undiluted (146 IU mL-1) product and 43.7% of the
initial activity for factor VIII diluted to 10 IU mL-1. For factor VIII diluted
to 2 IU mL-1, the amount of factor VIII activity remaining at 48 h was only 1.8%
of the initial activity. In contrast, 100% of factor VIII activity was recovered
after 48 h when undiluted reconstituted product (146 IU mL-1) was stored in a
syringe. To investigate the mechanism of factor VIII activity loss during
storage, factor VIII samples collected after 0, 3 and 48 h of storage were
analysed by immunoblotting with factor VIII antibodies. No evidence of factor
VIII proteolytic degradation during storage was found, however, large amounts of
factor VIII antigen were recovered from the empty PVC mini-bags following elution
with denaturing detergent. We conclude that clinically significant losses of
factor VIII activity occur during storage in PVC mini-bags and that the loss of
activity is most likely due to protein adsorption onto the plastic surface. This
loss of factor VIII activity during storage in PVC containers may substantially
affect the safety and potential cost savings of administering recombinant factor
VIII by continuous infusion.
PMID- 10781195
TI - Prevalence of human parvovirus B19 and TT virus in a group of young haemophiliacs
in South Africa.
AB - A well recognized hazard of transfusion with blood or blood products is the
acquisition of a viral infection. Parvovirus B19 and transfusion transmitted
virus (TTV) are two of several non-enveloped viruses that may on rare occasions
be present in coagulation factor concentrates. The prevalence of these viruses in
the South African Haemophilia population has not previously been studied. Thirty
nine Haemophiliac children were investigated for evidence of parvovirus and TTV
infection. 26 boys with Haemophilia A had been treated with cryoprecipitate or
intermediate purity factor VIII, and 13 boys with Haemophilia B had received
prothrombin complex concentrates. All the plasma products were prepared from
South African donors and were virally inactivated by heat or solvent/detergent
since 1992. A control group of 32 children who had not been transfused were also
studied. IgG antibodies to B19 were present in 29 of the 39 patients (74%), 18/26
(69%) with Haemophilia A and 12 of the 13 (85%) with Haemophilia B. None of the
patients was IgM antibody positive but two children were PCR positive for B19
DNA. Of the control children, 47% had IgG antibodies to B19, but none were IgM
antibody or B19 DNA positive. TTV viral DNA was found in 10.2% of patients and in
9% of the control group. The results indicate that our locally produced plasma
products are not a significant source of TTV transmitted infection but may
contribute to infection by B19 parvovirus.
PMID- 10781196
TI - Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with
haemophilia.
AB - Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection
through exposure to blood products. Havrix(R), an intramuscular hepatitis A
vaccine, is currently recommended for the prevention of disease caused by
hepatitis A virus. Because bleeding may complicate intramuscular injections in
those with bleeding disorders, we conducted a randomized, Phase IV clinical trial
to compare the safety and immunogenicity of Havrix(R) given by the subcutaneous
(s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia
were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were
vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6
months. All children were anti-HAV and anti-HIV negative at baseline, and the
haemophilic group did not differ from their siblings in alanine aminotransferase
(ALT; 25 IU L-1 vs. 22 IU L-1), or in age; 8.5 years vs. 8.7 years. The vaccine
was well tolerated, with minor adverse events being similar between groups; 21
(47%) vs. 24 (58%), P > 0.05. Local symptoms included soreness in 39 (45%),
erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no
differences between groups. The proportion seroconverting to anti-HAV IgG
positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at
month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre
was lower in those with Haemophilia, 185 vs. 233 mIU mL-1 at month 1; 68 vs. 94
mIU mL-1 at month 6; and 584 vs. 1082 mIU mL-1 at month 8, respectively. We
conclude that Havrix(R) is safe and immunogenic when administered s. c. in
children with Haemophilia.
PMID- 10781197
TI - Orthopaedic outcome of total knee replacement in haemophilia A.
AB - A consecutive series of 16 patients with classical Haemophilia underwent 21 total
knee replacements between 1989 and 1997 for haemophilic arthropathy. The patients
received Factor VIII replacement therapy via continuous infusion, and fibrin glue
was used to facilitate haemostasis. Three different types of prostheses were
used. A follow-up evaluation was undertaken between 2 and 10 years after the
operation (mean 5.6 years) and two patients with infection were excluded. Knee
scores averaged 77.5 (pre-operative 24. 1) and functional scores averaged 84.4
(preoperative 23.2). There were no cases with aseptic loosening of the
prosthesis. Complications included one early deep infection controlled by
conversion of the TKR into an arthrodesis, one case of late septic loosening that
had to be re-operated upon, one case of patellar dislocation, two cases of stiff
knee (fibro-arthrosis) that required manipulation under anaesthesia, one
postoperative hepatitis, one superficial infection treated by incision and
drainage and four febrile patients with no clear source of infection, who
responded to antibiotics alone. In conclusion, TKR offers haemophilic patients a
long-lasting improvement of their quality of life and we therefore advocate its
use with the appropriate indications.
PMID- 10781198
TI - Bell's palsy during interferon therapy for chronic hepatitis C infection in
patients with haemorrhagic disorders.
AB - Two adult patients with life-long severe haemorrhagic disorders commenced on
interferon-alpha2b therapy for chronic hepatitis C infection. Both developed
Bell's palsy several weeks after commencing therapy, They were started on
steroids and, in addition, the first patient discontinued interferon-alpha2b
therapy while the second patient elected to continue with therapy. In both cases
facial paralysis improved over the ensuing weeks. Bell's palsy is often
idiopathic but has been reported. in association with herpesviruses. It is not a
recognised complication of chronic hepatitis B or C infection, or interferon
alpha2b therapy. However, the interferons are associated with numerous adverse
reactions including various neuropsychiatric manifestations and neurological
syndromes. There are several reports of nerve palsies, including optic tract
neuropathy, occurring during interferon therapy, and immune-based mechanisms are
thought to play a role in the aetiopathogenesis. No reports of Bell's palsy in
association with interferon therapy were identified in our literature search,
although one possible case has been reported to the Committee of Safety in
Medicine. Although Bell's palsy in our patients may have occurred by chance, a
neuropathic effect of interferon-alpha2b on the facial nerve cannot be excluded
and we urge physicians using interferons to be aware of this potential side
effect.
PMID- 10781199
TI - High responding factor VIII inhibitors in mild haemophilia - is there a link with
recent changes in clinical practice?
AB - The development of high responding inhibitors is an increasingly recognized
complication of mild Haemophilia. Inhibitors tend to develop in adolescence and
adulthood and this is frequently preceded by high-intensity factor replacement
therapy. We report two patients with mild Haemophilia who developed high
responding inhibitors after continuous infusion with recombinant factor VIII
(Kogenate) as prophylaxis for surgery. We discuss whether recent changes in
clinical practice could be responsible for the apparent increase in high
responding inhibitors in mild Haemophilia.
PMID- 10781201
TI - Pitfalls in the management of a child with mild haemophilia A and a traumatic
hyphaema.
AB - A 12-year-old boy presented with a traumatic hyphaema that failed to settle with
the standard treatment. Subsequent investigation showed that despite a normal
APTT, he had a low factor VIII:C. Treatment with DDAVP precipitated further
bleeding despite correction of the fVIII:C to normal, possibly caused by the
vasodilation induced by the therapy. Bleeding was effectively treated with
recombinant fVIII concentrate. DDAVP may be contraindicated in mild Haemophilia
and von Willebrand patients for treatment of traumatic hyphaema.
PMID- 10781200
TI - HAART and Mycobacterium avium complex in an HIV infected patient with severe
factor VII deficiency.
AB - A clinical syndrome represented by the association of Mycobacterium avium complex
(MAC) infection with initiation of highly active antiretroviral therapy (HAART)
has been recently described in patients with advanced HIV disease. HAART
associated improvement of the immune status might convert a clinically silent MAC
infection into an active mycobacterial disease. A 40-year-old man with severe
factor VII deficiency, advanced HIV-1 disease, a CD4 + lymphocyte count of 15
cells microL-1 (CDC stage A3) and 470,000 HIV-RNA copies mL-1 (measurement by
NASBA system) underwent standard HAART (lamivudine, stavudine and ritonavir). Two
weeks after HAART onset, the patient developed enlargement of the lymph nodes
throughout the mesentery and after seven weeks a rapidly enlarging mass on the
left side of the neck. Culture from a needle aspirate specimen revealed MAC. His
CD4 + count had increased to 97 cells microL-1 and viraemia dropped to
undetectable HIV-RNA copies. While continuing antiviral therapy, multidrug
therapy for MAC infection (clarithromycin, ciprofloxacin, ethambutol, amikacin)
was started with progressive improvement and cure of the neck mycobacterial
infection and disappearance of the abdominal lymph nodes. HAART has been shown to
offer significant clinical and laboratory benefits in terms of HIV disease with
limited side-effects in Haemophiliacs. However, the clinical manifestation of an
opportunistic infection should be mentioned as a possible complication of HAART
in these patients, as well as in other categories of HIV infected patients, and
in patients with congenital coagulopathies.
PMID- 10781202
TI - High titre inhibitor after continuous factor VIII administration for surgery in a
young infant.
PMID- 10781203
TI - Images of absolute retardance L.Deltan, using the rotating polariser method
AB - Modulation techniques for measuring changes in optical birefringence, such as the
rotating-polariser method (Wood & Glazer, 1980, J. Appl. Crystallogr. 13, 217),
allow one to determine |sin delta|, delta = 2piLDeltan/lambda, Deltan = double
refraction, L = light path and lambda = wavelength. However, they generally
suffer from not providing absolute values of the optical retardance or are
limited to relatively low retardance values. In addition, knowledge of the
absolute phase is required when establishing the correct values of optical
orientation information. In this paper, it is shown how the phase delta, and thus
optical retardance, can be extracted from combining measurements of |sin delta|
at different wavelengths. The new approach works on each single point of a 2-D
picture without the need to correlate with neighbouring points. There is
virtually no limit to the retardance, and the computational efforts are small
compared with other methods (e.g. Ajovalasit et al. 1998, J. Strain Analysis 33,
75). When used with imaging techniques, such as the rotating polariser method of
Glazer, Lewis & Kaminsky 1996 (Proc. R. Soc. London Series A452, 2751) this
process has the potential to identify automatically optically anisotropic
substances under the microscope. The algorithm derived in this paper is valid not
only for birefringence studies, but can be applied to all studies of interfering
light waves.
PMID- 10781204
TI - Bituminous emulsions and their characterization by atomic force microscopy
AB - We present a new method for observing oil-in-water emulsions with a continuous
water phase and a dispersed bitumen phase. The fine polydispersed bitumen
micelles were adsorbed to an atomically smooth mica substrate and imaged in
solution by atomic force microscopy in a liquid cell. The height of the adsorbed
bitumen sheet in wet and dry states can be measured and the homogeneity of film
formation by coalescence can be determined. Localization of surfactant onto and
between bitumen micelles is also visualized.
PMID- 10781205
TI - The spatial distribution and resolution of coaxial backscattered electrons in
SEM, calculated by monte carlo simulations
AB - We simulate, within a sample, the trajectories of the backscattered electrons
detected in a scanning electron microscopy with a particular detection geometry.
Thus we obtain the depth and lateral distributions, according to the adjustable
parameter values, of the detected electrons. Finally, the scanline profile across
a chemical edge is drawn. The conditions corresponding to the best lateral
resolution are established; we obtain an ultimate resolution of the same order as
the beam diameter.
PMID- 10781206
TI - The reliability of cryoSEM for the observation and quantification of xylem
embolisms and quantitative analysis of xylem sap in situ.
AB - The reliability of cryoSEM for visualizing gas embolisms in xylem vessels of
intact, functioning roots is examined and discussed. The possibility that these
embolisms form as a result of freezing water columns under tension is discounted
by a double-freeze experiment. Two regions of the same root, one frozen under
tension, the other isolated from the tension by the first freeze, had the same
percentage of embolisms, as did also long pieces of root frozen simultaneously
along their length. The reliability of energy-dispersive X-ray analysis to
measure xylem sap concentration in situ in frozen tissue was established by
measurement of KCl standard solution frozen on stubs, and within xylem vessels.
Solute heterogeneity within the vessels varied with freezing procedure; deep
freeze > LN2 > cryopliers > liquid ethane, but only the deep-freeze method gave
unsatisfactory estimates of concentration for the standard solution. It is
concluded that cryoanalytical SEM is useful for direct observation of gas and
liquid-filled compartments, and for solute analyses at depth within intact plant
organs.
PMID- 10781207
TI - Tracking differential interference contrast diffraction line images with
nanometre sensitivity.
AB - This paper presents a computer vision framework for detecting and tracking
diffraction images of linear structures in differential interference contrast
(DIC) microscopy. The tracker can resolve image displacements of 1/10 of a pixel
despite the weak and orientation-dependent contrast in DIC, as well as the
variable blur in such image data caused by vertical specimen movement. In our
high numerical aperture, high magnification microscope set-up, this resolution
corresponds to 5 nm in object space. In video DIC similar resolution has been
reported hitherto only for rotationally symmetric targets such as bead images.
The tracker was developed for measuring deflections of clamped microtubules with
a freely moving second end. By analysing the thermal fluctuations of such
microtubules it was possible to derive their elasticity. The paper describes a
filtering scheme for the detection and localization of DIC diffraction line
images which represent loci of microtubules. For tracking the movements of the
extracted lines we adopted the sum of squared (brightness) differences algorithm
from computer vision. The analysis of the fluctuation measurements demonstrates
the high sensitivity of this tracking technique in quantifying positional and
orientational changes. We derived that the theoretical limit in tracking
displacements of such diffraction line images is 1.25 nm, four times below the
experimentally verified sensitivity. This indicates that the proposed tracker is
still suboptimal. Nevertheless, the tracking precision was sufficient to reveal
subtle deviations in the distribution of microtubule deflection from free
diffusion. They were induced by pivotal points and multiple positions of
relaxation. Also, the results suggest that there were defects in the polymer
structure which caused very small but significant bends in the microtubule axis.
PMID- 10781208
TI - An integral-geometric approach for the euler-Poincare characteristic of spatial
images
AB - The determination of the Euler-Poincare characteristic of a set can be based on
observations of a digitized image of that set. In the present paper the
correctness of the method is proved due to a strict integral-geometric approach.
Our result also provides a link to the methods which are used in image analysis
and are based on graph theory.
PMID- 10781209
TI - The influence of the regularization parameter and the first estimate on the
performance of tikhonov regularized non-linear image restoration algorithms
AB - This paper reports studies on the influence of the regularization parameter and
the first estimate on the performance of iterative image restoration algorithms.
We discuss regularization parameter estimation methods that have been developed
for the linear Tikhonov-Miller filter to restore images distorted by additive
Gaussian noise. We have performed experiments on synthetic data to show that
these methods can be used to determine the regularization parameter of non-linear
iterative image restoration algorithms, which we use to restore images
contaminated by Poisson noise. We conclude that the generalized cross-validation
method is an efficient method to determine a value of the regularization
parameter close to the optimal value. We have also derived a method to estimate
the regularization parameter of a Tikhonov regularized version of the Richardson
Lucy algorithm. These iterative image restoration algorithms need a first
estimate to start their iteration. An obvious and frequently used choice for the
first estimate is the acquired image. However, the restoration algorithm could be
sensitive to the noise present in this image, which may hamper the convergence of
the algorithm. We have therefore compared various choices of first estimates and
tested the convergence of various iterative restoration algorithms. We found that
most algorithms converged for most choices, but that smoothed first estimates
resulted in a faster convergence.
PMID- 10781210
TI - Third joint meeting of the European Tissue Repair Society and Wound Healing
Society: an opportunity to develop worldwide wound healing strategies.
PMID- 10781211
TI - A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard
to-heal venous ulcers.
AB - The efficacy of a bilayered, living skin construct (APLIGRAF(R) [Graftskin]) was
evaluated in patients (n = 120) with hard- to-heal venous leg ulcers of greater
than 1 year's duration. The study was prospective, randomized, and controlled.
Patients received Graftskin plus compression therapy, or standard compression
therapy (active control). Patients were evaluated for frequency and time to
complete (100%) wound closure. Treatment with Graftskin was significantly more
effective than active control in the percentage of patients healed by 6 months
(47% vs. 19%; p < 0.005) and the median time to complete wound closure (p <
0.005). Analysis with multivariate regression methods, adjusting for factors
generally thought to influence wound healing (duration, baseline area, depth,
location, fibrinous wound bed, and infection), showed that patients treated with
Graftskin were twice as likely to achieve complete wound closure by 6 months (p <
0.005), and over 60% more effective in achieving wound closure than active
control (p < 0.01). These data indicate that Graftskin is an effective treatment
for venous ulcers of greater than 1 year's duration.
PMID- 10781212
TI - Systemic treatment of venous leg ulcers with high doses of pentoxifylline:
efficacy in a randomized, placebo-controlled trial.
AB - Several small studies have indicated that the systemic administration of
pentoxifylline may accelerate healing of venous leg ulcers. The goal of this
study was to further evaluate these findings in a larger scale placebo controlled
trial and to explore the effect of the dose of pentoxifylline on healing. The
study used a prospective, randomized, double-blind, parallel group placebo
controlled design in a multicenter outpatient setting. Patients with one or more
venous ulcer were enrolled, with all patients receiving standardized compression
bandaging for treatment for their ulcers. Patients were also randomized to
receive either pentoxifylline 400 mg, pentoxifylline 800 mg (two 400 mg tablets),
or placebo tablets three times a day for up to 24 weeks. The main outcome measure
was time to complete healing of all leg ulcers, using life table analysis. The
study was completed as planned in 131 patients. Patients receiving 800 mg three
times a day of pentoxifylline healed faster than placebo (p = 0.043, Wilcoxon
test). The median time to complete healing was 100, 83, and 71 days for placebo,
pentoxifylline 400 mg, and pentoxifylline 800 mg three times a day, respectively.
Over half of all patients were ulcer free at week 16 (placebo) and at week 12 in
both pentoxifylline groups. Whereas the placebo group had only achieved complete
healing in half of the cases by week 16, all of the subjects remaining in the
group receiving the high dose of pentoxifylline had healed completely. Treatment
with pentoxifylline was well tolerated with similar drop-out rates in all three
treatment groups. Complete wound closure occurred at least 4 weeks earlier in the
majority of patients treated with pentoxifylline by comparison to placebo. A
higher dose of pentoxifylline (800 mg three times a day) was more effective than
the lower dose. We conclude that pentoxifylline is effective in accelerating
healing of leg ulcers.
PMID- 10781213
TI - A modified culture system for epidermal cells for grafting purposes: an in vitro
and in vivo study.
AB - A fully differentiated epithelium mimicking the features of native epidermis was
obtained in vitro by culturing human or porcine epidermal keratinocytes on
polyester filter substrate at the air-liquid interface. In addition, after 2
weeks of culture, hemidesmosome-like structures were formed along the basal area
of the plasma membrane of the basal cells at the cell-filter interface. When
grafted onto full-thickness skin wounds in pigs, the take of cell sheets detached
from the filter with dispase was significantly higher (about 70%) in comparison
to mechanically detached keratinocytes (about 15%). With dispase-treated
keratinocytes alone, basement membrane formation took place within 7 days
postgrafting as judged from the presence of a lamina lucida and positive staining
for type IV collagen. Also, numerous hemidesmosomes and anchoring fibrils were
observed at the basal cell-"neodermis" interface. The fully differentiated
epidermis, generated by culturing keratinocytes at the air-liquid interface and
detached from the substrate by dispase-treatment, is less fragile and easier to
handle than epidermal autografts obtained by conventional culturing methods.
Detachment by a short dispase-treatment appeared in our hands the only method for
successful and complete epithelial regeneration in full-thickness wounds.
PMID- 10781214
TI - Incubation of cultured skin substitutes in reduced humidity promotes
cornification in vitro and stable engraftment in athymic mice.
AB - Cultured skin substitutes have been used successfully for adjunctive treatment of
excised burns and chronic skin wounds. However, limitations inherent to all
models of cultured skin include deficient barrier function in vitro, and delayed
keratinization after grafting in comparison to native skin autografts.
Experimental conditions for incubation of skin substitutes were tested to
stimulate barrier development before grafting, and measure responses in function
and stability after grafting. Cultured skin substitutes consisted of human
keratinocytes and fibroblasts attached to collagen-glycosaminoglycan biopolymer
substrates. Parallel cultured skin substitutes were incubated at the air-liquid
interface in ambient (48-61%) or saturated (79-91%) relative humidity, and
grafted to athymic mice on culture day 14. Additional cultured skin substitutes
were incubated in the experimental conditions for a total of 28 days. Cadaveric
human skin and acellular biopolymer substrates served as controls. Epidermal
barrier was evaluated as the change in surface hydration by surface electrical
capacitance with the NOVA Dermal Phase Meter. Cultured skin substitutes and
cadaveric skin incubated in ambient humidity had lower baseline surface
electrical capacitance and less change in surface electrical capacitance than
parallel samples incubated in saturated humidity at all time points in vitro.
Data from healing cultured skin substitutes at 2, 4, 8 and 12 weeks after
grafting showed an earlier return to hydration levels comparable to native human
skin, and more stable engraftment for skin substitutes from ambient humidity. The
data indicate that cultured skin substitutes in ambient humidity have lower
surface electrical capacitance and greater stability in vitro, and that they
reform epidermal barrier more rapidly after grafting than cultured skin
substitutes in saturated humidity. These results suggest that restoration of
functional epidermis by cultured skin substitutes is stimulated by incubation in
reduced humidity in vitro.
PMID- 10781215
TI - Assessment of the potential for microbial resistance to topical use of multiple
antimicrobial agents.
AB - The goal of this study was to reduce the likelihood of the generation and/or
persistence of bacterial resistance to some antimicrobial components contained in
a topical antimicrobial mixture (neomycin, polymyxin B, mupirocin and
ciprofloxacin) for use with cultured skin grafts, by substitution of alternative
antimicrobials, specifically fusidic acid for mupirocin and ofloxacin for
ciprofloxacin. The alternative agents failed to serve that purpose. However, with
the exception of specific genera of bacteria, Proteus sp. and Providencia
stuartii, 90% or more of all other bacteria tested were susceptible to the action
of one or more of the individual antimicrobial agents contained in the original
mixture. This was true when bacteria were highly susceptible to the
antimicrobials, generally, or when bacteria resistant to specific antimicrobials
such as penicillin-class antibiotics and ciprofloxacin, were tested. These
results suggest that the redundancy of antimicrobials contained in this mixture
reduces the chance that resistant bacteria generated by the use of this mixture
or already present on wounds would persist when the mixture is used clinically.
PMID- 10781216
TI - Reader response to Carroll's "To be a nurse"
PMID- 10781217
TI - Reader response to Carroll's "To be a nurse"
PMID- 10781218
TI - Deadly secrets.
PMID- 10781219
TI - Intensive challenges down the road: pioneering a pathway to the future.
PMID- 10781220
TI - Screening for domestic violence during pregnancy.
AB - Domestic violence is an international social issue and significant cause of
trauma. Pregnant women are at risk for intentional trauma and pose unique
challenges for care. Patients are often not truthful about the mechanism of
injury and are reluctant to seek care. Prenatal and postpartum care can be
adversely affected if the woman continues in the abusive relationship. A careful
approach to screening all pregnant trauma patients is presented to help
clinicians with assessment for intentional trauma.
PMID- 10781221
TI - The implications of domestic violence for home care providers.
AB - The effects of domestic violence are revealed in shelters for battered women, but
with more emphasis on prevention, cues to violence may first be detected in home
settings. The most common injury sites involve the upper body. Based on a 2-year
record (N = 153) review at a shelter for battered women, prevalence of injuries,
health conditions and substance use were examined. Most women (82%) reported
injuries, and most had past injuries severe enough to require surgery or
hospitalization. This article educates home care providers about the types of
abuse they are likely to find in women from violent homes and their health
implications.
PMID- 10781222
TI - Child passenger safety.
PMID- 10781223
TI - Screening a simple fracture.
PMID- 10781224
TI - Crash testing: using computers to save lives.
PMID- 10781225
TI - Complications related to the use of vascular hemostasis devices.
PMID- 10781226
TI - Intimate partner violence fact sheet.
PMID- 10781228
TI - Another Woman.
PMID- 10781227
TI - Abstracts of the Literature.
PMID- 10781229
TI - Current controversies in diagnosis and management of neonatal seizures.
PMID- 10781230
TI - Polymerase chain reaction in the diagnosis of tuberculosis.
AB - OBJECTIVES: To evaluate efficacy of polymerase chain reaction (PCR), using the
insertion sequence IS6110 as target for DNA, to detect Mycobacterium tuberculosis
in body fluids of children with suspected tuberculosis (TB). SETTING:
Hospitalized patients. METHODS: A comparison of PCR on body fluids, Acid Fast
Bacilli staining (AFB), mycobacterial culture and clinical features, with special
emphasis on central nervous system (CNS) TB was done over 18 month period. A
total of 80 children were evaluated, 41 with probable TB disease and 39 controls.
Cases were defined by specific clinical criteria. Controls included patients free
of clinical TB. PCR was done on the clinical specimens and compared with clinical
findings, radiological features, Mantoux (Mx) testing, AFB staining and culture
on Lowenstein-Jensen (LJ) medium. RESULTS: Sensitivity of PCR in CSF samples was
100%, in gastric aspirate samples was 20% and in pleural fluid samples was 100%.
CONCLUSION: PCR technique may become a valuable diagnostic tool for the diagnosis
of tuberculosis in children especially in CNS TB.
PMID- 10781232
TI - Epidemiology of sickle cell disease in a rural hospital of central India.
AB - OBJECTIVE: To study the epidemiology of sickle cell disease in pediatric age
group in a rural hospital of Central India. DESIGN: Prospective descriptive
hospital based study. SUBJECTS: 99 admitted patients of sickle cell disease were
studied for a period of 1 year. RESULTS: Prevalence of sickle cell disease was
5.7% (99/1753) hospitalizations of which 61.6% (n=61) had homozygous sickle cell
disease (HbSS) whereas 38.4% (n=38) had heterozygous state (HbAS). Of these, 62
(63%) were below five years of age. Male : Female ratio was 1.65:1 in HbSS cases
and 1.71:1 in HbAS cases. History of consanguinity was present in 7 (7%) of which
5 (8.2%) had HbSS and 2 (5.2%) had HbAS. Incidence was maximum in the Mahar
community (70%) followed by Kunbi (8 %) and Teli (6%). Vascular occlusive crisis
(23. 3%) was the commonest crisis encountered followed by hyperhemolytic crisis
(16.3%). There was no correlation between hemoglobin levels and the occurrence of
vascular occlusive crisis. Maximum cases required their first blood transfusion
between second and third year of age. Requirement of blod transfusion was more in
HbSS cases. Four patients died of which three had HbSS and were below five years
of age. Splenic sequestration crisis was the commonest cause of death.
CONCLUSION: Sickle cell disease is prevalent in this area and most cases present
before 5 year of age. VOC is the commonest crisis seen, but death often occurs
due to sequestration crisis and usually below 5 years of age.
PMID- 10781231
TI - Evaluation of the WHO/UNICEF algorithm for integrated management of childhood
illness between the ages of one week to two months.
AB - OBJECTIVE: To evaluate the utility of the WHO/UNICEF algoritham for integrated
management of childhood illness (IMCI) between the ages of 1 week to 2 months.
DESIGN: Prospective observational. SETTING: The Outpatient Department and
Emergency Room of a medical college hospital. METHODS: 129 infants presenting to
Outpatient Department (n=70) or Emergency Room (n=59) were assessed and
classified as per 'IMCI' algorithm and treatment required was identified. A
detailed evaluation with all relevant investigations was also done for these
subjects. The final diagnoses made and therapies instituted on this basis served
as 'gold standard'. The diagnostic and therapeutic agreement between 'gold
standard and the 'IMCI' was computed. RESULTS: More than one illness was present
in 97(75.2%) of subjects as per 'gold standard' (mean 2.1). Subjects having any
referral criteria as per 'IMCI' algorithm had a greater (p=0.002) co-existence of
illnesses (mean 2.3 vs. 1.8 illnesses per child, respectively. IMCI algorithm
covered majority (81-84%) of the recorded diagnoses either partly (40-41%) or
fully (40-44%). The referral criteria proved quite sensitive (86-87%) in
predicting hospitalization but had a lower specificity (53-58%). a total
agreement with IMCI was found in 60-66% cases. The mismatch (34-40%) was more
commonly of overdiagnosis (21-23%) rather than underdiagnosis (15-21%). The
sensitivity of the algorithm to identify serious bacterial infection was high
(96.1-96.5%) while the specificity was relatively low (51. 8-59.7%). Upper
respiratory infection (URI)emerged as an important cause resulting in unnecessary
referrals (13 out of 21 cases). Of the 43 cases identified as diarrhea by the
algorithm, 6 had breast fed stools, which do not require any therapy. The 'IMCI'
algorithm had a provision for preventive services of immunization and
breastfeeding counseling (18% possibility of availing missed opportunities in
both). CONCLUSION: There is a sound scientific basis for adopting IMCI approach
even in young infants as there is a need to improve the specificity of referral
criteria. Two important conditions identified for possible refinement are URI and
breast fed stools
PMID- 10781233
TI - Acute lymphoblastic leukemia: current treatment concepts.
PMID- 10781234
TI - Ashy dermatosis.
PMID- 10781235
TI - Immunogenicity of hepatitis B vaccine incorporated into the expanded program of
immunization schedule.
PMID- 10781236
TI - Natural immunity to Haemophilus influenzae type b among healthy children in
Istanbul, Turkey.
PMID- 10781237
TI - Necrotising enterocolitis following ophthalmological examination in preterm
neonates.
PMID- 10781238
TI - Splenectomy and lieno-renal shunt for extra hepatic portal venous obstruction.
PMID- 10781239
TI - An appraisal of pediatric dermatological emergencies.
PMID- 10781240
TI - Hereditary angioedema 'Type I': report of a family with a fatal case.
PMID- 10781241
TI - Perianal streptococcal dermatitis.
PMID- 10781242
TI - Jansen's metaphyseal chondrodysplasia.
PMID- 10781243
TI - Colonic obstruction in classical malrotation.
PMID- 10781244
TI - Epitheloid sarcoma in a neonate.
PMID- 10781246
TI - Reply
PMID- 10781247
TI - Safeguard against tuberculosis for children in schools.
PMID- 10781245
TI - Influence of age and antitubercular therapy on BCG response.
PMID- 10781248
TI - Reply
PMID- 10781249
TI - Type of syringe for giving paraldehyde injection.
PMID- 10781250
TI - Reply
PMID- 10781251
TI - Magnesium sulphate for persistent pulmonary hypertension in newborns.
PMID- 10781252
TI - Unusual foreign body in the male urethra.
PMID- 10781254
TI - Reply
PMID- 10781255
TI - Fulminant hepatic failure.
PMID- 10781253
TI - Glucose and small for gestational age infants.
PMID- 10781256
TI - Reply
PMID- 10781257
TI - Nitrate kit for the diagnosis of urinary tract infection.
PMID- 10781258
TI - Reply
PMID- 10781259
TI - Cornelia de Lange syndrome: discordance in twins.
PMID- 10781260
TI - Cornelia de lange syndrome: discordance in twins
PMID- 10781261
TI - Influenza vaccination and asthma.
PMID- 10781262
TI - Difficult mask ventilation: an underestimated aspect of the problem of the
difficult airway?
PMID- 10781263
TI - Anesthetic concerns of spaceflight.
PMID- 10781264
TI - Isoflurane neuroprotection: a passing fantasy, again?
PMID- 10781265
TI - Thromboelastography: past, present, and future.
PMID- 10781266
TI - Prediction of difficult mask ventilation.
AB - BACKGROUND: Maintenance of airway patency and oxygenation are the main objectives
of face-mask ventilation. Because the incidence of difficult mask ventilation
(DMV) and the factors associated with it are not well known, we undertook this
prospective study. METHODS: Difficult mask ventilation was defined as the
inability of an unassisted anesthesiologist to maintain the measured oxygen
saturation as measured by pulse oximetry > 92% or to prevent or reverse signs of
inadequate ventilation during positive-pressure mask ventilation under general
anesthesia. A univariate analysis was performed to identify potential factors
predicting DMV, followed by a multivariate analysis, and odds ratio and 95%
confidence interval were calculated. RESULTS: A total of 1,502 patients were
prospectively included. DMV was reported in 75 patients (5%; 95% confidence
interval, 3.9-6.1%), with one case of impossible ventilation. DMV was anticipated
by the anesthesiologist in only 13 patients (17% of the DMV cases). Body mass
index, age, macroglossia, beard, lack of teeth, history of snoring, increased
Mallampati grade, and lower thyromental distance were identified in the
univariate analysis as potential DMV risk factors. Using a multivariate analysis,
five criteria were recognized as independent factors for a DMV (age older than 55
yr, body mass index > 26 kg/m2, beard, lack of teeth, history of snoring), the
presence of two indicating high likelihood of DMV (sensitivity, 0.72;
specificity, 0.73). CONCLUSION: In a general adult population, DMV was reported
in 5% of the patients. A simple DMV risk score was established. Being able to
more accurately predict DMV may improve the safety of airway management.
PMID- 10781267
TI - Airway management during spaceflight: A comparison of four airway devices in
simulated microgravity.
AB - BACKGROUND: The authors compared airway management in normogravity and simulated
microgravity with and without restraints for laryngoscope-guided tracheal
intubation, the cuffed oropharyngeal airway, the standard laryngeal mask airway,
and the intubating laryngeal mask airway. METHODS: Four trained anesthesiologist
divers participated in the study. Simulated microgravity during spaceflight was
obtained using a submerged, full-scale model of the International Space Station
Life Support Module and neutrally buoyant equipment and personnel. Customized,
full-torso manikins were used for performing airway management. Each
anesthesiologist-diver attempted airway management on 10 occasions with each
device in three experimental conditions: (1) with the manikin at the poolside
(poolside); (2) with the submerged manikin floating free (free-floating); and (3)
with the submerged manikin fixed to the floor using a restraint (restrained).
Airway management failure was defined as failed insertion after three attempts or
inadequate device placement after insertion. RESULTS: For the laryngoscope-guided
tracheal intubation, airway management failure occurred more frequently in the
free-floating (85%) condition than the restrained (8%) and poolside (0%)
conditions (both, P < 0.001). Airway management failure was similar among
conditions for the cuffed oropharyngeal airway (poolside, 10%; free-floating,
15%; restrained, 15%), laryngeal mask airway (poolside, 0%; free-floating, 3%;
restrained, 0%), and intubating laryngeal mask airway (poolside, 5%; free
floating, 5%; restrained, 10%). Airway management failure for the laryngoscope
guided tracheal intubation was usually caused by failed insertion (> 90%), and
for the cuffed oropharyngeal airway, laryngeal mask airway, and intubating
laryngeal mask airway, it was always a result of inadequate placement.
CONCLUSION: The emphasis placed on the use of restraints for conventional
tracheal intubation in microgravity is appropriate. Extratracheal airway devices
may be useful when restraints cannot be applied or intubation is difficult.
PMID- 10781268
TI - Citrate storage affects Thrombelastograph analysis.
AB - BACKGROUND: Thrombelastograph analysis (TEG) is used to evaluate blood
coagulation. Ideally, whole blood is immediately processed. If impossible, blood
may be citrated and assessed after recalcification. No data describe the effect
of such treatment and storage on TEG parameters. METHODS: Three studies were
performed in 90 surgical patients. In 30 patients, blood was citrated (1:10, 0.
129 M) and recalcified (20 microl 2 M CaCl2 to 340 microl citrated blood), and
TEG was performed with native blood and after recalcification after 0, 15, and 30
min of citrate storage. In another 30 patients, TEG was performed with citrated
blood recalcified immediately and after 1-72 h storage. In a third study,
thrombin-antithrombin complex, prothrombin fragment 1+2, and beta-thromboglobulin
were measured (using enzyme-linked immunoabsorbant assay tests) at corresponding
time points. Data were compared using repeated-measures analysis of variance and
post hocpaired t tests. RESULTS: TEG parameters were different in recalcified
citrated blood compared with native blood (P < 0.05) and changed significantly
during 30-min (P < 0.025) and 72-h (P < 0.001) citrate storage. TEG parameters
measured between 1 and 8 h of citrate storage were stable. Thrombin-antithrombin
complex and prothrombin fragment 1+2 values were not elevated in native blood.
After 30 min of citrate storage a gradual thrombin activation was observed, as
evidenced by increasing thrombin-antithrombin complex and prothrombin fragment
1+2 values (P < 0.05). beta-Thromboglobulin level was increased after 2 and 8 h
of citrate storage (P < 0.01). CONCLUSIONS: Analysis of native blood yields the
most reliable TEG results. Should immediate TEG processing not be possible,
citrated blood may be used if recalcified after 1-8 h.
PMID- 10781269
TI - Transesophageal echocardiographic hemodynamic monitoring during preoperative
acute normovolemic hemodilution.
AB - BACKGROUND: Preoperative acute normovolemic hemodilution may compromise oxygen
transport. The aims of our study were to describe the hemodynamic effects of
normovolemic hemodilution and to determine its effect on systolic and diastolic
cardiac function by multiplane transesophageal echocardiography. METHODS: In
eight anesthetized patients (aged 13-51 yr) without heart disease, hemoglobin was
reduced in steps from 123 +/- 8 (mean +/- SD) to 98 +/- 3 and to 79 +/- 5 g/l.
Hemodynamic measurements (intravascular pressures, thermodilution cardiac output,
and echocardiographic recordings) were obtained during a stabilization period and
at each level of hemodilution. Left ventricular wall motion was monitored
continuously, and Doppler variables, annular motion, and changes in ejection
fractional area were analyzed off-line. RESULTS: During hemodilution, cardiac
output by thermodilution increased by 16 +/- 7% and 26 +/- 10%, corresponding
well to the increase in cardiac output as measured by Doppler (difference, 0.32
+/- 1.2 l/min). Systemic vascular resistance fell 16 +/- 14% and 23 +/- 9% and
pulmonary capillary wedge pressure increased slightly (2 +/- 2 mmHg), whereas
other pressures, heart rate, wall motion, and diastolic Doppler variables
remained unchanged. Ejection fractional area change increased from 44 +/- 7% to
54 +/- 10% and 60 +/- 9% as a result of reduced end-systolic and increased end
diastolic left ventricular areas. CONCLUSIONS: A reduction in hemoglobin to 80
g/l during acute normovolemic hemodilution does not normally compromise systolic
or diastolic myocardial function as determined by transesophageal
echocardiography. Preload, left ventricular ejection fraction, and cardiac output
increase with a concomitant fall in systemic vascular resistance.
PMID- 10781270
TI - Neural mechanisms of antinociceptive effects of hypnosis.
AB - BACKGROUND: The neural mechanisms underlying the modulation of pain perception by
hypnosis remain obscure. In this study, we used positron emission tomography in
11 healthy volunteers to identify the brain areas in which hypnosis modulates
cerebral responses to a noxious stimulus. METHODS: The protocol used a factorial
design with two factors: state (hypnotic state, resting state, mental imagery)
and stimulation (warm non-noxious vs. hot noxious stimuli applied to right thenar
eminence). Two cerebral blood flow scans were obtained with the 15O-water
technique during each condition. After each scan, the subject was asked to rate
pain sensation and unpleasantness. Statistical parametric mapping was used to
determine the main effects of noxious stimulation and hypnotic state as well as
state-by-stimulation interactions (i.e., brain areas that would be more or less
activated in hypnosis than in control conditions, under noxious stimulation).
RESULTS: Hypnosis decreased both pain sensation and the unpleasantness of noxious
stimuli. Noxious stimulation caused an increase in regional cerebral blood flow
in the thalamic nuclei and anterior cingulate and insular cortices. The hypnotic
state induced a significant activation of a right-sided extrastriate area and the
anterior cingulate cortex. The interaction analysis showed that the activity in
the anterior (mid-)cingulate cortex was related to pain perception and
unpleasantness differently in the hypnotic state than in control situations.
CONCLUSIONS: Both intensity and unpleasantness of the noxious stimuli are reduced
during the hypnotic state. In addition, hypnotic modulation of pain is mediated
by the anterior cingulate cortex.
PMID- 10781271
TI - Smoking decreases alveolar macrophage function during anesthesia and surgery.
AB - BACKGROUND: Smoking changes numerous alveolar macrophage functions and is one of
the most important risk factors for postoperative pulmonary complications. The
current study tested the hypothesis that smoking impairs antimicrobial and
proinflammatory responses in alveolar macrophages during anesthesia and surgery.
METHOD: The authors studied 30 smoking and 30 nonsmoking patients during propofol
fentanyl general anesthesia. Alveolar immune cells were harvested by
bronchoalveolar lavage immediately and 2, 4, and 6 h after induction of
anesthesia and at the end of surgery. The types of alveolar immune cell and
macrophage aggregation were determined. The authors measured opsonized and
unopsonized phagocytosis. Microbicidal activity was determined as the ability of
the macrophages to kill Listeriamonocytogenes directly. Finally, RNA was
extracted from harvested cells and cDNA was synthesized by reverse transcription.
The expression of interleukin 1beta, 6, and 8, interferon gamma, and tumor
necrosis factor alpha were measured by semiquantitative polymerase chain reaction
using beta-actin as an internal standard. RESULTS: The fraction of aggregated
macrophages increased significantly over time in both groups, whereas
phagocytosis of opsonized and nonopsonized particles and microbicidal activity of
alveolar macrophages decreased significantly. The changes, though, were nearly
twice as great as in patients who smoked. Gene expression of all proinflammatory
cytokines in alveolar immune cells except interleukin 6 increased 2- to 20-fold
over time in both groups. The expression of interleukin 1beta, interferon gamma,
and tumor necrosis factor alpha, however, increased only half as much in smokers
as in nonsmokers. CONCLUSION: Smoking was associated with macrophage aggregation
but markedly reduced phagocytic and microbicidal activity-possibly because
expression of proinflammatory cytokines was reduced in these patients. Our data
thus suggest that smokers may have a limited ability to mount an effective
pulmonary immune defense after anesthesia and surgery.
PMID- 10781273
TI - Sinus nodal function and risk for atrial fibrillation after coronary artery
bypass graft surgery.
AB - BACKGROUND: Nonsurgical patients with sinus node dysfunction are at high risk for
atrial tachyarrhythmias, but whether a similar relation exists for atrial
fibrillation after coronary artery bypass graft surgery is not clear. The purpose
of this study was to evaluate sinus nodal function before and after coronary
artery bypass graft surgery and to evaluate its relation with the risk for
postoperative atrial arrhythmias. METHODS: Sixty patients without complications
having elective coronary artery bypass graft surgery underwent sinus nodal
function testing by measurement of sinoatrial conduction time (SACT) and
corrected sinus nodal recovery time (CSNRT). Patients were categorized based on
whether postoperative atrial fibrillation developed. RESULTS: Twenty patients
developed atrial fibrillation between postoperative days 1 through 3. For
patients remaining in sinus rhythm (n = 40), sinoatrial conduction times were no
different and corrected sinus nodal recovery times were shorter after surgery
when compared with measurements obtained after anesthesia induction. Sinus node
function test results before surgery were similar between the sinus rhythm and
the atrial fibrillation groups. After surgery, patients who later developed
atrial fibrillation had longer sinoatrial conduction times compared with the
sinus rhythm group (P = 0.006), but corrected sinus nodal recover time was not
different between these groups. A sinoatrial conduction time > 96 ms measured at
this time point was associated with a 7.3-fold increased risk of postoperative
atrial fibrillation (sensitivity, 62%; specificity, 81%; positive and negative
predictive values, 56% and 85%, respectively; area under the receiver operator
characteristic curve, 0.72). CONCLUSIONS: These data show that sinus nodal
function is not adversely affected by uncomplicated coronary artery bypass
surgery. Patients who later developed atrial fibrillation, however, had prolonged
sinoatrial conduction immediately after surgery compared with patients remaining
in sinus rhythm. These results suggest that injury to atrial conduction tissue at
the time of surgery predisposes to postoperative atrial fibrillation and that
assessment of sinoatrial conduction times could provide a means of identifying
patients at high risk for postoperative atrial fibrillation.
PMID- 10781272
TI - Ophthalmic regional anesthesia: medial canthus episcleral (sub-tenon) anesthesia
is more efficient than peribulbar anesthesia: A double-blind randomized study.
AB - BACKGROUND: Regional anesthesia and especially peribulbar anesthesia commonly is
used for cataract surgery. Failure rates and need for reinjection remains high,
however, with peribulbar anesthesia. Single-injection high-volume medial canthus
episcleral (sub-Tenon's) anesthesia has proven to be an efficient and safe
alternative to peribulbar anesthesia. METHODS: The authors, in a blind study,
compared the effectiveness of both techniques in 66 patients randomly assigned to
episcleral anesthesia or single-injection peribulbar anesthesia. Motor blockade
(akinesia) was used as the main index of anesthesia effectiveness. It was
assessed using an 18-point scale (0-3 for each of the four directions of the
gaze, lid opening, and lid closing, the total being from 0 = normal mobility to
18 = no movement at all). This score was compared between the groups 1, 5, 10,
and 15 min after injection and at the end of the surgical procedures. Time to
onset of the blockade also was compared between the two groups, as was the
incidence of incomplete blockade with a need for supplemental injection and the
satisfaction of the surgeon, patient, and anesthesiologist. RESULTS: Episcleral
anesthesia provided a quicker onset of anesthesia, a better akinesia score, and a
lower rate of incomplete blockade necessitating reinjection (0 vs. 39%; P <
0.0001) than peribulbar anesthesia. Even after supplemental injection, peribulbar
anesthesia had a lower akinesia score than did episcleral anesthesia. Peribulbar
anesthesia began to wear off during surgery, whereas episcleral anesthesia did
not. CONCLUSION: Medial canthus single-injection episcleral anesthesia is a
suitable alternative to peribulbar anesthesia. It provides better akinesia, with
a quicker onset and more constancy in effectiveness.
PMID- 10781274
TI - Acoustic reflectometry profiles of endotracheal and esophageal intubation.
AB - BACKGROUND: Acoustic reflectometry can be used to create a "one-dimensional
image" of a cavity, such as the airway and lung, with the image displayed as an
area-length curve. This pilot study was undertaken to determine whether acoustic
reflectometry could be used to distinguish between an endotracheal and an
esophageal intubation. METHODS: Ten adult patients underwent general endotracheal
anesthesia and neuromuscular blockade. The reflectometer wavetube was attached to
an endotracheal tube, and a reflectometric profile was obtained of the
endotracheal tube and the airway and lung cavity. After confirmation of tracheal
intubation, a second endotracheal tube was placed in the esophagus. After four
breaths were administered, a reflectometric profile of the endotracheal tube
esophagus cavity was obtained. RESULTS: The acoustic reflectometric profiles for
tracheal and esophageal intubation profiles were distinctive and characteristic.
For an endotracheal tube-airway cavity, the profile shows a constant cross
sectional area throughout the length of the endotracheal tube, followed by a
rapid rise in the area past the carina. For an esophageal intubation, the profile
shows constant cross-sectional area throughout the length of the endotracheal
tube, followed by a sudden decrease in the cross-sectional area to zero.
CONCLUSIONS: In this pilot study, acoustic reflectometry within seconds, and
without resort to capnography, was able to generate characteristic and
distinctive area-length profiles for both endotracheal and esophageal intubation.
Acoustic reflectometry may have a role in the emergency imaging of the airway,
and in the immediate detection of esophageal intubations, particularly in cases
of cardiopulmonary arrest in which the usual techniques for confirmation of
breathing tube placement fail.
PMID- 10781275
TI - Changes in the auditory evoked potentials and the bispectral index following
propofol or propofol and alfentanil.
AB - BACKGROUND: Midlatency auditory evoked potentials (MLAEP) show graded changes
with increasing doses of hypnotics but little change with opioids. The effect of
their combination on the MLAEP was evaluated. Also, the bispectral index (BIS)
was compared with the ability of MLAEP to correlate with sedation and predict
loss of consciousness. METHODS: Twenty healthy volunteers were randomly assigned
to receive stepped increases in propofol concentration (10 subjects) or propofol
plus alfentanil 100 ng/ml (10 subjects). At baseline and at each targeted effect
site concentration the mean MLAEP, BIS, measures of sedation, and drug
concentration were obtained. The relation among MLAEP, BIS, and sedation score
was determined. The prediction probability (Pk) was calculated and compared for
BIS and MLAEP. RESULTS: The BIS and MLAEP patterns showed significant changes (Pa
and Nb decreased in amplitude and increased in latency) with increasing level of
sedation (P < 0.0001). The BIS correlated better with sedation scores (0.884)
than did the MLAEP (P < 0.05). Pa and Nb latencies showed the best correlation
with sedation levels (0.685 and 0.658, respectively). The addition of alfentanil
did not affect the relation between MLAEP and loss of consciousness (P > 0.15).
The BIS (Pk = 0.952) was a better predictor of loss of consciousness than were Pa
and Nb amplitude (P < 0.05) but were comparable to Pa and Nb latency (Pk = 0.869
and 0. 873, respectively). CONCLUSION: MLAEP changes, like the BIS, correlate
well with increasing sedation produced by propofol, and these changes in the
MLAEP are independent of the presence of an opioid. Among all the MLAEP
parameters, Pa and Nb latencies are the best predictors of increasing sedation
and loss of consciousness.
PMID- 10781276
TI - Patients with diabetic neuropathy are at risk of a greater intraoperative
reduction in core temperature.
AB - BACKGROUND: Core hypothermia develops after the induction of general anesthesia,
but intraoperative vasoconstriction usually prevents its progression. However,
diabetes mellitus is often associated with autonomic neuropathy, which leads to
abnormal peripheral neurovascular function. Accordingly, we tested the hypothesis
that diabetic patients experience a greater reduction in core temperature during
general anesthesia than nondiabetic patients. METHODS: We studied 36 nondiabetic
patients (control group) and 27 diabetic patients (diabetic group) undergoing
elective abdominal surgery. Both groups were divided into young (< 60 yr) and
older age (>/= 60 yr) groups. Standard noninvasive autonomic tests (heart rate
variation at deep periodical breathing, Valsalva maneuver, and head-up tilt) were
carried out for each patient. The relation between the results of these tests of
autonomic function and the tympanic membrane temperature during general
anesthesia was assessed in relation to peripheral vasoconstriction. RESULTS:
Thirteen patients in the diabetic group showed abnormal responses to two or more
of the basal autonomic function tests (patients with autonomic dysfunction).
Changes in core temperature among the groups were similar at 90 min after the
induction of anesthesia. However, the core temperature of the diabetic patients
with autonomic dysfunction was lower from 120 min (35.1 degrees C) onward
compared with the young or older nondiabetic patients and the diabetic patients
with normal autonomic function. Peripheral vasoconstriction, evaluated using the
forearm-fingertip skin surface temperature gradient, was delayed in patients with
autonomic dysfunction compared with the others. CONCLUSIONS: The current results
indicate that diabetic autonomic neuropathy is associated with more severe
intraoperative hypothermia. We postulate that diabetic patients become more
hypothermic because their peripheral neuropathy delays the onset of
thermoregulatory vasoconstriction and reduces its efficacy once triggered. These
patients may therefore fail to develop a normal core temperature plateau.
PMID- 10781277
TI - Jugular venous bulb oxygen saturation in patients with preexisting diabetes
mellitus or stroke during normothermic cardiopulmonary bypass.
AB - BACKGROUND: The authors hypothesized that patients with cerebrovascular
abnormalities or metabolic disorders may experience abnormality in cerebral
circulation more frequently than patients without these risks. The current study
attempted to assess jugular venous bulb oxygen saturation (SjvO2) in patients
with preexisting diabetes mellitus or stroke undergoing normothermic
cardiopulmonary bypass. METHODS: Thirty-nine patients undergoing elective
coronary artery bypass graft surgery were studied, including 19 age-matched
control patients, 10 diabetic patients, and 9 patients with preexisting stroke A
4.0-French fiberoptic oximetry oxygen saturation catheter was inserted into the
right jugular bulb to continuously monitor internal SjvO2. Hemodynamic parameters
and arterial and jugular venous blood gases were measured at seven time points:
(1) after the induction of anesthesia and before the start of surgery, (2) just
after the beginning of cardiopulmonary bypass, (3) 20 min after the beginning of
bypass, (4) 40 min after the beginning of bypass, (5) 60 min after the beginning
of bypass, (6) just after the cessation of bypass, and (7) at the end of the
operation. RESULTS: No significant differences were seen in mean arterial
pressure, arterial carbon dioxide tension (PaCO2), or hemoglobin concentration
among the three groups during the study. The SjvO2 value did not differ among the
three groups after anesthesia induction and before surgery, just after the
beginning of cardiopulmonary bypass, 60 min after the beginning of bypass, just
after the end of bypass, or at the end of the operation. Significant differences
between the control group and the diabetic and stroke groups were observed,
however, at 20 min and 40 min after the beginning of bypass (at 20 min: control
group 62.2 +/- 6.8%, diabetes group 48.4 +/- 5.1%, stroke group 45.9 +/- 6.3%; at
40 min: control group 62.6 +/- 5.2%, diabetes group 47.1 +/- 5.2%, stroke group
48.8 +/- 4.1% [values expressed as the mean +/- SD]; P < 0.05). Also, values in
the diabetes and stroke groups were decreased at 20 min and 40 min after the
beginning of bypass compared with before the start of surgery. CONCLUSIONS: A
reduced SjvO2 value was observed more frequently in patients with preexisting
diabetes mellitus or stroke during normothermic cardiopulmonary bypass. It is
possible that cerebral circulation during normothermic bypass is altered in
patients with risk factors for cerebrovascular disorder.
PMID- 10781278
TI - Predictors of hypothermia during spinal anesthesia.
AB - BACKGROUND: Body temperature often is ignored during regional anesthesia, despite
evidence that hypothermia occurs commonly. Because hypothermia is associated with
adverse clinical outcomes, it is important to recognize predictors of hypothermia
and to monitor and control body temperature in patients at risk. The current
study was designed to determine the predictors of core hypothermia in patients
receiving spinal anesthesia for radical retropubic prostatectomy. METHODS: Forty
four patients undergoing radical retropubic prostatectomy were studied. A lumbar
intrathecal injection of 18-22 mg bupivacaine, 0.75%, with 20 microg fentanyl was
given. No active warming measures were used other than intravenous fluid warming.
The following clinical variables were assessed as potential predictors of core
(tympanic) temperature at admission to the postanesthesia care unit: duration of
surgery, average ambient operating room temperature, body habitus, age, and
spinal blockade level. RESULTS: The mean core temperature at admission to the
postanesthesia care unit was 35.1 +/- 0.6 degrees C (range, 33.6-36.3 degrees C).
Duration of surgery, ambient operating room temperature, and body habitus were
not predictors of hypothermia. A high level of spinal blockade and increasing age
were predictors of hypothermia. For each incremental increase in block level,
core temperature decreased by 0.15 degrees C, and for each increase in age, core
temperature decreased by 0.3 degrees C. CONCLUSIONS: Although high-level spinal
blockade has been associated with decreased thermoregulatory thresholds, no
previous study has shown that a higher level of blockade is associated with a
greater magnitude of core hypothermia in the clinical setting. As with general
anesthesia, advanced age is associated with hypothermia during spinal anesthesia.
PMID- 10781279
TI - Isoflurane delays but does not prevent cerebral infarction in rats subjected to
focal ischemia.
AB - BACKGROUND: Several investigations have shown that volatile anesthetics can
reduce ischemic cerebral injury. In these studies, however, neurologic injury was
evaluated only after a short recovery period. Recent data suggest that injury
caused by ischemia is a dynamic process characterized by continual neuronal loss
for a prolonged period. Whether isoflurane-mediated neuroprotection is sustained
after a longer recovery period is not known. The current study was conducted to
compare the effect of isoflurane on brain injury after short (2-day) and long (14
day) recovery periods in rats subjected to focal ischemia. METHODS: Fasted Wistar
Kyoto rats were anesthetized with isoflurane and randomly allocated to an awake
(n = 36) or an isoflurane (n = 34) group. Animals in both groups were subjected
to focal ischemia by filament occlusion of the middle cerebral artery.
Pericranial temperature was servocontrolled at 37 degrees C throughout the
experiment. In the awake group, isoflurane was discontinued and the animals were
allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained
at 1.5 times the minimum alveolar concentration. After 70 min of focal ischemia,
the filament was removed. Animals were killed 2 days (awake, n = 18; isoflurane,
n = 17) and 14 days (awake, n = 18; isoflurane, n = 17) after ischemia. The
volumes of cerebral infarction and selective neuronal necrosis in the animals
were determined by image analysis of hematoxylin and eosin-stained coronal brain
sections. RESULTS: Cortical and subcortical volumes of infarction were
significantly less in the isoflurane 2-day group (26 +/- 23 mm3 and 17 +/- 6 mm3,
respectively) than in the awake 2-day group (58 +/- 35 mm3, P < 0. 01; and 28 +/-
12 mm3, P < 0.01, respectively). By contrast, cortical and subcortical volumes of
infarction in the awake (41 +/- 31 mm3 and 28 +/- 16 mm3, respectively) and
isoflurane (41 +/- 35 mm3 and 19 +/- 8 mm3, respectively) 14-day groups were not
different (cortex, P = 0.99; subcortex, P = 0.08). The volume of cortical tissue
in which selective neuronal necrosis was observed, however, was significantly
less in the isoflurane 14-day group (5 +/- 4 mm3) than in the awake 14-day group
(17 +/- 9 mm3, P < 0.01). The total number of necrotic neurons in the region of
selective neuronal necrosis was significantly smaller in the isoflurane 14-day
group than in the awake 14-day group (P < 0.01). CONCLUSION: Compared with the
awake state, isoflurane reduced the extent of infarction assessed 2 days after
focal ischemia in rats. At 14 days, however, only selective neuronal necrosis,
but not infarction, was reduced by isoflurane. These results suggest that
isoflurane delays but does not prevent cerebral infarction caused by focal
ischemia. Isoflurane may attenuate the delayed development of selective neuronal
necrosis in periinfarct areas in this animal model.
PMID- 10781280
TI - Anesthetics and mild hypothermia similarly prevent hippocampal neuron death in an
in vitro model of cerebral ischemia.
AB - BACKGROUND: General anesthetics reduce neuron loss following focal cerebral
ischemia in rodents. The relative efficacy of this action among different
anesthetics clinically used for neuroprotection is uncertain. In addition, it
remains unclear how anesthetics compare to neuroprotection afforded by mild
hypothermia. This study was performed to evaluate the comparative effects of
isoflurane, sodium pentothal, and mild hypothermia in a hippocampal slice model
of cerebral ischemia and to determine if the mechanism of neuroprotection of
isoflurane involves inhibition of glutamate excitotoxicity. METHODS: Survival and
morphology of CA1, CA3, and dentate gyrus neurons in rat hippocampal slices were
examined after 10 or 20 min of combined oxygen-glucose deprivation (in vitro
ischemia) followed by a 5-h recovery period. RESULTS: 10 or 20 min in vitro
ischemia at 37 degrees C killed 35-40% of neurons in CA1 (P < 0.001), 6% in CA3
(not significant) and 18% in dentate (P < 0.05). Isoflurane (0.7 and 2.0%,
approximately 0.45 and 1.5 minimum alveolar concentration), pentothal (50 microm,
approximately 1 minimum alveolar concentration equivalent) and mild hypothermia
(34 degrees C) all reduced CA1 cell loss and morphologic damage to similar
degrees in 10- and 20-min periods of ischemia (P < 0.001). The noncompetitive N
methyl-D-aspartate antagonist MK-801 prevented cell damage, showing that N-methyl
D-aspartate receptor activation is an important mechanism of injury in this
model. Glutamate (1 mm) produced cell loss similar to in vitro ischemia.
Isoflurane (2%) prevented cell damage from glutamate exposure. CONCLUSIONS: In
hippocampal slices, neuron death from simulated ischemia was predominately due to
activation of glutamate receptors. Isoflurane, sodium pentothal, an N-methyl-D
aspartate receptor antagonist, and mild hypothermia prevented cell death to
similar degrees. For isoflurane, the mechanism appears to involve attenuation of
glutamate excitotoxicity.
PMID- 10781281
TI - Spinal tonicaine: potency and differential blockade of sensory and motor
functions.
AB - BACKGROUND: Long-acting local anesthetics are beneficial for the management of
postoperative pain and chronic pain. The authors recently reported that a single
injection of N-beta-phenylethyl-lidocaine (tonicaine), a quaternary lidocaine
derivative, effectively blocks rat sciatic nerve function four to nine times
longer than lidocaine, with a predominance of sensory versusmotor blockade. The
purposes of this study were to measure directly the potency of this charged drug
by internal perfusion of cultured neuronal cells, and to evaluate the
differential blockade of sensory versus motor function via spinal route in rats.
METHODS: The tonic and additional use-dependent blockade of Na+ currents by
internal tonicaine was assayed in cultured GH3 cells during whole cell voltage
clamp conditions. In addition, tonicaine was injected into the intrathecal space
of rats at intervertebral space L4-L5, and the proprioceptive, motor, and sensory
functions, and tissue integrity, subsequently were evaluated. RESULTS: Internal
application of tonicaine in GH3 cells revealed that it was approximately 80 times
more potent in blocking Na+ currents than was externally applied lidocaine. In
vivotesting in a rat neuraxial anesthesia model showed that tonicaine at 0.5 mm
produced blockade that lasted much longer than that produced by bupivacaine even
at approximately a 55 times higher concentration (28.8 mm). Tonicaine spinal
block also produced a longer duration of sensory than motor blockade (112.5 +/-
16.3 min vs. 45.8 +/- 7.1 min). Evidence of neurotoxicity was seen at a
concentration of 1.0 mm. CONCLUSION: In vitro testing shows that tonicaine
displays a higher affinity for the local anesthetic binding site than does
lidocaine; in vivotesting indicates that tonicaine elicits sensory blockade of a
duration significantly longer than that elicited by bupivacaine. Tonicaine,
however, has a narrow therapeutic index, with substantial neurotoxicity at 1 mm
in rats, and may have limited clinical value.
PMID- 10781282
TI - FK506 (tacrolimus) increases halothane-induced Ca2+ release from skeletal muscle
sarcoplasmic reticulum.
AB - BACKGROUND: FK506 binding protein is closely associated with the sarcoplasmic
reticulum ryanodine receptor-channel and can modulate its function. The ryanodine
receptor is stabilized by its association with FK506 binding protein. The
immunosuppressant drugs FK506 (tacrolimus) and rapamycin can promote dissociation
of FK506 binding protein from the ryanodine receptor 1 and by this mechanism
increase sensitivity of ryanodine receptor 1 to agonists such as caffeine.
Furthermore, it was shown recently that treatment of normal human skeletal muscle
with FK506 and rapamycin increased halothane-induced contracture. The authors
investigated the effect of the immunosuppressants FK506 and rapamycin on
halothane-induced Ca2+ release in skeletal muscle sarcoplasmic reticulum
vesicles. METHODS: Skeletal muscle terminal cisterns were isolated from New
Zealand White rabbits. Ca2+ uptake and release was monitored in skeletal muscle
sarcoplasmic reticulum vesicles using the fluo-3 fluorescent technique. Western
Blot analysis of FK506 binding protein was performed using standard protocol.
RESULTS: The authors observed that treatment of skeletal muscle sarcoplasmic
reticulum vesicles with FK506 and rapamycin enhances halothane-induced Ca2+
release by about five times. Furthermore, the Ca2+ release induced by halothane
in the presence of FK506 was inhibited by several antagonists of the ryanodine
receptor, such as ruthenium red, spermine, and Mg2+. CONCLUSION: Dissociation of
FK506 binding protein from its binding site in skeletal muscle sarcoplasmic
reticulum vesicles can modulate halothane-induced Ca2+ release through the
ryanodine receptor. Data are discussed in relation to the role of the FK506
binding protein in modulating the effect of halothane on the ryanodine receptor
and the development of malignant hyperthermia phenotype.
PMID- 10781283
TI - Rapid and direct modulation of GABAA receptors by halothane.
AB - BACKGROUND: Hypotheses regarding the nature of channel modulation by volatile
anesthetics have focused primarily on "membrane actions" of anesthetics and more
recently on direct actions of volatile agents on receptor proteins themselves.
With the recognition that many channels are subject to modulation by
intracellular enzymes, such as protein kinases and phosphatases, and recent
demonstrations that the activity of these modulators themselves may be altered by
anesthetic agents, a third possibility has been suggested:-anesthetic actions on
channels may be indirect, produced, for example, via direct effects on
intracellular enzyme systems. METHODS: To determine the contribution of indirect
versus direct modulation, the authors compared effects of the volatile anesthetic
halothane on gamma-aminobutyric acid A receptors under two conditions: in the
whole cell configuration with intact intracellular regulatory systems, and in the
excised patch configuration, in which intracellular signaling systems have been
disrupted. They also evaluated the effects of rapid application and withdrawal of
anesthetic to determine the time course of onset and offset of the anesthetic
actions on these channels. RESULTS: Characteristic changes in gamma-aminobutyric
acid A receptor function occurred in excised patches as in whole cells, did not
require alteration of receptor phosphorylation, and were rapid (onset and offset
of anesthetic action occurred within milliseconds). CONCLUSIONS: These results
are not consistent with indirect modulation but rather indicate that volatile
agents modulate gamma-aminobutyric acid A receptors by direct action on the
channel complex or surrounding lipid membrane.
PMID- 10781284
TI - Intrathecal dexmedetomidine attenuates hypercapnic but not hypoxic cerebral
vasodilation in anesthetized rabbits.
AB - BACKGROUND: Systemic dexmedetomidine (DXM) attenuates the cerebral vasodilation
induced by hypercapnia and decreases the cerebral blood flow response to hypoxia.
We determined whether lumbar intrathecal DXM affected the cerebrovascular
reactivity to hypercapnia and hypoxia. METHODS: Rabbits (n = 55) anesthetized
with pentobarbital were prepared for measurement of pial vessel diameters using a
closed cranial window preparation. The first study evaluated the response to
hypercapnia after intrathecal administration of DXM (2 microg/kg; n = 7) or
normal saline (n = 8). The second evaluated the response to hypercapnia after
intrathecal DXM in the presence of yohimbine (20 microg/kg followed by DXM 2
microg/kg; n = 7). The third evaluated the response to mild or moderate hypoxia
after intrathecal DXM (2 microg/kg; n = 7) or normal saline (n = 7). The
hypercapnic responses were also examined in the presence of systemic DXM (2, 10
microg/kg; n = 6), topical DXM (10-8 m, 10-6 m; n = 6) and of intrathecal
clonidine (2 microg/kg; n = 7). RESULTS: The pial arteriolar dilator response to
hypercapnia was significantly attenuated after intrathecal administration of DXM.
Pretreatment with yohimbine completely blocked the decreased reactivity to
hypercapnia. Intrathecal clonidine, although less than DXM, also attenuate the
hypercapnic response. Intrathecal DXM did not affect the vasodilation of pial
arterioles induced by mild or moderate hypoxia. The systemic DXM 10 microg/kg and
topical DXM 10-6 m, but not systemic 2 microg/kg and topical 10-8 m, attenuated
hypercapnic vasodilation of pial arterioles. CONCLUSIONS: The presence of alpha2
adrenoceptor agonist administered intrathecally into the lumbar spinal region
attenuates hypercapnic but not hypoxic cerebral vasodilation, probably via a
stimulation of central alpha2-adrenergic receptors of the central nervous system.
PMID- 10781285
TI - Succinylcholine metabolite succinic acid alters steady state activation in muscle
sodium channels.
AB - BACKGROUND: Animal experiments revealed that succinylcholine produced masseter
muscle rigidity and activated myotonic discharges despite neuromuscular blockade
with a nondepolarizing blocker. These results suggest that either succinylcholine
or its metabolites might interfere directly with voltage-operated ion channels of
the sarcolemma. The aim of this study was to examine effects of one product of
succinylcholine hydrolysis, succinic acid, on voltage-gated muscle sodium (Na+)
channels. METHODS: Alpha subunits of human muscle sodium channels were
heterologously expressed in HEK293 cells. Activation of Na+ currents was examined
applying standard whole-cell voltage-clamp protocols in the absence (control and
washout) and presence of succinic acid in different concentrations (0.05-10 mm).
RESULTS: Succinic acid shifted the midpoints of steady state activation plots in
the direction of more negative test potentials, indicating that channels open
during smaller depolarizations in the presence of the drug. The maximum amount of
the negative shift in 10 mm succinic acid was -6.3 +/- 1.7 mV; the EC50 for this
effect was 0.39 mm. In addition, succinic acid (10 mm) significantly enhanced
maximum currents after depolarizations with respect to a series of control
experiments. CONCLUSION: Succinic acid facilitates voltage-dependent activation
in muscle sodium channels in vitro. This might lead to muscle hyperexcitability
in vivo.
PMID- 10781286
TI - Opiate-induced analgesia is increased and prolonged in mice lacking P
glycoprotein.
AB - BACKGROUND: P-glycoprotein is a transmembrane protein expressed by multiple
mammalian cell types, including the endothelial cells that comprise the blood
brain-barrier. P-glycoprotein functions to actively pump a diverse array of
xenobiotics out of the cells in which it is expressed. The purpose of this study
was to determine if P-glycoprotein alters the analgesic efficacy of clinically
useful opioids. METHODS: Using a standard hot-plate method, the magnitude and
duration of analgesia from morphine, morphine-6-glucuronide, methadone,
meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice
and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as
the percent maximal possible effect (%MPE) over time, and these data were used to
calculate the area under the analgesia versus time curves (AUC) for all opioids
studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100
mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also
determined. RESULTS: Morphine induced greater analgesia in knockout mice compared
with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and
morphine brain concentrations were greater in knockout mice. Analgesia was also
greater in knockout mice treated with methadone and fentanyl but not meperidine
or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine
analgesia in wild-type mice but had no effect in knockout mice. CONCLUSIONS:
These results suggest that P-glycoprotein acts to limit the entry of some opiates
into the brain and that acute administration of P-glycoprotein inhibitors can
increase the sensitivity to these opiates.
PMID- 10781287
TI - Isoflurane preconditions myocardium against infarction via activation of
inhibitory guanine nucleotide binding proteins.
AB - BACKGROUND: Isoflurane-induced myocardial protection during ischemia is mediated
by adenosine triphosphate-regulated potassium (KATP) channels; however, the
intracellular signal transduction cascade responsible for this process has been
incompletely evaluated. The authors tested the hypothesis that isoflurane reduces
myocardial infarct size through a Gi protein-mediated process. METHODS: Forty
eight hours after pretreatment with vehicle (0.9% saline) or the Gi protein
inhibitor pertussis toxin (10 microg/kg intravenously), barbiturate-anesthetized
dogs (n = 43) were instrumented for measurement of aortic and left ventricular
pressures and maximum rate of increase of left ventricular pressure. All dogs
were subjected to a 60-min left anterior descending coronary artery occlusion
followed by 3-h reperfusion. In four separate groups, vehicle- or pertussis toxin
pretreated dogs were studied with or without administration of 1 minimum alveolar
concentration isoflurane. In two additional groups, dogs received the direct KATP
channel agonist nicorandil (100 microg/kg bolus and 10 microg x kg-1 x min-1
intravenous infusion) in the presence or absence of pertussis toxin pretreatment.
Myocardial perfusion and infarct size were measured with radioactive microspheres
and triphenyltetrazolium staining, respectively. RESULTS: Isoflurane
significantly (P < 0.05) decreased infarct size to 7 +/- 2% of the area at risk
compared with control experiments (26 +/- 2%). Pertussis toxin pretreatment alone
had no effects on myocardial infarct size (31 +/- 4%) but blocked the beneficial
effects of isoflurane (21 +/- 3%). Nicorandil decreased infarct size (11 +/- 2%),
but, in contrast to isoflurane, this effect was independent of pertussis toxin
pretreatment (11 +/- 1%). CONCLUSION: Isoflurane reduces myocardial infarct size
by a Gi protein-mediated mechanism in vivo.
PMID- 10781288
TI - Differential neurotoxic effects of propofol on dissociated cortical cells and
organotypic hippocampal cultures.
AB - BACKGROUND: Propofol is a widely used anesthetic agent for adults and children.
Although extensive clinical use has demonstrated its safety, neurologic
dysfunctions have been described after the use of this agent. A recent study on a
model of aggregating cell cultures reported that propofol might cause
irreversible lesions of gamma-aminobutyric acid-mediated (GABAergic) neurons when
administered at a critical phase of brain development. We investigated this issue
by comparing the effects of long-term propofol treatment on two models of brain
cultures: dissociated neonatal cortical cell cultures and organotypic slice
cultures. METHODS: Survival of GABAergic neurons in dissociated cultures of
newborn rat cortex (postnatal age, 1 day) treated for 3 days with different
concentrations of propofol was assessed using histologic and cytochemical
methods. For hippocampal organotypic slice cultures (postnatal age, 1 and 7
days), cell survival was assessed by measuring functional and morphologic
parameters: extracellular and intracellular electrophysiology, propidium staining
of dying cells, and light and electron microscopy. RESULTS: In dissociated
neonatal cell cultures, propofol induced dose-dependent lesions of GABAergic
neurons and of glial cells. In contrast, no evidence for neurotoxic effects of
propofol were found after long-term treatment of organotypic slice cultures.
Excitatory transmission was not affected by propofol, and inhibitory transmission
was still functional. Histologic preparations showed no evidence for cell
degeneration or death. CONCLUSION: Although long-term applications of propofol to
dissociated cortical cell cultures produced degeneration and death of GABAergic
neurons and glial cells, no such lesions were found when using a model of
postnatal organotypic slice cultures. This conclusion is based on both functional
and morphologic tests.
PMID- 10781289
TI - Intravenous anesthetics differentially modulate ligand-gated ion channels.
AB - BACKGROUND: Heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) are
potently inhibited by volatile anesthetics, but it is not known whether they are
affected by intravenous anesthetics. Ketamine potentiates gamma-aminobutyric acid
type A (GABAA) receptors at high concentrations, but it is unknown whether there
is potentiation at clinically relevant concentrations. Information about the
effects of intravenous anesthetics with different behavioral profiles on specific
ligand-gated ion channels may lead to hypotheses as to which ion channel effect
produces a specific anesthetic behavior. METHODS: A heteromeric nAChR composed of
alpha4 and beta4 subunits was expressed heterologously in Xenopus laevis oocytes.
Using the two-electrode voltage clamp technique, peak ACh-gated current was
measured before and during application of ketamine, etomidate, or thiopental. The
response to GABA of alpha1beta2gamma2s GABAA receptors expressed in human
embryonic kidney cells and Xenopus oocytes was compared with and without
coapplication of ketamine from 1 microm to 10 mm. RESULTS: Ketamine caused
potent, concentration-dependent inhibition of the alpha4beta4 nAChR current with
an IC50 of 0.24 microm. The inhibition by ketamine was use-dependent; the
antagonist was more effective when the channel had been opened by agonist.
Ketamine did not modulate the alpha1beta2gamma2s GABAA receptor response in the
clinically relevant concentration range. Thiopental caused 27% inhibition of ACh
response at its clinical EC50. Etomidate did not modulate the alpha4beta4 nAChR
response in the clinically relevant concentration range, although there was
inhibition at very high concentrations. CONCLUSIONS: The alpha4beta4 nAChR, which
is predominantly found in the central nervous system (CNS), is differentially
affected by clinically relevant concentrations of intravenous anesthetics.
Ketamine, commonly known to be an inhibitor at the N-methyl-D-aspartate receptor,
is also a potent inhibitor at a central nAChR. It has little effect on a common
CNS GABAA receptor in a clinically relevant concentration range. Interaction
between ketamine and specific subtypes of nAChRs in the CNS may result in
anesthetic behaviors such as inattention to surgical stimulus and in analgesia.
Thiopental causes minor inhibition at the alpha4beta4 nAChR. Modulation of the
alpha4beta4 nAChR by etomidate is unlikely to be important in anesthesia practice
based on the insensitivity of this receptor to clinically used concentrations.
PMID- 10781290
TI - The action of sevoflurane on vascular smooth muscle of isolated mesenteric
resistance arteries (part 1): role of endothelium.
AB - BACKGROUND: The direct action of sevoflurane on systemic resistance arteries is
not fully understood. METHODS: Isometric force was recorded in isolated rat small
mesenteric arteries. RESULTS: Sevoflurane (2-5%) enhanced contractile response to
norepinephrine only in the presence of endothelium, but inhibited it in its
absence. Sevoflurane still enhanced the norepinephrine response after inhibitions
of the nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase
and lipoxygenase pathways, or after blockade of either endothelin-1 ET-1),
angiotensin-II, or sevotonin receptors. Sevoflurane (3-5%) inhibited contractile
response to potassium chloride only in the absence of endothelium but did not
influence it in its presence. In the endothelium-intact strips, inhibition of the
norepinephrine response, which was enhanced during application of sevoflurane,
was observed after washout of sevoflurane and persisted for approximately 15 min.
In the endothelium-denuded strips, the inhibition of norepinephrine response was
similarly prolonged after washout of sevoflurane. However, no significant
inhibitions of potassium chloride response were observed after washout of
sevoflurane in both the endothelium-intact and the endothelium-denuded strips.
CONCLUSIONS: The action of sevoflurane on norepinephrine contractile response
consists of endothelium-dependent vasoconstricting and endothelium-independent
vasodilating components. In the presence of endothelium, the former predominates
over the latter, enhancing the norepinephrine response. The endothelium
independent component persisted after washout of sevoflurane, leading to
prolonged inhibition of the norepinephrine response. The mechanisms behind the
sevoflurane-induced inhibition of norepinephrine response are at least in part
different from those behind its inhibition of potassium chloride response. Nitric
oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase products,
lipoxygenase products, endothelin-1, angiotensin-II, and serotonin are not
involved in the vasoconstricting action. (Key words: Halogenated volatile
anesthetics; sympathetic nervous system; systemic hypotension; vascular
endothelium.)
PMID- 10781291
TI - The action of sevoflurane on vascular smooth muscle of isolated mesenteric
resistance arteries (part 2): mechanisms of endothelium-independent
vasorelaxation.
AB - BACKGROUND: The precise mechanisms behind the direct inhibitory action of
sevoflurane on vascular smooth muscle have not been fully elucidated. METHODS:
Endothelium-denuded smooth muscle strips were prepared from rat small mesenteric
arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were
measured simultaneously in the fura-2-loaded strips. In another series of
experiments, only isometric force was measured in the beta-escin-membrane
permeabilized strips. RESULTS: Sevoflurane (3-5%) inhibited the increases in both
the [Ca2+]i and the force induced by either norepinephrine (0.5-10 microm) or 40
mm K+. Sevoflurane still inhibited the increase in [Ca2+]i induced by
norepinephrine after depletion of intracellular Ca2+ stores with ionomycin,
although it little influenced the increase in [Ca2+]i induced by norepinephrine
after treatment with verapamil. In the fura-2-loaded membrane-intact muscle,
sevoflurane caused a rightward shift of Ca2+-force relation during force
development to stepwise increment of extracellular Ca2+ concentration during 40
mm K+ depolarization in either the presence or the absence of norepinephrine. In
contrast, sevoflurane did not influence Ca2+-activated contraction in the beta
escin-permeabilized muscle, in which alpha-adrenergic receptor coupling was not
retained. CONCLUSIONS: The inhibitory effects of sevoflurane on both
norepinephrine- and potassium chloride (KCl)-induced contractions are caused by
reduction of [Ca2+]i in vascular smooth muscle and inhibition of the myofilament
Ca2+ sensitivity. The [Ca2+]i-reducing effect of sevoflurane observed in both the
norepinephrine- and the K+-stimulated muscle is mainly caused by inhibition of
voltage-gated Ca2+ influx. The inhibitory effect of sevoflurane on Ca2+
activation of contractile proteins seems to be mediated by the cell membrane or
by some diffusible substances that are lost in the beta-escin-permeabilized
cells.
PMID- 10781293
TI - Preventing postoperative pulmonary complications: the role of the
anesthesiologist.
PMID- 10781292
TI - Surgeon and type of anesthesia predict variability in surgical procedure times.
AB - BACKGROUND: Variability in surgical procedure times increases the cost of
healthcare delivery by increasing both the underutilization and overutilization
of expensive surgical resources. To reduce variability in surgical procedure
times, we must identify and study its sources. METHODS: Our data set consisted of
all surgeries performed over a 7-yr period at a large teaching hospital,
resulting in 46,322 surgical cases. To study factors associated with variability
in surgical procedure times, data mining techniques were used to segment and
focus the data so that the analyses would be both technically and intellectually
feasible. The data were subdivided into 40 representative segments of manageable
size and variability based on headers adopted from the common procedural
terminology classification. Each data segment was then analyzed using a main
effects linear model to identify and quantify specific sources of variability in
surgical procedure times. RESULTS: The single most important source of
variability in surgical procedure times was surgeon effect. Type of anesthesia,
age, gender, and American Society of Anesthesiologists risk class were additional
sources of variability. Intrinsic case-specific variability, unexplained by any
of the preceding factors, was found to be highest for shorter surgeries relative
to longer procedures. Variability in procedure times among surgeons was a
multiplicative function (proportionate to time) of surgical time and total
procedure time, such that as procedure times increased, variability in surgeons'
surgical time increased proportionately. CONCLUSIONS: Surgeon-specific
variability should be considered when building scheduling heuristics for longer
surgeries. Results concerning variability in surgical procedure times due to
factors such as type of anesthesia, age, gender, and American Society of
Anesthesiologists risk class may be extrapolated to scheduling in other
institutions, although specifics on individual surgeons may not. This research
identifies factors associated with variability in surgical procedure times,
knowledge of which may ultimately be used to improve surgical scheduling and
operating room utilization.
PMID- 10781294
TI - Insidious intoxication after morphine treatment in renal failure: delayed onset
of morphine-6-glucuronide action.
PMID- 10781295
TI - Dilated nonreactive pupils secondary to neuromuscular blockade.
PMID- 10781296
TI - Massive hemoptysis after the initiation of positive pressure ventilation in a
patient with pulmonary tuberculosis.
PMID- 10781297
TI - Thoracic epidural anesthesia for thoracoscopy, rib resection, and thoracotomy in
a patient with a bronchopleural fistula postpneumonectomy.
PMID- 10781298
TI - Electromyographic activity falsely elevates the bispectral index.
PMID- 10781299
TI - Vasoconstrictive versus vasodilatory effects of alpha-2 adrenergic agonists on
the spinal microcirculation.
PMID- 10781300
TI - Bias in a further model for predicting PONV may not advance current knowledge.
PMID- 10781301
TI - Perturbation of lipid and protein structure by general anesthetics: how little is
too little?
PMID- 10781302
TI - Is the system at fault, or its players?
PMID- 10781303
TI - The purpose of peer review.
PMID- 10781304
TI - Postoperative metastasis risk: more than immunosuppression.
PMID- 10781305
TI - Does perioperative antithrombotic therapy increase the likelihood of a
postoperative coagulopathy after cardiac surgery?
PMID- 10781306
TI - Inadvertent misconnection of the scavenger hose: A cause for increased pressure
in the breathing circuit.
PMID- 10781307
TI - Use of esophageal stethoscope as an introducer during nasotracheal intubation.
PMID- 10781308
TI - Preparation for nasotracheal intubation.
PMID- 10781309
TI - Middle turbinectomy: A complication of IMPROPER nasal intubation?
PMID- 10781310
TI - A linguistic crisis? Maybe. A linguistic crises? Definitely not!
PMID- 10781311
TI - Arytenoid subluxation caused by laryngoscopy and intubation.
PMID- 10781312
TI - Potency of cisatracurium: a correction.
PMID- 10781313
TI - A simple towel headrest for infants and children.
PMID- 10781315
TI - Author correction
PMID- 10781314
TI - Radial to femoral arterial pressure gradient from massive ascites.
PMID- 10781316
TI - Pyrazoline reception: a possible role of opioid receptors of sensory neurons.
PMID- 10781317
TI - Generation of the semantic content of an utterance in patients with focal lesions
in the frontal and occipital areas of the right and left hemispheres.
PMID- 10781318
TI - Hearing characteristics of the harbor porpoise Phocoena phocoena.
PMID- 10781319
TI - Decreased concentration of high-energy phosphates prevents a decrease in redox
potential of skeletal muscles under gravitational unloading.
PMID- 10781320
TI - Caffeine effect on the cholinergic postsynaptic membrane of a mouse neuromuscular
synapse.
PMID- 10781321
TI - Effects of intranasal administration of pineal-gland peptides on aggressive
defensive behavior of unilaterally adrenalectomized rats.
PMID- 10781322
TI - The role of calcium binding to the external membrane in the regulation of electro
mechanical connection in early myogenesis.
PMID- 10781323
TI - Changes in optical spectra of gamma-globulin and possible mechanisms of its
physiological effects in organisms exposed to gamma-radiation.
PMID- 10781324
TI - Transitive inference in hooded crows: preliminary data.
PMID- 10781326
TI - Effects of dermorphin and its analogues on spontaneous behavior in white rats.
PMID- 10781325
TI - Ultrastructural study of the endoplasmic reticulum in Mauthner cells of fish
after fatigue and restoration of the function.
PMID- 10781327
TI - Effect of ambient pressure on the membrane state and liver cytochrome P450
activity in a series of vertebrates.
PMID- 10781328
TI - Heterosis as the cause of the secular trend in humans.
PMID- 10781329
TI - The vole species Microtus arvalis and Microtus rossiaemeridionalis in the Urals:
hybridization in the wild.
PMID- 10781330
TI - Vertical and geographical distribution patterns of vestimentiferans (Pogonophora,
Vestimentifera).
PMID- 10781331
TI - Theriological survey along the Northern Sea Route in 1999.
PMID- 10781332
TI - Specific features of roach (Rutilus rutilus L.) behavior in the turbulence
intensity gradient over the flow depth.
PMID- 10781333
TI - Mechanism of formation of chimeric mobile elements responsible for the extremely
unstable mutations in Drosophila melanogaster.
PMID- 10781334
TI - Spine architectonics in some rodents (Rodentia: Myomorpha, Hystricomorpha).
PMID- 10781335
TI - Ecological and geographical aspects of the plague agent Yersinia pestis
speciation.
PMID- 10781336
TI - Ecological mechanisms of soil biota tolerance to metal contamination.
PMID- 10781337
TI - Comparative characteristics of the muscular tissue in bony fishes with different
nutrition types.
PMID- 10781338
TI - Genomic organization of the mouse ubi-d4/requiem gene.
PMID- 10781339
TI - An experience of compilation of a database on plankton studies in the arctic
basin.
PMID- 10781340
TI - Characteristics of microevolution in the polymorphic species Archips podana Scop.
(Lepidoptera: Tortricidae).
PMID- 10781341
TI - The abundance-size relationship in crustaceans from the order Euphausiacea.
PMID- 10781342
TI - Characteristics of lipids from green alga Botryococcus braunii synthesizing
liquid hydrocarbons.
PMID- 10781343
TI - Nonmonotonic changes of lipid metabolism in thymocyte nuclei of rats exposed to
chronic gamma-radiation.
PMID- 10781344
TI - The right atrial/transoesophagael approach for conversion of atrial fibrillation:
a hybrid method for compromise?
PMID- 10781345
TI - The unresolved mystery of stress-induced ST segment elevation after myocardial
infarction.
PMID- 10781346
TI - Diabetes, coronary heart disease and sulphonylureas-not the final word.
PMID- 10781347
TI - Should we transfer patients with acute myocardial infarction to a tertiary care
hospital for primary angioplasty?
PMID- 10781348
TI - Obesity, Cinderella of CHD risk factors.
PMID- 10781349
TI - The optimal management of cardioversion of atrial fibrillation or flutter: still
a 'stunning' problem.
PMID- 10781350
TI - Troponins in pericarditis: implications for diagnosis and management of chest
pains patients.
PMID- 10781351
TI - Clinical developments in cardiac activation mapping.
PMID- 10781352
TI - Overweight and obesity: a major challenge for coronary heart disease secondary
prevention in clinical practice in Europe.
AB - AIMS: To evaluate the management of overweight and obesity in coronary artery
disease patients in Europe. METHODS AND RESULTS: The EUROASPIRE Study is a
multicentre epidemiological study involving nine European countries. The major
cardiovascular risk factors and their management were collected from hospital
records and measured at least 6 months after hospitalization during a specific
interview. A total of 4863 consecutive records from men and women with coronary
artery disease, under 71 years of age, were reviewed. Interviews were obtained
for 3569 (73%). Body mass index was computed from height and weight noted in the
medical records and measured at interview. Management of overweight and obesity
was recorded at interview. At least 6 months after hospitalization, 75% of women
and 80% of men were overweight and 33% of women and 23% of men were obese. Height
noted in medical records was over-estimated, inducing an under-estimation of
obesity in 16% of men and 33% of women. Advice from a nutritionist was offered in
less than 20% of obese patients. The same trends were observed in all
participating countries. CONCLUSIONS: Prevalences of overweight and obesity are
high in coronary artery disease patients in Europe. A systematic measurement of
height and weight is a prerequisite to a better management of this common
modifiable risk factor.
PMID- 10781353
TI - Dobutamine- vs exercise-induced ST segment elevation early after Q wave
myocardial infarction. Prediction of functional recovery after revascularization.
AB - AIMS: The association between stress-induced ST elevation and functional recovery
following revascularization after myocardial infarction remains unclear. We
assessed the relative accuracy of dobutamine- and exercise-induced ST elevation
in Q wave leads in predicting functional recovery following revascularization,
and we investigated the relationship of ST elevation to different wall motion
responses to dobutamine. METHODS AND RESULTS: Thirty-nine patients underwent
dobutamine stress echo and exercise test 8+/-2 days after Q wave myocardial
infarction. All patients underwent angiography and subsequent revascularization.
Follow-up echocardiograms were obtained 7+/-4 weeks after revascularization.
Functional recovery was assessed by the difference between the baseline and the
follow-up asynergy index. Nineteen patients (48%) developed dobutamine- and
exercise-induced ST elevation. There was significant agreement between the tests
(k=0.58, P<0.001). We found a significant correlation between dobutamine and
exercise-induced ST elevation with functional recovery following
revascularization (r=0. 45, P<0.005 and r=0.7, P<0.001, respectively). The
parameters with the highest predictive value for functional recovery were: (a)
the biphasic response during dobutamine infusion, (b) the development of ST
elevation in both tests, and (c) the development of exercise-induced ST elevation
in more than three leads. CONCLUSION: There is a strong association between
dobutamine- and exercise-induced ST elevation with functional recovery following
revascularization. Exercise-induced ST elevation in more than three leads and a
biphasic response during dobutamine infusion accurately predict functional
recovery.
PMID- 10781354
TI - Multicentre randomized trial comparing transport to primary angioplasty vs
immediate thrombolysis vs combined strategy for patients with acute myocardial
infarction presenting to a community hospital without a catheterization
laboratory. The PRAGUE study.
AB - BACKGROUND: Primary coronary angioplasty is an effective reperfusion strategy in
acute myocardial infarction. However, its availability is limited, and
transporting patients to an angioplasty centre in the acute phase of myocardial
infarction has not yet been proved safe. METHODS: The PRAGUE study (PRimary
Angioplasty in patients transferred from General community hospitals to
specialized PTCA Units with or without Emergency thrombolysis) compared three
reperfusion strategies in patients with acute myocardial infarction, presenting
within 6 h of symptom onset at community hospitals without a catheterization
laboratory: group A - thrombolytic therapy in community hospitals (n=99), group B
- thrombolytic therapy during transportation to angioplasty (n=100), group C -
immediate transportation for primary angioplasty without pre-treatment with
thrombolysis (n=101). RESULTS: No complications occurred during transportation in
group C. Two ventricular fibrillations occurred during transportation in group B.
Median admission-reperfusion time in transported patients (group B 106 min, group
C 96 min) compared favourably with the anticipated >90 min in group A. The
combined primary end-point (death/reinfarction/stroke at 30 days) was less
frequent in group C (8%) compared to groups B (15%) and A (23%, P<0. 02). The
incidence of reinfarction was markedly reduced by transport to primary
angioplasty (1% in group C vs 7% in group B vs 10% in group A, P<0.03).
CONCLUSIONS: Transferring patients from community hospitals to a tertiary
angioplasty centre in the acute phase of myocardial infarction is feasible and
safe. This strategy is associated with a significant reduction in the incidence
of reinfarction and the combined clinical end-point of death/reinfarction/stroke
at 30 days when compared to standard thrombolytic therapy at the community
hospital.
PMID- 10781355
TI - Serum cardiac troponin I and ST-segment elevation in patients with acute
pericarditis.
AB - OBJECTIVE: ST-segment elevation in acute pericarditis is believed to be caused by
superficial myocardial inflammation or epicardial injury. We used cardiac
troponin I, a sensitive and specific marker of myocardial injury, to assess
myocardial lesions in idiopathic acute pericarditis and its relationship to ST
segment elevation. PATIENTS AND METHODS: Sixty-nine consecutive patients (53 men,
48+/-17 years) with idiopathic acute pericarditis were included. We used an
enzymoimmunoflurometric method to measure serum cardiac troponin I on admission
(myocardial infarction threshold was 1.5 ng. ml(-1)). RESULTS: Cardiac troponin I
was detectable in 34 patients (49%) and was beyond the 1.5 ng. ml(-1)threshold in
15 (22%). Coronary angiography performed in seven of these 15 patients was normal
in all of them. ST-segment elevation was observed in 93% of the patients with
cardiac troponin I >1.5 ng. ml(-1)vs 57% of those without (P<0.01). Sensitivity
of ST-segment elevation to detect myocardial injury was 93% and specificity 43%.
Patients with a cardiac troponin I increase higher than 1.5 ng. ml(-1)were more
likely to have had a recent infection (66% vs 31%;P=0.01) and were younger (37+/
14 vs 52+/-16 years;P=0.002). There was no significant relationship with other
parameters such as pericardial friction rub, fever, PR segment abnormalities,
echocardiographic findings or C-reactive protein. CONCLUSION: In patients with
idiopathic acute pericarditis, an increase in cardiac troponin I is frequently
observed, especially in younger patients and those with a recent infection.
Although ST-segment elevation does not reliably indicate myocardial injury, a
significant cardiac troponin I increase is only seen in these patients.
PMID- 10781356
TI - Transoesophageal echocardiography-guided cardioversion of atrial fibrillation or
flutter. Selection of a low-risk group for immediate cardioversion.
AB - AIMS: Despite exclusion of left atrial thrombi by transoesophageal
echocardiography, cardioversion-related thromboembolism has been reported in
atrial fibrillation or flutter. To define a low-risk group for cardioversion
without previous anticoagulation, patients were selected for immediate
cardioversion if there were no thrombi, no echo spontaneous contrast and the
outflow velocity of the left atrial appendage was greater than 0.25 m. s(-1)on
transoesophageal echocardiography. METHODS AND RESULTS: Two hundred and forty-two
consecutive patients referred for cardioversion of atrial fibrillation or flutter
with a duration of more than 2 days and no anticoagulation therapy were examined
with transoesophageal echocardiography. After the transoesophageal
echocardiography examination, patients who were eligible for immediate
cardioversion were anticoagulated with low molecular weight heparin (dalteparin)
subcutaneously, together with warfarin prior to cardioversion. Dalteparin
treatment was continued until the patient had reached therapeutic prothrombin
values. Based on the transoesophageal echocardiographic findings the patients
were divided into two groups: immediate cardioversion, group A, with a mean age
of 62+/-13 years (n=162); or conventional warfarin treatment before
cardioversion, group B, with a mean age of 67+/-10 years (P<0.05) (n=80). In
group A, lone atrial fibrillation or flutter was more common (53%; 95% CI: 45-61)
compared to group B (34%; 95% CI: 23-44, P<0.05), while heart disease was more
common in group B (45%; 95% CI: 34-56) compared to group A (31%; 95% CI: 24-39,
P<0.05). Echocardiography revealed thrombi in 5% (95% CI: 2.6-8) of the patients,
left atrial size was larger, fractional shortening lower, and a higher proportion
had impaired left ventricular function in group B. No thromboembolic event
occurred at or after cardioversion in any of the patients; however, before
planned cardioversion one transitory ischaemic attack, one lethal stroke and one
cardiac death occurred in three of the patients with thrombi despite warfarin
therapy. One-month follow-up maintenance of sinus rhythm was 75% in group A
compared to 45% in group B (P<0.01). CONCLUSION: After using our transoesophageal
echocardiographic exclusion criteria (no thrombi, no spontaneous echo contrast
and left atrial appendage outflow velocity > or = 25 m. s(-1)) cardioversion can
safely be performed in 2/3 of patients with atrial fibrillation or flutter
without previous anticoagulation therapy. These patients maintained sinus rhythm
significantly better after 1 month compared to patients with prolonged warfarin
therapy before cardioversion.
PMID- 10781357
TI - Transoesophageal low-energy cardioversion of atrial fibrillation. Results with
the oesophageal-right atrial lead configuration.
AB - BACKGROUND: Low energy internal cardioversion is a safe and effective procedure
to restore sinus rhythm in patients with atrial fibrillation refractory to
external cardioversion. However the procedure is invasive and fluoroscopy is
mandatory. Aim of the study To assess the efficacy, safety and tolerability of a
new simplified procedure of low energy internal cardioversion. METHODS: Twenty
five consecutive patients (19 males and 6 females) with persistent atrial
fibrillation were submitted to low energy internal cardioversion using a step-up
protocol (in steps of 50 V, starting from 300 V). A large surface area lead
(cathode) was positioned in the oesophagus, 45 cm from the nasal orifice. A
second large surface area lead (anode) was positioned in the right atrium. A
quadripolar lead was positioned at the right ventricular apex to achieve
ventricular synchronization and back-up pacing. Oesophageal endoscopy was
performed within 24 h of the end of the procedure and repeated after 48 h, if
injury to the oesophageal mucosa had occurred. RESULTS: Sinus rhythm was restored
in 23 patients (92%) with a mean delivered energy of 15.74 J (range 5-27) and a
mean impedance of 48 Omega. In two patients, endoscopy revealed that small burns
had occurred in the oesophageal mucosa. Such lesions spontaneously healed after
48 h. CONCLUSIONS: This new technique of performing low energy internal
cardioversion is effective and safe and avoids the positioning of a lead in the
coronary sinus or in the left pulmonary artery, thereby simplifying the
procedure.
PMID- 10781358
TI - Nitric oxide synthase in CHF.
PMID- 10781359
TI - Classification of acute MI.
PMID- 10781360
TI - A reply
PMID- 10781361
TI - Digoxin and mortality in idiopathic dilated cardiomyopathy.
PMID- 10781362
TI - A reply
PMID- 10781363
TI - Stress echo training - need for a better gold standard: the invasive viewpoint.
PMID- 10781365
TI - ESC news and appointments
PMID- 10781364
TI - Cardiac rehabilitation.
PMID- 10781366
TI - Association of Academic Surgery presidential address: an attitude of gratitude.
PMID- 10781367
TI - AcademicSurgery@Leadership.you.
PMID- 10781368
TI - The outcome of research training during surgical residency.
AB - BACKGROUND/PURPOSE: Graduates of a university surgical residency program were
surveyed to identify the timing of specialty selection and the impact that
studying in a research laboratory had on subsequent acceptance into a fellowship
program. METHODS: Between 1975 and 1990, 86 residents completed general surgery
training at UCLA Medical Center. A survey was sent to all graduates to determine
the focus of their previous laboratory research and when they selected their
eventual surgical specialty. Responses were received from 67 of the 86 graduates
(78%). RESULTS: Forty-eight of the sixty-seven respondents (72%) took one or more
years of surgical research during residency. Postresidency fellowship training
was selected by 55 of 67 (82%); 50 applied to fewer than five programs; 49 of 55
(89%) received one of their top three choices. Twenty-seven of the sixty-seven
residents pursued an academic career (40%). Residents who performed at least 2
years of research were more likely to become academicians (53%) than residents
who did 1 year or less of research (22%). Only 39 of 67 residents (58%) had
selected a specialty after 2 years of clinical training; 28 more made the
selection after the third clinical year. All residents interested in cardiac
surgery (n = 18) or plastic surgery (n = 4) prior to research were accepted into
fellowships in those specialities, whereas only 37% of those who had an interest
in other fields pursued the same specialty (P < 0.0001). Residents performing
research in general surgery (n = 9), surgical oncology (n = 18), cardiac surgery
(n = 14), and plastic surgery (n = 3) were more likely to practice in that
specialty than those doing research in other specialty laboratories. CONCLUSIONS:
General surgery residents performing research in a specialty laboratory are
likely to pursue fellowship training relating to that field. Those who select a
career in cardiac or plastic surgery prior to research are most likely to enter
into these fields as their eventual specialty. Residents who perform 2 or more
years of laboratory research publish more papers and often pursue an academic
career.
PMID- 10781369
TI - Signaling mechanisms of glucagon-like peptide 2-induced intestinal epithelial
cell proliferation.
AB - BACKGROUND: Glucagon-like peptide 2 (GLP-2) stimulates intestinal epithelial
growth with high potency and specificity. However, the intracellular signaling
pathways responsible for the growth-stimulatory action of GLP-2 are not clearly
understood. Here we report possible signaling pathways mediating GLP-2's
proliferative actions in the human intestinal epithelial cell line Caco-2.
MATERIALS AND METHODS: Caco-2 cells were subcultured under serum-deprived
conditions in the presence or absence of GLP-2 (10 microM) and varying
concentrations of inhibitors of three candidate kinases: genistein, a global
tyrosine kinase inhibitor; LY294002, a phosphatidylinositide (PI) 3-kinase
inhibitor; and PD 098059, a mitogen-activated/extracellular signal-regulated
kinase (MEK) inhibitor. Proliferation was assessed using [(3)H]thymidine
incorporation. Relative abundance of the phosphorylated forms of two specific
mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, was assessed by Western
blotting. RESULTS: GLP-2-treated cells demonstrated a greater than 10-fold
increase in proliferation. This response was inhibited by genistein, LY294002,
and PD 098059 in a dose-dependent fashion. A significantly greater abundance of
the phosphorylated forms of both ERK-1 and ERK-2 was present in cells within 5
min of treatment with GLP-2. CONCLUSIONS: GLP-2 stimulates the proliferation of
Caco-2 cells in vitro. This increase in Caco-2 proliferation in response to GLP-2
may be due, at least in part, to the involvement of both the PI 3-kinase and the
MAPK pathways.
PMID- 10781370
TI - Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism.
AB - BACKGROUND: Hepatic innervation plays an essential role in insulin extraction and
glucose production, but the specific role of hepatic cholinergic innervation
remains unclear. We sought to establish a model of isolated hepatic cholinergic
denervation (IHCD), and to assess whether glycogen storage or the control of net
hepatic glucose production (HGP) was altered by IHCD. MATERIALS AND METHODS:
Sprague-Dawley rats underwent either hepatic vagotomy or sham operation. Liver
tissue was stained for vesicular acetylcholine transporter (VAChT) and
(nonspecific neural) protein gene product 9. 5 (PGP) for verification of IHCD.
Liver glycogen content was quantified in fed and fasted IHCD or sham-operated
animals. HGP was determined after single-pass isolated liver perfusion, during
which a 30-min 12 ng/ml glucagon infusion was begun after equilibration, and
after 10 min, a 200 microU/ml insulin infusion was added. RESULTS: Uniform
staining of PGP and absence of VAChT staining in hepatic vagotomized rats
demonstrated the validity of our model. Glycogen content of sham-operated livers
(n = 8) increased from 6.0 +/- 1.7 in the fasting state to 10.6 +/- 1.8 mg/g
liver, after feeding (P < 0.05). IHCD livers (n = 8) showed no comparable
increase (3.5 +/- 0.6 to 4.0 +/- 0.7 mg/g liver). Perfusion with glucagon alone
resulted in less HGP in IHCD livers (n = 12) compared with sham-operated livers
(n = 10) (integrated HGP 3.3 +/- 0.3 mg/g liver min(-1) vs 5.1 +/- 0.5 mg/g liver
min(-1), P < 0.05). Insulin infusion revealed impaired responsiveness to insulin
after IHCD; the ratio of HGP in the final 10 min of perfusion (glucagon and
insulin) to HGP in the initial 10 min (glucagon alone) was 90.3 +/- 2.4% for IHCD
livers versus 68.1 +/- 4.4% for sham-operated controls, respectively (P =
0.0002). CONCLUSIONS: Our study shows that IHCD results in significant impairment
in liver glycogen storage and impaired hepatic sensitivity to glucagon and,
possibly, to insulin. We conclude that hepatic cholinergic integrity is essential
to normal hepatic glucose metabolism.
PMID- 10781371
TI - Iron deficiency diminishes gallbladder neuronal nitric oxide synthase.
AB - BACKGROUND: Iron deficiency has been demonstrated in the prairie dog to result in
cholesterol crystal formation and altered biliary motility. Gallbladder filling
and emptying are influenced by both inhibitory and excitatory stimuli, with
nitric oxide (NO) playing a key role in normal relaxation. Iron is a cofactor for
nitric oxide synthase. Therefore, we tested the hypothesis that iron deficiency
would result in diminished levels of gallbladder neuronal nitric oxide synthase
(nNOS) but would not influence the gallbladder's response to excitatory stimuli.
MATERIALS AND METHODS: Twenty adult female prairie dogs were fed either an iron
supplemented (Fe(+)) (200 ppm) control diet (n = 10) or an iron-deficient (Fe-)
(8 ppm) diet (n = 10) for 8 weeks. Fasting gallbladder volume was measured.
Gallbladder muscle strips were harvested for response to excitatory stimuli and
measurement of nNOS protein levels by Western blotting. Muscle strip response to
a spectrum of doses of cholecystokinin, acetylcholine, and electrical field
stimuli was determined, and the areas under the response curves were calculated.
RESULTS: Gallbladder volume increased in the iron-deficient prairie dogs compared
with the iron-supplemented group (1.45 +/- 0.27 mL vs 0.80 +/- 0.13 mL, P <
0.05). Iron deficiency diminished the ratio of gallbladder nNOS to beta-actin
protein levels (0.05 +/- 0.01 vs 3.48 +/- 1.02, P < 0.05) but resulted in a
normal response to excitatory stimuli. CONCLUSIONS: We conclude that diminished
gallbladder neuronal nitric oxide synthase contributes to the gallbladder stasis
that occurs with iron deficiency. This phenomenon may contribute to the increased
incidence of gallstones in premenopausal women.
PMID- 10781373
TI - Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent.
AB - BACKGROUND: Genetic mutations found in pancreatic cancer (K-ras, p16, p53) lead
to inappropriate cellular proliferation. Mitogens stimulate proliferation via the
phosphatidylinositol 3-kinase (PI3K)- and/or the p44/42-mitogen-activated protein
kinase [p44/42-MAPK or extracellular signal-regulated kinase (ERK)] signaling
pathways. We examined whether inhibition of either PI3K or ERK could limit
proliferation in human pancreatic cancer. METHODS: Proliferation was stimulated
in quiescent human pancreatic cancer cell lines (BxPC3 and Panc-1) by 10% fetal
calf serum (FCS). In certain samples, PD98059 (an ERK inhibitor) or LY294002 (a
PI3K inhibitor) was also added. AKT phosphorylation (indicating PI3K activity)
and ERK phosphorylation (ERK activation) were determined by Western blot. Cell
viability was determined by MTT assay. Cell cycle progression and apoptosis were
determined by flow cytometry. A two-tailed t test was used for statistical
analysis of the data (significance P < 0.05). RESULTS: LY294002 inhibited the
PI3K pathway without affecting ERK activation in response to serum. PD98059
inhibited the ERK pathway specifically. In both BxPC-3 and Panc-1 cell lines,
LY294002 inhibited serum-induced proliferation. This was associated with G(1)
cell cycle arrest and with an increase in the rate of apoptosis. PD98059
inhibited proliferation only in BxPC3 cells, and to a lesser degree than did
LY294002. CONCLUSIONS: PI3K signaling appears to be necessary for G(1)-to-S phase
progression and proliferation in pancreatic cancer cells. ERK plays a lesser role
in mitogen-induced proliferation. Pharmacological inhibition of PI3K may decrease
proliferation, increase apoptosis, and potentially confer therapeutic benefit in
pancreatic cancer.
PMID- 10781372
TI - Neutrophils regulate their own apoptosis via preservation of CXC receptors.
AB - BACKGROUND: Dysregulated neutrophil (PMN) apoptosis is thought to contribute to
an exaggerated inflammatory response in diseases such as acute respiratory
distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). The CXC
chemokines, interleukin-8 (IL-8) and growth-related oncogene alpha (Gro-alpha),
contribute to the inflammatory response and suppress PMN apoptosis. We
hypothesized that PMN generation of CXC chemokines is an autocrine/paracrine
mechanism for amplification of the PMN inflammatory response via suppression of
apoptosis. METHODS: Freshly isolated human PMNs from healthy donors were
incubated with IL-8 or Gro-alpha (100 ng/ml) for 0-12 h, and apoptosis was
analyzed at 24 h. De novo synthesis of IL-8 or Gro-alpha was measured using an
ELISA. To determine if receptors were available to bind these newly synthesized
ligands (125)I radiolabeled monoclonal antibodies specific for each receptor
(CXCRI, CXCRII) were used to determine PMN receptor density. Comparison was by
one-way ANOVA. RESULTS: Significant suppression of apoptosis was seen at 24 h
with only 4 h exposure to IL-8 or Gro-alpha (n = 5, P < 0.05). PMNs cultured with
IL-8 for 4 h produced 31 +/- 4.3 ng/ml IL-8 by 24 h; PMNs cultured with Gro-alpha
produced 19.7 +/- 4.0 ng/ml Gro-alpha (n = 6, P < 0. 05). Neither chemokine
induced significant production of the other chemokine. The addition of either
ligand promoted upregulation of CXCR1 (n = 4, P < 0.05) at 24 h. However, CXCR2
was downregulated by Gro-alpha and IL-8 to 71 +/- 7.5 and 79 +/- 6.3% of control,
respectively (P < 0.05). CONCLUSION: IL-8 and Gro-alpha, which suppress
apoptosis, stimulate their own production after short-term incubation with PMNs.
PMNs maintain the ability to respond to these chemokines through expression of
the CXC receptors which suggests that PMNs are active participants in the
suppression of apoptosis at inflammatory sites. CXCRI remains upregulated after
prolonged stimulation and may be an important target for mediating neutrophil
responses to IL-8.
PMID- 10781374
TI - p21 (WAF1/CIP1) is required for the mitogenic response to intestinal resection.
AB - BACKGROUND: Increased enterocyte proliferation and apoptosis characterize the
intestinal adaptive response to massive small bowel resection (SBR). Since p21
(WAF1/CIP1) has been implicated to play a role in cellular differentiation and
apoptosis, this study tested the hypothesis that p21 is obligatory for adaptation
to occur. MATERIALS AND METHODS: p21-null (n = 36) and wild-type (C57B1/6, n =
19) mice underwent a 50% SBR or sham operation. After 3 days, parameters of
adaptation (ileal wet weight, villus/crypt morphology, and ileal protein
content), an enterocyte proliferation index (PI), and an apoptotic index (AI)
were determined in the residual ileum. In a separate set of experiments, p21-null
(n = 11) and control (n = 20) mice underwent the aforementioned operative
procedures and the remnant intestine was subjected to a reverse transcription
polymerase chain reaction for p27 (KIP1). RESULTS: Both AI and PI increased after
SBR in the wild-type mice. In the p21-null mice, SBR increased AI, but did not
affect the PI. After SBR, adaptive parameters increased in the wild-type mice,
but failed to increase in the p21-null mice. The absence of p21 caused a baseline
increase in p27 mRNA, which did not change after SBR. CONCLUSION: p21 appears to
be required to increase enterocyte proliferation and to augment the other
parameters of intestinal adaptation. In the absence of p21, the proliferative and
apoptotic responses to SBR are uncoupled. These results suggest a differential
mechanism for the regulation of enterocyte proliferation and apoptosis in the
adapting intestine.
PMID- 10781375
TI - Inhibition of alveolar neutrophil immigration in endotoxemia is macrophage
inflammatory protein 2 independent.
AB - BACKGROUND: Altered transendothelial migration and delayed apoptosis of
neutrophils (PMN) have been implicated as contributing to infection in patients
with gram-negative sepsis. Macrophage inflammatory protein 2 (MIP-2) signals PMN
immigration and may alter other PMN functions. We tested the hypothesis that
sequential endotoxin challenge in vivo alters PMN apoptosis and chemotactic
responses. MATERIALS AND METHODS: Endotoxemia was induced in male Wistar rats
(250 g) via intraperitoneal (IP) administration of LPS (4 mg/kg). After 18 h,
intratracheal (IT) injection of LPS (400 microg/kg) was performed. Control
animals received saline injections. Four hours after IT-LPS, circulating and
bronchoalveolar lavage (BAL) PMN were isolated. PMN yields were calculated, and
apoptosis was quantified after 18 h in culture by annexin V-fluorescein
isothiocyanate FACS analysis. BAL MIP-2 concentrations were determined by ELISA.
PMN chemotaxis to MIP-2 and IL-8 was determined using a fluorescent in vitro
migration assay. RESULTS: Endotoxemia (IP-LPS) significantly decreases BAL PMN
yield in response to an in vivo IT-LPS challenge. IT-LPS inhibits BAL PMN
apoptosis to the same extent as sequential IP/IT-LPS. Alveolar MIP-2
concentrations are similar in the two groups. In vitro migration to IL-8 and MIP
2 was inhibited in PMN from endotoxemic versus control animals. CONCLUSIONS:
These data demonstrate that endotoxemia inhibits PMN migration despite similar
MIP-2 concentrations in the alveolus. Sequential insults do not affect the
inhibition of apoptosis. In vitro, PMN from endotoxemic animals display impaired
chemotaxis to MIP-2 and interleukin-8. This may result in an inadequate host
defense that contributes to increased ICU-acquired pneumonia in septic patients.
PMID- 10781376
TI - Hypoosmotic stress activates p38, ERK 1 and 2, and SAPK/JNK in rat hepatocytes.
AB - BACKGROUND: Following hepatocyte injury, changes in the perihepatocyte milieu
modulate cell volume and influence growth. Hypoosmotic stress activates nuclear
factor-kappa B (NF-kappaB), a transcription factor believed to prime cell cycle
progression in hepatocytes. In this study, we investigate the role of mitogen
activated protein kinases (MAPKs) in the activation of NF-kappaB. MATERIALS AND
METHODS: Quiescent primary hepatocytes were exposed to hypoosmotic serum-free
William's E (WE) medium (200 mOsm/liter), with or without a 1-h pretreatment with
either PD 98059 (15 microM) or SB 202190 (3 microM). Parallel experiments were
conducted using hepatocyte growth factor (HGF) at 0.1 mg/ml and normoosmotic WE
medium as positive and negative controls, respectively (n = 3). Relative
densitometries of Western blots measured phosphorylated cytoplasmic p38, ERK 1
and 2, and SAPK/JNK. Electromobility shift assays examined nuclear NF-kappaB
activation. RESULTS: (i) Hypoosmolar WE medium phosphorylated p38, ERK 1 and 2,
and SAPK/JNK by 5 min. (ii) Hypoosmolar WE medium activated NF-kappaB at 60 min.
(iii) HGF phosphorylated all three MAPKs and activated NF-kappaB with profiles
similar to those of hypoosmotic stress. (iv) Both PD 98059 and SB 202190
abrogated the activation of NF-kappaB in HGF-stimulated cells but not in
hypoosmotically stressed cells. CONCLUSION: (i) Both hypoosmotic cell swelling
and HGF phosphorylate p38, ERK 1 and 2, and SAPK/JNK, and (ii) HGF, but not
hypoosmotic stress, activates NF-kappaB via p38 and ERK 1 and 2 phosphorylation.
These data suggest that cell swelling activates NF-kappaB through a pathway
separate from that of growth factors.
PMID- 10781377
TI - Role of stasis and oxidative stress in ileal pouch inflammation.
AB - BACKGROUND: Although ileal pouch-anal anastomosis has become the operation of
choice for patients with chronic ulcerative colitis and familial adenomatous
polyposis coli, ileal pouch inflammation or pouchitis remains a significant
postoperative complication. Numerous factors such as fecal stasis have been
implicated in the etiology of pouchitis; however, pouchitis remains poorly
understood due to the lack of a small animal model. One of the primary goals of
this study was to surgically create a reservoir or U-pouch in the ileum of a rat
in which stasis would occur in a manner that was unimpeded by other complicating
factors such as a colectomy. This model would allow investigation of the
hypothesis that intestinal stasis leads to biochemical changes that predispose
the ileal pouch to inflammation and oxidative stress. MATERIALS AND METHODS: A U
pouch was surgically created in the terminal ileum of Lewis rats just proximal to
the ileocecal valve without a colectomy. Stasis was assessed by serial barium
radiographs over 48 h. Thirty days after surgery, mucosa was obtained from the
ileal U-pouches and nonoperated ileum to assess inflammation and neutrophil
infiltration histologically and by measuring myeloperoxidase activity. Oxidative
stress was assessed by measuring 8-isoprostane levels in urine. Once the model
was validated and it was established that stasis and inflammation occurred in the
pouch, either vitamin E or allopurinol was administered for 30 days after which
myeloperoxidase and 8-isoprostane levels were again measured. RESULTS: In our
experimental model, ileal stasis resulted in increases in both mucosal
myeloperoxidase activity and urinary 8-isoprostane levels, suggesting that
oxidative stress was associated with stasis. Thirty-day treatment with vitamin E
or allopurinol reduced ileal myeloperoxidase activity and urinary 8-isoprostane
levels. CONCLUSION: These studies demonstrated that stasis in the ileum occurred
and was associated with neutrophil infiltration and oxidative stress. Antioxidant
treatment reduced the inflammatory response suggesting a role for antioxidant
therapy in the treatment of pouchitis.
PMID- 10781379
TI - Difficulty with negative feedback: face-to-face evaluation of junior medical
student clinical performance results in grade inflation.
AB - HYPOTHESIS: Direct, face-to-face feedback regarding a medical students' clinical
performance will not increase critical, objective analysis of their performance.
METHODS: A new ward evaluation system (NS) was used concurrently with our
standard written ward evaluation system (OS). The two methods were directly
compared using a standard t test. The OS is a subjective written evaluation of
clinical performance, with a summary grade of 1-6 given as a final grade, with 1
= fail and 6 = honors. The NS retains the 1-6 grading scale; however, students
met with individual faculty and residents and received a face-to-face evaluation
of their performance, as well as a written summary. Twenty-four third-year
medical students rotating on general surgery at the University of Michigan
Medical Center participated in the study. RESULTS: There was a significant degree
of grade inflation with the NS, particularly for students with poorer
performance. The average grade using the OS was 5.11 +/- 0. 11; with the NS, the
average grade was 5.62 +/- 0.07 (P < 0.001). If students with grades of 5.0 or
less in the OS are studied, then the average grade using the OS is 4.24 +/- 0.32,
in contrast to 5.47 +/- 0.14 with the NS (P < 0.005). An additional interesting
finding was noted: among the students who failed to participate in the face-to
face interviews (n = 4), the average grade using the OS was 4.36 +/- 0.29 (P <
0.05 vs OS total). CONCLUSIONS: While students desire more timely, direct
feedback on their clinical performance, faculty are poor at giving direct,
objective, face-to-face feedback, particularly when it involves negative
feedback, with resultant grade inflation.
PMID- 10781378
TI - Chlamydia pneumoniae activates nuclear factor kappaB and activator protein 1 in
human vascular smooth muscle and induces cellular proliferation.
AB - BACKGROUND: Observational data strongly suggest an association between Chlamydia
pneumoniae and atherosclerotic cardiovascular disease. However, few studies have
mechanistically linked C. pneumoniae to vascular remodeling. The purpose of the
present study was to examine the mechanistic relationship between C. pneumoniae
and human vascular smooth muscle cell (VSMC) physiology. We sought to determine
the influence of human VSMC infection by C. pneumoniae on (1) VSMC proliferation
and (2) activation of the proinflammatory and proliferative transcription factors
nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND
METHODS: C. pneumoniae was grown and isolated from Hep 2 cells. Human aortic
VSMCs were inoculated with C. pneumoniae in the presence and absence of the
azalide antibiotic azithromycin. Cell proliferation was assayed by direct cell
counting 48 h following infection. Two hours following infection, nuclear
extracts were isolated, and activation of both NF-kappaB and AP-1 was assessed by
electrophoretic mobility shift assay. RESULTS: Compared with control, C.
pneumoniae infection stimulated VSMC proliferation (P < 0.05) and induced both NF
kappaB and AP-1 DNA binding activity. These effects were eliminated by concurrent
treatment with azithromycin. CONCLUSIONS: VSMC infection with C. pneumoniae
activates proliferative intracellular signals and stimulates cell growth. These
data implicate C. pneumoniae as a pathogenic mediator and a potential therapeutic
target in the prevention of atherosclerotic disease.
PMID- 10781380
TI - Effects of intestinal ischemia/reperfusion injury on gastric acid secretion.
AB - BACKGROUND: The mechanism responsible for gastric colonization in critically
injured ICU patients remains to be fully elucidated. Moreover, the effects of gut
ischemia/reperfusion (I/R) injury on gastric function are unclear. It was our
hypothesis that gut I/R injury would cause gastric dysfunction. MATERIALS AND
METHODS: Rats were anesthetized and, via laparotomy, the superior mesenteric
artery (SMA) was clamped at its aortic origin for 45 min followed by clamp
removal. Rats were allowed to awaken and then killed after 6 h of reperfusion.
Control rats underwent laparotomy with SMA isolation. Stomachs were removed,
gastric fluid was aspirated, and the volume, pH, and protein, bicarbonate, and
glucose contents were determined. Serum and antral mucosa were prepared for
gastrin radioimmunoassay and the glandular mucosa was assessed for morphologic
injury. RESULTS: SMA I/R injury caused significant accumulation of gastric
luminal fluid that was alkaline and rich in protein, glucose, and bicarbonate
content when compared with sham controls. SMA I/R injury also caused gastric
surface epithelial cell injury and significantly increased serum and antral
gastrin levels. In additional rats, gut I/R injury inhibited basal acid secretion
and blunted the acid secretory response to pentagastrin. CONCLUSIONS: This study
demonstrated for the first time that small intestinal I/R injury causes
significant gastric dysfunction. The findings suggest that this type of injury, a
frequent occurrence in critically injured ICU patients, may predispose patients
to gastric colonization due to stasis and loss of the natural bactericidal
effects of gastric acid.
PMID- 10781381
TI - S-Nitrosothiols: a class of nitric oxide-donor drugs.
AB - Nitric oxide (NO) was originally described as the principal endothelium-derived
relaxing factor, but it is now known to subserve a variety of functions
throughout the body, both physiological and pathophysiological. NO-donor drugs
decompose in the body, by a variety of mechanisms, to generate NO. Such drugs
have been used for many years in cardiovascular therapeutics, in particular the
organic nitrates for the prevention and treatment of angina pectoris and sodium
nitroprusside for the treatment of hypertensive emergencies. However, patients
taking long-term nitrates often develop tolerance, and prolonged nitroprusside
administration can give rise to cyanide accumulation in the body. Newer NO-donor
drugs, in particular the S-nitrosothiols, offer advantages over the existing
drugs, since they do not share these drawbacks, and initial small clinical
studies suggest that they may be of benefit in a variety of cardiovascular
disorders. Here we briefly review the chemistry and physiology of NO, and discuss
the chemistry and clinical possibilities of the S-nitrosothiols.
PMID- 10781382
TI - Plasma soluble adhesion molecules and endothelium-dependent vasodilation in early
human atherosclerosis.
AB - Levels of soluble cellular adhesion molecules are increased in patients with
atherosclerosis, and have been found to predict coronary heart disease. Therefore
these molecules have been suggested to represent laboratory markers for
inflammation and activation of endothelial cells. Impaired endothelium-dependent
vasodilation has been demonstrated to be an early marker of atherosclerosis. We
hypothesized that soluble adhesion molecules are related to impaired endothelium
dependent vasodilation and may serve as an early marker of atherosclerosis.
Patients (n=52) with moderate and uncomplicated hypercholesterolaemia [low
density lipoprotein (LDL)-cholesterol 4.89+/-1.26 mmol/l] were compared with
healthy controls (n=43; LDL-cholesterol 2.44+/-0.79 mmol/l). Endothelium
dependent vasodilation of the forearm vasculature was assessed by intra-arterial
infusion of acetylcholine (12 and 48 microg/min). Forearm blood flow was measured
by venous occlusion plethysmography. Plasma concentrations of the soluble forms
of ICAM-1 (intercellular cell adhesion molecule-1), VCAM-1 (vascular cell
adhesion molecule-1) and E-selectin were measured by ELISA. Hypercholesterolaemic
patients had impaired endothelium-dependent vasodilation in comparison with
healthy controls (forearm blood flow after 48 microg/min acetylcholine: 21.3+/
10.6 and 30.4+/-16.3 ml. min(-1).100 ml(-1) respectively; P=0.002). Plasma
concentrations of soluble adhesion molecules were not different between
hypercholesterolaemic patients and controls (ICAM-1, 196+/-56 and 180+/-38 ng/ml
respectively; VCAM-1, 431+/-137 and 405+/-65 ng/ml respectively; E-selectin, 39+/
17 and 37+/-12 ng/ml respectively). Moreover, levels of soluble adhesion
molecules were not correlated with endothelium-dependent vasodilation. Thus, in
hypercholesterolaemic patients without clinical atherosclerosis, levels of
soluble adhesion molecules were not elevated in comparison with healthy controls.
In addition, these markers of endothelial inflammation were not related to
impaired endothelium-dependent vasodilation. Our data indicate that measurement
of levels of soluble adhesion molecules cannot replace assessment of endothelium
dependent vasodilation in detection of early hypercholesterolaemic
atherosclerosis.
PMID- 10781383
TI - Endothelial dysfunction as a possible link between C-reactive protein levels and
cardiovascular disease.
AB - Low-grade chronic inflammation, characterized by elevated plasma concentrations
of C-reactive protein (CRP), is associated with an increased risk of
atherosclerotic cardiovascular disease. Endothelial cell activation is an early
event in atherogenesis, and previous studies have reported correlations between
indirect markers of endothelial cell activation and CRP concentration. Therefore,
in the present study, we measured CRP concentration (and leptin concentration as
an index of fat mass) in nine healthy subjects (mean age 53+/-8.1 years; body
mass index 27+/-3.2 kg/m(2); mean arterial blood pressure 101+/-9.0 mmHg)
undergoing measurement of basal endothelial nitric oxide (NO) synthesis using
intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate
inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control
vasoconstrictor). In univariate analysis, CRP concentration was correlated with
(i) the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion
(r=0.85, P=0.004); and (ii) the serum leptin concentration (r=0.65, P=0.05). In
multivariate analysis, the relationship between CRP concentration and the FBF
response to L-NMMA remained significant when age and leptin (t=2.65, P=0.045),
age and BMI (t=3.69, P=0.014), or age and low-density-lipoprotein-cholesterol
plus high-density-lipoprotein-cholesterol (t=3.37, P=0.044), were included in
regression models. In contrast, the response of FBF to noradrenaline was not
significantly related to CRP concentration. These data demonstrate for the first
time a relationship between low-grade chronic inflammation and basal endothelial
NO synthesis (measured using an invasive method), and support the notion that
endothelial dysfunction is a critical intermediate phenotype in the relationship
between inflammation and cardiovascular disease.
PMID- 10781384
TI - Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female
guinea-pigs.
AB - Naturally occurring hydroxystilbenes have been shown to induce vasorelaxation.
Here, we studied the mechanism of resveratrol-induced vasorelaxation in different
types of blood vessels, namely mesenteric (resistance) and main uterine
(conductance) arteries, from female guinea-pigs on day 7 and day 15 of the
oestrous cycle. Resveratrol (5-70 micromol/l) induced concentration-dependent
relaxation of both mesenteric and uterine arteries preconstricted with either
noradrenaline (NA; 10 micromol/l) or KCl (125 mmol/l). Resveratrol was 2-fold
more potent in inducing relaxation of mesenteric arteries than of uterine
arteries. Its effects on uterine arteries from both day-7 and day-15 guinea-pigs
were similar, irrespective of the constrictor used, but it was significantly
(P<0.01) more potent in inducing relaxation of mesenteric arteries contracted
with NA compared with those constricted with KCl. In day-7 arteries precontracted
with NA, N(G)-nitro-L-arginine methyl ester (L-NAME; 10 micromol/l) had no
effects on the time course of resveratrol-induced vasorelaxation in either
mesenteric or uterine arteries. However, indomethacin (50 micromol/l)
significantly (P<0.05) potentiated resveratrol's effect on mesenteric, but not
uterine, arteries. Indomethacin had no effect on resveratrol-induced
vasorelaxation of arteries contracted with KCl, whereas L-NAME significantly
(P<0.05) reduced the effects of resveratrol on uterine, but not on mesenteric,
arteries. In day-15 arteries, L-NAME significantly (P<0.01) attenuated the
effects of resveratrol on mesenteric arteries contracted with NA. Indomethacin
had no effect on resveratrol activity. This study indicates that: (a) the effect
of resveratrol on resistance arteries is greater than that on conductance
arteries; (b) the effects of resveratrol are not mediated via prostanoids, but NO
may play a role; and (c) the stage of the oestrous cycle has no influence on
resveratrol-induced vasorelaxation.
PMID- 10781385
TI - Non-invasive measurement of stroke volume during exercise in heart failure
patients.
AB - The objective of the present study was to determine the variability of the
arterio-venous O(2) concentration difference [C(a-v)O(2)] at anaerobic threshold
and at peak oxygen uptake (VO(2)) during a progressively increasing cycle
ergometer exercise test, with the purpose of assessing the possible error in
estimating stroke volume from measurements of VO(2) alone. We sampled mixed
venous and systemic arterial blood every 1 min during a progressively increasing
cycle ergometer exercise test and measured, in each blood sample, haemoglobin
concentration and blood gas data. Ventilation, VO(2) and CO(2) uptake were also
measured continuously. We studied 40 patients with normal haemoglobin
concentrations and with stable heart failure due to ischaemic or idiopathic
cardiomyopathy. Mean values (+/-S.D.) for C(a-v)O(2) were 7.8+/-2.6, 13.0+/-2.4
and 15. 0+/-2.7 ml/100 ml at rest, anaerobic threshold and peak VO(2)
respectively. The patients with heart failure were divided into classes according
to their peak VO(2). Classes A, B and C contained patients with peak VO(2) values
of>20, 15-20 and 10-15 ml.min(-1). kg(-1) respectively. At anaerobic threshold,
C(a-v)O(2) was 12.3+/-1. 3, 13.1+/-2.7 and 13.5+/-2.6 ml/100 ml for classes A, B
and C respectively (class A significantly different from classes B and C;
P<0.05). At peak exercise C(a-v)O(2) was 13.6+/-1.4, 15.6+/-2.5 and 15.4+/-3.2
ml/100 ml for classes A, B and C respectively (class A significantly different
from classes B and C; P<0.05). Stroke volume was estimated for each subject using
the mean values of the measured C(a-v)O(2) in each functional class and
individual values of VO(2) and heart rate using the Fick formulation. The average
difference between the stroke volume estimated from mean C(a-v)O(2) and that
obtained using the patient's actual C(a-v)O(2) value was 9.2+/-9.7, 1.0+/-8.8 and
-0.2+/-6.1 ml at anaerobic threshold, and -1.9+/-11.3, 0.9+/-10.0 and -2.3+/-8.5
ml at peak exercise, in classes A, B and C respectively. Among the various
classes, the most precise estimation of stroke volume was observed for class C
patients. We conclude that stroke volume during exercise can be estimated with
the accuracy needed for most purposes from measurement of VO(2) at the anaerobic
threshold and at peak exercise, and from population-estimated mean values for C(a
v)O(2) in heart failure patients.
PMID- 10781386
TI - Differential timing for programming of glucose homoeostasis, sensitivity to
insulin and blood pressure by in utero exposure to dexamethasone in sheep.
AB - Numerous epidemiological studies have related an increased risk of adult-onset
cardiovascular and metabolic disease to an adverse intra-uterine environment at
critical periods. We have shown that fetal sheep exposed to dexamethasone for
only 2 days at 27 days of gestation (term approximately 150 days) became
hypertensive adults, whereas those exposed at 64 days of gestation remained
normotensive, as did controls. In the same sheep, now nearly 5 years old, we
performed glucose tolerance tests and hyperinsulinaemic euglycaemic clamps to
study the insulin sensitivity of glucose, amino acid and non-esterified fatty
acid metabolism. Glucose tolerance, calculated as the area under the curve, after
intravenous administration of bolus glucose and insulin secretion in response to
a glucose challenge were not altered in any group. There were no significant
differences in the insulin sensitivity of net whole-body glucose or amino acid
uptake. However, suppression of lipolysis by insulin, measured as the
proportional decrease in the circulating concentration of non-esterified fatty
acids during the hyperinsulinaemic clamp, was 69+/-1.2% at steady-state plasma
insulin levels ( approximately 1000 m-units/l) in the group exposed to
dexamethasone at 27 days of gestation, but only 50.8+/-6.5% in the controls
(P<0.05). In the group exposed to dexamethasone at 64 days of gestation, the
decrease was 66.4+/-5.1%, which did not reach significance compared with the
controls (P=0.10). Thus brief dexamethasone exposure during early gestation
programmed hypertension independently of insulin resistance of glucose or amino
acid metabolism; however, it did lead to increased insulin sensitivity of the
inhibition of lipolysis, which may increase susceptibility to the development of
obesity postnatally.
PMID- 10781387
TI - A new treatment for unresectable liver tumours: long-term studies of electrolytic
lesions in the pig liver.
AB - The majority of liver tumours are inoperable and an alternative treatment to
surgical resection is urgently needed. Electrolysis has been investigated in a
rat model and the procedure is safe, with accurate and predictable effects. The
necrosis produced has also been shown to cause destruction of tumour deposits in
the rat liver. A similar evaluation in a large animal model was necessary before
clinical trials could commence. Using platinum electrodes connected to a d.c.
generator, areas of hepatic necrosis were created in the pig liver. Animals were
killed at various time points after treatment to assess the extent of healing.
Treatment was uneventful and all animals made a full recovery. No animal died
from the treatment or had to be killed prematurely. After 2 days of treatment,
healing was minimal but at successive time points there was progressive evidence
of healing, such that after 4 months, the original electrolytic lesion was
greatly reduced in size and the large area of necrosis seen at the early time
points was largely replaced by a fibrous scar with only small islands of necrotic
tissue. In a large animal model, electrolysis is a safe method for creating areas
of hepatic necrosis. The lesions heal with time and are associated with minimal
morbidity. The results support a trial of electrolysis in patients with
unresectable liver tumours.
PMID- 10781388
TI - Comparison of four sequential methods allowing for early stopping of comparative
clinical trials.
AB - Phase III trials aim to assess whether a new treatment has superior efficacy than
a standard treatment. Sequential methods, such as the sequential probability
ratio test (SPRT), the triangular test (TT) and so-called one-parameter
boundaries (OPB), now allow early stopping of such trials, both in the case of
efficacy (alternative hypothesis; H(1)) and in the case of lack of efficacy (null
hypothesis; H(0)). We compared the statistical properties of the SPRT and the TT,
and of OPB with Pocock (OPB(Delta=0.5)) and O'Brien and Fleming (OPB(Delta=0))
type boundaries, in the setting of one-sided comparative trials with normal
response. We studied the type I error (alpha), power (1-beta), average sample
number (ASN) and 90th percentile (P90) of the number of patients required to
reach a conclusion using simulations. The four tests were also compared with the
corresponding single-stage design (SSD). All sequential tests display alpha and 1
beta close to nominal values and, as compared with SSD, allow important decreases
in ASN: for example, -48%, -42%, -40% and -31% under H(0) and H(1) for SPRT, TT,
OPB(Delta=0.5) and OPB(Delta=0) respectively. For situations between H(0) and
H(1), ASNs of all sequential tests were still smaller than the sample size
required by SSD, with the TT displaying the largest decrease (-25%). The P90s of
the TT and OPB(Delta=0) under H(0) and H(1) were smaller than the P90s of the
SPRT and OPB(Delta=0.5), which were similar to the sample size required by SSD.
If all sequential tests display approximately similar features, the TT is the
most appealing regarding decreases in sample size, especially for situations
between H(0) and H(1).
PMID- 10781389
TI - Muscle function during fatigue in myoadenylate deaminase-deficient Dutch
subjects.
AB - Myoadenylate deaminase (MAD) is an enzyme active in skeletal muscle, probably
during exercise of moderate intensity but certainly during vigorous exercise,
when the deamination of AMP leads to increased levels of IMP and ammonia. There
is controversy about the clinical significance of MAD deficiency. The main
objective of the present study was to investigate the extent to which genetically
confirmed MAD deficiency affects muscle function under conditions of maximal
short-term electrically induced activation. The left hand was immobilized and
adductor pollicis muscle function was investigated. To exclude the influence of
central factors, such as the patient's motivation, the ulnar nerve was maximally
electrically activated and force output was measured at the thumb. Sixty rapid
shortening contractions resulted in a decrease of maximal power to 34.2+/-5.4%
and 33.3+/-6.3% (means+/-S.D.) of the values for unfatigued muscle in the control
and MAD-deficient subjects respectively (P>0.05; n=7). Maximal isometric forces
and shortening velocities did not differ between groups in unfatigued, fatigued
or recovered muscle. None of the subjects experienced exercise-related muscle
aches or cramps. In conclusion, MAD deficiency does not appear to affect adductor
pollicis muscle force, shortening velocity and relaxation, either during or after
maximal short-term activation.
PMID- 10781390
TI - Determinants of the acetate recovery factor: implications for estimation of
[13C]substrate oxidation.
AB - When using (13)C or (14)C tracers to study substrate metabolism, an acetate
correction factor should be applied to correct for loss of label in the exchange
pathways of the tricarboxylic acid cycle. We have shown recently that the
[(13)C]acetate recovery factor has a high inter-individual variability and should
therefore be determined in every subject. In the present study we examined the
factors that might explain some of the variability between subjects in acetate
recovery factor. Data were pooled from four different studies with identical
protocols, in which the acetate recovery factor was measured, prior to an
intervention, to correct plasma fatty acid oxidation rates. Acetate recovery was
measured after 2 h of [1, 2-(13)C]acetate infusion at rest followed by 1 h of
cycling exercise at 40-50% of maximal oxygen uptake. Inter-individual variance in
acetate recovery was 12.0% at rest and 16.1% during exercise. Stepwise regression
revealed that, at rest, 37.1% of the acetate recovery could be accounted for by
basal metabolic rate adjusted for fat-free mass, percentage body fat and
respiratory quotient (RQ). During exercise, 69.1% of the variance in acetate
recovery could be accounted for by energy expenditure adjusted for fat-free mass,
% body fat and RQ. In conclusion, we show that the acetate recovery factor has a
high inter-individual variability, both at rest and during exercise, which can
partly be accounted for by metabolic rate, RQ and % body fat. These data indicate
that the acetate recovery factor needs to be determined in every subject, under
similar conditions as used for the tracer-derived determination of substrate
oxidation. Failure to do this might result in large under- or over-estimation of
plasma substrate oxidation, and hence to artificial differences between groups.
PMID- 10781391
TI - Effects of organic and inorganic selenium supplementation on selenoenzyme
activity in blood lymphocytes, granulocytes, platelets and erythrocytes.
AB - The blood selenium (Se) concentration in the U.K. population has declined by
approx. 50% between 1974 and 1991, reflecting a large decrease in dietary Se
supply, with intakes only half the reference nutrient intake of 1 microg/kg body
weight. Tissue levels of Se are readily influenced by dietary intake. Therefore
selenoprotein activity may be sub-optimal due to low Se status, and thus
compromise normal cell function. To examine the effects of changing Se intake on
selenoproteins, we have determined the relative effectiveness of organic
selenomethionine and inorganic sodium selenite (50 microg of Se daily for 28
days) in modulating glutathione peroxidase activities in blood cells from 45
healthy men and women, from a U.K. population. Transient and acute changes in
lymphocyte, granulocyte and platelet phospholipid-hydroperoxide glutathione
peroxidase (GPx4) activity occurred by day 7 or 14 of sodium selenite treatment
and by day 7 in lymphocytes from selenomethionine-treated subjects compared with
controls taking a placebo. In contrast, GPx4 activity in granulocytes and
platelets in the selenomethionine group increased gradually over the 28 days.
Cytosolic glutathione peroxidase (GPx1) activity in these blood cells from both
treatment groups increased gradually over the 28 days. For each cellular
selenoenzyme activity a significant inter-individual difference (P<0.001) in the
extent of the response to Se supplementation was observed, but this was not
related to blood Se concentrations either before or after treatments. Significant
inverse correlations were evident between baseline enzyme activities and
percentage change in activity after 28 days of supplementation [e.g. lymphocyte
GPx4, r=-0.695 (P<0.001)], indicating that pre-treatment activity may be sub
optimal as a result of poor Se status. The different and contrasting effects that
Se supplementation had on blood selenoenzyme activities may be indicative of a
difference in metabolic need for Se regulated at the level of Se-dependent cell
function.
PMID- 10781392
TI - Widespread elevated expression of the human papilloma virus (HPV)-activating
cellular transcription factor Brn-3a in the cervix of women with CIN3 (cervical
intraepithelial neoplasia stage 3).
PMID- 10781393
TI - Prolongation of the QT interval in heart failure occurs at low but not at high
heart rates.
AB - Abnormal left ventricular structure and function as in, for example, left
ventricular hypertrophy or chronic heart failure, is associated with sudden
cardiac death and, when the ejection fraction is depressed, with prolongation of
the QT interval. The dependence on heart rate of QT interval prolongation in
these conditions, and the relationship of any abnormalities either to deranged
autonomic nervous system function or to an adverse prognosis, has not been well
studied. We therefore investigated (1) the dependence on heart rate of the QT
interval, and (2) the relationship between both QT interval and the QT/heart rate
slope and markers of adverse prognosis in these two conditions. The QT interval
was measured at rest and during exercise in 34 subjects with heart failure, 16
subjects with left ventricular hypertrophy and 16 age-matched controls with
normal left ventricular structure and function. QTc (corrected QT) intervals at
rest were significantly longer in heart failure patients (471+/-10 ms) than in
controls (421+/-6 ms) or in subjects with hypertrophy (420+/-6 ms) (P<0.05). At
peak exercise, despite the attainment of similar heart rates, the QT intervals no
longer differed from each other, being 281+/-7 ms for controls, 296+/-11 ms in
hypertrophy and 303+/-10 ms in heart failure (no significant difference). The
QT/heart rate slope was significantly increased in heart failure [2.3+/-0.1
ms.(beats/min)(-1)] compared with controls [1.55+/-0.06 ms.(beats/min)(-1)] and
hypertrophy [1. 66+/-0.1 ms.(beats/min)(-1)] (P<0.001). In left ventricular
hypertrophy, despite animal data suggesting that QT interval prolongation should
occur, no abnormalities were found in QT intervals at rest or during exercise.
The QT/heart rate slope did not relate to any markers for an adverse prognosis,
except that of prolongation of QT interval. Long QT intervals were associated
principally with impairment of left ventricular systolic function. Our data
emphasize the dynamic nature of the QT interval abnormalities found in heart
failure.
PMID- 10781395
TI - Persistent, progressive hypophosphataemia after voluntary hyperventilation.
AB - Hyperventilation (HV) and respiratory alkalosis are associated with
hypophosphataemia, although the extent and duration of HV required to produce
changes in serum phosphate levels are not known. We sought to characterize the
effects of HV, with or without dextrose loading, on serum phosphate levels and
other biochemical parameters. HV was monitored by controlling the end-tidal
partial pressure of carbon dioxide (PETCO(2)). The effect of dextrose was studied
because infusion of a glucose load is known to promote a fall in serum phosphate
via stimulation of glycolysis. Eight healthy volunteers were enrolled in four
study protocols: (1) HV for 20 min to a PETCO(2) of 25-30 mmHg (mild); (2) HV for
20 min to a PETCO(2) of 15-20 mmHg (severe); (3) mild HV with intravenous
dextrose loading, and (4) dextrose loading alone. Periodic measurements of serum
phosphate, venous pH, serum 2,3-diphosphoglycerate (2,3-DPG) and other parameters
were made. Serum phosphate fell during HV and continued to decline after
cessation of HV. Dextrose loading alone caused a fall in serum phosphate that
continued for at least 30 min after cessation of the infusion (P<0.0002). HV
combined with dextrose resulted in a greater decline in serum phosphate than
either variable alone (P=0.003). The maximal decline in serum phosphate occurred
in severe HV, with a mean decrease of 0.38 mmol/l at 20 min after cessation of HV
(P<0.0001). Serum phosphate was still significantly lowered compared with
baseline at 90 min after cessation of HV (P=0.001). Other significant changes
seen with HV included a decrease in serum glucose (P<0.01), a decrease in serum
potassium (P<0.05) and an increase in venous pH (P<0.007). Serum 2, 3-DPG levels
did not change significantly in any study protocol. Thus relatively mild acute HV
produces significant changes in serum phosphate. In both mild and severe HV this
effect is progressive after cessation of HV. This phenomenon has not been shown
before, and may have significant clinical implications.
PMID- 10781394
TI - Haemodynamic and renal evolution of the bile duct-ligated rat.
AB - In the present study we have characterized the evolution of changes in systemic
haemodynamics (thermodilution in conscious animals) and sodium balance (metabolic
cages) in a model of liver cirrhosis induced by chronic bile duct ligation (BDL).
Mean arterial pressure (BDL, 111.5+/-4.7 mmHg; sham-operated, 122.9+/-3.0 mmHg)
and peripheral vascular resistance (BDL, 2.63+/-0.08 units; sham-operated, 2.93+/
0.09 units) were lower in BDL rats from day 12 after surgery and decreased
progressively throughout the following days. Portal hypertension was evident
earlier in BDL rats and was maintained throughout the study period. Cardiac index
(BDL, 58.8+/-3. 9 ml.min(-1).100 g(-1); sham-operated, 43.9+/-1.5 ml.min(-1).100
g(-1)) and stroke volume (BDL, 147.2+/-12.7 ml.beat(-1).100 g(-1); sham-operated,
109.0+/-4.2 ml.beat(-1).100 g(-1)) were significantly elevated in the BDL rats
only from day 18 after surgery. There were no significant differences in sodium
balance between the groups until day 16 after surgery, at which time BDL animals
started to retain significantly more sodium than the controls. Sodium retention
increased progressively, and at day 20 BDL rats had retained 0.7 mmol/100 g more
than the control animals (accumulated retention: BDL, 2.2+/-0.2 mmol/100 g; sham
operated, 1.5+/-0.2 mmol/100 g). Plasma renin activity and aldosterone
concentration were not elevated in the BDL animals at days 12, 16 or 20 after
surgery. These data indicate that the BDL rat model shows early portal
hypertension, peripheral vasodilation and arterial hypotension, several days
before sodium retention is detectable, and in the absence of changes in plasma
levels of renin and aldosterone. Overall, these data suggest that, in the BDL rat
model, sodium retention is secondary to portal hypertension and peripheral
vasodilation.
PMID- 10781396
TI - The increase in sympathetic nerve activity after glucose ingestion is reduced in
type I diabetes.
AB - Food intake is followed by an increase in baroreflex-governed sympathetic outflow
to muscle vessels. It is established that insulin contributes to this
stimulation; however, the increase occurs (to a lesser degree) even in the
absence of enhanced insulin secretion. To further elucidate the role of insulin,
muscle nerve sympathetic activity was recorded by microneurography, and the
increase after an oral 100-g glucose load in eight C-peptide-negative patients
with type I diabetes without any signs of neuropathy was compared with that in 16
healthy control subjects. The level of sympathetic activity at rest was similar
in the two groups (type I diabetes patients, 19.5+/-2.4 bursts/min; controls,
20.4+/-4.8 bursts/min; means+/-S.D.). Following glucose intake there was a
significant increase in activity in both groups, with maximum values at 30 min of
24.3+/-3.7 bursts/min for type I diabetes patients and 34.4+/-9.1 bursts/min for
controls. The summarized response (during 90 min) of the diabetic patients was
less than half that of the control subjects (P=0.0003). It is concluded that the
response of muscle nerve sympathetic activity to glucose ingestion is reduced to
about half of its normal strength in the absence of insulin, and that there is no
difference in sympathetic outflow at rest between healthy subjects and diabetic
patients without polyneuropathy.
PMID- 10781397
TI - Tec family kinases in lymphocyte signaling and function.
AB - The Tec kinases are required for full Ca(2+) mobilization in lymphocytes. Recent
data suggest that this process occurs via a multiprotein complex that includes
LAT and SLP-76 in T cells and BLNK/SLP-65 in B cells. Mutational analyses have
revealed critical roles for Tec kinases in lymphocyte development and function.
PMID- 10781399
TI - Signal transduction by the TCR for antigen.
AB - The past several years have seen the beginning of a shift in the way that TCR
signal transduction is studied. Although many investigators continue to identify
new molecules, particularly adaptor proteins, others have attempted to look at
signaling events in a larger cellular context. Thus the identification of
distinct formations of signaling molecules at junctions between T cells and
antigen-presenting cells, the role of the cytoskeleton and the partitioning of
molecules into specialized lipid subdomains have been the subjects of many
publications. Such concepts are helping to assemble a blueprint of how the myriad
adaptors and kinases fit together to effect T cell activation.
PMID- 10781398
TI - The role of fas ligand in vivo as a cause and regulator of pathogenesis.
AB - Recent studies have significantly advanced our understanding of the physiological
and pathogenic functions of Fas and Fas ligand (FasL) in vivo. In particular,
roles for Fas-FasL interactions both in the induction and regulation of organ
specific autoimmune diseases have been defined and in some cases the specific
targets and effectors of these interactions have been identified. Understanding
the dynamic role of the Fas-FasL pathway in autoimmunity will provide insight
into how best to modulate this interaction to achieve therapeutic benefits.
PMID- 10781400
TI - Inflammation, a prototype for organogenesis of the lymphopoietic/hematopoietic
system.
PMID- 10781401
TI - Membrane rafts and signaling by the multichain immune recognition receptors.
AB - The recent recognition of the presence of rafts in the plasma membrane and of
their involvement in cell signaling has strongly stimulated the search for their
function in receptor-mediated signal transduction in lymphocytes. Recent progress
suggests that a general feature of membrane rafts is to serve as platforms
wherein the signaling cascades triggered through different multichain immune
recognition receptors (e.g. the TCR, BCR and FcepsilonRI) are initiated and
organized.
PMID- 10781402
TI - Regulation of T cell function by NK cell receptors for classical MHC class I
molecules.
AB - Inhibitory receptors for MHC class I molecules were initially characterised on NK
cells. Human and mouse NK cell receptors (NKRs) are also expressed on T cells,
predominantly on a subset of memory-phenotype CD8(+) T cells. This review focuses
on the precise determination of interactions between NKRs and MHC class I, as
well as on the unexpected in vivo function of NKRs on T cells.
PMID- 10781403
TI - Proapoptotic functions of cytotoxic lymphocyte granule constituents in vitro and
in vivo.
AB - Recent advances in our understanding of cytolytic effector mechanisms include the
partial characterization of caspase-independent apoptotic pathways triggered by
granzymes, a realization of the vital importance of perforin and granzymes in the
defence against certain virus infections in vivo and the first description of
hereditary immunodeficiency due to disordered perforin expression in humans.
PMID- 10781404
TI - Adapter proteins in lymphocyte antigen-receptor signaling.
AB - Adapter molecules contain discrete modular domains that direct specific
intermolecular interactions to orchestrate assembly of signaling complexes. A
number of adapter proteins play critical roles in both positive and negative
regulation of antigen-receptor signaling, influencing lymphocyte development and
function.
PMID- 10781405
TI - Transcriptional control of T cell development.
AB - Transcriptional control of T cell development is a complex and rapidly moving
area of investigation. Recent advances reveal critical roles for several
transcription factors in T cell commitment, differentiation and selection. In
particular, new roles for E proteins as well as members of the Notch signaling
pathway have been described. Additionally, a unique function of Ikaros in
chromatin remodeling reveals a novel mechanism by which transcriptional control
may be exerted.
PMID- 10781406
TI - T cell life and death signalling via TNF-receptor family members.
AB - An effective immune response requires the rapid and accurate mobilisation of
millions of effector cells in an antigen driven fashion. These effector cells
must be kept alive long enough to fulfil their function but the majority must
then be eliminated, a process known as activation-induced cell death. Recent
advances in the field of lymphocyte biology have shed light onto how this balance
is maintained and onto the consequences for disease if the homeostatic mechanisms
become disturbed.
PMID- 10781407
TI - Chemokines in tissue-specific and microenvironment-specific lymphocyte homing.
AB - This review describes recent breakthroughs in our understanding of the roles
played by chemokines in lymphocyte trafficking. These include the first
demonstration that chemokines control lymphocyte/vascular recognition by shear
resistant rapid adhesion; the first example of specialized tissue-specific homing
mediated by chemokines; and the implication that chemokines may control
microenvironmental segregation within lymphoid organs.
PMID- 10781408
TI - Functional dissection of BCR signaling pathways.
AB - Signal transduction by the BCR is critical for progression through developmental
checkpoints as well as for immune responses. Recent results obtained in mice
deficient either in an adaptor molecule, BLNK (alternatively named SLP-65 or
BASH), or in phosphatidylinositol 3-kinase have revealed similar - though not
identical - phenotypes to those of Btk(-/-) mice, suggesting a functional link
between BLNK, Btk and phosphatidylinositol 3-kinase.
PMID- 10781409
TI - Regulation of B cell function by linker proteins.
AB - Studies over the past few years have demonstrated the importance of linker or
adaptor proteins in the signaling pathways activated by the B cell antigen
receptor. These proteins direct the appropriate subcellular localization of
enzymatic complexes, amplify signaling pathways and integrate the functions of
distinct signaling complexes. Many of the recently identified linker proteins
function through these distinct mechanisms to upregulate the BCR signaling
pathway. In addition, linker proteins facilitate the influences of co-receptors
that augment or dampen the BCR signaling pathway.
PMID- 10781412
TI - Acute pyelonephritis
PMID- 10781410
TI - Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell
signal transduction.
AB - One of the areas of greatest recent progress in immunology has been the
elucidation of inhibitory receptors and their mode of signal transduction. A
common feature of members of this growing family is expression of a conserved
cytoplasmic sequence motif, the immunoreceptor tyrosine-based inhibitory motif,
which functions to recruit and activate phosphatases that mediate the receptors'
function. Family members include the protein tyrosine phosphatases SHP-1 (Src
homology-2-domain-containing protein tyrosine phosphatase 1) and SHP-2, which
function to dephosphorylate key intermediaries in antigen receptor signaling
pathways. Surprisingly, whereas most data to date support a role for SHP-1 in
inhibitory signaling, SHP-2 exhibits distinct functions that appear to positively
regulate receptor function.
PMID- 10781411
TI - Ras regulation and function in lymphocytes.
AB - The GTPase, Ras, is rapidly activated in antigen receptor stimulated T. cells, B
cells and mast cells. Ras can bind to diverse effector molecules when activated
and thereby switch on multiple downstream effector pathways. In lymphocytes Ras
plays an important role in the signalling pathways that activate transcription
factors involved in cytokine gene induction. Ras is also a key component of the
complex regulatory networks that control T and B cell development.
PMID- 10781413
TI - Continuing medical education exercise, february 2000
PMID- 10781414
TI - Type I membranoproliferative glomerulonephritis in a renal allograft: A
recurrence induced by a cytomegalovirus infection?
AB - A 40-year-old white woman with end-stage renal disease from idiopathic type I
membranoproliferative glomerulonephritis (MPGN) developed proteinuria and renal
dysfunction 7 weeks after cadaveric donor renal transplantation. At the same
time, a primary cytomegalovirus (CMV) infection was diagnosed. Complement levels
were low. A renal biopsy disclosed an acute exudative proliferative
glomerulonephritis with influx of polymorphonuclear granulocytes (PMNs), with
granular deposits of C3, C1q, IgG, and IgM. The immunofluorescence (IF) and
electron microscopy (EM) findings were compatible with an early stage of a type I
MPGN. CMV could not be detected in the glomeruli nor elsewhere in the kidney by
IF or EM. The patient was treated with ganciclovir. In a renal biopsy 3 weeks
later, the exudative lesions had disappeared, and some glomeruli now showed the
characteristic lesions of a type I MPGN with an increase of mesangial cells and
matrix, and reduplication of the glomerular basement membrane. Over the following
period, repeated biopsies were performed. The activity of the glomerular
inflammation and immune complex deposits paralleled the waxing and waning of the
CMV viral load. After 10.5 months, the graft was removed because of a life
threatening systemic fungal infection. At that time, the CMV infection had
cleared, and in the transplantectomy material, the membranoproliferative pattern
of injury had disappeared, and in the glomeruli hardly any deposits were found.
These data strongly suggest that a primary CMV virus infection can induce an
apparent recurrence of type I MPGN.
PMID- 10781415
TI - Publishing in the journals of the APS: why are authors charged fees?
PMID- 10781416
TI - Aquaporin water channels and lung physiology.
AB - Fluid transport across epithelial and endothelial barriers occurs in the neonatal
and adult lungs. Biophysical measurements in the intact lung and cell isolates
have indicated that osmotic water permeability is exceptionally high across
alveolar epithelia and endothelia and moderately high across airway epithelia.
This review is focused on the role of membrane water-transporting proteins, the
aquaporins (AQPs), in high lung water permeability and lung physiology. The lung
expresses several AQPs: AQP1 in microvascular endothelia, AQP3 in large airways,
AQP4 in large- and small-airway epithelia, and AQP5 in type I alveolar epithelial
cells. Lung phenotype analysis of transgenic mice lacking each of these AQPs has
been informative. Osmotically driven water permeability between the air space and
capillary compartments is reduced approximately 10-fold by deletion of AQP1 or
AQP5 and reduced even more by deletion of AQP1 and AQP4 or AQP1 and AQP5
together. AQP1 deletion greatly reduces osmotically driven water transport across
alveolar capillaries but has only a minor effect on hydrostatic lung filtration,
which primarily involves paracellular water movement. However, despite the major
role of AQPs in lung osmotic water permeabilities, AQP deletion has little or no
effect on physiologically important lung functions, such as alveolar fluid
clearance in adult and neonatal lung, and edema accumulation after lung injury.
Although AQPs play a major role in renal and central nervous system physiology,
the data to date on AQP knockout mice do not support an important role of high
lung water permeabilities or AQPs in lung physiology. However, there remain
unresolved questions about possible non-water-transporting roles of AQPs and
about the role of AQPs in airway physiology, pleural fluid dynamics, and edema
after lung infection.
PMID- 10781417
TI - Lipopolysaccharide induces relaxation in lung pericytes by an iNOS-independent
mechanism.
AB - Lipopolysaccharide (LPS)-regulated contractility in pericytes may play an
important role in mediating pulmonary microvascular fluid hemodynamics during
inflammation and sepsis. LPS has been shown to regulate inducible nitric oxide
(NO) synthase (iNOS) in various cell types, leading to NO generation, which is
associated with vasodilatation. The purpose of this study was to test the
hypothesis that LPS can regulate relaxation in lung pericytes and to determine
whether this relaxation is mediated through the iNOS pathway. As predicted, LPS
stimulated NO synthesis and reduced basal tension by 49% (P < 0.001). However,
the NO synthase inhibitors N (omega)-nitro-L-arginine methyl ester,
aminoguanidine, and N (omega)-monomethyl-L-arginine did not block the relaxation
produced by LPS. In fact, aminoguanidine and N (omega)-monomethyl-L-arginine
potentiated the LPS response. The possibility that NO might mediate either
contraction or relaxation of the pericyte was further investigated through the
use of NO donor compounds; however, neither sodium nitroprusside nor S-nitroso-N
acetylpenicillamine had any significant effect on pericyte contraction. The
inhibitory effect of aminoguanidine on LPS-stimulated NO production was
confirmed. This ability of LPS to inhibit contractility independent of iNOS was
also demonstrated in lung pericytes derived from iNOS-deficient mice. This
suggests the presence of an iNOS-independent but as yet undetermined pathway by
which lung pericyte contractility is regulated.
PMID- 10781418
TI - Histamine alters endothelial barrier function at cell-cell and cell-matrix sites.
AB - To determine how histamine regulates endothelial barrier function through an
integrative cytoskeletal network, we mathematically modeled the resistance across
an endothelial cell-covered electrode as a function of cell-cell, cell-matrix,
and transcellular resistances. Based on this approach, histamine initiated a
rapid decrease in transendothelial resistance predominantly through decreases in
cell-cell resistance in confluent cultured human umbilical vein endothelial cells
(HUVECs). Restoration of resistance was characterized by initially increasing
cell-matrix resistance, with later increases in cell-cell resistance. Thus
histamine disrupts barrier function by specifically disrupting cell-cell adhesion
and restores barrier function in part through direct effects on cell-matrix
adhesion. To validate the precision of our technique, histamine increased the
resistance in subconfluent HUVECs in which there was no cell-cell contact.
Exposure of confluent monolayers to an antibody against cadherin-5 caused a
predominant decrease in cell-cell resistance, whereas the resistance was
unaffected by the antibody to cadherin-5 in subconfluent cells. Furthermore, we
observed an increase predominantly in cell-cell resistance in ECV304 cells that
were transfected with a plasmid containing a glucocorticoid-inducible promoter
controlling expression of E-cadherin. Transmission electron microscopy confirmed
tens of nanometer displacements between adjacent cells at a time point in which
histamine maximally decreased cell-cell resistance.
PMID- 10781419
TI - NO(+) but not NO radical relaxes airway smooth muscle via cGMP-independent
release of internal Ca(2+).
AB - We compared the effects of two redox forms of nitric oxide, NO(+) [liberated by S
nitroso-N-acetyl-penicillamine (SNAP)] and NO. [liberated by 3
morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on
cytosolic concentration of Ca(2+) ([Ca(2+)](i); single cells) and tone (intact
strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked
a rise in [Ca(2+)](i) that was unaffected by removing external Ca(2+) but was
markedly reduced by depleting the internal Ca(2+) pool using cyclopiazonic acid
(10(-5) M). Dithiothreitol (1 mM) also antagonized the Ca(2+) transient as well
as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but
not those to 60 mM KCl, suggesting the involvement of an electromechanical
coupling mechanism rather than a direct effect on the contractile apparatus or on
Ca(2+) channels. SNAP relaxations were sensitive to charybdotoxin (10(-7) M) or
tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8
bromoguanosine 3',5'-cyclic monophosphate had any significant effect on resting
[Ca(2+)](i), although both of these agents were able to completely reverse tone
evoked by carbachol (10(-7) M). We conclude that NO(+) causes release of internal
Ca(2+) in a cGMP-independent fashion, leading to activation of Ca(2+)-dependent
K(+) channels and relaxation, whereas NO. relaxes the airways through a cGMP
dependent, Ca(2+)-independent pathway.
PMID- 10781420
TI - Increased expression of inflammatory mediators in small-airway epithelium from
tobacco smokers.
AB - To study the inflammatory responses of small-airway epithelium in smokers, we
harvested enough living epithelial cells (1.97 x 10(6) +/- 0.74 x 10(6)) with a
new ultrathin fiberscope from the very peripheral airways of 22 current smokers
and 17 subjects who never smoked after informed consent was obtained. The cells
were keratin positive and composed mainly of nonciliated cells. The expression
levels of inflammatory markers [interleukin (IL)-8 and intercellular adhesion
molecule (ICAM)-1] were evaluated with RT-PCR. The magnitude of the mRNA levels
corrected by beta-actin transcripts of IL-8 and ICAM-1 was significantly higher
in the smokers than in the nonsmokers (P < 0.001). Furthermore, among current
smokers, IL-8 mRNA levels correlated positively with the extent of smoking
history [in pack. years (packs/day x no. of years of smoking); r = 0.754, P <
0.001]. Spontaneously released IL-8 and soluble ICAM-1 levels (n = 12) from
cultured epithelial cells were elevated in subjects with a smoking history than
in those without it (IL-8, 1,580 +/- 29.6 vs. 354 +/- 39.4 pg. 10(6) cells(-1).
24 h(-1); P < 0.001; soluble ICAM-1, 356.0 +/- 45.9 vs. 112.9 +/- 12.9 pg. 10(6)
cells(-1). 24 h(-1); P < 0.01 by Student's t-test ). In contrast, the epithelial
cells from the main bronchi did not show such differences between smokers and
nonsmokers. Our study highlighted a close link between smoking and the expression
of inflammatory mediators such as IL-8 and ICAM-1 in small airways. Our results
also suggested that this new ultrathin bronchofiberscope promised a good approach
for the evaluation of cellular changes in the small airways.
PMID- 10781421
TI - Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced
lung injury in vivo.
AB - Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We
investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury
model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10
expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ)
was intraperitoneally injected into mice on day -3. This was followed by
intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase
activity of bronchoalveolar lavage fluid and tumor necrosis factor-alpha mRNA
expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline
content of the whole lung on day 21 were inhibited significantly by hIL10-HVJ
treatment. However, Cont-HVJ treatment could not suppress any of these
parameters. We also examined the in vitro effects of IL-10 on the human lung
fibroblast cell line WI-38. IL-10 significantly reduced constitutive and
transforming growth factor-beta-stimulated type I collagen mRNA expression.
However, IL-10 did not affect the proliferation of WI-38 cells induced by
platelet-derived growth factor. These data suggested that exogenous IL-10 may be
useful in the treatment of pulmonary fibrosis.
PMID- 10781422
TI - ET(A)-receptor blockade and ET(B)-receptor stimulation in experimental congenital
diaphragmatic hernia.
AB - The aim of this study was to assess the role of nitric oxide (NO) and endothelin
(ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn
in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH).
The pulmonary vascular response to various agonists and antagonists was assessed
in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as
control animals. Control and CDH lambs had similar pulmonary vasodilator
responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole.
The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary
vasodilatation in CDH than in control animals. The ET(B)-receptor agonist
sarafotoxin 6c induced a biphasic response, with a sustained pulmonary
vasoconstriction after a transient pulmonary vasodilatation that was not seen in
CDH animals. We conclude that the NO signaling pathway in vivo is intact in
experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor
stimulation significantly differed in CDH animals compared with control animals.
Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather
than altered NO-mediated pulmonary vasodilatation is likely to account for
persistent pulmonary hypertension of the newborn in fetal lambs with a surgically
created CDH.
PMID- 10781423
TI - Human SP-C gene sequences that confer lung epithelium-specific expression in
transgenic mice.
AB - We used transgenic mice to identify cis-active regions of the human pulmonary
surfactant protein C (SP-C) gene that impart tissue- and cell-specific expression
in vivo in the lung. Approximately 3.7 kb of genomic SP-C DNA upstream of the
transcription start site was sufficient to direct chloramphenicol
acetyltransferase (CAT) reporter gene expression specifically in bronchiolar and
alveolar epithelial cells of the lung. To further define cis-active regulatory
elements that mediate cell-specific expression, we tested deletions of the
parental 3.7-kb human SP-C sequence in transgenic mice. Tissue CAT assays of mice
generated with truncations or overlapping internal deletions of the 3.7-kb
construct functionally map alveolar cell-specific regulatory elements to within
215 bp of the SP-C promoter. Analysis of SP-C promoter deletions demonstrate that
sequences between -3.7 kb and -1.9 kb contain enhancer sequences that stimulate
SP-C transgene expression. In situ hybridization studies demonstrate that
deletion of the -1,910- to -215-bp region abolishes the ectopic bronchiolar
expression seen with the original 3.7-kb SP-C promoter construct. Comparison of
sequences from -215 to +1 bp identified consensus binding sites for the
homeodomain transcription factor thyroid transcription factor-1 (TTF-1).
Cotransfection assays of the human 3.7-kb SP-C or -1,910- to -215-bp SP-C
deletion construct with a TTF-1 expression plasmid demonstrates that TTF-1
transactivates the human SP-C gene. These results suggest that the TTF-1 cis
active sites are important in directing cell-specific expression of the SP-C gene
in vivo.
PMID- 10781425
TI - Retinoic acid treatment partially rescues failed septation in rats and in mice.
AB - Pulmonary alveoli are formed in part by subdivision (septation) of the gas
exchange saccules of the immature lung. Septation results in smaller, more
numerous structures (alveoli) and is developmentally regulated in mammals
including humans, rats, and mice; if it fails to occur at the appropriate time,
there is no spontaneous post hoc septation nor has there been a means of inducing
septation after it has failed to occur. We measured lung volume, the volume of
individual alveoli, and alveolar surface area and calculated alveolar number in
neonatal rats in which septation had been blocked by treatment with a
glucocorticosteroid hormone and in adult tight-skin mice that have a genetic
failure of septation. We tested the hypothesis that treatment with all-trans
retinoic acid induces post hoc septation. In both models of failed septation,
hence in two species, and in immature and adult animals, treatment with all-trans
retinoic acid induced post hoc septation, offering the possibility of a similar
effect in premature infants.
PMID- 10781424
TI - Human SP-A protein variants derived from one or both genes stimulate TNF-alpha
production in the THP-1 cell line.
AB - In humans, two functional genes of surfactant protein (SP) A, SP-A1 and SP-A2,
and several alleles of each functional gene have been characterized. SP-A is a
multimeric molecule consisting of six trimers. Each trimer contains two SP-A1
molecules and one SP-A2 molecule. Until now, it has been unclear whether a single
SP-A gene product is functional or whether there are functional differences
either among alleles or between single-gene SP-A products and SP-A products
derived from both genes. We tested the ability of in vitro expressed SP-A
variants to stimulate tumor necrosis factor (TNF)-alpha production by THP-1
cells. We observed that 1) single-gene products and products derived from both
genes stimulate TNF-alpha production, 2) there are differences among SP-A1 and SP
A2 alleles in their ability to stimulate TNF-alpha production, and 3) the
increases in TNF-alpha production are lower after treatment with the SP-A1
alleles than after treatment with the SP-A2 alleles. Furthermore, coexpressed SP
As from SP-A1 and SP-A2 genes have a higher activity compared with SP-As from
individual alleles or mixed SP-As from SP-A1 and SP-A2 genes. These data suggest
that the SP-A-induced increases in TNF-alpha levels differ among SP-A variants
and appear to be affected by SP-A genotype and whether SP-A is derived from one
or both genes.
PMID- 10781427
TI - Mediators of alkalosis-induced relaxation of piglet pulmonary veins.
AB - Pulmonary venous constriction leads to significant pulmonary hypertension and
increased edema formation in several models using newborns. Although alkalosis is
widely used in treating neonatal and pediatric pulmonary hypertension, its
effects on pulmonary venous tone have not previously been directly measured. This
study sought to determine whether alkalosis caused pulmonary venous relaxation
and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500
microm external diameter) were isolated from 1-wk-old piglets and precontracted
with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then
measured under control conditions after inhibition of endothelium-derived
modulator activity or K(+) channels. In control rings, alkalosis caused a 34.4 +/
4.8% decrease in the U-46619-induced contraction. This relaxation was
significantly blunted in rings without functional endothelium and in rings
treated with nitric oxide synthase or guanylate cyclase inhibitors. However,
neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or
ATP-dependent K(+)-channel inhibitors altered alkalosis-induced relaxation. These
data suggest that alkalosis caused significant dilation of piglet pulmonary veins
that was mediated by the nitric oxide-cGMP pathway.
PMID- 10781426
TI - Plasma proteins modified by tyrosine nitration in acute respiratory distress
syndrome.
AB - The present study identifies proteins modified by nitration in the plasma of
patients with ongoing acute respiratory distress syndrome (ARDS). The proteins
modified by nitration in ARDS were revealed by microsequencing and specific
antibody detection to be ceruloplasmin, transferrin, alpha(1)-protease inhibitor,
alpha(1)-antichymotrypsin, and beta-chain fibrinogen. Exposure to nitrating
agents did not deter the chymotrypsin-inhibiting activity of alpha(1)
antichymotrypsin. However, the ferroxidase activity of ceruloplasmin and the
elastase-inhibiting activity of alpha(1)-protease inhibitor were reduced to 50.3
+/- 1.6 and 60.3 +/- 5.3% of control after exposure to the nitrating agent. In
contrast, the rate of interaction of fibrinogen with thrombin was increased to
193.4 +/- 8.5% of the control value after exposure of fibrinogen to nitration.
Ferroxidase activity of ceruloplasmin and elastase-inhibiting activity of the
alpha(1)-protease inhibitor in the ARDS patients were significantly reduced (by
81 and 44%, respectively), whereas alpha(1)-antichymotrypsin activity was not
significantly altered. Posttranslational modifications of plasma proteins
mediated by nitrating agents may offer a biochemical explanation for the reported
diminished ferroxidase activity, elevated levels of elastase, and fibrin deposits
detected in patients with ongoing ARDS.
PMID- 10781428
TI - Mechanical strain and dexamethasone selectively increase surfactant protein C and
tropoelastin gene expression.
AB - Physical forces derived from fetal breathing movements and hormones such as
glucocorticoids are implicated in regulating fetal lung development. To elucidate
whether the different signaling pathways activated by physical and hormonal
factors are integrated and coordinated at the cellular and transcriptional
levels, organotypic cultures of mixed fetal rat lung cells were subjected to
static culture or mechanical strain in the presence and absence of dexamethasone.
Tropoelastin and collagen type I were used as marker genes for fibroblasts,
whereas surfactant protein (SP) A and SP-C were used as marker genes for distal
epithelial cells. Mechanical strain, but not dexamethasone, significantly
increased SP-C mRNA expression. Tropoelastin mRNA expression was upregulated by
both mechanical strain and dexamethasone. No additive or synergistic effect was
observed when cells were subjected to mechanical stretch in the presence of
dexamethasone. Neither mechanical strain nor dexamethasone alone or in
combination had any significant effect on the expression of SP-A mRNA.
Dexamethasone decreased collagen type I mRNA expression, whereas mechanical
strain had no effect. The increases in tropoelastin and SP-C mRNA levels induced
by mechanical strain and/or dexamethasone were accompanied by increases in their
heterogeneous nuclear RNA. In addition, the stretch- and glucocorticoid-induced
alterations in tropoelastin and SP-C mRNA expression were abrogated with 10
microg/ml actinomycin D. These findings suggest that tropoelastin and SP-C genes
are selectively stimulated by physical and/or hormonal factors at the
transcriptional level in fetal lung fibroblasts and distal epithelial cells,
respectively.
PMID- 10781429
TI - Vascular remodeling and ET-1 expression in rat strains with different responses
to chronic hypoxia.
AB - Chronic hypoxia leads to a greater degree of pulmonary hypertension in the Wistar
Kyoto (WKY) rat than in the Fischer 344 (F-344) rat. We questioned whether this
difference is associated with baseline differences in pulmonary artery anatomy, a
greater degree of hypoxia-induced pulmonary vascular remodeling in the WKY rat,
and/or differences in expression of endothelin (ET)-1. Male F-344 and WKY rats
were maintained in normoxia or normobaric hypoxia for 21 days. Morphometry
revealed that baseline pulmonary artery anatomy was similar in the two strains.
However, during chronic hypoxia, the WKY rats developed a greater degree of
muscularization of small pulmonary arteries. Baseline plasma and lung
immunoreactive ET-1 levels were similar in the WKY and F-344 rats and increased
significantly during hypoxia in the WKY rats. Northern analysis demonstrated
increased lung preproET-1 mRNA during hypoxia in both strains, with a greater
increase in WKY rats. Immunostaining demonstrated increased ET-1 in bronchial
epithelium and peripheral pulmonary arteries during hypoxia, although to a
greater degree in the WKY rats. We conclude that the WKY strain demonstrates
increased susceptibility to hypoxia-induced pulmonary vascular remodeling
compared with the F-344 strain and that increased lung and circulating ET-1
levels during hypoxia may partly explain this difference.
PMID- 10781430
TI - KGF pretreatment decreases B7 and granzyme B expression and hastens repair in
lungs of mice after allogeneic BMT.
AB - We investigated keratinocyte growth factor (KGF) as a pretreatment therapy for
idiopathic pneumonia syndrome (IPS) generated as a result of lung damage and
allogeneic T cell-dependent inflammatory events occurring in the early peri-bone
marrow (BM) transplant (BMT) period. B10.BR (H2(k)) recipient mice were
transplanted with C57BL/6 (H2(b)) BM with spleen cells after lethal irradiation
with and without cyclophosphamide conditioning with and without subcutaneous KGF
pretreatment. KGF-pretreated mice had fewer injured alveolar type II (ATII) cells
at the time of BMT and exhibited ATII cell hyperplasia at day 3 post-BMT. The
composition of infiltrating cells on day 7 post-BMT was not altered by KGF
pretreatment, but the frequencies of cells expressing the T-cell costimulatory
molecules B7.1 and B7.2 and mRNA for the cytolysin granzyme B (usually increased
in IPS) were decreased by KGF. Sera from KGF-treated mice had increases in the
Th2 cytokines interleukin (IL)-4, IL-6, and IL-13 4 days after cessation of KGF
administration (i.e., at the time of BMT). These data suggest that KGF hinders
IPS by two modes: 1) stimulation of alveolar epithelialization and 2) attenuation
of immune-mediated injury as a consequence of failure to upregulate cytolytic
molecules and B7 ligand expression and the induction of anti-inflammatory Th2
cytokines in situ.
PMID- 10781432
TI - Perflubron attenuates neutrophil adhesion to activated endothelial cells in
vitro.
AB - Infiltration of activated neutrophils into the lung appears to be a key element
in the severe lung injury that develops in animal models of acute lung injury.
Partial liquid ventilation with perflubron has been shown to ameliorate tissue
damage compared with conventional mechanical ventilation in acute lung injury
models. Pilot experiments indicated that indirect exposure to perflubron could
modulate the degree to which subsequent neutrophil binding to endothelial cell
monolayers was upregulated after lipopolysaccharide activation. Endothelial cell
monolayers preexposed to perflubron showed >40% reductions in the surface steady
state levels of E-selectin and intercellular adhesion molecule-1 achieved after
proinflammatory activation (P < 0.05), which correlated with a reduction in the
real-time association constants measured by biosensor techniques. These results
indicate that direct contact with the perflubron liquid phase is not necessary to
attenuate inflammatory responses. Rather, diffusion of perflubron from the
alveolar space into the adjacent pulmonary vascular endothelial layer may
modulate neutrophil adhesion and thereby reduce the rate of infiltration of
activated neutrophils into the injured lung.
PMID- 10781431
TI - Angiogenesis and morphogenesis of murine fetal distal lung in an allograft model.
AB - Neovascularization is crucial to lung morphogenesis; however, factors determining
vessel growth and formation are poorly understood. The goal of our study was to
develop an allograft model that would include maturation of the distal lung,
thereby ultimately allowing us to study alveolar development, including
microvascular formation. We transplanted 14-day gestational age embryonic mouse
lung primordia subcutaneously into the back of nude mice for 3.5-14 days. Lung
morphogenesis and neovascularization were evaluated by light microscopy, in situ
hybridization, and immunohistochemical techniques. Embryonic 14-day gestational
age control lungs had immature structural features consistent with
pseudoglandular stage of lung development. In contrast, 14 days after
subcutaneous transplantation of a 14-day gestational age lung, the allograft
underwent significant structural morphogenesis and neovascularization. This was
demonstrated by continued neovascularization and cellular differentiation,
resulting in mature alveoli similar to those noted in the 2-day postnatal
neonatal lung. Confirmation of maturation of the allograft was provided by
progressive type II epithelial cell differentiation as evidenced by enhanced
local expression of mRNA for surfactant protein C and a threefold (P < 0.008)
increase in vessel formation as determined by immunocytochemical detection of
platelet endothelial cell adhesion molecule-1 expression. Using the tyrosine
kinase Flk-1 receptor (flk-1) LacZ transgene embryos, we determined that the
neovascularization within the allograft was from the committed embryonic lung
endothelium. Therefore, we have developed a defined murine allograft model that
can be used to study distal lung development, including neovascularization. The
model may be useful when used in conjunction with an altered genetic background
(knockout or knock in) of the allograft and has the further decided advantage of
bypassing placental barriers for introduction of pharmacological agents or DNA
directly into the lung itself.
PMID- 10781433
TI - In vitro cellular effects of perfluorochemicals correlate with their lipid
solubility.
AB - Preclinical studies comparing perflubron partial liquid ventilation with
conventional mechanical ventilation have indicated that perflubron partial liquid
ventilation may exert some anti-inflammatory effects. To assess whether these
effects were related to the lipid solubility properties of perflubron rather than
to nonspecific biophysical properties of the perfluorocarbon (PFC) liquid phase,
we studied the effects of PFCs with varying lipid solubilities on the platelet
aggregation response to various procoagulants and the erythrocyte hemolytic
response to osmotic stress. In both cases, the degree of the response was
directly related to the lipid solubility of the PFC. All the perflubron content
of erythrocytes was found to be associated with the membrane compartment. The
time to reach a maximum effect on hemolysis with perflubron was relatively slow
(2-4 h), which paralleled the time for perflubron to accumulate in erythrocyte
membranes. The rate and extent of perflubron partitioning into lecithin liposomes
were similar to those of erythrocyte membranes, supporting the hypothesis that
perflubron was partitioning into the lipid component of the membranes. Thus some
of the potential modulatory effects of perflubron on excessive inflammatory
responses that occur during acute lung injury and acute respiratory distress
syndrome may be influenced in part by the extent of PFC partitioning into the
lipid bilayers of cellular membranes.
PMID- 10781435
TI - Sodium nitroprusside augments human lung fibroblast collagen gel contraction
independently of NO-cGMP pathway.
AB - Nitric oxide (NO) relaxes vascular smooth muscle in part through an accumulation
of cGMP in the target cells. We hypothesized that a similar effect may also exist
on collagen gel contraction mediated by human fetal lung (HFL1) fibroblasts, a
model of wound contraction. To evaluate this, HFL1 cells were cultured in three
dimensional type I collagen gels and floated in serum-free DMEM with and without
various NO donors. Gel size was measured with an image analyzer. Sodium
nitroprusside (SNP, 100 microM) significantly augmented collagen gel contraction
by HFL1 cells (78.5 +/- 0.8 vs. 58.3 +/- 2. 1, P < 0.01), whereas S-nitroso-N
acetylpenicillamine, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride,
NONOate, and N(G)-monomethyl-L-arginine did not affect the contraction. Sodium
ferricyanide, sodium nitrate, or sodium nitrite was not active. The augmentory
effect of SNP could not be blocked by 1H-[1,2, 4]-oxadiazolo-[4,3-a]-quinoxalin-1
one, whereas it was partially reversed by 8-(4-chlorophenylthio) (CPT)-cGMP. To
further explore the mechanisms by which SNP acted, fibronectin and PGE(2)
production were measured by immunoassay after 2 days of gel contraction. SNP
inhibited PGE(2) production and increased fibronectin production by HFL1 cells in
a concentration-dependent manner. CPT-cGMP had opposite effects on fibronectin
and PGE(2) production. Addition of exogenous PGE(2) blocked SNP-augmented
contraction and fibronectin production by HFL1 cells. Therefore, SNP was able to
augment human lung fibroblast-mediated collagen gel contraction, an effect that
appears to be independent of NO production and not mediated through cGMP.
Decreased PGE(2) production and augmented fibronectin production may have a role
in this effect. These data suggest that human lung fibroblasts in three
dimensional type I collagen gels respond distinctly to SNP by mechanisms
unrelated to the NO-cGMP pathway.
PMID- 10781434
TI - Carbon dioxide enhances nitration of surfactant protein A by activated alveolar
macrophages.
AB - We assessed whether reactive oxygen-nitrogen intermediates generated by alveolar
macrophages (AMs) oxidized and nitrated human surfactant protein (SP) A. SP-A was
exposed to lipopolysaccharide (100 ng/ml)-activated AMs in 15 mM HEPES (pH 7.4)
for 30 min in the presence and absence of 1.2 mM CO(2). In the presence of CO(2),
lipopolysaccharide-stimulated AMs had significantly higher nitric oxide synthase
(NOS) activity (as quantified by the conversion of L-[U-(14)C]arginine to L-[U
(14)C]citrulline) and secreted threefold higher levels of nitrate plus nitrite in
the medium [28 +/- 3 vs. 6 +/- 1 (SE) nmol. 6.5 h(-1). 10(6) AMs(-1)]. Western
blotting studies of immunoprecipitated SP-A indicated that CO(2) enhanced SP-A
nitration by AMs and decreased carbonyl formation. CO(2) (0-1.2 mM) also
augmented peroxynitrite (0.5 mM)-induced SP-A nitration in a dose-dependent
fashion. Peroxynitrite decreased the ability of SP-A to aggregate lipids, and
this inhibition was augmented by 1.2 mM CO(2). Mass spectrometry analysis of
chymotryptic fragments of peroxynitrite-exposed SP-A showed nitration of two
tyrosines (Tyr(164) and Tyr(166)) in the absence of CO(2) and three tyrosines
(Tyr(164), Tyr(166), and Tyr(161)) in the presence of 1.2 mM CO(2). These
findings indicate that physiological levels of peroxynitrite, produced by
activated AMs, nitrate SP-A and that CO(2) increased nitration, at least
partially, by enhancing enzymatic nitric oxide production.
PMID- 10781436
TI - Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro.
AB - The antiarrhythmic amiodarone (AM) and its metabolite desethylamiodarone (Des)
are known to cause AM-induced pulmonary toxicity, but the mechanisms underlying
this disorder remain unclear. We hypothesized that AM might cause AM-induced
pulmonary toxicity in part through the induction of apoptosis or necrosis in
alveolar epithelial cells (AECs). Two models of type II pneumocytes, the human
AEC-derived A549 cell line and primary AECs isolated from adult Wistar rats, were
incubated with AM or Des for 20 h. Apoptotic cells were determined by
morphological assessment of nuclear fragmentation with propidium iodide on
ethanol-fixed cells. Necrotic cells were quantitated by loss of dye exclusion.
Both AM and Des caused dose-dependent necrosis starting at 2.5 and 0.1 microg/ml,
respectively, in primary rat AECs and at 10 and 5 microg/ml in subconfluent A549
cells (P < 0.05 and P < 0.01, respectively). AM and Des also induced dose
dependent apoptosis beginning at 2.5 microg/ml in the primary AECs (P < 0.05 for
both compounds) and at 10 and 5 microg/ml, respectively, in the A549 cell line (P
< 0.01). The two compounds also caused significant net cell loss (up to 80% over
20 h of incubation) by either cell type at drug concentrations near or below the
therapeutic serum concentration for AM. The cell loss was not due to detachment
but was blocked by the broad-spectrum caspase inhibitor Z-Val-Ala-Asp
fluoromethylketone. Furthermore, the angiotensin-converting enzyme inhibitor
captopril (500 ng/ml) and the angiotensin-receptor antagonist saralasin (50
microg/ml) significantly inhibited both the induction of apoptosis and net cell
loss in response to AM. These results are consistent with recent work from this
laboratory demonstrating potent inhibition of apoptosis in human AECs by
captopril (Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn
K, and Filippatos G. Am J Physiol Lung Cell Mol Physiol 275: L1013-L1017, 1998).
They also suggested that the accumulation of AM and/or its primary metabolite Des
in lung tissue may induce cytotoxicity of AECs that might be inhibitable by
angiotensin-converting enzyme inhibitors or other antagonists of the renin
angiotensin system.
PMID- 10781437
TI - TRAIL expression in vascular smooth muscle.
AB - TRAIL is a cell-associated tumor necrosis factor-related apoptosis-inducing
ligand originally identified in immune cells. The ligand has the capacity to
induce apoptosis after binding to cell surface receptors. To examine TRAIL
expression in murine vascular tissue, we employed in situ hybridization and
immunohistochemistry. In these studies, we found that TRAIL mRNA and protein were
specifically localized throughout the medial smooth muscle cell layer of the
pulmonary artery. Notably, a similar pattern of expression was observed in the
mouse aorta. Consistent with these findings, we found that cultures of primary
human aorta and pulmonary artery smooth muscle cells express abundant TRAIL mRNA
and protein. We also found that these cells and endothelial cells undergo cell
lysis in response to exogenous addition of TRAIL. Last, we confirmed that TRAIL
specifically activated a death program by confirming poly(ADP ribose) polymerase
cleavage. Overall, we believe that these findings are relevant to understanding
the factors that regulate cell turnover in the vessel wall.
PMID- 10781438
TI - Diminished injury in hypotransferrinemic mice after exposure to a metal-rich
particle.
AB - Using the hypotransferrinemic (Hp) mouse model, we studied the effect of altered
iron homeostasis on the defense of the lung against a catalytically active metal.
The homozygotic (hpx/hpx) Hp mice had greatly diminished concentrations of both
serum and lavage fluid transferrin relative to wild-type mice and heterozygotes.
Fifty micrograms of a particle containing abundant concentrations of metals (a
residual oil fly ash) was instilled into wild-type mice and heterozygotic and
homozygotic Hp animals. There was an oxidative stress associated with particle
exposure as manifested by decreased lavage fluid concentrations of ascorbate.
However, rather than an increase in lung injury, diminished transferrin
concentrations in homozygotic Hp mice were associated with decreased indexes of
damage, including concentrations of relevant cytokines, inflammatory cell influx,
lavage fluid protein, and lavage fluid lactate dehydrogenase. Comparable to other
organs in the homozygotic Hp mouse, siderosis of the lung was evident, with
elevated concentrations of lavage fluid and tissue iron. Consequent to these
increased concentrations of iron, proteins to store and transport iron, ferritin,
and lactoferrin, respectively, were increased when assayed by immunoprecipitation
and immunohistochemistry. We conclude that the lack of transferrin in Hp mice did
not predispose the animals to lung injury after exposure to a particle abundant
in metals. Rather, these mice demonstrated a diminished injury that was
associated with an increase in the metal storage and transport proteins.
PMID- 10781439
TI - Protein phosphatase inhibitors arrest cell cycle and reduce branching
morphogenesis in fetal rat lung cultures.
AB - Protein phosphatase 2A (PP2A) is a key signal transduction intermediate in the
regulation of cellular proliferation and differentiation in vitro. However, the
role of PP2A in the context of a developing organ is unknown. To explore the role
of PP2A in the regulation of lung development, we studied the effect of PP2A
inhibition on new airway branching, induction of apoptosis, DNA synthesis, and
expression of epithelial marker genes in whole organ explant cultures of
embryonic (E14) rat lung. Microdissected lung primordia were cultured in medium
containing one of either two PP2A inhibitors, okadaic acid (OA, 0-9 nM) or
cantharidin (Can, 0-3,600 nM), or with the PP2B inhibitor deltamethrin (Del, 0-10
microM) as a control for a PP2A-specific effect for 48 h. PP2A inhibition with OA
and Can significantly inhibited airway branching and overall lung growth. PP2B
inhibition with Del did not affect lung growth or new airway development.
Histologically, both PP2A- and PP2B-inhibited explants were similar to controls.
Increased apoptosis was not the mechanism of decreased lung growth and new airway
branching inasmuch as OA-treated explant sections subjected to the terminal
deoxynucleotidyltransferase dUTP nick end labeling reaction demonstrated a
decrease in apoptosis. However, PP2A inhibition with OA increased DNA content and
5-bromo-2'-deoxyuridine uptake that correlated with a G(2)/M cell cycle arrest.
PP2A inhibition also resulted in altered differentiation of the respiratory
epithelium as evidenced by decreased mRNA levels of the early epithelial marker
surfactant protein C. These findings suggest that inhibition of protein
phosphatases with OA and Can halted mesenchymal cell cycle progression and
reduced branching morphogenesis in fetal rat lung explant culture.
PMID- 10781440
TI - Alterations of nitric oxide synthase expression and activity during rat lung
transplantation.
AB - Decreased nitric oxide (NO) production has been reported during lung
transplantation in patients. To study the effects of ischemia and reperfusion on
endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung
injury model for transplantation were used. Donor rat lungs were flushed with
cold low-potassium dextran solution and subjected to either cold (4 degrees C for
12 h) or warm (21 degrees C for 4 h) ischemic preservation followed by
reperfusion with an ex vivo model. A significant increase in inducible NOS and a
decrease in endothelial NOS mRNA was found after reperfusion. These results were
confirmed in a rat single-lung transplant model after warm preservation.
Interestingly, protein contents of both inducible NOS and endothelial NOS
increased in the transplanted lung after 2 h of reperfusion. However, the total
activity of NOS in the transplanted lungs remained at very low levels. We
conclude that ischemic lung preservation and reperfusion result in altered NOS
gene and protein expression with inhibited NOS activity, which may contribute to
the injury of lung transplants.
PMID- 10781441
TI - Ablation of tumor necrosis factor receptor type I (p55) alters oxygen-induced
lung injury.
AB - Hyperoxic lung injury, believed to be mediated by reactive oxygen species,
inflammatory cell activation, and release of cytotoxic cytokines, complicates the
care of many critically ill patients. The cytokine tumor necrosis factor (TNF)
alpha is induced in lungs exposed to high concentrations of oxygen; however, its
contribution to hyperoxia-induced lung injury remains unclear. Both TNF-alpha
treatment and blockade with anti-TNF antibodies increased survival in mice
exposed to hyperoxia. In the current study, to determine if pulmonary oxygen
toxicity is dependent on either of the TNF receptors, type I (TNFR-I) or type II
(TNFR-II), TNFR-I or TNFR-II gene-ablated [(-/-)] mice and wild-type control mice
(WT; C57BL/6) were studied in >95% oxygen. There was no difference in average
length of survival, although early survival was better for TNFR-I(-/-) mice than
for either TNFR-II(-/-) or WT mice. At 48 h of hyperoxia, slightly more alveolar
septal thickening and peribronchiolar and periarteriolar edema were detected in
WT than in TNFR-I(-/-) lungs. By 84 h of oxygen exposure, TNFR-I(-/-) mice
demonstrated greater alveolar debris, inflammation, and edema than WT mice. TNFR
I was necessary for induction of cytokine interleukin (IL)-1beta, IL-1 receptor
antagonist, chemokine macrophage inflammatory protein (MIP)-1beta, MIP-2,
interferon-gamma-induced protein-10 (IP-10), and monocyte chemoattractant protein
(MCP)-1 mRNA in response to intratracheal administration of recombinant murine
TNF-alpha. However, IL-1beta, IL-6, macrophage migration inhibitory factor, MIP
1alpha, MIP-2, and MCP-1 mRNAs were comparably induced by hyperoxia in TNFR-I(-/
) and WT lungs. In contrast, mRNA for manganese superoxide dismutase and
intercellular adhesion molecule-1 were induced by hyperoxia only in WT mice.
Differences in early survival and toxicity suggest that pulmonary oxygen toxicity
is in part mediated by TNFR-I. However, induction of specific cytokine and
chemokine mRNA and lethality in response to severe hyperoxia was independent of
TNFR-I expression. The current study supports the prediction that therapeutic
efforts to block TNF-alpha receptor function will not protect against pulmonary
oxygen toxicity.
PMID- 10781442
TI - Selective restoration of calcium coupling to muscarinic M(3) receptors in
contractile cultured airway myocytes.
AB - We previously demonstrated that after several days of serum deprivation about one
sixth of confluent cultured canine tracheal myocytes acquire an elongated,
structurally and functionally contractile phenotype. These myocytes demonstrated
significant shortening on ACh exposure. To evaluate the mechanism by which these
myocytes acquire responsiveness to ACh, we assessed receptor-Ca(2+) coupling
using fura 2-AM fluorescence imaging and muscarinic receptor expression using
Western analysis. Cells were grown to confluence in 10% fetal bovine serum and
then maintained for 7-13 days in serum-free medium. A fraction of serum-deprived
cells exhibited reproducible intracellular Ca(2+) mobilization in response to ACh
that was uniformly absent from airway myocytes before serum deprivation. The
Ca(2+) response to 10(-4) M ACh was ablated by inositol 1,4,5-trisphosphate
(IP(3)) receptor blockade using 10(-6) M xestospongin C but not by removal of
extracellular Ca(2+). Also, 10(-7) M atropine or 10(-7) M 4-diphenylacetoxy-N
methylpiperidine completely blocked the response to ACh, but intracellular Ca(2+)
mobilization was not ablated by 10(-6) M pirenzepine or 10(-6) M methoctramine.
In contrast, 10(-5) M bradykinin (BK) was without effect in these ACh-responsive
myocytes. Interestingly, myocytes that did not respond to ACh demonstrated robust
increases in intracellular Ca(2+) on exposure to 10(-5) M BK that were blocked by
removal of extracellular Ca(2+) and were only modestly affected by IP(3) receptor
blockade. Serum deprivation increased the abundance of M(3) receptor protein and
of BK(2) receptor protein by two- to threefold in whole cell lysates within 2
days of serum deprivation, whereas M(2) receptor protein fell by >75%. An
increase in M(3) receptor abundance and restoration of M(3) receptor-mediated
Ca(2+) mobilization occur concomitant with reacquisition of a contractile
phenotype during prolonged serum deprivation. These data demonstrate plasticity
in muscarinic surface receptor expression and function in a subpopulation of
airway myocytes that show mutually exclusive physiological and pharmacological
diversity with other cells in the same culture.
PMID- 10781444
TI - Neuraxial blockade for pediatric cardiac surgery: lessons yet to be learned.
PMID- 10781443
TI - Dexamethasone potentiates high-affinity beta-agonist binding and g(s)alpha
protein expression in airway smooth muscle.
AB - Corticosteroids enhance beta-adrenergic responses by actions at both beta
adrenoceptor (beta-AR) and post-beta-AR sites. The present study investigated the
effects of dexamethasone on beta-AR density, high-affinity beta-agonist binding,
G(s)alpha and G(i)alpha protein expression, and cAMP responses in bovine tracheal
smooth muscle (bTSM). Dexamethasone treatment of cultured bTSM cells increased
total beta-AR density 1.6- to 1.9-fold as assessed by the saturation binding of
[(3)H]CGP-12177 and by displacement of radioligand binding with isoproterenol.
Isoproterenol bound to the beta-AR at two sites, a high-affinity site with a
density of 5.9 +/- 1.2 fmol/mg protein and a low-affinity site with a density of
16.9 +/- 1. 0 fmol/mg protein. Dexamethasone increased both high- and low
affinity isoproterenol binding sites to 11.1 +/- 2.2 and 25.9 +/- 2.1 fmol/mg
protein, respectively, without influencing agonist binding affinities.
Dexamethasone also selectively increased G(s)alpha protein levels from 0.99 +/-
0.14 to 1.46 +/- 0.17 microg/mg protein without affecting G(i)alpha levels. The
net effect of these changes was a 1.8-fold increase in maximal isoproterenol
induced cAMP generation in dexamethasone-treated bTSM cells. These findings
provide new insights into the corticosteroid regulation of beta-adrenergic
signaling pathways in airway smooth muscle.
PMID- 10781445
TI - A report of two hundred twenty cases of regional anesthesia in pediatric cardiac
surgery.
AB - The use of regional anesthesia (ie, epidural, spinal, or caudal) has been
reported in a few small series of children undergoing cardiac surgery, but not in
larger studies. In this retrospective, descriptive study, we report the results
of the use of regional anesthesia in 220 pediatric cardiac operations. We
reviewed the records of children receiving a regional anesthetic for
cardiothoracic surgery at Stanford Medical Center between January 1993 and
February 1997. All patients were targeted for early tracheal extubation. A
variety of regional techniques were used. Time to extubation, control of pain,
incidence of respiratory depression and other complications, and length of
hospital stay were determined. There were no deaths. Eighty-nine percent of the
patients were tracheally extubated in the operating room; 4.1% of whom required
reintubation within 24 h. Ninety-five percent +/-2.5% of the patients had pain
scores < or =4.0 at all intervals postoperatively. Adverse effects of regional
anesthesia included emesis (39%), pruritus (10%), urinary retention (7%),
postoperative transient paresthesia (3%), and respiratory depression (1.8%). The
incidence of peridural hematoma was zero. The rate of adverse effects was lower
in the thoracic catheter epidural approach as compared with various caudal,
lumbar epidural, and spinal approaches. Hospital duration of stay was not
effected by the presence of regional anesthetic complications. In this study,
regional anesthesia was safe and effective in the management of pediatric
patients undergoing cardiac surgery.
PMID- 10781446
TI - A retrospective examination of regional plus general anesthesia in children
undergoing open heart surgery.
AB - The use of regional anesthesia in combination with general anesthesia for
children undergoing cardiac surgery is receiving increasing attention from
clinicians. The addition of regional anesthesia may improve clinical outcomes and
decrease costs as a result of the reduced need for postoperative mechanical
ventilation. The goal of this retrospective chart review was to evaluate whether
spinal anesthesia (SAB) or epidural anesthesia (EPID) in combination with general
anesthesia was associated with circulatory stability, satisfactory postoperative
sedation/analgesia, and a low incidence of adverse effects. The medical records
of 50 consecutive children having open heart surgery with SAB or EPID and general
anesthesia between September 1996 and December 1997 were reviewed. We found no
significant differences in the incidence of clinically significant changes in
vital signs, oxygen desaturation, hypercarbia, or vomiting. Patients in the SAB
group received significantly more sedative/analgesic interventions than those in
the EPID group.
PMID- 10781447
TI - Analgesia for pediatric thoracostomy tube removal.
AB - Eutectic mixture of local anesthetics (EMLA; Astra Pharmaceuticals, Wayne, PA)
has been shown to reduce the pain of blood draws in children. We investigated the
use of EMLA versus IV morphine for providing analgesia during chest tube removal
(CTR) in children. One hundred twenty pediatric cardiothoracic surgery patients
were enrolled. Patients were randomly assigned to receive either morphine (0.1
mg/kg up to 10 mg IV 30 min before CTR) or EMLA cream (5 g per chest tube
cutaneously 3 h before CTR). A single, trained observer rated the patient's pain
before, during, and after CTR using a 10-cm visual analog scale. The sites were
evaluated for adverse effect. Methylhemoglobin levels were monitored in infants.
Before CTR, the pain scores of the children who received morphine were rated
lower than those who received EMLA (P < 0.01). During CTR, there was no
difference in the pain score between the morphine or EMLA group. The change from
baseline pain score in the morphine group was significantly larger than in the
EMLA group (P < 0.01). We conclude that EMLA is safe and useful for blunting the
pain of CTR.
PMID- 10781448
TI - Does the addition of fentanyl to bupivacaine in caudal epidural block have an
effect on the plasma level of catecholamines in children?
AB - We evaluated the effect of adding fentanyl to bupivacaine, compared with
bupivacaine alone, on the stress response. The effect was evaluated by
determining blood levels of epinephrine (E) and norepinephrine (NE) in pediatric
patients receiving caudal epidural blocks. Sixty children, 1-8 yr of age,
scheduled for elective herniorrhaphy, were randomly allocated to two groups of 30
patients each. Group A received inhaled anesthesia and caudal epidural block with
bupivacaine 0.25% alone, 1.0 mL/kg. Group B received identical anesthesia;
however, fentanyl 1 microg/kg was added to the bupivacaine in the caudal block.
Blood samples for E and NE plasma levels were drawn at induction time (H(0)), at
the end of surgery (H(1)), and in the postanesthesia care unit (H(2)). In both
groups, there was a significant decrease in the E and NE plasma levels, when
comparing H(1) and H(2) with H(0) within the same group (P < 0.001). There were
no significant differences in the E and NE plasma levels between the two groups
at H(0), H(1), and H(2) (P = 0.5, P = 0.12, P = 0.5, respectively). Pain scores
(modified Children's Hospital of Eastern Ontario Pain Score) were also similar in
both groups (P = 0. 19). This study suggests that adding fentanyl 1 microg/kg to
bupivacaine in the caudal epidural block in children does not influence plasma
levels of E and NE, nor does it improve the analgesic intensity of the caudal
block.
PMID- 10781449
TI - The effects of ropivacaine on sodium currents in dorsal horn neurons of neonatal
rats.
AB - We used a whole cell patch clamp technique to study the effects of ropivacaine on
rat dorsal horn neurons. Under voltage clamp, ropivacaine (10-400 microM)
produced a dose-dependent inhibition of sodium current. From a holding potential
(V(h)) of -80 mV, sodium currents evoked by test pulses to 0 mV were inhibited by
ropivacaine with a mean drug concentration required to produce 50% current
inhibition (IC(50)) value of 117.3 microM, which was more than the value of the
bupivacaine (IC(50) 53.7 microM). The inhibition effect of ropivacaine was also
voltage-dependent. Current evoked from a V(h) of -60 mV was inhibited by
ropivacaine with a mean IC(50) value of 74.3 microM, which was less than that
obtained at the V(h) of -80 mV. The inhibition effect of ropivacaine on sodium
current was use dependent. Repeated activation by a train of depolarizing pulses
(5 Hz, 20 ms) increased the inhibitory effects of ropivacaine. The ratio
amplitudes of the 20th to the first pulse were 91.2% and 71.1%, respectively, in
the absence and presence of ropivacaine (50 microM). Ropivacaine also produced a
significant hyperpolarizing shift of 11 mV in the steady-state inactivation curve
of sodium current. The inhibition of ropivacaine on the sodium channel may
contribute to the mechanism of action of local anesthetics during epidural and
spinal anesthesia.
PMID- 10781450
TI - Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory
cytokines.
AB - Cardiopulmonary bypass (CPB) impairs pulmonary endothelial injury in part by
increasing expression of adhesion molecules that results in neutrophil influx.
Although numerous proinflammatory cytokines up-regulate these responses, the
extent to which systemic and pulmonary proinflammatory cytokines increase remains
unknown. We therefore examined systemic and pulmonary gene expression and
production of proinflammatory cytokines during CPB. Bronchoalveolar lavage and
peripheral blood sampling were performed just after the induction of anesthesia
and at the end of surgery in 80 patients undergoing CPB. RNA was extracted from
harvested cells and cDNA was synthesized by reverse transcription. The expression
of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) was
measured by semiquantitative polymerase chain reaction using beta-actin as an
internal standard. We also measured these cytokines in cultured alveolar
macrophages and plasma monocytes in standard medium alone, or in the presence of
lipopolysaccharide. We found 2- to 20-fold increases in gene expression for these
cytokines in both plasma and alveolar leukocytes at the end of surgery. However,
the increases were 4-8 times greater in alveolar than plasma leukocytes. Alveolar
macrophages obtained at the end of surgery produced 1.5-3 times more IL-6, IL-8,
and TNF-alpha than those obtained at the beginning (P < 0.0001). Although plasma
monocytes produced more IL-8 at the end of surgery (P < 0.001), TNF-alpha and IL
6 did not increase. The production of all cytokines was 1.5-3 times greater in
alveolar macrophages obtained at the end of surgery than in plasma monocytes
obtained simultaneously (P < 0.005). Our data thus suggest that CPB provokes a
greater pulmonary than systemic inflammatory response.
PMID- 10781451
TI - Neutrophil number and interleukin-8 and elastase concentrations in
bronchoalveolar lavage fluid correlate with decreased arterial oxygenation after
cardiopulmonary bypass.
AB - Atelectasis is a major cause of decreased arterial oxygenation after
cardiopulmonary bypass (CPB). There is a close relationship between atelectasis
and inflammatory responses. We therefore tested the hypothesis that neutrophil
number and the concentrations of proinflammatory cytokines and elastase in plasma
and bronchoalveolar lavage fluid correlate with changes in arterial oxygenation.
Bronchoalveolar lavage was performed just after the induction of anesthesia and
at the end of surgery in 80 patients undergoing CPB. Peripheral blood was sampled
simultaneously. Arterial oxygenation was quantified by PaO(2)/fraction of
inspired oxygen (FIO(2)) and intrapulmonary shunt (Q(s)/Q(t)). PaO(2)/FIO(2) and
Q(s)/Q(t) decreased significantly at the end of surgery, whereas neutrophil
number, interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and elastase
concentrations in the lavage fluid increased significantly. The increase in
neutrophil count from the lavage fluid correlated significantly with the
increases in IL-8 and elastase concentrations. The increase in neutrophil number
and IL-8 and elastase concentrations in the lavage fluid correlated significantly
with PaO(2)/FIO(2) and Q(s)/Q(t) at the end of surgery. In contrast, none of the
plasma values correlated with these variables. Significant correlation between
immune mediators and decreased arterial oxygenation suggests that inflammatory
responses in the distal airway are strongly related to a decrease in arterial
oxygenation after CPB.
PMID- 10781452
TI - A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac
surgical patients.
AB - Organ dysfunction and multiple organ failure are the main causes of prolonged
hospital stay after cardiac surgery, which increases resource use and health care
costs. Increased levels of oxygen delivery and consumption are associated with
improved outcome in different groups of postoperative patients. Cardiac surgical
patients are at risk of inadequate perioperative oxygen delivery caused by
extracorporeal circulation and limited cardiovascular reserves. The purpose of
our study was to test whether increasing oxygen delivery immediately after
cardiac surgery would shorten hospital and intensive care unit (ICU) stay. Four
hundred three elective cardiac surgical patients were enrolled in the study and
randomly assigned to either the control or the protocol group. Goals of the
protocol group were to maintain SvO(2) >70% and lactate concentration < or =2.0
mmol/L from admission to the ICU and up to 8 h thereafter. Hemodynamics, oxygen
transport data, and organ dysfunctions were recorded. The median hospital stay
was shorter in the protocol group (6 vs 7 days, P < 0.05), and patients were
discharged faster from the hospital than those in the control group (P < 0.05).
Discharge from the ICU was similar between groups (P = 0. 8). Morbidity was less
frequent at the time of hospital discharge in the protocol group (1.1% vs 6.1%, P
< 0.01). Increasing oxygen delivery to achieve normal SvO(2) values and lactate
concentration during the immediate postoperative period after cardiac surgery can
shorten the length of hospital stay. IMPLICATIONS: Health care economics has
challenged clinicians to reduce costs and improve resource use in cardiac surgery
and anesthesia in a patient population increasing in age and in severity of
disease. Optimizing cardiovascular function to maintain adequate oxygen delivery
during the immediate postoperative period after cardiac surgery can decrease
morbidity and reduce length of hospital stay.
PMID- 10781453
TI - The effect of alpha(2) agonist-induced sedation and its reversal with an alpha(2)
antagonist on organ blood flow in sheep.
AB - We investigated changes in cardiac output and organ blood flow induced by
medetomidine in sheep and determined changes in cardiac output and organ blood
flow after reversal of medetomidine-induced sedation by atipamezole. Eight sheep
were chronically instrumented. Medetomidine was infused IV to target plasma
levels of 0, 0.8, 1.6, 3.2, 6.4, and 12.8 ng/mL for 25 min each, followed by a 5
min infusion of atipamezole. Hemodynamic values and organ blood flow (using
colored microspheres) were measured just before medetomidine infusion (baseline),
at the end of each medetomidine infusion step, and 30 min after the
administration of atipamezole. Medetomidine (12. 8 ng/mL) decreased cardiac
output from 6.3 +/- 1.0 to 3.2 +/- 0.7 L/min (P < 0.0001) and increased systemic
vascular resistance from 1310 +/- 207 to 3467 +/- 1299 dynes. s(-1). cm(-5) (P <
0.0001). Blood flow decreased in the cerebral cortex from 1.29 +/- 0.40 to 0. 66
+/- 0.12 mL. g(-1). min(-1) (P < 0.0001), left ventricle from 2. 11 +/- 0.61 to
1.40 +/- 0.40 mL. g(-1). min(-1) (P < 0.0001), kidney from 8.28 +/- 3.17 to 6.07
+/- 2.65 mL. g(-1). min(-1) (P < 0.0001), skin from 0.09 +/- 0.04 to 0.05 +/-
0.02 mL. g(-1). min(-1) (P < 0. 0001), intestine from 0.56 +/- 0.13 to 0.27 +/-
0.07 mL. g(-1). min(-1) (P < 0.0001), and skeletal muscle from 0.28 +/- 0.15 to
0.04 +/- 0.01 mL. g(-1). min(-1) (P < 0.0001). Blood flow in the liver (hepatic
artery) increased from 0.05 +/- 0.03 to 0.24 +/- 0.16 mL. g(-1). min(-1) (P <
0.0001). After atipamezole infusion, cardiac output and systemic vascular
resistance returned to baseline, but the cerebral cortex, left ventricle, and
renal blood flows remained below baseline at 0.89 +/- 0.22, 1.37 +/- 0.50, and
6.25 +/- 2.76 mL. g(-1). min(-1), respectively; skeletal muscle blood flow
increased above baseline to 0.44 +/- 0.27 mL. g(-1). min(-1), spleen blood flow
decreased below baseline to 1.65 +/- 0.61 mL. g(-1). min(-1) (P < 0.0001), and
liver, intestine, and lung blood flows returned to baseline values. In
conclusion, medetomidine decreased and redistributed organ blood flow in sheep.
Atipamezole reversed the medetomidine-induced hemodynamic changes, but
redistributed blood flow from the brain, heart, and kidney to the skeletal
muscle.
PMID- 10781454
TI - The effects of repeated doses of vasopressin or epinephrine on ventricular
fibrillation in a porcine model of prolonged cardiopulmonary resuscitation.
AB - This study evaluated ventricular fibrillation mean frequency and amplitude to
predict defibrillation success in a porcine cardiopulmonary resuscitation (CPR)
model using repeated administration of vasopressin or epinephrine. After 4 min of
cardiac arrest and 3 min of CPR, 10 pigs were randomly assigned to receive either
vasopressin (early vasopressin: 0.4, 0.4, and 0.8 units/kg, respectively, n = 5)
or epinephrine (early epinephrine: 45, 45, and 200 microg/kg, respectively, n =
5). Another 11 animals were randomly allocated after 4 min of cardiac arrest and
8 min of CPR to receive every 5 min either vasopressin (late vasopressin: 0.4 and
0. 8 units/kg, respectively, n = 5) or epinephrine (late epinephrine: 45 and 200
microg/kg, n = 6). Ventricular fibrillation mean frequency and amplitude on
defibrillation were significantly higher in the vasopressin groups than in the
epinephrine groups, respectively. In vasopressin versus epinephrine animals, mean
frequency immediately before defibrillation was 9.6 +/- 1.5 Hz vs 7. 0 +/- 0.7 Hz
(P < 0.001), mean amplitude was 0.65 +/- 0.26 mV vs 0. 21 +/- 0.14 mV (P < 0.001,
and coronary perfusion pressure was 27 +/- 9 mm Hg vs 8 +/- 4 mm Hg (P <
0.00001), respectively. In contrast to no epinephrine animals, all vasopressin
animals were successfully defibrillated and survived 1 h (P < 0.05). Mean
fibrillation frequency and amplitude predicted successful defibrillation and may
serve as noninvasive markers to monitor continuing CPR efforts. Furthermore,
vasopressin was superior to epinephrine in maintaining these variables above a
threshold necessary for successful defibrillation.
PMID- 10781455
TI - The in vitro effects of antithrombin III on the activated coagulation time in
patients on heparin therapy.
AB - Heparin requires antithrombin III (AT) to achieve anticoagulation, and patients
on continuous small-dose heparin preoperatively experience decreased levels of AT
causing heparin resistance. When this occurs, 2-4 units of fresh frozen plasma (
approximately 1000 units of AT) are often administered to increase AT levels and
restore heparin responsiveness. We evaluated purified human AT concentrate
(Thrombate III; Bayer, Inc., Elkhart, IN) to restore in vitro anticoagulation
responses in patients receiving heparin. Blood samples were obtained from cardiac
surgery patients including 22 patients receiving heparin and 21 patients not
receiving heparin preoperatively. Heparin was added to blood in final
concentrations of 4.1, 5.4, and 6.8 U/mL (equivalent to 300, 400, and 500 U/kg),
and kaolin-activated clotting times (ACTs) were determined with and without AT at
a final concentration of 0.2 units/mL to mimic fresh frozen plasma
administration. The mean duration of preoperative heparin therapy was 4.0 days
(range 2-10 days). AT activity was 69% +/- 9% in patients receiving heparin and
92% +/- 8% in patients not receiving heparin (P < 0.01). Heparin >4.1 U/mL failed
to further increase ACT values in all patients. Attempts to increase ACT in
patients receiving heparin may require supplemental AT administration. Purified
AT even in small doses significantly prolongs the ACT response to heparin.
IMPLICATIONS: In vitro addition of antithrombin III (0.2 U/mL) to heparinized
blood samples (4.1-6.8 units of heparin/mL) from patients on previous heparin
therapy increases sensitivity to supplemental heparin as reflected by
significantly prolonged activated clotting time.
PMID- 10781456
TI - Myocyte endothelin exposure during cardioplegic arrest exacerbates contractile
dysfunction after reperfusion.
AB - Transient left ventricular (LV) dysfunction can occur after cardioplegic arrest.
The contributory mechanisms for this phenomenon are not completely understood. We
tested the hypothesis that exposure of LV myocytes to endothelin (ET) during
simulated cardioplegic arrest would have direct effects on contractile processes
with subsequent reperfusion. LV porcine myocytes were randomly assigned to three
groups: 1) CONTROL: normothermic (37 degrees C) cell media (n = 204); 2)
Cardioplegia: simulated cardioplegic arrest (K(+) 24 mEq/L, 4 degrees C x 2 h)
followed by reperfusion and rewarming with cell media (n = 164); and 3)
Cardioplegia/ ET: simulated cardioplegic arrest in the presence of ET (200 pM)
followed by reperfusion with cell media containing ET (n = 171). Myocyte
contractility was measured by computer-assisted video microscopy. In a subset of
experiments, myocyte intracellular calcium was determined after Fluo-3 (Molecular
Probes, Eugene, OR) loading by digital fluorescence image analysis. Myocyte
shortening velocity was reduced after cardioplegic arrest compared with controls
(52 +/- 2 vs 84 +/- 3 microm/s, respectively; P < 0.05) and was further reduced
with cardioplegic arrest and ET exposure (43 +/- 2 microm/s, P < 0.05).
Intracellular calcium was significantly increased in myocytes exposed to
cardioplegia compared with normothermic control myocytes and was further
augmented by cardioplegia with ET supplementation (P < 0.05). Exposure of the LV
myocyte to ET during cardioplegic arrest directly contributed to contractile
dysfunction after reperfusion. Moreover, alterations in intracellular calcium may
play a role in potentiating the myocyte contractile dysfunction associated with
ET exposure during cardioplegic arrest.
PMID- 10781457
TI - The use of citrated whole blood in thromboelastography.
PMID- 10781458
TI - Reduction of postischemic contractile dysfunction of the isolated rat heart by
sevoflurane: comparison with halothane.
AB - Our aims were to evaluate the effect of sevoflurane on postcardioplegic
functional recovery of the isolated rat heart including the role of the adenosine
triphosphate regulated potassium (K(ATP)) channels and to compare the
cardioprotective effects of equipotent concentrations of halothane and
sevoflurane. Isolated perfused rat hearts were subjected to 45 or 60 min
normothermic cardioplegic arrest and 30 min reperfusion. Sevoflurane (0.9% and 1.
7%), halothane (0.4% and 0.8%), or sevoflurane (0.9%) plus glibenclamide (10
microM) (a K(ATP) channel blocker) were administered at different time intervals.
Measurements of mechanical activity were made before and after arrest. Function
during reperfusion after cardioplegic arrest was significantly depressed in both
untreated and treated hearts. However, sevoflurane administered both before and
after arrest, or before only, significantly improved functional recovery after 45
min of cardioplegia. This protective effect was abolished by simultaneous
administration of glibenclamide, suggesting a role of the K(ATP) channel.
Sevoflurane was as effective as halothane in improving postcardioplegic
functional performance. After 45 min of arrest, hearts exposed to either
anesthetic at both concentrations had a significantly higher work performance on
discontinuation of their administration than untreated controls. After 60 min of
arrest, neither anesthetic elicited protection.
PMID- 10781459
TI - Antiphospholipid syndrome and cardiac surgery: management of anticoagulation in
two patients.
PMID- 10781460
TI - Postoperative analgesia for outpatient arthroscopic knee surgery with
intraarticular clonidine and/or morphine.
AB - Both clonidine, an alpha(2) agonist, and morphine, an opioid agonist, provide
enhanced patient analgesia after arthroscopic knee surgery when administered via
the intraarticular (IA) route. Clonidine potentiates morphine analgesia in the
animal model. We designed this study to determine whether clonidine or morphine
results in better analgesia and whether their combination would provide superior
analgesia to either drug alone. We evaluated 60 patients undergoing arthroscopic
knee meniscus repair under local anesthesia with sedation. After surgery,
patients were randomized into four IA groups: Group B received 30 mL 0.25%
bupivacaine; Group BC received 30 mL 0.25% bupivacaine and clonidine 1 microg/kg;
Group BM received 30 mL 0.25% bupivacaine and morphine 3 mg; and Group BCM
received 30 mL 0.25% bupivacaine, clonidine 1 microg/kg, and morphine 3 mg. This
study revealed a significant benefit from the individual IA administration of
both clonidine and morphine. The combination of these drugs resulted in decreased
postoperative pain and analgesic use, as well as an increased analgesic duration
compared with either drug alone. We conclude that IA clonidine and morphine
improved comfort compared with either drug alone in patients undergoing knee
arthroscopy.
PMID- 10781461
TI - The effect of ketorolac on recovery after anorectal surgery: intravenous versus
local administration.
PMID- 10781462
TI - Remifentanil infusion facilitates early recovery for obese outpatients undergoing
laparoscopic cholecystectomy.
PMID- 10781463
TI - Depth of anesthesia and bispectral index monitoring.
PMID- 10781465
TI - Novel analgesic adjuncts for brachial plexus block: a systematic review.
AB - This article reviews current evidence for the efficacy of adding novel analgesic
adjuncts to brachial plexus block, the goal of which is to prolong analgesic
effect without the disadvantage of systemic side effects or prolonged motor
block. It may also allow for a reduction in the total dose of local anesthetic
used. Novel adjuncts studied to date include opioids, clonidine, neostigmine, and
tramadol. Twenty-four studies were reviewed and assessed by using specific
inclusion criteria, and only those studies satisfying these criteria were
included in the final assessment. Satisfactory studies were then assessed for
inclusion of a systemic control group to determine peripheral effect, as opposed
to possible systemic effect, of an adjunct administered peripherally. Evidence
regarding the analgesic benefit of opioid adjuncts remains equivocal and more
evidence is required before their routine use can be recommended. Clonidine
appears to have significant analgesic benefit and to cause minimal adverse
effects when used in doses up to 150 microg. Data regarding other drugs, such as
tramadol and neostigmine, are not sufficient to allow for any recommendations,
and further studies are required.
PMID- 10781464
TI - Sedation with sufentanil and midazolam decreases pain in patients undergoing
upper limb surgery under multiple nerve block.
AB - Multiple nerve blocks may be painful and a source of discomfort. We assessed the
efficacy of sufentanil 5 microg combined with midazolam 1 mg in decreasing pain
in outpatients after a midhumeral multiple nerve stimulation technique. Visual
analog scores for pain were significantly lower in those patients who received
sedation before the block, both at the time of block performance (14 +/- 1 vs 27
+/- 2 mm, P < 0.0001) and at discharge (11 +/- 1 vs 24 +/- 2 mm, P < 0. 0001). We
conclude that the association of sufentanil and midazolam produced minimal
sedation while significantly reducing pain experienced by patients undergoing
multiple nerve stimulation.
PMID- 10781466
TI - A decrease in seizure susceptibility to lidocaine in kindled epileptic rats.
AB - Lidocaine induces electroencephalographic seizures and generalized convulsions at
large doses. It is possible that epileptic patients are more susceptible to the
proconvulsant effect of lidocaine. Using a kindling model of epilepsy, we
examined whether the seizure susceptibility to lidocaine increases in epileptic
rats. Kindled epileptic rats were prepared by repeated, initially subconvulsive,
electrical stimulations applied to the amygdala for 9-14 days through a
chronically implanted electrode, resulting in the establishment of a long-lasting
epileptic focus. Unexpectedly, kindled rats had significantly less susceptibility
to the proconvulsant action of IV lidocaine. Lidocaine-induced convulsions were
observed in 11%, 75%, and 77% of control rats at 7.5, 10.0, and 12.5 mg/kg,
respectively, compared with 0%, 25%, and 37% of amygdala-kindled rats,
respectively. We also demonstrated that small doses of lidocaine suppressed
kindled seizures in a dose-dependent manner. We conclude that the critical
mechanisms underlying lidocaine-induced seizures differ from the mechanisms
underlying kindled epileptogenesis. Furthermore, the establishment of a kindled
epileptic focus decreases susceptibility to the proconvulsant action of
lidocaine.
PMID- 10781467
TI - Determining minimum effective anesthetic concentration of hyperbaric bupivacaine
for spinal anesthesia.
AB - We determined the minimum effective anesthetic concentration (MEAC) of
bupivacaine for spinal anesthesia, defined as the median effective concentration
at which a spinal anesthetic produces surgically equivalent anesthesia within 20
min of administration in 50% of human subjects. Two doses of spinal bupivacaine
(7.5 mg and 10 mg) were administered to 45 volunteers (19-39 yr) in a randomized,
double-blinded fashion. Hyperbaric bupivacaine solutions of 0.1% to 0.75%
containing 8.25% dextrose were administered intrathecally and MEAC established by
using the Dixon's up-and-down method. Complete anesthesia was defined as: 1)
pinprick anesthesia at or higher than T12; 2) anesthesia to transcutaneous
tetanic electric stimulation (50 Hz at 60 mA for 5 s) in the knees; and 3)
complete leg paralysis, all occurring in both lower extremities within 20 min of
intrathecal injection. We found that the MEAC of spinal bupivacaine was 0.43%
(95% confidence interval 0.24-0.62) when 10 mg was administered. At this dose, a
concentration as low as 0.1% could provide complete anesthesia, but consistent
blockade was obtained only with the 0.7% solution. The 7.5-mg dose failed to
provide complete anesthesia consistently, even in the presence of 0.75%
(maximum). The current commercially available 0.75% concentration of hyperbaric
bupivacaine seems to be clinically optimal when 10 mg is used if complete
bilateral lower extremity blockade is desired.
PMID- 10781468
TI - The effect of diclofenac on the expression of spinal cord c-fos-like
immunoreactivity after ischemia-reperfusion-induced acute hyperalgesia in the rat
tail.
AB - Ischemia-reperfusion of the rat tail for 20 min induces local acute hyperalgesia
of approximately 1-h duration. We studied how this stimulus affected the
expression of c-fos-like immunoreactivity (c-fos-LI) labeling of neurons of the
sacral spinal cord, and how diclofenac pretreatment influenced the outcome. After
ischemia, the number of c-fos-LI-labeled neurons was significantly increased when
assessed at 60, 90, and 120 min after reperfusion (to 183%, 283%, and 164% of
control, respectively; all P < 0.01). At 90 min, the number of regional c-fos-LI
labeled neurons was increased to 585% in laminae I-II, 183% in laminae III-IV,
270% in laminae V-X, and 286% in total, compared with respective control values
(all P < 0.01). After diclofenac pretreatment (subcutaneous 40 mg/Kg, 30 min
before insult) the number of c-fos-LI-labeled neurons at 90 min was increased to
424% in laminae I-II, 150% in laminae III-IV, 142% in laminae V-X, and 183% in
total (all P < 0.01). Thus diclofenac pretreatment partially prevented the insult
induced increase in total and regional neuronal c-fos-LI. This acute nociceptive
model involves only natural algogens. However, the results were similar to acute
chemically induced or chronic adjuvant induced arthritic inflammatory pain models
in which increases in c-Fos were partially inhibited by nonsteroidal
antiinflammatory drugs.
PMID- 10781470
TI - Antagonism of antinociception produced by intrathecal clonidine by ketorolac in
the rat: the role of the opioid system.
AB - The management of severe pain may require "balanced analgesia," involving the use
of analgesics with different modes of action. Clonidine, an alpha(2)
adrenoreceptor agonist produces analgesia by itself as well as when given with
morphine and local anesthetics. Ketorolac is indicated for the management of
moderately severe acute pain and causes analgesia equivalent to morphine. This
study was designed to investigate whether the addition of ketorolac promotes
antinociception produced by intrathecal administration of clonidine in male
Sprague-Dawley rats. Intrathecal injection of clonidine (1-30 microg) induced a
dose-dependent increase in antinociception as measured by the tail flick (TF) and
hot plate tests. Ketorolac alone (150-600 microg) increased the antinociception
by 50%-60% only in the TF test. Ketorolac (10 microg) decreased clonidine (10
microg)-induced antinociception from 69.1% +/- 7.8% to 23.5% +/- 1. 6% (P < 0.05)
in the TF test and 35.7% +/- 4.7% to 4.5% +/- 0.1% (P < 0.05) maximum possible
effect in the hot plate test. Ketorolac also antagonized the effect of 30 microg
of clonidine. The opioid receptor antagonist naloxone antagonized the
antinociceptive effect of clonidine and ketorolac, indicating the involvement of
the opioid system in the antinociception produced by clonidine or ketorolac.
However, neither clonidine nor ketorolac (10(-8) to 10(-3) M) inhibited the
binding of specific ligands to mu-, delta-, and kappa-opioid receptors,
indicating a lack of direct interaction of clonidine and ketorolac with opioid
receptors. These results suggest that intrathecal injection of ketorolac
antagonizes the antinociception produced by clonidine.
PMID- 10781469
TI - Antinociceptive action of epidural K+(ATP) channel openers via interaction with
morphine and an alpha(2)- adrenergic agonist in rats.
AB - Potassium (K(+)) channels may play some role in the analgesic actions of mu
opioid agonists and alpha(2)-adrenergic agonists (alpha(2) agonists). We examined
whether the adenosine triphosphate-sensitive K(+)(K(+)(ATP)) channel openers,
levcromakalim and nicorandil, (given epidurally), might have antinociceptive
effects in a tail flick test in adult male Sprague-Dawley rats implanted with a
lumbar epidural catheter. The interactions with morphine and an alpha(2) agonist
were also examined. The epidural administration of levcromakalim (10 microg, 100
microg) or nicorandil (10 microg, 100 microg) alone did not produce
antinociception, but 100 microg levcromakalim or nicorandil did potentiate the
antinociceptive effect induced by epidural morphine. Epidural glibenclamide (10
microg), a K(+)(ATP) channel blocker, or naloxone (10 microg) antagonized this
potentiation. Systemic administration of levcromakalim or nicorandil (at the same
dose as that given into the epidural space) did not potentiate the epidural
morphine-induced analgesia. A combination of epidural dexmedetomidine (1 microg)
and morphine (1 microg) (each at a subantinociceptive dose) had a significant
antinociceptive effect, and epidural glibenclamide (10 microg) partly antagonized
this antinociception. These data suggest that levcromakalim and nicorandil
potentiate the analgesic action of both morphine and dexmedetomidine, probably
via an activation of K(+)(ATP) channels at the spinal cord level.
PMID- 10781471
TI - The combined effect of age and premedication on the propofol requirements for
induction by target-controlled infusion.
AB - In this prospective study, we evaluated the combined influence of age and
premedication on propofol requirements for the induction of anesthesia and their
hemodynamic effects using a target-controlled infusion. We studied 180 patients
separated into three age groups: 20-39 yr, 40-59 yr, and more than 59 yr. In each
age group, patients were randomly allocated to receive either no premedication (n
= 20), fentanyl (2 microg/kg) (n = 20), or midazolam (0.03 mg/kg) plus fentanyl
(2 microg/kg) (n = 20). The concentration of propofol targeted for the induction
was 5 microg/mL, to be reached in 2 min. The dose, time, and predicted plasma
concentration of propofol at hypnosis were measured. Baseline and postinduction
heart rate and arterial blood pressure were registered. Computer simulation was
used to calculate the effect site propofol concentration at hypnosis. The
concentration of propofol, effect site propofol concentration, time, and
induction dose and their hemodynamic effect were significantly different among
groups with respect to age and premedication. The combined effect of the two
factors was additive, but without significant interaction. The propofol
requirements were significantly less in the midazolam-fentanyl groups, regardless
of age, and among the premedicated patients older than 60 yr compared with the
other age groups. We conclude that the combined effect of age and premedication
on the requirements of propofol for the induction of anesthesia should be
considered when the concentration is targeted with a target-controlled infusion
system.
PMID- 10781472
TI - Intrathecal fentanyl is superior to intravenous ondansetron for the prevention of
perioperative nausea during cesarean delivery with spinal anesthesia.
AB - This study compares intrathecal (IT) fentanyl with IV ondansetron for preventing
intraoperative nausea and vomiting during cesarean deliveries performed with
spinal anesthesia. Thirty healthy parturients presenting for elective cesarean
delivery with standardized bupivacaine spinal anesthesia were randomized to
receive 20 microg IT fentanyl (Group F) or 4 mg IV ondansetron (Group O) by using
double-blinded methodology. At eight specific intervals during the surgery, a
blinded observer questioned the patient about nausea (1 = nausea, 0 = no nausea),
observed for the presence of retching or vomiting (1 = vomiting or retching, 0 =
no vomiting or retching), and recorded a verbal pain score (0-10, 0 = no pain, 10
= worst pain imaginable). Cumulative nausea, vomiting, and pain scores were
calculated as the sum of the eight measurements. Intraoperative nausea was
decreased in the IT fentanyl group compared with the IV ondansetron group: the
median (interquartile range) difference in nausea scores was 1 (1, 2), P = 0.03.
The incidence of vomiting and treatment for vomiting was not different (P = 0.7).
The IT fentanyl group had a lower cumulative perioperative pain score than the IV
ondansetron group; the median difference in the cumulative pain score was 12 (8,
16) (P = 0.0007). The IT fentanyl group required less supplementary
intraoperative analgesia. The median difference in the cumulative fentanyl dose
was 100 (75, 100) microg fentanyl, (P = 0.0002).
PMID- 10781473
TI - Alfentanil given immediately before the induction of anesthesia for elective
cesarean delivery.
AB - Opioids are routinely omitted at the induction of general anesthesia for cesarean
delivery because of concerns about neonatal respiratory depression. The
subsequent unmodified maternal stress response to tracheal intubation reduces
placental perfusion. The short-acting opioid alfentanil may afford advantages at
the induction, without subsequent neonatal depression. In this double-blinded
study of elective cesarean deliveries, 40 patients were allocated randomly to
receive either alfentanil 10 microg/kg (n = 18) or placebo (n = 22), 1 min before
the induction of anesthesia with thiopental 4 mg/kg and succinylcholine 1.5
mg/kg. Anesthesia was maintained with 50% nitrous oxide, 0.5% isoflurane in
oxygen, and atracurium. Neonates were assessed by using Apgar scores, Neurologic
and Adaptive Capacity Scores, and umbilical cord blood gas and catecholamine
analysis. After intubation, mothers receiving alfentanil had a smaller increase
in mean arterial blood pressure, (11 +/- 15 vs 31 +/- 13 mm Hg, P < 0.001) and
lower plasma norepinephrine concentrations, (336 +/- 152 vs 486 +/- 241 pg/mL, P
< 0.05). Neonates in the alfentanil group had greater umbilical arterial oxygen
tensions (27.8 +/- 7.0 vs 22.6 +/- 7.4 mm Hg), slightly reduced Apgar scores
(both P < 0.05), but similar Neurologic and Adaptive Capacity Scores. One neonate
in the alfentanil group required naloxone. The maternal stress response was
attenuated in the alfentanil group but at the cost of early neonatal depression.
However, all neonates should be monitored for possible immediate, but transient,
respiratory depression.
PMID- 10781474
TI - Tension pneumothorax in a parturient undergoing cesarean delivery.
PMID- 10781475
TI - Mental status change and aphasia after labor analgesia with intrathecal
sufentanil/bupivacaine.
PMID- 10781476
TI - The effects of pentobarbital, isoflurane, and propofol on immediate-early gene
expression in the vital organs of the rat.
AB - General anesthetics are known to transiently increase the expression of messenger
ribonucleic acids (mRNAs) of immediate-early genes in the brain. We investigated
whether the expression of two immediate-early genes in vital organs were
modulated by various anesthetics. Inhaled isoflurane (n = 20), intraperitoneal
pentobarbital (n = 20), and IV propofol (n = 20) were administered to male
Sprague-Dawley rats, and five from each group were decapitated at 5, 30, 60, or
120 min after the induction of anesthesia. Control, nonanesthetized rats (n = 5)
were handled gently and then decapitated. Reverse transcriptase-polymerase chain
reactions were performed on total RNA from samples of the brain, heart, liver,
and kidney to detect the expressions of c-fos and c-jun mRNAs. As internal
control, cyclophilin mRNA was amplified simultaneously. The products were
separated by electrophoresis, and the optical density of the bands was
quantified. The expression of c-fos mRNA was transiently increased in the brain,
and more strikingly and for longer times, in the kidney with all three
anesthetics; the expression of c-fos mRNA was decreased in the heart with
isoflurane and pentobarbital and increased in the liver with isoflurane and
propofol. The expression of c-jun mRNA was increased in the heart, liver, and
kidney with isoflurane, increased in the heart and kidney with pentobarbital,
increased in the heart, liver, and kidney with propofol, and decreased in the
brain with pentobarbital. Our results suggest that the appropriate anesthetics to
be used to anesthetize animals differ in accord with the target organs in which
the expressions of immediate-early genes in response to stimuli were studied.
PMID- 10781477
TI - Dual action of isoflurane on the gamma-aminobutyric acid (GABA)-mediated currents
through recombinant alpha(1)beta(2)gamma(2L)-GABA(A)-receptor channels.
AB - Isoflurane (ISO) increased the agonist-induced chloride flux through the gamma
aminobutyric acid A receptor (GABA(A)R). This may reflect an anesthetic-induced
increase in the apparent agonist affinity. A dual effect of anesthetics was
postulated for both the nicotinic acetylcholine receptor (nAChR) and the
GABA(A)R. We tested the hypothesis that, in addition to a blocking effect, ISO
increases gamma-aminobutyric acid (GABA)-gated currents through recombinant
GABA(A)R channels. HEK293 cells were transfected with rat cDNA for
alpha(1),beta(2),gamma(2L) subunits. Currents elicited by 1 mM or 0. 01 mM GABA,
respectively, alone, or with increasing concentrations of ISO, were recorded by
using standard patch clamp techniques. ISO reduced the peak current elicited by 1
mM GABA. Currents induced by 0.01 mM GABA were potentiated by small ISO (twofold
at 0.5 mM ISO) and inhibited by larger concentrations. Withdrawal of ISO and GABA
induced rebound currents, suggesting an open-channel block by ISO. These currents
increased with increasing concentrations of ISO. At large concentrations of ISO,
the inhibitory effect predominated and was caused by, at least partly, an open
channel block. At small concentrations of ISO, potentiation of the GABA-gated
currents was more prominent. This dual action of ISO indicates different binding
sites at the GABA(A)R. The balance between potentiation and block depends on the
concentrations of both ISO and GABA.
PMID- 10781478
TI - An alternate method for estimating the dose-response relationships of
neuromuscular blocking drugs.
AB - Slopes of the dose-response relationships for all available neuromuscular
blocking drugs appear to be essentially parallel and to approximate a log
dose/logit value of 4.75. We tested the possibility of estimating both 50%
effective dose (ED(50)) and 95% effective dose (ED(95)) values from a single dose
response data point when that slope is postulated. We compared the ED(50) and
ED(95) values of rocuronium and succinylcholine calculated by using traditional
log-dose/logit regression analysis with the same values obtained by averaging
individual estimates of potency as determined by using the Hill equation. After
the induction of anesthesia (propofol/alfentanil), tracheal intubation was
accomplished without the administration of neuromuscular blocking drugs.
Anesthesia was maintained with nitrous oxide and propofol. The evoked
electromyographic response to 0.10-Hz single stimuli was continuously recorded.
After baseline stabilization, a single IV bolus of succinylcholine (0.08-0.26
mg/kg, n = 50) or rocuronium (0. 13-0.30 mg/kg, n = 40) was administered and the
peak effect noted. By using log-dose/logit regression analysis, we calculated
ED(50) and ED(95) values for rocuronium of 0.17 and 0.33 mg/kg and 0.14 and 0.27
mg/kg for succinylcholine. When potency was calculated from the Hill equation,
the resultant ED(50) and ED(95) values did not differ by more than +/-4% from
those obtained by using regression analysis. Averaging of single-dose estimates
of neuromuscular potency provides a useful adjunct and reasonable alternative to
conventional regression analysis.
PMID- 10781479
TI - Hepatic blood flow and function in elderly patients undergoing laparoscopic
cholecystectomy.
AB - Laparoscopic cholecystectomy (LC) has been widely accepted as an alternative to
laparotomy and has many advantages, including short hospital stay and very
limited surgical invasion. However, this procedure may impair hepatic function in
elderly patients because high pressure is maintained in the peritoneal cavity for
an extended period. We observed the effect of pneumoperitoneum on the middle
hepatic venous blood flow (MHVBF) in elderly patients undergoing LC. LC patients
were anesthesized with inhaled and epidural anesthesia, after which MHVBF was
continuously measured by transesophageal echocardiography. MHVBF decreased
significantly during a period of high intraperitoneal pressure, and recovery of
MHVBF after deflation was significantly lower in elderly patients (65-75 yr), but
not in younger patients (24-62 yr). In contrast, MHVBF remained almost constant
in elderly patients during open cholecystectomy, and thus was significantly
different from that in patients who underwent LC with pneumoperitoneum.
Laparoscopic cholecystectomy may impair hepatic function in elderly patients
because high pressure is maintained in the peritoneal cavity for an extended
period.
PMID- 10781480
TI - A comparison of hemodynamic changes after endotracheal intubation by using the
lightwand device and the laryngoscope in normotensive and hypertensive patients.
AB - We compared the effects of the lightwand technique on hemodynamic responses, time
to-intubation, number of attempts, and complications during tracheal intubation
with those of direct-vision laryngoscopy in normotensive (LN and TN group; n =
20, respectively) and hypertensive (LH and TH group; n = 20, respectively)
patients. Lightwand or laryngoscopic oral endotracheal intubation was performed
after the induction of anesthesia with fentanyl and propofol and muscle
relaxation with vecuronium. Systolic blood pressure, diastolic blood pressure,
and heart rate were recorded, and the change from "before intubation" to
"immediately after intubation" (DeltaP) in each variable was calculated. In
normotensive patients, significantly larger DeltaP in systolic blood pressure was
observed in the LN group than in the TN group (P < 0. 05). In hypertensive
patients, there were no significant differences between the LH group and the TH
group in DeltaP after intubation. The time-to-intubation and number of attempts
in the lightwand groups were significantly longer and more frequent than those in
the laryngoscope groups (P < 0.05). The number of patients who complained of
hoarseness was larger in the lightwand groups than in the laryngoscope groups (P
< 0.05). We conclude that the lightwand technique significantly attenuates
hemodynamic changes after intubation in comparison with the laryngoscopic
technique in normotensive patients. However, in hypertensive patients, there is
no difference in hemodynamic changes between the two techniques.
PMID- 10781481
TI - Intravenous chloroprocaine attenuates hemodynamic changes associated with direct
laryngoscopy and tracheal intubation.
AB - We compared the effects of an IV administration of chloroprocaine and lidocaine
on circulatory responses associated with endotracheal intubation. Thirty patients
were randomly allocated to receive normal saline (placebo), lidocaine (1.5
mg/kg), or preservative-free chloroprocaine (4.5 mg/kg) 45 s before endotracheal
intubation. Blood pressures and heart rate and rhythm were recorded before
laryngoscopy and at 0.5, 1, 1.5, 2, 3, and 5 min after intubation. Blood samples
were analyzed for catecholamine and chloroprocaine concentrations. Chloroprocaine
reduced increases in blood pressure in response to intubation when compared with
patients receiving normal saline and lidocaine. Systolic blood pressures at 0.5
and 1 min after intubation were significantly lower in the chloroprocaine group
when compared with both the control and lidocaine groups (P < 0.05). Diastolic
and mean blood pressures were significantly lower in the chloroprocaine group at
all time points until 5 min after intubation (P < 0.05). Chloroprocaine and, to a
lesser degree, lidocaine, produced marked attenuation of intubation-induced
increases in plasma concentration of epinephrine and norepinephrine. Plasma
concentrations of norepinephrine were significantly smaller in the chloroprocaine
group at 0.5, 1, and 1.5 min, and plasma concentrations of epinephrine were
significantly smaller at 0.5 after intubation when compared with control and
lidocaine groups (P < 0.05). Measurable concentrations of chloroprocaine were
recorded in plasma samples for 2 min after its administration. No adverse
chloroprocaine effects (i.e., circulatory disturbances, venous irritation) were
detected. The IV administration of chloroprocaine effectively blunted
cardiovascular response produced by laryngoscopy and endotracheal intubation, and
this effect was more pronounced when compared with IV lidocaine.
PMID- 10781482
TI - Inhaling nitrous oxide reduces the induction dose requirements of propofol.
AB - Inhaling nitrous oxide (N(2)O) before propofol induction appears to decrease
propofol usage. To investigate the efficacy of N(2)O as a component of the drugs
used to induce anesthesia, the effect of inhaling a N(2)O:oxygen (O(2)) mixture
on the dose of propofol required to induce anesthesia was determined in a double
blinded manner. We randomized 117 unpremedicated patients scheduled for elective
surgery into three groups. Group FN received 1 microg/kg fentanyl and breathed 4
L/min N(2)O + 2 L/min O(2). Group PN received placebo and breathed 4 L/min N(2)O
+ 2 L/min O(2). Group FO received 1 microg/kg fentanyl and breathed 6 L/min O(2).
Propofol was infused at 20 mg/min after 1 min of gas mixture inhalation, and the
infusion stopped when there was loss of response to verbal command. The mean (SD)
propofol dose was 0.75 (0.30), 0.84 (0.26), and 1.33 (0.51) mg/kg, and the
induction time 133 (57), 142 (47), and 226 (78) s for Groups FN, PN, and FO,
respectively. We conclude that inhalation of 66% N(2)O in O(2) 1 min before the
IV induction of anesthesia with propofol at 20 mg/min, reduces the induction dose
of propofol by 44% and decreases the time required for the induction of
anesthesia (P < 0.001).
PMID- 10781483
TI - The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine.
AB - Administration of ephedrine prior to rocuronium decreases the onset time of
neuromuscular blockade from rocuronium by 26%. This effect was attributed to a
increased cardiac output. If so, beta adrenergic-blocking drugs, which decrease
cardiac output, should prolong the onset time of rocuronium. In a double-blind
study, 60 patients were randomly assigned to three groups (n = 20) to receive
either 70 microg. kg(-1) of ephedrine, 0.5 mg. kg(-1) esmolol or placebo, 30 s
before induction of anesthesia. Onset time of rocuronium was defined as the time
from the end of its injection to disappearance of all four twitches of the train
of-four. The onset time of rocuronium was significantly shorter after ephedrine
(22%) and longer after esmolol (26%), as compared to placebo. No differences were
observed among the three groups with regard to heart rate, systolic, diastolic or
mean blood pressure. We concluded that a dose of 0.5 mg. kg(-1) of esmolol
significantly prolongs the onset time of rocuronium with minimal hemodynamic
changes.
PMID- 10781484
TI - The laryngeal tube: a new simple airway device.
PMID- 10781485
TI - An AIDS-associated cause of the difficult airway: supraglottic Kaposi's sarcoma.
PMID- 10781486
TI - An unusual cause of respiratory distress: live leech in the larynx.
PMID- 10781487
TI - Cardiovascular anesthesiology in the 1990s and beyond.
PMID- 10781488
TI - Pediatric anesthesia: where do we go from here?
PMID- 10781489
TI - Ambulatory anesthesia advances into the new millennium.
PMID- 10781490
TI - Intensive care medicine 2000: first signs of maturity?
PMID- 10781491
TI - Neuroanesthesia 2000.
PMID- 10781492
TI - Obstetric anesthesiology in the new millennium.
PMID- 10781493
TI - Regional anesthesia and pain management: reviewing the past decade and predicting
the future.
PMID- 10781494
TI - Femoral nerve palsy after femoral vein cannulation.
PMID- 10781495
TI - Quality of medical information on the Internet.
PMID- 10781496
TI - Curling the tip anteriorly does not facilitate laryngeal mask insertion.
PMID- 10781497
TI - Intraoperative variables and morbidity and mortality after coronary artery bypass
surgery.
PMID- 10781498
TI - Five-grade scoring system is still confusing: does ASE/SCA set up a double
standard?
PMID- 10781499
TI - Postdural puncture headache (PDPH) and combined spinal-epidural (CSE)
PMID- 10781500
TI - An economical substitute for Ayre's T piece.
PMID- 10781501
TI - Hidden damage to a reinforced LMA-Fastrach endotracheal tube.
PMID- 10781502
TI - Epidural hematoma after catheter removal.
PMID- 10781504
TI - Immunology and thyroid ophthalmopathy: where will the footprints lead us?
PMID- 10781503
TI - Ups and downs of optokinetic nystagmus.
PMID- 10781505
TI - Sympathetic ophthalmia risk following vitrectomy: should we counsel patients?
PMID- 10781506
TI - Abnormal vertical optokinetic nystagmus in infants and children.
AB - AIMS: To determine if testing vertical optokinetic nystagmus (VOKN) has a role in
the clinical assessment of infants and children. METHODS: A large field
projection system was developed with which optokinetic nystagmus (OKN) could be
stimulated in any direction. Gross abnormalities in the response were detected
simply by observation. RESULTS: VOKN was tested in 144 children using this OKN
projection system. 26 of these children had abnormal VOKN; 13 had a vertical
saccade initiation failure "ocular motor apraxia" (in either direction, up/down,
or in both) and 13 had absent VOKN (in either direction, up/down, or in both).
Nine of the children with an up and/or down vertical saccade initiation failure
(VSIF) had a neurometabolic disease (two had Niemann-Pick disease type C, five
had Gaucher disease type III, one had Gaucher disease type II, and one had
Gaucher disease type I). Five children with a VSIF had an abnormality identified
by a magnetic resonance imaging (MRI) scan of the brain. In two of these children
there was a focal lesion of the rostral midbrain. In 11 of the children with
absent up and/or down VOKN an MRI scan revealed an abnormality. This involved the
brainstem and/or the cerebellum in 10. Absent up and/or down VOKN was found in
association with Joubert syndrome, Leigh disease, and cerebral palsy. CONCLUSION:
VOKN testing has a useful role in detecting neurological abnormalities in infants
and children. Detection of abnormal VOKN should indicate further investigations
for a neurometabolic disease or an abnormality involving the cortex, brainstem,
and/or cerebellum. Abnormal VOKN but normal horizontal OKN is highly suggestive
of a rostral midbrain lesion.
PMID- 10781507
TI - The Bristol shared care glaucoma study: outcome at follow up at 2 years.
AB - AIM: To examine the outcome of care for patients with glaucoma followed up by the
hospital eye service compared with those followed up by community optometrists.
METHODS: A randomised study with patients allocated to follow up by the hospital
eye service or community optometrists was carried out in the former county of
Avon in south west England. 403 patients with established or suspected primary
open angle glaucoma attending Bristol Eye Hospital and meeting defined inclusion
and exclusion criteria were studied. The mean number of missed points on visual
field testing in the better eye (using a "better/worse" eye analysis) in each
group were measured. The visual field was measured using the Henson semiautomated
central field analyser (CFA 3000). Measurements were made by the research team on
all patients at baseline before randomisation and again 2 years after
randomisation. The mean number of missed points on visual field testing in the
worse eye, mean intraocular pressure (mm Hg), and cup disc ratio using a
"better/worse" eye analysis in each group at 2 years were also measured.
Measurements were made by the research team on all patients at baseline before
randomisation and again 2 years after randomisation. An analysis of covariance
comparing method of follow up taking into account baseline measurements of
outcome variables was carried out. Additional control was considered for age,
sex, diagnostic group (glaucoma suspect/established primary open angle glaucoma),
and treatment (any/none). RESULTS: From examination of patient notes, 2780
patients with established or suspected glaucoma were identified. Of these, 752
(27.1%) fulfilled the entry criteria. For hospital and community follow up group
respectively, mean number of missed points on visual field testing at 2 year
follow up for better eye was 7.9 points and 6.8 points; for the worse eye 20.2
points and 18.4 points. Similarly, intraocular pressure was 19.3 mm Hg and 19.3
mm Hg (better eye), and 19.1 mm Hg and 19.0 mm Hg (worse eye); cup disc ratio at
2 year follow up was 0.72 and 0.72 (better eye), and 0.74 and 0.74 for hospital
and community follow up group respectively. No significant differences in any of
the key visual variables were found between the two groups before or after
adjusting for baseline values and age, sex, treatment, and type of glaucoma.
CONCLUSIONS: It is feasible to set and run shared care schemes for a proportion
of patients with suspected and established glaucoma using community optometrists.
After 2 years (a relatively short time in the life of a patient with glaucoma),
there were no marked or statistically significant differences in outcome between
patients followed up in the hospital eye service or by community optometrists.
Decisions to implement such schemes need to be based on careful consideration of
the costs of such schemes and local circumstances, including geographical access
and the current organisation of glaucoma care within the hospital eye service.
PMID- 10781508
TI - Discriminant analysis models for early detection of glaucomatous optic disc
changes.
AB - AIM: To evaluate and compare four different mathematical formulas for the early
detection of morphometric optic nerve head changes in chronic open angle
glaucoma. METHODS: The optic nerve heads of 161 patients with perimetrically
defined glaucomatous optic nerve damage and of 194 normal subjects were examined
by confocal laser scanning tomography. Using four formulas of linear discriminant
analysis and the optic cup shape measure as the single optic disc variable, the
predictive power of each of these methods was examined to differentiate between
the normal eyes and the glaucoma eyes. RESULTS: The highest predictive power had
an optic disc sector based formula, in particular in eyes with medium and large
optic discs. This optic disc sector based formula was the one with the best
agreement with the other formulas examined. It achieved a better predictability
than any single optic disc variable evaluated. CONCLUSIONS: Combining
quantitative optic disc variables by discriminant analysis functions, the
predictive power of semiautomatic quantitative optic nerve head evaluation can be
improved by providing the ophthalmologist with a diagnostic score for the
detection of glaucomatous optic nerve damage. Because of the pattern of
glaucomatous neuroretinal rim loss, an optic disc sector based discriminant
formula may have a higher diagnostic precision than other formulas in detecting
early glaucomatous damage.
PMID- 10781509
TI - Asymmetries of the retinal nerve fibre layer thickness in normal eyes.
AB - AIMS: To investigate the variation in the retinal nerve fibre layer thickness in
detail in normal eyes with a scanning laser polarimeter. METHODS: The retinal
nerve fibre layer thickness (RNFLT) was measured in 94 normal volunteers with a
scanning laser polarimeter. The mean RNFLT around a 10 pixel-wide ellipse located
concentrically with the disc of 1.5 disc diameters was calculated for 16 sectors
each of 22.5 degrees. The symmetry of the RNFLT distribution with respect to the
horizontal midline for individual eyes and to the vertical meridian for the two
eyes was examined. RESULTS: The RNFLT was thicker on the inferior side than on
the superior side for the temporal four pairs of 22.5 degrees sectors, and the
differences were significant in two of the four temporal pairs (p<0.007). The
RNFLT was thicker in the superior than in the inferior side for the nasal four
pairs of the sectors, and the differences were significant in three of the four
nasal pairs (p<0.04). The mean RNFLT was significantly thicker in the right eyes
than in the left eyes in the four temporal sectors (p<0.02), and significantly
thicker in the left eyes than in the right eyes in the inferior two nasal sectors
(p<0.01). CONCLUSIONS: Asymmetries of the RNFLT in normal eyes with respect to
the horizontal midline and to the vertical meridian for the two eyes were found.
These asymmetries should be considered when retinal nerve fibre layer loss is
evaluated during the course of a disease process.
PMID- 10781510
TI - Relation of optic disc topography and age to thickness of retinal nerve fibre
layer as measured using scanning laser polarimetry, in normal subjects.
AB - AIMS: To evaluate the relation of the optic nerve head topographic measurements
and age with the thickness of the retinal nerve fibre layer (RNFL) in normal
Caucasoid subjects by means of scanning laser polarimetry and tomography.
METHODS: Topographic optic disc measurements and RNFL thickness values of 38
normal Caucasoid subjects of both sexes aged 20 to 78 were measured using a
confocal scanning laser ophthalmoscope and a confocal scanning laser polarimeter.
One eye was randomly selected for statistical analysis. The effects of optic disc
size, age, and optic disc head topographic measurements of total and regional
RNFL thickness were evaluated. RESULTS: Age showed a significant correlation with
the integral of the total RNFL thickness (R=-0.341, p<0.05). The optic disc size
showed a significant correlation with the integral of the total, superior, and
inferior quadrant RNFL thickness (R=0.425, p<0.01), (R=0.361, p<0.05), (R=0.468,
p<0.05). Neuroretinal rim area (NRA) had a correlation with the superior and
inferior quadrant RNFL thickness values (R=0.339, p<0.05) (R=0.393, p<0.05).
There was no significant correlation between the other optic disc topographic
measurements and RNFL thickness values (p>0.05). CONCLUSION: The thickness of
total as well as superior and inferior quadrant peripapillary RNFL as measured by
scanning laser polarimetry increased significantly with an increase in optic disc
size. The cross sectional area occupied by superior and inferior polar RNFL
increased significantly with an increase in NRA. The total cross sectional area
occupied by RNFL decreased significantly with an increase in age. The effects of
optic disc size, age, and NRA should be considered when the peripapillary RNFL
thickness is evaluated.
PMID- 10781511
TI - Polypoidal choroidal vasculopathy in exudative and haemorrhagic pigment
epithelial detachments.
AB - AIMS: To determine the prevalence of polypoidal choroidopathy in consecutive
patients presenting with large haemorrhagic and exudative neurosensory retinal
and retinal pigment epithelial detachments (PEDs) of over 2 mm in diameter in the
absence of drusen. METHODS: 40 patients were identified over a 5 month period of
which 29 had haemorrhagic detachments, and 11 had purely exudative detachments.
All had indocyanine green (ICG) angiography, and the presence was sought of large
blood vessels in the choroid associated with localised dilated terminals that
filled slowly and leaked ICG. RESULTS: In 34 cases (85%) there was an appearance
consistent with previous descriptions of idiopathic polypoidal choroidal
vasculopathy. Of the six without polypoidal lesions the disorder was attributed
to choroidal neovascularisation in four, chorioretinitis in one, and a
fibrovascular PED in one. Of those with polypoidal lesions 20 (65%) were female,
the mean age was 65.4 years (range 44-88), and 25 (74%) were white, seven (20%)
black, and two (6%) east Asian. Eight had a history of hypertension. Visual
acuity varied from 6/6 to counting fingers in the involved eye (mean 6/24).
Bilateral polypoidal choroidal lesions were demonstrated in 16 patients (47%).
The predominant location for these lesions was the macular region in 23 patients
(68%). Polypoidal vasculopathy was found in 16 patients (47%) who had a previous
diagnosis of age related macular disease (AMD). No patients had evidence of
intraocular inflammation. CONCLUSIONS: In a largely white patient population a
high proportion of patients with haemorrhagic and exudative PEDs has evidence of
polypoidal lesions on ICG angiography.
PMID- 10781512
TI - Bullous variant of idiopathic central serous chorioretinopathy.
AB - BACKGROUND: Spontaneous bullous serous retinal detachment (RD) with subretinal
exudation complicating idiopathic central serous chorioretinopathy (ICSC) is a
rare and infrequently described clinical entity. Clinical observations are
described on this variant form in 11 patients, the largest series reported to
date. METHODS: 13 eyes of 11 Indian patients having this entity were followed up
clinically and angiographically for 12-24 months (retrospective, longitudinal).
None of the patients had any previous history of other diseases nor were they on
any medications. Four eyes received laser treatment (group A); nine eyes were not
treated (group B). RESULTS: All 11 patients were male, aged 23-49 years (median
37 years). The clinical and photographic records revealed subretinal exudation
and inferior bullous serous RD complicating ICSC with evidence of large, single
or multiple, leaking retinal pigment epithelial detachments (PEDs) in all the
cases. In group A, resolution of serous RD occurred in 12 weeks (median) with a
visual recovery of >/=20/30 in three out of four eyes while in group B resolution
of serous retinal detachment was observed in 14 weeks (median) with eight out of
nine eyes achieving a visual acuity of >/=20/30. Subretinal fibrosis developed in
two eyes in group A and none of the eyes in group B. CONCLUSION: The disease is
an exaggerated form of ICSC and can occur spontaneously without any history of
corticosteroid therapy. Recognition of this atypical presentation is important to
avoid inappropriate treatment. These observations suggest that with respect to
the duration of the disease and the final visual outcome laser therapy offers no
additional benefit over the natural course of this variant form of ICSC.
PMID- 10781514
TI - A controlled study of vigabatrin and visual abnormalities.
AB - AIMS: To assess the visual function in epileptic patients who have received
vigabatrin; to compare this with the visual function in similar epileptic
patients who have never received vigabatrin; to investigate whether the severity
of visual field defect (VFD) is related to the dose of vigabatrin; to consider
other factors that may correlate with the severity of VFD. METHODS: 21
consecutive patients who had taken vigabatrin at some time in their lives were
enrolled from the epilepsy clinic of the Royal Shrewsbury Hospital and were
compared with a group of 11 otherwise similar patients with epilepsy who had
never received vigabatrin. One patient taking vigabatrin was excluded from the
study because her visual field results were unreliable because of multi-infarct
dementia. 15 patients were taking vigabatrin at the time of the study (VC), the
other five had taken vigabatrin some time in the past (VP). Each patient
underwent static perimetry using either the two point or the three point full
field 120 screening program on the Humphrey visual field analyser, followed by an
ophthalmic examination to rule out ocular causes for VFDs. The visual fields from
each patient were then analysed using a method devised to convert the VFD into
percentage defect in both eyes. In patients with known cerebral pathology that
may affect the visual pathway, only the unaffected homonymous hemifield was used.
RESULTS: Nine of 20 (45%) patients in the vigabatrin group (VC and VP) complained
of blurring of vision compared with two of 11 (18%) controls. Four patients (20%)
in the vigabatrin group described flickering lights compared with one control
(9%). None had a posterior vitreous detachment. Three of 30 (7.5%) eyes in the VC
group had distant visual acuity of 6/12 or worse compared with three of 22 (9%)
controls and five of 30 (16.7%) had near visual acuity worse than N6 compared
with one of 22 (4.5%) in the control group. A mean of 1.73 Ishihara plates were
misread in VC patients compared with 0.2 in the VP group and 0.18 in the
controls. 11 of 15 (73.3%) patients in the VC group had greater than 10% VFDs as
opposed to one of 11 (9.1%) controls (chi(2) test, p=0. 002). In 12 of 15 (80%)
VC patients the percentage VFD was greater in the nasal hemifields than the
temporal hemifields compared with six of 11 (54.5%) controls. Significant
correlation was found between the severity of VFD and the total dose of
vigabatrin ingested for the 20 patients exposed to vigabatrin (VC and VP:
Spearman correlation coefficient=0.525; p=0.002), for the 15 patients taking
vigabatrin at the time of examination (VC: Spearman correlation
coefficient=0.568; p=0.002). CONCLUSION: This pilot study suggested that
epileptic patients taking vigabatrin are at much higher risk of developing VFDs
compared with epileptic patients on other antiepileptic drugs. The total ingested
dose of vigabatrin correlated significantly with the severity of VFDs especially
in those patients who had not stopped taking vigabatrin. In our group we found
that those who had taken a total dose of 1500 g or more of vigabatrin were at
risk of developing significant visual field defects.
PMID- 10781513
TI - Ocular haemodynamics and colour contrast sensitivity in patients with type 1
diabetes.
AB - BACKGROUND: There is evidence that altered ocular blood flow is involved in the
development and progression of diabetic retinopathy. However, the nature of these
perfusion abnormalities is still a matter of controversy. Ocular haemodynamics
were characterised with two recently introduced methods. METHODS: The cross
sectional study was performed in 59 patients with type 1 diabetes with a diabetes
duration between 12 and 17 years and an age less than 32 years and a group of 25
age matched healthy controls. Scanning laser Doppler flowmetry and laser
interferometric measurement of fundus pulsation amplitude were used to assess
retinal and pulsatile choroidal blood flow, respectively. In addition, colour
contrast sensitivity along the tritan axis was determined. RESULTS: Fundus
pulsation amplitude, but not retinal blood flow, increased with the progression
of diabetic retinopathy. Retinal blood flow was influenced by plasma glucose
levels (r = 0.32), whereas fundus pulsation amplitude was associated with HbA(1c)
(r = 0.30). In addition, a negative correlation between the colour contrast
sensitivity along the tritan axis and retinal blood flow was observed.
CONCLUSIONS: The present study indicates that pulsatile choroidal blood flow
increases with the progression of diabetic retinopathy. Increased retinal blood
flow appears to be related to loss of colour sensitivity in patents with type 1
diabetes.
PMID- 10781515
TI - Risk factors for proliferative vitreoretinopathy after primary vitrectomy: a
prospective study.
AB - AIM: To assess clinical variables and vitreous protein as risk factors for the
development of postoperative proliferative vitreoretinopathy (PVR). METHODS: A
prospective study was conducted on 140 patients with a rhegmatogenous retinal
detachment in whom a primary vitrectomy was performed. 12 clinical variables were
recorded and vitreous samples obtained for measurement of protein concentration.
Univariate and multivariate logistic regression analysis was used to determine
the risk factors for PVR. RESULTS: Complete data were available for 136 of 140
patients. 40 of the 136 patients (29.4%) developed postoperative PVR. Univariate
regression revealed that significant (p<0.05) risk factors included aphakia,
presence of preoperative PVR, size of detachment, the use of silicone oil, and
high vitreous protein level. Multivariate regression analysis revealed only
aphakia (odds ratio 2.72), the presence of preoperative PVR (odds ratio 3.01),
and high vitreous protein concentration (odds ratio 1.11) to be significant
(p<0.05) independent, predictive risk factors for the development of PVR.
CONCLUSIONS: This study has shown that the significant risk factors for PVR are
preoperative PVR, aphakia, and high vitreous protein levels. Two models (clinical
factors only and clinical factors and vitreous protein) were constructed to
predict the probability of developing postoperative PVR and may be used to
identify those at risk for possible intravitreal pharmacological treatment.
PMID- 10781516
TI - 3 year simvastatin treatment and lens nuclear back scattering.
AB - AIM: To determine if 3 year treatment of hypercholesterolaemia with simvastatin
causes an increase of lens nuclear back scattering. METHODS: 160 patients with
hypercholesterolaemia in the Scandinavian Simvastatin Survival Study (4S) were
followed for 3 years. Half (80) of the patients took simvastatin and half (80)
received placebo. The lens was photographed with a Topcon SL-45 slit lamp camera
at the beginning and at 1 year intervals. A common lens nuclear area was used for
measuring lens nuclear back scattering. RESULTS: Nuclear back scattering
increased with age and there was more pronounced scattering in women than in men.
Lens nuclear back scattering did not differ significantly between the simvastatin
and placebo groups, but the power was low (0.2). Lens nuclear back scattering
increased during the study period independently of baseline back scattering, age,
and sex for both groups. CONCLUSION: Although no significant difference was found
between the simvastatin and placebo groups, the currently available data are
insufficient for exclusion of the possibility that taking simvastatin during a 3
year period increases nuclear back scattering. However, a possible minor increase
of nuclear back scattering is clinically irrelevant considering known beneficial
effects of simvastatin on coronary heart disease.
PMID- 10781517
TI - T cells and fibroblasts in affected extraocular muscles in early and late thyroid
associated ophthalmopathy.
AB - AIM: To determine whether there are differences in the lymphocytic cell
infiltrate present in affected extraocular muscles (EOM) during early and late
stages of thyroid associated ophthalmopathy (TAO). METHODS: 17 biopsies of
affected EOMs were collected from two groups of TAO patients (n=14): the first of
five patients with early, active TAO, and the second of nine patients with late,
inactive TAO. The control group was of EOM biopsies taken from 14 non-TAO
patients undergoing squint surgery. Immunohistochemical analysis was undertaken
using the relevant monoclonal antibodies and an avidin-biotin system and the
three groups compared. RESULTS: Both CD4+ and CD8+ T cells were found in the
cellular infiltrate in early, active TAO specimens which were much less evident
either in late, inactive stage disease or in control tissue. There was also a
significant increase in both CD45RO+ and CD45RB+ cells and macrophages in early
TAO compared with the others. Increased expression of HLA-DR antigen by
interstitial cells including fibroblasts was detected in both early and late
disease but the EOM fibres remained morphologically intact and did not express
MHC class II antigens at any time. CONCLUSION: These results demonstrate that T
cells are only significantly present in early disease but increased HLA-DR
antigen expression on fibroblasts is observed at all stages. This suggests that T
cells are much more involved in the early than the later stages of the disease
process and that early activation of fibroblasts occurs. Early intervention with
immunosuppressive therapy to downregulate cytokine production by T cells may
significantly influence the sequelae caused by EOM fibrosis.
PMID- 10781518
TI - Investigation of beta defensin gene expression in the ocular anterior segment by
semiquantitative RT-PCR.
AB - AIM: To determine if beta defensins are expressed in the anterior segment of the
eye and to determine the temporal pattern of expression using a real time
semiquantitative reverse transcription polymerase chain reaction (RT-PCR).
METHODS: Ocular tissue (corneal epithelium, conjunctiva, iris, and lens capsule)
was collected from 23 patients undergoing surgery. Serial corneal or conjunctival
impression cytology was performed on a separate group of 10 patients undergoing
corneal tunnel phacoemulsification or trabeculectomy. The samples were analysed
for beta defensin mRNA by semiquantitative RT-PCR and the mRNA standardised for
cell numbers. RESULTS: RT-PCR amplified beta defensin 1 mRNA from all lens
capsule (six) and corneal (five) samples and all but one of the conjunctival
(six) and iris samples (six). beta Defensin 2 mRNA was amplified from three of
five corneal, two of six conjunctival, and none of the iris or capsule samples.
The impression cytology samples demonstrated a decline in defensin expression
over the three time points studied. There were no false positive results from
either the no-RT or negative control samples. CONCLUSIONS: This preliminary study
confirms that natural antibacterial peptides are expressed in the anterior
segment of the eye. There appears to be a pattern to the expression with
inducible beta defensin 2 not expressed intraocularly and higher levels of beta
defensin 1 than beta defensin 2 expressed in extraocular tissue. The implication
is that beta defensin 1 is constitutively produced in ocular tissues and
represents a key component of the innate immune system.
PMID- 10781519
TI - A novel keratin 12 mutation in a German kindred with Meesmann's corneal
dystrophy.
AB - AIM: To study a kindred with Meesmann's corneal dystrophy (MCD) to determine if a
mutation within the cornea specific K3 or K12 genes is responsible for the
disease phenotype. METHODS: Slit lamp examination of the cornea in four members
of the kindred was carried out to confirm the diagnosis of MCD. The region
encoding the helix initiation motif (HIM) of the K12 polypeptide was polymerase
chain reaction (PCR) amplified from genomic DNA derived from affected individuals
in the kindred. PCR products generated were subjected to direct automated
sequencing. Restriction enzyme analysis employing Ban I was used to confirm the
presence of the mutation in affected individuals of the family. RESULTS:
Sequencing of the K12 gene in an affected individual from the family revealed a
novel heterozygous missense mutation (413A-->C), predicting the substitution of a
proline for a glutamine at codon 130 (Q130P) in the HIM of the K12 protein. The
mutation was excluded from 50 normal, unaffected individuals by restriction
enyzme analysis and was therefore unlikely to be a common polymorphism.
CONCLUSION: A novel missense mutation in the K12 gene leads to MCD in a German
kindred. Missense mutations have now been identified within the region encoding
the helix initiation motif of the K12 protein in eight of 11 MCD kindreds
analysed at the molecular level.
PMID- 10781520
TI - Lupus anticoagulant positivity in insulin dependent diabetic patients: an
additional risk factor in the pathogenesis of diabetic retinopathy?
AB - AIMS: To investigate whether lupus anticoagulant (LA) positivity, a marker of
endothelial dysfunction, might be relevant to the pathogenesis of diabetic
retinopathy (DR). METHODS: 32 IDDM patients were examined for LA, fibrinogen,
prothrombin (PT), PTT, prothrombin degradation products (F1+2), and activated
protein C (APC). RESULTS: APC decreased and F1+2 increased significantly in LA
positive but not in LA negative patients; 60% of LA positive and 18% of LA
negative subjects had DR. PT, PTT, and fibrinogen levels were insignificant.
CONCLUSION: These preliminary findings suggest that LA positivity could represent
an additional risk factor for DR, acting as a link between the immunological and
haemostatic systems.
PMID- 10781521
TI - Variable pattern of visual recovery of Leber's hereditary optic neuropathy.
AB - AIMS: To investigate pattern of visual recovery of nine patients with Leber's
hereditary optic neuropathy (LHON) and a mitochondrial DNA mutation at 11778.
METHODS: Recovery was judged significant when a gain of two lines or more in the
Landolt ring chart, 10 dB or more improvement of the mean deviation of static
perimetry, or improvement of critical flicker frequency (CFF) over 35 Hz was
shown. RESULTS: All three visual functions tested dramatically recovered in one
patient. Two other patients exhibited isolated improvement of CFF or visual
field, respectively. CONCLUSION: Partial improvement of visual function may be
more widespread than previously recognised in LHON patients with the 11778
mutation.
PMID- 10781522
TI - Early surgery for infantile esotropia.
AB - AIM: To investigate the postoperative eye alignment and binocular visual function
after early surgery for infantile esotropia. METHODS: Both the postoperative eye
position and stereopsis were reviewed using the Titmus stereo test in nine
patients who received uniocular medial rectus recession and lateral rectus
resection under general anaesthesia before 8 months of age and were followed up
for a minimum of 4 years. RESULTS: Orthophoria was attained in three cases,
whereas esotropia was found in four patients. Dissociated vertical deviation was
noted in two other cases at the final examination. Static stereoacuity was
achieved in five cases. These results also showed that most infants in whom
stereopsis was attained had satisfactory eye alignment during the follow up
period and at the final examination. Infants who did not achieve stereopsis still
had deviation throughout the follow up period. CONCLUSIONS: It was concluded that
early surgery in infantile esotropia is beneficial to achieve binocular visual
function, but it is necessary to confirm a stable angle of deviation with
accurate preoperative evaluation, and to maintain good postoperative eye
alignment throughout the follow up period.
PMID- 10781523
TI - Efficacy of a contact lens cleaning device and its enhancement of the performance
of contact lens care products.
AB - BACKGROUND: Corneal infections due to contact lens contamination are risks
associated with contact lens wear. Care systems which reduce these risks are
desirable. METHODS: This study evaluated a contact lens cleaning device using
normal saline initially and then four contact lens solutions. RESULTS: Using
saline, six out of 10 tests resulted in complete removal of challenge organisms
or showed reductions to 10 cfu/ml or <10 cfu/ml. Tests upon organism using
multipurpose solutions showed >6 log reductions in 2-3 minutes. With laboratory
made biofilms, similar results were obtained. CONCLUSIONS: This device improves
lens cleaning and enhances lens care solutions. When used correctly it should
lead to significant reductions in microbial keratitis associated with inadequate
contact lens hygiene.
PMID- 10781525
TI - Intraocular lens implants and risk of endophthalmitis.
PMID- 10781526
TI - Pupillary abnormality.
PMID- 10781527
TI - "Cyclodiode".
PMID- 10781524
TI - Macular oedema: the role of soluble mediators.
PMID- 10781528
TI - Is non-arteritic anterior ischaemic optic neuropathy related to homocysteine?
PMID- 10781530
TI - Clinical ophthalmology
PMID- 10781529
TI - Laser pointers: not to be taken lightly.
PMID- 10781531
TI - The rise and fall of modern medicine
PMID- 10781532
TI - Biofilm, city of microbes.
PMID- 10781533
TI - Assessment of flhDC mRNA levels in Serratia liquefaciens swarm cells.
AB - We reported previously that artificial overexpression of the flhDC operon in
liquid-grown Serratia liquefaciens resulted in the formation of filamentous,
multinucleated, and hyperflagellated cells that were indistinguishable from
surface-induced swarm cells (L. Eberl, G. Christiansen, S. Molin, and M. Givskov,
J. Bacteriol. 178:554-559, 1996). In the present report we show by means of
reporter gene measurements, Northern analysis, and in situ reverse transcription
PCR that the amount of flhDC mRNA in surface-grown swarm cells does not exceed
the maximum level found in nondifferentiated, vegetative cells. This suggests
that surface-induced S. liquefaciens swarm cell differentiation, although
dependent on flhDC gene expression, does not occur through elevated flhDC mRNA
levels.
PMID- 10781534
TI - Deletion analysis of the Escherichia coli taurine and alkanesulfonate transport
systems.
AB - The Escherichia coli tauABCD and ssuEADCB gene clusters are required for the
utilization of taurine and alkanesulfonates as sulfur sources and are expressed
only under conditions of sulfate or cysteine starvation. tauD and ssuD encode an
alpha-ketoglutarate-dependent taurine dioxygenase and a reduced flavin
mononucleotide-dependent alkanesulfonate monooxygenase, respectively. These
enzymes are responsible for the desulfonation of taurine and alkanesulfonates.
The amino acid sequences of SsuABC and TauABC exhibit similarity to those of
components of the ATP-binding cassette transporter superfamily, suggesting that
two uptake systems for alkanesulfonates are present in E. coli. Chromosomally
located in-frame deletions of the tauABC and ssuABC genes were constructed in E.
coli strain EC1250, and the growth properties of the mutants were studied to
investigate the requirement for the TauABC and SsuABC proteins for growth on
alkanesulfonates as sulfur sources. Complementation analysis of in-frame deletion
mutants confirmed that the growth phenotypes obtained were the result of the in
frame deletions constructed. The range of substrates transported by these two
uptake systems was largely reflected in the substrate specificities of the TauD
and SsuD desulfonation systems. However, certain known substrates of TauD were
transported exclusively by the SsuABC system. Mutants in which only formation of
hybrid transporters was possible were unable to grow with sulfonates, indicating
that the individual components of the two transport systems were not functionally
exchangeable. The TauABCD and SsuEADCB systems involved in alkanesulfonate uptake
and desulfonation thus are complementary to each other at the levels of both
transport and desulfonation.
PMID- 10781535
TI - A mutation in the Corynebacterium glutamicum ltsA gene causes susceptibility to
lysozyme, temperature-sensitive growth, and L-glutamate production.
AB - The Corynebacterium glutamicum mutant KY9714, originally isolated as a lysozyme
sensitive mutant, does not grow at 37 degrees C. Complementation tests and DNA
sequencing analysis revealed that a mutation in a single gene of 1,920 bp, ltsA
(lysozyme and temperature sensitive), was responsible for its lysozyme
sensitivity and temperature sensitivity. The ltsA gene encodes a protein
homologous to the glutamine-dependent asparagine synthetases of various
organisms, but it could not rescue the asparagine auxotrophy of an Escherichia
coli asnA asnB double mutant. Replacement of the N-terminal Cys residue (which is
conserved in glutamine-dependent amidotransferases and is essential for enzyme
activity) by an Ala residue resulted in the loss of complementation in C.
glutamicum. The mutant ltsA gene has an amber mutation, and the disruption of the
ltsA gene caused lysozyme and temperature sensitivity similar to that in the
KY9714 mutant. L-Glutamate production was induced by elevating growth temperature
in the disruptant. These results indicate that the ltsA gene encodes a novel
glutamine-dependent amidotransferase that is involved in the mechanisms of
formation of rigid cell wall structure and in the L-glutamate production of C.
glutamicum.
PMID- 10781537
TI - Conjugative junctions in RP4-mediated mating of Escherichia coli.
AB - The physical association of bacteria during conjugation mediated by the IncPalpha
plasmid RP4 was investigated. Escherichia coli mating aggregates prepared on
semisolid medium were ultrarapidly frozen using copper block freezing, followed
by freeze substitution, thin sectioning, and transmission electron microscopy. In
matings where the donor bacteria contained conjugative plasmids, distinctive
junctions were observed between the outer membranes of the aggregates of mating
cells. An electron-dense layer linked the stiffly parallel outer membranes in the
junction zone, but there were no cytoplasmic bridges nor apparent breaks in the
cell walls or membranes. In control experiments where the donors lacked
conjugative plasmids, junctions were not observed. Previous studies have shown
that plasmid RP4 carries operons for both plasmid DNA processing (Tra1) and
mating pair formation (Tra2). In matings where donor strains carried Tra2 only or
Tra2 plus the pilin-processing protease TraF, junctions were found but they were
shorter and more interrupted than the wild type. If the donor strain had the
pilin gene knocked out (trbC), junctions were still found. Thus, it appears that
the electron-dense layer between the outer membranes of the conjugating cells is
not composed of pilin.
PMID- 10781536
TI - The Pseudomonas quinolone signal regulates rhl quorum sensing in Pseudomonas
aeruginosa.
AB - The opportunistic pathogen Pseudomonas aeruginosa uses intercellular signals to
control the density-dependent expression of many virulence factors. The las and
rhl quorum-sensing systems function, respectively, through the autoinducers N-(3
oxododecanoyl)-L-homoserine lactone and N-butyryl-L-homoserine lactone (C(4)
HSL), which are known to positively regulate the transcription of the elastase
encoding gene, lasB. Recently, we reported that a second type of intercellular
signal is involved in lasB induction. This signal was identified as 2-heptyl-3
hydroxy-4-quinolone and designated the Pseudomonas quinolone signal (PQS). PQS
was determined to be part of the quorum-sensing hierarchy since its production
and bioactivity depended on the las and rhl quorum-sensing systems, respectively.
In order to define the role of PQS in the P. aeruginosa quorum-sensing cascade,
lacZ gene fusions were used to determine the effect of PQS on the transcription
of the quorum-sensing system genes lasR, lasI, rhlR, and rhlI. We found that in
P. aeruginosa, PQS caused a major induction of rhlI'-lacZ and had lesser effects
on the transcription of lasR'-lacZ and rhlR'-lacZ. We also observed that the
transcription of both rhlI'-lacZ and lasB'-lacZ was cooperatively effected by
C(4)-HSL and PQS. Additionally, we present data indicating that PQS was not
produced maximally until cultures reached the late stationary phase of growth.
Taken together, our results imply that PQS acts as a link between the las and rhl
quorum-sensing systems and that this signal is not involved in sensing cell
density.
PMID- 10781539
TI - Haloalkane-utilizing Rhodococcus strains isolated from geographically distinct
locations possess a highly conserved gene cluster encoding haloalkane catabolism.
AB - The sequences of the 16S rRNA and haloalkane dehalogenase (dhaA) genes of five
gram-positive haloalkane-utilizing bacteria isolated from contaminated sites in
Europe, Japan, and the United States and of the archetypal haloalkane-degrading
bacterium Rhodococcus sp. strain NCIMB13064 were compared. The 16S rRNA gene
sequences showed less than 1% sequence divergence, and all haloalkane degraders
clearly belonged to the genus Rhodococcus. All strains shared a completely
conserved dhaA gene, suggesting that the dhaA genes were recently derived from a
common ancestor. The genetic organization of the dhaA gene region in each of the
haloalkane degraders was examined by hybridization analysis and DNA sequencing.
Three different groups could be defined on the basis of the extent of the
conserved dhaA segment. The minimal structure present in all strains consisted of
a conserved region of 12.5 kb, which included the haloalkane-degradative gene
cluster that was previously found in strain NCIMB13064. Plasmids of different
sizes were found in all strains. Southern hybridization analysis with a dhaA gene
probe suggested that all haloalkane degraders carry the dhaA gene region both on
the chromosome and on a plasmid (70 to 100 kb). This suggests that an ancestral
plasmid was transferred between these Rhodococcus strains and subsequently has
undergone insertions or deletions. In addition, transposition events and/or
plasmid integration may be responsible for positioning the dhaA gene region on
the chromosome. The data suggest that the haloalkane dehalogenase gene regions of
these gram-positive haloalkane-utilizing bacteria are composed of a single
catabolic gene cluster that was recently distributed worldwide.
PMID- 10781538
TI - The H(2) sensor of Ralstonia eutropha is a member of the subclass of regulatory
[NiFe] hydrogenases.
AB - Two energy-generating hydrogenases enable the aerobic hydrogen bacterium
Ralstonia eutropha (formerly Alcaligenes eutrophus) to use molecular hydrogen as
the sole energy source. The complex synthesis of the nickel-iron-containing
enzymes has to be efficiently regulated in response to H(2), which is available
in low amounts in aerobic environments. H(2) sensing in R. eutropha is achieved
by a hydrogenase-like protein which controls the hydrogenase gene expression in
concert with a two-component regulatory system. In this study we show that the
H(2) sensor of R. eutropha is a cytoplasmic protein. Although capable of H(2)
oxidation with redox dyes as electron acceptors, the protein did not support
lithoautotrophic growth in the absence of the energy-generating hydrogenases. A
specifically designed overexpression system for R. eutropha provided the basis
for identifying the H(2) sensor as a nickel-containing regulatory protein. The
data support previous results which showed that the sensor has an active site
similar to that of prototypic [NiFe] hydrogenases (A. J. Pierik, M. Schmelz, O.
Lenz, B. Friedrich, and S. P. J. Albracht, FEBS Lett. 438:231-235, 1998). It is
demonstrated that in addition to the enzymatic activity the regulatory function
of the H(2) sensor is nickel dependent. The results suggest that H(2) sensing
requires an active [NiFe] hydrogenase, leaving the question open whether only
H(2) binding or subsequent H(2) oxidation and electron transfer processes are
necessary for signaling. The regulatory role of the H(2)-sensing hydrogenase of
R. eutropha, which has also been investigated in other hydrogen-oxidizing
bacteria, is intimately correlated with a set of typical structural features.
Thus, the family of H(2) sensors represents a novel subclass of [NiFe]
hydrogenases denoted as the "regulatory hydrogenases."
PMID- 10781540
TI - Identification of genes encoding exported Mycobacterium tuberculosis proteins
using a Tn552'phoA in vitro transposition system.
AB - Secreted and cell envelope-associated proteins are important to both
Mycobacterium tuberculosis pathogenesis and the generation of protective immunity
to M. tuberculosis. We used an in vitro Tn552'phoA transposition system to
identify exported proteins of M. tuberculosis. The system is simple and
efficient, and the transposon inserts randomly into target DNA. M. tuberculosis
genomic libraries were targeted with Tn552'phoA transposons, and these libraries
were screened in M. smegmatis for active PhoA translational fusions. Thirty-two
different M. tuberculosis open reading frames were identified; eight contain
standard signal peptides, six contain lipoprotein signal peptides, and seventeen
contain one or more transmembrane domains. Four of these proteins had not yet
been assigned as exported proteins in the M. tuberculosis databases. This
collection of exported proteins includes factors that are known to participate in
the immune response of M. tuberculosis and proteins with homologies, suggesting a
role in pathogenesis. Nine of the proteins appear to be unique to mycobacteria
and represent promising candidates for factors that participate in protective
immunity and virulence. This technology of creating comprehensive fusion
libraries should be applicable to other organisms.
PMID- 10781542
TI - The promoter of the yeast INO4 regulatory gene: a model of the simplest yeast
promoter.
AB - In Saccharomyces cerevisiae, the phospholipid biosynthetic genes are
transcriptionally regulated in response to inositol and choline. This regulation
requires the transcriptional activator proteins Ino4p and Ino2p, which form a
heterodimer that binds to the UAS(INO) element. We have previously shown that the
promoters of the INO4 and INO2 genes are among the weakest promoters
characterized in yeast. Because little is known about the promoters of weakly
expressed yeast genes, we report here the analysis of the constitutive INO4
promoter. Promoter deletion constructs scanning 1,000 bp upstream of the INO4
gene identified a small region (-58 to -46) that is absolutely required for
expression. S1 nuclease mapping shows that this region contains the transcription
start sites for the INO4 gene. An additional element (-114 to -86) modestly
enhances INO4 promoter activity (fivefold). Thus, the region required for INO4
transcription is limited to 68 bp. These studies also found that INO4 gene
expression is not autoregulated by Ino2p and Ino4p, despite the presence of a
putative UAS(INO) element in the INO4 promoter. We further report that the INO4
steady-state transcript levels and Ino4p levels are regulated twofold in response
to inositol and choline, suggesting a posttranscriptional mechanism of
regulation.
PMID- 10781541
TI - Regulation of the Escherichia coli K5 capsule gene cluster: evidence for the
roles of H-NS, BipA, and integration host factor in regulation of group 2 capsule
gene clusters in pathogenic E. coli.
AB - The expression of Escherichia coli group 2 capsules (K antigens) is temperature
dependent, with capsules only being expressed at temperatures above 20 degrees C.
Thermoregulation is at the level of transcription, with no detectable
transcription at 20 degrees C. Using the E. coli K5 capsule gene cluster as a
model system, we have shown that the nucleoid-associated protein H-NS plays a
dual role in regulating transcription of group 2 capsule gene clusters at 37 and
20 degrees C. At 37 degrees C H-NS is required for maximal transcription of group
2 capsule gene clusters, whereas at 20 degrees C H-NS functions to repress
transcription. The BipA protein, previously identified as a tyrosine
phosphorylated GTPase and essential for virulence in enteropathogenic E. coli,
was shown to play a similar role to H-NS in regulating transcription at 37 and 20
degrees C. The binding of integration host factor (IHF) to the region 1 promoter
was necessary to potentiate transcription at 37 degrees C and IHF binding
demonstrated by bandshift assays. The IHF binding site was 3' to the site of
transcription initiation, suggesting that sequences in the 5' end of the first
gene (kpsF) in region 1 may play a role in regulating transcription from this
promoter at 37 degrees C. Two additional cis-acting sequences, conserved in both
the region 1 and 3 promoters, were identified, suggesting a role for these
sequences in the coordinate regulation of transcription from these promoters.
These results indicate that a complex regulatory network involving a number of
global regulators exists for the control of expression of group 2 capsules in E.
coli.
PMID- 10781543
TI - 2-Hydroxycyclohexanecarboxyl coenzyme A dehydrogenase, an enzyme characteristic
of the anaerobic benzoate degradation pathway used by Rhodopseudomonas palustris.
AB - A gene, badH, whose predicted product is a member of the short-chain
dehydrogenase/reductase family of enzymes, was recently discovered during studies
of anaerobic benzoate degradation by the photoheterotrophic bacterium
Rhodopseudomonas palustris. Purified histidine-tagged BadH protein catalyzed the
oxidation of 2-hydroxycyclohexanecarboxyl coenzyme A (2-hydroxychc-CoA) to 2
ketocyclohexanecarboxyl-CoA. These compounds are proposed intermediates of a
series of three reactions that are shared by the pathways of
cyclohexanecarboxylate and benzoate degradation used by R. palustris. The 2
hydroxychc-CoA dehydrogenase activity encoded by badH was dependent on the
presence of NAD(+); no activity was detected with NADP(+) as a cofactor. The
dehydrogenase activity was not sensitive to oxygen. The enzyme has apparent K(m)
values of 10 and 200 microM for 2-hydroxychc-CoA and NAD(+), respectively.
Western blot analysis with antisera raised against purified His-BadH identified a
27-kDa protein that was present in benzoate- and cyclohexanecarboxylate-grown but
not in succinate-grown R. palustris cell extracts. The active form of the enzyme
is a homotetramer. badH was determined to be the first gene in an operon, termed
the cyclohexanecarboxylate degradation operon, containing genes required for both
benzoate and cyclohexanecarboxylate degradation. A nonpolar R. palustris badH
mutant was unable to grow on benzoate or cyclohexanecarboxylate but had wild-type
growth rates on succinate. Cells blocked in expression of the entire
cyclohexanecarboxylate degradation operon excreted cyclohex-1-ene-1-carboxylate
into the growth medium when given benzoate. This confirms that cyclohex-1-ene-1
carboxyl-CoA is an intermediate of anaerobic benzoate degradation by R.
palustris. This compound had previously been shown not to be formed by Thauera
aromatica, a denitrifying bacterium that degrades benzoate by a pathway that is
slightly different from the R. palustris pathway. 2-Hydroxychc-CoA dehydrogenase
does not participate in anaerobic benzoate degradation by T. aromatica and thus
may serve as a useful indicator of an R. palustris-type benzoate degradation
pathway.
PMID- 10781544
TI - Enzymology of type IV macromolecule secretion systems: the conjugative transfer
regions of plasmids RP4 and R388 and the cag pathogenicity island of Helicobacter
pylori encode structurally and functionally related nucleoside triphosphate
hydrolases.
AB - Type IV secretion systems direct transport of protein or nucleoprotein complexes
across the cell envelopes of prokaryotic donor and eukaryotic or prokaryotic
recipient cells. The process is mediated by a membrane-spanning multiprotein
assembly. Potential NTPases belonging to the VirB11 family are an essential part
of the membrane-spanning complex. Three representatives of these NTPases
originating from the conjugative transfer regions of plasmids RP4 (TrbB) and R388
(TrwD) and from the cag pathogenicity island of Helicobacter pylori (HP0525) were
overproduced and purified in native form. The proteins display NTPase activity
with distinct substrate specificities in vitro. TrbB shows its highest specific
hydrolase activity with dATP, and the preferred substrate for HP0525 is ATP.
Analysis of defined TrbB mutations altered in motifs conserved within the VirB11
protein family shows that there is a correlation between the loss or reduction of
NTPase activity and transfer frequency. Tryptophan fluorescence spectroscopy of
TrbB and HP0525 suggests that both interact with phospholipid membranes, changing
their conformation. NTPase activity of both proteins was stimulated by the
addition of certain phospholipids. According to our results, Virb11-like proteins
seem to most likely be involved in the assembly of the membrane-spanning
multiprotein complex.
PMID- 10781545
TI - The Bacillus subtilis GTP binding protein obg and regulators of the sigma(B)
stress response transcription factor cofractionate with ribosomes.
AB - Obg, an essential GTP binding protein of Bacillus subtilis, is necessary for
stress activation of the sigma(B) transcription factor. We investigated Obg's
cellular associations by differential centrifugation of crude B. subtilis
extracts, using an anti-Obg antibody as a probe to monitor Obg during the
fractionation, and by fluorescent microscopy of a B. subtilis strain in which Obg
was fused to green fluorescent protein. The results indicated that Obg is part of
a large cytoplasmic complex. In subsequent analyses, Obg coeluted with ribosomal
subunits during gel filtration of B. subtilis lysates on Sephacryl S-400 and
specifically bound to ribosomal protein L13 in an affinity blot assay. Probing
the gel filtration fractions with antibodies specific for sigma(B) and its
coexpressed regulators (Rsb proteins) revealed coincident elution of the upstream
components of the sigma(B) stress activation pathway (RsbR, -S, and -T) with Obg
and the ribosomal subunits. The data implicate ribosome function as a possible
mediator of the activity of Obg and the stress induction of sigma(B).
PMID- 10781546
TI - Transcriptional control of expression of genes for photosynthetic reaction center
and light-harvesting proteins in the purple bacterium Rhodovulum sulfidophilum.
AB - The purple photosynthetic bacterium Rhodovulum sulfidophilum synthesizes
photosynthetic apparatus even under highly aerated conditions in the dark. To
understand the oxygen-independent expression of photosynthetic genes, the
expression of the puf operon coding for the light-harvesting 1 and reaction
center proteins was analyzed. Northern blot hybridization analysis showed that
puf mRNA synthesis was not significantly repressed by oxygen in this bacterium.
High-resolution 5' mapping of the puf mRNA transcriptional initiation sites and
DNA sequence analysis of the puf upstream regulatory region indicated that there
are three possible promoters for the puf operon expression, two of which have a
high degree of sequence similarity with those of Rhodobacter capsulatus, which
shows a high level of oxygen repression of photosystem synthesis. Deletion
analysis showed that the third promoter is oxygen independent, but the activity
of this promoter was not enough to explain the aerobic level of mRNA. The
posttranscriptional puf mRNA degradation is not significantly influenced by
oxygen in R. sulfidophilum. From these results, we conclude that puf operon
expression in R. sulfidophilum is weakly repressed by oxygen, perhaps as a result
of the following: (i) there are three promoters for puf operon transcription, at
least one of which is oxygen independent; (ii) readthrough transcripts which may
not be affected by oxygen may be significant in maintaining the puf mRNA levels;
and (iii) the puf mRNA is fairly stable even under aerobic conditions.
PMID- 10781547
TI - Purification and characterization of the R64 shufflon-specific recombinase.
AB - The shufflon, a multiple DNA inversion system in plasmid R64, consists of four
invertible DNA segments which are separated and flanked by seven 19-bp repeat
sequences. The product of a site-specific recombinase gene, rci, promotes site
specific recombination between any two of the inverted 19-bp repeat sequences of
the shufflon. To analyze the molecular mechanism of this recombination reaction,
Rci protein was overproduced and purified. The purified Rci protein promoted the
in vitro recombination reaction between the inverted 19-bp repeats of supercoiled
DNA of a plasmid carrying segment A of the R64 shufflon. The recombination
reaction was enhanced by the bacterial host factor HU. Gel electrophoretic
analysis indicated that the Rci protein specifically binds to the DNA segments
carrying the 19-bp sequences. The binding affinity of the Rci protein to the four
shufflon segments as well as four synthetic 19-bp sequences differed greatly:
among the four 19-bp repeat sequences, the repeat-a and -d sequences displayed
higher affinity to Rci protein. These results suggest that the differences in the
affinity of Rci protein for the 19-bp repeat sequences determine the inversion
frequencies of the four segments.
PMID- 10781548
TI - Real-time imaging of fluorescent flagellar filaments.
AB - Bacteria swim by rotating flagellar filaments that are several micrometers long,
but only about 20 nm in diameter. The filaments can exist in different
polymorphic forms, having distinct values of curvature and twist. Rotation rates
are on the order of 100 Hz. In the past, the motion of individual filaments has
been visualized by dark-field or differential-interference-contrast microscopy,
methods hampered by intense scattering from the cell body or shallow depth of
field, respectively. We have found a simple procedure for fluorescently labeling
cells and filaments that allows recording their motion in real time with an
inexpensive video camera and an ordinary fluorescence microscope with mercury-arc
or strobed laser illumination. We report our initial findings with cells of
Escherichia coli. Tumbles (events that enable swimming cells to alter course) are
remarkably varied. Not every filament on a cell needs to change its direction of
rotation: different filaments can change directions at different times, and a
tumble can result from the change in direction of only one. Polymorphic
transformations tend to occur in the sequence normal, semicoiled, curly 1, with
changes in the direction of movement of the cell body correlated with
transformations to the semicoiled form.
PMID- 10781549
TI - Characterization of an extracellular lipase encoded by LIP2 in Yarrowia
lipolytica.
AB - We isolated the LIP2 gene from the lipolytic yeast Yarrowia lipolytica. It was
found to encode a 334-amino-acid precursor protein. The secreted lipase is a 301
amino-acid glycosylated polypeptide which is a member of the triacylglycerol
hydrolase family (EC 3.1.1.3). The Lip2p precursor protein is processed by the
KEX2-like endoprotease encoded by XPR6. Deletion of the XPR6 gene resulted in the
secretion of an active but less stable proenzyme. Thus, the pro region does not
inhibit lipase secretion and activity. However, it does play an essential role in
the production of a stable enzyme. Processing was found to be correct in LIP2(A)
(multiple LIP2 copy integrant)-overexpressing strains, which secreted 100 times
more activity than the wild type, demonstrating that XPR6 maturation was not
limiting. No extracellular lipase activity was detected with the lip2 knockout
(KO) strain, strongly suggesting that extracellular lipase activity results from
expression of the LIP2 gene. Nevertheless, the lip2 KO strain is still able to
grow on triglycerides, suggesting an alternative pathway for triglyceride
utilization in Y. lipolytica.
PMID- 10781551
TI - In vivo analysis of the mechanisms for oxidation of cytosolic NADH by
Saccharomyces cerevisiae mitochondria.
AB - During respiratory glucose dissimilation, eukaryotes produce cytosolic NADH via
glycolysis. This NADH has to be reoxidized outside the mitochondria, because the
mitochondrial inner membrane is impermeable to NADH. In Saccharomyces cerevisiae,
this may involve external NADH dehydrogenases (Nde1p or Nde2p) and/or a glycerol
3-phosphate shuttle consisting of soluble (Gpd1p or Gpd2p) and membrane-bound
(Gut2p) glycerol-3-phosphate dehydrogenases. This study addresses the
physiological relevance of these mechanisms and the possible involvement of
alternative routes for mitochondrial oxidation of cytosolic NADH. Aerobic,
glucose-limited chemostat cultures of a gut2Delta mutant exhibited fully
respiratory growth at low specific growth rates. Alcoholic fermentation set in at
the same specific growth rate as in wild-type cultures (0.3 h(-1)). Apparently,
the glycerol-3-phosphate shuttle is not essential for respiratory glucose
dissimilation. An nde1Delta nde2Delta mutant already produced glycerol at
specific growth rates of 0.10 h(-1) and above, indicating a requirement for
external NADH dehydrogenase to sustain fully respiratory growth. An nde1Delta
nde2Delta gut2Delta mutant produced even larger amounts of glycerol at specific
growth rates ranging from 0.05 to 0.15 h(-1). Apparently, even at a low
glycolytic flux, alternative mechanisms could not fully replace the external NADH
dehydrogenases and glycerol-3-phosphate shuttle. However, at low dilution rates,
the nde1Delta nde2Delta gut2Delta mutant did not produce ethanol. Since glycerol
production could not account for all glycolytic NADH, another NADH-oxidizing
system has to be present. Two alternative mechanisms for reoxidizing cytosolic
NADH are discussed: (i) cytosolic production of ethanol followed by its
intramitochondrial oxidation and (ii) a redox shuttle linking cytosolic NADH
oxidation to the internal NADH dehydrogenase.
PMID- 10781550
TI - LuxR- and acyl-homoserine-lactone-controlled non-lux genes define a quorum
sensing regulon in Vibrio fischeri.
AB - The luminescence (lux) operon (luxICDABEG) of the symbiotic bacterium Vibrio
fischeri is regulated by the transcriptional activator LuxR and two acyl
homoserine lactone (acyl-HSL) autoinducers (the luxI-dependent 3-oxo-hexanoyl-HSL
[3-oxo-C6-HSL] and the ainS-dependent octanoyl-HSL [C8-HSL]) in a population
density-responsive manner called quorum sensing. To identify quorum-sensing
regulated (QSR) proteins different from those encoded by lux genes, we examined
the protein patterns of V. fischeri quorum-sensing mutants defective in luxI,
ainS, and luxR by two-dimensional polyacrylamide gel electrophoresis. Five non
Lux QSR proteins, QsrP, RibB, AcfA, QsrV, and QSR 7, were identified; their
production occurred preferentially at high population density, required both LuxR
and 3-oxo-C6-HSL, and was inhibited by C8-HSL at low population density. The
genes encoding two of the QSR proteins were characterized: qsrP directs cells to
synthesize an apparently novel periplasmic protein, and ribB is a homolog of the
Escherichia coli gene for 3,4-dihydroxy-2-butanone 4-phosphate synthase, a key
enzyme for riboflavin synthesis. The qsrP and ribB promoter regions each
contained a sequence similar to the lux operon lux box, a 20-bp region of dyad
symmetry necessary for LuxR/3-oxo-C6-HSL-dependent activation of lux operon
transcription. V. fischeri qsrP and ribB mutants exhibited no distinct phenotype
in culture. However, a qsrP mutant, in competition with its parent strain, was
less successful in colonizing Euprymna scolopes, the symbiotic host of V.
fischeri. The newly identified QSR genes, together with the lux operon, define a
LuxR/acyl-HSL-responsive quorum-sensing regulon in V. fischeri.
PMID- 10781553
TI - Catabolism of alpha-ketoglutarate by a sucA mutant of Bradyrhizobium japonicum:
evidence for an alternative tricarboxylic acid cycle.
AB - A complete tricarboxylic acid (TCA) cycle is generally considered necessary for
energy production from the dicarboxylic acid substrates malate, succinate, and
fumarate. However, a Bradyrhizobium japonicum sucA mutant that is missing alpha
ketoglutarate dehydrogenase is able to grow on malate as its sole source of
carbon. This mutant also fixes nitrogen in symbiosis with soybean, where
dicarboxylic acids are its principal carbon substrate. Using a flow chamber
system to make direct measurements of oxygen consumption and ammonium excretion,
we confirmed that bacteroids formed by the sucA mutant displayed wild-type rates
of respiration and nitrogen fixation. Despite the absence of alpha-ketoglutarate
dehydrogenase activity, whole cells of the mutant were able to decarboxylate
alpha-[U-(14)C]ketoglutarate and [U-(14)C]glutamate at rates similar to those of
wild-type B. japonicum, indicating that there was an alternative route for alpha
ketoglutarate catabolism. Because cell extracts from B. japonicum decarboxylated
[U-(14)C]glutamate very slowly, the gamma-aminobutyrate shunt is unlikely to be
the pathway responsible for alpha-ketoglutarate catabolism in the mutant. In
contrast, cell extracts from both the wild type and mutant showed a coenzyme A
(CoA)-independent alpha-ketoglutarate decarboxylation activity. This activity was
independent of pyridine nucleotides and was stimulated by thiamine PP(i). Thin
layer chromatography showed that the product of alpha-ketoglutarate
decarboxylation was succinic semialdehyde. The CoA-independent alpha
ketoglutarate decarboxylase, along with succinate semialdehyde dehydrogenase, may
form an alternative pathway for alpha-ketoglutarate catabolism, and this pathway
may enhance TCA cycle function during symbiotic nitrogen fixation.
PMID- 10781552
TI - Expression of uptake hydrogenase and molybdenum nitrogenase in Rhodobacter
capsulatus is coregulated by the RegB-RegA two-component regulatory system.
AB - Purple photosynthetic bacteria are capable of generating cellular energy from
several sources, including photosynthesis, respiration, and H(2) oxidation. Under
nutrient-limiting conditions, cellular energy can be used to assimilate carbon
and nitrogen. This study provides the first evidence of a molecular link for the
coregulation of nitrogenase and hydrogenase biosynthesis in an anoxygenic
photosynthetic bacterium. We demonstrated that molybdenum nitrogenase
biosynthesis is under the control of the RegB-RegA two-component regulatory
system in Rhodobacter capsulatus. Footprint analyses and in vivo transcription
studies showed that RegA indirectly activates nitrogenase synthesis by binding to
and activating the expression of nifA2, which encodes one of the two functional
copies of the nif-specific transcriptional activator, NifA. Expression of nifA2
but not nifA1 is reduced in the reg mutants up to eightfold under derepressing
conditions and is also reduced under repressing conditions. Thus, although NtrC
is absolutely required for nifA2 expression, RegA acts as a coactivator of nifA2.
We also demonstrated that in reg mutants, [NiFe]hydrogenase synthesis and
activity are increased up to sixfold. RegA binds to the promoter of the
hydrogenase gene operon and therefore directly represses its expression. Thus,
the RegB-RegA system controls such diverse processes as energy-generating
photosynthesis and H(2) oxidation, as well as the energy-demanding processes of
N(2) fixation and CO(2) assimilation.
PMID- 10781554
TI - Efficient spore synthesis in Bacillus subtilis depends on the CcdA protein.
AB - CcdA is known to be required for the synthesis of c-type cytochromes in Bacillus
subtilis, but the exact function of this membrane protein is not known. We show
that CcdA also plays a role in spore synthesis. The expression of ccdA and the
two downstream genes yneI and yneJ was analyzed. There is a promoter for each
gene, but there is only one transcription terminator, located after the yneJ
gene. The promoter for ccdA was found to be weak and was active mainly during the
transition from exponential growth to stationary phase. The promoters for yneI
and yneJ were both active in the exponential growth phase. The levels of the CcdA
and YneJ proteins in the membrane were consistent with the observed promoter
activities. The ccdA promoter activity was independent of whether the ccdA-yneI
yneJ gene products were absent or overproduced in the cell. It is shown that the
four known cytochromes c in B. subtilis and the YneI and YneJ proteins are not
required for sporulation. The combined data from analysis of sporulation-specific
sigma factor activity, resistance properties of spores, and spore morphology
indicate that CcdA deficiency affects stage V in sporulation. We conclude that
CcdA, YneI, and YneJ are functionally unrelated proteins and that the role of
CcdA in cytochrome c and spore synthesis probably relates to sulfhydryl redox
chemistry on the outer surface of the cytoplasmic membrane.
PMID- 10781556
TI - Cloning and characterization of the CSF1 gene of Saccharomyces cerevisiae, which
is required for nutrient uptake at low temperature.
AB - We have isolated cold-sensitive fermentation mutants (Csf mutants) of a
commercial baker's yeast that have practically no fermentation capacity at 5
degrees C and return to their normal capacity at 25 to 40 degrees C. CSF1 was
cloned by functional complementation of the Csf phenotype. CSF1 contain an open
reading frame of 8,874 nucleotides, encoding a protein of 2,958 amino acids. The
nucleotide sequence was identical to that of the YLR087C gene in the
Saccharomyces genome database, but there was no information about the function of
the predicted CSF1 (YLR087C) protein. Gene disruption shows that CSF1 is required
for growth and fermentation only at low temperatures. Permeabilized cells of the
disruptant showed nearly the same ethanol production rate as those of the parent
strain, even at 10 degrees C. The disruptant cells had the same glucose uptake
rates as the parental cells at 30 degrees C, but three- to fivefold-lower rates
than the parental cells at 10 degrees C. These findings suggest that CSF1
associates with a new nutrient transport system which exists on the plasma
membrane and is required only at low temperature.
PMID- 10781555
TI - Biosynthesis of lipoteichoic acid in Lactobacillus rhamnosus: role of DltD in D
alanylation.
AB - The dlt operon (dltA to dltD) of Lactobacillus rhamnosus 7469 encodes four
proteins responsible for the esterification of lipoteichoic acid (LTA) by D
alanine. These esters play an important role in controlling the net anionic
charge of the poly (GroP) moiety of LTA. dltA and dltC encode the D-alanine-D
alanyl carrier protein ligase (Dcl) and D-alanyl carrier protein (Dcp),
respectively. Whereas the functions of DltA and DltC are defined, the functions
of DltB and DltD are unknown. To define the role of DltD, the gene was cloned and
sequenced and a mutant was constructed by insertional mutagenesis of dltD from
Lactobacillus casei 102S. Permeabilized cells of a dltD::erm mutant lacked the
ability to incorporate D-alanine into LTA. This defect was complemented by the
expression of DltD from pNZ123/dlt. In in vitro assays, DltD bound Dcp for
ligation with D-alanine by Dcl in the presence of ATP. In contrast, the homologue
of Dcp, the Escherichia coli acyl carrier protein (ACP), involved in fatty acid
biosynthesis, was not bound to DltD and thus was not ligated with D-alanine. DltD
also catalyzed the hydrolysis of the mischarged D-alanyl-ACP. The hydrophobic N
terminal sequence of DltD was required for anchoring the protein in the membrane.
It is hypothesized that this membrane-associated DltD facilitates the binding of
Dcp and Dcl for ligation of Dcp with D-alanine and that the resulting D-alanyl
Dcp is translocated to the primary site of D-alanylation.
PMID- 10781557
TI - The ssu locus plays a key role in organosulfur metabolism in Pseudomonas putida S
313.
AB - Pseudomonas putida S-313 can utilize a broad range of aromatic sulfonates as
sulfur sources for growth in sulfate-free minimal medium. The sulfonates are
cleaved monooxygenolytically to yield the corresponding phenols. miniTn5 mutants
of strain S-313 which were no longer able to desulfurize arylsulfonates were
isolated and were found to carry transposon insertions in the ssuEADCBF operon,
which contained genes for an ATP-binding cassette-type transporter (ssuABC), a
two-component reduced flavin mononucleotide-dependent monooxygenase (ssuED)
closely related to the Escherichia coli alkanesulfonatase, and a protein related
to clostridial molybdopterin-binding proteins (ssuF). These mutants were also
deficient in growth with a variety of other organosulfur sources, including
aromatic and aliphatic sulfate esters, methionine, and aliphatic sulfonates other
than the natural sulfonates taurine and cysteate. This pleiotropic phenotype was
complemented by the ssu operon, confirming its key role in organosulfur
metabolism in this species. Further complementation analysis revealed that the
ssuF gene product was required for growth with all of the tested substrates
except methionine and that the oxygenase encoded by ssuD was required for growth
with sulfonates or methionine. The flavin reductase SsuE was not required for
growth with aliphatic sulfonates or methionine but was needed for growth with
arylsulfonates, suggesting that an alternative isozyme exists for the former
compounds that is not active in transformation of the latter substrates. Aryl
sulfate ester utilization was catalyzed by an arylsulfotransferase, and not by an
arylsulfatase as in the related species Pseudomonas aeruginosa.
PMID- 10781558
TI - Contribution of cysteine desulfurase (NifS protein) to the biotin synthase
reaction of Escherichia coli.
AB - The contribution of cysteine desulfurase, the NifS protein of Klebsiella
pneumoniae and the IscS protein of Escherichia coli, to the biotin synthase
reaction was investigated in in vitro and in vivo reaction systems with E. coli.
When the nifS and nifU genes of K. pneumoniae were coexpressed in E. coli, NifS
and NifU proteins in complex (NifU/S complex) and NifU monomer forms were
observed. Both the NifU/S complex and the NifU monomer stimulated the biotin
synthase reaction in the presence of L-cysteine in an in vitro reaction system.
The NifU/S complex enhanced the production of biotin from dethiobiotin by the
cells growing in an in vivo reaction system. Moreover, the IscS protein of E.
coli stimulated the biotin synthase reaction in the presence of L-cysteine in the
cell-free system. These results strongly suggest that cysteine desulfurase
participates in the biotin synthase reaction, probably by supplying sulfur to the
iron-sulfur cluster of biotin synthase.
PMID- 10781560
TI - Growth phase-coupled changes of the ribosome profile in natural isolates and
laboratory strains of Escherichia coli.
AB - The growth phase-dependent change in sucrose density gradient centrifugation
patterns of ribosomes was analyzed for both laboratory strains of Escherichia
coli and natural isolates from the ECOR collection. All of the natural isolates
examined formed 100S ribosome dimers in the stationary phase, and ribosome
modulation factor (RMF) was associated with the ribosome dimers in the ECOR
strains as in the laboratory strain W3110. The ribosome profile (70S monomers
versus 100S dimers) follows a defined pattern over time during lengthy culture in
both the laboratory strains and natural isolates. There are four discrete stages:
(i) formation of 100S dimers in the early stationary phase; (ii) transient
decrease in the dimer level; (iii) return of dimers to the maximum level; and
(iv) dissociation of 100S dimers into 70S ribosomes, which are quickly degraded
into subassemblies. The total time for this cycle of ribosome profile change,
however, varied from strain to strain, resulting in apparent differences in the
ribosome profiles when observed at a fixed time point. A correlation was noted in
all strains between the decay of 100S ribosomes and the subsequent loss of cell
viability. Two types of E. coli mutants defective in ribosome dimerization were
identified, both of which were unable to survive for a prolonged period in
stationary phase. The W3110 mutant, with a disrupted rmf gene, has a defect in
ribosome dimerization because of lack of RMF, while strain Q13 is unable to form
ribosome dimers due to a ribosomal defect in binding RMF.
PMID- 10781559
TI - Initiation of protein synthesis in Saccharomyces cerevisiae mitochondria without
formylation of the initiator tRNA.
AB - Protein synthesis in eukaryotic organelles such as mitochondria and chloroplasts
is widely believed to require a formylated initiator methionyl tRNA (fMet
tRNA(fMet)) for initiation. Here we show that initiation of protein synthesis in
yeast mitochondria can occur without formylation of the initiator methionyl-tRNA
(Met-tRNA(fMet)). The formylation reaction is catalyzed by methionyl-tRNA
formyltransferase (MTF) located in mitochondria and uses N(10)
formyltetrahydrofolate (10-formyl-THF) as the formyl donor. We have studied yeast
mutants carrying chromosomal disruptions of the genes encoding the mitochondrial
C(1)-tetrahydrofolate (C(1)-THF) synthase (MIS1), necessary for synthesis of 10
formyl-THF, and the methionyl-tRNA formyltransferase (open reading frame YBL013W;
designated FMT1). A direct analysis of mitochondrial tRNAs using gel
electrophoresis systems that can separate fMet-tRNA(fMet), Met-tRNA(fMet), and
tRNA(fMet) shows that there is no formylation in vivo of the mitochondrial
initiator Met-tRNA in these strains. In contrast, the initiator Met-tRNA is
formylated in the respective "wild-type" parental strains. In spite of the
absence of fMet-tRNA(fMet), the mutant strains exhibited normal mitochondrial
protein synthesis and function, as evidenced by normal growth on nonfermentable
carbon sources in rich media and normal frequencies of generation of petite
colonies. The only growth phenotype observed was a longer lag time during growth
on nonfermentable carbon sources in minimal media for the mis1 deletion strain
but not for the fmt1 deletion strain.
PMID- 10781561
TI - Gene rearrangements in the vsa locus of Mycoplasma pulmonis.
AB - The vsa genes of Mycoplasma pulmonis encode the V-1 lipoproteins. Most V-1
proteins contain repetitive domains and are thought to be involved in mycoplasma
host cell interactions. Previously, we have reported the isolation and
characterization of six vsa genes comprising a 10-kb region of the genome of M.
pulmonis strain KD735-15. In the current study, vsa-specific probes were used to
clone several fragments from a genomic library of KD735-15 DNA and assemble a
single 20-kb contig containing 11 vsa genes. The middle region of the vsa locus
contains a large open reading frame (ORF) that is not a vsa gene and has
undergone an internal deletion in some strains. The ORF is predicted to encode a
membrane protein that may have a role in disease pathogenesis. To examine vsa
genes in a strain of M. pulmonis that is unrelated to KD735-15, strain CT was
studied. Through Southern hybridization and genomic cloning analyses, CT was
found to possess homologs of the KD735-15 vsaA, -C, -E, and -F genes and two
unique genes (vsaG and vsaH) that were not found in KD735-15. High-frequency,
site-specific DNA inversions serve to regulate the phase-variable production of
individual V-1 proteins. As a result of the sequence analysis of vsa
recombination products, a model in which DNA inversion arises from strand
exchange involving at least six nucleotides of the vrs box is proposed.
PMID- 10781562
TI - Altered stationary-phase response in a Borrelia burgdorferi rpoS mutant.
AB - The homolog of the chromosomally encoded stationary-phase sigma factor RpoS in
Borrelia burgdorferi was inactivated using gyrB(r) as a selectable marker. Two
dimensional nonequilibrium pH gradient electrophoresis of stationary-phase cell
lysates identified at least 11 differences between the protein profiles of the
rpoS mutant and wild-type organisms. Wild-type B. burgdorferi had a growth phase
dependent resistance to 1 N NaCl, similar to the stationary-phase response
reported for other bacteria. The B. burgdorferi rpoS mutant strain was less
resistant to osmotic stress in stationary phase than the isogenic rpoS wild-type
organism. The results indicate that the B. burgdorferi rpoS homolog influences
protein composition and participates in stationary-phase-dependent osmotic
resistance. This rpoS mutant will be useful for studying regulation of gene
expression in response to changing environmental conditions.
PMID- 10781563
TI - A dispensable role for forespore-specific gene expression in engulfment of the
forespore during sporulation of Bacillus subtilis.
AB - During the stage of engulfment in the Bacillus subtilis spore formation pathway,
the larger mother cell engulfs the smaller forespore. We have tested the role of
forespore-specific gene expression in engulfment using two separate approaches.
First, using an assay that unambiguously detects sporangia that have completed
engulfment, we found that a mutant lacking the only forespore-expressed
engulfment protein identified thus far, SpoIIQ, is able to efficiently complete
engulfment under certain sporulation conditions. However, we have found that the
mutant is defective, under all conditions, in the expression of the late
forespore-specific transcription factor sigma(G); thus, SpoIIQ is essential for
spore production. Second, to determine if engulfment could proceed in the absence
of forespore-specific gene expression, we made use of a strain in which
activation of the mother cell-specific sigma factor sigma(E) was uncoupled from
forespore-specific gene expression. Remarkably, engulfment occurred in the
complete absence of sigma(F)-directed gene expression under the same conditions
permissive for engulfment in the absence of SpoIIQ. Our results demonstrate that
forespore-specific gene expression is not essential for engulfment, suggesting
that the machinery used to move the membranes around the forespore is within the
mother cell.
PMID- 10781564
TI - Multiple-locus variable-number tandem repeat analysis reveals genetic
relationships within Bacillus anthracis.
AB - Bacillus anthracis is one of the most genetically homogeneous pathogens
described, making strain discrimination particularly difficult. In this paper, we
present a novel molecular typing system based on rapidly evolving variable-number
tandem repeat (VNTR) loci. Multiple-locus VNTR analysis (MLVA) uses the combined
power of multiple alleles at several marker loci. In our system, fluorescently
labeled PCR primers are used to produce PCR amplification products from eight
VNTR regions in the B. anthracis genome. These are detected and their sizes are
determined using an ABI377 automated DNA sequencer. Five of these eight loci were
discovered by sequence characterization of molecular markers (vrrC(1), vrrC(2),
vrrB(1), vrrB(2), and CG3), two were discovered by searching complete plasmid
nucleotide sequences (pXO1-aat and pXO2-at), and one was known previously (vrrA).
MLVA characterization of 426 B. anthracis isolates identified 89 distinct
genotypes. VNTR markers frequently identified multiple alleles (from two to
nine), with Nei's diversity values between 0.3 and 0.8. Unweighted pair-group
method arithmetic average cluster analysis identified six genetically distinct
groups that appear to be derived from clones. Some of these clones show worldwide
distribution, while others are restricted to particular geographic regions. Human
commerce doubtlessly has contributed to the dispersal of particular clones in
ancient and modern times.
PMID- 10781566
TI - Pressure regulation of soluble cytochromes c in a deep-Sea piezophilic bacterium,
Shewanella violacea.
AB - Two c-type cytochromes from the soluble fraction of a deep-sea moderately
piezophilic bacterium, Shewanella violacea, were purified and characterized, and
the genes coding for these cytochromes were cloned and sequenced. One of the
cytochromes, designated cytochrome c(A), was found to have a molecular mass of
approximately 8.3 kDa, and it contained one heme c per molecule. The other,
designated cytochrome c(B), was found to have a molecular mass of approximately
23 kDa, and it contained two heme c molecules per protein molecule. The amount of
cytochrome c(B) expressed in cells grown at high hydrostatic pressure (50 MPa)
was less than that in cells grown at atmospheric pressure, whereas cytochrome
c(A) was constitutively expressed under all pressure conditions examined. The
results of Northern blotting analysis were consistent with the above-mentioned
observations and suggested that the pressure regulation of cytochrome c(B) gene
expression occurred at the transcriptional level. These results suggest that the
components of the respiratory chain of moderately piezophilic S. violacea could
be exchanged according to the growth pressure conditions.
PMID- 10781565
TI - NhaA, an Na(+)/H(+) antiporter involved in environmental survival of Vibrio
cholerae.
AB - Vibrio cholerae, the agent of cholera, is a normal inhabitant of aquatic
environments, in which it survives under a wide range of conditions of pH and
salinity. In this work, we identified the nhaA gene in a wild-type epidemic
strain of V. cholerae O1. nhaA encodes a protein of 382 amino acids that is very
similar to the proteins NhaA of Vibrio parahaemolyticus, Vibrio alginolyticus (
approximately 87% identity), and Escherichia coli (56% identity). V. cholerae
NhaA complements an E. coli nhaA mutant, enabling it to grow in 700 mM NaCl, pH
7.5, indicating functional homology to E. coli NhaA. However, unlike E. coli, the
growth of a nhaA-inactivated mutant of V. cholerae was not restricted at various
pH and NaCl concentrations, although it was inhibited in the presence of 120 mM
LiCl at pH 8.5. Nevertheless, using a nhaA'-lacZ transcriptional fusion, we
observed induction of nhaA transcription by Na(+), Li(+), and K(+). These results
strongly suggest that NhaA is an Na(+)/H(+) antiporter contributing to the
Na(+)/H(+) homeostasis of V. cholerae. nhaA-related sequences were detected in
all strains of V. cholerae from the various serogroups. This gene is presumably
involved in the survival and persistence of free-living bacteria in their natural
habitat.
PMID- 10781567
TI - Interaction of the FimB integrase with the fimS invertible DNA element in
Escherichia coli in vivo and in vitro.
AB - The FimB protein is a site-specific recombinase that inverts the fimS genetic
switch in Escherichia coli. Based on amino acid sequence analysis alone, FimB has
been assigned to the integrase family of tyrosine recombinases. We show that
amino acid substitutions at positions R47, H141, R144, and Y176, corresponding to
highly conserved members of the catalytic motif of integrase proteins, render
FimB incapable of inverting the fimS element in vivo. The arginine substitutions
reduced the ability of FimB to bind to fimS in vivo or in vitro, while the
substitution R144Q resulted in a protein unable to bind independently to the half
sites located at the left end of fimS in phase-on bacteria. These data confirm
that FimB is an integrase and suggest that residue R144 has a role in binding to
a specific component of the fim switch.
PMID- 10781569
TI - Prephenate dehydratase from the aphid endosymbiont (Buchnera) displays changes in
the regulatory domain that suggest its desensitization to inhibition by
phenylalanine.
AB - Buchnera aphidicola, the prokaryotic endosymbiont of aphids, complements dietary
deficiencies with the synthesis and provision of several essential amino acids.
We have cloned and sequenced a region of the genome of B. aphidicola isolated
from Acyrthosiphon pisum which includes the two-domain aroQ/pheA gene. This gene
encodes the bifunctional chorismate mutase-prephenate dehydratase protein, which
plays a central role in L-phenylalanine biosynthesis. Two changes involved in the
overproduction of this amino acid have been detected. First, the absence of an
attenuator region suggests a constitutive expression of this gene. Second, the
regulatory domain of the Buchnera prephenate dehydratase shows changes in the
ESRP sequence, which is involved in the allosteric binding of phenylalanine and
is strongly conserved in prephenate dehydratase proteins from practically all
known organisms. These changes suggest the desensitization of the enzyme to
inhibition by phenylalanine and would permit the bacterial endosymbiont to
overproduce phenylalanine.
PMID- 10781568
TI - The ArcB sensor kinase of Escherichia coli: genetic exploration of the
transmembrane region.
AB - The Arc two-component signal transduction system of Escherichia coli regulates
the expression of numerous operons in response to respiratory growth conditions.
Cellular redox state or proton motive force (Delta(H(+))) has been proposed to be
the signal for the membrane-associated ArcB sensor kinase. This study provided
evidence for a short ArcB periplasmic bridge that contains a His47. The
dispensability of this amino acid, the only amino acid with a pK in the
physiological range, renders the Delta(H(+)) model unlikely. Furthermore, results
from substituting membrane segments of ArcB with counterparts of MalF indicate
that the region does not play a stereospecific role in signal reception.
PMID- 10781570
TI - Complete nucleotide sequence of Tn10.
AB - The complete nucleotide sequence of Tn10 has been determined. The dinucleotide
signature and percent G+C of the sequence had no discontinuities, indicating that
Tn10 constitutes a homogeneous unit. The new sequence contained three new open
reading frames corresponding to a glutamate permease, repressors of heavy metal
resistance operons, and a hypothetical protein in Bacillus subtilis. The
glutamate permease was fully functional when expressed, but Tn10 did not protect
Escherichia coli from the toxic effects of various metals.
PMID- 10781571
TI - A study of the CopF repressor of plasmid pAMbeta1 by phage display.
AB - We studied DNA binding of a transcriptional repressor, CopF, displayed on a
filamentous phage. Mutagenesis of a putative helix-turn-helix motif of CopF and
of certain bases of the operator abolished the protein-DNA interaction,
establishing the elements involved in CopF function and showing that phage
display can be used to study repressor proteins.
PMID- 10781572
TI - FabG, an NADPH-dependent 3-ketoacyl reductase of Pseudomonas aeruginosa, provides
precursors for medium-chain-length poly-3-hydroxyalkanoate biosynthesis in
Escherichia coli.
AB - Escherichia coli hosts expressing fabG of Pseudomonas aeruginosa showed 3
ketoacyl coenzyme A (CoA) reductase activity toward R-3-hydroxyoctanoyl-CoA.
Furthermore, E. coli recombinants carrying the poly-3-hydroxyalkanoate (PHA)
polymerase-encoding gene phaC in addition to fabG accumulated medium-chain-length
PHAs (mcl-PHAs) from alkanoates. When E. coli fadB or fadA mutants, which are
deficient in steps downstream or upstream of the 3-ketoacyl-CoA formation step
during beta-oxidation, respectively, were transformed with fabG, higher levels of
PHA were synthesized in E. coli fadA, whereas similar levels of PHA were found in
E. coli fadB, compared with those of the corresponding mutants carrying phaC
alone. These results strongly suggest that FabG of P. aeruginosa is able to
reduce mcl-3-ketoacyl-CoAs generated by the beta-oxidation to 3-hydroxyacyl-CoAs
to provide precursors for the PHA polymerase.
PMID- 10781573
TI - Positioning of region 4 of the Escherichia coli RNA polymerase sigma(70) subunit
by a transcription activator.
AB - A DNA cleavage reagent, specifically tethered to residue 581 of the Escherichia
coli RNA polymerase sigma(70) subunit, has been used to investigate the location
of sigma(70) region 4 in different complexes at the galp(1) promoter and the
effect of the cyclic AMP receptor protein. The positions of DNA cleavage by the
reagent are not affected by the cyclic AMP receptor protein. We conclude that
transcription activation at the galp(1) promoter by the cyclic AMP receptor
protein does not involve major conformation changes in or repositioning of
sigma(70) region 4.
PMID- 10781574
TI - Sulfolobicins, specific proteinaceous toxins produced by strains of the extremely
thermophilic archaeal genus Sulfolobus.
AB - Several novel strains of "Sulfolobus islandicus" produced proteinaceous toxins,
termed sulfolobicins, which killed cells of other strains of the same species, as
well as of Sulfolobus solfataricus P1 and Sulfolobus shibatae B12, but not of the
producer strains and of Sulfolobus acidocaldarius DSM639. The sulfolobicin
purified from the strain HEN2/2 had a molecular mass of about 20 kDa. It was
found to be associated with the producer cells as well as with cell-derived S
layer-coated spherical membrane vesicles 90 to 180 nm in diameter and was not
released from the cells in soluble form.
PMID- 10781575
TI - Control of initiation of sporulation by replication initiation genes in Bacillus
subtilis.
AB - Initiation of spore formation in Bacillus subtilis appears to depend on
initiation of DNA replication. This regulation was first identified using a
temperature-sensitive mutation in dnaB. We found that mutations in the
replication initiation genes dnaA and dnaD also inhibit sporulation, indicating
that inhibition of sporulation is triggered by general defects in the function of
replication initiation proteins.
PMID- 10781576
TI - Comparison of folding rates of homologous prokaryotic and eukaryotic proteins.
AB - The rate of polypeptide chain elongation is up to one order of magnitude faster
in prokaryotic cells than in eukaryotes. Here we report that the rates of in
vitro refolding of orthologous prokaryotic and eukaryotic proteins correlate with
their differential rates of biosynthesis. The mitochondrial and cytosolic
aspartate aminotransferases of chicken and aspartate aminotransferase of
Escherichia coli show pairwise sequence identities of 41-48% and nearly identical
three-dimensional structures. Nevertheless, the prokaryotic enzyme refolded 6
times faster (at 25 degrees C) than the eukaryotic isoenzymes after denaturation
in 6 m guanidine hydrochloride. Prokaryotic malate dehydrogenase and lactate
dehydrogenase also renatured faster than their orthologous eukaryotic
counterparts, suggesting that evolutionary pressure has adapted the rate of
folding to the rate of elongation of polypeptide chains.
PMID- 10781577
TI - Kinetic analyses of a truncated mammalian myosin I suggest a novel isomerization
event preceding nucleotide binding.
AB - MI(1IQ) is a complex of calmodulin and an epitope-tagged 85-kDa fragment
representing the amino-terminal catalytic motor domain and the first of 6
calmodulin-binding IQ domains of the mammalian myosin I gene, rat myr-1 (130-kDa
myosin I or MI(130)). We have determined the transient kinetic parameters that
dictate the ATP hydrolysis cycle of mammalian myosin I by examining the
properties of MI(1IQ). Transient kinetics reveal that the affinity of MI(1IQ) for
actin is 12 nm. The ATP-induced dissociation of actin-MI(1IQ) is biphasic. The
fast phase is dependent upon [ATP], whereas the slow phase is not; both phases
show a Ca(2+) sensitivity. The fast phase is eliminated by the addition of ADP,
10 micrometer being required for half-saturation of the effect in the presence of
Ca(2+) and 3 micrometer ADP in the absence of Ca(2+). The slow phase shares the
same rate constant as ADP release (8 and 3 s(-)(1) in the presence and absence of
Ca(2+), respectively), but cannot be eliminated by decreasing [ADP]. We interpret
these results to suggest that actin-myosin I exists in two forms in equilibrium,
one of which is unable to bind nucleotide. These results also indicate that the
absence of the COOH-terminal 5 calmodulin binding domains of myr-1 do not
influence the kinetic properties of MI(130) and that the Ca(2+) sensitivity of
the kinetics are in all likelihood due to Ca(2+) binding to the first IQ domain.
PMID- 10781578
TI - Paxillin binding to a conserved sequence motif in the alpha 4 integrin
cytoplasmic domain.
AB - alpha(4)beta(1) integrin-mediated cell adhesion results in increased cell
migration, reduced cell spreading, and focal adhesion formation relative to other
beta(1) integrins. Paxillin, a signaling adapter protein, binds tightly to the
alpha(4) cytoplasmic domain and is implicated in alpha(4) integrin signaling. We
now report the mapping of a paxillin-binding site in the alpha(4) cytoplasmic
domain and an assessment of its role in the alpha(4) tail-specific integrin
functions. By using truncation mutants and a peptide competition assay, we found
that a region of 9 amino acid residues (Glu(983)-Tyr(991)) within the alpha(4)
cytoplasmic domain contains a minimal sequence sufficient for paxillin binding.
Alanine scanning of this region implicated Tyr(991) and Glu(983) as critical
residues. The role of these residues was confirmed by introducing these Ala
substitutions into the full-length alpha(4) tail sequence. Y991A or E983A
substitution disrupted the interaction of alpha(4) integrins with paxillin. These
same two point mutations reversed the effects of the alpha(4) tail on cell
spreading. The key features of the identified paxillin-binding sequence are
present in all alpha(4) integrins sequenced to date, including that from Xenopus
laevis. The maintenance of this sequence motif suggests that paxillin binding is
an evolutionarily conserved function of alpha(4) integrins.
PMID- 10781579
TI - Thrombin-mediated feedback activation of factor XI on the activated platelet
surface is preferred over contact activation by factor XIIa or factor XIa.
AB - To study the pathways for initiation of intrinsic blood coagulation, activated
human platelets were compared with dextran sulfate as surfaces for factor XI
activation by factor XIIa, factor XIa, or thrombin. Activated gel-filtered
platelets promoted the activation of factor XI (60 nm) by thrombin (0.02-10 nm,
EC(50) approximately 100 pm, threshold concentration approximately 10 pm) at
initial rates 2- to 3-fold greater than those obtained with dextran sulfate in
the presence of either high molecular weight kininogen (45 nm) and ZnCl(2) (25
micrometer) or prothrombin (1.2 micrometer) and CaCl(2) (2 mm). The maximum rates
of factor XI activation achieved in the presence of activated gel-filtered
platelets were 30 nm.min(-1) with thrombin, 6 nm.min(-1) with factor XIIa and 2
nm.min(-1) with factor XIa. Values of turnover number calculated at various
enzyme concentrations (0.05-1 nm) were 24-167 (mean = 86) min(-1) for thrombin,
4.6-50 (mean = 21) min(-1) for factor XIIa, and 1.3-14 (mean = 8) min(-1) for
factor XIa. A physiological concentration of fibrinogen (9.0 micrometer)
inhibited factor XI activation by thrombin (but not by factor XIIa) in the
presence of dextran sulfate but not in the presence of gel-filtered platelets.
Compared with factors XIIa and XIa, thrombin is the preferred factor XI
activator, and activated platelets are a relevant physiological surface for
thrombin-mediated initiation of intrinsic coagulation in vivo.
PMID- 10781580
TI - GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott
Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex.
AB - Proteins of the Wiskott-Aldrich Syndrome protein (WASp) family connect signaling
pathways to the actin polymerization-driven cell motility. The ubiquitous homolog
of WASp, N-WASp, is a multidomain protein that interacts with the Arp2/3 complex
and G-actin via its C-terminal WA domain to stimulate actin polymerization. The
activity of N-WASp is enhanced by the binding of effectors like Cdc42-guanosine
5'-3-O-(thio)triphosphate, phosphatidylinositol bisphosphate, or the Shigella
IcsA protein. Here we show that the SH3-SH2-SH3 adaptor Grb2 is another activator
of N-WASp that stimulates actin polymerization by increasing the amount of N
WASp. Arp2/3 complex. The concentration dependence of N-WASp activity,
sedimentation velocity and cross-linking experiments together suggest that N-WASp
is subject to self-association, and Grb2 enhances N-WASp activity by binding
preferentially to its active monomeric form. Use of peptide inhibitors, mutated
Grb2, and isolated SH3 domains demonstrate that the effect of Grb2 is mediated by
the interaction of its C-terminal SH3 domain with the proline-rich region of N
WASp. Cdc42 and Grb2 bind simultaneously to N-WASp and enhance actin
polymerization synergistically. Grb2 shortens the delay preceding the onset of
Escherichia coli (IcsA) actin-based reconstituted movement. These results suggest
that Grb2 may activate Arp2/3 complex-mediated actin polymerization downstream
from the receptor tyrosine kinase signaling pathway.
PMID- 10781581
TI - Identification of a sequence of apolipoprotein A-I associated with the activation
of Lecithin:Cholesterol acyltransferase.
AB - We aimed to distinguish between the effects of mutations in apoA-I on the
requirements for the secondary structure and a specific amino acid sequence for
lecithin:cholesterol acyltransferase (LCAT) activation. Several mutants were
constructed targeting region 140-150: (i) two mutations affecting alpha-helical
structure, deletion of amino acids 140-150 and substitution of Ala(143) for
proline; (ii) two mutations not affecting alpha-helical structure, substitution
of Val(149) for arginine and substitution of amino acids 63-73 for sequence 140
150; and (iii) a mutation in a similar region away from the target area, deletion
of amino acids 63-73. All mutations affecting region 140-150 resulted in a 4-42
fold reduction in LCAT activation. Three mutations, apoA-I(Delta140-150), apoA
I(P143A), and apoA-I(140-150 --> 63-73), affected both the apparent V(max) and
K(m), whereas the mutation apoA-I(R149V) affected only the V(max). The mutation
apoA-I(Delta63-73) caused only a 5-fold increase in the K(m). All mutants, except
apoA-I(P143A) and apoA-I(Delta63-73), were active in phospholipid binding assay.
All mutants, except apoA-I(P143A), formed normal discoidal complexes with
phospholipid. The mutation apoA-I(Delta63-73) caused a significant reduction in
the stability of apoA-I.phospholipid complexes in denaturation experiments.
Combined, our results strongly suggest that although the correct conformation and
orientation of apoA-I in the complex with lipids are crucial for activation of
LCAT, when these conditions are fulfilled, activation also strongly depends on
the sequence that includes amino acids 140-150.
PMID- 10781582
TI - ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV
radiation.
AB - Phosphorylation of the p53 tumor suppressor protein is likely to play an
important role in regulating its activity. Serine 15 phosphorylation of p53 leads
to a stabilization of p53 by reducing its interaction with murine double minute
2, a negative regulatory partner. Recently, p53 was reported to be activated and
phosphorylated at serine 15 following UV radiation. However, the signaling
pathway that mediates UV-induced phosphorylation is less well characterized.
Here, we provide evidence that UVB-induced phosphorylation of p53 at serine 15 is
mediated directly by ERKs and p38 kinase. We find that in a mouse JB6 epidermal
cell line, ERKs and p38 kinase form a complex with p53 following UVB radiation.
Inhibition of ERKs or p38 kinase activity by the use of a dominant negative
mutant of ERK2 or p38 kinase or their respective specific inhibitor, PD98059 or
SB202190, results in abrogation of UVB-induced phosphorylation of p53 at serine
15. Strikingly, incubation of UVB-activated ERKs or p38 kinase immunoprecipitated
complex with exogenous p53 shows serine 15 phosphorylation of both exogenous and
co-precipitated endogenous p53 protein. Additionally, active recombinant ERK1/2
and p38 kinase but not JNKs are also able to phosphorylate p53 at serine 15 in
vitro. Furthermore, pretreatment of cells with PD98059 or SB202190 blocks p53
dependent transcription activity but increases the level of p53 co-precipitated
murine double minute. These results strongly suggest that both ERKs and p38
kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in
vivo.
PMID- 10781583
TI - Allosteric interactions between the two non-equivalent nucleotide binding domains
of multidrug resistance protein MRP1.
AB - Membrane transporters of the adenine nucleotide binding cassette (ABC)
superfamily utilize two either identical or homologous nucleotide binding domains
(NBDs). Although the hydrolysis of ATP by these domains is believed to drive
transport of solute, it is unknown why two rather than a single NBD is required.
In the well studied P-glycoprotein multidrug transporter, the two appear to be
functionally equivalent, and a strongly supported model proposes that ATP
hydrolysis occurs alternately at each NBD (Senior, A. E., al-Shawi, M. K., and
Urbatsch, I. L. (1995) FEBS Lett 377, 285-289). To assess how applicable this
model may be to other ABC transporters, we have examined adenine nucleotide
interactions with the multidrug resistance protein, MRP1, a member of a different
ABC family that transports conjugated organic anions and in which sequences of
the two NBDs are much less similar than in P-glycoprotein. Photoaffinity labeling
experiments with 8-azido-ATP, which strongly supports transport revealed ATP
binding exclusively at NBD1 and ADP trapping predominantly at NBD2. Despite this
apparent asymmetry in the two domains, they are entirely interdependent as
substitution of key lysine residues in the Walker A motif of either impaired both
ATP binding and ADP trapping. Furthermore, the interaction of ADP at NBD2 appears
to allosterically enhance the binding of ATP at NBD1. Glutathione, which supports
drug transport by the protein, does not enhance ATP binding but stimulates the
trapping of ADP. Thus MRP1 may employ a more complex mechanism of coupling ATP
utilization to the export of agents from cells than P-glycoprotein.
PMID- 10781584
TI - Formation of the catecholamine release-inhibitory peptide catestatin from
chromogranin A. Determination of proteolytic cleavage sites in hormone storage
granules.
AB - The catestatin fragment of chromogranin A is an inhibitor of catecholamine
release, but its occurrence in vivo has not yet been verified, nor have its
precise cleavage sites been established. Here we found extensive processing of
catestatin in chromogranin A, as judged by catestatin radioimmunoassay of size
fractionated chromaffin granules. On mass spectrometry, a major catestatin form
was bovine chromogranin A(332-364); identity of the peptide was confirmed by
diagnostic Met(346) oxidation. Further analysis revealed two additional forms:
bovine chromogranin A(333-364) and A(343-362). Synthetic longer (chromogranin
A(332-364)) and shorter (chromogranin A(344-364)) versions of catestatin each
inhibited catecholamine release from chromaffin cells, with superior potency for
the shorter version (IC(50) approximately 2.01 versus approximately 0.35 microm).
Radioimmunoassay demonstrated catestatin release from the regulated secretory
pathway in chromaffin cells. Human catestatin was cleaved in pheochromocytoma
chromaffin granules, with the major form, human chromogranin A(340-372), bounded
by dibasic sites. We conclude that catestatin is cleaved extensively in vivo, and
the peptide is released by exocytosis. In chromaffin granules, the major form of
catestatin is cleaved at dibasic sites, while smaller carboxyl-terminal forms
also occur. Knowledge of cleavage sites of catestatin from chromogranin A may
provide a useful starting point in analysis of the relationship between structure
and function for this peptide.
PMID- 10781585
TI - Differential expression of B1-containing transcripts in Leishmania-exposed
macrophages.
AB - When the parasitic protozoan Leishmania infect host macrophage cells,
establishment of the infection requires alteration in the expression of genes in
both the parasite and the host cells. In the early phase of infection of
macrophages in vitro, Leishmania exposure affects the expression of a group of
mouse macrophage genes containing the repetitive transposable element designated
B1 sequence. In Leishmania-exposed macrophages compared with unexposed
macrophages, small (approximately 0.5 kilobase) B1-containing RNAs (small B1
RNAs) are down-regulated, and large (1-4 kilobases) B1-containing RNAs (large B1
RNA) are up-regulated. The down-regulation of small B1-RNAs precedes the up
regulation of large B1-RNAs in Leishmania-exposed macrophages. These differential
B1-containing gene expressions in Leishmania-exposed macrophages were verified
using individual small-B1-RNA and large B1-RNA. The differential expressions of
the B1-containing RNAs at the early phase of Leishmania-macrophage interaction
may associate the establishment of the leishmanial infection.
PMID- 10781586
TI - Association of L-glutamic acid decarboxylase to the 70-kDa heat shock protein as
a potential anchoring mechanism to synaptic vesicles.
AB - Recently we have reported that the membrane-associated form of the gamma
aminobutyric acid-synthesizing enzyme, l-glutamate decarboxylase (MGAD), is
regulated by the vesicular proton gradient (Hsu, C. C., Thomas, C., Chen, W.,
Davis, K. M., Foos, T., Chen, J. L., Wu, E., Floor, E., Schloss, J. V., and Wu,
J. Y. (1999) J. Biol. Chem. 274, 24366-24371). In this report, several lines of
evidence are presented to indicate that l-glutamate decarboxylase (GAD) can
become membrane-associated to synaptic vesicles first through complex formation
with the heat shock protein 70 family, specifically heat shock cognate 70
(HSC70), followed by interaction with cysteine string protein (CSP), an integral
protein of the synaptic vesicle. The first line of evidence comes from
purification of MGAD in which HSC70, as identified from amino acid sequencing, co
purified with GAD. Second, in reconstitution studies, HSC70 was found to form
complex with GAD(65) as shown by gel mobility shift in non-denaturing gradient
gel electrophoresis. Third, in immunoprecipitation studies, again, HSC70 was co
immunoprecipitated with GAD by a GAD(65)-specific monoclonal antibody. Fourth,
HSC70 and CSP were co-purified with GAD by specific anti-GAD immunoaffinity
columns. Furthermore, studies here suggest that both GAD(65) and GAD(67) are
associated with synaptic vesicles along with HSC70 and CSP. Based on these
findings, a model is proposed to link anchorage of MGAD to synaptic vesicles in
relation to its role in gamma-aminobutyric acid neurotransmission.
PMID- 10781587
TI - Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2).
AB - We report the identification and characterization of a novel CC chemokine
designated CCL28 and its receptor CCR10, known previously as orphan G-protein
coupled receptor GPR2. Human and mouse CCL28 share 83% identity at the amino acid
and 76% at the nucleic acid levels. We also identified the mouse homologues of
CCL28 and of CCR10, which map to mouse chromosomes 13 and 11, respectively. CCL28
is expressed in a variety of human and mouse tissues, and it appears to be
predominantly produced by epithelial cells. Both human and mouse CCL28 induce
calcium mobilization in human and mouse CCR10-expressing transfectants. CCL28
desensitized the calcium mobilization induced in CCR10 transfectants by CCL27,
indicating that these chemokines share this new chemokine receptor. In vitro,
recombinant human CCL28 displays chemotactic activity for resting CD4 or CD8 T
cells.
PMID- 10781588
TI - Pivotal role of reactive oxygen species as intracellular mediators of
hyperthermia-induced apoptosis.
AB - The effects of cellular antioxidant capacity on hyperthermia (HT)-induced
apoptosis and production of antiapoptotic heat shock proteins (HSPs) were
investigated in HL-60 cells and in HL-60AR cells that are characterized by an
elevated endogenous catalase activity. Exposure of both cell lines to 43 degrees
C for 1 h initiated apoptosis. Apoptosis peaked at 3-6 h after heat exposure in
the HL-60 cells. Whereas HL-60AR cells were partially protected against HT
induced apoptosis at these early time points, maximal levels of apoptosis were
detected later, i.e. 12-18 h after heat exposure. This differential induction of
apoptosis was directly correlated to the induction of the antiapoptotic HSP27 and
HSP70. In particular, in the HL-60 cells HSP27 was significantly induced at 12-18
h after exposure to 43 degrees C when apoptosis dropped. In contrast, coinciding
with the late onset of apoptosis in HL-60AR cells at that time HL-60AR cells
lacked a similar HSP response. In line with the higher antioxidant capacity HL
60AR cells accumulated reactive oxygen species to a lesser degree than HL-60
cells after heat treatment. Protection from HT-induced apoptosis as well as
diminished heat-induced HSP27 expression was also observed after cotreatment of
HL-60 cells with 43 degrees C and catalase but not with superoxide dismutase.
These data emphasize the pivotal role of reactive oxygen species for HT induced
pro- and antiapoptotic pathways.
PMID- 10781589
TI - Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and
caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin
stimulated displacement of eNOS from caveolin-1.
AB - The activity of endothelial nitric-oxide synthase (eNOS) is regulated by its
subcellular localization, phosphorylation and through its interaction with
different proteins. The association of eNOS with caveolin-1 (Cav) is believed to
maintain eNOS in an inactive state; however, increased association of eNOS to
heat shock protein 90 (hsp90) is observed following activation. In this study, we
investigate the relationship between caveolin and hsp90 as opposing regulatory
proteins on eNOS function. Immunoprecipitation of Cav-1 from bovine lung
microvascular endothelial cells shows that eNOS and hsp90 are present in the Cav
1 complex. eNOS and hsp90 from the lysate also interact with exogenous
glutathione S-transferase-linked caveolin-1 (GST-Cav), and the addition of
calcium-activated calmodulin (CaM) to the GST-Cav complex partially inhibited the
association of eNOS and hsp90. Purified eNOS associates with GST-Cav specifically
through the caveolin-scaffolding domain (residues 82-101); however, the addition
of CaM slightly, but nonstatistically, reduces eNOS binding to GST-Cav. When
hsp90 is present in the binding reaction, the addition of increasing
concentrations of CaM significantly displaces eNOS and hsp90 from GST-Cav. eNOS
enzymatic activity is also less sensitive to inhibition by the caveolin
scaffolding peptide (residues 82-101) when eNOS is prebound to hsp90.
Collectively, our results show that the actions of CaM on eNOS dissociation from
caveolin are facilitated in the presence of hsp90.
PMID- 10781590
TI - Identification of CIP-1-associated regulator of cyclin B (CARB), a novel p21
binding protein acting in the G2 phase of the cell cycle.
AB - The cyclin-dependent kinase inhibitor p21(cip1) regulates cell cycle progression,
DNA replication, and DNA repair by binding to specific cellular proteins through
distinct amino- and carboxyl-terminal protein binding motifs. We have identified
a novel human gene, CARB (CIP-1-associated regulator of cyclin B), whose product
interacts with the p21 carboxyl terminus. Immunocytochemical analysis
demonstrates that the CARB protein is perinuclear and predominantly associated
with the centrosome and mitotic spindle poles. In addition, CARB is also able to
associate with cyclin B1, a key regulator of mitosis. However, cyclin B1-CARB
complex formation occurs preferentially in the absence of p21. Unexpectedly,
overexpression of CARB is associated with a growth-inhibitory and ultimately
lethal phenotype in p21(-/-) cells but not in p21(+/+) cells. These data identify
a novel mechanism that may underlie the effects of p21 in the G(2)/M phases of
the cell cycle.
PMID- 10781591
TI - Purification and molecular cloning of a novel essential component of the
apolipoprotein B mRNA editing enzyme-complex.
AB - Editing of apolipoprotein B (apoB) mRNA requires the catalytic component APOBEC-1
together with "auxiliary" proteins that have not been conclusively characterized
so far. Here we report the purification of these additional components of the
apoB mRNA editing enzyme-complex from rat liver and the cDNA cloning of the novel
APOBEC-1-stimulating protein (ASP). Two proteins copurified into the final active
fraction and were characterized by peptide sequencing and mass spectrometry:
KSRP, a 75-kDa protein originally described as a splicing regulating factor, and
ASP, a hitherto unknown 65-kDa protein. Separation of these two proteins resulted
in a reduction of APOBEC-1-stimulating activity. ASP represents a novel type of
RNA-binding protein and contains three single-stranded RNA-binding domains in the
amino-terminal half and a putative double-stranded RNA-binding domain at the
carboxyl terminus. Purified recombinant glutathione S-transferase (GST)-ASP, but
not recombinant GST-KSRP, stimulated recombinant GST-APOBEC-1 to edit apoB RNA in
vitro. These data demonstrate that ASP is the second essential component of the
apoB mRNA editing enzyme-complex. In rat liver, ASP is apparently associated with
KSRP, which may confer stability to the editing enzyme-complex with its substrate
apoB RNA serving as an additional auxiliary component.
PMID- 10781593
TI - Requirement of PIG-F and PIG-O for transferring phosphoethanolamine to the third
mannose in glycosylphosphatidylinositol.
AB - Many eukaryotic proteins are anchored by glycosylphosphatidylinositol (GPI) to
the cell surface membrane. The GPI anchor is linked to proteins by an amide bond
formed between the carboxyl terminus and phosphoethanolamine attached to the
third mannose. Here, we report the roles of two mammalian genes involved in
transfer of phosphoethanolamine to the third mannose in GPI. We cloned a mouse
gene termed Pig-o that encodes a 1101-amino acid PIG-O protein bearing regions
conserved in various phosphodiesterases. Pig-o knockout F9 embryonal carcinoma
cells expressed very little GPI-anchored proteins and accumulated the same major
GPI intermediate as the mouse class F mutant cell, which is defective in
transferring phosphoethanolamine to the third mannose due to mutant Pig-f gene.
PIG-O and PIG-F proteins associate with each other, and the stability of PIG-O
was dependent upon PIG-F. However, the class F cell is completely deficient in
the surface expression of GPI-anchored proteins. A minor GPI intermediate seen in
Pig-o knockout but not class F cells had more than three mannoses with
phosphoethanolamines on the first and third mannoses, suggesting that this GPI
may account for the low expression of GPI-anchored proteins. Therefore, mammalian
cells have redundant activities in transferring phosphoethanolamine to the third
mannose, both of which require PIG-F.
PMID- 10781592
TI - Regulated association of microtubule-associated protein 2 (MAP2) with Src and
Grb2: evidence for MAP2 as a scaffolding protein.
AB - Microtubule-associated protein 2 (MAP2) and tau, which is involved in Alzheimer's
disease, are major cytoskeletal proteins in neurons. These proteins are involved
in microtubule assembly and stability. To further characterize MAP2, we took a
strategy of identifying potential MAP2 binding partners. The low molecular weight
MAP2c protein has 11 PXXP motifs that are conserved across species, and these
PXXP motifs could be potential ligands for Src homology 3 (SH3) domains. We
tested for MAP2 interaction with SH3 domain-containing proteins. All neuronal
MAP2 isoforms bound specifically to the SH3 domains of c-Src and Grb2 in an in
vitro glutathione S-transferase-SH3 pull-down assay. Interactions between
endogenous proteins were confirmed by co-immunoprecipitation using brain lysate.
All three proteins were also found co-expressed in neuronal cell bodies and
dendrites. Surprisingly, the SH3 domain-binding site was mapped to the
microtubule-binding domain that contains no PXXP motif. Src bound primarily the
soluble, non-microtubule-associated MAP2c in vitro. This specific MAP2/SH3 domain
interaction was inhibited by phosphorylation of MAP2c by the mitogen-activated
protein kinase extracellular signal-regulated kinase 2 but not by protein kinase
A. This phosphorylation-regulated association of MAP2 with proteins of
intracellular signal transduction pathways suggests a possible link between
cellular signaling and neuronal cytoskeleton, with MAP2 perhaps acting as a
molecular scaffold upon which cytoskeleton-modifying proteins assemble and
dissociate in response to neuronal activity.
PMID- 10781594
TI - Characterization of a phosphoinositide-mediated odor transduction pathway reveals
plasma membrane localization of an inositol 1,4, 5-trisphosphate receptor in
lobster olfactory receptor neurons.
AB - The role of phosphoinositide signaling in olfactory transduction is still being
resolved. Compelling functional evidence for the transduction of odor signals via
phosphoinositide pathways in olfactory transduction comes from invertebrate
olfactory systems, in particular lobster olfactory receptor neurons. We now
provide molecular evidence for two components of the phosphoinositide signaling
pathway in lobster olfactory receptor neurons, a G protein alpha subunit of the
G(q) family and an inositol 1,4, 5-trisphosphate-gated channel or an inositol
1,4,5-trisphosphate (IP(3)) receptor. Both proteins localize to the site of
olfactory transduction, the outer dendrite of the olfactory receptor neurons.
Furthermore, the IP(3) receptor localizes to membranes in the ciliary
transduction compartment of these cells at both the light microscopic and
electron microscopic levels. Given the absence of intracellular organelles in the
sub-micron diameter olfactory cilia, this finding indicates that the IP(3)
receptor is associated with the plasma membrane and provides the first definitive
evidence for plasma membrane localization of an IP(3)R in neurons. The
association of the IP(3) receptor with the plasma membrane may be a novel
mechanism for regulating intracellular cations in restricted cellular
compartments of neurons.
PMID- 10781595
TI - The molecular chaperones Hsp90 and Hsc70 are both necessary and sufficient to
activate hormone binding by glucocorticoid receptor.
AB - Glucocorticoid receptors must be complexed with Hsp90 in order to bind steroids,
and it has been reported that at least three other proteins, Hop, Hsc70, and a J
domain protein (either Hsp40 or Ydj1), are required for formation of active Hsp90
steroid receptor complex. In the present study, we reinvestigated activation of
stripped steroid receptors isolated from either L cells or WCL2 cells.
Surprisingly, we found, using highly purified proteins, that only Hsp90 and Hsc70
are required for the activation of glucocorticoid receptors in the presence of
steroids; in the absence of steroids, either p23 or molybdate are also required
as reported previously. Addition of Hop or Ydj1 had no affect on the rate or
magnitude of the activation of the stripped receptors, and quantitative Western
blots confirmed that neither Hop or Hsp40 were present in our protein
preparations or in the stripped receptors. Furthermore, a truncated recombinant
Hsp70 that does not bind Hop or Hsp40 was as effective as wild-type Hsp70 in
activating stripped receptor. Since Hsc70 does not bind directly to Hsp90 but
both proteins bind to Hop, it has been suggested that Hop acts as a bridge
between Hsp90 and Hsp70. However, we found that after Hsc70 or Hsp90 bind
directly to the stripped receptors, they are fully reactivated by Hsp90 or Hsc70,
respectively. We, therefore, conclude that Hsp90 and Hsc70 bind independently to
stripped glucocorticoid receptors and alone are sufficient to activate them to
bind steroids.
PMID- 10781596
TI - Molecular cloning and expression of a novel chondroitin 6-O-sulfotransferase.
AB - A novel human chondroitin 6-O-sulfotransferase, designated C6ST-2, was identified
by BLAST analysis of expressed sequence tag using the sequence of a previously
described human chondroitin 6-O-sulfotransferase (C6ST-1) as a probe. The new
cDNA sequence revealed an open reading frame coding for a protein of 486 amino
acids with a type II transmembrane protein topology. The amino acid sequence
displayed 24% identity to the human C6ST-1, and the highest sequence identity was
found in the COOH-terminal catalytic domain. The expression of a soluble
recombinant form of the protein in COS-1 cells produced an active
sulfotransferase with marked specificity for polymer chondroitin. In contrast,
keratan sulfate and oligosaccharides containing the Galbeta1-4GlcNAc sequence,
which are good acceptor substrates for the C6ST-1, hardly served as acceptors.
The identification of the reaction product indicated that the enzyme is a novel
chondroitin 6-O-sulfotransferase (C6ST-2) that mainly transfers sulfate to N
acetylgalactosamine. The coding region of C6ST-2 was contained in a single exon
and localized to chromosome Xp11. Northern blot analysis of human brain
poly(A)(+) RNA revealed a single transcript of 2.4 kilobase pairs. Reverse
transcription-polymerase chain reaction analysis showed that C6ST-2 is
developmentally regulated in various tissues with expression persisting through
adulthood in the spleen. Thus, we demonstrated the redundancy in chondroitin 6-O
sulfotransferases capable of forming chondroitin 6-sulfate, which is important
for understanding the mechanisms leading to specific changes in the sulfation
profile of chondroitin sulfate chains in various tissues during development and
malignant transformation.
PMID- 10781597
TI - Oncogenic Ras-mediated cell growth arrest and apoptosis are associated with
increased ubiquitin-dependent cyclin D1 degradation.
AB - The cellular responses to activated Ras vary depending on cell type. Normal cells
are often induced into pathways that lead to cell growth arrest, senescence,
and/or apoptosis in response to activated Ras expression. These are important
protective anti-tumorigenic responses that restrict the propagation of cells
bearing activated oncogenes. Here we show that induction of Ha-Ras(Val-12) in Rat
1 fibroblasts resulted in G(1) growth arrest and apoptosis with loss of viable
cells that is accompanied by a marked decrease in cyclin D1 levels via increased
ubiquitin-proteasome-dependent cyclin D1 turnover. This is in contrast with a rat
intestinal epithelial cell line in which induction of Ha-Ras(Val-12) results in
transformation associated with sustained proliferation and increased levels of
cyclin D1, that is not accompanied by anoikis or apoptosis. Expression of the
cyclin D1 mutant (T286A) that contains an alanine for threonine 286 substitution
and is resistant to ubiquitin-proteasome degradation in the Ha-Ras(Val-12)
expressing Rat-1 cells resulted in a sustained transformed phenotype with no
accumulation of cells in G(1). Inhibition of mitogen-activated protein kinase
(MEK1/2) pathway partially reversed the Ras-mediated decrease in cyclin D1.
Induction of Ha-Ras(Val-12) resulted in activation of Akt kinase and inactivation
of glycogen-synthase-3beta kinase that are associated with reduction of cyclin D1
protein. These results suggest that Ras-mediated cyclin D1 degradation in Rat-1
cells appears to be partially dependent on activation of mitogen-activated
protein kinase pathway and independent of glycogen-synthase-3beta kinase pathway.
PMID- 10781598
TI - The H subunit (Vma13p) of the yeast V-ATPase inhibits the ATPase activity of
cytosolic V1 complexes.
AB - V-ATPases are composed of a peripheral complex containing the ATP-binding sites,
the V(1) sector, attached to a membrane complex containing the proton pore, the
V(o) sector. In vivo, free, inactive V(1) and V(o) sectors exist in dynamic
equilibrium with fully assembled, active V(1) V(o) complexes, and this
equilibrium can be perturbed by changes in carbon source. Free V(1) complexes
were isolated from the cytosol of wild-type yeast cells and mutant strains
lacking V(o) subunit c (Vma3p) or V(1) subunit H (Vma13p). V(1) complexes from
wild-type or vma3Delta mutant cells were very similar, and contained all
previously identified yeast V(1) subunits except subunit C (Vma5p). These V(1)
complexes hydrolyzed CaATP but not MgATP, and CaATP hydrolysis rapidly
decelerated with time. V(1) complexes from vma13Delta cells contained all V(1)
subunits except C and H, and had markedly different catalytic properties. The
initial rate of CaATP hydrolysis was maintained for much longer. The complexes
also hydrolyzed MgATP, but showed a rapid deceleration in hydrolysis. These
results indicate that the H subunit plays an important role in silencing
unproductive ATP hydrolysis by cytosolic V(1) complexes, but suggest that other
mechanisms, such as product inhibition, may also play a role in silencing in
vivo.
PMID- 10781599
TI - Endoplasmic reticulum retention determinants in the transmembrane and linker
domains of cytochrome P450 2C1.
AB - The cytochrome P450 2C1 N-terminal signal anchor sequence mediates direct
retention of the protein in the endoplasmic reticulum and consists of a
hydrophobic transmembrane domain, residues 3-20, followed by a hydrophilic
linker, residues 21-28. Fusions of the N-terminal 21 or 28 amino acids of P450
2C1 to green fluorescent protein resulted in endoplasmic reticulum localization
of the chimera in transfected cells. Disruption of microtubules by nocodazole
treatment resulted in redistribution into a punctate pattern for the 1-21, but
not for the 1-28, chimera indicating that the linker was preventing transport
from the endoplasmic reticulum but was not required for retrieval to the
endoplasmic reticulum from the pre-Golgi compartment. In the 1-28 chimera,
mutations of residues 21-23 (KQS) in the linker resulted in redistribution of the
chimera after nocodazole treatment. Mutations in the transmembrane domain
affected both direct retention in the endoplasmic reticulum and retrieval from
the pre-Golgi compartment, and although structural requirements for each process
are distinct, in both cases the arrangement of amino acids and distribution of
hydrophobicity are critical. In contrast, the linker region exhibits a sequence
specific requirement for direct retention in the endoplasmic reticulum.
PMID- 10781600
TI - Signaling from G protein-coupled receptors to ERK5/Big MAPK 1 involves Galpha q
and Galpha 12/13 families of heterotrimeric G proteins. Evidence for the
existence of a novel Ras AND Rho-independent pathway.
AB - The regulation of gene expression by cell surface receptors often involves the
stimulation of signaling pathways including one or more members of the MAPK
superfamily of serine-threonine kinases. Upon their activation in the cytosol,
MAPKs can translocate to the nucleus and affect the activity of a variety of
transcription factors. Recently, it has been observed that a novel member of the
MAPK superfamily, ERK5, can be potently activated by transforming G protein
coupled receptors (GPCRs) and that ERK5 participates in the regulation of c-jun
expression through the activation of MEF2 transcription factors. How cell surface
receptors, including GPCRs, stimulate ERK5 is still poorly understood. In this
study, we have used transiently transfected COS-7 cells to begin delineating the
biochemical route linking GPCRs to ERK5. We show that receptors that can couple
to the G(q) and G(12/13) families of heterotrimeric G proteins, m1 and thrombin
receptors, respectively, but not those coupled to G(i), such as m2 receptors, are
able to regulate the activity of ERK5. To investigate which heterotrimeric G
proteins signal to ERK5, we used a chimeric system by which Galpha(q)- and
Galpha(13)-mediated signaling pathways can be conditionally activated upon ligand
stimulation. Using this system, as well as the expression of activated forms of G
protein subunits, we show that the Galpha(q) and Galpha(12/13) families of
heterotrimeric G proteins, but not the Galpha(i), Galpha(s), and betagamma
subunits, are able to regulate ERK5. Furthermore, we provide evidence that the
stimulation of ERK5 by GPCRs involves a novel signaling pathway, which is
distinct from those regulated by Ras and Rho GTPases.
PMID- 10781601
TI - Molecular cloning and expression of two distinct human chondroitin 4-O
sulfotransferases that belong to the HNK-1 sulfotransferase gene family.
AB - Using an expression cloning strategy, the cDNA encoding the human HNK-1
sulfotransferase (HNK-1ST) has been cloned. During this cloning we found that HNK
1ST and other Golgi-associated sulfotransferases cloned before share homologous
sequences including the RDP motif (Ong, E., Yeh, J.-C., Ding, Y., Hindsgaul, O.,
and Fukuda, M. (1998) J. Biol. Chem. 223, 5190-5195). Using this conserved
sequence in HNK-1ST as a probe, we identified two expressed sequence tags in EST
data base which have 31.6 and 30.7% identity with HNK-1ST at the amino acid
levels. Expression of these two full-length cDNAs failed to form HNK-1 glycan nor
to add sulfate to CD34 or NCAM. Surprisingly, proteins expressed by these cDNAs
transferred sulfate to the C-4 position of N-acetylgalactosamine in chondroitin
and desulfated dermatan sulfate, thus we named these two enzymes, chondroitin 4-O
sulfotransferase 1 and -2 (C4ST-1 and C4ST-2). Both C4ST-1 and C4ST-2, however,
did not form 4, 6-di-O-sulfated N-acetylgalactosamine when chondroitin sulfate C
was used as an acceptor. Moreover, analysis of (35)S-labeled dermatan sulfate
formed by C4ST-1 indicate that sulfation preferentially took place in GlcA-
>GalNAc unit than in IdoA-->GalNAc unit, suggesting that 4-O-sulfation at N
acetylgalactosamine may precede epimerization of glucuronic acid to iduronic acid
during dermatan sulfate biosynthesis. Northern analysis demonstrated that the
transcript for C4ST-1 is predominantly expressed in peripheral leukocytes and
hematopoietic tissues while the C4ST-2 transcript is more widely expressed in
various tissues. These results indicate C4ST-1 and C4ST-2 play complementary
roles in chondroitin and dermatan sulfate synthesis in different tissues.
PMID- 10781602
TI - The C terminus of mouse macrophage inducible nitric-oxide synthase attenuates
electron flow through the flavin domain.
AB - The sequences of nitric-oxide synthase (NOS) flavin domains closely resemble that
of NADPH-cytochrome P450 reductase (CPR), with the exception of a few regions.
One such region is the C terminus; all NOS isoforms are 20-40 amino acids longer
than CPR, forming a "tail" that is absent in CPR. To investigate its function, we
removed the 21-amino acid C-terminal tail from murine macrophage inducible NOS
(iNOS) holoenzyme and from a flavin domain construct. Both the truncated
holoenzyme and reductase domain exhibited cytochrome c reductase activities that
were 7-10-fold higher than the nontruncated forms. The truncated holoenzyme
catalyzed NO formation approximately 20% faster than the intact form. Using
stopped-flow spectrophotometry, we demonstrated that electron transfer into and
between the two flavins and from the flavin to the heme domain is 2-5-fold faster
in the absence of the C-terminal tail. The heme-nitrosyl complex, formed in all
NOS isoforms during NO catalysis, is 5-fold less stable in truncated iNOS.
Although both CPR and intact NOS can exist in a stable, one electron-reduced
semiquinone form, neither the truncated holoenzyme nor the truncated flavin
domain demonstrate such a form. We propose that this C-terminal tail curls back
to interact with the flavin domain in such a way as to modulate the interaction
between the two flavin moieties.
PMID- 10781603
TI - Type II cAMP-dependent protein kinase-deficient Drosophila are viable but show
developmental, circadian, and drug response phenotypes.
AB - We identified a unique type II cAMP-dependent protein kinase regulatory subunit
(PKA-RII) gene in Drosophila melanogaster and a severely hypomorphic if not null
mutation, pka-RII(EP(2)2162). Extracts from pka- RII(EP(2)2162) flies selectively
lack RII-specific autophosphorylation activity and show significantly reduced
cAMP binding activity, attributable to the loss of functional PKA-RII. pka
RII(EP(2)2162) shows 2-fold increased basal PKA activity and approximately 40% of
normal cAMP-inducible PKA activity. pka-RII(EP(2)2162) is fully viable but
displays abnormalities of ovarian development and multiple behavioral phenotypes
including arrhythmic circadian locomotor activity, decreased sensitivity to
ethanol and cocaine, and a lack of sensitization to repeated cocaine exposures.
These findings implicate type II PKA activity in these processes in Drosophila
and imply a common role for PKA signaling in regulating responsiveness to cocaine
and alcohol.
PMID- 10781604
TI - Rsp5 WW domains interact directly with the carboxyl-terminal domain of RNA
polymerase II.
AB - RSP5 is an essential gene in Saccharomyces cerevisiae and was recently shown to
form a physical and functional complex with RNA polymerase II (RNA pol II). The
amino-terminal half of Rsp5 consists of four domains: a C2 domain, which binds
membrane phospholipids; and three WW domains, which are protein interaction
modules that bind proline-rich ligands. The carboxyl-terminal half of Rsp5
contains a HECT (homologous to E6-AP carboxyl terminus) domain that catalytically
ligates ubiquitin to proteins and functionally classifies Rsp5 as an E3 ubiquitin
protein ligase. The C2 and WW domains are presumed to act as membrane
localization and substrate recognition modules, respectively. We report that the
second (and possibly third) Rsp5 WW domain mediates binding to the carboxyl
terminal domain (CTD) of the RNA pol II large subunit. The CTD comprises a
heptamer (YSPTSPS) repeated 26 times and a PXY core that is critical for
interaction with a specific group of WW domains. An analysis of synthetic
peptides revealed a minimal CTD sequence that is sufficient to bind to the second
Rsp5 WW domain (Rsp5 WW2) in vitro and in yeast two-hybrid assays. Furthermore,
we found that specific "imperfect" CTD repeats can form a complex with Rsp5 WW2.
In addition, we have shown that phosphorylation of this minimal CTD sequence on
serine, threonine and tyrosine residues acts as a negative regulator of the Rsp5
WW2-CTD interaction. In view of the recent data pertaining to phosphorylation
driven interactions between the RNA pol II CTD and the WW domain of Ess1/Pin1, we
suggest that CTD dephosphorylation may be a prerequisite for targeted RNA pol II
degradation.
PMID- 10781605
TI - Kinetics of the interaction of translation factor SelB from Escherichia coli with
guanosine nucleotides and selenocysteine insertion sequence RNA.
AB - The kinetics of the interaction of GTP and GDP with SelB, the specific
translation factor for the incorporation of selenocysteine into proteins, have
been investigated using the stopped-flow method. Useful signals were obtained
using intrinsic (i.e. tryptophan) fluorescence, the fluorescence of
methylanthraniloyl derivatives of nucleotides, or fluorescence resonance energy
transfer from tryptophan to the methylanthraniloyl group. The affinities of SelB
for GTP (K(d) = 0.74 micrometer) and GDP (K(d) = 13.4 micrometer) were
considerably lower than those of other translation factors. Of functional
significance is the fact that the rate constant for GDP release from its complex
with SelB (15 s(-)(1)) is many orders of magnitude larger than for elongation
factor Tu, explaining why a GDP/GTP exchange factor is not required for the
action of SelB. In contrast, the rate of release of GTP is 2 orders of magnitude
slower and not significantly faster than for elongation factor Tu. Using a
fluorescently labeled 17-nucleotide RNA minihelix that represents a binding site
for the protein and that is part of the fdhF selenocysteine insertion sequence
element positioned immediately downstream of the UGA triplet coding for
selenocysteine incorporation, the kinetics of the interaction were studied. The
high affinity of the interaction (K(d) approximately 1 nm) appeared to be
increased even further when selenocysteyl-tRNA(Sec) was bound to SelB, but to be
independent of the presence or nature of the guanosine nucleotide at the active
site. These results suggest that the affinity of SelB for its RNA binding site is
maximized when charged tRNA is bound and decreases to allow dissociation and
reading of codons downstream of the selenocysteine codon after selenocysteine
peptide bond formation.
PMID- 10781607
TI - The iscS gene in Escherichia coli is required for the biosynthesis of 4
thiouridine, thiamin, and NAD.
AB - IscS, a cysteine desulfurase implicated in the repair of Fe-S clusters, was
recently shown to act as a sulfurtransferase in the biosynthesis of 4-thiouridine
(s(4)U) in tRNA (Kambampati, R., and Lauhon, C. T. (1999) Biochemistry 38, 16561
16568). In frame deletion of the iscS gene in Escherichia coli results in a
mutant strain that lacks s(4)U in its tRNA. Assays of cell-free extracts isolated
from the iscS(-) strain confirm the complete loss of tRNA sulfurtransferase
activity. In addition to lacking s(4)U, the iscS(-) strain requires thiamin and
nicotinic acid for growth in minimal media. The thiamin requirement can be
relieved by the addition of the thiamin precursor 5-hydroxyethyl-4
methylthiazole, indicating that iscS is required specifically for thiazole
biosynthesis. The growth rate of the iscS(-) strain is half that of the parent
strain in rich medium. When the iscS(-) strain is switched from rich to minimal
medium containing thiamin and nicotinate, growth is preceded by a considerable
lag period relative to the parent strain. Addition of isoleucine results in a
significant reduction in the duration of this lag phase. To examine the thiazole
requirement, we have reconstituted the in vitro biosynthesis of ThiS
thiocarboxylate, the ultimate sulfur donor in thiazole biosynthesis, and we show
that IscS mobilizes sulfur for transfer to the C-terminal carboxylate of ThiS.
ThiI, a known factor involved in both thiazole and s(4)U synthesis, stimulates
this sulfur transfer step by 7-fold. Extracts from the iscS(-) strain show
significantly reduced activity in the in vitro synthesis of ThiS thiocarboxylate.
Transformation of the iscS(-) strain with an iscS expression plasmid complemented
all of the observed phenotypic effects of the deletion mutant. Of the remaining
two nifS-like genes in E. coli, neither can complement loss of iscS when each is
overexpressed in the iscS(-) strain. Thus, IscS plays a significant and specific
role at the top of a potentially broad sulfur transfer cascade that is required
for the biosynthesis of thiamin, NAD, Fe-S clusters, and thionucleosides.
PMID- 10781606
TI - Molecular cloning and characterization of a human mitochondrial ceramidase.
AB - We have recently purified a rat brain membrane-bound nonlysosomal ceramidase (El
Bawab, S., Bielawska, A., and Y. A. Hannun (1999) J. Biol. Chem. 274, 27948
27955). Using peptide sequences obtained from the purified rat brain enzyme, we
report here the cloning of the human isoform. The deduced amino acid sequence of
the protein did not show any similarity with proteins of known function but was
homologous to three putative proteins from Arabidospis thaliana, Mycobacterium
tuberculosis, and Dictyostelium discoideum. Several blocks of amino acids were
highly conserved in all of these proteins. Analysis of the protein sequence
revealed the presence at the N terminus of a signal peptide followed by a
putative myristoylation site and a putative mitochondrial targeting sequence. The
predicted molecular mass was 84 kDa, and the isoelectric point was 6.69, in
agreement with rat brain purified enzyme. Northern blot analysis of multiple
human tissues showed the presence of a major band corresponding to a size of 3.5
kilobase. Analysis of this major band on the blot indicated that the enzyme is
ubiquitously expressed with higher levels in kidney, skeletal muscle, and heart.
The enzyme was then overexpressed in HEK 293 and MCF7 cells using the pcDNA3.
1/His-ceramidase construct, and ceramidase activity (at pH 9.5) increased by 50-
and 12-fold, respectively. Next, the enzyme was characterized using lysate of
overexpressing cells. The results confirmed that the enzyme catalyzes the
hydrolysis of ceramide in the neutral alkaline range and is independent of
cations. Finally, a green fluorescent protein-ceramidase fusion protein was
constructed to investigate the localization of this enzyme. The results showed
that the green fluorescent protein-ceramidase fusion protein presented a
mitochondrial localization pattern and colocalized with mitochondrial specific
probes. These results demonstrate that this novel ceramidase is a mitochondrial
enzyme, and they suggest the existence of a topologically restricted pathways of
sphingolipid metabolism.
PMID- 10781608
TI - The top of the inserted-like domain of the integrin lymphocyte function
associated antigen-1 beta subunit contacts the alpha subunit beta -propeller
domain near beta-sheet 3.
AB - We find that monoclonal antibody YTA-1 recognizes an epitope formed by a
combination of the integrin alpha(L) and beta(2) subunits of LFA-1. Using
human/mouse chimeras of the alpha(L) and beta(2) subunits, we determined that YTA
1 binds to the predicted inserted (I)-like domain of the beta(2) subunit and the
predicted beta-propeller domain of the alpha(L) subunit. Substitution into mouse
LFA-1 of human residues Ser(302) and Arg(303) of the beta(2) subunit and Pro(78),
Thr(79), Asp(80), Ile(365), and Asn(367) of the alpha(L) subunit is sufficient to
completely reconstitute YTA-1 reactivity. Antibodies that bind to epitopes that
are nearby in models of the I-like and beta-propeller domains compete with YTA-1
monoclonal antibody for binding. The predicted beta-propeller domain of integrin
alpha subunits contains seven beta-sheets arranged like blades of a propeller
around a pseudosymmetry axis. The antigenic residues cluster on the bottom of
this domain in the 1-2 loop of blade 2, and on the side of the domain in beta
strand 4 of blade 3. The I domain is inserted between these blades on the top of
the beta-propeller domain. The antigenic residues in the beta subunit localize to
the top of the I-like domain near the putative Mg(2+) ion binding site. Thus, the
I-like domain contacts the bottom or side of the beta-propeller domain near beta
sheets 2 and 3. YTA-1 preferentially reacts with activated LFA-1 and is a
function-blocking antibody, suggesting that conformational movements occur near
the interface it defines between the LFA-1 alpha and beta subunits.
PMID- 10781609
TI - Up-regulation of caveolin attenuates epidermal growth factor signaling in
senescent cells.
AB - Senescent human diploid fibroblasts do not respond to growth factors like
epidermal growth factor (EGF), although they have a normal level of receptors and
downstream signaling molecules. To examine the mechanism of signaling
attenuation, we investigated Erk activation after EGF stimulation in senescent
cells. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation,
whereas young cells did. In those senescent cells, we found an increased level of
caveolin proteins and strong interactions between caveolin-1 and EGF receptor.
Electron microscopic analysis demonstrated an increased number of caveolae
structures in senescent cells. More interestingly, brain, spleen, and lung from
26-month-old rats showed substantial increases of caveolin proteins. However, in
the case of p53-induced senescence, caveolin-1 was not induced, and EGF
stimulation phosphorylated Erk-1/2 as much as young control cells. Finally, we
overexpressed caveolin-1 in young human diploid fibroblasts in which the
activation of Erk-1/2 upon EGF stimulation was significantly suppressed. These
results suggest that the unresponsiveness of senescent fibroblasts to EGF
stimulation may be due to the overexpression of caveolins, which seems to be
independent of growth arrest and other aging phenotypes.
PMID- 10781610
TI - Identification of the enzymatic active site of CD38 by site-directed mutagenesis.
AB - CD38 is a ubiquitous protein originally identified as a lymphocyte antigen and
recently also found to be a multifunctional enzyme participating in the synthesis
and metabolism of two Ca(2+) messengers, cyclic ADP-ribose (cADPR) and nicotinic
acid adenine dinucleotide phosphate. It is homologous to Aplysia ADP-ribosyl
cyclase, where the crystal structure has been determined. Residues of CD38
corresponding to those at the active site of the Aplysia cyclase were
mutagenized. Changing Glu-226, which corresponded to the catalytic residue of the
cyclase, to Asp, Asn, Gln, Leu, or Gly eliminated essentially all enzymatic
activities of CD38, indicating it is most likely the catalytic residue.
Photoaffinity labeling showed that E226G, nevertheless, retained substantial NAD
binding activity. The secondary structures of these inactive mutants as measured
by circular dichroism were essentially unperturbed as compared with the wild
type. Other nearby residues were also investigated. The mutants D147V and E146L
showed 7- and 19-fold reduction in NADase activity, respectively. The cADPR
hydrolase activity of the two mutants was similarly reduced. Asp-155, on the
other hand, was crucial for the GDP-ribosyl cyclase activity since its
substitution with either Glu, Asn, or Gln stimulated the activity 3-15-fold,
whereas other activities remained essentially unchanged. In addition to these
acidic residues, two tryptophans were also important, since all enzyme activities
of W125F, W125Y, W189G and W189Y were substantially reduced. This is consistent
with the two tryptophans serving a substrate positioning function. A good
correlation was observed when the NADase activity of all the mutants was plotted
against the cADPR hydrolase activity. Homology modeling revealed all these
critical residues are clustered in a pocket near the center of the CD38 molecule.
The results indicate a strong structural homology between the active sites of
CD38 and the Aplysia cyclase.
PMID- 10781611
TI - The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in
myeloid cells.
AB - FcgammaR clustering in monocytes initiates a cascade of signaling events that
culminate in biological responses such as phagocytosis, production of
inflammatory cytokines, and generation of reactive oxygen species. We have
identified and determined the function of the adapter protein linker of
activation of T cell (LAT) in FcgammaR-mediated signaling and function.
Clustering of FcgammaRs on the human monocytic cell line, THP-1, induces
phosphorylation of a major 36-kDa protein which immunoreacts with anti-LAT
antisera. Our data indicate that although both the 36-kDa and 38-kDa isoforms of
LAT are expressed in THP-1 and U937 human monocytic cells, FcgammaR clustering
induces phosphorylation of the 36-kDa isoform only. Co-immunoprecipitation
experiments revealed a constitutive association of p36 LAT with both FcgammaRI
and FcgammaRIIa immunoprecipitates, and an activation-induced association of LAT
with PLCgamma1, Grb2, and the p85 subunit of phosphatidylinositol 3-kinase.
Transient transfection experiments in COS-7 cells indicated that overexpression
of a wild type but not a dominant-negative LAT, that is incapable of binding to
p85, enhances phagocytosis by FcgammaRI. Furthermore, bone marrow-derived
macrophages from LAT-deficient mice displayed reduced phagocytic efficiency in
comparison to the macrophages from wild-type mice. Thus, we conclude that p36 LAT
serves to enhance FcgammaR-induced signal transduction in myeloid cells.
PMID- 10781612
TI - Identification and developmental expression of inhibitor of caspase-activated
DNase (ICAD) in Drosophila melanogaster.
AB - DNA fragmentation, a hallmark of apoptosis, is regulated by a specific nuclease
called caspase-activated DNase (CAD) and its inhibitor (ICAD). When cell lysates
from Drosophila S2 cells were chemically denatured and the denatured proteins
were removed after dialysis, the supernatant inhibited Drosophila CAD (dCAD). To
identify the inhibitor, we tested recombinant DREP-1, which was previously
identified using the Drosophila EST data base and found it also inhibited dCAD
DNase. An antibody against DREP-1 inhibited the ICAD activity in the S2 cell
extracts, confirming the identification of DREP-1 as a Drosophila homolog of ICAD
(dICAD). The recombinant DREP-1/dICAD was cleaved at a specific site by human
caspase 3 as well as by extracts prepared from S2 cells undergoing apoptosis.
Biochemical fractionation and immunoprecipitation of dICAD from S2 cell extracts
indicated that dICAD is complexed with dCAD in proliferating cells. The
expression of the caspase-resistant form of dICAD/DREP-1 in a Drosophila neuronal
cell line prevented the apoptotic DNA fragmentation. Northern hybridization and
the immunohistochemical analyses revealed that the expression of the dICAD gene
is developmentally regulated.
PMID- 10781613
TI - Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated
killer T-cell-originated protein kinase, specifically expressed in the testis and
activated lymphoid cells.
AB - A novel protein kinase, TOPK (T-LAK cell-originated protein kinase), was isolated
from a lymphokine-activated killer T (T-LAK) cell subtraction cDNA fragment
library. The open reading frame of the TOPK gene encodes a protein of 322 amino
acids, possessing a protein kinase domain profile. The cap site analysis of the
5'-end of TOPK mRNA revealed two forms, a major full-length form and a minor
spliced form at the 5'-site, both encoding the same protein. A BLAST homology
search and phylogenetic analysis indicated that TOPK is related to dual specific
mitogen-activated protein kinase kinase (MAPKK). The transfection of the TOPK
gene to COS-7 cells up-regulated a phosphorylation of p38 MAPK but not ERK1/2 or
SAPK/JNK. Gel precipitation study indicated that TOPK protein can be associated
with p38 in vitro. Tissue distribution of TOPK mRNA expression was specific for
the testis, T-LAK cells, activated lymphoid cells, and lymphoid tumors. On the
other hand, deactivated T-LAK cells did not show TOPK mRNA expression. These data
suggest that TOPK is a newly identified member of a novel MEK3/6-related MAPKK
that may be enrolled in the activation of lymphoid cells and support testicular
functions.
PMID- 10781615
TI - The homeodomain protein Barx2 contains activator and repressor domains and
interacts with members of the CREB family.
AB - Barx1 and Barx2 are homeodomain proteins originally identified using regulatory
elements of genes encoding certain cell adhesion molecules (CAMs). In the present
study, we characterize regions of Barx2 that bind to regulatory elements of genes
encoding three CAMs, L1, neuron-glia CAM (Ng-CAM), and neural CAM (N-CAM), and
identify domains of Barx2 that regulate N-CAM transcription. The homeodomain of
Barx2 was sufficient for binding to homeodomain binding sites (HBS) from all
three CAM genes. The presence of a 17-amino acid Barx basic region resulted in a
2-fold decrease in binding to HBS sequences from the Ng-CAM and L1 genes, whereas
it led to a 6.5-fold increase in binding to the HBS from the N-CAM promoter.
Thus, the Barx basic region influences the strength and specificity of Barx2
binding to DNA. In co-transfection experiments, Barx2 repressed N-CAM promoter
activity. A 24-residue N-terminal region of Barx2 was essential for repression.
When this region was absent, Barx2 activated the N-CAM promoter. A 63-residue C
terminal domain was required for this activation. In GST pull-down experiments,
Barx2 bound to proteins of the CREB family, CREB1 and ATF2. Overall, these
findings provide a framework for understanding developmental and physiological
contexts that influence repressor or activator functions of Barx2.
PMID- 10781614
TI - p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and
release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac
myocyte model system.
AB - In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates
the transcription factor, NF-kappaB, and protects cells from apoptosis. In the
present study in primary neonatal rat cardiac myocytes, constitutively active
MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities
to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB
dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent
manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha,
which activates both NF-kappaB and p38, also induced p38-dependent IL-6
expression and release and protected myocytes from apoptotis. While TNF-alpha was
relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold,
indicating a probable role for this transcription factor in IL-6-mediated
protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a
kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1),
which is known to activate p38 and NF-kappaB in other cell types. Thus, by
stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha,
can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may
then function in an autocrine and/or paracrine fashion to augment myocardial cell
survival during stresses that activate p38.
PMID- 10781616
TI - A novel binding factor facilitates nuclear translocation and transcriptional
activation function of the pituitary tumor-transforming gene product.
AB - Pituitary tumor-transforming gene (PTTG) is a recently characterized oncogene
whose expression product contains a transcriptional activation domain at the C
terminus. To understand the mechanisms involved in PTTG biological functions, we
used yeast two-hybrid screening to identify proteins that interact with PTTG.
This study reports the isolation and characterization of a novel PTTG-binding
factor (PBF). PBF contains an open reading frame of 179 amino acids with a
predicted molecular mass of 22 kDa. In Northern blot analyses, PBF mRNA was
ubiquitously expressed in human tissues. Glutathione S-transferase pull-down and
co-immunoprecipitation assays demonstrate that PBF interacts specifically with
PTTG under both in vitro and in vivo conditions. The PTTG binding domain in PBF
was located within the C-terminal 30-amino acid region that contain a nuclear
localization signal. Immunofluorescence and subcellular fractionation studies
showed that PTTG is predominantly expressed in the cytoplasm with partial nuclear
localization, whereas PBF is localized both in the cytoplasm and the nucleus. The
interaction between PBF and PTTG facilitated PTTG translocation from the
cytoplasm to the nucleus. Furthermore, PBF is required for transcriptional
activation of basic fibroblast growth factor by PTTG. In summary, we have
characterized a novel PTTG-binding protein that facilitates PTTG nuclear
translocation and potentiates its transcriptional activation function.
PMID- 10781617
TI - The pgdA gene encodes for a peptidoglycan N-acetylglucosamine deacetylase in
Streptococcus pneumoniae.
AB - Analytical work on the fractionation of the glycan strands of Streptococcus
pneumoniae cell wall has led to the observation that an unusually high proportion
of hexosamine units (over 80% of the glucosamine and 10% of the muramic acid
residues) was not N-acetylated, explaining the resistance of the peptidoglycan to
the hydrolytic action of lysozyme, a muramidase that cleaves in the glycan
backbone. A gene, pgdA, was identified as encoding for the peptidoglycan N
acetylglucosamine deacetylase A with amino acid sequence similarity to fungal
chitin deacetylases and rhizobial NodB chitooligosaccharide deacetylases.
Pneumococci in which pgdA was inactivated by insertion duplication mutagenesis
produced fully N-acetylated glycan and became hypersensitive to exogenous
lysozyme in the stationary phase of growth. The pgdA gene may contribute to
pneumococcal virulence by providing protection against host lysozyme, which is
known to accumulate in high concentrations at infection sites.
PMID- 10781618
TI - Clinical features of Nipah virus encephalitis among pig farmers in Malaysia.
AB - BACKGROUND: Between September 1998 and June 1999, there was an outbreak of severe
viral encephalitis due to Nipah virus, a newly discovered paramyxovirus, in
Malaysia. METHODS: We studied the clinical features of the patients with Nipah
virus encephalitis who were admitted to a medical center in Kuala Lumpur. The
case definition was based on epidemiologic, clinical, cerebrospinal fluid, and
neuroimaging findings. RESULTS: Ninety-four patients with Nipah virus infection
were seen from February to June 1999 (mean age, 37 years; ratio of male patients
to female patients, 4.5 to 1). Ninety-three percent had had direct contact with
pigs, usually in the two weeks before the onset of illness, suggesting that there
was direct viral transmission from pigs to humans and a short incubation period.
The main presenting features were fever, headache, dizziness, and vomiting. Fifty
two patients (55 percent) had a reduced level of consciousness and prominent
brain-stem dysfunction. Distinctive clinical signs included segmental myoclonus,
areflexia and hypotonia, hypertension, and tachycardia and thus suggest the
involvement of the brain stem and the upper cervical spinal cord. The initial
cerebrospinal fluid findings were abnormal in 75 percent of patients. Antibodies
against Hendra virus were detected in serum or cerebrospinal fluid in 76 percent
of 83 patients tested. Thirty patients (32 percent) died after rapid
deterioration in their condition. An abnormal doll's-eye reflex and tachycardia
were factors associated with a poor prognosis. Death was probably due to severe
brain-stem involvement. Neurologic relapse occurred after initially mild disease
in three patients. Fifty patients (53 percent) recovered fully, and 14 (15
percent) had persistent neurologic deficits. CONCLUSIONS: Nipah virus causes a
severe, rapidly progressive encephalitis with a high mortality rate and features
that suggest involvement of the brain stem. The infection is associated with
recent contact with pigs.
PMID- 10781619
TI - An outbreak of febrile gastroenteritis associated with corn contaminated by
Listeria monocytogenes.
AB - BACKGROUND: On May 21, 1997, numerous cases of febrile gastrointestinal illness
were reported among the students and staff of two primary schools in northern
Italy, all of whom had eaten at cafeterias served by the same caterer. METHODS:
We interviewed people who ate at the cafeterias about symptoms and foods consumed
on May 20. There were no samples of foods left at the cafeterias, but we tested
routine samples taken on May 20 by the caterer and environmental specimens at the
catering plant. The hospitalized patients were tested for common enteropathogens
and toxins. RESULTS: Of the 2189 persons interviewed (82 percent of those
exposed), 1566 (72 percent) reported symptoms; of these, 292 (19 percent) were
hospitalized. Among samples obtained from hospitalized patients, all but two of
the stool specimens and all blood specimens were negative for common
enteropathogens. Listeria monocytogenes was isolated from one blood specimen and
from 123 of the 141 stool specimens. Consumption of a cold salad of corn and tuna
was associated with the development of symptoms (relative risk, 6.19; 95 percent
confidence interval, 4.81 to 7.98; P<0.001). L. monocytogenes was isolated from
the caterer's sample of the salad and from environmental specimens collected from
the catering plant. All listeria isolates were serotype 4b and were found to be
identical on DNA analysis. Experimental contamination of sterile samples of the
implicated foods showed that L. monocytogenes grew on corn when kept for at least
10 hours at 25 degrees C. CONCLUSIONS: Food-borne infection with L. monocytogenes
can cause febrile illness with gastroenteritis in immunocompetent persons.
PMID- 10781620
TI - Ceftriaxone-resistant salmonella infection acquired by a child from cattle.
AB - BACKGROUND: The emergence of resistance to antimicrobial agents within the
salmonellae is a worldwide problem that has been associated with the use of
antibiotics in livestock. Resistance to ceftriaxone and the fluoroquinolones,
which are used to treat invasive salmonella infections, is rare in the United
States. We analyzed the molecular characteristics of a ceftriaxone-resistant
strain of Salmonella enterica serotype typhimurium isolated from a 12-year-old
boy with fever, abdominal pain, and diarrhea. METHODS: We used pulsed-field gel
electrophoresis and analysis of plasmids and beta-lactamases to compare the
ceftriaxone-resistant S. enterica serotype typhimurium from the child with four
isolates of this strain obtained from cattle during a local outbreak of
salmonellosis. RESULTS: The ceftriaxone-resistant isolate from the child was
indistinguishable from one of the isolates from cattle, which was also resistant
to ceftriaxone. Both ceftriaxone-resistant isolates were resistant to 13
antimicrobial agents; all but one of the resistance determinants were on a
conjugative plasmid of 160 kb that encoded the functional group 1 beta-lactamase
CMY-2. Both ceftriaxone-resistant isolates were closely related to the three
other salmonella isolates obtained from cattle, all of which were susceptible to
ceftriaxone. CONCLUSIONS: This study provides additional evidence that antibiotic
resistant strains of salmonella in the United States evolve primarily in
livestock. Resistance to ceftriaxone, the drug of choice for invasive salmonella
disease, is a public health concern, especially with respect to children, since
fluoroquinolones, which can also be used to treat this disease, are not approved
for use in children.
PMID- 10781621
TI - Enteritis necroticans (pigbel) in a diabetic child.
AB - BACKGROUND AND METHODS: Enteritis necroticans (pigbel), an often fatal illness
characterized by hemorrhagic, inflammatory, or ischemic necrosis of the jejunum,
occurs in developing countries but is rare in developed countries, where its
occurrence is confined to adults with chronic illnesses. The causative organism
of enteritis necroticans is Clostridium perfringens type C, an anaerobic gram
positive bacillus. In December 1998, enteritis necroticans developed in a 12-year
old boy with poorly controlled diabetes mellitus after he consumed pig intestines
(chitterlings). He presented with hematemesis, abdominal distention, and severe
diabetic ketoacidosis with hypotension. At laparotomy, extensive jejunal necrosis
required bowel resection, jejunostomy, and ileostomy. Samples were obtained for
histopathological examination. Polymerase-chain-reaction (PCR) assay was
performed on paraffin-embedded bowel tissue with primers specific for the cpa and
cpb genes, which code for the alpha and beta toxins produced by C. perfringens.
RESULTS: Histologic examination of resected bowel tissue showed extensive mucosal
necrosis, the formation of pseudomembrane, pneumatosis, and areas of epithelial
regeneration that alternated with necrotic segments--findings consistent with a
diagnosis of enteritis necroticans. Gram's staining showed large gram-positive
bacilli whose features were consistent with those of clostridium species. Through
PCR amplification, we detected products of the cpa and cpb genes, which indicated
the presence of C. perfringens type C. Assay of ileal tissue obtained during
surgery to restore the continuity of the patient's bowel was negative for C.
perfringens. CONCLUSIONS: The preparation or consumption of chitterlings by
diabetic patients and other chronically ill persons can result in potentially
life-threatening infectious complications.
PMID- 10781622
TI - Images in clinical medicine. African trypanosomiasis in Australia.
PMID- 10781623
TI - Myelofibrosis with myeloid metaplasia.
PMID- 10781624
TI - Evaluation of abnormal liver-enzyme results in asymptomatic patients.
PMID- 10781625
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 13-2000. A 26-year-old woman with bouts of abdominal pain,
vomiting, and diarrhea.
PMID- 10781626
TI - Emerging infections--another warning.
PMID- 10781627
TI - Telomeres, telomerase, and cancer.
PMID- 10781629
TI - Correction: A Randomized Study of the Prevention of Sudden Death in Patients with
Coronary Artery Disease.
PMID- 10781630
TI - Pioneer research in Britain into atherosclerosis and coronary heart disease--an
historical review.
PMID- 10781631
TI - Relative roles of mitochondrial and peroxisomal fatty acid oxidation in the
metabolism of chylomicron remnants in rats and mice as assessed by a stable
isotope breath test.
AB - We have developed a stable isotope breath test to trace physiological remnant
metabolism. Validity of the test depends on the injected lipid emulsion mimicking
chylomicron remnant (CR) clearance and on subsequent metabolism of the emulsion
cholesteryl ester (CE). Oxidation of CE fatty acids could involve both
mitochondrial and peroxisomal pathways. In the present studies various agents
were used to inhibit the binding of remnants, CE hydrolysis or mitochondrial
fatty acid oxidation. Treatment of mice with suramin or lactoferrin markedly
delayed the clearance and metabolism of remnants as shown by the significantly
lower enrichment of 13CO(2) in the breath when compared with untreated mice. In
hepatectomized rats injected with remnant-like emulsions, enrichment with 13CO(2)
was virtually abolished. Treatment of mice with chloroquine or rats with methyl
palmoxirate (an inhibitor of mitochondrial fatty acid oxidation) markedly
impaired the recovery of label in the breath. Compared with mice fasted
overnight, Intralipid by gavage decreased the breath enrichment with 13CO(2)
consistent with competition between endogenous CR and the injected emulsion
particles. These findings show that the breath test reliably measures the
metabolism of CR and that CE fatty acid is metabolised by mitochondrial pathways.
PMID- 10781632
TI - CD143 in the development of atherosclerosis.
AB - The expression of CD143 (angiotensin-I-converting enzyme, ACE) in cardiovascular
diseases may be an important determinant of local angiotensin and kinin
concentrations. Much of the experimental and clinical evidence suggests a crucial
role for Ang II in fibrogenesis and the development of atherosclerosis.
Therefore, we have studied the distribution of CD143 in atherosclerotic and non
atherosclerotic segments isolated from different parts of the human vascular
tree, including aorta and coronary, carotid, brachial, renal, iliac and femoral
arteries, and staged according to the AHA. Two hundred and thirty native and
formalin-fixed specimens of 80 patients were analysed by sensitive APAAP
technique using ten different monoclonal and polyclonal antibodies to human CD143
and several controls. In non-atherosclerotic segments or intimal thickening,
CD143 was found almost restricted to the endothelial cells of adventitial
arterioles and small muscular arteries. In contrast, a striking accumulation of
CD143 was detected in all early and advanced atherosclerotic lesions. This de
novo occurrence of CD143 within the intimal vascular wall was caused by spindle
shaped subendothelial cells with macrophagic/histocytic features, activated
macrophages and foam cells. In addition, advanced lesions of atherosclerosis
showed a marked neo-expression of CD143 in newly formed intimal microvessels.
Hypocellular fibrotic plaques depleted in microvessels and macrophages showed
only little CD143. The de-novo occurrence of CD143 was dependent on the stage of
atherosclerosis but not on its particular localisation within the vascular
system. This early and obligatory CD143 expression at an unusual vascular site
may contribute to unusual tissue levels of angiotensins as indicated by co
localisation of immunoreactive Ang II. Thus, it may be an important pathogenetic
step in the development of atherosclerosis and an established target for
pharmacological prevention.
PMID- 10781633
TI - Expression of intercellular adhesion molecules in human saphenous veins: effects
of inflammatory cytokines and neointima formation in culture.
AB - Atherosclerosis causes occlusions in as many as 50% of human saphenous vein
coronary artery bypass grafts. Monocyte infiltration is an early step in
saphenous vein-graft atherosclerosis, however, comparatively little is known of
its underlying mechanisms. As a first approach, we sought to define the
occurrence, location and regulation of leukocyte adhesion molecules in human
saphenous vein before and after surgical preparation for grafting, during
neointima formation in culture and on stimulation with inflammatory cytokines. We
compared the distribution of intercellular adhesion molecule (ICAM-1), vascular
cell adhesion molecule (VCAM-1) and platelet endothelial cell adhesion molecule
(PECAM-1 or CD-31) in endothelial cells and smooth muscle cells (SMCs), using
immunocytochemistry. ICAM-1 was expressed on endothelial cells before culture and
on both endothelial cells and medial or neointimal SMCs after culturing vein for
14 days in 30% foetal bovine serum or after culturing for 24 h with TNF-alpha.
Relative tissue levels of ICAM-1 measured by Western blotting were significantly
elevated by culturing freshly-isolated (0.02+/-0.01 to 0.18+/-0.03) and
surgically-prepared (0.02+/-0.01 to 0.14+/-0.03; n=6) veins or following TNF
alpha treatment of surgically-prepared veins (0.04+/-0.01 to 0.32+/-0.11, n=7).
VCAM-1 was undetectable before or after culturing but was strongly upregulated on
endothelial cells by incubation with the cytokines TNF-alpha, IL-1alpha or
interferon-gamma. PECAM-1 was expressed constitutively on endothelial cells. We
conclude that human saphenous vein expresses several adhesion molecules capable
of mediating monocyte migration. The increased expression of ICAM-1 in SMC after
culturing or cytokine treatment and of VCAM-1 in endothelial cells suggests that
interactions with beta1 and beta2 integrins are important pathways for stimulated
monocyte ingress into human saphenous vein grafts.
PMID- 10781634
TI - Neural reorganisation in porcine vein grafts: a potential role for endothelin-1.
AB - Vein grafts are associated with adventitial remodelling which may influence
innervation of the graft. Since there is also evidence that endothelin-1 (ET-1)
plays a role in the adventitial remodelling process, we investigated neural
distribution in porcine vein grafts 1 and 6 months after implantation, as well as
the localisation of immunoreactive ET-1 and its receptors in the same tissues.
Saphenous vein-carotid artery interposition grafting was performed in Landrace
pigs. One and 6 months after surgery, vein grafts and ungrafted saphenous veins
were excised; neural tissue and ET-1 were identified by immunocytochemistry and
ET receptors were identified using in vitro autoradiography. In ungrafted
saphenous veins, abundant perivascular nerves were located in the outer region of
the media with only a few paravascular nerves in the adventitia. In vein grafts
at 1 month after implantation, there was almost complete depletion of
perivascular nerves in the media. In contrast, in the neoadventitia, there was an
emphatic appearance of large paravascular nerve bundles and a marked increase in
small paravascular nerves. These changes were more pronounced at 6 months after
surgery, although the principal changes had occurred within 1 month.
Immunoreactive ET-1 (index of ET-1 content) was associated with paravascular
nerve bundles, appearing as a dark, dense ring at the perineurium. Furthermore,
within the nerve bundles, positive ET-1 immunoreactivity was associated with
positive alpha-actin staining, indicating that ET-1 is associated with (neural)
microvessels. Also, dense 125I-labelled BQ3020 (ET(B)-selective) binding to nerve
bundles was observed, indicating the presence of ET(B) receptor subtypes. ET(A)
receptor subtypes were not detected in neural tissue. These data demonstrate
neural reorganisation in vein grafts and indicate that ET-1 content and binding
may play a role in this process. The functional consequences of these changes on
neointima formation, a major cause of vein graft failure, remain to be
determined.
PMID- 10781635
TI - New model of atherosclerosis in insulin resistant sand rats: hypercholesterolemia
combined with D2 vitamin.
AB - To overcome the sand rats' resistance to cholesterol induced atherosclerosis,
animals were given D2 vitamin at 2000 IU/rat per day associated with cholesterol
enriched diet for 45 days, following 45 days of high cholesterol diet alone. At
days 0, 45 and 90, plasma parameters, aortic and heart morphology were examined.
Other animals receiving a high cholesterol diet alone were used as a control
group. Results showed at day 45 severe hypercholesterolemia, elevated plasma LDL
and VLDL-cholesterol, oxidized LDL and calcium levels, a rise of lecithin
cholesterol acyl transferase activity and moderate hyperinsulinemia. Lesions were
characterized by widening of the first interlamellar spaces in the aorta,
fibrosis of coronary arterial wall and recent foci of myocardial fibrosis. At day
90, plasma calcium level decreased and oxidized LDL were more enhanced. Insulin
resistance development was associated with glucose intolerance and
hyperinsulinemia. The D2 vitamin administration induced advanced atherosclerotic
lesions in arterial wall, represented by the rupture of elastic lamellae, smooth
muscle cell proliferation and lipid-calcic core. The complicated plaque
frequently evolved into ulcerations. The ischaemic effects were represented by
acute myocardial infarction. D2 vitamin is an atherogenic agent which, when
associated with hypercholesterolemia, allows the development of advanced
atherosclerotic lesions in sand rat which resembles human plaque.
PMID- 10781636
TI - Interaction between human monocytes and vascular smooth muscle cells induces
vascular endothelial growth factor expression.
AB - The objective of this study was to investigate whether synthesis of vascular
endothelial growth factor (VEGF), a major mitogen for vascular endothelial cells,
was induced by a cell-to-cell interaction between monocytes and vascular smooth
muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cell) were
cocultured. VEGF levels in the coculture medium were determined by enzyme-linked
immunosorbent assay. Northern blot analysis of VEGF mRNA was performed using a
specific cDNA probe. Immunohistochemistry was performed to determine which types
of cell produce VEGF. Adding THP-1 cells to VSMCs for 24 h increased VEGF levels
of the culture media, 8- and 10-fold relative to those of THP-1 cells and VSMCs
alone, respectively. Northern blot analysis showed that VEGF mRNA expression was
induced in the cocultured cells and peaked after 12 h. Immunohistochemistry
disclosed that both types of cell in the coculture produced VEGF. Separate
coculture experiments revealed that both direct contact and a soluble factor(s)
contributed to VEGF production. Neutralizing anti-interleukin (IL)-6 antibody
inhibited VEGF production by the coculture of THP-1 cells and VSMCs. A cell-to
cell interaction between monocytes and VSMCs induced VEGF synthesis in both types
of cell. An IL-6 mediated mechanism is at least partially involved in VEGF
production by the cocultures. Local VEGF production induced by a monocyte-VSMC
interaction may play an important role in atherosclerosis and vascular
remodeling.
PMID- 10781637
TI - Accelerated atherosclerosis in C57Bl/6 mice transplanted with ApoE-deficient bone
marrow.
AB - Apolipoprotein E (apoE), a high affinity ligand for lipoprotein receptors, is
synthesized by the liver and extrahepatic tissues, including cells of the
monocyte/macrophage cell lineage. The role of monocyte/macrophage-derived apoE in
atherogenesis was assessed by transplantation of apoE-deficient (apoE-/-) bone
marrow into normolipidemic C57Bl/6 mice. No significant effect could be
demonstrated on serum apoE levels in C57Bl/6 mice, transplanted with apoE
deficient bone marrow compared with control transplanted mice. Furthermore, no
consistent effect on serum cholesteryl esters and triglyceride concentrations
could be demonstrated on either a standard chow diet or a high cholesterol diet.
Quantitative analysis of atherosclerosis in mice transplanted with apoE-deficient
bone marrow, after two months on a high cholesterol diet, revealed a 4-fold
increase in the atherosclerotic lesion area as compared to animals transplanted
with apoE+/+ bone marrow. Analysis of the ability of apoE-deficient macrophages
to release cholesterol after loading with acetylated LDL revealed that the
release of cholesterol from apoE-deficient macrophages was impaired as compared
to wild-type macrophages in the absence and the presence of specific cholesterol
acceptors. In conclusion, apoE production by macrophages retards the formation of
atherosclerotic plaques, possibly by mediating cholesterol efflux. We anticipate
that pharmacological approaches to increase apoE synthesis and/or secretion by
macrophages might be beneficial for the treatment of atherosclerosis.
PMID- 10781638
TI - Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits.
AB - BACKGROUND: Hypercholesterolemia predisposes to coronary artery disease and
causes endothelial dysfunction; some reports suggest that endothelial derived
substances are involved in ischemic preconditioning. OBJECTIVE: Our aim was to
examine the possibility that preconditioning maybe attenuated in a clinically
relevant animal model of hypercholesterolemia with atherosclerosis. METHODS: Male
rabbits were fed with cholesterol enriched diet and then divided into two groups
(A and B) without and with preconditioning, respectively. A second series of
rabbits fed a normal diet were similarly divided into two groups (C and D)
without and with preconditioning, respectively. All the animals were subjected to
30 min ischemia and 180 min reperfusion. Blood samples were collected for
cholesterol assessment; arterial and heart samples were harvested at the end for
histopathological examination. Infarct (I) and risk areas (R) were delineated
with Zn-Cd particles and TTC staining. RESULTS: Cholesterol in groups A and B was
58.3+/-8.7 mg% at baseline and 1402+/-125 mg% at 8 weeks (P<0.0001) and in groups
C and D 57.5+/-5.8 mg% before the surgical procedure. I/R% was 39. 3+/-6.3% in
group A, 16.7+/-3.9% in B (P<0.01), 41.4+/-7.5% in C and 10.8+/-3.3% in D
(P<0.01). CONCLUSION: We conclude that preconditioning is unlikely to be
attenuated by hypercholesterolemia.
PMID- 10781639
TI - Macrophage-released proteoglycans enhance LDL aggregation: studies in aorta from
apolipoprotein E-deficient mice.
AB - Aggregated low-density lipoprotein (LDL) was shown to be present in the
atherosclerotic lesion, but the mechanism responsible for its formation in vivo
is not known yet. To find out whether LDL aggregation occurs in the arterial wall
during atherogenesis, LDLs were extracted from the aortas of apolipoprotein E
deficient (E(0)) mice during their aging (and the development of
atherosclerosis), and were analyzed for their aggregation states, in comparison
to LDLs isolated from aortas of control mice. LDL isolated from aortas of E(0)
mice was already aggregated at 1 month of age and its aggregation state
substantially increased with age, with 3-fold elevation at 6 months of age
compared to younger, 1-month-old, mice. Only minimal aggregation could be
detected in LDL derived from control mice. Electron microscopy examination
revealed that LDL particles from aortas of the E(0) mice were heterogeneous in
their size, ranging between 20 and 300 nm. The mouse aortic LDL contained
proteoglycans (PGs) and their content increased with the age of the mice, with
about 2-fold higher levels than those found in LDLs derived from aortas of
control mice. Macrophage-released PGs were previously demonstrated to enhance LDL
aggregation in vitro. However, their involvement in LDL aggregation in vivo has
not been studied yet. Thus, we next studied the effect of arterial macrophage
released PGs on the susceptibility of plasma LDL to aggregation by Bacillus
cereus sphingomyelinase (SMase). Foam cell macrophages were isolated from aortas
of the atherosclerotic E(0) mice at 6 months of age and were found to be loaded
with cholesterol and to contain oxidized lipids. To analyze the effect of
macrophage-released PGs on LDL aggregation, PGs were prelabeled by cell
incubation with [35S]sulfate, followed by incubation of macrophage-released PGs
with E(0) mouse plasma LDL (200 microg protein/ml) for 1 h at 37 degrees C.
[35S]Sulfated PGs were found to be LDL-associated and the susceptibility of PG
associated LDL to aggregation by SMase was increased by up to 45% in comparison
to control LDL. Similar results demonstrating the involvement of PGs in LDL
aggregation were obtained upon incubation of LDL with increasing concentrations
of PGs that were isolated from the entire aorta of E(o) mice (rather than the
isolated macrophages). The stimulatory effect of macrophage-released PGs on LDL
aggregation was markedly reduced when the PGs were pretreated with the
glycosaminoglycan-hydrolyzing enzymes, chondroitinase ABC or chondroitinase AC,
and to a much lesser extent with heparinase. We thus conclude that macrophage
released chondroitin sulfate PG can contribute to the formation of atherogenic
aggregated LDL in the arterial wall.
PMID- 10781640
TI - Effects of combination therapy with estrogen plus simvastatin on lipoprotein
metabolism in postmenopausal women with type IIa hypercholesterolemia.
AB - We investigated the effects of estrogen and simvastatin, administered both alone
and in combination, on the plasma lipid levels and lipoprotein-related enzymes in
45 postmenopausal women with type IIa hypercholesterolemia. They received 0.625
mg conjugated equine estrogen (n=15), 5 mg simvastatin (n=15), or the combination
(n=15) daily for 3 months. We measured the concentrations of cholesterol and
triglyceride in the plasma, and in the very low-density lipoprotein (VLDL),
intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)1
(1.019T (m allele)
mutation in the plasma PAF-AH gene, which results in a Val(279)-->Phe
substitution in the mature protein, leads to a loss of catalytic activity. To
elucidate the relationships among PAF-AH enzyme activity, genotype, age, and
atherosclerosis, we assayed these parameters in a large Japanese population
(n=3932) that consisted of three groups; a control group (healthy individuals;
n=1684), a risk-factor group (individuals having at least one conventional risk
factor for atherosclerosis; n=1398), and a diseased group (patients who had
suffered a myocardial infarction or stroke; n=850). We observed a significantly
increased frequency of the m allele in the diseased group as compared with the
control or risk-factor groups. Plasma PAF-AH activity increased significantly
with age in women in the control group with the MM and Mm genotypes, and in men
in the control group with the MM genotype, but not in men with the Mm genotype.
In both the risk-factor and diseased groups, however, no correlation was observed
between plasma PAF-AH activity and age in subjects with either genotype. These
results suggest that in individuals with the MM genotype, plasma PAF-AH activity
may be increased in response to stresses induced by PAF and/or oxidized
phospholipids that might accumulate with age, but that this response is not
evident or reduced in healthy individuals with the m allele, or in subjects with
atherosclerotic disease, or having risk factors. Together with our previous
findings, the G(994)-->T mutation in the PAF-AH gene may be one of the genetic
determinants for atherosclerotic disease in the Japanese population.
PMID- 10781654
TI - Alpha-tocopherol supplementation decreases the oxidative susceptibility of LDL in
renal failure patients on dialysis therapy.
AB - Atherosclerotic cardiovascular disease is the leading cause of death in patients
with end stage renal disease (ESRD) who have undergone dialysis treatment. The
oxidation of low density lipoprotein (LDL) appears to be a crucial step in the
pathogenesis of atherosclerosis. The increased oxidative stress and attendant
increased oxidizability of lipoproteins, such as LDL could contribute to the
accelerated atherosclerosis in dialysis patients. Since alpha-tocopherol (AT) is
the major antioxidant in LDL, the aim of the present study was to test the
effectiveness of RRR-AT supplementation (800 I.U. per day) for 12 weeks on the
susceptibility of LDL to oxidation. The study subjects comprised patients with
chronic renal failure on hemodialysis (HD), peritoneal dialysis (PD), and age and
sex matched controls (C). Plasma fatty acids, lipoproteins and AT levels were
measured in these subjects before and after supplementation. Also, LDL AT and
oxidizability was studied. LDL was isolated by ultracentrifugation at baseline
and after 12 weeks of supplementation, and subjected to a 5-h time course of
copper catalyzed oxidation. Oxidation was measured by the formation of conjugated
dienes (CD) and lipid peroxides (LP). Supplementation with AT did not alter the
plasma lipid or lipoprotein profile of these subjects. Plasma lipid-standardized
AT and LDL AT concentrations were not different among the groups at baseline. AT
supplementation significantly increased plasma lipid-standardized AT (C=150%,
HD=149%, PD=217%, P<0.001) and LDL AT concentrations (C=94%, HD=94%, PD=135%,
P<0.003). AT enrichment of LDL resulted in a significant prolongation in
conjugated diene lag phase in all groups (C=34%, HD=21%, PD=54%, P<0.02). Lipid
peroxide lag phase was also increased significantly in C (27%,) and PD (40%)
groups after AT supplementation (P<0.01). There was a significant positive
correlation between plasma lipid standardized AT and lag phase (r=0. 54,
P=0.0003). Overall, AT decreased the susceptibility of LDL to oxidation in
patients with chronic renal failure but the benefit appears to be greater in
patients on PD. Therefore, AT supplementation may also provide a measure of
protection against CAD in patients with chronic renal failure on dialysis
therapy.
PMID- 10781655
TI - What pathological components indicate carotid atheroma activity and can these be
identified reliably using ultrasound?
AB - OBJECTIVE: The aim of this project was to determine whether histological features
of 'active' plaque as described in the coronary circulation following acute
myocardial infarction were similar in the carotid circulation, and whether these
factors could be detected ultrasonically. METHOD: Endarterectomy specimens were
prospectively collected, and examined histologically and assessed by two
observers for ulceration, inflammation, size of necrotic core, thickness of
fibrous cap, haemorrhage and luminal thrombosis. Ultrasound of the plaque
obtained preoperatively was similarly coded (blind to pathology) and compared
with the pathology. RESULTS: In 42 endarterectomy specimens, there was a highly
significant relationship between a thin fibrous cap and a large necrotic core
(P<0.002), irregular plaque contour (P<0.05) and ulceration (P<0.01) and between
a large necrotic core (P<0.002) and ulceration and inflammation (P<0.05).
Increasing amounts of necrosis were associated with more surface thrombosis
(P<0.02). Ultrasound detected the thickness of the fibrous cap and 'any necrosis
or haemorrhage' with some reliability (kappas are 0.53 and 0.5, respectively),
but not ulceration, necrosis or haemorrhage on their own. CONCLUSION: Features
corresponding to active atheromatous plaque are similar in the carotid and
coronary arteries, and some of these, namely lucent areas in the plaque
(corresponding to necrosis or haemorrhage) and the thickness of the fibrous cap,
can be determined reliably with ultrasound.
PMID- 10781656
TI - Doppler monitoring of the vascular resistance in the lower limbs during
dipyridamole test in preparation for myocardial tomoscintigraphy.
AB - OBJECTIVE: the aim of this work was to quantify the intensity of the vasodilation
induced by dipyridamole used to simulate a stress test during a myocardial
tomoscintigraphy. METHODS: Doppler measurements of the femoral artery and the
thoracic aorta were made on 26 patients (11 men, 15 women), using transducers
attached to the skin, measurements being performed every 2 min during the 10 min
of the stress test. The following parameters were measured: (a) the vascular
resistance index of the lower limbs defined as R(fa)=D/S with S and D,
respectively, the maximum amplitude of the systolic wave and the maximum
amplitude of the diastolic reflux measured on the Doppler femoral spectrogram;
(b) the aortic and femoral blood flows obtained from the mean velocity on the
Doppler spectrogram. RESULTS: 14 of the 26 patients (54%) showed a significant
vasodilation (i.e. a decrease of R(fa) of more than 10%). Eighty-seven percent of
the patients with a positive myocardial scintigraphy showed a vasodilation. Sixty
six percent of patients who had prior vasodilator treatment showed no
vasodilation. A slight decrease in blood pressure was observed for vasodilated
patients but also for non-vasodilated patients. The aortic flow increased
slightly for all patients. CONCLUSIONS: Doppler monitoring of femoral vascular
resistance is a useful method for quantifying the dipyridamole-induced
vasodilation, and hence the stress level upon which the diagnostic efficiency of
myocardial scintigraphy is depending. Our study demonstrates that testing with
dipyridamole was inconclusive in 66% of patients who had already vasodilator
treatment.
PMID- 10781657
TI - Improved characterisation of focal liver tumours: dynamic power Doppler imaging
using NC100100 echo-enhancer.
AB - OBJECTIVE: To assess the vascularisation of focal hepatic tumours using NC100100,
enhanced power Doppler imaging. METHODS: Twenty-two patients with focal liver
tumours (12 metastases and ten hemangiomas) were studied. Using standardised
settings, power Doppler imaging with ATL HDI3000 was performed before and after
intravenous administration of NC100100 contrast agent. The video-recorded
examinations were digitised for off-line analysis on a personal computer. Regions
of interest were defined over the entire tumour and a neighbouring area of the
normal liver parenchyma. The temporal changes of the mean power Doppler signal
intensity (PDSI) was quantified to provide contrast agent wash-in (PDSI-time)
curves for the initial 40 s. RESULTS: Liver metastases were characterised by a
rapid increase in PDSI, while the PDSI-time curves within hemangiomas were flat.
The PDSI within the tumour increased significantly in ten subjects with liver
metastases and only one subject with hemangioma. An enhanced rim around
hemangiomas was seen in four subjects. There was no clear relationship between
the contrast agent dose and the peak PDSI within metastases. CONCLUSIONS: Power
Doppler imaging with NC100100 contrast agent enhances tumour visualisation and
may aid differential diagnosis of focal liver lesions.
PMID- 10781658
TI - Evaluation of left ventricular systolic function by 3D echocardiography: a
comparative study with X-ray angiography and radionuclide angiography.
AB - OBJECTIVE: the aim of this study was to evaluate left ventricular systolic
function by 3D ultrasound as compared to with radionuclide and X-ray
angiographies. METHODS: one hundred and four patients were examinated by 3D
ultrasound (3D-US) but only 72 examinations were successful. Thirty patients were
investigated by 3D-US, M-mode US or bidimensional (2D) US, and X-ray angiography
(group I) and 42 patients were investigated by 3D-US, M-mode, or 2D, and
radionuclide angiography (group II). RESULTS: the correlation between ejection
fraction (EF) evaluated by 3D-US and reference methods was found to be good and
similar for the two groups (r=0.75; P<10(-4) for group I and r=0.76; P<10(-4) for
group II). The correlation between EF calculated by conventional 2D-US and by
reference methods was lower (r=0.60; P=0.04 for group I and r=0.54; P=0.001 for
group II). The correlation between EF evaluated by 3D- and 2D-US was modest (r=0.
55; P=0.001 for the whole group). The correlation between 3D-US left ventricle
end-diastolic volume (EDV) and end-systolic volume (ESV) and those evaluated by X
ray angiography was also modest (r=0.33; NS for EDV and r=0.60; P<10(-4) for
ESV). The correlations between EDV and ESV in 3D-US, and those evaluated from
radionuclide angiography were fairly good and in the same range (r=0.76; P<10(-4)
and r=0.87; P<10(-4)). CONCLUSION: the 3D-US system using a rotating probe in an
apical view is valuable for evaluation of left ventricular systolic function.
PMID- 10781659
TI - Power Doppler sonography in the diagnosis of Graves' disease.
AB - In addition to color and pulsed Doppler sonography findings, we aimed to describe
power Doppler sonography findings in Graves' disease in this study. Twenty-three
patients with Graves' disease were imaged with gray-scale, color and power
Doppler sonography. Twenty normal volunteers were examined by the same equipment
and the same technique as a control group. A subjective grading system was used
to categorize the vascularization in pulsed Doppler sonography images from normal
to markedly increased vascularization. Power Doppler sonography exhibited diffuse
hypervascularity in the thyroid gland in all patients. The flow was covering
about all the parenchyma. Four patients showed mild, 12 patients moderate and
seven patients marked vascularity. The intensity of power Doppler flow pattern
was not correlated with the severity of the disease. This study demonstrated that
power Doppler sonography is a convenient, time saving, inexpensive and
noninvasive method as compared with isotope scan and some other laboratory tests
for confirmation of Graves' disease.
PMID- 10781660
TI - Ultrasonography of Zenker's diverticulum: special reference to differential
diagnosis from thyroid nodules.
AB - There have been only two case reports so far in literature on ultrasonographic
features of Zenker's diverticulum. We report a case of Zenker's diverticulum and
discuss the ultrasonographic images in comparison with those of thyroid nodules.
Awareness of changeable internal echoes and not mistaking strong echogenic foci
caused by air for calcification were most important for making the differential
diagnosis of Zenker's diverticulum from thyroid nodules.
PMID- 10781661
TI - Comparison of the efficacy of two air-based contrast agents in dogs.
AB - OBJECTIVE: The aim of this study was to evaluate the differences of the in vivo
efficacies of Levovist(SH U 508 A) and Albunex, air-based contrast agents (CAs)
with different shell materials, by direct comparison. METHODS: SH U 508 A, 300
mg/ml, and Albunex were injected intravenously at doses of 0.1 and 0.15 ml/kg,
respectively, into the same dogs (n=6). Contrast enhancement in the left
ventricle was evaluated visually and by off-line measurement of brightness.
RESULTS: Both CAs yielded good peak contrast, while the duration of contrast
enhancement with SH U 508 A was seven times that with Albunex. With Albunex,
reduction of contrast enhancement at end-systole and in the late phase of
diastole during one heartbeat was observed, and a positive correlation was
observed between contrast enhancement and heart rate. Contrast enhancement was
nearly constant during one heartbeat with SH U 508 A. CONCLUSION: SH U 508 A
yielded consistent and longer contrast enhancement in the left ventricle than
Albunex under the same conditions.
PMID- 10781662
TI - The three-dimensional ultrasound evaluation of the rotator cuff--an experimental
study.
AB - OBJECTIVE: An accurate sonographic diagnosis of rotator cuff lesions
significantly depends on image quality and on the experience of the operator. The
present study was performed to determine whether the use of three dimensional
(3D) sonography further increases the diagnostic yield of ultrasound. METHODS: In
an experimental study 22 artificial rotator cuff lesions (seven full thickness
and 15 partial thickness tears) of cadaveric shoulder joints were evaluated by
ultrasound with two and three dimensional imaging in a water basin. RESULTS: With
3D ultrasound, rotator cuff lesions were more often correctly diagnosed
(sensitivity of 77%) than with conventional 2D sonography (sensitivity of 64%).
Specificity was 85 and 69%, respectively. In partial thickness tears in
particular, 3D imaging was the superior method reaching a sensitivity and
specificity of 73 and 77%, respectively, compared to 53 and 61%, respectively,
with 2D ultrasound. With 2D and 3D ultrasound eight and 11 out of 13 tendons,
respectively, were correctly diagnosed as intact confirmed by histopathological
examination. CONCLUSION: Although the results of an experimental study may not
reflect the clinical situation, 3D ultrasound appears to facilitate diagnosis of
partial thickness rotator cuff tears.
PMID- 10781663
TI - Ultrasonic parameters and relationship between compressive strength,
microstructure of gall bladder stones.
AB - Patients with symptomatic stones are at a great risk for complications and these
complications are a major cause of morbidity. The gall bladder stones may have a
complex structure and variable composition. In the present investigation stones
have been grouped into three categories namely cholesterol, bilirubinate and
mixed, and a correlation between the surface structure, ultrasonic parameters and
compressive strength is estimated. A double-probe through-transmission technique
was used for the ultrasonic parameters study, a universal testing instrument for
hardness and a scanning electron microscope (SEM) for microstructure study. Gall
bladder stones of mixed type with higher ultrasonic velocity, less attenuation
and higher crushing strength were found to be more difficult to break in
comparison to other types of stones. SEM of mixed type stones showed rough
surface as compared to bilirubinate and cholesterol stones. The results obtained
as well as the relationship might be useful in the design of a focussed
ultrasonic 0lithotripter.
PMID- 10781665
TI - EFSUMB reviews of recent safety literature. European committee for medical
ultrasound safety (ECMUS)
PMID- 10781664
TI - Hand gripping effect on cerebral blood flow in normal subjects.
AB - The changes of regional cerebral blood flow (rCBF) related to metabolic demand
depend on both integrity of neuronal function and vascular blood flow. Therefore,
we assessed the motor stimulus to blood flow velocity (BFv) changes of bilateral
middle cerebral arteries (MCA) by transcranial Doppler (TCD) sonography in normal
subjects. Eighteen subjects (nine female, aged 48.0+/-3.8 years; nine male, aged
54.4+/-4.8 years) were investigated. Bilateral TCD sonography from both MCA were
monitored during ten cycles of 20 s when subjects were performing bilateral hand
gripping with a frequency of one per second, and subsequently 20 s when they were
rest. Bilateral hand gripping showed a significant BFv increase on both MCA
(P<0.001). These values were (19+/-2)% on both sides. There was no significant
side to side difference between the absolute BFv values both at rest and during
bilateral hand gripping. Additionally, the absolute BFvs and BFv increases were
not significantly different between male and female subjects. This study was
based on a small sample size, and the method requires the subject cooperation.
Our results suggest that bilateral hand gripping may affect blood flow in both
MCA without side to side differences. Finally, our suggestion is that test might
be useful to assess the neurovascular integrity.
PMID- 10781666
TI - Changes in rat brain energetic metabolism after exposure to anandamide or
Delta(9)-tetrahydrocannabinol.
AB - The objective of this study was to investigate whether single and repeated
administration of the cannabinoids anandamide or Delta(9)-tetrahydrocannabinol
affected brain energetic metabolism. Single administration of either anandamide
(20 mg/kg) or Delta(9)-tetrahydrocannabinol (10 mg/kg) in rats induced a
behaviour typical with cannabinoids. An increase in both brain mitochondria
oxidative phosphorylation and cerebral lipoperoxidation was shown ex vivo. The
cannabinoid CB(1) receptor-specific antagonist, N-piperidino-5-(4-chlorophenyl)-1
(2, 4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A; 3 mg/kg),
reversed the anandamide-induced metabolic effects. Prolonged exposure to
anandamide (20 mg/kg, 16 days) induced behavioural tolerance and the
disappearance of the increased mitochondria oxygen uptake and lipoperoxidation.
Repeated Delta(9)-tetrahydrocannabinol injection (10 mg/kg, twice daily, 4.5
days) reduced brain metabolism and uncoupled respiration from oxidative
phosphorylation. The present findings showed that both anandamide and Delta(9)
tetrahydrocannabinol enhanced the energetic brain metabolism, probably via the
cannabinoid CB(1) receptor; the anandamide-tolerant brain of rats showed
tolerance to the drug for metabolic effects, while the brain of Delta(9)
tetrahydrocannabinol-tolerant rats showed metabolic signs of neuronal damage,
i.e. low energy production.
PMID- 10781667
TI - Evidence for the participation of the nitric oxide-cyclic GMP pathway in the
antinociceptive action of meloxicam in the formalin test.
AB - The involvement of the nitric oxide-cyclic GMP pathway in the antinociceptive
action of the cyclooxygenase-2 preferential inhibitor meloxicam was assessed in
the rat formalin test. Rats received local pretreatment with saline or meloxicam
and then 50 microl of dilute formalin (1%). Local administration of meloxicam
produced a dose-dependent antinociception in the second phase of the formalin
test. The antinociception produced by meloxicam was due to a local action as its
administration in the contralateral paw was ineffective. Local pretreatment of
the paws with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not
affect the antinociception produced by meloxicam. However, N(G)-L-nitro-arginine
methyl ester (L-NAME, a NO synthesis inhibitor) or 1H-(1,2,4)-oxadiazolo(4,2
a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) blocked in a dose
dependent way the effect of meloxicam. It is concluded that the peripheral
antinociceptive effect of meloxicam involves a local NO-cyclic GMP pathway.
PMID- 10781668
TI - Melatonin reversal of lipopolysacharides-induced thermal and behavioral
hyperalgesia in mice.
AB - The perception of pain sensation (threshold), whether local or central, is
altered by inflammatory processes. Anti-inflammatory drugs block this by raising
the pain threshold and by reducing the inflammatory process. Melatonin is claimed
to have anti-inflammatory activity in animal models of acute and chronic
inflammation. However, it is not known whether melatonin can reverse the
hyperalgesia that is secondary to the inflammation. The present study aimed to
assess the modulatory effect of melatonin on lipopolysaccharides-induced
alteration of pain perception in mice. Central perception of pain was assessed
with the tail-flick and hot-plate methods and local hyperalgesia was assessed by
noting the animal's reactions such as paw licking and rearing after the
intraplantar injection of lipopolysaccharides (5 microg/paw). Local
administration (intraplantar) of lipopolysacharides induced hyperalgesia when
measured by both central effects and behavioral reactions. Melatonin (5 and 10
mg/kg), like dexamethasone (0.5 mg/kg), given 30 min prior to, and 4 and 8 h
after lipopolysaccharides (5 microg/paw) challenge attenuated central and
behavioural hyperalgesia. The attenuation of lipopolysaccharides-induced
hyperalgesia by melatonin was not reversed by naltrexone (4 mg/kg). In vitro
studies showed that melatonin, in concentrations ranging from 100 to 1000 nM,
suppressed tumor necrosis factor-alpha (TNF-alpha) without affecting the nitric
oxide (NO) release in lipopolysaccharides-activated murine peritoneal
macrophages. Taken together, the present results demonstrated that melatonin
reverses lipopolysaccharides-induced hyperalgesia.
PMID- 10781669
TI - Effect of acute treatment with YM992 on extracellular serotonin levels in the rat
frontal cortex.
AB - (S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine monohydrochloride (YM992) is a
novel putative antidepressant exhibiting both selective serotonin (5
hydroxytryptamine, 5-HT) reuptake inhibition and 5-HT(2A) receptor antagonism. In
vivo microdialysis revealed that a single treatment with YM992 (3, 10, 30 mg/kg
i.p.) dose-dependently increased extracellular 5-HT levels in the rat frontal
cortex. Fluoxetine, citalopram and venlafaxine also produced significant
increases in 5-HT levels at doses of 10-30 mg/kg. However, the increase in 5-HT
levels induced by YM992 was significantly larger than increases elicited by these
three compounds at 30 mg/kg. The combined administration of R-(+)-alpha-(2, 3
dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol (MDL100,907)
(a selective 5-HT(2A) receptor antagonist) and citalopram produced no additional
increase in 5-HT levels compared with citalopram treatment alone. YM992
moderately enhanced [3H]5-HT release from rat cerebral cortex synaptosomes using
different mechanisms than p-chloroamphetamine. In comparison, 10-microM
fluoxetine markedly induced 5-HT release in vitro, while citalopram and
venlafaxine had no noticeable effect on release. YM992 produces a more robust
increase of 5-HT levels acutely than other antidepressants in vivo and the effect
may be due to 5-HT releasing properties of the drug.
PMID- 10781670
TI - Effect of acute treatment with YM992 on extracellular norepinephrine levels in
the rat frontal cortex.
AB - The effects of acute treatment with (S)-2-[[(7-fluoroindan-4
yl)oxy]methyl]morpholine monohydrochloride (YM992), venlafaxine, fluoxetine and
citalopram on extracellular norepinephrine levels were examined in the rat
frontal cortex by in vivo microdialysis. YM992 (3, 10, 30 mg/kg, i.p.) dose
dependently increased extracellular norepinephrine levels (3-fold at 10 mg/kg, 5.
5-fold at 30 mg/kg). While venlafaxine and 30 mg/kg fluoxetine also produced
significant increases in norepinephrine levels, 30 mg/kg citalopram had no
effect. The combined administration of MDL100,907 (a selective 5-HT(2A) receptor
antagonist) and citalopram did significantly increase norepinephrine levels
compared with either saline or citalopram treatment. Therefore, a synergistic
effect due to 5-HT reuptake inhibition and 5-HT(2A) receptor antagonism of YM992
may partly contribute to the increase of extracellular norepinephrine levels.
YM992 enhances the neurotransmission of not only 5-HT system but also
norepinephrine, and as such may have a preclinical profile different from that of
a selective serotonin reuptake inhibitor.
PMID- 10781671
TI - Effects of MK-801 on clozapine-induced potentiation of excitatory synaptic
responses in the perforant path-dentate gyrus pathway in chronically prepared
rabbits.
AB - We previously found that the atypical antipsychotic drug, clozapine, when
intraperitoneally (i.p.) injected, long-lastingly potentiated excitatory synaptic
responses elicited in the dentate gyrus by single electrical stimulations to the
perforant path in chronically prepared rabbits, and called this phenomenon
'clozapine-induced potentiation'. In the present study, we likewise examined
whether clozapine-induced potentiation is caused by NMDA receptor-mediated
neurotransmission in the perforant path-dentate gyrus pathway of chronically
prepared rabbits. The non-competitive NMDA receptor antagonist - 5-methyl-10,11
dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imino hydrogen maleate (MK-801; 1.0
mg/kg, i.p.) - completely prevented the potentiation of synaptic responses
induced by subsequent administration of 20 mg/kg clozapine, whereas the 0.5 mg/kg
dose had virtually no effect on the potentiation. These results suggest that the
effect of clozapine requires NMDA receptor activation.
PMID- 10781672
TI - Ventral subiculum administration of the somatostatin receptor agonist MK-678
increases dopamine levels in the nucleus accumbens.
AB - Somatostatin (or somatotropin-release inhibitory factor, SRIF) binding and in
situ hybridisation studies have indicated a high expression of receptor subtypes
throughout the rat brain and, in particular, in subregions of the hippocampus and
subiculum. In vitro, somatostatin and related peptides, including seglitide (MK
678), hyperpolarize subicular neurones of the burst firing type-a response, which
may have functional consequences for their output. One major projection from the
subiculum is to the nucleus accumbens. The functional consequence of somatostatin
receptor stimulation in the ventral subiculum has been assessed by measuring
extracellular levels of dopamine in the ipsilateral nucleus accumbens. In
anaesthetised rats, administration of seglitide (MK-678), a somatostatin analogue
with selectivity for the SRIF-1 receptor (comprising somatostatin sst2, sst3 and
sst5 subtypes) significantly increased extracellular levels of dopamine in the
ipsilateral nucleus accumbens shell. The result suggests that hyperpolarization
of subicular neurones by MK-678 may lead to activation of the subiculo-accumbens
projection system, and an associated increase in dopaminergic function.
PMID- 10781673
TI - Involvement of mast cells, sensory afferents and sympathetic mechanisms in paw
oedema induced by adenosine A(1) and A(2B/3) receptor agonists.
AB - Both the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine and the
adenosine A(2B/3) receptor agonist N(6)-benzyl-5'-N-ethylcarboxamido adenosine
(N(6)-B-NECA) produce an acute paw oedema response following local s.c. injection
into the rat hindpaw. This study characterized aspects of the mechanisms by which
these responses occur by determining the effect of compound 48/80 (mast cell
depleting agent), capsaicin (sensory neurotoxin) and 6-hydroxydopamine
(sympathetic nervous system neurotoxin) on the paw oedema response produced by
these agents. Compound 48/80 markedly reduced the increase in paw volume produced
by both N(6)-cyclopentyladenosine and N(6)-B-NECA. Capsaicin significantly
reduced paw oedema induced by N(6)-cyclopentyladenosine but not N(6)-B-NECA. In
contrast, 6-hydroxydopamine reduced paw oedema induced by N(6)-B-NECA but not
N(6)-cyclopentyladenosine. These results indicate an involvement of mast cells in
paw oedema produced by both adenosine A(1) and A(2B/3) receptor agonists. For
N(6)-cyclopentyladenosine, this involvement may be a secondary involvement due to
activation of a neurogenic mechanism, but for N(6)-B-NECA, it may be a direct
effect on mast cells. The nature of the involvement of the sympathetic nervous
system in the action of N(6)-B-NECA is not entirely clear.
PMID- 10781674
TI - Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in
models of venous and arteriovenous thrombosis.
AB - Thrombin plays a central role in venous and arterial thrombosis. We utilized two
different rabbit models of in vivo thrombosis to investigate the effect of
inhibitors of thrombin generation and thrombin activity. The agents tested were
specific inhibitors of factor Xa (fXa) [N2-[(phenylmethyl)sulfonyl]-D-arginyl-N
[(1S)-4-[(aminoiminomethyl++ +)a mino]-1-(2-thiazolylcarbonyl)butyl]-glycinamide
(C921-78)] and thrombin [D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1
(chloroacetyl)but yl]-L-prolinamide (PPACK)], as well as drugs that affect both
thrombin and fXa, unfractionated and low molecular weight (enoxaparin) heparin.
The agents administered as constant intravenous infusion were evaluated for
antithrombotic efficacy in anesthetized rabbits. All four agents were capable of
dose dependent inhibition of thrombosis in venous and arteriovenous thrombosis
models. However, due to the more aggressive nature of thrombotic stimulation in
the arteriovenous shunt model, complete cessation of thrombus growth was not
achieved for any of the agents at the doses tested. Comparison between the agents
focused on the differences in extension of coagulation parameters (activated
partial thromboplastin time, prothrombin time, thrombin clotting time), changes
in hematological parameters, and extension of rabbit cuticle bleeding time at
doses required to produce maximum inhibition in the thrombosis models. In the
venous thrombosis model at the maximally effective dose, C921-78 had minimal
extension of ex vivo clotting parameters, while enoxaparin and unfractionated
heparin demonstrated a two to sevenfold increase in activated partial
thromboplastin times, and PPACK had a threefold extension of thrombin clotting
times. In addition, unlike the other three agents, which exhibited no significant
changes in hematological parameters, PPACK demonstrated dose dependent
thrombocytopenia. A standardized cuticle bleeding time was used as a measure of
perturbation of hemostasis. The agents were evaluated for significant increases
in bleeding time at doses up to eight times that needed to completely inhibit
venous thrombus formation. Unfractionated heparin displayed a significant
bleeding time effect at the dose required to inhibit venous thrombosis (100
u/kg+2 u/kg/min). Enoxaparin and PPACK caused significant bleeding time
extensions at four times the fully efficacious venous dose (800 u/kg+8 u/kg/min
and 30 microg/kg/min). By contrast, C921-78 did not significantly increase
bleeding time even at eight times the maximally effective dose (240 microg/kg+7.2
microg/kg/min). Our results demonstrate that specific inhibition of fXa can be
utilized to derive potent antithrombotic activity without disrupting
extravascular hemostasis.
PMID- 10781675
TI - Neurogenic vasodilation in rabbit basilar isolated artery: involvement of
calcitonin-gene related peptide.
AB - Neurogenic vasodilation in cranial arteries may be an important mechanism in the
pathogenesis of migraine headache. We describe a novel, in vitro assay to
characterise neurogenic vasodilator responses in endothelium-denuded segments of
rabbit isolated basilar artery, with particular focus on calcitonin-gene related
peptide (CGRP). In arterial segments precontracted with prostaglandin F(2alpha),
relaxations evoked by exogenously applied alphaCGRP (EC(50)=2.9 nM) were
inhibited by alphaCGRP-(8-37) (pA(2)=6.49) or by desensitisation resulting from
prior exposure to alphaCGRP. Relaxations evoked by exogenously applied vasoactive
intestinal polypeptide (VIP) (EC(50)=2.5 nM) were inhibited by VIP-(7-28) 1
microM. The 5-HT(1) receptor agonists L-771,331 ((3S)-3[N-(S)-alpha
methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1, 3-oxazolidin-4-ylmethyl)-1H-indol
3-yl)ethyl]pyrrolidine) and sumatriptan exerted contractile effects (EC(50)=293
and 95 nM, respectively). In neurogenic experiments, vasodilation evoked by
electrical field stimulation was markedly attenuated by pre-treatment with
capsaicin (10 microM) or by prior CGRP receptor desensitisation and to a lesser
extent by pre-treatment with VIP-(7-28) 1 microM. L-771,331 (100 nM) exerted a
weak inhibitory effect, marked only by a short reduction in the recovery time
(post-electrical stimulation) and sumatriptan (30 nM) had no effect. The
neurogenic response was potentiated by alphaCGRP-(8-37) 1 microM (reversible on
wash-out). Short application (5-10 min) of capsaicin (10 microM) produced
vasodilation that was inhibited by alphaCGRP-(8-37) 1 microM. These data suggest
that electrically evoked neurogenic vasodilation in rabbit basilar artery has a
large component resulting from the release of sensory neuropeptides in particular
CGRP and a smaller component involving the release of VIP.
PMID- 10781676
TI - Alpha(1)-adrenoceptor subtypes mediating contractions of the rat mesenteric
artery.
AB - The alpha(1)-adrenoceptor subtype(s) mediating contractions of the rat mesenteric
artery were investigated using the agonists methoxamine, cirazoline, P7480 (N-(4
pyridinyl)-1H-indol-1-amine) and subtype-selective antagonists including BMY 7378
(8-(-2(-4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4, 5)decane-7,9,dione
dihydrochloride). pA(2) or apparent pK(B) values of antagonists against
methoxamine contractions correlated best with its pK(i) values at the cloned
alpha(1b)-(0.88), with cirazoline, antagonists affinities correlated equally well
with those at alpha(1a)-(0.79) or the alpha(1b)-(0.81) while with P7480
antagonist affinities correlated best with the alpha(1d)-adrenoceptor subtype
(0.94). The low affinity estimate for 5-methylurapidil (7.5) against the
alpha(1a)-selective cirazoline suggests an alpha(1A)-subtype mediating
contraction is unlikely. Shallow Schild plot slopes of subtype selective
antagonists against all three agonists are consistent with heterogeneity of
alpha(1)-adrenoceptors. P7480 (putative alpha(1D)-adrenoceptor-selective) acts
primarily at this subtype and at another which is more likely to be an alpha(1B)-
than an alpha(1A)-adrenoceptor. The results with both agonists and antagonists
are consistent with contractions of the rat mesenteric artery being mediated via
the alpha(1D)- and possibly alpha(1B)-adrenoceptor.
PMID- 10781677
TI - Pituitary adenylate cyclase activating peptide mediates inhibitory nonadrenergic
noncholinergic relaxation.
AB - We investigated the contribution of pituitary adenylate cyclase activating
peptide (PACAP) to inhibitory nonadrenergic noncholinergic (inhibitory-NANC)
relaxation of tracheal smooth muscle in cats. We also investigated the roles of
vasoactive intestinal peptide (VIP) and nitric oxide (NO) on this function.
Smooth muscle strips prepared from feline trachea were precontracted with 1
microM serotonin, and inhibitory-NANC relaxation was induced by electrical-field
stimulation in the presence of atropine and propranolol. PACAP-(6-38) (a
selective antagonist of PACAP; 1, 3 and 10 microM), VIP-(10-28) (a selective
antagonist of VIP; 1, 3 and 10 microM) and N(omega)-nitro-L-arginine methyl ester
(L-NAME, a selective NO synthase inhibitor; 3, 10 and 30 microM) each partially
but significantly attenuated the amplitude of inhibitory-NANC relaxation. The
effects of PACAP-(6-38) and VIP-(10-28) were additive. Addition of PACAP-(6-38)
and/or VIP-(10-28) further attenuated relaxation in the presence of L-NAME. These
results suggest that PACAP, VIP and NO contribute to the relaxation induced by
inhibitory-NANC in tracheal smooth muscle in cats, and that they mediate this
relaxation via different pathways.
PMID- 10781679
TI - Variations in the low levels of cyclin D1/BCL1 have prognostic value in chronic
lymphocytic leukemia.
AB - Cyclin D1 (CyD1)/BCL1 (PRAD1) is expressed at high levels in almost all cases of
mantle cell leukemia/lymphoma (MCL) and in rare cases of chronic lymphocytic
leukemia (CLL). The CyD1/BCL1 protein plays an important role in the progression
of cells through the G1 phase of cell cycle. Most of the CyD1/BCL1 protein
expression studies are performed using immunohistochemistry. We used a sensitive
solid-phase radioimmunoassay (RIA) to quantify CyD1 protein expression in 199
patients with CLL. Of these 137 patients were previously untreated with the rest
having had standard chemotherapeutic regimens including alkylating agents and
fludarabine before being referred to our center. Median white cell count in these
patients was 49x10(3) /microl (range 3.0-438.5x10(3)/microl), hemoglobin level
13.1 g/dl (range 5.2-17.3 g/dl), platelet count 157x10(3) /microl (range 10
377x10(3) /microl), age 58 (range 26-89), and beta2-microglobulin 2.75 mg/dl
(range 1.1-14.3). The median radioactivity (CPM) of mononuclear cells obtained
from 56 normal individuals was assigned a value of 1. There was no significant
variation in CyD1 levels among normal individuals (SD=0. 12). While most CyD1
levels in MCL varied from 6.5 to 15.6, the median CyD1/BCL1 in CLL was 1.4 with
75th percentile under 2.12. Rare CLL cases (3.5%) showed levels between 4 and
8.83. When divided into two groups at the median level, patients with higher
CyD1/BCL1 expression had shorter survival (P = 0.03). This remained true when
applied only to the previously untreated patients (P=0.05). Despite the
relatively low expression, the CyD1/BCL1 levels in univariate analysis were as
good or better predictors of survival than Binet (P = 0.03) or Rai (P = 0.05)
staging. Furthermore, CyD1/BCL1 levels correlated with serum beta2-microglobulin
(P = 0.001), white blood cell count (P = 0.004) and hemoglobin levels at the time
of collection (P = 0.0003) but not with lymphocyte count, platelet count or age.
The data demonstrate that CyD1/BCL1 is likely to play a significant role in the
biology of CLL and can be used as a prognostic indicator. Further studies to
clarify the role of CyD1 in the biology of CLL and its value as a prognostic
indicator at the time of diagnosis are encouraged.
PMID- 10781678
TI - Correlation of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of
oxidative DNA damage, and clinical features of hematological disorders: a pilot
study.
AB - The 8-hydroxy-2'-deoxyguanosine (8-OHdG), presently the most popular marker for
oxidative DNA damage, level has been reported to be elevated in patients with
various malignancies. In the present study, urinary 8-OHdG was examined in 44
patients with hematological disorders (13 malignant lymphoma, 11 adult T cell
leukemia/lymphoma (ATL), 10 acute leukemia, and 10 myelodysplastic syndrome
(MDS)) by an enzyme-linked immunosorbent assay. The pre-therapy level of urinary
8-OHdG in ATL patients was significantly elevated compared with normal controls
(25.3+/-12.9 vs. 11.9+/-7.3 ng/mg, P<0.05). Although patients with lymphoma,
acute leukemia and MDS also showed higher urinary 8-OHdG levels than normal
controls, the differences were not significant. However, two patients with
refractory anemia with excess blasts in transformation (RAEB-t) having extreme
monocytosis and neutrophilia showed exceptionally high urinary 8-OHdG levels
(161.0 and 218.9 ng/mg). Urinary 8-OHdG excretion increased transiently with
chemotherapy, and this fluctuation was significant irrespective of the disorder
(P<0.05). Interestingly, lymphoma patients with high LDH, advanced stage, poor
performance status or International Prognostic Index (IPI) of high/high
intermediate risk had significantly elevated urinary 8-OHdG levels (P<0.05
<0.001). These latter results suggest that urinary 8-OHdG may be a reliable
prognostic marker in lymphoma patients and should encourage large scale and long
term follow up studies.
PMID- 10781680
TI - Detection of t(14;18) in turkish follicular lymphomas using the polymerase chain
reaction.
AB - A t(14;18) translocation is closely associated with the follicular lymphoma but
is also seen in diffuse B cell lymphomas with a previous history of a follicular
lymphoma as well as de novo diffuse lymphomas. Estimation of the frequency of
t(14;18) in follicular lymphoma vary widely from 33 to 89%. Furthermore, no
extensive data have been published on the frequency of t(14;18) in Turkish cases
of follicular lymphoma. Representative tissue blocks from 67 patients with
follicular lymphoma, 12 cases of diffuse large B cell lymphomas and 11 cases of
reactive hyperplasias were examined for the presence of this translocation using
PCR. DNA probes capable of detecting rearrangement at both the major and minor
break point regions were employed. We could detect t(14;18) in 46 out of 67 cases
(68.7%) of follicular and 25% of diffuse large B cell lymphomas. In follicular
lymphomas 64.2% of these break points were at mbr and 4.5% were at the mcr
region. Review of the literature showed that comparable results have been
obtained previously using molecular techniques. Our data showed that despite the
relative infrequency of follicular lymphomas in the Turkish population these
lymphomas share a common molecular pathogenesis with involvement of bcl-2 gene
and background incidence of such rearrangement is similar in all populations,
regardless the incidence of folicular lymphoma.
PMID- 10781681
TI - Allogeneic stem cell transplantation for relapsed and refractory acute myeloid
leukemia patients with 11q23 abnormalities.
AB - Abnormalities involving chromosome band 11q23 are seen in de novo and therapy
related acute myeloid leukemia (AML). The role of hematopoietic stem cell
transplantation (SCT) in AML with 11q23 abnormalities is not well defined. We
present here the outcome of 14 AML patients with 11q23 abnormalities transplanted
beyond first complete remission (CR) or with primarily refractory disease. Eleven
cases were de novo and three therapy-related AML. At transplant, five patients
were in first untreated relapse, one second CR, one second relapse and seven had
refractory disease. All 14 patients underwent allogeneic SCT. Total body
irradiation was used in 93% of patients and cyclosporine-methotrexate for graft
versus-host disease prophylaxis in 71%. The relapse rate of engrafted patients
was 58%. Five year survival and disease-free survival were 14 and 7%,
respectively. Allogeneic SCT for AML with 11q23 abnormalities was of limited
benefit in this cohort of patients transplanted beyond first CR or with primarily
refractory disease.
PMID- 10781682
TI - 154 chromosome anomalies in hematologic malignancies.
PMID- 10781683
TI - Safety and efficacy of splenic irradiation in the treatment of patients with
idiopathic myelofibrosis: a report on 15 patients.
AB - Splenic irradiation in idiopathic myelofibrosis (IMF) has often been use d in
selected situations when other therapies were unefficient or contraindicated.
This could improve quality of life of patients, but literature remains rare in
this field. We have assessed the impact of splenic irradiation in 15 patients
with IMF. All of them were no longer responsive to usual treatments, and they
presented at least one of the following features: constitutional symptoms,
splenic pain, large splenic size, and anemia requiring >2 units of red blood cell
transfusion per month. The planned schedule of radiotherapy consisted in daily
fractions of 0.4-1 Gy. The median dose of radiotherapy per treatment was 9.8 Gy
(range, 0.6-30.5). The overall response rate was 59% with a median duration of 10
months (range, 1-19). Splenic irradiation was more effective on constitutional
symptoms, splenic pain, and spleen size. The best responses were noted when full
doses of radiotherapy could be delivered, and when patients were previously fewly
transfused. Splenic irradiation effectively palliates IMF-related symptoms, and
constitute an alternative therapy for patients refractory to usual treatments.
PMID- 10781685
TI - Enhanced ex vivo apoptosis of peripheral granulocytes is a sufficient factor of
neutropenia following myeloablative chemotherapy.
AB - Fourteen patients with hemopoietic and solid malignancies underwent dose
intensive chemotherapy, followed by haemopoietic stem cell grafting. Granulocyte
apoptosis was assessed as nuclear chromatin condensation, after ex vivo
incubation of blood samples for 3 h, followed by Acridine Orange staining.
Myeloablative therapy caused time-dependent increase in ex vivo granulocyte
apoptosis, being maximal at D+7 to D+9, thus preceding the development of
neutropenia (nadir values on D+13 to D+15). In vivo administration of G-CSF
(Neupogen) resulted into short-term decrease in apoptotic granulocyte numbers.
Hence, granulocyte apoptosis is an important factor of therapy-induced leukopenia
and could be modified by the G-CSF treatment.
PMID- 10781684
TI - Identification of acute myeloid leukemia patients with diminished expression of
CD13 myeloid transcripts by competitive reverse transcription polymerase chain
reaction (RT-PCR).
AB - Normal myeloid cells of monocytic and granulocytic origin express the
metallopeptidase cluster of differentiation 13 (CD13) on the surface just as
leukemic blasts in most acute myeloid leukemias (AML). A minor percentage of AML
patients, however, lack the surface expression of CD13 antigen. To study this
difference in CD13 surface expression, specific CD13 mRNA from 44 individuals
were quantified by competitive reverse transcription polymerase chain reaction
(RT-PCR). Absolute values for CD13 transcripts were normalised against
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcript levels to control for
variations in sample preparation and mRNA degradation. By correlating normalised
CD13 transcript levels and CD13 surface expression, a subgroup of AML patients
was identified, having simultaneous diminished levels of myeloid CD13 transcripts
and surface expression of the corresponding antigen. For this subgroup we suggest
CD13/aminopeptidase N (APN) gene expression to be restricted primarily by limited
amounts of transcripts. For the majority of AML patients determinants in addition
to transcript levels must be involved in regulating CD13/APN gene expression.
PMID- 10781686
TI - p53 gene deletions in paraffin-preserved lymphoid tumors from irradiated mice.
AB - Experiments were performed to measure deletions in the p53 gene in paraffin
embedded tissues (tumors and control) derived from mice exposed to gamma-rays or
neutrons up to 28 years ago. Deletions in exons 1, 3, 4, 5, 6, 7 and 9 were
monitored by PCR and Southern blotting techniques. The results of these
experiments demonstrated p53 deletions in only 1/6 spontaneous tumors but in 5/6
gamma-ray-induced and 5/6 neutron-induced tumors. Exons deleted in tumors from
gamma-ray exposed mice were similar to those deleted in tumors from neutron
exposed mice. They document differences in spectra of p53 deletions in comparing
spontaneous radiation-induced tumors.
PMID- 10781687
TI - Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic
cell line.
AB - Amifostine (AMF), a phosphorylated aminothiol, has been used to treat
myelodysplastic syndrome (MDS), where it produces a stimulatory effect on
hematopoiesis in bone marrow. To determine if AMF also produced a direct effect
on human MDS cells, we planned a study to evaluate the effect of a continuous
exposure to AMF on a human MDS cell line. AMF was shown to have a growth
inhibitory effect on MDS cells, with an IC(50) of 14 microM after a 5 day
exposure. Cell cycle analysis revealed that a 5 day exposure to 20 microM AMF
increased the percentage of cells in G0/G1 and this was accompanied by a decrease
in the percentage of cells in S phase. Cytoflorometric and agarose-gel
electrophoretic analysis revealed that this effect correlated with cell membrane
alterations and DNA fragmentation consistent with an induction of apoptosis
without affecting the expression of p53 protein or inducing any lymphoid or
myeloid differentiation in the MDS cell line. We conclude that the continuous
exposure of a human MDS cell line to AMF is cytotoxic and associated with an
induction of apoptosis independent of alterations in p53 expression.
PMID- 10781688
TI - The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required
to induce apoptosis in chronic myelogenous leukemic K562 cells.
AB - In this study, the downstream signaling of Bcr-Abl tyrosine kinase responsible
for apoptosis resistance was investigated. DNA fragmentation, a hallmark of
apoptosis, was observed after 2 days of herbimycin A treatment with a peak on 3
day. During the apoptosis induced by the treatment of herbimycin A, stress
activated protein kinase (SAPK) and p38 kinase were activated time- and dose
dependently, while extracellular signal-regulated kinase (ERK) was inhibited.
However, apoptosis was induced by the treatment of PD98059, a specific inhibitor
of MEK (MAPK or ERK kinase), not by the treatment of sorbitol, a strong activator
of SAPK and p38 kinase. Although K562 cells were very resistant to sorbitol
induced apoptosis, DNA fragmentation was induced rapidly in Jurkat, HL-60 and
U937 cells after exposure to sorbitol, despite that these apoptosis-sensitive
cells have similar or lower activities of JNK/SAPK and p38 kinase compared with
K562 cells after treatment of sorbitol. K562 cells had a much higher basal
activity of ERK/MAPK than other apoptosis-sensitive cell lines, which were very
susceptible to apoptosis induced by low dose of PD98059 compared with K562 cells.
In HL-60 cells, sorbitol-induced apoptosis was prevented by the treatment of
phorbol myristate 13-acetate (PMA), which activates the ERK/MAPK pathway, and
this was blocked by PD98059. From these results, it could be suggested that the
inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to
induce apoptosis in K562 cells.
PMID- 10781689
TI - In vitro leukemia cell models of Ara-C resistance.
AB - Cells of the human leukemia line K562 were continuously exposed to cytosine
arabinoside (Ara-C) at increasing concentrations for 3 months. The resulting cell
line, termed K562/AC, showed 48-fold resistance to Ara-C, compared with the
parental K562 cells. The sensitivities of K562/AC to adriamycin (ADR),
vincristine (VCR) and etoposide (VP16) were similar to those of parental K562.
Gene analysis revealed that this cell line lacked expression of the deoxycytidine
kinase (dCK) gene, which was evident in Ara-C-sensitive cells. As in K562 cells,
multidrug resistance (MDR-1) and multidrug resistance protein (MRP) genes were
not expressed in K562/AC. We also established an in vitro model of Ara-C
resistance using phosphorothioate antisense oligonucleotides to dCK (dCK-AS).
Treatment of K562 with dCK-AS caused decreased dCK expression and 6- to 10-fold
increases in resistance to Ara-C, compared with that in cells treated with sense
oligonucleotides to dCK (dCK-S) or in non-transfected cells. The cells described
here may contribute to the study of a novel mechanism associated with Ara-C
resistance, in which reduced dCK activity may play an important role.
PMID- 10781690
TI - Partial restoration of all trans retinoic acid (ATRA) sensitivity by compactin in
ATRA-resistant leukemic cells (ATRA-R HL-60).
AB - The resistance to all trans retinoic acid (ATRA) differentiating treatment is a
consequence, in most of the cases, of either increased catabolism or down
regulation of ATRA uptake. Recently, we have shown that ATRA efficiency to
differentiate HL-60 cells was enhanced about 30 times after its incorporation
into Low Density Lipoprotein (ATRA-LDL). Here, we attempted to differentiate the
ATRA-resistant HL-60 cells by ATRA-LDL at high concentrations up to 10 microM. No
significant differentiating effect was observed, although the LDL receptor sites
were evidenced in these cells. To increase the number of LDL receptors, the cells
were pre-incubated in lipoprotein-deprived serum medium and compactin (2 microM),
both ATRA and ATRA-LDL induced gradual increase of cell differentiation (35%+/-1
and 51.5%+/-5 at 10 microM of ATRA and ATRA-LDL respectively). At 2 and 8 microM,
the intracellular concentrations of ATRA were respectively three and four times
higher when incorporated into LDL. In addition, ATRA-LDL, in the medium, was
better protected against degradation than ATRA. The surprising restoration of
free ATRA sensitivity after treatment with compactin suggested the implication of
new mechanisms unrelated to the LDL-receptor endocytosis but involving the non
sterol pathway.
PMID- 10781691
TI - Animal models of acute drug-induced akathisia - a review.
AB - Akathisia is a complex neurobehavioural side effect of neuroleptics and some
other drugs which is characterised by subjective report and objective
manifestations of restlessness. Its pathophysiology is poorly understood and
there are many limitations to its investigation in humans. This paper reviews the
various attempts that have been made in modelling acute akathisia in animals.
Homologous as well as isomorphic models have been attempted, but most models are
partial as they reproduce either the subjective or the objective features of the
syndrome. None of the available models has been fully validated. Neuroleptic
induced defecation in the rat, even though constrained by a lack of symptom
similarity and thereby face validity, has been most studied as a model of
subjective akathisia. Rat models of restlessness, in particular those involving
the use of serotonergic drugs or lesions of the ventral tegmentum or medial
prefrontal cortex, are interesting partial models that should be further
investigated. Neuroleptic-induced akathisia is observed in primates and has been
modelled in dogs, and these should be studied further for their validation. It is
also necessary to consider the subtypes of akathisia in the attempts to develop
these models.
PMID- 10781692
TI - Contingent tolerance to amphetamine hypophagia: new insights into the role of
environmental context in the expression of stereotypy.
AB - A growing literature attests to the fact that the environment in which a drug is
given can have a profound effect on the development and expression of tolerance
and sensitization. The dominant paradigm for studying such context-dependency is
based on Pavlovian conditioning, in which a distinctive environment serves as a
conditioned stimulus. Context dependency is demonstrated when tolerance or
sensitization is expressed only in the environment in which the drug was given
chronically. An alternative paradigm for studying context-dependency is to
manipulate the contingencies of reinforcement operating in the environment in
which the drug is administered. For example, tolerance to amphetamine-induced
hypophagia is contingent on having access to food while intoxicated [Carlton PL,
Wolgin DL. Contingent tolerance to the anorexigenic effects of amphetamine.
Physiol Behav 1971;7:221-223]. Such context-dependency can be explained in terms
of an instrumental (or operant) conditioning model, in which food serves as a
reinforcer for the learned suppression of stereotyped movements that interfere
with ingestion. Research based on this model suggests that the expression of
sensitized stereotyped responses is subject to an operant level of control.
PMID- 10781693
TI - Neuronal-glial interactions and behaviour.
AB - Both neurons and glia interact dynamically to enable information processing and
behaviour. They have had increasingly intimate, numerous and differentiated
associations during brain evolution. Radial glia form a scaffold for neuronal
developmental migration and astrocytes enable later synapse elimination.
Functionally syncytial glial cells are depolarised by elevated potassium to
generate slow potential shifts that are quantitatively related to arousal, levels
of motivation and accompany learning. Potassium stimulates astrocytic
glycogenolysis and neuronal oxidative metabolism, the former of which is
necessary for passive avoidance learning in chicks. Neurons oxidatively
metabolise lactate/pyruvate derived from astrocytic glycolysis as their major
energy source, stimulated by elevated glutamate. In astrocytes, noradrenaline
activates both glycogenolysis and oxidative metabolism. Neuronal glutamate
depends crucially on the supply of astrocytically derived glutamine. Released
glutamate depolarises astrocytes and their handling of potassium and induces
waves of elevated intracellular calcium. Serotonin causes astrocytic
hyperpolarisation. Astrocytes alter their physical relationships with neurons to
regulate neuronal communication in the hypothalamus during lactation, parturition
and dehydration and in response to steroid hormones. There is also structural
plasticity of astrocytes during learning in cortex and cerebellum.
PMID- 10781694
TI - Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding
behavior: possible mechanisms of action.
AB - Serotonin (5-HT) receptor agonists with high affinity for the different subtypes
(i.e. 5-HT(1A-1F), 5-HT(2A-2C)) of the 5-HT(1)- and 5-HT(2) receptor families
have been shown to affect ingestive behavior. It has been assumed that: (1)
stimulation of hypothalamic 5-HT(2C) or 5-HT(1B) receptors leads to a
behaviorally specific hypophagic effect by accelerating satiety processes; (2)
stimulation of 5-HT(2A) receptors leads to a disruption of the feeding cascade;
and (3) stimulation of 5-HT(1A) and 5-HT(2B) receptors leads to a hyperphagic
effect. The present paper reviews studies performed with the relatively selective
receptor agonists ipsapirone (5-HT(1A)), CP-94,253 (5-HT(1B)), BW 723C86 (5
HT(2B)) and ORG 37684 (5-HT(2C)), as well as the nonselective receptor agonists
TFMPP (5-HT(1B/2C)), m-CPP (5-HT(2C/1B)) and DOI (5-HT(2A/2C)) in a variety of
feeding paradigms in rats, both after systemic and local injection. These studies
support a role for other neuroanatomical regions (i.e. brain stem) and behavioral
mechanisms (i.e. appetitive processes) in the hypophagic effects of these
compounds, possibly as a function of the administered dose. Studies with 5-HT
receptor antagonists indicate that the proposed role of particular 5-HT(1/2)
receptor subtypes in the hypophagic effects of these 5-HT receptor agonists may
be more complicated than originally thought. Further characterization of the role
of 5-HT(1/2) receptor subtypes in the control of ingestive behavior will require
extensive pharmacological and behavioral studies, using more selective receptor
agonists and antagonists and different behavioral procedures, as well as
verification in transgenic animals.
PMID- 10781695
TI - The amygdala theory of autism.
AB - Brothers (Brothers L. Concepts in Neuroscience 1990;1:27-51) proposed a network
of neural regions that comprise the "social brain", which includes the amygdala.
Since the childhood psychiatric condition of autism involves deficits in "social
intelligence", it is plausible that autism may be caused by an amygdala
abnormality. In this paper we review the evidence for a social function of the
amygdala. This includes reference to the Kluver-Bucy syndrome (which Hetzler and
Griffin suggested may serve as an animal model of autism). We then review
evidence for an amygdala deficit in people with autism, who are well known to
have deficits in social behaviour. This includes a detailed summary of our recent
functional magnetic resonance imaging (fMRI) study involving judging from the
expressions of another person's eyes what that other person might be thinking or
feeling. In this study, patients with autism or AS did not activate the amygdala
when making mentalistic inferences from the eyes, whilst people without autism
did show amygdala activity. The amygdala is therefore proposed to be one of
several neural regions that are abnormal in autism. We conclude that the amygdala
theory of autism contains promise and suggest some new lines of research.
PMID- 10781696
TI - The neuropsychology of preclinical Alzheimer's disease and mild cognitive
impairment.
AB - Subjects in the preclinical stages of Alzheimer's disease (AD) typically record
neuropsychological performance between that of healthy older individuals and
demented patients. More specifically, deficits on measures of verbal episodic
memory are commonly reported in these patients, while other cognitive functions
(e.g. language, praxis and executive function) seem to be spared. A similar
neuropsychological profile is observed in elderly subjects with mild cognitive
impairment (MCI), a disorder that is attracting increasing research interest.
Evidence from lesion and functional imaging studies, as well as volumetric
imaging in probable AD and MCI patients, suggests that the cognitive deficits
observed in these disorders may be related to medial temporal lobe dysfunction.
An issue currently under investigation is whether MCI represents the preclinical
stages of AD or a distinct and static cognitive aetiology. In an attempt to
address this issue, present investigations are adopting a convergent approach to
the detection of preclinical AD, where multiple risk factors are considered when
making a diagnosis.
PMID- 10781697
TI - Sex differences in thermal nociception and morphine antinociception in rodents
depend on genotype.
AB - It has been appreciated for some time that the sexes can differ in their
sensitivity to pain and its inhibition. Both the human and rodent literatures
remain quite contentious, with many investigators failing to observe sex
differences that others document clearly. Recent data from our laboratory have
pointed to an interaction between sex and genotype in rodents, such that sex
differences are observed in some strains but not others. However, these studies
employed inbred mouse strains and are thus not directly relevant to existing
data. We presently examined whether the observation of statistically significant
sex differences in nociception and morphine antinociception might depend on the
particular outbred rodent population chosen for study. Rats of both sexes and
three common outbred strains were obtained from three suppliers (Long Evans,
Simonsen; Sprague Dawley, Harlan; Wistar Kyoto, Taconic) and tested for
nociceptive sensitivity on the 49 degrees C tail-withdrawal assay, and
antinociception following morphine (1-10mg/kg, i.p.). In further studies, three
outbred populations of mice (CD-1, Harlan; Swiss Webster, Harlan; Swiss Webster,
Simonsen) were bred in our vivarium for several generations and tested for tail
withdrawal sensitivity and morphine antinociception (1-20male, and no significant
difference. In a separate study in which the estrous cycle was tracked in female
mice, we found evidence for an interaction between genotype and estrous phase
relevant to morphine antinociception. However, estrous cyclicity did not explain
the observed sex differences. These data are discussed with respect to the
existing sex difference and pain literature, and also as they pertain to future
investigations of these phenomena.
PMID- 10781698
TI - Depression and health-related quality of life in ethnic minorities seeking care
in general medical settings.
AB - BACKGROUND: To examine ethnic groups differences in (a) prevalence of depressive
disorders and (b) health related quality of life in fee-for-service and managed
care patients (n=21504) seeking care in general medical settings. METHODS: Data
are from the Medical Outcomes Study, a multi-site observational study of
outpatient practices. The study screened patients of clinicians (family practice,
internal medicine, cardiology, diabetology and endocrinology) for four chronic
medical conditions; depression, coronary heart disease, hypertension and
diabetes. A brief eight-item depression screener followed by the Diagnostic
Interview Schedule-Depression Section (DIS) for screener positives identified
depressed patients (n=2195). The Short Form Health Survey (SF-36) assessed health
related quality of life. Patient self-report determined ethnicity. RESULTS:
Before adjusting for demographic factors, African-Americans and Hispanics had
highest rates of depressive symptoms. Asian-Americans had the lowest. After
adjusting for demographics (particularly gender and income), we found few
statistically significant differences in prevalence or severity of depression.
However, among the depressed, Whites were the most, and African-Americans the
least likely to report suicidal ideation (p<0. 01), and Hispanics and Whites were
more likely to have melancholia (p<0.01). African-Americans reported the poorest
quality of life. LIMITATIONS: DSM III criteria (though few changes in DSM IV),
and relatively small sample size of Asian-Americans compared to other groups.
CONCLUSIONS: Gender and socioeconomic status are more significant factors than
ethnicity in determining risk for depressive disorder. However, ethnic
differences in symptom presentation, and health-related quality of life could
have clinical and social consequences, and merit further study.
PMID- 10781699
TI - History of childhood attention deficit hyperactivity disorder (ADHD) features
among adults with panic disorder.
AB - BACKGROUND: The prevalence of ADHD features during childhood and its relationship
to the course and presentation of panic in adults with panic disorder was
examined. METHODS: The presence of DSM-III-R ADHD was retrospectively ascertained
in a cohort of 85 adults with panic disorder by structured interview. RESULTS:
Childhood ADHD features occurred in 23.5% of panic subjects; 9.4% satisfied full
DSM-III-R criteria for ADHD, 14.1% had 'subthreshold' diagnoses. Two-thirds of
panic patients with ADHD indicated persistence of symptoms into adulthood. Fewer
had married or completed college than those with panic alone. There was no
significant difference in clinical pattern and severity of panic, or comorbidity
of adult Axis I and childhood anxiety disorders in both groups. CONCLUSION: Given
its frequency and persistence, ADHD comorbidity is an important clinical
consideration in all panic patients. Its co-occurrence does not influence the
clinical pattern of panic, but may contribute to adverse social outcome.
PMID- 10781701
TI - The development of major depressive episodes during the course of dysthymic and
episodic major depressive disorders: a retrospective examination of life events.
AB - BACKGROUND: The present study examined whether stressful life events are
associated with the development of major depressive episodes (MDEs) in a
longitudinal, retrospective study of dysthymic and episodic major depressive
disorders. METHODS: Sixty-seven outpatients with DSM-III-R dysthymia and 38
outpatients with non-chronic major depression were followed up 30-60 months after
entry into the study. Follow-up assessments included a modified version of
Paykel's (1997) Interview for Recent Life Events (IRLE) and Keller et al.'s
(1987) Longitudinal Interval Follow-up Evaluation. Life events were assessed
retrospectively in the 6 months before the most recent MDE or in the 6 months
before follow-up for patients without a MDE. RESULTS: In dysthymic patients, MDEs
were significantly associated with a new life event in the context of an ongoing
chronic stressor. In episodic major depressive patients, relapses were associated
with new life events regardless of an ongoing chronic stressor. LIMITATIONS: This
was a retrospective study. It was also a conservative test of the association
between life events and MDEs as the follow-up period over which life events were
assessed was long, increasing the possibility of forgetting; events occurring
less than 1 month before relapse were excluded to avoid confounding the event
with the MDE; life events were assessed for a more distant time period for
patients who experienced MDEs than those who did not; and an abbreviated version
of the IRLE was used which may have failed to identify less severe events.
CONCLUSIONS: This study suggests that life events may play a role in the onset of
MDEs in persons with dysthymic disorder and those with major depressive disorder.
Thus, clinicians should monitor dysthymic patients after a stressful life event,
particularly if it occurs in the context of a chronic, ongoing stressor.
PMID- 10781700
TI - Study of the concurrent validity of the Calgary Depression Scale for
Schizophrenics (CDSS).
AB - The aim of this study was to investigate the concurrent validity of the French
language version of the Calgary Depression Scale for Schizophrenics (CDSS).
Ninety-five schizophrenic patients meeting the DSM-III-R criteria were enrolled
in the study. The depressive symptoms were evaluated using the Calgary Depression
Scale for Schizophrenics (CDSS), Hamilton Depression Rating Scale (HDRS),
Montgomery and Asberg Rating Scale (MADRS), and Widlocher Psychomotor Retardation
Scale (ERD). The psychotic symptoms were evaluated with the Positive and Negative
Syndrome Scale (PANSS) and the extrapyramidal symptoms with the Extrapyramidal
Syndrome Rating Scale (ESRS). The CDDS was significantly correlated with all the
conventional depression-rating scales. We only found significant positive
correlations between the CDSS and the PANSS-positive sub-scale. The CDSS total
score was significantly correlated with some PANSS-positive items (delusions and
hallucinatory behaviour). No significant correlation between the depression
rating scales and the PANSS-negative sub-scale was observed. For all the
depression-rating scales, no correlation with the extrapyramidal symptom was
evidenced. The results confirmed the validity of the CDSS in the evaluation of
depression in schizophrenia. The relationship between depression and the positive
symptoms of schizophrenia is discussed.
PMID- 10781702
TI - Who becomes depressed? The Islington community study of older people.
AB - BACKGROUND: Depression in older people is common and debilitating and associated
with physical ill health. This is the first study of risk factors for depression
in a representative sample of older people selected for high vulnerability
because of physical ill health. METHOD: Subjects identified in an epidemiological
community survey of morbidity in people > or =65 years old, who had activity
limitation (ADL) but no psychiatric morbidity were reinterviewed after 3 years.
RESULTS: 79 (90%) of subjects were interviewed. Ten percent developed pervasive
depression and 24% screened positive for depression. This latter group were more
likely to consult doctors than others with similar levels of disability (P<0.005)
mainly because of an acute physical illness. Frequent pain was associated with
the development of depression (P<0.02). CONCLUSION: Older people who are ADL
limited are known to be at high risk for depression. For the majority who do not
become depressed, chronicity of illness does not lead to depression. Those who
become depressed are most likely to be those with an acute illness and those who
are in pain. They will usually increase their consultation rate with doctors but
will not complain of depression. They may be undertreated for both pain and
depression. Further studies are needed to confirm other risk factors.
PMID- 10781703
TI - Comparison of neurochemical effects of the monoamine oxidase inhibitors
phenelzine, moclobemide and brofaromine in the rat after short- and long-term
administration.
AB - BACKGROUND: Chronic administration of several irreversible monoamine oxidase
(MAO) inhibitors induces a down-regulation of tryptamine and 5
hydroxytryptamine(2) receptors in rat brain, but there is a paucity of
information available on the effects of reversible MAO-A inhibitors on these
receptors. METHODS: Acute and chronic experiments were conducted in rats and the
effects of the irreversible monoamine oxidase inhibitor, phenelzine and the
reversible MAO type-A inhibitors, moclobemide and brofaromine, on tryptamine and
5-hydroxytryptamine(2) receptors were analysed using radioligand binding
techniques. In addition, activities of MAO-A and -B were determined
radiochemically and brain and/or urine levels of tryptamine, 5-hydroxytryptamine,
3-methoxy-4-hydroxyphenylglycol (MHPG), beta-phenylethylamine, brofaromine and
moclobemide were determined by chromatographic procedures. RESULTS: After 30 days
of administration, moclobemide and brofaromine selectively inhibited brain MAO-A
activity and phenelzine inhibited MAO-A and -B to equal extents. All three drugs
caused a significant down-regulation of tryptamine receptors, whereas only
phenelzine significantly down-regulated 5-hydroxytryptamine(2) receptors. In a
comparison of phenelzine and brofaromine, both caused marked elevations of
urinary tryptamine and decreases of urinary MHPG levels, while only phenelzine
increased beta-phenylethylamine levels. After 14 days of administration,
phenelzine, but not moclobemide or brofaromine, significantly increased levels of
tryptamine in brain; all three drugs significantly increased 5-HT levels.
LIMITATIONS: 24-h urine samples were not collected for moclobemide-treated
animals and brain levels of tryptamine were not measured after 30-day
administration. CONCLUSIONS: These studies revealed marked neurochemical
differences among phenelzine, moclobemide and brofaromine which could contribute
to their actions in the clinical setting.
PMID- 10781704
TI - Postnatal depression in Japanese women. Detecting the early onset of postnatal
depression by closely monitoring the postpartum mood.
AB - OBJECTIVES: The terminology and definition of mood disturbance during the early
postpartum period has yet to be clearly elucidated among clinical practitioners.
Criteria for maternity blues have not been well established, and it may overlap
with the beginning of a postnatal depression. The aims of the present study, are
firstly to survey the symptomatic features of mood disturbance in the very early
postpartum period and secondary, to develop a guideline for detecting and
predicting postnatal depression during the same period using a simple screening
technique. SUBJECTS AND METHODS: Eighty-eight mothers recruited from a maternity
ward for the prospective study completed the whole protocol. Two methods were
used to survey the symptomatic features of mood disturbance; (1) interview and
(2) self-report questionnaires. The interviews were carried out twice. At three
weeks postpartum, the Schedule for Affective Disorder and Schizophrenia
(SADS)/Research Diagnostic Criteria was administered, together with an interview
of the symptoms of "maternity blues". The SADS interview was re-administered at
three months postnatally. Two self-report questionnaires addressing mood
disturbance were administered: (1) Maternity Blues Scale; (Stein, 1980). (2)
Edinburgh Postnatal Depression Scale (EPDS; Cox et al., 1987). The Maternity
Blues Scale was administered on the first five consecutive postnatal days. The
EPDS was administered on the fifth day, one month and three months postnatally.
In addition, the Life Event Scale (Burgha et al., 1985) was also administered at
one month postnatally. Obstetric notes were also examined. RESULTS: At the first
interview, 12 mothers were diagnosed with postnatal depression and 10 of these
had their onset within one week. At the second interview three additional mothers
were newly diagnosed with depression. In all mothers, depression was detected at
one month using the EPDS, with a cut-off of 8/9. The EPDS scores on the fifth
postnatal day were also higher in the depressed mothers and could detect early
onset of postnatal depression. CONCLUSION: The use of the EPDS during the early
postnatal days, can be a simple and useful screening instrument for the onset of
early postnatal depression.
PMID- 10781705
TI - A note on suicidal deterioration with recovered memory treatment.
AB - BACKGROUND: Many patients who have been told they have Multiple
Personality/Dissociative Identity Disorder (MPD/DID) seem to have deteriorated
clinically after being so diagnosed. We report here the results of a survey of
suicide attempts in patients diagnosed as having MPD and a comparison group
hospitalized with a mood disorder. METHODS: Twenty individuals who had been
diagnosed as having MPD, had developed false memories, and had relinquished them,
were surveyed with respect to suicide attempts before and after the diagnosis.
Twelve of those approached agreed to provide data and were compared with 12
patients from an in-patient mood disorders unit, matched for age and sex.
RESULTS: In the MPD group more patients attempted suicide after being diagnosed
than before and they made more separate attempts at suicide than before. The
reverse was true in the comparison group with patients and suicide attempts
before and after hospitalization. Comparing the numbers of attempts in the groups
before diagnosis/hospitalization and afterward Chi(2)=20.177, DF=1, P<0.001.
LIMITATIONS AND CONCLUSIONS: Both samples were highly selected, and the
comparison group does not provide an exact control. Nevertheless, the results
support a trend in the literature that finds the diagnosis of multiple
personality disorder and the use of recovered memory treatment are harmful.
PMID- 10781706
TI - Depressive episodes of bipolar disorder in early teenage years: changes with
increasing age and the significance of IQ.
AB - BACKGROUND: Depressive (or depression-like) episodes are the most common
manifestations of bipolar affective disorder in early teenage years. The present
paper analyses the clinical features and their changes over time in these
episodes. METHODS: By a prospective study on children who had their first
affective or psychotic episodes between the ages of ten and fifteen, those who
eventually met the ICD 10 diagnostic criteria for bipolar disorder were selected
and followed up. RESULTS: There were three boys and nine girls. Their early
depressive episodes were characterised by psychotic features and clinging to the
mother in most cases, and in some by brief episodes and/or a good response to
sulpiride. However, these characteristics tended to disappear with increasing
age. Five children (42%) had an IQ of 61-75. LIMITATIONS: Generalisability of the
results is limited because of the small number of patients and the lack of
control groups. CONCLUSIONS: Bipolar disorder in early teenage years may show
clinical features and a drug response that are different from those in adulthood.
Low IQ may expedite the onset of bipolar disorder.
PMID- 10781708
TI - Thrombosis prophylaxis in hospitalised medical patients: does prophylaxis in all
patients make sense?
AB - BACKGROUND: Most studies on thrombosis prophylaxis focus on postoperative venous
thrombosis. In medical wards thrombosis prophylaxis is generally restricted to
patients who are immobilised. Our primary aim was to investigate the incidence of
venous thrombosis in a general internal ward, to assess whether more rigorous
prophylaxis would be feasible. METHODS: We investigated the incidence of venous
thrombosis in patients hospitalised from 1992 to 1996 and related our findings to
literature reports. RESULTS: The incidence of symptomatic venous thrombosis in
internal patients during hospitalisation was 39/6332 (0.6%). Among these 39
patients, 24 had a malignancy, whereas 876 out of all 6332 patients had a known
malignancy. So, the incidence in this group with cancer was 2.7% compared with
0.3% (15/5456) in the non-cancer group (relative risk for venous thrombosis due
to malignancy was 10.0 (95%C.I. 5.3-18.9). CONCLUSION: The incidence of venous
thrombosis during hospitalisation in a department of general internal medicine is
low and does not justify prophylaxis in all internal patients. Cancer is a strong
risk factor for hospital-acquired thrombosis in the medical ward. Further studies
may answer the question as to whether thrombosis prophylaxis in this subgroup is
feasible.
PMID- 10781707
TI - Serum cholesterol levels and panic symptoms in patients with panic disorder: a
preliminary study.
AB - BACKGROUND: Although some previous research has focused on the relationship
between panic disorder (PD) and a high total cholesterol (TC) level, it is still
controversial. Recently, researchers have reported the heterogeneity of clinical
symptoms in PD and the complexity of the correlations found among them.
Therefore, the controversy on the TC level in PD may be due to the existence of
clinical subgroups in PD. It is important to ascertain whether or not an elevated
TC level in patients with PD is associated with specific panic symptoms. METHODS:
In 104 drug-free patients with PD, we examined the relationship between TC level
and each of several panic symptoms occurring at the time of panic attacks (PAs),
which included anticipatory anxiety, agoraphobia, and 13 panic symptoms based on
the DSM-III-R. RESULTS: Stepwise regression analysis revealed a significant
effect of the presence of the symptom 'fear of dying' on TC levels. Patients with
a fear of dying had a significantly higher TC level than those without it.
LIMITATIONS: The relatively small sample size may limit the generalizability of
our findings. DISCUSSION: These data suggest that TC level may be associated with
panic symptoms in patients with PD.
PMID- 10781709
TI - High-frequency oscillatory ventilation in pediatric patients.
AB - BACKGROUND: High-frequency oscillatory ventilation (HFOV) is a ventilatory mode
using small tidal volumes with low phasic pressures at supraphysiological
frequencies. Beyond the neonatal period there are distinct lung diseases for
which HFOV is used. Data of 35 children who deteriorated on conventional
ventilation were retrospectively analysed in two tertiary pediatric intensive
care units. METHODS: Depending on the underlying pulmonary pathophysiology, three
strategies were employed. First, the 'open-lung' strategy designed to rapidly
recruit and maintain optimal lung volume in DAD (n=27) and pulmonary hemorrhage
(n=5). Second, the 'low-volume' strategy in persistent air leak (n=1) where,
after an initial identical approach, mean airway pressure (MAP) is reduced until
the air leak ceases. Third, the 'open-airway' strategy in obstructive airway
disease (n=5) where MAP is used to recruit and stent the airways. RESULTS: Seven
patients died, two due to respiratory failure. Three patients developed an air
leak. Nine patients developed chronic lung disease. There was a significant
decrease of the oxygenation index (OI) in the survivors. In the two patients who
died of respiratory failure, the OI increased. CONCLUSION: If certain conditions
are met, HFOV appears a safe and effective mode of ventilation in pediatric
respiratory failure.
PMID- 10781710
TI - Need to increase awareness among family doctors and medical specialists of
rickettsioses as an import disease in non-endemic areas.
AB - Europeans travelling to (sub)-tropical countries have an increased risk for
infections with Rickettsia. As serious consequences are associated with delay in
specific antibiotic therapy, unequivocal diagnosis of this condition is needed.
We focus here on the benefits of early, and consequences of late laboratory
diagnosis, and emphasise the need of an increased awareness of rickettsioses
among family doctors, as well as medical specialists, in non-endemic areas when
evaluating patients with travel associated fever.
PMID- 10781711
TI - Acute epiglottitis as a cause of airway obstruction in an adult patient.
AB - Epiglottitis in adults is a dangerous infectious disease with a rising incidence
and potential fatal complications as illustrated in this case report. Like in
children, skilled and aggressive airway protection with appropriate antibiotic
therapy have been effective in reducing mortality.
PMID- 10781712
TI - Pulmonary alveolar proteinosis: a complication in patients with hematologic
malignancy.
AB - We present the case of a patient with acute myeloid leukemia and secondary
Pulmonary Alveolar Proteinosis (PAP), which is an underestimated cause of a
persistent pulmonary infiltrate in patients with hematologic malignancies often
accompanied by neutropenia due to therapy. Diagnosis is established by performing
Periodic Acid-Schiff reaction (PAS) stains and transmission electron microscopy
(EM) on bronchoalveolar lavage (BAL) fluid. We wish to stress the importance of
the early recognition of PAP, which is potentially reversible, and routinely
performing PAS staining on BAL fluid in patients with a hematologic disease
especially myeloid disorders and a persistent lung infiltrate.
PMID- 10781713
TI - Diagnosis and treatment of brucellosis.
PMID- 10781714
TI - Speciation of elements in NIST particulate matter SRMs 1648 and 1650
AB - X-ray absorption fine structure (XAFS) spectra for S, Cl, V, Cr, Mn, Cu, Zn, As,
Br, Cd and Pb and Mossbauer spectra for Fe have been obtained for two National
Institute of Standards and Technology (NIST) particulate matter (PM) standard
reference materials (SRMs): urban PM (SRM 1648) and diesel PM (SRM 1650). The
spectral data, complemented by information on elemental concentrations from
proton-induced X-ray-emission (PIXE) spectroscopy, were used to interpret the
speciation of these elements in these complex materials. It appears that all the
metallic elements investigated occur in oxidized forms, principally as sulfates
in the diesel PM SRM and as sulfates, oxides, and possibly other forms (e.g.
clays?) in the urban PM. A minor fraction of the sulfur and major fractions of
the halogens, Cl and Br, occur as organosulfide (thiophene) and organohalide
occurrences, respectively, that must be associated with the abundant carbonaceous
matter that constitutes the major component of the two PM SRMs. Most of the
sulfur, however, occurs as sulfate in the urban PM and as bisulfate in the diesel
PM. In addition, elemental oxidation states have been determined directly by the
spectroscopic techniques. Such information is often the key parameter in
determining the toxicity and solubility of specific elements in PM, both of which
are important in understanding the threat that such elements may pose to human
health. For the two HAP elements, Cr and As, for which the toxicity depends
greatly on oxidation state, the XAFS data showed that both elements are present
in both SRMs predominantly in the less toxic oxidation states, Cr(III) and As(V).
The potential of the XAFS spectra for use as source apportionment signatures is
illustrated by reference to chromium, which exists in these two PM SRMs in very
different forms.
PMID- 10781715
TI - Chemical speciation of nickel in fly ash by phase separation and carbon paste
electrode voltammetry
AB - In a risk-based approach to cost-effective management of power plant emissions,
chemical speciation of fly ash is required. A quantitative but indirect
separation of nickel phases by sequential extraction was undertaken in
conjunction with direct analysis of the sulfidic nickel phase by carbon paste
electrode voltammetry (CPEV). Four ash samples produced in a laboratory
combustion system from burning high- and low-sulfur residual oil at excess O(2)
of 1 and 2-3 mol% were studied. The extractions yielded five phases of nickel.
The CPEV analysis of sulfidic nickel in the ash and extraction residues was
performed in pH 5 acetate. The anodic peak (-0.1 V) unique to Ni(3)S(2),
distinguishing it from NiS and NiS(2), was found to be absent from these ash
samples. The CPEV method was consistent with phase extraction, which showed
NiSO(4) being predominant with very low proportions of sulfidic nickel.
PMID- 10781717
TI - Partitioning behavior of trace elements during pilot-scale combustion of
pulverized coal and coal-water slurry fuel
AB - Release pathways for inorganic hazardous air pollutants (IHAPs) from a pilot
scale, down-fired combustor (DFC) when firing pulverized coal (PC) and coal-water
slurry fuel (CWSF) were identified and quantified to demonstrate the effect of
fuel form on IHAP partitioning, enrichment and emissions. The baghouse capturing
efficiency for each element was calculated to determine the effectiveness of IHAP
emission control. Most of the IHAPs were enriched in the fly ash and depleted in
the bottom ash. Mercury was found to be enriched in the flue gas, and
preferentially emitted in the vapor phase. When firing CWSF, more IHAPs were
partitioned in the bottom ash than when firing PC. Significant reduction of Hg
emissions during CWSF combustion was also observed.
PMID- 10781716
TI - Interlaboratory comparison of HPLC-fluorescence detection and GC/MS: analysis of
PAH compounds present in diesel exhaust.
AB - For laboratories involved in polycyclic aromatic hydrocarbon (PAH) analyses in
environmental samples, it is very useful to participate in interlaboratory
comparison studies which provide a mechanism for comparing analytical methods.
This is particularly important when PAH analyses are routinely done using a
single technique. The results are reported for such an interlaboratory comparison
study, in which the four selected participating laboratories quantitatively
analyzed several PAH compounds in diesel exhaust samples. The samples included
particle and vapor phase extracts collected and prepared at Michigan
Technological University (MTU PE and MTU VE, respectively), a diesel particle
extract prepared by the National Institute for Standards and Technology (NIST,
SRM 1975), and a fully characterized diesel particle sample (NIST SRM 1650). One
of the laboratories used only HPLC-FLD, one used only GC/MS and two laboratories
used both methods for the routine analysis of PAH in environmental samples. Data
were obtained for five PAH compounds: fluoranthene, pyrene, benz[a]anthracene,
benzo[a]pyrene, and benzo[g, h,i]perylene. The mean PAH levels found for SRM 1650
were outside the range reported by NIST. The range in the reported means was from
24% lower than certified for benz[a]anthracene to 41% higher for
benzo[g,h,i]perylene. For the previously uncharacterized samples in this study
(SRM 1975, MTU PE and MTU VE), two-thirds of the reported results were higher for
the HPLC-FLD method than for the GC/MS. The range in differences between methods
was from-54 to+31% calculated as the difference in GC/MS value relative to the
HPLC value for each of the compared compounds. Coefficients of variation for the
uncharacterized samples appeared to be higher, in most (but not all) cases, for
the HPLC-FLD than for the GC/MS. The resolution of certain PAH isomers (e.g.
benz[a]anthracene and chrysene, or the benzofluoranthenes), was better, as
expected, for HPLC than for GC. Generally lower detection limits (by an order of
magnitude or more) were reported for GC/MS than for HPLC-FLD. On the basis of
this limited study, it seems as though significant differences may exist between
laboratories, if not between methods, in the analysis of certain PAH compounds in
real diesel samples by HPLC-FLD compared to GC/MS. If possible, measurements
should be made using both methods. This is particularly important where potential
interferences are undefined or subject to change, as is frequently the case with
real environmental samples.
PMID- 10781718
TI - Catalytic effects of carbon sorbents for mercury capture
AB - Activated carbon sorbents have the potential to be an effective means of mercury
control in combustion systems. Reactions of activated carbons in flow systems
with mercury and gas stream components were investigated to determine the types
of chemical interactions that occur on the sorbent surface. The effects of carbon
type, particle size, temperature, and reactive gases were studied. Sorption
kinetics and capacities for lignite- and bituminous-based carbons were compared
with those for catalytic carbons at temperatures of 107 degrees C, 150 degrees C,
and 163 degrees C. In the air and baseline gas studies, the catalytic carbons
exhibited far better sorption than the lignite- and bituminous-derived carbons.
With the catalytic carbons, the greater sorption kinetics and capacity in an air
stream or baseline gas composition compared with nitrogen provides a clear
demonstration that O(2) is required in the gas stream for higher reactivities and
capacities. Thus, a catalytic chemisorption mechanism predominates for the
sorption of mercury at these conditions. The reaction kinetics are inversely
proportional to the temperature, indicating that a preliminary physisorption step
with mercury associating with a surface site is rate-determining. In synthetic
flue gas streams containing HCl (50 ppm), the sorption kinetics of the catalytic
carbon are slightly inferior to those of lignite-based carbon. Thus, the reaction
is dominated by a different interaction, where HCl reacts with mercury on the
carbon surface and the oxidation sites on the catalytic carbon apparently have no
advantage. Granular and fine-particle carbons gave similar results in flue gas
streams.
PMID- 10781719
TI - Control of nitric oxide, nitrous oxide, and ammonia emissions using microwave
plasmas
AB - The subject of this paper is mitigation of the undesirable side-effects of
selective non-catalytic reduction (SNCR) and selective catalytic reduction (SCR):
ammonia slip, residual NO(x), and N(2)O emissions. The use of microwave-plasma
discharge within the flue gas was explored as a potential pollution-control
method. The key issues addressed were: (1) N(2)O, NH(3), and NO removal
efficiencies; and (2) sustaining a stable plasma at atmospheric, or close to
atmospheric, pressure. In non-oxidizing atmospheres, removal efficiencies were
always close to 100% for all species. In the presence of oxygen, however,
appreciable amounts of nitric oxide and ammonia were formed. Methods leading to
preventing these undesirable effects were examined. In a number of runs, stable
plasma operation was attained at pressures close to atmospheric.
PMID- 10781720
TI - An investigation on polycyclic aromatic hydrocarbon emissions from pulverized
coal combustion systems
AB - Results from a series of tests conducted to study the emission of polynuclear or
polycyclic aromatic hydrocarbons (PAHs) from bench-scale and small industrial,
water-tube boiler are discussed. A Middle Kittanning, and Upper Freeport seam
coals were used in the study. Samples were extracted from the reactor outlet and
from the inlet and outlet sides of the research boiler's (RB) baghouse using EPA
promulgated methods.Only acenaphthene and fluoranthene were detected in down
fired combustor (DFC) samples. In addition to these two, naphthalene was detected
in the RB samples. Emission factors ranged from 80 to 320 &mgr;g/kg of fuel
fired. Although there were minor trends in the emissions' data, given the
reproducibility limits for PAH compounds, no significant differences were found
in the emissions with respect to the fuel type or form (pulverized coal (PC) vs.
coal-water slurry fuel (CWSF), and raw vs. cleaned coal) and firing conditions
(high and low excess air). The PAH emissions showed a decrease with increase in
the firing rate.A bench-scale drop-tube reactor (DTR) was used to study the
effects of temperature and residence time on PAH formation. The results revealed
near constant PAH concentrations in the solid-phase samples, while the PAH
concentrations in the vapor-phase samples increased as a function of temperature.
At a temperature of around 1300 degrees C, the rate of PAH formation was exceeded
by the rate of PAH oxidation, and PAH concentrations in the vapor phase began to
decrease.
PMID- 10781721
TI - Effect of geological processes on coal quality and utilization potential: review
with examples from western Canada.
AB - This review article compares the elemental and radionuclide concentrations in
coals from western Canada, the vast majority of which are used for power
generation in Alberta. The coals range in age from lower Cretaceous to middle
Eocene, and in rank from subbituminous to high volatile bituminous. Some of the
coals were deposited in deltaic lagoonal to marine settings while others formed
under lacustrine conditions in intermontane graben settings or in alluvial
plains. The role of source rock (provenance), depositional environment, tectonic
regime and hydrologic conditions on elemental concentration and distribution will
be discussed, with specific examples from western Canada. In addition, the effect
of natural weathering, igneous intrusion and self-burning (spontaneous
combustion) on the enrichment and/or depletion of elements will be presented. The
emphasis throughout this review article will be on the fate of elements of
environmental concern and interest (e.g. As, Ba, B, Cl, Co, Cr, Cu, Mn, Mo, Se,
Th, U, V and Zn) and of radionuclides of the U and Th series upon coal
utilization. This article is also intended for those not familiar with the
geological or environmental sciences, particularly as related to fossil fuel
utilization.
PMID- 10781723
TI - Introduction
PMID- 10781722
TI - Comparing and assessing acid rain-sensitive ponds.
AB - Changes in pH and temperature were monitored in two freshwater ponds in
Southeastern Massachusetts from 1990 to 1993 using a remote-sensing system that
collected data on a continuous basis. The sensing system included a combination
electrode, pH meter and portable computer powered by a marine battery.
Temperature and pH information from the pH meter were acquired every 10 min and
stored in the computer. The two ponds, located within 2 km of one another, have a
different average pH and sensitivity to acid precipitation. Maquan Pond has an
average pH of 6.0 and an alkalinity of 7.4 mg/l, while Furnace Pond has an
average pH of 6.9 and alkalinity of 14.9 mg/l. The pH of both ponds varied
seasonally and showed diel changes due to the photosynthetic and respiratory
activity of aquatic organisms. Precipitation events did not change the pH of
Furnace Pond. Maquan Pond on the other hand, did exhibit changes in surface water
pH due to specific acidic precipitation events. During certain rainstorms, the pH
of Maquan surface waters dropped to values as low as pH 4. In addition to the
transient changes in pH, the acid-sensitive pond also exhibited differences in
planktonic distribution patterns.
PMID- 10781724
TI - Molecular characterization of Brazilian isolates of orf virus.
AB - Outbreaks of an epidermic disease suggesting parapox virus infections have been
observed in all major herds of sheep and goats from different geographical areas
of Brazil. Clinical samples (dried scabs) were collected and orf virus was
isolated and characterized by electron microscopy in previous work. In order to
characterize these viruses at the molecular level, a modified methodology for
genomic DNA extraction directly from scabs was used and such DNA was used to
derive the restriction enzyme digestion patterns for clinical samples from three
distinct geographic origins. Pulsed field gel electrophoresis was used to
separate restriction enzyme DNA fragments and heterogeneity among isolates from
different geographic areas could be observed on stained gels. The HindIII-G DNA
fragment from orf-A virus genome was cloned and hybridized to DNA of other orf
virus isolates. Further heterogeneity was confirmed by these hybridizations.
PMID- 10781725
TI - Detection and differentiation of Leptospira spp. serovars in bovine semen by
polymerase chain reaction and restriction fragment length polymorphism.
AB - In view of the importance of venereal transmission of bovine leptospirosis, the
objective of the present study was to apply the polymerase chain reaction (PCR)
to 26 serovars of Leptospira interrogans, L. borgpetersenii, L. santarosai, L.
noguchii and L. biflexa, to determine the detection threshold in semen samples
and to evaluate the possibility of differentiation among serovars using 19
restriction endonucleases. The results showed that all serovars were amplified
and the detection threshold in semen samples of a bull was 100 bacteria/ml. Using
endonucleases we could classify the 26 serovars into eight groups. The present
results show that PCR is a method of great potential for the detection of
Leptospira spp. at bovine artificial insemination centers.
PMID- 10781726
TI - Preferential infection of neuronal and astroglia cells by Akabane virus in
primary cultures of fetal bovine brain.
AB - Akabane virus is a member of the genus Bunyavirus; it is pathogenic for ruminants
and transmitted by arthropod vectors. Infection of adult cattle and sheep causes
a transient viremia without obvious clinical signs, while infection of pregnant
animals often causes fetal abnormalities including hydranencephaly, poliomyelitis
and arthrogryposis. Infectious virus or viral antigens is present in the brain,
spinal cord and skeletal muscle of infected fetuses. To understand the
interaction between Akabane virus and bovine brain cells, we investigated the
viral tropism using primary cultures of fetal bovine brain. The cultured neuronal
cells, astroglia cells and microglia cells were distinguished by cell type
specific antisera. Akabane virus was found to infect neuronal cells and astroglia
cells, which led to degenerative death. No microglia cells were found infected.
In some brain cultures, we observed different sensitivities of the cells to two
Akabane virus strains: an attenuated strain infected and spread more readily than
wild type virus. This difference was not observed in a hamster fibroblast cell
line. Both viral and host determinants might be involved in the different
susceptibility of brain cells to Akabane virus infection.
PMID- 10781727
TI - An isolated epizootic of hemorrhagic-like fever in cats caused by a novel and
highly virulent strain of feline calicivirus.
AB - An isolated epizootic of a highly fatal feline calicivirus (FCV) infection,
manifested in its severest form by a systemic hemorrhagic-like fever, occurred
over a 1-month period among six cats owned by two different employees and a
client of a private veterinary practice. The infection may have started with an
unowned shelter kitten that was hospitalized during this same period for a severe
atypical upper respiratory infection. The causative agent was isolated from blood
and nasal swabs from two cats; the electron microscopic appearance was typical
for FCV and capsid gene sequencing showed it to be genetically similar to other
less pathogenic field strains. An identical disease syndrome was recreated in
laboratory cats through oral inoculation with tissue culture grown virus. During
the course of transmission studies in experimental cats, the agent was
inadvertently spread by caretakers to an adjoining room containing a group of
four normal adult cats. One of the four older cats was found dead and a second
was moribund within 48-72h in spite of symptomatic treatment; lesions in these
animals were similar to those of the field cats but with the added feature of
severe pancreatitis. The mortality in field cats, deliberately infected
laboratory cats, and inadvertently infected laboratory cats ranged from 33-50%.
This new isolate of calicivirus, named FCV-Ari, was neutralized at negligible to
low titer by antiserum against the universal FCV-F9 vaccine strain. Cats orally
immunized with FCV-F9, and then challenge-exposed shortly thereafter with FCV
Ari, developed a milder self-limiting form of disease, indicating partial
protection. However, all of the field cats, including the three that died, had
been previously immunized with parenteral FCV-F9 vaccine. FCV-Ari caused a
disease that was reminiscent of Rabbit Hemorrhagic Disease, a highly fatal
calicivirus infection of older rabbits.
PMID- 10781728
TI - Identification of the copper-zinc superoxide dismutase activity in Mycoplasma
hyopneumoniae.
AB - Copper-zinc superoxide dismutase (Cu/ZnSOD), a key enzyme in defense against
toxic oxygen-free radicals, is widespread in eukaryotes and several species of
gram-negative bacteria. The presence of this enzyme in Mycoplasma hyopneumoniae
(M. hyopneumoniae), the primary pathogen of mycoplasmal pneumonia in pigs, was
examined since the polyclonal antibody against bovine Cu/ZnSOD was dominantly
cross-reactive with the M. hyopneumoniae Cu/ZnSOD from whole cellular proteins.
In situ activity staining on SDS-PAGE showed that the molecular mass of M.
hyopneumoniae Cu/ZnSOD in reducing form was approximately 17kDa. The presence of
Cu and Zn ions at the active site of the enzyme was confirmed on the basis of
inhibition by KCN and by H(2)O(2). The activity of M. hyopneumoniae Cu/ZnSOD on
both SDS- and native-polyacrylamide gels was completely inhibited by 2mM KCN and
the gels showed no iron-containing SOD (FeSOD) or manganese-containing SOD
(MnSOD) in the crude extracts. The activity of M. hyopneumoniae Cu/ZnSOD in crude
extract was 70units/mg protein and was 55% inhibited by 5mM KCN and 56%
inactivated by 40mM H(2)O(2). This enzyme was growth-stage dependent and
evidenced markedly higher production during the early log phase. Different
expression levels of Cu/ZnSOD activity in field isolates were also detected.
Taken together, the presence of Cu/ZnSOD in M. hyopneumoniae was identified for
the first time.
PMID- 10781730
TI - Identification of virulence associated markers in the cell wall of pigeon
Streptococcus gallolyticus strains.
AB - The cell wall protein profiles of 56 isolates of Streptococcus gallolyticus of
differing virulence for pigeons were compared by SDS-PAGE. Additionally, Western
blot analysis was performed on the cell wall proteins of 14 strains using sera of
pigeons, experimentally infected with A(+)T1 or A(-)T2 strains of S.
gallolyticus. The profile of silver stained gels exhibited a complex array of 20
50 bands ranging from less than 6.5-210kDa. A band with molecular mass of 114kDa
was only observed in isolates that belonged to the highly virulent A(+)T1,
A(+)T2, A(+)T3 and A(-)T1 culture supernatant groups. A band with a slightly
higher molecular mass (115kDa) as well as a 207kDa band were only detected in
isolates that belonged to the moderately A(-)T3 or low A(-)T2 virulent culture
supernatant groups. The 114 and 115kDa band were recognised by all homologous and
heterologous pigeon sera used whereas the 207kDa band was only recognised by sera
of pigeons infected with a A(-)T2 strain. These findings may indicate that the
114, 115 and 207kDa bands are useful as additional virulence associated markers
for pigeon S. gallolyticus strains.
PMID- 10781729
TI - Detection of Mycoplasma synoviae in poultry environment samples by culture and
polymerase chain reaction.
AB - Successful detection of Mycoplasma synoviae (MS) by culture and PCR from samples
collected in the environment of experimentally infected chickens and turkeys, or
under field conditions, is described. Results showed that in the experimental
infection, 10/96 and 46/96 samples of food, drinking water, feathers, droppings
or dust were positive by culture and Mycoplasma-PCR. In field conditions, the
number of positive results for environmental samples were respectively 7/28 and
17/28. These observations highlight the high disseminating capacities of this
mycoplasma and show the usefulness of the PCR method for epidemiological studies.
PMID- 10781731
TI - Identification of the F17 fimbrial subunit- and adhesin-encoding (f17A and f17G)
gene variants in necrotoxigenic Escherichia coli from cattle, pigs and humans.
AB - Putative colonization factors of the F17 family of fimbrial adhesins have been
identified in necrotoxigenic Escherichia coli Type 1 and Type 2 (NTEC1 and NTEC2)
from calves, pigs, and humans. The f17A and f17G gene variants, coding
respectively for the major subunit and for the adhesin of the F17 fimbriae, were
typed in 70 E. coli carrying f17-related sequences (15 NTEC1, 51 NTEC2, and four
non-NTEC) by colony hybridisation with gene probes derived from the different
f17A gene variants (a, b, c, and d) and by PCRs specific for each f17A and f17G
(I and II) gene variants. Typing of f17A genes was not possible by colony
hybridisation, as most 70 E. coli were positive with more than one gene probe. On
the other hand, the PCRs allowed the typing of the f17A gene in 37 E. coli and of
the f17G gene in all 70 E. coli. The f17Ab gene variant was detected in 13 NTEC2;
the f17Ac, in all 15 NTEC1, six NTEC2 and two non-NTEC; and the f17Ad, in one non
NTEC. Seven additional NTEC2 were positive with the PCRs for two variants: f17Ab
and f17Ac in three of them; f17Ac and f17Ad in four of them. Either these seven
NTEC2 harbour two variants or the variant present can be detected by two PCRs.
The remaining 25 NTEC2 and one non-NTEC tested negative with the PCRs for the
four f17A gene variants, suggesting the existence of other variant(s). In
contrast, all 70 E. coli were positive with the PCR for the f17GII gene variant
and none with the PCR for the f17GI gene variant. The f17-related sequences were
present on the CNF2/Vir plasmids in 27 out of the 46 NTEC2 from which plasmid DNA
could be extracted: all but one of those positive for the f17Ab gene variant and
various proportions of those positive for other variants. In contrast, no plasmid
carried f17-related sequences in NTEC1 and non-NTEC.
PMID- 10781732
TI - A PCR assay used to study aerosol transmission of Actinobacillus pleuropneumoniae
from samples of live pigs under experimental conditions.
AB - The study describes a polymerase chain reaction (PCR) assay for the detection of
Actinobacillus pleuropneumoniae. The test is based on the amplification of the
omlA gene coding for an outer membrane protein of A. pleuropneumoniae. To test
the specificity of the reaction, 19 other bacterial species related to A.
pleuropneumoniae or isolated from pigs were assayed. They were all found negative
in the PCR assay. The detection threshold of the test was 10(2) A.
pleuropneumoniae CFU/assay. The test was then applied to the detection of A.
pleuropneumoniae from tonsillar biopsies and tracheobronchial lavage fluids of
pigs without a culture step. The detection of A. pleuropneumoniae in these
samples was performed by PCR, by conventional culture and by bacteriology with
immunomagnetic beads. The number of samples that were found positive by PCR was
almost three times higher than the number of samples from which A.
pleuropneumoniae was isolated by both bacteriological techniques. The detection
of A. pleuropneumoniae in these samples allowed us to demonstrate its aerosol
transmission to pigs under experimental conditions. The trial involved 18
specific pathogen free pigs. Six pigs, infected with A. pleuropneumoniae, were
located in a unit A, together with four non-infected animals (contact pigs).
Eight non-infected pigs (reporter pigs) were located in a unit B, adjacent to A.
We detected A. pleuropneumoniae in samples from infected animals but also from
'contact' (unit A) and 'reporter' (unit B) pigs. The results of this study show
that the simple preparation of the samples followed by the PCR assay may be a
useful tool for epidemiological studies.
PMID- 10781733
TI - Nitric oxide synthase distribution in the cat superior colliculus and co
localization with choline acetyltransferase.
AB - Nitric oxide and acetylcholine are important neuromodulators implicated in brain
plasticity and disease. We have examined the cellular and fiber localization of
nitric oxide in the cat superior colliculus (SC) and its degree of co
localization with ACh using nicotinamide adenine dinucleotide phosphate
diaphorase (NADPHd) histochemistry and an antibody to neuronal nitric oxide
synthase. ACh was localized using an antibody against choline acetyltransferase.
We also made injections of biocytin into the region of the parabrachial brainstem
to confirm that this region is a source of nitric oxide containing fibers in SC.
NADPHd labeled neurons within the superficial layers of the superior colliculus
included pyriform, vertical fusiform, and horizontal morphologies. Labeled
neurons in the intermediate gray layer were small to medium in size, and mostly
of stellate morphology. Neurons in the deepest layers had mostly vertical or
stellate morphologies. NADPHd labeled fibers formed dense patches of terminal
boutons within the intermediate gray layer and streams of fibers within the
deepest layers of SC. Choline acetyltransferase antibody labeling in adjacent
sections indicated that many fibers must contain both labels. Over 94% of neurons
in the pedunculopontine tegmental and lateral dorsal tegmental nuclei were also
labeled by both NADPHd and choline acetyltransferase. In addition, biocytin
labeled fibers from this region were localized in the NADPHd labeled patches. We
conclude that nitric oxide is contained in a variety of cell types in SC and that
both nitric oxide and ACh likely serve as co-modulators in this midbrain
structure.
PMID- 10781734
TI - Substance P-immunoreactive neurons in the rostromedian area of the midbrain send
axons to the lower spinal cord in the chicken.
AB - Substance P-immunoreactivity in neurons projecting to the spinal cord was
examined using retrograde tract-tracing method combined with immunohistochemical
techniques in chickens. Many small substance P-immunoreactive neurons were
densely clustered in the midline area in the rostral midbrain, the rostromedian
area (80% of the neurons in the rostromedian area). Some of these substance P
immunoreactive neurons in the rostromedian area (about 20% of substance P
immunoreactive neurons) were retrogradely labeled by small injections of wheat
germ agglutinin conjugated horseradish peroxidase into the central part of the
lumber segments including the intermediomedial nucleus, suggesting the
projections from the rostromedian area to the lower spinal preganglionic regions.
From the present data and mammalian previous studies, it was suggested that the
midline area in the midbrain has fiber connections with the regions related
autonomic functions, and all of which exhibit substance P-immunoreactivity.
PMID- 10781735
TI - Temporal, regional, and cell-specific changes of iNOS expression after
intrastriatal microinjection of interferon gamma and bacterial
lipopolysaccharide.
AB - Here we study expression of the inducible isoform of nitric oxide synthases after
intrastriatal microinjection of interferon-gamma and bacterial lipopolysaccharide
in the rat at different time points to detect time- and localisation-dependent
changes of iNOS expression. Three different areas in the striatum and the corpus
callosum were evaluated. Antibodies against the glial fibrillary acidic protein
and the microglia/brain macrophage epitope ED1 were used to detect colocalization
of inducible nitric oxide synthase with astrocytes or activated microglia/brain
macrophages, respectively. Inducible nitric oxide synthase-positive cells
occurred first in intravascular and perivascular cells at 4 h. Perivascular and
parenchymal inducible nitric oxide synthase expression increased up to 24 h in
the striatum, whereas in the corpus callosum inducible nitric oxide synthase
expression was maximal after 16 h. Inducible nitric oxide synthase was still
present in perivascular cells 7 days after immunostimulation. At all time points,
inducible nitric oxide synthase was predominantly detected in ED1-positive
microglia/brain. Nitrotyrosine immunohistochemistry was performed to detect NO
mediated nitration of proteins at all time points. Nitrotyrosine-positive neurons
and microglial cells were detected from 24 h until 7 days after immunostimulation
and were absent in controls. Detailed knowledge of the changes in the time course
and cellular source of inducible nitric oxide synthase expression following brain
immunostimulation provide a basis for establishing treatment strategies and
windows of therapeutic intervention during neuroinflammation.
PMID- 10781736
TI - Immunocytochemical mapping of endomorphin-2-immunoreactivity in rat brain.
AB - Endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) is a novel endogenous opioid with high
affinity and selectivity for the mu-opioid receptor. Immunocytochemical studies
have located this peptide in spinal cord, brainstem and selected brain regions.
However, there are disagreements regarding its distribution between published
reports. Furthermore, the distributions reported for the endomorphins resemble
that of neuropeptide FF, suggesting that some of the previous findings might be
due to cross-reactivity with the latter substance. In the present study, the
distribution of endomorphin-2-immunoreactivity (ir) was examined throughout the
entire rat brain using an affinity-purified antiserum that appeared not to cross
react with neuropeptide FF. Endomorphin-2-ir cell somata were most prominent in
the hypothalamus and the nucleus of the solitary tract (NTS). Endomorphin-2-ir
varicose fibers were observed in such areas as the bed nucleus of the stria
terminalis, the septal nuclei, the periaqueductal gray, the locus coeruleus, the
lateral parabrachial nucleus, the NTS, and the substantia gelatinosa of the
medulla. More modest immunoreactivity was seen in substantia nigra, nucleus raphe
magnus, the ventral tegmental area, the pontine nuclei and the amygdala. Fibers
were also observed in the ventral cerebellum. Of note was the negligible
immunoreactivity in the striatum, a region known to express high levels of mu
opioid receptors. Thus, endomorphin-2-ir was widely, but not uniformly,
distributed throughout the central nervous system and was associated largely, but
not exclusively, with regions expressing mu-opioid receptors. Based on its
distribution, it may have a role in the control of neuroendocrine, cardiovascular
and respiratory functions, and mood, feeding, sexual behavior and pain.
PMID- 10781737
TI - Ontogenic profile of the expression of the mu opioid receptor gene in the rat
telencephalon and diencephalon: an in situ hybridization study.
AB - The developmental profile of mu (mu) opioid receptor gene expression has been
characterized in the embryonic, postnatal and adult rat brain by in situ
hybridization histochemistry. By ED12, mu opioid receptor mRNA was detectable in
the deep neuroepithelium of the cortical plate. In the developing rat central
nervous system (ED13-PD40), transcripts were seen over numerous telencephalic and
diencephalic structures, such as the olfactory bulb, caudate-putamen, nucleus
accumbens, amygdaloid complex, hippocampal formation, hypothalamus and thalamus.
In the vast majority of brain regions examined, the developmental profile of the
mu opioid receptor gene expression is similar to that of its translated protein
as established using receptor autoradiography. Once a hybridization signal is
detected in the prenatal period, it gradually increased to reach maximal levels
during the second and third postnatal weeks. By the end of the third postnatal
week, mu opioid receptor mRNA levels decreased to reach amounts seen in
adulthood. Our study demonstrates that mu opioid receptor gene expression is seen
very early on in the embryonic rat brain with transient increases observed during
the critical period of neurogenesis, neuronal migration and synaptogenesis,
suggesting a role of this opioid receptor subtype in brain developmental
processes.
PMID- 10781738
TI - Frequency of the prolificacy gene in flocks of Indonesian thin tail sheep: a
review.
AB - Indonesian thin tail (ITT) sheep have a major prolificacy gene (FecJ(F)), the
frequency of which is higher in the new born lambs, than in the remainder of the
flock when mating is random, because carrier ewes produce more progeny than do
non carriers. The frequency of the gene may vary between flocks, but remains
relatively stable in flocks with established husbandry procedures. The
countermanding selection pressures maintaining the equilibrium value for the
frequency of FecJ(F) are mainly those deriving from higher mortality rates of
lambs in larger litters. Embryo survival is not significantly different across
the range of ovulation rates in ITT ewes, in contrast to observations in other
prolific breeds. Generation intervals and the incidences of metabolic and
infectious diseases in ewes carrying larger litters can also affect the frequency
of FecJ(F) in flocks. In turn, each of the factors affecting the frequency of
FecJ(F) is modulated by the level of nutrition and management in each flock. The
distribution of prolificacy genotypes in the ewes of a standard flock is
calculated as FecJ(F)FecJ(F)/12; FecJ(F)FecJ(+)/44; FecJ(+)FecJ(+)/44 giving a
frequency of 0.34 for FecJ(F). The frequency of FecJ(F) is then 0.43 in the lambs
at birth, when their numbers have been amplified in the carrier ewes. There are
heavier metabolic demands on ewes carrying larger litters and the foetuses
constitute a higher proportion of weight gain during pregnancy. Consequently,
more of the lambs of carrier ewes are smaller and weaker at birth, and the
reserves of the ewes for colostrum and milk production are depleted. When low
lamb survival rates in larger litters are considered, the frequency of FecJ(F)
falls to 0.35 in the lambs at weaning in lean years and 0.38 in middling years.
At a high level of husbandry, ewe weight gains during pregnancy and lamb survival
rates improve substantially, and after 3 years, the frequency of FecJ(F) in the
lambs at birth is estimated to have risen to 0.49; and 0.47 at weaning.
PMID- 10781739
TI - Reproductive characteristics of Ethiopian highland sheep. I. Genetic parameters
of testicular measurements in ram lambs and relationship with age at puberty in
ewe lambs.
AB - A study was conducted to estimate heritabilities of, and genetic correlations
among, body weight (WT) and testicular measurements - scrotal circumference (SC),
testicular diameter (TD), testicular length (TL) and epididymal diameter (ED) -
in ram lambs between 6, 9 and 12 months old, and relationship of the testicular
traits with age at puberty in ewe lambs (AP). Two fat-tailed sheep breeds, the
Horro and Menz, indigenous to the Ethiopian highlands were studied. Experimental
lambs were produced by mating 250 oestrus-synchronized ewes of each breed to 10
sires in a single-sire mating system over three mating periods which produced,
for this study, a total of 361 ram lambs and 148 ewe lambs, with substantial
pedigree information, in two dry seasons (October/November 1992 and 1993) and one
wet season (June/July 1993). Mean AP was 322.7 days. Breed was not significant
(P0.05) for all testicular measurements, except ED at 9 months for which the
Horro had a higher (P<0.01) value (20.6, s.e. 0.38 versus 19.3 s.e. 0.30). Horro
ewe lambs had their first oestrus 28 days earlier (P<0.05) than the Menz.
Heritability estimates were obtained from a sire model (M1) and from an
individual animal model with additive direct and maternal effects (M2). The
maternal effect was not fitted in M2 for AP. Repeatability and heritability
estimates were also obtained by analysing records at the three ages in a repeated
measures model (M3). M1 and M2 heritability estimates were generally low to
moderate but were associated with large standard errors. Heritability estimates
for testicular measurements were generally similar to those for WT. Among the
testicular measurements, SC had the highest heritability estimates at 6 (0.45,
s.e. 0.24 for M1) and at 12 months (0.41, s.e. 0.21 and 0.41, s.e. 0.20 for M1
and M2, respectively). Model 3 heritability estimates were 0.29 (s.e. 0.14), 0.24
(s.e. 0.12), 0.09 (s.e. 0.07), 0.11 (s.e. 0.08) and 0.12 (s.e. 0.08) for WT, SC,
TD, TL and ED, respectively. Only repeatability estimates for WT (0.34, s.e.
0.02) and SC (0.25, s.e. 0.03) were significant. Heritability of AP was estimated
at 0.16 (s.e. 0.21) by M1 and 0.14 (s.e. 0.19) by M2. Genetic correlations of AP
with testicular measurements, especially with SC (-0.57, s.e. 0.38 and -0.78,
s.e. 0.33, at 9 and 12 months, respectively) and TD (-0.72, s.e. 0.33 and -0.83,
s.e. 0.48), were desirable and generally high. Adjustment of testicular
measurements for liveweight consistently resulted in a reduction in estimates of
heritability and genetic correlations. SC was suggested as the most appropriate
selection candidate for the genetic improvement of both male and female
reproductive performance in these breeds.
PMID- 10781740
TI - Clinical, cardiopulmonary, hematological and serum biochemical effects of
sevoflurane and isoflurane anesthesia in oxygen under spontaneous breathing in
sheep.
AB - Effects of sevoflurane and isoflurane anesthesia in oxygen on clinical,
cardiopulmonary, hematological, and serum biochemical findings were compared in
sheep breathing spontaneously undergoing minor surgical operations during short
term (60-80min) or long-term (3-4h) anesthesia. All sheep were premedicated with
atropine sulfate (0.1mg/kg) intramuscularly, and 10min later, induced to
anesthesia by intravenous infusion of sodium thiopental (mean 14.1+/-3.4 S.D.
mg/kg). After intubation, they were anesthetized with either isoflurane or
sevoflurane in oxygen at a total gas flow rate of 1.5l/min. The results revealed
that recovery time with sevoflurane was more rapid than with isoflurane.
Respiration rates, tidal volume, minute ventilation and heart rates during
sevoflurane anesthesia were similar to those during isoflurane anesthesia. The
degree of respiratory acidosis during sevoflurane anesthesia was also similar to
that during isoflurane anesthesia. There were no significant differences between
sevoflurane and isoflurane anesthesia in hematological and serum biochemical
values.
PMID- 10781741
TI - Metabolizable energy of roughage in Taiwan.
AB - The fixed metabolizable energy (ME) values from the NRC do not represent the true
ME values of the various feedstuff used in livestock rations. Therefore, a rapid
and effective method for evaluating the ME value of forage crops is required for
proper ration formulation to improve production efficiency. Dairy goat digestion
trials were conducted as the in vivo reference using the method of Menke and
Steingass (1988) [Menke, K.H., Steingass, H., 1988. Feed Sci. Technol. 28, 91-97]
which derived the amount of gas produced from in vitro fermentation. This method
was adapted in this study to evaluate the ME value. In the goat digestion trial,
six dairy goats were used for each roughage sample in a total fecal collection
trial to determine the digestible nutrients, including energy (DE) and total
digestible nutrient (TDN). The in vivo ME value was calculated using the method
of Shiemann et al. (1971) [Shiemann, R., Nehring, K., Hoffmann, L., Jentsch, W.,
Chudy, A., 1971. Energetische Futterbewertung und Energienormen. VEB Deutscher
Land-wirtschaftsverlag, Berlin, p. 75. (in German)] (ME(1)
(MJ/kg)=5.2DCP+34.2DEE+12.8DCF+15.9DNFE, g/g). The in vitro ME value was then
estimated from the chemical composition of the feed and amount of gas produced
(G(b)) from in vitro fermentation. The value calculated from both with (ME(3))
and without (ME(2)) the inclusion of nitrogen free extracts (NFE) in the
prediction equation. (ME(2) (MJ/kg)=0.145G(b)+4.12CP+6.5CP(2)+20.6EE+1.54, g/g;
ME(3) (MJ/kg)=0.118G(b)+8.75CP+19.21EE+3.38NFE+0.691, g/g). The 12 roughage
samples consisted different growth stages of Napier grass Taishi No. 2: (day of
harvest; 40, 50, 60 and 65), dwarf Napier grass Taishi No. 1: (Day 40 and 65) and
Pangola grass (Day 45) hay (Day 70), corn silage, imported alfalfa hay, timothy
hay and Bermuda hay. The correlation between the ME values calculated from in
vivo and in vitro without NFE was lower than with NFE inclusion in the equation.
A higher correlation between the ME values calculated from in vivo and in vitro
without NFE inclusion than with NFE inclusion in the prediction equation was
obtained when alfalfa and corn silage were not included. This indicated that the
ME value of forage could be estimated rapidly using this in vitro gas method
adapted from Menke and Steingass (1988) [Menke, K.H., Steingass, H., 1988. Feed
Sci. Technol. 28, 91-97] for practical applications in ration formulation.
PMID- 10781742
TI - Dry matter intake, apparent digestibility and excretion of purine derivatives in
sheep fed tropical legume hay.
AB - Four ruminally cannulated wethers (31+/-1.3kg) were used in an experiment with a
4x4 Latin square design to estimate the DM intake, apparent digestibility,
nitrogen balance, rumen ammonia and microbial protein production. The sheep had
ad libitum access to either Cassia rotundifolia (Cassia), Lablab purpureus
(Lablab), Macroptilium atropurpureum (Siratro) or Stylosanthes guianensis
(Stylo). Dry matter intake of cassia was lower (P<0.001) than that of lablab,
siratro and stylo hays. Organic matter intake was greater (P<0.001) for lablab,
siratro and stylo hays than that of cassia. Dry matter digestibility was higher
(P<0.05) for lablab hay, than that of cassia, siratro and stylo hays. The organic
matter digestibility ranged from 0.579 for cassia hay to 0.617 for stylo hay and
there were no differences (P0.05) among the legume hays. Nitrogen intake was
highest (P<0.05) in sheep given stylo hay and least in sheep fed cassia hay.
Animals given lablab, siratro and stylo hays had higher (P<0.05) faecal and
urinary N compared to those on cassia hay. Rumen ammonia N concentration was
highest (P<0.05) in sheep given lablab while sheep offered siratro and stylo had
intermediate values, and least in animals fed cassia hay. The ammonia levels were
above the recommended optimal level of 50mg N/l. The total purine derivative
excretion in the urine and microbial N supply was not different (P0.05) among
treatments. From the presented findings it is concluded that the intake and
digestibility in sheep of the four legume hays are variable and provide adequate
rumen ammonia N for maximum rumen microbial growth making then ideal protein
supplements to ruminants fed low quality roughages.
PMID- 10781743
TI - Effect of buck stimulus on mature and pre-pubertal norgestomet-treated goats.
AB - Two experiments were conducted to assess the effect of buck exposure to
synchronize estrus in mature and pre-pubertal norgestomet-treated crossbred
(criolloxdairy breeds) goats. In experiment 1, 100 mature goats (25 per group)
under range conditions were either teased at 48 or 24h before Sincromate-B (SMB;
9 days treatment of 2mg norgestomet) implant withdrawal. A third group was
exposed to bucks 1 day after SMB treatment and another group was only exposed to
bucks (control). Does exposed to bucks 1 day after SMB treatment tended to have a
lower percentage of estrus (70% compared to 80% and 92% in other groups) and
lower pregnancy rate (57.9 compared to 78.3 and 82.6 in other groups). At 156
days post-joining a significant (P<0.05) difference in cumulative kidding
percentage was found between does teased 48h before implant removal (88.9%) and
does teased 24h before implant removal (56.3%). Teasing without norgestomet was
completely effective at stimulating estrus activity. In experiment 2, pre
pubertal does (n=36; mean 16.6kg BW) treated with SMB+PMSG+teasing tended to have
a higher estrus response than SMB+PMSG treated female goat kids (91.6% vs. 66.6%;
P=0.13). The results of this study indicate that, during the transitional period,
the male effect was as effective as the synchronizing treatments involving SMB in
inducing estrus in goats with reduced seasonal inhibition of reproduction. Also,
buck exposure potentiates the effect of PMSG to induce estrus in norgestomet
primed pre-pubertal does.
PMID- 10781744
TI - The effect of breed slaughter weight and nutritional management on cholesterol
content of lamb carcasses.
AB - This study was carried out to assess the effect of breed, sex, post-weaning
nutrition, live weight at slaughter and their interactions on the cholesterol
content in carcass fat of lambs. The carcasses were obtained from lambs of three
indigenous Greek dairy breeds of sheep, the Boutsko (B), Serres (S) and
Karagouniko (K) breed. After weaning (at approximately 42 days), the lambs of the
three breeds had been reared under different conditions of housing and
nutritional management in three consecutive experiments between 1992 and 1994. In
experiment 1, lambs (males and females) were individually penned and fed ad
libitum on a concentrate ration (11.3MJ Metabolizable Energy (ME)/kg DM and 192g
crude protein (CP)/kg DM) together with 100g per day of Lucerne hay (8.3MJ ME/kg
DM and 182g CP/kg DM). In experiment 2, lambs (males only) were also individually
penned but were fed on three different levels of concentrate and ad libitum on
Lucerne hay. In experiment 3, lambs (males only) were initially group fed indoors
for 63 days on three different levels of concentrate together with ad libitum
Lucerne hay, and thereafter the lambs finished on irrigated, sown pasture (Lolium
perrene+Trifolium repens). Lambs were assigned to be slaughtered at one of five
standard proportions of estimated mature weight for each breed in experiment 1;
at three fixed live weights, common for all breeds in experiment 2 and at two
fixed proportions of breed mature weight in experiment 3. The right-hand side of
the lamb carcasses was minced and 150 lamb carcasses were selected out of a total
of 300 minced carcasses. The concentration of total cholesterol content in
carcass fat was determined by HPLC in samples of these 150 lamb carcasses. Mean
cholesterol content of carcass fat in the three breeds, B, S and K, extracted
from the whole ground carcasses samples, was 3.33, 4.41, 3.34mg/g of carcass fat
(s.e.d. 0.18), respectively in experiment 1, whereas this content was 3.42, 4.50,
3.59mg/g of carcass fat (s.e.d. 0.19) in experiment 2 and 4.38, 3.47, 3.78mg/g of
carcass fat (s.e.d. 0.22) in experiment 3. Cholesterol content differed
significantly (P<0.001 in experiments 1 and 2, P<0.05 in experiment 3) between
breeds. It was also significantly affected (P<0.05) by the sex of lambs
(experiment 1). Live weight of lambs at slaughter had a significant effect on
cholesterol content (P<0.001 in experiment 1 and P<0.05 in experiment 2). There
was a general trend for cholesterol content to be lower in fat samples extracted
from carcasses as target slaughter weight increased. The different levels of
concentrate feed affected significantly (P<0.00l) the cholesterol content in
carcass fat in experiment 2. The results suggest that there are possibilities of
modifying body composition by manipulation of post-weaning nutrition, especially
reducing the cholesterol content, in carcass fat of lambs slaughtered at a wide
range of live weights. In such a situation, however, as nutritional management
and degree of maturity change, breed remains the main factor that determines the
cholesterol content in carcass fat.
PMID- 10781745
TI - Variation of mohair quality over the body in Angora goats.
AB - Forty female Angora goats were selected at random from the experimental nucleus
of the National Institute of Agricultural Technology (Pilcaniyeu, Argentina),
with the aim of analyzing the variability of main fleece characteristics of the
Angora goats and establishing an optimum sampling site. Samples were taken at the
first and second shearings (12 and 18 months of age) from the following parts of
the fleece: neck, midrib, back, britch, belly and shoulder. For each sample the
following determinations were made: oven-dry yield (YLD); average (AFD); standard
deviation (SDAFD) and coefficient of variation (CVAFD) of fiber diameter;
percentage of medullated fibers (MFT); characterization of three types of
medullated fibers: continuous (MFC), interrupted (MFD) and kemp (KEMP) by
estimating their proportion, average fiber diameter, standard deviation and
coefficient of variation of fiber diameter; wax (WAX); suint (SUINT); humidity
(HMD); staple length (STAPLE); degree of brightness (Y) and degree of yellowness
(Y-Z). All variables studied showed statistically significant variability among
to the sampling position (P<0.05), except of Y-Z, proportion of FMC, average
fiber diameter of MFD and KEMP, and standard deviation of fiber diameter of KEMP
at 12 months of age, at 18 months old for STAPLE and standard deviation of fiber
diameter of MFD, and for CVAFD at the two ages of shearing (P0.05). The results
showed that sampling from the midrib of Angora goats gave adequate representation
for most of the fleece variables analyzed.
PMID- 10781746
TI - Immunology and immunotherapy of human cancer: present concepts and clinical
developments.
AB - Immunotherapy of cancer is entering into a new phase of active investigation both
at the pre-clinical and clinical level. This is due to the exciting developments
in basic immunology and tumour biology that have allowed a tremendous increase in
our understanding of mechanisms of interactions between the immune system and
tumour cells. This review briefly summarizes the state of the art in basic tumour
immunology before discussing the clinical applications of the new concepts in the
clinical setting. Clinical approaches are diverse but can now be based on strong
scientific rationales. The analysis of the available clinical results suggests
that, despite some disappointments, there is room for optimism that both active
immunotherapy (vaccination) and adoptive immunotherapy may soon become part of
the therapeutic arsenal to combat cancer in a more efficient way.
PMID- 10781747
TI - Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic
implications.
AB - Epstein-Barr virus (EBV), a ubiquitous B-lymphotrophic herpesvirus, has been
found in the tumor cells of a heterogeneous group of malignancies (Burkitt's
lymphoma, lymphomas associated with immunosuppression, other non-Hodgkin's
lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, gastric adenocarcinoma,
lymphoepithelioma-like carcinomas, and immunodeficiency-related leiomyosarcoma).
As the epidemiologic characteristics of these cancers have not been considered
together, this review seeks to relate their incidence patterns and risk factors
to EBV biology and virus-host interaction in an attempt to help elucidate factors
involved in EBV-related carcinogenesis. We include a brief review of EBV virology
and primary infection to provide a biologic context for considering the
epidemiology, summarize the most salient epidemiologic features of each
malignancy, synthesize epidemiologic data by risk factor to uncover commonalities
and informative contrasts across the diseases, and propose hypotheses regarding
etiologic mechanisms, based on the possible effect of the risk factors at various
stages in the viral life cycle.
PMID- 10781748
TI - Aspergillosis in bone marrow transplant recipients.
AB - Invasive aspergillosis in bone marrow transplant recipient is associated with a
high mortality. Diagnosis is often delayed because the inflammatory response is
blunted by immunosuppression. The gold standard of tissue biopsy is often
considered too in invasive as the procedure is often complicated by bleeding and
secondary infection. Recent finding on non-invasive tests such as serial
measurement of peripheral blood galactomannan antigen or DNA appears to be
promising. However, the limited availability of such tests and requirement for
expertise are still hampering their use in routine clinical management. More
often than not, initiation of antifungal therapy is empirical and based on
suggestive radiological changes. Amphotericin B remains the gold standard of
therapy but liposconal preparation may prove to be less nephrotoxic and equally
effective. Treatment outcome depends more on the acceleration of the recovery of
the immune system and the reduction of anti-GVHD therapy than the antifungal
agent followed by surgical resection. The efficacy of many reported anti
aspergillosis prophylactic regimen has not been proved in randomized control
trials. Despite the absence of data, such policy should still be considered in
transplant units with high incidence of aspergillus or undergoing renovation.
PMID- 10781749
TI - Mental neuropathy: report of five cases and review of the literature.
AB - Mental nerve neuropathy, also referred to as numb chin syndrome, is a rare,
seemingly harmless symptom. It is more often associated with cancer, either as
first symptom or during the outcome, than with benign diseases. In this review,
we will focus on the numb chin syndrome presenting as an isolated neurological
symptom. We report five patients with mental nerve neuropathy associated with
metastatic disease (small cell lung cancer, prostatic cancer and breast cancer).
In one patient, numb chin syndrome preceded the discovery of the disease, while,
in the four others, it occurred as a sign of relapse or progression. Isolated
mental nerve neuropathy, frequently associated with breast cancer and
lymphoproliferative diseases, is generally thought to be the consequence of bone
metastases or leptomeningeal seeding, but may also present without an obvious
cause, most often secondary to the involvement of the mental nerve itself.
Although various therapies may lead to the resolution of this symptom, median
survival after diagnosis is generally less than 1 year. The appearance of a
mental nerve neuropathy should never be considered as a 'banal' symptom and
investigations to detect a possible cancer should be mandatory.
PMID- 10781750
TI - Patterns of atherosclerosis: effect of risk factors on recurrence and survival
analysis of 11,890 cases with more than 25-year follow-up.
AB - A series of 11,890 patients from the senior investigator's surgical service
between 1949 and 1998 is analyzed for the significance of distinct risk factors
for recurrence of, and survival from, atherosclerotic occlusive disease. Eight
risk factors have been assessed for their importance in 4 defined arterial
categories (the coronary arterial bed, the branches of the aorta, the abdominal
visceral [celiac, superior mesenteric, and renal] arteries, and the terminal
abdominal aorta and its major branches) in determining survival rate of the
entire group and their impact on rate of recurrence of atherosclerosis in a
subgroup of 5,568 patients who had > or =1 postoperative arteriogram, permitting
precise identification of changes in the atherosclerotic process. Patients in
these 2 groups were followed for > or =25 years; univariate and multivariate
analyses were used. On admission all patients had symptomatic atherosclerotic
occlusive disease in a single vascular category. Each patient was treated
surgically for alleviation of the disease. Two primary outcomes are included: (1)
survival, by atherosclerosis category, in all 11,890 patients; and (2)
recurrence, also by category, in the subset of 5,568 patients. Multivariate
results for recurrence showed little consistency across categories. Only 1 risk
factor, diabetes, appeared in 2 of the 3 categories fully analyzed. Other
variables that are significant in only a single category are male sex,
cholesterol, hypertension, and smoking. Survival showed much greater consistency,
with age, diabetes, and hypertension significant in all 3 categories, male sex
and smoking in 2, and cholesterol in only Category I. Univariate results followed
much the same trend. For recurrence and survival, the response of the arterial
bed to the risk factors in each of the 4 categories is distinctly different, an
observation that we have not found to be previously reported.
PMID- 10781751
TI - Increased platelet aggregability in response to shear stress in acute myocardial
infarction and its inhibition by combined therapy with aspirin and cilostazol
after coronary intervention.
AB - Although antiplatelet therapy with a specific inhibitor of phosphodiesterase-3
cilostazol improves stent patency compared with use of aspirin (ASA) alone, the
specific role of cilostazol on platelet aggregation in patients with acute
myocardial infarction (AMI) is less well understood. Thirty-six patients with AMI
who were successfully treated with primary angioplasty were randomized to 3
antiplatelet regimens: ASA alone (n = 12), ASA + ticlopidine (n = 12), and ASA +
cilostazol (n = 12). We measured shear stress-induced platelet aggregation (SIPA)
using a modified cone-plate viscometer on admission and on day 7, and evaluated
the inhibitory effects of combination therapy with ASA + cilostazol on SIPA.
Compared with cases of stable coronary artery disease, significant increases in
SIPA and plasma von Willebrand factor activity were observed in patients with AMI
before they received antiplatelet therapy. On day 7 after primary angioplasty,
ASA did not inhibit SIPA (65 +/- 15% vs 57 +/- 11%, p = 0.086), whereas both
combination therapies of ASA + ticlopidine and ASA + cilostazol significantly
inhibited SIPA in patients with AMI (ASA + ticlopidine: 61 +/- 15% vs 45 +/- 13%,
p <0. 0001; ASA + cilostazol: 64 +/- 14% vs 43 +/- 9%, p <0.005). There was a
significant correlation of SIPA with adenosine diphosphate (ADP)-induced platelet
aggregation (r = 0.412, p = 0.003) and with plasma von Willebrand factor activity
(r = 0.461, p = 0.0008). These data suggest that patients with AMI have increased
platelet aggregability in response to high shear stress. Combined antiplatelet
therapy with ASA + cilostazol appears to be as effective as therapy with ASA +
ticlopidine for reducing SIPA in patients with AMI who are undergoing primary
angioplasty.
PMID- 10781752
TI - The benefit of abciximab in percutaneous coronary revascularization is not device
specific.
AB - Abciximab has been shown to decrease adverse outcomes after percutaneous coronary
interventions, but it is unclear whether this beneficial effect is more or less
pronounced with specific devices. This study sought to determine the relative
magnitude of the benefit of abciximab among different interventional devices.
Data from the 5 placebo-controlled trials of abciximab during coronary
intervention were pooled. Patients were divided into groups based on whether they
received balloon angioplasty alone, elective stenting, bailout stenting, or
directional coronary atherectomy. In the patients undergoing balloon angioplasty,
the 30-day hazard ratio for death or myocardial infarction (MI) in the group
randomized to abciximab versus the placebo-treated group was 0.52 (p <0.001), for
elective stenting the hazard ratio was 0.51 (p <0.001), for bailout stenting the
hazard ratio was 0.38 (p <0.001), and for directional coronary atherectomy the
hazard ratio was 0.38 (p = 0.007). A Cox proportional-hazards model revealed that
overall, the use of abciximab decreased the composite end point of 30-day death
or MI rates (hazard ratio 0.55, 95% confidence interval 0.43 to 0.69, p <0. 001).
However, bailout stenting and directional coronary atherectomy were associated
with increased rates of death or MI compared with balloon angioplasty, as was
elective stenting in women compared with men. There was no significant increase
in major bleeding episodes associated with abciximab in any of the device
categories. These findings from all the controlled coronary revascularization
trials using abciximab demonstrate that a decrease in death and MI is achieved
with abciximab regardless of the type of device used, without an increase in
significant bleeding complications.
PMID- 10781753
TI - Long-term outcome in patients treated by intracoronary stenting with ticlopidine
and aspirin, and deleterious prognostic role of unstable angina pectoris.
AB - Compared with stable clinical conditions, unstable angina carries an increased
risk of immediate and delayed cardiac adverse events after balloon coronary
angioplasty. The influence of stent use in reducing these differences remains
unknown. We analyzed the early (30 days) and late outcome of a cohort of 459
consecutive patients who underwent stent placement with ticlopidine and aspirin
as antithrombotic regimen according to the presence (group 1, n = 151) or absence
(group 2, n = 308) of unstable angina at rest (Braunwald classes II and III).
Group 1 patients were older and more likely to be current or former smokers. In
group 2, prior myocardial infarction was more frequent. Procedural, in-hospital
results, and early outcome were similar in the 2 groups. However, over the long
term, the incidence of myocardial infarction (11% vs 6%, p <0.04), target lesion
revascularization (19% vs 13%, p <0.04), or any revascularization (30% vs 20%, p
<0.01) was significantly higher in group 1. Kaplan-Meier probabilities of
survival without myocardial infarction (85% vs 91%, p <0.05), survival without
revascularization of the target lesion (73% vs 83%, p <0.01), survival without
any revascularization (65% vs 77%, p <0.006), and survival without any events
(61% vs 73%, p <0.009) were significantly worse in group 1. In addition, Cox
multivariate analysis showed that unstable angina at rest was an independent
predictor of target lesion revascularization, of survival without any
revascularization, and without any events. Thus, unstable angina at rest remains
an adverse prognostic indicator in patients treated with intracoronary stents,
particularly with regard to subsequent requirement of revascularization
procedures and event-free survival.
PMID- 10781754
TI - Impaired forearm reactive hyperemia is related to late restenosis after coronary
stenting.
AB - To investigate whether systemic endothelial function on forearm resistance
vessels is related to angiographic restenosis after coronary stenting, 47 men who
underwent elective coronary stenting were divided into 2 groups according to the
presence (n = 20) or absence (n = 27) of in-stent restenosis 6 months after the
procedure. Another 19 risk factor-matched men with normal coronary angiograms
served as the control group. Forearm blood flow was assessed by venous occlusive
plethysmography. Basal forearm blood flow was similar between restenosis,
nonrestenosis, and control groups (2.63 +/- 0.19, 2.58 +/- 0.14, and 3.23 +/-
0.13 ml/100 ml forearm tissue per minute, respectively). In all 3 groups, forearm
blood flow increased significantly during reactive hyperemia (5.75 +/- 0.7, 11.
32 +/- 1.23, and 14.52 +/- 1.36 ml/100 ml forearm tissue per minute, p <0.05,
respectively) and remained unchanged after sublingual administration of
nitroglycerin. The percentage change of forearm blood flow during reactive
hyperemia was significantly lower in the restenosis group (117.3 +/- 18.3%) than
in the nonrestenosis group (354.2 +/- 46.5%, p <0.01). This difference was still
present after sublingual nitroglycerin (37.6 +/- 21.2% vs 226.4 +/- 40.5%, p <0.
01). In contrast, percentage change of hyperemic forearm blood flow was
significantly lower in patients with angina (117.5 +/- 49.5%) than in those
without angina (290.1 +/- 37.4%, p <0.05) at follow-up. In all patients, the
angiographic loss index was correlated negatively to the percentage change of
hyperemic forearm blood flow (r = -0.33, p <0.01) and positively to the
percentage change of forearm vascular resistance during reactive hyperemia (r =
0.33, p <0.01). In patients with angiographic restenosis after coronary stenting,
forearm reactive hyperemia was more impaired compared with those without
angiographic restenosis. Systemic endothelial dysfunction might be either a
marker or one of the confounding factors in the development of late restenosis
after coronary stenting.
PMID- 10781755
TI - Prognostic value of cardiac troponin-I levels following catheter-based coronary
interventions.
AB - This study has examined the prognostic significance of troponin-I (Tn-I) levels
after catheter-based coronary interventions in coronary arteries and saphenous
vein grafts lesions. Tn-I and creatine kinase-MB (CK-MB) fraction levels were
measured at 6 and 18 to 24 hours after catheter-based coronary intervention in
1,129 consecutive patients with normal preintervention plasma levels of Tn-I, and
CK-MB levels below the cutoff for myocardial infarction. Patients were stratified
according to maximal postangioplasty Tn-I levels. Group I (n = 784) had no
elevated Tn-I (<0.15 ng/ml), group II (n = 170) had Tn-I at 0.15 to 0.45 ng/ml,
and group III (n = 175) had Tn-I elevation >0.45 ng/ml. Major in-hospital
complications (death, 0-wave infarction, and emergent coronary bypass grafting)
and out-of-hospital intermediate-term (8 months) outcomes were compared between
the 3 groups. Tn-I elevation >0.45 ng/ml was associated with increased risk of
mortality (group III, 1.6%; group II, 0.6%; and group I, 0.1%; p = 0.019) and
major in-hospital complications (3.2%, 1.7%, and 0.5%; p = 0.004). There was no
difference in death (1.8%, 3.2%, and 2.4%; p = 0.74), Q-wave infarction (0.6%,
0%, and 0.3%; p = 0.66), or target lesion revascularization (10.1%, 9.0%, and
9.3%; p = 0.86) between the 3 groups at follow-up. Cardiac event-free survival
was similar between groups (p = 0.3). By multivariate analysis, Tn-I >0.45 ng/ml
was an independent predictor for major in-hospital complications (odds ratio 2.1,
95% confidence interval 1.2 to 3.9, p = 0.01). The degree of risk was also
associated with the conjoint elevation of Tn-I and CK-MB levels (odds ratio 1.1,
95% confidence interval 1.02 to 1.2, p = 0.01). We conclude that Tn-I levels >3
times the normal limit and conjoint elevation of Tn-I and CK-MB levels after
coronary angioplasty are associated with increased risk of major in-hospital
complications, but have no incremental risk of adverse intermediate-term (8
months) clinical outcomes.
PMID- 10781757
TI - Angiotensin-converting enzyme and apolipoprotein B polymorphisms in coronary
artery disease.
AB - The association between angiotensin-converting enzyme (ACE) as well as
apolipoprotein B polymorphisms and dyslipidemia and coronary artery disease (CAD)
is controversial. We assessed the distribution of ACE insertion and/or deletion,
apolipoprotein B signal peptide insertion and/or deletion, and apolipoprotein B
XbaI restriction fragment length polymorphisms in 388 nondiabetic patients. We
studied 112 patients with angiographically defined asymptomatic CAD or with
stable functional classes I and II angina and 139 patients with acute myocardial
infarction who were age matched to 137 control subjects. Univariate analysis
showed higher prevalence of Xba50% reduction of lumen diameter. Overall,
multivariable regression disclosed traditional risk factors and elevated levels
of apolipoprotein B for men and reduced levels of apolipoprotein AI for women as
independent variables for CAD. After adjustment for the most important subset of
risk factors (age, hypertension, hypercholesterolemia, and smoking),
apolipoprotein B XbaI polymorphism was disclosed as an independent variable for
CAD. Apolipoprotein B XbaI was also selected as an independent variable for acute
myocardial infarction after adjusting for age, hypertension,
hypercholesterolemia, and smoking. Thus, in addition to traditional coronary risk
factors, apolipoproteins B and AI, and apolipoprotein B XbaI polymorphism could
be considered predictors of CAD.
PMID- 10781756
TI - Effect of coronary angiography on use of lipid-lowering agents in women: a report
from the Women's Ischemia Syndrome Evaluation (WISE) study. For the WISE
Investigators.
AB - We sought to assess the impact of coronary angiography results on use of lipid
lowering agents among women enrolled in the Women's Ischemia Syndrome Evaluation
[WISE] study. WISE is a multicenter study designed to evaluate new diagnostic
modalities among women undergoing angiography for suspected coronary artery
disease (CAD). History of atherosclerosis, risk factors for CAD, and low-density
lipoprotein (LDL) cholesterol are determined at baseline. The percentage of women
at LDL cholesterol goal, use of lipid-lowering agents, and eligibility for lipid
lowering therapy were determined based on National Cholesterol Education Program
II guidelines at baseline and 6-week follow-up. Among the 212 women for whom
angiographic data were available, 84 had known atherosclerosis, 80 had no history
of atherosclerosis but > or =2 risk factors (high risk), and 48 had no history of
atherosclerosis and <2 risk factors (low risk). At baseline, LDL cholesterol
goals were met in 24% women with atherosclerosis, in 56% high-risk women, and in
88% low-risk women. Angiography revealed previously undiagnosed CAD in 70% of the
high-risk and in 42% of the low-risk women. After angiography results were
available, 6 women started lipid-lowering therapy and 2 stopped. Based on
National Cholesterol Education Program II guidelines, 63 additional women would
have been eligible for pharmacologic lipid-lowering therapy. Intensification of
lipid-lowering therapy was not apparent 6 weeks after coronary angiography in
women with newly diagnosed CAD or among women whose diagnosis was confirmed.
PMID- 10781758
TI - Value of QT dispersion in the interpretation of treadmill exercise
electrocardiograms of patients without exercise-induced chest pain or ST-segment
depression.
AB - It has recently been reported that increased QT dispersion seen on standard 12
lead electrocardiograms (ECGs) reflects transient myocardial ischemia. The
present study investigates whether increased QT dispersion induced by exercise is
a useful indicator for detecting significant coronary stenosis in patients who do
not have chest pain or significant ST-segment depression in response to exercise.
We studied 135 consecutive patients (mean age +/- SD, 55 +/- 9 years; 97 men and
38 women) who complained of anginal chest pain and who did not have exercise
induced chest pain or significant ST-segment depression during treadmill exercise
electrocardiography. Coronary angiography was performed in all of patients. Of
the 135 patients, 97 had no significant coronary stenosis, 25 had 1-vessel
coronary artery disease (CAD), and 13 had multivessel CAD. QT dispersion
immediately after exercise was significantly greater in the group with
significant coronary stenosis than without significant coronary stenosis (62 +/-
13 vs 40 +/- 14 ms, p <0.0001). When QT dispersion >/=60 ms immediately after
exercise was considered a positive result, this indicator had a sensitivity of
74%, a specificity of 85%, and an accuracy of 81% for the diagnosis of
significant coronary stenosis. In conclusion, we have shown that QT dispersion
immediately after exercise is useful for detecting significant CAD in patients
who do not have exercise-induced chest pain or significant ST-segment depression.
PMID- 10781759
TI - Multiple-dose efficacy and safety of an extended-release form of niacin in the
management of hyperlipidemia.
AB - This multicenter trial evaluated the safety and efficacy of escalating doses of
Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at
bedtime) in patients with primary hyperlipidemia on the percent change from
baseline in levels of low-density lipoprotein (LDL) cholesterol and
apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day,
raised to 500 mg/day, and further increased in 500-mg increments at 4-week
intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended
release niacin; n = 44, placebo) were treated for 25 weeks with study medication
after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL
cholesterol stability phase. Significant decreases from baseline in levels of LDL
cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and
were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%,
respectively, at the 3,000-mg/day dose. Significant increases from baseline in
levels of high-density lipoprotein cholesterol became apparent with the 500
mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching
30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides
and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all
subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000
mg dose. The most common adverse events were flushing and gastrointestinal
disturbance. Transaminase increases were relatively small, and the proportion of
patients who developed liver function abnormalities on extended-release niacin
was not significantly different from placebo. Thus, extended-release niacin was
generally well tolerated and demonstrated a dose-related ability to alter
favorably most elements of the lipid profile.
PMID- 10781760
TI - Acute hemodynamic effects of right ventricular pacing site and pacing mode in
patients with congestive heart failure secondary to either ischemic or idiopathic
dilated cardiomyopathy.
AB - The hemodynamic effects of pacing in patients with congestive heart failure (CHF)
remain controversial. Early studies reported that pacing from the right
ventricular (RV) apex improved acute hemodynamic parameters in patients with left
ventricular systolic dysfunction, but these findings were not confirmed in
subsequent controlled studies. More recently, it has been proposed that pacing
from the RV side of the ventricular septum improves hemodynamic function compared
with intrinsic conduction or apical pacing. Either dual-chamber or ventricular
pacing have been evaluated, again with inconsistent findings. To assess the
effects of pacing site and mode on acute hemodynamic function, we evaluated 21
subjects with CHF and intrinsic conduction disease. Hemodynamics were compared in
AAI, VVI, and DDD modes with pacing from the RV apex or high septum. The pacing
rate was constant in each patient and the order of testing was randomized. In the
absence of ventricular pacing (AAI mode), the mean systemic arterial pressure was
85 +/- 11 mm Hg, the right atrial pressure was 11 +/- 4 mm Hg, the pulmonary
capillary wedge pressure was 18 +/- 8 mm Hg and the cardiac index was 2.4 +/- 0.7
L/min/m(2). Compared with AAI pacing, there were no improvements in any
hemodynamic parameter with DDD pacing from either RV site. Hemodynamic function
worsened with VVI pacing from both RV sites. Subgroup analyses of patients with
dilated cardiomyopathy, with prolonged PR interval, or with significant mitral
regurgitation also failed to demonstrate an improvement with pacing. We conclude
that pacing mode but not RV pacing site affects acute hemodynamic function.
Pacing in the DDD mode prevents the deleterious effects of VVI pacing in this
patient population.
PMID- 10781762
TI - Alcohol abuse and dilated cardiomyopathy in men.
AB - Excessive ethanol intake is reported in 3% to 40% of patients with idiopathic
dilated cardiomyopathy (IDC). In the prevasodilator era, the prognosis was
reportedly better in alcoholic than in IDC patients, an advantage limited to
abstinent patients. No large series of patients systematically treated with
angiotensin-converting enzyme inhibitors has since been described. We analyzed
long-term outcome according to alcohol abuse in male patients with IDC. Among 338
men who had been prospectively enrolled in a multicenter registry, 79 (23%) were
defined as alcohol abusers and further classified at follow-up as having stopped
(AAS) or continued (AAC) abuse. AAC subjects at enrollment reported a higher
daily alcohol intake than AAS subjects (178 +/- 113 vs 127 +/- 54 g/day, p =
0.012). During a mean of 59 +/- 35 months, 102 patients died and 45 underwent
transplantation. Seven-year transplant-free survival was significantly lower in
alcohol abusers (41%) than in patients with IDC (53%, p = 0.026), and
significantly lower in AAC subjects (27%) than in either patients with IDC or AAS
(45%) (p = 0. 018). Although IDC patients had beneficial changes in left
ventricular function at follow-up, only AAS patients had significant improvement
in ejection fraction. In this large series of patients treated with angiotensin
converting enzyme inhibitors and prospectively followed up, excessive alcohol
intake was found in about one fourth of cases and persistent alcohol abuse
correlated with a worse prognosis and function at follow-up.
PMID- 10781761
TI - Correlates and impact on outcomes of worsening renal function in patients > or
=65 years of age with heart failure.
AB - 1.5 mg/dl. Based on the number of these factors, a patient's risk for developing
worsening renal function ranged between 16% (< or =1 factor) and 53% (> or =5
factors). After adjusting for confounding effects, worsening renal function was
associated with a significantly longer length of stay by 2.3 days, higher in
hospital cost by $1,758, and an increased risk of in-hospital mortality (odds
ratio 2.72; 95% confidence interval 1.62 to 4.58). In conclusion, worsening renal
function, an event that frequently occurs in elderly patients hospitalized with
heart failure, confers a substantial burden to patients and the healthcare system
and can be predicted by 6 admission characteristics.
PMID- 10781763
TI - Serial echocardiographic measurements of the pulmonary autograft in the aortic
valve position after the Ross operation in a pediatric population using normal
pulmonary artery dimensions as the reference standard.
AB - Serial echocardiographic measurements of the annulus and sinus were obtained in
children before the Ross operation, and early and late postoperatively. Values
were compared with normal standards for the aorta and pulmonary artery (PA).
There was no significant difference between PA annulus measurements before
surgery and the corresponding autograft immediately afterward (1.73 +/- 0.60 cm
preoperatively; 1. 63 +/- 0.58 cm postoperatively, p = NS). Late after surgery
the mean annulus diameter was enlarged compared with the normal aorta (DeltaZ 1.9
+/- 2.4), but remained relatively unchanged compared with the normal PA (DeltaZ
0.7 +/- 1.1, p <0.01). In contrast, the autograft sinus was dilated early after
surgery (1.83 +/- 0.58 cm preoperatively; 2.18 +/- 0.73 cm postoperatively, p
<0.01). Mean sinus Z score further increased compared with both the aorta (DeltaZ
1.3 +/- 1.7) and PA (DeltaZ 1.3 +/- 1.6). Use of standard PA measurements may be
important in the assessment of autograft enlargement. Minimal change in autograft
Z scores over time suggests that annulus enlargement is mainly due to somatic
growth. In contrast, the autograft sinus showed an immediate and continued
disproportionate increase in size over time, suggesting that sinus enlargement is
largely due to passive dilation.
PMID- 10781764
TI - Surgical validation and implications for transcatheter closure of quantitative
echocardiographic evaluation of atrial septal defect.
AB - Accurate evaluation of secundum atrial septal defect (ASD) is important for the
success of transcatheter closure. The purpose of this study was (1) to describe a
quantitative evaluation by transthoracic (TTE) and transesophageal (TEE)
echocardiography of the various morphologic features of ASD that might be
important for patient selection for transcatheter closure, and (2) to assess the
reliability of these 2 methods by surgical findings. Preoperative TTE and TEE
were used to evaluate the ASD of 27 children undergoing surgical closure.
Measurements included the diameters of ASD and the atrial septal lengths in the
transverse and longitudinal axis, and the width of the superior, inferior,
anteroinferior, and posterior septal margins. The shape and location of the ASD
and the adequacy of the septal margins for anchoring occluding devices were
determined. Echocardiographic data were compared with corresponding surgical
measurements. No significant difference occurred in the means of all the
parameters measured with the 3 methods, except for the transverse ASD diameter (p
<0.05). Good agreement occurred between TTE and TEE and surgical data, except for
the transverse ASD diameter, transverse atrial septal length, and the posterior
septal margin on TTE. Intraclass correlations between TTE and TEE and surgical
measurements of all parameters were good, except for the transverse ASD diameter.
The accuracy in determining shape and location of the ASD by TTE and TEE were
100%, whereas that for determining the adequacy of septal margins was 98% and
97%, respectively. In conclusion, TTE and TEE are reliable methods for
quantitative evaluation of ASD.
PMID- 10781765
TI - Pulsed Doppler tissue imaging in endurance athletes: relation between left
ventricular preload and myocardial regional diastolic function.
AB - The aim of this study was to assess the effects of endurance training on
myocardial regional systolic and diastolic function by pulsed Doppler tissue
imaging (DTI). Twenty male water polo players and 20 male control subjects
underwent standard Doppler echocardiography and pulsed DTI, performed in apical
views by placing a sample volume on left ventricular (LV) basal septal and
inferior walls. Age, body surface area, and blood pressure were comparable
between the 2 groups, with lower heart rate in athletes (p <0.001). They had
significantly increased LV mass index (due to both higher wall thickness and end
diastolic diameter), greater endocardial fractional shortening, higher
transmitral early/atrial (E/A) peak velocities ratio. In athletes, DTI analysis
showed significantly prolonged myocardial deceleration time and greater
myocardial E/A peak velocity ratio of septal and inferior walls, whereas
myocardial early peak velocity was increased (p <0.01) only at the inferior wall.
In the overall group, we found univariate relations of septal and inferior E/A
peak velocity ratio and myocardial deceleration time with LV mass levels, and, in
particular, with the sum of wall thickness. By separate multivariate analyses,
however, these relations disappeared, being dependent on heart rate degree.
Another association found between LV end-diastolic diameter and myocardial early
diastolic wave peak velocity of the inferior wall (r = 0.68, p <0.0001) remained
significant (standardized beta coefficient 0.60, p <0.00001), even after
adjusting for heart rate, body surface area, age, and stroke volume (R(2) = 0.71,
p <0.00001). In conclusion, DTI is a useful tool for detecting regional changes
in myocardial function induced by training, because athletes present with an
improvement in diastolic passive properties of myocardium. The higher early
diastolic velocity of the inferior wall and its relation to increased preload may
represent an indicator of aerobic training, allowing quantification of the degree
of LV adaptation to endurance exercise.
PMID- 10781766
TI - In the long run not everybody is dead.
PMID- 10781767
TI - Compensatory enlargement of the coronary artery in acute myocardial infarction.
AB - Compensatory enlargement occurred in 71% of lesions in patients with acute
myocardial infarction and was more common in these patients than in patients with
stable effort angina pectoris. These results suggest that compensatory
enlargement may be associated with plaque rupture and subsequent acute myocardial
infarction.
PMID- 10781768
TI - Immediate and long-term results of "T" stenting for bifurcation coronary lesions.
AB - The technique of "T" stenting, which incorporates wiring both the branches of a
bifurcation lesion, dilating a balloon in the main branch during stent deployment
in the side branch followed by deployment of stent in the main branch, provides
excellent immediate results in terms of technical and procedural success.
However, further innovations are mandated to optimize the long-term outcome,
which with a restenosis rate of 63%, can be described as not encouraging.
PMID- 10781769
TI - A randomized study comparing two guidewire strategies for angioplasty of chronic
total coronary occlusion.
AB - Chronic total coronary occlusions were more frequently crossed using the
Crosswire as a primary guidewire strategy than with the conventional strategy.
This strategy resulted in a lower number of guidewires being used, a trend toward
shorter procedural and fluoroscopy times, and decreased use of contrast media.
PMID- 10781770
TI - Changes in plasma norepinephrine and endothelin levels and metabolic profile
after AT1-receptor blockade in human hypertension.
AB - In essential hypertensive subjects, acute and chronic administration of losartan
was followed by favorable neurohormonal (norepinephrine, endothelin-1) and
metabolic changes (microalbuminuria).
PMID- 10781771
TI - Generic antiarrhythmics are not therapeutically equivalent for the treatment of
tachyarrhythmias.
AB - The consequences of antiarrhythmic drug formulation substitution were assessed by
survey of 130 experts on arrhythmias. Fifty-four arrhythmia recurrences, 7
proarrhythmic events, and 3 deaths resulting from generic substitution are
reported, thus raising serious concerns about both antiarrhythmic drug
substitution and the adequacy of the generic drug approval process.
PMID- 10781772
TI - Comparative effects of permanent biventricular pacing for refractory heart
failure in patients with stable sinus rhythm or chronic atrial fibrillation.
AB - This study aimed to compare the long-term benefit of biventricular pacing in drug
refractory heart failure in patients with dilated cardiomyopathy who were in
stable sinus rhythm or had persistent atrial fibrillation. The results showed
that permanent biventricular pacing in such patients significantly improves
exercise tolerance in both groups of patients; however, the benefit tended to be
greater in patients with atrial fibrillation.
PMID- 10781773
TI - Comparison of risk of orthostatic hypotension in elderly depressed hypertensive
women treated with nortriptyline and thiazides versus elderly depressed
normotensive women treated with nortriptyline.
AB - This is a nonblind, case-controlled study comparing the risk of orthostatic
hypotension (OH) in 2 groups of elderly depressed women: 22 normotensive and 21
hypertensive patients receiving thiazides. Blood pressure measurements and tilt
table tests produced similar results: increased drop in systolic blood pressure
(SBP) after standing (p <0.001), with no significant differences between the
groups (p = 0.523). There were no changes on diastolic blood pressure (DBP) after
standing, or in SBP or DBP at rest. Dizziness was reported by 23 subjects (53.5%)
before treatment, and by 16 subjects (38.1%) at week 8. Complaints of dizziness
were not associated with OH (Kappa = 0.07).
PMID- 10781774
TI - Premature closure of the foramen ovale associated with aortic stenosis, left
ventricular dilation with thrombus, and early mortality.
AB - Premature foramen ovale (FO) closure has been postulated as a cause of
hypoplastic left heart syndrome. We suggest that premature FO closure is also
associated with left ventricular (LV) dilation and LV thrombus formation, and
that FO closure in patients with aortic stenosis and LV dilation is a secondary
event that occurs later in gestation than that seen with the hypoplastic left
heart.
PMID- 10781775
TI - Routine use of anaerobic blood cultures: are they still indicated?
AB - PURPOSE: To determine the number of patients with bacteremia and fungemia and to
evaluate the utility of routine anaerobic blood cultures as part of the work-up
for suspected bacteremia. SUBJECTS AND METHODS: Retrospective review of
microbiology data followed by selective chart review at a university-affiliated
Veterans Affairs Medical Center. We determined the number of bacterial blood
cultures drawn from January 1, 1994, to December 31, 1996, and the number of
anaerobic, aerobic, and fungal isolates. Chart reviews were then performed on all
patients with a positive anaerobic result. RESULTS: There were 6,891 sets of
blood cultures processed through the laboratory, yielding 1,626 patients with
positive results. Anaerobic isolates were recovered from 36 patients (2.2%) in 48
bottles. Aerobic isolates were recovered from 1550 patients (95.3%), and fungal
isolates were recovered from 40 patients (2.5%). Seven patients (0.4%) had true
anaerobic bacteremia. All seven patients had an obvious source of anaerobic
infection that was known or suspected before the cultures were drawn. Antibiotic
changes were made in four of these patients after the positive anaerobic results
were known. Antibiotic changes led to clinical improvement in one patient.
CONCLUSIONS: Routine use of anaerobic blood cultures rarely results in clinically
important diagnostic or therapeutic benefits, based on the low incidence of
anaerobic bacteremia in patients who are not at increased risk. Anaerobic blood
cultures should be selectively ordered in patients at risk for anaerobic
infections.
PMID- 10781776
TI - A randomized trial of distant healing for skin warts.
AB - PURPOSE: Distant healing, a treatment that is transmitted by a healer to a
patient at another location, is widely used, although good scientific evidence of
its efficacy is sparse. This trial was aimed at assessing the efficacy of one
form of distant healing on common skin warts. SUBJECTS AND METHODS: A total of 84
patients with warts were randomly assigned either to a group that received 6
weeks of distant healing by one of 10 experienced healers or to a control group
that received a similar preliminary assessment but no distant healing. The
primary outcomes were the number of warts and their mean size at the end of the
treatment period. Secondary outcomes were the change in Hospital Anxiety and
Depression Scale and patients' subjective experiences. Both the patients and the
evaluator were blinded to group assignment. RESULTS: The baseline characteristics
of the patients were similar in the distant healing (n = 41) and control groups
(n = 43). The mean number and size of warts per person did not change
significantly during the study. The number of warts increased by 0.2 in the
healing group and decreased by 1.1 in the control group (difference [healing to
control] = -1.3; 95% confidence interval = -1.0 to 3.6, P = 0.25). Six patients
in the distant healing group and 8 in the control group reported a subjective
improvement (P = 0.63). There were no significant between-group differences in
the depression and anxiety scores. CONCLUSION: Distant healing from experienced
healers had no effect on the number or size of patients' warts.
PMID- 10781777
TI - Effect of clarithromycin on experimental rhinovirus-16 colds: a randomized,
double-blind, controlled trial.
AB - PURPOSE: Macrolide antibiotics are frequently prescribed to patients with
symptoms of a common cold. Despite their lack of proven antiviral activity,
macrolide antibiotics may have anti-inflammatory actions, such as inhibition of
mucus secretion and production of interleukins 6 and 8 by epithelial cells.
Because the symptoms of rhinovirus colds are attributed to the inflammatory
response to infection, we studied the effects of treatment with clarithromycin on
the symptomatic and inflammatory response to nasal inoculation with rhinovirus.
SUBJECTS AND METHODS: We performed a prospective, double-blind, controlled trial
in 24 healthy subjects who were seronegative for antibodies to rhinovirus-16.
Subjects were randomly assigned to receive either clarithromycin (500 mg) or
trimethoprim-sulfamethoxazole (800/160 mg, as a control antibiotic) twice a day
for 8 days, beginning 24 hours before inoculation with rhinovirus-16. RESULTS:
All 12 subjects in each group were infected and developed symptomatic colds. The
groups did not differ in the intensity of cold symptoms (median [25th to 75th
percentile] score in the clarithromycin group of 25 [5 to 33] versus 21 [11 to
26] in the trimethoprim-sulfamethoxazole group, P = 0.86), weight of nasal
secretions (25 g [8 to 56 g] versus 12 g [5 to 28 g], P = 0.27), or decline in
nasal peak flow during the 8 days following viral inoculation. In both groups,
similar and significant increases from baseline were observed in the numbers of
total cells and neutrophils, and in the concentrations of interleukins 6 and 8,
in nasal lavage fluid during the cold. The changes that we observed did not
differ from those in an untreated historical control group. CONCLUSIONS: We
conclude that clarithromycin treatment has little or no effect on the severity of
cold symptoms or the intensity of neutrophilic nasal inflammation in experimental
rhinovirus-16 colds.
PMID- 10781778
TI - Care and outcomes of elderly patients with acute myocardial infarction by
physician specialty: the effects of comorbidity and functional limitations.
AB - PURPOSE: Whether patients with acute myocardial infarction who are treated by
cardiologists have better outcomes than patients treated by generalist physicians
is controversial. Because some of the survival benefit associated with cardiology
care may be due to baseline differences in patient characteristics, we evaluated
how differences in case-mix of comorbid illness and functional limitations may
explain the association between specialty care and survival. MATERIALS AND
METHODS: We examined the records of 109,243 Medicare beneficiaries hospitalized
for myocardial infarction from 1994 to 1995 from the national Cooperative
Cardiovascular Project to evaluate the association of physician specialty with 30
day and 1-year mortality. We assessed the extent to which this relation was
mediated by differences in the use of guideline-supported therapies (aspirin,
beta-blockers, reperfusion, angiotensin-converting enzyme inhibitors) or
differences in the clinical characteristics of the patients. RESULTS: Patients
who had board-certified cardiologists as attending physicians had the least
number of comorbid conditions, whereas patients who had general practitioners or
internal medicine subspecialists as attending physicians usually had the most
comorbidities. Cardiologists had the greatest use of most guideline-supported
therapies, and general practitioners had the lowest use. After adjustment for
severity of myocardial infarction, clinical presentation, and hospital
characteristics, patients treated by cardiologists were less likely to die within
1 year (relative risk [RR] = 0.92, 95%, confidence interval [CI]: 0.89 to 0. 95),
and patients cared for by other general practitioners were more likely to die
within 1 year (RR = 1.09, 95% CI: 1.03 to 1.14), than patients cared for by
general internists. After adjusting for additional measures of comorbid illness
and functional limitations, the 1-year survival benefit associated with
cardiology care was attenuated relative to internists (RR = 0.97, 95% CI: 0.94 to
1.0), and the excess mortality associated with general practitioners decreased
(RR = 1.05, 95% CI: 1.00 to 1.11). After further adjustment for the use of
guideline-supported therapies, both differences in 1-year survival between
patients treated by cardiologists or general practitioners were not significantly
different from those of patients treated by internists. CONCLUSION: Studies
comparing outcomes by physician specialties that do not adjust adequately for
differences in patient characteristics may attribute more benefit than is
appropriate to specialists who treat patients who have fewer comorbid conditions.
Some of the remaining benefit-at least among patients with myocardial infarction
may be attributable to greater use of recommended therapies.
PMID- 10781779
TI - Patient centeredness in medical encounters requiring an interpreter.
AB - PURPOSE: Patient-centered interviewing is associated with greater patient
satisfaction and better medical outcomes than traditional encounters, but
actively seeking patients' views of their illnesses and encouraging patients to
express expectations, thoughts, and feelings is difficult in encounters that
require an interpreter. We sought to examine physicians' use of the patient
centered approach with patients who required the assistance of an interpreter.
SUBJECTS AND METHODS: A cross-sectional sample of patients was videorecorded
during visits with physicians at a multi-ethnic, university-affiliated, primary
care clinic. Nineteen medical encounters of Spanish-speaking patients who
required an interpreter and 19 matched English-speaking encounters were coded for
frequency that patients mentioned symptoms, feelings, expectations, and thoughts
(collectively called "offers"). Physicians' responses were coded as ignoring,
closed, open, or facilitative of further discussion. RESULTS: English-speaking
patients made a mean (+/- SD) of 20 +/- 11 offers, compared with 7 +/- 4 for
Spanish-speaking patients (P = 0.001). Spanish-speaking patients also were less
likely to receive facilitation from their physicians and were more likely to have
their comments ignored (P <0.005). English-speaking patients usually received an
answer or acknowledgment to their questions even if the physicians did not
encourage further discussion on the topic. CONCLUSION: Spanish-speaking patients
are at a double disadvantage in encounters with English-speaking physicians:
these patients make fewer comments, and the ones they do make are more likely to
be ignored. The communication difficulties may result in lower adherence rates
and poorer medical outcomes among Spanish-speaking patients.
PMID- 10781780
TI - The sound that failed.
PMID- 10781781
TI - Ursodeoxycholic acid therapy in hepatobiliary disease.
AB - Ursodeoxycholic acid is a hydrophilic bile acid that under normal circumstances
represents a small fraction of the bile acid pool in humans. It is effective in
dissolving cholesterol gallstones in appropriately selected patients.
Ursodeoxycholic acid improves serum alkaline phosphatase and aminotransferase
levels in primary biliary cirrhosis, but its effects on rates of liver
transplantation and death are less certain. Ursodeoxycholic acid has had
promising [corrected] effects in several other cholestatic liver diseases, such
as cystic fibrosis and intrahepatic cholestasis of pregnancy, but data are too
preliminary to make recommendations about its routine use in these conditions.
Its effects are mediated by amelioration of damage to cell membranes caused by
retained toxic bile acids. Ursodeoxycholic acid improves biliary secretion of
bile acids, may improve bile flow, and it has immunomodulatory properties that
may reduce immune-mediated liver damage. However, its use in the treatment of
cholestatic liver disease remains uncertain pending additional randomized trials.
PMID- 10781782
TI - Thalidomide: current and potential clinical applications.
AB - More than three decades after its withdrawal from the world marketplace,
thalidomide is attracting growing interest because of its reported
immunomodulatory and anti-inflammatory properties. Current evidence indicates
that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis
factor (TNF)-alpha by accelerating the degradation of its messenger RNA.
Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale
in the United States for the treatment of erythema nodosum leprosum, an
inflammatory complication of Hansen's disease. However, it has long been used
successfully in several other dermatologic disorders, including aphthous
stomatitis, Behcet's syndrome, chronic cutaneous systemic lupus erythematosus,
and graft-versus-host disease, the apparent shared characteristic of which is
immune dysregulation. Many recent studies have evaluated thalidomide in patients
with human immunodeficiency virus (HIV) infection; the drug is efficacious
against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related
diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive
program has been established to control access to the drug, including
registration of prescribing physicians, dispensing pharmacies, and patients;
mandatory informed consent and education procedures; and limitation of the
quantity of drug dispensed. Clinical and, in some patients, electrophysiologic
monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other
adverse effects include sedation and constipation. With appropriate safeguards,
thalidomide may benefit patients with a broad variety of disorders for which
existing treatments are inadequate.
PMID- 10781783
TI - Use of cholesterol-lowering medications in the United States from 1991 to 1997.
PMID- 10781784
TI - Effective teaching for preceptors of ambulatory care: a survey of medical
students.
PMID- 10781786
TI - Diagnostic dilemma
AB - In those issues in which our regular Case of the Month does not appear, The Green
Journal will present a Diagnostic Dilemma-an electrocardiogram and/or radiograph
with a brief case history-as a challenge for our readers to solve. The correct
answer appears on p. 512.If you would like to contribute a Diagnostic Dilemma,
please submit a high-quality copy of the EKG or radiograph with a brief synopsis
(<250 words) of the case to The American Journal of Medicine's editorial office.
PMID- 10781785
TI - Diagnostic dilemma
AB - In those issues in which our regular Case of the Month does not appear, The Green
Journal will present a Diagnostic Dilemma-an electrocardiogram and/or radiograph
with a brief case history-for our readers to solve. The correct answer appears on
p. 511 of this issue.If you would like to contribute a Diagnostic Dilemma, please
submit a high-quality copy of the EKG or radiograph with a brief synopsis (<250
words) of the case to The American Journal of Medicine's editorial office.
PMID- 10781787
TI - The controversy regarding routine anaerobic blood cultures.
PMID- 10781788
TI - Distant healing: an unlikely hypothesis.
PMID- 10781790
TI - Answer to diagnostic dilemma: radiograph
PMID- 10781789
TI - Interpreters and communication in the clinical encounter.
PMID- 10781791
TI - Answer to diagnostic dilemma: EKG
PMID- 10781792
TI - Academic internal medicine: challenges and opportunities- part I
PMID- 10781793
TI - A central role for the endothelial NADPH oxidase in atherosclerosis.
AB - An increasing body of evidence has demonstrated that NADPH oxidase plays a
critical role in several early steps leading toward the development of
atherosclerosis. These effects appear to be carried out by both the ability of O2
to act as a small second messenger molecule, and potentially the oxidation of
low density lipoprotein by O2-. We describe a model for the initiation and
development of atherosclerosis that suggests targeted inhibition of NADPH oxidase
as a powerful site for prevention and treatment of this disease.
PMID- 10781794
TI - Mg(2+) induces intermembrane electron transport by cytochrome c desorption in
mitochondria with the ruptured outer membrane.
AB - The mechanism of external NADH oxidation in rat liver mitochondria is not clear
yet, but it evidently includes the intermembrane electron transport (IMET). We
showed that Mg(2+) significantly stimulated IMET insensitive to rotenone
antimycin A-myxothiazol in mitochondria with the hypotonically damaged outer
membrane, even in the absence of exogenous cytochrome c. This effect was more
specific than simply ionic strength increase. Direct evidence for cytochrome c
desorption from mitochondrial membranes under 4 mM Mg(2+) influence was obtained
to explain the stimulatory effect of Mg(2+) on external NADH oxidation that was
coupled to the inner membrane potential generation. Obtained data suggest that
cytochrome b(5) is normally oriented towards the cytosol in the outer membrane,
and can be accessible for endogenous cytochrome c reduction only through the
outer membrane rupture or permeabilization, to activate external NADH oxidation.
PMID- 10781795
TI - Efp as a primary estrogen-responsive gene in human breast cancer.
AB - We have previously isolated the efp (estrogen-responsive finger protein) that is
required for the normal estrogen-induced cell proliferation. Here, we show the
genomic organization of the human efp gene which consists of nine exons. The efp
mRNA was expressed in human breast tumors and the estrogen-induced expression of
the efp was found in MCF-7 human breast cancer cells. Moreover, efp promoter
activity was enhanced through the estrogen-responsive element dependent on
estrogen and estrogen receptor. These results suggest that the efp can mediate
estrogen actions such as cell growth in human breast cancer as a primary
responsive gene.
PMID- 10781796
TI - Large accumulation of mRNA and DNA point modifications in a plant senescent
tissue.
AB - Although nucleic acids are the paradigm of genetic information conservation, they
are inherently unstable molecules that suffer intrinsic and environmental damage.
Oxidative stress has been related to senescence and aging and, recently, it has
been shown that mutations accumulate at high frequency in mitochondrial DNA with
age. We investigated RNA and DNA modifications in cork, a senescent plant tissue
under high endogenous oxidative stress conditions. When compared to normally
growing young tissue, cork revealed an unexpected high frequency of point
modifications in both cDNA (Pn = 1/1784) and nuclear DNA (Pn = 1/1520). Cork
should be viewed as a mosaic of genetically heterogeneous cells. This has
biological implications: it supports somatic mutation models for aging and
challenges 'single cDNA clone' as descriptor for the molecular genetics of
senescent tissues.
PMID- 10781798
TI - The sequences of enterohemorrhagic Escherichia coli and Yersinia pestis that are
homologous to the enteroaggregative E. coli heat-stable enterotoxin gene: cross
species transfer in evolution.
AB - The enteroaggregative Escherichia coli heat-stable enterotoxin 1 (EAST1) gene is
widely distributed among diarrheagenic E. coli. In this study, we examined the
sequences of enterohemorrhagic E. coli (EHEC) strains by PCR and sequencing. All
the EHEC strains possessed the EAST1 gene homologues but with two types of
mutations. One of the mutation types was strongly associated with the large
outbreak episodes in 1996 in Japan. Sequence comparison showed that the EHEC
sequences are a branch of the EAST1 gene sequence family that showed the cross
species transfer in evolution among E. coli and Yersinia pestis.
PMID- 10781797
TI - Further studies on the reconstitution of glucosylceramidase activity by Sap C and
anionic phospholipids.
AB - The reconstitution of the activity of the lysosomal enzyme glucosylceramidase
requires anionic phospholipids and, at least, a protein factor, saposin C (Sap
C). We have previously proposed a mechanism for the glucosylceramidase activation
[Vaccaro et al. (1993) FEBS Lett. 336, 159-162] which implies that Sap C promotes
the association of the enzyme with anionic phospholipid-containing membranes,
thus favoring the contact between the enzyme and its lipid substrate,
glucosylceramide. We have further investigated the properties of Sap C using a
fluorescent hydrophobic probe such as 4, 4'-dianilino-1,1'-binaphthyl-5,5'
disulfonic acid (bis-ANS). The binding between bis-ANS and Sap C was pH
dependent, indicating that protonation leads to increased exposure of hydrophobic
surfaces of Sap C. The interaction of Sap C with membranes, triggered by the
development of hydrophobic properties at low pH values, was affected by the
content of anionic phospholipids, such as phosphatidylserine or
phosphatidylinositol, suggesting that anionic phospholipids have the potential to
modulate the insertion of Sap C in the hydrophobic environment of lysosomal
membranes. We previously showed that Sap C and anionic phospholipids are both
required for the binding of glucosylceramidase to large vesicles. We have
presently observed that Sap C is able to promote the association of
glucosylceramidase with the lipid surface only when anionic phospholipids exceed
a concentration of 5-10%. This level can be reached by summing lower amounts of
individual anionic phospholipids, since they have additive effects. The present
data extend and refine our model of the mechanism of glucosylceramidase
activation and stress the key role of pH, Sap C and anionic phospholipids in
promoting the interaction of the enzyme with membranes.
PMID- 10781800
TI - F-ATPase: specific observation of the rotating c subunit oligomer of EF(o)EF(1).
AB - The rotary motion in response to ATP hydrolysis of the ring of c subunits of the
membrane portion, F(o), of ATP synthase, F(o)F(1), is still under contention. It
was studied with EF(o)EF(1) (Escherichia coli) using microvideography with a
fluorescent actin filament. To overcome the limited specificity of actin
attachment through a Cys-maleimide couple which might have hampered the
interpretation of previous work, we engineered a 'strep-tag' sequence into the C
terminal end of subunit c. It served (a) to purify the holoenzyme and (b) to
monospecifically attach a fluorescent actin filament to subunit c. EF(o)EF(1) was
immobilized on a Ni-NTA-coated glass slide by the engineered His-tag at the N
terminus of subunit beta. In the presence of MgATP we observed up to five
counterclockwise rotating actin filaments per picture frame of 2000 microm(2)
size, in some cases yielding a proportion of 5% rotating over total filaments.
The rotation was unequivocally attributable to the ring of subunit c. The new,
doubly engineered construct serves as a firmer basis for ongoing studies on
torque and angular elastic distortions between F(1) and F(o).
PMID- 10781799
TI - Hydrogen exchange monitored by MALDI-TOF mass spectrometry for rapid
characterization of the stability and conformation of proteins.
AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
(MALDI-TOF MS) has been used to monitor hydrogen exchange on entire proteins. Two
alternative methods have been used to carry out the hydrogen exchange studies,
exchanging deuteron (H to D experiments) or proton (D to H experiments). In the
former case, the use of a deuterated matrix has made possible to overcome back
exchange problems and attain reproducible results. The methods presented have
been used to determine the slow exchange core of the potato carboxypeptidase
inhibitor in different folding states, and to differentially compare the
activation domain of human procarboxypeptidase A2 versus three site-directed
mutants of different conformational stability. In this work, we show that by
using MALDI-TOF MS to monitor hydrogen exchange in entire proteins, it is
possible to rapidly check the folding state of a protein and characterize
mutational effects on protein conformation and stability, while requiring minimal
amounts of sample.
PMID- 10781801
TI - Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and
caspase-3.
AB - Anandamide (arachidonoylethanolamide), an endogenous cannabinoid receptor ligand
has been suggested to have physiological role in mammalian nervous system.
However, little is known about the role of anandamide on neuronal cells. Here, we
demonstrate that anandamide causes death of PC-12 cells, showing marked DNA
condensation and fragmentation, appearance of cells at sub-G(0)/G(1) and
redistribution of phosphatidyl serine, the hallmark features of apoptosis.
Anandamide raised intracellular superoxide level and CPP32-like protease activity
in PC-12 cells markedly. Furthermore, antioxidant N-acetyl cysteine prevented
anandamide-induced superoxide anion formation and cell death, implying that
intracellular superoxide is a novel mediator of anandamide-induced apoptosis of
PC-12 cells.
PMID- 10781802
TI - Involvement of SH2-SH2-SH3 domain of phospholipase cgamma1 in NF-kappaB
signaling.
AB - To directly define the role of phospholipase Cgamma1 (PLCgamma1) in NF-kappaB
activation, NF-kappaB promoted luciferase reporter gene plasmid (pNF-kappaB-Luc)
was transfected into rat-3Y1 fibroblasts that overexpress whole PLCgamma1
(PLCgamma1-3Y1), src homology domains SH2-SH2-SH3 of PLCgamma1 (SH223-3Y1) and v
src (Src-3Y1). Transient transfection with pNF-kappaB-Luc remarkably increased
the luciferase activity in all three transformants compared with normal rat-3Y1
cells. Pretreatment with inhibitors of protein tyrosine kinase reduced this
increase in luciferase activity, but U73122 (a PLC inhibitor) did not. While
PD98059, an inhibitor of mitogen activated protein kinase (MAPK), significantly
reduced the luciferase activity, there was no effect by wortmannin and Ro-31
8220, inhibitors of phosphatidylinositol 3-kinase (PI3K) and protein kinase C
(PKC), respectively. This study shows a direct evidence that the SH2-SH2-SH3
region of PLCgamma1 contributes to the NF-kappaB signaling and that MAPK, but not
PI3K and PKC, is involved in SH2-SH2-SH3 mediated NF-kappaB activation in these
cells.
PMID- 10781804
TI - Myocyte enhancer factor 2C upregulates MASH-1 expression and induces neurogenesis
in P19 cells.
AB - MEF2C is a transcription factor expressed in neural lineages. After transient
transfection, the MEF2 family of factors can act synergistically with the neural
specific transcription factor, MASH-1, and activate exogenous neural-specific
promoters. To determine whether MEF2C is capable of modulating endogenous gene
expression, P19 cell lines were analyzed that overexpressed MEF2C, termed
P19[MEF2C] cells. Here we show that P19[MEF2C] cells differentiate into neurons
when aggregated with ME(2)SO. MEF2C-induced neurons expressed neurofilament
protein, the nuclear antigen NeuN, as well as MASH-1. Our results indicate that
MEF2C can directly or indirectly activate the expression of MASH-1, leading to
neurogenesis.
PMID- 10781803
TI - MAPK-dependent expression of p21(WAF) and p27(kip1) in PMA-induced
differentiation of HL60 cells.
AB - Treatment of HL60 cells with phorbol 12-myristate 13-acetate (PMA) results in
growth arrest and differentiation towards the macrophage lineage. PMA-induced
changes are easily monitored by morphological changes while cells in suspension
start adhering onto substrate. PMA induces rapid activation of the extracellular
signal-regulated kinases (ERKs). Activation of the ERK pathway is essential to
PMA-induced differentiation of HL60 cells. PMA also induces the expression of the
cyclin-dependent kinase inhibitors p21(WAF) and p27(kip1), which is modulated by
the use of an inhibitor of the ERK cascade. This implies that a link exists
between ERK activation and p21(WAF) and p27(kip1) induction in the process of
terminal differentiation.
PMID- 10781805
TI - Enhanced sensitivity of Streptomyces seoulensis to menadione by superfluous
lipoamide dehydrogenase.
AB - Lipoamide dehydrogenase from Streptomyces seoulensis could facilitate menadione
mediated cytochrome c reduction, which was mostly inhibited by superoxide
dismutase, indicating the obvious involvement of superoxide radical anion. In
this reaction, the production of superoxide radical anion occurred via a
menadione semiquinone radical anion. When exposed to menadione, lipoamide
dehydrogenase-overexpressing cells showed a much lower survival rate with a
concomitant decrease of intracellular protein thiol than the wild-type strain.
These results suggest that lipoamide dehydrogenase is a facilitating agent in the
redox cycling of quinone compounds in vivo as well as in vitro and could
inevitably increase the potential toxicity of the compounds.
PMID- 10781806
TI - Identification of the goldfish 20S proteasome beta6 subunit bound to nuclear
matrix.
AB - Proteasomes are large, multisubunit particles that act as the proteolytic
machinery for most of the regulated intracellular protein breakdown in eukaryotic
cells. Proteasomes are present in both the nucleus and cytoplasm. When we
analyzed the molecular composition of protein constituents of the nuclear matrix
preparation of goldfish oocytes by two-dimensional polyacrylamide gel
electrophoresis followed by sequence analysis, we found a 26 kDa spot identical
in amino acid sequence to the beta6 subunits of the 20S proteasome. No spot of
other subunits of 20S proteasome was detected. Here we describe the cloning,
sequencing and expression analysis of Carassius auratus, beta6_ca, which encodes
one of the proteasome beta subunits from goldfish ovary. From the screening of an
ovarian cDNA library, two types of cDNA were obtained, one 941 bp and the other
884 bp long. The deduced amino acid sequences comprise 239 and 238 residues,
respectively. These deduced amino acid sequences are highly homologous to those
of beta6 subunits of other vertebrates. Immunoblot analysis of nuclear matrix
using anti-proteasome antibodies showed only a spot of beta6_ca. These results
suggest that the beta6 subunit of the goldfish 20S proteasome, beta6_ca, is
responsible for anchoring proteasomes in the nucleus.
PMID- 10781807
TI - Acceleration of oxidative folding of bovine pancreatic ribonuclease A by anion
induced stabilization and formation of structured native-like intermediates.
AB - Phosphate anions accelerate the oxidative folding of reduced bovine pancreatic
ribonuclease A with dithiothreitol at several temperatures and ionic strengths.
The addition of 400 mM phosphate at pH 8.1 increased the regeneration rate of
native protein 2.5-fold at 15 degrees C, 3.5-fold at 25 degrees C, and 20-fold at
37 degrees C, compared to the rate in the absence of phosphate. In addition, the
effects of other ions on the oxidative folding of RNase A were examined. Fluoride
was found to accelerate the formation of native protein under the same oxidizing
conditions. In contrast, cations of high charge density or ions with low charge
density appear to have an opposite effect on the folding of RNase A. The
catalysis of oxidative folding results largely from an anion-dependent
stabilization and formation of tertiary structure in productive disulfide
intermediates (des-species). Phosphate and fluoride also accelerate the initial
equilibration of unstructured disulfide ensembles, presumably due to non-specific
electrostatic and hydrogen bonding effects on the protein and solvent.
PMID- 10781808
TI - Surface plasmon resonance studies prove the interaction of skeletal muscle
sarcoplasmic reticular Ca(2+) release channel/ryanodine receptor with
calsequestrin.
AB - A high affinity molecular interaction is demonstrated between calsequestrin and
the sarcoplasmic reticular Ca(2+) release channel/ryanodine receptor (RyR) by
surface plasmon resonance. K(D) values of 92 nM and 102 nM for the phosphorylated
and dephosphorylated calsequestrin have been determined, respectively.
Phosphorylation of calsequestrin seems not to influence this high affinity
interaction, i.e. calsequestrin might always be bound to RyR. However, the
phosphorylation state of calsequestrin determines the amount of Ca(2+) released
from the lumen. Dephosphorylation of approximately 1% of the phosphorylated
calsequestrin could be enough to activate the RyR channel half-maximally, as we
have shown previously [Szegedi et al., Biochem. J. 337 (1999) 19].
PMID- 10781809
TI - MerF is a mercury transport protein: different structures but a common mechanism
for mercuric ion transporters?
AB - Mercury resistance determinants are widespread in Gram-negative bacteria, but
vary in the number and identity of genes present. We have shown that the merF
gene from plasmid pMER327/419 encodes a 8.7 kDa mercury transport protein, by
determining in vivo mercury volatilisation when MerF is expressed in the presence
of mercuric reductase. We have confirmed that MerC of Tn21 is also a mercuric ion
transporter. We have been able to detect interaction of the periplasmic protein
MerP only with the MerT transporter, and not with MerF or MerC. Hydropathy
analysis led to the prediction of models for MerT, MerC and MerF having three,
four and two transmembrane regions respectively. In all three cases one pair of
cysteine residues is predicted to be within the inner membrane with a second pair
of cysteine residues on the cytoplasmic face, and the second helix contains a
proline and at least one charged residue. The mechanisms of mercuric ion
transport may be similar in these transporters even though their structures in
the membrane differ.
PMID- 10781810
TI - Pore mutations affecting tetrameric assembly and functioning of the potassium
channel KcsA from Streptomyces lividans.
AB - Designed mutations within the Streptomyces lividans kcsA gene resulted in a set
of mutant proteins, which were characterized in respect to their assembly and
channel activities. (i) The amino acid residue leucine 81 located at the external
side of KcsA was found to be exchangeable by a cysteine residue without affecting
the channel characteristics. (ii) Substitution of the first glycine (G77) residue
within the GYG motif by an alanine or substitution of the tyrosine (Y) residue 78
by a phenylalanine (F) led to mutant proteins which form tetramers of reduced
stability. In contrast to the AYG mutant protein, GFG functions as an active K(+)
channel whose characteristics correspond to those of the wild-type KcsA channel.
(iii) The investigated mutant proteins, which carry different mutations (T72A,
T72C, V76A, V76E, G77E, Y78A, G79A, G79D, G79E) within the signature sequence of
the pore region, do not at all or only to a very small degree assemble as
tetramers and lack channel activity.
PMID- 10781811
TI - Subunit interactions in the twin-arginine translocase complex of Escherichia
coli.
AB - A subset of Escherichia coli proteins, in particular cofactor-binding proteins
with so-called twin-arginine signal peptides, is transported to the periplasm via
the twin-arginine translocation (Tat) pathway. The tatA and tatB genes encode
important components of the export system and we have analysed whether the
proteins encoded by these genes physically interact. Using co-immunoprecipitation
experiments, we show that TatA and TatB do indeed associate with each other. Gel
filtration chromatography demonstrates that both proteins are present in a large
complex with an apparent molecular mass of approximately 600 kDa, indicating the
presence of other components and/or several TatA and TatB subunits. Finally, we
show that TatA is stable in the absence of TatB and may participate in a separate
complex lacking TatB in wild-type cells.
PMID- 10781812
TI - Mdm2 binding to a conformationally sensitive domain on p53 can be modulated by
RNA.
AB - Biochemical characterisation of the interaction of mdm2 protein with p53 protein
has demonstrated that full-length mdm2 does not bind stably to p53-DNA complexes,
contrasting with C-terminal truncations of mdm2 which do bind stably to p53-DNA
complexes. In addition, tetrameric forms of the p53His175 mutant protein in the
PAb1620+ conformation are reduced in binding to mdm2 protein. These data suggest
that the mdm2 binding site in the BOX-I domain of p53 becomes concealed when
either p53 binds to DNA or when the core domain of p53 is unfolded by missense
mutation. This further suggests that the C-terminus of mdm2 protein contains a
negative regulatory domain that affects mdm2 protein binding to a second,
conformationally sensitive interaction site in the core domain of p53. We
investigated whether there was a second docking site on p53 for mdm2 protein by
examining the interaction of full-length mdm2 with p53 lacking the BOX-I domain.
Although mdm2 protein did bind very weakly to p53 protein lacking the BOX-I
domain, addition of RNA activated mdm2 protein binding to this truncated form of
p53. These data provide evidence for three previously undefined regulatory stages
in the p53-mdm2 binding reaction: (1) conformational changes in p53 protein due
to DNA binding or point mutation conceals a secondary docking site of mdm2
protein; (2) the C-terminus of mdm2 is the primary determinant which confers this
property upon mdm2 protein; and (3) mdm2 protein binding to this secondary
interaction site within p53 can be stabilised by RNA.
PMID- 10781813
TI - Identification of the Drosophila melanogaster homologue of the mammalian signal
transducer protein, Vav.
AB - Mammalian Vav signal transducer protein couples tyrosine kinase signals with the
activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or
proliferation. We have isolated and characterized the DroVav gene, the homologue
of hVav in Drosophila melanogaster. DroVav encodes a protein (793 residues) whose
similarity with hVav is 47% and with hVav2 and hVav3 is 45%. DroVav preserves the
unique, complex structure of hVav proteins, including the 'calponin homology',
dbl homology, pleckstrin homology; SH2 and SH3 domains in addition to regions
that are acidic rich, proline rich and cysteine rich. DroVav is located on the X
chromosome in polytene interval 18A5;18B and is expressed in all stages of
development and in all tissues. In mammalian cells, DroVav is tyrosine
phosphorylated in response to epidermal growth factor receptor (EGFR) induction;
in vitro, the DroVav SH2 region is associated with tyrosine-phosphorylated EGFR.
Thus, DroVav probably plays a pivotal role as a signal transducer protein during
fruit fly development.
PMID- 10781814
TI - Molecular cloning and functional expression of beta1, 2-xylosyltransferase cDNA
from Arabidopsis thaliana.
AB - The transfer of xylose from UDP-xylose to the core beta-linked mannose of N
linked oligosaccharides by beta1,2-xylosyltransferase (XylT) is a widespread
feature of plant glycoproteins which renders them immunogenic and allergenic in
man. Here, we report the isolation of the Arabidopsis thaliana XylT gene, which
contains two introns and encodes a 60.2 kDa protein with a predicted type II
transmembrane protein topology typical for Golgi glycosyltransferases. Upon
expression of A. thaliana XylT cDNA in the baculovirus/insect cell system, a
recombinant protein was produced that exhibited XylT activity in vitro.
Furthermore, the recombinant enzyme displayed XylT activity in vivo in the insect
cells, as judged by the acquired cross-reaction of cellular glycoproteins with
antibodies against the beta1,2-xylose epitope. The cloned XylT cDNA as well as
the recombinant enzyme are essential tools to study the role of beta1,2-xylose in
the immunogenicity and allergenicity of plant glycoproteins at the molecular
level.
PMID- 10781815
TI - Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats.
AB - To examine the possible involvement of a redox regulating mechanism in the
pathogenesis of immune-mediated myocarditis, myocarditis was induced by
immunization of porcine cardiac myosin in rats and immunohistochemistry and
Western blot for thioredoxin (TRX) were performed. Immunohistochemistry for 8
hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor kappa-B (NF-kappaB) was
also performed. TRX was upregulated in the acute stage, but not in the chronic
stage, and the expression was correlated with the severity of the disease.
Damaged myocytes were strongly immunostained for 8-OHdG and NF-kappaB. Thus, TRX
may be specifically induced by acute inflammatory stimuli, and the development of
acute immune-mediated myocarditis may be regulated by the cellular redox state
via TRX.
PMID- 10781816
TI - Structure of the photosynthetic reaction centre from Rhodobacter sphaeroides
reconstituted with anthraquinone as primary quinone Q(A).
AB - In the photosynthetic reaction centre (RC) from the purple bacterium Rhodobacter
sphaeroides, the primary quinone, a ubiquinone-10 (Q(A)), has been substituted by
anthraquinone. Three-dimensional crystals have been grown from the modified RC
and its structure has been determined by X-ray crystallography to 2.4 A
resolution. The bindings of the head-group from ubiquinone-10 and of the
anthraquinone ring are very similar. In particular, both rings are parallel to
each other and the hydrogen bonds connecting the native ubiquinone-10 molecule to
AlaM260 and HisM219 are conserved in the anthraquinone containing RC. The space
of the phytyl tail missing in the anthraquinone exchanged RC is occupied by the
alkyl chain of a detergent molecule. Other structural changes of the Q(A)-binding
site are within the limit of resolution. Our structural data bring strong credit
to the very large amount of spectroscopic data previously achieved in
anthraquinone-replaced RCs and which have participated in the determination of
the energetics of the quinone system in bacterial RCs.
PMID- 10781817
TI - Phosphorylation of the p190 RhoGAP N-terminal domain by c-Src results in a loss
of GTP binding activity.
AB - p190 RhoGAP is a multi-domain protein that is thought to regulate actin
cytoskeleton dynamics. It can be phosphorylated both in vitro and in vivo at
multiple sites by the Src tyrosine kinase and one or more of these sites is
postulated to modulate p190 function. One of the regions which is multiply
phosphorylated by Src in vitro is the N-terminal GTP binding domain. Using a
partially purified, bacterially expressed recombinant protein that includes the
GTP binding domain (residues 1-389), we show that GTP binds to this fragment in a
specific and saturable manner that is both time- and dose-dependent and that
tyrosine phosphorylation of this fragment by c-Src results in a loss of GTP
binding activity. These findings suggest that tyrosine phosphorylation of the
p190 N-terminal domain can alter its ability to bind GTP.
PMID- 10781818
TI - Molecular characterization of an additional shrimp hyperglycemic hormone: cDNA
cloning, gene organization, expression and biological assay of recombinant
proteins.
AB - The crustacean eyestalk CHH/MIH/GIH neurohormone gene family represents a unique
group of neuropeptides identified mainly in crustaceans. In this study, we report
the cloning and characterization of the cDNA and the gene encoding the
hyperglycemic hormone (MeCHH-B) of the shrimp Metapenaeus ensis. The amino acid
sequence of MeCHH-B shows 85% identity to that of MeCHH-A (formerly MeCHH-like
neuropeptide). Two separate but identical MeCHH-B genes were identified in the
genome of shrimp by library screening and they are located on different CHH gene
clusters. The organization of the MeCHH-B gene is identical to other members of
the CHH/MIH/GIH neurohormone family. MeCHH-B is expressed at a constant level in
the eyestalks of juveniles and mature females. Unlike the MeCHH-A gene, a low
level of MeCHH-B transcripts can also be detected in the central nervous system.
Interestingly, the expression pattern of MeCHH-B in the eyestalk of vitellogenic
females is reversed to that of the MeCHH-A gene. At the middle stage of gonad
maturation, a minimum level of MeCHH-B transcript was recorded and a maximum
level of MeCHH-A transcript was detected. Recombinant proteins for MeCHH-A and
MeCHH-B were produced by a bacterial expression system. The hemolymph glucose
level of bilaterally eyestalk-ablated shrimp increased two-fold 1 h after the
rCHH injection and then returned to normal after 2 h. The hyperglycemic effect of
these fusion proteins is comparable to that of de-stalked shrimp injected with
crude extract from a single sinus gland.
PMID- 10781819
TI - Involvement of the platelet-derived growth factor receptor in angiotensin II
induced activation of extracellular regulated kinases 1 and 2 in human mesangial
cells.
AB - In mesangial cells angiotensin II (Ang II) has been shown to activate
extracellular regulated kinases 1 and 2 (ERK1/2). Here, we studied the role of
the epidermal growth factor receptor (EGFR) and platelet-derived growth factor
receptor (PDGFR) in Ang II-induced ERK1/2 activation in human mesangial cells.
Ang II induced activation of ERK1/2 via the AT(1) receptor, and this response was
blocked by the PDGFR-selective tyrosine kinase inhibitor AG1295, but not by
AG1478, an EGFR-selective tyrosine kinase inhibitor, indicating participation of
the PDGFR, but not of the EGFR in Ang II-induced ERK1/2 activation. In agreement
with this assumption, Ang II caused tyrosine phosphorylation of the PDGFR and the
adapter protein Shc in an AG1295-sensitive fashion. In conclusion, our data show
that Ang II-induced activation of mitogenic signalling cascade in human mesangial
cells involves ligand-independent activation of the PDGFR, but not of the
coexpressed EGFR.
PMID- 10781820
TI - Protective roles for ATM in cellular response to oxidative stress.
AB - ATM (ataxia telangiectasia mutated), the gene mutated in ataxia telangiectasia,
is related to a family of large phosphatidylinositol 3-kinase domain-containing
proteins involved in cell cycle control and DNA repair. We found that ATM(-/-)
DT40 cells were more susceptible than wild-type cells to apoptosis induced not
only by ionizing radiation and bleomycin but also by non-DNA-damaging apoptotic
stimuli such as C(2)-ceramide. Furthermore, the apoptosis induced by C(2)
ceramide and H(2)O(2) was blocked by anti-oxidants, indicating that the ATM(-/-)
DT40 cells had a heightened susceptibility to apoptosis induced by reactive
oxygen intermediates (ROI), presumably due to defective ROI-detoxification
activities. In support of this hypothesis, we found that more ROI were generated
in ATM(-/-) DT40 cells than in wild-type cells, following treatment with the
above apoptotic stimuli. These results indicate that ATM plays important roles in
the maintenance of the cell homeostasis in response to oxidative damage.
PMID- 10781821
TI - Requirement of the Fas ligand-expressing luteal immune cells for regression of
corpus luteum.
AB - Apoptosis in corpus luteum (CL) is induced by prolactin (PRL) in female rats. PRL
induced apoptosis in CL is mediated by the Fas/Fas ligand (FasL) system. The CL
consists of steroidogenic and non-steroidogenic cells, including immunocytes. Fas
mRNA was detected only in the luteal steroidogenic cells, and FasL mRNA was
expressed only by the non-steroidogenic CD3-positive luteal immunocytes. Removing
the luteal immune cells from the luteal cells inhibited PRL-induced luteal cell
apoptosis effectively. Thus, FasL-expressing non-steroidogenic luteal immunocytes
are required for PRL-induced luteal cell apoptosis and heterogeneous induction of
apoptosis by Fas/FasL in CL.
PMID- 10781822
TI - Nerve growth factor induces sphingomyelin accumulation in pheochromocytoma cells.
AB - The pheochromocytoma cells are a well-known model for studying the nerve growth
factor (NGF)-induced molecular changes during the differentiation process. The
involvement of sphingomyelin (SM) was studied using the fluorescent analogue of
ceramide, i.e. N-lissamine rhodaminyl-(12-aminododecanoyl) D-erythro-sphingosine
(C12-LRh-Cer). This fluorescent analogue is metabolically active and can be used
to follow the biosynthesis of SM in intact cells. NGF induces a 4-fold increase
of fluorescent SM content in PC12 cells, when loaded with C12-LRh-Cer. Treatment
of PC12 cells with actinomycin D or cycloheximide completely abolishes the NGF
induced elevation of SM. Inhibition of p140(trkA) receptor by AG-879 prevents
extracellular signal-regulated kinase 1/2 phosphorylation and suppresses the
increase of SM. Inhibition of protein kinase C (PKC), protein kinase A (PKA) and
phosphatidylinositol 3-kinase does not have any effect on NGF-induced C12-LRh-SM
accumulation. On the other hand, activation of PKA or PKC with simultaneous
treatment with NGF has a synergistic effect on increase of SM content. The NGF
induced SM increase in PC12 cells is an effect promoted by other differentiating
agents like dibutyryl cyclic AMP or fibroblast growth factor-2 but not by a
mitogenic agent like epidermal growth factor.
PMID- 10781823
TI - Conformational requirements for Ca(2+)/calmodulin binding and activation of
myosin light chain kinase.
AB - Myosin light chain kinase contains a regulatory segment consisting of an
autoinhibitory region and a calmodulin-binding sequence that folds back on its
catalytic core to inhibit kinase activity. It has been proposed that alpha-helix
formation may be involved in displacement of the regulatory segment and
activation of the kinase by Ca(2+)/calmodulin. Proline mutations were introduced
at putative non-interacting residues in the regulatory segment to disrupt helix
formation. Substitution of proline residues immediately N-terminal of the Trp in
the calmodulin-binding sequence had most significant effects on Ca(2+)/calmodulin
binding and activation. Formation of an alpha-helix in this region upon
Ca(2+)/calmodulin binding may be necessary for displacement of the regulatory
segment allowing phosphorylation of myosin regulatory light chain.
PMID- 10781824
TI - Okadaic acid inhibits insulin-induced glucose transport in fetal brown adipocytes
in an Akt-independent and protein kinase C zeta-dependent manner.
AB - In the present study we have investigated the effect of increased
serine/threonine phosphorylation of insulin receptor substrates-1 and -2 (IRS-1
and IRS-2) by okadaic acid pretreatment on brown adipocyte insulin signalling
leading to glucose transport, an important metabolic effect of insulin in brown
adipose tissue. Okadaic acid pretreatment before insulin stimulation decreased
IRS-1 and IRS-2 tyrosine phosphorylation in parallel to a decrease in their
sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility. IRS-1/IRS-2
associated p85alpha and phosphatidylinositol (PI) 3-kinase enzymatic activity
were partly reduced in brown adipocytes pretreated with okadaic acid upon
stimulation with insulin. Furthermore, insulin-induced glucose uptake was totally
abolished by the inhibitor in parallel with a total inhibition of insulin-induced
protein kinase C (PKC) zeta activity. However, activation of Akt/PKB or p70 S6
kinase (p70(s6k)) by insulin remained unaltered. Our results suggest that
downstream of PI 3-kinase, insulin signalling diverges into at least two
independent pathways through Akt/PKB and PKC zeta, the PKC zeta pathway
contributing to glucose transport induced by insulin in fetal brown adipocytes.
PMID- 10781826
TI - Structure of polyglutamine.
PMID- 10781825
TI - Stimulation of the yeast high osmolarity glycerol (HOG) pathway: evidence for a
signal generated by a change in turgor rather than by water stress.
AB - The Saccharomyces cerevisiae HOG pathway controls responses to osmotic shock such
as production of the osmolyte glycerol. Here we show that the HOG pathway can be
stimulated by addition of glycerol. This stimulation was strongly diminished in
cells expressing an unregulated Fps1p glycerol channel, presumably because
glycerol rapidly equilibrated across the plasma membrane. Ethanol, which passes
the plasma membrane readily and causes water stress by disturbing the hydration
of biomolecules, did not activate the HOG pathway. These observations suggest
that stimulation of the HOG pathway is mediated by a turgor change and not by
water stress per se.
PMID- 10781827
TI - Probing the polyglutamine puzzle in neurological disorders.
PMID- 10781828
TI - Solution structure and dynamics of biomolecules from Raman optical activity.
AB - Raman optical activity (ROA) measures vibrational optical activity by means of a
small difference in the intensity of Raman scattering from chiral molecules in
right and left circularly polarized incident laser light. The ROA spectra of a
wide range of biomolecules in aqueous solution can now be measured routinely.
Because of its sensitivity to the chiral elements of biomolecular structure, ROA
provides new information about solution structure and dynamics complementary to
that supplied by conventional spectroscopic techniques. This article provides a
brief introduction to the theory and practice of ROA spectroscopy followed by a
review of recent ROA results on polypeptides, proteins, carbohydrates, nucleic
acids and viruses which illustrate how new insight into current problems of
structure, folding and function may be obtained from ROA studies.
PMID- 10781829
TI - Targeted intracellular delivery of photosensitizers.
PMID- 10781830
TI - The Jak-STAT pathway.
AB - A variety of important cellular functions are regulated by cytokines. The Jak
STAT pathway is one of the important signaling pathways downstream of cytokine
receptors. Following binding of a ligand to its cognate receptor, receptor
associated Jaks are activated. STAT proteins are then in turn activated by
tyrosine phosphorylation by Jak kinases, allowing their dimerization and
subsequent translocation into the nucleus, where they modulate expression of
target genes. Indispensable functions of Jaks and STATs in cytokine signaling in
vivo have been revealed through knockout mouse studies. Moreover, the recent
discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to
understanding how this pathway is negatively regulated.
PMID- 10781831
TI - PA28alphabeta double and PA28beta single transfectant mouse B8 cell lines reveal
enhanced presentation of a mouse cytomegalovirus (MCMV) pp89 MHC class I epitope.
AB - PA28 is an interferon-gamma inducible modulator of proteasome function composed
of two subunits, i.e. PA28alpha and PA28beta. Previously we showed that stabile
overexpression of the PA28alpha subunit alone supported MHC class I antigen
presentation of two viral epitopes. However, no information was obtained on the
consequences when PA28alpha and PA28beta function in concert or when PA28beta is
overexpressed on its own. Here we demonstrate that overexpression of PA28alpha
and beta together is similarly efficient in supporting MHC class I antigen
presentation of the MCMV pp89 9mer epitope as PA28alpha alone, excluding a
potentially potentiating role of PA28beta. Surprisingly, and despite the fact
that PA28beta alone was thought to be inactive and to only stabilize PA28
activity, overexpression of PA28beta also resulted in improved antigen
presentation. However, by northernblot and immunoprecipitation experiments we
show that while PA28alpha is able to act alone the observed effect in the
PA28beta and PA28alphabeta transfectant cell lines is due to increased levels of
PA28alphabeta complexes.
PMID- 10781832
TI - Proteomic analysis of T cell activation in the presence of cyclosporin A:
immunosuppressor and activator removal induces de novo protein synthesis.
AB - Cyclosporin A (CsA), a fungal metabolite used in organ transplantation, blocks
the immune responses by interfering with early activation signals preventing the
induction of the IL2 gene. We have previously reported that the removal of the
immunosuppressor provokes the transcription of the IL2 encoding gene. We have now
investigated whether the transcription and translation of other genes accompanies
this process. Withdrawal of CsA and Concanavalin A (ConA) from cultures of murine
T cells activated by ConA in the presence of CsA leads to substantial changes in
the pattern of radio-labelled proteins. A large number of polypeptides were
synthesised de novo. In addition, a set of polypeptides detected prior to
immunosuppressor elimination was not anymore synthesised. Finally, besides these
qualitative changes, quantitative differences in terms of increased or decreased
polypeptide abundance were also observed. The results demonstrate that activation
in the presence of CsA has programmed the T cells to transcribe and translate a
large number of genes, without further reactivation, once the immunosuppressor
and the activator were removed.
PMID- 10781834
TI - Complement factor H: sequence analysis of 221 kb of human genomic DNA containing
the entire fH, fHR-1 and fHR-3 genes.
AB - Complement factor H (fH) is a member of a family of proteins involved in the
regulation of complement activation (RCA). These proteins share a common
structural motif, the Short Consensus Repeat (SCR), which is structurally
conserved among related genes and between phylogenetically divergent species. fH
is composed of 20 such SCRs and a variety of biological functions have been
localised to specific SCR domains. The majority of individual SCRs identified are
encoded by single exons, and processes such as gene conversion, duplication and
exon shuffling have been implicated in the evolution and genomic radiation of SCR
encoding genes. We have analysed two GenBank sequence entries relating to two
overlapping PAC clones sequenced at the Sanger Centre which contain the entire
human fH gene and two adjacent fH-related (fHR) genes, fHR-1 and fHR-3. Here, we
report the detailed analysis of the assembled 221 kb of contiguous, ungapped
genomic sequence from human chromosome 1q32, in part employing the RUMMAGE-DP
automated annotation tool. Genomic duplications involving fH and fHR exons were
identified and Alu/L1 repeat dating established that the duplications occurred
after the separation of rodent and primate lineages. The analysis indicates that
retrotransposition as well as single and multiple exon duplication events are
likely to have been involved in SCR radiation and RCA gene evolution, facilitated
by conservation of splice-phasing and the single-exon, single-SCR nature of the
encoded domains.
PMID- 10781833
TI - Individual V(H) promoters vary in strength, but the frequency of rearrangement of
those V(H) genes does not correlate with promoter strength nor enhancer
independence.
AB - The process of V(D)J recombination is highly regulated. Germline transcription of
unrearranged gene segments precedes V(D)J rearrangement, and the correlation
between germline transcription and accessibility for recombination is strong;
thus it has been suggested that germline transcription may be required for
rearrangement. If germline transcription is essential for rearrangement, then the
level of transcription of individual gene segments might affect the relative
frequency of recombination of those genes. Also, since the intronic enhancer,
E(mu), is very distant from V(H) genes before they rearrange, then any promoters
which were enhancer dependent might have a transcriptional advantage. Here we
study in luciferase vectors the promoters of three functional genes of the
V(H)S107 family, and compare them to that of the most frequently rearranging gene
in the mouse I(g)H locus, V(H)81X, and to a V(H)J558 gene. Within the V(H)S107
family, the three V(H) genes rearrange with very different relative frequencies,
with V1 rearranging the most, and V13 seldom rearranging. We show that only the
strong V(H)J558 promoter has significant luciferase reporter gene activity in the
absence of E(mu). V1 has only 20% as much activity as J558 in the absence of
E(mu), and the other promoters have less than 8% of the activity of J558.
Notably, the 81X promoter has essentially no enhancer-independent activity. In
the presence of E(mu), V1 has equivalent activity to J558, while the other
promoters show much less activity. Again, 81X is the weakest promoter of all,
despite being the most frequently rearranging gene. Finally, we show that the
steady state level of V(H)S107 and V(H)7183 germline transcripts in vivo is very
low. Thus, these data show little correlation between the strength or enhancer
independence of these V(H) promoters and the relative frequency of recombination
of the corresponding V(H) genes. In addition, the data show that individual V(H)
promoters have different strengths even in the presence of E(mu), demonstrating
that even promoters within a single V(H) family can be quite heterogeneous.
PMID- 10781836
TI - Phosphorylation of class I MHC molecules in the absence of phorbol esters is an
intracellular event and may be characteristic of trafficking molecules.
AB - Class I Major Histocompatibility Complex (MHC) molecules are displayed at the
cell surface where they present antigenic peptides to T lymphocytes. Class I MHC
molecules undergo cytoplasmic domain phosphorylation on a serine residue late in
their biosynthesis. Here we show that phosphorylation occurs on mature, beta(2)
microglobulin-associated class I MHC molecules in a mouse lymphoid cell line.
Both recently synthesized class I MHC molecules and molecules which are at least
3 h old become phosphorylated. Approximately 14% of phosphorylated class I MHC
molecules occur at the cell surface. Density gradient analysis indicates that
phosphorylated class I MHC molecules also occur in lamp(+) intracellular
compartments and in fractions containing rab4, a GTP-binding protein associated
with recycling endosomes. Class I MHC molecules are endocytosed and recycled to
the cell surface in these cells. Furthermore, the lysosomotropic drug,
primaquine, inhibits both class I MHC phosphorylation and its recycling back to
the cell surface, suggesting that phosphorylation is related to class I MHC
recycling. These observations are intriguing since several studies have shown
that class I MHC molecules can acquire antigenic peptides in NH(4)Cl-sensitive
compartments. Hence, class I MHC phosphorylation may play a role in regulating
intracellular sorting through these compartments.
PMID- 10781835
TI - Expansion of epitope cross-reactivity by anti-idiotype modulation of the primary
humoral response.
AB - The primary humoral response produces antigen-specific antibodies so to clear the
initial infection, and generates a population of corresponding memory cells to
prevent infection by future encounters with the same pathogen. The continuous
genetic modification of a pathogen's exterior, however, is one mechanism used to
evade the immune defenses of its host. Here we describe a novel means, involving
anti-idiotypic antibodies, by which the host can counteract such pathogen genetic
alterations by modulation of its primary humoral response. An autoimmune response
against primary antibodies, Ab1's, creates anti-idiotypic antibodies (Ab2's),
some of which (designated Ab2alpha) are able to bind the Ab1/antigen complex. We
have discovered that binding of Ab2alpha to its corresponding Ab1 can expand
Ab1's ability to bind variations of its antigen. This expanded epitope cross
reactivity is shown not only to increase the binding activity of Ab1 but also its
ability to neutralize a variant infectious virus. MAb M77 is an Ab1, which is
highly strain-specific for the HIV-1 envelope protein gp120(IIIB). This Ab1 can
be rendered cross-reactive and neutralizing for an otherwise resistant HIV strain
by its interaction with a unique anti-idiotypic Ab2alpha (GV12). Furthermore,
molecular characterization of this expanded cross-reactivity was accomplished
using combinatorial phage display peptide libraries.
PMID- 10781837
TI - TRAF-3 interacts with p62 nucleoporin, a component of the nuclear pore central
plug that binds classical NLS-containing import complexes.
AB - The TRAF-3 gene encodes a number of splice-variant isoforms that function as
adapter molecules in NF-kappaB signaling, in part by associating with the
cytoplasmic tails of CD40 or other TNF-receptor (TNF-R) family members. To
identify downstream molecules in TRAF-3 signaling, a yeast two-hybrid library was
screened with a full-length TRAF-3 construct. Nine independent TRAF-3 interacting
clones encoded fragments of p62 Nucleoporin (p62), a 522 amino acid (aa)
component of the nuclear pore central plug, that is known to bind karyopherin
beta/classical-NLS import factor complexes. The interaction of p62 with TRAF-3
was specific, since p62 failed to interact with TRAF-2, -4, -5, or -6. Deletional
analysis in yeast revealed that the p62:TRAF-3 interaction is mediated by a p62
carboxy (C)-terminal coiled-coil domain and TRAF-3's fifth zinc (Zn) finger and
coiled-coil domain. In human 293 T cells, recombinant TRAF-3 or p62 specifically
co-immunoprecipitates the other species. In addition, endogenous p62 co
precipitates over-expressed TRAF-3. The functional effects of over-expressing a
TRAF-3 binding fragment, p62(aa 336-522) were studied on NF-kappaB-dependent, or
control STAT1-dependent reporter activity in 293 T cells, either resting or after
stimulation by CD40 or IFN-gamma, respectively. Over-expression of p62(aa 336
522) induces NF-kappaB activation in resting cells and augments CD40-induced NF
kappaB activation, but has no effect on control STAT1 reporter activity, either
at baseline or after IFN-gamma induction. The finding that TRAF-3 binds p62,
suggests that TRAF-3 may serve as an adapter molecule at the nuclear membrane, in
addition to its known adapter function at the plasma membrane.
PMID- 10781839
TI - Complement-endothelial cell interactions: pathophysiological implications.
PMID- 10781838
TI - Restoration of thymic development in an Lck(-/-) thymoma overexpressing ZAP-70.
AB - Thymic development is strictly controlled by Src and Syk family protein tyrosine
kinases. The major players in this process are Lck and ZAP-70, which regulate
critical differentiation steps of thymopoiesis. Notwithstanding the critical role
of Lck and ZAP-70 in thymocyte development as compared to the related kinases Fyn
and Syk, a partial functional redundancy between members of the same family of
protein tyrosine kinases has emerged from studies on genetically manipulated
mouse models. Furthermore, a close functional interplay between Lck and ZAP-70 in
intracellular signaling has been shown to occur in thymocytes. Here we present
the characterization of a thymoma from an Lck(-/-) mouse, where the block in
thymocyte development is overcome and the transition between the CD4(-)CD8(-) and
CD4(+)CD8(+) stages is fully restored. Determination of the expression levels of
Fyn, ZAP-70 and Syk in thymocytes form the Lck(-/-) thymoma revealed high levels
of ZAP-70 overexpression and recovery of a specific subset of phosphoproteins as
compared to Lck(-/-) thymocytes. Hence ZAP-70 overexpression in thymocytes is
associated with recovery from the developmental arrest caused by the absence of
Lck, suggesting a role for ZAP-70 downstream of Lck in the maturation of
CD4(+)CD8(+) thymocytes.
PMID- 10781840
TI - Adeno-associated virus mediated gene transfer into primary rat brain neuronal and
glial cultures: enhancement with the pH-sensitive surfactant dodecyl 2-(1'
imidazolyl) propionate.
AB - This study evaluated the effects of a novel, pH-sensitive surfactant, dodecyl 2
(1'-imidazolyl) propionate (DIP), on cationic lipid mediated transfection in
primary rat brain neuronal and glial cultures. The cationic lipid complex
DOTAP/DOPE (1, 2-dioleoyl-3-trimethylammonium propionate and dioleoyl
phosphatidylethanolamine, respectively) was added over a range of concentrations
(0-120 microg/ml) with DNA concentration kept constant (1.6 microg/ml). The
neuron-specific enolase (NSE) and cytomegalovirus (CMV) promoters were found to
drive green fluorescent protein (GFP) expression in neuron-enriched and glial
cultures, respectively, using adeno-associated virus (AAV) derived constructs.
NSE-driven GFP expression was not observed in glial cultures. Addition of
DOTAP/DOPE increased transfection efficiency over a wide range of lipid
concentrations (5-50 microg/ml) keeping DNA concentration constant (1.6
microg/ml). Addition of DIP to the lipid/DNA complex increased maximum
transfection efficiencies in glial and neuronal cultures 2-3-fold. Transfection
efficiencies were at their maximum with a similar total lipid concentration (50
microg/ml) in both cell-types in the presence of DIP. Neuronal cultures were more
sensitive than glia to the toxic actions of DOTAP/DOPE, with or without DIP.
These results indicate that AAV-mediated gene-transfer to neurons and glia can be
facilitated by addition of a pH-sensitive surfactant to cationic liposome/DNA
complexes and that endosomal escape could be a limiting factor in transgene
expression.
PMID- 10781841
TI - GluR2 protein synthesis and metabolism in rat hippocampus following transient
ischemia and ischemic tolerance induction.
AB - In this study we have determined the metabolic half-life, protein synthesis and
expression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)
receptor subunit GluR2 in the hippocampus of the living rat. Synthesized proteins
were pulse labeled in vivo using intracarotid infusion or intrahippocampal
injection of L-[(35)S] labeled amino acids, and the GluR2 protein
immunoprecipitated in order to measure the tracer incorporation at different
survival time-points. A limited time course study suggested a metabolic half-life
of 144 and 108 h in the CA1 region in control animals following carotid artery
infusion and intrahippocampal injection, respectively. Twenty-four hours
following a moderate ischemic insult, GluR2 protein synthesis was decreased
significantly in both the CA1 and DG/CA3 region, whereas the total protein
synthesis was decreased significantly only in the CA1 region. Twenty-four hours
following ischemic tolerance induction, a significant increase in GluR2
expression was found in the CA1 region using quantitative Western blotting, while
no change was found in the dentate gyrus (DG)/CA3 or in expression of GluR1
protein. Data from labeling experiments did not reveal the reason for the
increased amount of GluR2 in the CA1 region of the tolerant animals. This study
shows that following global ischemia the GluR2 synthesis is decreased both in the
CA1 and DG/CA3, which, together with the found GluR2 metabolic half-life,
contradict a selective loss of GluR2 protein as a triggering mechanism for the
delayed CA1 pyramidal cell death. Twenty-four hours following tolerance
induction, we found an increased GluR2 expression in the CA1 region, suggesting
that GluR2 plays a role in the acquisition of ischemic tolerance. Our study
suggests the ability of neurons to regulate the AMPA receptor subunit expression
through changes in protein synthesis and stability.
PMID- 10781842
TI - A frontal variant of Alzheimer's disease exhibits decreased calcium-independent
phospholipase A2 activity in the prefrontal cortex.
AB - A frontal variant of Alzheimer's disease (AD) has recently been identified on
neuropathological and neuropsychological grounds (Johnson, J.K., Head, E., Kim,
R., Starr, A., Cotman, C.W., 1999. Clinical and pathological evidence for a
frontal variant of Alzheimer Disease. Arch. Neurol. 56, 1233-1239). Frontal AD
differs strikingly from typical AD by the occurrence of neurofibrillary tangle
densities in the frontal cortex as high or higher than in the entorhinal cortex.
Since cerebrocortical membranes are commonly abnormal in Alzheimer's disease
(AD), we assayed frontal AD cases for enzymes regulating membrane phospholipid
composition. We specifically measured activity of phospholipase A2s (PLA2s) in
dorsolateral prefrontal and lateral temporal cortices of frontal AD cases (n=12),
which have respectively high and low densities of neurofibrillary tangles. In
neither cortical area was Ca(2+)-dependent PLA2 activity abnormal compared to
controls (n=12). In contrast, a significant 42% decrease in Ca(2+)-independent
PLA2 activity was found in the dorsolateral prefrontal, but not the lateral
temporal, cortex of the frontal AD cases. Similarly, the dorsolateral prefrontal
cortex, but not the lateral temporal cortex of the frontal AD cases suffered a
42% decrease in total free fatty acid content, though neither that decrease nor
those in any one species of free fatty acid was significant. The observed
biochemical changes probably occurred in neurons given (a) our finding that PLA2
activity of cultured human NT2 neurons is virtually all Ca(2+)-independent and
(b) the finding of others that nearly all Ca(2+)-independent PLA2 in brain gray
matter is neuronal. The decrease in Ca(2+)-independent PLA2 activity is not
readily attributable to Group VI or VIII iPLA2s since neither NT2N neurons nor
our brain homogenates were greatly inhibited by drugs potently suppressing those
iPLA2s. Decreased Ca(2+)-independent PLA2 activity in frontal AD may reflect a
compensatory response to pathologically accelerated phospholipid metabolism early
in the disorder. That could cause an early elevation of prefrontal free fatty
acids, which can stimulate polymerization of tau and thus promote the prefrontal
neurofibrillary tangle formation characteristic of frontal AD.
PMID- 10781843
TI - Negative allosteric modulators of AMPA-preferring receptors inhibit [(3)H]GABA
release in rat striatum.
AB - The effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a
selective glutamate receptor agonist, on the release of previously incorporated
[(3)H]GABA was examined in superfused striatal slices of the rat. The slices were
loaded with [(3)H]GABA in the presence of beta-alanine (1 mM) and superfused with
Krebs-bicarbonate buffer containing nipecotic acid (0.1 mM) and aminooxyacetic
acid (0.1 mM) to inhibit GABA uptake and metabolism. AMPA (0.01 to 3 mM)
increased basal [(3)H]GABA outflow and nipecotic acid potentiated this effect.
The [(3)H]GABA releasing effect of AMPA was an external Ca(2+)-dependent process
in the absence but not in the presence of nipecotic acid. Cyclothiazide (0.03
mM), a positive modulator of AMPA receptors, failed to evoke [(3)H]GABA release
by itself, but it dose-dependently potentiated the [(3)H]GABA releasing effect of
AMPA. The AMPA (0.3 mM)-induced [(3)H]GABA release was antagonized by NBQX (0.01
mM) in a competitive fashion (pA(2) 5.08). The negative modulator of AMPA
receptors, GYKI-53784 (0.01 mM) reversed the AMPA-induced [(3)H]GABA release by a
non-competitive manner (pD'(2) 5.44). GYKI-53784 (0. 01-0.1 mM) also decreased
striatal [(3)H]GABA outflow on its own right, this effect was stereoselective and
was not influenced by concomitant administration of 0.03 mM cyclothiazide. GYKI
52466 (0. 03-0.3 mM), another negative modulator at AMPA receptors, also
inhibited basal [(3)H]GABA efflux whereas NBQX (0.1 mM) by itself was ineffective
in alteration of [(3)H]GABA outflow. The present data indicate that AMPA evokes
GABA release from the vesicular pool in neostriatal GABAergic neurons. They also
confirm that multiple interactions may exist between the agonist binding sites
and the positive and negative modulatory sites but no such interaction was
detected between the positive and negative allosteric modulators. Since GYKI
53784, but not NBQX, inhibited [(3)H]GABA release by itself, AMPA receptors
located on striatal GABAergic neurons may be in sensitized state and phasically
controlled by endogenous glutamate. It is also postulated that these AMPA
receptors are located extrasynaptically on GABAergic striatal neurons.
PMID- 10781844
TI - Differential stereoselectivity of D- and L-myo-inositol 1,2,4, 5
tetrakisphosphate binding to the inositol 1,4,5-trisphosphate receptor and 3
kinase.
AB - D- and L-myo-inositol 1,2,4,5-tetrakisphosphate (Ins(1,2,4,5)P(4)) were
investigated for their ability to bind to the D-myo-inositol 1, 4,5-trisphosphate
(Ins(1,4,5)P(3)) receptor in a bovine adrenal cortical membrane fraction, to
mobilize intracellular Ca(2+) stores in Xenopus oocytes, and to bind to the rat
brain Ins(1,4,5)P(3) 3-kinase overexpressed and purified in E. coli. In
competitive binding experiments with the Ins(1,4,5)P(3) receptor, D-Ins(1,2,4,
5)P(4) effectively displaced [(3)H]Ins(1,4,5)P(3) in a concentration-dependent
manner with a potency comparable to that of D-Ins(1,4,5)P(3), while L
Ins(1,2,4,5)P(4) was approximately 50-fold less effective than D-Ins(1,4,5)P(3)
and D-Ins(1,2,4,5)P(4). The DL-Ins(1,2,4,5)P(4) racemate bound to the
Ins(1,4,5)P(3) receptor with an apparent intermediate efficiency. Injection of D
Ins(1,2,4, 5)P(4) into oocytes evoked a chloride current dependent on
intracellular Ca(2+) mobilization in which the agonists ranked in a similar order
of potency as in the Ins(1,4,5)P(3) receptor binding. On the other hand, D
Ins(1,2,4,5)P(4) only inhibited the binding of [(3)H]Ins(1,4,5)P(3) to 3-kinase
very weakly with a markedly reduced potency compared to D-Ins(1,4,5)P(3),
indicating that D-Ins(1,2,4, 5)P(4) is not an effective competitor in the
phosphorylation of [(3)H]-Ins(1,4,5)P(3) by 3-kinase. The results, therefore,
clearly indicate that D-Ins(1,2,4,5)P(4) is as effective as D-Ins(1,4,5)P(3) in
the binding to the receptor but not 3-kinase, and access of Ins(1, 2,4,5)P(4)
over the Ins(1,4,5)P(3) receptor calls for stringent stereospecificity with D
Ins(1,2,4,5)P(4) being the active form in DL-Ins(1,2,4,5)P(4)-mediated Ca(2+)
mobilization.
PMID- 10781845
TI - Quinolinic acid lesion induces changes in rat striatal glutathione metabolism.
AB - Although the involvement of oxidative mechanisms in the cytotoxicity of
excitatory amino acids has been well documented, it is not known whether the
intrastriatal injection of quinolinic acid (QA) induces changes in glutathione
(GSH) metabolism. In this work, the activities of the enzymes GSH reductase
(GRD), GSH peroxidase (GPX), and GSH S-transferase (GST), as well as the GSH
content, were studied in the striatum, hippocampus, and frontal cortex of rats 1
and 6 weeks following the intrastriatal injection of QA (225 nmol). One group of
animals remained untreated. This lesion resulted in a 20% decrease in striatal
GRD activity at both the 1- and 6-week postlesion times, whereas GST exhibited a
30% activity increase in the lesioned striatum observable only 6 weeks after the
lesion. GPX activity remained unchanged. In addition, the QA injection elicited a
30% fall in GSH level at the 1-week postlesion time. GSH related enzyme
activities and GSH content from other areas outside the lesioned striatum were
not affected. GST activation could represent a beneficial compensatory response
to neutralize some of the oxidant agents generated by the lesion. However, this
effect together with the reduction in GRD activity could be the cause or a
contributing factor to the observed QA-induced deficit in GSH availability and,
consequently, further disrupt the oxidant homeostasis of the injured striatal
tissue. Therefore, these results provide evidence that the in vivo excitotoxic
injury to the brain might affect oxidant/antioxidant equilibrium by eliciting
changes in glutathione metabolism.
PMID- 10781846
TI - Footshock-induced changes in brain catecholamines and indoleamines are not
mediated by CRF or ACTH.
AB - Stressful treatments have long been associated with increased activity of brain
catecholaminergic and serotonergic neurons. An intracerebroventricular (icv)
injection of the corticotropin-releasing factor (CRF) also activates brain
catecholaminergic neurons. Because brain CRF-containing neurons appear to be
activated during stress, it is possible that CRF mediates the catecholaminergic
activation. This hypothesis has been tested by assessing the responses in brain
catecholamines and indoleamines to footshock in mice pretreated icv with a CRF
receptor antagonist, and in mice lacking the gene for CRF (CRFko mice).
Consistent with earlier results, icv administration of CRF increased catabolites
of dopamine and norepinephrine, but failed to alter tryptophan concentrations or
serotonin catabolism. A brief period of footshock increased plasma corticosterone
and the concentrations of tryptophan and the catabolites of dopamine,
norepinephrine and serotonin in several brain regions. Mice injected icv with 25
microg alpha-helical CRF(9-41) prior to footshock had neurochemical responses
that were indistinguishable from controls injected with vehicle, while the
increase in plasma corticosterone was slightly attenuated in some experiments.
CRFko mice exhibited neurochemical responses to footshock that were
indistinguishable from wild-type mice. However, whereas wild-type mice showed the
expected increase in plasma corticosterone, there was no such increase in CRFko
mice. Similarly, hypophysectomized mice also showed normal neurochemical
responses to footshock, but no increase in plasma corticosterone. Hypophysectomy
itself elevated brain tryptophan and catecholamine and serotonin metabolism.
Treatment with ACTH icv or peripherally failed to induce any changes in cerebral
catecholamines and indoleamines. These results suggest that CRF and its
receptors, and ACTH and other pituitary hormones, are not involved in the
catecholamine and serotonin responses to a brief period of footshock.
PMID- 10781847
TI - Sustained depolarisation induces changes in the extracellular concentrations of
purine and pyrimidine nucleosides in the rat thalamus.
AB - ATP and adenosine are well-known neuroactive compounds. Other nucleotides and
nucleosides may also be involved in different brain functions. This paper reports
on extracellular concentrations of nucleobases and nucleosides (uracil,
hypoxanthine, xanthine, uridine, 2'-deoxycytidine, 2'-deoxyuridine, inosine,
guanosine, thymidine, adenosine) in response to sustained depolarisation, using
in vivo brain microdialysis technique in the rat thalamus. High-potassium
solution, the glutamate agonist kainate, and the Na(+)/K(+) ATPase blocker
ouabain were applied in the perfusate of microdialysis probes and induced release
of various purine and pyrimidine nucleosides. All three types of depolarisation
increased the level of hypoxanthine, uridine, inosine, guanosine and adenosine.
The levels of measured deoxynucleosides (2'-deoxycytidine, 2'-deoxyuridine and
thymidine) decreased or did not change, depending on the type of depolarisation.
Kainate-induced changes were TTX insensitive, and ouabain-induced changes for
inosine, guanosine, 2'-deoxycytidine and 2'-deoxyuridine were TTX sensitive. In
contrast, TTX application without depolarisation decreased the extracellular
concentrations of hypoxanthine, uridine, inosine, guanosine and adenosine. Our
data suggest that various nucleosides may be released from cells exposed to
excessive activity and, thus, support several different lines of research
concerning the regulatory roles of nucleosides.
PMID- 10781848
TI - The introduction of new vaccines into developing countries II. Vaccine financing.
AB - The development of new vaccines for important childhood diseases presents an
unparalleled opportunity for disease control but also a significant problem for
developing countries: how to pay for them. To help address this problem, the
William H. Gates Foundation has established a Global Fund for Children's Vaccine.
In this paper, we discuss the allocation of this and other similar funds, which
we call Global Funds. We propose that allocation of the Global Funds to
individual countries be guided in part by a Vaccine Procurement Baseline (VPB).
The VPB would set a minimum of 0.01% of gross national product (GNP) as an amount
each developing country would devote to its own vaccine procurement. When this
amount is not sufficient to procure the vaccines needed by a developing country,
the Global Funds would meet the shortfall. The amount required of donors to
maintain the Global Funds would be about $403 million per year for both existing
EPI vaccines as well as for a hypothetical group of five new vaccines costing
$0.50 per dose and requiring three doses per child. Including program costs, poor
developing countries currently spend about 0.13% of GNP on EPI immunizations. In
contrast, the United States, as one example donor country, spends about 0.035% of
GNP for childhood immunization including several new vaccines. This paper
analyzes the Global Funds requirements for hepatitis B and Haemophilus influenzae
type b (Hib) vaccines. After a ramp-up period, needier countries would eventually
require about $62 million for hepatitis B and $282 million for Hib at current
prices. Various additional criteria could be used to qualify countries for
participation in the Global Funds.
PMID- 10781849
TI - Immune responses induced by recombinant BCG strains according to level of
production of a foreign antigen: malE.
AB - A variety of viral, bacterial and parasitic antigens have been expressed in BCG
and the capacity of these recombinant bacteria to induce immune responses has
been well documented. However, little is known about the parameters influencing
the induction of immune responses by recombinant BCG (rBCG), such as level of
production and localization of the recombinant antigen. In the present study, we
have constructed several rBCG strains expressing the malE gene from Escherichia
coli which is either secreted or targeted to the cytoplasm or plasma membrane.
Expression of malE was quantified by ELISA and localization was analyzed by flow
cytometry. Even when using the same promoter, levels of cytoplasmic or membrane
MalE production were far less than those from secreting strains using either
mycobacterial or E. coli secretion signals. Stronger and more rapid immune
responses were induced by rBCG strains with the highest levels of secreted MalE
compared to cytoplasmic or membrane constructs, including both good humoral and
proliferative responses in BALB/c, C57BL6 and even C3H mice, previously shown to
be poor MalE responders. These results suggest that the levels of foreign antigen
production play an important role in the induction of immune responses by rBCG
strains.
PMID- 10781851
TI - Seroconversion and duration of immunity after vaccination against group C
meningococcal infection in young children.
AB - An increase in the incidence of group C meningococcal disease was observed in the
Murcia Region (Spain) during 1996-1997. In September 1997, a massive vaccination
campaign was implemented among the population aged 18 months to 19 years. The aim
of this study was to assess the seroconversion rate of children aged 18-59 months
and the persistence of immune response 1 year after vaccination. A total of 296
children were included. Blood samples were obtained before vaccination and 1
month and 1 year after vaccination. Three point seven percent of the children had
bactericidal antibody titres of >/=1:8 before vaccination. One month after
vaccination seroconversion was 63.7%, with a growing trend related to age at
vaccination (p<0.0001). The increase in antibody titres was shown to be
quantitatively greater above the age of 36 months (p<0.0001). One year after
vaccination only 4.3% of the children who initially seroconverted still had
bactericidal activity. Seroconversion in children under 5 increases with age but
antibodies decline rapidly in the year following vaccination.
PMID- 10781850
TI - Influence of live respiratory syncytial virus priming on the immune response
generated by a recombinant vaccine candidate, BBG2Na.
AB - Respiratory syncytial virus is one of the major respiratory pathogens for infants
and immunocompromized children. With the exception of young children, all the
population has encountered RSV and is seropositive. Recent reports have
demonstrated however that the virus also affects the elderly and represents a
major cause of illness associated with an excess of morbidity and mortality. We
have generated a recombinant RSV vaccine, BBG2Na, which is highly protective in
rodents against RSV infection. The aim of this study was to evaluate the ability
of the vaccine to increase anti-RSV protection in RSV-primed mice and to
characterize the induced immune responses. Immunization with BBG2Na increased the
anti-RSV-A serum antibody titers of RSV-primed mice with induction of both IgG1
and IgG2a antibodies attesting for a mixed Th response. Moreover, the level of
the induced anti-G2Na antibodies was greater in seropositive mice. Finally, sera
from RSV-primed mice displayed a higher protective efficacy after transfer into
naive mice following subsequent immunization with BBG2Na than sera of mice
immunized with RSV-A only. Our results demonstrate that BBG2Na is immunogenic and
increases the protective efficacy of serum antibodies in RSV-primed mice; they
support the possibility of performing clinical trials in the seropositive human
population.
PMID- 10781852
TI - Predictive factors for the neutralizing antibody response following pre-exposure
rabies immunization: validation of a new booster dose strategy.
AB - A prospective cohort of 312 subjects who received pre-exposure rabies
immunization and who were monitored serologically with a 10-year follow-up was
assessed using multivariate analysis. The aim was to propose a new booster dose
strategy by identifying predictive factors for the durability of the neutralizing
antibody response. Evaluation bore on several factors relating to: (1)
demographic characteristics: age, gender; (2) vaccines: type of vaccine (HDCV or
PVRV), injection regimen (D0-D28-D365 or D0-D7-D28-D365) and vaccine lots'
antigenic potency; and (3) resulting antibody titers. Logistic regression
analysis enabled the authors to establish a predictive model for immunized
subjects' serological status at ten years' follow-up expressed as a P probability
for seroreversion (antibody titer <0.5 IU/ml). Highly significant factors were
the immunization regimen, the type of vaccine used and the antibody titer at
D379. A P value <0.4 identified subjects as "good" responders who were sure to be
have satisfactory antibody titers at 10 years and who required a single booster
dose every 10 years. A P value >/=0.4 identified subjects as "poor" responders in
whom a specific follow-up and booster dose strategy is proposed. This new
immunization strategy could at least be applied to subjects with a frequent risk
of exposure, as defined by institutional recommendations. This new immunization
strategy should nevertheless undergo an external validation and a cost
effectiveness evaluation.
PMID- 10781853
TI - Antibody responses to Yersinia pestis F1-antigen expressed in Salmonella
typhimurium aroA from in vivo-inducible promoters.
AB - Attenuated mutants of Salmonella typhimurium are being evaluated as delivery
systems for a variety of heterologous vaccine antigens. Gene promoters which are
induced in vivo can direct the stable expression of genes encoding these
antigens. We have investigated the utility of the phoP, ompC, pagC and lacZ gene
promoters for expression of the Y. pestis F1-antigen in S. typhimurium SL3261
(aroA). After i.g. (intragastric) dosing the highest level of spleen colonisation
was found with recombinant Salmonella expressing F1-antigen from the phoP gene
promoter, and this recombinant was most effective in inducing serum and mucosal
antibody responses. The use of the pagC gene promoter to direct expression of F1
antigen resulted in the induction of serum and mucosal antibody responses even
though the recombinant Salmonella were unable to colonise spleen tissues
suggesting that colonisation of these tissues is not essential for the induction
of antibody responses.
PMID- 10781854
TI - Further development of the Helicobacter pylori mouse vaccination model.
AB - Immunisation against Helicobacter infection in mouse models has thus far produced
neither complete protection against the bacteria, nor a complete prevention of
the associated gastritis. This study aimed firstly to compare the sensitivities
of the various methods used to assess H. pylori infection in the mouse model, and
secondly to develop the experimental design to induce a more effective immunity,
aimed at further reducing bacterial burden in the gastric tissue. Various mouse
strains were prophylactically immunised with whole bacterial sonicate and cholera
toxin before challenge with H. pylori-SS1. The relative sensitivities of the
urease assay, histological assessment and the colony forming assay to detect
levels of H. pylori colonisation were compared. Comparisons of different antigen
doses and different timecourses of immunisation were performed. The colony
forming assay was found to be far more sensitive than either the urease assay or
histological assessment for determining the protective efficacies of
immunisation. Mice which had 10(5) H. pylori per gram of stomach by colony assay
were negative by histology and urease. Lower doses of whole cell sonicate were
more protective than high doses and more effective immunisation was achieved by
leaving at least 3 weeks between immunisation instead of weekly immunisations. In
conclusion, for assessment of H. pylori colonisation in the mouse model, the
colony forming assay should be used. The experimental protocol for immunisation
has been altered to produce a significant improvement in protection. However,
full protection has still not yet been achieved and more work is still required.
PMID- 10781855
TI - Immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine
compared with a group A+C meningococcal polysaccharide vaccine in adolescents in
a randomised observer-blind controlled trial.
AB - This study evaluated the immunogenicity and reactogenicity of a group C
meningococcal conjugate vaccine (MenC) compared with a group A+C meningococcal
polysaccharide vaccine (MenPS) in healthy adolescents. Subjects were randomised
to receive one dose of either MenC (n=92) or MenPS (n=90). Group C meningococcal
IgG antibody concentrations and bactericidal titres were higher in the MenC group
than the MenPS group at 1 month (22.8 U/ml vs 4.0 U/ml, p<0.001, and 87 vs 20,
p<0.001, respectively) and 12 months (6.1 U/ml vs 3.0 U/ml, p<0.001, and 81.3 vs
20.2, p<0.001, respectively). No differences in post immunisation reaction rates
were noted between the two vaccinated groups. This study demonstrated the safety
and enhanced immunogenicity of the candidate meningococcal conjugate vaccine as
compared with the licensed polysaccharide vaccine in adolescents.
PMID- 10781856
TI - Increasing the potency of MHC class II-presented epitopes by linkage to Ii-Key
peptide.
AB - We previously found that peptide Ii77-92 from the immunoregulatory Ii protein
significantly enhances the binding of antigenic peptides to MHC class II
molecules. Now a series of hybrids have been constructed linking LRMK, the active
core region of the Ii77-92 peptide, to an antigenic epitope of cytochrome C. In
vitro T cell hybridoma stimulation by some of these hybrids is up to 250 times
more potent than by the antigenic peptide. The biological activities of the
hybrids were tested in terms of length and composition of the linker. Simple
spacers containing a polymethylene bridge (-HN-CH(2)-CH(2)-CH(2)-CH(2)-CO(2)-)
were fully active in these hybrids which can enhance vaccination with MHC class
II-presented epitopes.
PMID- 10781857
TI - A possible explanation for the discrepancy between ELISA and neutralising
antibodies to tetanus toxin.
AB - The structure and protective activity of tetanus antibodies elicited in rabbits
after whole-cell pertussis diphtheria-tetanus vaccine (DTPw) vaccination was
studied. ELISA antibody levels and toxin neutralisation activity (TNT) were
measured in individual serum samples. The ratio of symmetric and asymmetric
(functionally monovalent) IgG molecules was determined by concanavalin A (Con A)
chromatography. This test is based on the fact that the carbohydrate group
responsible for the molecular asymmetry has high affinity for the lectin Con A.
Asymmetric molecule ratio was observed to increase with immunisation time, as
well as differences between TNT and ELISA levels. All serum samples were
overestimated by ELISA as compared to TNT assay, in line with the markedly higher
proportion of asymmetric molecules which have lower toxin neutralising activity.
Protective levels could not be predicted reasonably from ELISA results below 0.
222 IU/ml, because this methodology fails to discriminate between both types of
antibodies and only an in vivo serum neutralisation procedure (TNT) reflects the
true neutralising serum activity.
PMID- 10781858
TI - Safety and immunogenicity of an oral, inactivated enterotoxigenic Escherichia
coli plus cholera toxin B subunit vaccine in Bangladeshi adults and children.
AB - We have compared the B cell responses evoked in Bangladeshi, adults (n=11, median
age 25 years) and children (n=21, median age 4.5 years), 7 days after intake of
each of two doses of an oral, inactivated enterotoxigenic Escherichia coli (ETEC)
vaccine composed of formalin-killed ETEC strains expressing the colonization
factors, CFA/I, CFA/II and CFA/IV together with 1 mg of recombinant cholera toxin
B-subunit (rCTB). The vaccine was well tolerated and only gave rise to negligible
side effects. Peak antibody-secreting cell (ASC) response of the IgA isotype were
seen 7 days after the first dose of the vaccine. The ASC responses to the
different colonization factors (CFs) increased from a 29- to 46-fold (responder
frequency 90-100%) in the adults and 13- to 24-fold (responder frequency 67-90%)
in the children. The IgA-ASC response to rCTB also peaked after the first dose in
the adults (426-fold, responder frequency 100%) and the children (46-fold,
responder frequency 95%). Increased IgA antibody levels against CFA/I as well as
IgA and IgG antibody levels to rCTB were seen in plasma after immunisation. About
86% of the children and 80% of the adults responded with faecal antibodies to
rCTB, whereas about 67% of both groups responded to CFA/I. These results show
that a single dose of the ETEC vaccine may elicit significant mucosal immune
responses in both children and adults residing in an ETEC-endemic country such as
Bangladesh.
PMID- 10781859
TI - Induction of innate immunity by nasal influenza vaccine administered in
combination with an adjuvant (cholera toxin).
AB - Inactivated influenza vaccine was administered intranasally to BALB/c mice
together with an adjuvant (cholera toxin B subunit [CTB] supplemented with a
trace amount of the whole toxin, CTB*) and its ability to induce innate immunity
and confer protection against influenza was examined. Nasal wash virus titres 3
days after inoculation of homologous viruses were measured as an index of the
ability of the vaccine to confer protection in mice immunized with either CTB*
combined vaccine or CTB* alone 1-21 days previously. The results were as follows.
(1) Partial but significant reduction of the nasal-wash virus titres (prevention)
was detected beginning 3 days after the vaccination, that is, 2 days earlier than
the appearance of both virus-specific antibody-forming cells (AFCs) in the nasal
associated lymphoid tissue (NALT) and virus-specific IgA antibody responses in
the nasal washes of mice immunized with the CTB*-combined vaccine. (2) The
protection, detected on day 3 and peaking on day 5 but lost by day 21, was also
conferred in mice immunized with CTB* alone. (3) The non-specific prevention was
detected at doses of more than 0.3 microg of CTB*/mouse. (4) The nonspecific
protection beginning 3 days after the immunization involved the enhanced
expression of cytokine mRNAs (IL-15 and IL-18), considered responsible for
natural killer (NK) cell activation, by the non-T cell populations in the NALT.
(5) Normal NALT cells, when cultured in vitro with CTB*, secreted IL-1beta within
a few hours in culture. These results demonstrate that the CTB*-combined vaccine,
when given intranasally into mice, can confer nonspecific protection against
influenza beginning 3 days after the vaccination and that CTB* also possessed
this ability to confer protection non-specifically and temporarily by inducing
the secretion of IL-1beta, one of the most important cytokines that initiates
both innate and adaptive immunity, and also NK cell activity.
PMID- 10781860
TI - Effective mucosal immunization against respiratory syncytial virus using purified
F protein and a genetically detoxified cholera holotoxin, CT-E29H.
AB - We exploited the powerful adjuvant properties of cholera holotoxin (CT) to create
a mucosally administered subunit vaccine against respiratory syncytial virus
(RSV). A genetically detoxified mutant CT with an E to H substitution at amino
acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity
and potential use as an intranasal (IN) adjuvant for the natural fusion (F)
protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H
binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was
11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent
mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H
induced serum anti-CT and anti-F protein antibodies that were comparable to those
obtained after vaccination with equivalent doses of CT. Vaccinations containing
CT-E29H at doses of 0.1 microg were statistically equivalent to 1.0 microg in
enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV
neutralizing antibodies were detected in nasal washes and sera, respectively, of
mice that had received F protein and 0.1 or 1.0 microg of CT-E29H. Anti-F protein
IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 microg
CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the
formulation of purified F protein and CT-E29H (0.1 and 1.0 microg) facilitated
protection of both mouse lung and nose from live RSV challenge. Collectively, the
data have important implications for vaccine strategies that use genetically
detoxified mutant cholera holotoxins for the mucosal delivery of highly purified
RSV antigens.
PMID- 10781861
TI - Influence of administration dose and route on the immunogenicity and protective
efficacy of BBG2Na, a recombinant respiratory syncytial virus subunit vaccine
candidate.
AB - The immunogenicity and protective efficacy of BBG2Na, a novel recombinant
respiratory syncytial virus subunit vaccine candidate, was assessed in BALB/c
mice under various conditions of dose, administration route and number of
immunisations. A single intra-peritoneal (i.p.) dose of 2 microg, or two doses of
0.2 microg, were sufficient to induce elevated RSV-A serum antibodies and
sterilising lung protective immunity. Serum antibody titres were significantly
boosted following second immunisations, but not a third. Of three routes of
immunisation, i.p. induced the highest RSV-A antibody titres, followed in
efficacy by the intra-muscular (i. m.) and subcutaneous (s.c.) routes.
Nonetheless, all three routes induced comparable and sterilising lung protection.
In contrast, upper respiratory tract protection was observed only after i.p.
vaccination, although significant viral titre reductions were evident following
i.m. or s.c. immunisations. Interestingly, Pepscan analyses indicated that
antibody epitope usage was highest in i.p. and lowest in i.m. immunised mice,
respectively. Nonetheless, all routes resulted in antibody responses to known
lung protective epitopes (protectopes). Thus, the prevention of serious lower
respiratory tract disease, the principle goal of a RSV vaccine, but not URT
infection, is dose dependent but unlikely to be influenced by the route of BBG2Na
administration.
PMID- 10781862
TI - Partial protection to respiratory syncytial virus (RSV) elicited in mice by
intranasal immunization using live staphylococci with surface-displayed RSV
peptides.
AB - A live bacterial vaccine-delivery system based on the food-grade bacterium
Staphylococcus carnosus was used for delivery of peptides from the G glycoprotein
of human respiratory syncytial virus, subtype A (RSV-A). Three peptides,
corresponding to the G protein amino acids, 144-159 (denoted G5), 190-203 (G9)
and 171-188 (G4 S), the latter with four cysteine residues substituted for
serines, were expressed by recombinant means as surface-exposed on three
different bacteria, and their surface accessibility on the bacteria was verified
by fluorescence-activated cell sorting (FACS). Intranasal immunization of mice
with the live recombinant staphylococci elicited significant anti-peptide as well
as anti-virus serum IgG responses of balanced IgG1/IgG2a isotype profiles, and
upon viral challenge with 10(5) tissue culture infectious doses(50) (TCID(50)),
lung protection was demonstrated for approximately half of the mice in the G9 and
G4 S immunization groups. To our knowledge, this is the first study in which
protective immunity to a viral pathogen has been evoked using food-grade bacteria
as vaccine-delivery vehicles.
PMID- 10781863
TI - The induction of systemic and mucosal immune responses to antigen-adjuvant
compositions administered into the skin: alterations in the migratory properties
of dendritic cells appears to be important for stimulating mucosal immunity.
AB - The properties of various vaccine-adjuvant formulations that are capable of
inducing both systemic and common mucosal immunity subsequent to their
intradermal administration are described. Effective mucosal adjuvants, including
bacterial toxins, chemical enhancers of cyclic AMP, and the active form of
vitamin D3, all shared the ability to promote dendritic cell migration from the
skin to Peyer's patches subsequent to antigen induced maturation. Our data
suggests that skin dendritic cells may function as effective antigen presenting
cells for the induction of mucosal immune responses, if microenvironmental
conditions are appropriately manipulated subsequent to their stimulation by
antigen.
PMID- 10781865
TI - In honour of the past European editor: K.J. Netter.
PMID- 10781866
TI - Studies on pyrazinoylguanidine: a novel antihypertensive, hypoglycemic and
lipolytic drug intended for adjunctive use in hypertensive patients with type 2
diabetes mellitus.
AB - Herein are described the development and certain properties of a new drug,
pyrazinoylguanidine (PZG), intended for use as an adjunct in the treatment of
hypertensive patients with type 2 diabetes, formerly called noninsulin dependent
diabetes mellitus. PZG is an analog of the potassium sparing diuretic, amiloride.
However, in diabetic patients, amiloride exacerbates hyperglycemia and
hyperlipidemia, whereas PZG reduces them. In several studies, PZG not only
reduced elevated blood pressure in subjects with essential hypertension, but also
downregulated the glucose fatty acid cycle in hypertensive patients with type 2
diabetes. PZG was well tolerated in all patients, as well as in normal subjects
whose blood pressures and glucose metabolism were unaffected by PZG. However, in
normal subjects made hyperglycemic by giving them hydrochlorothiazide,
coadministration of PZG returned blood glucose concentrations to normal.
Mechanisms for these effects of PZG in human subjects were investigated in both
normal Sprague-Dawley rats and rats made diabetic with streptozotocin (STZ). In
isolated rat adipocytes stimulated with theophylline, PZG downregulated both
lipolysis and cyclic AMP concentrations. PZG, as well as insulin, increased
adipose cyclic nucleotide phosphodiesterase activity, whereas theophylline
reduced it. In perfused rat liver, PZG decreased gluconeogenesis and cyclic AMP
concentrations. Collectively, these studies illustrate how the side effects
(toxicity) of certain drugs, such as the tendency of thiazide diuretics to cause
hyperglycemia and hyperlipidemia, can be modulated and even reversed by slight
changes in the chemical structure of the molecule, specifically by removal of the
3,5-diamino and 6-chloro substituents on the benzene ring of amiloride to produce
PZG.
PMID- 10781864
TI - Development of a multi-specificity opsonophagocytic killing assay.
AB - The opsonophagocytic-killing assay (OPKA) is one of the primary surrogate assays
for evaluating the pneumococcal capsular polysaccharide-protein conjugates under
development as vaccines. Because each vaccine contains seven or more different
conjugates, multiple OPKA must be performed on each serum. Moreover, the large
number of assays can deplete serum samples from infants. To reduce the amount of
serum and effort required to conduct OPKA we developed a multi-specificity OPKA
using antibiotic resistant pneumococci. Equal numbers of optochin-resistant
serotype 6B and streptomycin-resistant 19F pneumococci were used as the target
bacteria. Surviving bacteria of each serotype were enumerated by plating on agar
containing the appropriate antibiotic. In an examination of 25 immune sera the
results obtained with this new assay correlated well with those obtained when
bacterial targets were examined individually. By using additional antibiotic
resistance markers, more than two specificities can be examined in a single
assay.
PMID- 10781867
TI - Use of suppression-PCR subtractive hybridisation to identify genes that
demonstrate altered expression in male rat and guinea pig livers following
exposure to Wy-14,643, a peroxisome proliferator and non-genotoxic
hepatocarcinogen.
AB - Understanding the genetic profile of a cell at all stages of normal and
carcinogenic development should provide an essential aid to developing new
strategies for the prevention, early detection, diagnosis and treatment of
cancers. We have attempted to identify some of the genes that may be involved in
peroxisome-proliferator (PP)-induced non-genotoxic hepatocarcinogenesis using
suppression PCR subtractive hybridisation (SSH). Wistar rats (male) were chosen
as a representative susceptible species and Duncan-Hartley guinea pigs (male) as
a resistant species to the hepatocarcinogenic effects of the PP, [4-chloro-6-(2,3
xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643). In each case, groups of
four test animals were administered a single dose of Wy-14,643 (250 mg/kg per day
in corn oil) by gastric intubation for 3 consecutive days. The control animals
received corn oil only. On the fourth day the animals were killed and liver mRNA
extracted. SSH was carried out using mRNA extracted from the rat and guinea pig
livers, and used to isolate genes that were up and downregulated following Wy
14,643 treatment. These genes included some predictable (and hence positive
control) species such as CYP4A1 and CYP2C11 (upregulated and downregulated in rat
liver, respectively). Several genes that may be implicated in
hepatocarcinogenesis have also been identified, as have some unidentified
species. This work thus provides a starting point for developing a molecular
profile of the early effects of a non-genotoxic carcinogen in sensitive and
resistant species that could ultimately lead to a short-term assay for this type
of toxicity.
PMID- 10781868
TI - Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and
CYP1B1.
AB - Interactions of six naturally occurring flavonoids (acacetin, diosmetin,
eriodictyol, hesperetin, homoeriodictyol, and naringenin) with human cytochrome
P450 (CYP1) enzymes were studied. The flavones acacetin and diosmetin were potent
inhibitors of ethoxyresorufin O-dealkylase (EROD) activity of CYP1A and CYP1B1.
Hydroxy and/or methoxy substitutions at the 3' and 4' positions in the flavonoid
structures were the major factors involved in conveying selectivity for the
different cytochrome P450 enzymes. Eriodictyol, homoeriodictyol and naringenin
were very poor inhibitors of human CYP1A EROD activity (IC(50)4 microM).
Hesperetin and homoeriodictyol selectively inhibited human CYP1A1 and CYP1B1.
Only homoeriodictyol selectively inhibited human CYP1B1 (IC(50) 0.24 microM).
Hesperetin was O-demethylated by both human CYP1A1 and 1B1 to eriodictyol, which
was then further metabolized by the same enzymes. Hesperetin was not metabolized
by human CYP1A2 or CYP3A4.
PMID- 10781869
TI - Estimation of human exposure to styrene and ethylbenzene.
AB - In the present studies, human exposure to styrene and to ethylbenzene (EB) is
assessed on the basis of literature data. Total styrene and total EB exposure
result from inhalation and from food intake. Styrene and EB inhaled represent the
greatest proportion of the total intake. Styrene and EB content in food is mainly
caused by migration from polymer packaging material. The daily styrene exposure
is estimated to range from 18.2 to 55.2 microg/person, corresponding to an annual
exposure of 6.7 to 20.2 mg/person. The daily EB exposure is estimated to be about
130 microg/person, corresponding to an annual exposure of 46 mg/person. Cigarette
smoking is another important factor for styrene and EB intake by smokers.
PMID- 10781870
TI - Density-dependent growth of normal and nodular hepatocytes.
AB - To elucidate factors responsible for altered proliferation of preneoplastic
hepatocytes in rat hepatocarcinogenesis in vivo, EGF-stimulated DNA synthesis of
normal and nodular hepatocytes in primary culture was studied. In addition, the
influence of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated to
clarify whether this potent tumor promoter differentially affects normal and
nodular hepatocyte cultures. Unexpectedly it was found that in nodular
hepatocytes spontaneous and EGF-stimulated DNA synthesis was enhanced with
increasing cell density while DNA synthesis was inhibited in dense cultures of
normal hepatocytes. Mitogenic responses were detected both by [3H]thymidine
incorporation into DNA and by 5-bromo-2'-deoxyuridine labeling indices. TCDD (1
nM) acted as a mitoinhibitor both in normal and in nodular hepatocytes. The
results suggest marked differences in growth behavior of nodular versus normal
hepatocyte cultures probably due to paracrine stimulation by growth factors and
altered cell-cell interaction.
PMID- 10781871
TI - Effect of selenium supplementation on the activities of glutathione metabolizing
enzymes in human hepatoma Hep G2 cell line.
AB - Cell culture is an important tool for studying injury to cells exposed to
oxidative stress. The human hepatoblastoma derived Hep G2 cells retain their
morphology and most of their function in culture and are therefore widely used as
an in vitro model of human hepatocytes. Conventional cell culture media are
deficient in selenium, which is essential for activation of glutathione
peroxidase (GPx), a key enzyme in the defense against oxidative stress.
Supplementation of the culture media with 1 microM sodium selenite increased the
activities of total GPx by threefold and the selenium-dependent GPx by fourfold
as compared to cells cultured in control media. The non-selenium-dependent GPx
activity was unchanged. The activities of the other glutathione (GSH)-related
enzymes were practically unchanged despite a tendency toward elevation. The
activities of oxidized glutathione (GSSG) reductase and catalase increased by
22.4 and 27.4%, respectively. These relatively small increases did not carry
statistical significance. Supplementation of tissue culture media with selenium
may prove important, particularly for cell protection against oxidative stress.
PMID- 10781873
TI - Molecular and structural aspects of xenobiotic carbonyl metabolizing enzymes.
Role of reductases and dehydrogenases in xenobiotic phase I reactions.
AB - The major metabolic pathways involved in synthesis and disposition of carbonyl
and hydroxyl group containing compounds are presented, and structural and
functional characteristics of the enzyme families involved are discussed. Alcohol
and aldehyde dehydrogenases (ADH, ALDH) participate in oxidative pathways,
whereas reductive routes are accomplished by members of the aldo-keto reductase
(AKR), short-chain dehydrogenases/reductases (SDR) and quinone reductase (QR)
superfamilies. A wealth of biochemical, genetic and structural data now
establishes these families to constitute important phase I enzymes.
PMID- 10781872
TI - Heterogeneity of 11beta-hydroxysteroid dehydrogenase type 1/microsomal carbonyl
reductase (11beta-HSD/CR) in guinea pig tissues. Purification of the liver form
suggests modification in the cosubstrate binding site.
AB - 11beta-hydroxysteroid dehydrogenase (11beta-HSD) and xenobiotic carbonyl
reductase activities were determined in guinea pig tissue microsomes. The data
indicate the presence of a NADP(H) dependent form, distinct from the known type I
isozyme. Purification of 11beta-HSD-1 from liver microsomes resulted in two
distinct peaks, resolved by dye-ligand chromatography, indicating differences in
the cosubstrate binding site. Immunoblot analysis using anti 11beta-HSD-1
antibodies reveals the presence of similar structural determinants between the
enzyme forms. Both have an apparent molecular mass of 32 kDa, suggesting protein
modifications occurring in the type 1 isozyme which account for the differences
in chromatographic behaviour.
PMID- 10781874
TI - Use of precision-cut tissue slices in organ culture to study metabolism of 4
(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3
pyridyl)-1-butanol (NNAL) by hamster lung, liver and kidney.
AB - The pharmacokinetics of in vitro metabolism of the tobacco-specific nitrosamine,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; concentration range 0.03-250
microM) and its proximal metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1
butanol (NNAL; 0.04-250 microM), were determined in Syrian golden hamster liver,
lung, and kidney tissue slices in organ culture under identical experimental
conditions. In the lung, a target organ for NNK animal carcinogenesis, total NNK
metabolism was relatively low (maximum 23%) and oxidative metabolism by alpha
hydroxylation to DNA-reactive intermediates accounted for 13-31% of metabolism.
The liver, a non-target organ for NNK carcinogenesis, showed the highest capacity
to metabolise NNK (total metabolism 80%), and alpha-hydroxylation accounted for
12-25% of metabolism. The kidney, another non-target organ, also showed a low
capacity for NNK metabolism (maximum 32%) and alpha-hydroxylation accounted for
<3% of metabolism. Detoxification of NNK by pyridyl N-oxidation was similar in
lung (5-22%) and liver (5-23%), and negligible in kidney (<2%), while carbonyl
reduction of NNK to NNAL was greatest in the kidney (95-100%), followed by liver
(59-79%) and lung (47-81%). NNAL is devoid of biological activity in the hamster
and total metabolism was about tenfold lower than that of NNK in all tissues
(<13% liver; <4% lung and kidney). In the liver, alpha-hydroxylation was the
predominant pathway of NNAL metabolism at almost all concentrations (31-68% of
total metabolism), whereas N-oxidation prevailed in the kidney (47-68%). In the
lung, a concentration dependent decrease in the relative amount of alpha
hydroxylation (23-72%) with increasing NNAL concentrations occurred at the
expense of N-oxidation (25-72%). Little or no metabolism of NNAL back to NNK was
evident in any tissue.
PMID- 10781875
TI - Induction of cytochrome P450 2B1-mRNA and pentoxyresorufin O-depentylation after
exposure of precision-cut rat liver slices to phenobarbital.
AB - Precision-cut rat liver slices were prepared from male Wistar rats with a
Krumdieck slicer and cultured in William's medium E for up to 24 h. In untreated
control slices, CYP2B1-mRNA concentration, which was quantified by competitive RT
PCR, did not decrease during this time. After exposure of the slices to 100
microM phenobarbital, CYP2B1-mRNA increased by about 10- or 60-fold after 6 or 24
h, respectively. The extent of this in vitro induction was similar to that after
in vivo administration of 60 mg/kg phenobarbital. Pentoxyresorufin O
depentylation (PROD) was also inducible in vitro after 24 h, but to a lesser
extent than the corresponding CYP-mRNA. Precision-cut liver slices proved to be a
simple and reliable in vitro system for the sensitive detection of an induction
by phenobarbital.
PMID- 10781876
TI - Effects of cotinine at cholinergic nicotinic receptors of the sympathetic
superior cervical ganglion of the mouse.
AB - Nicotine, the principal alkaloid in tobacco, is generally accepted to be
responsible for most neuropharmacological effects due to tobacco use. Little is
known about the action of cotinine, the major metabolite from nicotine, at
neuronal structures. To evaluate the mode of action of cotinine at neuronal
receptors, its effect on the surface compound potential of the sympathetic
superior cervical ganglion (SCG) of the mouse was studied. The modulation of
nicotine induced surface potentials by cotinine was tested. It was found that 2
min applications of cotinine (0.1-30 mmol/l) induced concentration dependent
depolarizations at the SCG (EC(50)=1.7 mmol/l) which were followed by
hyperpolarizations and weak afterdepolarizations. The intrinsic activity of
cotinine compares to that induced by much lower concentrations of nicotine
(EC(50)=21 micromol/l). These cotinine effects may be mediated at least in part
by nicotine impurities which were found by capillary electrophoresis to be 0.1
and 0.8% in different batches of cotinine. Continuous application of 300
micromol/l cotinine shifted the concentration-response curve of nicotine to the
right and reduced (IC(50)=302 micromol/l) the effects of submaximal nicotine
concentrations (30 micromol/l). This effect could not be mimicked by continuous
application of a nicotine concentration (0.3 micromol/l) equivalent to the lower
impurity in cotinine. Therefore, the antagonistic action of cotinine at
peripheral neuronal nicotinic receptors is at least in part independent of
nicotine impurity. The observed antagonistic effect of cotinine at nicotinic
receptors likely contributes to the neuropharmacological effects of smoking.
PMID- 10781877
TI - Environmental inhibition of 11beta-hydroxysteroid dehydrogenase.
AB - Gossypol, a polyphenolic compound from cotton seed, caused hypokalemia in some
men receiving it in a trial of its contraceptive activity. Searching for the
mechanism for its hypokalemic action led to the observation that it inhibited
11beta-hydroxysteroid dehydrogenase. This would enhance mineralocorticoid effect
in the kidney. Many other polyphenols also inhibit this enzyme including those in
grapefruit juice. Ingesting 1-2 l of grapefruit juice inhibited this enzyme in
two men in a clinical experiment. Tea polyphenols inhibit this enzyme and add to
the inhibition caused by gossypol. Men in China have lower serum potassium values
than men elsewhere and this is due to the environment, presumably the diet, in
China. The importance of dietary and other exogenous inhibitors of this enzyme in
electrolyte metabolism remains to be determined.
PMID- 10781878
TI - Human 11beta-hydroxysteroid dehydrogenase 1/carbonyl reductase: recombinant
expression in the yeast Pichia pastoris and Escherichia coli.
AB - Detoxification of aldehydes and ketones generally proceeds via reduction to their
corresponding alcohols, which are then conjugated and eliminated. We focused our
interest on 11beta-hydroxysteroid-dehydrogenase type 1 (11beta-HSD 1), a
pluripotent enzyme which physiologically performs the interconversion of active
and inactive glucocorticoid hormones, and which also participates in xenobiotic
carbonyl compound detoxification. 11beta-HSD 1 belongs to the protein superfamily
of the short-chain dehydrogenases/reductases (SDR), and has been structurally and
functionally characterized. 11beta-HSD 1 is a glycosylated membrane protein which
is very difficult to purify in an active state. In addition, expression levels in
humans differ in a wide range. In order to facilitate biochemical and molecular
studies on the significance of human 11beta-HSD 1 in detoxification processes, we
have successfully performed the overexpression of recombinant human 11beta-HSD 1
in the yeast Pichia pastoris and in Escherichia coli. Recombinant 11beta-HSD 1
from E. coli was purified to homogeneity and used to generate a polyclonal
antibody. The enzyme had no enzymatic activity, possibly due to the lack of
glycosylation and/or incorrect folding in E. coli. In contrast, 11beta-HSD 1
overexpressed in P. pastoris was enzymatically active towards its physiological
glucocorticoid substrates as well as towards xenobiotic carbonyl compounds. In
western blot experiments the antibody crossreacted with both recombinant 11beta
HSD 1 forms and with the native enzyme from mouse and human liver. In conclusion,
recombinant 11beta-HSD 1 from P. pastoris serves as a valuable tool for future
studies on carbonyl compound detoxification.
PMID- 10781879
TI - Toxicologic evidence of developmental neurotoxicity of environmental chemicals.
AB - Developmental neurotoxicity constitutes effects occurring in the offspring
primarily as a result of exposure of the mother during pregnancy and lactation.
To exert their effect, these chemicals or their metabolites must pass the
placenta and/or the blood-brain barrier. In experimental animals, exposure to
neurotoxic chemicals during critical periods of brain development has induced
permanent functional disturbances in the CNS. Although available data suggest
that proper animal models exist, only few chemicals have been tested.
Neurotoxicity testing is not required by national authorities for classification
of chemicals. Epidemiological evidence is very limited, but severe irreversible
effects have been observed in humans following in utero exposures to a few known
developmental neurotoxicants. The large number of chemicals with a potential for
developmental neurotoxicity in humans stresses the importance of generating basic
kinetic data on these chemicals based on relevant experimental models. First of
all, data are needed on their ability to pass the placenta and the developing
blood-brain barrier, to accumulate, and to be metabolized in the placenta and/or
the fetus. These kinetic data will be essential in establishing a scientifically
based hazard evaluation and risk assessment.
PMID- 10781880
TI - Genetic polymorphism of CYP2A6 in the German population.
AB - Genetic polymorphism of drug metabolizing enzymes (DME) can lead to severe
toxicity or therapeutic failure of pharmacotherapy. Additionally, genetically
determined differences in the activity of the metabolic enzymes can increase an
individual's susceptibility to certain types of chemically induced cancers and
possibly other diseases. Cytochrome P450 is one of the most important metabolic
systems of the organism involved in the oxidation of different xenobiotics. This
contribution summarizes and updates the information concerning the genetic
polymorphism of the CYP2A6 isoform of the cytochrome P450. A special emphasis is
put upon the genotyping techniques of CYP2A6 with a comparative analysis of their
predictable sensitivity and specificity given on the example of the German
population.
PMID- 10781881
TI - CYP2A6: a human coumarin 7-hydroxylase.
AB - Coumarin 7-hydroxylation is catalysed by a high-affinity CYP2A6 enzyme in human
liver microsomes. CYP2A6 is the only enzyme catalysing this reaction and
consequently the formation of 7-hydroxycoumarin can be used as 'an in vitro and
in vivo probe' for CYP2A6. CYP2A6 is a major contributor to the oxidative
metabolism of nicotine and cotinine, and it also contributes, to a larger or
smaller extent, to the metabolism of a few pharmaceuticals (e.g. fadrozole),
nitrosamines, other carcinogens (e.g. aflatoxin B1) and a number of coumarin-type
alkaloids. CYP2A6 may be inducible by antiepileptic drugs and it is decreased in
alcohol-induced severe liver cirrhosis. Several mutated or deleted CYP2A6 alleles
have been characterized. Although CYP2A6 represent up to 15% of human microsomes
P450 proteins, it is still one of the less well characterised cytochrome P450
enzymes.
PMID- 10781883
TI - Confounding variables in the environmental toxicology of arsenic.
AB - Arsenic is one of the most important global environmental toxicants. For example,
in regions of West Bengal and Inner Mongolia, more than 100000 persons are
chronically exposed to well water often strongly contaminated with As.
Unfortunately, a toxicologically safe risk assessment and standard setting,
especially for long-term and low-dose exposures to arsenic, is not possible. One
reason is that the key mechanism of arsenic's tumorigenicity still is not
elucidated. Experimental data indicate that either DNA repair inhibition or DNA
methylation status alteration may be causal explanations. Moreover, when
comparing epidemiological data, it cannot be ruled out that the susceptibility to
arsenic's carcinogenicity may be different between Mexican and Taiwanese people.
Some other studies indicate that some Andean populations do not develop skin
cancer after long-term exposure to As. It is not known yet how this resistance
could be mediated. Finally, the situation is even more complicated when taking
into consideration that there are several compounds suspected to modulate the
chronic environmental toxicity of arsenic, variables that may either enhance or
suppress the in vivo genotoxicity and carcinogenicity of the metalloid. Among
them are nutritional factors like selenium and zinc as well as drinking water co
contaminants like antimony. Further, yet unidentified factors influencing the
body burden and/or the excretion of arsenic are possibly prevailing: preliminary
data from own human biomonitoring studies showed a peaking of As in urine samples
of non-exposed people which was not caused by elevated exposure to As through
seafood consumption. The relevance of these putative confounding variables cannot
be finally evaluated yet. Further experimental as well as epidemiological studies
are needed to answer these questions. This would help to conduct a
toxicologically improved risk assessment, especially for low-dose and long-term
exposures to arsenic.
PMID- 10781882
TI - Laryngeal mucosa of head and neck cancer patients shows increased DNA damage as
detected by single cell microgel electrophoresis.
AB - Major risk factors for cancer of the oral cavity, pharynx and larynx are smoking
and excess alcohol consumption. Since long-term survival rates of head and neck
cancer patients have not substantially been improved, new preventive strategies
including the use of cancer chemopreventive agents have to be developed. With the
aim of developing biomarkers which can verify the efficacy of chemopreventive
interventions, a standardised alkaline microgel electrophoresis (MGE) assay was
applied as a sensitive and rapid tool to detect DNA damage on a single cell
level. Macroscopically normal laryngeal mucosa biopsies obtained by surgery from
head and neck cancer patients (n=29) and from hospital controls (n=22) were
analysed by MGE in a pilot study. As compared to controls, cells from head and
neck cancer patients showed a significantly elevated DNA damage without any
further genotoxic treatment (P<0.01). We conclude that this increased background
DNA damage in laryngeal epithelia could result from genetic alterations caused by
smoking and alcohol leading, in accord with the field cancerisation hypothesis,
to a gradual decrease of genomic stability and malignancy. MGE should now be
explored as a rapid screening method in larger clinical studies: (i) to identify
high-risk subjects carrying cells with decreased genomic stability and (ii) to
verify the efficacy of chemopreventive regimens to prevent or slow down the
development of head and neck cancer in high-risk persons.
PMID- 10781884
TI - Lack of quinone reductase activity suggests that amyloid-beta peptide/ERAB
induced lipid peroxidation is not directly related to production of reactive
oxygen species by redoxcycling.
AB - Mitochondrial type II hydroxyacyl-CoA dehydrogenase (ERAB) has recently been
shown to mediate amyloid-beta peptide (Abeta) induced apoptosis and
neurodegeneration. The precise mechanism of cell death induction is unknown,
however, Abeta inhibits ERAB activities and as a result of ERAB-Abeta
interactions, enhanced formation of lipid peroxidation products occur. The
possibility that ERAB mediates quinone reduction is therefore investigated, thus
giving the potential of redoxcycling and production of reactive oxygen species,
leading to lipid peroxidation. Recombinant human ERAB was produced in a bacterial
expression system and enzymological properties were evaluated. Using several
orthoquinones as substrates, no ERAB mediated quinone reductase activity was
found either in the presence or absence of Abeta, suggesting that the observed in
vivo lipid peroxidation is a result of other mechanisms than redoxcycling by
quinones.
PMID- 10781885
TI - Dose and time as variables of toxicity.
AB - Recognizing that if there is no exposure, there is no toxicity leads us to the
conclusion that if there is exposure, toxicity can ensue when exposure exceeds a
certain dose and/or time and that it will be dependent on toxicokinetics and
toxicodynamics. Analysis of the fundamental description of toxicity
(dT/dE=dT/dDxdD/dKxdK/dE, where T stands for toxicity, D for toxicodynamics, K
for toxicokinetics and E for exposure) yields the recognition of three
independent time scales, the first being an intrinsic property of a given
compound (what does the chemical do to the organism), which is the dynamic time
scale. The second time scale is an intrinsic property of a the organism (what
does the organism do to the chemical), which represents the kinetic time scale.
The frequency of exposure denotes the third time scale, which is independent of
the dynamic and kinetic time scales. Frequency of exposure depends on the
experimental design or on nature, but not on the organism or substance. A liminal
condition occurs when the frequency becomes so high that it is indistinguishable
from continuous exposure. Continuous exposure forces the two other time scales to
become synchronized thereby reducing complexity to three variables: dose, effect
and one time scale. Keeping one of those variables constant allows for the study
of the other two variables reproducibly under isoeffective or isodosic or
isotemporal conditions. However, any departure from continuous exposure will
introduce the full complexity of four independent variables (dose and kinetic,
dynamic and frequency time scales) impacting on the effect (dependent variable)
at the same time. The examples discussed in this paper demonstrate how nature in
the form of long half-lives provides liminal conditions when either kinetic or
dynamic half lives force synchronization of all three time scales. However, for
compounds having very short dynamic or kinetic half-lives, only continuous
exposure will provide a synchronized time scale. A decision tree-type approach is
being used to illustrate how to reduce the enormous complexity generated by five
variables (dose, effect and up to three time scales) in toxicology to manageable
proportions by identifying and modeling the rate-determining (-limiting) step(s)
in the manifestation of toxicity.
PMID- 10781887
TI - Modulation of daunorubicin toxicity by liposomal encapsulation and use of
specific inhibitors in vitro.
AB - Anthracyclines serve as a valuable tool in chemotherapy, but their usefulness is
often limited by the occurrence of resistance mechanisms in tumor cells.
Resistance of tumor cells is a multifactorial event, where several mechanisms act
concurrently, including drug efflux and enzymatic drug inactivation. Liposomal
encapsulation of anthracyclines has been discussed as a successful regimen to
overcome drug resistance. Our investigations were carried out on a daunorubicin
(DRC) sensitive breast cancer cell line and two DRC resistant sublines generated
thereof. In all three cell lines, the extent of DRC detoxification via carbonyl
reduction to daunorubicinol (DRCOL) was determined. In addition, rutin, the most
effective inhibitor of carbonyl reducing enzymes, was tested to affect DRCOL
formation. DRC IC(50) values were determined in relation to several combinations
of DRC administration, (a) liposomal encapsulated DRC, (b) addition of verapamil
(inhibitor of drug efflux), (c) addition of rutin (inhibitor of DRC carbonyl
reduction). We could show that DRC sensitive and resistant breast cancer cell
lines are able to catalyze DRC detoxification via carbonyl reduction to DRCOL.
Rutin was shown to inhibit this reaction, but could not serve as an enhancer of
DRC toxicity in MTT tests. Verapamil was effective only in resistant cells due to
the overexpression of P-glycoprotein 170. Liposomal encapsulation of DRC did not
show the expected increase in DRC toxicity in the present tumor cell model.
PMID- 10781886
TI - Tissue distribution of 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione
(NTBC) and its effect on enzymes involved in tyrosine catabolism in the mouse.
AB - Administration of a single oral dose of 2-(2-nitro-4-trifluoromethyl-benzoyl)
cyclohexane-1,3-dione (NTBC) to mice increases the concentration of tyrosine in
the plasma and aqueous humour. The tyrosinaemia is both time and dose-dependent
with a single dose of 30 micromol NTBC/kg (10 mg/kg) producing maximal
concentrations of tyrosine in plasma of about 1200 nmol/ml and in aqueous humour
of about 2200 nmol/ml at 16 h after dosing. Analysis of the key hepatic enzymes
involved in tyrosine catabolism, following a single dose of 30 micromol NTBC/kg,
showed that 4-hydroxyphenylpyruvate dioxygenase (HPPD) was markedly inhibited
soon after dosing and that the activity recovered very slowly. In response to the
tyrosinaemia, the activity of hepatic tyrosine aminotransferase (TAT) was induced
about two-fold, while the activity of hepatic homogentisic acid oxidase (HGO) was
reduced at 4 and 5 days after dosing. Daily oral administration of NTBC at doses
up to 480 micromol NTBC/kg (160mg/kg/day) to mice produced a maximal tyrosinaemia
of about 600-700nmol/ml plasma, showing some adaptation relative to a single
dose. Unlike the rat, no treatment-related corneal lesions of the eye were seen
at any dose levels up to 6 weeks. Administration of a single oral dose of [14C]
NTBC at 30 micromol/kg led to selective retention of radiolabel in the liver and
to a lesser extent the kidneys. Our studies show that NTBC is a potent inhibitor
of mouse liver HPPD, which following repeat exposure produces a marked and
persistent tyrosinaemia, which does not result in ocular toxicity.
PMID- 10781888
TI - Structural characteristics of human P450s involved in drug metabolism: QSARs and
lipophilicity profiles.
AB - The factors with human P450 substrate selectivity are reviewed, together with
extensive tabulation of quantitative relationships between structure and activity
for many species of P450 substrates, inducers and inhibitors. In addition, the
physicochemical characteristics (logP and pK(a) values) of heptic microsomal P450
substrates are collated, such that comparisons can be made on the grounds of
compound lipophilicities.
PMID- 10781889
TI - Reduction of gastrointestinal toxicity of NSAIDs via molecular modifications
leading to antioxidant anti-inflammatory drugs.
AB - Reactive oxygen species and free radical reactions are related to several
pathologic conditions including inflammation and gastric ulceration. The latter
is the major undesired side-effect of almost all NSAIDs. Since this effect of
NSAIDs is greatly influenced not only by the type of cyclooxygenase which is
inhibited but also by the acidic nature of the molecule, we considered it
interesting to modify their structure in such a way that it would lead to an
antioxidant, neutral molecule or a molecule with greatly reduced acidic
character. Thus, we synthesized amide derivatives of four well-known NSAIDs, i.e.
diclofenac acid, tolfenamic acid, ibuprofen and indomethacin, with cysteamine, a
well-known antioxidant. The synthesized derivatives, with demonstrated good anti
inflammatory and antioxidant activities, showed very significant reduction of
ulcerogenicity in the investigation of gastrointestinal (GI) toxicity. As indices
of ulcerogenic toxicity in rats, we used the mortality (%), the incidence of GI
ulcers (%), body weight reduction (g/100 g BW) and the incidence of melena. All
amide derivatives of the NSAIDs with cysteamine were almost non-toxic in the GI
tract, under our experimental conditions, in contrast to their parent NSAIDs.
These results are attributed to the acquired antioxidant activity as well as to
the reduction of acidic character compared with the parent compounds. Therefore,
it can be concluded that the combination of these two properties, anti
inflammatory and antioxidant activity, with a simultaneous drastic reduction of
acidic character, may lead to the development of novel, useful anti-inflammatory
and cytoprotective pharmacomolecules, with potentially important therapeutic
applications.
PMID- 10781890
TI - Enhanced expression of CYP1B1 in Escherichia coli.
AB - Conditions for the optimal expression of the human CYP1B1 hemoprotein in
Escherichia coli have been investigated. CYP1B1 cDNA was prepared from a retinal
cDNA template and used to generate cDNA fragments with modified 5'-sequences
reported to allow enhanced expression in E. coli DH5alpha. Plasmids were
constructed, using the pCWori+ expression vector and were used to examine
necessity for thiamine, delta-aminolevulinic acid (ALA), and IPTG. The optimal
shaking speed in an orbital incubator was 150 rpm at 30 degrees C. Higher speeds
resulted in increased cell death and lower speeds resulted in lower expression of
cytochrome P450. IPTG was necessary for this expression system, which makes use
of the lac repressor, but levels above 0.5 mM were without additional benefit. We
were able to show thiamine to be unnecessary in this expression system, although
included by others expressing CYP1B1. ALA has been reported to enhance expression
of several different forms of cytochrome P450. We examined the dependence of
CYP1B1 expression on ALA. The expression proved to be highly dependent upon this
heme precursor, with levels of CYP1B1 increasing approximately 20-fold, to 920
nmol/l in the presence of up to 2.5 mM ALA. The question of whether heme
synthesis and apoprotein synthesis were coupled was then investigated. It could
be shown that although heme synthesis was not limiting (CYP101 holoenzyme
expression in the absence of ALA was four times higher than the ALA-supported
CYP1B1 holoenzyme expression), it was necessary for optimal expression of CYP1B1.
CYP1B1 protein synthesis appears to be coupled to heme precursor availability, as
seen by SDS-PAGE, because in the absence of heme precursor apocytochrome P450 1B1
does not accumulate.
PMID- 10781891
TI - Reversal of HER-2 over-expression renders human ovarian cancer cells highly
resistant to taxol.
AB - Currently, the treatment options for advanced ovarian cancer are limited. Thus,
the majority of the patients are treated with drugs with considerable side
effects but in many cases without clinical benefit. The relationship between
activation of an oncogene like the HER-2 receptor and drug sensitivity, is of
considerable interest as this molecular marker may allow to better predict
response to chemotherapy. The aim of this study was to evaluate whether over
expression of the HER-2 receptor would modulate drug responsiveness to
doxorubicin, cisplatin and taxol in ovarian cancer cells. An anti-HER-2-targeted
ribozyme approach was used to abrogate HER-2 expression in human SK-OV-3 ovarian
cancer cells. SK-OV-3 cells expressing very low residual levels of HER-2 protein,
were then assessed for their sensitivity to doxorubicin, cisplatin and taxol and
compared to control cells. HER-2 expression had no effect on the cytotoxicity of
doxorubicin (IC50=10 nM) or cisplatin (IC50=5 microM) in proliferation assays. In
contrast, the sensitivity to taxol was increased approximately 70-fold in SK-OV-3
ovarian cancer cells expressing high levels of HER-2 (IC50=10(-5) nM) compared to
HER-2 depleted cells (IC50=7x10(-4) nM). If these findings can be confirmed in
patients, it could be possible that HER-2 expression may serve as a marker for
response to taxol treatment in ovarian cancer patients.
PMID- 10781892
TI - Monitoring of cytochrome P-450 1A activity by determination of the urinary
pattern of caffeine metabolites in Wistar and hyperbilirubinemic Gunn rats.
AB - Various studies suggest that induction of cytochrome P-450 1A (CYP1A) might be a
valuable therapeutic modality for reducing the hyperbilirubinemia of infants with
Crigler-Najjar syndrome type I (CNS-I), a severe form of congenital jaundice. To
evaluate inducers of CYP1A as possible tools in the treatment of
hyperbilirubinemia, a novel assay was established, based on the analysis of the
urinary pattern of caffeine metabolites in rats. Wistar rats received [1-Me
(14)C]-caffeine (10 mg/kg i.p.), before and 48h after administration of the
potent CYP1A inducer 5,6-benzoflavone (BNF) (80 mg/kg, i.p.). A substantial
increase in the fractions of the terminal caffeine metabolites 1-methyluric acid
(1-U), 1-methylxanthine (1-X), and a concomitant decrease in the caffeine
demethylation product 1,7-dimethylxanthine (1,7-X) was observed after application
of BNF. The ratio of the caffeine metabolites (1-U+1-X)/1,7-X may serve as an
index of CYP1A activity in rats in vivo. Hyperbilirubinemic, homozygous (jj) Gunn
rats are an accepted model for human CNS-I. In male jj Gunn rats treated with BNF
or with indole-3-carbinol (I3C, 80 mg/kg, oral gavage), the inducing effect of
BNF and 13C on CYP1A activity was confirmed by the urinary pattern of caffeine
metabolites, and was parallelled by a decrease in plasma bilirubin levels. These
data demonstrate the usefulness of the established caffeine assay for the
evaluation of inducers of CYP1A as tools for reducing hyperbilirubinemia and
further confirm the potential value of I3C in the treatment of CNS-I.
PMID- 10781893
TI - Meeting report on an NHLBI workshop on ex vivo expansion of stem cells, July 29,
1999, Washington, D.C. National Heart Lung and Blood Institute.
PMID- 10781894
TI - The gp130-stimulating designer cytokine hyper-IL-6 promotes the expansion of
human hematopoietic progenitor cells capable to differentiate into functional
dendritic cells.
AB - OBJECTIVE: Hyper-IL-6, a fusion protein of interleukin-6 and its specific
receptor, together with stem cell factor leads to the proliferation of primitive
hematopoietic progenitor cells. Based on these findings, the current study
examined whether hyper-IL-6 promotes the growth of precursor cells that can be
further differentiated into dendritic cells in the presence of additional
cytokines. METHODS: Dendritic cell cultures were generated from CD34(+)
hematopoietic progenitor cells derived either from bone marrow or from peripheral
blood. CD34(+) cells were cultured in the presence of cytokines for 2 weeks and
then used for phenotyping and T-cell stimulation assays. RESULTS: Hyper-IL-6 in
the presence of stem cell factor induced a 60- to 80-fold expansion of CD34(+)
progenitor cells following 2 weeks of culture in serum-free medium. The addition
of granulocyte-macrophage colony-stimulating factor to hyper-IL-6 and stem cell
factor was essential for the differentiation of expanded progenitor cells into
antigen presenting cells capable of inducing a primary T-cell response to soluble
protein, which is a typical feature of dendritic cells. Phenotypic analyses
confirmed the expansion of immature dendritic cells, which could be further
differentiated into mature CD83(+) dendritic cells under the influence of
interleukin-4, interleukin-1beta, tumor necrosis factor-alpha, and prostaglandin
E(2). The capacity of expanded dendritic cells to stimulate protein-specific
CD4(+) T cells was used to stimulate a primary T-helper cell response to the
recombinant protein of the hepatitis-B core antigen in healthy donors.
CONCLUSION: The expansion and differentiation of functional dendritic cells from
CD34(+) progenitor cells under serum-free culture conditions allow for the
possibility to develop more effective ways to immunize against viral infections
and tumor diseases.
PMID- 10781896
TI - Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow
mesenchymal progenitor cells.
AB - OBJECTIVE: Based on their differentiation properties and facilely of ex vivo
expansion, human bone marrow mesenchymal progenitor cells (MPC), are considered
as attractive targets to deliver foreign genes to the bone marrow or other
mesenchymal tissues. In this study we investigated the feasibility of transduce
MPC with adenoviral vectors (Adv). METHODS: MPC were expanded ex vivo and
transduced with replication-defective Adv-containing reporter genes (lacZ or GFP)
under the control of CMV promoter. Transfection efficiency was assessed by
microscopical scoring or by flow cytometry. Expression and involvement of Adv
attachment (CAR) and Adv-internalization (integrins alphav) receptors were
evaluated by flow cytometric studies. RESULTS: Transgene expression analysis
showed that only 19%+/-3% of cells expressed the transgenes at high levels. MPC
express the attachment and internalization receptors required for Adv infection.
While integrins alphavbeta3 and alphavbeta5 are expressed by all MPC, CAR is
solely expressed by a fraction of low size cells. Antibodies against CAR and
alphavbeta5, but not against alphavbeta3, blocked Adv-mediated gene transfer into
MPC, showing that CAR and alphavbeta5 are required for infection. Because
alphavbeta5, as compared with CAR, is overexpressed in MPC, the results suggest
that the efficiency of Adv-mediated gene transfer into MPC depends on the level
of CAR expression. CONCLUSION: These findings demonstrate that Adv may be useful
to engineer a subpopulation of ex vivo expanded human mesenchymal progenitors,
with a high level of transgene expression.
PMID- 10781895
TI - Low level of gene transfer to and engraftment of murine bone marrow cells from
long-term bone marrow cultures.
AB - OBJECTIVE: We wanted to determine whether the long-term bone marrow culture
(LTBMC) transduction system would lead to efficient gene transfer and engraftment
of murine repopulating hematopoietic stem cells (HSC), particularly in nonablated
recipients. MATERIALS AND METHODS: Congenic mouse strains expressing Ly 5.1 or Ly
5.2 and the GP+E86 cell line producing the MGirL22Y vector carrying the gene for
enhanced GFP were used. Murine LTBMCs were established and demi-depopulated on
days 7 and 14 with addition of vector supernatant on days 8 and 15. RESULTS: Cell
recovery on day 21 was 21.3%+/-3.8% of input cells and CFU-C recovery was 9.7+/
3.4% as compared with CFU-C of input cells. In vitro transduction efficiency
determined by CFU-C expressing GFP was 22.2%+/-1.6%. In irradiated (950 cGy) mice
transplanted with 2x10(6) LTBMC cells, 94% of nucleated cells in the blood at
week 16 were of donor origin. However, GFP was only detected at low level in a
few animals at week 4 and not later. Analysis of bone marrow from these mice at
week 20 did not show any GFP expression and semiquantitative PCR revealed a
transgene level of <1%. When 3.5-20.8x10(6) LTBMC cells (corresponding to 20
100x10(6) fresh cells) were transplanted to nonablated recipients, no engraftment
or GFP expression were detected. Competitive repopulation experiments showed that
the long-term repopulation ability (LTRA) of the LTMC cells was only 7% of fresh
cells. CONCLUSION: These results indicate that LTBMC transduction of murine cells
leads to low-level transduction of progenitors, no gene transfer to repopulating
stem cells, and reduction in LTRA in ablated and nonablated recipients.
PMID- 10781897
TI - Augmentation of human leukemic cell invasion by activation of a small GTP-binding
protein Rho.
AB - OBJECTIVE: The functions of a small GTP-binding protein, Rho, in human leukemic
cell invasion was investigated in vivo and in vitro. MATERIALS AND METHODS: Human
leukemic KM3 and Reh cells (derived from B-cell-type common acute lymphoid
leukemias) were inoculated into severe combined immundeficiency (SCID) mice.
Alteration of invasion in SCID mice inoculated with KM3 cells that were
introduced with the expression vector for Rho Val14 (Rho V14), an activated
mutant form of Rho, was observed. RESULTS: SCID mice inoculated with KM3 and Reh
cells developed paraplegia 21 days after inoculation. All died by day 26-27. The
leukemic cells were localized to bone marrow and around the spinal cord, with no
infiltration into peripheral blood, spleen, liver, thymus, or lymph nodes. SCID
mice inoculated with Rho V14-transfected KM3 cells showed a 5-day reduction in
the time to paraplegia and death compared with SCID mice inoculated with
hygromycin-resistance gene-transfected KM3 (hyg(r)) cells. In addition, the mice
inoculated with Rho V14 cells showed leukemic cell infiltration, not only into
bone marrow and around the spinal cord but also into peripheral blood, liver, and
spleen. There were no in vitro or in vivo differences in growth rates of Rho V14
and hyg(r) cells. However, the Rho V14 cells showed markedly increased cell
adhesion compared to the hyg(r) cells. CONCLUSION: Results suggest that Rho
activation accelerates human leukemic cell invasion via augmentation of cell
adhesion.
PMID- 10781898
TI - Regulation of megakaryocytopoiesis in an in vitro stroma model: preferential
adhesion of megakaryocytic progenitors and subsequent inhibition of maturation.
AB - OBJECTIVE: Studies of megakaryocytic progenitor cell interactions have focused on
single receptor-ligand interactions using isolated components of the
extracellular matrix. To approach a physiologic condition, we studied
megakaryocytic development of human progenitor cells cultured on two stromal cell
lines and on human bone marrow stroma. MATERIALS AND METHODS: Human CD34(+) cells
were cocultured with stromal layers in the presence of thrombopoietin.
Megakaryocytes were quantified by monoclonal antibodies against glycoprotein (GP)
IIb/IIIa (CD41) and GPIX (CD42a). Megakaryocytic clonogenic capacity (burst
forming unit-megakaryocyte and colony-forming unit-megakaryocyte) was determined
using fibrin clot assays. RESULTS: After 6 days, a higher percentage of
megakaryocytes and more megakaryocytic colonies were recovered from the adherent
cell fraction compared to the nonadherent cell fraction. In contrast,
significantly more granulocytic and erythroid colonies were recovered from the
nonadherent cell fraction. Repeated replating of nonadherent cells onto fresh
stroma showed a decline in megakaryocytic recovery of the remaining adherent
cells, pointing toward selective adhesion of megakaryocytic progenitors. This was
supported further by the finding that burst-forming unit and colony-forming unit
megakaryocytes were preferentially recovered from the adherent cell fraction at
24 hours. No effect of blocking the beta(1) integrins VLA-4 and VLA-5 on human
progenitor cells was observed. A higher expression of CD42a antigen and a higher
percentage of morphologically recognizable polyploid megakaryocytes were found
when cells were grown in noncontact cultures compared to when grown adhered to
stroma. CONCLUSION: In contrast to granulocytic and erythroid progenitors, both
very early and more mature megakaryocytic progenitors are preferentially located
in the adherent fraction in an in vitro stromal model, leading to inhibition of
maturation of megakaryocytes. This suggests that the presence of stroma
components in ex vivo expansion cultures, aimed at preservation and expansion of
megakaryocytic progenitors, might be a prerequisite.
PMID- 10781899
TI - Characterization of prostaglandin endoperoxide H synthase-1 enzyme expression
during differentiation of the megakaryocytic cell line MEG-01.
AB - OBJECTIVE: Because the prostaglandin endoperoxide H synthase-1 (PGHS-1)-dependent
formation of thromboxane A(2) is an important modulator of platelet function,
this pathway represents a pharmacologic target for the inhibition of platelet
function by aspirin. The objective of our research was to study how PGHS-1
expression is regulated in platelets. MATERIALS AND METHODS: Because platelets
are anucleated, their protein content is a consequence of gene expression in
precursor cells known as megakaryocytes. We used the immortalized human
megakaryoblastic cell line MEG-01 as a model to study the expression of PGHS-1,
because MEG-01 cells can be induced to differentiate into platelet-like
structures by adding nanomolar concentrations of 12-0-tetradecanoylphorbol-13
acetate (TPA). We determined the expression profiles of PGHS-1 protein and mRNA
in the cells comprising the three different populations of MEG-01 cultures:
nucleated floating, nucleated attached, and platelet-like structures. RESULTS: We
determined that PGHS-1 protein levels were higher in the nucleated adherent
population than in the nucleated floating population. PGHS-1 protein levels were
greatest in the anucleated platelet-like population. In contrast, we found that
PGHS-1 mRNA levels were highest in the cells that comprised the nucleated
adherent population. Addition of TPA induced the expression of PGHS-1 protein and
mRNA in all three populations but did not change the relationship of the amount
of PGHS-1 protein or mRNA expressed in a given population relative to the other
two fractions. We measured the expression of PGHS-1 protein on a cell-by-cell
basis in the nucleated MEG-01 populations. We found that the percentage of MEG-01
cells expressing PGHS-1 protein in the adherent population was greater than in
the floating population. We measured a time-dependent increase in the percentage
of cells that expressed PGHS-1 over a period of 8 days after singular addition of
TPA (1.6x10(-8)M). Importantly, we observed that TPA treatment stimulated
floating MEG-01 to adhere to the surface of the tissue culture vessel and that,
after such treatment, only floating MEG-01 cells suffered a compromised
viability. We found that a high percentage of control cells expressed
glycoprotein IIb/IIIa and that TPA treatment did not significantly alter this
percentage. We did not detect glycoprotein Ib in control cells but did measure a
slight increase in the percentage of MEG-01 cells that expressed this antigen in
the TPA-treated population. CONCLUSION: We established a correlation between the
level of PGHS-1 expression and the overall level of differentiation of MEG-01
cells. PGHS-1 protein expression, which increases consistently over the full
course of differentiation, now may be used as an additional and perhaps better
index by which to survey megakaryocytes.
PMID- 10781900
TI - Molecular analysis of the hematopoiesis supporting osteoblastic cell line U2-OS.
AB - OBJECTIVE: Osteoblasts play an important role in regulating hematopoiesis in the
bone marrow. Here we show that U2-OS, a widely used osteoblastic cell line
derived from an osteosarcoma, has the capacity to support proliferation of human
hematopoietic progenitor cells in vitro. In this study, U2-OS cells are
characterized at the molecular level to unravel the molecular mechanisms
underlying the support of hematopoiesis. MATERIALS AND METHODS: U2-OS was
analyzed in great detail using RT-PCR and flow cytometry. In addition, a cDNA
library was constructed and randomly sequenced to obtain insight in the
repertoire of expressed molecules. RESULTS: A broad panel of growth factors and
cytokines is expressed by U2-OS. TGF-beta, GM-CSF, c-kit ligand, and IL-7 are
produced constitutively and IL-1beta, IL-6, IL-8, TNF-alpha, IFN-gamma, and MIP1
alpha are upregulated upon stimulation. In addition to those, mRNAs of the CC
chemokine LARC and leukemia inhibitory factor were identified. U2-OS cells
express high levels of beta1-integrins at the cell surface: VLA-2, VLA-3, VLA-4,
VLA-5, VLA-6, and the integrin alphavbeta3. Besides integrins, ALCAM and NCAM are
detected on the cell surface of U2-OS. Interestingly, we show that CD34(+)
progenitor cells expressing ALCAM are highly proliferative when compared with
CD34(+) ALCAM(low) cells, hinting at a role for ALCAM in anchoring progenitor
cells to the bone marrow stroma. Interestingly, random sequencing of an U2-OS
cDNA library yielded almost 10% of novel cDNAs with a potential role in
hematopoiesis. The involvement of these novel molecules in hematopoiesis is an
interesting target for future investigations. CONCLUSIONS: We conclude that U2-OS
supports outgrowth of hematopoietic progenitor cells and accordingly expresses
adhesion molecules and growth factors and a number of novel, as yet
uncharacterized potentially interesting genes.
PMID- 10781901
TI - Overexpression of the homeobox gene DLX-7 inhibits apoptosis by induced
expression of intercellular adhesion molecule-1.
AB - OBJECTIVE: DLX genes constitute a subfamily of divergent homeobox genes. We have
previously reported that inhibition of DLX-7 expression by an antisense
oligonucleotide caused apoptosis in the K562 erythroleukemia cell line, which
highly expresses DLX-7. In this study, we have constructed an expression vector
encoding human DLX-7, and examined the effects of overexpression of DLX-7 in the
IL-3-dependent lymphoid precursor cell line Ba/F3. METHODS: DLX-7 expression
vector was electroporated into Ba/F3 cells, and generate a DLX-7 expressing Ba/F3
cells. Northern blot analysis was performed to determine DLX-7 gene expression.
WST-1 assay was used to cell proliferation assay. To detect apoptosis, we
performed TUNEL assay. Expression of cell surface adhesion molecules was examined
by FACS analysis. RESULTS: Growth properties of DLX-7-transfected Ba/F3 cells in
the presence of IL-3, did not differ from those of control Ba/F3 cells. However,
in the absence of IL-3, DLX-7-transfected cells abrogated growth dependence on
cytokines due to inhibition of apoptosis. Because adhesion properties of DLX-7
transfected cells increase, we examined expression of adhesion molecules in these
cells. Expression of intercellular adhesion molecule (ICAM)-1 and ICAM-2 were
markedly upregulated in DLX-7-transfected cells. Both anti-ICAM-1 antibody and
anti-LFA-1 antibody blocked the aggregation of DLX-7-transfected cells. Moreover,
in the absence of IL-3, cytokine-independent cell growth was blocked by anti-ICAM
1 antibody. CONCLUSION: These results indicate that DLX-7 overexpression blocks
apoptosis and that ICAM-1 expression induced by DLX-7 contributes to this
antiapoptotic effect.
PMID- 10781902
TI - Genetic regulation of primitive hematopoietic stem cell senescence.
AB - OBJECTIVE: To define effects of strain on PHSC (primitive hematopoietic stem
cells) senescence (decline in function with age) in vivo, and to map a locus that
regulates PHSC senescence. MATERIALS AND METHODS: Long-term function and self
renewal were compared in bone marrow cells (BMC) from old and young mice of three
strains: BALB/cBy (BALB), DBA/2 (D2) and C57BL/6 (B6), using competitive
repopulation and serial transplantation in vivo. BMC from each old or young donor
were mixed with standard doses of congenic, genetically marked BMC and
transplanted into lethally recipients. Percentages of donor-type erythrocytes and
lymphocytes in the recipients determined the functional ability of donor PHSC
relative to the standard, where one repopulating unit (RU) of donor BMC equals
the repopulating ability of 100,000 standard competitor BMC. Using similar
techniques, repopulating abilities of old and young recombinant inbred (RI)
donors of 12 strains derived from BALB and B6 were compared in NK-depleted
BALBxB6 Fl recipients to map a locus that appears to have a major role in PHSC
senescence. RESULTS: PHSC function declined about 2 fold with age in BALB and D2
BMC, and increased more than 2-fold with age in B6 BMC, with all old/young strain
differences significant, p<.01. Ten months after serial transplantation, young
B6, BALB, and D2 PHSC had self-renewed 1.6-, 4.2-, and 3.2-fold better than old,
with BALB and D2 old/young differences p<.01. Young B6 PHSC self-renewed 1.9- and
2.9-fold better than young BALB and D2 PHSC. The PHSC senescence phenotypes
(old/young RU ratios) for 12 CXB RI strains suggested a genetic linkage to
D12Nyul7 on Chromosome 12. CONCLUSION: PHSC senescence is genetically regulated,
and is much delayed in the B6 strain compared to the BALB and D2 strains. A locus
on Chromosome 12 may regulate PHSC senescence.
PMID- 10781903
TI - Docetaxel-induced mobilization of hematopoietic stem cells in a murine model:
kinetics, dose titration, and toxicity.
AB - OBJECTIVE: Docetaxel (DXT) is an anticancer agent that has demonstrated
therapeutic efficacy against solid tumors, particularly breast cancer. Based on
the use of hematopoietic stem cell (HSC) transplantation to restore hematopoietic
reconstitution after myeloablative therapy, this study was performed to determine
if DXT could mobilize HSCs in vivo. MATERIALS AND METHODS: C57Bl/6 mice were
injected intraperitoneally with varying doses of DXT (equivalent to human doses
of 40 to 120 mg/m(2)). Spleens were harvested on days 2, 4, 6, 8, 10, and 12
after DXT administration for recovery of mononuclear cells (MNCs). The number of
HSCs present within the MNCs was determined by clonogenic assay for colony
forming units in culture (CFU-C) and by FACS analysis for CD34(+) cells.
Peripheral blood samples were obtained at the time of spleen harvest to determine
the hematologic profile. Liver and renal function tests were performed to monitor
toxicity. RESULTS: DXT mobilize d HSCs in a dose- and time-dependent manner. When
measured by the CFU-C assay, maximal mobilization of HSC (>10-fold increase in
control; p<0.01) was observed at a dose of 30 mg/kg (equivalent to human dose of
75 mg/m(2)) on day 7. The number of mobilized HSCs peaked on days 6 to 8 at all
doses of DXT tested. There was no evidence of weight loss, liver, or renal
toxicity at any of the DXT doses tested. CONCLUSION: These results indicate that
DXT efficiently mobilizes HSCs in a murine model and provide the rationale for
similar studies in a clinical trial.
PMID- 10781904
TI - Effective ex vivo generation of granulopoietic postprogenitor cells from
mobilized peripheral blood CD34(+) cells.
AB - OBJECTIVE: Neutropenia following high-dose chemotherapy and peripheral blood
progenitor cell (PBPC) transplantation might be abrogated by an additional
transplantation of ex vivo generated granulopoietic postprogenitor cells (GPPC).
Therefore, the ex vivo expansion of CD34(+) PBPC was systematically studied
aiming for optimum GPPC production. MATERIALS AND METHODS: CD34(+) PBPC were
cultured in serum-free medium comparing different (n = 32) combinations of stem
cell factor (S), interleukin 1 (1), interleukin 3 (IL-3) (3), interleukin-6 (6),
erythropoietin (E), granulocyte colony-stimulating factor (G), granulate
macrophage colony-stimulating factor (GM), daniplestim (D, a novel IL-3 receptor
agonist), and Flt3 ligand (FL) under various culture conditions. Ex vivo
generated cells were assessed by flow cytometry, morphology, and progenitor cell
assays. RESULTS: Addition of G +/- GM but not GM alone to cultures stimulated
with S163E effectively induced the generation of GPPC. GPPC production was
maximum after 12 to 14 days. Best expansion rates were observed when cells were
cultured at 1.5x10(4)/mL in 21% O(2). Modifications of culture conditions were
either less or equally effective (i.e., modification of starting cell
concentrations, low oxygen, addition of serum albumin or autologous plasma,
repetitive feeding). Comparison of different cytokine combinations revealed that
the optimum GPPC expansion cocktail consisted of S6GD+FL (day 12: 130-fold
cellular expansion, 32% myeloblasts/promyelocytes, 49.4%
myelocytes/metamyelocytes, 12.4% bands/segmented), which furthermore expanded
CD34(+) cells (3.4-fold) and clonogenic progenitors (13.4-fold). CONCLUSION:
Using the S6DG+FL expansion cocktail, GPPC could be effectively produced ex vivo
starting from positively selected CD34 PBPC, possibly enabling amelioration or
even abrogation of posttransplant neutropenia.
PMID- 10781905
TI - The use of non-pharmacological therapies by pain specialists.
PMID- 10781906
TI - Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of
the art.
AB - In an attempt to explain how and why some individuals with musculoskeletal pain
develop a chronic pain syndrome, Lethem et al. (Lethem J, Slade PD, Troup JDG,
Bentley G. Outline of fear-avoidance model of exaggerated pain perceptions. Behav
Res Ther 1983; 21: 401-408).ntroduced a so-called 'fear-avoidance' model. The
central concept of their model is fear of pain. 'Confrontation' and 'avoidance'
are postulated as the two extreme responses to this fear, of which the former
leads to the reduction of fear over time. The latter, however, leads to the
maintenance or exacerbation of fear, possibly generating a phobic state. In the
last decade, an increasing number of investigations have corroborated and refined
the fear-avoidance model. The aim of this paper is to review the existing
evidence for the mediating role of pain-related fear, and its immediate and long
term consequences in the initiation and maintenance of chronic pain disability.
We first highlight possible precursors of pain-related fear including the role
negative appraisal of internal and external stimuli, negative affectivity and
anxiety sensitivity may play. Subsequently, a number of fear-related processes
will be discussed including escape and avoidance behaviors resulting in poor
behavioral performance, hypervigilance to internal and external illness
information, muscular reactivity, and physical disuse in terms of deconditioning
and guarded movement. We also review the available assessment methods for the
quantification of pain-related fear and avoidance. Finally, we discuss the
implications of the recent findings for the prevention and treatment of chronic
musculoskeletal pain. Although there are still a number of unresolved issues
which merit future research attention, pain-related fear and avoidance appear to
be an essential feature of the development of a chronic problem for a substantial
number of patients with musculoskeletal pain.
PMID- 10781907
TI - A new animal model for assessing mechanisms and management of muscle
hyperalgesia.
AB - Musculoskeletal pain is one of the most frequent symptoms for which medical
assistance is sought. Yet, the majority of our knowledge regarding pain
physiology is based on studies of cutaneous tissue. Comparatively little is known
about activation of visceral, joint and perhaps least of all, musculoskeletal
nociceptors although clinically-treated pain originates principally in these
structures. Studies elucidating the mechanisms of muscle hyperalgesia have been
hampered by the lack of an animal model that permits the evaluation of hypotheses
using behavioral, biochemical, pharmacological, anatomical and molecular
experimental approaches. Here we describe an animal model of muscle hyperalgesia
we recently developed that permits such multidisciplinary investigation. This
model employs the intramuscular injection of carrageenan, a chemical stimulus
which evokes a well recognized model of cutaneous inflammation and is reported to
activate muscle nociceptors. Intramuscular carrageenan evokes a time- and dose
dependent reduction in forelimb grip force that is anatomically specific. The
carrageenan-evoked reduction in grip force is blocked by the mu-opioid agonist
levorphanol in a dose-dependent, stereoselective and naltrexone-reversible
manner. This behavioral dependent measure is also significantly reversed by
agents used clinically to treat muscle pain, indomethacin and dexamethasone, as
well as the non-competitive N-methyl-D-aspartate receptor antagonist MK801.
Finally, evidence that reduction in grip force is in part mediated by small,
unmyelinated afferents is provided by the demonstration that neonatal capsaicin
treatment significantly reduced carrageenan-evoked behavioral hyperalgesia (
approximately 45% reduction) and reduced muscle content of immunoreactive CGRP (
approximately 60% reduction) relative to control levels. Collectively, these
findings provide converging lines of evidence for the validity of this animal
model to investigate mechanisms involved in the development of muscle
hyperalgesia.
PMID- 10781908
TI - The alpha(2A) adrenoceptor and the sympathetic postganglionic neuron contribute
to the development of neuropathic heat hyperalgesia in mice.
AB - We have addressed the role of the sympathetic nervous system in the development
and maintenance of neuropathic pain. Using a new neuropathic mouse model, we
examined the development of hyperalgesia in transgenic mice lacking functional
alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if
sympathetic-sensory coupling generates hyperalgesia. The development of
neuropathic heat hyperalgesia required the presence of both the alpha(2A)
adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the
development of mechanical hyperalgesia did not require either the alpha(2A)
adrenoceptor or the SPGN, indicating different mechanisms of sensitization. These
results suggest that the development of neuropathic heat hyperalgesia, but not
mechanical hyperalgesia, requires sympathetic-sensory coupling in the peripheral
nervous system. Nerve injury enhanced the analgesic efficacy of the alpha(2)
adrenoceptor agonist dexmedetomidine, and paradoxically also induced an analgesic
response to alpha(2) adrenoceptor antagonists. The alpha(2) agonist-evoked
analgesia to mechanical stimuli was mediated by activating central alpha(2A)
adrenoceptors, possibly at the spinal level. The peripherally restricted alpha(2)
antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli,
findings which support the hypothesis that the peripheral alpha(2) adrenoceptor
plays a role in both the development and the maintenance of neuropathic heat
hyperalgesia. The alpha(2) antagonist-evoked analgesia for heat stimuli was
mediated by blocking peripheral and probably central alpha(2) adrenoceptors,
while the analgesia for mechanical stimuli was mediated by blocking central
alpha(2A) adrenoceptors. Intradermal injections with an alpha(2) agonist or
antagonist had no effect on nociceptive thresholds, indicating that sympathetic
sensory coupling at the level of the cutaneous nociceptor did not contribute to
the maintenance of neuropathic hyperalgesia.
PMID- 10781909
TI - An fMRI study of the anterior cingulate cortex and surrounding medial wall
activations evoked by noxious cutaneous heat and cold stimuli.
AB - The anterior cingulate cortex (ACC) and adjacent regions in the medial wall have
been implicated in sensory, motor and cognitive processes, including pain. Our
previous functional magnetic resonance imaging (fMRI) studies have demonstrated
pain-related activation of the posterior portion of the ACC during transcutaneous
electrical nerve stimulation (TENS) and variable patterns of cortical activation
with innocuous and noxious thermal stimuli in individual subjects. The present
study represents the companion paper to our recent study of pain- and thermal
related cortical activations with the aim to use fMRI to delineate the
activations in the ACC and surrounding regions of the medial wall during
application of innocuous and noxious thermal stimuli as well as during
performance of a motor task in individual subjects. Ten normal subjects were
imaged on a conventional 1.5 T GE 'echospeed' system. Functional images were
obtained from sagittal sections through each hemisphere centered at approximately
3-5 and 7-9 mm from midline. Each subject was imaged during innocuous (cool,
warm) and noxious thermal (cold, hot) stimulation of the thenar eminence, and
execution of a motor (sequential finger-thumb opposition) task. Task-related
activations were mostly confined to contralateral and medial ipsilateral images.
Although the present results demonstrate intersubject variability in the task
related activations, some general modality-specific patterns were apparent: (i)
innocuous thermal-related activations were located mainly in the anterior ACC;
(ii) noxious thermal-related activations were primarily located in the anterior
ACC, the ventral portion of the posterior ACC, and the supplementary motor area
(SMA); (iii) motor-related activations were primarily located in the SMA and
dorsal portion of the posterior ACC. These results indicate that specific spatial
patterns of activation exist within the ACC and surrounding regions of the medial
wall for innocuous and noxious thermal stimuli, and that noxious thermal- and
motor-related activations appear to be segregated within the ACC. Therefore, we
propose a segregation of the ACC into an anterior non-specific attention/arousal
system and a posterior pain system.
PMID- 10781910
TI - Cognitive factors and the experience of pain and suffering in older persons.
AB - Cognitive factors are thought to play an important mediational role between pain
and consequent levels of suffering, yet there has been little investigation of
these issues in older chronic pain patients. The present study sought to examine
the reliability and validity of the Pain Locus of Control (PLOC) scale when used
with older patients, to explore age differences in PLOC orientation, and examine
the relationship between cognitive beliefs and levels of pain and suffering. 169
older patients attending a pain management clinic completed a comprehensive
psychometric battery prior to admission. Principal components analysis replicated
the original factor structure of the PLOC previously identified in young adult
samples, suggesting that older patients adopt the same underlying constructs of
control. The internal item consistency of the 36 item scale was shown to be very
good to excellent. Older adults endorsed a higher chance locus of control, but
this orientation was amenable to change following a cognitive-behavioural
treatment program. PLOC orientation was related to use of coping strategies,
levels of pain and depression, functional and psychosocial impact as well as
compliance with treatment protocols. Stepwise regression analysis revealed that
self perceived interference from pain and internal PLOC were the best predictors
of depressive symptoms in older adults. In combination, these findings suggest
that cognitive factors are of importance in older chronic pain patients and
extend the relevance of cognitive-behavioural models of pain across the entire
adult age spectrum.
PMID- 10781911
TI - Presynaptic inhibition by baclofen of miniature EPSCs and IPSCs in substantia
gelatinosa neurons of the adult rat spinal dorsal horn.
AB - Intrathecal administration of baclofen, a GABA(B)-receptor agonist, affects pain
behavior induced by formalin in a biphasic manner; baclofen at low doses enhances
pain while producing antinociception at high doses. This may be due to the fact
that baclofen modulates each of excitatory and inhibitory transmission in the
dorsal horn of the spinal cord with a distinct sensitivity, resulting in a
biphasic action on pain transmission. To address this issue, we examined the
actions of baclofen on miniature excitatory (glutamatergic) and inhibitory
(GABAergic) postsynaptic currents (mEPSCs and mIPSCs, respectively) in substantia
gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell
voltage-clamp technique. Baclofen reduced the frequency of both mEPSC and mIPSC
without a change in their amplitudes. These actions were dose-dependent in a
concentration range of 0.1-100 microM; the effective concentrations for the half
inhibition of mEPSC and mIPSC frequency were 4.44+/-0. 60 microM (n=7) and 4.31+/
0.77 microM (n=6), respectively. These results indicate that each of
glutamatergic and GABAergic nerve terminals in the SG is endowed with the GABA(B)
receptor, the activation of which depresses the release of neurotransmitter from
the terminal; this provides a cellular basis for the modulation of pain by
baclofen. It is suggested from a similar affinity for baclofen of the GABA(B)
receptors on both terminals that the baclofen-induced biphasic action on pain
behaviors cannot be accounted for by only its presynaptic actions in the SG and
that other actions such as an inhibitory action of baclofen on postsynaptic
neurons also have to be taken into consideration.
PMID- 10781912
TI - Spinal PKC activity and expression: role in tolerance produced by continuous
spinal morphine infusion.
AB - It has been hypothesized that spinal morphine tolerance results from protein
kinase C (PKC) mediated phosphorylation. Chronic lumbar intrathecal (i.t.)
infusion of morphine (20 nmol/microl/h) was shown to produce antinociception on
day 1 (d1) that disappeared by d5 (tolerance). On d6, a bolus i.t. probe dose of
morphine (60 nmol) produced a more profound antinociception in saline-infused
rats than in morphine-infused rats. Coinfusion of morphine with a PKC inhibitor,
chelerythrine, prevented tolerance to the probe morphine dose. Bolus i.t.
chelerythrine or GF109203X (GF), another PKC inhibitor, on d5, but not the
inactive homologue of GF Bisindolymaleimide V, also blocked development of
tolerance after 24 h. I.t. morphine infusion, but not saline, produced a 2-fold
increase in dorsal horn PKC phosphorylating activity and in the expression of
PKCalpha/gamma. Bolus chelerythrine on d5 after spinal morphine infusion blocked
upon an increase in PKC activity, confirming that at the behaviorally active dose
the drug had the intended biochemical effect upon spinal PKC activity. PKC
activity and protein expression did not change when assessed 1 h after bolus i.t.
morphine in naive rats. Thus, tolerance produced by morphine infusion is
dependent upon an increase in local phosphorylating activity by PKC. Blocking the
PKC activity prevents expression of the morphine tolerance.
PMID- 10781913
TI - Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal
horn.
AB - We investigated the effects of gabapentin (GBP) on glutamatergic synaptic
transmission in the dorsal horn of the rat spinal cord. Patch clamp whole cell
recordings were made from superficial and deep dorsal horn neurons of rat spinal
cord slices. In the majority of neurons in the superficial lamina, GBP decreased
the amplitudes of evoked excitatory postsynaptic currents (evoked EPSCs) mediated
by either non-NMDA or NMDA receptors. In contrast, neurons in the deep lamina
showed variable effects, with a lower incidence of decrease in amplitude of
evoked EPSCs and a subset of neurons showing an increase in amplitude of evoked
NMDA receptor-mediated EPSCs. No enhancement of evoked non-NMDA receptor-mediated
EPSCs was observed in either lamina. To determine whether the observed effects of
GBP are presynaptic and/or postsynaptic, spontaneous miniature excitatory
postsynaptic currents (mEPSCs) were studied. In neurons that showed a decrease in
its frequency of mEPSCs by GBP, no change in the amplitude or shape accompanied
the effect. On the other hand, in neurons that showed an increase in the
frequency of NMDA receptor-mediated mEPSCs, the effect accompanied an increase in
amplitude. These results suggest that GBP presynaptically inhibits glutamatergic
synaptic transmission predominantly in the superficial lamina, while
postsynaptically enhancing NMDA receptor-mediated transmission in some neurons of
the deep lamina. The antinociceptive effects of GBP may involve the inhibition of
the release of excitatory amino acids from presynaptic terminals.
PMID- 10781914
TI - An evaluation of homogeneity tests in meta-analyses in pain using simulations of
individual patient data.
AB - In this paper we consider the validity and power of some commonly used statistics
for assessing the degree of homogeneity between trials in a meta-analysis. We
show, using simulated individual patient data typical of that occurring in
randomized controlled trials in pain, that the most commonly used statistics do
not give the expected levels of statistical significance (i.e. the proportion of
trials giving a significant result is not equal to the proportion expected due to
random chance) when used with truly homogeneous data. In addition, all such
statistics are shown to have extremely low power to detect true heterogeneity
even when that heterogeneity is very large. Since, in most practical situations,
failure to detect heterogeneity does not allow us to say with any helpful degree
of certainty that the data is truly homogeneous, we advocate the quantitative
combination of results only where the trials contained in a meta-analysis can be
shown to be clinically homogeneous. We propose as a definition of clinical
homogeneity that all trials have (i) fixed and clearly defined inclusion criteria
and (ii) fixed and clearly defined outcomes or outcome measures. In pain relief,
for example, the first of these would be satisfied by all patients having
moderate or severe pain, whilst the second would be satisfied by using at least
50% pain relief as the successful outcome measure.
PMID- 10781915
TI - Effects of midazolam in the spinal nerve ligation model of neuropathic pain in
rats.
AB - Potential changes in the spinal GABAergic activity after nerve injury were
studied by comparing the effects of systemic administration of the benzodiazepine
midazolam on the noxious evoked responses of dorsal horn in rats with spinal
nerve ligation of neuropathy and control animals. The tight ligation of the L(5)
and L6 spinal nerves was performed in adult male Sprague-Dawley rats and
resulting mechanical and cold allodynia were assessed with von Frey hairs and the
acetone drop test. Single unit extracellular recordings of dorsal horn neurones
were performed 15-18 days after the surgery under halothane anaesthesia using
transcutaneous electrical stimulation of the receptive field at three times the C
fibre threshold. The rats in the spinal nerve ligation group, but not in the sham
operated control group developed mechanical and cold allodynia. Subcutaneous
administration of midazolam 0.1-3.0 mg/kg reduced the Adelta-fibre evoked
activity in a dose-related manner in all study groups, but the C-fibre evoked
activity was significantly reduced only in the spinal nerve ligation group. The
inhibitory effects of s.c. midazolam were significantly reversed by i.t.
administration of flumazenil, suggesting a spinal site of action. Midazolam
reduced C-fibre evoked firing significantly more in the spinal nerve ligation
model than in the non-operated or sham controls. These results indicate changes
in the spinal GABAergic system in the neuropathic animals and could be of
importance in the development of new treatments for neuropathic pain.
PMID- 10781916
TI - Unaltered peripheral excitatory actions of nociceptin contrast with enhanced
spinal inhibitory effects after carrageenan inflammation: an electrophysiological
study in the rat.
AB - Nociceptin (orphanin FQ) is the endogenous agonist of the opioid receptor-like
(ORL-1) receptor. The actions of this peptide have been studied extensively at a
number of sites with diverse actions being reported. Here, in a rat model of
peripheral inflammation, we examine the effects of nociceptin on the responses of
dorsal horn neurones when applied directly to the spinal cord and, in separate
studies, into the peripheral receptive fields in the hindpaw of the halothane
anaesthetized rat. As changes in the receptor density and expression of the
message for nociceptin have been reported after inflammation we have compared
these actions to previously reported effects in normal animals. The dose
dependent inhibitory actions of nociceptin on C-fibre evoked responses and input
(measures of presumed pre-synaptic excitability) are increased 3-4 h after
inflammation whereas its inhibitory effects on post-synaptic mechanisms (wind-up)
remain unchanged. These inhibitory effects were partly reversible by high doses
of naloxone. This increased potency of nociceptin after inflammation is
consistent with an increased receptor density in the superficial spinal cord. In
contrast, the peripheral administration of nociceptin produced dose-dependent
excitations of dorsal horn neurones and a degree of sensitization to mechanical
stimuli. This peripheral action was unchanged after inflammation. These diverse
site-dependent actions of nociceptin further emphasize the complexities of this
novel opioid system.
PMID- 10781917
TI - Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats.
AB - The present study directly compared the antinociceptive and toxic effects of the
neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmethoxy)-2
chloropyridine) with (-)-nicotine and (+)-epibatidine. Like (-)-nicotine (0.8 and
1.6 mg/kg s.c.) and (+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05
and 0.1 mg/kg s.c.) increased response latencies in the hot-plate test in rats,
indicating that it has antinociceptive activity. In contrast to (-)-nicotine and
(+)-epibatidine, ABT-594 did not cause rotarod impairment at antinociceptive
doses but did cause hypothermia and life-threatening adverse effects including
seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent
increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1
and 0. 03 mg/kg i.v.) and (+)-epibatidine (0.001 and 0.003 mg/kg i.v.). Both the
antinociceptive and toxic effects (convulsions and hypertension) were abolished
by pretreatment with the brain penetrant neuronal nAChR antagonist mecamylamine
(1 mg/kg s.c.; i.v. for cardiovascular studies), demonstrating that these actions
of ABT-594 were mediated via activation of neuronal nicotinic receptors.
Continuous infusion of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days
followed by challenge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like
abstinence syndrome suggesting that ABT-594 has nicotine-like dependence
liability. These findings indicate that the acute safety profile of ABT-594 is
not significantly improved over other nicotinic analgesics.
PMID- 10781918
TI - Some empirical evidence regarding the validity of the Spanish version of the
McGill Pain Questionnaire (MPQ-SV).
AB - Despite the fact that the McGill Pain Questionnaire (MPQ) is a useful pain
assessment tool with widespread acceptance, empirical analyses have questioned
its validity because they have not consistently supported the three a priori
factors that guided its construction. The Spanish version that has followed the
most systematic and rigorous reconstruction process (Lazaro C, Bosch F, Torrubia
R, Banos JE. The development of a Spanish Questionnaire for assessing pain:
preliminary data concerning reliability and validity. Eur J Psychol Assess,
1994;10:145-151) lacks evidence to support its construct validity. In the present
study, the internal structure of the Spanish version of the McGill Pain
Questionnaire (Lazaro C, Bosch F, Torrubia R, Banos JE. The development of a
Spanish Questionnaire for assessing pain: preliminary data concerning reliability
and validity. Eur J Psychol Assess, 1994;10:145-151) was examined in a sample of
202 acute pain patients and 207 chronic pain patients. Confirmatory factor
analyses were carried out to compare alternative models postulating different
internal structures (one-factor model, the classic three-factor model, and the
semantic model inspired by the alternative structure found by Donaldson in 1995
(Donaldson GW. The factorial structure and stability of the McGill Pain
Questionnaire in patients experiencing oral mucositis following bone marrow
transplantation. Pain 1995;62:101-109)). Results from the LISREL CFA analysis
indicated that the semantic model fitted better than the other models. On the
other hand, intercorrelations between scales were smaller than the reliability
indexes. In relation to concurrent evidence, significant correlations (0.001)
were found between each subscale and the criteria measurements of every pain
dimension. Only the affective subscale presented discriminant validity. Evidence
supports the validity of the affective and sensory subscales but not the
evaluative scale.
PMID- 10781919
TI - Simple pain rating scales hide complex idiosyncratic meanings.
AB - Assumptions of reliability and consistency of self-report of pain by patients
using visual analogue scales (VAS) and numerical rating scales (NRS) are based on
narrow considerations of possible sources of error. This study examined patients'
use of VASs and NRSs, by their own description, with particular attention to
rating of multiple pains, of different dimensions of pain, and of interpretation
and use of lower and upper endpoints and increments on the scales. These have
implications for the approximation of the scales to psychometric requirements. An
interview developed from a small pilot project was given to 78 volunteer chronic
pain patients embarking on a pain management course, and consisted of both forced
choice questions and free response. Data are described with reference to lack of
concordance between patients and of consistency within patients; responses
suggested that ratings incorporate multiple partially differentiated dimensions
of pain, with particular importance placed on function or mobility. Labels
assigned to scale endpoints by researchers, whether lexical or numerical,
appeared to affect their use; however, covert relabelling of scale points was
revealed in free response. The action of arriving at a rating is better
conceptualised as an attempt to construct meaning, influenced by and with
reference to a range of internal and external factors and private meanings,
rather than as a task of matching a distance or number to a discrete internal
stimulus.
PMID- 10781920
TI - Synergistic effect of cholecystokinin octapeptide and angiotensin II in reversal
of morphine induced analgesia in rats.
AB - The aim of this paper is to study the synergistic anti-analgesic effect of
angiotensin II (Ang II) plus cholecystokinin octapeptide (CCK-8). Our previous
studies have shown that both CCK-8 and Ang II are potent anti-opioid substances.
Intracerebroventricular (i.c.v.) injection of CCK-8 or Ang II dose-dependently
antagonizes morphine-induced analgesia (MIA). In the present study, we observed
the combined effect of CCK-8 and Ang II in antagonizing MIA. CCK-8 and Ang II
were injected intracerebroventricularly to rats in various proportions and doses.
The results were analyzed with isobolographic analysis. Combined injection of CCK
8 and Ang II in a ratio of 1 ng: 2.5 microg or 1 ng: 5 microg produced
significantly greater effect in antagonizing MIA. The ED(50) of the two ratios
are only 18.5% and 27.5%, respectively, of the theoretical dose of simple
addition. We conclude that CCK-8 and Ang II used in such dose ratios may
antagonize MIA synergistically.
PMID- 10781921
TI - Alexithymia is associated with low tolerance to experimental painful stimulation.
AB - Alexithymics are known to report more somatic complaints than individuals scoring
low on alexithymia. It was examined whether alexithymia would also be associated
with enhanced sensitivity to an externally administered unpleasant physical
stimulus. Forty-one healthy male and female subjects with a mean age of 33.9
years completed the 20-item version of the Toronto Alexithymia Scale and
participated in a laboratory protocol consisting of exposure to painful electric
stimulation. Multiple stepwise regression analyses revealed that after
controlling for sensory threshold, duration of stimulation, and self-reported
caffeine consumption, alexithymia predicted significantly pain tolerance level
(beta=-0.33, P=0.01). Externally oriented thinking and difficulty identifying
feelings, but not difficulty communicating feelings, were responsible for this
association. Previous findings and the present results together indicate that
alexithymia may be associated with an enhanced sensitivity to both internal
(somatic) unpleasant sensations and externally induced pain, suggesting a
potential general hypersensitivity to unpleasant stimuli in individuals scoring
high on this trait.
PMID- 10781922
TI - Hyperalgesia and upregulation of cytokines and nerve growth factor by cutaneous
leishmaniasis in mice.
AB - Classical description of syndromes produced by cutaneous leishmaniasis (CL) does
not include sensory manifestations such as pain and/or itching, despite the
evident upregulation of proinflammatory cytokines. Using a murine model of CL we
report on evident hyperalgesia, as assessed by acute pain tests, and sustained
upregulation of interleukin (IL-1beta) and nerve growth factor (NGF). This
upregulation, especially that of NGF, may explain the observed hyperalgesia, in
the light of recent evidence on the role of cytokines in the sensitization of
nerve afferents and the subsequent hyperalgesia.
PMID- 10781923
TI - Ketamine reduces muscle pain, temporal summation, and referred pain in
fibromyalgia patients.
AB - Central mechanisms related to referred muscle pain and temporal summation of
muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS)
patients. The present study assessed the effects of an NMDA-antagonist (ketamine)
on these central mechanisms. FMS patients received either i.v. placebo or
ketamine (0.3 mg/kg, Ketalar((R))50% decrease in pain intensity at rest by active
drug on two consecutive VAS assessments). Fifteen out of 17 ketamine-responders
were included in the second part of the study. Before and after ketamine or
placebo, experimental local and referred pain was induced by intramuscular (i.m.)
infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA)
muscle. The saline-induced pain intensity was assessed on an electronic VAS, and
the distribution of pain drawn by the subject. In addition, the pain threshold
(PT) to i.m. electrical stimulation was determined for single stimulus and five
repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was
determined, and the pressure PT and pressure pain tolerance threshold were
determined at three bilaterally located tenderpoints (knee, epicondyle, and mid
upper trapezius). VAS scores of pain at rest were progressively reduced during
ketamine infusion compared with placebo infusion. Pain intensity (area under the
VAS curve) to the post-drug infusion of hypertonic saline was reduced by ketamine
(-18. 4+/-0.3% of pre-drug VAS area) compared with placebo (29.9+/-18.8%,
P<0.02). Local and referred pain areas were reduced by ketamine (-12. 0+/-14.6%
of pre-drug pain areas) compared with placebo (126.3+/-83. 2%, P<0.03). Ketamine
had no significant effect on the PT to single i.m. electrical stimulation.
However, the span between the PT to single and repeated i.m. stimuli was
significantly decreased by the ketamine (-42.3+/-15.0% of pre-drug PT) compared
with placebo (50. 5+/-49.2%, P<0.03) indicating a predominant effect on temporal
summation. Mean pressure pain tolerance from the three paired tenderpoints was
increased by ketamine (16.6+/-6.2% of pre-drug thresholds) compared with placebo
(-2.3+/-4.9%, P<0.009). The pressure PT at the TA muscle was increased after
ketamine (42.4+/-9. 2% of pre-drug PT) compared with placebo (7.0+/-6.6%,
P<0.011). The present study showed that mechanisms involved in referred pain,
temporal summation, muscular hyperalgesia, and muscle pain at rest were
attenuated by the NMDA-antagonist in FMS patients. It suggested a link between
central hyperexcitability and the mechanisms for facilitated referred pain and
temporal summation in a sub-group of the fibromyalgia syndrome patients. Whether
this is specific for FMS patients or a general phenomena in painful
musculoskeletal disorders is not known.
PMID- 10781924
TI - Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not
dependent on input from injured nerve fibers.
AB - An injury to a peripheral nerve in animals often leads to signs of neuropathic
pain including hyperalgesia to heat, cold and mechanical stimuli. The role of
injured and intact nerve fibers in mechanical hyperalgesia was evaluated in rats
subjected to an L5 spinal nerve ligation-and-cut ('modified SNL lesion'). To
assess the contribution of injured afferents, an L5 dorsal rhizotomy was
performed immediately before, or 7 days after the modified SNL lesion. To study
the role of adjacent intact spinal nerves, an L4 dorsal rhizotomy was performed 7
days after the modified SNL lesion. The up-down method of Dixon (Dixon WJ, Annu
Rev Pharmacol Toxicol 1980;20:441-462) was used to measure the paw withdrawal
threshold to mechanical stimuli at three sites on the rat hindpaw corresponding
to the L3, L4, and L5 dermatomes. We found that the modified SNL lesion produced
a significant, lasting (20 days) decrease of the mechanical withdrawal threshold.
The severity and duration of mechanical hyperalgesia varied across testing sites.
The L5 and L4 dermatome test sites developed the most severe and lasting
mechanical hyperalgesia. In contrast, the L3 testing site developed significantly
less severe and shorter lasting mechanical hyperalgesia. L5 dorsal rhizotomy, by
itself, produced a transient decrease in mechanical withdrawal thresholds. L5
dorsal rhizotomy performed before, or 7 days after, the modified SNL lesion did
not prevent or resolve the observed decrease in mechanical withdrawal thresholds.
L4 dorsal rhizotomy performed 7 days after the modified SNL lesion resulted in an
immediate reversal of mechanical withdrawal thresholds back to baseline values.
These results suggest that, after L5 spinal nerve ligation-and-cut, mechanical
hyperalgesia develops and persists independent of input from injured afferents.
We propose that the Wallerian degeneration that develops after a nerve injury
leads to interactions between the degenerating fibers of the injured spinal nerve
and the intact fibers of adjacent spinal nerves. This leads to changes in the
intact fibers that play a critical role for both initiation and maintenance of
mechanical hyperalgesia.
PMID- 10781925
TI - Tactile allodynia in the absence of C-fiber activation: altered firing properties
of DRG neurons following spinal nerve injury.
AB - We examined the relation between ectopic afferent firing and tactile allodynia in
the Chung model of neuropathic pain. Transection of the L5 spinal nerve in rats
triggered a sharp, four- to six-fold increase in the spontaneous ectopic
discharge recorded in vivo in sensory axons in the ipsilateral L5 dorsal root
(DR). The increase, which was not yet apparent 16 h postoperatively, was complete
by 24 h. This indicates rapid modification of the electrical properties of the
neurons. Only A-neurons, primarily rapidly conducting A-neurons, contributed to
the discharge. No spontaneously active C-neurons were encountered. Tactile
allodynia in hindlimb skin emerged during precisely the same time window after
spinal nerve section as the ectopia, suggesting that ectopic activity in injured
myelinated afferents can trigger central sensitization, the mechanism believed to
be responsible for tactile allodynia in the Chung model. Most of the spike
activity originated in the somata of axotomized DRG neurons; the spinal nerve end
neuroma accounted for only a quarter of the overall ectopic barrage.
Intracellular recordings from afferent neuron somata in excised DRGs in vitro
revealed changes in excitability that closely paralleled those seen in the DR
axon recordings in vivo. Corresponding changes in biophysical characteristics of
the axotomized neurons were catalogued. Axotomy carried out at a distance from
the DRG, in the mid-portion of the sciatic nerve, also triggered increased
afferent excitability. However, this increase occurred at a later time following
axotomy, and the relative contribution of DRG neuronal somata, as opposed to
neuroma endings, was smaller. Axotomy triggers a wide variety of changes in the
neurochemistry and physiology of primary afferent neurons. Investigators studying
DRG neurons in culture need to be alert to the rapidity with which axotomy, an
inevitable consequence of DRG excision and dissociation, alters key properties of
these neurons. Our identification of a specific population of neurons whose
firing properties change suddenly and synchronously following axotomy, and whose
activity is associated with tactile allodynia, provides a powerful vehicle for
defining the specific cascade of cellular and molecular events that underlie
neuropathic pain.
PMID- 10781926
TI - Regulation of adenylyl cyclase in the central nervous system.
AB - Adenylyl cyclases (ACs) are a family of enzymes that synthesize one of the major
second messengers, cAMP, upon stimulation. Since the report of the first adenylyl
cyclase (AC) gene in 1989, tremendous efforts have been devoted to identifying
and characterizing more AC isozymes. In the past decade, significant knowledge
regarding the basic structure, tissue distribution, and regulation of AC isozymes
has been accumulated. Because members of the AC superfamily are tightly
controlled by various signals, one of the most important impacts of these AC
isozymes is their contribution to the complexity and fine-tuning of cellular
signalling, especially in the central nervous system (CNS) where multiple signals
constantly occur. This review focuses on recent progress toward understanding the
physiological roles of ACs in the CNS.
PMID- 10781927
TI - Activation of mitogen-activated protein kinase by oxidized low-density
lipoprotein in canine cultured vascular smooth muscle cells.
AB - Oxidized low-density lipoprotein (OX-LDL) contributes significantly to the
development of atherosclerosis. However, the mechanisms of OX-LDL-induced
vascular smooth muscle cell (VSMC) proliferation are not completely understood.
Therefore, we investigated the effect of OX-LDL on cell proliferation associated
with a specific pattern of mitogen-activated protein kinase (MAPK) by
[3H]thymidine incorporation and p42/p44 MAPK phosphorylation in canine cultured
VSMCs. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK
phosphorylation in a time- and concentration-dependent manner in VSMCs.
Pretreatment of these cells with pertussis toxin (PTX) for 24 hours attenuated
the OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation,
indicating that these responses were mediated through a receptor coupled to a PTX
sensitive G protein. In cells pretreated with PMA for 24 h and with either the
PKC inhibitor staurosporine or the tyrosine kinase inhibitor genistein for 1h,
substantially reduced the [3H]thymidine incorporation and p42/p44 MAPK
phosphorylation in response to OX-LDL. Removal of Ca(2+) by addition of BAPTA/AM
plus EGTA significantly inhibited OX-LDL-induced [3H]thymidine incorporation and
p42/p44 MAPK phosphorylation, indicating the requirement of Ca(2+) for these
responses. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK
phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2) and
SB203580 (an inhibitor of p38 MAPK). Furthermore, we also showed that
overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301)
completely suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and
PDGF-BB, indicating that Ras and Raf may be required for activation of these
kinases. Taken together, these results suggest that the mitogenic effect of OX
LDL is mediated through a PTX-sensitive G-protein-coupled receptor that involves
the activation o Ras/Raf/MEK/MAPK pathway similar to those of PDGF-BB in canine
cultured VSMCs.
PMID- 10781929
TI - Effect of pertussis toxin on insulin-induced signal transduction in rat
adipocytes and soleus muscles.
AB - It has been reported that pertussis toxin (PTX) suppresses the function of
trimeric guanine nucleotide binding protein (G-protein). We examined the effect
of PTX on insulin-induced glucose uptake, diacylglycerol (DG)-protein kinase C
(PKC) signalling, phosphatidylinositol (PI) 3-kinase and PKC zeta activation and
insulin-induced tyrosine phosphorylation of Gialpha to clarify the role of G
protein for insulin-mediated signal transduction mechanism in rat adipocytes and
soleus muscles. Isolated adipocytes and soleus muscles were preincubated with
0.01 approximately 1 ng/ml PTX for 2 hours, followed by stimulation with 10-100
nM insulin or 1 microM tetradecanoyl phorbol-13-acetate (TPA). Pretreatment with
PTX resulted in dose-responsive decreases in insulin-stimulated [3H]2
deoxyglucose (DOG) uptake, and unchanged TPA-stimulated [3H]2-DOG uptake, without
affecting basal [3H]2-DOG uptake. In adipocytes, insulin-induced DG-PKC
signalling, PI 3-kinase activation and PKC zeta translocation from cytosol to the
membrane were suppressed when treated with PTX, despite no changes in
[125I]insulin-specific binding and insulin receptor tyrosine kinase activity.
Moreover, to elucidate insulin-stimulated tyrosine phosphorylation of 40 kDa
alpha-subunit of G-protein (Gialpha-2), adipocytes were stimulated with 10 nM
insulin for 10 minutes, homogenized, immunoprecipitated with anti-phosphotyrosine
antibody, and immunoblotted with anti-Gialpha-2 antibody. Insulin-induced
tyrosine phosphorylation of Gialpha-2 was found by immunoblot analysis with anti
Gialpha-2 antibody. These results suggest that G-protein regulates DG-PKC
signalling by binding of Gialpha-2 with GTP and PI 3-kinase-PKC zeta signalling
by releasing of Gbetagamma via dissociation of trimeric G-protein after insulin
receptor tyrosine phosphorylation in insulin-sensitive tissues.
PMID- 10781928
TI - Increase of [Ca(2+)]i and release of arachidonic acid via activation of M2
receptor coupled to Gi and rho proteins in oesophageal muscle.
AB - We have previously shown that acetylcholine-induced contraction of oesophageal
circular muscle depends on activation of phosphatidylcholine selective
phospholipase C and D, which result in formation of diacylglycerol, and of
phospholipase 2 which produces arachidonic acid. Diacylglycerol and arachidonic
acid interact synergistically to activate protein kinase C. We have therefore
investigated the relationship between cytosolic Ca(2+) and activation of
phospholipase A(2) in response to acetylcholine-induced stimulation, by measuring
the intracellular free Ca(2+) ([Ca(2+)]i), muscle tension, and [3H] arachidonic
acid release. Acetylcholine-induced contraction was associated with increased
[Ca(2+)]i and arachidonic acid release in a dose-dependent manner. In Ca(2+)-free
medium, acetylcholine did not produce contraction, [Ca(2+)]i increase, and
arachidonic acid release. In contrast, after depletion of Ca(2+) stores by
thapsigargin (3 microM), acetylcholine caused a normal contraction, [Ca(2+)]i
increase and arachidonic acid release. The increase in [Ca(2+)]i and arachidonic
acid release were attenuated by the M2 receptor antagonist methoctramine, but not
by the M3 receptor antagonist p-fluoro-hexahydro siladifenidol. Increase in
[Ca(2+)]i and arachidonic acid release by acetylcholine were inhibited by
pertussis toxin and C3 toxin. These findings indicate that contraction and
arachidonic acid release are mediated through muscarinic M2 coupled to Gi or rho
protein activation and Ca(2+) influx. Acetylcholine-induced contraction and the
associated increase in [Ca(2+)]i and release of arachidonic acid were completely
reduced by the combination treatment with a phospholipase A(2) inhibitor
dimethyleicosadienoic acid and a phospholipase D inhibitor pCMB. They increased
by the action of the inhibitor of diacylglycerol kinase R59949, whereas they
decreased by a protein kinase C inhibitor chelerythrine. These data suggest that
in oesophageal circular muscle acetylcholine-induced [Ca(2+)]i increase and
arachidonic acid release are mediated through activation of M2 receptor coupled
to Gi or rho protein, resulting in the activation of phospholipase A(2) and
phospholipase D to activate protein kinase C.
PMID- 10781930
TI - Nitric oxide selectively inhibits adenylyl cyclase isoforms 5 and 6.
AB - We have previously shown that N18TG2 neuroblastoma cells express the type 6
adenylyl cyclase and that preincubation with nitric oxide (NO) attenuates Gs- and
forskolin-stimulated activity. Here we show that this inhibition reflects a
direct action of NO on the adenylyl cyclase. Preincubation of N18TG2 cell
membranes and insect cell membranes expressing recombinant type 5 and type 6
isoforms with NO donors leads to an inhibition of forskolin-stimulated adenylyl
cyclase activity. NO donors do not alter the type 1 (representative of the type
1,3,8 family) or type 2 (representative of the type 2,4, 7 family) isoforms
expressed in insect cells, even under conditions of compromised assay conditions
or a range of temperatures. Thus, the ability of NO to inhibit adenylyl cyclase
stimulation is dependent upon the nature of the isoform present, and appears to
represent a unique regulation of the type 5,6 isoform family.
PMID- 10781931
TI - Mastoparan transiently permeabilizes Swiss 3T3 cells and induces c-fos proto
oncogene expression. Role of calcium and G protein activation.
AB - Mastoparan, a widely used tetradecapeptide activator of Gi/Go G proteins, has
been reported to be a potent co-mitogen for Swiss 3T3 fibroblasts. However, we
have previously shown that the peptide promotes the release of lactate
dehydrogenase from Swiss 3T3 cells and evokes only a modest and delayed increase
in DNA. We suggested that the ability of the peptide to permeabilise these cells
may account for its mitogenic action. Here we show that mastoparan caused a rapid
release of fluorescein from cells which had been pre-incubated with fluorescein
diacetate, indicating that the peptide increases membrane permeability to small
molecules. Furthermore, the release of lactate dehydrogenase evoked by mastoparan
was lost after prolonged (24 h) incubation of cells with the peptide. Together,
these data indicate that mastoparan-induced cell permeabilisation is both rapid
and transient. We have also shown that mastoparan increased c-fos mRNA
accumulation and that this response was not influenced by pertussis toxin or
indomethacin. Although mastoparan increased the intracellular calcium
concentration, the removal of extracellular calcium had no effect on mastoparan
stimulated c-fos mRNA accumulation. These data show that mastoparan-induced c-fos
mRNA accumulation is not mediated by activation of a G protein and subsequent
activation of phospholipase D nor by a non-selective increase in calcium influx.
The data have significance for the interpretation of studies in which mastoparan
is, or has been, used as an activator of Gi/Go.
PMID- 10781932
TI - Role and regulation of Rel/NF-kappaB activity in anti-immunoglobulin-induced
apoptosis in WEHI-231 B lymphoma cells.
AB - In WEHI-231 cells, anti-immunoglobulin (anti-Ig) treatment leads to both a
decrease in the DNA-binding activity of p50/c-Rel/p53 protein complexes and a
transient enhancement in the DNA-binding activity of p50 homodimeric complexes.
These cells subsequently undergo apoptosis. Because IkappaB-alpha plays a pivotal
role in the regulation of Rel/NF-kappaB activity, we have characterized both the
nature and kinetics of the expression of IkappaB-alpha following anti-Ig-induced
apoptosis in WEHI-231 cells. Anti-Ig treatment of WEHI-231 cells decreased the
steady-state level of IkappaB-alpha mRNA, but enhanced the stability of IkappaB
alpha, leading to an accumulation of IkappaB-alpha in both the cytosol and
nucleus. Concomitant with the increase in IkappaB-alpha expression there was a
gradual decline in the nuclear expression of c-Rel. Because c-Rel plays an
important role in the survival of WEHI-231 cells, these results suggest that post
transcriptional regulation of IkappaB-alpha expression might play a role in the
anti-Ig-induced apoptosis in WEHI-231 cells.
PMID- 10781934
TI - Novel effects of propranolol. Release of internal Ca(2+) followed by activation
of capacitative Ca(2+) entry in Madin Darby canine kidney cells.
AB - The effect of propranolol on Ca(2+) signalling in Madin Darby canine kidney
(MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Propranolol
increased cytosolic free Ca(2+) levels ([Ca(2+)](i)) in a concentration-dependent
manner between 0.1 and 1 mM. The response was partly inhibited by external Ca(2+)
removal. In Ca(2+)-free medium pretreatment with 0.2 mM propranolol partly
inhibited the [Ca(2+)](i) rise induced by 1 microM thapsigargin, an inhibitor of
the endoplasmic reticulum Ca(2+) pump; but pretreatment with thapsigargin
abolished propranolol-induced Ca(2+) release. Addition of 3 mM Ca(2+) induced a
[Ca(2+)](i) rise after pretreatment with 0.2 mM propranolol in Ca(2+)-free
medium. Propranolol (0.2 mM) inhibited 25% of thapsigargin-induced capacitative
Ca(2+) entry. Suppression of 1,4,5-trisphosphate (IP(3)) formation by 2 microM
U73122, a phospholipase C inhibitor, did not alter 0.2 mM propranolol-induced
internal Ca(2+) release. Propranolol (1 mM) also increased [Ca(2+)](i) in human
neutrophils. Collectively, we have found that 0.2 mM propranolol increased
[Ca(2+)](i) in MDCK cells by releasing Ca(2+) from thapsigargin-sensitive Ca(2+)
stores in an IP(3)-independent manner, followed by Ca(2+) influx from external
space. Independently, propranolol was able to inhibit thapsigargin-induced
capacitative Ca(2+) entry.
PMID- 10781933
TI - Novel action of pituitary adenylate cyclase-activating polypeptide. Stimulation
of extracellular acidification in rat pituitary GH4C1 cells.
AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the
vasoactive intestinal peptide/secretin family. Using microphysiometry, we have
found that PACAP acutely (1 min) increased the extracellular acidification rate
(ECAR) in GH4C1 cells approximately 40% above basal in a concentration-dependent
manner. ECAR, maximally induced by PACAP, can be increased further by thyrotropin
releasing hormone (TRH), indicating that the signalling pathways for these two
neuropeptides are not identical. In studies on the mechanism of PACAP-enhanced
ECAR, we found that maximum stimulation of the cAMP/PKA pathway by treatment with
FSK, or the PKC pathway with PMA, did not inhibit the ECAR response to PACAP. The
PKC inhibitor calphostin C and the MAP kinase inhibitor PD98059 had no effect on
the ECAR response to PACAP. Furthermore, PACAP induced little or no change in
cytosolic Ca(2+) ([Ca(2+)](i)), while TRH induced a large increase in
[Ca(2+)](i). However, the tyrosine kinase inhibitor genistein completely blocked
PACAP-induced ECAR, suggesting involvement of tyrosine kinase(s). We conclude
that PACAP causes an increase in ECAR in GH4C1 rat pituitary cells, which is not
dependent on the PKA, PKC, MAP kinase or Ca(2+) signalling pathways, but does
require tyrosine kinase activity.
PMID- 10781935
TI - Dorsal induction from dorsal vegetal cells in Xenopus occurs after mid-blastula
transition.
AB - We performed some experiments to investigate the temporal and spatial details of
the dorsal induction exerted by dorsal vegetal cells in Xenopus embryo. Two
dorsal vegetal cells (D1 cells) were transplanted into the ventral vegetal region
of a recipient at the 32-cell stage. At various times after transplantation, the
ventral animal-equatorial part was explanted and cultured. The explants isolated
5.5 h after transplantation (time 5.5) elongated and formed somites. In RT-PCR
analysis, the expression of dorsal gene, chordin was activated in the explants
isolated after time 4.0 (about the 4000-cell stage which corresponds to the mid
blastula transition (MBT)) at control stage 10. In another series of experiments,
ventral animal-equatorial and dorsal vegetal parts were isolated from the 4000
cell stage embryos and they were combined for 2.0-2.5 h. These ventral animal
equatorial explants elongated and formed somites. The chordin expression was also
observed in the explants. But the 32- and 256-cell stage dorsal vegetal cells
failed to exert the dorsalizing activity within the 2.0-2.5 h of the conjugation.
These results suggest that 2 h contact after MBT is necessary and sufficient for
the dorsal induction from the dorsal vegetal cells and it occurs as a result of
the zygotic gene expression. Consistent with this idea, the zygotic dorsal genes,
siamois and chordin were expressed on the upper regions of the transplanted D1
descendants at stage 10. Furthermore, this region began to gastrulate when the D1
cell was transplanted with upside-down orientation. Our data indicate that the
upper region of the D1 descendants by itself act as the Spemann organizer rather
than the Nieuwkoop center.
PMID- 10781936
TI - Drosophila null slimb clones transiently deregulate Hedgehog-independent
transcription of wingless in all limb discs, and induce decapentaplegic
transcription linked to imaginal disc regeneration.
AB - Drosophila Slimb (Slmb) is a F-box/WD40 protein which potentially participates in
the ubiquitin proteolysis machinery. During development, Slmb is required in limb
discs to repress Hedgehog (Hh) target genes, i.e. wingless (wg) and
decapentaplegic (dpp), as well as the Wg signal transduction pathway. These
repression functions have been proposed from studies using weak slmb alleles.
Interestingly, experiments with strong slmb alleles have revealed additional
mechanisms in which slmb is required, such as leg dorsal-ventral restriction. We
have isolated new alleles of the slmb gene in a screen for new negative
regulators of dpp: several amorphs (characterized by genetic and molecular
criteria) and a cold-sensitive hypomorph. By performing somatic clone experiments
with these new amorphic slmb alleles, we have determined that regulation of Dpp
and Wg morphogens by Slmb could be different from what has already been
published. We show here that in leg discs, lack of slmb function derepresses the
transcription of wg independently of Hh signaling. We present evidence that
ectopic legs resulting from slmb(-) clone induction only come from wg
misexpression in the normal dpp domain, as ectopic proximo-distal axis are
induced dorsally, and adult ectopic legs are often perfect with respect to antero
posterior polarity. In wing discs, transcription of wg, which is normally
independent of Hh signaling, is also derepressed in the absence of slmb function.
We also describe, in discs bearing amorphic slmb clones and in discs of two other
slmb(-) contexts, a novel pattern of dpp expression consisting of an enlargement
of the normal dpp domain. Strong evidence indicates that this dpp modification
can be linked to imaginal disc regeneration following slmb(-) cell elimination.
We have investigated the fate of slmb(-) clones, which disappear before
adulthood, and found that two mechanisms of cell elimination can account for
imaginal cell regeneration: an early apoptosis and a mechanism of sorting-out
which excludes all slmb(-) clones from all imaginal discs. This result suggests
that Slmb is likely to be involved, in addition to its repression role on Dpp and
Wg, in some other essential cellular mechanism, as in the absence of Slmb, cell
affinities are dramatically modified regardless of the deregulated morphogen and
of the type of imaginal disc.
PMID- 10781937
TI - A screen for targets of the Xenopus T-box gene Xbra.
AB - Brachyury (T), a member of the T-box gene family, is essential for the formation
of posterior mesoderm and notochord in vertebrate development. Expression of the
Xenopus homologue of Brachyury, Xbra, causes ectopic ventral and lateral mesoderm
formation in animal cap explants and co-expression of Xbra with Pintallavis, a
forkhead/HNF3beta-related transcription factor, induces notochord. Although eFGF
and the Bix genes are thought to be direct targets of Xbra, no other target genes
have been identified. Here, we describe the use of hormone-inducible versions of
Xbra and Pintallavis to construct cDNA libraries enriched for targets of these
transcription factors. Five putative targets were isolated: Xwnt11, the homeobox
gene Bix1, the zinc-finger transcription factor Xegr-1, a putative homologue of
the antiproliferative gene BTG1 called Xbtg1, and BIG3/1A11, a gene of unknown
function. Expression of Xegr-1 and Xbtg1 is controlled by Pintallavis alone as
well as by a combination of Xbra and Pintallavis. Overexpression of Xbtg1
perturbed gastrulation and caused defects in posterior tissues and in notochord
and muscle formation, a phenotype reminiscent of that observed with a dominant
negative version of Pintallavis called Pintallavis-En(R). The Brachyury-inducible
genes we have isolated shed light on the mechanism of Brachyury function during
mesoderm formation. Specification of mesodermal cells is regulated by targets
including Bix1-4 and eFGF, while gastrulation movements and perhaps cell division
are regulated by Xwnt11 and Xbtg1.
PMID- 10781938
TI - FGF and genes encoding transcription factors in early limb specification.
AB - SnR, twist and Fgf10 are expressed in presumptive limb territories of early chick
embryos. When FGF-2/FGF-8 beads are implanted in chick flank, an ectopic limb
develops and SnR is irreversibly activated as early as 1 h. Ectopic Fgf10 and
twist expression are activated much later at 17 and 20 h, respectively. FGF-10
can also induce SnR, but much later, and in this case activation occurs
simultaneously with that of twist and Fgf10 via the Fgf8- expressing ridge. Tbx-4
and Tbx-5 are expressed in leg and wing forming regions, respectively, in a
similar pattern to SnR and twist. FGF-2 leads to ectopic expression of Tbx-4 and
Tbx-5 as rapidly as ectopic expression of SnR, but the patterns of ectopic
transcripts suggest that induction of SnR and Tbx gene expression occur via
different pathways.
PMID- 10781939
TI - Neuroectodermal specification and regionalization of the Spemann organizer in
Xenopus.
AB - During gastrulation in Xenopus convergence and extension movements, mediated by
mediolateral intercalations, are the driving force for early neural plate
morphogenesis. Here we show that the winged helix transcriptional regulator, Xfd
12' is dynamically expressed in medial neural plate precursors that undergo
convergence and extension movements. These medial neuraxial progenitors are
specified in and beyond the Spemann organizer prior to specification of the basal
anlage of the neural plate. The initiation of Xfd-12' expression coincides with
the induction of mesendoderm by Nodal-related growth factors at the late blastula
stage. Comparative expression analysis suggests that cellular rearrangements at
the pre-gastrulation stage account for regionalization of the Spemann organizer
into head and trunk organizer compartments, the latter in which medial neural
plate progenitors reside. While the maintenance of Xfd-12' expression in the
dorsal non-involuting marginal zone requires FGF signalling, its subsequent
positioning along the medial aspect of the neuraxis depends on signalling by Wnt
and Nodal-related family members. Based on these findings we propose that XFD-12'
is a trunk organizer component that might control convergence and extension
movements of medial neural plate precursors during gastrulation.
PMID- 10781940
TI - Expanded retina territory by midbrain transformation upon overexpression of Six6
(Optx2) in Xenopus embryos.
AB - During vertebrate eye development, the expression of the homeobox gene Six6 is
restricted to the neural retina and is initiated later than Rx and Pax6 in the
presumptive retina field. We show here that overexpression of mouse Six6 in
Xenopus embryos can induce transformation of competent tissue of the anterior
neural plate into retinal tissue. In Six6 injected embryos, the molecular
identity of the presumptive midbrain and rostral hindbrain regions was lost, as
shown by the absence of XEn-2 and Xpax2 expression, being replaced by the ectopic
expression of the retinal markers Xpax6 and Xrx. When allowed to grow further,
Six6 injected embryos developed ectopic eye-like structures in the rostral brain
and showed a transformation of the midbrain into retina. Similar results were
obtained upon overexpression of Six3 or Xsix3, revealing a possible redundance of
Six3 and Six6 activities. Taken together, results obtained suggest that during
normal retina development, the relatively late expressed Six6 gene becomes part
of a network of retinal homeobox genes that are linked together by positive
feedback loops. Furthermore, our results demonstrate that the primitive neural
ectoderm of the future midbrain and rostral hindbrain is competent to form
retinal tissue.
PMID- 10781941
TI - Smad7 is a TGF-beta-inducible attenuator of Smad2/3-mediated inhibition of
embryonic lung morphogenesis.
AB - Smad7 was recently shown to antagonize TGF-beta-induced activation of signal
transducing Smad2 and Smad3 proteins. However, the biological function of Smad7
in the process of lung organogenesis is not known. Since Smad2/3-mediated TGF
beta signaling is known to inhibit embryonic lung branching morphogenesis, we
tested the hypothesis that Smad7 regulates early lung development by modulating
TGF-beta signal transduction. An antisense oligodeoxynucleotide (ODN) was
designed to specifically block endogenous Smad7 gene expression at both
transcriptional and translational levels in embryonic mouse lungs in culture. TGF
beta-mediated inhibition of lung branching morphogenesis was significantly
potentiated in cultured embryonic lungs in the absence of Smad7 gene expression:
abrogation of Smad7 potentiated TGF-beta-mediated inhibition of lung branching
morphogenesis from 76 to 52% of the basal level in lungs cultured in the presence
of 5 ng/ml TGF-beta1 ligand. Likewise, TGF-beta1 EC(50) (concentration of TGF
beta1 that induced half maximal branching inhibition) was reduced from 5 to 1
ng/ml when Smad7 gene expression was abrogated in lung culture, indicating an
enhanced level of TGF-beta signaling in lung tissue with abolished Smad7 gene
expression. By immunocytochemistry, Smad7 protein was co-localized with both
Smad2 and Smad3 in distal bronchial epithelial cells, supporting the concept that
Smad7 inhibits TGF-beta signaling by competing locally with Smad2 and Smad3 for
TGF-beta receptor complex binding during lung morphogenesis. Furthermore,
antisense Smad7 ODN increased the negative effect of TGF-beta1 on epithelial cell
growth in developing lungs in culture. We also demonstrated that Smad7 mRNA
levels were rapidly and potently induced upon TGF-beta1 stimulation of lungs in
culture, suggesting that Smad7 regulates TGF-beta responses in a negative
feedback loop. These studies define a novel function for Smad7 as an
intracellular antagonist of TGF-beta-induced, Smad2/3-mediated inhibition of
murine embryonic lung growth and branching morphogenesis in culture. The
optimization of TGF-beta signaling during early lung development therefore
requires a finely-regulated competitive balance between both permissive and
inhibitory members of the Smad family.
PMID- 10781942
TI - Distinct role of protein phosphatase 2A subunit Calpha in the regulation of E
cadherin and beta-catenin during development.
AB - Protein phosphatase 2A (PP2A) plays central roles in development, cell growth and
transformation. Inactivation of the gene encoding the PP2A catalytic subunit
Calpha by gene targeting generates a lethal embryonic phenotype. No mesoderm is
formed in Calpha(-/-) embryos. Here, we found that during normal early embryonic
development Calpha was predominantly present at the plasma membrane whereas the
highly homologous isoform Cbeta was localized to the cytoplasm and nuclei,
suggesting the inability of Cbeta to compensate for vital functions of Calpha in
Calpha(-/-) embryos. In addition, PP2A was found in a complex containing the PP2A
substrates E-cadherin and beta-catenin. In Calpha(-/-) embryos, E-cadherin and
beta-catenin were redistributed from the plasma membrane to the cytosol.
Cytosolic concentrations of beta-catenin were low. Our results suggest that
Calpha is required for stabilization of E-cadherin/beta-catenin complexes at the
plasma membrane.
PMID- 10781943
TI - Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal
semaphorin 3A.
AB - In the developing nervous system axons navigate with great precision over large
distances to reach their target areas. Chemorepulsive signals such as the
semaphorins play an essential role in this process. The effects of one of these
repulsive cues, semaphorin 3A (Sema3A), are mediated by the membrane protein
neuropilin-1 (Npn-1). Recent work has shown that neuropilin-1 is essential but
not sufficient to form functional Sema3A receptors and indicates that additional
components are required to transduce signals from the cell surface to the
cytoskeleton. Here we show that members of the plexin family interact with the
neuropilins and act as co-receptors for Sema3A. Neuropilin/plexin interaction
restricts the binding specificity of neuropilin-1 and allows the receptor complex
to discriminate between two different semaphorins. Deletion of the highly
conserved cytoplasmic domain of Plexin-A1 or -A2 creates a dominant negative
Sema3A receptor that renders sensory axons resistant to the repulsive effects of
Sema3A when expressed in sensory ganglia. These data suggest that functional
semaphorin receptors contain plexins as signal-transducing and neuropilins as
ligand-binding subunits.
PMID- 10781944
TI - Disrupted development of the cerebral hemispheres in transgenic mice expressing
the mammalian Groucho homologue transducin-like-enhancer of split 1 in
postmitotic neurons.
AB - Transducin-like Enhancer of split (TLE) 1 is a mammalian transcriptional
corepressor homologous to Drosophila Groucho. In Drosophila, Groucho acts
together with bHLH proteins of the Hairy/Enhancer of split (HES) family to
negatively regulate neuronal differentiation. Loss of the functions of Groucho or
HES proteins results in supernumerary central and peripheral neurons. This
suggests that mammalian TLE/Groucho family members may also be involved in the
regulation of neuronal differentiation. Consistent with this possibility, TLE1 is
expressed in proliferating neural progenitor cells of the central nervous system,
but its expression is transiently down-regulated in newly generated postmitotic
neurons. Based on these observations, we investigated whether persistent TLE1
expression in postmitotic neurons would perturb the normal course of neuronal
development. Transgenic mice were derived in which the human TLE1 gene is
regulated by the promoter of the Talpha1 alpha-tubulin gene, which is exclusively
expressed in postmitotic neurons. In these mice, constitutive expression of TLE1
inhibits neuronal development in the embryonic forebrain leading to increased
apoptosis and neuronal loss in the ventral and dorsal telencephalon. These
results provide the first direct evidence that TLE1 is an important negative
regulator of postmitotic neuronal differentiation in the mammalian central
nervous system.
PMID- 10781945
TI - Identification of a C-rich element as a novel cytoplasmic polyadenylation element
in Xenopus embryos.
AB - During Xenopus early development, the length of the poly(A) tail of maternal
mRNAs is a key element of translational control. Several sequence elements
(cytoplasmic polyadenylation elements) localized in 3' untranslated regions have
been shown to be responsible for the cytoplasmic polyadenylation of certain
maternal mRNAs. Here, we demonstrate that the mRNA encoding the catalytic subunit
of phosphatase 2A is polyadenylated after fertilization of Xenopus eggs. This
polyadenylation is mediated by the additive effects of two cis elements, one
being similar to already described cytoplasmic polyadenylation elements and the
other consisting of a polycytosine motif. Finally, a candidate specificity factor
for polycytosine-mediated cytoplasmic polyadenylation has been purified and
identified as the Xenopus homologue of human alpha-CP2.
PMID- 10781946
TI - Involvement of pannier and u-shaped in regulation of decapentaplegic-dependent
wingless expression in developing Drosophila notum.
AB - In developing Drosophila notum, wingless expression is regulated by
Decapentaplegic signaling positively and negatively so that only notal cells
receiving optimal levels of Decapentaplegic signals express wingless (Sato et
al., 1999b. Development 126, 1457-1466). Here, we show evidence that this
Decapentaplegic-dependent regulation of notal wingless expression includes plural
mechanisms, involving pannier and u-shaped. In the medial notum, Pannier and U
shaped form a complex (Haenlin et al., 1997. Genes Dev. 11, 3096-3108). The
expression of pannier and u-shaped is positively regulated by Decapentaplegic
signals emanating from the dorsal-most region. The Pannier/U-shaped complex
serves as a repressor and a transcriptional activator, respectively, for wingless
and u-shaped expression. In the more lateral region, wingless expression is up
regulated by U-shaped-unbound Pannier. wingless expression is also weakly
regulated by its own signaling.
PMID- 10781947
TI - Expression and intracellular localization of mouse Vasa-homologue protein during
germ cell development.
AB - To demonstrate the cellular and subcellular localization of mouse vasa homologue
protein during germ cell development, specific antibody was raised against the
full-length MVH protein. The immunohistochemical analyses demonstrated that MVH
protein was exclusively expressed in primordial germ cells just after their
colonization of embryonic gonads and in germ cells undergoing gametogenic
processes until the post-meiotic stage in both males and females. The co-culture
of EG cells with gonadal somatic cells indicated inductive MVH expression caused
by an intercellular interaction with gonadal somatic cells. In adult testis, MVH
protein was localized in the cytoplasm of spermatogenic cells, including
chromatoid bodies in spermatids, known to be a perinuclear nuage structure which
includes polar granules that contain VASA protein in Drosophila.
PMID- 10781948
TI - A green fluorescent protein enhancer trap screen in Drosophila photoreceptor
cells.
AB - The Drosophila ommatidia contain two classes of photoreceptor cells (PR's), the
outer and the inner PR's. We performed an enhancer trap screen in order to target
genes specifically expressed in PR's. Using the UAS/GAL4 method with enhanced
green fluorescent protein (eGFP) as a vital marker, we screened 180000 flies. Out
of 2730 lines exhibiting new eGFP patterns, we focused on 16 lines expressing
eGFP in particular subsets of PR's. In particular, we describe three lines
inserted near the spalt major, m-spondin and furrowed genes, whose respective
expression patterns resemble those genes. These genes had not been reported to be
expressed in the adult eye. These examples clearly show the ability of our screen
to target genes expressed in the adult Drosophila eye.
PMID- 10781949
TI - Expression of zebrafish fkd6 in neural crest-derived glia.
AB - The zebrafish fkd6 gene is a marker for premigratory neural crest. In this study,
we analyze later expression in putative glia of the peripheral nervous system.
Prior to neural crest migration, fkd6 expression is downregulated in crest cells.
Subsequently, expression appears initially in loose clusters of cells in
positions corresponding to cranial ganglia. Double labelling with a neuronal
marker shows that fkd6-expressing cells are not differentiated neurones and
generally lie peripheral to neurones in ganglia. Later, expression appears
associated with the posterior lateral line and other cranial nerves. For the
posterior lateral line nerve, we show that fkd6-labeling extends caudally along
this nerve in tight correlation with lateral line primordium migration and axon
elongation. Expression in colourless mutant embryos is consistent with these
cells being satellite glia and Schwann cells.
PMID- 10781950
TI - Expression domains of murine ephrin-A5 in the pituitary and hypothalamus.
AB - Using in situ hybridization on whole-mounts and sections of mouse embryos we have
visualized the pattern of expression for the Eph receptor ligand ephrin-A5. Non
neuronal expression domains include the ectoderm of the branchial arches, the
ectoderm and mesenchyme surrounding the dorsal root ganglia, the intervertebral
discs, maxillary and mandibulary mesenchymal elements as well as the nasal
mesenchyme and ectoderm. Within the developing nervous system, ephrin-A5
expression is very dynamic. Besides the midbrain it is also expressed in the
hypothalamus, and the neurohypophysis that we studied here in more detail.
Hypothalamus expression of ephrin-A5 demarks distinct nuclei, persists throughout
embryonic development, and can be seen also in the adult.
PMID- 10781952
TI - A novel member of the testis specific serine kinase family, tssk-3, expressed in
the Leydig cells of sexually mature mice.
AB - We have recently characterized two members of a novel family of murine testis
specific serine kinases, tssk-1 and tssk-2, expressed exclusively in spermatids
undergoing spermiogenesis. Using a differential screening approach we have
isolated a third family member, tssk-3. The open reading frame of tssk-3 encodes
a protein of 275 amino acids, consisting essentially of a serine/threonine
protein kinase domain only. In contrast, tssk-1 and -2 have distinct,
approximately 100 amino acid domains located C-terminally to the kinase domain.
Immunoprecipitation experiments revealed that while tssk-1 and tssk-2 form
detergent resistant complexes, tssk-3 is not associated with either protein.
Expression of tssk-3 was induced at puberty, persisted during adulthood and was
restricted to the interstitial Leydig cells of post-pubertal males.
PMID- 10781951
TI - Glycosylation of phytepsin and expression of dad1, dad2 and ost1 during onset of
cell death in germinating barley scutella.
AB - Dysfunction and downregulation of dad (defending against death) has been linked
to programmed cell death (PCD) in animals and plants. As DAD is an essential
subunit of the oligosaccharyltransferase that is located in the ER membrane, the
results have raised the possibility that downregulation of N-linked glycosylation
could be involved in the regulation of PCD. Here we show that the 16 kDa subunit
of phytepsin, a vacuolar proteinase, is normally processed and glycosylated at
the onset of DNA fragmentation in germinating barley scutella. Two cDNA clones
encoding dad (dad1, dad2), and one cDNA encoding another subunit of the same
oligosaccharyltransferase complex (ost1) were isolated from barley. Northern
analysis of germinating scutella show that the expression of only dad1 is
declining before onset of DNA fragmentation. In contrast to this, the expression
of both dad2 and ost1 increase before onset of DNA fragmentation.
PMID- 10781953
TI - Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1
genes.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly
inherited renal diseases. At least two genes, PKD2 and PKD1 are implicated in the
development of this disease. Our pathogenetic studies showed that the human and
murine polycystic kidney disease (PKD) involves failure to switch out of a renal
developmental program. We have thus undertaken a detailed comparative expression
analysis of Pkd2 and Pkd1 from the morula stage to adulthood. Pkd2 expression was
detected as early as the morula and blastocyst stages as observed for Pkd1.
Strong Pkd2 expression, similar to Pkd1, was displayed in all mesenchymal and
cartilaginous tissues during mouse development. However major differences in Pkd2
expression in comparison to Pkd1 were identified. First, in contrast to Pkd1, the
neural crest cell-derived tissues displayed a low to undetectable Pkd2 expression
at all ages. Second, no increase in Pkd2 expression was detected during
mesenchymal condensation. Third, high Pkd2 expression in the kidneys was
localized mainly to the tubular epithelium of the cortical region from murine
development to adulthood.
PMID- 10781954
TI - A Drosophila group E Sox gene is dynamically expressed in the embryonic
alimentary canal.
AB - We have identified a novel Drosophila Sox-domain gene, Sox100B, related to the
vertebrate group E genes Sox9 and Sox10. In vertebrates, group E Sox genes are
expressed in the developing gonad, adult kidney and gut as well as other tissues.
During embryogenesis in Drosophila, Sox100B is expressed in two rows of large
intestinal cells, in midgut basophilic cells, in the Malpighian tubules and at
the posterior cap of gonadal mesoderm. Our observations indicate that aspects of
tissue-specific expression, as well as sequence, are conserved between vertebrate
and invertebrate group E Sox proteins.
PMID- 10781955
TI - Regional and cellular specificity of the expression of TPRD, the
tetratricopeptide Down syndrome gene, during human embryonic development.
AB - The TPRD gene (tetratricopeptide (TPR) containing Down syndrome gene) is one of
the candidate genes in the Down syndrome chromosomal region-1. Duplication of
this gene may be the cause of major phenotypic features of Down syndrome. Here we
show that the TPRD expression is developmentally regulated during human
embryogenesis. At the earliest stages of development (Carnegie 8-12) TPRD
expression is ubiquitous. At later developmental stages (Carnegie stages 14, 16
and 18), it becomes restricted to the nervous system, as is the case for the
mtprd gene during mouse development. We extended our analysis of TPRD expression
during fetal development of the human nervous system (13, 22 and 24 weeks). A new
oblique illumination technique was used to compare signal intensity and cell
density. Some regions of the nervous system such as the external cortical layers
of the brain, and the inner neuroblastic layer of the eye, strongly express the
TPRD gene.
PMID- 10781956
TI - Characterization of avian frizzled genes in cranial placode development.
AB - To determine the possible role of Wnt signaling in cranial placode development,
we have cloned several chick frizzled genes, a family of putative Wnt receptor
molecules, and analyzed their expression during chick embryogenesis. Chick
frizzled-2 (cFz-2) and frizzled-7 (cFz-7) are expressed broadly in cranial
ectoderm, tissue that is competent to express markers of the trigeminal placode
(Stark et al., 1997. Development 124, 4287-4295; Baker et al., 1999. Development
126, 147-156). In addition, cFz-2 and cFz-7 are uniquely expressed in other
cranial placodes, including the olfactory, lens, and otic placodes. Chick
frizzled-1 (cFz-1) is expressed in the lens, otic placode and, along with cFz-7,
in epibranchial placodes. Each frizzled gene expressed in the otic placode
displays a unique domain of expression: cFz-1 transcripts are detected in the
medial wall of the vesicle, cFz-2 in the rostral rim of the vesicle, and cFz-7 in
the lateral half of the vesicle. Other chick frizzled family members cloned that
do not show striking expression in cranial placodes include frizzled-4 (cFz-4),
frizzled-8 (cFz-8), frizzled-9 (cFz-9), and frizzled-10 (cFz-10). A brief summary
of their expression is given, along with a brief summary of non-placodal
expression of cFz-1, cFz-2, and cFz-7. In all, frizzled genes show dynamic
expression at key times during embryonic development, particularly in the cranial
placodes.
PMID- 10781957
TI - Cloning and expression of a novel zinc finger gene, Fez, transcribed in the
forebrain of Xenopus and mouse embryos.
AB - We have identified and cloned a novel zinc finger gene, Fez (forebrain embryonic
zinc-finger), as a potential downstream determinant of anterior neural plate
formation in Xenopus. Fez was isolated as one of several neural-specific genes
that was induced by the neuralizing factor, noggin (Smith and Harland, 1992. Cell
70, 829-840), in uncommitted ectoderm. Fez has an open reading frame comprising
466 amino acids, and contains six C(2)H(2) type zinc finger domains, which are
highly conserved among Drosophila, zebrafish, mouse, and human. In Xenopus, the
expression of Fez begins at stage 12 in the rostral end of the neural plate, and
by stage 45, it is localized to several telencephalic regions, including the
olfactory bulbs, nervus terminalis, and ventricular zone. The mouse homologue of
Fez is similarly expressed in the mouse forebrain by embryonic day 11.
PMID- 10781958
TI - Vegetal localization of the maternal mRNA encoding an EDEN-BP/Bruno-like protein
in zebrafish.
AB - Asymmetric distribution of maternal mRNAs has not been well documented in
zebrafish. Recently, we have shown that dazl mRNA is localized at the vegetal
pole. Here we report a novel zebrafish gene, bruno-like (brul), which provides
another example of vegetal mRNA localization. brul encodes an Elav-type RNA
binding protein that belongs to the Bruno-like family that includes mammalian CUG
BP, Xenopus EDEN-BP, and Drosophila Bruno. At 24 hpf, brul mRNA was abundant in
lens fiber cells. At the onset of embryogenesis, maternal brul mRNA was detected
at the vegetal pole, and it then migrated rapidly toward the blastoderm through
yolk cytoplasmic streams. During oogenesis, brul mRNA became localized at the
vegetal cortex at stage II, later than dazl mRNA. We found that anchoring of brul
mRNA was dependent on microfilaments.
PMID- 10781960
TI - Sox neuro, a new Drosophila Sox gene expressed in the developing central nervous
system.
AB - We describe the identification and detailed expression pattern of a second
Drosophila Sox gene, SoxNeuro (SoxN), highly related to mammalian group B Sox1,
2, 3 genes. SoxN is expressed in a highly dynamic pattern during embyogenesis,
being associated with the development of the central nervous system (CNS), from
the early steps onwards. We present strong evidence that the early SoxN
neuroectoderm expression is controlled by the zygotic dorso-ventral patterning
genes (dpp, sog, brk, twi).
PMID- 10781959
TI - The HMG-box transcription factor XTcf-4 demarcates the forebrain-midbrain
boundary.
AB - A small subfamily of HMG-box transcription factors, the LEF/TCF group, serves as
nuclear transducer of the Wnt-1/Wg signaling cascade. Upon Wnt-1/Wg signaling
their members interact with beta-catenin and regulate the expression of Xenopus
target genes siamois, twin, nodal related-3 or fibronectin. We have isolated a
new HMG-box transcription factor in Xenopus that will be addressed XTcf-4 based
on its homology to human and murine Tcf-4. Unlike XTcf-3, which is a maternal
gene, and XLef-1 that is expressed after mid blastula transition (Molenaar et
al., 1998. Mech. Dev. 75, 151-154), XTcf-4 expression starts at late neurula
stage and is restricted to the anterior most midbrain demarcating the forebrain
midbrain boundary. The expression partially overlaps with a broad set of Xenopus
Wnt family members in distinct patterns. XTcf-4 transcripts were also found
partially co-localized with those of Xaxin, an intracellular antagonist of Wnt
1/Wg signaling.
PMID- 10781961
TI - Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly
expressed in the developing and adult central nervous system.
AB - Formin-1 is the founding member of a family of genes of emerging biological and
medical importance that share specific domains of homology, allowing them to be
classified together as the formin homology proteins. Although deficiency
mutations in formin-1 lead to profound developmental defects in limb and kidney
formation, similar deficiency mutations in more distantly related members of this
family (diaphanous and cappuccino in Drosophila and BNI1 in yeast) have
ostensibly unrelated phenotypes. Here we describe murine and human formin-2
(Fmn2), a gene which bears a high degree of similarity to formin-1 and
cappuccino. The mouse gene, which encodes a putative 1567-amino-acid open reading
frame and maps to mouse Chromosome 1, is expressed almost exclusively in the
developing and mature central nervous system. Expression begins at embryonic day
9. 5 in the developing spinal cord and brain structures and continues in neonatal
and adult brain structures including the olfactory bulb, cortex, thalamus,
hypothalamus, hippocampus and cerebellum. Human formin-2 has a similar expression
pattern.
PMID- 10781962
TI - Xerl: a novel secretory protein expressed in eye and brain of Xenopus embryo.
AB - A novel gene, Xerl (Xenopus EGF-like repeat with laminin-G domain protein) was
isolated from a Xenopus head cDNA library prepared from tailbud. This gene
encoded 779 amino acids including a potential signal sequence, twelve EGF-like
repeats, a laminin-G domain, a RGD sequence and a VWF motif. In the EGF-like
repeat and the laminin-G domain, Xerl showed similarity to those of Drosophila
Crumbs, respectively. Zygotic expression of Xerl began at late gastrula, and
increased through neurula up to the tailbud stage. In adult organs, Xerl was
detected in brain and eye. Whole-mount in situ hybridization showed that Xerl
expression occurred first in the anterior bilateral region of neurula and
gradually localized to retina and forebrain and boundaries of midbrain and
hindbrain.
PMID- 10781963
TI - A century of change - a future of challenge.
PMID- 10781964
TI - Contraception - consumer perspectives; past, present and future.
PMID- 10781965
TI - Estimating the balance of general practice versus family planning clinic coverage
of contraception services in London.
AB - OBJECTIVE: To compare levels of provision of contraception from general practice
and family planning clinics for the populations of the 32 London Boroughs.
METHOD: Retrospective analysis of routine activity data, including the estimated
numbers of first attendance, for 295 family planning clinics (managed by 28 NHS
Trusts) and more than 1800 GP partnerships in Greater London, supplemented by
data from a survey of family planning clinics. The results were expressed as the
estimated percentage of women aged 16-49 obtaining advice on contraception from
GPs and family planning clinics. These results were compared to those expected
based on results in the General Household Survey. RESULTS: Across London in
1995/96, 12% of women aged 16-49 obtained contraception services from family
planning clinics, and 24% obtained contraception services from a GP. At a borough
level there was variation from 11% to 25% in coverage by family planning clinics,
and from 11% to 41% in coverage by GPs. Estimates of the proportion of women in
this age group not using NHS-provided medical or surgical contraception ranged
from 0 to 30%. Across all boroughs, there was no consistent relationship between
levels of GP activity and family planning clinic activity. CONCLUSION: The
results indicate substantial variations between boroughs in the proportion of
women using NHS-provided medical or surgical methods of contraception. The
absence of any clear inverse relationship between activity in family planning
clinics and activity in general practice suggests that changes to one will not be
compensated by changes in the other. More specifically, health authorities that
opt to purchase lower levels of family planning clinic activity cannot assume
that women may opt to use GPs as an alternative. Such a strategy may increase the
likelihood that women who would have used family planning clinic services will
either not use contraception at all, or will use less effective 'over the
counter' methods.
PMID- 10781966
TI - Quality of information on emergency contraception on the Internet.
AB - OBJECTIVE: To evaluate the quality of patient information about emergency
contraception on the Internet. DESIGN: We performed an on-line search of the
Internet and found relevant World Wide Web sites by combining the key phrases
'emergency contraception' and 'patient information' in two Web subject guides and
two search engines. We defined quality as the extent to which the characteristics
of a Web site satisfied its stated and implied objectives. Our assessment focused
on credibility and content of each Web site. Credibility was assessed by source,
currency and editorial review process and content of Web site was assessed by
hierarchy and accuracy of evidence. RESULTS: Our search revealed 32 relevant Web
sites, none of which complied with all of the criteria for quality of credibility
and content. Twenty-eight Web sites displayed the source clearly, 17 Web sites
showed currency, and none of the Web sites had an editorial review process. Only
six of the 32 sites mentioned hierarchy of evidence. None of the Web sites
depicted all the criteria for accuracy of contents. CONCLUSION: None of the Web
sites provided complete information to patients about emergency contraception
according to the quality criteria used in this study. As previous studies have
shown, people need to be wary about the quality of information on the Internet.
PMID- 10781967
TI - Sexual and reproductive rights: statements, rhetoric and responsibilities.
AB - The current international movement for the promotion of reproductive health has
great potential for improving sexual and reproductive rights. Health
professionals should play a major role in applying international human rights
instruments at the country level. Being at the front line of service delivery,
health professionals have a duty to ensure that those rights are articulated in
routine care by empowering individuals, lobbying for legislation, promoting
policies and reporting violations of human rights treaties.
PMID- 10781968
TI - Depo provera discussion paper on clinical care, effectiveness and side effects
AB - Recent changes to the health services have led to an increased provision of
clinical care in family planning clinics. While some women may only require
contraceptive services, others may demand advice on a breadth of lifestyle
issues, including diet and nutrition. Obesity affects 17% of women of
childbearing age in Scotland and being overweight during pregnancy has
significant health risks. A postal survey of 227 nurses identified as working in
family planning clinics in Scotland was conducted in 1998. After a mail shot and
one reminder, a net response rate of 64% (n = 145) was achieved. Overall, it was
found that obesity was perceived as the most extensive problem in women of
childbearing age. Seventy nurses (48%) reported that, in addition to offering
family planning services, they gave dietary advice 'frequently' or 'always' to
their clients without being asked. There were differences in nutrition-related
activities in consultations between nurses offering family planning services only
and those who routinely offered nutritional advice. Over half (61%) of the nurses
reported that they would give advice regarding weight management even if the
patients were not seeking help, although there was no significant difference
between the two comparison groups. In some cases, the nutritional advice offered
to clients highlighted a deficit in training. Most nutrition education came from
diploma and/or training courses and scientific literature, followed by
'experience'. Those nurses already embracing a nutritional advice and guidance
role were more interested in further nutrition training (p = 0.018) than the
other nurses. However, overall, 67% of the nurses wished to train further in
nutrition and weight management. The findings suggest that family planning nurses
should be supported to develop nutritional advice and guidance skills, and that
there is a pressing need for training in public health nutrition and weight
management for nurses working in family planning services.
PMID- 10781969
TI - 'CE-Marking' on contraceptive devices: what does it mean?
PMID- 10781970
TI - Contraceptive devices and the medical devices directive.
AB - The Medical Devices Agency (MDA), an executive agency of the Department of
Health, has responsibility for the safety of medical devices within the UK. The
MDA is responsible for enforcing the European Medical Devices Directive (MDD)
within the UK. Contraceptive devices such as copper-containing IUDs and condoms
are regulated by the MDD, and this brief report is an introduction to it.
PMID- 10781971
TI - Endoscopy--40 years since fiber optics. Any light at the end of the tunnel?
PMID- 10781972
TI - Abdominal stoma fashioned by a used circular stapler.
AB - A method of application of a used circular stapler in abdominal stoma formation
is described. The procedure is rapid, simple, carries less tissue trauma than the
conventional methods and does not involve any additional cost. It allows for a
precise circular aperture in the abdominal wall which may be optimally adjusted
to the bowel diameter. This method seems to minimize the occurrence of stomal
complications and particularly the incidence of troublesome parastomal hernias.
PMID- 10781973
TI - Differences between experts and trainees in the motion pattern of the dominant
upper limb during intracorporeal endoscopic knotting.
AB - BACKGROUND: Very little research has been carried out on the ergonomics of
surgeon-instrument interface. The aim of this study is to investigate the effect
of experience on the motion pattern of the dominant upper limb during endoscopic
intracorporeal knot tying. METHODS: Two groups of 5 surgeons (expert consultants
and higher surgical trainees) tied 360 surgeon's knots inside an endoscopic
trainer in a random sequence. Motion analysis at the elbow and shoulder joints of
the dominant upper limb was carried out using 3-dimensional kinemetrix system.
Each knot was distracted using a tensiometer. The endpoints were the execution
time, knot quality score, angular velocity and range of movement. Kruskal-Wallis
one-way analysis of variance and Mann-Whitney U test were used for analysis.
RESULTS: The expert group had a better knot quality score (p < 0.005) and shorter
execution time (p < 0.0001) than beginners. Motion analysis at the shoulder joint
showed that experts had a higher angular velocity (p < 0.05) and a wider range of
movement with more adduction (p < 0.01) compared to beginners. No significant
differences were found at the elbow. CONCLUSION: The better task performance by
expert surgeons is associated with controlled rapid manipulations and a wider
range of movement at the shoulder joint of the dominant upper limb.
PMID- 10781974
TI - Seromuscular enteric pedicles and prosthetic aortic graft complications in a
porcine abdominal trauma model. An experimental study.
AB - BACKGROUND/AIMS: Abdominal vascular trauma may require prosthetic grafting
despite peritoneal contamination by concurrent visceral injury. This study tested
the use of vascularized, seromuscular enteric pedicles (VSEP) against the
development of vascular prosthetic complications, in a porcine abdominal trauma
model. METHODS: Eight pigs underwent aortic transection and reconstruction with a
Dacron interposition graft (DIG). A standard bacterial inoculum soaked the DIG in
situ. An enteric segment was isolated on its mesenteric pedicle, and the mucosa
stripped. This VSEP was wrapped around the DIG and oversewn. Animals received
antibiotics for 5 days. Endpoints were 2-week survival, or evidence of sepsis.
The animals underwent explantation of the DIG, VSEP, and native aorta for the
purposes of histological, and microbiological analyses, and scanning electron
microscopy (SEM). Outcome measures were graft infection, graft thrombosis, tissue
incorporation, and anastomotic integrity. RESULTS: Two pigs were excluded for
perioperative death. All study group animals (n = 6), survived 2 weeks. Infection
and thrombosis were found in 0/6 (0%). Incorporation and anastomotic integrity
were evident in 6/6 (100%). VSEP had intact blood supplies. SEM demonstrated
viable muscle, microcirculation, and fibroplasia in VSEP. CONCLUSION: We conclude
that VSEP may help prevent prosthetic graft complications in the contaminated
setting.
PMID- 10781975
TI - Perforated gastric ulcer.
AB - BACKGROUND/AIMS: Reports about perforated gastric ulcer are scarce and thus it is
difficult to settle for a uniform model of operative management. The purpose of
the study was to review our experience with perforated gastric ulcer and evaluate
the results of gastric resection vs. oversewing of the perforation. METHODS:
Within 36 years 77 patients with peritonitis caused by histologically confirmed
perforated gastric ulcer were operated. Furthermore, in another 7 microscopic
examination revealed that perforation occurred within the gastric cancer. There
were twice as many male as female patients. RESULTS: Recently, the overall
postoperative mortality (20. 8%) tended to decrease markedly. 32 patients (mean
age 49.9 years) were submitted to gastric resection and this procedure was
associated with 2.9% mortality. All 3 subjects in whom vagotomy, pyloroplasty and
wedge resection of the ulcer had been performed survived. In 40 patients (mean
age 61.5 years) only a suture of the ulcer was performed. This procedure was
associated with high mortality (1/3 of patients died). Selection criteria
included poor general medical status, age, comorbidities, and substantial
progression of the inflammatory process. CONCLUSION: Authors believe that
emergency gastrectomy is a safe procedure; however, it might be performed without
excessive operative risk in only half of the patients.
PMID- 10781976
TI - Hepatectomy using an ultrasonically activated scalpel for hepatocellular
carcinoma.
AB - BACKGROUND: The first retrospective studies were performed to compare the
efficacy of the ultrasonic cavitational aspirator (aspirator group) and the
ultrasonically activated scalpel (scalpel group) for hepatic resection in
patients with hepatocellular carcinoma. PATIENTS AND METHODS: The aspirator group
consisted of 8 patients (6 with liver cirrhosis and 2 with chronic hepatitis in
the nontumorous liver), and the scalpel group of 7 patients (6 with liver
cirrhosis and 1 with chronic hepatitis). All patients underwent limited hepatic
resection, and the intermittent Pringle maneuver was applied during hepatic
transection. RESULTS: There were no significant differences in preoperative
hepatic function, type of hepatectomy, tumor size and maximum cross-sectional
area of the resected specimen between the 2 groups. The amount of intraoperative
blood loss was significantly less in the scalpel group than in the aspirator
group (684 versus 1,859 ml, p < 0.05). The operation time was significanly
shorter in the scalpel group than in the aspirator group (176 versus 262 min, p <
0.05). There were no significant differences in postoperative liver function and
morbidity between the 2 groups. CONCLUSIONS: The ultrasonically activated scalpel
is effective in reducing blood loss and in shortening the time of operation, and
can be employed during limited resection of the liver with cirrhosis or chronic
hepatitis.
PMID- 10781977
TI - A continuing role for surgical bypass in the palliative treatment of pancreatic
carcinoma.
AB - BACKGROUND: The use of palliative surgery for irresectable pancreatic cancer has
been challenged by the advent of non-operative stenting, but it may still be
appropriate for selected patients. METHODS: Single-loop biliary and gastric
bypass was carried out in 56 patients (mean age 60 years) with carcinomas of the
pancreatic head that were irresectable because of vascular invasion or distant
spread. In 42 patients without a preoperative tissue diagnosis, ductal carcinoma
was confirmed by biopsy of the primary (n = 20) or secondary (n = 22) tumour.
Preoperative biliary decompression in 31 patients led to positive bile cultures
in 22 of 24 patients sampled. RESULTS: There were no deaths in hospital or within
30 days. Complications in 20 patients (35%) included three biliary leaks, two of
which required temporary percutaneous stents. The median postoperative hospital
stay was 14 days. No re-operations were required before death, though 2 patients
required percutaneous stenting of the biliary anastomosis for recurrent jaundice,
1 of whom had a radiation-induced stricture. The median survival was 6 (range 2
21) months. CONCLUSION: Combined biliary and gastric bypass can be carried out
with reasonable safety and remains a useful option for patients with potentially
resectable tumours and an anticipated life expectancy of at least 6 months.
PMID- 10781978
TI - Poor outcome of a defunctioning stoma after pouch construction for ulcerative
colitis.
AB - BACKGROUND: Restorative proctocolectomy for ulcerative colitis can have
complications necessitating a later defunctioning ileostomy with uncertain
outcome. This analysis was undertaken to assess the outcome in patients needing a
later defunctioning ileostomy after pouch construction in patients with
ulcerative colitis. METHOD: The notes of our series of 154 patients who underwent
restorative proctocolectomy and ileal pouch-anal anastomosis for ulcerative
colitis were reviewed and 28 patients identified who needed a later defunctioning
ileostomy to deal with complications. RESULTS: A later defunctioning ileostomy
was necessary in 28 patients to deal with the following complications: sepsis in
11 patients (5 pouches failed), fistulas in 7 (5 pouches failed), poor function
including ileoanal stenosis in 5 (all 5 failed), postoperative intraabdominal
bleeding in 2 (both saved), pouchitis in 2 (1 excised) and small bowel
obstruction in 1 (saved). 16 pouches were eventually excised or permanently
defunctioned (59%). CONCLUSION: Complications necessitating a later defunctioning
stoma after pouch construction carry a poor prognosis, especially when used for
ileoanal stenosis and fistulae.
PMID- 10781979
TI - Three-year evaluation of a rapid-access coloproctology clinic.
AB - BACKGROUND/AIMS: Evolving surgical practice has placed increasing pressures on
surgical outpatient clinics. This article provides a prospective evaluation of a
rapid-access coloproctology clinic over a 3-year period. METHODS: Primary care
physicians (PCP) were circulated details of the clinic, and invited to refer any
patient presenting with colorectal or anorectal symptoms, or with a family
history of bowel cancer wishing advice about screening. Data were collected
prospectively and patients and the referring PCPs were invited to complete a self
administered structured questionnaire. RESULTS: In all, 3,119 patients were
referred, the main indications being rectal bleeding (67%), abdominal pain (16%)
and change in bowel habit (15%). The average time interval between PCP visit and
specialist consultation was 2 days and neoplastic disease was detected in 7.1% of
patients. 70% of patients with haemorrhoids and 39% of those with other minor
diseases were discharged back to their PCPs after definitive treatment at the
time of their visit to the clinic. The majority of PCPs and patients expressed
satisfaction with the service as evidenced by the returned questionnaires.
CONCLUSION: These data show that a more universal implementation of such clinics
may result in improved care of colorectal disease and considerable savings of
outpatient time and resources.
PMID- 10781980
TI - Effects of perioperative treatment with TNP-470 on the resistance of colonic
anastomoses in rats.
AB - AIMS: The present study was designed to evaluate the effects of perioperative
treatment with TNP-470 on the resistance of colonic anastomoses. TNP-470 is a
drug that was developed as an inhibitor of angiogenesis. METHODS: A colonic
anastomosis was constructed in Sprague-Dawley rats. From 4 days before surgery to
4 days afterwards, each animal received daily intraperitoneal treatment that
differed according to the group to which it belonged: the control group, which
received gum arabic, or the TNP group, which received 30 mg/kg TNP-470 in gum
arabic. The size of the cecum and the diameters of the pre-anastomotic and post
anastomotic colon were measured at operation and 4 days after surgery, when all
animals were sacrificed. At this time the presence of adhesions was also
investigated. Each segment containing an anastomosis was removed and the bursting
pressure (BP) and bursting wall tension (BWT) were determined. RESULTS: Loss of
cecum caliber and decreases in pre-anastomotic diameter were significantly
greater in the TNP group than in the control group (p = 0.017 and p = 0.004,
respectively). Dilatation and obstruction of the colon were more frequent in the
control group, but the difference between the groups was significant only with
respect to dilatation (p = 0.005). Moreover, loss of body weight was greater in
the TNP group than in the control group (p < 0.001). BP and BWT were
significantly lower in animals that had received TNP-470 (p = 0.04 and p = 0.005,
respectively). With respect to post-anastomotic diameter, general adhesions and
adhesions to the anastomotic line, there were no statistically significant
differences between the groups. CONCLUSIONS: Perioperative treatment with TNP
470, an inhibitor of angiogenesis, affects the healing and reduces the resistance
of colonic anastomoses.
PMID- 10781981
TI - Acute abdomen and Clostridium difficile colitis: still a lethal combination.
AB - BACKGROUND: With the steadily prevalent appropriate and inappropriate use of
antimicrobial agents, Clostridium difficile colitis has continued to be noticed
as a common problem in hospitalized patients. The aim of this communication is to
highlight a subset of C. difficile colitis patients who presented with an acute
abdomen. METHODS: This is a retrospective study of 10 patients who underwent
laparotomy for an 'acute abdomen' with an intraoperative or postoperative
diagnosis of C. difficile colitis. RESULTS: All patients received antibiotics
(mean 9.5 days) for other illnesses. The mean APACHE II score was 18.8 (range 8
25) and the mortality rate was 80%. Two patients had colostomies created. One
patient underwent a subtotal colectomy, and another underwent a Hartmann
procedure; the rest had a nontherapeutic procedure. CONCLUSION: We conclude that
C. difficile colitis presenting as an 'acute abdomen' still represents a lethal
entity. Patients who present with an 'acute abdomen', with a history of recent or
current antibiotic intake, and without findings which mandate an exploration
should have C. difficile colitis urgently excluded. Timely diagnosis of C.
difficile colitis through bedside sigmoidoscopy or a CT scan could spare the
critically ill patient an unneccessary and risky operation. Furthermore, if
laparotomy is subsequently needed then having a preoperative diagnosis of C.
difficile colitis will allow appropriate surgical therapy to be implemented.
PMID- 10781983
TI - A case of trans-omental hernia: an incarcerated bowel condition detected by
computed tomography.
PMID- 10781982
TI - Cost-effectiveness study of imipenem/cilastatin versus meropenem in intra
abdominal infections.
AB - BACKGROUND: The efficacy of two carbapenems, imipenem/cilastatin (I/C, 1.5 g
daily) versus meropenem (3 g daily) in intra-abdominal infections was assessed in
a recent multicenter randomized clinical trial. The aim of this article is to
perform a cost-effectiveness analysis as in real-world practice according to the
findings of this clinical trial. METHODS: A decision tree was used to estimate
the clinical outcomes and direct costs of treating intra-abdominal infections
using the two carbapenems from the perspective of the Italian National Health
Service (INHS) or a private insurance company (PIC). RESULTS: In a population of
30,000 patients with intra-abdominal infections in Italy, it was estimated that
97 potential deaths/year could be avoided if these patients were treated with I/C
versus meropenem. In addition, from the perspective of INHS, the total costs of
treatment were estimated as ITL 106,874 million and 134,042 million for I/C and
meropenem, respectively. In favor of the PIC point of view, the total costs were
estimated as ITL 110,500 million and 135,899 million for I/C and meropenem,
respectively. CONCLUSION: The treatment of intra-abdominal infections with I/C is
shown to be more effective (97 deaths avoided/year) and less costly than with
meropenem (with a saving of ITL 27,168 and 25,399 million/year for INHS and PIC,
respectively).
PMID- 10781985
TI - Safe laparoscopic cholecystectomy in the presence of a cholecysto-enteric
fistula.
PMID- 10781984
TI - Gallstone disease masking malignant bile duct tumors: a rare but important
coincidence.
PMID- 10781986
TI - Spontaneous spleen rupture after bacterial endocarditis.
PMID- 10781987
TI - Splenic autotransplantation in Gaucher's disease.
PMID- 10781988
TI - Tuberculosis of the pancreas presenting as metastatic pancreatic carcinoma. A
case report and review of the literature.
PMID- 10781989
TI - Hydatid cyst of the pancreas.
AB - A rare case of hydatid cyst of the pancreas is reported. Although ultrasonography
and computerised tomography scan confirmed the presence of a cystic mass in the
body and tail of the pancreas, diagnosis was made only on laparotomy. A distal
pancreatectomy was done and the diagnosis of hydatid cyst of the pancreas was
confirmed by histopathology. Though very rare, pancreatic hydatidosis should be
considered in the differential diagnosis of cystic lesions of the pancreas in the
appropriate epidemiological setting.
PMID- 10781990
TI - Hyperintense basal ganglia on T1-weighted magnetic resonance images following
postoperative parenteral nutrition in a pancreatoduodenectomized patient.
AB - The authors reported the magnetic resonance imaging (MRI) detection of manganese
(Mn) deposition in the basal ganglia of a pancreatoduodenectomized patient
following 30-day parenteral nutrition. A multi-trace element supplement solution
including 20 micromol Mn/day was parenterally administered for 30 days
postoperatively. The serum level of total bilirubin normalized on the 3rd
postoperative day, while the level of alkaline phosphatase continued to exceed
the higher limit of normal controls even 2 months after operation. T1-weighted
MRI on the 49th postoperative day demonstrated bilateral and symmetrical
hyperintense lesions in the globus pallidus. The whole-blood Mn level on the 67th
postoperative day was 3.1 (normal range 0.8-2.5) microg/l. T1-weighted MRI on the
103rd postoperative day revealed improvement in the hyperintense lesions, and MRI
on the 225th postoperative day revealed no abnormality. The blood Mn level
normalized on the 194th postoperative day. Even short-term postoperative
parenteral nutrition may result in Mn deposition in the brain, especially in
patients with cholestasis following pancreatoduodenectomy.
PMID- 10781991
TI - Anorectal avulsion: an unusual rectal injury.
AB - Traumatic injuries to the rectum although uncommon can result in virulent
complications and even death. Diverting colostomy, presacral drainage, distal
wash out and rectal repair, when feasible, have become the standard treatment for
rectal injuries. We report an unusual case of rectal injury resulting in
anorectal avulsion from skin and surrounding tissues.
PMID- 10781992
TI - Malignant melanoma of the anorectal area. Report of two cases.
AB - BACKGROUND/AIMS: Primary anorectal melanoma is a very rare malignant tumor with
no more than 300 cases reported in the literature. METHODS: Two cases of
anorectal melanoma are reported herein. RESULTS: Both patients, aged 44 and 74
years, presented at the outpatient department with anal bleeding, one after being
treated for 3 months with antihemorrhoidal drugs. The diagnosis was established
with proctoscopy and biopsy, and a palliative abdominoperineal resection in the
presence of lymph node metastases was performed followed by chemotherapy with
vindesine. Although the procedures were not curative, both patients had an
uneventful postoperative recovery, and lived 4 years and 21 months, respectively,
without bleeding problems albeit with the inconvenience of a colostomy.
CONCLUSIONS: For the time being there is no convincing proof of the value of
either types of proposed surgical management. We agree with those who believe
that abdominal perineal resection has an advantage regarding the prognosis and
quality of life.
PMID- 10781993
TI - Fecal impaction causing megarectum-producing colorectal catastrophes. A report of
two cases.
AB - PURPOSE: Massive fecal impaction leading to surgical catastrophes has rarely been
reported. We present 2 such patients to remind physicians that neglected
accumulation of fecal matter in the rectum may lead to ischemia and perforation
of the colon and rectum. METHODS: Report of 2 patients and a MEDLINE search of
the literature. RESULTS: In the 1st case massive fecal impaction produced an
abdominal compartment syndrome and rectal necrosis. In the 2nd patient fecal
impaction resulted in colonic obstruction and ischemia. In both, an operation was
life-saving. CONCLUSION: Neglected fecal impaction may lead to a megarectum
causing an abdominal compartment syndrome and colorectal obstruction, perforation
or necrosis. Measures to prevent fecal impaction are of paramount importance and
prompt manual disimpaction before the above complications develop is mandatory.
Appropriate operative treatment may be life-saving.
PMID- 10781994
TI - Continuous monitoring of fetal pH, pO(2) and pCO(2) using a fiberoptic
multiparameter sensor in animal models reproducing in utero conditions.
AB - OBJECTIVES: To evaluate the feasibility and accuracy of continuous fetal
monitoring with a multiparameter intravascular sensor (MPIS) in animal models
mimicking the fetal metabolic status. METHODS: First, the accuracy of the MPIS in
hypoxic conditions was tested in adult rabbits (n = 6). The carotid artery (n =
4) or vein (n = 2) was catheterized with a 20-gauge cannula, housing a 500-microm
Neotrend((R)) fiberoptic sensor for pCO(2), pO(2), pH and temperature. Fiberoptic
readings were compared with arterial blood-gas (ABG) analyses. Secondly, the
feasibility of continuous fetal fiberoptic sensing was tested during experimental
fetoscopic surgery in lambs (n = 4). An identical sensor was introduced in a
chorionic artery and readings were compared to ABG analyses of fetal blood
samples. RESULTS: The overall bias and precision in the first experiment (147
measurement pairs) were -4.2 and 10.9 mm Hg for pO(2), +1.6 and 8.2 mm Hg for
pCO(2) and -0.015 and 0.031 for pH, respectively. In the sheep experiments,
continuous readings for all parameters were only available during 50% of the
operation time, mainly due to disturbances induced by movement, contact with
vessel wall and interference by endoscopic light. 20 sample pairs were obtained
resulting in an overall bias and precision of -3.9 and 4.3 mm Hg for pO(2), -0.74
and 3.68 mm Hg for pCO(2) and -0.0032 and 0. 02 for pH. CONCLUSIONS: Fiberoptic
microsensors are potentially useful for monitoring acid-base status in the low
pO(2) range present in fetal life.
PMID- 10781995
TI - B19 parvovirus-induced fetal hydrops:good outcome after intrauterine blood
transfusion at 18 weeks of gestation.
AB - We report a successful treatment of a B19 parvovirus-induced fetal hydrops
diagnosed at 16 weeks of gestation. This disease could be corrected by means of a
unique intraperitoneal blood transfusion performed at 18 weeks, once diagnosis
was established. The delivery occurred at 36 weeks, leading to the birth of a
healthy baby. This case suggests that transfusion should be attempted, as the
spontaneous fetal recovery remains uncertain and shows that intraperitoneal blood
transfusion is an effective therapeutic option of the B19 parvovirus-induced
anemia, in the absence of a viral myocarditis.
PMID- 10781997
TI - Contrast-enhanced ultrasonography of uteroplacental circulation does not evoke
harmful CTG changes or perinatal events.
AB - OBJECTIVE: To determine whether an intravascular ultrasound contrast agent used
in the examination of uteroplacental circulation in late pregnancy has any effect
on fetal cardiotocographic (CTG) parameters or fetal well-being. METHODS: The
uteroplacental circulation of 69 women with singleton third trimester pregnancies
was examined by power Doppler with contrast agent (Levovist((R)); Schering AG,
Berlin, Germany) enhancement. Computed CTG examination using Dawes/Redman
criteria was recorded just before and after ultrasonographic examination in 25
subjects examined with contrast agent and in 15 control patients who were given
only physiological saline injection during ultrasonography. Umbilical artery
blood flow velocity waveform was examined in 15 subjects before and 5 min after
maternal contrast agent injection. Obstetric outcome of all the 69 subjects was
evaluated by birthweight, placental weight, fetal and neonatal distress, prenatal
hemorrhages, cord arterial and venous blood pH and macroscopic placental
examination. RESULTS: No apparent fetal or maternal harmful effects caused by the
contrast-enhanced ultrasonography were observed. In CTG examination there was a
statistically significant increase in the number of accelerations and fetal
movements and in short-term variation after administration of the contrast agent
in both subjects and controls. There were no significant changes in the umbilical
artery blood flow velocity waveform after administration of the contrast agent.
CONCLUSIONS: Contrast agent enhancement in the examination of uteroplacental
circulation does not produce any harmful fetal or placental effects in late
pregnancy. Ultrasonographic examination itself, obviously due to maternal stress
reaction, is associated with a slight activation of fetal behavioral status.
PMID- 10781996
TI - Hepatic mesenchymal hamartoma associated with mesenchymal stem villous
hyperplasia of the placenta.
AB - A rare case of prenatally diagnosed hepatic mesenchymal hamartoma associated with
mesenchymal stem villous hyperplasia of the placenta is presented and the
literature reviewed. The placenta was noticed to have multiple cysts at 16 weeks'
gestation and elevated maternal serum alpha-fetoprotein was present. Cystic liver
masses were first detected in the fetus at 34 weeks' gestation. The liver mass
showed a progressive enlargement during the third trimester and after birth,
necessitating extended left hepatic trisegmentectomy at 3 months of age.
Histological examination established the diagnosis of mesenchymal hamartoma of
the liver and mesenchymal stem villous hyperplasia of the placenta. This is the
first report of this association in which both lesions were diagnosed in utero
and confirmed by histology after delivery. The likely pathogenesis of these
strikingly similar lesions is discussed.
PMID- 10781998
TI - Prenatal diagnosis and elective termination of neural tube defects in Hawaii,
1986-1997.
AB - OBJECTIVE: To determine the influence of various factors on the prenatal
diagnosis and elective termination of neural tube defects (NTDs) in Hawaii in
1986-1997. METHODS: Data from a birth defects registry were analyzed and included
245 cases. RESULTS: 74% of the cases were prenatally diagnosed and 48% were
terminated. Anencephaly was more likely to be prenatally diagnosed and electively
terminated than spina bifida or encephalocele. Other factors such as maternal
age, race/ethnicity, place of residence, and elevated maternal serum alpha
fetoprotein influenced the prenatal diagnosis and/or elective termination of NTD
affected pregnancies. However, a given factor may influence prenatal diagnosis
and elective termination in different ways. CONCLUSIONS: Various diagnostic and
demographic factors can influence the prenatal diagnosis and the subsequent
termination of NTD-affected pregnancies.
PMID- 10781999
TI - In utero diagnosis of trichothiodystrophy by endoscopically-guided fetal eyebrow
biopsy.
AB - OBJECTIVE: To describe the prenatal diagnosis of trichothiodystrophy (TTD)
through endoscopically-guided fetal eyebrow biopsy. MATERIALS AND METHODS: A 32
year-old patient, gravida 4, para 3, with a history of 2 previous infants
affected with TTD was referred at 17(5)/(7) weeks for fetal hair biopsy. DNA
repair studies had been normal in the previous children. Four 1-mm biopsies were
obtained from the external aspect of the fetal eyebrows under direct endoscopic
guidance. Fetal hair samples were assessed with polarized microscopy, electron
microscopy, hematoxylin and eosin staining, and were also sent for analysis of
sulfur content (cystine levels). RESULTS: The fetal eyebrows were the only
adequate source of hair in the early second trimester. The biopsy samples yielded
adequate material for all tests. Polarized microscopy showed characteristic
banding patterns, but trichoschisis was not apparent. Cystine levels (19
micromol/l) in the biopsy sample were significantly lower than an age-matched
(fresh spontaneous abortion) control (368 micromol/l). CONCLUSION: Prenatal
diagnosis of TTD is possible in the second trimester through endoscopically
guided eyebrow biopsy. An adequate amount of hair is present in the eyebrows by
then, and the disease is already manifest. Analysis of sulfur content of the hair
samples is preferred over polarized or electron microscopy, as many classic
microscopic findings of TTD may not be present in the early second trimester.
PMID- 10782001
TI - Correlation of Doppler velocimetry findings in twin pregnancies including course
of pregnancy and fetal outcome.
AB - OBJECTIVE: Subject of the study was the significance of umbilical artery Doppler
velocimetry findings for the further course of pregnancy and fetal outcome in
cases of twin pregnancies. METHODS: In 206 cases of twin pregnancy, the umbilical
artery was examined using Doppler velocimetry in the median 9 days prior to
delivery, and the result was correlated with the further course of pregnancy and
fetal outcome. 174 pregnancies showed normal Doppler findings of the umbilical
artery (group A), 32 twin pregnancies showed pathological Doppler findings of at
least one twin (group B). The median of the maternal age and the parity between
the groups were not different. RESULTS: In group B (pathological Doppler
findings), intrauterine growth retardation and pre-eclampsia occurred 5 times
more often than in group A (normal Doppler findings). The total rate of cesarean
sections was not different between the study populations; the rate of deliveries
by cesarean section in group B was significantly increased by a factor of 2.4 due
to a pathological CTG. The median birth weight and the gestational age at birth
were significantly lower in group B (1,660 g; 35 weeks) as compared to group A
(2,460 g; 37 weeks; p<0.001). In group B, the rate of premature deliveries up to
reaching the 34th week of gestation was 3. 4 times higher; the rate of SGA
newborns was 6.3 times higher. Perinatal mortality was increased by a factor of
1.5 in group B compared to group A. CONCLUSION: The Doppler velocimetry findings
have considerable effects on the further course of a multiple pregnancy. In case
of pathological Doppler findings, early hospitalization and close monitoring of
the pregnancy should be performed. In cases of additional pathological findings
(maternal illness, pathological Doppler findings of fetal blood vessels),
termination of the pregnancy has to be considered.
PMID- 10782000
TI - Detection of skin over cysts with Spina bifida may be useful not only for
preventing neurological damage during labor but also for predicting fetal
prognosis.
AB - Spina bifida is one of the most common open neural tube defects. There are two
common types of spina bifida cystica, myelomeningocele and meningocele. Special
attention to the thickness of the cystic sac (presence of intact skin and
subcutaneous tissue) on magnetic resonance imaging is advantageous for
determination of whether the child will profit from cesarean section in order to
prevent neurological change (infection and drying of nerve tissue) and for
management of spina bifida (most meningocele) during the perinatal period.
Furthermore, skin detection may help to predict the prognosis of spina bifida
after birth. Meningocele, with intact skin over the cyst, has a better clinical
course than myelomeningocele. Some myelomeningoceles with neural tube defects in
a lower position, also frequently having an intact skin over the cyst, have
almost the same clinical course as a meningocele. From this, we hypothesize that
a baby with spina bifida who has intact skin over the cyst might have a good
prognosis neurologically. In this report, we concentrate attention on the skin
over cysts in 3 cases (1 meningocele and 2 myelomeningoceles).
PMID- 10782002
TI - Nucleated red blood cells in growth-restricted fetuses: associations with short
term neonatal outcome.
AB - OBJECTIVE: To determine the utility of the neonatal nucleated red blood cell
(NRBC) count as an independent predictor of short-term perinatal outcome in
growth-restricted fetuses. METHODS: Hospital charts of neonates with a discharge
diagnosis indicating a birth weight <10th percentile were reviewed for perinatal
outcome. We studied all eligible neonates who had a complete blood count on the
first day of life. After multiple gestations, anomalous fetuses and diabetic
pregnancies were excluded; 73 neonates comprised the study group. Statistical
analysis included ANOVA, simple and stepwise regression. RESULTS: Elevated NRBC
counts were significantly associated with cesarean section for non-reassuring
fetal status, neonatal intensive care unit admission and duration of neonatal
intensive care unit stay, respiratory distress and intubation, thrombocytopenia,
hyperbilirubinemia, intraventricular hemorrhage and neonatal death. Stepwise
regression analysis including gestational age at birth, birth weight and NRBC
count demonstrated that in growth-restricted fetuses, NRBC count was the
strongest predictor of neonatal intraventricular hemorrhage, neonatal respiratory
distress and neonatal death. CONCLUSION: An elevated NRBC count independently
predicts adverse perinatal outcome in growth-restricted fetuses.
PMID- 10782003
TI - Assessment of risk for chromosomal abnormalities at 10-14 weeks of gestation by
nuchal translucency and maternal age in 5,210 fetuses at a single centre.
AB - OBJECTIVE: To evaluate the screening of chromosomal abnormalities by nuchal
translucency (NT) measurement. METHODS: Assessment of risk for chromosomal
abnormalities by NT and maternal age in 5,210 single fetuses with karyotype and
outcome already known. RESULTS: Risk was > or =1 in 300 in 640 (12.2%) of all
fetuses, in 575 (11.1%) of the normal fetuses, in 38 (80.8%) of the fetuses
affected by trisomy 21, and in 65 (89%) of the fetuses affected by chromosomal
abnormalities. Risk was > or =1 in 200 in 477 (9.1%) of all fetuses, in 418
(8.1%) of the normal fetuses, in 35 (74.4%) of the fetuses affected by trisomy
21, and in 59 (80.8%) of the fetuses affected by chromosomal abnormalities. Risk
was > or =1 in 100 in 270 (5.1%) of all fetuses, in 216 (4.2%) of the normal
fetuses, in 33 (70.2%) of the fetuses affected by trisomy 21, and in 54 (73.9%)
of the fetuses affected by chromosomal abnormalities. CONCLUSIONS: Risk generated
by NT and maternal age is effective in screening for chromosomal abnormalities.
PMID- 10782004
TI - Multiple cardiac rhabdomyomas detected in utero.
AB - Prenatal fetal echocardiography studies detected large multiple cardiac
rhabdomyomas and led to the diagnosis of tuberous sclerosis. Despite episodes of
bradyarrhythmias and severe lung compression in utero, the neonate did well and
was discharged home on day 20 of life. On day 30 of life, the infant expired at
home from cardiac arrest secondary to arrhythmia.
PMID- 10782005
TI - Cord ultrasonic transection procedure for selective termination of a
monochorionic twin.
AB - Placental vascular communications can present a life-threatening problem in
monochorionic twins when one fetus has a lethal anomaly. Although selective
feticide is the best option for salvaging the normal twin, techniques normally
employed (i.e. intracardiac potassium, air embolism) are not prudent given the
common circulatory system. Furthermore, in monoamniotic, monochorionic twin
gestations it is important to transect the umbilical cord completely to prevent
entanglement of the dead fetus around the cord of the normal twin. We present two
cases of monochorionic twins in which the cords were transected with a harmonic
scalpel under ultrasonic guidance via one trocar. The harmonic scalpel is an
instrument which can simultaneously coagulate and cut blood vessels or tissues.
The cord ultrasonic transection procedure is a novel, minimally invasive
technique which offers several advantages over the methods currently used for
selective feticide in discordant monochorionic twin gestations.
PMID- 10782006
TI - Predictive factors of fetal urethral obstruction: a multivariate analysis.
AB - OBJECTIVE: The purpose of this study was to identify predictive factors of fetal
urethral obstruction. METHODS: One hundred and forty-eight children with fetal
hydronephrosis were admitted, submitted to a systematic protocol and
prospectively followed. Possible predictive factors of urethral obstruction
associated with fetal echography and clinical findings on admission were studied.
The analysis was conducted in two steps. In a univariate analysis, variables
associated with urethral obstruction were identified by the chi(2) test or by
Fisher's exact test. Then, the variables that were significantly associated with
urethral obstruction were included in a multiple logistic regression analysis.
RESULTS: After final adjustment by multiple logistic regression analysis, only
two variables were identified as independent predictors of fetal urethral
obstruction: oligohydramnios (odds ratio, OR = 5, 95% confidence interval, CI, =
1.3-15, p = 0.01) and megacystis (OR = 9, 95% CI = 2.0-40, p = 0.004). The
sensitivity and specificity of the combination of both variables were 60 and
98.5%, respectively. CONCLUSIONS: The presence of oligohydramnios and megacystis
on prenatal ultrasound is highly predictive of fetal urethral obstruction.
PMID- 10782007
TI - In utero repair of rectal atresia after complete resection of a sacrococcygeal
teratoma.
AB - PURPOSE: A case of a fetus with a prenatally diagnosed sacrococcygeal teratoma
that produced high-output cardiac failure, hydrops, rectal atresia, and urinary
tract obstruction is presented. The unique prenatal surgical management along
with the embryogenesis of tumor-related rectal atresia is discussed. CASE REPORT:
A large fetal sacrococcygeal teratoma with a significant intrapelvic component
was detected at routine ultrasound in a 35-year-old gravida 3 para 2. Fetal
hydrops developed rapidly due to high-output cardiac failure from the vascular
'steal' by the growing tumor. The urinary tract was obstructed due to the
intrapelvic tumors mass. At 27 weeks' gestation, the female fetus underwent
hysterotomy, resection of the entire mass and urinary diversion via bilateral
flank ureterostomies. The rectum was found to be completely atretic due to
apparent encasement by the tumor. Pull-through anorectoplasty was carried out
concurrently. At 30 weeks' gestation, the mother developed preterm labor and a
1.8-kg was delivered by cesarean section. The baby did very well for 3 days but
had a cardiac arrest and died due to an atrial perforation by a transfemoral
venous catheter. CONCLUSIONS: To our knowledge this is the first report of a
complete prenatal resection of a sacrococcygeal teratoma with concomitant pull
through anorectoplasty for rectal atresia.
PMID- 10782008
TI - [Reduction of stuttering frequency using frequency-shifted and delayed auditory
feedback].
AB - In 12 stuttering subjects the fluency enhancing effect of delayed auditory
feedback (DAF) and frequency-shifted auditory feedback (FAF) was compared. The
subjects had to read three passages consisting of 300 syllables under
simultaneous auditory feedback, DAF (delay time: 53 ms) and FAF (frequency shift:
-(1/2) octave). Stuttering frequency and percentage of discontinuous speech time
were determined. Only under DAF a fluency enhancing effect in the mean values was
observed, but not under FAF. However, in 4 subjects a reduction in stuttering
frequency of 50% occurred. The conclusion is drawn that the use of FAF as a
prosthetic device is limited. The relationship between prolonged speech and
fluency enhancing is discussed.
PMID- 10782009
TI - Prevalence and characteristics of dysarthria in a multiple-sclerosis incidence
cohort: relation to neurological data.
AB - Few attempts have been made to use degree and type of multiple sclerosis (MS)
dysarthria in neurological evaluation. In the present study, 77 individuals drawn
from an MS population were examined both by a speech pathologist and a
neurologist, and data from three sources of information were subsequently
combined: (1) a clinical dysarthria test procedure, (2) a perceptual analysis of
speech characteristics in continuous speech, and (3) neurological deficit
scoring. The speech of 15 age- and gender-matched healthy control subjects was
also investigated. It was concluded that: (1) the prevalence of mild to severe
dysarthria in this cohort was 51% and occurred in all components of speech
production: respiration, phonation, prosody, articulation and nasality. (2) The
clinical dysarthria test was sensitive in detecting subclinical speech signs. The
prevalence of pathologic speech signs found on the basis of the test was found to
be 62%. The prevalence of dysarthria based on the neurological evaluation alone
was 20%. (3) The dysarthria of MS was a predominantly mixed dysarthria, with both
ataxic and spastic speech signs frequently present in the speech of a given
individual. (4) Furthermore, when a predominant type of dysarthria existed, it
was not generally associated with a characteristic profile of neurological
deficits. Rather, severity of speech deviation was positively correlated to
overall severity of neurological involvement, type of disease course, and number
of years in progression.
PMID- 10782010
TI - Evoked potentials and electroencephalography in stuttering.
AB - The study was aimed at finding what factors in evoked potentials and EEG related
to stuttering in subjects 6-25 years of age. Thirty-seven subjects who stuttered
and 25 nonstuttering subjects, matched for age, sex and education, were evaluated
employing visual evoked potentials, auditory evoked potentials, event-related
potentials (P(300)), WISC-(IQ), and electroencephalography. A significant
reduction of amplitude of P(100) of visual evoked potentials was found in
stutterers with a significant prolongation of wave latencies I, III, V and
interpeak latencies I-III and I-V in brainstem auditory evoked potentials. No
significant abnormalities were recorded in P(200), N(200) and P(300) of event
related potentials in stutterers compared with the control group. The dominant
EEG rhythm was slower in stutterers with a significant interhemispheric asymmetry
compared with the control group. Fifty-four percent of the stutterers had
pathological EEG. Epileptiform activities were recorded in 16.2% of stuttering
subjects. Focal left temporal spike activity was recorded in 5.4% of stuttering
subjects. The findings of this study point to a possible role of an organic
etiopathogenesis of stuttering.
PMID- 10782011
TI - Speech disorders following severe traumatic brain injury: kinematic analysis of
syllable repetitions using electromagnetic articulography.
AB - Using electromagnetic articulography, the lips, the tip of the tongue, and the
tongue dorsum were tracked during repetitions of the syllables [pa], [ta] and
[ka] in 10 speakers with dysarthria following severe traumatic brain injury and
in 10 age-matched control subjects. When asked to produce the syllable trains as
fast as possible, the patient group showed a rather homogeneous pattern of
movement abnormalities including prolonged syllable durations and reduced peak
velocity/amplitude ratios. Most presumably, limited speed generation gives rise
to the impaired ability to increase speech rate. During the habitual speaking
condition, reduced velocity/amplitude ratios were restricted to the tongue tip
and tongue dorsum. Obviously, the tongue and the lips are differentially affected
in dysarthria following severe traumatic brain injury.
PMID- 10782012
TI - A unified approach to adjusting association tests for population admixture with
arbitrary pedigree structure and arbitrary missing marker information.
AB - A general approach to family-based examinations of association between marker
alleles and traits is proposed. The approach is based on computing p values by
comparing test statistics for association to their conditional distributions
given the minimal sufficient statistic under the null hypothesis for the genetic
model, sampling plan and population admixture. The approach can be applied with
any test statistic, so any kind of phenotype and multi-allelic markers may be
examined, and covariates may be included in analyses. By virtue of the
conditioning, the approach results in correct type I error probabilities
regardless of population admixture, the true genetic model and the sampling
strategy. An algorithm for computing the conditional distributions is described,
and the results of the algorithm for configurations of nuclear families are
presented. The algorithm is applicable with all pedigree structures and all
patterns of missing marker allele information.
PMID- 10782013
TI - Apolipoprotein B 3'-VNTR polymorphism in the Udmurt population.
AB - An analysis of a highly polymorphic region of the apolipoprotein B gene 3'-end
DNA (Apo B 3'-VNTR), represented by 10 alleles, was carried out using the
polymerase chain reaction. Data inferred from the principal component analysis
indicate that the Udmurts occupy an isolated position among the populations
constituting the northern branch of Caucasoid peoples.
PMID- 10782014
TI - Adjusting for confounding due to population admixture when estimating the effect
of candidate genes on quantitative traits.
AB - When analyzing the relationship between allelic variability and traits, a
potential source of confounding is population admixture. An approach to adjusting
for potential confounding due to population admixture when estimating the
influence of allelic variability at a candidate gene is presented. The approach
involves augmenting linear regression models with additional regressors. Family
genotype data are used to define the regressors, and inclusion of the regressors
ensures that, even in the presence of population admixture, the estimates of the
regression coefficients that parameterize the influence of allelic variability on
the trait are unbiased. The approach is illustrated through an analysis of the
influence of apolipoprotein E genotype on plasma low density lipoprotein
cholesterol concentrations.
PMID- 10782015
TI - K5 D328E: a novel missense mutation in the linker 12 domain of keratin 5
associated with epidermolysis bullosa simplex (Weber-Cockayne).
AB - A novel missense mutation was detected in the L12 region of keratin 5 (K5) in a
Slovene family diagnosed with a Weber-Cockayne variant of epidermolysis bullosa
simplex (EBS). Direct sequencing identified a heterozygous GAC to GAA
substitution altering codon 328 of K5 from Asp to Glu in all affected family
members, while no mutation was observed either in the healthy individual or the
50 unrelated control samples. Asp(328) of K5 (position 12 in the L12 domain) is
remarkably conserved among all type II keratins. K5 L12:D12E is the third
mutation found to affect this residue in K5-related EBS, indicating the
importance of Asp(328) for K5 structure and the dramatic effect that fine changes
can have on keratin intermediate filament integrity.
PMID- 10782016
TI - Molecular heterogeneity of the glucose-6-phosphate dehydrogenase deficiency in
the Hellenic population.
AB - We report results from a systematic study to identify the molecular basis of
glucose-6-phosphate dehydrogenase (G6PD) deficiency on a sample of 299 male
subjects from the Hellenic population. Our stepwise approach involved partial
biochemical characterization and quantitation of the enzyme's activity, MboII
restriction endonuclease digestion to identify the G6PD Mediterranean variant,
which represents the most frequent G6PD variant in our population and a
nonradioactive polymerase chain reaction-single-strand conformation polymorphism
methodology for the detection of the underlying molecular defect(s) in the rest
of the non-Mediterranean G6PD-deficient individuals. Through this approach, six
different G6PD variants were identified (G6PD Mediterranean, G6PD Hermoupolis,
G6PD Cassano, G6PD Seattle, G6PD Ierapetra and G6PD Acrokorinthos), two of which
were new (G6PD Hermoupolis, G6PD Acrokorinthos). In essence, this study
underlines the remarkable genetic heterogeneity of the G6PD deficiency in the
Hellenic population, while the finding of the double mutant, G6PD Hermoupolis,
may help to outline the relationship and evolution of mutations in the human G6PD
locus.
PMID- 10782017
TI - High frequency of HLA-DQB1 non-Asp(57) alleles in Kuwaiti children with insulin
dependent diabetes mellitus.
AB - The prevalence of polymorphic amino acids at position 57 of the HLA DQB1 in
Kuwaiti children with insulin-dependent diabetes mellitus (IDDM) and nondiabetic
controls has been determined using a polymerase chain reaction-sequence-specific
primers (PCR-SSP) method. Using this approach, 34/55 (62%) IDDM children were
found to be homozygous Ala/Ala and 19/55 (35%) were heterozygous with various
combinations. Amongst the IDDM children with heterozygous genotype at codon 57 of
HLA DQB1, 6/55 (11%) had Asp/Ala, 8/55 (15%) had Ala/Val, 4/55 (7%) had Ala/Ser
and 1/55 had Asp/Val allelic combinations. When considered collectively, the
nonaspartate (NA) alleles were represented in 87% of the IDDM cases and only 13%
cases had Asp(57) allele in different heterozygous combinations, while none of
the IDDM subjects had a homozygous Asp genotype. In nondiabetic controls,
homozygous non-Asp (NA) alleles were represented in 44% subjects, 37% of the
controls were heterozygous (NA/A) and 19% had a homozygous (A/A) genotype. These
differences between the IDDM group and the control group were found to be
statistically significant. Our data report one of the highest frequency of NA/NA
residues at this locus compared with that from different world populations
(Sardinians, Norwegians, US Caucasians, US Blacks and Chinese).
PMID- 10782018
TI - Identification of a prevalent nonsense mutation (W283X) and two novel mutations
in the porphobilinogen deaminase gene of Swiss patients with acute intermittent
porphyria.
AB - Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by
decreased activity of porphobilinogen deaminase (PBGD), the third enzyme in the
heme biosynthetic pathway. We report the first molecular analysis of PBGD gene
mutations in AIP patients of Swiss origin. The PBGD gene of 18 Swiss AIP patients
was analyzed by denaturing gradient gel electrophoresis screening of the genomic
DNA and direct sequencing. Thirteen of the 18 patients (72%) carried a nonsense
mutation G(849)-->A, W283X. In addition, 4 different mutations including 2 novel
mutations (Q217L and Q292X), were identified in the 5 remaining AIP patients
originating from both German- and Italian-speaking regions of Switzerland.
PMID- 10782019
TI - Linkage analysis of quantitative trait loci: sib pairs or sibships?
AB - Sib pair linkage studies are now widely used to investigate the genetic factors
implicated in complex quantitative traits. To increase the power of these
approaches, it has been proposed to select extremely discordant (ED) sib pairs
which are expected to contain the highest linkage information. However, it is
known that sibships of larger size contain more linkage information than
independent sib pairs. In this paper we compare, in terms of power and cost
considerations, the ED strategy, which uses information on sib pairs only, to the
recently developed 'Maximum Likelihood Binomial' sibship-oriented method
performed on the whole sibships from which the ED sib pairs have been extracted.
We show that the use of these whole sibships is an efficient alternative to
approaches focusing on ED sib pairs only.
PMID- 10782020
TI - A study on the degree of relationship between two individuals.
AB - The paper studies the likely degree of relationship between two individuals who
could possibly be half sibs. The possible common ancestor was dead, which further
complicated the problem. The model used was devised by Thompson [in Rao and
Chakraborty (eds): Handbook of Statistics, North-Holland, Amsterdam, 1991] and
establishes a correspondence between the possible degree of relationship and
certain feasible probability distributions on the number of identical by descent
genes. Two statistical approaches are considered: the classical one, in which the
maximum likelihood estimation for the parameters of Thompson's model are
obtained, and the Bayesian one, in which the test of the hypothesis of half sibs
is accompanied by a robustness study.
PMID- 10782021
TI - Haptoglobin 1F allele frequency is high among indigenous populations in the state
of Durango, Mexico.
AB - We studied haptoglobin polymorphism in Mexican populations with high Indian
ancestry living in isolated and urban areas in the state of Durango. Analysis
with respect to the HP*1F and HP*1S allelic subtypes by isoelectric focusing
showed unusually high HP*1F allele frequencies among urban (0.370) and isolated
Mexican Indians (0.383). Comparison with other population studies demonstrated a
geographical cline of the HP*1F allele increasing in the same direction of the
HP*1 allele, while HP*1S frequency does not show racial differences.
PMID- 10782022
TI - A novel mutation (2409delT) in exon 14 of the factor VIII gene causes severe
haemophilia A.
PMID- 10782023
TI - The 677 C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in
five Chinese ethnic groups.
PMID- 10782024
TI - Five-year survival results of subcutaneous low-dose immunotherapy with
interleukin-2 alone in metastatic renal cell cancer patients.
AB - After the discovery of its essential role in anticancer immunity, IL-2 cancer
immunotherapy has shown that comparable results may be obtained with different
schedules, including intravenous high-dose IL-2 as a bolus or as a 24-hour
intravenous infusion or prolonged subcutaneous injection of low-dose IL-2 with or
without IFN-alpha. This study shows the long-term results obtained in 92
metastatic renal cell cancer (RCC) patients with low-dose subcutaneous IL-2,
which was given at 3 million IU twice/day for 5 days/week for 6 consecutive
weeks. In nonprogressing patients, a second cycle was planned after a 21-day rest
period, followed by maintenance therapy consisting of 5 days of treatment every
month until disease progression. Complete response (CR) was achieved in only 2/92
(2%) patients, and partial response (PR) was observed in 19 patients (21%).
Therefore, the response rate (CR + PR) was 21/92 (23%), with a median duration of
response of 25 months. Stable disease (SD) occurred in 37 patients (40%), whereas
the other 34 (37%) had a progressive disease (PD). The response rate was
significantly higher in patients with a disease-free interval of >1 year than in
those with a lower interval, in patients with a high performance status (PS) than
in those with a low PS, and in patients with sites of disease other than the
liver. A 5-year survival was obtained in 9/92 (9%) patients, and the percent of
survival was significantly higher in patients with a response or SD than in those
with PD. The treatment was well tolerated in all patients. This study confirms
that low-dose subcutaneous IL-2 alone in an effective and well tolerated therapy
of metastatic RCC, with results comparable to those described with more
aggressive and toxic IL-2 schedules.
PMID- 10782025
TI - Renal cell carcinoma in cases of adult polycystic kidney disease: changing
diagnostic and therapeutic implications.
AB - Renal cell carcinoma in adult polycystic kidney disease is of rare occurrence and
poses a diagnostic and therapeutic challenge. We have treated three such patients
in our department. One was male and two were females ranging in age from 20 to 60
years. All were diagnosed preoperatively with ultrasonography or contrast
enhanced CT. Radical nephrectomy was performed in all patients. During the follow
up no patient had recurrence in the contralateral kidney. One patient had local
recurrence in the renal fossa and was treated with local radiotherapy and
immunotherapy. In the past due to difficulty in diagnosis, invasive
investigations like angiography were recommended and prophylactic contralateral
nephrectomy was often undertaken. With the availability of reliable noninvasive
investigations these patients can be diagnosed accurately and the contralateral
kidney saved in most cases.
PMID- 10782026
TI - The correlation of p53 protein overexpression and p53 antibodies in serum of
patients with transitional cell carcinoma of the urinary bladder.
AB - BACKGROUND: Mutations of p53 gene were demonstrated in many solid tumors with
varying frequency. We analyzed the relationship between p53 protein expression in
bladder cancer tissue, p53 autoantibodies in serum and the clinical course of 32
patients with and 10 patients without transitional cell carcinoma of the urinary
bladder. MATERIALS AND METHODS: In the 32 patients studied, bladder cancer was
diagnosed as pTaG1-2 in 8 cases, pT1G2 in 6, pT1G3 in 7, pT2G2-3 in 7, pT3G2-3 in
3 and pT4 in 1 patient. Anti-p53 antibodies were detected by an enzyme-linked
immunosorbent assay. Immunohistochemical staining was performed using a
standardized alkaline phosphatase monoclonal anti-alkaline phosphatase method. To
prove the statistical significance of tumor grading and staging, the Kruskal
Wallis test was applied (p < 0.01). The mean follow-up was 26 months. RESULTS: We
found 12.5% p53 autoantibody-positive sera without a statistically significant
correlation with tumor grade (p = 0.0569) and category (p = 0.612). Three of 4
patients who had p53 autoantibody-positive sera died within 9 months. All of
these sera-positive patients had p53 protein-positive tumor tissue. Control sera
were all negative for p53 autoantibodies. CONCLUSION: This study shows a strong
relationship between p53 protein overexpression and the occurrence of p53
autoantibody in bladder cancer. The expression of p53 autoantibodies seems to be
an event in cases of bladder cancer with an unfavorable tumor-specific outcome.
Because of the small number of cases and the short follow-up time, further
quantitative studies will hopefully demonstrate whether this might be of
prognostic importance.
PMID- 10782027
TI - Value of free prostate-specific antigen (Hybritech Tandem-R) in symptomatic
patients consulting the urologist.
AB - INTRODUCTION: Prostate-specific antigen (PSA) is a widely used tumor marker in
the detection and follow-up of adenocarcinoma of the prostate. Selection of
candidates for prostate biopsies is hampered by the lack of specificity resulting
in a large number of unnecessary biopsies. The intention of our study was to
compare the percent free PSA (f-PSA; Hybritech Tandem-R) with total PSA and age
specific PSA reference values to evaluate the clinical benefit in detecting
patients with prostate cancer (PC) in a selected group of patients consulting the
urologist. The question was whether cutoff points are influenced by this
selection of patients. METHODS: A total of 188 patients, 114 with benign prostate
hyperplasia (BPH) and 74 with PC were selected. It is a selected group of
patients consulting the urologist. Diagnosis was confirmed in the BPH and PC
groups by either ultrasound-guided biopsy or transurethral resection of the
prostate or suprapubic adenomectomy or cystoprostatectomy. Total PSA (t-PSA) and
f-PSA of all patients were measured before any manipulation by Tandem-R assay for
f-PSA and Tandem-E assay for t-PSA (Hybritech). Mean values of age, prostate
volume, t-PSA, f-PSA, percent f-PSA were compared in patients with BPH and PC by
Mann-Whitney U test. The sensitivity and specificity of t-PSA and age-specific
PSA were compared to the sensitivities and specificities of different cutoff
points of percent f-PSA. RESULTS: The mean value of t-PSA, f-PSA and percent f
PSA in patients with BPH (n = 114) and PC (n = 74) were statistically
significantly different. At PSA levels between 4 and 10 ng/ml 19% of negative
biopsies could be avoided by the use of percent f-PSA (cutoff point 25%). There
was no additional benefit of age-specific PSA. At a PSA of <4 ng/ml 6 of 7 PCs
could be diagnosed by percent f-PSA (cutoff point 25%), whereas only 1 patient
would be diagnosed by age-specific PSA. CONCLUSION: Percent f-PSA seems to
decrease the biopsy rate at PSA levels from 4 to 10 ng/ml without missing a
relevant number of cancers and to increase the detection rate at PSA <4 ng/ml.
Our data indicate that it might be necessary to choose high cutoff points (25%;
Tandem-E and R assay, Hybritech) in a selected study population consulting the
urologist with large glands and a high prevalence of disease. However, this
situation is not comparable to testing of screening populations. No benefit of
age-specific PSA could be observed in this study.
PMID- 10782028
TI - Effect of transrectal ultrasonography of the prostate on serum prostate-specific
antigen levels and free/total prostate-specific antigen ratio.
AB - To study the effect of transrectal ultrasonography (TRUS) on serum total prostate
specific antigen (PSA), free PSA and free/total (f/t) PSA ratio and to determine
the reliability of serum total and free PSA levels and f/t PSA ratio after such
interventions, serum free and total PSA levels and f/t PSA ratios were determined
before, immediately after and 24 h after TRUS in 44 patients who were referred to
our department by their general practitioner for prostate screening. The duration
of TRUS procedure and prostate volume and age were evaluated to determine whether
the serum PSA levels following TRUS had changed. The total PSA and free PSA
levels and f/t PSA ratio did not show any significant rise immediately after DRE
and TRUS. The duration of the TRUS procedure did not appear to affect the PSA
values. Age and prostate volume were not correlated with the PSA levels. Our
findings revealed no significant changes in f/t PSA ratio and serum free and
total PSA level, suggesting that serum free and total PSA levels and f/t PSA
ratio may be more reliable parameters in the early period after TRUS.
PMID- 10782029
TI - Urologic complications of extravesical ureteroneocystostomy in renal
transplantation from living related donors.
AB - INTRODUCTION: Reconstruction of the urinary system during renal transplantation
is usually performed with antirefluxive ureteroneocystostomy techniques and
extravesical methods are usually preferred. MATERIAL AND METHODS: Between 1983
and 1997, 241 renal transplantations from living donors were performed at our
institution. A variation of the Lich-Gregoir technique was used as the
ureteroneocystostomy method in all cases. RESULTS: A total of 12 (4.9%) urologic
complications were observed. Urinary fistula developed in 5 (2%) cases and were
explored surgically during the early postoperative period. Postoperative
vesicoureteral reflux (VUR) to the transplanted kidney was identified in 7 (2.9%)
cases. Either endoscopic or surgical interventions resolved VUR in 4 cases while
the other 3 did not need further treatment. No ureteral stenosis was observed.
There was no loss of graft due to urologic complications. CONCLUSIONS: Urologic
complications after renal transplantation are reported to be about 7% and
ischemia is blamed as the major contributing factor. Preparation of the native
ureter during donor nephrectomy and preservation of distal periureteral fatty
tissue, anastomosis technique variations in vascular anatomy, rejections and
medications are the major factors determining the ischemia.
PMID- 10782031
TI - Extracorporeal shock wave lithotripsy monotherapy of 'stoned' internal ureteral
stent in children. Case report.
AB - A case of ESWL treatment, as monotherapy, of a 'stoned' ureteral stent in a 12
year-old boy was described. Two years previously, the patient had pyelolithotomy
with staghorn stone removal, and double-J stent was left indwelling
intraoperatively. The patient was lost for follow-up for 2 years, when he had
multiple stone formation adherent to the whole length of the stent. Four ESWL
sessions were required before the stent was freed for removal.
PMID- 10782030
TI - Carcinoma following augmentation ileocystoplasty.
AB - Carcinoma of the bladder following augmentation cystoplasty is rare. Only 15
cases have been reported worldwide. We report a further 2 cases, 1 of which, a
squamous cell carcinoma, has not previously been described in this context.
PMID- 10782032
TI - Focal xanthogranulomatous pyelonephritis with associated bone metaplasia.
AB - Focal xanthogranulomatous pyelonephritis of the left lower pole was accidentally
discovered in a 34-year-old woman at sonography. The patient had no history of
stones and urinary tract infection and both conventional radiology and CT scan
revealed radiated calcifications within a well-circumscribed mass. Surgical
treatment consisted of enucleoresection of the lesion, and histopathology
revealed a nucleus of bone metaplasia. To the best of our knowledge, metaplastic
bone formation has never been documented before with xanthogranulomatous
pyelonephritis.
PMID- 10782033
TI - Leiomyoma of the ureter.
AB - We report a case of leiomyoma of the ureter, and the patient underwent partial
ureteral resection. This is the 8th case reported after 1955, and the clinical
features of ureteral leiomyomas of these 8 cases are discussed.
PMID- 10782034
TI - Open thumb forceps. An unusual foreign body in the urethra: technique of its
removal.
AB - A great variety of foreign bodies in the urethra have been reported in the
literature. Mostly, these cases were reported to emphasize the unusual nature of
the objects requiring technical modifications for their removal. We report an
interesting case of self introduced open thumb forceps into the urethra and
technique of its retrieval.
PMID- 10782035
TI - Treatment of a delayed zipper injury.
AB - Penile zipper injuries have been reported occurring usually in the pediatric
population, and occasionally in adults. Usually, the zipper can be dislodged with
mineral oil or by breaking the median bar. When these attempts fail, a small
elliptical incision may be used to remove the zipper and any devitalized tissue.
PMID- 10782036
TI - Primary adenosquamous and squamous cell carcinoma of the upper urinary tract.
Report on three cases.
AB - Three cases of adenosquamous cell carcinoma and squamous cell carcinoma of the
upper urinary tract are presented. The fact that the urothelium normally has no
glandular or squamous structures renders the pathogenesis of these tumours
interesting. The process is assumed to begin with an urothelial metaplasia
resulting from a reaction to chronic irritation, leading to dedifferentiation,
dysplasias and, in the end, to a squamous cell carcinoma or adenocarcinoma. The
relevant medical histories include chronic episodes of pyelonephritis or
nephrolithiasis. Diagnosis, therapeutic approaches and prognosis of these rare
tumours are discussed.
PMID- 10782037
TI - Incidental prostate cancer: the importance of complete prostatic removal at
cystoprostatectomy for bladder cancer.
AB - Patients with invasive bladder cancer could be at a higher risk for a second
malignancy such as an unsuspec- ted prostate cancer. We report a case of muscle
invasive transitional cell carcinoma of the urinary bladder with incidental
adenocarcinoma of prostate, and review the literature to highlight the importance
of complete prostatic removal to prevent residual disease.
PMID- 10782038
TI - Metastatic malignant melanoma presenting as bilateral incidentalomas.
AB - Incidentally discovered adrenal masses often pose a diagnostic challenge in the
asymptomatic patient. The majority represent functional adrenal adenomas but
primary or secondary malignancy must be considered. Bilateral incidentalomas are
rare, and a case of asymptomatic bilateral adrenal melanoma metastases is
presented. The diagnostic and treatment strategies relevant to this clinical
problem are presented and discussed.
PMID- 10782039
TI - An unusual retroperitoneal cystic tumor.
AB - This report describes a case of textiloma (term given to an inflammatory swelling
caused by a retained textile foreign body) in a 60-year-old patient who had
undergone surgery for a perforated gastroduodenal ulcer 17 years earlier. On
examination the presence of a large mass was detected on the left hypochondria. A
CT scan confirmed a cystic tumor with images suggesting detritus or necrosis in
its lower part, as well as calcifications. Transperitoneal midline laparotomy was
performed with extension by thoracophrenolaparotomy. Splenectomy was necessary.
Macroscopic examination showed a spherical mass. After opening the tumor,
retained surgical gauze was found. The histopathological diagnosis was
granulomatosis reaction to a foreign body.
PMID- 10782040
TI - Cardiac opioids.
AB - Opioid peptides have long been considered as neuropeptides or neurotransmitters.
The more recent discovery of these same peptides in non-neuronal tissue suggests
that the peptides may have autocrine, paracrine, or endocrine functions as well.
The opioid peptides, enkephalins, dynorphins, and endorphins, have been found in
isolated cardiac myocytes and heart tissue. This review will cover the recent
literature on opioid peptides in respect to cardiac distribution, biochemistry,
and function.
PMID- 10782041
TI - Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A
reductase: the concept of cholesterol buffering capacity.
AB - Regulation of the expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase by the major end product of the biosynthetic pathway,
cholesterol, and by various hormones is critical to maintaining constant serum
and tissue cholesterol levels in the face of an ever-changing external
environment. The ability to downregulate this enzyme provides a means to buffer
the body against the serum cholesterol-raising action of dietary cholesterol. The
higher the basal expression of hepatic HMG-CoA reductase, the greater the
"cholesterol buffering capacity" and the greater the resistance to dietary
cholesterol. This review focuses on the mechanisms of feedback and hormonal
regulation of HMG-CoA reductase in intact animals rather than in cultured cells
and presents the evidence that leads to the proposal that regulation of hepatic
HMG-CoA reductase acts as a cholesterol buffer. Recent studies with animals have
shown that feedback regulation of hepatic HMG-CoA reductase occurs at the level
of translation in addition to transcription. The translational efficiency of HMG
CoA reductase mRNA is diminished through the action of dietary cholesterol.
Oxylanosterols appear to be involved in this translational regulation. Feedback
regulation by dietary cholesterol does not appear to involve changes in the state
of phosphorylation of hepatic HMG-CoA reductase or in the rate of degradation of
this enzyme. Several hormones act to alter the expression of hepatic HMG-CoA
reductase in animals. These include insulin, glucagon, glucocorticoids, thyroid
hormone and estrogen. Insulin stimulates HMG-CoA reductase activity likely by
increasing the rate of transcription, whereas glucagon acts by opposing this
effect. Hepatic HMG-CoA reductase activity undergoes a significant diurnal
variation due to changes in the level of immunoreactive protein primarily
mediated by changes in insulin and glucagon levels. Thyroid hormone increases
hepatic HMG-CoA reductase levels by acting to increase both transcription and
stability of the mRNA. Glucocorticoids act to decrease hepatic HMG-CoA reductase
expression by destabilizing reductase mRNA. Estrogen acts to increase hepatic HMG
CoA reductase activity primarily by stabilizing the mRNA. Deficiencies in those
hormones that act to increase hepatic HMG-CoA reductase gene expression lead to
elevations in serum cholesterol levels. High basal expression of hepatic HMG-CoA
reductase, whether due to genetic or hormonal factors, appears to result in
greater cholesterol buffering capacity and thus increased resistance to dietary
cholesterol.
PMID- 10782042
TI - Does the insulin-like growth factor system interact with prostaglandins and
proinflammatory cytokines during neurodegeneration?
AB - Prostaglandins and proinflammatory cytokines are implicated in the etiology of
neurodegenerative diseases, such as Alzheimer's disease. Signaling cascades
initiated by these factors may result in reactive oxygen species generation and
cell death. The insulin-like growth factors (IGF) are ubiquitous polypeptides
involved in all aspects of growth and development. Additionally, the IGF are
regarded as survival factors that display potent antiapoptotic activity.
Interfering with IGF production, distribution, or signaling may result in greater
susceptibility to apoptotic stimuli. In neurodegenerative conditions, the IGF
appear to be antagonized by prostaglandins and proinflammatory cytokines. In this
review, the relationship among specific prostaglandins, the proinflammatory
factors, tumor necrosis factor, interleukin-1, and interleukin-6, and the IGF
system will be investigated.
PMID- 10782043
TI - Topical insulin and accumulation of excitotoxic and other amino acids in ischemic
rat cerebral cortex.
AB - Insulin plays a neuroprotectant role in the brain and spinal cord during
ischemia. However, studies have shown insulin to increase the sensitivity of
cultured cortical cells to glutamate toxicity. The present study looked at the
relationship between topically administered insulin (1 mIU insulin/ml and 100 mIU
insulin/ml) during a four-vessel model of global ischemia and the accumulation of
amino acids, especially glutamate, from the ischemic rat cerebral cortex. The
lower dose of insulin was found to attenuate the release of excitotoxic and other
amino acids from the cortex in ischemia/reperfusion. This may occur because
insulin increases glucose availability to glial cells resulting in maintenance of
glycolysis and ionic pumps that can reduce glutamate release and maintain uptake
during ischemia/reperfusion. The higher dose of insulin, which significantly
increased the amount of aspartate, glutamate, taurine, and GABA during
reperfusion, may act to stimulate the amount of glycogen stored in astrocytes,
reducing the availability of glucose for metabolic purposes.
PMID- 10782044
TI - The familial mediterranean fever protein interacts and colocalizes with a
putative Golgi transporter.
AB - The biological function of pyrin, the protein mutated in Familial Mediterranean
Fever (FMF), has not been elucidated. Based on sequence homology, a transcription
factor activity was proposed for this neutrophil-specific protein. In a yeast two
hybrid assay, neither transcription activation activity nor any self interaction
was detected for pyrin. Screening of an expression cDNA library of peripheral
blood leukocytes using as bait the carboxyl portion of pyrin (amino acids 557
781), which contains most of the FMF mutations, led to the identification of P/M
IP1 (pyrin/marenostrin interacting protein 1). A splice variant of P/M-IP1, GTC
90, had previously been described as a component of the 13S hetero-oligomeric
protein complex that stimulates in vitro Golgi transport. We have now shown that
P/M-IP1 colocalizes with pyrin in the perinuclear cytoplasm of Cos-7 cells and
that the interaction between these two proteins is impaired by FMF causing
mutations in pyrin. These data suggest that, at some stage of its functional
pathway, pyrin resides in the cytoplasm and might be involved in, or impacted by,
cellular protein sorting by the Golgi apparatus. The data also imply that P/M-IP1
may be involved in the abnormal inflammatory response that occurs in patients
with FMF.
PMID- 10782045
TI - Prolactin stimulation of iodide uptake and incorporation into protein is
polyamine-dependent in mouse mammary gland explants.
AB - Previous studies have demonstrated that the prolactin stimulation of most
lactational processes (casein, lactose, and triglyceride synthesis) requires an
earlier stimulating effect of prolactin on the synthesis of the polyamines.
Spermidine appears to be the specific polyamine required for prolactin to enhance
milk product synthesis. Inorganic iodide is present in milk at more than an order
of magnitude higher concentration than that of the maternal plasma. Since
prolactin stimulates iodide accumulation in milk, the goal of these studies was
to determine the role of the polyamines in this hormone response. Two drugs were
employed in these studies: DFMO (difluoromethylornithine), which inhibits
ornithine decarboxylase, and MGBG [methylglyoxal bis(guanyl-hydrazone)], which
inhibits S-adenosyl methionine decarboxylase. In mammary gland explants from
midpregnant (10-14 days of pregnancy) mice, MGBG at 100 microM abolished the
prolactin stimulation of iodide uptake and incorporation into milk proteins,
whereas DFMO caused a concentration-dependent inhibition of the PRL response.
Selected sensitivity of the MGBG and DFMO inhibitions was validated by a reversal
of the drug inhibitions with the addition of 1 mM spermidine to the culture
medium. These data suggest that the polyamine signaling pathway is involved in
the prolactin stimulation of iodide uptake into milk.
PMID- 10782046
TI - Anticancer agents suppressive for adult parasites of filariasis in Mongolian
jirds.
AB - Eight chemical structures not previously reported to possess antifilarial
activity have been identified. A total of 79 compounds with anticancer properties
were evaluated for possible macrofilaricidal activity against Brugia pahangi and
Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones
unguiculatus). All eight active compounds were suppressive for the onchocerciasis
type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the
lymphatic form (Brugia pahangi). These new structures may represent a nucleus
around which effective drugs can be synthesized.
PMID- 10782047
TI - Intraluteal administration of a nitric oxide synthase blocker stimulates
progesterone and oxytocin secretion and prolongs the life span of the bovine
corpus luteum.
AB - To test the role of nitric oxide (NO) in secretory functions of bovine corpora
lutea (CL), two groups of four Holstein heifers each were treated as follows:
Group 1, Nomega-Nitro-L-Arginine Methyl Ester (L-NAME), an inhibitor of nitric
oxide synthase (NOS), on Day 11 or 12 of the cycle and Group 2, L-NAME on Days 17
and 18 of the cycle. All treatments were administered by an intraluteal
microdialysis system (MDS). Drugs were infused for 4-hr periods on the designated
days, and the treatment periods were preceded and followed by 4-hr control
periods. Perfusate and jugular blood samples were collected at half-hour
intervals. Perfusate samples were analyzed for progesterone (P4), oxytocin (OT),
prostaglandin F2alpha (PGF2alpha), and leukotriene C4 (LTC4); jugular plasma
samples were analyzed for P4, OT, and LH. Perfusion of L-NAME on Day 11 or 12
consistently increased P4 concentration in the perfusate, but had no effect on
the life span of the CL. Perfusion of L-NAME on Days 17-18 also elevated P4
levels in the perfusate, and in addition, maintained P4 levels in the plasma of
three of the four treated animals through Day 25 of the cycle. L-NAME perfusion
also increased OT release concomitant with P4 into the perfusate at both the mid-
and late-luteal phase treatments. For the most part, concentrations of LH, OT,
and P4 in the jugular plasma samples collected during the perfusions were
unaffected by treatments. L-NAME perfusion caused small, but significant (P <
0.05) increases in perfusate PGF2alpha and LTC4 at Days 17 and 18 and in LTC4 on
Day 11 or 12. These data indicate that NO plays a direct luteolytic role in
regression of the bovine CL.
PMID- 10782048
TI - CD27: a memory B-cell marker.
PMID- 10782049
TI - The IL-1 receptor/toll-like receptor superfamily: crucial receptors for
inflammation and host defense.
PMID- 10782050
TI - Clinical immunology: a unified vision for Europe.
PMID- 10782052
TI - Putting priming into perspective - from cellular heterogeneity to cellular
plasticity.
AB - The concept of priming is widely used in cell biology and has come to mean the
functional enhancement of a given cell by cytokines. 'Primed' cells have a number
of other cellular alterations, although the relationship between functional and
phenotypical diversity has not been established. Here, Claus Kroegel and
colleagues discuss the dynamic nature of inflammatory-cell priming, which might
be part of a broader means of comprehending cell function in disease.
PMID- 10782051
TI - How can dendritic cells cause autoimmune disease?
AB - Immune responses against foreign antigens are initiated and controlled by
dendritic cells (DCs). Accumulating evidence suggests that autoimmunity,
involving T cells directed against self, can also be primed by DCs. We propose
that DCs could induce autoimmunity following their differentiation by certain
cytokines, or because of intrinsic defects in genes controlling DC function. Both
processes result in DCs that behave deviantly.
PMID- 10782053
TI - Searching for significance in TCR-cytoskeleton interactions.
AB - Two T-cell receptor (TCR) populations are expressed on T cells; one is linked to
the cytoskeleton via its zeta chain. These cytoskeleton-linked receptors (30-40%
of the total number of TCRs) might be important in TCR-mediated signaling and/or
concurrent events. Here, differences between the two populations are summarized,
and new data are examined to speculate on the functional significance of
cytoskeleton-linked TCRs.
PMID- 10782055
TI - CCL chemokines and asthma.
AB - Airway eosinophilia is a characteristic of bronchial asthma. Eosinophils are
considered to cause tissue damage through the release of toxic proteases, lipid
mediators, cytokines and oxygen free radicals. The discovery of chemokines and
the demonstration that some members of this cytokine superfamily are implicated
in the recruitment of eosinophils offers an opportunity for a novel therapeutic
approach in asthma.
PMID- 10782054
TI - Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis.
AB - Natural killer (NK) cells can detect whether cells have undergone tumour
transformation or viral infection. The discovery of specific inhibitory receptors
for major histocompatibility complex class I molecules clarified the basis of
this discrimination. However, the receptors responsible for NK-cell triggering in
the process of natural cytotoxicity remained elusive until recently. Here,
Alessandro Moretta and colleagues describe the identification and
characterization of several such receptors.
PMID- 10782056
TI - Poxviral mimicry of complement and chemokine system components: what's the end
game?
AB - Numerous viral proteins mimic host immunoregulatory proteins, both structurally
and functionally. This phenomenon appears to underlie viral evasion of host
defense. These viral immunomodulatory proteins block viral neutralization and
destruction of infected cells, and are also able to influence their habitat,
preserving habitats that favor their growth and that of their progeny. The end
game seems to vary widely among viruses.
PMID- 10782057
TI - Clean living increases more than just atopic disease.
PMID- 10782058
TI - Reply to rook
PMID- 10782059
TI - Tryptophan degradation to control T-cell responsiveness.
PMID- 10782060
TI - Popping a pill to regulate therapeutic protein delivery.
PMID- 10782061
TI - Pneumococci self-destruct.
PMID- 10782062
TI - Engineered macrophages: a new weapon in the war on cancer?
PMID- 10782063
TI - Mitochondrial gene linked to rare hereditary tumour.
PMID- 10782064
TI - Mucosal protection against HIV - a new role for IgG?
PMID- 10782065
TI - Virtual molecular medicine in developing countries: the Mexican initiative.
AB - The limited resources of developing countries are forcing them to search for
different options to keep up with the accelerating pace of research into genetic
medicine. In Mexico, one such option is the Mexican Network of Molecular
Biomedicine (MNMB). With the Internet as a means of communication and a source of
information, the MNMB aims to provide a program based on cooperation, high
quality service and patient care.
PMID- 10782066
TI - Fragile X syndrome at the turn of the century.
AB - Fragile X syndrome is not only the most common form of inherited cognitive
impairment, it is also one of the most frequent single gene disorders. It is
caused by a stretch of CGG-repeats within the fragile X gene, which increases in
length as it is transmitted from generation to generation. Once the repeat
exceeds a threshold length, no fragile X protein is produced and disease results.
Since the mutation was discovered, nearly a decade of research has revealed a
wealth of information regarding the fragile X gene and its possible function
within the cell. The fragile X story also provides a sobering example of how much
time and effort might be necessary to develop beneficial treatment through
understanding gene function.
PMID- 10782067
TI - Xenotransplantation: is the risk of viral infection as great as we thought?
AB - Two major hurdles remain before xenotransplantation can enter the clinic. The
first is the more technical issue of being able to overcome the human immune
response that leads to rejection of transplanted organs/cells from other species.
The second, reviewed here, concerns the potential risk of inadvertent transfer of
animal viruses present in the xenotransplant that are able to infect the human
recipient. The threat from viruses is a particularly contentious topic because it
poses a risk not only to those individuals who receive xenotransplants, but also
to healthy individuals who come into contact, either directly or indirectly, with
the xenotransplant recipient. In this review, we describe some of the virus
types, in addition to the much discussed porcine endogenous retroviruses that
might cross the species barrier, and assess the risk of such viruses causing
disease in human hosts.
PMID- 10782068
TI - The NC/Nga mouse: a model for atopic dermatitis.
PMID- 10782069
TI - Molecular approaches to malaria.
PMID- 10782070
TI - Wolbachia bacteria of filarial nematodes: a target for control?
PMID- 10782072
TI - Parasite genomes: A special issue of international journal of parasitology
PMID- 10782071
TI - What should schools do about malaria?
PMID- 10782073
TI - Situation analysis of malaria in school-aged children in Kenya - what can be
done?
PMID- 10782074
TI - The link between helminthic infection and atopy.
PMID- 10782075
TI - The strange case of Leishmania chagasi.
PMID- 10782076
TI - Albumax and global warming on the Web
PMID- 10782077
TI - Vaccination against cysticercosis and hydatid disease.
AB - Infections with the larval stages of taeniid cestode parasites cause substantial
human morbidity as well as economic losses in domestic livestock species. Despite
ongoing efforts around the world, few countries have been able substantially to
reduce or eradicate these infections through the use of anthelmintics and
lifestyle changes. Vaccines offer an additional potential tool to assist with the
control of parasite transmission. Here, Marshall Lightowlers and colleagues
review the substantial progress that has been made towards developing practical
vaccines against hydatid disease in sheep and cysticercosis in sheep and cattle.
Recombinant antigens have been used to induce more than 90% protection against
challenge infections. Such success in animals encourages investigation of the
potential use of vaccines in humans to prevent hydatid disease arising from
infection with Echinococcus granulosus and cysticercosis from infection with
Taenia solium.
PMID- 10782078
TI - The journey of the malaria parasite in the mosquito: hopes for the new century.
AB - In this review, Anil Ghosh, Marten Edwards and Marcelo Jacobs-Lorena follow the
journey of the Plasmodium parasite in the mosquito vector. At each developmental
step, they highlight some of the major unanswered questions currently challenging
cell and molecular biologists. A more thorough understanding of Plasmodium
mosquito interactions might lead to the development of mosquitoes unable to
support parasite development.
PMID- 10782080
TI - The role of eosinophils in parasitic helminth infections: insights from
genetically modified mice.
AB - Eosinophilia - an increase in the number of eosinophils in the blood or tissues -
has historically been recognized as a distinctive feature of helminth infections
in mammals. Yet the precise functions of these cells are still poorly understood.
Many scientists consider that their primary function is protection against
parasites, although there is little unequivocal in vivo evidence to prove this.
Eosinophils are also responsible for considerable pathology in mammals because
they are inevitably present in large numbers in inflammatory lesions associated
with helminth infections or allergic conditions. In this review, Carolyn Behm and
Karen Ovington outline some of the cellular and biological properties of
eosinophils and evaluate the evidence for their role(s) in parasitic infections.
PMID- 10782081
TI - Nomenclature and genetic groupings of Giardia infecting mammals.
AB - Giardia is a ubiquitous and well-known enteric parasite affecting humans and a
range of domestic and wild mammals. It is one of the most common parasites of
domestic dogs and dairy cattle and a frequently recognized waterborne pathogen.
Giardiasis is considered to be a re-emerging infection because of its association
with outbreaks of diarrhoea in child-care centres. Although only a single species
has been recognized as causing disease in humans and most other mammals,
molecular characterization of morphologically identical isolates from humans and
numerous other species of mammals has confirmed the heterogeneity of this
parasite and provided a basis for a clearer understanding of the taxonomy and
zoonotic potential of Giardia.
PMID- 10782082
TI - Giardia vaccination.
AB - Recently, a Giardia vaccine has become commercially available in the USA for
prevention of clinical signs of giardiasis and reduction of cyst shedding in dogs
and cats. The vaccine is based upon the current state of knowledge of Giardia
antigenicity and immunology. Here, Merle Olson, Howard Ceri and Douglas Morck
describe studies that led to the development of this vaccine and subsequent
efficacy studies. Immunoprophylaxis and immunotherapeutic application of the
vaccine are discussed.
PMID- 10782084
TI - Reply
PMID- 10782083
TI - The concept of virulence.
PMID- 10782086
TI - Chaperone substrates inside the cell.
PMID- 10782085
TI - Footprints of aminoacyl-tRNA synthetases are everywhere.
PMID- 10782087
TI - The changing face of mitochondrial research.
PMID- 10782088
TI - Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate
connection.
AB - New live-cell imaging techniques indicate that mitochondria exist in the living
cell as a continuous interconnected mitochondrial reticulum, or 'MR', closely
associated with the endoplasmic reticulum (ER). Ca2+ ions released from the ER in
response to hormonal stimulation might thus be preferentially transferred into
the mitochondrial matrix causing the local activation of ATP synthesis. Ca2+
uptake into the MR might also subtly modify the activity of ER Ca2+ release
channels and thus the dynamics of cytosolic Ca2+ oscillations and waves.
PMID- 10782089
TI - Paul Sigler (1934-2000).
PMID- 10782090
TI - The NACHT family - a new group of predicted NTPases implicated in apoptosis and
MHC transcription activation.
PMID- 10782091
TI - FAT: a novel domain in PIK-related kinases.
PMID- 10782092
TI - Nuclear receptors arose from pre-existing protein modules during evolution.
PMID- 10782093
TI - Phosphoinositide signaling and the regulation of membrane trafficking in yeast.
AB - Phosphoinositides are key regulators of diverse cellular processes in eukaryotic
cells. Genetic studies in yeast have advanced our understanding of how
phosphoinositide-signaling pathways regulate membrane trafficking. Enzymes
required for the synthesis (kinases) and turnover (phosphatases) of distinct
phosphoinositides have been identified and several downstream effector molecules
linked to phosphoinositide signaling have recently been characterized.
PMID- 10782094
TI - 'Florigen' enters the molecular age: long-distance signals that cause plants to
flower.
AB - The transition from vegetative to reproductive growth is a critical event in the
life cycle of plants. Previous physiological studies have deduced that hormone
like substances mediate this important transition but the biochemical nature of
the putative signaling molecules has remained elusive. Recent molecular and
genetic studies of key flowering-time genes offer new approaches to understanding
the mechanisms underlying the initiation of flowering.
PMID- 10782096
TI - Proteins binding to duplexed RNA: one motif, multiple functions.
AB - Highly structured and double-stranded (ds) RNAs are adaptable and potent
biochemical entities. They interact with dsRNA-binding proteins (RBPs), the great
majority of which contain a sequence called the dsRNA-binding motif (dsRBM). This
approximately 70-amino-acid sequence motif forms a tertiary structure that
interacts with dsRNA, with partially duplexed RNA and, in some cases, with RNA
DNA hybrids, generally without obvious RNA sequence specificity. At least nine
families of functionally diverse proteins contain one or more dsRBMs. The motif
also participates in complex formation through protein-protein interactions.
PMID- 10782098
TI - Protein Annotators' assistant.
PMID- 10782097
TI - AAA proteases: cellular machines for degrading membrane proteins.
AB - AAA proteases are a conserved class of ATP-dependent proteases that mediate the
degradation of membrane proteins in bacteria, mitochondria and chloroplasts. They
combine proteolytic and chaperone-like activities and thus form a membrane
integrated quality-control system. Inactivation of AAA proteases causes severe
defects in various organisms, including neurodegeneration in humans. Proteolysis
by AAA proteases is modulated by another membrane-protein complex that is
composed of prohibitins in eukaryotic cells and related proteins in bacteria.
PMID- 10782099
TI - A contribution to chemical defence in World War II.
PMID- 10782100
TI - On the immunity principle: a view from a robot.
PMID- 10782101
TI - Reply to Cole, Sacks and Waterman.
PMID- 10782102
TI - Contextual cueing of visual attention.
AB - Visual context information constrains what to expect and where to look,
facilitating search for and recognition of objects embedded in complex displays.
This article reviews a new paradigm called contextual cueing, which presents well
defined, novel visual contexts and aims to understand how contextual information
is learned and how it guides the deployment of visual attention. In addition, the
contextual cueing task is well suited to the study of the neural substrate of
contextual learning. For example, amnesic patients with hippocampal damage are
impaired in their learning of novel contextual information, even though learning
in the contextual cueing task does not appear to rely on conscious retrieval of
contextual memory traces. We argue that contextual information is important
because it embodies invariant properties of the visual environment such as stable
spatial layout information as well as object covariation information. Sensitivity
to these statistical regularities allows us to interact more effectively with the
visual world.
PMID- 10782103
TI - Infant artificial language learning and language acquisition.
AB - The rapidity with which children acquire language is one of the mysteries of
human cognition. A view held widely for the past 30 years is that children master
language by means of a language-specific learning device. An earlier proposal,
which has generated renewed interest, is that children make use of domain
general, associative learning mechanisms. However, our current lack of knowledge
of the actual learning mechanisms involved during infancy makes it difficult to
determine the relative contributions of innate and acquired knowledge. A recent
approach to studying this problem exposes infants to artificial languages and
assesses the resulting learning. In this article, we review studies using this
paradigm that have led to a number of exciting discoveries regarding the learning
mechanisms available during infancy. These studies raise important issues with
respect to whether such mechanisms are general or specific to language, the
extent to which they reflect statistical learning versus symbol manipulation, and
the extent to which such mechanisms change with development. The fine-grained
characterizations of infant learning mechanisms that this approach permits should
result in a better understanding of the relative contributions of, and the
dynamic between, innate and learned factors in language acquisition.
PMID- 10782105
TI - On the relation of speech to language.
AB - There are two widely divergent theories about the relation of speech to language.
The more conventional view holds that the elements of speech are sounds that rely
for their production and perception on two wholly separate processes, neither of
which is distinctly linguistic. Accordingly, the primary motor and perceptual
representations are inappropriate for linguistic purposes until a cognitive
process of some sort has connected them to language and to each other. The less
conventional theory takes the speech elements to be articulatory gestures that
are the primary objects of both production and perception. Those gestures form a
natural class that serves a linguistic function and no other. Therefore, their
representations are immediately linguistic, requiring no cognitive intervention
to make them appropriate for use by the other components of the language system.
The unconventional view provides the more plausible answers to three important
questions: (1) How was the necessary parity between speaker and listener
established in evolution, and how maintained? (2) How does speech meet the
special requirements that underlie its ability, unique among natural
communication systems, to encode an indefinitely large number of meanings? (3)
What biological properties of speech make it easier than the reading and writing
of its alphabetic transcription?
PMID- 10782106
TI - Situating vision in the world.
AB - Recently, there has been a great deal of interest in what has been called
'situated cognition', which has included claims that certain forms of
representation are inadequate for modeling active organisms or agents such as
humans and robots. In this article, I suggest that a weakness in classical
theories of visual representation is the way in which representations connect
with the real world, which may account for many of the concerns expressed by the
situated cognition community. Specifically, I claim that what current theories
lack is any provision for a certain form of direct, preconceptual connection
between objects in the visual world (visual objects or proto-objects) and their
representations in the visual system. This type of connection is akin to what
philosophers and semanticists have referred to as an 'indexical' or
'demonstrative' reference and what some cognitive scientists have referred to as
'deictic pointers'. I explain why such a mechanism is needed and suggest that
many workers have, in fact, been studying precisely this under the term 'visual
index'. The visual index hypothesis is illustrated with the results of some
relevant experiments, including multiple object tracking, visual routines and
subset-selected visual searches. Indexing theory provides a synthesis that has
profound implications for explaining a wide range of psychophysical findings,
certain results in infant cognitive development and also some ancient problems in
the philosophy of mind.
PMID- 10782107
TI - Just the right size: cell counting in Dictyostelium.
AB - The regulation of tissue and organism size plays an essential, but poorly
understood, role in multicellular development. Genes have been identified that
affect body and organ size in a number of animals. Two recently identified genes,
smlA and countin, are required for the proper function of a cell-counting
mechanism that regulates organism size in the eukaryotic microorganism
Dictyostelium discoideum. The discovery of this process now allows the study of
size regulation in a simple multicellular system.
PMID- 10782108
TI - Dyskeratosis congenita, telomeres and human ageing.
AB - As normal humans age, telomeres shorten in tissues that contain dividing cells,
and this has been proposed both as a cause of ageing and as a tumor-suppressor
mechanism. The surprising finding that cells from individuals with the rare
inherited disorder dyskeratosis congenita (DKC) have reduced levels of telomerase
and shortened telomeres might provide the first direct genetic test of the
function of telomeres in intact humans.
PMID- 10782109
TI - Horizontal transfer of catalase-peroxidase genes between archaea and pathogenic
bacteria.
PMID- 10782110
TI - Towards a structural basis of human non-synonymous single nucleotide
polymorphisms.
PMID- 10782111
TI - Unified nomenclature for the COP9 signalosome and its subunits: an essential
regulator of development.
PMID- 10782112
TI - Author's correction
PMID- 10782114
TI - Proteoglycans and pattern formation: sugar biochemistry meets developmental
genetics.
AB - While it has been long appreciated that sugar-modified proteins coat the cell
surface, their functions are poorly understood. Here, I describe recent genetic
studies that demonstrate that one class of sugar-modified proteins, cell-surface
proteoglycans, play crucial roles in morphogenesis, growth regulation and tumor
suppression. Mutations that affect individual proteoglycans or the enzymes
required for glycosaminoglycan synthesis regulate Wingless and Decapentaplegic
signaling in Drosophila, and body size in mice and humans. Compromising
proteoglycan function is also associated with the development of Wilm's tumors
and hereditary multiple exostoses. In this review, these biological findings are
placed in the context of proteoglycan biochemistry and molecular function.
PMID- 10782115
TI - The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency
diseases.
AB - Werner syndrome (WS) is an autosomal recessive genetic disorder that is
manifested by genetic instability and premature onset of age-related diseases,
including atherosclerosis and cancer. The gene that is mutated in WS cells (WRN)
has been identified recently. Characterizations of the WRN gene product indicate
that WRN encodes both a 3'-->5' DNA helicase, belonging to the Escherichiacoli
RecQ helicase family, and a 3'-->5' DNA exonuclease. Studies to define the
molecular mechanism of WRN-DNA transactions are currently underway in many
laboratories. Preliminary results indicate that WRN functions as a key factor in
resolving aberrant DNA structures that arise from DNA metabolic processes such as
replication, recombination and/or repair, to preserve the genetic integrity in
cells.
PMID- 10782116
TI - A genetic programme for neuronal connectivity.
AB - What is the nature of the genetic programme that allows neurons to extend their
axons and connect to other neurons with a high degree of specificity? Work on the
sensory neurons of the fly has shown how the control of neuronal identity is
embedded in the general developmental programme of the organism. The ongoing
analysis of pathfinding mutants suggests plausible mechanisms for the translation
of neuronal identity into axonal behaviour.
PMID- 10782117
TI - Homology a personal view on some of the problems.
AB - There are many problems relating to defining the terminology used to describe
various biological relationships and getting agreement on which definitions are
best. Here, I examine 15 terminological problems, all of which are current, and
all of which relate to the usage of homology and its associated terms. I suggest
a set of definitions that are intended to be totally consistent among themselves
and also as consistent as possible with most current usage.
PMID- 10782118
TI - Virtual biology in the CAVE.
PMID- 10782119
TI - Gene transfer into neurones for the molecular analysis of behaviour: focus on
herpes simplex vectors.
AB - The use of viral vectors to transfect genes into specific brain-cell populations
is a novel approach that can be used to investigate the molecular and cellular
basis of brain function. Ideal vectors should be targetable and capable of
regulated transgene expression. From the viral vectors developed so far, this
article focuses on herpes simplex virus 1 (HSV-1)-based vectors. HSV-1 vectors
can be engineered for gene transfer to the brain, which makes them suitable for
neuroscience research applications. In particular, genetic manipulations of the
virus can almost eliminate toxicity and allow expression of multiple transgenes
simultaneously. In some instances, transfection of selected neuronal populations
is also possible. Specific alterations in behaviour and in disease models have
been described after the viral-vector-mediated expression of specific genes
within highly localized brain regions.
PMID- 10782120
TI - Long-term plasticity of postsynaptic GABAA-receptor function in the adult brain:
insights from the oxytocin neurone.
AB - The subunit switching of ligand-gated receptors is a potentially important
mechanism through which synaptic plasticity can be achieved in the nervous
system. Although established in an activity-dependent manner for
neurotransmission that is mediated by excitatory amino acids, there is much less
direct evidence for a role of subunit switching in long-term plasticity of GABAA
receptors in the adult. We argue that the hypothalamic oxytocin neurones, which
exhibit marked plasticity through each reproductive cycle, provide an excellent
model of both presynaptic and postsynaptic long-term plasticity of GABA-mediated
transmission in the mature nervous system. The postsynaptic plasticity involves
GABAA-receptor-subunit switching in an activity-independent manner. It also has
profound effects on the electrical behaviour of the oxytocin neurones and, thus,
the neural control of pregnancy and lactation.
PMID- 10782122
TI - Reply
PMID- 10782121
TI - Human retrosplenial cortex: where is it and is it involved in emotion?
PMID- 10782124
TI - Reply
PMID- 10782123
TI - Dendritic spine density in Purkinje cells.
PMID- 10782125
TI - Central control components of a 'simple' stretch reflex.
AB - The monosynaptic stretch reflex is a fundamental feature of sensory-motor
organization in most animal groups. In isolation, it serves largely as a negative
feedback devoted to postural controls; however, when it is involved in diverse
movements, it can be modified by central command circuits. In order to understand
the implications of such modifications, a model system has been chosen that has
been studied at many different levels: the crayfish walking system. Recent
studies have revealed several levels of control and modulation (for example, at
the levels of the sensory afferent and the output synapse from the sensory
afferent, and via changes in the membrane properties of the postsynaptic neuron)
that operate complex and highly adaptive sensory-motor processing. During a given
motor task, such mechanisms reshape the sensory message completely, such that the
stretch reflex becomes a part of the central motor command.
PMID- 10782126
TI - Ascorbate regulation and its neuroprotective role in the brain.
AB - Ascorbic acid (vitamin C) occurs physiologically as the ascorbate anion: a water
soluble antioxidant that is found throughout the body. However, despite the high,
homeostatically regulated levels of brain ascorbate, its specific functions in
the CNS are only beginning to be elucidated. Certainly, it acts as part of the
intracellular antioxidant network, and as such is normally neuroprotective. There
is also evidence that it acts as a neuromodulator. A possibly unique role it
might have is as an antioxidant in the brain extracellular microenvironment,
where its concentration is modulated by glutamate-ascorbate heteroexchange at
glutamate uptake sites. Ongoing studies of ascorbate and glutamate transporters
should lead to rapid progress in understanding ascorbate regulation and function.
PMID- 10782127
TI - Resonance, oscillation and the intrinsic frequency preferences of neurons.
AB - The realization that different behavioural and perceptual states of the brain are
associated with different brain rhythms has sparked growing interest in the
oscillatory behaviours of neurons. Recent research has uncovered a close
association between electrical oscillations and resonance in neurons. Resonance
is an easily measurable property that describes the ability of neurons to respond
selectively to inputs at preferred frequencies. A variety of ionic mechanisms
support resonance and oscillation in neurons. Understanding the basic principles
involved in the production of resonance allows for a simplified classification of
these mechanisms. The characterization of resonance and frequency preference
captures those essential properties of neurons that can serve as a substrate for
coordinating network activity around a particular frequency in the brain.
PMID- 10782129
TI - How learning mechanisms might affect evolutionary processes.
PMID- 10782128
TI - Calcium signaling in the ER: its role in neuronal plasticity and
neurodegenerative disorders.
AB - Endoplasmic reticulum (ER) is a multifaceted organelle that regulates protein
synthesis and trafficking, cellular responses to stress, and intracellular Ca2+
levels. In neurons, it is distributed between the cellular compartments that
regulate plasticity and survival, which include axons, dendrites, growth cones
and synaptic terminals. Intriguing communication networks between ER,
mitochondria and plasma membrane are being revealed that provide mechanisms for
the precise regulation of temporal and spatial aspects of Ca2+ signaling.
Alterations in Ca2+ homeostasis in ER contribute to neuronal apoptosis and
excitotoxicity, and are being linked to the pathogenesis of several different
neurodegenerative disorders, including Alzheimer's disease and stroke.
PMID- 10782130
TI - Human mitochondrial DNA recombination: can it be true?
PMID- 10782131
TI - Niche versus chance and tree diversity in forest gaps.
AB - Studies that are unprecedented in scale, detail or approach show that niche
partitioning contributes less, and chance events more, than expected to
maintaining tree species richness via gap dynamics in tropical and temperate
forests. Some tree species are differentially adapted for regeneration in
different gap microenvironments. However, the stochastic availability of gaps,
and limited recruitment of juveniles, mean that gaps are filled mostly by chance
occupants rather than by best adapted species. This chance survival can slow
competitive exclusion and maintain tree diversity. Gap dynamics do not explain
the latitudinal gradient in tree richness.
PMID- 10782133
TI - Palaeoclimatic records from peat bogs.
AB - The palaeoclimatic record for the past 6000 years, implemented from peat-bog
stratigraphy, has been limited by imprecision in dating and climatic
interpretation. Recently, dating problems have been addressed by 'wiggle-matched'
radiocarbon dates and by volcanic ash layers, promising much tighter correlation
between records from different regions. Recent research shows key dates of
significant climatic change and tentative evidence for periodicity. Application
of time-series analysis, generalized linear modelling and transfer function
models to the proxy climate data show how improved climatic reconstructions can
be obtained. Peat-derived palaeoclimatic data might explain, as well as describe,
climatic changes over timescales of 102-103 years.
PMID- 10782139
TI - An evolutionary no man's land.
PMID- 10782134
TI - Efficient genetic markers for population biology.
AB - Population genetics has come of age. Three important components have come
together: efficient techniques to examine informative segments of DNA, statistics
to analyse DNA data and the availability of easy-to-use computer packages. Single
locus genetic markers and those that produce gene genealogies yield information
that is truly comparable among studies. These markers answer biological questions
most efficiently and also contribute to much broader investigations of
evolutionary, population and conservation biology. For these reasons, single
locus and genealogical markers should be the focus of the intensive genetic data
collection that has begun owing to the power of genetics in population biology.
PMID- 10782132
TI - Evolution of the avian sex chromosomes and their role in sex determination.
AB - Is it the female-specific W chromosome of birds that causes the avian embryo to
develop a female phenotype, analogous to the dominance mode of genic sex
differentiation seen in mammals? Or is it the number of Z chromosomes that
triggers male development, similar to the balance mode of differentiation seen in
Drosophila and Caenorhabditis elegans? Although definite answers to these
questions cannot be given yet, some recent data have provided support for the
latter hypothesis. Moreover, despite the potentially common features of sex
determination in mammals and birds, comparative mapping shows that the avian sex
chromosomes have a different autosomal origin than the mammalian X and Y
chromosomes.
PMID- 10782135
TI - No inconsistencies in sensitivity analysis.
PMID- 10782138
TI - Reply from R. Carroll.
PMID- 10782136
TI - Reply from M. Mesterton-Gibbons.
PMID- 10782137
TI - A new evolutionary synthesis: do we need one?
PMID- 10782140
TI - Reply from L.G. Harshman and A.A. Hoffmann.
PMID- 10782141
TI - Transgenic organisms in evolutionary ecology.
AB - Evolutionary ecology aims to understand how phenotypes are designed for
reproductive success and survival. Perhaps the most powerful approach towards
this goal is to alter a character genetically and observe the resulting change in
reproduction, survival, growth, defense or competitive ability. Until recently,
this strategy was not practical. Transgenic manipulation now offers a solution -
novel genes are introduced into the germ line and are then expressed in the
developing organism. This technique is already available in model and
agricultural organisms. The challenge for molecular evolutionary ecologists is to
find ways to adopt these powerful systems to understand the mechanisms underlying
adaptive traits and their evolution.
PMID- 10782142
TI - Fatal pulmonary tumor embolism caused by chondroblastic osteosarcoma.
PMID- 10782143
TI - The extraordinary career of Dr Purkinje.
PMID- 10782145
TI - Follow-up of abnormal gynecologic cytology: a college of American pathologists Q
probes study of 16132 cases from 306 laboratories.
AB - OBJECTIVES: To measure the percentage of women with abnormal gynecologic cytology
who have follow-up within 1 year and to identify patient and laboratory
characteristics associated with higher percentages of follow-up. DESIGN AND
SETTING: Retrospective identification of patients with abnormal cervicovaginal
cytology and identification of the initial clinical follow-up activity during the
12 months following the cytologic diagnosis. MAIN OUTCOME MEASURE: Percentage of
women receiving follow-up. RESULTS: Three hundred six laboratories reported
follow-up information on 16 132 patients with gynecologic cytology diagnoses of
carcinoma, high-grade squamous intraepithelial lesion, low-grade squamous
intraepithelial lesion, or glandular intraepithelial lesion. The following
percentages of women received follow-up within 1 year: 85.6% of patients with
cytologic diagnoses of carcinoma, 87.2% with diagnoses of high-grade squamous
intraepithelial lesion, 82.7% with diagnoses of low-grade squamous
intraepithelial lesion, and 84.9% with diagnoses of glandular intraepithelial
lesion. Within 6 months, 82.2% of patients with cytologic diagnoses of carcinoma,
82.4% with diagnoses of high-grade squamous intraepithelial lesion, 71.9% with
diagnoses of low-grade squamous intraepithelial lesion, and 74.7% with diagnoses
of glandular intra-epithelial lesion received follow-up. Overall, 90. 8% of
patients who received follow-up within the 1-year time frame of this study had
their follow-up completed within 6 months. Specific follow-up activities and
their frequencies are listed for each diagnostic category. Patients 30 years old
or younger and pregnant patients had lower follow-up percentages. CONCLUSIONS:
With less than 83% of patients with high-grade squamous intraepithelial lesion or
carcinoma cytology findings having available documentation of follow-up within 6
months, and less than 88% within 1 year, there is room for improvement in this
area of health care. Monitoring and critical analysis of the follow-up process is
a starting point for improvement.
PMID- 10782146
TI - Quality management in gynecologic cytology using interlaboratory comparison.
AB - OBJECTIVE: To describe a comprehensive integrated laboratory quality management
plan for gynecologic cytology. DESIGN AND SETTING: Cytopathology laboratory
performance monitors with interlaboratory comparison. RESULTS: Utilizing College
of American Pathologists Q-Probes studies, the College of American Pathologists
Interlaboratory Comparison Program in Cervicovaginal Cytology, and other
published data, a quality management program for gynecologic cytology involving
diagnostic statistics, screening limits and competency assessment, retrospective
rescreening, real-time rescreening, cytology-biopsy correlation, follow-up of
patients with abnormal cytology results, turnaround time, examination of unknown
slides (survey programs), and new technology is described. CONCLUSION: Regular
coordinated monitoring of performance, with longitudinal and interlaboratory
comparison utilizing the methods described, provides an opportunity to optimize
gynecologic cytology service.
PMID- 10782147
TI - Synchronous occurrence of epithelial and stromal tumors in the stomach: a report
of 6 cases.
AB - OBJECTIVE: The synchronous development of epithelial and stromal tumors in the
stomach has been reported rarely in the literature. A series of 6 such cases is
described in this article. METHODS: Clinical and pathologic data were recorded
and the literature was reviewed. RESULTS: Five cases featured the simultaneous
occurrence of stromal tumors (1 benign, 3 borderline, 1 malignant) and
adenocarcinomas, whereas the stromal tumor in the sixth case was found in
association with a carcinoid. No collision tumors were observed. In 2 cases,
tumors arose from the same site and were closely juxtaposed, but in 4 patients
they developed from different areas of the stomach. A preoperative histologic
diagnosis of both tumors was not achieved in any case. Two patients harbored
occult infiltrative epithelial lesions (1 diffuse-type adenocarcinoma, 1
carcinoid), which were detected only at pathologic examination of the gastric
mucosa adjacent to the stromal tumor. CONCLUSIONS: The simultaneous occurrence of
epithelial and stromal tumors in the stomach can be less rare than usually
expected. Coincidence alone could account for such an association, particularly
in areas with high incidence rates of gastric cancer. The hypothesis that a
single carcinogenic agent might interact with two neighboring tissues in the
stomach inducing the development of tumors of different histotype cannot be
theoretically discarded.
PMID- 10782148
TI - Fas (APO-1/CD95) ligand and Fas expression in renal cell carcinomas: correlation
with the prognostic factors.
AB - BACKGROUND AND OBJECTIVE: Fas ligand (FasL, CD95L) is a type II transmembrane
protein of the tumor necrosis factor family that induces cells to send an
apoptotic signal to cells expressing Fas (CD95, APO-1). It has been shown that
cancers have a dysregulated expression of Fas and FasL system, conferring a
survival advantage. It is important to understand FasL and Fas expression in
tumors, because the growth of cancer might be controlled by Fas-mediated
apoptosis. METHODS: The expressions of FasL and Fas were studied by
immunohistochemical analyses in 51 cases of renal cell carcinomas and the
adjacent normal renal tissues, respectively. In addition, their expressions were
compared with prognostic factors, such as tumor size, nuclear grade, TNM stage,
and histologic types. RESULTS: In nonneoplastic renal tissues, FasL was expressed
in all nephron segments, whereas Fas also expressed in all tubules, except for
glomeruli. In renal cell carcinomas, FasL protein was detected in 50 (98.0%) of
51 cases, whereas Fas expressed in 38 (74.5%) of 51 cases. In fact, the
immunostaining of Fas was less intense than that in the adjacent normal segments
of all cases. The staining pattern showing both high expression of FasL and low
expression of Fas was found in 36 (70.6%) (P = .04) of 51 cases, most of which
were Fuhrman grade 2 or 3 tumors. However, the expression pattern did not
correlate statistically with the tumor size, histologic type, or clinical stage.
On the other hand, most grade 4 tumors displayed high expression of both FasL and
Fas (P<.001). CONCLUSION: These data indicate that high expression of FasL and
low expression of Fas protein in renal cell carcinomas may play a role in evading
surveillance of the immune system. In addition, the FasL and Fas expressions
appear to have a therapeutic implication for high-grade tumors rather than a
prognostic one.
PMID- 10782149
TI - Testicular regression syndrome: a clinical and pathologic study of 11 cases.
AB - CONTEXT: The vanishing or regressed testis is an entity well known to urologists
and pediatric surgeons, affecting approximately 5% of patients with
cryptorchidism. However, there is little review and discussion of this entity
among pathologists with only 2 of 40 published reviews of testicular regression
syndrome (TRS) found in the pathologic literature. OBJECTIVES: To assess
recognition of TRS among a subset of pathologists and to determine the
applicability of histologic criteria for TRS as published. DESIGN: An 8-year
retrospective review of cases submitted as atrophic or regressed testis was
performed. Original diagnosis and diagnosis after review were compared to assess
pathologic recognition of TRS. Pathologic assessment included identification of
vas deferens, epididymis, dystrophic calcification, hemosiderin, dominant vein,
pampiniform plexus-like vessels, and vascularized fibrous nodule formation. At
minimum, the presence of a vascularized fibrous nodule (VFN) with calcification
or hemosiderin or VFN with cord element(s) was required for diagnosis. SETTING
AND PARTICIPANTS: Medical records and pathologic specimens of patients undergoing
surgery for cryptorchidism or with specimens reviewed at a medium-sized
university hospital were analyzed. RESULTS: The original diagnosis in 3 (23%) of
13 cases was that of TRS. On secondary review, 11 (85%) of 13 cases showed
features consistent with TRS. The diagnoses both before and after review showed a
concurrence of 23% (3/13 cases). Two (15%) of 13 cases were correctly recognized
and diagnosed as TRS at primary review; 1 case originally thought to represent
TRS was not confirmed. Pathologic features correlated well with those reported in
the literature. Among all 13 cases, the 11 confirmed TRS cases showed VFN in 11
(85%), intranodular calcification in 8 (62%), intranodular hemosiderin in 9
(69%), vas deferens in 9 (69%), epididymal structures in 5 (38%), and a dominant
venous structure in 11 (85%). The average size of the VFN was 1.1 cm. CONCLUSION:
A urologic and pediatric surgical problem, TRS may be unrecognized by many
practicing pathologists. In the typical situation in which a blind ending
spermatic cord is submitted for tissue analysis, characterization of such cases
as consistent with regressed testis is desirable and achievable in a high
percentage of cases. Pathologists may play a pivotal role in management of these
patients since histologic confirmation of the testis as regressed reassures the
surgeon and the family of the correctness of diagnosis and can eliminate the
necessity for further intervention.
PMID- 10782150
TI - Liposarcoma of the pleural cavity: clinical and pathologic features of 4 cases
with a review of the literature.
AB - BACKGROUND: Primary liposarcomas of the pleura are extremely rare malignancies,
and relatively few reports appear in the world literature. DESIGN: We compiled a
small series of 4 cases of primary pleural liposarcoma from the files of the
Armed Forces Institute of Pathology (Washington, DC) and compared the
histopathologic and clinical features of these 4 cases with those of 9 previously
published cases. RESULTS: Our investigation included the case studies of 9 men
and 4 women, aged 19 to 80 years (average, 49 years). Histologic subtypes in the
9 cases with available information included 5 myxoid liposarcomas, 1 well
differentiated liposarcoma, and 3 liposarcomas with mixtures of histologic types.
Surgical resection with or without chemotherapy appeared to be the most common
form of treatment, although radiation therapy was used in some cases and seemed
beneficial. Survival information was available for 11 cases; 4 patients died of
disease at 7, 9, 12, and 19 months; 1 died of heart failure 2 days after
presentation; 1 died of unknown causes 16 months after presentation; and 3
patients were alive without tumor at 5, 16, and 66 months after diagnosis. One
patient had local recurrence at 2 years. A second surgical resection in this
patient failed, and he died of disease 9 years after initial presentation. A
second patient experienced recurrence at 4 years and was free of disease 4 years
after the second surgical resection. CONCLUSIONS: Primary pleural liposarcomas
occur predominantly in older men, and the myxoid histologic subtype is the most
common. Radiographic or surgical evaluation is important to distinguish primary
pleural liposarcoma from chest wall or mediastinal sarcomas, as well as
metastases from other sites. Although further investigation is needed, evidence
from the cases reviewed here indicates that surgical resection with adjuvant
radiation therapy may benefit patients with primary pleural liposarcoma.
PMID- 10782151
TI - Immunoperoxidase detection of CD10 in Precursor T-lymphoblastic
lymphoma/leukemia: a clinicopathologic study of 24 cases.
AB - CONTEXT: CD10 was originally reported in non-T-cell lymphoblastic
lymphomas/leukemias. It has since been identified, however, in a minority of
cases of T-lympho-blastic lymphoma/leukemia and other hematopoietic and
nonhematopoietic entities. The usual method for the detection of CD10 previously
required fresh tissue. A new antibody for CD10 (56C6) in paraffin embedded tissue
sections, however, has recently become available. OBJECTIVE: To study the
expression of CD10 in paraffin sections of T-lymphoblastic lymphoma/leukemia
using monoclonal antibody 56C6. DESIGN: Twenty-four cases of T-lymphoblastic
lymphoma/leukemia in various anatomic sites were studied. Immunohistochemical
analysis with CD10 and a panel of other hematolymphoid antibodies was performed
in all 24 cases. Gene rearrangement studies for the T-cell receptor by the
polymerase chain reaction were performed in 18 of 24 cases. RESULTS: All cases
were positive with at least 2 T-cell markers. In 15 (63%) of 24 cases CD10 was
positive. T-cell receptor gene rearrangement was detected in 10 of 18 cases.
CONCLUSIONS: Immunodetection of CD10 in T-lympho-blastic lymphoma/leukemia using
monoclonal antibody 56C6 is common. This finding is useful in the evaluation of T
cell neoplasms.
PMID- 10782152
TI - Granular cell traumatic neuroma: a lesion occurring in mastectomy scars.
AB - BACKGROUND: Granular cell changes can be observed in a variety of benign and
malignant tumors, and are seen more commonly in granular cell tumors, which in
about 5% of cases develop in the breast. Granular cells also have been observed
in sites of previous trauma, such as surgery, and are found to be inflammatory
reactions of histiocytic origin. METHODS AND RESULTS: We investigated,
morphologically and immunohistochemically, 2 granular cell lesions occurring in
mastectomy scars after surgery for carcinoma. Both lesions were composed of
strands and nests of large granular cells, haphazardly set in a background of
fibrous tissue, with sparse inflammatory infiltrates. Several tortuous
hypertrophic nerve bundles were also embedded in the fibrous tissue. A few of
these nerve bundles showed degenerative changes and contained granular cells.
Immunohistochemically, granular cells were positive for S100 protein, neuron
specific enolase, vimentin, and CD68 antigen. CONCLUSIONS: We consider these
proliferative lesions of peripheral nerves to have the features of both granular
cell tumor and traumatic neuroma. These cases indicate that traumatic neuroma can
undergo extensive granular cell changes and constitute a previously unrecognized
entity, which we provisionally label granular cell traumatic neuroma. Granular
cell traumatic neuroma has to be taken into consideration when evaluating lesions
occurring at mastectomy scars and should be differentiated from malignant tumors
with granular cells, such as apocrine carcinoma and alveolar soft part sarcoma.
PMID- 10782153
TI - Pyogenic spondylodiskitis: a radiologic/pathologic and culture correlation study.
AB - BACKGROUND: Intervertebral disk tissue is resistant to hematogenous infection
because of its avascularity. However, spondylodiskitis is being diagnosed with
increasing frequency because of advancement in magnetic resonance imaging
technology. There is a dearth of information regarding the bacteriology,
histomorphologic features, and radiopathologic correlation of spondylodiskitis.
DESIGN: The study population consisted of 20 patients diagnosed as having
spondylodiskitis by magnetic resonance imaging with and without gadolinium 67
enhancement and bone scans with technetium Tc 99m or gallium citrate Ga 67.
Twenty-seven biopsy and debridement specimens were obtained from these patients.
The specimens were cultured for microorganisms and also processed for
histopathologic testing. Tissue sections were examined with hematoxylin-eosin and
stains for infectious agents (Gomori's methenamine-silver, Gram, and Ziehl
Neelsen stains). RESULTS: Where intervertebral disk tissue was present (23 of 27
cases), the morphologic changes included vascularization (with or without
granulation tissue), myxoid degeneration, and necrosis. Chronic osteomyelitis was
present in all 27 specimens and was associated with acute osteomyelitis in 7
cases (25%). Twenty-one of 27 cases had positive culture results (mostly pyogenic
bacteria), but special stains revealed microorganisms in sections of the disk in
only 4 cases (3 cases with gram-positive cocci and 1 with yeast consistent with
Blastomyces). Florid acute inflammation was present in all the 4 cases.
CONCLUSION: Histopathologic features of acute spondylodiskitis include vascular
proliferation, myxoid degeneration, and necrosis of the disk tissue with adjacent
chronic osteomyelitis. Acute inflammation is variable and when florid is usually
associated with identifiable organisms on histologic examination. At biopsy,
tissue should be submitted for culture, since culture has a high sensitivity and
specificity for detecting the etiologic organism.
PMID- 10782154
TI - Pulmonary vasculopathy in idiopathic spontaneous pneumothorax in young subjects.
AB - BACKGROUND: We have encountered instances where young subjects with idiopathic
spontaneous pneumothorax have been needlessly referred for investigation of
pulmonary hypertension because surgical pathologists have misinterpreted the
significance of medial hypertrophy and intimal fibrosis of muscular pulmonary
arteries in lung resection specimens. METHODS: We reviewed 20 cases of idiopathic
spontaneous pneumothorax and determined the prevalence and severity of medial and
intimal lesions in the pulmonary arteries and pulmonary veins. We correlated the
vascular changes with inflammation and fibrosis in the lung. RESULTS: Pulmonary
artery medial hypertrophy was seen in 15% of cases, pulmonary artery intimal
fibrosis in 90% of cases, and pulmonary vein intimal fibrosis in 80% of cases. In
95% of cases, the lung showed some fibrosis and chronic inflammation. There was a
significant positive correlation between pulmonary artery medial thickness and
lung fibrosis and inflammation scores. CONCLUSIONS: Pulmonary artery medial
hypertrophy and intimal fibrosis of pulmonary arteries and pulmonary veins are
commonly seen in resected lung tissue from patients with idiopathic spontaneous
pneumothorax. The vascular lesions are probably secondary to chronic inflammation
and fibrosis in the adjacent lung. They are not clinically significant and do not
represent hypertensive pulmonary vascular disease.
PMID- 10782155
TI - Human papillomavirus type, proliferative activity, and p53: potential markers of
aggressive papillomatosis.
AB - CONTEXT: The predictive value of nuclear proliferation antigen (Ki-67), tumor
suppressor gene product p53, and human papillomavirus type has not been evaluated
for outcome of laryngeal papilloma. OBJECTIVE: This study was designed to
determine whether immunohistochemical analysis of Ki-67 and p53 and human
papillomavirus typing by polymerase chain reaction are able to identify patients
with a more aggressive course of laryngeal papillomatosis. DESIGN:
Immunohistochemistry and polymerase chain reaction were performed on archival,
paraffin-embedded, laryngeal papillomatosis biopsy specimens at the time of
diagnosis, at an intermediate time during treatment, and at the last procedure
available. Staining indexes for Ki-67 and p53 were determined, and human
papillomavirus type was analyzed for all biopsies. PATIENTS: Twelve patients with
recurrent laryngeal papillomatosis for at least 5 years were selected from
patients treated at our institution during the last 20 years. MAIN OUTCOME
MEASURES: Separate analyses were conducted comparing average Ki-67 and p53
indexes against disease outcome, viral type, or average number of procedures per
year. Associations were analyzed between virus type, average number of procedures
per year, outcome, and histology. RESULTS: No statistically significant
associations were noted in Ki-67 or p53 indexes and outcome. Weak associations
were noted for p53 indexes and procedures per year and virus type. Weak
associations also were noted between virus type and development of neoplasia.
CONCLUSIONS: Our observations suggest that human papillomavirus typing may be
helpful in identifying patients with aggressive recurrent laryngeal
papillomatosis. The weak association between p53 indexes and procedures per year
and virus type may have some predictive value in identifying aggressive lesions.
PMID- 10782156
TI - Retrorectal cystic hamartoma: report of 5 cases with malignancy arising in 2.
AB - BACKGROUND: Retrorectal cystic hamartomas, or tailgut cysts, are rare congenital
lesions that typically present as presacral masses. These lesions are frequently
clinically unrecognized and misdiagnosed. Malignant change is extremely rare.
Only 10 additional cases with associated malignancy were recovered from the
literature. We describe the clinicopathologic features of 5 cases, including 2
cases with malignant transformation. RESULTS: All patients were women (age range,
36-69 years). The most common symptoms were pain with defecation and rectal
bleeding. One patient was asymptomatic. All lesions presented as multicystic
presacral masses and all were surgically resected. The lesions varied in size
from approximately 2 to 12 cm (average, 9.5 cm) and overall had similar histology
composed of a variety of epithelial linings (stratified squamous, transitional,
and simple or ciliated pseudostratified columnar). Skin adnexa, neural elements,
and heterologous mesenchymal tissue, discriminators between retrorectal cystic
hamartoma and teratoma, were not identified. Arising in association with the
cysts was a focus of adenocarcinoma in one case and a neuroendocrine carcinoma in
another. CONCLUSIONS: The clinical diagnoses in our cases were often delayed,
which in part may be due to unfamiliarity with this entity. The main diagnostic
difficulty is distinction from presacral mature cystic teratomas and rectal
duplication cysts. Tailgut cysts require complete surgical excisions to prevent
future recurrences and to preclude possible malignant transformation. Meticulous
gross examination and adequate sampling are important to document the exact
nature of these cysts and to rule out possible coexisting malignancies, which may
be focal.
PMID- 10782157
TI - Acquired hemophilia in patients with hematologic malignancies.
AB - OBJECTIVES: To evaluate the occurrence of acquired hemophilia in patients with
hematologic malignancies and to assess their response to treatment. DESIGN: Data
on 8 patients with hematologic neoplastic disorders and inhibitor against factor
VIII were analyzed retrospectively. SETTING: Three large tertiary-care centers.
RESULTS: All 8 patients presented with spontaneous or posttraumatic hemorrhages.
The mean inhibitor titer at the time of diagnosis was 79 Bethesda units (BU), and
residual factor VIII activity was detectable in 3 patients. The inhibitor
disappeared in 5 patients after a mean of 92 days, but persisted in the 3 other
patients. The patients who achieved complete resolution of their circulating
anticoagulant had lower mean inhibitor titers at the time of diagnosis than those
who had persistent inhibitor (27 BU vs. 167 BU, respectively). Two patients died
as a result of major hemorrhages that did not respond to treatment. CONCLUSIONS:
Antibodies against factor VIII may be responsible for some bleeding episodes in
patients with lymphoid or myeloid malignancies. Acquired hemophilia in this
setting should be differentiated from other causes of bleeding because the
approach to treatment is different. No conclusion can be drawn regarding the
association between the activity of the underlying illness and the inhibitor
titer, although it appears that at least in some patients such a relationship may
exist. The underlying pathogenetic mechanisms responsible for the production of
autoantibodies against factor VIII remain unclear, but we provide a few
explanations in this article.
PMID- 10782158
TI - Non-hodgkin malignant lymphoma with tissue neutrophilia: a report of 3 cases.
AB - CONTEXT: Neutrophils, in the absence of necrosis, are uncommon in non-Hodgkin
malignant lymphoma. Recently, a neutrophil-rich type of Ki-1 (CD30)-positive,
anaplastic large cell lymphoma was described. OBJECTIVES: We report 3 cases of
nonanaplastic large cell lymphoma with an abundance of tissue neutrophils; 2
cases were associated with breast carcinoma and possible infection. RESULTS:
Peripheral blood neutrophilia was noted in only 1 of these 3 patients.
Neutrophilia in the lymph nodes occurred in either a sinusoidal or interstitial
pattern. Multiple biopsies were available for review in 2 patients; however,
tissue neutrophilia was present in only 1 biopsy each. CONCLUSION: These findings
suggest that nonanaplastic large cell lymphoma-related tissue neutrophilia is a
transient phenomenon.
PMID- 10782159
TI - Declining autopsy rate in a French hospital: physician's attitudes to the autopsy
and use of autopsy material in research publications.
AB - CONTEXT: Autopsy rates have been declining throughout the world, although
preservation of the autopsy is considered a fundamental principle of medical
care. In France, the 1994 bioethics law requires physicians to inform relatives
before performing an autopsy. OBJECTIVE: To analyze the following factors that
potentially influence hospital autopsy rates: legal constraints, autopsy
reporting times, opinions of physicians requesting autopsies and pathologists
regarding the usefulness of autopsy in patient care, and use of autopsy material
in research publications. DESIGN: Record of the annual numbers of deaths and
autopsies during a 10-year period (1988-1997). Record of the delays for
transmission of final autopsy report to the requesting physician. Questionnaire
analyzing the possible factors influencing autopsy rate. Categorization of
articles published by pathologists according to the use of autopsy material.
SETTING: A 1000-bed, university teaching hospital in the Paris, France, area.
PARTICIPANTS: Questionnaire addressed to physicians, head nurses, and mortuary
staff. RESULTS: A total of 1454 autopsies were reviewed. The autopsy rate
declined from 15.4% in 1988 to 3.7% in 1997. This decline was marked after 1994
and tended to be slower for neurologic indications than for other indications.
The final report had not been communicated within 180 days in 620 (42.6%) of 1454
autopsies. Fifty-five of 105 respondents considered that the bioethics law was
one cause of the recent decrease of autopsy rate. Considering the contribution of
autopsy to medical research, 94 (81%) of 116 articles dealing with central
nervous system but only 28 (6%) of 464 articles dealing with other organs used
autopsy-derived material. CONCLUSIONS: The 1994 bioethics law seems to contribute
to the decline of autopsy. Inadequate delays for communicating autopsy results
are frequent. Except for neuropathologists, autopsy is a minor source of research
material.
PMID- 10782160
TI - Lymphoepithelioma-like carcinoma of the uterine cervix: a case report studied by
in situ hybridization and polymerase chain reaction for Epstein-Barr virus.
AB - Lymphoepithelioma-like carcinomas have been reported outside the nasopharynx in
many sites, including the uterine cervix. The association with the Epstein-Barr
virus in the latter site is still controversial. To date, Epstein-Barr virus
genome has only been demonstrated in Asian patients. We report a case of
lymphoepithelioma-like carcinoma of the uterine cervix in a white woman in whom
the Epstein-Barr virus infection was tested for by in situ hybridization and
polymerase chain reaction. The results of both techniques were negative. Our case
and a review of the literature support the contention that cervical
lymphoepithelioma-like carcinoma is not associated with Epstein-Barr virus
infection in non-Asian patients.
PMID- 10782161
TI - Blastic transformation of splenic marginal zone B-cell lymphoma.
AB - To our knowledge, blastic transformation of splenic marginal zone lymphoma, a
recently characterized low-grade lymphoproliferative disorder, has not been
reported previously. In this regard, we report the unique case of a 70-year-old
woman whose untreated splenic marginal zone lymphoma underwent blastic
transformation 3 years after diagnosis. Her hematologic medical history started
in 1988 as thrombocytopenia refractory to steroids associated with atypical
lymphoid infiltrate in the bone marrow. She underwent splenectomy in 1989, which
revealed splenic marginal zone lymphoma. One year later, the patient developed
lymphadenopathy noted in the chest, axillary, abdominal, and retroperitoneal
lymph nodes. Because she was asymptomatic, treatment was limited to a
conservative supportive regimen. The nodal lymphoma cells had features associated
with marginal zone lymphoma and expressed B-cell monotypic kappa light chain. She
was readmitted for the last time 2 years later with findings of 16% blasts in the
peripheral blood and massive infiltration of the bone marrow by large blastoid
cells. The blasts showed dispersed chromatin and prominent nucleoli, and
possessed a moderate amount of clear cytoplasm. The blasts, like the previous
nodal and splenic lymphomas, had a CD20-, CD19-, IgM-positive phenotype, but
lacked reactivity for CD5, CD10, and CD23. The patient displayed clinical
remission after treatment with vincristine and prednisone, but died of aspiration
pneumonia 1 month later. These observations suggest that, similar to the other
low-grade lymphoproliferative disorders, an untreated splenic marginal zone
lymphoma may undergo high-grade blastic transformation.
PMID- 10782162
TI - Early peripheral lymph node involvement of human herpesvirus 8-associated, body
cavity-based lymphoma in a human immunodeficiency virus-negative patient.
AB - Human herpesvirus 8 (HHV-8), or Kaposi sarcoma-associated herpesvirus, is a gamma
herpesvirus first detected in a specimen of Kaposi sarcoma from a human
immunodeficiency virus (HIV)-positive patient. Human herpesvirus 8 is also found
in an unusual clinicopathologic form of body cavity-based B-cell lymphoma, which
has been named primary effusion lymphoma (PEL) and occurs primarily in HIV
positive patients. PEL is characterized by the formation of lymphomatous
effusions, without obvious lymphadenopathy, tumor masses, or bone marrow
involvement. Only a few cases of PEL in HIV-seronegative patients have been
reported. We describe a case of an HHV-8-associated lymphoma, with ascites,
pleural effusion, and axillary lymphadenopathy in an HIV-negative patient. The
patient was a 68-year-old Jewish man of North African extraction, with a previous
history of coronary bypass surgery and multiple blood transfusions. The pleural
fluid contained large atypical lymphoid cells and was suggestive of lymphoma but
could not provide a conclusive diagnosis of PEL. The lymph node contained groups
of large anaplastic lymphoid cells. Polymerase chain reaction for HHV-8 performed
on the lymph node specimen was positive, establishing the diagnosis of PEL.
Polymerase chain reaction for Epstein-Barr virus was negative. Results of a
gallium scan were normal. The patient did not respond to combination chemotherapy
with cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone and
progressively developed, massive intra-abdominal solid tumor formation. To our
knowledge, this is the first report of a case of PEL that demonstrates peripheral
lymph node involvement at diagnosis and the first report of PEL in an Israeli
patient.
PMID- 10782163
TI - Solitary fibrous tumor of the orbit with a t(9;22)(q31;p13).
AB - Solitary fibrous tumors are well-described neoplasms found predominantly in the
subpleural region but also in many other body sites. They generally behave in a
benign fashion, although a few cases that exhibit a malignant course have been
reported. Genetic information on solitary fibrous tumors is sparse. This case
illustrates a previously unreported finding of a tumor-specific t(9;22)(q31;p13)
in a solitary fibrous tumor of the orbit of a 58-year-old man.
PMID- 10782164
TI - Diagnostic value of immunocytochemistry in leptomeningeal tumor dissemination.
AB - Differentiating chronic aseptic meningitis from leptomeningeal carcinomatosis or
gliomatosis can be difficult, particularly when the differentiation is based
solely on routine cytologic examination. The diagnosis of cerebrospinal fluid
tumor dissemination in at-risk patients requires cytologic examination of
cerebrospinal fluid and radiography of the leptomeninges. Routine cytologic
examination alone has proven less than desirable, in most instances providing
confirmation in as little as 50% of cases in the first lumbar puncture. This
percentage increases to 85% to 90% after multiple lumbar punctures. We
retrospectively reviewed 2 cases of leptomeningeal dissemination (one
gliomatosis, the other carcinomatosis) with initial false-negative test results.
However, after further examination of the cerebrospinal fluid by selected battery
of immunocytochemical stains, both cases were identified as positive for
malignancy (ie, false negatives). Immunocytochemistry can be useful in
distinguishing chronic aseptic meningitis from leptomeningeal carcinomatosis or
gliomatosis in patients at risk or when abnormal cells are seen on routine
cerebrospinal fluid cytologic examination.
PMID- 10782165
TI - Primary meningeal rhabdomyosarcoma in a child with hypomelanosis of Ito.
AB - Intracranial rhabdomyosarcomas are rare neoplasms, and those thought to be
primary meningeal tumors are even more rare. Hypomelanosis of Ito is a
neurocutaneous disorder believed to involve a defect in cells of neural crest
origin. We report the case of a 15-month-old boy with hypomelanosis of Ito who
developed a primary meningeal rhabdomyosarcoma. The patient initially presented
with hydrocephalus and 2 months later developed neurologic signs localizing to
the spinal cord. Radiologic studies revealed widespread leptomeningeal
enhancement with compression of the spinal cord at C5-C7. A brain biopsy revealed
a tumor diffusely involving the meninges. Microscopically, the tumor was composed
of rhabdomyoblasts, many of which showed prominent cross-striations on routine
hematoxylin-eosin staining. To the best of our knowledge, this is the first
reported case of meningeal rhabdomyosarcoma in a patient with hypomelanosis of
Ito and the fourth reported case of a primary meningeal rhabdomyosarcoma reported
in the world literature.
PMID- 10782166
TI - Unilocular retroperitoneal cyst of mesothelial origin presenting as a renal mass.
AB - We report the first 2 cases, to our knowledge, of retroperitoneal cysts with
features of mesothelial differentiation that clinically mimic renal masses. The
first lesion occurred in a 71-year-old man who presented with flank pain.
Ultrasound and magnetic resonance imaging studies showed a unilocular cystic
structure arising from the upper pole of the left kidney. The second lesion was
in a 44-year-old woman who presented with left flank pain. Imaging studies
revealed an 8-cm hemorrhagic cyst at the lower pole of the left kidney.
Histologic examination of the nephrectomy specimens in each case revealed a
unilocular cyst with intracystic and pericystic hemorrhage. In each case, the
cyst was lined by a single layer of cells with ample eosinophilic cytoplasm and
benign nuclear features without mucinous or mullerian differentiation.
Histochemical staining showed Alcian blue positivity on the cell surface, which
was sensitive to hyaluronidase digestion. Intracytoplasmic mucin, however, was
not detected. Immunostaining showed that the cyst lining cells were positive for
keratin, vimentin, HBME-1, WT1, and thrombomodulin but negative for
carcinoembryonic antigen, B72.3, Leu-M1, and BerEP4. The first case was positive
for calretinin, whereas the second was negative. These findings support the
mesothelial nature of the cysts.
PMID- 10782167
TI - Coexisting thymic and gastric lymphomas of mucosa-associated lymphoid tissues in
a patient with Sjogren syndrome.
AB - Lymphomas of mucosa-associated lymphoid tissues (MALTomas) arising from the
thymus are extremely rare. In this case report, we describe a 36-year-old woman
with an 11-year history of Sjogren syndrome who was found to have a thymic
MALToma coexisting with a gastric MALToma. Both tumors shared similar histologic
features, showing clusters of centrocytic-like B cells, lymphoepithelial lesions,
and prominent plasmacytic differentiation. They also showed the following
identical immunohistochemical features: CD20(+), IgA/lambda(+), CD5(-), and CD43(
). Molecular studies using polymerase chain reaction methods revealed monoclonal
gene rearrangement of the immunoglobulin heavy chain in the gastric MALToma, but
not in the thymic MALToma. The possible pathogenesis of this unusual case is
discussed.
PMID- 10782168
TI - Staining method to demonstrate urate crystals in formalin-fixed, paraffin
embedded tissue sections.
PMID- 10782169
TI - Evaluation of a combined acid-fast-trichrome stain for detection of microsporidia
and Cryptosporidium parvum.
PMID- 10782172
TI - Tumors of the lymph nodes and spleen (CD-ROM)
PMID- 10782173
TI - Tumors of the lower respiratory tract (CD-ROM)
PMID- 10782174
TI - Pathologic quiz case: a large cystic thigh mass in a 10-year-old boy.
PMID- 10782175
TI - Pathologic quiz case: a testicular mass in a 19-year-old man.
PMID- 10782176
TI - Pathologic quiz case: a 46-year-old woman with a brain tumor.
PMID- 10782177
TI - Efficacy and safety of patient-controlled analgesia for morbidly obese patients
following gastric bypass surgery.
AB - BACKGROUND: Adequate postoperative pain control is important to reduce potential
cardiopulmonary complications. It is often difficult to determine dosages of
narcotics for morbidly obese patients following Roux-en-Y gastric bypass (RYGBP)
due to respiratory depression. Individualization of analgesic therapy, patient
controlled analgesia (PCA), can provide optimal dosage for pain control and
minimize the side-effects. METHOD: 25 morbidly obese patients who received PCA
with morphine sulfate following RYGBP. PCA settings we re as follows: morphine,
20 microg/kg of ideal body weight, 10-minute lock out interval and 80 % of a
calculated amount for a 4-hour limit. W e measured arterial blood gas, heart
rate, mean arterial pressure, arterial oxygen saturation, respiratory rate,
opioid amount, patient satisfaction, visual analog pain scale (VAS), and the
incidence of nausea, vomiting, pruritus and sedation. RESULTS: Average morphine
usage was 44.2+/-28.7 mg during the day of surgery (DOS); 49.1+/-27.4 mg during
POD (postoperative day) #1; and 36.6+/-22.8 mg during POD#2 (p < 0.01). 24
patients were satisfied with their pain control on POD#1. VAS was 5.4+/-2.1 on
the day of surgery, but remained below 4 thereafter. Arterial oxygen saturation
and vital signs were maintained without significant changes. 5 patients
experienced mild sedation on the day of surgery and 3 patients experienced mild
sedation on POD#1. 1 patient experienced nausea and vomiting and 4 patients had
pruritus; however, none required treatment. CONCLUSION: PCA is safe and effective
for morbidly obese patients following RYGBP.
PMID- 10782178
TI - Variables affecting BMI evolution at 2 and 5 years after vertical banded
gastroplasty.
AB - BACKGROUND: Vertical banded gastroplasty (VBG) has been found to result in
significant reduction in body mass index (BMI) during the first postoperative
year. We investigated the impact of some intrinsic and extrinsic factors on long
term BMI evolution in morbidly obese patients who underwent VBG, with the aim of
establishing a long-term weight-loss prognosis. METHODS: 67 consecutive morbidly
obese patients who underwent VBG were followed for 2 years; of these, 34 were
followed 3 more years, for a total follow-up of 5 years. BMI was monitored and
correlated with demographic (preoperative BMI, obese relatives, age and gender)
and lifestyle variables (physical activity, habitual dietary transgression and
occupational status). RESULTS: Global BMI fell from 47.5 at the time of the
intervention to 32.1 when patients were examined 12 months after surgery. From
the second year, an upward trend was observed, and at 5 years, mean BMI was above
35, considered in the high-risk range. Modifiable variables affecting lifestyle
have shown significantly favorable effects on BMI evolution. Among intrinsic
variables, BMI before surgery and obese parents also affect long-term evolution.
CONCLUSION: Different variables should be considered in order to establish a long
term weight-loss prognosis for each patient, thus making it possible to act more
specifically on modifiable variables.
PMID- 10782179
TI - Gastroscopic band removal after intragastric migration of adjustable gastric
band: a new minimal invasive technique.
AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is the most used
procedure for bariatric surgery in Europe. Although a low complication rate is
reported, band migration within the first 2 years after LAGB is still observed in
nearly 5% of cases, requiring operative band removal. To avoid increased risk of
complications due to laparotomy, we propose a minimally invasive technique for
this purpose. METHODS: We performed this operation in five patients who suffered
from band migration after LAGB (1.9% in our series of 211 patients, one patient
was operated elsewhere). The described method consists of gastroscopic band and
tube removal, combined with removal of the port under local anesthesia. RESULTS:
The described procedure was developed in the endoscopy unit without additional
equipment. The mean operating-time ranged from 65 to 180 minutes (mean 135
minutes). No perioperative complication were observed. In-patient treatment was
necessary for 4 days. CONCLUSIONS: A novel technique for minimally invasive band
removal after adjustable gastric band migration is described, offering the
patient a low-risk procedure and a better chance for further laparoscopic
approaches.
PMID- 10782180
TI - Adjustable gastric banding: 5-year experience.
AB - BACKGROUND: From 1993 to 1999, 172 patients underwent adjustable silicone gastric
banding (ASGB) or laparoscopic adjustable silicone gastric banding (LASGB). In
109 patients the adjustable band was placed via laparoscopy; in the other
patients it was placed via laparotomy (prelaparoscopic era, conversions from
other bariatric operations, conversions for laparoscopic failure). The conversion
rate from laparoscopy to laparotomy was 9.3%, occurring in the early part of our
experience. METHODS: Mean age was 37.9 years, weight 135 +/- 14.8 kg (82-218) and
BMI 46.3 +/- 5.4 (35.1-69.5). All patients had multiple band adjustments,
temporary antisecretive, electrolyte and vitamin therapy, and follow-up per
routine. RESULTS: Weight loss at 3 years was 30.2%; mean percent loss of excess
weight was 62.5%. There was no mortality. The most important technical
complications were: gastric pouch dilatation that required band replacement or
removal (5.8 %); mild gastric pouch dilatation reversible with adequate dietary
and pharmacological treatment (4.6%); intraoperative gastric perforation (2.3%);
band migration (0.6%). The band was removed in 2.3%, with conversion to another
bariatric procedure in 1.1%. CONCLUSIONS: Results have been satisfactory thus
far.
PMID- 10782181
TI - Facilitated vertical gastric pouch construction for gastric bypass.
AB - BACKGROUND: Efforts to simplify and reduce surgical risk of gastric pouch
construction in super obese patients have led to technical changes which are
described. METHODS: Operative technique of vertical gastric pouch construction
and hand-sewn Roux gastrojejunostomy are described. RESULTS: 171 patients with
average BMI = 55 have undergone gastric bypass with the modified technique, a
majority with double stapling of the gastric pouch. Staple-line dehiscence is
reduced and operative morbidity is limited. CONCLUSIONS: Technical changes
described have shortened operative time, reduced intraoperative frustrations, and
produced limited postoperative morbidity.
PMID- 10782182
TI - Failure of biliopancreatic diversion in Prader-Willi syndrome.
AB - BACKGROUND: Prader-Willi syndrome (PWS) is the most common genetic obesity.
Excessive weight gain follows failure-to-thrive in early infancy; in adolescents
and young adults, excess body weight can exceed 100%. The hyperphagia associated
with PWS is responsible for the early mortality. Dietary restriction, alone or
combined with anorexic drugs, are ineffective to induce a permanent weight loss.
Thus, surgical treatment of morbid obesity in PWS has been attempted, but gastric
restrictive operations are unable to produce stable weight loss. In a small
number of patients, favorable results have been reported with biliopancreatic
diversion (BPD). CASE REPORT: A 24-year-old woman with PWS, Pickwickian, at age
21 weighed 80 kg (BMI= 50) and underwent BPD. RESULTS: 3 years after the BPD she
regained 21 of the 26 kg lost; somnolence and respiratory difficulties were the
same as before surgery. The patient now presents severe reduction of bone mass
density, hypochromic anemia, hypoproteinemia, and diarrhea associated with
eating. CONCLUSION: The regain of weight following BPD suggests that this
procedure alone is not adequate for long-term control of obesity in PWS.
PMID- 10782183
TI - BPD and prader willi syndrome
PMID- 10782184
TI - Experience with the Roux-en-Y gastric bypass, and commentary on current trends.
PMID- 10782185
TI - Transactions in a support group meeting: a case study.
AB - Following bariatric surgery, the inclusion of a support group as part of the
treatment plan makes after-care easier and more efficient for the patients, as
well as for the physicians. The following is presented for the education of the
medical community. It represents one exemplary session which incorporates the
elements necessary for effective after-care: 1. Encouragement for compliance and
praise for success. 2. Education about life-after-surgery, including nutrition,
exercise and dieting techniques. 3. Identification of problems. 4. Identification
and development of new kinds of self-nurturing. 5. Participation in a forum where
others really "understand" the challenges and difficulties associated with
"change," even when the change is for the better. 6. Creation of a "safe harbor"
where patients can bring spouses, parents and significant others so that they may
also understand, encourage continuing success, and recognize their own personal
issues related to the major changes that they are also experiencing with their
loved one. 7. Opportunity for curious potential patients in the community to come
and learn from the "experts" in an atmosphere of true caring and concern.
PMID- 10782187
TI - Time trends analysis of hearing loss: an alternative approach to evaluating
hearing loss prevention programs.
AB - Two general approaches for evaluating the performance of hearing loss prevention
programs (HLPPs) are described in the literature: (1) a comparison of the rate of
hearing loss in an HLPP with a reference population and (2) a comparison of
audiometric variability or annual incidence of hearing loss with an established
set of criteria that rank HLPP performance on a graded scale. This article
discusses a third method, time trends analysis, which assesses patterns in
hearing loss over time. Patterns may reflect program improvement (decreased
hearing loss incidence over time), deterioration (a pattern of increased
incidence), or stasis (unchanged incidence). To demonstrate this method, a time
trends analysis was conducted on a population of 44,547 industrial workers.
Subjects were divided into 11 subgroups based on year of enrollment in the HLPP
(1980-1990) and followed retrospectively for 3 years to determine the incidence
of hearing loss. Hazard ratios (HRs) were estimated for each subgroup by gender
using the Cox Proportional Hazards model and adjusting for age, race, and hearing
threshold at enrollment in the HLPP. For women, plots of adjusted HRs against
enrollment years produced a statistically significant (p < 0.05) quadratic trend
of an initial increase in hearing loss, followed by decreasing incidence over
time. For men, there was a statistically significant linear trend of decreasing
hearing loss over time. The downward trend, particularly during the late 1980s,
indicates improved HLPP performance during the latter portion of the decade. Time
trends analysis can be a valuable tool for assessing HLPP performance for those
with access to follow-up data and ability to work with statistical models.
PMID- 10782186
TI - Lung fibrosis reported in a dental technician.
PMID- 10782188
TI - Construction and evaluation of an aerosol generating apparatus for combustion
products from polyurethane foam.
AB - A system has been constructed and evaluated for generating aerosols from
combustion or pyrolysis of various cross-linked polymers. The system consists of
an aerosol generator and an aerosol chamber with a sampling compartment designed
for various samplers and sampling probes. A geared electric motor assembly is
used to lower a polymer strip into the controlled atmosphere of a quartz-lined
furnace. The polymer used in this investigation was a polyurethane foam (PUF)
based on toluene diisocyanate (TDI). Combustion of the PUF was conducted in
filtered air at a temperature of 300 degrees C. The particle number concentration
of the generated aerosol was measured by light scattering in the particle size
range from 0.1 micron to greater than 5 microns. Air samples were collected
periodically in impinger flasks using dibutylamine (DBA) in toluene as
derivatization reagent. The TDI-DBA derivatives from the impinger samples were
analyzed with high performance liquid chromatography. The aerosol generating
system was found to generate a stable, reproducible, and predictable
concentration of particles and TDI monomer. Three partial least squares models
were created to evaluate the generator. The investigated responses were the TDI
concentration, the particle number concentration, and the stability of the
particle number concentration during the generating process. The factor with most
impact on the concentrations of the generated aerosol was found to be the
interaction between linear feeding rate of the polymer strip and the flow rate of
combustion gas. For stability the linear feeding rate was the most important.
PMID- 10782189
TI - The impact of work environment, utility, and sampling design on occupational
magnetic field exposure summaries.
AB - Most recent epidemiologic studies investigating the potential health effects of
occupational magnetic field (MF) exposure have relied on MF measurement data
linked to job titles. These measurements are summarized by occupational
categories, which represent similar groups of job titles. However, job titles
alone explain only a small proportion of exposure variability. A comprehensive MF
occupational exposure database was used to (1) develop summary job-specific
estimates of magnetic field exposure, (2) evaluate the impact of incorporating
work environment data to improve electric and magnetic field exposure assessment,
and (3) evaluate the use of random versus nonrandom sampling when estimating mean
MF exposure levels by occupational categories. Uniform classification systems
were developed for occupational and work environment data. A factorial design was
used to summarize and calculate arithmetic means and 95% confidence intervals for
occupational MF data, assuming that the total variation in MF exposure resulted
from variation in occupation, work environment, utility, worker, and day.
Occupation-specific means varied across different work environments, particularly
for craft workers. Although within-worker and between-worker variability account
for a large proportion (over 50%) of exposure variation, work environment (24%)
accounted for more exposure variability than occupation (4.9%) or utility (15%).
Some differences were observed when results were compared from surveys that used
random and nonrandom sampling; however, these differences were not consistent or
systematic. It was concluded that MF exposure assessment should consider work
environment in addition to job title to reduce exposure misclassification.
PMID- 10782190
TI - Experimental validation of potential and turbulent flow models for a two
dimensional jet enhanced exhaust hood.
AB - A two-dimensional jet-reinforced slot exhaust hood was modeled using a
mathematical model based on potential flow theory and with a computational fluid
dynamics (CFD) model using the standard k-epsilon model for turbulence closure.
The accuracy of the calculations was verified by air velocity and capture
efficiency measurements. The comparisons show that, for normal operating
conditions, both the models predicted the mean airflows in front of the hood
well. However, the CFD model gave more realistic results in the jet flow region
and also of the short-circuiting flow. Both models became increasingly inaccurate
when the ratio of the supply jet momentum to the exhaust flow rate increased. The
jet enhancement proved to be a very efficient way to increase the effective
control range of exhaust hoods. Controlled air movements can be created at
distances that are two to three times larger than with conventional suction alone
without increasing the exhaust flow rate.
PMID- 10782191
TI - Personal monitoring instrument for the selective measurement of multiple organic
vapors.
AB - Development and laboratory testing of a small instrument capable of recognizing
and quantifying multiple organic vapors at low- and sub-ppm concentrations is
described. The instrument is slightly larger than a standard personal sampling
pump and employs an array of three polymer-coated surface-acoustic-wave
microsensors for vapor detection. Vapors are first trapped on a miniature
adsorbent preconcentrator housed within the instrument and then thermally
desorbed for analysis by the microsensor array. Each measurement cycle requires
5.5 min. The collective responses from the array are stored and then analyzed
using pattern recognition methods to yield the identities and concentrations of
collected vapors and vapor mixture components. Following initial optimization of
instrument operating parameters, calibrations were performed with 16 organic
solvent vapors and selected mixtures to establish a response library for each of
two identical instruments. Limits of detection < or = 0.1 x threshold limit value
were obtained for most vapors. In a series of 90 subsequent exposure tests,
vapors were recognized with an error of < 6% (individual vapor challenges) and <
16% (binary mixture challenges) and quantified with an average error of < 10%.
Monte Carlo simulations were coupled with pattern recognition analyses to predict
the performance for many possible vapor mixtures and sensor combinations.
Predicted recognition errors ranged from < 1 to 24%. Performance is shown to
depend significantly on the interfacial polymer layers deposited on the sensors
in the array and the nature and complexity of the vapor mixtures being analyzed.
Results establish the capability of this technology to provide selective
multivapor monitoring of personal exposures in workplace environments.
PMID- 10782192
TI - Mycobacterial contamination of metalworking fluids: involvement of a possible new
taxon of rapidly growing mycobacteria.
AB - Contamination of air and metalworking fluid (MWF) systems with a rapidly growing
mycobacterium (RGM) was detected in 1995 in a single manufacturing plant with
recent cases of hypersensitivity pneumonitis (HP). Extensive environmental
sampling was performed to determine the extent of the contamination and its
variability over time. RGM were present in multiple indoor air samples, 100% of
the central MWF storage tanks, and 75% of the freestanding cutting, drilling, and
grinding machines. With one exception, contamination was limited to a recently
introduced formulation (brand) of semisynthetic MWF used in 95% of the facility's
machining operations. In general, the mycobacterial counts were stable over time,
with the degree of contamination ranging from 10(2)-10(7) colony forming units
(CFU)/mL. A few systems were culture positive for the mycobacterium (> 10(1)
CFU/mL), changed to culture negative (< 10(1) CFU/mL), then changed back to
culture positive without explanation. Samples obtained from diluted (5%) but
unused MWF, a replenishment line with 2% unused MWF, an MWF pasteurizer, city
water, and deionized water were culture negative for this species of
mycobacterium. Inoculation and growth studies demonstrated that this
mycobacterium does not grow in liquid samples of 5% unused MWF. By molecular
techniques, the mycobacterial isolates consisted of a single strain and
represented a previously undescribed taxon closely related to Mycobacterium
chelonae/abscessus. The relationship of this mycobacterium to the cases of HP is
unknown.
PMID- 10782193
TI - Carbonless copy paper: a review of its chemical components and health hazards.
AB - The components of carbonless copy paper (CCP) and the chemistry involved in its
manufacture are reviewed. Claims that the routine use of CCP can cause health
problems ranging from skin, eye, and lung irritation to severe headaches and
neurological damage are described; yet no definitive studies have been conducted
that show correlation between CCP use and these symptoms. The toxicological
properties of CCP components, many of them precursors to the dye-containing
microcapsules or dye solvents that may be causing these problems, are discussed.
Recommendations for the minimization of possible physiological reactions to CCP
include reduction of usage time; use of the CCP in a well-ventilated area;
storing large quantities of CCP, both new or archived, away from work area; and
the practice good hand hygiene.
PMID- 10782195
TI - Workplace risk factors and occupational musculoskeletal disorders, Part 2: A
review of biomechanical and psychophysical research on risk factors associated
with upper extremity disorders.
AB - Injuries and disorders caused by overexertion and repetitive motion are the
leading causes of compensable lost-time cases in the United States.
Epidemiological and laboratory-based research methods have been used to evaluate
the significance of various risk factors associated with overuse injuries and
disorders. The National Institute for Occupational Safety and Health performed a
comprehensive review of over 600 epidemiological studies in 1997 and concluded
that there was evidence of a causal relationship between workplace exposures to
forceful exertions, repetition, awkward posture, and vibration and disorders of
the neck, shoulder, and upper extremities. Although epidemiological studies
provide important insights to understanding the causes of work-related overuse
disorders, they are sometimes criticized for their inability to measure precisely
how people respond to specific risk factors found in the workplace. This article
presents a review of recent laboratory studies and biomechanical models of work
factors believed to be associated with increased risk of upper extremity injuries
and disorders. Biomechanical models and laboratory studies do not replace
epidemiological studies. However, these approaches provide important
complementary information that is needed to understand the complex process of how
exposures to physical risk factors result in strain that may ultimately lead to
injury or disease. These studies also provide important insights as to how people
react and respond to specific physical risk factors found in the workplace.
Combined with epidemiological research, laboratory studies are an essential
element in understanding the causes and prevention of work-related overexertion
injuries.
PMID- 10782194
TI - Computer users' postures and associations with workstation characteristics.
AB - This investigation tested the hypotheses that (1) physical workstation dimensions
are important determinants of operator posture, (2) specific workstation
characteristics systematically affect worker posture, and (3) computer operators
assume "neutral" upper limb postures while keying. Operator head, neck, and upper
extremity posture and selected workstation dimensions and characteristics were
measured among 379 computer users. Operator postures were measured with manual
goniometers, workstation characteristics were evaluated by observation, and
workstation dimensions by direct measurement. Considerably greater variability in
all postures was observed than was expected from application of basic geometric
principles to measured workstation dimensions. Few strong correlations were
observed between worker posture and workstation physical dimensions; findings
suggest that preference is given to keyboard placement with respect to the eyes
(r = 0.60 for association between keyboard height and seated elbow height)
compared with monitor placement with respect to the eyes (r = 0.18 for
association between monitor height and seated eye height). Wrist extension was
weakly correlated with keyboard height (r = -0.24) and virtually not at all with
keyboard thickness (r = 0.07). Use of a wrist rest was associated with decreased
wrist flexion (21.9 versus 25.1 degrees, p < 0.01). Participants who had easily
adjustable chairs had essentially the same neck and upper limb postures as did
those with nonadjustable chairs. Sixty-one percent of computer operators were
observed in nonneutral shoulder postures and 41% in nonneutral wrist postures.
Findings suggest that (1) workstation dimensions are not strong determinants of
at least several neck and upper extremity postures among computer operators, (2)
only some workstation characteristics affect posture, and (3) contrary to common
recommendations, a large proportion of computer users do not work in so-called
neutral postures.
PMID- 10782196
TI - Chronic beryllium disease and beryllium sensitization at Rocky Flats: a case
control study.
AB - A case-control study was conducted to evaluate the risk of chronic beryllium
disease (CBD) and beryllium sensitization (SENS) associated with various levels
of historical beryllium exposure at the Rocky Flats nuclear weapons facility.
Fifty CBD and 74 SENS cases were matched to controls of the same age group, race,
gender, and smoking status. A job exposure matrix was developed from job history
data and fixed airhead (FAH) exposure data available from 1960 to 1988. Job
titles and building areas were assigned factors based on exposure relative to a
machinist in the Building 444 Beryllium Shop. Concurrence on these factors was
obtained from past and present Rocky Flats industrial hygienists. Using the
matrix, long-term mean and cumulative exposures were estimated for each subject.
Both exposure estimates (p < 0.0001) and years of employment (p = 0.010) were
found to be significantly higher for CBD cases as compared with their controls,
but not so for the SENS cases as compared with their controls. Logistic
regression analyses showed statistically significant relationships between both
cumulative and mean exposure and CBD, but not for SENS. These findings suggest
that reduced worker exposures might lower the future incidence of CBD, but may
not necessarily lower the incidence of SENS.
PMID- 10782197
TI - Benzene and total hydrocarbon exposures in the upstream petroleum oil and gas
industry.
AB - Occupational exposures to benzene and total hydrocarbons (THC) in the Canadian
upstream petroleum industry are described in this article. A total of 1547 air
samples taken by 5 oil companies in various sectors (i.e., conventional oil/gas,
conventional gas, heavy oil processing, drilling and pipelines) were evaluated
and summarized. The data includes personal long- and short-term samples and area
long-term samples. The percentage of samples over the occupational exposure limit
(OEL) of 3.2 mg/m3 or one part per million for benzene, for personal long-term
samples ranges from 0 to 0.7% in the different sectors, and area long-term
samples range from 0 to 13%. For short-term personal samples, the exceedance for
benzene is at 5% with respect to the OEL of 16 mg/m3 or five parts per million in
the conventional gas sector and none in the remaining sectors. THC levels were
not available for all sectors and had limited data points in others. The
percentage exceedance of the OEL of 280 mg/m3 or 100 parts per million for THC as
gasoline ranged from 0 to 2.6% for personal long-term samples. It is recommended
that certain operations such as glycol dehydrators be carefully monitored and
that a task-based monitoring program be included along with the traditional long-
and short-term personal exposure sampling.
PMID- 10782198
TI - Communication using a telephone while wearing a respirator.
AB - Respirators have been found to degrade communication effectiveness when wearers
speak face-to-face. However, little is known about communication effectiveness
when using the telephone and wearing a respirator. Eleven pairs of subjects were
asked to pronounce and identify words chosen from Modified Rhyme Test lists. Each
word appeared on a computer screen in one room and the speaker said the word into
the telephone. The listener in another room identified the word and typed it into
a computer linked with the first. Subjects wore U.S. Army M40 full-facepiece air
purifying respirators with hoods. Three different speech diaphragm arrangements
and two hood materials were tested. Results show that accuracy suffered by about
10% when respirators and hoods were worn compared with the control condition.
Word identification speed was one-third to one-half of the control (no respirator
or hood) condition depending on specific equipment worn.
PMID- 10782200
TI - Mist control at a machining center, Part 1: Mist characterization.
AB - At a machining center used to produce transmission parts, aerosol instrumentation
was used to quantitatively study mist generation and to evaluate the performance
of an air cleaner for controlling the mist. This machining center drilled and
tapped holes at rotational speeds of 1000 to 3000 rpm. During most machining
operations, the metal-working fluid (MWF) was flooded over the part. To
facilitate metal chip removal during some operations, MWF was pumped through the
orifices in some tools at a pressure of 800 psi. These machining operations were
performed in a nearly complete enclosure that was exhausted to an air cleaner at
a flow rate of 1.1 m3/sec (2400 ft3/m). Although the use of high-pressure MWF
increased the mist concentration by about 200%, it did not affect the mist size
distribution. The observed penetration through the air cleaner appeared to be
mostly consistent with the manufacturer's specifications on the air cleaner's
filters. During the testing, MWF was observed to accumulate in the bottom of the
filter housing and may have been reentrained due to air motion or mechanical
vibration.
PMID- 10782199
TI - Field evaluation of a portable photoionization detector for assessing exposure to
solvent mixtures.
AB - To evaluate a portable photoionization detector for assessing personal exposure
to solvent mixtures, a set of 26 side-by-side, time-weighted average (TWA)
personal breathing zone samples were collected during various construction
painting tasks by two different sampling methods: (1) standard charcoal sorbent
tubes analyzed by gas chromatography (CST/GC), and (2) a direct-reading
photoionization detector coupled with an extended data-logger (PID). The TWA
concentrations of the hydrocarbons detected by CST/GC analysis were summed for
comparison with the TWA concentration obtained from the direct-reading PID. Based
on linear regression between the log TWA concentrations of the two sampling
methods, the data were highly correlated (r2 = 0.95). Since the solvents had
effects that may be considered additive, threshold limit values (TLVs) for
mixtures were developed using American Conference of Governmental Industrial
Hygienists formulas to evaluate solvent exposure. The logs of the TLV mixture
data from the sampling methods were highly correlated (r2 = 0.94). Based on the
linear regression analyses, the response of the portable PID was highly
correlated to the CST/GC results for hydrocarbon mixtures encountered during
various painting tasks. Due to the short duration of tasks, highly fluctuating
exposures, and complexity of the mixtures, the PID may provide the most cost
effective, detailed exposure assessment for solvent mixtures.
PMID- 10782201
TI - Mist control at a machining center, Part 2: Mist control following installation
of air cleaners.
AB - At a machining center used to produce transaxle and transmission parts, aerosol
instrumentation was used to quantitatively evaluate size-dependent mist
generation of a synthetic metalworking fluid (MWF) consisting primarily of water
and triethanolamine (TEA). This information was used to select an air cleaner for
controlling the mist. During most machining operations, the MWF was flooded over
the part. These machining operations were performed in a nearly complete
enclosure that was exhausted to an air cleaner consisting of three sections: a
fall-out chamber, a trifilter section to capture metal chips and mist, and a 1.13
m3/sec (2400 ft3/min) blower. The partnering company requested that National
Institute for Occupational Safety and Health (NIOSH) researchers perform an
evaluation of the effectiveness of a commercially available air cleaner. After
NIOSH researchers characterized mist generation at the machining centers and
found that performance of a test air cleaner appeared to be suitable, the company
installed more than 25 air cleaners on different machining centers in this plant
and enclosed the corresponding fluid filtration unit. The facility also has
implemented a maintenance program for the air cleaners that involves regularly
scheduled filter changes; performance is ensured by monitoring static pressure. A
NIOSH-conducted air sampling evaluation showed that area TEA concentrations were
reduced from a geometric mean of 0.25 to 0.03 mg/m3. Personal total particulate
concentrations were reduced from a geometric mean of 0.22 to 0.06 mg/m3. These
results show the effectiveness of this combination of enclosure, ventilation, and
filtration to greatly reduce the exposure to MWF mist generated in modern
machining centers.
PMID- 10782203
TI - Proficiency Analytical Testing (PAT) Program November 1999.
PMID- 10782202
TI - Short-term efficacy of back injury intervention project for patient care
providers at one hospital.
AB - A one-year Back Injury Prevention Program was initiated at a 440-bed acute care
hospital in 1996 in response to concerns over high incidence and severity of back
injuries among nursing staff and others. The program included an ergonomic
evaluation of patient handling, pilot testing and purchase of new equipment, a
train-the-trainer program, and training of 374 nurses and other patient handling
staff (approximately one-half of the nursing staff). An impact evaluation,
measured by comparing self-reported knowledge, work practices, and back pain
among a subset of trainees and controls revealed an increase in knowledge of risk
factors, a marginal increase in the use of mechanical devices to transfer
patients, and a significant decrease in repositioning of patients in bed among
trained versus control subjects (p = .017). Over the course of the program, the
number of back injuries was 30% below the average of the prior 3 years, with the
number of reported injuries in the final quarter (immediately following the
training program) approximately one-seventh of the three prior quarters. It is
concluded that back injury training may increase knowledge of risk factors and
controls and may impact behaviors over which individuals have control (e.g., how
often they move patients). However, training effectiveness is limited when
engineering controls such as patient transfer devices are unavailable.
PMID- 10782204
TI - Environmental Lead Proficiency Analytical Testing (ELPAT) Program September 1999.
PMID- 10782205
TI - Localization of the locus responsible for Chediak-Higashi syndrome in cattle to
bovine chromosome 28.
AB - Chediak-Higashi syndrome in Japanese black cattle is a hereditary disease with
prolonged bleeding time and partial albinism. In the present study, we mapped the
locus responsible for the disease (CHS) by linkage analysis using microsatellite
genotypes of paternal half-sib pedigrees obtained from commercial herds. Analysis
revealed significant linkage between the CHS locus and marker loci on the
proximal end of bovine chromosome 28. The CHS locus was mapped on the region
incorporating the microsatellite markers BMC6020, BM2892, and RM016 with
recombination fraction 0 and lod score 4.9-11.2. We also assigned the bovine
CHS1/LYST, the homologue of the gene responsible for human Chediak-Higashi
syndrome, to bovine chromosome 28 using a bovine/murine somatic cell hybrid
panel. These findings suggest that a mutation in the CHS1/LYST gene is likely to
be responsible for Chediak-Higashi syndrome in Japanese black cattle.
PMID- 10782206
TI - Genetic mapping of a locus associated with bovine chronic interstitial nephritis
to chromosome 1.
AB - Chronic interstitial nephritis with diffuse zonal fibrosis (CINF) occurs in
Japanese Black cattle (Wagyu) as an autosomal recessive disorder leading to death
prior to puberty, first six months or a year of life. We performed a genome-wide
scan using microsatellite markers in a Wagyu pedigree segregating for CINF and
mapped the CINF locus to bovine chromosome 1. CINF was closest to microsatellites
BM9019 and INRA49 (Z score = 12.0; P < 3.4 x 10(-10)).
PMID- 10782207
TI - Differences in gene density on chicken macrochromosomes and microchromosomes.
AB - The chicken karyotype comprises six pairs of large macrochromosomes and 33 pairs
of smaller microchromosomes. Cytogenetic evidence suggests that microchromosomes
may be more gene-dense than macrochromosomes. In this paper, we compare the gene
densities on macrochromosomes and microchromosomes based on sequence sampling of
cloned genomic DNA, and from the distribution of genes mapped by genetic linkage
and physical mapping. From these different approaches we estimate that
microchromosomes are twice as gene-dense as macrochromosomes and show that
sequence sampling is an effective means of gene discovery in the chicken. Using
this method we have also detected a conserved linkage between the genes for
serotonin 1D receptor (HTR1D) and the platelet-activating factor receptor protein
gene (PTAFR) on chicken chromosome 5 and human chromosome 1p34.3. Taken together
with its advantages as an experimental animal, and public access to genetic and
physical mapping resources, the chicken is a useful model genome for studies on
the structure, function and evolution of the vertebrate genome.
PMID- 10782208
TI - Localization of Xho1 repetitive sequences on autosomes in addition to the W
chromosome in chickens and its relevance for sex diagnosis.
AB - Repetitive sequences of the Xho1 family comprise about 70% of the W chromosome in
chickens, are considered to be restricted to this sex chromosome and are used in
sex diagnosis. This study investigated the reliability of sex diagnosis on small
cell numbers. Fluorescent in situ hybridizations (FISH) with the Xho1 repeat
sequence were performed on metaphases and signals were detected on the W
chromosome and on some autosomes. Differences in signal intensity suggested that
the number of repeats ranged from several thousand on the W chromosome to only a
few on the autosomes. These results confirm the report from Clinton (1994) of
minor male products in sex specific PCR of the Xho1 repeat. We adopted his PCR
protocol to analyze small numbers of cells. FISH on blastomeres and on blood
cells from E3 to E11 embryos were compared to PCR results. The FISH procedure as
well as the PCR protocol are suitable for sexing. For single cells FISH was
slightly more consistent.
PMID- 10782209
TI - Patterns of ribosomal gene variation in elite commercial chicken pure line
populations.
AB - The nucleolus organizer region (NOR) encodes the tandemly repeated 18S, 5.8S and
28S ribosomal (r) RNA genes. The NORs of broiler and layer commercial chicken
pure lines were studied to establish the type and extent of genetic variation at
this important locus. The parameters studied were gene copy number, repeat size,
and diversity of NOR-types. The populations were organized into three groups for
analysis including brown-egg broiler (13 lines), brown-egg layer (six lines), and
white-egg layer (eight lines). The ribosomal gene copy number average of the
white-egg layer populations was significantly lower (329 genes) than that of the
brown-egg layers (372 genes); the brown-egg broiler ribosomal gene average was
intermediate (350 genes). The white-egg layer populations exhibited a ribosomal
repeat unit average size of 36 kb, significantly different from the brown-egg
layer and brown-egg broiler average repeat unit size of 32.5 and 33.9 kb,
respectively. NOR array size was similar among the three groups (6 mb). The brown
egg broiler populations exhibited polymorphic NOR patterns, intra- and interline,
whereas the white-egg layer populations were essentially monomorphic for NOR
type; brown-egg layers exhibited an intermediate level of NOR diversity. Some NOR
array characteristics may be a function of breed origin as brown-egg commercial
populations, both broilers and layers, have similar breed origins and exhibited
similarities for predominant repeat unit size as compared with white-egg layer
populations. However, the finding that brown-egg broiler lines typically exhibit
a greater number of segregating NOR-types than brown-egg layer lines suggests
that the selection schemes of broiler vs. layer pure line populations may also
have influenced the degree of variation at this gene complex.
PMID- 10782210
TI - Characterization of Iberian pig genotypes using AFLP markers.
AB - The use of the AFLP (amplified fragment length polymorphism) technique for the
characterization of highly inbred Iberian pig breed genotypes and the detection
of strain-specific polymorphisms is demonstrated. Twelve different primer
combinations were used on individual DNA samples from animals belonging to two
black hairless Iberian pig strains, Guadyerbas and Coronado. These amplification
reactions allowed the detection of more than 1700 amplification products of which
26 were identified as strain-specific markers, present in all individuals of one
strain and absent in the other. Comparison of male and female amplification
products within one strain also allowed the identification of 8 male-specific
amplified bands. AFLP showed a great power of marker detection due to a high
multiplex ratio and high reproducibility. Comparison of similarity and co
ancestry coefficient matrices also showed the usefulness of AFLP markers to
estimate genetic relationships between individuals pigs.
PMID- 10782211
TI - Chromosomal assignment of canine TSC2, PKD1 and CLN3 genes by radiation hybrid-
and linkage analyses.
AB - The canine tuberous sclerosis 2 (TSC2) gene has been mapped to canine chromosome
6 using a canine whole genome radiation hybrid panel. There is close linkage
between canine TSC2 and the polycystic kidney disease 1 gene (PKD1), as has been
observed in humans and other mammalian species. The gene responsible for the
human juvenile form of neuronal ceroid lipofuscinosis (CLN3), maps close to TSC2
and PKD1 in humans, and is also syntenic in the dog. We further demonstrate
linkage to a group of polymorphic markers assigned to canine chromosome 6 (CFA6).
PMID- 10782212
TI - Y-specific microsatellite polymorphisms in a range of bovid species.
AB - At least five dinucleotide (CA)n microsatellite repeat arrays have been assigned
to the bovine Y-chromosome, with one marker (INRA124) shown to be polymorphic. We
describe here the assessment of a panel of four Y-specific microsatellite markers
for polymorphism in a range of cattle and related species. It was possible to
amplify all the markers in the animals sampled and all showed variation. Three of
the microsatellite loci (INRA124, INRA189 and BM861) displayed putative taurine-
and zebu-specific alleles which can be useful indicators of male-mediated gene
flow in hybrid populations. In the future these microsatellites, in combination
with other Y-specific markers should provide a high-resolution Y haplotype system
for evolutionary studies in both domesticated cattle and other related species.
PMID- 10782213
TI - Resolution of conflicting assignments for the bovine casein kinase II alpha
(CSNK2A2) gene.
AB - The casein kinase II alpha' gene (CSNK2A2), which physically maps to human
chromosome 16 (HSA16), has previously been mapped to bovine chromosome 5 (BTA5).
Based on these results, a new segment of homology between the human and bovine
genomes was suggested. In this paper we demonstrate linkage between CSNK2A2 and
several markers on BTA18. Our result is supported by the extensive conservation
of synteny between HSA16q and BTA18. Bovine chromosome 18 markers used in this
study included several microsatellites, as well as the MC1R gene previously
mapped to HSA16q24.3. Sequencing of the PCR-fragment mapped to BTA5 reveals that
a CSNK-like retroposon was responsible for the conflicting assignments. The
present results further extend the observed conservation of synteny between
HSA16q and BTA18.
PMID- 10782215
TI - Eight new dinucleotide microsatellite loci in turkey (Meleagris gallopavo).
PMID- 10782214
TI - Exclusion of the PDE6A gene for generalised progressive retinal atrophy in 11
breeds of dog.
AB - The cyclic guanosine monophosphate specific phosphodiesterase (cGMP-specific PDE)
is a key enzyme in the phototransduction cascade of the vertebrate retina. This
enzyme consists of two catalytic alpha and beta subunits, two identical
inhibitory gamma subunits as well as a delta subunit. Mutations in PDE6A and the
PDE6B genes lead to autosomal recessive (ar) forms of retinitis pigmentosa (RP)
in human and to the homologous disease in dogs, designated generalised
progressive retinal atrophy (gPRA). We investigated the PDE6A gene in 13 gPRA
affected dog breeds including healthy animals, obligate gPRA carriers and gPRA
affected dogs. In the coding region of PDE6A only a rare sequence variation
(G103A; Asp35Asn) was found in exon 1 of two healthy Tibet Terriers and one
affected Cocker Spaniel. Using single-stranded conformation polymorphism (SSCP)
analyses we detected several sequence variations in eight of the PDE6A introns in
different investigated breeds. Most informative for excluding the PDE6A gene as a
cause for gPRA was a polymorphic microsatellite ((GT)10CG(GT)2CG(GT)12) in intron
14 and four sequence variations in intron 18 for almost all breeds investigated.
The sequence variations of PDE6A did not segregate together with gPRA in 11
breeds. Since diseased animals were heterozygous for the polymorphisms, the PDE6A
gene is unlikely to harbour the critical mutation causing gPRA in the following
breeds: Chesapeake Bay Retriever. Entlebucher Sennenhund, Labrador Retriever.
Tibet Mastiff, Dachshund (long- and wire-haired), Tibetan Terrier, Miniature
Poodle. Australian Cattle Dog, Cocker Spaniel, Saarloos/Wolfshound, Sloughi.
PMID- 10782216
TI - Genetic variations in the ovine calpain regulatory subunit.
PMID- 10782217
TI - Twenty-one new equine dinucleotide repeat microsatellites.
PMID- 10782218
TI - Polymorphic microsatellites associated with the equine CKM and CMA1 genes.
PMID- 10782219
TI - The gene encoding a chicken chemokine with homology to human SCYC1 maps to
chromosome 1.
PMID- 10782220
TI - Two polymorphic microsatellite markers from novel Penaeus monodon ESTs.
PMID- 10782221
TI - Chromosomal assignments and polymorphism information content in sheep for 12
cattle microsatellites.
PMID- 10782222
TI - Linkage mapping of goat ChirUCO, LSCV and SR-CRSP microsatellites in sheep.
PMID- 10782223
TI - Ten equine dinucleotide microsatellite repeats HTG18-19, HTG22-24, HTG26-27,
HGT29-30 and HTG32.
PMID- 10782224
TI - A TaqI PCR-RFLP at the bovine myogenic factor (MYF5) gene.
PMID- 10782225
TI - The porcine adenosine monophosphate deaminase 1 (AMPD1) gene maps to chromosome
4.
PMID- 10782226
TI - Dinucleotide repeat polymorphism at the ovine McMA1, McMA2, McMA5, McMA8, McMA9,
McMA11, McMA14, McMA20, McMA24, McMA26 loci.
PMID- 10782227
TI - The isolation and characterization of 18 equine microsatellite loci, TKY272
TKY289.
PMID- 10782228
TI - A NciI PCR-RFLP within intron 2 of the porcine insulin-like growth factor 2
(IGF2) gene.
PMID- 10782229
TI - Broad taxonomic applicability of microsatellites developed for the highly
polymorphic neotropical cichlid, Amphilophus citrinellum.
PMID- 10782231
TI - A PCR test for mitochondrial heteroplasmy in sturgeon.
PMID- 10782230
TI - Two polymorphic markers for the horse SLC11A1 (NRAMP1) gene.
PMID- 10782232
TI - Mapping of the oncogene c-myc (MYC) and the breast cancer susceptibility gene
(BRCA2) in the pig by FISH.
PMID- 10782233
TI - HpaII PCR-RFLP within a Bov-A2 element in the promoter of the bovine CYP21
(steroid 21-hydroxylase) gene.
PMID- 10782234
TI - Four PCR-RFLPs and a sequence polymorphism in the porcine c-myc proto-oncogene
and confirmation of the chromosomal localisation on SSC4 by linkage mapping.
PMID- 10782236
TI - [Cardiopulmonary resuscitation: anecdote or public health problem?].
PMID- 10782235
TI - Linkage mapping of an AvaI PCR-RFLP within the porcine uncoupling protein 3
(UCP3) gene.
PMID- 10782237
TI - [Colonization by methicillin-resistant Staphylococcus aureus is a predictive
factor for the resistance phenotype of an infectious strain of S. aureus].
AB - OBJECTIVE: To assess the predictive value of a previous colonization with
methicillin-resistant Staphylococcus aureus for the resistance pattern of a
bacteriological specimen significantly positive to S. aureus. STUDY DESIGN:
Retrospective study of patients' files. PATIENTS: Patients admitted for at least
48 hours in a surgical intensive care unit from April 1, 1996 to December 31,
1997. METHODS: Collection of patients' characteristics and chronology of positive
microbiological specimens with methicillin-susceptible (MSSA) or -resistant
(MRSA) S. aureus from medical and laboratory records. During the study period,
screening for nasal or perineal colonization with MRSA was systematically
performed on admission and weekly thereafter. RESULTS: The files of 540 patients
were reviewed. MSSA and MRSA infections occurred in 7% (39/540) and 4% (20/540)
of the patients respectively. By opposition with MSSA infections, MRSA infections
occurred more frequently in patients previously colonized with MRSA (13
infections in 63 colonized patients [21%] versus 7 infections in 477 non
colonized patients [2%], odds ratio = 18, confidence interval: 6-51, P < 0.0001).
The median delay between colonization and infection was 5 days. The positive and
negative predictive values for previous colonization with MRSA to predict
infection with MRSA in presence of a bacteriological specimen significantly
positive with S. aureus were 81 and 84%, respectively. CONCLUSION: The
probabilistic use of a glycopeptide in presence of a bacteriological specimen
significantly positive with S. aureus should be limited to patients already
colonized with MRSA, in order to decrease the abusive administration of these
antibiotics.
PMID- 10782238
TI - [Effect of bronchial drainage on the improvement in gas exchange observed in
ventral decubitus in ARDS].
AB - OBJECTIVES: A bronchial secretion draining effect is frequently suggested as a
mechanism for oxygenation improvement during prone positioning (PP) in patients
with acute respiratory distress syndrome (ARDS). Nevertheless, it has never
really been evaluated. The aim of this study was to search for an
interrelationship between the volume of the bronchial secretion and the
improvement of the PaO2/FIO2 ratio during prone positioning, with NO inhalation
or not. STUDY DESIGN: Open prospective clinical study. PATIENTS: The study
included 15 consecutive patients with severe ARDS (PaO2/FIO2 < 200 after alveolar
recruitment, Murray score > 2.5). METHODS: They were returned to the prone
position for 4 hours (h0-h4) combined with an inhalation of 5 ppm NO during 1
hour (h2-h3). Tracheal suction were performed hourly between h-2 and h6 and
weighed on a precision scale from h-1 to h6. Haemodynamic, blood gas and
respiratory compliance were recorded at h0, h2, h3, h4 and h6. RESULTS: No
significant haemodynamic changes were observed in the various phases. Compared
with the baseline condition at h0, PP and PP + NO respectively improved PaO2/FIO2
by 102 +/- 62% at h2 (P < 0.005) and 156 +/- 79% at h3 (P < 0.005/h0 and <
0.01/h2). 14/15 patients responded to PP and 15/15 to PP + NO (gain in PaO2/FIO2
> 10%). Concerning secretions, we collected 3.0 +/- 7.5 g, 4.4 +/- 6.1 g, 1.7 +/-
1.4 g and 1.7 +/- 1.6 between h-2 and h0, h0 and h2, h2 and h4, h4 and h6.
Individual assessments showed no relationship between the PaO2/FIO2 evolution at
any time and the quantity of secretions obtained during the first 2 hours in the
prone position. Six patients presented secretions of less than 1 g between h0 and
h2, and for whom the improvement in oxygenation was higher than average (115 +/-
53% at h2). CONCLUSION: In patients with little or moderate secretions, the
improvement observed in oxygenation, with or without NO, does not depend on their
volume.
PMID- 10782239
TI - [Effect of a lung contusion on the prognosis of severe head injury in the child].
AB - OBJECTIVES: To assess the effects of a pulmonary contusion (PC) on the outcome of
a severe head trauma (SHT) in children less than 15-year-old. STUDY DESIGN:
Retrospective study. PATIENTS: The study included 30 severely head injured
children with a Glasgow Coma Scale score (GCS) < or = 8, associated with a PC
(PC+) diagnosed on a thoracic CT-scan and 30 severely head injured children
without PC (PC-). METHODS: Outcome was assessed using the Glasgow Outcome Scale
(GOS), on discharge and six months later. Age, body weight, gender, GCS, PTS,
ISS, hypoxaemia, arterial hypotension, the results of the cerebral CT-scan, the
main treatment administered, complications, the duration of tracheal intubation
as well as the duration of stay in the intensive care unit (ICU) and in the
hospital were compared between groups. RESULTS: GCS median was lower (6 vs 8, P =
0.001) and ISS median higher (25 vs 23, P = 0.0004) in the PC+ group. Hypoxaemia
was more frequent in the PC+ group (n = 12 vs n = 0, P = 0.0001). There was no
difference between groups regarding the results of cerebral CT scan. Blood
transfusion was more frequently used in the PC+ group (n = 14 vs n = 5, P =
0.03). Median duration of tracheal intubation, and of stay in the ICU and in the
hospital were shorter in the PC- group (respectively 8 vs 6 days, P = 0.03; 10 vs
7.5 days, P = 0.008; 13.5 vs 10.5 days, P = 0.01). No difference was observed
regarding complications between groups. GOS on discharge was higher in the PC+
group (3 vs 2, P = 0.01). There was an increase in GOS at six months in the two
groups, however GOS remained significantly higher in the PC+ group (median values
2 vs 1, P = 0.002). A favourable outcome occurred less frequently in the PC+
group on discharge and at six months (respectively n = 14 vs 25, P = 0.006; n =
20 vs 28, P = 0.02). CONCLUSION: The association of a PC to a severe head trauma
is responsible for a poorer outcome in children, probably because, at least in
part, a higher incidence of hypoxaemia.
PMID- 10782240
TI - [Equipment surveillance of implantable catheter ports (1996-1998). Members of Sub
Commissions 4a and 4b for Equipment Surveillance].
AB - We analyse all incident reports to the French Health Ministry over the 1996-1998
period, concerning implantable catheter ports. They represent 7% of all reports
in the field of anaesthesia and intensive care. Two hundred eleven reports have
been analysed. There were 93 catheter ruptures with 77 intravascular migrations.
In more than 50% of cases, a pinch-off syndrome mechanism was responsible of
these ruptures and a displacement of the O'ring was involved in 25%. Additional
minor complications were reported and discussed in regard to literature. We
conclude that implantable catheter ports may lead to serious incidents which are
preventable in most cases.
PMID- 10782242
TI - [Puffer fish poisoning].
AB - We report three cases of a collective tetrodotoxin poisoning, after ingestion of
puffer fish eggs. This neurotoxin is the most potent membrane stabilizer,
blocking the nervous conduction and resulting in death from respiratory paralysis
in case of massive ingestion. The father died at admission, the mother and her
daughter presented an acute respiratory failure and a flaccid tetraplegia, with
favourable outcome after 24 hours.
PMID- 10782243
TI - [Diagnosis of a persistent left superior vena cava in the operating room during a
central venous catheterization].
AB - A 2-year-old boy was admitted for surgical excision of a hepatoblastome. A
central venous catheter was inserted by a subclavian approach, without
difficulty. The chest radiograph showed the catheter positioned along the left
heart border. The diagnosis of persistent left superior vena cava was suspected
after analysis of the central venous pressure curve. An postoperative chest X-ray
confirmed the diagnosis. The catheter was maintained for five days without any
complication.
PMID- 10782241
TI - [Glycopeptides].
AB - OBJECTIVES: To review pharmacology, pharmacokinetic and therapeutic use of
glycopeptides in intensive care units. DATA SOURCES: Extraction from Medline
database of French and English articles on glycopeptides and search along with
major review articles. DATA SELECTION: The collected articles were reviewed and
selected according to their quality and originality. The more recent data were
selected. DATA SYNTHESIS: Glycopeptides are bactericidal antibiotics which are
only active against Gram positive species acting by inhibiting peptidoglycan
synthesis. They had been in clinical use for almost 30 years without high-level
resistance underlining. For ten years, there have been disturbing reports of
first, resistance to vancomycin in enterococcal species and more recently in
strains of Staphylococcus aureus by complex and large mechanisms of action. This
new resistances may lead to a therapeutic impasse and a fatal issue for infected
patients. The only response to this situation is the respect of prescription
rules and the careful use of antibiotics. CONCLUSION: Considering their spectrum,
glycopeptides are an antibiotic family which importance is fundamental to treat
infected patients of intensive care units. Staff members of intensive care units
are responsible for their good use.
PMID- 10782244
TI - [Multi-recurrent cardiac arrest: when to discontinue cardiopulmonary
resuscitation?].
AB - A 52-year-old man developed an out-of-hospital cardiac arrest complicating a
myocardial infarction. After prolonged cardiopulmonary resuscitation, he was
admitted to an intensive care unit, where 25 episodes of cardiac arrests occurred
within a few hours. Finally the outcome was favourable. This case raises the
question of the duration a cardiopulmonary resuscitation in case of out-of
hospital and in-hospital cardiac arrest. The question is to determine how long
resuscitation efforts must be prolonged after recurrent cardiac arrests.
PMID- 10782245
TI - [Chance discovery of methanol poisoning during a state of inebriation].
AB - We report a case of wood alcohol (methylated spirits) poisoning in a 40-year-old
chronic alcoholic. The initial diagnosis of state of drunkenness was supported by
the increased plasma level of ethanol (4.66 g.L-1) obtained with enzymatic
method. The confirmation, using gas chromatography (GC), showed an unexpected
peak with a retention time at 1.19 min, characteristic of methanol (0.41 g.L-1).
The GC analysis of the absorbed beverage revealed a 5% methanol content. The
osmolal gap was 115 mOsm.kg-1, with 13 mOsm.kg-1 due to methanol and 90 mOsm.kg-1
to ethanol. Seven hours after the ingestion, the anion gap was at 13 mmol-1. This
result reflected the inhibition of methanol oxidation by alcohol-dehydrogenase,
when the plasma ethanol concentration was above 1 g.L-1. This concentration was
maintained by continuous intravenous administration of (Curethyl-A) a 95% ethanol
containing solution, until methanol concentration decreased below 0.2 g.L-1. The
outcome was favourable without neurological and ophthalmological sequelae.
PMID- 10782246
TI - [Is an authorization for care necessary for the incapacitated adult?].
AB - We report the case of a 30-year-old mentally disabled patient who presented for
diagnostic colonoscopy. This patient raised the problem of authorization for such
a procedure and the related anaesthetic. The French law of 1968 on the protection
of severely incapacitated persons does not clearly solve the problem of the
consent for procedures with a therapeutic finality. The distinction relies
usually on the extent of the planned act, for asking for an agreement of the
guardian, judge of guardianship or the family board. In such cases the problem of
the practice of an anaesthetic remains unsolved. For scheduled procedures it is
recommended to obtain the written consent of the guardian before any medical act.
PMID- 10782247
TI - [Possibility of an incorrect connection between certain respiratory filters and
the expiratory segment of the Ambu-A non-rebreathing valve].
AB - Several models among the contemporary disposable bacterial filters, heat and
moisture exchangers can be inadvertently inserted into the expiratory port of the
Ambu A nonrebreathing valve. Such a misconnection, which does not allow
expiration, is made possible because of the respective sizes of the connection
ports of the devices. International standards and French regulations specify
neither the internal diameter of the expiratory port of the nonrebreathing
valves, nor the external diameter of the circuit connecting port of the
respiratory filters.
PMID- 10782248
TI - [How to read a scientific paper. Committee for Clinical References of the French
Anesthesia and Resuscitation Society].
AB - Every scientific article has to undergo a critical reading before its conclusions
can be accepted. This article discusses the tools for assessing the scientific
value of a study. A sequence of methodological criteria allows quality evaluation
of an article and its classification in a scale of level of proof.
PMID- 10782249
TI - [Interactions between the opioid and cannabinoid systems].
PMID- 10782250
TI - [Compartment syndrome and rhabdomyolysis in pediatric neurosurgery].
PMID- 10782251
TI - [Severe hypernatremia secondary to gastric lavage].
PMID- 10782252
TI - [An experience of training in locoregional anesthesia in an African country].
PMID- 10782254
TI - Which retinal and extra-retinal information is crucial for circular vection?
AB - In contradistinction to conventional wisdom, we propose that retinal image slip
of a visual scene (optokinetic pattern, OP) does not constitute the only crucial
input for visually induced percepts of self-motion (vection). Instead, the
hypothesis is investigated that there are three input factors: 1) OP retinal
image slip, 2) motion of the ocular orbital shadows across the retinae, and 3)
smooth pursuit eye movements (efference copy). To test this hypothesis, we
visually induced percepts of sinusoidal rotatory self-motion (circular vection,
CV) in the absence of vestibular stimulation. Subjects were presented with three
concurrent stimuli: a large visual OP, a fixation point to be pursued with the
eyes (both projected in superposition on a semi-circular screen), and a dark
window frame placed close to the eyes to create artificial visual field
boundaries that simulate ocular orbital rim boundary shadows, but which could be
moved across the retinae independent from eye movements. In different
combinations these stimuli were independently moved or kept stationary. When
moved together (horizontally and sinusoidally around the subject's head), they
did so in precise temporal synchrony at 0.05 Hz. The results show that the
occurrence of CV requires retinal slip of the OP and/or relative motion between
the orbital boundary shadows and the OP. On the other hand, CV does not develop
when the two retinal slip signals equal each other (no relative motion) and
concur with pursuit eye movements (as it is the case, e.g., when we follow with
the eyes the motion of a target on a stationary visual scene). The findings were
formalized in terms of a simulation model. In the model two signals coding
relative motion between OP and head are fused and fed into the mechanism for CV,
a visuo-oculomotor one, derived from OP retinal slip and eye movement efference
copy, and a purely visual signal of relative motion between the orbital rims
(head) and the OP. The latter signal is also used, together with a version of the
oculomotor efference copy, for a mechanism that suppresses CV at a later stage of
processing in conditions in which the retinal slip signals are self-generated by
smooth pursuit eye movements.
PMID- 10782253
TI - Morphology of lumbar-projecting lateral vestibulospinal neurons in the brainstem
and cervical spinal cord in the squirrel monkey.
AB - The lateral vestibulospinal tract (LVST) is one of the major descending pathways
controlling the extensor musculature of the body. To determine whether individual
LVST neurons terminating in the lumbosacral spinal segments issue collaterals
more rostrally to exert an influence of the cervical ventral horn intracellular
recording and biocytin labeling techniques were used in the squirrel monkey. Only
neurons monosynaptically related to the 8th nerve and antidromically identified
to project below T12 were selected for study. The axon course through the
brainstem and cervical spinal cord was examined in 37 LVST neurons. The average
distance of recovered axon was 17.3 mm (4.5-31.7 mm). None could be
antidromically activated from shocks applied to the rostral medial longitudinal
fasciculus near the 3rd nuclei; and no collaterals were observed in the
brainstem. Of the 37 neurons, only 1 axon issued a collateral to innervate the
ventral horn, primarily in the region of the spinal accessory motoneurons; this
single collateral provided a relatively minor input compared to that of LVST
neurons terminating in the cervical cord. Thus, secondary, caudal-projecting LVST
neurons represent a private, and mostly rapid, communication pathway between
dorsal Deiters' nucleus and the motor circuits controlling the lower limbs and
tail.
PMID- 10782255
TI - Visual contributions to human self-motion perception during horizontal body
rotation.
AB - It is still an enigma how human subjects combine visual and vestibular inputs for
their self-motion perception. Visual cues have the benefit of high spatial
resolution but entail the danger of self motion illusions. We performed
psychophysical experiments (verbal estimates as well as pointer indications of
perceived self-motion in space) in normal subjects (Ns) and patients with loss of
vestibular function (Ps). Subjects were presented with horizontal sinusoidal
rotations of an optokinetic pattern (OKP) alone (visual stimulus; 0.025-3.2 Hz;
displacement amplitude, 8 degrees) or in combinations with rotations of a Barany
chair (vestibular stimulus; 0.025-0.4 Hz; +/- 8 degrees). We found that specific
instructions to the subjects created different perceptual states in which their
self-motion perception essentially reflected three processing steps during pure
visual stimulation: i) When Ns were primed by a procedure based on induced motion
and then they estimated perceived self-rotation upon pure optokinetic stimulation
(circular vection, CV), the CV has a gain close to unity up to frequencies of
almost 0.8 Hz, followed by a sharp decrease at higher frequencies (i.e.,
characteristics resembling those of the optokinetic reflex, OKR, and of smooth
pursuit, SP). ii) When Ns were instructed to "stare through" the optokinetic
pattern, CV was absent at high frequency, but increasingly developed as frequency
was decreased below 0.1 Hz. iii) When Ns "looked at" the optokinetic pattern
(accurately tracked it with their eyes) CV was usually absent, even at low
frequency. CV in Ps showed similar dynamics as in Ns in condition i),
independently of the instruction. During vestibular stimulation, self-motion
perception in Ns fell from a maximum at 0.4 Hz to zero at 0.025 Hz. When
vestibular stimulation was combined with visual stimulation while Ns "stared
through" OKP, perception at low frequencies became modulated in magnitude. When
Ns "looked" at OKP, this modulation was reduced, apart from the synergistic
stimulus combination (OKP stationary) where magnitude was similar as during
"staring". The obtained gain and phase curves of the perception were incompatible
with linear systems prediction. We therefore describe the present findings by a
non-linear dynamic model in which the visual input is processed in three steps:
i) It shows dynamics similar to those of OKR and SP; ii) it is shaped to
complement the vestibular dynamics and is fused with a vestibular signal by
linear summation; and iii) it can be suppressed by a visual-vestibular conflict
mechanism when the visual scene is moving in space. Finally, an important element
of the model is a velocity threshold of about 1.2 degrees/s which is instrumental
in maintaining perceptual stability and in explaining the observed dynamics of
perception. We conclude from the experimental and theoretical evidence that self
motion perception normally is related to the visual scene as a reference, while
the vestibular input is used to check the kinematic state of the scene; if the
scene appears to move, the visual signal becomes suppressed and perception is
based on the vestibular cue.
PMID- 10782256
TI - Behavioural motor effects of MK-801 and DNQX parenteral administration in adult
cats: dose-response analysis. Modulatory role of dopaminergic D1 and D2
antagonists on MK-801 induced motor behaviours.
AB - 1. Administration of MK-801 a selective antagonist of the NMDA receptors (50, 100
and 150 micrograms/kg, s.c.) elicited in adult cats ataxia and loss of
equilibrium. A dose-response effect was observed. 2. Administration of DNQX, a
selective antagonist of the non-NMDA receptors, even with doses 20 times higher
than those employed with MK-801, did not produce any behavioural disturbances. 3.
Previous injection of SCH 23390, a selective parenteral antagonist of dopamine D1
receptor, reduced significantly the intense ataxic effects of MK-801, while
sulpiride only increased the latency of the symptoms. 4. The results are
discussed considering the reported interactions between the dopaminergic and
glutamatergic systems.
PMID- 10782257
TI - Copper sensitivity in dorsal hippocampus slices.
AB - The action of copper on the pyramidal neurons in CA1 of the hippocampus is little
understood. Our main aim was to study the possible interaction of copper on the
synaptic network in CA1 pyramidal neurons. We used Wistar rats hippocampus slices
in a recording chamber. The population response ("population of spikes")
collected by an extracellular micropipette under baseline conditions served as
control. Copper, GABA, bicuculline and picrotoxin were delivered in different
experimental conditions to the slice. One, 10 and 100 microM of copper
concentration decreased significantly the amplitude and duration of the
population spikes in relation to the control response. This effect did not show
concentration dependency. Copper in bicuculline medium decreased significantly
the duration response in relation to the control response and in relation to
copper effect in a free bicuculline medium. This phenomenon emphasizes the copper
action on the GABA (B) and (C) receptors. Copper in a picrotoxin medium increased
significantly the excitability of the response. This new effect suggests that
copper acts on non-GABA receptors, an effect that could be detected when the GABA
receptors were inactivated. As a result of these findings it appears that, under
our experimental conditions, copper generated transient sensitivity changes in
pyramidal neurons of CA1 dorsal hippocampus.
PMID- 10782258
TI - Mapping of alpha-melanocyte-stimulating hormone-like immunoreactivity in the cat
brainstem.
AB - The distribution of alpha-melanocyte-stimulating hormone-like immunoreactive
structures was studied in the brainstem of the cat using an indirect
immunoperoxidase technique. Immunoreactivity was observed in several brainstem
nuclei of the cat in which no immunoreactivity had been previously reported.
Immunoreactive fibres were observed in the following; the inferior central
nucleus; the pontine gray nuclei; the Kolliker-Fuse nucleus; the motor trigeminal
nucleus, the anteroventral cochlear nucleus; the abducens nucleus; the
retrofacial nucleus; the superior, lateral, inferior, and medial vestibular
nuclei; the lateral nucleus of the superior olive; the external cuneate nucleus;
the nucleus of the trapezoid body; the postpyramidal nucleus of the raphe; the
medial accessory inferior olive; the dorsal accessory nucleus of the inferior
olive; the nucleus ambiguus; the principal nucleus of the inferior olive; the
preolivary nucleus; the nucleus ruber; the substantia nigra; and in the area
postrema. Our results point to a more widespread distribution of alpha-melanocyte
stimulating hormone-like immunoreactive structures in the cat brainstem than that
reported in previous studies carried out in the same region of the cat, rat and
humans.
PMID- 10782260
TI - ["Smoking I await..."].
PMID- 10782259
TI - An intracellular study of pudendal afferent inputs onto tail motoneurons in the
spinalized cat.
AB - Postsynaptic potentials, elicited by stimulation of the sensory pudendal (SPud)
and superficial perineal nerves (SPeri) on both sides, were recorded from
motoneurons innervating tail muscles in the non-anaesthetized and spinalized cat.
The stimulation of SPud and SPeri on both sides predominantly produced excitatory
postsynaptic potentials (EPSPs) in all kinds of tail motoneurons (70-95%). The
inhibitory postsynaptic potentials (IPSPs) were often observed in motoneurons
innervating ventral tail muscles (30-33%). The means of averaged central
latencies of EPSPs and IPSPs ranged from 4.3 to 7.3 ms, and from 4.6 to 8.4 ms,
respectively. The findings suggests that polysynaptic neuronal pathways from
pudendal nerve to tail motoneurons produce tonic activities of all tail muscles
to raise the tail in micturation, defecation and sexual movements which are
induced by stimulation of pudendal nerves.
PMID- 10782261
TI - [School-age smoking in the province of Seville. Epidemiology and influence of
personal and social environment (smoking prevention campaign, 1998-1999)].
AB - OBJECTIVE: To study the prevalence os smoking in school children in Sevilla and
the influence of personal and social environment on smoking patterns. METHODS:
This study was part of a preventative anti-smoking campaign in schools. Students
filled in anonymous questionnaires based on the World Health Organization survey
instrument for population attitudes and habits. RESULTS: We surveyed 3385
students between 10 and 19 years of age at 47 schools in Seville and 28 villages
in the surrounding province. Current smoking was reported by 19.1% of the
students; slightly more girls (19.8%) than boys (18.3%) smoked. Smoking was
related to having an older brother or sister who smoked and particularly to
having friends who smoked (OR 20.5). The adolescents reported that parents were
less permissive than the rest of their environment. Smokers associated tobacco
with values such as independence and freedom; they believed that smoking might
have an impact on health, although their conviction was less strong than that of
non-smokers, regular smokers had high expectations of continuing. CONCLUSIONS: We
found a high proportion of smokers among students of both sexes. Starting and
continuing to smoke during adolescence is considerably influenced by the social
environment of peers and is possibly affected by messages of independence and
freedom transmitted through tobacco industry advertising.
PMID- 10782262
TI - [Minimal intervention in smoking in Spain].
AB - OBJECTIVE: To determine the percentage of smokers who have been counseled by a
physician to quit, among patients who visit a variety od specialist clinica; to
identify the characteristics associated with a history of minimal intervention.
PATIENTS AND METHODS: An anonymous survey of 501 patients over 14 years of age
(230 men, 271 women; mean age of 51.4 yr) who were out patients in cardiology
(61), neurology (68), digestive medicine (124), endocrinology (22), internal
medicine (14), otorhinolaryngology (53) and dermatology (159) over a period of
one week. The questionnaire asked if the patient smoked currently and if so, if a
physician had ever recommended quitting. The association between a history or
minimal intervention and other variables was evaluated using Spearman a
correlation coefficient. RESULTS: 1) One hundred fifteen (22.9%) were smokers. 2)
Only 49 (42.6%) of the smokers reported that a physician had advised quitting and
66 (57.4%) reported that none had done so. 3) We found an association between a
history of minimal intervention and older age (rs = -0.246; p = 0.008) and male
sex (rs = 0.244; p = 0.009). CONCLUSIONS: The infrequency with which physicians
counsel patients to quit in our setting suggests an urgent need for the Spanish
health authorities to develop programs aimed at minimal intervention.
PMID- 10782263
TI - [Individual treatment of smoking addiction. Results using 2 and 4 mg nicotine
gum].
AB - We present the results of an open follow-up study aimed at analyzing the efficacy
of combining psychological counseling with prescription of 2 and 4 mg nicotine
gum to treat smokers. Two groups of smokers wer studied. Group A contained 124
subjects (74 men, 50 women) with a mean age of 37.4 (15.3) yr who were smokers of
15.3 (8.7) cigarettes/day. In this group physical addiction to nicotine was low,
assessed as 1.7 (1.3) on the Fagerstrom test. Group B consisted of 107 subjects
(61 men, 46 women) with a mean age of 38.9 (14.6) who were smokers of 26.9 (9.3)
cigarettes/day and whose level of physical addiction to nicotine was moderate-to
high, assessed as 6.1 (2.4) on the Fagerstrom test. Standard deviations are shown
between parentheses. Both groups were given minimal psychological counseling;
additionally, patients were prescribed one piece of nicotine gum very 90 to 120
minutes during waking hours (2 mg in group A and 4 mg in group B). The dose was
gradually reduced after the sixth to the eight week. The subjects were seen eight
times over the first year (first day of consultation and during the first,
second, fourth, eight and twelfth weeks after quitting, and again after six and
twelve months). After twelve weeks of follow-up, sixty-one subjects (49%) in
group A and 50 (47%) in group B were still abstinent. These proportions fell to
56 (45%) and 46 (43%), respectively, after one year of follow-up. Eighty-one
percent of group A patients who were successful after three months of follow-up,
and 87% of the successful group B patients, had used the nicotine gum as
prescribed. Oropharyngeal, dental, and temporo-mandibular joint symptoms,
hiccoughins, flatulence and heartburn were the most frequent side effects
(ranging from 3% to 18%). Side effects were always slight and were not detected
after the eighth week of treatment. In conclusion, combined therapy (minimal
psychological counseling plus use of 2 or 4 mg nicotine gum depending on the
level of physical addiction) yields a success rate between 43% and 45% still
abstaining after one year of follow-up. Side effects are few and mild.
PMID- 10782264
TI - [Attitudes to smoking and characteristics of the habit among a group of young
asthmatics compared to a group of non-asthmatics].
AB - OBJECTIVE: To compare the attitudes toward smoking and smoking patterns of young
male asthmatics with the attitudes and habits of a group previously studied non
asthmatic men. POPULATION AND METHODS: Volunteers responded individually to as
anonymous questionnaire. RESULTS: Responses were received from 488 asthmatics men
(55.83%) of the sample, with 11 not responding) and 386 non-asthmatics (44.16%,
with 27 not responding). The mean age of subjects was 19.91 +/- 2.76 yr. Smoking
asthmatics numbered 154 (31.56%) non-asthmatic smokers numbered 207 (53.6%) (p <
0.001). Eighteen asthmatics (3.68%) and 6 (1.55%) non-asthmatics were ex-smokers.
The mean age of initiation was 15.20 +/- 2.42 for asthmatics and 15.08 +/- 2.41
for non-asthmatics. Smoking was established at a mean age of 16.56 +/- 2.04 yr
for asthmatics and 16.47 +/- 2.18 yr for non-asthmatics. Sixty-two percent of
asthmatics smoked fewer than 10 cigarettes/day whereas 55% of non-asthmatics
smoked between 11 and 20 cigarettes/day. The mean Fagerstrom score were 2.59 +/-
2.2 for asthmatics and 4.66 +/- 2.2 for non-asthmatics (p < 0.001). Fifty-four
percent of asthmatics and 47% non-asthmatics were considering quitting. Sixty
five percent of asthmatics and 44% of non-asthmatics had previously tried to quit
(p < 0.01) and mean duration of abstinence was 4.6 +/- 3.8 months and 3.8 +/-
4.6, respectively (p < 0.05). No differences were found in the reason for
starting to smoke. We found that the companions and friends of asthmatics smoked
less than did the friend and acquaintances of non-asthmatics (p < 0.001),
although that differences was not found for relatives, the friends, relatives and
companions of smoking asthmatics smoked more than did those of non-smoking
asthmatics. CONCLUSIONS: The prevalence of smoking is lower among asthmatics than
among non-asthmatics and asthmatics smoke fewer cigarettes/day and have a lower
level of addiction. There are no differences in age of or reasons for starting to
smoke. Asthmatics have fewer smoking friends than do non-asthmatics and non
smoking asthmatics have fever still. the desire to quit smoking is high in both
groups.
PMID- 10782265
TI - [High prevalence of long-term domiciliary oxygen therapy with a low percentage of
inappropriate prescription in the Madrid health care area. Evaluation of the
correct use].
AB - The efficacy of long-term domiciliary oxygen therapy (DOT) has been confirmed in
patients who comply with guidelines; however, the prevalence in different
populations varies greatly although no satisfactory explanation has been found
for this. OBJECTIVES: To assess the prevalence of inappropriate use of DOT in the
health care area of the Community of Madrid, where demographic and health care
features are well-defined. MATERIAL AND METHODS: Descriptive, transversal
population study enrolling all patients with DOT in our health care area over a
period of one year (May 1995 to Mayo 1995). Inappropriate use was defined as
characterized by at least one of the following conditions: inappropriate
prescription, poor compliance or continued smoking. RESULTS: The total number of
patients was 860, the prevalence of DOT use being 178.3 per 100,000 inhabitants
for the period. Ninety-three refused to participate. Nearly half the patients ha
been using oxygen therapy for over two years. Seventy percent were followed by
pneumologists. Seventy-four percent were men, with a mean age of 70 +/- 9 yr.
Criteria for prescription were not followed in 9.7% of the cases. Chronic
obstructive pulmonary disease was the reason for prescribing DOT in 59.7%. Use
was appropriate in 719 cases. Use was inappropriate in 337 (46.9%), related to
poor compliance in 60.5%, current smoking in 11%, and inappropriate prescription
in 5.6% and for more than one criterion in 22.8%. CONCLUSIONS: The prevalence of
DOT use in our health care area is very high. The percentage of inappropriate use
is high, although similar to that of other populations, and highly related to
poor compliance. The percentage of inappropriate prescription is low. Possible
reasons for the high prevalence are discussed.
PMID- 10782266
TI - [Functional assessment of respiratory muscles].
PMID- 10782267
TI - [Is tuberculosis contagious or not?].
PMID- 10782268
TI - [Bilateral lung reduction by video-assisted thoracoscopy in a patient with non
bullous pulmonary emphysema and laryngeal neoplasia].
AB - Lung reduction has been show to be a promising treatment for the final phases of
non-bullous pulmonary emphysema. The role of video-assisted thoracoscopy (VAT) in
this disease has not yet been established. We report a case of bilateral non
bullous pulmonary emphysema in which transplantation was ruled out because of
laryngeal neoplasm treated three months earlier. Using VAT, we performed
bilateral lung reduction in the apical zones with good therapeutic results. We
find that in patients reduction by VAT, although not a curative treatment, leads
to immediate postoperative improvement in lung function and dyspnea, and does not
exclude the possibility of later performing lung transplantation.
PMID- 10782269
TI - [Mediastinal cystic lymphangioma].
PMID- 10782270
TI - [Migratory pulmonary infiltrates due to bronchiolitis obliterans organizing
pneumonia after radiotherapy].
PMID- 10782271
TI - [Tobacco and advertising].
PMID- 10782273
TI - [Sarcoidosis with the 25-year course].
PMID- 10782272
TI - [Treatment of COPD in primary care].
PMID- 10782274
TI - [Physician workforce and population aging in Switzerland].
AB - The number of physicians in private practice per 100,000 populations will raise
to 210 in the year 2005 and to 235-265 in the year 2020, from 187 in 1998. The
feeling of manpower surplus is spreading in Switzerland and some commentators are
voicy as concerns aggravated oversupply in the future. During the period 1990
2020, the Swiss population will increase +12% but the population aged 65 and over
will increase +57%. Even if the elderly in the forthcoming decades will be in
better health than their today's counterparts, most probably the demand for
health services will increase. Social change, medical technology progress and
growth in the population-doctor ratio itself will fuel the process.
PMID- 10782275
TI - [Health expenditures in Spain at the dawn of the 3d millennium].
AB - In 1997, per capita health expenditures reached in Spain 805 Euros as compared to
1146 Euros in the entire European Union. In terms of percent GDP, Spanish health
expenditures amounted to 7.4 percent, as compared to 7.9 in the European Union.
About 80% of Spanish health expenditures are public-funded. Since 1993 onwards,
there is a political consensus for keeping at the same pace health expenditures
increase and GDP growth. However it is not certain that such a consensus can be
maintained, as trade unions are increasingly voicy for a strong growth of
salaries in the public sector. There will be also pressure on the demand side,
both in the short term (the Spanish people are increasingly expecting to raise
their consumption of health services to the level of other European countries)
and in the long run (impact of population aging).
PMID- 10782276
TI - [The risks of good health in France in the year 2020].
AB - Since 1995 onwards, health cost containment is the order of the day in France.
Successively, the Right and the Left were implementing strong policies aimed at
curbing hospital costs, controlling drug prescriptions, promoting early
retirement of practicing doctors.... As expected, all these actions have
encountered hard resistances from health professionals (As a matter of fact, the
demand side was not affected by cost containment policies). The inertia of all
the system and the resistance from health personnel made it clear that cost
containment measures will obtain a significant impact only after 2003 or 2005.
Precisely, at that date, or some years later, the medical profession will start a
sharp decrease of its numbers as the graduate-boom cohorts of the period 1975
1990 will arrive at retirement age. On the demand side, the French population
will accelerate its aging process as the baby-boomers born during the period 1945
1965 will reach successively their 60th anniversary. In other words, the decade
2010-2020 will see a sharp growth of the demand for health services and a
decrease in the supply. As cost containment is a painful and long-harvesting
process, the health authorities of the decade 2010-2020 will probably not let
"the horse run freely again". Most probably, supply of health care will be kept
under strict control. Will France then adopt the British model (health
expenditures kept at low level and queuing for care)? Or will the nation be
innovative enough to invent a new model for its health system?
PMID- 10782277
TI - [Physician workforce and population aging in Greece].
AB - In 1996, there were 41,511 medical doctors in Greece i.e. 340 doctors per 100,000
population. Recent forecasts showed that in 2001, there would be 46,558 doctors
in the country i.e. 422 doctors per 100,000 population. There is currently no
numerous clauses at the start of medical training. Medical workforce growth is
fueling increase in health expenditures and the underground activities of
doctors. In the upcoming decades, population aging will accelerate the growth of
health expenditures. All these moves will no doubt impose upon a restructuring of
all the health care system.
PMID- 10782278
TI - [Trends in supply and demand for physicians in Belgium].
AB - Belgium is experiencing a strong medical workforce oversupply. At the end of
1998, there were 345 active physicians per 100,000 population and the ratio is
even higher in the francophone area of the country (433 active physicians per
100,000 population). Health expenditures are steadily raising. A numerous clauses
system was established in the medical schools in 1996 but its will not affect the
annual number of graduates before 2004. During the next two decades, for various
reasons, population aging will have only a slight effect on the growth of health
care expenditures. However, most probably, more doctors will be needed. Given the
current manpower oversupply, such forecasts are not easily accepted.
PMID- 10782279
TI - Novel practical synthesis of Kdn2en and its C-4 nitrogen-modified derivatives.
AB - A practical synthesis of Kdn2en and 4-amino-4-deoxy-Kdn2en has been achieved via
a key intermediate, methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhydro-3-deoxy-D-glycero
D-galacto-non-2- enonate, which has been prepared from Kdn in three steps in 91%
overall yield.
PMID- 10782281
TI - Synthesis of ethyl 2-acetamido-6-S-(5-amino-5-deoxy-beta-D- arabinopyranosyl)-2
deoxy-1,6-dithio-beta-D-glucopyranoside: a sulfur-linked 5-amino-5
deoxyglycopyranosyl disaccharide.
AB - A novel pseudo-disaccharide having an imino sugar residue at the non-reducing
end, namely, a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide, which is
a potential specific inhibitor for glycosidases that recognize not only the
glycosidic linkage but also the aglycone moiety, was synthesized. Glycosidation
of N-Boc-5-amino-5-deoxy-D-arabinose with ethyl 2-acetamido-3,4-di-O-acetyl-2
deoxy-1,6-dithio-beta-D- glucopyranoside in the presence of TsOH gave exclusively
the corresponding 1,2-cis-linked thioglycoside. The interglycosidic linkage
proved stable enough under conditions for the deprotection of the N-Boc group
with TFA. This pseudodisaccharide was unstable at pH > 5, but stable at lower pH.
The sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide was shown to be
formed from 5-amino-5-deoxy-D-arabinose and ethyl 2-acetamido-2-deoxy-1,6-dithio
beta-D-glucopyranoside in an acidic buffer solution.
PMID- 10782280
TI - Synthesis of 4-nitrophenyl beta-D-fucofuranoside and beta-D-fucofuranosyl-(1-->3)
D-mannopyranose: modified substrates for studies on catalytic requirements of
beta-D-galactofuranosidase.
AB - Syntheses of 4-nitrophenyl beta-D-fucofuranoside (6) and beta-D-fucofuranosyl-(1-
>3)-D-mannopyranose (10) are reported. These compounds, as analogues of
galactofuranosides, were used for studying the influence of the hydroxyl group at
C-6 in the interaction of the substrate with beta-D-galactofuranosidase. For the
synthesis of the fucofuranosides, 2,3,5-tri-O-benzoyl-6-bromo-6-deoxy-D-galactono
1,4-lactone (1) was the key intermediate, which upon reduction of the lactone
group with diisoamylborane, acetylation of the anomeric hydroxyl group, and
catalytic hydrogenolysis of the bromine at C-6, led to 1-O-acetyl-2,3,5-tri-O
benzoyl-alpha,beta-D-fucofuranose (4), a convenient derivative for the
preparation of fucofuranosides. Compound 4 was glycosylated in the presence of
SnCl4, either with 4-nitrophenol for the preparation of 6, or with 2,5,6-tri-O
benzoyl-D-mannono-1,4-lactone (7), for the synthesis of disaccharide 10, via the
glycosyl-aldonolactone approach. The synthetic route developed for the beta-D
fucofuranosides is simple and efficient. Compound 6 was not hydrolyzed by
incubation with the exo beta-D-galactofuranosidase from Penicillium fellutanum,
showing that HO-6 is essential for interaction of the substrate with the enzyme.
PMID- 10782282
TI - Synthesis of a tetrasaccharide representing a minimal epitope of an
arabinogalactan.
AB - The hydrophobic alkyl chain-containing tetrasaccharide, dodecyl beta-D
galactopyranosyl-(1-->6)-beta-D-galactopyranosyl-(1-->6)-[alpha-L -
arabinofuranosyl-(1-->2)]-beta-D-galactopyranoside, was synthesized efficiently
using a convergent strategy. In coupling reactions, protected
trichloroacetimidates proved to be better donors than their corresponding
bromides in the preparation of the dodecyl disaccharide and trisaccharide.
Zemplen deacylation provided the target tetramer in good overall yield.
PMID- 10782283
TI - 3,4-anhydro-1,2-O-isopropylidene-beta-D-tagatopyranose and 4,5-Anhydro-1,2-O
isopropylidene-beta-D-fructopyranose.
AB - 3,4-Anhydro-1,2-O-isopropylidene-beta-D-tagatopyranose (8) and 4,5-anhydro-1,2-O
isopropylidene-beta-D-fructopyranose (10) have been prepared by treatment of 3,5
di-O-acetyl-1,2-O- isopropylidene-4-O-toluene-p-sulfonyl-beta-D-fructopyranose
with methanolic sodium methoxide. The structures of 8 and 10 were assigned by 1H
and 13C NMR spectroscopy and that of 10 by X-ray crystallography; both exist in
half-chair conformations. Compounds 8 and 10 interconvert in aqueous sodium
hydroxide, giving a ratio of 1:2 at equilibrium. The monoacetates of 8 and 10 (5
O-acetyl-3,4-anhydro-1,2-O-isopropylidene-beta-D-tagatopyranose and 3-O-acetyl
4,5-anhydro-1,2-O-isopropylidene-beta-D-fructopyranose) undergo stereospecific
epoxide ring opening in 80% acetic acid to give mainly the axial monoacetates 5-O
acetyl-1,2-O-isopropylidene-beta-D-fructopyranose and 4-O-acetyl-1,2-O
isopropylidene-beta-D-tagatopyranose, respectively.
PMID- 10782284
TI - Galactosyl transfer ability of beta-(1-->4)-galactosyltransferase toward 5a-carba
sugars.
AB - Bovine beta-(1-->4)-galactosyltransferase was assayed with a series of 5a-carba
sugars, i.e., sugar analogues in which the ring oxygen of pyranose is replaced by
a methylene group. The analogues are 5a-carba-sugar of 2-acetamido-2-deoxy-alpha
DL-galactopyranose, both alpha and beta anomers of 2-acetamido-2-deoxy-DL
glucopyranose (5a-carba-DL-GlcNAc), and 2-acetamido-2-deoxy-DL-mannopyranose. Of
these analogues, both alpha and beta anomers of 5a-carba-DL-GlcNAc act as an
acceptor. Enzymatic synthesis using the alpha and beta anomers of 5a-carba-DL
GlcNAc afforded the corresponding D-Gal-beta-(1-->4)-5a-carba-alpha-D-GlcNAc and
D-Gal-beta-(1-->4)-5a-carba-beta-D-GlcNAc on a practical scale, and these
structures were confirmed by NMR spectroscopy. These results indicate that the
ring oxygen atom in the 5a-carba-D-GlcNAc is not used for specific recognition by
bovine beta-(1-->4)-galactosyltransferase.
PMID- 10782285
TI - Effects of various saccharides on cycloinulo-oligosaccharide fructanotransferase
reaction: production of beta-inulotriosyl-alpha-D-mannopyranoside and 1-O-beta
inulotriosyl-alpha-L-sorbopyranose.
AB - The effects of various saccharides on the reaction of cycloinulo-oligosaccharide
fructanotransferase with cycloinu-lohexaose were examined. In addition to beta-D
fructofuranosides and methyl alpha-D-glucopyranoside, D-mannose and L-sorbose
were found to be effective acceptors in the reactions, and they enhanced the
hydrolytic activity as effectively as methyl alpha-D-glucopyranoside. Hetero
tetrasaccharides were isolated as the major transfer products from both reaction
mixtures. The isolates were identified by NMR spectroscopy as beta-inulotriosyl
alpha-D-mannopyranoside and 1-O-beta-inulotriosyl-alpha-L-sorbopyranose. Methyl
beta-D-glucopyranoside was slightly effective and methyl alpha-D-mannopyranoside
was not effective at all as the acceptor, but these saccharides strongly enhanced
the hydrolytic activity. D-Glucosamine inhibited the enzyme activity.
PMID- 10782286
TI - A new bioactive steroidal saponin, furcreastatin, from the plant Furcraea
foetida.
AB - Microbial and plant secondary metabolites were screened for compounds that are
selectively cytotoxic to mutant p53-expressing mouse fibroblasts. As a result,
furcreastatin, a novel steroidal saponin, was isolated from an EtOH extract of
the leaves of Furcraea foetida. Furcreastatin consisted of hecogenin as the
aglycone and a hexasaccharide containing D-galactose, L-rhamnose and four D
glucose residues. The structure was determined to be (3 beta,5 alpha,25R)- 3
hydroxyspirostan-12-one 3-O-[alpha-L-Rhap-(1-->4)-beta-D-Glcp-(1-->3)-?beta-D
Glcp-(1-->3) -beta-D- Glcp-(1-->2)?-beta-D-Glcp-(1-->4)-beta-D-Galp] by extensive
NMR spectroscopic studies. Furcreastatin decreased the viability of mutant p53
over-expressing cells with an ED50 of 4.0 micrograms/mL, and decreased that of
the parental cell-line with an ED50 of 9.6 micrograms/mL.
PMID- 10782287
TI - Evidence for covalent binding between copper ions and cyclodextrin cavity: a
vibrational circular dichroism study.
AB - Vibrational absorption and circular dichroism (VCD) spectra were obtained for
parent cyclodextrins, hydroxyl deuterated alpha-cyclodextrin, cyclodextrin-copper
complexes, and for the cyclodextrin inclusion complexes with Methyl Orange,
methyloxirane, 1-propanol, and substituted cyclohexanones, in the solution phase.
Changes in the VCD spectra, reflecting perturbations of cyclodextrin cavity, were
found in the case of an inclusion complex with Methyl Orange, but for the
remaining inclusion complexes measurable changes in VCD were not found.
Significant changes observed in the VCD spectra of cyclodextrin-copper complexes
suggest that the covalent binding of copper ions to the hydroxyl groups of
cyclodextrin is involved.
PMID- 10782288
TI - Homonojirimycin analogues and their glucosides from Lobelia sessilifolia and
Adenophora spp. (Campanulaceae).
AB - 2,6-Dideoxy-7-O-(beta-D-glucopyranosyl) 2,6-imino-D-glycero-L-gulo- heptitol (7-O
beta-D-glucopyranosyl-alpha-homonojirimycin, 1) was isolated from the 50%
methanol extract of the whole plant of Lobelia sessilifolia (Campanulaceae),
which was found to potently inhibit rice alpha-glucosidase. Adenophorae radix,
roots of Adenophora spp. (Campanulaceae), yielded new homonojirimycin
derivatives, adenophorine (2), 1-deoxyadenophorine (3), 5-deoxyadenophorine (4),
1-C-(5-amino-5-deoxy-beta-D-galactopyranosyl)butane (beta-1-C-butyl
deoxygalactonojirimycin, 5), and the 1-O-beta-D-glucosides of 2 (6) and 4 (7), in
addition to the recently discovered alpha-1-C-ethylfagomine (8) and the known 1
deoxymannojirimycin (9) and 2R,5R-bis(hydroxymethyl)-3R,4R- dihydroxypyrrolidine
(DMDP, 10). Compound 4 is a potent inhibitor of coffee bean alpha-galactosidase
(IC50 = 6.4 microM) and a reasonably good inhibitor of bovine liver beta
galactosidase (IC50 = 34 microM). Compound 5 is a very specific and potent
inhibitor of coffee bean alpha-galactosidase (IC50 = 0.71 microM). The glucosides
1 and 7 were potent inhibitors of various alpha-glucosidases, with IC50 values
ranging from 1 to 0.1 microM. Furthermore, 1 potently inhibited porcine kidney
trehalase (IC50 = 0.013 microM) but failed to inhibit alpha-galactosidase,
whereas 7 was a potent inhibitor of alpha-galactosidase (IC50 = 1.7 microM)
without trehalase inhibitory activity.
PMID- 10782289
TI - Structure of the O-specific polysaccharide of Proteus mirabilis O11, another
Proteus O-antigen containing an amide of D-galacturonic acid with L-threonine.
AB - The O-specific polysaccharide of Proteus mirabilis O11 was studied by sugar
analysis, Smith degradation, 1H and 13C NMR spectroscopy, including two
dimensional COSY, TOCSY, NOESY, and 1H-detected 1H, 13C HMQC experiments. The
following structure of a pentasaccharide repeating unit of the polysaccharide was
established: [formual: see text] where D-GalA6LThr is N-(D-galacturonoyl)-L
threonine. ELISA with anti-P. mirabilis O11 serum showed that D-GalA6LThr is of
minor importance for manifesting the O11 immunospecificity.
PMID- 10782290
TI - Separation and structural analysis of some saponins from Quillaja saponaria
Molina.
AB - A fraction of saponins from Quillaja saponaria Molina, QH-B, was fractionated by
consecutive separations on three different reverse-phase HPLC systems. Eight
compounds were isolated and the structures of these were elucidated mainly by
sugar analysis and NMR spectroscopy. The structures consisted of a quillaic acid
substituted with two different trisaccharides at C-3, beta-D-Galp-(1-->2)-[alpha
L-Rhap-(1-->3)]-beta-D-GlcpA and beta-D-Galp-(1-->2)-[beta-D-Xylp-(1-->3)]-beta-D
GlcpA, and a tetra- or pentasaccharide at C-28, beta-D-Xylp-(1-->4)-[beta-D-Glcp
(1-->3)]-alpha-L-Rhap-(1--> 2)-beta-D-Fucp and beta-D-Apif-(1-->3)-beta-D-Xylp-(1
->4)-[beta-D-Glcp-(1-->3) ]-alpha-L- Rhap-(1-->2)-beta-D-Fucp. These compounds
were further substituted with an acyl group either at O-3 or O-4 of the fucose
residue, which is the sugar linked to C-28 of the quillaic acid.
PMID- 10782291
TI - Structures of the O21 and O25 antigens of Stenotrophomonas maltophilia.
AB - The O-specific side-chain polymers from Stenotrophomonas maltophilia serogroups
O21 and O25 were isolated from the lipopolysaccharides of the reference strains.
The O21 polymer contained D-arabinose, 2-amino-2-deoxy-D-glucose and 2-amino-2
deoxy-D-galactose in equal proportions. Methylation analysis and NMR spectroscopy
showed that the polysaccharide is based on a branched trisaccharide repeating
unit of the structure shown below. The O25 polymer is linear with a disaccharide
repeating unit identical to that forming the backbone of the O21 polymer.
PMID- 10782292
TI - The structure of the O-specific polysaccharide of Escherichia coli O117:K98:H4.
AB - The primary structure of the O-antigen of Escherichia coli O117 was shown by
monosaccharide analysis, methylation analysis, and by 1D and 2D 1H and 13C NMR
spectroscopy to be composed of linear pentasaccharide repeating units with the
structure: -->3)-alpha-D-GalpNAc-(1-->4)-beta-D-GalpNAc-(1-->3)-alpha-L-Rhap- (1-
>4)- alpha-D-Glcp-(1-->4)-beta-D-Galp-(1-->
PMID- 10782293
TI - N-linked oligosaccharide structures in the diamine oxidase from porcine kidney.
AB - Structures of the N-linked glycans released from porcine kidney diamine oxidase
(DAO) were characterized utilizing various analytical techniques, including
matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
(MALDI/TOF-MS), high-performance capillary electrophoresis (HPCE), and high-pH
anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). The
oligosaccharide sequences present in DAO were conclusively determined using
specific exoglycosidases in conjunction with MALDI/TOF-MS. The structures found
in the glycoprotein are primarily linear, di-, or tribranched fucosylated complex
type. MS analysis of the esterified N-glycan pool derived from DAO indicated the
presence of several di- and trisialylated structures.
PMID- 10782294
TI - Characterization of pectin, flash-extracted from orange albedo by microwave
heating, under pressure.
AB - Pectin was acid extracted from orange albedo by microwave heating under pressure.
Extraction times ranged from 2.5 to 8 min. Solubilized pectin was characterized
for molar mass (M), rms radius of gyration (Rg) and intrinsic viscosity [eta] by
HPSEC with online light scattering and viscosity detection. M, Rg and [eta] all
decreased with increasing extraction time. Nevertheless, at heating times of 2.5
and 3.0 min, M, Rg and [eta] were significantly higher than a commercial citrus
pectin when the albedo:solvent ratio was 1:25 (w/v). At the heating time of 2.5
min Mw was 3.6 x 10(5), Rgz was 38 nm and [eta]w was 10.8 dL/g. Chromatography
revealed that solubilized pectin distributions were bimodal in nature and that
the low-molar-mass fraction increased at the expense of the high-molar-mass
fraction with increasing extraction time. Scaling law exponents revealed that the
high-molar-mass fraction was extremely compact in shape, whereas the low-molar
mass fraction was more asymmetric in shape. Possibly these results indicated that
at short extraction times, pectin was solubilized as compact aggregated network
structures that were broken down to their more asymmetric components with
increased heating times.
PMID- 10782295
TI - Studies on the primary structure of short polysaccharides using SEC MALDI mass
spectroscopy.
AB - The introduction of size-exclusion chromatography (SEC) analysis of
polysaccharides prior to MALDI mass spectroscopy accounts for the determination
of the molecular mass of the repeating unit when neutral homopolymers are
investigated. In the case of natural polysaccharides characterised by more
complicated structural features (presence of non-carbohydrate substituents,
charged groups, etc.), this mass value usually is in agreement with more than one
sugar composition. Therefore, it is not sufficient to give the correct
monosaccharidic composition of the polysaccharide investigated. To solve this
problem, MALDI spectra were recorded on the permethylated sample and post-source
decay experiments were performed on precursor ions. In this way, the composition
(in terms of Hex, HexNAc, etc.), size and sequence of the repeating unit were
determined.
PMID- 10782296
TI - The use of NMR residual dipolar couplings in aqueous dilute liquid crystalline
medium for conformational studies of complex oligosaccharides.
AB - C-H dipolar coupling values were measured for a natural-abundance sample of the
pentasaccharide beta-D-Galp-(1-->3)-[alpha-L-Fucp-(1-->4)]-beta-D-GlcNAcp-(1 -
>3)-beta-D- Galp-(1-->4)-beta-D-Glcp ('lacto-N-fucopentaose 2') (LNF-2), in a
7.5% solution of dimyristoyl phosphatidylcholine-dihexanoyl phosphatidylcholine
bicelle liquid crystals oriented in the NMR magnetic field. Interpretation of the
dipolar coupling data and NOE confirms the conformational model for the Lewis(a)
trisaccharide epitope based on NOE, molecular dynamics simulations, and scalar
coupling data and provided new structural information for the remaining residues
of the pentasaccharide. Since residual dipolar coupling provides information on
long-range order, it is a valuable complement to other types of NMR data such as
NOE and scalar coupling for exploring conformations of complex oligosaccharides.
PMID- 10782297
TI - Degree of acetylation of heteropolysaccharides.
AB - The acetyl groups in polysaccharides and glycoproteins have been determined using
4 N HCl at 120 degrees C for acid hydrolysis. Acetic acid and hexosamine were
determined by high-performance cation-exchange chromatography with UV detection
and high-performance anion-exchange chromatography with pulsed amperomeric
detection, respectively. The method compares well with other procedures and shows
an additional advantage of being able to analyze for hexosamine in the same
hydrolyzate, thus permitting the degree of acetylation of hexosamine-containing
biopolymers to be determined directly without correction for additional
components in the material of interest.
PMID- 10782298
TI - Structure-properties relationship in cross-linked high-amylose starch for use in
controlled drug release.
AB - Cross-linked high-amylose starch (CLHAS), obtained by high-amylose starch cross
linking, was recently introduced as an excipient (Contramid) for monolithic
dosage forms that are able to control drug release over 18-24 h. These control
properties are related to tablet swelling and are strongly dependent on the
degree of the cross-linking of CLHAS. The permeability of solutes through CLHAS
hydrogels depends on the chemical structure of the polymer. The aim of this study
was to obtain a better understanding of how modifications in CLHAS molecular
structures at the level of long-range and short-range order during the cross
linking and processing conditions relate to the release properties of the CLHAS
matrices. Structural parameters such as crystallinity contribute significantly to
the physical and mechanical aspects of starch products. X-ray diffractometry,
FTIR spectroscopy, dissolution tests in vitro, and mechanical hardness (of dry
tablets) were found to be sensitive to the cross-linking degree (cld) variation.
Best release properties and highest mechanical hardness were obtained from CLHAS
matrices with low-to-moderate crystallinity, where the V- and the B-type
structures coexist with amorphous regions. X-ray and FTIR profiles of dry CLHAS
powders were found to be predictive for release properties of CLHAS tablets.
PMID- 10782300
TI - Effect of stereochemistry on the anti-freeze characteristics of carbohydrates. A
thermal study of aqueous monosaccharides at subzero temperatures.
AB - Thermal behavior at subzero temperatures has been investigated for aqueous
solutions of various monosaccharides. The heat of fusion of ice measured with
differential scanning calorimetry has given linear plots against sugar
concentration (wt.%), from which the amount of unfrozen water, Uw, has been
determined for each monosaccharide. The results for Uw are analyzed by employing,
as a measure of hydration characteristics, known physico-chemical properties of
aqueous monosaccharides, such as partial molar compressibilities, etc. It was
revealed that the anti-freeze characteristics of carbohydrates depend on their
stereochemistry. More water remains unfrozen in the aqueous solutions of
carbohydrates having poorer compatibility with the three-dimensional hydrogen
bond network of water. Monosaccharides studied can be subdivided into three
groups according to the extent of the anti-freeze effect. These results are
rationalized in terms of a modified stereospecific hydration model.
PMID- 10782299
TI - Synthesis of homogeneous glycopeptides and their utility as DNA condensing
agents.
AB - Two glycopeptides were synthesized by attaching purified glycosylamines (N
glycans) to a 20 amino acid peptide. Triantennary and Man9 Boc-tyrosinamide N
glycans were treated with trifluoroacetic acid to remove the Boc group and expose
a tyrosinamide amine. The amine group was coupled with iodoacetic acid to produce
N-iodoacetyl-oligosaccharides. These were reacted with the sulfhydryl group of a
cysteine-containing peptide (CWK18), resulting in the formation of glycopeptides
in good yield that were characterized by 1H NMR and ESIMS. Both glycopeptides
were able to bind to plasmid DNA and form DNA condensates of approximately 110 nm
mean diameter with zeta potential of +31 mV. The resulting homogeneous
glycopeptide DNA condensates will be valuable as receptor-mediated gene-delivery
agents.
PMID- 10782301
TI - Crystal structures and thermotropic properties of alkyl alpha-D-glucopyranosides
and their hydrates.
AB - Thermotropic properties and crystal structures of alkyl alpha-D-glucopyranosides
and their hydrates were estimated by X-ray, DSC and thermogravimetric
measurements (TGA). Monohydrates rapidly lose their crystal water several degrees
below the melting point of the anhydrous glucopyranosides. The melting points of
the monohydrates measured in DSC pressure cells (chain length longer than seven)
are lower, and the clearing points higher than those of the anhydrous glucosides.
Layer distances of smectic and crystalline phases of anhydrous compounds were
established. Melting points, densities and layer distances of the crystalline
anhydrous glucopyranosides display strong even-odd effects. The strong decrease
of these effects in the case of the monohydrates can be elucidated by the results
of X-ray crystal structure analysis.
PMID- 10782302
TI - Stereoselective synthesis of C-[2-S-(p-tolyl)-2-thio-beta-D-galactopyranosyl]
compounds using the reaction of TolSCl adducts of D-galactal with C-nucleophiles.
AB - Pyranosyl chlorides prepared in situ from tri-O-benzyl-D-galactal and TolSCl
react with silyl enol ethers, allyltrimethylsilane, and vinyl ethers to give a
mixture of beta-C-galacto and alpha-C-talopyranosides in a ratio of 19:1.
PMID- 10782303
TI - Synthesis of methyl alpha-L-vancosaminide.
AB - The synthesis of methyl alpha-L-vancosaminide from di-O-acetyl-L-rhamnal is
described. The allylic alcohol methyl 2,3,6-trideoxy-3-C-methyl-alpha-L-threo-hex
2-enopyranoside was prepared from the glycal, 1,5-anhydro-1,2,6-trideoxy-3-C
methyl-L-ribo-hex-1-enitol, and converted to its N,N-dimethylisourea derivative.
The cis amino alcohol functionality in vancosamine was introduced by the
electrophilic cyclization of the isourea, followed by hydrolysis of the resulting
oxazoline.
PMID- 10782304
TI - Efficient syntheses of 1-bromodeoxy-, 1-azidodeoxy- and 1-aminodeoxypentitols
from unprotected D-pentono-1,4-lactones.
AB - The reduction of unprotected 5-bromo-5-deoxy-D-ribono, D-arabinono and D-xylono
1,4-lactones was achieved with NaBH4 in water-EtOH. The corresponding 1-bromo-1
deoxypentitols were isolated after acetylation in good overall yields (60-90%). 1
Azido-1-deoxypentitols were obtained quantitatively either by nucleophilic
substitution by azide ion and deacetylation of the corresponding
monobromopentitols or by reduction of the corresponding 5-azido-5-deoxy-D-pentono
1,4-lactones. The reduction of the monoazidopentitols by catalytic hydrogen
transfer gave the monoaminopentitol analogues in quantitative yield.
PMID- 10782306
TI - 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuran ose, a convenient
precursor for the stereospecific synthesis of nucleoside analogues with the
unnatural beta-L-configuration.
AB - The title compound 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-L-erythro-pentofuranose
(5), a useful precursor for the stereospecific synthesis of beta-L-nucleoside
analogues as potential antiviral agents, has been synthesised by a multi-step
reaction sequence from L-xylose with a 38% overall yield. The preparation
involved conversion of L-xylose to 1,2-O-isopropylidene-alpha-L-xylofuranose
which, upon selective 5-O-benzoylation and subsequent radical deoxygenation,
provided the protected 3-deoxy sugar derivative. Finally, cleavage of the
acetonide group gave the resulting 5-O-benzoyl-3-deoxy-L-erythro-pentose which
was acetylated to afford crystalline alpha,beta-5.
PMID- 10782305
TI - Synthesis of 6,7-dideoxy-7-isothiocyanatoheptoses: stable fully unprotected
monosaccharide isothiocyanates.
AB - Methyl 6,7-dideoxy-7-isothiocyanato-alpha-D-gluco (manno)(galacto)
heptopyranosides have been synthesized in four steps by homologation of the
respective methyl hexopyranosides via the corresponding
heptopyranosydurononitriles. Neither intra- nor intermolecular thiocarbamate
formation was observed, even under rather strenuous acidic or basic conditions.
The reducing derivative 6,7-dideoxy-7-isothiocyanato-alpha-D-gluco-heptopyranose
was also a stable compound in aqueous solution in the absence of base. Formation
of a six-membered intramolecular cyclic thiocarbamate was achieved in DMF
solution in the presence of triethylamine. The title compounds are the first
examples of stable fully unprotected monosaccharide isothiocyanates.
PMID- 10782307
TI - Synthesis, X-ray structure and high-resolution NMR spectroscopy of methyl 3-azido
2,3-dideoxy-alpha-D-arabino-hexopyranoside.
AB - The synthesis, crystal structure data and 1H and 13C NMR spectroscopy of methyl 3
azido-2,3-dideoxy-alpha-D-arabino-hexopyranoside (5b) is reported. This compound
adopts the 4C1 conformation. Hydrogen-bonded molecules of 5b form helices around
the crystallographic 4(1) axis.
PMID- 10782308
TI - Structure of the O-chain polysaccharide of the lipopolysaccharide of Xanthomonas
campestris pv. manihotis GSPB 2755 and GSPB 2364.
AB - The O-chain polysaccharide of the lipopolysaccharide of Xanthomonas campestris
pv. manihotis strains GSPB 2755 and GSPB 2364 was studied by sugar and
methylation analyses and 1H and 13C NMR spectroscopy, including 2D COSY, TOCSY,
NOESY, and H-detected 1H, 13C heteronuclear multiple-quantum coherence (HMQC)
experiments. The polysaccharide was found to contain L-rhamnose and L-xylose in
the ratio 3:1, and the following structure of the tetrasaccharide repeating unit
was established: [formula: see text]
PMID- 10782309
TI - Crystal structure of hexakis(2,6-di-O-methyl)-alpha-cyclodextrin-acetonitrile
dihydrate: a channel formed by methyl groups harbors a chain of five partially
occupied water sites.
AB - Hexakis(2,6-di-O-methyl)-alpha-cyclodextrin (DIMEA) crystallizes from 1:1 water
acetonitrile as DIMEA-acetonetril-dihydrate in the orthorhombic space group
P2(1)2(1)2(1), unit cell dimensions a = 14.2775(5), b = 15.7312(5), c =
31.1494(11) A. Refinement of the structure against 5540 X-ray diffraction data
converged at an R factor of 0.083. The macrocycle exhibits a 'round' conformation
and is stabilized by intramolecular, interglucose O-3-H(n)...O-2(n + 1) and C-6
H(n)...O-5(n + 1) hydrogen bonds. Acetonitrile is included in the central cavity
of DIMEA and held in position by C-5-H...N interactions. The two water molecules
in the asymmetric units are distributed over six sites. One is fully occupied due
to hydrogen bonding to O-3 groups of two symmetry-related DIMEA molecules,
whereas the five remaining sites show occupancies between 0.15 and 0.25. These
sites are in hydrogen bonding contact with O...O distances between 2.59 and 3.50
A and are located in infinite, hydrophobic channels parallel to the alpha-axis,
which are coated with methyl groups of symmetry-related DIMEA.
PMID- 10782310
TI - Foundation science for medicine in the 21st century. Proceedings of a workshop.
Hamilton, Ontario, Canada. May 21-23, 1999.
PMID- 10782311
TI - Opening remarks: establishing a scientific foundation for clinical medicine in
the medical curriculum.
PMID- 10782312
TI - A Toronto perspective.
PMID- 10782313
TI - Basic science in medical education.
PMID- 10782314
TI - A new curriculum for the MD degree at the University of Alberta.
PMID- 10782315
TI - Basic science and medical education: dinosaurs, departments and definitions--a
McMaster view.
PMID- 10782316
TI - "Give us good measure": the basic medical sciences and the overloaded curriculum.
PMID- 10782317
TI - The essential role of basic science in medical education: the perspective from
psychology.
PMID- 10782319
TI - The evolution of medicine--a geneticist's point of view.
PMID- 10782318
TI - Physiology: the basic science of health.
PMID- 10782320
TI - Evaluation: the engine that drives us forward--or back.
PMID- 10782321
TI - The challenges of teaching an old subject in a new world--a personal perspective.
PMID- 10782322
TI - Co-tutors in the basis of medicine.
AB - In 1994 the McGill University preclinical medical curriculum was changed from
predominantly didactic, discipline-based instruction to a problem-based approach,
in which the emphasis lies in student discussion of clinical cases with physician
mentors. Although the new curriculum has rapidly gained favour with students, it
has also generated some problems. Foremost among the problems is the diminishing
pool of physician-scientist tutors to facilitate the ever-increasing number of
small-group discussions. From the concepts embodied in educational theories of
situated learning and learning communities, this paper has proposed that
physicians in clinical practice and PhD scientists engaged in biomedical
research, be trained to co-facilitate small-group discussions. Their
complementary knowledge and similar training, should provide a forum through
which medical students will develop clinical reasoning skills, based on sound
scientific knowledge, early in their training.
PMID- 10782323
TI - Presentation and discussion of pharmacology.
PMID- 10782324
TI - Foundation science for medicine: a family medicine perspective.
PMID- 10782325
TI - Integration at the faculty level.
PMID- 10782326
TI - The student's perspective.
PMID- 10782327
TI - Identical germ-line mutations in the triosephosphate isomerase alleles of two
brothers are associated with distinct clinical phenotypes.
AB - We describe here a new stop mutation at triosephosphate isomerase (TPI) position
145 in a Hungarian family for which the first mutation (240 Phe-->Leu) was
published earlier. The entire genomic TPI locus (exons, introns and promoter) was
sequenced and found to be identical in the two compound-heterozygote brothers.
Both brothers have the same well-compensated level of non-spherocytic hemolytic
anemia and very high levels of the TPI substrate dihydroxyacetonephosphate
(DHAP), but only one brother manifests neurologic disorders. Differences in
nonsense-mediated mRNA decay may be at the basis of the differences in phenotype
expression although it cannot be excluded the interaction with a modifier gene.
Based on our earlier results, the development of neurodegeneration may be
decisively modulated by the cellular environment of the mutant proteins
initiating the process of focal apoptosis of neurons in glycolytic, peroxisomal
and prion-induced neurological diseases.
PMID- 10782328
TI - [In vitro androgenesis response of durum wheat disomic substitution].
AB - The variety 'Langdon' and its substitution series were used to evaluate the
effect of each substituted chromosome of the A and B genomes on the in vitro
androgenetic potential. This study showed the implication of chromosomes 1B and
5B in repressing embryogenesis. Genes located on these chromosomes seem to have
an inhibitor effect. The substitution of these chromosomes by their homeologous
ones from the D genome increased the number of embryos while with the presence of
the original genes the number of embryos was less than in the control. Chromosome
5B is also especially involved in the regeneration of green plants. The genetic
control is inhibitory; this explains the difficulty of obtaining good levels of
in vitro androgenesis in durum wheat. In this study no effect of the D genome on
the androgenetic response of the substitution lines was observed.
PMID- 10782329
TI - Time-co-ordinated control of glycogen synthase, protein phosphatase 2A and
protein kinase CK2 during culture growth in Yarrowia lipolytica in relation to
glycogen metabolism.
AB - In the growth course of the lipolytic yeast Yarrowia lipolytica, the activities
of protein phosphatase 2A (PP2A) and glycogen synthase (GS) rise during the
exponential phase and concomitantly glycogen storage occurs in the cells. There
is also an increase in the independence ratio (RI) indicating a shift from an
inactive phosphorylated GS form to an active dephosphorylated GS form. During the
early stationary phase, an increase in protein kinase CK2 (CK2) activity, a
reversion of RI variation and a glycogen content decrease are observed. GS
activity proved to be a good indicator of early culture growth phase. Experiments
carried out with enzymes purified from Y. lipolytica show strong RI variations
upon the action of CK2 and PP2Ac, and 32P incorporation into GS protein through
phosphorylation by CK2. GS activity would be controlled by the sequential action
of PP2A and CK2.
PMID- 10782331
TI - Morphometrics of a neotropical sandfly subspecies, Lutzomyia carrerai thula.
AB - In spite of obvious and frequently observed morphological variation in geographic
populations of sand flies, taxonomists are reluctant to create subspecies. In
doing so they avoid confusion caused by the accumulation of new taxa, but they
also obscure natural processes, some of them related to probable species
emergence. We investigated here how far the partitioning of size, shape and form
could be a relevant technique for exploring early evolutionary processes. We used
a typical case of species, subspecies and cryptic species among three related
taxa: Lutzomyia carrerai, its subspecies L. carrerai thula and L. yucumensis, a
cryptic species of L. carrerai. Univariate and multivariate metric analyses
showed global size differences, even between sympatric taxa (L. carrerai and L.
yucumensis). When allometric effects were discounted, the subspecies L. c. thula
still disclosed important differences from its putative type species, more
pronounced than those existing between the two cryptic species, L. yucumensis and
L. carrerai. A similar result was obtained after removing isometric size. These
analyses question the validity of L. carrerai thula as a subspecies, and show
that morphometrics may be a useful tool for separating simple geographic
variation from evolutionary divergence.
PMID- 10782330
TI - Effects of intracerebroventricular injections of des-His1 (Glu9) glucagon amide
on the regulatory thermogenesis in muscovy ducklings.
AB - Recent investigations have demonstrated a modulatory action of glucagon on
shivering via the central nervous system in ducklings. Such an action could be
mediated by glucagon receptors that have been recently detected in several brain
areas involved in the central control of the involuntary motricity in this avian
species. The present study using des-His1 (Glu9) glucagon amide, was performed to
investigate the central mechanisms of glucagon on shivering. This glucagon analog
was found to be an antagonist of glucagon devoid of adenylate cyclase activity
(GR2) by triggering the breakdown of inositol phosphate (GR1) in mammals
hepatocytes. The intracerebroventricular administration of des-His1 (Glu9)
glucagon amide or glucagon induced a marked inhibition of shivering in ducklings
exposed to cold. It seems likely that GR1 receptors contribute to decreased
shivering in ducklings exposed to cold. Central glucagon or des-His1 (Glu9)
glucagon amide were devoid of thermogenic effect at thermoneutrality.
PMID- 10782332
TI - [Phenotypic convergence among pentacrines Endoxocrinus and Diplocrinus related to
environmental constraints].
AB - Morphological converging and diverging trends are demonstrated using detailed
biometric analyses of the skeleton in pentacrinid populations of the
Diplocrininae subfamily living in tropical western Atlantic and in the Pacific
Ocean. According to environmental data obtained by in situ submersible
observations, water flow characteristics (laminar or with eddies) appear to be
the main factor controlling phenotypes through ontogeny. Evidence of convergence
between different taxa may be explained by ecological niches with eddies.
PMID- 10782334
TI - Extraordinary feeding behaviour in Diptera Sciomyzidae, snail-killing flies.
AB - In the laboratory, the larva of Sepedonella nana, Diptera Sciomyzidae, were only
able to develop at the expense of small aquatic oligochets collected in adult
habitats. Up till now, larval cycles have been elucidated for 38% of the
Sciomyzidae; all these larvae proved to be strict consumers of aquatic or
terrestrial molluscs (including slugs). This specific predation was considered as
a major distinguishing characteristic of Sciomyzidae among Diptera. The unusual
nutritional behaviour of S. nana reported in the present note is in contradiction
with well-established prior knowledge. The species presented all the
characteristics of the family, particularly the ventral arch sclerite present on
the larva cephalopharyngeal skeleton. It was considered as a derived species;
this behaviour, probably of secondary type, revealed new nutritional types for
Afrotropical Sciomyzidae for which the biology of only five species was
elucidated out of about 60 species described.
PMID- 10782333
TI - Phylogenetic relationships in the Ranidae. Independent origin of direct
development in the genera Philautus and Taylorana.
AB - Phylogenetic relationships within a group of Ranidae were studied, particularly
between the genera Philautus and Taylorana, to determine whether their original
reproductive mode (direct development) appeared independently. To study these
relationships, we used the DNA sequences of the 5' end of the gene coding for
mitochondrial ribosome small subunit in 28 species. Parsimony analysis resulted
in two equiparsimonious trees, 867 steps long (CI = 0.382; RI = 0.429). Data
saturation was studied and we applied weighting (weight of 5 for transversions
and 1 for transitions) to enhance the phylogenetic information. The tree we
obtained (2,212 steps long, CI = 0.408; RI = 0.482) is best supported and allows
us to determine clearly that direct development has appeared independently in
Philautus and Taylorana. In addition, it is confirmed that the genus Rana sensu
lato is heterogeneous. The genera Occidozyga and Phrynoglossus form a clade basal
to all the group but this position is not supported. The inclusion of the
Rhacophorinae in the Ranidae is confirmed. Finally, this study confirms that the
relationships within the group Tomopterna sensu Boulenger, 1918 should be re
evaluated.
PMID- 10782335
TI - [Zonation of macrobenthic communities along two bays in an insular coral reef
ecosystem (Moorea, French Polynesia)].
AB - Zonation of macrobenthic communities (corals, algae, molluscs, sponges and
echinoderms) on fringing reefs was investigated in two bays in a coral reef
ecosystem (Moorea, French Polynesia). Species richness, abundance and coral
cover, and species richness of macroalgae increased from the bayhead to the bay
entrance. For molluscs and sponges, no general trend was observed. Species
richness and abundance of echinoderms increased from the head to the entrance of
Opunohu Bay, but this trend was less pronounced in Cook Bay. The gradients
observed for corals, macroalgae and echinoderms were correlated with one or
several of the following abiotic factors: salinity, turbidity, concentration of
silicates in surface waters, and concentrations of organic carbon, carbohydrates
and amino acids in the sediments. These factors are associated with terrestrial
run-off via river discharge that occurs at the bayheads, where the major river is
located. The high degree of confinement in the bayheads allowed the establishment
of only a few tolerant macrobenthic species. Although the low diversity and
abundance of corals and echinoderms seem to be a characteristic of Polynesian
bays, a high diversity of corals can be found in the vicinity of the bayheads in
coral reefs of the western Pacific.
PMID- 10782336
TI - Extensive gene flow within sibling species in the deep-sea fish Beryx splendens.
AB - Molecular markers allow insights into the population biology and ecology of deep
sea organisms, which are usually hardly accessible to direct observation and
poorly known. Such a study was undertaken here for the deep-sea fish Beryx
splendens, a species of growing interest to fisheries. B. splendens populations
were sampled on seamounts and continental margins in the southwestern Pacific
(New Caledonia, New Zealand, southeastern Australia) and in the northeastern
Atlantic. Two hundred and fifty individuals were characterised by their single
strand DNA conformation (SSCP) of a approximately 360-base-pair (bp) fragment of
the mitochondrial cytochrome b gene, amplified by the polymerase chain reaction
(PCR). Two major SSCP haplotypes were observed in New Caledonia, a and w, whose
frequencies were negatively correlated along a north-to-south cline. All SSCP
haplotypes in the total sample were sequenced on 273 bp. The phylogenetic tree of
B. splendens haplotype sequences, rooted by two B. decadactylus sequences, showed
that a and w belong to distinct mitochondrial clades, A and W, which are
separated by approximately 4-6% nucleotide divergence. Thirty individuals from
New Caledonia were characterised by their DNA fingerprint from arbitrary-primed
PCR. The distribution of individual-pairwise similarity indices was strongly
bimodal. The larger similarity values all corresponded to comparisons within a
clade (A or W) while the lower values were all between clades. Therefore, there
was a strict association between the mitochondrial type and the DNA (presumably,
nuclear DNA) fingerprint of an individual. Altogether, these results point to the
existence of two biological species (sp. A and sp. W) within the current taxon B.
splendens. No within-species differentiation was detected at the regional scale
(New Caledonia). A remarkable result is that the three cytochrome b haplotypes of
northeastern Atlantic B. cf. splendens sp. A were also the three commonest in the
southwestern Pacific populations of this species. Such a level of homogeneity in
the distribution of haplotypes suggests there is, or recently has been, gene flow
at the inter-oceanic scale.
PMID- 10782337
TI - [Hybridization and introgression between "full-fledged species". The case of
Parnassius apollo and P. phoebus].
AB - Two butterfly species living in the Alps, Parnassius apollo and P. phoebus,
frequently hybridize in certain localities of this region. The features of this
phenomenon have been previously studied by biometry and starch gel
electrophoresis, but some points remained obscure. We present them in a study
combining results from cellulose acetate electrophoresis and wing pattern
biometry with a determination of the mitochondrial haplotype by a PCR-RFLP
analysis in a sample of butterflies from the southern French Alps. It was already
known that the male hybrids are fecund and thus that interspecific gene exchange
could take place via backcrosses with the parent species. In the present case,
combining the identification of mtDNA with the analysis of nuclear genotypes
allows us to demonstrate that hybridization can involve both sexes of both
species. Moreover, it suggests that at least some female hybrids are not sterile.
The impact of Haldane's rule is therefore not very strong in the present case.
However, although the prerequisites for introgression between the concerned
species are fulfilled, at the level of both nuclear and mitochondrial genomes, no
indication of such a phenomenon could be gathered in the studied sample.
PMID- 10782338
TI - The exoskeleton of bacterial cells (the sacculus): still a highly attractive
target for antibacterial agents that will last for a long time.
AB - Most bacteria are entirely surrounded by a strong cell wall held together by
covalent bonds of strength similar to those holding the atoms in a diamond
together. This exoskeleton is a coat of armor or corset and is usually called a
sacculus. It protects the bacterium from the stresses resulting from the higher
osmotic pressure of the cytoplasm when compared with its environment. This
strategy of constructing an external mechanical support has the weakness that the
wall barrier has to be cleaved and new wall material inserted outside of the cell
proper in order for the bacterium to grow and divide. Because of the unique
chemistry and the necessity of selectively cleaving old stress-bearing wall for
growth, the wall of the bacterial cell has been a key target for chemotherapeutic
treatment of bacterial diseases. Currently, many infectious organisms are
becoming resistant to overused antibiotics. Still the wall is a good target, and
there could possibly be several entirely new classes of antibiotics targeted
toward other parts of wall metabolism and function. The essential autolysins may
be a particularly relevant target. To find chemotherapeutic agents we must use
and extend our present understanding of the structural mechanics of bacterial
wall and their biophysics, biochemistry, and physiology. Moreover, if we use our
knowledge of biophysics/genetics and of the evolution of antibiotic resistance
mutations that occurred millions of years ago, as well as our knowledge of ones
that have arisen recently, quite novel antibiotics may be designed.
PMID- 10782339
TI - Molecular techniques for determining microbial diversity and community structure
in natural environments.
AB - The ability to quantify the number and kinds of microorganisms within a community
is fundamental to the understanding of the structure and function of an
ecosystem. The simple morphology of most microbes provides few clues for their
identification and physiological traits are often ambiguous. In addition, many
organisms resist cultivation, which is essential to their characterization.
Recombinant DNA techniques have provided a means whereby many of the obstacles
associated with cultivation and description can be overcome and subsequently has
allowed many new insights into the complexity of natural microbial communities.
Molecular approaches based on 16S ribosomal RNA (rRNA) sequence analysis allow
direct investigation of the community structure, diversity, and phylogeny of
microorganisms in almost any environment, while quantification of the individual
types of microorganisms or entire microbial communities may be addressed by
nucleic acid hybridization techniques. Furthermore, the use of fluorescently
labeled population-specific rRNA probes allows microscopic examination of
individual cells in complex microbial assemblages as well as their interactions
in situ. In this review, we discuss strategies for characterizing microbial
communities without the need for cultivation.
PMID- 10782340
TI - The role of Candida dubliniensis in oral candidiasis in human immunodeficiency
virus-infected individuals.
AB - There is an increasing interest in non-albicans Candida species because of the
increasing number of fungal infections they cause. Most of these infections can
be found in immunocompromised individuals, especially in those infected with
human immunodeficiency virus (HIV). Candida dubliniensis is a recently identified
yeast, mostly isolated in HIV-positive individuals with oral candidiasis. Candida
dubliniensis is a germ tube- and chlamydospore-form yeast. Thus, it shares
diagnostic characteristics with Candida albicans. Probably, Candida dubliniensis
has been present in the community for a long time and has been misidentified as
Candida albicans. Significant phenotypic characteristics of Candida dubliniensis
(difference in the carbohydrate assimilation profile, difference in colony color
on CHROMagar Candida, and positive tetrazolium test, etc.) have been found, but
none of them seem to be sufficient alone for the definitive identification of the
species. Recently, PCR tests were developed to discriminate Candida albicans from
Candida dubliniensis. However, these prove difficult in the context of routine
mycological diagnostics. Moreover, an increased resistance to antifungal drugs
has been described. This shows the importance of identification of Candida
dubliniensis. To elucidate the current insight into Candida dubliniensis, the
phenotypic and genotypic characteristics as well as the prevalence and the
antifungal drug susceptibilities of this species are discussed from a clinical
standpoint.
PMID- 10782341
TI - The haemocytic origin of lymphoid organ spheroid cells in the penaeid prawn
Penaeus monodon.
AB - Studies on lymphoid organ spheroid (LOS) cells of Penaeus monodon were
undertaken. Phenoloxidase and peroxidase assays showed that LOS cells have
characteristics similar to semi-granular and, in particular, large granular
haemocytes. The mean percentage of LOS cells positive for phenoloxidase and
peroxidase was 85 +/- 23 and 82 +/- 23%, respectively. There was no significant
difference between the sites of phenoloxidase and peroxidase activity in LOS
cells (t = 1.617, df = 29, p > 0.05). The relative sectional area occupied by LOS
cells relative to that of the stromal matrix cells from both laboratory-held and
farmed prawns was not correlated to increasing weight or total length of the
prawns (p > 0.05). An apoptosis detection assay showed that LOS cells were often
apoptotic whilst stromal matrix cells were not. There was a significant
difference (t = -5.533, df = 58, p < 0.05) in the mean percentage of apoptotic
spheroid cells between laboratory-held prawns (52 +/- 24%) and farmed prawns with
midcrop mortality syndrome (MCMS) (80 +/- 12%). In conclusion, LOS cells have the
characteristics of exocytosed, granular haemocytes that have phagocytosed foreign
material, particularly viruses, and probably constitute a major mechanism for
penaeid antiviral defense.
PMID- 10782342
TI - Diagnosis of Penaeus monodon-type baculovirus by PCR and by ELISA of occlusion
bodies.
AB - The black tiger prawn Penaeus monodon is a valuable aquaculture product in
Taiwan. Two specific diagnostic methods were established for P. monodon-type
baculovirus, one using polymerase chain reaction (PCR) technology and the other
enzyme-linked immunosorbent assay (ELISA) technology. Monodon-type baculovirus
(MBV) was purified by sucrose gradient centrifugation from occlusion bodies of
MBV-infected postlarvae of P. monodon. MBV DNA was subsequently purified from the
occlusion bodies and its presence was confirmed by PCR using primers of the
polyhedrin gene. Based on conserved sequences of the DNA polymerase genes of
Autographa californica nuclear polyhedrosis virus (AcMNPV) and Lymantria dispar
nuclear polyhedrosis virus (LdMNPV), primers were designed and synthesized to
yield a 714 bp PCR fragment from MBV. However, the sequence of this fragment
revealed low homology with that of LdMNPV and AcMNPV. From the DNA sequence of
this fragment, a second set of primers was designed, and using these primers, a
511 bp DNA fragment was amplified only when MBV DNA was the template. DNA
templates from AcMNPV, white spot syndrome diseased shrimp, or PMO cells (a cell
line derived from the Oka organ of Penaeus monodon) did not give any amplified
DNA fragment. Therefore, this primer pair was specific for the diagnosis of MBV.
By using intraspleenic immunization of rabbits with purified MBV occlusion
bodies, a polyclonal rabbit antiserum against MBV was obtained. This antiserum
could detect nanogram levels of MBV, but did not cross react with white spot
syndrome virus (WSSV), homogenates of PMO cells, postlarvae, hepatopancreatic
tissue or intestinal tissue of black tiger prawns by competitive ELISA. This
sensitive method could detect MBV even in tissue homogenates.
PMID- 10782343
TI - Toxic factors of Vibrio strains pathogenic to shrimp.
AB - Vibriosis is a major disease problem in shrimp aquaculture. 'Syndrome 93' is a
seasonal juvenile vibriosis caused by Vibrio penaeicida which affects Litopenaeus
stylirostris in grow-out ponds in New Caledonia. This study assessed the toxic
activities of extracellular products (ECPs) from V. penaeicida, V. alginolyticus
and V. nigripulchritudo using in vivo injections in healthy juvenile L.
stylirostris (= Penaeus stylirostris) and in vitro assays on shrimp primary cell
cultures and the fish cell line epithelioma papulosum cyprini (EPC). Toxic
effects of ECPs were demonstrated for all pathogenic Vibrio strains tested both
in vivo and in vitro, but for shrimp only; no effect was observed on the fish
cell line. ECP toxicity for New Caledonian V. penaeicida was found only after
cultivation at low temperature (20 degrees C) and not at higher temperature (30
degrees C). This points to the fact that 'Syndrome 93' episodes are triggered by
temperature drops. The assays used here demonstrate the usefulness of primary
shrimp cell cultures to study virulence mechanisms of shrimp pathogenic bacteria.
PMID- 10782344
TI - Rapid and sensitive PCR detection of Vibrio penaeicida, the putative etiological
agent of syndrome 93 in New Caledonia.
AB - Experimental infections of Penaeus (Litopenaeus) stylirostris were performed with
a Vibrio penaeicida strain (AM101) isolated in New Caledonia from Syndrome 93
diseased shrimp. Cumulative mortalities resulting from intramuscular injection or
immersion of shrimp in bacterial suspensions demonstrated high virulence for this
bacterial strain and suggested that V. penaeicida could be the etiological agent
of Syndrome 93. The median lethal dose (LD50) for AM101 was 1.3 x 10(4) CFU
(colony forming units) ml-1 by immersion and less than 5 CFU shrimp-1 by
intramuscular challenge, with mortality outbreaks at 48 and 22 h after challenge,
respectively. A polymerase chain reaction (PCR) detection assay using a primer
set designed from the 16S ribosomal RNA gene of V. penaeicida was developed. It
gave an expected amplicon of approximately 310 bp in ethidium bromide-stained
agarose gels. The specificity of these primers was assessed with different Vibrio
species. Furthermore, DNA extracted by the Chelex method could be used to detect
fewer than 20 cultured Vibrio cells in sea-water or shrimp hemolymph by this
assay. It appears to be a reliable screening method for detecting V. penaeicida
in shrimp and from the aquatic environment.
PMID- 10782345
TI - Antigenic characterization of Sphaerospora dicentrarchi (Myxosporea:
Bivalvulida), a parasite from European sea bass Dicentrarchus labrax (Teleostei:
Serranidae).
AB - The biochemical composition of Sphaerospora dicentrarchi was studied. Periodate
and Proteinase K treatments as well as lectin blots were used to analyse
carbohydrate terminals. Zymography was applied to detect proteases. Four
polyclonal antisera, raised against S. dicentrarchi (RaSdic), S. testicularis
(RaStest), Ceratomyxa labracis (RaClab) and C. sparusaurati (RaCspr), were used
in SDS polyacrylamide gel electrophoresis and immunoblot. Bands with molecular
weight (MW) between 32 and 130 kDa were detected by electrophoresis. After
Proteinase K treatment, apparent digestion of bands heavier than 43 kDa took
place. RaSdic and RaStest detected similar bands with MW between 20 and 50 kDa,
whereas RaClab and RaCspr recognized bands between 50 and 140 kDa. The 50 kDa
band was recognized by all the polyclonal antisera, suggesting that it could
correspond to an antigen shared by several myxosporean parasites. Four proteases
were observed by zymography. From the 5 lectins assayed, binding was only
observed using Con-A, which detected 2 bands of 96 and 78 kDa. Periodate
treatment did not produce any effect on the binding of RaSdic and RaStest, but a
high decrease of intensity in the antibody binding occurred at a concentration of
10 and 20 mM periodate when RaClab and RaCspr were tested. These results give
information on the antigenic composition of S. dicentrarchi which could be useful
for further diagnostic or immunoprevention studies.
PMID- 10782346
TI - Ribosomal DNA sequences of Glugea anomala, G. stephani, G. americanus and
Spraguea lophii (Microsporidia): phylogenetic reconstruction.
AB - The microsporidian species Glugea anomala, G. stephani, G. americanus and
Spraguea lophii were compared by using sequence data derived from their small
subunit rDNA genes which were amplified by polymerase chain reaction and directly
sequenced. These sequence data and published data of G. atherinae were analyzed
and were used to infer a phylogenetic tree. The 5 microsporidian fish parasites
appeared to be closely related. The higher sequence similarities demonstrated
among G. anomala, G. stephani and G. atherinae suggest that these 3 parasites are
in fact only 1 species of Glugea. Moreover, the higher sequence similarities
between S. lophii and G. americanus support the transfer of the latter Glugea
species into the genus Spraguea.
PMID- 10782347
TI - Experimental and natural host specificity of Loma salmonae (Microsporidia).
AB - The microsporidian Loma salmonae (Putz, Hoffman & Dunbar, 1965) Morrison &
Sprague, 1981 has caused significant gill disease in Pacific salmon Oncorhynchus
spp. Host specificity of the parasite was examined experimentally by per os
challenge of selected salmonids and non-salmonids with infective chinook salmon
O. tshawytscha gill material. Pink Oncorhynchus gorbuscha and chum salmon O.
keta, brown Salmo trutta and brook trout Salvelinus fontinalis, and chinook
salmon (controls) were positive, whereas Atlantic salmon Salmo salar and Arctic
char Salvelinus alpinus were negative. In addition, no non-salmonids were
susceptible to experimental exposure. Wild Pacific salmon species in British
Columbia, Canada, were examined for L. salmonae during their freshwater life
history stages (smolts, prespawning, spawning). All stages were infected,
although infections in smolts were only detectable using a L. salmonae-specific
PCR test. Many previous Loma spp. described from Oncorhychus spp. are likely L.
salmonae based on host, parasite morphology, and site of infection.
PMID- 10782348
TI - Molecular detection of Marteilia sydneyi, pathogen of Sydney rock oysters.
AB - The life cycle of Marteilia sydneyi, the aetiological agent of QX disease in the
Sydney rock oyster Saccostrea commercialis, is not known. We have developed and
optimised 2 diagnostic assays, the polymerase chain reaction (PCR) and in situ
hybridisation, for use in investigating the role of possible alternative hosts in
the life cycle of this pathogen. PCR primers, designed within the ITS1 rDNA of M.
sydneyi, amplified a 195 bp fragment. Sensitivity of the PCR assay was assessed
using DNA extracted from known numbers of sporonts purified from infected oyster
digestive gland. DNA equivalent to 0.01 sporonts was detectable following agarose
gel electrophoresis. The potential inhibitory effect of the presence of host DNA
on the PCR assay was tested by the addition of oyster genomic DNA during
amplification. Concentrations of host DNA in excess of 50 ng per 20 microliters
reaction reduced the sensitivity of the test. Environmental validation of the PCR
assay was demonstrated by the amplification of M. sydneyi DNA from 50 ng of
genomic DNA extracted from QX-infected oysters. A DNA probe was constructed using
the M. sydneyi unique primers and was able to detect 10 pg of M. sydneyi PCR
amplified DNA in dot-blot hybridisations. The probe hybridised with
presporulating and sporulating M. sydneyi stages in paraffin sections of oyster
digestive gland. No non-specific binding was observed. Hybridisation consistency
and signal intensity decreased as sporonts matured. While the high sensitivity
and specificity of the PCR test will allow rapid screening of large numbers of
potential alternative hosts for the presence of parasite DNA, it does not
actually identify infective stages. In situ hybridisation conducted on paraffin
sections will determine the location of the parasite within the host for
morphological characterisation.
PMID- 10782349
TI - Lympholeukemia in madai Pagrus major in Japan.
AB - Lympholeukemia has been occurring to an epizootic extent with mass mortality in 1
and 2 yr old madai (= Japanese red sea bream) Pagrus major in the winter season
(October-May) in the western regions of Japan since 1975. Diseased fish displayed
severe anemia and markedly increased numbers of neoplastic lymphocytoid and
lymphoblastoid cells in the blood. Neoplastic cells originated in the splenic
lymphatic cells and systemically caused severe metastatic lesions in the heart,
liver, kidney, digestive tracts, gills and the lateral musculature. Electron
microscopy revealed adeno-like viral particles (78 to 83 nm in diameter) in the
nucleus of lymphoblastoid cells which appeared in the early prevalent stage but
no viral particles in the lymphocytoid cells or plasmacytoid cells, which
subsequently increased in number. In this paper, we describe light and electron
microscopic features of neoplasms and neoplastic cells.
PMID- 10782350
TI - Natural and experimental infection of white spot syndrome virus (WSSV) in benthic
larvae of mud crab Scylla serrata.
AB - White spot syndrome virus (WSSV), the causative agent of white spot syndrome in
shrimp, has a wide host range which extends to crabs, copepods and other
arthropods. In this study, benthic larvae of the mud crab Scylla serrata were
captured from Taiwan's coastal waters and screened for the presence of WSSV by
polymerase chain reaction (PCR) and in situ hybridization. WSSV was detected in
around 60% of the larvae, and this prevalence rate remained fairly constant when
the captured larvae were subsequently maintained in an aerated system in the
laboratory. WSSV-free larvae obtained from a hatchery were challenged by
immersion in a WSSV inoculum. Fifteen days after challenge, cumulative mortality
in the experimental group reached 43% compared to 20% in the control group. PCR
detection of WSSV in both moribund and surviving specimens clearly implicated the
virus as the cause of death in most cases. Histological and in situ hybridization
data confirmed that WSSV tissue tropism in Scylla serrata crab larvae is similar
to that found in shrimp.
PMID- 10782351
TI - The use of fractional parameter in analyzing motor unit discharge pattern in
stroke patients: a correlation with the functional independence measurement.
AB - BACKGROUND: We have previously demonstrated that the fractional parameter has
significant correlation with the muscle strength of patients with stroke. In this
study, we have investigated whether fractional parameter can be used to
objectively document stroke patients' functional level (using FIM scores).
METHODS: Sixty motor units were recorded in abductor pollicis brevis, first
dorsal interosseous, and abductor digiti minimi muscles in 18 stroke patients.
Patients' FIM scores, obtained fractional parameters, and serial correlation
coefficients were analyzed and statistical determination was made. RESULTS:
Statistical significance was found between fractional parameters and motor items
of FIMs (except selfcare category); no statistical significant correlation was
found between SSC and FIM scores. CONCLUSION: Fractional parameter could be a
useful tool for measuring motor function at a single motor unit level.
PMID- 10782352
TI - Hyperexcitability of cervical motor neurons during neck flexion in patients with
Hirayama disease.
AB - We recorded the motor evoked potentials (MEPs) from the affected thenar muscles
during neck flexion in 4 patients in the early progressive phase of Hirayama
disease. The MEP size significantly increased during neck flexion in patients
compared with normal controls. In 2 patients who were treated with a neck collar,
the intrinsic muscle atrophy gradually recovered together with increased grip
power, and the time course of changes in MEP during neck flexion became normal
after treatment with a neck collar for 7-16 months. The technique described here
would be useful for evaluating the vulnerability of cervical motor neurons and
the therapeutic effect of the neck collar in Hirayama disease.
PMID- 10782353
TI - The diagnostic value of stapedius reflex and stapedius reflex exhaustion in
myasthenia gravis.
AB - Authors studies impedance, stapedius reflex thresholds and stapedius muscle
exhaustion on 31 ears of 16 MG patients. Investigations were carried out using
GSI 33 computer-assisted middle ear analyzator. Stapedius reflex threshold values
were increased in 93% of patients. Stapedius exhaustion was observed in 71% of
patients. After the administration of the reversible cholinesterase inhibitor
Mestinon (60 mg pyridostigmin bromide), reflex threshold decreased and exhaustion
occurred in only 50% of cases. Authors review the literature in context with the
audiometric diagnostics of MG and also recommend the use of these methods in more
complicated ocular and bulbar cases of MG.
PMID- 10782354
TI - Proximal receptors and the mechanical stimulation of the fingers: a somatosensory
evoked potential study.
AB - OBJECTIVE: To characterize scalp responses to mechanical stimulation of the
fingers and evaluate the contribution of different receptors. DESIGN AND METHODS:
Somatosensory evoked responses to mechanical stimulation of the right third
finger were recorded from a P3-P4 montage (n = 15) and from a F3-P4 montage (n =
9) as well as after electrical stimulation (n = 9). Responses after mechanical
stimulation of the distal region of the finger, with the hand at different
positions, were also recorded (n = 8). Complementary experiments in a small
number of individuals included EMG and accelerometer recordings as well as
anaesthesia of the finger. RESULTS: Scalp responses characterized by an initial
sequence of waves, here called NI-PI-NII, were recorded from the P3-P4 montage.
Mean peak latencies were 20, 23 and 26 ms, respectively; electrical stimulation
of the same region evoked an initial negativity (mean peak latency 23 ms). EMG
recordings suggested the involvement of different receptors in response to
electrical and mechanical stimulation. Accelerometer recordings showed the spread
of a sizable mechanical wave at the forearm. Anaesthesia did not change the
responses to mechanical stimulation. CONCLUSIONS: Relatively small mechanical
stimuli applied at distal phalanxes may activate proximal receptors which
generate scalp recorded responses that may completely occlude the contribution of
the distal receptors.
PMID- 10782355
TI - Silent period in carpal tunnel syndrome.
AB - The silent period is a misunderstood electrophysiological phenomenon leading to
several different hypotheses explaining its electrogenesis. It has been studied
by different authors and different methodologies giving a wide variability of
results, therefore an exact pattern of its normal values does not exist. This
work was undertaken to define the normal morphology and duration of the silent
period obtained by supramaximal stimulus of the median nerve, during maximum
isometric effort of the abductor pollicis brevis muscle against resistance, using
20 adult volunteers without neurological alterations. The normal median duration
was 104.6 milliseconds. The same methodology was applied to 20 hands from 20
patients with carpal tunnel syndrome. The silent period showed many types of
morphological alterations, but the major alteration observed was a tendency to
temporal elongation. No correlation between the severity of the carpal tunnel
syndrome and the silent period alterations were observed.
PMID- 10782356
TI - The sensitivity of sympathetic skin responses and standard electrophysiological
methods in diagnosis of diabetic neuropathy.
AB - This study was planned to compare the sensitivity of standard electrophysiologic
methods and sympathetic skin responses (SSRs) in the diagnosis of diabetic
neuropathy. Randomly selected 49 patients, who were followed by Haydarpasa Numune
Hospital Diabetes Outpatient Department and age matched 26 healthy persons were
included in the study. All of the patients and control subjects were assessed by
standard electrophysiologic methods (nerve conduction velocities, H-reflex, F
waves) and SSRs parameters. The abnormality ratios were 85.8% for standard
electrophysiological methods, and 76.2% for SSRs. The higher abnormality ratio
for SSRs was found important. As a result, it was concluded that standard
electrophysiologic methods (including F-wave latency) and SSRs investigations for
the early diagnosis of diabetic neuropathy, could be very useful in the
prevention of morbidity.
PMID- 10782357
TI - The F response parameters in Behcet's disease.
AB - The F response parameters may provide a sensitive method for detection of mild
neuropathy in patients with otherwise normal nerve conduction studies. We
investigated conventional nerve conduction studies and F response parameters in
patients with Behcet's disease (BD), but without neurologic involvement. The
results indicate that ulnar motor and sensory, tibial motor and sural sensory
nerve conduction studies failed to differentiate the patients with BD and
controls. In the ulnar nerve, the F response parameters were not significantly
different for the populations. In the tibial nerve, the F response latency and
chronodispersion were increased while F amplitude, duration, and persistence were
all decreased in patients with BD. The results suggests that, (1) peripheral
nerve dysfunction occurred especially in lower extremities in patients with
Behcet's disease. (2) The F response parameters were considered the most
sensitive method for the detection of neuropathy in Behcet's disease.
PMID- 10782358
TI - The effects of leg angular velocity on mean power frequency and amplitude of the
mechanomyographic signal.
AB - The purpose of the present investigation was to examine the effects of leg
angular velocity on the mean power frequency (MPF) and amplitude of the
mechanomyographic (MMG) signal during maximal concentric (CON) isokinetic muscle
actions. Sixteen adult subjects performed maximal CON leg extensions on a
calibrated Cybex 6000 dynamometer at leg angular velocities of 60 and 300
degrees.s-1. MMG was detected by a piezoelectric crystal contact sensor placed
over the mid-portion of the vastus lateralis muscle. The results indicated a
significant (p < 0.05) velocity-related decrease in peak torque (PT) and increase
in MMG amplitude from 60 to 300 degrees.s-1. There was, however, no velocity
related change (p > 0.05) in MMG MPF. These findings did not support our
hypothesis that increases across velocity in MMG amplitude were due to decreases
in muscle stiffness as a result of a shift in the contribution of slow and fast
twitch muscle fibers to PT production. Future research should examine the
potential influence of actin-myosin cycling rate as well as limb movement on the
MPF and amplitude of the MMG signal.
PMID- 10782359
TI - Tethered median nerve stress test in the diagnosis of carpal tunnel syndrome.
AB - The sensitivity of the Median Nerve Stress Test (Stress Test) described by La Ban
et al. and performed hyperextending for one minute the supinated wrist and the
distal interphalangeal joint of the index finger and looking for pain in the
proximal forearm was evaluated in 140 arms with Carpal Tunnel Syndrome confirmed
electrophysiologically. The Stress Test was positive in 60 hands (42.8%), the
Phalen's sign in 79 (56.4%) and the Tinel's sign in 59 (42.1%). Hypoaesthesia to
pinprick in the distribution of the median nerve was found in 45 hands (32.1%)
and weakness or hypotrophia of thenar eminence in 17 (12.1%). In spite of his low
sensitivity, in some cases the Stress Test was the only clinical positive sign
and, in addition to electrophysiological examination, may be helpful in clinical
practice.
PMID- 10782360
TI - Sensory potential can be preserved in severe common peroneal neuropathy.
AB - Neuropathy of Common Peroneal Nerve (CPN) is a frequent clinical condition,
generally caused by compression at the fibula head. Three neurophysiological
patterns were described: 1) segmental demyelination with conduction block; 2)
axonal damage with loss of motor units and sensory potential; 3) a mixed pattern.
We report 5 patients with foot drop in whom CPN neuropathy was identified. In 3
in spite of impressive abnormalities in various motor branches and fascicles of
the nerve, the peroneus nerve sensory potential remained well preserved. Focal
neuropathies can be remarkably selective in terms of motor and sensory deficits,
the reason can rely on a different location of the fibres or be related to a
distinct histological-biochemical constitution. A preserved SPSP should not
exclude a CPN neuropathy.
PMID- 10782361
TI - Birth and death of bone cells: basic regulatory mechanisms and implications for
the pathogenesis and treatment of osteoporosis.
AB - The adult skeleton regenerates by temporary cellular structures that comprise
teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone
with new. A considerable body of evidence accumulated during the last decade has
shown that the rate of genesis of these two highly specialized cell types, as
well as the prevalence of their apoptosis, is essential for the maintenance of
bone homeostasis; and that common metabolic bone disorders such as osteoporosis
result largely from a derangement in the birth or death of these cells. The
purpose of this article is 3-fold: 1) to review the role and the molecular
mechanism of action of regulatory molecules, such as cytokines and hormones, in
osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the
contribution of changes in bone cell birth or death to the pathogenesis of the
most common forms of osteoporosis; and 3) to highlight the implications of bone
cell birth and death for a better understanding of the mechanism of action and
efficacy of present and future pharmacotherapeutic agents for osteoporosis.
PMID- 10782362
TI - Adrenomedullin, a multifunctional regulatory peptide.
AB - Since the discovery of adrenomedullin in 1993 several hundred papers have been
published regarding the regulation of its secretion and the multiplicity of its
actions. It has been shown to be an almost ubiquitous peptide, with the number of
tissues and cell types synthesizing adrenomedullin far exceeding those that do
not. In Section II of this paper we give a comprehensive review both of tissues
and cell lines secreting adrenomedullin and of the mechanisms regulating gene
expression. The data on circulating adrenomedullin, obtained with the various
assays available, are also reviewed, and the disease states in which plasma
adrenomedullin is elevated are listed. In Section III the pharmacology and
biochemistry of adrenomedullin binding sites, both specific sites and calcitonin
gene-related peptide (CGRP) receptors, are discussed. In particular, the putative
adrenomedullin receptor clones and signal transduction pathways are described. In
Section IV the various actions of adrenomedullin are discussed: its actions on
cellular growth, the cardiovascular system, the central nervous system, and the
endocrine system are all considered. Finally, in Section V, we consider some
unresolved issues and propose future areas for research.
PMID- 10782363
TI - Management of Graves' ophthalmopathy: reality and perspectives.
AB - Graves' ophthalmopathy is an debilitating disease impairing the quality of life
of affected individuals. Despite recent progress in the understanding of its
pathogenesis, treatment is often not satisfactory. In mild cases, local
therapeutic measures (artificial tears and ointments, sunglasses, nocturnal
taping of the eyes, prisms) can control symptoms and signs. In severe forms of
the disease (3-5%), aggressive measures are required. If the disease is active,
high-dose glucocorticoids and/or orbital radiotherapy, or orbital decompression
represent the mainstay of treatment. If the disease is severe but inactive,
orbital decompression is preferred. Novel treatments such as somatostatin analogs
or intravenous immunoglobulins are under evaluation. Rehabilitative (extraocular
muscle or eyelid) surgery is often needed after treatment and inactivation of eye
disease. Correction of both hyper- and hypothyroidism is crucial for the
ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course
of the ophthalmopathy, whereas radioiodine treatment may cause the progression of
preexisting ophthalmopathy, especially in smokers. The exacerbation, however, is
prevented by glucocorticoids. In addition, thyroid ablation may prove beneficial
for the ophthalmopathy in view of the pathogenetic model relating eye disease to
autoimmune reactions directed against antigens shared by the thyroid and the
orbit.
PMID- 10782364
TI - Initial and cyclic recruitment of ovarian follicles.
AB - Mammalian ovaries consist of follicles as basic functional units. The total
number of ovarian follicles is determined early in life, and the depletion of
this pool leads to reproductive senescence. Each follicle develops to either
ovulate or, more likely, to undergo degeneration. The dynamics of ovarian
follicle development have interested endocrinologists and developmental
biologists for many years. With the advent of assisted reproductive techniques in
humans, the possibility of regulating follicle development in vivo and in vitro
has gained clinical relevance. In this review, we focus upon key branching points
during the development of ovarian follicles as well as factors involved in
determining the eventual destiny of individual follicles. We discuss
inconsistencies in the literature regarding the definitions of follicle
recruitment and selection and propose to name the two major steps of follicle
development as initial and cyclic recruitment, respectively. Because some of
these disparities have arisen due to differences in the animal systems studied,
we also compare the development of the ovarian follicles of both humans and rats.
We also review the status of knowledge of several puzzling clinical issues that
may provide important clues toward unlocking the mechanisms of follicle
development.
PMID- 10782365
TI - End-of-life care seen from broader perspective.
PMID- 10782366
TI - Sharing the mystery of death with new acquaintances.
PMID- 10782367
TI - Preventing the difficult learning situation.
PMID- 10782368
TI - Teacher comfort in teaching sexuality: reflections from an STFM seminar.
PMID- 10782369
TI - Challenges to academic family medicine in the current health care environment.
AB - BACKGROUND: Changes in health care delivery and funding have placed strains on
academic medical centers' ability to meet their multiple missions. To gain
insight into how this new academic landscape is affecting academic primary care,
this study examined the current status and perceived challenges at nine
departments of family medicine at allopathic and osteopathic medical schools.
METHODS: Site visits were made to nine academic departments of family medicine
where key informant interviews were conducted with several individuals in key
leadership positions. Sites were chosen to maximize diversity among departments
along a variety of factors, such as location, size, mission, and type of school
(private versus public). Interviews were transcribed and analyzed by a three
person multidisciplinary team for key themes. RESULTS: Analysis of interviews
revealed five major challenges for academic departments of family medicine: 1)
adjusting to new clinical demands in the academic health center, 2) organizing
and administering new initiatives in community-based education, 3) recruiting and
retaining faculty, 4) developing and maintaining research capacity, and 5)
serving multiple missions (education, clinical care, and academic pursuits) in
times of financial restraint. CONCLUSIONS: Significant challenges face academic
departments of family medicine. The success or failure of departments of family
medicine to meet these challenges could serve as a bellwether for how primary
care fits into the future overall scheme of academic health centers.
PMID- 10782370
TI - Long-term effects of a primary health care intervention program for women: lower
blood pressure and stable weight.
AB - BACKGROUND: In Stromstad, with 10,000 inhabitants, a cardiovascular prevention
program was launched during 1985-1987 because of high rates of cardiovascular
disease. To study long-term effects in women, an 8-year follow-up was conducted.
METHODS: Participants (n = 114) and nonparticipants (n = 269) in the lifestyle
intervention program in 1985-1987 (both groups with cardiovascular risk factors)
were compared regarding risk factor levels after 8 years. Effects were also
compared to another community not exposed to intervention. RESULTS: After 8
years, intervention participants showed significant reduction of mean systolic
blood pressure compared to the control group and had higher intake of dietary
fibers and more-positive attitudes to and better knowledge of healthy diets.
There was no increase of mean body weight or serum triglyceride levels whatsoever
in the intervention group. Compared with another female population not exposed to
intervention, body weight and systolic blood pressure changed in a significantly
more favorable way. CONCLUSIONS: Results from the prevention program could be
discerned after 8 years. Advantages in risk factor changes could also be found
when comparing with another female population. Given the high level of stroke in
women within the community, the blood pressure advantage in the intervention
group is particularly encouraging.
PMID- 10782372
TI - Recruitment behavior and program directors: how ethical are their perspectives
about the match process?
AB - OBJECTIVE: This study examined family practice residency directors' perspectives
on the 1999 National Resident Matching Program (NRMP) process and identified
directors' expectations for students' recruitment behavior. METHODS: Subjects
were the family practice residency program directors. A 22-item written
questionnaire was mailed to each director. The questions related to the
directors' perceptions of the following issues: applicants interviewing in more
than one specialty, communication initiated by programs or applicants,
commitments made to applicants and by applicants, ethical dilemmas faced by the
program director, and the NRMP process itself. Descriptive statistics were
reported. RESULTS: Only a few of the residency program directors (9.1%) felt that
it was ethically wrong for an applicant to interview in more than one specialty.
However, most program directors (83%) indicated that the knowledge of an
applicant interviewing in more than one specialty had a "significant" negative or
"some" negative effect on the applicant's rank order. Ninety-five percent of
program directors indicated that they engage in follow-up communication with
applicants following the formal interview. Almost all program directors (98%)
reported that at least some applicants contact them following the formal
interview to inform them that the program was a "high" or No. 1 rank-order
choice. The majority of program directors (94%) felt that the NRMP process placed
their program in the position of having to be dishonest with applicants to match
their top choices. CONCLUSIONS: The results of the study indicate that the
actions of many program directors and applicants may not be consistent with the
written policies of the NRMP.
PMID- 10782371
TI - Prevalence of the use of herbal products in a low-income population.
AB - OBJECTIVES: This study determined the prevalence of herb/supplement use in a low
income population and determined the providers' level of knowledge about
herbs/supplements. METHODS: Adult English-speaking patients seen at a rural
family practice residency clinic were offered an anonymous survey. Another survey
was developed for the clinic providers. Data were analyzed using the chi-square
test. RESULTS: Fifty-six percent of a low-income population use
herbs/supplements; 41% of all users cited friends or relatives as their main
source of information, and 53% of users had not informed their provider. In the
provider survey, 69% of the providers indicated that they had received no
education about herbs/supplements, yet 71% were asked about them by patients at
least twice a month. CONCLUSIONS: Because herb/supplement use occurs across all
demographic groups, all patients should be questioned about their use of such
substances. Currently, few providers are prepared to guide their patients about
herbs/supplements. Efforts should be made to educate health care providers about
common herbs/supplements.
PMID- 10782373
TI - A comparison of resident and faculty attitudes toward physician-assisted suicide
and active voluntary euthanasia.
AB - PURPOSE: Assisted death practices such as physician-assisted suicide (PAS) and
active voluntary euthanasia (AVE) are becoming more acceptable to the public and
the medical profession. This study compared the attitudes and practices of
resident house staff physicians with the medical staff physicians responsible for
teaching them regarding PAS and AVE. METHODS: A convenience sample of 372 medical
staff and 105 resident house staff from a multi-residency community teaching
hospital were anonymously surveyed. The overall response rate was 47%. The
questionnaire consisted of 10 questions that examined the subjects' professional
and legal values, willingness to participate in assisted death practices, and
personal preferences for assisted death practices. RESULTS: The resident house
staff differed significantly from the medical staff in attitudes toward assisted
death practices. The resident house staff was less likely to support the
traditional prohibitions against PAS and AVE. The resident house staff was also
more likely to offer assisted death practices if they were legal. There was no
significant difference, however, in the participation of assisted death practices
between the groups respectively for PAS and AVE. The residents were more likely
to request PAS or AVE for themselves or family members. CONCLUSIONS: There are
significant differences in attitudes and practices between resident physicians
and medical staff physicians concerning PAS and AVE. These differences could lead
to professional conflicts when setting clinical goals for end-of-life care and
could compromise patient care.
PMID- 10782374
TI - Applied medical informatics and computing skills of students, residents, and
faculty.
AB - BACKGROUND AND OBJECTIVES: Little is known regarding the applied medical
informatics and computing skills of family practice residents and faculty, yet
such information is critical when planning a medical informatics curriculum. We
conducted a survey at our institution to collect this information. METHODS: An
applied medical informatics and computing skills survey was administered to 93
first-year medical students, 42 family practice residents, and 14 family medicine
faculty. Responses were compared between groups before and after stratification
by age and gender. RESULTS: A total of 92% of students, 100% of residents, and
79% of faculty responded. Faculty had the highest rate of computer ownership
(91%), followed by students (86%) and family practice residents (79%). Students
and interns had the highest overall confidence using computers, followed by
faculty and then senior residents. Faculty, students, and junior residents were
significantly more confident than senior residents in their ability to perform
several specific tasks, such as conducting a MEDLINE search. Residents perceived
lack of money and time as barriers to improving their skills. CONCLUSIONS:
Current senior residents may require remedial training to graduate with the
computer skills specified in curricular guidelines. While upcoming medical
students and interns will demand more advanced training, faculty may not have the
skills to provide it.
PMID- 10782375
TI - Core curriculum guidelines: minimum standards, practical goals, or lofty ideals?
PMID- 10782376
TI - Quinoxaline chemistry. Part 13: 3-Carboxy-2-benzylamino-substituted quinoxalines
and N-[4-[(3-carboxyquinoxalin-2-yl) aminomethyl]benzoyl]-L-glutamates: synthesis
and evaluation of in vitro anticancer activity.
AB - Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a
substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position
2 of the ring and various substituents at C-6, 7 positions, 21 were selected at
the National Cancer Institute for evaluation of their in vitro anticancer
activity. The results obtained seem to confirm that the carboxy or carbethoxy
group on position 3 is not helpful, with a few exceptions, for the anticancer
activity.
PMID- 10782377
TI - Quantitation of pharmaceutically important phenothiazines by oxidimetry.
AB - A new spectrophotometric method for the assay of phenothiazines in pure form as
well as in pharmaceutical formulations with the chromium(VI)-metol-sulfanilic
acid system has been developed. The method is based on the oxidation of the drugs
by a known excess of chromium(VI) and subsequent determination of the unreacted
oxidant by interacting with metol and sulfanilic acid. The reacted oxidant
corresponds to the drug content. The coloured species exhibits maximum absorbance
at 530 nm. Beer's law is obeyed over the concentration range 5-60 micrograms ml-1
and the relative standard deviation is found to be less than 2%. The apparent
molar absorptivities are in the range 3.77 x 10(3)-3.98 x 10(3) l mol-1 cm-1, the
detection limits being in the range 0.6133-1.1349 micrograms ml-1. The method was
successfully applied to the determination of the studied drugs in their
formulations and the mean percentage recoveries were found to be 97.32-102.80%.
PMID- 10782378
TI - Synthesis and antimicrobial activity of novel arylideneisothiosemicarbazones.
AB - Arylidenimidazoles bearing a thioethereal function in the position 2 of the
imidazole ring show good antimicrobial activity. We now report on the synthesis
and the biological properties of some novel arylidenisothiosemicarbazones,
structurally related to the arylideneiminoimidazoles of which they can be
considered the linear precursors. Particular attention has been put on the
influence of structural modifications on the biological activity.
PMID- 10782379
TI - Potentiometric determination of nitrate in products used for the treatment of
dentinal hypersensitivity.
AB - In this paper, a rapid, simple and inexpensive potentiometric method for the
determination of the potassium nitrate contained in different dentinal
desensitizer products is described. The nitrate-selective electrode, using a
tetraoctylammonium salt as sensor, was constructed without an internal filling
solution. The ionic strength of the sample solutions was fixed by means of a 0.33
mol 1(-1) K2SO4 solution and direct potentiometry was used as the analytical
technique of measurement. Precision and accuracy of the method developed were
adequate since the mean of the relative standard deviations was 1.2% and the
average percentage of spike recoveries was 100.9%. Eleven samples of toothpastes,
gels and mouthwashes were analyzed by the proposed potentiometric method and the
quality of the results was compared by means of linear regression analysis with
those obtained by high-performance liquid chromatography (HPLC), adopted as the
reference technique. Satisfactory agreement was observed.
PMID- 10782381
TI - Synthesis of some new thiazolo[3,2-a]pyridines and related heterocyclic systems.
AB - New 2,7-disubstituted 5-amino-6,8-dicyano-2,3-dihydro-3-oxo thiazolo[3,2
a]pyridines have been prepared. Their cyclization with formamide, nitrous acid
and triethylorthoformate afforded a series of polycyclic heterocycles containing
condensed pyrimidine and triazine rings. Antifungal tests were also performed.
PMID- 10782380
TI - Synthesis and antiviral properties of 9-[(2-methyleneaminoxyethoxy)methyl]guanine
derivatives as novel Acyclovir analogues.
AB - This paper reports the synthesis and the antiviral properties of a series of 9
[(2-methyleneaminoxyethoxy)methyl]guanine derivatives, which can be viewed as
analogues of the antiherpes drug Acyclovir (ACV) from which they differ in the
replacement of its hydroxy group with variously substituted methyleneaminoxy
moieties. Some of the newly synthesized compounds proved to possess a certain
activity against HSV-1, albeit lower than that of ACV.
PMID- 10782382
TI - Disoxaril-related 3-(diethylamino)-5-phenylisoxazoles.
AB - Previous research has shown that 3-(dialkylamino)-5-phenylisoxazoles possessing a
compact structure were active against HRV-2 and, consequently, presented a type B
activity. In this paper, 3-(diethylamino)-5-phenylisoxazoles, which are
structurally more elongated and related to Disoxaril, were synthesized in view to
attempt type A activity against HRV-14. Unfortunately, all tested compounds were
devoid of activity against HRV-14 (and HIV-1) or exhibited great toxicity.
PMID- 10782384
TI - UV derivative spectrophotometric study of the photochemical degradation of
nisoldipine.
AB - The photodecomposition of nisoldipine ((+/-)3-isobutyl-5-methyl-1,4- dihydro-2,6
dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate), whereby its 4-(2
nitrosophenyl) pyridine analogue is obtained as the photolytic product, was
investigated under daylight exposure by means of UV derivative spectrophotometry.
The optimal instrumental parameters (120 nm/min scan speed; 2 nm slit width;
delta gamma = 10 nm and 5 s response time) for analogue derivative spectra were
established for amplitudes 1D285 and 2D291 (measured to the baseline) of the
nitroso analogue assay, as well as for 1D386 of the parent compound-nisoldipine
assay. Using the first-order derivative spectrum, the minimum detectable amount
of nitroso analogue in the presence of nisoldipine was equivalent to an impurity
level of 5% and by the second-order derivative spectrum, the determination limit
was equivalent to an impurity level of 2%. The degradation of nisoldipine
followed within 30 days and the calculated maximal degradation rate was 1.6% per
day for nisoldipine raw material, but significantly lower values of 0.19 and
0.15% per day were obtained for Nisoldin tablets (10 and 5 mg, respectively).
PMID- 10782383
TI - Determination of fluocortolone pivalate and fluocortolone hexanoate in
suppositories using reverse-phase HPLC.
AB - Fluocortolone and its esters are synthetic corticosteroids used topically in the
treatment of various skin disorders. A method that can be successfully used for
the separation and determination of fluocortolone pivalate and fluocortolone
hexanoate in suppositories was developed. This method is based on reverse-phase
HPLC on Supelcosil LC-18 (25 cm x 4.6 mm, 5 microns), using methanol-acetonitrile
water-glacial acetic acid (17:46:37:0.4 v/v/v/v) as mobile phase at a flow rate
of 3.0 ml/min. Detection was carried out using a UV detector at 238 nm. The
method developed was validated, and calibration curves were established dependent
on peak area. The validated ranges for fluocortolone pivalate and fluocortolone
hexanoate are 15-305 micrograms/ml (r = 0.9995) and 15-315 micrograms/ml (r =
0.9996), respectively. The limits of detection and the limits of quantification
for both esters were also determined.
PMID- 10782385
TI - An efficient method for the synthesis of sulbactam pivoxil.
AB - Sulbactam pivoxil, a prodrug of the beta-lactamase inhibitor sulbactam, was
prepared in high yield by reacting the sodium salt of sulbactam with chloromethyl
pivalate in a polar solvent, then diluting the reaction mixture with water and
isolating the product by filtration. Dimethyl sulfoxide was found to be the
solvent of choice among several aprotic organic solvents.
PMID- 10782386
TI - Comparative LC-MS and HPLC analyses of selected antiepileptics and beta-blocking
drugs.
AB - A highly sensitive and specific assay procedure based on the combination of
liquid chromatography and mass spectrometry (LC-MS) has been developed for the
quantitative analysis of selected antiepileptics (carbamazepine and phenytoin)
and beta-blocking drugs (acebutolol, atenolol, pindolol and propranolol) using
APCI as an ionization process. The measured concentration range was 100-300 ng ml
1 for all drugs except phenytoin (0.5-1.5 micrograms ml-1). Analysis was based on
direct injection of methanolic solutions of drugs into the mass spectrometer with
the subsequent elution with a mobile phase consisting of methanol and 1% acetic
acid solution (4:1) at a flow rate 1 ml min-1. The mass spectrometer was
programmed to permit detection and determination of either fragment or molecular
ions of carbamazepine, phenytoin, acebutolol, atenolol, pindolol and propranolol
at m/e 194.3, 252.9, 337.2, 267.1, 249.1 and 260.1, respectively. The recorded
chromatograms exhibited well-resolved peaks at retention times < 1 min. The peak
area was correlated linearly to the drug concentration. Intraday precision gave
relative standard deviations in the range 1.75-4.02%. Compared to HPLC, the
described LC-MS was faster, more sensitive and specific. Unlike HPLC, LC-MS could
be applied to analyze incompletely resolved mixtures. The absolute detection
limits for LC-MS and HPLC were 0.2-0.5 and 10-25 ng, respectively. Recovery
studies of the investigated compounds in pharmaceutical products using LC-MS and
HPLC gave mean percentages of 97.5-102.0 and 98.4-103.3, respectively.
Statistical analysis of the data using t- and F-tests showed insignificant
differences between both methods for the analysis of carbamazepine, phenytoin,
acebutolol and atenolol in pharmaceutical formulations. However, LC-MS gave more
accurate results than HPLC for determination of pindolol in tablets. Propranolol
could only be determined in tablets using LC-MS.
PMID- 10782387
TI - Synthesis and antimicrobial activity of 1,4-diaryl-2-azetidinones.
AB - Cycloaddition of substituted 4,4-benzylidene-anilines to in situ prepared
dichloroketenes in the presence of dichloroacetyl chloride and triethylamine
affords a variety of 2-azetidinones. All the compounds were characterized by IR
and 1H NMR. Their antimicrobial activity, against Gram(+) and Gram(-) bacteria
and fungi, was tested.
PMID- 10782388
TI - Synthesis and antimicrobial activity of (E)-acetoxystilbenes and alpha,alpha'
dibromoacetoxybibenzyls.
AB - The synthesis of 13 new (E)-acetoxystilbenes and alpha,alpha'
dibromoacetoxybibenzyls and their antimicrobial activity are reported. The
results of microbiological screening of 17 (E)-stilbenols and (E)
acetoxystilbenes, unknown in the literature, have also been discussed. In
particular, coumpounds 1c, 1g, 2a, 3a, 3b, 4a, 6a, 6b showed good antibacterial
activity against Staphylococcus aureus and 1c also against Bacillus subtilis.
PMID- 10782389
TI - Tick-borne viral encephalitis--the threat of summer.
PMID- 10782390
TI - Procalcitonin and C-reactive protein levels in community-acquired pneumonia:
correlation with etiology and prognosis.
AB - BACKGROUND: The diagnostic value of admission serum levels of procalcitonin (PCT)
and C-reactive protein (CRP) as indicators of the etiology and prognosis was
prospectively investigated. PATIENTS: 96 patients, 50-85 years of age, treated in
the hospital for community-acquired pneumonia (CAP). RESULTS: On admission, all
patients had elevated CRP levels (> 10 mg/l), but only 60 patients (54%) had
elevated PCT levels (> 0.1 microgram/l). The severity of disease measured by
APACHE II score was strongly associated with admission levels of PCT (p = 0.006),
but not with CRP. Eight of nine patients with pneumonia caused by atypical agents
had PCT levels < 0.5 microgram/l compared with 6/27 patients with pneumonia
caused by classic bacterial pathogens, mainly Streptococcus pneumoniae (p =
0.03). No such correlation between CRP levels and etiology was found. CONCLUSION:
Our data indicate that in patients admitted to the hospital with CAP, measurement
of PCT gives information about the severity of the disease, and may aid the
physician to differentiate typical bacterial etiology from atypical etiology, and
thereby to choose appropriate initial antibiotic treatment.
PMID- 10782391
TI - Comparison of the epidemiological and clinical features of tick-borne
encephalitis in children and adults.
AB - The aim of this prospective study was to compare epidemiological data and
clinical features in children and adults with tick-borne encephalitis (TBE).
Patients with aseptic meningitis diagnosed at the University Medical Centre,
Department of Infectious Diseases, Ljubljana, Slovenia, from June to August 1997,
in whom the diagnosis of TBE was ascertained by the presence of serum IgM
antibodies against TBE virus, who were serologically negative for Borrelia
burgdorferi sensu lato and had a negative PCR CSF result on enteroviral
infection, were included in the study. Out of 213 patients with aseptic
meningitis, 80 (37.56%) fulfilled inclusion criteria. There were 20 children and
60 adults. In both groups males predominated. Virtually all patients had headache
and fever, and more than 50% suffered from vomiting. The majority of patients in
both groups recalled a tick bite, had a biphasic course of the illness, and was
found to have obviously expressed meningeal signs. In both groups the median CSF
leukocyte count was somewhat lower than 100 x 10(6)/l with a predominance of
lymphocytes. Children were more often given antibiotics during the initial phase
of TBE than adults (p = 0.0095). Several other statistically significant
distinctions (p < 0.05) were found including the frequency of fatigue, malaise,
vertigo, photophobia, myalgias, arthralgias, as well as elevated CSF albumin and
protein concentration, elevated albumin quotient and IgG quotient; all these
findings were more often present in adults. In addition a longer duration of
fever, more frequent need for anti-edematous treatment and longer hospitalization
were found in adults. Direct comparison of clinical and epidemiological
characteristics of TBE in children and adults revealed differences in several
clinical and laboratory features and corroborates the previous conclusion that
TBE in childhood is a milder illness than TBE in adults.
PMID- 10782392
TI - Laboratory findings in tick-borne encephalitis--correlation with clinical
outcome.
AB - Infection with the tick-borne encephalitis virus (TBEV) can result in various
neurological complications. At present, there are little data available on
laboratory findings that might help predict the clinical course and prognosis of
tick-borne encephalitis (TBE). In the present study 100 patients with TBE were
examined in respect to various laboratory parameters potentially characteristic
for the disease and indicative for the prognosis in TBE. Pleocytosis, impairment
of the blood-CSF barrier and intrathecal synthesis of immunoglobulins (IgM > IgG,
IgA) were common findings in most patients. On admission to the hospital, 84% of
the patients presented with an intrathecal synthesis of TBEV-specific IgM and/or
IgG antibodies in the CSF. At follow-up, intrathecal synthesis of TBEV-specific
antibodies was demonstrated in all patients studied within 15 days after the
first examination, but changes of CSF parameters did not correlate with the
clinical course of disease. In contrast to those with moderate course of disease,
patients with severe courses of TBE displayed higher cell counts in the CSF and
lower concentrations of neutralizing antibodies in serum, and more frequently
revealed an intrathecal synthesis of total IgG. TBE-specific oligoclonal IgG
antibodies in the CSF were demonstrated only in three patients with prior,
incomplete, vaccination against TBE. The severe course of disease in individual
patients with TBE may result from a slow or low production of neutralizing
antibodies. In these patients, the more intense damage of the CNS tissue is
reflected by higher cell counts in the CSF. At onset of disease the presence of a
low concentration of neutralizing antibodies in serum and a high cell count in
the CSF might indicate an unfavorable course of TBE.
PMID- 10782394
TI - Pilot study assessing TNF gene polymorphism as a prognostic marker for disease
progression in neonates with sepsis.
AB - In adult postoperative intensive care patients, the biallelic Ncol polymorphism
within the tumor necrosis factor (TNF) locus has been shown to be a genomic
marker for individuals with increased TNF-alpha response and poor prognosis in
severe sepsis. We characterized the genomic distribution and allele frequency of
the Ncol polymorphism in 23 preterm and term neonatal intensive care unit (NICU)
patients with culture-proven sepsis and compared it with clinical and laboratory
characteristics to assess its prognostic value for disease progression. Genotype
analysis demonstrated the following absolute (relative) frequencies: 7 (0.31)
infants were homozygous for the allele TNFB2 (Group A). 12 (0.52) infants were
heterozygous (TNFB1/TNFB2) and four (0.17) infants homozygous for the allele
TNFB1 (Group B). There was no significant difference compared to adult intensive
care patients with severe sepsis (p = 0.31). The median gestational age of all
infants (13 female and ten male) as well as for either group was 28 weeks (range
23-37) with a median birth weight of 845 g (range 560-2,720). The study
population included a total of 16 very low birth weight (VLBW) infants, four in
Group A and 12 in Group B. However, there was no significant difference for
gestational age and birth weight in both groups (p = 0.82 and 0.71,
respectively). Laboratory parameters as maximum and minimum leukocyte and
thrombocyte counts, maximum immature to total neutrophil ratios (ITR), maximum C
reactive protein (CRP) levels, days of CRP levels > 5 mg/l and total days of
antibiotic treatment, were not statistically different in both groups. In total,
three infants (13%) died in consequence of their underlying disease. Two infants
belonged to Group A and one to Group B. The statistical analysis of outcome
variables (mortality, neurological impairment, failure to thrive) was not
possible, because the study population was small and the reasons for poor outcome
and death in these high-risk patients had to be considered multifactorial. In
conclusion, in this pilot study the biallelic Ncol polymorphism within the TNF
locus was not a prognostic marker for disease progression in high-risk NICU
admitted term and preterm infants with culture-proven sepsis. In order to detect
differences in outcome similar to adult postsurgical patients with severe sepsis,
an unfeasibly high number of NICU patients with culture-proven sepsis would need
to be included for a similar study.
PMID- 10782393
TI - Fast and type-specific analysis of herpes simplex virus types 1 and 2 by rapid
PCR and fluorescence melting-curve-analysis.
AB - Diagnosis of central nervous system (CNS) infection with herpes simplex virus
(HSV) requires sensitive and rapid techniques. PCR therefore is considered to be
the diagnostic gold standard in these cases. However, current PCR protocols are
time-consuming and labor-intensive. In addition, the need for post-amplification
manipulations increases the risk of laboratory contaminations with amplified
products. In order to improve conventional PCR techniques we compared our current
semiautomated HSV-PCR-ELISA assay with a new micro-volume rapid-cycle PCR system
that combines real-time monitoring and fluorescence melting-curve analysis
without the need for post-amplification sample manipulations. Spiking experiments
with supernatants of tissue culture-grown HSV type 1 (HSV-1) and type 2 (HSV-2)
in HSV-negative control cerebrospinal fluid (CSF) and sterile water revealed that
the new rapid cycle PCR protocol is as sensitive and specific as the PCR-ELISA.
Furthermore, a mismatch (G:T) within the probe-targeted region of the HSV-2
glycoprotein B gene decreases the probe/product melting temperature (Tm) from 69
degrees C for HSV-1 to 64 degrees C for HSV-2, enabling the simultaneous
identification of the two HSV genotypes by melting-curve analysis within one run.
This type specificity of the system was confirmed with 30 genital swabs
previously analyzed for the presence of HSV-1/2 in cell culture. While our
current PCR-ELISA method needs up to 1 day from sample preparation to result
generation, the new procedure takes only 1 h. We consider this system as a
promising new tool for the analysis of HSV DNA in CSF and in other human body
fluids as well as for the diagnosis of other infectious agents where rapid
diagnosis, high sensitivity and specificity are required.
PMID- 10782395
TI - Low correlation of serology with detection of Chlamydia trachomatis by ligase
chain reaction and antigen EIA.
AB - The aim of the present study was to evaluate the diagnostic accuracy of serology
by using new assays for the detection of genus and species-specific IgG, IgM, IgA
and secretory IgA antibody in female sex workers. Cervical swabs and first void
urine (FVU) from 314 female sex workers were submitted to nucleic acid
amplification by ligase chain reaction (LCx, Abbott). Concomittantly, blood
samples were tested for the presence of IgG, IgM and IgA antibodies using a genus
specific assay (rELISA, Medac) and species-specific test (SeroCT, Orgenics).
Chlamydia trachomatis infection was detected in a total of 30 (9.6%) female sex
workers by LCR. With rELISA, seroprevalences for IgG, IgM, and IgA antibody to
Chlamydia were 88.9%, 19.1% and 62.7%, respectively. IgG and IgA antibody
prevalences against C. trachomatis (SeroCT) were 65.0% and 23.9%, respectively.
In comparison to the positive LCR results obtained from cervical swab and/or FVU,
the sensitivity of rELISA for Chlamydia IgG, IgA and IgM detection was 93.3%,
83.3% and 16.7%, respectively. With SeroCT, the sensitivity for C. trachomatis
specific IgG and IgA detection was 86.7% and 33.3%, respectively. The
specificities of both serologic tests in comparison to LCR were very low. In
conclusion, the correlation of serology with active C. trachomatis infection of
the lower genital tract is very low. According to our results, serologic testing
for Chlamydia can exclude active infection of the lower genital tract with a high
reliability (> or = 95%). However, detection of C. trachomatis can only be
reliably achieved by nucleic acid amplification assays.
PMID- 10782396
TI - Tuberculosis in an area bordering east London: significant local variations when
compared to national data.
AB - From September 1996 to June 1997, in an area bordering East London, we
prospectively collected epidemiological, clinical and microbiological data on all
patients with newly diagnosed culture-positive tuberculosis and compared these to
national data based on notifications. The significant differences were that
tuberculosis was diagnosed almost exclusively in non-Caucasian patients (42/47
[89%]) and that there was a high percentage of extrapulmonary tuberculosis (27/47
[57%]) including four cases of tuberculous meningitis and five cases of
osteomyelitis. We also observed that 19/27 (70%) of patients with extrapulmonary
tuberculosis had normal chest X-rays, 3/17 (18%) sub-Saharan Africans were HIV
antibody-positive and drug resistance strains were isolated from six sub-Saharan
Africans and one Caucasian. Figures for treatment failures and mortality compared
favorably to national averages at 6 months. National data do not accurately
reflect local epidemiology and clinical presentations. Hospital-based
surveillance and promoting awareness of local differences is essential to prevent
delayed diagnosis, inappropriate management and poor clinical outcome.
PMID- 10782397
TI - Hospitalization and complications in children under 2 years of age with
Bordetella pertussis infection.
AB - We prospectively followed 725 children under 2 years of age with laboratory
diagnosed Bordetella pertussis infection to investigate the hospitalization rate
and complications. Diagnosis was made by culture and polymerase chain reaction
(PCR) from nasopharyngeal swabs in 11,016 children who presented with > or = 7
days of cough at 63 pediatric practices in Germany. Of these children, 33 (4.5%)
were hospitalized at a mean age of 4.8 months (range, 17 days to 19.5 months).
Complications occurred in 16 (48%) of the 33 patients. Pneumonia developed in two
(6%) children and a convulsion was observed in one (3%). Intensive care
monitoring was required for 23 (70%) children. Further complications were
bradycardia (21%), apnea (12%), conjunctivitis (12%), loss of weight (12%),
otitis media (6%), atelectasis (3%) and dehydration (3%). Children aged 6-24
months who had not received any dose of pertussis vaccine had a ten-fold
increased risk of hospitalization compared to those who had been partially or
fully immunized (p < 0.05). Pertussis immunization should be given at an early
point in time and completely in order to prevent severe courses of pertussis and
hospitalization in young children.
PMID- 10782398
TI - Polymerase chain reaction as a diagnostic tool for detecting Leishmania.
AB - Polymerase chain reaction (PCR) has been used to identify a Leishmania parasite
in a cutaneous ulcer from a 27-year-old patient infected during travel in Peru.
The available classical diagnostic methods could not confirm the diagnosis in a
sufficiently short time. Therefore, two sets of oligonucleotides were designed
and with both of them fragments of the expected size were obtained. The sequence
of the fragment derived from kinetoplast DNA corresponds to the Leishmania
Viannia complex. Polymerase chain reaction has advantages over classical
diagnostic methods, which makes it an important technique in those hospitals and
clinical laboratories in Europe which lack standard diagnostic tests for
Leishmania.
PMID- 10782399
TI - Streptococcus pneumoniae peritonitis postpartum.
AB - A peritonitis caused by an ascending infection is a rare complication postpartum.
A 37-year-old woman presented with a secondary peritonitis due to Streptococcus
pneumoniae. The patient had given birth to a healthy boy 4 weeks before and
showed no symptoms of a bronchitis on admission. An operation was performed after
the patient developed an acute abdomen, showing a diffuse peritonitis. High
vaginal swabs and blood cultures taken on admission were positive for S.
pneumoniae as well as the specimen taken during the operation. Thus we concluded
that this was a case of an ascending infection. After antibiotic therapy with
penicillin the patient could be discharged 8 days after the operation.
PMID- 10782400
TI - Visceral manifestation of cat scratch disease in children. A consequence of
altered immunological state?
AB - A 12-year-old girl with a 2-month history of fever and abdominal pain was
admitted to our hospital. Ultrasound and CT scans of the abdomen showed multiple
hypoechoic lesions of liver and spleen. Screening for zoonosis revealed high
positive titers to Bartonella henselae. T-cell deficiency was demonstrated and
remained almost unchanged during a follow-up of 11 months. A review of the
literature shows that disseminated visceral affection is a rare presentation of
cat scratch disease (CSD) in childhood and adolescence. Further immunological
investigations are needed in more patients with CSD to confirm whether an altered
immunological state may be responsible for the atypical visceral manifestation of
CSD.
PMID- 10782401
TI - A case of paracoccidioidomycosis: experience with long-term therapy.
AB - We describe long-term therapy for paracoccidioidomycosis occurring in a 61-year
old house-painter from Venezuela. The diagnostic examinations made in South
America had shown pulmonary granulomatous lesions and an osteolytic pattern of
the left knee that had been considered suspect of malignant disease with an
indication for limb amputation. With the aid of fine needle aspiration biopsy
(FNAB) and culture examination we diagnosed an osteomyelitis by Paracoccidioides
brasiliensis and initiated therapy with itraconazole, 400 mg per day, reduced to
200 mg per day after 2 months. At the end of 2 years of drug therapy, we observed
complete regression of the pulmonary lesions and of the osteolytic area of the
left knee. Moreover, we have periodically observed our patient to verify his
clinical development and he is still in good health. We suggest that this
pathology be considered in differential diagnosis of leprosy, tuberculosis,
leishmaniasis, and systemic mycoses, even in non-endemic areas.
PMID- 10782403
TI - Cutaneous manifestations in brucellosis: case report and review of the
literature.
AB - Brucellosis is a classical common zoonotic disease of worldwide distribution.
Skin complications are infrequent and affect less than 5% of patients with
brucellosis, although they may occasionally occur during the clinical course of
the disease. Here, we report a case of a shepherd presenting with fever and a
diffuse maculopapular rash due to Brucella melitensis infection, and we provide a
review of the relevant literature.
PMID- 10782402
TI - Listeria meningitis in children: report of two cases.
AB - We report two cases of meningitis caused by Listeria monocytogenes in children.
The first patient was a healthy 14-month-old boy and the second patient a 3-year
old girl with Byler disease which, however, is not reported as a predisposing
factor for listeriosis. We present these cases because Listeria infection,
although common in neonates, is extremely infrequent during infancy and
childhood.
PMID- 10782404
TI - Expression of retinoic acid receptors in non-neoplastic epithelial disorders of
the vulva and normal vulvar skin.
AB - Retinoids and their nuclear retinoic receptors (RARs) are important modulators of
epidermal cell proliferation and terminal differentiation. Aberrant expression of
RARs in the epidermis has been found to be associated with altered
differentiation capacity of keratinocytes. In this study, the expression of the
various types of RARs (RAR-alpha, RAR-beta, and RAR-gamma) was investigated in
surgical specimens from 17 patients with vulvar lichen sclerosus, 12 patients
with vulvar squamous cell hyperplasia, and 11 specimens of normal vulvar skin by
nonradioactive in situ hybridization. The results demonstrate that RAR-alpha
expression is significantly decreased in lichen sclerosus (p < 0.0001) and
squamous cell hyperplasia (p = 0.007) compared with normal vulvar skin.
Furthermore, in normal vulvar skin RAR-alpha mRNA is mainly located in the
suprabasal epidermal cell layers, whereas in lichen sclerosus RAR-alpha is
expressed predominantly in the basal cell layers. In squamous cell hyperplasia
RAR-alpha expression occurs in all cell layers. Compared with normal vulvar skin,
RAR-gamma expression is higher in lichen sclerosus (p = 0.026), but no
statistically significant differences are seen in squamous cell hyperplasia.
These results suggest that partial loss and abnormal localization of RAR-alpha
expression as well as increased RAR-gamma expression may play a role in the
etiology of non-neoplastic epithelial disorders of the vulva.
PMID- 10782405
TI - Primary vulvar and vaginal extraosseous Ewing's sarcoma/peripheral
neuroectodermal tumor: diagnostic confirmation with CD99 immunostaining and
reverse transcriptase-polymerase chain reaction.
AB - Two cases of extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor
arising in unusual, superficial sites are reported. One tumor involved the
vaginal wall of a 35-year-old woman, and the other neoplasm arose in the dermis
of the vulva in a 28-year-old woman. The tumors showed characteristic microscopic
features of Ewing's sarcoma/peripheral neuroectodermal tumor with nodular
monotonous proliferations of undifferentiated, small, round, hyperchromatic cells
with a low mitotic index. Rare rosette-like formations were apparent only in the
vulvar neoplasm. The tumors displayed intense immunoreactivity in a membranous
pattern for CD99, the cell surface glycoprotein encoded by the MIC2 gene.
Genetically, the tumors expressed the EWS/FLI-1 chimeric transcript, derived from
the t(11;22)(q24;q12) chromosomal translocation. Both patients had localized
disease treated with wide local excision; one received postoperative
chemotherapy, and the other received chemotherapy and radiotherapy. To date, 18
and 19 months after diagnosis, neither patient has had clinical evidence of local
recurrence or metastasis. To our knowledge, these are the first reported cases of
vaginal and vulvar Ewing's sarcoma/peripheral neuroectodermal tumor, confirmed
with molecular genetic analysis, in the English literature.
PMID- 10782406
TI - Well-differentiated villoglandular adenocarcinoma of the uterine cervix:
oncogene/tumor suppressor gene alterations and human papillomavirus genotyping.
AB - Twelve well-differentiated villoglandular adenocarcinomas (WDVAs) of the uterine
cervix were retrospectively analyzed for the presence and specific genotype of
human papillomavirus (HPV), tumor suppressor loss (p53, MCC, APC, BRCA1), cancer
gene mutation (K-ras-2, exons 1 and 2, p53 exons 5 to 8), and oncogene
amplification (c-erbB-2/HER-2/neu, int-2). Tissue for genetic evaluation was
obtained by microdissection, using 4-micron-thick histology sections of archival,
formalin-fixed, paraffin-embedded specimens. Genotyping involved nucleic acid
amplification and DNA sequencing with gene-specific oligonucleotides and L1
region consensus primers for common strains of HPV. Point mutation and HPV strain
determination were accomplished by DNA sequence analysis. Tumor suppressor gene
loss and oncogene amplification were performed by allelic imbalance analysis in
informative subjects based on DNA sequence and microsatellite-length
polymorphisms. HPV was present in all tumors and consisted of type 16 (n = 5,
42%) and type 18 (n = 7, 58%) strains, which have been closely associated with
cervical neoplasia. K-ras-2 and p53 genes did not manifest point mutational
damage. There was no evidence of oncogene amplification or tumor suppressor gene
loss. The presence of HPV in all 12 tumors supports the role of HPV infection in
the molecular pathogenesis of this uncommon neoplasm. The absence of associated
oncogene or tumor suppressor gene damage is consistent with indolent biological
behavior and the favorable prognosis of this unusual tumor.
PMID- 10782407
TI - The patterns of expression of an apoptosis-related CK18 neoepitope, the bcl-2
proto-oncogene, and the Ki67 proliferation marker in normal, hyperplastic, and
malignant endometrium.
AB - Expression of a neoepitope on cytokeratin 18, recognized by the monoclonal
antibody M30, is an early indicator of apoptosis in epithelial cells. The aim of
this study was to determine the equilibrium between apoptosis (M30), anti
apoptosis (bcl-2), and proliferation (Ki-67) in different endometrial conditions.
Paraffin-embedded samples (n = 107), representing proliferative endometrium (18),
secretory endometrium (19), postmenopausal endometrium (15), disordered
proliferative endometrium (6), simple hyperplasia (12), complex hyperplasia (8),
and endometrial adenocarcinoma (29), were evaluated immunohistochemically. The
indirect streptavidin-biotin-horseradish peroxidase technique, with 3-amino-9
ethylcarbazole as the chromogen, was used to visualize the reactions.
Proliferative endometrium showed high bcl-2 and Ki-67 expression levels with no
M30. In the secretory phase, the balance was tipped in favor of M30 with a
decrease of bcl-2 and Ki-67. Postmenopausal endometrium revealed high Ki-67 and
bcl-2 expression levels and no M30. In complex hyperplasia, M30, bcl-2, and Ki-67
showed increased expression. In endometrial carcinoma, an increasing reactivity
for M30 and Ki-67 was seen as the grade progressed. bcl-2 reacted weakly and only
in grade 1 cancer. Immunohistochemistry facilitates the study of the expression
of proteins related to cyclic endometrial activity. Interruption of these cyclic
events is associated with specific disturbances in the expression patterns of
these proteins.
PMID- 10782408
TI - Endometrial endometrioid carcinomas associated with Ewing sarcoma/peripheral
primitive neuroectodermal tumor.
AB - Three uterine tumors, each consisting of endometrioid carcinoma and Ewing's
sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) are described. The
diagnosis of ES/pPNET in each case was first established in the hysterectomy
specimen because each ES/pPNET was misinterpreted on the endometrial biopsy
specimens as a high-grade homologous sarcoma. The ES/pPNET element in each case
consisted of solid masses of small- to medium-sized round cells without Homer
Wright pseudorosettes, glial or ganglion cells, true rosettes with central
lumens, or medulloepithelial tubules. Each ES/pPNET exhibited focal positive
immunostaining for neuron-specific enolase, diffuse staining for vimentin, and
strong cell membrane immunoreactivity for O13 (CD99), the last finding providing
the first clue to the diagnosis of ES/pPNET in each case. The diagnosis in each
case was confirmed by detection of EWS/FLI-1 fusion transcript through reverse
transcription polymerase chain reaction. We also examined O13 immunoreactivity
retrospectively in 40 cases of malignant mixed mullerian tumors (MMMT) with
homologous or heterologous elements. O13 immunoreactivity was not observed in the
malignant epithelium or in the homologous or heterologous sarcomas. The
immunoreactivity of O13 in round cell endometrial sarcomas provides a clue to the
diagnosis of ES/pPNET.
PMID- 10782409
TI - Endometrial carcinoma and non-Hodgkin's lymphoma involving the female genital
tract: a report of three cases.
AB - The occurrence of both non-Hodgkin's lymphoma and carcinoma involving the female
genital tract of the same patient is rare; we describe three such cases. In case
1, a 56-year-old woman with endometrioid endometrial carcinoma had synchronous
follicular lymphoma of the uterus and ovary. In case 2, a 57-year-old woman with
diffuse large B-cell lymphoma of the uterine cervix presented 5 years later with
an endometrioid endometrial carcinoma. In case 3, a 69-year-old woman with an
endometrioid endometrial carcinoma presented with a diffuse large B-cell lymphoma
of the vagina 3 years later. In two patients, the non-Hodgkin's lymphoma was
unsuspected clinically and would have been missed without biopsy and tissue
diagnosis.
PMID- 10782410
TI - Mucosal epithelial proliferation of the fallopian tube: prevalence, clinical
associations, and optimal strategy for histopathologic assessment.
AB - The prevalence and clinical significance of mucosal epithelial proliferation or
hyperplasia of the fallopian tube are controversial in the few studies reported.
Some authors have retrospectively examined "routine" sections (one or two
submitted from each tube), whereas others have prospectively blocked the entire
tubes. In the current study, we prospectively studied a total of 168 tubes from
98 women who had various indications for salpingectomy and compared the diagnosis
in an initial single section (to simulate the usual practice) with that in the
remainder of the entirely sectioned and submitted tube (mean total number of
sections, 9.0). Some degree of mucosal epithelial proliferation was found in 83%
of all tubes examined, with no difference between the tubes removed for routine
tubal ligation and those in women who had benign ovarian lesions, malignant
gynecologic tumors, uterine leiomyomata, or benign tubal lesions (salpingitis or
ectopic pregnancy). Mucosal epithelial proliferation graded as more than mild,
however, was seen in only 4.5% of the otherwise normal ligated tubes versus 35 to
46% of tubes associated with the other lesions. When the initial sections were
compared with the subsequent ones, the diagnosis was identical in 96 tubes (57%).
In the other 72 tubes (43%), the difference in diagnosis was never greater than
one grade (no, mild, moderate, severe mucosal epithelial proliferation), with the
diagnosis more often upgraded (50 tubes) than downgraded (22 tubes) in the
additional sections. It is concluded that there is no reason to submit an entire
tube for histologic examination to detect clinically significant lesions, and the
usual practice of submission of one or two sections is clinically appropriate.
PMID- 10782411
TI - Recurrent fallopian tube carcinoma: TP53 mutation and clinical course.
AB - Primary fallopian tube carcinoma is a rare, aggressive gynecological cancer;
little is known about its cause. Previous studies have indicated that p53
immunopositivity is correlated with short-term survival in primary fallopian tube
carcinoma. We examined p53 and p21/WAF1 immunostaining and TP53 mutation in exons
5 to 8 by single-stranded conformation polymorphism and constant denaturant gel
electrophoresis in nine cases of primary fallopian tube carcinoma and their
metastases/recurrences from patients who survived for between a few months and
more than 20 years after diagnosis. We found that 1.) p53 immunopositivity
without detectable p21/WAF1 immunostaining did not correlate with TP53 mutations
in the conserved domains; 2.) mutations in TP53 occurred in two
metastases/recurrences but not in their corresponding primary tumors; 3.) in two
cancers, a TP53 mutation was observed in the primary tumor but not in the
metastases/recurrences; 4.) constant denaturant gel electrophoresis seems to be
more sensitive than single-stranded conformation polymorphism in detecting TP53
mutations; and 5.) in the nine cases studied, p53 immunoreactivity and/or TP53
mutation analysis did not correlate with tumor progression, survival, or response
to treatment.
PMID- 10782412
TI - Loss of heterozygosity on chromosome 17q in epithelial ovarian tumors:
association with carcinomas with serous differentiation.
AB - Loss of heterozygosity (LOH) on chromosome 17q is frequent in epithelial ovarian
tumors, but its clinicopathologic significance remains to be elucidated. DNA of
50 patients with epithelial ovarian tumors was extracted from blood and from
fresh-frozen and paraffin-embedded tissue (14 benign, 7 borderline, and 29
malignant). Six microsatellite loci were amplified by PCR (D17S250, TRHA1,
D17S800, D17S855, D17S579, D17S513). LOH was scored by the absence or reduction
of the signal to less than 50% of one of the alleles in tumor DNA compared with
normal DNA. LOH was identified on chromosome 17q in at least one locus in 12
tumors (24%), all of them carcinomas (12 of 29 tumors, 41.3%). It occurred more
frequently among high-grade serous carcinomas (8 of 14 tumors, 57%) and mixed
endometrioid-serous carcinomas (2 of 5, 40%). LOH was detected in all informative
markers of 10 tumors, suggesting the complete loss of an entire chromosome 17
homologue. Patients with LOH-positive carcinomas were older than those with LOH
negative malignant tumors (mean ages 67 and 49). The results support the
hypothesis that LOH on chromosome 17q may be associated with the development of
ovarian cancers in elderly patients, particularly with high-grade serous or mixed
endometrioid-serous carcinomas.
PMID- 10782413
TI - Immunohistochemical detection of the Wilms' tumor gene (WT1) in epithelial
ovarian tumors.
AB - The Wilms' tumor gene WT1 plays multiple roles in the development of the
genitourinary organs and Wilms' tumors. The aims of this study were to
immunohistochemically evaluate WT1 expression in normal female genital tissues
and in epithelial ovarian tumors and to look for correlations between WT1
expression and histologic subtypes and cell proliferation in epithelial ovarian
tumors. In normal female genital organs, WT1 expression was recognized in ovarian
surface epithelium, the lining of inclusion cysts, and tubal epithelium, but not
in the cervical or endometrial epithelium. In epithelial ovarian tumors, serous
tumors generally revealed a high WT1 expression. Among adenocarcinomas, serous
carcinoma revealed a significantly higher WT1 expression than the other
histologic subtypes. There were no significant correlations between the WT1
labeling index and the Ki-67 labeling index, and no significant difference in
survival between those showing high and low WT1 expression among the malignant
cases. These results suggest that WT1 expression may be related to cell
differentiation, and that the histologic subtypes of epithelial ovarian
carcinomas may differ considerably in their biological characteristics.
PMID- 10782414
TI - Atypical solitary fibrous tumor of the vulva.
AB - An atypical solitary fibrous tumor (SFT) was encountered as a slow-growing, 15
cm, well-demarcated, vulvar tumor in a 70-year-old woman. The tumor was highly
cellular and composed predominantly of hemangiopericytomatous and capillary
hemangioma-like proliferations and short fascicular arrangements of spindled
cells. Multinucleated giant cells and tumor necrosis also were present. The tumor
cells were positive for vimentin, CD34, progesterone receptors, and bcl-2 and
were diploid by flow cytometry. The patient was well without disease 9 months
after surgery. Awareness of the occurrence of atypical SFT in the vulva is
important so that confusion with other neoplasms can be avoided.
PMID- 10782415
TI - Primary ovarian rhabdomyosarcoma associated with clear cell carcinoma of the
ovary: a case report and review of the literature.
AB - The clinicopathologic and immunohistochemical findings of a case of coexistent
primary ovarian rhabdomyosarcoma and clear cell carcinoma of the ovary are
reported. The tumor was detected in a 41-year-old premenopausal woman who had a 1
year history of pelvic pain. On physical examination, a 14.0-cm left adnexal mass
was found for which a hysterectomy with bilateral salpingo-oophorectomy and
staging biopsies were performed. The tumor was composed of solid and cystic
areas, and two distinct microscopic components were identified: clear cell
carcinoma and rhabdomyosarcoma. Immunoperoxidase studies demonstrated that the
neoplastic cells in the latter component were positive for desmin, muscle
specific actin, and myoglobin. A biopsy taken from the pelvic peritoneum revealed
rhabdomyosarcoma (FIGO stage IIB). Despite two cycles of chemotherapy, the
disease persisted in the pelvis 4 months after diagnosis.
PMID- 10782416
TI - Adenocarcinoma of the uterine cervix with choriocarcinomatous and hepatoid
differentiation: report of a case.
AB - A case of adenocarcinoma of the uterine cervix that showed choriocarcinomatous
and hepatoid differentiation was encountered in a 65-year-old woman. She
presented with genital bleeding and had multiple metastatic nodules in the lungs.
At operation, a large, hemorrhagic, and necrotic tumor was found in the uterine
cervix. The major portion of the tumor consisted of typical choriocarcinoma
admixed with minor areas of hepatoid carcinoma and endocervical adenocarcinoma.
Human chorionic gonadotropin and alpha-fetoprotein were detected in tumor cells
in the choriocarcinomatous and hepatoid areas, respectively. The patient died of
pulmonary metastasis 4 months after the operation. The coexistence of
choriocarcinomatous and hepatoid carcinoma in an endocervical adenocarcinoma has
not been reported previously. Both heterotopic components were probably derived
from aberrant differentiation (or neometaplasia) of the somatic epithelial cells
of the endocervical adenocarcinoma.
PMID- 10782417
TI - Ectopic production and localization of beta-human chorionic gonadotropin in
lymphoepithelioma-like carcinoma of the cervix: a case report.
AB - A 32-year-old woman underwent a suction curettage for missed abortion. The
initial serum human chorionic gonadotropin (beta-hCG) level was 40 IU/ml. The
histologic examination of the uterine curettage specimen showed scant strips of a
poorly differentiated malignant neoplasm and no chorionic villi. The tumor showed
strong immunoreactivity for cytokeratin (AE1/AE3) and beta-hCG but no reactivity
for human placental lactogen. The combination of histologic appearance, beta-hCG
immunoreactivity, and elevation of serum beta-hCG raised a strong suspicion for
epithelioid trophoblastic tumor (ETT). Postcurettage serial serum beta-hCG levels
remained in the range of 20 to 45 micrograms/ml. Computerized tomographic scan
showed a 1.0-cm circumscribed mass in the upper endocervix. A radical
hysterectomy and pelvic lymphadenectomy were performed. Gross examination of the
hysterectomy specimen likewise showed a well-circumscribed mass in the upper
endocervix. Histologic examination revealed an undifferentiated carcinoma
accompanied by intense lymphoplasmacytic infiltrate. A final diagnosis of
lymphoepithelioma-like carcinoma (LELC) was rendered. LELC with elevated serum
beta-hCG level and immunoreactivity to beta-hCG should be distinguished from ETT
in a small endocervical curettage sample.
PMID- 10782419
TI - Bizarre leiomyoma of the vagina: report of a case.
AB - Smooth muscle tumors are the most common mesenchymal tumors of the adult vagina,
but no case of bizarre (also referred to as atypical, symplastic, or pleomorphic)
leiomyoma has been described at this site. We present such a case in a 44-year
old woman.
PMID- 10782418
TI - Uterine adenolipoleiomyoma: a rare hamartomatous lesion.
AB - An apparently unique intramural uterine lesion is described for which we propose
the name adenolipoleiomyoma. On gross examination, a well-circumscribed white
intramural mass contained focal fatty areas. Histology showed the mass to be
composed of smooth muscle, adipose tissue, and endometrial, endocervical, and
tubal type glands. The endometrial glands were surrounded by typical endometrial
stroma. There was no evidence of adenomyosis in the uterus outside the lesion.
This is only the second report of such a lesion within the uterus and the first
with an intramural location. We believe it to be a benign hamartomatous lesion.
PMID- 10782420
TI - Unilateral salpingitis due to enterobius vermicularis.
AB - A case of unilateral salpingitis caused by Enterobius vermicularis presenting as
a painful adnexal mass in a 28-year-old woman is reported.
PMID- 10782421
TI - Ovarian dysplasia identified by cul-de-sac aspiration: a reexamination of
previously reported cases.
PMID- 10782422
TI - Tumor markers in ovaries at risk of developing carcinoma.
PMID- 10782423
TI - Psychosocial care by general practitioners--where are the problems? Results of a
demonstration project on quality management in psychosocial primary care.
AB - OBJECTIVE: Since 1987, psychosocial services have been a part of the primary care
setting in Germany. In the framework of an eight-center national demonstration
program, problems in the diagnosis and therapy of psychosocial problems and
psychosomatic disorders were assessed. Methods to improve quality were also
implemented. METHOD: General practitioners (n = 191) from six regions
participated in the study. One thousand three hundred and forty-one treatment
episodes of patients with predominantly psychosocial symptoms were documented.
Differences between psychosocial strain, treatment, and outcome were determined
by analyses of variance. RESULTS: Anxiety (62%), depression (51%), and
marital/family conflicts (44%) were the most frequent symptoms. Psychosocial
treatment was offered more often to those patients who had the highest level of
anxiety and depression. Patients with pain and without a psychological
attribution to their illnesses were offered less psychosocial treatment and
suffered worse results. Partners and family members were rarely integrated into
therapy. The procedures employed to improve outcome were quality circles, family
oriented case conferences, consultation services, and collaborative groups.
CONCLUSIONS: These initial results are promising. A process of internal quality
management has been initiated. Some of the physicians still resist documenting
the data. Patients with somatic symptoms without psychological attribution may
need special psychosocial interventions to improve their outcomes.
PMID- 10782425
TI - Burnout in nursing staff: is there a relationship between depression and burnout?
AB - OBJECTIVE: There is evidence that burnout may be a clinical entity with
pathological stress reaction features related to the inability in finding
pleasure from work. The purpose of this study was to investigate the relationship
between burnout and depression. METHODS: The study took place in the general
hospital AHEPA of Thessaloniki. All members of the nursing staff (in total 368
subjects) took part. The protocol was self-reported and anonymous, in order to
obtain as valid data as possible and included the Maslach Burnout Inventory (MBI)
to assess the level of burnout, the Eysenck Personality Questionnaire (EPQ) to
assess personality traits, and the Zung Self-Rating Depression Scale to assess
depressive symptomatology. RESULTS: The analysis revealed a weak but significant
relationship between burnout and depression. CONCLUSIONS: Depression is a
pervasive disorder that affects almost every aspect of the patient's life. On the
contrary, burnout is, by definition, a syndrome restricted to the patient's
professional environment. However, it seems that there may be two distinct types
of burnout syndromes, of which the one comprising the majority of nurses has
little or no common features with depression. The second type consists of
individuals with a predisposition to develop burnout. The latter is characterized
by more severe symptomatology, phenotypic similarity to depression and presumably
common etiological mechanisms.
PMID- 10782424
TI - Psychological distress in healthy women with familial breast cancer: like mother,
like daughter?
AB - OBJECTIVE: In 1977, the Israel Cancer Association held a one-day conference, on
the subject of familial breast cancer, for healthy women with at least one first
degree relative diagnosed with breast cancer. The objective of this study was to
assess the psychological distress of a sample of the women who attended. METHOD:
Of the 333 healthy women present at the conference, 230 completed three
questionnaires: one on sociodemographic data and the medical history of the first
degree relative(s) (mother and/or sister), and two that measure psychological
distress: the Brief Symptom Inventory and the Impact of Events Scale. SAMPLE: The
subjects were divided into three categorical groups: those whose mother had
breast cancer (group A, N = 176), those whose sister had breast cancer (group B,
N = 34), and those whose mother and sister both had the disease (group C, N =
20). In addition, subjects were divided into two groups according to the
psychological distress level. RESULTS: Analysis of results (using ANOVA and a Chi
square test for categorical variables and both univariate and multivariate
procedures for psychological distress assessment) showed elevated levels of
distress and persistent intrusive thoughts in all groups, and particularly in
group C. CONCLUSION: There is a need to promote genetic diagnostic and
appropriate counseling, notwithstanding the potential risks that genetic
counseling poses for such women.
PMID- 10782426
TI - Multiple sclerosis presenting as catatonia.
AB - OBJECTIVE: Catatonic disorder due to general medical condition must be excluded
in psychiatric patients presenting with this movement disorder. This report
emphasizes the association of catatonia with multiple sclerosis. METHOD: A
patient with catatonia, psychotic depression, and the subsequent diagnosis of
multiple sclerosis is described and the literature reviewed. RESULTS: Mutism,
immobility, cataplexy, waxy flexibility, and other aspects of catatonia occur in
multiple sclerosis, usually as a consequence of a severe mood disorder and
extensive cerebral demyelination. These symptoms may be the presenting
manifestations of multiple sclerosis. CONCLUSIONS: A high index of suspicion for
neurological disease is indicated in patients with new-onset catatonia.
Neuroimaging and other studies may reveal underlying demyelination requiring
specific therapy.
PMID- 10782427
TI - Comment: Global climate warming and the efficacy of therapeutic agents in
psychiatry.
PMID- 10782428
TI - Seeing things from a different angle: the pigeon's recognition of single geons
rotated in depth.
AB - In 2 experiments involving computer-rendered versions of single shapes or
"geons," the extent to which depth rotation affects the visual discrimination
performance of pigeons in both go/no-go and forced-choice tasks was documented.
The pigeons were able to recognize geons at most rotations in depth; however, the
pigeons' recognition performance was better at the training view than at most
other views. Aspects of these results are both consistent with and problematic
for object-centered and viewer-centered theories of object recognition.
PMID- 10782429
TI - Display variability and spatial organization as contributors to the pigeon's
discrimination of complex visual stimuli.
AB - Three experiments assessed the contributions of display variability and spatial
organization to the pigeon's discrimination of 16-icon visual displays. After
training to discriminate 4 x 4 arrays of same and different computer icons, 4
pigeons were shown testing displays that systematically manipulated the
variability of the depicted icons and their spatial organization on the display
screen. Display variability and spatial organization each reliably controlled the
pigeon's behavior. These seemingly separate effects could be collectively
explained by the pigeon's discriminating the amount of variability or entropy in
localized regions of the display.
PMID- 10782430
TI - Conditioning the unconditioned response: modification of the rabbit's
(Oryctolagus cuniculus) unconditioned nictitating membrane response.
AB - Conditioning-specific reflex modification (CRM) occurs when classical
conditioning modifies responding to an unconditioned stimulus (US) in the absence
of a conditioned stimulus (CS). Three experiments monitored rabbit nictitating
(Oryctolagus cuniculus) membrane unconditioned responses to 5 intensities and 4
durations of periorbital electrical stimulation before and after CS or US
manipulation. CRM occurred after 12 days of CS-US pairings but not following
unpaired CS/US presentations or restraint. CRM survived CS-alone and CS/US
unpaired extinction of the conditioned response (CR) but not presentations of the
US alone, although CRs remained intact. Thus, CRs could be weakened without
eliminating CRM and CRM could be weakened without eliminating CRs. Data indicate
CRM is a reliable, associative effect that is more than a generalized CR and may
not be explained by habituation, stimulus generalization, contextual
conditioning, or bidirectional conditioning.
PMID- 10782431
TI - Contextual control over conditioned responding in a latent inhibition paradigm.
AB - We used 1-, 2-, and 3-context designs to study the control exerted by contexts
over freezing in rats exposed to a conditioned stimulus (CS) in advance of its
pairing with a shock unconditioned stimulus. The latent inhibition observed when
preexposure, conditioning, and testing occurred in the same context was
attenuated if preexposure occurred in a different context to conditioning and
testing. Latent inhibition (i.e., attenuated performance) was restored in a CS
specific manner if preexposure and testing occurred in the same context and
conditioning in a different one. Latent inhibition was also reduced by a long
retention interval but remained specific for a particular context-CS relation.
Finally, CS preexposure resulted in contextual control over the expression of
excitatory conditioned performance. The results are discussed in terms of memory,
associative, and associative-performance models of CS-preexposure effects.
PMID- 10782432
TI - Contextual control over conditioned responding in an extinction paradigm.
AB - Four experiments studied contextual control over rats' freezing to conditioned
stimuli (CSs) that had been paired with shock and were then extinguished. In
Experiment 1, rats were exposed to a CS A-shock and a CS B-shock pairing in
Context C. CS A was then extinguished in Context A, and CS B in Context B.
Freezing was renewed when each CS was presented in the context where the other CS
had been extinguished. In Experiments 2-4, rats were exposed to a CS A-shock
pairing in A and a CS B-shock pairing in B. They were then exposed to Context C
where one, both, or neither of the CSs were extinguished, or where both CSs
continued to be reinforced. On test, the rats froze more to CS A than to CS B in
Context A, and more to CS B than to CS A in Context B, but only if the CSs had
been extinguished. Thus, after extinction, rats use contexts to regulate
retrieval not only of their memory for extinction, but also of their memory for
the original conditioning episode.
PMID- 10782433
TI - The influence of passive preexposure on escape from a Morris pool.
AB - In 3 experiments rats were preexposed to the landmarks that surround a Morris
pool by being placed on a submerged platform within the pool. They were then
required to escape from the pool by swimming to the platform, which was in a
location that had not been used during preexposure. Preexposure facilitated
subsequent escape from the pool, provided that the platform was not moved during
preexposure and the relative position of the landmarks to each other remained
constant throughout preexposure. In contrast, if during preexposure the platform
was moved from session to session (Experiment 1), or the array of landmarks was
altered unsystematically from trial to trial (Experiments 2 and 3), then
subsequent learning to escape from the pool was disrupted. These findings suggest
that the effects of preexposure to the landmarks in a Morris pool is determined
by whether or not they are of relevance for identifying the location of the
platform. When they are relevant, then subsequent learning is facilitated, but
when they are irrelevant, then subsequent learning is disrupted.
PMID- 10782434
TI - Quantitative analysis of risk sensitivity in honeybees (Apis mellifera) with
variability in concentration and amount of reward.
AB - Free-flying honeybees (Apis mellifera) were trained in a series of experiments
designed to look for evidence of risk sensitivity in foraging for sucrose
solution. The suitability of the choice method used was established in 3
preliminary experiments with differences in concentration, amount, and
probability of reward. Of 5 subsequent experiments in which 2 alternatives
provided the same mean concentration of sucrose solution with different variance,
3 showed risk indifference, and 2 showed risk aversion (preference for consistent
reward). Of 2 final experiments in which the alternatives provided the same mean
amount of sucrose solution with different variance, both showed risk aversion.
Performance could be simulated quantitatively with a simple choice model
developed by P. A. Couvillon and M. E. Bitterman (1991) to account for the
results of a wide range of previous experiments on discriminative learning in
honeybees.
PMID- 10782435
TI - Stimulus and temporal cues in classical conditioning.
AB - In 2 experiments, separate groups of rats were given stimulus conditioning,
temporal conditioning, untreated control and (in Experiment 2) learned
irrelevance control procedures, followed by a compound with both stimulus and
temporal cues. Stimulus conditioning consisted of a random 15-s duration
conditioned stimulus (CS) followed by food; temporal conditioning consisted of
food-food intervals of fixed 90 s (Experiment 1) or fixed 75 + random 15 s
(Experiment 2). The stimulus group abruptly increased responding after CS onset,
and the temporal group gradually increased responding over the food-food
interval. When the food-food interval was fixed 90 s, the temporal cue exerted
stronger control in the compound, whereas when the food-food interval was fixed
75 + random 15 s, the stimulus cue exerted stronger control. The strength of
conditioning, temporal gradients of responding, and cue competition effects
appear to reflect simultaneous timing of multiple intervals.
PMID- 10782436
TI - Stimulus repetition effects on texture-based visual search by pigeons.
AB - Four experiments investigated the effects of within-session stimulus repetition
on texture discrimination. Six pigeons (Columba livia) searched for a contrasting
target region (color or shape) randomly embedded within a larger distractor
region for food reinforcement. Experiment 1 found that repeating features of the
distractors, but not those of the target, across trials increased the accuracy of
target localization relative to baseline. Experiment 2 found that subsequently
switching the identity of a repeated distractor feature to the target decreased
accuracy. Experiment 3 found that the effects of repeating a distractor feature
influenced search performance for at least 60 trials after this learning.
Experiment 4 found that differential stimulus-outcome relations can produce
control by repeated target features. The results are discussed in terms of the
factors and strategies involved in the control of avian visual search behavior.
PMID- 10782437
TI - Evaluative conditioning in the picture-picture paradigm with random assignment of
conditioned stimuli to unconditioned stimuli.
AB - Human participants were allocated to 1 of 3 groups. In the conditioning group,
each conditioned stimulus (CS)-unconditioned stimulus (US) pair was presented 7
times during the acquisition phase. Participants who were assigned to the
extinction group saw 5 additional presentations of each CS in isolation after the
7 presentations of each CS-US pair. In the latent inhibition group, the CS-only
trials were presented before the CS-US trials. Overall, a significant evaluative
conditioning effect was observed. This effect cannot be dismissed on the basis of
the arguments developed by A. P. Field and G. C. L. Davey (1997, 1998, 1999), and
the results thus provide strong evidence for the associative nature of evaluative
conditioning. The results are also in line with other findings, which showed that
evaluative conditioning is resistant to extinction.
PMID- 10782438
TI - Study for verification testing of the helmet-mounted display in the Japanese
Experimental Module.
AB - Our purpose is to propose a research and development project in the field of
telemedicine. The proposed Multimedia Telemedicine Experiment for Extra-Vehicular
Activity will entail experiments designed to support astronaut health management
during Extra-Vehicular Activity (EVA). Experiments will have relevant
applications to the Japanese Experimental Module (JEM) operated by National Space
Development Agency of Japan (NASDA) for the International Space Station (ISS). In
essence, this is a proposal for verification testing of the Helmet-Mounted
Display (HMD), which enables astronauts to verify their own blood pressures and
electrocardiograms, and to view a display of instructions from the ground station
and listings of work procedures. Specifically, HMD is a device designed to
project images and data inside the astronaut's helmet. We consider this R&D
proposal to be one of the most suitable projects under consideration in response
to NASDA's open invitation calling for medical experiments to be conducted on
JEM.
PMID- 10782439
TI - Electromagnetic interference with electronic medical equipment induced by
automatic conveyance systems.
AB - Electromagnetic interference (EMI) with electronic medical equipment induced by
automatic conveyance systems is estimated. We measured the electric intensities
of electromagnetic waves transmitted by three self-controlled electric truck
systems. We also observed EMI with an infusion pump and a syringe pump set 1 m
from the rail. The maximum electric field intensity was observed at the supplied
current frequency in two systems with non-contact power supply mechanisms. The
highest value, 137.0 dB microV/m, was measured just beside the rail. This is
higher than the international electromagnetic immunity standard limit for
electronic medical equipment. EMI may occur if electronic medical equipment is
used within 2 m of the rail when the system contains an inductive power supply
mechanism. With a contact power supply mechanism, the electric field intensity
was much lower than that of the immunity standard. EMI should not occur even when
electronic medical equipment is used just beside the rail.
PMID- 10782440
TI - A question and answer E-mail system for responding to query from the general
public with which the system manager can identify delayed replies.
AB - We constructed a question and answer system for direct delivery of E-mail queries
from the general public to the proper hospital representative and with which the
system administrator can monitor E-mail replies. The system consists of two sub
systems; one is an E-mail questionnaire sub-system that automatically delivers E
mail queries to the proper person and an E-mail reply monitor sub-system with
which the system administrator can monitor the E-mail replies. The monitor system
compares the origin address of the E-mail reply and the destination address on a
questionnaire filled out at the time the query is made. In a test of the system,
56 queries were received in 31 days, with 37 replied to. The interval from
receipt of an E-mail query to reply was calculated. Nineteen replies were
submitted within 2 days.
PMID- 10782441
TI - Redesigning the medical office for improved efficiency: an object-oriented event
driven messaging system.
AB - Medical practitioners are under ever increasing pressure to maximize patient
care, while minimizing costs. One productivity area that has not previously
undergone thorough investigation is the efficient utilization of time for intra
office communication. Medical office personnel typically need to communicate
patient information and resource requests, as well as personal messages. An intra
office communication system is designed that reduces time-waste typically
incurred in medical office environments. Redesigning medical offices with intra
office communication systems provides time savings of several man hours per day.
The subsequent increase in time efficiency enables higher quality of patient care
and larger patient loads to be managed by existing medical staff.
PMID- 10782442
TI - A simple client-server system using a personal computer as the server.
AB - Hospital information systems have recently grown into huge, complex systems. As a
result, the cost of development and maintenance of application programs has
increased and become a serious problem. We have constructed an order entry system
using server-client architecture as part of a hospital intranet information
system in which a personal computer is used as a server. Using a commercial
database management system and software development tools, an easily maintained
order entry system was developed within only three months by one programmer.
Since slow response when the number of clients increased was possible, we
measured turn-around times when one or ten clients accessed simultaneously. Turn
around times were 8 and 10 sec, respectively. Because we expect much better
performance from personal computers in the near future, application systems using
personal computers as Intranet servers will be cost and time effective and easy
to develop and maintain.
PMID- 10782443
TI - The art of building decision trees.
AB - Decision support systems that help physicians are becoming a very important part
of medical decision making. They are based on different models and the best of
them are providing an explanation together with an accurate, reliable, and quick
response. One of the most viable among models are decision trees, already
successfully used for many medical decision-making purposes. Although effective
and reliable, the traditional decision tree construction approach still contains
several deficiencies. Therefore we decided to develop and compare several
decision support models using four different approaches. We took statistical
analysis, a MtDeciT, in our laboratory developed tool for building decision trees
with a classical method, the well-known C5.0 tool and a self-adapting
evolutionary decision support model that uses evolutionary principles for the
induction of decision trees. Several solutions were evolved for the
classification of metabolic and respiratory acidosis (MRA). A comparison between
developed models and obtained results has shown that our approach can be
considered as a good choice for different kinds of real-world medical decision
making.
PMID- 10782444
TI - Validation of the Spanish version of the Changes in Sexual Functioning
Questionnaire (CSFQ).
AB - The aim of this study is to adapt and validate the Changes in Sexual Functioning
Questionnaire (CSFQ) in Spanish. The CSFQ was administered to 206 depressed
patients in different Spanish cities, to 326 health sciences students at the
University of Oviedo, and to 48 workers undergoing routine health check-ups. The
Hamilton Depression Rating Scale (HAM-D) was administered to the depressed
patients. The average time spent answering the CSFQ was 15.19 minutes. The CSFQ
discriminated the depressed patients from the workers and university students. In
the three areas of reliability (internal, test-retest, and inter-rater), the
coefficients obtained were greater than 0.80. The factor analysis demonstrated
differences in the internal construct of the American CSFQ and its Spanish
equivalent. The psychometrc properties of the Spanish version of the CSFQ
indicate that it is a valid instrument for clinical use in treating depressed
patients.
PMID- 10782445
TI - Sildenafil for psychotropic-induced sexual dysfunction in 31 women and 61 men.
AB - Ninety-two outpatients (31 women, 61 men) who were treated with oral sildenafil
for psychotropic-induced sexual dysfunction (PISD) completed ratings of their
sexual functioning pre- and posttreatment. Both women and men reported
significant improvements (p = .001) in all domains of sexual functioning, with
88% reporting improvement in overall sexual satisfaction. Significant
improvements were reported regardless of psychotropic medication type. However,
patients taking selective serotonin re-uptake inhibitors reported less
improvement in arousal, libido, and overall sexual satisfaction than did other
patients, whereas patients taking benzodiazepines reported significantly more
improvement in libido and overall sexual satisfaction. Oral sildenafil may be an
effective treatment for PISD.
PMID- 10782446
TI - Satisfaction in the sex life of a general population sample.
AB - A questionnaire asking about satisfaction and problems in the sex lives of
respondents and their partners was sent to 4,000 adults registered with general
practices in England. A quarter of respondents said that they were dissatisfied
with their sex lives, men more so than women, particularly with the frequency of
intercourse. Respondents were more likely to be dissatisfied with their sex life
if they perceived their partner to have a sexual problem. Respondents who were
dissatisfied were more likely to report that their partner was dissatisfied with
their sex life. The benefits of treating sexual problems have wide implications
for both partners in a relationship.
PMID- 10782447
TI - Characteristics of the ideal sex partner: gender differences and perceptions of
the preferences of the other gender.
AB - The objective of the current study was to further examine gender differences in
preferences for particular characteristics in a sexual partner and to investigate
the extent to which men and women accurately estimate the preferences of the
other gender. Heterosexual college students (185 men, 244 women) rated a diverse
set of characteristics in a hypothetical sexual partner with whom they were
presumed to be involved in an ongoing relationship. Participants also responded
to the same set of items with regard to estimates of the ratings of the other
gender (order of presentation was counter-balanced). Although there was notable
similarity in what men and women most valued in a potential long-term sex
partner, there were gender differences with regard to ratings of several of the
items. Also, men and women under- or overestimated the ratings of the other
gender with regard to several characteristics. Results are discussed with regard
to implications for intervention as well as directions for future research.
PMID- 10782449
TI - Perceived premarital counseling outcomes among recently married army personnel.
AB - Data from 1,285 recently married soldiers who participated in the 1989 Army
Family Research Program survey indicated that premarital counseling by itself had
little effect on subsequent marital satisfaction. However, those who had
premarital counseling were more likely to use marital and family therapy
services, at both subclinical and clinical levels of distress, than others who
had not had such counseling before marriage.
PMID- 10782448
TI - The relationship between perceived dysfunctional family-of-origin rules and
intimacy in young adult dating relationships.
AB - This study examined the relationship between perceived dysfunctional family-of
origin rules and intimacy in single young adult dating relationships. A sample of
754 single, Caucasian-American young adults completed measures of perceived
dysfunctional family-of-origin rules and emotional, intellectual, and sexual
intimacy in dating relationships. When controlling for the effects of gender and
age, results showed that perceived dysfunctional family-of-origin rules had a
negative impact on the perceived expression and experience of these three kinds
of intimacy in dating relationships. Implications for relationship therapy are
discussed.
PMID- 10782450
TI - Evaluation of clitoral blood flow by color Doppler ultrasonography.
AB - The feasibility of reliably measuring clitoral blood flow using standard color
Doppler ultrasonography was evaluated by two independent assessors in a sample of
40 pre- and post-menopausal women. High positive correlations with no significant
mean differences between examiners were found for three major standard blood flow
measures including maximum velocity, resistance, and pulsatility indices. With
further methodological refinements, ultrasonographic evaluation of clitoral blood
flow will be adaptable for clinical and research use and is likely to become the
standard physiological measure of female sexual arousal.
PMID- 10782451
TI - The Female Sexual Function Index (FSFI): a multidimensional self-report
instrument for the assessment of female sexual function.
AB - This article presents the development of a brief, self-report measure of female
sexual function. Initial face validity testing of questionnaire items, identified
by an expert panel, was followed by a study aimed at further refining the
questionnaire. It was administered to 131 normal controls and 128 age-matched
subjects with female sexual arousal disorder (FSAD) at five research centers.
Based on clinical interpretations of a principal components analysis, a 6-domain
structure was identified, which included desire, subjective arousal, lubrication,
orgasm, satisfaction, and pain. Overall test-retest reliability coefficients were
high for each of the individual domains (r = 0.79 to 0.86) and a high degree of
internal consistency was observed (Cronbach's alpha values of 0.82 and higher)
Good construct validity was demonstrated by highly significant mean difference
scores between the FSAD and control groups for each of the domains (p < or =
0.001). Additionally, divergent validity with a scale of marital satisfaction was
observed. These results support the reliability and psychometric (as well as
clinical) validity of the Female Sexual Function Index (FSFI) in the assessment
of key dimensions of female sexual function in clinical and nonclinical samples.
Our findings also suggest important gender differences in the patterning of
female sexual function in comparison with similar questionnaire studies in males.
PMID- 10782452
TI - [Clinical characteristics of familial rheumatoid arthritis in Spain. A study of
73 families. Spanish Consortium for Rheumatoid Arthritis (CEAR) and European
Consortium for Familial Rheumatoid Arthritis (ECRAF)].
AB - OBJECTIVE: To describe clinical characteristics and the homogeneity of disease
expression between involved members in multicase Spanish rheumatoid arthritis
(RA) families. PATIENTS AND METHODS: 73 families with two or more siblings with
RA were found, with a total of 149 patients distributed in 79 pairs (70 sib
pairs, and 3 sib trios). Demographic, clinical and radiological characteristics
were recorded in a standard questionnaire. RESULTS: Clinical characteristics were
similar to those of sporadic RA with a high frequency of women (78%), positive
rheumatoid factor (RF) (86%), erosions (89%) and a 25% of the patients having
extraarticular disease. The most important variable in disease severity was
disease duration. The concordance between family members of the same age and
calendar year of disease onset, and the pattern of disease expression, was not
higher than expected, showing that the disease is heterogenic. CONCLUSION:
Environmental factors seem to be more important in RA susceptibility. Clinical
characteristics of familiar RA in Spain do not seem to be different from sporadic
RA, although differences were found in disease expression within families that
may be due to variation of genetic or environmental factors, responsible for the
susceptibility and disease duration.
PMID- 10782453
TI - [Lowering high levels of fasting total homocysteine with folic acid and vitamins
B in patients with venous thromboembolism: relationship between response and the
C677T methylenetetrahydrofolate reductase (MTHRF) genotype].
AB - BACKGROUND: High levels of plasma total homocysteine (tHcy) are involved in
arterial or venous occlusive diseases. It essentially depends on the nutritional
status of folic acid (FA) and vitamins B12 or B6, but also on the
methylenetetrahydrofolate reductase (MTHFR) enzymatic activity. We aim to
evaluate the response of the hyperhomocysteinemia (HHcy) to a standard schedule
of vitamin supplementation, according with the MTHFR genotype. PATIENTS AND
METHODS: 227 patients, diagnosed with venous thromboembolism (VTE) were analysed
for tHcy (in fasting conditions), and for the MTHFR-C677T gene polymorphism. When
the tHcy exceeded the cut-off point (men = 16, women = 15 mumol/l), the patients
were supplemented with a dose equivalent to 1 mg FA, 0.2 mg B12 and 100 mg of B6,
daily by 6 weeks. Afterwards they were reanalysed and the reduction was
stratified by MTHFR genotype, looking for any difference in the response.
RESULTS: The mean fasting tHcy was 12.3 mumol/l (SD = 8). The 51
hyperhomocysteinemic patients (22%) were older (65.1 y) than the normal ones
(55.0 y) (p = 0.0001). The treatment was carried out properly in 46 patients
(90%). The pre-treatment mean Hcy was 23.2 (SD = 10.5) mumol/l, and it was
reduced to 13.0 (SD = 5.9) (p = 0.0001) (mean reduction = 42.1%). By genotype,
the C/C reduced from 21.0 to 13.2 mumol/l (37%) (n = 18), the C/T from 25.0 to
12.6 mumol/l (46%) (n = 24), and the abnormal homozygotes T/T from 22.7 to 14.5
mumol/l (39%) (n = 4), although no statistical significant differences were
found. In 80% of cases (37/46), tHcy values normalised. A negative correlation (r
= -0.471) (p = 0.005) was observed between age and response. CONCLUSIONS: The
FA/B6/B12 based therapy reduces in a simple, quick and effective way (> 40% in 6
weeks) the pathologic tHcy levels on a VTE population and this is not influenced
by the MTHFR genotype. As HHcy seems related with recurrences of venous
thrombosis, we could speculate if it would be useful to analyse routinely the
tHcy, attempting reduction in selected cases.
PMID- 10782454
TI - [Phenotypic expression of Lp(a) in Spanish children and adolescents].
AB - BACKGROUND: To know the distribution of phenotypes Lp(a) in an young population.
METHODS: Lipoprotein levels, lipoprotein(a), apolipoproteins and the Lp(a)
phenotypes were determined in 105 children, selected according to their
cholesterol concentrations. RESULTS: The Lp(a) concentrations were significantly
higher in group with low molecular weight respect to group with high molecular
weight. The most frequent isoform was S3. CONCLUSIONS: The Lp(a) concentrations
correlate inversely with the molecular weight of Apo(a) isoforms.
PMID- 10782455
TI - [Genetics of rheumatoid arthritis].
PMID- 10782456
TI - [Hodgkin's disease in patients infected by the human immunodeficiency virus.
Study of fifteen cases].
AB - BACKGROUND: In spite of not being considered as an AIDS defining illness,
Hodgkin's disease (HD) has specific clinical and biological features in HIV
infected patients. PATIENTS AND METHODS: Study of clinicopathologic and analytic
characteristics, Epstein-Barr virus (EBV) detection (polymerase chain reaction),
and prognosis in 15 patients with HD and HIV infection. RESULTS: Thirteen
patients had B symptoms, 10 extranodal involvement and 12 advanced HD. The most
frequent histologic subtypes were mixed cellularity (6) and lymphocyte depletion
(6). The mean (SD) of CD4 lymphocytes was 0.10 (0.08) x 10(9)/l. The presence of
EBV in lymph node biopsy was demonstrated in 3 out of 4 patients investigated.
Complete remission (CR) was achieved in 7 out of 14 treated cases (50%), the
median overall survival was 26 months and the 2 year event-free survival
probability was 60%. CONCLUSIONS: In HIV-infected patients, HD presents in
advanced stages, unfavourable histologic subtypes, frequent extranodal
involvement and B symptoms. The prognosis is poor, mainly because of a low CR
rate.
PMID- 10782457
TI - [Sociologic overview of quality life].
PMID- 10782458
TI - [New perspectives in the nonpharmacological treatment of atrial fibrillation].
PMID- 10782459
TI - [What are cryptogenic hepatic diseases?].
PMID- 10782460
TI - [Penetrating aortic ulcer: an unreported cause of massive digestive hemorrhage].
PMID- 10782461
TI - [Exchange blood transfusion and P. falciparum malaria].
PMID- 10782463
TI - [Usefulness of bone marrow examination in the diagnosis of fever of unknown
origin in patients infected by human immunodeficiency virus].
PMID- 10782462
TI - [Acute bilateral ophthalmoplegia with raised anti-GQ1b antibodies].
PMID- 10782464
TI - Prognostic implication of human papillomavirus infection in squamous cell
carcinoma of the lung.
AB - On the subtropical island of Okinawa, squamous cell carcinoma (SCC), particularly
the well-differentiated form, is the most frequent type of lung cancer, while
this form is relatively rare on the Japanese mainland and in other countries.
Furthermore, in Okinawa, in 1993, 80% of SCC cases of the lung were found to be
infected with human papillomavirus (HPV). We studied the prognosis of SCC of the
lung with HPV infection (n = 25) and compared it with non-HPV-infected SCC (n =
16). Using the Kaplan-Meier method (Wilcoxon analysis), the prognosis of HPV
infected cases was found to be better than that of the non-infected cases. In the
virus-infected cases, apoptosis and infiltration of a large number of Langerhans
cells were demonstrated. In addition to these findings, the virus-infected tumors
were demonstrated to be histologically well-differentiated, perhaps contributing
to the favorable prognosis. However, among the virus-infected cases, the type 16
virus-infected cases showed a poorer prognosis, compared to those infected with
other HPV types. p53 gene mutation was also examined, and was considered to be an
unfavorable prognostic factor, as reported elsewhere. However, in Okinawa, HPV
positive cases with p53 mutations showed a slightly better prognosis than did non
viral infected cases with p53 mutations. The TNM staging system was also useful
for categorizing the virus-infected cases. The prognosis of stage III (A and B)
cases was poor. All of our present cases received surgical treatment.
Chemotherapy and radiation therapy were not performed. Such treatment, however,
might be effective, because virus-infected uterine cervical carcinomas have been
routinely treated with chemotherapy and radiation. Furthermore, if the
immunological basis of increased Langerhans cell infiltration in HPV-infected
cases is elucidated, a clinical trial with immunotherapy may be favorable for the
clinical outcome.
PMID- 10782465
TI - Expression of stromelysin and urokinase type plasminogen activator protein in
resection specimens and biopsies at different stages of osteoarthritis of the
knee.
AB - This study aimed at assessing the possible diagnostic value of cartilage biopsies
as a convenient marker for cartilage matrix degradation. We therefore examined
cartilage specimens from 56 patients with primary osteoarthritis (OA) of the
knee. Resection and biopsy cartilage specimens obtained during joint replacement
surgery were used for this study. In addition to histomorphology,
immunohistochemistry (ICH) was performed to determine the expression levels and
distribution patterns of stromelysin and u-PA protein. The latter data were
compared with the degree of histomorphological changes in osteoarthritic
cartilage samples, based on a modified version of Mankin's grading score.
Compared to the cartilage resection specimens, the biopsies showed comparable
expression patterns for both proteinases: the strongest signals were noted in the
superficial zone and, as matrix destruction increased, also in the chondrocytes
of the transition and deep zones. The strongest signals were ascertained in cell
clusters beneath deep matrix fissures. At the immunohistochemical level, we found
a direct correlation in the expression of MMP-3 and u-PA between resection
specimens and biopsies. Furthermore, in both types of cartilage samples, we
noticed a positive relationship between the expression of both proteins and the
Mankin score. Analysis of the expression levels revealed significant differences
between deep, transition and superficial zones. Histomorphological and
immunohistochemical examinations of MMP-3 and u-PA in biopsies of osteoarthritic
cartilage turned out to be useful for estimating the pathological changes within
osteoarthritic knee joints. Therefore, in future, cartilage biopsies from
osteoarthritic knee joints might serve as a diagnostic tool and thus have an
influence on further therapeutic strategies.
PMID- 10782466
TI - Evaluation of numerical abnormalities of chromosomes 1 and 17 in proliferative
epithelial breast lesions using fluorescence in situ hybridization.
AB - Our aim was to investigate the putative role of chromosome abnormalities of
chromosomes 1 and 17 in the process of breast carcinogenesis. Numerical
abnormalities of chromosomes 1 and 17 were investigated using fluorescence in
situ hybridisation (FISH) in a series of 16 primary invasive breast carcinomas
associated with intraductal proliferative epithelial lesions. Chromosome 1
aneusomy was detected in 55.6% of ductal hyperplasia (DH), 81.8% of ductal
carcinomas in situ (DCIS) and 87.5% of invasive ductal carcinomas (IDC).
Chromosome 17 aneusomy was not detected in the cases of DH and was present in
90.9% of DCIS and in 87.5% of IDC. Simultaneous aneusomy of chromosome 1 and 17
was found in 81.8% of DCIS and in 75.0% of IDC. Our results showed that the
number of chromosome 1 and 17 copies increases from normal epithelium to invasive
cancer. The numerical abnormalities of chromosome 1 were already detected in DH,
suggesting that a gain in the copy number of chromosome 1 may be involved early
in breast carcinogenesis.
PMID- 10782467
TI - T311--an anti-tyrosinase monoclonal antibody for the detection of melanocytic
lesions in paraffin embedded tissues.
AB - Tyrosinase is a key enzyme in melanin biosynthesis and represents a marker of
melanocytic differentiation. We previously generated T311, a murine monoclonal
antibody to the tyrosinase recombinant protein. This study was performed to
evaluate T311 as a diagnostic immunohistochemical reagent for use on formalin
fixed paraffin-embedded pathological material. We analyzed the specificity of the
antibody on a panel of normal and neoplastic tissues, and we assessed its
sensitivity in a large number of metastatic and primary malignant melanomas,
nevi, three angiomyolipomas, and two vitiligo specimens. T311 revealed intense
reactivity on paraffin-embedded material. Immunoreactivity was limited to cells
of melanocytic differentiation and no immunostaining was present in unrelated
normal tissues and tumors. Eighty-four percent of metastatic malignant melanomas
were immunoreactive with T311 and showed predominantly a homogeneous expression
pattern. However, in primary melanomas of the desmoplastic/spindle cell type,
T311 revealed a poor immunoreactivity. Nevi showed intense staining at the
junctional zone, while the dermal component revealed decreasing reactivity
towards deeper areas. Only one angiomyolipoma was focally immunoreactive with
T311. Vitiligo specimens were immunonegative. We conclude that T311 is a specific
and sensitive marker for the detection of melanocytic lesions in formalin-fixed
paraffin-embedded tissues and a useful serological reagent for diagnostic
pathology.
PMID- 10782469
TI - Increased fractal complexity of the epithelial-connective tissue interface in the
tongue of 4NQO-treated rats.
AB - The effect of the carcinogen 4-nitroquinoline 1-oxide (0.001% in drinking water)
on the irregularity of the epithelial connective tissue interface (ECTI) of the
ventral surface of the tongue was quantified in Dark Agouti and Wistar Furth
rats. Histological tongue sections stained with the Azan-Mallory method were
digitised (111 images, resolution 1 pixel = 3.1 microns), and the limit between
epithelium and stroma of the ventral surface was extracted and analysed using a
fractal geometry technique (local connected dimension). The results showed that
although none of the images included carcinomas on the ventral surface of the
tongue (all cases had other oral carcinomas), the epithelial profiles of the
treated cases showed a statistically significant increase in irregularity when
compared to controls. Canonical discriminant analysis of the parameters
describing the irregularity of the ECTI classified 81.1% of the images in the
original groups (treated or control). Fractal analysis is capable of detecting
subtle architectural changes in the oral epithelium of the rat occurring after
exposure to the carcinogen, even when full malignant transformation has not yet
taken place. Fractal analysis, which may prove useful for monitoring the
progression of carcinogenesis in this animal model, is a morphometrical parameter
in the diagnosis of oral epithelial dysplasia.
PMID- 10782468
TI - Expression of p27kip1 and p53 in medulloblastoma: relationship with cell
proliferation and survival.
AB - p27kip1 and p21cip1 are cyclin-dependent kinase (cdk) inhibitors which along with
p53 play critical roles in the control of cell cycle progression. Accumulation of
p27kip1 in post-mitotic neurons is a major event of neurogenesis. We hypothesized
that a dysregulation of the expression of p53 and these cdk inhibitors underlies
cellular proliferation in medulloblastomas, and tested this hypothesis by
investigating p27kip1, p21cip1, Bcl2 and p53 immunoreactivity in 14
medulloblastoma tumors. We noted an inverse relationship between p27kip1
expression and cellular proliferation (MIB1). Focal islands of neuroblastic or
glial differentiation expressed high levels of p27kip1, while the
undifferentiated, highly-proliferative population of tumor cells showed no
detectable p27kip1 expression, thus suggesting a role for p27kip1 in cell cycle
control in medulloblastoma. In addition, there was no detectable p21cip1
expression in any of the medulloblastomas studied. The low level of apoptosis
displayed by these tumors was not associated with the expression of Bcl-2. A
significant relationship was found between detection of p53 protein and poor
survival. Since, p21cip1 and p27kip1 are often co-expressed with other INK4
family of cdk inhibitors during the induction of cellular differentiation and are
synergistic in their effect, a deregulation of their coordinate expression may
underlie the lack of complete differentiation in medulloblastoma.
PMID- 10782470
TI - The role of sialylated Lewis antigens on hematogenous metastases of human
pancreas carcinoma cell lines in vivo.
AB - Previous studies have shown that sialyl Lewis a (SLea) and sialyl Lewis x (SLex)
correlated to hematogenous metastasis of human cancers. Although SLea/SLex and E
selectin act as a set of adhesion molecules in vitro, it is not clear whether the
in vivo correlation is exclusively mediated by the adhesion function. To address
this issue, we investigated whether or not the role of SLea/SLex antigens on
hematogenous metastasis to the liver in SCID mice was exclusively mediated by
adhesion by using antibodies for these antigens and SLea/SLEx-negative, human
pancreas adenocarcinoma cell line PCI-6. The absence of SLea/SLex expression was
supported by the absent flow cytometric detection of the antigens as well as by
the absent attachment augmentation to activated endothelial cells. PCI-6 cells
are xenotransplantable to nude and SCID mice and produce vascular endothelial
cell growth factor (VEGF) in a significant amount. PCI-6 cells, 1 x 10(6), were
injected into the spleens of SCID mice, and resultant liver metastases were
evaluated six weeks later. We observed an inhibitory effect on the establishment
and growth of metastatic colonies when anti-SLea or anti-SLex antibody was
administered. This indicates that SLea/x antigens have an important in vivo role,
even in the metastasis of SLea/SLex-negative tumor cells. This implies that there
may be an in vivo function of SLea/x antigens other than that of the attachment
between tumor and endothelial cells.
PMID- 10782471
TI - Adult mesoblastic nephroma with ciliated epithelium. A case report.
AB - A case of renal pelvic tumors occurring in a 44-year-old man is reported. There
were two polypoid renal pelvic tumors which consisted of glandular and stromal
components. Some glands in the tumors had ciliated epithelium and were quite
similar to the epididymal tubules. Other glands in the tumors resembled the
collecting duct or the mesonephric remnant seen in female genitalia.
Immunohistochemistry and electron microscopy revealed smooth muscle
differentiation of the stromal cells of these tumors. Some psammoma bodies were
seen in the glands of the tumors. We diagnosed these tumors as adult mesoblastic
nephroma (MN). The patient has been followed up for 14 months, showing no
evidence of recurrence. Differentiation of the tumors from angiomyolipoma,
leiomyoma, and nephrogenic adenofibroma is discussed. Adult renal tumors that
consist of epithelial and stromal components have been reported under various
names. They constitute clinicopathologically different entities originating from
pediatric MN. We suggest that these tumors should be termed "adult MN".
PMID- 10782472
TI - Parachordoma of the tibia: report of a rare case.
AB - We report a case of recurrent parachordoma of the left anterior tibial region in
a 64-year-old male patient. The tumor was a periosteal tender mass, and,
histologically, displayed vague nodules of spindle to rounded eosinophilic cells
embedded in a myxoid matrix. Large vacuolated (physalphorouslike) cells were
noted as in sacrococcygeal chordoma. This tumor should be differentiated from
myxoid chondrosarcoma, myxoid liposarcoma, chondromyxoid fibroma, and metastatic
chordoma. The presence of physaliphorous cells in the tumor with positive
immunoreactions caused by cytokeratin rules out the diagnosis of another myxoid
tumor. The differential diagnosis from metastatic chordoma is basically made by
clinicians. Even though parachordoma is usually regarded as a benign soft tissue
neoplasm, two recurrences occurred in our case. Since the reported cases,
including ours, have diverse clinical courses, it is essential to follow-up the
patient carefully.
PMID- 10782473
TI - Benign mixed epithelial and stromal tumor of the kidney.
PMID- 10782474
TI - Growth charts, low birth weight, and international adoption.
PMID- 10782475
TI - The risks are many, but the joys are great.
PMID- 10782476
TI - Preadoption review of medical records.
PMID- 10782477
TI - Medical evaluation and infectious considerations on arrival.
PMID- 10782478
TI - Initial assessment of growth, development, and the effects of
institutionalization in internationally adopted children.
PMID- 10782479
TI - Long-term medical issues in international adoptees.
PMID- 10782480
TI - Behavioral sequelae of orphanage life.
PMID- 10782481
TI - The Internet and international adoption information.
PMID- 10782482
TI - Resident's column: international adoption.
PMID- 10782483
TI - A comparative multi-centre study of the efficacy of propolis, acyclovir and
placebo in the treatment of genital herpes (HSV).
AB - Ninety men and women with recurrent genital HSV type 2 participated in a
randomized, single-blind, masked investigator, controlled multi-centre study
comparing the efficacy of ointment of Canadian propolis containing natural
flavonoids with ointments of acyclovir and placebo (vehicle) on healing ability
and capacity to remedy symptoms. Thirty individuals were randomized to each
group. Treatment was intended to start in the blister phase. All participants had
HSV type 2 isolated, confirmed by serum immunoglobulin levels. The participants
were examined on the 3rd, 7th and 10th days of treatment by gynaecologists,
dermatovenerologists or urologists at seven different medical centres. Apart from
clinical symptoms the number and size of the herpetic lesions were noted. At each
examination the lesions were classified into four stages: vesicular, ulcerated,
crusted and healed. The study ointments were applied to affected areas four times
daily. In women with vaginal or cervical lesions a tampon with the appropriate
ointment was inserted four times daily for 10 days. Endpoint variables were
healing time and time until loss of symptoms. RESULTS: On Day 10, 24 out of 30
individuals in the propolis group had healed. In the acyclovir group 14 out of 30
and in the placebo group 12 out of 30 had healed. (p = 0.0015). The healing
process appeared to be faster in the propolis group. In the propolis group 15
individuals had crusted lesions on Day 3 compared to 8 individuals in the
acyclovir group and none in the placebo group (p = 0.0006). On Day 7, 10
participants in the propolis group, 4 in the acyclovir group and 3 in the placebo
group had healed. At the initial examination all patients had local symptoms and
28% general symptoms. At Day 3, 3 patients in the propolis group had local
symptoms compared to 8 and 9 in the acyclovir and placebo groups respectively. Of
the women, 66% had vaginal superinfections of microbial pathogens at the initial
examination. In the acyclovir and placebo groups no change in the vaginal flora
was found following treatment whereas in the propolis group the incidence of
superinfection was reduced by 55%. (p = 0.10 n.s.). CONCLUSION: An ointment
containing flavonoids appeared to be more effective than both acyclovir and
placebo ointments in healing genital herpetic lesions, and in reducing local
symptoms.
PMID- 10782484
TI - Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum
Linn.
AB - Anti-oxidant bioassay-directed extraction of the fresh leaves and stems of Ocimum
sanctum and purification of the extract yielded the following compounds;
cirsilineol [1], cirsimaritin [2], isothymusin [3], isothymonin [4], apigenin
[5], rosmarinic acid [6], and appreciable quantities of eugenol. The structures
of compounds 1-6 were established using spectroscopic methods. Compounds 1 and 5
were isolated previously from O. sanctum whereas compounds 2 and 3 are here
identified for the first time from O. sanctum. Eugenol, a major component of the
volatile oil, and compounds 1, 3, 4, and 6 demonstrated good antioxidant activity
at 10-microM concentrations. Anti-inflammatory activity or cyclooxygenase
inhibitory activity of these compounds were observed. Eugenol demonstrated 97%
cyclooxygenase-1 inhibitory activity when assayed at 1000-microM concentrations.
Compounds 1, 2, and 4-6 displayed 37, 50, 37, 65, and 58% cyclooxygenase-1
inhibitory activity, respectively, when assayed at 1000-microM concentrations.
Eugenol and compounds 1, 2, 5, and 6 demonstrated cyclooxygenase-2 inhibitory
activity at slightly higher levels when assayed at 1000-microM concentrations.
The activities of compounds 1-6 were comparable to ibuprofen, naproxen, and
aspirin at 10-, 10-, and 1000-microM concentrations, respectively. These results
support traditional uses of O. sanctum and identify the compounds responsible.
PMID- 10782485
TI - Cyclooxygenase active bioflavonoids from Balaton tart cherry and their structure
activity relationships.
AB - Several flavonoids and isoflavonoids isolated from Balaton tart cherry were
assayed for prostaglandin H endoperoxide synthase (PGHS-1) enzyme or
cyclooxygenase isoform-1 (COX-1) activity. Genistein showed the highest COX-1
inhibitory activity among the isoflavonoids studied, with an IC50 value of 80
microM. Kaempferol gave the highest COX-1 inhibitory activity among the
flavonoids tested, with an IC50 value of 180 microM. The structure-activity
relationships of flavonoids and isoflavonoids revealed that hydroxyl groups at
C4', C5 and C7 in isoflavonoids were essential for appreciable COX-1 inhibitory
activity. Also, the C2-C3 double bond in flavonoids is important for COX-1
inhibitory activity. However, a hydroxyl group at the position decreased COX-1
inhibitory activity by flavonoids.
PMID- 10782486
TI - Anti-inflammatory and anti-arthritic activities of silymarin acting through
inhibition of 5-lipoxygenase.
AB - Silymarin, a mixture of flavonolignans, comprised mainly of three isomers,
silybin, silydianin and silychristin isolated from the fruits of Silybum
marianum, is currently in therapeutic use as a hepatoprotective agent. Silymarin
on evaluation exhibited significant antiinflammatory and antiarthritic activities
in the papaya latex induced model of inflammation and mycobacterial adjuvant
induced arthritis in rats. Results of the study indicate its action through
inhibition of 5-lipoxygenase for antiinflammatory and antiarthritic activities.
PMID- 10782487
TI - Isolation and hypoglycemic activity of 5, 7,3'-trihydroxy-3,6,4'
trimethoxyflavone from Brickellia veronicaefolia.
AB - Hypoglycemic activity-guided fractionation together with chemical analysis led to
the isolation of one flavone (5, 7,3'-trihydroxy-3,6,4'-trimethoxyflavone) from
the chloroform extract of the leaves of Brikkellia veronicaefolia. Identification
was based on spectroscopic methods. The isolated flavone was tested for
hypoglycemic activity in normal and alloxan-diabetic CD1 mice (25-30 g) were
administered in doses of 10, 25 and 50 mg/kg body weight. The blood glucose
levels were determined before and 1.5, 3, 4.5 and 24 hours after drug
administration. The results showed that the flavone produces a significant
hypoglycemic effect in normal as well as in diabetic mice. Comparison was made
between the action of the flavone and a known hypoglycemic drug as tolbutamide
(50 mg/kg). The flavone was found to be slow and less effective than tolbutamide.
PMID- 10782488
TI - Antiamoebic and spasmolytic activities of extracts from some antidiarrhoeal
traditional preparations used in Kinshasa, Congo.
AB - Three major extracts from some traditional preparations, based on medicinal
plants, used as antidiarrhoeal agents were investigated for their putative
antiamoebic and spasmolytic activities in vitro. Results indicated that both
biological activities are concentrated in the polyphenolic fraction, and not in
the saponin or alkaloid containing fractions. The most active polyphenolic
extracts were those from Euphorbia hirta whole plant, leaves of Alchornea
cordifolia, Crossopteryx febrifuga, Nauclea latifolia, Psidium guajava, Tithonia
diversifolia, stem bark of Harungana madagascariensis, Mangifera indica,
Maprounea africana and Psidium guajava, inhibiting Entamoeba histolytica growth
with MAC < 10 micrograms/ml. The same extracts, at a concentration of 80
micrograms/ml in an organ bath, also exhibited more than 70% inhibition of
acetylcholine and/or KCl solution-induced contractions on isolated guinea-pig
ileum.
PMID- 10782489
TI - Cytotoxic activity of hydrolyzable tannins against human oral tumor cell lines--a
possible mechanism.
AB - Hydrolyzable tannins showed higher cytotoxic activity against human oral squamous
cell carcinoma and salivary gland tumor cell lines than against normal human
gingival fibroblasts, whereas gallic acid, a component unit of tannins, showed
much weaker selective cytotoxicity. The cytotoxic activity of dimeric compounds
was generally higher than that of monomeric compounds. Macrocyclic ellagitannin
oligomers, such as oenothein B, woodfordin C and woodfordin D showed the greatest
cytotoxic activity, and their activity (per given number of molecules) was one
order higher than those of gallic acid and epigallocatechin gallate, a major
component of green tea. These compounds induced apoptotic cell death
characterized by DNA fragmentation (as demonstrated by the TUNEL method) and
cleavage of cytokeratin 18 by activated caspase(s) (as demonstrated by M30
monoclonal antibody). ESR spectroscopy revealed that these macrocyclic compounds
at higher concentrations produced their own radicals and significantly enhanced
the radical intensity of sodium ascorbate, possibly by their prooxidant actions.
Catalase failed to eliminate their apoptosis-inducing activity, reducing the
possibility of the involvement of hydrogen peroxide production in the
extracellular fraction. These observations suggested that the antitumor activity
of macrocyclic ellagitannin oligomers reported previously might be explained by
their apoptosis-inducing activity.
PMID- 10782490
TI - Effects of luteolin on arylamine N-acetyltransferase activity in rat blood and
liver.
AB - In this study we investigated inhibition of Arylamine N-acetyltransferase (NAT)
activity in rat blood and liver tissue cytosols by luteolin. Using high
performance liquid chromatography, NAT activity for acetylation of 2
aminofluorene and remaining unacetylated 2-aminofluorene were examined. The NAT
activity in rat blood and liver tissue was inhibited by luteolin in a dose
dependent manner: higher concentrations of luteolin in the reaction resulted in
greater inhibition of NAT activities in both examined tissues. The data also
indicated that luteolin decreased apparent Km and Vmax of NAT enzymes from rat
blood and liver tissue cytosols. This report is the first demonstration that
luteolin can affect rat blood and liver tissue NAT activity.
PMID- 10782491
TI - Role of Salviae Miltiorrhizae Radix extract and its compounds in enhancing nitric
oxide expression.
AB - Excessive production of nitric oxide (NO) and its peroxidant product,
peroxynitrite, has been implicated in the pathology of acute and chronic renal
failure, and inhibitors of NO production have been shown to exert protective and
ameliorative effects against renal epithelial cell damage mediated by enhanced
generation of NO. Salviae Miltiorrhizae Radix has exhibited a beneficial effect
in the improvement of renal failure. In order to clarify the mechanism
responsible, we investigated whether Salviae Miltiorrhizae Radix extract and
several of its related compounds, including caffeic acid and its polymers which
were isolated by our research group, can regulate the generation and release of
NO. The results demonstrated that Salviae Miltiorrhizae Radix extract and these
compounds suppressed NO effectively in the systems employing activated
macrophages and the arginine-hydrogen peroxide, and that, furthermore, the
activity shown by the compounds was higher than that shown by the extract. In
addition, direct scavenging of NO was also observed. The present findings suggest
that Salviae Miltiorrhizae Radix extract and its compounds are potent NO
inhibitors, and that their inhibitory effect on the generation and release of NO
may contribute to the previously reported pharmacological effect of Salviae
Miltiorrhizae Radix in improving renal function.
PMID- 10782494
TI - The psychodynamic and pharmacodynamic effects of drugs: a differentiated
evaluation of the efficacy of phytotherapy.
AB - The therapeutic usefulness of medicines is nowadays usually measured in terms of
parameters devised in the artificial surroundings of a double blind clinical
trial. The difference between the active drug and the placebo is accepted as
being the same as the desired overall effect. Yet, when applied to whole
categories of medicines, this yardstick can be misleading, as has become apparent
from the discussion which has recently arisen regarding the genuine and the
illusory pharmacodynamic effects of synthetic antidepressants. Differentiated
analysis of a representative number of placebo-controlled studies has shown that
when used for depressive conditions, the psychodynamic components contribute far
more to the overall effect than do the pharmacodynamic components. In this
respect, modern synthetic antidepressants are no better than Hypericum products
of plant origin. Among other things, this means that for depressive states and
similar indications, the safety, tolerability and acceptability of a medicine
must be given much greater weight than its pharmacodynamic effects as assessed
simply by testing against a placebo. The quantification of the two therapeutic
components, as can be accomplished by a placebo-controlled drug trial, has
revealed that the overall outcome of therapy for various important indications of
this kind is attributable predominantly to the psychodynamic component. It may
reasonably be assumed that the contribution made by the pharmacodynamic effects
to the overall therapeutic response will amount to only about 20-50%. This raises
questions regarding the clinical relevance and economic value of placebo
controlled studies. When assessing data on drug efficacy for the purpose of
licensing applications, greater attention should be given to this reality.
PMID- 10782492
TI - Mechanisms of the contractile effect of the hydroalcoholic extract of Cissampelos
sympodialis Eichl. in the rat aorta.
AB - In the present work the effect of the aqueous fraction of the ethanolic extract
of the leaves (AFL) of Cissampelos sympodialis Eichl. was investigated in the rat
aorta. In the presence of functional endothelium, AFL produced concentration
dependent contractions (EC50 value of 76.6 +/- 17.8 micrograms/ml). In the
absence of functional endothelium, the concentration-response curves to AFL were
significantly shifted to the left (EC50 values of 1.3 +/- 0.9 micrograms/ml)
without modification of its maximal contractile effect. In the presence of L-NAME
(300 microM) and of indomethacin (10 mM), the concentration-response curves
produced by AFL were also shifted to the left (EC50 values of 21.8 +/- 6.2 and
24.3 +/- 13.2 micrograms/ml, respectively). The treatment of the aortas with L
NAME (300 microM) plus indomethacin (10 microM) produced a significant shift to
the left of the concentration-dependent curves of AFL (EC50 value of 4.9 +/- 2.2
micrograms/ml), similar to that observed in the absence of the vascular
endothelium. In addition, AFL-induced contraction was abolished in the presence
of prazosin (1 microM), and significantly shifted to the right in the presence of
yohimbine (EC50 value of 723.6 +/- 76.4 micrograms/ml). Thus, based on these
results, it can be concluded that contractions induced by AFL in the rat aorta
were due to activation of alpha-adrenoceptors. Furthermore, these results also
showed that the AFL-induced contractions were modulated by the endothelium, via
the release of NO and of a cyclooxygenase-derived relaxant product. Finally, it
can be concluded that the contractile effects of AFL on vascular smooth muscle
may play an important role in the hypertensive effects of this plant in vivo.
PMID- 10782493
TI - Effect of shitei-to, a traditional Chinese medicine formulation, on
pentylenetetrazol-induced kindling in mice.
AB - This study measured the effects of Shitei-To (STT), a traditional Chinese
Medicine, which is a mixture of extracts from three medicinal herbs, Shitei (SI,
Kaki Calyx; calyx of Diospyros kaki L. f.), Shokyo (SK, Zingiberis Rhizoma;
rhizome of Zingiber officinale Roscoe) and Choji (CJ, Caryophylli flos; flowerbud
of Syzygium aromaticum [L.] Merrill et. Perry), has long been used for the
treatment of hiccups in Japan and China, against fully pentylenetetrazol-kindled
seizures and on the development of pentylenetetrazol kindling in mice. Repeated
administration of STT (3.0 g/kg p.o.) mildly retards the development of
pentylenetetrazol-induced kindling in mice. STT also decreased the number of
tonic-clonic convulsions resulting from progression kindling. On the other hand,
STT had no effect on convulsions in fully pentylenetetrazol-kindled mice. These
findings suggest that STT protects against the development of convulsions, and
that STT may have therapeutic effects in the prevention of secondarily
generalized seizures.
PMID- 10782495
TI - Functional and structural aspects of the Kell blood group system.
AB - Two covalently linked proteins, Kell and XK, constitute the Kell blood group
system. Kell, a 93-Kd type II glycoprotein, is highly polymorphic and carries all
but 1 of the known Kell antigens, and XK, which traverses the membrane 10 times,
carries a single antigen, the ubiquitous Kx. The Kell/XK complex is not limited
to erythroid tissues and may have multiple physiological roles. Absence of one of
the component proteins, XK, is associated with abnormal red cell morphology and
late-onset forms of nerve and muscle abnormalities, whereas the other protein
component, Kell, is an enzyme whose principal known function is the production of
a potent bioactive peptide, ET-3.
PMID- 10782496
TI - Food and Drug Administration's proposed approach to regulation of hematopoietic
stem/progenitor cell products for therapeutic use.
PMID- 10782497
TI - The cytomegalovirus-"safe" blood product: is leukoreduction equivalent to
antibody screening?
PMID- 10782498
TI - Multicenter randomized controlled trials in transfusion medicine.
PMID- 10782499
TI - Indeterminate results in blood donor testing: what you don't know can hurt you.
PMID- 10782500
TI - Cross-reactivity of antibodies to human and primate red cell antigens.
PMID- 10782502
TI - [Quality assurance in geriatrics--a further challenge!].
PMID- 10782501
TI - The evaluation and management of platelet refractoriness and alloimmunization.
PMID- 10782503
TI - [Quality assurance in geriatric rehabilitation hospital treatment. Long-term
medical and functional outcome].
AB - Clinical geriatric therapy has shown to be beneficial and cost-effective.
However, little is known about its long-term results. Based on GEMIDAS (Geriatric
Minimal Data Set), a multicenter-Database of the German Federal Association of
140 Clinical Geriatric Institutions, we conducted a one-year-follow-up pilot
study focusing on medical and functional results, including needs of technical
aids and nursing. Mortality was 16% at 1 year. Two thirds of the deceased had
died during the first half year, many with severe stroke. Among the 840
survivors, 81.1% lived in their private housing, 14.5% in nursing homes, 4.4%
were actually hospitalized. 37.3% suffered from recurrent diseases such as stroke
(5.2%), bone fractures (4.5%), heart attacks (2.1%), severe infections (1.1%),
needing hospitalization in 31.9%, repeatedly in 6.9% of the survivors. Technical
aids were regularly used in about 80%. Personal help was often necessary and was
provided by relatives (66.9%), professional nursing (39.8%), neighbors (5.7%),
only 6% of the patients needed no help. The initial functional gain (mean Barthel
Index from 53.4 to 72.3 points) diminished to 59.6 points during follow-up, with
similar patterns for most of the single Barthel-items. Our results confirm the
initial benefit and clearly show a significant long-term effect of clinical
geriatric rehabilitation. For stabilization and further functional improvement,
specific and continuous rehabilitation efforts seem to be crucial.
PMID- 10782504
TI - [Documentation and quality assurance in clinical routine].
AB - Quality assurance by documentation in the clinical routine may no longer be
regarded as a tedious additional duty providing only little practical value in
medical care. This leads to users' resistance and to statistics of doubtful
validity. Therefore, the great significance of the primary medical documentation
for the quality assurance has to be emphasized and should be the focus of an
efficient documentation-management. Requirements for such a documentation
management are described and their implementation in the Albertinen-Haus is
shown. This institution uses conventional paper-documents as well as their
electronic counterparts. An efficient documentation-management shows the
advantage of a quality assurance for the daily routine in hospitals. Data
required for the statistical quality assurance should merely be a by-product of
the usual documentation. This can only be achieved by an increased computer
support in the clinical routine, but it also requires programmes which fill the
needs of all the team members.
PMID- 10782505
TI - [Geriatric oncology].
AB - The demographic development will result in a major increase in the number of
elderly cancer patients. Age is the main risk factor for the development of a
malignant disease. The incidence of the main cancer diagnosis increases with
advancing age. Treatment of elderly cancer patients is an exquisite task. On the
one hand, an increased morbidity and mortality may be the result of an
unreflected transfer into the geriatric setting of treatment schedules developed
for younger patients. On the other hand, reduction of dose intensity can result
in decreased survival, life prolongation or insufficient palliation. Elderly
people are a very heterogeneous group. Some are in a very good health status.
Others are impaired, dependent, suffer from a number of comorbidities and have to
take a variety of drugs. Those conditions and not the chronological age influence
tolerance against tumour therapy. For elderly patients maintenance of
independence and quality of life is more important than disease free survival and
prolongation of life.
PMID- 10782506
TI - [External quality management in inpatient geriatric care--the SIESTA instrument].
AB - Continuous quality improvement in long term care facilities requires systematic
cooperation of internal and external quality management. We designed SIESTA to
assist skilled nursing care and management in their effort to measure and develop
the quality of care in their facility in a rational way.
PMID- 10782507
TI - [Patient care evaluation studies--a comprehensive concept for evaluation of
oncologic patient management].
AB - As part of the oncological patient care, tumor documentation has been attributed
growing importance as a means of quality assurance. The extended organ specific
tumor documentation can serve to answer some specific clinical questions. The
rational of the so called Patient Care Evaluation Studies (PCES) carried out by
the Commission on Cancer of the American College of Surgeons in the US will be
shown in this article and the objectives of an initial study being carried out in
the Federal Republic of Germany simultaneously with the US-study will be
demonstrated. PCES are a way to compare actual patient care with idealized
recommendations of Clinical Practice Guidelines. Thus, the application of
Practice Guidelines in the clinical routine as one aspect of evidence based
medicine can be analyzed.
PMID- 10782508
TI - [Primary psychosomatic management in general practice. Results of a German
nationwide demonstration project of quality assurance].
AB - In the frame of a national demonstration program, psychosocial care of patients
with psychological and psychosomatic problems were assessed. General
practitioners (n = 191) from six regions participated in the study. 1341
treatment episodes of patients with predominately psychosocial symptoms were
documented. Anxiety (62%), depression (51%) and marital/family conflicts (44%)
were the most frequent symptoms. Somatic treatment and psychosocial intervention
were offered equally. Patients with psychosocial treatment achieved better
results. Partners and family members were rarely integrated into therapy. The
procedures employed to improve outcome were quality circles, family-orientated
case conferences, consultation services and collaborative groups.
PMID- 10782509
TI - [Practice guideline--acute respiratory tract infections. From recommendations for
therapy of acute respiratory tract infections by the Drug Committee of German
Physicians. Drug Committee of German Physicians].
PMID- 10782510
TI - [Managing risks in clinical routine practice and effect of guidelines].
AB - Four steps of risk management are known at present in the clinical practice. For
all forms guidelines are important--these could be national guidelines or in
house guidelines. All guidelines are respected to perform reliable and steady
quality and to reduce risks.
PMID- 10782511
TI - [Problem-based learning in graduate general practice education: the why and how].
AB - This paper describes the experiences with different concepts of problem oriented
learning in a postgraduate training course in general practice in Hamburg. It is
argued that for postgraduate training of general practitioners a four-step-model
is more adequate than the "classical" seven-step-model.
PMID- 10782512
TI - [The problem of anosmia].
AB - Olfactory problems have deleterious consequences to systemic health, nutritional
status and quality of life. Olfactory disorders are not as rare as generally
assumed. Chemosensory dysfunction is most often secondary to one of only a few
causes: nasal/sinus disease, viral infection, toxic chemical exposure, head
trauma, as well as medication-related and idiopathic conditions. Many olfactory
disorders are secondary to a wide variety of diseases, e.g. Alzheimer's disease.
The patient's history may provide clues to these and other problems (e.g. toxin
exposure, congenital dysosmia). Therapy should not begin until a standardized
test has been established the impairment of the sense of smell. Treatment of the
underlying diseases may restore chemosensory function. The only truly reversible
cause is inflammation, which is confirmed when smell returns after administration
of corticosteroids. Reference is made to the need for adequate psychologic
guidance of patients with chemosensorial problems. If restoration of their sense
of smell is unlikely, patients should be educated to ensure safety in regard to
such dangers as gas leaks, smoke, and spoiled foods.
PMID- 10782513
TI - [Autopsy in peri- and neonatology--an essential step in quality control. Data on
autopsy frequency in Saxony].
AB - In the framework of a general quality assurance compaign the working group for
peri- and neonatology at the General Medical Council of Saxony has investigated
the frequency, conclusiveness and development of autopsies in Saxony between 1992
and 1997/98. There were observable different autopsy rates depending on the
degree of neonate maturity. Thus, the autopsy rate of stillbirths having birth
weights from 500 to 999 g amounted to 79.7%, and that of stillbirths above 1000 g
birth weight to only 59.4%. The abduction rate of neonates dying before day 7 of
life was 65.7%. It is remarkable that the abduction rates declines from 79.1 to
62.9% in all weight classes of premature and full-term neonates from 1992 to
1997. The possible reasons for the decline of autopsies and the problems emerging
for quality assurance are discussed.
PMID- 10782514
TI - [Surgical quality assurance in the largest federal district of Austria-
introduction of a project].
AB - On the basis of permanently rising costs in health care on the one hand and
limited budgets on the other hand as well as the increasing importance of correct
and comprehensive quality assurance, we developed protocols for nine different
surgical tracer-diagnosis. These protocols include the minimum standards of the
medical, nursing and administrative area per day of treatment. After one year of
trial at three surgical departments of different capacity, treatment-spectrum and
equipment, revised protocols will be implemented at all 23 surgical departments
in our federal state if necessary.
PMID- 10782515
TI - Chronic urticaria in childhood.
PMID- 10782516
TI - Role of tachykinins in asthma.
AB - The sensory neuropeptides substance P (SP) and neurokinin A (NKA) are localized
to sensory airway nerves, from which they can be released by a variety of
stimuli, including allergen, ozone, or inflammatory mediators. Sensory nerves
containing these peptides are relatively scarce in human airways, but it is
becoming increasingly evident that inflammatory cells such as eosinophils,
macrophages, lymphocytes, and dendritic cells can produce the tachykinins SP and
NKA. Moreover, immune stimuli can boost the production and secretion of SP and
NKA. SP and NKA have potent effects on bronchomotor tone, airway secretions, and
bronchial circulation (vasodilation and microvascular leakage) and on
inflammatory and immune cells. Following their release, tachykinins are degraded
by neutral endopeptidase (NEP) and angiotensin-converting enzyme. The airway
effects of the tachykinins are largely mediated by tachykinin NK1 and NK2
receptors. Tachykinins contract smooth muscle mainly by interaction with NK2
receptors, while the vascular and proinflammatory effects are mediated by the NK1
receptor. In view of their potent effects on the airways, tachykinins have been
put forward as possible mediators of asthma, and tachykinin receptor antagonists
are a potential new class of antiasthmatic medication.
PMID- 10782517
TI - Position statement: UEMS- Section of Allergology and Clinical Immunology.
European specialist care in allergology and clinical immunology in the new
millennium.
PMID- 10782519
TI - Identification of bovine IgG as a major cross-reactive vertebrate meat allergen.
AB - BACKGROUND: Although beef is a main source of protein in Western diets, very
little has been published on allergic reactions to beef or the main allergens
implicated in these reactions. The aim was to evaluate the IgE antibody response
to beef in suspected meat-allergic subjects and assess cross-reactivity of beef
with other vertebrate meats. METHODS: Fifty-seven sera from suspected meat
allergic subjects were tested by grid blot for specific IgE antibodies to
vertebrate meats (beef, lamb, pork, venison, and chicken), and the patterns of
recognition of meat proteins were assessed by immunoblot studies. RESULTS: A 160
kDa band, identified as bovine IgG, was detected in raw beef in 83% (10/12) of
beef-allergic subjects but in only 24% of the beef-tolerant subjects. IgE
reactivity to a band of similar mol. mass was detected also in lamb and venison,
but rarely in pork or chicken. Complete inhibition of the IgE reactivity to the
bovine IgG was obtained with lamb, venison, and milk. IgE reactivity to this band
also completely disappeared when beef or lamb extracts were separated under
reducing conditions, indicating conformational epitopes. CONCLUSIONS: Bovine IgG
appears to be a major cross-reacting meat allergen that could predict beef
allergy. Further studies with oral IgG challenges should be performed to document
the conclusion that in vitro reactivity correlates with clinical
hypersensitivity. The role of bovine IgG in other bovine products such as milk,
dander, or hair must also be studied, and the hypothesis that it is a cross
reacting allergen with other mammalian products validated.
PMID- 10782518
TI - Evaluation of the allergenicity of tropical pollen and airborne spores in
Singapore.
AB - BACKGROUND: Sensitization to pollen and spores of the Southeast Asian tropical
region is not well documented. This study evaluated the allergenicity of the
tropical airspora in Singapore. METHODS: On the basis of the results of an
aerobiologic survey of the airspora profile of Singapore, crude extracts of 23
main spore (fungal and fern) and pollen types were prepared. A total of 231
patients with asthma and/or allergic rhinitis and 76 healthy controls were
evaluated by skin prick test (SPT). Total and specific IgE levels were also
quantified by the fluorescence allergosorbent test (FAST). RESULTS: All 23
allergenic extracts tested elicited positive SPT responses. Among the patients
with atopic diseases, extracts of oil-palm pollen (Elaeis guineensis) were
observed to have the highest frequency of positive reactions (40%), followed by
extracts of resam-fern spores (Dicranopteris linearis) (34%) and sea-teak pollen
(Podocarpus polystachyus) (33.8%). Fungal spores with the highest SPT responses
were Curvularia spp. (26-32%) and Drechslera-like spores (31%). Positive
responses to these extracts correlated with total serum IgE levels of the
subjects and were significantly associated with the presence of atopic disease.
CONCLUSIONS: We have documented sensitization to tropical pollen and spores in
our population. Its association with atopy suggests that it has a role in
allergic diseases in the tropics.
PMID- 10782520
TI - Airway inflammation in asthma and perennial allergic rhinitis. Relationship with
nonspecific bronchial responsiveness and maximal airway narrowing.
AB - BACKGROUND: Eosinophilic airway inflammation is the hallmark of asthma, but it
has also been reported in other conditions such as allergic rhinitis. We have
tested whether the analysis of cells and chemicals in sputum can distinguish
between patients with mild allergic asthma, those with allergic rhinitis, and
healthy controls. The relationship between inflammation markers in sputum and
nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal
response plateau [MRP] values) was also evaluated. METHODS: We selected 31 mild
asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control
group, we studied 10 healthy subjects. Every subject underwent the methacholine
bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and
serum ECP levels were measured. Sputum cell differentials were assessed, and
eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5
levels were measured in the entire sputum supernatant. RESULTS: Blood eosinophils
and serum ECP levels were higher in asthma patients and rhinitis than in healthy
controls, but no difference between asthma patients and rhinitis patients was
found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels
in sputum than rhinitis patients or control subjects. Sputum albumin levels were
higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum
eosinophils than healthy controls. An association between sputum eosinophil
numbers and MPR values (r= -0.57) was detected, and a trend toward correlation
between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis
group, but not in asthmatics. No correlation between blood eosinophilic
inflammation and lung functional indices was found. CONCLUSIONS: Induced sputum
is an accurate method to study bronchial inflammation, allowing one to
distinguish between rhinitis patients and mildly asthmatic patients. The fact
that no relationship was detected between sputum inflammation and BHR suggests
that other factors, such as airway remodeling, may be at least partly responsible
for BHR in asthma.
PMID- 10782521
TI - Glucocorticosteroids rapidly inhibit allergen-induced expression of E-selectin in
vitro in a mucosal model of allergic rhinitis.
AB - BACKGROUND: Transendothelial migration of cells to sites of inflammation is a
hallmark of the allergic reaction. The adhesion cascade involves the initial
expression of the adhesion molecule E-selectin on endothelial cells. The aim of
the study was to determine the efficacy of a 30-min preincubation of the
glucocorticosteroids (GCS) fluticasone, prednisolone, and fluocortin butyl on
allergen- and interleukin (IL)-1beta-induced E-selectin expression in allergic
rhinitis. METHODS: Freshly taken nasal inferior turbinate mucosa of 19 subjects
with allergic rhinitis was cut into small cubes and preincubated for 30 min with
prednisolone (n = 6), fluticasone (n = 5), and fluocortin butyl (n = 3) in
different concentrations, followed by allergen exposure at a concentration of
1000 BU/ml for 1 and 2 h. Additionally, fluticasone-preincubated tissues were
exposed to recombinant human rhIL-1beta (n = 5) at a concentration of 2 pg/ml.
The expression of E-selectin was assessed by immunohistochemistry (APAAP
technique) and computerized image evaluation. RESULTS: In this model, E-selectin
expression was significantly upregulated by allergen and rhIL- 1beta within 1 and
2 h. After 30-min preincubation with prednisolone and fluocortin butyl at drug
concentrations of 10-8 mol/1, we found a significant (> or = 50%) reduction of
the E-selectin expression after 1 and 2 h. Allergen-induced E-selectin expression
was nearly abolished at concentrations of 10-5 (prednisolone) and 10-4 mol/l
(fluocortin butyl). Fluticasone significantly inhibited E-selectin expression by
> or = 50% at concentrations of 10-14 and 10-12 mol/l after 1 and 2 h, and
abolished E-selectin induction at concentrations of 10-12 and 10-10 mol/l,
respectively. Exposure of mucosal cubes to rhIL-lbeta (n = 5) also induced rapid
upregulation of E-selectin expression, an effect which could be only partially
suppressed by fluticasone preincubation at concentrations of 10-l0 mol/l.
CONCLUSIONS: Allergen-induced E-selectin expression is significantly and rapidly
inhibited by GCS preincubation, fluticasone being more potent than prednisolone
and fluocortin butyl. We suggest that this rapid effect is mainly indirect,
possibly by inhibition of allergen-induced cytokine release.
PMID- 10782522
TI - House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a
double-blind, placebo-controlled study.
AB - BACKGROUND: The safety and efficacy of sublingual-swallow immunotherapy (SLIT) in
rhinitis caused by house-dust mite were evaluated in a double-blind, placebo
controlled study including 75 patients for 24 months. METHODS: Patients received
either placebo or SLIT with a standardized Dermatophagoides pteronyssinus (D.pt.)
- D. farinae (D.f) 50/50 extract. The mean cumulative dose was 90,000 IR,
equivalent to 2.2 mg of Der p 1 and 1.7 mg of Der f I. Symptom and medication
scores were assessed throughout the study. Exposure to house-dust mite, skin
sensitivity, and serum specific IgE and IgG4 were assessed before starting
treatment and after 12 and 24 months. RESULTS: Seventy-two patients (36 active-36
placebo) were eligible for intent-to-treat analysis. Thirty-six patients dropped
out of the study. The number of patients who dropped out due to lack of efficacy
was eight out of 37 (21.6%) in the active treatment group compared to 15 out of
38 (39.5%) in the placebo group (chi-square=2.81, P=0.09). Total symptom and
medication scores decreased significantly after 12 and 24 months (P<0.05) of
treatment in both groups, but no significant difference was observed between the
active and placebo groups. After 24 months, the number of patients with high
levels of indoor allergenic load decreased significantly in both groups compared
to baseline data (P=0.01). Specific IgE (D.pt. and D.f.) increased significantly
in the active treatment group after 12 and 24 months, while no change was
observed in the placebo group. Specific IgG4 levels were not significantly
modified in either group. Two patients in each group reported mild adverse
effects. No severe adverse effects were reported. CONCLUSIONS: We conclude that
SLIT in rhinitis caused by house-dust mite was safe, but there was a lack of
consistent clinical benefit compared to placebo, probably due to the impact of
the allergen avoidance measures that lowered the allergen burden.
PMID- 10782523
TI - Sensitization and lung function in workers occupationally exposed to natural
thickening products.
AB - BACKGROUND: Three workers engaged in the manufacture of natural thickener
products (Cassia spp., guar, and tamarind flour) were occupationally sensitized
to Cassia spp. Therefore, a cross-sectional study on the prevalence of
sensitization among and respiratory health of the employees of this plant was
conducted. METHODS AND RESULTS: Sixty-two workers (36 with high, 26 with low
exposure) participated in the survey. Skin prick tests and specific IgE tests
with extracts of these components revealed that 11.3% were sensitized to Cassia
spp. and 9.7% to at least one species of storage mites, with a significantly
higher portion of atopic subjects in the sensitized group. Overall, 55% of the
subjects reported work-related symptoms (upper and lower airways, eyes, or skin).
FVC % pred. was significantly lower in highly exposed workers, while RV % pred.
and RV%TLC % pred. were significantly higher in this group. In the multivariate
model, sensitization was not a risk factor for impairment of lung function.
CONCLUSIONS: Dust exposure to flours may not only cause allergic sensitization
but also induce chronic changes in lung function.
PMID- 10782524
TI - Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and
healthy subjects.
AB - BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When
applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is
poorly affected by previous H1-blockade. The aim of this study was to compare the
possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to
BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a
randomized, double-blind, crossover study, eight atopic and eight healthy
subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous
tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20
nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100
mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive
controls and saline as negative control. The skin responses were monitored by
measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced
wheal and flare reactions in all placebo-treated subjects. Histamine elicited
larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to
sixfold larger wheal and flare reaction than PT. No differences in BK-induced
wheal and flare were observed between atopic and healthy subjects. In atopic
subjects, cetirizine induced a significant reduction of flare reactions after the
BK test (80% for IDT, and 94% for PT [P < 0.01]). Moreover, cetirizine reduced
significantly BK-induced wheals by 70% for IDT (P < 0.01) and 65% for PT (P <
0.01). A similar inhibiting effect of cetirizine was also observed in healthy
subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions
induced by BK challenge were markedly inhibited by previous intake of cetirizine.
The mechanism by which this effect is mediated cannot be established at present.
PMID- 10782525
TI - Antigliadin IgE--indicator of wheat allergy in atopic dermatitis.
AB - BACKGROUND: Cereal grains are recognized as the cause of adverse reactions in
some patients exposed to grain or flour by either inhalation or ingestion. Cereal
related diseases, such as celiac disease and baker's asthma, have been well
studied and the causative cereal proteins have been characterized. Although
cereals form an essential part of daily nutrition, the allergenic proteins
causing symptoms on ingestion in atopic dermatitis (AD) have remained obscure. In
this study, we have investigated the allergenic fraction of wheat in AD. METHODS:
Skin prick tests (SPT) with a NaCl wheat suspension and the ethanol-soluble wheat
gliadin were performed on 18 wheat-challenge-positive or -negative children with
AD, six adult AD patients with suspected cereal allergy, and one adult with wheat
dependent exercise-induced urticaria/anaphylaxis. Serum total IgE and specific
IgE-antibody levels to wheat and gluten were measured with the
radioallergosorbent test (RAST) simultaneously. In addition serum samples of all
25 patients were analyzed by IgE immunoblotting with the ethanol-soluble wheat
protein extract. RESULTS: Thirteen of the AD children were wheat-challenge
positive, 11/12 of them appeared to be positive with gliadin SPT, and all had an
elevated gluten RAST value. Those challenge-negative were negative with both
gliadin SPT and gluten RAST. Positive wheat SPT and RAST alone were not
associated with positive challenges. Four of the adult patients responded to a
cereal-free diet, although only two of them appeared to be positive with gliadin
SPT and gluten RAST. A broad and intensive staining of gliadin peptides in IgE
immunoblotting studies was seen in challenge-positive children with positive
gliadin SPT and/ or gluten RAST. Besides staining of peptides in the main gliadin
area of 30-46 kDa, a characteristic finding was the staining of small, <14-kDa
proteins with sera of challenge- and gliadin-SPT-positive patients. CONCLUSIONS:
We found that wheat-allergic AD patients have IgE antibodies against gliadin that
can be detected by both SPT and the sensitive immunoblotting method. This
suggests that gliadin peptides are important allergens, and ingestion of wheat
causes symptoms of AD. A broad and intensive IgE staining was seen of gliadin
peptides against both the previously characterized peptides in the main gliadin
area and small, previously uncharacterized peptides of less than 14 kDa. The
gliadin SPT and gluten RAST are good screening methods. Further characterization
of the IgE-stained gliadin proteins is needed.
PMID- 10782526
TI - Eotaxin in induced sputum of asthmatics: relationship with eosinophils and
eosinophil cationic protein in sputum.
AB - BACKGROUND: Eosinophilic inflammation is a crucial aspect of allergic diseases
such as bronchial asthma. An eosinophil-active chemokine, eotaxin, may play a
role in the pathogenesis of the tissue eosinophilia accompanying asthma. METHODS:
Induced sputa were obtained from 53 patients with atopic asthma and six healthy
subjects, and the concentration of eotaxin in the sputum was measured by ELISA.
We investigated whether the sputum content of eotaxin is related to 1) asthma
status or corticosteroid therapy, and 2) other sputum indices, including
percentage of eosinophils and concentration of eosinophil cationic protein (ECP).
RESULTS: The patients with stable or unstable asthma showed significantly higher
concentrations of sputum eotaxin than the normal controls. The level of sputum
eotaxin demonstrated a positive correlation with the percentage of eosinophils in
stable asthmatics not receiving corticosteroid therapy, but not in stable
patients treated with corticosteroids, or in unstable patients. Sputum eotaxin
demonstrated a positive correlation with ECP in asthmatic patients who were
either in a stable state or not receiving steroid therapy. CONCLUSIONS: The
elevated level of eotaxin detected in association with increased eosinophils and
ECP in the sputum of asthmatics suggests that eotaxin is involved in the
pathogenesis of eosinophilic airway inflammation. The relationship of eotaxin to
airway eosinophilia may be modified by the stability status of asthma and
corticosteroid therapy.
PMID- 10782527
TI - Pocket 4 in the HLA-DRB1 antigen-binding groove: an association with atopy.
AB - BACKGROUND: Many studies have attempted to identify an association between HLA
genes and atopy, given the role of HLA molecules in the regulation of the immune
response. In the case of house-dust mites, it is difficult to find an association
with a particular HLA allele, due to the complexity of the allergen. The
objective was to investigate whether HLA-DRB1 functional groups are better
correlated with the atopic disease in our population than DRB1 alleles. METHODS:
The method was reanalysis of the HLA-DRB1 data of a previous case/ control study.
RESULTS: The "Dr" group was found to be associated with the atopic disease in our
population. CONCLUSIONS: Grouping HLA-DRB1 alleles into functional categories may
assist in the search for predictive factors in relation to atopic disease.
PMID- 10782528
TI - Indoor exposure to formaldehyde and risk of allergy.
PMID- 10782530
TI - Asthma caused by a pet bat.
PMID- 10782529
TI - Allergic rhinitis to turtle food.
PMID- 10782531
TI - Occupational rhinitis/asthma to courgette.
PMID- 10782532
TI - Intrauterine cow's milk sensitization.
PMID- 10782533
TI - Advantage of insulin lispro in suspected insulin allergy.
PMID- 10782534
TI - Allergy to cypress pollen.
PMID- 10782535
TI - Occupational allergy to cyclamen.
PMID- 10782536
TI - Selective hypersensitivity to diclofenac.
PMID- 10782537
TI - Diclofenac-induced fever.
PMID- 10782538
TI - Allergy to gelatin.
PMID- 10782539
TI - Selective immediate hypersensitivity to ceftriaxone.
PMID- 10782541
TI - Asthma to tetramethrin.
PMID- 10782540
TI - Fever and urticaria to codeine.
PMID- 10782542
TI - Immediate hypersensitivity to ceftriaxone.
PMID- 10782543
TI - Do we still need psychiatric case registers?
PMID- 10782544
TI - Combination of antidepressants and psychological treatments for bulimia nervosa:
a systematic review.
AB - This review assessed the effect of a combination of antidepressants plus
psychological approaches compared to each single treatment for bulimia nervosa.
METHOD: Trials were included in two meta-analyses: single antidepressants versus
combination and single psychological approaches versus combination.
Methodological quality and homogeneity of results were assessed. Dichotomous
outcomes were analysed by calculating relative risks (RR). RESULT: Five trials
were included in meta-analysis 1 and 7 in meta-analysis 2. Remission rates were
42% for combination versus 23% for antidepressants (RR = 1.38; 95% CI=0.98-1.93;
P=0.06) and 36% for psychological approaches compared to 49% for combination (RR=
1.21; P=0.03). Drop-out rates were 16% for psychological approaches and 30% for
combination (RR =0.57; 95% CI = 0.38-0.088; P=0.11). CONCLUSION: Efficacy of
combined treatments was superior to single approaches. When antidepressants were
combined to treatment, acceptability of psychological approaches was
significantly reduced.
PMID- 10782545
TI - Cognitive impairment and syndromal depression in estimates of active life
expectancy: the 13-year follow-up of the Baltimore Epidemiologic Catchment Area
sample.
AB - OBJECTIVE: Our hypothesis was that including cognitive status and syndromal
depression in specifying functional impairment would result in significant
differences in estimates of active life expectancy from specifications that
included only standard functional measures (such as activities of daily living).
METHOD: The subjects were the 3481 continuing participants of the Baltimore
Epidemiologic Catchment Area Program. Interviews included criterion-based
diagnosis of depression, assessment of cognitive status and standard survey
questions on function. RESULTS: Estimates of active life expectancy decreased
from 9.8 years to 8.9 years at age 65 years for men, and from 10 years to 8.4
years at age 65 years for women, when the definition of active life expectancy
included measures of cognitive impairment and syndromal depression. CONCLUSION:
Measurements of active life expectancy tend to ignore dependencies related to
psychological causes, and should move beyond mere enumeration of activities of
daily living and instrumental activities of daily living.
PMID- 10782546
TI - Cognitive dysfunctions and white matter lesions in patients with bipolar disorder
in remission.
AB - OBJECTIVE: To compare cognitive functioning in relation to white matter lesions
in bipolar disorder in remission and schizophrenia. METHOD: Cognitive performance
and the occurrence of white matter lesions on MRI images of the brain were
assessed in 22 patients with bipolar disorder in remission, 22 patients with
schizophrenia and 22 healthy volunteers. RESULTS: Performance of tests of memory,
speed and cognitive flexibility was significantly impaired in both patient
groups. The frequency of white matter lesions did not differ significantly
between the three groups. No differences in cognitive performance were found
between patients with white matter lesions and patients without such lesions.
CONCLUSION: White matter lesions apparently do not underlie cognitive deficits
that are found in patients with bipolar disorder in remission and in patients
with schizophrenia.
PMID- 10782547
TI - Cognitive dysfunction in obsessive-compulsive disorder.
AB - OBJECTIVE: Assessment of cognitive functions among obsessive-compulsive disorder
(OCD) patients would help in understanding the neurobiology and brain areas
involved in that disorder. The objective of this work was to study the cognitive
dysfunction in OCD patients and to identify its correlation with both the
clinical picture and the severity of the disorder. METHOD: Neuropsychological and
electrophysiological event-related potentials were tested in 30 OCD patients and
compared with 30 normal volunteers of a matched gender, age and education.
RESULTS: Results showed a defective visuospatial recognition, which worsens with
chronicity, deteriorated set-shifting abilities, overfocused attention to
irrelevant stimuli and delayed selective attention to relevant tasks. Mild cases
showed better selective attention than severe cases. Obsessive cases had a
defective visual memory, while compulsive cases had delayed perception of task
relevant stimuli. Mixed cases showed disturbed information-processing both early
and late. CONCLUSION: OCD patients have a characteristic pattern of cognitive
dysfunction that differs among patients of varied severity, chronicity and
symptom type. We suggest a striatofrontoparietal neural pathophysiology. OCD
seems to be a heterogeneous disorder, both clinically and pathophysiologically.
PMID- 10782548
TI - Sex differences in late-life depression.
AB - OBJECTIVE: The primary aim of this study was to assess sex differences in
depression in later life. METHOD: In a random, age and sex-stratified community
sample of 3056 older Dutch people (55 85 years) the prevalence, symptom-reporting
and risk factors associated with depression in later life were studied.
Depression was measured with the Center for Epidemiologic Studies Depression
scale (CES-D). Bivariate, multivariate and factor analyses were used. RESULTS:
Prevalence of depression in women was almost twice as high as in men. Controlling
for age and competing risk factors reduced the relative risk for females with
more than half. Symptom-patterns in men and women were very much alike. Sex
differences in associations with risk factors were small, but exposure to these
risk factors was considerably higher in females. CONCLUSION: Very little evidence
for a typical 'female depression' was found. Female preponderance in depression
was related to a greater exposure to risk factors.
PMID- 10782549
TI - Regional differences in schizophrenia incidence in Denmark.
AB - OBJECTIVE: To examine the regional distribution of schizophrenia incidence in
Denmark. METHOD: A cohort consisting of 2441 Danish psychiatric patients, with
first-time admissions between January 1, 1978 and December 31, 1982, and
diagnosed as having schizophrenia (ICD-8) at least once in a 10-year period of
observation was divided into three regional groups by degree of urbanization.
RESULTS: Incidence increased for both sexes with increasing urbanization. A
diagnostic delay was most pronounced in the least urbanized areas and was most
pronounced for women. CONCLUSION: Our study confirms the existence of regional
differences in schizophrenia incidence on a national basis. Marked regional
differences in diagnostic delay were also demonstrated. A possible explanation
could be regional differences in diagnostic procedures, underlining the
importance of uniform diagnostic patterns as a means for reliable mapping of
psychiatric morbidity and, hopefully, adequate treatment.
PMID- 10782550
TI - Changes in negative symptoms and the risk of tardive dyskinesia: a longitudinal
study. UK700 Group.
AB - OBJECTIVE: To examine whether the development of tardive dyskinesia (TD) is
accompanied by a parallel process of worsening negative symptoms in a
longitudinal study. METHOD: A sample of 708 psychotic patients were followed over
a period of 2 years, using the Abnormal Involuntary Movement Scale and the Scale
for the Assessment of Negative Symptoms (SANS). RESULTS: Of 361 individuals with
no prior evidence of dyskinesia, 46 (13%) developed TD by year 2. Independent of
the effects of male sex (odds ratio (OR)=2.18, 95% confidence interval: 1.00
4.74), age (OR per quartile group = 1.39, 95% CI: 1.01-1.90), duration of
exposure to antipsychotic medication (OR = 2.35 per 8 months, 95% CI: 1.17-4.72)
and average SANS score (OR per quartile group = 1.38, 95% CI: 0.99-1.93),
worsening of negative symptoms over the 2 previous years was associated with TD
onset (OR per quartile group = 1.46, 95% CI: 1.07-2.00). CONCLUSION: The
development of TD is linked, independent of the effect of antipsychotics and
older age, to an illness-related pathological process, characterized by worsening
negative symptoms.
PMID- 10782551
TI - Quantitative EEG in 'positive' and 'negative' schizophrenia.
AB - OBJECTIVE: Quantitative EEG has yielded different results in schizophrenia. The
method of quantitative EEG has been relatively poorly used in the studies of the
dichotomy into positive and negative schizophrenia. METHOD: Amplitude values of
any particular frequency band (after fast Fourier transformation, FFT) were
observed in 47 schizophrenic patients (25 patients with positive and 22 patients
with negative schizophrenia) and in 50 normal subjects. The frontal, temporal,
parietal and occipital regions (F3, F4, C3, C4, T3, T4, P3, P4, O1 and O2) were
observed. RESULTS: Positive and negative schizophrenia were found to differ only
in the delta and theta bands over frontal regions. Positive and negative
schizophrenic patients were found to differ from normal subjects in delta, theta,
alpha and beta 2 bands. CONCLUSION: Delta and theta activity may play a role as a
marker in differentiating between positive and negative schizophrenia.
PMID- 10782552
TI - Heterogeneity in schizophrenia; mixture modelling of age-at-first-admission,
gender and diagnosis.
AB - OBJECTIVE: Identifying and explaining sources of heterogeneity in schizophrenia
would help elucidate its aetiology and course. In this paper we examine
heterogeneity in terms of age-at-first-admission, diagnosis and gender by
decomposing a large dataset using mixture modelling. METHOD: Using the Queensland
Mental Health Statistics System, we first extracted age-at-first-admission data
for schizophrenia (ICD8/9 295) to represent a 'narrow' definition of
schizophrenia (N= 7651); we then added paraphrenia (297) and other non-organic
psychoses (298) for a 'broad' definition (N= 10 199). Mixture models were fitted
to these narrowly and broadly defined distributions for both males and females.
RESULTS: For narrowly defined schizophrenia a three-component model best fitted
both male and female distributions. While the mean ages of these components were
very similar for both males and females, the ratios of males to females crossed
from an excess of males in the 'youngest' component to an excess of females in
the 'oldest' component. When using the broad definition, four components best
fitted the underlying distributions. While the first three were similar to those
found for narrowly defined schizophrenia, the additional fourth component
reverted to a male excess; however, the mean age for males was 10 years younger
than for females. CONCLUSION: Our findings suggest that subtypes based on age-at
first-admission can be identified, although the number identified depends on how
inclusively schizophrenia is defined. While there appear to be the same number
with similar mean ages for both genders, there are differences in the proportions
of males to females. Further work to fully characterize their nature is
warranted.
PMID- 10782553
TI - Effects of a coping-orientated group therapy for schizophrenia and
schizoaffective patients: a pilot study.
AB - OBJECTIVE: This controlled pilot study was designed, first, to examine the
efficacy of two different group therapy formats for schizophrenia and
schizoaffective patients: a patient-centred, psychoeducative and coping
orientated group therapy approach and a supportive therapy group. Secondly, it
intended to establish preliminary hypotheses on the therapeutically relevant
factors. METHOD: In a sample of 32 patients suffering from schizophrenia or a
schizoaffective disorder the effect sizes of the coping-orientated therapy
approach and a supportive group therapy on several outcome variables were
examined and the predictive power of different effect variables on outcome was
analysed. RESULTS: The effect sizes show improvements in the cognizance of the
disorder and the related pharmacotherapy, the psychopathology and the social
functioning for both therapy conditions. Moreover, outcome as measured after 1
year was best predicted by the patient's mastery of active, problem-focused
coping strategies. CONCLUSION: The results corroborate the appropriateness of
focusing on aspects of coping-behaviour in psychological interventions.
PMID- 10782555
TI - Patient satisfaction: a valid index of quality of care in a psychiatric service.
AB - OBJECTIVE: To assess patients', clinicians' and referrers' satisfaction with care
in newly referred psychiatric patients and to compare these with standard quality
indicators such as waiting times used by the service. METHOD: A random sample of
all new adult psychiatric patients presenting over a 4-month period in 2
successive years to an inner-city psychiatric service was assessed. RESULTS: One
hundred and thirteen (68%) of 167 randomly selected patients were seen.
Independent evidence of service performance showed that patient satisfaction, but
not clinician or referrer satisfaction, was a more accurate indicator of quality
of care than standard indicators. CONCLUSION: Simple ratings of patient
satisfaction alone may be useful indicators of quality of psychiatric care.
PMID- 10782554
TI - Development, reliability and acceptability of a new version of the DSM-IV Social
and Occupational Functioning Assessment Scale (SOFAS) to assess routine social
functioning.
AB - OBJECTIVE: Development of a scale to assess patients' social functioning, the
Personal and Social Performance scale (PSP). METHOD: PSP has been developed
through focus groups and reliability studies on the basis of the social
functioning component of the DSM-IV Social and Occupational Functioning
Assessment Scale (SOFAS). The last reliability study was carried out by 39
workers with different professional roles on a sample of 61 psychiatric patients
admitted to the rehabilitation unit. Each patient was rated independently on the
scale by the two workers who knew them best. RESULTS: The PSP is a 100-point
single-item rating scale, subdivided into 10 equal intervals. The ratings are
based mainly on the assessment of patient's functioning in four main areas: 1)
socially useful activities; 2) personal and social relationships; 3) self-care;
and 4) disturbing and aggressive behaviours. Operational criteria to rate the
levels of disabilities have been defined for the above-mentioned areas. Excellent
inter-rater reliability was also obtained in less educated workers. CONCLUSION:
Compared to SOFAS, PSP has better face validity and psychometric properties. It
was found to be an acceptable, quick and valid measure of patients' personal and
social functioning.
PMID- 10782556
TI - Clozapine and risperidone: combination/augmentation treatment of refractory
schizophrenia: a preliminary observation.
AB - OBJECTIVE: Clozapine and risperidone were the first two antipsychotic drugs of a
new class of agents for the pharmacotherapy of schizophrenia. It has been
suggested that refractory schizophrenic patients who fail to respond to neither
clozapine nor risperidone may respond to a combination/augmentation strategy of
both medicaments. METHOD: Three cases of individuals with unremittent
schizophrenia treated via this combination are presented. Response was evaluated
by clinical follow-up and PANSS rating scale. RESULTS: Good clinical results with
no noticeable adverse side effects, ascertained by a reduction from baseline
scores of the Positive and Negative Syndrome Scale (PANSS) were obtained in all
three patients. CONCLUSION: The findings from this pilot study suggest this
combination as a possible therapeutic approach for treating resistant
schizophrenic patients.
PMID- 10782557
TI - Progressive brain atrophy and VBR increase in schizophrenia?
PMID- 10782558
TI - Interactive educational diabetes simulators: future possibilities.
AB - In 1996 an interactive educational diabetes simulator called AIDA was released
without charge on the Internet as a non-commercial contribution to continuing
diabetes education. Over the past 3 years over 30,000 people have visited the
AIDA Web site-- http://www.diabetic.org.uk/aida.htm--and over 10,000 copies of
the program have been downloaded from there free-of-charge. This review builds on
the experience gained from the AIDA development and the World Wide Web
distribution of the software, and looks to the future, highlighting features
which users might expect to see in future generations of such interactive
educational diabetes programs. Novel functions already described in the
literature are overviewed, and possible applications using personal computers and
the Internet are discussed. The importance of the user interface is stressed. The
concept of a "virtual diabetic patient" that provides an electronic
representation of a patient with diabetes--and which can be used for self
learning/teaching/demonstration purposes--is highlighted.
PMID- 10782559
TI - Dexamethasone-induced changes in FAD-glycerophosphate dehydrogenase mRNA, content
and activity, and insulin release in human pancreatic islets.
AB - Human pancreatic islets were cultured for 63 hr at 2.8 or 16.7 mM D-glucose in
the absence or presence of dexamethasone. In the 1.0 to 10 microM range,
dexamethasone caused a concentration-related decrease in the FAD (flavin adenine
dinucleotide)-linked mitochondrial glycerophosphate dehydrogenase (mGDH) mRNA
content of the islets, and decreased both the mGDH content of the islets and the
catalytic activity of the enzyme in islet homogenates, these effects being often
more marked in islets cultured at 16.7 mM, rather than 2.8 mM, D-glucose. Even
after culture in the presence of no more than 10 nM dexamethasone, namely under
conditions in which the mGDH mRNA content and activity were both virtually
unaffected, the corticosteroid restored the capacity of the beta-cells to display
an increase in insulin output in response to a rise in D-glucose concentration in
islets first cultured at 2.8 mM D-glucose but suppressed the insulinotropic
action of the hexose in islets first cultured at 16.7 mM D-glucose. Whilst
revealing an untoward effect of high concentrations of dexamethasone upon mGDH
mRNA, content and activity in human islets, these findings also document a dual
effect of a low concentration of the corticosteroid (10 nM) upon the secretory
responsiveness of human islets to D-glucose, independently of any significant
change in mGDH gene expression. It is proposed that such a dual action may
account, in part at least, for both the well known increase in insulin output
found in hypercorticism and the more recently discovered unfavourable direct
effect of corticosteroid hormones on the secretory activity of islet beta-cells.
PMID- 10782560
TI - A study on lymphocyte subpopulation in diabetic mothers at delivery and in their
newborn.
AB - Despite the importance of immunological aspects in pregnancy, until now few
studies have been reported on the cellular immune modifications of diabetic
pregnancy and on the newborn of diabetic mothers. Therefore, we thought it of
interest to evaluate cell immunity in diabetic pregnant women and in their
newborn children. Fourteen pregnant women with Type 1 diabetes (T1DM), mean age
(+/-SD) 30-4 yr, mean disease duration (+/-SD) 12+/-5 yr, 15 with gestational
diabetes mellitus (GDM) (mean age 33+/-6 yr), and 21 healthy pregnant women (mean
age 29+/-4 yr) were studied and their metabolic and immunological parameters were
evaluated. Fifty newborn babies were examined for immunological evaluation. Mean
fasting plasma glucose and HbA1c values were higher in T1DM and GDM patients than
in controls. Total lymphocyte subsets were higher in T1DM and GDM patients,
although there were no significant differences between the percentual values. In
children of T1DM and GDM mothers absolute lymphocyte values were increased,
whereas the natural killer (NK) subset had decreased values in both absolute and
percentual terms. Our work shows that, with respect to healthy controls, both GDM
and T1DM mothers have a significant increase in total lymphocytes, and newborns
have a reduced number of NK lymphocytes. Lower numbers of NK lymphocytes are
probably related to altered production of lymphokines during foetal life and may
also represent a real immune deficit in monitoring against viral infections.
PMID- 10782561
TI - A strong inverse relationship between PAI-1 and Lp(a) in hypertensive Type 2
diabetic patients.
AB - Thrombophilia with a contemporary reduction of fibrinolytic activity has been
observed both in diabetes mellitus and hypertension. Previously, we found a
relationship between plasminogen activator inhibitor Type 1 (PAI-1) and
lipoprotein(a) [Lp(a)] in Type 2 diabetes mellitus patients without
complications. We hypothesised that this relationship could be due to a
compensatory mechanism able to lower the risk of hypofibrinolysis as found in
Type 2 diabetes mellitus. The present work was aimed at investigating the
influence of concurrent hypertension and diabetes mellitus on the plasma levels
of these two fibrinolytic inhibitors. In addition, other risk factors, known to
influence the fibrinolytic parameters, were taken into account. Forty-nine Type 2
nonhypertensive diabetic patients without complications, 47 Type 2 hypertensive
diabetic patients without complications, 54 non-diabetic hypertensive subjects
without complications as well as 87 control subjects were studied. Plasma
concentrations of Lp(a), PAI-1 antigen and activity, and the main parameters of
oxidative, lipo- and glycometabolic balance were determined. Significant
statistical differences between diabetic and non-diabetic subjects were found
concerning triglycerides and antioxidant defence (p<0.01). Analysis of variance
showed the F test statistically significant in evaluating the Log PAI-1/Lp(a) (p
= 0.02). Correlation analysis between Log PAI-1 antigen and Lp(a) was significant
in non-hypertensive diabetic patients, as expected (r = -0.38, p<0.01), and even
stronger in hypertensive diabetic patients (r = -O.72,p<0.01). These results
allow to hypothesise that the relationship between PAI-1/Lp(a) could be
determinant in avoiding vascular complications due to diabetes mellitus and
hypertension.
PMID- 10782562
TI - Atorvastatin for the management of Type 2 diabetic patients with dyslipidaemia. A
mid-term (9 months) treatment experience.
AB - Dyslipidaemia, particularly increased triglycerides (TG) and low HDL-cholesterol
(HDL-C), represents an important risk factor for Type 2 diabetes (T2DM)
macrovascular complications. Our aim was to evaluate the effects of atorvastatin
in a population of T2DM patients according to their cardiovascular risk: evidence
of myocardial or coronary lesions (group A); evidence of familiar
hypercholesterolaemia (group B); evidence of stable cardiovascular risk (group
C). The mean age was 64+/-7 yr, mean disease duration 9.5+/-3 yr, the mean body
mass index (BMI) 27.7+/-1.3 kg/m2, mean HbA1c 8+/-0.6%; total cholesterol 256+/
24 mg/dl in group A, 298+/-30 and 244+/-31 in groups B and C, respectively
(p<0.05 B vs. A and C). Moreover, mean HDL-C values were about 45+/-7 mg/dl, TG
225+/-20 mg/dl, systolic and diastolic blood pressure 144+/-7 mm Hg and 84+/-8 mm
Hg, respectively; fibrinogen values 330+/-23 mg/dl and microalbuminuria 58+/-9
mg/l. Lipid profile improved significantly during the treatment with personalised
doses of atorvastatin (generally 10 mg/day) designed to achieve the therapeutic
goals: the reduction of total cholesterol, TG (p<0.01), LDL-cholesterol (LDL-C)
(p<0.01) and an increase of HDL-C were measured. The treatment with atorvastatin
induced significant reduction of microalbuminuria and fibrinogen levels (p<0.01).
Moreover, in the subgroup of patients with hypertension, diastolic blood pressure
values were reduced without modification of antihypertensive treatment. This
preliminary study suggests that the management of hypercholesterolaemia with
atorvastatin in T2DM patients may be useful both for the primary and secondary
prevention of chronic complications of T2DM.
PMID- 10782563
TI - Changes of autoantibodies against oxidatively modified low density lipoproteins
during long-term LDL-apheresis.
AB - The oxidation of low-density lipoproteins (LDL) is considered a key event in the
initiation of atherosclerosis. The aim of this study was to follow-up the
biological marker of in vivo LDL oxidation (oxidatively modified LDL autoantibody
titres) during long-term LDL-apheresis treatment. A patient suffering from severe
combined hyperlipidaemia underwent LDL-apheresis biweekly and was followed for
two years. The significant reduction of baseline total cholesterol (58%), total
triglycerides (80%), LDL-cholesterol (48%), apoprotein B (50%) and apolipoprotein
(a) (61%) may be considered as a good response to the treatment. The titre of
autoantibodies (IgG) against oxidatively modified LDL (malondialdehyde-derived
LDL) was followed throughout the study and showed dynamic changes. The measured
values were multiple compared as mean+/-SD over each semester of apheresis
application: I semester 70.0+/-8.3 U/ml, n = 12; II semester 58.0+/-13.8 U/ml, n
= 12; III semester 37.6+/-6.0 U/ml, n=12; IV semester 34.3+/-7.0 U/ml, n = 12;
ANOVA: I vs. II semester p<0.083, II vs. III semester p<0.00053, III vs. IV
semester p<0.248. In parallel to the changes in this biochemical parameter,
regression of numerous xanthomas was clinically observed. In spite of this, the
presence of oxidised-LDL (oxLDL) antibodies was enhanced in comparison to
antibody titre detected in a group of age-matched normolipaemic healthy controls
(n = 15; 19.4+/-8.6; p<0.01). Classical lipoprotein parameters were correlated
with the titre of autoantibodies against oxLDL and showed low correlation
coefficients: total cholesterol vs. oxLDLab, r = 0.36; triglycerides vs. oxLDLab,
r = 0.43; LDL cholesterol vs. oxLDLab, r = 0.14; HDL cholesterol vs. oxLDLab, r =
-0.33; apo B vs. oxLDLab, r = 0.25; apo (a) vs. oxLDLab, r = -0.05. Our study
showed an additional benefit of LDL-apheresis therapy. The production of
autoantibodies against oxLDL was reduced during the treatment, indicating a lower
level of the atherogenic antigen.
PMID- 10782564
TI - Florid diabetic retinopathy and its systemic implications.
PMID- 10782565
TI - Insulin regulation of protein metabolism in vivo.
PMID- 10782567
TI - Optimum protein intake in chronic renal failure.
PMID- 10782566
TI - Protein metabolism in Type 1 and Type 2 diabetes mellitus in the fasted and fed
states.
PMID- 10782568
TI - Is it possible to correct protein metabolism in cirrhotic patients?
PMID- 10782569
TI - Male infertility and environmental exposure to lead and cadmium.
AB - Humans are exposed occupationally and environmentally to metal aerosols including
lead (Pb2+) and cadmium (Cd2+). These toxicants accumulate in male reproductive
organs. Epidemiological studies have been equivocal about effects of Pb2+ and
Cd2+ on hormone concentrations, male fertility and sperm parameters. Comparison
of Pb2+ and Cd2+ concentrations in fertile and infertile men are problematic.
Problem areas include failure to control confounding variables, but genetic
polymorphisms as in somatic diseases may modulate Pb2+ and Cd2+ damage. Multiple
calcium (Ca2+) and potassium (K+) channel isoforms have been identified in human
testes and spermatozoa. These Ca2+ and K+ channels are involved in early events
of acrosome reactions. Ca2+ channel are susceptible to Cd2+ poisoning and K+
channels to Pb2+. These channels offer entry paths for metallic toxicants into
mature spermatozoa. Ion channel polymorphisms may cause differential
sensitivities to Cd2+ and Pb2+, explaining in part prospective blinded studies
showing high Cd2+ in varicocele-related human infertility and high Pb2+ in
unexplained infertility. In both forms of male infertility the ability to undergo
an acrosome reaction decreases. Reverse transcriptase-polymerase chain reaction
assays for Ca2+ and K+ channel isoforms may identify susceptibility subgroups
with lower resistance to environmental exposures.
PMID- 10782570
TI - Smoking and reproduction: gene damage to human gametes and embryos.
AB - Assisted conception is a useful methodology for detecting disturbances in
clinical outcome, meiotic maturation, and genetic integrity of human gametes.
Germinal cells are vulnerable to genetic damage from smoking, but can repair
damage during meiosis. In ejaculated spermatozoa, repair capacity declines
drastically. Smoking alters the meiotic spindle of oocytes and spermatozoa,
leading to chromosome errors which affect reproductive outcomes. Smoking is
associated with reduced numbers of retrieved oocytes, leading to early age of
menopause. Oocyte elimination occurs preferentially during meiosis I, a period
sensitive to genetic damage. Smoking inhibits embryo fragmentation; inhibition
may confer survival advantage to embryos genetically altered. Smoking is
associated with low sperm quality, but clinical effects are not recognized.
Cadmium (a heavy metal), nicotine (a toxic alkaloid), and its metabolite
cotinine, are detectable in gonadal tissues and fluids in association with
smoking. Cotinine incorporates into ovarian granulosa-lutein cells, compromising
the developmental potential of follicles. Benzo[a]pyrene is a carcinogenic
polycyclic aromatic hydrocarbon resulting from cigarette combustion. Its reactive
metabolite binds covalently to DNA, forming adducts. Smoking-related adducts were
detectable in ovarian granulosa-lutein cells, oocytes, spermatozoa and
preimplantation embryos. Transmission of altered DNA from smoking by spermatozoa
was demonstrated in preimplantation embryos and in association with increased
risk of childhood cancer.
PMID- 10782571
TI - Physiological and pharmacological aspects of local transfer of substances in the
ovarian adnexa in women.
AB - An intimate arrangement between the utero-ovarian vein and the ovarian artery has
been found in many species. The anatomical structure suggests the existence of a
counter-current system of exchange, and many animal experiments point to a
physiological importance of this transfer system. In man, the utero-ovarian vein
forms a plexus around the ovarian artery. In-vitro experiments have demonstrated
a local transfer of progesterone; in-vivo experiments have proved that krypton
and progesterone can be transferred from the utero-ovarian vein to the ovarian
artery. The physiological and pharmacological importance of the counter-current
system is still under evaluation, and further investigations are needed. It has
been suggested that counter-current transfer facilitates local communication
between the ovary, Fallopian tube, and uterus. This may be important in a context
of luteolysis, follicular selection and maturation, fertilization, and the
recognition and maintenance of pregnancy. The pharmacological and therapeutic
potential may be limited, as the ovarian adnexa are relatively difficult to
access. Instillation of hormones into the uterine lumen will probably induce a
higher plasma concentration in the ovarian arterial blood than in peripheral
arterial plasma. A culdoscopic or endoscopic approach might permit introduction
of long-acting depots in the uterine fundus near the Fallopian tubes and/or
ovaries.
PMID- 10782572
TI - Comparison between different routes of progesterone administration as luteal
phase support in infertility treatments.
AB - Different routes of natural progesterone supplementation have been tried as
luteal phase support in infertility treatments. Orally administered progesterone
is rapidly metabolized in the gastrointestinal tract and its use has proved to be
inferior to i.m. and vaginal routes. Progesterone i.m. achieves serum
progesterone values that are within the range of luteal phase and results in
sufficient secretory transformation of the endometrium and satisfactory pregnancy
rates. The comparison between i.m. and vaginal progesterone has led to
controversial results as regards the superiority of one or the other in inducing
secretory endometrial transformation. However, there is increasing evidence in
the literature to favour the use of vaginal progesterone. Vaginally administered
progesterone achieves adequate endometrial secretory transformation but its
pharmacokinetic properties are greatly dependent on the formulation used. After
vaginal progesterone application, discrepancies have been detected between serum
progesterone values and histological endometrial features. Vaginally administered
progesterone results in adequate secretory endometrial transformation, despite
serum progesterone values lower than those observed after i.m. administration,
even if they are lower than those observed during the luteal phase of the natural
cycle. This discrepancy is indicative of the first uterine pass effect and
therefore of a better bioavailability of progesterone in the uterus, with minimal
systematic undesirable effects.
PMID- 10782573
TI - The role of heat shock proteins in reproduction.
AB - Heat shock proteins (HSP) were first identified in cells after exposure to
elevated temperature. Subsequently HSP have been identified as a critical
component of a very complex and highly conserved cellular defence mechanism to
preserve cell survival under adverse environmental conditions. HSP are
preferentially expressed in response to an array of insults, including
hyperthermia, free oxygen radicals, heavy metals, ethanol, amino acid analogues,
inflammation and infection. HSP interact with intracellular polypeptides and
prevent their denaturation or incorrect assembly. In addition HSP are also
involved in several processes essential for cellular function under physiological
conditions. HSP production is enhanced during in-vitro embryo culture and they
are among the first proteins produced during mammalian embryo growth. The
spontaneous expression of HSP as an essential part of embryo development is well
documented and the presence or absence of HSP influences various aspects of
reproduction in many species. Finally, HSP are immunodominant antigens of
numerous microbial pathogens, e.g. Chlamydia trachomatis, which have been
recognized as the main cause of tubal infertility. Many couples with fertility
problems have had a previous genital tract infection, have become sensitized to
microbial HSP, and a prolonged and asymptomatic infection may trigger immunity to
microbial HSP epitopes that are also expressed in man. Antibodies to both
bacterial and human HSP are present at high titres in sera and hydrosalpinx fluid
of many patients undergoing in-vitro fertilization (IVF). In a mouse in-vitro
embryo culture model, these antibodies impaired the mouse embryo development at
unique developmental stages. Recent studies indicate an association between a
previous infection, immunity to HSP and reproductive failure.
PMID- 10782574
TI - Sperm function assays and their predictive value for fertilization outcome in IVF
therapy: a meta-analysis.
AB - The prevalence of male infertility and the availability of new, highly successful
therapeutic options make the testing of sperm functional competence mandatory. An
objective, outcome-based examination of the validity of the currently available
assays was performed based upon the results obtained from 2906 subjects evaluated
in 34 prospectively designed, controlled studies. The aim was carried out through
a meta-analytical approach that examined the predictive value of four categories
of sperm functional assays: computer-aided sperm motion analysis (CASA); induced
acrosome reaction testing; sperm penetration assay (SPA); and sperm-zona
pellucida binding assays for IVF outcome. Results demonstrated a high predictive
power of the sperm-zona pellucida binding and the induced-acrosome reaction
assays for fertilization outcome. On the other hand, the findings indicated a
poor clinical value of the SPA as predictor of fertilization and a real need for
standardization and further investigation of the potential clinical utility of
CASA systems. This analysis points out to limitations of the current tests and
the need for standardization of methodologies and provides objective evidence on
which clinical management and future research can be based.
PMID- 10782575
TI - The metabolic effect of antenatal corticosteroid therapy.
AB - The use of antenatal dexamethasone to mature the fetal lung in pregnancies likely
to deliver before 34 weeks is almost universal. It reduces the incidence of
respiratory distress syndrome in the newborn and results in an overall
improvement in neonatal morbidity and mortality. Although considered to be
generally safe, there are concerns about adverse maternal and fetal effects. In a
series of studies, we have found that antenatal dexamethasone administration is
associated with reduced placental hormone production and maternal bone formation,
impaired glucose tolerance and altered function of the hypothalamic-pituitary
adrenal axis. In this article, we have compared our data with other reports in
the human and reviewed the relevant animal data. We conclude that further studies
on the long-term effects of antenatal dexamethasone therapy in the human are
warranted with particular emphasis on the long-term effects on the fetus.
PMID- 10782576
TI - Haemodynamic evaluation of the first trimester fetus with special emphasis on
venous return.
AB - Knowledge of the fetal circulation is a prerequisite for understanding the
physiological behaviour of the developing fetus. In this overview dealing with
Colour and Power Doppler ultrasound findings in the first trimester of pregnancy
and its pathophysiological background, we aim to report on the methodological
aspects, normal blood flow waveform patterns, normal reference values for
haemodynamic parameters and potential clinical applications for both arterial and
venous flow information (umbilical artery, descending aorta, middle cerebral
artery, umbilical vein, inferior vena cava, ductus venosus) and atrioventricular
valves. Particular emphasis is devoted to the venous return to the heart.
Alterations in venous waveforms, particularly in the ductus venosus, are
correlated with the pathophysiology of some fetal diseases and are suggested as a
promising tool for the screening of cardiac impairment and as an alternative
method for fetal biophysical surveillance.
PMID- 10782577
TI - Cost-effective infertility care.
AB - Cost-effective healthcare has become a principal paradigm in all areas of
medicine. In order to establish cost-effective care, clinical outcomes under
various cost conditions have to be examined. Such a process cannot be static
since it has to consider ever evolving treatments and outcome results. In
infertility, the evaluation of cost-effective care should be simpler than in most
other areas of medicine since treatment end-points are easily defined.
Nevertheless, the field is lagging in the establishment of cost-effective
treatment algorithms. In this review, an effort is made to define the current
state of the art of cost effective infertility care, to suggest steps that can be
taken to drive the process forward and to encourage the introduction of even
limited processes to further the concept of outcome-dependent cost assessment
within a practice setting. The limited availability of resources mandates their
judicious use throughout medicine. In a field like infertility, by many (rightly
or wrongly) perceived as 'elective', the judicious use of resources seems even
more necessary since it would permit the treatment of larger patient populations
than have currently access to care without further expense to third-party
payments.
PMID- 10782578
TI - Leukotrienes in gynaecology: the hypothetical value of anti-leukotriene therapy
in dysmenorrhoea and endometriosis.
AB - The lipoxygenase products (leukotrienes) have been demonstrated in many mammalian
tissues including humans. They are widely distributed in the lungs, gut, uterus,
kidneys, skin, heart and the liver. Their roles as mediators of inflammation have
made them therapeutic targets. Significant amounts of leukotrienes have been
demonstrated in the endometrium of women with primary dysmenorrhoea who do not
respond to treatment with anti-prostaglandins. Also, in endometriosis, cytokines,
which can initiate the cascade for the biosynthesis of leukotrienes, have been
shown to be elevated. It is estimated that 10-30% of patients with painful
periods fail to respond to prostaglandin (PG) synthetase inhibitors. Of adult
females approximately 40% have painful menstruation and 10% of these are
incapacitated for 1-3 days per month, and approximately 10% of women aged between
15-45 years suffer from endometriosis, which is a significant cause of
infertility. Leukotriene receptor antagonists have recently been licensed for the
treatment of asthma in the UK. In this review, we present the case for the
potential use of these products in the management of primary dysmenorrhoea
(especially in patients who are not responding to the traditional treatment using
PG synthetase inhibitors) and possibly also in cases of endometriosis.
PMID- 10782579
TI - Survival of Acinetobacter on three clinically related inanimate surfaces.
PMID- 10782580
TI - Creutzfeldt-Jakob disease: management of accidental contamination of
neurosurgical instruments, pathology equipment, and solutions.
PMID- 10782581
TI - Disinfection of hospital laundry using ozone: microbiological evaluation.
PMID- 10782582
TI - Impact of nosocomial infections on outcome: myths and evidence.
PMID- 10782583
TI - Reasons that healthcare workers decline influenza vaccination in a New Zealand
hospital environment.
PMID- 10782584
TI - Risk factors for nosocomial infection in a high-risk nursery.
PMID- 10782585
TI - Once MRSA, always MRSA? Setting up a hospital preadmission questionnaire.
PMID- 10782586
TI - Good antimicrobial stewardship in the hospital: fitting, but flagrantly flagging.
PMID- 10782587
TI - Practices to improve antimicrobial use at 47 US hospitals: the status of the 1997
SHEA/IDSA position paper recommendations. Society for Healthcare Epidemiology of
America/Infectious Diseases Society of America.
AB - OBJECTIVE: To determine the status of programs to improve antimicrobial
prescribing at select US hospitals. DESIGN: Cross-sectional survey. PARTICIPANTS
AND SETTING: Pharmacy and infection control staff at all 47 hospitals
participating in phase 3 of Project Intensive Care Antimicrobial Resistance
Epidemiology. RESULTS: All 47 hospitals had some programs to improve
antimicrobial use, but the practices reported varied considerably. All used a
formulary, and 43 (91%) used it in conjunction with at least one of the other
three antimicrobial-use policies evaluated: stop orders, restriction, and
criteria-based clinical practice guidelines (CPGs). CPGs were reported most
commonly (70%), followed by stop orders (60%) and restriction policies (40%).
Although consultation with an infectious disease physician (70%) or pharmacist
(66%) was commonly used to influence initial antimicrobial choice, few (40%)
reported a system to measure compliance with these consultations. CONCLUSIONS: In
most hospitals surveyed, practices to improve antimicrobial use, although
present, were inadequate based on recommendations in a Society for Healthcare
Epidemiology of America and Infectious Disease Society of America joint position
paper. There is room to improve antimicrobial-use stewardship at US hospitals.
PMID- 10782588
TI - Nosocomial infections in pediatric patients: a European, multicenter prospective
study. European Study Group.
AB - OBJECTIVES: To determine the site and bacterial epidemiology of nosocomial
infections (NIs) in children. DESIGN: 6-month prospective study with periodic
chart review during hospitalization using a uniform prospective questionnaire in
each unit, analyzed at a coordinating center. SETTING: 20 units in eight European
countries: 5 pediatric intensive care units (PICUs), 7 neonatal units, 2
hematology-oncology units, 8 general pediatric units. PARTICIPANTS: All children
hospitalized during the study period with an NI according to Centers for Disease
Control and Prevention criteria. RESULTS: The overall incidence of NI was 2.5%,
ranging from 1% in general pediatric units to 23.6% in PICUs. Bacteria were
responsible for 68% (gram-negative bacilli, 37%; gram-positive cocci, 31%),
Candida for 9%, and viruses for 22% of cases. The proportion of lower respiratory
tract infections was 13% in general pediatric units and 53% in PICUs. Bloodstream
infections were most frequent in neonatal units (71% of NIs) and were associated
with a central venous catheter in 66% of cases. Coagulase-negative Staphylococcus
(CNS) was the main pathogen. Eleven percent of NI were urinary tract infections.
Gastrointestinal infections were most commonly viral and accounted for 76% of NIs
in general pediatric units. The prevalence of antimicrobial resistance depended
on the type of unit. The highest rates were observed in PICUs: 26.3% of
Staphylococcus aureus and 89% of CNS were methicillin-resistant, and 37.5% of
Klebsiella pneumoniae had an extended-spectrum beta-lactamase. Mortality due to
NI was 10% in PICUs and 17% in neonatal units. CONCLUSIONS: We found large
differences in NI frequency and microbial epidemiology in this European study.
Viruses were the main pathogens in general pediatrics units. Catheter-related
sepsis and CNS were frequent in newborns. A high frequency of multiresistant
bacteria was observed in some units. Clinical monitoring of NIs and bacterial
resistance profiles are required in all pediatric units.
PMID- 10782589
TI - Comparison of higher-dose intradermal hepatitis B vaccination to standard
intramuscular vaccination of healthcare workers.
AB - OBJECTIVE: To compare the immunogenicity of hepatitis B vaccine administered via
intradermal (ID) versus intramuscular (IM) route. METHODS: Subjects chose either
to specify the route of immunization or to undergo random allocation to
vaccination by the ID (0.15 mL) or the IM (1.0 mL) route. Yeast-derived
recombinant hepatitis B vaccine was given at 0, 30, and 180 days. Hepatitis B
surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) were measured by
microparticle enzyme immunoassay. RESULTS: 763 subjects were enrolled. Baseline
screening identified 65 subjects (8%) who were positive for HBsAb or HBcAb.
Vaccination was completed by 590 (85%) of 698 enrollees (370 ID, 220 IM).
Seroconversion rates (geometric mean titers [GMT]>0 IU/mL HBsAb) for those
vaccinated ID were 99% and 96% for screening at 9 months and 1 year post
vaccination, respectively; subjects vaccinated intramuscularly had similar rates
of 95% and 96%. Seropositivity rates (GMT > or = 10 IU/mL HBsAb) showed a similar
pattern, with 95%, 92%, and 73% at 9 months and 1 and 2 years, respectively, for
those vaccinated ID, and 94%, 93%, and 81% for those having IM vaccination. GMT
for HBsAb was significantly higher for individuals vaccinated IM than for those
vaccinated ID (P<.0001). The GMT ratio for the IM and ID routes decreased over
time, being 9.3 at 9 months, 7.8 at 1 year, and 5.9 at 2 years. An unanticipated
side effect of intradermal vaccination was skin discoloration at injection sites,
which persisted for at least 2 years postvaccination. Two thirds (112/166) of
respondents reported that they would have selected the ID route despite the
discoloration. CONCLUSIONS: Higher-dose ID vaccination (3 vs 1 microg per
injection) uses one sixth of the dose required for standard IM vaccination. It is
a cost-effective way to vaccinate populations against hepatitis B virus, but the
long-term efficacy of the ID route must still be investigated.
PMID- 10782590
TI - Evidence of delays in transferring patients with methicillin-resistant
Staphylococcus aureus or vancomycin-resistant Enterococcus to long-term-care
facilities.
AB - This retrospective case-control study examined whether there was a difference in
length of time awaiting long-term-care placement for patients identified as
having methicillin-resistant Staphylococcus aureus or vancomycin-resistant
Enterococcus compared to controls. Thirty-nine patients with methicillin
resistant Staphylococcus aureus or vancomycin-resistant Enterococcus waited for
placement an average of 61 days longer than controls (P<.0002). The average
number of requests for placement was 2.5 compared to 1.7 for controls (P=.015).
PMID- 10782591
TI - The incidence and risk factors of ventilator-associated pneumonia in a Riyadh
hospital.
AB - We report the incidence of, and risk factors for, ventilator-associated pneumonia
(VAP) at the King Fahad National Guard Hospital. Of the 202 patients studied, 41
(25.2%) had VAP. The incidence density was 16.8/1,000 person-days of ventilation.
Variables significantly associated with VAP were serious injury from motor
vehicle accident, enteral feeding, and length of ventilation. The avoidance of
unnecessary enteral nutrition could help to reduce VAP.
PMID- 10782592
TI - O2 in Y2K: not an airtight case.
PMID- 10782593
TI - Diagnostic tests: distinguishing good tests from bad and even ugly ones.
AB - This article focuses on the selection and interpretation of diagnostic tests,
emphasizing the importance of understanding how their mathematical parameters
affect the information they provide in various settings. The utility and
limitations of sensitivity, specificity, predictive value, and receiver operating
characteristic (ROC) curves are discussed using catheter-related bloodstream
infections as an example. ROC curves have been used for selecting optimal cutoff
values for a positive result and for selecting among several alternative
diagnostic tests. For example, 16 different tests have been proposed for
diagnosis of catheter-related bloodstream infection; ROC analysis provides an
effective way to determine which test offers the best overall performance.
PMID- 10782594
TI - Attitudes of Finnish dog-owners about programs to control canine genetic
diseases.
AB - A mailed questionnaire survey was done to study dog-owners' knowledge of canine
inherited diseases and the present screening and control programs in Finland, as
well as to study the importance of health-related matters and well-being to dog
owners. The purpose was also to study the owners' role in programs and the
influence of health and well-being in their decision-making process and choices
when purchasing a puppy. This study showed that dog-owners highly valued health
related matters and well-being. The present programs were considered to have a
positive effect on the prevention of canine inherited diseases. Dog-owners
estimated that their own knowledge could be better but they believed in
veterinarians' and dog-breeders' ability to inform them. Inherited skeletal and
ocular diseases were thought to be important to canine well-being; the importance
of other diseases or behaviour problems was assessed to be lower. In choosing a
suitable breed, behaviour and temperament were the most-important factors but
health-related matters were essential in actually choosing a puppy's breeder and
the litter. Well-being and health were also considered very important to the
image of the dog hobby.
PMID- 10782595
TI - Attitudes of Finnish dog-breeders about programs to control canine genetic
diseases.
AB - A questionnaire was mailed to 320 Finnish dog-breeders to study breeders'
knowledge of canine inherited diseases and of the present screening and control
programs in Finland. The purpose was also to study the breeders' attitudes about
and compliance with such programs. Breeders estimated that their knowledge was
quite good, and they also believed in their ability to influence other groups and
to promote the programs. The present programs were considered to have a positive
effect on the prevention of canine inherited diseases, but information given to
breeders and other key groups could produce even better results. Inherited
skeletal and ocular diseases were thought to be important to canine well-being;
the importance of other diseases was assessed to be lower.
PMID- 10782596
TI - Risk factors for fecal shedding of Salmonella in 91 US dairy herds in 1996.
AB - In 1996, data on management practices used on US dairy operations were collected
and analyzed for association with fecal shedding of Salmonella by dairy cows. A
total of 4299 fecal samples from 91 herds was cultured for Salmonella isolation.
Herd-size (adjusted odds ratios (OR) = 5.8, 95% CI 1.1, 31.3), region (OR = 5.7,
CI 1.4, 23.5), use of flush water systems (OR = 3.5, CI 0.9, 14.7), and feeding
brewers' products to lactating cows (OR = 3.4, CI 0.9, 12.9) were identified as
the most important predictive risk factors. The population attributable risks
(PARs) for herd-size, region, flush water system, and feeding brewers' products
to lactating cows were 0.76, 0.46, 0.37, and 0.42, respectively. The estimated
PAR for all four risk factors combined was 0.95. The effects of these factors
need to be more-closely evaluated in more-controlled studies, in order to develop
intervention programs that reduce Salmonella shedding.
PMID- 10782597
TI - Time-space clustering of reported blowfly strike in Queensland sheep flocks.
AB - The reported occurrence of blowfly strike in 57 sheep flocks in Queensland,
Australia, was investigated for time-space clustering in an exploratory study
using Knox's method. Flystrike occurrence peaked in late spring and early summer,
with an additional late-autumn peak in southern-Queensland flocks. A total of
1596 case-pairs was examined. Significant clustering (P = 0.07) was only detected
for case-pairs occurring within 3 months and 150 km of each other; 164 case-pairs
were declared close compared to an expectation of 151. We suggest that factors
common to a district (such as rainfall and temperature) are responsible for
clustering of flystrike in Queensland.
PMID- 10782598
TI - A clinical trial to evaluate the effects of flumethrin or ivermectin treatment on
hemoparasites, gastrointestinal parasites, conception and daily weight gain in a
dairy farm in Japan.
AB - A clinical trial was performed to compare the effects of flumethrin and
ivermectin treatments of grazing heifers at one farm in central Japan. 64 heifers
were randomly allocated into two groups. Flumethrin (1 mg/kg pour on) was applied
approximately once every 3 weeks to heifers in one group and heifers in the
second group were injected approximately once every month with ivermectin (200
microg/kg; id). Between groups, no significant differences were detected in the
proportions of animals that showed parasitemia of Theileria sergenti and
conception risks. Significantly lower average log-transformed nematode-egg counts
and higher average daily weight gain were observed in the ivermectin-treated
group. Animals with higher body weight at the start of grazing and lower log
transformed total nematode-egg and coccidia-oocyst counts had higher odds of
conceiving. Animals with ivermectin treatment, lower body weight at the start of
grazing and lower log-transformed coccidia-oocyst count had higher daily weight
gain. Ivermectin may be more useful in this farm because of the higher
productivity for cattle and lower cost for its usage.
PMID- 10782599
TI - Use of a non-linear spline regression to model time-varying fluctuations in
mammary-secretion element concentrations of periparturient mares in Michigan,
USA.
AB - A study was designed to model the fluctuations of nine specific element
concentrations in mammary secretions from periparturient mares over time. During
the 1992 foaling season, serial samples of mammary secretions were collected from
all 18 pregnant Arabian mares at the Michigan State University equine teaching
and research center. Non-linear regression techniques were used to model the
relationship between element concentration in mammary secretions and days from
foaling (which connected two separate sigmoid curves with a spline function);
indicator variables were included for mare and mare parity. Element
concentrations in mammary secretions varied significantly during the
periparturient period in mares. Both time trends and individual variability
explained a significant portion of the variation in these element concentrations.
Multiparous mares had lower concentrations of K and Zn, but higher concentrations
of Na. Substantial serial and spatial correlation were detected in spite of
modeling efforts to avoid the problem. As a result, p-values obtained for
parameter estimates were likely biased toward zero. Nonetheless, results of this
analysis indicate that monitoring changes in mammary-secretion element
concentrations might reasonably be used as a predictor of impending parturition
in the mare. In addition, these results suggest that element concentrations
warrant attention in the development of neonatal milk-replacement therapies. This
study demonstrates that non-linear regression can be used successfully to model
time-series data in animal-health management. This approach should be considered
by investigators facing similar analytical challenges.
PMID- 10782600
TI - EMSC partnership for children: National Association of EMS Physicians model
pediatric protocols.
PMID- 10782601
TI - Usage of emergency medical services by children with special health care needs.
AB - OBJECTIVE: To describe the usage of emergency medical services (EMS) by children
with special health care needs (CSHCN). METHODS: All EMS runs and related
hospital records for children aged 0-17 years in Utah in 1991-92 were linked. The
CSHCN status was determined from ICD-9 diagnoses using three available
definitions. The amounts of EMS usage were compared between CSHCN and other
children. A pediatric intensive care practitioner determined CSHCN status by
chart review for 915 children transported by EMS to a pediatric tertiary care
hospital, and his classification was compared with the CSHCN status assigned by
the three ICD-9-based definitions. RESULTS: The three definitions assigned CSHCN
status for 2% to 24% of children using EMS. When compared with other children,
CSHCN were more likely to be admitted to the hospital, more likely to use EMS for
transfer between health care facilities, and more likely to receive prehospital
procedures such as intravenous therapy. In the group of children whose charts
were reviewed individually, one ICD-9-based definition most closely agreed to
determination of CSHCN status by a pediatric intensive care practitioner.
CONCLUSIONS: Children with special health care needs who use EMS are more likely
to receive advanced life support service, to receive prehospital procedures, and
to be transferred from one health care facility to another. There is need for a
specific and measurable definition of CSHCN that can be applied to existing
health data.
PMID- 10782602
TI - U.S. Army air ambulance operations in El Paso, Texas: a descriptive study and
system review.
AB - OBJECTIVES: To analyze a high-volume military air ambulance unit and review the
U.S. Army air medical transport system and Military Assistance to Safety and
Traffic (MAST) program. METHODS: The setting was a remote medical system with
numerous ground emergency medical services. All patients transported between
January 1, 1996, and February 28, 1998, were included. Patients who were dead on
scene or for whom records were unavailable were excluded. A retrospective review
of transport and available inpatient records was conducted. RESULTS: Five hundred
seventeen patients were transported during the study period; 461 patients met
inclusion criteria (89%). Of these, 70% were classified as trauma; 30% possessed
medical or other surgical diagnoses. Prehospital responses numbered 71.6%, while
28.4% were interhospital transfers. Missions averaged 23.4 minutes per flight,
with no major aircraft mishaps. Prehospital utilization review showed appropriate
use; 35% of interhospital trauma and 11% of interhospital nontrauma missions were
staffed inadequately by these criteria. Time intervals, procedures, and program
impact are discussed. CONCLUSION: This and similar units participating in the
MAST program provide effective air transport in settings underserved by civilian
programs. Quality and wartime readiness could be improved by centralized medical
direction, treatment and transfer protocols, and enhanced training of medics.
Further investigations of the clinical impact of advanced training and a two
medic aircrew model are warranted.
PMID- 10782603
TI - Study design and outcomes in out-of-hospital emergency medicine research: a ten
year analysis.
AB - OBJECTIVE: Lack of rigorous study design and failure to follow diverse patient
outcomes have been identified as critical gaps in the medical research
literature. This study sought to determine whether similar gaps exist in the
literature for out-of-hospital interventions. METHODS: A computerized MEDLINE
search was conducted for the ten-year period 1985 through 1994 using the MeSH
terms "emergency medical services," "prehospital," and "transportation of
patients." Using a standard abstraction form, two investigators independently
analyzed articles meeting these inclusion criteria: original research evaluating
an out-of-hospital intervention and measuring a patient outcome. Study design was
categorized in order of scientific rigor, moving from case series to randomized
trial. Measures of outcomes were classified into the six Ds: death, disease,
discomfort, disability, dissatisfaction, and debt (cost). RESULTS: Interobserver
agreement was high (kappa = 0.80). For the ten-year period, 3,686 titles, 1,454
abstracts, and 373 articles were examined serially; all 285 studies meeting
inclusion criteria were analyzed. Case series (44%) was the most frequently used
design, while only 15% were randomized trials. The majority of the studies were
retrospective (53%). A single outcome was assessed in 45% of the articles; 41%
measured two outcomes, 13% three outcomes, and 1% four outcomes. Death and
disease were the most common outcomes evaluated. Disability, debt, discomfort,
and dissatisfaction were infrequently measured. CONCLUSION: Studies of out-of
hospital emergency medical interventions are limited in the scientific rigor of
study design and the diversity of patient outcomes measured. To adequately assess
the effectiveness of out-of-hospital care, efforts should be directed toward
strengthening study designs and examining the full range of patient outcomes.
PMID- 10782604
TI - Justification of pulse oximeter costs for paramedic prehospital providers.
AB - OBJECTIVE: To assess the potential cost savings of decreasing prehospital oxygen
utilization by using pulse oximetry to identify those patients who do not require
supplemental oxygen. METHODS: A prospective, controlled trial was performed
comparing rates of oxygen utilization by paramedics with and without access to
pulse oximetry. Consecutive patient encounters over a ten-week period were
randomized by day of presentation. Pulse oximeters were made available on
alternate days. On those days, patients whose oxygen saturations were less than
95% were treated with supplemental oxygen. RESULTS: The use of pulse oximeters
incurred a saving of 0.14 "D"-size oxygen cylinders per call. For the authors'
service, this translates to a potential saving of $2,324 (C)/vehicle/year.
CONCLUSION: For regions with patient demographics similar to the authors', the
initial cost of providing paramedics with pulse oximeters may be offset by
savings in oxygen consumption. A formula is provided to allow individual
ambulance services to calculate the potential savings for their service.
PMID- 10782605
TI - Appropriateness of intravenous cannulation by paramedics: a London study.
AB - INTRODUCTION: The number of patients undergoing intravenous (IV) cannulation by
paramedics has increased dramatically over recent years in the UK. Treatment
protocols for cannulation in the field are loosely defined. Variation in practice
may lead to patients' receiving differential treatment according to customary
practice, rather than according to their clinical conditions. OBJECTIVES: To
explore variations in practice and assess level of appropriatenesss of IV
cannulation by London Ambulance Service (LAS) paramedics; to revise treatment
protocols and work toward clinical guidelines, if indicated by study findings.
METHODS: Skill usage data were analyzed for all LAS paramedics for 1995-96. All
patients who were IV-cannulated and transported to three hospitals by LAS during
March 1996 were identified. A panel of accident and emergency (A&E) and
prehospital specialists judged each case for appropriateness. RESULTS: Variation
during the year was wide, with a range of 1 to 221 (mean 47) patients cannulated
per paramedic, although the majority showed some consistency in frequency of
skill usage. A sample of 183 cases was reviewed. The majority judged 149 (81.4%)
to be appropriate, although there was considerable disagreement between reviewers
(kappa = 0.43, p < 0.001). Data suggested that those paramedics who cannulate
more frequently cannulated less appropriately during the study period (lowest
30%: 73.9% appropriate; highest 30%: 45.8% appropriate, p = 0.05). CONCLUSION:
Despite wide variation between paramedics, the panel judged overall
appropriateness of cannulation to be high. The audit advisory group judged that
new clinical guidelines might not achieve an improvement in practice and were not
supported by study findings. It was recommended that variations be addressed
through individual practice review.
PMID- 10782606
TI - An assessment of paramedic performance during invasive airway management.
AB - OBJECTIVE: To assess the performance of paramedics, in a newly-initiated
prehospital program, during invasive airway management. METHODS: An audit of
paramedic call reports for a 12-month period from January to December 1997 was
performed. Call reports that documented invasive airway management were retrieved
and relevant data were extracted using a preformulated data-entry form. RESULTS:
Paramedics attempted tracheal intubation in 453 patients and were successful in
408 (90.1%); 331 of the patients were in cardiopulmonary arrest with vital signs
absent (VSA), 101 had medical emergencies, and 21 had trauma-related problems. In
the VSA cohort, the tracheas of 96% of the patients were intubated successfully;
80.1% on the first attempt, 10.6% on the second, 4.5% on the third, and 0.9%
after more than three attempts. In the medical cohort, the tracheas of 74.3% of
the patients were intubated; 60.4% on the first attempt, 11.9% on the second, and
2.9% on the third. In the trauma cohort, 71.4% of the intubations were
successful; 66.6% on the first attempt, 26.6% on the second, and 6.6% on the
third. There was a difference (p < 0.001) in the incidence of successful
intubations comparing the VSA cohort with the medical/trauma cohorts. There was
also a difference (p < 0.001) between the success rate for nasal intubations (43
of 68, 63% of patients successfully intubated) and that for oral intubation (365
of 385, 94% of patients). CONCLUSION: This study demonstrated a difference in the
paramedics' success rates for tracheal intubation in VSA patients compared with
those with preserved airway reflexes and a lower success rate for nasal vs oral
tracheal intubation. These differences may be due to inadequate training,
technical difficulties experienced in the field, or lack of sufficient exposure
to medical/trauma scenarios to gain management experience. Future training to
address these issues, both in the initial training phase and in the continuing
education program, may be beneficial in improving performance.
PMID- 10782607
TI - The laryngeal tube: a new adjunct for airway management.
AB - INTRODUCTION: A prototype of the laryngeal tube was tested for simple and
reliable use for ventilation in a mannequin. One possible use of this tube will
be the management of the difficult airway. In spite of blind insertion, an
inadvertent tracheal positioning should not occur due to the form of the tube. A
pharyngeal cuff provides a proximal seal of the airway, while an esophageal cuff
seals the airway distally and prevents aspiration of gastric contents. A ventral
opening between both cuffs is used for ventilation. OBJECTIVE: To examine the
reliability of the laryngeal tube for airway management in a mannequin. METHODS:
Fifty physicians and nurses were included in this study and inserted the
laryngeal tube blindly during ten consecutive attempts in an advanced life
support mannequin. All participants used the laryngeal tube for the first time.
RESULTS: During 500 insertions of the tube, correct placement and sufficient
ventilation were achieved 478 times in the first attempt (95.6%); 18 times
(3.6%), inflating the proximal balloon with an additional 50 mL of air led to
sufficient ventilation. In four attempts (0.8%), sufficient ventilation was still
not possible due to the tube's not being placed deep enough (according to the
printed ring marks on the tube). In each case, the tube was placed correctly in
the following attempt. Neither a tracheal intubation nor ventilation of the
stomach could be observed. The average time for positioning the laryngeal tube
was 27.15 seconds for all 500 attempts (average time of the 50 participants for
the tenth attempt: 23.85 seconds). CONCLUSION: The laryngeal tube may be a fast,
reliable, and easy device for airway management. Further research is necessary.
PMID- 10782608
TI - A new system for sternal intraosseous infusion in adults.
AB - BACKGROUND: Intraosseous (IO) infusion provides an alternative route for the
administration of fluids and medications when difficulty with peripheral or
central lines is encountered during resuscitation of critically ill and injured
patients. OBJECTIVE: To report the first 50 uses of a new system for emergency IO
infusion into the sternum in adults, the Pyng F.A.S.T.1 IO infusion system.
METHODS: Six emergency departments and five prehospital emergency medical
services (EMS) sites in Canada and the United States provided clinical and/or
research data on their use of the IO system in a pilot study of success rates,
insertion times, and complications. Indications for use included adult patient,
urgent need for fluids or medications, and unacceptable delay or inability to
achieve standard vascular access. A basic data set was standardized for all
sites, and some sites collected additional data. RESULTS: The overall success
rate for achieving vascular access with the system was 84%. Success rates were
74% for first-time users, and 95% for experienced users. Failure to achieve
vascular access occurred most frequently in patients (5 of 9) described
subjectively by the user as "very obese," in whom there was a thick layer of
tissue overlying the sternum. Mean time to achieve vascular access was 77
seconds. Flow rates of up to 80 mL/min were reported for gravity drip, and more
than 150 mL/min by syringe bolus. Pressure cuffs were also used successfully,
although fluid rate was controlled by clamping the line. Further research on flow
rates is needed. No complications or complaints were reported at two-month follow
up. CONCLUSION: These early data indicate that sternal IO infusion using the new
F.A.S.T.1 IO system may provide rapid, safe vascular access and may be a useful
technique for reducing unacceptable delays in the provision of emergency
treatment.
PMID- 10782609
TI - Training paramedics: emergency care for children with special health care needs.
AB - OBJECTIVE: To enhance knowledge and comfort related to the emergency care of
children with special health care needs (CSHCN) through an innovative continuing
education program for paramedics. METHODS: A self-study program presenting in
depth information about common problems that affect the assessment and management
of a child's airway, breathing, circulation, disability, and environment
(ABCDEs), regardless of the child's diagnosis, was developed. This program used a
manual, a video, practice mannequins, and skills evaluations to teach skills to
paramedics employed at a municipal fire department. RESULTS: Pre- and
posttraining surveys found that the paramedics were significantly more
comfortable with the assessment and management of CSHCN after the completion of
the self-study program, with a pretraining average of 2.83 and posttraining
average of 4.20 on a five-point Likert-type scale, t(37) = 12.87, p < 0.001. A
skills evaluation showed that skills performance varied widely across 21 skills,
ranging from skills mastery to low skills knowledge. On the posttraining survey,
between 74% and 94% of the paramedics rated each topic (tracheostomies,
indwelling central venous catheters, cerebrospinal fluid shunts, gastrostomies,
child abuse, and latex allergy) as applicable to their practices as paramedics.
CONCLUSION: Given the growing population of CSHCN, it is important to provide
specialized education to increase an EMS provider's preparedness to respond to
emergency situations involving children with special health care needs.
PMID- 10782610
TI - The use of emergency medical dispatch protocols to reduce the number of
inappropriate scene responses made by advanced life support personnel.
AB - OBJECTIVES: To determine whether implementation of an emergency medical dispatch
(EMD) system would reduce the rate of inappropriate advanced life support (ALS)
utilization, and enable more accurate identification of those patients requiring
ALS care. METHODS: An emergency medical services (EMS) site providing basic life
support (BLS) and ALS care to a population of 200,000 served as the study site
for calendar year 1996. This study compared the prospective identification of
patients as ALS or BLS using EMD with that using chief complaint-based dispatch
criteria. Each patient served as his or her own control. The ALS or BLS priority
was assigned using both chief complaint and EMD criteria. Chief complaint-based
dispatching meant that all patients with preestablished chief complaints received
ALS without further triage questions, while EMD allowed the dispatchers to
question callers using a scripted set of questions. The outcome measures included
the number of calls categorized as ALS or BLS, the number of calls cancelled by
BLS, and the number of ALS calls released to BLS care. Yates-corrected chi-square
was used for statistical analysis. RESULTS: There were 11,174 patients enrolled.
The use of EMD was associated with a significant decrease in the proportion of
calls designated as ALS (44.7% vs 55.8%, p < 0.0001), as well as a significant
decrease in the number of ALS responses cancelled by BLS (9.2% vs 23.8%, p <
0.0001) and patients released to BLS by medical control (4.7% vs 7.3%, p <
0.0001). CONCLUSIONS: Implementation of an EMD system significantly decreased
inappropriate ALS dispatching, as defined by decreased rate of ALS cancellations
and BLS releases. Further study is needed to see whether other EMD dispatch
models may further refine ALS dispatch.
PMID- 10782611
TI - Termination of resuscitation in the prehospital setting for adult patients
suffering nontraumatic cardiac arrest. National Association of EMS Physicians
Standards and Clinical Practice Committee.
AB - The National Association of EMS Physicians (NAEMSP) supports out-of-hospital
termination of resuscitation for adult, nontraumatic cardiac arrest patients who
have not responded to full resuscitative efforts. The following factors should be
considered in establishing termination of resuscitation protocols: 1) Termination
of resuscitation may be considered for any adult patient who suffers sudden
cardiac death that is likely to be medical. 2) Unwitnessed cardiac arrest with
delayed initiation of cardiopulmonary resuscitation (CPR) beyond 6 minutes and
delayed defibrillation beyond 8 minutes has a poor prognosis. 3) In the absence
of "do not resuscitate" or advanced directives, a full resuscitative effort
including CPR, definitive airway management, medication administration,
defibrillation if necessary, and at least 20 minutes of treatment following
Advanced Cardiac Life Support (ACLS) guidelines should be performed prior to
declaring the patient dead. 4) A patient whose rhythm changes to, or remains in,
ventricular fibrillation or ventricular tachycardia should have continued
resuscitative efforts. Patients in asystole or pulseless electrical activity
should be strongly considered for out-of-hospital termination of resuscitation.
5) Logistic factors should be considered, such as collapse in a public place,
family wishes, and safety of the crew and public. 6) Online medical direction
should be established prior to termination of resuscitation. The decision to
terminate efforts should be a consensus between the on-scene paramedic and the
online physician. 7) The on-scene providers and family should have access to
resources, such as clergy, crisis workers, and social workers. 8) Quality review
is necessary to ensure appropriate application of the termination protocol, law
enforcement notification, medical examiner or coroner involvement, and family
counseling.
PMID- 10782612
TI - Refractory asystole and death following the prehospital administration of
adenosine.
PMID- 10782613
TI - Misplaced tubes.
PMID- 10782614
TI - Reconstruction algorithm for polychromatic CT imaging: application to beam
hardening correction.
AB - This paper presents a new reconstruction algorithm for both single- and dual
energy computed tomography (CT) imaging. By incorporating the polychromatic
characteristics of the X-ray beam into the reconstruction process, the algorithm
is capable of eliminating beam hardening artifacts. The single energy version of
the algorithm assumes that each voxel in the scan field can be expressed as a
mixture of two known substances, for example, a mixture of trabecular bone and
marrow, or a mixture of fat and flesh. These assumptions are easily satisfied in
a quantitative computed tomography (QCT) setting. We have compared our algorithm
to three commonly used single-energy correction techniques. Experimental results
show that our algorithm is much more robust and accurate. We have also shown that
QCT measurements obtained using our algorithm are five times more accurate than
that from current QCT systems (using calibration). The dual-energy mode does not
require any prior knowledge of the object in the scan field, and can be used to
estimate the attenuation coefficient function of unknown materials. We have
tested the dual-energy setup to obtain an accurate estimate for the attenuation
coefficient function of K2 HPO4 solution.
PMID- 10782615
TI - Volume rendering quantification algorithm for reconstruction of CT volume
rendered structures: Part I. Cerebral arteriovenous malformations.
AB - Volume rendering is a visualization technique that has important applications in
diagnostic radiology and in radiotherapy but has not achieved widespread use due,
in part, to the lack of volumetric analysis tools for comparison of volume
rendering to conventional visualization techniques. The volume rendering
quantification algorithm (VRQA), a technique for three-dimensional (3-D)
reconstruction of a structure identified on six principal volume-rendered views,
is introduced and described. VRQA involves three major steps: 1) preprocessing of
the partial surfaces constructed from each of six volume-rendered images; 2)
merging these processed partial surfaces to define the boundaries of a volume;
and 3) computation of the volume of the structure from this boundary information.
After testing on phantoms, VRQA was applied to CT data of patients with cerebral
arteriovenous malformations (AVM's). Because volumetric visualization of the
cerebral AVM is relatively insensitive to operator dependencies, such as the
choice of opacity transfer function, and because precise volumetric definition of
the AVM is necessary for radiosurgical treatment planning, it is representative
of a class of structures that is ideal for testing and calibration of VRQA. AVM
volumes obtained using VRQA are intermediate to those obtained using axial
contouring and those obtained using CT-correlated biplanar angiography (two
routinely used visualization techniques for treatment planning for AVM's).
Applications and potential expansions of VRQA are discussed.
PMID- 10782616
TI - Probabilistic modeling of single-trial fMRI data.
AB - This paper describes a probabilistic framework for modeling single-trial
functional magnetic resonance (fMR) images based on a parametric model for the
hemodynamic response and Markov random field (MRF) image models. The model is
fitted to image data by maximizing a lower bound on the log likelihood. The
result is an approximate maximum a posteriori estimate of the joint distribution
over the model parameters and pixel labels. Examples show how this technique can
used to segment two-dimensional (2-D) fMR images, or parts thereof, into regions
with different characteristics of their hemodynamic response.
PMID- 10782617
TI - Point-tracked quantitative analysis of left ventricular surface motion from 3-D
image sequences.
AB - We propose and validate the hypothesis that we can use differential shape
properties of the myocardial surfaces to recover dense field motion from standard
three-dimensional (3-D) image sequences (MRI and CT). Quantitative measures of
left ventricular regional function can be further inferred from the point
correspondence maps. The noninvasive, algorithm-derived results are validated on
two levels. First, the motion trajectories are compared to those of implanted
imaging-opaque markers of a canine model in two imaging modalities, where
subpixel accuracy is achieved. Second, the validity of using motion parameters
(path length and thickness changes) for detecting myocardial injury area is
tested by comparing algorithms derived results to postmortem analysis TTC
staining of myocardial tissue, where the achieved Pearson product-moment
correlation value is 0.968.
PMID- 10782618
TI - Consistency conditions and linear reconstruction methods in diffraction
tomography.
AB - Because an image can be reconstructed from knowledge of its Radon transform (RT),
the task of reconstructing an image is tantamount to that of estimating its RT.
Based upon the Fourier diffraction projection (FDP) theorem, from the statistical
perspective of unbiased reduction of image variance, we previously proposed an
infinite family of estimation methods for obtaining the RT from the scattered
data in diffraction tomography (DT). In this work, using the FDP theorem, we
define the diffraction Radon transform (DRT), which can be treated as the data
function in DT. Subsequently, using strategies similar to those that analyze the
consistency conditions on the exponential Radon transform in two-dimensional (2
D) single-photon emission computed tomography with uniform attenuation, we
studied the consistency condition on the DRT and we show that there is a
hierarchy of estimation methods that actually project the noisy data function
onto its consistency space in different ways. In terms of a weighted inner
product of the consistency and inconsistency parts of a noisy data function, we
further demonstrate that a subset of the family of estimation methods can be
interpreted as orthogonal projections onto the consistency space of the DRT. In
particular, the statistically suboptimal estimation method in the family
corresponds to an orthogonal projection associated with an ordinary inner product
of the consistency and inconsistency parts of a noisy data function.
PMID- 10782619
TI - An ultra-fast user-steered image segmentation paradigm: live wire on the fly.
AB - We have been developing general user steered image segmentation strategies for
routine use in applications involving a large number of data sets. In the past,
we have presented three segmentation paradigms: live wire, live lane, and a three
dimensional (3-D) extension of the live-wire method. In this paper, we introduce
an ultra-fast live-wire method, referred to as live wire on the fly, for further
reducing user's time compared to the basic live-wire method. In live wire, 3
D/four-dimensional (4-D) object boundaries are segmented in a slice-by-slice
fashion. To segment a two-dimensional (2-D) boundary, the user initially picks a
point on the boundary and all possible minimum-cost paths from this point to all
other points in the image are computed via Dijkstra's algorithm. Subsequently, a
live wire is displayed in real time from the initial point to any subsequent
position taken by the cursor. If the cursor is close to the desired boundary, the
live wire snaps on to the boundary. The cursor is then deposited and a new live
wire segment is found next. The entire 2-D boundary is specified via a set of
live-wire segments in this fashion. A drawback of this method is that the speed
of optimal path computation depends on image size. On modestly powered computers,
for images of even modest size, some sluggishness appears in user interaction,
which reduces the overall segmentation efficiency. In this work, we solve this
problem by exploiting some known properties of graphs to avoid unnecessary
minimum-cost path computation during segmentation. In live wire on the fly, when
the user selects a point on the boundary the live-wire segment is computed and
displayed in real time from the selected point to any subsequent position of the
cursor in the image, even for large images and even on low-powered computers.
Based on 492 tracing experiments from an actual medical application, we
demonstrate that live wire on the fly is 1.3-31 times faster than live wire for
actual segmentation for varying image sizes, although the pure computational part
alone is found to be about 120 times faster.
PMID- 10782620
TI - Computer-aided stereotactic functional neurosurgery enhanced by the use of the
multiple brain atlas database.
AB - This paper introduces a computer-aided atlas-based functional neurosurgery
methodology and describes NeuroPlanner, a software system which supports it.
NeuroPlanner provides four groups of functions: 1) data-related for data reading,
interpolation, reformatting, and image processing; 2) atlas-related for multiple
atlases reading, atlas-to-data global and local registrations, two-way anatomical
indexing, and multiple labeling in two and three dimensions; 3) atlas-data
exploration-related for three-dimensional (3-D) display and real-time
manipulation of cerebral structures, continuous navigation, two-dimensional (2
D), triplanar, 3-D presentations, and 2-D interaction in four views; and 4)
neurosurgery-related for targeting, trajectory planning, mensuration, simulating
the insertion of microelectrode, and simulating therapeutic lesioning. All
operations, excluding atlas and data reading, are real time. The combined
anatomical index of the multiple brain atlas database containing complementary 2
D and 3-D atlases has about 1000 structures per hemisphere, and over 400 sulcal
patterns. Neurosurgical planning with mutually preregistered multiple brain
atlases in all three orthogonal orientations is novel. The approach is validated
with 24 intraoperative and postoperative datasets for thalamotomies, thalamic
stimulations, pallidotomies, and pallidal stimulations. Its potential benefits
include increased accuracy of target definition, reduced time of the surgical
procedure by decreasing the number of tracts, facilitated planning of more
sophisticated trajectories, lowered cost by reducing the number of
microelectrodes used, reduced surgical complications, and the extra degree of
confidence given to the neurosurgeon.
PMID- 10782621
TI - Hypotony: What is it? How should we manage it?
PMID- 10782622
TI - Large diurnal fluctuations in intraocular pressure are an independent risk factor
in patients with glaucoma.
AB - PURPOSE: To study the risk associated with diurnal intraocular pressure (IOP)
variations in patients with open-angle glaucoma. PATIENTS AND METHODS: Sixty-four
patients (105 eyes) from the practices of two glaucoma specialists successfully
performed home tonometry with a self-tonometer five times a day for 5 days. All
patients had open-angle glaucoma and documented IOP below 25 mm Hg over a mean
follow-up period of 5 years. Baseline status and time to progression of visual
field loss were identified from the clinical charts. The level and variability of
diurnal IOP obtained using home tonometry were characterized. Risk of progression
was analyzed using a nonparametric time-to-event model, incorporating methods for
correlated outcomes. RESULTS: Although mean home IOP and baseline office IOP were
similar (16.4 +/- 3.6 mm Hg and 17.6 +/- 3.2 mm Hg, respectively), the average
IOP range over the 5 days of home tonometry was 10.0 +/- 2.9 mm Hg. Baseline
office IOP had no predictive value (relative hazard, 0.98). The diurnal IOP range
and the IOP range over multiple days were significant risk factors for
progression, even after adjusting for office IOP, age, race, gender, and visual
field damage at baseline (relative hazards [95% confidence intervals], 5.69
[1.86, 17.35] and 5.76 [2.21, 14.98]). Eighty-eight percent of patients in the
upper twenty-fifth percentile of IOP and 57% of patients in the lower twenty
fifth percentile progressed within 8 years. CONCLUSIONS: In patients with
glaucoma with office IOP in the normal range, large fluctuations in diurnal IOP
are a significant risk factor, independent of parameters obtained in the office.
Fluctuations in IOP may be important in managing patients with glaucoma.
Development of methods to control fluctuations in IOP may be warranted.
PMID- 10782623
TI - Crete, Greece glaucoma study.
AB - PURPOSE: To investigate the prevalence of primary open-angle glaucoma (POAG) in a
randomized sample of the inhabitants of the island of Crete. PATIENTS AND
METHODS: In 18 different villages in all four prefectures of the island of Crete,
patients were randomly selected from 1993 through 1998, and an in situ study was
accomplished. The sampling fraction (covered by the 1991 census) in each village
was approximately 5%. Patients were considered to have POAG when the morphologic
aspect of a glaucomatous optic disc was present, and/or a nerve fiber layer
defect and a visual field defect was present. The presence of Pseudoexfoliation
syndrome (PEX) and pseudoexfoliative glaucoma (PEXG) was also investigated.
RESULTS: The prevalence of glaucoma in Crete was 2.80%. Of those diagnosed with
POAG, 9.67% had an intraocular pressure (IOP) under 21 mm Hg, and 25.80% had PEX.
The prevalence of simple ocular hypertension without glaucoma was found in 6.58%
of the patients. The ratio of subjects with hypertensive glaucoma to those with
simple ocular hypertension was 1:2.6. CONCLUSION: The prevalence of POAG and
exfoliation glaucoma appears to be quite high in Crete. Further research will be
needed to set more accurate criteria for earlier diagnosis and to enable more
efficient organization of the health care system.
PMID- 10782625
TI - Diffuse and localized nerve fiber layer loss measured with a scanning laser
polarimeter: sensitivity and specificity of detecting glaucoma.
AB - PURPOSE: To differentiate normal from diseased retinal nerve fiber layers (NFL)
using a new method of analyzing polarimetry data that specifically targets
patterns of diffuse and localized NFL loss. METHODS: The NFL from a sample of 34
patients with primary open-angle glaucoma (POAG), 34 patients with ocular
hypertension, and 34 normal subjects were imaged using a scanning laser
polarimeter (GDx; Laser Diagnostic Technologies, Inc., San Diego, CA). Diffuse
loss was defined as a reduction in the peak-to-trough amplitude of the double
hump NFL pattern, and localized loss was defined as a lowering of the correlation
of thickness values between local regions shown previously to correspond in
normal subjects. RESULTS: Significant differences were found between the groups
of normal subjects, patients with hypertension, and patients for both the
amplitude and the correlational measures. The sensitivity and specificity
calculated using optimal criterion values were 94% and 91%, respectively.
CONCLUSIONS: These results suggest that NFL analysis targeting specific patterns
of loss may be beneficial for differentiating normal NFL patterns from diseased
NFL patterns, as well as for identifying patients at high risk.
PMID- 10782624
TI - Cost analysis of glaucoma medications.
AB - PURPOSE: To evaluate the yearly cost in 1998 of glaucoma medications to patients
and to the Health Plan at a university-affiliated teaching hospital with its own
health maintenance organization. MATERIALS AND METHODS: Data concerning Health
Plan glaucoma-medication prescriptions for 1998 were retrieved from the hospital
pharmacy database. RESULTS: The most costly medication per patient per year was
latanoprost (Xalatan; Pharmacia & Upjohn, Kalamazoo, MI [$337]), followed by
betaxolol hydrochloride (Betoptic-S; Alcon, Fort Worth, TX [$336]), dorzolamide
(Trusopt; Merck & Co., West Point, PA [$288]), brimonidine tartrate (Alphagan;
Allergan Pharmaceuticals, Irvine, CA [$260]), timolol maleate 0.5% in a gel
forming solution (Timoptic-XE 0.5%; Merck & Co., West Point, PA [$199]),
levobunolol hydrochloride (Betagan; Allergan Pharmaceuticals, Irvine, CA [$195]),
and generic timolol maleate 0.5% ($132). Cost per unit was greatest for Betoptic
S ($51), exceeding that of Trusopt ($43) and Xalatan ($43), Alphagan ($42),
Betagan ($38), Timoptic-XE 0.5% ($32), and timolol maleate 0.5% ($27).
CONCLUSION: Variability in the cost of medications may influence the long-term
medical management of glaucoma patients.
PMID- 10782626
TI - Electrophysiologic assessment of photoreceptor function in patients with primary
open-angle glaucoma.
AB - PURPOSE: Electroretinograms to high-intensity flashes were obtained to determine
the extent of rod and cone photoreceptor and postreceptor dysfunction in patients
with primary open-angle glaucoma. METHODS: Full-field flash electroretinograms
were obtained using brief high-intensity flashes. Dark-adapted (rod-dominated)
and light-adapted (cone-dominated) electroretinogram responses were recorded to a
"white" light as a function of flash intensity. The a-wave data were fitted with
a model based on photopigment transduction to obtain values for the parameters of
log Rmax (the maximum response) and log S (sensitivity). Oscillatory potentials
were measured to the cone-dominated high-intensity flashes. Standard clinical 30
Hz flicker electroretinogram responses were recorded using a Grass
photostimulator. RESULTS: Analysis of rod and cone a-wave data showed that log
Rmax and log S values were within the normal range in nearly all of the patients.
For some patients, oscillatory potentials were delayed beyond the normal range.
CONCLUSION: Our results provide little evidence for widespread photoreceptor
abnormalities in primary open-angle glaucoma.
PMID- 10782627
TI - Excisional bleb revision to correct overfiltration or leakage.
AB - OBJECTIVES: To evaluate the effectiveness of excisional revision of filtering
blebs for hypotony or leakage when more conservative measures have failed.
PATIENTS AND METHODS: Retrospective review of all patients who underwent
excisional revision of a filtering bleb for hypotony (intraocular pressure [IOP]
< 5 mm Hg) or leakage during a 3 year period. The revision consisted of excision
of the avascular bleb, mobilization of the surrounding conjunctiva, and suturing
of the conjunctiva at the limbus. RESULTS: Sixteen patients were included in the
study. The average age was 66.3 +/- 14.8 years (range, 39-83). Revision followed
trabeculectomy in 11 cases, combined phacoemulsification-trabeculectomy in three
cases, and inadvertent blebs in two cases. Five cases had bleb leaks without
hypotony, four cases had hypotony alone, and seven cases had both hypotony and a
bleb leak. Average follow-up after bleb revision was 25 +/- 11 months (range, 9
43). Average IOP increased from 3.8 +/- 5.6 mm Hg (range, 0-22) to 11.9 +/- 4.1
mm Hg (range, 3-18), with an average of 1.1 +/- 1.1 medication (range, 0-3). The
IOP at the last visit was < 15 mm Hg in all but two patients, with 10 of the 16
patients requiring medications. At the last follow-up examination, visual acuity
had improved > or = two lines in nine patients and was reduced two lines in one
patient. Five patients had early postoperative limbal wound leaks; resuturing was
required in one case. CONCLUSIONS: Excisional bleb revision is an effective
technique to correct hypotony or leakage after filtering surgery when other
methods have failed. Intraocular pressure control is often maintained with the
use of medications.
PMID- 10782628
TI - Long-term topical timolol and blood lipids: the Blue Mountains Eye Study.
AB - OBJECTIVES: To examine whether an association exists between long-term use of
topical timolol and blood lipids, including high-density lipoprotein cholesterol
(HDL-C), cholesterol, and triglycerides, among participants of the Blue Mountains
Eye Study. METHODS: From 1992 through 1994, a detailed medical and eye
examination was performed in 3,654 people aged 49 years or older, representing
82% of permanent residents in two postcode areas west of Sydney. Glaucoma and
ocular hypertension were diagnosed, and an ophthalmic history was taken,
including use of topical timolol. Fasting blood tests were performed in 89% of
subjects. Lipid levels were compared in subjects using topical timolol for at
least 1 year with those not using timolol, after excluding people using oral beta
blockers, topical beta1-selective agents, or oral lipid-lowering medications.
RESULTS: Analyses compared blood lipids of 63 people who had used topical timolol
for at least 1 year with 2,597 nonusers. No statistically significant differences
were found in any blood lipid mean levels between treated and untreated people,
after multivariate adjustment. However, subgroup analyses of men and women
separately showed that male timolol users had a mean value of HDL-C 0.13 mmol/L
(11%) lower then the mean value of male nonusers, while female timolol users had
a mean value of HDL-C 0.09 mmol/L (5%) higher than the mean for female nonusers.
There were no statistically significant associations between timolol treatment
duration and HDL-C or other lipid levels. Previously reported adverse effects of
oral beta-blockers on blood lipid levels were confirmed. CONCLUSIONS: These
population-based data suggest that long-term administration of topical timolol
for glaucoma or ocular hypertension can cause adverse effects on HDL-C in men,
but not in women. The magnitude of the effect in men was similar to that
previously described in a number of short-term studies.
PMID- 10782629
TI - Effect of latanoprost on intraocular pressure in steroid-induced glaucoma.
AB - PURPOSE: To study the effect of monotherapy with latanoprost 0.005% on
intraocular pressure (IOP) in a prospective nonrandomized clinical trial of
patients newly diagnosed with steroid-induced secondary open-angle glaucoma.
PATIENTS AND METHODS: Eight patients (16 eyes) with newly diagnosed steroid
associated secondary open-angle glaucoma were prescribed latanoprost 0.005% once
a day in each eye. The initial IOP before treatment served as an internal control
for each eye. Intraocular pressure was remeasured after 1 month of monotherapy
with latanoprost. Investigators (WJS) were blinded to initial IOP at the time of
remeasurement. After discontinuation of steroids, IOP was rechecked. If IOP was
stable, latanoprost was discontinued. Intraocular pressure was rechecked 2 to 4
weeks later to confirm an association with steroid use. RESULTS: Intraocular
pressure was significantly decreased after treatment with latanoprost (18.3 +/-
2.8 mm Hg) compared with initial IOP (25.3 +/- 9.1 mm Hg). This change
represented a 28% decrease in IOP compared with baseline levels. Average IOP
after discontinuation of steroids and latanoprost (17.3 +/- 1.4 mm Hg) did not
differ from IOP measured during treatment with latanoprost, but it was
significantly less than the initial IOP before treatment. No adverse effects were
noted. CONCLUSIONS: Monotherapy with latanoprost is safe and effective in
patients with steroid-induced glaucoma. Advantages include lack of systemic side
effects and convenient once-daily dosing.
PMID- 10782630
TI - Additive effect of latanoprost to the combination of timolol and dorzolamide.
AB - PURPOSE: To study the additive effect of latanoprost 0.005% in patients who have
uncontrolled intraocular pressure (IOP) using timolol 0.5% and dorzolamide 2%.
METHODS: Fifty-two consecutive patients with open-angle glaucoma who were using
timolol and dorzolamide and were considered to have IOP above their defined
target pressure were included in this study. After a baseline diurnal tension
curve (DTC) was performed, latanoprost once a day was added to the treatment, and
a second DTC was performed 1 week later. RESULTS: Five patients (9.6%) were
discontinued from treatment because of side effects. The remaining 47 patients
showed a significant IOP reduction of 3.1 mm Hg (16%) from a baseline of 19.3 mm
Hg (mean IOP registered during DTC; P < or = 0.0001). Seventeen patients (36.3%)
showed a mean IOP reduction greater than 20%. CONCLUSIONS: Latanoprost had an
additive effect when used as a third drug for patients on timolol and dorzolamide
who were in need of further IOP reduction. These results suggest that latanoprost
may be very effective in some patients with poorly controlled glaucoma on
multiple therapy.
PMID- 10782632
TI - Glaucoma associated with elevated episcleral venous pressure.
PMID- 10782631
TI - How low can we get? Tonometry in the Thomson gazelle (Gazella thomsoni).
AB - PURPOSE: To establish a normal reference range of intraocular pressure estimates
in Thomson gazelles (Gazella thomsoni). MATERIALS AND METHODS: Applanation
tonometry was conducted in 22 eyes of 11 gazelles anesthetized for transportation
purposes with a mixture of etorphine hydrochloride and acepromazine maleate. Five
sequential readings using a Tono-Pen XL (Mentor Ophthalmics, Inc., Norwell, MA)
were obtained from each eye. Results were analyzed for the effect of age, weight,
gender, side, and replicate readings and were compared with estimates in other
species. RESULTS: Mean (+/- standard deviation) intraocular pressure estimate in
22 eyes of 11 gazelles was 7.6 +/- 1.6 mm Hg. None of the variables tested had a
significant effect on the results. CONCLUSIONS: To date, the intraocular pressure
estimates in the Thomson gazelle are the lowest reported in any species.
PMID- 10782633
TI - Financing new drug development in ophthalmology.
AB - Previously, the author presented an overview of the procedural aspects of
ophthalmic drug development. In that article, aspects of drug discovery and
development were discussed, including application of the scientific method,
compound selection, biological evaluation, pharmaceutical formulation, clinical
development, and regulatory approval. An important part of drug discovery and
development is funding the work. In this article, the author presents key issues
involved in this funding process.
PMID- 10782634
TI - Postoperative Descemet membrane detachment with maintenance of corneal clarity
after trabeculectomy.
AB - This case report describes an unusual complication of Descemet membrane
detachment after anterior chamber reformation to treat a flat anterior chamber
and hypotony from a trabeculectomy. This large Descemet membrane detachment was
unexpectedly associated with a clear cornea. Treatment was conservative, and the
Descemet membrane detachment spontaneously resolved in 6 months.
PMID- 10782635
TI - The relationship between optic disc area and open-angle glaucoma.
PMID- 10782636
TI - Successive approximations for charged particle motion
AB - Single-particle dynamics in electron microscopes, ion or electron lithographic
instruments, particle accelerators, and particle spectrographs is described by
weakly nonlinear ordinary differential equations. Therefore, the linear part of
the equation of motion is usually solved and the nonlinear effects are then found
in successive order by iteration methods. When synchrotron radiation is not
important, the equation can be derived from a Hamiltonian or a Lagrangian. The
Hamiltonian nature can lead to simplified computations of particle transport
through an optical device when a suitable computational method is used. H. Rose
and his school have contributed to these techniques by developing and intensively
using the eikonal method [1-3]. Many ingenious microscopic and lithographic
devices were found by Rose and his group due to the simple structure of this
method [4-6]. The particle optical eikonal method is either derived by
propagating the electron wave or by the principle of Maupertuis for time
independent fields. Maybe because of the time-dependent fields which are often
required, in the area of accelerator physics the eikonal method has never become
popular, although Lagrange methods had been used sometimes already in early days
[7]. In this area classical Hamilitonian dynamics is usually used to compute
nonlinear particle motion. Here the author will therefore derive the eikonal
method from a Hamiltonian quite familiar to the accelerator physics community and
reformulate it in a simplifying way. With the event of high-energy polarized
electron beams [8] and plans for high-energy proton beams [9], nonlinear effects
in spin motion have become important in high-energy accelerators. The author
introduces a successive approximation for the nonlinear effects in the coupled
spin and orbit motion of charged particles which resembles some of the
simplifications resulting from the eikonal method for the pure orbit motion.
PMID- 10782637
TI - Initial resolution measurements of an improved magnetic-electrostatic detector
objective lens for LVSEM
AB - In this paper we present some initial resolution measurements of an improved
magnetic-electrostatic detector objective lens for a low-voltage scanning
electron microscope. The electron optical design of the lens was already proposed
by the authors [G. Knell, E. Plies, Nucl. Instr. & Meth. A 427 (1999) 99]. The
magnetic circuit of this lens has a radially arranged pole-piece gap. Thus, the
specimen is immersed in a strong magnetic field of 106 mT (working distance: 1
mm, primary electron energy: 200 eV). The electrostatic field strength of our
optimized lens variant amounts to a moderate value of 100 V/mm for a working
distance of 1 mm. At a final beam energy of 1 keV a resolution of 3 nm, at 260 eV
a resolution of 5 nm was obtained.
PMID- 10782638
TI - Construction and characterization of the fringe field monochromator for a field
emission gun
AB - Although some microscopes have shown stabilities sufficient to attain below 0.1
eV spectral resolution in high-resolution electron energy loss spectroscopy, the
intrinsic energy width of the high brightness source (0.3-0.6 eV) has been
limiting the resolution. To lower the energy width of the source to 50 meV
without unnecessary loss of brightness, a monochromator has been designed
consisting of a short (4 mm) fringe field Wien filter and a 150 nm energy
selection slit (nanoslit) both to be incorporated in the gun area of the
microscope. A prototype has been built and tested in an ultra-high-vacuum setup
(10(-9) mbar). The monochromator, operating on a Schottky field emission gun,
showed stable and reproducible operation. The nanoslits did not contaminate and
the structure remained stable. By measuring the current through the slit
structure a direct image of the beam in the monochromator could be attained and
the monochromator could be aligned without the use of a microscope. Good
dispersed imaging conditions were found indicating an ultimate resolution of 55
meV. A Mark II fringe field monochromator (FFM) was designed and constructed
compatible with the cold tungsten field emitter of the VG scanning transmission
microscope. The monochromator was incorporated in the gun area of the microscope
at IBM T.J. Watson research center, New York. The monochromator was aligned on
100 kV and the energy distribution measured using the monochromator displayed a
below 50 meV filtering capability. The retarding Wien filter spectrometer was
used to show a 61 meV EELS system resolution. The FFM is shown to be a
monochromator which can be aligned without the use of the electron microscope.
This makes it directly applicable for scanning transmission microscopy and low
voltage scanning electron microscopy, where it can lower the resolution loss
which is caused by chromatic blur of the spot.
PMID- 10782639
TI - Nanosecond electron microscopes
AB - Combining electron optics, fast electronics and pulsed lasers, a transmission and
a photoelectron emission microscope were built, which visualize events in thin
films and on surfaces with a time resolution of several nanoseconds. The high
speed electron microscopy is capable to track fast laser-induced processes in
metals below the ablation threshold, which are difficult to detect by other
imaging techniques. The material response to nano- and femtosecond laser pulses
was found to be very different. It was dominated by thermo/chemocapillary flow
and chemical reactions in the case of nanosecond pulses, and by mechanical
deformations and non-thermal electron emission after a femtosecond pulse.
PMID- 10782640
TI - Measurement of lens aberrations by means of image displacements in beam-tilt
series
AB - Electron microscope image aberrations are determined by means of the beam
tilt/image displacement method with respect to the precision required to obtain a
resolution of 1 A. The method simultaneously yields all image aberrations to the
fourth order and it is independent of the material used for the procedure. The
experimental procedure using amorphous carbon is described and errors in
measuring beam-tilt angles, magnifications and image displacements can be kept
sufficiently small to achieve the required accuracy. The method is applied to
determine aberration constants of a CM300 FEG/UT microscope with correction of
the three-fold astigmatism. The coefficient of spherical aberration and the
modulus of the three-fold astigmatism were measured to 0.60 (+/- 0.02) mm and 150
(+/- 50) nm, respectively. The beam tilt/image displacement procedure is also
computer simulated using an amorphous model structure yielding the same values
for the lens aberrations which are used for imaging. However, a coefficient of
spherical aberration of 0.67 mm is obtained by applying the focus
variation/diffractogram analysis on the same model.
PMID- 10782641
TI - Upper limits for the residual aberrations of a high-resolution aberration
corrected STEM
AB - The development of correctors for electron optical systems has already brought
the improvement of resolution for a low-voltage scanning electron microscope and
a commercially available transmission electron microscope and is anticipated in
the near future for a dedicated scanning transmission electron microscope (STEM).
The resolution attainable especially of a probe-forming system at 200 kV cannot
only be estimated from calculations ignoring all non-rotationally symmetric axial
aberrations in an electron optical system. For a certain resolution, one would
like to attain, the influence of the deviations from the ideal, aberration-free
system has to be investigated. Therefore, in the following we have carried out
the evaluation of the required accuracy for the compensation of the various
residual aberrations in order to achieve a resolution in the sub-Angstrom regime
with a probe-forming system.
PMID- 10782642
TI - Inelastic electron holography
AB - Coherence of inelastically scattered electrons was investigated by means of
biprism interference experiments performed in a transmission electron microscope
equipped with a highly coherent field emission gun and an imaging filter. The
experimental results show that within the wave inelastically scattered at
aluminium plasmons there is in fact an area of about 10 nm diameter with
coherence sufficient to take electron holograms.
PMID- 10782643
TI - Inelastic scattering and holography
AB - The controversy about whether or not an inelastically scattered electron wave can
still interfere with a reference wave is solved by treating the whole problem
rigorously and describing electron, source and object in one Hamiltonian. It
turns out that, in principle, interference can occur between an inelastically
scattered wave and a reference wave from the incident beam spectrum provided the
energy difference is smaller than about 10(-15) eV. However, it is argued that
the density of states in source object and electron wave is much too small to
make this effect observable.
PMID- 10782644
TI - Can high-angle annular dark field scattering be represented by a local operator?
AB - High-angle annular dark field imaging has become an invaluable technique for
recording atomic resolution STEM images. Many analyses of high-angle annular dark
field images assume that the signal is the result of a local scattering operator
and can be represented as a simple convolution of a probe function with a set of
atomic columns. The apparent simplicity of the technique and the straightforward
increase in signal with atomic number have lead to the belief that it is possible
to quantify impurity concentrations at atomic column resolution. The limitations
in these assumptions are examined on the basis of approximations starting from a
complete theory for high-angle scattering based on multi phonon excitations. Not
surprisingly, the accuracy of the local scattering operator approximation
improves as the inner cut-off angle is increased.
PMID- 10782645
TI - Zero-loss image formation and modified contrast transfer theory in EFTEM.
AB - For a weak phase/weak amplitude object the information transfer in the imaging
process of TEM is described by the common formalism of the contrast transfer
function (CTF). So far the effects of inelastic scattering were not accounted for
in this formalism. In conventional imaging they were simply neglected. In energy
filtering TEM (EFTEM), where removal of inelastic electrons leads to higher
specimen contrast, they were modelled by a global increase of the elastic
amplitude contrast. Thus, the description of inelastic and elastic scattering was
mixed. Here a new ansatz is proposed which treats elastic and inelastic contrast
transfer separately by adding an inelastic contribution to the scattering
potentials. In EFTEM this has the effect of adding a filter contrast which
depends on the characteristics of the inelastic scattering. For samples with
dominant plasmon loss the additional filter contrast is restricted to low
resolution. Because of its strong dependence on the nature of the inelastic
scattering process, the filter contrast cannot in general be unified with the
conventional elastic amplitude contrast. The modified CTF theory for EFTEM was
tested experimentally on a variety of samples. Images of amorphous layers of
copper, aluminium, and carbon films, as well as zero-loss images of proteins
embedded in amorphous ice were evaluated. The values of the parameters of the
additional filter contrast were determined for carbon film and proteins embedded
in vitrified ice. Comparison of different CTF models used to reconstruct 3D
volumes from zero-loss images confirmed that best agreement with the atomic model
is attained with the new, modified CTF theory.
PMID- 10782646
TI - Computation of contrasts in atomic resolution electron spectroscopic images of
planar defects in crystalline specimens
AB - The image obtained in a conventional transmission electron microscope contains
contributions from elastically and from inelastically scattered electrons. The
electron spectroscopic imaging mode of an energy-filtering transmission electron
microscope allows us to separate these two different contributions by inserting
an energy-selecting slit in the energy-dispersive plane of an imaging energy
filter. Selecting a specific energy loss corresponding to the ionization of the
inner shell of a particular element one can obtain information on the
distribution of the element within the specimen. The contrast is then caused by
inelastically scattered electrons. For crystalline specimens, however, the
contrast will be influenced additionally by the elastic contrast. This elastic
contrast arises from electron diffraction and increases with increasing crystal
thickness. Therefore the intensity distribution in the image cannot directly be
interpreted as an elemental map. For a reliable interpretation of contrast
formation in elemental maps it is therefore necessary to compute theoretical
energy-loss images for various crystal thicknesses and compare these images with
the experimental images. As an example we discuss the influence of electron
diffraction effects on energy-loss images of two crystals with planar defects.
Linescans are computed for various thicknesses of these crystals. Our
calculations are performed using first-order perturbation theory to describe the
transitions between the Bloch-wave states of the incident electron. The computed
linescans for various crystal thicknesses show clearly that the influence of the
elastic contrast on an image increases when we investigate thicker specimens.
Furthermore, the comparison between elastic and energy-loss images demonstrates
the partial preservation of the elastic contrast as a function of thickness. We
find that for specimens thicker than about one third of the extinction length
(here approximately 80-100 A) it is impossible to interpret an energy-loss image
directly as elemental map.
PMID- 10782647
TI - Surface structural sensitivity of convergent-beam RHEED: Si (0 0 1) 2 x 1 models
compared with dynamical simulations
AB - The aim of this work is to evaluate the sensitivity of convergent-beam RHEED for
the refinement of surface atomic structure. We have compared experimental and
theoretical convergent-beam RHEED patterns from the silicon (0 0 1) reconstructed
surface. The experiment was carried out in a custom designed UHV diffraction
camera,using a micron sized probe. Both experimental and theoretical CB-RHEED
patterns show complex details, highly sensitive to the surface structure. The
multiple scattering simulations were based on two experimental structural models
which make different assumptions for dimer tilt, one derived from X-ray
diffraction results, and another from LEED data. The simulated CB-RHEED patterns
using the X-ray model were found to be in closer agreement with our experiment
than the LEED model. However, the agreement is not entirely satisfactory,
suggesting that further improvement on this model is necessary.
PMID- 10782648
TI - Analysis of local strain in aluminium interconnects by energy filtered CBED
AB - Energy filtered convergent beam electron diffraction (CBED) was used to
investigate localised strain in aluminium interconnects. The quantitative
analysis of the experimental patterns is based on a multi-step evaluation
procedure which is the main subject of the present paper. The improvements which
were made to the analysis method aim at increasing both the automation and the
accuracy. The detection of the higher order Laue zone (HOLZ) line positions is
performed by means of the Hough transform. The required sub-pixel resolution can
be achieved routinely and the achievable accuracy is only limited by the line
width and the amount of noise in the patterns. The determination of the strain
state is performed via a refinement algorithm which is based on varying the
strain state in the sample coordinate system and simulating the patterns for the
individual grains until a best fit with the experiment is obtained. For the
simulation we have developed a new correction scheme in which the dynamical
effects are treated separately for each individual HOLZ line. The results show
that the main source of the observed strains is the difference in thermal
expansion coefficients. The strain is substantially reduced underneath a hillock
in the interconnect. Asymmetries in the strain distribution around the hillock
show that the unidirectional diffusion during electromigration tests causes peak
strains in areas next to the hillock which may be possible failure sites.
PMID- 10782650
TI - Investigation of thermoelectric silicide thin films by means of analytical
transmission electron microscopy
AB - The microstructure of rhenium silicide thin films and its progress by annealing
were investigated by means of analytical transmission electron microscopy.
Sputtered amorphous films were characterised by analysis of the radial
distribution function (RDF). The position of the first maximum of RDF represents
the most probable distance between neighbouring atoms and decreases from 2.75 to
2.62 A in films with an increasing Si-content from 60 to 75 at%. This decrease
correlates with the change of the temperature coefficient (TC) of the electrical
resistivity. During in situ annealing, the formation of nanocrystals in films
with different Si-contents was observed. In thin films with 64 at% the quantity
of nanocrystals increases after 1 h at 900 K whereas their sizes remain
unchanged. The crystallisation in Re-rich thin films proceeds lower and produces
larger crystals than in films near to the ReSi1.75 stoichiometry. Sputtered
epitaxial ReSi1.75 films on Si (1 0 0) consist of crystals with nanometer size
and an azimuthal torsion of 45 degrees.
PMID- 10782649
TI - Rietveld analysis of electron powder diffraction data from nanocrystalline
anatase, TiO2
AB - The structure of nanocrystalline anatase (TiO2) was successfully refined from
electron powder diffraction data using the Rietveld technique. A polycrystalline
sample (average crystal size about 70 A) was characterised by selected area
electron diffraction in a conventional transmission electron microscope operated
at 300 kV. Radially integrated intensities were extracted from digitised
photographic films and used in the course of structure refinements by a standard
program for Rietveld analysis. The structure was refined in space group I4(1)/amd
(#141) with lattice parameters a = 3.7710(9) A and c = 9.430(2) A. The
reliability factors of the refinement are Rwp = 5.2% and R(B) = 2.6%. The close
agreement of the refined structural parameters with previous results obtained
from neutron diffraction on coarse-grained powders proves the applicability of
the method for characterising nanocrystalline powders. The present study shows
that Rietveld analysis on electron powder data is a good compliment to the
existing methods for accurate structural investigations on nanocrystalline
materials and thin films.
PMID- 10782651
TI - TEM analysis of epitaxial semiconductor layers with high stacking fault densities
considering artifacts induced by the cross-section geometry
AB - Epitaxial semiconductor layers, in particular II-VI compound semiconductors with
the component Se deposited on III-V semiconductor substrates like GaAs or InAs,
can contain high densities of stacking faults. CdxMg(1-x)Se layers with Cd
concentrations x of 93% and 57% on InAs(0 0 1) substrates were investigated as
typical representatives of this class of heterostructures. The defect structure
of the layers is dominated by a high density of stacking fault (SF) pairs bound
by Shockley partial dislocations with Burgers vectors b = 1/6 <1 1 2> and a stair
rod dislocation with b = 1/6 <1 1 0> at the intersection line of the pairs. Plan
view transmission electron microscopy (TEM) is generally applied to obtain
information about the type, density and arrangement of the stacking faults in
thin epilayers up to moderate SF densities. Cross-section TEM is more frequently
carried out for thick layers and at high SF densities. It will be demonstrated by
a detailed analysis of cross-section images that a careful interpretation of the
observed SF morphologies is necessary due to artifacts induced by the cross
section geometry.
PMID- 10782652
TI - Electron microscope characterization of CdSe/ZnSe quantum dots based on molecular
dynamics structure relaxations
AB - Molecular dynamics simulations using empirical potentials are applied to
characterize the structure, the energy relaxation and the stability of pyramidal
shaped quantum dots in the CdSe/ZnSe system. The relaxed structure models are
used for a reliable interpretation of electron microscope investigations to
analyze the size, the shape and the strain fields of the quantum dots. Though the
elastic strains modify the electron microsope image contrast by creating virtual
truncations of the pyramids or additional black-white lobes, optimum imaging
conditions chosen will reveal the shape and the size of the dots.
PMID- 10782654
TI - Ammunition from the cancer wars: live and spent bullets.
PMID- 10782653
TI - Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer:
results from a controlled trial (Finland)
AB - BACKGROUND: Some epidemiological investigations suggest that higher intake or
biochemical status of vitamin E and beta-carotene might be associated with
reduced risk of colorectal cancer. METHODS: We tested the effects of alpha
tocopherol and beta-carotene supplementation on the incidence of colorectal
cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a
double-blind, placebo-controlled trial among 29,133 50-69-year-old male cigarette
smokers. Participants were randomly assigned to receive alpha-tocopherol (50 mg),
beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years. Incident
colorectal cancers (n = 135) were identified through the nationwide cancer
registry, and 99% were histologically confirmed. Intervention effects were
evaluated using survival analysis and proportional hazards models. RESULTS:
Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm
compared to the no alpha-tocopherol arm, but this finding was not statistically
significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55-1.09;
log-rank test p = 0.15). Beta-carotene had no effect on colorectal cancer
incidence (RR = 1.05, 95% CI 0.75-1.47; log-rank test p = 0.78). There was no
interaction between the two substances. CONCLUSION: Our study found no evidence
of a beneficial or harmful effect for beta-carotene in colorectal cancer in older
male smokers, but does provide suggestive evidence that vitamin E supplementation
may have had a modest preventive effect. The latter finding is in accord with
previous research linking higher vitamin E status to reduced colorectal cancer
risk.
PMID- 10782655
TI - Passive and active smoking and breast cancer risk in Canada, 1994-97.
AB - BACKGROUND: Studies comparing ever smokers with never smokers have found little
increase in breast cancer risk. However, the five published studies examining
passive smoking and breast cancer have all suggested associations with both
passive and active smoking, particularly premenopausal risk. METHODS: We analyzed
data collected through the Canadian National Enhanced Cancer Surveillance System,
from 805 premenopausal and 1512 postmenopausal women with newly diagnosed
(incident), histologically confirmed, primary breast cancer and 2438 population
controls. The mailed questionnaire included questions on breast cancer risk
factors and a lifetime residential and occupational history of exposure to
passive smoking. RESULTS: Among premenopausal women who were never active
smokers, regular exposure to passive smoke was associated with an adjusted breast
cancer odds ratio (OR) of 2.3 (95% confidence interval [CI] 1.2-4.6). Passive
exposure showed a strong dose-response trend (test for trend p = 0.0007) with an
OR of 2.9 (95% CI 1.3-6.6) for more than 35 years of passive residential and/or
occupational exposure. When premenopausal women who had ever actively smoked were
compared with women never regularly exposed to passive or active smoke, the
adjusted OR for breast cancer was also 2.3 (95% CI 1.2-4.5). Among postmenopausal
women who were never-active smokers, regular exposure to passive smoke was
associated with an adjusted breast cancer OR of 1.2 (95% CI 0.8-1.8) and an OR of
1.4 (95% CI 0.9-2.3) for the most highly exposed quartile of women. The adjusted
OR for postmenopausal breast cancer risk for ever-active smokers compared with
women never regularly exposed to passive or active smoke was 1.5 (95% CI 1.0
2.3). Statistically significant dose-response relationships were observed with
increasing years of smoking, increasing pack-years and decreasing years since
quitting. Women with 35 or more years of smoking had an adjusted OR of 1.7 (95%
CI 1.1-2.7). CONCLUSIONS: Active and passive smoking may be associated with
increased breast cancer risk, particularly premenopausal risk.
PMID- 10782656
TI - Effects of social support, regular physician and health-related attitudes on
cervical cancer screening in an Asian population.
AB - OBJECTIVE: Out primary objective was to examine sociodemographic and attitudinal
factors that affect uptake of the Pap smear in a multi-ethnic Asian population.
METHODS: We conducted a prevalence survey among women aged 50-64 years living in
Singapore and ascertained by means of an in-person questionnaire interview their
Pap screening history, demographic characteristics, informal social support and
attitudes towards early detection. RESULTS: We found that, after adjusting for
demographic variables known to be predictors of Pap screening, women who reported
ever having a Pap smear were more likely to have close friends with whom they
could discuss health (adjusted odds ratio (OR) 2.1, 95% confidence intervals (CI)
1.2-3.6), and have a regular physician (adjusted OR 2.3 (1.3-4.1)). Based on
responses to four indices measuring health attitudes, they were significantly
less likely to express a fatalistic viewpoint towards health and illness
(adjusted OR for highest vs. lowest tertile 0.3 (95% CI 0.1-0.7)), and more
likely to believe that early detection could improve the outcome (adjusted OR 3.3
(95% CI 1.4-7.8)). The nature of the test itself was a significant barrier to
having a Pap smear, but only among women with fewer years of education.
CONCLUSIONS: Our results suggest that, within this Asian population, a multi
pronged approach is required to reach unscreened women. The role of physicians
and close friends should be emphasized, and health messages should be formulated
to address specific, relevant attitudinal barriers to Pap screening.
PMID- 10782658
TI - Alcohol consumption and risk of breast cancer: a cohort study.
AB - OBJECTIVES: To study the association between alcohol consumption and breast
cancer risk. METHODS: A case-cohort analysis was undertaken within the cohort of
56,837 women who were enrolled in the Canadian National Breast Screening Study
(NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is
a randomized controlled trial of screening for breast cancer in women aged 40-59
at recruitment.) The cohort was recruited between 1980 and 1985, and during
follow-up to the end of 1993 a total of 1469 women in the dietary cohort were
diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes
a subcohort consisting of a random sample of 5681 women was selected from the
full dietary cohort. After exclusions for various reasons the analyses were based
on 1336 cases and 5238 noncases. RESULTS: When compared to nondrinkers the
adjusted incidence rate ratios (95% confidence intervals) for those consuming > 0
and < or = 10 g of alcohol/day, > 10 and < or = 20 g/day, > 20 and < or = 30
g/day, > 30 and < or = 40 g/day, > 40 and < or = 50 g/day, and > 50 g/day were
1.01 (0.84-1.22), 1.16 (0.91-1.47), 1.27 (0.91-1.78), 0.77 (0.51-1.16), 1.00
(0.57-1.75), and 1.70 (0.97-2.98), respectively; the associated p value for the
test for trend was 0.351. Similar findings were obtained when analyses were
conducted separately in the screened and control arms of the NBSS, in
premenopausal and postmenopausal women, for screen-detected and interval-detected
breast cancer, and by levels of other breast cancer risk factors. CONCLUSIONS:
The results of this study suggest that alcohol consumption might be associated
with increased risk of breast cancer at relatively high levels of intake.
PMID- 10782657
TI - Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of
esophageal and gastric cancer.
AB - OBJECTIVE: The incidence of esophageal adenocarcinoma has risen rapidly in the
past two decades, for unknown reasons. The goal of this analysis was to determine
whether gastroesophageal reflux disease (GERD) or the medications used to treat
it are associated with an increased risk of esophageal or gastric cancer, using
data from a large population-based case-control study. METHODS: Cases were aged
30-79 years, newly diagnosed with esophageal adenocarcinoma (n = 293), esophageal
squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or
non-cardia gastric adenocarcinoma (n = 368) in three areas with population-based
tumor registries. Controls (n = 695) were chosen by random digit dialing and from
Health Care Financing Administration rosters. Data were collected using an in
person structured interview. RESULTS: History of gastric ulcer was associated
with an increased risk of non-cardia gastric adenocarcinoma (OR 2.1, 95% CI 1.4
3.2). Risk of esophageal adenocarcinoma increased with frequency of GERD
symptoms; the odds ratio in those reporting daily symptoms was 5.5 (95% CI 3.2
9.3). Ever having used H2 blockers was unassociated with esophageal
adenocarcinoma risk (OR 0.9, 95% CI 0.5-1.5). The odds ratio was 1.3 (95% CI 0.6
2.8) in long-term (4 or more years) users, but increased to 2.1 (95% CI 0.8-5.6)
when use in the 5 years prior to the interview was disregarded. Risk was also
modestly increased among users of antacids. Neither GERD symptoms nor use of H2
blockers or antacids was associated with risk of the other three tumor types.
CONCLUSIONS: Individuals with long-standing GERD are at increased risk of
esophageal adenocarcinoma, whether or not the symptoms are treated with H2
blockers or antacids.
PMID- 10782659
TI - NSAIDs and risk of colorectal cancer according to presence or absence of family
history of the disease.
AB - BACKGROUND: We undertook the present analyses to determine whether family history
of colorectal cancer in a parent or sibling modifies the inverse association of
nonsteroidal anti-inflammatory drug (NSAID) use with colorectal cancer risk.
METHODS: We used data from two case-control studies of colorectal cancer. The
hospital-based Case Control Surveillance Study included 1526 patients with
primary colorectal cancer, 4192 cancer controls and 6036 noncancer controls. A
population-based study conducted in Massachusetts enrolled 1201 incident cases of
colorectal cancer and 1201 community controls. Data on NSAID use and risk factors
for colorectal cancer were collected by interview. RESULTS: In both studies there
was a reduction in the odds ratios among subjects who used NSAIDs regularly
continuing into the previous year, regardless of family history. In the Case
Control Surveillance data, the odds ratio was 0.4 (95% CI 0.2-0.9) among subjects
with a family history and 0.5 (95% CI 0.4-0.7) among subjects without a family
history. The comparable odds ratios in the Massachusetts data were 0.5 (95% CI
0.3-0.9) and 0.7 (95% CI 0.6-0.9). CONCLUSIONS: These data indicate that regular
continuing NSAID use is associated with a reduced risk of colorectal cancer among
persons with a family history of the disease, as well as those without such a
history.
PMID- 10782660
TI - Cancer control research 2001.
AB - OBJECTIVES: Major societal changes, including the changing demographics of US
society and the genetics and communications revolutions, are providing new
opportunities to control cancer both in the United States and around the world.
This article examines the implications of these trends and other issues in the
context of cancer control research. A seven-item strategy for cancer control
research is proposed. RESULTS: Epidemiology, statistics, genetics, and bio
behavioral research are central disciplines for cancer control research. The
identification of particular at-risk populations is increasingly possible. Cancer
control research must focus on increasing fundamental knowledge in order to
accelerate improvements in cancer prevention and early detection. Cancer control
research also must be used to conduct trials of new cancer detection methods,
overcome differential participation in cancer screening, develop evidence-based
strategies to improve decision-making, and develop evidence-based cancer
communications. A comprehensive cancer surveillance system is the foundation for
cancer control research. Cancer control research must aim to reduce cancer risk,
incidence, and mortality, and improve quality of life. These are important
challenges for the new millennium.
PMID- 10782661
TI - The associations of adolescent cigarette smoking, alcoholic beverage consumption,
environmental tobacco smoke, and ionizing radiation with subsequent breast cancer
risk (United States).
AB - OBJECTIVES: Studies of breast cancer among survivors of the World War II atomic
bomb blasts over Japan suggest that the adolescent breast may be particularly
sensitive to carcinogenic insult. To further explore that possibility we examined
the relationships of cigarette smoking, alcohol consumption, environmental
tobacco smoke (ETS) exposure, and medical treatment with ionizing radiation
during adolescence with subsequent breast cancer risk. METHODS: Data from the
Carolina Breast Cancer Study, a population-based, case-control study of breast
cancer in North Carolina women aged 20-74 years (864 cases, 790 controls), were
analyzed. RESULTS: A modest increase in breast cancer risk was suggested for
women who began to smoke cigarettes between the ages of 10 and 14 years (OR: 1.5,
CI: 0.9-2.5), and for women exposed to ionizing radiation between ages 10 and 19
years to treat or monitor a medical condition (OR: 1.6, CI: 0.5-2.5). Neither
exposure to ETS at home prior to age 18 years (OR: 1.1, CI: 0.9-1.3) nor
initiation of alcoholic beverage consumption between ages 10 and 15 years (OR:
1.1, CI: 0.6-1.8) appeared to increase risk. CONCLUSIONS: Our results are
consistent with previous evidence suggesting that some adolescent exposures could
influence future breast cancer risk.
PMID- 10782663
TI - Update: master settlement agreement between the states and the tobacco industry
(United States).
PMID- 10782662
TI - A prospective study of plasma ascorbic acid concentrations and breast cancer
(United States).
AB - OBJECTIVES: To investigate the association between prediagnostic plasma ascorbic
acid concentrations and subsequent breast cancer risk in a nested case-control
study. METHODS: Female volunteer residents of Washington County, MD, donated
14,625 non-fasting blood samples in 1989. Incident breast cancer cases (n = 115)
and controls (n = 115) were matched by age, menopausal status at donation, and
date and hour of blood donation. RESULTS: Median ascorbic acid concentrations
were similar between cases and controls (1.44 mg/dl vs. 1.39 mg/dl. p = 0.78).
There was no evidence for a dose-response relationship between higher plasma
ascorbic acid concentrations and breast cancer risk [highest vs. lowest fifths:
ORadjusted = 0.90, Ptrend = 0.98). CONCLUSIONS: Findings from this prospective
study do not suggest a protective association between prediagnostic plasma
ascorbic acid concentrations and breast cancer risk in the subsequent 5 years of
follow-up.
PMID- 10782665
TI - Solid-phase synthesis of oligomeric deoxynucleic-thiourea (DNT) and deoxynucleic
S-methylthiourea (DNmt): a neutral/polycationic analogue of DNA.
AB - A solid-phase synthesis for oligomeric DNmt is reported. Synthesis proceeds in 3'
5' direction and involves coupling of a protected 3'-isothiocyanate with the
corresponding 5'-amine of the growing oligo chain. The difference in oligomeric
thiourea/S-methylthiourea binding to DNA is investigated.
PMID- 10782664
TI - Isoxazolines and isoxazoles as factor Xa inhibitors.
AB - 3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and
evaluated for their in vitro and in vivo antithrombotic efficacy. They were
compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and
potency. They were also compared in an arterio-venous (A-V) shunt model of
thrombosis.
PMID- 10782666
TI - The synthesis and vasopressin (AVP) antagonist activity of a novel series of N
aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines.
AB - Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y
l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists
are discussed. Potent orally active AVP receptor antagonists are produced when
the benzamide moiety contains a phenyl group at the 2-position. Similar analogues
of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.
PMID- 10782667
TI - Antitumor agents. Part 202: novel 2'-amino chalcones: design, synthesis and
biological evaluation.
AB - New 4',5',2,3,4-substituted 2'-amino chalcones were synthesized and evaluated for
cytotoxicity against a panel of human tumor cell lines. Several compounds
displayed significant cytotoxicity. The most promising lead molecule (10) also
had high activity toward multi-drug resistant KB-VIN, and ovarian 1A9 cell lines.
2'-Amino chalcones demonstrated significantly increased antitumor activity
compared with the corresponding chalcones, while, the epoxide derivatives
generally showed greatly reduced activity.
PMID- 10782668
TI - Suitably functionalised pyrimidines as potential antimycotic agents.
AB - Various suitably functionalized pyrimidine derivatives have been synthesized to
explore their potential as antimycotic agents. Some of the synthesized compounds
4c, 4d, 8a-e have shown highly significant in vitro antifungal activity against
five human pathogenic fungi.
PMID- 10782669
TI - Synthesis and biological activity of fluoro-substituted pyrrolo[2,3
d]pyrimidines: the development of potential positron emission tomography imaging
agents for the corticotropin-releasing hormone type 1 receptor.
AB - A series of fluoro-substituted 4-(dialkylamino)pyrrolo[2,3-d]pyrimidines was
synthesized and their binding affinity for corticotropin-releasing hormone type 1
receptor (CRHR1) was investigated. Compounds 11a and 11b possessed very high
CRHR1 affinity (Ki=3.5, 0.91 nM, respectively). They are promising candidates for
the development of 18F-containing nonpeptide PET radioligands for CRHR1.
PMID- 10782670
TI - Alpha-ketoamides, alpha-ketoesters and alpha-diketones as HCV NS3 protease
inhibitors.
AB - Peptide-based alpha-ketoamides, alpha-ketoesters and alpha-diketones were
designed, synthesized and evaluated against HCV NS3 protease. Alpha-ketoamides
have the highest affinity among the three classes, with 8 being the most potent
inhibitor with an IC50 of 340 nM.
PMID- 10782671
TI - 4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB.
AB - 4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the
bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the
enzyme in vitro. This activity, coupled with the design principles of the
thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized
as diphosphate mimics by a biological selector.
PMID- 10782672
TI - Heterocyclic bibenzimidazole derivatives as topoisomerase I inhibitors.
AB - A series of 2'-heterocyclic derivatives of 5-phenyl-2,5'-1H-bibenzimidazoles were
evaluated for topoisomerase I poisoning activity and cytotoxicity. Topo I
poisoning activity was associated with 2'-derivatives that possessed a hydrogen
atom capable of hydrogen bond formation, suggesting that the interatomic
distances between such hydrogen atoms and the heteroatoms on the adjacent
benzimidazole influence activity.
PMID- 10782673
TI - N-acyl phenylalanine analogues as potent small molecule VLA-4 antagonists.
AB - We have identified a series of low molecular weight (Mr < 500) N
acylphenylalanines that are effective inhibitors of the VCAM-VLA-4 interaction.
Investigation of the SAR of the N-acyl moiety led to the identification of N
benzylpyroglutamyl derivatives as being particularly potent.
PMID- 10782674
TI - N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.
AB - A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives
was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron
deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency
in an ELISA assay and low-microM activity in a cell based assay.
PMID- 10782675
TI - High incorporation of L-amino acids to cereulide, an emetic toxin from Bacillus
cereus.
AB - Cereulide is a principal toxin causing emetic syndrome produced by Bacillus
cereus. This paper deals with biosynthetic studies on this unusual cyclic
depsipeptide toxin from 13C labeled L-amino acid precursors (Val, Leu, Ala) upon
cultivation in synthetic media. The analyses were made at atomic level of the
constituent amino- or oxy-acids through NMR and ESI-MS/MS spectroscopic methods
on cereulide and its hydrolysate dipeptides. The incorporation of the 13C atom
was 95% in each O-Val, O-Leu and L-Val, while 40% in D-Ala of cereulide.
PMID- 10782676
TI - Cyclodextrin-peptide hybrid as a hydrolytic catalyst having multiple functional
groups.
AB - A designed cyclodextrin peptide hybrid, which has multiple functional groups on
its alpha-helix peptide backbone, has been synthesized as a catalyst for ester
hydrolysis. Kinetic study revealed that the carboxylate group plays a key role in
this system.
PMID- 10782677
TI - Guanylpiperidine peptidomimetics: potent and selective bis-cation inhibitors of
factor Xa.
AB - A novel series of rigid P3-guanylpiperidine peptide mimics 3-14 was designed as
potential factor Xa and prothrombinase inhibitors. Incorporation into a P2-gly-P1
argininal motif led to highly potent and selective inhibitors. The synthesis and
biological activities of these derivatives are reported herein.
PMID- 10782679
TI - Structural comparison between type I and type II antagonists: possible
implications in the drug design of AT1 antagonists.
AB - Analogues of sarilesin (type I AT1 antagonists), and sarmesin (type II AT1
antagonists) with homoserine (hSer) at position 8 were prepared and bioassayed.
The presence of a Tyr4-Ile5-His6 bend found in sarmesin but not in sarilesin was
identified. The obtained results coupled with conformational analysis studies,
using a combination of NMR spectroscopy and computational chemistry, propose
important conformational and stereoelectronic properties for agonist and
antagonist activity at AT1 receptors.
PMID- 10782678
TI - Conversion of a polysaccharide to nitric oxide-releasing form. Dual-mechanism
anticoagulant activity of diazeniumdiolated heparin.
AB - We describe heparin/diazeniumdiolate conjugates that generate nitric oxide (NO)
at physiological pH. Like the heparin from which they were prepared, they inhibit
thrombin-induced blood coagulation. Unlike heparin, they can also inhibit and
reverse ADP-induced platelet aggregation (as expected for an NO-releasing agent),
suggesting potential utility as dual-action antithrombotics.
PMID- 10782680
TI - Macrocarpins A-D, new cytotoxic nor-triterpenes from Maytenus macrocarpa.
AB - Macrocarpins A (1), B (2), C (3) and D (4), four new nor-triterpenes, have been
isolated from the roots of Maytenus macrocarpa. The structures were established
by spectroscopic examinations. Natural compounds 1, 2, 4 and the acetyl
derivative 1a are cytotoxic against four tumoral cell lines with IC50 values
ranging between 0.4 and 5.2 microM.
PMID- 10782681
TI - The abasic site as a target for generation of locally multiply damaged sites.
AB - Abasic sites in DNA have been specifically targeted by synthetic compounds able
to cleave DNA at abasic sites and to induce photodamages in the vicinity of the
lesion. The synthesis and the photoactivity of the drugs on abasic sites
containing DNA and oligonucleotides are reported.
PMID- 10782682
TI - QSAR of 1,1'-(1,2-ethylenebisbenzyl)bis(4-substitutedpyridinium) dibromides as
choline kinase inhibitors: a different approach for antiproliferative drug
design.
AB - Ten new structures of a series of the title compounds were synthesized and
screened for their activity to inhibit choline kinase under ex vivo conditions.
Their inhibitory potency correlates with the 13C chemical shifts (in CD3OD) of
the methylene group bearing the positively charged nitrogen. The inhibitory
effect on proliferation against the HT-29 cell line is strongly dependent on its
ability to inhibit the production of phosphorylcholine.
PMID- 10782683
TI - Synthesis and pharmacology of new enantiopure delta(3)-4-arylkainoids.
AB - Seven delta(3)-4-arylkainoids possessing various 4-position aromatic and
heteroaromatic groups were synthesized and their apparent affinities were
measured in order to explore the influences of 4-position electron density and
stereochemistry on receptor affinity and specificity. Kainoids 1a-f were shown to
be selective agonists at the NMDA receptor and the electron rich furanyl and
thienyl analogues exhibited the highest affinities. Naphthylkainoid 1g proved to
be a nonselective antagonist at the iGluRs.
PMID- 10782684
TI - Serendipitous synthesis of novel dehydro- and dechloro-pseudomycin B (PSB)
derivatives.
AB - The syntheses and preliminary investigation of antifungal activities of two
dehydro PSB derivatives 8 and 10 as well as one 3-imido-9-dechloro PSB analogue
13 are described.
PMID- 10782685
TI - Synthesis of a cyanopeptide-analogue with trypsin activating properties.
AB - An efficient synthesis of a peptidic analogue of cyanobacterial metabolites with
proposed serine protease inhibitory activity has been developed. Surprisingly,
one trypsin activating compound was obtained.
PMID- 10782687
TI - Synthesis and transfection properties of novel non-toxic monocationic lipids.
Variation of lipid anchor, spacer and head group structure.
AB - This report describes the synthesis and the transfection properties of novel
monocationic non-toxic lipids. We have carried out structural variations in all
three units of the transfection lipid, the lipid anchor, the spacer moiety and
the positively charged head group. Our results lead to the conclusion that
systematic modification of structural subunits is a promising way to enhance the
transfection efficiency.
PMID- 10782686
TI - The design, synthesis and physical chemical properties of novel human vasopressin
V2-receptor antagonists optimized for parenteral delivery.
AB - Ionizable groups were introduced onto the 10,11-dihydro-5H-pyrrolo[2,1
c][1,4]benzodiazepine scaffold of the vasopressin V2-antagonist WAY-VPA-985 in
the search for molecules optimized for parenteral formulation. The synthesis and
structure activity relationships (SAR) are presented together with solubility
data in a model parenteral system. The amine, WAY-140288 (4f), was chosen for
further development. p6
PMID- 10782688
TI - N-p-nitrobenzyloxycarbonyl galactosamine imidate as a glycosyl donor for the
efficient synthesis of mucin core-2 analogue.
AB - An efficient synthesis of the mucin core-2 analogue 1a was accomplished using N-p
nitrobenzyloxycarbonyl(PNZ)-protected trichloroacetimidate 4 as a novel glycosyl
donor.
PMID- 10782689
TI - 5'-[2-(2-Nitrophenyl)-2-methylpropionyl]-2'-deoxy-5-fluorouridine as a potential
bioreductively activated prodrug of FUDR: synthesis, stability and reductive
activation.
AB - 5'-[2-(2-Nitrophenyl)-2-methylpropionyl]-2'-deoxy-5-fluorouridine was synthesized
as a potential bioreductively activated prodrug of 5-fluoro-2'-deoxyuridine
(FUDR). The target compound was stable in both phosphate buffer and human serum
and was found to release quickly the parent drug FUDR in quantitative yield upon
mild chemical reduction.
PMID- 10782691
TI - Novel 3-(4-piperidinylthio)-1H-indoles as potent nonopioid orally active central
analgesics.
AB - A series of 3-(4-piperidinylthio)-1H-indoles was synthesized and evaluated in
mice in the phenylbenzoquinone(PBQ)-induced writhing and hot plate tests. Most of
these compounds are good analgesics with activities comparable to that of
morphine. Among them compound 1i (UP 237-61), which has a strong serotonin
binding profile, has an interesting antinociceptive activity which is not
reversed by naloxone.
PMID- 10782690
TI - Incorporation of a 4-hydroxy-N-acetylprolinol nucleotide analogue improves the 3'
exonuclease stability of 2'-5'-oligoadenylate-antisense conjugates.
AB - Incorporation of a 4-hydroxy-N-acetylprolinol nucleotide analogue at the 3'
terminus of DNA or 2-5A-DNA sequences resulted in a significantly enhanced 3'
exonuclease resistance while the affinity for complementary RNA was only slightly
decreased. Furthermore, the binding to and activation of human RNase L by thus
modified 2-5A-DNA conjugates was not altered as compared to the parent unmodified
2-5A-DNAs.
PMID- 10782692
TI - Leukotriene B4 photoaffinity probes: design, synthesis and evaluation of new
arylazide-1,3-disubstituted cyclohexanes.
AB - The synthesis and the binding affinities of new leukotriene B4 receptor
photoaffinity probes, where a 1,3-disubstituted cyclohexane ring replaces the
conjugated delta6,7 and delta8,9 double bonds of the natural eicosanoid, are
described. One enantiomeric compound, 4b alpha, is specifically cross-linked upon
photolysis to the recombinant leukotriene B4 receptor from human origin (h-BLTR)
solubilized in a micellar medium. This probe appears as a good candidate for
identifying the ligand binding site of this receptor.
PMID- 10782693
TI - Synthesis and antibacterial activity of novel 6-O-substituted erythromycin A
derivatives.
AB - A series of novel 6-O-substituted erythromycin A derivatives has been
synthesized. Good in vitro antibacterial activity has been demonstrated for
analogues incorporating a variety of structural features. The methodology
disclosed is expected to find application in the design of future macrolide
antibiotics that target the prevalent bacterial resistance problem.
PMID- 10782694
TI - Design, synthesis, and structure-activity relationship studies of ATP analogues
as DNA gyrase inhibitors.
AB - We report herein the design and synthesis of ATP-analogues, namely 4-amino
pyrazolo[3,4-d]pyrimidines and 4-amino-pyrazolo[1,5-a][1,3,5]triazines, with DNA
gyrase inhibitory activity. Among these series, some compounds exhibited
promising antibacterial activity.
PMID- 10782695
TI - Chemo- and enzymatic synthesis of partially and fully N-deacetylated 4
methylumbelliferyl chitobiosides: fluorogenic substrates for chitinase.
AB - Partially and fully N-deacetylated 4-methylumberlliferyl chitobioside (1)
derivatives, such as GlcN-GlcNAc-UMB (2), GlcNAc-GlcN-UMB (3), and (GlcN)2-UMB
(4), were synthesized using chemo- and enzymatic procedure. Fluorescent aglycon
was released from the chitobiosides 1, 2 and 3 by the action of chitinase. These
UMB glycosides of heterochitobiose were versatile probes for the investigation of
substrate binding chitinase from various sources.
PMID- 10782696
TI - ORL1 receptor ligands: structure-activity relationships of 8-cycloalkyl-1-phenyl
1,3,8-triaza-spiro[4.5]decan-4-ones.
AB - We have investigated 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o nes
as ligands for the ORL1 receptor. These unsophisticated, achiral compounds show
remarkable affinity for the ORL1 receptor. Optimizing for selectivity we show
that the maximum of affinity and selectivity versus the other opioid receptors is
achieved for 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-o ne 2e and 8
(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one 2q. The
identified compounds (2e, 2q) are more or less equipotent to the natural ligand
itself, both in the binding assay and in the functional GTPgammaS assay.
PMID- 10782697
TI - A convenient extension of the Wessely-Moser rearrangement for the synthesis of
substituted alkylaminoflavones as neuroprotective agents in vitro.
AB - A series of 8-alkylamino-5,7-dihydroxyflavones was prepared from chrysine via a
seven step sequence. The synthesis of their 6-alkylamino isomers could be
subsequently accomplished through a convenient extension of the Wessely-Moser
rearrangement. These compounds were found to be efficient neuroprotective agents
in vitro.
PMID- 10782698
TI - Synthesis and antifungal activity of a ferrocene-fluconazole analogue.
AB - A novel ferrocene fluconazole analogue was synthesized and its antifungal
properties investigated against yeast strains of medical importance, including
those intrinsically resistant to fluconazole. In vitro tests revealed a slight
increase in fungal growth and a reversal of the effect of fluconazole at minimal
inhibitory concentrations.
PMID- 10782699
TI - Dynamics and control of the global tuberculosis epidemic.
AB - Studies of disease burden have reaffirmed that tuberculosis is among the top 10
causes of death in the world. The tuberculosis epidemic in most countries could
eventually be brought under control by implementing the World Health
Organization's (WHO) directly observed therapy, short course (DOTS) strategy,
although tuberculosis linked to human immunodeficiency virus (HIV) in Africa and
multidrug-resistant tuberculosis (MDR-TB) in the former Soviet Union urgently
demand adaptations and extensions of DOTS. Most high-incidence countries have
achieved treatment success rates approaching the WHO 85% target in pilot
projects. In the long term, we may have better diagnostics, drugs, and vaccines
to control the disease; for the next 5 years, the central problem in global
tuberculosis control is to expand DOTS coverage in high-incidence countries.
Improved case finding and diagnosis, coupled with best-practice short-course
chemotherapy, could quickly and dramatically cut the number of years of healthy
life lost due to tuberculosis, especially by preventing death.
PMID- 10782700
TI - Adult tuberculosis overview: African versus Western perspectives.
AB - Tuberculosis is currently an enormous global health problem. In industrialized
countries in Western Europe and North America, tuberculosis case rates are low
and an increasing proportion of cases now occur in foreign-born individuals and
in marginalized populations, including the homeless, prisoners, drug users, and
persons with human immunodeficiency virus (HIV) infection or acquired
immunodeficiency syndrome (AIDS). In contrast, the burden of tuberculosis in sub
Saharan Africa continues to grow, largely fueled by the HIV pandemic and poor
public health infrastructure. Use of the World Health Organization's (WHO)
directly observed therapy, short course (DOTS) strategy has been successful in
improving outcomes and preventing the emergence of acquired drug resistance in
several African countries; however, case rates are increasing throughout most of
the region. It is clear that control of tuberculosis in Africa is closely linked
to control of HIV and AIDS. Substantial external donor support and innovative
approaches to enhance interactions between HIV/AIDS prevention and treatment
efforts and tuberculosis control programs will be needed to improve the current
tuberculosis situation in Africa. The purpose of this review is to provide a
synopsis of recent developments in these areas and to serve as a reference source
for interested readers.
PMID- 10782701
TI - Childhood tuberculosis.
AB - Childhood tuberculosis will reflect the incidence of cavitating pulmonary
tuberculosis in adults and will consequently be encountered most frequently in
those areas with a high incidence of tuberculosis. Problem areas include our
continuing inability to confirm the diagnosis of tuberculosis in many children,
the escalating interaction of the human immunodeficiency virus (HIV) pandemic and
tuberculosis, which is now evident with greater frequency in childhood, and the
scarcity of data relating to antituberculosis therapy in childhood, which
necessitates reliance on adult studies in many cases. This review highlights
several options for obtaining material for culture of Mycobacterium tuberculosis
in children, aspects of tuberculin testing, which remains one of the cornerstones
supporting a diagnosis of tuberculosis in childhood, the potential importance of
therapeutic drug monitoring in problem cases, new data giving epidemiologic and
clinical details of the interaction of HIV infection and tuberculosis in
children, and studies describing the epidemiology of tuberculosis in the
developed and developing world.
PMID- 10782702
TI - Advances in the management of tuberculosis: clinical trials and beyond.
AB - Modern short-course treatment for tuberculosis is highly effective and cost
effective, yet the disease remains a leading cause of suffering and death. The
problem has been exacerbated in recent years by the human immunodeficiency virus
(HIV) pandemic and the increasing prevalence of multidrug-resistant tuberculosis.
Improvements in diagnosis, vaccination, chemoprophylaxis, and therapy are thus
urgently needed. Molecular techniques are facilitating the development of rapid
and sensitive diagnostic tests and the rational approach to the production of new
vaccines. New forms of treatment are being investigated and there is also
considerable emphasis on optimizing the deployment of the available treatment
regimens. This has resulted in the World Health Organization's five-point
directly observed therapy, short course (DOTS) strategy and proposed
modifications (DOTS-plus) for the management of multidrug-resistant (MDR)
tuberculosis. Despite these advances, it is becoming abundantly clear that the
failure to control tuberculosis is a direct consequence of the gross inequities
in the distribution of wealth and health care provision worldwide, which do not
allow for putting advances in the management of tuberculosis into practice. The
control of tuberculosis will therefore require attention to justice and human
rights as well as greatly increased technical and financial support from the
developed nations.
PMID- 10782703
TI - Drug-resistant tuberculosis.
AB - There is increasing concern in many countries about the problem of drug-resistant
tuberculosis, particularly so because no new classes of drugs have been developed
for the treatment of tuberculosis since the 1960s. Although drug resistance is
thought to be fairly common in some countries and rare in others, the global
extent of this condition is not precisely known. This problem is currently being
investigated by a combined initiative of the World Health Organization and the
International Union Against Tuberculosis and Lung Disease. Recently, there have
been advances in the understanding of the genetic basis of drug-resistant
tuberculosis. With the sequencing of the whole genome of Mycobacterium
tuberculosis, the possibility of new targets for drug development has emerged.
For the present, however, cure rates on average remain modest, and nonadherence
with chemotherapy remains a major problem. Drug resistance is a man-made problem
and efforts to prevent it through directly observed therapy, short course are
essential.
PMID- 10782704
TI - Tuberculosis vaccines: developmental work and the future.
AB - The last year in tuberculosis vaccine research has witnessed the initial
flowering of the benefits promised by the tuberculosis genome sequencing product.
Although the real benefits in terms of clinical treatments are yet to be
realized, genomics is making its presence felt in the rapid identification and
expression of proteins with vaccine potential from Mycobacterium tuberculosis,
the definition of species-specific antigens for diagnostic use, and the
construction of a variety of novel living vectors for vaccination. At the same
time, the recent increase in work on animal models with more direct applicability
to the situations likely to be encountered in human vaccine trials are providing
the basic underpinnings needed for the assessment of these new vaccines.
PMID- 10782705
TI - Advances in understanding pulmonary host defense mechanisms: dendritic cell
function and immunomodulation.
AB - Mucosal host immunity in the respiratory tract can probably be manipulated to
better improve defense against microbes and other antigens or particulates that
cause infection and respiratory illness. An evolving strategy is to target the
extensive network of dendritic cells in the lungs, especially dendritic cells
located in the airway epithelium, which are super antigen-presenting cells that
can initiate specific T-lymphocyte immune responses. Also, dendritic cells can
elaborate cytokines such as interleukin 12 which drive other components of the
immune response including antibody production. However, dendritic cells can be
counter-regulated by inhibitory cytokines or certain microbes that create a
dynamic interplay. This review emphasizes human studies and relevant animal
models that provide a framework for future planning of experimental approaches to
enhancing antimicrobial immunity and respiratory host defense.
PMID- 10782706
TI - Sinusitis in adults.
AB - Symptoms of sinusitis are among the most common reasons for patients presenting
to primary care physicians. There is considerable controversy regarding
appropriate management of both acute and chronic sinus disease. This article
reviews etiologic mechanisms in these conditions and presents recent evidence to
provide a logical basis on which to make decisions regarding medical and surgical
therapy.
PMID- 10782707
TI - Acute and chronic sinusitis in children.
AB - There is one subject in recent publications on pediatric sinusitis on which most
authors agree, and that is that the public cannot continue to receive antibiotics
on demand solely because of purulent nasal discharge, and that clinicians cannot
continue to prescribe broad-spectrum and expensive antibiotics for minimal
indications. Two publications show that the prevalence of various anatomical
variations is no greater in children with rhinosinusitis than in a control group.
This mirrors recent work in adults and implies that immunity and the way the
mucosa reacts to pathogens is likely to be of primary importance, rather than the
anatomy. Several good reviews on the management of rhinosinusitis in children all
emphasize the need for medical and not surgical management of these patients
except in cases in which the complications of sinusitis develop. The fact that
computed tomography is poor at diagnosing sinusitis in children is also a
recurring theme.
PMID- 10782708
TI - Community-acquired pneumonia.
AB - Community-acquired pneumonia (CAP) remains a leading cause of morbidity and
mortality worldwide and has significant financial implications for health-care
systems. The epidemiology and fundamental biology of the disease has evolved,
reflecting the human immunodeficiency virus pandemic, increasing world travel,
and, as always, poverty. The promise held out by molecular diagnostic technology
has yet to deliver in this arena, and antibiotic resistance continues to drive
the quest for new antimicrobial agents. The emergence of multidrug-resistant
Streptococcus pneumoniae, the microorganism most often implicated as a cause of
CAP, continues to threaten treatment options. The evolution of this organism, the
persistently high mortality rate associated with CAP, and increasing health-care
costs have prompted the publication of guidelines by various authorities that can
be used to assist in the initial assessment of the patient and then guide
empirical antimicrobial therapy. It is unclear whether these guidelines will have
significant impact on cost and mortality, although the trend toward a rational
and evidence-based approach to antimicrobial therapy must be a goal to aspire to.
PMID- 10782709
TI - Pyogenic lung infections: factors for predicting clinical outcome of lung abscess
and thoracic empyema.
AB - Lung abscess and thoracic empyema continue to cause significant morbidity and
mortality despite appropriate antibiotic therapy and various options for drainage
of empyema. Multiple factors, including the patient's general state of health,
the presence of underlying disease, the virulence of the pathogen responsible,
and the promptness of drainage of empyema, appear to dictate the clinical
outcome. However, the available data are derived from uncontrolled, retrospective
studies and the high morbidity and mortality rates underscore the need for large
prospective studies to better evaluate factors that may predict the clinical
outcome of these conditions.
PMID- 10782710
TI - Human immunodeficiency virus and respiratory infection.
AB - Pulmonary disease remains a major problem for the 33 million individuals who are
thought to be infected with human immunodeficiency virus (HIV) worldwide.
Respiratory infections are responsible for a large number of the 2 million deaths
that occur each year in association with HIV disease. In countries where the
majority of the population can access highly active antiretroviral therapy,
morbidity and mortality rates have been cut by up to 80%. This has allowed the
withdrawal of specific opportunistic infection prophylaxis when immune
restoration is deemed to be adequate. Recommendations have been published
concerning Pneumocystis carinii prophylaxis. This year has also seen further
reports of drug-resistant isolates of Pneumocystis carinii. The clinical
relevance of this is still debated. Tuberculosis remains a global problem. The
complexity of the interactions between specific anti-HIV and anti-tuberculous
treatment have been highlighted. In the developing world, the importance of
immunization and prophylaxis (against bacteria and mycobacteria) have recently
been further defined in a number of studies.
PMID- 10782711
TI - Respiratory infections in the traveler.
AB - The growth of travel of recent years has been unprecedented and presents new
challenges to health professionals worldwide. More travelers of diverse
backgrounds are visiting exotic locales rarely encountered before. This poses new
risks to health, in addition to potentially aiding the spread of emerging
respiratory infections. Travelers such as immunocompromised individuals and
members of ethnic minorities are at significant risk for travel-related
infections. Respiratory illnesses are some of the most common infections
affecting human beings, yet little information has been published on them in
relation to travel. Multidisciplinary approaches and collaboration across
different sectors are needed to address the many issues involved in travel
related respiratory infections. This article discusses some of the topical issues
of respiratory tract infections occurring in travelers.
PMID- 10782712
TI - Advances in antimicrobial therapy for respiratory tract infections.
AB - Even at the turn of the millennium, respiratory infections exact a heavy toll on
the American public. Pneumonia is the leading infectious disease cause of death,
and influenza costs Medicare more than $1 billion each year. This article
highlights some of the advances this past year in antimicrobial therapy for
respiratory tract infections. Efforts are targeted at shortening the length of
treatment and reducing costs for pneumonia. A promising new class of antivirals
has been introduced for the treatment of influenza, and alternative medicine
continues to receive more scientific scrutiny. Antimicrobials alone are not the
answer, and preliminary work on immunomodulatory therapies may usher in a new era
of multifaceted treatment approaches.
PMID- 10782713
TI - Bibliography. Current world literature. Infectious diseases.
PMID- 10782714
TI - Perspectives in suicidology: families, mental illness, and suicide.
AB - The ways in which the key words "family," "mental illness," and "suicide" are
interpreted in the context of research into suicide will influence the formation
of theories, the interpretation of results, and the development of suicide
prevention strategies. It is argued that there is no general agreement about the
meaning of these words.
PMID- 10782715
TI - Collaborating to prevent suicide: a clinical-research perspective.
AB - It is argued that suicidality is essentially a relational phenomenon; the
presence or absence of certain key relationships paradoxically can be both
suicide causing and suicide preventive. The relational aspects of suicide are
especially poignant in clinical work with suicidal patients. However, when
suicidality is involved, there are a number of issues that can interfere with
effective clinical practice. Fortunately, a new paradigm has begun to emerge in
contemporary clinical suicidology, which objectifies suicidality and emphasizes
the phenomenology of suicidal states. Moreover, from an increasingly empirical
perspective, this approach is creating new and better ways to effectively assess
and treat suicidal conditions.
PMID- 10782716
TI - The suicidal mode: a cognitive-behavioral model of suicidality.
AB - This article discusses the theoretical foundation and potential clinical
application of the suicidal mode, a cognitive behavioral theory of suicidality.
The model presented represents a specific elaboration of Beck's modal theory of
psychopathology. In addition to discussing the fundamental requirements of a
theory of suicidality, the theoretical assumptions of the suicidal mode are
identified, its component parts defined, its inherent strengths emphasized, and
its application in clinical settings detailed. Definition of a modal theory of
suicidality represents the growing influence of cognitive-behavioral theory in
efforts at psychotherapeutic integration in clinical suicidology.
PMID- 10782717
TI - Depression, suicide, and suicide prevention in schizophrenia.
AB - Suicide is the single largest cause of premature death among individuals with
schizophrenia. Furthermore, epidemiological data indicate that nearly 80% of
patients with the diagnosis of schizophrenia will experience a major depressive
episode at some time during their lifetime. This report reviews recent findings
relative to the risk of suicide in schizophrenia, including data from the
Chestnut Lodge longitudinal study of schizophrenia subtypes and symptom domains.
Paradoxically, those patients with schizophrenia who are most likely to recover
or experience a good outcome are also those at greatest risk for suicide. The
reduction of morbidity and mortality in schizophrenia should include depression
and suicidality as targets for both psychopharmacological and psychosocial
treatment.
PMID- 10782718
TI - Writing projects: lessening undergraduates' unique suicidal bereavement.
AB - To assess if writing projects lessen undergraduates' grief following a loved
one's suicide, 40 students whose loved one died by suicide in the past 2 years
wrote on four occasions over 2 weeks about profound topics (e.g., events and
emotions surrounding the death) or trivial topics (e.g., description of the
previous meal). All participants completed pre- and posttest measures of grief
and self-reported health visits, and 75% completed the same measures at 6-week
mailed follow-up. As expected, individuals in the profound condition reported
less grief associated with suicide at follow-up than those in the trivial
condition. However, the trivial and profound groups were not significantly
different in general grief or health visits. Writing about grief associated with
the suicide of a loved one appeared to reduce suicidal grief associated with this
event. However, this benefit did not extend to general grief or physical health.
PMID- 10782720
TI - Suicide among adolescents and young adults: a cross-national comparison of 34
countries.
AB - Few cross-national reports have examined suicide rates among adolescents and
young adults. A survey of suicides among 15-24-year-olds in 34 of the wealthiest
nations demonstrated that 15,555 youths killed themselves in a 1-year study
period. Thirty-four percent of these suicides were firearm-related. Finland led
the participating nations in total and firearm-related suicide rates. An
association was found between divorce rates and youth suicide rates, firearm
related suicide among youths, and suicide rates among young males. For a smaller
sample of countries, an association was found between firearm availability and
firearm-related suicide rates among youths and suicide rates among young males.
PMID- 10782719
TI - Suicidal behavior in the municipality of Baerum, Norway: a 12-year prospective
study of parasuicide and suicide.
AB - The present 12-year (1984-1995) surveillance study includes all hospitalized
parasuicide patients (n = 1,031) as well as all suicides (n = 161) in the
municipality of Baerum, a suburb of Oslo. The parasuicide rate decreased from 170
per 100,000 in 1984 to 79 per 100,000 in 1995 (53.5%). The parasuicide rates were
lower than those in several comparable studies. Rates were higher for divorced
females and separated males compared to married and other marital states, and the
pattern of relative risk of parasuicide with respect to marital status was
stable. Unemployment and substance abuse were positively correlated with
parasuicidal behavior for both males and females. Approximately 33% reported one
or more previous parasuicidal acts, and 21% repeated the parasuicide during the
observation period. Ninety-four percent used self-poisoning as parasuicide
method. A total of 2.4% of the parasuiciders committed suicide during the
observation period. The mean annual suicide rate in Baerum was 19.0 per 100,000
compared to the national average of 14.7. The results support the notion of
parasuicide and suicide being two different but overlapping populations. The
implementation of a follow-up system for parasuiciders may have contributed to
the reduced parasuicide rate during the study period.
PMID- 10782721
TI - Mansur Zaskar: a man almost bored to death.
PMID- 10782722
TI - Magnetic resonance imaging of the normal temporal bone.
AB - Recent advances in magnetic resonance imaging (MRI) technology has allowed the
development of imaging sequences tailored to the assessment of exquisite anatomic
detail of the temporal bone structures. This article describes MRI of the normal
temporal bone anatomy, with emphasis on common anatomic variants and clinically
relevant structures.
PMID- 10782724
TI - Magnetic resonance imaging for evaluation of otic labyrinth pathology.
AB - The auditory (cochlear) labyrinth, the cochlea, holds the hearing sensory
receptors. The vestibular labyrinth contains the sensory receptors for balance,
which lie in the three semicircular canals and in the otolithic organs (the
saccule and utricle). Pure tone audiometry and brain stem evoked audiometry can
help to differentiate a peripheral cochlear disorder from central lesion. The
type of nystagmus, severity of postural instability, and neurological evaluation
can help to differentiate a peripheral vestibular disorder from a central
vestibular lesion. The decision whether to perform an appropriate imaging such as
brain imaging versus labyrinthine imaging depends on the clinical and
paraclinical information provided to the radiologist by the neurotologist,
neurologist, or other clinicians. The magnetic resonance imaging characteristics
of peripheral cochlear and vestibular lesions are the main focus of this article.
PMID- 10782723
TI - Congenital sensorineural hearing loss and enlarged endolymphatic sac and duct:
role of magnetic resonance imaging and computed tomography.
AB - During the past 20 years, there have been significant advances in cochlear
implants as the treatment of choice for profoundly hearing-impaired children. The
increasing application of cochlear implant has brought with it an increase in the
investigational use of computed tomography and magnetic resonance imaging. In
this article, the author reviews (a) the anatomy and embryology of the inner ear,
(b) the pathological changes associated with congenital sensorineural hearing
loss (SNHL), and (c) the spectrum of imaging findings in patients with SNHL.
PMID- 10782725
TI - Value of imaging in disorders of the facial nerve.
AB - Imaging of the facial nerve has proved its usefulness to physicians in the
evaluation of pathological conditions of this nerve. Magnetic resonance imaging
(MRI) of the facial nerve should always be obtained selectively and should
include the parotid gland in case of peripheral facial nerve palsy. Gadolinium
DTPA contrast pulse sequence is the most informative MRI study for evaluation of
facial nerve pathology. This article reviews the imaging anatomy of the facial
nerve and describes the clinical features and MR characteristics of common
disorders of the facial nerve.
PMID- 10782726
TI - Magnetic resonance imaging of the internal auditory canal.
AB - Magnetic resonance imaging (MRI) is presently the study of choice for assessment
of the internal auditory canal (IAC). MRI provides excellent assessment of the
IAC and the bony changes occurring in the canal walls, and it provides excellent
demonstration of the content of the canal. Pathological processes arising within
the IAC are well visualized by various MR sequences. The possibility of
demonstrating masses as small as 2 mm has propelled MRI into the leading role for
diagnosis of vestibular schwannoma. Unfortunately, the high cost of MR has been a
limiting factor in its use as a screening test for patients with sensorineural
hearing loss (SNHL) of unknown origin. Auditory brain stem response has been
widely used as a screening procedure, but this test fails to recognize small
lesions and cannot be used whenever hearing loss is severe. In this article, we
will discuss our approach to assessment of the IAC in patients with retrocochlear
SNHL or vestibular symptoms of central origin, review the pathological processes
involving the IAC walls or arising within the canal, emphasizing the appropriate
MRI sequences used for diagnosis.
PMID- 10782727
TI - Langerhans histiocytosis of temporal bone: role of magnetic resonance imaging.
AB - Langerhans cell histiocytosis (LCH) may involve nearly every organ of the body.
In children, head and neck involvement has been reported in as many as 82% of
patients. Sites of head and neck involvement include skull, temporal bone, orbit,
mandible, maxilla and cervical nodes. In addition, patients may have coexisting
central nervous system (CNS) involvement adjacent to, or remote from, osseous
lesions. Magnetic resonance imaging (MRI) of the temporal bone in patients with
LCH is ideal for evaluating the extracranial extent of the soft-tissue mass and
is complementary to computed tomography (CT) in the assessment of osseous
erosion. MRI is superb in the evaluation of intracranial extension, usually into
the middle cranial fossa, and of patency of adjacent vascular structures. It is
the imaging modality of choice to evaluate patients with suspected CNS
involvement of LCH, which includes lesions of the infundibulum, cerebrum,
cerebellum, and extra-axial spaces.
PMID- 10782728
TI - Increasing access to renal transplantation in the 21st century.
PMID- 10782729
TI - Maintenance immunosuppression: new agents and persistent dilemmas.
AB - Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil,
tacrolimus, and sirolimus, have been approved for maintenance immunosuppression
in renal transplant recipients. All 3 agents decrease the incidence of early
acute allograft rejection. An increase in intermediate and long-term graft
survival has not been shown. However, survival data from these clinical trials
should be interpreted with caution because the studies were not designed for this
purpose. All 3 drugs have significant, albeit different, safety profiles. It
remains to be seen whether, the lower incidence of hypertension and
hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and
severity of the cardiovascular disease experienced by renal transplant
recipients. Sirolimus causes severe hyperlipidemia, and the long-term
consequences both on the pathogenesis of cardiovascular disease and on lipid
associated renal injury have yet to be determined. Tacrolimus and mycophenolate
mofetil appear to increase graft survival in pancreas-kidney recipients but their
efficacy in another high-risk group, African-American recipients, has not yet
been clearly shown. However, the trend toward improved graft survival in African
American recipients treated with tacrolimus is encouraging. Steroid-withdrawal
remains a goal in the posttransplant period. The available data from steroid
withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal
can be achieved in about 50% of patients on a cyclosporine-based
immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus,
mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may
be more successful than that achieved in patients receiving Sandimmune (Novartis
Pharmaceuticals). Further studies are needed in this area.
PMID- 10782730
TI - Expanded criteria donors: attempts to increase the renal transplant donor pool.
AB - There is a growing disparity between the demand for and the supply of kidneys for
transplantation. The demographics of the donor pool are also changing. The
average potential cadaveric organ donor is now more likely to be older, at
greater risk for co-morbid conditions such as hypertension or viral infections,
and more likely to die from cerebrovascular disease. These factors have led to an
expansion of the criteria that defines the suitable organ donor. Expanded
criteria donors are defined as the following: (1) at the upper and lower extremes
in age; (2) having a history of hypertension or diabetes; (3) hemodynamically
unstable; (4) non-heartbeating (cardiopulmonary death rather than brain death);
(5) seropositive for hepatitis B or C; (6) having systemic infections; (7) having
displayed high-risk social behavior for HIV infection; (8) having a history of
malignancy; (9) having abnormal organ function; or (10) with renal anatomic
anomalies or injuries. Use of kidneys from these "expanded criteria donors" is a
two-edged sword. While they provide more organs for transplantation, the risk of
suboptimal recipient outcome is increased. A rational approach to the use of each
of these types of kidneys and proper selection of recipients is essential to
obtain acceptable results. The article reviews the factors that have contributed
to the successful transplantation of kidneys procured from expanded criteria
organ donors and how these organs can be allocated most efficaciously to the
appropriate recipients.
PMID- 10782731
TI - Infectious complications in renal transplant recipients.
AB - Infectious complications present major challenges to physicians caring for renal
transplant recipients. The high rate of infection reflects the net state of
immunosuppression associated with end-stage renal disease, transplantation, donor
and environmental exposure. An understanding of the factors that affect the
patients' overall state of immunosuppression is essential to prevent and treat
infectious complications, which may lead to significant morbidity, graft
dysfunction, or mortality. Familiarity with the various pathogens, clinical
presentation, diagnostic options, treatment, and prophylaxis is important to care
for renal transplant patients. The authors present their approach, based on
review of current literature, to these issues.
PMID- 10782733
TI - Israel (Sol) Penn (1930-1999).
PMID- 10782732
TI - Cancers in renal transplant recipients.
AB - Data regarding posttransplant cancers are reviewed from the Cincinnati Transplant
Tumor Registry (CTTR) and from the literature. The CTTR has data on 9,688 types
of cancer that developed in 9,032 renal allograft recipients. The predominant
tumors are lymphomas and lymphoproliferations (PTLD), carcinomas of the skin and
lips, carcinomas of the vulva and perineum, in situ carcinomas of the cervix of
the uterus, Kaposi's sarcoma (KS), hepatocellular carcinomas, renal carcinomas,
and various sarcomas (excluding KS). Prominent features of the PTLD cases are
their high incidence, frequent involvement of extranodal sites, a marked
predilection for the brain, and frequent involvement of the allograft by tumor.
Skin cancers also present unusual features, a remarkable high frequency of KS,
reversal of the ratio of basal cell carcinomas to squamous cell carcinomas that
is seen in the general population, the young age of the patients, the high
incidence of multiple tumors (in 44% of patients), and the aggressive behavior of
some squamous cell carcinomas. Cancers of the vulva and perineum occur at a much
younger age than in the general population and are preceded by a history of
condyloma acuminatum in over 57% of cases. Reduction or cessation of
immunosuppressive therapy is of value in some patients with PTLD or KS but
carries the risk of allograft rejection.
PMID- 10782734
TI - Progress in renal transplantation for children.
AB - Renal transplantation continues to be the goal of therapy for children with end
stage renal disease. Patient age, primary renal disease, psychosocial status,
living versus cadaver donor allograft, immunosuppressive therapy, urologic
status, and maximization of growth and development must be considered in
determining the optimal time for transplantation. Immunizations should be up to
date, and the immune status of both the donor and the recipient with regard to
Epstein Barr virus (EBV), cytomegalovirus (CMV), varicella, human
immunodeficiency virus (HIV) and Hepatitis A, B, and C must be known. Prednisone;
cyclosporine or tacrolimus; and mycophenolate mofetil or azathioprine remain the
mainstays of immunosuppression. However, new therapies such as sirolimus are
under investigation for use in pediatric renal transplantation. Induction
therapies include T-cell antibodies as well as the more recent addition of
interleukin-2 receptor blockers. Complications including infection, rejection,
and malignancy continue to be problematic in pediatric renal transplantation.
There continues to be a strong focus on optimizing growth and development after
transplant. Although patient and graft survival have improved over time, outcomes
in pediatric renal transplantation continue to lag behind those in adults.
PMID- 10782735
TI - The role of the advanced practice nurse in the care of organ transplant
recipients.
AB - The role of the advanced practice nurse (APN) in transplantation has evolved from
the role of the clinical transplant coordinator. This report attempts to define
the credentials, practice domains, barriers to practice, and reimbursement issues
related to APN practice while contrasting the role with that of clinical
transplant coordinator. The nephrology APN working in a collaborative transplant
practice can be an integral part of a multidisciplinary health care team. The
APN's education and credentials empower them to provide a wider scope of services
than transplant coordinators who are "experts by experience." These services can
include providing primary care and performing procedures such as percutaneous
transplant biopsies, insertion of peripheral and central venous catheters, and
wound debridement as well as management of patients along their continuum of
transplant care. Patient education and advocacy also are key components of APN
practice. In addition, the services the APN provides generally are reimbursable
and therefore can provide revenue for the practice.
PMID- 10782736
TI - Patient-nephrologist discussions about kidney transplantation as a treatment
option.
AB - Little is known about how nephrologists discuss transplantation as a treatment
option with end-stage renal disease patients. The authors sought to describe the
content and manner of patient-nephrologist discussions about transplantation.
Using a cross-sectional study design, we interviewed 79 chronic hemodialysis
patients and 12 nephrologists using a semistructured questionnaire that focused
on nephrologist and patient reports of discussions about transplantation. The
authors found that nephrologists provided information on treatment options
gradually over several weeks to months. They generally presented the option of
dialysis first, then transplantation, but avoided discussing mortality data.
Nephrologists said they encouraged most patients, but especially young patients,
to seek transplantation. Of all patients, 68% reported being encouraged to seek
transplantation by nephrologists. Low socioeconomic status patients were less
likely to report being encouraged to seek transplantation even after adjustment
for transplant suitability. Both nephrologists and patients avoided discussing
life expectancy data. In conclusion, patient age and socioeconomic status appear
to influence discussions of transplantation as a treatment option. Further work
is needed to determine how the content and manner of such discussions affect
treatment decisions.
PMID- 10782737
TI - The ECB renal patient questionnaire: an assessment tool to determine renal
patients' needs for immediate social work intervention.
AB - Medicare mandates that all persons with end-stage renal disease (ESRD) receive
clinical social work assessment and intervention for psychosocial needs. Crisis
intervention rather than preventative social service often occurs because of an
annual increase in the number of patients diagnosed with ESRD, tightening of
social work budgets, larger and more complex case loads, diminishing resources
and staff, increased patient acuity, and emphasis on outpatient care. To decrease
crisis intervention episodes, enhance allocation of time and resources, and
improve quality of patient care, the authors investigated the creation of a
short, self-administered, easily scored instrument to predict ESRD patients in
need of immediate social work intervention. In 4 research phases, from 1986 to
1994, with 791 subjects from all ESRD treatment modalities, the ECB Renal Patient
Questionnaire (ECB) was developed. The ECB is a 30-item questionnaire that is
highly reliable, valid, easy to administer and score, and is accurate with
frequent use. It has been tested nationally to establish scoring norms. The
research phases are reported here to make the ECB more widely available to renal
health care professionals.
PMID- 10782738
TI - Traditional intravaginal practices and the heterosexual transmission of disease:
a review.
AB - OBJECTIVE: To review reports on the use and effects of traditional intravaginal
substances and practices. METHOD: The medical and social science literature of
the past 50 years regarding use and effects of traditional intravaginal
substances and practices is reviewed. RESULTS: Traditional intravaginal practices
have been described in 11 countries of sub-Saharan Africa, and also in Qatar,
Indonesia, Thailand, Haiti, the Dominican Republic, and the United States.
Women's reasons for the practices include personal hygiene, disease prevention or
treatment, and enhancement of sexual experience. Few studies document damage to
the vaginal epithelium or changes in vaginal flora due to these practices. No
prospective studies link these practices to disease transmission. CONCLUSION: The
determination of how these practices affect disease transmission will require
precise definition of independent variables, which is difficult because of the
diversity of the practices. It is appropriate to search for intervening
variables; specifically, the effects on the vaginal pH, flora, and epithelium.
PMID- 10782739
TI - Potential for community-based screening, treatment, and antibiotic prophylaxis
for syphilis prevention.
AB - BACKGROUND: The recent syphilis epidemic in Louisiana occurred predominantly
among disadvantaged African Americans who may distrust public health agencies and
prevention efforts. OBJECTIVES: To determine community perceptions regarding
trust and use of public health clinics, to assess whether race of provider is
important to persons at risk for syphilis, and to assess the willingness of
persons to participate in syphilis screening, treatment, and antibiotic
prophylaxis. STUDY DESIGN: Qualitative interviews were conducted with 18
community leaders and 38 community members who were at risk for syphilis.
Quantitative surveys were completed by persons with primary or secondary syphilis
(n = 92), their sexual contacts (n = 56), and with neighborhood controls (n =
143). Three possible programs for syphilis screening and antibiotic prophylaxis
were proposed (1) bar setting; (2) home setting, and (3) mobile health-van
setting in high-risk communities. RESULTS: In qualitative interviews, community
leaders and community members reported a high degree of trust in the public
sexually transmitted disease clinic. A majority of respondents felt that race was
not a factor in choosing healthcare providers. Respondents favored the provision
of services in a mobile health van over in a bar or in their homes. In
quantitative interviews, more than 80% of community members surveyed reported
that they would go to a mobile health van for syphilis testing. Nearly two thirds
of respondents reported that they would be willing to take oral prophylaxis for
syphilis, and more than half of respondents reported that they would accept an
injection. CONCLUSIONS: Community members trust the public sexually transmitted
disease (STD) clinic, are generally not concerned with the race of healthcare
providers, and are supportive of community-based STD screening, treatment, and
antibiotic prophylaxis provided from a mobile clinic.
PMID- 10782741
TI - Gonorrhea in male adolescents and young adults in Newark, New Jersey:
implications of risk factors and patient preferences for prevention strategies.
AB - BACKGROUND: Although the national rate of gonorrhea declined 68% from 1975 to
1995, rates remain high in many inner-city areas. In 1995, the gonorrhea rate in
Newark, NJ, was five times the US rate. OBJECTIVE: To determine factors
associated with acquisition of gonorrhea by men in Newark. STUDY DESIGN: A case
control study conducted at the sexually transmitted disease (STD) clinic in
Newark, comparing males 15 to 29 years with culture-confirmed gonorrhea to
controls with no STD. RESULTS: Compared with controls, males with gonorrhea more
frequently reported at least 1 casual sex partner within the preceding month
(adjusted odds ratio [OR], 3.2; 95% CI, 1.8-5.7), sex after using marijuana
during the preceding month (OR, 2.4; 95% CI, 1.1-5.3), and a history of
incarceration (OR, 2.1; 95% CI, 1.2-3.7). Of males with casual partners, having a
new casual sexual relationship (onset within the past month) was particularly
risky for gonorrhea (OR, 3.9; 95% CI, 1.2-12.7). Incorrect condom use was highly
prevalent for both cases and controls. Many persons with gonorrhea reported that
they were not willing to consistently use condoms or to have only one partner.
CONCLUSIONS: Sex with casual partners is associated with gonorrhea in males, and
may be a difficult practice to change. Condoms are often used incorrectly, if at
all, in this population. Prevention strategies, in addition to the promotion of
condom use and monogamy, may be necessary.
PMID- 10782740
TI - To notify or not to notify: STD patients' perspectives of partner notification in
Seattle.
AB - BACKGROUND AND OBJECTIVES: To obtain patients' perspectives on why only some
partners are notified in partner-notification programs, the cornerstone of
sexually transmitted disease (STD) control, although low proportions of partners
are located and evaluated. GOALS: To describe patterns of partner notification
reported by persons with STD infection. STUDY DESIGN: In-depth interviews
conducted in Seattle with 60 heterosexual men and women with gonorrhea,
chlamydial infection, or nongonoccocal urethritis, and 19 men with gonorrhea
reporting sex with men (MSM) were tape recorded, transcribed verbatim, and
content analyzed. RESULTS: The typical notification pattern was to notify a main
partner but not others. Least likely to be notified were partners perceived as
transmitters, contacts preceding the onset of symptoms, the oral sex and
anonymous contacts of MSM, one-time partners of men, and incarcerated and former
partners of women. Fears among young heterosexual participants included gossip
and violence (women). Fears among MSM included rejection. CONCLUSIONS: Partner
notification programs should develop innovative approaches for partners perceived
as transmitters, oral-sex only contacts of MSM, and contacts preceding symptom
onset.
PMID- 10782742
TI - A prospective study on condom slippage and breakage among female brothel-based
sex workers in Singapore.
AB - BACKGROUND: Concerns about the effectiveness of condoms in preventing sexually
transmitted diseases have been raised. Data are lacking on condom failure and its
associated factors among sex workers in Southeast Asia. GOAL: To assess factors
associated with condom breakage and slippage. STUDY DESIGN: A prospective study
on condom breakage and slippage over a 1-day period was conducted among 219
female brothel-based sex workers in Singapore in 1997. RESULTS: Condom breakage
and slippage rates among 1,885 episodes of condom use were 1.2% (95% CI, 0.7-1.8)
and 2.1% (95% CI, 1.2-3.0), respectively. After adjusting for intracluster
effects and confounders, condom breakage and slippage were significantly
associated with duration of sex work and spontaneity of clients to use condoms.
CONCLUSION: Condom use among sex workers should be promoted in view of the low
failure rates. Strategies to reduce condom breakage and slippage should be
directed at sex workers with increased risk of condom failure.
PMID- 10782744
TI - Gonorrhea, chlamydia and the sexual network: pushing the envelope.
PMID- 10782743
TI - Comparative epidemiology of heterosexual gonococcal and chlamydial networks:
implications for transmission patterns.
AB - OBJECTIVE: Networks of sex-partner interaction affect differential risk of
acquiring sexually transmitted infections. The authors evaluated sociodemographic
and behavioral factors that correlated with membership in networks of gonococcal
and chlamydial transmission. METHODS: Face-to-face interviews were conducted with
127 patients with gonorrhea and 184 patients with chlamydia (index cases) and
their named sex partners, as well as the partners of infected partners. Detailed
information was obtained regarding demographic, behavioral, and sexual-history
characteristics of all respondents. RESULTS: Gonococcal-network members differed
significantly from chlamydial-network members in a number of demographic
variables, including race or ethnicity, education, and unemployment status.
Gonococcal-network members were more likely to report past history of crack
cocaine use, sexual assault, and having been in jail. Gonococcal-network members
also reported having more sex partners during the past 1 year and 3 months than
did chlamydial-network members. Gonococcal and chlamydial mixing matrices
demonstrated assortativeness for sex partner selection by race or ethnicity but
not by sexual activity level, and no systematic differences between networks were
noted. Gonococcal networks were larger than chlamydial networks. CONCLUSIONS:
Network analyses of gonococcal and chlamydial infections demonstrated significant
differences in sociodemographic and behavioral variables. Further research is
required to delineate specific predictors of network membership among persons at
risk for sexually transmitted infections.
PMID- 10782745
TI - Mycoplasma genitalium in males with nongonococcal urethritis: prevalence and
clinical efficacy of eradication.
AB - BACKGROUND: Mycoplasma genitalium is regarded as a potential pathogen of the
human urogenital tract based on prevalence findings of several European studies.
GOAL: To determine the prevalence of M genitalium in urethral specimens of
symptomatic patients with nongonococcal urethritis and from asymptomatic patients
attending a sexually transmitted disease clinic in Milan, and to verify the
clinical efficacy of M genitalium eradication by antibiotic treatment. STUDY
DESIGN: From May 1998 to late April 1999, a routine analysis for M genitalium by
DNA amplification (polymerase chain reaction) was performed in patients attending
the Institute of Dermatological Science in Milan. The authors examined urethral
swabs from 178 symptomatic and 23 asymptomatic males. M genitalium-positive
patients were clinically and microbiologically tested after treatment with either
doxycycline or azithromycin. RESULTS: Among males with nongonococcal urethritis,
M genitalium was detected in 14.0% of patients as the only agent; in 15.1% of
patients in association with Chlamydia trachomatis and/or Ureaplasma urealyticum;
and in 1 asymptomatic patient. In all symptomatic M genitalium-positive patients,
antibiotic treatment eradicated the infection and cured clinical symptoms.
CONCLUSION: These data reveal the high prevalence of M genitalium in symptomatic
patients, the rarity of asymptomatic carriers, the high susceptibility to
antibiotic treatment, and the clinical efficacy of M genitalium eradication.
Moreover, data confirm the etiologic role of M genitalium in inflammatory
processes of the human urogenital tract in the Mediterranean area.
PMID- 10782746
TI - Candida vaginitis: self-reported incidence and associated costs.
AB - BACKGROUND AND OBJECTIVES: Incidence of Candida vaginitis by age and racial or
ethnic group is poorly described. GOAL: Estimate incidence, cumulative
probability of presumed C vaginitis by age, racial or ethnic group, and
associated costs. STUDY DESIGN: Random digit-dialing survey of 2000 US women.
RESULTS: A total of 6.5 percent (95% CI, 5.4-7.5%) of women older than 18 years
reported a least one episode of presumed C vaginitis during the previous 2
months. Women reporting a 1-year period with four or more episodes comprised 8.0%
of the sample but accounted for 37.2% of women reporting episodes. Black women
reported approximately three times more yeast infections in the previous 2 months
(17.4%; 95% CI, 11.2-23.5%) than white women (5.8%; 95% CI, 4.7-6.9%).
CONCLUSION: The high incidence and the propensity for recurrence underscore the
need for a better understanding of the epidemiology and pathogenesis, and stress
the need for the development of more accurate, rapid diagnostics and effective
treatments.
PMID- 10782747
TI - Comparative prevalence of infection with Trichomonas vaginalis among men
attending a sexually transmitted diseases clinic.
AB - OBJECTIVE: Although established in women as a common cause of vaginal discharge,
the prevalence of Trichomonas vaginalis (TV) in men compared with other classic
urethral pathogens has not been well characterized. To assess this issue, the
authors compared the prevalence of Neisseria gonorrhoeae (GC), Chlamydia
trachomatis (CT), and TV in consecutive men attending a sexually transmitted
diseases (STD) clinic. METHODS: From June 1, 1998 to July 27, 1998, 454
consecutive men presenting to the Denver Metro Health Clinic with a new problem
were tested for GC by urethral swab culture, for CT by polymerase chain reaction
of urine, and for TV by urine sediment culture. RESULTS: GC, CT, and TV were
detected in 23 (5.1%), 34 (7.5%), and 13 (2.8%) of men, respectively. There were
significant differences by age for both CT (11.3% in men younger than 30 years
versus 3.3% in men 30 years and older, P < 0.05) and TV (0.8% in men younger than
30 years versus 5.1% in men 30 years and older, P < 0.05). In 50 men 30 years or
older with symptoms of urethral discharge, TV prevalence (12.0%) rivalled that of
GC (12.0%) and CT (14.0%). In 45 men 30 years and older with nongonococcal
urethritis, the prevalence of TV and CT were each 13.3%. Multivariate logistical
regression analysis showed the presence of discharge and nongonococcal urethritis
in men 30 years and older to be an independent predictor of TV. CONCLUSIONS: TV
is common in men attending sexually transmitted disease clinics, especially in
those 30 years or older, in whom it may account for as much urethritis as GC or
CT. These findings suggest that in older men with nongonococcal urethritis,
diagnostic evaluation, empiric treatment, and partner management should include
the possibility of TV infection.
PMID- 10782748
TI - Consider diagnosis and treatment of trichomoniasis in men.
PMID- 10782749
TI - Calcium channel blockers in diabetic subjects: innocent at last?
AB - Calcium antagonists are indicted as a potential trigger of a variety of
complications spanning from myocardial infarction to bleeding and cancer. Three
randomised controlled trials, the MIDAS, the FACET and the ABCD trial, seem to
suggest that the risk for myocardial infarction is increased in diabetics on
calcium antagonists. These trials in aggregate totalled only 92 cardiovascular
events and it is possible that the observed differences were due to random
errors. Most of the patients of the ABCD trial discontinued the medication to
which they were initially randomised before the end of the study, which raised
the possibility of systematic bias. In both the MIDAS and ABCD studies
cardiovascular events were secondary end-points and the apparent adverse effects
were identified only by subgroup analyses. Furthermore, in both studies, patients
in the control groups were being treated with ACE inhibitors. The lack of a
placebo group makes it impossible to establish whether the observed effects were
due to the harmful influence of calcium antagonism or to the favourable effects
of ACE inhibition. New data abstracted from the PIUMA database show that the rate
of total cardiovascular and cardiac events did not differ between diabetics on
calcium antagonists and diabetics not using these drugs. These new data are in
keeping with findings in the HOT study where an impressive degree of cardiac
protection was observed in diabetic patients on felodipine.
PMID- 10782750
TI - Peripheral insulin sensitivity is decreased by elevated non-esterified fatty acid
level in dexamethasone-treated rats.
AB - The pathogenesis of glucocorticoid-induced insulin resistance in the peripheral
tissue was studied by perfusion experiments of the isolated rat hindquarter and
insulin tolerance tests in the rat with the cutting off operation of blood
supplies to the liver, kidneys, intestines and pancreas. The rat was injected
with 0.5 mg/kg dexamethasone for 7 days. Just after the multiple functional
organectomies, insulin was loaded in doses of 0.1 and 0.5 U/kg. Plasma insulin
levels during 0-10 min were approximately 100-20 and 500-100 microU/ml,
respectively. The decreasing rates in plasma glucose level after injections of
saline and 0.1 U/kg insulin were much smaller in dexamethasone-treated than
control rats (0.0+/-7.2 vs 13.3+/-3.4%/10 min, p<0.05, and 8.0+/-5.8 vs 39.4+/
3.7%/10 min, p<0.01 respectively). The decreasing rate after 0.5 U/kg insulin
loads was similar between both groups (40.2+/-10.0 in dexamethasone-treated and
52.3+/-7.3%/10 min in control rats). Plasma non-esterified fatty acids were
raised in dexamethasone-treated compared to control rats (1.23+/-0.23 vs 0.73+/
0.08 mM, p<0.01). In the hindquarter perfusion study, glucose uptake in the
dexamethasone-treated rat leg was no less than in the normal rat leg under a
palmitate-free condition, and was decreased by the addition of 1.0 mM palmitate
without and together with 100 and 500 microU/ml insulin. These results suggest
that the glucocorticoid-induced peripheral insulin resistance is characterised by
the decreased sensitivity and the preserved responsiveness to insulin, and is
caused mainly by an elevated non-esterified fatty acid level.
PMID- 10782751
TI - The effect of flavonoid treatment on the glycation and antioxidant status in Type
1 diabetic patients.
AB - Amongst the numerous co-adjuvant therapies which could influence the incidence
and progression of diabetic complications, antioxidants and flavonoids are
currently being tested in several clinical trials. In this study we investigated
the effects of Daflon 500, which is made up of the flavonoids diosmin (90%) and
hesperidin (10%), in a group of 28 Type 1 diabetic patients in a double blind
placebo-controlled study. Parameters of glycation and oxidative stress were
measured before and after the intervention. Treatment with this flavonoid had no
side effects and was followed by a decrease in HbA1c, from 8.85+/-1.57 to 8.47+/
1.40% (p=0.017). This decrease was more pronounced in the patients with higher
initial HbA1c but was unrelated to glycaemic control as monitored by the mean and
fluctuations of daily glycaemia. Decrease in HbA1c was accompanied by an increase
in glutathione peroxidase activity, from 119+/-68 to 145+/-42 U/l haemolysate
(p=0.015), a tendency for increase in plasma protein thiols and an increase in
the lag time of the copper-induced in vitro oxidability of non-HDL lipoproteins,
from 96+/-24 to 111+/-28 min (p=0.005). These parameters did not change
significantly after receiving placebo. Other parameters of antioxidant capacity
such as blood GSH, catalase and superoxide dismutase activities, as well as in
vitro formation of thiobarbituric acid reactive substances (TBARS), were
unaffected by either flavonoid or placebo. Our results suggest that the flavonoid
induced decrease in glycation is associated with an increase in the antioxidant
component dependent on the levels and activities of thiol-containing proteins
such as glutathione peroxidase. One mechanism which could explain these effects
is the protection of vitamin C and E from consumption by oxidative processes.
PMID- 10782752
TI - Glucose tolerance and insulin secretion in pregnancy.
AB - The authors have studied the behaviour of plasma glucose, insulinaemia and
insulin-glucose ratio in 2 groups of pregnant women with BMI values > or = or
<26, respectively. Each group was divided into 3 subgroups on the basis of an
oral glucose tolerance test (OGTT) response: GIGT (gestational impaired glucose
tolerance), GD (gestational diabetes), and C (normal controls). Data from non
obese pregnant women demonstrate that both basal and OGTT-stimulated glucose
levels were significantly different in all subgroups. The total insulin amount in
the GIGT and GD subgroups is quite similar to or greater than the controls, but
with a significant reduction of the insulin-glucose ratio. In GD also an absolute
deficiency of insulin rise at 30 min during the glucose load, as in subjects with
Type 2 diabetes mellitus (T2DM), was observed. The behaviour of these parameters
in obese pregnant women seems to be similar, even though with some significant
differences: in these subjects, there is a less clear-cut differentiation among
all subgroups, and the appearance of gestational diabetes is not accompanied by a
significant decrease of insulin secretion at 30 min. Our data seem to demonstrate
that insulin resistance with an inadequate hyperinsulinaemia is a common factor
for the alterations of carbohydrate metabolism during pregnancy. Only in the non
obese patients with gestational diabetes, is there an absolute defect of early
insulin response to the glucose load, as it is seen in T2DM.
PMID- 10782753
TI - Growth hormone and IGF-I in diabetic children with and without microalbuminuria.
AB - In order to evaluate the relationship between urinary GH, urinary IGF-I and
plasma IGF-I levels and presence of incipient diabetic nephropathy in paediatric
age, we studied fifty (25 male and 25 female) prepubertal patients with insulin
dependent diabetes mellitus (T1DM). The patients were subdivided into two groups
according to the presence of persistent microalbuminuria defined as albumin
excretion rate (AER) >20 microg/min in at least 5 urine collections in the 6
months prior to the beginning of the study: Group A: 18 patients with
microalbuminuria; Group B: 32 patients without microalbuminuria. A group of 20
healthy subjects, sex-, age- and pubertal stage-matched, served as control. No
difference was observed between the urinary output of IGF-I and GH and plasma IGF
I values between normoalbuminuric and control subjects (normoalbuminuric vs
controls: urinary GH: mean+/-SD 7.9+/-0.7 ng/day vs 8.1+/-0.6; urinary IGF-I:
178.3+/-19.7 ng/day vs 175.5+/-20.3; plasma IGF-I: 203.9+/-31.2 ng/ml vs 199.4+/
43.2), but a significant difference was observed between the urinary output of
IGF-I and GH and plasma IGF-I levels between microalbuminuric patients and
normoalbuminuric and controls (microalbuminuric subjects: urinary GH: 13.1+/-1.4
p<0.01; urinary IGF-I: 451.3+/-45.9 p<0.001; plasma IGF-I: 326.5+/-63.2 p<0.01).
Moreover, plasma IGF-I, urinary GH and urinary IGF-I were not significantly
associated with microalbuminuria, while plasma IGF-I levels were positively
related to glomerular filtration rate (GFR) (p<0.05). In conclusion, our study
demonstrates that microalbuminuric patients have higher levels of urinary IGF-I,
urinary GH, plasma IGF-I than normoalbuminuric diabetic subjects. These data
support the hypothesis that IGF-I can have a role in the changes of renal
function observed in patients with persistent microalbuminuria.
PMID- 10782754
TI - Effects of acarbose treatment in Type 2 diabetic patients under dietary training:
a multicentre, double-blind, placebo-controlled, 2-year study.
AB - This 24-months, placebo-controlled, double-blind, randomised, group comparison
study investigated the effect of acarbose vs placebo for improving metabolic
control in patients with Type 2 diabetes under dietary training insufficiently
controlled by diet alone. Patients randomised to acarbose had their dose
increased in a stepwise manner to week 5. From week 5 onwards, they received 100
mg three times daily. This incremental dosing scheme was matched in the placebo
group. All patients received specialist, intensive, continuous dietary training
and counselling throughout the 2 yr of the study. Of the 74 patients randomised,
60 were included in the per-protocol analysis (28 receiving acarbose; 32
receiving placebo). HbA1c was the primary target variable. Per-protocol analysis
found that, after 24 months, the mean difference in HbA1c relative to baseline
value was -1.71+/-1.6% in the acarbose group and -0.82+/-1.1% in the placebo
group. End-point values were 6.85+/-1.7% in the acarbose group and 7.41+/-1.1% in
the placebo group. This difference between acarbose and placebo was statistically
significant (p=0.02). Patients were defined as responders if they did not require
additional treatment with an antidiabetic agent during the study. The responder
rate under acarbose therapy was 89%, compared with 47% for placebo (p=0.0005).
Acarbose-treated responders improved their HbA1c level to 6.45+/-0.82% after 24
months. The efficacy of acarbose was consistent throughout the study; decreasing
efficacy was not evident. The results demonstrate the efficacy of acarbose for
improving metabolic control in patients with Type 2 diabetes, even when such
patients receive good dietary treatment and counselling.
PMID- 10782755
TI - Hyperuricaemia in Type 2 diabetes mellitus.
AB - This study was undertaken to find the significant parameters associated with
hyperuricaemia in patients with Type 2 diabetes, and hence to determine if
hyperuricaemia is associated with poor control of diabetes or increased coronary
heart disease. All the diabetic patients seen at a Family Medicine Teaching
Clinic within the period January to September 1997 were recruited into the study.
In 273 Type 2 diabetics, serum uric acid was analysed against basic demographic
data (age, sex, smoking and alcohol habits, body mass index, number of years
since the diagnosis of diabetes), present medications, control of diabetic state
(attending physician's estimation of the patient's diet compliance, fasting serum
sugar, HbA1c), and complications (serum creatinine, total cholesterol,
triglyceride, urine proteinuria, retinopathy, last blood pressure readings,
history of hypertension, coronary heart disease, stroke). Serum uric acid was
significantly associated with body mass index, history of hypertension, serum
triglyceride and serum creatinine, but was not related to coronary heart disease,
stroke or control of the diabetic state. Female diabetics were more likely to
have elevated uric acid. There is not enough evidence for monitoring serum uric
acid or for intervention to lower asymptomatic hyperuricaemia in Type 2 diabetic
patients.
PMID- 10782757
TI - On grassroots activism and health policy: a case study.
PMID- 10782756
TI - Calcium antagonists and cardiovascular risk in patients with hypertension and
Type 2 diabetes mellitus: evidence from the PIUMA Study. Progetto Ipertensione
Umbria Monitoraggio Ambulatoriale.
AB - We conducted a retrospective analysis of all subjects with essential hypertension
and Type 2 diabetes mellitus enrolled in the PIUMA (Progetto Ipertensione Umbria
Monitoraggio Ambulatoriale) registry, in order to evaluate whether the use of
calcium antagonists is associated with an increase in cardiovascular risk in
these subjects. One hundred and sixty-four consecutive subjects with no previous
cardiovascular morbid events and coexistence of essential hypertension and Type 2
diabetes mellitus were studied before therapy and followed for up to 12 years
(mean 5). There were periodical contacts with family doctors and patients in
order to ascertain the occurrence of major cardiovascular events. The use of
calcium antagonists that preceded the event was considered for classification.
None of the patients was lost to follow-up. At entry, the patients who were
subsequently given calcium antagonists (n=50) had a higher clinical (174/98 vs
161/92 mmHg, both p<0.01) and 24-hr ambulatory blood pressure (150/90 vs 141/84
mmHg, both p<0.01) than those who were not. During follow-up there were 53 major
cardiovascular morbid events (6.46 per 100 person-years). The rate of total
cardiovascular events [5.6 vs 6.8 events per 100 person-years, relative risk 0.88
(95% CI: 0.47-1.61)] and that of cardiac events [4.0 vs 3.3 events per 100 person
years, relative risk 1.33 (95% CI: 0.62-2.89)] did not differ between users of
calcium antagonists and non-users. The use of angiotensin converting enzyme
inhibitors (n=66) was unrelated to the risk of cardiovascular events (relative
risk 1.24, 95% CI: 0.71-2.16). In a Cox multivariate analysis, only age (p=0.002)
and 24-hr pulse pressure (p=0.04) were independent predictors of cardiovascular
events. In conclusion, this cohort study does not support the hypothesis that use
of calcium antagonists is associated with an excess risk of adverse
cardiovascular events in uncomplicated subjects with essential hypertension and
Type 2 diabetes mellitus.
PMID- 10782758
TI - Comparison of student outcomes and preferences in a traditional vs. World Wide
Web-based baccalaureate nursing research course.
AB - The purpose of this project was to compare student outcomes in an undergraduate
research course taught using both World Wide Web-based distance learning
technology and traditional pedagogy. Reasons given for enrolling in the
traditional classroom section included the perception of increased opportunity
for interaction, decreased opportunity to procrastinate, immediate feedback, and
more meaningful learning activities. Reasons for selecting the Web group section
included cost, convenience, and flexibility. Overall, there was no significant
difference in examination scores between the two groups on the three multiple
choice examinations or for the course grades (t = -.96, P = .343). Students who
reported that they were self-directed and had the ability to maintain their own
pace and avoid procrastination were most suited to Web-based courses. The Web
based classes can help provide opportunities for methods of communication that
are not traditionally nurtured in traditional classroom settings. Secondary
benefits of the World Wide Web-based course were to increase student confidence
with the computer, and introduce them to skills and opportunities they would not
have had in the classroom. Additionally, over time and with practice, student's
writing skills improved.
PMID- 10782759
TI - An experience of peer mentoring with student nurses: enhancement of personal and
professional growth.
AB - This article discusses the importance of peer mentoring in nursing education. The
current literature is reviewed and areas for further research are identified.
Most specifically, the article explores the results of a recent research study
conducted at Southern Cross University in Australia. The research investigated
the relationship between personal and professional growth and peer mentoring with
a group of women nurses. Seven nurses participated in this qualitative research
project. Six of the participants were student nurses enrolled in an undergraduate
nursing degree and the seventh participant was the degree program coordinator.
The research was conducted over a 12-week period and was located in critical
paradigm. The research methods used were reflective journaling and interviewing.
The results indicated that the process of peer mentoring in nursing education
demonstrated a strong relationship to personal and professional growth for all of
the participants. Characteristics of the peer mentoring process such as shared
learning, shared caring, reciprocity, commitment to each other's personal and
professional growth, and friendship, are discussed.
PMID- 10782760
TI - Experiences and comfort with culturally diverse groups in undergraduate pre
nursing students.
AB - A sample of approximately 200 undergraduate students beginning their nursing
education responded to questionnaire items concerning experience and levels of
comfort working with diverse client groups. Students reported little discomfort
with racial/ethnic groups, but reported they would have considerable difficulty
working with lesbian, gay, or bisexual clients, and patients with human
immunodeficiency virus. Their reasons for discomfort were examined.
PMID- 10782761
TI - Does constructivist epistemology have a place in nurse education?
AB - Nursing students who undertake the bachelor of nursing degree program are adults,
many of whom are considered mature students. As such, they have significant life
experiences and a vast amount of knowledge that has been acquired both formally
and informally. Much of formal education historically, and even today, is content
and curriculum driven, and teacher focused. Constructivist epistemology offers an
alternative to traditional pedagogy in that it is student focused and considers
previous learning done by the students as a foundation upon which to modify,
build, and expand new knowledge. Constructivism also appears to be congruent with
adult education theory and therefore offers great potential for the enhancement
of self-directed learning. It enhances empowered learning because of the
consideration of prior knowledge and the ownership of learning by the students.
Implicit in this is the development of metacognitive skills that are an important
facet of active and self-directed learning. As a result of undergraduate learning
within a constructivist framework, there are likely to be benefits for nurses in
the practice setting for making the transition from inexperienced to experienced
practitioners. Constructivist learning frameworks provide learning skills that
enhance knowledge acquisition with understanding.
PMID- 10782762
TI - Domestic violence and the nursing curriculum: tuning in and tuning up.
AB - Domestic violence is a major health, social, and criminal justice problem in the
United States. Although not confined to women, it is a growing concern of women
and those who care for women. Nurses are often the first health care provider
with whom the battered woman and her family interact. Reports of several studies
indicate educational preparation of nurses is inadequate to assure sensitive,
quality, and effective nursing care to those who have survived domestic violence.
One purpose of this qualitative study was to identify and describe the essential
knowledge and skills needed by nurses to provide competent, sensitive care.
Interviews were conducted with 13 informants who were considered experts in
violence-related care. Their responses were analyzed for categories of response
and themes related to their feelings about domestic violence and the essential
knowledge and skills nurses need to provide appropriate care. Findings provide
data that can form the empirical bases for review of current curriculum content
and strategies, indicate needed revisions, and serve as a framework for future
curriculum development.
PMID- 10782763
TI - Students' collaborative clinical experience.
PMID- 10782764
TI - The National Council Licensure Examinations/differential item functioning
process.
AB - The National Council of State Boards of Nursing, Inc., is committed to
administering licensure examinations that test minimum, essential entry level
nursing competence. The item development process used by the National Council
includes extensive procedures that are designed to minimize the possibility that
test items contain factors unrelated to the purpose of the examination. This
article described one of those procedures, known as the NCLEX DIF process. The
NCLEX DIF process combines a statistical review with a judgmental review to
detect items that may be measuring other than the intended construct. National
Council Licensure Examinations are closely scrutinized to ensure fairness and
validity. While it may not be possible to conduct DIF analyses on classroom test
items, nursing educators should endeavor to review all items for potential item
bias by examining them for stereotypical and sensitive material. Guidelines to
assist the nursing educator in the review process to prevent item bias are
available (Wendt, Holz, Worcester, 1996; Shepard, 1982).
PMID- 10782765
TI - Social work graduate students' beliefs regarding responsibilities of professional
nursing.
PMID- 10782766
TI - Is peripheral spinal cord hypointensity a sign of venous hypertensive myelopathy?
PMID- 10782767
TI - Comparisons between carotid duplex sonography and cerebral angiography in
assessing the degree of carotid stenosis.
PMID- 10782768
TI - Applying functional MR imaging to brain-behavioral research: can we do better
than simple clinical measures?
PMID- 10782770
TI - Absence of selective deep white matter ischemia in chronic carotid disease: a
positron emission tomographic study of regional oxygen extraction.
AB - BACKGROUND AND PURPOSE: Deep white matter may be the location of an internal
arterial border zone. The purpose of this study was to determine whether the deep
white matter was subject to a greater degree of ischemia than was the cortex
among patients with chronic carotid occlusion. METHODS: Thirty-six patients with
carotid occlusion and structurally normal deep white matter were studied with
positron emission tomography. Measurements of oxygen extraction fraction were
made in superficial (cortical and subcortical) regions in the middle cerebral
artery territory and in deep white matter (internal border zone) regions. The
presence of selective ischemia of the deep white matter was assessed by the ratio
of deep white matter:superficial oxygen extraction fraction. Ipsilateral
hemispheric ratios among patients were assessed as a group as compared with
contralateral hemispheric ratios and as compared with normal hemispheric ratios
from 15 control volunteers. RESULTS: Mean deep white matter to superficial oxygen
extraction fraction ratios (+/-95% confidence limits) were 0.99 (+/-0.07), 1.01
(+/-0.06), and 1.02 (+/-0.08) for ipsilateral, contralateral, and normal
hemispheres, respectively. No statistically significant difference was found
between ipsilateral and contralateral (P = .691) or normal hemispheres (P = .68),
nor was any statistically significant difference found when the analysis was
limited to patients with increased superficial oxygen extraction fraction (n =
9). Individual deep white matter:superficial ratios were within the normal range
for all patients. CONCLUSION: Normal deep white matter among patients with
carotid occlusion is not subject to a greater degree of ischemia than is the
overlying cortex. It is unlikely that deep white matter infarctions observed
among patients with carotid occlusion are owing to chronic selective hemodynamic
compromise occurring at an internal arterial border zone.
PMID- 10782769
TI - Subcortical ischemic vascular dementia: assessment with quantitative MR imaging
and 1H MR spectroscopy.
AB - BACKGROUND AND PURPOSE: Subcortical ischemic vascular dementia is associated with
cortical hypometabolism and hypoperfusion, and this reduced cortical metabolism
or blood flow can be detected with functional imaging such as positron emission
tomography. The aim of this study was to characterize, by means of MR imaging and
1H MR spectroscopy, the structural and metabolic brain changes that occur among
patients with subcortical ischemic vascular dementia compared with those of
elderly control volunteers and patients with Alzheimer's disease. METHODS:
Patients with dementia and lacunes (n = 11), cognitive impairment and lacunes (n
= 14), and dementia without lacunes (n = 18) and healthy age-matched control
volunteers (n = 20) underwent MR imaging and 1H MR spectroscopy. 1H MR
spectroscopy data were coanalyzed with coregistered segmented MR images to
account for atrophy and tissue composition. RESULTS: Compared with healthy
control volunteers, patients with dementia and lacunes had 11.74% lower N
acetylaspartate/creatine ratios (NAA/Cr) (P = .007) and 10.25% lower N
acetylaspartate measurements (NAA) in the cerebral cortex (P = .03). In white
matter, patients with dementia and lacunes showed a 10.56% NAA/Cr reduction (P =
.01) and a 12.64% NAA reduction (P = .04) compared with control subjects. NAA in
the frontal cortex was negatively correlated with the volume of white matter
signal hyperintensity among patients with cognitive impairment and lacunes (P =
.002). Patients with dementia, but not patients with dementia and lacunes, showed
a 10.33% NAA/Cr decrease (P = .02) in the hippocampus compared with healthy
control volunteers. CONCLUSION: Patients with dementia and lacunes have reduced
NAA and NAA/Cr in both cortical and white matter regions. Cortical changes may
result from cortical ischemia/infarction, retrograde or trans-synaptic injury (or
both) secondary to subcortical neuronal loss, or concurrent Alzheimer's
pathologic abnormalities. Cortical derangement may contribute to dementia among
patients with subcortical infarction.
PMID- 10782771
TI - Evaluation of carotid stenosis by angiography: potential bias toward
overestimated measurements introduced by prior interpretation of Doppler
sonograms.
AB - BACKGROUND AND PURPOSE: Doppler sonography of the carotid arteries is routinely
performed before catheter angiography, and its results may bias the subsequent
interpretation of angiograms. We attempt to establish that Doppler sonography may
show an exaggerated degree of carotid stenosis, introducing bias to the
evaluation of carotid stenosis by subsequent catheter angiography. METHODS:
Angiograms of the carotid arteries obtained to evaluate potential carotid
stenosis in patients who had undergone Doppler sonography of the carotid arteries
were retrospectively reviewed (from 1993 to 1998). Readers who were blinded to
the previous interpretations of the angiography and Doppler sonography results
measured carotid stenosis. The results of Doppler sonography of the carotid
arteries were not re-evaluated. Based on the original Doppler sonograms, stenoses
were categorized as normal/mild (<30%), moderate (30-59%), severe (60-79%), and
critical (80-99%). Within these categories, the differences between the original
percent stenosis, as determined by angiography, and the blinded measurements were
determined. RESULTS: A total of 106 patients with angiographically measurable
stenoses in 128 vessels were identified. The difference between the blinded
readers was 3% (+/-8%), with no category statistically different from the other.
The difference between original and remeasured stenoses in carotid arteries in
the Doppler categories were as follows: mild stenosis, 2% (+/-9%); moderate
stenosis, 6% (+/-15%); severe stenosis, 8% (+/-15%); and critical stenosis, 22%
(+/-12%). A significant overestimation occurred in the severe (P < .05) and
critical (P < .0001) stenosis categories. One third of patients with stenoses in
the severe or critical Doppler category had significant stenoses on the original
angiograms that were less than 60%, according to blinded remeasurement.
CONCLUSION: Doppler sonography of the carotid arteries has the potential to bias
the subsequent interpretation of catheter angiography. Care must be taken to
measure stenosis accurately, using strict criteria to determine the potential
benefit of carotid endarterectomy for the individual patient and to ensure that
the criteria for Doppler sonography of the carotid arteries are based on accurate
catheter angiography measurements.
PMID- 10782772
TI - A standardized method for measuring intracranial arterial stenosis.
AB - BACKGROUND AND PURPOSE: Atherosclerosis of the major intracranial arteries is an
important cause of ischemic stroke. We established measurement criteria to assess
percent stenosis of a major intracranial artery (carotid, middle cerebral,
vertebral, basilar) and determined the interobserver/intraobserver agreements and
interclass/intraclass correlations of these measurements. METHODS: We defined
percent stenosis of an intracranial artery as follows: percent stenosis = [(1 -
(D(stenosis)/D(normal)))] x 100, where D(stenosis) = the diameter of the artery
at the site of the most severe stenosis and D(normal) = the diameter of the
proximal normal artery. If the proximal segment was diseased, contingency sites
were chosen to measure D(normal): distal artery (second choice), feeding artery
(third choice). Using a hand-held digital caliper, three neuroradiologists
independently measured D(stenosis) and D(normal) of 24 stenotic intracranial
arteries. Each observer repeated the readings 4 weeks later. We determined how
frequently two observers' measurements of percent stenosis of each of the 24
diseased arteries differed by 10% or less. RESULTS: Among the three pairs of
observers, interobserver agreements were 88% (observer 1 versus observer 2), 79%
(observer 1 versus observer 3), 75% (observer 2 versus observer 3) for the first
reading and were 75% (observer 1 versus observer 2), 100% (observer 1 versus
observer 3), and 71% (observer 2 versus observer 3) for the second reading.
Intraobserver agreement for each of the observers was 88%, 83%, and 100%.
Interclass correlation was 85% (first reading) and 87% (second reading).
Intraclass correlation was 92% (first and second readings combined). CONCLUSION:
This method shows good interobserver and intraobserver agreements for the
measurement of intracranial stenosis of a major artery. If validated in
subsequent studies, this method may serve as a standard for the measurement of
percent stenosis of an intracranial artery.
PMID- 10782774
TI - Correlation between choline level measured by proton MR spectroscopy and Ki-67
labeling index in gliomas.
AB - BACKGROUND AND PURPOSE: The clinical relevance of proton MR spectroscopy needs
further clarification as to its usefulness and limitations. The purpose of this
study was to investigate the correlation between the semiquantitative choline
containing compound level (Cho value) measured by MR spectroscopy and the Ki-67
labeling index in gliomas. METHODS: Localized proton spectra were obtained in 26
consecutive patients with glioma who subsequently underwent surgery for tumor
removal. Metabolic values in the spectra were measured semiquantitatively using
an external standard of reference. The Ki-67 labeling index was measured in the
surgical specimen. Because the semiquantitative metabolic values may be affected
by tissue components included in the spectroscopic voxel, the MR imaging
appearance of the voxel within the tumor was classed as homogeneous or
heterogeneous through visual evaluation of the presence of necrosis, cyst,
hemorrhage, and calcification, and pattern of enhancement. RESULTS: We found a
strong linear correlation between the Cho value and the Ki-67 labeling index in
the 18 homogeneous gliomas, but no correlation was found in the eight
heterogeneous gliomas, which turned out to be malignant. CONCLUSION: The
semiquantitative Cho value is a reliable predictor of proliferative activity of
gliomas when the tumor appears homogeneous on MR images.
PMID- 10782773
TI - MR imaging and localized proton spectroscopy of the precentral gyrus in
amyotrophic lateral sclerosis.
AB - BACKGROUND AND PURPOSE: In the search for a diagnostic test for amyotrophic
lateral sclerosis (ALS), especially upper motor neuron (UMN) involvement, MR
imaging and proton spectroscopy techniques have each received attention, but
their findings have not been correlated. The purpose of this study was to
identify relationships among the results of current techniques, taking into
account the severity of clinical UMN disease, so that objective measures of the
pathogenesis of ALS may be established. METHODS: Eighteen subjects with
clinically diagnosed ALS and 12 healthy volunteers underwent MR imaging of the
brain and localized proton MR spectroscopy. Water-suppressed spectra from the
left precentral gyrus and from the left cuneus gyrus were analyzed with the
LCModel method, yielding concentrations for N-acetyl (NA), total creatine (Cr),
choline (Cho), glutamate (Glu), glutamine (Gin), and myo-inositol (Ins) metabolic
substrates. Signal intensities of the precentral gyrus on T2-weighted images were
assessed qualitatively in a blinded fashion. RESULTS: For the precentral gyrus,
mean Cho (1.3 mM) and Ins (3.25 mM) for the ALS group were significantly
increased. After adjustment for Cr covariance, mean Glu (5.08 mM) and NA (6.31
mM) were decreased. For the cuneus gyrus, no difference in metabolite
concentrations between groups was observed. Trend analysis of the precentral
gyrus metabolite concentrations revealed significant increases in Cho and Ins and
decreases in NA and Glu with respect to the severity of clinical UMN signs.
Metabolic changes were greater in the subset of ALS patients with precentral
gyrus signal changes on imaging, and significantly increased Ins was associated
with cortical hypointensity on fast spin-echo images. CONCLUSION: Mean metabolite
concentrations determined from precentral gyrus spectra reflect clinical and
pathologic changes that occur in ALS. Imaging findings, while related to the
spectral and clinical results, are not specific to ALS.
PMID- 10782775
TI - MR imaging- and MR spectroscopy-revealed changes in meningiomas for which
embolization was performed without subsequent surgery.
AB - We describe our experience with follow-up MR imaging and MR spectroscopy in two
patients after embolization of meningiomas without subsequent surgery. In both
patients there was a marked reduction in tumor size and a decrease in contrast
enhancement associated with spectroscopic signs of fatty degeneration. We did not
observe regrowth; however, in one patient with incomplete angiographic
devascularization, residual vital tumor tissue was seen at follow-up
examinations.
PMID- 10782776
TI - Highly active antiretroviral therapy for patients with AIDS dementia complex:
effect on MR imaging findings and clinical course.
AB - BACKGROUND AND PURPOSE: Recent studies have reported the clinical improvement in
patients with AIDS treated with a combination of antiretroviral regimens. The
purpose of our study was to describe the effects of highly active antiretroviral
therapy on MR images in patients with HIV encephalopathy and to compare the
clinical course with follow-up neuroimaging studies. METHODS: Initial and follow
up MR imaging findings are described in four patients with AIDS dementia complex
at baseline and after antiretroviral therapy, and correlated with clinical and
immunologic findings. RESULTS: Initial MR imaging revealed white matter signal
abnormalities on long-TR images without mass effect and without enhancement on
postcontrast images, consistent with HIV encephalopathy. Lesions were located in
the basal ganglia and posterior fossa in two patients. All four patients showed
progression of white matter disease on the first follow-up MR scan (mean, 6
months). On subsequent scans, regression was seen in three patients and
stabilization of white matter disease was observed in one patient. Increases in
CD4+ count and decreases in viral load below the limit of quantification were
present in all patients. CONCLUSION: Although our patient population was small,
the results suggest that disease regression in patients with AIDS dementia
complex after treatment with highly active antiretroviral therapy can be
characterized and monitored by MR imaging.
PMID- 10782777
TI - Improved detection of intraventricular cysticercal cysts with the use of three
dimensional constructive interference in steady state MR sequences.
AB - BACKGROUND AND PURPOSE: Before the advent of MR imaging, intraventricular cysts
were difficult to diagnose noninvasively. Among the invasive procedures used were
contrast ventriculography and CT ventriculography. MR imaging, with its
multiplanar imaging capabilities, excellent depiction of tissue contrast, and
versatile parameters, is an important tool in the assessment of intraventricular
cystic lesions. We investigated the role of three-dimensional constructive
interference in steady state (3D-CISS) MR sequences in the evaluation of
intraventricular cysticercal cysts. METHODS: The study group comprised 11
patients with intraventricular cysticercal cysts. MR studies included spin-echo
(SE) T1-weighted, turbo-SE T2-weighted, and 3D-CISS sequences. All images were
obtained on a superconducting 1.5-T MR unit. The routine and 3D-CISS sequences
were reviewed and interpreted separately by two neuroradiologists. RESULTS: All
patients underwent surgery for excision of intraventricular cysticercal cysts.
Eight patients had cysts in the fourth ventricle, two in the lateral ventricle,
and one in the third ventricle. SE T1-weighted images showed the cystic wall in
nine cases, the scolex in four, and the cystic fluid in two. Turbo-SE T2-weighted
images showed the cystic wall and scolex in three and four cases, respectively.
The routine sequences did not show the scolex, cystic wall, or cystic fluid
together in any of the 11 patients. 3D-CISS images showed the scolex in all 11
patients and the cystic wall and cystic fluid in eight patients each. In seven of
the 11 patients, 3D-CISS images showed the scolex, cystic wall, and fluid
together. CONCLUSION: The 3D-CISS sequence is more sensitive and specific than
routine SE sequences in the diagnosis of intraventricular cysticercal cysts.
PMID- 10782778
TI - Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing
hormone receptor gene.
AB - BACKGROUND AND PURPOSE: Several anatomic abnormalities of the pituitary gland
have been described as occurring in association with congenital growth hormone
deficiency, including hypoplasia of the adenohypophysis, truncation of the
pituitary stalk, and ectopia of the neurohypophysis. Their pathogenesis, however,
is obscure. Normal pituitary development is dependent on the sequential
expression of a series of ontogenetic factors. Growth hormone-releasing hormone
(GHRH) is known to stimulate somatotroph proliferation, and a dwarf mouse model
with a mutant GHRH receptor, the "little mouse," has a small anterior pituitary
due to hypoplasia of the somatotrophs. We recently described the human homolog of
the little mouse (dwarfism of Sindh), caused by a homozygous nonsense mutation in
the GHRH receptor gene in a Pakistani kindred. We investigated MR imaging
characteristics to gain information regarding the potential role of GHRH in human
pituitary organogenesis. METHODS: MR images of the head were obtained of four
affected male patients (age range, 22-29 years). Maximal anterior pituitary
dimensions were determined from sagittal and coronal images, and pituitary
volumes were estimated from cubic and ellipsoid formulae. The measurements were
compared with normative values matched for age and sex. RESULTS: The
adenohypophysis was small in each of the four patients. The maximal height for
the anterior pituitary was 3 mm in three patients and 2 mm in one (mean +/- SD,
2.75 +/- 0.5 mm), which is significantly (P < .001) less than the expected height
of 5.6 +/- 1.0 mm for men in this age group. Estimates of anterior pituitary
volume in the patients ranged from 75 to 124 mm3 (104 +/- 21 mm3), which
corresponds to 35% to 52% of the normal mean volume corrected for small head size
(P < .005). No other cranial abnormalities were identified. CONCLUSION: We
describe significant hypoplasia of the adenohypophysis occurring in four dwarfs
with a nonsense mutation in the GHRH receptor. In addition to isolated growth
hormone deficiency and severe dwarfism, affected patients have anterior pituitary
hypoplasia, presumably due to somatotroph maldevelopment. Resistance to GHRH
explains the hypoplasia of the adenohypophysis--a feature that contributes to
growth hormone deficiency in this syndrome. This is one of the few instances in
which the molecular basis of pituitary dysmorphogenesis has been identified.
PMID- 10782779
TI - Adrenocorticotropic hormone-dependent Cushing's syndrome: sensitivity and
specificity of inferior petrosal sinus sampling.
AB - BACKGROUND AND PURPOSE: Determining the cause of Cushing's syndrome can be
difficult. Bilateral inferior petrosal sinus (IPS) sampling after ovine
corticotropin-releasing hormone (oCRH) stimulation is an established technique
for the differentiation of pituitary from nonpituitary sources of
adrenocorticotropic hormone (ACTH) production. The purpose of this study was to
review our experience to determine the sensitivity and specificity of bilateral
IPS sampling. METHODS: Between January 1990 and February 1997, 92 patients
underwent 94 IPS sampling procedures. Indications for these patients with
Cushing's syndrome included no discrete lesion on MR images or CT scans, a
discrete lesion present on images but equivocal peripheral ACTH sampling after
oCRH stimulation, and persistent Cushing's syndrome after trans-sphenoidal
surgery. RESULTS: IPS sampling yielded six false-negative results and one false
positive result, manifesting an overall sensitivity of 92.2% and a specificity of
90.0% for detection of a pituitary source of ACTH after oCRH stimulation.
Microadenoma lateralization by IPS sampling after oCRH stimulation agreed with
the surgical location in 70.0% of the patients. The technical success rate of
initial (presampling) bilateral IPS catheterization was 93.6%. Two serious
complications occurred and consisted of a venous subarachnoid hemorrhage and a
lower extremity deep venous thrombosis. CONCLUSION: Bilateral IPS sampling after
oCRH stimulation is helpful in the evaluation of ACTH-dependent Cushing's
syndrome. False-negative results, however, suggest that the possibility of a
pituitary source must still be considered when no response to oCRH is documented.
Interpetrosal ACTH gradient alone is not sufficient to lateralize the tumor
reliably.
PMID- 10782780
TI - Structural changes of the substantia nigra in Parkinson's disease as revealed by
MR imaging.
AB - BACKGROUND AND PURPOSE: The possibility of using MR imaging as a sensitive marker
of the structural changes in Parkinson's disease has been a long-sought goal. We
describe a new method for imaging and quantifying the morphologic changes of the
substantia nigra in Parkinson's disease and compare radiologic findings with
clinical evaluation. METHODS: Using a combination of two MR imaging inversion
recovery pulse sequences, the substantia nigra was imaged in six patients with
Parkinson's disease and six age-related control participants. A radiologic index
was defined and used to quantify the signal changes that were observed in the
patients. The radiologic index was compared with clinical scores obtained from
the Unified Parkinson's Disease Rating Scale. RESULTS: The images showed loss of
signal in a lateral-to-medial gradient in cases of Parkinson's disease,
corresponding to the known neuropathologic pattern of degeneration. The
radiologic index was highly correlated with the Unified Parkinson's Disease
Rating Scale score, and there was no overlap in radiologic indices between the
patient and the control groups (P < .00005). CONCLUSION: This study suggests that
MR imaging is sensitive to structural changes in even the earliest cases of
Parkinson's disease, thereby indicating the potential for detecting
presymptomatic disease. Furthermore, a radiologic measure has been defined that
correlates with the conventional clinical measure of disease severity. Therefore,
MR imaging could prove to be a sensitive biological marker for objective staging
of the disease.
PMID- 10782781
TI - Isolated demyelinating syndromes: comparison of different MR imaging criteria to
predict conversion to clinically definite multiple sclerosis.
AB - BACKGROUND AND PURPOSE: Various authors have developed criteria to classify MR
imaging findings that suggest the possibility of multiple sclerosis. The purpose
of this study was to evaluate and compare the capacity of three sets of MR
imaging criteria for predicting the conversion of isolated demyelinating
syndromes to clinically definite multiple sclerosis. METHODS: Seventy patients
with clinically isolated neurologic symptoms suggestive of multiple sclerosis
were prospectively studied with MR imaging. The MR imaging findings were
evaluated by two independent neuroradiologists who were blinded to clinical
follow-up data. Based on the clinical outcome at follow-up (presence of a second
attack that established clinically definite multiple sclerosis), the sensitivity,
specificity, accuracy, positive predictive value, and negative predictive value
of the criteria proposed by Paty et al, Fazekas et al, and Barkhof et al were
calculated. RESULTS: Clinically definite multiple sclerosis developed in 22 (31%)
patients after a mean follow-up time of 28.3 months. The criteria proposed by
Paty et al and those proposed by Fazekas et al showed identical results:
sensitivity, 86%; specificity, 54%; accuracy, 64%; positive predictive value,
46%; and negative predictive value, 89%. The criteria proposed by Barkhof et al
showed the following: sensitivity, 73%; specificity, 73%; accuracy, 73%; positive
predictive value, 55%; and negative predictive value, 85%. CONCLUSION: The four
dichotomized MR imaging parameters proposed by Barkhof et al are more specific
and accurate than the criteria proposed by Paty et al or Fazekas et al for
predicting conversion to clinically definite multiple sclerosis.
PMID- 10782782
TI - MR digital subtraction angiography of cerebral arteriovenous malformations.
AB - BACKGROUND AND PURPOSE: Although phase-contrast MR angiography provides some
information regarding hemodynamics of cerebral arteriovenous malformations
(AVMs), most conventional MR angiographic techniques have not been helpful in
this respect. We attempted to determine the value of MR digital subtraction
angiography (DSA) in assessing AVM hemodynamics. METHODS: We developed an MR DSA
technique by combining rapid thick-section T1-weighted imaging with a bolus
injection of contrast material. The temporal resolution was 0.56 to 0.61 seconds
per scan. MR DSA images obtained from 14 patients with AVMs were reviewed.
Anatomic depiction of each component of the AVM was rated using a four-point
grading scale (excellent = 3, good = 2, fair = 1, poor = 0) to compare
conventional vs MR angiograms. RESULTS: We were able to obtain serial images in
which passage of contrast material was evident within the AVM, although the
sequence we used allowed images to be obtained in only one projection. The
average score for feeders, nidi, and drainers was 1.6, 2.4, and 2.3,
respectively, with an overall average of 2.1. CONCLUSION: The spatial resolution
of our technique may fall below the level needed for identification of small
vascular components of an AVM. Additionally, the limited slab may restrict
application of the technique to assessment of large or very small AVMs. MR DSA,
however, can show the hemodynamics of AVMs and may serve as a supplement to
conventional MR imaging in the diagnosis of cerebral AVMs.
PMID- 10782783
TI - Carotid-cavernous fistulas: diagnosis with spiral CT angiography.
AB - Four cases in which the diagnosis of carotid-cavernous fistula was made by using
CT angiography are illustrated. The diagnosis was confirmed by digital
subtraction angiography in all four instances. To our knowledge, this is the
first report of the CT angiographic appearance of carotid-cavernous fistulas.
PMID- 10782784
TI - High uptake of 123I-metaiodobenzylguanidine related to olfactory neuroblastoma
revealed by single-photon emission CT.
AB - We studied a case of olfactory neuroblastoma by noting 123I
metaiodobenzylguanidine (MIBG) uptake revealed by single-photon emission CT
(SPECT). MR imaging revealed an enhancing tumor extending from the left nasal
cavity to the bilateral anterior frontal cranial fossae. SPECT revealed high 123I
MIBG uptake in the enhancing tumor. SPECT-revealed 123I-MIBG uptake appears to be
clinically useful for distinguishing olfactory neuroblastomas from other tumors,
especially suprasellar meningiomas.
PMID- 10782785
TI - The adult radiographic shuntogram.
AB - We describe the adult radiographic shuntogram, a simple method to evaluate the
function and patency of a ventriculoperitoneal or ventriculoatrial shunt. The
procedure involves placing contrast material into the valve of a shunt system and
following the flow for appropriate clearing of contrast agent from the shunt
tubing. Twenty-three studies were obtained in 15 patients in whom shunt
malfunction was suspected. The method can be used to establish valve malfunction,
ventricular or distal catheter obstruction, and peritoneal encystment.
PMID- 10782786
TI - Percutaneous transluminal angioplasty and stenting of the proximal vertebral
artery for symptomatic stenosis.
AB - BACKGROUND AND PURPOSE: Percutaneous transluminal angioplasty (PTA) for
significant stenosis involving the origin of the vertebral artery is now a well
established treatment for selected patients when posterior cerebral arterial
circulation is compromised. Arterial spasm, dissection, and restenosis may occur
in some instances, with subsequent hemodynamic compromise. To prevent these
potential complications, we combined PTA of the vertebral artery with primary
stenting, using coronary stents, in seven patients. We herein present our short-
and intermediate-term results. METHODS: A total of seven lesions affecting the
origin of the vertebral artery were treated by primary trans-stenotic coronary
stent placement. All patients were symptomatic, fulfilling the general criteria
for vertebral artery angioplasty. Patients were followed for up to 36 months
after treatment. RESULTS: All seven lesions were successfully dilated. Residual
stenosis was never greater than 20% in diameter. No perioperative complications
occurred. Clinical follow-up showed immediate resolution or improvement of
symptoms in all patients. One patient's condition deteriorated 15 months after
stent placement because of atheromatous stenosis of the prevertebral segment in
the ipsilateral subclavian artery. CONCLUSION: Stent placement to treat
significant stenosis involving the origin of the vertebral artery is safe and
effective for alleviating symptoms and improving blood flow to the posterior
cerebral circulation. Coronary stent design seems to be particularly well suited
to cover atherosclerotic lesions of the origin of the vertebral artery. The stent
mesh probably prevents elastic recoil and early restenosis after PTA, as it does
in coronary arteries.
PMID- 10782787
TI - Endovascular stenting for carotid artery stenosis: preliminary experience using
the shape-memory- alloy-recoverable-technology (SMART) stent.
AB - We describe our initial clinical experience using the newly available self
expanding, Nitinol, shape-memory-, alloy-recoverable-technology (SMART) stent in
treating carotid artery occlusive disease. Five stents were used in four carotid
arteries in four consecutive patients with carotid stenosis of at least 70%.
Technical success (<20% residual stenosis) was achieved in all cases. No
procedural complications specifically related to use of the SMART stent were
encountered. All patients remained symptom-free, with no evidence of transient
ischemic attacks or new strokes during an average follow-up period of 6 months.
Excellent performance of the SMART stent for the endovascular treatment of
carotid artery stenosis has been shown based on our early experience. Validation
with greater numbers and longer-term follow-up is required. The specific
technical characteristics, potential advantages, and disadvantages of this stent
are discussed and compared with other currently used carotid artery stents.
PMID- 10782788
TI - Occlusion of experimentally created fusiform aneurysms with porous metallic
stents.
AB - BACKGROUND AND PURPOSE: Carotid fusiform aneurysms are most commonly treated with
occlusion of the parent vessel. The purpose of our study was to assess the
effectiveness of self-expanding, cobalt-alloy stents in the ablation of
experimental fusiform aneurysms with preservation of the parent vessel in a
carotid artery model. METHODS: Porous metallic stents were placed endovascularly
along the lengths of experimentally created fusiform aneurysms in the carotid
arteries of dogs; aneurysms were also created in the animals' opposite carotid
arteries to serve as controls. RESULTS: Before stent placement, angiography of
the carotid arteries showed large fusiform aneurysms along the lengths of the
common carotid arteries and complex patterns of flow. Immediately after stent
placement there was disruption of the usual flow patterns within the lumens of
the fusiform aneurysms. The lumen between the wall of the aneurysm and stented
carotid showed stasis of contrast material and blood. Near-complete ablation of
all aneurysms was observed 8 weeks after stent placement. The stented carotid
arteries remained widely patent; control aneurysms and carotid arteries were
patent and unchanged. Histopathologic analysis revealed fibrotic reactive scar
tissue filling the space between the stent wires and outer wall of the fusiform
aneurysm. CONCLUSION: Changing blood flow dynamics within an aneurysm can promote
thrombus formation. The stent promotes stasis and thrombus within the residual
lumen between the stent wall and the outer wall of the aneurysm because its woven
wire mesh interferes with usual blood flow patterns, which then promotes
formation of thrombus and fibrosis within the residual aneurysmal lumen.
PMID- 10782789
TI - Three-dimensional time-of-flight MR angiography in the evaluation of intracranial
aneurysms treated with Guglielmi detachable coils.
AB - BACKGROUND AND PURPOSE: Intravascular treatment of intracranial aneurysms is a
relatively new therapeutic technique and long-term controlled angiographic trials
are needed to assess persistence of aneurysm occlusion. Our purpose was to
evaluate the effectiveness of 3D time-of-flight (3D-TOF) MR angiography as a
noninvasive screening tool in the follow-up of cerebral aneurysms treated with
Guglielmi detachable coils (GDCs). METHODS: Forty-nine patients with 50
intracranial aneurysms previously treated with GDCs were studied with both DSA
and 3D-TOF MR angiography. In 14 cases, a second follow-up examination was
performed, for a total of 64 aneurysms evaluated. In 25 aneurysms, both pre- and
postcontrast MR angiographic studies were obtained. RESULTS: In seven of 64
aneurysms, the MR angiographic studies were considered to be unreliable owing to
the presence of artifacts that obscured part of the parent artery and did not
allow an accurate evaluation of the aneurysm neck. These seven aneurysms,
however, all were shown to be completely occluded at digital subtraction
angiography (DSA). In the remaining 57 aneurysms, DSA revealed complete occlusion
in 39 and the presence of residual patency in 18, whereas MR angiography showed
complete occlusion in 38 and residual patency in 19. Enhanced MR angiography
proved to be useful in evaluating residual patency in large and giant aneurysms
and in better depicting the distal branch arteries. CONCLUSION: Although
artifacts related to the presence of coils are evident on a considerable number
of imaging studies, our findings indicate that MR angiography is useful in the
evaluation of residual patency of cerebral aneurysms treated with GDCs and may
eventually prove valuable in the follow-up of those cases in which a good initial
correlation with DSA was demonstrated.
PMID- 10782790
TI - Endovascular treatment of a ruptured paraclinoid aneurysm of the carotid syphon
achieved using endovascular stent and endosaccular coil placement.
AB - We herein report a case of a ruptured superior hypophyseal aneurysm of the left
supraclinoid carotid artery that could not be treated with a Guglielmi detachable
coil (GDC), even in combination with a supporting nondetachable balloon. After an
unsuccessful attempt at surgical clipping, treatment consisted of the placement
of a stent over the neck of the aneurysm, advancement of a microcatheter through
the stent mesh, and endosaccular embolization with a GDC. The late clinical
outcome was excellent.
PMID- 10782791
TI - Dense packing of cerebral aneurysms: an in vitro study with detachable platinum
coils.
AB - Aneurysm models were used to study the density of packing after coil
embolization. Platinum coils were introduced until the point of minimally dense
packing, indicated by aneurysmal circulatory exclusion. Packing was continued up
to the point of maximal density, indicated by protrusion into the parent artery.
Volumetric ratios (coil volume/aneurysmal volume) were calculated for minimally
and maximally dense packing. Maximally dense packing ratios were a little higher
than the minimally dense ratios, but less than 37%.
PMID- 10782792
TI - Transvenous embolization of a dural arteriovenous fistula of the anterior cranial
fossa: preliminary results.
AB - We report two cases of a dural arteriovenous fistula of the anterior cranial
fossa, one causing subarachnoid hemorrhage and one detected accidentally. The
first case was incompletely treated by neurosurgery, and the second one was
referred for endovascular therapy. Both fistulas were successfully occluded by
transvenous embolization by using electrolytically detachable coils.
PMID- 10782793
TI - MR imaging of patients with carotidynia.
AB - BACKGROUND AND PURPOSE: Carotidynia is an idiopathic neck pain syndrome
associated with tenderness to palpation over the carotid bifurcation. Although
well known in the otolaryngology and neurology literature, the validity of the
entity has recently been questioned, in part because of the almost uniform
absence of radiologic or pathologic findings. We report the MR findings in five
patients with carotidynia. METHODS: During a period of 44 months, five patients
with clinical signs and symptoms consistent with carotidynia were referred for
imaging from the otolaryngology service. Each patient underwent MR imaging of the
neck on a 1.5-T system. The studies included, as a minimum, pre- and postcontrast
axial and postcontrast coronal T1-weighted images. Two patients also had axial T2
weighted imaging and another two patients underwent duplex sonography of the
carotids. RESULTS: All five patients had abnormal enhancing tissue surrounding
the symptomatic carotid artery centered at the level of the distal common carotid
and carotid bifurcation. This tissue had intermediate signal intensity on T1
weighted images and showed marked enhancement. In all patients, the remaining
visualized portions of the carotid artery were normal. Normal flow voids were
present throughout the vessel, and the caliber of the vessels was always within
normal limits. There was no evidence of intramural hematoma, cervical
lymphadenopathy, or atherosclerotic disease of the vessel. In one patient, repeat
imaging after resolution of symptoms showed an absence of the previous
abnormality. CONCLUSION: The MR findings in these patients, along with the lack
of any findings to suggest alternative diagnoses, support the existence of
carotidynia as a distinct clinical entity.
PMID- 10782794
TI - The CT and MR imaging features of carcinoma arising in thyroglossal duct
remnants.
AB - BACKGROUND AND PURPOSE: Carcinoma arising in thyroglossal duct remnants is a well
described entity in the pathology and surgery literature, but it has little
recognition in the radiology literature. Preoperative diagnosis may alter
surgical management, although this diagnosis is rarely made. This study was
undertaken to determine the radiologic features that might differentiate
carcinoma from benign thyroglossal duct cysts. METHODS: Twenty-one cases of
nonpediatric thyroglossal duct anomalies imaged at our institution during a 15
year period were reviewed retrospectively. The images were assessed for lesion
wall thickness, enhancement, soft-tissue component, calcification, and loculation
of the cystic component. Three additional cases of thyroglossal duct carcinoma
obtained from outside institutions were reviewed for these features also.
RESULTS: Six cases of thyroglossal duct carcinoma were reviewed. All cases of
carcinoma had solid soft-tissue elements visible on CT scans or MR images,
compared with three of 18 cases of benign thyroglossal duct cysts. The malignant
component was seen as a small peripherally based mass in relation to a cyst, a
solid mass in the expected course of the thyroglossal duct, or a complex invasive
mass also in the midline of the neck. CT only revealed calcification in cases of
carcinoma, within either the primary carcinoma mass or a metastatic node.
CONCLUSION: Thyroglossal duct carcinoma should be suspected in an adult patient
in the presence of a solid nodule or invasive features in association with a
thyroglossal duct lesion visible on CT scans or MR images. The presence of
calcification, which is seen best on CT scans, may be a specific marker for
carcinoma.
PMID- 10782795
TI - Imaging of nonlaryngeal neuroendocrine carcinoma.
AB - The imaging and pathologic features of three cases of nonlaryngeal neuroendocrine
carcinoma of the head and neck are described. Neuroendocrine carcinomas represent
malignant epithelial neuroendocrine neoplasms and are classified as three types:
typical carcinoid (well differentiated), atypical carcinoid (moderately
differentiated), and small cell neuroendocrine (poorly differentiated)
carcinomas. The CT and MR imaging features of these tumors are nonspecific.
Paranasal sinus neuroendocrine carcinomas showed expansion and destruction of the
sinus, whereas metastatic neuroendocrine carcinomas to an intraparotid lymph node
presented as a circumscribed parotid mass on CT scans.
PMID- 10782797
TI - Peripheral spinal cord hypointensity on T2-weighted MR images: a reliable imaging
sign of venous hypertensive myelopathy.
AB - BACKGROUND AND PURPOSE: MR findings reported in conjunction with spinal dural
arteriovenous fistula (SDAVF) include cord swelling, increased T2 signal within
the spinal cord, and parenchymal enhancement, each of which is nonspecific.
Enlarged vessels on the cord surface, the most specific MR finding, is noted in
only half of SDAVF patients. Nevertheless, we have frequently observed MR
peripheral hypointensity of the spinal cord in SDAVF on T2-weighted images, which
is not characteristic of nonvascular or nonhemorrhagic causes of myelopathy and
which has not been described in association with SDAVF. We hypothesized that
peripheral cord hypointensity might reliably suggest the diagnosis of SDAVF or
other causes of venous hypertensive myelopathy. METHODS: We reviewed the MR
findings in 11 consecutive cases of angiographically confirmed symptomatic SDAVF
and in four cases of intracranial dural arteriovenous fistula with spinal
drainage, a lesion that also causes spinal cord deficits mediated by venous
hypertensive myelopathy. RESULTS: In each case, T2 hypointensity involving the
cord periphery was present. This sign has not been previously described in
association with either SDAVF or other causes of venous hypertensive myelopathy.
It appears, however, to be a relatively constant imaging feature of SDAVF.
CONCLUSION: In the absence of spinal hemorrhage, T2 hypointensity involving the
periphery of the spinal cord suggests venous hypertensive myelopathy as a cause
of spinal cord dysfunction.
PMID- 10782796
TI - CT-revealed choroidal effusions as a sign of carotid cavernous fistula.
AB - Choroidal effusions may appear as subtle abnormalities on CT scans. Recognition
of choroidal effusions, however, is critical because they may be an early sign of
ocular pathologic abnormality. After detection, the various causes of choroidal
effusions, such as carotid cavernous fistulas, ocular hypotony, tumors, and
inflammatory conditions, should be considered.
PMID- 10782798
TI - Giant cervical epidural veins after lumbar puncture in a case of intracranial
hypotension.
AB - A 29-year-old woman presented with dilated epidural veins and incapacitating
headache after undergoing a lumbar puncture. Two months later, the results of
follow-up MR imaging were normal. These findings suggest that temporary dilation
of the epidural vein may occur in association with post-lumbar puncture
intracranial hypotension syndrome. In these cases, it seems useful to confirm
whether the patient has recently undergone a lumbar puncture.
PMID- 10782799
TI - Intracranial calcifications in childhood medulloblastoma: relation to nevoid
basal cell carcinoma syndrome.
AB - BACKGROUND AND PURPOSE: Medulloblastoma is one of the most common posterior fossa
tumors to occur in children. Our purpose was to document the frequency, location,
and time of occurrence of intracranial calcifications in cranial CT studies of
children with medulloblastoma. METHODS: We retrospectively reviewed cranial CT
studies of 56 patients diagnosed with medulloblastoma from 1983 through 1997 for
the presence of intracranial calcifications. The findings were compared with 159
cranial CT studies of patients who were evaluated in the emergency department
(control group). Thirty-two patients with medulloblastoma without shunts were
compared with 118 patients from the control group without shunts. Similarly, 24
patients with medulloblastoma with shunts were compared with 41 patients from the
control group with shunts. RESULTS: Overall, three (9%) patients with
medulloblastoma without shunts, four (16%) patients with medulloblastoma with
shunts, and four (10%) patients from the control group with shunts had falx
calcification. Only the two children carrying the diagnoses of medulloblastoma
and nevoid basal cell carcinoma syndrome, however, had calcification of the falx
cerebri shown on the cranial CT scans obtained during the peridiagnostic period.
Both were diagnosed with medulloblastoma before the age of 3 years and later
developed jaw cysts and multiple basal cell carcinomas in the radiation field.
CONCLUSION: Previous studies have shown that falx calcification is a major
component of nevoid basal cell carcinoma syndrome. Our two cases illustrate the
importance of considering the diagnosis of nevoid basal cell carcinoma syndrome
when falx calcification is present in young patients with medulloblastoma. If the
concomitant diagnosis of nevoid basal cell carcinoma syndrome is made,
alternative types of therapy should be sought to minimize radiation therapy
sequelae.
PMID- 10782800
TI - Acute identification of cranial burst fracture: comparison between CT and MR
imaging findings.
AB - BACKGROUND AND PURPOSE: Scalp swelling associated with cranial burst fracture, a
widely diastatic skull fracture of infants associated with dural laceration and
acute cerebral extrusion, may be confused with that of a simple subgaleal
hematoma. Both conditions can also be associated with hemorrhagic shock. We
sought to improve the early evaluation of infants believed to have sustained
cranial burst fracture by including MR imaging, since this study clearly
delineates the dural-cortical interface, the site of injury. METHODS: Seven
infants aged 1 through 11 months who sustained cranial burst fractures, all
initially imaged with skull radiography and CT, were studied or treated from 1992
through 1996. MR imaging was obtained after resuscitation and stabilization.
RESULTS: Surgery or autopsy confirmed MR findings (dural laceration and
extracalvarial cerebral tissue) in all seven infants. CONCLUSION: MR imaging
allows early diagnosis of skull fracture associated with acute cerebral
extrusion.
PMID- 10782801
TI - A proposal for developing a large patient population cohort for longterm safety
monitoring in rheumatoid arthritis.
PMID- 10782802
TI - Longterm safety monitoring in rheumatoid arthritis. A proposal from OMERACT.
PMID- 10782803
TI - Is the progression of osteoarthritis phasic? Evidence and implications.
PMID- 10782804
TI - The case for classification of polymyalgia rheumatica and remitting seronegative
symmetrical synovitis with pitting edema as primarily capsular/entheseal based
pathologies.
PMID- 10782805
TI - Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of
patients with rheumatoid arthritis receiving methotrexate therapy.
AB - OBJECTIVE: To evaluate the safety and efficacy of single and multiple doses of a
chimeric anti-TNF-alpha monoclonal antibody (infliximab) in patients with
rheumatoid arthritis (RA) who had active disease despite therapy with
methotrexate (MTX). METHODS: Twenty-eight patients with active RA despite
receiving therapy with 10 mg/week of MTX were randomized to receive a single,
blinded infusion of either placebo or 5, 10, or 20 mg/kg infliximab. Twenty-three
patients who completed the blinded study entered an open, multiple dose extension
study in which they received up to 3 additional infusions of 10 mg/kg infliximab
at Weeks 12, 20, and 28. Safety, efficacy, and pharmacokinetics were evaluated
during the blinded and open trial. RESULTS: There were no serious infusion
related reactions. In the blinded phase, 17 (81.0%) of 21 patients receiving
infliximab achieved an American College of Rheumatology (ACR) 20% response at
some point during the 12 weeks of followup compared to one (14.3%) of 7 patients
receiving placebo (p = 0.003). Clinical improvement was evident by the first week
and was sustained through Week 12. For the 19 patients who received infliximab
during the blinded part of the trial and continued into the open label trial, 53%
maintained an ACR 20% response with multiple infusions of 10 mg/kg infliximab
through Week 40. Three patients withdrew from the trial during the open
continuation phase because of adverse events: cellulitis, infusion related
dizziness and headache, and vasculitic rash. Infliximab in doses of 5 to 20 mg/kg
had a mean terminal half-life ranging from 9 to 12 days and was detectable in
sera from most patients 8 to 12 weeks after dosing. CONCLUSION: Infliximab is
generally well tolerated during 40 weeks of therapy. A single infusion of 5 to 20
mg/kg infliximab significantly decreases the signs and symptoms of RA compared to
placebo in patients with active disease receiving MTX. Multiple doses of
infliximab produce sustained clinical benefit for up to 40 weeks.
PMID- 10782806
TI - Bucillamine suppresses human Th1 cell development by a hydrogen peroxide
independent mechanism.
AB - OBJECTIVE: To clarify the effect of bucillamine, an antirheumatic drug related to
D-penicillamine, on the development of human Th1 and Th2 cells in vitro. METHODS:
Peripheral blood mononuclear cells (PBMC) or purified CD4+ T cells were subjected
to the priming culture in which cells were stimulated with anti-CD3 and anti-CD28
monoclonal antibodies for 3 days and expanded for 4 days in the presence of
interleukin-2. Cytokine production by the generated cells was determined on a
flow cytometer using intracellular cytokine staining. The effects of bucillamine
were determined by adding it for the first 3 days of the priming culture.
RESULTS: Bucillamine decreased the frequency of interferon-gamma (IFN-gamma)
producing CD4+ T cells among generated CD4+ T cells after the priming culture of
PBMC, although D-penicillamine did not. This effect of bucillamine was
independent of hydrogen peroxide since it was not reversed by a catalase
treatment. One of the bucillamine metabolites, SA981, which exerts its effects by
a hydrogen peroxide-independent mechanism, decreased the frequency of IFN-gamma
producing CD4+ T cells more potently than bucillamine. Bucillamine reduced the
frequency of Th1 cells after the priming culture of purified CD4+CD45RO- T cells,
indicating that bucillamine exerts the effect in the absence of monocytes or B
cells. CONCLUSION: Bucillamine directly acts on CD4+CD45RO- T cells to suppress
Th1 cell development by a hydrogen peroxide-independent mechanism. This
previously unknown action may explain the in vivo effect of bucillamine in the
treatment of rheumatoid arthritis.
PMID- 10782807
TI - Cathepsin B and its endogenous inhibitor cystatin C in rheumatoid arthritis
synovium.
AB - OBJECTIVE: To compare the expression of cathepsin B and its endogenous inhibitor
cystatin C in synovial tissue of patients with rheumatoid arthritis (RA) and to
determine the cell type expressing cystatin C. METHODS: The expression of
cathepsin B and cystatin C was studied by immunohistochemistry in synovial tissue
of 10 patients with RA and compared to healthy controls. Applying double labeling
methods, the expression of cathepsin B was compared to that of cystatin C. To
determine the cell type expressing cystatin C, double labeling with anti-CD68 (PG
M1) was performed. RESULTS: Both cystatin C and cathepsin B were strongly
expressed in synoviocytes of patients with RA. Furthermore, fibroproliferative
tissue at the site of cartilage and bone destruction contained fibroblast-like
and macrophage-like cells positive for cystatin C and cathepsin B, whereas normal
synovial tissue exhibited only limited expression of these molecules. Osteoclasts
revealed positive staining for CD68 and cystatin C, but not for cathepsin B.
CONCLUSION: Cystatin C is a product of both macrophage-like and fibroblast-like
synoviocytes. The strong expression of both the matrix degrading cysteine
proteinase cathepsin B and the cysteine proteinase inhibitor cystatin C in
rheumatoid synovium, particularly at the sites of bone and cartilage erosion,
suggests that cystatin C--although increased--is not sufficient to prevent matrix
degradation by cathepsin B.
PMID- 10782808
TI - Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial
fluid cells, and synovial membranes of patients with rheumatoid arthritis.
AB - OBJECTIVE: Different infectious agents have been proposed to be involved in the
pathogenesis of rheumatoid arthritis (RA). We investigated the role of latent
Epstein-Barr virus (EBV) infection in patients with RA. METHODS: Sera of 55
patients with RA and 60 age and sex matched healthy controls were examined for
antibodies against EBV encoded antigens (EBNA-1, VCA, and EA) by ELISA. The
presence of viral DNA was analyzed by polymerase chain amplification of DNA
isolated from peripheral blood mononuclear cells (PBMC) of these samples and from
cells of synovial fluid (SF) specimens. Paraffin sections of synovial membranes
from 25 patients were subjected to in situ hybridization analysis for the EBV
encoded small RNA EBER1 and EBER2. RESULTS: Two-fold increased values of IgG
antibodies against EBNA-1 were found in patients with RA in comparison to healthy
controls (p = 0.029). No statistically significant difference could be observed
for antibody levels against EBV-VCA. Fourteen (24.1%) of 55 patients with RA had
serological evidence of reactivated EBV infection in comparison to none of the
control group (p = 0.028). In PBMC, EBV DNA was detected in a significantly
higher proportion in the patient group (50.9 vs. 30%; p = 0.02). In addition, SF
cells harbored the viral DNA in 30% of RA cases compared to 16.6% of control
cases (p = 0.02). However, EBER1/2 transcripts could only be found within
synovial membranes of 2 (8%) of 25 patients with RA. CONCLUSION: These findings
support the hypothesis that EBV infection may be involved in the pathogenesis of
RA. Further studies may define the precise pathogenetic mechanisms of viral
infection for the development of inflammatory arthritis.
PMID- 10782809
TI - Synovial hyperplasia in HTLV-I associated arthropathy is induced by tumor
necrosis factor-alpha produced by HTLV-I infected CD68+ cells.
AB - OBJECTIVE: To investigate the pathogenic role of macrophage lineage (CD68+) cells
in synovial proliferation in patients with human T cell leukemia virus I (HTLV-I)
associated arthropathy (HAAP). METHODS: Synovial tissues obtained from 3 patients
with HAAP and 3 patients with osteoarthritis (OA) were examined for the
expression of tumor necrosis factor-alpha (TNF-alpha) mRNA, HTLV-I tax/rex mRNA,
and number of CD68 by in situ reverse transcription assay and
immunohistochemistry. Western blot and flow cytometric analyses were used to
determine TNF-alpha production in HTLV-I infected synoviocytes. Changes in CD68+
cell population were examined by flow cytometric analysis. Proliferative effects
of supernatants of HTLV-I infected synoviocytes on normal synoviocytes were also
determined. RESULTS: TNF-alpha and HTLV-I tax/rex mRNA were preferentially
expressed in CD68+ cells in HAAP synovia. Infection of OA synoviocytes by HTLV-I
resulted in preferential expression in CD68+ cells, and these cells produced TNF
alpha. Supernatants of HTLV-I infected synoviocytes significantly enhanced the
proliferation of normal synoviocytes through a TNF-alpha dependent pathway.
CONCLUSION: Our results suggest HTLV-I viral tropism for CD68+ cells, and that
HTLV-I infected synoviocytes were induced to produce TNF-alpha, which enhances
synovial proliferation in HAAP.
PMID- 10782810
TI - High serum levels of pro-matrix metalloproteinase-3 are associated with greater
radiographic damage and the presence of the shared epitope in patients with
rheumatoid arthritis.
AB - OBJECTIVE: To determine if there is a relationship between serum pro-matrix
metalloproteinase-3 (proMMP-3) levels and radiographic damage in rheumatoid
arthritis (RA), and to investigate whether high levels are associated with
presence of the HLA-DRB1 shared epitope (SE). METHODS: Serum proMMP-3 levels were
measured by ELISA on 45 RA patients with early disease and 292 with established
disease. Early RA was arbitrarily defined as disease duration <3 years. Clinical
and laboratory measures of disease activity and severity were obtained.
Radiographic damage was assessed by scoring radiographs of the hands and feet
using the method of Larsen. HLA-DRB1 typing was performed by sequence-specific
oligonucleotide probing. Data were analyzed by multiple regression analysis.
RESULTS: In all patients, there was a correlation (r = 0.318, p<0.0001) between
serum proMMP-3 levels and Larsen scores. Other correlations were found with
Health Assessment Questionnaire score (r = 0.261, p<0.0001) and C-reactive
protein (CRP) (r = 0.357, p<0.0001) levels. ProMMP-3 levels were significantly
higher in SE+/+ patients than in those completely lacking the SE, with the
highest levels in patients carrying an HLA-DRI+/DR4+ phenotype. The greatest
difference in proMMP-3 levels between SE+/+ and SE-/- patients was in those with
a disease duration <3 years (381.6 vs. 71.7 ng/ml; p = 0.02). CONCLUSION: Our
data indicate that there is a significant relationship between radiographic
damage and serum levels of proMMP-3. As well, higher circulating levels of proMMP
3 are found in patients positive for the SE, particularly in early RA, and this
may partly explain the association between the SE and more erosive disease.
PMID- 10782811
TI - Matrix metalloproteinase-3 serum levels are correlated with disease activity and
predict clinical response in rheumatoid arthritis.
AB - OBJECTIVE: To demonstrate that serum matrix metalloproteinase-3 (MMP-3) is a
variable associated with disease activity and with the response to treatment in
rheumatoid arthritis (RA). METHODS: Serum MMP-3 levels were measured and compared
to biological and clinical disease activity variables in 20 patients with active
RA assessed serially during a one year prospective open label trial with
methotrexate or tenidap. RESULTS: MMP-3 levels were significantly correlated with
C-reactive protein (CRP) and interleukin 6 serum levels as well as with the
disease activity score (DAS), not only at start in untreated patients but also
during the 12 month followup period in both treated groups. Early changes (after
0.5, 1, 2, or 3 months) in MMP-3 levels were significantly associated with change
in DAS observed 4 to 6 months later. CONCLUSION: In addition to CRP, a systemic
marker of inflammation, serum MMP-3 may serve as a consistent synovial derived
marker of RA disease activity, early changes of which predict disease outcome.
PMID- 10782812
TI - High macrophage-colony stimulating factor levels in synovial fluid of loose
artificial hip joints.
AB - OBJECTIVE: To clarify a macrophage-colony stimulating factor (M-CSF) related
mechanism of aseptic loosening of artificial hip joints. METHODS: Synovium-like
interface tissues between bone and prosthesis, regenerated pseudocapsular
tissues, and synovial fluid (SF) were collected from 9 patients with loose
artificial hip joint at revision surgery. Tissue distribution, production site,
and SF level of M-CSF in loose hip joints were investigated by
immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR),
and ELISA, respectively. For a comparative assessment of the M-CSF level in loose
hip joints, SF of active rheumatoid arthritis (RA) and mild osteoarthritis (OA)
also were analyzed by ELISA. RESULTS: Immunohistochemical analysis showed the
presence of M-CSF immunoreactive cells mainly in the interface tissues between
bone and prosthesis and inner pseudocapsular tissues, both of which were in
contact with joint fluid. RT-PCR analysis confirmed the local production of M-CSF
in these periprosthetic tissues. Significantly higher M-CSF level in loose hip
joint fluid than in active RA and mild OA fluid was revealed by ELISA.
CONCLUSION: High M-CSF level in loose hip joint fluid suggests transportation of
M-CSF from production sites to joint fluid. This indicates that not only
polyethylene wear particles (reported to induce foreign body reaction at the bone
prosthesis interface), but also M-CSF, abundant in joint fluid, are transported
to and affect the interface. Thus, M-CSF is locally produced in periprosthetic
tissues of loose hip joints and possibly contributes to periprosthetic weakening
and osteolysis via joint fluid, leading to prosthetic loosening.
PMID- 10782813
TI - Lupus nephritis outcomes: health maintenance organizations compared to non-health
maintenance organizations.
AB - OBJECTIVE: Patients with systemic lupus erythematosus (SLE) in USA increasingly
have their care centered in health maintenance organizations (HMO). We examined
whether HMO and non-HMO SLE patients with renal involvement, who had the same
university rheumatologist, differed in their utilization of health care or renal
outcomes. METHODS: Consecutive patients with SLE with renal involvement (n = 24),
10 enrolled in an HMO, 14 not, were studied. Laboratory values were prospectively
determined. RESULTS: At the first visit to the rheumatologist, there was no
significant difference between HMO and non-HMO patients in laboratory values.
There was no difference in the 2 groups in the final prednisone dose (HMO 12 mg
vs non-HMO 15.9 mg) or use of azathioprine (20% vs. 57%; p = 0.07) or
cyclophosphamide (60% vs. 57%). The serum creatinine was higher in the HMO
patients (HMO 1.1 mg/dl vs. non-HMO 0.78 mg/dl; p = 0.05). No difference was
found in the number of rheumatology visits. There was a significant difference in
the number of communications from the rheumatologist to the HMO versus the HMO to
the rheumatologist (p = 0.026). CONCLUSION: Other than the serum creatinine,
there are no differences in the treatment or renal outcomes for HMO compared to
non-HMO patients with SLE seeing the same rheumatologist. There is a potential
barrier in physician communication, however, with the majority of communications
going from the rheumatologist to the HMO provider.
PMID- 10782814
TI - Altered function of the hypothalamic stress axes in patients with moderately
active systemic lupus erythematosus. I. The hypothalamus-autonomic nervous system
axis.
AB - OBJECTIVE: To determine the human corticotropin releasing hormone (hCRH) induced
stress response of the hypothalamus-autonomic nervous system axis (HANS) in
patients with moderately active systemic lupus erythematosus (SLE). METHODS:
Cardiovascular and pupillary function variables were measured by standardized
computer procedures before and during an hCRH test (6 time points). The results
of 12 patients with SLE were compared to 24 healthy subjects with (HS+P, n = 12)
and without (HS, n = 12) prior administration of prednisolone 3 days before the
test. RESULTS: At baseline, diastolic blood pressure was significantly higher in
SLE than in HS or HS+P (p<0.001). During the hCRH test, patients with SLE had
increased heart rates and systolic and diastolic blood pressure responses
compared to HS+P and HS (p<0.001 for all comparisons). Moreover, heart rate
variation was decreased at rest, during the lying-to-standing procedure, and
during the 2 applied respiratory tests (p<0.01 vs. HS). Compared to HS+P and HS,
latency time of the pupillary light reflex was prolonged and maximal pupillary
area was increased, revealing sympathetic hyperreactivity. CONCLUSION: This study
found an altered autonomic nervous system response at baseline, which was more
pronounced during the hCRH stress test in patients with moderately active SLE
compared to healthy subjects. Baseline and stress responses are characterized by
a sympathetic overstimulation. Such a hypersympathetic reaction may lead to
increased risk of cardiovascular diseases in patients with moderately active SLE,
which needs to be investigated in longitudinal studies.
PMID- 10782815
TI - Altered function of the hypothalamic stress axes in patients with moderately
active systemic lupus erythematosus. II. Dissociation between androstenedione,
cortisol, or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor.
AB - OBJECTIVE: To investigate adrenocorticotropin, androstenedione (ASD), cortisol,
or dehydroepiandrosterone sulfate (DHEAS) before and during a corticotropin
releasing hormone (hCRH) test in patients with moderately active systemic lupus
erythematosus (SLE) undergoing low dose longterm glucocorticoid therapy, and to
examine these hormones in relation to interleukin 6 (IL-6) or tumor necrosis
factor (TNF). METHODS: Serum levels of hormones and cytokines were measured
before and during an hCRH test. The results of 12 patients with SLE were compared
to 12 healthy subjects (HS) and 12 healthy subjects given prior short term
prednisolone (HS+P). RESULTS: Baseline and stimulated serum ASD, cortisol, and
DHEAS were lower in patients with SLE vs. HS (p<0.005), but baseline and
stimulated plasma adrenocorticotropin was normal in SLE. In SLE, but not in HS+P
or HS, baseline and stimulated DHEAS was low in relation to cortisol or ASD
(i.e., shift from DHEAS to cortisol or ASD). In patients with SLE, baseline and
stimulated serum levels of adrenal hormones were lower in relation to IL-6 or TNF
compared to HS or HS+P (p< 0.001). In contrast, in SLE patients, the baseline and
stimulated pituitary hormone adrenocorticotropin was normal in relation to these
cytokines. CONCLUSION: We found marked adrenal insufficiency and a shift in
steroidogenesis to cortisol in patients with SLE, but a completely normal
pituitary function (in absolute values and in relation to IL-6 or TNF). This may
depend in part on prior longterm glucocorticoid therapy and changes of
steroidogenesis due to cytokines. The situation in patients with SLE was not
mimicked by high dose short term prednisolone in healthy subjects. Further
longitudinal studies in untreated patients are needed to investigate the
endocrine-immune interplay and its consequences during the course of SLE.
PMID- 10782816
TI - Outcome of total hip replacement for avascular necrosis in systemic lupus
erythematosus.
AB - OBJECTIVE: To describe the short and medium term results of total hip
arthroplasty (THA) for avascular necrosis in patients with systemic lupus
erythematosus (SLE). METHODS: Nineteen patients with SLE and avascular necrosis
of the femoral head (AVNFH), who underwent 26 THA were retrospectively reviewed
with a minimum followup of 2 years. To determine whether these patients had
results similar to those of patients with other conditions, we formed a control
group of 19 patients who had 29 THA. They were matched for age, sex, and followup
to the patients with SLE. Controls had THA for juvenile rheumatoid arthritis (n =
7), osteoarthritis (5), adult onset rheumatoid arthritis (8), developmental
dysplasia of the hip (4), and other diagnoses (5). Outcome measures included a 10
point visual analog scale (VAS) for pain, the Harris hip score, and the SF-36
self-administered health outcome questionnaire. We used the methods of Delee,
Harris, and Engh for radiological assessment. RESULTS: Mean age at surgery was 46
years (range 21-71 years) and average followup was 4 years, 7 months (range 1 yr
9 mo to 9 yrs 6 mo), similar in both groups. Technical problems, mostly
consisting of small, nonpropagating cracks of the calcar in uncemented stems,
were encountered in 4 SLE hips and 1 control hip. Six complications were noted in
the SLE group, including 2 early, nonrecurrent dislocations, 1 patient with thigh
pain for 1 year, 1 pericarditis, 1 sick-sinus syndrome, and 1 urinary tract
infection. There was one case of urinary tract infection in the control group.
One SLE patient developed a low grade prosthetic infection and underwent
successful revision 2 years after primary surgery. Clinical outcome measures had
similar scores in the 2 groups: average VAS pain score = 2.00 in SLE hips
(maximum 10) and 1.97 in control hips; mean Harris hip score = 86.7 in SLE
patients (maximum 100) and 81.9 in controls; average SF-36 score = 63.4 in SLE
patients (maximum 100) and 60.5 in controls. There was no radiological evidence
of implant loosening in controls; there was 1 asymptomatic cup migration in the
SLE group. CONCLUSION: In the short and medium term, patients with SLE and AVN
had good results after THA. Results were similar in patients who had hip
replacement for other diagnoses. Less favorable clinical outcomes of hip
replacement have been reported in young patients who have AVN of other etiology
(e.g., alcoholic, post-traumatic), but this was not the case in our young
patients who had AVN and SLE. Thus, AVNFH and SLE should not constitute a
contraindication to hip replacement.
PMID- 10782817
TI - Antiprothrombin and antiannexin V antibodies imply risk of thrombosis in patients
with systemic autoimmune diseases.
AB - OBJECTIVE: To investigate the relationship between antiprothrombin (aPT) and
antiannexin V (aANX) autoantibodies of IgG isotype and thrombosis in patients
with systemic autoimmune diseases. To compare the clinical relevance of these
antibodies to that of anticardiolipin (aCL), anti-beta2-glycoprotein I antibodies
(anti-beta2-GPI), and lupus anticoagulant (LAC). METHODS: Serum IgG aPT, aANX,
aCL, and anti-beta2-GPI levels were measured by solid phase enzyme immunoassay in
the sera of 70 patients with systemic autoimmune diseases, 35 with
antiphospholipid syndrome (APS) and 35 without APS. Medical records were
analyzed, and associations of the antibodies with clinical features of APS were
assessed. RESULTS: Patients with APS had higher frequency of aPT (p = 0.001) and
aANX (p = 0.002) compared to patients without APS. Thrombotic events occurred
more frequently in those with aPT or aANX than those without (p = 0.005, p =
0.006, respectively). The presence of aPT and aANX was found to be highly
specific for APS. CONCLUSION: Measurement of aPT and aANX antibodies may be of
value in confirming the diagnosis of APS, and in evaluating risk of venous and
arterial thrombosis in patients with systemic autoimmune diseases.
PMID- 10782819
TI - Increased serum levels of interleukin 10 in Sjogren's syndrome; correlation with
increased IgG1.
AB - OBJECTIVE: To determine levels of interleukin 10 (IL-10) and IgG subclasses in
serum from 53 patients with primary Sjogren's syndrome (SS). METHODS: Serum
levels of IL-10 were measured using specific sandwich ELISA in 25 patients with
"definite" SS, 28 with "possible" SS, and 32 healthy controls. Interferon-gamma
(IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were also measured
by immunoassays. Immunoglobulin classes, IgG subclasses, and C-reactive protein
were measured by nephelometry. RESULTS: Circulating IL-10 was elevated in 25
patients. The increase reached significance in the group with possible SS (p =
0.03) versus controls. In the group with definite SS, IL-10 level was correlated
with IgG1 level (p = 0.01, r = 0.67) and with focus score (p = 0.01). IFN-gamma
was undetectable in most patients. TGF-beta1 was higher (not significantly) in
possible SS than in definite SS. CONCLUSION: IL-10 is increased in SS and may
account for the overproduction of IgG1 in the syndrome. High IL-10 in the absence
of increased IgG1 in possible SS suggests that IL-10 may be necessary but not
sufficient for IgG1 overproduction and that other factors are involved. Whereas
the correlation of IL-10 level with focus score was expected, it is intriguing
that IL-10 was more frequently increased in the incomplete (possible) form of SS
than the complete (definite) form. Elevated IL-10 may characterize the lower
stage of eccrine dysfunction and perhaps contributes to limiting its severity.
PMID- 10782818
TI - Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in
patients with systemic sclerosis.
AB - OBJECTIVE: KL-6 is a mucin-like glycoprotein that is strongly expressed on type
II pneumocytes in the lung. Circulating KL-6 has been shown to be a sensitive
marker of the disease activity of interstitial lung diseases. We determined the
serum levels of KL-6 in patients with systemic sclerosis (SSc) and investigated
whether these levels would serve as a useful marker of pulmonary fibrosis (PF) in
patients with SSc. METHODS: The serum KL-6 levels were determined using a
specific ELISA in 91 patients with SSc, and in 38 healthy controls. RESULTS: The
serum levels of KL-6 were significantly higher in patients with SSc than in
healthy controls (923+/-860 vs. 382+/-55 U/ml; p<0.0001). The serum KL-6 levels
of the patients with diffuse cutaneous SSc (dSSc) tended to be higher than those
with limited cutaneous SSc (ISSc) (1054+/-1000 vs. 800+/-694 U/ml), but there was
no significant difference between these 2 groups. The serum KL-6 levels in the
patients with PF were significantly elevated compared to those without PF (1283+/
1056 vs. 520+/-148 U/ml; p<0.0001). Moreover, DLCO and VC were also significantly
decreased in the patients with elevated KL-6 levels compared to those with normal
levels (62+/-22% vs. 72+/-17%, p<0.05; 87 +/-20% vs. 100+/-18%, p<0.01,
respectively). CONCLUSION: Serum KL-6 level may be a useful serum marker for
evaluating pulmonary fibrosis in patients with SSc.
PMID- 10782820
TI - Increased expression of interleukin 1alpha and MHC class I in muscle tissue of
patients with chronic, inactive polymyositis and dermatomyositis.
AB - OBJECTIVE: To investigate if there is a molecular correlate in muscle tissue to
the persisting decreased muscle function in patients with chronic, inactive
polymyositis (PM) and dermatomyositis (DM). METHODS: Muscle function was assessed
using a muscle function index of myositis. To assess disease activity both
histopathological investigation of muscle biopsies and magnetic resonance imaging
(MRI) scans of the thigh muscles were performed. Inactive chronic disease was
defined as persisting muscle weakness and absence of inflammatory infiltrates in
muscle biopsy and absence of signs of inflammation on MRI. Expression of
interleukin 1alpha (IL-1alpha), IL-1beta,, adhesion molecules, and MHC class I
molecules in muscle tissue was investigated with immunohistochemistry. RESULTS:
Muscle weakness was confirmed by a reduction of muscle function score. No signs
of inflammation typical for myositis were observed. The most striking finding in
our study was the strong expression of IL-1alpha and MHC class I molecules in
muscle tissue from patients with inactive chronic PM and DM. Increased IL-1alpha
expression was evident in capillaries and increased MHC class I expression was
detected in muscle fiber membranes. CONCLUSION: IL-1alpha and MHC class I
molecules may have an importance in the pathogenesis of the chronic muscle
weakness and fatigue in patients with PM and DM.
PMID- 10782822
TI - Lack of association between infection and onset of polymyalgia rheumatica.
AB - OBJECTIVE: The etiology of giant cell arteritis (GCA) is unknown, but its sudden
onset and the wide variation in incidence reported from various parts of the
world suggest a genetic predisposition and/or the influence of environmental
factors, such as infectious agents or a seasonal effect. We analyzed the
influence of season on GCA in our area over the period 1985-97, as well as the
possible association between infection and onset. METHODS: Retrospective study of
143 cases of GCA diagnosed from 1985 to 1997. To evaluate seasonal variation in
disease onset, the month of onset of the first symptoms related to GCA was used
to calculate season-specific incidence rates. Differences between season
incidence rates were assessed by chi-square test. To test for an association
between infection and GCA onset, we considered only infections that occurred
within 2 months before the onset of disease. Because of the difficulty in
determining whether an infection was present using only the clinical and
laboratory data recorded in patients' medical charts, we categorized the
likelihood of patients having infection into 3 groups: no infection, probable
infection, and definite infection. RESULTS: Between 1985 and 1997 (both years
included), a total of 143 patients (88 women, 55 men) were diagnosed with GCA. Of
these, 85 had isolated polymyalgia rheumatica (PMR), 22 had temporal arteritis
(TA) without PMR, and 36 had PMR associated with TA. The main clinical features
in our population were similar to those reported in other studies. We found no
seasonal variation in disease onset during the 13 year period. Moreover, only one
(0.7%) of 143 patients was categorized as a probable infection, whereas definite
infection was not observed in any case. From these results, the hypothesis of an
infectious cause for GCA seems highly improbable. CONCLUSION: We were unable to
observe a seasonal pattern or an association between infection and the onset of
GCA.
PMID- 10782821
TI - Amyloid myopathy masquerading as polymyositis.
AB - OBJECTIVE: It is not well appreciated that the clinical presentation of amyloid
myopathy can mimic that of polymyositis. By retrospective clinicopathologic
analysis we determined distinctive features of amyloid myopathy that
differentiate the 2 diseases. METHODS: Two patients with clinical and histologic
evidence of an inflammatory myopathy had fatal outcomes despite appropriate
treatment for polymyositis. Their clinical course and original pathologic
specimens were reviewed. In addition, original tissue samples were obtained and
analyzed using Congo red staining and immunoperoxidase. RESULTS: The initial
diagnosis of polymyositis was supported in both cases by muscle biopsies showing
inflammatory infiltrates and elevations of creatine phosphokinase and by classic
electromyography. Retrospective evaluation of the initial muscle biopsies
disclosed subtle but incontrovertible evidence of vascular amyloid. Further
analysis of the original specimens confirmed the presence of immunoglobin light
chain (AL) amyloid. CONCLUSION: Amyloid myopathy can mimic polymyositis. Both can
have similar clinical symptoms, as well as inflammatory infiltrates on muscle
biopsy. Failure to recognize amyloid myopathy deprives patients of potentially
life prolonging treatment. Congo red staining and immunohistochemical analysis of
tissue could prevent misdiagnosis.
PMID- 10782823
TI - The relationship between patient satisfaction with health and clinical measures
of function and disease status in patients with psoriatic arthritis.
AB - OBJECTIVE: To investigate whether patient satisfaction with health is a distinct
aspect of clinical or health status in a sample of patients with psoriatic
arthritis (PsA). METHODS: One hundred sixty-nine consecutive outpatients
attending the University of Toronto PsA Clinic completed the Arthritis Impact
Measurement Scales II (AIMS2), which includes both a global rating of patient
satisfaction with health and a scale that assesses satisfaction with functioning
in 12 health domains. Clinical, laboratory, and radiological assessments of
function, pain, inflammation, and damage were also performed according to a
standard protocol. RESULTS: Logistic regression analysis indicated that the AIMS2
global ratings of patient satisfaction with health were not associated with
traditional clinical measures of inflammation and damage, but were associated
with American College of Rheumatology (ACR) functional class and number of
fibromyalgia tender points. Patient satisfaction was also related to annual
family income and use of retinoids or corticosteroids. Similarly, linear
regression analysis showed that scores on the AIMS2 satisfaction scale were
unrelated to traditional clinical measures of inflammation and damage, with the
exception of total number of actively inflamed joints. ACR functional class,
annual family income, and comorbidity were also related to scores on the
satisfaction scale. CONCLUSION: Patient satisfaction with health appears to be
relatively independent of traditional clinical measures of physical functioning,
pain, and disease status.
PMID- 10782824
TI - Type and outcome of reconstructive surgery for different patterns of psoriatic
arthritis.
AB - OBJECTIVE: To describe our experience of musculoskeletal surgery in patients with
different patterns of psoriatic arthritis (PsA). METHODS: From 1986 to 1996, 71
operations in 43 patients with established PsA were performed at our institution.
The patterns of PsA recognized in this patient group were: distal PsA,
oligoarticular PsA, and polyarticular PsA, with or without associated
spondylitis. Surgical findings and procedure, intra- and postoperative
complications were recorded. Nineteen patients were available for clinical
evaluation, both by conventional surgeon generated and by patient generated self
administered questionnaires. RESULTS: The majority of patients had polyarticular
PsA. All operations in patients with distal PsA were distal interphalangeal (DIP)
and proximal interphalangeal (PIP) joint fusions. All operations in patients with
oligoarticular PsA involved the hip or knee. Polyarticular patients underwent a
range of procedures. Soft tissue contractures and bone loss required specific
attention in 14 procedures. In the 19 patients who were reviewed clinically,
conventional scoring of individual procedures showed good to excellent results.
Patient oriented outcomes had low scores compared to a disease-free general
population. CONCLUSION: The 3 principal patterns of PsA are associated with
different types of surgery. Although traditional surgeon generated scores
evaluating individual procedures indicated results comparable to patients who
have osteoarthritis, patient generated outcome measures of global health and
function scored substantially lower than a general, arthritis-free population,
reflecting the burden of polyarticular involvement.
PMID- 10782825
TI - Discovertebral erosions and destruction in psoriatic arthritis.
AB - OBJECTIVE: To evaluate the prevalence and clinical features of destructive
abnormalities of the discovertebral junction in psoriatic arthritis (PsA).
METHODS: One hundred consecutive patients with PsA (38 with spondylitis, 48 with
polyarthritis, 14 with oligoarthritis; 52 men and 48 women; mean age 45.74 years,
range 18-76, mean duration of disease 79.84 mo, range 8-336) were evaluated. The
study protocol included a questionnaire on the patient's usual work, occurrence
of previous trauma or infection to the spine, characteristics of articular
involvement, and presence and characteristics of back pain. Radiographic study of
involved joints and of the spine was performed and lesions occurring at the
discovertebral junction were classified according to Cawley's suggestions.
RESULTS: Twelve patients showed destructive abnormalities of the discovertebral
junction (12.0%). These patients had age and disease duration significantly
greater than the patients without abnormalities (p = 0.0001 and 0.0001,
respectively). Nine of them had spondylitis and 3 polyarthritis (p = 0.02).
Cervical tract was affected in 4 cases (33.3%) and thoracic in 12 (100%). Lumbar
spine changes occurred in 6 patients (50%). Lesions were localized to only one
level in 4 cases and at multiple levels in the remaining 8. According to Cawley's
classification type 1 lesions involved 6 thoracic discovertebral junctions, type
2 involved 15 junctions (4 cervical, 5 thoracic, 6 lumbar), type 3 only one
thoracic junction. Back pain occurred in only 5 cases (41.6%), all belonging to
the spondylitic subset. Pain was localized to those tracts of the spine with
radiographically documented disease and was exacerbated with physical activity.
CONCLUSION: Discovertebral erosions seem to be another characteristic aspect of
spondyloarthropathies. In PsA, the lesions occur markedly in older spondylitic
patients with a greater duration of disease and may often be totally
asymptomatic.
PMID- 10782826
TI - Gene delivery to human chondrocytes by an adeno associated virus vector.
AB - OBJECTIVE: To investigate the efficiency of gene transduction to human
chondrocytes using an adeno associated virus (AAV) vector. METHODS: We transduced
green fluorescent protein (GFP) gene using AAV vector to primary human
chondrocytes as well as human cartilage organ cultures, in which chondrocytes are
surrounded by extracellular matrix. Expression of GFP gene was analyzed at
various time points after transduction by fluorescence microscopy and
immunohistochemistry. RESULTS: In primary chondrocytes, the percentages of GFP
positive cells were 15.9% or 16.0% on Day 1 and 95.0% or 93.7% on Day 7 after
gene transduction. In cartilage organ cultures, gene delivery was observed in
cells located not only in the superficial layer but also in the deep layer within
the cartilage tissue. Up to 45.3+/-7.4% or 46.0+/-3.9% of chondrocytes expressed
GFP for at least 28 days. CONCLUSION: AAV vector could be useful for direct gene
delivery to chondrocytes in situ.
PMID- 10782827
TI - Empirical advantages of adeno associated viral vectors in vivo gene therapy for
arthritis.
AB - OBJECTIVE: To evaluate the utility of the adeno associated viral (AAV) vector for
gene delivery to joint cells in vivo and in vitro, and to assess its potential as
a vector for arthritis gene therapy. METHODS: A recombinant AAV (rAAV) vector
expressing the bacterial beta-galactosidase (beta-gal) gene (rAAV-CMV-LacZ) was
directly introduced into healthy-normal mouse knees, or arthritic knees in mice
overexpressing tumor necrosis factor-alpha (hTNFalpha-Tg). Beta-gal expression
levels were determined by immunohistochemistry and chemiluminescence. The
transduction efficiency of this vector on primary fibroblast-like synoviocytes
(FLS) in vitro was determined by FACS. The effects of UV and gamma-irradiation as
well as TNF-alpha on transduction efficiency were determined using the same
methods. RESULTS: We found little evidence of rAAV transduction in the joint
cells of healthy mice. Target gene expression was detected in all animals at Day
3, and peaked at Day 7 before returning to baseline levels 21 days after
injection. In contrast, synoviocytes, articular chondrocytes, and meniscal cells
of diseased mice were transduced by rAAV-CMV-LacZ in hTNFalpha-Tg animals.
Transduction efficiencies correlated with joint damage, and target gene
expression was up to 10-fold greater than that seen in the normal mice. In vitro,
we found that rAAV transduction of FLS can be enhanced by pretreatment with UV or
gamma-irradiation and TNF-alpha stimulation. CONCLUSION: We find that rAAV
vectors have several empirical advantages for in vivo gene therapy for arthritis:
(1) rAAV preferentially transduces arthritic joint cells in vivo. (2) rAAV can
transduce both FLS and chondrocytes in vivo. (3) rAAV transduction of FLS can be
augmented by pretreatment with agents that induce DNA repair enzymes.
PMID- 10782828
TI - Ex vivo gene delivery using an adenovirus vector in treatment for cartilage
defects.
AB - OBJECTIVE: To realize local selective gene expression in grafted chondrocytes for
cartilage defect, we investigated the usefulness of an ex vivo gene delivery
method using an adenovirus vector. METHODS: Beta-galactosidase gene (LacZ) was
transfected using an adenovirus vector to chondrocytes isolated from rat joints.
The cells were then embedded into collagen gel, and LacZ expression in the gel
was examined using 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal)
staining; beta-galactosidase activity was also measured. The collagen gel
containing transfected chondrocytes was grafted to the experimental cartilage
defects, and the expression of delivered gene was histologically examined after X
gal staining of the tissue containing the grafted area. RESULTS: X-gal positive
chondrocytes in the gel accounted for 82% at one week and 55% at 8 weeks after
gene delivery. Beta-galactosidase activity decreased with time, but its
expression was maintained even at 8 weeks after gene delivery. Chondrocytes used
in the allograft maintained their morphology, and the expression of delivered
gene continued during the 8 week period. CONCLUSION: In this ex vivo method,
delivered gene can be expressed efficiently for a long time; this method would be
useful in allografts for cartilage defects.
PMID- 10782829
TI - Hyaluronic acid inhibits the expression of u-PA, PAI-1, and u-PAR in human
synovial fibroblasts of osteoarthritis and rheumatoid arthritis.
AB - OBJECTIVE: Intraarticular administration of hyaluronic acid (HA) has been widely
used for the treatment of osteoarthritis (OA). Fibrinolysis is closely related to
the pericellular proteolysis involved in inflammation. However, the role of HA in
the regulation of fibrinolytic factors is not yet known. We investigated the
effect of HA on the pericellular fibrinolytic system of human synovial
fibroblasts derived from OA and rheumatoid arthritis (RA). METHODS: Human
synovial fibroblasts obtained from OA and RA were cultured in the presence and
absence of HA. The antigen of urokinase-type plasminogen activator (u-PA) and
plasminogen activator inhibitor-1 (PAI-1) were measured by ELISA, and u-PA
activity was evaluated by electrophoretic enzymography. The binding assay of u-PA
and the immunohistochemical analysis of u-PA were employed to detect u-PA
receptor (u-PAR). RESULTS: HA suppressed the secretion of both u-PA and PAI-1
antigens from the synovial fibroblasts of OA to their conditioned medium.
Suppression of u-PA activity in OA synovial fibroblasts was more marked than in
those of RA. The u-PA binding assay of OA and RA synovial fibroblasts revealed a
single class of binding site: dissociation constant (Kd) 23.7 nM, maximal number
of binding sites (Bmax) 3.11x10(4) binding sites/cell; Kd 16.5 nM, Bmax of
9.88x10(4) binding sites/cell, respectively. HA decreased Bmax in fibroblasts of
both OA and RA. Immunohistochemical analysis showed that u-PAR was constitutively
expressed in both synovial fibroblasts, but if these cells were treated with HA,
the decrease of the staining of u-PAR was more pronounced in the cells of RA than
in OA. CONCLUSION: Pericellular fibrinolytic activity mediated by the u-PA/u-PAR
system and PAI-1 was attenuated by HA in synovial fibroblasts derived from OA and
RA. Thus, HA may be a useful agent to inhibit the inflammation of arthritis.
PMID- 10782830
TI - Apoptotic chondrocytes from osteoarthrotic human articular cartilage and abnormal
calcification of subchondral bone.
AB - OBJECTIVE: Osteoarthrosis (OA) is accompanied by altered subchondral bone
remodeling. We investigated the role of chondrocytes in the mechanism of abnormal
cartilage calcification. METHODS: Knee articular cartilage samples from OA and
normal tissue were studied. Macroscopic and microscopic observations, alkaline
phosphatase staining for light and electron microscopy (bright and dark fields).
TUNEL technique, electron diffraction, and x-ray microanalyses were performed.
RESULTS: Chondrocytes from patients displayed a morphology of apoptosis and
showed abundant alkaline phosphatase (ALP)-rich matrix vesicles (MV) budding from
the plasma membrane with hydroxyapatite microcrystals on their surface. Farther
from the cells, hydroxyapatite crystals were detected on the MV surface and
increased as they approached the subchondral bone. The concentration of Ca and P
and their ratio increased inside the ALP-rich MV in relation to the proximity to
subchondral bone. In the OA subchondral bone the ratio Ca/P varied from 3.936 to
0.974. In normal tissue the ratio was very homogeneous (maximum 1.973, minimum
1.781). CONCLUSION: In situ, apoptotic chondrocytes correlate with factors known
to be involved in the calcification of the extracellular matrix. This suggests
that apoptosis is involved in the abnormal calcification of OA cartilage, and
consequently in the altered remodeling of the subchondral bone.
PMID- 10782831
TI - Preference for nonsteroidal antiinflammatory drugs versus acetaminophen and
concomitant use of both types of drugs in patients with osteoarthritis.
AB - OBJECTIVE: To analyze results of treatment of osteoarthritis (OA) with
acetaminophen and the nonsteroidal antiinflammatory drugs (NSAID) through a
patient survey. METHODS: A 15 minute telephone survey was conducted with 300
patients, including 172 with confirmed OA. RESULTS: Twenty-four percent of
patients who took acetaminophen rated it as "very helpful," compared to 31% for
ibuprofen, 30% for naproxen, and 56% for diclofenac. Drug continuation beyond 24
months was reported by 33% of patients for acetaminophen, 21% for ibuprofen, 17%
for naproxen, and 19% for diclofenac. Acetaminophen was significantly less likely
to be discontinued because of toxicity than NSAID. Patients who indicated that
they would not take a drug again, and therefore be unlikely to participate in a
clinical trial involving this drug, were 26% for acetaminophen, 40% for
ibuprofen, 38% for naproxen, and 28% for diclofenac. About 30% of patients who
took acetaminophen reported concurrent use of ibuprofen, naproxen, or diclofenac.
Among the 67% of patients who identified a drug as "most helpful," 80% named an
NSAID, compared to 20% who named acetaminophen or another analgesic as the "most
helpful" drug. CONCLUSION: Patients take many different drugs for OA, most of
which are not continued beyond 2 years. Many patients take both acetaminophen and
an NSAID. Most patients who identified a drug as "most helpful" named an NSAID
rather than acetaminophen or an analgesic drug. These findings may be of value in
further development of management strategies and guidelines for OA.
PMID- 10782832
TI - Bone mineral density in women with ankylosing spondylitis.
AB - OBJECTIVE: To determine bone mineral density (BMD) in premenopausal women with
early ankylosing spondylitis (AS). METHODS: Eighteen premenopausal women with AS
without syndesmophytes, interapophysiary arthritis, and/or coxofemoral joint
destruction were studied. BMD was analyzed at lumbar spine and femoral neck by
dual energy x-ray absorptiometry (Hologic QDR 1000). Z scores and T scores
related to the general Spanish population were recorded. Comparisons were
performed using the Student t test. Pearson's correlation coefficients were used
to study the correlation between BMD and the variables. Following the WHO
classification, osteopenia was diagnosed in patients with T score between -1 and
2.5 and osteoporosis in those with T score < -2.5 at lumbar spine or femoral
neck. RESULTS: The mean Z score for spine BMD was -0.19+/-0.7, and -0.03+/-0.85
for femoral neck BMD. There were no significant differences of Z score values
compared to the general population. No significant correlation was found between
BMD and disease duration, radiology sacroiliac score, and spine mobility.
Densitometry showed osteopenia in 2 patients and osteoporosis in none.
CONCLUSION: We found a slight reduction in BMD in premenopausal women with early
AS, but the difference was not statistically significant. We discuss the factors
related to its pathogenesis.
PMID- 10782833
TI - Bone mineral density and risk of incident and progressive radiographic knee
osteoarthritis in women: the Framingham Study.
AB - OBJECTIVE: To examine the relations of bone mineral density (BMD) and change in
BMD to risk of incident and progressive radiographic knee osteoarthritis (OA) in
a longitudinal cohort study. METHODS: Female participants aged 63 to 91 years
(mean age 71) in the Framingham Study received anteroposterior weight bearing
knee radiographs at biennial examinations 18 (1983-85) and 22 (1992-93). Knee
radiographs were given scores for global severity of OA (Kellgren-Lawrence scale:
range 0 to 4) and for the presence of osteophytes and joint space narrowing
(range 0 to 3). Femoral neck BMD was assessed using dual photon absorptiometry at
examination 20 and dual x-ray absorptiometry at examination 22. We examined the
relations of BMD at examination 20 and its change between examination 20 and
examination 22 to incident and progressive knee OA, as well as to worsening of
individual radiographic features adjusting for age, body mass index, and other
potential confounding factors. RESULTS: In total, 473 women (ages 63 to 91 yrs)
had complete assessments. Over 8 years of followup, risk of incident radiographic
knee OA increased from 5.6% among women in the lowest age-specific quartile of
BMD to 14.2, 10.3, and 11.8% among women in the 2nd, 3rd, and highest quartiles,
respectively. Multivariate adjusted OR of incident OA for each increase quartile
of BMD were 1.0, 2.5, 2.0, and 2.3, respectively (p for trend = 0.222). This was
mainly reflected in an increased risk of osteophyte development. However, risk of
progressive OA decreased from 34.4 to 22.0, 20.3, and 18.9% as BMD increased.
Compared to those in the lowest quartile of BMD, adjusted OR for progressive
disease were 0.3, 0.2, and 0.1 among women in the 2nd, 3rd, and highest quartiles
(p for trend <0.001), respectively, mainly due to its effect on lowering the risk
of joint space loss. Compared to those who lost BMD >0.04 g/cm2 over the followup
period, women who gained BMD were at increased risk of incident but at a
significantly decreased risk of progressive knee OA. BMD change was not
associated with osteophyte development, but gain in BMD lowered the risk of joint
space loss. CONCLUSION: High BMD and BMD gain decreased the risk of progression
of radiographic knee OA, but may be associated with an increased risk of incident
knee OA. The protective effect was mainly through its influence on reducing the
risk of joint space loss. Our results offer insights into how bone may affect the
course of the most common joint disease, and thus may have potential therapeutic
implications.
PMID- 10782834
TI - Comparison of nasal and oral tolerance for the prevention of collagen induced
murine arthritis.
AB - OBJECTIVE: Administration of bovine type II collagen (CII) or of its peptide
either orally or nasally has been reported to suppress the development of
collagen induced arthritis (CIA) in mice and rats. We examined the inhibitory
effects of CII delivered by each route on CIA in DBA/1J mice to determine which
route was superior. METHODS: Male mice were injected twice with CII in Freund's
complete adjuvant to induce CIA. Before induction of CIA, 1, 10, or 40 microg of
CII were administered nasally 15 times and 10, 100, 500, or 1000 microg of CII
were given 10 times orally. The development of arthritis, arthritis score, CII
specific delayed-type hypersensitivity (DTH) response, and CII-specific antibody
levels were examined. RESULTS: Nasal administration of 10 microg of CII 15 times
had the most prominent suppressive effects, reducing disease incidence by 50% and
inhibiting both CII-specific IgG antibody and DTH responses. Of all the mice
undergoing oral administration, those receiving 500 microg of CII 10 times showed
the greatest suppressive potential. However, the treatment only delayed disease
onset for roughly 3 weeks, lowering CII-specific IgG antibody levels but failing
to suppress DTH responses. CONCLUSION: Nasal administration of CII reduced CIA
development and inhibited CII-specific T cell and antibody responses to a greater
degree than did oral administration.
PMID- 10782835
TI - Community based epidemiological study on hyperuricemia and gout in Kin-Hu,
Kinmen.
AB - OBJECTIVE: This is a population survey conducted in 1991-92 among residents aged
> or =30 years in Kin-Hu, Kinmen, with a 77.7% response rate to study the
prevalence of hyperuricemia and hyperuricemia associated gout. A stratified
analysis based on sex and age was used to assess the interaction and analyze the
associated risk factors for hyperuricemia and gout. METHODS: Hyperuricemia was
defined as uric acid > or =7.0 mg/dl for men and > or =6.0 mg/dl for women. Gout
was clinically diagnosed by a senior rheumatologist based on patient's history
and examination according to the clinical criteria of Wallace. Basic demographic
and lifestyle variables as well as biochemical data were collected. RESULTS: The
prevalence of hyperuricemia was 25.8% (391/1515) in men and 15.0% (250/1670) in
women. The prevalence of gout among hyperuricemic subjects was 11.5% for men and
3% for women. According to age spectrum, the risk factor for hyperuricemia was
hyperlipidemia in young adults (30-39 yrs); lifestyle and some clinical syndromes
played a significant role in middle aged persons (40-59 yrs). The different risk
factors between the sexes in middle age were alcohol consumption effect in men
and menopause effect in women. Impaired renal function and use of diuretics
became the important factors in the elderly (> or =60 yrs). The risk factors for
gout among either the general population or subjects with hyperuricemia were
concentration of serum uric acid, alcohol consumption, and central obesity.
CONCLUSION: Risk factors for hyperuricemia tended to be different with respect to
sex and age. Alcohol consumption and central obesity were independent predictors
of gout among hyperuricemic subjects irrespective of uric acid level.
PMID- 10782836
TI - Attributions in chronic fatigue syndrome and fibromyalgia syndrome in tertiary
care.
AB - OBJECTIVE: To evaluate the attributions of patients with chronic fatigue syndrome
(CFS) and fibromyalgia (FM) consulting at a university fatigue and pain clinic.
METHODS: Consecutive attenders (n = 192) who met the CFS criteria (n = 95) or FM
criteria (n = 56) or who had medically unexplained chronic pain and/or fatigue
without meeting both criteria (CPF) (n = 41) were evaluated. All subjects
completed an extended form of the Cause of Illness Inventory. Descriptive
statistics, frequency analyses, chi-square tests, one-way analysis of variance,
and sequential Fisher least significant difference tests were performed. RESULTS:
In total, 48 patients reported physical causes only and 10 patients psychosocial
causes only; the majority (70%) mentioned both types of causes. With regard to
the contents, "a chemical imbalance in my body" (61%), "a virus" (51%), "stress"
(61%), and "emotional confusion" (40%) were reported most frequently. The
diagnostic label did not have a significant influence on number and type of
attributions. Small to moderate effect sizes were registered concerning the
association of specific attributions and diagnosis, sex, duration of the
symptoms, contact with a self-help group, and premorbid depression. CONCLUSION:
The majority of patients with CFS, FM, and CPF reported a great diversity of
attributions open to a preferably personalized cognitive behavioral approach.
Special attention should be paid to patients with symptoms existing for more than
one year and those who had previous contacts with a self-help group. They
particularly show external, stable, and global attributions that may compromise
feelings of self-efficacy in dealing with the illness.
PMID- 10782837
TI - The role of generalized pain and pain behavior in tender point scores in
fibromyalgia.
AB - OBJECTIVE: To determine and assess the significance of the independent role of
pain, pain behavior, depression, and weekly stress in tender point scores in
objectively diagnosed fibromyalgia (FM) patients. METHODS: One hundred eleven
patients with FM recruited from the community and private and university based
clinics participated in a comprehensive evaluation of their pain, psychological
distress, and pain behavior. Tender point assessment was carried out across 18
discrete sites according to American College of Rheumatology criteria. Pain was
assessed with a composite index of 4 pain measures; psychological distress
consisted of measures of stress and depression, and pain behavior was measured by
an objective index derived from a 10 minute videotaped sequence in which 5 pain
behaviors were recorded. RESULTS: Multiple regression analyses revealed that high
pain, high pain behavior, and shorter illness duration were related independently
to tender point scores. Measures of depression and weekly stress were not
independently related to tender point scores. CONCLUSION: Tender point scores are
related to generalized pain and pain behavior tendencies in patients with FM, and
do not independently reflect generalized psychological distress.
PMID- 10782838
TI - Skeletal muscle infarction in diabetes mellitus.
AB - OBJECTIVE: To analyze the risk factors, clinical features, and methods of
diagnosis of diabetic muscle infarction (DMI). METHODS: Three patients with
diabetes mellitus (DM) and skeletal muscle infarction were studied, and 49
additional cases reported in the English literature (Medline database search)
were reviewed. RESULTS: Review of all 52 patients with DMI revealed a number of
typical features: equal sex distribution; mean age 41.5 years (range 19-81 yrs);
a number of risk factors [long duration of DM (mean 15.2 yrs), poor control and
microvascular diabetic complications (neuropathy, retinopathy, nephropathy)
(94%), and insulin dependent type I DM (77%)]; a characteristic clinical
presentation with painful diffuse muscle swelling (100%); and sometimes a muscle
mass (44%), predilection for quadriceps (62%), hip adductors (13%) and leg
muscles (13%), elevated serum creatine phosphokinase (47%), abnormal sonograms
(81%), abnormal magnetic resonance image (MRI) findings (100%), typical
histopathologic findings of a muscle infarct (100%) (ultrastructural evidence of
microangiography in one patient); and a tendency toward spontaneous resolution
although recurrences are common (51%). CONCLUSION: Skeletal muscle infarction is
a rare complication of long standing, poorly controlled DM associated with
multiple end organ microvascular sequelae. Increased clinical awareness is
important for early recognition, particularly in a diabetic patient presenting
with a painful thigh or leg swelling. MR imaging is the diagnostic study of
choice, and in the appropriate clinical setting, may obviate the need for a
muscle biopsy.
PMID- 10782839
TI - Validation of the proposed ILAR classification criteria for juvenile idiopathic
arthritis. International League of Associations for Rheumatology.
AB - OBJECTIVE: The new International League of Associations for Rheumatology (ILAR)
classification criteria were proposed to facilitate communication among pediatric
rheumatologists. Before they are applied in daily practice they should be
clinically validated. METHODS: We retrospectively applied the proposed criteria
on our pediatric rheumatology patient population seen between June 1 and August
31, 1998. RESULTS: We saw 67 patients with oligoarticular (oJRA), 6 with
polyarticular/RF negative (pJRA), and 8 with systemic juvenile rheumatoid
arthritis (sJRA), all classified according to American College of Rheumatology
criteria, 5 with juvenile psoriatic arthritis (PsA) according to the Vancouver
criteria, and 11 with juvenile spondyloarthritis (SP) according to the European
Spondylarthropathy Study Group preliminary criteria. Of the 97 patients, 85 could
be clearly classified according to the ILAR criteria. Twelve patients (12%) were
classified as "other." Six patients could not be classified as "oligo" because of
a family history of psoriasis, and did not fulfill the criteria for PsA either.
All 6 "other" patients fulfilled criteria for 2 different categories. CONCLUSION:
With this ILAR proposed classification criteria 88% of patients could be
classified. In patients classified as "other," the psoriatic trait caused the
most difficulty in classification.
PMID- 10782841
TI - The value of echocardiography in the diagnosis and followup of rheumatic carditis
in children and adolescents: a 2 year prospective study.
AB - OBJECTIVE: To evaluate echocardiographic/Doppler findings in patients with
rheumatic fever whether or not clinical manifestations of carditis were present,
and the followup of these findings 24 months after the acute phase. METHODS:
Twenty-two patients with rheumatic fever (13 boys, 9 girls, mean age 11.0 years)
were evaluated at baseline (at diagnosis) and after 3 and 6 mo of disease.
Eighteen patients were reevaluated 24 mo later. The assessment included physical
and cardiac examination, electrocardiogram, chest radiography, and color
ECHO/Doppler performed blindly by different investigators. The control group
included 15 healthy children. RESULTS: We observed clinical carditis in 8
patients (36.4%): Group 1, all with ECHO abnormalities. We observed no clinical
cardiac manifestations in 14 patients (Group 2), but 5 (35.7%) had positive
ECHO/Doppler abnormalities that persisted at least 6 mo in followup assessments.
Mitral and aortic were the most frequently involved valves. In Group 1 we
observed normalization of the ECHO/Doppler in 3 patients, improvement in 2, no
change in 2, and worsening in one. Twelve of 14 patients without clinical
carditis were reevaluated, including the 5 patients with ECHO/Doppler
abnormalities during the initial evaluations; normalization or improvement was
observed in 2 patients, no change in 2, and worsening in one. We observed no
ECHO/Doppler abnormalities in the control group. CONCLUSION: This blind
prospective study suggests the existence of asymptomatic carditis in some
patients with rheumatic fever and the role ECHO/Doppler investigation could play
in diagnosis and followup.
PMID- 10782842
TI - Seropositive rheumatoid arthritis with dermatomyositis sine myositis,
angioimmunoblastic lymphadenopathy with dysproteinemia-type T cell lymphoma, and
B cell lymphoma of the oropharynx.
AB - Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a rare
lymphoproliferative disorder that often progresses to high grade T cell lymphoma.
We describe a 63-year-old woman with longstanding seropositive rheumatoid
arthritis who developed fever, cutaneous findings of dermatomyositis, a diffuse
pruritic maculopapular rash, enlarged lymph nodes, polyclonal elevated serum
gammaglobulins, and an IgG lambda paraprotein. Lymph node biopsies yielded tissue
with characteristic changes of AILD and T cell lymphoma. Interleukin 6 (IL-6) was
present during the early, active phase of disease, and circulating IL-6 and IL-2
were detected one month before tumor recurrence. Two years after AILD and T cell
lymphoma were diagnosed, she developed a B cell lymphoma that involved the
oropharynx.
PMID- 10782840
TI - Bone mineral content and bone mineral metabolism: changes after growth hormone
treatment in juvenile chronic arthritis.
AB - OBJECTIVE: To determine whether growth hormone (rhGH) affects bone mineral
metabolism and bone mineral content (BMC, g/cm) in a therapeutic trial of
recombinant growth hormone in growth retarded children with juvenile chronic
arthritis (JCA) treated with steroid. METHODS: BMC was measured in 20 children
(of whom 17 were treated with corticosteroid) before and after one year of rhGH.
Children were randomized to receive either low dose (12 IU/m2/week) or high dose
(24 IU/m2/week) for one year. Three monthly assessments were made of disease
activity and anthropomorphic measurements. Blood and urine samples were also
obtained to measure indicators of disease activity, bone remodeling, and vitamin
D and parathyroid hormone (PTH) status. RESULTS: BMC increased during the
treatment period and correlated with increasing height. Osteocalcin levels,
normally indicators of bone formation, increased after rhGH treatment and
correlated significantly with height velocity, particularly for the high dose
treatment group. In contrast, osteocalcin levels were negatively correlated with
C-reactive protein levels, both before and during treatment. Height velocity,
vitamin D, PTH, and osteocalcin levels were significantly lower than age matched
controls before treatment. CONCLUSION: Steroid treated children with both JCA and
severe growth retardation have reduced vitamin D, PTH, and osteocalcin levels.
After treatment with rhGH, height velocity increased, as did BMC. Growth hormone
might be a useful adjunct in the treatment of severe growth retardation and
osteoporosis in children with JCA. The longterm benefits of rhGH in the treatment
of osteoporosis remain unclear.
PMID- 10782843
TI - Hypocomplementemic panniculitis with paraprotein.
AB - Two episodes of severe panniculitis accompanied by fever and an acute phase
response were the main clinical features in a patient who had an unusual IgG
kappa paraprotein. Both episodes responded promptly to steroids. Complement
proteins of the early classical pathway were depleted in the patient's serum, and
in vitro experiments indicated that the IgG kappa paraprotein activated
complement directly. The association of recurrent panniculitis and
paraproteinemia-hypocomplementemia has been described in 2 other patients. It
should be recognized since its response to steroids is immediate.
PMID- 10782844
TI - Synovial cyst of the proximal tibiofibular joint.
AB - We describe a case of an unusual synovial cyst originating from the proximal
tibiofibular joint. This cyst presented as a painless, soft tissue swelling just
distal to the fibular head. We review the literature on this topic regarding
clinical presentation, imaging, and management.
PMID- 10782845
TI - Oral granuloma associated with intestinal Behcet's disease.
PMID- 10782846
TI - Intravenous gammaglobulin in the treatment of central nervous system vasculitis
associated with Sjogren's syndrome.
PMID- 10782848
TI - Innovative strategies for trial design.
AB - Most clinical trial designs used in evaluating therapies require large numbers of
subjects. Childhood rheumatic diseases are rare and large numbers of subjects are
not available. We have largely been unsuccessful in developing evidence based
therapeutics for pediatric rheumatology. Because these diseases are rare, it is
important for each clinical trial to enroll all possible subjects, and it is
important to extract as much information as possible from each subject. Placebo
controlled randomized studies are sometimes seen as unacceptable to physicians
and patients. We need study designs that are more acceptable and that will
increase accrual. Some clinical trial designs, especially those that involve
crossover treatment assignments, can increase the amount of information that each
subject contributes. These types of studies can only be used for treatments that
are reversible. For treatments that may permanently affect the disease course, I
propose the randomized placebo phase design as one way of increasing study
acceptability and accrual.
PMID- 10782847
TI - A new clinical manifestation of the Dobrin's syndrome?
PMID- 10782849
TI - Outcomes assessment: meeting the challenge of accountability in pediatric
rheumatology.
AB - As providers of health services, pediatric rheumatologists must learn to manage
financial risk, deliver quality services, and provide value to a number of
healthcare stakeholders. What these deliverables mean in a competitive healthcare
environment are explained. Ways to achieve these goals, provide excellent care to
children with rheumatic conditions, and differentiate pediatric rheumatologists
in the marketplace are discussed.
PMID- 10782850
TI - Update on functional assessment tools.
AB - In recent years, there has been a tremendous growth in the development of
measurement instruments that evaluate health status, functional status,
disability, and quality of life in adults with rheumatic diseases. In the past
decade, similar measures have been developed for application in children with
rheumatic diseases. These include the Childhood Arthritis Impact Measurement
Scales (CHAIMS), the Childhood Health Assessment Questionnaire (CHAQ), the
Juvenile Arthritis Functional Assessment Report (JAFAR), the Juvenile Arthritis
Self-report Index (JASI), the Juvenile Arthritis Quality of Life Questionnaire
(JAQQ), and the Childhood Arthritis Health Profile (CAHP). The latter 2
instruments assess health related quality of life (HRQOL) and they are discussed
here. The need to adapt this kind of instrument for use in an international
climate creates an interesting dilemma and this is discussed.
PMID- 10782851
TI - Premature atherosclerosis in systemic lupus erythematosus.
AB - Premature atherosclerosis is a recognized complication of systemic lupus
erythematosus (SLE). Since life expectancy in SLE is improving, premature
atherosclerosis is emerging as an ever more important clinical issue.
Atherosclerosis begins in the pediatric age group, and interventions directed at
prevention should begin in childhood as well. Possible etiologies include
dyslipoproteinemia (DL) from the underlying chronic inflammatory disease or from
corticosteroid therapy, hypercoagulation due to antiphospholipid antibodies or
nephrotic syndrome, vasculitis, and hypertension. A relationship between DL and
presence of anticardiolipin antibodies (aCL) has been reported. Dietary therapy
is helpful, but many patients continue to have significant DL after both dietary
modification and fish oil supplementation. Lipid lowering drugs may be indicated
in this subgroup. Potential mechanisms of the DL are discussed. Other strategies
to prevent atherosclerosis and its complications are reviewed.
PMID- 10782852
TI - The antiphospholipid syndrome: immunologic and clinical aspects. Clinical
spectrum and treatment.
AB - Antiphospholipid antibodies (aPL) have been associated with clinical conditions
that involve arterial or venous thrombotic events and pregnancy morbidity
including fetal loss and preeclampsia. These antibodies are detected by various
functional tests for the lupus anticoagulant, the anticardiolipin ELISA, the anti
beta2-glycoprotein I ELISA, or ELISA tests for other aPL. The pathogenic
mechanisms are poorly understood. A "2 hit" hypothesis has been entertained in
which there is underlying vascular (endothelial) damage, and in the presence of
an aPL, a thrombotic complication emerges. Although the role of immunologic
processes and autoimmunity appears important, immunosuppressive therapy has not
proven very effective. Treatment options are limited to antiplatelet therapy
(primarily for arterial events) and anticoagulation (with coumadin, heparin, or
low molecular weight heparins) because of lack of understanding of the inciting
factors and the pathogenesis of the process.
PMID- 10782853
TI - The pain puzzle: a visual and conceptual metaphor for understanding and treating
pain in pediatric rheumatic disease.
AB - Chronic pain is a primary clinical manifestation of pediatric rheumatic diseases
that for some children persists into adulthood and is associated with increased
disability. The "pain puzzle" is presented as a visual and conceptual metaphor
for understanding and treating pediatric rheumatic disease related pain. This
metaphor is consistent with a biobehavioral model of pain that focuses on the
unique and interactive components of nociceptive activity, emotions, cognitions,
and behavior in the experience of pain. We describe the parts of the pain puzzle
and review the implications for treating pediatric rheumatic disease related
pain.
PMID- 10782854
TI - Bone mineral status in juvenile rheumatoid arthritis.
AB - Osteoporosis can be thought of as a disease of childhood with manifestations in
the adult years. One strategy in prevention of osteoporosis is to maximize peak
bone mass with interventions focused during the childhood and adolescent years,
taking advantage of this unique window of opportunity to maximize bone mass
accrual, maximize peak bone mass, and theoretically decrease fracture risk for
life. Factors important in the development of peak bone mass in children are
reviewed. Studies examining bone metabolism and bone density in children with
juvenile rheumatoid arthritis (JRA) are summarized. There is much work to be done
before the best treatments for the osteoporosis of JRA are defined. Optimizing
calcium intake and physical activity, along with corticosteroid avoidance and
control of disease activity, is sound management for children with JRA.
PMID- 10782855
TI - Effects of rheumatic disease and corticosteroid treatment on calcium metabolism
and bone density in children assessed one year after diagnosis, using stable
isotopes and dual energy x-ray absorptiometry.
AB - OBJECTIVE: To evaluate calcium (Ca) metabolism and bone mineral density (BMD) in
children with rheumatic disease (RD) at diagnosis and one year later, and effects
of different therapies. METHODS: We used dual tracer isotope studies and dual
energy x-ray absorptiometry (DEXA) to measure Ca metabolism and BMD in 13
children with RD at diagnosis and one year later. Seven subjects were treated
with steroids (RD-ST), 6 with antiinflammatory agents (RD-NS), excluding
steroids. RESULTS: Ca balance data for RD subjects were not significantly
different from data reported previously for healthy sex and age matched controls.
True Ca absorption (Va) was slightly but not significantly greater at study entry
in RD-NS subjects (313+/-67 vs 239+/-112 mg/day in RD-ST subjects; p = 0.13).
Calculated Ca balance retention (Vbal) was higher at entry in RD-NS (200+/-51 vs
RD-ST 60+/-125 mg/day; p = 0.08). One year later, Vbal remained higher in RD-NS
(202+/-77 mg/day vs RD-ST 101+/-157 mg/day; p = 0.02). BMD was similar in both
groups at entry (RD-NS 0.81+/-0.06 g/cm2 vs RD-ST 0.89+/-0.1 g/cm2; p = 0.07).
One year later, BMD was 0.86+/-0.6 g/cm2 in RD-NS versus 0.89+/-0.08 g/cm2 in RD
ST; p = 0.07. Ca kinetic and DEXA studies did not reveal significant alteration
of Ca kinetics or significantly lower BMD in steroid treated subjects versus non
steroid treated subjects. However, slightly lower Va and Vbal indicated a
possible risk of bone demineralization in steroid treated subjects. CONCLUSION:
Children with RD who are treated with steroids may be at greater risk of bone
demineralization at diagnosis that persists through the first year. However, bone
loss may take years to manifest when measured by quantitative methods such as
DEXA.
PMID- 10782856
TI - An overview of amplified musculoskeletal pain syndromes.
AB - Children may have a wide variety of amplified musculoskeletal pain syndromes that
may or may not be associated with overt autonomic signs and may be diffuse or
localized to one body part. It is most common in pre- to adolescent girls.
Hallmarks of the diagnosis include increasing pain over time, allodynia, an
incongruent affect, disproportional dysfunction, and the absence of other causes.
Psychological distress within the child or family is apparent in most, but not
all, since it also is associated with injury or illness. Once the diagnosis is
established, all medicines and testing are stopped. A sympathetically driven pain
model is used to explain the pain to make it understandable. Treatment is an
intense exercise program; ours is 5 hours daily. We focus on functional aerobic
training specifically using the involved body part such as sports related drills,
running, play activities, and swimming. Allodynia is treated with desensitization
such as towel rubbing. A psychological evaluation is done and specific
psychotherapy is recommended if indicated. The average duration of the daily
program is 2 weeks with a 1 hour home program being done for another 2 to 8
weeks. After one month roughly 80% of the children have no pain and are fully
functional, another 15% are fully functional with mild or recurrent pain; 5% are
not better. Significant relapses are infrequent; 15% require retreatment. Five to
10% of the children will develop a different symptom of psychological distress.
At 5 years, 90% are doing well.
PMID- 10782858
TI - Gene therapy for juvenile rheumatoid arthritis?
AB - Gene therapy shows promise as a means of improving the treatment of a number of
rheumatic diseases, including adult rheumatoid arthritis (RA). We summarize these
developments and discuss the merits of extending such approaches to the treatment
of juvenile RA. The special issues that arise when treating children by
experimental new procedures predicate a cautious approach using strategies first
shown to be safe in adults. Patients with severe, erosive, nonremitting
pauciarticular juvenile RA might be suitable first candidates for gene therapy.
PMID- 10782859
TI - Unfinished business: challenges into the next century.
PMID- 10782857
TI - The role of bone marrow transplantation in pediatric rheumatic diseases.
AB - Recent advances in bone marrow transplantation have led to improvement in its
safety and it is now being used for rheumatologic disorders resistant to standard
medical management. I describe some of the theories underlying its use and review
the current data supporting its use.
PMID- 10782860
TI - Quo vadis? Whither goest thou, rheumatologist?
PMID- 10782861
TI - Initial steps in lymph node metastasis formation in an experimental system:
possible involvement of recognition by macrophage C-type lectins.
AB - We used histological observations and experiments with fluorescent cell tracers
to investigate the roles of tissue macrophages in recognition through a
galactose/N-acetylgalactosamine-specific C-type lectin (mMGL) in lymph node
metastasis formation by mouse ovarian tumor OV2944-HM-1 (HM-1) cells. Lymph node
metastasis from subcutaneous sites was shown to be initiated by the entry of
tumor cells into the subcapsular sinus of lymph nodes where mMGL-positive cells
were mainly located. To investigate whether mMGL-positive cells contributed to
host resistance against lymph node metastasis, we repeatedly treated mice bearing
transplanted tumors with an mMGL-blocking monoclonal antibody that was known to
inhibit mMGL binding to its ligands. The number of HM-1 cells recovered from
lymph nodes 2 weeks after subcutaneous injections was significantly greater when
the mice were treated with the blocking anti-mMGL antibody. These results
suggested that mMGL-positive macrophages contributed to the host's defense
against lymph node metastasis.
PMID- 10782863
TI - Immune gene therapy of experimental mouse brain tumor with adenovirus-mediated
gene transfer of murine interleukin-4.
AB - We examined the antitumor activity of replication-deficient adenoviral vectors
carrying the murine interleukin-4 (IL-4) gene (AdCIL4) using a syngeneic brain
tumor model in mice. Mice implanted with malignant astrocytoma cells infected
with AdCIL4 survived significantly longer than those in the control groups.
Immunocytochemical analysis of the tumors showed that AdCIL4 caused the strong up
regulation of MHC class II antigen expression by the tumor cells and macrophages,
and consequent infiltration by CD8+ T lymphocytes. This study demonstrates the
efficacy of IL-4 gene transfection mediated by adenoviral vectors for
intracerebral tumor and characterizes the immunoreaction caused by AdCIL4.
PMID- 10782862
TI - B7-2 expression on tumor cells is important for the acquisition of cytotoxic T
lymphocyte activity by spleen cells from low-dose-melphalan-treated MOPC-315
tumor bearers via a mechanism that requires either B7-1 or B7-2 expression on
host antigen-presenting cells.
AB - We have previously shown that B7-2 (CD86) and, to a lesser extent, B7-1 (CD80)
contribute to the curative effectiveness of low-dose melphalan (L-phenylalanine
mustard) for mice bearing a large MOPC-315 tumor under conditions that lead to
the acquisition of potent cytotoxic T lymphocyte (CTL) activity at the tumor
site. Since B7-1 and B7-2 are expressed on both tumor cells and host antigen
presenting cells (APC), the current studies were undertaken to examine the
relative importance of each costimulatory molecule on tumor cells and on host APC
for the acquisition of anti-MOPC-315 CTL activity. Utilizing an in vitro system
for the acquisition of CTL activity, we found that B7 expression on host APC is
important for the development of CTL activity in stimulation cultures of spleen
cells from low-dose-melphalan-treated MOPC-315 tumor bearers, although the
expression of either B7-1 or B7-2 is sufficient. In addition, we found that B7-2,
which is expressed at high levels on stimulator tumor cells, but not B7-1, which
is expressed at much lower levels, is also important for the acquisition of CTL
activity. However, the vast majority of the CTL activity acquired in vitro in
response to stimulation with the B7-2-expressing MOPC-315 tumor cells was found
to depend on B7-expressing host APC. Thus, it is likely that B7-2, which is
expressed at high levels on MOPC-315 tumor cells, promotes the rapid lysis of
MOPC-315 stimulator tumor cells, thereby making tumor-associated antigens more
readily available for efficient presentation by B7-expressing host APC which, in
turn, stimulate the acquisition of CTL activity by spleen cells from low-dose
melphalan-treated MOPC-315 tumor bearers.
PMID- 10782864
TI - Immunotherapy with vaccines combining MHC class II/CD80+ tumor cells with
interleukin-12 reduces established metastatic disease and stimulates immune
effectors and monokine induced by interferon gamma.
AB - Because they are difficult to treat, animal models of widespread, established
metastatic cancer are rarely used to test novel immunotherapies. Two such mouse
models are used in this report to demonstrate the therapeutic efficacy and to
probe the mechanisms of a novel combination immunotherapy consisting of the
cytokine interleukin-12 (IL-12) combined with a previously described vaccine
based on MHC class II, CD80-expressing cells. BALB/c mice with 3-week established
primary 4T1 mammary carcinomas up to 6 mm in diameter and with extensive,
spontaneous lung metastases show a significant reduction in lung metastases
following a 3-week course of immunotherapy consisting of weekly injections of the
cell-based vaccine plus injections of IL-12 three times per week. C57BL/6 mice
with 7-day established intravenous B16 melF10 lung metastases show a similar
response following immunotherapy with IL-12 plus a vaccine based on B16 MHC class
II, CD80-expressing cells. In both systems the combination therapy of cells plus
IL-12 is more effective than IL-12 or the cellular vaccine alone, although, in
the 4T1 system, optimal activity does not require MHC class II and CD80
expression in the vaccine cells. The cell-based vaccines were originally designed
to activate tumor-specific CD4+ T lymphocytes specifically and thereby provide
helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the
therapy to facilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo
depletion experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and
tumor challenge experiments in beige/nude/XID immunodeficient mice demonstrate
that the therapeutic effect is not exclusively dependent on a single cell
population, suggesting that T and NK cells are acting together to optimize the
response. IL-12 may also be enhancing the immunotherapy via induction of the
chemokine Mig (monokine induced by interferon gamma), because reverse PCR
experiments demonstrate that Mig is present in the lungs of mice receiving
therapy and is most likely synthesized by the tumor cells. These results
demonstrate that the combination therapy of systemic IL-12 and a cell-based
vaccine is an effective agent for the treatment of advanced, disseminated
metastatic cancers in experimental mouse models and that multiple effector cell
populations and anti-angiostatic factors are likely to mediate the effect.
PMID- 10782865
TI - Tumor-derived Fas ligand induces toxicity in lymphoid organs and plays an
important role in successful chemotherapy.
AB - Recent studies have suggested that Fas ligand (FasL-) tumor cells can induce
apoptosis in Fas+ T cells. However, the effect of growth of FasL+ tumors in vivo,
on lymphoid tissues of the host is not clear and therefore was the subject of
this investigation. Injection of FasL+ LSA tumor caused a significant decrease in
cellularity of the thymus and spleen, resulting from marked apoptosis, in
syngeneic C57BL/6+/+ (wildtype) but not C57BL/6-lpr/lpr (Fas-deficient) mice. The
tumor-induced toxicity resulted from tumor-derived rather than host-derived FasL,
inasmuch as LSA tumor growth in C57BL/6-gld/gld (FasL-defective) mice, induced
marked apoptosis and toxicity in the thymus and spleen. The LSA tumor growth
induced a significant decrease in the percentage of CD4+CD8+ T cells in the
thymus of C57BL/6+/+ mice and an increase in the percentage of CD4+, CD8+ and CD4
CD8- T cells. Of the four subpopulations tested, the CD4+CD8+ T cells showed
maximum apoptosis. The LSA (FasL+) but not P815(FasL-) tumor cell lysates and
culture supernatants induced marked apoptosis in Fas+ thymocytes, when tested
both in vitro and in vivo. The LSA-tumor-induced apoptosis in vitro was inhibited
by antibodies against FasL or by caspase and other inhibitors of apoptosis.
Chemotherapy of LSA-tumor-bearing C57BL/ 6+/+ mice at advanced stages of tumor
growth failed to cure the mice, whereas, more than 80% of LSA-tumor-bearing
C57BL/6-lpr/lpr mice, similarly treated, survived. Together, the current study
demonstrates that FasL produced by LSA tumor cells is functional in vivo and can
cause severe toxicity in lymphoid organs of the host. Also, Fas/FasL interactions
may play an important role in the successful chemotherapy of FasL-bearing tumor.
PMID- 10782866
TI - Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic
colorectal cancer.
AB - INTRODUCTION: Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of
peritoneal carcinomatosis from colon cancer. We performed a phase I trial of IL-2
and high-dose arginine butyrate (ArgB) in patients with advanced metastatic
colorectal cancer. PATIENTS AND METHODS: From April to July 1997, six patients
were included in the trail; they had a median age of 52 years, four had a
performance status of 0, two had a performance status of 1 with normal biological
functions. All patients had received at least two prior lines of chemotherapy. A
fixed dose of 18 MIU/m2 IL-2,was administered by subcutaneous injection and ArgB
was delivered via continuous intravenous infusion on days 1-6 with escalating
doses starting at 2 g kg(-1) day(-1). RESULTS: The planned dose escalation was
not possible because of toxicities. A daily ArgB dose of 2 g/kg was delivered for
nine cycles. Level 2 (4 g/kg) could not be delivered in three of the six patients
because of liver toxicity. The dose-limiting toxicities were fatigue and liver
function disturbances. The maximum tolerated dose for ArgB was 3 g kg(-1) day(
1), in combination with IL-2 at 12 MIU m2 day(-1). No clinical response was seen.
Pharmacokinetic analysis showed large intra- and interindividual variations.
CONCLUSION: This schedule with a high dose of ArgB proved to be highly toxic with
liver insufficiency. We will be running another trial with lower doses of ArgB
calculated from the schedule used in the experimental model, starting at a dose
of 20 mg kg(-1) day(-1) for ArgB and 200000 UI kg(-1) day(-1) IL-2, every 8 h.
PMID- 10782867
TI - Top 10 tips for successful grantsmanship.
PMID- 10782868
TI - Application of the Omaha System in acute care.
AB - Although effective as a standardized language for documentation in community and
public health settings, the Omaha System has not been evaluated in acute care
settings. The purpose of this study was to evaluate the utility of the Omaha
System to code the terms used by nurses when documenting hospital care. The
nursing documentation in 30 hospital records was content analyzed for signs and
symptoms, patient problems, and nursing interventions, then coded into the
categories of the Omaha System. Degree of match was evaluated using concept match
scores, and utility was determined using empirical, operational, and pragmatic
criteria. Study findings suggest several strengths (i.e., high reliability, coded
97% of the problems, easy to use) and some limitations (lack of mutual
exclusivity among terms, lack of semantic clarity, the need for three new
problems). This study has important implications in demonstrating the utility of
the Omaha System for possible expansion into acute care to standardize
communication between the hospital setting and home care.
PMID- 10782869
TI - Age-related changes in initiation and maintenance of sleep: a meta-analysis.
AB - The purpose of this meta-analysis was to determine the magnitude of change over
the adult life span in four key sleep characteristics and to explore research
design features that may account for variability in reported age-related sleep
change. Forty-one published studies (combined N = 3293) provided 99 correlational
effect sizes. Waking frequency and duration increased with age as previously
concluded by narrative reviewers. Although narrative reviewers were less certain
whether nighttime sleep amount or the ability to initiate sleep decreased with
age, the meta-analysis suggested that both decreased. When sleep variables were
measured by polysomnography rather than self-report, larger age-related changes
were found. Few researchers who studied normal sleep controlled for important
health moderators or studied women.
PMID- 10782870
TI - Acculturation and perinatal health outcomes among rural women of Mexican descent.
AB - Research has shown that health outcomes for urban women of Mexican descent are
related to acculturation. The purpose of this research was to compare perinatal
outcomes of 773 women of Mexican descent who gave birth in three rural northern
California hospitals, in relation to acculturation measured three different ways:
by place of birth, by language spoken, and by the two factors combined as an
Acculturation Index (AI). The prenatal and birth records of 773 Mexico-born or
U.S.-born women of Mexican descent were reviewed. Results showed that language
spoken was a less useful indicator of acculturation associated with perinatal
complications than place of birth or the AI. The categorization of acculturation
with the AI enhanced understanding of more specific groups of rural women and
their particular health outcomes.
PMID- 10782871
TI - Narratives of smoking relapse: the stories of postpartum women.
AB - Many women who stop smoking during pregnancy relapse soon after the birth of
their infants. Using narrative research, experiences of smoking relapse were
explored using interviews with 27 postpartum women. The stories of relapse were
analyzed to identify important components, paying attention to commonalities,
differences, and areas of emphasis. Five general story lines were identified: (1)
controlling one's smoking (starting with a "puff" and consciously restricting the
amount smoked); (2) being vulnerable to smoking(relapsing because of an inability
to resist cigarettes); (3) nostalgia for one's former self(relapsing to recapture
feelings of freedom and happier times); (4) smoking for relief(relapsing to
manage emotions and stress); and (5) never really having quit (relapsing because
they did not quit for themselves). The findings of this study provide support for
the claim that the experiences of smoking cessation and relapse among postpartum
women may be unique and, consequently, may require specialized intervention.
PMID- 10782872
TI - Challenging the rules: women's prodromal and acute symptoms of myocardial
infarction.
AB - In this qualitative study the researcher identified symptoms women experienced
prior to and during an acute myocardial infarction (AMI). The purposive
nonprobability sample for this descriptive naturalistic study consisted of 40
women. Using content analysis and constant comparison, the researcher identified
specific symptoms and grouped them according to time of occurrence, prodromal and
acute. Thirty-seven women experienced prodromal symptoms, beginning from a few
weeks to 2 years prior to their AMI and ranging from 0 to 11 symptoms per woman.
The most frequent prodromal symptoms were unusual fatigue (n = 27), discomfort in
the shoulder blade area (n = 21), and chest sensations (n = 20), whereas the most
frequent acute symptoms were chest sensations (n = 26), shortness of breath (n =
22), feeling hot and flushed (n = 21), and unusual fatigue (n = 18). Only 11
women experienced severe pain during their AMI. Conclusions of this study are
threefold: (a) women identified classic and unique symptoms of AMI, which
challenge the content of current educational literature; (b) women experienced a
gradual progression of number and severity of AMI symptoms; and (c) women need
sufficient time to recognize their prodromal symptoms of their AMI.
PMID- 10782873
TI - Expert decision making in relation to unanticipated blood glucose levels.
AB - How people (N = 22) with long-standing Type I diabetes make everyday self-care
decisions, specifically in regard to unanticipated blood glucose levels (UBGLs)
was investigated using grounded theory. Participants differentiated between
decisions made in familiar and typical situations and those made in novel
situations. Decisions made in familiar situations were straightforward, arising
from a confident appraisal of the cause of the UBGL. The primary focus of
decision making in response to an UBGL in familiar situations was the decision
about the course of action. The focus in unfamiliar situations was the appraisal
of the cause of the UBGL. It was characterized by the participants' lack of
confidence and by a non-linear progression in which the individual retraced
previous phases of the decision-making process or proceeded to tangential steps.
Participants matched the features of previously encountered situations to
construct a story that explained the events in order to generate some plausible
hypotheses. A number of contextual and mediating variables were identified as
influencing the decision-making process and the decisions they made. The findings
of this research demonstrate that the decision maker's familiarity with the
situation influences the nature of the decision-making processes that are used.
PMID- 10782874
TI - Description of retained abilities in older persons with dementia.
AB - There have been suggestions in the literature that the care of people with
dementia must be focused on abilities as opposed to disabilities. However, this
approach has not been carefully defined in terms of what constitutes remaining
abilities. This article provides a description of the abilities in people with
dementia, which is based on a descriptive analysis of data derived from a larger
study regarding the psychometric evaluation of an abilities assessment
instrument. The sample comprised 112 male veterans with dementia who were living
in a long-term care facility. Their mean age was 75 years. Data were collected in
the areas of self-care, social, interactional, and interpretive abilities.
Abilities were retained in all four areas. Furthermore, abilities were
differently affected and varied considerably across subjects, which is consistent
with evidence pertaining to cognitive changes in dementia. Our results provide
support for an individualized, abilities-focused approach to the care of people
with dementia.
PMID- 10782875
TI - An evaluation of a self-generated identification code.
AB - We describe a self-generated coding form used in a study of HIV prevention
practices of college students and provide information on the success rate of
matching questionnaires over a 3-year period using the form. The data for this
study were from a longitudinal study of HIV risk-reduction practices of college
students. In order to match questionnaires over the 3-year study period while
maintaining anonymity, participants were asked to complete a self-generated
identification form at each data collection point. In the second year of the
project, we were able to successfully match 74.3% of the questionnaires to those
returned during the first year using 6 to 8 of the code elements on the form, and
in the third year, we were able to match 73% of questionnaires to those returned
in the second year. Participants for whom questionnaires matched were more likely
than participants with unmatched questionnaires to be white students enrolled as
underclassmen.
PMID- 10782876
TI - Re: Research utilization.
PMID- 10782877
TI - Human herpes virus 8: a new virus discloses its face.
AB - The human herpes virus 8 (HHV8) or Kaposi's sarcoma-associated herpes virus
(KSHV) is present in all Kaposi's sarcoma, and the detection of the virus using
polymerase chain reaction or in situ hybridization is a highly sensitive and
specific diagnostic test for the diagnosis of this neoplasm. HHV8 is furthermore
invariably present in primary effusion lymphoma (PEL) and has also been detected
in patients with acquired immunodeficiency syndrome (AIDS)-associated
multicentric Castleman's disease (MCD) as well as, to a lesser extent, in non
AIDS MCD. In contrast to Kaposi's sarcoma, in which the tumor cells show
primarily latent HHV8 infection, a higher rate of lytically infected cells can be
observed in MCD. Epidemiological surveys indicate that the seroprevalence for
HHV8 parallels the risk of developing Kaposi's sarcoma--5-10% in the general
population of the Western world but ranging up to 20-70% in homosexual human
immunodeficiency virus (HIV)-infected patients, and the infection precedes the
development of Kaposis's sarcoma. Finally, HHV8 has been reported in a number of
other diseases, especially in multiple myeloma. However, the highly controversial
role of HHV8 in these lesions has to be clarified. Based on the data available
today, HHV8 can be assigned as a new human virus, associated with tumors.
PMID- 10782878
TI - Altered intercellular glycoconjugates and dilated intercellular spaces of
esophageal epithelium in reflux disease.
AB - BACKGROUND AND AIMS: The usefulness of histological diagnosis of gastroesophageal
reflux disease (GERD) is limited by poor specificity or sensitivity of available
diagnostic tools. Recently, ultrastructural morphometry showed interstitial space
dilation (ISD) to be a reliable sign of reflux disease. Aims of this study were
to (a) search for a light microscopy equivalent of ISD, (b) test its diagnostic
value, and (c) look for a possible role of intercellular glycoconjugates in its
genesis. METHODS: Esophageal grasp biopsies were taken during endoscopy, 2-3 cm
and 6-7 cm above the squamocolumnar junction, from patients under investigation
for GERD symptoms. The biopsies were fixed in aldehyde solutions and embedded in
resin for electron microscopy or in paraffin for routine histology, and the
glycoconjugates underwent immunohistochemistry using 3-fucosyl-N-acetylactosamine
antibodies. RESULTS: Irregular intercellular space dilation was detected in the
basal and prickle layers using both light and electron microscopy. Hematoxylin
eosin preparations showed ISD in 20 of 22 (90%) erosive esophagitis cases, 30 of
44 (68%) endoscopy negative GERD cases, and 1 of 12 (8%) controls, with good
interobserver (K = 0.75) and bioptic site reproducibility. ISD correlated with
loss or rearrangement of intercellular glycoconjugates of the overlying layers
and with granulocyte (eosinophil and/or neutrophil) infiltration. CONCLUSIONS:
Light microscopy ISD is a suitable index of GERD. Alterations of intercellular
glycoconjugates are likely to have a role in the genesis of ISD and GERD.
PMID- 10782879
TI - Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like
cell tumors.
AB - The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent
accumulation of biogenic amine inside the secretory granules of endocrine cells
and neurons and was demonstrated in the histamine-producing enterochromaffin-like
(ECL) cells of the stomach. In the present investigation, VMAT2
immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well
differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated
(neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the
stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2
parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2
immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal
pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid
body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12
of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic
neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach
(differentiated cells only). No VMAT2 immunoreactivity was observed in five
gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the
gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths,
and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2
immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell
tumors, separating them from all other endocrine tumors arising in the
gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of
which proved essentially negative.
PMID- 10782880
TI - Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in
human colon carcinomas.
AB - Tumour growth is regulated by a balance between proliferation, growth arrest and
programmed cell death (apoptosis). Until recently, the majority of the studies
dealing with oncogenesis has been focused on the regulation of cell
proliferation. There is now growing understanding that control of growth arrest
and apoptosis play key roles in the development of human cancer and in cancer
treatment. Some of the more heavily studied proteins of importance for the
control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations
in the p53 protein may lead to malignant transformation and defect therapy
response, most likely as a result of defective p53-dependent apoptosis. In
addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in
induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are
also important for normal apoptosis. Overexpression of bcl-2 protein is thought
to reduce the apoptotic capacity, while bax protein seems to be necessary for
induction of apoptosis. In this study, we have immunostained tissues from 93
primary colon carcinomas and have examined the expression of p53, p21
(WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon
cancer progression. A highly significant association between p53 accumulation and
downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association
between reduced/absent p21 and the development of metastases and death due to
cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent
prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship.
The results of the present study indicate that reduced p21 protein levels play an
important role in progression of colon cancer. We concluded that evaluation of
p21 expression in primary colon carcinomas at the time of surgery might be a
valuable tool in defining patients with a high risk of developing metastases.
PMID- 10782881
TI - Anal cancer subtype reproducibility study.
AB - For histological subtyping of anal squamous carcinomas the WHO advocates a six
way subdivision, but it has been suspected that the six types cannot be reliably
discriminated in practice. We conducted a blinded study involving slides from 103
consecutive cases, each slide being examined by three experts (from Denmark,
Australia and UK) on two occasions at least 8 months apart. Agreement on subtypes
was low: 72% between rounds within pathologist, 61% between pathologists. Even
for the commonest, and most stably diagnosed, type, viz. large-cell keratinising
squamous carcinoma, the intra- and interpathologist frequencies of confirmation
were only 81% and 71%, respectively. The pathologist marked the picture as
typical and his subtype diagnosis as certain 41% of times: even then confirmation
frequencies were only 88% and 74%, respectively. Calculations, including kappa
analyses, suggest that 26% of the typing variation was noise. The WHO scheme must
be even more unreliable in everyday practice. We finally mention a recently
demonstrated link between human papilloma virus (HPV) and certain types of anal
cancer, which may well provide an additional argument for revising existing
subtyping schemes.
PMID- 10782882
TI - Gastrointestinal pacemaker cell tumor: clinicopathological, immunohistochemical,
and ultrastructural study with special reference to c-kit receptor antibody.
AB - Recent studies indicate that a subgroup of gastrointestinal stromal tumors,
including gastrointestinal autonomic nerve tumors (GANTs), originate from stem
cells that differentiate toward a pacemaker-cell phenotype. These pacemaker cells
form a complex network intercalated between the autonomic nerves and the muscle
walls of the gastrointestinal tract and are called interstitial cells of Cajal
(ICC). The c-kit receptor (CD117) is a sensitive marker for ICC. The aim of our
study was to support the hypothesis that GANTs show ICC differentiation. Seven
GANTs without convincing smooth muscle or neural differentiation all showed
homogeneous reactivity for the c-kit receptor. CD34 was positive in three cases.
On electron microscopy, the typical features of GANT were present. Six tumors
contained skeinoid fibers. Most tumors were related to the small bowel. They
presented as single (two cases) or multiple (five cases) tumors. The presenting
symptoms were abdominal bleeding (2), abdominal mass (2), anemia (1), and small
bowel perforation (1). In two cases, liver metastases developed. Because of the
close immunohistochemical and electron microscopic similarities of these tumors
to the interstitial cells of Cajal, the term gastrointestinal pacemaker cell
tumor seems appropriate.
PMID- 10782883
TI - Association of vascular endothelial growth factor and mast cells with
angiogenesis in laryngeal squamous cell carcinoma.
AB - We investigated the expression of vascular endothelial growth factor (VEGF) and
microvascular density in 54 cases of invasive laryngeal squamous cell carcinoma
(SCC) and in ten samples of normal laryngeal tissue using immunohistochemistry
methods. The study also focused on the distribution of mast cells in and around
the SCCs. The microvascular density in laryngeal carcinoma tissue was higher than
that in normal tissue (P = 0.02). VEGF was localized in SCCs, stromal cells,
endothelial cells, minor salivary glands, and non-cancer epithelium adjacent to
the tumor. VEGF expression in the tumor cells was found in 13 of 54 cases
(24.1%), whereas mast cells around the carcinomas were VEGF positive in all 54
cases. Staining of VEGF in SCCs was strong in the area of high microvascular
density (P = 0.0002). Using a multi-labeling subtraction immunostaining method,
VEGF-positive stromal cells were classified mostly as mast cells and, in a few
instances, as macrophages. VEGF staining in SCCs was associated with the mast
cell count (P = 0.0001). There was no distinct correlation between VEGF
expression and pTNM stage of an SCC. In conclusion, the results suggest that VEGF
might be an important angiogenic factor in cancer invasion. Laryngeal cancer
cells and mast cells may control the angiogenic response by releasing VEGF.
PMID- 10782884
TI - Light and electron microscopic examination of endothelial cells from bovine
retinal vessels in long-term cultures.
AB - The aim of the present work was to examine and compare the ultrastructure of
bovine retinal endothelial cells (BRECs) in vitro during several passages in a
medium selective for endothelial cells. The identity of the endothelial cells was
confirmed immunohistochemically, up to the tenth passage. Changes in their
ultrastructure in comparison to endothelial cells in vivo occurred at the onset
of culturing and not progressively with repeated passages. The cultured BRECs
show high metabolic activity in all passages. While retaining their identity as
endothelial cells, they modify their lipid metabolism, so that lipids are stored.
This change in lipid metabolism was induced by the medium.
PMID- 10782885
TI - Ultrastructure and molecular histology of rabbit hind-limb collateral artery
growth (arteriogenesis).
AB - Previous studies in the canine heart had shown that the growth of collateral
arteries occurs via proliferative enlargement of pre-existing arteriolar
connections (arteriogenesis). In the present study, we investigated the
ultrastructure and molecular histology of growing and remodeling collateral
arteries that develop after femoral artery occlusion in rabbits as a function of
time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals
had a diameter of about 50 microm. They consisted of one to two layers of smooth
muscle cells (SMCs) and were morphologically indistinguishable from normal
arterioles. The stages of arteriogenesis consisted of arteriolar thinning,
followed by transformation of SMCs from the contractile- into the proliferative-
and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs
migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and
vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which
was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and
SMCs started about 24 h after occlusion, whereas adhesion molecule expression and
monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of
monocytes in vascular cell proliferation. Treatment of rabbits with the pro
inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular
remodeling. In vitro shear-stress experiments in cultured ECs revealed an
increased phosphorylation of the focal contacts after 30 min and induction of
ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting
that shear stress may be the initiating event. We conclude that the process of
arteriogenesis, which leads to the positive remodeling of an arteriole into an
artery up to 12 times its original size, can be modified by modulators of
inflammation.
PMID- 10782886
TI - Feasibility of simultaneous fluorescence immunophenotyping and fluorescence in
situ hybridization study for the detection of estrogen receptor expression and
deletions of the estrogen receptor gene in breast carcinoma cell lines.
AB - For the first time, combined immunophenotyping and fluorescence in situ
hybridization (FISH) technique according to the "fluorescence immunophenotyping
and interphase cytogenetics as a tool for investigation of neoplasms" (FICTION)
technique have been successfully applied in solid tumors. Thus, we were able to
visualize the antigen expression of cells with chromosomal deletions of a tumor
suppressor region directly. In six breast carcinoma cell lines, we investigated
the correlation between estrogen receptor (ER) expression status and deletions of
the estrogen receptor gene (ESR). To screen for deletions of the ESR gene, dual
color FISH was performed with a YAC (yeast artificial chromosome) probe
containing the ESR gene and, as internal control, with a centromeric probe of
chromosome 6. Deletions of the ESR gene were detected in four of six cell lines.
For direct comparison of ER expression with the copy number of the ESR gene at
the single cell level, immunophenotyping with mouse anti-human ER antibody was
combined with FISH with the YAC probe containing the ESR gene according to the
FICTION technique. There was no correlation between lack of or reduced ER
expression and deletions of the ESR gene. One cell line with deletions of the ESR
gene did express ER on the protein level, while another cell line without a
deletion did not. Cells with deletions of the ESR gene were either ER expression
positive or negative. The staining intensity of ER expression was not associated
with the copy number of the ESR gene. Thus, this FICTION study unequivocally
shows that deletions of the ESR gene are not the major cause of absent or reduced
ER expression in breast carcinoma cell lines.
PMID- 10782887
TI - Testicular diffuse large cell lymphoma with tubule preservation--molecular
genetic evidence of transformation from previous follicular lymphoma.
AB - Testicular lymphomas usually occur in older men and are mostly diffuse large B
cell lymphomas (DLBL). They may be primary manifestation of lymphoma or represent
a relapse of a previous non-Hodgkin's lymphoma. This report details a testicular
large cell lymphoma, which was proven to be large cell transformation of a low
grade follicular lymphoma biopsied 8 years earlier. Initially, a 38-year old man
was diagnosed with cervical lymphadenopathy, and biopsy was interpreted as
reactive follicular hyperplasia; no treatment was given, and the lymphadenopathy
resolved spontaneously. Eight years later, the patient underwent surgery for a
left testicular mass and gastroscopy for gastric symptoms. The patient died 7
months later with evidence for intra-abdominal and central nervous system
lymphoma after a brief but temporary response to M-BACOD chemotherapy.
Orchiectomy specimen and gastroscopic biopsy showed diffuse large B-cell lymphoma
(CD20+), which infiltrated between well-preserved tubules in the testis.
Histological comparison with 20 testicular lymphomas without previous lymphoma
showed tubule infiltration in all cases, suggesting that the tubule-preserving
infiltration pattern could be a histological marker for secondary lymphoma
involvement in testis. On re-examination, the lymph node 8 years prior was
verified as follicular, predominantly small, cleaved cell lymphoma with bcl2
positive follicles. The earlier follicular lymphoma and the subsequent diffuse
large cell lymphoma were analyzed using polymerase chain reaction and showed
identical sequences of the t(14;18) translocation and immunoglobulin heavy chain
gene rearrangement. Analysis of the VH-gene sequences from the follicular
lymphoma revealed sequence heterogeneity consistent with ongoing mutation.
However, the transformed diffuse large cell lymphoma had no intraclonal
variation, with the sequence matching with one of the subclones from the low
grade follicular lymphoma. These results confirm that the large cell
transformation of follicular lymphoma occurs in a single follicular lymphoma
cell. This case also indicates that the selection of the transformed clone can be
part of the natural history of disease and can occur without exposure to
chemotherapy.
PMID- 10782888
TI - Progesterone receptor expression in orbital cavernous hemangiomas.
AB - Orbital cavernous hemangiomas (OCH) have thick and highly cellular vascular
walls. Ultrastructural studies have demonstrated the smooth muscle nature of
these cells. Vascular neoplasms can modify their morphological and clinical
features under hormonal stimulation. The purpose of the present study was to
investigate the presence of smooth muscle markers and sex steroid receptors in 12
cases of OCH. Orbital cases were compared with cutaneous hemangiomas and
subcutaneous angioleiomyomas. Smooth muscle actin (SMA) and desmin were localized
in spindle cells of the vascular walls of all 12 cases studied. OCH showed
immunohistochemical positivity with progesterone receptor (PR) antibody both in
smooth muscular and in endothelial cells. For comparison, sex steroid receptors
were studied in 10 cases of cutaneous cavernous hemangioma and in 10 cases of
subcutaneous angioleiomyoma. PR was found in smooth muscle and endothelial cells
of 6 out of 10 cases of subcutaneous angioleiomyoma and in none of the cases of
cutaneous cavernous hemangioma. No positivity was obtained with estrogen receptor
(ER) antibody in any of the cases tested. The present data suggest that OCH share
morphological and immunohistochemical features with subcutaneous angioleiomyomas.
Furthermore, immunohistochemical positivity with PR antibody indicates that OCH
have to be added to the list of mesenchymal lesions that express sex steroid
receptors.
PMID- 10782889
TI - Peripheral papillary tumor of type-II pneumocytes: a rare neoplasm of
undetermined malignant potential.
AB - Peripheral papillary adenomas of the lung are uncommon neoplasms (only ten cases
have been described so far in the English literature) composed predominantly of
type-II pneumocytes and generally considered benign. We describe here two
additional cases of this lung tumor. In both cases histological examination
revealed an encapsulated papillary neoplasm with invasion of the capsule and, in
one case, invasion of the adjacent alveoli and visceral pleura too. The
proliferative index (Ki67) was less than 2% and the epithelial cells were
positive for cytokeratins, surfactant apoproteins (SP), and nuclear thyroid
transcription factor-1 (TTF- 1). Ultrastructurally, the epithelial cells showed
the characteristic surface microvilli and cytoplasmic lamellar inclusions of type
II cells. Review of the literature has revealed two other cases of peripheral
papillary adenoma of type-II pneumocytes with infiltrative features. Thus, we
propose replacing the term peripheral papillary adenoma with peripheral papillary
tumor of undetermined malignant potential.
PMID- 10782890
TI - Defective DNA repair genes in a primary culture of human renal cell carcinoma.
AB - PURPOSE: Genomic stability is maintained by error-free DNA replication, repair,
and recombination. To determine if repair genes contribute to genomic
instability, we used a newly established cell line RCC-AJR (from clear-cell renal
cell carcinoma) to examine hMSH2 (a mismatch-repair gene) and the gene encoding
DNA beta polymerase (polbeta; a known contributor to base-excision repair).
METHODS: Coding sequences of hMSH2 and polbeta were amplified by the polymerase
chain reaction (PCR) using RNA from RCC-AJR cells and matched normal kidney (NK)
cells from the same patient. Nucleotide sequences of the PCR products were
determined by the dideoxy-DNA method and direct sequencing. Expressions of repair
genes were assayed by Western blotting. Microsatellite stability in RCC-AJR cells
was assayed by alteration in (CA)n repeats. RESULTS: In the RCC-AJR cells, we
detected (a) a deletion of 1476 bp encoding 492 amino acids of hMSH2 cDNA, (b) an
87-bp deletion in the polbeta coding sequence, (c) truncated forms of hMSH2 and
polbeta proteins, and (d) microsatellite instability. CONCLUSIONS: This study
provides evidence of alterations in hMSH2 and polbeta in the homogeneous cell
population of an RCC-AJR tumor culture. The data indicate that repair genes may
help preserve genomic stability in this cell line. We believe that this new
primary RCC-AJR cell line will prove a useful model for investigating the cascade
of genetic events in renal cells that leads to renal carcinogenesis.
PMID- 10782891
TI - Cycloprodigiosin hydrochloride, a H+/Cl- symporter, induces apoptosis in human
breast cancer cell lines.
AB - The effect of cycloprodigiosin hydrochloride (cPrG.HCl), a H+/Cl- symporter, on
five human breast cancer cell lines (KPL-1, T-47D, MCF-7, MKL-F, and MDA-MB-231),
a human breast epithelial cell line (HBL-100), and a human fibroblast cell line
(WI-38-40) was examined. cPrG.HCl inhibited the growth of all five breast cancer
cell lines (IC50: 0.46-0.62 microM) and slightly inhibited HBL-100 and WI-38-40
cell growth (IC50: 1.75 microM and 2.26 microM respectively). cPrG.HCl treatment
in KPL-1 cells increased the pH of acidic organelles, decreased intracellular pH,
and caused apoptosis, which was confirmed by the appearance of a sub-G1
population by flow cytometry and DNA fragmentation. In addition, cPrG.HCl-induced
apoptosis was strongly suppressed by imidazole, a cell-permeable base, suggesting
that intracellular acidification was essential for the apoptosis. Further,
cPrG.HCl treatment up-regulated Bax and Bak expression, down-regulated Bcl-2
expression, and activated caspase-3. Therefore, the intracellular acidification
by cPrG.HCl treatment suppressed the growth of human breast cancer cell lines by
inducing apoptosis.
PMID- 10782892
TI - Differential modulation of chemosensitivity to alkylating agents and platinum
compounds by DNA repair modulators in human lung cancer cell lines.
AB - PURPOSE: Modulation of DNA repair represents one strategy to overcome cellular
drug resistance to alkylating agents and platinum compounds. The effects of
different known DNA repair modulators such as O6-benzylguanine (6 microg/ml),
fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 microg/ml)
and methoxamine (12.4 microg/ml) on the cytotoxicity of mafosfamide,
chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and
carboplatin were tested in human lung cancer cell lines. METHODS:
Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin
resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P
and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT
colorimetric assay. RESULTS: O6-benzylguanine, an inhibitor of O6-alkylguanine
DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the
cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change
the chemosensitivity of the parental and cisplatin-resistant cell lines to any
cytotoxic drug tested. Interestingly, O6-benzylguanine enhanced the
chemoresistance of parental and cisplatin-resistant cell lines to platinum
compounds. Also, pentoxifylline increased resistance of the MOR cell lines to
mafosfamide. CONCLUSIONS: Modulation of DNA repair elicits not only
chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.
PMID- 10782893
TI - Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor
survival.
AB - BACKGROUND/AIMS: The family of erbB receptors includes four transmembrane
glycoproteins with tyrosine kinase activity. These receptors are widely expressed
in normal tissues, but they also have been implicated in the development of
several human adenocarcinomas. c-erbB-3/HER-3 has been detected to a greater or
lesser extent in many tissues from the digestive, urinary, reproductive and
respiratory tracts. The overexpression of c-erbB-3/HER-3 protein has also been
shown in 53%-88% of colorectal adenocarcinomas. In this study we investigated the
expression of the c-erbB-3/ HER-3 gene product in colorectal tumour samples, and
compared the results obtained with several clinicopathological parameters,
including the survival of patients. METHODS: Paraffin-embedded tissue sections
were analysed immunohistochemically, using monoclonal antibody RTJ1 to human erbB
3 protein. Antibody RTJ1 specificity was confirmed by immunoprecipitation
followed by Western blotting analysis. Amplification of the erbB-3 oncogene was
tested by dot-blot hybridization. RESULTS: Adenocarcinomas of the colon were
positive for erbB-3 protein in 78% of samples examined. Dot-blot analysis showed
no amplification of the erbB-3 gene in colon adenocarcinomas. Statistical
analysis showed that patients with tumours that could not be stained for erbB-3
protein survived significantly longer (P<0.05) than patients with tumours
staining positive for the erbB-3 protein. A Cox proportional-hazards model with
stepwise variable selection identified age, sex and erbB-3 expression as
important prognostic factors. CONCLUSION: These findings demonstrate that erbB-3
protein expression could serve as a prognostic factor in colorectal malignancies.
PMID- 10782894
TI - Sensitive detection of micrometastases in bone marrow from patients with breast
cancer using immunomagnetic isolation of tumor cells in combination with reverse
transcriptase/polymerase chain reaction for cytokeratin-19.
AB - We report a highly sensitive method to detect rare human breast cancer cells,
which combines an immunomagnetic separation (IMS) using antibody BM2 against MUC
1 with cytokeratin-19 (CK19) and the reverse transcriptase/polymerase chain
reaction (RT-PCR). The IMS-RT-PCR technique allows the detection of 1 tumor
cell/10(7)-10(8) mononuclear cells. This is at least ten times more sensitive
than CK19 RT-PCR alone, or immunocytochemistry. All 117 peripheral blood and 8
bone marrow samples obtained from healthy donors as negative controls were
positive for beta2-microglobulin by RT-PCR but negative for CK19 by IMS-RT-PCR or
RT-PCR alone. Out of 26 bone marrow samples from breast cancer patients, 18 had
CK19 transcripts detectable by IMS-RT-PCR. In contrast, only 14 and 13 samples
from the 26 were found to be positive by RT-PCR alone or by routine
immunocytochemical staining. In conclusion, IMS-RT-PCR for CK19 is a highly
sensitive and specific method for detecting very low numbers of micrometastatic
breast cancer cells in bone marrow amidst an excess of nonmalignant cells. For
the early diagnosis of disseminating disease, this assay is more efficient than
RT-PCR alone and routine immunocytochemistry.
PMID- 10782895
TI - Patterns of expression and secretion of vascular endothelial growth factor in
malignant soft-tissue tumours.
AB - Vascular endothelial growth factor (VEGF) is an important cytokine especially in
the process of tumour angiogenesis. A total of 46 soft-tissue sarcomas were
analysed for the expression and possible secretion of VEGF by
immunohistochemistry, in-situ hybridisation, and enzyme-linked immunosorbent
assays (ELISA). VEGF was demonstrated immunohistochemically in tumour tissue in
45 of 46 cases. The detection of mRNA transcripts yielded evidence of synthesis
of VEGF in these sarcomas. ELISA could be performed in 21 cases. Higher
concentrations of VEGF were found in tumour-related intraoperatively sampled
venous blood in 16 out of 21 patients (76%) than in systemic concentrations taken
preoperatively. The results indicated the secretion of VEGF by tumour cells
although these raised concentrations were not statistically significant. In 12
out of these 16 patients (75%) a concurrent moderate to strong immunoexpression
of VEGF was detected. The relevance of VEGF blood concentrations as a potential
"progress parameter" for the course of disease remains questionable. This is
mainly due to the lack of statistical significance in the difference between
systemic VEGF concentrations in patients and those of a control group. Further
long-term follow-up studies are needed, which should include patients with tumour
recurrences.
PMID- 10782896
TI - Wilms' tumor gene (WT1) expression in lung cancer, colon cancer and glioblastoma
cell lines compared to freshly isolated tumor specimens.
AB - The Wilms' tumor gene (WT1) encodes a transcriptional regulator involved in
growth and differentiation of various tissue types. A continuous over-expression
of WT1 was found in leukemic blasts, thus suggesting an oncogenic function. Solid
cancer entities have also been described as expressing WT1. We systematically
analyzed WT1 expression in small-cell and non-small-cell lung cancer, colon
cancer and glioblastoma patients and in the respective tumor cell lines. Using
reverse transcription/polymerase chain reaction, we found WT1 expression in
glioblastoma (5 of 8), lung (5 of 11), and colon cancer (5 of 15) cell lines.
While WT1 was expressed in only 1 of 12 lung cancer and 1 of 5 glioblastoma
specimens, it was not detected in colon cancer or macroscopically tumor-free
colon and lung tissue. In addition, HT29 colon cancer cells showed a loss of WT1
expression when grown to confluence or induced to differentiate by sodium
butyrate. From this evidence, testing for WT1 expression is not clinically
relevant for colon cancer, lung cancer, or glioblastoma patients. WT1 expression
in cancer cell lines can probably be attributed to optimized in vitro growth
conditions.
PMID- 10782897
TI - Gastric cancer in very young adults: apropos four patients and a review of the
literature.
AB - Whether gastric cancer in young adults differs from gastric cancer in older
patients has been a controversial issue. It has long been suspected that young
patients with gastric cancer have different biological features with a more
aggressive course of disease and a poorer prognosis than older patients. This,
however, has not been firmly substantiated. We report on the clinical course of
four patients (three female and one male) with locally advanced (n = 1) or
metastasized (n = 3) non-resectable gastric cancer diagnosed under the age of 29
years (23, 25, 27, 28 years). Prior to diagnosis, all three women had recently
been pregnant (1-22 months). Diagnosis was endoscopically biopsy-proven and
staging work-up was performed by primary explorative surgery (n = 1), laparoscopy
and explorative surgery (n = 1) or CAT scan and ultrasound (n = 2). The delay
between initial symptoms and diagnosis was 8-22 weeks (median, 10 weeks). The
histology was signet-ring cell (n = 2) or undifferentiated (n = 2) gastric
cancer. All patients had the diffuse type of gastric cancer according to Lauren.
Patients were treated with the FLAP polychemotherapy regimen consisting of
leucovorin, 5-fluorouracil, doxorubicin and cisplatinum, as previously reported.
The best response after chemotherapy was partial in two patients. Two patients
showed progressive disease. Secondary surgery was performed in three responding
patients (one of them responded only locally). One patient achieved no evidence
of disease after complete tumor resection (R0). In two patients surgery was
palliative (R2/exploration). Three patients died 6, 4 and 8 months after
diagnosis. One patient is still alive. In our series, very young adults with
gastric cancer had adverse clinical and pathological features. In accordance with
other reports, we observed a predominance of female patients and a possible
association with recent pregnancies. Though the delay between the first symptoms
and diagnosis in our patients was no different from that reported for older
patients, special emphasis should be given to prompt referral and diagnostic
investigations, ensuring the diagnosis of gastric cancer early in the course of
disease.
PMID- 10782898
TI - p53 tumour-suppressor gene in non-small-cell lung cancer with neoadjuvant
therapy.
AB - In a phase II study for optimizing therapeutic management of locally advanced non
small-cell lung cancer the prognostic and therapeutic relevance of the p53 status
was investigated. Biopsy or mediastinoscopy samples, collected prior to
neoadjuvant chemoradiotherapy and corresponding resection specimens, were
analysed immunohistochemically (CM1 antiserum) for p53 accumulation and molecular
biologically (polymerase chain reaction/single-strand conformation polymorphism)
for p53 mutations. The results were correlated to the response to therapy
(regression grade) and to the survival times. p53 accumulation was found in 41.7%
(prior to neoadjuvant therapy) and in 40.0% (after surgery) of the tumours. p53
mutation was demonstrated in 45.4% (prior to neoadjuvant therapy) and in 46.4%
(after surgery) of the investigated tumours. Neither before nor after therapy was
any correlation to the survival times or to the response to therapy seen in the
collective analysed. Thus, such investigations are not suitable for identifying
patients with locally advanced non-small-cell lung cancer who might benefit, to
different extents, from neoadjuvant therapy.
PMID- 10782899
TI - Evidence of carcinogenicity of DDT in nonhuman primates.
PMID- 10782900
TI - CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.
AB - BACKGROUND/AIM: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic
liver disease thought to develop through a complex interaction of genetic and
environmental factors. It is characterised by T-cell-mediated non-suppurative
destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte
associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital
negative regulator of T-cell activation, as a candidate susceptibility locus for
PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with
susceptibility to both type 1 diabetes and autoimmune thyroid disease. METHODS:
The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine,
respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC
patients and 200 non-related geographically matched Caucasoid controls. RESULTS:
There was significant overrepresentation of the G/A and G/G genotypes in PBC
patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio
(OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a
significant difference in allele frequencies (G encoding alanine at codon 17, PBC
0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained
significant (p=0.00027) when patients with autoimmune thyroid disease were
excluded from the analysis. CONCLUSIONS: The CTLA-4 exon 1 polymorphism is the
first non-major histocompatibility complex gene to be identified as a
susceptibility locus for PBC. Our data support the hypothesis that clinically
distinct autoimmune disease may be controlled by a common set of susceptibility
genes.
PMID- 10782902
TI - Role of glutathione and oxidative stress in phalloidin-induced cholestasis.
AB - BACKGROUND/AIMS: Biliary glutathione is an important generator of the bile-salt
independent flow, and is known to be regulated by the hepatic glutathione
availability. We investigated, in an acute model of phalloidin-induced
cholestasis, biliary glutathione secretion and the role of hepatic glutathione,
oxidative stress, and protein kinase c activation, which have been implicated in
many hepatotoxin-induced hepatic dysfunctions. METHODS: Rats were given a single
dose of 80 microg/100 g body weight of phalloidin and the hepatic thiols and
glutathione content, redox state and vesicular activity were evaluated during
both development of and recovery from cholestasis. The prophylactic effect of N
acetylcysteine (a precursor of glutathione synthesis and an antioxidant) was also
examined. In addition, in the isolated perfused rat liver, we studied the
prophylactic effect of the PKc inhibitor H7 on phalloidin-induced cholestasis.
RESULTS: In the early stages of cholestasis, phalloidin induced a decline in bile
flow, mainly related to a disruption of biliary glutathione secretion. The
decline in biliary glutathione content was not associated with increased
glutathione degradation, indicated by a parallel decline in biliary non-protein
thiols and by the lack of an increase in biliary gamma-glutamyltranspeptidase.
There was also no evidence of hepatic depletion of glutathione or of oxidative
stress, as measured by the oxidized-to-reduced glutathione ratio. Moreover,
phalloidin resulted in inhibition of vascular transcytosis as assessed by
horseradish peroxidase labeling. Pre-treatment with N-acetylcysteine did not
counteract the decline in biliary glutathione secretion and bile flow produced by
phalloidin, supporting the view that the hepatic availability of glutathione and
oxidative stress injury are not implicated in the early stages of cholestatic
injury. Moreover, treatment with H-7 did not alter the biliary glutathione
output, or the decline in bile flow induced by the toxin. CONCLUSIONS: This study
suggests that the phalloidin-induced inhibition of bile formation may be
attributed to rapid disruption of the hepatocanalicular transport of glutathione.
PMID- 10782901
TI - Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy,
in normal pregnancies and in healthy individuals, in Chile.
AB - BACKGROUND/AIMS: Low blood Se levels have been previously shown in normal
pregnancies (third trimester) and significantly lower levels in patients with
intrahepatic cholestasis of pregnancy (ICP), in Finland and in Chile, suggesting
that a low or marginal dietary availability of Se may contribute to the
pathogenesis of this disease. The aim of this study was to investigate whether a
temporal change in plasma concentration of Se, and seasonal fluctuations in
plasma concentrations of Se, Zn and Cu, could coincide with changes in the
prevalence of ICP. METHODS: A cross-sectional cohort study was done including 21
ICP patients, 98 women in the third trimester of a normal pregnancy, 29 non
pregnant women, and also 13 individuals (seven non-pregnant women and six men)
who had been studied 9 years before. Plasma Se, Zn and Cu were measured by atomic
spectroscopy. Plasma Se levels in the present study were compared to the results
obtained 5 to 7 years before, employing identical methodology in similar
population samples. RESULTS: Plasma Se concentrations in non-pregnant women were
higher than in the previous study: 1.43+/-0.34 micromol/l vs 0.85+/-0.13;
p<0.001. In comparison to non-pregnant women, normal pregnancies near term had
lower plasma levels of Se: 1.08+/-0.25 micromol/l; p<0.01, and Zn: 17.90+/-3.61
micromol/l vs 19.71+/-3.21; p<0.05, but higher plasma levels of Cu: 34.35+/-7.12
micromol/l vs 20.62+/-3.34; p<0.01. In normal pregnancies, plasma Se
concentration was significantly higher in summer (1.34+/-0.19 micromol/l) than in
the other seasons, while Zn and Cu diminished. Similar to previous studies, ICP
patients had significantly lower Se plasma levels than normal pregnancies: 0.94+/
0.12 micromol/l, p<0.05, and Cu levels were significantly higher: 50.80+/-7.02
micromol/l, p<0.01. Cu plasma levels correlated with the biochemical severity of
the disease. Zn did not change in ICP. CONCLUSIONS: The present study shows that
the decrease in the prevalence of ICP in Chile during the last decade coincides
with an increase in plasma Se levels. Its lower incidence during summer coincides
with a higher plasma Se concentration in summer than in other seasons, as
observed in normal pregnancies.
PMID- 10782904
TI - Oxygen regulation of rat hepatocyte iNOS gene expression.
AB - BACKGROUND/AIMS: The human iNOS promoter contains a consensus sequence for
binding the hypoxia inducible factor. The aim of this study was to see whether
iNOS gene expression is triggered by oxygen tension in rat hepatocytes exposed in
vivo to high (periportal) and low (perivenous) oxygen tension. METHODS:
Hepatocytes transfected or not with a plasmid containing rat iNOS promoter linked
to chloramphenicol acetyltransferase were cultured at 21% and 5% oxygen tension.
In normal hepatocytes, iNOS protein, mRNA and activity were detected. In
transfected cells, chloramphenicol acetyltransferase activity was measured.
RESULTS: In cells cultured in a hypoxic environment, both iNOS protein and mRNA
increased, whereas the nitrite level in the medium decreased. However, electron
paramagnetic resonance analysis and in vitro iNOS activity indicated that iNOS
was active. Transfection experiments showed that the expression of
chloramphenicol acetyltransferase driven by iNOS promoter was increased in cells
maintained at low oxygen tension. CONCLUSIONS: Our experiments show that in rat
hepatocytes: 1) iNOS is induced by low oxygen tension; 2) the modification occurs
at the transcriptional level; 3) the enzyme at 5% oxygen is able to catalyze the
synthesis of NO, although no nitrites are accumulated in the medium. These
findings could have physiopathological relevance, e.g. in determining the
resistance of perivenous hepatocytes to ischemia injury.
PMID- 10782903
TI - Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results
of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the
Spanish Association for the Study of the Liver.
AB - BACKGROUND/AIM: The aim of this study was to assess the efficacy of
ursodeoxycholic acid (UDCA) for primary biliary cirrhosis in a randomized, double
blind placebo-controlled trial. METHODS: Consecutive patients (n=192) were
randomized to receive 14-16 mg UDCA/kg/day or placebo. Patients underwent a
complete history, physical examination, liver chemistries, immunological
determinations and liver biopsy at entry and at the end of the trial, which
lasted for at least 2 years. Patients were seen every 3 months and the median
follow-up was 3.4 years (range 0.3 to 6.1 years). RESULTS: Patients receiving
UDCA (99) or placebo (93) were comparable with regard to age, sex, biochemical
parameters and liver histology. UDCA treatment was associated with decreases in
alkaline phosphatase, gammaglutamyl transferase, alanine aminotransferase, and
cholesterol levels, effects which were conspicuous after 3 months of treatment
and remained similar during the follow-up. During the study 31 patients (10
receiving UDCA and 21 placebo) discontinued the trial because of noncompliance
(n=11), voluntary withdrawal (n=19) or adverse effects (n=1). Treatment failure
(death or liver transplantation) was observed in 17 patients receiving UDCA and
in 11 patients receiving placebo. Times to death or liver transplantation and to
clinical complications were not significantly different in patients receiving
UDCA or placebo. Histological analysis indicates that UDCA improved portal
inflammation and prevented histological stage progression. By contrast,
histological stage as well as ductular proliferation and ductopenia progressed in
patients receiving placebo. CONCLUSIONS: Although UDCA treatment did not
significantly affect time to death or liver transplantation and to clinical
complications, the effects on both cholestasis and liver histology suggest that
UDCA is safe and may be useful for preventing the progression of primary biliary
cirrhosis.
PMID- 10782906
TI - Blood neutrophil functions and cytokine release in severe alcoholic hepatitis:
effect of corticosteroids.
AB - BACKGROUND/AIMS: Several observations point to an important role of interactions
between polymorphonuclear neutrophils and cytokines in severe alcoholic
hepatitis. The polymorphonuclear neutrophil activation status and the local and
systemic pro- and anti-inflammatory cytokine responses were quantified. The
effect of corticosteroids, widely used in this setting, was evaluated using these
parameters. METHODS: We studied blood polymorphonuclear neutrophil functions in
terms of L-selectin and beta2-integrin expression, H2O2 production and IL-8 and
tumor necrosis factor alpha synthesis capacity. We also measured IL-8, tumor
necrosis factor alpha and IL-10 plasma and liver tissue levels. Fifteen patients
with alcoholic hepatitis were compared to 15 patients with alcoholic cirrhosis
without alcoholic hepatitis, and to 10 healthy volunteers. The impact of a 28-day
course of corticosteroids on blood neutrophils activation status and cytokine
levels was evaluated in patients with alcoholic hepatitis. RESULTS: Blood
polymorphonuclear neutrophils were activated, as shown by increased H2O2
production (48+/-6 vs 29+/-6 MFI in healthy controls), and decreased L-selectin
expression (300+/-61 vs 449+/-59 in healthy controls). Upon stimulation,
polymorphonuclear neutrophils synthesized large amounts of IL-8 (21.7+/-9.2 ng/ml
vs 8.8+/-10 ng/ml in healthy controls) and tumor necrosis factor alpha (524+/-132
pg/ml vs 79+/-144 pg/ml in healthy controls). Tumor necrosis factor alpha and IL
8 plasma and tissue levels were markedly increased as IL-10 was barely detectable
in alcoholic hepatitis patients, compared to cirrhotic patients and healthy
controls. During steroid therapy, plasma levels of the pro-inflammatory cytokine
IL-8 fell as early as day 14, while levels of the anti-inflammatory cytokine IL
10 increased on day 21. Finally, polymorphonuclear neutrophil functions returned
to normal after treatment. CONCLUSION: Severe alcoholic hepatitis appears to be
associated with polymorphonuclear neutrophil activation and an imbalance between
pro- and anti-inflammatory cytokines; during steroid therapy a normalization of
these parameters was observed.
PMID- 10782905
TI - Flow cytometric analysis of autonomous growth of erythroid precursors in liquid
culture detects occult polycythemia vera in the Budd-Chiari syndrome.
AB - BACKGROUND/AIMS: Hepatic vein thrombosis (Budd-Chiari syndrome) is associated
with various hypercoagulable states, such as polycythemia vera (PV), presence of
the lupus anticoagulant, paroxysmal nocturnal hemoglobinuria (PNH) and
deficiencies of antithrombin III, protein C and protein S. In recent years, it
has become evident that patients with the Budd-Chiari syndrome may have more than
one risk factor that may cause a state of hypercoagulability. The aim of the
current study was to assess the prevalence of occult PV in patients with Budd
Chiari syndrome using a novel method for the detection of spontaneous erythroid
growth. METHODS: Twenty-two patients with Budd-Chiari syndrome were evaluated. As
controls, we studied normal donors and four patients with liver cirrhosis and
five patients with right-side heart failure, two conditions that in part mimic
Budd-Chiari syndrome. The presence of PV was determined by flow cytometric
analysis of autonomous growth of erythroid precursors. Patients were considered
as having occult PV if they had spontaneous erythroid cell growth in the absence
of erythropoietin and with no features of overt PV. RESULTS: Cells from ten
patients with Budd-Chiari syndrome demonstrated spontaneous erythroid cell
growth; eight patients (32%) were found to have occult PV and two patients had
overt PV. None of the controls had spontaneous erythroid growth. Of the eight
Budd-Chiari patients with occult PV, six had one or more additional recognized
hypercoagulable states. Seven patients (32%) had protein C deficiency, six
patients (27%) had activated protein C resistance, five (23%) had anti
cardiolipin antibodies, five (23%) had antithrombin III deficiency, and four
patients (18%) had protein S deficiency. Three patients (14%) were homozygous to
methyltetra hydrofolate reductase and ten (45.5%) were heterozygous. One patient
had PNH. Overall, in 12 patients there were two or more combined risk factors.
CONCLUSIONS: Using a flow cytometric analysis of autonomous growth of erythroid
precursors we found a clear correlation between Budd-Chiari syndrome and occult
PV.
PMID- 10782907
TI - Suppression of hepatic lesions in a murine graft-versus-host reaction by
antibodies against adhesion molecules.
AB - BACKGROUND/AIMS: The injection of parental CD4+ T cells into major
histocompatibility complex (MHC) class II disparate F1 hybrid mice induced an
autoimmune graft-versus-host reaction (GVHR) which is analogous to autoimmune
liver diseases. The interaction of adhesion molecules such as vascular cell
adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) has been known to be
profoundly involved in the trafficking of lymphocytes into the inflammatory
tissues. The aim of this study was to clarify the role of VLA4 or VCAM-1 in the
development of GVHR-induced hepatic lesions in our model. METHODS: B6 T spleen
cells were injected into (B6.C-H-2bm12xB6) F1 mice intravenously. Anti-VLA-4 mAbs
and/or anti-VCAM-1 mAbs were injected intraperitoneally at a dose of 2.5 mg/kg of
each mAbs per body weight of mouse. We examined the changes in GVHR-induced
hepatic lesions, serum levels of antimitochondrial antibodies (AMA) and cytokine
mRNA expressions of liver-infiltrating lymphocytes using H.E. and
immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), and
reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS:
Hepatic lesions of anti-VLA-4 mAbs-treated mice were inhibited compared with
those of GVHR mice. However, the administration of mAbs did not interfere with
the induction of splenomegaly, the invasion of CD4+, CD8+, B220+, or Mac-1+ cells
around bile ducts, nor the production of AMA. Liver-infiltrating CD4+ T cells
obtained from these treated mice did not alter the expression of T helper (Th)1
and Th2 cytokine mRNA. CONCLUSION: The results suggest that treatment with
antibodies against these adhesion molecules could inhibit the infiltration of
lymphocytes without affecting the Th1/Th2 balance. The blockade of VLA-4-mediated
cell infiltration into the liver in this model may have a possible novel
therapeutic role of VLA-4 mAbs.
PMID- 10782908
TI - Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial
infections in cirrhotic patients.
AB - BACKGROUND/AIM: Cefotaxime is considered the first-choice antibiotic for
empirical treatment in cirrhotic patients developing bacterial infections. It has
been suggested that amoxicillin-clavulanic acid could be an alternative to
cefotaxime, particularly in patients developing bacterial infections while on
prophylactic norfloxacin. The aim of the present study was to compare amoxicillin
clavulanic acid with cefotaxime in the treatment of bacterial infections in
cirrhosis. METHODS: Ninety-six hospitalized cirrhotic patients with suspicion of
bacterial infection were prospectively included and randomized into two groups:
one group (n=48) received amoxicillin-clavulanic acid, first intravenously 1 g
0.2 g every 8 h, and then orally 500 mg-125 mg every 8 h, and the other group
(n=48) received intravenous cefotaxime 1 g every 6 h. Patients were stratified
for previous prophylaxis with norfloxacin and ascitic fluid infection. RESULTS:
Sixteen patients were excluded from the analysis because bacterial infection was
not demonstrated or because of secondary peritonitis. Therefore, 38 patients from
the amoxicillin-clavulanic acid group and 42 from the cefotaxime group were
finally analyzed. There were 24 ascitic fluid infections in each group. Infection
resolution (86.8% vs 88%, 95% CI: -0.15 to 0.13, p NS), spontaneous bacterial
peritonitis resolution (87.5% vs 83.3%, 95% CI: -0.15 to 0.24, p NS), duration of
treatment, incidence of complications, time of hospitalization and hospital
mortality were similar in both groups. Considering patients on prophylactic
norfloxacin, infection resolution was also similar (100% vs 83.3%, 95% CI: -0.04
to 0.37, p NS). No adverse events were observed in either of the two groups. The
cost of antibiotics was statistically lower in the amoxicillin-clavulanic acid
group (p<0.001). CONCLUSIONS: Amoxicillin-clavulanic acid is as effective as
cefotaxime in the treatment of bacterial infections in cirrhotic patients, but is
less expensive and can be administered orally. These results suggest that
amoxicillin-clavulanic acid is an effective alternative to cefotaxime for the
empirical treatment of bacterial infections in cirrhosis.
PMID- 10782909
TI - Dexamethasone coupled to albumin is selectively taken up by rat nonparenchymal
liver cells and attenuates LPS-induced activation of hepatic cells.
AB - BACKGROUND/AIMS: The human serum albumin (HSA) conjugate Dexa10-HSA was designed
to specifically deliver the anti-inflammatory drug dexamethasone (Dexa) to
nonparenchymal cells (NPC) in the rat liver. NPC play an important role in the
pathogenesis of acute and chronic inflammatory liver diseases like fibrosis.
Targeting Dexa to these cells might reduce its adverse effects and increase the
efficacy. METHODS: Tissue and intrahepatic distributions of Dexa10-HSA were
assessed in normal and fibrotic rats with 125I-labelled conjugate and by
immunohistochemistry. The effect of the conjugate on lipopolysaccharide (LPS)
induced inflammation and cell activation was studied in vitro with precision-cut
liver slices and in vivo. RESULTS: Ten minutes after i.v. injection 72+/-13% and
65+/-12% of a tracer dose of Dexa10-HSA had been taken up in normal and fibrotic
livers, respectively. Unconjugated Dexa also accumulated in livers, but cellular
distribution studies revealed an accumulation in parenchymal cells (NPC vs.
parenchymal cell (PC) ratio=0.29+/-11, p<0.005) whereas Dexa10-HSA accumulated in
nonparenchymal cells (NPC/PC ratio=7.9+/-3.1). Both coupled and uncoupled Dexa
showed effective inhibition of LPS-induced NOx and TNFalpha production in
precision-cut liver slices. At low concentrations (0.02 microM), however, Dexa10
HSA was more efficient at inhibiting TNFalpha production than uncoupled Dexa. In
fibrotic rats Dexa10-HSA (3 mg/kg) and an equimolar amount of uncoupled Dexa
(0.22 mg/kg) both significantly promoted survival after LPS-induced acute
inflammation. CONCLUSION: Dexa10-HSA was at least as effective as uncoupled Dexa
at inhibiting LPS-induced effects, which indicates that HSA-bound Dexa is
pharmacologically active. Coupling Dexa to HSA shifted the accumulation of Dexa
from the PC to the NPC of livers. Since mediator release from NPC is crucial in
the initiation and propagation of the fibrotic process, selective delivery of
Dexa in NPC may improve the efficacy and safety of corticosteroid treatment of
liver fibrosis.
PMID- 10782910
TI - Expression of MAGE, GAGE and BAGE genes in human liver diseases: utility as
molecular markers for hepatocellular carcinoma.
AB - BACKGROUND/AIMS: The MAGE, GAGE and BAGE genes encode tumor antigens recognized
by autologous cytotoxic T lymphocytes. The aim of this study was to evaluate the
possibility of using these genes as molecular markers and as the targets of
specific immunotherapy for human hepatocellular carcinoma (HCC). METHODS: The
expressions of MAGE-1, MAGE-3, GAGE1-6, GAGE1-2 and BAGE mRNA in 33 surgically
resected HCC samples and 26 of their corresponding non-cancerous samples (11
liver cirrhosis and 15 chronic hepatitis) were studied by a reverse-transcription
polymerase chain reaction, and were compared with clinicopathological parameters.
The expression of MAGE-1 was also examined in 16 biopsied HCC samples. RESULTS:
MAGE-1, MAGE-3, GAGE1-6, GAGE1-2 and BAGE mRNA were expressed in 67%, 39%, 36%,
30%, and 21% of the HCC, respectively. At least one transcript was detected in
88% of the HCC, while no expression was observed in the non-cancerous livers.
There was no significant correlation between the expression of any of the tumor
antigens examined and the differentiation stage or size of the HCC. Especially,
MAGE-1 was highly expressed in small HCC with a diameter of less than 2 cm and in
well-differentiated HCC (81% and 70%, respectively), and was also expressed even
in alpha-fetoprotein-negative and PIVKA-II-negative HCC (58% and 76%,
respectively). The MAGE-1 expression was detected in 69% of biopsied HCC samples
and the expression was high in both small and well-differentiated HCC.
CONCLUSIONS: These tumor-specific antigens can be useful as molecular markers and
as the possible target molecules for the specific immunotherapy of human HCC.
PMID- 10782911
TI - Growth hormone induces CCAAT/enhancer binding protein alpha (C/EBPalpha) in
cultured rat hepatocytes.
AB - BACKGROUND/AIMS: The transcription factor CCAAT/enhancer binding protein alpha
(C/EBPalpha) is a transactivator of several genes in the liver, which are
regulated by growth hormone. METHODS: Growth hormone (100 ng/ml) was added to
primary rat hepatocytes cultured on a laminin-rich matrix. C/EBP mRNA and protein
levels were measured by RNase protection assay and Western blotting,
respectively. DNA binding activity was measured by electrophoretic mobility shift
assay (EMSA). RESULTS: Growth hormone treatment for 6 h to 3 days increased
C/EBPalpha mRNA levels. Addition of growth hormone for 24 h and 4 days also
enhanced the levels of the 42 and 30 kDa isoforms of immunoreactive C/EBPalpha.
EMSA showed that addition of growth hormone for 24 h enhanced the abundance of a
protein complex binding to a consensus C/EBP binding DNA oligonucleotide. This
protein complex was supershifted by antibodies directed against C/EBPalpha but
not against C/EBPbeta. There were no consistent effects on C/EBPbeta mRNA or
protein at any timepoint. The growth hormone effect on C/EBPalpha expression was
not affected by simultaneous incubation with insulin or glucocorticoids, two
hormones that previously have been reported to affect C/EBPs. CONCLUSIONS: Growth
hormone enhances the levels of C/EBPalpha mRNA and protein as well as the DNA
binding activity of C/EBPalpha in cultured rat hepatocytes.
PMID- 10782912
TI - The extent of synchronous initiation and termination of DNA synthesis in
regenerating mouse liver is dependent on connexin32 expressing gap junctions.
AB - BACKGROUND/AIMS: It has previously been shown in rat liver that the gap
junctional proteins connexin32 and connexin26 are downregulated when murine
hepatocytes are in the S-phase of the cell cycle. Therefore, it has been
hypothesized that loss of functional gap junctions could affect proliferation of
hepatocytes. This study aimed to check this hypothesis. METHODS: We searched for
differences in liver regeneration after two-thirds partial hepatectomy between
connexin32-deficient and wild-type mice. RESULTS: The ratio of liver to body
weight in regenerating liver was not affected by loss of the connexin32 gene. The
peak of DNA synthesis occurred at the same time, i.e. 36 to 96 h after partial
hepatectomy, in connexin32-deficient and wild-type liver. During this time,
however, only about half as many nuclei of hepatocytes in connexin32-deficient
liver incorporated bromodeoxyuridine, compared to wild-type liver. Furthermore, 1
2 weeks after full recovery of liver mass, we detected a higher level of
bromodeoxyuridine incorporation into hepatocytes of connexin32-deficient than in
wild-type liver. CONCLUSIONS: Loss of connexin32 protein and/or diminished
expression of connexin26 did not promote G0/1-S transition of hepatocytes in two
thirds hepatectomized mouse livers. Instead, the extent of synchronous initiation
and termination of DNA synthesis in regenerating liver was altered in connexin32
deficient mice.
PMID- 10782914
TI - Epidermal growth factor and insulin-like growth factor I upregulate the
expression of the epidermal growth factor system in rat liver.
AB - BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I
play a role in connection with the liver. In the present study, the possible
interaction of these two growth factor systems was studied by investigating the
effect of epidermal growth factor or insulin-like growth factor I treatment on
the expression of the epidermal growth factor receptor, and its activating
ligands, transforming growth factor-alpha and epidermal growth factor. METHODS:
Fifty-five male rats received no treatment, human recombinant epidermal growth
factor or human recombinant insulin-like growth factor I for either 3 or 7 days.
The amount of epidermal growth factor receptor, transforming growth factor-alpha,
and epidermal growth factor mRNA was quantitated by a calibrated user-friendly RT
PCR assay (CURT-PCR), and the expression of transforming growth factor-alpha and
epidermal growth factor peptides was quantitated by ELISA. RESULTS: Control liver
(n=16) contained a mean (+/-SD) value of 12.7+/-7.4x10(-18) mol epidermal growth
factor receptor mRNA, 3.8+/-2.0x10(-18) mol transforming growth factor-alpha mRNA
and 0.8+/-0.4x10(-18) mol epidermal growth factor mRNA per microg total RNA and
9.8+/-1.6 fmol/mg protein epidermal growth factor and 144+/-22 fmol/mg protein
transforming growth factor-alpha. Both epidermal growth factor and insulin-like
growth factor I treatment increased the expression of mRNA for transforming
growth factor-alpha and epidermal growth factor receptor, as well as the
expression of transforming growth factor-alpha peptide. The level of epidermal
growth factor receptor and transforming growth factor-alpha mRNA expression was
found to correlate both in control and growth factor-treated animals, whereas the
expression of epidermal growth factor receptor and epidermal growth factor showed
no correlation. Marked differences were seen upon activation of the two growth
factor systems, as epidermal growth factor, but not insulin-like growth factor I
treatment, increased the plasma concentration of urea and decreased the
concentration of insulin-like growth factor I and the liver enzymes, alanine
aminotransferase and alkaline phosphatase. CONCLUSION: Our results show that
epidermal growth factor and insulin-like growth factor I, which belong to two
different growth factor systems, both induce a correlated upregulation of
transforming growth factor-alpha and epidermal growth factor receptor mRNA in rat
liver. Although marked differences were observed after treatment with either
epidermal growth factor or insulin-like growth factor I on the liver as reflected
in the plasma concentrations of e.g. liver enzymes, a common motif in their
action involves an upregulation of the expression of the epidermal growth factor
system.
PMID- 10782913
TI - Differential suppression of liver-specific genes in regenerating rat liver
induced by extended hepatectomy.
AB - BACKGROUND/AIMS: The function of the remnant liver is critical to survival of
patients following an extended hepatectomy. The aim of this study was to
determine whether proliferating hepatocytes in the remnant liver preserve the
expression of liver-specific genes. METHODS: Using regenerating rat livers after
30, 70, and 90% partial hepatectomy (PHx), Northern blot analyses were performed
with probes for seven liver-specific genes, six growth-related genes, two
housekeeping genes and two acute phase reactant protein genes. RESULTS: During
the regeneration after 90% PHx, the transcription of liver-specific genes showed
three chronological patterns: transcription of serum albumin and cytochrome P450
2B decreased rapidly and reached a nadir at 6 to 24 h after PHx; those of
apolipoprotein A-1, phosphoenolpyruvate carboxykinase and ornithine
transcarbamylase decreased gradually until 24 to 48 h; those of UDP
glucuronosyltransferase and hepatocyte nuclear factor 4 did not show any changes
until 48 h after PHx. In contrast, expression levels of all the growth-related
genes and of housekeeping genes increased rapidly after PHx. After 30 and 70%
PHx, expression of these genes changed in a similar manner to the 90% PHx case
but to a lower extent. CONCLUSIONS: Based upon the fractions of Ki-67 positive
hepatocytes in remnant livers, we could estimate the degree of expression of each
liver-specific gene in the proliferating hepatocytes. The serum albumin gene was
completely suppressed, while that encoding UDP-glucuronosyltransferase was not
affected. These results correlated well with the patterns of albumin and
bilirubin in rat serum after PHx. Other liver-specific genes were moderately
suppressed in proliferating hepatocytes. Thus, expression of liver-specific gene
is differentially suppressed when hepatocytes enter a proliferation cycle. Those
that are unaffected may be indispensable for maintaining the homeostasis of the
living organism.
PMID- 10782915
TI - Liver xenotransplantation: changes in lipid and lipoprotein concentration after
long-term graft survival.
AB - BACKGROUND/AIMS: Today, scientists devote considerable effort to the study of
mechanisms of xenograft rejection, but with liver xenotransplantation (XTx)
researchers face the added problem of metabolic incompatibility between species.
To date, there have been few studies of molecular xenogeneic interactions,
perhaps because little progress has been made in solving immunological problems.
This study is an initial analysis of lipoprotein metabolism in a hamster-to-rat
hepatic xenotransplantation model. METHODS: There were 6 experimental groups
(n=8): (1) male Sprague-Dawley (S.D.) rats (220-280 g); (2) male Golden Syrian
hamsters (100-150 g); (3) S.D. rats, "sham" operation with immunosuppression; (4)
S.D. rat-to-S.D. rat alloTx; (5) S.D. rat-to-S.D. rat alloTx with
immunosuppression; (6) XTx hamster G.S-to-S.D. rat with immunosuppression.
Mofetil mycophenolate (25 mg/kg/d) was administered for 14 days and FK506 (0.2
mg/kg/d) for 45 days (groups 3, 5 and 6). After 24 h fasting, animals were
sacrificed (day +50 postransplantation) and a complete lipoprotein profile was
determined. Serum lipoproteins were subfractioned by ultracentrifugation in
density gradient. RESULTS: There was a large increase in serum lipid levels in
xenografted rats compared with control rats and allografted rats. Xenografted
rats presented a severely altered lipoprotein profile compared with normal rats.
Surprisingly, the characterisation of lipoproteins in xenografted rats displayed
the same composition as donor animals. Histological study did not show signs of
alteration of the hepatic architecture. CONCLUSIONS: Since the liver is the main
solid organ co-ordinator of metabolic pathways, such as lipid metabolism, hepatic
xenotransplantation makes changes in lipid concentrations in the recipient and
also changes in lipid compositions of lipoproteins. Hepatic xenotransplantation
is not a feasible solution given the organ's metabolic complexity.
PMID- 10782916
TI - TTV infection in patients with acute hepatitis of defined aetiology and in acute
non-A-E hepatitis.
AB - BACKGROUND/AIMS: Recently, the presence of a novel nonenveloped single-stranded
DNA virus (TTV) has been associated with either acute or chronic hepatitis of
unknown aetiology, suggesting a possible aetiological role. The aim of this study
was to evaluate the prevalence, the significance and the clinical impact of TTV
infection in patients with acute viral hepatitis of defined aetiology and in
patients with non-A-E acute hepatitis. METHODS: TTV-DNA was tested by hemi-nested
PCR in serum samples collected from 121 patients during and after acute hepatitis
(103 with acute viral hepatitis of defined aetiology and 18 with acute non-A-E
hepatitis) and in 30 healthy controls. RESULTS: Overall, the rate of TTV
infection was 12.6% (13/103) in patients with acute hepatitis of defined
aetiology, 16.6% (3/18) in patients with non-A-E acute hepatitis and 6.6% (2/30)
in the healthy control group, (p=n.s). TTV-DNA was detected in the following
proportions: hepatitis B, 13.2% (7/53); hepatitis C, 16.6% (4/24); hepatitis A,
4.7% (1/21); hepatitis E 20% (1/5). Moreover, acute hepatitis with and without
TTV infection/coinfection were comparable in terms of both liver biochemistry and
chronicity rate. The results of TTV re-testing after serial dilutions of six TTV
DNA positive serum samples during and after the peak of liver transaminases
failed to demonstrate a correlation between liver damage and viral titre.
CONCLUSIONS: The prevalence of TTV infection appeared to be comparable in
patients with non-A-E hepatitis, in acute hepatitis of defined aetiology and in
the control group. Hence, an aetiological role of TTV for acute hepatitis of
unknown aetiology seems questionable. Moreover, TTV infection does not modify the
natural history of acute hepatitis of defined aetiology.
PMID- 10782917
TI - Changes in serum tissue inhibitor of matrix metalloproteinase-1 after interferon
alpha treatment in chronic hepatitis C.
AB - BACKGROUND/AIMS: The aim of this study was to evaluate the effect of interferon
alpha on the metabolism of hepatic fibrosis in chronic hepatitis C, monitoring
serum tissue inhibitor of matrix metalloproteinase-1(TIMP-1) and N-terminal
propeptide of type III procollagen (PIIINP) reflecting fibrolysis and
fibrogenesis, respectively. METHODS: Serum levels of TIMP-1 and PIIINP were
serially measured in 112 treated and 31 untreated patients with chronic hepatitis
C during and after interferon alpha treatment. Furthermore, the relationships
between these serum markers and the grades of hepatic fibrosis after interferon
therapy were also investigated. RESULTS: Serum pretreatment levels of TIMP-1 and
PIIINP in non-responders were significantly higher than those in sustained and
transient responders, but these levels were not different in the latter two
groups. Serum TIMP-1 levels decreased significantly during and after treatment in
sustained responders, and decreased temporarily at the end of treatment in
transient responders, although these levels were unchanged during and after
treatment in non-responders and untreated patients. In contrast, serum PIIINP
levels decreased significantly during and after treatment in all treated groups,
but were unchanged in untreated patients. Histological examination 12 months
after interferon was completed demonstrated that hepatic fibrosis improved in
sustained responders and was unchanged in transient and non-responders, but
progressed in untreated patients. CONCLUSION: These results suggest that
interferon alpha treatment of chronic hepatitis C may improve hepatic fibrosis in
sustained responders by the acceleration of fibrolysis as well as the inhibition
of fibrogenesis, and that it may suppress the progression of hepatic fibrosis in
non-sustained responders by the inhibition of fibrogenesis.
PMID- 10782919
TI - Ursodeoxycholic acid for primary biliary cirrhosis: lessons from the past--issues
for the future.
PMID- 10782920
TI - Mallory bodies revisited.
PMID- 10782918
TI - HCV-related fibrosis progression following liver transplantation: increase in
recent years.
AB - BACKGROUND/AIMS: The natural history and predictors of HCV-related disease
severity post-transplantation are uncertain. The aims of this study were to
define the natural history of post-transplantation HCV infection by assessing the
rate of fibrosis progression, to determine if the post-transplantation natural
history differs from that observed pre-transplantation, and to identify
predictors of post-transplantation disease progression. METHODS: Post
transplantation biopsies (mean: 3+/-1.6/patient) from 284 patients were scored
according to histologic stage, using the method of Desmet et al. Change in
fibrosis score (fibrosis progression/year) post-transplantation was used as the
primary outcome. Predictors analyzed included viral factors (genotype and viral
load at transplantation), patient demographics, year of transplantation, country
of transplantation, pre-transplantation fibrosis progression, immunosuppression
and laboratory data. RESULTS: There was a linear association between change in
fibrosis score and time from transplantation, with a median rate of fibrosis
progression per year of 0.3 (0.004-2.19/year). Using parametric time-to-event
analysis, the expected median duration to cirrhosis was 10 years. The rate of
post-transplantation fibrosis progression was significantly higher than pre
transplantation (0.2/year (0.09-0.8) p<0.0001), and higher in Spanish than US
centers (0.48 (0.01-2.19) vs 0.28 (0.004-2.08); p=0.09) despite similar
progression rates prior to transplantation. Variables independently associated
with post-transplantation progression included year of transplantation
(p=0.0001), race (p=0.02), number of methyl-prednisolone boluses (p=0.03), and
HCV RNA levels at transplantation (p=0.01). CONCLUSIONS: HCV-related disease
progression is accelerated in immunocompromised compared to immunocompetent
patients, with a progressive increase in patients who have recently undergone
liver transplantation. Changes in patient management post-transplantation over
time and between transplant centers may account for the increase in fibrosis
progression observed in recent years.
PMID- 10782921
TI - Undetectable serum caeruloplasmin in a woman with chronic hepatitis C infection.
AB - There are many causes of a low serum caeruloplasmin. Not only may this be a
feature of Wilson's disease, but a low level may be found in association with
chronic liver disease of any cause. We report here a case where undetectable
serum caeruloplasmin was found during routine investigation of a woman with
hepatitis C viral infection.
PMID- 10782922
TI - Images in hepatology. Acute cholecystitis revealing a diaphragm disinsertion.
PMID- 10782923
TI - The genetics of osteoporosis: 'complexities and difficulties'.
AB - Osteoporosis is characterized by a decrease in bone mass as well as a
deterioration of the bone architecture resulting in an increased risk of
fracture. Although the disease is multifactorial, twin studies have shown that
genetic factors account for up to 80% of the variance in bone mineral density,
the best known predictor of the risk of osteoporosis. Some loci, such as the
vitamin D and estrogen receptor genes, as well as the collagen type Ialpha1
locus, are promising genetic determinants of bone mass, and possibly other bone
phenotypes, but this is controversial and the molecular basis of osteoporosis
remains largely undefined. Considering that the effect of each candidate gene is
expected to be modest, discrepancies between allelic association studies may have
arisen because different populations carry different genetic backgrounds and
exposure to environmental factors. Also, we realize the importance of gene-gene
as well as gene-environment interactions as significant determinants of bone
density and risk of osteoporosis. The use of new tools such as small nucleotide
polymorphism maps now allows the possibility to perform allelic association
studies in the context of whole-genome search. However, specific study design
strategies in large epidemiological studies as well as the best statistical
approach will need to be established. We may expect the development of population
specific at-risk profiles for osteoporosis that would include genetic and
environmental factors, as well as their interactions. This should eventually lead
to better prevention strategies and more adapted therapies against osteoporosis.
PMID- 10782924
TI - Xolotl: god of monstrosities.
PMID- 10782925
TI - Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD,
ODD and conduct disorder: multivariate regression analysis of 20 genes.
AB - The present study is based on the proposal that complex disorders resulting from
the effects of multiple genes are best investigated by simultaneously examining
multiple candidate genes in the same group of subjects. We have examined the
effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a
quantitative score for attention deficit hyperactivity disorder (ADHD) in 336
unrelated Caucasian subjects. The genotypes of each gene were assigned a score
from 0 to 2, based on results from the literature or studies in an independent
set of subjects (literature-based scoring), or results based on analysis of
variance for the sample (optimized gene scoring). Multivariate linear regression
analysis with backward elimination was used to determine which genes contributed
most to the phenotype for both coding methods. For optimized gene scoring, three
dopamine genes contributed to 2.3% of the variance, p = 0.052; three serotonin
genes contributed to 3%, p = 0.015; and six adrenergic genes contributed to 6.9%,
p = 0.0006. For all genes combined, 12 genes contributed to 11.6% of the
variance, p = 0.0001. These results indicate that the adrenergic genes play a
greater role in ADHD than either the dopaminergic or serotonergic genes combined.
The results using literature-based gene scoring were similar. An examination of
two additional comorbid phenotypes, conduct disorder and oppositional defiant
disorder (ODD), indicated they shared genes with ADHD. For ODD different
genotypes of the same genes were often used. These results support the value of
the simultaneous examination of multiple candidate genes.
PMID- 10782926
TI - A pilot study of the possible role of familial defects in anticoagulation as a
cause for terminal limb reduction malformations.
AB - Terminal limb deficiency defects affect between three and eight babies per 10000
births and are an important cause of disability. Established causes for these
malformations include single gene disorders, chromosome abnormalities,
teratogens, and amniotic bands. However, the etiology remains unknown in a
significant proportion of cases. Several authors have hypothesized that vascular
accidents, either bleeds or vessel occlusions, may underlie a substantial number
of cases; but, for the most part, the origin of such events remains obscure. Over
the past several years, an increasing number of genetic thrombophilias have been
recognized and have been associated with increased risks of peri- and post-natal
occlusive disease, and with higher rates of recurrent pregnancy loss. The
hypothesis to be examined in this pilot study was whether the inherited
thrombophilias might be associated with a vascular cause of some terminal limb
deficiency defects. Towards that end, protein C, protein S, antithrombin III,
factor V Leiden mutation, prothrombin (G20210A) variant,
methylenetetrahydrofolate reductase variant, plasma homocysteine, anticardiolipin
IgM and IgG antibodies, and lipoprotein (a) were measured in 24 mother-child
pairs in which the child had a terminal limb defect. The results provided some
evidence that there may be an excess of thrombophilias present in such families
and that they may play some etiological role in a subset of these types of limb
malformations.
PMID- 10782928
TI - A rapid fluorescent multiplexed-PCR analysis (FMPA) for founder mutations in the
BRCA1 and BRCA2 genes.
AB - Mutations of the BRCA1 and BRCA2 genes account for approximately 80% of
hereditary breast/ovarian cancer families, but the size of these two genes makes
mutation analysis time-consuming and technically challenging. In some populations
such as the Ashkenazi Jewish and the French-Canadian, a small number of recurrent
founder mutations account for the majority of mutations in cancer families. We
have therefore developed two rapid genetic screening tests, which allow us to
detect three frequent frameshift mutations in the Ashkenazi Jewish population and
five frameshift mutations in the French-Canadian population. These fluorescent
non-radioactive methods permit the simultaneous detection of multiple mutations
by generating multiplexed PCR-amplified gene fragments, and by discriminating
these on the basis of their size in a denaturing polyacrylamide gel. Using these
methods, we were able to correctly identify all mutants in a blinded analysis of
276 DNA samples, including 30 derived from paraffin-embedded tumor samples and 10
from buccal-cell brushes, with no false positive or false negative results. These
techniques designed for the direct detection of recurrent mutations in the BRCA1
and BRCA2 genes, have the advantages of being efficient, sensitive, cost
effective, and are applicable to large scale screening for epidemiologic studies.
PMID- 10782927
TI - A germline mutation at the extreme 3' end of the APC gene results in a severe
desmoid phenotype and is associated with overexpression of beta-catenin in the
desmoid tumor.
AB - Desmoid tumors arise sporadically or as part of the extraintestinal
manifestations of familial adenomatous polyposis (FAP). In FAP, two distinct
clinical presentations of the desmoid phenotype are seen: 1) one or a few desmoid
tumors present predominantly in the abdominal wall or the abdomen; 2) a florid
proliferation of tumors early in life, mostly near the axial skeleton or
extremities. These different phenotypes have been associated with different sites
of germline mutations in the adenomatous polyposis coli gene (APC gene). We
present a large, French-Canadian kindred with a florid desmoid tumor phenotype
caused by a germline mutation at codon 2643-2644 of the APC gene. The phenotype
was characterized by the early onset of multiple tumors, arising near the axial
skeleton and in proximal extremities. The penetrance of desmoid tumors was near
100% in this kindred. However, the expression of the disease was variable amongst
the different affected relatives. Many gene carriers had cutaneous cysts.
Polyposis of the colon was rarely observed in the affected individuals and we did
not document upper gastro-intestinal polyps. The mutant APC allele did not
express a stable truncated protein in vivo. Molecular analysis of the proband's
tumor DNA revealed a somatic inactivating mutation of the wild-type allele.
Immunohistochemistry on the tumor also demonstrated elevated levels of beta
catenin. The present study demonstrates that this extreme 3' APC mutation is
associated with a severely penetrant desmoid phenotype and attenuated polyposis
coli. It also suggests the involvement of the beta-catenin pathway in the
development of desmoid tumors in FAP. The natural history of the disease is
variable between individuals, and surgical interventions have to be timed
appropriately due to the frequent recurrences.
PMID- 10782929
TI - Molecular analysis of the 5'-flanking region of the neurofibromatosis type 1
(NF1) gene: identification of five sequence variants.
AB - Dideoxy fingerprinting was used to analyse the 5' flanking region of the
neurofibromin (NF1) gene in a panel of 380 neurofibromatosis type 1 (NF1)
patients. Five polymorphisms/rare variants were identified at positions -412, -
402, + 16, + 25 and + 132, but control data indicated that these were unlikely to
be of pathological significance. Promoter mutations in the NF1 gene are not,
therefore, a common cause of NF1. This notwithstanding, a reporter gene assay was
performed to determine if these variants could affect the expression of the NF1
gene, and all three changes in the 5'-untranslated region (UTR) (+ 16, + 25, +
132) were found to be associated with a 60-70% increase in reporter gene
expression.
PMID- 10782930
TI - Identification of four novel mutations of the low-density lipoprotein receptor
gene in Korean patients with familial hypercholesterolemia.
AB - To obtain insight into the genetic variation of the low-density lipoprotein (LDL)
receptor gene in Korean patients with familial hypercholesterolemia (FH), we used
single-strand conformation polymorphism to screen all 18 exons and a promotor of
the LDL receptor gene in 20 unrelated Korean FH patients. Four novel point
mutations were detected in 5 FH patients and were characterized by sequence
analysis. Of them, one is a nonsense mutation, a Glu-->Stop (CAG-->TAG) at codon
161, and results in a large deletion. The other three, which were a Ala-->Glu
(GCG-->GAG) mutation at signal peptide, Cys-->Tyr (TGC-->TAC) at codon 210, and
Pro-->Leu (CTG-->CCG) at codon 584, were novel missense mutations, which modified
the highly conserved region of the LDL receptor gene. All these mutations were
absent in normolipidemic controls and were associated in heterozygote carriers
with clinical signs of FH. Identification of these novel mutations provides
another example of the molecular heterogeneity of the LDL receptor gene mutations
causing FH.
PMID- 10782931
TI - Spina bifida and common mutations at the homocysteine metabolism pathway.
PMID- 10782932
TI - Pseudodominant inheritance of DFNB1 deafness due to the common 35delG mutation.
PMID- 10782933
TI - Identification of cystic fibrosis mutations in Oman.
PMID- 10782934
TI - Systematic review of aetiology and treatment of post-stroke hand oedema and
shoulder-hand syndrome.
AB - Studies on the aetiology and treatment of post-stroke hand oedema and shoulder
hand syndrome (SHS) published from January 1973 until August 1998 were
identified. Eleven studies were included with at least some control for
confounding. These were evaluated on 11 methodological criteria and by
standardized effect sizes. There were five aetiological studies: four cohort
studies and one study consisting of two case series using a within-subjects
design. The matters investigated included lymph scintigraphy in hand oedema, bone
scintigraphy, putative risk factors and the existence of autonomic dysregulation
and peripheral nerve lesions in SHS. There were six therapeutic studies: one
randomized controlled trial, one non-randomized controlled trial, one cohort
study and three case series, of which two studies used a within-subjects design.
These studies investigated continuous passive motion and neuromuscular
stimulation in hand oedema as well as oral corticosteroids, intramuscular
calcitonin and trauma prevention in SHS. A great diversity of pathophysiological
and therapeutic insight was found. Based on systematic analysis of the
literature, the following conclusions seem justified: (i) the shoulder is
involved in only half of the cases with painful swelling of wrist and hand,
suggesting a "wrist-hand syndrome" between simple hand oedema and SHS; (ii) hand
oedema is not lymphoedema; (iii) SHS usually coincides with increased arterial
blood flow; (iv) trauma causes aseptic joint inflammations in SHS; (v) no
specific treatment has yet proven its advantage over other physical methods for
reducing hand oedema; and (vi) oral corticosteroids are the most effective
treatment for SHS.
PMID- 10782935
TI - Effect of swallowing training on swallowing disorders in Parkinson's disease.
AB - The purpose of the present study was to determine whether swallowing training
improves swallowing function in patients with Parkinson's disease. Ten patients
(5 males, 5 females) who had symptoms of dysphagia and 12 healthy volunteers were
studied. The initiation time of the swallowing reflex, the "premotor time" (PMT),
was calculated from an electromyogram of the submental muscles before and after
swallowing training. Patients with Parkinson's disease had a significantly longer
PMT (p = 0.0014) than did healthy controls. There was no correlation between PMT
and the duration of the disease (r = -0.146; p = 0.6867) or the patient's age (r
= 0.602; p = 0.0653). After swallowing training, the patients' PMTs decreased
significantly (p = 0.0051).
PMID- 10782936
TI - Effect of cooling suit treatment in patients with multiple sclerosis evaluated by
evoked potentials.
AB - The aim of the present study was to determine whether any significant alterations
of evoked potentials could be detected after treatment of patients with multiple
sclerosis with a cooling suit. All patients had previously experienced a positive
effect of this treatment. Six patients were investigated with visual, sensory and
motor evoked potentials and six further patients with only motor evoked
potentials. All patients had relevant clinical lesions. The mean values for the
group of patients were similar before and after cooling, but a few individuals
showed a substantial improvement of motor evoked potentials after cooling, with
increased amplitude and/or shortened central motor conduction time. There was
also a weak, but significant, correlation between temperature decrements and the
reduction of central motor conduction time. However, since the central motor
conduction times of most patients were only slightly affected, this effect could
explain only a small part of the beneficial effect of cooling. Effects on
cognition and executive ability or improvement of spasticity may be of greater
importance.
PMID- 10782937
TI - Cooling suit for multiple sclerosis: functional improvement in daily living?
AB - Eight cryopositive patients with multiple sclerosis used cooling suits for 40
minutes regularly one or more times daily for a six-week period. The patients
were given repeated motor and mental tests by a physiotherapist in order to
determine whether they had a continuous beneficial effect of cooling during this
period. Additionally, selected activities of daily living performed in the
patient's homes were evaluated and registered according to Assessment of Motor
and Process Skills (AMPS). Six out of eight patients improved in at least one
motor test and all patients improved according to AMPS. For one of the patients,
who was profoundly handicapped, the effect of cooling was evaluated differently.
PMID- 10782938
TI - Simple assessment of outcome after acute brain injury using the Glasgow Outcome
Scale.
AB - To evaluate alternative methods of determining Glasgow Outcome Scale scores, a
postal survey was made of 288 general practitioners and 128 relatives of patients
who had sustained acute brain injuries 5-7 years previously. The Glasgow Outcome
Scale score from the general practitioner and relative were compared with that
calculated from questionnaire information by an experienced rater. There was poor
agreement between general practitioner and rater (K = 0.17) and relative and
rater (K = 0.35) scores. Both general practitioners and relatives indicated more
favourable outcomes than the rater, with a higher level of agreement (K = 0.61)
between them. When Glasgow Outcome Scale scores are used, the methods employed
should be valid and reliable; failure to ensure this may be responsible for a
considerable proportion of variability in reported studies of brain injury
outcome.
PMID- 10782939
TI - Functional electrical stimulation-assisted walking for persons with incomplete
spinal injuries: longitudinal changes in maximal overground walking speed.
AB - This study investigated the changes in maximal overground walking speed (MOWS)
that occurred during walking training with a functional electrical stimulation
(FES) orthosis by chronic spinal cord injured persons with incomplete motor
function loss. The average walking speed over a distance of 10 m was calculated
while the participants (n = 14) used their FES orthosis with and without power as
well as with the various ambulatory assistive devices available. Within the first
year of use, walking with an FES orthosis facilitated use of more advanced
ambulatory assistive devices (10/14), improvements in functional mobility (12/14)
and increases in the combined (0.26 m/s) and therapeutic (0.25 m/s) MOWS that
were correlated (combined: r = 0.57; therapeutic: r = 0.69) with their respective
initial MOWS. A longitudinal analysis showed that increases in MOWS followed a
pattern of changes best described by either an exponential association (8/12) or
a linear (4/12) model. These changes were similar for the combined and
therapeutic MOWS (7/11) as well as for the different ambulatory assistive devices
(8/9). It is concluded that the increased MOWS during walking training using the
FES orthosis is mostly due to a therapeutic effect, implying that mechanisms of
plasticity occur during such a training paradigm.
PMID- 10782940
TI - Quadriceps strength in women with a previous hip fracture: relationships to
physical ability and bone mass.
AB - Associations between physical ability, level of current physical activity and
bone mass were examined in 47 elderly women (mean age 80 years) who had suffered
from a hip fracture 3-36 months (mean 17 months) previously. Measures of physical
ability included isokinetic quadriceps strength of both the non-fractured and
fractured leg, and walking and stair climbing speed. An estimate of current
physical activity was made using the Northwick Park activity index questionnaire
specifically designed for hip fracture patients. Bone mineral density of the
spine and hip (Ward's triangle, femoral neck and trochanter) was assessed by dual
energy X-ray absorptiometry. Relationships between the measured parameters were
analysed using multiple regression analyses, taking into account the confounding
effects of age, height, weight and months since fracture. Quadriceps strength of
the fractured leg was on average 18% lower than that of the contralateral leg (p
< 0.001). Quadriceps strength of the fractured leg proved to be the most robust
predictor of walking speed (Rpartial = 0.69, p < 0.0001), stair climbing speed
(Rpartial = 0.46, p < 0.001) and the activity index (Rpartial = 0.56, p <
0.0001). Bone mineral density was independently predicted only by body weight
(Rpartial range: 0.45-0.72, p < 0.001), not by any of the parameters of physical
ability or by the Northwick Park activity index. In conclusion, quadriceps
strength is markedly affected in women with a previous hip fracture and is
associated with walking ability and level of physical activity. This study showed
that bone mass is linked to body weight, not to physical ability and activity.
Thus, the main benefit of muscle strengthening exercises in these women may be to
promote mobility.
PMID- 10782941
TI - Impact of age on improvement in health-related quality of life 5 years after
coronary artery bypass grafting.
AB - The aim of this study was to describe the relief of symptoms and improvement in
other aspects of health-related quality of life 5 years after coronary artery by
pass grafting in relation to age. Patients in western Sweden were approached with
an inquiry prior to surgery and 5 years after the operation. Health-related
quality of life was estimated with 3 different instruments: Physical Activity
Score (PAS), Nottingham Health Profile (NHP), Psychological General Well-Being
Index (PGWB). Prior to surgery patients were approached either in the ward or by
post and 5 years after surgery they were approached by post. A total of 1719
patients were available for the survey, of whom 876 (51%) responded to the survey
both prior to and after 5 years. Among the 876 respondents 287 were <60 years,
331 were 60-67 years and 258 were >67 years. In terms of physical activity, chest
pain and dyspnoea, a similar improvement was observed regardless of age. In terms
of health-related quality of life questionnaires, there was an inverse
association between age and improvement when using PAS and a similar trend was
observed with NHP and PGWB. In conclusion, 5 years after coronary artery bypass
grafting relief of symptoms and improvement in physical activity was not
associated with age, whereas improvement in other aspects of health-related
quality of life tended to be less marked in elderly people. Overall age seemed to
have a small impact on the improved well-being 5 years after coronary surgery.
However, due to the limited response rate the results may not be applicable to a
non-selected coronary artery bypass grafting population.
PMID- 10782942
TI - The forensic anthropology legacy of T. Dale Stewart (1901-1997).
AB - T. Dale Stewart (1901-1997) began his Smithsonian career as a temporary aide to
Ales Hrdlicka (1869-1943) in 1924. At the time of his death in 1997, he was
regarded world-wide as an authority who led the professional development of
American forensic anthropology. He was a prodigious researcher, best known for
his meticulous attention to detail, balanced scientific judgment, keen sense of
research design, and ability for synthesis. Stewart's publications, extensive
casework for the FBI and others, his court testimony, publications, professional
contacts, and organizational activity merit him a prominent place in the history
of American forensic anthropology.
PMID- 10782943
TI - Becoming respectable: T. Dale Stewart and the acceptance of forensic anthropology
in the academic community.
AB - Before World War II, forensic anthropology was of peripheral interest to a few
anthropologists willing to assist in investigations by law enforcement agencies.
A strong bias that "police work" was unbecoming to the scholarly pursuits of
academics persisted into the post-war years. Changes took place as a consequence
of T. Dale Stewart's case work in the identification of human remains with the
FBI from 1943 to 1969, his directorship of the National Museum of Natural History
(Smithsonian Institution) beginning in 1962, and his work with the Armed Forces
after 1948. This paper discusses the historic period of transition of attitudes
and practices in the contexts of Stewart's contributions and the cases and
teaching programs of one of his contemporaries. Theodore D. McCown at the
University of California at Berkeley, during the period of 1939 to 1969. The
establishment of the Physical Anthropology Section within the American Academy of
Forensic Sciences in 1972 and the creation of the T. Dale Stewart award for
distinguished service in forensic anthropology advanced those laboratory research
programs and medical-legal investigations conducted by present-day forensic
anthropologists.
PMID- 10782944
TI - Dr. T. Dale Stewart's travels.
AB - Renowned forensic physical anthropologist Dr. T. Dale Stewart traveled
extensively to countries all over the world. The reasons for his journeys were
manifold. He did fieldwork, took part in congresses, visited scientific
institutions, and lectured by invitation at various universities. This paper
deals with his journeys in general and with his four visits to Czechoslovakia in
particular. Three of them were undertaken in connection with scientific
congresses dedicated to Dr. Ales Hrdlicka. Dr. Stewart, as Hrdlicka's successor
in the Smithsonian Institution, always chose an appropriate topic for his
lecture. His visits to Hrdlicka's native country and town contributed to better
mutual understanding and exchange of ideas between physical anthropologists and
anatomists from both countries, the USA and Czechoslovakia (the today separate
Czech and Slovak Republics).
PMID- 10782947
TI - T. Dale Stewart's perspective on his career as a forensic anthropologist at the
Smithsonian.
AB - T. D. Stewart (1901-1997) is internationally recognized as an early leader in
forensic anthropology. In a series of taped interviews in 1975 and in 1986,
Stewart discusses his professional development. The interviews document his early
education in Delta, Pennsylvania, his long career at the Smithsonian Institution
in Washington, DC and aspects of his many contributions to forensic anthropology.
His well-known careful editorial work and exhaustive, problem-oriented research
approach may have been influenced by his early training in his hometown bank and
his many years of apprenticeship under Ales Hrdlicka (1869-1943). Stewart
describes aspects of the difficulties of working for Hrdlicka, yet credits the
work ethic established by him as a formative factor in his own prodigious
productivity.
PMID- 10782948
TI - Publications of T. Dale Stewart (1901-1997).
AB - T. D. Stewart (1901-1997) published at least 394 works between the years 1929 and
1992. These include 118 reviews, 40 abstracts, 227 articles or book chapters,
five edited volumes, and four books or monographs.
PMID- 10782946
TI - Archaeology, science and forensic anthropology: a tribute to Dr T. Dale Stewart.
AB - The name, T. Dale Stewart is synonymous with physical anthropology. To many
members of the physical anthropology section, particularly those born in the
latter half of this century, he is perhaps best known for his 1979 Essentials of
Forensic Anthropology. Without a doubt, much of the foundation of this discipline
rests upon his teachings and influence. Few knew him in the capacity that William
M. Bass did, as T. Dale Stewart was a member of Bass doctoral committee. Bass was
greatly influenced during the time he spent working with Dr. Stewart in the
1950's and the instruction and guidance Stewart instilled in Bass has and will
continue to be passed on to subsequent generations. Research was Dale Stewart's
main emphasis and he succeeded in demonstrating the value of investigation and
how results were crucial in explaining many of the processes manifest on skeletal
material. Clearly his hypothesis-based approach became essential to skeletal
biology and numerous procedures and methods employed in the field are synonymous
with the teachings of Dr. T. Dale Stewart. By reflecting on several recently
completed interdisciplinary research projects, the far-reaching impact of his
knowledge and instruction can be demonstrated.
PMID- 10782945
TI - T. Dale Stewart: remembrances of a scholar and colleague.
AB - T. Dale Stewart's contributions had a considerable influence on the development
and early evolution of the field of forensic anthropology. This composition
provides a perception of Stewart from the viewpoint of an advanced graduate
student and then a young colleague. It explains, in part, the quiet leadership
and assistance that Stewart provided at various professional and familiar levels
to one individual and is indicative of the broad effect that Stewart had on
generations of students and professionals in anthropology, osteology and forensic
anthropology.
PMID- 10782949
TI - Sex differences in proximal humeral outline shape: elliptical Fourier functions.
AB - A method is presented for the numerical analysis of sex differences in size and
shape of the proximal humeral outlines using elliptical Fourier functions (EFFs).
A skeletal sample consisting of right and left humeri pairs of 69 individuals, 36
males and 33 females, was used. The proximal superior view in the plane of the
proximo-distal axis of each humerus was photographed and then 54 boundary points
were located on the two-dimensional outline tracings. These points were digitized
and used to compute EFFs with 27 harmonics. From the EFFs, a set of expected
points on the proximal humeral outline was generated using the centroid as an
origin. Superimposition of the male and female outlines on this centroid provided
a detailed picture of the relative sex differences in size and shape with respect
to that center. The bounded area of the proximal humeral outline showed
statistically significant sex differences. Additionally, statistical results of
the amplitudes derived from the "area-standardized" EFFs and visual assessments
of the mean outline plots indicated significant sex differences in shape of the
proximal humeral outlines. Focusing on localized regional differences, the
greater tubercle was located more postero-medially and the lesser tubercle was
located more anteriorly in the males compared to the females. Sex determinations
from the proximal humeri were also examined with discriminant functions based on
the amplitudes, which represent shape characteristics of the outline, and the
hounded area. Using a cross-validation method, predictions of the percentages of
cases correctly classified with the discriminant functions were ranged from 92.8%
to 95.7% for the right and left humeral data. These results suggest that
differences in size and shape of the proximal humeral outlines may be better
predictors of sex when compared with conventional measurements of the humerus.
PMID- 10782950
TI - Age estimation by occlusal tooth wear.
AB - The purpose of the present investigation was to test the accuracy of a new
scoring system in recording tooth wear for age estimation. The material consisted
of dental stone casts of 383 volunteers who had sound premolars and molars with
normal occlusion. The degree of occlusal wear for all premolar and molar teeth
was scored with the new system. The high intra- and inter-examiner concordances
showed that the new score system was very reliable. The degree of tooth wear
showed a significant positive correlation with age in each and every examined
tooth of both males and females. Tooth wear scores of males were higher than
those of females. Calculating tables for age estimation were designed and the
accuracy of age estimation was obtained with the General Linear Models
procedures. Our system could provide estimation of an individual's age within +/
3 years in 42.4% of males and 49.4% of females, within +/-5 years in 61.8% of
males and 63.3% of females. When the subjects were divided into two age groups
and data were re-treated, the accuracy of age estimation was increased.
Collectively, it was shown that our new system for scoring tooth wear is a
reliable and accurate method for age estimation.
PMID- 10782951
TI - Secondary ion mass spectrometric characterization of nail polishes and paint
surfaces.
AB - A variety of paint and fingernail polish samples, which were visually similar,
but had different chemical compositions and formulations, was analyzed using
quadrupole static secondary ion mass spectrometry (SIMS). Coating distinction was
easily achieved in many cases because of the presence of dominant ions derived
from the components of the coating, which could be observed in the SIMS spectra.
In other instances, coating distinction was difficult within a product line
because of spectral complexity; for this reason and because of the large numbers
of spectra generated in this study, multivariate statistical techniques were
employed, which allowed the meaningful classification and comparison of spectra.
Partial Least Squares (PLS) and Principal Component Analysis (PCA) were applied
to quadrupole SIMS data. PCA showed distinct spectral differences between most
spectral groups, and also emphasized the reproducibility of the SIMS spectra.
When using PLS analysis, reasonably accurate coating identification was achieved
with the data. Overall, the PLS model is more than 90% effective in identifying
the spectrum of a particular coating, and nearly 100% effective at telling which
coating components represented in the PLS models are not present in a spectrum.
The level of spectral variation caused by sample bombardment in the SIMS analysis
was investigated using Fourier transform infrared spectroscopy (FT-IR) and
quadrupole static SIMS. Changes in the FT-IR spectra were observed and were most
likely a result of a number of factors involving the static SIMS analysis.
However, the bulk of the sample is unaltered and may be used for further testing.
PMID- 10782952
TI - Physical and chemical evidence remaining after the explosion of large improvised
bombs. Part 1: firings of ammonium nitrate/sugar and urea nitrate.
AB - Recent criminal acts in the United Kingdom, United States and other countries
have demonstrated the dangers to public safety from the criminal use of
improvised explosives on a large scale. Four sets of trials were carried out over
four years, partly in collaboration with the United States Federal Bureau of
Investigation, involving the firing of large bombs, mostly fertilizer based. The
principal objectives of the firings were to measure the physical effects of the
explosions upon objects representative of those that would be found at a real
bomb scene and to recover any chemical traces deposited on these objects. The
results are intended for use as an aid in determining the approximate size and
type of an explosive employed in a terrorist attack. This paper describes the
background behind the trials, the procedures for preparation of witness materials
and charges, and the collection and analysis of physical and chemical evidence.
PMID- 10782953
TI - Physical and chemical evidence remaining after the explosion of large improvised
bombs. Part 2: Firings of calcium ammonium nitrate/sugar mixtures.
AB - Six test firings of large improvised explosive devices were carried out. The
principal objectives of the firings were to measure the physical effects of the
explosions upon representative objects placed nearby and to recover any chemical
traces deposited on these objects. The results are intended for use as an aid in
determining the approximate size and type of an explosive employed in terrorist
attacks. Three 454 kg charges of a mixture of calcium ammonium nitrate (CAN)
fertilizer and sugar, and three 2268 kg charges of a similar mixture, all
confined in cylindrical steel containers were fired. Each charge was surrounded
by 19 road signs mounted on posts and four vehicles, to act as witness materials.
The analysis of aqueous swab extracts taken from the witness materials after
firing showed the recovery of nitrate, ammonium and low levels of glucose. No
sucrose was detected. Nitrate was usually recovered in greater quantities than
ammonium and recovery generally decreased with increasing distance from the
charges in any given direction. Quantities recovered from objects placed at the
same distance in different directions varied considerably. Patterns of physical
damage to the witness materials could be discerned according to their distance
from the charge and the size of the charge. The velocities of detonation and air
blast effects were measured.
PMID- 10782956
TI - The role of the dental hygienist in mass disasters.
AB - The authors examine the specialty of dental hygiene and address its role in the
identification of mass-disaster fatalities. Very little exists in the literature
on what dental hygienists can often and what they have contributed as members of
dental-identification teams. To encourage forensic dentists to seek out the
valuable assistance of these highly trained professionals, the authors illustrate
how their services can be used in mass disasters.
PMID- 10782955
TI - Fingerprint enhancement revisited and the effects of blood enhancement chemicals
on subsequent profiler Plus fluorescent short tandem repeat DNA analysis of fresh
and aged bloody fingerprints.
AB - This study was aimed at determining the effect of seven blood enhancement
reagents on the subsequent Profiler Plus fluorescent STR DNA analysis of fresh or
aged bloody fingerprints deposited on various porous and nonporous surfaces.
Amido Black, Crowle's Double Stain. 1,8-diazafluoren-9-one (DFO), Hungarian Red,
leucomalachite green, luminol and ninhydrin were tested on linoleum, glass,
metal, wood (pine, painted white), clothing (85% polyester/15% cotton, 65%
polyester/35% cotton, and blue denim) and paper (Scott 2-ply and Xerox-grade).
Preliminary experiments were designed to determine the optimal blood dilutions to
use to ensure a DNA typing result following chemical enhancement. A 1:200 blood
dilution deposited on linoleum and enhanced with Crowle's Double Stain generated
enough DNA for one to two rounds of Profiler Plus PCR amplification. A
comparative study of the DNA yields before and after treatment indicated that the
quantity of DNA recovered from bloody fingerprints following enhancement was
reduced by a factor of 2 to 12. Such a reduction in the DNA yields could
potentially compromise DNA typing analysis in the case of small stains. The blood
enhancement chemicals selected were also evaluated for their capability to reveal
bloodmarks on the various porous and nonporous surfaces chosen in this study.
Luminol. Amido Black and Crowle's Double Stain showed the highest sensitivity of
all seven chemicals tested and revealed highly diluted (1:200) bloody
fingerprints. Both luminol and Amido Black produced excellent results on both
porous and nonporous surfaces, but Crowle's Double Stain failed to produce any
results on porous substrates. Hungarian Red, DFO, leucomalachite green and
ninhydrin showed lower sensitivities. Enhancement of bloodmarks using any of the
chemicals selected, and short-term exposure to these same chemicals (i.e., less
than 54 days), had no adverse effects on the PCR amplification of the nine STR
systems surveyed (D3S 1358, HumvWA, HumFGA, D8S1179, D21S11, D18S51, D5S818,
D13S317, D7S820) or of the gender determination marker Amelogenin. The intensity
of the fluorescent signals was very similar and the allele size measurements
remained constant and identical to those of untreated bloody fingerprints. No
additional background fluorescence was noted. Continuous exposure (for 54 days)
to two of the seven enhancement chemicals selected (i.e., Crowle's Double Stain
and Hungarian Red) slightly reduced the amplification efficiency of the longer
STR loci in profiles of fresh and 7 to 14-day-old bloodprints. This suggests that
long-term exposure to these chemicals possibly affects the integrity of the DNA
molecules. This study indicates that significant evidence can be obtained from
fresh or aged bloody fingerprints applied to a variety of absorbent and
nonabsorbent surfaces which are exposed to different enhancement chemicals for
short or long periods of time. It also reaffirms that PCR STR DNA typing
procedures are robust and provide excellent results when used in concert with
fluorescence-based detection assays after fingerprint identification has taken
place.
PMID- 10782954
TI - The relationship between substance use, drug selling, and lethal violence in 25
juvenile murderers.
AB - The goal of the present study was to determine the relationship between substance
use, drug selling, and lethal violence in adolescent male homicide offenders and
their victims. The study employed a retrospective review of criminal justice
databases and medical examiner records for murders committed by 25 adolescent
males incarcerated in the Commonwealth of Virginia juvenile correctional centers
from February 1992 to July 1996. The perpetrator sample was 84% African American
and 16% white. The average age at the time of the offense was 15.0 years (range =
13.0 to 17.7 years). The victims were 84% male, 60% African American and 32%
white. The median victim age was 28.0 years (mean = 34.8, range = 17 months to 75
years). The results indicated that 52% of the murders were committed by juveniles
with identified involvement in drug selling, and 28% of the murders were drug
related. Toxicology results indicated recent drug or alcohol use in 27% of the
victims; while 74% of the perpetrators reported substance use, 35% indicating
daily use. Using discriminant analysis, it was possible to accurately classify
86% of the drug-related murders with the variables of recent victim drug use and
perpetrator substance use history. The results indicated that adolescent males
involved in the sale and distribution of illegal drugs comprised a significant
percentage of those incarcerated for murder. Recent victim drug use and
perpetrator substance use may be important variables in identifying drug-related
juvenile homicides. These results underscore the link between substance use, drug
selling, and lethal violence.
PMID- 10782957
TI - Clinical and forensic indicators of "suicide by cop".
AB - This paper reviews the literature pertaining to the phenomenon of "suicide by
cop"--any incident in which a suicidal individual attempts to get law enforcement
to kill him. This article defines the term "suicide by cop," discusses the
various motivations of individuals who engage in this type of behavior, presents
the risk factors and indicators for suicide and violence, and describes specific
indicators for suicide by cop. Proper recognition of these events, prior and
subsequent to their occurrence, has important implications for prevention,
officer safety, equivocal death analysis and psychological autopsy, civil
litigation, criminal justice proceedings, and community stability. This paper
presents seven case studies which demonstrate the clinical and forensic
indicators of this phenomenon.
PMID- 10782959
TI - A review of crane deaths in Jefferson County, Alabama.
AB - Cranes are machines used to move heavy objects. Cranes are operated by crane
operators, usually working in conjunction with an assistant guiding the movements
of the crane from his vantage point outside the crane. Few jurisdictions require
that crane operators be either licensed or certified. We conducted a
retrospective study of those dying of crane-related injuries in our jurisdiction
during the 16 years from 1981 to 1996. All ten decedents were male, and the
manner of each death was accidental. Neither ethanol nor drugs of abuse were
detected in any case. Eight of the ten decedents died due to blunt force
injuries, one due to mechanical asphyxia, and one due to thermal burns.
Investigation by the Occupational Safety and Health Administration (OSHA) led to
fines ranging from $80 to $2700 in six of the ten cases. Nationwide,
electrocution is the most common cause of crane-related death, but no crane
related death in Jefferson County was caused by electrocution in our study. The
absence of electrocutions was due to the planned, routine suspension of power to
electrical lines in the vicinity of a crane during the crane's operation, a
practice saving an estimated seven lives. Nevertheless, human error or lack of
planning was still responsible for most of the deaths in our study. In addition
to careful planning and adherence to safety standards established by planning, we
recommend the mandatory licensure and certification of professional crane
operators and the assessment of larger fines by OSHA for safety standard
violations.
PMID- 10782958
TI - Aging and homicide rates.
AB - There are no published studies concerning the effect of mortality rate on the
rate of homicide by habitually violent offenders. On the basis of nation-wide
statistics in Finland, the frequency of homicide is 61% lower among 50-year old
males than among 30-year old males. However, when the 4.9-fold mortality of
habitually violent offenders is taken into account, the homicide rate is only 43%
lower among 50-year old males than among 30-year old males. This is an important
issue in forensic psychiatry and that requires further attention, as age is used
a predictive factor when assessing the risk of violent behavior.
PMID- 10782960
TI - A 36-year history of fatal road rage in Marion County, Oregon: 1963-1998.
AB - This paper documents the 36-year history, with five examples, of fatal road rage
in Marion County, Oregon. Relevant details (all that were available) from each
case are presented. Alcohol intoxication was present in four of our five cases.
We include two deaths by gunshot at close range, two deaths as a result of a
motor vehicle traffic accident, and one natural death. All subjects were males.
Three were Caucasian and two were Hispanic. The three subjects in Cases 1, 2 and
3 were complete strangers to the occupants of the other involved vehicles. The
subjects in Cases 4 and 5 (along with the occupants of their own vehicles) were
acquaintances of the occupants of the involved vehicle. There appears to be no
previous forensic, medical or psychiatric literature on road rage as such. We
present an initial psychiatric evaluation of the perpetrators of this type of
fatal assault. There are no specific statutes in Oregon, at the state or county
levels, regarding road rage. However, the city of Gresham, Oregon, recently
enacted an ordinance regarding road rage. We stress the need for further study of
this phenomenon, especially through the use of the psychological-psychiatric
autopsy.
PMID- 10782961
TI - Hair analysis: self-reported use of "speed" and "ecstasy" compared with
laboratory findings.
AB - Drug use histories were collected from 100 subjects recruited from the "dance
scene" in and around Glasgow, Scotland. In addition, each subject donated a hair
sample which was analyzed by gas chromatography/mass spectrometry (GC/MS) for
amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), 3,4
methylenedioxymethamphetamine (MD MA) and 3,4-methylenedioxyethylamphetamine
(MDEA). The hair samples were analyzed in two 6 cm segments or in full, ranging
from 1.5 to 12 cm depending on the length of the hair. Approximately 10 mg of
hair was ground to a fine powder before treatment with beta-glucuronidase/aryl
sulfatase. A solid-phase extraction procedure was carried out followed by
derivatization with pentafluoropropionic anhydride (PFPA). All extracts were
analyzed by gas chromatography/mass spectrometry (GC/MS). Of the 139 segments
analyzed, 77 (52.5%) were positive for at least one of the five amphetamines. The
drug concentrations found in the hair were compared with the self-reported drug
histories. A concordance of greater than 50% was found between the self-report
data and levels detected in hair. However, no correlation was found between the
reported number of "ecstasy" tablets consumed and the drug levels detected in
hair. An increase in the average drug levels measured was observed from low to
high use (number of "ecstasy" tablets/month). A large number of false negatives
and a low number of false positives were observed.
PMID- 10782963
TI - Solid-phase extraction for profiling of ecstasy tablets.
AB - A solid-phase extraction (SPE) procedure has been developed for impurity
profiling of illicit tablets containing 3,4-methylenedioxy-N-methyl-amphetamine
(MDMA, ecstasy). Following initial comparison of liquid-liquid extraction and
solid-phase extraction, SPE was found to be preferable because it afforded higher
extraction efficiencies and shorter extraction times. Procedure blank samples
were also analyzed to identify constituents of the extracts which did not
originate in the ecstasy tablets. The developed procedure was subsequently
applied to 12 samples of seized ecstasy tablets and a comparison was made of
these samples to determine similarities and obtain inferences with respect to
commonality of origin.
PMID- 10782962
TI - Analysis of morphine by RIA and HPLC in fingernail clippings obtained from heroin
users.
AB - Heroin is abused around the world and is frequently reported as the cause of
death in overdose cases. Analysis of morphine in hair has been used in the past
in forensic toxicology to study the addiction history of heroin addicts. The
purpose of the present study was to evaluate the usefulness of the nail as an
analytical specimen in the identification and quantification of morphine in
fingernail clippings of known heroin users. Fingernail clippings were obtained
from 26 consenting patients of the Glasgow Drug Problem Service. At the time of
sampling, the participants provided answers to a questionnaire regarding their
drug use patterns. Samples were decontaminated by sonication in SDS, deionized
water and methanol, and the methanolic washes were screened for analyte presence.
The washed nail clippings were then hydrolyzed and extracted. RIA was used for
the screening and HPLC for the confirmation of morphine. Positive RIA results
were obtained with nail clippings from 25 of the 26 heroin users. The levels
ranged from 0.06 to 4.69 ng/mg with a mean morphine concentration of 1.67 ng/mg.
HPLC results were positive for 22 of the 26 nail samples. The mean morphine level
by HPLC was 2.11 ng/mg with a range from 0.14 to 6.90 ng/mg. Based on these
results, we suggest that nails have the potential of becoming a powerful
alternative to hair for the detection of past heroin use in forensic cases.
PMID- 10782965
TI - The FAA's postmortem forensic toxicology self-evaluated proficiency test program:
the first seven years.
AB - Existing proficiency-testing (PT) programs do not address the complexity of
postmortem forensic toxicology. These programs do not include decomposed samples
and solid tissues. Therefore, the Federal Aviation Administration in July 1991
started such a needed PT program. This program is used to: (i) professionally
develop and maintain technical currency on a voluntary, interlaboratory, and self
evaluation basis, and (ii) quantifiably assess methods in the absence and
presence of interfering substances. There are currently about 30 laboratories in
the program. Functioning under various governmental/non-governmental agencies and
academic institutions, these laboratories represent a broad cross-section of the
country. PT samples are distributed quarterly, and result summaries are sent to
the participants, while maintaining their anonymity. Since the inception of the
program, 28 PT samples encompassing whole blood, plasma, urine, kidney, or liver,
with (or without) drugs, metabolites, and common chemicals (nicotine, caffeine,
beta-phenylethylamine, etc.) have been analyzed by the participants. Analytical
findings were generally consistent with the anticipated values, but they were
dependent on the nature and conditions of the specimens and types of the added
analytes. Some incidences of false positives of concern were noted, as well. This
PT program is one of the few programs recommended by the American Board of
Forensic Toxicology in which laboratories may participate for their accreditation
by the Board. It is anticipated that this PT program will continue to play a
critical part in supporting the quality assurance/quality control (QA/QC)
component of forensic toxicology, thereby enhancing operational performance.
PMID- 10782964
TI - Olanzapine concentrations in clinical serum and postmortem blood specimens--when
does therapeutic become toxic?
AB - The concentration of olanzapine (Zyprexa) was determined in 1653 clinical serum
specimens during routine drug monitoring, and in 58 postmortem whole blood
specimens as part of routine toxicological analysis. The analysis of olanzapine
was performed by the solid-phase extraction of 1.0 mL of buffered serum or blood,
followed by gas chromatography separation with nitrogen-phosphorus detection. The
analysis of the clinical serum samples showed that 86% of positive serum values
were within the range of 5 to 75 ng/mL, with a mean and median of 36 and 26
ng/mL, respectively. These data suggest that the concentrations of olanzapine
expected during therapy may be higher than those previously reported. In 58
postmortem whole blood specimens the mean olanzapine concentration was 358 ng/mL
with a range of 10 to 5200 ng/mL. Further, investigation of deaths involving
olanzapine suggest that potential toxicity should be considered at concentrations
above 100 ng/mL. Although the majority of the olanzapine-related deaths were
associated with many other drugs, death primarily due to olanzapine toxicity was
determined at concentrations in post-mortem blood as low as 160 ng/mL.
PMID- 10782966
TI - Population frequency for the short tandem repeat loci D18S849, D3S1744, and
D12S1090 in Caucasian-Mestizo and African descent populations of Colombia.
AB - Blood samples from 489 unrelated Caucasian Mestizo and 252 individuals of African
descent in Colombia were amplified and typed for three short tandem repeat (STR)
markers (D12S1090, D3S1744, and D18S849). All markers conformed to Hardy-Weinberg
equilibrium expectations in both populations studied. In addition,
heterozygosity, mean exclusion chance, polymorphism information content,
discrimination power, and the assumption of independence within and between loci
were determined. The mean exclusion chance for all three STR markers is 0.9750 in
the Caucasian Mestizo population and 0.9731 in the African Colombian Population.
The discrimination power is 0.999925 and 0.999911 in the Caucasian Mestizo and
African Colombian respectively.
PMID- 10782968
TI - Swiss allele frequencies and haplotypes of 7 Y-specific STRs.
AB - In view of application to personal identification and paternal analysis, the
allele distribution of the loci DYS 19, DYS389 I and II, DYS390, DYS391, DYS392,
and DYS393 were determined in a sample of 126 unrelated males from the area of
Bern (Switzerland). The 7 Y-STR loci were coamplified in a total of two multiplex
reactions using fluorescently-labeled primers. PCR products were separated and
detected on a capillary electrophoresis ABI Prism 310 instrument. All loci were
polymorphic and the allele distributions are similar to other caucasian data.
PMID- 10782967
TI - Population genetics of nine STR loci in two populations from Brazil.
AB - The Short Tandem Repeats (STRs) D3S1358, HUMvWA31/A, HUMFIBRA/FGA, D8S 1179,
D2S11, D18S51, D5S818, D13S317, and D7S820 were studied in two Brazilian
populations (from Amazonia and S. Paulo) using the "AmpF1 STR Profiler Plus PCR
Amplification Kit." The nine loci showed a combined discrimination power greater
than 0.9999999999 and a chance of exclusion of 0.9999.
PMID- 10782969
TI - The distribution of D1S80 and VWA alleles in a Karen population from Northern
Thailand.
AB - The DIS80 and VWA loci were studied in a Karen population from Northern Thailand
by the polymerase chain reaction and polyacrylamide gel electrophoresis. Twelve
DIS80 and six VWA alleles were found. No deviations from the Hardy-Weinberg and
linkage equilibrium were observed. The power of exclusion (PE) from the analysis
of the DIS80 and VWA locus is 0.67 and 0.45, respectively, the power of
discrimination (PD) is 0.95 and 0.85, respectively, with a combined PD of 0.99
and PE of 0.82.
PMID- 10782970
TI - Population genetics of the D1S1656, D12S391, and D18S535 loci in Asturias (North
Spain).
AB - Allele and genotype frequencies for three recently described short tandem repeat
loci D1S1656, D12S391, and D18S535 were determined in a population sample from
Asturias (North Spain). The loci were amplified using a fluorescence based PCR
method and were typed automatically. No deviation from Hardy-Weinberg
expectations were observed. The three loci proved to be highly discriminating and
the allele frequencies observed are similar to those of the other European
populations that have been typed for these loci to date.
PMID- 10782971
TI - Threat mail and forensic science: DNA profiling from items of evidence after
treatment with DFO.
AB - Two cases of threatening letters with their accompanying envelopes were received
to the Division of Forensic Identification unit of the Israel Police. The
envelopes, including the stamps, and the letters were initially examined for
latent fingerprints by the DFO reagent, known to cause degradation of DNA.
Although no latent fingerprints could be visualized on any of the items, the
biology laboratory using organic DNA extraction, was successful in defining
genetic profiles from all the items employing six STR loci, even after treatment
with DFO. In a controlled experiment, a known donor attached a stamp, by licking,
to an envelope. This item was treated with DFO and then profiled using STR loci.
The results showed that previous DFO treatment on the control stamp before DNA
analysis had no negative effects on obtaining the DNA profile of the known donor
using STR loci.
PMID- 10782972
TI - Analysis of primer residue from lead free ammunition by X-ray microfluorescence.
AB - In forensic science, the analysis of gunshot residues was traditionally done by
the detection of lead (Pb), antimony (Sb) and barium (Ba) usually found in a
primer. However, the recent development of lead-free ammunition represents a new
challenge for ballistic specialists. This analysis study gunshot residues from
primers and ammunitions in the area surrounding bullet holes, a very important
tool to determine the shooting distance. The ammunitions used were 9 mm Luger and
.38 spl + p calibers, where lead in the primer was replaced with strontium (Sr)
and where the lead bullet was plated with copper (Total Metal Jacket). Gunshot
analysis results were obtained using an energy dispersive X-ray microfluorescence
spectrometer. The method allows the detection and quantification of strontium
residues on the target up to a distance of 45 cm.
PMID- 10782973
TI - The detection and analysis of ignitable liquid residues extracted from human skin
using SPME/GC.
AB - A simple, fast, inexpensive, and sensitive technique for the detection and
identification of flammable or combustible liquid residues on the skin of arson
suspects is presented. The use of solid phase microextraction (SPME) for the
analysis of ignitable liquid residues has been demonstrated and it is shown in
this work that this technique is effective in extracting these liquid residues at
extremely low quantities. Microliter quantities of controlled spikes of gasoline,
diesel fuel, and charcoal lighter fluid were deposited on the hands of a
volunteer and extracted after several time intervals. The SPME technique can
recover very small amounts of liquid deposits on skin up to 3.5 h after exposure,
depending on the class of the ignitable liquid residue used.
PMID- 10782974
TI - Sex variation in the second cervical vertebra.
AB - The second cervical vertebra can be used to estimate sex with 83% accuracy in
unidentified human skeletal remains. Reported here are the necessary statistics,
based on 8 dimensions taken from 400 second cervical vertebrae, for the
computation of customized discriminant functions. Discriminant function equations
developed using variables selected in a stepwise procedure are also presented
here as an example of the usefulness of this bone in estimating sex.
PMID- 10782975
TI - Use of radiographic atlases in a mass fatality.
AB - In May and June of 1996, a forensic anthropology team from the C.A. Pound Human
Identification Laboratory at the University of Florida identified 9 of 10
juveniles from the crash of ValuJet 592. The team relied primarily on a
radiographic atlas developed and used by clinical practitioners to determine
skeletal age. Postmortem radiographs of the juvenile victims were compared with
radiographic standards to determine skeletal age. Skeletal age was then compared
to a passenger list indicating the sex, weight, height, and chronological age of
each individual. Tentative identifications based on the atlas method were
organized into an exclusion matrix. Final identifications were based on this
assessment in conjunction with other anthropological data such as appearance and
fusion of ossification centers and estimation of stature.
PMID- 10782976
TI - The chain saw: an uncommon means of committing suicide.
AB - A suicide committed with a power saw is an uncommonly reported incident: and the
use of a chain saw in particular has been extremely rare. We report two cases of
suicide that were committed by using chain saws. In each case the victim had a
history of depression or of a prior suicide attempt, and applied the chain saw to
his neck to kill himself. We summarize the findings of the two death
investigations and the world literature pertaining to suicide committed with
power saws.
PMID- 10782977
TI - A fatal case of chlorate poisoning: confirmation by ion chromatography of body
fluids.
AB - A 49-year-old male chemical industry worker was admitted to intensive care with a
24-hour history of respiratory failure, vomiting, headache, stupor, arterial
hypotension, and cyanosed face and limbs. He had acute haemolysis (3.9 g/L plasma
haemoglobin concentration) and 30% methaemoglobinaemia. Whereas the search for
alcohol, barbiturates and opiates was negative, benzodiazepines and tricyclic
antidepressants were present. The patient was in fact being treated with
fluvoxamine, amitryptiline, and alprazolam. As the clinical and biological signs
suggested chlorate poisoning, chlorate was looked for by using an aniline color
reaction. It was found in gastric content and urine. Treatment consisted in
mechanical ventilation, vasoactive amines, methylene blue, plasma exchange,
exchange transfusion, and haemodialysis. Despite this, the patient had several
cardiac arrests and refractory metabolic acidosis. He died 12 h after his
admission. Specific ion chromatography was used afterhand to assay the chlorate
in various body fluids. The technique was based on a separation on an ion
exchange Dionex AS 12A column coupled with conductivity detection. A quantitative
estimation was carried out by using external calibration with a four-point
calibration curve which was linear between 1 and 15 mg/L. The measured plasma
levels of chlorate were 78 and 29 mg/L respectively before and after exchange
transfusion. Gastric-lavage liquid contained 1300 mg/L of chlorate and urine 4300
mg/L. Ion chromatography, which is routinely used in environmental studies helped
to confirm a massive oral intake of chlorate by measuring the corresponding blood
and urine chlorate concentrations, data which had only rarely been reported
previously.
PMID- 10782979
TI - Keyhole defect production in tubular bone.
AB - Fracture characteristics, reported primarily for the cranium, are valuable
indicators of bullet direction. A bullet striking the vault tangentially produces
an irregular opening, termed a "keyhole defect." with the circular portion of the
defect being the initial point of impact. Identifying this feature in tubular
bone (long bone) can also demonstrate bullet direction and the position of the
bone at the time of the shooting. This case study involving a tangential shot
(i.e., a keyhole fracture) to the humerus demonstrates some of the same fracture
mechanics seen in the cranium.
PMID- 10782978
TI - Fatal aspiration of sardine fry in a patient with lung cancer.
AB - We report a fatal case of death due to unusual aspiration of sardine fry in an
elderly Japanese man with lung cancer. The cause of death was sudden respiratory
arrest while eating. Autopsy revealed peculiar materials with cell nests and
pigmented particles, together with striated muscle and skin, in the ectatic
bronchioles of the left lower lobe. Serial histologic sections suggested that the
structures observed were the eyeballs of small animals that appeared to have been
inhaled. The patient had habitually eaten sardine fry and rice gruel, which were
also detected in the gastric contents. Therefore, the eyes were considered to be
those of the fry, which is a popular food item in Japan. This was confirmed by
histologic examination of fry that were obtained commercially.
PMID- 10782980
TI - The postmortem fate of Pat Gregory: a disinterred Native American.
AB - In late June 1990, the Mono County Sheriffs Department in Bridgeport, CA
contacted the Physical Anthropology Human Identification Laboratory (PAHIL) at
California State University, Chico to seek assistance in the identification of a
recently discovered skull. To assist with possible identification, the cranium
received a classic physical anthropological/morphological analysis to suggest the
decedent's sex, age at death, ancestral affiliation, and uniqueness. It was
concluded the cranium was that of an older male, and someone with mixed ancestry,
probably Native American/White. Suggested uniquenesses were an eroded and greasy
texture, with adhering white sand, evidence of healed antemortem nasal fractures,
and a bifid left occipital condyle. The cranium was confiscated from a man
suspected of vandalizing a Native American cemetery just south of the community
of Lee Vining. The cemetery was established in the mid-1800's by local Native
American tribes. Although ownership of the land was disputed by the US Forest
Service (the Inyo National Forest), and the Los Angeles Department of Water and
Power (LADWP), county authorities claimed that because the incident involved the
desecration of a cemetery and human remains, it was a legal issue, and therefore,
the Sheriff's Department had jurisdiction over the case if not the land. The
suspect pled guilty to the possession of Native American remains but claimed not
to have desecrated a grave. Over the next year and a half, members of the Native
American community representing various tribes sought the return of the cranium,
while also seeking assurance that it belonged to the vandalized grave. While
county, US Forest Service, and LADWP officials continued to argue over whom had
jurisdiction of the remains the superior court judge ordered the county to pay
for any analysis necessary to determine if the cranium belonged to the decedent
in question. This report addresses the conclusions of that analysis and the
disposition of the case. Furthermore, the report addresses the forensic value to
Native Americans of the continued study of a wide variety of human skeletal
remains.
PMID- 10782981
TI - The use of microscopic postmortem changes in anagen hair roots to associate
questioned hairs with known hairs and reconstruct events in two murder cases.
AB - In two cases investigated by the New Orleans Police Department Crime Lab, hairs
recovered from crime scenes were found to exhibit microscopic postmortem changes
in anagen hair roots. These microscopic characteristics were used to associate
these hairs with various victims in the cases. In addition to associating
questioned hairs with known hairs, the fact that the victims were dead when the
hairs were pulled helped investigators reconstruct events in both crimes and
corroborate statements made by the arrested subjects in each case.
PMID- 10782982
TI - Signature murders: a report of the 1984 Cranbrook, British Columbia cases.
AB - Two females, Denean Worms and Brenda Hughes, were murdered in separate events in
Cranbrook, British Columbia in 1984 within three months of each other. Terrence
Wayne Burlingham was found guilty of both murders and he appealed. The Supreme
Court of Canada granted Burlingham a new trial in the Worms case, but no evidence
from Burlingham's confession nor the murder weapon could be used. The Crown
counsel requested an evaluation of the two murders to determine if they were
committed by the same person. The analyses of those murders revealed that they
were linked by a personal "signature" of the killer. The murder cases reported
here demonstrate a control-oriented signature. The killer used a .410 shotgun as
his method of control and death, engaged in overkill of each victim by shooting
them twice in the head, and left the victims in sexually degrading positions.
Another signature feature was the absence of typical wounds to the victims which
would be expected from a serial sex offender. All of these characteristics, in
combination, accounted for this killer's personal expression.
PMID- 10782983
TI - Han Chinese population data in Chongqing China for nine STR loci.
PMID- 10782984
TI - Increasing the identification potential from human foot remains.
PMID- 10782986
TI - Commentary on Wu AHB, Hill DW, Crouch D, Hodnett CN, McCurdy HH. Minimal
standards for the performance and interpretation of toxicology tests in legal
proceedings. J Forensic Sci 1999;44(3):516-522.
PMID- 10782987
TI - Commentary on Keto RO. Analysis and comparison of bullet leads by inductively
coupled plasma mass spectrometry. J Forensic Sci 1999;44(5):1020-6.
PMID- 10782985
TI - Practical implications of charge transport model for electrostatic detection
apparatus (ESDA).
PMID- 10782988
TI - Verbal conventions for handwriting opinions.
PMID- 10782989
TI - Interaction of E. coli single-stranded DNA binding protein (SSB) with exonuclease
I. The carboxy-terminus of SSB is the recognition site for the nuclease.
AB - The 3'-5' single-stranded DNA(ssDNA) degrading exonuclease I of E. coli directly
interacts with the E. coli ssDNA binding protein (EcoSSB). Analytical
ultracentrifugation shows that all 4 carboxy-termini of an EcoSSB tetramer bind
exonuclease I. Binding is weakened by increasing salt concentrations, indicating
the involvement of the negatively charged amino acids of the carboxy-terminus of
SSB. Mutant SSB proteins EcoSSBP176S (ssb-113) and EcoSSBF177C do not
bindtoexonuclease I while EcoSSBG15D (ssb-3) does bind. In a co-precipitation
assay we show that the absence of the lastten amino acids (PMDFDDDIPF) completely
abolishes binding of EcoSSB to exonuclease I. The interaction does not depend on
the presence of the correct amino-terminal DNA binding domain or the amino acid
sequences between the DNA binding domain and the last ten amino acids. A
synthetic peptide (WMDFDDDIPF), corresponding to the last nine amino acids of
EcoSSB, specifically inhibits the interaction. Both EcoSSBP176S and EcoSSBF177C
SSBs bind DNA similar to wild-type EcoSSB, indicating that the phenotype of ssb
113 is not an indication of altered DNA binding. The repair deficiency of either
ssb-3 or ssb-113 strain can be complemented by overexpression of the respective
other mutant.
PMID- 10782990
TI - p38/SAPK2-dependent gene expression in Jurkat T cells.
AB - The stress-activated protein kinase p38/SAPK2 is known to regulate the activity
of transcription factors and to control expression of several genes at the
transcriptional or post-transcriptional level. In order to identify genes whose
expression is under the control of p38/SAPK2 activity, we have compared the mRNA
levels of a pattern of 588 genes between human Jurkat T cells with anisomycin
activated p38/SAPK2 and cells in which p38/SAPK2 was inhibited by the compound
SB203580. Genes strongly expressed at the transcript level as a result of
p38/SAPK2 activation are the transcription factors c-jun, fos-related antigen 1
(fra-1), the growth-arrest and DNA-damage gene gadd153 and early-growth-related
gene 1 (egr-1) as well as the c-srk kinase csk and the nucleotide exchange factor
ras-GRF. mRNAs significantly down-regulated include the insulin receptor IR, the
adapter grb2, the transcription factor c-myc and the defender against apoptotic
death, dad-1. For six selected genes, p38/SAPK2-regulated expression was
confirmed and further analysed by Northern blot experiments, demonstrating a
complex regulation of these genes under stress conditions.
PMID- 10782993
TI - Structural investigations of the highly flexible recombinant ribosomal protein
L12 from Thermotoga maritima.
AB - Ribosomal protein L7/L12, the only multicopy component of the ribosome, is
involved in translation factor binding and in the ribosomal GTPase center. The
gene for L7/L12 from Thermotoga maritima was cloned and the protein expressed at
high levels in Escherichia coli. Purification of L7/L12 was achieved under non
denaturing conditions via heat treatment and two chromatographic steps. Circular
dichroism melting profiles were monitored at 222 nm, showing the melting
temperature of the protein at pH 7.5 around 110 degrees C, compared to
approximately 60 degrees C for the highly homologous Escherichia coli protein.
The unfolding was reversible and renaturation closely followed the path of the
thermal melting. Dynamic light scattering, gel filtration chromatography, and
crosslinking experiments suggested that under physiological buffer conditions
Thermotoga maritima L7/L12 exists as a tetramer. The protein was crystallized
under two conditions, yielding an orthorhombic (C222(1)) and a cubic (12(1)3)
space group with an estimated two and three to four L7/L12 molecules per
asymmetric unit, respectively. The crystals contained the full-length protein,
and cryogenic buffers were developed which improved the mosaic spreads and the
resolution limits. For the structure solution isoleucine was mutated to
methionine at two separate positions, the mutant forms expressed as
selenomethionine variants and crystallized.
PMID- 10782991
TI - The first laminin G-type domain in the SHBG-like region of protein S contains
residues essential for activation of the receptor tyrosine kinase sky.
AB - Vitamin K-dependent protein S and the product of growth-arrest-specific gene 6
(Gas6) both possess the ability to phosphorylate members of the Axl/Sky subfamily
of receptor tyrosine kinases. However, Gas6 appears to be the bona fide ligand
for these receptors in man, as human protein S has been demonstrated to activate
murine Sky but not the human orthologue. In contrast, bovine protein S is able to
stimulate human Sky despite its high degree of sequence identity with human
protein S. The domain organisations of protein S and Gas6 are virtually identical
and the C-terminal SHBG-like region, containing two globular (G) domains, has
been shown to play a crucial role in the receptor stimulation. In order to
further localise the area responsible for the interaction, a number of protein
chimeras were used to stimulate human Sky. Each chimera had one part of the human
protein S SHBG-like region replaced by the corresponding part of bovine protein S
or human Gas6. We found that human protein S may indeed activate human Sky but
only above physiological plasma concentrations. The human-bovine protein S
chimeras provided new information implying that the first G domain contains
critical residues for the interaction with the Sky receptor. Moreover, these
residues do not seem to be clustered but rather to be distributed at various
positions in the first G domain.
PMID- 10782996
TI - Stability of bacteriophage T4 short tail fiber.
AB - Adsorption of T-even bacteriophages to the E. coli host cell is mediated by long
and short tail fibers. Bacteriophage T4 short tail fiber protein p12 was used to
investigate the stability against thermal and chemical denaturation. Purified p12
is thermostable with a melting point of 78 degrees C. Guanidinium chloride
induced denaturation displayed strong hysteresis and an intermediate between 2
and 3 M denaturant. The transitions occur at 1.5 and 3.2 M denaturant as revealed
by fluorescence spectroscopy and circular dichroism. The data suggest an
equilibrium unfolding intermediate with a separate unfolding of the C-terminal
knob domain and the shaft region.
PMID- 10782994
TI - Polyhistidine-tagged hepatitis B core particles as carriers of HIV-1/gp120
epitopes of different HIV-1 subtypes.
AB - The hepatitis B core antigen is a widely accepted carrier particle to enhance the
immunogenicity of foreign epitopes. From electron cryomicroscopy, the
immunodominant region between amino acid positions 79 to 81 is known to protrude
from the surface of the shells. It can be replaced by heterologous sequences
without interfering with the particle-forming capacity in many cases. Here we
have introduced various V3 sequences of the envelope protein of different
subtypes (A, B, O) of HIV-1/gp120 in order to enhance their immunogenicity and
broaden the immune response against the virus. To improve purification efficiency
and solubility of the E. coli-expressed hybrids, six histidine residues were
fused to amino acid 156. An adjustable purification scheme was utilised including
denaturation, Ni(2+)-NTA affinity chromatography and particle renaturation under
high salt conditions, resulting in highly pure antigen preparations. The hybrids
reacted specifically with sera of HIV-1-infected patients. They further induced
an autologous, subtype-specific anti-HIV-1 antibody response superior to that of
Keyhole limpet-haemocyanine-coupled peptides.
PMID- 10782992
TI - Permutation of the active site motif of tryparedoxin 2.
AB - Tryparedoxins (TXN) are thioredoxin-related proteins which, as
trypanothione:peroxiredoxin oxidoreductases, constitute the trypanothione
dependent antioxidant defense and may also serve as substrates for ribonucleotide
reductase in trypanosomatids. The active site motif of TXN2, 40WCPPCR45, of
Crithidia fasciculata was mutated by site-directed mutagenesis and eight
corresponding muteins were expressed in E. coli as terminally His-tagged
proteins, purified to homogeneity by nickel chelate chromatography, and
characterized in terms of specific activity, specificity and, if possible,
kinetics. Exchange of Cys41 and Cys44 by serine yielded inactive products
confirming their presumed involvement in catalysis. Exchange of Arg45 by
aspartate resulted in loss of activity, suggesting an activation of active site
cysteines by the positive charge of Arg45. Substitution of Trp40 by phenylalanine
or tyrosine resulted in moderate decrease of specific activity, as did exchange
of Pro42 by glycine. Kinetic analysis of these three muteins revealed that
primarilythe reaction with trypanothione is affected by the mutations. Simulation
of thioredoxin or glutaredoxin-like active sites in TXN2 (P42G and W40T/P43Y,
respectively) did not result in thioredoxin or glutaredoxin-like activities.
These data underscore that TXNs, although belonging to the thioredoxin
superfamily, represent a group of enzymes distinct from thioredoxins and
glutaredoxins in terms of specificity, and appear attractive as molecular targets
for the design of trypanocidal compounds.
PMID- 10782995
TI - 'In vitro evolution' of ligands for HCV-specific serum antibodies.
AB - We developed a strategy to improve the properties of ligands selected from phage
displayed random peptide libraries. A site-directed mutagenesis protocol that
introduces mutations and extends the size of a target sequence has been set up to
generate diversity in a single or in a population of clones. The pool of mutants
thus created is screened to identify variants with the desired properties. We
refer to this strategy as in vitro evolution' of ligands. Here we report the
application of this in vitro evolution protocol to the identification of improved
ligands for HCV-specific serum antibodies. A single clone or population of clones
were processed to generate a secondary library. Screening of these libraries with
sera from HCV-infected patients identified peptides with an enhanced and
broadened ability to detect HCV-specific serum antibodies.
PMID- 10782997
TI - Analysis of the RNase T1 mediated cleavage of an immobilized gapped heteroduplex
via fluorescence correlation spectroscopy.
AB - We report a new method for studying the activity of hydrolytic enzymes.
Fluorescence correlation spectroscopy was used to observe online the
hydrolyzation of a rhodamine B-labeled substrate by ribonuclease T1. A gapped
heteroduplex substrate - a hybrid of a ribooligonucleotide and two smaller
complementary deoxyribooligonucleotides - was immobilized via biotin to a
streptavidin-coated surface of a coverslip. The reported method opens the
possibility to study the cleavage of small substrates differing only slightly in
molecular weight from the enzyme reaction product. The use of fluorescence
correlation spectroscopy allows the detection of very low enzyme concentrations
(down to 10(-21) mol 0.05 fM of RNase T1, corresponding to about 600 RNase T1
molecules in 0.02 ml).
PMID- 10782998
TI - Binding of selenoprotein P to heparin: characterization with surface plasmon
resonance.
AB - The binding of selenoprotein P to glycosaminoglycans using heparin as a model
compound was studied by surface plasmon resonance. It was found that heparin
contains two binding sites for selenoprotein P, a high-affinity, low-capacity
site (Kd approximately 1 nM) and a low-affinity, high-capacity site (Kd
approximately 140 nM). Binding at both sites is sensitive to pH and ionic
strength, and the high-affinity site is abolished by histidine carbethoxylation
with diethylpyrocarbonate. The pH and salt dependence of binding suggests
electrostatic interactions with heparin. The concentrations of selenoprotein P in
plasma (approximately 50 nM) are sufficiently high to facilitate binding of
selenoprotein P to proteoglycans on the vascular endothelium, and this may
contribute to the formation of a protective barrier against oxidants such as
peroxynitrite or hydroperoxides.
PMID- 10782999
TI - Biotin-avidin microplate assay for the quantitative analysis of enzymatic
methylation of DNA by DNA methyltransferases.
AB - An assay is described to measure methylation of biotinylated oligonucleotide
substrates by DNA methyltransferases using [methyl-3H]-AdoMet. After the
methylation reaction the oligonucleotides are immobilized on an avidin-coated
microplate. The incorporation of [3H] into the DNA is quenched by addition of
unlabeled AdoMet to the binding buffer. Unreacted AdoMet and enzyme are removed
by washing. To release the radioactivity incorporated into the DNA, the wells are
incubated with a non-specific endonuclease and the radioactivity determined by
liquid scintillation counting. As an example, we have studied methylation of DNA
by the EcoRV DNA methyltransferase. The reaction progress curves measured with
this assay are linear with respect to time. Methylation rates linearly increase
with enzyme concentration. The rates are comparable to results obtained with the
same enzyme using a different assay. The biotin-avidin assay is inexpensive,
convenient, quantitative, fast and well suited to process many samples in
parallel. The accuracy of the assay is high, allowing to reproduce results within
+/- 10%. The assay is very sensitive as demonstrated by the detection of
incorporation of 0.8 fmol methyl groups into the DNA. Under the experimental
conditions, this corresponds to methylation of only 0.03% of all target sites of
the substrate. Using this assay, the DNA methylation activity of some M.EcoRV
variants could be detected that was not visible by other in vitro methylation
assays.
PMID- 10783000
TI - Biochemical modifications and transcriptional alterations attendant to sterol
feeding in Phytophthora parasitica.
AB - Phytophthora species are eukaryotic sterol auxotrophs that possess the ability to
grow, albeit poorly, in the complete absence of sterols. Growth of Phytophthora
is often improved substantially when an exogenous source of sterol is provided.
Additionally, sterols may be required for sexual and asexual sporulation in
Phytophthora. Our research has been focused on identifying and characterizing the
immediate physiological effects following sterol addition to cultures of P.
parasitica. Through gas chromatographic analysis of extracts from P. parasitica
cultures that were fed various sterols, we have obtained evidence for sterol C5
desaturase and delta7 reductase activities in this organism. Zoo blots were
probed with DNA sequences encoding these enzymes, from Saccharomyces cerevisiae
and Arabidopsis thaliana. Hybridization of a S. cerevisiae ERG3 probe to P.
parasitica DNA was observed, implicating sequence similarity between the sterol
C5 desaturase encoding genes. Differential display experiments, using RNA from P.
parasitica, have demonstrated a pattern of altered gene expression between
cultures grown in the presence and absence of sitosterol. Characterization of
sterol-related metabolic effects and sterol functions in Phytophthora should lead
to improved measures for control of this important group of plant pathogens.
PMID- 10783001
TI - Cloning and characterization of the Dictyostelium discoideum cycloartenol
synthase cDNA.
AB - Cycloartenol synthase converts oxidosqualene to cycloartenol, the first
carbocyclic intermediate en route to sterols in plants and many protists.
Presented here is the first cycloartenol synthase gene identified from a protist,
the cellular slime mold Dictyostelium discoideum. The cDNA encodes an 81-kDa
predicted protein 50-52% identical to known higher plant cycloartenol synthases
and 40-49% identical to known lanosterol synthases from fungi and mammals. The
encoded protein expressed in transgenic Saccharomyces cerevisiae converted
synthetic oxidosqualene to cycloartenol in vitro. This product was characterized
by 1H and 13C nuclear magnetic resonance and gas chromatography-mass
spectrometry. The predicted protein sequence diverges sufficiently from the known
cycloartenol synthase sequences to dramatically reduce the number of residues
that are candidates for the catalytic difference between cycloartenol and
lanosterol formation.
PMID- 10783002
TI - Cloning and sequencing of the Candida albicans C-4 sterol methyl oxidase gene
(ERG25) and expression of an ERG25 conditional lethal mutation in Saccharomyces
cerevisiae.
AB - The ERG25 gene encoding the Candida albicans C-4 sterol methyl oxidase was cloned
and sequenced by complementing a Saccharomyces cerevisiae erg25 mutant with a C.
albicans genomic library. The Erg25p is comprised of 308 amino acids and shows 65
and 38% homology to the enzymes from S. cerevisiae and Homo sapiens,
respectively. The protein contains three histidine clusters common to nonheme
iron-binding enzymes and an endoplasmic reticulum retrieval signal as do the
proteins from S. cerevisiae and humans. A temperature-sensitive (ts) conditional
lethal mutation of the C. albicans ERG25 was isolated and expressed in S.
cerevisiae. Sequence analysis of the ts mutant indicated an amino acid
substitution within the region of the protein encompassed by the histidine
clusters involved in iron binding. Results indicate that plasmid-borne
conditional lethal mutants of target genes have potential use in the rescue of
Candida mutations in genes that are essential for viability.
PMID- 10783003
TI - Plant sterol-C24-methyl transferases: different profiles of tobacco transformed
with SMT1 or SMT2.
AB - Higher plant cells contain a mixture of 24-desmethyl, 24-methyl(ene), and 24
ethyl(idene) sterols in given proportions according to species but also to cell
type. As a first step to investigate the function of such sterol compositions in
the physiology of a plant, we have illustrated in the present work the
coexistence of two distinct (S)-adenosyl-L-methionine sterol-C24
methyltransferases (SMT) in transgenic Nicotiana tabacum L. Indeed, modulation of
the expression of the tobacco gene SMT1-1, which encodes a cycloartenol-C24
methyltransferase, results in variations of the proportion of cycloartenol and a
concomitant effect on the proportion of 24-ethyl sterols. Overexpression in
tobacco of the Arabidopsis thaliana (L.) Heynh. gene SMT2-1 which encodes a 24
methylene lophenol-C24(1)-methyltransferase, results in a dramatic modification
of the ratio of 24-methyl cholesterol to sitosterol associated with a reduced
growth, a topic discussed in the present work.
PMID- 10783004
TI - Design and synthesis of new steroidal inhibitors of estrogen synthase
(aromatase).
AB - The estrogen synthase (aromatase) enzyme system is responsible for the
biosynthesis of estrogen hormones in human females. Estrogens are vital for
normal growth and development, but will promote the growth of certain breast
cancers. Approximately 30-50% of breast cancers are considered to be hormone
dependent. Consequently regulation of estrogen biosynthesis has advanced as a
potential therapeutic strategy. This has led to the development of active-site
inhibitors, which may have potential for the control of breast cancer. We have
recently prepared a number of new steroidal inhibitors that have been evaluated
as aromatase inhibitors. These include steroidal A/B-ring isoxazoles and a series
of A/B-ring pyrazoles with alkyl- and aryl-substituted nitrogen. In addition, we
have developed new chemical procedures for the synthesis of 6beta-hydroxy
steroids, which could be key intermediates in the preparation of C-19 inhibitors
of aromatase activity.
PMID- 10783005
TI - Biosynthesis of sterols and ecdysteroids in Ajuga hairy roots.
AB - Hairy roots of Ajuga reptans var. atropurpurea produce clerosterol, 22
dehydroclerosterol, and cholesterol as sterol constituents, and 20
hydroxyecdysone, cyasterone, isocyasterone, and 29-norcyasterone as ecdysteroid
constituents. To better understand the biosynthesis of these steroidal compounds,
we carried out feeding studies of variously 2H- and 13C-labeled sterol substrates
with Ajuga hairy roots. In this article, we review our studies in this field.
Feeding of labeled desmosterols, 24-methylenecholesterol, and 13C2-acetate
established the mechanism of the biosynthesis of the two C29-sterols and a newly
accumulated codisterol, including the metabolic correlation of C-26 and C-27
methyl groups. In Ajuga hairy roots, 3alpha-, 4alpha-, and 4beta-hydrogens of
cholesterol were all retained at their original positions after conversion into
20-hydroxyecdysone, in contrast to the observations in a fern and an insect.
Furthermore, the origin of 5beta-H of 20-hydroxyecdysone was found to be C-6
hydrogen of cholesterol exclusively, which is inconsistent with the results in
the fern and the insect. These data strongly support the intermediacy of 7
dehydrocholesterol 5alpha,6alpha-epoxide. Moreover, 7-dehydrocholesterol, 3beta
hydroxy-5beta-cholest-7-en-6-one (5beta-ketol), and 3beta,14alpha-dihydroxy-5beta
cholest-7-en-6-one (5beta-ketodiol) were converted into 20-hydroxyecdysone. Thus,
the pathway cholesterol-->7-dehydrocholesterol-->7-dehydrocholesterol
5alpha,6alpha-epoxide-->5beta-ketol-->5beta-k etodiol is proposed for the early
stages of 20-hydroxyecdysone biosynthesis. 3beta-Hydroxy-5beta-cholestan-6-one
was also incorporated into 20-hydroxyecdysone, suggesting that the introduction
of a 7-ene function is not necessarily next to cholesterol. C-25 Hydroxylation
during 20-hydroxyecdysone biosynthesis was found to proceed with ca. 70%
retention and 30% inversion. Finally, clerosterol was shown to be a precursor of
cyasterone and isocyasterone.
PMID- 10783006
TI - Cholesterol synthesis in the vertebrate retina: effects of U18666A on rat retinal
structure, photoreceptor membrane assembly, and sterol metabolism and
composition.
AB - Treatment of neonatal rats with U18666A, an inhibitor of desmosterol delta24
reductase, results in accumulation of desmosterol (delta5,24) and depletion of
cholesterol (delta5) in various bodily tissues and also causes cataracts. We
evaluated the effects of U18666A on the sterol composition, de novo sterol
synthesis, and histological structure of the retina. Neonatal Sprague-Dawley rats
were injected subcutaneously with U18666A (15 mg/kg, in olive oil ) every other
day from birth through 3 wk of age; in parallel, control rats received olive oil
alone. At 21 d, treated and control groups each were subdivided into two groups:
one group of each was injected intravitreally with [3H]acetate; retinas were
removed 20 h later and nonsaponifiable lipids (NSL) were analyzed by radio-high
performance liquid chromatography. The other group was injected intravitreally
with [3H]leucine; 4 d later, one eye of each animal was evaluated by light and
electron microscopy and light microscopic autoradiography, while contralateral
retinas and rod outer segment (ROS) membranes prepared therefrom were analyzed by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis/fluorography. In the
treated group, the delta5/delta5,24 mole ratio of retinas was ca. 1.0, and >88%
of the NSL radioactivity was in delta5,24; in contrast, control retinas had
delta5/delta5,24 >170, with >80% of the NSL radioactivity in delta5. Retinal
histology, ultrastructure, ROS renewal rates, and rhodopsin synthesis and
intracellular trafficking were comparable in both treated and control animals.
These results suggest that desmosterol can either substitute functionally for
cholesterol in the retina or it can complement subthreshold levels of cholesterol
by sterol synergism.
PMID- 10783007
TI - Rationally designed inhibitors as tools for comparing the mechanism of squalene
hopene cyclase with oxidosqualene cyclase.
AB - The inhibition of squalene-hopene cyclase (SHC) (E.C. 5.4.99.-), an enzyme of
bacterial membranes catalyzing the formation of pentacyclic sterol-like
triterpenes, was studied by using different classes of compounds originally
developed as inhibitors of oxidosqualene cyclase (OSC) (E.C. 5.4.99.7), the
enzyme of eukaryotes responsible for the formation of tetracyclic precursors of
sterols. The mechanism of cyclization of squalene by SHC, beginning with a
protonation of the 2,3 double bond by an acidic residue of the enzyme, followed
by a series of electrophilic additions of the carbocationic intermediates to the
double bonds, is similar to the mechanism of cyclization of 2,3-oxidosqualene by
OSC. The inhibitors studied included: (i) analogs of the carbocationic
intermediates formed during cyclization, such as aza-analogs of squalene and 2,3
oxidosqualene; (ii) affinity-labeling inhibitors bearing a methylidene reactive
group; and (iii) vinyldioxidosqualenes and vinylsulfide derivatives of the
substrates. Comparison of the results obtained with the two enzymes, SHC and OSC,
showed that many of the most effective inhibitors of OSC were also able to
inhibit SHC, while some derivatives acted as specific inhibitors. Differences
could be easily explained on the basis of the different substrate specificity of
the two enzymes.
PMID- 10783008
TI - Structure-apoptotic potency evaluations of novel sterols using human leukemic
cells.
AB - Three oxidized analogs of cholesterol have been characterized for their ability
to cause apoptotic cell death in CEM-C7-14 human leukemic cells. In addition to
testing 15-ketocholestenol (K15), 15-ketocholestenol hydroxyethyl ether (CK15),
and 7-ketocholesterol hydroxyethyl ether (CK7), an oxysterol of known apoptotic
response, 25-hydroxycholesterol (25OHC), served as a standard for comparison.
Growth studies based on dye exclusion by viable cells while using a sublethal
concentration of oxysterols ranked their potency for cell kill as 25OHC > K15 >
CK15 > CK7. Both the TUNEL assay (terminal deoxynucleotidyl transferase-mediated
dUTP-X nick end labeling), which quantifies the amount of DNA nicks caused by a
toxic agent, and the MTT assay, which measures cell metabolism and thus reflects
cell viability, substantiated the same rank order. An ELISA assay for evaluating
release of DNA fragments into the cytosol after treatment gave a similar potency
order. The oncogene c-myc mRNA was suppressed by all three oxysterols, with 25OHC
and K15 being the most potent suppressors. Hoechst and Annexin V staining
documented that these oxysterols kill cells by an apoptotic pathway as evidenced
by condensation of nuclear chromatin and plasma membrane inversion, respectively.
From these in vitro studies, we believe that 25OHC, K15, and possibly CK15 have
the potential to be chemotherapeutic agents.
PMID- 10783009
TI - C27 to C32 sterols found in Pneumocystis, an opportunistic pathogen of
immunocompromised mammals.
AB - Pneumocystis carinii is the paradigm of opportunistic infections in
immunocompromised mammals. Prior to the acquired immunodeficiency syndrome (AIDS)
pandemic and the use of immunosuppressive therapy in organ transplant and cancer
patients, P. carinii was regarded as a curiosity, rarely observed clinically.
Interest in this organism exploded when it was identified as the agent of P.
carinii pneumonia (PcP), the direct cause of death among many AIDS patients.
Aggressive prophylaxis has decreased the number of acute PcP cases, but it
remains among the most prevalent opportunistic infections found within this
patient population. The taxonomic assignment of P. carinii has long been argued;
molecular genetics data now demonstrate that it is a fungus. Several antimycotic
drugs are targeted against ergosterol or its biosynthesis, but these are not as
effective against PcP as they are against other fungal infections. This can now
be explained in part by the identification of the sterols of P. carinii. The
organism lacks ergosterol but contains distinct C28 and C29 delta7 24
alkylsterols. Also, 24-methylenelanost-8-en-3beta-ol (C31) and pneumocysterol,
(24Z)-ethylidenelanost-8-en-3beta-ol (C32) were recently identified in organisms
infecting humans. Together, the delta7 24-alkylsterols and pneumocysterol are
regarded as signature lipids of the pathogen that can be useful for the diagnosis
of PcP, since no other lung pathogen is known to contain them. Cholesterol (C27),
the dominant sterol component in P. carinii, is probably totally scavenged from
the host. De novo synthesis of sterols has been demonstrated by the presence of
lovastatin-sensitive 3-hydroxy-3-methylglutaryl-CoA reductase activity, the
incorporation of radiolabeled mevalonate and squalene into P. carinii sterols,
and the reduction in cellular ATP in cells treated with inhibitors of enzymes in
sterol biosynthesis.
PMID- 10783010
TI - The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune
system, and aging.
AB - With the passage of the U.S. Dietary Supplement Health and Education Act of 1994,
dehydroepiandrosterone (DHEA, 5-androsten-3beta-ol-17-one) has become widely
available, and a large and growing market has developed for this "fountain of
youth." DHEA has been shown to have significant beneficial effects in animals,
which may lead to clinical uses in man. Historically, the U.S. Food and Drug
Administration removed DHEA from the over-the-counter market in 1985 because
there was no support for the health claims that were made for this product.
Almost all of the biological data was on animals and there was a lack of
demonstrated efficacy in humans. Recently there have been a number of small
clinical trials in humans but the results have not been as positive as in the
animal tests. This review will be restricted to the effects of DHEA on
carcinogenesis, obesity, the immune system, and aging. Four hypotheses have been
proposed to explain the underlying biochemical mechanism(s) by which DHEA exerts
its beneficial properties. The first is based on the inhibitory effect of DHEA on
mammalian glucose-6-phosphate dehydrogenase. This mechanism can explain the
antiinitiation and antipromotion steps in some cases of carcinogenesis. The
second biochemical mechanism involves the induction of peroxisomes and peroxisome
associated enzymes. The third explanation is that DHEA works in a similar fashion
to the known anticarcinogenic action of food restriction. An antiglucocorticoid
mechanism has also been suggested. A hypothesis for the increase followed by the
decrease in the levels of DHEA with age is proposed. A number of new synthetic
DHEA analogs have been synthesized and tested. They offer the best hope for the
development of a clinically useful drug based on the properties of DHEA.
PMID- 10783011
TI - Plasma oxysterols and tocopherol in patients with diabetes mellitus and
hyperlipidemia.
AB - The plasma levels of free oxysterols (7-ketocholesterol; 7alpha-hydroxy-, 7beta
hydroxy-, 25-hydroxy-, and 27-hydroxycholesterol; and 5alpha,6alpha
epoxycholestanol) in patients with diabetes mellitus and hypercholesterolemia
were determined using gas chromatography-mass spectrometry with selective ion
monitoring. We studied 39 patients with diabetes mellitus, 20 nondiabetic
patients with hypercholesterolemia, and 37 normal controls. Plasma cholesterol
levels in diabetic and hypercholesterolemic patients showed no statistical
difference. Plasma 7-ketocholesterol was significantly higher in patients with
diabetes (31.6+/-2.8 ng/mL) or hypercholesterolemia (52.3+/-5.9) than in the
control group (22.4+/-1.2). The increased plasma cholesterol can be regarded as
an oxidation substrate for the oxidant stress and the higher absolute levels of
oxysterols in hypercholesterolemic plasma compared with the control plasma. This
difference disappeared when 7-ketocholesterol was expressed in proportion to
total cholesterol. The oxidizability of plasma cholesterol was evaluated by
comparing the increased ratio of 7-ketocholesterol after CuSO4 oxidation to the
ratio before. We demonstrated that the patients with diabetes showed increased
oxidizability (77.5%) compared with the control (36.6%) or hyperlipemic group
(45.3%), which is likely due to the lower amounts of alpha-tocopherol in the
diabetics. Measurement of oxysterols may serve as a marker for in vivo oxidized
lipoproteins in diabetes and hyperlipemia.
PMID- 10783013
TI - Challenges of evaluating homeopathic treatment of acute otitis media.
PMID- 10783012
TI - Use of a 13C tracer to quantify the plasma appearance of a physiological dose of
lutein in humans.
AB - Increased intake of lutein from vegetables promotes increased density of the
macular pigment and therefore may protect against age-related macular
degeneration. Our objective was to use a 13C tracer and high-precision gas
chromatography-combustion interfaced-isotope ratio mass spectrometry (GC-C-IRMS)
to investigate metabolism of a lutein dose equivalent to that absorbed from
vegetables. Biosynthetic per-labeled (>99% 13C) lutein was purified from a
commercially available extract of algal biomass. Subjects (n = 4) ingested 3 mg
of [13C]lutein with a standardized low-carotenoid breakfast. Blood samples were
collected at baseline and then hourly for 12 h; additional blood samples were
drawn at 16, 24, 48, 72, 96, 192, 360, and 528 h. To produce perhydro-beta
carotene suitable for analysis by GC-C-IRMS, the plasma lutein fraction was
hydrogenated on palladium-on-carbon catalyst with acid-catalyzed hydrogenolysis.
The stable carbon isotope (13C/12C) ratio measured by GC-C-IRMS was used to
calculate the plasma concentration of [13C]lutein. There was a rapid increase in
[13C]lutein in plasma until peak enrichment at 16 h followed by a decline to the
next measurement at 24 h. At 528 h, small changes in 13C enrichment from baseline
could still be measured in plasma lutein. High-precision GC-C-IRMS enables
complete definition of the appearance and disappearance of [13C]lutein in plasma
after ingestion of a dose similar to that absorbed from foods.
PMID- 10783014
TI - Adult formulation of a five component acellular pertussis vaccine combined with
diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and
immunogenic in adolescents and adults.
AB - BACKGROUND: Pertussis is increasingly recognized as an important cause of cough
illness in adolescents and adults. PURPOSE: To evaluate the safety and antibody
response to a single dose of an adult formulation of a five component (pertussis
toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular
pertussis vaccine (aP) combined with diphtheria and tetanus toxoids (TdaP) and
inactivated poliovirus vaccine (TdaP-IPV) in adolescents and adults and to assess
the response to a second dose of the acellular pertussis vaccine in a subset of
the adults. POPULATION AND SETTING: The study addressed 1207 healthy participants
(736 adults and 466 adolescents) recruited in five Canadian communities. STUDY
DESIGN: In a randomized, observer-blind, controlled clinical trial, adult
participants received Td followed at a separate visit by aP, TdaP followed by IPV
or TdaP-IPV; adolescents received Td-IPV followed at a separate visit by aP or
TdaP-IPV. A subgroup of adults was given a booster of aP 1 month after TdaP.
OUTCOME MEASURES: Antibody titers measured before and 1 month after each
immunization; adverse events enumerated at 24 h, 72 h and 8 to 10 days. RESULTS:
The aP vaccine given by itself was associated with adverse events less frequently
than were Td, Td-IPV, TdaP or TdaP-IPV vaccines, but reaction rates did not
differ significantly among the latter products. The antibody response against
Bordetella pertussis antigens was vigorous in all groups, although adults given
the TdaP-IPV vaccine had lower antibody titers against filamentous hemagglutinin,
pertactin, diphtheria and tetanus antibodies than those given TdaP vaccine.
Similarly adolescents given TdaP-IPV had lower antibody titers against pertussis
toxin, filamentous hemagglutinin, fimbriae and agglutinins than those given Td
IPV and aP alone. A second dose of acellular pertussis vaccine was not associated
with increased adverse events in adults but elicited increased antibody titers
over that achieved by a single dose only against pertussis toxin. CONCLUSIONS:
This adult formulation five component aP vaccine given as TdaP-IPV is safe and
immunogenic in adolescents and adults and is a candidate vaccine for adolescent
and adult immunization programs.
PMID- 10783015
TI - Vitamin A supplementation of South African children with severe diarrhea: optimum
timing for improving biochemical and clinical recovery and subsequent vitamin A
status.
AB - BACKGROUND: Vitamin A has well-recognized benefits for prevention of diarrhea,
but the impact of therapeutic doses given during diarrhea on biochemical and
clinical outcomes is less clear. We investigated these potential therapeutic
benefits within a study of the optimum time for vitamin A supplementation to
promote vitamin A status. METHODS: Young children with severe diarrhea were
randomized to receive 60 mg of retinol as retinyl palmitate during acute diarrhea
or once symptoms had resolved, usually after 5 to 8 days. Either during acute
diarrhea or after its resolution, children not receiving vitamin A were given
identical placebo. On Days 0 and 3 we measured urinary neopterin, plasma retinol
and acute phase proteins and intestinal permeability by the lactulose/mannitol
test. Eight weeks after discharge children returned to hospital for a modified
dose response test of vitamin A stores. RESULTS: Most children presented with
watery diarrhea and grossly abnormal intestinal permeability and immune
activation markers. At 8 weeks plasma retinol concentrations of children
receiving vitamin A during acute diarrhea, compared with those receiving it in
early convalescence [0.67 (95% confidence interval, 0.58 to 0.76) micromol/l vs.
0.68 (95% confidence interval, 0.59 to 0.79) micromol/l], and the proportion of
children with deficient vitamin A stores (7 of 34 vs. 8 of 34) did not differ.
Clinical features, lactulose/mannitol tests and urinary neopterin concentrations
on Day 3 also did not differ significantly when vitamin A was given early or
late. CONCLUSIONS: Even when it was given during severe diarrhea, a large dose of
vitamin A improved vitamin A stores in a population in whom vitamin A deficiency
is a public health problem. Vitamin A did not significantly improve early
clinical or biochemical recovery from severe diarrhea.
PMID- 10783016
TI - More laboratory testing: greater cost but not necessarily better.
AB - BACKGROUND: The bacterial latex agglutination assay is ordered predominantly on
the pediatric population, for rapid screening for bacterial surface antigens in
cerebrospinal fluid (CSF) or urine specimens. The high cost of this assay and
questions raised in the literature regarding its accuracy led to a retrospective
review of the use of this assay at a medium-sized midwest teaching hospital. The
results of 6,370 bacterial latex agglutination tests performed between May, 1995,
and November, 1996, and charts of patients being tested were reviewed. RESULTS:
This study demonstrated a sensitivity and specificity of 28.6% and 86.7% for
urine specimens and 70.0% and 99.4% for CSF specimens. A total of 11 pathogens
were accurately detected (7 CSF and 4 urine). There were 13 false negatives and
59 false positives. None of the true positives had a discernible effect on either
treatment or hospital course; however, several of the erroneous tests resulted in
delayed or unnecessary treatment and workup of the involved patients. The annual
billed cost of this test at this institution (fiscal years 1995 to 1997) averaged
$167,000 per annum. This does not include indirect costs associated with
increased length of hospital stay, overutilization of antibiotics and excess
laboratory tests ordered as a result of false positives. CONCLUSIONS: Bacterial
antigen latex agglutination testing is neither sufficiently sensitive nor
specific to be used as a screening test. Accurate results have no demonstrable
clinical impact, whereas numerous inaccurate results are often generated at great
cost. The continued use of the latex agglutination assay should be seriously
questioned in an era when cost containment and clinical efficiency are becoming
increasingly important.
PMID- 10783017
TI - Etiology of community-acquired pneumonia in 254 hospitalized children.
AB - BACKGROUND: Childhood community-acquired pneumonia is a common illness, but there
have been relatively few comprehensive studies of the viral and bacterial
etiology in developed countries. The aim of the present investigation was to
determine the etiology of community-acquired pneumonia in hospitalized children
by several laboratory methods. METHODS: In a 3-year prospective study a
nasopharyngeal aspirate for viral studies and acute and convalescent serum
samples for viral and bacterial serology were taken from 254 children with
symptoms of acute infection and infiltrates compatible with pneumonia in the
chest radiograph. The role of 17 microbes was investigated. RESULTS: A potential
causative agent was detected in 215 (85%) of the 254 patients. Sixty-two percent
of the patients had viral infection, 53% had bacterial infection and 30% had
evidence of concomitant viral-bacterial infection. Streptococcus pneumoniae
(37%), respiratory syncytial virus (29%) and rhinovirus (24%) were the most
common agents associated with community-acquired pneumonia. Only one patient had
a positive blood culture (S. pneumoniae) of 125 cultured. A dual viral infection
was detected in 35 patients, and a dual bacterial infection was detected in 19
patients. CONCLUSIONS: The possible causative agent of childhood community
acquired pneumonia can be detected in most cases. Further studies are warranted
to determine what etiologic investigations would aid in the management of
pneumonia. With effective immunization for S. pneumoniae and respiratory
syncytial virus infections, more than one-half of the pneumonia cases in this
study could have been prevented.
PMID- 10783018
TI - Predictive value of pneumococcal nasopharyngeal cultures for the assessment of
nonresponsive acute otitis media in children.
AB - BACKGROUND: Nonresponsive acute otitis media (NR-AOM) is reported in > 10% of
children with AOM treated with antibiotics. Drug-resistant Streptococcus
pneumoniae is currently considered the leading cause of antibiotic failures in
AOM. Nasopharyngeal colonization with S. pneumoniae was found to increase
significantly during episodes of AOM. OBJECTIVES: To investigate the
nasopharyngeal colonization with S. pneumoniae during NR-AOM and compare it with
that found in AOM not recently treated with antibiotics (NT-AOM); to assess the
predictive value of nasopharyngeal pneumococcal cultures results for the
bacteriologic assessment of NR-AOM. MATERIALS AND METHODS: Patients age 3 to 48
months with NT-AOM and NR-AOM were prospectively studied. Simultaneous
nasopharyngeal cultures for S. pneumoniae and middle ear fluid cultures were
obtained at enrollment. Antibiotic susceptibility testing was performed in all S.
pneumoniae isolates. Penicillin and ceftriaxone MICs for S. pneumoniae were
determined by E-test. The sensitivity, specificity and positive and negative
predictive values of positive or negative nasopharyngeal cultures for the
presence of S. pneumoniae in middle ear fluid were calculated. RESULTS: We
studied 362 and 217 children with NT-AOM and NR-AOM, respectively. Of the
children with NT-AOM and NR-AOM, 95 and 97%, respectively, were younger than 2
years of age. S. pneumoniae was isolated in the nasopharynx of 66 and 58% of
children with NT-AOM and NR-AOM, respectively. Penicillin-nonsusceptible S.
pneumoniae was isolated more frequently from the nasopharynx of patients with NR
AOM than from those with NT-AOM (84% vs. 47%; P < 0.01). Antibiotic
susceptibility patterns were similar for S. pneumoniae isolates recovered from
the nasopharynx and those from the middle ear fluid in both NT-AOM and NR-AOM. A
positive nasopharyngeal culture had only little predictive value for the presence
of S. pneumoniae in middle ear fluid (41 and 51% for NT-AOM and NR-AOM,
respectively). However, the negative predictive value of nasopharyngeal cultures
for recovery of S. pneumoniae in NR-AOM was high and significantly higher in NR
AOM than in NT-AOM (91% vs. 78%, respectively; P = 0.009). The negative
predictive value of nasopharyngeal cultures for recovery of antibiotic-resistant
S. pneumoniae was 95 and 93% in NT-AOM and NR-AOM, respectively. Conclusions. A
significantly higher nasopharyngeal colonization rate with antibiotic-resistant
S. pneumoniae was found in patients with NR-AOM than in those with NT-AOM.
Negative nasopharyngeal culture for antibiotic-resistant S. pneumoniae
practically rules out its presence in middle ear fluid.
PMID- 10783019
TI - Effect of rapid diagnosis on management of influenza A infections.
AB - BACKGROUND: Few studies have examined the impact of rapid viral diagnostic tests
on patient management. OBJECTIVE: To assess the effect of rapid diagnosis of
influenza A infections on patient management. METHODS: The medical records of
children with respiratory infections who were evaluated at a children's hospital
between July 1, 1995, and June 30, 1997, were reviewed. Children (n = 56)
evaluated in the Emergency Department (ED) who had a positive influenza A enzyme
immunoassay (EIA) were compared with two control groups for the likelihood of
admission, antibiotic use and duration of hospitalization and antibiotic
administration. RESULTS: Patients discharged from the ED with a positive EIA test
were less likely to receive antibiotics than those with a negative EIA test (20%
vs. 53%; P = 0.04). Patients admitted to the hospital with a positive EIA test
were as likely to receive antibiotics as those without a rapid diagnosis, but the
duration of antibiotic administration was significantly shorter in the group with
a positive EIA test (3.5 vs. 5.4 days; P = 0.03). Patients with a positive EIA
test also were more likely to receive antiviral therapy than either control group
(25% vs. 0 and 1.8%; P < 0.001). CONCLUSIONS: The detection of influenza A by EIA
has a positive impact on medical management by decreasing antibiotic use in
pediatric patients evaluated in an ED, by decreasing the duration of antibiotic
use in hospitalized patients and by encouraging antiviral therapy.
PMID- 10783020
TI - Viral infections in children undergoing hematopoietic stem cell transplant.
AB - BACKGROUND: Although viral infection is a major clinical problem for
hematopoietic stem cell transplant recipients, there are few large series
reporting on these infections in the pediatric population. We performed a
retrospective analysis of the impact of viral infections in this patient
population in our center, managed by a uniform antiviral prophylaxis protocol.
METHOD: We reviewed the medical records of consecutive children and adolescents
who received hematopoietic stem cell transplantation at the Division of
Pediatrics, The University of Texas M. D. Anderson Cancer Center in Houston, TX,
from July, 1992 to August, 1996. RESULTS: During the study period there were 70
episodes of viral infections in 96 transplants. The viruses most commonly
encountered were cytomegalovirus (24), varicella-zoster (21) and herpes simplex
(10). Fifty of these episodes resulted in clinically apparent diseases, affecting
39 patients. The Kaplan-Meier estimated probability for the development of viral
diseases was 62%. Ten percent of these patients died as a direct result of the
infectious process, all within 4 months of transplant. Significant factors for
development of viral disease were the development of acute graft-vs.-host disease
and the duration of preengraftment neutropenia. CONCLUSIONS: Viruses are common
pathogens after hematopoietic stem cell transplantation in the pediatric
population. Despite routine antiviral prophylaxis the morbidity and mortality of
viral infections remain high. Enhancement of immune recovery after hematopoietic
stem cell transplantation together with the development of new classes of
antiviral agents may impact the incidence and prognosis of viral infections in
this setting.
PMID- 10783021
TI - Bacteremia in febrile Malawian children: clinical and microbiologic features.
AB - BACKGROUND: There are no published data for the incidence or etiology of
childhood bacteremia in Malawi. We describe the clinical and microbiologic
features of children admitted to hospital from whom blood cultures yielded
bacterial pathogens. METHODS: Any neonate or child admitted to the pediatric
wards of the Queen Elizabeth Central Hospital had a blood culture taken in the
event of fever without obvious clinical explanation. Clinical and microbiologic
data were prospectively collected for children with a significant positive
culture. RESULTS: Between September, 1996, and August, 1997, we processed 2,123
cultures. Of these, 365 (17.2%) grew a pathogen. Non-typhi salmonellae (NTS) and
enteric Gram-negative bacilli constituted 67.4% of isolates, and Streptococcus
pneumoniae constituted 16.4%. More than two-thirds of NTS episodes coincided with
the peak malaria transmission season (January to June); 67% of bacteremic
children were malnourished, 28% severely so. Patients with NTS bacteremia were
significantly more likely to have coincident malaria and to have splenomegaly and
anemia than children with other infecting organisms. The overall mortality was
38% but varied considerably according to age and nutritional status. Prior
antibiotic use, coincident malaria or meningitis did not adversely affect
outcome. In vitro resistance to the commonly available antibiotics ampicillin and
trimethoprim-sulfamethoxazole was found in 76 and 71% of NTS isolates. Screening
tests for penicillin resistance suggested a rate of 21% among pneumococci.
CONCLUSIONS: Bacteremia is common in hospitalized Malawian children and has a
high mortality. There are high rates of resistance to some of the commonly used
antibacterial agents.
PMID- 10783022
TI - Risk factors for candidemia in Neonatal Intensive Care Unit patients. The
National Epidemiology of Mycosis Survey study group.
AB - BACKGROUND: Candida species are important nosocomial pathogens in neonatal
intensive care unit (NICU) patients. METHODS: A prospective cohort study was
performed in six geographically diverse NICUs from 1993 to 1995 to determine the
incidence of and risk factors for candidemia, including the role of
gastrointestinal (GI) tract colonization. Study procedures included rectal swabs
to detect fungal colonization and active surveillance to identify risk factors
for candidemia. Candida strains obtained from the GI tract and blood were
analyzed by pulsed field gel electrophoresis to determine whether colonizing
strains caused candidemia. RESULTS: In all, 2,847 infants were enrolled and 35
(1.2%) developed candidemia (12.3 cases per 1,000 patient discharges or 0.63 case
per 1,000 catheter days) including 23 of 421 (5.5%) babies < or =1,000 g. After
adjusting for birth weight and abdominal surgery, forward multivariate logistic
regression analysis demonstrated significant risk factors, including gestational
age <32 weeks, 5-min Apgar <5; shock, disseminated intravascular coagulopathy,
prior use of intralipid, parenteral nutrition, central venous catheters, H2
blockers, intubation or length of stay > 7 days before candidemia (P < 0.05).
Catheters, steroids and GI tract colonization were not independent risk factors,
but GI tract colonization preceded candidemia in 15 of 35 (43%) case patients.
CONCLUSIONS: Candida spp. are an important cause of late onset sepsis in NICU
patients. The incidence of candidemia might be decreased by the judicious use of
treatments identified as risk factors and avoiding H2 blockers.
PMID- 10783023
TI - Meningococcal disease in Dallas County, Texas: results of a six-year population
based study.
AB - OBJECTIVE: Neisseria meningitidis is an important cause of serious bacterial
infection in children and adults in the US. From 1992 to 1997 invasive disease
caused by N. meningitidis was studied among 1.9 million residents of Dallas
County, TX METHODS: The demographic characteristics and diagnoses of 151 patients
were identified through active, population-based surveillance and review of
medical records. Serogroups were determined for strains infecting 129 (85%)
patients. RESULTS: The average annualized incidence rate was 1.3 cases per
100,000 person years and was highest for children <1 year (13 cases/100,000
person years). Older patients (50+ years old) were more likely to present with
pneumonia and less likely to present with meningitis than younger patients.
Neither the fatality rate nor the duration of hospitalization for surviving
patients was associated with age. Among patients with a known serogroup,
serogroup C disease was found in 35% of cases <1 year old, 64% of those 1 to 49
years old and 44% of those 50+ years old. Serogroup B strains were isolated from
26% of patients <1 year, 17% of patients 1 to 49 years old and none of the
patients 50+ years old. Serogroup Y disease increased from 22% to 35% of cases
between 1992 and 1997 (P = 0.03). This serogroup was identified in 26% of
patients <1 year old, 17% of patients 1 to 49 years old and in 50% of patients
50+ years old. Serogroup C and Y accounted for 61% of cases in children <1 year
old and for 79% of cases in all age groups. CONCLUSION: The results underscore
the importance of conjugate vaccines for serogroups C and Y.
PMID- 10783024
TI - Streptococcus pneumoniae antimicrobial susceptibility testing.
PMID- 10783025
TI - Pneumococcal conjugate vaccines.
PMID- 10783026
TI - Vaccines for prevention of meningococcal disease.
PMID- 10783027
TI - Neonatal gonococcal arthritis after negative prenatal screening and despite
conjunctival prophylaxis.
PMID- 10783028
TI - Kawasaki disease associated with measles virus infection in a monozygotic twin.
PMID- 10783029
TI - Costs of otitis media in a managed care population.
PMID- 10783030
TI - Genetic analysis of sin nombre hantavirus in Iowa.
PMID- 10783031
TI - Rash and petechiae as presenting signs of Q fever.
PMID- 10783032
TI - Early onset neonatal sepsis caused by serotype VIII group B streptococci.
PMID- 10783033
TI - Home monitoring of the middle ear system with spectral gradient acoustic
reflectometry: distinguishing acute otitis media from upper respiratory
infection.
PMID- 10783034
TI - Pseudomonas folliculitis in a young child.
PMID- 10783036
TI - Diagnosis of Helicobacter pylori infection with a novel stool antigen-based assay
in children.
PMID- 10783035
TI - Genotypic characterization of human immunodeficiency virus type 1 isolated from
vertically infected children with antiretroviral therapy experience.
PMID- 10783037
TI - Flurithromycin-induced acute interstitial nephritis.
PMID- 10783038
TI - Etiology and treatment of pneumonia.
AB - BACKGROUND: Lower respiratory tract infections are a common cause of morbidity
among children. Among these infections pneumonia is the most serious illness and
can be difficult to diagnose. The etiology of pneumonia is still partly unknown,
primarily because of difficulty in obtaining adequate samples and lack of
reliable diagnostic methods. ETIOLOGY OF PNEUMONIA: Streptococcus pneumoniae is
recognized as an important cause of pediatric pneumonia regardless of age in both
the inpatient and outpatient setting. In developed countries S. pneumoniae
probably accounts for 25 to 30% of cases of pediatric community-acquired
pneumonia. Viruses (mostly respiratory syncytial virus) are responsible for
approximately 20% of cases, and Chlamydia pneumoniae and Mycoplasma pneumoniae
occur commonly in older children. FUTURE CHALLENGES: Despite the effectiveness of
antimicrobial therapy, the emergence of resistant bacterial pathogens has
resulted in increased interest in developing more effective vaccines. If
conjugate pneumococcal vaccines prove effective at eradicating carriage of
pneumococci in the nasopharynx, immunization may be an important tool against the
spread of pneumococcal disease. Future challenges include implementation of
effective intervention strategies, production of simple diagnostic tools and
development of effective vaccines.
PMID- 10783039
TI - Clinical significance of resistant organisms in otitis media.
AB - BACKGROUND: Otitis media is an important health care problem of childhood. The
bacteriology of otitis media comprises three main pathogens: Streptococcus
pneumoniae, nontypable Haemophilus influenzae and Moraxella catarrhalis. Although
the prevalence of resistant strains varies geographically and temporally,
antimicrobial resistance is widespread and increasing. RESISTANCE TO ANTIBIOTIC
DRUGS: Among the risk factors for development of resistance in otitis media are
antimicrobial use, young age, day-care attendance and prior hospitalization. The
increasing rate of resistance to antibiotic drugs is associated with a decreased
rate of successful eradication of pathogens from middle ear fluid, which is
associated with clinical failure. A bacteriologic cure rate of 80 to 85% is
observed for S. pneumoniae and nontypable H. influenzae when serum concentrations
exceed the MIC for 40 to 50% of dosing interval. Comparative trials indicate that
some of the beta-lactams can achieve bacteriologic eradication in acute otitis
media, although major differences in outcome exist among agents based on
pathogen, beta-lactamase status and MIC values. ANTIBIOTIC CHOICE: Overall the
choice of antibiotics for treatment of otitis media should take into
consideration their in vitro activity against the locally prevalent organisms,
especially resistant organisms, and results obtained from studies in which
bacteriologic outcome was used as the endpoint.
PMID- 10783040
TI - Management of otitis media: 2000 and beyond.
AB - BACKGROUND: In the next few years what will alter our modes of diagnosis, choice
of therapies and strategies for prevention of acute otitis media (AOM)? These
issues, as well as whether antibiotic resistance will continue to threaten the
efficacy of currently available antimicrobial agents, whether industry and
academia will be able to respond to bacterial resistance with effective new
antimicrobial drugs and whether the pneumococcal conjugate vaccine will
substantially reduce the incidence of AOM provide a basis for discussing the
problems and possible solutions related to AOM. ANTIMICROBIAL DRUGS: Bacteria and
viruses will continue to find ways to survive the activity of currently available
antimicrobial drugs. Among the new antibacterial drugs under consideration are
ketolides, oxazolodinones and quinolones. Guidelines stress limiting usage of
antimicrobial agents to diseases that are likely caused by bacterial pathogens.
Antiviral drugs are now available against influenza virus and respiratory
syncytial virus infections. DIAGNOSIS: Tympanometry and/or acoustic reflectometry
are adjunctive techniques for assisting in the diagnosis of middle ear effusion
in children whose otoscopic examination is ambiguous. Laser myringotomy has been
used in several hundred children; however, there are no published studies of
randomized trials. NEW VACCINES: Investigators have evaluated the safety and
efficacy of a heptavalent pneumococcal polysaccharide vaccine conjugated with
CRM197 (a diphtheria toxin mutant). The results showed a reduction in the overall
burden of severe and recurrent AOM. Respiratory syncytial virus is the viral
pathogen most frequently associated with AOM. For this reason safe and effective
viral vaccines are needed to complement the efficacy of bacterial vaccines for
prevention of AOM. CONCLUSIONS: Parents influence decisions by pediatricians to
use antimicrobial agents and should be informed about the appropriate usage of
antibiotics. Educators and public health officials must find techniques to
distinguish WebSites that provide information of value from those that are not
credible. Of paramount importance is the development of techniques to increase
the accuracy of clinical and microbiologic diagnosis. Finally there is a need for
studies of appropriate scientific design that can assess the efficacy and safety
of alternative therapies.
PMID- 10783041
TI - Immunogenicity of pneumococcal conjugate vaccines.
AB - BACKGROUND: Prevention of pneumococcal infections is a public health priority
because of the high impact of the disease and because of the increasing problems
due to antimicrobial resistance. Traditional vaccines, consisting of purified
capsular polysaccharides (PSs) of Streptococcus pneumoniae, are not immunogenic
in young children. In addition they confer only limited protection in patients
with immunodeficiencies and hematologic malignancies. IMMUNOGENICITY OF
PNEUMOCOCCAL CONJUGATE VACCINES: Immunogenicity of the PS vaccine has been
enhanced by coupling pneumococcal PSs to proteins to produce a conjugate vaccine.
Conjugate molecules are designed to possess T cell dependent properties, such as
immunogenicity in early infancy, stimulation of high levels of IgG isotype
antibodies and enhanced immunologic memory responses. In the clinical studies
multivalent pneumococcal conjugate vaccines have been shown to induce an IgG
dominating serum antibody response against common pneumococcal serotypes causing
infections in children. A booster dose later in life creates a robust and rapid
antibody response, indicating the existence of immunologic memory in primed
children. Antibodies induced by conjugate vaccines are functionally active, as
demonstrated by their high avidity and opsonophagocytic activity.
PMID- 10783042
TI - Efficacy of pneumococcal conjugate vaccines in large scale field trials.
AB - BACKGROUND: Each year Streptococcus pneumoniae causes approximately 1.2 million
deaths worldwide from pneumonia. In the United States S. pneumoniae is estimated
to cause 500,000 cases of pneumonia and 7 million episodes of acute otitis media
annually. CONJUGATE VACCINES: The current pneumococcal polysaccharide vaccine is
ineffective in children <2 years old and may not produce an adequate antibody
response until children reach the age of 5 years. Pneumococcal conjugate vaccines
are immunogenic after primary and booster vaccination in young children and in
children and adults with immunodeficiencies. Immunization with conjugate vaccines
also induces a strong and rapid anamnestic response and enhanced functional
activity of antibodies. Two large scale field trials of pneumococcal conjugate
vaccines were initiated in 1995, 1 in California and 1 in Finland. The California
trial, involving 37,868 children, evaluated the efficacy of a 7-valent conjugate
for the prevention of invasive pneumococcal disease and secondarily evaluated its
efficacy for acute otitis media and pneumonia. RESULTS: Preliminary results
indicate 94% efficacy against invasive pneumococcal disease caused by serotypes
included in the vaccine in fully or partially vaccinated children. Preliminary
evidence from large scale field trials indicates that pneumococcal conjugate
vaccines are effective in reducing invasive pneumococcal disease as well as acute
otitis media and pneumonia in children and represents a significant advance in
the prevention of childhood infectious diseases.
PMID- 10783043
TI - Prevalence of migraine and Raynaud's phenomenon in Japanese patients with
vasospastic angina.
AB - The prevalence of migraine and Raynaud's phenomenon in Japanese patients with
vasospastic angina (group I) were compared with those in 2 control groups: one
with effort angina (group II) and the other group without known ischemic heart
disease (group III). There were no significant differences among the 3 groups
with respect to age and sex. The prevalence of migraine in group I was 23 of 100,
as compared with 4 of 100 in group II (p<0.01) and 11 of 100 in group III
(p<0.05). The prevalence of Raynaud's phenomenon in group I was 9 of 100, as
compared with 3 of 100 in group II and 4 of 100 in group III. Thus, in Japan, the
prevalence of migraine in patients with vasospastic angina was higher than those
in the 2 control groups, whereas the prevalence of Raynaud's phenomenon did not
differ significantly among the 3 groups. The prevalence of Raynaud's phenomenon
in Japanese patients with vasospastic angina was different from that reported
from North America, although the prevalence of migraine was the same. This may be
partially explained by racial differences.
PMID- 10783044
TI - Ultrasonographic study of carotid artery structural changes with natural
longevity.
AB - The changes in carotid artery structure during the natural longevity of the
Uighurs people were compared with other ethnic groups. The 419 subjects were
divided into (1) longevity and (2) older groups as follows: Uighurs longevity
group in Hotan (ULH); and Uighurs, Hans and Kazaks older groups in Hotan or
Balikun (UOH, HOH, HOB and KOB). The wall thickness of the common carotid artery
(CCA) was measured by ultrasonography. Risk factors were evaluated by measuring
total cholesterol (T-C), high-density lipoprotein cholesterol (HDL-C), low
density lipoprotein cholesterol (LDL-C), triglyceride (TG) and fasting glucose,
and by 24-h ambulatory blood pressure monitoring. Wall thickness and blood
pressure were greater in the Balikun groups than in the Hotan groups. The CCA
wall was thicker in Uighurs and Kazaks than in Hans, in the ULH than in the UOH.
There was no significant difference in blood pressure among the Hotan groups. LDL
C and glucose were higher and HDL-C was lower in the Hotan groups than in the
Balikun groups. T-C, LDL-C, TG and glucose were higher in the HOH than in the ULH
and UOH. Systolic blood pressure and LDL-C were higher and TG was lower in the
KOB than in the HOB. These results suggest that an increased CCA wall thickness
can be attributed to age in Hotan, and to a higher blood pressure level in
Balikun, and that the higher blood pressure affected the Balikun groups more than
the Hotan groups.
PMID- 10783045
TI - Hemodynamic effects of phosphodiesterase III inhibitor in patients with a large
ventricular left-to-right shunt.
AB - The hemodynamic effects of olprinone, a newly synthesized phosphodiesterase (PDE)
III inhibitor, were assessed in patients with a large cardiac left-to-right
shunt. Ten patients with a large ventricular septal defect (VSD) were evaluated
during cardiac catheterization. Olprinone was administered as a bolus, 20
microg/kg body weight, and hemodynamic data were obtained before and after the
administration. Heart rate and systemic flow increased significantly after
administration. On the other hand, olprinone significantly reduced left and right
atrial pressure, the systolic pulmonary/arterial pressure ratio, and systemic
vascular resistance. However, pulmonary flow and pulmonary vascular resistance
were not changed. These results suggested that olprinone had a positive inotropic
effect and selective vasodilator effect on patients with a large ventricular left
to-right shunt. Thus, PDE inhibitors may be beneficial for the treatment of
patients with a large VSD.
PMID- 10783046
TI - Clinical characteristics of patients with fresh left ventricular thrombus.
AB - The present study analyzed the clinical backgrounds of 9 patients with fresh left
ventricular thrombus (LVT) detected by two-dimensional echocardiography during
the past 5 years. Patients with acute myocardial infarction were excluded. Left
ventricular systolic function was disturbed either diffusely or segmentally in
all patients with a mean ejection fraction of 33%. In 7 patients,
echocardiography was performed shortly after furosemide therapy for New York
Heart Association class IV congestive heart failure; echocardiography was also
performed just before treatment in 4 of the 7 patients and LVT was not detected
in any of them. Two patients died of underlying disorders within 2 months of
detection of the thrombus. However, the LVT disappeared in the other 7 patients
without any thromboembolic episodes during the 6 months after starting
anticoagulant therapy. As fresh LVT developed shortly after diuretic therapy in
patients with severe congestive heart failure associated with left ventricular
systolic dysfunction, concomitant anticoagulant therapy is recommended.
PMID- 10783047
TI - A low amplitude His-bundle potential predicts failure of the right-sided approach
for atrioventricular junction ablation.
AB - In 30 patients with drug refractory atrial fibrillation-flutter who underwent
radiofrequency (RF) ablation of the atrioventricular (AV) junction, 23 were
successfully ablated using the conventional right-sided approach (group A). Seven
patients required a left-sided approach (group B) after multiple applications
from the conventional right-sided approach failed to produce complete AV block.
The amplitude of the His-bundle potential recorded at the ablation site differed
significantly between the 2 groups (0.23+/-0.11 mV in group A vs 0.12+/-0.04 mV
in group B; p<0.005). Also, the amplitude of the His-bundle potential recorded in
the standard position across the tricuspid annulus differed significantly between
the 2 groups (0.27+/-0.35 mV in group A vs 0.11+/-0.44 mV in group B; p<0.007).
There was no significant difference in the amplitude of the ventricular potential
between the 2 groups. The probability of successful ablation of the AV junction
with a conventional right-sided approach was 6 out of 12 patients (50%) if the
His amplitude was <0.12mV, and 17 out of 18 patients (94%) if the His amplitude
was >0.12mV (p<0.005). Patients in group B had a mean of 20.5+/-13.0 failed right
sided RF applications (5-33 applications), but required a mean of only 2
subsequent RF applications for success on the left side (1-6 applications). The
His-amplitude recorded from the left side using the same catheter was
significantly greater than that on the corresponding right-side (0.22+/-0.09 mV
on the left side vs 0.12+/-0.04 mV on the right side: p<0.05). Total mean
fluoroscopic time was 62+/-12min for group B and 20+/-13min for group A patients.
In patients that underwent RF ablation of the AV junction, a maximum His
amplitude <0.12 mV predicted a success rate of approximately 50% in the present
study. An early switch to a left-sided approach may avoid multiple RF
applications and prolonged fluoroscopic time in patients with a low amplitude His
bundle potential.
PMID- 10783048
TI - Endothelialization of the coils used to occlude a persistent ductus arteriosus:
an angiographic study.
AB - To assess the endothelialization of the coils used to close a persistent ductus
arteriosus (PDA), the present study comprised a review of the follow-up
aortograms and pulmonary angiograms in 25 patients who underwent coil occlusion.
The minimal diameter and the length of the PDA were measured prior to the
procedure, and the shortest distance between the aortic end of the deployed coil
and the aortic end of the PDA was measured after coil deployment. Evidence of
endothelial coverage of the coil was sought on follow-up angiograms performed 6
24 (15+/-5) months later and the factors that determined the thickness of the
endothelial coverage on the aortic end were investigated. Separation of the coil
and the contrast column were detected at the aortic end in all cases and at the
pulmonary end in 18 of 25 cases. The thickness of the separation ranged from 0.4
to 1.3 (0.7+/-0.2) mm at the aortic end and 0.3 to 0.8 (0.6+/-0.2) mm at the
pulmonary end. The length of the ductus and of the ampulla had a significant
positive correlation with the thickness of the aortic end separation. Apparent
endothelial coverage of the coil was completed by 6 months after coil occlusion.
Infective endocarditis or thromboembolism is an unlikely complication once
endothelium covers the implanted coil.
PMID- 10783049
TI - The effect of the atrioventricular interval during atrioventricular sequential
pacing on the hemodynamics in dynamic obstruction of the left ventricular outflow
tract in dogs.
AB - The present study was performed to clarify the mechanism involved in the
reduction of the pressure gradient in the left ventricular outflow tract of
patients with hypertrophic obstructive cardiomyopathy when treated with
atrioventricular (AV) sequential pacing. The effect of AV sequential pacing with
variable AV intervals on the hemodynamics and dyssynchronous wall motion was
experimentally studied using echocardiography in the dynamic obstruction of the
left ventricular outflow tract created by dobutamine infusion in 17 dogs. The
pressure gradient of the left ventricular outflow tract decreased with shortening
of the AV interval during AV sequential pacing. Also, the dyssynchrony time,
defined as the difference in the time between the intraventricular septum and
posterior wall during the systolic phase recorded with M-mode echocardiography,
increased with shortening of the AV interval during AV sequential pacing.
However, very short AV intervals produced a significant decrease in the aortic
pressure and increase in the pulmonary capillary wedge pressure. The dyssynchrony
time showed a positive liner correlation with the percentage reduction in the
pressure gradient of the left ventricular outflow tract (R=0.794, p<0.0001). It
was concluded that dyssynchronous wall motion in the left ventricle was produced
by pacing from the right ventricular apex and resulted in a reduction in the
pressure gradient of the left ventricular outflow tract. Optimization of the AV
interval during AV sequential pacing may play an important role in improving the
hemodynamics in dynamic obstruction of the left ventricular outflow tract.
PMID- 10783050
TI - Effect of angiotensin converting enzyme inhibitor and angiotensin II type 1
receptor antagonist on metabolism and contraction in ischemia-reperfused rabbit
heart.
AB - The effect of angiotensin converting enzyme (ACE) inhibitor, temocaprilat and/or
angiotensin II type 1 (AT1) receptor antagonist, CV-11974 on myocardial
metabolism and contraction during ischemia and reperfusion was examined by
phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts.
After normothermic 15 min global ischemia, postischemic reperfusion of 60min was
carried out. Temocaprilat and/or CV-11974 were administered from 40 min prior to
the global ischemia. Adenosine triphosphate (ATP), creatine phosphate (PCr),
inorganic phosphate (Pi), intracellular pH (pHi), left ventricular developed
pressure (LVDevP), left ventricular end-diastolic pressure (LVEDP) and coronary
flow were measured. Twenty-eight hearts were divided into 4 experimental groups
consisting of 7 hearts each: group I consisted of controls, group II was perfused
with temocaprilat (10(-6)mol/L), group III was perfused with CV-11974 (10(
6)mol/L), and group IV was perfused with temocaprilat (10(-6)mol/L) in
combination with CV-11974 (10(-6) mol/L). Groups II and III showed a significant
(p<0.05) inhibition of an overshoot phenomenon of PCr during postischemic
reperfusion compared with group I. Group IV also showed a more pronounced
significant (p<0.01) inhibition of the overshoot of PCr during reperfusion
compared with group I. Groups II, III and IV showed a significant (p<0.05)
inhibition of the decrease in ATP during global ischemia (59+/-2, 54+/-3 and 54+/
7%, respectively) compared with group I (45+/-3%). Groups II and IV showed a
significant (p<0.05) early recovery of ATP during reperfusion (81+/-2, 80+/-6%)
compared with group I (71+/-3%) and group II (73+/-2%). Group IV showed no more
significant recovery in ATP than group III. There were no differences in LVDevP,
LVEDP and coronary flow among these groups. In conclusion, temocaprilat in
combination with CV-11974 has significant potential for improving myocardial
energy metabolism during both myocardial ischemia and reperfusion.
PMID- 10783051
TI - Strain difference in rats with experimental giant cell myocarditis.
AB - Immunogenetic mechanisms may be involved in the pathogenesis of myocarditis and
dilated cardiomyopathy. The present study investigated the incidence,
histopathology and histocompatibility characteristics of experimental giant cell
myocarditis in various strains of rats. Experimental giant cell myocarditis was
induced by immunization with porcine cardiac myosin in Lewis (RT-1(l)), Dahl
(DIR/Eis) (RT-1(l)), Fisher (RT-1(lv 1)) rats, but not in Dahl (DIS/Eis) (RT
1(l)) or Brown Norway (RT-1(n)). Myocarditis was most severe in the Lewis rats
and their heart weight/body weight ratio was significantly higher than that of
control rats immunized with Freund's complete adjuvant alone. In conclusion, this
study provides evidence that the expression and severity of experimental giant
cell myocarditis may be determined mainly by genetic factors, including both
major histocompatibility complex genes as well as other genes, which may be
controlled by an immune mechanism.
PMID- 10783052
TI - Anisotropic conduction prolongs ventricular repolarization and increases its
spatial gradient in the intact canine heart.
AB - The effects of the activation sequence on ventricular repolarization and its
spatial gradient were examined in anesthetized open-chest dogs. Unipolar and
bipolar electrograms were recorded from 47 epicardial sites on the anterior left
ventricular wall using a mapping electrode. The local QT interval (QT) and the
activation time (AT) at each site were measured on the unipolar and bipolar
electrograms, respectively. The QT index (QTI) was defined as the QT minus AT
interval, and was used as a measure of local repolarization. QTI was longer at
each site during propagation that was longitudinal (L) (219+/-21 ms) than during
propagation transverse (T) (202+/-22 ms, p<0.001) to the epicardial fiber
orientation or during atrial pacing (165+/-20 ms, p<0.001). During L-propagation,
the QTI shortened as a function of the distance from the stimulus. The spatial
gradient was steeper during T-propagation (p<0.05). Monophasic action potentials
(MAP) were also recorded simultaneously at 4 epicardial sites. The MAP duration
during ventricular pacing was longer than during atrial pacing at sites within
1.5 cm of the pacing site. This difference disappeared at more distant sites and
was attenuated by a simultaneous stimulus from a site symmetrically aligned along
the fiber. These findings indicate that anisotropic conduction prolongs
ventricular repolarization and increases its spatial gradient in the intact
heart. An electrotonic downstream effect appears to be the cause.
PMID- 10783053
TI - Electrogram characteristics indicative of a recurrent conduction site after
ablation of the inferior vena cava-tricuspid annulus isthmus: a study in the
canine blood-perfused atrioventricular preparation.
AB - Analysis of the electrograms recorded along the ablation line can identify a
recurrent conduction site after ablation of the isthmus between the inferior vena
cava (IVC) and tricuspid annulus (TA) for atrial flutter. The present study
examined the relationship between the activation sequence and electrogram
characteristics using a model of recurrent conduction in the isthmus. The canine
heart was isolated (n=8) and cross-circulated with the arterial blood of a
support dog. A plaque electrode was placed at the isthmus, and 42 bipolar
electrograms (filtered and unfiltered) were recorded during pacing at
120beats/min from the lateral right atrium before and after creating a narrow gap
by 2 discontinuous incisions from the TA to the IVC. All bipolar electrodes, with
the cathode in the TA side and the anode in the IVC side, were placed
perpendicular to the TA. Before creating the incisions, the wavefront (WF) from
the pacing impulse traveled uniformly in the isthmus and almost in parallel to
the TA, and the filtered electrogram at each site showed a single potential.
After creating the incisions, the WF propagated through the gap and spread
radially to the area distal to the incisions. In close proximity to the incision
lines opposite to the pacing site, the WF advanced from the gap towards the TA
and IVC perpendicularly to the TA. Filtered electrograms on the incision lines
showed double or split potentials, whereas those on the gap showed a single or
fractionated potential. In unfiltered electrograms recorded from the TA to the
IVC in close proximity to the incision lines opposite the pacing site, reversal
of electrogram polarity was noted at the gap. A single or fractionated potential
between double potentials indicates a gap between lines of conduction block.
Electrogram polarity reversal along the ablation line indicates the presence of 2
opposing WF arising from the gap.
PMID- 10783054
TI - Five-year intra-individual variability in C-reactive protein levels in a Japanese
population-based study: the Jichi Medical School Cohort Study at Yamato, 1993
1998.
AB - C-reactive protein (CRP) is an acute-phase reactant that is related to future
cardiovascular events. However, little is known about the long-term intra
individual stability of CRP in community residents. The 5-year intra-individual
correlation of CRP levels was examined in the Jichi Medical School Cohort Study
in Japan. CRP measurements were obtained in 1993 and in 1998 from 388
presumptively healthy individuals aged 30-69 years at baseline. The Pearson's
correlation coefficient of CRP between baseline and follow-up measurements was
0.43 (95% confidence interval (CI): 0.34-0.51). Additional analyses by sex and
smoking status at baseline revealed similar coefficients. The correlation
coefficient of CRP was lower than that of other classical risk factors, such as
body-mass index (BMI), blood pressure, and total and high-density lipoprotein
(HDL) cholesterol. A subgroup of individuals with higher levels of CRP at both
baseline and follow-up measurements had higher BMI, hemoglobin Alc, and plasma
fibrinogen, and lower levels of HDL-cholesterol than others, even after adjusting
for age, sex, and smoking status in a multiple logistic model. In conclusion, the
stability of CRP levels was statistically significant in a long-term population
based study. A subgroup with higher levels of CRP who had an aggregation of
cardiovascular risk factors was identified by the 2 measurements.
PMID- 10783055
TI - Severe thrombocytopenia caused by digitoxin intoxication in a patient with heart
failure associated with Sjogren's syndrome.
AB - Congestive heart failure (CHF) related to Sjogren's syndrome is extremely rare.
This report concerns a patient who presented with CHF and severe thrombocytopenia
(5,000/microl). Serum concentrations of K, Mg and digitoxin were 3.2mmol/L,
1.4mg/L and 57.2ng/ml, respectively. Digitoxin intoxication was evident,
seemingly evoked by hypokalemia, hypomagnesemia, hepatorenal dysfunction and
hypothyroidism. The severe thrombocytopenia was considered to have been caused by
this intoxication, as it disappeared soon after the digitoxin was discontinued
and potassium was supplemented.
PMID- 10783056
TI - Oozing type cardiac rupture repaired with percutaneous injection of fibrin-glue
into the pericardial space: case report.
AB - Two patients, a 56-year-old man and an 81-year-old woman who were admitted to
hospital because of anteroseptal acute myocardial infarction, were initially
treated successfully with direct percutaneous transluminal coronary angioplasty.
However, both patients later developed sudden cardiogenic shock due to cardiac
tamponade caused by left ventricular free wall rupture (LVFWR). Prompt, life
saving pericardiocentesis was performed, then fibrin-glue was percutaneously
injected into the pericardial space. After the procedure, there was no detectable
pericardial effusion on echocardiography and the hemodynamic state became stable.
The surgical treatment was the standard procedure for LVFWR, but percutaneous
fibrin-glue therapy can also be considered for oozing type LVFWR.
PMID- 10783057
TI - Aorto-coronary dissection during angioplasty in a patient with myxedema.
AB - A 67-year-old man with overt hypothyroidism and medically controlled hypertension
was admitted for coronary angiography because of exertional angina. His
triiodothyronine (T3) and thyroxine (T4) levels had been low for 4 years.
Although signs and symptoms of hypothyroidism were apparent, his
hypercholesterolemia was mild. Coronary angiography revealed an eccentric
stenosis in the distal portion of the right coronary artery and it was decided to
perform angioplasty because his angina had continued in spite of medication. The
dissection appeared at the lesion site after the first nominal inflation, and a
subsequent image disclosed a spiral dissection from the dilated site to the
aortic sinus and peripheral coronary artery. Although emergency stenting could
not prevent the extension near the origin of the brachiocephalic artery, the
false lumen thrombosed and then diminished with conservative therapy. Aorto
coronary dissection is potentially life-threatening and has been recently
reported as a complication during cardiac catheterization procedures. Chronic
hypothyroid insufficiency may be one of the risk factors for this complication.
PMID- 10783058
TI - Interferon treatment for dilated cardiomyopathy and striated myopathy associated
with hepatitis C virus infection based on serial measurements of serum
concentrations of cardiac troponin T.
AB - The present authors recently suggested, on the basis of studies using polymerase
chain reaction (PCR), that hepatitis C virus (HCV) infection is involved in the
etiology or pathogenesis of cardiomyopathic disorders. They have also reported
that the serum concentration of cardiac troponin T is an indicator of ongoing
myocyte degeneration in patients with dilated cardiomyopathy (DCM) and
hypothesized that its serial measurement may be a marker of therapeutic efficacy.
This is the first case report of DCM and striated myopathy, associated with HCV
infection, treated with interferon therapy guided by monitoring of serial serum
concentrations of cardiac troponin T. Positive-plus strands of HCV RNA were found
in the patient's myocardium, as well as plus and minus strands in the quadriceps
muscle specimens. Serum levels of creatine kinase (CK), CK-MB and cardiac
troponin T fell as serum HCV titers decreased during treatment with interferon,
whereas conventional treatment of heart failure had no effect. Monitoring of
serial serum concentrations of cardiac troponin T may allow the earlier diagnosis
and treatment of patients with HCV-associated cardiomyopathy and improve their
clinical course.
PMID- 10783059
TI - Catalytic mechanism of class A beta-lactamase. I. The role of Glu166 and Serl30
in the deacylation reaction.
AB - The tetrahedral intermediate formation process, which is the first step in the
deacylation reaction by class A beta-lactamase, was investigated by the ab initio
molecular orbital method. In this study, benzyl penicillin was used as the
substrate. From the results of our molecular dynamics study of the structure of
beta-lactam antibiotics-beta-lactamase complex, the substrate, Ser70, Lys73,
Ser130, Glu166 and a water molecule for the deacylation reaction were considered
for construction of a model for calculation. The calculation results indicated
that Glu166 plays a role in holding a water molecule, which is necessary for the
deacylation reaction, and that the hydrogen bond network among Lys73Nzeta,
Ser130Ogamma, and the carboxyl group of the beta-lactam antibiotics was formed by
the uptake of beta-lactam antibiotics by beta-lactamase. The activation energy
for this reaction was 33.3 kcal/mol, and it is very likely that the reaction
occurred at body temperature. Subsequent calculation results obtained by using
the model excluding Ser130 and the carboxyl group of the substrate indicated that
the activation energy for this reaction was 40.8 kcal/mol, which is 7.5 kcal/mol
higher than that of the previous reaction. It was found that the hydrogen bond
network plays an important role in decreasing the activation energy for the
tetrahedral intermediate formation reaction. Lys73Nzeta, which is located at the
edge of the hydrogen bond network, played a role in forming a hydrogen bond with
Glu166Oepsilon in order to help the deacylation reaction. The role of amino acid
residues around the active site of class A beta-lactamase was also discussed.
PMID- 10783060
TI - Enzymatic reactivity and anti-tumor activity of 1-(beta-D-arabinofuranosyl)-2
thiocytosine derivatives.
AB - Sixteen derivatives of 1-(beta-D-arabinofuranosyl)-2-thiocytosine (araSC),
including five 5'-esters, three 3'-esters, five N4-amides and three 5'
phosphodiesters, were synthesized and their reactivity to mouse tissue
homogenates, including plasma, liver and intestine, and antitumor activity in
mice bearing P388 cells were measured. The ester derivatives had a potent effect
on the enzyme systems while the amide and phosphodiester derivatives were less
active. The reactivity of ester derivatives was highly dependent on their
chemical structure. The reactivity of amides and phosphodiester derivatives on
mouse plasma and intestinal homogenate was also dependent on the chemical
structure, although their action on intestinal enzymes was very similar. Two of
eight ester derivatives showed considerable antitumor activity in vivo, although
they also showed serious toxicity indicated by a weight loss in the mice. Four
out of five amides and two out of three phosphodiesters showed antitumor
activity, and two were highly effective (>200% in T/C, the ratio of the mean
survival time of the treated group to that of the control group) with only a very
slight weight loss.
PMID- 10783061
TI - A comparison of cellactose with two ad hoc processed lactose-cellulose blends as
direct compression excipients.
AB - Three processed lactose-cellulose blends of similar composition, particle size
and true density were compared as direct compression excipients: one was prepared
by dry granulation, one by extrusion-spheronization, and the commercial product
Cellactose. Differences among their flow properties depended solely on their
different sphericities. Unlike those of the other blends, Cellactose particles
exhibited numerous macropores. The mean yield pressures of all three blends were
similar to those of direct compression lactoses. Cellactose tablets prepared at a
punch pressure that largely eliminated macropores (pores >1 microm) had better
mechanical properties but much poorer disintegration than tablets of the other
blends prepared at the same punch pressure. However, the tensile strength and
disintegration time of Cellactose tablets both fell rapidly as macropore volume
was increased by reducing punch pressure, while the enthalpy of
wetting/dissolution rose. The strength and water-resistance of well-compacted
Cellactose tablets is attributed to the spatial distribution of lactose and
cellulose in Cellactose particles, rather than to beta-lactose content or extra
particular structural features.
PMID- 10783062
TI - Studies on thermal aggregation of bovine serum albumin as a drug carrier.
AB - The irreversible thermal aggregation rate and process of bovine serum albumin
(BSA) were investigated by means of light scattering technique as a function of
temperature. The increasing rate of particle radius was affected by the
aggregation temperature, concentration and the presence of fatty acid. The
particle radius was larger and the aggregation rate was faster for fatty acid
free BSA at higher temperature and concentration. Two thermal aggregation
processes were observed at relatively low temperature and concentration, both for
fatty acid containing (C-BSA) and fatty acid free BSA (F-BSA). The first process
proceeds by an inter-monomer aggregation mechanism, and the second process by
inter-aggregates aggregation. The first process is represented by a power law as
Rhapp proportional to t(z), which is diffusion limited cluster aggregation
(DLCA).
PMID- 10783063
TI - Quantitative analysis of the kinetic constant of the reaction of N,N'
propylenedinicotinamide with the hydroxyl radical using dimethyl sulfoxide and
deduction of its structure in chloroform.
AB - N,N'-Propylenedinicotinamide (Nicaraven) is presently being developed for the
treatment of cerebral stroke including subarachnoid hemorrhage. This drug is
promising because some data suggest it to have an ability to scavenge the
hydroxyl radical under physiological conditions in vivo, while it also has a high
permeability through the blood brain barrier. Using the kinetic constant of the
reaction between the hydroxyl radical and dimethyl sulfoxide, the formula derived
by Babbs and Griffin (Free Rad. Biol. Med., 6 1989) was applied to obtain the
kinetic constant of Nicaraven with the hydroxyl radical using a dimethyl
sulfoxide-xanthine oxidase-hypoxanthine-Fe system, and this yielded the kinetic
constant 3.4x10(9) M(-1) s(-1) (1 M=1 mol dm(-3)) for Nicaraven. Structurally
related compounds were also investigated. The amide group of Nicaraven was thus
found to play an important part in the reaction with the hydroxyl radical.
Methanesulfinic acid, which was obtained from the reaction between dimethyl
sulfoxide and the hydroxyl radical, was found to be stable under this adopted
experimental condition and therefore was used to quantify the kinetic constant of
Nicaraven. The structure of Nicaraven has also been investigated in CDCl3 using
IR spectra, computer calculations and 1H-NMR analysis, and Nicaraven was thus
shown to have an intramolecular hydrogen bond which forms a 7-membered ring that
resembles a part of the 1H-1,4-benzodiazepines. This structure may play an
important role in the penetration through the blood brain barrier.
PMID- 10783064
TI - Effect of the linking position of a side chain in
bis(quinolylmethyl)ethylenediamine as a DNA binding agent.
AB - Two bisquinoline derivatives, N,N'-bis(2-quinolylmethyl)ethylenediamine (2-BQME)
and N,N'-bis(8-quinolylmethyl)ethylenediamine (8-BQME) have been synthesized, and
their ability to bind to duplex DNA was studied. 8-BQME bound to DNA more
strongly than 2-BQME, judging from the extent of increase in the melting
temperature of duplex DNA, the UV-vis spectral change, and ethidium displacement
assay. These compounds exhibited apparent AT-specificity suggesting minor groove
binding in addition to intercalation.
PMID- 10783065
TI - Molecular dynamics simulations of bovine cathepsin B and its complex with CA074.
AB - To promote our better understanding of the dynamic stability of the bovine
cathepsin B structure, which is characterized by an extra disulfide bond at
Cys148-Cys252 from the other species, and of the binding stability of CA074 (a
cathepsin B-specific inhibitor), molecular dynamics (MD) simulations were
performed for the enzyme and its CA074 complex, assuming a system in aqueous
solution at 300 K. The MD simulation covering 400 ps indicated that the existence
of a Cys148-Cys252 disulfide bond increases the conformational flexibility of the
occluding loop, although the conformational stability of the overall structure is
little affected. The structural characteristics of the complex elucidated by X
ray analysis were suggested to be also intrinsic and stable in the dynamic state;
the hydrogen bonding/electrostatic interactions between the main and side chains
of CA074 and the Sn and Sn' subsites of the enzyme were maintained throughout the
MD simulation. Furthermore, the simulation made clear that the binding of CA074
significantly restricted the conformational flexibility of the substrate binding
region, especially the occluding loop, of cathepsin B. Statistical analyses
during the simulation suggest that the selectivity of CA074 for cathepsin B stems
from the tight P1'-S1' and P2'-S2' interactions, assisted in particular by double
hydrogen bonds between the carboxyl two oxygens of the CA074 C-terminus and the
imidazole NH groups of His110 and His111 residues.
PMID- 10783066
TI - Podophyllotoxin aza-analogue, a novel DNA topoisomerase II inhibitor.
AB - The pendant E-ring moiety of the podophyllotoxin aza-analogue 1 that is a potent
inhibitor of microtubule assembly was modified in order to acquire inhibitory
activity of DNA topoisomerase II. The monophenolic analogue 2 did not exhibit
human topoisomerase II inhibition, while the ortho-quinone 3 that was obtained by
oxidation of 2 inhibited its catalytic activity (decatenation) in a dose
dependent manner and stimulated double strand DNA breaks in supercoiled circular
plasmid DNA, resulting in the production of linear DNA. These results showed that
the topoisomerase II inhibition of the ortho-quinone 3 is due to stabilization of
the topoisomerase II-DNA covalent binary complex. On the other hand, the ortho
quinone 3 did not inhibit the relaxation process of supercoiled DNA by
topoisomerase I at concentrations up to 400 microM, nor was intercalation
observed in unwinding measurements of 3. Therefore, the ortho-quinone 3 was shown
to be a novel nonintercalative topoisomerase II specific inhibitor that
stabilizes the cleavable complex. The present results suggest that the 4'-free
hydroxyl group on the E-ring and the sugar moiety on the C-ring are not a
prerequisite for topoisomerase II inhibition by podophyllotoxin derivatives.
PMID- 10783067
TI - Novel potassium channel opener prodrugs with a slow onset and prolonged duration
of action.
AB - (-)-(3S,4R,1'R,6'S)-4-(4-Benzyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2 -yloxy)
3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbo nitrile and its
derivatives with a modified benzyl group were synthesized with the objective of
discovering novel ATP-sensitive potassium channel openers (PCOs) with a slow
onset of action and a reduced tendency to induce tachycardia. Among the compounds
synthesized, 4-(2-chlorobenzyl) derivative 5bB had potent hypotensive activity in
spontaneously hypertensive rats (SHRs). In addition, compound 5bB showed the
desired pharmacological profile with a slow onset and long duration of action and
induction of only mild tachycardia. Compound 5bB was found to be quantitatively
metabolized in rats to give active des-2-chlorobenzyl derivative 6B. These
results suggest that the incorporation of an N-benzyl group is a useful method
for the preparation of prodrugs, the function of which is to delay the onset and
prolong the duration of action of the active substance.
PMID- 10783068
TI - Methyl quadrangularates A-D and related triterpenes from Combretum quadrangulare.
AB - From the MeOH extract of leaves of Combretum quadrangulare, fifteen new
cycloartane-type triterpenes, methyl quadrangularates A-D (1-4) and N-P (8, 6,
12), methyl 24-epiquadrangularate C (5), quadrangularic acid E (9), 23
deoxojessic acid (10), 1-O-acetyl-23-deoxojessic acid (11), quadragularols A (7)
and B (13) and norquadrangularic acids B (14) and C (15) were isolated together
with two known cycloartane-type triterpenes, methyl 23-deoxojessate (16) and
4beta,14alpha-dimethyl-5alpha-ergosta-9beta++ +,19-cyclo-24(31)-en-3beta-hydroxy
4alpha-carboxylic acid (17). Betulinic acid (18), beta-sitosterol (19),
kamatakenin (20), isokaempferide (21), 5,7,4'-trihydroxy-3,3'-dimethoxyflavone
(22) and 5,4'-dihydroxy-3,7,3'-trimethoxyflavone (23) were also obtained from the
same extract. The structures of the new compounds were elucidated on the basis of
spectral analysis and chemical conversions. All the isolated compounds were
tested for their cytotoxicity towards highly liver metastatic murine colon 26-L5
carcinoma cells, and the cycloartane-type triterpenes showed various degrees of
cytotoxicity, whereas all the flavonoids possessed strong cytotoxicity with ED50
values equal to or less than 6 microM.
PMID- 10783069
TI - Structures of 4-aryl-coumarin (neoflavone) dimers isolated from Pistacia
chinensis BUNGE and their estrogen-like activity.
AB - Activity-guided fractionation of twigs of Pistacia chinensis resulted in the
isolation and characterization of two novel ingredients as potent estrogen
agonists. On the basis of spectral analysis and comparison with a related
compound their structures were elucidated as 3,3''-dimers of 4
aryldihydrocoumarins (3,4-dihydro-4-(4'-hydroxyphenyl)-7-hydroxycoumarin)
differing only in the stereochemical disposition of the linkage between the two 4
arylcoumarin moieties. These compounds are the first examples of bis-flavonoids
which have been proven to possess estrogen-like activity.
PMID- 10783070
TI - 4-Sulfenyl-2-carbamoyl-4-isoxazolin-3-ones: biological isostere to 4-chloro-2
carbamoyl-4-isoxazolin-3-ones.
AB - 4-Sulfenyl-2-carbamoyl-4-isoxazolin-3-ones (4) were designed on the basis of
biological isosterism and prepared in four steps. Some of these compounds showed
sufficient pre-emergent herbicidal activities against various kinds of weeds.
Among the synthesized compounds, 2-(N-(4-chlorophenyl)-N-isopropylcarbamoyl)-4
ethylthio-5-methyl-4 -isoxazolin-3-one (4cd) exhibited the most promising
activity.
PMID- 10783071
TI - Cardenolide and oxypregnane glycosides from the root of Asclepias incarnata L.
AB - Twenty-nine new oxypregnane glycosides were obtained along with two known
cardenolides, frugoside and gofruside, and three known 12-O-acylated pregnane
glycosides from the roots of Asclepias incarnata L. (Asclepiadaceae). By detailed
studies of the 1H- and 13C-NMR spectra, the structures were determined to be tri-
to penta glycosides of isolineolon, 12-O-acetyllineolon, ikemagenin, 12-O
benzoylisolineolon, and two new 12-O-acylated pregnanes.
PMID- 10783072
TI - Studies on the reaction of benzo[x]quinoline N-oxides (X = f, h, and g) with
methylsulfinyl carbanion using the semi-empirical molecular orbital method.
Liberation of the N-oxide group.
AB - The mechanism of the liberation reaction of the N-oxide group has been studied
and compared with the methylation reaction using a semi-empirical molecular
orbital PM3 method. By comparing the calculated values of Gibbs free energy of
activation, we can determine whether a liberation reaction or methylation
reaction occurs.
PMID- 10783073
TI - Improved synthesis of paroxetine hydrochloride propan-2-ol solvate through one of
metabolites in humans, and characterization of the solvate crystals.
AB - Paroxetine, a potent and selective inhibitor of 5-hydroxytryptamine (serotonin)
uptake, was prepared through a piperidine derivative, which was reported to be
one of the paroxetine metabolites in humans. Thus, the piperidine derivative was
converted to its N-tert-butoxycarbonyl (N-Boc) derivative, which was then
converted to N-Boc paroxetine. Paroxetine hydrochloride propan-2-ol (isopropyl
alcohol (IPA)) solvate crystals were directly obtained from the N-Boc paroxetine
by adding hydrogen chloride to the N-Boc paroxetine IPA solution. The amount of
IPA content in the crystals was reduced by drying with a continuous change of
powder X-ray diffraction patterns. Other characterizations of the solvate
crystals were also conducted.
PMID- 10783074
TI - Structural and spectral characteristics of the electrogenerated
tetracyanoethylene dianion.
AB - Structural and spectral characteristics of the electrogenerated
tetracyanoethylene dianion (TCNE2-) were experimentally and theoretically
examined. Spectroelectrochemistry of TCNE gives the spectra of TCNE2- in CH3CN at
220 nm, and in CH2Cl2 at 300 nm. These spectral characteristics are well
explained by CIS/6-31G(d) and semiempirical CNDO/S-CI calculations. The bands in
CH3CN and in CH2Cl2 are assigned to the degenerate 1E<--1A1 transition at the D2d
structure and the 1B2u<--1Ag transition at the D2h structure, respectively. The
rotation barrier of the C=C bond in TCNE2- is estimated by Hartree-Fock (HF),
second-order Moller-Plesset perturbation (MP2) and fourth-order MP (MP4)
calculations with 6-31G(d), 6-31+G(d) and 6-311+G(d) basis sets as 42-51 kJ mol(
1). The D2d structure is most stable, and the D2h structure represents the
transition state of the internal rotation. The calculations reveal that the two
electron addition to the antibonding LUMO of TCNE causes an easy rotation around
the C=C bond of TCNE2- characterized by the formal single bond. These results
show that TCNE2- preferentially adopts D2d and D2h structures in solvents
depending upon the solvent nature by virtue of the easy rotation around the C=C
bond.
PMID- 10783075
TI - Megastigmane, benzyl and phenethyl alcohol glycosides, and 4,4'-dimethoxy-beta
truxinic acid catalpol diester from the leaves of Premna subscandens MERR.
AB - Extensive isolation work on the n-BuOH-soluble fraction obtained from the leaves
of Premna subscandens, collected on Ishigaki island, Okinawa, afforded six
compounds. Two were identified as megastigmane glucosides, 7-(3,5-dihydroxy-1,1,5
trimethylcyclohexylidene)-9-methylprop++ +-8-enyl 9-O-beta-D-glucopyranoside and
3-hydroxy-5,6-epoxy-beta-ionol 9-O-beta-D-glucopyranoside. The structures of the
remaining four new compounds were elucidated to be a 2'-O-beta-D-apiofuranosyl
derivative of 3-hydroxy-5,6-epoxy-beta-ionol 9-O-beta-D-glucopyranoside, named
premnaionoside, benzyl alcohol beta-D-(2'-O-beta-D-xylopyranosyl)glucopyranoside,
phenethyl alcohol beta-D-(2'-O-beta-D-glucopyranosyl)glucopyranoside, and 4,4'
dimethoxy-beta-truxinic acid catalpol diester by spectroscopic analyses.
PMID- 10783076
TI - Glochidionolactones A-F: butenolide glucosides from leaves of Glochidion
zeylanicum (GAERTN) A. JUSS.
AB - From the leaves of Glochidion zeylanicum, six new butenolide glucoside, named
glochidionolactones A-F, were isolated along with a known related compound,
phyllanthurinolactone. The structures of glochidionolactones A-D and F were
elucidated mainly by spectroscopic analyses. The absolute stereochemistry of
glochidionolactone E was established by X-ray crystallographic analysis.
PMID- 10783077
TI - Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors.
AB - A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton
were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity
relationships for these compounds in terms of rat epididymis (type 2) 5alpha
reductase inhibitory activities reveal that 1) the substitution pattern at the 11
position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the
tricyclic skeleton improved potency, whereas the existence of a basic nitrogen
atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at
the 8 positon of the azepine skeleton was tolerated. Among the tricyclic
compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11
dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most
potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.
PMID- 10783078
TI - Cholestane glycosides from Solanum abutiloides. III.
AB - Four new cholestane glycosides, named abutilosides D (1), E (2), F (3) and G (4),
were isolated from the fresh roots of Solanum abutiloides. By chemical and
spectroscopic evidence, their structures were elucidated as 26-O-beta-D
glucopyranosyl 3beta,16alpha,26-trihydroxy-5alpha-cholestan-22-one 3-O-beta-D
xylopyranosyl-(1-->2)-alpha-L-rhamnopyranosyl-(1-->4)-beta-D- glucopyranoside and
its desxylosyl compound (1 and 3, respectively), 26-O-beta-D-glucopyranosyl
3beta,16alpha,26-trihydroxycholest-5-en-22-one 3-O-beta-D-xylopyranosyl-(1-->2)
alpha-L-rhamnopyranosyl-(1-->4)-beta-D- glucopyranoside and its desxylosyl
compound (2 and 4, respectively). These compounds were regarded as precursors of
a dormantinone type compound on a hypothetical pathway of steroid biogenesis.
PMID- 10783079
TI - Butyrolactones from Aspergillus terreus.
AB - In the process development of lovastatin using Aspergillus terreus DRCC 152 in
solid state fermentation, we have isolated a new butyrolactone-IV (3) along with
the previously reported butyrolactone-I (1) and butyrolactone-II (2) produced
under submerged conditions. The structure of compound 3 has been characterized as
3-hydroxy-5-[2-(1-hydroxy-1-methylethyl)-2(R)-2,3-dihydro-benzo[b]furan- 5
ylmethyl]-4-(4-hydroxyphenyl)-5-methoxycarbonyl-(5R)-2,5-dihydro-2 -furanone on
the basis of spectroscopic studies. The absolute stereochemistry has been
determined by single crystal X-ray diffraction studies. The cytotoxic and
antibacterial activities of these compounds were determined.
PMID- 10783080
TI - Efficient synthesis of a key intermediate of DV-7751 via optical resolution or
microbial reduction.
AB - Two efficient and practical methods of synthesis of the C-10 substituent of DV
7751 (1), a novel quinolone carboxylic acid, were established. The first method
utilizes an optical resolution of racemic 8-amino-6-benzyl-6-azaspiro[3.4]octane
(13), while the second employs an enantioselective microbial reduction of 6
benzyl-5,8-dioxo-6-azaspiro[3.4]octane (8b). The enantiomeric excess of (S)-8
amino-6-benzyl-6-azaspiro[3.4]octane (11) with each method of synthesis is
greater than 96%.
PMID- 10783081
TI - Differentiation inducing activities of isocoumarins from Hydrangea Dulcis Folium.
AB - In the course of searching for differentiation inducers against leukemic cells
from plants, we have recognized the differentiation inducing activities of the
methanolic extract of Hydrangea Dulcis Folium. Activity guided separation of the
extract was carried out using M1 cells, and seven isocoumarins were isolated as
active substances. These isocoumarins showed the activities at the concentration
of 100 microM and non-cytotoxic effects even at 300 microM.
PMID- 10783082
TI - Studies on the constituents of solanaceous plants. (46). Steroidal glycosides
from the fruits of Solanum anguivi.
AB - Three new glycosides named anguiviosides A-C were isolated from the fruits of
Solanum anguivi and characterized as follows:3-O-beta-chacotrioside (1), 3-O-[4-O
maloyl-alpha-L-rhamnopyranosyl(1-->2)]-alpha-L-rhamnopyra nosyl(1-->4)-beta-D
glucopyranoside (2) and 3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-xylopyranosyl(1
->3)]-beta-D-+ ++glucopyranoide (3), of (25R,26R)-spirost-5-en-3beta,26-diol.
PMID- 10783083
TI - Stereoselective reactions. XXXII. Enantioselective deprotonation of 4-tert
butylcyclohexanone by fluorine-containing chiral lithium amides derived from 1
phenylethylamine and 1-(1-naphthyl)ethylamine.
AB - Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1
phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides
having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium
amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily
accessible in both enantiomeric forms, and were found to induce good
enantioselectivity in the present reaction.
PMID- 10783084
TI - Two novel C-glycosides of aureolic acid repress transcription of the MDR1 gene.
AB - In the search for compounds which repress MDR1 gene expression, two novel aryl C
glycosides were isolated from a broth of Streptomyces sp. They had the
characteristic structure of a dideoxy-carbohydrate (oliose or olivose) linked
directly to chromomycinone, an aglycone of aureolic acids. Further investigation
revealed that they were artifacts yielded from an aureolic acid, mithramycin.
Acid and methanol were necessary to yield the C-glycosides. This reaction would
contribute to the design of useful aryl C-glycosides.
PMID- 10783085
TI - The controlled release of a drug from biodegradable chitosan gel beads.
AB - Chitosan (CS) forms a gel in solutions with a pH above 12, and the gelation
occurs at pH of about 9 in 10% amino acid solutions. In this paper, we
investigated the enzymatic degradation and the drug release profile of this novel
CS gel beads. The degradability of the CS gel beads was affected by the CS
properties, e.g. the degree of deacetylation. The release of prednisolone (PS),
as a model drug, from the CS gel beads was sustained significantly compared with
the gel prepared with NaOH only. However, the release was not able to be
sustained by the increment of NaOH concentration in the solution employed for the
preparation of CS gel beads. We also investigated the control of drug release
from CS gel beads by application of a complex formed between chondroitin sulfate
(Cho) and CS. The release of PS from the CS gel beads treated with Cho was
prolonged, and the release pattern was not affected by the treatment time. The
time to 50% drug release was about 5 min with PS powder, about 200 min in CS gel
beads with 10% glycine (Gly) (pH 9.0), and about 330 min in the CS gel beads with
10% Gly (pH 9.0) treated with Cho. Thus CS gel beads appear promising as a
vehicle for sustained drug delivery, and the degradation of CS gel beads may be
controlled by the degree of deacetylation of CS.
PMID- 10783086
TI - Four new furanone-coumarins from Clausena excavata.
AB - Four new furanone-coumarins, clauslactones-N (4), -O (5), -P (6) and -Q (7) were
isolated from the leaves and twigs of Clausena excavata BURM. f. (Rutaceae)
collected in Indonesia and their structures were elucidated by spectroscopic
analysis.
PMID- 10783087
TI - Temperature-induced crystallization and compactibility of spray dried composite
particles composed of amorphous lactose and various types of water-soluble
polymer.
AB - The purpose of this study was to investigate the temperature-induced
crystallization and the compactibility of the composite particles containing
amorphous lactose and various types of polymers. The composite particles were
prepared by spray-drying an aqueous solution of lactose and various types of gel
forming water-soluble polymers at various formulating ratios. The stabilizing
effect of hydroxypropylcellulose (HPC) and polyvinyl pyrrolidone (PVP) on
amorphous lactose in the composite particles was smaller than that of sodium
alginate in comparing at the same formulating ratios. The difference in the
stability of amorphous lactose in the composite particles was attributed to the
difference in the glass transition temperature (Tg) of the composite particles
caused by the polymers formulated. The tensile strength of compacted spray-dried
composite particles containing the polymers was higher than commercial lactose
for direct tabletting (DCL21). The tensile strength of the composite particles
was increased with an increase in water content in the particles. The difference
in compactibility of the composite particles containing the different amount of
polymer and water could be explained by the difference in Tg of the particles.
PMID- 10783088
TI - An efficient synthesis of the anti-asthmatic agent T-440: a selective N
alkylation of 2-pyridone.
AB - 6,7-Diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin- 4-yl]naphthalene-2,3
dimethanol [T-440, (1)] is a potential anti-asthmatic agent based on selective
phosphodiesterase 4 inhibition. It was necessary for the further evaluation of 1
to develop an efficient synthetic route for 1, especially the construction of the
1-(2-methoxyethyl)-2-pyridone moiety. We examined an N-selective alkylation of
pyridone derivative (2) in basic media. 2-Methoxyethylation of 2 with 2
methoxyethyl iodide utilizing LiH as the base gave predominantly an N-alkyl
pyridone derivative (3a) in 82% yield (N/O-alkylation=92/8), which is compatible
with an ab initio calculation of transition-state structures for the methylation
of 2-pyridone. Single crystallization of a crude mixture of 3a and 4a furnished
pure 3a, which is a key synthetic intermediate of 1.
PMID- 10783089
TI - An outcome-based study of aesthetic surgery in a clinic setting.
AB - Previous studies have addressed the difficulties in training residents in
aesthetic surgery. The purpose of this study is to analyze patient satisfaction
with cosmetic surgery at an inner city teaching hospital as well as to evaluate
referral patterns. The patients included in this study underwent aesthetic
surgical procedures through the Kings County Hospital Plastic Surgery Clinic
(KCHC) from January 1, 1997, to June 30, 1998. Patients were informed that the
procedure would be performed by a plastic surgery resident with attending
supervision. Data were obtained in a retrospective fashion using telephone
surveys. Fifty-five patients participated in the study, which accounted for 68
aesthetic procedures. Sixty percent of patients considered the results of surgery
as excellent or good. On a patient satisfaction scale from 0 (unhappy) to 10
(exceedingly happy), patients' self-reporting average was 6.59. This mean value
may not be completely indicative of patient satisfaction. Eighty-nine percent of
patients would refer a friend and 78% of patients would have the same procedure
performed again. Sixty-nine percent of the patients had been referred by past
KCHC patients. All of these numbers tend to convey a higher degree of patient
satisfaction. The results of the study appear to convey the importance of
developing residents' ability to accurately explain to patients the anticipated
results of aesthetic surgery.
PMID- 10783090
TI - Replantation of avulsed scalps and secondary aesthetic correction.
AB - Five patients with avulsed scalps were treated with replantation between 1992 and
1998. All patients were women age 20 to 36 years. The percentage of the avulsed
scalp ranged from 50% to 100% of the whole scalp. The vessels chosen for
anastomosis were the superficial temporal artery, occipital artery, and
superficial temporal vein. A vein graft harvested from the cephalic vein of the
forearm was performed on the venous and arterial sides in 1 patient. Two patients
experienced complete survival of the replanted scalp. Three patients showed 40%,
50%, and 80% survival areas, with the remaining defects resurfaced as split
thickness skin grafts. Six months later, the scar areas in the last 3 patients
were reconstructed with an expansion of the normal or replanted scalp. The follow
up period ranged from 1 to 7 years. In 4 patients a partial return of sensation
in the replanted scalp and motor function of the frontalis muscle were observed.
All patients were satisfied with the aesthetic results of their surgery.
PMID- 10783092
TI - Neural anatomy of the radial forearm flap.
AB - Typically the lateral antebrachial cutaneous nerve alone is used to innervate the
radial forearm free flap when a sensate flap is required. The authors desired, by
means of fresh cadaveric microdissections and by means of local anesthetic
injections in living subjects, to map the sensory nerve territories of this flap.
Eight radial forearm flaps were elevated and the medial antebrachial cutaneous
nerve (MABC), lateral antebrachial cutaneous nerve (LABC), and superficial radial
sensory nerve (SRSN) were dissected with the aid of an operating microscope (2.5
10x) and traced to their dermal insertions. In the injection study, the MABC,
LABC, and SRSN in eight forearms of 4 subjects were blocked sequentially with 2%
lidocaine injections. The resulting sensory deficit from each injection was
mapped on the skin and superimposed on the marked radial forearm flap territory.
Distribution of the three dissected nerve regions and the sensory deficit after
injection were determined by digital images and computer analysis. During flap
dissections, mean nerve distributions of total flap area were as follows: LABC,
61.8% (range, 48.3-71.6%); MABC, 33.8% (range, 30.5-38.9%); and SRSN, 34.6%
(range, 26.8-44.1%). After nerve block the mapped sensory areas were as follows:
LABC, 62.3% (range, 44.5-88.5%); MABC, 19.6% (range, 8.0-35.8%); and SRSN, 19.5%
(range, 9.9-26.3%). At least 40% of the total flap area was not innervated by the
LABC as identified both by nerve dissection and sensory local anesthetic
blockade. By including the LABC, MABC, and SRSN in the radial forearm flap, both
the theoretical and the clinically determined useful sensory innervation of the
radial forearm flap potentially would be increased.
PMID- 10783091
TI - Distally based fasciocutaneous flap of the calf for cutaneous coverage of the
lower leg and dorsum of the foot.
AB - Cutaneous injuries of the inferior third of the leg and dorsum of the foot
represent a great challenge for plastic surgeons. The poor vascularization and
subsequent poor healing encountered in these regions demand detailed knowledge of
the local anatomy to select the best surgical alternative for each patient. In
patients in whom local or free muscular flaps are not suitable, the
fasciocutaneous flaps seem to be a good alternative. The distal pedicled
fasciocutaneous flap of the calf was used to cover skin defects of the leg and
foot in 22 patients. In 4 patients the authors designed an island flap to prevent
a large defect in the donor area and to decrease the time of hospitalization and
recovery of the patient. In a severe defect, the flap was used as a cross-leg
flap. The results were satisfactory because the flap provided stable coverage for
different defects with few complications. The island flap is a good option for
achieving a better aesthetic result and can be used in select patients.
PMID- 10783093
TI - Surgical treatment of urethral fistulas following hypospadias repair.
AB - Development of urethral fistulas is one of the most common late complications of
hypospadias surgery. A total of 161 male patients who had 186 urethrocutaneous
fistulas were first classified according to the fistula classification of Horton
and colleagues and then treated with three types of procedures: simple closure,
local rotation flaps, or tube graft reconstruction. With initial surgical
intervention, 156 of 186 fistulas were treated successfully. The remaining 30
fistulas (16.1%) recurred during the follow-up period. In the recurrent cases,
immediate closure was not preferred, and an average of 6 months was waited before
considering any additional surgical attempt. Distal cases had a higher failure
rate, and the simple closure technique failed to show a success rate as high as
local flap or tube graft repair. The high recurrence of distal cases was
attributed mainly to the lack of adequate soft tissue adjacent to the fistula,
which is vital for safe closure. In addition, the traction effect of erection on
the skin and urethra, which is more prominent distally than proximally, is also
believed to play an additive role. To increase success, the selection of
appropriate treatment modality and customization of techniques for each patient
cannot be overemphasized. However, the authors conclude that careful presurgical
assessment of the patient, a 6-month delay before any secondary surgical attempt,
inversion of the urethral mucosa, avoidance of any overlapping suture lines,
urinary diversion proximal to the repair site for 5 to 11 days, and usage of
thin, absorbable suture materials are the main criteria that should be met for a
satisfactory hypospadias fistula repair.
PMID- 10783094
TI - Periprosthetic breast capsules contain the fibrogenic cytokines TGF-beta1 and TGF
beta2, suggesting possible new treatment approaches.
AB - Periprosthetic breast capsules composed of fibrotic collagenous material with
increased collagen production are not dissimilar to other fibrotic conditions
occurring in other organs. Fibrosis in the lung, liver, kidney, and skin has been
associated with overproduction of the fibrogenic isoforms of transforming growth
factor beta (TGF-beta1 and TGF-beta2). If periprosthetic breast capsules
contained high levels of these cytokines, possibly new treatment approaches for
capsular contraction could be proposed. Breast implant capsules of 35 patients
harvested at the time of explantation were examined using indirect
immunohistochemistry. Staining intensity for TGF-beta1 and TGF-beta2 was measured
in all specimens. Immunohistochemical staining for TGF-beta1 and TGF-beta2
revealed that these two cytokines were present in all capsules analyzed. Minimal
TGF-beta1 and TGF-beta2 were found in normal breast tissue. Levels of control vs.
TGF-beta1 and control vs. TGF-beta2 were significant (p = 0.004 and p < 0.001
respectively). The presence of TGF-beta isoforms that are known to be fibrogenic
may suggest new therapeutic approaches, which are being investigated for other
fibrotic conditions.
PMID- 10783095
TI - Skin flap prefabrication using acellular dermal matrix and cultured keratinocytes
in a porcine model.
AB - In an effort to minimize the amount of autogenous tissue that is sacrificed in
using a random skin flap, the authors, in a porcine model, implanted 3.0 x 7.0-cm
(median thickness, 1 mm) sheets of commercially available nonmeshed acellular
dermal matrix (AlloDerm) subcutaneously. After a vascularization period of 2
weeks, the implants were elevated and used as turnover dermal flaps to cover
adjacent 3.0 x 3.0-cm full-thickness skin defects. Sheets of autogenous cultured
keratinocytes were used for epithelium. The AlloDerm-cultured keratinocyte
complex flaps healed without any complications. Measurements for percent
contraction of the wound to determine the suitability of AlloDerm as a dermal
flap showed that the wounds had contracted an average of 18 +/- 3.6% at 24 weeks.
Histological evaluation revealed multilayered keratinocytes and indurations
between the cultured keratinocytes and AlloDerm. Fibroblast infiltration and the
presence of luminal spaces surrounded by capillary endothelium characteristic of
neovascularization of the matrix were also noted. This preliminary study may form
the basis for developing other types of prefabricated flaps using AlloDerm and
cultured keratinocytes.
PMID- 10783096
TI - Comparison of immune response to nerve allograft segments in fetal and adult
rabbits: a histological study.
AB - Fetuses, as opposed to adults, are immature immunologically and it has been
proved that they can tolerate allograft materials much better than adults. In
this study the rejection phenomenon of nerve allografts was compared
histologically in fetuses and adults. The study was performed in 60 New Zealand
rabbits (30 pregnant and 30 nonpregnant), and allograft nerve segments were
obtained from Chinchilla rabbits. The animals were divided into fetal and adult
groups. Each group was studied at various time periods. Nerve allografts were
placed under the panniculus carnosus in the interscapular region of the fetuses
and adults. In both fetal and adult groups, the nerve allograft segments were
assessed histologically after 1, 7, and 30 days. The criteria used during the
evaluation were the degenerative findings in the myelinated axons (large, medium,
and small axons), changes in Schwann's cells, and the quantity of infiltrating
cells. The changes were graded microscopically from 0 (no change) to 3 (severe
destruction and cellular infiltration). Cellular infiltration was more extensive
in the adult groups than in the fetal groups. Earlier fetal groups showed minimal
infiltration, but the response became more extensive in the later fetal groups.
This is probably related to the removal of the fetuses from their intrauterine
environment. When comparing fetal and adult groups, the results were significant
(p < 0.05). The fetuses tolerated the nerve allograft segments better than the
adults. This may be related to the immature immune system of the fetuses.
PMID- 10783097
TI - Platelet supernatant promotes proliferation of auricular chondrocytes and
formation of chondrocyte mass.
AB - Recently proposed procedures for in vitro generation of new cartilage may be
difficult to perform in humans because so many chondrocytes are needed for tissue
engineering. In this study the authors investigated new, efficient, low-cost
techniques for the isolation and culture of chondrocytes from the ear cartilage
of the rabbit. They performed a low-density monolayer culture with a low
concentration (0.5%, 1%) of human platelet supernatant and observed cell
proliferation (seeding efficiency, deoxyribonucleic acid synthesis), matrix
synthesis (glycosaminoglycan synthesis), and the expression of type I and type II
collagen (reverse transcriptase polymerase chain reaction). Seeding efficiency
was increased in 1% of platelet supernatant-treated cultures by two to three
times compared with untreated controls. One percent platelet supernatant had
increased the incorporation of [3H]-thymidine by 1.9 to 2.5 times at 72 hours
compared with controls. Glycosaminoglycan synthesis was increased in platelet
supernatant-treated chondrocytes at 96 hours compared with controls. Chondrocytes
treated with 1% platelet supernatant showed a decreased expression of the type II
collagen gene. Supplementation with a high concentration (10%) of the platelet
supernatant provided the conditions for in vitro chondrocyte mass formation.
These results indicate that proliferation and matrix synthesis of auricular
chondrocytes is stimulated by a low concentration of platelet supernatant. On the
other hand, chondrocytes were immobilized by a high concentration of platelet
supernatant. Platelet supernatant may be useful as an inexpensive autologous
source of multiple growth factors to enhance chondrocyte proliferation, and also
may play the role of scaffold for chondrocytes. Additional investigation is
underway to generate culture conditions that promote the differentiation as well
as the proliferation of chondrocytes.
PMID- 10783099
TI - Transsacral usage of a pure island TRAM flap for a large sacral defect: a case
report.
AB - A pedicled transverse rectus abdominis musculocutaneous (TRAM) flap was used to
reconstruct a large sacral defect retroperitoneally. Muscle and superiorly
located skin were elevated on the deep inferior epigastric pedicle. The flap was
transposed retroperitoneally from the abdominal wall to the sacral region of the
patient. The selection criteria for this particular flap are discussed and
compared with other reconstructive choices.
PMID- 10783098
TI - Filleted toe flap for chronic forefoot ulcer reconstruction.
AB - Chronic plantar and dorsal forefoot ulcer may result from injury, structural
deformity, and abnormal sensation or circulation. It is not uncommon that the
distal portion of the affected toes is deficient functionally in these patients.
A filleted toe flap from the expendable functionless toe can provide a durable,
stable, and sensate skin flap of 4 to 5.5 cm for coverage of the forefoot defect.
In this report, five cases of dorsal forefoot defects and four cases of plantar
forefoot defects due to ischemia (N = 3), trophic change (N = 2), and diabetes (N
= 4) were treated with filleted toe flaps. One flap failed due to postoperative
deep infection. The other eight filleted toe flaps survived but 2 patients
underwent secondary amputations 7 months and 2 two years later because of
secondary diabetic foot infections.
PMID- 10783100
TI - Combined pedicled flaps for grade IIIB tibial fractures in children: a report of
two patients.
AB - Severe open tibial fractures in children are associated with notable morbidity
and require early aggressive management to ensure a successful outcome. Free
flaps are currently the gold standard in distal extremity reconstruction in which
large soft-tissue defects exist, as is often the case with grade IIIB fractures.
In severe lower limb trauma, however, free flaps are associated with a relatively
high risk of failure, particularly when definitive soft-tissue coverage is
delayed. Alternative methods of soft-tissue reconstruction may, therefore,
occasionally require consideration. The authors describe the combined use of
three pedicled flaps to attain soft-tissue coverage in 2 children with grade IIIB
tibial fractures. These three flaps are individually in common use for lower limb
soft-tissue coverage, are simple to raise, and in combination can cover extensive
soft-tissue defects of the lower extremity. The major vascular axes of the limb
are not sacrificed; however, the aesthetic result is modest.
PMID- 10783101
TI - Reverse radial forearm flap as a source of soft tissue and blood supply for thumb
reconstruction.
AB - Soft-tissue deficiency is sometimes a major problem in thumb reconstructive cases
with toe-to-thumb transfer. In the patient presented, a reverse radial forearm
flap was used to provide a vascular pedicle for anastomosis with the second toe
vessels. The flap also provided soft-tissue coverage for the metatarsal bone of
the transferred toe. The radial artery and concomitant vein were used for the
dorsalis pedis artery and vein anastomosis. The skin island of the forearm flap
was wrapped around the transferred metatarsal bone. Using this technique, two
limiting problems in toe-to-hand transfers were solved at the same time. In the
crushed hand, sometimes it is not possible to find enough soft tissue and a good
vascular pedicle for a new thumb, and this option seems to be a reasonable
choice.
PMID- 10783102
TI - Aggressive basal cell carcinoma of the temporal region in a patient with Gorlin
Goltz syndrome.
AB - Gorlin-Goltz syndrome is an autosomal dominant disorder with variable penetration
characterized primarily by five major findings: multiple basal cell carcinomas
presenting at a young age, pits on the palms and soles, skeletal abnormalities,
jaw cysts, and ectopic calcification of the falx cerebri and other structures.
When the basal cell carcinomas are located in the head and neck there is a high
risk of invasion of deep structures if early and radical treatment is not
performed. The authors present a 59-year-old man affected by basal cell carcinoma
in the context of Gorlin-Goltz syndrome. Although patients with this syndrome can
present aggressive basal cell carcinomas, it is unusual to find them involving
the craniofacial bones. In this patient the basal cell carcinoma involved the
middle ear, the intrapetrous aspect of the facial nerve, and the dura mater. The
reconstruction of a wide three-dimensional defect, in which the brain was
exposed, was achieved with local flaps and a free musculocutaneous rectus
abdominis flap. Factors affecting reconstruction in the lateral cranial base are
discussed.
PMID- 10783103
TI - Salvage of ear replantation using the temporoparietal fascia flap.
AB - The authors report a case involving a 46-year-old man who sustained a traumatic
amputation of approximately 60% of his ear from a human bite. The ear was
replanted microsurgically without the benefit of venous anastomosis. Blood
transfusion was not required despite the use of leech therapy and systemic
anticoagulation. The replantation appeared to be a success at the time of his
discharge from the hospital, but during the late postoperative period the
replanted ear became progressively necrotic. The failing ear replantation was
rescued successfully with the use of temporoparietal fascia flap reconstruction.
PMID- 10783104
TI - Large myxofibroma of the mandible treated with segmental mandibular resection and
vascularized fibular graft.
AB - This report summarizes a case of large myxofibroma of the mandible. On the basis
of the clinical appearance, radiographic findings, and biopsy specimen, the
lesion was diagnosed as a myxofibroma. Segmental mandibular resection and
immediate reconstruction by vascularized fibular graft were performed. At the 18
month follow-up there was no evidence of recurrence of the tumor, and good
functional and aesthetic results were maintained.
PMID- 10783105
TI - Trapezoid bone fracture.
AB - Fractures of the carpal bones involve only a single bone or complex bones with or
without ligament rupture. However, fractures of the trapezoid are rarely seen.
Because the trapezoid is fastened to the trapezium, capitate, and scaphoid by
strong ligaments, fracture or dislocation is limited by this rigid fixation. The
authors present a single bone fracture of the trapezoid in a 40-year-old man. A
tomogram of the carpal bone was useful in diagnosing the trapezoid fracture. The
mechanism for development of fracture of the trapezoid alone is unknown. However,
fracture of the trapezoid seemed to occur when the wrist joint was forced with
excessive flexion stress that was placed on the trapezoid through the second
metacarpal bone indirectly. This occurred in the same manner that a walnut is
broken with nutcrackers.
PMID- 10783106
TI - Granular cell tumor in a child's finger.
AB - Granular cell tumor is an uncommon tumor found in the hand. It is probably of
Schwann cell origin and may be associated with a peripheral nerve. Although it is
often described as a painless tumor of the oral cavity and skin, its presentation
in the fingers or hand is often painful--a characteristic not well recognized.
PMID- 10783107
TI - Reconstruction of aplasia cutis congenita of the trunk in a newborn infant using
acellular allogenic dermal graft and cultured epithelial autografts.
AB - Aplasia cutis congenita, a congenital condition characterized by the absence of
all skin layers, occurs mostly on the scalp, but may also involve the trunk and
extremities. Conservative treatment using silver sulfadiazine with daily dressing
change has been recommended to avoid donor site morbidity and operative risks to
the neonate who may have other congenital defects. Others have proposed early
surgical intervention to prevent problems associated with delayed wound healing.
In this case of a newborn, the authors used an alternative therapy to avoid
delayed wound healing and multiple surgical interventions. During one operative
procedure, a 130-cm2 lesion on the trunk was covered with allogeneic dermis and
cultured epithelial autografts (CEAs). After 2.5 weeks and with three additional
applications of CEAs at bedside, 90% of the wound had healed. At 27 months, the
grafted area was smooth, and pliable with normal skin texture.
PMID- 10783108
TI - Technical refinements in the surgical treatment of gynecomastia.
AB - The authors present their experience with liposuction of breast fat followed by
sharp excision of the breast gland, when needed. Liposuction is performed,
introducing a short uterine curette through a hemicircular periareolar incision.
The suction is carried out as close as possible to the glandular tissue and all
around the areola in a fan shape until the boundaries of the mammary region are
reached in all directions to allow better skin redraping. Because the fat layers
are encased in the fibrous septi of the superficial fascial system, suction of
the fat lobules allows shrinkage of the septi and also enables skin retraction in
patients with marked gynecomastia and considerable skin redundancy. Moreover,
because liposuction causes an increase of coagulative factors in the treated
area, it plays an important role in spontaneous hemostasis. In fact, the
hypercoagulative state of the fat treated by liposuction implies minimal bleeding
in additional surgery. The removal of the residual mammary gland is very easy,
hemostasis is usually not needed, and drains are usually not used.
PMID- 10783109
TI - Reel people.
PMID- 10783110
TI - Re: Skin-sparing mastectomy with sun flap closure.
PMID- 10783111
TI - Re: Earlobe epidermal inclusion cyst excision using a Desmarres clamp.
PMID- 10783112
TI - Bilateral well-leg compartment syndrome after supine position surgery.
PMID- 10783113
TI - Flap model with a scar-induced invariable necrotic pattern.
PMID- 10783114
TI - Preoperative patient education: a study in reduction mammaplasty.
PMID- 10783115
TI - Recurrent, discharging congenital frontotemporal dermoid cyst.
PMID- 10783116
TI - Simple vacuum drainage of hematoma or seroma.
PMID- 10783117
TI - The effects of protease inhibitor therapy on human immunodeficiency virus type 1
levels in semen (AIDS clinical trials group protocol 850).
AB - Antiretroviral therapy may lead to decreased shedding of human immunodeficiency
virus type 1 (HIV-1) in genital secretions. Thirty men, 19 receiving amprenavir
and 11 receiving amprenavir, zidovudine, and lamivudine, donated blood and semen
while undergoing treatment, to evaluate the effects of these medications on HIV-1
shedding in semen. Before therapy, 4 men had HIV-1 RNA levels in seminal plasma
>6.0 log10 (1 million) copies/mL, markedly higher than levels in blood plasma.
Most men (77%) had HIV-1 RNA levels in seminal plasma below the limit of
quantification during therapy. Amprenavir alone suppressed HIV-1 RNA levels to
<400 copies/mL in seminal plasma in the majority of patients, the first direct
demonstration of the antiretroviral effects of a protease inhibitor in the male
genital tract. However, 8 men (27%) had measurable HIV-1 in seminal plasma at
their last study visit, 4 with increasing levels. Persistent replication of HIV
in the genital tract may have implications for the selection of resistant virus
and sexual transmission of HIV-1.
PMID- 10783118
TI - Absence of antibody against human papillomavirus type 16 E6 and E7 in patients
with cervical cancer is independent of sequence variations.
AB - It is not known whether the lack of antibody response against human
papillomavirus (HPV) type 16 E6 and E7 among some cervical cancer patients is due
to naturally existing sequence variations. In this study, naturally occurring HPV
16 E6 and E7 variants (including the prototype) were cloned, antigens were
expressed by in vitro transcription and translation, and the humoral immune
response of 34 HPV-16-positive cervical cancer patients was analyzed by
radioimmunoprecipitation assay (RIPA). In addition, the RIPA results were
compared with those of a sandwich-protein ELISA, to further substantiate antibody
status. Sera lacking E6 reactivity by RIPA remained negative by protein ELISA.
All E6 antigens (the prototype and the variants 350G?L83V, 131G?R10G/350G?L83V,
335T?H78Y/350G?L83V, 345G?Y81C/350G?L83V, and African 2 ?Af2) showed cross
reactivity by RIPA. The lack of HPV-16 E6 or E7 antibodies is independent of
naturally occurring variants in cervical cancer patients. Thus, testing for HPV
16 E6 or E7 prototype antigens seems to be sufficient in serological assays.
PMID- 10783120
TI - Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2
family proteins.
PMID- 10783119
TI - Cationic proteins and bronchial hyperresponsiveness.
PMID- 10783121
TI - Pulmonary fibrosis: pathways are slowly coming into light.
PMID- 10783122
TI - Tumor antigens in thoracic malignancy.
PMID- 10783123
TI - Suppression of maxi-K channel and membrane depolarization by synthetic
polycations in single tracheal myocytes.
AB - Polycationic proteins, e.g., major basic protein from eosinophils or cathepsin G
from neutrophils, have been shown to increase nonspecific airway responsiveness.
Along with several indirect manners of action, polycations were reported to
contract smooth-muscle strips and to raise the cellular Ca(2+) concentration as a
direct action on airway smooth muscle. However, the mechanistic basis for the
direct behavior remains to be elucidated. To address this issue, we examined the
effects of synthetic cationic polypeptides poly-L-arginine and poly-L-lysine on
fresh single smooth-muscle cells from bovine trachea using a patch-clamp
technique. Both of the polycations significantly depolarized the membrane from a
baseline of about -40 to -20 mV in a dose-dependent manner. The polycations also
suppressed whole-cell spontaneous transient outward currents as well as both the
conductance (from a baseline of about 130 to 70 pS) and open-state probability
(about 25% of control values) of large-conductance Ca(2+)-dependent K(+) channel
(maxi-K channel) on excised outside-out patch membranes. The polycations were
without effect on the whole-cell Ca(2+) currents induced by depolarizing voltage
pulses. We concluded that the synthetic polycations had at least two sites of
action; one is the delayed rectifier K(+) channel that is responsible for the
membrane depolarization that increases Ca(2+) influx, and the other is the maxi-K
channel the suppression of which inhibits muscle relaxation. These results may
explain the direct contractile action and, therefore, one of the mechanisms
underlying the airway hyperresponsiveness induced by various polycationic
proteins.
PMID- 10783124
TI - Interleukin-6-induced protection in hyperoxic acute lung injury.
AB - Hyperoxic lung injury is commonly encountered in patients who require treatment
with high concentrations of inspired oxygen. To determine whether interleukin
(IL)-6 is protective in oxygen toxicity, we compared the effects of 100% O(2) in
transgenic mice that overexpress IL-6 in the lung and transgene (-) controls. IL
6 markedly enhanced survival, with 100% of transgene (-) animals dying within 72
to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90%
of transgene (+) animals living longer than 12 d. This protection was associated
with markedly diminished alveolar-capillary protein leak, endothelial and
epithelial membrane injury, and lung lipid peroxidation. Hyperoxia also caused
cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-6
markedly diminished this cytopathic response. The protective effects of IL-6 were
not associated with significant alterations in the activities of copper/ zinc
superoxide dismutase (SOD) or manganese SOD. They were, however, associated with
the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell
death stimulator BAX, and with the heightened accumulation of the cell-death
regulator tissue inhibitor of metalloproteinase-1 (TIMP-1). These studies
demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this
protection is associated with a marked diminution in hyperoxia-induced cell death
and DNA fragmentation. They also demonstrate that this protection is not
associated with significant alterations in SOD activity, but is associated with
the induction of Bcl-2 and TIMP-1.
PMID- 10783125
TI - Bleomycin-mediated pulmonary toxicity: evidence for a p53-mediated response.
AB - Bleomycin damages DNA and causes lung injury and fibrosis. To determine whether
bleomycin is associated with the appearance of DNA damage-inducible proteins, C3H
mice received either 0.4 mg bleomycin or normal saline intratracheally and were
killed 1 to 14 d later. The lungs were examined for expression of p53,
p21(WAF1/PiCl), and proliferating cell nuclear antigen (PCNA) using
immunohistochemistry and Western blotting. p53-positive cells first appeared at 5
d after treatment and peaked at 7 d; PCNA-positive cells appeared at 1 d after
treatment and peaked at 7 d; and p21-positive cells appeared at 5 d and peaked at
9 d. Western blot analysis confirmed that bleomycin upregulated the DNA damage
inducible proteins in a similar fashion. This is the first evidence that
bleomycin causes a p53-dependent response associated with acute injury in the
lung.
PMID- 10783126
TI - Serologic responses in patients with malignant mesothelioma: evidence for both
public and private specificities.
AB - Malignant mesothelioma (MM) is a pulmonary malignancy that appears to be
immunogenic based on a large number of studies in both animals and humans. This
notion is supported by our recent demonstration using Western blot analysis of
immunoglobulin G antibodies reactive with a variety of autoantigens in many
patients with MM. In view of the enormous potential of such antigens in early
diagnosis, immunotherapy, and vaccination of at-risk individuals, it was
essential to identify these antigens. We therefore applied the SEREX technique
(serologic identification by recombinant expression cloning), using a serum pool
from six patients as the probe against an expressed complementary DNA library
derived from a cloned MM cell line. We screened over one million recombinants and
obtained sequence information on eight antigens that had provoked immunoglobulin
heavy chain class switching, presumably as a consequence of T-cell recognition.
Six of these antigens were identifiable (U2AF[65], Siah binding protein,
topoisomerase IIbeta, ZFM1, mIre1, and pendulin), and of the others, one was
found as a single EST from a myotube library (Jemm-1); the other (Jemm-2) was not
represented in any EST database even as a weak homolog. Consistent with our
previous findings, each of the characterizable antigens would be expected to be
associated with the cell nucleus. Each of the autoantibody specificities was
uniquely associated with a single patient with the exception of antibodies to
TOPIIbeta and U2AF(65). We found 13 of 14 (93%) patients with MM had antibodies
to TOPIIbeta and two of 14 (14%) patients had antibodies to U2AF(65). The number
of serum reactivities, taken as a measure of the complexity of the immune
response, correlates with patient survival and with an index of systemic
inflammation. These data suggest that a broader range of serologic reactivities
reflects a more active host response to the presence of tumor.
PMID- 10783128
TI - A novel function of thyrotropin as a potentiator of electrolyte secretion from
the tracheal gland.
AB - Accumulating evidence suggests that thyrotropin (thyroid-stimulating hormone
[TSH]) plays some roles in immunoregulation by an extrathyroidal action. Because
airway submucosal glands are responsible for nonspecific and specific airway
defense, we tested the effect of TSH on feline tracheal submucosal gland using a
whole-cell patch-clamp technique, immunohistochemistry, and reverse
transcription/polymerase chain reaction (RT-PCR). TSH potentiated
neurotransmitter-induced ionic currents significantly in a dose-dependent manner.
Acetylcholine (10(-)(8) M)- and norepinephrine (10(-)(7) M)-induced inward
current (I(i)), which we previously showed to be a Cl(-) current, were increased
to about 3-fold the pre-TSH control responses, respectively, by 2.0 ng/ml TSH;
and to 6- and 23-fold the control values by 20.0 ng/ml TSH, respectively. TSH
alone was without effect up to 20.0 ng/ml. Follicular stimulating hormone only
slightly affected the I(i) (1. 5-fold the control). Analyses with
immunohistochemistry and RT-PCR failed to identify TSH receptors on the glandular
tissue. Maneuvers to raise the cellular adenosine 3',5'-cyclic monophosphate also
failed to mimic the TSH-mediated potentiation. The TSH effect appeared to be
mediated by a signaling pathway involving tyrosine kinase because its inhibitors
(genistein and herbimycin A) abolished the augmentation completely, and
interferon-gamma, a tyrosine kinase activator, imitated the TSH action on
submucosal gland. Thus, TSH may be an important regulator of airway fluid
secretion.
PMID- 10783127
TI - Matrix-associated transforming growth factor-beta1 primes mouse bone marrow
derived mast cells for increased high-affinity Fc receptor for immunoglobulin E
dependent eicosanoid biosynthesis.
AB - Mast cells at different tissue locations are heterogeneous with respect to
histochemical staining characteristics, granule protease and proteoglycan
content, and eicosanoid biosynthesis. We used Matrigel, an extract from the
Engelbreth-Holm-Swarm mouse sarcoma that is enriched in basement-membrane
proteins, to investigate the effect of tissue matrix proteins on the
differentiation of mouse mast cells, with particular attention to eicosanoid
biosynthesis. Culture of mouse bone-marrow cells in interleukin-3 on Matrigel for
3 to 4 wk provided a population of mast cells with more intense metachromasia and
increased safranin counterstaining compared with mast cells derived in the
absence of Matrigel (bone marrow-derived mast cells [BMMC]). High-affinity Fc
receptor for immunoglobulin E-dependent biosynthesis of prostaglandin D(2) and
leukotriene (LT) C(4) was 6- and 11-fold higher, respectively, from mast cells
derived in the presence of Matrigel compared with conventional BMMC derived in
its absence. BMMC derived in the presence of Matrigel also generated substantial
quantities of 6-trans-LTB(4) diastereoisomers and LTB(4), which were minimally
generated by conventional BMMC. When conventional BMMC derived in the absence of
Matrigel were then cultured on Matrigel for 5 d, eicosanoid biosynthesis was
upregulated without any change in granule staining characteristics. This
upregulation in eicosanoid biosynthesis was inhibited by neutralizing anti-
transforming growth factor (TGF)-beta1-specific antibodies, was reproduced by 1
ng/ml TGF-beta1, and was attributed to increased expression of cytosolic
phospholipase A(2).
PMID- 10783129
TI - Genetic linkage analysis of susceptibility to particle exposure in mice.
AB - Particle-induced increases in respiratory morbidity and mortality have been
observed worldwide in industrialized cities but the toxicologic mechanisms have
not been elucidated. It is hypothesized that subpopulations including the elderly
and individuals with cardiopulmonary disease are particularly at risk to the
effects of exposure. Genetic background is another important host factor that may
contribute to interindividual responsivity to particulate exposure. This study
was designed to identify susceptibility loci for alveolar macrophage (AM) immune
dysfunction induced by inhalation of sulfate-associated carbon particles in
susceptible C57BL/6J and resistant C3H/ HeJ inbred mice. AMs were chosen for
study because they represent an important component of host defense, and
compromised host defense has been hypothesized to be an important factor in
particle-induced respiratory morbidity. The quantitative phenotype for these
studies was Fc receptor-mediated phagocytic function, an index of AM integrity.
Analyses of macrophage dysfunction phenotypes of segregant and nonsegregant
populations derived from these two strains indicate that two unlinked genes
control susceptibility. A genome-wide linkage analysis of an intercross (F(2))
cohort identified significant and suggestive quantitative trait loci (QTLs) on
chromosomes 17 and 11, respectively. Candidate susceptibility genes were
identified for mice and humans by comparative mapping. Importantly, both QTLs
overlap previously identified QTLs for susceptibility to another common
pollutant, ozone. This is the first demonstration that genetic background is an
important determinant of responsiveness to particle-induced immune dysfunction,
and it has important implications for understanding the epidemiologic
associations between particulates and morbidity and mortality.
PMID- 10783130
TI - Molecular regulation of granulocyte macrophage colony-stimulating factor in human
lung epithelial cells by interleukin (IL)-1beta, IL-4, and IL-13 involves both
transcriptional and post-transcriptional mechanisms.
AB - Interleukin (IL)-1beta stimulates the release of granulocyte macrophage colony
stimulating factor (GM-CSF) from lung epithelial cells. To investigate the
molecular mechanisms underlying GM-CSF regulation, we studied GM-CSF production,
messenger RNA (mRNA) expression levels, and GM-CSF promoter activity in A549
human alveolar carcinoma cells stimulated with IL-1beta. Coincubation with IL-4
or IL-13 dose-dependently inhibited IL-1beta-induced GM-CSF release. Time-course
studies of intracellular and extracellular protein release and mRNA expression
indicated tight coupling of protein and mRNA synthesis within 6 h after
stimulation. IL-4 and IL-13 both inhibited expression of GM-CSF mRNA and protein
by 2 h after stimulation. Stable transfection of A549 cells, with GM-CSF
promoter/ enhancer constructs containing up to 3.3 kb upstream of the
transcription start site, revealed maximal activation by IL-1beta and phorbol 12
myristate 13-acetate (PMA) with a reporter containing the proximal promoter (-627
to +35). This excludes sequences further upstream from a major regulatory role in
GM-CSF promoter activation by IL-1beta or PMA in these cells. IL-4 and IL-13
downregulated promoter activation but had no effect on GM-CSF mRNA half-life.
However, IL-1beta activation of all constructs was far less pronounced than in
Jurkat T cells, suggesting a requirement for additional mechanisms, possibly post
transcriptional, to potentiate the observed transcriptional induction.
PMID- 10783131
TI - Mechanism of extracellular signal-regulated kinase (ERK)-1 and ERK-2 activation
by vanadium pentoxide in rat pulmonary myofibroblasts.
AB - Vanadium pentoxide (V(2)O(5)) is a cause of occupational asthma and chronic
bronchitis, yet the molecular mechanisms through which V(2)O(5) exerts its
effects on cell function are unclear. In this study we investigated the potential
of V(2)O(5) to activate the extracellular signal-regulated kinases 1 and 2 (ERK
1/2) in rat pulmonary myofibroblasts. Treatment of myofibroblasts with V(2)O(5)
resulted in the activation of ERK-1/2, yet the inert metal titanium dioxide had
no effect on ERK-1/2 activation. V(2)O(5)-induced ERK-1/2 activation was
abolished by pretreatment with forskolin or PD98059, indicating a dependence on
Raf and mitogen-activated protein (MAP) kinase kinase, respectively. Depletion of
conventional protein kinase C activity with phorbol 12-myristate 13-acetate did
not inhibit V(2)O(5)-induced ERK-1/2 activation. ERK-1/2 activation by V(2)O(5)
was inhibited > 70% with the epidermal growth factor receptor (EGF-R) tyrosine
kinase inhibitor AG1478. Phosphorylation of the 170-kD EGF-R by V(2)O(5) was
detected after immunoprecipitation with an anti-EGF-R antibody followed by
phosphotyrosine Western blotting. V(2)O(5) strongly tyrosine-phosphorylated a 115
kD protein (p115) and activation of p115 was inhibited 60 to 70% by AG1478,
indicating that this protein was an EGF-R substrate. Phosphorylation of p115 was
also observed in EGF-stimulated cells. Immunoprecipitation of V(2)O(5)- or EGF
treated cell lysates with an antibody against Src homology 2 protein tyrosine
phosphatase (SH-PTP2) identified p115 as a SH-PTP2-binding protein. Pretreatment
of cells with the antioxidant N-acetyl-L-cysteine blocked V(2)O(5)-induced MAP
kinase activation and p115 phosphorylation > 90%. These data suggest that
V(2)O(5) activation of ERK-1/2 is oxidant-dependent and mediated through tyrosine
phosphorylation of EGF-R and an EGF-R substrate which we identified as a 115-kD
SH-PTP2-binding protein.
PMID- 10783132
TI - Induction of cell cornification and enhanced squamous-cell marker SPRR1 gene
expression by phorbol ester are regulated by different signaling pathways in
human conducting airway epithelial cells.
AB - Phorbol ester is a strong inducer for both cell cornification and squamous-cell
marker SPRR1 gene expression in conducting airway epithelial cells. However, the
signaling pathways involved in the regulation of both events have not been
completely elucidated. The current study focuses on the common and divergent
pathways involved in the induction of these two activities by phorbol-13
myristate-12-acetate (PMA). Using a protein kinase (PK) C inhibitor,
bisindolylmaleimide I, PMA-induced cell cornification and SPRR1 gene expression
were abolished. Further, a PKC activator, indolactam V, induced cell
cornification in the absence of PMA treatment. These results suggest a PKC
dependent signaling pathway for both gene induction and enhanced cell
cornification by PMA. However, a mitogen-activated protein kinase-specific
inhibitor, PD98059, could only block the gene induction event but failed to
prevent cell cornification induced by PMA. These results suggest that diverse
signaling pathways after PKC activation by PMA are involved in the regulation of
these two events.
PMID- 10783133
TI - Modification of the inflammatory response to allergen challenge after exposure to
bacterial lipopolysaccharide.
AB - The potential role of respiratory infections in altering the development of atopy
and asthma is complex. Infections have been suggested to be effective in
preventing the induction of T-helper 2-polarized allergen-specific immunity in
early life, but also to exacerbate asthma in older, sensitized individuals. The
mechanism(s) underlying these effects are poorly defined. The aim of this work
was to determine the influence of lipopolysaccharide (LPS) exposure on the
development of sensitization to allergen and the response to allergen challenge
in vivo. Piebald-Virol-Glaxo rats were exposed to a single aerosol of LPS 1 d
before or 1, 2, 4, 6, 8, or 10 d after sensitization with ovalbumin (OVA). On Day
11 animals were exposed to 1% OVA and responses to allergen were measured 24 h
later, monitoring inflammatory cell influx and microvascular leakage into
bronchoalveolar lavage (BAL) fluid as well as pulmonary responses to methacholine
using the forced oscillation technique. Histologic analysis was included to
complement the BAL results. Single aerosol exposure to LPS 1 d before and up to 4
d after intraperitoneal injection of OVA protected against the development of OVA
specific immunoglobulin (Ig) E. LPS exposure 6, 8, or 10 d after sensitization
further exacerbated the OVA-induced cellular influx, resulting in neutrophilia
and increased Evans Blue dye leakage with no effect on serum IgE levels. In
addition, LPS abolished the OVA-induced hyperresponsiveness in sensitized animals
when given 18 h after OVA challenge. This study demonstrates that exposure to LPS
can modify the development of allergic inflammation in vivo by two independent
mechanisms. Exposure early in the sensitization process, up to Day 6 after
exposure to allergen, prevented allergen sensitization. Exposure to LPS after
allergen challenge in sensitized animals abolished the hyperresponsiveness and
modified the inflammatory cell influx characteristic of late-phase response to
allergen.
PMID- 10783134
TI - Adenoviral gene transfer is inhibited by soluble factors in malignant pleural
effusions.
AB - Direct in vivo gene delivery is a prerequisite for many gene therapy strategies;
however, efficacy has been limited by a lack of therapeutic gene transfer. In
studying intrapleural malignancy as a model for the gene therapy of non-small
cell lung cancer, we previously identified soluble chondroitin sulfate
proteoglycans/glycosaminoglycans (CS-PG/GAGs) in malignant pleural effusions
(MPE) as factors that inhibit retroviral vector (RV) transduction. Similarly, we
have observed inhibition to gene transfer in the fluid component of MPE using
adenoviral (Ad) vectors. Analyses indicate that the factors responsible for the
block are filterable, soluble, titrable, and heat stable (56 degrees C). Passage
through microporous membranes fractionates the inhibitory factors into large (>
100 kD) components of the effusions. In contrast to RV transduction, hyaluronic
acid or CS-PG/GAGs are not the inhibitors because the block is not reversed by
pretreatment of the effusions with mammalian hyaluronidase, and exogenous
addition of GAGs into the transduction media does not diminish Ad transduction.
In considering the mechanism of action of the inhibitory factors, we observe that
Ad entry, and specifically the binding of radiolabeled Ad to its target cell, is
inhibited in the presence of MPE. Ad internalization may also be impaired;
however, these studies exclude soluble fibronectin in MPE as a competitive
inhibitor of Ad transduction. Lastly, sepharose A- mediated immunoglobulin
depletion of MPE only partially reverses the block, and significant inhibition to
Ad gene transfer persists at lower adenovirus:target cell ratios. Identifying the
structural and functional basis for inhibition to Ad gene transfer may yield
specific strategies to enable better in vivo translation of gene therapy
approaches.
PMID- 10783135
TI - Genetic susceptibility to ozone-induced lung hyperpermeability: role of toll-like
receptor 4.
AB - The pollutant ozone (O(3)) induces lung hyperpermeability and inflammation in
humans and animal models. Among inbred strains of mice, there is a 3-fold
difference in total protein (a marker of permeability) recovered in
bronchoalveolar lavage (BAL) fluid after a 72-h exposure to 0.3 ppm O(3). To
determine the chromosomal locations of susceptibility genes, we performed a
genome screen using recombinant inbred (RI) strains of mice derived from O(3)
susceptible C57BL/6J (B6) and O(3)-resistant C3H/HeJ (HeJ) progenitors. Each RI
strain was phenotyped for O(3)-induced hyperpermeability, and linkage was
assessed for 558 markers using Map Manager QTb27. A significant quantitative
trait locus (QTL) was identified on chromosome 4. The likelihood ratio chi(2)
statistic (16.6) for the peak of the QTL was greater than the significance
threshold (16.3) determined empirically by permutation test. This QTL contains a
candidate gene, Toll-like receptor 4 (Tlr4 ), that recently has been implicated
in innate immunity and endotoxin susceptibility. The amount of the total trait
variance explained by the QTL at Tlr4, the gene with the highest likelihood ratio
statistic in the QTL, was approximately 70%. To test the role of Tlr4 in O(3)
induced hyperpermeability, BAL protein responses to O(3) were compared in
C3H/HeOuJ (OuJ) and HeJ mice that differ only at a polymorphism in the coding
region of Tlr4. Significantly greater protein concentrations (430 +/- 35
microg/ml) were found in OuJ mice compared with HeJ mice (258 +/- 18 microg/ml)
after exposure to O(3). Furthermore, reverse transcriptase/polymerase chain
reaction analysis demonstrated differential expression of Tlr4 message levels
between HeJ and OuJ mice after O(3) exposure. Together, results indicate that a
QTL on mouse chromosome 4 explains a significant portion of the genetic variance
in O(3)-induced hyperpermeability, and support a role for Tlr4 as a strong
candidate susceptibility gene.
PMID- 10783137
TI - Drusen associated with aging and age-related macular degeneration contain
proteins common to extracellular deposits associated with atherosclerosis,
elastosis, amyloidosis, and dense deposit disease.
AB - Age-related macular degeneration (AMD), a blinding disorder that compromises
central vision, is characterized by the accumulation of extracellular deposits,
termed drusen, between the retinal pigmented epithelium and the choroid. Recent
studies in this laboratory revealed that vitronectin is a major component of
drusen. Because vitronectin is also a constituent of abnormal deposits associated
with a variety of diseases, drusen from human donor eyes were examined for
compositional similarities with other extracellular disease deposits. Thirty-four
antibodies to 29 different proteins or protein complexes were tested for
immunoreactivity with hard and soft drusen phenotypes. These analyses provide a
partial profile of the molecular composition of drusen. Serum amyloid P
component, apolipoprotein E, immunoglobulin light chains, Factor X, and
complement proteins (C5 and C5b-9 complex) were identified in all drusen
phenotypes. Transcripts encoding some of these molecules were also found to be
synthesized by the retina, retinal pigmented epithelium, and/or choroid. The
compositional similarity between drusen and other disease deposits may be
significant in view of the recently established correlation between AMD and
atherosclerosis. This study suggests that similar pathways may be involved in the
etiologies of AMD and other age-related diseases.
PMID- 10783136
TI - Different expression of TNF-alpha receptors and prostaglandin E(2 )Production in
normal and fibrotic lung fibroblasts: potential implications for the evolution of
the inflammatory process.
AB - Normal human lung fibroblasts downregulate the production of tumor necrosis
factor (TNF)-alpha by activated monocytes through the production of prostaglandin
E(2) (PGE(2)), contributing to the local control of the inflammatory process. In
this study, we provide evidence that fibroblasts derived from diseased tissue,
such as fibrotic lung fibroblasts, exhibit different functional features compared
with normal cells, with particular regard to their modulatory role. Indeed,
fibrotic fibroblasts (FF) spontaneously produced less PGE(2) (3,300 +/- 410
pg/ml) compared with normal fibroblasts (NF) (7,500 +/- 270 pg/ml) and, as a
consequence, they showed a reduced ability to downregulate the production of TNF
alpha by lipopolysaccharide (LPS)- activated monocytes. The percentage of
inhibition induced by normal cells on the production of TNF-alpha by LPS
activated monocytes was 61 +/- 5.9%, whereas the inhibitory effect exerted by
fibrotic cells was reduced to 32 +/- 4% (P < 0.01). We have also observed that
the ability of TNF-alpha to induce PGE(2) was impaired in FF and was related to a
reduced expression of cyclooxygenase 2. This was possibly due to the reduction of
the expression of TNF receptors (TNFRs) in fibrotic cell lines compared with
normal cell lines. Flow cytometry revealed that the mean fluorescence intensity
(MFI) of both isoforms of TNFR was significantly lower in FF compared with NF.
The MFI of TNFR1 was 3. 55 +/- 0.12 for NF and 1.78 +/- 0.35 for FF (P < 0.001).
The MFI of TNFR2 was 1.95 +/- 0.27 for NF and 0.99 +/- 0.16 for FF (P < 0.01).
The analysis of the effect of TNF-alpha on some functions associated with
collagen metabolism in NF and FF showed an increase of the expression of the
receptor for collagen type I (alpha(2)beta(1) integrin) in NF (42 +/- 10%) and an
even larger increase in FF (102 +/- 23%) (P < 0.05). Interestingly, unlike NF,
TNF-alpha failed to increase matrix metalloproteinase 1 levels in FF and did not
cause any growth inhibition in these cells. The reduced capability of fibrotic
cells to produce PGE(2) either spontaneously or after TNF-alpha treatment may
lead to an unrestrained release of TNF-alpha from activated monocytes and, as a
result of the reduced expression of TNFRs, to a different response of these cells
to TNF-alpha. These changes may be important in the evolution of the inflammatory
process, potentially contributing to its transformation into a chronic and self
perpetuating process.
PMID- 10783138
TI - Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen
species followed by mitochondrial permeability transition, cytochrome c release,
and caspase activation.
AB - Glycosphingolipids, including gangliosides, are emerging as signaling
intermediates of extracellular stimuli. Because mitochondria play a key role in
the orchestration of death signals, we assessed the interaction of GD3
ganglioside (GD3) with mitochondria and the subsequent cascade of events that
culminate in cell death. In vitro studies with isolated mitochondria from rat
liver demonstrate that GD3 elicited a burst of peroxide production within 15-30
min, which preceded the opening of the mitochondrial permeability transition,
followed by cytochrome c (cyt c) release. These effects were mimicked by
lactosylceramide and N-acetyl-sphingosine but not by sphinganine or sphingosine
and were prevented by cyclosporin A and butylated hydroxytoluene (BHT).
Reconstitution of mitochondria pre-exposed to GD3 with cytosol from rat liver in
a cell-free system resulted in the proteolytic processing of procaspase 3 and
subsequent caspase 3 activation. Intact hepatocytes or U937 cells selectively
depleted of glutathione in mitochondria by 3-hydroxyl-4-pentenoate (HP) with the
sparing of cytosol reduced glutathione (GSH) were sensitized to GD3, manifested
as an apoptotic death. Inhibition of caspase 3 prevented the apoptotic phenotype
of HP-treated cells caused by GD3 without affecting cell survival; in contrast,
BHT fully protected HP-treated cells to GD3 treatment. Treatment of cells with
tumor necrosis factor increased the level of GD3, whereas blockers of
mitochondrial respiration at complex I and II protected sensitized cells to GD3
treatment. Thus, the effect of GD3 as a lipid death effector is determined by its
interaction with mitochondria leading to oxidant-dependent caspase activation.
Mitochondrial glutathione plays a key role in controlling cell survival through
modulation of the oxidative stress induced by glycosphingolipids.
PMID- 10783139
TI - High-affinity LPS binding domain(s) in recombinant factor C of a horseshoe crab
neutralizes LPS-induced lethality.
AB - SSCrFCES is a biologically active, recombinant fragment of factor C, which is the
endotoxin-sensitive serine protease of the LAL coagulation cascade. The
approximately 38 kDa protein represents the LPS binding domain of factor C. A
novel secretory signal directs the secretion of SSCrFCES into the culture
supernatant of Drosophila cells, and hence it is readily purified. By
differential ultrafiltration followed by preparative isoelectric membrane
electrophoresis, SSCrFCES was purified as an isoelectrically homogeneous and
stable monomeric protein. The ability of SSCrFCES to bind lipid A was analyzed
using an ELISA-based assay as well as surface plasmon resonance. SSCrFCES
exhibits high positive cooperativity of binding to two or three lipid A
molecules, with a Hill's coefficient of 2.2. The 50% endotoxin-neutralizing
concentration of SSCrFCES against 200 EU of endotoxin is approximately 0.069
microM, suggesting that SSCrFCES is an effective inhibitor of LAL coagulation
cascade. Although partially attenuated by human serum, as little as 1 microM of
SSCrFCES inhibits the LPS-induced secretion of hTNF-alpha and hIL-8 by THP-1 and
human peripheral blood mononuclear cells with greater potency than polymyxin B.
SSCrFCES is noncytotoxic, with a clearance rate of 4.7 ml/min. The L.D.(90) of
SSCrFCES for LPS lethality is achieved at 2 microM. These results demonstrate the
endotoxin-neutralizing capability of SSCrFCES in vitro and in vivo and its
potential use for the treatment of endotoxin-induced septic shock.
PMID- 10783140
TI - Genetic heterogeneity of angiogenesis in mice.
AB - Many diseases, including cancer, are dependent on the growth of new blood
vessels, a process known as angiogenesis. Differences in an individual's ability
to grow new blood vessels may influence the rate of progression of these
diseases. Here we show that different strains of inbred mice have an
approximately 10-fold range of response to growth factor-stimulated angiogenesis
in the corneal micropocket assay. The in vitro migratory activity of endothelial
cells from aortic rings of selected strains correlated with the in vivo
responsiveness. Further, a differential sensitivity to angiogenesis inhibitors
was seen between strains, with one strain demonstrating resistance to both TNP
470 and thalidomide. These results suggest the presence of genetic factors that
control individual angiogenic potential.
PMID- 10783141
TI - Sustained mammary gland-directed, ponasterone A-inducible expression in
transgenic mice.
AB - The ability to regulate temporal- and spatial-specific expression of target genes
in transgenic mice will facilitate analysis of gene function and enable the
generation of murine models of human diseases. The genetic analysis of mammary
gland tumorigenesis requires the development of mammary gland-specific
transgenics, which are tightly regulated throughout the adult mammary epithelium.
Analysis of genes implicated in mammary gland tumorigenesis has been hampered by
mosaic transgene expression and the findings that homozygous deletion of several
candidate genes (cyclin D1, Stat5A, prolactin receptor) abrogates normal mammary
gland development. We describe the development of transgenic mouse lines in which
sustained transgene expression was inducibly regulated, both specifically and
homogeneously, in the adult mammary gland epithelium. Transgenes encoding
RXRalpha and a chimeric ecdysone receptor under control of a modified MMTV-LTR,
which targets mammary gland expression, were used. These transgenic 'receptor'
lines were crossed with transgenic 'enhancer' lines in which the ecdysone/RXR
binding site induced ligand-dependent expression of transgenic beta
galactosidase. Pharmacokinetic analysis of a highly bioactive ligand (ponasterone
A), identified through screening ecdysteroids from local plants, demonstrated
sustained release and transgene expression in vivo. This transgenic model with
both tightly regulated and homogeneous transgene expression, which was sustained
in vivo using ligands readily extracted from local flora, has broad practical
applicability for genetic analysis of mammary gland disease.
PMID- 10783142
TI - Endothelial K(+) channel lacks the Ca(2+) sensitivity-regulating beta subunit.
AB - Hyperpolarizing large-conductance, Ca(2+)-activated K(+) channels (BK) are
important modulators of vascular smooth muscle and endothelial cell function. In
vascular smooth muscle cells, BK are composed of pore-forming alpha subunits and
modulatory beta subunits. However, expression, composition, and function of BK
subunits in endothelium have not been studied so far. In patch-clamp experiments
we identified BK (283 pS) in intact endothelium of porcine aortic tissue slices.
The BK opener DHS-I (0.05-0.3 micromol/l), stimulating BK activity only in the
presence of beta subunits, had no effect on BK in endothelium whereas the alpha
subunit selective BK opener NS1619 (20 micromol/l) markedly increased channel
activity. Correspondingly, mRNA expression of the beta subunit was undetectable
in endothelium, whereas alpha subunit expression was demonstrated. To investigate
the functional role of beta subunits, we transfected the beta subunit into a
human endothelial cell line (EA.hy 926). beta subunit expression resulted in an
increased Ca(2+) sensitivity of BK activity: the potential of half-maximal
activation (V(1/2)) shifted from 73.4 mV to 49.6 mV at 1 micromol/l [Ca(2+)](i)
and an decrease of the EC(50) value for [Ca(2+)](i) by 1 microM at +60 mV was
observed. This study demonstrates that BK channels in endothelium are composed of
alpha subunits without association to beta subunits. The lack of the beta subunit
indicates a substantially different channel regulation in endothelial cells
compared to vascular smooth muscle cells.
PMID- 10783143
TI - Increased phosphoinositide 3-kinase activity induces a lymphoproliferative
disorder and contributes to tumor generation in vivo.
AB - Alterations in the cell division:cell death ratio induce multiple autoimmune and
transformation processes. Phosphoinositide 3-kinase (PI3K) controls cell division
and cell death in vitro, but its effect on the function of the cellular immune
system and on tumor formation in mammals is poorly characterized. Here we show
that transgenic mice expressing in T lymphocytes an active form of PI3K derived
from a thymic lymphoma, p65(PI3K), developed an infiltrating lymphoproliferative
disorder and autoimmune renal disease with an increased number of T lymphocytes
exhibiting a memory phenotype and reduced apoptosis. This pathology was
strikingly similar to that described in mice exhibiting heterozygous loss of the
tumor suppressor PTEN, a lipid and protein phosphatase. We show that
overexpression of PTEN selectively blocks p65(PI3K)-induced 3T3 fibroblast
transformation. Moreover, the early development of T cell lymphomas in p65(PI3K)
Tg p53(-/-) mice indicated that PI3K contributes to tumor development. These
observations demonstrate that constitutive activation of PI3K extends T cell
survival in vivo, affects T cell homeostasis, and contributes to tumor
generation, supporting a model in which selective increases in one type of PTEN
substrate, the PI3K-derived lipid products, induce tumorigenesis. PI3K thus
emerges as a potential target in autoimmune disease and cancer therapy.
PMID- 10783144
TI - Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which
interacts with and affects the growth suppression function of Rb.
AB - hRPB11 is a core subunit of RNA polymerase II (pol II) specifically down
regulated on doxorubicin (dox) treatment. Levels of this protein profoundly
affect cell differentiation, cell proliferation, and tumorigenicity in vivo. Here
we describe Che-1, a novel human protein that interacts with hRPB11. Che-1
possesses a domain of high homology with Escherichia coli RNA polymerase final
sigma-factor 70 and SV40 large T antigen. In addition, we report that Che-1
interacts with the retinoblastoma susceptibility gene (Rb) by two distinct
domains. Functionally, we demonstrate that Che-1 represses the growth suppression
function of Rb, counteracting the inhibitory action of Rb on the trans-activation
function of E2F1. These results identify a novel protein that binds Rb and the
core of pol II, and suggest that Che-1 may be part of transcription regulatory
complex.
PMID- 10783145
TI - The prostate apoptosis response-4 protein participates in motor neuron
degeneration in amyotrophic lateral sclerosis.
AB - Prostate apoptosis response-4 (Par-4), a protein containing a leucine zipper
domain within a death domain, is up-regulated in prostate cancer cells and
hippocampal neurons induced to undergo apoptosis. Here, we report higher Par-4
levels in lumbar spinal cord samples from patients with amyotrophic lateral
sclerosis (ALS) than in lumbar spinal cord samples from neurologically normal
patients. We also compared the levels of Par-4 in lumbar spinal cord samples from
wild-type and transgenic mice expressing the human Cu/Zn-superoxide dismutase
gene with a familial ALS mutation. Relative to control samples, higher Par-4
levels were observed in lumbar spinal cord samples prepared from the transgenic
mice at a time when they had hind-limb paralysis. Immunohistochemical analyses of
human and mouse lumbar spinal cord sections revealed that Par-4 is localized to
motor neurons in the ventral horn region. In culture studies, exposure of primary
mouse spinal cord motor neurons or NSC-19 motor neuron cells to oxidative insults
resulted in a rapid and large increase in Par-4 levels that preceded apoptosis.
Pretreatment of the motor neuron cells with a Par-4 antisense oligonucleotide
prevented oxidative stress-induced apoptosis and reversed oxidative stress
induced mitochondrial dysfunction that preceded apoptosis. Collectively, these
data suggest a role for Par-4 in models of motor neuron injury relevant to ALS.
PMID- 10783146
TI - Various effects of angiotensin II on amygdaloid neuronal activity in normotensive
control and hypertensive transgenic [TGR(mREN-2)27] rats.
AB - The effects of iontophoretically ejected angiotensin II (Ang II) on the firing
rate of neurons in the basolateral complex and the central and cortical amygdala
were investigated in two strains of urethane anesthetized rats. In normotensive
Sprague-Dawley rats, Ang II induced a significant increase in the discharge rate
of responsive amygdaloid neurons. In contrast, in the hypertensive transgenic
[TGR(mREN-2)27] rats with higher brain Ang II level, Ang II more often caused
inhibitory effects on the amygdaloid firing rate in comparison with controls. The
distribution of nonresponsive, excited, and inhibited neurons differed
significantly in the two rat strains. Moreover, the responsiveness of amygdaloid
neurons was significantly higher in transgenic rats in comparison with controls.
Both the increase and the decrease in the firing rate caused by Ang II could be
blocked either by angiotensin AT(1) or by AT(2) receptor-specific antagonists. In
many cases, the Ang II-induced decrease in the firing rate was antagonized by
bicuculline, a gamma-aminobutyric acid (GABA(A)) antagonist. The higher
responsiveness of amygdaloid neurons in transgenic rats as well as the
predominance of inhibitory effects, presumedly mediated by GABAergic
interneurons, could change the output of the amygdala and its influence on
thirst, kidney, and cardiovascular function or on processes of learning and
anxiety.
PMID- 10783148
TI - Elevated serum free fatty acid concentrations inhibit T lymphocyte signaling.
AB - Unbound cis-unsaturated free (i.e., nonesterified) fatty acids (FFA) inhibit T
lymphocyte activation in vitro and therefore may exert immunosuppressive effects.
However, in blood serum the major proportion of FFA is tightly bound to albumin,
whereas unbound FFA are hardly detectable. Since serum FFA elevation occurs under
pathological conditions like insulin resistance or cancer, which are often
associated with a disturbed immune response, we addressed the question of whether
increased serum FFA concentrations could affect T lymphocyte activation under in
vivo conditions. Our studies revealed that 1) addition of pure long-chain cis
unsaturated FFA in the absence of albumin inhibited calcium response in cultured
Jurkat T cells. 2) In healthy volunteers, serum FFA elevation by a lipid/heparin
infusion, including predominantly unsaturated fatty acids, decreased calcium
response of cultured T cells in contrast to studies without heparin. 3) Most
notably, stepwise increasing serum FFA by lipid/heparin infusion also inhibited
calcium response of simultaneously isolated autologous peripheral blood T
lymphocytes as well as their CD4(+) and CD8(+) subsets. In conclusion, our data
emphasize that serum FFA elevation is able to exert immunosuppressive effects in
vivo.
PMID- 10783147
TI - A protein kinase G-sensitive channel mediates flow-induced Ca(2+) entry into
vascular endothelial cells.
AB - The hemodynamic force generated by blood flow is considered to be the
physiologically most important stimulus for the release of nitric oxide (NO) and
prostacyclin (PGI(2)) from vascular endothelial cells (1). NO and PGI(2) then act
on the underlying smooth muscle cells, causing vasodilation and thus lowering
blood pressure (2, 3). One critical early event occurring in this flow-induced
regulation of vascular tone is that blood flow induces Ca(2+) entry into vascular
endothelial cells, which in turn leads to the formation of NO (4, 5). Here we
report a mechanosensitive Ca(2+)-permeable channel in vascular endothelial cells.
The activity of the channel was inhibited by 8-Br-cGMP, a membrane-permeant
activator of protein kinase G (PKG), in cell-attached membrane patches. The
inhibition could be reversed by PKG inhibitor KT5823 or H-8. A direct application
of active PKG in inside-out patches blocked the channel activity. Gd(3+), Ni(2+),
or SK&F-96365 also inhibited the channel activity. A study of fluorescent Ca(2+)
entry revealed a striking pharmacological similarity between the Ca(2+) entry
elicited by flow and the mechanosensitive Ca(2+)-permeable channel we identified,
suggesting that this channel is the primary pathway mediating flow-induced Ca(2+)
entry into vascular endothelial cells.
PMID- 10783149
TI - IL-4 regulates VIP receptor subtype 2 mRNA (VPAC2) expression in T cells in
murine schistosomiasis.
AB - In murine schistosomiasis, granuloma T cells express VPAC2 mRNA, whereas there is
none in splenocytes. This suggests that T cell VPAC2 mRNA is inducible. To
address this issue, splenocytes from schistosome-infected mice were incubated
with anti-CD3 to induce VPAC2 mRNA, which only appeared when cell cultures also
contained anti-IL-4 mAb. Granuloma cells expressed VPAC2 mRNA. This natural
expression decreased substantially when cells were cultured 3 days in vitro.
However, granuloma cells cultured with anti-IL-4 mAb strongly expressed VPAC2
mRNA. IL-4 KO mice were examined to further address the importance of IL-4 in
VPAC2 regulation. Splenocytes and dispersed granuloma cells from IL-4 KO animals
had substantially more VPAC2 mRNA than those in wild-type controls. VPAC2 mRNA
content decreased when cells were cultured with rIL-4. VPAC2 mRNA localized to
CD4+ T cells. Th1 cell lines expressed VPAC2 mRNA much stronger than Th2 cells.
Anti-IL-4 mAb increased VPAC2 mRNA expression in Th2 cells cultured in vitro.
However, rIL-4 could not suppress VPAC2 mRNA expression in Th1 cells. Thus, VPAC2
is an inducible CD4+ T cell receptor, and IL-4 down-modulates VPAC2 mRNA
expression in Th2 cells.
PMID- 10783151
TI - GFAT as a target molecule of methylmercury toxicity in Saccharomyces cerevisiae.
AB - Using a genomic library constructed from Saccharomyces cerevisiae, we have
identified a gene GFA1 that confers resistance to methylmercury toxicity. GFA1
encodes L-glutamine:D-fructose-6-phosphate amidotransferase (GFAT) and catalyzes
synthesis of glucosamine-6-phosphate. Transformed yeast cells expressing GFA1
demonstrated resistance to methylmercury but no resistance to p
chloromercuribenzoate, a GFAT inhibitor. The cytotoxicity of methylmercury was
inhibited by loading excess glucosamine 6-phosphate into yeast. Considering that
GFAT is an essential cellular enzyme, our findings suggest that GFAT is the major
target molecule of methylmercury in yeasts. This report is the first to identify
the target molecule of methylmercury toxicity in eukaryotic cells.
PMID- 10783150
TI - Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat
brain.
AB - Experimental stroke using a focal cerebral ischemia and reperfusion (FCIR) model
was induced in male Long-Evans rats by a bilateral occlusion of both common
carotid arteries and the right middle cerebral artery for 30-90 min, followed by
various periods of reperfusion. Oxidative DNA lesions in the ipsilateral cortex
were demonstrated using Escherichia coli formamidopyrimidine DNA N-glycosylase
(Fpg protein)-sensitive sites (FPGSS), as labeled in situ using digoxigenin-dUTP
and detected using antibodies against digoxigenin. Because Fpg protein removes 8
hydroxy-2'-deoxyguanine (oh8dG) and other lesions in DNA, FPGSS measure oxidative
DNA damage. The number of FPGSS-positive cells in the cortex from the sham
operated control group was 3 +/- 3 (mean +/- SD per mm(2)). In animals that
received 90 min occlusion and 15 min of reperfusion (FCIR 90/15), FPGSS-positive
cells were significantly increased by 200-fold. Oxidative DNA damage was
confirmed by using monoclonal antibodies against 8-hydroxy-guanosine (oh8G) and
oh8dG. A pretreatment of RNase A (100 microg/ml) to the tissue reduced, but did
not abolish, the oh8dG signal. The number of animals with positive FPGSS or oh8dG
was significantly (P<0.01) higher in the FCIR group than in the sham-operated
control group. We detected few FPGSS of oh8dG-positive cells in the animals
treated with FCIR of 90/60. No terminal UTP nicked-end labeling (TUNEL)-positive
cells, as a detection of cell death, were detected at this early reperfusion
time. Our data suggest that early oxidative DNA lesions elicited by experimental
stroke could be repaired. Therefore, the oxidative DNA lesions observed in the
nuclear and mitochondrial DNA of the brain are different from the DNA
fragmentation detected using TUNEL.
PMID- 10783152
TI - Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of
juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors.
AB - The discoidin domain receptor (DDR1) is characterized by a discoidin I motif in
the extracellular domain, an unusually long cytoplasmic juxtamembrane (JM)
region, and a kinase domain that is 45% identical to that of the NGF receptor,
TrkA. DDR1 also has a major splice form, which has a 37 amino acid insert in the
JM region with a consensus Shc PTB site that is lacking in the shorter receptor.
One class of ligands for the DDR receptors has recently been identified as being
derived from the collagen family, but neither native PC12 cells, which express
modest amounts of DDR1, nor transfected PC12 cells, which express much larger
amounts of DDR1, respond to this ligand. A chimeric receptor, containing the
extracellular domain of hPDGFRbeta fused to the transmembrane and intracellular
regions of DDR1, also fails to mediate neuronal-like differentiation in stably
transfected PC12 cells and is only weakly autophosphorylated. However, chimeric
receptors, which are composed of combinations of intracellular regions from DDR1
and TrkA (with the extracellular domain of hPDGFRbeta), in some cases provided
ligand (PDGF) -inducible receptor responses. Those with the TrkA kinase domain
and the DDR1 JM regions were able to produce differentiation to varying degrees,
whereas the opposite combination did not. Analysis of the signaling responses of
the two chimeras with DDR1 JM sequences (with and without the insert) indicated
that the shorter sequence bound and activated FRS2 whereas the insert-containing
form activated Shc instead. Both activated PLCgamma through the carboxyl-terminal
tyrosine of the TrkA domain (Y785 in TrkA residue numbering). Mutation of this
site (Y-->F) eliminated PLCgamma activation (indicating there are no other
cryptic binding sites for PLCgamma in the DDR1 sequences) and markedly reduced
the differentiative activity of the receptor. This is in contrast to TrkA (or
PDGFRbeta/TrkA chimeras), where ablation of this pathway has no notable effect on
PC12 cell morphogenic responses. Thus, the activation of FRS2 and Shc (leading to
MAPK activation) is weaker in the DDR1/TrkA chimeras than in TrkA alone, and the
PLCgamma contribution becomes essential for full response. Nonetheless, both DDR1
JM regions contain potentially usable signaling sites, albeit they apparently are
not activated directly in DDR1 (or DDR1 chimeras) in a ligand-dependent fashion.
These findings suggest that the DDR1 receptors do have signaling capacity but may
require additional components or altered conditions to fully activate their
kinase domains and/or sustain the activation of the JM sites.
PMID- 10783153
TI - Is creatine kinase responsible for fatigue? Studies of isolated skeletal muscle
deficient in creatine kinase.
AB - Creatine kinase (CK) is a key enzyme for maintaining a constant ATP/ADP ratio
during rapid energy turnover. To investigate the role of CK in skeletal muscle
fatigue, we used isolated whole muscles and intact single fibers from CK
deficient mice (CK(-/-)). With high-intensity electrical stimulation, single
fibers from CK(-/-) mice displayed a transient decrease in both tetanic free
myoplasmic [Ca(2+)] ([Ca(2+)](i), measured with the fluorescent dye indo-1) and
force that was not observed in wild-type fibers. With less intense, repeated
tetanic stimulation single fibers and EDL muscles, both of which are fast-twitch,
fatigued more slowly in CK(-/-) than in wild-type mice; on the other hand, the
slow-twitch soleus muscle fatigued more rapidly in CK(-/-) mice. In single wild
type fibers, tetanic force decreased and [Ca(2+)](i) increased during the first
10 fatiguing tetani, but this was not observed in CK(-/-) fibers. Fatigue was not
accompanied by phosphocreatine breakdown and accumulation of inorganic phosphate
in CK(-/-) muscles. In conclusion, CK is important for avoiding fatigue at the
onset of high-intensity stimulation. However, during more prolonged stimulation,
CK may contribute to the fatigue process by increasing the myoplasmic
concentration of inorganic phosphate.
PMID- 10783154
TI - Stretch-induced endothelin B receptor-mediated apoptosis in vascular smooth
muscle cells.
AB - Growing evidence suggests that a pressure-induced increase in the synthesis of
endothelin (ET-1) is involved in arterial remodeling and, as a consequence, in
the manifestation of chronic hypertension. To study potential stretch-induced
changes in gene expression and their functional consequences, we have cultured
rat aortic smooth muscle cells (raSMC) and porcine aortic endothelial cells
(PAEC) on flexible elastomer membranes. The cells were periodically stretched (up
to 20% elongation, 0.5 Hz, 6 h) and the expression of prepro-ET-1 and that of the
endothelin A and B receptors (ET(A)-R and ET(B)-R) were analyzed by semi
quantitative RT-PCR analysis and ELISA (ET-1). In contrast to PAEC where ET-1
synthesis was up-regulated up to eightfold on exposure to cyclic stretch, ET-1
synthesis in raSMC was decreased by more than 80% under these conditions. ET(A) R
-mRNA expression in stretched raSMC declined to 50% whereas ET(B) R -mRNA levels
were increased up to 10-fold. One functional consequence of this apparent shift
in receptor abundance was an apoptosis-promoting action of exogenous ET-1 (10
nM), as judged by the appearance of subdiploid peaks during FACS analysis,
caspase-3 activation and chromatin condensation. This ET-1-induced apoptosis
appeared to be ET(B)-R mediated, as it was completely suppressed by the ET(B)-R
antagonist BQ 788 but not by the ET(A)-R antagonist BQ 123. Moreover, raSMC
derived from homozygous spotting lethal rats, which lack a functional ET(B)-R,
showed no signs of apoptosis after exposure to cyclic strain and exogenous ET-1.
These findings suggest a central role for the endothelin system in the onset of
hypertension-induced remodeling in conduit arteries, which may proceed via an
initial stretch-induced apoptosis of the smooth muscle cells.
PMID- 10783155
TI - Intrinsic metabolic depression in cells isolated from the hepatopancreas of
estivating snails.
AB - Many animals across the phylogenetic scale are routinely capable of depressing
their metabolic rate to 5-15% of that at rest, remaining in this state sometimes
for years. However, despite its widespread occurrence, the biochemical processes
associated with metabolic depression remain obscure. We demonstrate here the
development of an isolated cell model for the study of metabolic depression. The
isolated cells from the hepatopancreas (digestive gland) of the land snail (Helix
aspersa) are oxygen conformers; i.e., their rate of respiration depends on pO(2).
Cells isolated from estivating snails show a stable metabolic depression to 30%
of control (despite the long and invasive process of cell isolation) when
metabolic rate at the physiological pH and pO(2) of the hemolymph of estivating
snails is compared with metabolic rate at the physiological pH and pO(2) of the
hemolymph of control snails. When the extrinsic effects of pH and pO(2) are
excluded, the intrinsic metabolic depression of the cells from estivating snails
is still to below 50% of control snails. The in vitro effect of pO(2) on
metabolic rate is independent of pH and state (awake or estivating), but the
effects of pH and state significantly interact. This suggests that pH and state
change affect metabolic depression by similar mechanisms but that the metabolic
depression by hypoxia involves a separate mechanism.
PMID- 10783156
TI - Covalent cross-linking of secreted bovine thyroglobulin by transglutaminase.
AB - Extracellular storage of thyroglobulin (TG) is a prerequisite for maintaining
constant levels of thyroid hormones in vertebrates. Storage of TG within the
follicle lumen is achieved by compactation and by the formation of covalent cross
links between TG molecules. In bovine thyroids, approximately 75% of the cross
links are other than disulfide bonds (J. Cell Biol. 180, 1071-1081). We have now
shown that polymeric TG contains a large number of N(epsilon)(gamma
glutamyl)lysine cross-links and that only traces of these can be found in the
soluble form of TG. Because such isopeptide bridges are generated usually by the
action of a transglutaminase, it is reasonable to propose that the covalent
polymerization of TG in the globules is under the control of this enzyme. Soluble
TG was shown to be a substrate for transglutaminase in vitro; moreover, the
presence of transglutaminase was demonstrated by immunofluorescence and by
immunoblotting in freshly isolated bovine thyroid globules. With immunoelectron
microscopy, transglutaminase was detected in the cytoplasm of thyrocytes, but not
in compartments of the secretory pathway. Only one messenger RNA for
transglutaminase was found by Northern blotting. Sequencing of the cloned gene
failed to reveal a secretory signal, which supports the notion that the thyroid
transglutaminase is the cytosolic type. Apparently, the enzyme reaches the lumen
of the follicle by an as yet unknown pathway to catalyze the covalent cross
linking of thyroid globules in this extracellular compartment.
PMID- 10783157
TI - Insulin regulates soluble amyloid precursor protein release via phosphatidyl
inositol 3 kinase-dependent pathway.
AB - Several lines of biochemical evidence correlate the presence of energy metabolic
defects with the functional alterations associated with brain aging and with the
pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within
this context we tested the ability of insulin to regulate the amyloid precursor
protein (APP) processing in SH-SY5Y neuroblastoma cells. Our findings show that
insulin promotes APP metabolism by a glucose-independent mechanism. We
demonstrate a novel intracellular pathway that increases the rate of secretion of
soluble APP through the activity of phosphatidyl-inositol 3 kinase (PI3-K). This
pathway, downstream of insulin receptor tyrosine kinase activity, does not
involve either the activation of protein kinase C or the mitogen-activated
protein kinase (MAP-K) pathway. Because of the physiological role of PI3-K in the
translocation of glucose transporter-containing vesicles, we speculate that PI3-K
involvement in APP metabolism may act at the level of vesicular trafficking.
PMID- 10783159
TI - ASBMB/ASPET 2000 june 4-8, 2000 boston, massachusetts
PMID- 10783158
TI - Suppression of neurocognitive damage in LP-BM5-infected mice with a targeted
deletion of the TNF-alpha gene.
AB - Brain levels of TNF-alpha increase in many inflammatory conditions, including HIV
1 infection, and may contribute to neurodegenerative processes. The paucity of
agents that can selectively and potently block TNF-alpha processing or its
receptors has led us to investigate the role of TNF-alpha in chronic
neurodegeneration associated with retroviral infection using mice with targeted
deletions of the TNF-alpha gene. Infection of wild-type C57BL/6 mice with the LP
BM5 murine leukemia retrovirus mixture leads to the development of a severe
immunodeficiency as well as cognitive deficits and neuronal damage. TNF-alpha-(-/
) mice infected with LP-BM5 developed a systemic immunopathology
indistinguishable in severity from that observed in contemporaneously infected
wild-type mice. In contrast, the performance of infected TNF-alpha-(-/-) mice in
the Y-maze and Morris water maze was not different from that of uninfected TNF
alpha-(-/-) mice. The extent of glial activation in the striatum, as indicated by
the increase in density of peripheral benzodiazepine receptors, was equivalent in
both groups of LP-BM5-infected mice. However, the decrease in striatal MAP-2
expression, a marker of neurodegeneration observed in infected wild-type mice,
was not found in infected TNF-alpha-(-/-) mice. While the loss of TNF-alpha
appeared to have no effect on the course or severity of the central or peripheral
immunopathology resulting from LP-BM5 infection, the behavioral and biochemical
manifestations were substantially curtailed in the TNF-alpha-(-/-) mice. These
findings directly support a role for TNF-alpha in the neurodegenerative processes
associated with viral infections such as HIV-1.
PMID- 10783160
TI - Side-branching in the mammary gland: the progesterone-Wnt connection.
PMID- 10783161
TI - The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a
complex with Ras and Raf.
AB - Caenorhabditis elegans sur-8 encodes a positive regulator of Ras signaling. We
investigated the mechanism by which the human Sur-8 homolog can positively
regulate Ras-MAP kinase signaling in mammalian cells. Sur-8 expression enhances
Ras- or EGF-induced Raf and ERK activation but has no effect on ERK activation
induced by active Raf or MEK. Furthermore, Sur-8 expression does not increase AKT
or JNK activation. Sur-8 interacts with Ras and Raf and is able to form a ternary
complex with the two proteins. Thus, Sur-8 may function as a scaffold that
enhances Ras-MAP kinase signal transduction by facilitating the interaction
between Ras and Raf.
PMID- 10783162
TI - Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by
TRA-3.
AB - The Caenorhabditis elegans tra-3 gene promotes female development in XX
hermaphrodites and encodes an atypical calpain regulatory protease lacking
calcium-binding EF hands. We report that despite the absence of EF hands, TRA-3
has calcium-dependent proteolytic activity and its proteolytic domain is
essential for in vivo function. We show that the membrane protein TRA-2A, which
promotes XX female development by repressing the masculinizing protein FEM-3, is
a TRA-3 substrate. Cleavage of TRA-2A by TRA-3 generates a peptide predicted to
have feminizing activity. These results indicate that proteolysis regulated by
calcium may control some aspects of sexual cell fate in C. elegans.
PMID- 10783163
TI - Ku complex interacts with and stimulates the Werner protein.
AB - Werner syndrome (WS) is the hallmark premature aging disorder in which affected
humans appear older than their chronological age. The protein WRNp, defective in
WS, has helicase function, DNA-dependent ATPase, and exonuclease activity.
Although WRNp functions in nucleic acid metabolism, there is little or no
information about the pathways or protein interactions in which it participates.
Here we identify Ku70 and Ku86 as proteins that interact with WRNp. Although Ku
proteins had no effect on ATPase or helicase activity, they strongly stimulated
specific exonuclease activity. These results suggest that WRNp and the Ku complex
participate in a common DNA metabolic pathway.
PMID- 10783164
TI - Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release
replication factors from origins.
AB - MCM2-7, a complex of six subunits, is an essential component of the
prereplication chromatin that is assembled at Saccharomyces cerevisiae
replication origins during G(1) phase. It is also believed to be the processive
helicase at growing forks. To elucidate the action of MCM2-7 during the
transition from initiation to elongation replication, we have focused our studies
on Mcm10, a replication initiation protein that physically interacts with members
of the MCM2-7 complex. We show that Mcm10 is a chromatin-associated protein that
mediates the association of the MCM2-7 complex with replication origins.
Furthermore, diminished interaction between Mcm10 and Mcm7, a subunit of the MCM2
7 complex, by a mutation in either Mcm10 or Mcm7 inhibits replication initiation.
Surprisingly, a double mutant containing both the mcm10-1 and mcm7-1 (cdc47-1)
alleles restores interaction between Mcm10 and Mcm7 and corrects all of the
defects exhibited by each of the single mutants, including the stalling of
replication forks at replication origins typically seen in mcm10-1 cells. This
mutual compensation of defects between two independently isolated mutations is
allele specific. These results suggest that Mcm10, like Mcm7, is a critical
component of the prereplication chromatin and that interaction between Mcm10 and
Mcm7 is required for proper replication initiation and prompt release of origin
bound factors.
PMID- 10783165
TI - BASC, a super complex of BRCA1-associated proteins involved in the recognition
and repair of aberrant DNA structures.
AB - We report the identities of the members of a group of proteins that associate
with BRCA1 to form a large complex that we have named BASC (BRCA1-associated
genome surveillance complex). This complex includes tumor suppressors and DNA
damage repair proteins MSH2, MSH6, MLH1, ATM, BLM, and the RAD50-MRE11-NBS1
protein complex. In addition, DNA replication factor C (RFC), a protein complex
that facilitates the loading of PCNA onto DNA, is also part of BASC. We find that
BRCA1, the BLM helicase, and the RAD50-MRE11-NBS1 complex colocalize to large
nuclear foci that contain PCNA when cells are treated with agents that interfere
with DNA synthesis. The association of BRCA1 with MSH2 and MSH6, which are
required for transcription-coupled repair, provides a possible explanation for
the role of BRCA1 in this pathway. Strikingly, all members of this complex have
roles in recognition of abnormal DNA structures or damaged DNA, suggesting that
BASC may serve as a sensor for DNA damage. Several of these proteins also have
roles in DNA replication-associated repair. Collectively, these results suggest
that BRCA1 may function as a coordinator of multiple activities required for
maintenance of genomic integrity during the process of DNA replication and point
to a central role for BRCA1 in DNA repair.
PMID- 10783166
TI - Nuclear localization and histone acetylation: a pathway for chromatin opening and
transcriptional activation of the human beta-globin locus.
AB - We have investigated the mechanism, structural correlates, and cis-acting
elements involved in chromatin opening and gene activation, using the human beta
globin locus as a model. Full transcriptional activity of the human beta-globin
locus requires the locus control region (LCR), composed of a series of nuclease
hypersensitive sites located upstream of this globin gene cluster. Our previous
analysis of naturally occurring and targeted LCR deletions revealed that
chromatin opening and transcriptional activity in the endogenous beta-globin
locus are dissociable and dependent on distinct cis-acting elements. We now
report that general histone H3/H4 acetylation and relocation of the locus away
from centromeric heterochromatin in the interphase nucleus are correlated and do
not require the LCR. In contrast, LCR-dependent promoter activation is associated
with localized histone H3 hyperacetylation at the LCR and the transcribed beta
globin-promoter and gene. On the basis of these results, we suggest a multistep
model for gene activation; localization away from centromeric heterochromatin is
required to achieve general hyperacetylation and an open chromatin structure of
the locus, whereas a mechanism involving LCR/promoter histone H3 hyperacetylation
is required for high-level transcription of the beta-globin genes.
PMID- 10783167
TI - Bromodomain factor 1 corresponds to a missing piece of yeast TFIID.
AB - The basal transcription factor TFIID consists of the TATA-binding protein (TBP)
and TBP-associated factors (TAFs). Yeast Taf67 is homologous to mammalian
TAF(II)55. Using a yeast two-hybrid screen to identify proteins that interact
with Taf67, we isolated Bromodomain factor 1 (Bdf1) and its homolog (Bdf2). The
Bdf proteins are genetically redundant, as cells are inviable without at least
one of the two BDF genes. Both proteins contain two bromodomains, a motif found
in several proteins involved in transcription and chromatin modification. The BDF
genes interact genetically with TAF67. Furthermore, Bdf1 associates with TFIID
and is recruited to a TATA-containing promoter. Deletion of Bdf1 or the Taf67 Bdf
interacting domain leads to defects in gene expression. Interestingly, the higher
eukaryotic TAF(II)250 has an acetyltransferase activity, two bromodomains, and an
associated kinase activity. Its yeast homolog, Taf145, has acetyltransferase
activity but lacks the bromodomains and kinase. Bdf1, like TAF(II)250, has a
kinase activity that maps carboxy-terminal to the bromodomains. The structural
and functional similarities suggest that Bdf1 corresponds to the carboxy-terminal
region of higher eukaryotic TAF(II)250 and that the interaction between TFIID and
Bdf1 is important for proper gene expression.
PMID- 10783168
TI - Leptin-specific patterns of gene expression in white adipose tissue.
AB - Leptin is a hormone that regulates body weight by decreasing food intake and
increasing energy expenditure. ob/ob mice carry leptin mutations and are obese
and hyperphagic. Leptin administration to lean and ob/ob mice activates a novel
metabolic program that depletes adipose tissue. Although this response is
physiologically distinct from that evident after food restriction, the molecular
nature of these differences is as yet unknown. Expression monitoring of 6500
genes using oligonucleotide microarrays in wild-type, ob/ob, and transgenic mice
expressing low levels of leptin revealed that differences in ambient leptin
levels have dramatic effects on the phenotype of white adipose tissue. These data
identified a large number of genes that are differentially expressed in ob/ob
mice. To delineate the components of the transcriptional program specifically
affected by leptin, the level of the same 6500 genes was monitored in wild-type
and ob/ob mice at various times after leptin treatment or food restriction. A
novel application of k-means clustering identified 8 clusters of adipose tissue
genes whose expression was different between leptin treatment and food
restriction in ob/ob mice and 10 such clusters in wild-type experiments. One of
the clusters was repressed specifically by leptin in both wild-type and ob/ob
mice and included several genes known to be regulated by SREBP-1/ADD1. Further
studies confirmed that leptin decreases the levels of SREBP-1/ADD1 RNA and
transcriptionally active SREBP-1/ADD1 protein in white adipose tissue. Future
studies of the molecular basis for the apparent coordinate regulation of the
other clusters of leptin-regulated genes may reveal additional mechanisms by
which leptin exerts its weight-reducing effects.
PMID- 10783169
TI - Analysis of p53-regulated gene expression patterns using oligonucleotide arrays.
AB - Oligonucleotide microarrays were employed to quantitate mRNA levels from a large
number of genes regulated by the p53 transcription factor. Responses to DNA
damage and to zinc-inducible p53 were compared for their transcription patterns
in cell culture. A cluster analysis of these data demonstrates that genes induced
by gamma radiation, UV radiation, and the zinc-induced p53 form distinct sets and
subsets with a few genes in common to all these treatments. Cell type- or cell
line-specific p53 responses were detected. When p53 proteins were induced with
zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes
fell into eight distinct classes, five different kinetics of induction, and three
different kinetics of repression. In addition, low levels of p53 in a cell
induced or repressed only a subset of genes observed at higher p53 levels. The
results of this study demonstrate that the nature of the p53 response in diverse
mRNA species depends on the levels of p53 protein in a cell, the type of inducing
agent or event, and the cell type employed. Of 6000 genes examined for p53
regulatory responses, 107 induced and 54 repressed genes fell into categories of
apoptosis and growth arrest, cytoskeletal functions, growth factors and their
inhibitors, extracellular matrix, and adhesion genes.
PMID- 10783170
TI - Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of
Rb in the external granular layer cells of the cerebellum.
AB - Medulloblastomas are among the most common malignancies in childhood, and they
are associated with substantial mortality and morbidity. The molecular
pathogenesis as well as the ontogeny of these neoplasms is still poorly
understood. We have generated a mouse model for medulloblastoma by Cre-LoxP
mediated inactivation of Rb and p53 tumor suppressor genes in the cerebellar
external granular layer (EGL) cells. GFAP-Cre-mediated recombination was found
both in astrocytes and in immature precursor cells of the EGL in the developing
cerebellum. GFAP-Cre;Rb(LoxP/LoxP);p53(-/- or LoxP/LoxP) mice developed highly
aggressive embryonal tumors of the cerebellum with typical features of
medulloblastoma. These tumors were identified as early as 7 weeks of age on the
outer surface of the molecular layer, corresponding to the location of the EGL
cells during development. Our results demonstrate that loss of function of RB is
essential for medulloblastoma development in the mouse and strongly support the
hypothesis that medulloblastomas arise from multipotent precursor cells located
in the EGL.
PMID- 10783172
TI - Fragmented responsibility, deteriorating care.
PMID- 10783171
TI - Inhibitor of striate conditionally suppresses cell proliferation in variegated
maize.
AB - Since the work done by R.A. Emerson in the 1930s, Inhibitor of striate (Isr) has
been recognized as a dose-dependent genetic modifier of variegation in chlorotic
leaf striping mutants of maize such as striate2 (sr2). We have shown that Isr
specifically inhibits proliferation and differentiation of plastid defective
cells in sr2 mutants. Leaf narrowing is due to loss of intermediate veins and
ground tissue located at leaf margins, and the few remaining plastid defective
cells are of irregular size and aberrant organization. The Isr gene has been
cloned by targeted transposon tagging. Isr mRNA is expressed throughout young
leaves, but Isr chimeras indicate that the expression of Isr at leaf margins is
sufficient to suppress both the lateral expansion of sr2 leaves and the extent of
striping. Isr protein appears to encode a chloroplast protein with sequence
similarity to a family of bacterial phosphatases involved in carbon catabolite
repression or in carbon metabolism. We propose that the action of Isr in nuclear
and plastid communication could be triggered by carbon stress.
PMID- 10783173
TI - Personal accounts: first-person accounts in the Journal's first quarter-century.
PMID- 10783174
TI - Datapoints: Estimates of children and adolescents with school-related behavioral
problems.
PMID- 10783176
TI - Best practices: Population density as a factor in the rehospitalization of
persons with serious and persistent mental illness.
PMID- 10783177
TI - Rehab rounds: Behavioral management of aggression through teaching interpersonal
skills.
PMID- 10783178
TI - Trends in community mental health programs.
PMID- 10783179
TI - Whatever happened to community mental health?
PMID- 10783180
TI - Utilization management in a large managed behavioral health organization.
AB - OBJECTIVE: The utilization management process of a managed behavioral health
organization was examined to determine the frequency and types of reviews and the
extent to which rationing of service was achieved through the denial of services.
METHODS: A case study of the utilization management program of a large managed
behavioral health organization was done. Information was gathered from claims for
1997, and utilization review data were drawn from 51 plans. Data were examined by
review type and authorization actions. RESULTS: The utilization management
program performed a total of 9, 639 reviews. The most common type was concurrent
review for additional outpatient therapy visits (46 percent). The second most
common type was concurrent facility review (12.9 percent). The vast majority of
authorizations were approved at the level requested by the provider (91.8
percent). Very few services were denied (.8 percent) or approved at a level lower
than requested by the provider (1.3 percent). CONCLUSIONS: Although concerns have
been raised about the high denial rates of utilization management programs, this
study found very low denial rates. Further studies are needed to determine the
precise mechanisms used in utilization management programs to control
utilization. In addition, the large number of reviews raises questions about the
time and opportunity costs of the review process.
PMID- 10783181
TI - A review of pharmacotherapy of major depression in children and adolescents.
AB - OBJECTIVE: The review examined the historical progression and current status of
pharmacotherapy of child and adolescent major affective disorder. METHODS: A
MEDLINE search was used to identify double-blind, placebo-controlled studies of
child and adolescent major depression. Only studies that used reliable diagnostic
and recovery parameters were included. RESULTS: Few well-designed studies have
compared placebo and tricyclic antidepressants in the treatment of major
depressive disorder in children and adolescents. However, results consistently
suggest that tricyclic antidepressants are not efficacious. Early results of
double-blind placebo-controlled trials with fluoxetine and paroxetine have shown
a significant drug effect. However, the results are inconsistent, which could
reflect the ways that response to medication is defined, the ways that rating
scales measure recovery, and uncertainties of dosing strategies with second
generation antidepressants. Hypothesized reasons for the unique response pattern
in youths include the changing hormonal status of children, the differential
maturation of the noradrenergic versus serotonergic neurotransmitter systems, and
the possibility that a large proportion of depressed youths are in the early
stages of bipolar disorder, which is not effectively treated by these
medications. CONCLUSIONS: Tricyclic antidepressants are not superior to placebo
for the treatment of child and adolescent major depressive disorder. Although two
of three trials of second-generation antidepressants in this age group have had
negative results, data suggest that these drugs may be more promising. It is too
early in our investigation to know whether these agents will be effective in
treating major depressive disorder in children and adolescents.
PMID- 10783182
TI - Changes in use of valproate and other mood stabilizers for patients with
schizophrenia from 1994 to 1998.
AB - OBJECTIVE: The study describes changes over time in the adjunctive use of
valproate and other mood stabilizers-lithium, carbamazepine, and gabapentin-
among hospitalized psychiatric patients with a diagnosis of schizophrenia.
METHODS: For each calendar year from 1994 through 1998, data were drawn from a
database containing clinical and drug prescription information for every
inpatient in the adult civil facilities of the New York State Office of Mental
Health. RESULTS: In 1994 a total of 26.2 percent of inpatients diagnosed as
having schizophrenia received a mood stabilizer, compared with 43.4 percent in
1998. In 1994 lithium was the most commonly prescribed mood stabilizer, for 13.2
percent of patients, followed by valproate, for 12.3 percent. In 1998 valproate
was the most commonly prescribed, for 35 percent of patients, followed by
lithium, for 11.3 percent. On average, patients received valproate for about two
thirds of their hospital stay, at a mean dose of 1,520 mg per day. CONCLUSIONS:
The adjunctive use of valproate nearly tripled from 1994 to 1998 among patients
with a diagnosis of schizophrenia. Valproate has become the most commonly
prescribed mood stabilizer for this population, despite the paucity of evidence
in the literature for efficacy in this use. Controlled clinical trials are needed
to examine the adjunctive use of mood stabilizers, in particular valproate, among
patients with schizophrenia.
PMID- 10783183
TI - Effects of substance dependence on outcomes of patients in a randomized trial of
two case management models.
AB - OBJECTIVE: The effectiveness of a community-based intensive clinical case
management program was compared with that of a hospital-based expanded brokerage
case management program for seriously mentally ill adults with and without
substance dependence. METHODS: The sample of 268 frequently hospitalized
psychiatric patients was recruited during acute psychiatric hospitalization. More
than half of the sample (53 percent) was diagnosed as having at least one current
DSM-III-R substance dependence disorder co-occurring with their primary major
mental disorder. Subjects were stratified by substance dependence status and
randomly assigned to one of the case management programs. They were interviewed
before hospital discharge and at one, two, and six months after discharge to
assess psychosocial and drug use variables. Subjects' service use was examined
for the six months before and after hospitalization. RESULTS: The hypothesis that
substance-dependent subjects would benefit more from intensive clinical case
management was not supported. Substance dependence predicted negative outcomes
independent of the case management intervention. The hypothesis that the two case
management approaches would be equally effective for subjects not dependent on
substances was also not borne out. Intensive clinical case management was the
superior treatment for subjects who were not dependent on substances. Fewer of
them required psychiatric hospitalization in the six-month postdischarge period
than in the six-month period before hospital admission. CONCLUSIONS: The negative
outcomes for substance-dependent subjects in both programs suggest that the two
case management models were relatively ineffective for these patients. Results
suggest that intensive clinical case management can be effective within the first
six months for nondependent adults with serious mental illness.
PMID- 10783184
TI - Comparing outcomes of major models of police responses to mental health
emergencies.
AB - OBJECTIVE: The study compared three models of police responses to incidents
involving people thought to have mental illnesses to determine how often
specialized professionals responded and how often they were able to resolve cases
without arrest. METHODS: Three study sites representing distinct approaches to
police handling of incidents involving persons with mental illness were examined
Birmingham, Alabama; and Knoxville and Memphis, Tennessee. At each site, records
were examined for approximately 100 police dispatch calls for "emotionally
disturbed persons" to examine the extent to which the specially trained
professionals responded. To determine differences in case dispositions, records
were also examined for 100 incidents at each site that involved a specialized
response. RESULTS: Large differences were found across sites in the proportion of
calls that resulted in a specialized response-28 percent for Birmingham, 40
percent for Knoxville, and 95 percent for Memphis. One reason for the differences
was the availability in Memphis of a crisis drop-off center for persons with
mental illness that had a no-refusal policy for police cases. All three programs
had relatively low arrest rates when a specialized response was made, 13 percent
for Birmingham, 5 percent for Knoxville, and 2 percent for Memphis. Birmingham's
program was most likely to resolve an incident on the scene, whereas Knoxville's
program predominantly referred individuals to mental health specialists.
CONCLUSIONS: Our data strongly suggest that collaborations between the criminal
justice system, the mental health system, and the advocacy community plus
essential services reduce the inappropriate use of U.S. jails to house persons
with acute symptoms of mental illness.
PMID- 10783185
TI - Comparing quality of mental health care for public-sector and privately insured
populations.
AB - OBJECTIVE: This study examined the methodological difficulties of comparing
quality of care in large health care systems. It demonstrated methods for
measuring quality of mental health care and, using these measures, compared
patients from Department of Veterans Affairs (VA) hospitals with privately
insured patients. METHODS: Individuals receiving VA inpatient mental health care
during the first six months of each fiscal year from 1993 to 1997 were identified
from discharge abstracts. A similar cohort of privately insured individuals was
identified using MEDSTAT's MarketScan database from 1993 to 1995. Individuals in
both cohorts were tracked for six months after discharge. Length of stay,
readmission rates, and access to outpatient services were calculated. RESULTS:
The private sector outperformed VA on most quality measures, although differences
were modest and can likely be explained by the greater severity of illness and
social disadvantages of VA patients. Readmission rates increased considerably
over time in the private sector, whereas they declined for VA patients. Quality
measures varied by diagnosis, with VA performing better than the private sector
in treating patients diagnosed with substance abuse and mental disorders not
elsewhere classified but worse in treating patients diagnosed with depression.
CONCLUSIONS: Although the private sector modestly outperformed VA on most quality
measures, VA treats a more troubled population, and it improved markedly over
time compared with the private sector. As health systems strive to reduce costs
of care, methods for comparing and evaluating the quality of care become
increasingly important. However, methodological challenges remain substantial.
PMID- 10783186
TI - A Delphi approach to describing service models of community mental health
practice.
AB - OBJECTIVE: The activities of mental health practitioners are poorly understood
and described because of a lack of generally accepted and understandable
categories. Greater precision is needed for accountability, planning, and
evaluation. The objective of this study was to identify a valid and reliable set
of categories to describe the clinical work practices of intensive case managers
in the United Kingdom. METHODS: Eight intensive case managers participated in a
Delphi process to produce a set of categories that described their clinical work
practices. They each completed three questionnaires and participated in a final
group discussion. RESULTS: The initial open questionnaire generated 38 potential
categories after exact duplicates were removed. In round 2, the intensive case
managers each rated the 38 categories from 1 to 5 (essential to unimportant). A
high degree of consensus on the relative importance of the 38 suggested practice
categories was rapidly achieved. In round 3, they re-rated the categories in the
light of group medians and their own round 2 ratings. In a structured face-to
face discussion group, the intensive case managers then reduced the 38 potential
categories to ten comprehensive and mutually exclusive categories that were
judged to adequately and accurately reflect work practices. They were housing,
finance, daily living skills, criminal justice system, occupation and leisure,
engagement, physical health, caregivers and significant others, specific mental
health intervention or assessment, and medication. CONCLUSIONS: Delphi methods
were effective and relatively straightforward in producing an agreed-on set of
categories with which to record clinical activity and inform care planning.
PMID- 10783187
TI - Treatment of acute schizophrenia in open general medical wards in Jamaica.
AB - OBJECTIVE: The study assessed the efficacy of treating acute psychotic illness in
open medical wards of general hospitals. METHODS: The sample consisted of 120
patients with schizophrenia whose first contact with a psychiatric service in
Jamaica was in 1992 and who were treated as inpatients during the acute phase of
their illness. Based on the geographic catchment area where they lived, patients
were admitted to open medical wards in general hospitals, to psychiatric units in
general hospitals, or to acute care wards in a custodial mental hospital. At
first contact, patients' severity of illness was assessed, and sociodemographic
variables, pathways to care, and legal status were determined. At discharge and
for the subsequent 12 months, patients' outcomes were assessed by blinded
observers using variables that included relapse, length of stay, employment
status after discharge, and clinical status. RESULTS: More than half (53 percent)
of the patients were admitted to the mental hospital, 28 percent to general
hospital medical wards, and 19 percent to psychiatric units in general hospitals.
The three groups did not differ significantly in geographic incidence rates,
patterns of symptoms, and severity of psychosis. The mean length of stay was 90.9
days for patients in the mental hospital, 27.9 days in the general hospital
psychiatric units, and 17.3 days in the general hospital medical wards. Clinical
outcome variables were significantly better for patients treated in the general
hospital medical wards than for those treated in the mental hospital, as were
outpatient compliance and gainful employment. CONCLUSIONS: While allowing for
possible differences in the three patient groups and the clinical settings, it
appears that treatment in general hospital medical wards results in outcome that
is at least equivalent to, and for some patients superior to, the outcome of
treatment in conventional psychiatric facilities.
PMID- 10783188
TI - The cost of access to mental health services in managed care.
AB - Managed care has controlled the cost of specialty mental health services, but its
impact on access to care is not well described. In a retrospective design, the
study used empirical data to demonstrate a direct relationship between managed
care plans' claims costs per member per month and the proportion of plan members
who use specialty mental health services annually. Each increment of $1 per
member per month in spending on claims was associated with a.9 percent increase
in the proportion of enrollees receiving specialty mental health treatment. These
data raise concerns that plans with low per-member per-month costs may unduly
restrict access to specialty treatment.
PMID- 10783189
TI - Subjective experiences of clozapine treatment by patients with chronic
schizophrenia.
AB - A 37-item survey covering a variety of somatopsychic domains was constructed to
explore patients' subjective response to treatment with clozapine. The survey was
administered to 130 patients with diagnoses of chronic schizophrenic or
schizoaffective disorders who were on a stable clozapine regimen. The majority
reported improvement in their level of satisfaction, quality of life, compliance
with treatment, thinking, mood, and alertness. Most patients reported worsening
in nocturnal salivation, and smaller numbers reported worsening in various
gastrointestinal and urinary symptoms and weight gain. This general health survey
highlights the patients' positive regard for clozapine, despite adverse bodily
experiences. Subjective reports are a useful component of outcome measures of
drug treatment.
PMID- 10783190
TI - An assessment of clinical practice of clozapine therapy for veterans.
AB - Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was
examined over a five-year period in the Veterans Affairs health care system.
Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the
Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for
522 patients, indicated a significant improvement, as did AIMS scores, which were
available for 252 patients. Compared with individuals who showed a modest
improvement, those with a more robust response to clozapine had higher initial
BPRS scores and were three times more likely to have been suicidal in the month
before starting clozapine therapy.
PMID- 10783191
TI - Acceptability of telepsychiatry to a rural population.
AB - Sixty-seven residents of a rural Midwestern state were surveyed by telephone to
determine which factors influence their willingness to receive mental health
services through live, two-way audio and video transmission. Two-thirds of the
survey respondents were willing to participate in telepsychiatry. Many expressed
reluctance, however. They were concerned about maintaining confidentiality, and
they perceived telepsychiatry as impersonal. Medicare enrollees and older survey
respondents were less willing than younger respondents to endorse the use of
telemedicine.
PMID- 10783192
TI - Unusual case report: Nonpharmacologic effects of sildenafil.
AB - Sildenafil (Viagra), by virtue of its conflict-laden symbolic meanings, may be
particularly likely to have psychosocial consequences, either therapeutic or
disruptive. The author presents two cases of men in their mid-seventies who took
sildenafil and who were admitted to a locked geropsychiatry unit because of
homicidal ideation toward their wives that occurred while they were not under the
direct effect of the drug. In one case, a wife's rejection of her husband's
advances seemed to uncover many hidden resentments that they bore toward each
other. In the other, sildenafil failed to restore potency to a patient with
diabetes, and he developed a jealous delusion that his wife was having an affair.
PMID- 10783193
TI - The high cost of care.
PMID- 10783195
TI - The high cost of care
PMID- 10783194
TI - Involuntary hospitalization or aversive incarceration?
PMID- 10783196
TI - "Patient" versus "client".
PMID- 10783197
TI - "Patient" versus "client".
PMID- 10783198
TI - "Patient" versus "Client"
PMID- 10783199
TI - The corporate life.
PMID- 10783200
TI - Separating subculture from psychopathology.
PMID- 10783201
TI - The corporate life
PMID- 10783202
TI - Ideas of reference about newscasters.
PMID- 10783203
TI - Clinical trials in acute myocardial infarction: should we adjust for baseline
characteristics?
AB - BACKGROUND: Clinical trials concerning acute myocardial infarction often evaluate
short-term death. Several baseline characteristics are predictors of death, most
notably age. Adjustment for one or more predictors in a multivariable analysis
may be considered to correct the estimate of the treatment effect for any
imbalance that by chance may have occurred between the randomized groups.
Moreover, adjustment results in a stratified estimate of the effect of treatment.
METHODS AND RESULTS: The effects of adjustment (correction for imbalance and
stratification) were studied with logistic regression analysis in the Global Use
of Strategies to Open Occluded Coronary Arteries (GUSTO)-I trial. The primary end
point was 30-day death, which occurred in 6.3% of 10,348 patients randomly
assigned to tissue plasminogen activator and 7.3% of 20,162 patients randomly
assigned to streptokinase thrombolytic therapy. This is equivalent to an
unadjusted odds ratio of 0.853. No significant imbalance had occurred for any of
17 baseline characteristics considered, including well-known demographic,
presenting, and history characteristics. Adjusted for age, the odds ratio was
0.829, which is an 18% increase in estimated effect on the logistic scale. When
adjusted for 17 characteristics, the odds ratio was 0.820, an increase of 25%.
The increase in effect estimate was largely explained by the stratification
effect and only partly by imbalance of predictors. CONCLUSIONS: Adjustment for
predictive baseline characteristics, even when largely balanced, may lead to
clearly different estimates of the treatment effect on mortality rates.
Adjustment for important predictors such as age is recommended in clinical trials
studying patients with acute myocardial infarction.
PMID- 10783204
TI - Appropriate outcome measures in trials evaluating treatment of atrial
fibrillation.
AB - BACKGROUND: Atrial fibrillation (AF) is a widespread disease that has only
recently received the focused attention of arrhythmia specialists despite being
the most frequently occurring significant cardiac arrhythmia. METHODS AND
RESULTS: The wide variety of trial designs used to evaluate AF treatment is a
reflection of the diverse outcomes associated with this condition. The best
trials assess the impact of treatment on a clearly measured outcome that is of
clinical relevance to patients. This review discusses the different designs of AF
treatment trials and analyzes the utility of the various outcomes that can be
assessed. CONCLUSIONS: A sensible goal of AF treatment is to reduce the frequency
of recurrences and to prolong the time between them. The most appropriate trials
focus on AF recurrences that are symptomatic and therefore relevant to the
patient. We still do not know if there is value in AF prevention, beyond
preventing symptoms. However, ongoing and future studies will show whether AF
suppression reduces the longer-term risks of stroke or death and improves patient
quality of life. Cost of care will increasingly be studied in future trials of AF
management.
PMID- 10783205
TI - Clinical trials in acute myocardial infarction: when should we adjust for
baseline characteristics?
PMID- 10783206
TI - Understanding racial differences in cardiovascular care and outcomes: issues for
the new millennium.
PMID- 10783207
TI - Monitoring trends in severity of acute myocardial infarction: challenges for the
next millennium.
PMID- 10783208
TI - When is angina good? Preconditioning in acute myocardial infarction.
PMID- 10783210
TI - Transpulmonary passage of Albunex as a marker of intracardiac hemodynamics and
outcome in chronic congestive heart failure.
AB - BACKGROUND: Aggressive management to reduce pulmonary artery systolic pressure
(PASP) and pulmonary capillary wedge pressure (PCWP) reduces hospitalization
rates and is crucial for patients awaiting transplantation but may require
periodic invasive monitoring with right heart catheterization. METHODS: The
purpose of this study was to define the relation of transpulmonary passage of
Albunex (Mallinckrodt Medical, St Louis, Mo) to intracardiac hemodynamics and
clinical outcome in patients with chronic congestive heart failure (CHF).
Patients (n = 38) with chronic CHF underwent graded dobutamine infusion
(baseline, 5, 10, 20 microg/kg per minute; 5-minute stages) with 5.0 mL Albunex
injected intravenously at each stage. The dobutamine dose at which Albunex
appeared in the left ventricle was determined. All patients had right heart
catheterization to determine PASP and PCWP. RESULTS: Transpulmonary passage of
Albunex at baseline or at 5 microg/kg per minute dobutamine infusion predicted
PCWP <20 mm Hg with a positive predictive value of 100% and a negative predictive
value of 79%. Initial appearance of Albunex in the left ventricle at a dobutamine
dose of 20 microg/kg per minute or failure to appear at any dose predicted a PCWP
>20 mm Hg with a positive predictive value of 100% and a negative predictive
value of 94%. No patient with Albunex passage at baseline sustained a major
adverse event. Major adverse events occurred in 11 of 21 patients in whom Albunex
either failed to cross or crossed the pulmonary bed at a dose of 20 microg/kg per
minute of dobutamine. CONCLUSION: In patients with chronic CHF, transpulmonary
passage of Albunex during dobutamine infusion can be used to predict both
elevated and normal intracardiac pressures and to identify a subset of patients
at high risk for an adverse outcome.
PMID- 10783209
TI - Strategy for optimal aortic regurgitation quantification by Doppler
echocardiography: agreement among different methods.
AB - BACKGROUND: Although different Doppler methods have been validated for aortic
regurgitation quantification, the benefit of combining information from different
methods has not been defined. METHODS: Our study included 2 phases. In the
initial phase (60 patients), Doppler parameters (jet width, short-axis jet area,
apical jet area, regurgitant fraction from pulmonary and mitral flow, and
deceleration slope) were correlated with angiography; range values for each
severity grade were defined and intraobserver and interobserver and intermachine
variability were studied. In the validation phase (158 patients), defined value
ranges were prospectively tested and a strategy based on considering as the
definitive severity grade that in which the two best methods agreed was tested.
RESULTS: Jet width had the best correlation with angiography (r = 0.91), and its
ratio with the left ventricular outflow diameter did not improve the correlation
(r = 0.85) and decreased reproducibility. Apical jet area and regurgitant
fraction from pulmonary flow permitted acceptable quantification (r = 0.87 and
0.86, respectively) but with worse reproducibility. The other methods were not
assessable in 20% to 30% of studies. Concordance with angiography decreased in
jet width when the jet was eccentric (90% vs 77%, P <.01), in apical jet area
when mitral valve disease was present (84% vs 65%, P <.02), and in short-axis jet
area and regurgitant fraction from pulmonary flow with concomitant aortic
stenosis (77% vs 44%, P <.002 and 77% vs 53%, P <.02, respectively). Agreement
with angiography was very high (94 [95%] of 99) when severity grade coincided in
both jet width and apical jet area. In 59 cases without concordance, regurgitant
fraction from pulmonary flow was used as a third method. Overall, this strategy
permitted concordance with angiography in 146 patients (92%). CONCLUSIONS: Jet
width is the best predictor in aortic regurgitation quantification by Doppler
echocardiography. However, better results were obtained when a strategy based on
concordance between jet width and another Doppler method was established,
particularly when the jet was eccentric.
PMID- 10783211
TI - Prehospital delay time in acute myocardial infarction: an exploratory study on
relation to hospital outcomes and cost.
AB - BACKGROUND: Short prehospital delay is associated with improved outcomes in
myocardial infarction, but the impact on cost has not been tested. Shortening
delay time could reduce health care expenditures. METHODS AND RESULTS: Two
hundred ninety-eight patients were examined with the use of a historic
prospective design at 2 hospital sites. A secondary analysis was performed that
used patients with confirmed myocardial infarction from the National Register of
Myocardial Infarction and direct and indirect costs from the accounting system at
the hospitals. Chi-square, Mann Whitney U, and Fisher exact tests were used for
comparisons. Delay and 4 sets of variables were regressed on cost with the
significant predictors used to construct a final model. The mean age was 71 +/-
14 years old; 62% were men. There were no major differences in demographics,
cardiac history, risk factors, and admission characteristics between short and
long delayers. Resource utilization and clinical outcomes were similar between
the 2 groups; there was no difference in cost. Additional diagnostic procedures
(odds ratio 2.92; 95% confidence interval 1.65-5.15) and complications (odds
ratio 3.43; 95% confidence interval 2.03-5.82) were significant predictors of
cost. Delay was not a predictor of high cost. CONCLUSIONS: Short prehospital
delay was not associated with improved clinical outcomes, nor did it predict
cost. Explanations include (1) the low utilization of early reperfusion therapy
in the short delay group, (2) the study lacked sufficient power to detect a
difference in cost between short and long delayers, and (3) the severity of
illness could not be adequately measured. This issue warrants further study
because of the potential impacts on health care expenditures.
PMID- 10783212
TI - Inappropriate therapy from atrial fibrillation and sinus tachycardia in automated
implantable cardioverter defibrillators.
AB - BACKGROUND: Inappropriate therapy from supraventricular tachyarrhythmias (atrial
fibrillation [AF] and sinus tachycardia [ST]) in patients with implanted
cardioverter defibrillators is a major challenge. We tested the performance of
stability algorithms from 3 manufacturers for episodes of inappropriate therapy
delivered because of AF and an onset algorithm for all episodes of inappropriate
therapy caused by ST. METHODS: Therapy was classified as caused by ventricular
tachycardia (VT), ST, or AF from review of stored intracardiac electrograms,
history, clinical information, and R-R data before study inception. By using 30
to 60 R-R intervals before therapy, sensitivity and specificity for a family of
stability values and percentage of onset values were calculated for each
manufacturer and receiver operating characteristic curves generated. RESULTS: Of
the 217 patients monitored, 62 (29%) received inappropriate therapy, and 40 had
complete R-R information available. Of the 40 patients, 21 patients received
therapy for AF, 19 for ST, and 1 patient for noise; 15 (38%) also received
appropriate therapy for VT. We analyzed 83 episodes of VT from 18 patients, 94
episodes of AF from 21 patients, and 56 episodes of ST from 19 patients.
Specificity, in the clinically relevant sensitivity range of >/=95%, was
comparable across manufacturers at about 40%. An onset value of 80% was
associated with 91% sensitivity and 95% specificity for the specific algorithm
tested. CONCLUSIONS: Inappropriate therapy is a common problem in implantable
cardiac defibrillators. The performance of the stability algorithms used to
differentiate AF from VT was less than ideal, though comparable across
manufacturers. The onset algorithm accurately differentiates ST from VT.
PMID- 10783213
TI - Determinants of outcome in patients with sustained ventricular tachyarrhythmias:
the antiarrhythmics versus implantable defibrillators (AVID) study registry.
AB - BACKGROUND: The prognosis of patients with sustained ventricular tachyarrhythmias
varies according to clinical characteristics. We sought to identify predictors of
survival in a large population of patients with documented sustained ventricular
tachyarrhythmias not related to reversible or correctable causes included in the
Antiarrhythmics Versus Implantable Defibrillators (AVID) Registry. METHODS AND
RESULTS: We analyzed the impact of 36 demographic, clinical, and discharge
treatment variables on the outcome for 3559 patients. Survival status was
assessed with the use of the National Death Index. Multivariate analyses were
performed with the use of the Cox proportional hazards model. After a mean follow
up of 17 +/- 12 months, 631 patients died. Actuarial survival was 0.86 (95%
confidence interval [CI] 0.85 to 0.88), 0.79 (95% CI 0.78 to 0.81), and 0.72 (95%
CI 0.70 to 0.74) at 1, 2, and 3 years. Multivariate predictors of worse survival
included older age, severe left ventricular dysfunction, lower systolic blood
pressure, history of congestive heart failure, diabetes, smoking or atrial
fibrillation, and preexistent pacemaker. The hemodynamic impact of the qualifying
arrhythmia was not a predictor of outcome. Defibrillator implantation and
hospital discharge while the patient was taking a beta-blocker or an angiotensin
converting enzyme inhibitor were associated with better prognosis. CONCLUSIONS:
Despite therapeutic advances, the mortality rates of patients with sustained
ventricular tachyarrhythmias remain high. Prognosis depends on the severity of
underlying heart disease, as reflected by the extent of left ventricular
dysfunction and the presence of heart failure. Well-tolerated ventricular
tachycardia in patients with structural heart disease does not carry a
significantly better prognosis than ventricular tachyarrhythmia with more severe
hemodynamic consequences.
PMID- 10783214
TI - Clinical study to investigate the predictive parameters for the onset of atrial
fibrillation in patients with essential hypertension.
AB - BACKGROUND: The risk factors involved in the onset of atrial fibrillation (AF)
are well known, but the predictive clinical and paraclinical parameters for the
onset of AF in hypertensive patients have not been investigated specifically.
METHODS AND RESULTS: We retrospectively analyzed 97 consecutive patients with
hypertension and no known history of AF or cardiovascular events who attended the
cardiology outpatient clinic. The analysis was based on clinical data, the
noninvasive ambulatory 24-hour measurement of blood pressure (AMBP), a standard
12-lead electrocardiogram, and a Doppler echocardiogram. After a mean follow-up
of 25 +/- 3 months, 19 (19. 5%) patients had AF, 3 (15.8%) of whom had a
cerebrovascular accident. The patients with AF were older than the others and
their AMBP showed higher mean systolic diurnal and nocturnal blood pressures,
though no differences in the clinical blood pressure readings were present. On
the electrocardiogram, the maximum duration of the P wave and its dispersion were
more prolonged in the patients with AF. On the Doppler echocardiogram, left
ventricular mass and left atrial dimension were higher in the patients with AF,
and the A-wave velocity of diastolic mitral flow was reduced in these patients.
In the multivariate analysis, age (odds ratio 3.28, P <.001), diurnal systolic
blood pressure (odds ratio 1.35, P <.01) and nocturnal systolic blood pressure
(odds ratio 1.16, P <.01), maximum duration of the P wave (odds ratio 2.09, P
<.01), dispersion of the P wave (odds ratio 2.52, P <.001), echocardiographic
left ventricular mass (odds ratio 1.43, P <.01), left atrial dimension (odds
ratio 2.81, P <.001), and velocity of the A wave (odds ratio 2. 24, P <.01) were
independent predictors for the onset of AF. After correction for age, maximum
duration of the P wave (odds ratio 1.34, P <.01), dispersion of the P wave (odds
ratio 1.63, P <.001), and the velocity of the A wave (odds ratio 1.42, P <.01)
remained independent predictors for the onset of AF. CONCLUSIONS: In patients
with hypertension, age and the level of diurnal and nocturnal systolic blood
pressures measured by 24-hour AMBP are important independent predictors for the
onset of AF. Independent of age, increases in left atrial dimension and left
ventricular mass, prolongation of the maximum duration and dispersion of the P
wave and reduced A-wave velocity are also predictors for the onset of AF.
PMID- 10783215
TI - Collaborative angiographic patency trial of recombinant staphylokinase (CAPTORS).
AB - BACKGROUND: We undertook an angiographic, dose-finding study of staphylokinase
(SAK42D variant) to evaluate its efficacy and safety in patients with acute ST
segment myocardial infarction. METHODS AND RESULTS: Patients were studied within
6 hours of symptom onset and received SAK42D as a 30-minute infusion with 20% of
the total dose given as a bolus. Eighty-two patients with a median age of 60
years (interquartile range 52 to 69 years), 84% male and 43% with an anterior
myocardial infarction, were studied at a median time from symptom onset of 2.7
hours. There was a high degree of Thrombolysis in Myocardial Infarction (TIMI) 3
flow achieved with 15 mg of SAK42D, that is, 62%. Therefore after 21 patients had
been studied at this dose the next dose of 30 mg was used and 65% TIMI 3 patency
was achieved. At the peak dose of 45 mg, TIMI 3 90-minute patency was 63%. There
were no allergic reactions, and no patient had intracranial hemorrhage. Four
patients had major and 9 moderate bleeding during the study; 2 of the major and 5
of the moderate bleeding events occurred within 48 hours of commencement of
treatment. The majority (62%) of these were related to vascular instrumentation,
and there was no relation between the extent of bleeding and dose of SAK42D used.
Forty-five minutes after cessation of SAK42D, there were small percent decrements
in plasma fibrinogen and plasminogen levels that did not reach statistical
significance. However, there were dose-related changes in alpha(2) anti-plasmin
that revealed a borderline significant reduction that was dose related (P =.053).
CONCLUSION: These data revealed similar fibrinolytic efficacy across a 3-fold
increment in dose, indicating that this study operated on a flat portion of the
dose-response curve. The favorable efficacy/safety profile achieved with
staphylokinase is encouraging, and further investigation is warranted.
PMID- 10783216
TI - Reduced thrombus burden with abciximab delivered locally before percutaneous
intervention in saphenous vein grafts.
AB - BACKGROUND: Existing thrombus can complicate percutaneous saphenous vein graft
(SVG) intervention. Local delivery of thrombolytics has been used to reduce the
thrombus burden often associated with these interventions. We sought to determine
whether local delivery of a platelet glycoprotein IIb/IIIa inhibitor is feasible
and can reduce thrombus burden before percutaneous SVG intervention. METHODS: We
performed a multicenter pilot study of abciximab (0.25 mg/kg) given by local
delivery catheter before percutaneous intervention for de novo SVG stenoses
followed by intravenous infusion. All patients (n = 58) had >/=60% stenosis and
Thrombolysis In Myocardial Infarction (TIMI) grade >0 flow in an SVG of 3 to 4 mm
in diameter. Percent diameter stenosis, TIMI thrombus grade, and TIMI flow grade
were measured before and after delivery of abciximab and after intervention.
RESULTS: Median percent diameter stenosis improved from 69% to 45% (P =.0001)
after local delivery, and TIMI thrombus grade >/=1 incidence reduced from 68% to
34% (P =.0001). TIMI flow grade was not significantly affected (P =.12). All
patients had a successful intervention (/=3.0 mm in diameter, the
outcome of stent placement in smaller vessels remains largely unclear. METHODS
AND RESULTS: We sought to specifically determine the early and long-term clinical
outcomes in a large series of 197 consecutive patients who underwent stent
placement in 207 vessels <3.0 mm in diameter. Procedural success, accomplished in
97.3%, was accompanied by a significant reduction in lesion severity from 85% +/-
9% before to 3% +/- 7% diameter stenosis after the procedure (P =.0001) and a
0.5% incidence of subacute stent thrombosis. At 1 and 2 years of follow-up,
survival rate without major target lesion-driven events was observed in 77.3% and
73.9% of patients, respectively. Repeat revascularization procedures accounted
for most of these events; cardiac deaths (including those related to subacute
stent thrombosis) and late (>30 days) myocardial infarctions were infrequent
(2.4% and 1.0%, respectively). The 6-month angiographic binary instent restenosis
rate was 30.1%. On multivariate analysis, diabetes mellitus (P =. 0275), small
baseline reference vessel size (P =.0300), and stent size /=80. In addition, we examined whether age had an impact on the efficacy of
eptifibatide therapy. RESULTS: Eptifibatide improved outcome at 30 days (P =.04).
There was no interaction among age and treatment (placebo vs eptifibatide) and
adjusted outcome (P =.16 for death or [re]infarction at 30 days). Despite their
worse clinical profile, older patients were less likely to undergo coronary
angiography at 30 days: 936 (71%), 1489 (68%), 1969 (65%), 1357 (57%), and 193
(38%) in the respective age groups. Death or (re)infarction at 30 days occurred
in 121 (9%), 255 (12%), 447 (15%), 460 (19%), and 134 (26%) in the respective age
groups, and at 6 months in 149 (11%), 301 (14%), 547 (18%), 575 (24%), and 162
(32%). For a 10-year difference in age group, the adjusted odds for death or
(re)infarction were greater by 33% within 30 days and by 34% within 6 months.
These trends persisted for patients with or without myocardial infarction on
presentation. CONCLUSIONS: Age did not significantly affect the efficacy of
eptifibatide. Older age among patients with acute coronary syndromes was
associated with worse baseline characteristics, fewer invasive procedures, and
worse outcome.
PMID- 10783221
TI - Effect of leukocytosis at initial examination on prognosis in patients with
primary unstable angina.
AB - BACKGROUND: Leukocytosis with acute myocardial infarction at initial examination
predicts adverse prognosis, but it is unknown whether it predicts outcome in
patients with primary unstable angina. METHODS AND RESULTS: We studied 414
consecutive patients with unstable angina admitted through the emergency
department to telemetry and intensive care units of an urban academic hospital.
To study primary unstable angina, we excluded 134 patients with precipitants (eg,
urosepsis, pneumonia) that may cause leukocytosis. Of 280 patients, 96 (34%) had
leukocytosis (leukocyte count >10,000 per microL) at initial examination. A total
of 30 patients (11%) died and 47 (17%) died or had nonfatal myocardial infarction
within 12 months of initial examination. In a univariate Cox model, patients with
leukocytosis had a hazard ratio (HR) of 2.6 (95% confidence interval [CI] 1.3
5.4) for death by 1 year. In a multivariate Cox model the only significant
predictors of 1-year death were congestive heart failure at initial examination
(HR 7.8; 95% CI 2.8-22) and elevated creatinine (HR 2.7; 95% CI 1.3-5.7); in this
model, the relation between leukocytosis and prognosis was markedly attenuated
(HR 1.4; 95% CI 0.6-2.9). The adjusted HR for leukocytosis was 1.3 (95% CI 0. 7
2.3) for death or nonfatal MI by 1 year. CONCLUSIONS: Leukocytosis at initial
examination is associated with adverse prognosis in patients with primary
unstable angina. However, the association is confounded by other important
predictors of prognosis. Leukocytosis may be a marker of stress associated with
more severe cases of unstable angina or comorbid conditions.
PMID- 10783222
TI - Trends in severity of hospitalized myocardial infarction: the atherosclerosis
risk in communities (ARIC) study, 1987-1994.
AB - BACKGROUND: Declining mortality rates of coronary heart disease in the United
States could be attributable to declining incidence, declining severity, and/or
improvements in treatment. METHODS: We examined trends in severity of patients
hospitalized for myocardial infarction to characterize its contribution to this
decline by using data from the Atherosclerosis Risk in Communities (ARIC) study.
RESULTS: No significant change in the proportion having systolic blood pressure
<100 mm Hg or an abnormal pulse at presentation was noted. The proportion with ST
segment elevation on the initial electrocardiogram increased 10% per year (P
<.001), and the proportion with a diagnostic or evolving diagnostic
electrocardiogram abnormality increased 4% per year (P <.01); the proportion that
had a new Q-wave infarction develop remained unchanged. The mean peak creatine
kinase level decreased 5% per year (P <.001), the proportion with abnormal enzyme
levels decreased 10% per year (P <.001), and the proportion that met criteria for
definite myocardial infarction decreased 4% per year (P <.05). The proportion
that had cardiogenic shock decreased 10.9% per year (P <. 01), but the proportion
that had an acute episode of congestive heart failure was stable. CONCLUSIONS:
With stable hemodynamic indicators, worsening electrocardiographic indicators,
and improving enzymatic indicators, these results provide mixed support for
decreases in the severity of myocardial infarction.
PMID- 10783223
TI - Beneficial effect of prodromal angina pectoris is lost in elderly patients with
acute myocardial infarction.
AB - BACKGROUND: Prodromal angina pectoris occurring shortly before the onset of acute
myocardial infarction is associated with a favorable outcome by the mechanism of
ischemic preconditioning. Recent experiments have reported that the beneficial
effect of ischemic preconditioning are reversed in the aged heart. METHODS: We
studied 990 patients who underwent coronary angiography within 12 hours after the
onset of acute myocardial infarction. Patients were divided into 2 groups: those
aged <70 years (nonelderly patients, n = 722) and those aged >/=70 years (elderly
patients, n = 268). Prodromal angina in the 24 hours before infarction was found
in 190 of 722 nonelderly patients and in 66 of 268 elderly patients (26% vs 25%,
P =.61). RESULTS: In nonelderly patients, prodromal angina was associated with
lower peak creatine kinase levels (2438 +/- 1939 IU/L vs 2837 +/- 2341 IU/L, P
=.04), lower in-hospital mortality rates (3.7% vs 8.8%, P =.02), and better 5
year survival rates (P =. 007). On the contrary, in elderly patients there was no
significant difference in peak creatine kinase levels (2427 +/- 2142 IU/L vs 2256
+/- 1551 IU/L, P =.51), in-hospital mortality rate (21.2% vs 17. 4%, P =.49), and
5-year survival rates (P =.47). A multivariate analysis showed that prodromal
angina in the 24 hours before infarction was associated with 5-year survival rate
in nonelderly patients (odds ratio 0.49, P =.009) but not in elderly patients
(odds ratio l.12, P =.65). CONCLUSIONS: In nonelderly patients, prodromal angina
in the 24 hours before infarction was associated with a smaller infarct size and
better short- and long-term survival, suggesting a relation to ischemic
preconditioning. However, such a beneficial effect was not observed in elderly
patients.
PMID- 10783224
TI - Determinants of delayed improvement in exercise capacity after percutaneous
transvenous mitral commissurotomy.
AB - BACKGROUND: Percutaneous transvenous mitral commissurotomy (PTMC) results in
short-term hemodynamic and symptomatic improvements. We have previously shown
that the immediate symptomatic relief is related to the improvement in excessive
exercise ventilation. The exercise capacity, however, does not improve in the
short term but does improve gradually over several months. The pathophysiologic
basis for the delayed improvement in exercise capacity has not been fully
evaluated. METHODS: To elucidate the determinants of improvement in exercise
capacity late after PTMC, maximal ergometer exercise with respiratory gas
analysis and exercise hemodynamic measurements were performed in 22 patients with
symptomatic mitral stenosis before, immediately after, and 7 months after PTMC.
RESULTS: Mitral valve area increased from 0.9 +/- 0.2 cm(2) to 1.7 +/- 0.4 cm(2)
after PTMC (P <.01). Significant improvements were observed in symptoms, cardiac
output at peak exercise (6.6 +/- 1.5 L/min vs 8.6 +/- 1.9 L/min, P <.01), and
mean pulmonary artery pressure at peak exercise (54.1 +/- 15.6 mm Hg vs 42.3 +/-
9.5 mm Hg, P <.01) immediately after PTMC. Excessive exercise ventilation, as
assessed by the slope of the regression line between expired minute ventilation
and carbon dioxide output (VE-VCo(2)), decreased significantly from 38.2 +/- 8.2
to 33.3 +/- 4.9 (P <.01). There were no significant changes in peak oxygen uptake
(from 17.5 +/- 3.2 mL/kg per minute to 17.9 +/- 3.6 mL/kg per minute) immediately
after PTMC. At 7 months, improved mitral valve area, symptoms, cardiac output at
peak exercise, mean pulmonary artery pressure at peak exercise, and VE-VCo(2)
were unchanged compared with values immediate after PTMC. Significant improvement
was observed in peak oxygen uptake (19.7 +/- 3.0 mL/kg per minute [P <.01
compared with pre-PTMC or immediate post-PTMC values]). The increase in exercise
cardiac output or the decrease in pulmonary artery pressure was not correlated
with the late improvement in peak oxygen uptake. The short- or long-term
improvements in VE-VCo(2), however, were significantly correlated with the late
improvement in peak oxygen uptake. CONCLUSIONS: Our results suggest that
ventilatory improvement, not increased exercise cardiac output, contributed at
least in part to the late improvement in exercise capacity after PTMC.
PMID- 10783225
TI - Differential clinical prognostic classifications in dilated and ischemic advanced
heart failure: the EPICAL study.
AB - BACKGROUND: The clinical management of severe congestive heart failure (CHF)
should be graded according to the prognosis of each individual patient. Our
objective was to elaborate a prognostic rating system for severe CHF. METHODS:
The EPICAL program (Epidemiologie de l'Insuffisance Cardiaque Avancee en
Lorraine) identified patients with severe CHF defined by hospitalization
accompanied by class III/IV dyspnea, edema, or hypertension; an ejection fraction
/=60%. Baseline variables were tested in Cox
multivariate models. RESULTS: Patients with ischemic heart disease (n = 219) had
a lower 1-year survival rate (57.6%) than patients with dilated cardiomyopathy (n
= 182) (69. 1%). Multivariate analysis identified 5 prognostic factors for
ischemic CHF and 7 for CHF caused by dilated cardiomyopathy. These variables were
used to classify patients within prognostic subgroups of good (>75%),
intermediate, or poor (55 mm. All underwent
echocardiography and a treadmill cardiopulmonary exercise test within a 4-week
interval (baseline) and again after a period of >/=4 months (median of 14
months). At baseline, the group as a whole had moderate to severe LV dysfunction
with an EDD of 70 +/- 9 mm, end-systolic diameter (ESD) of 60 +/- 11 mm, and LV
mass of 500 +/- 200 g. The mean peak oxygen consumption (Vo (2), 18 +/- 6 mL/kg
per minute) was unrelated to LV cavity size or mass. EDD increased in 37 (63%) of
the patients and fell in 22 (37%) patients from the initial to the second test.
The absolute magnitude of changes over time averaged 7 mm for EDD, 125 g for
mass, and 6 mL/kg per minute for peak Vo(2). Changes in LV size and mass per year
were significantly related to those in peak Vo(2) (r = -0.49 for EDD, r = -0.56
for ESD, and r = -0.44 for LV mass, respectively, all P <.001) and ventilatory
response to exercise (r = 0.60, r = 0.58, and r = 0.72 for EDD, ESD, and LV mass;
respectively, all P <.001). CONCLUSIONS: Changes over time in objective measures
of LV dimensions and mass, in patients with CHF are significantly related to
those in exercise capacity and respiratory efficiency.
PMID- 10783228
TI - Pericardial and pleural effusions in decompensated chronic heart failure.
AB - BACKGROUND: In decompensated chronic heart failure, there is controversy
regarding the incidence and amount of pericardial fluid. Moreover, the relation
of pericardial effusion to pleural effusion has not yet been clarified. The
current study examined the incidence and amount of pericardial effusion in
patients with decompensated chronic heart failure as a function of the volume of
pleural effusion. METHODS AND RESULTS: The study subjects were 60 consecutive
patients with chronic heart failure requiring diuresis to improve the symptoms
and signs of congestion. Pericardial effusion was semiquantified on the basis of
M-mode echocardiographic findings and the volume of thoracic effusion drawn from
computed tomographic images of the chest with Simpson's method. Causes of
decompensated chronic heart failure in the 60 patients included cardiac valve
disease (n = 26), arterial hypertension (n = 12), chronic ischemic heart disease
(n = 9), and others (n = 13). As many as 52 (87%) of the 60 patients had pleural
effusion; of these, 45 had bilateral effusion, 5 had right-sided effusion only,
and 2 had left-sided effusion only. In contrast, only 12 (20%) patients had small
(n = 9) or moderate (n = 3) pericardial effusion. There was no significant
association between the amount of pleural effusion and the semiquantified
pericardial effusion (chi-square 3.27, P =.775). CONCLUSIONS: In this series of
patients with congestive heart failure, small pericardial effusion was sometimes
observed, but moderate to large effusion was uncommon, and there was no
significant association between a given amount of pleural effusion and the volume
of pericardial effusion.
PMID- 10783229
TI - Effect of pregnancy on the duration of bovine pericardial bioprostheses.
PMID- 10783231
TI - Helicobacter pylori and chronic immune activation.
PMID- 10783235
TI - The molecular motor dynein is involved in targeting swallow and bicoid RNA to the
anterior pole of Drosophila oocytes.
AB - Localization of bicoid (bcd) messenger RNA to the anterior pole of the Drosophila
oocyte requires the exuperantia ( exu), swallow (swa) and staufen (stau) genes.
We show here that Swa protein transiently co-localizes with bcd RNA in mid
oogenesis. Swa also localizes to the anterior pole of the oocyte in the absence
of bcd RNA. This localization does not require Exu, but depends on intact
microtubules. In mutant ovaries with duplicated polarity of microtubules, Swa and
bcd RNA are ectopically localized at the posterior pole, as well as being present
at the anterior pole. We identify dynein light chain-1 (Ddlc-1), a component of
the minus-end-directed microtubule motor cytoplasmic dynein, as a Swa-binding
protein. We propose that Swa acts as an adaptor for the dynein complex and
thereby enables dynein to transport bcd RNA along microtubules to their minus
ends at the anterior pole of the oocyte.
PMID- 10783236
TI - Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts.
AB - Here we use time-lapse microscopy to analyse cell-matrix adhesions in cells
expressing one of two different cytoskeletal proteins, paxillin or tensin, tagged
with green fluorescent protein (GFP). Use of GFP-paxillin to analyse focal
contacts and GFP-tensin to study fibrillar adhesions reveals that both types of
major adhesion are highly dynamic. Small focal contacts often translocate, by
extending centripetally and contracting peripherally, at a mean rate of 19
micrometers per hour. Fibrillar adhesions arise from the medial ends of
stationary focal contacts, contain alpha5beta1 integrin and tensin but not other
focal-contact components, and associate with fibronectin fibrils. Fibrillar
adhesions translocate centripetally at a mean rate of 18 micrometers per hour in
an actomyosin-dependent manner. We propose a dynamic model for the regulation of
cell-matrix adhesions and for transitions between focal contacts and fibrillar
adhesions, with the ability of the matrix to deform functioning as a mechanical
switch.
PMID- 10783237
TI - Real-time measurements of vesicle-SNARE recycling in synapses of the central
nervous system.
AB - Following the fusion of synaptic vesicles with the presynaptic plasma membrane of
nerve terminals by the process of exocytosis, synaptic-vesicle components are
recycled to replenish the vesicle pool. Here we use a pH-sensitive green
fluorescent protein to measure the residence time of VAMP, a vesicle-associated
SNARE protein important for membrane fusion, on the surfaces of synaptic
terminals of hippocampal neurons following exocytosis. The time course of VAMP
retrieval depends linearly on the amount of VAMP that is added to the plasma
membrane, with retrieval occurring between about 4 seconds and 90 seconds after
exocytosis, and newly internalized vesicles are rapidly acidified. These data are
well described by a model in which endocytosis appears to be saturable, but
proceeds with an initial maximum velocity of about one vesicle per second. We
also find that, following exocytosis, a portion of the newly inserted VAMP
appears on the surface of the axon.
PMID- 10783238
TI - Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid
precursor protein and Notch.
AB - Mutations in the presenilin-1 (PS1) gene are associated with Alzheimer's disease
and cause increased secretion of the neurotoxic amyloid-beta peptide (Abeta).
Critical intramembraneous aspartates at residues 257 and 385 are required for the
function of PS1 protein. Here we investigate the biological function of a
naturally occurring PS1 splice variant (PS1 Deltaexon 8), which lacks the
critical aspartate 257. Cell lines that stably express PS1 Deltaexon 8 or a PS1
protein in which aspartate residue 257 is mutated secrete significant levels of
Abeta, whereas Abeta generation is severely reduced in cells transfected with PS1
containing a mutation of aspartate 385. In contrast, endoproteolytic processing
of Notch is almost completely inhibited in cell lines expressing any of the PS1
variants that lack one of the critical aspartates. These data indicate that PS1
may differentially facilitate gamma-secretase-mediated generation of Abeta and
endoproteolysis of Notch.
PMID- 10783239
TI - A new ABC transporter mediating the detachment of lipid-modified proteins from
membranes.
AB - Lipoproteins in Escherichia coli are anchored to the periplasmic side of either
the inner or the outer membrane by a lipid moiety that is covalently attached to
the amino-terminal cysteine residue. Membrane specificity depends on a sorting
signal at position 2 of the lipoprotein. Lipoproteins directed to the outer
membrane are released from the inner membrane in an ATP-dependent manner through
the formation of a complex with LolA, a periplasmic chaperone. However, the
ATPase involved in this reaction has not been identified. Here we show, using
reconstituted proteoliposomes, that a new complex, LolCDE, belonging to the ATP
binding cassette (ABC) transporter family, catalyses the release of lipoproteins
in LolA- and sorting-signal-dependent manners. The LolCDE complex differs
mechanistically from all other ABC transporters as it is not involved in the
transmembrane transport of substrates. This new mechanism is evolutionarily
conserved in other gram-negative bacteria.
PMID- 10783240
TI - Noelin-1 is a secreted glycoprotein involved in generation of the neural crest.
AB - The vertebrate neural crest arises at the border of the neural plate during early
stages of nervous system development; however, little is known about the
molecular mechanisms underlying neural crest formation. Here we identify a
secreted protein, Noelin-1, which has the ability to prolong neural crest
production. Noelin-1 messenger RNA is expressed in a graded pattern in the
closing neural tube. It subsequently becomes restricted to the dorsal neural
folds and migrating neural crest. Over expression of Noelin-1 using recombinant
retroviruses causes an excess of neural crest emigration and extends the time
that the neural tube is competent to generate as well as regenerate neural crest
cells. These results support an important role for Noelin-1 in regulating the
production of neural crest cells by the neural tube.
PMID- 10783241
TI - A new self-assembled peroxisomal vesicle required for efficient resealing of the
plasma membrane.
AB - The Woronin body is a membrane-bound organelle that has been observed in over 50
species of filamentous fungi. However, neither the composition nor the precise
function of the Woronin body has yet been determined. Here we purify the Woronin
body from Neurospora crassa and isolate Hex1, a new protein containing a
consensus sequence known as peroxisome-targeting signal-1 (PTS1). We show that
Hex1 is localized to the matrix of the Woronin body by immunoelectron microscopy,
and that a green fluorescent protein- (GFP-)Hex1 fusion protein is targeted to
yeast peroxisomes in a PTS1- and peroxin-dependent manner. The expression of the
HEX1 gene in yeast generates hexagonal vesicles that are morphologically similar
to the native Woronin body, implying a Hex1-encoded mechanism of Woronin-body
assembly. Deletion of HEX1 in N. crassa eliminates Woronin bodies from the
cytoplasm and results in hyphae that exhibit a cytoplasmic-bleeding phenotype in
response to cell lysis. Our results show that the Woronin body represents a new
category of peroxisome with a function in the maintenance of cellular integrity.
PMID- 10783242
TI - Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP
co-activators.
AB - The E2F proteins form a family of transcription factors that regulate the
transition from the G1 to the S phase in the cell cycle. E2F activity is
regulated by members of the retinoblastoma protein (pRb) family, ensuring the
tight control of E2F-responsive genes. During the G1 phase, phosphorylation of
pRb by cyclin-dependent kinases (CDKs), most notably cyclin D-CDK complexes,
releases pRb from E2F, facilitating cell-cycle progression by the timely
induction of E2F-targeted genes such as cyclin E. However, it is not known
whether E2F proteins are directly targeted by CDKs. Here we show that E2F-5 is
phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1
phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A
phosphorylation site in the trans-activation domain of E2F-5 stimulates
transcription and cell-cycle progression by the recruitment of the p300/CBP
family of co-activators, whose binding to E2F-5 is stabilized upon
phosphorylation by cyclin E-Cdk2. These results indicate that E2F activity may be
directly regulated by cyclin E-Cdk2, and imply an autoregulatory mechanism for
cell-cycle-dependent transcription through the CDK-stimulated interaction of E2F
with p300/CBP co-activators.
PMID- 10783244
TI - Detection of S-phase cells in tissue sections by in situ DNA replication.
PMID- 10783243
TI - TRAIL receptor-2 signals apoptosis through FADD and caspase-8.
PMID- 10783245
TI - Involvement of the Arp2/3 complex in phagocytosis mediated by FcgammaR or CR3.
PMID- 10783246
TI - Draining resources.
PMID- 10783247
TI - Drosophila genome takes flight.
AB - In the March 24 issue of Science, a flurry of papers report on the impending
completion of the Drosophila melanogaster genome sequence. This historic
achievement is the result of a unique collaboration between the Berkeley
Drosophila Genome Project (BDGP), led by Gerry Rubin, and the genomics company
Celera, headed by Craig Venter. With its genome almost completely sequenced ahead
of schedule, Drosophila is another important model organism to enter the
postgenomic age, and represents the largest genome sequenced to date.
PMID- 10783248
TI - mRNA export: the long and winding road.
AB - To the growing list of factors required for the export of messenger RNA from
nucleus to cytoplasm can now be added Yra1. Yeast Yra1 and its metazoan
orthologues bind mRNAs and interact with multiple mRNA export factors. Transport
of proteins and small RNAs does not require Yra1 or any other proteins required
for mRNA export, suggesting that mRNA export may proceed by a different
mechanism. The finding that Yra1 has a role in mRNA export moves us one step
closer to identifying all the proteins required for this process.
PMID- 10783249
TI - Matchmakers for sister-chromatid cohesion.
PMID- 10783250
TI - Teaching tumour suppressors new tricks.
AB - Examination of the tumour suppressor adenomatous polyposis coli (APC) has shown
that it may be multifunctional. Recent work has demonstrated dynamic interactions
of APC with the microtubule cytoskeleton, supporting the idea that APC has an
important function in cell migration.
PMID- 10783251
TI - Swallowing dynein: a missing link in RNA localization?
AB - Localization of bicoid messenger RNA to the anterior cortex of the developing
oocyte is essential for correct anterior-posterior patterning of the Drosophila
embryo. It now seems that the Swallow protein functions as an adaptor, bridging
bicoid mRNA to dynein, a molecular motor that would transport the complex
anteriorly along microtubules.
PMID- 10783252
TI - Unsheathing WASP's sting.
PMID- 10783253
TI - Control of apoptotic DNA degradation.
AB - Apoptotic DNA degradation has been thought to be a cell-autonomous process.
Recent evidence suggests that heterophagic recognition and engulfment of dying
cells by non-apoptotic cells may be critical for the activation and/or action of
apoptogenic DNases.
PMID- 10783254
TI - Rb function in cell-cycle regulation and apoptosis.
AB - Loss of cell-cycle control is a hallmark of neoplastic cells. One regulator of
the critical G1 to S-phase transition in the cell cycle is the retinoblastoma
tumour suppressor protein Rb, which interacts with the E2F family of cell-cycle
transcription factors to repress gene transcription required for this transition.
Through its interaction with E2F, Rb also regulates genes that control apoptosis.
Here we review the roles of Rb in regulating the cell cycle and apoptosis and
discuss recent results linking these Rb functions to chromatin-remodelling
enzymes.
PMID- 10783255
TI - Construction and characterization of a Schistosoma mansoni bacterial artificial
chromosome library.
AB - A bacterial artificial chromosome (BAC) library has been established from genomic
DNA isolated from the trematode parasite of human, Schistosoma mansoni. This
library consists of more than 21,000 recombinant clones carrying inserts in the
pBeloBAC11 vector. The mean insert size was 100 kb, representing an approximate
7.95-fold genome coverage. Library screening with eight chromosome-specific or
single-copy gene probes yielded between 1 and 9 positive clones, and none of
those tested was absent from the library. End sequences were obtained for 93
randomly selected clones, and 37 showed sequence identity to S. mansoni sequences
(ESTs, genes, or repetitive sequences). A preliminary analysis by fluorescence in
situ hybridization localized 8 clones on schistosome chromosomes 1 (2 clones), 2,
3, 5, Z, and W (3 clones). This library provides a new resource for the physical
mapping and sequencing of the genome of this important human pathogen.
PMID- 10783256
TI - Somatic versus germline mutation processes at minisatellite CEB1 (D2S90) in
humans and transgenic mice.
AB - The most variable human minisatellites show extreme germline instability
dominated by complex intra-allelic rearrangements plus a lower frequency of inter
allelic transfers of repeat units. In contrast, little is known about somatic
instability at such loci. We have therefore used single-molecule PCR to analyze
mutation at minisatellite CEB1 (D2S90) in human blood DNA. Somatic mutants were
rare and involved only relatively simple intra-allelic events, with no bias
toward expansions, in sharp contrast to the complex gain-biased rearrangements
seen in sperm. Somatic and germline mutation processes were further analyzed in
mice transgenic for a cosmid insert containing CEB1. Mutant molecules in
transgenic sperm and blood were detected but only at the low frequencies seen in
human blood and arose mainly by simple duplications and deletions as seen for
somatic mutations in human. These data suggest distinct pathways for germline and
somatic CEB1 mutations with germline instability involving recombination-based
repair of meiotic double-strand breaks and somatic mutation arising by
replication slippage or mitotic recombination. The problem of transferring
germline-specific features of minisatellite instability from human to mouse
suggests, with other recent observations, that long-range chromatin conformation
may be required for the recombination-based mode of germline instability at human
minisatellites.
PMID- 10783258
TI - Molecular cloning of a novel NF2/ERM/4.1 superfamily gene, ehm2, that is
expressed in high-metastatic K1735 murine melanoma cells.
AB - We have cloned a novel gene, Ehm2, that is expressed in high-metastatic but not
in low-metastatic K-1735 murine melanoma cells. The Ehm2 gene encodes a protein
of 527 amino acid residues, showing up to 41% amino acid identity with the FERM
domain of NF2/ERM/4.1 superfamily proteins, which have the function of connecting
cell surface transmembrane proteins to cytoskeletal molecules. The Ehm2 gene was
mapped to chromosome 4 and was expressed in the liver, lung, kidney, and testis
and in 7- to 17-day embryos. The highest level of homology was observed with
NBL4, which is a new subfamily protein of the NF2/ERM/4.1 superfamily. A human
homologue of the mouse Ehm2 gene, showing significant homology (83% identity),
was identified in the genomic DNA and EST databases. Furthermore, seven rat EST
clones and one pig EST clone in the GenBank EST database were identified as
having 83-92% sequence homology with the cDNA sequence of the mouse Ehm2 gene.
Thus, Ehm2 is a highly conserved gene that encodes a novel member of the
NF2/ERM/4.1 superfamily proteins.
PMID- 10783257
TI - Functional and genomic analysis of the human mitochondrial intermediate
peptidase, a putative protein partner of frataxin.
AB - We showed recently that the yeast mitochondrial intermediate peptidase (YMIP
polypeptide; gene symbol, OCT1) promotes mitochondrial iron uptake by catalyzing
the maturation of iron-utilizing proteins and exacerbates the mitochondrial iron
accumulation that results from loss of yeast frataxin, a mitochondrial protein
required for mitochondrial iron efflux. This suggests that the human MIP (HMIP
polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the
clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive
neurodegenerative disease caused by lack of human frataxin. To begin to test this
hypothesis, we have characterized HMIP at the functional and genomic levels. We
show that HMIP can complement a yeast knock-out mutant lacking YMIP,
demonstrating that HMIP and YMIP are functional homologues. The MIPEP gene spans
57 kb and consists of 19 exons that correlate with the functional domains of
HMIP. Primer extension analysis has identified a major transcript of the MIPEP
gene expressed differentially and predominantly in tissues with high oxygen
consumption, while sequence analysis of approximately 2 kb of 5'-flanking DNA has
revealed putative Mt1/3/4, NF-kappaB, and AP-1 elements that may regulate MIPEP
expression in these tissues. Using a new polymorphic (CA)(n) repeat in intron 4,
MIPEP has been genetically mapped within a 7-cM interval between markers D13S283
and D13S217 on 13q12. This work provides the basis for molecular analysis of
MIPEP in FRDA and possibly other neurodegenerative diseases.
PMID- 10783259
TI - Sequence and expression pattern of a novel human orphan G-protein-coupled
receptor, GPRC5B, a family C receptor with a short amino-terminal domain.
AB - Query of GenBank with the amino acid sequence of human metabotropic glutamate
receptor subtype 2 (mGluR2) identified a predicted gene product of unknown
function on BAC clone CIT987SK-A-69G12 (located on chromosome band 16p12) as a
homologous protein. The transcript, entitled GPRC5B, was cloned from an expressed
sequence tag clone that contained the entire open reading frame of the transcript
encoding a protein of 395 amino acids. Analysis of the protein sequence reveal
that GPRC5B contains a signal peptide and seven transmembrane alpha-helices,
which is a hallmark of G-protein-coupled receptors (GPCRs). GPRC5B displays
homology to retinoic acid-inducible gene 1 (RAIG1, 33% sequence identity) and to
several family C (mGluR-like) GPCRs (20-25% sequence identity). Both RAIG1 and
GPRC5B have short extracellular amino-terminal domains (ATDs) that contrast the
very long ATDs characterizing the receptors currently assigned to family C.
However, our results strongly indicate that RAIG1 and GPRC5B form a new subgroup
of family C characterized by short ATDs. GPRC5B mRNA is widely expressed in
peripheral and central tissues with highest abundance in kidney, pancreas, and
testis. This mRNA expression pattern is markedly different from that of RAIG1,
which shows a slightly more restricted expression pattern with highest abundance
in lung tissue.
PMID- 10783260
TI - A sequence-ready physical map of the region containing the human natural killer
gene complex on chromosome 12p12.3-p13.2.
AB - We developed a sequence-ready physical map of a part of human chromosome 12p12.3
p13.2 where the natural killer gene complex (NKC) is located. The NKC includes a
cluster of genes with structure similar to that of the Ca(2+)-dependent lectin
superfamily of glycoproteins that are expressed on the surface of most natural
killer (NK) cells and a subset of T cells. These killer cell lectin-like
receptors (KLR) are involved in NK target cell recognition, leading to activation
or inhibition of NK cell function. We used a number of sequence-tagged site (STS)
markers from this region to screen two large insert bacterial artificial
chromosome (BAC) libraries and a bacteriophage P1-derived (PAC) chromosome
library. The clones were assembled into contiguous sets by STS content analysis.
The 72-BAC and 11-PAC contig covers nearly 2 Mb of DNA and provides an average
marker resolution of 26 kb. We have precisely localized 17 genes, 5 expressed
sequence tags, and 49 STSs within this contig. Of this total number of STS, 30
are newly developed by clone-end sequencing. We established the order of the
genes as tel-M6PR-MAFAL (HGMW-approved symbol KLRG1)-A2M-PZP-A2MP-NKRP1A (HGMW
approved symbol KLRB1)-CD69-AICL (HGMW-approved symbol CLECSF2)-KLRF1-OLR1-CD94
(HGMW-approved symbol KLRD1)-NKG2D (HGMW-approved symbol D12S2489E)-PGFL-NKG2F
(HGMW-approved symbol KLRC4)-NKG2E (HGMW-approved symbol KLRC3)-NKG2A (HGMW
approved symbol KLRC1)-LY49L (HGMW-approved symbol KLRA1)-cen. This map would
facilitate the cloning of new KLR genes and the complete sequencing of this
region.
PMID- 10783261
TI - Evidence for a Niemann-pick C (NPC) gene family: identification and
characterization of NPC1L1.
AB - Niemann-Pick type C1 (NPC1) disease is caused by defects in the NPC1 protein,
which result in perturbation of subcellular cholesterol transport. To identify
related proteins that may be involved in subcellular cholesterol trafficking, the
expressed sequence tag (EST) database was searched to find homologues of human
NPC1. A short, weakly similar EST was identified and used to obtain a full-length
human cDNA of about 5 kb and two alternatively spliced transcripts. The gene,
named NPC1L1, was mapped to chromosome 7p13, contained 20 exons, including an
unusually large 1526-bp exon 2, and spanned approximately 29 kb. In contrast to
NPC1, the NPC1L1 putative promoter region contained a sterol-regulatory element.
The predicted protein shared 42% identity and 51% similarity with NPC1.
Interestingly, NPC1L1 contains the conserved amino-terminal "NPC1 domain" and the
putative sterol-sensing domain, providing strong evidence that it is related to
human NPC1 and suggesting that these may comprise a new family of NPC1-related
proteins. However, the two differ with respect to their putative intracellular
targeting signals. Collectively, these data suggest that NPC1L1 and NPC1 form
part of a family of related proteins that may have similar functions at different
subcellular locations, perhaps at sequential steps of the same cholesterol
transport pathway.
PMID- 10783262
TI - Characterization of human retinal fascin gene (FSCN2) at 17q25: close physical
linkage of fascin and cytoplasmic actin genes.
AB - Retinal fascin is a newly identified photoreceptor-specific paralog of the actin
bundling protein fascin. Fascins crosslink f-actin into highly ordered bundles
within dynamic cell extensions such as neuronal growth cone filopodia. We have
isolated cDNA and genomic clones of human retinal fascin and characterized the
structure of the human retinal fascin gene (FSCN2). The cDNA predicts a protein
of 492 amino acids and molecular mass 55,057 that shows 94% identity to bovine
retinal fascin and 56% identity to human fascin. Promoter analysis reveals a
consensus retinoic acid response element and several potential binding sites for
transcription factors Crx and Nrl, which correlates with the retina-specific
expression of FSCN2 mRNA. Fluorescence in situ hybridization analysis and genomic
clone sequencing indicate that the FSCN2 gene lies within 200 kb of the actin
gene ACTG1 at 17q25. Database searches revealed that the human fascin gene FSCN1
and actin gene ACTB at 7p22 also coexist within a 200-kb genomic clone. The close
physical linkage of these fascin/actin gene pairs suggests that they derive from
a common gene duplication event and allows comparison of fascin and actin
phylogenetic analyses. Finally, a possible link to the retinitis pigmentosa 17
allele (RP17) at distal 17q was excluded by demonstration of multiple independent
segregation events in two RP17 kindreds. Informative FSCN2 polymorphisms were
identified and will serve as useful markers in future linkage studies. The likely
function of retinal fascin, in light of known fascin roles in other cell types,
is to assemble actin microfilaments in support of photoreceptor disk
morphogenesis.
PMID- 10783264
TI - Cloning and chromosomal mapping of human glucuronyltransferase involved in
biosynthesis of the HNK-1 carbohydrate epitope.
AB - The HNK-1 carbohydrate is expressed on various cell adhesion molecules in the
nervous system and is suggested to play a role in cell-cell and cell-substrate
interactions. Here we describe the isolation of a cDNA encoding human
glucuronyltransferase (GlcAT-P), which is a key enzyme in the biosynthesis of the
HNK-1 carbohydrate. The primary structure deduced from the cDNA sequence
predicted a type II transmembrane protein of 334 amino acids. Human GlcAT-P was
98.2% identical with rat GlcAT-P in amino acid sequence, the exception being the
length of the cytoplasmic tail. Northern blot analysis indicated that human GlcAT
P is expressed mainly in the brain. There is a single copy of the human GlcAT-P
gene (HGMW-approved symbol B3GAT1), and it was mapped to chromosome 11q25.
PMID- 10783263
TI - Human sulfotransferases SULT1C1 and SULT1C2: cDNA characterization, gene cloning,
and chromosomal localization.
AB - Sulfate conjugation catalyzed by sulfotransferase (SULT) enzymes is an important
pathway in the biotransformation of many drugs, other xenobiotics,
neurotransmitters, and hormones. We previously described a human cDNA, SULT1C1,
that encoded a protein similar in sequence to that of rat ST1C1. Subsequently, a
related human cDNA, SULT1C2, was reported. In the present study, we set out to
characterize further the human SULT1C1 cDNA and then to clone, structurally
characterize, and map its gene. As an initial step, we performed 5'- and 3'-RACE
with SULT1C1 cDNA. Those experiments demonstrated that a small number of SULT1C1
transcripts contained an "insert," which we later showed resulted from
alternative splicing that involved an Alu sequence in intron 3 of SULT1C1. We
then cloned and structurally characterized the SULT1C1 gene from a human genomic
BAC library. Because the sequence of SULT1C2 was closely related to that of
SULT1C1 and because the genes for other human SULT paralogues occur in clusters,
we screened the BAC clones that had been positive for SULT1C1 to search for
SULT1C2 and discovered a clone that contained both genes. That BAC was used to
sequence and structurally characterize SULT1C2. SULT1C1 and SULT1C2 were
approximately 21 and 10 kb in length, respectively. Both genes contained seven
exons that encoded protein, and both had structures that were similar to those of
other genes that encode members of the SULT1 family. Finally, human SULT1C1 and
SULT1C2 mapped to 2q11.2 by fluorescence in situ hybridization. The cloning and
structural characterization of SULT1C1 and SULT1C2 will now make it possible to
perform molecular genetic and pharmacogenomic studies of these sulfate
conjugating enzymes in humans.
PMID- 10783266
TI - The expanded human kallikrein gene family: locus characterization and molecular
cloning of a new member, KLK-L3 (KLK9).
AB - In rodents, kallikreins are encoded by a large multigene family but in humans,
only three kallikrein genes were thought to exist. Based on the homology between
the human and the rodent kallikrein loci, we defined a 300-kb human kallikrein
gene region on chromosome 19q13. 3-q13.4. By using linear sequence information,
restriction analysis, PCR, and blotting techniques, we were able to construct the
first detailed map of the human kallikrein gene locus. Comparative analysis of
genes located in this area enabled us to expand the human kallikrein multigene
family with some recently identified serine proteases and establish common
structural features. We further identified a new kallikrein-like gene, named
kallikrein-like gene 3 (KLK-L3; HGMW-approved symbol KLK9). We describe the
structural characterization of the KLK-L3 gene, together with its precise
chromosomal localization in relation to other kallikreins and its tissue
expression pattern and hormonal regulation.
PMID- 10783265
TI - Identification of a testis-specific gene (C15orf2) in the Prader-Willi syndrome
region on chromosome 15.
AB - Prader-Willi syndrome (PWS) results from the loss of paternal contributions for a
2-Mb imprinted region on the proximal long arm of human chromosome 15. Hitherto,
five paternally active genes have been identified in this region (ZNF127, NDN,
MAGEL2, SNURF-SNRPN, and IPW). Here we report the identification of a novel gene
in the PWS critical region, which has been designated "chromosome 15 open reading
frame 2" (C15orf2). C15orf2 is an intronless gene located between MAGEL2 and
SNURF-SNRPN. It is associated with a CpG island, which is methylated in all
tissues tested except for germ cells. C15orf2 is transcribed as a 7.5-kb mRNA and
contains an open reading frame encoding a predicted 1156-amino-acid protein of
unknown function. Transcription of C15orf2 occurs exclusively in the testis, and
in adult testis samples, we observed biallelic expression. By zoo-blot analysis,
we found related sequences in DNA from other primates, but not in nonprimate DNA.
We conclude that C15orf2 may play a role in primate spermatogenesis.
PMID- 10783267
TI - Design of a high-power NMR probe for low-temperature studies.
AB - A low-temperature, high-power NMR probe head design is described which eliminates
the problem of electric arc discharge commonly experienced during radiofrequency
pulse cycling in a helium environment. A polychlorotrifluoroethylene (Kel-F) coil
former, fitted with a solenoid coil, is heat-shrunk onto stainless-steel flanges
and spot-welded inside a stainless-steel probe head assembly connected to a
hollow coaxial transmission-line probe shaft. By this means, the sample coil and
all high-voltage elements can effectively be isolated in a vacuum, while at the
same time permitting good thermal contact between the sample and cryogenic gas.
This design was used in NMR studies in the 4.6 K < or = T < or = 77 K temperature
range for RF pulse durations < or = 50 ms (and longer for low RF amplitudes) and
amplitudes up to approximately 60 G.
PMID- 10783268
TI - t(1) noise and sensitivity in pulsed field gradient experiments.
AB - In this paper, a calculation routine based on product operator formalism and
coherence pathway is presented, which describes t(1) noise and sensitivity in
pulsed field gradient experiments. Several examples including the absolute value
mode pulsed field gradient COSY, MQF-COSY, MQC, HMQC, and NOESY sequences are
investigated to study the t(1) noise stemming from the phase errors of
radiofrequency (RF) pulses and the sensitivity affected by RF pulse rotation
angles. Our theoretical results indicate that the t(1) noises in P-type COSY,
multiple-quantum-filtered (MQF)-COSY, and multiple-quantum coherence (MQC) are
lower than those in the N-type corresponding experiments, while in HMQC and NOESY
there is no difference in t(1) noise effects between P-type and N-type spectra.
Meanwhile, from the calculations, we obtained the optimized RF pulse rotation
angles in those sequences. In MQF-COSY, an increase in sensitivity of about
4(cos(2)θ sin(q-1)2θ)(2) - 1 (θ = arc cot can be achieved by
using the optimized angles. In MQC, the increase is 2 cos(2)θ sin(q
1)2θ - 1 (θ = arc cot. MQF-COSY experiments are also carried out to
support our corresponding theoretical results.
PMID- 10783269
TI - (1)H-(17)O nuclear-quadrupole double-resonance study of hydrogen disorder in 2
nitrobenzoic acid.
AB - Temperature dependence of (17)O nuclear quadrupole resonance frequencies was
measured in solid 2-nitrobenzoic acid by a (1)H-(17)O nuclear quadrupole double
resonance technique. The experimental results show the presence of a fast
exchange of hydrogen atoms between two nonequivalent positions within the O-H
ellipsis O hydrogen bonds. The hydrogen disorder is ascribed to concerted jumps
of two hydrogen atoms within the hydrogen bonds connecting two molecules in a
dimer. The energy difference DeltaE of the two hydrogen configurations is equal
to DeltaE = 60 meV = 5.8 kJ/mol. The dipole structure of the (17)O NQR lines from
the C-O-H oxygen positions was also measured at -100 degrees C and at room
temperature. The orientation of the principal axes of the electric field gradient
tensor with respect to the O-H bond and the sign of the quadrupole coupling
constant were determined. The oxygen-hydrogen distance R(O-H), as determined from
the dipole structure of the (17)O NQR lines is at -100 degrees C equal to 0.099
nm. At room temperature we observe a longer distance, R(O-H) = 0.101 nm, in
agreement with the hydrogen intrabond exchange.
PMID- 10783270
TI - Jones matrix formalism for quasioptical EPR.
AB - The Jones matrix formalism that has been used to analyze quasioptical millimeter
wave circuits is extended for specific application to high-frequency electron
paramagnetic resonance (EPR). A survey of general expressions for Jones matrices
of elements commonly used in quasioptical EPR spectrometers is given. The Jones
matrix representations of quasioptical transmission and reflection cavities are
derived, and their relationship to the equivalent circuit and transmission line
representations used for conventional EPR cavities is demonstrated. The formalism
is applied to selected quasioptical EPR spectrometer designs and experimental
tests of the formalism are presented for two configurations of a quasioptical
spectrometer operating at 220 GHz.
PMID- 10783271
TI - Automatic correction for phase shifts, frequency shifts, and lineshape
distortions across a series of single resonance lines in large spectral data
sets.
AB - A new model-free method is presented that automatically corrects for phase
shifts, frequency shifts, and additional lineshape distortions of one single
resonance peak across a series of in vivo NMR spectra. All separate phase and
frequency variations are quickly and directly derived from the common lineshape
in the data set using principal component analysis and linear regression. First,
the new approach is evaluated on simulated data in order to quantitatively assess
the phase and frequency shifts which can be removed by the proposed correction
procedure. Subsequently, the value of the method is demonstrated on in vivo (31)P
NMR spectra from skeletal muscle of the hind leg of the mouse focusing on the
phosphocreatine resonance which is distorted by the experimental procedure. Phase
shifts, frequency shifts, and lineshape distortions with respect to the common
lineshape in the spectral data set could successfully be removed.
PMID- 10783272
TI - Two-pulse nutation echoes generated by gradients of the radiofrequency amplitude
and of the main magnetic field.
AB - A two-pulse NMR nutation spectroscopy scheme is suggested that leads to a new
type of spin echoes. The amplitude of the radiofrequency (RF) pulses as well as
the external magnetic field are assumed to be subject to gradients G(1) and G(0),
respectively, in the same but otherwise arbitrary direction. Multiple echoes are
predicted and observed at times k(G(1)/G(0))tau(1) and tau -/+ k(G(1)/G(0))tau(1)
(k = 1, 2, 3, ...) after the second RF pulse, where tau(1) represents the
radiofrequency pulse duration, and tau is the spacing of the RF pulses. Based on
these echoes, a method for diffusion measurements is proposed that simultaneously
provides the spin-lattice relaxation time and the self-diffusion coefficient.
PMID- 10783273
TI - Remote tuning of NMR probe circuits.
AB - There are many circumstances in which the probe tuning adjustments cannot be
located near the rf NMR coil. These may occur in high-temperature NMR, low
temperature NMR, and in the use of magnets with small diameter access bores. We
address here circuitry for connecting a fixed-tuned probe circuit by a
transmission line to a remotely located tuning network. In particular, the
bandwidth over which the probe may be remotely tuned while keeping the losses in
the transmission line acceptably low is considered. The results show that for all
resonant circuit geometries (series, parallel, series-parallel), overcoupling of
the line to the tuned circuit is key to obtaining a large tuning bandwidth. At
equivalent extents of overcoupling, all resonant circuit geometries have nearly
equal remote tuning bandwidths. Particularly for the case of low-loss
transmission line, the tuning bandwidth can be many times the tuned circuit's
bandwidth, f(o)/Q.
PMID- 10783274
TI - Multiple quantum and high-resolution NMR, molecular structure, and order
parameters of partially oriented ortho and meta dimethyl-, dichloro-, and
chloromethylbenzenes codissolved in nematic liquid crystals.
AB - We develop a strategy for analyzing complex nuclear magnetic resonance (NMR)
spectra of several solutes codissolved in liquid-crystal phases. Spectral
parameters of solutes m- or o-xylene were estimated by analyzing 2D multiple
quantum NMR spectra using a modified version of a least-squares fitting routine
which adjusts chemical shifts, order parameters, structural parameters, and/or
dipolar couplings independently. These estimates were used to facilitate analysis
of the high-resolution spectra which contain resonances from many solutes.
Calculated spectra of m- or o-xylene were subtracted from the experimental high
resolution spectra leaving resonances from the other solutes readily visible.
Accurate spectral parameters of all codissolved solutes were determined from the
high-resolution spectra. Order parameters and structural parameters (including
vibrationally corrected parameters) of m- and o-xylene, m- and o-chlorotoluene,
and m- and o-dichlorobenzene were calculated from the dipolar couplings.
PMID- 10783275
TI - Electron nuclear quadruple resonance for assignment of overlapping spectra.
AB - Multiple resonance methods are important tools in EPR for revealing the network
of hyperfine levels of free radicals and paramagnetic centers. The variations of
electron nuclear double resonance (ENDOR) or electron spin-echo envelope
modulation (ESEEM) techniques help to correlate nuclear frequencies with each
other. These methods have limited utility when there is extensive overlap or
suspected overlap in the EPR spectrum between different species or different
orientations. In the ENDOR spectrum, overlap and second-order shifts of lines
also leads to ambiguity in assignment and interpretation. A new electron nuclear
multiple resonance method is presented here that is based on population transfer
ENDOR. It is a quadruple resonance method that correlates ENDOR lines and reveals
the network of hyperfine levels in samples with unoriented paramagnetic species
and in samples with overlapping EPR or ENDOR lines.
PMID- 10783276
TI - An L-band crossed-loop (Bimodal) EPR resonator.
AB - Our crossed-loop resonator design has been enhanced to increase the filling
factor and has been extended from S-band to L-band. High isolation between the
two modes results in shorter dead time in pulsed EPR experiments than would occur
with a reflection resonator of the same Q.
PMID- 10783277
TI - Off-resonance effects of the radiofrequency pulses used in spectral editing with
double-quantum coherence transfer.
AB - Spectral editing using gradient selected double-quantum (DQ) coherence transfer
is often used for the selective observation of metabolites in vivo. In attempting
to optimize the detection sensitivity of a conventional DQ spectral editing
sequence, the effects of using radiofrequency (RF) pulses that are not at the
resonance frequency of the observed peaks were investigated both theoretically
and experimentally. The results show that spectral editing using pulses at the
frequency of the observed resonance does not necessarily give the optimal
detection sensitivity. At 7 T, the detection sensitivity of lactate observed
using a DQ editing method can be increased by up to 30% by setting the RF pulses
off resonance at the proper frequency. The results also suggest that slice
selective RF pulses used in DQ spectral editing combined with PRESS localization
may have slice profiles different from those when the same pulses are used for
standard PRESS spatial localization.
PMID- 10783278
TI - Correlation time and diffusion coefficient imaging: application to a granular
flow system.
AB - A parametric method for spatially resolved measurements for velocity
autocorrelation functions, R(u)(tau) = , expressed as a sum of
exponentials, is presented. The method is applied to a granular flow system of 2
mm oil-filled spheres rotated in a half-filled horizontal cylinder, which is an
Ornstein-Uhlenbeck process with velocity autocorrelation function R(u)(tau) =
e(- ||tau ||/tau(c)), where tau(c) is the correlation time and D =
tau(c) is the diffusion coefficient. The pulsed-field-gradient NMR method
consists of applying three different gradient pulse sequences of varying motion
sensitivity to distinguish the range of correlation times present for particle
motion. Time-dependent apparent diffusion coefficients are measured for these
three sequences and tau(c) and D are then calculated from the apparent diffusion
coefficient images. For the cylinder rotation rate of 2.3 rad/s, the axial
diffusion coefficient at the top center of the free surface was 5.5 x 10(-6)
m(2)/s, the correlation time was 3 ms, and the velocity fluctuation or granular
temperature was 1.8 x 10(-3) m(2)/s(2). This method is also applicable to
study transport in systems involving turbulence and porous media flows.
PMID- 10783279
TI - Relaxation effects on transverse magnetization using RF pulses long compared to
T(2).
AB - The transverse relaxation effects which occur during the application of optimized
slice-selective Shinnar-Le Roux pulses are studied. The behavior of both
longitudinal and transverse magnetization is examined, focusing the attention on
changes which affect the absorption and dispersion components. Besides the
reduction in amplitude, the absorption component was found to be unaffected by
transverse relaxation times, whereas the dispersion component was strongly
distorted. A comparison between the distortion components from pulses having same
length but different bandwidths is given.
PMID- 10783280
TI - Electron spin-lattice relaxation rates for high-spin Fe(III) complexes in glassy
solvents at temperatures between 6 and 298 K.
AB - The temperature dependence of spin-lattice relaxation rates was analyzed for four
high-spin nonheme iron proteins between 5 and 20 K, for three high-spin iron
porphyrins between 5 and 118 K, and for four high-spin heme proteins between 5
and 150 to 298 K. For the nonheme proteins the zero-field splittings, D, are less
than 0.7 cm(-1), and the relaxation is dominated by the Orbach and Raman
processes. For the iron porphyrins and heme proteins D is between 4 and 12 cm(-1)
and the relaxation is dominated by the Orbach process between about 5 and 100 K
and by a local mode at higher temperatures. The relaxation rates for the heme
proteins in glassy matrices extrapolated to values at room temperature that are
similar to values obtained by NMR relaxivity in fluid solution. This similarity
suggests that for high-spin Fe(III) heme proteins with effective intramolecular
spin-lattice relaxation processes, the additional motional freedom gained when a
relatively large protein goes from glassy solid to liquid solution at room
temperature has little impact on spin-lattice relaxation.
PMID- 10783281
TI - Clean TROSY: compensation for relaxation-induced artifacts.
AB - TROSY pulse sequences for recording, e.g., (1)H-(15)N chemical shift correlation
spectra of proteins are designed to select only one of four two-dimensional
multiplet components. However, all of the variants published so far are prone to
relaxation-induced artifacts at the positions of two of the other multiplet
components. This article introduces modifications to the two spin-state-selective
coherence transfer building blocks of the TROSY mixing sequence resulting in a
clean TROSY spectrum with the artifacts largely suppressed. It works by having
the new mixing sequence generate peaks of opposite phase at the positions of the
relaxation artifacts. The clean TROSY pulse sequence is marginally shorter than
the original one and contains the same pulses. Experimental demonstration is
presented for the (15)N-labeled proteins RAP 17-97 (N-terminal domain of alpha(2)
macroglobulin receptor associated protein) and EQT, equinatoxin II, from the
Mediterranean anemone Actinia equina.
PMID- 10783282
TI - 1H NMR relaxation investigation of inhibitors interacting with Torpedo
californica acetylcholinesterase.
AB - Two naphthyridines interacting with Torpedo californica acetylcholinesterase
(AChE) were investigated. (1)H NMR spectra were recorded and nonselective,
selective, and double-selective spin-lattice relaxation rates were measured. The
enhancement of selective relaxation rates could be titrated by different ligand
concentrations at constant AChE (yielding 0.22 and 1.53 mM for the dissociation
constants) and was providing evidence of a diverse mode of interaction. The
double-selective relaxation rates were used to evaluate the motional correlation
times of bound ligands at 34.9 and 36.5 ns at 300 K. Selective relaxation rates
of bound inhibitors could be interpreted also in terms of dipole-dipole
interactions with protons in the enzyme active site.
PMID- 10783283
TI - High-frequency dynamic nuclear polarization in the nuclear rotating frame.
AB - A proton dynamic nuclear polarization (DNP) NMR signal enhancement (epsilon)
close to thermal equilibrium, epsilon = 0.89, has been obtained at high field
(B(0) = 5 T, nu(epr) = 139.5 GHz) using 15 mM trityl radical in a 40:60
water/glycerol frozen solution at 11 K. The electron-nuclear polarization
transfer is performed in the nuclear rotating frame with microwave irradiation
during a nuclear spin-lock pulse. The growth of the signal enhancement is
governed by the rotating frame nuclear spin-lattice relaxation time (T(1rho)),
which is four orders of magnitude shorter than the nuclear spin-lattice
relaxation time (T(1n)). Due to the rapid polarization transfer in the nuclear
rotating frame the experiment can be recycled at a rate of 1/T(1rho) and is not
limited by the much slower lab frame nuclear spin-lattice relaxation rate
(1/T(1n)). The increased repetition rate allowed in the nuclear rotating frame
provides an effective enhancement per unit time(1/2) of epsilon(t) = 197. The
nuclear rotating frame-DNP experiment does not require high microwave power;
significant signal enhancements were obtained with a low-power (20 mW) Gunn diode
microwave source and no microwave resonant structure. The symmetric trityl
radical used as the polarization source is water-soluble and has a narrow EPR
linewidth of 10 G at 139.5 GHz making it an ideal polarization source for high
field DNP/NMR studies of biological systems.
PMID- 10783284
TI - Combining PGSE NMR with homonuclear dipolar decoupling.
AB - A new robust approach for combining multiple-pulse homonuclear decoupling and
PGSE NMR is introduced for accurately measuring molecular diffusion coefficients
in systems with nonvanishing static homonuclear dipolar couplings. Homonuclear
decoupling suppresses dipolar dephasing during the gradient pulses but its
efficiency and scaling factor for the effective gradient vary across the sample
because of the large variation of the frequency offset caused by the gradient.
The resulting artifacts are reduced by introducing a slice selection scheme. The
method is demonstrated by (19)F PGSE NMR experiments in a lyotropic liquid
crystal.
PMID- 10783285
TI - A solid-state NMR index of helical membrane protein structure and topology.
AB - The secondary structure and topology of membrane proteins can be described by
inspection of two-dimensional (1)H-(15)N dipolar coupling/(15)N chemical shift
polarization inversion spin exchange at the magic angle spectra obtained from
uniformly (15)N-labeled samples in oriented bilayers. The characteristic wheel
like patterns of resonances observed in these spectra reflect helical wheel
projections of residues in both transmembrane and in-plane helices and hence
provide direct indices of the secondary structure and topology of membrane
proteins in phospholipid bilayers. We refer to these patterns as PISA (polarity
index slant angle) wheels. The transmembrane helix of the M2 peptide
corresponding to the pore-lining segment of the acetylcholine receptor and the
membrane surface helix of the antibiotic peptide magainin are used as examples.
PMID- 10783286
TI - Three-dimensional solid-state NMR spectroscopy is essential for resolution of
resonances from in-plane residues in uniformly (15)N-labeled helical membrane
proteins in oriented lipid bilayers.
AB - Uniformly (15)N-labeled samples of membrane proteins with helices aligned
parallel to the membrane surface give two-dimensional PISEMA spectra that are
highly overlapped due to limited dispersions of (1)H-(15)N dipolar coupling and
(15)N chemical shift frequencies. However, resolution is greatly improved in
three-dimensional (1)H chemical shift/(1)H-(15)N dipolar coupling/(15)N chemical
shift correlation spectra. The 23-residue antibiotic peptide magainin and a 54
residue polypeptide corresponding to the cytoplasmic domain of the HIV-1
accessory protein Vpu are used as examples. Both polypeptides consist almost
entirely of alpha-helices, with their axes aligned parallel to the membrane
surface. The measurement of three orientationally dependent frequencies for Val17
of magainin enabled the three-dimensional orientation of this helical peptide to
be determined in the lipid bilayer.
PMID- 10783287
TI - Imaging membrane protein helical wheels.
AB - Resonance patterns have been observed in 2D solid-state NMR spectra of the
transmembrane segment of M2 protein from Influenza A virus in oriented samples
reflecting the helical wheel of this alpha-helix. The center of this pattern
uniquely defines the helical tilt with respect to the bilayer normal without a
need for resonance assignments. The distribution of resonances from amino acid
specific labels around the "PISA wheel" defines the rotational orientation of the
helix and yields preliminary site-specific assignments. With assignments high
resolution structural detail, such as differences in tilt and rotational
orientation along the helical axis leading to an assessment of helical coiling,
can be obtained.
PMID- 10783288
TI - Time-shared X(omega(1))-half-filter for improved sensitivity in subspectral
editing.
AB - Experiments with X-half-filter elements allow the separation of the resonances
from protons bound and unbound to a spin X into different subspectra. This
Communication presents a modified half-filter element where the filter delay is
simultaneously used for chemical shift labeling and scalar coupling evolution in
a semi-constant time experiment. The filter element is demonstrated with a (1)H
NOESY spectrum of a 28.5-kDa 2:1 complex between the uniformly (13)C-labeled N
terminal domain of Escherichia coli arginine repressor and operator DNA.
PMID- 10783289
TI - Suppression of diagonal peaks in three-dimensional protein NMR TROSY-type HCCH
correlation experiments.
AB - A novel method for suppression of (13)C-(13)C diagonal peaks without sensitivity
loss in three-dimensional HCCH TROSY-type NMR correlation experiments involving
aromatic side chains in proteins (Pervushin et al., J. Am. Chem. Soc. 120, 6394
6400 (1998)) is presented. The key element is a spin-state-selective filter in
the (13)C-(13)C mixing sequence with the dual effect of selecting the TROSY
resonance in the preceding evolution period and interchanging TROSY and anti
TROSY resonances. The cross peaks are invariant to this filter but diagonal peak
coherence gets concentrated on the anti-TROSY transition so that it can be
eliminated by a (13)C --> (1)H TROSY transfer element. The new method is
demonstrated using a (13)C,(15)N-labeled protein sample, RAP 18-112 (N-terminal
domain of alpha(2)-macroglobulin receptor associated protein), at 750 MHz.
PMID- 10783290
TI - An iterative fitting procedure for the determination of longitudinal NMR cross
correlation rates.
AB - We present a method to measure (15)N-(1)H dipolar/(15)N CSA longitudinal cross
correlation rates in protonated proteins. The method depends on the measurement
of four observables: the cumulative proton-proton cross relaxation rates, the
(15)N R(1) relaxation rate, the multiexponential decay of 2N(Z)H(N)(Z) spin
order, and multiexponential buildup of 2N(Z)H(N)(Z) spin-order. The (15)N-(1)H
dipolar/(15)N CSA longitudinal cross-correlation rate is extracted from these
measurements by an iterative fitting procedure to the solution of differential
equations describing the coupled relaxation dynamics of the z-magnetization of
the (15)N nucleus, the two-spin-order 2N(Z)H(N)(Z), and a two-spin-order term
2N(Z)H(Q)(Z) describing the interaction with remote protons. The method is
applied to the microbial ribonuclease binase. The method can also extract
longitudinal cross-correlation rates for those amide protons that are involved in
rapid solvent exchange. The experiment that serves for extracting proton-proton
cross-relaxation rates is a modification of 3D (15)N-resolved NOESY-HSQC. The
experiment restores the solvent magnetization to its equilibrium state during
data detection for all phase cycling steps and all values of NOE mixing times and
is recommended for use in standard applications as well.
PMID- 10783291
TI - The future of genetic analysis of neurological disorders.
AB - Molecular genetic analysis has allowed the elucidation of the etiology of many
single-gene, neurodegenerative syndromes. However, as yet, it has had little
direct impact on our understanding of the etiology in cases with more complex
modes of inheritance. With the completion of the sequence of the human genome, it
should be possible to start to attack these more complex problems. In this
article, we review the genetic methods that may be used to dissect the etiologies
of these diseases and outline what types of clinical samples will be needed for
this quest.
PMID- 10783292
TI - Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic
mice.
AB - Histological analyses were performed on the brains of APP(V717F) transgenic
(Tg)mice previously studied in a battery of behavioral tests. We describe here
the regional and age-dependent deposition of amyloid in both heterozygous and
homozygous Tg mice. We also report that Tg mice show significant and age
dependent changes in synaptic density measured by synaptophysin immunoreactivity.
Surprisingly, a rather marked hippocampal atrophy is observed as early as 3
months of age in Tg mice (20-40%). Statistical analyses revealed that the
deficits in object recognition memory are related to the number of amyloid
deposits in specific brain regions, whereas deficits in spatial reference and
working memory are related to the changes in synaptic density and hippocampal
atrophy. Our study suggests that the behavioral deficits observed in Tg mice are
only in part related to amyloid deposition, but are also related to
neuroanatomical alterations secondary to overexpression of the APP(V717F)
transgene and independent of amyloid deposition.
PMID- 10783294
TI - Subcellular localization of presenilins: association with a unique membrane pool
in cultured cells.
AB - We have investigated the subcellular distribution of presenilin-1 (PS1) and
presenilin-2 (PS2) in a variety of mammalian cell lines. In Iodixanol-based
density gradients, PS1 derivatives show a biphasic distribution, cofractionating
with membranes containing ER-resident proteins and an additional population of
membranes with low buoyant density that do not contain markers of the Golgi
complex, ERGIC, COP II vesicles, ER exit compartment, COP II receptor, Golgi
SNARE, trans-Golgi network, caveolar membranes, or endocytic vesicles. Confocal
immunofluorescence and immunoelectron microscopy studies fully supported the
fractionation studies. These data suggest that PS1 fragments accumulate in a
unique subcompartment(s) of the ER or ER to Golgi trafficking intermediates.
Interestingly, the FAD-linked PS1 variants show a marked redistribution toward
the heavier region of the gradient. Finally, and in contrast to PS1, PS2
fragments are detected preponderantly in more densely sedimenting membranes,
suggesting that the subcellular compartments in which these molecules accumulate
are distinct.
PMID- 10783293
TI - Characterization of pathology in transgenic mice over-expressing human genomic
and cDNA tau transgenes.
AB - To examine the normal cellular function of tau and its role in pathogenesis, we
have created transgenic mice that overexpress a tau transgene derived from a
human PAC that contains the coding sequence, intronic regions, and regulatory
regions of the human gene. All six isoforms of human tau are represented in the
transgenic mouse brain at the mRNA and protein level and the human tau is
distributed in neurites and at synapses, but is absent from cell bodies. A
comparison between the genomic tau mice and mice that overexpress a tau cDNA
transgene shows that overall, the distribution of tau is similar in the two
lines, but human tau is located in the somatodendritic compartment of many
neurons in the cDNA mice. Tau-immunoreactive axonal swellings were found in the
spinal cords of the cDNA mice, which correlated with a hind-limb abnormality,
whereas neuropathology was essentially normal in the genomic mice up to 8 months
of age.
PMID- 10783295
TI - Functional phenotype in transgenic mice expressing mutant human presenilin-1.
AB - Mutations in the presenilin-1 (PS1) gene cause approximately 50% of cases of
early onset familial Alzheimer's disease. The function of this protein remains
unknown. We have made an electrophysiological study of hippocampal slices from
transgenic mice expressing either a normal human PS1 transgene (WT) or one of two
human PS1 transgenes bearing pathogenic mutations at codon M146 (M146L and
M146V). Medium and late afterhyperpolarizations in CA3 pyramidal cells were
larger in mice expressing either mutant form compared with WT and nontransgenic
controls. Calcium responses to depolarization were larger in M146L mice compared
with nontransgenic littermates; synaptic potentiation of the CA3 to CA1
projection was also stronger. These results demonstrate disruption of the control
of intracellular calcium and electrophysiological dysfunction in PS1 mutant mice.
PMID- 10783296
TI - EBV-based plasmid DNA rearrangements after transfection of eukaryotic cells.
AB - The cDNA encoding influenza virus (A/Udorn/307/72 strain) M2 protein was
subcloned into the EBV-based vector pREP9. Three continuous kidney cellular lines
of different origin were transfected with recombinant plasmid pREP9-M2. One and 5
months after transfection plasmid DNA rearrangements were detected by means of
restriction analysis of recovered plasmids and their hybridization with an
influenza-virus-specific radioactive probe. Deletions were the most frequent type
of pREP9-M2 mutations. PCR with primers corresponding to cellular genome and
plasmid DNA followed by Southern blot analysis with the [(32)P]-labeled M2
fragment allowed host DNA rearrangements to be revealed in transfected cells.
PMID- 10783297
TI - Expression of bacillar glutamyl endopeptidase genes in Bacillus subtilis by a new
mobilizable single-replicon vector pLF.
AB - The pLF1311 natural plasmid from Lactobacillus fermentum 1311 was used to
construct a single-replicon vector suitable for rapid cloning in a wide range of
gram-positive hosts and Escherichia coli. The new vector is capable of
conjugative mobilization from E. coli to various hosts by conjugal transfer. The
final vector (3.4 kb) showed a high segregational and structural stability and a
high copy number. Glutamyl endopeptidase genes from Bacillus licheniformis
(gseBL) and B. intermedius (gseBI) were cloned in both pLF9 and pLF14 vectors and
introduced to B. subtilis. The yield of enzymes in the pLF-derived producers was
6- to 30-fold more than in the natural producers and reached 100-150 mg/L of
mature protease.
PMID- 10783298
TI - Plasmid R1 is present as clusters in the cells of Escherichia coli.
AB - Fluorescence microscopy was used to determine the location(s) of the replication
origin of plasmid R1 in exponentially growing cells of Escherichia coli. The
number of oriR1 foci per cell was smaller than the number of R1 copies per cell
and was found to be the same for a copA mutant of R1 and for the wild-type
plasmid. The intensities of individual foci were stronger for the cop mutant than
for the wild type. We interpreted these results to imply that the plasmid DNA
molecules were localized in small groups/clusters, a result that seems contrary
to the earlier observations that plasmid R1 replicates randomly and segregates as
a single-copy unit. The implications for the quantitative behavior of plasmid R1
in stability, incompatibility tests, replication, and partition experiments are
discussed.
PMID- 10783299
TI - Construction of a tightly regulated plasmid vector for Streptococcus pneumoniae:
controlled expression of the green fluorescent protein.
AB - We have constructed a regulated plasmid vector for Streptococcus pneumoniae,
based on the streptococcal broad-host-range replicon pLS1. As a reporter gene, we
subcloned the gfp gene from Aequorea victoria, encoding the green fluorescent
protein. This gene was placed under the control of the inducible P(M) promoter of
the S. pneumoniae malMP operon which, in turn, is regulated by the product of the
pneumococcal malR gene. Binding of MalR protein to the P(M) promoter is
inactivated by growing the cells in maltose-containing media. Highly regulated
gene expression was achieved by cloning in the same plasmid the P(M)-gfp cassette
and the malR gene, thus providing the MalR regulator in cis. Pneumococcal cells
harboring this vector gave a linear response of GFP synthesis in a maltose
dependent mode without detectable background levels in the absence of the
inducer.
PMID- 10783300
TI - Identification of a potential membrane-targeting region of the replication
initiator protein (TrfA) of broad-host-range plasmid RK2.
AB - Plasmid RK2 codes for two species of the replication initiator protein TrfA (33
and 44 kDa). Both polypeptides are strongly associated with membrane fractions of
Escherichia coli host cells (W. Firshein and P. Kim, Mol. Microbiol. 23, 1-10,
1997). We investigated the role of a 12-amino-acid hydrophobic region (HR) in the
membrane association of TrfA. Epitope-tagged polypeptide fragments of TrfA that
contained HR were expressed and found to be associated with membrane fractions.
Site-directed mutagenesis of trfA revealed that changes of specific amino acids
in HR can affect both TrfA association with the membrane and its ability to
support replication of an RK2 oriV plasmid in vivo. These results are consistent
with the hypothesis that membrane association of TrfA is functionally relevant
and that the HR region of TrfA is involved in membrane association and DNA
replication in vivo.
PMID- 10783301
TI - Cloning and characterization of the replicon of the Nocardia italica plasmid,
pNI100.
AB - A 19-kb plasmid, pNI100, was isolated from Nocardia italica CCRC12359; its
replicon was cloned and characterized as having a single open reading frame (ORF)
of 1188 bp specifying 396 amino acids (aa). Analyses of the deduced aa sequence
of the Rep protein indicated that characteristics of three consensus sequences
and a P-loop-like motif in the Rep protein of plasmid pSG5, a conjugative plasmid
involving a rolling-circle replication mechanism, were conserved in those of
plasmid pNI100. Phenotypically, a pock structure was produced in the regenerated
mycelium by introducing pNI100 DNA into the Streptomyces lividans protoplast.
This result strongly suggests that pNI100 is a conjugative plasmid and probably
replicates by a rolling-circle replication mechanism. By using the replicon of
pNI100, a bifunctional plasmid pNI105 that could replicate in both Escherichia
coli and S. lividans was constructed and found to be a useful cloning shuttle
vector.
PMID- 10783302
TI - Identification and characterization of a native Dichelobacter nodosus plasmid,
pDN1.
AB - The gram-negative anaerobe Dichelobacter nodosus is the primary causative agent
of ovine footrot, a mixed bacterial infection of the hoof. We report here the
characterization of a novel native plasmid, pDN1, from D. nodosus. Sequence
analysis has revealed that pDN1 has a high degree of similarity to broad-host
range plasmids belonging, or related, to Escherichia coli incompatibility group
Q. However, in contrast to these plasmids, pDN1 encodes no antibiotic resistance
determinants, lacks genes E and F, and hence is smaller than all previously
reported IncQ plasmids. In addition, pDN1 belongs to a different incompatibility
group than the IncQ plasmids to which it is related. However, pDN1 does contain
the replication and mobilization genes that are responsible for the extremely
broad host range characteristic of IncQ plasmids, and derivatives of pDN1
replicate in E. coli. In addition, the mobilization determinants of pDN1 are
functional, since derivatives of pDN1 are mobilized by the IncPalpha plasmid RP4
in E. coli.
PMID- 10783303
TI - Analysis of the complete nucleotide sequence of the tetracycline-resistance
transposon Tn10.
AB - An analysis of the complete nucleotide sequence of the composite tetracycline
resistance transposon Tn10 (9147 bp) from the Salmonella typhi conjugative
plasmid R27 is presented. A comparison of the protein sequences from IS10-right
and IS10-left transposases has identified four amino acid differences. These
residues appear to play an important role in normal transposase function and may
account for the differences in exhibited transposition activities. The
tetracycline determinants encoded by this version of Tn10 share >99% identity
with those of Tn10(R100), demonstrating the conservation that exists between
these transposons. A previously uncharacterized approximately 3000-bp region of
Tn10 contains four putative open reading frames. One of these open reading frames
shares 55% identity with the glutamate permease protein sequence from Haemophilus
influenzae although it was unable to complement an Escherichia coli glutamate
permease mutant, with which it shares 51% identity. The three remaining putative
open reading frames are arranged as a discrete genetic unit adjacent to the
glutamate permease homolog and are transcribed in the opposite direction. Two of
these open reading frames are homologous with Bacillus subtilis proteins of
unknown functions while the other has no homologs in the database. The presence
of an aminoacyl-tRNA synthetase class II motif in one of these open reading
frames in combination with the glutamate permease homolog allows us to postulate
that this region of Tn10 could once have played a role in amino acid metabolism.
PMID- 10783304
TI - Disorders in cell circuitry during multistage carcinogenesis: the role of
homeostasis.
AB - The multistage process of carcinogenesis involves the progressive acquisition of
mutations, and epigenetic abnormalities in the expression, of multiple genes that
have highly diverse functions. An important group of these genes are involved in
cell cycle control. Thus, cyclin D1 is frequently overexpressed in a varety of
human cancers. Cylin D1 plays a critical role in carcinogenesis because (i)
overexpression enhances cell transformation and tumorigenesis, and enhances the
amplification of other genes, and (ii) an antisense cyclin D1 cDNA reverts the
malignant phenotype of carcinoma cells. Therefore, cyclin D1 may be a useful
biomarker in molecular epidemiology studies, and inhibitors of its function may
be useful in both cancer chemoprevention and therapy. We discovered a paradoxical
increase in the cell cycle inhibitors protein p27(Kip1) in a subset of human
cancers, and obtained evidence for homeostatic feedback loops between cyclins D1
or E and p27(Kip1). Furthermore, derivatives of HT29 colon cancer cells with
increased levels of p27(Kip1) showed increased sensitivity to induction of
differentiation. This may explain why decreased p27(Kip1) in a subset of human
cancers is associated with a high grade (poorly differentiated) histology and
poor prognosis. Agents that increase cellular levels of p27(Kip1) may, therefore,
also be useful in cancer therapy. Using an antisense Rb oligonucleotide we
obtained evidence that the paradoxical increase in pRb often seen in human colon
cancers protects these cells from growth inhibition and apopotosis. On the basis
of these, and other findings, we hypothesize that homeostatic feedback mechanisms
play a critical role in multistage carcinogenesis. Furthermore, because of their
bizarre circuitry, cancer cells suffer from 'gene addiction' and 'gene
hypersensitivity' disorders that might be exploited in both cancer prevention and
chemotherapy.
PMID- 10783305
TI - The INK4a/ARF locus in murine tumorigenesis.
AB - The INK4a/ARF locus is regarded as one of the most important anti-tumoral
defenses that mammalian organisms possess. The characterization of its two gene
products, p16(INK4a) and p19(ARF), has provided a great insight on the
functioning of the tumor suppressors Rb and p53, respectively. Present evidence
indicates that the INK4a/ARF locus is transcriptionally activated by oncogenic
stresses, resulting in cell-cycle arrest or apoptosis. Here, I review the
evidence accumulated on the involvement of the INK4a/ARF locus in murine
tumorigenesis. Also, I summarize the phenotype of the different transgenic mouse
models based on the inactivation of the INK4a/ARF locus.
PMID- 10783306
TI - Activation of NF-kappaB/Rel occurs early during neoplastic transformation of
mammary cells.
AB - NF-kappaB/Rel is a family of transcription factors which are expressed in all
cells; however, in most non-B cells, they are sequestered in the cytoplasm in
inactive complexes with specific inhibitory proteins, termed IkappaBs. We have
recently shown that NF-kappaB/Rel factors are aberrantly activated in human
breast cancer and rodent mammary tumors, and function to promote tumor cell
survival and proliferation. Here, we have examined the time-course of induction
of NF-kappaB/Rel factors upon carcinogen treatment of female Sprague-Dawley (S-D)
rats in vivo and in human mammary epithelial cells (HMECs) in culture. We
observed that NF-kappaB/Rel activation is an early event, occurring prior to
malignant transformation. In S-D rats, increased NF-kappaB/Rel binding was
detected in nuclear extracts of mammary glands from 40% of animals 3 weeks post
treatment with 15 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA); this is prior to
formation of tumors which normally begin to be detected after 7-9 weeks. In non
tumorigenic MCF-10F cells, in vitro malignant transformation upon treatment with
either DMBA or benzo[a]pyrene (B[a]P) resulted in a 4- to 12-fold increase in
activity of classical NF-kappaB (p65/p50). NF-kappaB induction was corrrelated
with a decrease in the stability of the NF-kappaB-specific inhibitory protein
IkappaB-alpha. Ectopic expression of the transactivating p65 subunit of NF-kappaB
in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF
kappaB elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty
derived HMECs, immortalized following B[a]P exposure, showed dysregulated
induction of classical NF-kappaB prior to malignant transformation. Together
these findings suggest that activation of NF-kappaB plays an early, critical role
in the carcinogen-driven transformation of mammary glands.
PMID- 10783307
TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits growth factor withdrawal
induced apoptosis in the human mammary epithelial cell line, MCF-10A.
AB - Previous studies have demonstrated that 2,3,7, 8-tetrachlorodibenzo-p-dioxin
(TCDD) increases cell recovery in the human mammary epithelial cell line MCF-10A
grown under growth factor-restricted conditions. TCDD was also found to mimic
growth factor signaling pathways by stimulating the tyrosine phosphorylation of
numerous effector molecules, and increased phosphatidylinositol 3-kinase (PI3K)
activity in the absence of exogenously added growth factors. In the present
studies, we have expanded on these initial results to show that TCDD (3-30 nM)
increases cell recovery on days 2-6 by as much as 80% when insulin or epidermal
growth factor (EGF) was removed from the media. The mechanism for this effect
appears to be complex as TCDD inhibited apoptosis stimulated by EGF, or EGF and
insulin, withdrawal by almost 80% as determined by Annexin V binding. However,
withdrawal of insulin alone did not induce apoptosis even though TCDD did
increase cell number in its absence. These results were corroborated by
immunoblot analysis of poly(ADP-ribose) polymerase cleavage. Since TCDD
stimulates PI3K activity, the phosphorylation status of Akt, a serine/threonine
kinase that mediates PI3K-dependent inhibition of apoptosis, was examined.
Immunoblot analysis revealed that TCDD causes a transient increase in the
phosphorylated form of Akt that peaks at 6 h and disappears by 12 h. It appears
that EGF stimulates an anti-apoptotic pathway, while insulin signals a pro
mitogenic pathway. By stimulating or mimicking one or both of these pathways TCDD
may alter tightly regulated growth pathways in the MCF-10A cell line.
PMID- 10783308
TI - Effect of a tyrosine 155 to phenylalanine mutation of protein kinase cdelta on
the proliferative and tumorigenic properties of NIH 3T3 fibroblasts.
AB - Tyrosine phosphorylation has emerged as an important mechanism in the regulation
of enzyme function. In this paper, we describe a mutant of PKCdelta altered at a
single tyrosine residue which has the opposite effect compared with wild-type
PKCdelta on the growth characteristics of NIH 3T3 cells. Overexpression of wild
type PKCdelta results in a decreased growth rate and a lower cell density at
confluency. On the other hand, overexpression of PKCdelta with a mutation from
tyrosine to phenylalanine at position 155 results in a significantly higher rate
of growth and a higher density at confluency compared with vector controls.
Moreover, these cells are able to grow in soft agar and to form tumors in nude
mice. In contrast to kinase negative PKC constructs, this mutant maintains in
vitro kinase activity and shows a subcellular localization and a translocation
pattern that are similar to those of the wild-type PKCdelta. Whether the altered
biological effect is due to the missing phosphorylation on tyrosine or the
mutation from tyrosine to phenylalanine per se remains under investigation.
PMID- 10783309
TI - Cell activation via CD44 occurs in advanced stages of squamous cell
carcinogenesis.
AB - Squamous cell carcinoma (SCC) derives from dysplastic or metaplastic stratified
epithelia. The process of squamous cell carcinogenesis has been investigated for
the potential role of the adhesion molecule CD44, whose standard form (CD44s) and
isoforms generated by alternative splicing of variant exons are known to display
altered expression during tumorigenesis in other systems. We have utilized an in
vitro correlate of squamous cell carcinogenesis, in which progression stages from
normal squamous epithelium to dysplastic lesions and to SCC are represented by
primary cultures of normal keratinocytes, by human papilloma virus-immortalized
keratinocytes (UP) and by HPVimmortalized/v-Ha-ras transfected tumorigenic
keratinocytes (UPR). We investigated expression of CD44 and of variant isoforms,
from mRNA to intracellular and surface protein levels, and found no relationship
between expression of CD44 and stages of squamous cell carcinogenesis. However,
when the function of CD44 was analyzed as Ca(2+) mobilization ability upon
monoclonal antibody binding and crosslinking, signal transduction via CD44 was
found only for the neoplastic stage (UPR cells). Ca(2+) mobilization was
completely independent of density of surface CD44. We have performed similar
analyses in an in vitro model of SCC in which four squamous tumor cell lines and
UPR cells were sorted according to increasing resistance to external cytotoxic
stimuli, i.e. starving conditions, treatment with the retinoid N-(4
hydroxyphenyl)retinamide and cytolytic activity of effector lymphokine-activated
killer cells. No relationship between expression of CD44 and level of cell
resistance against external cell death-inducing stimuli was found, while CD44
mediated Ca(2+) mobilization ability was restricted to the highly resistant tumor
cell lines. Our results indicate that the role(s) of CD44 in squamous cell
proliferative disorders can be evinced from the functional features of the
molecule, rather than from its phenotypic repertoire.
PMID- 10783310
TI - Influence of DNA structure on hypoxanthine and 1,N(6)-ethenoadenine removal by
murine 3-methyladenine DNA glycosylase.
AB - 3-Methyladenine DNA glycosylases initiate base excision repair by flipping the
nucleotide bearing the target base out of double-stranded DNA into an active site
pocket for glycosylic bond cleavage and base release. Substrate bases for the
murine 3-methyladenine DNA glycosylase (other than 3-methyladenine) include
hypoxanthine and 1,N(6)-ethenoadenine, two mutagenic adducts formed by both
endogenous and exogenous agents. Using double-stranded DNA oligonucleotides
containing damaged bases at specific sites, we studied the relative removal rates
for these two adducts when located in different sequence contexts. One of the
sequence contexts was an A:T tract, chosen because DNA secondary structure is
known to change along the length of this tract, due to a progressive narrowing of
the minor groove. Here we report that removal rates for hypoxanthine, but not for
1,N(6)-ethenoadenine, are dramatically affected by its location within the A:T
tract. In addition, the removal rates of hypoxanthine and 1,N(6)-ethenoadenine
when paired opposite thymine or cytosine were examined, and in each sequence
context hypoxanthine removal decreased by at least 20-fold when paired opposite
cytosine versus thymine. In contrast, 1, N(6)-ethenoadenine removal was
unaffected by the identity of the opposing pyrimidine. We conclude that the
removal of certain bases by the mouse 3-methyladenine DNA glycosylase can be
modulated by both adjacent and opposing sequence contexts. The influence of DNA
sequence context upon DNA repair rates, such as those described here, may
contribute to the creation of mutational hot spots in mammalian cells.
PMID- 10783311
TI - Dietary antioxidant depletion: enhancement of tumor apoptosis and inhibition of
brain tumor growth in transgenic mice.
AB - Apoptosis, or regulated cell suicide, eliminates unwanted and damaged cells,
including precancerous and cancerous cells. Since reactive oxygen species (ROS)
act as essential apoptotic mediators, we reasoned that increasing the ROS level
might enhance apoptosis and thereby slow down tumor growth. Here, using a defined
transgenic brain tumor model with known tumor apoptosis rates, we test the impact
of antioxidant-depleted diet, capable of increasing ROS levels, or antioxidant
enriched diets on tumor growth. Dramatically increased apoptosis occurs within
tumors, but not in normal tissues of antioxidant-depleted mice. The presence of
detectable increased oxidant stress within tumors indicates that the likely
mechanism of enhanced tumor apoptosis is via ROS and DNA oxidative impairment.
Importantly, due to the ROS-enhanced apoptosis, tumor growth is inhibited in mice
fed an antioxidant-depleted diet. In clear contrast, an antioxidant-rich diet had
no impact on tumor growth.
PMID- 10783312
TI - (-)-Epigallocatechin gallate can prevent cisplatin-induced lung tumorigenesis in
A/J mice.
AB - Risks of secondary lung cancer in patients with non-small cell lung cancer and
small cell lung cancer are estimated to be 1-2% and 2-10% per patient per year,
respectively. Cisplatin is widely used in the treatment of lung cancer and is
also known as a carcinogen in experimental animals. In this study, the effect of
(-)-epigallocatechin gallate (EGCG) on cisplatin-induced lung tumors in A/J mice
was investigated. Female A/J mice (4 weeks old) were divided into four groups:
group 1, control without treatment; group 2, EGCG treatment (1 mg/ml in tap
water); group 3, weekly cisplatin treatment (1.62 mg/kg body wt, i.p.) for 10
weeks; group 4, cisplatin plus EGCG treatment (EGCG was started 2 weeks before
cisplatin treatment). Four groups of mice were killed at week 30 after treatment.
Tumor incidence was 26.3% (5/19) in group 1, 30% (6/20) in group 2, 100% (19/19)
in group 3 and 94.4% (17/18) in group 4. Tumor multiplicity (the number of tumors
per mouse, mean +/- SD) was 0.4 +/- 0.8 in group 1, 0.4 +/- 0.8 in group 2, 5.1
+/- 2.1 in group 3 and 2.8 +/- 2.3 in group 4. Tumor multiplicity was
significantly reduced by adding EGCG to cisplatin-treated mice (P < 0.01).
Furthermore, EGCG significantly reduced cisplatin-induced weight loss from 24.7
26.3% (cisplatin treatment) to 10.8-11.6% (cisplatin plus EGCG treatment) (P <
0.01). These findings suggest that EGCG can inhibit cisplatin-induced weight loss
and lung tumorigenesis in A/J mice.
PMID- 10783313
TI - Plant phenolics decrease intestinal tumors in an animal model of familial
adenomatous polyposis.
AB - Epidemiological studies consistently indicate that consumption of fruits and
vegetables lowers cancer risk in humans and suggest that certain dietary
constituents may be effective in preventing colon cancer. Plant-derived phenolic
compounds manifest many beneficial effects and can potentially inhibit several
stages of carcinogenesis in vivo. In this study, we investigated the efficacy of
several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE),
curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+
(Min/+) mice. These animals bear a germline mutation in the Apc gene and
spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a
dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%.
Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both
failed to alter tumor formation at dietary levels of 2%. Examination of
intestinal tissue from the treated animals showed that tumor prevention by CAPE
and curcumin was associated with increased enterocyte apoptosis and
proliferation. CAPE and curcumin also decreased expression of the oncoprotein
beta-catenin in the enterocytes of the Min/+ mouse, an observation previously
associated with an antitumor effect. These data place the plant phenolics CAPE
and curcumin among a growing list of anti-inflammatory agents that suppress Apc
associated intestinal carcinogenesis.
PMID- 10783314
TI - Effect of intact and isoflavone-depleted soy protein on NMU-induced rat mammary
tumorigenesis.
AB - Experiments in animal models of carcinogenesis suggest that soy consumption
decreases tumor number and incidence. Genistein, an isoflavone which is present
in soy at high concentrations, has been considered to be the primary antitumor
constituent in soy. In the present study, the N-nitroso-N-methylurea (NMU)
induced mammary tumor model was used as a means to determine whether the
chemopreventive effect of soy was attributable specifically to its high content
of isoflavones. Five groups of rats (30/group) were fed the following modified
AIN-93G diets: group 1, 20% intact soy protein (SP); group 2, 10% SP; group 3,
20% isoflavone-depleted soy protein (IDSP); group 4, 10% IDSP; group 5, the
casein-based AIN-93G diet. The SP contained 1.07 and IDSP 0.073 mg genistein/g
isolate, respectively. Experimental diets were initiated 1 week prior to NMU
administration (at 50 days of age) and continued for another 18 weeks. No
significant differences were found among the five groups when assessed in terms
of tumor incidence, latency, multiplicity or volume. A trend towards inhibition
was observed in both the 20 and 10% SP and IDSP groups when assessed in terms of
total tumors/group, tumor volume and latency, but this trend did not achieve
statistical significance. The results of this model study do not support the
hypothesis that the isoflavone components of soy protein, or soy protein itself,
inhibit chemically induced mammary tumor development.
PMID- 10783315
TI - Inhibitory effects of Bifidobacterium-fermented soy milk on 2-amino-1-methyl-6
phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial
contribution of its component isoflavones.
AB - High consumption of soybean and soybean-related products is hypothesized to
contribute to protection against breast cancer. Soybean is a rich source of
genistein, a putative cancer chemopreventive agent. Fermented soy milk (FSM),
which is made of soy milk fermented with the Bifidobacterium breve strain Yakult,
contains larger amounts of the isoflavone aglycones genistein and daidzein than
unfermented soy milk. In the present study, we examined the effects of FSM and
its component isoflavone mixture (genistein:daidzein 4:1) on 2-amino-1-methyl-6
phenylimidazo[4, 5-b]pyridine (PhIP)-induced mammary carcinogenesis in rats.
Starting at 7 weeks of age, female Sprague-Dawley rats were given PhIP at a dose
of 85 mg/kg body wt by intragastric administration four times a week for 2 weeks.
They were fed control high fat basal diet or experimental high fat diet
containing 10% FSM or 0.02 or 0.04% isoflavone mixture during and after
carcinogen exposure. The incidences (percentage of rats with tumors) of mammary
gland tumors were 71% in the control diet group, 51% in the FSM group and 68 and
61% in the groups treated with isoflavone mixture at 0.02 and 0.04%,
respectively. Mammary tumor multiplicities (number of tumors per rat) were 1.2 +/
0.2 for 10% FSM, 2.2 +/- 0.4 for 0.02% isoflavone mixture and 1.5 +/- 0.3 for
0.04% isoflavone mixture, being clearly smaller than the control diet value (2.6
+/- 0.5). Furthermore, feeding of FSM and the isoflavone mixture at both doses
reduced the sizes of mammary tumors. Since the amounts of isoflavones in 10% FSM
are approximately equivalent to those in the 0.02% isoflavone mixture, the
chemopreventive activity of FSM could be partly attributable to the presence of
isoflavones such as genistein and daidzein.
PMID- 10783316
TI - Antiproliferative and apoptotic effects of O-Trensox, a new synthetic iron
chelator, on differentiated human hepatoma cell lines.
AB - We investigated the effects of a new iron chelator, O-Trensox (TRX), compared
with desferrioxamine (DFO), on proliferation and apoptosis in cultures of the
human hepatoblastoma HepG2 and hepatocarcinoma HBG cell lines. Our results show
that TRX decreased DNA synthesis in a time- and dose-dependent manner and with a
higher efficiency than DFO. Mitotic index was also strongly decreased by TRX and,
unexpectedly, DFO inhibited mitotic activity to the same extent as TRX, thus
there is a discrepancy between the slight reduction in DNA synthesis and a large
decrease in mitotic index after DFO treatment. In addition, we found that TRX
induced accumulation of cells in the G(1) and G(2) phases of the cell cycle
whereas DFO arrested cells in G(1) and during progression through S phase. These
data suggest that the partial inhibition of DNA replication observed after
exposure to DFO may be due to a lower efficiency of metal chelation and/or that
it does not inhibit the G(1)/S transition but arrests cells in late S phase. The
effects of both TRX and DFO on DNA synthesis and mitotic index were reversible
after removing the chelators from the culture medium. An apoptotic effect of TRX
was strongly suggested by analysis of DNA content by flow cytometry, nuclear
fragmentation and DNA degradation in oligonucleosomes and confirmed by the
induction of a high level of caspase 3-like activity. TRX induced apoptosis in a
dose- and time-dependent manner in proliferating HepG2 cells. In HBG cells, TRX
induced apoptosis in proliferating and confluent cells arrested in the G(1) phase
of the cell cycle, demonstrating that inhibition of proliferation and induction
of apoptosis occurred independently. DFO induced DNA alterations only at
concentrations >100 microM and without induction of caspase 3-like activity,
indicating that DFO is not a strong inducer of apoptosis. Addition of Fe or Zn to
the culture medium during TRX treatment led to a complete restoration of
proliferation rate and inhibition of apoptosis, demonstrating that Fe/Zn
saturated TRX was not toxic in the absence of metal depletion. These data show
that TRX, at concentrations of 20-50 microM, strongly inhibits cell proliferation
and induces apoptosis in proliferating and non-proliferating HepG2 and HBG cells,
respectively.
PMID- 10783317
TI - Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474)
by a novel COX-2 inhibitor, JTE-522.
AB - Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in
the occurrence of sporadic colon cancer. Various Apc knockout strains of mice
have been created to better understand the function of this gene. In the present
study, using gene targeting, we disrupted the mouse Apc gene at the end of exon
10 to compare its effect with the effects of other types of Apc gene disruption,
all of which are on exon 15. The mice expressed a mutant form of mRNA that
encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In
addition, these Apc(Delta474) knockout mice developed intestinal and mammary
tumors. Since the most severe cases of familial adenomatous polyposis are
associated with mutations on exon 15, our mutation at exon 10 was expected to
result in a mild phenotype. However, the number of polyps that our mice developed
was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309)
mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma.
Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor,
showed a significantly reduced number of polyps. These results suggest that COX-2
plays an important role in polypogenesis and COX-2-selective inhibitors can be
used as new preventive therapeutics against colorectal tumors.
PMID- 10783318
TI - Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in
colon cancer cells by chemopreventive agents with a resorcin-type structure.
AB - Cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells. It has
been reported that inhibition of COX-2 enzyme activity is shown to prevent colon
carcinogenesis. Thus, suppression of COX-2 expression may also be an effective
chemopreventive strategy. In the present study, we constructed a beta
galactosidase reporter gene system in human colon cancer DLD-1 cells, and
measured COX-2 promoter-dependent transcriptional activity in the cells.
Interferon gamma suppressed this COX-2 promoter activity, while 12-O
tetradecanoylphorbol-13-acetate and transforming growth factor alpha (TGFalpha)
exerted enhancing effects. We then tested the influence of 14 candidate cancer
chemopreventive compounds on COX-2 promoter activity. Chemopreventive agents such
as quercetin, kaempferol, genistein, resveratrol and resorcinol, all having a
common resorcin moiety, were found to effectively suppress the COX-2 promoter
activity with and without TGFalpha-stimulation in DLD-1 cells. Since all these
compounds have a resorcin moiety as a common structure, a resorcin-type structure
may play an active role in the inhibition of COX-2 expression in colon cancer
cells.
PMID- 10783319
TI - Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA
damage in human blood mononuclear cells.
AB - Polymorphisms in several DNA repair genes have recently been identified, but
little is known about their phenotypic significance. To determine whether
variation in DNA repair genes is related to host DNA damage, we studied the
association between polymorphisms in XRCC1 (codon 399) and ERCC2 (codon 751) and
two markers of DNA damage, sister chromatid exchange (SCE) frequencies (n = 76)
and polyphenol DNA adducts (n = 61). SCE frequencies were determined using a
modified fluorescence-Giemsa method and polyphenol DNA adducts were determined
using a P1-enhanced (32)P-post-labeling procedure. XRCC1 and ERCC2 genotypes were
identified using PCR-RFLP. Mean SCE frequencies among current smokers who were
homozygous carriers of the 399Gln allele in XRCC1 were greater than those in
399Arg/Arg current smokers. We also observed a possible gene-dosage effect for
XRCC1 399Gln and detectable DNA adducts, and significantly more adducts among
older subjects who were carriers of the 399Gln allele than in younger subjects
with the 399Arg/Arg genotype. The polymorphism in ERCC2 was unrelated to SCE
frequency or DNA adduct level. Our results suggest that carriers of the
polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age
related DNA damage.
PMID- 10783320
TI - The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine
formation, and stimulates apoptosis in mucosa during early colonic inflammation
in rats.
AB - As we have shown previously [Tardieu,D., Jaeg,J.P., Cadet,J., Embvani,E.,
Corpet,D.E. and Petit,C. (1998) Cancer Lett, 134, 1-5], a 48-h treatment of 6%
dextran sodium sulphate (DSS) in drinking water led to a reproducible 2-fold
increase of the mutagenic oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8
oxodGuo) in colonic mucosa DNA of rats in vivo. The aim of this study was to test
the effect of nimesulide, a preferential COX-2 inhibitor, on the DSS-induced 8
oxodGuo increase. We show that nimesulide when administered orally,
simultaneously with DSS at 5 mg/kg/day, not only totally prevents 8-oxodGuo
formation but also suppresses the 5-fold increase of superoxide induced by DSS in
the colonic mucosa. This was measured by in vivo formazan blue precipitation (P <
0.01 in the Wilcoxon test). Moreover, nimesulide enhances apoptosis by
approximately 30% as compared with the already high level induced by DSS
treatment (P < 0.01). It is suggested that the significant increase in mutagenic
oxidative DNA damage, produced by mild acute colonic inflammation, could be
important in the initiation of colon cancer in both animals and man. These
effects may explain at least partly the well-documented protective action towards
colon cancer by preferential COX-2 inhibitors, either xenobiotics such as
nimesulide or natural nutrients.
PMID- 10783321
TI - Chemoprevention of tobacco-smoke lung carcinogenesis in mice after cessation of
smoke exposure.
AB - Male strain A/J mice were exposed for 6 h per day, 5 days per week to a mixture
of 89% cigarette sidestream smoke and 11% mainstream smoke. Total suspended
particulate concentrations were 137 mg/m(3). In experiment 1, animals were
exposed for 5 months to tobacco smoke and given a 4 month recovery period in air.
Lung tumor multiplicity was 2.4 and incidence 89%. Animals exposed to filtered
air had 1.0 tumor per lung (65% incidence). In animals kept for 5 months in
smoke, removed into air and then fed a diet containing a mixture of myoinositol
and dexamethasone, tumor multiplicity was 1.0 and incidence was 62%. These values
were significantly (P < 0.01) lower than in animals exposed to smoke and
identical to values seen in controls. In animals fed a diet containing 250 mg/kg
each of phenethyl isothiocyanate and benzyl isothiocyanate during the entire 9
months, lung tumor multiplicity was 2.1 and incidence 96%, not significantly
different from animals exposed to smoke and fed control diet. In experiment 2,
animals were exposed for 5 months to smoke, followed by a 4 month recovery period
in air and were fed during the entire period a diet containing either D-limonene
or 1, 4-phenylenebis(methylene)selenoisocyanate (p-XSC). In animals exposed to
tobacco smoke and fed control diet, lung tumor multiplicity was 2.8, whereas in
the animals fed D-limonene it was 2. 6 and in the animals fed p-XSC it was 2.4.
The differences to the controls were statistically not significant. It was
concluded that myoinositol-dexamethasone successfully prevents the development of
tobacco smoke-induced lung tumors even if administered when the animals have
'quit' smoking. On the other hand, agents otherwise shown to prevent lung tumor
formation following administration of 4-(methylnitrosamino)-1-(3-pyridyl)-1
butanone or benzo[a]pyrene were ineffective against tobacco smoke.
PMID- 10783322
TI - Dietary choline restriction causes complex I dysfunction and increased H(2)O(2)
generation in liver mitochondria.
AB - Removal of choline from the diet results in accumulation of triglycerides in the
liver, and chronic dietary deficiency produces a non-genotoxic model of
hepatocellular carcinoma. An early event in choline deficiency is the appearance
of oxidized lipid, DNA and protein, suggesting that increased oxidative stress
may facilitate neoplasia in the choline deficient liver. In this study, we find
that mitochondria isolated from rats fed a choline-deficient, L-amino acid
defined diet (CDAA) demonstrate impaired respiratory function, particularly in
regard to complex I-linked (NADH-dependent) respiration. This impairment in
mitochondrial electron transport occurs coincidentally with alterations in
phosphatidylcholine metabolism as indicated by an increased ratio of long-chain
to short-chain mitochondrial phosphatidylcholine. Moreover, hydrogen peroxide
(H(2)O(2)) generation is significantly increased in mitochondria isolated from
CDAA rats compared with mitochondrial from normal rats, and the NADH-specific
yield of H(2)O(2) is increased by at least 2.5-fold. These findings suggest an
explanation for the rapid onset of oxidative stress and energy compromise in the
choline deficiency model of hepatocellular carcinoma and indicate that dietary
choline withdrawal may be a useful paradigm for the study of mitochondrial
pathophysiology in carcinogenesis.
PMID- 10783323
TI - One-electron oxidation is not a major route of metabolic activation and DNA
binding for the carcinogen 7H-dibenzo[c,g]carbazole in vitro and in mouse liver
and lung.
AB - 7H-Dibenzo[c,g]carbazole (DBC) is a potent multi-site, multi-species carcinogen
present in a variety of complex mixtures derived from the incomplete combustion
of organic matter. Like many carcinogens, DBC requires metabolic activation to an
electrophilic species to exert its mutagenic and carcinogenic effects. One
electron oxidation, leading to the formation of radical cation intermediates, has
been proposed as a mechanism of metabolic activation for DBC in vitro resulting
in unstable DNA adducts. The purpose of this research was to determine whether
one-electron oxidation is a mechanism of activation and DNA binding for DBC in
vivo. Specific depurinating DBC-DNA adducts formed by one-electron oxidation were
analyzed in mouse liver at 4 h following a single i.p. dose of 40 mg/kg of 11
microCi [(14)C]DBC. In addition to five previously published adduct standards,
two newly identified adduct standards were characterized by mass spectrometry and
NMR, namely DBC-6-N7-Ade and DBC-6-N1-Ade; however, neither was observed in mouse
liver. Only the DBC-5-N7-Gua adduct was observed in mouse liver extracts at a
level of 6.5 +/- 1. 8 adducts/10(6) nucleotides. In addition, the formation of AP
sites and stable DBC-DNA adducts was analyzed in mouse liver and lung at 4, 12
and 24 h following a single i.p. dose of 0.4, 4 or 40 mg/kg DBC (n = 3/group).
There was a distinct time- and dose-response of stable DBC-DNA adducts detected
by (32)P-post-labeling. There was not a clear dose-response for formation of AP
sites; however, a significant increase over control levels was observed at the 4
and 40 mg/kg dose groups at 4 and 12 h post dosing, respectively. Quantitative
comparisons indicate that the depurinating DBC-5-N7-Gua adduct constitutes
approximately 0.4% of total adducts measured whereas the stable adducts detected
by (32)P-post-labeling constitute 99.6% of total adducts measured following a 40
mg/kg dose and a 4 h time-point. The data indicate that one-electron oxidation
does occur in mouse liver in vivo. However, one-electron oxidation is a minor
mechanism of activation in that the percentage of total adducts formed through
this route constitutes a minor percentage of the total adducts formed.
PMID- 10783324
TI - The effect of lithocholic acid on proliferation and apoptosis during the early
stages of colon carcinogenesis: differential effect on apoptosis in the presence
of a colon carcinogen.
AB - Lithocholic acid (LCA) is implicated in human and experimental animal
carcinogenesis. Its effect on apoptosis and proliferation of the colonic
epithelium was studied in a 1,2-dimethylhydrazine (DMH)-induced murine
carcinogenesis model. Four groups of mice, control, LCA, DMH and DMH+LCA, were
studied for 4 weeks, a period corresponding to early stages of carcinogenesis.
Apoptosis (AI) and proliferation (PI) indices in the colon were determined by
immunohistochemistry. LCA stimulated apoptosis [AI = 1.2 +/- 0.3% (all values are
the mean +/- SEM) versus control 0.5 +/- 0.1%, P < 0. 05], as did DMH (4.3 +/-
0.8%, P < 0.02). DMH increased apoptosis at the base of the crypt nearly 50-fold,
with no effect at the lumenal third. In mice receiving DMH, LCA suppressed
apoptosis almost completely (0.1 +/- 0.03%); this suppression was complete at the
lower two-thirds of the crypt (AI = 0) and 60% at the lumenal third. LCA
increased proliferation (PI = 22.2 +/- 4.6% versus 15.4 +/- 1% in controls), but
this did not reach statistical significance. DMH increased proliferation (PI =
34.6 +/- 2.3%, P < 0.01). In mice receiving DMH, proliferation (41 +/- 2.9%) was
about two-thirds of the additive effect. LCA affected proliferation, mainly in
the middle third of the crypt; DMH's effect was similar in distribution, but more
pronounced. In mice receiving DMH, LCA shifts proliferation upward, extending it
to the lumenal third of the crypt. LCA's main cell kinetic effect in the colon is
on apoptosis; this effect differs in normal (stimulation) and pre-malignant colon
(nearly complete suppression). LCA does not significantly stimulate proliferation
in either normal or pre-malignant colon. The differential effect of LCA on
apoptosis in the presence of a carcinogen partially explains its effect as a
promoter on colon carcinogenesis in animal models, and may have important
implications for human carcinogenesis.
PMID- 10783325
TI - Exploring the relationship between the inhibition of gap junctional intercellular
communication and other biological phenomena.
AB - The mechanistic relationship of the inhibition of gap junctional intercellular
communication (GJIC) to other toxicological phenomena was explored using a
recently developed method that models the properties of a large population of
molecules chosen to represent the 'universe of chemicals'. The analyses indicate
that inhibition of GJIC is strongly linked to the carcinogenic process in
rodents, to cellular but not systemic toxicity, to biological phenomena that may
involve inflammatory processes and to development effects. The inhibition of GJIC
appears not to be associated with genotoxic mechanisms. With respect to cancer
causation, integration of the analyses suggests that inhibition of GJIC is
involved in non-genotoxic cancer induction or in the non-genotoxic phases of the
carcinogenic process (such as inflammation, cell toxicity, cell proliferation,
inhibition of cell differentiation and apoptosis).
PMID- 10783327
TI - Modulation of base excision repair by low density lipoprotein, oxidized low
density lipoprotein and antioxidants in mouse monocytes.
AB - In the present study, we found that oxidized low density lipoprotein, but not low
density lipoprotein, down-regulated base excision repair activity in extracts of
mouse monocyte cell line PU5-1.8. An enzyme required in this pathway, DNA
polymerase beta, was also down-regulated. In contrast, treatment of monocytes
with a combination of ascorbate and alpha-tocopherol up-regulated base excision
repair activity and expression of DNA polymerase beta. Co-treatment of monocytes
with antioxidants plus oxidized low density lipoprotein prevented down-regulation
by oxidized low density lipoprotein. Oxidative DNA damage, as measured by 8
hydroxyguanine accumulation in genomic DNA, was found in cells treated with
oxidized low density lipoprotein; 8-hydroxyguanine was not found in the cells
treated with low density lipoprotein, antioxidants or oxidized low density
lipoprotein plus antioxidants. These results establish a linkage between the DNA
base excision repair pathway, oxidative DNA damage and oxidized low density
lipoprotein treatment in mouse monocytes. Since oxidized low density lipoprotein
is implicated in chronic disease conditions such as atherogenesis, these findings
facilitate understanding of genetic toxicology mechanisms related to human health
and disease.
PMID- 10783326
TI - Induction of murine intestinal and hepatic peroxiredoxin MSP23 by dietary
butylated hydroxyanisole.
AB - Feeding mice with 2(3)-t-butyl-4-hydroxyanisole (BHA) induces phase II
detoxifying enzymes that inhibit the action of carcinogens. We have found that
dietary BHA induces intestinal and hepatic MSP23 (also called peroxiredoxin I), a
stress-inducible antioxidant, in a manner similar to the induction of glutathione
S-transferases (GSTs). The levels of MSP23 in the proximal intestine and liver,
estimated by immunoblotting, increased approximately 1.9- and 1.3-fold,
respectively, in mice fed a diet containing 0.7% (w/w) BHA for 7 days. The level
of MSP23 mRNA in these tissues also increased more than 2-fold after mice were
fed BHA, suggesting that the induction of MSP23 is controlled at the
transcription level. Immunostaining of the small intestine shows that MSP23 is
expressed mainly in the columnar epithelial cells. The induction of MSP23 may be
important to protect the cells and tissues against toxic electrophiles and
reactive oxygen species.
PMID- 10783328
TI - mRNA expression patterns in different stages of asbestos-induced carcinogenesis
in rats.
AB - Human malignant mesotheliomas are induced almost exclusively by fibrous dusts.
The nature of interactions between fibers and target cells, and the molecular
mechanisms leading to tumorigenesis, are not yet understood. Here, the mRNA
expression patterns at different stages of asbestos-induced carcinogenesis in
rats were monitored by suppression subtractive hybridization (SSH) and array
assay. Several genes were upregulated in pretumorous tissues from asbestos
treated rats, in asbestos-induced tumors and in cells treated with asbestos in
vitro. The upregulation of the proto-oncogene c-myc, fra-1 and egfr in fiber
induced carcinogenesis was demonstrated at different stages of carcinogenesis. A
possible role of Fra-1 as one of the dimeric proteins generating the AP-1
transcription factor was substantiated by its dose-dependent expression in
mesothelial cells treated with asbestos in vitro. The upregulation of osteopontin
(an extracellular matrix protein) and of zyxin and integrin-linked kinase
(intracellular proteins associated with the focal adhesion contact), indicate
that fibers may affect integrin-linked signal transduction and extracellular
matrix proteins.
PMID- 10783329
TI - Suprabasal expression of the human papillomavirus type 16 oncoproteins in mouse
epidermis alters expression of cell cycle regulatory proteins.
AB - Human papillomavirus (HPV) survives by reactivating DNA replication in post
mitotic cells. In the present study, we describe a mouse model of HPV-dependent
disease. In these mice, DNA synthesis is activated in suprabasal keratinocytes,
leading to acanthosis, parakeratosis and enhanced desquamation. The full-length
E6/E7 transcript and two alternately spliced products are produced and in most
lines the predominant product is E6*. In the present study, we examine the
effects of E6/E7 on cell cycle regulatory protein expression. E6/E7 expression in
mouse epidermis is correlated with increased levels of the p53, p21, p27, cdk2,
cdk4, cdk6, cyclin D1 and cyclin E regulatory proteins. Hyperproliferation is
also observed in the buccal mucosa and the tongue epithelia of E6/E7 mice, and
p53 levels are markedly increased in these epithelia. These results suggest that
the major changes in cell cycle regulatory protein expression are in response to
the presence of E7 and that E6 has a lesser impact.
PMID- 10783330
TI - Rapid induction of uterine tumors with p53 point mutations in heterozygous p53
deficient CBA mice given a single intraperitoneal administration of N-ethyl-N
nitrosourea.
AB - To investigate the sensitivity of heterozygous p53-deficient CBA mice to
carcinogens, 20 female mice [p53(+/-)] and 20 wild-type littermates [p53(+/+)]
were given an intraperitoneal injection of 120 mg/kg body wt of N-ethyl-N
nitrosourea (ENU) and were maintained without any other treatment for a further
26 weeks. Histopathology showed that uterine tumors (endometrial polyps and
stromal sarcomas) and lung adenomas were induced in both p53(+/-) and p53(+/+)
mice. The incidence of uterine tumors and lung adenomas (94% and 81%,
respectively) in p53(+/-) mice was significantly greater than that in p53 (+/+)
mice (37% and 42%, respectively). Malignant lymphomas were only induced in p53(+/
) mice, at an incidence of 31%. Concerning uterine tumors and preneoplastic
lesions, there were endometrial stromal sarcomas and atypical hyperplasias of the
endometrial gland in 90% and 63%, respectively, of p53(+/-) mice, with
significantly greater incidences than in p53(+/+) mice. Gene analysis revealed
GCG-->GTG point mutations in codon 135 of exon 5 of the p53 allele in all of the
uterine endometrial stromal sarcomas examined. Our results suggest that female
p53(+/-) CBA mice are very susceptible to uterine carcinogenesis, providing a
useful model for ENU-induced uterine tumors.
PMID- 10783331
TI - Radiation-induced mammary tumors in virgin and parous rats administered
contraceptive steroids, 17alpha-ethinylestradiol and norethisterone.
AB - Oral contraceptives are used among women worldwide, and radiation is being used
increasingly for diagnosis or therapy. We have investigated the effects of
contraceptive steroids on the risk of mammary tumors initiated by radiation.
Virgin rats received whole-body irradiation with 2.6 Gy gamma-rays 1 month after
the administration of low- or high-dose pellets of contraceptive steroids, such
as 17alpha-ethinylestradiol (EE(2)) combined with 19-norethisterone (NET). The
high-dose pellet was removed 1 month after irradiation, but administration of the
low-dose pellet was continued for up to 1 year. The incidence (33.3%) of mammary
tumors initiated with radiation was not modified by the long-term administration
of the low-dose pellets. However, the incidence (58. 3%) was increased
significantly by the irradiation during administration of the high-dose pellets,
but no significant difference in the proportion of adenocarcinoma and
fibroadenoma was observed. Meanwhile, parous rats were irradiated with 2.6 Gy
gamma-rays at weaning, a period of greater susceptibility to radiation, and then
were implanted with the low-dose pellets 1 month later. The highest incidence
(90%) of mammary tumors was detected in the parous rats. The proportion of
adenocarcinomas in the parous irradiated rats increased significantly on
treatment with the low-dose pellets. The results suggest that administration of
the high-dose pellets of EE(2)-NET, but not of the low-dose pellets, enhances
susceptibility to the initiation by gamma-rays of mammary tumors in virgin rats,
and that the low-dose pellets act as a tumor promoter in the mammary glands of
parous rats irradiated at weaning.
PMID- 10783332
TI - Cadmium mutagenicity and human nucleotide excision repair protein XPA: CD, EXAFS
and (1)H/(15)N-NMR spectroscopic studies on the zinc(II)- and cadmium(II)
associated minimal DNA-binding domain (M98-F219).
AB - Human XPA is a 31 kDa protein involved in nucleotide excision repair (NER), a
ubiquitous, multi-enzyme pathway responsible for processing multiple types of DNA
damage in the eukaryotic genome. A zinc-associated, C4-type motif (C105-X(2)-C108
X(17)-C126-X(2)-C129) located in the minimal DNA-binding region (M98-F219) of XPA
(XPA-MBD) is essential for damaged DNA recognition. Cadmium is a known carcinogen
and can displace the zinc in many metal-binding proteins. It has been suggested
that the carcinogenic properties of cadmium may result from structural changes
effected in XPA when Cd(2+) is substituted for Zn(2+) in the metal-binding site.
The solution structure of XPA-MBD containing zinc(II) has recently been
determined [Buchko et al., (1998) Nucleic Acids Res., 26, 2779-2788; Buchko et
al., (1999) Biochemistry, 38, 15116-15128]. To assess the effects of cadmium(II)
substitution on the structure of XPA-MBD, XPA-MBD was expressed in minimal medium
supplemented with cadmium acetate to yield a protein that was almost exclusively
(>95%) associated with cadmium(II) (CdXPA-MBD). Extended X-ray absorption fine
structure spectra collected on ZnXPA-MBD and CdXPA-MBD in frozen (77 K) 15%
aqueous glycerol solution show that the metal is coordinated to the sulfur atoms
of four cysteine residues with an average metal-sulfur bond length of 2.34 +/-
0.01 and 2.54 +/- 0.01 A, respectively. Comparison of the circular dichroism, two
dimensional (1)H,(15)N-HSQC, and three-dimensional (15)N-edited HSQC-NOESY
spectra of ZnXPA-MBD and CdXPA-MBD show that there are no structural differences
between the two proteins. The absence of major structural changes upon
substituting cadmium(II) for zinc(II) in XPA suggests that cadmium-induced
mutagenesis is probably not due to structural perturbations to the zinc-binding
core of XPA.
PMID- 10783333
TI - Oxidative DNA damage in fetal tissues after transplacental exposure to 3'-azido
3'-deoxythymidine (AZT).
AB - The nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) has been used
successfully to reduce the incidence of transplacental and perinatal transmission
of the HIV virus. However, prolonged treatment with high doses of AZT is utilized
in this therapy, and AZT has been found to be a perinatal carcinogen in mice. Any
possible perinatal carcinogenic side effects in the human can best be managed if
the mechanism is understood. AZT targets mitochondria and might cause increased
intracellular production of reactive oxygen species (ROS). We tested whether
transplacental AZT may cause oxidative damage in nuclear DNA of fetal tissues. CD
1 Swiss pregnant mice were treated with the transplacental carcinogenesis regimen
(25 mg/day AZT, for gestation days 12-18) and tissues collected on the day of
birth. Significant increases in 8-oxo-2'-deoxyguano- sine (8-oxo-dG) were found
in the livers, a target tissue for transplacental carcinogenesis, and in the
kidneys. A non-significant increase occurred in brain, with no change in lung.
Tissues were also obtained from fetal patas monkeys (Erythrocebus patas), whose
mothers had received 10 mg AZT/day during the last half of gestation. Although
limited numbers of samples were available, possible increases in 8-oxo-dG were
noted, relative to controls, for placenta and for fetal lung and brain (P = 0.055
for treatment-related increases in these tissues). These results suggest that an
increase in reactive oxygen species could contribute to the mechanism of
transplacental carcinogenesis by AZT in mice, and that this may also occur in
primates.
PMID- 10783334
TI - Expression of PGF(2alpha) receptor mRNA in normal, hyperplastic and neoplastic
skin.
AB - Reverse transcription polymerase chain reaction (RT-PCR) and Northern blot
analysis was used to determine the level of expression of prostaglandin F(2alpha)
(FP) receptor mRNA in various mouse tissues, including normal, hyperplastic and
neoplastic mouse epidermis. Steady-state concentrations of FP receptor mRNA were
low in normal and hyperplastic epidermis. The response of the epidermis to the
phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was biphasic in that FP
receptor mRNA was increased immediately after treatment, followed by a long
lasting down-regulation at later time points. FP receptor mRNA was down-regulated
in the majority of papillomas obtained by the mouse skin carcinogenesis
initiation-promotion protocol. In carcinomas, FP receptor mRNA expression was
similar to that in normal epidermis. The steady-state concentration of FP mRNA
was inversely correlated with PGF(2alpha) levels in normal and hyperplastic
epidermis and in papillomas, indicating that FP mRNA expression is regulated by
this eicosanoid.
PMID- 10783336
TI - Resignation
PMID- 10783335
TI - Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions:
further insights into the role for oxidative stress in Fanconi's anaemia
phenotype.
AB - Evidence for redox-dependent toxicities of mitomycin C (MMC) and diepoxybutane
(DEB), through different mechanisms, has been related to the phenotypic defect(s)
of Fanconi's anaemia (FA) cells, due to their excess sensitivity to these agents.
Recent data have pointed to interactions of the FANCC protein (encoded by the FA
complementation group C gene, FA-C) with NADPH cytochrome P450 reductase and
glutathione S-transferase (GST), two activities involved in either triggering or
detoxifying reactive intermediates, including xenobiotics and reactive oxygen
species. A body of evidence points to: (i) oxygen hypersensitivity of FA cells;
(ii) oxygen-dependent MMC and DEB toxicity; (iii) excess oxidative DNA damage in
FA cells; and (iv) DEB-induced glutathione depletion and GST inhibition. The
available evidence corroborates the previously suggested role for oxidative
stress in FA phenotype and disease progression, shedding new light on the redox
dependent mechanisms in MMC and DEB toxicities, and suggesting a direct
association of oxidative stress with the primary genetic defect in FA.
PMID- 10783337
TI - In appreciation of professor R.G.Edwards, founding editor of the human
reproduction journals
PMID- 10783338
TI - What are the ownership rights for gametes and embryos? Advance directives and the
disposition of cryopreserved gametes and embryos.
PMID- 10783339
TI - Gender reassignment and assisted reproduction. Evaluation of multiple aspects.
PMID- 10783340
TI - Alternative sources of gametes: reality or science fiction?
AB - Although great progress has been made in both the investigation and treatment of
infertility, a considerable number of patients still fail to conceive.
Spermatogenic failure and/or oocyte ageing appear to be responsible for a large
proportion of cases. The use of donor gametes may bring legal, ethical and even
social problems of acceptance that can discourage infertile couples from the
donor route. Fortunately, emerging reproductive technologies and preliminary
results from animal experiments provide some hope for alternative sources of
gametes through which these infertile patients can finally conceive their own
genetic child. In conjunction with intracytoplasmic sperm injection (ICSI),
fertilization of human oocytes with immature sperm precursors, e.g. spermatids
and even secondary spermatocytes, has resulted in healthy babies. Pregnancies
have also resulted from the use of spermatids derived from in-vitro
spermatogenesis. In the mouse, even primary spermatocytes appear able to
participate in normal embryogenesis. In view of the possibility for
transplantation and even xenotransplantation of spermatogonia to a host testis in
animals, a similar use of human male stem cells might provide an attractive
source for the treatment of males with arrested spermatogenesis, as well as male
cancer patients. Transplantation of somatic cell nuclei and their haploidization
within oocytes may prove to be a practical way of eradicating age-related
aneuploidy and so constitute an innovative source of healthy oocytes. Most
importantly, however, the safety of the procedures described here needs to be
proven before their application to the human arena. Finally, we discuss the
implications of cytoplasmic quality and of genetic imprinting in the context of
these manipulations.
PMID- 10783341
TI - Empty follicle syndrome: evidence for recurrence.
AB - The empty follicle syndrome (EFS) is a frustrating condition in which no oocytes
are retrieved in an IVF cycle. Although this is an infrequent event in IVF
patients, the economic consequences as well as the emotional frustration of a
cancelled cycle due to the inability to obtain oocytes are enormous. The
mechanisms responsible for EFS remain obscure, though many hypotheses have been
put forward ranging from dysfunctional folliculogenesis to a drug-related
problem. We found that the EFS is a rare event (1.8% of oocyte retrievals) but
with profound implications for counselling the couple about their future
reproductive performance. The chances of recurrence of EFS increase with the age
of the patient (24% recurrence rate for the 35-39 year age group, and 57% for
those over 40 years). We postulate that ovarian ageing, through altered
folliculogenesis, may be implicated in the aetiology of EFS and its recurrence.
PMID- 10783342
TI - Increased risk of early pregnancy loss by profound suppression of luteinizing
hormone during ovarian stimulation in normogonadotrophic women undergoing
assisted reproduction.
AB - The impact of suppressed concentrations of circulating luteinizing hormone (LH)
during ovarian stimulation on the outcome of in-vitro fertilization or
intracytoplasmic sperm injection treatment in 200 consecutive, normogonadotrophic
women (couples) was analysed retrospectively. A standard stimulation protocol
with mid-luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation
and ovarian stimulation with recombinant follicle stimulating hormone (FSH) was
used in all cases. Blood was sampled from each woman on stimulation days 1 and 8
for analysis of oestradiol and LH in serum. A threshold value of serum LH of 0.5
IU/l on stimulation day 8 (S8) was chosen to discriminate between women with low
or 'normal' LH concentrations. Low concentrations of LH on S8 (<0.5 IU/l) were
found in 49% (98/200) of the women. This group of women was comparable with the
normal LH group with regard to pre-treatment clinical parameters, and to the
parameters characterizing the stimulation protocol with the exception of serum
oestradiol concentration, which on S8 was significantly lower than in the normal
LH group (P < 0.001). The proportion of positive pregnancy tests was similar in
the two groups (30% versus 34% per started cycle), but the final clinical
treatment outcome was significantly different, with a five-fold higher risk of
early pregnancy loss (45% versus 9%; P < 0.005) in the low LH group and
consequently a significantly poorer chance of delivery than in the normal LH
group. It is concluded that a substantial proportion of normogonadotrophic women
treated with GnRH agonist down-regulation in combination with FSH, devoid of LH
activity, experience LH suppression, which compromises the treatment outcome.
Whether these women would benefit from supplementation with recombinant LH or
human menopausal gonadotrophin during ovarian stimulation, remains to be proven
in the future by prospective randomized trials.
PMID- 10783343
TI - Consequences on gonadotrophin secretion of an early discontinuation of
gonadotrophin-releasing hormone agonist administration in short-term protocol for
in-vitro fertilization.
AB - Administration of gonadotrophin-releasing hormone (GnRHa) agonists, used in IVF
short-term protocols to initiate follicular recruitment, may be restricted to the
early follicular phase without any further risk of LH surge. However,
consequences of an early discontinuation upon residual endogenous gonadotrophin
secretion are still unknown. Here, the effects of early cessation of GnRH agonist
upon gonadotrophin secretion and ovarian parameters of IVF cycles were
investigated. A total of 230 normo-ovulatory women were prospectively allocated
to one of the two regimens: decapeptyl-GnRH (100 microgram) was daily injected
either from day 1 to the triggering of ovulation (group 1) or for the first 7
days (group 2). Exogenous gonadotrophins (150 IU) were administered on day 4 and
5 with a subsequent adjustment. Detections of free alpha subunit and dimeric LH
were performed by highly specific 'two site' monoclonal immunoradiometric assays.
The results show that early discontinuation of GnRH agonist administration was
associated with a sharp decrease in both plasma free alpha subunit and dimeric LH
concentrations while plasma oestradiol response to exogenous gonadotrophins was
reduced. Other ovarian parameters and pregnancy rate were unchanged. These data
indicate that endogenous LH secretion is maintained by a daily administration of
GnRH agonist and may contribute to the final follicular maturation.
PMID- 10783344
TI - Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle
administration of the GnRH antagonist cetrorelix according to the multiple dose
protocol: a prospective uncontrolled phase III study.
AB - A total of 346 women with normal ovulatory function was stimulated with human
menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or
intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle
day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective
multiple dose of 0. 25 mg/day, was administered daily until induction of
ovulation. In total, 333 patients (96.2%) reached the day of HCG administration,
and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was
applied for a mean of 10.4 days. Cetrorelix was administered for a mean time
lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group
and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an
ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical
implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH)
(>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed
after initiation of Cetrorelix administration, reflecting an incidence of
premature luteinization of 0.9%. The abortion rate was 17%. The incidence of
severe ovarian hyperstimulation syndrome (World Health Organization grade III)
was as low as 0.6%.
PMID- 10783345
TI - Induction of ovulation in women undergoing assisted reproductive techniques:
recombinant human FSH (follitropin alpha) versus highly purified urinary FSH
(urofollitropin HP).
AB - This multicentre, open, randomized, study compared the efficacy and safety of
recombinant follicle stimulating hormone (rFSH; follitropin alpha) with highly
purified urinary human FSH (uFSH; urofollitropin HP) in women undergoing
ovulation induction for assisted reproductive techniques. Following long down
regulation with buserelin, patients received two ampoules of 75 IU (150 IU) s.c.
rFSH or highly purified uFSH for 6 days, after which the dose could be increased
until they fulfilled the criteria for human chorionic gonadotrophin (HCG)
administration. Of 168 patients recruited, 155 received at least one dose of FSH,
and 137 received HCG [68: rFSH (85%); 69: uFSH (92%)]. Following oocyte retrieval
and fertilization, up to three embryos were replaced/patient and luteal support
was given. The mean number of oocytes retrieved/patient was 10.2 +/- 6.0 for rFSH
patients compared with 10.8 +/- 6.1 in the uFSH group (not significant). There
was a trend towards fewer ampoules used (22.3 +/- 6.5 versus 24.3 +/- 6.5),
higher pregnancy (44.3 versus 41.4%) and live birth rates (33.8 versus 26.7%), as
well as a lower miscarriage rate (0.0 versus 16.7%) in favour of rFSH. However,
no significant differences in efficacy parameters were recorded. Ovarian
hyperstimulation syndrome occurred in 8.6% and 7.9% of rFSH and uFSH patients
respectively. In conclusion, this protocol was effective in inducing multiple
follicular development and high numbers of oocytes were retrieved with both
drugs.
PMID- 10783346
TI - Safety and efficacy of oestriol for symptoms of natural or surgically induced
menopause.
AB - To assess the safety and efficacy of oestriol in relieving post-menopausal
symptoms 53 post-menopausal Japanese women with climacteric symptoms, 27 with
natural menopause (group I) and 26 with surgically induced menopause (group II),
received oral oestriol, 2 mg daily for 12 months. Clinical parameters including
Kupperman index (KI) and the degree of satisfaction with symptomatic relief;
serum concentrations of oestradiol, FSH and LH; serum lipids; blood pressure;
bone mineral density, serum calcium (Ca), alkaline phosphatase (ALP), and urinary
Ca were compared between the two groups. Oestriol improved KI in groups I and II
by 49 and 80% respectively. Satisfaction with treatment was 85% in group I and
93% in group II. For both parameters, values were significantly different between
groups I and II (P < 0.05 for both). Serum concentrations of oestradiol, FSH and
LH changed in group I versus group II 6 months after initiation. A significant
decrease in serum ALP and Ca/Cr was observed in group I at 6 months. Except for
serum triglycerides, oestriol had no significant effect on lipids. Systolic and
diastolic blood pressures were significantly decreased in group I at 3 months
versus baseline. Slight vaginal bleeding occurred in 14.3% of group I.
Histological evaluation of the endometrium in all women of group I and ultrasound
assessment of the breasts following 12 months of oestriol treatment found normal
results in all women. Therefore, oestriol appeared to be safe and effective in
relieving symptoms of menopausal women. The beneficial biochemical effects of
oestriol were marked in the natural menopause. Overall, oestriol may serve as a
good choice for hormone replacement therapy to protect against other climacteric
symptoms in post-menopausal women who do not need medication for osteoporosis or
coronary artery disease.
PMID- 10783347
TI - Value of serum and follicular fluid cytokine profile in the prediction of
moderate to severe ovarian hyperstimulation syndrome.
AB - The aim of this study was to examine the role of serum and follicular fluid pro
inflammatory cytokines and vascular endothelial growth factor (VEGF) in the
prediction of ovarian hyperstimulation syndrome (OHSS). A total of 156
consecutive women undergoing in-vitro fertilization were recruited. The study
group comprised 12 women who subsequently developed moderate (n = 7) or severe (n
= 5) OHSS. The two control groups were comprised of a randomized selection of 12
high-risk and 12 low-risk women in whom OHSS did not develop. Serum was collected
on days of human chorionic gonadotrophin, oocyte retrieval, and embryo transfer.
Serum and follicular fluid concentrations of interleukin (IL)-6, IL-8, tumour
necrosis factor-alpha (TNF-alpha), and VEGF were measured. Follicular fluid IL-6
concentrations at the time of oocyte retrieval and serum IL-8 concentrations at
the time of embryo transfer were significantly higher in the OHSS compared to the
two control groups (P = 0.026 and P = 0.017 respectively). Serum concentrations
of TNF-alpha and VEGF showed no statistically significant difference between the
OHSS group and the controls at any studied time point. This study suggests that
follicular fluid IL-6 concentrations at the time of oocyte retrieval and serum IL
8 concentrations on the day of embryo transfer may serve as early predictors for
this syndrome.
PMID- 10783349
TI - Ovarian antibodies, FSH and inhibin B: independent markers associated with
unexplained infertility.
AB - Premature menopause and unexplained infertility are associated with ovarian
antibodies, a marker of ovarian autoimmunity. In premature menopause, FSH is also
elevated while in unexplained infertility FSH concentrations are often normal.
The relationship of ovarian antibodies and FSH and inhibin B, as markers of
follicle function, was investigated in unexplained infertility. Ovarian
antibodies were determined by immunoassay in comparison to normal controls (n =
12); 51.9% were positive at two SD (P < 0.05) and 38.5% were positive at three SD
above the control mean (P < 0.01). In this study three SD above the control mean
was considered positive. In unexplained infertility, three out of 10 (30%) had
elevated day 3 FSH (>10 mIU/ml) and ovarian antibodies, while 17/42 (40%) had
normal FSH (<10 mIU/ml) and ovarian antibodies. In women with normal FSH, two out
of seven (29%) had low inhibin B concentrations (<33 pg/ml) and ovarian
antibodies, and 15/35 (43%) had normal inhibin B concentrations (> 33 pg/ml) and
ovarian antibodies. Similarly, when women with and without ovarian antibodies
were compared there was no difference in mean FSH or mean inhibin B
concentrations. Thus, unlike other endocrine autoimmune disorders, hormone
concentrations are not predictors of potential ovarian autoimmunity. This
suggests that in unexplained infertility ovarian antibodies are an independent
marker of potential ovarian failure, and may precede changes in regulatory
hormones.
PMID- 10783348
TI - Hyperreactio luteinalis despite the absence of a corpus luteum and suppressed
serum follicle stimulating concentrations in a triplet pregnancy.
AB - Hyperreactio luteinalis is characterized by moderate to marked cystic enlargement
of the ovaries related to multiple theca lutein cysts and is associated with very
high sex steroid concentrations. It is a rare condition especially in the first
trimester. The case described below is believed to be the only case of
hyperreactio luteinalis reported following frozen embryo transfer. This case
provides an opportunity to gain further insight into the mechanism responsible
for this unusual condition. The 30 year old woman demonstrated a slightly
elevated LH/FSH ratio (5 and 3 mIU/ml respectively) and normal baseline androgen
concentrations. Two years following oocyte retrieval she had a second frozen
embryo transfer. The ovaries were normal size when the embryos were transferred
and androgens were still normal. The ovaries did not begin to enlarge until 51
days from transfer. A dichorionic intrauterine pregnancy with monozygotic twins
in the left gestational sac was seen. Eventually, 86 days from transfer, the
ovaries enlarged to 145x103x116 mm right; and 83x95x117 mm left. Serum oestradiol
was 30 078 pg/ml, beta-human chorionic gonadotrophin (HCG) 239 920 mIU/ml, serum
progesterone >160 ng/ml, total testosterone 2254 ng/dl, free testosterone 42.3
pg/ml and androstenedione 7328 ng/dl. Throughout the first trimester, serum FSH
was <1 mIU/ml. Thus, neither FSH nor a corpus luteum is necessary to initiate
this syndrome.
PMID- 10783350
TI - Changes in serum inhibin, activin and follistatin concentrations during puberty
in girls.
AB - Serum concentrations of inhibin A, inhibin B, activin A and follistatin were
determined using two-site enzyme-linked immunosorbent assays (ELISA) during
pubertal ovarian development in 28 girls and five follicular phase women. Blood
obtained every 15 to 20 min overnight was pooled for peptide determination. Serum
inhibin A concentrations increased in mid puberty, exhibiting positive
correlations with bone age (r = 0.527, P = 0.0016) and oestradiol concentrations
(r = 0.581, P = 0.0005). Inhibin B concentrations peaked in mid puberty and
declined thereafter, but remained greater than concentrations seen in prepubertal
girls, and correlating positively with oestradiol (r = 0.362, P = 0.046) and
follicle stimulating hormone (FSH) concentrations (r = 0.369, P = 0.038). Total
activin A concentrations did not vary significantly across pubertal stages. Total
follistatin concentrations, determined by radioimmunoassay, decreased with
advancing puberty, exhibiting negative correlations with bone age (r = -0.634, P
= 0.0001) and oestradiol concentration (r = -0.687, P = 0.0001). Follistatin
concentrations determined by an ELISA specific for follistatin 288 were greatest
in mid-pubertal girls, but concentrations in late puberty were less than those in
early puberty. The free follistatin assay indicated that all circulating
follistatin was activin-bound. These results suggest that significant changes in
serum concentrations of FSH-regulatory peptides accompany the onset of puberty.
PMID- 10783351
TI - A tale of two syndromes: ovarian hyperstimulation and abdominal compartment.
AB - Abdominal compartment syndrome complicated severe ovarian hyperstimulation in a
35 year old woman with multiple bowel resections due to Crohn's disease. Pain
from ovarian enlargement necessitated hospital admission. Despite intravenous
fluid administration and heparin prophylaxis, ilio-femoral deep vein thrombosis
developed. Treatment by intravenous heparin was complicated by repeated intra
ovarian bleeding, anaemia and acute renal failure requiring haemodialysis. Intra
abdominal pressures were elevated. After placement of an inferior vena caval
filter and discontinuation of heparin, there was slow spontaneous recovery
without surgery.
PMID- 10783352
TI - Transfer of zona-free embryos improves outcome in poor prognosis patients: a
prospective randomized controlled study.
AB - Assisted zona hatching (AZH) has been used in IVF programmes for several years.
Recently one group has reported successful pregnancies after transfer of zona
free blastocysts. The aim of our study was to evaluate outcomes after transfer of
zona-free day 3 embryos. Two groups of women undergoing intracytoplasmic sperm
injection (ICSI) were included in the study. Group A consisted of 52 women under
the age of 40 years undergoing their first ICSI attempt. They were alternately
randomized to receive zona-free embryos (27 women) and zona-intact embryos (25
women). The second group (group B) included 71 women with a poor prognosis, as
defined by age 40 years or more, and/or at least two previous failed IVF/ICSI
attempts. They were randomized in a 3:4 ratio (30 zona-free, 41 zona-intact).
Acid Tyrode's solution was used to remove the zona pellucida before embryo
transfer on day 3 after oocyte collection. The pregnancy rate in group A was not
significantly improved when the zona pellucida was removed. However, in the poor
prognosis group B, zona removal resulted in a significantly higher pregnancy rate
when compared with controls (23 versus 7.3%). We conclude that complete removal
of the zona pellucida can improve pregnancy rates in women with poor IVF/ICSI
prognosis.
PMID- 10783353
TI - External validation of the templeton model for predicting success after IVF.
AB - This study aimed to externally validate the prognostic model presented by
Templeton in 1996 for live births resulting from IVF treatment. Data were used
from the University Hospital, Nijmegen, The Netherlands, from March 1991 to
January 1999. The predictive capacity of the model in our population
discriminated between those women with a low probability of success and those
with a relatively high probability. Despite these encouraging findings, our data
show that implementation of the model in clinical decision-making remains
difficult. The Templeton model is not applicable or usable in daily clinical
practice, because the model did not give more information about the prognosis for
the vast majority of the patients. Therefore, the search for better prognostic
factors resulting in better predictive models should continue.
PMID- 10783354
TI - Non-homogeneous hyperechogenic pattern 3 days after embryo transfer is associated
with lower pregnancy rates.
AB - The purpose of this study was to investigate the relationship between mid-luteal
phase echo patterns and IVF-embryo transfer outcome in women who have
demonstrated adequate endometrial development by the late proliferative phase. A
prospective study was carried out of 86 patients undergoing IVF-embryo transfer
and 86 patients undergoing frozen embryo transfer who all underwent sonographic
monitoring of the endometrium 3 days after embryo transfer. The cycles were
classified into two groups: those with the homogeneous hyperechogenic (HH)
pattern and those without it. The women who had an HH pattern had higher clinical
pregnancy (32.8 versus 10.7%, P < 0.05) and implantation rates in stimulated
cycles (14.3 versus 4.1%, P < 0.05 respectively) than those that did not. There
was no significant difference in the clinical pregnancy or implantation rates by
echo pattern (18.2 and 8.1% for non-HH and 18. 7 and 8.0% for HH respectively) in
frozen embryo transfer cycles. These data demonstrate that in embryo transfer
cycles where ovarian stimulation was used, there were decreased pregnancy and
implantation rates in cycles where the HH pattern was not observed 3 days after
transfer. The failure of the endometrium to display this pattern may indicate
some endometrial abnormality resulting in implantation defects.
PMID- 10783355
TI - Fifteen years experience with an in-vitro fertilization surrogate gestational
pregnancy programme.
AB - The purpose of our study was to review and evaluate retrospectively the
experience of an in-vitro fertilization (IVF) surrogate gestational programme in
a tertiary care and academic centre. In a 15 year period from 1984 to 1999, a
total of 180 cycles of IVF surrogate gestational pregnancy was started in 112
couples. On average, the women were 34.4 +/- 4.4 years of age, had 11.1 +/- 0.72
oocytes obtained per retrieval, 7.1 +/- 0.5 oocytes fertilized and 5. 8 +/- 0.4
embryos subsequently cleaved. Sixteen cycles (8.9%) were cancelled due to poor
stimulation. Except for six cycles (3.3%) where there were no embryos available,
an average of 3.2 +/- 0.1 embryos was transferred to each individual recipient.
The overall pregnancy rate per cycle after IVF surrogacy was 24% (38 of 158),
with a clinical pregnancy rate of 19% (30 of 158), and a live birth rate of 15.8%
(25 of 158). When compared to patients who underwent a hysterectomy, individuals
with congenital absence of the uterus had significantly more oocytes retrieved (P
< 0.006), fertilized, cleaved and more embryos available for transfer despite
being of comparable age. IVF surrogate gestation is an established, yet still
controversial, approach to the care of infertile couples. Take-home baby rates
are comparable to conventional IVF over the same 15 year span in our programme.
Patients with congenital absence of the uterus responded to ovulation induction
better than patients who underwent a hysterectomy, perhaps due in part to ovarian
compromise from previous surgical procedures.
PMID- 10783356
TI - The value of Chlamydia trachomatis antibody testing as part of routine
infertility investigations.
AB - Laparoscopy is considered the gold standard for the evaluation of tubal disease
but it is an invasive and costly procedure. Chlamydia trachomatis antibody
testing is simple and inexpensive and causes minimal inconvenience to the
patient. Using the micro-immunofluorescence technique we assessed the
significance of positive serology. There was a marked association between the
titre and the likelihood of tubal damage. In the group with low titres (1 in 32)
there was only a 5% incidence of tubal damage; however, there was a progressive
increase in the incidence of tubal damage in those with higher titres. Twenty out
of 57 patients with titres higher than 1 in 32 had tubal damage (35%). The
difference between the two groups was statistically significant (P < 0.0001,
chi(2) test). By using C. trachomatis antibody testing more widely it may be
possible to reduce the number of laparoscopies performed. It should therefore
become an integral part of the fertility work-up.
PMID- 10783357
TI - Transmissions of hepatitis C virus during the ancillary procedures for assisted
conception.
AB - Since mother to child transmissions of hepatitis C virus (HCV) have been reported
to be low, teams involved in assisted reproductive technologies have accepted HCV
positive patients into their programmes. We report in the present paper two cases
of undoubted patient to patient HCV transmission while patients were attending
for assisted conception. In both cases, HCV genotyping and sequencing of the
first hypervariable region of the HCV genome provided molecular evidence for
nosocomial transmission. Investigations made to elucidate the route of
contamination have shown that the most likely route of contamination is through
healthcare workers. Such nosocomial HCV infection has been reported in other
healthcare situations, mainly in dialysis units, and physical proximity was also
suspected to be at the origin of the infection. We conclude that assisted
reproduction teams must be very prudent when including such patients in their
programmes.
PMID- 10783358
TI - The measurement of endometrial perfusion in norplant users: a pilot study.
AB - The use of progestogens without oestrogen is commonly associated with irregular
menstrual bleeding. Oestrogens and progestogens are both thought to influence
endometrial perfusion; changes in endometrial perfusion may contribute to
vascular fragility and breakdown. In this study, endometrial perfusion was
measured using laser-Doppler fluxmetry in women in the secretory phase of the
menstrual cycle before and 4-6 weeks after insertion of the low-dose long-acting
levonorgestrel contraceptive implant system, Norplant. Endometrial perfusion was
also measured in women exposed to Norplant for up to 19 months. There was no
significant difference between endometrial perfusion in control cycles (27.2 flux
units +/- 5.5, SEM) and at 4-6 weeks after Norplant insertion (16.3 flux units +/
5.0), a time when irregular bleeding and spotting are common. Endometrial
perfusion was no different from controls after longer periods of Norplant
exposure (35.7 flux units +/- 7.2). No direct relationships between endometrial
perfusion and plasma concentrations of ovarian steroid hormones were
demonstrated. Short-term endometrial vasomotion was largely abolished during
Norplant exposure.
PMID- 10783360
TI - Circulating concentrations of the antiprogestins CDB-2914 and mifepristone in the
female rhesus monkey following various routes of administration.
AB - The overall aim of these studies was to investigate the oral and i.m.
bioavailability of CDB-2914 in intact female rhesus monkeys, and to compare the
serum concentrations of CDB-2914 with that of mifepristone following oral
administration. In the first study, a 50 mg bolus of CDB-2914 per monkey was
administered intravenously, orally or intramuscularly. The area under the serum
concentration-time curve for 72 h (AUC(0-72)) following i.v. injection was 18 320
+/- 2718 ng/ml*h, and that for oral administration was 10 464 +/- 3248 ng/ml*h.
Thus, the oral bioavailability of CDB-2914 equivalents was 56%. The AUC(0-168 h)
following i.m. injection was 11 226 +/- 1130 ng/ml*h. Therefore, the i.m.
bioavailability of CDB-2914 equivalents was 62%. In the second study, the serum
concentrations of CDB-2914 and mifepristone equivalents were compared following
an oral bolus dose in two different formulations. When administered at 5 mg/kg in
aqueous suspending vehicle (ASV), the mean peak serum concentration (C(max)) of
CDB-2914 equivalents (192 +/- 64 ng/ml) occurred at 5 +/- 1 h, whereas the C(max)
of mifepristone equivalents (82 +/- 25 ng/ml) occurred at 3 +/- 1 h. Following
administration in gelatin capsules (35 mg/monkey), the C(max) of CDB-2914
equivalents (129 +/- 24 ng/ml) occurred at 5 +/- 1 h, while the C(max) of
mifepristone equivalents (31 +/- 8 ng/ml) occurred at 3 +/- 1 h. The serum
concentration (AUC(0-120 h)) of CDB-2914 equivalents was 4.7- or 5. 3-fold
greater than that of mifepristone equivalents when administered orally in ASV or
gelatin capsules respectively. The serum protein binding characteristics of CDB
2914 were also studied. CDB-2914 bound to human alpha(1)-acid glycoprotein (AAG),
but not with as high an affinity as mifepristone. In contrast, neither CDB-2914
nor mifepristone bound with high affinity to AAG, corticosteroid binding globulin
or sex hormone binding globulin in monkey serum. Collectively, these results
indicated that CDB-2914 was more efficiently absorbed than mifepristone following
oral administration to female rhesus monkeys.
PMID- 10783359
TI - A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits
folliculogenesis and endometrial differentiation in normally cycling women.
AB - Previous studies in women have shown that the antiprogestin mifepristone delays
or inhibits folliculogenesis. The purpose of this study was to explore whether a
new analogue, CDB-2914, has similar effects on folliculogenesis, ovulation, or on
subsequent luteal phase endometrial maturation. Forty-four normally cycling,
healthy women recorded urine LH and vaginal bleeding during pre-treatment,
treatment, and post-treatment cycles. At a lead follicle diameter of 14-16 mm, a
single oral dose (10, 50, 100 mg) of CDB-2914 or placebo was given, and daily
ultrasound, oestradiol and progesterone were obtained until follicular collapse;
an endometrial biopsy was obtained 5-7 days later. Single doses of CDB-2914 were
well tolerated. Mid-follicular CDB-2914 suppressed lead follicle growth, causing
a dose-dependent delay in folliculogenesis and suppression of plasma oestradiol.
At higher doses, a new lead follicle was often recruited. Although luteinized
unruptured follicles were observed at the 100 mg dose, all women had follicular
collapse. There was a significant delay in endometrial maturation after CDB-2914
at all doses. The treatment cycle was lengthened by 1-2 weeks in 30% at 100, 27%
at 50 and 9% at 10 mg. CDB-2914 altered ovarian and endometrial physiology
without major effects on menstrual cyclicity and may have therapeutic utility.
PMID- 10783361
TI - Analysis of chromosomal abnormalities in human spermatozoa using multi-colour
fluorescence in-situ hybridization.
AB - There is concern that intracytoplasmic sperm injection (ICSI) may lead to
offspring with a high frequency of chromosomal abnormalities. Accordingly, we
studied spermatozoa sampled from eight infertile men with
oligoasthenoteratozoospermia (OAT) by multi-colour fluorescence in-situ
hybridization (FISH), using DNA probes for chromosomes 13, 18, 21, X and Y.
Results were compared with those of spermatozoa sampled from 10 healthy men with
normal semen profiles. Analysis of the diploidy values was repeated twice in each
of the 18 men. There was no significant difference in the two diploidy estimates;
thus the FISH technique appeared to be accurate and reliable for determining
aneuploidy in human spermatozoa. We found the average frequencies of disomy for
chromosomes 13, 18, 21 and X or Y to be 0.13, 0.12, 0.24 and 0.59% respectively
for the OAT group and 0.09, 0.13, 0.19 and 0.38% respectively for the control
group. The diploidy rate was 0.29% in the OAT group, and 0.16% in the control
group. Thus, the OAT group showed a significantly higher frequency of disomy for
chromosomes 13 (P < 0.001), 21 (P < 0.05), sex (P < 0.001), and diploidy (P <
0.005) than the control group. This finding suggests there may be some risk of
aneuploidy in the offspring conceived by the ICSI technique.
PMID- 10783362
TI - The use of two density gradient centrifugation techniques and the swim-up method
to separate spermatozoa with chromatin and nuclear DNA anomalies.
AB - Human semen is heterogeneous in quality, not only between males but also within a
single ejaculate. Differences in quality are evident, both when examining the
classical parameters of sperm number, motility and morphology and in the
integrity of the sperm nucleus. The aim of this study was to determine the
efficiency of the PureSperm((R)), Percoll((R)) and swim-up preparation techniques
to eliminate spermatozoa with nuclear anomalies. Semen samples were collected,
washed and one part of the semen spread on a slide, the remainder was prepared
using the swim-up, PureSperm((R)) or Percoll((R)) techniques. Spermatozoa from
different fractions were fixed on slides and assessed. Sperm samples (n) from
different men were stained using the chromomycin A(3) (CMA(3)) fluorochrome,
which indirectly demonstrates a decreased presence of protamine (n = 31 for swim
up; n = 45 for PureSperm((R)); n = 39 for Percoll((R))). Spermatozoa prepared
using PureSperm((R)) (n = 35) and Percoll((R)) (n = 37) were also examined for
the presence of endogenous DNA nicks. Good quality spermatozoa should not possess
DNA nicks and not stain (i.e. fluoresce) with CMA(3). When prepared using the
swim-up technique the spermatozoa recovered showed no significant improvement
with the CMA(3) staining. When spermatozoa were prepared using the PureSperm((R))
and Percoll((R)) techniques, a significant (P < 0.001) decrease in both CMA(3)
positivity and DNA strand breakage was observed. These results indicate that both
the PureSperm((R)) and Percoll((R)) techniques can enrich the sperm population by
separating out those with nicked DNA and with poorly condensed chromatin.
PMID- 10783363
TI - Enhancement of zona binding using 2-hydroxypropyl- beta-cyclodextrin.
AB - Since membrane cholesterol depletion is known to play an important role in sperm
capacitation, we have investigated the effect of 2-hydroxypropyl-beta
cyclodextrin, a cyclic oligosaccharide that mediates cholesterol efflux, on sperm
functions. Sperm treatment with cyclodextrin did not affect the motility patterns
but induced an increase in sperm binding to zona pellucida (24 +/- 5 versus 13 +/
4 in control, P < 0.01). Cyclodextrin treatment was associated with an increase
in spontaneous acrosome reaction (32 +/- 8% versus 22 +/- 4% in controls after a
4 h incubation, P < 0.05; 61 +/- 10% versus 50 +/- 11% in controls after a 24 h
incubation, NS) but with a decrease in acrosome response to ionophore challenge
(44 +/- 5% versus 51 +/- 3% in controls, P < 0.05). Concerning cell sterols,
cyclodextrin induced a rapid and dramatic fall in the cholesterol and desmosterol
content of spermatozoa. We conclude that cyclodextrin is a powerful capacitating
agent, but since it induces an increase in spontaneous acrosome loss, it needs to
be further evaluated before routine use in assisted reproductive technology
media.
PMID- 10783364
TI - Chromosome analysis of spermatozoa extracted from testes of men with non
obstructive azoospermia.
AB - Infertile men with azoospermia now have the possibility of fathering children by
testicular sperm extraction combined with intracytoplasmic sperm injection.
However, there are concerns about the risk of chromosomal abnormalities in their
spermatozoa. We have studied aneuploidy frequencies for chromosomes 13, 21, X and
Y by multicolour fluorescence in-situ hybridization (FISH) in testicular
spermatozoa extracted from three men with non-obstructive azoospermia. The men
were 34-37 years of age and had normal follicle-stimulating hormone (FSH)
concentrations and normal 46,XY somatic karyotypes. A total of 3324 spermatozoa
was analysed. The infertile patients had an elevated frequency of disomy for
chromosomes 13, 21, XY disomy compared to controls but none of these reached
statistical significance. Also there was no significant difference in the sex
ratio or the frequency of diploidy in azoospermic patients compared to normal
control donors. This first report on chromosomal aneuploidy in spermatozoa
extracted from testes of patients with non-obstructive azoospermia suggests that
some azoospermic men do not have a substantially increased risk of chromosomally
abnormal spermatozoa.
PMID- 10783365
TI - The effect of extracellular ice and cryoprotective agents on the water
permeability parameters of human sperm plasma membrane during freezing.
AB - A firm biophysical basis for the cryopreservation of human spermatozoa is limited
by a lack of knowledge regarding the water permeability characteristics during
freezing in the presence of extracellular ice and cryoprotective agents (CPA).
Cryomicroscopy cannot be used to measure dehydration during freezing in human
spermatozoa because of their highly non-spherical shape and their small
dimensions which are at the limits of light microscopic resolution. Using a new
shape-independent differential scanning calorimeter (DSC) technique, volumetric
shrinkage during freezing of human sperm cell suspensions was obtained at cooling
rates of 5 and 10 degrees C/min in the presence of extracellular ice and CPA.
Using previously published data, the human sperm cell was modelled as a cylinder
of length 40.2 micrometer and a radius of 0.42 micrometer with an osmotically
inactive cell volume, V(b), of 0.23V(o), where V(o) is the isotonic cell volume.
By fitting a model of water transport to the experimentally obtained volumetric
shrinkage data, the best fit membrane permeability parameters (L(pg) and E(Lp))
were determined. The 'combined best fit' membrane permeability parameters at 5
and 10 degrees C/min for human sperm cells in modified media are: L(pg) = 2.
4x10(-14) m(3)/Ns (0.14 micrometer/min-atm) and E(Lp) = 357.7 kJ/mol (85. 5
kcal/mol) (R(2) = 0.98), and in CPA media (with 6% glycerol and 10% egg yolk) are
L(pg)[cpa] = 0.67x10(-14) m(3)/Ns (0.04 micrometer/min-atm) and E(Lp)[cpa] =
138.9 kJ/mol (33.2 kcal/mol) (R(2) = 0.98). These parameters are significantly
different from previously published parameters for human spermatozoa obtained at
suprazero temperatures and at subzero temperatures in the absence of
extracellular ice. The parameters obtained in this study also suggest that
damaging intracellular ice formation (IIF) could occur in human sperm cells at
cooling rates as low as 25-45 degrees C/min, depending on the concentrations of
the CPA. This may help to explain the discrepancy between the empirically
determined optimal cryopreservation cooling rates (<100 degrees C/min) and the
numerically predicted optimal cooling rates (>7000 degrees C/min) obtained using
previously published suprazero human sperm permeability parameters which do not
account for the presence of extracellular ice.
PMID- 10783366
TI - Chromosome analysis of human spermatozoa from an oligoasthenozoospermic carrier
for a 13;14 Robertsonian translocation by their injection into mouse oocytes.
AB - We present a case of a 46,XY der(13;14) Robertsonian translocation carrier whose
spermatozoa were karyotyped after injection into mouse oocytes. Fresh semen
samples as well as recovered samples were used. There was no significant
difference in the survival rate of mouse oocytes (fresh: 78.1% versus frozen:
81.7%), activation rate (fresh: 84.0% versus frozen: 90.6%), fertilization rate
(fresh: 72.0% versus thawing of frozen: 76.5%) between fresh or frozen
spermatozoa. Metaphase chromosome spreads from 45 spermatozoa were analysed. The
frequency of spermatozoa that were chromosomally unbalanced with respect to the
translocation was 8.9%, and the frequency of abnormalities unrelated to
translocation was 4.4%. An excess of spermatozoa with balanced chromosomes was
observed: compared with normal, 23 (51.1%) versus 16 (35.6%) respectively; but
this segregation difference was not statistically significant (chi(2) = 0.9, P >
0.3). After genetic counselling with the carrier and his partner,
intracytoplasmic sperm injection treatment was performed. Healthy female and male
infants were delivered at 36 weeks gestation via a Caesarean section. Both babies
were carriers for the balanced Robertsonian translocations detected for prenatal
diagnosis at 16 weeks gestation. The present study demonstrates that patients can
be given further information about the proportion of the spermatozoa which carry
a chromosomal abnormality.
PMID- 10783367
TI - Effect of recombinant human gonadotrophins on human, bovine and murine oocyte
meiosis, fertilization and embryonic development in vitro.
AB - The response of murine, bovine and human oocytes to pure recombinant preparations
of human follicle stimulating hormone (rFSH) and luteinizing hormone (rLH) for
meiotic maturation and subsequent developmental competence in vitro were examined
in the present experiments. Maturation of immature bovine oocytes to the
metaphase II stage was significantly increased by the addition of 1 IU/ml of rFSH
in combination with either 1 IU/ml rLH or 10 IU/ml rLH. Similarly, embryonic
development to the blastocyst stage was improved in bovine oocytes treated with a
1:10 combination of rFSH:rLH. However, no significant difference was observed in
the number of inner cell mass or trophectoderm cells of the resulting
blastocysts. Although the increased maturation to metaphase II was not
significant, human embryonic developmental competence was improved by maturing
oocytes in the presence of a 1:10 ratio of rFSH:rLH as only those oocytes exposed
to a 1:10 ratio of rFSH: rLH during maturation showed normal cleavage patterns
beyond day 2. In addition, 1 IU/ml rFSH and 1 IU/ml rLH increased the expression
of oocyte proteins in human oocytes. The inclusion of recombinant gonadotrophins,
either singly or in combination, had no significant effect on the maturation,
fertilization or embryonic development of in-vitro matured mouse oocytes. These
data provide support for the responsiveness of human and bovine oocytes to
gonadotrophins in vitro and the need to consider variations in the relative
concentrations for optimization of oocyte developmental competence.
PMID- 10783368
TI - Chemically and mechanically induced membrane fusion: non-activating methods for
nuclear transfer in mature human oocytes.
AB - Most current studies of nuclear transfer in mammalian oocytes have used
electrofusion to incorporate donor cell nuclei into enucleated oocyte cytoplasts.
However, the application of electrofusion to human oocytes is hampered by the
relative ease with which this procedure induces oocyte activation. Here we tested
a previously described chemical fusion technique and an original mechanical
fusion procedure in this application. Enucleated metaphase II oocytes were first
agglutinated with karyoplasts originating from other metaphase II oocytes and
then induced to fuse with the use of polyethylene glycol or by micromanipulation
with an intracytoplasmic sperm injection (ICSI) micropipette. Both techniques
yielded a high frequency of fusion and did not cause oocyte activation. Moreover,
the reconstructed oocytes were easily activated by subsequent treatment with
ionophore A23187 and 6-dimethylaminopurine. These techniques may be used in
attempts to alleviate female infertility due to insufficiency of ooplasmic
factors by nuclear transfer from patients' oocytes to enucleated donor oocyte
cytoplasts. For eventual future use in human cloning, they would ensure prolonged
exposure of transferred nuclei to metaphase promoting factor, which appears to be
required for optimal nuclear reprogramming.
PMID- 10783369
TI - Hyaluronan in the nuchal skin of chromosomally abnormal fetuses.
AB - Nuchal skin oedema at 10-14 weeks gestation, observed by ultrasonography as
increased nuchal translucency (NT), is found in approximately 70% of fetuses with
trisomies 21, 18 and 13 as well as those with Turner's syndrome. This study
investigates the possibility that one mechanism for increased translucency is an
altered composition of the skin with a higher concentration of hyaluronan; large
amounts of hyaluronan can lead to excessive hydration of the extracellular
matrix. We isolated the hyaluronic acid binding region (HABR) from aggrecan in
the extracellular matrix of hyaline cartilage and used it in a biotinylated form
in combination with a fluorescent probe as a marker for hyaluronan.
Immunohistochemistry was then used to examine the nuchal skin of chromosomally
abnormal and normal fetuses, obtained after termination of pregnancy. In fetuses
with trisomy 21 there was a substantial increase in hyaluronan, whereas in
trisomies 18 and 13 and Turner's syndrome the amount was similar to that in
chromosomally normal controls. This finding suggests that hyaluronan may be
implicated in the pathogenesis of increased NT in fetuses with trisomy 21, but
the common phenotypic expression of increased translucency in different
chromosomal abnormalities may be the consequence of other mechanisms.
PMID- 10783370
TI - Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation:
efficacy and acceptability.
AB - Misoprostol and mifepristone have been shown to be effective for medical abortion
up to 9 weeks of gestation. When used alone, the successful complete abortion
rate dropped to approximately 60%. It has been demonstrated that by adding water
to misoprostol, the success rate rose to 92%. This is the first randomized study
to investigate the efficacy of misoprostol and water versus misoprostol alone for
first trimester medical abortion in women at /=11 microg/L) was 90% and specificity 61%. The proportion of
false-negative results (10%) was independent of symptom duration. Age, positive
ECG findings, and increased admission TnI levels were predictive for in-hospital
mortality. CONCLUSION: The commonly available biochemical and ECG criteria allow
risk stratification of patients with a suspected acute ischemic event. The data
analysis can easily be automated and is independent of patient delay.
PMID- 10783403
TI - Atomized lidocaine as topical anesthesia for nasogastric tube placement: A
randomized, double-blind, placebo-controlled trial.
AB - STUDY OBJECTIVE: To evaluate the efficacy of topical atomized 4% lidocaine in
reducing the pain associated with nasogastric tube (NGT) placement. METHODS: This
prospective, randomized, double-blind, placebo-controlled trial was conducted in
the emergency department of a university teaching hospital. Study participants
were alert, hemodynamically stable adult patients requiring NGT placement for
diagnostic or therapeutic purposes. Atomized 4% lidocaine or normal saline
solution was administered in the nasopharynx and oropharynx before NGT placement.
All patients also received topical 2% lidocaine jelly intranasally after
atomization. The pain of NGT placement was measured using a standard 100-mm
visual analog scale. RESULTS: A total of 40 patients were enrolled in the study,
with 20 in the lidocaine group and 20 in the placebo group. Mean pain scores were
37.4 mm (95% confidence interval [CI] 25.4 to 49.4) for atomized lidocaine and
64.5 mm (95% CI 51.8 to 77.1) for placebo with a mean difference of 27.1 mm (95%
CI 14.8 to 39.4), achieving both clinical and statistical significance.
CONCLUSION: Atomized nasopharyngeal and oropharyngeal 4% lidocaine results in
clinically and statistically significant reductions in pain during NGT placement.
PMID- 10783404
TI - Determinants of patient satisfaction and willingness to return with emergency
care.
AB - STUDY OBJECTIVE: To identify emergency department process of care measures that
are significantly associated with satisfaction and willingness to return.
METHODS: Patient satisfaction and willingness to return at 5 urban, teaching
hospital EDs were assessed. Baseline questionnaire, chart review, and 10-day
follow-up telephone interviews were performed, and 38 process of care measures
and 30 patient characteristic were collected for each respondent. Overall
satisfaction was modeled with ordinal logistic regression. Willingness to return
was modeled with logistic regression. RESULTS: During a 1-month study period,
2,899 (84% of eligible) on-site questionnaires were completed. Telephone
interviews were completed by 2,333 patients (80% of patients who completed a
questionnaire). Patient-reported problems that were highly correlated with
satisfaction included help not received when needed (odds ratio [OR] 0.345; 95%
confidence interval [CI] 0.261 to 0.456), poor explanation of causes of problem
(OR 0.434; 95% CI 0.345 to 0.546), not told about potential wait time (OR 0.479;
95% CI 0.399 to 0.577), not told when to resume normal activities (OR 0.691; 95%
CI 0.531 to 0.901), poor explanation of test results (OR 0.647; 95% CI 0.495 to
0.845), and not told when to return to the ED (OR 0.656; 95% CI 0. 494 to 0.871).
Other process of care measures correlated with satisfaction include nonacute
triage status (OR 0.701, 95% CI 0.578 to 0.851) and number of treatments in the
ED (OR 1.164 per treatment; 95% CI 1.073 to 1.263). Patient characteristics that
significantly predicted less satisfaction included younger age and black race.
Determinants of willingness to return include poor explanation of causes of
problem (OR 0.328; 95% CI 0.217 to 0.495), unable to leave a message for family
(OR 0.391; 95% CI 0.226 to 0. 677), not told about potential wait time (OR 0.561;
95% CI 0.381 to 0.825), poor explanation of test results (OR 0.541; 95% CI 0.347
to 0.846), and help not received when needed (OR 0.537; 95% CI 0.340 to 0.846).
Patients with a chief complaint of hand laceration were less willing to return
compared with a reference population of patients with abdominal pain. Willingness
to return is strongly predicted by overall satisfaction (OR 2.601; 95% CI 2.292
to 2.951). CONCLUSION: These data identify specific process of care measures that
are determinants of patient satisfaction and willingness to return. Efforts to
increase patient satisfaction and willingness to return should focus on improving
ED performance on these identified process measures.
PMID- 10783405
TI - Gastric lavage for liquid poisons.
AB - STUDY OBJECTIVE: This study was conducted to determine whether gastric lavage
reduces the absorption of ingested liquids. METHODS: The study design was a
randomized controlled human volunteer crossover study in 10 subjects. On 2
separate occasions 2 weeks apart, the volunteers ingested a solution of 4.0 g of
acetaminophen in 60 mL of water. Eight blood specimens were obtained over the
initial 8 hours for determination of serum acetaminophen concentrations, which
were used to calculate routine pharmacokinetic parameters. One hour after 1 drug
ingestion, gastric lavage was performed through a 34-F orogastric tube. Serum
acetaminophen concentrations were measured by high-performance liquid
chromatography and a 2-tailed t test was used for statistical analysis. RESULTS:
The mean values for area under the concentration curve (+/-SD) for the control
and gastric lavage groups were 195+/-31 and 154+/-52 mg/L.hour, respectively (P
<.05). The mean reduction in acetaminophen bioavailability because of gastric
lavage was 20%+/-28% (95% confidence interval 3 to 37). CONCLUSION: In this
experimental model for the ingestion of liquids, gastric lavage at 1 hour
resulted in a significant decrease in the mean serum bioavailability of
acetaminophen. Nonetheless, this treatment effect is unlikely to be of clinical
value because of its modest extent, unreliable performance, and the availability
of a more effective, less risky alternative, activated charcoal.
PMID- 10783406
TI - Poisoning mortality in the United States: comparison of national mortality
statistics and poison control center reports.
AB - STUDY OBJECTIVE: To determine whether the distributions of age and poisoning
categories for poisoning deaths are similar in death certificates as compiled by
the National Center for Health Statistics (NCHS) and US poison control centers as
reported by the Toxic Exposure Surveillance System (TESS). METHODS: Data from
both databases for 1994 were examined. Mortality data from NCHS were identified
by applicable E-codes of the International Classification of Diseases-ninth
revision (ICD-9). All fatalities described in the TESS report were coded to
conform to the ICD-9 system. RESULTS: A total of 16,527 poisoning deaths were
recorded by NCHS; 766 deaths were reported by TESS. For NCHS and TESS,
respectively, the age distribution of unintentional drug poisonings (N=7,823;
155) and unintentional non-drug poisonings (N=1,234; 102) differed (P <.001),
whereas those for intentional poisonings (N=5,320; 413) did not differ
significantly. In the NCHS and TESS data sets, respectively, the relative
distribution of death circumstances differed (P <.001) for unintentional drug
poisonings (47% versus 20%), unintentional non-drug poisonings (8% versus 14%),
intentional poisonings (32% versus 54%), and unknown or other circumstances (13%
versus 12%). The distributions of poisoning circumstances and age categories were
dependent on the data source (P <.001). There was no statistical agreement
between the data sets in rankings of the 12 most frequent ICD-9 codes and toxins
associated with poisoning deaths. CONCLUSION: Deaths reported in TESS represent
5% of the poisoning deaths tabulated by NCHS. Differences observed in the 2 data
sets may lead to differing health policies to address poisoning hazards.
PMID- 10783407
TI - Chest pain centers: diagnosis of acute coronary syndromes.
AB - Chest pain centers in the emergency department have generally been accepted as a
safe, cost-effective, and rapid approach to the evaluation, triage, and
management of patients with potential acute coronary syndromes. These centers
were initially designed to enhance patient care by decreasing time to treatment
for acute myocardial infarction (AMI) and rapidly identifying patients with
unstable angina. They also included community outreach and educational objectives
designed to reduce time from the onset of chest pain to ED presentation. In the
past decade, health care financial constraints have created additional impetus to
the development of chest pain centers. Cost reduction efforts have occurred to
reduce hospitalizations, lengths of stay, and unnecessary treatments and
procedures. Practitioners and administrators try to balance these goals with the
imperative to provide high-quality patient care. Protocol-driven approaches have
been developed for specific disease processes in emergency settings. The chest
pain center concept is such an approach for patients with chest pain. Chest pain
is the second most common ED presenting complaint and is a symptom related to the
leading cause of death in the United States, coronary artery disease (CAD). One
third of ED patients with chest pain will eventually have a diagnosis of acute
coronary syndrome. Many patients with acute coronary syndromes have atypical
presentations that are not diagnosed in the ED with the traditional diagnostic
evaluation of a history, physical examination, and 12-lead ECG. If they are not
admitted to the hospital for further evaluation, the diagnosis may be missed. The
2% to 5% of AMI patients who are inadvertently released home often have poor
outcomes and result in a leading cause of malpractice suits in emergency
medicine. More than one half of ED patients with chest pain have clinical
findings after their initial evaluation consistent with acute coronary syndromes
and are admitted to the hospital. Approximately one half of these patients, after
evaluation in the hospital, are found not to have acute coronary syndromes. The
cost for these negative inpatient cardiac evaluations has been estimated to be $6
billion in the United States each year. Today, chest pain centers serve as an
integral component of many EDs. Their success and safety is the result of a
focused, protocol-driven approach directed at the acute coronary syndrome
continuum from unstable angina to transmural Q-wave myocardial infarction. New
therapies for acute coronary syndromes make ED triage and risk stratification
increasingly important. Although different chest pain center protocols have
proved effective, all address the diagnosis and rapid treatment of acute
myocardial necrosis, rest ischemia, and exercise-induced ischemia. Identifying
patients with coronary artery disease in one of these stages in the spectrum of
myocardial ischemia is the foundation for a successful chest pain center in the
ED.
PMID- 10783408
TI - National Heart Attack Alert Program position paper: chest pain centers and
programs for the evaluation of acute cardiac ischemia.
AB - The National Heart Attack Alert Program (NHAAP), which is coordinated by the
National Heart, Lung, and Blood Institute (NHLBI), promotes the early detection
and optimal treatment of patients with acute myocardial infarction and other
acute coronary ischemic syndromes. The NHAAP, having observed the development and
growth of chest pain centers in emergency departments with special interest,
created a task force to evaluate such centers and make recommendations pertaining
to the management of patients with acute cardiac ischemia. This position paper
offers recommendations to assist emergency physicians in EDs, including those
with chest pain centers, in providing comprehensive care for patients with acute
cardiac ischemia.
PMID- 10783409
TI - Cardiac arrest and the role of thrombolytic agents.
AB - Thrombolytic agents may have clinically significant beneficial effects in cardiac
arrest. The application of thrombolytic drugs in the setting of current and
antecedent cardiopulmonary resuscitation is well documented; however, it has not
been systematically studied nor has it been widely considered. We provide a
literature review of thrombolytic agents and cardiopulmonary resuscitation to
discuss the need for randomized controlled trials and the possibility of benefits
in acute resuscitation.
PMID- 10783410
TI - Report of the Task Force on Residency Training Information (1999-2000), American
Board of Emergency Medicine.
AB - The American Board of Emergency Medicine gathers extensive background information
on emergency medicine residents and the programs in which they train. We present
the third annual report on the status of US emergency medicine residency
programs. [American Board of Emergency Medicine. Report of the Task Force on
Residency Training Information (1999-2000), American Board of Emergency Medicine.
Ann Emerg Med. May 2000;35:481-498.]
PMID- 10783411
TI - Emergency department customer satisfaction: the point of view paradox.
PMID- 10783412
TI - Tissue plasminogen activator in pediatric myocardial infarction.
AB - Children rarely present to emergency physicians during an acute myocardial
infarction. However, this may occur in the setting of Kawasaki disease with
thrombosed coronary aneurysms. We present the first case in which intravenous
tissue plasminogen activator was used to successfully treat a 7-year-old child
having an acute myocardial infarction caused by a thrombosed coronary aneurysm.
PMID- 10783413
TI - Geographic variation in penicillin resistance in Streptococcus pneumoniae:
selected sites, United States, 1997.
PMID- 10783414
TI - Are we, as physicians, entitled to our frame of reference?
PMID- 10783415
TI - Small-dose inhaled nitric oxide and pulmonary embolism.
PMID- 10783416
TI - Small-dose inhaled nitric oxide and pulmonary embolism
PMID- 10783417
TI - Harmonization of data collection on poisonings.
PMID- 10783418
TI - Meeting the SAEM ultrasound guidelines. Society for Academic Emergency Medicine.
PMID- 10783419
TI - Clinical policy: critical issues in the evaluation and management of adult
patients presenting with suspected acute myocardial infarction or unstable
angina. American College of Emergency Physicians.
AB - This clinical policy focuses on critical issues in the evaluation and management
of patients with acute myocardial infarction or unstable angina. A MEDLINE search
for articles published between January 1993 and December 1998 was performed using
combinations of the key words chest pain, acute myocardial infarction, unstable
angina, thrombolytics, primary angioplasty, 12-lead ECG, ST-segment monitoring,
cardiac serum markers, and chest pain centers. Subcommittee members and expert
peer reviewers also supplied articles with direct bearing on the policy. This
policy focuses on 5 areas of current interest and/or controversy: (1) ECG
eligibility criteria for fibrinolytic therapy, (2) role of primary angioplasty in
patients with acute myocardial infarction, (3) use of serum markers to diagnose
acute myocardial infarction, (4) serial 12-lead ECGs during the initial
evaluation, and (5) chest pain evaluation units. Recommendations for patient
management are provided for each of these 5 topics based on strength of evidence
(Standards, Guidelines, Options). Standards represent patient management
principles that reflect a high degree of clinical certainty; Guidelines represent
patient management principles that reflect moderate clinical certainty; and
Options represent other patient management strategies based on preliminary,
inconclusive, or conflicting evidence, or based on panel consensus. This
guideline is intended for physicians working in hospital-based emergency
departments or chest pain evaluation units.
PMID- 10783420
TI - ECG eligibility criteria for emergent fibrinolytic therapy. American College of
Emergency Physicians.
PMID- 10783421
TI - The role of primary angioplasty in patients presenting with acute myocardial
infarction. American College of Emergency Physicians.
AB - The role of primary coronary angioplasty in AMI patients presenting to the ED in
cardiogenic shock or who have an absolute contraindication to fibrinolytic
administration is well established. (1,2) In contrast, the role of primary
angioplasty in patients with AMI eligible for fibrinolytic therapy is
controversial.(3) A number of prospective trials have been conducted to address
the issue of primary angioplasty versus fibrinolytic therapy with varying
results. (4-12) Several of these studies have found modest but statistically
significant benefits in short-term mortality, reinfarction rates, infarct size,
and/or complication rates.(4-8) Other studies failed to confirm these benefits
and found the 2 therapies to be of equal value.(9-12) Emergency physicians who
practice in centers that offer primary angioplasty are frequently faced with the
conundrum of whether to activate the emergency cardiac catheterization team or
give fibrinolytic therapy in the ED. Likewise, emergency physicians who practice
in a hospital that does not offer angioplasty face a similar dilemma if they have
a patient with an AMI who they believe might benefit from immediate transfer to a
facility with cardiac catheterization capabilities. A recent meta-analysis
analyzed 10 prospective studies comparing primary angioplasty with intravenous
fibrinolytic therapy and found that the mortality rate for 30 days or less was
4.4% for 1,290 patients treated with primary angioplasty compared with 6.5% for
1,316 patients treated with fibrinolytic agents (95% confidence intervals 0.46 to
0.49, P =.02).(13) When death was combined with nonfatal reinfarction, the rates
were 7.2% for angioplasty and 11.9% for fibrinolytic therapy. In addition,
angioplasty was associated with a statistically significant reduction in total
strokes (0.7% versus 2.0%) and hemorrhagic stroke (0.1% versus 1.1%). Although
the apparent benefit of primary angioplasty found in this analysis is enticing, 3
caveats must be considered before reaching a definitive conclusion. First, there
is acknowledged potential for bias in both the quantitative review techniques and
the enrollment practices of the individual studies reviewed.(14) Second, the time
from presentation to the ED to inflation of the balloon in the angiography suite
is relatively rapid in most of the studies used for the analysis, and in order
for a center to duplicate these results, it is reasonable to presume they must be
able to consistently equal or improve on the door-to-balloon times in the
published studies. Although no clinical study definitively establishes the ideal
door-to-balloon time, it may be reasonable to extrapolate that the balloon time
ideally would be less than 90 minutes from time of ED diagnosis of AMI. Likewise,
the experience of the interventionist is of critical importance and the procedure
must be done at a high-volume center similar to those used in the reported
trials. Third, there continue to be advances in interventional techniques, such
as the use of platelet inhibitors and coronary stents, that may modify future
results. Currently it can be concluded that primary angioplasty, when conducted
in a timely manner in experienced hands, is a viable alternative to fibrinolytic
therapy. When the element of time or experience is uncertain or cannot meet
stringent criteria, fibrinolytic therapy remains the treatment of choice.
PMID- 10783422
TI - Serum marker analysis in acute myocardial infarction. American College of
Emergency Physicians.
PMID- 10783423
TI - Serial 12-lead ECGS in the emergency department. American College of Emergency
Physicians.
PMID- 10783424
TI - Chest pain evaluation units. American College of Emergency Physicians.
PMID- 10783425
TI - The case for hospice care in long-term care environments.
AB - Hospice care typically is underused in long-term care facilities. Although these
programs do provide other quality services, routine measurement of important
parameters of end-of-life care, such as pain control, dyspnea, and spiritual and
psychosocial issues, should also occur. Health care providers working in long
term care facilities should be held accountable for high-quality care for dying
residents. In this environment, the benefits of hospice or hospicelike services
may become immediately apparent. Continued attention to changes in the Medicare
Hospice Benefits to improve patient access to hospice services and health care
delivery for those living in long-term care facilities is warranted.
PMID- 10783426
TI - Care of the dying in long-term care settings.
AB - A team of caregivers provides health care in nursing homes. This team is led by a
nurse and includes a physician, nursing assistants, and other nursing home staff.
Given the future demand for palliative care in this setting, the roles of all
caregivers need to be supported with meaningful training, improved working
conditions, and respect for each caregiver's contribution.
PMID- 10783427
TI - Talking to the older adult about advance directives.
AB - Discussing advance care plans with elderly patients can improve the experience of
end-of-life care for patients, families, and health care teams. Specific goals
for any particular discussion should be based on patients' particular clinical
circumstances. Physicians should focus on patients' overall values and goals and
should provide emotional support during the discussion. Decisions made during the
advance care planning process should be documented.
PMID- 10783428
TI - Advance directives: older adults with dementia.
AB - The benefits and risks for older adults with dementia executing advance
directives are discussed. Salient issues related to decision-specific capacity
and models for advance planning and end-of-life decisions by cognitively impaired
older adults are presented.
PMID- 10783429
TI - Advances in pain management for older adult patients.
AB - Management of pain is crucial to the success of any program of care and support
for dying patients and their families. Pain can be controlled in more than 90% of
older adults. Components of an effective program include comprehensive, repeated
pain assessment; detection and treatment of complicating medical and
psychological disorders (e.g., delirium); spiritual concerns; and the judicious
use of nonpharmacologic and pharmacologic therapies, radiation, and
radiopharmaceuticals. Strategies that enable clinicians to prevent and treat the
expected complications of nonsteroidal anti-inflammatory and opioid therapies are
reviewed. Strategies to change opioid agents or routes to minimize opioid-induced
side effects and to provide effective pain relief as death nears are presented.
PMID- 10783430
TI - Nutrition and hydration in terminally ill patients: an update.
AB - Many health care professionals lack knowledge about artificial nutrition and
hydration at the end of life or may hold different attitudes about artificial
nutrition and hydration compared with other treatments. Consequently, they may
convey inaccurate or misleading information to patients or their surrogate
decision makers. An updated understanding about artificial nutrition and
hydration in light of prevailing medical evidence is presented.
PMID- 10783431
TI - Antisecretory agents in gastrointestinal obstruction.
AB - Gastrointestinal obstruction is associated with nausea, vomiting, and abdominal
pain. Antisecretory agents can relieve these symptoms, even in the absence of
surgical or mechanical intervention. These medical management approaches are
outlined, and recommendations are made.
PMID- 10783432
TI - Depression and the dying older patient.
AB - Depression remains a source of considerable suffering among dying older adults.
Unfortunately, clinical depression commonly is overlooked in this vulnerable
population and often goes untreated. An overview of diagnosing depression in
older patients is presented. Various risk factors for depression in the
palliative care setting are examined. The somatic therapies that are available
for treatment consideration in older, depressed adults nearing death are
reviewed.
PMID- 10783433
TI - Delirium in the terminally ill.
AB - Delirium is highly prevalent in terminally ill patients, especially in the last
weeks of life, when some cognitive impairment develops in as many as 85% of
patients. Delirium is associated with increased morbidity in terminally ill
patients and can interfere with pain and symptom control. The cause of delirium
is usually multifactorial and often cannot be found or reversed in dying
patients. Nonpharmacologic and pharmacologic interventions are effective in
controlling the symptoms of delirium in terminally ill patients. Haloperidol and
other newer neuroleptics are safe and effective in eliminating delirium for some
patients. In approximately one third of patients, delirium can be managed
successfully only by providing sedation.
PMID- 10783434
TI - Palliative care for advanced dementia.
AB - Dementia is a common, devastating, and ultimately fatal illness. Although no cure
exists for most causes of dementia, palliative interventions for the predictable
complications of the illness can effectively reduce the suffering of patients and
families. Care of patients with end-stage dementia is clinically and conceptually
consistent with hospice and palliative care, and this approach to care for
patients with terminal dementia is preferred. Although the 6-month risk for
mortality can be predicted (to satisfy current American hospice eligibility
requirements), palliative care interventions are appropriate much earlier in the
course of deterioration from dementia.
PMID- 10783435
TI - Measuring quality in end-of-life care.
AB - Scrutiny of the quality of medical care near the end of life is increasing.
Experts have begun to define and conceptualize quality of care for dying patients
and are developing measurement tools to assess quality of care in this
population. Definitions and conceptual models of quality of care at the end of
life are reviewed. Approaches for measuring the processes and outcomes of end-of
life care are discussed. Approaches for initiating quality assessment of end-of
life care among geriatric patients are suggested.
PMID- 10783436
TI - Citation for the Down Surgical Prize 1998--Michael Wake.
PMID- 10783437
TI - Citation for the BAOMS Surgery Prize 1998--Mark McGurk.
PMID- 10783438
TI - Helix rim advancement for reconstruction of marginal defects of the pinna.
AB - Helical rim defects commonly result from excision of neoplasms or from injury.
Various techniques for reconstruction of such defects have been described. The
wedge excision technique that is commonly described in texts causes butterfly
deformity, webbing and cupping of the pinna and the authors believe that it
should be abandoned. Helix rim advancement flaps were first described 30 years
ago and offer a simple and versatile method for reconstruction with excellent
cosmetic results. Line drawings and photographs show the operative sequence and
the end results of such flaps.
PMID- 10783439
TI - Burkitt's lymphoma presenting as mandibular swelling--report of a case and review
of publications.
AB - Burkitt's lymphoma in a 4-year-old Chinese boy presented with acute mandibular
swelling but no associated systemic disturbance. A review of published reports
shows that the diagnosis should be suspected in jaw lesions with no obvious
cause.
PMID- 10783440
TI - Clinical and functional staging of oral submucous fibrosis.
AB - OBJECTIVE: To investigate the association of location of bands in oral submucous
fibrosis and extent of mouth-opening. DESIGN: Cross-sectional study. SETTING:
University hospital, Pakistan. SUBJECTS: 325 patients who presented with oral
submucous fibrosis in Karachi between January 1992 and October 1994, of whom 288
had data sufficient for analysis. MAIN MEASURES: Location of fibrous bands in the
mouth and interincisal distance (mm). RESULTS: All subjects with labial bands had
bands in the fauces, and all but one who had labial bands also had buccal bands.
All those with buccal bands also had bands in the fauces. Of those with buccal
bands, 42% did not have labial bands. The proportion of patients with bands in
all three sites increased from functional stage A (interincisal opening < or = 10
mm) to stage C (interincisal opening > or = 20 mm) with a simultaneous reduction
in the proportion of people with bands in one or two sites (X2 = 105, df = 4, P <
0.0001). CONCLUSIONS: Bands are common at the back of the mouth in mild cases of
oral submucous fibrosis and, as the disease increases in severity, are more
likely to be found anteriorly as well.
PMID- 10783441
TI - Bone grafting technique to increase interdental alveolar bone height for
placement of an implant.
AB - We have developed a simple, one-step technique for chin bone onlay grafting
combined with simultaneous implant placement to increase alveolar bone height
without any support system. We have used it to place 14 implants in nine
patients; eight recovered uneventfully but, in the other one, the wound broke
down and the exposed chin bone necrosed. After a mean follow-up period of three
years (range 1.5-4.7) the clinical and radiological outcome has remained good in
those eight patients.
PMID- 10783442
TI - Clinicopathological study of peripheral odontogenic fibromas (WHO-type) in
Malaysians (1967-95).
AB - Analysis of case records of 46 patients with peripheral odontogenic fibroma (1967
95) diagnosed in the Division of Stomatology, Institute for Medical Research,
Kuala Lumpur, disclosed a relatively young age of onset (mean, 32.2 years; range
5 months-64 years; peak incidence second decade of life), a slight female
preponderance (M:F ratio 1:1.3), no racial predilection, a slight bias towards
location in the mandible (52%) and a wide histomorphological range. All cases
were treated by simple excision. Follow-up records were generally not available,
so we do not know what the recurrence rate is.
PMID- 10783443
TI - Maternal risk factors in cleft lip and palate: case control study.
AB - Three hundred and six mothers who gave birth to babies with cleft lip, or palate,
or both, were matched with 306 who gave birth to healthy babies in the same area
during the same time period. Significantly more babies in the cleft group had a
family history of clefts (48/306 compared with 7/306, P<0.0001). In the cases
studied, combined cleft lip and palate was significantly more common among boys
(82/157 compared with 57/149, P=0.02) and cleft palate alone among girls (48/149
compared with 22/157, P=0.0002). Significantly more mothers reported some sort of
illness during early pregnancy (101/306 compared with 74/306, P=0.02). There were
no differences between the groups as far as dietary preferences were concerned
but during early pregnancy the mothers who gave birth to babies with defects
tended to drink less alcohol (<1 unit/week) (236 compared with 199, P=0.001) and
less coffee (<1 cup/week) (159/306 compared with 131, P=0.03). However, in each
case similar proportions gave up once the pregnancy was confirmed. Large
multicentre studies are required to confirm or refute these findings.
PMID- 10783444
TI - A comparison of growth impairment and orthodontic results in adult patients with
clefts of palate and unilateral clefts of lip, palate and alveolus.
AB - OBJECTIVE: To evaluate and compare the long-term aesthetic and functional results
of surgical and orthodontic treatment in patients with cleft palate and
unilateral cleft lip, palate, and alveolus. DESIGN: 30 patients with unilateral
cleft lip, palate, and alveolus and 30 patients with isolated cleft palate, mean
age of 18.9 years, were evaluated by cephalometric and model analysis a mean of
1.5 years after orthodontic treatment. In each group the surgical treatment has
been similar. RESULTS: Model analysis: The sum of every mesiodistal tooth
diameter in the maxilla and in the mandible was recorded according to the Bolton
analysis. Twenty patients with unilateral cleft lip, palate and alveolus had
relatively large upper dental arches and nine had relatively large lower dental
arches. Twenty-two patients with cleft palates had large upper dental arches and
seven had large mandibular arches. Eleven patients with unilateral cleft lip,
palate, and alveolus and 18 patients with cleft palate had a negative space
supply (the sum of the mesiodistal tooth diameters compared with the sagittal
length of the alveolar ridge) in the region of the lateral teeth. All patients
had persistent transverse space deficits that were increased on the side of the
cleft in patients with cleft lip, palate, and alveolus. These unilateral
transversal space deficits were recorded in 22 patients with unilateral cleft
lip, palate, and alveolus and in 8 patients with isolated cleft palate. Sagittal
measurements were reduced in 26 patients with unilateral cleft lip, palate, and
alveolus and in 23 patients with cleft palate alone. The alveolar midline of the
maxilla and the mandible were displaced in 25 patients with unilateral cleft lip,
palate, and alveolus and in 19 patients with isolated cleft palate. Lateral
cephalometric analysis: The lateral cephalograms taken at the same time as the
models showed a mean SNA of 76.8 degrees and a NL-NSL angle of 8.7 degrees,
indications of a tendency towards maxillary retrognathia in patients with
unilateral cleft lip, palate, and alveolus. Patients with cleft palate had a mean
SNA of 79.6 degrees and NL-NSL angle of 8.1 degrees. The anterior facial vertical
index was within normal limits in patients with cleft lip, palate, and alveolus
(44% vs 56%). An anterior facial height index of 42% compared with 58% in
patients with isolated cleft palate indicated a slight reduction in midface
height with an increase in the lower face as a consequence. CONCLUSION:
Orthodontic and surgical treatment can result in satisfactory results on model
analysis. However, there is specific growth impairment of the maxilla 1.5 years
after termination of orthodontic treatment and this influences the final
cephalometric analysis, particularly in patients with cleft lip, palate, and
alveolus.
PMID- 10783445
TI - Pull-through technique of scapular osteocutaneous flap to decrease frequency of
positioning change.
AB - During reconstructions of the head and neck regions with a scapular or a scapular
osteocutaneous flap, it is usually necessary to reposition the patient twice and
prepare the operating field three times for removal of tumor, harvesting the
flap, and reconstruction. This is one of the main disadvantages of the scapular
flap. We have used the pull-through technique to reduce the number of changes in
position that are required. In addition, the ischaemic time of the flap is also
substantially reduced. The flap is first raised and then tunneled through the
axilla to lie passively on the chest while the tumor is excised. These procedures
have been followed in 13 cases of scapular and scapular osteocutaneous flap with
no problems.
PMID- 10783446
TI - Progress of ossification and epithelialization of wounds after simple or surgical
extractions of teeth in rats with chronic renal failure: an experimental study.
AB - Our aim was to investigate the progress of wound healing after simple and
surgical removal of the first two molars of the right and left maxillary
segments, respectively, in Wistar rats with experimentally induced moderate
chronic renal failure (CRF). Sixty Wistar rats were divided into two groups of 30
rats each: experimental and control. CRF was induced in the experimental group by
an intraperitoneal injection of cisplatin, 5 mg/kg body weight (BW) initially and
then with two maintenance doses of 2.5 mg/kg BW at intervals of one month. The
teeth were extracted one month after the last dose of cisplatin. The sockets and
the kidneys of all the rats of both groups were evaluated. The mandibles of the
15 rats in the experimental group that developed moderate CRF, together with
those of two controls, were evaluated for abnormalities that suggested renal
osteodystrophy. The histopathological examination showed: (a) that there were no
significant differences in the pattern of wound healing no matter how the tooth
was extracted; (b) there were no specific abnormalities in the mandible to
indicate of secondary hyperparathyroidism or renal osteodystrophy; and (c) the
kidneys of the rats of the experimental group underwent histopathological changes
that were significantly different from those in the controls (P < 0.001). Our
results indicate that moderate CRF does not have any appreciable or significant
modifying effect on wound healing after tooth extraction in Wistar rats.
PMID- 10783447
TI - Exposure of high-density porous polyethylene (Medpor) used for contour
restoration and treatment.
AB - Porous high-density polyethylene (Medpor) is a biocompatible large-pore, high
density polyethylene implant. It is well tolerated by surrounding tissue, and its
porous structure is rapidly infiltrated by host tissue. It is a highly stable and
somewhat flexible porous alloplast that has rapid tissue ingrowth into its pores.
However, when the implant is placed under a thin cover of skin, there is a risk
of exposure. A total of 52 Medpor implants were placed in 31 patients over a four
year period. The implants were used for the chin, malar area, nasal
reconstruction, ear reconstruction, orbital reconstruction, and the correction of
mandibular contour deformities. Many of these implants were placed in areas
considered problematic, such as those with thin or atrophic soft-tissue coverage
and extensive scarring. There were nine complications, including three patients
in whom the implant was exposed; these are presented here.
PMID- 10783448
TI - Lack of correlation between water hardness and salivary calculi in England.
AB - Our aim was to test the hypothesis that residents of hard water areas are at
increased risk of developing salivary calculi. The evidence based on figures from
the Hospital Episode Statistics database for the years 1991 to 1994, suggests
that there is no such association. For example, in the South West Water area
(soft water) the incidence was 28.92/million/year compared with Yorkshire (hard
water) 31.64/million/year. The correlation coefficient shows that water hardness
is not significantly associated with either the incidence of salivary calculi (r
= 0.02, P = 0.9) or that of sialadenitis (n = 2.4, P = 0.4). The lack of
association holds for both men and women independently. However, the two
conditions have similar patterns of incidence (r = 0.5, P = 0.05), suggesting
some common but unknown similarity in aetiology.
PMID- 10783449
TI - Correction of recurrent dislocation of the mandible in elderly patients by the
Dautrey procedure.
AB - Twelve patients with recurrent mandibular dislocation, 11 of whom were over 50
years old, were treated by the Dautrey procedure using a temporal approach. None
experienced recurrence or developed complications such as restriction of mouth
opening, paresis of the facial nerve, or pain in the temporomandibular joint
during a follow-up period that ranged from 1.5 to 8 years.
PMID- 10783450
TI - The efficacy of Emla and 5% lignocaine gel for anaesthesia of human gingival
mucosa.
AB - OBJECTIVE: To compare the analgesic effect of a mixture of 2.5% lignocaine and
2.5% prilocaine (Emla) with that of lignocaine gel alone for minor operations on
the gingiva. DESIGN: Randomized double-blind trial. SETTING: Teaching hospital,
UK. SUBJECTS: 10 healthy dental students (7 men and 3 women, 20-21 years old).
INTERVENTIONS: Construction of a reservoir within a splint on each side of the
mouth and insertion of splints. The volunteers acted as their own controls, and
the sides used for each anaesthetic were chosen at random. MAIN OUTCOME MEASURES:
Measurement of pressure-pain threshold by a standard technique. RESULTS: The
median (range) duration of anaesthesia after Emla (22.5, 12-30) was significantly
longer than after lignocaine alone (12.5, 0-25) (P=0.01), and the area under the
curve for the pressure-pain threshold for Emla (2053, 199-4564) was significantly
greater than for lignocaine alone (986, 169-2942) (P=0.01). CONCLUSION: Emla is a
more effective topical anaesthetic agent than lignocaine alone. Although its
duration of action is relatively short it is adequate for minor operations on the
gingiva.
PMID- 10783451
TI - A retrospective study of unerupted maxillary incisors associated with
supernumerary teeth.
AB - We retrospectively reviewed the clinical records and radiographs of 100 patients
who had had supernumerary teeth removed. Their mean (SD) age was 9 years 3 months
(2). The 100 patients had a total of 127 unerupted maxillary incisors associated
with supernumerary teeth. The supernumerary tooth was removed without exposure of
the permanent tooth more often among the 79 younger children (aged 10 years or
less) (SND=3.52, P<0.01), and when the incisors were less mature (Cvek
classification 1, 2, and 3) (SND=5.27, P<0.01). Of these incisors with immature
roots that were treated conservatively, 60 (72%) erupted and 24 (28%) required
further operation. Of the mature incisors treated conservatively, 10 (63%)
required further operation. In this study, almost three-quarters of immature
incisors erupted spontaneously after removal of the associated supernumerary
teeth. Over half of the mature teeth required further operation. Mature teeth
should be exposed with or without bonding at the time of removal of the
supernumerary teeth.
PMID- 10783452
TI - Surgical and orthodontic rapid palatal expansion in adults using Glassman's
technique: retrospective study.
AB - In 1984, Glassman et al. described a conservative surgical method of separation
of the midpalatal suture in which an osteotomy is done only at the lateral and
anterior wall of the maxilla. Between 1991 and 1997, we have operated on 21
patients with maxillary transverse discrepancies using the method that they
described. This gave good results in 20 patients. The other, who was operated on
at the age of 38 years, developed a fracture of the alveolar process of the
maxilla on one side because of ossification of the midpalatal suture. The
surgically assisted rapid palatal expansion described by Glassman et al. is
suitable for patients up to the age of 30. Older patients require additional
surgical separation of the midpalatal suture.
PMID- 10783453
TI - Mechanical and biomechanical measurements of five currently available
osteosynthesis systems of self-tapping screws.
AB - Pressure force, uniaxial 'pullout', minimum torque, and peak torque tests were
done to evaluate the effectiveness of three popular monocortical and non
compressing self-tapping screw systems 2 mm in diameter (Champy, Centre-Drive,
and Wuerzburger) and two systems 1.5 mm in diameter (Champy and Wuerzburger). The
screw systems were all tested on polyvinylchloride plate, skull, and molar
mandibular bone from fresh human cadavers. The Champy screw 2 mm in diameter and
7 mm long produced the highest pressure force (mean (SD) 153.4 (58.5) N, n=40) of
the systems tested. The Centre-Drive screw of the same size showed the highest
retentive force in pullout tests (619.5 (169.9) N, n=40) and also the largest
difference between minimum and peak torque in skull and molar mandibular bone
(1.86 (0.65) kpcm, n=40). This was clinically relevant compared with reported
human bite-force (range 216-740 N). The results showed that, the screw diameter
and number of threads were the most important and significant of the mechanical
variables tested. The skull bone also exerted more retentive force than the molar
mandibular bone. The overall data indicate that there is no need to use screws
more than 7 mm long or wider than 2 mm in diameter for monocortical non
compressive osteosynthesis in the craniofacial and the mandibular region.
PMID- 10783455
TI - Contents list from the Japanese Journal of Oral and Maxillofacial Surgery (Volume
43 Number 12 1997).
PMID- 10783454
TI - Abstracts from Mund-, Kiefer- und Gesichtschirurgie(Volume 3, Number 6 1999).
PMID- 10783457
TI - Re: GDC specialist list.
PMID- 10783456
TI - Re: Peckitt. Stereoscopic lithography: customised titanium implants in orofacial
reconstruction: a new surgical technique without flap cover.
PMID- 10783458
TI - Reply to Carter & Holmes. Re: Stereoscopic lithography: customized implants in
orofacial reconstruction - a new surgical technique without flap cover.
PMID- 10783459
TI - Angiocentric T cell lymphoma of the paranasal sinuses: a difficult diagnosis.
PMID- 10783460
TI - Orbital floor injury with extraocular muscle entrapment following functional
endoscopic sinus surgery.
PMID- 10783461
TI - CT image of nasoalveolar cyst.
PMID- 10783463
TI - Bright light as an inhibitor of adenosine transport.
AB - The administration of bright light rapidly improves subjective alertness and is
likely to have direct effects on the activity of neurons in the suprachiasmatic
nucleus (SCN). Bright light may enhance wakefulness by interrupting the increase
in extracellular adenosine concentration with brain metabolism during the day.
Exposure to bright light is hypothesized to induce the inhibition of adenosine
transport, promoting both subjective alertness and activation measured
objectively, and to activate the cholinergic neurons of the reticular system and
those using gamma-aminobutyric acid as a neurotransmitter in the SCN.
PMID- 10783464
TI - Mechanisms of sudden infant death and the contamination of inspired air with
exhaled air.
AB - The physiological effects on an infant of repeatedly sleeping in an environment
consisting of a mixture of exhaled air and fresh air is examined. It is found
that adaptation can be predicted. A possible outcome of the adaptation is shown
to be the development of hypoxia when the conditions change during sleep from a
state with carbon dioxide contamination of inspired air to one without. This
hypoxia can be associated with apnoea: this apnoea can provide an explanation for
some instances of sudden infant death. This explanation is consistent with the
known epidemiology and environmental associations of a proportion of sudden
infant death syndrome. Safety precautions for the prevention of re-breathing are
given.
PMID- 10783465
TI - Proto-metastatic core and comet effect: new theoretical model of the mechanism of
metastasis generation.
AB - One important aspect of cancer is its capacity to generate metastasis. The
mechanism by which one or several neoplastic cells escape from the primitive
tumor to start the metastatic process is still a matter of discussion, hence the
need to reconsider under which circumstances and conditions 'lethal escape' is
produced. Thus we introduce two concepts: proto-metastatic core and comet effect.
We maintain that only one group of cells (proto-metastatic core) could escape
passively from the tumor focus when they enter the bloodstream together with
other detritus. The proto-metastatic core disintegrates through friction with the
blood (comet effect). There are two mechanism of metastasis. In the first, only
one cell leaves the vessel joined to white blood cells as it moves through an
inflamed area. The second, from the proto-metastatic core, could form venous
thrombus. We believe that this new theoretical model of the etiopathology of
cancer will contribute to future therapies.
PMID- 10783466
TI - What is the material base of acupuncture? The nerves!
AB - Acupuncture is a traditional Chinese medical method which has been used in the
treatment of patients for thousands of years. It is rejected by modern science
for lack of solid material background. In recent years, more and more laboratory
proof has accumulated that acupuncture can change the charge and potential of
neurons, the concentrations of K(+), Na(+), Ca(++) and the content of neuro
transmitters such as aspartate, and taurine and the quantities of neuro-peptides
such as beta-endorphin and leu-enkephalin. All these phenomena are directly
related to nerve cells. Now the lengthy discussion may conclude that nerve cells
and the central nervous system are the real material base of acupuncture.
PMID- 10783467
TI - Is fractal geometry useful in medicine and biomedical sciences?
AB - Fractal geometry has become very useful in the understanding of many phenomena in
various fields such as astrophysics, economy or agriculture and recently in
medicine. After a brief intuitive introduction to the basis of fractal geometry,
the clue is made about the correlation between Df and the complexity or the
irregularity of a structure. However, fractal analysis must be applied with
certain caution in natural objects such as bio-medical ones. The cardio-vascular
system remains one of the most important fields of application of these kinds of
approach. Spectral analysis of the R-R interval, morphology of the distal
coronary arteries constitute two examples. Other very interesting applications
are founded in bacteriology, medical imaging or ophthalmology. In our
institution, we apply fractal analysis in order to quantitate angiogenesis and
other vascular processes.
PMID- 10783468
TI - A new diagnostic system for psychiatry.
AB - The objective of this work is to apply theoretical concepts from system theories
to psychiatry, and formulate a novel diagnostic system that will combine the
advantages of descriptive diagnosis and biopsychosocial diagnosis in psychiatry.
Biopsychosocial factors and symptoms of mental disorders are described as
instabilities and perturbations in a system (i.e. the nervous system). The author
reviews certain basic concepts from system theories and applies them to clinical
concepts in psychiatry. Biopsychosocial factors are perceived as agitators of
organization in the nervous system, and symptoms are described as emergent
properties out of these perturbations. A profile of biopsychosocial factors is
plotted to correlate with a profile of perturbations and their related symptoms.
This agitator versus perturbation mapping is advantageous as a diagnostic system
for psychiatry. The proposed diagnostic system is of value in dealing with the
clinical complexity of mental disorders, has a potential for increasing
predictive validity in psychiatry, and may contribute to etiological brain
research of mental disorders.
PMID- 10783469
TI - Field recognition of pathogen and HIV self.
AB - There is evidence to suggest that the HIV virus is never presented clearly and
completely to the immune system. It is possible there is an additional
recognition system in skin it misses. By bypassing the skin in inoculation or
neutralizing skin presentation in semen, an envelope that may modify immune
response, pathogen may get by this additional field recognition system. In an
effort to engage this additional recognition system for more information about
the virus, the immune system may end up purposefully mutating the virus for the
wrong reason inadvertently establishing a repertoire of HIV self. The unique
circumstances of HIV presentation may cause this proposed additional normally
compatible recognition system to turn into a competing system.
PMID- 10783470
TI - Biophysical body-brain-mind unity: theory and practice.
AB - A novel substance-attributed biophysical theory of brain-mind unity is presented.
We separate spiritualism and matters of the soul from the medical sphere.
Biophysical principles are responsible for the body's operational regimen (BOR)
in the homeostatic state which allows for materialization and emergence of the
mind; Excitation and/or inhibition modulate 8 BOR stages. There is automatic
(somatic) and non-automatic (biophysical and psychological) Circadian cycle
control. Computer-analog input and output occurs in wired neuronal electric
pathways. Biotechnological devices located in emotional neurons positively signal
homeostatic and negatively signal deranged BOR and biophysical mind operations.
Macro and/or micro cerebral lesions which affect homeostasis may cause
psychopathology, which can be treated with 'instrumental psychotherapy' (IPT)
which enables recovery from homeostatic disorder in Phase 1, refining EGO in
Phase 2, and social competence in Phase 3. The theory of brain-mind unity and
practice of IPT is geared to medical workers and biophysical psychologists.
PMID- 10783471
TI - Immunoregulation via 'bystander suppression' needs minute amounts of substances-
a basis for homeopathic therapy?
AB - One of the main characteristics of homeopathic drugs is the low concentration of
substances they contain. In most discussions this serves as the predominant
argument against homeopathic treatments. The small amount of ingredients is in
most instances considered not to be able to induce significant changes in
classical pharmacological models. A few years ago researchers at the Harvard
Medical School in Boston observed that the auto-reactivity ofT-cells is managed
by the immune system in at least two different ways that obviously were dependent
upon the concentration of the antigen they encounter: If they see high
concentrations of a self-antigen they are deleted (killed), but when given low
doses they undergo a special kind of active inhibition (called 'bystander
suppression'). We feel that this type of regulation induced by very low substance
concentrations could serve as a model to explain the way in which at least some
homeopathic pharmaceuticals mediate their therapeutic effects.
PMID- 10783472
TI - Biocryptography.
AB - A new cryptology that uses biomolecules as carriers of hidden information is
described here. The huge dimension of biopolymers permits the insertion there of
private messages and the rapidity and specificity of biomolecular interactions
facilitate the identification of classified communications. Otherwise, this
process can be implemented in a virtual context.
PMID- 10783473
TI - Considerations upon the anatomical model of reward-based learning in the basal
ganglia.
AB - The nigrostriatal pathway appears to be very important in the reward-based
learning. The dopaminergic neurons in the substantia nigra pars compacta (SNC)
fire in relation to primary rewards and reward-conditioned stimuli, but not to
rewards that are expected. It has been hypothesized that the anatomical framework
for the selective response of these neurons is organized in the projections from
some paralimbic areas in the frontal lobe to the striosomes of the caudate
nucleus, which are also directly connected with the dopaminergic neurons of the
SNC. Here, we present two additional pathways that may be related with this
neurophysiological finding. We hypothesize that the connections of the paralimbic
cortices with the ventral system of the basal ganglia and then with the thalamus
and the hypothalamus, and the circuit ventral striatum-substantia nigra pars
reticulata-thalamus-striatum could be also involved in the reward-based learning.
PMID- 10783474
TI - Errors and biases in the diagnosis of cancer of the lung and their influence on
risk estimates.
AB - When diagnosed as primary lung cancer, metastases from the abdomen, plus false
negative cases have little effect on epidemiology studies of male smokers, but
may result in a severe dilution of the lung cancers among women and nonsmokers.
We have attempted to quantitate this handicap for epidemiological studies using
two approaches. The relative frequency of diagnosed primary lung and abdominal
cancer among males, women, and nonsmokers differs substantially and is used here
to calculate magnitude. The second approach postulates that the ratio of
nonsmokers among persons with squamous cell lung cancer and primary
adenocarcinoma of the lung would be constant by sex if there were no distortion
by abdominal metastases. These two approaches indicate that the much higher ratio
of metastatic disease diagnosed as primary lung cancer among nonsmoking women
(factor of 15 to 20), makes it more difficult to identify an environmental
carcinogen among women or nonsmokers than among male smokers in case-control
studies.
PMID- 10783475
TI - Siblings of sudden infant death syndrome and near miss in about 30 families: is
there a genetic factor?
AB - The purposes of this study were: (1) to compare our data with those reported in
the general population; (2) to find a factor implicated in repetitive accidents;
(3) to look for a possible genetic factor; and (4) to evaluate whether or not the
risk of recurrence was the same in a family with two or more infants having died
of sudden intant death syndrome (SIDS) as in the general population. We study
retrospectively 77 files which constitute a group of 30 families which was
analysed with reference to a list of data laid out in the shape of genealogical
trees. Our study shows that risk factors are similar to those described
previously and repetitive among siblings or cousins. The rate of recurrence is
not available for the general population. On studying some family trees, we can
speculate on the existence of an autosomal dominant gene with incomplete
penetrance.
PMID- 10783476
TI - Cancer incidences in the digestive tube: is cobalamin a small intestine
cytoprotector?
AB - Malignancies are common in the digestive tube, although with unequal distribution
among segments. The aim of this paper was to compare available interpretations of
the low cancer incidence in the small bowel and high in the large bowel. Supposed
mechanisms include relatively small bacterial population, large secretion of
liquid and rapid transit in the small bowel. Small bowel mucosa is the main
absorptive part of the digestive tube with absorption rates for various nutrients
so high that they can even be considered as clearances from the intestinal
content. Consequently, these nutrients are not present in the large bowel. An
alternative explanation is that an absorbable protective substance from the
intraluminal content, might protect the mucosa from malignant transformations. It
can be speculated that if there are any cytoprotective substances in the digested
food their effect would be expressed mostly in the absorptive small intestine,
leaving the large bowel mucosa unprotected. Vitamin B12 might be a possible
candidate for this role. Cobalamin molecules are initially bound to haptocorrin
(Hc) in the stomach, but in the small intestine B12 is transferred to intrinsic
factor (IF) after the action of pancreatic trypsin on Hc. Cobalamin-IF complexes
are absorbed in the terminal ileum leaving only a small fraction of B12 to enter
the large bowel. We have tried to summarize available data regarding cancer
incidences in digestive tube, segmental length and transit times of tube content.
Cancer density is calculated as incidence per length and transit speed as length
per transit time. Cancer incidences for seven intestinal segments were considered
low if they were below one case per 100 000 inhabitants annually, while the low
cancer density meant less than six cases per 100 000 inhabitants per metre. For
instance, transverse colon was considered as a high cancer incidence place (2.15
cases), with low cancer density (4.3 cases/m). Transit speed more than 0.3
metre/hour was associated with low cancer incidences (accuracy 0.85) and low
cancer density segments (accuracy 1.00). Cobalamin availability showed similar
distribution, available in low incidence segments and unavailable in high
incidence segments. Experimental studies are needed to quantify B12 availability
in the large bowel and to determine whether small amounts of B12-IF or, perhaps,
B12-haptocorrin complexes are absorbed by the small bowel mucosa. Without that,
no cytoprotective effects of B12 in the digestive tube can be expected.
PMID- 10783477
TI - A cycle of cerebrospinal fluid: supporting evidence and theoretical
considerations.
AB - An entrenched theory of cerebrospinal fluid (CSF) absorption by the arachnoid
villi fails to explain observations regarding the movement of substances in the
fluid. Experiments that demonstrated the arachnoid villi as the site of
absorption were based on non-physiologic methods. CSF does not flow through the
arachnoid villi, because villi require bulk flow and bulk flow of CSF does not
exist. CSF is transported through the choroid fissure and recycled through the
tela choroidae by the choroid plexus, with reentry into the ventricular system.
Observed failures of the effete arachnoid villus theory can be readily explained
by the cycling theory. A complete cycle of CSF is suggested to pace the 90 to 100
minute ultradian rhythms found in human physiology.
PMID- 10783478
TI - Ex vivo expanded allogeneic cord blood progenitor cell transplantation with a non
myeloablative conditioning regimen would cure autoimmune diseases.
AB - Loss of self-tolerance is the basis for autoimmune disease. Autologous as well as
allogeneic stem cell transplantation is increasingly being considered and used
for therapy of autoimmune disease. Non-myeloablative conditioning has been shown
in the context of malignant diseases to be feasible. Cord blood transplantation
has been associated with significantly less graft-versus-host disease (GVHD) than
other forms of allotransplantation. Ex-vivo expansion of this limited resource is
increasingly becoming feasible. It is being hypothesized that ex-vivo expanded
cord blood progenitor cell transplantation using a non-myeloablative conditioning
regimen would be curative in autoimmune diseases.
PMID- 10783479
TI - Long-term relapses of breast cancer: a neglected but important issue.
AB - The relatively frequent finding of long-term relapses from breast cancer, eight
years or more after the mastectomy, could indicate that breast cancer is a
particular neoplasm and even suggests that it could be a systemic disease. The
study of receptors in cases of long-term relapses instead indicate that breast
cancer, with the exception of the presence of hormonal receptors which influence
the clinical behavior, is similar to neoplasms that arise in other parts of the
body. It is possible that the presence of receptors indirectly conditions the
formation of antimitotic factors more effective than those known today, up to
determining in some cases the phenomenon of long-term relapses. Such factors are
presumably active also for neoplasms arising in other parts of the body.
PMID- 10783480
TI - Involvement of polyglutamine endolysis followed by pyroglutamate formation in the
pathogenesis of triplet repeat/polyglutamine-expansion diseases.
AB - The mechanism by which polyglutamine expansions in several proteins lead to
neurodegenerative disorders remains largely unknown. The biochemical properties
of polyglutamine repeats suggest one possible explanation; endolytic cleavage at
a glutaminyl-glutaminyl bond followed by pyroglutamate formation may contribute
to the pathogenesis through augmenting the catabolic stability, hydrophobicity,
amyloidogenicity, and neurotoxicity of the polyglutaminyl proteins. The
hypothesis points out novel therapeutic strategies to delay disease onset in
genetically diagnosed presymptomatic patients.
PMID- 10783481
TI - Rice hurts the stomach by its stickiness.
AB - Rice masses remove mucus from the stomach and duodenum as the sticky starch binds
the sticky mucus, weakening the defense against acid and pepsin which may in turn
cause heartburn and ulcer. Such unwanted effect can be avoided by taking enough
water with rice meal as water converts rice masses into slurry.
PMID- 10783482
TI - How calcium from calcium carbonate and milk benefit peptic ulcer patients.
AB - Calcium from calcium containing antacids and milk enhance the integrity of
gastrointestinal mucosa and mucus, as it is the natural linker agent of these
structures, which strengthens their defense function.
PMID- 10783483
TI - Lessons from the follow-up of developmental dyslexics.
AB - The follow-up of developmental dyslexics from childhood to maturity reveals
interesting and important facts. One of the main conclusions which can be reached
on considering these facts is that reading and writing can be acquired without
phonology. Many developmental dyslexics manage to reach high levels of literacy
while remaining seriously handicapped in their phonological skills. The
suggestion presented in this paper advocates the adoption of the practical
strategies employed by the dyslexics as the basis of the remedial methods to be
used in schools.
PMID- 10783484
TI - Pheromones cause disease: the exocrinology of anorexia nervosa.
AB - The aetiology of anorexia nervosa is exocrinological. This notion is supported by
physical evidence in animal models with directly comparable symptomatology.
Anorexia nervosa (AN) syndrome would be a puberty delay caused by reception and
autoreception of conspecific pheromone emissions: a pheromone-induced puberty
delay (PIPD). As such, it would be amenable to medical treatment drawing from
forty years of research in animals. This hypothesis is testable. For instance,
since food ad libitum is a prerequisite for PIPD, occasional supervised fasting
in healthy peripuberal subjects should prevent AN. Besides, tolerating an
untestable thought disease (1,2) with symptoms of a curable well-understood
animal condition would be anti-scientific and perpetuates medical disaster. Even
their endocrinologies are identical. Pheromone feedback tunes animal appetites
and immunity to available resources and prospects. In addition to timing puberty,
pheromones regulate fertility. Pheromones will probably be implicated in the
aetiology of the psychiatric and autoimmune diseases. This is the second in a
series of twelve papers to explore this contention systematically.
PMID- 10783485
TI - Cholinergic regulation of biological hydrodynamics.
AB - The structures of biological life are formed in water. Their function depends on
changes in the entropy of water. It is regulated by the cholinergic system. The
initiating event is the ChE-splitting of water with liberation of free protons.
They will draw electrons from the fairly inert dioxygen. The induced oxygen
reactivity will give liberation and transfer of electrons and hydrodynamic pH
dependent changes in protein configurations. A multitude of sub-systems will be
activated. The sequence of events normally ends with the formation of water, thus
preventing uncontrolled radical chain reactions. Cholinergic receptors appear as
restricting units of the general disordering entropy tendency. ChE-induced
hydrodynamics is propagated to the inner of cells by the water soluble protons
and the electrolytes. Especially Ca appear to have a strong influence on the
hydrodynamic dipole moment of water. Because water is an integral structure of
DNA genetics also will be influenced. Conditions caused by deprivation of oxygen
or of reactive oxygen and disorders by hyperactivity and inactivity are briefly
discussed. The CNS takes the shape of a large-scale quantum computer with a
function far beyond our ability of immediate perception. The atomic nuclear
proportions of quantum bits (qubits) will admit the functional one-cell unit of
immune memory cells. Cholinergic hydrodynamics appear to substantiate the much
discussed chaos theory.
PMID- 10783486
TI - Vaginal douching and preterm birth: an intriguing hypothesis.
AB - The rate of preterm birth has risen in recent years and is twice as high among
black women as among white women. Neither the underlying causes nor the reasons
for the racial disparity are clearly understood. Further, preventable risk
factors have not been identified. We hypothesize that vaginal douching plays a
key role in the risk of infection-related spontaneous preterm birth. Vaginal
douching is a common behavior, twice as prevalent among black women as among
white women. Douching may be an important mechanism by which vaginal pathogens
gain access to the upper genital tract. Douching increases the risk of acquiring
bacterial vaginosis. It may also facilitate the ascent of microorganisms into the
upper genital tract, resulting in a chronic bacterial colonization inside the
uterus. During pregnancy, the host inflammatory response is initiated, which
stimulates preterm labor and birth. Douching, a potentially preventable risk
factor, may explain a substantial proportion of the black-white disparity in
preterm birth.
PMID- 10783487
TI - Are proteases used as anti-inflammatory agents in reality accelerating the
inflammatory process?
AB - A possible anti-inflammatory effect of intraduodenally administered trypsin was
investigated using the paw oedema and pleurisy models of carrageenan-induced
inflammation in rats. No anti-inflammatory effect was detected by plethysmography
or on the basis of pleural leukocyte migration in treated animals compared to a
sham group. The groups were implanted with an intraduodenal catheter after
treatment with metopyrone, an inhibitor of endogenous corticosteroid synthesis.
Since surgical stress induces an anti-inflammatory effect of its own; the sham
group was an important control. Metopyrone antagonized surgical stress, and
trypsin inhibited oedema by about 16% four hours after carrageenan
administration, a nonsignificant reduction. Evans blue dye protein leakage into
the peritoneal cavity as a measure of vascular permeability demonstrated a pro
inflammatory effect of trypsin. The present results lead us to propose that
trypsin may be acting not as anti-inflammatory agent but by accelerating the
inflammatory process, thereby reducing the duration of the process.
PMID- 10783488
TI - Resistance of cancer cells to immune recognition and killing.
AB - It is well recognized that, in order for a wound to heal, the fibrin clot must be
eliminated by fibrinolytic enzymes. In certain instances, however, fibrin is
ineffectively degraded or even not degraded. For example, in pregnancy, the
placenta contains a layer of fibrin (Nitabuck's layer) which presents as 'self'
to the immune system. Similar situations have been observed in many solid tumors.
A hypothesis is presented according to which tumor cells can escape detection and
attack by the immune system in most cancer patients. The tumor dons a 'coat' of
the host's own protein on its cell surface. The coat is composed of fibrin and of
a polymeric form of human serum albumin (HSA) which, by contrast to pure fibrin,
is resistant to fibrinolytic degradation. Such a coated tumor appears as 'self'
to the immune system, and thus is not detected as a tumor by the immune system
(i.e. natural killer cells). When tumors are prepared for in vitro assays against
drugs, they are routinely treated with proteolytic enzymes (e.g. pepsin, or
chymotrypsin, etc.) which dissolve the protein coat, exposing the tumor cell
surface to the drug. Thus, the in vivo existence of a coat on the tumor surface
may explain why some drugs have little or no effect in vivo, while the same drugs
are active in vitro.
PMID- 10783489
TI - Ionizing radiation and mitogenetic radiation: two links of the same energetic
chain in a biological cell.
AB - Present research demonstrates that the excitation of living systems by high
energy/low doses of ionizing radiation (IR) initiates prolonged secondary
ultraviolet (UV) range emission that influences biota. When doses of this energy
are too high, the process of energy or radiation absorption by the cells causes
negative changes (i.e. negative mutations or death). When these doses are
sufficiently low, vital processes inside the cells are stimulated and can create
positive changes. This paper proposes a common denomination for mechanisms of UV
and ionizing radiation when interacting with living cells, underlying both its
mitogenetic effect and radiation hormesis. Data from radon exposure in
chronically exposed nuclear workers, acutely exposed Hiroshima and Nagasaki
victims and observers of atmospheric nuclear explosions, combined with animal
results, present irrefutable evidence that low doses of IR are beneficial. As a
conclusion the author postulates the possibility of new methods of therapy
regarding the use of IR and mitogenetic radiation. This paper has been written to
encourage debate regarding possible future benefits that may be derived from low
level doses of IR exposure in the general population.
PMID- 10783490
TI - Colon heat and colon cancer.
AB - Epidemiological findings on the relation between foods and colon cancer are
inconsistent. Many, but far from all, found positive associations for meat and
fat and negative ones for vegetables and fruits. Explanations so far have focused
on direct biochemical conversions in the colon or transit time, but they remain
unable to explain the contradictory observations. One aspect grossly ignored has
been bacterially produced heat which is beyond somatic control. A present day
affluent lifestyle includes a more sedentary life, the strongest of all risk
factors for colon cancer, with more sitting and less diffusion of bacterial heat,
more fat and sugar, rich in energy and less of energy poor foods like cereals. A
temperature higher by less than 1 degrees C in the colon over decades may promote
tumour growth to a distinguishable extent.
PMID- 10783491
TI - Glutarimide: a carrier transporting drug through cell membranes.
AB - It is suggested that glutarimide moiety (2,6-piperidinedione) with the intact
imide group (OC-NH-CO) and substituted at alpha or beta position in the ring, is
acting as the carrier molecule (vector), which transports biologically active
substituents (functional groups) through cell membranes. The results obtained
from quantum chemical calculations and experimental studies indicate that
structural features and physicochemical properties of glutarimide moiety are
remarkably similar with those of uracil derivatives. Therefore, glutarimide drug
may interact with specific receptors involved in transport of uracil and thymine
nucleosides and it may easily cross biological membranes. (c) 2000 Harcourt
Publishers Ltd.
PMID- 10783492
TI - Parathyroid hormone may be a cancer promoter - an explanation for the decrease in
cancer risk associated with ultraviolet light, calcium, and vitamin D.
AB - Epidemiological studies reporting an inverse association between sunlight
exposure and risk for cancers of the breast, colon, and prostate, have not yet
been explained. Since ultraviolet (UV) light promotes dermal vitamin D
generation, studies suggesting that dietary calcium and vitamin D may likewise
have cancer-preventive activity are potentially of relevance. UV light, calcium,
and vitamin D have the common property of suppressing parathyroid hormone (PTH)
production; these considerations raise the possibility that PTH may have
promotional activity for certain cancers. PTH might function indirectly in this
regard, by increasing hepatic production of the progression growth factor IGF-I,
a likely cancer promoter. A more direct role is suggested by recent evidence that
many cancers express receptors for PTH/PTH-related protein; these receptors
mediate co-mitogenic and/or pro-invasive signals in some cancers. High risk for
previous or concurrent neoplasms has been reported in patients with parathyroid
adenomas. In light of the increase in cancer risk associated with hypertension,
it is notable that PTH levels are typically increased in salt-sensitive
hypertensives. Prospective case-control studies examining serum PTH in relation
to subsequent cancer risk appear warranted.
PMID- 10783493
TI - Toward a wholly nutritional therapy for type 2 diabetes.
AB - It may now be feasible to target specific supplemental nutrients to each of the
key dysfunctions which conspire to maintain hyperglycemia in type 2 diabetes:
bioactive chromium for skeletal muscle insulin resistance, conjugated linoleic
acid for adipocyte insulin resistance, high-dose biotin for excessive hepatic
glucose output, and coenzyme Q(10) for beta cell failure. Nutritional strategies
which disinhibit hepatic fatty acid oxidation (involving hydroxycitrate,
carnitine, pyruvate, and other adjuvants) may likewise prove beneficial - in the
short term, by decreasing serum free fatty acids and, in the longer term, by
promoting regression of visceral obesity. The nutrients and food factors
recommended here appear to be safe and well tolerated, and thus may have
particular utility for diabetes prevention.
PMID- 10783494
TI - The origins of western obesity: a role for animal protein?
AB - A reduced propensity to oxidize fat, as indicated by a relatively high fasting
respiratory quotient, is a major risk factor for weight gain. Increased insulin
secretion works in various ways to impede fat oxidation and promote fat storage.
The substantial 'spontaneous' weight loss often seen with very-low-fat dietary
regimens may reflect not only a reduced rate of fat ingestion, but also an
improved insulin sensitivity of skeletal muscle that down-regulates insulin
secretion. Reduction of diurnal insulin secretion may also play a role in the fat
loss often achieved with exercise training, low-glycemic-index diets,
supplementation with soluble fiber or chromium, low-carbohydrate regimens, and
biguanide therapy. The exceptional leanness of vegan cultures may reflect an
additional factor - the absence of animal protein. Although dietary protein by
itself provokes relatively little insulin release, it can markedly potentiate the
insulin response to co-ingested carbohydrate; Western meals typically unite
starchy foods with an animal protein-based main course. Thus, postprandial
insulin secretion may be reduced by either avoiding animal protein, or
segregating it in low-carbohydrate meals; the latter practice is a feature of fad
diets stressing 'food combining'. Vegan diets tend to be relatively low in
protein, legume protein may be slowly absorbed, and, as compared to animal
protein, isolated soy protein provokes a greater release of glucagon, an enhancer
of fat oxidation. The low insulin response to rice may mirror its low protein
content. Minimizing diurnal insulin secretion in the context of a low fat intake
may represent an effective strategy for achieving and maintaining leanness.
PMID- 10783495
TI - The worldwide controversy about the polymorphism of the vitamin D receptor gene
and bone mineral density.
PMID- 10783496
TI - Maternal serum alpha-fetoprotein and altitude.
AB - Maternal serum alpha-fetoprotein (MS-alphaFP) testing is widely used to screen
for fetal defects. MS-alphaFP concentrations are affected by a number of
variables such as gestational age, maternal weight, number of fetuses, race, and
insulin-dependent diabetes. Undefined geographic factors may also influence MS
alphaFP. We have examined the effect of altitude in a sample of 1063 MS-alphaFP
results selected to span a range of altitudes. The study sample was subjected to
linear regression with and without a term for altitude, and multiple-of-the
median (MoM) values were calculated before and after adjusting for altitude. The
median MS-alphaFP was found to decrease an average of 1 ng/mL for every 1100 ft
increase in altitude, a change approximately equivalent to that seen with an
increase in maternal weight of 6 lb. Adjusting for altitude resulted in the
reclassification of 36 of 1063 patient results (3.4%), although the clinical
utility of this adjustment remains unexamined.
PMID- 10783497
TI - Antisense antiviral agents: about the optimal approach.
AB - The vast majority of recent efforts to synthesize effective antisense
preparations for antiviral therapy have been made by using oligonucleotides,
agents able to inhibit only a relatively small portion of the viral genome. That
is the main reason why this approach is far from optimal. The optimal approach,
however, is the accomplishment of the total inhibition of the viral genome. Here,
a general protocol for preparation of the antisense antiviral agents with optimal
properties for in vivo application is proposed, irrespective of the viral genome
nucleotide sequence.
PMID- 10783498
TI - Adequate selection of anticancer agents: a task which can be fulfilled by
changing selection criteria.
AB - An analysis of anticancer agents' selection based on the effect on tumor cell
colony formation inhibition after exposure to the agent under investigation is
performed. The real significance of such a method, as well as the probable
negative clinical consequences of its use for screening of agents for cancer
therapy are pointed out. Also, principles of overcoming the inadequacy of tumor
cell clones' expansion inhibition tests and their equivalents are proposed.
PMID- 10783499
TI - Immunologic memory in the placenta: a lymphocyte recirculation hypothesis.
AB - The placenta is an immunologically unique organ where a balance between maternal
immunity and fetoplacental well-being must be maintained for successful pregnancy
to occur. The intervillous blood is important in this context, yet little is
known about local immunologic processes, particularly how placenta-specific
memory immune responses are maintained. Using malaria as an illustrative case, we
describe an hypothetical model in which recirculation of memory T lymphocytes
from the intervillous blood to local lymphoid tissue facilitates maintenance of
local memory immunity. This explains how memory cells might be retained when the
placenta is expelled at parturition and thus remain available for rapid recall
from the local lymphoid tissue to the intervillous space when exposure to the
same antigenic stimulus occurs in subsequent pregnancies. Study of cell-mediated
immunity to infections like malaria in the intervillous blood and the use of
animal models will be necessary to provide proof for this hypothesis.
PMID- 10783500
TI - Effects of electrostatic potentials generated on the surface of the skin by
wearing synthetic and semisynthetic fabrics on physical condition, mood and
behavior: role of acupuncture points.
AB - Synthetic and semisynthetic fabrics generate electrostatic potentials on the
surface of the skin. The author suggests that the effects of electrostatic
potentials on physical and psychological condition are mediated by acupuncture
points. The author further suggests that electrostatic charges on the surface of
the skin may affect virtually all physiological functions, mood, and behavior.
PMID- 10783501
TI - Pitfalls in the determination of common analytes in the critically ill.
AB - In the critically ill, the pre-analytical aspects of blood gas analysis still
require attention from the clinician. Sampling and transport remain critical
factors. Use of drugs may create analytical interferences for common analytes
like glucose and protein. Icterus may falsely reduce creatinine and albumin
values. Changes in the serum or plasma matrix (reduction of protein, increased
covolume of solutes, ...) may furthermore cause important effects on the
distribution of electrolytes. Enzyme activity measurements may be erroneous due
to lack of essential oligoelements or reducing substances. Immunoassays may
suffer from interferences caused by auto-antibodies. In case of hemolysis, a
careful interpretation of test results is mandatory.
PMID- 10783502
TI - From obesity to diabetes: why, when and who?
AB - Obesity is considered as the most important risk factor for type 2 diabetes. We
will briefly discuss why does obesity predispose to diabetes, when does diabetes
occur in obese subjects and who among obese individuals is particularly prone to
develop diabetes. Obesity, especially intraabdominal adiposity, is associated
with increased FFA plasma concentrations which exert a major negative effect on
insulin sensitivity at both muscular and hepatic sites. Various metabolic,
haemodynamic and hormonal theories have been proposed to explain insulin
resistance in obese subjects. A specific role of TNF-alpha has been recently
suggested. However, besides insulin resistance, defective insulin secretion is a
prerequisie for the development of overt type 2 diabetes. Both lipotoxicity and
glucotoxicity may initiate and perpetuate a vicious circle responsible for the
metabolic deterioration. Diabetes occurs as a late phenomenon in obesity and is
preceded by years of impaired glucose tolerance. The progression to diabetes is
heralded by an inability of the B cell to maintain its previously high rate of
insulin secretion in response to glucose in face of insulin resistance. This
propensity to develop type 2 diabetes may be genetically determined and/or
triggered by environmental factors. The evolution from obesity to diabetes
represents a continuum that progresses through different phases in which defects
in both insulin action and insulin secretion play a critical interaction and must
be looked at in concert.
PMID- 10783503
TI - Comparative in vitro activity of cefepime against strains isolated from intensive
care and haematology patients.
AB - The aim of the study was to evaluate cefepime, a "fourth generation"
cephalosporin, for its in vitro activity in comparison with 5 other broad
spectrum antibiotics against clinical isolates from ICU and haematology patients.
The strains were isolated from blood (8%), lower respiratory tract (41%), upper
respiratory tract (14%), urine (20%) and other sites (17%). They were divided
into: 28 non-inducible Enterobacteriaceae, 35 inducible Enterobacteriaceae, 20
non-fermenters, 10 S. aureus and 10 Streptococcus spp. The MIC-values were
determined by E-test. Overall, the rank order of susceptibility was cefepime
(93%), imipenem (90%), piperacillin-tazobactam (81%), ciprofloxacin (79%),
ceftriaxone (75%) and ceftazidime (74%). Only cefepime was able to inhibit all
inducible Enterobacteriaceae. Against Pseudomonas aeruginosa, cefepime had the
same activity as ceftazidime. With the exception of ceftazidime (65%), all beta
lactams demonstrated good activity against Gram positive cocci. The excellent
activity against most Gram negative and Gram positive pathogens suggests that
cefepime may be useful in the treatment of serious infections in the described
patient population.
PMID- 10783504
TI - Hereditary angioneurotic edema: review of the literature.
AB - Congenital C1-inhibitor deficiency, or hereditary angioneurotic edema (HAE), is a
rare autosomal dominant disease due to alterations in the C1 inhibitor gene that
results in a deficiency of antigenic and/or functional C1-INH. Affected patients
are heterozygous, and their deficiency is incomplete, many of them having up to
20% of the normal amount of the inhibitor. The disease is characterised by
recurrent, circumscribed, non-pitting, and non-pruritic subepithelial swellings
of sudden onset, which fade during the course of 48-72 hours, but can persist up
to 1 week. Lesions can be solitary or multiple and primarily involve the
extremities, larynx, face, and bowel wall. Bradykinin is believed to be the main,
but certainly not the sole, mediator responsible for the bouts of edema in HAE.
The diagnosis is suggested by family history, the lack of accompanying pruritus
or urticaria, the presence of recurrent gastrointestinal attacks of colics, and
episodes of laryngeal edema. Diminished C4 concentrations during symptomatic
periods are highly suggestive for the diagnosis. Further laboratory diagnosis
depends on demonstrating a deficiency of C1-INH antigen (type I) in most
kindreds, but some kindreds have an antigenically intact but dysfunctional
protein (type II) and require a functional assay to establish the diagnosis.
Prophylactic administration of either attenuated androgens or protease inhibitors
has proved useful in reducing frequency or severity of attacks. Infusions of a
vapour-heated C1-INH concentrate are safe and effective means of both preventing
and treating attacks. Nevertheless, this treatment is expensive and this extract
is not readily available. It is emphasised that administration of angiotensin
converting enzyme inhibitors is contraindicated in patients suffering from
protease inhibitor deficiency states.
PMID- 10783505
TI - Q fever after a journey in Syria: a diagnosis suggested by bone marrow biopsy.
AB - A Belgian patient developed Q fever after a journey in Syria. Coxiella burnetii
infection was diagnosed because of the presence of granulomas with a central
vacuole in a bone marrow biopsy. During doxycycline treatment all his symptoms
disappeared.
PMID- 10783507
TI - [Rieger's nasal flap. History, technical refinements and indications].
AB - Rieger's flap, described by Rieger as a nasal rotation flap, has often been given
other names and descriptions in the literature. We consequently felt an overview
of the development, characteristics and technique of Rieger's flap was in order,
with the goal of helping surgeons use it to best avail. Rieger's flap is
irreplaceable for reconstructing defects of the lower third of the nose located
on or near the midline. Variants of Rieger's flap can be used to treat defects
located higher up on the nose. Four cases are reported to illustrate these
indications.
PMID- 10783506
TI - Multidrug-resistant tuberculosis spondylitis.
AB - We report a case of multidrug-resistant spinal tuberculosis complicated by
epiduritis and paraspinal abscess in a 68-year-old black woman. Multidrug
resistant tuberculous spondylitis is still rare in Belgium. Two others cases were
reported from 1992 to 1997. The optimal therapy is not standardized and the
mandatory duration of treatment is not known. Clinical presentation, radiological
findings, and treatment are presented. The need for prompt diagnosis and optimal
therapy is emphasized.
PMID- 10783508
TI - [Homage to Leon Tripier. Description of the first musculocutaneous flap and
current indications].
AB - The double pedicle flap taken from the upper lid was described for the first time
in 1888 by Tripier. To our knowledge, it is the first case of reconstruction by a
myocutaneous flap described in the literature. Other authors subsequently
modified the first description. The same flap taken with a single inner pedicle
is now usually employed. For the authors, the Tripier's flap, with a double and
permanent pedicle, still has some indications in eyelid reconstruction.
PMID- 10783509
TI - [Indications for the Schmid-Meyer frontal-temporal flap for nasal reconstruction.
Four clinical cases].
AB - The fronto-temporal flap described by Schmid and modified by Meyer is a tubular
flap with an internal supraciliary pedicle which allows the transposition of the
temporal skin with the addition of ear cartilage on the tip of the nose or the
ala nasi. This meticulous reconstruction requires four stages which are workable
under local anesthesia. Four clinical cases allow to specify the advantages and
the drawbacks of this technique. They place this technique in the therapeutic
possibilities between the composite grafts and various local and distant flaps.
PMID- 10783510
TI - [Survivorship of breast implants used in breast reconstruction. 949 implants].
AB - The authors present from a series of 949 implants their method to calculate the
life span of a mammary implant in the framework of breast reconstruction after
cancer. In this statistical study, they have calculated the median life span of
breast implants (loss of half of staff) by distinguishing it according to each
type of implant (content, brand, indication...). The global median life span of a
breast implant is 127 months. The median life span of a silicone gel-filled
implant is superior than a saline implant because the frequency of deflation of
saline implants is more important than the first one, despite that the real
rupture percentage of silicone gel-filled implants is under-evaluated by the
number of asymptomatic rupture. For saline implants, the median life span is
clearly decreased by the initial under-inflation (108 months against 127 months)
doubling the secondary deflation risk. In this series, the authors have been able
to compare the evolution of implants according to their initial indication
(reconstruction or aesthetic) and sometimes at a same patient, they have not
observed significant difference of the median life span over a period of five
years for an implant used in breast reconstruction after cancer or for an implant
used in symmetricalization. In this series, the life span of saline implants is
significant different in function of the brand of the implant demonstrating the
comparative study usefulness by brands.
PMID- 10783511
TI - [The modiolus. Comparative anatomy, embryological and physiological review,
surgical importance].
AB - Monkeys, imitators of man's gesture never shared smile with him and their facial
expressions only result in grimaces. Study of animal anatomy may explain why
subtle expressions of the lips are a more man's special gift than laughter. These
fine movements are related to a subcutaneous muscular structure termed modiolus,
which is the meeting point of muscles involved in the motion of mouth and
comparative anatomy shows this structure to be better defined in Man than in
other primates. Embryologically, muscles that form the modiolus derive from a
cellular concentration in the region of the second branchial arch. It is then
logical to see these muscles converge to the corner of the mouth to form the
modiolus, as they emerge from a common area. Functioning of the modiolus is
complex, as its position may change many times in a minute to allow the
orbicularis oris muscle to take any position and do any movement as if it was
inserted on bone. With its complex physiology, the modiolus is of critical
importance in the subtle expressions of the lips and must be preserved or
reconstructed when performing repair of full-thickness tissue defects of lips.
PMID- 10783512
TI - [Eyelid sebaceous carcinoma. A case report with literature review].
AB - Sebaceous carcinoma of the eyelids is a rare malignancy of which most cases
require extensive excision followed by usually complete eyelid reconstruction. We
report a case developed from the Meibomius glands of the lower eyelid. Complete
excision was achieved by removing the entire eyelid 'en bloc'. Reconstruction was
with a composite, chondromucosal septal graft layered on an upper eyelid,
musculocutaneous, transposition flap based on a lateral pedicle. After a brief
review of the relevant literature, the advantages and disadvantages of the
various methods of complete lower eyelid reconstruction are discussed.
PMID- 10783513
TI - [Radial antibrachial islet flap based on distal perforating arteries. A clinical
case].
AB - The frequency of the hand trauma involving tissue losses generated the research
for developing new technical solutions more simple and economic. The regional
flaps, such as the distal pedicle Chinese flap, are usually surgeon's first
choice whenever the local resources are over passed. Still, this type of Chinese
flap would claim a major disadvantage as they involve the sacrifice of a vascular
axis of the hand, sometimes even the dominant one. The operating team, would be
able to avoid this inconvenience when using distal perforators based-on
antibrachial radial flap; moreover, this technique would allow the covering of
the substance losses, as far as the metacarpophalangeal joints. The authors
report a clinical case.
PMID- 10783514
TI - [From a single vertical scar to vertical mammaplasty. From Louis Dartigues (1869
1940) to Claude Lassus (1933)].
AB - The cutaneous sequelae left by mammaplasties have always constituted a major
problem as well for the patients as for the surgeons. Since the turn of the
century and the birth of modern mammary corrections, surgeons have tried to
reduce these scars, while avoiding the impairment of the vascularisation of the
mammary gland, the nipple-areola complex and the skin. L. Dartigues proposed, in
1924, the use of a single subareolar vertical scar for the correction of limited
mammary ptosis. F. Lotsch introduced, in 1923, the rudiments of the future
vertical mammaplasty by associating a peri-areolar scar to the single vertical
subareolar scar. In 1971, C. Lassus, who had become interested and had been using
Lotsch's technique since 1964, abandoned the technique for a while, but returned
to these basic technique of Lotsch which he modified over the years and made it
applicable in 1980 to ptosed and most hypertrophied breasts. This article is also
concerned with the historic evolution of the scars left by mammary corrections
and with the mastopexy procedures.
PMID- 10783515
TI - [Medical demographics and plastic surgery in France: current situation and
projections].
PMID- 10783517
TI - Photochemical and chemical oxidation of mexiletine and tocainide. Structure
elucidation of the major products.
AB - Mexiletine (mex) and tocainide (toc) are antiarrhythmic drugs of closely related
structure. Several degradation products are formed by interaction with both light
and oxidizing agents in the case of mex, and only by oxidants with toc. On the
basis of the identified structures, the decomposition reactions can be classified
into two types (Scheme 1). Type I is an oxidative cyclization reaction producing
the oxazepine derivative 1 from mex and the diazepine derivative 3 from toc. In
reaction type II side chain oxidized products (2 or 4 and 5) are formed. While
tocainide.HCl has proved to be photostable, in solid mexiletine HCl the oxazepine
derivative was observed after several days' exposure to direct sunlight. The
pharmacopoeias (Ph.Eur.3, USP 23), however, do not prescribe light-protection for
mex.HCl.
PMID- 10783516
TI - Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors.
AB - A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is
structurally related to 2,3,4,4a,5,6-hexahydrothieno [3,2-h]cinnolin-3-one 1, a
weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil
collagenase). Preliminary SAR studies have shown that while C4a-methyl, C7
acetylamino, C7 and C8-nitro substitution, and C4-C4a olefination provided no
increase in activity relative to 1, C8-acetylamino substitution as in 5 and 8 was
favourable. Moreover, to predict how the thieno[3,2-h]cinnolinone inhibitors
might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8
crystal structure. These studies revealed that inhibitor 9 does not seem to be
able to coordinate the catalytically-active zinc ion but preferably interact with
the peptide-binding region of the active site.
PMID- 10783518
TI - Design and synthesis of some oxadiazolyl, thiadiazolyl, thiazolidinyl, and
thiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents.
AB - Four series of 1H-pyrazole derivatives have been synthesized. The first series
was prepared by cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-1H
pyrazole-4-carbaldehyde aroyl-hydrazone 4a-c with acetic anhydride to afford the
corresponding oxadiazoline derivatives 5a-c. The other series were prepared by
the cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-4-substituted
thiocarbamoylhydrazonomethyl-1H-pyrazole 6a-c with acetic anhydride, ethyl
bromoacetate or phenacyl bromide giving rise to 3-(5-bromo-2-thienyl)-1-phenyl-4
[3-acetyl-5-(N-substituted acetamido)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-1H
pyrazoles 7a-c, 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted- 4-oxothiazolidin
2-ylidenehydrazonomethyl)-1H-pyrazoles 8a-c, or 3-(5-bromo-2-thienyl)-1-phenyl-4
(3-substituted-4- phenyl-2,3-dihydrothiazol-2-ylidenehydrazonomethyl)-1H-pyraz
oles 9a-c respectively. Some of these compounds showed anti-inflammatory,
antibacterial or antifungal activities comparable to that of Proquazone,
Ampicillin, or Clotrimazole respectively.
PMID- 10783519
TI - Studies on the chemistry of thienoannelated O,N- and S,N-containing heterocycles.
Part 19: thieno[2,3-b][1,4]thiazines with calcium antagonistic and potassium
opening activities.
AB - In this study novel substituted 6-benzyl-thieno[2,3-b][1,4]thiazines with an urea
moiety were synthesized. Structural modifications of the amino side chain were
carried out with the aim of finding tissue specific compounds. The effects on
papillary muscles, right atria, aortic strips, and terminal ilea were
investigated. Compounds 10c and 10d showed the most potent negative inotropic
effect. The calcium antagonism of all derivatives occurred in a non-competitive
manner, which may indicate that they also have potassium channel opening
activities.
PMID- 10783520
TI - Hypochlorous acid, a major oxidant produced by activated neutrophils, has low
effect on two pyridobenzazepine derivatives, JL 3 and JL 13.
AB - JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]- [1,5]benzoxazepine
fumarate) and JL 3 (10-(4-methylpiperazin-1- yl)pyrido[4,3
b][1,4]benzothiazepine), two pyridobenzazepine derivatives structurally related
to clozapine, were selected for further development. Due to their structural
similarity to clozapine, they are haunted by the spectre of clozapine-induced
agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to
oxidation than clozapine. In the present paper, using an in vitro procedure, we
report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both
drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are
very slow and little secondary product is formed. Moreover, in contrast to
clozapine, the products that were formed are not reactive and thus do not react
with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug
induced agranulocytosis is due to a reactive metabolite formed by neutrophils or
their precursors, JL 3 and JL 13 would not be expected to cause the same adverse
reaction.
PMID- 10783521
TI - Does [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-
dichloroplatinum(II) act on the hormone-sensitive, murine breast cancer as a
biological response modifier? Part 1: The MXT-M-3.2 breast cancer stimulates the
growth of an identical second graft; [meso-1,2-bis(2,6-dichloro-4
hydroxyphenyl)ethylenediamine]dichloroplat inum (II) inhibits this process.
AB - The MXT-M-3.2 breast cancer implanted into female B6D2F1 mice accelerates the
growth of an identical second tumor. This process is inhibited by [meso-1,2
bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II). The
possible modes of action of this compound as a biological response modifier are
discussed.
PMID- 10783522
TI - Protecting the legacy: the nurse-patient relationship and the therapeutic
alliance.
PMID- 10783523
TI - Effect of cognitive therapy on depression in rural, battered women.
AB - The purpose of this pilot study was to explore the feasibility of a future
randomized trial to determine the effect of a 20-week cognitive therapy
intervention (INSIGHT) on depression in battered women. An experimental, 2 group
pretest and posttest design was used in this study with 18 rural women who have
experienced battering and 9 rural women who have not. The results of this study
lend feasibility to other studies using INSIGHT with a larger, randomized sample.
The 50% attrition rate for the battered women suggests the need for phase
specific sensitivity in future research.
PMID- 10783524
TI - Predicting substance abuse and comorbidity in rural women.
AB - Substance abuse in women is underdiagnosed. Moreover, women are more likely to
have a primary comorbid psychiatric disorder that complicates diagnosis and
treatment. The purpose of this study was to identify risk factors that would
predict substance abuse and primary comorbid psychiatric disorders in rural
women. Discriminant function analysis identified 2 factors, alcohol beliefs and
threats of minor violence, which correctly identified substance abusing women
from nonsubstance abusing women, and women with nonsubstance use psychiatric
disorders from those with no psychiatric disorder. These 2 functions correctly
classified 69% of women in the study. Psychiatric diagnoses and nursing
implications are discussed.
PMID- 10783526
TI - Symptom development in bulimia nervosa: a comparison of women with and without a
history of anorexia nervosa.
AB - Identifying women at risk for developing bulimia nervosa (BN) is an important
area of study for psychiatric-mental health nurses. Of those who develop BN, a
large proportion of women have been diagnosed earlier with anorexia nervosa (AN).
It has been posited that women who are treated for AN are often only partially
recovered. Although their weights become clinically acceptable, they often
continue to restrict food; this typically leads to a binge eating and purging
cycle and the development of BN. A history of AN is viewed as a possible risk
factor for the development of BN. This study compared women seeking treatment for
BN with a prior history of AN, and those without this history on selected
variables. A profile emerged and is described supporting a distinct subgroup with
prior AN. Findings from this study have implications for early detection of and
extended follow-up care after treatment for AN.
PMID- 10783525
TI - African American grandmothers' perceptions of caregiver concerns associated with
rearing adolescent grandchildren.
AB - In 1996, grandparents were the sole providers of care for 269,000 grandchildren.
Research findings indicate that grandmothers are usually the primary caretakers
of grandchildren. Previous issues associated with raising grandchildren vary, but
usually relate to the grandparents' health, financial concerns, or lack of social
support. This qualitative descriptive study was designed to describe African
American grandmothers' perceptions about the burdens of raising adolescent
grandchildren. Using this approach, the researchers were able to study the
richness and diversity of the grandmothers' perceptions. Data were collected from
35 grandmothers through a focus group (n = 7) and during a 4-day intervention
research study (n = 28) entitled "Grandmother-Grandchild Health Promotion
Program." Numerous concerns were voiced by both groups, but those stated most
frequently were associated with the well-being of grandchildren (grandchildren's
sexual behavior, potential drug use, and potential risk of encountering violence)
and relational conflicts with adult children. Unexpected findings were the
absence of stated concerns associated with the grandmothers' financial situation
or health. Recommendations for intervention, clinical practice, and research are
discussed.
PMID- 10783527
TI - Aversiveness of traditional psychiatric patient restriction.
AB - This article is a literature review of traditional psychiatric patient
restriction and the consequential harm that the patient experiences. Though the
obtainment of theoretical objectives and short-term overt behavioral results
appear to be gained through psychiatric constraint measures, injurious effects to
the patient have been recorded with resultant impediment to the restoration of
psychological health. This article asserts the necessity for the use of
alternative measures, which have been shown to be successful in restoring control
while maintaining and promoting the dignity and psychological health of the
patient.
PMID- 10783528
TI - Cost-effectiveness analysis of case management versus a routine community care
organization for patients with chronic schizophrenia.
AB - This article reports the economic analysis of a study on the implementation of
case management in the Community Psychiatric Nursing Service (CPNS) caring for
chronic schizophrenic clients in Hong Kong. The purpose of the study was to
compare the outcome of case management service with the conventional practice
CPNS. Sixty-two subjects participated in the analysis. Cost-effectiveness
analysis showed that case management costs more in Hong Kong $3,600 (US$450) per
person and that over a 5-month period, case management was associated with
improvements in psychological and functional outcomes and patient satisfaction.
The results of this study will inform policy makers about resource allocation and
policy development in the implementation of case management for the care of
mentally ill clients.
PMID- 10783529
TI - Origin of Finnish mutations causing aspartylglucosaminuria.
AB - Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease
highly enriched in Finland where one mutation AGUFin major is responsible for 98%
of the AGUFin alleles. Another mutation AGUFin minor has been identified in eight
compound heterozygote patients who have AGUFin major mutation in their other
allele. In addition four compound heterozygote patients have AGUFin major in one
allele and unknown AGUFin mutation in the other allele. To study the origin of
these mutations the haplotype analysis was performed on six patients with AGUFin
minor mutation and four patients with unknown AGUFin mutation using nine
microsatellite markers on the 7.6 cM chromosome region on 4q28-4qter. The
haplotype data suggest that one founder mutation is responsible of all AGUFin
minor alleles. Allelic association was also observed in AGUFin major chromosomes.
Patients with unknown mutation did not share a common haplotype and therefore
most likely have different origin.
PMID- 10783530
TI - Inheritance of species differences in female receptivity and song requirement
between Drosophila virilis and D. montana.
AB - Females of two Drosophila virilis group species, D. virilis and D. montana, have
different requirements for the courting males. In the present study we have
examined species differences in female receptivity and male courtship song
requirement using females' acceptance signal instead of copulation for measuring
female readiness to mate. Behavior of D. virilis and D. montana females and F1
and backcross hybrid females was observed in a single-pair courtships with D.
virilis and D. montana males and normal and wingless (mute) F1 hybrid males. D.
virilis females were very receptive and they commonly accepted the courtship of
males unable to produce courtship song. D. montana females, on the contrary, had
a low receptivity and these females accepted the courting male only after hearing
his song. Interspecific F1 and backcross (BCm) females resembled D. virilis more
than D. montana in their receptivity. These females, however, resembled D.
montana in their song requirement. These findings suggest that female song
requirement and female receptivity are determined by different genetic factors.
PMID- 10783531
TI - Autosomal and sex chromosomal polymorphisms with multiple rearrangements and a
new karyotype in the genus Rhipidomys (Sigmodontinae, Rodentia).
AB - Two diploid numbers and five karyomorphs were found in ten specimens of
Rhipidomys (Sigmodontinae, Rodentia) from three states in Brazil: 2n = 50 from
Amazonas, and 2n = 44 from Mato Grosso and Bahia. CBG, GTG, and RBG-banding and
Ag-NOR analyses were performed, as well as fluorescence in situ: hybridization
with (T2AG3)7 probes. The new diploid number of 2n = 50 was associated with two
different fundamental numbers (FN = 71 and 72) as a result of pericentric
inversions and addition/deletion of constitutive heterochromatin. The samples
from two localities (Aripuana and Vila Rica) in the state of Mato Grosso shared
2n = 44 and FN = 52, but their karyotypes differed because of pericentric
inversions. Although the single specimen from Bahia had the same diploid number
as the samples from Mato Grosso, its karyotype and FN were completely
distinctive. Karyological comparison of GTG-banding patterns revealed total
homology between the karyotypes of the specimens from Bahia and Mato Grosso,
implying the occurrence of 14 autosomal pericentric inversions. Homologies
between ten of the autosomes in the karyotypes with 2n = 50 (FN = 72) and 2n = 44
(from Vila Rica, MT) were demonstrated. The differentiation between 2n = 44 and
2n = 50 involved five pericentric inversions, addition/deletion of constitutive
heterochromatin in both autosomes and sex chromosomes, at least one Robertsonian
rearrangement and other not detected rearrangements. Despite the remarkable
number of rearrangements, interstitial telomeric sites (ITS) were not detected.
Sex chromosomes also exhibited polymorphism in size and morphology.
PMID- 10783533
TI - Genomic compatibility between two phyllotine rodent species evaluated through
their hybrids.
AB - In order to investigate the genomic compatibility between allopatric rodent
species, Phyllotis darwini and Phyllotis magister, we have studied several
cytogenetic and reproductive features of their laboratory hybrids. Of thirty-one
pairings between species, only five were successful, producing eleven newborns.
Like parents, hybrids had 38 metacentric chromosomes, except for the
subtelocentric Y chromosome inherited from P. magister. There was almost total C
and G band correspondence between homeologous autosomes. However, parental sex
chromosomes had different morphology, C and G bands. Ag-NOR bands appeared as
small telomeric Ag+ regions, distributed in four chromosomal pairs of darwini,
three of magister and four homeologous chromosomes of the hybrids. The three
forms had similar indexes of NOR activity per cell, in spite of the variability
in NOR expression which was always detected. Usually, only one member of parental
homologous chromosomes showed AgNOR+; nevertheless, both homeologous chromosomes
were active in many hybrid cells. The frequencies of cells that expressed their
ribosomal genes in the two homologous or homeologous NOR chromosomes were similar
in parental and hybrid cells. These results strongly suggest that ribosomal genes
of both parental genomes would function codominantly in the hybrids. The gonad
histological and morphometric analyses showed that hybrids conformed to Haldane's
rule, since females were fertile and males were infertile. Our results indicate
that P. darwini and P. magister genomes can function in relative harmony and
compatibility when they are placed together in their laboratory generated
hybrids, suggesting that these species have few genetic differences, probably
because they have recently diverged.
PMID- 10783532
TI - Ribosomal RNA gene loci and silver-stained nucleolar organizer regions associated
with heterochromatin in Alaskan char Salvelinus malma and chum salmon
Oncorhynchus keta.
AB - Nucleolus-forming 5.8S, 18S and 28S ribosomal RNA gene (rDNA) loci were assigned
by fluorescence in situ hybridization (FISH) to the distal half of the short arms
of a large-sized submetacentric pair in the Alaskan char (Salvelinus malma) and
to the distal region of the long arms of a medium-sized submetacentric pair in
the chum salmon (Oncorhynchus keta), respectively. In each species, heteromorphic
FISH signals, spanning whole satellite region and secondary constriction, imply
an intraspecific variation in the size of rDNA loci. Size variation of silver
stained nucleolar organizer regions (AgNORs) was also apparent between or within
the assigned rDNA loci in each species, suggesting a possible inter- or
intralocus inactivation of rDNAs. C-band positivity of assigned rDNA loci and
AgNORs unequivocally showed their association with heterochromatin in these
species.
PMID- 10783534
TI - Applicant self-selection: correlates of withdrawal from a multiple hurdle
process.
AB - The authors examined applicant self-selection from a multiple hurdle hiring
process. The relationships of the selection status of 3,550 police applicants
(self-selected out prior to 1 of the hurdles, passing, or failing) and
perceptions of the organization, commitment to a law enforcement job,
expectations regarding the job, employment status, the need to relocate, the
opinions of family and friends, and perceptions of the hiring process were
examined. Differences between those who stayed in the process and those who self
selected out were observed in most areas, and those who self-selected out at
early stages differed from those self-selecting out at later stages. African
Americans' and women's perceptions also differed from the majority group,
indicating some of the difficulties an organization faces in attempting to
diversify.
PMID- 10783535
TI - Adapting the cognitive interview to enhance long-term (35 years) recall of
physical activities.
AB - The cognitive interview (CI) was modified for use in an epidemiological study in
which respondents were asked to recall their daily physical activities from the
distant past (35 years ago). In comparison to a traditional epidemiological
interview, the CI elicited many more responses and also more precise responses.
Several practical costs, however, were incurred by the CI: additional time to
train interviewers and to conduct interviews and difficulties in coding the
responses. The costs and benefits of conducting the CI are addressed, along with
conceptual and methodological challenges. The article ends with an existential
question: Is the CI a singular technique if it can be modified so radically for
different settings?
PMID- 10783536
TI - Interindividual differences in intraindividual changes in proactivity during
organizational entry: a latent growth modeling approach to understanding newcomer
adaptation.
AB - Intraindividual change over time is the essence of the change phenomenon
hypothesized to occur in the individual newcomer adaptation process. Many
important adaptation questions cannot be answered without an adequate
conceptualization and assessment of intraindividual change. Using a latent growth
modeling approach to data collected from 146 doctoral program newcomers over 4
repeated measurements spaced at 1-month intervals, the authors explicitly modeled
interindividual differences in intraindividual changes in newcomer proactivities
(information seeking, relationship building) and proximal adaptation outcomes
(task mastery, role clarity, social integration) during organizational entry.
Results indicated that changes in proactivity may be related to newcomer
characteristics and adaptation outcomes in interesting ways that have not been
previously examined.
PMID- 10783537
TI - A longitudinal study of relations between job stressors and job strains while
controlling for prior negative affectivity and strains.
AB - Interpretation of observed relations between job stressors and job strains in
cross-sectional surveys is often ambiguous because of possible 3rd variables
(both stable background factors, such as personality, and transitory occasion
factors, such as mood). In this longitudinal study, negative affectivity (NA) and
strains were assessed both in college and later on the job. Stressors were
assessed only on the job. Evidence was found that some background factors
affected measures of job stressors and job strains in that college measures were
significantly related to subsequent measures on the job. Relations between job
stressors and job strains, however, were in most cases not affected significantly
when prior strains and NA were controlled for. Furthermore, the results suggested
that NA measures are subject to occasion factors.
PMID- 10783538
TI - Selection based on merit versus demography: implications across race and gender
lines.
AB - In a replication and extension of the study by M. E. Heilman, M. C. Simon, and D.
P. Repper (1987), 201 undergraduates participated in a simulation in which they
experienced differing selection procedures and outcome feedback. Selection
procedures did not have the deleterious effects on women that were found
previously. Instead, race interacted with gender to moderate this relationship,
and outcome played a significant role in participant self-evaluations. Black
participants rated their leadership ability highest when both chosen
preferentially and given negative outcome feedback, apparently because of a
desire to maintain positive self-esteem. The latter explanation was supported in
a follow-up study in which undergraduates (n = 80) worked in groups and received
negative outcome feedback from either a racially similar or racially different
experimenter. Theoretical and practical implications relating to diversity and
self-appraisal management are discussed.
PMID- 10783539
TI - Conscientiousness and agreeableness as predictors of rating leniency.
AB - The authors studied the relationship between the Big Five personality factors and
rating elevation among 111 students making peer evaluations. It was hypothesized
that Conscientiousness (C) scores would be negatively correlated with rating
level and that Agreeableness (A) scores would be positively correlated with
rating level. We further predicted that individuals who were low on C and high on
A would produce the most elevated ratings. As predicted, A scores were positively
related to rating level (.33, p < .01) and C scores were negatively correlated
with rating level (-.37, p < .01). Using the strong hypothesis test (P. Bobko,
1986), the authors found that ratings by low C and high A individuals were more
elevated than all other groups of students combined (p < .01).
PMID- 10783540
TI - Personality and job satisfaction: the mediating role of job characteristics.
AB - This study tested a model of the relationship between core self-evaluations,
intrinsic job characteristics, and job satisfaction. Core self-evaluations was
assumed to be a broad personality concept manifested in 4 specific traits: self
esteem, generalized self-efficacy, locus of control, and low neuroticism. The
model hypothesized that both subjective (perceived) job characteristics and job
complexity mediate the relationship between core self-evaluations and job
satisfaction. Two studies were conducted to test the model. Results from Study 1
supported the hypothesized model but also suggested that alternative models fit
the data well. Results from Study 2 revealed that core self-evaluations measured
in childhood and in early adulthood were linked to job satisfaction measured in
middle adulthood. Furthermore, in Study 2 job complexity mediated part of the
relationship between both assessments of core self-evaluations and job
satisfaction.
PMID- 10783541
TI - Action-state orientation: construct validity of a revised measure and its
relationship to work-related variables.
AB - Data from 6 studies (N = 945) were combined to examine the factor structure and
construct validity of J. Kuhl's (1994a) measure of action-state orientation, the
Action Control Scale (ACS). Initial confirmatory factor analysis (CFA) of 4
models showed poor fit with the data. Items that did not perform well were
dropped, and the 4 CFA models were retested, resulting in support for a 3-factor
solution corresponding to the Preoccupation, Hesitation, and Volatility
subscales. Regression analyses demonstrated that the revised ACS subscales
measure a construct distinct from cognitive ability and personality. The revised
subscales showed differential statistically significant relationships with (a)
self-regulatory and self-focus variables and (b) job attitudes and ratings of job
performance. The authors conclude that action-state orientation is a construct
relevant to applied settings and that future research should further examine this
construct.
PMID- 10783542
TI - "I knew we would win": hindsight bias for favorable and unfavorable team decision
outcomes.
AB - This study examined hindsight bias for team decisions in a competitive setting in
which groups attempted to outperform each other. It was anticipated that, because
of self-serving mechanisms, individuals would show hindsight bias only when
decision outcomes allowed them to take credit for their own team's success or to
downgrade another team for being unsuccessful. MBA students playing a market
simulation game made hindsight estimates regarding the likelihood that either
their own or another team would perform well. Consistent with a self-serving
interpretation, when decision outcomes were favorable individuals evaluating
their own team, but not those evaluating another, showed hindsight bias. When
outcomes were unfavorable individuals evaluating their own team did not show
hindsight bias, but those evaluating another team did. Discussion focuses on
implications of hindsight bias in team decision-making settings.
PMID- 10783543
TI - The influence of shared mental models on team process and performance.
AB - The influence of teammates' shared mental models on team processes and
performance was tested using 56 undergraduate dyads who "flew" a series of
missions on a personal-computer-based flight-combat simulation. The authors both
conceptually and empirically distinguished between teammates' task- and team
based mental models and indexed their convergence or "sharedness" using
individually completed paired-comparisons matrices analyzed using a network-based
algorithm. The results illustrated that both shared-team- and task-based mental
models related positively to subsequent team process and performance.
Furthermore, team processes fully mediated the relationship between mental model
convergence and team effectiveness. Results are discussed in terms of the role of
shared cognitions in team effectiveness and the applicability of different
interventions designed to achieve such convergence.
PMID- 10783544
TI - Employee attitude surveys: examining the attitudes of noncompliant employees.
AB - Employees (N = 194) from a wide variety of organizations participated in this
study aimed at describing the attitudes of individuals who refuse to respond to
an employee survey request (noncompliants). Noncompliants, in comparison with
those individuals who would comply with the survey request, possessed greater
intentions to quit, less organizational commitment, and less satisfaction toward
supervisors and their own jobs. Noncompliants also possessed more negative
beliefs regarding how their organization handles employee survey data (e.g., does
not act on survey data). No significant differences were found for work-related
demographic variables, satisfaction with pay, and satisfaction with promotion
opportunities. Implications for survey research are discussed along with methods
to address nonresponse and noncmpliance.
PMID- 10783545
TI - The effect of organizational structure on perceptions of procedural fairness.
AB - This study explored the relationship between 3 dimensions of organizational
structure--centralization, formalization, and size--and perceptions of procedural
and interactional fairness. Data from 11 organizations (N = 209) indicated that,
as predicted, centralization was negatively related to perceptions of procedural
fairness, and organizational size was negatively related to interactional
fairness. However, contrary to predictions, formalization was not related to
perceptions of procedural fairness. Results suggest that organizational structure
and design should play a more prominent role in our thinking about organizational
fairness.
PMID- 10783546
TI - Does computerizing paper-and-pencil job attitude scales make a difference? New
IRT analyses offer insight.
AB - The measurement equivalence of 2 scales of the Job Descriptive Index (JDI; P. C.
Smith, L. M. Kendall, & C. L. Hulin, 1969), the Supervisor Satisfaction scale and
the Coworker Satisfaction scale, was examined across computerized and paper-and
pencil administrations. In this study, employees in 2 organizations (N = 1,777)
were administered paper-and-pencil versions of the scales, and employees in a
third organization (N = 509) were administered a computerized version. A newly
developed item response theory (IRT) technique for examining differential test
functioning (N. S. Raju, W. J. van der Linden, & P. F. Fleer, 1995) was used to
examine measurement equivalence across media. Results support the measurement
equivalence of the JDI Supervisor and Coworker scales across administration
media. The implications of these findings for both practitioners and
organizational researchers are discussed.
PMID- 10783547
TI - Ancient Pygmalion joins contemporary management: a meta-analysis of the result.
AB - To determine the existence and relative magnitude of the Pygmalion effect among
adults within management contexts, a meta-analysis of 17 relevant studies (58
effect sizes; N = 2,874) was conducted to provide an estimate of the population
mean effect size and variation from Pygmalion interventions. Performance measures
in these studies included exam scores, performance appraisals, and physical
output. Results indicate that Pygmalion effects can be fairly strong within some
management contexts (average d = 1.13) but may vary widely depending on
moderating variables. Specifically, results were stronger in the military, with
men, and when involving persons for whom low expectations were initially held.
Findings also highlight the need for more research in ongoing work contexts (vs.
training) and in for-profit organizations (vs. the military). Suggestions are
given to help overcome possible hurdles in conducting research in these areas.
PMID- 10783548
TI - [What is your diagnosis? Trigeminal neuralgia caused by a hematoma in Meckel's
cavity].
PMID- 10783549
TI - [Low visual acuity, disorders of the visual field: how to adapt the imaging of
optical pathways to clinical practice?].
PMID- 10783550
TI - [Vertebro-epidural lumbosacral vascular malformations. An unusual cause of lumbo
sciatic pain].
AB - Sciatica is most commonly caused by nerve root compression secondary to herniated
disk. Rarely, it can be due to a lumbosacral vascular malformation. We present
five cases with such a malformation, presenting as a chronic lumboradiculagia.
The patients were explored with computed tomography, MRI and selective spinal
angiography. Polymorphic anatomic and hemodynamic aspect of these cases are
reported: 1. One vertebral hemangioma with epidural extension; 2. Three purely
epidural malformations: a) one epidural cavernous hemangioma, b) one epidural
arteriovenous malformation, c) one epidural varix; 3. One paravertebral
arteriovenous fistula with epidural venous drainage. Diagnosis of these rare
malformations may be difficult. A multiplanar cross-sectional magnetic resonance
and computed tomography scan with contrast enhancement can show characteristic
abnormalities and may assist in recognition these malformations. Selective spinal
angiography confirms the diagnosis, allows to classify the malformation and is
required to evaluate endovascular therapeutic possibilities.
PMID- 10783551
TI - Hemodynamic changes around cerebral arteriovenous malformation before and after
embolization measured with PET.
AB - To estimate the changes in regional cerebral blood flow (rCBF) around cerebral
arteriovenous malformation (AVM) before and after embolization, 6 patients with
AVM were sequentially examined with positron emission tomography (PET). PET
depicted the remodeling of rCBF in the ipsilateral hemisphere of AVM after
embolization. Decrease of rCBF in the ipsilateral hemisphere was also detected in
patients with focal symptoms before embolization, and improvement of clinical
symptoms after embolization corresponded to disappearance of rCBF decrease. PET
can detect hemodynamic changes after embolization, and has a possibility to
estimate the effect of embolization in patients with AVM.
PMID- 10783552
TI - [Diffusion MRI and cerebral ischemia. When to calculate the coefficient of
diffusion?].
AB - INTRODUCTION: There are two types of diffusion images: so-called "diffusion
weighted" images (DWI) and apparent diffusion coefficient (ADC) images. For
certain authors, ADC mapping is crucial for interpreting diffusion images while
for others the ADC map adds no further sensitivity or specificity compared with
diffusion weighted images. The objective of this work was to determine those
situations where ADC mapping modifies image interpretation. MATERIAL AND METHODS:
T2-weighted and diffusion-weighted (DIF) MRI sequences were acquired in 197
patients with suspected cerebral ischemia (< or = 48 hr). For each lesion (239
lesions in the 197 patients), we analyzed MRI interpretation with and without ADC
mapping and compared the interpretations with the final diagnosis established on
clinical data and complementary explorations. RESULTS: We observed 3 groups. In
group A (36% of the lesions), ADC mapping did not change image interpretation.
This group was subdivided into 3 subgroups. A1: T2 and DIF weighted images are
normal: no lesions and normal ACD map (n = 38 patients); A2: High intensity
signal on T2 and low intensity signal on DIF: ischemic sequelae, ADC always
increased (n = 32 lesions); A3: T2 normal and high intensity signal on DIF: hyper
acute ischemia and ADC always decreased (n = 16 patients) In group B (high
intensity signal on T2 and DIF, 54.5% of the lesions), ADC mapping changed the
MRI interpretation: there was acute ischemia if the ADC was decreased (n = 113)
and "pseudo-ischemic" lesions if the ADC was normal or increased (n = 17
patients). Group C was comprised of 23 lesions with a false negative ADC (9.5%).
These lesions were always small recent ischemic lesions (< or = 5 mm) with a high
intensity signal on DIF and a strictly normal ADC map. CONCLUSION: ADC mapping
was found to be useful in 54.5% of the lesions and should not be considered as
solely a research tool but also as a useful tool for routine clinical practice.
PMID- 10783553
TI - [The value of MRI for the diagnosis of meningeal hemorrhage during vasospasm].
AB - Retrospectively, subarachnoidal hemorrhage can be misdiagnosed when the acute
event did not bring the patient to medical attention, when clinical history is
unclear and the CT scan is normal. Moreover, days after subarachnoid hemorrhage,
cerebral vasospasm can result in neurological deficits that are indistinguishable
from that produced by other causes of stroke. We report our experience with two
patients who presented with symptoms of ischemia due to an arterial vasospasm
that followed unrecognized rupture of an intracranial aneurysm. In both cases, CT
scan failed to detect subarachnoid hemorrhage while MR detected the presence of
signal changes in the subarachnoidal spaces associated with an ischemic stroke in
one case. Neurological symptoms resolved completely after aneurysm treatment. MR
can be a critical for the diagnosis of stroke secondary to vasospasm in order to
prescribe an adapted treatment, avoid anticoagulant or thrombolytic therapy, and
rapidly exclude the recently ruptured aneurysm to protect the patient from the
risk of rebleeding.
PMID- 10783555
TI - Intramedullary cavernous malformations.
AB - Five cases of intramedullary cavernous malformations were retrospectively
reviewed. There were 4 women and one man ranging in age from 30 to 67 years.
Thoracic spinal cord was involved twice and cervical cord in three cases. Four of
them underwent surgery: two improved, one remained stable and symptoms worsened
in one. Clinical, radiological features and surgical management are discussed in
the light of the follow-up and literature analysis. The role of T2* weighted
sequence in MR diagnosis of intramedullary cavernomas is emphasised.
PMID- 10783554
TI - [Capillary telangiectasis, angiographically occult vascular malformations. MRI
symptomatology apropos of 7 cases].
AB - OBJECTIVE: Describe the MRI findings in capillary telangiectasias. MATERIALS AND
METHODS: Between 1996 and 1999, we observed 9 cases of capillary telangiectasia
in 7 patients explored 5 times for posterior fossa symptoms. In two cases
capillary telangiectasia was a fortuitous discovery. All patients were explored
by MRI with T1 sequences with and without gadolinium injections, turbo spin echo
T2 coupled in 5 cases with a double echo gradient echo T2 sequence (TR: 970 ms,
TE: 15 and 35 ms). Two patients also underwent vertebral angiography. RESULTS:
The telangiectasia gave a low intensity signal on T1 sequences in 2 of the 9
cases and a discretely high intensity signal on T2 sequences in all cases. After
gadolinium injection, 9 telangiectasias showed homogeneous or speckled
enhancement. The echo-gradient T2 images showed a very low intensity signal in 7
out of 7 cases on the second echo. At the first echo, 4 capillary telangiectasias
were undetectable. The two vertebral angiographies were normal and the follow-up
MRI in 5 patients showed lesion stability. CONCLUSION: Pontile lesions with no
mass effect showing enhancement after gadolinium injection and with or without a
discrete T2 high intensity signal but with a frank echo-gradient T2 signal
strongly suggest capillary telangiectasia.
PMID- 10783556
TI - [Diffusion imaging in asymptomatic focal vasospasm. Apropos of a case].
AB - We report a case of an asymptomatic vasospasm with a focal, reversible apparent
diffusion coefficient (ADC) decrease after a middle cerebral artery aneurysm
rupture. This isolated decrease of ADC has not yet been reported in this
pathological situation. It could be interesting to predict the risk of ischemic
delayed complications of vasospasm.
PMID- 10783557
TI - [Cerebral panthrombophlebitis in a paucisymptomatic patient].
AB - In most cases, extensive cerebral venous thrombosis present themselves with a
severe clinical outcome and poor prognosis. We present the case of a 59-years-old
patient with a slight rather unrevealing symptoms but suffering from a cerebral
thrombosis impacting on both superficial and deep venous system. The etiologic
assessment revealed activated protein C resistance. Clinical evolution under
systemic anticoagulation was prompt, with complete repermeabilization of the
various venous structures.
PMID- 10783558
TI - Isolated histiocytosis X of the pituitary stalk.
AB - A case of histiocytosis X granuloma localized in the pituitary stalk is reported.
Coronal and sagittal magnetic resonance imaging views were useful to determine
the precise size and location of the mass lesion. The diagnosis was established
immunohistochemically and the patient was treated with low-dose irradiation
therapy. After irradiation, the patient improved well without endocrine
replacement treatment. The pituitary stalk recovered its normal size with no
evidence of recurrence on MRI at 7-year follow-up. We emphasize the importance of
MRI before initiating therapy to evaluate the pituitary mass lesion and the
effectiveness of low-dose irradiation for isolated histiocytosis X.
PMID- 10783559
TI - Periodontal relevance of anterior crowding.
AB - The periodontal relevance of anterior and posterior crowding concerns 3 main
aspects: 1. oral hygiene/plaque retention, 2. altered topography of gingiva,
septum and orofacial alveolar bone and 3. periodontal therapy (scaling, root
planing, regenerative approaches). These aspects are discussed with regard to the
literature and to the author's own clinical and histological findings. Present
day knowledge suggests that the following positive periodontal effects can be
expected from correction of orthodontic crowding: better access for oral hygiene,
improved morphology of soft and hard periodontal tissues; future research has to
substantiate the value of this benefit, simplified mechanical and surgical
therapy (scaling, root planing, curettage), more favorable conditions for
periodontal regeneration.
PMID- 10783560
TI - Efficacy of protection by latex gloves during orthodontic therapy.
AB - The wearing of gloves during orthodontic or dental treatment is generally
indicated for reasons of hygiene and protection against infection. This study was
aimed at determining the extent and localization of perforations caused by the
various orthodontic treatment techniques and interrupting the infection barrier.
The impermeability was tested by means of a water retention test according to
European standard EN 455, Part 1, performed on 1600 Centramed (Centramed,
Koblenz), Tekmedic and SafeEx non-sterile disposable latex gloves (both by Safe
Med, Switzerland) and Safe Gan latex gloves with an additional acrylate coating
(also by Safe Med). The perforation rate in unused gloves was between 0.5% and
7.5%, rising on average to 11% with increasing use. 36% of the total number of
lesions resulted from handling removable appliances, and 57% from handling fixed
appliances, especially when replacing arch wires and elastics. Most lesions were
in the thumb, index finger and palm region. Only 18% of the defects were noticed
by the dentists themselves. The gloves worn by beginners in their first year of
postgraduate orthodontic training had about twice as many defects as those worn
by qualified orthodontists. When patients with an increased risk of infection are
to be treated, additional hand disinfection measures should be taken and 2 pairs
of gloves worn in view of the relatively unreliable protection offered by
commercially available latex gloves.
PMID- 10783561
TI - Prospective study on the reproducibility of cephalometric landmarks on
conventional and digital lateral headfilms.
AB - The introduction of digital X-ray techniques offered a variety of new
possibilities for digital image enhancement and exposure reduction. In order to
compare the reproducibility of cephalometric landmarks on conventional and
digital lateral headfilms 100 digital and 100 conventional lateral headfilms of
patients attending our clinic were randomly selected. The digital cephalograms
were obtained using storage phosphor plates in standard X-ray cassettes. All X
rays had been taken at 77 kV. For the digital images the mAs settings for
conventional images minus 4 mAs were used. Two orthodontists traced each X-ray
twice (21 reference points) at an interval of at least 1 week. The tracings were
superimposed and the distances between the tracings of identical reference points
were registered. The average reproducibility of cephalometric landmarks was
significantly higher on the digitally obtained images, despite a reduction of
radiation exposure of 23.7% in the digital images.
PMID- 10783562
TI - Transcutaneous electrical nerve stimulation (TENS): its short-term and long-term
effects on the masticatory muscles.
AB - In an electromyographic study on subjects with no functional disturbances of the
masticatory muscles, the duration of the post-therapeutic effects of
transcutaneous electrical nerve stimulation (= TENS) on the superficial masseter
and anterior temporal muscle was analyzed. The myoelectric signals were
registered from 20 healthy volunteers in 3 different mandibular positions. The
recordings were performed before a 20-minute TENS application with the J-4
Myomonitor and continued with a sequence of follow-up registrations with
increasing interval to the initial stimulation. The EMG signals underwent
computer-aided analysis and were evaluated by determining the integrated values
as a parameter of muscle activity, and after Fourier transformation by 7
describing parameters of the power spectrum (e.g. mean power frequency = MPF). A
detailed analysis of variance of all data was used to investigate significant
changes of the parameters during the observation period. Muscular response to
TENS includes a decrease in muscular activity (= reduction in integrated EMG
signals) and a shift in the power spectrum to higher frequencies (increase in
MPF). These changes were statistically highly significant for both analyzed
muscles and for all different mandibular exercises. As these reactions to TENS
are contrary to muscle fatigue, the results can be interpreted as indicating that
this type of therapy stimulates a change in the biochemical and physiological
muscular conditions, which leads to muscle relaxation. Electromyographically, the
post-therapeutic effect lasted for 2 hours in case of normal masticatory muscle
activity but for more than 7 hours in case of low muscular loading. The
alterations of the integrated EMG values were more persistent than those of the
parameters of the power spectrum.
PMID- 10783563
TI - Follow-up control of patients with unilateral posterior cross-bite treated with
expansion plates or the quad-helix appliance.
AB - The aim of this study was to evaluate the long-term stability of the occlusion
after correction of posterior cross-bite with either a removable expansion plate
or a quad-helix appliance and to compare the transversal development of the jaws
in the plate group, the quad-helix group and a control group. At the start of
treatment there were 22 children in each of the treated groups. Two children in
the plate group and 1 child in the quad-helix group discontinued the treatment.
Two children treated with the quad-helix appliance and 1 child in the plate group
could not be reached for the follow-up registration, so the collective finally
consisted of 30 boys and 27 girls: 19 subjects in the plate group, 19 in the quad
helix group and 19 controls. The treatment groups were studied with the help of
plaster models before treatment, immediately after treatment and at the last
registration about 5.5 years after treatment. The control group was studied with
the help of plaster models on 2 occasions, at the mean age of 8.8 years and 15.9
years respectively. This was about the same age as the first and the last
registrations in the treatment groups. In all children, the posterior cross-bite
was corrected by the end of the treatment. At the last registration, the
corrected posterior cross-bite had relapsed in 1 child in the plate group and in
3 children in the quad-helix group. The degree of expansion was similar for both
groups. The mean treatment time was longer in the plate group than in the quad
helix group: 12.5 months and 7.7 months respectively. Despite a transversal
expansion in the treatment groups, the width of the maxillary dental arch did not
reach the mean width in the control group, and even at the last registration the
width of the maxillary dental arch was significantly greater in the control group
than in the treated groups. The conclusions of this study are: 1. The long-term
treatment effect in children with posterior cross-bite was somewhat better when
they were treated with the removable expansion plate in comparison with treatment
with the quad-helix appliance. 2. Both immediately after treatment and at the
last registration 5.5 years later, the width of the maxillary dental arch was
significantly greater in the control group than in the plate group or the quad
helix group while the width of the mandibular dental arch was equal in all 3
groups.
PMID- 10783564
TI - Pain in orthodontics. A review and discussion of the literature.
AB - This literature review focuses on previous studies of pain and pain perception in
dentistry with special emphasis on orthodontic treatment. The prevalence of pain
and background factors such as age, gender and culture/society, in addition to
pain physiology and the influence of concomitant emotional and cognitive factors,
is examined. Pain during orthodontic tooth movement is reported from the point of
view of its physiology and character and different assessment methods. These
aspects are described both generally and specifically in relation to the type of
orthodontic forces and to the experience of discomfort other than pain. Since the
orthodontic treatment may cause some degree of suffering for the patients, it is
important for orthodontists to handle this situation in the best possible way.
Some ideas about the possibilities of avoiding, reducing or alleviating pain in
orthodontics are discussed.
PMID- 10783565
TI - The influence of a 0.2% chlorhexidine mouthrinse on plaque regrowth in
orthodontic patients. A randomized prospective study. Part II: Bacteriological
parameters.
AB - In a prospective plaque regrowth study focusing on oral hygiene during fixed
appliance therapy 12 adolescent patients (mean age 14.1 +/- 1.5 years) were
evaluated twice over 2-day test periods. In the randomized, double-blind study
the influences of a 0.2% chlorhexidine mouthrinse (Corsodyl, CHX) and a
commercially available dentifrice supplementing fluoride (Odol-med-3) were
compared intra- and interindividually in a crossover design with regard to the
bacteriological parameters. The bacteriological parameters of vital fluorescence,
bacteriological counts (BC), colony forming units (CFU), plating efficiency (PE)
and mutans streptococci (MS) were related to the clinically assessed indices of
plaque and gingivitis. All parameters analyzed demonstrated significant
differences between the control and the test (chlorhexidine) group. Where-as the
values of BC, CFU, and PE progressively increased in the control group from T0 to
T2, these parameters distinctly decreased in the chlorhexidine group. All values
of vital flora (VF) scored around 75% in the control group compared to values of
30% in the test group. BC, CFU und PE correlated significantly. The score of
mutans streptococci persisted or increased in the controls whereas mutans
streptococci approached 0 in the chlorhexidine group. Until the 5th day of
washout a clear-cut carry over of the chlorhexidine rinse on mutans streptococci
as well as on the gingival index was evident. Since dead microorganisms remain on
the tooth surface and in order to maintain oral health, chlorhexidine application
might advisedly be supplemented by mechanical plaque control.
PMID- 10783566
TI - [Single-blood-sample method for the determination of glomerular filtration rate
using 99mTc-DTPA in Japanese].
AB - The study was aimed to evaluate glomerular filtration rate with 99mTc-DTPA by
means of a single-plasma-sample method in Japanese. Three were 50 patients (29
males and 21 females, age range being 25 to 91 years) with diabetes mellitus of
various degree of the renal function. 99mTc-DTPA of 300 MBq/2 ml that was
prepared in our hospital was injected. Dynamic renal scintigraphy was carried out
and 10 blood samples were taken after the injection. Blood clearance (true GFR)
of 99mTc-DTPA was determined from plasma concentration which was fitted to the
biexponential curve by a non-linear least squares method. Plasma concentration
(ml/min/1.73 m2) after 75 min-post injection showed very higher linear regression
and linear correlation with true GFR than 0.900. The best linear regression and
linear correlation was observed with 180 min-sample (r = 0.989). As general, the
following equation was obtained; Y = A + Bln(X), A = 436.1217 - 3.45817t +
0.01205t2 - 0.000015t3, B = -212.601 + 1.42518t - 0.04834t2 + 0.0000062t3, X =
plasma concentration at sampling time t (%ID/L/1.73 m2), t = sampling time from
75 to 300 min (r > 0.900). This is the new equation of single-plasma-sample
method for the determination of GFR using 99mTc-DTPA for Japanese. The clinical
feasibility should be accessed in a field of a nuclear medicine practice.
PMID- 10783567
TI - [Evaluation of technetium-99m-MIBI scintigraphy in metastatic differentiated
thyroid cancer--comparison study with 131I and 201Tl].
AB - Detectability of metastasis in differentiated thyroid cancer using technetium-99m
methoxyisobutyl isonitrile (99mTc-MIBI) was compared with that of 131I and 201Tl.
Forty patients after total thyroidectomy were evaluated. The scan results were
compared with those of 131I and 201Tl whole body scintigraphy per patient. The
positive rate was 68% in 99mTc-MIBI, 84% in 131I, 60% in 201Tl respectively. As
to the lymph node metastasis, the positive rates were 56% in 99mTc-MIBI, 78% in
131I, 39% in 201Tl. In lung metastasis, the positive rate was 46% in 99mTc-MIBI,
82% in 131I and 55% in 201Tl. Serum thyroglobulin (Tg) was significantly higher
in 201Tl and/or 99mTc-MIBI positive group compared to that of negative group
independent of 131I scan results. Although the detectability of both 99mTc-MIBI
and 201Tl were inferior to that of 131I, 9 to 22% of metastasis were detected
only by these radiopharmaceuticals. Both 99mTc-MIBI and 201Tl, therefore, should
be used in cases with high serum Tg even with negative 131I uptake. Basing on the
fact there was no prominent difference between 99mTc-MIBI and 201Tl in the
detectability of metastasis, 99mTc-MIBI might be more suitable tracer because of
better quality image.
PMID- 10783568
TI - [Is the cardiac function improvement after PTCA predictable by the quantitative
indices from exercise stress 201Tl myocardial SPECT, in patients with old
myocardial infarction?].
AB - PURPOSE: We examined whether the improvement of left ventricular function after
percutaneous transluminal coronary angioplasty (PTCA) in patients with one
diseased vessel can be predicted by the quantitative indices from exercise stress
201Tl single photon emission computed tomography (SPECT) and radionuclide
angiography (RNA) before PTCA. METHODS: Exercise stress 201Tl myocardial SPECT
and RNA were performed before and after PTCA in 28 patients with old myocardial
infarction (OMI). The patients were divided into two groups according to the
results of coronary angiogram performed at 3 to 6 months after PTCA; patency was
confirmed in 22 patients (Group P) and restenosis was observed in the remaining 6
patients (Group S). RESULTS: In Group P, the count ratios defined as 201Tl uptake
in the PTCA region divided by the uptake in the normal region were significantly
improved at 1 week and 3 to 6 months after PTCA in the initial image. 201Tl
washout rates in the normal regions were significantly increased at 1 week after
PTCA in Group S, and these rates in the PTCA regions were significantly increased
at 1 week after PTCA in Group P. Left ventricular ejection fractions (LVEF)
obtained from RNA were significantly improved 1 week and 3 to 6 months after PTCA
in Group P. The changes of LVEF between pre-PTCA and 3 to 6 months after PTCA
(delta LVEF) were significantly correlated with the count ratios of both initial
and delayed SPECT images in Group P (r = 0.652; p < 0.01, r = 0.645; p < 0.01
respectively). From the multiple regression analysis using stepwise methods, the
count ratio in delayed image and the LVEF before PTCA were selected as
independent predictive variables for delta LVEF (multiple correlation coefficient
= 0.776). CONCLUSION: Thus, the improvement of LVEF after PTCA may be predictable
by the count ratio in the delayed SPECT image and LVEF before PTCA when the
treated vessel is persistently patent.
PMID- 10783569
TI - [The outcome of treatment with adjusted dose of 131I to thyroid weight for
Graves' disease by estimation of effective half life using a single radioiodine
uptake measurement].
AB - In the determination of therapeutic 131I doses, it takes several days to measure
effective half life (EHL) of radioiodine in thyroid glands (Ordinary method). We
suggested the new method to estimate EHL by a single radioiodine uptake
measurement (INDEX method). We evaluated the outcome of 131I treatment with these
two methods in outpatients with Graves' disease. Eighty outpatients were treated
with INDEX method (Group I) and 108 outpatients with Ordinary method (Group O).
At the 5-yr follow up, the incidence of hypothyroidism in Group I was 22.5%,
subclinical hypothyroidism 8.8%, euthyroidism 30.0%, subclinical hyperthyroidism
13.7% and hyperthyroidism 25.0%. In Group O, 17.6% of the patients were
hypothyroid, 16.7% subclinical hypothyroid, 30.5% euthyroid, 9.3% subclinical
hyperthyroid and 25.9% hyperthyroid. There were no significant differences
between these two methods. We conclude that INDEX method surpasses Ordinary
method in timesaver and is equal in effectiveness.
PMID- 10783570
TI - [Impairment of septal uptake and washout on 123I-BMIPP myocardial SPECT after
pacemaker implantation: report of two cases].
AB - Case 1 involved a 62-year-old woman with complete atrioventricular block and case
2 involved a 70-year-old woman with sick sinus syndrome. In both cases,
echocardiography, 123I-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP)
and 99mTc-tetrofosmin myocardial single photon emission computed tomographic
(SPECT) findings were normal. Coronary arteriography and left ventriculography
also revealed normal in both cases. After pacemaker implantation (DDD-type in
case 1 and VVI-type in case 2), both patient's electrocardiograms revealed left
bundle branch block-type conduction disturbance, and echocardiography showed
asynchronous hypokinesia in the septal region. One year later, although both
patient's ATP loading tetrofosmin SPECT were normal, BMIPP SPECT showed reduced
uptake and increased washout in the septal region. These findings suggest that
these changes of BMIPP SPECT might be caused by left bundle branch block-type
conduction disturbance after pacemaker implantation.
PMID- 10783571
TI - [111InCl3 uptake in ununited fractures: a case report].
AB - 111InCl3 scintigraphy was performed in a 37-year-old male with pancytopenia.
Intense tracer uptake in the ununited rib fractures was recognized. There are few
descriptions of 111InCl3 uptake in ununited fracture, and this case indicated
that ununited fracture should be added to the differential diagnosis of 111InCl3
uptake.
PMID- 10783572
TI - [Dopamine transporter SPECT in patients with Parkinson's disease].
AB - The major neuropathological feature in Parkinson's disease (PD) is severe
degeneration of the dopamine (DA) neurons in the substantia nigra. Dopamine
transporter (DAT) is an important protein in the regulation of DA
neurotransmission. It has been reported that PD patients show a loss of DAT in
striatum. We report here the findings of single photon emission computed
tomography (SPECT) of the DAT with 2 beta-carboxymethoxy-3 beta
(4[123I]iodophenyl)tropane ([123I] beta-CIT) to investigate striatal DAT in 10
patients with PD, one patient with vascular parkinsonism (VP), and one patient
with dystonia syndrome. Patients were evaluated using the Webster rating scale.
Specific/nondisplaceable striatal binding ratio (V3") was obtained in each case.
In PD patients, the uptake of [123I] beta-CIT was reduced, especially in the tail
of putamen compared with caudate nucleus. Even in the early stage of PD, the
uptake of beta-CIT was reduced not only in the severely affected side, but also
in the mildly disturbed side of the brain. Putamen caudate ratio was generally
low in PD patients. In VP patient, the uptake was reduced, but putamen caudate
ratio was not decreased. V3" values showed significant correlation with the
severity of clinical symptoms such as self-care, facies, posture, gait, speech,
and Hoehn-Yahr's stage. On the other hand, V3" values were not significantly
correlated with the degree of tremor, seborrhea, and duration of the illness. In
conclusion, we found that SPECT of the [123I] beta-CIT is a useful method for the
diagnosis in the patients presenting parkinsonism, and for the clinico
physiological estimation of parkinsonian symptoms such as self-care, facies,
posture, gait, and speech.
PMID- 10783573
TI - [Comparison of scatter and attenuation correction methods in single photon
emission CT--simulation study].
AB - Quantitative SPECT requires an accurate and appropriate attenuation correction
and scatter correction. This paper compares scatter corrected images combined
with attenuation correction. The scatter correction methods used here were the
deconvolution method, dual energy window subtraction method, triple energy window
method, and dual photopeak window method. The attenuation correction methods used
were Sorenson's method, iterative Chang's method, and Bellini's method. The
numerical phantoms used were the cold spot, hot spot, star, and MCAT phantom.
These correction methods were assessed by using profiles and images, contrast
values, and linearity of SPECT values.
PMID- 10783574
TI - [Quantitative evaluation for scatter and attenuation correction in 99mTc SPECT-
multicenter cooperation phantom study].
AB - A multicenter cooperation phantom study was conducted to evaluate the accuracy of
a triple energy window scatter correction technique in combination with various
attenuation correction methods for 99mTc single photon emission computed
tomography (SPECT) imaging. Six centers participated in this research and the
data obtained with seven SPECT instruments were analyzed. The phantom used in the
experiment was a 20 x 10 cm cylinder filled with homogeneous 99mTc solution,
containing two kinds of cold spots (cold rod phantoms). One had a water-filled
cylinder 5.5 cm in diameter positioned 2.5 cm from the center. The other
contained 6 water-filled cylinders of various sizes. Contrasts of cold regions
were in the range from 74% to 120% (true 100%). Another phantom had the shape of
a pie-chart divided into six chambers symmetrically positioned in a cylinder 20
cm in diameter and 10 cm in height. Each chamber had volume of 480 ml and
contained homogeneous 99mTc solution of different concentrations. This phantom
was used to test for linearity between the radio activity concentration and
reconstructed count density (linearity phantom). The intercept of the regression
line obtained from the linearity phantom was 8.4 kBq ml-1 without scatter
correction and -6.8 kBq ml-1 with scatter correction. Contrast was in the range
from 78% to 132% (true 100%). The mean relative error for the measured activity
concentration was 4.9% +/- 3.5% (mean +/- sd).
PMID- 10783575
TI - [Clinical features of 25 patients with cytomegalovirus infection complicating
hematological diseases unrelated to allogeneic bone marrow transplantation].
AB - The clinical features of 25 cases of cytomegalovirus (CMV) infection complicating
hematological diseases were analyzed. These cases did not undergo allogeneic bone
marrow transplantation. 21 cases (84%) had a lymphoid tumor including 16 cases
(64%) of malignant lymphoma and three cases of adult T-cell leukemia. All
patients but one have received corticosteroid or antineoplastic agents before the
occurrence of CMV infection. The types of CMV infections were interstitial
pneumonia (23 cases), retinitis (2 cases), enteritis (one case), and persistent
pyrexia (one case). Nine cases were diagnosed by histopathology and 5 of these 9
cases were discovered as having a CMV infection at autopsy. 20 cases were treated
with ganciclovir for CMV infection, but only 9 cases improved. Of the 9 cases
diagnosed by CMV-antigenemia, which had been introduced in the late 1994, 4 cases
whose lymphoid tumor had been controlled responded to ganciclovir and survived
but others with uncontrollable disease died. The present study indicates that the
progress in the treatment of CMV infection was achieved in patients with
controllable hematological disease but not in patients with refractory disease
even after introduction of CMV-antigenemia.
PMID- 10783576
TI - [Evaluation of a new method for antifungal drugs susceptibility testing to
yeasts].
AB - We compared the Etest with a broth microdilution method (FP panel), performed
according to the National Committee for modified Clinical Laboratory Standards
(NCCLS) document M27-P guidelines, for determining the MICs of 81 clinical
isolates of yeasts (7 Candida albicans, 8 Candida glabrata, 10 Candida
parapsilosis, 6 Pichia anomala, 10 Candida tropicalis, 4 Candida guilliermondii,
4 Candida krusei, 6 Trichosporon cutaneum, 5 Candida ciferrii, 3 Candida famata,
4 Candida norvegensis, 2 Rhodotorula rubra, 3 Candida lusitaniae, 2 Candida
curvata, 1 Candida inconspicua, 1 Candida intermedia, 1 Candida colliculosa, 1
Cryptococcus spp, 1 Tricosporon capitatum, 1 Pichia ohmeri, 1 Saccharomyces
cerevisiae). The Etest results for 6 ATCC standard strains correlated well with
reference MICs except those of flucytosine (5-FC) for C. krusei, which tended to
be 1 to 2 log2 dilution higher than the MIC range determined by NCCLS guidelines.
However, the best agreement between the results for clinical isolates was seen
with 5-FC (100% agreement [Within +/- 2 log2 dilutions] between the results of
the two methods). There was a 91.4% agreement between the results of the two
methods with amphotericin B (Etest MICs tended to be 1 to 2 log2 dilution lower
than those of the FP panel). The Etest results with litraconazole for clinical
isolates except C. tropicalis were similar to MICs of the FP panel (Etest for C.
tropicalis showed 1 to 2 log2 dilution lower than FP panel). Also, the Etest
results with fluconazole for clinical isolates except C. tropicalis were similar
of 1 log2 dilution higher than MICs of the FP panel (Etest for C. tropicalis
showed more than 2 log2 dilution lower than FP panel). These results showed a
good level of overall agreement between the Etest method and the broth
microdilution test (FP panel). Since the Etest is a less laborintensive and much
simpler method, it appears to be a useful procedure for testing the
susceptibility of yeasts to antifungal agents.
PMID- 10783577
TI - [Clinical study of an outbreak of aseptic meningitis due to echovirus type 30 in
Munakata City in 1997-1998].
AB - From October, 1997 through July, 1998, an outbreak of aseptic meningitis due to
echovirus type 30 occurred in the northern part of Kyushu area in Japan. In this
outbreak, clinical and virologic observations were carried out on 157 in-patients
with aseptic meningitis at our hospital. The age of the patients ranged from 1
year and 9 months to 57-year old. One hundred and twenty out of 157 cases were
the children under 15 years of age, and in this age group, male/female ratio was
2:1. The largest proportion of cases occurred in the 5- to 9-year age group. The
number of cases reached a peak in December, 1997, but the epidemic extended to
the next summer. In 12 families, more than one person became ill (total 22
cases). Virus isolation from cerebrospinal fluid (CSF) was tried on 130 out of
157 cases. Echovirus 30 was isolated in 74 cases (58 children, 16 adults), and
echovirus 18 in 9 cases from June, 1998 until the end of the study. Paired acute
and convalescent sera were available from the 25 patients with negative virus
isolation, and 7 out of 25 patients had a fourfold or greater rise in
neutralizing antibodies. Headache, fever, vomiting, nuchal rigidity were
detectable in most cases, but in this outbreak, continued severe headache was
characteristic. Eye pain was experienced by 2% of the total cases. In children,
gastrointestinal symptoms were noted in 12% of the cases, but were not in adult
patients. The CSF cell counts ranged from 2 to 3,478 cells per cubic millimeter.
Fifty-eight percent were predominantly lymphocytic, while 42% were
polymorphonuclear predominant. Virus was highly isolated from the CSF when the
specimens were obtained within three days after the onset of the acute illness,
but in one case, virus was isolated on day 7. In a few cases, virus was isolated
without pleocytosis in CSF.
PMID- 10783578
TI - [A study of anti-HIV compounds which interfere the virus entry via coreceptor
CXCR4].
AB - T22 is an anti-HIV polypeptide which was synthesized with chemical modification
from the horse shoe hemocytic polypeptides, polyphemusin II as a lead compound.
T22 was found to block T-tropic HIV-1 entry into target cells as a CXCR4
antagonist. We synthesized T134, a small sized analog of T22 with reduced
positive charges. T134 exhibited highly potent activity and significantly less
cytotoxicity when compared to T22. It was shown that bicyclam AMD3100 and ALX40
4C are antagonists of CXCR4, and vMIP II which is coded chemokine in HHV8/KSHV
effects antagonistically both CXCR4 and CCR5. We examined the anti-HIV activity
of these CXCR4 antagonists. All of them inhibit the binding of anti-CXCR4
antibody (12G5) to PBMC, but have no effect on the binding of anti-CCR5 antibody
(2D7) except for vMIP II. vMIP II decreased the binding of both 12G5 and 2D7. In
these compounds, T134 showed the most potency to anti-HIV activity. We also
attempted to clarify the cross resistance between these antagonists, using HIV-1
resistant to AMD3100. T134, ALX40-4C and vMIP II are active against the AMD3100
resistant strain. This observation indicates the potential of using these the
inhibitors as a new type of agent preventing HIV entry.
PMID- 10783579
TI - [Why there were few isolations of tubercle bacilli in young children with
pulmonary tuberculosis?].
AB - We retrospectively evaluated the factors influencing the isolation of tubercle
bacilli in 51 children under 14 years of age with pulmonary tuberculosis who were
admitted to Yokohama City University Hospital from 1975 to 1998. Young children
(0-6 years of age) with pulmonary tuberculosis were significantly less positive
by smear and culture than elder children (7-14 years of age) with pulmonary
tuberculosis. According to the Japanese Society for Tuberculosis classification
of finding on chest X-ray film for pulmonary tuberculosis, the culture-positive
patients with type II (cavitary lesions) were found in all, the culture-positive
patients with type III (non-cavitary lesions) in 39.3%, and the culture-positive
patients with type H (hilar and mediastinal lymphadenopathys) in 35.3%. Patients
with cavitary lesions (type II) were significantly more positive by smear and
culture than patients with non-cavitary lesions (type III + type H). Only 15.8%
of the young children with pulmonary tuberculosis had received BCG vaccine and
all had non-cavitary lesions (type III and type H). But, 84.6% out of the older
children had received BCG vaccine and half had cavitary lesions. Taken together,
the result was that there were few isolation of tubercle bacilli in young
children with pulmonary tuberculosis because they had non-cavitary tuberculosis
without delayed-type hypersensitivity to tubercle bacilli.
PMID- 10783580
TI - [Detection of extended spectrum beta-lactamases producing Enterobacteriaceae in
feces].
AB - A study was made of 366 feces for detection of extended spectrum beta-lactamases
producing Enterobacteriaceae from feces. The selective agar was used for modified
drigalski agar (Eiken Chemical Co., LTD) with 2 micrograms/ml cefotaxime (ESBL
screen agar). 92 strains of Enterobacteriaceae, 41 Escherichia coli, 15
Citrobacter freundii, 13 Enterobacter cloacae, 11 Klebsiella pneumoniae, and
other 12, were isolated from ESBL screen agar. And, R-plasmid that were selected
by 2 micrograms/ml cefotaxime were transferred by conjugation from two of the 92
strains. These strain were E. coli TH9809927 and Proteus mirabilis TH9808262 that
were amplified by "Toho-1 type" primer. The clude enzyme from two strains (donor)
and transconjugants were especially hydrolysed cepharoridine and cefotaxime.
Accordingly, two strains (0.5%) were detected as ESBL producers. We think that
the result of our survey suggests the increase of ESBLs producing bacterial
infection in Japan, and believe that there is a trend of infection of its by
surveilance of the feces.
PMID- 10783581
TI - [Two cases of hypoxemic acute bronchiolitis due to Mycoplasma pneumoniae].
AB - Two males with acute bronchiolitis due to Mycoplasma (M.) pneumoniae, aged 24 and
39 years were reported. They presented prolonged cough and fever in the early
stage of the disease. Chest X-rays of those patients showed diffused nodular
shadows. Chest CT scan showed diffused nodular shadows and thickning of
bronchovascular marking. Blood-gas analysis indicated hypoxemia without abnormal
A-aDO2. We diagnosed two patients as M. pneumoniae infection by antibody assays.
The Eosinophil cationic protein (ECP) level and IgE level were high. Eosinophilia
and endotoxemia were also observed in two patients. We speculated that the
allergic reaction and endotoxemia may be related to hypoxemia and the clinical
severity of M. pneumoniae infection.
PMID- 10783582
TI - [A case with infectious mononucleosis-like syndrome caused by human herpes virus
6 infection].
AB - A 26-year-old female was admitted because of multiple fractures in lower
extremities. While in the hospital, she developed a high fever and generalized
skin eruption. Physical examination revealed bilateral cervical lymphadenopathy
and mild hepatosplenomegaly. The white cell count was 11,200 with 11% atypical
lymphocytes. Serum GOT, GPT, LDH were markedly elevated. Infectious mononucleosis
was suspected, but the serological test for EB virus did not show evidence of
acute EB virus infection. Anti-HSV, CMV, hepatitis A virus antibody titers also
did not show significant change during the coarse. The serological test for HHV-6
only showed increased titer of IgM and IgG antibodies. Rapidly elevated IgG
antibody titer was indicative of reactivation of HHV-6. So, she was diagnosed as
mononucleosis-like syndrome caused by HHV-6, probably reactivated infection. Her
symptoms gradually disappeared during a month.
PMID- 10783583
TI - [A case report of Campylobacter fetus subspecies fetus oophoritis].
AB - A 45-year-old female with oophoritis (pelvic inflammatory disease) caused by
Campylobacter fetus (C. fetus) is reported. She was admitted to the hospital
because of high fever and an acute abdomen. On admission, severe inflammation was
observed by the laboratory findings, and abdominal X-ray and CT scan revealed
ileus with marked swelling of the right ovary. Laparotomy was performed with
adonexooophrectomy due to the tubo-ovarian abscesses. C. fetus was isolated from
the right ovary, salpinx and ascites. Erythromycin was administered after a
sensitive test of C. fetus as the bacteria was isolated at operation. She was
discharged on the 17th day after her admission. Indirect immunofluorescent test
with hyperimmune rabbit sera to isolated C. fetus revealed a fine to coarse
granular immunoreaction in the cytoplasm of the macrophages infiltrated in the
tissue. This result was interpreted as the existence and growth of bacteria in
the right ovarian tissue. Oophoritis due to C. fetus subspecies fetus is very
rare. To our knowledge, this case is the second case reported in Japan.
PMID- 10783584
TI - [A case of pulmonary Nocardia farcinica infection in a patient with non
tuberculous mycobacteriosis].
AB - A 64 years old woman without systemic immunological disorders was admitted to our
hospital because of a productive cough, low grade fever and bloody sputum. Chest
X-ray revealed multiple nodules with calcification, infiltrates and
bronchiectasis. Laboratory findings showed mild hypoproteinemia and elevated
sedimentation rate. Both Nocardia farcinica and Mycobacterium intracellulare were
isolated from the bronchial lavage fluid. Administration of sulfamethoxazole
trimethoprim improved her symptoms. In a recurrent study of bronchial lavage N.
farcinica was not isolated, but M. intracellurale was still isolated. We believe
that N. farcinica may cause infectious exacerbation of chronic lung disease: non
tuberculous mycobacteriosis and bronchiectasis.
PMID- 10783585
TI - Outbreak of Japanese spotted fever in the southeastern part of Awaji Island.
PMID- 10783586
TI - The natural and the supernatural in melancholic genius. A debate in sixteenth
century Spanish medicine and its antecedents.
PMID- 10783588
TI - Professional ethics and discipline: the Prussian medical courts of honour, 1899
1920.
PMID- 10783587
TI - [Learning before enlightenment? On the popular medicine manuscripts of the
physician and best selling author Christoph von Hellwig (1663-1721)].
PMID- 10783590
TI - [Nucleotides and lactation milk].
PMID- 10783589
TI - Assessing neuropathological research carried out on victims of the 'euthanasia'
programme. With two lists of publications from Institutes in Berlin, Munich and
Hamburg.
PMID- 10783591
TI - [Cisapride and risk of cardiac complications].
AB - Cisapride is a prokinetic agent thought to be without severe side effects.
Recently, rare cisapride-induced cardiotoxic effects (QT interval prolongation,
ventricular arrhythmias) have been reported, raising questions about its safety.
Some risk factors have been reported: overdosage of cisapride, association with
some drugs inhibiting hepatic metabolism via the cytochrome P450 3A4 enzymatic
system (such as azole antifungals, macrolide antibiotics, non sedating
antihistamines), other pharmacological agents increasing the parasympathetic tone
by raising the effect of cisapride (such as ranitidine and cimetidine),
electrolyte abnormalities (such as low serum levels of calcium, potassium and
magnesium in the blood), liver dysfunctions, congenital long QT syndrome, and
infants born before 36 weeks' gestation, for three months after birth.
Physicians, prescribing cisapride should pay attention to these risk factors, to
avoid the possibility of a rare cardiac adverse effect.
PMID- 10783592
TI - Langer-Giedion syndrome. A patient without mental retardation and a large 8q23.2
q24.22 deletion.
AB - Mental retardation (MR) is a typical feature of Langer-Giedion syndrome (LGS).
Only 18 cases of LGS without MR have been reported. All of them either had normal
karyotype or carried a deletion not exceeding the 8q24 band. Thus, it has been
proposed that MR in LGS patients is associated with larger deletions. A patient
with LGS and a large 8q23.2-q24.22 deletion but without MR is reported. This case
suggests that there is not any particular gene which alone is responsible for MR
in LGS patients, but it is the reduced expression of a large number of genes
which predisposes to MR.
PMID- 10783593
TI - Bone marrow hypoplasia associated with acute viral hepatitis in four children.
AB - Four cases of children, aged 2 to 11 years, with acute viral hepatitis and bone
marrow hypoplasia are reported. Three patients presented only jaundice and
hepatomegaly; one also had liver failure. All the four patients underwent bone
marrow aspiration which showed bone marrow aplasia. In two of the four patients a
liver biopsy revealed patchy necrosis with inflammatory mononuclear cell
infiltrate. Half of the patients received a bone marrow transplantation; the
remaining patients were treated by intravenous infusion of immunoglobulins,
growth factors and steroids. The main epidemiological and etiological features of
such association are also reported.
PMID- 10783595
TI - Issues resonate with physician.
PMID- 10783594
TI - [Feeding].
PMID- 10783596
TI - The decline and fall of HMOs.
PMID- 10783597
TI - Long-term outcome following pancreas surgery.
PMID- 10783598
TI - Showtime
PMID- 10783599
TI - Medical consumers browse a chaotic cyberspace.
PMID- 10783600
TI - Mini med school. For that little bit of doctor in everyone.
PMID- 10783601
TI - Lessons from the heart.
PMID- 10783602
TI - Health policy hub.
PMID- 10783603
TI - Leading the way.
PMID- 10783604
TI - Regional differences in cardiovascular mortality in Minnesota.
AB - Cardiovascular disease is the leading cause of death in the United States.
Initial results from our health survey in the Red River Valley of Minnesota
suggested elevated cardiovascular mortality in men and women in younger age
groups there compared with the rest of the state. Similarly, earlier published
longitudinal studies of cardiovascular mortality in Minnesota revealed increased
cardiovascular mortality in counties west of a diagonal line drawn through the
tip of the arrowhead region (northeast Minnesota) to the southwest corner of the
state. In this study we examined cardiovascular mortality by geographic region
with respect to economic factors, residence patterns, and ethnic group. Since
these regions vary in geology and major land use, environmental factors were
considered as well. Our present data show a significant elevation in
cardiovascular mortality from 1987-1997 in men and women aged 25-59 in northwest
and northeast Minnesota counties compared with central-metro counties. In
contrast, south-central Minnesota shows a rate of cardiovascular mortality for
that age group similar to that seen in the central-metro region. The increase in
cardiovascular deaths from myocardial infarct in the younger groups in the more
rural, less affluent areas of northwest Minnesota is nearly two times higher than
in the central-metro counties. Genetic factors may play a role in the increased
mortality recorded for northeast Minnesota. Environmental contaminants such as
pesticides are additional considerations. Finally, our data suggest the need to
address long-standing regional cardiovascular mortality differences and rural
health care access in Minnesota.
PMID- 10783605
TI - Loneliness: an overlooked and costly health risk factor.
PMID- 10783606
TI - [Treatment of benign prostatic hyperplasia syndrome. 2: Interventional therapy].
AB - The invasive treatment modalities available fur BPH can be divided into
interstitial therapy without removal of tissue (e.g. stents), and those involving
delayed tissue ablation (thermal/coagulation procedures, e.g. laser ablation,
microwave thermo-ablation, high-intensity ultrasound). The latter procedures
(coagulation) more often permit a nonbloody intervention, the sphincter usually
remains uninjured, and retrograde ejaculation is less frequent. A third group of
options is interventional treatment, with immediate ablation of tissue
(vaporization, resection), which is more invasive and associated with a higher
risk of complications than the two first-mentioned groups. An advantage of these
options is the avoidance of a longer-term catheterization with its associated
risks. Help is provided for deciding which procedure should be used in which
patient.
PMID- 10783607
TI - [Carbohydrate-deficient glycoprotein syndrome (CDGS) type Ib. A hereditary
metabolic disease and its therapy].
AB - Underlying the carbohydrate-deficient glycoprotein syndrome (CDGS) type 1b is a
defect in phosphomannose isomerase (PMI), an enzyme of mannose metabolism. The
clinical manifestations include exudative gastroenteropathy, thromboses and
hemorrhages. In contrast to other forms of the CDGS syndrome, neurological
symptoms are completely lacking. The condition responds to a simple dietetic
treatment employing the monosaccharide mannose.
PMID- 10783608
TI - [Phase II ambulatory cardiac rehabilitation (Cologne model). 3 year results after
conclusion of the intervention].
AB - BASELINE: Of a total of 101 patients with CAD who participated in an ambulatory
cardiac rehabilitation program (ACR) ("Cologne model") between 1992 and 1994, 76
(75.2%) were examined 36 months after concluding ACR. RESULTS: The significant
improvement in exercise tolerance from 118.4 +/- 30.1 to 131.9 +/- 34.1 W
achieved with the ACR was maintained at the 3-year examination. ACR also
significantly decreased plasma cholesterol levels from 228.9 +/- 48.3 to 211.7 +/
37.0 mg%; 3 years after ACR the corresponding figures were 219.1 +/- 39.3 mg%.
In the high-risk group the significant reduction in plasma cholesterol levels
from 265 +/- 43.6 to 231.9 +/- 35.4 mg% observed immediately after ACR was
maintained over the three-year period (234.6 +/- 37.7 mg%). Similar patterns were
observed for other parameters of lipid metabolism. Before the cardiac event 63.2%
of the patients smoked; at the 3-year examination the percentage was 30.3%.
Before ACR, 73.7% of the patients were gainfully employed. Within the first 6
months after ACR, 71.4% returned to work, and this percentage increased to 73.2%
after one year. Three years later, 64.3% were still working. DISCUSSION: The
results demonstrate that the lifestyle changes achieved with 4-weeks of ACR may,
at least in part, be maintained over a period of 36 months.
PMID- 10783609
TI - [Individual outcome-oriented cardiologic rehabilitation treatment].
AB - Cardiac rehabilitation and subsequent intensified aftercare is capable, of
increasing the rate of occupational reintegration not only over the short-term,
but also over a period of two years. In addition to improving physical
performance, this enhances the patient's self-confidence, decreases anxiety and
reduces depression. Since, two years after completion of cardiac rehabilitation
and aftercare, the percentage of those lost to gainful employment and in need of
an early pension is appreciably less in the interventional group as compared with
controls, this program would appear to be of particular economic importance for
social security/national insurance carriers. For this reason, the Westphalian
Social Security Carrier has initiated the regular use of this concept in its
cardiological hospitals.
PMID- 10783611
TI - [Amoxicillin/clavulanic acid in therapy of bacterial infections of the diabetic
foot. Results of an observational study].
AB - The results of an observational study of amoxicillin/clavulanic acid (Augmentan)
in 191 patients are presented. The average duration of treatment was 15 days
(median). Healing or improvement was observed in 76% of the cases. In view of the
fact that the condition often has a multifactorial genesis and neural and
vascular changes impair healing, this result must be considered a clinical
success. Variables with an influence on the efficacy of the treatment were the
incidence of manifestation and pathogenesis of the ulcer, renal function, blood
pressure and smoking. Amoxicillin/clavulanic acid was well tolerated, with
adverse events being observed in only 9 out of 193 patients (4.7%). Treatment was
abandoned because of adverse events in 3 out of 193 patients (1.6%). Overall,
treatment of the infected diabetic foot with amoxicillin/clavulanic acid was well
tolerated and effective.
PMID- 10783610
TI - [What do general practitioners expect from a psychiatric clinic? Wish for closer
cooperation].
AB - OBJECTIVE: In the present study the views of family doctors on what constitutes
"ideal" cooperation with a psychiatric hospital were investigated. METHOD: The
views expressed by 24 family doctors and recorded in interviews were analyzed
qualitatively with the aim of assessing their importance. RESULTS: Regular
exchange of information between family doctor and psychiatrist, prompt receipt of
the discharge report, a named contact person on admission and during
hospitalization, competent psychiatric inpatient care, and the possibility of
being able to directly refer patients were felt to be the most important points.
Almost a half of all the views expressed related to intercommunication.
CONCLUSION: Psychiatric hospitals should give more consideration to the views and
wishes of family doctors as a means to resolving possible problems of interaction
and to improving the care afforded mentally sick patients.
PMID- 10783612
TI - [Stage-adapted reconstruction of the stomach after gastrectomy].
AB - The only realistic chance of a cure for cancer of the stomach is gastrectomy with
a wide margin of clearance. The question as to what constitutes the ideal
reconstruction of a substitute stomach, however, remains unanswered. A number of
prospective randomized studies show that patients operated on in curative intent
and with a good long-term prognosis, should be given a substitute stomach in the
form of a pouch constructed from small bowel, with restoration of duodenal
passage. On account of the shorter operating time, patients receiving palliative
surgery should be treated with a simple oesophagojejunostomy without such a small
bowel pouch substitute stomach.
PMID- 10783613
TI - [ALLHAT Study: doxazosin arm is discontinued. Alpha blocker is less effective
than a diuretic].
PMID- 10783614
TI - [Calcium antagonist in heart failure. No improvement, no damage].
PMID- 10783615
TI - [ASS or clopidogrel? In high vascular risk it is best to give both].
PMID- 10783616
TI - [Phytotherapy and homeopathy on the internet. Alternative medicine for physicians
and patients].
PMID- 10783617
TI - [Myocardial infarct--seizure--psychosis. The drug emergency has many faces].
PMID- 10783618
TI - [Fatal fibroelastoma].
PMID- 10783619
TI - [Diabetic retinopathy--screening is a requirement. Don't wait until vision
becomes impaired].
AB - Diabetic retinopathy is the most common systemic disease capable of leading to
blindness. Laser treatment of diabetic retinopathy is standardized; in most cases
it can prevent blindness, provided the diagnosis is made in good time. Since
impairment of vision is a late complication, systemic screening examinations are
of particular importance if we are to reliably determine the optimal time for
treatment. Advances in vitreoretinal surgery make possible the treatment of such
late manifestations as vitreous hemorrhage and tractive retinal detachment.
Provided that stage-oriented and timely treatment is forthcoming, these formerly
hopeless cases should become a rare exception. The currently sole confirmed
medical treatment is optimal control of blood sugar--based on the HBA1c value-
and of blood pressure. The clinical efficacy of inhibitors of angiotensin
converting enzyme or protein kinase C is presently undergoing investigation.
PMID- 10783620
TI - [Management of the diabetic patient. When consult the general practitioner, when
the specialist practice?].
AB - The perception that in type 2 diabetes mellitus the prognosis with regard to
micro-angiopathic and macro-angiopathic complications significantly depends on
the quality of metabolism and the level of the blood pressure, should prompt all
of us to considerably intensify our efforts to ensure optimal treatment for the
diabetic. For example, insulin will have to administered at an earlier time-point
and to a much greater extent than formerly. In order to meet the objectives
specified in the St. Vincent Declaration of 1989, not only close cooperations
between family doctors and diabetologists in specialist practices and hospitals,
but also comprehensive quality control measures will be needed. In new diabetes
contracts, for example the interface model, attempts are being made to take
account of these facts. The various tasks of family doctors and specialized
diabetes practices are discussed on the basis of the interface model.
PMID- 10783621
TI - [Synopsis of vasculitis. When the immune system attacks autologous blood
vessels].
PMID- 10783622
TI - [Unstable angina pectoris: preventing the infarct. Thrombosis ABC, 14].
PMID- 10783623
TI - [An unusual cause for dysphagia. Enlargement of the left atrium].
PMID- 10783624
TI - [Colleagues, return the certification and work only for cash!. Interview by
Werner Loosen].
PMID- 10783625
TI - [Lipid therapy is effective in concomitant risk. In this way statins can be
prescribed in a budget-appropriate manner].
PMID- 10783626
TI - [Diphtheria, tetanus and pertussis. Booster vaccination!].
PMID- 10783627
TI - [No sodium--no pain. New guidelines in bone and muscle pain].
PMID- 10783628
TI - [New concept in chronic heart failure. Blocking the function of tumor necrosis
factor].
PMID- 10783630
TI - [Suggestions about the function of local centers of public health activities].
PMID- 10783629
TI - [A physician who relocated to campaign against epidemic leprosy. Armauer Hansen
discovered leprosy bacteria].
PMID- 10783631
TI - [Factors in continuation of home health care for patients with intractable
neurological diseases].
AB - OBJECTIVE: This study was carried out to elucidate factors related to difficulty
in continuing home health care and to investigate problems of the corresponding
support system for patients with intractable neurological diseases. SUBJECTS AND
METHODS: Subjects were 139 cases of amyotrophic lateral sclerosis (ALS), 376
cases of spino-cerebellar degeneration (SCD) and 1,048 cases of Parkinson's
disease (PD) who were collected from the nationwide survey of health and social
service needs of the patients with intractable diseases in 1995. Factors and
problems related to limited activity due to diseases and necessity for medical
care were analysed. The need for facilities of long-term care was also studied.
RESULTS: The characteristic conditions of patients with ALS were shorter duration
of the illness, higher percentage of conditions requiring medical care and
disorders of swallowing or respiration and full nursing care in daily life
compared with the other two diseases. The characteristics of PD were higher
percentage of female and older age in both patients and their family caregivers.
The proportion of cases for whom health care was judged to be prone to difficulty
was 23.0% in ALS, 10.9% in PD and 7.2% in SCD, respectively. Regarding the
factors related to difficulty in continuing home health care, conditions
requiring medical care, the need for full nursing care in daily life, and the
duration of the illness were recognized in ALS. In SCD, 5 factors, including
conditions requiring medical care, the need for full nursing care in daily life,
patients age greater than 65 years, the duration of the illness, and patients
being nursed by their sons or daughters were detected. In PD, 4 factors, such as
conditions requiring medical care, the need for full nursing care in daily life,
the patients being nursed by persons other than the spouse, and the need of
nursing care were found. CONCLUSION: These results suggest the necessity of
social functions of medical care, nursing and family support that can be supplied
at home effectively according to symptoms in progress, and the need for
facilities of long-term care of patients for whom continuation of home health
care may become difficult, which will work as a support system for long-term care
of patients with intractable neurological diseases.
PMID- 10783632
TI - [Characteristics of "Tojikomori" and "Tojikomerare" among home disabled elderly:
daily life of housebound elderly].
AB - BACKGROUND AND PURPOSE: A Japanese word Tojikomori means shutting oneself in a
room or house, or generally withdrawing. It has been pointed out that Tojikomori
results in a decline in mobility among disabled elderly living at home. As a
result of the qualitative study, we have attempted to define two types of
Tojikomori. The first type, or the narrowly defined Tojikomori, is the elderly
who are housebound-inactive but have a high mobility level. The second type,
Tojikomerare (the passive of Tojikomori), is the elderly who are housebound
inactive because of their low mobility. The purpose of this study is to describe
characteristics of Tojikomori and Tojikomerare. METHODS: 321 disabled elderly
(male: 122, female: 199, mean age 78.8) were interviewed at home by nurses in
Wajima City, Japan, in 1998. The subjects were selected from the list of used in
a screening survey, the Whole Wajima Elderly Survey. Mobility, life space,
activity, physical function, psychosocial factors, caregiver's burden and
caregiver's care to elderly were measured. The Tojikomerare subjects were
operationally defined as the housebound-inactive elderly who were unable to walk.
The Tojikomori were identified as the housebound-inactive elderly who were able
to walk 5 yards but were unable to take a bus. RESULTS: Results obtained were as
follows: 1. Housebound were not found among elders able to go out bus. There were
16 Tojikomori (10.1%) in subjects who were able to walk 5 yards (n = 153). Among
the subjects who were unable to walk (n = 72), 49 people (68.1%) were classified
as Tojikomerare. 2. The physical function, autonomy and social network of the
Tojikomerare subjects were lowest among subjects unable to walk. They used day
care least and received least care from their caregivers. In addition, their
caregivers' burdens were modest. 3. Among the elderly who were able to walk 5
yards, autonomy and social network of the Tojikomori ranked lowest, although
physical function was not low. CONCLUSION: Tojikomerare had lowest physical and
psychosocial function, but they were cared for the least by caregivers.
Tojikomori had the lowest psychosocial function among elderly who can walk 5
yards. The results suggest that it is important to evaluate the mobility, life
space, and activity of the housebound elderly when providing community-based
services.
PMID- 10783633
TI - [Validity and reproducibility of a semi-quantitative food frequency questionnaire
for nutritional education of patients of diabetes mellitus (FFQW65)].
AB - BACKGROUND: A self-administered semi-quantitative food frequency questionnaire
with 65 food lists (FFQW65) was developed for the nutritional education of
patients of diabetes mellitus. METHODS: Relative validity and reproducibility of
nutrient intakes as assessed by FFQW65 were investigated in volunteers of 71
males. To assess the relative validity, a one-week diet record was used as a
reference. The FFQW65 was administered twice at an interval of 10 month in order
to assess the reproducibility. Log transformed data was used to obtain Pearson
correlation coefficients. RESULTS: As for the validity, Pearson correlation
coefficient of total energy intake of breakfast was 0.74 and the relative
difference between predicted value and diet record was relatively small (the
difference was -5 kcal and relative difference rate was 1.1%). Compared with
breakfast, those for lunch, supper and one-day total energy intakes were
relatively lower (0.52, 0.66 and 0.64, respectively) and the relative differences
were around 10%, respectively. The one-day intakes of sixteen nutrients (except
for potassium and niacin) ranged from 0.28 to 0.64. Energy adjusted correlation
coefficients for protein, iron and cholesterol were low (0.16, 0.14 and 0.19,
respectively). Those for the other thirteen nutrients ranged from 0.26 to 0.65.
As for the reproducibility, the second survey using FFQW65 was administered to 64
males. Pearson correlation coefficient of one-day total energy intake was 0.76
and those for the other nutrients ranged from 0.54 (vitamin D) to 0.81 (calcium).
CONCLUSION: The results suggest that FFQW65 can be used for the evaluation of
energy intake by usual meals for nutrition education of patients of diabetes
mellitus.
PMID- 10783634
TI - [Current state and related factors in examinations of those who have had contact
with tuberculosis].
AB - OBJECTIVE: This study investigated the current conditions of identifying
tuberculosis contacts and enforcing their examinations in Public Health Centers
and examined related factors. METHODS: The study subjects were 431 index cases
with tuberculosis who were newly registered between 1995 and 1997 at four Public
Health Centers in Tokyo and Yokohama. Based on case registration card information
and interviews with public health nurses in charge, the data of identification of
contacts and enforcement of examination of their contacts were collected.
RESULTS: The proportion of index cases with insufficient identification of
contacts was 28.3%, particularly the non-family contact data being insufficient.
From logistic regression analysis: index cases aged 20-39 years; contact with
many people; "a moderate risk index of infection" cases; and being homeless were
factors significantly related to insufficient identification of contacts. The
proportion of contacts who were examined in individual contact examinations was
59.1%, that of mass contact examinations was 80.4%. From logistic regression
analysis: negative index cases on sputum smear; and no history of routine health
examinations for the past 3 years or a complete lack of information were factors
significantly related to insufficient enforcement of individual contact
examinations. As to mass contact examinations, not interviewing index cases was a
factor significantly related to insufficient enforcement. Further individual and
mass contact examinations differed in quality according to Public Health Center.
The incidence in close contacts with active tuberculosis was 1.0%, and was
especially high in members of the same household and friends of the newly
diagnosed. CONCLUSIONS: This study showed that the current contact examinations
for tuberculosis are insufficient. In addition it was shown that an adequate
identification of contacts and a complete enforcement of contact examinations are
urgent needs in Japan.
PMID- 10783635
TI - [Inadequate care by family caregiver of frail elderly living at home].
AB - In order to elucidate the present situation and background of inadequate care of
frail elderly living at home by family caregivers, a questionnaire survey was
performed on family caregivers. A total of 408 family caregivers were analyzed.
The major results of this survey were as follows; 1. Thirty two percent of
caregivers were associated with inadequate care. The percentage of main details
of inadequate care were "ignoring" was 19%, "the infliction of mental anguish
(e.g. insulting or verbal aggression)" was 14% and "physical injury (e.g. slap,
pinch or kick)" was 8%. 2. As a result of the analysis of answers to open-ended
questions by caregivers, the reason for inadequate care were classified roughly
into three groups as follows; 1. stress and feelings of the caregiver 2. behavior
or characteristics of the elderly 3. human relationship between the caregiver and
the elderly or the caregiver and the relatives. 3. Frequency of caregiver's
emotion of animosity to elderly were "often" was 3.9%, "sometimes" was 18.1%,
"occasionally" was 39.2%, "rarely" was 22.5%, "none" was 11.5%. The main reason
for animosity were "elderly happened to be angry or complained", "not able to
understand caregivers talk", "irritated due to being busy" or "there is no
feeling of appreciation in the elderly". 4. The relation of inadequate care and
emotion of animosity was large (chi 2 test, P < 0.0001) and correlation of degree
of animosity and experience of inadequate care was linear.
PMID- 10783636
TI - [ADL and actual life styles of all Japanese centenarians as determined by a
visitation interview survey].
AB - A visiting interview survey was performed on all centenarians living in Japan to
investigate their Activities of Daily Life (ADL). 2,851 centenarians, 92.9% of
all subjects completed the interview. They were divided into three groups, good
ADL (almost independent in daily life), moderate ADL (almost independent in
indoor life), and inferior ADL (bed fast) by the condition of ADL. Some factors
of health conditions, family size, frequency of use of public welfare services,
and life styles were compared among these three groups. Both the good and the
moderate ADL groups accounted for about 20% each, and the inferior ADL group was
about 60% of the subjects. The condition of ADL of men was better than that of
women. The inferior ADL group showed a significantly higher percentage of chronic
diseases. High ratios of cerebral vascular disease and dementia were seen in this
group, and many had no teeth. While two thirds of all the centenarians lived at
home, over 90% of the good ADL group lived at home. The mode of family size was
three including the person oneself. An average of 21% of men and 27% of women
used public health welfare services. However 40% of the centenarians in the
inferior ADL group used those services. Men had better dietary habits for health
than women. The good ADL group showed the most desirable dietary habits among the
three groups and had the highest percentage of drinkers and smokers. Men
practiced a greater number of ideal habits for longevity than women. Of the ADL
groups, centenarians in the good ADL group had the highest percentage of ideal
habits for longevity. The centenarians who maintained good ADL had the following
characteristics: There were fewer people under medical treatment. They had
maintained their own teeth. Almost all of them were living at their home with
their family. They had continued good dietary habits and daily life for health
and longevity. For the maintenance and improvement of ADL of centenarians,
adequate social welfare support in a local area for centenarians and their family
seemed to be vital in addition to health management and guidance of healthy life
style of the aged.
PMID- 10783637
TI - [Brain tumors: update 6 years after the publication of the WHO blue book].
PMID- 10783638
TI - [Transmission and scanning microscopy of elastofibroma ultrastructure].
AB - Elastofibroma is a rare benign tumor of soft tissues that has the elective
localization in peri- or interscapular region. It is characterized by the
proliferation of fibroblast-like cells which appear enveloped by abundant elastic
and collagen fibers. Here we present a case of elastofibroma, observed in a 63
year old woman in the interscapular region. The neoformation has been studied by
transmission electron microscopy (TEM) and scanning electron microscopy (SEM).
Our hypothesis is the possibility that elastofibroma is the consequence of active
neoformation of fibers elastic normal in the quality that subsequently is meet to
progressive degenerative phenomenons.
PMID- 10783639
TI - [Central core disease. Report of 2 cases in adults].
AB - "Central core disease" (CCD) is a rare disease of infancy and childhood and
represents the prototypic member of a group of muscular disorders known as
"congenital, benign (non progressive) myopathies". It is very uncommon to
diagnose cases affected by CCD in youth and adulthood. The disease is mainly
familial with a dominant autosomal pattern of inheritance, but sporadic cases are
known to occur. The candidate gene has been localized on chromosome 19q13.1, and
is allelic with RYR-1 ("ryanodine receptor" [calcium release channel gene]), the
gene responsible of the susceptibility to malignant hyperthermia. In some
familial cases of CCD a susceptibility to malignant hyperthermia was also
recognized. The diagnosis is only made based on muscular biopsy, which documents
some peculiar morphological abnormalities, i.e. focal losses of oxidative enzyme
activities, exclusively in type I muscular fibres. The basis for the loss of such
activities is represented by an almost total absence of mitochondria and
sarcoplasmic reticulum in those focal regions of muscle fibres. Cores may be
"structured" and "unstructured" based on the reactivity with myosin ATPases,
which ultrastructurally means preservation or destruction of myofilaments. Both
structured and unstructured cores qualify this disease in the same way. The
authors have observed two cases of CCD in patients in their non infantile age.
Both diagnoses were accomplished by means of muscular biopsy, and the results of
their studies in both cases are herein presented and discussed.
PMID- 10783640
TI - [Cell-block immunocytochemical characterization of effusions. Use of antibody
panel: calretinin, Ber-EP4, keratin and CD68].
AB - An anticorpal panel formed by Calretinin, Ber-EP4, Keratin and CD 68 has been
applied to differentiate mesothelial hyperplasia/mesothelioma from metastastic
carcinoma in cavity effusions. The study was performed in 86 cases in which
paraffinated cell-blocks were obtained. All cases positive for malignancy had
histological confirmation. The series included 2 malignant mesothelioma, 54
reactive mesothelial hyperplasia, and 30 metastatic carcinoma. All cases of
reactive mesothelial showed strong cytoplasmatic positivity for Calretinin, and
hyperplasia negativity for Ber-EP4. The 2 cases of mesothelioma were positive for
Calretinin and negative for Ber-EP4. In contrast, all cases of metastatic
carcinoma had membrane or cytoplasmatic positivity for Ber-EP4. The sensitivity
(100%) and specificity (100%) of reactivity for Calretinin and Ber-EP4 showed
that the immunocytochemical results on paraffin embedded material from cavity
effusions are very reliable, so that the tested immunocytochemical panel can be
useful in cytological differential diagnosis between reactive mesothelial
hyperplasia/mesothelioma and metastatic carcinoma.
PMID- 10783641
TI - [Intestinal brushing. Technical-cytological contribution in the pathological
study of Vater's ampulla, common bile duct, and pancreatic system].
AB - OBJECTIVE: This experience shows the effectiveness of the cytological examination
in the diagnosis of biliary and pancreatic neoplasm on samples obtained from
Vater's papilla through endoscopic intestinal brushing. STUDY DESIGN: From June
1997 to October 1998, 28 patients, suffering from suspicious neoplasm of Vater's
papilla or biliary system, were studied. Each sample was obtained through
intestinal brushing during an Endoscopic Retrograde Colangio-Pancreatography
(ERCP) and processed with the technique of direct smear stained with
Papanicolaou's method. The sample was followed by the corresponding biopsy in 16
cases and by surgical specimens in 8 cases. RESULTS: 27 patients out of 28 were
correctly classified by the intestinal brushing. The method carried out a
positive predictive value of 100% and a sensitivity of 93%. The sensitivity of
biopsy turned out to be 80%. CONCLUSIONS: The intestinal brushing is an effective
method of diagnosis, which turned out to be relevant as a support and, in several
cases, as a substitute of the biopsy. We think, therefore, that the brushing
should be carried out whenever a lesion of the Vater's papilla or of the biliary
system is suspected during an ERCP.
PMID- 10783642
TI - [Orbital embryonal rhabdomyosarcoma in adults. Report of 2 cases].
AB - Rhabdomyosarcoma (RMS) is the most frequent sarcoma of infancy. Embryonal RMS is
generally correlated with a better response to chemotherapy. In the present paper
two cases of embryonal RMS of the orbit affecting adult patients are reported.
Both patients are male, aged 22 and 24 years respectively. In Case 1 the lesion
arose primitively in the orbit, in Case 2 the orbit was affected by secondary
involvement. Both patients presented a rapid response to chemotherapy, with
reduction of the neoplastic mass and regression of symptoms.
PMID- 10783643
TI - [Hypophyseal hyperplasia].
PMID- 10783644
TI - [Cervix adenocarcinoma and squamous cell carcinoma: 2 different morphologic
entities?].
PMID- 10783646
TI - [Luck and genius in research: rethinking about Camillo Golgi 100 years after the
discovery of his apparatus].
PMID- 10783645
TI - [Origin of modern pathologic anatomy: a dangerous misunderstanding].
PMID- 10783647
TI - [Trends in pathology research].
PMID- 10783648
TI - [Randomized double-blind study (third place blinded) to examine the effectiveness
and side effects of methacholine in the nonspecific bronchial provocation test].
AB - Softly and effectiveness of methacholine for the diagnosis of non-specific
bronchial hyperresponsiveness [BHR] were tested in a third place blinded study.
61 patients suspected to suffer from BHR took part. 56 subjects provided complete
data and were included in the study. 27 participants were challenged with
methacholine 0.33% (verum) and 29 patients received NaCl 0.9% (placebo). The
challenge was applied as 5-step-test using a storage bag. The doses were elevated
by doubling the aerosol volume. A positive test result was assumed when basal
specific airway resistance (sRt) reduplicated and simultaneously 2.0 (kPa*s) was
attained. Ten out of 27 subjects in the verum group (33.3%) had a positive test
result whereas in the placebo group only one subject showed a reaction (3.5%). A
statistically significant association between the change of sRt and the
cumulative methacholine dose was confirmed in the verum group (p < 0.002),
whereas this effect could not be observed in patients challenged with placebo (p
= 0.20). Side effects did not occur. We conclude that inhalative challenge with
methacholine 0.33% applied as a 5-step-test is suitable to objectify BHR. The
substantial benefit of the applied test scheme is the short range of time in
which the challenge can be performed (approximately 20 min) and that dilution
series of the test substance (methacholine 0.33%) are not required.
PMID- 10783650
TI - [Proposals for a rationale and for rational diagnosis of coughs].
AB - Cough is probably the most frequent symptom in chest diseases. Hence, a rational
and economical diagnostic procedure is essential to prevent unnecessary costs to
the health services, i.e. acute bronchitis, a self-limiting disease, which is the
most frequent cause for cough should not involve extensive per case costs.
History, physical examination, chest X-ray and lung function testing--which
constitute both the first and second, i.e. the basic level of a stepwise approach
-allows to diagnose causes in most patients with cough. Without evidence of the
cause after completing this basic diagnostic procedure patients with acute cough
may require blood gases analysis, electrocardiography, echocardiography, lung
perfusion study, spiral CT angiography, bronchoscopy or laboratory examinations
for diagnosis of pulmonary embolism, aspiration or (seldom) pleuritis sicca.
Chronic persistent cough (CPC) is diagnosed if the basic standard approach to
chronic cough fails to lead to final diagnosis. Patients will then need further
subtle diagnostic management, i.e. bronchial provocation testing, 24 hour pH
probe, ENT- or neurological examination, high resolution CT of the thorax and
bronchoscopy. We present two algorithms for the rational diagnostic approach to
acute (figure 1) and chronic (figure 2) cough. Each algorithm considers spectrum
and frequency of causes on the one hand, the positive predictive value, costs and
patient discomfort due to the examination on the other. Nonetheless, despite
extensive examination up to 20% of patients suffering from CPC the cause remains
unclear [11]. Frequently, the capsaicin cough challenge test can reveal an
idiopathic upregulation of the cough reflex as the hypothesised underlying
condition. Psychogenic cough however, a rare condition in adults should not
coincide with hypersensitivity of the cough reflex. Inconsistency and low
reproducibility of results of the capsaicin challenge in patients with
psychogenic cough preclude his routine clinical use. In conclusion, the very
common acute bronchitis and the ACE inhibitor-induced cough do not require any
other diagnostic procedure except patient history and physical examination. A
simple basic diagnostic approach will usually allow to evaluate acute and chronic
cough. In the remaining cases the proposed algorithm should be used for best
results and to prevent excessive costs.
PMID- 10783649
TI - [Effect of the long-acting beta-2 agonist inhalant formoterol on the quality of
sleep of patients with bronchial asthma].
AB - BACKGROUND: Patients with asthma bronchiale often complain of exacerbations
during the night. Some anti-asthmatic drugs are known to impair the quality of
sleep. HYPOTHESIS: The study was undertaken to prove the effect of the long
acting, inhaled beta-2-agonist formoterol on the quality of sleep in patients
with mild or moderate asthma bronchiale. METHODS: 20 patients with asthma
bronchiale (15 female, 21-75 years, O 33.3 years) without sleep disorder were
evaluated by polysomnography during 3 nights. After one adaptation night, the
patients were randomly assigned 24 micrograms of formoterol during one and
placebo during the other night. The frequency of respiratory disturbances,
arousals, sleep latency, sleep stages, sleep efficiency, motoric activity, and
subjective impression of sleep quality were compared in both groups. RESULTS:
Respiratory disturbances were less, and the subjective impression of sleep
quality was better with formoterol in 50% of the patients. The objective quality
of sleep was slightly better with formoterol, but not significant (Tab. 1).
CONCLUSIONS: In patients with mild or moderate asthma bronchiale, formoterol does
not impair, probably slightly improves the quality of sleep.
PMID- 10783651
TI - [Two out-of-the-ordinary (?) case reports an asthmatic disease].
AB - This is a report on two cases of asthmatic disease presented to a general
practitioner. After a prolonged course of many years during which the intensity
of asthma varied, Ms K. suffered from constantly recurring exacerbations that
required treatment with systemic corticosteroids. The reason was found to be an
adrenocortical insufficiency suspected to be of iatrogenic origin. After various
treatment attempts an optimal minimal therapy was found resulting in complete
freedom from complaints, namely, a combination of fluticasone and 3 mg
methylprednisolone. However, brief instruction and group training as well as
freedom from complaints remained unsuccessful in keeping the patient compliant.
Mr Pl had been suffering from allergic asthma since early childhood which
escalated in 1982. Beclomethasone diproprionate (BDP) and Budesonid were not
tolerated (hoarseness), so that polypharmacy became necessary. This could only be
reduced after finding out that Flunisolid (Fls) was tolerated, so that
stabilisation was achieved. Complaints were greatly reduced with sole inhalation
of Fls and salbutamol. After having changed over to fluticasone it became
possible to reduce salbutamol as stabilisation progressed, so that salbutamol was
used only if required. Depending on the intensity of allergen exposure,
complaints now occur in February/March only, requiring updating of the therapy in
respect of dosage and number of drugs used. During the remaining part of the year
a minimal therapy using one stroke of 250 micrograms fluticasone was found
sufficient to ensure lasting freedom from complaints. Both patients reduced or
terminated the treatment of their own accord despite freedom from complaints
under minimal therapy and were reconverted to therapy compliance only after the
peak flow values had dropped or the complaints had returned.
PMID- 10783652
TI - [Pathogenesis, diagnosis and therapy of COPD].
PMID- 10783653
TI - [Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to
pulmonary fibrosis].
AB - Pulmonary hypertension is a life-threatening complication of lung fibrosis.
Vasodilator therapy is difficult owing to systemic side effects and pulmonary
ventilation-perfusion mismatch. We compared the effects of intravenous
prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and,
in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs)
in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized
prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease
in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and
pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p <
0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and
pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were
not significantly changed. Inhaled NO similarly resulted in selective pulmonary
vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In
contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting
in a significant drop in arterial pressure. In addition PGI2 infusion caused a
marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long
acting PGI2 analog) resulted in unequivocal clinical improvement from a state of
immobilization and severe resting dyspnea in a patient with decompensated right
heart failure. We concluded that, in pulmonary hypertension secondary to lung
fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary
vasodilatation with maintenance of gas exchange and systemic arterial pressure.
Long-term therapy with inhaled iloprost may be life saving in decompensated right
heart failure from pulmonary hypertension secondary to lung fibrosis.
PMID- 10783655
TI - [Phenomenologic and functional variability of violence among children].
AB - Examination of ten-year old children's everyday interactions with peers observed
in natural settings of a school demonstrates that violence was present in many
situations of help, sanctions, and rough-and-tumble play. Thorough analysis
reveals diverse functions of violence in children's interactions: affirmation of
reciprocity and justice, experience of agency and control, preservation of
territories against intruders, clear messages, compensations of lacking
capacities, and defense of the self.
PMID- 10783654
TI - [Surveillance and rehabilitation in asbestos exposure--an underrated problem?].
PMID- 10783656
TI - [Violence in the school--an analysis and prevention].
AB - The "Forschungsgruppe Schulevaluation" (Research Group for School Evaluation,
Technical University of Dresden) conducted several empirical investigations which
led to rich knowledge concerning the amount of violence in schools, the different
forms of violence, roles that actors of and sufferers from violent action play
and the causes for violence. Besides the wellknown socialisatory influence of
families, media consumption and peers for the formation of violent behaviour of
pupils and of behaviour that has an affinity to violence a causal influence of
schools was detected. Questions concerning the prevention of violence, the
conducting of pilot studies on the latter point in one single school as well as
the evaluation of the preventory measures taken were important points in our
work. In the present study we will present the most important empirical results
and our experience with the prevention of violence.
PMID- 10783657
TI - [Violence in the school--imported or self-produced?].
AB - The empirical results of the Bielefeld Research Project "Violence in Schools"
provide information about the kind and frequency of violent behaviors of pupils,
about a possible increase in the level of violence in German schools since the
1970s and about relevant risk factors inside and outside of the school which
influence the number of violent acts committed by pupils. The identification of
specific conditions in different areas of socialization makes it possible to
determine to what degree violence is imported into the school from outside or is
produced from within. On the basis of these findings, recommendations are made
for the prevention of violence in schools.
PMID- 10783658
TI - [Weapons in school--experiences and approaches in Berlin].
AB - On the background of current and often dramatized media reports on the subject of
guns in schools this article deals with acts of violence, with guns which were
discussed publicly last year in Berlin. In addition the authors have included
statistical data from the Berlin school administration on acts of violence at
Berlin schools which were reported 1996 to 1999. These were all incidents where
guns were mentioned. On the one hand detailed analyses of these reports show that
guns are used only exceptionally. On the other hand, surveys among students and
studies on arming in general and also the willingness to arm oneself, which
should be taken seriously, showed a wide-spread feeling of being threatened among
teenagers and especially male teenagers try to prepare themselves this. With the
example of Berlin this article describes which measures the school administration
uses in view of increasing offences committed by children and teenagers regarding
concrete acts of violence. Recommendations on steps appropriate to dealing with
incidents with gun threats and what kinds of resources schools can turn to in
cases of serious acts of violences are also included in this article. In the end
it becomes clear that schools free of guns and violence can only be realized if
children, youths and teachers can count on parents, media and the politically
responsible to reliably support this goal.
PMID- 10783660
TI - [Two cases of classical polyarteritis nodosa associated with a low titre of MPO
ANCA].
AB - We studied two autopsy cases, each with a low titre of myeloperoxidase anti
neutrophil cytoplasmic antibody (MPO-ANCA) associated with systemic vasculitis.
It was difficult to distinguish these cases from classic polyarteritis nodosa.
The patients had suffered from continuous fever, malaise, and weight loss:
however, their renal insufficiency was clinically mild over the course of their
disease. The patients were diagnosed initially as having MPO-ANCA-associated
vasculitis and were treated with prednisolone. Their clinical status improved,
but unfortunately, they died of an infectious disease. Autopsies revealed
systemic vasculitis in small arteries with no signs of necrotizing and crescentic
glomerulonephritis. Our pathologist subsequently diagnosed both cases as classic
polyarteritis nodosa. Systemic vasculitis associated with MPO-ANCA is usually
considered to be a microscopic polyarteritis. However, classic polyarteritis
nodosa should always be considered as a possibility for those patients with mild
renal insufficiency and a low titre of MPO-ANCA.
PMID- 10783659
TI - [Therapeutic effect and clinical findings in patients with MPO-ANCA associated
vasculitis syndrome].
AB - We investigated to clarify the clinical findings, course and therapeutic effect
in the patients with MPO (myeloperoxidase)-ANCA (anti-neutrophil cytoplasmic
antibody) associated vasculitis syndrome. We analyzed clinical findings and data
of 19 cases of MPO-ANCA associated vasculitis. These patients were diagnosed with
clinical symptoms (fever, arthralgia, body weight loss, etc.), laboratory data
(high titer of CRP, leukocytosis, thrombocytosis, and high titer of MPO-ANCA) and
pathologic findings of necrotizing vasculitis. They were 14 male and 5 female
aged 18 to 84 years (mean 65 years) and were treated with prednisolone and
immunosuppressive agents, and additional therapy included pulse therapy and
plasma exchange. Seven cases were dead within 3 months. Post-mortum examination
showed that these cases died of pneumonitis, cerebral events and gastric
bleeding. There was no mortal case induced by over-immunosuppression. In survival
cases, the MPO-ANCA levels decreased rapidly after these therapies and these
antibodies were maintained low levels (360 to 25 EU/l). Comparison of fatal cases
and survival cases, there were difference in the initial dose of prednisolone (27
mg/day vs. 56 mg/day), the ratio of double filtration plasmapheresis (14% vs.
42%), and the ratio of immunosuppressive therapy (14% vs. 83%). The measurement
of MPO-ANCA is useful makers of the diagnosis and effectiveness of the therapy in
patients with MPO-ANCA associated vasculitis. We recommend the aggressive
therapy, including prednisolone, immunosuppressive agents and plasma exchange for
MPO-ANCA associated vasculitis. We believe that the aggressive therapy improve
the survival rate of the patients with MPO-ANCA associated vasculitis.
PMID- 10783661
TI - [The radiographic report of soft tissue tumor on the legs in a case of cutaneous
polyarteritis nodosa].
AB - A 55-year-old male was admitted to our hospital because of arthralgia, rash, and
painful tumor in the legs. On admission, skin lesions involving dark erythematous
macules and a tender mass of 3 by 5 cm were present. Laboratory findings included
hemoglobin of 11.2 g/dl, white blood cell count of 6200/microliter, erythrocyte
sedimentation rate (ESR) of 88 mm/hour, and normal results of renal function
tests. Hepatitis B surface antigen, anti-nuclear antibody (ANA), and perinuclear
pattern antineutrophil cytoplasmic autoantibody (ANCA) were negative. A T 1
weighted magnetic resonance image (MRI) showed iso-intensity areas that increased
in intensity on T 2-weighted images of the M. gastrocnemius. The angiographic
appearance of tumor staining with some degree of luminal irregularity in the
posterior tibial artery suggested a diagnosis of soft tissue neoplasm. Biopsy
specimens of the right leg lesion were consistent with necrotizing arteritis of
both small and medium-sized vessels. Treatment with prednisolone and
cyclophosphamide resulted in the disappearance of the skin lesions and the
improvement of laboratory data. At first, classical polyarteritis nodosa was
considered histologically. However, lesions were limited to skin, muscles, and
joints, and there has been no evidence of systemic disease for 1.5 years;
consequently, cutaneous form of polyarteritis nodosa was diagnosed. Reports of
soft tissue tumors on the legs of patients with polyarteritis nodosa are quite
rare. The interesting radiographic findings of cutaneous polyarteritis nodosa
were reported.
PMID- 10783662
TI - [Antiphospholipid antibody-associated hemophagocytic syndrome].
AB - Autoimmune diseases such as systemic lupus erythematosus (SLE) are known to be
causative disorders of reactive hemophagocytic syndrome (HPS). We recently
encountered a case of HPS associated with the presence of antiphospholipid
antibodies (aPL). This patient showed severe thrombocytopenia (0.2 x
10(4)/microliter) and moderate anemia (Hb; 7.6 g/dl). Bone marrow smears showed
normal cellularity and an increase in mature-looking histiocytes scattered among
the hematopoietic cells, which accounted for approximately 3% of all nucleated
cells and were distributed unevenly. These cells showed marked phagocytosis of
hematopoietic cells, including megakaryocytes, erythroblasts, and a few
neutrophils. In this patient, there is no possible causative factor of HPS (such
as viral infection, lymphoma, and systemic lupus erythematosus) except the
presence of aPL. There have been no previously reported cases describing the
relationship between aPL and HPS. This case indicate that attention should be
given to the possibility that certain patients with aPL-associated cytopenia may
display accompanying intramedullary hemophagocytic phenomena.
PMID- 10783663
TI - [Two cases of rheumatoid arthritis associated with IgA -type multiple myeloma].
AB - We report here two Japanese cases of rheumatoid arthritis (RA) associated with
IgA [symbol: see text]-type multiple myeloma (MM). Case 1. The patient was a 68
year-old man with eight-years history of RA. The M-proteinemia (IgA 2838 mg/dl)
in laboratory findings suggested a complication of MM which had been noticed
since four years ago. On May 1997, he was referred and admitted to our hospital
because of cough, right chest pain and dyspnea. Serum immunoelectrophoresis
showed monoclonal IgA[symbol: see text]-type light chain. Bone marrow aspirate
contained 6.5% atypical plasma cells. The X-ray findings revealed radiolucent
myelomatous foci in the skull. From these findings, IgA[symbol: see text]-type MM
was diagnosed. His condition was recovered by administration of antibiotics for
bacterial pleuritis. Case 2. The patient was a 75-year-old woman with twelve
years history of RA. The laboratory findings of M-proteinemia (IgA 1215 mg/dl)
with the decrease of other serum immunoglobulin level (IgG 611 mg/dl, IgM 60
mg/dl) and monoclonal IgA[symbol: see text]-type light chain in serum
immunoelectrophoresis suggested MM four years ago. Bone marrow aspirate contained
5% plasma cells. From these findings, IgA[symbol: see text]-type MM was
diagnosed. In the review of reported Japanese cases of RA associated with MM, it
might be characteristic that IgA type MM was found more frequently in RA patients
than other immunoglobulin types.
PMID- 10783664
TI - [Osteoclastic bone resorption in joint destruction of rheumatoid arthritis].
PMID- 10783665
TI - [Dermatological aspects on systemic sclerosis].
PMID- 10783666
TI - [Revised Japan criteria for Sjogren syndrome].
PMID- 10783667
TI - [Study on Japan Rheumatism Association diagnostic criteria for early rheumatoid
arthritis. Prospective evaluation of diagnostic criteria for early rheumatoid
arthritis].
PMID- 10783668
TI - [Nonsurgical occlusion of an atrial septal defect in childhood: initial Swiss
experiences].
AB - The initial experience with catheter closure of an atrial septal defect (ASD) in
children, performed at two Swiss centers is presented. The ASD closures were
performed according to international multicenter study protocols. 14 children,
aged 3.9-17.5 years underwent closure by catheter. The defect size varied between
12 and 22 mm (balloon sized), the ratio between pulmonary and systemic blood flow
showed a mean of 2.2 (1.5-3.5). Catheter closure was done using three different
occlusion devices. More recently only the Amplatzer occluder was used at both
institutions. In 12 children (86%) defect closure was successful and after a
follow-up of 3-32 months (mean 17) only one child had a trivial residual
interatrial shunt. In all children, echocardiographic follow-up showed an
unchanged and correct device position on both sides of the atrial septum. In two
children, a floppy aortic segment of the atrial septal rim led to instable device
position: both children underwent surgical defect closure later. The children
with successful device closure showed no complications during the catheterization
or during follow-up. There were no thrombotic complications on the surfaces of
the devices. Catheter closure of an ASD during childhood is a safe and efficient
alternative to standard surgical treatment.
PMID- 10783669
TI - [Value of ultrasound study and dual energy x-ray absorptiometry (DEXA) for
assessment of risk of osteoporosis].
AB - Screening postmenopausal women for preventing osteoporosis at an early stage is
the main topic of several studies. The present paper evaluates the place of
ultrasound measurements in comparison with Dual Energy X-ray-absorptiometry
(DEXA). METHODS: 247 women (41 women < or = 50 yrs, 103 women 50-60 yrs, 103
women > 60 yrs) underwent DEXA of the vertebrae and hip and concommittantly
ultrasound measurements of the calcaneus. RESULTS: The DEXA values in the
vertebral column vary considerably and are lowest in L1 and highest in L4. The
femur on the other hand shows lowest values in the Ward triangle (T = -1.6 SD),
and highest in the trochanter (T = -0.3 SD). Speed of sound (SOS) gives lower T
values (-1.2 SD) than broadband ultrasound attenuation (BUA) (-0.3 SD).
Statistical analysis (Spearman, Pearson) shows no correlation between ultrasound
and DEXA measurements and therefore do not permit analogies between hip and
vertebral column and vice versa. CONCLUSIONS: Our data show that the fracture
risk of an individual woman can be adequately ascertained only by DEXA
measurement of vertebrae and femur. Ultrasound measurement today cannot be
recommended as routine screening or diagnostic method.
PMID- 10783670
TI - [Differential diagnosis of unilateral hearing loss].
AB - There are two main kinds of hearing disorders: sensorineural and conductive.
Sensorineural hearing loss is a common disorder that results from damage to the
inner ear in over 95% of all cases; therefore, retrocochlear hearing disorders
are rare and cannot be differentiated from sensory losses by clinical symptoms
alone. Unilateral hearing loss entails many problems in hearing during the entire
life of the affected patients. Conductive deafness has a readily determined
etiology in most cases. In contrast, unilateral sensorineural hearing loss
requires more refined and extensive investigation. The etiology of an asymmetric
sensorineural hearing loss can often be difficult to determine. Because a wide
variety of pathologic processes may be responsible for the hearing loss, numerous
diagnostic tests are usually used during initial evaluation, including pure-tone
audiometry, acoustic reflex testing, imaging, serologic testing, and auditory
brainstem response testing. The most frequent causes of unilateral sensorineural
hearing loss were sudden deafness, Meniere's disease and cerebellopontine angle
tumors. Early diagnosis of acoustic neuroma or other lesions of the internal
auditory meatus or cerebello-pontine angle requires special attention. The
patient with an acoustic neuroma may present to the otologist with a variety of
clinical features. Classically these include a retrocochlear pattern of
sensorineural hearing loss, reduced vestibular response on caloric testing and a
pathological auditory brainstem response. Magnetic resonance imaging offers
greater specificity than computed tomography. Therapy of unilateral sensorineural
hearing loss includes efforts to treat known causes either medically or
surgically.
PMID- 10783671
TI - [Retrosternal pressure, dyspnea and palpitations. Small cell bronchial
carcinoma].
PMID- 10783672
TI - Results of revision total knee arthroplasty.
AB - BACKGROUND/AIM OF STUDY: The results of primary total knee arthroplasties have
improved over the years but some still fail, requiring revision. Revision total
knee arthroplasty is technically more difficult and has not enjoyed the same
success rates as the index operation. The aim of this retrospective study was to
review the results of revision total knee arthroplasties carried out at our
centre. This is the first study in Singapore on revision total knee arthroplasty.
METHODS: A retrospective study where 17 patients (18 knees) had been followed up
since their revision operations were clinically assessed. Based on the Knee
Society Clinical Scoring System, they were assigned separate knee and function
scores (each having a maximum possible 100). RESULTS: The mean knee score was 76
(range 35-93), which rates as good. Of the 18 knees, 67% had excellent or good
knee scores. By comparison, the mean function score was 56 (range 0-90) which
rates as poor and 33% had excellent or good function scores. CONCLUSION: Revision
total knee arthroplasty achieves good and excellent results in spite of technical
difficulties often associated with the revision operation. The difference in mean
knee and function scores emphasises that many other factors such as physical
strength and stamina affect function. Nevertheless, 15 patients were able to walk
out of their house and around their neighbourhood for varying distances. This
satisfied their expectations and the poor mean function score may reflect
different expectations of patients overseas from whence this scoring system
originated.
PMID- 10783673
TI - Effects of an ethanolic extract of Gynura procumbens on serum glucose,
cholesterol and triglyceride levels in normal and streptozotocin-induced diabetic
rats.
AB - AIM OF STUDY: The aim was to demonstrate the effects of the leaves of Gynura
procumbens (Lour.) Merr. on blood sugar and lipid levels in experimental animals.
METHODOLOGY: We obtained an ethanolic extract of the leaves of G. procumbens and
monitored the effects of an oral administration of (i) different single doses of
the extract on oral glucose tolerance in streptozotocin-induced diabetic and
normal rats and (ii) fourteen doses over 7 days on serum cholesterol and
triglyceride levels in streptozotocin-induced diabetic rats. Metformin and
glibenclamide were used as positive control drugs. RESULTS: The extract, at
single doses of 50, 150 and 300 mg/kg orally, significantly suppressed the
elevated serum glucose levels in diabetic rats; 150 mg/kg was found to be the
optimum hypoglycaemic dose. The extract however did not significantly suppress
the elevated serum glucose levels in normal rats, unlike glibenclamide.
Metformin, but not glibenclamide, improved glucose tolerance in the diabetic
rats. When the optimum dose was given to diabetic rats for 7 days, the extract
significantly reduced serum cholesterol and triglyceride levels in these rats.
CONCLUSION: These results indicate that the leaves of G. procumbens may have
biguanide-like activity.
PMID- 10783674
TI - Surgical approach and results of surgery in adenocarcinoma of the gastro
oesophageal junction.
AB - AIM OF STUDY: This paper attempts to determine the appropriate surgical procedure
in relation to the pathological types of adenocarcinoma of the gastro-oesophageal
junction in Singapore. METHODS: Data on population characteristics, clinical
presentation, pathology, surgical procedures and results of treatment were
gathered from the case records of a personal series of 32 patients resected for
adenocarcinoma of the gastro-oesophageal junction. RESULTS: The 32 patients with
adenocarcinoma of the gastro-oesophageal junction (Type I, 9; II, 20 and III, 3),
presented at a late stage (Stage I-II, 5; III, 14; IV, 13). In 19 patients with
Stages I-III disease, attempted curative surgery was performed--extended total
gastrectomy for Types II and III disease (13 patients) and oesophagectomy for
Type I (6 patients). There was one operative mortality following curative
resection. Palliative resection was performed on 13 patients with Stage IV
disease with one operative mortality. The main operative morbidity was
anastomotic leakage, occurring in 5 patients; both operative deaths were
associated with this complication. The actuarial 5-year survival was 20%.
CONCLUSION: Although gastro-oesophageal cancer presents late, it can be resected
safely by extended total gastrectomy for Types II and III disease and
oesophagectomy for Type I disease, taking precautions to minimise anastomotic
leakage. Although usually palliative, Stages I and II and to a lesser extent
Stage III, are curable by these surgical procedures which ensure a tumour free
surgical margin and adequate lymphadenectomy.
PMID- 10783675
TI - The diagnostic yield of pleural fluid cytology in malignant pleural effusions.
AB - BACKGROUND: The development of a pleural effusion in a patient with a known
malignancy often raises the possibility that the effusion is due to malignant
involvement of the pleura. Accurate diagnosis of the cause of the pleural
effusion in such a patient is essential as the treatment and prognosis may vary.
Currently, thoracentesis and cytologic analysis of pleural fluid cytology is
usually the initial diagnostic step. AIM: To assess the diagnostic yield of
pleural fluid cytologic examination in patients with suspected malignant pleural
effusions seen at our centre. METHODS: Retrospective review of the results of
pleural fluid cytologic examination performed on 103 patients who presented with
suspected malignant pleural effusions. RESULTS: The underlying malignancies in
these patients were as follows: bronchogenic carcinoma (51.5%), breast carcinoma
(29.1%), hepatocellular carcinoma (1.9%), carcinoma of the stomach (1.9%),
malignant mesothelioma, nasopharyngeal carcinoma, renal cell carcinoma, carcinoma
of the oesophagus, lymphoma, carcinoma of the colon (1% each), unknown (9.7%).
Initial pleural fluid cytology was positive for malignancy in 48.5% of patients.
The yield of this diagnostic procedure was improved with repeated pleural fluid
cytologic specimens and when combined with a percutaneous pleural biopsy. There
was no statistically significant difference in the clinical features and pleural
fluid characteristics of patients with malignant pleural effusions and those in
whom the pleural effusions were paramalignant. CONCLUSION: Pleural fluid
cytologic examination is a useful initial step in the diagnostic work-up of
patients with suspected malignant pleural effusions. The diagnostic yield of such
examination is improved with repeated pleural fluid cytologic specimens and when
combined with a percutaneous pleural biopsy. Clinical presentation and pleural
fluid characteristics were inadequate in differentiating between malignant and
paramalignant effusions.
PMID- 10783676
TI - Flashlamp-pumped pulsed dye laser (585nm) for the treatment of portwine stains--a
study of treatment outcome in 94 Asian patients in Singapore.
AB - BACKGROUND: This is a report of a prospective study on the treatment outcome of
94 Asian skin Types III and IV patients with port-wine stains with the 585 nm
flashlamp-pumped pulsed dye laser in Singapore. RESULTS: All patients had
completed at least 1 year of follow-up post treatment and had received treatment
at 8-12 weekly intervals under topical lodocaine-prilocaine anaesthesia. Our
patients received an average of 4 treatments sessions. At the end of each
treatment (8-12 weeks after the last laser treatment/before the next laser
treatment) and on completion of the last treatment (8-12 weeks after the final
laser treatment), patients were assessed for response based on a subjective
scoring system where excellent = > 75% improvement, good = 50% to 75%
improvement, fair = 25% to 49% improvement and poor = < 25% improvement and the
same = no observable improvement. The dermatologist also recorded scores after
each treatment in a similar way. On completion of the final treatment, patients
were asked to score (8-12 weeks after the final laser treatment) the overall
response to the treatment themselves using the same scoring system. The mean age
was 26.4 years (range 1 year to 58 years). The mean initial treatment energy
density dose was 6.24 J/cm2. Eighty percent of our patients experienced excellent
or good response to treatment after the initial treatment and further
improvements were observed with each subsequent treatment. RESULTS: The author
scored 86% of our patients having "excellent" or "good" response while 83% of our
patients scored "excellent" or "good" response upon completion of their
treatment. The dermatologist generally recorded better improvement scores than
the patients. The dermatologist scored 36% and 50% of our patients having
"excellent" and "good" response respectively. The corresponding treatment
response scores by our patients were 22% ("excellent") and 61% ("good").
CONCLUSION: Macular lesions appear to respond better than papular/nodular
lesions, but the difference was not statistically significant probably due to the
small study cohort. Light coloured port-wine stains tended to respond better to
treatment than darker lesions (not statistically significant), but overall, all
colour lesions responded well to treatment. Patients' expectation of improvements
was generally higher than the dermatologist's.
PMID- 10783677
TI - Adolescent pregnancies managed at KK Hospital.
AB - AIM OF STUDY: The aim was to analyse the pregnancy outcome among girls, aged 17
and below, at KK Hospital. METHODOLOGY: This is a retrospective study. A total of
108 adolescent pregnancies were analysed with regards to pregnancy order,
antenatal complications, mode of delivery and pregnancy outcome. RESULTS: The 2
most common antenatal complications were anaemia and preterm labour. The repeat
pregnancy rate was 15.7%. Vaginal delivery was achieved in 7.2%; 21.2% of babies
born weighed less than 2.5 kg. CONCLUSIONS: Adolescent pregnancies accounted for
only a small proportion of all deliveries in our hospital. Late or non-existent
antenatal care was a feature in most pregnancies. The incidence of repeat
pregnancies reflects the need for a more effective counselling on contraception.
PMID- 10783678
TI - Giant cell arteritis causing bilateral sequential anterior ischaemic optic
neuropathy--a case report.
AB - Giant cell arteritis is a chronic granulomatous inflammation of unknown aetiology
involving large and medium size arteries in the elderly. It causes acute visual
loss from ischaemia to the optic nerves or central retinal artery occlusion. This
is a rare cause of anterior ischaemic optic neuropathy in our local population.
We present a patient who had bilateral loss of vision from sequential arteritic
ischaemic optic neuropathy. She was treated with intravenous steroids
immediately. Diagnosis was based on histopathological studies of temporal artery
biopsies.
PMID- 10783679
TI - Morbidity after a bite from a 'non-venomous' pet snake.
AB - We report the first recorded case of morbidity from the bite of a red-neck
keelback snake (Rhabdophis subminiatus) from South East Asia. This is a species
of the Colubrid family which originated from South East Asia. Severe envenomation
from this snake was reported as poisonous in the West as far back as 1978 but it
is still being classified as non-venomous. This classification led our patient to
keep this 'harmless' snake as a pet. We recommend that this snake be reclassified
as 'venomous' or at least warnings be issued to the public not to keep it as a
pet.
PMID- 10783680
TI - Hybrid cardiac revascularisation surgery.
AB - Currently, 3 methods of myocardial revascularisation are available for the
treatment of coronary artery disease: i) coronary artery bypass grafting (CABG);
ii) percutaneous transluminal coronary angiography (PTCA), and iii)
transmyocardial laser revascularisation (TMR). Until recently, these procedures
were performed exclusive to one another. We report 2 cases of minimally invasive
direct coronary artery bypass grafting with subsequent PTCA, and 1 case of staged
PTCA followed by TMR performed at our institution. We discuss the role of hybrid
procedures in the current era of treatment of ischaemic heart disease.
PMID- 10783681
TI - An unusual manifestation of severe caustic injury.
AB - Knowledge of the sequelae of caustic ingestion is of relevance to staff of the
Emergency Room, Intensive Care Unit, surgical and gastroenterology services. It
poses a considerable management problem and may result in life-threatening
complications such as visceral perforation. This case report demonstrates an
unusual and previously unreported manifestation of caustic injury.
PMID- 10783682
TI - Inferior vena cava filters--percutaneous insertion?
AB - The incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) among
Chinese is much lower than in Caucasians. The total number of inferior vena cava
(IVC) filters inserted in regional hospitals in Canada (about 700 beds in Toronto
General Hospital) and Hong Kong (about 1,250 beds in Pamela Youde Nethersole
Eastern Hospital) also reflects this. Thirty-six IVC filters were deployed in
Toronto General Hospital, compared to 8 IVC filters inserted in Pamela Youde
Nethersole Eastern Hospital from August 1997 to September 1998. Despite this, the
physician may encounter patients with thromboembolic disease who require inferior
vena cava interruption. The usual indication will be pulmonary embolism with
contraindications to, or failure or complications of, anticoagulation therapy. It
is important for angiographers to be familiar with the technique of percutaneous
insertion of IVC filters. The types of IVC filters, techniques of insertion and
guidelines relating to the choice of a filter would be discussed.
PMID- 10783683
TI - Clinics in diagnostic imaging (45). Osmotic myelinolysis ( central potine
myelinolysis).
AB - A 65-year-old woman developed progressive neurological deterioration following
rapid correction of hyponatremia. Magnetic resonance imaging showed T2
hyperintense areas in the central pons, basal ganglia and deep white matter,
typical of osmotic myelinolysis (OM). Previously thought to be uniformly fatal,
there are increasing reports of non-fatal cases of OM. The recognition and
understanding of this entity is important to prevent or reduce the incidence of
its occurrence, as there is no specific treatment once it develops. The clinical
and radiological features of OM are reviewed.
PMID- 10783684
TI - Medical milestones of the last millennium.
PMID- 10783685
TI - The death of the party. All the rave, GHB's hazards go unheeded.
PMID- 10783686
TI - Tampon safety. TSS now rare, but women still should take care.
PMID- 10783687
TI - Your medicine cabinet needs an annual checkup, too.
PMID- 10783688
TI - Science at FDA. The key to making the right decisions.
PMID- 10783689
TI - Two companies caught in fish fraud case.
PMID- 10783690
TI - Models of nursing care: a century of vacillation.
PMID- 10783691
TI - Where will tomorrow's nurse managers come from?
PMID- 10783692
TI - Tips for successful merger integration.
PMID- 10783693
TI - Nurses' perceptions. Is your nurse uncomfortable or incompetent?
PMID- 10783694
TI - The demise of nursing administration programs. Reaction to the reaction!
PMID- 10783695
TI - Japan's healthcare system.
PMID- 10783696
TI - Nursing future search. Building a community of nurses in an integrated healthcare
system.
AB - Many models and approaches are available to manage change and plan for the
future. Large group intervention is one approach to tapping the collective wisdom
of a nursing system facing formidable adaptive challenges. Large group
interventions involve many people, and they include open sharing of information,
group problem-solving, participation, and sharing of power to create a shared
future. One model for creating a vision for the future is called "Future Search".
In this article, we describe the methodology of Future Search as a model to plan
for change. A case study illustrates the use of a Nursing Future Search by an
integrated, not-for-profit healthcare organization in northern Virginia. Results
and the outcomes of a 6-month follow-up conference reveal nine planning groups
that are moving a community of nurses to action.
PMID- 10783697
TI - Values expressed in philosophies of nursing services.
AB - Do nurses value "caring"? Does it matter that nurses respect individual rights
while caring for groups of patients? What values are shared by nurses and are
they evident in institutions? How important are nursing values in a changing
healthcare system? Should nurse administrators ensure that nursing values remain
integral to managed care? What is the nurse's responsibility for communicating
nursing values throughout the organization? The authors discuss the values
expressed in nursing service philosophies and how they reflect a changing
healthcare system.
PMID- 10783698
TI - Intuition in professional practice. Executive and staff perceptions.
AB - Intuition, as part of our thinking, is often misunderstood or held in mystical
regard. It is important to understand the aspects of this instinctual process and
to appreciate the differing perspectives of both the registered nurse in the
staff position and the executive in a leadership role. We compare responses to a
Socratic dialogue of the definition of intuition and offer suggestions for
nursing leaders to develop clinical judgment using nursing examples of intuition.
PMID- 10783699
TI - Hospital networking. Comparing the work of nurses with flexible and traditional
schedules.
AB - OBJECTIVE: This research study was conducted to contrast workplace socialization
of nurses working flexible (flex) and traditional schedules in an acute care
setting. The study illustrates the types of social networks used by both types of
nurses in a reengineered healthcare environment. SUMMARY BACKGROUND DATA:
Reengineering strategies, such as flex nurse staffing, add a new dimension to
workplace change and adaptation. Few studies have examined the similarities and
differences between nurses working flex and traditional schedules. The research
literature shows that workplace socialization significantly affects job
satisfaction, organizational commitment, and retention. No studies have examined
how the process of socialization--forming social networks--differs for nurses
working traditional or flex schedules. METHODS AND SUBJECTS: A convenience sample
of 120 nurses working traditional schedules and 46 nurses working flex schedules
from a pediatric, tertiary care setting completed the Social Network
Questionnaire (SNQ), a standardized instrument that records individuals' social
network composition and function. RESULTS: No significant differences were found
in the nurses' social network composition. Both types of nurses constructed peer
based networks and nurse managers were also present in their networks. Nurses
working traditional schedules used significantly more peer members for different
types of emotional support, such as reassurance and handling emotional upsets.
CONCLUSIONS: Workplace networks are important to both types of nurses. Nurses on
flex schedules may form less social attachments in order to manage the increased
demands of moving among multiple units. This group of nurses can provide clues
for adaptive change in reengineered environments.
PMID- 10783700
TI - Redesigning financial management education for the nursing administration
graduate student.
AB - The changes and expansion in the nurse administrator role indicate a need for a
specialized body of financial knowledge and skills for making system focused
decisions that integrate the clinical and business aspects of healthcare. A
survey of nurse administrators and chief executive officers showed high agreement
on the important financial management concepts to the nurse administrator role. A
graduate level financial management course that includes concepts for course
content and practice applications is proposed.
PMID- 10783701
TI - [Homage to Professor J.-Andre Thomas (1905-1999)].
PMID- 10783702
TI - [Animal toxins and ion channels].
AB - Animal venoms contain various toxins which act on ion-channels, responsible for
either sodium, potassium, calcium or chloride permeation. Structure determination
of these toxins demonstrate that they are organised around two different
structural motifs: potassium and sodium channel effectors are organised around an
alpha-helix connected by two disulfide bridges to a two- or three-stranded beta
sheet whereas calcium channels effectors are structured around an "Inhibitory
Cystine Knot" motif made of a dense disulfide-rich core from which emerge several
loops. Analysis of local structural modifications allows us to understand the
structural basis of the selectivity of these effectors towards the various ion
channels. This is the first step in the design of new synthetic molecules which
are potent therapeutic drugs for diseases involving ion channel dysfunctioning.
PMID- 10783703
TI - [Bacterial toxins: useful for studying G-proteins implicated in the mechanism of
exocytosis in neuroendocrine cells].
AB - In neuroendocrine cells, regulated exocytosis is a multistep process that
comprises the recruitment and priming of secretory granules, their docking to the
exocytotic sites, and the subsequent fusion of granules with the plasma membrane
leading to the release of secretory products into the extracellular space. Using
bacterial toxins which specially inactivate subsets of G proteins, we were able
to demonstrate that both trimeric and monomeric G proteins directly control the
late stages of exocytosis in chromaffin cells. Indeed, in secretagogue-stimulated
chromaffin cells, the subplasmalemmal actin cytoskeleton undergoes a specific
reorganization that is a prerequisite for exocytosis. Our results suggest that a
granule-bound trimeric Go protein controls the actin network surrounding
secretory granules through a pathway involving the GTPase RhoA and a downstream
phosphatidylinositol 4-kinase. Furthermore, the GTPase Cdc42 plays a active role
in exocytosis, most likely by providing specific actin structures to the late
docking and/or fusion steps. We propose that G proteins tightly control secretion
in neuroendocrine cells by coupling the actin cytoskeleton to the sequential
steps underlying membrane trafficking at the site of exocytosis. Our data
highlight the use of bacterial toxins, which proved to be powerful tools to
dissect the exocytotic machinery at the molecular level.
PMID- 10783704
TI - [Analysis of synaptic neurotransmitter release mechanisms using bacterial
toxins].
AB - Several bacterial toxins are powerful and highly specific tools for studying
basic mechanisms involved in cell biology. Whereas the clostridial neurotoxins
are widely used by neurobiologists, many other toxins (i.e. toxins acting on
small G-proteins or actin) are still overlooked. Botulinum neurotoxins (BoNT,
serotypes A-G) and tetanus neurotoxin (TeNT), known under the generic term of
clostridial neurotoxins, are characterized by their unique ability to selectively
block neurotransmitter release. These proteins are formed of a light (Mr
approximately 50) and a heavy (Mr approximately 100) chain which are disulfide
linked. The cellular action of BoNT and TeNT involves several steps: heavy chain
mediated binding to the nerve ending membrane, endocytosis, and translocation of
the light chain (their catalytic moiety) into the cytosol. The light chains each
cleaves one of three, highly conserved, proteins (VAMP/synaptobrevin, syntaxin,
and SNAP-25 also termed SNAREs) implicated in fusion of synaptic vesicles with
plasma membrane at the release site. Hence, when these neurotoxins are applied
extracellularly, they can be used as specific tools to inhibit evoked and
spontaneous transmitter release from certain neurones whereas, when the membrane
limiting steps are bypassed by the mean of intracellular applications, BoNTs
orTeNT can be used to affect regulated secretion in various cell types. Several
members of the Rho GTPase family have been involved in intracellular trafficking
of synaptic vesicles and secretory organelles. As they are natural targets for
several bacterial exoenzymes or cytotoxins, their role in neurotransmitter
release can be probed by examining the action of these toxins on
neurotransmission. Such toxins include: i) the non permeant C3 exoenzymes from C.
botulinum or C. limosum which ADP-ribosylate and thereby inactivate Rho, ii)
exoenzyme S from Pseudomonas aeruginosa which ADP-ribosylates different members
of the Ras, Rab, Ral and Rap families, iii) toxin B from C. difficile which
glucosylates Rho, Rac and CDC42, iv) lethal toxin from C. sordellii which
glucosylates Rac, Ras and to a lesser extent, Rap and Ral, but not on Rho or
CDC42, and v) CNF deamidases secreted by pathogenic strains of E. coli which
activate Rho and, to a lesser extent, CDC42. Since these toxins or exoenzymes
have no or little ability to enter into the neurones, they must be applied
intraneuronally to bypass the membrane limiting steps. Injection of several of
these toxins into Aplysia neurones allowed us to reveal a new role for Rac in the
control of exocytosis. ADP-ribosylating enzymes, which specifically act on
monomeric actin (C2 binary toxin from C. botulinum and iota toxin from C.
perfringens), are potential tools to probe the role of actin filaments during
secretion.
PMID- 10783705
TI - [Muscarinic modulation of cardiac activity].
AB - The goal of the present review is to report information concerning cardiac
innervation or more precisely to approach the modulation of cardiac electrical
and mechanical activity by parasympathetic innervation. Acetylcholine (ACh)
release by nerve endings from the vagus nerve hyperpolarizes the membrane,
shortens action potential (AP) duration and has a negative inotropic effect on
cardiac muscle. Toxins are usefull tools in the study of membrane signals. The
Caribbean ciguatoxin (C-CTX-1) has a muscarinic effect on frog atrial fibres. The
toxin evokes the release of ACh from motoneuron nerve terminals innervating this
tissue which allows us to propose a model, similar to the one of the
neuromuscular junction (nmj), to describe the events occurring during the
triggering and release of ACh. Trachynilysin (TLY) is a proteic toxin which
causes an influx of Ca2+ into the cells and releases ACh from nmj synaptic
vesicles. TLY has a muscarinic effect on atrial fibres which is explicated in the
release of neurotransmitter from the nerve endings generated by the TLY-induced
Ca2+ influx. It is known that ACh release from nmj is known to be due to
exocytosis of synaptic vesicles via the activation of a proteic complex blocked
by botulinum toxins. One of these proteins SNAP-25 is the target of type A
botulinum toxin (BoNT/A). The study of hearts isolated from BoNT/A poisoned frogs
show that atrial AP is lengthened and reveals the presence of SNAP-25 in nerve
endings of this tissue. Moreover, the electrical activity of ventricular muscle
is markedly altered; in BoNT/A treated frog, an important outward current
activated by internal Ca2+ develops. ACh released from nerve terminals binds to a
G protein coupled membrane receptor and activates a K+ channel and other
effectors. Five subtypes of muscarinic receptors have been cloned from different
tissue (M1, M2, M3, M4) subtypes have been identified in cardiac tissues
throughout many species. These receptors coupled with different G-proteins
activate different effectors. M1 receptors modulate the cardiac plateau and
therefore the magnitude of the peak contraction. M2 receptors are mainly involved
in the repolarization phase of the AP and modulate the duration of the peak
contraction. The roles of M3 and M4 are not yet clearly defined; however, they
may activate K+ currents. In conclusion, ACh releases from parasympathetic nerve
endings which innervate cardiac cells follows to similar events (Ca2+ influx;
presence of a SNAP-25 protein) to those which produce ACh release from nmj,
stimulates different G proteins coupled muscarinic receptors, and activates
different effectors involved in the modulation of cardiac electrical and
mechanical activity.
PMID- 10783706
TI - [Conus venoms: a source of toxins which interact with membrane- potential
dependent sodium channels].
AB - Marine snails of the genus Conus, as they are carnivorous predators, have a venom
apparatus used to capture their prey. The toxins contained in the venoms of
Conidae, called conotoxins, are of a particular high degree of diversity and
represent powerful tools in the neuroscience field. Indeed, these toxins
specifically bind with a high affinity to receptors and ionic channels.
Therefore, they provide original pharmacological tools which receive increasing
investigation both to identify and study some functions of the nervous systems
and to characterize new types and closely related subtypes of receptors or ionic
channels. The voltage-gated sodium channel, because of its fundamental role in
cell membrane excitability, is the specific target of a large number of animal
and vegetal toxins. Actually, at least seven toxin receptor sites have been
identified on this channel-protein. These toxins, and in particular conotoxins,
are used to precise the role of different types and/or closely related subtypes
of sodium channels in the peripheral and central nervous systems. The focus of
the present review is to summarize our current knowledge of the consequences of
physiological interactions between different conotoxin families and sodium
channels.
PMID- 10783707
TI - [Effect of ciguatoxins on the cardiocirculatory system].
AB - The aim of the present review was to collect the main observations reported until
now concerning the cardio-circulatory effects of polyether toxins, called
ciguatoxins, which are involved in an endemic intoxication named ciguatera found
in tropical and subtropical countries. Ciguatera is caused by the ingestion of
fishes contaminated with the dinoflagellate Gamberdiscus toxicus. Due to both
tropical fish exportation destined for food and tourism, the disease has now
spread out to temperate areas. Several toxins have been isolated and purified
from different fish species living in different geographical areas. They are
classified into three main groups by the nature of certain cycles of their carbon
skeleton. Clinical reports show evidence that ciguatera intoxication affect both
electrocardiograms and blood pressure. In most cases, ciguateric intoxication
mainly evoked bradycardia, hypotension, and the alteration of S-T segment in the
electrocardiogram. Isolated and purified ciguatoxins strongly altered the
morphology of cardiac tissue inducing swelling of the cells and alterations of
cellular organelles. These toxins impair the conduction of cardiac nerves and
increase the opening probability of Na+ channels in intracardiac ganglions.
Depending on the concentration applied, the substances exerted either a fast
positive inotropic effect or a negative inotropic effect on the contraction of
mammalian atrial and ventricular cardiac muscle. These effects were attributed to
a release of noradrenaline and acetylcholine from neural terminals of the
autonomic nervous system present in cardiac tissue. They also exert a slow
delayed inotropic effect on the contraction which has been attributed to a direct
effect of the toxins on tetrodotoxin-sensitive voltage-dependent Na+ channels of
cardiac membranes. Ciguatoxins depolarized the membrane of mammalian atrial and
ventricular preparations and shifted the threshold of sodium current activation
to more negative membrane potentials. In conclusion, the inotropic effects of
ciguatoxins on cardiac tissues mainly depend on the toxin concentration
sensitivity of autonomic nerve terminals, which released noradrenaline and/or
acetylcholine, while the ciguatoxin-induced increase of the sodium influx could
be involved in the cardiac cell swelling which coincides with reports in which
ciguatoxins induced a mannitol-inhibited swelling of the Node of Ranvier.
PMID- 10783708
TI - [The fasciculin-acetylcholinesterase interaction].
AB - Acetylcholinesterase (AChE) terminates the action of the neurotransmitter
acetylcholine at cholinergic synapses in the central and peripheral nervous
systems. Fasciculins, which belong to the family of "three-fingered" snake
toxins, selectively inhibit mammalian AChEs with Ki values in the picomolar
range. In solution, the cationic fasciculin appears to bind to the enzyme's
peripheral anionic site, located near the mouth of the gorge leading to the
active center, to inhibit catalysis either allosterically or by creating an
electrostatic barrier at the gorge entry (or both). Yet the crystal structure of
the fasciculin-mouse AChE complex, which shows that the central loop of
fasciculin fits snugly at the entrance of the gorge, suggests that the mode of
action of fasciculin is steric occlusion of substrate access to the active
center. Mutagenesis of the fasciculin molecule, undertaken to establish a
functional map of the binding surfaces, identified determinants common to those
identified by the structural approach and revealed that only a few of the many
fasciculin residues residing at the complex interface provide the strong contacts
required for high affinity binding and enzyme inhibition. However, it did not
reconcile the disparity between the kinetic and structural data. Finally, the
crystal structure of mouse AChE without bound fasciculin shows a tetrameric
assembly of subunits; within the tetramer, a short loop at the surface of a
subunit associates with the peripheral site of a facing subunit and sterically
occludes the entrance of the active center gorge. The position and
complementarity of the peripheral site-occluding loop mimic the characteristics
of the central loop of fasciculin bound to AChE. This suggests not only that the
peripheral site of AChE is a site for association of heterologous proteins with
interactive surface loops, but also that endogenous peptidic ligands of AChE
sharing structural features with the fasciculin molecule might exist.
PMID- 10783709
TI - [Tetanus and botulinum toxins are zinc metallopeptidases: molecular mechanisms
and inhibition of their neurotoxicity].
AB - The very high toxicity of tetanus neurotoxin (TeNT) and botulinum neurotoxin
(BoNT) are related to their nature of zinc metallopeptidases able to selectively
cleave small proteins involved in neurotransmitters exocytosis. At this time,
there is no efficient and selective therapy towards tetanos and tobulism as well
as protection against a possible spreading of the toxins. We have therefore
investigated the minimum sequences of TeNT and BoNT substrates allowing an
efficient and simple fluorescent dosage of the enzymatic activity to be
developed. Using synaptobrevin (93 amino acids) as substrate of TeNT and several
fragments synthesised by solid phase method, we have shown that the clostridial
neurotoxins behave as allosteric-type enzymes. This is the first example in zinc
metallopeptidases. Based on these results a strategy, including the use of
combinatorial chemistry, was carried out issuing in the design of the first
potent inhibitors of TeNT and BoNT.
PMID- 10783710
TI - [Induction of membrane excitability in Xenopus oocytes].
AB - Immature oocytes from the African toad Xenopus laevis are not known to be
excitable cells, which means that they do not generate an action potential in
response to small depolarizations. However, a regenerative response is produced
if successive depolarizing currents of large magnitude are applied to the oocyte
membrane. This response is characterized by the occurrence of a positive
transmembrane potential that can last for several minutes. The opening of voltage
dependent channels, highly selective for sodium ions, underlies the
depolarization thus obtained. These channels exhibit unconventional
electrophysiological and pharmacological properties, which set them apart from
other types of voltage-dependent sodium channels found in excitable tissues. The
opening of the oocyte sodium channels is a complex process, which includes an
induction phase. During this phase, the channels change from an electrical state
of inexcitability into an excitable voltage-dependent state. The induction
mechanism is modulated by the temperature of the bathing medium, by the
activation of enzymes (namely a phospholipase C and a protein kinase C) and by
the release of calcium ions from intracellular phosphatidyl-inositol
trisphosphate stores. The results summarized in this review point out the
possible role that these sodium channels may play in the physiology of the
oocyte.
PMID- 10783711
TI - [Bacillus thuringiensis: a biotechnology model].
AB - This paper is on the different biotechnological approaches that have been used to
improve Bacillus thuringiensis (Bt) for the control of agricultural insect pests
and have contributed to the successful use of this biological control agent; it
describes how a better knowledge of the high diversity of Bt strains and toxins
genes together with the development of efficient host-vector systems has made it
possible to overcome a number of the problems associated with Bt based insect
control measures. First we present an overview of the biology of Bt and of the
mode of action of its insecticidal toxins. We then describe some of the progress
that has been made in furthering our knowledge of the genetics of Bt and of its
insecticidal toxin genes and in the understanding of their regulation. The paper
then deals with the use of recombinant DNA technology to develop new Bt strains
for more effective pest control or to introduce the genes encoding partial
endotoxins directly into plants to produce insect-resistant trangenic plants.
Several examples describing how biotechnology has been used to increase the
production of insecticidal proteins in Bt or their persistence in the field by
protecting them against UV degradation are presented and discussed. Finally,
based on our knowledge of the mechanism of transposition of the Bt transposon
Tn4430, we describe the construction of a new generation of recombinant strains
of Bt, from which antibiotic resistance genes and other non-Bt DNA sequences were
selectively eliminated, using a new generation of site-specific recombination
vectors. In the future, continuing improvement of first generation products and
research into new sources of resistance is essential to ensure the long-term
control of insect pests. Chimeric toxins could also be produced so as to increase
toxin activity or direct resistance towards a particular type of insect. The
search for new insecticidal toxins, in Bt or other microorganisms, may also
provide new weapons for the fight against insect damage.
PMID- 10783712
TI - Bacterial resistance; an emerging health problem.
PMID- 10783713
TI - Antibiotic resistance: genetic mechanisms and mobility.
AB - Based on the current knowledge, resistance genes seems mainly to originate in the
organisms which produce antibiotics (Davies 1994). We lack considerably in the
understanding of how these genes were transferred to pathogenic bacteria, and due
to the enormous diversity of e.g. the soil flora, it is doubtful that we will
ever obtain more that a faint picture of this. In Gram negative bacteria, more
and more resistance genes are demonstrated to be located in integrons (e.g. beta
lactamase and streptomycin resistance genes in Salmonella Typhimurium DT104
(Sandvang et al. in press)). Integrons seem primarily to act as insertion sites
for resistance genes. The origin of integrons as well as the resistance gene
cassettes that are the other essential element of this system, is largely unknown
(Hall & Collis 1995). Integrons can be located in the chromosome, in transposons,
which have the ability to copy them themselves to other DNA molecules, or on
plasmids. The emergence of resistant bacteria normally happens because of
selection for a resistant clone of bacteria. Several mechanisms, however, exists
by which the resistance genes can be transferred from one bacteria to another.
Conjugation, mediated by plasmids or conjugative transposons, is currently the
most well established of these mechanisms. Still, however, the selection pressure
created by the use of antibiotics determines whether bacteria that have newly
acquired a resistance gene expand to dominate in the population or remains a
blink in history.
PMID- 10783714
TI - Current status of antibiotic resistance in animal production.
AB - It is generally accepted that the more antibiotics we use, the faster bacteria
will develop resistance. Further it has been more or less accepted that once an
antibiotic is withdrawn from the clinic, the resistance genes will eventually
disappear, [table: see text] since they will no more be of any survival value for
the bacterial cell. However, recent research has shown that after a long time
period of exposure to antibiotics, certain bacterial species may adapt to this
environment in such a way that they keep their resistance genes stably also after
the removal of antibiotics. Thus, there is reason to believe that once resistance
has developed it will not even in the long term be eradicated. What then can we
do not to increase further the already high level of antibiotic-resistant
bacteria in animals? We should of course encourage a prudent use of these
valuable drugs. In Sweden antibiotics are not used for growth promoting purposes
and are available only after veterinary prescription on strict indications.
Generally, antimicrobial treatment of animals on individual or on herd basis
should not be considered unless in connection with relevant diagnostics. The
amounts of antibiotics used and the development of resistance in important
pathogens should be closely monitored. Furthermore, resistance monitoring in
certain non-pathogenic intestinal bacteria, which may serve as a reservoir for
resistance genes is probably more important than hitherto anticipated. Once the
usage of or resistance to a certain antibiotic seems to increase in an alarming
way, steps should be taken to limit the usage of the drug in order to prevent
further spread of resistance genes in animals, humans and the environment. Better
methods for detecting and quantifying antibiotic resistance have to be developed.
Screening methods must be standardized and evaluated in order to obtain
comparable and reliable results from different countries. The genetic mechanisms
for development of resistance and spread of resistance genes should be studied in
detail. Research in these areas will lead to new ideas on how to inhibit the
resistance mechanisms. So far, it has been well established that a heavy
antimicrobial drug selective pressure in overcrowded populations of production
animals creates favourable environments both for the emergence and the spread of
antibiotic resistance genes.
PMID- 10783715
TI - Antibiotic resistance in aquaculture.
PMID- 10783716
TI - Antimicrobial resistance in bacteria from pets and horses.
PMID- 10783717
TI - Transfer of antibiotic resistant bacteria from animals to man.
AB - Antibiotic resistance develops in zoonotic bacteria in response to antibiotics
used in food animals. A close association exists between the amounts of
antibiotics used and the levels of resistance observed. The classes of
antibiotics routinely used for treatment of human infections are also used for
animals either for therapy or for growth promotion. Antibiotic resistance in
zoonotic bacteria constitute a public health hazard, primarily through the
increased risk of treatment failures. This paper describes the zoonotic bacteria,
salmonella, campylobacter, yersinia and entero-haemorrhagic E. coli (EHEC).
Infections with these agents do not generally require antibiotic therapy, but in
some cases antibiotics are essential to obtain a successful cure. The levels and
types of resistance observed in zoonotic bacteria in some countries, especially
the increasing levels of fluoroquinolone resistance in salmonella and
campylobacter, gives cause for concern. The principles of controlling resistance
development involve infection control at herd level and prudent use of
antibiotics.
PMID- 10783718
TI - Indirect transfer of antibiotic resistance genes to man.
PMID- 10783719
TI - Public health aspects of antibiotic resistance monitoring in the USA.
AB - Treatment of food-producing animals with antimicrobial agents that are important
in human therapy may present a public health risk by the transfer of resistant
zoonotic pathogens or resistant genes from animals to humans via consumption of
contaminated food. Resistant bacteria can diminish the effectiveness of
antibiotics and demand the use of more expensive or less safe alternatives. In
1996, the U. S. Food and Drug Administration (FDA), the Centers for Disease
Control and Prevention (CDC), and the Department of Agriculture (USDA)
established the National Antimicrobial Resistance Monitoring Program to
prospectively monitor changes in antimicrobial susceptibilities of zoonotic
enteric pathogens from human and animal clinical specimens, from healthy farm
animals, and from carcasses of food-producing animals at slaughter plants. Data
resulting from the monitoring program will be used to redirect antimicrobial drug
use, primarily through educational initiatives directed at health practitioners,
in order to diminish the development and spread of resistance. Veterinary testing
is conducted at USDA's Agricultural Research Service and CDC's Foodborne Disease
Laboratory is testing human isolates under contract to FDA. Both the CDC and USDA
laboratories are using a semi-automated system (Sensititre, Accumed, Westlake,
Ohio) for testing susceptibilities of the isolates to 17 antimicrobial agents on
a minimum inhibitory concentration plate. Comparable methods for isolate handling
are used in both laboratories. This paper describes the development,
implementation, and objectives of the National Antimicrobial Resistance
Monitoring Program, presents initial data generated by the program, and discusses
future plans.
PMID- 10783720
TI - Design of a system for monitoring antimicrobial resistance in pathogenic,
zoonotic and indicator bacteria from food animals.
AB - DANMAP is a Danish programme for integrated monitoring of and research on
antimicrobial resistance in bacteria from food animals, food and humans. The
paper describes how bacteria from broilers, pigs, and cattle are collected, as
well as the procedures for data handling and presentation of results. The
bacteria from animals include certain pathogens, selected so that they are
representative for submissions to Danish diagnostic laboratories, as well as
zoonotic bacteria (Campylobacter, Salmonella and Yersinia) and indicator bacteria
(E. coli, E. faecium and E. faecalis), from samples collected at abattoirs. The
latter samples are selected so that they are representative of the respective
animal populations. Therefore, the apparent prevalence of antimicrobial
resistance in the populations may be calculated. The isolates are identified to
species level and the results of susceptibility testing are stored as continuous
variables. All isolates are maintained in a strain collection so that they are
available for subsequent research projects. The data handling facilities makes it
possible to present results as percent resistant isolates or as the apparent
prevalence of resistance in the population, or alternatively as graphical
distributions of mm inhibition zones or MIC values. Computer routines have been
established that make it possible to detect specific phenotypic expressions of
resistance that may be of particular interest.
PMID- 10783721
TI - Antibiotics as growth promoters.
PMID- 10783722
TI - The animal health and animal welfare situation in the European Union.
PMID- 10783723
TI - Summary review of the chronology of the major measures in relation to bovine
spongiform encephalopathy (BSE) in the United Kingdom and the European Union.
PMID- 10783724
TI - Animal health conditions for trade within and import into the European Union of
live animals and animal products.
PMID- 10783725
TI - Role of the industry in preventing introduction of animal disease in Denmark.
PMID- 10783726
TI - The situation from Iceland's point of view.
PMID- 10783727
TI - The situation from Norway's point of view ecological and health consequences of
spreading of pathogenes and genes through an increasing trade in foods.
PMID- 10783728
TI - Veterinary service and animal health situation in Latvia (1990-1996).
PMID- 10783730
TI - Programmes to control or eradicate Salmonella in animal production in Denmark.
AB - The number of diagnosed cases of salmonella infections in humans has been
increasing during the latest 10 years, for the last 5 years mainly because of an
increase in infections with Salmonella Enteritidis. As far as Danish produced
animal products is concerned, it is assumed that the most important sources of
human salmonella infections are, in order of priority: eggs, poultry meat and
pork. In Denmark there are at the moment public and voluntary salmonella pre
harvest reduction programmes in the production of pigs, broilers and eggs. The
programme in the pig production is a control programme, that means that the aim
is to maintain a generally low level of salmonella in pig herds. At the same time
the goal of a low level of salmonella contamination of pork is also pursued
through general and specific hygiene measures in the slaughterhouses. The
programmes in the poultry production are limited to broilers and hens eggs. They
are, at least in theory, eradication programmes where the aim is total freedom
from salmonella. According to the rules of Council Directive 92/117/EEC, flocks
of hens producing eggs for hatching must be free from Salmonella Enteritidis and
Typhimurium, whereas according to the Danish national requirements (Veterinary
Service Orders to come into effect shortly), these two salmonella serotypes must
be eradicated from flocks of hens producing eggs for sale to consumers and all
salmonella serotypes must be eradicated from flocks of hens producing eggs for
hatching.
PMID- 10783729
TI - A common Salmonella control programme in Finland, Norway and Sweden.
PMID- 10783731
TI - Risk analysis, a tool for improved decision making.
PMID- 10783732
TI - [Metallothionein].
PMID- 10783733
TI - A new idea in the field of ACE inhibition: continuous drug administration
(perchronotherapy).
PMID- 10783734
TI - Expansion of haematopoietic stem cells in vitro: a challenge to stem cell
biologists.
AB - Expansion of haematopoietic stem cells from various sources has gained importance
so as to provide a clinically potential graft, which shows ideal growth kinetics,
resulting in reduction of the period of neutropenia and thrombocytopenia in any
autologous or allogenic transplant setting. Expansion also facilitates
transduction of genes for gene therapy. This review examines the various means
employed to achieve the expansion of stem cells, and the criteria used to score
the extent of expansion based on how stem cells are identified. It tries to
analyse the ideal manner in which expansion should be carried out, with emphasis
that expansion should not be at the expense of loss of stemness. It also attempts
to judge the roles played by the stromal elements and cytokines, which are both
part of the complex microenvironment, which in vivo has a strict regulation on
haematopoiesis.
PMID- 10783735
TI - Light sensitivity of the photoperiodic response system in higher vertebrates:
wavelength and intensity effects.
AB - Most species use daily light in one way or the other in regulation of their short
and/or long term activities. Light is perceived by pigment(s) present in the
retinal (RP) and/or extra-retinal photoreceptors (ERPs). ERPs may be located at
various sites in the body but in non-mammalian vertebrates they are found
predominantly in the pineal body and hypothalamic region of the brain, Light
radiations directly penetrate brain tissues to reach and stimulate the
hypothalamic (deep-brain) photoreceptors. How does light information finally
reach to the clock is not fully understood in many vertebrate groups? In mammals,
however, the light information from the retina to the clock (the hypothalamic
suprachiasmatic nuclei, SCN) is relayed through the retino-hypothalamic tract
(RHT) which originates from the retinal ganglion cells, and through the geniculo
hypothalamic tract (GHT) which originates from the photically responsive cells of
a portion of the lateral geniculate nucleus (LGN), called the intergeniculate
leaflet (IGL). A response to light (the photoperiodic response) is the result of
the interpretation of light information by the photoperiodic system. Apart from
the duration, the animals use the gradual shifts in the intensity and wavelength
of daily light to regulate their photoperiodic clock system. The wavelengths to
which photoreceptors are maximally sensitive or the wavelengths which have
greater access to the photoreceptors can induce a maximal response. There can
also be differential effects of wavelength and intensity of light on circadian
process(es) involved in the entrainment and induction of the photoperiodic clock.
This may have some adaptive implications. Entrainment to daily light-dark (LD)
cycle may be achieved at dawn or dusk, depending whether the animal is day- or
night-active, when there is relatively low intensity of light. By contrast,
photoperiodic induction in many species occurs during long days of spring and
summer when plenty of daylight at higher intensity is available later in the day.
PMID- 10783736
TI - Effect of thiocyanate induced hypothyroidism on 5'deiodinase activity and T3
receptors in developing rat brain.
AB - Experiments were performed in weaning rats to understand the influence of
thiocyanate, an hydrolytic product of glucosinolates present in foods, on the
generation of T3 in situ by type II 5'deiodinase and the binding of 125I T3 to
specific nuclear receptors in developing brain. Feeding of thiocyanate through
gestation and lactation resulted in an increase in type II 5'deiodinase activity
in cerebrum, cerebellum and brainstem of the 21 day old pups compared to
controls. Hypothyroidism induced by thiocyanate further resulted in augmentation
of the maximum binding capacity of receptors in the cerebrum of the weaning pups.
Affinity constants for binding of 125I T3 were however, unaltered. Increase in
type II 5'deiodinase activity and the number of binding sites point to an
adaptive increase in response to thiocyanate induced hypothyroidism to maintain
the cellular T3 levels within a narrow limit.
PMID- 10783737
TI - Effect of phenobarbitone administration to pregnant rats on anxiety in
offsprings.
AB - Adults Charles-Foster rats were prenatally treated to phenobarbitone (10 mg/kg,
i.p.) from day 13 to 21 of gestation, this being the critical period of neural
development. Pregnant control rats were similarly treated with equal volume of
vehicle. Adult rat offsprings at 8-9 weeks of age were subjected to open-field
exploratory behaviour, elevated plus-maze and elevated zero-maze tests. The rat
offsprings displayed significantly increased ambulation and rearings in an open
field arena when compared to control offsprings whereas self-grooming and faecal
droppings remain unchanged. On elevated plus-maze test these prenatally treated
rat offsprings spent significantly less time on open arms and more time and more
number of entries in enclosed arms as compared to controls. Prenatally exposed
rats also showed significant less time on open arms, less number of head dips and
stretched attend postures on elevated zero-maze test indicating increased
anxiogenic behavioural pattern in these animals. The results suggest that
prenatal exposure to phenobarbitone leaves a lasting effect on the anxiety state
of the offsprings.
PMID- 10783738
TI - Perturbations in phosphoinositide metabolism and protein kinase C activity in
mouse liver following whole body irradiation.
AB - The involvement of the signal transduction pathway in mouse liver following whole
body irradition was investigated. Mice were exposed to 60Co gamma rays (3 Gy) and
sacrificed after different time intervals. Various elements of phosphatidyl
inositol signal transduction pathway were investigated. Alterations could be seen
as early as 15 min of irradiation. These changes are reflected in elevation in
DAG levels and increased activation of PKC, an enzyme which is involved in
tumorigenesis. The chronological appearance of various transducers following
whole body irradiation is of significance since these early effects may set the
stage for radiation-induced tumorigenesis and hence may be used to manipulate
tumor response to radiotherapy.
PMID- 10783739
TI - Effect of aqueous extract of Ipomoea carnea leaf on isolated frog and mouse
heart.
AB - Ipomoea carnea fam. Convolvulaceae is a poisonous plant and its toxicity is
supposed to be due to the cardiac and respiratory failure. The present paper
describes the cardiac effect of aqueous extract of the fresh leaves of I. carnea
using mouse and frog heart. The aqueous extract produced an initial blockade of
isolated frog heart for 5-10 sec followed by dose dependent increase in both
amplitude and rate that lasts up to 2 min. Atropine (1 microgram/ml) blocked the
initial depressant phase and potentiated the stimulant effect of the aqueous
extract. The dose dependent increase in cardiac contractility of aqueous extract
was not altered by propranolol or calcium channel blockers like nifedipine or
diltiazem. The decrease in sodium chloride concentration or increase in potassium
chloride concentration or calcium chloride concentration in physiological salt
solution inhibited the responses to aqueous extract while an increase in sodium
chloride concentration or decrease in potassium chloride or calcium chloride
concentration in physiological salt solution potentiated the responses to the
aqueous extract of I. carnea. It may be suggested from the data that aqueous
extract of I. carnea produces positive inotropic effect on isolate frog heart
possibly by sodium extrusion or release of the intracellular calcium.
PMID- 10783740
TI - Sperm-mediated gene transfer into oocytes of the golden hamster: assessment of
sperm function.
AB - The possibility of sperm as a vehicle to deliver foreign DNA to oocytes was
tested in hamsters. Epididymal spermatozoa, incubated with linearized plasmid DNA
encoding ovine growth hormone (pCMXoGH), showed a spontaneous tendency to
interact with DNA. Kinetics of sperm uptake of DNA was determined by using [32P]
labeled DNA. Spermatozoa took up the added DNA by 15-30 min and the uptake was
inhibited by human seminal fluid in a dose dependent manner. Addition of DNA did
not affect the functional competence of spermatozoa, in terms of their ability to
undergo capacitation and acrosome reaction (34.5% +/- 2.2 vs 35% +/- 1.5). The
fertilizing ability of DNA treated-spermatozoa from hamsters and humans was
assessed by zona-free hamster egg penetration assay. Number of sperm penetrated
per oocyte were 23 +/- 4.5 and 1.4 +/- 1.3 for hamster and human spermatozoa,
respectively. Penetrated oocytes harbored sperm-treated DNA both with hamster
(30.2 cpm/oocyte) and human (19.2 cpm/oocyte) spermatozoa. These results show
that the hamster and human spermatozoa have a strong tendency to interact with
exogenous (foreign) DNA and are able to transfer DNA to oocytes. Sperm may be
used as a vector for DNA transfer and this approach has potential in the
production of transgenic animals.
PMID- 10783741
TI - Subpopulations of physiological and ovarian follicular fluid peptide induced
apoptotic cells.
AB - Ovarian follicular fluid peptide (OFFP) purified from sheep ovaries enhances
apoptotic changes in ovarian granulosa cells of mice. To get an insight into the
cell subpopulations responding to OFFP, the heterogeneity of granulosa cells was
resolved. Subpopulations of granulosa cells were obtained from ovaries of
immature mice treated with PMSG alone and autopsied 48 hr (control) and 72 hr
after injection (atretic) and from animals injected OFFP 24 hr after PMSG
injection and autopsied 24 hr later (OFFP treated) by separation on discontinuous
Percoll gradient. Four fractions were collected and studied for their relative
distributions and percent apoptotic cells measured by acridine orange staining.
FSH binding to granulosa cell (sedimenting as a major) fraction was studied by
radio receptor assay. There is a difference in densities in subpopulations of
apoptotic cells induced by OFFP and those generated during the physiological
process of atresia. This difference may be a reflection of different granulosa
cell subpopulations involved in peptide response or differences in phases as the
cells transit from normal to apoptotic phenotype. FSH binding to granulosa cells
from OFFP treated animals was significantly less than those from control and
atretic group.
PMID- 10783742
TI - Neem (Azadirachta indica) extract as an antibacterial agent against fish
pathogenic bacteria.
AB - Aquaneem, an emulsified product prepared from the neem (A. indica) kernel was
tested against four pathogenic bacteria of fish (i.e. Aeromonas hydrophila,
Pseudomonas fluorescens, Escherichia coli and Myxobacteria spp.) to test its
efficacy as an antibacterial agent. Growth inhibitory property of the product at
10, 15 and 20 ppm has been noticed and recorded. The percentage reduction of
bacterial cell population was noted to be maximum on 9th day at 20 ppm
concentration (i.e. 70.14%, 74.15% and 61.75% for A. hydrophila, P. fluorescens
and E. coli respectively) with the only exception of myxobacteria which showed
maximum reduction percentage (63.90%) on 15th day. Among all the bacteria tested
A. hydrophila, P. fluorescens and Myxobacteria spp. exhibited maximum sensitivity
to Aquaneem in terms of percentage reduction of bacterial cell population in
comparison to E. coli.
PMID- 10783743
TI - Induction of Salmonella enterotoxin (stn) gene expression by epithelial cells
(IEC-6).
AB - Prevalence of Salmonella enterotoxin (stn) gene among Salmonella enterica and S.
bongori was investigated by polymerase chain reaction (PCR) and gene probe and
its status of phenotypic expression was examined on chinese hamster ovary cells
by cultivating the strains with conventional method for enterotoxin production
and by cultivating the organisms in contact with intestinal epithelial cells of
rats (IEC-6). All the 19 strains and serovars of S. enterica such as Typhimurium,
Enteritidis, Newport, Weltevreden, Indiana, Gallinarum and Kentucky were found to
carry stn gene as examined by PCR and gene probe but only a limited number of
strains (13 out of 19) expressed phenotypically the enterotoxin when cultured by
conventional method. Cultivation of organisms in contact with epithelial cells
induced expression of stn gene phenotypically in all the 19 strains. In contrast
to S. enterica, strains of S. bongori were found neither genotypically (stn) nor
phenotypically (Stn) positive.
PMID- 10783744
TI - Assessment of protein quality of infant milk food formula supplemented with
lactulose.
AB - To examine the protein quality of infant food formula supplemented with lactulose
(bifidogenic factor), groups of 21 day male weanling rats were fed diet
containing lactulose at 0.5% for 4 weeks. The gain in body weight of rats fed
lactulose supplemented diet were similar to that of rats fed lactulose free and
skim milk powder fed diet as controls. No difference in overall acceptability
pattern was also observed in studies conducted with human subjects for
organoleptic evaluation. The results suggest that supplementation of lactulose in
infant food formula does not affect either the protein quality as indicated by
protein efficiency ratio in rats as compared to control formulae or overall
acceptability by human subjects.
PMID- 10783745
TI - Passive immunization of piglets against enterotoxigenic colibacillosis by
vaccinating dams with K88ac pili bearing bacterins.
AB - Day-old-piglets were passively immunized by vaccinating the pregnant sows with
K88ac enterotoxigenic Escherichia coli (ETEC) vaccine. High level of ETEC
specific antibodies was excreted in colostrum (3733.33 +/- 1152.13) and
maintained a detectable level (100.00 +/- 0.00) up to 21 day post partum (DPP).
The IgG was the predominant immunoglobulin followed by IgA and IgM. Piglets born
of vaccinated dam (group A) and unvaccinated dam (group B) were challenged in 7
day of age. Clinical and faecal scores were significantly (P < 0.01) low in group
A than that of group B. Piglets of group A developed mild diarrhoea (33.33%),
while all the control piglets developed profuse diarrhoea and 3 of these died
before 14 day of challenge infection.
PMID- 10783746
TI - Effect of Ocimum sanctum fixed oil on vascular permeability and leucocytes
migration.
AB - Ocimum sanctum fixed oil significantly inhibited the rise in protein
concentration and dye leakage in peritoneal fluid in experimentally induced
peritoneal inflammation in mice. In carrageenan-induced pleurisy in rats, the
fixed oil showed significant inhibition of leucocytes migration in the pleural
exudate. The results suggest that the fixed oil can inhibit enhancement of the
vascular/capillary permability and leucocyte migration following inflammatory
stimulus.
PMID- 10783747
TI - Studies on cytochrome oxidase in carbon tetrachloride treated rats.
AB - Cytochrome c oxidase was purified from control and CCl4 treated rats and its
kinetic properties were studied. The activity of the enzyme was inhibited by 51%
in CCl4 (4 g per kg body weight for 24 hr) treated rats. Studies on the kinetic
properties showed that the K(m) of the enzyme increased by 60% while Vmax
decreased by 44% in CCl4 treated rats compared to controls. The content of
cytochrome aa3 was decreased by 34% while cytochrome b and c were not affected by
CCl4 treatment. Phosphatidylcholine, phosphatidylethanolamine and cardiolipin
were decreased significantly by 40%, 49% and 60% respectively in CCl4 treated
rats. A decrease in the cytochrome aa3 content and a change in the lipid
environment of the membrane are probably responsible for a decreased rate of
electron transfer from cytochrome c to oxygen.
PMID- 10783748
TI - Estimation of different degrees of provocation by DEC (diethyl carbamazine
citrate) medication in bancroftian filariasis in Vellore, Tamilnadu.
AB - DEC in general has the power to bringout the filarial worms into the peripheral
blood when administered. The provocative effect was observed in 86.8% of the mf
positive cases. Optimum provocative effect was noticed in the age group above 12
years and there was no influence on sex. The maximum effect of provocation was
seen at 60 min after the administration 2 mg/kg body weight DEC. The mf rate was
high in the blood collected after the administration of DEC during day time, than
that during night.
PMID- 10783749
TI - Effect of entomopathogenic fungus, Beauveria bassiana on larvae of three species
of mosquitoes.
AB - Beauveria bassiana, an entomopathogenic fungus, was evaluated for its potential
against second and third instar larvae of Culex quinquefasciatus, Anopheles
stephensi and Aedes aegypti. Conidiospores of this fungus were effective in
causing infection leading to mortality of different larval instars. Larvae of Cx.
quinquefasciatus were more susceptible to infection than An. stephensi and the
second instar larvae of these two species were more susceptible than third instar
larvae. Larvae of Ae. aegypti were resistant to infection by B. bassiana.
PMID- 10783750
TI - Turritella attenuata (Kasinathan): as biological indicator of marine pollution--a
trace metal analytical study.
AB - A study to monitor marine pollution with reference to trace elements (Fe, Zn, Mn
and Cu) on T. attenuata, commonly called as screw shell over a period of one year
on the whole body and various organs, viz. digestive diverticula, foot, mantle
and ovary was conducted from the sandy beach of Porto Novo Coast (Lat 11 degrees
29' N Long: 79 degrees 46' E) of Peninsular India using Atomic Absorption
Spectrophotometer (AAS). Higher concentration of all the four trace metals
analysed were recorded in the digestive diverticula, whereas lower concentration
of zinc and manganese were recorded in the ovary during the monsoon period. The
higher level of trace metal concentration in the monsoon period may be due to the
presence of these pollutants in large amounts in water. The accumulation of
selected trace metals varies in different seasons according to the extent of
pollution load in the marine environment.
PMID- 10783751
TI - Factors influencing adherence of Candida spp. to host tissues and plastic
surfaces.
AB - Attachment of Candida spp. to host tissues and plastic surfaces is the first and
a crucial step that initiates colonization by yeast cells and subsequent
development of disseminated fungal infection. These infections are associated
with high degree of morbidity, mortality and extra cost. Modern trends have
focused not only on how best to treat but also on how to prevent Candida
infections. To achieve this goal, the factors that influence the adherence of
Candida spp. to biological and non biological surfaces have been studied. C.
albicans adheres at a degree higher than that of the other Candida spp. and C.
tropicalis adheres to a lesser extent. This may reflect the higher pathogenicity
of C. albicans compared to the other Candida spp. Germinated C. albicans cells
adhere to host tissue more readily than do yeast-phase. Sugars play an important
role in the adherence of Candida spp. Overall, galactose was found to promote the
adherence of Candida spp. to host tissues and plastic surfaces more than any
other mono or disaccharide. Amino sugars on the other hand inhibit the adherence
of the yeast cells. Divalent ions such as Ca2+ and Mg2+ promote the adherence of
Candida spp. more than monovalent ions. Candida spp. express on their surface
receptors, which interact with a wide variety of host proteins including
fibrinogen, fibronectin, lamanin, and type I and IV collagen thus binding Candida
spp. To glycoproteinaceous conditioning film at the blood-polymer interface.
Coaggregation of Candida spp. with other bacteria promotes colonization of yeast
cells to oral biofilm, host tissues, and to surfaces of the indwelling vascular
catheters. These factors form the basis for the interference with the adherence
of Candida spp.
PMID- 10783752
TI - Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in
shock-induced depression.
AB - In the past few years, literature has accumulated describing manifestation of
seizures following administration of certain antidepressants. Such reports are of
particular importance because depression is a frequent psychiatric problem
associated with epilepsy. Therefore, in the view of the fact that NMDA receptor
antagonists have been reported to reduce behavioural deficits and have been shown
to be anticonvulsant, it was considered imperative to study their antidepressant
effect using shock-induced depression model in mice. Presentation of inescapable
foot shock significantly reduced ambulation and rearing in the open field arena
and increased immobility duration in the FST. Pretreatment with imipramine, MK
801 and ketamine significantly prevented the effect of shock. Also, the
combination of imipramine with either of the NMDA antagonists antagonised the
effect of shock. Haloperidol, prazosin and ketanserin pretreatment modified the
effect of these agents. These findings suggest an antidepressant effect of the
NMDA receptor antagonists, and a complexity of neurotransmitter mechanisms, which
are responsible for the occurrence of behavioural effects in shock-induced
depression model.
PMID- 10783753
TI - Immunosuppressive activity in buffalo placenta.
AB - Immunosuppressive activity in buffalo placenta was evaluated by measuring
proliferation of lymphocytes in presence of phytohaemagglutinin (PHA) alone or
PHA plus placental proteins. The immunosuppressive activity was dose-dependent
over the protein concentration range of 10-50 micrograms/ml. Proteins from both
cotyledon and non-cotyledon portions of placenta exhibited immunosuppressive
activity. Fractions obtained with 0-40, 40-60 and 60-80% saturated ammonium
sulphate exhibited 70, 73 and 75% suppression, respectively. PBS-soluble
placental proteins were resolved on G-100 column into three peaks that exhibited
69 (peak 1), 55 (peak 2) and 73% (peak 3) suppression. Exogenously added
interleukin-1 (IL-1) failed to reverse the suppression caused by buffalo
placental proteins.
PMID- 10783754
TI - Effect of flavone in a canine model of myocardial stunning.
AB - Putative cardioprotective action of flavone (10, 20 and 30 mg/kg) was
investigated in a canine model of regional ischemia (20 min) followed by 60 min
of reperfusion. In animals pretreated with vehicle, myocardial stunning was
evidenced by significant changes in hemodynamic parameters (depressed mean
arterial pressure, LV peak (+) dP/dt, LV peak (-) dP/dt and elevated LV end
diastolic pressure) and biochemical parameters (decreased myocardial ATP and rise
in plasma malondialdehyde or MDA; a marker of free radical-induced injury). A
reduction in plasma MDA was noted with 20 and 30 mg/kg flavone, although
attenuation of myocardial dysfunction was evident with all the three doses. The
results suggest that besides a significant dose-dependent antioxidant effect,
flavone may also have some cardioprotective actions per se, which needs to be
further investigated.
PMID- 10783755
TI - Effects of intranasal challenge with group A beta haemolytic streptococcus M type
49 in Swiss albino mice.
AB - Mice are susceptible to natural infections with streptococci and therefore can
serve as suitable animal models to study experimental streptococcal infections.
In an earlier study, we had shown the development of pharyngeal colonization,
antibody response and histopathological changes in the heart following intranasal
(IN) challenge with a rheumatogenic serotype of group A beta haemolytic
streptococcus, the M type 18. To determine if nonpharyngitis associated serotypes
can also elicit similar responses, 30 Swiss albino mice were challenged
intranasally with 2 x 10(7) colony forming units of a skin associated serotype of
group A beta haemolytic streptococcus, the M type 49. Pharyngeal colonization
varied from 64% (n = 30) in the first week to 69% (n = 16) during the fourth week
after IN challenge. Eleven (36.7%) of the 30 animals studied showed antibody
response to DNase B (ADNB) with peak titers varying from 150 to 1200 units. Wide
variations were seen in ADNB titers in individual mice. Histopathological
evidence for cardiac lesions were seen in three animals. The changes were mild
and varied from mild to chronic endocardial inflammation to calcification. The
study shows that Swiss albino mice are also susceptible to IN challenge with skin
associated strains of GABHS and therefore can serve as useful models to study the
effects of experimental infection with diverse serotypes of GABHS.
PMID- 10783756
TI - Apoptosis in bovine herpesvirus-1 infected bovine peripheral blood mononuclear
cells.
AB - Apoptosis is a process whereby cells die in a controlled manner in response to
various stimuli like cytotoxins, viral antigens and normal physiological signals
during differentiation and development. Virus induced immunosuppression has been
reported for various viral diseases including Bovine Herpesvirus-1 (BHV-1). In
the present study, BHV-1 was found to cause apoptosis in ConA stimulated bovine
peripheral blood mononuclear cells (PBMCs). Apoptotic index quantified by
fluorescent dyes revealed a significant (P < 0.001) increase in percent apoptotic
cells at 2, 24 and 48 hr post infection as compared to their respective non
infected controls. Apoptosis specific internucleosomal laddering in DNA from BHV
1 infected PBMCs was seen in agarose gel electrophoresis. No DNA fragmentation
was observed in control non-infected PBMCs.
PMID- 10783757
TI - Effect of bracken (Pteridium a quilinum) and dryopteris (Dryopteris juxtaposita)
fern toxicity in laboratory rabbits.
AB - Experimental studies with Bracken and Dryopteris ferns @ 25% concentrate ration
mixture were conducted in rabbits. Fern fed rabbits showed progressive anaemia,
leukopaenia, lymphopaenia and relative heterophilia. Significant elevations in
serum enzymes like serum glutamate oxaloactate transminase (SGOT), serum
glutamate pyruvate transminase (SGPT), alkaline phosphatase (ALP), urea and
creatinine levels were seen. Histopathologically, rabbits showed mild to moderate
vascular changes in most of visceral organs, vacuolar degenerative changes in
hepatocytes, hypersecretory activity in intestine, presence of casts in renal
tubules and degenerative changes in renal tubular lining epithelial cells.
Dryopteris fed rabbits showed somewhat more severe degenerative and vascular
changes in different intervals. A low level of toxic principle ptaquiloside was
detected in Bracken and Dryopteris ferns by thin layer chromatography (TLC) and
high-pressure liquid chromatography (HPLC) methods.
PMID- 10783758
TI - Growth response of African catfish, Clarias gariepinus (Burchell) to varied
protein and lipid levels.
AB - To study the growth response of African catfish (Clarias gariepinus) to the diets
containing two protein (30 and 35%) and two lipid levels (12 and 18%) in a closed
recirculatory system for 60 days, fish were fed to satiation twice daily. The
experiment was carried out in triplicate groups. Fortnightly sampling of fish and
water samples was carried out. The best result in terms of growth was obtained
with the diet containing 34.62% protein and 12.12% lipid. The protein to lipid
ratio was 18.57 in the diet that gave best percentage weight gain. However best
survival, food conversion ratio and protein efficiency ratio were recorded in the
diet containing 29.86% protein and 18.08% lipid.
PMID- 10783759
TI - Evidence for integration of IS1 and IS10 in recombinant plasmid containing
rearrangement hot-spot(rhs) common-shared block(CSB) in Escherichia coli K-12.
AB - The integration of IS1 and IS10 was reported in the recombinant plasmid
containing the 3070 bp rearrangement hotspot(rhs) common-shared block(CSB) in
Escherichia coli K-12. The integration of IS1 was found to be in rhs(CSB)
portion, whereas the integration of IS10 was found to be in both rhs(CSB) and
vector portions. The bacterial cells containing the recombinant plasmid grew very
slowly. But the integration of IS1 or IS10 in rhs(CSB) portion made the host grow
rapidly and overgrew the slow-growing population inheriting the recombinant
plasmids without IS-sequences. The sites of integration of IS1 and IS10 were
different as was judged from restriction endonuclease mapping. These are rare
examples of interchromosomal mobilisation of IS1 and IS10 from host chromosome
into plasmid.
PMID- 10783760
TI - Hepatoprotective activity of ellagic acid against carbon tetrachloride induced
hepatotoxicity in rats.
AB - Administration of CCl4 to normal rats and consequent oral feeding with ellagic
acid (50 mg/kg) provided a significant protection against the biochemical
alterations in serum and liver produced by CCl4. In vitro experiments showed that
liver microsomes from animals treated with ellagic acid and CCl4, decreased lipid
peroxidation compared to microsome prepared from rats exposed to CCl4 alone.
PMID- 10783761
TI - Coordinate production of cephamycin c and clavulanic acid by Streptomyces
clavuligerus.
AB - Production of cephamycin c and clavulanic acid by Streptomyces clavuligerus was
investigated using different media in shake flask condition. Highest cell growth
(3.8 g/L) was observed in glycerol, sucrose, proline and glutamic acid (GSPG)
medium. Although, GSPG medium supported maximum growth, it was least effective
for the synthesis of both cephamycin and clavulanic acid. Yield of cephamycin and
clavulanic acid was maximum in dextrin and K medium, respectively. High and low
level of constituents of dextrin medium, affected production of both cephamycin
and clavulanic acid. Biosynthesis of clavulanic acid was associated with
production of cephamycin c.
PMID- 10783762
TI - Monoclonal antibody based dot-enzyme linked immunosorbent assay (Dot-ELISA) and
agar gel precipitation test (AGPT) for identification of Newcastle disease virus
(NDV).
AB - Two mouse monoclonal antibodies (MAbs), viz. 2B7 and 2 D10 raised against
haemagglutinin-neuraminidase glycoprotein of Newcastle disease virus (NDV) were
used to identify several other field isolates and vaccine strains of NDV. These
MAbs reacted specifically with all the NDV strains/isolates in Dot-ELISA whereas,
only MAb 2D10 reacted with all the NDV strains/isolates in agar gel precipitation
test. These two tests employing the MAbs were standardised for rapid diagnosis
and identification of NDV.
PMID- 10783763
TI - Gamma-interferon bioassay for detection of bovine tuberculosis in cattle:
kinetics of production and dose response in whole blood culture.
AB - Stimulation with Mycobacterium bovis PPD sensitised lymphocytes (whole blood or
peripheral blood lymphocytes) results in release of gamma-interferon that can be
detected by simple bioassay. The optimum concentration of bovine PPD was 20
micrograms ml and the optimum incubation period was 24 hr for maximum production
of gamma-interferon in whole blood culture (128 units/ml) and peripheral blood
culture (64 units/ml).
PMID- 10783764
TI - Long-term feeding effect of thermally oxidised oils on antioxidant enzymes in
rats.
AB - Long term feeding effect of thermally oxidised oils on activities of hepatic
antioxidant enzymes viz. catalase, glutathione peroxidase (GPX), glutathione-S
transferase (GST) and superoxide dismutase (SOD) at 5 and 20% level for 20 weeks
was studied in laboratory rats. Activity of catalase increased in heated and
fried oil fed group of rats, whereas activities of GPX, GST and SOD decreased in
both heated and fried oil groups. Increase or decrease in activities of these
enzymes may be related to several factors like heating and frying conditions,
nature of fat, extent of peroxidation, presence of antioxidants, duration of
feeding, beside other factors.
PMID- 10783765
TI - A non-radioactive method for mapping restriction fragment length polymorphic
genetic markers in Anopheles gambiae.
AB - A non-radioactive method for in situ hybridisation of Restriction Fragment Length
Polymorphic (RFLP) markers to the polytene chromosome of Anopheles gambiae, the
important malaria vector, which yielded good readable quality of chromosomal
bands is reported. The methodology adopted was a Biotin-Streptavidin-Alkaline
Phosphatase system which yielded fluorescent signals when stained with dyes such
as Nitro Blue Tetrazolium and Bromo Chloro Indolyl Phosphate.
PMID- 10783766
TI - Twin reversed arterial perfusion syndrome.
AB - Twin reversed arterial perfusion (TRAP) syndrome is a rare but severe
complication of monozygotic monochorionic twin pregnancies. The outcome is
invariably fatal for the abnormal twins and for 50-75% of the normal co-twins.
The prenatal diagnosis of the TRAP always has to be presumed in a multiple
pregnancy within which a twin pair grows whenever cardiac activity can not be
proved echographically. We present discuss--based upon literature research-
pathogenic mechanisms, pathologic-anatomic, echographic diagnosis and management
of these high-risk pregnancies.
PMID- 10783767
TI - Magnetic resonance imaging of cerebral central sulci: a study of monozygotic
twins.
AB - The cerebral central sulci, seat of the sensorimotor cortex, vary anatomically in
form, length and depth among individuals and present a left/right asymmetry. The
purpose of this work was to measure central sulcus's lengths, at the surface and
in-depth, in each hemisphere of monozygotic twins in order to evaluate the
influence of environmental factors on the morphometry and asymmetry of this
structure. A measurement technique on MR images of the brains using 3 D software
was developed. Two operators applied this technique to measure central sulcus
lengths at the surface of the brain and in-depth in each hemisphere. Besides the
fact that the technique developed gave high Intraclass Correlation Coefficients
(ICC) for the surface lengths (mean value 0.94), and slightly less high for the
in-depth length (mean value 0.87), we found a weak (from 0.57 to 0.73 for raw
data) but significant ICC between homologous sulci in pairs of twins. In
addition, the ICC for asymmetry indices were not significant. Hence, if central
sulcus morphometry is in part genetically influenced, these results show that
nongenetic factors are nonetheless important in their development.
PMID- 10783768
TI - A comparative study of twinning and triplet rates in 17 countries, 1972-1996.
AB - Secular changes in twinning and triplet rates were analyzed using vital
statistics in Austria, the Czech Republic, the Slovak Republic, England and
Wales, Germany, the Netherlands, Switzerland, Denmark, Finland, Norway, Sweden,
Canada, Australia, Hong Kong, Israel, Japan, and Singapore during the period from
1972 to 1996. Among those 17 countries, the twinning and triplet rates in the
Czech Republic and in the Slovak Republic remained constant from 1972 to 1994,
whereas these rates increased significantly year by year in the other 15
countries during the examined period in each country. Twinning rates increased
from 1.2-fold in Austria to 2-fold in Denmark from 1972 to 1996. As for triplets,
the rate increased from 3-fold in Denmark to 9-fold in Norway during that period.
With one exception, that being the Slovak Republic, the triplet rate was highest
in the Scandinavian countries, followed by the other European and Asian
countries. The rising twinning and triplet rates have been attributed to the
higher proportion of mothers treated with ovulation-inducing hormones and
partially attributed to IVF.
PMID- 10783769
TI - Quantitative estimates of ABH secretion in saliva of human twins.
AB - Blood and saliva samples of 122 like-sexed twin pairs (65 MZ and 57 DZ) living in
Chandigarh (India) were analyzed for ABH polymorphism. The results indicated that
ABH secretions were independent of ABO blood groups though there was an
indication of higher incidence of non-secretors among 'O' blood group twin
individuals. No significant differences were observed between twins and
singletons in secretor gene frequency estimates. The quantitative data revealed
that mean titre scores for H substances were lower than that for A and B
substances. F test contrasting intra-pair variance between zygosities for ABH
quantitative secretions was highly significant indicating stronger genetic
component of variation. The results suggested that quantitative assay of ABH
secretions would be a better indicator for zygosity determination than mere
qualitative differentiation.
PMID- 10783770
TI - Mosaic partial trisomy of chromosome 5 (q33-q ter) associated with fetal
polycystic kidneys.
AB - A case of de novo mosaic partial trisomy of chromosome 5 (q33-q ter) in a
stillborn male fetus with bilateral polycystic kidneys, and atrial septal defect,
is reported. Fetal cord blood sampling was carried out at 25 weeks of gestation
because of bilateral polycystic kidneys with severe oligohydramnios observed on
ultrasound examination of the fetus. The family history was notable for the
presence of similar phenotypic abnormality in the mother and sibling. However, no
chromosomal abnormality was detected in other family members. Significance of
this rare chromosomal abnormality and its association with congenital
malformations in the fetus and in the family is being discussed.
PMID- 10783771
TI - Wildlife population assessment: past developments and future directions.
AB - We review the major developments in wildlife population assessment in the past
century. Three major areas are considered: mark-recapture, distance sampling, and
harvest models. We speculate on how these fields will develop in the next
century. Topics for which we expect to see methodological advances include
integration of modeling with Geographic Information Systems, automated survey
design algorithms, advances in model-based inference from sample survey data, a
common inferential framework for wildlife population assessment methods, improved
methods for estimating population trends, the embedding of biological process
models into inference, substantially improved models for conservation management,
advanced spatiotemporal models of ecosystems, and greater emphasis on
incorporating model selection uncertainty into inference. We discuss the kind of
developments that might be anticipated in these topics.
PMID- 10783772
TI - Bayesian detection of clusters and discontinuities in disease maps.
AB - An interesting epidemiological problem is the analysis of geographical variation
in rates of disease incidence or mortality. One goal of such an analysis is to
detect clusters of elevated (or lowered) risk in order to identify unknown risk
factors regarding the disease. We propose a nonparametric Bayesian approach for
the detection of such clusters based on Green's (1995, Biometrika 82, 711-732)
reversible jump MCMC methodology. The prior model assumes that geographical
regions can be combined in clusters with constant relative risk within a cluster.
The number of clusters, the location of the clusters, and the risk within each
cluster is unknown. This specification can be seen as a change-point problem of
variable dimension in irregular, discrete space. We illustrate our method through
an analysis of oral cavity cancer mortality rates in Germany and compare the
results with those obtained by the commonly used Bayesian disease mapping method
of Besag, York, and Mollie (1991, Annals of the Institute of Statistical
Mathematics, 43, 1-59).
PMID- 10783773
TI - Methodology for estimating the abundance of rare animals: seabird nesting on
north east Herald Cay.
AB - We discuss the problem of estimating the number of nests of different species of
seabirds on North East Herald Cay based on the data from a 1996 survey of
quadrats along transects and data from similar past surveys. We consider three
approaches based on different plausible models, namely a conditional negative
binomial model that allows for additional zeroes in the data, a weighting
approach (based on a heteroscedastic regression model), and a transform-both
sides regression approach. We find that the conditional negative binomial
approach and a linear regression approach work well but that the transform-both
sides approach should not be used. We apply the conditional negative binomial and
linear regression approaches with poststratification based on data quality and
availability to estimate the number of frigatebird nests on North East Herald
Cay.
PMID- 10783774
TI - Semiparametric regression for periodic longitudinal hormone data from multiple
menstrual cycles.
AB - We consider semiparametric regression for periodic longitudinal data. Parametric
fixed effects are used to model the covariate effects and a periodic
nonparametric smooth function is used to model the time effect. The within
subject correlation is modeled using subject-specific random effects and a random
stochastic process with a periodic variance function. We use maximum penalized
likelihood to estimate the regression coefficients and the periodic nonparametric
time function, whose estimator is shown to be a periodic cubic smoothing spline.
We use restricted maximum likelihood to simultaneously estimate the smoothing
parameter and the variance components. We show that all model parameters can be
easily obtained by fitting a linear mixed model. A common problem in the analysis
of longitudinal data is to compare the time profiles of two groups, e.g., between
treatment and placebo. We develop a scaled chi-squared test for the equality of
two nonparametric time functions. The proposed model and the test are illustrated
by analyzing hormone data collected during two consecutive menstrual cycles and
their performance is evaluated through simulations.
PMID- 10783775
TI - Localization of a quantitative trait locus via a Bayesian approach.
AB - A Bayesian approach to the direct mapping of a quantitative trait locus (QTL),
fully utilizing information from multiple linked gene markers, is presented in
this paper. The joint posterior distribution (a mixture distribution modeling the
linkage between a biallelic QTL and N gene markers) is computationally
challenging and invites exploration via Markov chain Monte Carlo methods. The
parameter's complete marginal posterior densities are obtained, allowing a
diverse range of inferences. Parameters estimated include the QTL genotype
probabilities for the sires and the offspring, the allele frequencies for the
QTL, and the position and additive and dominance effects of the QTL. The
methodology is applied through simulation to a half-sib design to form an outbred
pedigree structure where there is an entire class of missing information. The
capacity of the technique to accurately estimate parameters is examined for a
range of scenarios.
PMID- 10783776
TI - Accounting for variability in the use of permutation testing to detect
quantitative trait loci.
AB - Locating quantitative trait loci (QTL), or genomic regions associated with known
molecular markers, is of increasing interest in a wide variety of applications
ranging from human genetics to agricultural genetics. The hope of locating QTL
(or genes) affecting a quantitative trait is that it will lead to
characterization and possible manipulations of these genes. However, the
complexity of both statistical and genetic issues surrounding the location of
these regions calls into question the asymptotic statistical results supplying
the distribution of the test statistics employed. Coupled with the power of
current-day computing, permutation theory was reintroduced for the purpose of
estimating the distribution of any test statistic used to test for the location
of QTL. Permutation techniques have offered an attractive alternative to
significance measures based on asymptotic theory. The ideas of permutation
testing are extended in this application to include confidence intervals for the
thresholds and p-values estimated in permutation testing procedures. The
confidence intervals developed account for the Monte Carlo error associated with
practical applications of permutation testing and lead to an effective method of
determining an efficient permutation sample size.
PMID- 10783777
TI - Estimation of age-specific breeding probabilities from capture-recapture data.
AB - We provide a new method for estimating the age-specific breeding probabilities
from recaptures or resightings of animals marked as young. Our method is more
direct than previous methods and allows the modeler to fit and compare models
where the age-specific breeding proportions are equal over different cohorts or
are a function of external covariates.
PMID- 10783778
TI - Estimating data transformations in nonlinear mixed effects models.
AB - A routine practice in the analysis of repeated measurement data is to represent
individual responses by a mixed effects model on some transformed scale. For
example, for pharmacokinetic, growth, and other data, both the response and the
regression model are typically transformed to achieve approximate within
individual normality and constant variance on the new scale; however, the choice
of transformation is often made subjectively or by default, with adoption of a
standard choice such as the log. We propose a mixed effects framework based on
the transform-both-sides model, where the transformation is represented by a
monotone parametric function and is estimated from the data. For this model, we
describe a practical fitting strategy based on approximation of the marginal
likelihood. Inference is complicated by the fact that estimation of the
transformation requires modification of the usual standard errors for estimators
of fixed effects; however, we show that, under conditions relevant to common
applications, this complication is asymptotically negligible, allowing
straightforward implementation via standard software.
PMID- 10783779
TI - Random effects modeling of multiple binomial responses using the multivariate
binomial logit-normal distribution.
AB - The multivariate binomial logit-normal distribution is a mixture distribution for
which, (i) conditional on a set of success probabilities and sample size indices,
a vector of counts is independent binomial variates, and (ii) the vector of
logits of the parameters has a multivariate normal distribution. We use this
distribution to model multivariate binomial-type responses using a vector of
random effects. The vector of logits of parameters has a mean that is a linear
function of explanatory variables and has an unspecified or partly specified
covariance matrix. The model generalizes and provides greater flexibility than
the univariate model that uses a normal random effect to account for positive
correlations in clustered data. The multivariate model is useful when different
elements of the response vector refer to different characteristics, each of which
may naturally have its own random effect. It is also useful for repeated binary
measurement of a single response when there is a nonexchangeable association
structure, such as one often expects with longitudinal data or when negative
association exists for at least one pair of responses. We apply the model to an
influenza study with repeated responses in which some pairs are negatively
associated and to a developmental toxicity study with continuation-ratio logits
applied to an ordinal response with clustered observations.
PMID- 10783780
TI - Generalized nonlinear models for pharmacokinetic data.
AB - Phase I trials to study the pharmacokinetic properties of a new drug generally
involve a restricted number of healthy volunteers. Because of the nature of the
group involved in such studies, the appropriate distributional assumptions are
not always obvious. These model assumptions include the actual distribution but
also the ways in which the dispersion of responses is allowed to vary over time
and the fact that small concentrations of a substance are not easily detectable
and hence are left censored. We propose that a reasonably wide class of
generalized nonlinear models allowing for left censoring be considered now that
this is feasible with current computer power and sophisticated statistical
packages. These modelling strategies are applied to a Phase I study of the drug
flosequinan and its metabolite. This drug was developed for the treatment of
heart failure. Because the metabolite also exhibits an active pharmacologic
effect, study of both the parent drug and the metabolite is of interest.
PMID- 10783781
TI - Self-modeling for two-dimensional response curves.
AB - Two-dimensional response curves are an important experimental outcome in speech
kinematics and other areas of research. These parameterized curves are usually
obtained by recording the two-dimensional location of an object over time. In
this setting, time is the independent variable and the x and y locations on
specified coordinate axes define the multivariate response. Collections of such
parameterized curves can be obtained either from one subject or from a number of
different subjects, each producing one or several realizations of the response
curve. When only one dependent variable is observed over time and no parametric
model is specified, self-modeling regression (SEMOR) is an attractive modeling
approach. SEMOR assumes that each of a collection of curves differs from a
smooth, average shape function by some simple parametric transformation of the
coordinate axes (usually linear). We will describe the extension of SEMOR to two
dimensional parameterized curves using affine transformations of a two
dimensional, time-parameterized shape function.
PMID- 10783782
TI - Conditional-cumulant-of-exposure method in logistic missing covariate regression.
AB - We consider estimation in logistic regression where some covariate variables may
be missing at random. Satten and Kupper (1993, Journal of the American
Statistical Association 88, 200-208) proposed estimating odds ratio parameters
using methods based on the probability of exposure. By approximating a partial
likelihood, we extend their idea and propose a method that estimates the cumulant
generating function of the missing covariate given observed covariates and
surrogates in the controls. Our proposed method first estimates some lower order
cumulants of the conditional distribution of the unobserved data and then solves
a resulting estimating equation for the logistic regression parameter. A simple
version of the proposed method is to replace a missing covariate by the summation
of its conditional mean and conditional variance given observed data in the
controls. We note that one important property of the proposed method is that,
when the validation is only on controls, a class of inverse selection probability
weighted semiparametric estimators cannot be applied because selection
probabilities on cases are zeroes. The proposed estimator performs well unless
the relative risk parameters are large, even though it is technically
inconsistent. Small-sample simulations are conducted. We illustrate the method by
an example of real data analysis.
PMID- 10783783
TI - Weighted normality-based estimator in correcting correlation coefficient
estimation between incomplete nutrient measurements.
AB - Consider the problem of estimating the correlation between two nutrient
measurements, such as the percent energy from fat obtained from a food frequency
questionnaire (FFQ) and that from repeated food records or 24-hour recalls. Under
a classical additive model for repeated food records, it is known that there is
an attenuation effect on the correlation estimation if the sample average of
repeated food records for each subject is used to estimate the underlying long
term average. This paper considers the case in which the selection probability of
a subject for participation in the calibration study, in which repeated food
records are measured, depends on the corresponding FFQ value, and the repeated
longitudinal measurement errors have an autoregressive structure. This paper
investigates a normality-based estimator and compares it with a simple method of
moments. Both methods are consistent if the first two moments of nutrient
measurements exist. Furthermore, joint estimating equations are applied to
estimate the correlation coefficient and related nuisance parameters
simultaneously. This approach provides a simple sandwich formula for the
covariance estimation of the estimator. Finite sample performance is examined via
a simulation study, and the proposed weighted normality-based estimator performs
well under various distributional assumptions. The methods are applied to real
data from a dietary assessment study.
PMID- 10783784
TI - A graphical method for finding maximin efficiency designs.
AB - We consider the problem of designing an experiment when there are two competing
optimality criteria. Designs that maximize the minimum efficiencies under the two
criteria are proposed along with a graphical method for finding these maximin
designs.
PMID- 10783785
TI - Substantial gains in bias reduction from matching with a variable number of
controls.
AB - In observational studies that match several controls to each treated subject,
substantially greater bias reduction is possible if the number of controls is not
fixed but rather is allowed to vary from one matched set to another. In certain
cases, matching with a fixed number of controls may remove only 50% of the bias
in a covariate, whereas matching with a variable number of controls may remove
90% of the bias, even though both control groups have the same number of controls
in total. An example of matching in a study of surgical mortality is discussed in
detail.
PMID- 10783786
TI - Estimation and testing with overdispersed proportions using the beta-logistic
regression model of Heckman and Willis.
AB - Methods are presented for modeling dose-related effects in proportion data when
extra-binomial variability is a concern. Motivation is taken from experiments in
developmental toxicology, where similarity among conceptuses within a litter
leads to intralitter correlations and to overdispersion in the observed
proportions. Appeal is made to the well-known beta-binomial distribution to
represent the overdispersion. From this, an exponential function of the linear
predictor is used to model the dose-response relationship. The specification was
introduced previously for econometric applications by Heckman and Willis; it
induces a form of logistic regression for the mean response, together with a
reciprocal biexponential model for the intralitter correlation. Large-sample,
likelihood-based methods for estimating and testing the joint proportion
correlation response are studied. A developmental toxicity data set illustrates
the methods.
PMID- 10783787
TI - A homogeneity test in overviews with group sequentially monitored clinical
trials.
AB - It is known that using statistical stopping rules in clinical trials can create
an artificial heterogeneity of treatment effects in overviews of related trials
(Hughes, Freedman, and Pocock, 1992, Biometrics 48, 41-53). If the true treatment
effect being tested is small, as is often the case, the homogeneity test by
DerSimonian and Laird (1986, Controlled Clinical Trials 7, 177-188) violates the
size of the test very severely. This paper provides a new homogeneity test, which
preserves the size of the test more accurately. The operating characteristics of
the new test are examined through simulations.
PMID- 10783788
TI - Negative binomial additive models.
AB - The generalized additive model is extended to handle negative binomial responses.
The extension is complicated by the fact that the negative binomial distribution
has two parameters and is not in the exponential family. The methodology is
applied to data involving DNA adduct counts and smoking variables among ex
smokers with lung cancer. A more detailed investigation is made of the parametric
relationship between the number of adducts and years since quitting while
retaining a smooth relationship between adducts and the other covariates.
PMID- 10783789
TI - Testing for differences in survival with delayed ascertainment.
AB - During the interim stages of most large-scale clinical trials, knowledge that a
patient is alive or dead is usually not up-to-date. This is due to the pattern of
patient visits to hospitals as well as the administrative set-up used by the
study to obtain information on vital status. On a two-armed study, if the process
of ascertaining vital status is not the same in both treatment groups, then the
standard method of testing based on the logrank statistic may not be applicable.
Instead, an ad hoc modification to the logrank test, which artificially truncates
follow-up prior to the time of analysis, is often used. These approaches have not
been formally addressed in the literature. In the early stages of a clinical
trial, severe bias or loss of power may result. For this situation, we propose a
class of test statistics that extends the usual class of U statistics. Asymptotic
normality is derived by reformulating the statistics in terms of counting
processes and employing the theory of U statistics along with martingale
techniques. For early interim analyses, a numerical study indicates that the new
tests can be more powerful than the current practice when differential
ascertainment is present. To illustrate the potential loss of information when
lagging follow-up to control for ascertainment delays, we reanalyze an AIDS
clinical trial with the truncated logrank and the new statistics.
PMID- 10783790
TI - Testing equality of survival functions based on both paired and unpaired censored
data.
AB - We introduce two test procedures for comparing two survival distributions on the
basis of randomly right-censored data consisting of both paired and unpaired
observations. Our procedures are based on generalizations of a pooled rank test
statistic previously proposed for uncensored data. One generalization adapts the
Prentice-Wilcoxon score, while the other adapts the Akritas score. The use of
these particular scoring systems in pooled rank tests with randomly right
censored paired data has been advocated by several researchers. Our test
procedures utilize the permutation distributions of the test statistics based on
a novel manner of permuting the scores. Permutation versions of tests for right
censored paired data and for two independent right-censored samples that use the
proposed scoring systems are obtained as special cases of our test procedures.
Simulation results show that our test procedures have high power for detecting
scale and location shifts in exponential and log-logistic distributions for the
survival times. We also demonstrate the advantages of our test procedures in
terms of utilizing randomly occurring unpaired observations that are discarded in
test procedures for paired data. The tests are applied to skin graft data
previously reported elsewhere.
PMID- 10783791
TI - A linear mixed-effects model for multivariate censored data.
AB - We apply a linear mixed-effects model to multivariate failure time data.
Computation of the regression parameters involves the Buckley-James method in an
iterated Monte Carlo expectation-maximization algorithm, wherein the Monte Carlo
E-step is implemented using the Metropolis-Hastings algorithm. From simulation
studies, this approach compares favorably with the marginal independence
approach, especially when there is a strong within-cluster correlation.
PMID- 10783792
TI - Estimation of sojourn time in chronic disease screening without data on interval
cases.
AB - Estimation of the sojourn time on the preclinical detectable period in disease
screening or transition rates for the natural history of chronic disease usually
rely on interval cases (diagnosed between screens). However, to ascertain such
cases might be difficult in developing countries due to incomplete registration
systems and difficulties in follow-up. To overcome this problem, we propose three
Markov models to estimate parameters without using interval cases. A three-state
Markov model, a five-state Markov model related to regional lymph node spread,
and a five-state Markov model pertaining to tumor size are applied to data on
breast cancer screening in female relatives of breast cancer cases in Taiwan.
Results based on a three-state Markov model give mean sojourn time (MST) 1.90
(95% CI: 1.18-4.86) years for this high-risk group. Validation of these models on
the basis of data on breast cancer screening in the age groups 50-59 and 60-69
years from the Swedish Two-County Trial shows the estimates from a three-state
Markov model that does not use interval cases are very close to those from
previous Markov models taking interval cancers into account. For the five-state
Markov model, a reparameterized procedure using auxiliary information on
clinically detected cancers is performed to estimate relevant parameters. A good
fit of internal and external validation demonstrates the feasibility of using
these models to estimate parameters that have previously required interval
cancers. This method can be applied to other screening data in which there are no
data on interval cases.
PMID- 10783793
TI - Variance and sample size calculations in quality-of-life--adjusted survival
analysis (Q-TWiST).
AB - The Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) statistic
previously introduced by Glasziou, Simes and Gelber (1990, Statistics in Medicine
9, 1259-1276) combines toxicity, disease-free survival, and overall survival
information in assessing the impact of treatments on the lives of patients. This
methodology has received positive reviews from clinicians as intuitive and
useful, but to date, the variance of this statistic has remained unspecified. We
review aspects of the Q-TWiST method for analyzing clinical trial data, extend
the method to accommodate multiple treatment arms, and provide closed-form
asymptotic variance formulas. We also provide a framework for designing Q-TWiST
clinical trials with sample sizes determined using the derived asymptotic
variance formulas. Trials currently collecting quality of life data did not have
the benefit of these sample size calculation techniques in designing their
studies.
PMID- 10783794
TI - A two-sample comparison for multiple ordered event data.
AB - A longitudinal study is conducted to compare the process of particular disease
between two groups. The process of the disease is monitored according to which of
several ordered events occur. In the paper, the sojourn time between two
successive events is considered as the outcome of interest. The group effects on
the sojourn times of the multiple events are parameterized by scale changes in a
semiparametric accelerated failure time model where the dependence structure
among the multivariate sojourn times is unspecified. Suppose that the sojourn
times are subject to dependent censoring and the censoring times are observed for
all subjects. A log-rank-type estimating approach by rescaling the sojourn times
and the dependent censoring times into the same distribution is constructed to
estimate the group effects and the corresponding estimators are consistent and
asymptotically normal. Without the dependent censoring, the independent censoring
times in general are not available for the uncensored data. In order to complete
the censoring information, pseudo-censoring times are generated from the
corresponding nonparametrically estimated survival function in each group, and we
can still obtained unbiased estimating functions for the group effects. A real
application and a simulation study are conducted to illustrate the proposed
methods.
PMID- 10783795
TI - Analysis of a two-stage case-control study with cluster sampling of controls:
application to nonmelanoma skin cancer.
AB - We present a pseudolikelihood approach for analyzing a two-stage population-based
case-control study with cluster sampling of controls. These methods were
developed to analyze data from a study of nonmelanoma skin cancer (NMSC). This
study was designed to evaluate the role of ultraviolet radiation (UVB) on NMSC
risk while adjusting for age group, which is known for all subjects, and for
other individual-level factors, such as susceptibility to sunburn, which are
known only for participants in the case-control study. The methods presented
yield estimates of relative and absolute risk, with standard errors, while
accounting naturally for the two-stage sampling of the cohort and cluster
sampling of controls.
PMID- 10783796
TI - A multiple imputation approach to Cox regression with interval-censored data.
AB - We propose a general semiparametric method based on multiple imputation for Cox
regression with interval-censored data. The method consists of iterating the
following two steps. First, from finite-interval-censored (but not right
censored) data, exact failure times are imputed using Tanner and Wei's poor man's
or asymptotic normal data augmentation scheme based on the current estimates of
the regression coefficient and the baseline survival curve. Second, a standard
statistical procedure for right-censored data, such as the Cox partial likelihood
method, is applied to imputed data to update the estimates. Through simulation,
we demonstrate that the resulting estimate of the regression coefficient and its
associated standard error provide a promising alternative to the nonparametric
maximum likelihood estimate. Our proposal is easily implemented by taking
advantage of existing computer programs for right-censored data.
PMID- 10783798
TI - Approximate Bayesian evaluation of multiple treatment effects.
AB - We propose an approximate Bayesian method for comparing an experimental treatment
to a control based on a randomized clinical trial with multivariate patient
outcomes. Overall treatment effect is characterized by a vector of parameters
corresponding to effects on the individual patient outcomes. We partition the
parameter space into four sets where, respectively, the experimental treatment is
superior to the control, the control is superior to the experimental, the two
treatments are equivalent, and the treatment effects are discordant. We compute
posterior probabilities of the parameter sets by treating an estimator of the
parameter vector like a random variable in the Bayesian paradigm. The
approximation may be used in any setting where a consistent, asymptotically
normal estimator of the parameter vector is available. The method is illustrated
by application to a breast cancer data set consisting of multiple time-to-event
outcomes with covariates and to count data arising from a cross-classification of
response, infection, and treatment in an acute leukemia trial.
PMID- 10783797
TI - Use of binomial group testing in tests of hypotheses for classification or
quantitative covariables.
AB - In group testing, the test unit consists of a group of individuals. If the group
test is positive, then one or more individuals in the group are assumed to be
positive. A group observation in binomial group testing can be, say, the test
result (positive or negative) for a pool of blood samples that come from several
different individuals. It has been shown that, when the proportion (p) of
infected individuals is low, group testing is often preferable to individual
testing for identifying infected individuals and for estimating proportions of
those infected. We extend the potential applications of group testing to
hypothesis-testing problems wherein one wants to test for a relationship between
p and a classification or quantitative covariable. Asymptotic relative
efficiencies (AREs) of tests based on group testing versus the usual individual
testing are obtained. The Pitman ARE strongly favors group testing in many cases.
Small-sample results from simulation studies are given and are consistent with
the large-sample (asymptotic) findings. We illustrate the potential advantages of
group testing in hypothesis testing using HIV-1 seroprevalence data.
PMID- 10783799
TI - Bayesian nonparametric inference on the dose level with specified response rate.
AB - The richness of nonparametric Bayesian models has attracted many different
applications. Its application in dose-finding studies has been hindered due to
lack of methodologies on the nonparametric Bayesian inference on percentiles. The
primary interest in dose-finding studies focuses inference on the unknown
toxicity or efficacy dose level corresponding to a prespecified rate. This paper
shows how this problem may generally be handled by deriving inference on
percentiles of a distribution following a Dirichlet process prior. In particular,
theoretical results are derived to obtain the nonparametric Bayesian inference of
the unknown dose level. This is followed by a description of the numerical
implementation of that theory. The method also allows efficient estimation of the
entire potency curve. Finally, the usefulness of the approach is demonstrated via
an experimental data example.
PMID- 10783800
TI - Estimation in a Cox proportional hazards cure model.
AB - Some failure time data come from a population that consists of some subjects who
are susceptible to and others who are nonsusceptible to the event of interest.
The data typically have heavy censoring at the end of the follow-up period, and a
standard survival analysis would not always be appropriate. In such situations
where there is good scientific or empirical evidence of a nonsusceptible
population, the mixture or cure model can be used (Farewell, 1982, Biometrics 38,
1041-1046). It assumes a binary distribution to model the incidence probability
and a parametric failure time distribution to model the latency. Kuk and Chen
(1992, Biometrika 79, 531-541) extended the model by using Cox's proportional
hazards regression for the latency. We develop maximum likelihood techniques for
the joint estimation of the incidence and latency regression parameters in this
model using the nonparametric form of the likelihood and an EM algorithm. A zero
tail constraint is used to reduce the near nonidentifiability of the problem. The
inverse of the observed information matrix is used to compute the standard
errors. A simulation study shows that the methods are competitive to the
parametric methods under ideal conditions and are generally better when censoring
from loss to follow-up is heavy. The methods are applied to a data set of tonsil
cancer patients treated with radiation therapy.
PMID- 10783801
TI - A nonparametric mixture model for cure rate estimation.
AB - Nonparametric methods have attracted less attention than their parametric
counterparts for cure rate analysis. In this paper, we study a general
nonparametric mixture model. The proportional hazards assumption is employed in
modeling the effect of covariates on the failure time of patients who are not
cured. The EM algorithm, the marginal likelihood approach, and multiple
imputations are employed to estimate parameters of interest in the model. This
model extends models and improves estimation methods proposed by other
researchers. It also extends Cox's proportional hazards regression model by
allowing a proportion of event-free patients and investigating covariate effects
on that proportion. The model and its estimation method are investigated by
simulations. An application to breast cancer data, including comparisons with
previous analyses using a parametric model and an existing nonparametric model by
other researchers, confirms the conclusions from the parametric model but not
those from the existing nonparametric model.
PMID- 10783802
TI - Active life expectancy from annual follow-up data with missing responses.
AB - Active life expectancy (ALE) at a given age is defined as the expected remaining
years free of disability. In this study, three categories of health status are
defined according to the ability to perform activities of daily living
independently. Several studies have used increment-decrement life tables to
estimate ALE, without error analysis, from only a baseline and one follow-up
interview. The present work conducts an individual-level covariate analysis using
a three-state Markov chain model for multiple follow-up data. Using a logistic
link, the model estimates single-year transition probabilities among states of
health, accounting for missing interviews. This approach has the advantages of
smoothing subsequent estimates and increased power by using all follow-ups. We
compute ALE and total life expectancy from these estimated single-year transition
probabilities. Variance estimates are computed using the delta method. Data from
the Iowa Established Population for the Epidemiologic Study of the Elderly are
used to test the effects of smoking on ALE on all 5-year age groups past 65
years, controlling for sex and education.
PMID- 10783803
TI - Predictive accuracy and explained variation in Cox regression.
AB - We suggest a new measure of the proportion of the variation of possibly censored
survival times explained by a given proportional hazards model. The proposed
measure, termed V, shares several favorable properties with an earlier V1 but
also improves the handling of censoring. The statistic contrasts distance
measures between individual 1/0 survival processes and fitted survival curves
with and without covariate information. These distance measures, Dx and D,
respectively, are themselves informative as summaries of absolute rather than
relative predictive accuracy. We recommend graphical comparisons of survival
curves for prognostic index groups to improve the understanding of obtained
values for V, Dx, and D. Their use and interpretation is exemplified for a
Yorkshire lung cancer study on survival. From this and an overview for several
well-known clinical data sets, we show that the likely amount of relative or
absolute predictive accuracy is often low even if there are highly significant
and relatively strong prognostic factors.
PMID- 10783804
TI - Bayesian information criterion for censored survival models.
AB - We investigate the Bayesian Information Criterion (BIC) for variable selection in
models for censored survival data. Kass and Wasserman (1995, Journal of the
American Statistical Association 90, 928-934) showed that BIC provides a close
approximation to the Bayes factor when a unit-information prior on the parameter
space is used. We propose a revision of the penalty term in BIC so that it is
defined in terms of the number of uncensored events instead of the number of
observations. For a simple censored data model, this revision results in a better
approximation to the exact Bayes factor based on a conjugate unit-information
prior. In the Cox proportional hazards regression model, we propose defining BIC
in terms of the maximized partial likelihood. Using the number of deaths rather
than the number of individuals in the BIC penalty term corresponds to a more
realistic prior on the parameter space and is shown to improve predictive
performance for assessing stroke risk in the Cardiovascular Health Study.
PMID- 10783805
TI - The combination of population pharmacokinetic studies.
AB - Pharmacokinetic data consist of drug concentrations with associated known
sampling times and are collected following the administration of known dosage
regimens. Population pharmacokinetic data consist of such data on a number of
individuals, possibly along with individual-specific characteristics. During drug
development, a number of population pharmacokinetic studies are typically carried
out and the combination of such studies is of great importance for characterizing
the drug and, in particular, for the design of future studies. In this paper, we
describe a model that may be used to combine population pharmacokinetic data. The
model is illustrated using six phase I studies of the antiasthmatic drug
fluticasone propionate. Our approach is Bayesian and computation is carried out
using Markov chain Monte Carlo. We provide a number of simplifications to the
model that may be made in order to ease simulation from the posterior
distribution.
PMID- 10783806
TI - The impact of restrictive entry criterion during the placebo lead-in period.
AB - In the study of depression, most randomized clinical trials have design features
that attempt to sample from a stable patient population. One commonly used design
feature is to require patients to maintain some minimum baseline symptom severity
score during a placebo lead-in period. One intent of this design feature is to
evaluate the behavior of patients prior to administration of active medication.
If, during the lead-in period, patients do not maintain minimum symptom severity,
the patients are excluded from the remainder of the study, the theory being that
the excluded patients are not part of a stable patient population and hence are
not likely to demonstrate efficacy of a truly effective treatment. This
presentation investigates the effectiveness of a restrictive entry criterion and
proposes an alternative explanation for what is usually defined as placebo
response.
PMID- 10783807
TI - Mixed effects logistic regression models for longitudinal ordinal functional
response data with multiple-cause drop-out from the longitudinal study of aging.
AB - In the context of analyzing ordinal functional limitation responses from the
Longitudinal Study of Aging, we investigate the association between current
functional limitation and previous year's limitation and its modification by
physical activity and multiple causes of drop-out. We accommodate the
longitudinal nature of the multiple causes of informative drop-out (death and
unknown loss-to-follow-up) with a mixed effects logistic model. Under the
proposed model with a random intercept and slope, the ordinal functional outcome
and multiple discrete time survival profiles share a common random effect
structure. This shared parameter selection model assumes that the multiple causes
of drop-out are conditionally independent of the functional limitation outcome
given the underlying random effect representing an individual's trajectory of
general health status across time. Although it is not possible to fully assess
the adequacy of this assumption, we assess the robustness of the approach by
varying the assumptions underlying the proposed model, such as the random effects
distribution and the drop-out component. It appears that between-subject
differences in initial functional limitation are strongly associated with future
functional limitation and that this association is stronger for those who do not
have physical activity regardless of the random effects and informative drop-out
specifications. In contrast, the association between current functional
limitation and previous trajectory of functional status within an individual is
weaker and more sensitive to changes in the random effects and drop-out
assumptions.
PMID- 10783808
TI - Modeling human fertility in the presence of measurement error.
AB - The probability of conception in a given menstrual cycle is closely related to
the timing of intercourse relative to ovulation. Although commonly used markers
of time of ovulation are known to be error prone, most fertility models assume
the day of ovulation is measured without error. We develop a mixture model that
allows the day to be misspecified. We assume that the measurement errors are
i.i.d. across menstrual cycles. Heterogeneity among couples in the per cycle
likelihood of conception is accounted for using a beta mixture model. Bayesian
estimation is straightforward using Markov chain Monte Carlo techniques. The
methods are applied to a prospective study of couples at risk of pregnancy. In
the absence of validation data or multiple independent markers of ovulation, the
identifiability of the measurement error distribution depends on the assumed
model. Thus, the results of studies relating the timing of intercourse to the
probability of conception should be interpreted cautiously.
PMID- 10783809
TI - A comparison study of models and fitting procedures for biphasic viral dynamics
in HIV-1 infected patients treated with antiviral therapies.
AB - The study of HIV dynamics is one of the most important developments in recent
AIDS research. It has led to a new understanding of the pathogenesis of HIV
infection. But, although important findings in HIV dynamics have been published
in prestigious scientific journals in the last 5 years, the model-fitting
procedures used in these publications have not been studied in any detail. In
this paper, we evaluate the performance of four model-fitting procedures proposed
and used in biphasic HIV dynamic data analysis via extensive Monte Carlo
simulations. We propose some guidelines for practitioners to select an
appropriate method for their own data analysis. Real data examples from an AIDS
clinical trial are provided as illustrations.
PMID- 10783810
TI - Comment on Quan and Shih's "Assessing reproducibility by the within-subject
coefficient of variation with random effects models".
PMID- 10783811
TI - Computer-assisted analysis of mixtures.
PMID- 10783812
TI - Estimating risk difference in multicenter studies under baseline-risk
heterogeneity.
AB - In this paper, we consider the case of efficient estimation of the risk
difference in a multicenter study allowing for baseline heterogeneity. We
consider the optimally weighted estimator for the common risk difference and show
that this estimator has considerable bias when the true weights (which are
inversely proportional to the variances of the center-specific risk difference
estimates) are replaced by their sample estimates. In addition, we propose a new
estimator for this situation of the Mantel-Haenszel type that is unbiased and, in
addition, has a smaller variance for small sample sizes within the study centers.
Simulations illustrate these findings.
PMID- 10783813
TI - A revisit on tests for homogeneity of the risk difference.
AB - Lipsitz et al. (1998, Biometrics 54, 148-160) discussed testing the homogeneity
of the risk difference for a series of 2 x 2 tables. They proposed and evaluated
several weighted test statistics, including the commonly used weighted least
squares test statistic. Here we suggest various important improvements on these
test statistics. First, we propose using the one-sided analogues of the test
procedures proposed by Lipsitz et al. because we should only reject the null
hypothesis of homogeneity when the variation of the estimated risk differences
between centers is large. Second, we generalize their study by redesigning the
simulations to include the situations considered by Lipsitz et al. (1998) as
special cases. Third, we consider a logarithmic transformation of the weighted
least squares test statistic to improve the normal approximation of its sampling
distribution. On the basis of Monte Carlo simulations, we note that, as long as
the mean treatment group size per table is moderate or large (> or = 16), this
simple test statistic, in conjunction with the commonly used adjustment procedure
for sparse data, can be useful when the number of 2 x 2 tables is small or
moderate (< or = 32). In these situations, in fact, we find that our proposed
method generally outperforms all the statistics considered by Lipsitz et al.
Finally, we include a general guideline about which test statistic should be used
in a variety of situations.
PMID- 10783814
TI - Understanding and managing cancer pain.
PMID- 10783815
TI - Neurophysiology of cancer pain.
AB - BACKGROUND: Recent basic science research has greatly added to our knowledge of
pain mechanisms. Application of this knowledge to cancer pain syndromes has led
to new and innovative approaches to cancer pain management. METHODS: The
mechanisms involved in the three main cancer pain syndromes (somatic, visceral,
and neuropathic) are reviewed, and various therapeutic options are discussed.
RESULTS: Advances in knowledge in neurophysiology, neuroanatomy, and pharmacology
have allowed a greater understanding of the peripheral and central mechanisms of
pain. New drugs and interventional techniques based on this knowledge have
improved the control of cancer pain. CONCLUSIONS: Understanding the
neurophysiology of cancer pain promotes use of the most appropriate palliative
measures for pain control.
PMID- 10783816
TI - Cancer pain management.
AB - BACKGROUND: Controlling pain in cancer patients is often inadequate. A recent
multicenter study of patients with metastatic disease who were experiencing pain
reported that 36% still had pain severe enough to compromise their daily
function. METHODS: The author draws on his experiences as well as those of others
to review general guidelines and provide specific recommendations for cancer pain
management. RESULTS: Three components are critical to managing cancer pain:
assessing pain, establishing an appropriate therapeutic opioid regimen, and
integrating with other therapies. An appropriate therapeutic opioid regimen
involves initiating, consolidating and maintaining therapy. Other strategies
(e.g., advanced pharmacological, adjuvant, interventional, and psychological) can
be added to opioid therapy. CONCLUSIONS: A revision of the Agency for Health Care
Policy and Research Cancer Pain Guidelines is currently underway. The management
of pain in cancer patients should include more frequent reassessment of both
analgesia and side effects to ensure optimal cancer pain relief.
PMID- 10783817
TI - Routes of opioid analgesic therapy in the management of cancer pain.
AB - BACKGROUND: The availability of various routes of administration of opioid
analgesics can be confusing when determining an appropriate, efficacious, and
cost-effective regimen to manage cancer pain. METHODS: The indications,
contraindications, and pharmacokinetic properties of oral, intravenous,
subcutaneous, transdermal, transmucosal, rectal, and perispinal routes of opioid
administration are reviewed. RESULTS: To determine the most efficacious, cost
effective, and user-friendly option to manage cancer pain, several factors must
be considered: the ability of the patient to use a specific type of delivery
system, the efficacy of that system to deliver acceptable analgesia, the ease of
use for the patient and family, the potential or actual complications associated
with that system, and the cost. CONCLUSIONS: Administering opioids to manage
cancer pain requires knowledge of potency relative to morphine and
bioavailability of the route chosen. Changes in the route, dosage, or opioid used
should be accompanied with close patient follow-up.
PMID- 10783818
TI - Critical evaluation of chemical neurolysis of the sympathetic axis for cancer
pain.
AB - BACKGROUND: Patients with pain caused by cancer frequently experience visceral
pain. In addition to oral pharmacologic therapy to manage pain, neurolytic blocks
of the sympathetic axis are also effective in controlling visceral cancer pain.
METHODS: Four types of neurolytic blocks (interpleural phenol, celiac plexus,
superior hypogastric plexus, and ganglion impar) used in the treatment of
visceral cancer pain are reviewed. RESULTS: Several studies have documented the
efficacy of neurolytic blocks in reducing pain intensity and opioid consumption.
However, the narrow risk-benefit ratio associated with neurolysis techniques
requires knowledge of the implications associated with the different neurolytic
blocks to minimize undesirable effects. CONCLUSIONS: Neurolysis of the
sympathetic axis has been shown to be an effective and safe approach to treat
visceral pain in cancer patients and should be incorporated in the armamentarium
of the pain specialist as a useful adjunct to oral pharmacologic therapy.
PMID- 10783819
TI - Interventional treatment of cancer pain: the fourth step in the World Health
Organization analgesic ladder?
AB - BACKGROUND: For most patients with cancer pain, the World Health Organization's
three-step analgesic ladder provides adequate management with oral or transdermal
options. However, some cancer patients are not well palliated with these
approaches. METHODS: The author reviews interventional options that include nerve
blocks, spinal administration of local anesthetics, opioids, alpha-2 agonists,
spinal cord stimulation, and surgical interventions. RESULTS: Numerous
interventional options are readily accessible and most can be performed on an
outpatient basis. They can be used as sole agents for the control of cancer pain
or as useful adjuncts to supplement analgesia provided by opioids, thus
decreasing opioid dose requirements and side effects. CONCLUSIONS: Cancer-related
pain can be controlled with several interventions when oral or transdermal
opioids are inadequate. A risk:benefit ratio should be considered before
implementing invasive analgesic methods.
PMID- 10783820
TI - Nonpharmacological interventions with chronic cancer pain in adults.
AB - BACKGROUND: Pain is often poorly controlled in cancer patients. Chronic pain
affects adult patients at all stages of cancer management. Optimal pain
management may require attention to psychosocial variables and the inclusion of
nonpharmacological techniques. METHODS: Three nonpharmacological strategies that
are effective in reducing pain caused by cancer--patient psycho-education,
supportive psychotherapy, and cognitive-behavioral interventions--are reviewed.
Recommendations for physicians to facilitate a mental health referral are also
discussed. RESULTS: Effective treatment of cancer pain begins with assessing the
severity, characteristics, and impact of pain. Emotional distress (especially
anxiety, depression, and beliefs about pain) has emerged as predictive of patient
pain levels. Appropriate pain management may require a multidisciplinary
approach. CONCLUSIONS: Patient psycho-education has empowered patients to
actively participate in pain control strategies. Supportive psychotherapy can
assist patients in managing the stressors associated with cancer, and cognitive
behavioral therapy helps patients to recognize and modify the factors that
contribute to physical and emotional distress.
PMID- 10783821
TI - Intravenous to oral (iv:po) anti-infective conversion therapy.
PMID- 10783822
TI - Erectile dysfunction in the cancer patient.
PMID- 10783823
TI - Disseminated cutaneous Mycobacterium chelonae infection.
PMID- 10783824
TI - Strategies for combining chemotherapy and biotherapy in melanoma.
PMID- 10783825
TI - P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol
in humans.
AB - OBJECTIVE: Increased bioavailability of the P-glycoprotein (Pgp) substrates
digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim of
the present study was to investigate the effect of orally administered
erythromycin on the oral bioavailability of the beta-blocker talinolol. Talinolol
is a suitable model compound for Pgp drug-drug interaction studies due to its Pgp
related active intestinal secretion and lack of any significant metabolism.
METHODS: In a randomized crossover study, the oral pharmacokinetics of talinolol
(50 mg) after a concomitant single oral dose of erythromycin (2 g) or placebo
were investigated in 9 healthy men. Concentrations of talinolol were measured in
serum and urine by HPLC. RESULTS: The area under the curve of talinolol serum
concentrations from 0 to 24 h (AUC(0-24)) and the maximum serum concentrations
(Cmax) were significantly increased after administration of erythromycin compared
to placebo. t(max) values were significantly reduced. The renal clearance (CLR)
of talinolol was unchanged after co-administration of erythromycin and there was
a small but statistically significant decrease in elimination half-life (t1/2).
Serum pharmacokinetics correlate with the results derived from urine
concentration measurement. One subject suffered from moderate diarrhea after
erythromycin and was excluded from the analysis. CONCLUSION: We suggest that the
increase in oral bioavailability of talinolol after concomitant erythromycin is
caused by increased intestinal net absorption due to Pgp inhibition by
erythromycin.
PMID- 10783826
TI - Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs
and analogs, stereoisomers and metabolites.
AB - OBJECTIVES: The multidrug transporter P-glycoprotein (P-gp) appears to play a
significant role in drug absorption and disposition. Hence, it is of interest to
evaluate structure-affinity relationships for the purpose of making predictions.
METHODS: The affinity to P-gp of related molecular structures from various groups
of drugs was determined using competitive radioligand-binding assays. Structural
analogs, stereoisomers and metabolites of verapamil-type calcium antagonists,
beta-adrenoceptor antagonists as well as omeprazole, omeprazole enantiomers and
the sulfone metabolite of omeprazole were investigated. RESULTS: Whereas some
stereoselectivity was detected for the high-affinity P-gp substrates verapamil
and carvedilol, little or no differences were observed in the case of other beta
blockers. One of the 4 labetalol stereoisomers, the R,R-isomer dilevalol, had an
IC50 value half that of labetalol. CONCLUSIONS: Metabolites of verapamil,
gallopamil, carvedilol and omeprazole are characterized by having higher IC50
values (lower P-gp affinity) than the respective parent compounds. Only the
acebutolol metabolite, diacetolol, had a P-gp affinity comparable to that of the
parent compound.
PMID- 10783827
TI - Simultaneous measurement of cellular P-glycoprotein content and function by
multiparametric flow-cytometry.
AB - OBJECTIVE: A multiparametric approach was applied to simultaneously determine
expression and function of the drug efflux pump P-glycoprotein (PGP) in multidrug
resistant (MDR) human leukemic lymphoblast cell lines and isolated leukemic
blasts using flow-cytometry in a patient with acute myeloid leukemia (AML).
METHODS: The antigen was measured by staining PGP using the monoclonal antibody
4e3 which does not inhibit the function of PGP. The 4e3 antibody binds to an
external epitope of PGP and can therefore be used for staining living cells. Drug
transport, mediated by PGP, was determined simultaneously by measuring rhodamine
123 (rho123) efflux. The MDR cell lines, CEM/VLB10-2 and CEM/VBL100 are 10-fold
and 270-fold resistant to vinblastine (VBL), respectively, compared to the human
PGP-negative parent cell line CEM/WT and they express different amounts of PGP.
Initially, living cells were stained using the 4e3 antibody and a secondary
antibody labeled with 7-amino-4-methylcoumarin-3-acetic acid (AMCA). Cells were
then incubated for 60 min with rho123 (10 microM) and analyzed for rhodamine and
AMCA-derived fluorescence. The decrease in rho123 fluorescence was determined
after a further period of 30 min. RESULTS: CEM/VLB100 cells expressed larger
amounts of PGP, and rho123 fluorescence after 30 min was 85% lower than the
parent cell line. PGP expression and rho123 efflux were also detected in
CEM/VLB10-2 cells which display a low degree of resistance, thus reflecting the
high sensitivity of this method. PGP-expressing blasts and moderate rho123 efflux
were also observed in a specimen derived from a patient with clinically resistant
acute myeloid leukemia (AML). CONCLUSION: A multiparametric approach using flow
cytometry allows the reliable and sensitive measurement of both PGP expression
and function simultaneously in single cells.
PMID- 10783828
TI - Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells
expressing the multidrug resistance protein (MRP).
AB - Multidrug resistance (MDR) to cancer chemotherapy is frequently associated with
decreased drug accumulation in cancer cells due to drug expulsion by multidrug
transporters such as P-glycoprotein (Pgp) and multidrug resistance protein (MRP).
The novel resistance modifying agents PSC 833, 280-446, and LY 335979 are
primarily targeted at inhibition of Pgp, and their MRP inhibitory potential is
largely unknown. OBJECTIVE: In the present study we addressed the effect of these
agents on MRP-derived drug resistance. MATERIALS: Drug-resistant human leukemia
cells with Pgp+/MRP- (KG1a/200, K562/150) and Pgp-/MRP+ (HL60/130) phenotypes
were maintained in suspension cultures for experimental studies of drug
accumulation and drug sensitization by Pgp inhibitors. METHODS: Intracellular
accumulation of the fluorescent anthracycline daunorubicin was measured by flow
cytometry and fluorescence detection. Daunorubicin dose-response curves were
generated by non-linear regression of electronically measured cell counts of 72-
96-h cultures. The half-maximal growth inhibitory dose (GI50) was used as
measure of growth inhibition. RESULTS: All MDR phenotypes studied exercised
significant resistance to daunorubicin. PSC 833, 280-446 and LY335979 were equal
in sensitizing Pgp+/MRP- cells to daunorubicin-induced growth inhibition (p <
0.0001). The Pgp-/MRP+ cells responded to PSC 833 and 280-446 by increased
accumulation of daunorubicin (p = 0.0022 and p = 0.0005, respectively) and
sensitization to the drug (p = 0.0009 and p = 0.0007, respectively). Conversely,
LY335979 did not affect accumulation of daunorubicin in Pgp-/MRP+ cells nor
sensitize these cells to daunorubicin. CONCLUSION: Pgp inhibitory agents have
differential effects on MRP-derived drug resistance which could be exploited in
treatment of multidrug resistance in cancer patients.
PMID- 10783829
TI - Resistance modulation in CHO cells by R-verapamil and bile salts is associated
with physical and chemical changes in the cell membrane.
AB - OBJECTIVES: Changes in multidrug resistance by resistance modifiers such as R
verapamil cause changes in fluidity of the cell membrane. The extent to which
these changes involve structural alterations in membrane lipids has been
investigated in CHO cells. METHODS: Sensitive (AUXB1) and resistant (CH(R)C5)
chinese hamster ovary cells (CHO) were grown in culture. Incubations were carried
out with R-verapamil (0-10 microM) or the membrane perturbing agents tauro-cheno
deoxycholate (0-1.6 mM, TCDC) and tauro-urso-deoxycholate (0-3.5mM, TUDC). Cell
membrane fluidity was determined by electron-paramagnetic resonance spectroscopy
and membrane lipids by HPLC and TLC. RESULTS: The resistant CH(R)C5 subline had a
higher cell membrane order (lower fluidity, S = 0.7234) in the interface region
of the cell membrane than sensitive AUXB1 cells (S = 0.6984) determined using
EPR. The MDR-modulator R-verapamil and TCDC, but not TUDC, lowered cell membrane
order in a concentration-dependent manner and increased membrane fluidity of the
resistant CH(R)C5 subline. TCDC and R-verapamil were without effect on the cell
membrane fluidity of AUXB1 cells. These changes were accompanied by alterations
in the fatty acid composition of the plasma membrane. Untreated sensitive AUXB1
cells had higher levels of unsaturated fatty acids than resistant CH(R)C5 cells.
In CH(R)C5 cells, R-verapamil increased the content of poly-unsaturated fatty
acids and TCDC, but not TUDC, increased the content of mono-unsaturated fatty
acids. CONCLUSIONS: The results demonstrate that resistance modifiers such as
verapamil may influence cytostatic drug action by producing structural changes to
lipid domains in the plasma membrane.
PMID- 10783830
TI - Cytostatic sensitivity and MDR in bladder carcinoma cells: implications for tumor
therapy.
AB - The clinical success generally seen in chemotherapy of advanced bladder carcinoma
is far from optimal. The mechanism of resistance development is unclear and the
expression of P-170 glycoprotein is generally low. The aim of this study, carried
out in vitro in sensitive and cisplatin-resistant cell lines, was to examine
sensitivity modulation using R-verapamil and cell membrane perturbing agents.
Cell growth rates and changes in the order of the cell membrane, determined using
electron-paramagnetic resonance spectrometry, were recorded. R-verapamil
increased the toxic effect of doxorubicin in the cisplatin-resistant cell line
which showed the highest membrane order. Linolenic acid had a similar effect and
also increased sensitivity to cisplatin and methotrexate. Bile salts (tauro-cheno
deoxycholate,TCDC, and tauro-urso-deoxycholate TUDC), had little effect on
cytotoxicity. These results indicate that R-verapamil and linolenic acid can act
as sensitivity modulators in bladder carcinoma cells and that the action of these
agents may involve membrane fluidity changes, a phenomenon noted previously in
regard to sensitivity modulation in chinese hamster ovary cell lines.
PMID- 10783831
TI - Modulation of multidrug resistance in human leukemia cells with mdr1-targeted
antisense oligonucleotides using variable treatment schedules.
AB - OBJECTIVE: The purpose of the current study was to characterize the effect of
chimeric AS-ODNs encapsulated with cationic lipids on MDR in human leukemia cells
and to determine if this modification of the ODN alone or in combination with the
cationic lipid might offer advantages over classical ODN treatment with free
unmodulated or phosphorothiolated AS-ODNs. Furthermore, we extended the antisense
method to the use of AS-ODNs in the parental drug-sensitive leukemia cells which
express mdr1-mRNA at a relative low level and lack P170 expression to evaluate
the effectiveness of prophylactic AS-ODN treatment. METHODS: The effect of a 4
day AS-ODN treatment in drug-resistant human leukemia cells which exhibit the
classic MDR phenotype at a moderate level was examined. Twenty-four hours after
the last ODN administration the cells were analyzed for mdr1-mRNA (quantitative
RT-PCR) and P170 expression (FCM), for R123 accumulation/efflux capacity (FCM)
and for sensitivity to vincristine (MTT). In the parental drug-sensitive CCRF-CEM
cells the mdr1-mRNA expression was assessed 24, 48 and 72 h after AS-ODN
treatment administered as free phosphorothioate or conjugated with DMRIE-C.
RESULTS: Cationic lipids produced a clear increase in cellular ODN uptake but
also caused an increase in variability of uptake rates (30% vs. 10% variability
after free phosphorothioates). Both AS-ODNs inhibit P170 expression whereby the
antisense effect of the chimeric ODN seems to be stronger compared to the
phosphorothioate (30% vs. 22% MRK16 staining). Consistent with the inhibition of
P170 expression, an increased sensitivity to vincristine was observed. In
parental drug-sensitive cells, AS-ODN treatment caused nearly complete inhibition
of mdr1-mRNA expression (5% of control). CONCLUSION: The data demonstrate that it
is nearly impossible to achieve a complete reversal of the MDR phenotype in drug
resistant cells using AS-ODNs. A more promising approach seems to be the
prophylactic treatment with AS-ODNs.
PMID- 10783832
TI - Induction of apoptosis by idarubicin: how important is the plasma peak?
AB - OBJECTIVES: It is still not clear whether a high plasma peak or a prolonged
plasma presence of the drug is optimal for chemotherapy with anthracyclines. A
high plasma peak seems to correlate with the liberation of oxygen radicals and
cumulative delayed cardiotoxicity, and therefore, should be avoided. On the other
hand, its role in attaining the desired therapeutic effect, i.e. induction of
apoptosis in tumor cells, has not been clearly elucidated. METHODS: Idarubicin is
the only anthracycline that can be applied orally. We measured the DNA-binding of
idarubicin and idarubicinol and the induced apoptosis in the human promyelocytic
HL-60 leukemia cell line. Various pharmacokinetic profiles, with and without
clinically relevant peak concentrations, were simulated in vitro. RESULTS: The
concentration necessary for maximal DNA-binding and subsequent induction of
apoptosis was 1.5 microg/ml for 20 minutes which is well above the plasma
concentration achievable in therapy. A plateau of apoptosis was observed after 90
minutes of incubation; a prolongation above 90 minutes did not increase the rate
of apoptosis. We simulated a bolus application and a continuous infusion using
two different pharmacokinetic profiles of idarubicin with comparable AUCs (area
under the time curve). After 48 hours of total incubation, the viability of HL-60
cells was 56.88% with profile 1 (50 ng/ml idarubicin for 2 hours) and 83.00% with
profile 2 (4.25 ng/ml for 24 hours). CONCLUSIONS: Although these in vitro
experiments are not directly applicable to the clinical situation, they do
indicate that a prolongation of the application time up to at least 90 minutes,
either by continuous infusion or by oral application, may be acceptable as a
method of increasing apoptosis. On the other hand, the plasma peak seems to be an
important factor for the induction of apoptosis. Further studies are in progress
to define the minimal plasma peak necessary to induce a maximum of apoptosis.
PMID- 10783833
TI - Risk factors for drug-induced gingival overgrowth.
AB - BACKGROUND/AIMS: Drug-induced gingival overgrowth remains a significant problem
for the periodontologist. Many patients medicated with the drugs implicated in
this unwanted effect experience significant, recurrent gingival problems that
require repeated surgical excisions. In this review, we attempt to identify and
quantify the various "risk factors" associated with both the development and
expression of the drug-induced gingival changes. METHOD: The risk factors
appraised include age, sex, drug variables, concomitant medication, periodontal
variables and genetic factors. Elucidation of such factors may help to identify
"at risk patients" and then develop appropriate treatment strategies. RESULTS: Of
the factors identified, the only one that can be affected by the periodontologist
is the patents' periodontal condition. However, drug variables and concomitant
medication do impact upon the expression of gingival overgrowth. CONCLUSION: The
identification of risk factors associated with both the prevalence and severity
of drug-induced gingival overgrowth is important for all parties involved with
this unwanted effect. Both periodontologist and patient have an important role to
play in improving oral hygiene and gingival health. Likewise, there is always an
opportunity to establish a close liaison between the patient's physician and the
periodontologist to try and identify alternative drug regimens that can help
reduce the impact of this unwanted effect.
PMID- 10783834
TI - Radiographic detection and assessment of the periodontal endosseous defects.
AB - AIMS: The aim of the present study was to investigate the potential of
conventional radiography in detecting and accurately imaging periodontal
endosseous (or osseous) defects when compared to surgical measurements. A further
objective of the study was the selection of the most successful radiographic
method for the assessment of endosseous defects. METHOD: Surgical measurements,
during periodontal flap surgery, and radiographic measurements, from periapical
and panoramic radiographs, were obtained from 5,072 proximal surfaces of 100
patients presenting with periodontitis. RESULTS: Statistical evaluation of the
surgical and radiographic measurements revealed the following. (1) The ability of
the radiographs to detect periodontal osseous defects was relatively low. (2) For
periapical radiography, it depended, in descending order, on the depth and
buccolingual width of the defect, the number of osseous walls and the jaw
location. For panoramic radiography, it depended only on buccolingual width. (3)
Osseous defects of small depth and/or small buccolingual width were the most
difficult to detect radiographically. (4) Periapical radiography was more
successful than panoramic in detecting osseous defects, and more accurate in
assessing the defect dimensions (depth, mesiodistal width). (5) The difference in
the defect detection ability between the 2 radiographic methods, the accuracy of
the radiographic defect dimensions assessment as well as the degree of agreement
between periapical and panoramic assessment depended on defect location and
dimensions. CONCLUSIONS: Periapical radiography is superior to panoramic in
detecting and accurately imaging periodontal osseous destruction.
PMID- 10783835
TI - Dental and periodontal status of Sjogren's syndrome.
AB - BACKGROUND: Sjogren's syndrome (SS) is one of the most common systemic autoimmune
diseases in middle-aged women. The present study had the aim to examine the
dental and periodontal condition in patients with SS in comparison with disease
controls and to evaluate the influence of reduced salivary flow in the
periodontal tissues. METHOD: We examined 24 patients with primary or secondary SS
in comparison with 27 patients who had another autoimmune disease but no signs or
symptoms of SS, as well as with 29 subjects who had a subjective feeling of
xerostomia or xerophthalmia without exhibiting an underlying disease. The
clinical evaluation included examination of the oral mucosa, determination of
missing, decayed and filled teeth, fixed or removable prosthetic appliances,
plaque index, gingival index, probing pocket depth, probing attachment level,
oral hygiene habits and frequency of dental visits. Statistical analysis was
performed using the 2-tailed Fisher exact and Kruskal-Wallis tests. RESULTS: No
significant difference was found in the dental or periodontal condition of the 3
groups. The number of teeth, feelings and distal or mesial decay lesions
correlated negatively with age, while the number of fixed prosthetic appliances
correlated positively. The salivary flow was statistically lower in patients with
SS and exhibited a negative correlation with the number of cervical decay
lesions. It was also found that SS patients had better oral hygiene habits than
subjects of the control groups. CONCLUSIONS: No significant,difference could be
detected concerning the dental and periodontal status of SS patients, compared
with that of patients with other immune diseases as well as with that of controls
who had subjective xerostomia.
PMID- 10783836
TI - Laser Doppler flowmeter measurement of relative gingival and forehead skin blood
flow in light and heavy smokers during and after smoking.
AB - AIM: To determine the effect of the smoking experience on relative blood flow in
gingiva and to compare this to skin. METHOD: A laser Doppler flowmeter was used
to record relative blood flow to healthy gingiva and to forehead skin in smokers
and non-smoking controls. Smoking status was verified by quantitative analysis of
serum cotinine. Continuous measurements were made over sequential periods with
the subject at rest, during a sham smoking exercise, during smoking of a standard
research cigarette (2R1, University of Kentucky) for 5 min and throughout a
subsequent recovery period. Non-smoking controls sham smoked during the
equivalent 5 minute smoking period. RESULTS: No significant differences with
respect to the proportional changes of relative gingival blood flow between time
points were observed between the groups. However, between-group comparisons of
relative blood flow revealed a significant increase in the relative blood flow to
the forehead skin of light smokers (serum cotinine < or =60 ng/ml; n=6), when
compared to heavy smokers (serum cotinine > or = 100 ng/ml; n=9) or to non
smokers (serum cotinine < or = 10 ng/ml; n=6), 2 min following the smoking
experience (p = 0.007). CONCLUSION: The results do not seem to support the theory
that tobacco smoking causes localised vasoconstriction in the periodontal tissues
in humans. These data show that smoking causes an acute increase in relative
blood flow in forehead skin in light smokers compared to heavy smokers,
suggesting a potential induction of tolerance in regular users of tobacco.
PMID- 10783837
TI - Subgingival polishing with a teflon-coated sonic scaler insert in comparison to
conventional instruments as assessed on extracted teeth. (I) Residual deposits.
AB - BACKGROUND: Recent studies have shown that endotoxins are located on the
periodontally diseased root cementum and not within it. These studies led to the
suggestion that the root surface could be treated less aggressively during
periodontal therapy. Thus, we designed a teflon-tubed sonic scaler insert for
subgingival polishing. It was our objective to assess to which extent this new
instrument is capable of removing bacterial deposits in deep pockets in
comparison with conventional scaling instruments. METHOD: We compared the extent
to which plaque and calculus could be removed with a curette, a conventional
sonic and ultrasonic scaler insert, a Per-io-tor insert, and a teflon-tubed sonic
scaler insert. 84 teeth requiring extraction had been treated with one of these
instruments. After extraction, the teeth were stained with Malachite green, and
the following areas were assessed: area lacking plaque and calculus, calculus,
and area only covered with plaque. For statistical comparison, nonparametric
analyses were carried out. RESULTS: Curettes and conventional ultrasonic and
sonic-scaler inserts had more area lacking plaque and calculus (97.5%, 92.2%,
92.1%) than did the Per-io-tor (80.1%) or the teflon-coated sonic scaler insert
(84.4%). A similar effectivity sequence was observed for residual soft deposits
(curette: 1.9%, ultrasonic scaler: 6.1%, sonic scaler: 5.4%, teflon-coated sonic
scaler: 5.1% and Per-io-tor: 9.5%). CONCLUSIONS: The Per-io-tor and the teflon
coated sonic scaler insert seem to be suitable for the removal of soft deposits
on the root surface, but not for the removal of calculus.
PMID- 10783838
TI - Smoking and GCF levels of IL-1beta and IL-1ra in periodontal disease.
AB - AIMS: GCF levels of the cytokine IL-1beta and its receptor antagonist IL-1ra were
analyzed with respect to smoking in patients with moderate to severe periodontal
disease. The study population included 22 smokers and 18 non-smokers in the age
range 32-86 years. Concomitantly, the GCF levels of IgA, IgG, albumin and total
protein were analyzed. METHOD: Samples of GCF were obtained from 2 diseased sites
in each patient by means of an aspiration method. IL-1beta, IL-1ra, IgA and IgG
were determined with immunoelectrophoresis. Total protein was determined by the
BCA method. RESULTS: The clinical characteristics in terms of probing depth and
frequency of diseased sites and supragingival plaque did not differ between
smokers and non-smokers. Gingival bleeding, however, was significantly depressed
in smokers. IL-1beta was detected in GCF of 95% of both smokers and non-smokers
and IL-1ra in all patients. The GCF level of IL-1ra was approximately 1,000-fold
that of IL-1beta. The GCF levels of IL-1beta and IL-1ra were high in comparison
with those of TNF-alpha and IL-6 determined by the same method in our earlier
studies. CONCLUSION: Our observations did not reveal any influence of smoking on
the levels of IL-1beta and IL-1ra in GCF.
PMID- 10783839
TI - Determination of the in situ bactericidal activity of an essential oil mouthrinse
using a vital stain method.
AB - BACKGROUND: Recent research has indicated that bacteria within a biofilm may
undergo changes in susceptibility to antimicrobial agents when compared to
planktonic forms. This study was conducted to determine the bactericidal effect
of an essential oil-containing mouthrinse (Listerine Antiseptic) on dental plaque
bacteria in situ. METHODS: 1-day-old plaque in 17 subjects was sampled at
baseline from the buccal surfaces of diagonally contralateral maxillary and
mandibular bicuspids and 1st molars. Subjects were then randomly assigned either
an essential oil mouthrinse or a sterile saline negative control and rinsed under
supervision with 20 ml for 30 s. 30 min later, plaque was sampled from the
remaining contralateral posterior teeth. Subjects repeated these procedures with
their respective alternate rinse after 1 week. Pooled plaque samples from each
subject at each sampling period were stained with a commercially-available
fluorescent stain which fluoresces live and dead bacteria green and red,
respectively. The stained plaque specimens were analyzed using computerized image
analysis. A separate in vitro study was conducted to determine the relationship
between the % red stain per sample and bacterial viability. RESULTS: Analysis of
vital stained plaque specimens indicated that following rinsing with the
essential oil mouthrinse, 78.7% of bacteria were dead compared to 27.9% following
rinsing with the negative control (p<0.001). The in vitro findings demonstrated
that the % red stain per sample is reflective of actual bacterial kill.
CONCLUSIONS: This study confirms the findings of previous in vitro and in vivo
studies which demonstrated the essential oil mouthrinse to have significant
biocidal activity against oral micro-organisms. These studies all support the
primacy of a bactericidal mechanism in producing the plaque and gingivitis
reductions observed in numerous clinical trials conducted on the essential oil
mouthrinse.
PMID- 10783840
TI - Relationship of the substance P to indicators of host response in human gingival
crevicular fluid.
AB - BACKGROUND: The substance P (SP) level in human gingival crevicular fluid (GCF)
was studied in relation to clinical periodontal variables and to various
indicators of host response in the GCF. METHODS: GCF was collected from
periodontal sites with gingival inflammation and shallow or moderately deep
pocket in 48 subjects. The total amount of SP and the substances based on host
response factors in a 30-s sample were determined by ELISA and enzymatic methods.
RESULTS: Significant correlation was found between SP and probing depth (r=
0.637, p<0.001), while correlation was weak between SP and either gingival (r=
0.177, p=0.23) or plaque index (r=0.008, p=0.96). SP also showed significant
correlation with the indicators of host response: prostaglandin E2, aspartate
aminotransferase, alkaline phosphatase, myeloperoxidase, interleukin-1beta, tumor
necrosis factor-alpha, interleukin-8 and monocyte chemoattractant protein-1
(r=0.434-0.867, p<0.01-0.001). CONCLUSION: These results indicate that
neuropeptide SP in GCF may have a potential as an indicator of periodontal
inflammation and the host response.
PMID- 10783841
TI - Is there a relationship between rheumatoid arthritis and periodontal disease?
AB - AIM: The aim of this study was to determine whether there is a relationship
between disease experience of rheumatoid arthritis and periodontal disease.
METHODS: 1,412 individuals attending the University of Queensland's School of
Dentistry were assessed for the prevalence of periodontal disease and rheumatoid
arthritis. Analysis of data obtained from a self-reported health questionnaire
and dental records was carried out and included: number of individuals referred
for advanced periodontal care (test group); number of individuals attending for
routine dentistry; determination of rheumatoid arthritis, cardiovascular disease
and diabetes mellitus through self-reporting and assessment of prescription
medications; assessment of periodontal disease through assessment of existing
oral radiographs. RESULTS: In patients referred for periodontal treatment, the
prevalence of self-reported rheumatoid arthritis was 3.95% which is significantly
higher than that seen in patients not referred for periodontal treatment (0.66%)
and also that reported in the general population (1%). Of those referred patients
with rheumatoid arthritis, 62.5% had advanced forms of periodontal disease. These
results were mirrored in the results of the self-reported prevalence of
cardiovascular disease and diabetes mellitus which was consistent with the
published higher prevalence in periodontal patients. CONCLUSIONS: Based on data
derived from self-reported health conditions, and not withstanding the
limitations of such a study, we conclude that there is good evidence to suggest
that individuals with moderate to severe periodontal disease are at higher risk
of suffering from rheumatoid arthritis and vice versa.
PMID- 10783842
TI - A controlled study of relative periodontal attachment loss in people with HIV
infection.
AB - OBJECTIVE: To compare the progression of periodontal destruction in people with
and without HIV. METHOD: Relative attachment loss on 6 index teeth was compared
between 19 people with HIV and 17 people without HIV infection over 12 and 18
month follow ups. RESULTS: The proportions of sites with 1, 2 or 3 mm of relative
attachment loss were similar in the study and control groups. Mean maximum
relative attachment loss was similar in both groups after 12 months but greater
in the study group after 18 months. CONCLUSIONS: The data are not compelling
evidence of greater periodontal destruction associated with HIV infection. Large
scale cohort studies or meta-analyses would be more conclusive.
PMID- 10783843
TI - A laboratory and clinical investigation comparing 2 oscillating/rotating electric
toothbrushes.
AB - BACKGROUND/AIMS: The purpose of the study was to investigate the efficacy of
plaque removal by 2 different toothbrushes in a laboratory model and in a
clinical study. METHOD: The 2 brushes used were the Philips/Jordan HP 735 and the
Braun Oral-B Ultra Plaque Remover (D9). Both were compared in a laboratory study
(using a robot system) and a short-term clinical study. For the laboratory study,
plaque substitute was applied to the artificial teeth of ten typodonts, which
were cleaned by a robot for 2 min. The remaining plaque substitute was measured
on buccal and lingual/palatal surfaces, as well as gumline and interproximal
sites, using a computerized vision system. The clinical study included 23 non
dental students. All subjects received a single oral prophylaxis and were asked
not to brush their teeth for 48 h prior to their appointment. After the amount of
plaque had been evaluated at 6 sites per tooth, subjects brushed in a random
split-mouth order with the 2 electric toothbrushes, after which the amount of
plaque was re-evaluated. RESULTS: The results of the laboratory study showed
that, for all surfaces combined, the mean removal of plaque substitute for both
brushes was the same. However, at the vestibular and the approximal vestibular
surfaces, the reduction in plaque substitute was significantly higher (p<0.01)
with the Braun toothbrush compared to the Philips. In the clinical study, the
mean overall plaque reduction for the Braun toothbrush (74%) was significantly
higher than for the Philips (66%). Further analysis revealed that the significant
difference in favour of the Braun brush was mainly due to plaque removal from the
approximal vestibular and the approximal lingual sites. CONCLUSIONS: In
conclusion, both the laboratory and clinical study show that the Braun Oral-B
Ultra Plaque Remover (D9) is more effective than the Philips/Jordan HP 735. Both
study models indicate that this difference is greatest on the approximal
vestibular surfaces.
PMID- 10783844
TI - Calcium paradox disease: calcium deficiency prompting secondary
hyperparathyroidism and cellular calcium overload.
PMID- 10783845
TI - Trends in the incidence of hip fracture in Japan, 1987-1997: the third nationwide
survey.
AB - The third nationwide survey for hip fracture incidence was conducted in 1997
following the first such survey in 1987 and the second in 1992. The purpose of
this study was to investigate the trends in the incidence and regional
distribution of this disease during 10 years. Of 10271 orthopedic institutions in
Japan, 4503 were selected as subjects for the study using the optimum allocation
method. Questionnaires concerning new patients with hip fracture were mailed. The
replies were obtained from 2930 institutions by the end of December 1998; the
response rate was 65.1%. The number of new patients was estimated to be 89900
94900 [mean, 92400; 20100-21400 (20800) men and 69600-73600 (71600) women]. The
number of cases in 1997 was about 1.7 times higher than that in the first survey
and 1.2 times higher than that in the second survey. The age-specific incidence
(per 10000 per year) in men and women in 1997 was 0.30 and 0.13, respectively,
for age under 40 years; 0.91 and 0.60, 40-49 years; 2.00 and 2.39, 50-59 years;
5.12 and 9.07, 60-69 years; 17.3 and 40.8, 70-79 years; 57.4 and 147.8, 80-89
years; and 128.9 and 281.0, for age over 90 years. The incidence was increased
compared with that of the first survey, and similar to the second survey,
excepting that of women aged 80 years or older. Concerning regional differences,
hip fracture incidence was relatively low in the eastern area compared to the
western area in Japan, which was a trend identical to that in the previous
nationwide surveys.
PMID- 10783846
TI - Patterns of gene expression associated with BMP-2-induced osteoblast and
adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A.
AB - The pluripotent mesenchymal stem cells give rise to osteoblasts, adipocytes,
chondrocytes, and myoblasts. The differentiation of these stem cells into each of
the mature functional cells may be controlled by a distinctive master gene(s) and
is associated with temporal and spatial expression of diverse genes.
Identification of genes that are expressed during the differentiation of the
mesenchymal cells to osteoblasts is, therefore, important to obtain insights into
the molecular mechanisms of osteogenesis. The murine undifferentiated mesenchymal
cell 3T3-F442A, when treated with the bone morphogenetic protein 2 (BMP-2), a
well-characterized inducer of mesenchymal cell differentiation, exhibited both
osteoblastic and adipocytic differentiation. Using the SAGE (serial analysis of
gene expression) technique, which has been shown to enable quantitative analysis
of large numbers of genes in a simple and quick manner, we obtained 1600 sequence
tags representing 2107 individual nucleotide sequences from control and BMP-2
treated 3T3-F442A cells, respectively. By comparing the frequency of tag
occurrence, we found profiles of up- or downregulated genes associated with
osteoblast or adipocyte phenotype such as type I collagen, osteonectin and OSF-2,
or C/EBPbeta, aP2, fatty acid synthase, and lipoprotein lipase, respectively, in
BMP-2-treated 3T3-F442A cells. Our data show that BMP-2 induces not only
osteoblastic but also adipocytic differentiation in the 3T3-F442A cells. They
also show that the 3T3-F442A cells have bipotentials of differentiating toward
osteoblasts and adipocytes. The results, therefore, might explain the inverse
correlation between trabecular bone volume and fat volume in the bone marrow
cavity. The results also suggest that the SAGE may be a useful technique that
allows us a fast and efficient way to generate global and local views of gene
expression associated with cellular differentiation of the mesenchymal stem
cells.
PMID- 10783847
TI - Ultrastructural study on calcification of cartilage: comparing ICR and twy mice.
AB - Twy mice are autosomal recessive mutant mice that develop multiple progressive
abnormal calcification, mainly of the cartilage or tendons of the spine and
limbs. They finally succumb to severe deformation and ankylosis. We carried out
an ultrastructural study on the growth plate as well as the articular and spinal
disc cartilage of twy mice and control ICR mice. Knee and spinal specimens were
obtained from the animals, then prepared using standard procedures.
Ultrastructural observations were made on uranyl lead-stained sections and
elemental analysis was carried out on unstained sections. In both twy and ICR
mice, linked granules (chain granules) were observed at the pericellular matrix,
but there was no remarkable difference between their presence in the growth
cartilage. In the twy mice, however, chain granules were observed in the
pericellular matrix, cytoplasm, and nucleus of the articular and spinal disc
cartilage. These chain granules disappeared after decalcification. Elemental
analyses revealed significant amounts of calcium and phosphorus in these
granules. It may be significant for abnormal calcification that such chain
granules were observed in the articular and spinal disc cartilage of twy mice.
PMID- 10783848
TI - Osteoclastic resorption of equine cranial and postcranial bone in vitro.
AB - To address possible differences in the resorbability of cranial and postcranial
bone, slices of equine frontal bone and leg (first phalanx or third metacarpus)
were seeded with embryonic chick bone cells and cultured for 20-24h. After
removing the cells and drying the specimens, the areas and volumes of more than
800 resorption pits in each set were measured using a video-rate reflection
confocal microscope system. Relative mineralization densities were determined by
quantitative electron backscattering analysis. The mean mineralization density
was greater in the leg bone, but the mean depths for resorption pits in frontal
bone were smaller (median volume/area ratios, experiment 1 and experiment 2: 1.98
microm frontal and 3.79 microm leg versus 2.70 microm and 4.20 microm,
respectively; P < 0.0001, Mann-Whitney), even though the areas were greater in
the frontal (medians, 286 microm2 and 324 microm2, versus 242 microm2 and 201
microm2; P < 0.0001). This study has shown a difference between cranial and
postcranial equine bone in the shape and size of resorption pits formed in vitro.
Overall, it has shown that cranial bone may be resorbed at least as readily as
postcranial bone. This result is counter to the clinical impression that cranial
bone has a greater staying power than postcranial bone when used as a grafting
material.
PMID- 10783849
TI - Identification of a novel polymorphism of estrogen receptor-alpha gene that is
associated with calcium excretion in urine.
AB - A novel variation of the estrogen receptor-alpha (ERalpha) gene was identified by
polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP).
It is one base substitution in codon 325 (CCC [allele M] to CCG [allele m]) in
exon 4 of the human ERalpha gene. This substitution did not cause an amino acid
change. We categorized 306 unrelated Japanese postmenopausal women into three
genotypes: MM, Mm, and mm; the frequency of each genotype was 26.5%, 43.1%, and
30.4%, respectively. Then, the association of this polymorphism with bone mineral
density (BMD) of lumbar spine and bone-calcium metabolic markers was studied.
There was no significant difference in BMD of the lumbar spine or most of the
bone metabolic markers. However, the urinary calcium (Ca) excretion ratio (u
Ca/Cre) corrected by creatinine was significantly lower in the genotype mm group
compared with the genotype MM group (MM vs mm, 0.247 +/-0.158 vs 0.200 +/- 0.105;
P < 0.05). We examined the relationship of restriction fragment length
polymorphisms (RFLPs) (PvuII, XbaI) in intron 1 and the polymorphism in exon 4.
The frequency of genotype MM was higher in the genotype PPxx, which was reported
to be associated with lower BMD in the same population of Japanese postmenopausal
women. The ER polymorphism identified in this study might be related to some
biological mechanisms that regulate calcium metabolism.
PMID- 10783850
TI - Comparison of various biochemical measurements with bone mineral densitometry and
quantitative ultrasound for the assessment of vertebral fracture.
AB - We have retrospectively studied postmenopausal elderly Japanese women (n = 288;
age range, 60-75 years, 65.8 +/- 4.5 [mean +/- SD]) for the evaluation of
biochemical measurements in assessment of bone mass and vertebral fracture,
comparing with several bone mineral measurements and quantitative ultrasound
(QUS) measurement. Several biochemical parameters [red cell count (RBC),
hemoglobin (HB), albumin (ALB), and cholesterol (CHO)] positively correlated with
bone mass parameters, but only serum cholesterol showed association with the
presence of vertebral fracture. Urinary deoxypyridinoline (DPYD) and n
telopeptide (NTx) showed moderate negative correlation with bone mass parameters,
and DPYD showed association with vertebral fracture. All bone mineral
measurements (lumbar spine, total body, femoral neck by DXA, calcaneal bone by
SXA, distal radius by pQCT) and QUS measurement (os calcaneus by two different
QUS machines) showed a higher odds ratio and high chi2 value in logistic
regression analysis for association with vertebral fracture. Thus, bone mass
measurement is the principal method for assessment of fracture risk, and
biochemical measurement should be used for motivation of further bone mass
measurement. In biochemical measurements, measurement of serum cholesterol is
cheap and easy, and thus might have an advantage, although further study is
necessary.
PMID- 10783851
TI - Increase of intestinal calcium absorption and bone mineral density by heated
algal ingredient (HAI) in rats.
AB - Active absorbable calcium (AAACa) produced by adding HAI (heated algal
ingredient) to oyster shell calcium (AACa) is quite efficiently absorbed from the
intestine and can increase bone mineral density in elderly osteoporotic patients.
HAI was produced by heating the seaweed Cystophyllum fusiforme under reduced
pressure, extracting with 6N HCL, and partially neutralizing it. Butanol-ethanol
extraction then yielded active HAI fraction A, corresponding to about 1% in
weight. The active HAI fraction increased intestinal Ca absorption as shown by a
dose-dependent increase of plasma Ca in young male parathyroidectomized rats
maintained on a low-Ca diet by administration through a stomach tube with a
constant dose of AACa. The action of the active fraction A to maintain bone mass
was then tested in young male rats kept on a low-Ca diet for 2 weeks. Bone
weight, trabecular bone density, and strength-strain index as indices of bone
strength measured by peripheral computed tomography (pQCT) tended to increase
when the active HAI fraction was given along with Ca. HAI increased intestinal Ca
absorption and prevented the decrease of bone density in rats kept on a low-Ca
diet.
PMID- 10783852
TI - The relationship between spinal and appendicular bone mass modified by physical,
historical, and lifestyle factors.
AB - Spinal, radial, and calcaneal bone mineral density (BMD) measured by dual-energy
X-ray absorptiometry (DXA) and calcaneal bone mass measured by quantitative
ultrasound densitometry (QUS) were compared in 83 healthy Japanese female
volunteers. A significant and strong correlation was found within the same
methods (r = 0.619 for lumbar spine and radius by DXA, r = 0.760 for lumbar spine
and calcaneus by DXA, and r = 0.644 for calcaneus and radius by DXA), and within
the same site (r = 0.758 for calcaneus by DXA and QUS). A lesser correlation was
found when both the method and site were different (r = 0.521 for radius by DXA
and calcaneus by QUS, and r = 0.583 for lumbar spine by DXA and calcaneus by
QUS). Relations of spinal and appendicular bone mass were examined together with
physical, historical, and lifestyle factors. Multiple correlation coefficients
between bone mass at the lumbar spine and appendicular bone were 0.754 to 0.782,
and all these increased after modification by physical, historical, and lifestyle
factors in whichever appendicular bone. In the correlation between lumbar spine
and radial BMD, past weight-bearing activity, age at menarche, family history of
fractures, and body weight were chosen. Menstrual status, body weight, past
weight-bearing activity, and present arm-using activity were chosen to determine
the correlation between lumbar spine BMD and calcaneal bone mass by QUS. These
results suggest that the incorporation of those factors improved the correlation
between lumbar spine BMD and appendicular bone mass, especially in cases of
lumbar spine BMD versus radial BMD or calcaneal bone mass by QUS.
PMID- 10783854
TI - Framework lives, but does it learn?
PMID- 10783853
TI - Critics of 'gene foods' report are avoiding the real issues.
PMID- 10783855
TI - Critics challenge Celera's claims over human genome sequence...as biotech debate
splits along party lines.
PMID- 10783856
TI - US academy study finds GM foods are safe...but critics claim the panel was
biased.
PMID- 10783857
TI - Music software to come to genome aid?
PMID- 10783858
TI - Frustration grows over EU grant application procedures.
PMID- 10783859
TI - Deaths bring South African HIV drug trials to a premature halt.
PMID- 10783860
TI - Fake bird fossil highlights the problem of illegal trading.
PMID- 10783861
TI - Affymetrix loses first round of patent battle.
PMID- 10783862
TI - Storming the Tower of Babel.
PMID- 10783863
TI - Technology failures were caused by managers not listening to engineers.
PMID- 10783864
TI - No conflict between SLAC and Japan's KEK. Stanford Linear Accelerator Center
PMID- 10783865
TI - Venture funding for new ideas
PMID- 10783866
TI - Regenesis
PMID- 10783867
TI - Perfect use of imperfection.
PMID- 10783868
TI - Chaos in space and time
PMID- 10783869
TI - Plant biology. Shattering developments.
PMID- 10783870
TI - High-temperature superconductivity. Stripes defeat the Fermi liquid
PMID- 10783871
TI - Recognizing DNA in the library.
PMID- 10783872
TI - Freezing by heating
PMID- 10783873
TI - Immunology. Commit ye helpers.
PMID- 10783874
TI - Delaying the onset of Huntington's in mice.
PMID- 10783875
TI - Hexadecane decay by methanogenesis.
PMID- 10783876
TI - Parasitic honeybees get royal treatment.
PMID- 10783877
TI - Specificities of heparan sulphate proteoglycans in developmental processes.
AB - Heparan sulphate proteoglycans are abundant cell-surface molecules that consist
of a protein core to which heparan sulphate glycosaminoglycan chains are
attached. The functions of these molecules have remained mostly underappreciated
by developmental biologists; however, the actions of important signalling
molecules, for example Wnt and Hedgehog, depend on them. To understand both the
mechanisms by which ligands involved in development interact with their receptors
and how morphogens pattern tissues, biologists need to consider the functions of
heparan sulphate proteoglycans in signalling and developmental patterning.
PMID- 10783878
TI - One-dimensional nature of the magnetic fluctuations in YBa2Cu3O6.6
AB - There is increasing evidence that inhomogeneous distributions of charge and spin-
so-called 'striped phases'--play an important role in determining the properties
of the high-temperature superconductors. For example, recent neutron-scattering
measurements on the YBa2Cu3O(7-x) family of materials show both spin and charge
fluctuations that are consistent with the striped-phase picture. But the
fluctuations associated with a striped phase are expected to be one-dimensional,
whereas the magnetic fluctuations observed to date appear to display two
dimensional symmetry. We show here that this apparent two-dimensionality results
from measurements on twinned crystals, and that similar measurements on
substantially detwinned crystals of YBa2Cu3O6.6 reveal the one-dimensional
character of the magnetic fluctuations, thus greatly strengthening the striped
phase interpretation. Moreover, our results also suggest that superconductivity
originates in charge stripes that extend along the b crystal axis, where the
superfluid density is found to be substantially larger than for the a direction.
PMID- 10783879
TI - Magnetic field surrounding the starburst nucleus of the galaxy M82 from polarized
dust emission
AB - Magnetic fields may play an important role in the star-formation process,
especially in the central regions of 'starburst' galaxies where star formation is
vigorous. But the field directions are very difficult to determine in the dense
molecular gas out of which the stars form, so it has hitherto been impossible to
test this hypothesis. Dust grains in interstellar clouds tend to be magnetically
aligned, and it is possible to determine the alignment direction based on the
polarization of optical light due to preferential extinction along the long axes
of the aligned grains. This technique works, however, only for diffuse gas, not
for the dense molecular gas. Here we report observations of polarized thermal
emission from the aligned dust grains in the central region of M82, which
directly traces the magnetic field structure (as projected onto the plane of the
sky). Organized field lines are seen around the brightest star-forming regions,
while in the dusty halo the field lines form a giant magnetic bubble possibly
blown out by the galaxy's 'superwind'.
PMID- 10783880
TI - Mechanisms of extensive spatiotemporal chaos in Rayleigh-Benard convection
AB - Spatially extended dynamical systems exhibit complex behaviour in both space and
time--spatiotemporal chaos. Analysis of dynamical quantities (such as fractal
dimensions and Lyapunov exponents) has provided insights into low-dimensional
systems; but it has proven more difficult to understand spatiotemporal chaos in
high-dimensional systems, despite abundant data describing its statistical
properties. Initial attempts have been made to extend the dynamical approach to
higher-dimensional systems, demonstrating numerically that the spatiotemporal
chaos in several simple models is extensive (the number of dynamical degrees of
freedom scales with the system volume). Here we report a computational
investigation of a phenomenon found in nature, 'spiral defect' chaos in Rayleigh
Benard convection, in which we find that the spatiotemporal chaos in this state
is extensive and characterized by about a hundred dynamical degrees of freedom.
By studying the detailed space-time evolution of the dynamical degrees of
freedom, we find that the mechanism for the generation of chaotic disorder is
spatially and temporally localized to events associated with the creation and
annihilation of defects.
PMID- 10783881
TI - Phase transitions in the incoherent lattice fluctuations in YBa2Cu3O(7-delta)
AB - The growing body of experimental evidence for the existence of complex textures
of charges and spins in the high-temperature superconductors has drawn attention
to the so-called 'stripe-phase' models as a possible basis for the mechanism of
superconductivity in these materials. Such observations have until now been
restricted to systems where the texture dynamics are slow or suppressed
altogether, and do not include the important case of YBa2Cu3O(7-delta). It seems
likely that the dynamic behaviour of stripes, which has been suggested to undergo
several phase transitions as a function of temperature, should also be reflected
in the lattice properties of the host materials, and this forms the motivation
for our present experiments. Specifically, we use MeV helium ion channelling, an
ultrafast real-space probe of atomic displacements (with sub-picometre
resolution), to probe incoherent lattice fluctuations in YBa2Cu3O(7-delta) as a
function of temperature and oxygen doping. We detect lattice fluctuations that
are larger than the expected thermal vibration component, and which show
anomalies characteristic of the phase transitions anticipated for a dynamic
stripe phase. Comparison of our lattice results with single-particle-tunnelling
and photoemission data highlights the importance of spin-charge separation
phenomena in the copper oxide superconductors.
PMID- 10783882
TI - Complete photonic bandgaps in 12-fold symmetric quasicrystals
AB - Photonic crystals are attracting current interest for a variety of reasons, such
as their ability to inhibit the spontaneous emission of light. This and related
properties arise from the formation of photonic bandgaps, whereby multiple
scattering of photons by lattices of periodically varying refractive indices acts
to prevent the propagation of electromagnetic waves having certain wavelengths.
One route to forming photonic crystals is to etch two-dimensional periodic
lattices of vertical air holes into dielectric slab waveguides. Such structures
can show complete photonic bandgaps, but only for large-diameter air holes in
materials of high refractive index (such as gallium arsenide, n = 3.69), which
unfortunately leads to significantly reduced optical transmission when combined
with optical fibres of low refractive index. It has been suggested that
quasicrystalline (rather than periodic) lattices can also possess photonic
bandgaps. Here we demonstrate this concept experimentally and show that it
enables complete photonic bandgaps--non-directional and for any polarization--to
be realized with small air holes in silicon nitride (n = 2.02), and even glass (n
= 1.45). These properties make photonic quasicrystals promising for application
in a range of optical devices.
PMID- 10783883
TI - Manipulation of atoms across a surface at room temperature
AB - Since the realization that the tips of scanning probe microscopes can interact
with atoms at surfaces, there has been much interest in the possibility of
building or modifying nanostructures or molecules directly from single atoms.
Individual large molecules can be positioned on surfaces, and atoms can be
transferred controllably between the sample and probe tip. The most complex
structures are produced at cryogenic temperatures by sliding atoms across a
surface to chosen sites. But there are problems in manipulating atoms laterally
at higher temperatures--atoms that are sufficiently well bound to a surface to be
stable at higher temperatures require a stronger tip interaction to be moved.
This situation differs significantly from the idealized weakly interacting tips
of scanning tunnelling or atomic force microscopes. Here we demonstrate that
precise positioning of atoms on a copper surface is possible at room temperature.
The triggering mechanism for the atomic motion unexpectedly depends on the
tunnelling current density, rather than the electric field or proximity of tip
and surface.
PMID- 10783884
TI - Self-assembly of nanoparticles into structured spherical and network aggregates
AB - Multi-scale ordering of materials is central for the application of molecular
systems in macroscopic devices. Self-assembly based on selective control of non
covalent interactions provides a powerful tool for the creation of structured
systems at a molecular level, and application of this methodology to
macromolecular systems provides a means for extending such structures to
macroscopic length scale. Monolayer-functionalized nanoparticles can be made with
a wide variety of metallic and non-metallic cores, providing a versatile building
block for such approaches. Here we present a polymer-mediated 'bricks and mortar'
strategy for the ordering of nanoparticles into structured assemblies. This
methodology allows monolayer-protected gold particles to self-assemble into
structured aggregates while thermally controlling their size and morphology.
Using 2-nm gold particles as building blocks, we show that spherical aggregates
of size 97 +/- 17 nm can be produced at 23 degrees C, and that 0.5-1 microm
spherical assemblies with (5-40) x 10(5) individual subunits form at -20 degrees
C. Intriguingly, extended networks of approximately 50-nm subunits are formed at
10 degrees C, illustrating the potential of our approach for the formation of
diverse structural motifs such as wires and rods. These findings demonstrate that
the assembly process provides control over the resulting aggregates, while the
modularity of the 'bricks and mortar' approach allows combinatorial control over
the constituents, providing a versatile route to new materials systems.
PMID- 10783885
TI - Subduction erosion along the Middle America convergent margin
AB - 'Subduction erosion' has been invoked to explain material missing from some
continents along convergent margins. It has been suggested that this form of
tectonic erosion removes continental material at the front of the margin or along
the underside of the upper (continental) plate. Frontal erosion is interpreted
from disrupted topography at the base of a slope and is most evident in the wake
of subducting seamounts. In contrast, structures resulting from erosion at the
base of a continental plate are seldom recognized in seismic reflection images
because such images typically have poor resolution at distances greater than
approximately 5 km from the trench axis. Basal erosion from seamounts and ridges
has been inferred, but few large subducted bodies--let alone the eroded base of
the upper plate--are imaged convincingly. From seismic images we identify here
two mechanisms of basal erosion: erosion by seamount tunnelling and removal of
large rock lenses of a distending upper plate. Seismic cross-sections from Costa
Rica to Nicaragua indicate that erosion may extend along much of the Middle
America convergent margin.
PMID- 10783886
TI - Quantitative evidence for global amphibian population declines.
AB - Although there is growing concern that amphibian populations are declining
globally, much of the supporting evidence is either anecdotal or derived from
short-term studies at small geographical scales. This raises questions not only
about the difficulty of detecting temporal trends in populations which are
notoriously variable, but also about the validity of inferring global trends from
local or regional studies. Here we use data from 936 populations to assess large
scale temporal and spatial variations in amphibian population trends. On a global
scale, our results indicate relatively rapid declines from the late 1950s/early
1960s to the late 1960s, followed by a reduced rate of decline to the present.
Amphibian population trends during the 1960s were negative in western Europe
(including the United Kingdom) and North America, but only the latter populations
showed declines from the 1970s to the late 1990s. These results suggest that
while large-scale trends show considerable geographical and temporal variability,
amphibian populations are in fact declining--and that this decline has been
happening for several decades.
PMID- 10783887
TI - The metapopulation capacity of a fragmented landscape.
AB - Ecologists and conservation biologists have used many measures of landscape
structure to predict the population dynamic consequences of habitat loss and
fragmentation, but these measures are not well justified by population dynamic
theory. Here we introduce a new measure for highly fragmented landscapes, termed
the metapopulation capacity, which is rigorously derived from metapopulation
theory and can easily be applied to real networks of habitat fragments with known
areas and connectivities. Technically, metapopulation capacity is the leading
eigenvalue of an appropriate 'landscape' matrix. A species is predicted to
persist in a landscape if the metapopulation capacity of that landscape is
greater than a threshold value determined by the properties of the species.
Therefore, metapopulation capacity can conveniently be used to rank different
landscapes in terms of their capacity to support viable metapopulations. We
present an empirical example on multiple networks occupied by an endangered
species of butterfly. Using this theory, we may also calculate how the
metapopulation capacity is changed by removing habitat fragments from or adding
new ones into specific spatial locations, or by changing their areas. The
metapopulation capacity should find many applications in metapopulation ecology,
landscape ecology and conservation biology.
PMID- 10783888
TI - Asymmetric redirection of flow through the heart.
AB - Through cardiac looping during embryonic development, paths of flow through the
mature heart have direction changes and asymmetries whose topology and functional
significance remain relatively unexplored. Here we show, using magnetic resonance
velocity mapping, the asymmetric redirection of streaming blood in atrial and
ventricular cavities of the adult human heart, with sinuous, chirally asymmetric
paths of flow through the whole. On the basis of mapped flow fields and drawings
that illustrate spatial relations between flow paths, we propose that asymmetries
and curvatures of the looped heart have potential fluidic and dynamic advantages.
Patterns of atrial filling seem to be asymmetric in a manner that allows the
momentum of inflowing streams to be redirected towards atrio-ventricular valves,
and the change in direction at ventricular level is such that recoil away from
ejected blood is in a direction that can enhance rather than inhibit ventriculo
atrial coupling. Chiral asymmetry might help to minimize dissipative interaction
between entering, recirculating and outflowing streams. These factors might
combine to allow a reciprocating, sling-like, 'morphodynamic' mode of action to
come into effect when heart rate and output increase during exercise.
PMID- 10783889
TI - Interruption of a basal ganglia-forebrain circuit prevents plasticity of learned
vocalizations.
AB - Birdsong, like speech, is a learned vocal behaviour that relies greatly on
hearing; in both songbirds and humans the removal of auditory feedback by
deafening leads to a gradual deterioration of adult vocal production. Here we
investigate the neural mechanisms that contribute to the processing of auditory
feedback during the maintenance of song in adult zebra finches. We show that the
deleterious effects on song production that normally follow deafening can be
prevented by a second insult to the nervous system--the lesion of a basal ganglia
forebrain circuit. The results suggest that the removal of auditory feedback
leads to the generation of an instructive signal that actively drives non
adaptive changes in song; they also suggest that this instructive signal is
generated within (or conveyed through) the basal ganglia-forebrain pathway. Our
findings provide evidence that cortical-basal ganglia circuits may participate in
the evaluation of sensory feedback during calibration of motor performance, and
demonstrate that damage to such circuits can have little effect on previously
learned behaviour while conspicuously disrupting the capacity to adaptively
modify that behaviour.
PMID- 10783890
TI - SHATTERPROOF MADS-box genes control seed dispersal in Arabidopsis.
AB - The fruit, which mediates the maturation and dispersal of seeds, is a complex
structure unique to flowering plants. Seed dispersal in plants such as
Arabidopsis occurs by a process called fruit dehiscence, or pod shatter. Few
studies have focused on identifying genes that regulate this process, in spite of
the agronomic value of controlling seed dispersal in crop plants such as canola.
Here we show that the closely related SHATTERPROOF (SHP1) and SHATTERPROOF2
(SHP2) MADS-box genes are required for fruit dehiscence in Arabidopsis. Moreover,
SHP1 and SHP2 are functionally redundant, as neither single mutant displays a
novel phenotype. Our studies of shp1 shp2 fruit, and of plants constitutively
expressing SHP1 and SHP2, show that these two genes control dehiscence zone
differentiation and promote the lignification of adjacent cells. Our results
indicate that further analysis of the molecular events underlying fruit
dehiscence may allow genetic manipulation of pod shatter in crop plants.
PMID- 10783891
TI - Rapid degradation of a large fraction of newly synthesized proteins by
proteasomes.
AB - MHC class I molecules function to present peptides eight to ten residues long to
the immune system. These peptides originate primarily from a cytosolic pool of
proteins through the actions of proteasomes, and are transported into the
endoplasmic reticulum, where they assemble with nascent class I molecules. Most
peptides are generated from proteins that are apparently metabolically stable. To
explain this, we previously proposed that peptides arise from proteasomal
degradation of defective ribosomal products (DRiPs). DRiPs are polypeptides that
never attain native structure owing to errors in translation or post
translational processes necessary for proper protein folding. Here we show,
first, that DRiPs constitute upwards of 30% of newly synthesized proteins as
determined in a variety of cell types; second, that at least some DRiPs represent
ubiquitinated proteins; and last, that ubiquitinated DRiPs are formed from human
immunodeficiency virus Gag polyprotein, a long-lived viral protein that serves as
a source of antigenic peptides.
PMID- 10783892
TI - The major substrates for TAP in vivo are derived from newly synthesized proteins.
AB - The transporter associated with antigen processing (TAP) is a member of the
family of ABC transporters that translocate a large variety of substrates across
membranes. TAP transports peptides from the cytosol into the endoplasmic
reticulum for binding to MHC class I molecules and for subsequent presentation to
the immune system. Here we follow the lateral mobility of TAP in living cells.
TAP's mobility increases when it is inactive and decreases when it translocates
peptides. Because TAP activity is dependent on substrate, the mobility of TAP is
used to monitor the intracellular peptide content in vivo. Comparison of the
diffusion rates in peptide-free and peptide-saturated cells indicates that
normally about one-third of all TAP molecules actively translocate peptides.
However, during an acute influenza infection TAP becomes fully employed owing to
the production and degradation of viral proteins. Furthermore, TAP activity
depends on continuing protein translation. This implies that MHC class I
molecules mainly sample peptides that originate from newly synthesized proteins,
to ensure rapid presentation to the immune system.
PMID- 10783893
TI - NAK is an IkappaB kinase-activating kinase.
AB - Phosphorylation of IkappaB by the IkappaB kinase (IKK) complex is a critical step
leading to IkappaB degradation and activation of transcription factor NF-kappaB.
The IKK complex contains two catalytic subunits, IKKalpha and IKKbeta, the latter
being indispensable for NF-kappaB activation by pro-inflammatory cytokines.
Although IKK is activated by phosphorylation of the IKKbeta activation loop, the
physiological IKK kinases that mediate responses to extracellular stimuli remain
obscure. Here we describe an IKK-related kinase, named NAK (NF-kappaB-activating
kinase), that can activate IKK through direct phosphorylation. NAK induces
IkappaB degradation and NF-kappaB activity through IKKbeta. Endogenous NAK is
activated by phorbol ester tumour promoters and growth factors, whereas
catalytically inactive NAK specifically inhibits activation of NF-kappaB by
protein kinase C-epsilon (PKCepsilon). Thus, NAK is an IKK kinase that may
mediate IKK and NF-kappaB activation in response to growth factors that stimulate
PKCepsilon activity.
PMID- 10783894
TI - AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and
PKB through p27kip1.
AB - The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF
16, a Forkhead factor that regulates longevity in Caenorhabditis elegans. Here we
show that overexpression of these Forkhead transcription factors causes growth
suppression in a variety of cell lines, including a Ras-transformed cell line and
a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell
cycle progression at phase G1, independent of functional retinoblastoma protein
(pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX
transcriptionally activates p27kip1, resulting in increased protein levels. We
conclude that AFX-like proteins are involved in cell-cycle regulation and that
inactivation of these proteins is an important step in oncogenic transformation.
PMID- 10783896
TI - Universities encourage industrialists to come back to their roots.
PMID- 10783895
TI - Normalizing mitochondrial superoxide production blocks three pathways of
hyperglycaemic damage.
AB - Diabetic hyperglycaemia causes a variety of pathological changes in small
vessels, arteries and peripheral nerves. Vascular endothelial cells are an
important target of hyperglycaemic damage, but the mechanisms underlying this
damage are not fully understood. Three seemingly independent biochemical pathways
are involved in the pathogenesis: glucose-induced activation of protein kinase C
isoforms; increased formation of glucose-derived advanced glycation end-products;
and increased glucose flux through the aldose reductase pathway. The relevance of
each of these pathways is supported by animal studies in which pathway-specific
inhibitors prevent various hyperglycaemia-induced abnormalities. Hyperglycaemia
increases the production of reactive oxygen species inside cultured bovine aortic
endothelial cells. Here we show that this increase in reactive oxygen species is
prevented by an inhibitor of electron transport chain complex II, by an uncoupler
of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide
dismutase. Normalizing levels of mitochondrial reactive oxygen species with each
of these agents prevents glucose-induced activation of protein kinase C,
formation of advanced glycation end-products, sorbitol accumulation and NFkappaB
activation.
PMID- 10783897
TI - Georgia realizes the commercial potential of science.
PMID- 10783898
TI - Estrogen and substrate metabolism: a review of contradictory research.
AB - The increasing number of females participating in physical activity has
heightened our awareness of changes in the menstrual cycle which often accompany
physical activity. As such, there has been a considerable amount of research
investigating the relationships between menstrual cycle changes and bone mineral
density, performance, ventilation and substrate metabolism. A number of
researchers have concluded that there may be enhanced fat metabolism in
eumenorrhoeic versus amenorrhoeic females, or in the follicular phase versus the
luteal phase of the menstrual cycle, due to the theoretical estrogen level in
eumenorrhoeic versus amenorrhoeic females or the luteal phase versus the
follicular phase. However, a definite relationship between resting estrogen level
and substrate metabolism has not been clearly established. In addition, the
mechanisms which may be responsible for the effect of estrogen on substrate
metabolism have not been addressed. It appears that the effects of estrogen on
metabolism may be via the effect of estrogen on glucogenic hormones or lipolytic
enzymes. Therefore, the primary purpose of this review is to explore the effects
of estrogen on substrate metabolism. Menstrual cycle physiology and possible
mechanisms for the effects of estrogen on metabolism, as well as previous
research on estrogen and metabolism in rats and humans, will be discussed.
PMID- 10783900
TI - The physically-challenged athlete: medical issues and assessment.
AB - The rate and pattern of injuries is similar in both physically-challenged and
able-bodied athletic participation. However, understanding of the unique medical
issues faced by physically-challenged athletes is necessary in conducting
appropriate pre-participation evaluations and developing strategies for injury
prevention and medical management. Review of the literature provides insight for
choosing relevant tests and interpreting components of the physical examination
for this population. More research is needed in the management of medical
problems specific to the physically-challenged athlete.
PMID- 10783899
TI - Maximising the clinical use of exercise gaseous exchange testing in children with
repaired cyanotic congenital heart defects: the development of an appropriate
test strategy.
AB - Implicit in deciding upon an exercise test strategy to elucidate cardiopulmonary
function in children with congenital heart disease are appropriate application of
gas exchange techniques and the significance of the data collected to the
specific congenital heart disorder. Post-operative cardiopulmonary responses to
exercise in cyanotic disorders are complex and, despite a large body of extant
literature in paediatric patients, there has been much difficulty in achieving
quality and consistency of data. Maximal oxygen uptake is widely recognised as
the best single indicator of cardiopulmonary function and has therefore been the
focus of most clinical exercise tests in children. Many children with various
heart anomalies are able to exercise to maximum without adverse symptoms, and it
is essential that test termination is based on the same criteria for these
children. Choosing appropriate, valid indicators of maximum in children with
congenital heart disease is beset by difficulties. Such maximal intensity
exercise testing procedures have been challenged on the grounds that they do not
give a good indication of cardiopulmonary function that is relevant to real life
situations. Furthermore, they are prone to much interindividual variability and
error in the definition of maximal exertion. Alternative strategies have been
proposed which focus upon dynamic submaximal and kinetic cardiopulmonary
responses, which are thought to be less dependent on maximal voluntary effort and
more suited to the daily activity patterns of children. These methods are also
not without problems. Variability in anaerobic threshold measurements and
controversy regarding its physiological meaning have been debated. It is
recommended that an appropriate cardiopulmonary exercise gas exchange test
strategy, which provides clinically useful information for children with cyanotic
congenital heart disease, should include both maximal and submaximal data. The
inclusion of oxygen uptake kinetics and ventilatory data are encouraged, since
they may allow the distinction between a pulmonary, cardiovascular or inactivity
related exercise limitation.
PMID- 10783901
TI - Effects of throwing overweight and underweight baseballs on throwing velocity and
accuracy.
AB - The purpose of this review is to determine how throwing overweight and
underweight baseballs affects baseball throwing velocity and accuracy. Two
studies examined how a warm-up with overweight baseballs affected throwing
velocity and accuracy of 5 oz regulation baseballs. One of these studies showed
significant increases in throwing velocity and accuracy, while the other study
found no significant differences. Three training studies (6 to 12 weeks in
duration) using overweight baseballs were conducted to determine how they
affected ball accuracy while throwing regulation baseballs. No significant
differences were found in any study. From these data it is concluded that warming
up or training with overweight baseballs does not improve ball accuracy. Seven
overweight and 4 underweight training studies (6 to 12 weeks in duration) were
conducted to determine how throwing velocity of regulation baseballs was affected
due to training with these overweight and underweight baseballs. The overweight
baseballs ranged in weight from 5.25 to 17 oz, while the underweight baseballs
were between 4 and 4.75 oz. Data from these training studies strongly support the
practice of training with overweight and underweight baseballs to increase
throwing velocity of regulation baseballs. Since no injuries were reported
throughout the training studies, throwing overweight and underweight baseballs
may not be more stressful to the throwing arm compared to throwing regulation
baseballs. However, since currently there are no injury data related to throwing
overweight and underweight baseballs, this should be the focus of subsequent
studies. In addition, research should be initiated to determine whether throwing
kinematics and kinetics are different between throwing regulation baseballs and
throwing overweight and underweight baseballs.
PMID- 10783903
TI - The Zone Diet and athletic performance.
PMID- 10783902
TI - Recurrent posterior thigh symptoms detrimental to performance in rugby union:
predisposing factors.
AB - Recurrent hamstring injury is a very common problem in rugby union, but has been
largely ignored in the literature. It is concluded that a multifactorial
aetiology may be present, and that these symptoms may be part of a continuum of
symptoms that may lead to more serious injuries. Effective management needs to
focus not just locally, but include proximal issues such as lumbo-pelvic
stability and correcting lumbar spine dysfunction. The factors addressed in a
prevention programme are likely to contribute to performance gains.
PMID- 10783904
TI - Examining glucose transport in single vascular smooth muscle cells with a
fluorescent glucose analog.
AB - Changes in vascular smooth muscle glucose transport are thought to contribute to
the pathogenesis of vascular disease in conditions such as diabetes, yet no
single-cell assay for glucose uptake by VSM exists. Therefore, we examined the
uptake of the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4
yl)amino]-2-deoxyglucose (2-NBDG) in isolated pig vascular smooth muscle cells
(VSMC) using digital imaging microscopy. Uptake of 2-NBDG by VSMC was inhibited
by D-glucose but not by L-glucose, suggesting that 2-NBDG enters VSMC via glucose
transporters. Uptake of 2-NBDG was linear in the presence of 10 mM D-glucose
(n=6, R2=0.9408) but not in its absence (n=4, R2=0.9993), indicating that 2-NBDG
is not metabolized and accumulates within the cells. 2-NBDG fluorescence in VSMC
was often non-uniform and appeared to represent binding of 2-NBDG to some
cytoplasmic component. The present study demonstrates that 2-NBDG is a useful
tool for examining vascular smooth muscle glucose uptake at the single cell
level.
PMID- 10783905
TI - Differences between cation-osmotic hemolysis and filterability in exaprolol- and
glutaraldehyde-treated human red blood cells.
AB - The changes in human red blood cell microrheology in different glutaraldehyde
(3.0 and 5.0 x 10(-6) mol x l(-1)) and exaprolol (2.5 and 5.0 x 10(-4) mol x l(
1)) concentrations were studied. The method of millipore filtration was compared
with the method of cation-osmotic hemolysis. Both drugs prolonged the filtration
time. Cation-osmotic hemolysis in glutaraldehyde-treated cells was significantly
lower in comparison with the control group. On the other hand, there was a
significant increase in cation-osmotic hemolysis in exaprolol-treated cells.
Besides cation-osmotic hemolysis and filterability of erythrocytes, we evaluated
the medium cell volume (MCV) and the medium cell hemoglobin concentration (MCHC).
No changes in MCV and MCHC in glutaraldehyde-treated cells were observed.
However, the MCV was significantly lower and the MCHC was significantly higher in
exaprolol-treated cells. In conclusion, we suggest that the method of cation
osmotic hemolysis is more sensitive than the filtration method for determination
of red blood cell microrheology.
PMID- 10783906
TI - Effects of nitric oxide donor, isosorbide dinitrate, on energy metabolism of rat
reticulocytes.
AB - Since nitric oxide (NO) in many cells is involved in energy metabolism, the aim
of this study was to evaluate the role of isosorbide dinitrate (ISDN), a NO
donor, in energy metabolism of rat reticulocytes, particularly due to their high
content of hemoglobin--an effective scavenger of NO. Rat reticulocyte-rich red
blood cell suspensions were aerobically incubated in the absence (control) or in
the presence of different concentrations of ISDN. ISDN decreased total and
coupled oxygen consumption (p<0.05) while increased uncoupled oxygen consumption
(p<0.05) in a dose- and time-dependent manner. This was followed by enhancement
of glycolysis, as measured by increased glucose consumption and lactate
accumulation (p<0.05). Levels of all glycolytic intermediates in the presence of
ISDN indicate only stimulation of pyruvate kinase activity. ISDN did not alter
the concentration of ATP, while increased ADP and AMP levels (p>0.05). In rat
reticulocytes under steady-state conditions, 95.4% of overall energy was produced
by oxidative phosphorylation but only 4.6% by glycolysis. Due to a reduced
coupled oxygen consumption in the presence of ISDN, ATP production via oxidative
phosphorylation was significantly diminished. A simultaneous increase of
glycolytic ATP production is not enough to ensure constant ATP production. The
calculated mean ATP turnover time was prolonged by 199% in the presence of 1.5
mmol/l ISDN. In conclusion, ISDN a) inhibited total and coupled respiration but
enhanced uncoupled respiration, b) stimulated glycolysis, c) decreased ATP
production and d) prolonged ATP turnover time in rat reticulocytes. These effects
were mediated by NO as the effector molecule.
PMID- 10783907
TI - Enalapril in subantihypertensive dosage attenuates kidney proliferation and
functional recovery in normotensive ablation nephropathy of the rat.
AB - Most studies on the antiproliferative action of angiotensin converting enzyme
inhibitors (ACEI) were performed in a rat hypertensive remnant kidney model with
5/6 kidney ablation which raised objections about the antihypertensive effect of
ACEI and the influence of other antihypertensive drugs administered to remnant
kidney control rats. To prevent these objections, a normotensive 4/6 remnant
kidney model was elaborated and a subantihypertensive dosage of enalapril was
used to evaluate its antiproliferative action. Subtotally nephrectomized rats
(Nx) markedly increased the remnant kidney weight during a 4-week period and this
rise was prevented by the treatment with enalapril (NxE) (Nx +297+/-35 mg vs.
sham-operated +145+/-32 mg, p<0.001; NxE +154+/-35 mg vs. Nx p<0.001). While
collagen concentration in the kidney cortex was not increased in sham-operated
rats (Sham) in comparison with the control group (Ctrl) at the beginning of the
study, the subsequent increase was significant in the Nx group and enalapril did
not attenuate this increase (Sham 148+/-5 mg/100 g w.w. vs. Nx 164+/-2 mg/100 g
w.w., p<0.01; NxE 161+/-4 mg/100 g w.w. vs. Sham p<0.05). The tubular protein/DNA
ratio increase, which was significant in the Nx group, was inhibited by enalapril
(Nx 26.2+/-10.5 vs. NxE 15.3+/-2.6, p<0.05). The protein/DNA ratio was much lower
in glomeruli, with no significant changes in either the Nx or NxE groups. Serum
urea concentrations were slightly higher in the Nx group than in the sham
operated group, but markedly elevated in the NxE group (Nx 10.71+/-0.76 mmol/l
vs. Sham 6.10+/-0.33 mmol/l, p<0.001; NxE 28.9+/-2.6 mmol/l vs. Sham p<0.001).
Creatinine concentrations in the Nx group were increased in comparison with the
sham-operated group and markedly increased in the NxE group (Nx 63.7+/-3.56
micromol/l vs. Sham 37.2+/-2.84 micromol/l, p<0.001; NxE 107.0+/-5.2 micromol/l
vs. Sham p<0.001). The clearance of creatinine was lower in the Nx group than in
the sham-operated group and was markedly reduced in the NxE group (Nx 0.89+/-0.06
ml/min.g kidney wt. vs. Sham 1.05+/-0.16 ml/min x g kidney wt., p<0.01; NxE
0.58+/-0.029 ml/min x g kidney wt. vs. Sham, p<0.001). Enalapril improved
proteinuria in comparison with the Nx group (NxE 5.6+/-0.6 mg/24 h vs. Nx 16.1+/
3.4 mg/24 h, p<0.05). Thus remnant kidney proliferation is substantial even in
normotensive rats. It includes both proliferation and collagen accumulation with
partial recovery of kidney weight and function, but is accompanied by enhanced
proteinuria. Enalapril attenuates the proliferation and decreases proteinuria but
prolongs kidney function recovery.
PMID- 10783908
TI - Nephrotoxicity of cyclosporin A in hereditary hypertriglyceridemic rats.
AB - It has been suggested that cyclosporin A (CsA) nephrotoxicity can be reduced by
the concomitant administration of omega-3 fatty acids or vitamin E. The present
study was designed to establish whether the effect of the above substances can
also be demonstrated in rats with hereditary hypertriglyceridemia (HTG) whose
sensitivity to the nephrotoxic effect is greater than in control AVN rats. CsA
administration at a dose of 10 mg/kg/day to HTG rats resulted in a significant
rise (p<0.001) in serum levels of creatinine (from 66.0+/-7.6 to 108.4+/-11.6
micromol/l) and urea (from 8.3+/-0.7 to 22.3+/-18 mmol/l) which was not found in
AVN rats. The baseline values of systolic blood pressure (SBP) were significantly
higher in HTG rats. However, in both strains CsA administration was associated
with a similar SBP increase which was not prevented by omega-3 fatty acids (EPAX)
or vitamin E administration. Concomitant administration of CsA with EPAX at a
dose of 600 mg/kg b.w./day in HTG rats prevented the rise in the serum levels of
creatinine (65.4+/-14.7 micromol/l) and reduced the increase in the serum urea
levels (11.9+/-7.6 mmol/l). Concomitant administration of CsA and vitamin E (at a
dose of 25 mg/kg/day) also reduced the increase (p<0.05) in the serum levels of
creatinine (70.7+/-14.3 micromol/l) and urea (9.8+/-3.4 mmol/l) compared to the
effects elicited by the administration of CsA alone (p<0.05). Administration of
CsA alone or in combination with EPAX or vitamin E did not have a marked effect
on diuresis, proteinuria, urinary osmolality, urinary excretion of urea,
creatinine and potassium. Under all experimental conditions, the rate of urinary
excretion of sodium in HTG rats was significantly lower (p<0.01) than in AVN
rats. The results obtained support the assumption that omega-3 fatty acids and
vitamin E at the doses used reduce CsA nephrotoxicity in rats with hereditary
hypertriglyceridemia whose sensitivity to the nephrotoxic effect of CsA is
significantly higher than in AVN rats.
PMID- 10783909
TI - Hydrogen peroxide in the breath of rats: the effects of hypoxia and paraquat.
AB - The hypothesis that oxidative stress can be induced by hypoxia was tested by
measuring the concentration of hydrogen peroxide by a luminometric technique in
the breath samples of rats exposed to hypoxia and paraquat. The group of animals
(n=15) exposed to normobaric hypoxia (10% O2) for three days had an increased
amount of H2O2 (200%, P<0.001) in their breath in comparison to control animals.
After 7 days of recovery in air, the exposed animals still produced significantly
increased levels of H2O2 (152%, P<0.001). Paraquat administration was used as a
positive control, since it is a redox cycling compound producing free radicals.
In the animals treated with a toxic dose of paraquat, the peak H2O2 production
was observed 5 h after i.p. injection (156%, P<0.02). Within the next 2 h it
decreased to the control level and stayed constant for 48 h, when the animals
began to die. It is suggested that H2O2, observed in the breath samples, is a
product of a metabolic pathway that could itself be sensitive to oxidative
damage.
PMID- 10783910
TI - Role of intracerebroventricular vasopressin in the development of stress-induced
gastric lesions in rats.
AB - We investigated whether arginine vasopressin (AVP) has a central influence on the
development of gastric mucosal lesions evoked by restraint-cold stress in rats.
AVP and vasopressin V1 receptor antagonist were injected
intracerebroventricularly (i.c.v.) and the rats were exposed to restraint-cold
stress for five hours. After decapitation the stomachs were examined for gastric
mucosal lesions which were evaluated according to an ulcer score. Three different
doses of AVP and V1 receptor antagonist were administered in order to investigate
the effects of exogenous and endogenous AVP on stress-induced gastric mucosal
lesions. The intensity of gastric mucosal lesions was reduced when exogenous AVP
was injected intracerebroventricularly. On the other hand, vasopressin V1
receptor antagonist, which was administered by the same route, augmented gastric
mucosal lesions. Our findings indicate that AVP, injected centrally, plays a role
in preventing the formation of gastric mucosal lesions induced by stress via a
central V1 receptor.
PMID- 10783911
TI - Long- and medium-chain triacylglycerols in nutritional support of liver
regeneration of partially hepatectomized rats.
AB - An appropriate choice for a suitable diet during liver regeneration still remains
an enigma. To investigate the effect of isocaloric enteral feeding with medium
chain triacylglycerols (MCT) and long-chain triacylglycerols (LCT) supplement
(MCT+LCT, 40%:60% w:w) (178 kJ/kg b.w./24 h), rat liver regeneration was studied
24 and 72 h after partial hepatectomy. The liver DNA synthesis 24 h after partial
hepatectomy was significantly higher in the MCT+LCT-supplemented rats (30.2+/-8.2
x 10(3) dpm/mg liver DNA) compared to MCT-treated animals (18.1+/-5.7 x 10(3)
dpm/mg liver DNA). Liver protein synthesis was non-significantly elevated both 24
and 72 h after surgery in MCT+LCT-supplemented rats (13.7+/-1.1 and 10.9+/-3.1 x
10(3) dpm/mg liver protein). Seventy-two hours after partial hepatectomy, the
hepatocyte mitotic activity was significantly increased in MCT+LCT- supplemented
group vs. LCT- or MCT-fed rats (3.3+/-0.7 vs. 1.9+/-0.7 or 1.0+/-0.6 mitoses per
1000 hepatocytes), thus exhibiting an increased proliferative potential. The
results showed a qualitative difference according to the proportion of MCT to LCT
in the enteral supplements. Overfeeding with MCT decreased body weight, increased
liver weight by its fatty infiltration, increased rat mortality rate and reduced
spontaneous caloric intake. We conclude that the balanced supplement of MCT+LCT
(40%:60% w:w) preserves liver regeneration, whereas overfeeding with MCT seems to
be deleterious.
PMID- 10783912
TI - The role of human glutathione S-transferases M1 and T1 in individual
susceptibility to bladder cancer.
AB - Several genes involved in the metabolism of carcinogens have been found to be
polymorphic in the human population, and specific alleles are associated with
increased risk of cancer at various sites. This study is focused on the
polymorphic enzymes glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) that are
involved in the detoxification of many xenobiotics involved in the etiology of
bladder cancer. To investigate the role of GSTM1 and GSTT1 in bladder
carcinogenesis, the polymerase chain reaction was used to determine GSTM1 and
GSTT1 genotypes of cancer patients (n = 76) and controls (n = 248). The
proportion of putative risk GSTM1 null genotype in the case group was 52.6%,
compared to 49.6% in the control group, but the GSTT1 0/0 frequency in the
bladder cancer group was significantly higher (P = 0.04) in comparison with the
control group (27.6 vs 16.9%). Individuals lacking the GSTT1 gene are at an
approximately 1.9-fold higher risk (OR = 1.87, C.I. 95% = 1.03-3.42) of
developing bladder cancer in comparison with individuals with at least one active
allele in the GSTT1 locus. A significantly higher incidence of GSTM1 deletion
genotype (P = 0.02) was found in smokers with bladder cancer compared to the
controls (70.6 vs 49.6%). Smokers lacking the GSTM1 gene are at an approximately
2.4-fold higher risk of bladder cancer (OR = 2.44, C.I. 95% = 1.10-5.30). The
effect of smoking associated with the GSTT1 0/0 genotype was not found to affect
the risk of bladder cancer.
PMID- 10783913
TI - Early inflammatory cytokine and acute phase protein response under the stress of
thermal injury in rats.
AB - The acute inflammatory response associated with thermal injury was examined in
rats. The appearance of mediators of inflammation in the systemic circulation,
including cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF) and
interleukin-6 (IL-6) and acute phase proteins were assessed during initial 72 h
following thermal injury. Increased levels of activity were noted for all three
cytokines, but with a different time-course. While serum IL-1 activity was
elevated throughout the 3-day period of observation, the levels of serum TNF
activity were enhanced after 12 h and on days 1 and 3 following scalding injury.
The values of IL-6 were already increased one hour after thermal injury and
increased progressively up to day 1 following scalding. Alpha2-macroglobulin and
haptoglobin levels were increased 12 h after thermal injury, rising further on
days 1 and 3. Positive correlation was found between the time-course of increased
serum IL-6 activity and alpha2-macroglobulin, as well as between TNF and
haptoglobin in the serum.
PMID- 10783914
TI - Permanent alterations of spinal cord reflexes following nerve lesion in newborn
rats.
AB - Sciatic nerve lesion in newborn rats is known to cause degeneration of a large
number of axotomized motoneurones and spinal ganglion cells. Some of the
surviving motoneurones exhibit abnormal firing properties and the projection
pattern of central terminals of sensory neurones is altered. We report here on
long-term changes in spinal cord reflexes in adult rats following neonatal nerve
crush. In acutely spinalized and anaesthetized adult rats 4-6 months old in which
the sciatic nerve had been crushed on one side at birth, the tibial nerve, common
peroneal nerve or sural nerve were stimulated on the reinnervated and control
side and reflex responses were recorded from the L5 ventral spinal roots. Ventral
root responses (VRRs) to tibial and peroneal nerve stimulation on the side of the
nerve lesion were significantly smaller in amplitude representing only about 15%
of the mean amplitude of VRRs on the control side. The calculated central delay
of the first, presumably monosynaptic component of the VRR potential was 1.6 ms
on the control side while the earliest VRR wave on the side of the nerve lesion
appeared after a mean central latency of 4.0 ms that seems too long to be of
monosynaptic origin. These results suggest that neonatal sciatic nerve injury
markedly alters the physiological properties and synaptic connectivity in spinal
cord neurones and causes a marked depression of spinal cord responses to
peripheral nerve stimulation.
PMID- 10783915
TI - Midazolam suppresses spike-and-wave rhythm accompanying three different models of
epileptic seizures.
AB - The action of a water-soluble benzodiazepine midazolam (0.1 and 1 mg/kg i.p.) was
tested against three models of spike-and-wave rhythm in rats: rhythmic metrazol
activity (a model of human absence seizures), minimal metrazol seizures, and
epileptic afterdischarges induced by low-frequency cortical stimulation (probably
models of human myoclonic seizures). Midazolam was able to reduce spike-and-wave
activity in all three models, but there were quantitative differences: the lower
dose was effective only against rhythmic metrazol activity, but its action
against two other models was negligible, whereas the higher dose of midazolam
resulted in significant effects in all three models. These quantitative
differences are not sufficient to prove our hypothesis that the spike-and-wave
rhythm represents different phenomena in various models. A spread of epileptic
activity into brain structures other than the thalamocortical system determines
the type of epileptic seizures.
PMID- 10783916
TI - Antipentylenetetrazol action of clobazam in developing rats.
AB - Clobazam (0.5 to 7.5 mg/kg i.p.) was tested against motor seizures elicited by
pentylenetetrazol in rats 7, 12, 18, 25 and 90 days old. Minimal, predominantly
clonic seizures with preserved righting ability were reliably induced by
pentylenetetrazol and suppressed by clobazam in rats aged 18 days or more. The
incidence of minimal seizures after clobazam pretreatment was not increased in 7-
and 12-day-old rat pups. Generalized tonic-clonic seizures were markedly
suppressed by clobazam in all age groups. In 18-day-old and older animals
clobazam doses suppressing generalized seizures were always lower than those
necessary for exerting an effect on minimal seizures. The differences in clobazam
action appearing at various levels of maturation are only quantitative.
PMID- 10783917
TI - Regulation of Na+, K+-ATPase density by the extracellular ionic and osmotic
environment in bovine articular chondrocytes.
AB - The abundance of Na+, K+-ATPase in cartilage is controlled by the ionic
composition of the extracellular environment of chondrocytes, and specifically
depends on the local concentration of polyanionic matrix proteoglycans. In this
study, it was found that the plasma membrane density of Na+, K+-ATPase in
isolated chondrocytes is sensitive to both ionic and osmotic changes in the
extracellular environment. The upregulation observed experimentally was similar
in magnitude as measured by 3H-ouabain binding, which indicates that chondrocytes
respond adaptively to both ionic and osmotic stimuli. The precise mechanism for
this novel mode of Na+, K+-ATPase regulation has yet to be elucidated.
Physiological perturbation of the ionic and osmotic environment of chondrocytes
may alter intracellular Na+ concentration and this may be one of a number of
stimuli responsible for alterations to the expression and plasma membrane
abundance of Na+, K+-ATPase in the cells.
PMID- 10783918
TI - Effects of immobilization stress combined with water immersion and chronic
amphetamine treatment on the adenylyl cyclase activity in rat neurohypophysis.
AB - Several papers have indicated the participation of cyclic AMP as a second
messenger for the release of neurohypophysial hormones. Since very little is
known about the effects of stress and drugs of abuse on this process, we studied
the activity of adenylyl cyclase in the neurohypophyses after immobilization
stress and chronic amphetamine treatment. Our findings indicate the involvement
of cyclic AMP in the regulation of neurohypophysis as well as the increase in
total adenylyl cyclase both after application of immobilization stress combined
with water immersion and after chronic amphetamine treatment.
PMID- 10783919
TI - Unusual intrafusal fibres in human muscle spindles.
AB - We have studied the morphology and pattern of expression of myosin heavy chain
(MHC) isoforms of intrafusal fibres in a human first lumbrical muscle. Each
intrafusal fibre type, namely nuclear bag1, nuclear bag2 and nuclear chain
fibres, had a distinct MHC composition and distribution of different MHC isoforms
along the whole length of intrafusal fibres. However, most muscle spindles
analyzed also contained one or several intrafusal fibres exhibiting an extrafusal
or mixed pattern of immunoreactivity which did not correspond to any of the
described intrafusal fibre types. We conclude that the latter fibres do not
represent new intrafusal fibre types, but their morphology and expression of MHC
merely reflects the differences in their innervation owing to their unusual
localization at the edge or outside the axial bundle of intrafusal fibres.
PMID- 10783920
TI - Model of lymphocyte migration in Merino ewes under physiological conditions.
AB - The paper presents an example of a new type of a structured model containing time
delays in parallel branches. This model was selected as optimal to describe
mathematically the lymphocyte migration between the venous blood and prescapular
lymph in Merino ewes under physiological conditions. The model allowed to
identify and quantify several lymphocyte fractions exhibiting different migration
dynamics.
PMID- 10783921
TI - Performance of dual-microphone in-the-ear hearing aids.
AB - Fifty subjects with mild to moderate-severe sensorineural hearing loss and prior
experience with binaural amplification were evaluated at two sites (25 subjects
at each site). Signal-to-noise ratios (SNRs) were measured using the Hearing in
Noise Test (HINT) after each subject wore binaural in-the-ear hearing aids
programmed for omnidirectional and dual-microphone performance, for 4 weeks. Both
microphone conditions were evaluated under "ideal" (signal at 0 degrees; noise at
180 degrees) and "diffuse" (signal at 0 degrees; correlated noise at 45 , 135
degrees, 225 degrees, and 315 degrees) listening conditions. Results revealed
statistically significant mean improvements in SNRs between 3.7 and 3.5 dB at
Site I and 3.2 and 2.7 dB at Site II for the ideal and diffuse listening
conditions, respectively, for the dual-microphones in comparison to the
performance provided by the omnidirectional microphone.
PMID- 10783922
TI - Assessing growth of loudness in children by cross-modality matching.
AB - This study examined the clinical feasibility, validity, and reliability of
loudness growth assessment using cross-modality matching (CMM) between line
length and loudness in 16 children 4 to 12 years old with normal hearing or
bilateral sensorineural hearing losses ranging from moderate to severe in degree.
Eight adult listeners with normal hearing were used as a comparison group.
Loudness growth functions and real-ear measures were obtained for 500-Hz and
2,000-Hz narrowband noise stimuli for each individual. No significant differences
were found between the loudness slope values for the adults and children with
normal hearing. Loudness growth functions of the children with sensorineural
hearing loss were significantly steeper (larger) than the slopes obtained from
children with normal hearing. The numeric slope value of the loudness growth
function became larger and more variable as children's hearing threshold
increased and differed for children with similar thresholds. The loudness
functions obtained for retested participants at two different test sessions were
highly correlated. Real-ear measurements revealed that for equivalent input
stimulus levels, significantly higher stimulus levels were present in the ear
canals of children versus adults. Although adults and children with normal
hearing had similar overall rates of loudness growth, discrete points along the
loudness growth function were judged to be louder by the children. This
preliminary study suggests that measures of loudness growth using CMM between
line length and loudness are feasible, valid, and reliable in children with
normal hearing or sensorineural hearing loss. The individual variability noted in
slope values for children with hearing loss attests to the importance of
subjective assessments of loudness. The protocol used in this study may have
potential as a clinical tool for selecting and fitting amplification technology
for children with hearing loss as young as 6 years.
PMID- 10783923
TI - Effect of stimulation rate on cochlear implant recipients' thresholds and maximum
acceptable loudness levels.
AB - Clinically, speech processor programs are created using electrical thresholds and
maximum acceptable loudness levels (MALs) at several different stimulation rates
to determine what rate will provide cochlear implant recipients with the best
speech recognition when using fast-rate speech coding strategies. This study was
designed to determine the difference in thresholds and MALs (expressed in the
clinical unit, Current Level [CL]) for pairs of six rates spanning those
available with the Nucleus 24 device (i.e., 250 to 2,400 pps/ch) using monopolar,
25 microsec/phase stimulation. Test-retest measures of threshold and MAL for each
rate were obtained from seven adult Nucleus 24 recipients on each of 11
electrodes. The difference in threshold and in MAL between pairs of rates was
dependent on the absolute CL. Below approximately 190 CL, thresholds and MALs
decreased with increasing rate; above 210 CL, there was little change in
threshold or MAL with increasing rate. Based on these findings, an approach to
estimating threshold and MAL from one rate to another is suggested, pending
further research.
PMID- 10783924
TI - Improving audibility with nonlinear amplification for listeners with high
frequency loss.
AB - In contrast to fitting strategies for linear amplification that have been
frequently refined for listeners with different degrees of hearing loss, we know
relatively little about the effects of nonlinear amplification for differing
audiometric configurations. The purpose of the current study was to determine
whether increases in audibility with nonlinear amplification improved speech
recognition to a comparable degree for listeners with sloping sensorineural loss
as for a comparison group of listeners with flat sensorineural loss. Consonant
recognition was examined as a function of audibility with wide dynamic range
compression amplification and with linear amplification. For linearly amplified
speech, listeners with flat and sloping loss showed similar improvements in
recognition given the same increases in audibility. Results for nonlinearly
amplified speech indicated that the listeners with flat loss showed a greater
rate of improvement as audibility increases than the listeners with sloping loss.
This difference is largely due to superior performance by the listeners with
sloping loss for low-audibility speech in comparison to equivalent group
performance for high-audibility speech.
PMID- 10783925
TI - Articulation index and hearing handicap.
AB - This investigation examined the relationship between perceived hearing handicap
and the Articulation Index (AI) and the extent to which this relationship was
influenced by the variables age, gender, degree of hearing loss, and audiometric
slope. Subject age, gender, pure-tone thresholds, and scores for the Self
Assessment of Communication (SAC) and the Significant Other Assessment of
Communication (SOAC) were extracted retrospectively from 373 patient files (194
males, 179 females). Correlation analysis revealed a significant (p < .01)
negative relationship between AI values and both measures of hearing handicap,
and also indicated that SAC/SOAC total scores correlated significantly (p < .01)
with each other. Partial correlation analyses revealed that degree of hearing
loss was the only variable under study that had substantial influence on the
strength of AI/hearing handicap correlations.
PMID- 10783926
TI - Preferred listening levels of children who use hearing aids: comparison to
prescriptive targets.
AB - The preferred listening levels (PLLs) of children with sensorineural hearing loss
were elicited using conversation-level speech, heard through the children's own
hearing aids. All hearing aids were fitted using the desired sensation level
(DSL) method. Comparisons were made between the PLL and targets from the
following prescriptive formulae: DSL version 4.1 and two versions of the National
Acoustic Laboratories (NAL) procedure, including NAL revised for severe-profound
losses (NAL)-RP and NAL nonlinear NAL/NL1. Results for this sample of children
indicated that the PLL was similar to the DSL targets, and that, on average, NAL
RP/NL1 targets recommended less gain than that preferred by the majority of
children in this study. The implications of factors such as acclimatization, test
levels, and clinical procedures on these results are discussed.
PMID- 10783927
TI - Quality of life questionnaires for all respiratory diseases, every language and
ethnic minorities. Are alternatives available?
PMID- 10783928
TI - Pulmonary calcifications: a review.
AB - Pulmonary calcification is a common asymptomatic finding, usually discovered on
routine chest X-ray or at autopsy. Pulmonary calcifications are caused mainly by
two mechanisms: the dystrophic form and the metastatic form (1). Despite the
different aetiologies, the pulmonary function and clinical manifestations are
quite similar in both forms. We present a review of the clinical and radiology
findings of the different aspects of pulmonary calcifications according to its
pathogenesis and its anatomic distribution: parenchymal, lymphe node and pleural.
PMID- 10783929
TI - Inter-laboratory comparison of flow-volume curve measurements as quality control
procedure in the framework of an international epidemiological study (PEACE
project).
AB - The aim of this work was to describe the results of a simple quality control
procedure for the flow-volume curve adopted in a multicentre epidemiological
study (PEACE). In 14 centres, 8-15 individuals (n = 157) performed forced vital
capacity (FVC) manoeuvres following a standard protocol with both the local
spirometer/pneumotachograph and a portable spirometer (i.e. the 'reference
instrument' for this study). Deviances of measurements were assessed by computing
the differences (delta) between the former and the latter, the ratios of such
differences on portable spirometer values (delta %) and the coefficients of
variation (CV). The portable spirometer yielded lower mean AFVC and deltaFEV1
(forced in 1 sec) than local instruments (except for two and four centres,
respectively). In most instances, differences were statistically significant.
Absolute mean A%FVC ranged from 4.9-18.2%, while delta%FEV1 ranged from 2.3
18.5%. The Bland and Altman analysis showed a good agreement between the portable
and local instruments, except for two centres, where a systematic trend towards
higher individual absolute deltaFVC and deltaFEV1 was observed. The overall
variability, assessed by CV, was within 6.2% and 5.1% for FVC and FEV1,
respectively: it was similar to other quality control studies ranging from 2.0
5.5% for FVC and 2.2-5.8% for FEV1. Our results point out the importance of
performing interlaboratory comparisons as a quality control procedure in
multicentre epidemiological studies on lung function, and of stimulating
manufacturers to extend the accuracy and precision of the instruments.
PMID- 10783930
TI - Direct medical costs of chronic obstructive pulmonary disease: chronic bronchitis
and emphysema.
AB - In this study we aimed to estimate direct medical costs of Chronic Obstructive
Pulmonary Disease (COPD) by disease type; chronic bronchitis and emphysema. This
study estimates direct costs in 1996 dollars using a prevalence approach and both
aggregate and microcosting. A societal perspective is taken using prevalence, and
multiple national, state and local data sources are used to estimate health-care
utilization and costs. Chronic bronchitis and emphysema together account for
$14.5 billion in annual direct costs. Inpatient costs are greater than outpatient
and emergency costs ($8.3 vs. $7.8 billion) and hospital and medication costs
account for most resources spent. The high prevalence of chronic bronchitis
accounts for its larger total costs ($11.7 billion) compared with emphysema ($2.8
billion). Emphysema, which is more severe, has higher costs per prevalent case
($1341 vs. $816). Hospital stays account for the highest costs, $6.0 billion for
chronic bronchitis and $1.9 billion for emphysema. The hospitalization rate,
length of stay and average cost per prevalent case are higher for emphysema than
for chronic bronchitis. Medication costs are the second highest cost category
($4.4 billion for chronic bronchitis, $0.693 billion for emphysema). The high
hospitalization and low home care costs (0.2% of total) suggest underuse of home
care and room to shift from acute to preventive care. More attention to
healthcare management of chronic bronchitis and emphysema is suggested, and
improving inhaler and anti-smoking compliance might be important targets.
PMID- 10783931
TI - Assisted pressure control ventilation via a mini-tracheostomy tube for
postoperative respiratory management of lung cancer patients.
AB - Assisted pressure control ventilation (PCV) via a min-tracheostomy tube (MTT) was
conducted to improve gas exchange and reduce the work of breathing of lung cancer
patients after surgery. Thirty-two patients with lung cancer underwent lobectomy
and were managed postoperatively by assisted PCV via an MTT. On the basis of a
simulation study using a lung model for clinical use, we set the inspiratory
pressure to 20 cmH2O and inspiratory time to 1.0 sec to produce a 450-ml
supported volume via the MTT per breath. The blood gases and respiratory rate of
each patient were measured under three sets of conditions: PCV via an MTT
transtracheal oxygenation (TTO) via an MTT and a Venturi face mask with the same
FiO2. After PCV via an MTT overnight, the blood gases in the room air were
measured 2.5 h after withdrawing PCV. In order to determine the effect of PCV via
an MTT on gas exchange after PCV withdrawal, 32 other age and sex-matched lung
cancer patients, who had undergone lobectomy and oxygenation via a face mask
alone after surgery, were used as historical controls. The simulation study
showed that the ventilated volume provided by assisted PCV via an MTT was about
half that provided via a conventional endotracheal tube, even in the presence of
air leakage. The clinical application showed that the ventilated volume obtained
with the PCV via an MTT was significantly higher than that with spontaneous
breathing (P<0.001). PCV via an MTT increased the PaO2 and reduced both the PaCO2
and respiratory rate significantly in comparison with TTO via an MTT and a face
mask (P<0.001). After PCV withdrawal the morning after surgery, the PaO2 of the
PCV group was significantly higher than that of the historical controls
(P<0.001). No postoperative pulmonary complications were observed in either the
PCV or the control groups, however. In addition, no complications or morbidity
were seen related to either MTT insertion or PCV via an MTT. Assisted PVC via an
MTT increased the tidal volume, improved the gas exchange, reduced the
respiratory rate by providing adequate ventilatory support and increased the
PaO2, even after withdrawal following lung surgery. Even though we did not
observe any benefit of clinical outcome with PCV via an MTT in the present study,
this procedure appears to be a potentially useful respiratory management modality
for patients with high risk of postoperative pulmonary complications.
PMID- 10783932
TI - Frequency dependence of compliance in the evaluation of patients with unexplained
respiratory symptoms.
AB - Frequency dependence of compliance (FDC) reflects non-homogeneous ventilatory
distribution and, in the presence of a normal measured airway resistance,
suggests peripheral airways dysfunction. This study evaluated peripheral airway
function and bronchial reactivity in irritant exposed or non-exposed individuals
with normal routine pulmonary function tests (PFTs) who had persistent
unexplained lower respiratory symptoms. Twenty-two patients were identified with
persistent respiratory symptoms and with normal chest X-ray and PFTs. Twenty were
non-smokers; two had stopped smoking more than 10 years before evaluation. Twelve
patients had been exposed to irritants in their workplaces or at home. Non
specific bronchial hyper-reactivity (nsBHR) and FDC, pre- and post
bronchodilator, were measured in all patients. Studies were repeated in 6/12
irritant-exposed subjects after exposure removal and inhaled corticosteroid
treatment. Whereas 12/22 patients had nsBHR, all 22 subjects demonstrated FDC
[dynamic lung compliance/static lung compliance Cdyn,1 / Cst,1 at respiratory
frequency 60 min(-1) (f60), mean 46%, range 27-67%]. After bronchodilator
administration, a 15% improvement Cdyn,1 was observed most consistently at f60
(mean% improvement 26%, 95% CI 14-38%) and in subjects without nsBHR. However,
Cdyn,1 at f60 did not return to normal after inhaled bronchodilator. Irritant
exposed and unexposed individuals appeared similar in results of testing for FDC
and nsBHR. FDC and its response to bronchodilators provide objective
physiological measures of an airway abnormality which may provide a basis for
clinical symptoms in patients with normal routine pulmonary function studies. The
presence of persistently abnormal FDC after bronchodilator (BD) and on follow up
studies may reflect chronic inflammatory and/or structural changes in the airways
in addition to bronchoconstriction.
PMID- 10783933
TI - Osseous disease in patients with pulmonary sarcoidosis and musculoskeletal
symptoms.
AB - Little is known about the clinical manifestations and correlates of osseous
sarcoidosis and few data exist to guide pulmonologists in their evaluation of
patients for possible osseous involvement. To determine the relationship between
pulmonary and osseous sarcoidosis, and to develop an algorithm for use by
pulmonologists in assessing patients with suspected osseous sarcoidosis, we
conducted a retrospective, case control study of patients with pulmonary
sarcoidosis and musculoskeletal complaints who were evaluated for osseous
disease. All patients underwent a standard evaluation to include physical
examination, chest radiograph (CXR), spirometry (PFTs), bone scintigraphy and
plain radiographs of the hands and feet. Patients completed a health assessment
questionnaire and serum angiotenisin converting enzyme, erythrocyte sedimentation
rate, and C-reactive protein were measured. Patients eventually diagnosed with
osseous sarcoidosis were compared to those lacking osseous involvement. Osseous
involvement in patients with pulmonary sarcoidosis and musculoskeletal symptoms
was common and seen in 38.9% of subjects. Patients with osseous sarcoidosis were
more likely to concomitantly suffer from cutaneous sarcoidosis and to have
elevated ACE levels and ESRs. No measure of pulmonary involvement (CXR stage,
PFTs or symptoms) differentiated patients with osseous sarcoidosis from those
without this condition. In cases of osseous sarcoidosis, bone scintigraphy
identified a mean of four sites of osseous involvement, some of which would have
been missed with the use of plain radiographs limited to the hands and feet. We
conclude that in patients with pulmonary sarcoidosis who have significant
musculoskeletal complaints, osseous involvement is frequent. Pulmonary features
of sarcoidosis do not differ between patients with and without osseous disease.
Bone scintigraphy aids in the evaluation of these patients.
PMID- 10783934
TI - Lung volume and its correlation to nocturnal apnoea and desaturation.
AB - The cross-sectional area of the upper airway is known to be lung volume
dependent. If, and to what extent, lung volume variables correlate to nocturnal
obstructive apnoeas and oxygen desaturations independently of other factors known
to affect lung volumes and sleep disordered breathing is still unclear. A total
of 92 subjects were examined by ambulatory recording of nocturnal obstructive
apnoeas and desaturations. Sixty-nine of the subjects had a history of snoring
and 23 were healthy subjects without complaints of snoring and daytime
sleepiness. All subjects performed static and dynamic spirometry for measurements
of lung volumes. To evaluate the correlation between lung volume variables and
apnoea index (AI) and oxygen desaturation index (ODI), simple and multiple
regression analysis was performed. Expiratory reserve volume (ERV) was found to
be lower in subjects with snoring and apnoeas (ERV = 1.0 l) than in non-snoring
subjects (ERV = 1.7 l), (P<0.001). Forced expiratory volume in 1 sec (FEV1)/vital
capacity (VC) was slightly, but significantly (P = 0.031), lower in subjects with
snoring and nocturnal apnoeas and desaturations. In the multiple regression
analysis ERV was found to be independently correlated to both AI (R2=0.13;
P=0.001) and ODI (R2 = 0.11; P = 0.002). Multiple regression analysis also
revealed that ERV, body mass index (BMI) and habitual smoking together accounted
for 43% of the variation in AI and 48% of the variation in ODI. We find a
significant independent association between ERV and nocturnal obstructive apnoea
and oxygen desaturation frequency. Our results indicate that ERV is correlated to
these events to a similar extent, as is obesity.
PMID- 10783935
TI - Prevalence and mechanisms of diurnal hypercapnia in a sample of morbidly obese
subjects with obstructive sleep apnoea.
AB - It is well known that obstructive sleep apnoea is especially frequent in the
morbidly obese. In these subjects diurnal chronic hypercapnia, whose mechanism is
still debated, may be present. Our study was performed to evaluate the prevalence
and the mechanism of diurnal hypercapnia in the morbidly obese affected by
obstructive sleep apnoea. From a population referred to our centre because of
suspicion of sleep related breathing disorders, we selected 285 subjects without
cardiopulmonary, neuromuscular or endocrinological diseases: 89 (36 M and 53 F,
aged 46+/-13 years) had body mass index (BMI) > or = 40 kg m(-2) (MO group:
morbidly obese subjects) and 196 (99 M and 97 F, aged 48+/-16 years) had BMI <40
kg m(-2) (NMO group: non-morbidly obese subjects). Then the MO group was divided
into three subgroups: normocapnic subjects without obstructive sleep apnoea,
normocapnic subjects with obstructive sleep apnoea, hypercapnic subjects with
obstructive sleep apnoea; while we found no hypercapnic subject without
obstructive sleep apnoea. All subjects underwent anthropometric evaluations and
bioelectrical impedance analyses, respiratory function tests and arterial blood
gas analysis, a modified version of the Sleep and Healthy questionnaire and a
full night polysomnography. Our results showed that hypercapnia (PaCO2 > or = 45
mm Hg) associated with obstructive sleep apnoea [respiratory disturbance index
(RDI) > or = 10 h(-1)] was found in 27% of the morbidly obese subjects, but only
in 11% of the nonmorbidly obese ones (P<0.01). The comparison among the three
subgroups, in which we divided the morbidly obese subjects, shows that those with
hypercapnia and obstructive sleep apnoea had significantly more important
ventilatory restrictive defects [forced vital capacity (FVC)% of pred 73.27+/-14
81 vs. 82.37+/-16.93 vs. 87.25+/-18.14 respectively; total lung capacity (TLC)%
of pred 63.83+/-16.35 vs. 79.11+/-14.15 vs. 87.01+/-10.5], a significantly higher
respiratory disturbance index (RDI 46.34+/-26.90 vs. 31.79+/-22.47 vs. 4.98+/
3.29) a longer total sleep time with oxyhaemoglobin saturation<90% [total
sleeptime (TST)SaO2<90% 63.40+/-33.86 vs. 25.95+/-29.34 vs. 8.22+/-22.12] and a
lower rapid eye movement (REM) stage (9.5+/-1.2 vs. 14.0+/-0.9 vs. 17.05+/-1.2)
than normocapnic subjects with obstructive sleep apnoea or subjects without
obstructive sleep apnoea. The best model to predict PaCO2 resulted from a
combination of TSTSaO2<90% (r2 = 0.22, P<0.001), forced expiratory volume in 1
sec (FEV1)% of pred (r2 = 0.09, P<0.01), FVC % of pred (r2 = 0.075, P<0.01). In
conclusion our study suggests that diurnal hypercapnia is frequently associated
with obstructive sleep apnoea in the morbidly obese without chronic obstructive
pulmonary disorder (COPD) and that ventilatory restriction and sleep related
respiratory disturbances correlate to diurnal hypercapnia.
PMID- 10783936
TI - The economic impact of asthma and chronic obstructive pulmonary disease (COPD) in
Sweden in 1980 and 1991.
AB - This study was carried out to estimate the direct and indirect costs associated
with asthma and chronic obstructive pulmonary disease (COPD) in Sweden in 1980
and 1991, and to identify trends in the use of outpatient care, drugs and
inpatient care, and the development of temporary morbidity, permanent disability
and mortality for asthma and COPD. Routinely published administrative and
population data were used to estimate the costs of asthma and COPD, and these
figures were compared to corresponding estimates and trends for all respiratory
diseases as well as for all diseases. Asthma and COPD each accounted for about
SEK 3 billion, together roughly 2% of the economic cost of all diseases. Although
the total costs associated with each disease were similar, the distribution of
the different cost components and changes in each component over time differed.
During the 1980s, the cost of drugs and out-patient care increased for both
diseases. The cost of inpatient care for asthma decreased, whereas that for COPD
increased. This study shows that asthma therapy has changed from inpatient to
ambulatory care in Sweden, while the treatment of COPD to a higher degree still
is based on inpatient care.
PMID- 10783937
TI - Physiological and symptom determinants of exercise performance in patients with
chronic airway obstruction.
AB - To evaluate the physiological and symptom determinants of exercise performance
(EP) as measured by a 6-min walking test (6MWD), Watt(max), and peak oxygen
consumption (VO2 ml/min/kg), 105 patients with chronic airway obstruction (CAO)
[50 chronic obstructive pulmonary disease (COPD): 44 men, aged 63+/-7 years,
forced expiratory volume in 1 sec (FEV1) forced vital capacity (FVC)(-1)% 54+/
13; and 55 asthmatic: 23 men, aged 55+/-10 years, FEV1 FVC(-1) % 65+/-10]
underwent evaluation of 6MWD, symptom limited cyclo-ergometer exercise test,
spirometry, respiratory muscle function, arterial blood gases and sensation of
dyspnoea [using the Borg scale, Visual Analogue Scale (VAS) and Baseline Dyspnoea
Index (BDI)]. A hierarchical method of analysis identified the residual volume
(RV), total lung capacity (TLC)(-1) ratio, BDI and the patient's age as the
strongest and most consistent correlates of EP (r2 = 0.14-0.21). The correlation
between EP and its various determinants was not influenced by diagnosis. The
relationship between breathlessness and EP was different between men and women:
at any given level of exercise, women were more breathless than men. In
multivariate analyses that contained both RV TLC(-1) and BDI, the RV TLC(-1)
ratio was the strongest correlate of EP, although the BDI remained a significant
covariate. Overall, age was the major determinant of EP but inclusion of the RV
TLC(-1) ratio and the BDI into the model explained a further 9-15% of the
variance in EP. These three covariates together explained 26-34% of the variance
between patients. We conclude that in stable CAO patients, the prediction of
exercise capacity by anthropometric, demographic, clinical and physiological
variables is likely to be low. Age, pulmonary hyperinflation and dyspnoea are the
strongest and most consistent correlates of impaired exercise performance.
Airways obstruction, measured during expiration using FEV1, does not appear to be
a predictor of physiological impairment. These results underline the importance
of performing exercise evaluation in CAO patients.
PMID- 10783938
TI - The expression of lymphocyte surface antigens in bronchial biopsies,
bronchoalveolar lavage cells and blood cells in healthy smoking and never-smoking
men, 60 years old.
AB - In this study we investigated if smoking subjects with a normal or slightly
decreased lung function differ in the lymphocyte pattern compared to never
smokers. In a group of 'healthy' smokers (n = 58) and never-smokers (n = 34) 60
years old, we investigated the lymphocyte pattern in both BAL (n = 30 and n = 18
respectively), bronchial epithelium and lamina propria (n = 14 and n = 10
respectively) and blood. We found that all subjects, despite smoking history, had
a higher number of CD8+ cells per mm2 in the epithelium compared to the lamina
propria in the bronchial biopsies. In smokers, these CD8+ cells were
significantly negatively correlated to FEV1 (r = -0.56, P = 0.04). In smokers,
the number of CD8+ lymphocytes was higher and the T cell activation markers
(CD57+ and CD28+) were lower in BAL, than in never-smokers. This last finding was
also seen in blood for CD3+ 57+. We conclude, that in 'healthy' smokers the
lymphocyte patterns are different compared to never-smokers, to some extent in
BAL. There is also a relation between lymphocytes in the bronchial mucosa and
lung function. This has previously been shown in patients with chronic
obstructive pulmonary disease (COPD) and chronic bronchitis but not in
asymptomatic smokers.
PMID- 10783939
TI - Assessing health status and quality of life in idiopathic pulmonary fibrosis:
which measure should be used?
AB - Many studies conducted on the health status and quality of life (QOL) of patients
with certain chronic diseases have demonstrated that their disease had an impact
on their lives. However, less is known about the QOL and health status of
patients suffering from idiopathic pulmonary fibrosis (IPF). In the present
study, three focus groups of IPF patients (n=10) were run to identify the aspects
of QOL or health status that are relevant to this population and to establish
which measure is preferable to assess these aspects. The patients completed and
discussed the St. George's Respiratory Questionnaire (SGRQ) and the World Health
Organization Quality of Life assessment instrument (WHOQOL-100). Results
indicated that hobbies/leisure activities, mobility, transport, social
relationships, working capacity, energy and doing things slower were aspects
relevant to IPF patients' QOL. The WHOQOL-100, with an additional social support
questionnaire, appeared to be preferable.
PMID- 10783940
TI - Impact of patient education and self-management on morbidity in asthmatics and
patients with chronic obstructive pulmonary disease.
AB - The effect of patient education on morbidity in asthmatics and COPD patients has
not previously been investigated in a single study. We randomized 78 asthmatics
and 62 COPD patients after ordinary outpatient management. Intervention consisted
of educational group sessions and individual sessions administered by a trained
nurse and physiotherapist. A self-management plan was developed. The utilization
of health resources and absenteeism from work was self-reported monthly. During
the 12-month follow-up, approximately two (P= 0.001) and three (P= 0.001) times
as many uneducated asthmatics and COPD patients, respectively, visited their
general practitioner (GP) compared with educated. The mean reduction in GP
consultations for the educated were 73% (P<0.001) and 85% (P<0.0001) for the
asthma and COPD group, respectively, compared with uneducated. Fifty percent of
uneducated asthmatics reported absenteeism from work compared with 24% of the
educated (P = 0.06). The mean reduction in days offwork for the educated was 69%
(P = 0.03), compared with uneducated. A positive correlation was observed between
St George's Respiratory Questionnaire total score and number of GP visits for
both the asthma and COPD group (P < 0.001). We conclude that patient education in
asthmatics and COPD patients reduced the need for GP visits and kept a greater
proportion of patients independent of their GP. Patient education among
asthmatics also reduced the number of days off work and appeared to increase the
proportion of patients not reporting absenteeism from work at all. Increasing
number of GP visits was correlated with decreased health-related quality of life
as measured by the SGRQ for both the asthmatics and the COPD patients.
PMID- 10783941
TI - Asthma and airway hyper-responsiveness in adults who required hospital admission
for bronchiolitis in early childhood.
AB - Viral respiratory infections in infancy may contribute to the development of
airway hyper-responsiveness (AHR) in childhood but their effects on respiratory
function at the adult age are still uncertain. A group of 42 subjects aged 17-35
with a pediatrician-made diagnosis of severe bronchiolitis in infancy (Br) were
compared for the presence of asthma and AHR to a control group (C) paired for age
and gender, without evidence of lower respiratory disease in infancy. All had a
respiratory and environmental questionnaire, allergy skin prick tests, blood
eosinophil count, total serum IgE determination and measurements of expiratory
flows and airway response to methacholine. In Br and C groups, respectively, 38
and 12% of subjects had a physician-made diagnosis of asthma, 26 and 7% used
bronchodilators and 12 and 0% an inhaled corticosteroid; 71 and 67%,
respectively, were atopic, 50 and 24% were smokers and 43 and 17% had a first
degree relative with asthma. Mean baseline FEV1 and FEV1/FVC ratio were lower in
the Br than in the C group, with 94/103% (P=0.002) and 80/87 (P<0.0001) of the
predicted value, respectively. Geometric mean PC20 methacholine was significantly
lower in the Br than in the C group 3.9/20.3 mg ml(-1) (P<0.0001). Mean blood
eosinophil count and serum IgE levels were similar in both groups (P> 0.05). In
conclusion, asthma and AHR were found more frequently in young adults with a past
history of bronchiolitis, suggesting that this type of respiratory infection may
contribute to altered pulmonary function in adulthood, although it may also
represent an early manifestation of asthma. The influence of potential
confounding factors, such as familial predisposition and exposure to cigarette
smoke on the development of asthma and AHR in the Br group, cannot be excluded.
PMID- 10783942
TI - Diagnosis of vitreoretinal adhesions in macular disease with optical coherence
tomography.
AB - PURPOSE: To compare the relative incidence of vitreoretinal adhesions associated
with partial vitreous separation within the macula diagnosed with optical
coherence tomography (OCT) with that of those diagnosed with biomicroscopy.
METHODS: The authors obtained linear cross-sectional retinal images using OCT in
patients with selected macular diseases. Additional studies included
biomicroscopy, fundus photography, fluorescein angiography, and B-scan
ultrasonography. RESULTS: Optical coherence tomography was performed on 132 eyes
of 119 patients. Vitreoretinal adhesions within the macula were identified using
OCT in 39 eyes (30%) with the following diagnoses: idiopathic epiretinal membrane
(n = 13), diabetic retinopathy (n = 7), idiopathic macular hole (n = 7), cystoid
macular edema (n = 7), and vitreomacular traction syndrome (n = 5). Biomicroscopy
identified vitreoretinal adhesions in only 11 eyes (8%). Two distinct
vitreoretinal adhesion patterns were identified with OCT, each associated with
partial separation of the posterior hyaloid face: focal (n = 25) and multifocal
(n = 14). CONCLUSIONS: Optical coherence tomography is more sensitive than
biomicroscopy in identifying vitreoretinal adhesions associated with macular
disease.
PMID- 10783943
TI - Surgical treatment for severe diabetic macular edema with massive hard exudates.
AB - PURPOSE: Massive diabetic macular exudates respond poorly to conventional laser
treatment. The purpose of this study was to analyze the surgical results of eyes
with massive hard exudates secondary to diabetic macular edema treated with
combined pars plana vitrectomy, posterior hyaloid removal, focal endolaser
treatment, and panretinal photocoagulation. METHODS: The author retrospectively
analyzed the surgical outcome of 13 consecutive eyes (11 patients) with massive
diabetic macular exudates. All patients had had at least one session of focal
and/or grid laser treatment without any effect. Pars plana vitrectomy, posterior
hyaloid removal, focal macular endolaser treatment, and intraoperative panretinal
photocoagulation were performed. Postoperative visual acuity, evolution of
macular edema, and hard exudates were recorded. RESULTS: All 13 eyes showed
significant decreases in macular edema and hard exudates, a process that became
clinically obvious 3 months after the operation. Eleven eyes had improved vision
of at least two lines during an average follow-up period of 14.8 months.
Intraoperative and postoperative complications included angle closure glaucoma
(one eye), persistent vitreous hemorrhage (two eyes), choroidal detachment (one
eye), intravitreal fibrin formation (one eye), epiretinal membrane formation (one
eye), and neovascular glaucoma (one eye). CONCLUSION: Combined surgery may offer
an opportunity for improvement of vision and reduction of massive macular
exudates in patients with severe diabetic macular edema.
PMID- 10783944
TI - Resolution of diabetic macular edema after surgical removal of the posterior
hyaloid and the inner limiting membrane.
AB - PURPOSE: To evaluate the surgical results of pars plana vitrectomy with peeling
of the inner limiting membrane (ILM) in a preliminary series of 12 eyes with
diffuse diabetic macular edema. PATIENTS AND METHODS: Pars plana vitrectomy with
peeling of the ILM was performed in 12 eyes with diffuse diabetic macular edema.
In 10 eyes, the posterior hyaloid was attached and thickened. Six eyes had
undergone macular photocoagulation previously, and two other eyes had been
vitrectomized previously. Light and electron microscopy of the specimens obtained
during vitrectomy was performed. Visual acuity and retinal thickening were
monitored. RESULTS: Intraoperatively, the posterior hyaloid was found to be
thickened and completely attached to the macula in 10 eyes. Two previously
vitrectomized eyes showed a glistening reflex of the vitreoretinal interface but
no premacular membrane. The posterior hyaloid and the ILM were removed from the
macula. Postoperatively, retinal thickening resolved or decreased in all eyes.
Visual acuity improved by at least two lines in 11 eyes. Best-corrected
postoperative visual acuity developed within 4 to 12 weeks. No recurrence or
deterioration of macular edema or epiretinal membrane formation were observed
during the entire period of review (mean, 16 months; range, 8-31 months). Light
and electron microscopy showed the presence of the ILM associated with sparse and
mostly single-layered fibrous astrocytes. CONCLUSION: Vitrectomy including
removal of the ILM leads to expedited resolution of diffuse diabetic macular
edema and improvement of visual acuity without subsequent epiretinal membrane
formation. Complete release of tractional forces and inhibition of
reproliferation of fibrous astrocytes seem to be prudent in the eyes of patients
with diabetes and advanced vitreoretinal interface disease of the macula.
PMID- 10783945
TI - ICGA-guided laser photocoagulation of occult choroidal neovascularization in age
related macular degeneration. Indocyanine green angiography.
AB - PURPOSE: To evaluate the efficacy of indocyanine green angiography (ICGA)-guided
laser photocoagulation in eyes with fluorescein angiographic evidence of occult
choroidal neovascularization (O-CNV) in patients with age-related macular
degeneration (ARMD) with or without pigment epithelium detachment (PED). METHODS:
Eighty eyes of 79 consecutive patients with O-CNV underwent laser treatment of a
clearly outlined extrafoveal ICGA hyperfluorescent area, presumed to be focal
CNV. Four types of presumed CNV were treated: Group 1 (20 eyes), CNV beneath the
PED; Group 2 (23 eyes), CNV at the margin of the PED; Group 3 (10 eyes),
parapapillary CNV and PED; and Group 4 (27 eyes), macular CNV without PED. Median
follow-up was 17.5 months (range, 6-24 months). RESULTS: After 1 year, 15% of the
eyes in Group 1, 30% in Group 2, 100% in Group 3, and 52% in Group 4 had
obliteration of the presumed CNV. After 1 year, visual acuity was stable or
improved in 18% of Group 1, in 37.5% of Group 2, in 100% of Group 3, and in 73%
of Group 4. The remaining eyes worsened. CONCLUSIONS: Indocyanine green
angiography-guided laser treatment may improve or stabilize visual acuity in some
eyes with O-CNV. The best outcome is seen in eyes with presumed parapapillary
CNV, probably made up of choroidal telangiectases in many cases. The type and
location of the presumed CNV influence prognosis after laser treatment
considerably. A randomized, controlled clinical study appears necessary to
investigate the efficacy of ICGA-guided laser treatment in different types of
presumed CNV. The inclusion criteria for further trials need to be defined with
precision, as data from patients with different choroidal vascular abnormalities
have been pooled until now.
PMID- 10783946
TI - ICGA-guided laser photocoagulation of feeder vessels of choroidal neovascular
membranes in age-related macular degeneration. Indocyanine green angiography.
AB - PURPOSE: To report the ability of indocyanine green angiography (ICGA) with a
confocal scanning laser ophthalmoscope (SLO) to identify feeder vessels of
choroidal neovascular membranes (CNVM) secondary to age-related macular
degeneration (ARMD) and to show the feasibility of inducing complete closure of
the CNVM by photocoagulation targeted exclusively to the feeder vessels. METHODS:
Five consecutive patients with exudative ARMD in whom ICGA with the confocal SLO
showed extrafoveal feeder vessels supplying choroidal neovascular nets had laser
photocoagulation done only to the feeder vessels. In two patients, two separate
membranes were seen. RESULTS: Laser photocoagulation resulted in closure of the
feeder vessels and the CNVM in four patients. Complete closure was achieved with
one treatment in one patient and with two treatments in three patients. In one
patient, two treatments failed to close the feeder vessel and the CNVM, but a
third, more intense laser treatment resulted in temporary closure of the feeder
vessel and CNVM, which recanalized 2 to 4 weeks later with development of a large
rip in the retinal pigment epithelium. In one patient, two separate CNVMs grew
from the edge of the laser scars, but they were not directly related to the
original CNVM and its feeder vessel, and were treated successfully. The same eye
later developed subfoveal occult CNVM with gradual deterioration of visual
acuity. In the other four patients, visual acuity improved in two and was
unchanged in two. CONCLUSIONS: Indocyanine green angiography with the confocal
SLO can identify choroidal feeder vessels supplying CNVM secondary to ARMD. Laser
treatment to such extrafoveal feeder vessels, particularly in membranes that are
large or subfoveal, may be effective in closing the feeder vessel and CNVM with
preservation of the fovea and central vision. More than one treatment may be
required, however, and failures and complications may be expected with this
treatment modality.
PMID- 10783947
TI - Characterization of reactivation of cytomegalovirus retinitis in patients healed
after treatment with highly active antiretroviral therapy.
AB - PURPOSE: To delineate the immune parameters associated with reactivation of
cytomegalovirus (CMV) retinitis in patients for whom highly active antiretroviral
therapy (HAART) was not successful. METHODS: Prospective, longitudinal
observational study of a cohort of 102 patients with CMV retinitis treated with
HAART and being followed up at the AIDS Ocular Research Unit of the University of
California, San Diego from November 1995 to November 1998. The study included
serial clinical and fundus photographic examinations with CD4 T-lymphocyte counts
and HIV viral load measurements. RESULTS: Forty-seven of the 102 patients with
CMV retinitis responded to HAART. Thirty-five of the patients were successfully
withdrawn from anti-CMV therapy. During a median follow-up of 74.71 weeks (range,
4.86-144 weeks) after discontinuation of anti-CMV therapy, four patients
experienced a reactivation of CMV retinitis. In each case, the CD4 count
decreased before reactivation to a median of 31.5 cells/mm3 (mean, 31.25
cells/mm3; range, 23-39 cells/mm3). The association between the CD4 count
decreasing to less than 50 cells/mm3 and reactivation of CMV retinitis was
statistically significant (P < 0.0003). CONCLUSION: Four patients treated with
HAART experienced reactivation of CMV retinitis as their CD4 count decreased. The
threshold CD4 count below which reactivation of CMV retinitis occurred in
patients for whom HAART was not successful appeared to be 50 cells/mm3. Despite
an initial response to HAART, patients are still at risk for reactivation of CMV
retinitis if their CD4 count decreases to less than 50 cells/mm3. The HIV viral
load did not appear to predict CMV reactivation.
PMID- 10783948
TI - Anatomic results and complications in a long-term follow-up of pneumatic
retinopexy cases.
AB - BACKGROUND: The use of pneumatic retinopexy is controversial because 1)
intraocular gas could increase the risk of proliferate vitreoretinopathy and 2)
it has been reported to achieve low rates of success after a single procedure.
METHODS: A total of 219 consecutive cases of SF6 pneumatic retinopexy were
reviewed retrospectively. The follow-up period ranged from 2 to 5 years. RESULTS:
A total of 179 (81.73%) of 219 eyes were treated successfully with a single
procedure. The success rate increased with reoperations to 98.89%. Preoperative
factors related to primary failure or redetachment were aphakia or pseudophakia
(P = 0.0058) and breaks localized on horizontal meridia (P = 0.0305). Cryopexy
was significantly associated with failure (P = 0.0007). A total of 31.05% of eyes
showed early complications. The most frequent incidence was delay in subretinal
fluid reabsorption (36.76%), followed by new breaks (26.47%). Late complications
were observed in 6.84% of the eyes (six eyes with macular pucker, three with new
retinal detachments, three with cataracts, and three with new breaks without
detachment). CONCLUSIONS: Failures of pneumatic retinopexy were related to lens
status, localization of the break, and cryopexy. The occurrence of early and late
complications was similar to that in other procedures.
PMID- 10783949
TI - Improvement of visual acuity over time in patients with bilateral geographic
atrophy from age-related macular degeneration.
AB - PURPOSE: To study the improvement in visual acuity over time in patients with
central scotomas. METHODS: In a prospective natural history study of geographic
atrophy (GA) from age-related macular degeneration (ARMD) with annual follow-up,
36 patients with bilateral GA completed 3 years of follow-up. Protocol visual
acuity (VA) measurements were performed. Scanning laser ophthalmoscopy (SLO) was
performed, and the areas of GA were measured from fundus photographs. RESULTS:
Six eyes of six patients with VA ranging from 20/80 to 20/500 had a VA
improvement of two or more lines (mean, 3.2 lines). This was found only in the
worse-seeing eyes of the patients and was contemporaneous with the deterioration
in VA of the better-seeing eyes. Four of six eyes that improved in acuity had an
improvement in the ability to find and hold the fixation target in an area of
seeing retina, as assessed by SLO at follow-up, and a fifth eye changed from one
fixation site that had little functional retina to another site. CONCLUSIONS:
Spontaneous improvement in VA in eyes with bilateral GA and central scotomas may
occur. It appears to be related to deterioration in VA of the better-seeing
fellow eye and is associated with improvement of fixation in the worse-seeing
eye. The worse-seeing eye of a patient with bilateral ARMD may have the potential
for better vision than measured VA indicates. This finding may have implications
for the choice of patients in treatment trials, for interpretation of long-term
results, and for planning and assessment of low vision intervention.
PMID- 10783950
TI - Fixation patterns of idiopathic macular holes after vitreous surgery.
AB - BACKGROUND: Evaluation of idiopathic macular holes with the scanning laser
ophthalmoscope (SLO) has shown fixation to be located at or near the margin of
the hole and above the horizontal meridian in most cases. However, changes
between preoperative and postoperative fixation have not been well studied.
METHOD: We used SLO microperimetry to determine scotomas and fixation points in
13 patients with idiopathic macular holes before and after vitreous surgery. The
distance between preoperative and postoperative fixation points and the direction
of movement were measured. RESULTS: Preoperatively, fixation was found to be at
or near the margin of the macular hole in all eyes and was located above the
horizontal meridian in most (84.6%) eyes. Postoperatively, there was a shift in
the position of the fixation points. The distance between preoperative and
postoperative fixation correlated with the degree of visual improvement (P =
0.032), but the direction of movement was variable. CONCLUSION: A shift in the
position of fixation occurs after macular hole surgery, and the amount of shift
correlates with visual improvement. From this observation, we define the term
functional macular hole closure, characterized by centripetal movement of the
neurosensory retina and improvement in vision, and the broader term anatomic
macular hole closure, in which apparent hole closure may result from gliosis in
the absence of movement of the neurosensory retina, not associated with visual
improvement.
PMID- 10783951
TI - Macular hole retinal detachment in highly myopic eyes: ultrastructure of
surgically removed epiretinal membrane and clinicopathologic correlation.
AB - PURPOSE: To elucidate the pathogenesis of macular hole retinal detachment (RD) in
highly myopic eyes by investigating the ultrastructure of surgically removed
epiretinal membranes (ERM). METHODS: Five consecutive Japanese patients with
macular hole RD in highly myopic eyes underwent vitrectomy with attempted removal
of the ERM around the hole. The surgical specimens were examined by light
microscopy and by scanning and transmission electron microscopy. RESULTS:
Extremely thin, translucent sheets of epiretinal tissue were harvested from all
patients during surgery, resulting in successful retinal reattachment.
Ultrastructural examination revealed that the ERM consisted of cortical vitreous
and various cellular components. Fibrous astrocytes were the major cell
population and extended cytoplasmic processes with membrane-associated vesicles
onto the cortical vitreous. Gap junctions were observed between the
interdigitating processes of fibrous astrocytes. The cortical vitreous contained
abundant newly formed collagen, including fibrous long-spacing collagen,
surrounded by sparsely distributed native vitreous collagen. CONCLUSIONS: Active
synthesis of new collagen may be regulated by fibrous astrocytes by means of
transmission of metabolic substances through gap junctions and cytoplasmic
vesicles. The frequent occurrence of newly formed collagen aggregates may
subsequently lead to a diffusely condensed posterior cortical vitreous that
exerts tangential traction on the posterior retina, causing macular hole RD.
PMID- 10783952
TI - Familial spastic paraplegia and maculopathy with juxtafoveolar retinal
telangiectasis and subretinal neovascularization.
AB - PURPOSE: To describe a previously unreported condition involving familial spastic
paraplegia and a peculiar type of maculopathy. METHODS: Two pairs of siblings
were studied. All four cases underwent serial clinical examinations, fundus
photography, and fluorescein angiography. Two siblings had extensive
investigations. RESULTS: Characteristics of the four cases include spastic
paraplegia diagnosed in the first decade of life and visual loss at about age 9
due to a maculopathy with an abnormal vascular complex. In the early stages,
parafoveal dilatation of the capillary network was noted. The later stages were
characterized by cystic macular degeneration, and seven of eight eyes developed
fibrovascular scars with retinochoroidal anastomoses, pigment migration, and
atrophic changes. In two siblings, electro-oculographic findings were subnormal,
whereas results of electroretinography, magnetic resonance imaging of the brain
and spinal cord, and metabolic and karyotype studies were normal. These siblings
were an Indonesian girl and boy; the other siblings were white males. There was
no consanguinity of the parents and family history was unremarkable. CONCLUSIONS:
This study suggests that the two pairs of siblings have an identical familial and
probably recessive disorder with neurodegenerative changes that have caused
paraplegia and a peculiar maculopathy associated with anomalous retinal vascular
complexes, retinochoroidal anastomoses, and subretinal neovascularization.
PMID- 10783953
TI - Exudative retinal detachment and retinitis associated with acquired syphilitic
uveitis.
AB - PURPOSE: To describe three cases of exudative retinal detachment and focal
retinitis associated with acquired syphilitic uveitis. METHODS: Three patients
who were referred for evaluation of uveitis were examined. Slit-lamp examination,
ophthalmoscopy, B-scan ultrasonography, fundus photography, and fluorescein
angiography were performed before and after therapy. RESULTS: Each patient had
uveitis with exudative retinal detachment, periphlebitis, and focal retinitis.
Laboratory testing (fluorescent treponemal antibody absorption) revealed positive
serology for active syphilis in all cases. Human immunodeficiency virus antibody
testing was negative in all patients. Retinal detachment resolved in all cases
after treatment with intravenous penicillin. Despite resolution of subretinal
fluid, visual acuity remained poor in eyes in which the macula was detached.
CONCLUSION: Syphilis is a cause of exudative retinal detachment. Antibiotic
therapy can lead to retinal reattachment. Early recognition and treatment may
prevent severe vision loss.
PMID- 10783954
TI - Intravitreal injection of hyaluronidase cannot induce posterior vitreous
detachment in the rabbit.
AB - PURPOSE: To investigate whether intravitreal injection of hyaluronidase can
induce posterior vitreous detachment (PVD) in the rabbit. METHODS: One eye each
of 12 New Zealand white rabbits received intravitreal injection via the pars
plana of 20 IU of hyaluronidase (0.1 mL reconstituted in sterile balanced salt
solution [BSS]) into the midvitreous cavity. The fellow eye of each rabbit
received a vitreous injection of 0.1 mL of BSS. At 3 and 6 months after
intravitreal injection, four and eight rabbits were killed, respectively, and the
eyes were enucleated. After fixation, scanning electron microscopy was performed
to study the vitreoretinal interface. RESULTS: At 3 and 6 months after injection,
scanning electron microscopy showed that the retinal surfaces in eyes that
received either hyaluronidase or BSS were covered with vitreous collagen fibers.
No eyes, even those that received hyaluronidase over a period of 6 months, had
the smooth retinal surface consistent with a bare internal limiting lamina that
suggests the development of PVD. CONCLUSION: Hyaluronidase cannot induce PVD in
the rabbit over a 6-month period after vitreous injection.
PMID- 10783955
TI - Presumed parvovirus B19-associated retinal pigment epitheliopathy.
AB - PURPOSE: To describe a patient with a white dot syndrome associated with acute
erythema infectiosum. METHODS: A patient with a clinical history of erythema
infectiosum and multifocal punctate white lesions at the level of the retinal
pigment epithelium was followed up for an 8-month interval. Serum was tested for
immunoglobulin M (IgM) and IgG antibodies to parvovirus B19 at the time of the
initial evaluation and during convalescence using an indirect immunofluorescence
antibody technique. Serial photographs and fluorescein angiograms were obtained.
RESULTS: IgM and IgG antibodies to parvovirus were detected in the serum at the
time of initial evaluation; IgM antibodies had disappeared but IgG antibodies
persisted in serum obtained at 1-month follow-up. Fundus evaluation revealed
clinical disappearance of some lesions, with increased pigmentation of others
over the course of follow-up. CONCLUSION: The authors have identified an adult
patient who presented with a white dot syndrome associated with acute erythema
infectiosum documented by serologically proved parvovirus B19 infection.
PMID- 10783956
TI - Diagnostic and therapeutic challenges.
PMID- 10783957
TI - Diagnostic and therapeutic challenges.
PMID- 10783958
TI - Local recurrence of choroidal melanoma 13 years after successful xenon arc
photoablation.
PMID- 10783959
TI - Breast cancer metastatic to the choroid in a male patient.
PMID- 10783960
TI - Choroidal metastasis and retinal pigment epithelial tear in a patient with small
cell lung carcinoma.
PMID- 10783961
TI - Diffuse infiltrating retinoblastoma: an inherited case.
PMID- 10783962
TI - Choroidal neovascular membrane: a late complication of inactive Toxocara
chorioretinitis.
PMID- 10783963
TI - Improved visual acuity following pars plana vitrectomy for diabetic cystoid
macular edema and detached posterior hyaloid.
PMID- 10783964
TI - Metallic intraocular foreign body impacted in the retina: 12-year follow-up.
PMID- 10783965
TI - Suprachoroidal gas as a complication of pneumatic retinopexy.
PMID- 10783966
TI - Giant retinal tears after photorefractive keratectomy.
PMID- 10783967
TI - Histopathologic study of presumed parafoveal telangiectasis.
PMID- 10783968
TI - Creating local bibliographic databases: new tools for evidence-based health care.
AB - The Internet has created new opportunities for librarians to present literature
search results to clinicians. In order to take full advantage of these
opportunities, libraries need to create locally maintained bibliographic
databases. A simple method of creating a local bibliographic database and
publishing it on the Web is described. The method uses off-the-shelf software and
requires minimal programming. A hedge search strategy for outcome studies of
clinical process interventions is created, and Ovid is used to search MEDLINE.
The search results are saved and imported into EndNote libraries. The citations
are modified, exported to a Microsoft Access database, and published on the Web.
Clinicians can use a Web browser to search the database. The bibliographic
database contains 13,803 MEDLINE citations of outcome studies. Most searches take
between four and ten seconds and retrieve between ten and 100 citations. The
entire cost of the software is under $900. Locally maintained bibliographic
databases can be created easily and inexpensively. They significantly extend the
evidence-based health care services that libraries can offer to clinicians.
PMID- 10783969
TI - Monograph use at an academic health sciences library: the first three years of
shelf life.
AB - OBJECTIVE: To study the circulation of monographs during the first three years of
shelf life at an academic health sciences library. METHOD: A record was kept of
monographs added to the circulating collection from mid-1994 to mid-1995. After
three years, each monograph was located and the number of times it circulated
during the first, second, and third year of shelf life determined by counting
checkout stamps on the circulation slip. RESULTS: Of the 1,958 monographs
studied, 1,674 had complete data for the first three years of shelf life. Of
those 1,674 titles, 81.48% circulated at least once. A total of 7,659
circulations were recorded; 38.69% occurred in the first year of shelf life,
32.37% in the second year, and 28.95% in the third year. The data did not fit the
well-known 80/20 rule. Instead, approximately 38% of monographs accounted for 80%
of circulation. A small percentage, 2.21%, of monographs accounted for a
substantial percentage of circulation, 21.84%. CONCLUSIONS: A large percentage of
the monographs circulated and use did not decline sharply with age within the
first three years of shelf life, indicating a high demand for monographs at this
academic health sciences library. These results, combined with the findings of
earlier studies, suggested two possibilities. First, academic health sciences
libraries might exhibit use of a higher percentage of monograph acquisitions than
other types of libraries; or, second, a low monograph-to-user ratio might result
in a higher percentage of monographs being used. Perhaps both factors contributed
to the results found in this study. Further investigation would be needed to
determine the extent to which library type and monograph-to-user ratio influenced
monograph use.
PMID- 10783970
TI - A study comparing centralized CD-ROM and decentralized intranet access to
MEDLINE.
AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of a
decentralized intranet access in each medical department as opposed to
centralized unique MEDLINE access in the medical library. DESIGN: A two-phase
questionnaire to evaluate MEDLINE use was given to junior and senior physicians
at Rouen University Hospital (RUH). Phase I (August-October 1996) corresponded to
a time period when centralized access was the only means of access available and
phase II (August-October 1997) to a time period following the introduction of
decentralized intranet access. RESULTS: A total of 168 physicians filled out at
least one phase of the questionnaire, among whom 123 (73%) filled out both
phases. Use of MEDLINE significantly increased in 1997 (average of 10.2+/-1.1
searches in three months) versus 1996 (average of 4.9+/-0.7 searches in three
months, P<0.0001). The aim of searches changed, becoming significantly more care
oriented in phase II (P<0.0001). The number of searches performed by the
physicians alone increased (P<0.0001) and searches performed by the librarian
decreased (P<0.0001) in phase II. The method of searches also changed, as
searches by author (P< 0.0001), by journal (P = 0.0042), and by free word (P =
0.0027) increased in phase II. Knowledge of the following concepts of MEDLINE
significantly increased: explosion (P<0.0001), scope note (P<0.0001), Abridged
Index Medicus (AIM) journals (P<0.0001), Medical Subject Headings (MeSH)
qualifier (P<0.0001), and focus (P<0.0001). CONCLUSION: A decentralized intranet
access to MEDLINE increased the number of searches and knowledge of this
bibliographic database. MEDLINE intranet access modified the purpose and the
methods of searching.
PMID- 10783971
TI - A two-year experience teaching computer literacy to first-year medical students
using skill-based cohorts.
AB - Because it is widely accepted that providing information online will play a major
role in both the teaching and practice of medicine in the near future, a short
formal course of instruction in computer skills was proposed for the incoming
class of students entering medical school at the State University of New York at
Stony Brook. The syllabus was developed on the basis of a set of expected
outcomes, which was accepted by the dean of medicine and the curriculum committee
for classes beginning in the fall of 1997. Prior to their arrival, students were
asked to complete a self-assessment survey designed to elucidate their initial
skill base; the returned surveys showed students to have computer skills ranging
from complete novice to that of a systems engineer. The classes were taught
during the first three weeks of the semester to groups of students separated on
the basis of their knowledge of and comfort with computers. Areas covered
included computer basics, e-mail management, MEDLINE, and Internet search tools.
Each student received seven hours of hands-on training followed by a test. The
syllabus and emphasis of the classes were tailored to the initial skill base but
the final test was given at the same level to all students. Student
participation, test scores, and course evaluations indicated that this noncredit
program was successful in achieving an acceptable level of comfort in using a
computer for almost all of the student body.
PMID- 10783972
TI - Outreach to public health professionals: lessons learned from a collaborative
Iowa public health project.
AB - In 1995, the National Library of Medicine (NLM) and the Public Health Service
(PHS) recommended that special attention be given to the information needs of
unaffiliated public health professionals. In response, the National Network of
Libraries of Medicine (NN/LM) Greater Midwest Region initiated a collaborative
outreach program for public health professionals working in rural east and
central Iowa. Five public health agencies were provided equipment, training, and
support for accessing the Internet. Key factors in the success of this project
were: (1) the role of collaborating agencies in the implementation and ongoing
success of information access outreach projects; (2) knowledge of the socio
cultural factors that influence the information-seeking habits of project
participants (public health professionals); and (3) management of changing or
varying technological infrastructures. Working with their funding, personnel from
federal, state, and local governments enhanced the information-seeking skills of
public health professionals in rural eastern and central Iowa communities.
PMID- 10783973
TI - Mapping the literature of cytotechnology.
AB - The major purpose of this study was to identify and assess indexing coverage of
core journals in cytotechnology. It was part of a larger project sponsored by the
Nursing and Allied Health Resources Section of the Medical Library Association to
map the literature of allied health. Three representative journals in
cytotechnology were selected and subjected to citation analysis to determine what
journals, other publication types, and years were cited and how often. Bradford's
Law of Scattering was applied to the resulting list of cited journals to identify
core titles in the discipline, and five indexes were searched to assess coverage
of these core titles. Results indicated that the cytotechnology journal
literature had a small core but wide dispersion: one third of the 21,021 journal
citations appeared in only 3 titles; another third appeared in an additional 26
titles; the remaining third were scattered in 1,069 different titles. Science
Citation Index Expanded rated highest in indexing coverage of the core titles,
followed by MEDLINE, EMBASE/Excerpta Medica, HealthSTAR, and Cumulative Index to
Nursing and Allied Health Literature (CINAHL). The study's results also showed
that journals were the predominantly cited format and that citing authors relied
strongly on more recent literature.
PMID- 10783974
TI - The Research Funding Service: a model for expanded library services.
AB - Traditionally, libraries have provided a modest amount of information about
grants and funding opportunities to researchers in need of research funding. Ten
years ago, the University of Washington (UW) Health Sciences Libraries and
Information Center joined in a cooperative effort with the School of Medicine to
develop a complete, library-based grant and funding service for health sciences
researchers called the Research Funding Service. The library provided space,
access to the library collection, equipment, and electronic resources, and the
School of Medicine funded staff and operations. The range of services now
includes individual consultation appointments, an extensive Web site, classes on
funding database searching and writing grant applications, a discussion series
that frequently hosts guest speakers, a monthly newsletter with funding
opportunities of interest to the six health sciences schools, extensive files on
funding sources, and referral services.
PMID- 10783975
TI - Assessing electronic information access and use in long-term care facilities in
north Texas.
PMID- 10783976
TI - Development of a Web-based faculty publications database.
PMID- 10783977
TI - T. Scott Plutchak, twenty-third editor of the Bulletin of the Medical Library
Association.
PMID- 10783978
TI - Biosynthesis of riboflavin in plants. The ribA gene of Arabidopsis thaliana
specifies a bifunctional GTP cyclohydrolase II/3,4-dihydroxy-2-butanone 4
phosphate synthase.
AB - A cDNA segment from Arabidopsis thaliana with similarity to the ribA gene of
Bacillus subtilis was sequenced. A similar gene was cloned from tomato. The open
reading frame of A. thaliana was fused to the malE gene of Escherichia coli and
was expressed in a recombinant E. coli strain. The recombinant fusion protein was
purified and shown to have GTP cyclohydrolase II activity as well as 3,4
dihydroxy-2-butanone 4-phosphate synthase activity. The cognate gene was
amplified by polymerase chain reaction from chromosomal Arabidopsis DNA and was
shown to contain six introns. Intron 4 is located in the region connecting the
GTP cyclohydrolase II and 3,4-dihydroxy-2-butanone 4-phosphate synthase domain of
the putative domains catalyzing the two reaction steps. By comparison with the
bacterial ribA gene, the Arabidopsis gene contains an additional 5' element
specifying about 120 amino acid residues. This segment contains numerous serine
and threonine residues and does not show similarity with other known sequences.
The N-terminal segment is not required for catalytic activity and is likely to
serve as signal sequence for import into chloroplasts.
PMID- 10783979
TI - Biosynthesis of 20-hydroxyecdysone in Ajuga hairy roots: the possibility of 7-ene
introduction at a late stage.
AB - Administration of [3alpha-2H]-3beta-hydroxy-5beta-cholestan-6-one to hairy roots
of Ajuga reptans var. atropurpurea followed by 2H-NMR spectroscopic analysis of
the resulting 20-hydroxyecdysone so formed revealed that the substrate was
efficiently incorporated into the latter. Additionally, [5beta,7alpha,7beta-2H3]
2beta,3beta-dihydroxy-+ ++5beta-cholestan-6-one was converted into 20
hydroxyecdysone. These findings clearly indicate that Ajuga hairy roots are
capable of introducing a double bond at the 7-position at a late stage of 20
hydroxyecdysone biosynthesis, suggesting the possibility of an alternative
biosynthetic pathway which does not involve 7-dehydrocholesterol as an obligatory
intermediate.
PMID- 10783980
TI - Photo-induced synthesis of tomatidenol-based glycoalkaloids in Solanum phureja
tubers.
AB - The effect of light exposure on the steroidal glycoalkaloid content of Solanum
phureja tubers has been investigated and compared with that in domesticated
potato (Solanum tuberosum) tubers. The results indicated that the increase in the
concentration of solanidine-based glycoalkaloids, alpha-solanine and alpha
chaconine was broadly similar in both species. However, in the S. phureja tubers,
light exposure also induced the synthesis of tomatidenol-based glycoalkaloids.
These have been identified as alpha- and beta-solamarine. These glycoalkaloids
were not detected in tubers continually stored in darkness.
PMID- 10783981
TI - Fungicidal activity of natural and synthetic sesquiterpene lactone analogs.
AB - Fungicidal activity of 36 natural and synthetic sesquiterpene lactones with
guaianolide, trans, trans-germacranolide, cis, cis-germacranolide, melampolide,
and eudesmanolide carbon skeletons was evaluated against the phytopathogenic
fungi Colletotrichum acutatum, C. fragariae, C. gloeosporioides, Fusarium
oxysporum, Botrytis cinerea, and Phomopsis sp. Dose-response data for the active
compounds dehydrozaluzanin C, dehydrocostuslactone, 5alpha
hydroxydehydrocostuslacone, costunolide, and zaluzanin C are presented. A new 96
well microbioassay procedure for fast and easy evaluation of antifungal activity
was used to compare these compounds with commercial fungicide standards. Some
structure-activity conclusions are also presented.
PMID- 10783982
TI - Prenylflavonoid variation in Humulus lupulus: distribution and taxonomic
significance of xanthogalenol and 4'-O-methylxanthohumol.
AB - The resins produced by either lupulin or leaf glands of over 120 plants of
Humulus lupulus and one plant of H. japonicus (Cannabinaceae) were analyzed for
the presence of prenylated flavonoids. The H. lupulus taxa investigated were H.
lupulus var. lupulus from Europe, H. lupulus var. cordifolius from Japan, and H.
lupulus from North America. Fifty-two of the plants examined were cultivars of
European, American, and Japanese origin. Twenty-two flavonoids were detected in
the glandular exudates of H. lupulus by HPLC-MS MS. Xanthohumol (3'-prenyl-6'-O
methylchalconaringenin) was the principal prenylflavonoid in all H. lupulus
plants and was accompanied by 11 structurally similar chalcones. Ten flavonoids
were identified as the flavanone isomers of these chalcones. Three other
prenylchalcones were isolated from H. lupulus cv. 'Galena', one of which was
identified as 3'-prenyl-4'-O-methylchalconaringenin (named 'xanthogalenol'). The
distribution of three 4'-O-methylchalcones, i.e. xanthogalenol, 4'-O
methylxanthohumol, and 4',6'-di-O-methylchalconaringenin, was found to be limited
to wild American plants from the Missouri-Mississippi river basin, H. lupulus
var. cordifolius, and most of their descendents. These 4'-O-methylchalcones were
absent from cultivars of European origin, and from wild hops from Europe and
southwestern USA. The flavonoid dichotomy (presence versus absence of 4'-O
methylchalcones) indicates that there are at least two evolutionary lineages
within H. lupulus (European and Japanese American), which is in agreement with
morphological, molecular, and phytogeographical evidence. Leaf glands of H.
japonicus from eastern Asia did not produce the H. lupulus prenylflavonoids.
PMID- 10783983
TI - Biosynthetic studies on the tropane ring system of the tropane alkaloids from
Datura stramonium.
AB - Isotopic labelling experiments have been carried out in Datura stramonium root
cultures with the following isotopically labelled precursors; [2H3]- [2-13C, 2H3]
, [1-13C, 18O2]-acetates, 2H2O, [2H3-methyl]-methionine, [2-13C]-phenyllactate,
[3-2H]-tropine and [2'-13C, 3-2H]-littorine. The study explored the incorporation
of isotope into the tropane ring system of littorine 1 and hyoscyamine 2 and
revealed that deuterium from acetate is incorporated only into C-6 and C-7, and
not into C-2 and C-4 as previously reported. Oxygen-18 was not retained at a
detectable level into the C(3)-O bond from [1-13C, 18O2]-acetate. The
intramolecular nature of the rearrangement of littorine 1 to hyoscyamine 2 is
revealed again by a labelling study using [2'-13C, 3-2H]-littorine, [2-13C]
phenyllactate and [3-2H]-tropine.
PMID- 10783984
TI - Structure and synthesis of ether-linked proteracacinidin and promelacacinidin
proanthocyanidins from Acacia caffra.
AB - Two new ether-linked proanthocyanidins, epioritin-(4beta-->3)-epioritin-4beta-ol
and epimesquitol-(4beta-->4)-epioritin-4beta-ol, were isolated from the heartwood
of Acacia caffra. Their structures and absolute configurations were established
by spectroscopic methods and syntheses.
PMID- 10783985
TI - Structure and synthesis of the first procassinidin dimers based on epicatechin,
and gallo- and epigallo-catechin.
AB - The range of natural dimeric procassinidins is extended by identification of
cassiaflavan-(4alpha-->8)-epicatechin, cassiaflavan-(4alpha 8)-epigallocatechin,
cassiaflavan-(4beta-->8)-epicatechin, cassiaflavan-(4beta-->8)-epigallocatechin,
cassiaflavan-(4beta-->8)-gallocatechin, ent-cassiaflavan-(4beta-->8)-epicatechin
and cassiaflavan-(4alpha-->6)-epicatechin in the bark of Cassia petersiana. Their
structures and absolute configuration were confirmed by synthesis.
PMID- 10783986
TI - Triterpenoids from Tripterygium wilfordii.
AB - The extract (T(II)) of Tripterygium wilfordii Hook f. afforded four
triterpenoids: wilforic acid D (3beta,24-epoxy-2alpha-hydroxy-24R*-ethoxy-29
friedelanoic acid); (E) 3beta,24-epoxy-2-oxo-3alpha-hydroxy-29-friedelanoic acid;
(F) 2beta-hydroxy-3-oxo-friedelan-29-oic acid; 29-hydroxy-3-oxo-olean-12-en-28
oic acid and 17 known triterpenoids. Their structures were established on the
basis of spectroscopic studies. In a bioactivity analysis, only the known
dulcioic acid compound showed a significant inhibitory effect on cytokine
production.
PMID- 10783987
TI - 6-[omega-arylalkenyl]-5,6-dihydro-alpha-pyrones from Cryptocarya moschata
(Lauraceae).
AB - Eleven 6-[omega-arylalkenyl]-5,6-dihydro-alpha-pyrones, cryptomoscatones D2, E1,
E2, E3 and F1 and cryptopyranmoscatones A1, A2, A3, B1, B2 and B4, in addition to
goniothalamin and cryptofolione, were isolated from branch and stem bark of
Cryptocarya moschata, Lauraceae. Their structures were established by
spectroscopic methods.
PMID- 10783988
TI - Symptom control in advanced gastrointestinal cancer.
AB - Patients with advanced gastrointestinal cancer develop many symptoms as the
disease progresses. However, the common problems of pain, nausea and vomiting,
anorexia, constipation and intestinal obstruction can all be relieved by
appropriate pharmacological treatment.
PMID- 10783989
TI - The role of radiotherapy in the palliative treatment of gastrointestinal cancer.
AB - Gastrointestinal malignancy is the second commonest cancer and is associated with
a high mortality. Although definitive surgery could be offered for most tumour
sites in the gastrointestinal tract, the majority of patients will still develop
incurable recurrent or metastatic disease. Therefore, palliation is an important
part of management. Radiotherapy has long been recognized as an effective
palliative modality in gastrointestinal cancer. It was previously offered in
cases where surgical resection was not feasible either due to the advanced nature
of the disease or the presence of metastatic disease. Planning and delivery of
radiation techniques have improved over the years and it is now possible to offer
high-dose radiation to the tumour with acceptable side-effects. The dose of
radiation offered is important to achieve worthwhile palliation. The advent of
high-dose brachytherapy has contributed significantly to the role of radiotherapy
as an effective palliative modality used either alone or as a boost to external
beam radiotherapy. The addition of chemotherapy to radiation has been used in
most tumour sites in the gastrointestinal tract and has been shown to improve the
therapeutic ratio; however, one should be aware of the increased toxicity and
careful selection of patients is necessary. Chemoradiation could help to down
stage locally advanced tumours which are otherwise unresectable. This approach
has led to improved local control in certain tumour sites, e.g. anal canal and
oesophagus. Whether this translates into improvement in survival remains to be
seen. However, with increasing use of multi-modality therapy, increases in
toxicity to the patient and in cost to healthcare providers must be taken into
account.
PMID- 10783990
TI - Palliative chemotherapy in advanced gastrointestinal cancer.
AB - In this review, the role of chemotherapy in the palliative treatment of advanced
gastrointestinal cancer is discussed. Emphasis is placed on chemotherapy-related
problems, current chemo-therapy options, and new developments.
PMID- 10783991
TI - Endoscopic palliation of gastrointestinal malignancy.
AB - In this paper, we review a range of therapeutic options which may be employed at
endoscopy to alleviate the symptoms of gastrointestinal malignancy.
PMID- 10783992
TI - Surgical and interventional palliative treatment of upper gastrointestinal
malignancies.
AB - Malignancies of the upper gastrointestinal tract, including the oesophagus,
stomach, liver, bile ducts and pancreas, are highly virulent diseases. While
curative therapies relieve symptoms caused by these cancers, most of these
treatments prove unsuccessful in the control of tumour due to occult residual
disease. This review covers only planned palliative procedures for these
conditions where patient factors (e.g. performance status or patient wishes) or
tumour factors (e.g. locally advanced or known metastatic disease) prevent
potentially curative intervention. For most patients, palliation of luminal
obstruction, pain or other symptoms is the most worthwhile treatment that can be
offered with present therapies.
PMID- 10783993
TI - Surgical palliation of colorectal cancer.
PMID- 10783994
TI - What should the clinician know about the cytochrome P450 system?
AB - The cytochromes P450 are a superfamily of enzymes which catalyse mono-oxidation,
thus transforming fat-soluble toxins into water-soluble metabolites which are
excreted in urine. Cytochromes P450 are mainly located in the liver, they play a
major role in hepatotoxicity. The toxins (or the drugs) can be in part
transformed into reactive metabolites which destroy intrahepatocytic proteins
(metabolite-related hepatotoxicity) or form an immune complex that induces immune
reactions (immune-related hepatotoxicity).
PMID- 10783995
TI - Effect of L-arginine on lower oesophageal sphincter motility in man.
AB - OBJECTIVE: Inhibitory responses of the lower oesophageal sphincter (LOS) are
mediated via an L-arginine/nitric oxide (NO) pathway. L-arginine is known as the
precursor of NO. We have studied the effect of intravenous L-arginine on LOS
motility in man. DESIGN: Twelve healthy subjects participated in a double-blind,
placebo-controlled randomized study. METHODS: We investigated the effect of
continuous infusion of L-arginine (500 mg/kg body weight/120 min) in six subjects
under fasting conditions. Six other subjects were studied under postprandial
conditions. LOS pressure (LOSP), swallow-induced LOS relaxations and transient
lower oesophageal sphincter relaxations (TLOSR) were measured with sleeve
manometry combined with pH metry. The meal consisted of a carbohydrate-high fat
meal. Blood samples were taken before and after administration of L-arginine or
saline to determine plasma levels of amino acids, cholecystokinin and gastrin.
RESULTS: Plasma levels of arginine and citrulline significantly (P < 0.05)
increased during L-arginine infusion. L-arginine did not affect plasma hormone
levels. Under fasting conditions, LOSP and TLOSR were not influenced by L
arginine. Ingestion of the carbohydrate-high fat meal significantly decreased
LOSP. L-arginine did not significantly influence TLOSR frequency, either under
fasting conditions or postprandially. CONCLUSIONS: These results suggest that in
humans under fasting or postprandial conditions intravenous infusion of L
arginine does not influence LOS motility.
PMID- 10783996
TI - Pantoprazole 20 mg is an effective maintenance therapy for patients with gastro
oesophageal reflux disease.
AB - OBJECTIVES: To compare the efficacy of 20 mg with 40 mg pantoprazole in
maintaining symptomatic and endoscopic remission in patients with gastro
oesophageal reflux disease (GORD). STUDY DESIGN: Patients (18-84 years old; n =
433) with healed GORD II or III were included in this prospective multi-centre,
randomized, parallel, double-blind study. Pantoprazole was administered once
daily for up to 1 year as either a 20 mg or 40 mg enteric-coated tablet to 221
and 212 patients, respectively. Symptoms of GORD were assessed every 3 months.
Endoscopy was performed at entry, after 6 and 12 months, or when symptoms of GORD
were perceived on at least three consecutive days. The primary efficacy parameter
was the time until endoscopically proven relapse of GORD occurred (stage I or
greater); the secondary parameters included tolerability, safety, and time until
symptomatic relapse occurred. RESULTS: In the 20 mg treatment group, 87% and 75%
of patients were in endoscopic remission after 6 and 12 months, respectively; the
corresponding rates in the 40 mg treatment group were 91% and 78%. In both
treatment groups, GORD stage I accounted for about 50% of endoscopic relapses.
The symptomatic remission rates in the 20 mg group were estimated as 85% and 77%
after 6 and 12 months, respectively; the corresponding values in the 40 mg group
were 87% and 76%. No correlation was seen either between the endoscopically
proven relapse and perception of symptoms, or between the severity of the pre
treatment stage of GORD and the maintenance dose of pantoprazole. Both doses were
well tolerated. CONCLUSIONS: Both the 20 mg and 40 mg doses of pantoprazole are
safe and effective in maintaining patients with healed reflux oesophagitis in
remission. Moreover, for the majority of patients, the 20 mg dose provides
adequate long-term therapeutic efficacy at a minimal drug exposure and lower
costs.
PMID- 10783997
TI - Helicobacter pylori eradication therapy: a discrepancy between current guidelines
and clinical practice.
AB - BACKGROUND: Consensus guidelines recommend that patients with peptic ulcer
disease, and other causes of dyspepsia, should be treated with Helicobacter
pylori eradication regimens. However, it has not been firmly established whether
physicians have adapted their practice accordingly. OBJECTIVES: (1) To establish
the proportion of ulcer-healing prescriptions that H. pylori eradication regimens
accounted for, (2) to evaluate the composition of the eradication regimens used,
and (3) to compare the prescribing patterns of specialist and primary care
practitioners. METHODS: Seven community pharmacy practices were identified, and
all prescriptions for individual acid-suppressing agents and eradication regimens
were prospectively evaluated over an initial one-month period. Prospective
documentation and evaluation of eradication regimens only was then continued for
a further three-month period. RESULTS: The prescriptions for 585 patients were
evaluated. Proton-pump inhibitors and H2-receptor antagonists accounted for 261
(44.5%) and 307 (52.5%) of prescriptions respectively. H. pylori eradication
therapy was prescribed for 17 (2.9%) patients in this initial period. Sixty-six
eradication regimens were evaluated over four months: 48/66 (73%) of these were
initiated by primary care practitioners and 18/66 (27%) by specialists. Thirteen
different combinations of antibiotics and acid-suppressing agents were identified
- many of undocumented efficacy. Dual, triple and quadruple regimens accounted
for 15 (23%), 48 (72.5%) and 3 (4.5%) of patient prescriptions respectively.
CONCLUSION: H. pylori eradication therapy currently accounts for a very small
proportion of ulcer-healing medication in clinical practice. Most eradication
regimens are initiated by primary care practitioners. In comparison with
specialist practices, prescriptions from this source are more likely to be of
undocumented efficacy.
PMID- 10784000
TI - Short-acting general anaesthesia facilitates therapeutic ERCP in frail elderly
patients with benign extra-hepatic biliary disease.
AB - AIMS AND OBJECTIVES: To ascertain whether therapeutic endoscopic retrograde
cholangiopancreatography (ERCP) for benign biliary disease in frail elderly
patients with comorbid conditions can be safely undertaken in a district general
hospital, and whether the procedure is facilitated by the use of short-acting
general anaesthesia. SETTING: District general hospital in South East England.
DESIGN OF STUDY: Clinical study of 25 consecutive patients with benign biliary
disease. METHODS: Describes the process of bile duct clearance by therapeutic
ERCP under short-acting general anaesthesia in 25 patients with co-morbidity aged
> or = 80 years and gives details of the general anaesthesia and monitoring.
RESULTS: Twenty-two patients had their bile ducts successfully cleared locally
and one patient was stented for a benign biliary stricture. The ampullae of two
other patients were lying within diverticula, which hindered cannulation and only
pancreatograms were obtained; one of the patients had a successful bile duct
clearance at a tertiary centre, the other refused further intervention.
Complications (melaena, bronchopneumonia and a Clostridium difficile infection)
occurred in two patients (8%). There was no morbidity associated with the
anaesthesia, and no mortality occurred within 30 days of the procedure.
CONCLUSIONS: Bile duct clearance by therapeutic ERCP can be safely carried out in
frail elderly patients in a district general hospital and the process is
facilitated by the use of short-acting general anaesthesia. The importance of
optimizing the patient's condition before ERCP, and not overfilling the
pancreatic duct, is highlighted.
PMID- 10783998
TI - Assessment of the prevalence of infection with Helicobacter pylori in patients
with inflammatory bowel disease.
AB - OBJECTIVE: To determine the prevalence of Helicobacter pylori in patients with
inflammatory bowel disease (IBD) and compare this to the prevalence in a control
population with non-organic bowel symptoms, and to investigate the effect of
sulphasalazine and other 5-aminosalicylic acid (5-ASA) drugs on the prevalence of
H. pylori in IBD patients. DESIGN: Prospective, controlled trial. SETTING:
Gastroenterology out-patient department, City General Hospital, North
Staffordshire Hospitals NHS Trust, Stoke-on-Trent. PARTICIPANTS: The population
comprised 51 patients with ulcerative colitis, 42 patients with Crohn's disease
and 40 patients with irritable bowel syndrome as controls. Patients with X-ray-
and/or biopsy-proven disease were eligible to be entered into the study.
INTERVENTIONS: Subjects filled in a detailed questionnaire, were assessed for
seropositivity of H. pylori and underwent a C13 urea breath test (UBT). MAIN
OUTCOME MEASURES: Seropositivity for H. pylori and a positive C13 UBT result.
RESULTS: A quarter of the irritable bowel syndrome controls were seropositive for
H. pylori. Of the ulcerative colitis patients, 21.6% were currently H. pylori
positive on C13 UBT; 17.6% of the ulcerative colitis patients who had been
previously treated with sulphasalazine were positive while 23.1% of the
ulcerative colitis patients who had been treated with a non-sulphasalazine 5-ASA
drug were positive. Of the Crohn's patients, 11.9% were currently H. pylori
positive; 3.6% of the Crohn's patients who had been previously treated with
sulphasalazine were positive while 12.5% of the Crohn's patients who had been
treated with a non-sulphasalazine 5-ASA drug were positive. CONCLUSIONS: Patients
with IBD and Crohn's disease in particular were less likely to be H. pylori
positive than controls. Sulphasalazine treatment further decreased the prevalence
of H. pylori, although the reduced prevalence of H. pylori in IBD patients could
not be accounted for by this alone.
PMID- 10783999
TI - Transforming growth factor-beta and hepatocyte growth factor plasma levels in
patients with inflammatory bowel disease.
AB - OBJECTIVE: An increased mucosal expression of transforming growth factor-beta
(TGF-beta) and hepatocyte growth factor (HGF) has been reported in patients with
active inflammatory bowel diseases (IBD) and in proximity to injured gastric and
intestinal mucosal surfaces. The aim of this study was to measure systemic
concentrations of TGF-beta and HGF and to assess their potential value to predict
disease activity or severity of inflammation in patients with inflammatory bowel
diseases. DESIGN AND METHODS: Plasma HGF and TGF-beta1 peptide levels were
determined in 29 patients with ulcerative colitis, 45 patients with Crohn's
disease and 28 healthy controls using commercial ELISA assays. Peptide levels
were correlated with disease activity indices and various laboratory parameters.
RESULTS: HGF and TGF-beta1 plasma levels were detected in all control and IBD
subjects. Although a tendency towards increased HGF and TGF-beta1 peptide levels
in IBD patients was observed, differences between groups were not significant In
ulcerative colitis patients HGF plasma levels positively correlated with white
blood cell counts and negatively correlated with serum albumin concentrations and
haematocrit. In Crohn's disease patients, a positive correlation between TGF-beta
and platelet count was observed. CONCLUSIONS: HGF and TGF-beta1 plasma
concentrations are not significantly different in IBD and healthy control
subjects. Stratification of IBD patients according to disease activity did not
reveal any substantial differences, suggesting that HGF and TGF-beta plasma
levels have no value in the assessment of disease activity or severity of
inflammation in patients with IBD.
PMID- 10784001
TI - Neuropeptide Y and peptide YY, but not pancreatic polypeptide, substance P,
cholecystokinin and gastric inhibitory polypeptide, inhibit the glucagon- and
noradrenaline-dependent increase in glucose output in rat liver.
AB - OBJECTIVE: The gastrointestinal peptides neuropeptide Y (NPY), peptide YY (PYY),
pancreatic polypeptide (PP), substance P (SP), cholecystokinin (CCK) and gastric
inhibitory polypeptide (GIP) are released into the portal vein mainly during the
absorptive phase. Their direct actions and their hormone modulatory effects on
liver carbohydrate metabolism were investigated. METHODS: Isolated rat liver,
single-pass-perfused via both the hepatic artery (120 cm H2O, 30% flow) and the
portal vein (20 cm H2O, 70% flow) with a Krebs-Henseleit buffer containing 5 mM
glucose, 2 mM lactate and 0.2 mM pyruvate, NPY (5 nM), PYY (5 nM), PP (5 nM), SP
(100 nM), CCK (100 nM) and GIP (10 nM) was infused for 10 min via either vessel.
In additional experiments, insulin (100 nM), glucagon (1 nM) or noradrenaline (1
microM) were applied for 5 min via the portal vein during a 20 min portovenous
infusion of one of the peptides. RESULTS: Under basal conditions, neither
arterial nor portal NPY, PYY, PP, SP, CCK or GIP modified hepatic glucose and
lactate metabolism. Also, none of the peptides enabled an action of portal
insulin in the normally insulin-insensitive isolated perfused rat liver. NPY and
PYY, but not PP, SP, CCK or GIP, inhibited the increase in glucose release by
glucagon and noradrenaline. Under basal conditions, none of the peptides altered
hepatic flow. Only portal NPY and PYY enhanced slightly the noradrenaline
dependent reduction of portal flow. CONCLUSIONS: NPY, PYY, PP, SP, CCK and GIP do
not act directly as regulators of basal hepatic carbohydrate metabolism. NPY and
PYY act as signal factors of the absorptive phase function as antagonists of the
postabsorptive glucose regulatory hormones glucagon and noradrenaline.
PMID- 10784002
TI - Serum interferon gamma in primary biliary cirrhosis: effect of ursodeoxycholic
acid and prednisone therapy alone and in combination.
AB - BACKGROUND: Interferon-gamma may have immunopathogenic importance in primary
biliary cirrhosis, stimulating aberrant expression on biliary epithelium of class
II major histocompatibility molecules and inter-cellular adhesion molecule-1.
Liver transcripts for interferon-gamma are found in primary biliary cirrhosis.
Its serum level is increased in pretransplantation stages and decreases after
transplantation. OBJECTIVES: (1) To verify whether serum interferon-gamma levels
are increased in non-cirrhotic stages of primary biliary cirrhosis. (2) To
evaluate the effect of ursodeoxycholic acid and prednisone alone and in
combination on serum levels of interferon-gamma and soluble inter-cellular
adhesion molecule-1. METHODS: Nine non-cirrhotic, anicteric patients with primary
biliary cirrhosis (patient test group), 14 healthy, negative controls and 14
positive controls, with chronic hepatitis related to hepatitis C virus were
studied in basal condition. Primary biliary cirrhosis patients were treated with
ursodeoxycholic acid, prednisone and the association of the two drugs for three 4
week periods, each period separated by a 4-week wash-out. Interferon-gamma and
soluble inter-cellular adhesion molecule-1 were measured in serum by commercially
available immuno-enzymatic kits. RESULTS: Median interferon-gamma levels were
increased in patients with primary biliary cirrhosis compared with healthy
controls (44 vs 19 pg/ml; P < 0.01) but similar to those in chronic hepatitis
patients (47 pg/ml). Serum soluble inter-cellular adhesion molecule-1 was
significantly reduced by ursodeoxycholic acid, and an even greater reduction was
obtained on addition of prednisone. No treatment affected interferon-gamma
levels. CONCLUSION: Serum interferon-gamma is increased in noncirrhotic patients
with primary biliary cirrhosis, but this is not disease-specific. Neither
ursodeoxycholic acid, nor prednisone, nor the combination of the two drugs
influenced this immunological pathway of primary biliary cirrhosis.
PMID- 10784003
TI - Histological estimation of the efficacy of endoscopic laser coagulation therapy
for diffuse antral vascular ectasia.
AB - We present the case of a 72-year-old woman with successful control of repeated
episodes of bleeding from diffuse antral vascular ectasia (DAVE) by laser
coagulation therapy. In addition to DAVE, the patient also suffered from severe
iron deficiency anaemia (due to recurrent bleeding), liver cirrhosis, and huge
tumours of hepatocellular carcinoma (HCC). She was referred from another hospital
after failure to stop her bleeding episodes. Endoscopic examination revealed
diffuse speckled telangiectasia over most of the stomach (from antrum to the
upper portion of the body) and large numbers of blood clots. The patient had
received repeated blood transfusions, haemostatic drugs, and H2 receptor
antagonists at the other hospital, without improvement of the repeated bleeding.
She underwent three sessions of endoscopic laser coagulation therapy for the
lesions at our hospital after the final diagnosis of DAVE had been made based on
the characteristic histological findings of biopsied specimens. This treatment
improved her general condition and stopped the bleeding from the gastrointestinal
tract even without fasting. Unfortunately, however, her liver function gradually
worsened due to HCC and previous massive bleeding, and she finally died of liver
failure three months after the last laser session. Autopsied specimens obtained
from the patient's stomach revealed that macroscopic diffuse speckled
telangiectasia and microscopic typical vasodilatation in mucosal and submucosal
layers of gastric tissue had disappeared in the treated areas but not all
portions of the DAVE lesion. These histological findings for the treated areas,
in addition to the clinical improvement of bleeding, suggest that endoscopic
laser coagulation therapy may be useful and one of the first choices in treatment
for DAVE.
PMID- 10784004
TI - Prevalence of Helicobacter pylori infection in Hungarian gastroenterologists and
general practitioners.
PMID- 10784006
TI - Transfer of pigeons' matching to sample to novel sample locations.
AB - This study examined the conditions under which conditional stimulus control by
the sample stimuli in three-key matching-to-sample paradigms would generalize
across the different possible sample locations. In Experiments 1 and 2, the
samples appeared on the left and right side keys during initial training and then
on the center key during testing. Transfer of pigeons' matching performances to
the center-key samples was evident after both identity and symbolic matching
training. In Experiment 3, pigeons trained on symbolic matching with two side-key
samples or with a side-key and a center-key sample generally transferred their
learned matching performances to those samples when they subsequently appeared in
the remaining (novel) location. These results indicate that, when two-choice
conditional discriminations are learned with more than one sample location, the
visual characteristics of the sample per se predominantly come to control the
pigeons' comparison choices. This finding encourages the use of the multiple
location training procedure as a way of reducing control by location, thus
providing a more discriminating test of symmetry in animals.
PMID- 10784005
TI - Pigeons may not remember the stimuli that reinforced their recent behavior.
AB - In two experiments the conditioned reinforcing and delayed discriminative
stimulus functions of stimuli that signal delays to reinforcement were studied.
Pigeons' pecks to a center key produced delayed-matching-to-sample trials
according to a variable-interval 60-s (or 30-s in 1 pigeon) schedule (Experiment
1) or a multiple variable-interval 20-s variable-interval 120-s schedule
(Experiment 2). The trials consisted of a 2-s illumination of one of two sample
key colors followed by delays ranging across phases from 0.1 to 27.0 s followed
in turn by the presentation of matching and nonmatching comparison stimuli on the
side keys. Pecks to the key color that matched the sample were reinforced with 4
s access to grain. Under some conditions of Experiment 1, pecks to nonmatching
comparison stimuli produced a 4-s blackout and the start of the next interval.
Under other conditions of Experiment 1 and each condition of Experiment 2, pecks
to nonmatching stimuli had no effect and trials ended only when pigeons pecked
the other, matching stimulus and received food. The functions relating pretrial
response rates to delays differed markedly from those relating matching-to-sample
accuracy to delays. Specifically, response rates remained relatively high until
the longest delays (15.0 to 27.0 s) were arranged, at which point they fell to
low levels. Matching accuracy was high at short delays, but fell to chance at
delays between 3.0 and 9.0 s. In Experiment 2, both matching accuracy and
response rates remained high over a wider range of delays in the variable
interval 120-s component relative to the variable-interval 20-s component. The
difference in matching accuracy between the components was not due to an
increased tendency in the variable-interval 20-s component toward proactive
interference following short intervals. Thus, under these experimental conditions
the conditioned reinforcing and the delayed discriminative functions of the
sample stimulus depended on the same variables (delay and variable-interval
value), but were nevertheless dissociated.
PMID- 10784007
TI - Use of number by crows: investigation by matching and oddity learning.
AB - Hooded crows were trained in two-alternative simultaneous matching and oddity
tasks with stimulus sets of three different categories: color (black and white),
shape (Arabic Numerals 1 and 2, which were used as visual shapes only), and
number of elements (arrays of one and two items). These three sets were used for
training successively and repeatedly; the stimulus set was changed to the next
one after the criterion (80% correct or better over 30 consecutive trials) was
reached with the previous one. Training was continued until the criterion could
be reached within the first 30 to 50 trials for each of the three training sets.
During partial transfer tests, familiar stimuli (numerals and arrays in the range
from 1 to 2) were paired with novel ones (numerals and arrays in the range from 3
to 4). At the final stage of testing only novel stimuli were presented (numerals
and arrays in the range from 5 to 8). Four of 6 birds were able to transfer in
these tests, and their performance was significantly above chance. Moreover,
performance of the birds on the array stimuli did not differ from their
performance on the color or shape stimuli. They were capable of recognizing the
number of elements in arrays and comparing the stimuli by this attribute. It was
concluded that crows were able to apply the matching (or oddity) concept to
stimuli of numerical category.
PMID- 10784008
TI - Acquisition of arbitrary conditional discriminations by young normally developing
children.
AB - Three experiments investigated conditions designed to facilitate acquisition of
arbitrary conditional discriminations in 3- to 6-year-old normally developing
children. In Experiment 1, 6 subjects failed to master the arbitrary match-to
sample task under conditions of differential reinforcement alone, but 7 subjects
did so when instructions or instructions and sample naming were added. In
Experiment 2, sample naming introduced in a blocked-trial arrangement resulted in
acquisition, but only when the sample name was a nonsense syllable provided by
the experimenter (5 of 7 subjects) and not when the sample name was generated by
the subject (0 of 5 subjects). Experiment 3 demonstrated the effectiveness of a
training sequence involving thematically related stimuli as an intermediate step
facilitating the transition from identity to novel arbitrary relations. The
difficulties in mastering arbitrary conditional discriminations shown here imply
that further analyses with young children will be particularly important in
efforts to investigate the development of theoretically important stimulus
relations.
PMID- 10784009
TI - The spatial distribution of behavior under varying frequencies of temporally
scheduled water delivery.
AB - Two studies evaluated the effects of response-independent water deliveries on the
location (on the floor of the experimental chamber) and position (height) of
rats' behavior. In both experiments, fixed-time schedules delivered water in two
dispensers that were located at opposite ends of the chamber. In Experiment 1,
the two schedules provided complementary frequencies of water deliveries while
the overall number of deliveries stayed constant. In Experiment 2, one of the
schedules delivered water twice as frequently as the other; this proportion was
kept constant while the overall density of water deliveries changed
systematically. In both experiments, a single position (height) of behavior was
dominant. Also, the percentage of time allocated to each dispenser was roughly
proportional to the percentage of water deliveries associated with the
dispensers. These data and additional considerations support the importance of
examining the spatial properties and patterning of behavior.
PMID- 10784010
TI - Effects of compounding drug-related stimuli: escalation of heroin self
administration.
AB - Previous experiments have demonstrated that presenting independently established
discriminative stimuli in compound can substantially increase operant responding
maintained by food reinforcement or shock avoidance. Recently, this phenomenon
was also shown to occur with cocaine self-administration. The present study
further assessed the generality of these stimulus-compounding effects by
systematically replicating them with heroin self-administration. Rats' nose-poke
responses produced intravenous heroin (0.025 mg/kg per infusion) on a variable
ratio schedule when either a tone or a light was present. In the absence of these
stimuli, responding was not reinforced. Once discriminative control by the tone
and light had been established, the stimuli were presented in compound under
extinction (with heroin discontinued) or maintenance conditions (with heroin
available during test-stimulus presentations). In extinction, the tone-light
compound increased responding approximately threefold compared to tone or light
alone. Under maintenance conditions, compounding increased heroin intake
approximately twofold. These effects closely matched those obtained earlier with
cocaine. This consistency across pharmacological classes and across drug and
nondrug reinforcers further confirms that (a) self-administered drugs support
conditioning and learning in a manner similar to that supported by other
reinforcers; and (b) multiple drug-related cues interact in lawful and
predictable ways to affect drug seeking and consumption.
PMID- 10784011
TI - Varying wheel-running reinforcer duration within a session: effect on the
revolution-postreinforcement pause relation.
AB - Previous investigations of wheel-running reinforcement that manipulated
reinforcer duration across conditions showed a strong relation between wheel
running rate and average postreinforcement pause (PRP) duration. To determine if
the basis of this relation across conditions was a local effect of fatigue or
satiation, the correlation between revolutions run and the duration of the
immediately following PRP was investigated under conditions in which reinforcer
duration was either constant or variable within a session. Seven male Wistar rats
pressed a lever on a fixed-interval 60-s reinforcement schedule with the
opportunity to run for 60 s as the reinforcing consequence. In the constant
duration condition, the duration of the reinforcer was always 60 s. In the
variable-duration condition, the duration of the reinforcer varied between 2 and
240 s with a mean of 60 s. Mean correlations between revolutions run and the next
PRP duration for constant, variable, and constant conditions were -.07, .20, and
.07, respectively. Although the positive correlation in the variable-duration
condition is consistent with an effect of momentary fatigue or satiation, little
of the variance in PRP duration appears to be attributable to these factors.
PMID- 10784012
TI - Do not leave the operating room without it.
PMID- 10784013
TI - Hepatitis C virus infection: review and implications for the orthopedic surgeon.
AB - Hepatitis C virus (HCV), a single-stranded ribonucleic acid virus identified in
1989, is estimated to have infected 1%-2% of the United States population. The
incidence of HCV in patients requiring orthopedic surgery may be as high as 5%.
Surgeons and operating room personnel are at risk for blood-borne diseases
transmitted during surgery. The orthopedic surgeon must be aware of viral
infection with this pathogen for the safety of the entire operating room team.
Further, screening for HCV is routinely done when a patient donates autologous
blood prior to elective surgery, and the orthopedic surgeon is often the first or
only physician informed of a positive result. The surgeon should know how to
interpret the result, advise the patient, and incorporate the diagnosis of HCV
into the plan for the proposed surgery. We will review the natural history,
transmission, evaluation of, and current treatment for infection with this blood
borne virus.
PMID- 10784014
TI - Deep vein thrombosis prophylaxis: a comprehensive approach for total hip and
total knee arthroplasty patient populations.
AB - One of the most catastrophic complications after total joint arthroplasty is a
fatal pulmonary embolism. Thromboembolic disease is particularly a problem in
lower extremity joint arthroplasty secondary to the development of deep vein
thrombosis (DVT) and proximal propagation of the thrombus. The environment
created during total hip and knee arthroplasty fulfills the criteria for DVT
formation: vessel wall damage, venous stasis, and a hypercoagulable state.
Evidence that suggests the insult and primary event in thrombogenesis occurs
during surgery. Until recently, however, the main thrust of DVT prophylaxis has
concentrated on the immediate postoperative period. A more global approach to
patient care during the 6-week period beginning with surgery may result in more
effective DVT prophylaxis. Operative interventions that have proven to be
effective include hypotensive epidural anesthesia and intravenous administration
of heparin. Postoperative pharmaceutical interventions range from standard doses
of aspirin or warfarin to recently studied dosing regimens of low-molecular
weight heparins, antiplatelet agents, and antithrombotic agents. Mechanical
prophylaxis has also proved to be a valuable adjunct in DVT prophylaxis during
these periods. It is hoped that a more comprehensive approach incorporating
several of the aforementioned treatments into a strategy that encompasses the
intraoperative and early and late postoperative periods will maximize the
effectiveness of DVT prophylaxis.
PMID- 10784015
TI - Hepatitis C virus infection: knowledge in the orthopedic community.
AB - A survey with 14 questions pertaining to the natural history, infectiveness, and
diagnosis and treatment of hepatitis C viral infection was given to all
practicing orthopedic surgeons in Portland, Maine. Possible responses were
"true," "false," or "don't know" to the 14 statements. A question regarding any
interest in learning more about the hepatitis C virus was also posed. Most (82%,
23/28) surgeons completed the questionnaire. A total of 72% of the responses were
either wrong or marked "don't know"; most (83%) of the respondents wanted to know
more about the infection about hepatitis C viral infection. Not only are
orthopedic surgeons at risk for exposure to this virus, but also they are often
the first to notify a patient of a positive result after routine hepatitis C
testing of autologous predonated blood. Education programs and journal reviews
should be directed toward this goal.
PMID- 10784016
TI - Use of the entire width of the flexor carpi radialis tendon for the ligament
reconstruction tendon interposition arthroplasty does not impair wrist function.
AB - Although the original technical description of the ligament reconstruction tendon
interposition arthroplasty as treatment for osteoarthritis at the base of the
thumb included use of one half of the width of the flexor carpi radialis (FCR)
tendon, it has been recommended that the entire width be used to simplify harvest
and provide a larger piece of tissue for ligament reconstruction. The objective
of this study was to evaluate preoperative and postoperative wrist motion and
flexion strength, subjectively and objectively, to identify whether the use of
the entire width of the FCR tendon results in decline or weakness. Our findings
show neither subjective nor objective impairment of wrist motion or flexion
strength at 1-year follow-up; 6 months after the procedure, strength had returned
nearly to baseline.
PMID- 10784017
TI - Quantitative anatomy of the scapula.
AB - Thirty adult bony scapulae were used to report detailed bony dimensions of the
scapula. The measurements of bony dimensions of the scapula included the glenoid,
coracoid, spine, and body. The results of the measurements showed that the
thickest bony stock (posteroanterior diameter), with a mean value of 13 mm to 23
mm in the glenoid process, was found in the middle third of the area within 1 cm
medial to the glenoid rim. In the scapular spine region, the greatest
superoinferior diameter of the bone was noted in the lateral portion of the
spine, followed by the medial portion. It was also found that smallest
superoinferior diameter (2 mm to 7 mm) of the spine was located at the middle
portion between the base and ridge along the whole spine. On the lateral border
of the scapula, the posteroanterior diameter of bone was relatively greater for
the upper portion (8 mm) than for the lower portion, including the inferior angle
(6 mm). This information may be helpful in open reduction and internal fixation
of significantly displaced scapular fractures.
PMID- 10784018
TI - A case of recurrent trigger thumb.
AB - In this report we present a case of recurrent trigger thumb after surgical
release. A 3-year-old girl underwent surgical release of the first annular pulley
at another institution. The resected first annular pulley had been confirmed by
pathologic analysis. After surgery the triggering and locking recurred, and she
developed limited function due to persistent pain. The second operative release
revealed a fibrous band in the region of the previous first annular pulley and a
thickened flexor tendon sheath.
PMID- 10784019
TI - A bench-top method for evaluating modular total hip component combinations.
AB - A modular total hip prosthesis allows the surgeon to vary head size, neck length,
and acetabular coverage. Different combinations, however, may increase the risk
of impingement of the prosthesis neck on the acetabular liner, leading to
dislocation. We developed a bench-top model to test different modular component
combinations to determine how far the femoral component could travel within the
acetabular liner before impingement led to dislocation. We tested two hip
systems, each from a different manufacturer. Certain components increased the
risk of impingement and dislocation: skirted necks, smaller heads, and lipped
liners. While the contribution of each component was small, the risk was
additive, so that the combination of a small head with a skirted neck in a lipped
liner actually reduced the available range of motion by 18 degrees, from 146
degrees to 128 degrees, in the first system, and by 13 degrees, from 156 degrees
to 143 degrees in the other. This method could be adapted to test a wide range of
component configurations, from a number of manufacturers. These findings may be
useful in avoiding potentially unstable configurations when given a choice of
modular components.
PMID- 10784020
TI - Coma from fat embolism syndrome after hemiarthroplasty of the hip for metastatic
breast cancer to the proximal femur: a case report.
AB - We present a case report of fat embolism syndrome (FES) that resulted in
prolonged coma after cemented hemiarthroplasty in a patient with metastatic
breast cancer. After the cemented hip prosthesis was placed, the patient
developed decreased sensorium that progressed to coma in association with
hypoxemia and tachypnea. Pulmonary compromise was mild, and the patient required
only supplemental oxygen for support. The patient demonstrated no petechiae.
Magnetic imaging results were consistent with FES. While the pulmonary symptoms
resolved quickly, the patient remained unresponsive for 11 days without
purposeful motor function. After waking she recovered rapidly, and at her 2-month
follow-up appointment, demonstrated no adverse orthopedic, pulmonary, or
neurologic sequelae.
PMID- 10784021
TI - Massive subperiosteal hemorrhage and femoral shaft osteonecrosis: a complication
of tissue plasminogen activator therapy for purpura fulminans.
AB - We present the case of a child who developed a massive subperiosteal hemorrhage
and subsequent osteonecrosis of her right femur after treatment with tissue
plasminogen activator for post-varicella streptococcal purpura fulminans.
Radiographs showed posteromedial translation of the capital femoral epiphysis on
the necrotic shaft, and the hip was immobilized. The femur slowly remodeled and
has continued to grow. The child is independently ambulatory with a 2.1-cm leg
length discrepancy, a varus deformity of the hip, and a valgus distal femur.
PMID- 10784022
TI - Soft tissue hemangioma.
PMID- 10784023
TI - Delayed brachial plexus neurapraxia complicating malunion of the clavicle.
AB - Delayed brachial plexus neurapraxia is a rare complication of midshaft clavicular
fracture. The symptoms are variable and occur insidiously. Surgical decompression
to release the compression of brachial plexus is the treatment of choice and
usually has a good result. We report a patient whose brachial plexus was
compressed by malunion of the clavicle. This patient had a good outcome after
treatment with intramedullary nailing and Knowles pin fixation after corrective
osteotomy without bone grafting.
PMID- 10784024
TI - Extraction of a supracondylar nail through the proximal femur during total hip
arthroplasty.
AB - With the increasing popularity of supracondylar femoral intramedullary nails,
removal of these devices may become necessary during total hip arthroplasty. The
present article describes a technique for extracting these nails in a retrograde
fashion through the proximal femur, thus sparing the patient a knee arthrotomy.
PMID- 10784025
TI - Deamidation of a model hexapeptide in poly(vinyl alcohol) hydrogels and xerogels.
AB - Polymeric controlled release systems have been proposed to prolong the half-lives
of protein and peptide drugs in vivo and to deliver active drug at a controlled
rate. These systems are ineffective, however, if the drug is not stable during
storage and release. This study addresses the effect of poly(vinyl alcohol) on
the stability and release of an incorporated hexapeptide, VYPNGA, which undergoes
deamidation. Two types of peptide-loaded poly(vinyl alcohol) matrices were
formed, a semisolid hydrogel and a lower water content 'xerogel', and stored at
50 degrees C for up to 122 days. The hexapeptide was less stable in both
poly(vinyl alcohol) matrices than in aqueous buffer or lyophilized polymer-free
powders. The type of poly(vinyl alcohol) matrix appeared to influence the
degradation mechanism, since the product distributions differ in the hydrogel and
the xerogel. The results suggest that, rather than stabilizing this peptide,
incorporation in poly(vinyl alcohol) matrices reduces stability relative to
solution and lyophilized controls.
PMID- 10784026
TI - Bioactive fMLF-OMe analogs containing a N-terminal oximic or formylhydrazonic
moiety.
AB - In order to obtain chemotactic peptides with selective bioactivity, a new type of
structural modification was introduced at the N-terminal position of HCO-Nle-Leu
Phe-OMe. Two groups of analogs have been synthesized both containing a N-terminal
residue of the X=C(R)-CO-type replacing the native HCO-NH-CH(R)-CO-. In
particular, the A group of pseudopeptides (2a-d) possesses a N-terminal oximic
fragment (X=HO-N) and the B group (3a-d) a formylhydrazone fragment (X=HCO-NH-N).
These new ligands have been examined for their capacity to induce chemotaxis and
other cellular responses such as superoxide anion production and lysozyme
release; although significantly active as chemoattractants they have been found
to be practically devoid of secretagog activity, thus exhibiting selective
behavior. The adopted chemical modification seems extensible in designing a new
class of pseudopeptides (hydrazonopeptides) structurally related to both
hydrazinopeptides and peptides containing alpha,beta-unsaturated residues.
PMID- 10784027
TI - (1H-benzotriazol-1-yloxy)-N,N-dimethylmethaniminium hexachloroantimonate (BOMI),
a novel coupling reagent for solution and solid-phase peptide synthesis.
AB - A HOBt-based immonium-type compound,(1H-benzotriazol-1-yloxy)-N,N-dimethyl
methaniminium hexachloroantimonate (BOMI), was synthesized and successfully
applied to the synthesis of various oligopeptides with good yields. The
estimation of racemization and the influence of several reaction parameters such
as solvents, bases and temperature were studied by HPLC using a model reaction.
It was found that the reactivity of BOMI was much higher than that of HOBt-based
phosphonium- and uronium-type coupling reagents. Moreover, its racemization was
lower than that of other HOBt-derived coupling reagents. The effectiveness of
BOMI was also demonstrated by the synthesis of Leu-enkephalin both in solution
and in the solid-phase.
PMID- 10784028
TI - 1H-NMR determination of the solution structure and absolute configuration of
FR134043, a novel inhibitor of human leukocyte elastase.
AB - FR134043 is a semisynthetic disulfonated derivative of the natural product
FR901277, is isolated from the culture filtrate of Streptomyces resistomicificus
and has potent inhibitory activity against human leukocyte elastase. Although the
chemical structure of FR134043 was determined to be a unique bicyclic peptide
like compound consisting of seven amino acids by using several spectroscopic
analytical methods, the chiralities of three centers were unknown. A simple
simulated annealing protocol to determine the structure was applied to the eight
possible stereoisomers, and the one that best satisfied the NOE distance
constraints was determined to be the true stereoconfiguration of FR134043. The
solution structure showed that all Calpha atoms existed in the L configuration
and six of the seven side chains were located towards the outside of the bicyclic
framework, even though most of them are highly hydrophobic moieties. The
simulated annealing calculation described here is a frequently used method for
the determination of the solution structure of peptides or small proteins. We
show here that it is also applicable to the determination of the absolute
configuration of macrocyclic compounds produced from natural sources.
PMID- 10784029
TI - Solution stability of salmon calcitonin at high concentration for delivery in an
implantable system.
AB - Salmon calcitonin solutions (50 mg/mL and 100 mg/mL) were placed on stability at
37 degrees C for 1 year in a variety of solvent systems including water, ethanol,
glycerol, propylene glycol (PG) and dimethyl sulfoxide (DMSO). Calcitonin
degradation was monitored by RP-HPLC and size-exclusion chromatography. DMSO and
pH 3.3 solutions provided optimum stability. Conformational stability was also
monitored by FTIR over the 1 year time course and compared with chemical and
physical stability. After 12 months at 37 degrees C, four major conformations
were observed: a beta-sheet conformation (pH 3.3, pH 5.0, 70% DMSO and 70%
glycerol), an aggregate conformation (pH 7.0 water), a strong alpha-helical
conformation (70% EtOH, 70% PG) and a weak alpha-helical conformation (100%
DMSO). No correlation between structure and chemical stability was observed in
which both the beta-sheet structure (pH 3.3, water) and a loose alpha-helical
structure (100% DMSO) demonstrated good stability. However, some correlation was
observed between structure and physical stability, where co-solvents inducing an
alpha-helical structure resulted in a decrease in gelation. These two structural
states associated with improved stability and minimal gelation, indicated that
gelation can be reduced or eliminated by the use of pharmaceutically acceptable
co-solvents. Finally, salmon calcitonin (50 mg/mL) was formulated in 100% DMSO
and delivered from a DUROS implant over 4 months. Delivery at a target dose of 18
microg/day calcitonin at 37 degrees C was confirmed.
PMID- 10784030
TI - Alkylation of cysteine-containing peptides to mimic palmitoylation.
AB - Numerous proteins that are involved in cell signaling and viral replication
require post-translational modification by palmitoylation to function properly.
The molecular details by which this palmitoyl modification affects protein
function remain poorly understood. To facilitate in vitro biochemical and
structural studies of the role of palmitoylation on protein function, a method
was developed for alkylating peptides with saturated C16 groups at cysteine
residues and demonstrated using peptides derived from the palmitoylated region of
Sindbis virus E2 glycoprotein. The synthetic approach takes advantage of
disulfide chemistry to specifically modify only the cysteine residues within
peptides and covalently links C16 groups via disulfide bridges using a new
thioalkylating reagent, hexyldexyldithiopyridine. The chemistry presented here
takes place in solution under mild conditions without the need for protection of
the peptide functional groups. A method for purifying these modified peptides is
also described. This protocol can be of general use to investigators studying the
role of palmitoylation in biological systems.
PMID- 10784032
TI - Structure-activity relationship of truncated and substituted analogues of the
intracellular delivery vector Penetratin.
AB - Peptides derived from the third alpha-helix of the homeodomain (residues 43-58;
Penetratin) of Antennapedia, a Drosophila homeoprotein, were prepared by
simultaneous multiple synthesis. Sets of N- and C-terminally truncated peptides,
as well as a series of alanine substitution analogues, were studied. Cell
penetration assays using human cell cultures with these peptides revealed that
the C-terminal segment 52Arg-Arg-Met-Lys-Trp-Lys-Lys58 of the parent sequence was
necessary and sufficient for efficient cell membrane translocation. Individual
Ala substitutions of the peptide's basic residues led to markedly decreased cell
internalization ability, whereas replacement of hydrophobic residues was
tolerated surprisingly well. Subcellular localization was seen to be affected by
substitutions, with analogues being addressed preferentially to the cytosol or to
the nucleus. Conformational constriction of the Penetratin sequence through
placement and oxidation of flanking cysteine residues afforded a cyclic disulfide
peptide which had lost most of its membrane translocation capacity.
PMID- 10784031
TI - Novel, potent calmodulin antagonists derived from an all-D hexapeptide
combinatorial library that inhibit in vivo cell proliferation: activity and
structural characterization.
AB - Calmodulin is known to bind to various amphipathic helical peptide sequences, and
the calmodulin-peptide binding surface has been shown to be remarkably tolerant
sterically. D-Amino acid peptides, therefore, represent potential nonhydrolysable
intracellular antagonists of calmodulin. In the present study, synthetic
combinatorial libraries have been used to develop novel D-amino acid hexapeptide
antagonists to calmodulin-regulated phosphodiesterase activity. Five hexapeptides
were identified from a library containing over 52 million sequences. These
peptides inhibited cell proliferation both in cell culture using normal rat
kidney cells and by injection via the femoral vein following partial hepatectomy
of rat liver cells. These hexapeptides showed no toxic effect on the cells.
Despite their short length, the identified hexapeptides appear to adopt a partial
helical conformation similar to other known calmodulin-binding peptides, as shown
by CD spectroscopy in the presence of calmodulin and NMR spectroscopy in DMSO.
The present peptides are the shortest peptide calmodulin antagonists reported to
date showing potential in vivo activity.
PMID- 10784033
TI - Short synthetic glycopeptides successfully induce antibody responses to carcinoma
associated Tn antigen.
AB - Glycopeptides containing a tumor-associated carbohydrate antigen (mono-, tri- or
hexa-Tn antigen) as a B-cell epitope and a CD4+ T-cell epitope (PV: poliovirus or
TT: tetanus toxin) were prepared for immunological studies. Several Tn antigen
residues [FmocSer/Thr (alpha-GalNAc)-OH] were successively incorporated into the
peptide sequence with unprotected carbohydrate groups. The tri- and hexa-Tn
glycopeptides were recognized by MLS128, a Tn-specific monoclonal antibody. The
position of the tri-Tn motif in the peptide sequence and the peptide backbone
itself do not alter its antigenicity. As demonstrated by both ELISA and FACS
analysis, the glycopeptides induced high titers of anti-Tn antibodies in mice, in
the absence of a carrier molecule. In addition, the generated antibodies
recognized the native Tn antigen on cancer cells. The antibody response obtained
with a D-(Tn3)-PV glycopeptide containing three alpha-GalNAc-D-serine residues is
similar that obtained with the Tn6-PV glycopeptide. These results demonstrate
that short synthetic glycopeptides are able to induce anticancer antibody
responses.
PMID- 10784034
TI - Surface-active proteins enable microbial aerial hyphae to grow into the air.
PMID- 10784035
TI - Nicotinoprotein (NADH-containing) alcohol dehydrogenase from Rhodococcus
erythropolis DSM 1069: an efficient catalyst for coenzyme-independent oxidation
of a broad spectrum of alcohols and the interconversion of alcohols and
aldehydes.
AB - Extracts from benzyl-alcohol-grown Rhodococcus erythropolis DSM 1069 showed
NAD(P)-independent, N,N-dimethyl-4-nitrosoaniline (NDMA)-dependent alcohol
dehydrogenase activity. The enzyme exhibiting this activity was purified to
homogeneity and characterized. It appears to be a typical nicotinoprotein as it
contains tightly bound NADH acting as cofactor instead of coenzyme. Other
characteristics indicate that it is highly similar to the known nicotinoprotein
alcohol dehydrogenase (np-ADH) from Amycolatopsis methanolica: it is a
homotetramer of 150 kDa; N-terminal amino acid sequencing (22 residues) showed
that 77% of these amino acids are identical in the two enzymes; it has optimal
activity at pH 7.0; it lacks NAD(P)H-dependent aldehyde reductase activity; it
catalyses the oxidation of a broad range of (preferably) primary and secondary
alcohols, either aliphatic or aromatic, and formaldehyde, with the concomitant
reduction of the artificial electron acceptor NDMA. NDMA could be replaced by an
aldehyde, but not formaldehyde, the substrate specificity of the enzyme for the
aldehydes reflecting that for the corresponding alcohols. The latter also applied
to the low aldehyde dismutase activity displayed by the enzyme. From this,
together with the results of the induction studies, it is concluded that np-ADH
functions as the main alcohol-oxidizing enzyme in the dissimilation of many, but
not all, alcohols by R. erythropolis and may also catalyse coenzyme-independent
interconversion of alcohols and aldehydes under certain circumstances. It is
anticipated that the enzyme may be of even wider significance since structural
data indicate that np-ADH is also present in other (nocardioform) actinomycetes.
PMID- 10784036
TI - Ubiquinone limits oxidative stress in Escherichia coli.
AB - Ubiquinone is an essential redox component of the aerobic respiratory chains of
bacteria and mitochondria. It is well established that mammalian ubiquinone can
function in its reduced form (ubiquinol) as a lipid-soluble antioxidant
preventing lipid peroxidation. The objective of this study was to test the
hypothesis that prokaryotic ubiquinone is involved in the defence against
oxidative stress in the cytoplasmic membrane. The rate of superoxide production
by rapidly respiring wild-type Escherichia coli membranes was twofold higher than
in the slowly respiring membranes from a ubiCA knockout mutant. However, large
amounts of superoxide accumulated in the Ubi- membranes compared to wild-type
membranes, which possess superoxide-scavenging ubiquinol. Likewise, the rate of
H2O2 production was twofold higher in the wild-type, but the overall production
of H2O2 was again significantly higher in the Ubi- membranes. Inclusion of a
water-soluble ubiquinone homologue (UQ-1) effectively decreased the amount of
H2O2 produced in the Ubi- membranes in a concentration-dependent manner. Addition
of UQ-2 to the membranes was even more effective in limiting accumulation of H2O2
than was UQ-1, suggesting a role for the side-chain in conferring liposolubility
in the antioxidative defence mechanism. Intracellular H2O2 concentration was
increased 1.8-fold in the ubiCA mutant, and expression of the katG gene, encoding
the catalase hydroperoxidase I, as well as catalase enzyme activity, were
increased twofold in this mutant. The ubiCA mutant was hypersensitive to
oxidative stress mediated by CuSO4 or H2O2; sensitivity to the latter could be
abolished by addition of cysteine. This phenotype was also exhibited by a ubiG
mutant, defective in the last step of UQ biosynthesis and therefore expected to
accumulate several UQ biosynthetic intermediates. These observations support the
participation of reduced ubiquinone as an antioxidant in E. coli. The ubiCA
mutant exhibited a pleiotropic phenotype, being resistant to heat, linolenic acid
and phleomycin. Resistance to the two latter compounds is probably due to reduced
uptake. Like mutants unable to synthesize the quinol oxidase, cytochrome bd, the
ubiCA mutant was also sensitive to dithiothreitol, an effect that is attributed
to inability of the respiratory chain to maintain an appropriate redox balance in
the periplasm.
PMID- 10784037
TI - Incorporation of [2-3H]glycerol into cell surface components of Bacillus subtilis
168 and thermosensitive mutants affected in wall teichoic acid synthesis: effect
of tunicamycin.
AB - A method is described for measuring the synthesis of poly(glycerol phosphate)
[poly(groP)], the major wall teichoic acid (WTA), lipoteichoic acid (LTA) and
phospholipid (P-lipid), through fractionation of [2-3H]glycerol ([2-3H]gro)
labelled Bacillus subtilis cells. When cultures of certain temperature-sensitive
mutants defective in one of several tag genes, encoding enzymes involved in WTA
synthesis, were transferred to the restrictive temperature, the synthesis of WTA
underwent a specific, immediate, block, while that of LTA or P-lipid proceeded
unimpeded. These results, in addition to confirming the role of tag genes,
demonstrated, reciprocally, the specificity of the fractionation procedure used
to distinguish label in WTA from that in LTA or P-lipid. Results of analysis of
other, less severely affected, tag-deficient mutants, as well as of another
genetically unrelated mutant developing comparable morphological phenotypes in
non-permissive conditions, are discussed in relation to a possible mechanism
generating the latter phenotype. Fractionation of B. subtilis 168 cells labelled
either with [2-3H]gro or with [1-14C]N-acetylglucosamine, to which tunicamycin
was added at 0.5 microg ml(-1) (the MIC) revealed a specific and marked
inhibition of poly(groP) as well as of poly(3-O-beta-D-glucopyranosyl-N
acetylgalactosamine 1-phosphate), the minor WTA. However, for 60 min at least,
the syntheses of PG, LTA and P-lipid were barely affected.
PMID- 10784038
TI - The yexA gene product is required for phosphoribosylformylglycinamidine
synthetase activity in Bacillus subtilis.
AB - The yexA gene encodes an 84 amino acid reading frame; in Bacillus subtilis it is
positioned between the purC and purQ genes of the purine biosynthetic operon.
Disruption of yexA resulted in a purine-auxotrophic phenotype. When yexA was
expressed in trans it was able to complement a yexA mutation. Growth experiments
and enzyme analysis of yexA mutant strains revealed a defective
phosphoribosylformylglycinamidine synthetase (FGAM synthetase). In the organisms
in which FGAM synthetase has been studied a single polypeptide is responsible for
activity. In some organisms two separate genes - in B. subtilis the purL and purQ
genes - encode polypeptides with similarity to the N-terminal and the C-terminal
region, respectively, of the single-polypeptide FGAM synthetase. Thus, active
FGAM synthetase in B. subtilis requires the yexA gene product in addition to the
purL and purQ gene products. Open reading frames with sequence similarity to yexA
are found in other Gram-positive organisms, in a cyanobacterium and in
methanogenic archaea. The designation purS is proposed for this novel function in
purine biosynthesis in B. subtilis.
PMID- 10784039
TI - The Bacillus subtilis cysP gene encodes a novel sulphate permease related to the
inorganic phosphate transporter (Pit) family.
AB - Sulphate permeases in the plasma membrane are responsible for uptake of
environmental sulphate used in the sulphate assimilation pathway in bacteria and
plants. Here it is reported that the ORF designated cysP, located on the Bacillus
subtilis chromosome between cysH and five putative genes involved in sulphate
assimilation, encodes a sulphate permease. cysP is able to complement Escherichia
coli cysteine auxotrophs with mutations affecting either the membrane or
periplasmic components of the sulphate-thiosulphate permease. Transport studies
with cell suspensions of a cysA97 E. coli strain transformed with a plasmid
expressing the B. subtilis cysP gene indicated that CysP catalyses sulphate
uptake. Analysis of the primary sequence showed that CysP (354 amino acids,
estimated molecular mass 24 kDa) is a highly hydrophobic protein which has 11
putative transmembrane helices. Sequence comparisons revealed that CysP, together
with the phosphate permease of Neurospora crassa, Pho-4, and E. coli PitA,
belongs to the family of related transporters, the inorganic phosphate
transporter (Pit) family. Among the putative phosphate permeases, CysP shows a
similar size and the same domain organization as the archaeal transporters. This
is the first report of a sulphate permease in a Gram-positive organism.
PMID- 10784040
TI - RT-PCR as a tool for systematic transcriptional analysis of large regions of the
Bacillus subtilis genome.
AB - Transcriptional analysis of five different regions of the Bacillus subtilis 168
genome, comprising a total of 175 kb encoding newly identified genes, was carried
out using the RT-PCR technique as part of the functional analysis of the whole
genome of this bacterium. Amplification of mRNA fragments allowed the detection
of both highly and poorly transcribed genes covering 81% of putative ORFs, and
also the monitoring of variations in the expression level among genes
differentially expressed during particular bacterial growth phases.
PMID- 10784041
TI - Analysis of the Rhizobium leguminosarum siderophore-uptake gene fhuA:
differential expression in free-living bacteria and nitrogen-fixing bacteroids
and distribution of an fhuA pseudogene in different strains.
AB - A mutation was isolated in the Rhizobium leguminosarum gene fhuA, which appears
to specify the outer-membrane receptor for the siderophore vicibactin. The mutant
was defective in iron uptake and accumulated the siderophore vicibactin in the
extracellular medium. Expression of fhuA was regulated by Fe3+, transcription
being higher in iron-depleted cells. Transcription of fhuA was independent of a
functional copy of rpol, a neighbouring gene that specifies a putative ECF sigma
factor of RNA polymerase and which is involved in siderophore production in
Rhizobium. Mutations in fhuA did not detectably affect symbiotic N2 fixation on
peas. An fhuA::gus fusion was expressed by bacteria in the meristematic zone of
pea nodules but not in mature bacteroids. Some other strains of R. leguminosarum
also contain a pseudogene version of fhuA. The sequences of some of these and the
'real' fhuA genes were determined.
PMID- 10784042
TI - Expression and purification of four different rhizobial acyl carrier proteins.
AB - In rhizobia, besides the constitutive acyl carrier protein (AcpP) involved in the
biosynthesis and transfer of common fatty acids, there are at least three
specialized acyl carrier proteins (ACPs): (1) the flavonoid-inducible nodulation
protein NodF; (2) the RkpF protein, which is required for the biosynthesis of
rhizobial capsular polysaccharides; and (3) AcpXL, which transfers 27
hydroxyoctacosanoic acid to a sugar backbone during lipid A biosynthesis. Whereas
the nucleotide sequences encoding the three specialized ACPs are known, only the
amino acid sequence of the AcpP of Sinorhizobium meliloti was available. In this
study, using reverse genetics, the genes for the constitutive AcpPs of S.
meliloti and of Rhizobium leguminosarum were cloned and sequenced. Previously, it
had been shown that NodF and RkpF can be overproduced in Escherichia coli using
the T7 polymerase expression system. Using the same system, the constitutive
AcpPs of S. meliloti and of R. leguminosarum, together with the specialized ACP
AcpXL, were overproduced and purified. All the known ACPs of rhizobia can be
labelled in vivo during expression in E. coli with radioactive beta-alanine added
to the growth medium due to their modification with a 4'-phosphopantetheine
prosthetic group. The availability of all functionally different ACPs should help
to unravel how different fatty acids are targeted towards different biosynthetic
pathways in one organism.
PMID- 10784043
TI - Absence of translationally selected synonymous codon usage bias in Helicobacter
pylori.
AB - Synonymous codon usage in the complete genome of Helicobacter pylori was
investigated. The moderate A+T-richness of the genome (G+C=39 mol%) is reflected
in the overall synonymous codon usage but the frequencies of some codons cannot
be explained by simple mutational biases. A low level of heterogeneity among
genes was observed, but this does not appear to be due to varying mutational bias
or translational selection. Some of the heterogeneity was due to amino acid
composition variation among the encoded proteins, and some may be attributable to
recent acquisition of genes from other species. Since Hel. pylori codon usage is
not dominated by biased mutation patterns, the absence of evidence for
translationally mediated selection among synonymous codons is striking. This has
implications with regard to the life history of this species, and in particular
suggests that Hel. pylori strains are not subject to periods of competitive
exponential growth. Despite the lack of selected codon usage, base composition
immediately after the translation initiation site is skewed, consistent with
selection against secondary structure formation in this region.
PMID- 10784045
TI - Candida albicans CFL1 encodes a functional ferric reductase activity that can
rescue a Saccharomyces cerevisiae fre1 mutant.
AB - Candida albicans, like other pathogens, has to compete with the host for a
limited supply of available iron. Consequently, iron acquisition is likely to be
an important factor for the growth, survival and virulence of this organism. It
was previously demonstrated that C. albicans has a surface-associated ferric
reductase similar to that of Saccharomyces cerevisiae. Therefore, functional
rescue of a S. cerevisiae fre1 mutant was used to isolate a C. albicans ferric
reductase gene (CFL1). This gene has been previously identified. However, the
workers had not observed any functional reductase activity associated with the
gene. The discrepancy with the findings in this report appears to be due to the
clone previously reported carrying a non-contiguous piece of C. albicans DNA.
Results shown in this paper demonstrate that CFL1 transcription is regulated in
response to levels of iron and copper. This is the first demonstration of a
functional ferric reductase gene from C. albicans.
PMID- 10784044
TI - The alpha-amylase gene amyH of the moderate halophile Halomonas meridiana:
cloning and molecular characterization.
AB - Two types of Tn1732-induced mutants defective in extracellular amylase activity
were isolated from the moderate halophile Halomonas meridiana DSM 5425. Type I
mutants displayed amylase activity in the periplasm, and were unable to use any
of the carbon sources tested, including starch and its hydrolysis product
maltose. The type II mutant was affected in the gene responsible for the
synthesis of the extracellular alpha-amylase. This gene (amyH) was isolated by
functional complementation of mutant II and sequenced. The deduced protein (AmyH)
showed a high degree of homology to a proposed family of alpha-amylases
consisting of enzymes from Alteromonas (Pseudoalteromonas) haloplanktis,
Thermomonospora curvata, streptomycetes, insects and mammals. AmyH contained the
four highly conserved regions in amylases, as well as a high content of acidic
amino acids. The amyH gene was functional in the moderate halophile Halomonas
elongata and, when cloned in a multicopy vector, in Escherichia coli. AmyH is
believed to be the first extracellular-amylase-encoding gene isolated from a
moderate halophile, a group of extremophiles of great biotechnological potential.
In addition, H. meridiana and H. elongata were able to secrete the thermostable
alpha-amylase from Bacillus licheniformis, indicating that members of the genus
Halomonas are good candidates for use as cell factories to produce heterologous
extracellular enzymes.
PMID- 10784046
TI - Cellular lipid composition influences stress activation of the yeast general
stress response element (STRE).
AB - The heat inducibility of the yeast heat-shock response (HSR) pathway has been
shown to be critically dependent on the level of unsaturated fatty acids present
in the cell. Here the inducibility by heat or salt of the independently regulated
general stress response (GSR) pathway is shown to be affected in the same way. An
increase in the percentage of unsaturated fatty acids in heat- or salt-acclimated
cells correlated with a decrease in the induction of a general stress-response
promoter-element (STRE)-driven reporter gene by either stress. Despite inducing
reporter gene expression, sorbic acid treatment did not confer salt cross
tolerance on the cells. This failure correlated with a failure to increase the
percentage of unsaturated fatty acids in the cells, suggesting that GSR pathway
induction, in the absence of lipid changes, is insufficient for the induction of
cross-tolerance. Cells grown with fatty acid supplements under anaerobic
conditions provided further evidence for a potential role for lipids in the
acquisition of stress resistance. These cells contained different fatty acid
profiles depending on the fatty acid supplement supplied, exhibited differential
sensitivity to both heat and salt stress, but had not undergone STRE induction.
These results suggest that heat- and salt-stress induction of the GSR are
sensitive to the level of unsaturated fatty acids present in the cell and that
stress cross-tolerance may be a lipid-mediated phenomenon. Given that an
increased level of unsaturated fatty acids also down-regulates heat induction of
the HSR pathway, these observations lead to the provocative hypothesis that lipid
modifications, rather than HSR or GSR pathway induction, are a major contributor
to the induced heat and salt tolerance of yeast cells.
PMID- 10784047
TI - Novel genes involved in the regulation of pathogenicity factor production within
the rpf gene cluster of Xanthomonas campestris.
AB - The synthesis of extracellular enzymes and extracellular polysaccharide (EPS) in
Xanthomonas campestris pathovar campestris (Xcc) is subject to co-ordinate
regulation by a cluster of genes called rpf (for regulation of pathogenicity
factors). These genes are located within a 21.9 kb region of the chromosome
isolated as the cosmid clone pIJ3020. The genes in the left-hand section of this
region of the chromosome have previously been characterized. This paper reports
on the genes in the right-hand section and on the phenotypes of mutants with
transposon insertions in these genes. Sequence analysis identified eight genes or
ORFs with the gene order rpfD-orf1-orf2-orf3-orf4-recJ-rpf E-greA. RecJ and GreA
have established functions in recombination and transcriptional elongation,
respectively. rpfD encoded a protein with some amino acid sequence relatedness to
a hypothetical protein from Caulobacter crescentus and an autolysin response
regulator in Bacillus subtilis. The predicted protein products of orf1, 2 and 3
were related to each other and had substantial amino acid sequence relatedness to
hypothetical proteins from C. crescentus. Transposon insertions in orf1, 2 and 3
had no effect on the synthesis of extracellular enzymes or EPS. The predicted
proteins RpfE and Orf4 showed the highest amino acid sequence relatedness to
hypothetical proteins from Bordetella pertussis and Klebsiella pneumoniae,
respectively. Transposon insertions in rpfE led to reduced levels of some
extracellular enzymes (endoglucanase and protease) and increased levels of others
(polygalacturonate lyase). Transposon insertions in orf4 had no effect on
polygalacturonate lyase but led to reduced levels of protease and endoglucanase.
Levels of EPS were reduced in both rpfE and orf4 mutants. These alterations in
the levels of extracellular enzymes, which were relatively modest (between two-
and threefold), did not affect the pathogenicity of Xcc on turnip. It is proposed
that the gene designation should be rpfI for orf4.
PMID- 10784048
TI - Chromosome mapping of the sweet potato little leaf phytoplasma reveals genome
heterogeneity within the phytoplasmas.
AB - To further understand the genomic diversity and genetic architecture of
phytoplasmas, a physical and genetic map of the sweet potato little leaf (SPLL)
strain V4 phytoplasma chromosome was determined. PFGE was used to determine the
size of the SPLL-V4 genome, which was estimated to be 622 kb. A physical map was
prepared by two-dimensional reciprocal digestions using the restriction
endonucleases BssHII, Smal, Eagl and I-Ceul. Sixteen cleavage sites were located
on the map. Southern hybridizations of digested SPLL-V4 chromosomal DNA were done
using random clones and PCR-amplified genes as probes. This confirmed fragment
positions and located the two rRNA operons and the linked fus/tuf genes encoding
elongation factors G and Tu, respectively, on the physical map. An inversion of
one of the rRNA operons was observed from hybridization data. Sequence analysis
of one of the random clones identified a gid gene encoding a glucose-inhibited
division protein. Digestions of the tomato big bud (TBB) phytoplasma chromosome
with the same four enzymes revealed genome heterogeneity when compared to the
closely related SPLL-V4, and a preliminary chromosome size for the TBB
phytoplasma of 662 kb was estimated. This mapping information has revealed that
significant genome diversity exists within the phytoplasmas.
PMID- 10784049
TI - An acyl-coenzyme A carboxylase encoding gene associated with jadomycin
biosynthesis in Streptomyces venezuelae ISP5230.
AB - Analysis of a region of chromosomal DNA lying between jadR1 and jadI in the gene
cluster for jadomycin biosynthesis in Streptomyces venezuelae ISP5230 detected an
ORF encoding 584 amino acids similar in sequence to the biotin carboxylase (BC)
and biotin carboxyl carrier protein (BCCP) components of acyl-coenzyme A
carboxylases. Multiple sequence alignments of the deduced Jad protein with acyl
coenzyme A carboxylases from various sources located the BC and BCCP components
in the N- and C-terminal regions, respectively, of the deduced polypeptides. The
organization and amino acid sequence of the deduced polypeptide most closely
resembled those in other Gram-positive bacteria broadly classified as
actinomycetes. Disrupting the gene, designated jadJ, severely reduced but did not
eliminate jadomycin production. The disruption had no effect on growth or
morphology of the organism, implying that the product of jadJ is not essential
for fatty acid biosynthesis. It is concluded that jadJ supplies malonyl-coenzyme
A for biosynthesis of the polyketide intermediate that is eventually processed to
form the antibiotic jadomycin B.
PMID- 10784050
TI - The homologous terminal sequence of the Streptomyces lividans chromosome and SLP2
plasmid.
AB - The chromosome of Streptomyces lividans shares 15.4 kb homology with one end of
the linear plasmid SLP2, consisting of a 10.1 kb terminal sequence followed by
the 5.3 kb transposable element Tn4811. The 10.1 kb terminal sequence was
determined. The mean G+C content of this sequence is 67.9 mol% with a striking G
vs C bias in the last kb. The terminal 232 nt contained 10 palindromic sequences
with potential to form complex secondary structures. One typical Streptomyces
coding sequence (designated ORF1) of 2643 bp was predicted in the determined
sequence. The amino acid sequence of the ORF1 product contained a DEAH helicase
motif, and exhibited similarity to type I restriction enzyme HsdR subunits in the
database, suggesting a possible role in replication of the telomeres. However,
all the ORF1 sequences on the chromosome and SLP2 could be simultaneously knocked
out by targeted recombination without affecting the viability of the cells and
the linearity of the chromosome and SLP2. This ruled out ORF1 as an essential
component in the maintenance of the linear chromosome and plasmids.
PMID- 10784051
TI - The 1-kb-repeat-encoded DNA-binding protein as repressor of an alpha-glucosidase
operon flanking the amplifiable sequence AUD1 of Streptomyces lividans.
AB - High-copy-number amplification of the AUD1 element is frequently associated with
the large chromosomal deletions responsible for genetic instability in
Streptomyces lividans TK64. Five ORFs were found in a 7 kb region directly
adjacent to AUD1. The putative products of ORF1, ORF2 and ORF3 showed
similarities to ATP-binding cassette (ABC) sugar transporters, the deduced
protein sequence of ORF4 displayed similarities to alpha-glucosidases whilst no
homology to proteins with known functions was found for ORF5. ORF4 (renamed aglA)
was expressed in Escherichia coli and the protein purified and characterized. An
alpha-glucosidase activity was detected using the synthetic alpha-glucoside p
nitrophenyl alpha-D-glucopyranoside. Of the many oligosaccharides tested, only
sucrose was hydrolysed at a measurable rate [specific activity 32.4 units (mg
protein)(-1)] but no growth of S. lividans TK64 on sucrose was observed. A strain
in which aglA was disrupted showed the same low alpha-glucosidase activity as
strain TK64 and in both strains no stimulation of activity was seen by sucrose,
trehalose or maltose; dextrin increased alpha-glucosidase activity about 10-fold.
This probably resulted from induction of a second alpha-glucosidase-encoding
gene. The AUD1 element contains three 1 kb repeats which encode DNA-binding
proteins necessary for high-frequency amplification. In strains with a unique 1
kb repeat, disruption of the repeat led to a significant increase in the alpha
glucosidase activity. These results strongly suggest that the 1-kb-repeat-encoded
proteins of AUD1 have a dual function: they are the repressors of the agl genes
and they promote amplification of AUD1.
PMID- 10784052
TI - Six putative two-component regulatory systems isolated from Lactococcus lactis
subsp. cremoris MG1363.
AB - The genetic elements specifying six putative two-component regulatory systems
(2CSs) were identified on the chromosome of Lactococcus lactis MG1363. These 2CSs
appear to represent distinct loci, each containing a histidine kinase and
response-regulator-encoding gene pair. Transcriptional analysis of the six 2CSs
was performed either by generating transcriptional fusions to a reporter gene or
by primer extension. Two of the systems appeared to be expressed constitutively
at a high level, whilst the remaining four exhibited growth-phase-dependent
expression. Insertional mutagenesis established that the two constitutively
expressed 2CSs are necessary for normal cell growth and/or survival. Mutational
analysis of the remaining four systems revealed that they are implicated in
susceptibility to extreme pH, osmotic or oxidative conditions, or the regulation
of phosphatase activity in L. lactis.
PMID- 10784053
TI - Lactococcin 972, a bacteriocin that inhibits septum formation in lactococci.
AB - Addition of lactococcin 972 to exponentially growing sensitive cultures of
Lactococcus lactis resulted in cell elongation and widening. Thin sections
revealed that septum invagination was blocked. Cell growth progressed until most
cells showed equatorial constriction and even initial deposition of material at
the septum ring, although cell division did not proceed any further. The increase
in the incorporation of labelled precursors into the cell wall shifted from an
exponential to a linear mode in treated cultures, subsequently being arrested.
Gross degeneration of the cells was observed prior to cell death, followed by
slow lysis of the culture. In contrast, stationary-phase cultures remained
unaffected.
PMID- 10784054
TI - A Clostridium difficile gene encoding flagellin.
AB - Six strains of Clostridium difficile examined by electron microscopy were found
to carry flagella. The flagella of these strains were extracted and the N
terminal sequences of the flagellin proteins were determined. Four of the strains
carried the N-terminal sequence MRVNTNVSAL exhibiting up to 90% identity to
numerous flagellins. Using degenerate primers based on the N-terminal sequence
and the conserved C-terminal sequence of several flagellins, the gene encoding
the flagellum subunit (fliC) was isolated and sequenced from two virulent
strains. The two gene sequences exhibited 91% inter-strain identity. The gene
consists of 870 nt encoding a protein of 290 amino acids with an estimated
molecular mass of 31 kDa, while the extracted flagellin has an apparent molecular
mass of 39 kDa on SDS-PAGE. The FliC protein displays a high degree of identity
in the N- and C-terminal amino acids whereas the central region is variable. A
second ORF is present downstream of fliC displaying homology to
glycosyltransferases. The fliC gene was expressed in fusion with glutathione S
transferase, purified and a polyclonal monospecific antiserum was obtained.
Flagella of C. difficile do not play a role in adherence, since the antiserum
raised against the purified protein did not inhibit adherence to cultured cells.
PCR-RFLP analysis of amplified flagellin gene products and Southern analysis
revealed inter-strain heterogeneity; this could be useful for epidemiological and
phylogenetic studies of this organism.
PMID- 10784055
TI - Genetic characterization of pilin glycosylation in Neisseria meningitidis.
AB - Pili of Neisseria meningitidis are a key virulence factor, being the major
adhesin of this capsulate organism and contributing to specificity for the human
host. Pili are post-translationally modified by addition of an O-linked
trisaccharide, Gal(beta1-4)Gal(alpha1-3)2,4-diacetimido-2,4,6-trideoxyhexose++ +.
In a previous study the authors identified and characterized a gene, pglA,
encoding a galactosyltransferase involved in pilin glycosylation. In this study a
set of random genomic sequences from N. meningitidis strain MC58 was used to
search for further genes involved in pilin glycosylation. Initially, an open
reading frame was identified, and designated pglD (pilin glycosylation gene D),
which was homologous to genes involved in polysaccharide biosynthesis. The region
adjacent to this gene was cloned and nucleotide sequence analysis revealed two
further genes, pglB and pglC, which were also homologous with genes involved in
polysaccharide biosynthesis. Insertional mutations were constructed in pglB, pglC
and pglD in N. meningitidis C311#3, a strain with well-defined LPS and pilin
linked glycan structures, to determine whether these genes had a role in the
biosynthesis of either of these molecules. Analysis of these mutants revealed
that there was no alteration in the phenotype of LPS in any of the mutant strains
as judged by SDS-PAGE gel migration. In contrast, increased gel migration of the
pilin subunit molecules of pglB, pglC and pglD mutants by Western analysis was
observed. Pilin from each of the pglB, pglC and pglD mutants did not react with a
terminal-galactose-specific stain, confirming that the gel migration differences
were due to the alteration or absence of the pilin-linked trisaccharide structure
in these mutants. In addition, antisera specific for the C311#3 trisaccharide
failed to react with pilin from the pglB, pglC, pglD and galE mutants. Analysis
of nucleotide sequence homologies has suggested specific roles for pglB, pglC and
pglD in the biosynthesis of the 2,4-diacetimido-2,4,6-trideoxyhexose structure.
PMID- 10784056
TI - Identification of Staphylococcus aureus genes expressed during growth in milk: a
useful model for selection of genes important in bovine mastitis?
AB - Staphylococcus aureus is a major cause of bovine mastitis. Since gene expression
of many bacteria is known to be regulated by the environment, milk may play an
important role in the regulation of the early steps in the pathogenesis of bovine
mastitis by S. aureus. To get insight into the response of S. aureus to the milk
environment, a Tn917-lacZ mutant library was generated and screened for genes
specifically expressed during growth in milk. Twenty-eight mutants were
identified and analysed. Four groups of genes were found, involved in cell-wall
synthesis, nucleotide synthesis, transcriptional regulation and carbohydrate
metabolism. A fifth group contained genes with hypothetical or unknown functions.
Many of the genes identified belonged to biosynthetic pathways of S. aureus and
other bacterial species which have also been shown to play a role in vivo as
determined in murine infection models. Therefore, growth on milk may be an
attractive model for the identification of genes preferentially expressed during
bovine mastitis.
PMID- 10784057
TI - Biochemical characterization of different types of adherence of Vibrio species to
fish epithelial cells.
AB - Vibrio species are Gram-negative bacteria that cause a systemic infection in fish
called vibriosis. The authors previously demonstrated that internalization and
cytotoxicity are important virulence mechanisms in vibrio-fish epithelial cell
interactions. Adherence is a prerequisite for successful internalization. In this
study, the adherence capability of two invasive strains [V. anguillarum 811218-5W
and G/Virus/5(3)] was compared with that of two non-invasive strains [V. damselae
ATCC 33539 and V. anguillarum S2/5/93(2)] using adherence assays in three
different types of fish cells (epithelial papillosum of carp, EPC; grunt-fin
tissue, GF; and fat-head minnow epithelial cells, FHM). For all four strains
there was no significant difference (P>0.05) in the adherence to the different
cell lines. V. anguillarum 811218-5W exhibited the highest adherence, followed by
G/Virus/5(3) and S2/5/93(2); V. damselae ATCC 33539 showed the lowest adherence.
The super-adherence characteristic of V. anguillarum 811218-5W on EPC cells was
not affected by inhibitors, sugars, low temperature (4 degrees C) incubation, or
non-biological surfaces such as glass coverslips. The galactose-linked adherence
characteristic of V. anguillarum G/Virus/5(3) to the EPC cells was partially
inhibited by peptidase treatment of the fish cells, low-temperature incubation,
and addition of sugars that contained galactose (such as lactose and N-acetyl-D
galactosamine). De novo synthesis of bacterial protein, viable bacteria and
intact carbohydrate structure of vibrios were required for both super-adherence
and galactose-linked adherence. These adherence characteristics were also found
in ten other invasive vibrios, and galactose-linked adherence was found in nine
invasive vibrios.
PMID- 10784058
TI - Molecular analysis of genetic differences between virulent and avirulent strains
of Aeromonas hydrophila isolated from diseased fish.
AB - Aeromonas hydrophila, a normal inhabitant of aquatic environments, is an
opportunistic pathogen of a variety of aquatic and terrestrial animals, including
humans. A. hydrophila PPD134/91 is defined as virulent whereas PPD35/85 is
defined as avirulent on the basis of their different LD50 values in fish.
Suppression subtractive hybridization (SSH) was used to identify genetic
differences between these two strains. Sixty-nine genomic regions of differences
were absent in PPD35/85, and the DNA sequences of these regions were determined.
Sixteen ORFs encoded by 23 fragments showed high homology to known proteins of
other bacteria. ORFs encoded by the remaining 46 fragments were identified as new
proteins of A. hydrophila, showing no significant homology to any known proteins.
Among these PPD134/91-specific genes, 22 DNA fragments (21 ORFs) were present in
most of the eight virulent strains studied but mostly absent in the seven
avirulent strains, suggesting that they are universal virulence genes in A.
hydrophila. The PPD134/91-specific genes included five known virulence factors of
A. hydrophila: haemolysin (hlyA), protease (oligopeptidase A), outer-membrane
protein (Omp), multidrug-resistance protein and histone-like protein (HU-2).
Another 47 DNA fragments (44 ORFs) were mainly present in PPD134/91, indicating
the heterogeneity among motile aeromonads. Some of these fragments encoded
virulence determinants. These included genes for the synthesis of O-antigen and
type II restriction/modification system. The results indicated that SSH is
successful in identifying genetic differences and virulence genes among different
strains of A. hydrophila.
PMID- 10784059
TI - The gene encoding P27 lipoprotein and a putative antibiotic-resistance gene form
an operon in Mycobacterium tuberculosis and Mycobacterium bovis.
AB - P27 is an antigenic membrane lipoprotein synthesized by members of the
Mycobacterium tuberculosis complex. Northern blotting and RT-PCR experiments
indicated that the genes encoding P27 and a putative antibiotic transporter (P55)
form an operon. A promoter region was identified and characterized by deletion
analysis in Mycobacterium smegmatis. Two transcription initiation points were
mapped in Mycobacterium bovis BCG by primer extension analysis to 76 bp and 87 bp
upstream of the ATG initiation codon. Putative -10 and -35 promoter consensus
sequences associated with these showed 66% similarity to previously identified
mycobacterial promoters. These results suggest that the P27/P55 operon is
transcribed from two promoters in M. bovis BCG.
PMID- 10784060
TI - In vitro characterization of porcine hepatocyte function.
AB - The clinical consequences of acute liver failure are associated with high
mortality. Intensive medical intervention is required to treat the symptoms of
liver failure, including coagulopathy, metabolic instability, and encephalopathy.
Providing temporary liver support with an extracorporeal liver assist device
could stabilize the patient until a donor liver became available or the patient's
own liver was able to recover. The use of human hepatocytes as the biologic
component of the assist device is precluded by the scarcity of available tissue
and the limited proliferative potential of adult hepatocytes in vitro.
Consequently, porcine hepatocytes are being evaluated as a cell source for liver
assist devices. Maintaining differentiated function in isolated hepatocytes,
however, remains a challenge in the development of this technology and is
complicated by the fact that the key therapeutic functions for short-term
survival have not been well defined. Several approaches have been effective in
prolonging rodent hepatocyte function in vitro, including manipulation of
extracellular matrix. Here, we have investigated porcine hepatocyte function in
vitro with a specific emphasis on the response to exogenous collagen matrix. In
control cultures, albumin secretion increased during the first 7-10 days of
culture to an average of 50 +/- 17 microg/day/10(6) cells and then decreased over
the next 2 weeks. The pattern of urea synthesis was slightly different in that it
was highest in the first 1-3 days postisolation (140 +/- 19 microg/day/10(6)
cells) and then decreased by about 50% to a plateau level that was stable during
the next 3-4 weeks of culture. Cytochrome P450-mediated activities were the most
labile with time in culture and were undetectable after the first week in the
absence of pharmacological inducers. In contrast to results reported for rat
cells, porcine hepatocytes exhibited differentiated function in the absence of
any modification of the culture dish surface and function was not increased or
prolonged in the presence of exogenous collagen.
PMID- 10784061
TI - Optimal insulin treatment in syngeneic islet transplantation.
AB - Insulin-induced normoglycemia has shown to have a beneficial effect on the
outcome of pancreatic islets transplanted to diabetic recipients. The aim of the
study was to identify the insulin treatment that can maximize its beneficial
effect on islet transplants. Six groups of streptozotocin diabetic C57Bl/6 mice
were transplanted (Tx) with 100 syngeneic islets, an insufficient beta cell mass
to restore normoglycemia, and were treated with insulin as follows: group 1 (n =
9): from day 10 before Tx to day 14 after Tx; group 2 (n = 11): from day 6 before
Tx to Tx day; group 3 (n = 11): from Tx day to day 6 after Tx; group 4 (n = 7):
from Tx day to day 14 after Tx; group 5 (n = 8): from day 10 to day 24 after Tx;
group 6 (n = 18): Tx mice were not treated with insulin. Sixty days after Tx,
normoglycemia was achieved in 100% of mice in groups 1, 4, and 5, in 73% of mice
in group 2, and in only 45% and 33% of mice in groups 3 and 6, respectively (p <
0.01). Intraperitoneal glucose tolerance, determined only in normoglycemic mice,
was similar in groups 1, 2, 4, and normal controls. In contrast, normoglycemic
mice from groups 3, 5, and 6, exposed to more severe and prolonged hyperglycemia
after Tx, showed higher glucose values after glucose injection, suggesting that
hyperglycemia had a long-lasting deleterious effect on transplanted beta cell
function. The initially transplanted beta cell mass was maintained in the grafts
of normoglycemic mice, but was severely reduced in hyperglycemic mice.
Transplanted beta cell mass was similar in normoglycemic groups with normal or
impaired glucose tolerance, indicating that impaired glucose tolerance was not
due to reduced beta cell mass. In summary, the beneficial effect of insulin
induced normoglycemia on transplanted islets was maximal when insulin treatment
was maintained the initial 14 days after transplantation. Exposure to sustained
hyperglycemia initially after transplantation had a long-lasting deleterious
effect on transplanted islets.
PMID- 10784062
TI - The risks of total pancreatectomy and splenic islet autotransplantation.
AB - The intraportal site is the most common site for islet transplantation. Many
other sites have been tried experimentally, including the spleen, which has
successfully lead to insulin independence in a number of animal models.
Nevertheless, there are no detailed reports of total pancreatectomy and splenic
islet autotransplantation in humans. Five patients underwent total pancreatectomy
and splenic islet autotransplantation for chronic pancreatitis. Four patients had
a pylorus-preserving total pancreatectomy and one patient a duodenal-preserving
pancreatectomy. In three cases islets were embolized into both the portal vein
and spleen. Two patients received splenic islet transplants alone. Islets were
transplanted by retrograde venous infusion via the short gastric veins (n = 3),
splenic vein stump (n = 1), and the left gastroepiploic vein (n = 1). The total
volumes of transplanted pancreatic digest in those receiving combined intraportal
and splenic autografts (n = 3) were 15.8, 13.0, and 13.5 ml. The volumes in those
receiving a splenic-alone autograft (n = 2) were 12.0 and 5 ml. The mean rise in
portal pressure was 18 cm of water. Complications related to the splenic
autograft included a wedge splenic infarct, an emergency splenectomy, and a
portal vein thrombosis in one patient having a combined intraportal and splenic
autograft. Two patients developed insulin independence. two patients were still
insulin independent at 1-year follow-up, and all had normal HbA1c levels (mean
5.6, range 5.2-6.3). Splenic islet autotransplantation, after total
pancreatectomy, does lead to insulin independence. However, in our experience the
combined procedure has a high morbidity because of splenic infarction and venous
thrombosis.
PMID- 10784063
TI - Chitosan-polyvinyl pyrrolidone hydrogels as candidate for islet immunoisolation:
in vitro biocompatibility evaluation.
AB - The success of immunoisolation devices for islet transplantation depends on the
nature of semipermeable membranes, which permit the crossover of micronutrients,
glucose, and insulin and prevent the entry of immunocytes and other transplant
rejection mechanisms. In the present study we examined the properties of chitosan
polyvinyl pyrrolidone (PVP) hydrogels for possible application as an
immunoisolation device. Hydrogels with two different proportions of chitosan-PVP
(M1 1:1 and M2 2:1, v/v) were synthesized by cross-linking with glutaraldehyde.
Hydrogels were characterized for their hydrophilic nature, protein adsorption,
diffusion properties, cytotoxicity, and islet compatibility. Hydrogel membranes
were found to be hydrophilic as determined by high octane contact angle value
(M1: 142.9 +/- 0.46; M2: 143.6 +/- 0.49). Protein adsorption on the hydrogels was
found to be low (0.0143 +/- 0.0027 mg for M1 and 0.0136 +/- 0.0049 mg for M2)
compared to tissue culture polystyrene (TCPS) (0.0434 +/- 0.001 mg) and pure
chitosan (0.0214 +/- 0.0025 mg) control. Hydrogel M1 was tested as a
representative for diffusion studies. M1 allowed regulated transport of insulin
and did not allow anti-insulin antibodies to pass through. In vitro
biocompatibility of M1 and M2 was found to be excellent with no cytotoxic effects
on the HeLa cells as determined by MTT and NR assay. Mouse islets cultured on the
hydrogel membranes retained their integrity and intact morphology as assessed by
image analysis study. Viability of islets cultured on hydrogels was comparable to
that of controls (M1: 97%; M2: 90.4%) as assessed by trypan blue dye exclusion
test. Islets retained their functionality when cultured on hydrogels, as judged
by insulin secretion in response to glucose challenge (16.0 mM). Although in vivo
experiments are awaited, the present study provides sufficient documentation to
consider chitosan-PVP membranes as potential candidates for immunoisolation of
islets.
PMID- 10784064
TI - Storage and microencapsulation of islets for transplantation.
AB - Microencapsulation is an effective means of immunoisolation for pancreatic islet
transplants. However, the process of isolating, purifying, encapsulating, and
transplanting islets in a single day is labor intensive and difficult for routine
use. There is an apparent need for reliable methods of islet storage, and
cryopreservation has emerged as an attractive system of islet banking. While
studies have shown that cryopreserved islets are viable when tested
unencapsulated after thawing, it is not clear if the combination of freezing and
encapsulation would affect islet function. The purpose of the present study was
to determine the in vitro function of cryopreserved islets following thawing and
microencapsulation. Islets were isolated from the pancreata of Sprague-Dawley
rats and cryopreserved under liquid nitrogen for either 1 week or 1 month,
following an overnight culture at 37 degrees C. Upon thawing, the islets were
tested either unencapsulated or after encapsulation in polylysine-alginate
membrane. In all experiments islets were preperifused for 1 h at 37 degrees C
with a modified Krebs-Ringer bicarbonate buffer containing 3.3 mM (60 mg/dl)
glucose and maintained at pH 7.4 by continuous gassing with 95% air/5% CO2.
Following basal effluent sample collection on ice, the glucose concentration was
raised to 16.7 mM (300 mg/dl). It was found that, within 10 min of high glucose
stimulation, an average of twofold increase in insulin secretion (p < 0.01) was
obtained in islets within or without microcapsules. We conclude that islets
cryopreserved for 1 month prior to thawing and microencapsulation retained
functional viability as determined in in vitro experiments.
PMID- 10784065
TI - Chemotaxis activation of peritoneal murine macrophages induced by the
transplantation of free and encapsulated pancreatic rat islets.
AB - The present study concerns the influence of the transplantation of free and
encapsulated (AN69 membrane, Hospal) islets on the chemotaxis of peritoneal
macrophages. Fifty free or encapsulated rat islets, cultured for 24 h, were
transplanted in the peritoneal cavity of mice (n = 12). Three days after
transplantation, the chemotaxis of peritoneal murine macrophages was tested
towards formyl-methionyl-leucyl-phenylalanine (fMLP) and a culture medium
conditioned for 3 days by free rat islets isolated from the same rat donor. In
response to fMLP, the chemotactic indexes of macrophages from mice transplanted
with free or encapsulated islets were 8.09 +/- 2.10 and 9.45 +/- 2.76,
respectively. These values were significantly higher than those obtained when
macrophages from untreated mice were tested (2.42 +/- 0.23; p < 0.01). In
response to culture medium conditioned by free islets, the transplanted
encapsulated islets failed to enhance macrophage chemotaxis (2.41 +/- 0.53)
compared to transplanted free islets (7.00 +/- 2.63; p < 0.01). Thus,
encapsulation decreased the specific chemotactic activity of peritoneal
macrophages induced by free islet transplantation, probably by prohibiting the
diffusion of chemoattractants.
PMID- 10784066
TI - Increased survival of dopaminergic neurons in striatal grafts of fetal ventral
mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived
neurotrophic factor.
AB - The transplantation of fetal mesencephalic cell suspensions into the brain
striatal system is an emerging treatment for Parkinson's disease. However, one
objection to this procedure is the relatively poor survival of implanted cells.
The ability of neurotrophic factors to regulate developmental neuron survival and
differentiation suggests they could be used to enhance the success of cerebral
grafts. We studied the effects of neurotrophin-3 (NT-3) or glial cell line
derived neurotrophic factor (GDNF) on the survival of dopaminergic neurons from
rat fetal ventral mesencephalic cells (FMCs) implanted into the rat striatum. Two
conditions were tested: (a) incubation of FMCs in media containing NT-3 and GDNF,
prior to grafting, and (b) co-grafting of FMCs with cells engineered to
overexpress high levels of NT-3 or GDNF. One week after grafting into the rat
striatum, the survival of TH+ neurons was significantly increased by pretreatment
of ventral mesencephalic cells with NT-3 or GDNF. Similarly, co-graft of ventral
mesencephalic cells with NT-3- or GDNF-overexpressing cells, but not the mock
transfected control cell line, increased the survival of graft-derived
dopaminergic neurons. Interestingly, we also found that co-grafting of GDNF
overexpressing cells was less effective than NT-3 at improving the survival of
fetal dopaminergic neurons in the grafts, and that only GDNF induced intense TH
immunostaining in fibers and nerve endings of the host tissue surrounding the
implant. Thus, our results suggest that NT-3, by strongly enhancing survival, and
GDNF, by promoting both survival and sprouting, may improve the efficiency of
fetal transplants in the treatment of Parkinson's disease.
PMID- 10784067
TI - Survival, neuronal differentiation, and fiber outgrowth of propagated human
neural precursor grafts in an animal model of Huntington's disease.
AB - Expanded neural precursor cells provide an attractive alternative to primary
fetal tissue for cell replacement therapies in neurodegenerative diseases. In
this study we transplanted epigenetically propagated human neural precursor cells
into a rat model of Huntington's disease. Neural precursors survived
transplantation and large numbers differentiated to express neuronal antigens,
including some that expressed DARPP-32, indicating a mature striatal phenotype
had been adopted. Neuronal fibers from the grafts projected diffusely throughout
the host brain, although there was no evidence that outgrowth was specifically
target directed. This study supports the contention that propagated human neural
precursors may ultimately be of use in therapeutic neural transplantation
paradigms for diseases such as Huntington's disease.
PMID- 10784068
TI - Volume and differentiation of striatal grafts in rats: relationship to the number
of cells implanted.
AB - A growing body of evidence suggests that graft-mediated functional recovery in
animal models of Huntington's disease is influenced by the morphology of the
striatal grafts. Various parameters, including embryonic dissection, tissue
preparation, and surgical delivery into the brain, have been investigated with
the aim of increasing the proportion of the grafts comprising striatum-like
tissue. While growing evidence suggests that implants derived from the selective
dissection of the lateral ganglionic eminence (LGE) contain more striatal tissue,
the relationship between the quantity of LGE tissue implanted and the striatum
like proportion of the resultant grafts has not been formally investigated. In
this study the volume of striatum-like tissue within the grafts did not increase
in a linear manner with increasing numbers of cells implanted. The proportion of
the grafts that comprised the striatum-like patch compartment or P-zone remained
constant after an initial rapid increase as the number of LGE cells implanted was
increased. These results have important practical implications in determining the
optimum number of LGE cells to implant and hence in the design of any surgical
protocol for the clinical application of this technique.
PMID- 10784069
TI - Pretreatment with MK-801 or the lazaroid U-83836E does not enhance striatal graft
survival.
AB - A large proportion of grafted striatal neurons die, and mechanisms by which they
succumb may involve excitotoxicity and oxidative stress. We investigated the
effects of pretreatment of the graft tissue with the N-methyl-D-aspartate (NMDA)
receptor antagonist (+)dizocilpine hydrogen maleate (MK-801) and lipid
peroxidation inhibitor lazaroid U-83836E on the survival of transplanted striatal
neurons. Neither compound increased the survival of grafts, suggesting that NMDA
related excitotoxicity or oxidative stress may not be primary mediators of cell
death in striatal grafts.
PMID- 10784071
TI - Branched hybrid vessel: in vitro loaded hydrodynamic forces influence the tissue
architecture.
AB - This study was conducted to investigate how a continuous load of hydrodynamic
stresses influences the tissue architecture of a branched hybrid vessel in vitro.
Tubular hybrid medial tissue of small (3 mm) and large (6 mm) diameters, prepared
by thermal gelation of a cold mixed solution of bovine smooth muscle cells (SMCs)
and type I collagen in glass molds, was assembled into a branched hybrid medial
tissue by end-to-side anastomosis. After a 2-week culture period, bovine
endothelial cells (ECs) were seeded onto the luminal surface. The branched hybrid
vessel was connected to a mock circulatory loop system and tested for two modes
of flow: 1) low flow rate for 24 h, 2) high flow rate for 24 or 72 h. After
exposure to a low flow rate for 24 h, cobblestone appearance of the ECs was
dominant. After exposure to a high flow rate, EC alignment in the direction of
flow was observed in the branch region, except at the region of predicted flow
separation where ECs retained their polygonal configuration. Elongation of SMCs
with no preferential orientation was observed in the case of vessels exposed to a
high flow rate for 24 h, and circumferential orientation was prominent in those
exposed to a high flow rate for 72 h. On the other hand, collagen fibrils
exhibited no preferential orientation in either case. After injection of Evans
blue-albumin conjugate into the circulating medium, the luminal surface of the
hybrid vessel exposed to a high flow rate for 24 h was examined by confocal laser
scanning microscopy. The fluorescence intensity was low at the high shear zone in
the branch region, while at the flow separation region it was very high,
indicating the increased albumin permeability at the latter region. These
findings reflect region-specific tissue architecture in the branch region, in
response to the local flow pattern, and may provide an in vitro atherosclerosis
model as well as a fundamental basis for the development of functional branched
hybrid grafts.
PMID- 10784070
TI - Intrathecal grafting of unencapsulated adrenal medullary tissue can bring CD4 T
lymphocytes into CSF: a potentially deleterious event for the graft.
AB - Adrenal medullary tissue including chromaffin cells was grafted intrathecally in
cancer patients to relieve intractable pain. The central nervous system (CNS) is
considered an immune privileged site. Therefore, non-HLA-matched and
unencapsulated tissue was grafted in 15 patients and 1 sham control in a series
of at least 20 grafts. We observed an increase in CSF lymphocyte counts in 15/20
allografts (75%). In contrast to peripheral blood, CD4 T cells predominated in
the CSF, but failed to exhibit an activated phenotype (CD25+ CD45RO+ HLA-DR+).
The positive effect of graft on pain, the high met-enkephalin levels, the absence
of any increase in CSF cytokine levels particularly for IFN-gamma or IL-2 (but
not IL-10 and IL-6), indirectly indicated that the graft was tolerated despite
the presence of CSF lymphocytes. The single treatment failure and three of four
cases of partial efficacy occurred in grafts where CSF lymphocytes were present.
Moreover, when assayed (n = 7), the CD4+ CSF lymphocytes still retained the
capacity to exhibit ex vivo a normal or enhanced frequency of T CD4 cells
producing IFN-gamma and IL-2. Taken together, our observations indicate that
impairment of the local immunosuppressive balance can lead to activation of those
CSF CD4 T cells and drive a rejection process. This study suggests further work
on the purification and/or the immunoisolation of tissues grafted in the CNS will
be necessary, particularly when the possibility of long-term and repeated
grafting is considered.
PMID- 10784072
TI - Longitudinal studies on the microcirculation around the TheraCyte immunoisolation
device, using the laser Doppler technique.
AB - Encapsulation of cellular grafts in an immunoisolation membrane device may make
it possible to perform transplantation without having to give immunosuppressive
drugs. A common problem is the development of an avascular fibrotic zone around
the implants, leading to impaired graft survival. The TheraCyte
macroencapsulation device has therefore been designed to facilitate
neovascularization of the device's surface. In this study, we evaluated the
microcirculation around empty TheraCyte devices implanted SC in rats at various
times after implantation, using a laser Doppler probe introduced via the device
port. Studies were performed on day 1 or at 1, 2, and 4 weeks or at 2, 3, and 12
months after implantation. The mean flow was 158+/-42, 148+/-50, 133+/-28, 72+/
17, 138+/-41, 165+/-43, and 160+/-29 perfusion units (PU), respectively. Thus,
the microcirculation around the device was significantly reduced at 4 weeks after
implantation (p < 0.01) while, from 2 months onwards the circulation had improved
and did not differ significantly from that on day 1. The present study shows time
related changes in the microcirculatory flow around TheraCyte macroencapsulation
devices that agree with our previous microdialysis studies on in vivo exchange of
insulin and glucose between the device and the circulation. Laser Doppler
flowmetry seems to provide a reliable technique for screening blood perfusion
around macroencapsulation devices.
PMID- 10784073
TI - Improved vascularization of planar membrane diffusion devices following
continuous infusion of vascular endothelial growth factor.
AB - Improving blood vessel formation around an immunobarrier device should improve
the survival of the encapsulated tissue. In the present study we investigated the
formation of new blood vessels around a planar membrane diffusion device (the
Baxter Theracyte System) undergoing a continuous infusion of vascular endothelial
growth factor through the membranes and into the surrounding tissue. Each device
(20 microl) had both an inner immunoisolation membrane and an outer vascularizing
membrane. Human recombinant vascular endothelial growth factor-165 was infused at
100 ng/day (low dose: n = 6) and 500 ng/day (high dose: n = 7) for 10 days into
devices implanted s.c. in Sprague-Dawley rats; noninfused devices transplanted
for an identical period were used as controls (n = 5). Two days following the
termination of VEGF infusion, devices were loaded with 20 microl of Lispro
insulin (1 U/kg) and the kinetics of insulin release from the lumen of the device
was assessed. Devices were then explanted and the number of blood vessels
(capillary and noncapillary) was quantified using morphometry. High-dose vascular
endothelial growth factor infusion resulted in two- to threefold more blood
vessels around the device than that obtained with the noninfused devices and
devices infused with low-dose vascular endothelial growth factor. This increase
in the number of blood vessels was accompanied by a modest increase in insulin
diffusion from the device in the high-dose vascular endothelial growth factor
infusion group. We conclude that vascular endothelial growth factor can be used
to improve blood vessel formation adjacent to planar membrane diffusion devices.
PMID- 10784074
TI - Effects of flt-3 ligand in combination with TPO on the expansion of
megakaryocytic progenitors.
AB - As an early acting growth factor, flt-3 ligand (FL) promotes the ex vivo
expansion of hematopoietic stem and progenitor cells. The effect and mechanism of
FL on the development of the megakaryocytic lineage remain unclear. In this
study, we compared the effects of FL and stem cell factor (SCF) in combination
with other megakaryocyte-promoting cytokines on the differentiation and
proliferation of megakaryocytic progenitors and investigated the expression of
flt-3 receptors on megakaryocytic cell lines. In liquid cultures of enriched
CD34+ cells from human umbilical cord blood for 14 days, FL plus thrombopoietin
(TPO), interleukin-3 (IL-3), and IL-6 promoted the expansion of nucleated cells,
CD34+ cells, CD34+ CD38- cells, and megakaryocyte colony-forming units (CFU-MK)
by 300 +/- 115-, 23.8 +/- 11.3-, 33.9 +/- 28.6-, and 584 +/- 220-fold,
respectively. Replacing FL with SCF significantly decreased the yield of all cell
types. Using murine bone marrow (BM) cells, we demonstrated that FL at a range of
0-100 ng/ml had no significant mitogenic effect on CFU-MK formation. TPO
increased CFU-MK (p < 0.001) but the effect was not significantly modified by FL.
While one human acute lymphoblastic leukemia sample expressed high levels of flt
3 receptor, the four megakaryocytic cell lines (Meg-01, CHRF-288-11, M-07e, and
Dami) did not show any positive expression. Our data suggest that the present
cytokine combination and expansion conditions provide an effective and
potentially useful system for the clinical expansion of cord blood for bone
marrow transplantation (BMT). FL alone did not stimulate megakaryocytopoiesis,
possibly due to the lack of receptor expression on megakaryocytes. The effect of
FL in augmenting the expansion of CFU-MK in liquid culture might be due to the
early action of FL at the pluripotent stem cell stage.
PMID- 10784075
TI - The assessment and treatment of Post-traumatic Stress Disorder in children and
adolescents.
AB - Post-traumatic Stress Disorder (PTSD) is a syndrome defined by the intrusive re
experiencing of a trauma, avoidance of traumatic reminders, and persistent
physiological arousal. PTSD is associated with high levels of comorbidity and may
increase the risk for additional disorders over time. While controversies remain
regarding the applicability of the PTSD criteria to very young children, it has
proved to be a useful framework for guiding assessment and treatment research
with older children and adolescents. This article presents an overview of the
literature on the clinical characteristics, assessment, and treatment of PTSD in
children and adolescents.
PMID- 10784076
TI - School and neuropsychological performance of evacuated children in Kyiv 11 years
after the Chornobyl disaster.
AB - This paper examines the cognitive and neuropsychological functioning of children
who were in utero to age 15 months at the time of the Chornobyl disaster and were
evacuated to Kyiv from the 30-kilometer zone surrounding the plant. Specifically,
we compared 300 evacuee children at ages 10-12 with 300 non-evacuee Kyiv
classmates on objective and subjective measures of attention, memory, and school
performance. The evacuee children were not significantly different from their
classmates on the objective measures (grades; Symbolic Relations subtest of the
Detroit Test; forms 1 and 2 of the Visual Search and Attention Test; Benton Form
A; Trails A; Underline the Words Test) or on most of the subjective measures (the
attention subscale of the Child Behavior Checklist completed by mothers; the
attention items of the Iowa Conners Teacher's Rating Scale; mother and child
perceptions of school performance). The one exception was that 31.3% of evacuee
mothers compared to 7.4% of classmate mothers indicated that their child had a
memory problem. However, this subjective measure of memory problems was not
significantly related to neuropsychological or school performance. No significant
differences were found in comparisons of evacuees and classmates who were in
utero at the time of the explosion, children from Pripyat vs. other villages in
the 30-kilometer zone, and children manifesting greater generalized anxiety. For
both groups, children with greater Chornobyl-focused anxiety performed
significantly worse than children with less Chornobyl-focused anxiety on measures
of attention. The results thus fail to confirm two previous reports that
relatively more children from areas contaminated by radiation had cognitive
deficits compared to controls. Possible reasons for the differences in findings
among the studies are discussed.
PMID- 10784078
TI - Social functioning in children with a chronic illness.
AB - Behavioural, cognitive, and affective aspects of social functioning of 107
children with a chronic illness were studied. The aim of the study was twofold:
(1) to describe peer interaction of children with a chronic illness in comparison
with normative data of healthy children; (2) to examine whether peer interaction
was related to the illness characteristics physical restrictions and pain. Peer
interaction was assessed with measures of social activities (CBCL), parent
reported social skills (CABS), child-reported social skills (MESSY), social self
esteem (SPPC), and social anxiety (SASK). Results showed no differences between
diagnosis groups, suggesting that the social consequences of chronic illness are
not diagnosis specific. Compared with healthy norms, chronically ill children
reported less aggressive behaviour. The parent-report measures suggested a
similar trend. Children with chronic illness also tended to display more
submissive behaviour than healthy norms, as perceived by their parents. With
regard to illness characteristics, both physical restrictions and pain were
associated with restricted social activities, but not with other measures of
social peer interaction. Children who display submissive behaviour and children
who are restricted in their social activities should receive extra attention
because they are especially vulnerable for problems in their social development.
PMID- 10784077
TI - The mental health of the peers of suicide completers and attempters.
AB - This study examined the prevalence and risk of psychiatric disturbances and
suicidal behaviours among the peers of suicide attempters and completers. The
subjects were selected from high schools with and without history of student
suicides in the past 3 years. The psychiatric disturbances (as measured by the
YSR and CBCL), suicidal behaviours, drug use, and a wide range of potential risk
factors were measured. About a quarter of the peers of suicide completers and
attempters were probable psychiatric cases and 15-21% of them reported suicidal
acts. The increased risk of psychiatric disturbances and suicidal behaviours were
still evident after controlling for age, sex, and potential risk factors. The
presence of psychiatric disturbances could not wholly account for the increased
odds of suicidal behaviours. Peers of suicide attempters carried a higher risk
than peers of suicide completers. The close friends of suicide completers were
particularly at risk of internalising problems, whereas the close friends of
suicide attempters were at high risk of externalising problems. The peers of
suicide completers and attempters represent a high-risk group for psychiatric
disturbances and suicidal behaviours. The specific association of different types
of psychiatric disturbances in the peers of suicide completers and attempters
suggested that different risk mechanisms might be in operation within these peer
groups.
PMID- 10784079
TI - Multi-method psycho-educational intervention for preschool children with
disruptive behavior: preliminary results at post-treatment.
AB - Annual screenings of preschool children at kindergarten registration identified
158 children having high levels of aggressive, hyperactive, impulsive, and
inattentive behavior. These "disruptive" children were randomly assigned to four
treatment conditions lasting the kindergarten school year: no treatment, parent
training only, full-day treatment classroom only, and the combination of parent
training with the classroom treatment. Results showed that parent training
produced no significant treatment effects, probably owing largely to poor
attendance. The classroom treatment produced improvement in multiple domains:
parent ratings of adaptive behavior, teacher ratings of attention, aggression,
self-control, and social skills, as well as direct observations of externalizing
behavior in the classroom. Neither treatment improved academic achievement skills
or parent ratings of home behavior problems, nor were effects evident on any lab
measures of attention, impulse control, or mother-child interactions. It is
concluded that when parent training is offered at school registration to parents
of disruptive children identified through a brief school registration screening,
it may not be a useful approach to treating the home and community behavioral
problems of such children. The kindergarten classroom intervention was far more
effective in reducing the perceived behavioral problems and impaired social
skills of these children. Even so, most treatment effects were specific to the
school environment and did not affect achievement skills. These findings must be
viewed as tentative until follow-up evaluations can be done to determine the long
term outcomes of these interventions.
PMID- 10784080
TI - Cognitive and familial contributions to conduct disorder in children.
AB - Although young children with conduct disorder (CD) are suspected of having verbal
and executive function deficits, most studies that investigated this hypothesis
did not control for attention deficit hyperactivity disorder (ADHD). Furthermore,
relatively little is known about the interaction between cognitive deficits and
familial factors in explaining the onset and persistence of CD in children. The
participants in this study were 57 children with CD and 35 controls aged 7 to 12
years. At 1-year follow-up, 41 of the participants with CD were reassessed.
Children with CD were found to be significantly impaired in four of five
executive function measures after ADHD symptoms and socioeconomic status (SES)
were controlled. Executive function test performance, number of ADHD symptoms,
and familial characteristics (SES, parental punishment) together correctly
classified 90% of the participants. Only the number of ADHD symptoms was found to
significantly improve prediction of CD 1 year later beyond that afforded by
number of CD symptoms a year earlier. Findings indicate that children with CD and
ADHD symptoms are especially at risk for persistent antisocial behaviour. Results
also highlight the importance of treatment programs that cover both cognitive and
familial aspects associated with CD.
PMID- 10784081
TI - Gender self-concept profiles of adolescents suspended from high school.
AB - The gender self-concept profiles of 128 adolescents (107 males) whose persistent
behaviour problems led to suspension from school were investigated. Establishing
the students' percentile ratings in the 11 subscales of the Self-Description
Questionnaire overcame previous methodological weaknesses. For boys and girls
Physical Appearance, Opposite-sex Relationships, and Honesty and Trustworthiness
were in the average range, but Parent Relationships, General Self, and General
School self-concepts were low. Only girls were low for Same-sex Relationships and
Emotional Stability. The profiles suggest that boys' antisocial behaviours are
associated with striving for a masculine self-image, but girls' antisocial
behaviours are associated with greater social marginalisation. The issues of
multi-focused interventions, prosocial role models, the particular needs of
girls, and the relationship between self-control, self-enhancement, and
reputation enhancement theories are discussed.
PMID- 10784082
TI - The interface between ADHD and language impairment: an examination of language,
achievement, and cognitive processing.
AB - Language impairments are commonly observed among children referred for
psychiatric services. The most frequent psychiatric diagnosis of children with
language impairment (LI) is Attention Deficit Hyperactivity Disorder (ADHD). It
is not clear whether there are differences between children with ADHD and
comorbid LI and children with other psychiatric disorders who are also comorbid
for LI. In the present study the language, achievement, and cognitive processing
characteristics of 166 psychiatrically referred 7-14-year-old children were
examined using a 2 x 2 (ADHD, LI) design to examine four groups: children with
ADHD + LI, children with ADHD who have normally developing language, children
with psychiatric diagnoses other than ADHD with a language impairment (OPD + LI)
or without a LI (OPD). Results indicated that children with LI were at the most
disadvantage regardless of the nature of the psychiatric diagnosis. Contrary to
prediction, working memory measures, used to tap the core cognitive deficit of
ADHD in executive functions, were more closely associated with LI than with ADHD.
It was concluded that caution must be exercised in attributing to children with
ADHD what might be a reflection of problems for children with language impairment
generally. As most therapies are verbally based it is notable that language
competence is rarely evaluated systematically before such therapies are
undertaken.
PMID- 10784083
TI - Lack of attentional bias for emotional information in clinically depressed
children and adolescents on the dot probe task.
AB - The present study utilised a cognitive paradigm to investigate attentional biases
in clinically depressed children and adolescents. Two groups of children and
adolescents--clinically depressed (N = 19) and normal controls (N = 26)--were
asked to complete a computerised version of the attentional dot probe paradigm
similar to that used by MacLeod, Mathews, and Tata (1986). Results provided no
support for an attentional bias, either toward depression-related words or threat
words, in the depressed group. This finding is discussed in the context of
cognitive theories of anxiety and depression.
PMID- 10784084
TI - Verbal bias in recognition of facial emotions in children with Asperger syndrome.
AB - Thirteen children and adolescents with diagnoses of Asperger syndrome (AS) were
matched with 13 nonautistic control children on chronological age and verbal IQ.
They were tested on their ability to recognize simple facial emotions, as well as
facial emotions paired with matching, mismatching, or irrelevant verbal labels.
There were no differences between the groups at recognizing simple emotions but
the Asperger group performed significantly worse than the control group at
recognizing emotions when faces were paired with mismatching words (but not with
matching or irrelevant words). The results suggest that there are qualitative
differences from nonclinical populations in how children with AS process facial
expressions. When presented with a more demanding affective processing task,
individuals with AS showed a bias towards visual-verbal over visual-affective
information (i.e., words over faces). Thus, children with AS may be utilizing
compensatory strategies, such as verbal mediation, to process facial expressions
of emotion.
PMID- 10784085
TI - Stability and change of attachment at 14, 24, and 58 months of age: behavior,
representation, and life events.
AB - Stability and change of attachment was examined longitudinally in a group of 48
children at 14, 24, and 58 months of age. Whereas attachment classifications
showed stability between 14 and 24 months, lack of stability was the case between
either 14 or 24 months and 58 months. Mothers of children who did not exhibit
stability of attachment reported more negative and less positive life events. No
correspondence was found between attachment classification at 14 or 24 months and
mental representations at 58 months. However there was agreement between
representational and behavioral measures of attachment at 58 months, where mental
representations of attachment appeared to mirror and complement behavioral
classification of the attachment relationship with the mother. Evidence for
continuity of attachment from infancy to childhood internal representations was
found only in a subgroup of children who showed stability of secure attachment
between infancy and 58 months of age. These children exhibited greater Emotional
Openness in the SAT at 4.5 years. Findings are discussed in terms of different
positions in attachment theory and research regarding the stability and change of
attachment relationships.
PMID- 10784086
TI - Knowledge of display rules in prelingually deaf and hearing children.
AB - Deaf children of elementary and secondary school age participated in a study
designed to examine their understanding of display rules, the principles
governing the expression and concealment of emotion in social situations. The
results showed that deaf children's knowledge of display rules, as measured by
their reported concealment of emotion, was comparable to that of hearing children
of the same age. However, deaf children were less likely to report that they
would conceal happiness and anger. They were also less likely to produce reasons
for concealing emotion and a smaller proportion of their reasons were prosocial,
that is, relating to the feelings of others. The results suggest that the
understanding of display rules (which function to protect the feelings of other
people) may develop more gradually in deaf children raised in a spoken language
environment than it does in hearing children.
PMID- 10784087
TI - Selective microstimulation of central nervous system neurons.
AB - The goal of this study was to identify stimulus parameters and electrode
geometries that were effective in selectively stimulating targeted neuronal
populations within the central nervous system (CNS). Cable models of neurons that
included an axon, initial segment, soma, and branching dendritic tree, with
geometries and membrane dynamics derived from mammalian motoneurons, were used to
study excitation with extracellular electrodes. The models reproduced a wide
range of experimentally documented excitation patterns including current-distance
and strength-duration relationships. Evaluation of different stimulus paradigms
was performed using populations of fifty cells and fifty fibers of passage
randomly positioned about an extracellular electrode(s). Monophasic cathodic or
anodic stimuli enabled selective stimulation of fibers over cells or cells over
fibers, respectively. However, when a symmetrical charge-balancing stimulus phase
was incorporated, selectivity was greatly diminished. An anodic first, cathodic
second asymmetrical biphasic stimulus enabled selective stimulation of fibers,
while a cathodic first, anodic second asymmetrical biphasic stimulus enabled
selective stimulation of cells. These novel waveforms provided enhanced
selectivity while preserving charge balancing as is required to minimize the risk
of electrode corrosion and tissue injury. Furthermore, the models developed in
this study can predict the effectiveness of electrode geometries and stimulus
parameters for selective activation of specific neuronal populations, and in turn
represent useful tools for the design of electrodes and stimulus waveforms for
use in CNS neural prosthetic devices.
PMID- 10784088
TI - Integrin-dependent human macrophage migration induced by oscillatory electrical
stimulation.
AB - Electrical stimulation has been used to promote wound healing. The mechanisms by
which such stimulation could interact with biological systems to accelerate
healing have not been elucidated. One potential mechanism could involve
stimulation of macrophage migration to the site of a wound. Here we report that
oscillatory electric fields induce human macrophage migration. Macrophages
exposed to a 1 Hz, 2 V/cm field show an induced migration velocity of 5.2+/-0.4 x
10(-2) microm/min and a random motility coefficient of 4.8+/-1.4 x 10(-2)
microm2/min on a glass substrate. Electric field exposure induces reorganization
of microfilaments from ring-like structures at the cell periphery to podosomes
that are confined to the contact sites between cell and substrate, suggesting
that the cells are crawling on glass. Treatment of cells with monoclonal
antibodies directed against beta2-integrins prior to field exposure prevents cell
migration, indicating that integrin-dependent signaling pathways are involved.
Electric fields cause macrophage migration on laminin or fibronectin coated
substrates without inducing podosome formation or changes in cellular morphology.
The migration velocity is not significantly altered but the random movement is
suppressed, suggesting that cell movements on a laminin- or fibronectin-coated
surface are not mediated by cell crawling. It is suggested that electric field
induced macrophage migration utilizes several modes of cell movement, including
cell crawling and possibly cell rolling.
PMID- 10784089
TI - Influence of the electric axis of stimulation on the induced transmembrane
potentials in ellipsoidal bidomain heart.
AB - This theoretical study was provoked by and designed to interpret, complement and
extend the implications of recent experimental observations by Wikswo and Lin
(PACE, 21:940, 1998) on the epicardial surface of rabbit hearts. Using a
macroscopic bidomain representation of the cardiac structure and the finite
element method, we model the response of the heart to uniform electric fields
applied under different angles. To overcome intra- and interspecies differences
in the geometric and structural characteristics of the cardiac muscle, the
analysis is conducted for an idealized ellipsoidal heart. Although idealized,
this heart model incorporates important structural features, i.e., fiber
curvature, transmural fiber rotation, and unequal anisotropy for the intra- and
extracellular domains. This study shows that regions of maximum polarization of
opposite sign may develop along an axis, significantly deviating from the axis of
the applied electric field. The polarization evoked inside the ventricular wall
seems to be a major contributor to this phenomenon. Nonperiodic structural
inhomogeneities on multicellular level (endocardial "trabeculation" in our model)
result in local unaligned polarization dipoles weakening the magnitude of the
global polarization dipole and reducing its deviation from the axis of
stimulation. Our results might be helpful in improving current understanding of
defibrillation mechanisms.
PMID- 10784091
TI - Theoretical evaluation of contributions of heat conduction and countercurrent
heat exchange in selective brain cooling in humans.
AB - The purpose of this work is to evaluate the capacity of the heat loss from the
carotid artery in the human neck and thus, to provide indirect evidence of the
existence of selective brain cooling in humans during hyperthermia. A theoretical
model is developed to describe the effects of blood flow rate and vascular
geometry on the thermal equilibration in the carotid artery based on the blood
flow and the anatomical vascular geometry in the human neck. The potential for
cooling of blood in the carotid artery on its way to the brain by heat exchange
with the jugular vein and by radial heat conduction loss to the cool neck surface
is evaluated. It is shown that the cooling of the arterial blood can be as much
as 1.1 degrees C lower than the body core temperature, which is in agreement with
previous experimental measurements of the difference between the tympanic and
body core temperatures. The model also evaluates the relative contributions of
countercurrent heat exchange and radial heat conduction to selective brain
cooling. It is found that these mechanisms are comparable with each other.
Results of the present study will help provide a better understanding of the
thermoregulation during hyperthermia.
PMID- 10784090
TI - Advection and diffusion of substances in biological tissues with complex vascular
networks.
AB - For highly diffusive solutes the kinetics of blood-tissue exchange is only poorly
represented by a model consisting of sets of independent parallel capillary
tissue units. We constructed a more realistic multicapillary network model
conforming statistically to morphometric data. Flows through the tortuous paths
in the network were calculated based on constant resistance per unit length
throughout the network and the resulting advective intracapillary velocity field
was used as a framework for describing the extravascular diffusion of a substance
for which there is no barrier or permeability limitation. Simulated impulse
responses from the system, analogous to tracer water outflow dilution curves,
showed flow-limited behavior over a range of flows from about 2 to 5 ml min(-1)
g(-1), as is observed for water in the heart in vivo. The present model serves as
a reference standard against which to evaluate computationally simpler, less
physically realistic models. The simulated outflow curves from the network model,
like experimental water curves, were matched to outflow curves from the commonly
used axially distributed models only by setting the capillary wall permeability
surface area (PS) to a value so artifactually low that it is incompatible with
the experimental observations that transport is flow limited. However, simple
axially distributed models with appropriately high PSs will fit water outflow
dilution curves if axial diffusion coefficients are set at high enough values to
account for enhanced dispersion due to the complex geometry of the capillary
network. Without incorporating this enhanced dispersion, when applied to
experimental curves over a range of flows, the simpler models give a false
inference that there is recruitment of capillary surface area with increasing
flow. Thus distributed models must account for diffusional as well as permeation
processes to provide physiologically appropriate parameter estimates.
PMID- 10784092
TI - Mathematical modeling of the human body during water replacement and dehydration:
body water changes.
AB - A model of the human body that integrates the variables involved in temperature
regulation and blood gas transport within the cardiovascular and respiratory
systems is presented here. It expands upon previous work to describe the
competition between skin and muscles when both require increased blood flows
during exercise and/or heat stress. First, a detailed study of the control
relations used to predict skin blood flow was undertaken. Four other control
relations employed in the model were also examined and modified as indicated by
empirical results found in literature. Internal responses to exercise and/or heat
stress can affect both thermoregulation and the cardiorespiratory system.
Dehydration was studied in addition to complete water replacement during similar
environmental and exercise situations. Control relations for skin blood flow and
evaporative heat loss were modified and a water balance was added to study how
the loss of water through sweat can be limiting. Runoff from sweating as a
function of relative humidity was introduced along with evaporation, and these
results were compared to data to validate the model.
PMID- 10784093
TI - True arterial system compliance estimated from apparent arterial compliance.
AB - A new method has been developed to estimate total arterial compliance from
measured input pressure and flow. In contrast to other methods, this method does
not rely on fitting the elements of a lumped model to measured data. Instead, it
relies on measured input impedance and peripheral resistance to calculate the
relationship of arterial blood volume to input pressure. Generally, this transfer
function is a complex function of frequency and is called the apparent arterial
compliance. At very low frequencies, the confounding effect of pulse wave
reflection disappears, and apparent compliance becomes total arterial compliance.
This study reveals that frequency components of pressure and flow below heart
rate are generally necessary to obtain a valid estimate of compliance. Thus, the
ubiquitous practice of estimating total arterial compliance from a single cardiac
cycle is suspect under most circumstances, since a single cardiac cycle does not
contain these frequencies.
PMID- 10784094
TI - The effect of celiac and renal artery outflows on near-wall velocities in the
porcine iliac arteries.
AB - The effects of the outflow of aortic blood through the celiac and renal arteries
on the flow field in the external iliac arteries were studied under steady and
physiologically realistic pulsatile flow conditions. Laser Doppler velocimetry
(LDV) measurements were made close to the medial, lateral, ventral, and dorsal
walls of the external iliac branches of a clear, flow-through replica of a
porcine aorta and its daughter vessels. The outflow from each branch of the
replica was controlled so that the infrarenal aortic flow rate and the flow
partition at the aortic trifurcation were the same for all experiments. LDV
measurements were made with flow exiting through both the renal and celiac artery
ostia, only the celiac ostium, and neither ostium. The steady flow results
indicate that while the outflow through the renal arteries did not have a
significant effect on near wall shear rate in the external iliac arteries, the
flow through the celiac artery did. However, in pulsatile flow, three indices of
near wall velocity in the iliac arteries were unaffected by celiac artery
outflow, while a fourth showed a small effect that can be attributed to
differences in minimum velocity. These results indicate that reliable simulations
of blood flow in the external iliac arteries can be carried out without including
the renal and celiac vessels, provided that the correct infrarenal flow wave is
used. They also demonstrate that the flow field downstream of a region, such as a
branch, that strongly alters the flow, can be nearly independent of the velocity
field entering the region.
PMID- 10784095
TI - A micromechanical model of airway-parenchymal interdependence.
AB - The forces of parenchymal interdependence in the lung are potent inhibitors of
airway smooth muscle shortening, as evidenced by the marked dependence of
bronchial responsiveness on lung volume. In this study we developed a
mathematical-computer model of the effects of parenchymal interdependence on
airway smooth muscle shortening. A three-dimensional network of cuboidal alveolar
walls was tethered at its boundaries and surrounded a single airway with
mechanical properties identical to the alveolar parenchyma. The walls were
assigned highly nonlinear properties so that the pressure-volume behavior of the
model matched that measured in dogs. Constriction of the airway was achieved by
increasing the circumferential tension in the airway wall, and then solving the
force-balance equations of the model to calculate the equilibrium configurations
of the airway wall and all the interconnecting alveolar walls. The changes in
airway resistance predicted by the model at various transpulmonary pressures
(P(tp)) were compared to those obtained by the alveolar capsule oscillator
technique in dogs during induced bronchoconstriction at various P(tp) (Balassy et
al., J. Appl. Physiol. 78:875-880, 1995). The model matched the data reasonably
well at P(tp) values above about 0.5 kPa, but was too responsive at lower P(tp).
We were able to make the model match the data at all P(tp) by including an
additional stiffness term, such as might conceivably arise from the airway wall
itself.
PMID- 10784096
TI - Finite element simulation of location- and time-dependent mechanical behavior of
chondrocytes in unconfined compression tests.
AB - Experimental evidence suggests that cells are extremely sensitive to their
mechanical environment and react directly to mechanical stimuli. At present, it
is technically difficult to measure fluid pressure, stress, and strain in cells,
and to determine the time-dependent deformation of chondrocytes. For this reason,
there are no data in the published literature that show the dynamic behavior of
chondrocytes in articular cartilage. Similarly, the dynamic chondrocyte mechanics
have not been calculated using theoretical models that account for the influence
of cell volumetric fraction on cartilage mechanical properties. In the present
investigation, the location- and time-dependent stress-strain state and fluid
pressure distribution in chondrocytes in unconfined compression tests were
simulated numerically using a finite element method. The technique involved two
basic steps: first, cartilage was approximated as a macroscopically homogenized
material and the mechanical behavior of cartilage was obtained using the
homogenized model; second, the solution of the time-dependent displacements and
fluid pressure fields of the homogenized model was used as the time-dependent
boundary conditions for a microscopic submodel to obtain average location- and
time-dependent mechanical behavior of cells. Cells and extracellular matrix were
assumed to be biphasic materials composed of a fluid phase and a hyperelastic
solid phase. The hydraulic permeability was assumed to be deformation dependent
and the analysis was performed using a finite deformation approach. Numerical
tests were made using configurations similar to those of experiments described in
the literature. Our simulations show that the mechanical response of chondrocytes
to cartilage loading depends on time, fluid boundary conditions, and the
locations of the cells within the specimen. The present results are the first to
suggest that chondrocyte deformation in a stress-relaxation type test may exceed
the imposed system deformation by a factor of 3-4, that chondrocyte deformations
are highly dynamic and do not reach a steady state within about 20 min of steady
compression (in an unconfined test), and that cell deformations are very much
location dependent.
PMID- 10784098
TI - Stent-induced thromboembolism.
PMID- 10784097
TI - Facilitated diffusion and membrane permeation of fatty acid in albumin solutions.
AB - Facilitated transport is characteristic of most living systems, and usually
involves a series of consecutive adjacent transfer regions, each having different
transport properties. As a first step in the analysis of the multiregional
problem, we consider in a single unstirred layer the facilitated diffusion of
fatty acid (F) in albumin (A) solution under conditions of slow versus rapid
association-dissociation, accounting for differing diffusivities of the albumin
fatty acid complex (AF). Diffusion gradients become established in an unstirred
layer between a source of constant concentration of A, AF, and F in equilibrium,
and a membrane permeable to F. The posited system does not reduce to a thin- or
thick-layer approximation. The transient state is prolonged by slower on/off
binding rates and by increasing the thickness of the unstirred layer. Solutions
to transient and steady state depend upon the choice of boundary conditions,
especially for thin regions. When there are two regions (each with its specific
binding protein) separated by a permeable membrane, the steady-state fluxes and
concentration profiles depend on the rates of association and dissociation
reactions, on the diffusion coefficients, local consumption rates, and on the
membrane permeability. Sensitivity analysis reveals the relative importance of
these mechanisms.
PMID- 10784099
TI - Calcium-independent release of [3H]spermine from chick retina.
AB - Spermine has been shown to influence NMDA receptor function through an
interaction at the coagonist site for glycine in the central nervous system (CNS)
and the retina. In order to support a role for spermine as neurotransmitter or
neuromodulator in the chick retina, specific stimulated-release of spermine
should be demonstrated. Isolated chick retinas, preloaded with [3H]spermine, were
stimulated with 1 mM NMDA and other glutamate agonists at ionotropic receptors,
in a continuous superfusion system. [3H]spermine was released from the retina by
depolarization with 50 mM KCl, in a Ca2+-independent manner. Inhibition of Na+/K+
ATPase by ouabain or digitoxigenin also induced spermine release following 36 min
in the presence of the drugs; such effect seems unrelated to changes in Na+
electrochemical gradients, since nigericin and veratrine did not induce release
in Na+ containing medium. The lack of effect of glutamate, NMDA and kainate at 1
mM concentration, suggests that release of spermine in the retina is mediated by
the reversal of uptake and not necessarily linked to EAA-receptor activation.
PMID- 10784100
TI - Preferential inhibition of L- and N-type calcium channels in the rat hippocampal
neurons by cilnidipine.
AB - The effect of a dihydropyridine Ca2+ antagonist, cilnidipine, on voltage
dependent Ca2+ channels was studied in acutely dissociated rat CA1 pyramidal
neurons using the nystatin-perforated patch recording configuration under voltage
clamp conditions. Cilnidipine had no effect on low-voltage-activated (LVA) Ca2+
channels at the low concentrations under 10(-6) M. On the other hand, cilnidipine
inhibited the high-voltage-activated (HVA) Ca2+ current (I(Ca)) in a
concentration-dependent manner and the inhibition curve showed a step-wise
pattern; cilnidipine selectively reduced only L-type HVA I(Ca) at the low
concentrations under 10(-7) and 10(-6) M cilnidipine blocked not only L- but also
N-type HVA I(Ca). At the high concentration over 10(-6) M cilnidipine non
selectively blocked the T-type LVA and P/Q- and R-type HVA Ca2+ channels. This is
the first report that cilnidipine at lower concentration of 10(-6) M blocks both
L-and N-type HVA I(Ca) in the hippocampal neurons.
PMID- 10784101
TI - Spermine dependent activation of the N-methyl-D-aspartate receptor and the effect
of nitric oxide synthase inhibition during hypoxia in the cerebral cortex of
newborn piglets.
AB - This study tests the hypothesis that brain tissue hypoxia results in modification
of spermine-dependent activation of the cerebral N-methyl-D-aspartate (NMDA)
receptor ion-channel in newborn piglet brains and that pretreatment with N(omega)
nitro-L-arginine (NNLA), an inhibitor of nitric oxide synthase, will reduce the
hypoxia-induced modification of the spermine-dependent activation of the
receptor. Piglets were assigned to one of four groups; normoxia or hypoxia with
or without NNLA. The infusion of NNLA or vehicle lasted for 60 min while the
animals were ventilated under either hypoxic or normoxic conditions. Cerebral
tissue hypoxia was confirmed by measuring ATP and phosphocreatine (PCr) levels.
P2 membranes were isolated and 3H-MK-801 binding was measured in the presence of
spermine. Steady state 3H-MK-801 binding in the presence of spermine, showed an
increase in receptor affinity in both normoxic (47% of control) and hypoxic (42%
of control) animals without change in receptor density. During hypoxia, the
spermine-dependent increase in the maximal response of the 3H-MK-801 binding
correlated inversely with the ATP concentrations. NNLA pretreatment prior to
hypoxia, resulted in a decrease in the slope of the regression line describing
the relationship between cellular energy state (ATP) and percent change in
maximal response to spermine compared with vehicle treated animals indicating
attenuation of the response to hypoxia. We conclude that the spermine-dependent
modification of the affinity of the NMDA receptor ion-channel as assessed by 3H
MK-801 binding is similar in hypoxic and normoxic cortical tissue. NNLA
administration reduces the hypoxia-induced spermine-dependent activation of the
receptor indicating that nitric oxide mediates modification of the spermine site
activation of the NMDA receptor ion-channel complex.
PMID- 10784102
TI - A possible role for nerve growth factor in the augmentation of sodium channels in
models of chronic pain.
AB - Inflammation induces an upregulation of sodium channels in sensory neurons. This
most likely occurs as a result of the retrograde transport of cytochemical
mediators released during the inflammatory response. The purpose of this study
was to determine the effect of the subcutaneous administration of one such
mediator, nerve growth factor (NGF), on the production of sodium channels in
neurons of the rat dorsal root ganglion. For this, hindpaw withdrawal from either
a thermal or mechanical stimulus was measured in rats at selected intervals for
up to 2 weeks following injections of NGF. Sodium channel augmentation was then
examined in dorsal root ganglia using site-specific, anti-sodium channel
antibodies. Both thermal and mechanical allodynia was observed between 3 and 12 h
post-injection. The hyperalgesic response returned to baseline by approximately
24 h post-injection. Sodium channel labeling was found to increase dramatically
in the small neurons of the associated dorsal root ganglia beginning at 23 h,
reached maximum intensity by 1 week, and persisted for up to 3 months post
injection. Pre-blocking NGF with anti-NGF prevented the NGF-induced decrease in
paw withdrawal latencies and significantly reduced the intensity of sodium
channel labeling. The results indicate that NGF is an important mediator both in
the development of acute hyperalgesia and in the stimulation of sodium channel
production in dorsal root ganglia during inflammation.
PMID- 10784103
TI - Intracisternal PYY inhibits gastric lesions induced by ethanol in rats: role of
PYY-preferring receptors?
AB - We previously reported that intracisternal (i.c.) injection of peptide YY (PYY)
and low doses of thyrotropin-releasing hormone (TRH) or TRH analog, RX 77368,
increased the resistance of the gastric mucosa to ethanol injury through vagal
pathways in rats. The gastroprotective effect of i.c. injection of
PYY/neuropeptide NPY (NPY) agonists with differential in vitro affinity to the Y
receptor subtypes was examined in urethane-anesthetized rats. Intragastric
administration of ethanol (45%, 5 ml/kg) results in mucosal lesions covering 23+/
2% of the gastric corpus in 1 h. PYY (500 ng, i.c.) significantly reduced ethanol
induced gastric lesions by 52%. [Pro34]PYY (PYY-preferring/Y1/Y5/Y4 subtypes)
injected i.c. at 50, 100, 200 or 500 ng, reduced dose dependently gastric lesions
to 15.4+/-2.2%, 11.4+/-3.1%, 8.6+/-2.9% and 5.4+/-2.2%, respectively. PYY3-36,
(Y2/Y4 subtypes), [Leu31, Pro34]NPY (Y1/Y5), NPY (Y3/Y1/Y5/Y2) and pancreatic
polypeptide (PP, Y4) injected i.c. at 500 ng did not influence significantly
ethanol-induced gastric lesions. Combined i.c. injection of RX 77368 (1 ng) and
Pro34PYY (25 ng), at sub-threshold doses given singly, reduced ethanol-induced
gastric injury to 12.9+/-2.3% while RX 77368 (1 ng) plus PYY3-36 (500 ng) or
[Leu31, Pro34]NPY (25 ng) had no effect. These findings indicate that i.c. PYY
induced gastric protection against 45% ethanol is mediated by a Y receptor
subtype which bears similarity with the putative PYY-preferring receptor and
distinct from the currently defined Y1/Y5; in addition, there is a synergistic
interaction between activation of this PYY-preferring receptor and i.c. TRH to
increase the resistance of the gastric mucosa to injury caused by 45% ethanol.
PMID- 10784104
TI - Effects of acute and chronic treatment with fluoxetine on regional glucose
cerebral metabolism in rats: implications for clinical therapies.
AB - The wide therapeutic spectrum of fluoxetine (e.g., antidepressant, antipanic,
antiphobic, antiobsessive, analgesic, antimigraine) requires long-term
administration and adaptive changes. To test whether adaptation involves the
serotonin (5-HT) transporters, we measured the effects of fluoxetine on the
regional cerebral metabolic rate for glucose (rCMRglc) in control rats or in rats
pretreated for 2 weeks with fluoxetine (8 mg/kg, i.p., daily, 2 days wash out);
rCMRglc was measured in 56 brain regions, using the quantitative
[14C]deoxyglucose technique, at 30 min after i.p. administration of fluoxetine
0.4, 4 or 40 mg/kg, i.p., to non-pretreated rats or fluoxetine 4 mg/kg to
pretreated rats. In non-pretreated rats, fluoxetine reduced rCMRglc in a dose
dependent fashion in 4 (7%, mean decrease 11%), 28 (50%, mean decrease 23%) and
37 (66%, mean decrease 32%) brain regions. In chronic fluoxetine-pretreated rats,
fluoxetine decreased rCMRglc to a substantially lesser degree (eight regions,
14%; mean decrease, 10%). Subcortical brain regions (i.e., hypothalamic
paraventricular, locus coeruleus and basal ganglia nuclei) that mediate the
physiological responses to stress were very sensitive to fluoxetine acutely and
subsensitive after chronic treatment. As kinetic tolerance to fluoxetine does not
occur during chronic administration, the diminished rCMRglc responsivity to
fluoxetine reflects dynamic, adaptive tolerance of 5-HT transporters and,
consequently, increased synaptic 5-HT concentrations; the findings suggest that
fluoxetine may be therapeutic by increasing the 5-HT-negative modulation upon
areas that drive the abnormally hyperactive responses to stress found in several
neuropsychiatric conditions.
PMID- 10784105
TI - Role of calcium on the modulation of spontaneous acetylcholine efflux by the D2
dopamine receptor subtype in rat striatal synaptosomes.
AB - The role of calcium in the modulation of spontaneous [3H]acetylcholine ([3H]ACh)
efflux through presynaptic D2 dopamine hetero-receptors was investigated in rat
striatal synaptosomes. The kinetic studies of [3H]ACh efflux in the presence or
absence of Ca2+ were carried out in nonstimulating conditions. When Ca2+ was
omitted from the superfusion medium, a notable and significant (P<0.001) decrease
of tritium efflux (39%) was obtained. While [3H]ACh efflux was insensitive to
tetrodotoxin (TTX) 1 microM, cadmium (10 microM), a nonselective antagonist of
calcium channels, significantly reduced the tritium efflux by 24% (P<0.001),
while the L-type calcium antagonist, nifedipine, (30 microM) inhibited the
tritium efflux by only 10% (P<0.02). 2-(4-Fenylpiperidine)cyclohexanol
(vesamicol), an inhibitor of the vesicular [3H]ACh carrier, significantly
depressed the spontaneous tritium efflux in the presence of Ca2+ (60%; P<0.001)
and in a low-calcium medium (20%; P<0.001). Although 1 microM of 7-hydroxy-N,N-di
n-propyl-2-aminotetraline (7-OH-DPAT) inhibited spontaneous [3H]ACh efflux in the
presence of calcium, this dopaminergic agonist did not modify the
neurotransmitter release in either the low-Ca2+ medium or in the presence of
vesamicol. These results suggest that the spontaneous [3H]ACh efflux is a process
involving a Ca2+-dependent component (39%), sensitive to calcium channel-blockers
and vesamicol, in rat striatal synaptosomes. In addition, activation of the D2
dopamine hetero-receptor only modulates the calcium-dependent component of
spontaneous [3H]ACh efflux.
PMID- 10784106
TI - Simultaneous action of MK-801 (dizclopine) on dopamine, glutamate, aspartate and
GABA release from striatum isolated nerve endings.
AB - The simultaneous effect of MK-801 on the baseline- and depolarization (20 microM
veratridine or 30 mM high K+)-evoked release of endogenous dopamine, glutamate
(Glu), aspartate (Asp), and GABA is investigated in the same preparation of rat
striatum isolated nerve endings. MK-801, in the microM range, selectively
increases the baseline and high K+ depolarization-evoked release of dopamine,
without causing any effect on the baseline or on the high K+-evoked release of
Glu, Asp and GABA. In addition to this selective action on dopamine release, MK
801 inhibits the veratridine depolarization-evoked release of all the
neurotransmitters tested, including dopamine. In SBFI and fura-2 preloaded
striatal synaptosomes, MK-801 inhibits the elevation of internal Na+ (Na(i)) and
the elevation of internal Ca2+ (Ca(i)) induced by veratridine depolarization. The
elevation of Ca(i) induced by high K+ depolarization is unchanged by MK-801. This
study reveals two separate MK-801 actions. (1) The voltage-independent action,
which increases dopamine release selectively, and might contribute to the effects
of MK-801 on motor coordination. (2) The voltage-dependent action, which inhibits
all the veratridine-evoked responses including the evoked release of the
excitatory amino acids (which are particularly concentrated in striatum nerve
endings), and might contribute to the anticonvulsant and neuroprotective effects
of MK-801.
PMID- 10784107
TI - Cellular expression of ionotropic glutamate receptor subunits in subpopulations
of neurons in the rat substantia nigra pars reticulata.
AB - In order to characterize the expression of ionotropic glutamate receptor
immunoreactivity in subpopulations of neurons in the rat substantia nigra pars
reticulata (SNr), double labeling experiments were performed. Neurons in the
reticulata were found to display GluR1, GluR2, GluR2/3, GluR4, N-methyl-D
aspartate receptor 1 (NMDAR1) and NMDAR2B immunoreactivity. Some of the
reticulata neurons were shown to display GluR1 and GluR2 immunoreactivity or
GluR2 and GluR4 immunoreactivity at the single cell level. In addition,
subpopulations of reticulata neurons were characterized on the basis of the
strong expression of parvalbumin (PV) and GABA transaminase immunoreactivity. All
of the reticulata neurons that displayed strong immunoreactivity for PV or GABA
transaminase also displayed immunoreactivity for GluR1, GluR2/3, GluR4, NMDAR1
and NMDAR2B. A tiny portion (around 15%) of reticulata neurons that display
NMDAR1 immunoreactivity was found to be PV- or GABA-transaminase-negative. The
present results indicate that native alpha-amino-3-hydroxy-5-methyl-4-isoxazole
propionate (AMPA)-type receptors and NMDA-type receptors in the rat substantia
nigra are composed of heteromeric receptor subunits. The present findings further
demonstrate that most of the AMPA-type and NMDA-type glutamate receptor subunits
are primarily expressed by subpopulations of neurons in the rat SNr.
PMID- 10784108
TI - Transplantation of olfactory ensheathing cells or Schwann cells restores rapid
and secure conduction across the transected spinal cord.
AB - Olfactory ensheathing cells (OECs) or Schwann cells were transplanted into the
transected dorsal columns of the rat spinal cord to induce axonal regeneration.
Electrophysiological recordings were obtained in an isolated spinal cord
preparation. Without transplantation of cells, no impulse conduction was observed
across the transection site; but following cell transplantation, impulse
conduction was observed for over a centimeter beyond the lesion. Cell labelling
indicated that the regenerated axons were derived from the appropriate neuronal
source, and that donor cells migrated into the denervated host tract. As reported
in previous studies, the number of regenerated axons was limited. Conduction
velocity measurements and morphology indicated that the regenerated axons were
myelinated, but conducted faster and had larger axon areas than normal axons.
These results indicate that the regenerated spinal cord axons induced by cell
transplantation provide a quantitatively limited but rapidly conducting new
pathway across the transection site.
PMID- 10784109
TI - Amylin compared with calcitonin: competitive binding studies in rat brain and
antinociceptive activity.
AB - Binding studies for rat amylin (AMY) and salmon calcitonin (sCT) were performed
on rat membranes prepared from pons and medulla oblongata of rats. The aim was to
see whether specific binding sites for AMY and/or for sCT present in these areas
could be relevant to some of the biological activities of the two peptides.
Binding sites specific for [125I]AMY are present in the pons-medulla of rat brain
as AMY, but not sCT, was able to displace radiolabeled AMY binding with an IC50 =
3.7+/-0.5x10(-10) M. In contrast, binding of [125I]sCT was displaced by both sCT
and AMY, although with different potencies, the IC50 for sCT being 1+/-0.1x10(
11) M, and for AMY, 1.8+/-0.08x10(-7) M. The functional significance of the
presence of these binding sites was evaluated in two different nociceptive tests,
hot-plate and tail-flick. In the tail-flick test neither AMY (5-10 microg/rat,
i.c.v.) nor sCT (10 microg/rat i.c.v.) showed antinociceptive activity, whereas
in the hot-plate test AMY (10 microg/rat, i.c.v.) significantly increased the
response latencies as did sCT (250 ng/rat, i.c.v.). These results demonstrated
that a 40-fold greater dose of AMY is necessary to produce a comparable
antinociceptive effect to that exerted by sCT. These findings are in accordance
with the low affinity of AMY for sCT binding sites in rat pons-medulla. It is
therefore suggested that the central inhibitory activity of AMY on pain
perception involves interaction with sCT receptors whereas the selective AMY
binding sites subserve other (as yet unknown) functions.
PMID- 10784110
TI - Microinjections of an opiate receptor antagonist into the bed nucleus of the
stria terminalis suppress heroin self-administration in dependent rats.
AB - Recent anatomical evidence suggests that the shell of the nucleus accumbens, the
bed nucleus of the stria terminalis, and the central nucleus of the amygdala,
together referred to as the extended amygdala, may play a role in opiate
dependence. The bed nucleus of the stria terminalis and the shell of the nucleus
accumbens have a moderately high density of opiate receptors, which allows for
manipulation of opiate neurotransmission with receptor antagonists. The goal of
this study was to determine the role these regions play in opiate reinforcement,
and whether dependence alters the reinforcing effects of opiates by examining the
effect of local administration of the opiate receptor antagonist methylnaloxonium
on heroin self-administration in dependent and nondependent rats. Previous
studies revealed that blockade of the reinforcing effects of opiates with
systemic administration of opiate receptor antagonists results in an increase in
heroin self-administration in nondependent rats, and a greater increase in
dependent rats. In the present study, methylnaloxonium dose-dependently
suppressed heroin intake when injected into the bed nucleus of the stria
terminalis and shell of the nucleus accumbens of dependent rats, and had no
effect in nondependent rats. These results demonstrate that opiate receptors in
parts of the extended amygdala may be responsible for the reinforcing effects of
opiates in dependent animals and suggest that activity in this system may be
recruited during the development of dependence.
PMID- 10784111
TI - Differential distribution of metabotropic glutamate receptor subtype mRNAs in the
thalamus of the rat.
AB - L-Glutamate (L-Glu) is present in most excitatory synapses of the mammalian
brain, acting on several receptor subtypes. Height different genes encoding
metabotropic glutamate receptors (mGluRs) subtypes have been described (mGluR1
8), having a distinct distribution in the brain. In the present study, the
distribution of mGluR1, 3, 4, 5 and 7 mRNAs was determined in 20 thalamic nuclei
of adult rats by performing in situ hybridisation with subtype-specific 35S
labelled oligonucleotide probes. High expression of mGluR1 mRNA mainly occurred
in midline nuclei such as the centromedial/centrolateral (CM/CL) nuclei,
parafascicular and submedius nuclei, and in the ventroposteromedial (VPM) and
posterior (Po) nuclei. In contrast, mGluR5 mRNA was more uniformly distributed at
weak to moderate levels, except in the reuniens nucleus where a strong signal was
detected. The mGluR3 mRNA was highly expressed in the reticular thalamic nucleus
and almost not detectable in any other thalamic region. Additionally, mGluR3 mRNA
was found not only in neurones but also in putative glial cells. The mGluR4 mRNA
was abundant in most thalamic nuclei, with prominent expression in the CM/CL, Po
and ventrobasal complex (VPM and ventroposterolateral, VPL). Finally, mGluR7
transcripts were found evenly distributed throughout the thalamus at moderate
levels, the highest signal being detected in the paraventricular thalamic
nucleus, VPM, VPL and Po. This differential distribution of mGluR subtypes in the
rat thalamus may contribute to the heterogeneity of glutamate effects on thalamic
neurones. The mGluR1, mGluR4 and mGluR7 receptors may be involved in the
processing of somatosensory information because they are expressed in nuclei that
receive direct sensory input.
PMID- 10784112
TI - Effects of chlorobutanol on primary and secondary endings of isolated cat muscle
spindles.
AB - The effects of the preservative chlorobutanol on primary and secondary endings of
muscle spindles isolated from the tenuissimus muscle of the cat were investigated
in this study. Chlorobutanol was applied to the bathing solution in final
concentrations of between 10 and 100 microg/ml. It induced a reversible and dose
dependent decrease in the discharge frequency of both types of ending without any
visible length change in the sensory region of the receptor. The initial
activity, the peak dynamic discharge, the maximum static discharge value and the
final static discharge value were evaluated from an ending's discharge pattern
obtained during ramp-and-hold stretches. These four basic discharge frequencies
decreased in parallel with increasing concentrations of chlorobutanol. Their
sensitivities to chlorobutanol were similar (mean values: -0.11 to -0.29 imp/s
per microg/ml chlorobutanol) and were independent of the amplitude of stretch.
The dynamic response and the static response of both primary and secondary
endings remained unchanged, indicating that the sensitivity of the spindle to
stretch was not influenced by chlorobutanol. Chlorobutanol also reduced the
discharge activity of the muscle spindle afferents during sinusoidal stretches.
The amplitude of the receptor potential (AC component) remained unchanged under
chlorobutanol. With the available recording technique it was not possible to
measure slow shifts of the membrane potential. However, a hyperpolarization of
the ending's membrane might explain why the afferent discharge frequency is
reduced by chlorobutanol. The calcium dynamics of the spindle do not appear to be
altered by CB, as the effect exerted on the afferent discharge by a change in the
extracellular calcium concentration and a blockage of calcium channels was
different from the CB effect. As the inhibitory effect of CB was reduced by
ouabain, it is possible that CB activates the electrogenic Na/K pump or affects a
mechanism that is closely related to the activity of the pump. The properties of
the axonal membrane appear not to be altered, as chlorobutanol did not change the
shape of action potentials.
PMID- 10784113
TI - Corticotropin releasing hormone neurons in the paraventricular nucleus are direct
targets for neuropeptide Y neurons in the arcuate nucleus: an anterograde tracing
study.
AB - In the present study, anterograde tracing combined with triple label
immunofluorescent staining was conducted to examine the possible anatomical
interactions between Neuropeptide Y (NPY) neurons in the arcuate nucleus of the
hypothalamus (ARH) and the corticotropin releasing hormone (CRH) system in the
paraventricular nucleus of the hypothalamus (PVH). The anterograde tracer,
Phaseolus vulgaris leucoagglutinin (PHA-L), was iontophresed into the ARH of
female rats and triple label immunofluorescence staining with three different
fluorophores was performed to visualize PHA-L, NPY and CRH, with the aid of
confocal microscopy. In PVH, NPY and PHA-L double-labeled fibers were found
mainly in the parvocellular part of the PVH (PVHp). Confocal analysis
demonstrated that NPY/PHA-L double-labeled fibers came in close apposition to CRH
perikarya. In the median eminence, NPY/PHA-L double-labeled fibers were found
both in the inner and the outer zones of the median eminence. However, very few
double-labeled fibers were found in the proximity of CRH neuronal fibers in the
median eminence. Double label staining was also performed to determine if NPY Y1
receptors were expressed in CRH neurons. Two different fluorophores were used to
visualize CRH neurons and Y1 receptor. No convincing Y1-positive staining was
found in CRH cell bodies in the PVH, even though Y1-positive staining in numerous
fibers and cell bodies was observed throughout the region. However, Y1-positive
fibers were shown to make close contact with CRH cell bodies in the PVH. In the
ME, the majority of the Y1-positive fibers were located in the lateral portion of
the ME, whereas the CRH fibers were found mainly in the medial portion of the
external zone of the ME. The results of the present study suggest that ARH NPY
neurons provide direct input into CRH cell bodies in the PVH region. However, the
direct effects of NPY must be mediated by some receptor subtype other than Y1. Y1
receptor involvement in NPY modulation of CRH neuronal function in the PVH
appears to be indirect through modulation of neuronal afferents making contact
with CRH neurons.
PMID- 10784114
TI - Microanatomical localization of dopamine receptor protein immunoreactivity in the
rat cerebellar cortex.
AB - Dopamine (DA) receptor subtype localization was investigated in rat cerebellar
cortex using immunohistochemical techniques with antibodies raised against D1-D5
receptor protein. A faint D1 receptor protein immunoreactivity was developed in
molecular and Purkinje neurons layers. D2 receptor protein immunoreactivity was
found primarily in cerebellar white matter followed by molecular and granular
layers and Purkinje neurons. Antibodies against D2S receptor protein were
localized in molecular layer and to a lesser extent, in granular layer. A few
Purkinje neurons displayed a faint D2S receptor protein immunoreactivity. D3
receptor protein immunoreactivity was observed primarily in molecular and in
Purkinje neurons layers of lobules 9 and 10. A faint D3 receptor protein
immunoreactivity was also localized in Purkinje neurons and to a lesser extent,
in molecular and granular layers of cerebellar lobules 1-8. D4 receptor protein
immunoreactivity was found in cerebellar white matter. A pale immunostaining was
also visualized in molecular layer. D5 receptor protein immunoreactivity was
localized primarily in molecular and Purkinje neurons layers and to a lesser
extent, in granular layer and in white matter. The above results indicate that
rat cerebellar cortex expresses the DA receptor subtypes so far identified.
Purkinje neurons, which are the only efferent neurons of cerebellum, are richest
in DA receptor protein immunoreactivity. This suggests that dopaminergic
neurotransmission may modulate efferent inputs from cerebellum. The localization
of the majority of D2 and D4 and of a faint D5 protein receptor immunoreactivity
in cerebellar white matter suggests that these receptors may be presynaptic and
transported axonally.
PMID- 10784115
TI - Mitochondria buffer non-toxic calcium loads and release calcium through the
mitochondrial permeability transition pore and sodium/calcium exchanger in rat
basal forebrain neurons.
AB - Mitochondria participate in intracellular Ca2+ buffering and signalling. They are
also major mediators of cell death. Toxic Ca2+ accumulation in mitochondria is
widely believed to initiate cell death in many cell types by opening the
permeability transition pore (PTP). In non-neuronal cells, the PTP has been
implicated as a Ca2+ release mechanism in physiological Ca2+ signalling. In
neurons, Ca2+ release from mitochondria has been attributed primarily to
mitochondrial Na+/Ca2+ exchange. Using fura-2 ratiometric microfluorimetry in
acutely dissociated rat basal forebrain neurons, we show that mitochondria are
able to buffer non-toxic Ca2+ loads arising from caffeine-sensitive internal
stores or from extracellular influx through voltage gated channels. We also show
that these non-toxic Ca2+ loads are reversibly released from mitochondria through
the PTP and the Na+/Ca2+ exchanger. Evoked Ca2+ transients have characteristic
peak and shoulder features mediated by mitochondrial buffering and release.
Depolarizing mitochondria with carbonyl cyanide m-chlorophenylhydrazone (CCCP, 5
microM) causes release of mitochondrial Ca2+ and prevents Ca2+ uptake. In CCCP,
the magnitudes of evoked Ca2+ transients are increased, and the peak and shoulder
features are eliminated. The PTP antagonist, cyclosporin A, (CSA, 2 microM) and
the Na+/Ca2+ exchange blocker, clonazepam, (CLO, 20 microM) reversibly inhibited
both the shoulder features of evoked Ca2+ transients and Ca2+ transients
associated with CCCP application. We suggest that central neuronal mitochondria
buffer and release Ca2+ through the PTP and Na+/Ca2+ exchanger during
physiological Ca2+ signalling. We also suggest that CLO blocks both the PTP and
the mitochondrial Na+/Ca2+ exchanger.
PMID- 10784116
TI - Adenosine release upon spinal cord injury.
AB - The hypothesis that release of adenosine following spinal cord injury (SCI) may
provide neuroprotective feedback is explored. Consistent with this hypothesis,
substantial release of adenosine, estimated to reach 100 microM in the
extracellular space, was detected by microdialysis sampling immediately following
contusion SCI. There is also considerable release of excitatory amino acids
following SCI. The latter was not affected by administration of the general
adenosine receptor antagonist theophylline and the A1 antagonist 8-cyclopentyl
1,3-dipropylxanthine, implying that the adenosine released following SCI does not
significantly influence the release of neurotoxic amino acids. Administration of
the concentration of glutamate released upon SCI into the spinal cord caused only
about 1% as much release of adenosine as did injury, evidence that elevated
excitatory amino acids do not elicit an appreciable fraction of the release of
adenosine that follows SCI. Results obtained suggest that release of endogenous
adenosine is not neuroprotective by blocking release of excitatory amino acids
following SCI.
PMID- 10784117
TI - Strain differences to the effects of aversive frequency ultrasound on behaviour
and brain topography of c-fos expression in the rat.
AB - Previous studies have shown that ultrasound at 20 kHz produces an escape
(defence) response in the hooded Lister rat. This study compares the ultrasound
induced behavioural response in the hooded Lister and albino Wistar rat.
Ultrasound (continuous tone, square wave, 20 kHz) produced an initial
characteristic startle response (brisk running) in the hooded Lister rat that was
followed immediately after cessation of the ultrasound by a period of freezing
behaviour. In contrast, Wistar rats showed no initial escape response but a
prolonged period of freezing that started during the ultrasound and continued for
a period after the end of the ultrasound. Immunohistochemical assessment of c-fos
expression also showed a difference between the two strains with preferential
expression in the dorsal region of the rostral and caudal periaqueductal grey
(PAG) in the hooded Lister rat, while the expression occurred in the ventral PAG
in the Wistar rats. In summary, the two strains exhibit distinct defensive
behaviours and patterns of neuronal activation in response to the same aversive
signal. It remains to be determined whether these differences relate to neuronal
circuitry or perception of the signal, but analysis of the mechanisms involved
may help our understanding of the heterogeneity of anxiety disorders.
PMID- 10784118
TI - Enhancement of Ca2+-induced noradrenaline release by vanadate in PC12 cells:
possible involvement of tyrosine phosphorylation.
AB - Tyrosine phosphorylation has been shown to participate in the signal cascade
after receptor stimulation with neurotransmitters and neurotrophins. However, the
role of tyrosine phosphorylation in the process(es) of neurotransmitter release
has not been well established. The effects of orthovanadate (Na3VO4), an
inhibitor of protein-tyrosine phosphatases, on cytosolic free Ca2+ concentrations
([Ca2+]i), phosphotyrosine accumulation and noradrenaline (NA) release in
neurosecretory PC12 cells were investigated. Addition of Na3VO4 enhanced
ionomycin-stimulated [3H]NA release in a concentration-dependent manner, although
Na3VO4 alone had no effect. Na3VO4 also enhanced [3H]NA release induced by P2
receptor stimulation with adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) or by
depolarization with 50 mM KCl, which stimulated a [Ca2+]i increase. A cell
permeable inhibitor of protein-tyrosine phosphatases, L-p-bromotetramisole
oxalate, at 0.3 mM enhanced ionomycin-stimulated [3H]NA release, although
pervanadate had no effect. Addition of 5 mM Na3VO4 stimulated phosphotyrosine
accumulation in several protein bands such as p130cas, but did not increase
[Ca2+]i in PC12 cells. These findings suggest that the tyrosine phosphorylation
pathway regulates Ca2+-stimulated NA release without changes of [Ca2+]i in PC12
cells.
PMID- 10784119
TI - Activation of cardiac vagal afferents facilitates late vagal inhibition in
neurones of the rostral ventrolateral medulla oblongata bilaterally.
AB - A reduced activity of cardiac vagal afferent fibres is considered as one of the
pathophysiological causes of post-infarction complications [A. Head, Baroreflexes
and cardiovascular regulation in hypertension. J. Cardiovasc. Pharmacol. 26
(1995) S7-S16]. The mechanism of how a reduction of cardiac vagal activity leads
to enhanced sympathetic drive and systemic hypertension is however not yet clear.
Experimental data have shown that the rostral ventrolateral medulla oblongata
(RVLM) plays an important role in tonic blood pressure regulation, the control of
sympathetic vasoconstriction and cardiac performance. The aim of the study was to
determine whether activation of cardiac vagal afferents contributes to eliciting
the long-lasting late inhibition that we have previously shown to occur in
neurones of the RVLM [A. Zagon, K. Ishizuka, I. Rocha, K.M. Spyer, Late vagal
inhibition in neurones of the ventrolateral medulla oblongata in the rat.
Neurosci. 92 (1999) 877-888]. The experiments were carried out in terminally
anaesthetised and artificially ventilated rats using in vivo intracellular
recordings. The data confirmed that late vagal inhibition is elicited by
cumulative activation of functionally different vagal afferents, including those
that originate from cardiac receptors. It was also demonstrated that activation
of cardiac afferents could lead to a significant increase in the duration of this
long-lasting late response component. Facilitation of late vagal inhibition was
observed in RVLM neurones both ipsi- and contralateral to the stimulated nerve.
It is suggested that such facilitation of late vagal inhibition may be a
mechanism of how pulse-synchronous activation of cardiac afferents leads to a
tonic modulation of the activity of RVLM neurones. An attenuation of late vagal
inhibition during reduced activity of cardiac vagal afferents could lead to
enhanced excitability in these neurones which in turn can lead to an increase in
medullary sympathetic outflows towards the heart and peripheral blood vessels.
PMID- 10784120
TI - Mononuclear cell proliferation and hyperplasia during Wallerian degeneration in
the visual system of the goldfish in the presence or absence of regenerating
optic axons.
AB - Patterns of proliferation and changes in non-neuronal cell number in the visual
system of the goldfish have been quantitatively examined during optic axon
regeneration after an optic nerve crush (ONC). In addition, in order to examine
the effect of the regenerating axons on cellular responses in the visual
pathways, we did a similar analysis of animals with the right eye removed (ER).
Finally, we used double labeling protocols to demonstrate that the proliferating
cells that we were counting were mostly phagocytic cells of the mononuclear
lineage. In animals with an ONC, we observed an early burst of proliferation that
peaked between 7 and 14 days after surgery in all parts of the visual system. In
the optic tract, there was also a secondary rise that peaked at 21 days. Levels
of proliferation returned to normal by 32 days postoperative in the tract and
tectum, while they remained somewhat elevated in the optic nerve for at least 93
days. The total number of non-neuronal cells in the visual paths also rose to
peak values between 7 and 14 days after ONC surgery. In the optic tract and
tectum, the values fell rapidly after this time, while in the optic nerve, there
was a secondary peak at 32 days after which values remained elevated for the
duration of the experiment. As compared to animals with an ONC, enucleation
resulted in elevated proliferation and hyperplasia at early postoperative
intervals. However, because these differences occurred when axons had not yet
regenerated into the affected structures, these data do not provide strong
evidence for a direct effect of regenerating optic axons on the early cellular
responses during Wallerian degeneration in the goldfish. In addition, in the
tectum, there was an early increment in cell number that was not associated with
elevated levels of proliferation. We believe that this increment represents
immigration of resident microglia from other regions of the brain.
PMID- 10784121
TI - Expression of Fos protein in adrenal preganglionic neurons following chemical
stimulation of the rostral ventrolateral medulla of the rat.
AB - The ventrolateral medulla is known to be involved in the regulation of arterial
blood pressure, especially via its connections with sympathetic preganglionic
neurons (SPNs) mainly located in the intermediolateral nucleus of the spinal
cord. It has been shown that stimulation of the rostral part of the ventrolateral
medulla (RVLM) elicits a release of catecholamines from the adrenal medulla. The
aim of the present study was to demonstrate the existence of a functional pathway
between the RVLM and adrenal SPNs using the combination of a retrograde tract
tracing technique (cholera toxin B subunit) with the immunohistochemical
detection of Fos protein following the chemical stimulation of RVLM. The data
obtained showed that: (1) chemical stimulation of the RVLM induced Fos
immunoreactivity in the intermediolateral nucleus and particularly in SPNs
projecting to the adrenal medulla; (2) along the thoracic segments T2-T12, 26.1%
of retrogradely identified adrenal SPNs were Fos-immunoreactive with the greatest
percentage (30.9%) in the T8 segment. These results favored a functional control
of the RVLM on adrenal SPNs which may contribute to a substantial activation of
the cardiovascular system via the release of adrenal catecholamines.
PMID- 10784122
TI - Phorbol ester induced changes in tight and adherens junctions in the choroid
plexus epithelium and in the ependyma.
AB - The molecular composition and functional properties of cell-cell junctions of
choroid plexus epithelial cells and the ependyma of the lateral ventricular wall
were investigated in the rat brain. Expression studies of cadherin and alpha- and
beta-catenins, as well as expression of occludin and ZO-1, indicated that cell
adherens and tight junctions were present in both choroid plexus epithelial cells
and in ependymal cells. We then tested the hypothesis that phorbolester in vivo
can induce changes in the expression level of adherens and tight junction
molecules at the blood-cerebrospinal fluid (CSF) barrier as well as in the
ependyma. In addition, the functional properties of the ependymal junctions were
tested by injection of dextran 3000 into the striatum after phorbolester
application. Twenty-four hours after phorbolester-injection into the lateral
ventricle of the rat brain, the expression patterns of tight and adherens
junction molecules were markedly changed in the epithelial cells of the choroid
plexus. The adherens junction proteins cadherin and beta-catenin were reduced in
both the ependymal cells of the lateral ventricle and choroid plexus epithelial
cells. In addition, the occludin-immunoreactivity of the choroid plexus
epithelial cells was strongly reduced. However, the ZO-1 immunoreactivity was not
affected by the phorbol ester-treatment and the alpha-catenin immunoreactivity
was not changed. Furthermore, phorbol ester injection induced a reduction of the
volume of intrastriatal injected biotinylated dextran (m.w. 3000), which is
consistent with a modulatory influence of protein kinase C activation on the
clearance capacity of the brain.
PMID- 10784123
TI - Non-N-methyl-D-aspartate glutamate receptors mediate oxygen--glucose deprivation
induced oligodendroglial injury.
AB - Cells of oligodendroglial lineage are susceptible to oxygen and glucose
deprivation. When oligodendrocyte-like cells differentiated from CG-4
immortalized rat O-2A progenitor cells were exposed to hypoxia alone or glucose
deprivation alone for 48 h, release of lactate dehydrogenase (LDH) into the
culture medium did not increase. However, when cells were deprived of both oxygen
and glucose for 6 or 12 h preceding reoxygenation for 2 h, LDH release increased.
Adding glucose to the medium protected against cell death and increased lactate
production in a concentration-dependent manner. Cell damage induced by
deprivation of oxygen and glucose was prevented by calcium-free medium or by non
N-methyl-D-aspartate glutamate receptor (GluR) antagonists, such as 6-cyano-7
nitroquinoxaline-2,3-dione or LY293558, but not by the voltage-dependent calcium
channel blocker, nimodipine, or by the N-methyl-D-aspartate GluR antagonist, MK
801. The glutamate concentration in the medium from cells exposed to oxygen
glucose deprivation for 12 h was 49.70+/-3.04 microM/l, which is sufficient to
activate GluRs during deprivation of oxygen and glucose. Apoptotic cells detected
by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end
labeling (TUNEL) or Hoechst 33258 staining did not increase in cells exposed to
oxygen-glucose deprivation for 12 h and subsequent reoxygenation for 2 h. No DNA
laddering was detected by agarose gel electrophoresis from cells exposed to
deprivation of oxygen and glucose. Neither acetyl-YVAD-CHO, an inhibitor of
caspase-1-like proteases, nor acetyl-DEVD-CHO, an inhibitor of caspase-3-like
proteases, prevented oxygen-glucose deprivation-induced injury. Thus, oxygen and
glucose deprivation causes calcium-influx-induced necrotic cell damage in cells
of oligodendroglial lineage via non-N-methyl-D-aspartate GluR channels.
PMID- 10784124
TI - Calretinin is not a marker for subdivisions within the suprachiasmatic nucleus.
AB - In this study, we report the immunocytochemical localization of the calcium
binding protein calretinin (CAL) in the suprachiasmatic nuclei (SCN) of male and
female rodents including rats, mice, golden hamsters, and Arvicanthis niloticus.
The results revealed that CAL is present in different subdivisions of the SCN in
the different species studied and CAL can, therefore, not be considered a marker
for particular subdivisions within the SCN. No differences were found between
males and females.
PMID- 10784125
TI - Direct projections from the magnocellular division of the basal nucleus of the
amygdala to the principal part of the cortical masticatory area in the macaque
monkey.
AB - Direct projections from the amygdala to the cortical masticatory area were found
in the macaque monkey. Under the guidance of intracortical microstimulation,
retrograde tracers were injected into multiple jaw movement-related regions of
the frontal lobe. The cortical masticatory area, especially its principal part,
stimulation of which elicited rhythmic jaw movement, was the only site of
injection that produced neuronal labeling in the amygdala. The cells of origin of
such projections were localized in the medial aspect of the magnocellular
division of the basal nucleus through its rostral level. No labeled neurons were
observed in the amygdala after tracer injection into any other cortical jaw
movement-related region. The present results suggest that the amygdaloid input to
the cortical masticatory area may exert some modulatory influence on the
generation of masticatory rhythm.
PMID- 10784126
TI - A novel effect of an opioid receptor antagonist, naloxone, on the production of
reactive oxygen species by microglia: a study by electron paramagnetic resonance
spectroscopy.
AB - Microglia as the first line of defensive cells in the brain produce free radicals
including superoxide and nitric oxide (NO), contributing to neurodegeneration. An
opioid receptor antagonist, naloxone, has been considered pharmacologically
beneficial to endotoxin shock, experimental cerebral ischemia, and spinal cord
injury. However, the mechanisms underlying these beneficial effects of naloxone
are still not clear. This study explores the effects of naloxone on the
production of superoxide and NO by the murine microglial cell line, BV2,
stimulated with lipopolysaccharide (LPS) as measured by electron paramagnetic
resonance (EPR). The production of superoxide triggered by phobol-12-myristate-13
acetate (PMA) resulted in superoxide dismutase (SOD)-inhibitable, catalase
uninhibitable 5,5-dimethyl-1-pyrroline N-oxide (DMPO) hydroxyl radical adduct
formation. LPS enhanced the production of superoxide and triggered the formation
of non-heme iron-nitrosyl complex. Cells pre-treated with naloxone showed
significant reduction of superoxide production by 35%. However, it could not
significantly reduce the formation of non-heme iron-nitrosyl complex and nitrite.
Taken together, the results expand our understanding of the neuroprotective
effects of naloxone as it decreases superoxide production by microglia.
PMID- 10784127
TI - Field responses to perforant path stimulation in the rat dentate gyrus: role of
corticosterone and NMDA-receptor activation.
AB - Recent studies showed that corticosterone and NMDA receptor activation suppress
cell turn-over in the dentate gyrus through a common pathway, the NMDA receptor
acting downstream of the corticosteroids. The present data show that in the
absence of corticosteroids but not of NMDA receptor activation synaptic responses
of dentate cells are reduced. The reduced synaptic responsiveness in the absence
of corticosterone is therefore probably not caused by changes in cell turn-over.
PMID- 10784128
TI - The possible role of endogenous glutathione as an anticonvulsant in mice.
AB - We have recently found that intracerebroventricular (i.c.v.) administration of
glutathione (GSH) inhibits pentylenetetrazol-induced convulsions in mice,
suggesting that GSH has an anticonvulsive action. In the present study, we
investigated whether endogenous GSH play a role in regulating seizure
susceptibility, using L-buthionine-[S,R]-sulfoximine (BSO), a specific inhibitor
of GSH biosynthesis. BSO treatment (3.2 micromol i.c.v. x 2, 48 and 24 h prior to
experiments) decreased brain GSH level to 31.5% of control, and potentiated
pentylenetetrazol-induced convulsions. Potentiation of convulsions by BSO
treatment was recovered by supplying GSH (10 nmol, i.c.v.). These results suggest
that endogenous GSH functions as an anticonvulsant.
PMID- 10784129
TI - Region-specific changes of NOS-IR cells in the basal ganglia of the aged rat.
AB - Nitric oxide (NO) is a free radical postulated to act as a neurotransmitter,
neuromodulator, or second messenger molecule in the central nervous system.
Several findings suggest that NO production may be decreased in the aged rats. In
the present study, we investigated regional discrepancies in changes with aging
in the number of nitric oxide synthase-immunoreactive (NOS-IR) cells in the basal
ganglia of the aged rat by immunocytochemistry. The number of NOS-IR neurons in
the striatum and substantia innominata of the aged rat decreased. In contrast,
the number of NOS-IR neurons in the subthalamic nucleus increased in the aged
rat. On the other hand, the number of NOS-IR neurons in the nucleus accumbens and
olfactory tubercle did not change. Taken together, important functional changes
can be caused by the region-specific changes of NOS-IR neurons in the basal
ganglia with aging.
PMID- 10784130
TI - Hemorrhagic transformation after fibrinolytic therapy with tissue plasminogen
activator in a rat thromboembolic model of stroke.
AB - In this study, the effects of early vs. delayed tPA treatment on the development
of hemorrhagic transformation was compared in a rat thromboembolic model of
stroke. Fibrinolysis was performed by administering tPA intravenously at 2 or 6 h
after ischemic onset. Twenty-four hours later, confluent hemorrhagic infarction
was observed only in rats treated with tPA at 6 h at the rate of 50%. In this
delayed treatment group, significantly increased numbers of polymorphonuclear
leukocytes (PMNL) were observed to accumulate inside microvessels within the
ischemic core. PMNL accumulation may be related to the induction of hemorrhagic
infarction after delayed tPA treatment.
PMID- 10784131
TI - The antinociceptive effect of PAG-microinjected dipyrone in rats is mediated by
endogenous opioids of the rostral ventromedical medulla.
AB - Microinjection of non-opioid analgesics, such as dipyrone (DIP), into the
periaqueductal gray matter (PAG) in rats causes an inhibition of nociceptive
circuits in the spinal cord. We have herein investigated whether this effect is
mediated by opioidergic mechanisms in the rostral ventromedial medulla (RVM),
which is an important relay between the PAG and the spinal cord. The responses of
spinal wide-dynamic-range neurons to noxious stimulation of their receptive field
(RF) were inhibited by microinjection of DIP (100 microg/0.5 microl) into PAG.
Subsequent microinjection of naloxone (NAL; 0.5 microg/0.5 microl) into RVM
reversed this inhibition. The present and previous results suggest that non
opioid analgesics, as well as opiates, inhibit nociception by activating
descending opioidergic mechanisms in PAG and RVM.
PMID- 10784132
TI - Learning-specific decrease in synaptosomal ATP diphosphohydrolase activity from
hippocampus and entorhinal cortex of adult rats.
AB - Considering the involvement of extracellular ATP in the memory formation, we
analyzed the effect of inhibitory avoidance training on ectonucleotidase
activities in synaptosomes from hippocampus, entorhinal cortex and parietal
cortex. ATP diphosphohydrolase activity presented a decrease (33%) in hippocampal
synaptosomes of rats sacrificed 180 min after training. Our results also showed a
decrease in synaptosomal ATP diphosphohydrolase (30% and 42% for ATP and ADP,
respectively) in entorhinal cortex immediately after training. These findings
suggest an integrated action of ATP diphosphohydrolase from hippocampus and
entorhinal cortex in the formation of inhibitory avoidance memory.
PMID- 10784133
TI - Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures:
relevance to neuroprotection in Parkinson's disease.
AB - Vasoactive intestinal peptide (VIP) provides neuroprotection against beta-amyloid
toxicity in models of Alzheimer's disease. A superactive analogue, stearyl-Nle17
VIP (SNV) is a 100-fold more potent than VIP. In primary neuronal cultures, VIP
protective activity may be mediated by femtomolar-acting glial proteins such as
activity-dependent neurotrophic factor (ADNF), activity-dependent neuroprotective
protein (ADNP), peptide derivatives ADNF-9 (9aa) and NAP (8aa), respectively. It
has been hypothesized that beta-amyloid induces oxidative stress leading to
neuronal cell death. Similarly, dopamine and its oxidation products were
suggested to trigger dopaminergic nigral cell death in Parkinson's disease. We
now examined the possible protective effects of VIP against toxicity of dopamine,
6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP+) in neuronal
cultures [rat pheochromocytoma (PC12), human neuroblastoma (SH-SY5Y) and rat
cerebellar granular cells]. Remarkably low concentrations of VIP (10(-16)-10(-8)
M), ADNF-9 and NAP (10(-18)-10(-10) M) protected against dopamine and 6-OHDA
toxicity in PC12 and neuroblastoma cells. VIP (10(-11)-10(-9) M) and SNV (10(-13)
10(-11) M), protected cerebellar granule neurons against 6-OHDA. In contrast, VIP
did not rescue neurons from death associated with MPP+. Since dopamine toxicity
is linked to the red/ ox state of the cellular glutathione, we investigated
neuroprotection in cells depleted of reduced glutathione (GSH). Buthionine
sulfoximine (BSO), a selective inhibitor of glutathione synthesis, caused a
marked reduction in GSH in neuroblastoma cells and their viability decreased by
70-90%. VIP, SNV or NAP (over a wide concentration range) provided significant
neuroprotection against BSO toxicity. These results show that the mechanism of
neuroprotection by VIP/SNV/NAP may be mediated through raising cellular
resistance against oxidative stress. Our data suggest these compounds as
potential lead compounds for protective therapies against Parkinson's disease.
PMID- 10784134
TI - Velocity-difference induced focusing of nucleotides in capillary electrophoresis
with a dynamic pH junction.
AB - Velocity-difference induced focusing (V-DIF) of nucleotides was achieved by using
a dynamic pH junction in capillary electrophoresis (CE) with UV detection. The
influence of specific analyte properties, such as nucleotide base structure,
sugar structure, and degree of phosphorylation, is examined. The pKa values and
borate complexation with vicinal diols are important factors that caused the
focusing. Therefore, the pH and borate content in the sample and background
electrolyte can be adjusted to optimize the focusing effect. This method allows
the injection of large volumes of sample (approximately 300 nL), resulting in at
least 50-fold improvement in concentration sensitivity. The detection limit of
4.0 x 10(-8) M for nucleotides can be achieved in favorable conditions. V-DIF can
be also applied to nucleotide pool analysis from cell extracts to improve the
concentration sensitivity of CE and to reduce the time-consuming steps of
desalting and off-line preconcentration that are often required for assays of
nucleotides from biological samples.
PMID- 10784135
TI - Chiral separations of polar compounds by hydrophilic interaction chromatography
with evaporative light scattering detection.
AB - The chiral separations of drug substances and underivatized amino acids were
demonstrated in this study through the use of hydrophilic interaction
chromatography (HILIC). The polar character of the model compounds presented
challenges for their analysis by traditional modes of chromatography, but through
the employment of multimodal chromatography utilizing the HILIC mechanism and
cyclodextrin- or teicoplanin-derivatized stationary phases, effective resolution
was achieved. The analytes lacked sufficient ultraviolet chromophores, requiring
their determination by evaporative light scattering detection. HILIC was
demonstrated to represent a novel technique for the facilitation of chiral
chromatography by providing an environment of solubility and retention that could
not be achieved through the use of the traditional methods of reversed-phase,
normal-phase, or polar organic mode.
PMID- 10784136
TI - Examination of structural changes of polymeric amino acid-based surfactants on
enantioselectivity: effect of amino acid order, steric factors, and number and
position of chiral centers.
AB - In this study, a large number of polymeric chiral surfactants were examined and
their performances in terms of enantiomeric resolution compared for a variety of
chiral analytes. The surfactants investigated in this study include all possible
dipeptide combinations of the L-form of alanine, valine, leucine, and the achiral
amino acid glycine (except glycine-glycine). Also included in this study were the
single amino acid surfactants of alanine, valine, and leucine as well as the
single chiral center dipeptide surfactant poly(sodium undecyl-L-leucine-beta
alanine) (poly L-SULbetaA). Several different aspects of polymeric dipeptide
surfactants, as they pertain to chiral separations, are examined. Some of the
factors investigated in this report include the effect of position and number of
chiral centers, amino acid order, and steric effects.
PMID- 10784137
TI - Analytical reliability of mobile-phase recycling in liquid chromatography
AB - Although it is not officially condoned, mobile-phase (MP) recycling has become a
widespread practice that is not well documented in terms of its effects on sample
quantification. MP was spiked with three different concentrations of two
analytes, tartaric acid and sodium citrate, to simulate MP recycling. These MPs
were used to analyze eight different concentrations of these analytes in standard
solutions. When analyte concentration in the MP exceeds that in the sample, a
vacancy (negative) peak is observed, and when its concentration in the MP is
equal to that in the sample, no peak is observed for that analyte. The slopes of
the linear regression lines for standards in MPs with different concentrations of
analyte did not change, although the gamma-intercept values decrease with
increasing concentration of analyte in the MP. These results show that the
concentration of analytes in recycled MP can be determined by comparing the
absolute value of the gamma-intercept of the linear regression line with the
corresponding peak area from the linear regression line for clean (solute-free)
MP, provided other chromatographic parameters do not change. Suggestions are made
for determining when recycled MP should be discarded.
PMID- 10784138
TI - Element-specific detection in capillary electrophoresis using X-ray fluorescence
spectroscopy.
AB - X-ray fluorescence spectroscopy is demonstrated here as a novel, element-specific
detector for capillary electrophoresis. Monochromatic 10 keV X-rays from a
synchrotron light source are used to excite core electrons, causing emission of
characteristic Kalpha X-ray fluorescence (XRF) lines. Using this technique, XRF
energies provide elemental identification, while XRF intensities can be used to
quantitate the metal composition of each eluent. An X-ray transparent polymer
coupling is used to create a window for the on-line, X-ray detection. This
coupling contributes no measurable extra-column variance, and electrophoretic
mobilities for the metal complexes used as model solutes are highly reproducible.
The combination of XRF detection with capillary electrophoresis (CE-XRF) creates
the first on-line detection system that is element-specific, nondestructive, and
directly applicable to a broad range of applications including nonelectroactive
species. CE-XRF is successfully demonstrated here for high binding-constant
complexes of Fe(III), Co(II), Cu(II), and Zn(II). Within a single injection,
electropherograms are obtained for each element of interest, with the element
identity obtained directly from the emission energy. In contrast with ICPMS, this
detection technique is directly on-line and does not require volatilization of
the eluent. As a result, element-specific detection is not limited by the sample
or the buffer volatility or atomization efficiency. Simultaneous XRF and UV
absorbance detection can be used to provide an on-line determination of
metal/chelate ratios. Although XRF detection limits are presently only in the 0.1
mM (0.5 ng) range, both collection geometry and incident intensity have yet to be
optimized. Further optimization is expected to enhance this detection limit by
another 2-3 orders of magnitude. As a result, the advent of XRF detection
combined with the separating power of CE presents new possibilities for on-line,
element-specific analysis.
PMID- 10784139
TI - Enhancement of fluorescence in thin-layer chromatography induced by the
interaction between n-alkanes and an organic cation
AB - Fluorescence enhancement of a broad variety of solutes has been used extensively
in TLC although no thorough explanation has been proposed. In this work, we try
to understand it and explore new applications to which it can be put. In this
way, alkanes can be quantitatively determined by fluorescence scanning
densitometry using silica gel plates impregnated with berberine sulfate.
Molecular simulation and analysis of molecular orbitals allows this phenomenon to
be explained in this case and lays the groundwork to explain fluorescence
enhancements produced by other molecules. A ion-molecule interaction between
alkanes and berberine sulfate is responsible for the enhancement of fluorescence
produced by alkanes. Computational results suggest that the surrounding alkane
molecules provide an apolar environment to the berberine cation, thus enhancing
the intensity of the fluorescence signal. This proposed explanation has been
tested by extending the fluorescence determination to other compounds. These
include biologically interesting saturated and unsaturated fatty acids, steroids
and derivatives, prostaglandins, ceramides, galactocerebrosides, as well as
terpenes, and polypropylene glycols. In addition, according to the proposed
explanation, the properties required for alternative impregnants to berberine are
discussed.
PMID- 10784140
TI - Role of the carbohydrate moieties in chiral recognition on teicoplanin-based LC
stationary phases.
AB - For this study, we used the macrocyclic antibiotic teicoplanin, a molecule
consisting of an aglycone peptide "basket" with three attached carbohydrate
(sugar) moieties. The sugar units were removed and the aglycone was purified. Two
chiral stationary phases (CSPs) were prepared in a similar way, one with the
native teicoplanin molecule and the other with the aglycone. Twenty-six compounds
were evaluated on the two CSPs with seven RPLC mobile phases and two polar
organic mobile phases. The compounds were 13 amino acids or structurally related
compounds (including DOPA, folinic acid, etc.) and 13 other compounds (such as
carnitine, bromacil, etc.). The chromatographic results are given as the
retention, selectivity, and resolution factors along with the peak efficiency and
the enantioselective free energy difference corresponding to the separation of
the two enantiomers. The polarities of the two CSPs are similar. It is clearly
established that the aglycone is responsible for the enantioseparation of amino
acids. The difference in enantioselective free energy between the aglycone CSP
and the teicoplanin CSP was between 0.3 and 1 kcal/mol for amino acid
enantioseparations. This produced resolution factors 2-5 times higher with the
aglycone CSP. Four non amino acid compounds were separated only on the
teicoplanin CSP. Six and five compounds were better separated on the teicoplanin
and aglycone CSPs, respectively. Although the sugar units decrease the resolution
of alpha-amino acid enantiomers, they can contribute significantly to the
resolution of a number of non amino acid enantiomeric pairs.
PMID- 10784141
TI - A high-throughput screening method for the determination of aqueous drug
solubility using laser nephelometry in microtiter plates.
AB - The determination of aqueous solubility in a high-throughput screening
environment is invaluable in the selection of the most promising potential drug
candidates. We describe a fast method based on laser nephelometry that can
determine the solubility of potential drug candidates (usually from combinatorial
chemistry) supplied as dimethyl sulfoxide (DMSO) solutions in 96-well plates. In
the sample, the percent DMSO is kept constant allowing direct comparison of
results. The nephelometric method has been shown to produce results equivalent to
those produced by an HPLC method and to be largely unaffected by colored
solutions.
PMID- 10784142
TI - Speciation of alkyllead and inorganic lead by derivatization with deuterium
labeled sodium tetraethylborate and SPME-GC/MS.
AB - A method for full speciation and determination of alkyllead and inorganic
lead(II) in aqueous samples was developed. This was accomplished by in situ
derivatization with deuterium-labeled sodium tetraethylborate NaB(C2D5)4 (DSTEB).
The derivatization was carried out directly in the aqueous sample and the
derivatives were extracted from the headspace by a solid-phase microextraction
(SPME) fiber. The extracted analytes were then transferred to a GC/MS or a GC/FID
for separation and detection. The research presented demonstrates that SPME and
the derivatization reagent DSTEB can be used successfully for the speciation of
Pb2+, Pb(CH3)3+, Pb(C2H5)3+, and Pb(C2H5)4 in water samples. All derivatives,
Pb(C2D5)4, (CH3)3Pb(C2D5), (C2H5)3Pb(C2D5), and Pb(C2H5)4, are separated using an
SBP-5 column. This method was applied to monitor degradation of tetraethyllead in
water. This is the first report of ethylation by DSTEB for full speciation of
methyllead, ethyllead, and inorganic lead compounds. This approach can be
extended to other organometallic compounds as demonstrated for ethyltin
speciation. This full speciation method will aid in monitoring occurrence,
pathways, toxicity, and biological effects of these compounds in the environment.
It is easily adopted for field analysis.
PMID- 10784143
TI - Application of directly coupled HPLC-NMR-MS to the identification and
confirmation of quercetin glycosides and phloretin glycosides in apple peel.
AB - Directly coupled HPLC-NMR-MS was used to identify and confirm the presence of
quercetin O-glycosides and phloretin O-glycosides in an extract of apple peel.
From the MS and MS/MS data, the molecular weights of the intact molecules as well
as those of quercetin and phloretin and their sugar moieties were deduced. The
NMR data provided information on the identity of the compounds as well as the
alpha and beta conformations and the position of the glycosides on quercetin and
phloretin. The following O-glycosides of quercetin could be identified: quercetin
3-alpha-L-rhamnosyl-(1-->6)-beta-D-glucoside (rutin), quercetin-3-beta-D
galactoside (hyperin), quercetin-3-beta-D-glucoside (isoquercitrin), quercetin-3
beta-D-xyloside (reynoutrin), quercetin-3-alpha-L-arabinofuranoside (avicularin),
and quercetin-3-alpha-L-rhamnoside (quercitrin). Phloretin was present as
phloretin-2'-beta-D-glucoside (phloridzin) and the 2'-beta-D-xylosyl-(1-->6)-beta
D-glucoside. Concentrations were between 0.2 and 5 mg/g of apple peel.
PMID- 10784144
TI - AMACE1: versatile aminoacetamide electrophore reagent.
AB - Acetamide, 2-amino-N-[[3,5-bis(trifluoromethyl)phenyl]-methyl]-N-methyl-,
monohydrochloride, which we have named AMACE1, was synthesized in three steps
starting from N-tritylglycine. AMACE1 was coupled via its primary amine group
(pKa 8.2) under aqueous conditions to four model analytes for oxidative sugar
damage to DNA: glycolate, 3-hydroxy-2-butanone, 3-phenylbutyraldehyde, and alpha
hydroxy-gamma-butyrolactone, relying on cyanoborohydride for coupling to a keto
function and a water-soluble carbodiimide for coupling to a carboxyl function.
Further reaction with butyric anhydride led to products that could be detected by
gas chromatography/electron capture mass spectrometry when 1 microL of ethyl
acetate containing essentially 20 amol of each product was injected, on the basis
of selected ion monitoring of the analyte characteristic anion fragment from
dissociative loss of the 3,5-bis-(trifluoromethyl)phenylmethyl moiety: m/z 215,
289, 299, and 329, respectively. Since many small, organic analytes contain a
keto or carboxylic acid group, AMACE1 should be useful in general in the area of
trace organic analysis.
PMID- 10784145
TI - Retention of ionizable compounds on HPLC. 4. Mobile-phase pH measurement in
methanol/water
AB - The different procedures used in HPLC to measure the pH of a mobile phase are
evaluated in terms of the rigorous IUPAC definition of pH. The three procedures
evaluated are as follows: measurement of the pH of the aqueous HPLC buffer before
mixing it with the organic modifier, measurement of the pH of the HPLC buffer
after mixing it with the organic modifier using a pH electrode system calibrated
with aqueous buffers, and measurement of the pH of the HPLC buffer after mixing
it with the organic modifier but calibrating the electrode system with reference
buffers prepared in the same mixed solvent used as mobile phase. Following IUPAC
definitions and recommendations, the three pH values can be related with the pH
scales: w(w)pH, s(w)pH, and s(s)pH, respectively. The relationships between these
three pH scales are also presented. The retention of several compounds with
acid/base behavior in a C-18 and a polymeric column with buffered methanol/water
as mobile phase is related to the mobile phase pH value measured in the three pH
scales. It is demonstrated that the s(w)pH and s(s)pH scales give better
relationships than the w(w)pH scale (pH measured in the aqueous buffer before
mixing it with the organic modifier), commonly used on HPLC. The s(w)pH scale is
specially recommended because of its simplicity of measurement: the pH is
measured after mixing the aqueous buffer with the organic modifier, but the pH
calibration is performed with the common aqueous reference buffers.
PMID- 10784146
TI - Atrazine-selective polymers prepared by molecular imprinting of trialkylmelamines
as dummy template species of atrazine
AB - Synthetic polymer receptors selective for atrazine have been prepared by
molecular imprinting using trialkylmelamines as template molecules in place of
atrazine. Trialkylmelamines were shown to be useful as templates for introducing
affinity for atrazine into ethylene glycol dimethacrylate-methacrylic acid
copolymers. The polymers showed the selective binding capacity for triazine
herbicides including atrazine, whereas agrochemicals in other categories were not
adsorbed to the imprinted polymers. The group selectivity demonstrated was
comparable with that of the original atrazine imprinted polymers. Use of the
nonagrochemical template molecules as a substitution to atrazine has made it
possible to synthesize herbicide-receptor polymers free from troubles caused by
analyte contaminants, which are desired for analytical applications.
PMID- 10784147
TI - A reversed-phase high-performance liquid chromatographic method for the
determination of soya bean proteins in bovine milks.
AB - A reversed-phase high-performance liquid chromatographic method was designed for
the quantitation of soya bean proteins in bovine milks. The method consisted of a
linear binary gradient, acetonitrile-water-0.1% trifluoroacetic acid, at a flow
rate of 1 mL/min and a temperature of 50 degrees C which resulted in a separation
time for soya bean proteins of 11 min. Calibration by the external standard
method using a soya bean protein isolate as standard was employed, and the method
was validated by evaluating precision, accuracy, and robustness. This method was
shown to be useful for the analysis of soya bean proteins in bovine milks spiked
with soya bean protein isolate; soya bean protein concentrations of approximately
13 microg/g of bovine milk could be detected by using the optimized method. The
results obtained for some of the bovine milks were compared with those obtained
by the method of standard additions.
PMID- 10784148
TI - Improving the recovery of ionic solutes from aqueous media by modified
thermospray liquid-liquid extraction
AB - Our previously reported procedure for the extraction of charged compounds from
aqueous samples by thermospray liquid-liquid extraction (TSLLE) was essentially a
one-step extraction involving large sample volumes. In this report, recirculative
extraction, analysis of small sample volumes, the halide ion effect, and the
effect of solvency or solvent modification on the extraction efficiency of
benzoic acid (BA) by TSLLE were investigated. Compared to the one-step procedure
that resulted in an extraction efficiency of only 28% for BA in n-hexane,
recirculative TSLLE resulted in a BA recovery of 65% after five extraction
cycles. When applied to sample volumes of 5-10 mL, TSLLE extracted BAwith a
precision of 2.8-6.1%. NaF, NaCl, and NaBr were also used to enhance analyte
recovery. NaF gave the best recovery, 104%, for BA relative to the 88% obtained
by batch processing. Some improvements in the extraction efficiency was observed
when solvent modifiers such as methanol, ethanol, and 2-propanol were used.
PMID- 10784149
TI - Development of electrical field-flow fractionation
AB - Electrical field-flow fractionation (ElFFF) results for a series of polystyrene
latex beads are presented. To first approximation, retention behavior can be
related to conventional FFF theory, modified to account for a particle-wall
repulsion effect. Size selectivity and column efficiency were exceptionally high,
again approaching the upper limit predicted by theory. For the channel described
in the present study, application of small voltages (typically less than 2 V)
across the thin (131 microm) separation space defined by a Teflon spacer
generates nominal field strengths of 10(4) V m(-1). However, electrode
polarization reduces the effective field across the bulk of the channel to
approximately 3% of the nominal value in the system studied. The magnitude of the
applied field was calibrated by using standard latex beads of known size and
mobility. Perturbations to retention behavior, such as overloading, were
investigated. It was found that ideal separations occur at very dilute
concentrations of the sample plug and that working in systems of very low ionic
strength, the double-layer thickness adds significantly to the effective size of
a particle. Steric inversion was observed at a particle size of approximately 0.4
microm under the conditions employed.
PMID- 10784150
TI - Laser-activated voltammetry: measurement of the diffusion coefficients of
electropassivating species. Application to pyrrole and phenol in aqueous solution
AB - Clean electrode surfaces can be achieved during the electrolysis of otherwise
passivating species in aqueous and other solutions by means of surface ablation
using a 10-Hz pulsed Nd:YAG 532-nm laser. This ability to remove passivating
electrolytically generated layers on glassy carbon and platinum electrodes is
shown first by an investigation of the stripping peaks formed from the
electrogeneration of the neutral forms of methyl viologen and heptyl viologen
during reduction in aqueous solution of dications. Next, laser ablation was
conducted under well-defined hydrodynamic conditions using a channel flow cell to
identify laser power thresholds below which transport-limited currents could be
seen, which were in quantitative agreement with those expected in the absence of
irradiation. Levich plots recorded in the channel flow cell for K4Fe(CN)6 at
glassy carbon and platinum electrodes showed such agreement for laser intensities
lower than 0.17 and 0.65 W cm(-2), respectively. Working at intensities below
these thresholds, steady-state voltammetry was observed for the oxidation of both
phenol and pyrrole at glassy carbon and platinum electrodes, respectively, in
aqueous solution. The diffusion coefficients of these two species were then
measured under hydrodynamic conditions using laser ablation voltammetry to
continuously clean the surface. Diffusion coefficients were inferred using the
Levich equation. The result for phenol at a pH of 12 in aqueous solution was 0.9
(+/-0.1) x 10(-5) cm2 s(-1), which is in good agreement with an independent
nonelectrochemical method. The diffusion coefficient of pyrrole in aqueous
solution was similarly evaluated as 1.25 (+/-0.1) x 10(-5) cm2 s(-1).
PMID- 10784151
TI - Ion-partitioning membrane-based electrochemical sensors
AB - The application of ion-partitioning membranes on proton transducers for the
development of electrochemical sensors is presented. The ion-partitioning
membrane incorporates two different ionophores, one selective to protons and the
other to analyte cations, as well as the necessary anionic lipophilic sites. As
dictated by the electroneutrality principle, when the concentration of the
analyte cations in the sample increases, the analyte cations are extracted into
the membrane, displacing protons of equal charge out of the membrane. The pH
sensitive gate of a CHEMFET or the surface of a glass pH electrode is used as an
internal transducer for the monitoring of the membrane proton flux. The resulting
signal of the pH transducer is related to the concentration of the analyte cation
present in the sample. The experiments presented here indicate that the observed
CHEMFET's signal is affected by the interaction of the pH-sensitive sensor
element with protons released by the polymeric membrane.
PMID- 10784152
TI - Lifetime of ion-selective electrodes based on charged ionophores
AB - The lifetime of solvent polymeric ion-selective electrodes (ISEs) is limited by
leaching of the membrane components into the sample solutions. In this article,
leaching of charged ionophores is discussed. Because of the electroneutrality
principle, the loss of the charged ionophore into the sample must be accompanied
by parallel transport of an ion of the opposite charge sign into the sample or by
ion exchange with a sample ion of the same charge sign. Because ionic sites of
high lipophilicity are available, the loss of ionic sites is, in general, not a
concern. Therefore, it is assumed here that the cotransported or ion-exchanging
ions are primary or interfering ions forming complexes with the ionophore. A
general theory that allows quantification of ionophore lipophilicities and a
discussion of changes in the membrane composition and selectivity with time is
presented. A high complex stability and high analyte concentrations diminish the
rate of ionophore loss into the sample if a charged ionophore is coextracted from
the membrane into the sample together with an analyte ion of opposite charge. On
the other hand, if the charged ionophore has the same charge sign as the ion that
it binds, a large binding constant and high analyte concentrations enhance
ionophore leaching into the sample. The model is applied to interpret results for
an electrically charged ionophore, for which selectivity changes as a function of
the leaching time were observed and the lipophilicity was determined with
potentiometric measurements. Using the lipophilicities of neutral ionophores, as
described previously, and the lipophilicities of charged ionophores, as described
here, a direct comparison of the expected leaching rates of charged and neutral
ionophores has become possible.
PMID- 10784153
TI - Simulations of the frequency response of implantable glucose sensors.
AB - The response of enzyme electrode glucose sensors implanted in tissues to
physiologic blood glucose oscillations is simulated. Models describe both oxygen
based and peroxide-based glucose sensors in spatially homogeneous medium
simulating some mass transfer properties of tissue. Pass-through ratios and
delays are reported as a function of frequency for the oxygen-based sensor, and
the effects on continuous blood glucose monitoring are illustrated using data
from the literature. Certain peroxide-based sensor designs may produce common
signals for different glucose concentrations, a characteristic not found in
oxygen-based sensors. The dynamic response depends on the frequency of glucose
oscillation and is sensitive to sensor type, enzyme activity, and diffusional
resistance.
PMID- 10784154
TI - Development of chemical sensors based on redox-dependent receptors. Preparation
and characterization of phenanthrenequinone-modified electrodes
AB - The study of phenanthrenequinone(PQ)-modified electrodes, prepared by
electropolymerization of a phenanthrenequinone-pyrrole derivative, is described.
The surface-confined PQ is shown to behave similarly to PQ in solution, acting as
a redox-dependent receptor toward aromatic ureas in aprotic solvents. Large,
positive shifts in the E1/2 of the PQ0/- redox couple are observed in the
presence of these ureas, due to a strong hydrogen bonding interaction between the
PQ radical anion and urea. The effect is fully reversible. Of the substrates
examined, only aromatic ureas produce a significant shift. Nonaromatic ureas or
other HN and HO containing compounds have little effect on the E1/2. The
magnitude of the shift is also independent of electrode coverage, allowing
reproducible measurements to be made despite significant loss in material from
the surface.
PMID- 10784155
TI - On-column surface-enhanced Raman spectroscopy detection in capillary
electrophoresis using running buffers containing silver colloidal solutions
AB - Direct on-column surface-enhanced Raman spectroscopy (SERS) detection is
demonstrated in capillary electrophoresis (CE). Distinctive SERS spectra of two
test compounds, riboflavin and Rhodamine 6G, are obtained in 100 microm i.d.
fused-silica capillaries under CE conditions using running buffers that contain
silver colloidal solutions. Detection is performed using an unmodified commercial
Raman spectrometer in a confocal microscope mode of operation. The effects of
laser power, wavelength, spectra acquisition time, silver colloidal
concentration, and applied voltage (i.e., flow rate) on the quality of SERS
spectra are evaluated. Using laser powers of 17 mW (at the sample) at 515 nm and
employing 1 s spectral acquisition times, spectra with bands exhibiting signal-to
noise ratios greater than 10 could be obtained for 1.0 x 10(-6) M riboflavin and
very low nanomolar concentrations of Rhodamine 6G. This was accomplished without
optimization of silver colloidal solution compositions and by using a low
throughput spectrometer. Incorporation of the colloidal solutions into running
buffers is shown to have little effect on the separation of the test compounds as
monitored using a laser-induced fluorescence instrumental scheme. However, SERS
spectra degrade if the capillary is not rinsed between experiments. Riboflavin
and Rhodamine 6G spectra are obtained on-the-fly for actual CE separations. In
the case of the latter solute, the injected quantity was approximately 90 amol.
PMID- 10784156
TI - Separation and detection of explosives on a microchip using micellar
electrokinetic chromatography and indirect laser-induced fluorescence
AB - A new approach for sensitive detection on a microfabricated chip is presented.
Indirect laser-induced-fluorescence (IDLIF) was used to detect explosive
compounds after separation by micellar electrokinetic chromatography (MEKC). The
detection setup was used in an epifluorescence configuration with excitation
provided by a near-IR diode laser operating at 750 nm. To achieve indirect
detection, a low concentration of a dye (5 microM Cy7) was added to the running
buffer as a visualizing agent. Using this methodology, a sample containing 14
explosives (EPA 8330 mixture) was examined. Concentrations of 1 ppm of
trinitrobenzene (TNB), trinitrotoluene (TNT), dinitrobenzene (DNB), tetryl, and
2,4-dinitrotoluene (2,4-DNT) could be detected with S/N ratios between 3 and 10.
Analyses showing 10 peaks, with plate numbers on the order of 60000, were
completed within 60 s using a 65 mm long separation channel. The three isomers of
nitrotoluene (2-, 3-, and 4-nitrotoluene) were not resolved. Additionally, the
two nitramines (HMX and RDX) could only be detected at much higher
concentrations, likely due to the low fluorescence quenching efficiencies of
these compounds. The analysis method was also used to separate and detect
nitroaromatic compounds in extracts from spiked soil samples. The presence of 1
ppm (1 microg of analyte/1 g of soil) of TNB, DNB, TNT, tetryl, 2,4-DNT, 2,6-DNT,
2-NH2-4,6-DNT, and 4-NH2-2,6-DNT could readily be detected. In the interest of
increasing the sensitivity of the analysis, various on-chip injection schemes
were evaluated. It was found that a 250 microm double-T injector gave a 35%
increase in peak signal compared to a straight-cross injector, which is less than
expected based on injected volume.
PMID- 10784157
TI - Speciation of dissolved iron(III) and iron(II) in water by on-line coupling of
flow injection separation and preconcentration with inductively coupled plasma
mass spectrometry.
AB - A method has been developed for the speciation of trace dissolved Fe(II) and
Fe(II) in water by on-line coupling of flow injection separation and
preconcentration with inductively coupled plasma mass spectrometry (ICPMS).
Selective determination of Fe(III) in the presence of Fe(II) was made possible by
on-line formation and sorption of the Fe(III)-pyrrolidinecarbodithioate (PDC)
complex in a PTFE knotted reactor over a sample acidity range of 0.07-0.4 mol L(
1) HCl, elution with 1 mol L(-1) HNO3, and detection by ICPMS. Over a sample
acidity range of 0.001-0.004 mol L(-1) HCl, the sum of Fe(III) and Fe(II), i.e.,
Fe(III + II), could be determined without the need for preoxidation of Fe(II) to
Fe(III). The concentration of Fe(II) was obtained as the difference between those
of Fe(III + II) and Fe(III). With a sample flow rate of 5 mL min(-1) and a 30-s
preconcentration time, an enhancement factor of 12, a retention efficiency of
80%, and a detection limit (3s) of 0.08 microg L(-1) were obtained at a sampling
frequency of 21 samples h(-1). The relative standard deviation (n = 11) was 2.9%
at the 10 microg L(-1) Fe(III) level. Recoveries of spiked Fe(III) and Fe(II) in
local tap water, river water, and groundwater samples ranged from 95% to 103%.
The concentrations of Fe(III) and Fe(II) in synthetic aqueous mixtures obtained
by the proposed method were in good agreement with the spiked values. The result
for total iron concentration in the river water reference material SLRS-3 was in
good agreement with the certified value. The method was successfully applied to
the determination of trace dissolved Fe(III) and Fe(II) in local tap water, river
water, and groundwater samples.
PMID- 10784158
TI - A large bore-direct injection high efficiency nebulizer for inductively coupled
plasma spectrometry
AB - A large bore-direct injection high efficiency nebulizer (IB-DIHEN) is introduced
that is less prone to capillary blockage and optimally operates at low nebulizer
gas pressures compared with the conventional DIHEN used for inductively coupled
plasma (ICP) spectrometries. The aerosol quality is examined using a two
dimensional phase Doppler particle analyzer (2D PDPA), and analytical figures of
merits are acquired by ICP mass spectrometry. Compared with the DIHEN, the LB
DIHEN produces larger droplets, but the velocity distributions and mean droplet
velocities are narrower and lower, respectively, providing longer residence times
for the droplets in the plasma. High RF power (1500 W), low nebulizer gas flow
rates (0.25-0.35 L/min), and low solution uptake rates (80-110 microL/min) are
required to operate the LB-DIHEN at optimum conditions for ICPMS. Detection
limits and sensitivities measured with the LB-DIHEN are superior to those of a
conventional nebulizer-spray chamber combination, but precision is inferior. The
performance of the LB-DIHEN is further explored in the determination of trace
elements in an herbal extract.
PMID- 10784159
TI - Phosphorescent oxygen sensors utilizing sulfur-nitrogen-phosphorous polymer
matrixes: synthesis, characterization, and evaluation of poly(thionylphosphazene)
b-poly(tetrahydrofuran) block copolymers
AB - We examine the use of thionylphosphazene-based block copolymers as matrixes for
oxygen sensor applications. Poly(aminothionylphosphazene)-b-poly(tetrahydrofuran)
(PATPy-PTHFx) block copolymers were prepared via reaction of ring-opened
poly(chlorothionylphosphazene) with THF and subsequently with excess n-butylamine
(to form PBATPy-PTHFx) or methylamine (to form PMATPy-PTHFx). The block
copolymers were characterized by NMR, gel permeation chromatography, and
differential scanning calorimetry. Films of PBATPy-PTHFx block copolymers
containing platinum octaethylporphyrin or [Ru(dpp)3]Cl2 (dpp = 4,7-diphenyl-1,10
phenanthroline) as the oxygen-sensitive chromophore were prepared, and time-scan
experiments were carried out to determine the diffusion coefficients, Do2, and
solubilities, So2, of oxygen therein. Despite microphase separation, the data fit
well to a simple Fick's law description of oxygen diffusion and gave Do2 values
smaller than that for the n-butylamino-substituted PBATP635. For films freshly
annealed above the melting point of PTHFx, the Do2 values were 35-50% (dye
dependent) larger than after aging 3 days at room temperature. Films with
[Ru(dpp)3]Cl2 as the dye were evaluated as media for phosphorescent pressure
sensing. The dye-containing polymer films exhibit linear Stern-Volmer-like plots,
even at high dye concentrations, as well as good photostability, and
significantly higher sensitivity to oxygen quenching than simple mixtures of the
analogous homopolymers.
PMID- 10784160
TI - On-line characterization of organic aerosols formed from biogenic precursors
using atmospheric pressure chemical ionization mass spectrometry.
AB - A method to investigate the chemical composition of organic aerosols formed from
biogenic hydrocarbon oxidation using atmospheric pressure chemical ionization
mass spectrometry (APCI/MS) is described. The method involves the direct
introduction of aerosol particles into the ion source of the mass spectrometer.
Using this technique, reaction monitoring experiments of alpha-pinene ozonolysis
show the formation of hetero- and homomolecular cluster anions (dimers) of the
primary oxidation products (multifunctional carboxylic acids). Since the
formation of dimers plays a profound role in new particle formation processes by
homogeneous nucleation in the atmosphere and, at the same time, is an intrinsic
feature of APCI, it is essential to differentiate between both processes when on
line APCI/MS is applied. In this paper, we compare the results from the
investigations of organic aerosols and artificially generated dimer cluster ions
of the same compounds using identical ionization conditions. The clusters and
their formation processes are characterized by varying the analyte concentration,
investigating the thermal stability of dimers, and studying collisional
activation properties of both ion species. The investigations show a significant
difference in ion stability: dimer anions measured on-line have an estimated
stability that is 20 kJ mol(-1) higher than that of the corresponding
artificially generated cluster ions. Hence, the technique provides the
possibility to accurately characterize dimers as ionized reaction products from
biogenic hydrocarbon oxidation and allows an insight into the process of new
particle formation by homogeneous nucleation.
PMID- 10784161
TI - Automated 96-well SPE and LC-MS-MS for determination of protease inhibitors in
plasma and cartilage tissues.
AB - Bioanalytical methods based on automated solid-phase extraction (SPE) and high
performance liquid chromatography with electrospray tandem mass spectrometry (LC
MS-MS) have been developed and utilized for the determination of MMP inhibitors
in plasma and cartilage tissues. The SPE methods were automated using a 96-well
extraction plate and a 96-channel programmable liquid-handling workstation. The
LC-MS-MS methods were developed using a rapid gradient LC separation, followed by
sample introduction through an ionspray interface in the positive ion mode and
tandem mass spectrometric detection with selected reaction monitoring. In the
optimized SPE methods, crude plasma or ground cartilage supernatant samples were
loaded onto an SPE plate to remove proteins and other interfering components in
the matrixes to render relatively clean extracts for LC-MS-MS analysis. Compared
to the simple plasma protein precipitation method, the automated SPE method
afforded significant time-saving in sample preparation and improved sensitivity
in MS detection. The methods were validated and successfully applied to the
analysis of protease inhibitors in plasma and cartilage tissues.
PMID- 10784162
TI - Accurate mass multiplexed tandem mass spectrometry for high-throughput
polypeptide identification from mixtures.
AB - We report a new tandem mass spectrometric approach for the improved
identification of polypeptides from mixtures (e.g., using genomic databases). The
approach involves the dissociation of several species simultaneously in a single
experiment and provides both increased speed and sensitivity. The data analysis
makes use of the known fragmentation pathways for polypeptides and highly
accurate mass measurements for both the set of parent polypeptides and their
fragments. The accurate mass information makes it possible to attribute most
fragments to a specific parent species. We provide an initial demonstration of
this multiplexed tandem MS approach using an FTICR mass spectrometer with a
mixture of seven polypeptides dissociated using infrared irradiation from a CO2
laser. The peptides were added to, and then successfully identified from, the
largest genomic database yet available (C. elegans), which is equivalent in
complexity to that for a specific differentiated mammalian cell type.
Additionally, since only a few enzymatic fragments are necessary to unambiguously
identify a protein from an appropriate database, it is anticipated that the
multiplexed MS/MS method will allow the more rapid identification of complex
protein mixtures with on-line separation of their enzymatically produced
polypeptides.
PMID- 10784163
TI - A disposable amperometric sensor screen printed on a nitrocellulose strip: a
glucose biosensor employing lead oxide as an interference-removing agent.
AB - A new type of disposable amperometric sensor is devised by screen printing thick
film electrodes directly on a porous nitrocellulose (NC) strip. The
chromatographic NC strip is then utilized to introduce various sample
pretreatment layers. As a preliminary application, a glucose biosensor based on
hydrogen peroxide detection is constructed by immobilizing glucose oxidase (GOx)
on the NC electrode strip and by formulating a strong oxidation layer (i.e.,
PbO2) at the sample loading area, placed below the GOx reaction band. The screen
printed PbO2 paste serves as a sample pretreatment layer that removes
interference by its strong oxidizing ability. Samples applied are carried
chromatographically, via the PbO2 paste, to the GOx layer, and glucose is
catalyzed to liberate hydrogen peroxide, which is then detected at the electrode
surface. The proposed NC/PbO2 strip sensor is shown to be virtually insusceptible
to interfering species such as acetaminophen and ascorbic and uric acids and to
exhibit good performance, in terms of the sensor-to-sensor reproducibility
(standard deviation, +/-0.026 - +/-0.086 microA), the sensitivity (slope, -0.183
microA/mM), and the linearity (correlation coefficient, 0.994 in the range of 0
10 mM).
PMID- 10784164
TI - Room-temperature imprinting method for plastic microchannel fabrication
AB - A new plastic imprinting method using a silicon template is demonstrated. This
new approach obviates the necessity of heating the plastic substrate during the
stamping process, thus improving the device yield from approximately 10 devices
to above 100 devices per template. The dimensions of the imprinted microchannels
were found to be very reproducible, with variations of less than 2%. The channel
depths were dependent on the pressures applied and the materials used. Rather
than bonding the open channels with another piece of plastic, a flexible and
adhesive poly(dimethylsiloxane) film is used to seal the microchannels, which
offers many advantages. As an application, isoelectric focusing of green
fluorescence protein on these plastic microfluidic devices is illustrated.
PMID- 10784165
TI - Sweeping of neutral analytes in electrokinetic chromatography with high-salt
containing matrixes
AB - The concept of sweeping neutral analytes using a high-conductivity matrix or
under a reduced electric field in micellar electrokinetic chromatography (MEKC)
using anionic micelles and in the presence of electroosmotic flow is presented.
Three important processes are identified. First, stacking of the micelles at the
cathodic interface between the sample solution (S) and background solution (BGS)
zones is identified. This is then followed by the sweeping of analyte molecules
by the stacked micelles that enter the S zone. Finally, the destacking of the
stacked micelles at the anodic interface between the S and BGS zones occurs. The
stacking of the micelles improves the focusing effect of sweeping by a factor
approximately equal to the ratio of conductivities between the S and BGS zones
(ratio = enhancement factor = gamma'). However, the destacking of the stacked
micelles broadens the swept zones by a factor approximately equal to 1/gamma'. In
effect, the focusing effect of sweeping using a matrix with equal or higher
conductivity compared to the BGS will be roughly the same. The micelle stacking
and destacking mechanisms are verified experimentally. This paper also provides
comments on the mechanism of neutral analyte focusing under similar conditions
proposed by another group.
PMID- 10784166
TI - Artificial insemination outcomes in beef females using bovine sperm with a
detectable fertility-associated antigen.
AB - In this study, semen samples from 25 bulls that had passed a breeding soundness
evaluation were analyzed for the presence or absence of a 31-kDa protein, known
as fertility-associated antigen (FAA), on spermatozoal membranes. Eighteen bulls
had FAA on sperm (FAA-positive) and seven were devoid of FAA on sperm (FAA
negative). A single ejaculate from each bull was extended and frozen with 25 to
30 x 10(6) sperm in .5-mL straws. Crossbred replacement heifers (n = 865) were
estrus-synchronized and artificially inseminated either at timed AI or 12 h after
they were detected in estrus. Mature cows (n = 285) were inseminated 12 h after
they were detected in estrus during a 45-d AI period. Pregnancy rates (pooled) to
first AI service for females (n = 764) inseminated with FAA-positive sperm were
65.6% and were 49.7% for females (n = 386) inseminated with FAA-negative sperm (P
< .005). Among the estrus-synchronized replacement heifers, pregnancy rates to
synchronized AI service for heifers (n = 550) inseminated with FAA-positive sperm
were 62% and were 45.7% for heifers (n = 315) inseminated with FAA-negative sperm
(P < .005). These data indicate that pregnancy rates to first AI service at
spontaneous and synchronized estrus are higher when using semen from bulls with
detectable FAA on spermatozoal membranes compared to semen from bulls devoid of
FAA on membranes. Fertility-associated antigen is an important determinant for
fertility potential of sperm from bulls to be used in AI breeding programs.
PMID- 10784167
TI - Prediction of crude fat content of longissimus muscle of beef using the ratio of
fat area calculated from computer image analysis: comparison of regression
equations for prediction using different input devices at different stations.
AB - Crude fat content of longissimus (ribeye) muscle of beef cattle was predicted
from a ratio of fat area (RFA) to area of ribeye muscle calculated from computer
image analysis (CIA). Cross sections of 64 ribeyes taken from the 6-7th rib from
cattle at experiment station A and cross sections of 94 ribeyes taken from the 6
7th rib from cattle at Experiment Station B were used in this study. Slices (1 to
1.5 cm in thickness) of just the Longissimus dorsi were homogenized and sampled
for chemical estimation of crude fat content using petroleum ether. Crude fat
content as determined from chemical analysis was used as the true estimate of fat
content. A CCD (charge-coupled device) camera was used as the input device at
Experiment Station A, and a single-lens reflex camera was used at Experiment
Station B to photograph ribeyes for CIA. The contour comparison method, which
assigns a threshold value for each marbling particle, was used to obtain accurate
binarization in this study. Minimum and maximum of chemical measurements of crude
fat were 2.1 and 39.8%, and for CIA calculation of the RFA were 6.1 and 56.8%,
respectively. This range covered almost the complete range of the beef marbling
standard used in carcass grading in Japan. The equation for the regression of the
crude fat content (Y) on RFA (X) calculated from CIA for all of the data was Y =
.793X-3.04 with r2 = .96. Regression equations for prediction of crude fat
percentage from RFA taking into consideration the effect of experiment station
were Y = .741X-2.22 with r2 = .91 for Experiment Station A, and Y = .782X-2.54
with r2 = .91 for Experiment Station B. Analysis of covariance showed that the
effects of experiment stations on intercepts and slopes were not significant (P >
.10). The ranges of differences between actual and predicted crude fat content
from the prediction equation that was calculated without consideration of the
effect of station were -6.4 to 4.0%. CIA of cross sections of the ribeye muscle
seems to have potential for prediction of crude fat content.
PMID- 10784168
TI - Evaluation of calpastatin activity measures in ante- and postmortem muscle from
half-sib bulls and steers.
AB - Calpastatin activity measured at 24 h postmortem in bovine longissimus muscle
(PMLD24) is correlated with Warner-Bratzler shear force (WBS) measurements, an
objective measure of tenderness. A live-animal measurement of calpastatin
activity that correlates with 24-h postmortem activity would provide information
for selection programs without the expense of progeny testing. The purpose of
this study was to evaluate the effectiveness of calpastatin activity measurements
obtained on tissue samples from live animals and to determine the relationship
among various calpastatin activity measures and tenderness determined by WBS and
sensory panel. Biopsies (approximately 10 g) were obtained surgically 2 d before
slaughter from the supraspinatus muscle on the anterior surface of the scapula
(LISH0) from contemporary purebred Angus bulls (n = 12) and steers (n = 17).
Biopsies from a subset of these cattle (n = 12) were refrigerated at 4 degrees C
to simulate the postmortem cooling process for 24 h (LISH24) prior to extraction.
A rib section anterior to the 12 and 13th rib interface was collected from all
animals at the commercial abattoir between 22 and 23 h postmortem for PMLD24,
sensory panel, and WBS measurements. A postmortem shoulder muscle sample (PMSH24)
was collected at the same time. Calpastatin was extracted from all muscle samples
using a heated calpastatin activity protocol. Sensory panel tenderness, WBS,
LISH0, LISH24, and PMSH24 were not different between bulls and steers. However,
PMLD24 values were significantly different. Significant partial correlations were
found between WBS and sensory panel tenderness (-.55), between WBS and PMLD24 (
.43), and between LISH24 and PMLD24 (.78). Therefore, similar calpastatin
activity values are possible with ante- and postmortem tissue samples, suggesting
the possibility of using measurements from live-tissue biopsies from other than
the longissimus muscle to predict end product tenderness.
PMID- 10784169
TI - Polyethylene glycol as a means for reducing the impact of condensed tannins in
carob pulp: effects on lamb growth performance and meat quality.
AB - We conducted an experiment to evaluate the effects that a diet containing
condensed tannins with and without polyethylene glycol (PEG) has on lamb growth
and meat quality. Twenty-three male Comisana lambs were introduced to the three
experimental diets between 45 and 50 d of age. Eight were given a diet containing
56% of Ceratonia siliqua (carob) pulp (tannin group), another eight received the
same diet with a supplement of 40 g of PEG for each kilogram of diet (PEG group),
and the remaining seven lambs were given a conventional maize-based diet (maize
group). Voluntary feed intake and live weights were measured until slaughter at
105 d of age, and digestibility measurements were undertaken toward the end of
the feeding trial. Carcass yield, meat quality characteristics, and a taste panel
evaluation were conducted. The tannin-based diet contained 2.5% condensed tannins
(DM basis), and lambs given this diet had lower growth rates and poorer feed
efficiencies (P < .01) compared with the other treatment groups. Daily gain was
similar between the maize and PEG lambs, although the efficiency of feed
conversion was highest in the maize group. The digestibility of DM, N, and fiber
was reduced (P < .05) by the condensed tannins. Lambs fed the tannin diet had a
lower carcass yield (P < .05) and had less fat (P < .05), and the meat had a
higher ultimate pH (P < .01) than those given the PEG or maize diets. Condensed
tannins affected meat color, which was lighter (L*) than meat from lambs given
the PEG-containing diet (P < .01). Sensory evaluation showed that panelists
preferred meat from lambs receiving PEG and maize treatments compared with those
receiving the tannin diet, and this could be related to differences in meat
ultimate pH and carcass fatness. These results show that condensed tannins from
carob pulp are very detrimental to feed digestibility and lamb performance.
Inclusion of 40 g of PEG/kg diet eliminated the effects of condensed tannins so
that lamb performance and meat quality were similar to lambs given a maize-based
diet.
PMID- 10784170
TI - Endocrine studies in ivermectin-treated heifers from birth to puberty.
AB - Continuous treatment with ivermectin from birth to puberty advanced sexual
maturation by 3.7 wk in Holstein heifers grazing pastures naturally infected with
nematodes. Every 14 d jugular blood samples were taken from birth to 45 wk of age
from all heifers. No differences in serum FSH, estradiol, or thyroxine levels
were observed during the trial between the treated and untreated group. Mean LH
levels were diminished in untreated heifers 4 wk before the first estrus and the
amplitude of LH pulses was augmented in treated heifers when puberty was reached.
Serum IGF-I levels increased from birth to 22 wk of age and then reached a
plateau in both groups, but levels were consistently higher in treated heifers
from 26 wk of age onward. Body weight gain was retarded in parasitized heifers
and IGF-I values were positively correlated with body weight only during the
first 20 wk of life. We suggest that enhanced prepubertal IGF-I levels in
conjunction with increased prepubertal LH levels and pubertal LH pulse amplitude
might be involved in the accelerated somatic maturation and in puberty
advancement observed in ivermectin-treated heifers.
PMID- 10784171
TI - Effects of energy intake, implantation, and subcutaneous fat end point on feedlot
steer performance and carcass composition.
AB - The purpose of this experiment was to evaluate the effects of energy intake,
implantation, and fat end point on feedlot performance and carcass composition of
steers. Three hundred eighty-four yearling crossbred steers (368 +/- 23.1 kg)
were allotted in a completely randomized design. Treatments were arranged in a 2
x 3 x 2 factorial experiment. Main effect factors were two levels of intake,
three implant strategies, and two compositional fat end points at slaughter. The
levels of intake were ad libitum (AL) and restricted (RS) intake (90% ad
libitum). The three implant strategies were Revalor-S (REV) (120 mg trenbolone
acetate, 24 mg estradiol), Synovex-Plus (SYN) (200 mg trenbolone acetate, 28 mg
estradiol benzoate), and no implant (control). The compositional target end
points were 1.0 and 1.4 cm s.c. fat cover over the 12th and 13th rib. Restricted
intake steers consumed 9.2% less (P < .01) DM than AL steers. Ad libitum-intake
steers gained weight 15.5% more rapidly (P < .01) than RS-intake steers. Steers
implanted with REV tended (P < .07) to gain faster than SYN steers, who in turn
gained 15.2% more (P < .01) than control steers. Ad libitum-intake steers were
4.8% more (P < .01) efficient than RS steers. Steers fed to a targeted 1.4 cm
s.c. backfat cover were 2.9% less (P < .05) efficient than steers fed to 1.0 cm,
and steers implanted with either REV or SYN had similar (P = .47) feed
efficiencies, whereas control steers had lower (P < .01) feed efficiencies.
Steers fed to a targeted compositional fat end point of 1.4 cm had 1.3% higher (P
< .01) dressing percentage (DP) than steers fed to 1.0 cm. Control and SYN steers
had similar (P = .13) DP; however, REV steers had 6.1% greater (P < .01) DP than
SYN steers. Steers fed to 1.4 cm s.c. fat end point had higher (P < .01)
numerical yield grades than steers fed to 1.0 cm (3.34 vs 2.71). There was an
interaction (P < .01) for intake level and implant for marbling score. Marbling
scores were lower (P < .05) for RS x SYN and AL x REV than in other treatments.
Steers on the RS x REV treatment were intermediate in marbling to all treatments
except AL control, which was higher (P < .01) than RS x SYN, AL x REV, and RS x
REV. No interaction for dry matter intake level and anabolic implants was
observed for growth performance. The depression in carcass quality resulting from
implanting is reduced as backfat increases from 1.0 to 1.4 cm at slaughter.
PMID- 10784172
TI - Response to 13 generations of selection for increased 8-week body weight in lines
of mice carrying a sheep growth hormone-based transgene.
AB - The purpose of this study was to evaluate selection in lines of transgenic mice.
Two replicates of lines that either carried or did not carry the sheep
metallothionein-1a sheep growth hormone transgene (oMt1a-oGH) were established.
The host lines had been previously selected for rapid growth or selected
randomly. Within-litter selection for increased 8-wk body weight was carried out
for 13 generations. The frequency of oMt1a-oGH was monitored in all generations
in the transgenic lines, but no genotypic information regarding the transgene was
used as an aid to selection. The oMt1a-oGH was activated from weaning, at 3 wk,
until 8 wk of age by adding ZnSO4 to the drinking water. Zinc stimulation of the
transgene was not done during mating, gestation, or lactation. Data on body
weights and weight gains were analyzed with a conventional mixed model and with
an animal model. Genetic progress was achieved in all lines subjected to
directional selection. In the control background, response to selection for 8-wk
body weight was larger in the nontransgenic lines than in the transgenic lines,
whereas no difference was found in the selected background. The frequency of the
transgene was increased from the initial .5 to .62 in the randomly selected
background but decreased to .04 in lines from a selected background. The REML
estimates of variance components and genetic gain estimates varied greatly
between the two methods. In general, there was better agreement between the
realized heritability estimates and the heritability estimates obtained from the
conventional mixed model analysis than between realized heritability estimates
and results obtained using the animal model. Favorable correlated responses were
obtained for 3- and 6-wk body weights and on 3- to 6- and 6- to 8-wk weight
gains. Correlated responses to selection were larger in the selected than in the
nonselected background but were not affected by the presence of the transgene.
Results suggest that constructs similar to the oMt1a-oGH, which allow tight
regulation, may be successfully incorporated into commercial livestock and should
have larger effects in populations that have not been subject to selection.
PMID- 10784173
TI - Genetic parameters among weight, prolificacy, and wool traits of Columbia,
Polypay, Rambouillet, and Targhee sheep.
AB - Genetic parameters for Columbia, Polypay, Rambouillet, and Targhee sheep were
estimated using REML with animal models for prolificacy, weight, and wool traits.
All bivariate analyses included a covariance between additive genetic effects for
the two traits plus appropriate additional covariances. Number of observations by
breed ranged from 5,140 to 7,095 for prolificacy traits, from 7,750 to 9,530 for
weight traits, and from 4,603 to 34,746 for wool traits. Heritability estimates
ranged from .03 to .11 for prolificacy traits (litter size at birth and litter
size at weaning), from .09 to .26 for weight traits (birth weight and average
daily gain), and from .25 to .53 for wool traits (fleece weight, fleece grade and
staple length). Estimates of direct genetic correlations among prolificacy and
among weight traits were positive and ranged from .58 to 1.00 and .18 to 1.00,
respectively. Estimates of direct genetic correlation between fleece weight and
staple length were positive (.50 to .70) but were negative between fleece weight
and fleece grade (-.60 to -.34) and between staple length and fleece grade (-.72
and -.40). Prolificacy and wool traits were essentially uncorrelated. Weight and
prolificacy traits were slightly positively correlated. Weight traits had a
moderate positive direct genetic correlation with fleece weight and staple
length, but were uncorrelated with fleece grade. These estimates of genetic
parameters between prolificacy, weight, and wool traits can be used to construct
multiple-trait selection indexes for dual-purpose sheep.
PMID- 10784175
TI - Effects of eating space and availability of water in feeders on productivity and
eating behavior of grower/finisher pigs.
AB - Three experiments were conducted to determine the effects of eating space and
availability of water within feeders on the productivity and behavior of
growing/finishing pigs. In Exp. 1, 12 commercial feeders were classified as being
either single-space (SS) or multiple-space (MS), and either as dry (D) or wet/dry
(WD), resulting in two SS-D, four MS-D, three SS-WD and three MS-WD models. Each
model was evaluated using four pens of 12 pigs, which were fed a mash diet
throughout the growing/finishing period (25 to 106 kg). Pigs were videotaped when
they were approximately 40 and 80 kg in weight to determine eating behavior. The
number of feeding spaces did not affect the productivity of the pigs, but the
presence of water within the feeder resulted in increases in ADFI (P < .05) and
ADG (P < .05) and a reduction in carcass lean (P < .05). Pigs eating from SS
feeders spent 15% less time eating than those fed from two-space feeders (P <
.05), and occupancy rate for feeding spaces was increased by 75% (P < .05). The
WD feeders also resulted in a reduction (17%) in eatingtime compared to D models
(P < .01), and occupancy rate for WD feeders was similarly reduced (P < .05).
Pigs spent 16% less time eating when they weighed approximately 80 kg than when
they weighed 40 kg (P < .01). In Exp. 2, rate of eating was determined during a
short test on the same 12 feeder models for both small (48 kg) and large (90 kg)
pigs. Large pigs ate faster than small pigs, but eating rate was not affected by
feeding space or presence of water in the feeder. In Exp. 3, eating rate was
determined for small amounts of dry or wet feed. Premixing water with the feed
(1:1 ratio by weight) increased eating speed (P < .01). We concluded that 12 pigs
can be fed from a single-space feeder without affecting productivity. The
inclusion of water within a feeder decreases time spent eating, but it increases
ADFI and ADG. When pigs are small, they spend more time eating, and feeder
occupancy rates are higher than when they are large.
PMID- 10784174
TI - High dietary copper improves odor characteristics of swine waste.
AB - We conducted two experiments to determine the effects of dietary copper
concentration and source on odor characteristics of swine waste. In both
experiments, 192 weanling gilts and barrows were allotted to 24 pens. Pens were
randomly assigned to one of six dietary treatments, consisting of control (10 ppm
Cu as cupric sulfate, CuSO4), 66 or 225 ppm Cu as CuSO4, or 33, 66, or 100 ppm Cu
as cupric citrate (Cucitrate). An antibiotic was included in the diets for Exp.
1, but not Exp. 2. On d 28, fecal samples were randomly obtained from one pig per
pen and stored at -20 degrees C until preparation and evaluation by an odor
panel. The odor panel consisted of 10 individuals, and each panelist evaluated
the odor intensity, irritation intensity, and odor quality of the samples. In
Exp. 1, the odor and irritation intensity of the feces were lower (P < .05) from
animals consuming diets containing 225 ppm Cu as CuSO4 and 66 or 100 ppm Cu as Cu
citrate compared to the control. The odor quality of the waste from animals
consuming diets containing 225 ppm Cu as CuSO4 and 66 or 100 ppm Cu as Cu-citrate
was improved (P < .05) compared to the 33 ppm Cu treatment. In Exp. 2, the odor
intensity of the feces of pigs receiving diets supplemented with all
concentrations of Cu-citrate was lower (P < .05) than that of feces from the
control animals. Irritation intensity of the feces was not affected by treatment.
Odor quality of waste of pigs supplemented with 225 ppm Cu from CuSO4 and all
concentrations of Cu-citrate was improved (P < .05) compared to that of waste of
the control pigs. Two gilts and two barrows from each nursery pen in Exp. 1 were
continued through the growing-finishing phase on their respective experimental
diets. The growing-finishing phase lasted 103 d, and fecal samples were randomly
obtained from one pig per pen at the completion of the phase. During the growing
finishing phase, the odor intensity and the irritation intensity of the feces
were lower (P < .05) from pigs supplemented with 66 and 225 ppm Cu as CuSO4 and
66 and 100 ppm Cu from Cu-citrate than from the control pigs. The odor quality of
the waste was improved (P < .05) in all animals receiving supplemental Cu. These
data indicate an improvement in odor characteristics of swine waste with the
supplementation of Cu. In addition, lower concentrations of an organic nonsulfate
Cu source resulted in similar odor characteristics of swine waste as 225 ppm
CuSO4.
PMID- 10784176
TI - Effects of boar contact and housing conditions on estrus expression in weaned
sows.
AB - Our objective was to study the effects of housing conditions and the amount of
boar contact in a protocol for estrus detection on estrus detection rate, timing
of onset of estrus, duration of estrus, and timing of ovulation. After weaning,
130 multiparous sows were assigned to three treatments: HI, in which 52 sows were
housed individually in crates and received a high amount of boar contact during
estrus detection; HG, in which 52 sows were housed in groups and received a high
amount of boar contact; and NI, in which 26 sows were housed individually in
crates and received a normal amount of boar contact. Estrus detection was
performed every 8 h. For each treatment, the standing response to three levels of
stimuli was recorded: a back pressure test (BPT) by a man (man-estrus), presence
of a teaser boar (spontaneous-estrus), and BPT in the presence of a teaser boar
(boar-estrus). In addition, for HI and HG, the standing response to a fourth
level of stimuli was recorded: BPT in a detection-mating area, surrounded by four
boar pens (DMA-estrus). To detect ovulation, ultrasonography was performed every
4 h during estrus. Of 117 sows that ovulated, 46% showed man-estrus, 56%
spontaneous-estrus, 90% boar-estrus, and 97% DMA-estrus. Mean onset of man-estrus
was 107 h (SD 26) after weaning, of spontaneous-estrus was 106 h (SD 22) after
weaning, of boar-estrus was 99 h (SD 21) after weaning, and of DMA-estrus was 93
h (SD 22) after weaning. Duration of man-estrus was 22 h (SD 14), of spontaneous
estrus was 29 h (SD 16), of boar-estrus was 42 h (SD 20), and of DMA-estrus was
55 h (SD 18). The high amount of boar contact reduced the number of sows showing
man-estrus (P < .05; 41% for HG and HI vs 68% for NI) and reduced duration of
boar-estrus (P < .05; 43 h for HG and HI vs 52 h for NI). Duration of DMA-estrus
for HG and HI was similar to duration of boar-estrus for NI. Onset of estrus and
timing of ovulation were not affected by amount of boar contact. Group housing
did not affect detection rate and duration of estrus, but it did postpone average
onset of estrus by 10 h, paralleled by a postponement of ovulation. In
conclusion, estrus expression is similar at the highest level of stimuli in
different protocols for estrus detection. Including higher levels of stimuli in a
protocol reduces estrus expression at lower levels of stimuli. This reduction
indicates adaptation of sows to a given protocol for estrus detection. Group
housing can delay ovulation and related behavioral estrus.
PMID- 10784177
TI - Hand-feeding and gentling influence early-weaned lambs' attachment responses to
their stockperson.
AB - Artificially reared herbivores are highly dependent on the stockperson at an
early age in order to learn to drink from an artificial milk provider. This
period of training may be a determinant for the animals' subsequent responses
toward humans. However, long-term responses may also depend on the human contact
(e.g., visual, physical interactions, gentling, and handling) provided to the
young lambs after this training period. We examined whether different levels of
subsequent contact (no visual and physical contact, stroking, and feeding reward)
affect long-term attachment responses of lambs to the caretaker that provided the
subsequent contact, after a common initial training period for artificial feeding
provided by another person. Ewe lambs (n = 45) were artificially reared from
multinippled buckets in groups of three. All the lambs were trained by a
stockperson (S1) to suck from the bucket (4.4 +/- .3 sessions of 3 min per animal
for the first 2 d of life). Subsequently, 15 lambs received no further human
contact (T0). Fifteen other lambs received only stroking from a second
stockperson (S2) for 6 min three times a day during the first 4 wk (T1). The
remaining 15 lambs (T2) were stroked and bottle-fed by S2 during the same
posttraining period as for T1. Tests were performed at 4, 6 (just before
weaning), 9, and 13 wk of age in an unfamiliar arena marked in a grid pattern.
The test procedure included three successive parts: 1) isolation for 1 min; 2) S2
presence for 2 min; and 3) isolation for 1 min. The T0 lambs spent a similar
amount of time in the grid square close to S2 regardless of whether he was
present. The T1 and T2 lambs spent more time close to S2 than T0 (P < .01), and
T2 spent more time close than T1 (P < .05). In the presence of S2, T2 vocalized
less (P < .01) than T0, and T1 did not differ from either T2 or T0. The T2 lambs
also crossed fewer squares than T0. When S2 left the arena, T2 vocalized more (P
< .01) than T0 and more (P < .05) than T1, and T1 had a tendency to vocalize more
(P = .08) than T0. Differences persisted with increasing age. Human contact,
especially stroking and feeding, during the 4 wk following initial training
strongly and durably influenced the lambs' response not only to the appearance
but also to the disappearance of a familiar stockperson. This last result
supports the idea that lambs could form a social bond with their stockperson.
PMID- 10784178
TI - Culture of porcine stromal-vascular cells in serum-free medium: differential
action of various hormonal agents on adipose conversion.
AB - We developed a strictly controlled serum-free culture system and tested the
effects of adipogenic and antiadipogenic agents on the proliferation and(or)
adipose conversion of porcine stromal-vascular cells. To avoid any interference
with serum components, stromal-vascular cells were isolated, plated, and grown in
absence of serum. In these culture conditions, a very limited growth phase and
the absence of cell confluence were observed. However, when compared with
continuous culture in serum-containing medium, the serum-free conditions were
significantly more adipogenic as assessed by increased lipid content and
increased enzymatic activities for lipoprotein lipase, glycerol 3-phosphate
dehydrogenase, and malic enzyme. In serum-free medium, physiological
concentrations of insulin or IGF-I were sufficient to significantly increase the
percentage of lipid-containing cells, whereas triiodothyronine (T3) and GH had no
effect. Insulin, IGF-I, and, more moderately, T3 also accelerated the lipid
filling in the lipid-containing cells. In the presence of insulin, stimulation by
T3 or hydrocortisone alone had no effect on glycerol 3-phosphate dehydrogenase
activity, whereas their concomitant addition significantly increased it. Chronic
exposure to tumor necrosis factor-alpha dose-dependently stimulated cell
proliferation but clearly inhibited differentiation. Epidermal growth factor,
another known antiadipogenic agent, also significantly increased the
proliferation of stromal-vascular cells, but, surprisingly, this was not
correlated with inhibition of adipocyte differentiation. Indeed, epidermal growth
factor treatment did not decrease lipid filling and significantly improved
lipoprotein lipase and malic enzyme activities. Taken together, the results
obtained in these strictly controlled serum-free culture conditions point out
functions for insulin, IGF-I, hydrocortisone, and T3 during early and(or) later
steps of porcine adipose conversion. In addition, this study reports a positive
activity of epidermal growth factor on porcine adipocyte differentiation that is
in clear contrast with previous works performed with rodent cells.
PMID- 10784179
TI - Influence of feeding different amounts of first colostrum on metabolic,
endocrine, and health status and on growth performance in neonatal calves.
AB - Colostrum intake is important for health and postnatal development of neonatal
calves. We studied the effects of enhanced first colostrum feeding on growth,
health status, and metabolic and endocrine traits in calves during their 1st wk
of life. Calves of group CL (GrCL; n = 7) were fed colostrum of milkings 1 to 6
twice daily during the first 3 d of life, followed by milk replacer (MR) up to d
7. Calves of group CH (GrCH; n = 7) were fed colostrum of the first milking
during the first 3 d and then colostrum (of the first milking) twice daily, which
on d 4, 5, 6, and 7 was diluted with 25, 50, 75, and 75 parts of MR,
respectively. Pre- and postprandial blood samples were taken on d 1, 2, 3, and 7
for the determination of various metabolic and endocrine traits, and on d 5
intestinal absorption capacity was measured using the xylose absorption test.
Rectal temperatures and fecal scores were higher (P < .05) in GrCH than in GrCL.
Plasma concentrations of total protein and albumin were higher (P < .05) on d 7,
IgG on d 2 and 3, and urea on d 2, 3, and 7 in GrCH than in GrCL. Plasma
concentrations of triglycerides were higher (P < .05) on d 2 and of phospholipids
and cholesterol were higher (P < .01) on d 7 in GrCH than in GrCL. Plasma insulin
and glucagon concentrations were higher (P < .05) in GrCH than in GrCL, whereas
prolactin and growth hormone concentrations were higher (P < .05) in GrCL than in
GrCH. Enhanced colostrum intake had no effects on xylose absorption on d 5.
Higher plasma protein, urea, and lipid concentrations in GrCH partly mirrored
higher protein and fat intake but additionally pointed to higher protein
synthesis and lipid turnover.
PMID- 10784180
TI - Plasmid transfection and retroviral transduction of porcine muscle cells for cell
mediated gene transfer.
AB - Cell-mediated gene transfer is a potential tool for studying muscle growth, but
efficient genetic manipulation and implantation strategies have not been
developed for pigs. The objectives of the present study were to determine methods
for transient and stable incorporation of reporter genes into porcine muscle
cells and to investigate their use for cell-mediated gene transfer in pigs.
Porcine myoblasts and fibroblasts were isolated from muscle of 2-wk-old male
pigs. Myogenic cell lines were identified using muscle-specific monoclonal
antibodies, myotube fusion assays, and the presence of muscle-specific markers
(MyoD and desmin). Four commercial cationic liposomes (lipofectAMINE, lipofectin,
cellFECTIN, and DMRIE-C) were tested at different DNA:lipid ratios for their
ability to transfect myoblasts and fibroblasts transiently with a luciferase
reporter plasmid. LipofectAMINE resulted in the greatest (P < .01) transient
luciferase activity for both cell types. Electroporation of cells for transient
transfection resulted in less luciferase activity than cationic transfection.
Stable transfections were conducted using a green fluorescence protein (GFP)
reporter plasmid containing the neomycin resistance gene. LipofectAMINE
transfection resulted in stable GFP expression in 1:16,000 myoblasts and 1:33,000
fibroblasts. Stable electroporation resulted in efficiencies that were
significantly lower than established with cationic liposomes. Porcine cells were
transduced with GFP using vesicular stomatitis virus glycoprotein G pseudotyped
retrovirus and resulted in efficiencies of 1:1.2 for myoblasts and 1:1.1 for
fibroblasts. These results show that cationic liposomes are superior to
electroporation for transfection, but retroviral transduction produced stable
reporter gene expression in > 80% of porcine muscle cells. Transduced GFP
positive cells were separated from GFP-negative cells by fluorescence-activated
cell sorting and implanted into 2-wk-old male pigs. On d 4, implanted muscles
were removed and subjected to immunodetection of GFP protein. Fibroblast
implantation resulted in limited GFP expression within muscle, whereas myoblast
implantation resulted in GFP within muscle fibers. This suggests that cell
mediated gene transfer is possible in porcine muscle and may be useful as an
approach for studying muscle growth in pigs.
PMID- 10784181
TI - Modulation of porcine adipocyte beta-adrenergic receptors by a beta-adrenergic
agonist.
AB - Mammalian cells have several mechanisms to decrease the response to beta
adrenergic agonists. Agonists are metabolized or taken up by nerve endings. The
beta-adrenergic receptors (betaAR) are inactivated by phosphorylation and removed
from the cell membrane, and synthesis is decreased or degradation is increased.
Knowledge about adipocyte betaAR desensitization is mostly from rodent adipocytes
with > or = 90% beta3AR. Porcine adipocyte betaAR have functional and ligand
binding properties that are quite different from those in many other species.
Furthermore, the predominant betaAR subtype in the porcine adipocyte is the
beta1AR (70 to 80%). Given these species differences, it might be expected that
desensitization in porcine adipocytes would not be totally concordant with the
rodent-derived model. Isolated porcine adipocytes were incubated without or with
a betaAR agonist, isoproterenol. The total betaAR number, measured by ligand
binding in a crude membrane fraction, tended to be lower after 6 h of incubation
without isoproterenol. The addition of 10(-5) M isoproterenol during the
incubation caused the betaAR number to decrease 43% compared to cells incubated
without isoproterenol. The beta1AR and beta2AR transcript concentrations both
decreased 45% after 6 h of incubation without isoproterenol. There was no
decrease in mRNA when cells were incubated with isoproterenol. The results
suggest the betaAR were desensitized by incubation with isoproterenol, perhaps by
phosphorylation and removal from the membrane, but this was not accompanied by
modulation of the concentration of transcripts for beta1AR or beta2AR.
PMID- 10784182
TI - Modulation of porcine adipocyte beta-adrenergic receptors by hormones and
butyrate.
AB - The beta-adrenergic receptors (betaAR) on the surface of mammalian cells are
desensitized when the cell is stimulated by betaAR agonists to eliminate
excessive response by the cell. Investigations with adipocytes, primarily rodent
derived cells, indicate other hormones and substrates also can modulate the
individual betaAR subtypes. For example, glucocorticoids decrease the beta1AR and
the beta3AR but increase the beta2AR. Insulin decreases the beta3AR. Thyroid
hormones increase the beta3AR and butyrate increases beta1AR and beta2AR but
dramatically decreases beta3AR. Because porcine adipocytes have unique functional
and ligand-binding properties compared to rodent adipocytes and because porcine
adipocytes contain predominantly beta1AR, compared to rodent adipocytes with
predominantly beta3AR, we expect the regulation of porcine adipocyte betaAR by
hormones and substrates to be different from that in rodent adipocytes. Isolated
porcine adipocytes were incubated for 6 and 21 h without and with dexamethasone,
insulin, triiodothyronine, or butyrate. Cells incubated without hormone or
butyrate had a decreased betaAR number at 21 h. The beta1AR and beta2AR
transcript concentrations were decreased after 6 h and tended to rebound after 21
h of incubation. Dexamethasone did not change the total betaAR number but tended
to increase the beta1AR and beta2AR transcript concentrations. Insulin increased
the betaAR number and decreased both transcript concentrations at 21 h.
Triiodothyronine and butyrate did not change the receptor number or transcript
concentrations. The results indicate that betaAR transcript concentrations do not
accurately predict the betaAR protein concentration (estimated by ligand
binding). Results also indicate that betaAR in porcine adipocytes are relatively
unresponsive to hormones and butyrate compared to rodent-derived adipocytes
described in the literature.
PMID- 10784183
TI - Effect of feed restriction on adipose tissue transcript concentrations in
genetically lean and obese pigs.
AB - To determine possible genetic influences on the steady-state concentrations of
several key transcription factor transcripts and the transcript concentrations
for adipocyte-characteristic proteins, young, genetically obese and lean pigs
were given ad libitum access or feed or were restrictively fed at 50% of ad
libitum intake for 5 wk. Obese pigs were smaller and fatter than lean pigs,
whether intake was ad libitum or restrictive. Plasma protein, albumin, and
cholesterol concentrations were greater in obese than in lean pigs. Plasma NEFA,
blood urea nitrogen, triacylglycerols, and postprandial glucose and insulin
concentrations were less (P < .02) in pigs fed restrictively than in pigs with ad
libitum access to feed, regardless of genetic group. The adipose tissue glucose
transporter 4, fatty acid synthase, and leptin transcript concentrations were
greater (P < .05) in obese than in lean pigs. The CCAAT/enhancer binding proteins
beta and alpha, adipocyte fatty acid binding protein, hormone-sensitive lipase,
and the beta1-adrenergic receptor transcript concentrations tended (P < . 10) to
be greater in adipose tissue from obese than in that from lean pigs. Several
other transcripts were numerically greater in obese than in lean pigs. The data
collectively suggest that messenger RNA concentration for several adipose tissue
proteins is a contributing factor to the excess fat deposition in these obese
pigs. Restricted feeding did not change the concentration of any transcript
except that for adipocyte fatty acid binding protein, which was reduced. The
accretion of fat was markedly reduced in the restrictively fed pigs, but this
diminution does not seem to be regulated by modulation of messenger RNA
concentration.
PMID- 10784184
TI - Developmental changes in cholesterol 7alpha- and 27-hydroxylases in the piglet.
AB - Hepatic cholesterol 7alpha-hydroxylase (CYP7A) and sterol 27 hydroxylase
activities were measured in fetal, newborn, suckling, and weaned piglets from 76
d into gestation to 49 d of age. Hepatic CYP7A activity was not detected in fetal
microsomes, but it increased to 6.8 +/- 2.6 pmol/min x mg(-1) protein in suckling
piglets at 21 d of age and to 18.2 +/- 2.5 in weaned piglets at 49 d of age.
Hepatic CYP7A activity was not different between 49-d-old piglets weaned at 21 d
and piglets suckled for 49 d (18.9 +/- 2.6 and 18.2 +/- 2.5 pmol/min x mg
protein, respectively). Fasting for 14 h decreased CYP7A activity by 86% in both
suckled and weaned piglets. Cholesterol 7alpha-hydroxylase activity remained
decreased for at least 5 h after refeeding. Sterol 27-hydroxylase activity was
also undetectable near birth, but was detectable by 21 d of age. Postnatally,
sterol 27-hydroxylase activity was not influenced by age or suckling and weaning,
as was CYP7A. Sterol 27-hydroxylase was decreased by 80% in piglets deprived of
feed compared with piglets given free access. In contrast to CYP7A activity, 27
hydroxylase activity returned within 5 h after refeeding to levels observed in
piglets given ad libitum access to feed. Similar to CYP7A enzyme activity,
hepatic CYP7A mRNA was not detected in newborn piglets, but increased from 2.7 +/
1.7 pg mRNA/microg RNA in suckling piglets at 21 d to 13.7 +/- 1.2 in 49-d-old
piglets weaned at 21 d. As with enzyme activity, feed deprivation decreased CYP7A
mRNA to barely detectable levels (< .5 pg/microg RNA), and which remained
decreased for at least 5 h following refeeding (.6 +/- .3 and 2.67 +/- .4 pg
mRNA/microg RNA for suckled and weaned piglets, respectively). In piglets allowed
free access to feed, CYP7A mRNA concentrations were associated positively (P =
.001) with enzyme activity. These results suggest that developmental regulation
of CYP7A activity is the result of a pretranslational mechanism.
PMID- 10784185
TI - Injection of beef strip loins with solutions containing sodium tripolyphosphate,
sodium lactate, and sodium chloride to enhance palatability.
AB - Beef strip loins (46 U.S. Choice loins and 49 U.S. Select loins) were used to
evaluate the potential for enhancing beef tenderness, juiciness, and flavor by
injecting fresh cuts with solutions containing sodium tripolyphosphate, sodium
lactate, and sodium chloride. One half of each loin served as an untreated
control, and the other half was injected with either distilled water (110% of raw
weight) or a solution containing phosphate/lactate/chloride solution (107.5, 110,
112.5, or 115% of raw weight). All phosphate/lactate/chloride solutions were
formulated to produce injected product concentrations of .25% sodium
tripolyphosphate, .5% sodium chloride, and 2.5% sodium lactate. Ten additional
U.S. Select loins were injected to 110% of raw weight with a phosphate-only
solution (final product concentration of .25% sodium tripolyphosphate) for
comparison with Select loins injected to 110% with phosphate/lactate/chloride and
with distilled water. Steaks from each control and treated loin section were
cooked to two final internal temperatures (66 degrees C and 77 degrees C) for
sensory panel evaluation and shear force measurement. Injection of subprimal cuts
with phosphate/lactate/chloride solutions improved tenderness (P < .05),
juiciness (P < .05), and cooked beef flavor (P < .10) of strip loin steaks and
was especially effective for maintaining tenderness and juiciness of steaks
cooked to the higher final internal temperature. Injection of Select loins with a
solution containing only sodium tripolyphosphate was not effective for improving
beef tenderness or juiciness and tended to impart off-flavors characterized by
sensory panelists as soapy and sour. Injection of fresh cuts with
phosphate/lactate/chloride solutions could assist the beef industry's efforts to
improve product quality and consistency.
PMID- 10784186
TI - Variation in proteolysis, sarcomere length, collagen content, and tenderness
among major pork muscles.
AB - The objectives of this experiment were to determine the extent of variation in
proteolysis, sarcomere length, and collagen content among pork muscles and the
association of those factors with tenderness variation among muscles at 1 d
postmortem. Twenty-three white composite barrows were slaughtered and carcasses
(66 kg) were chilled at 0 degrees C for 24 h. At 1 d postmortem, the longissimus
lumborum, biceps femoris, semimembranosus, semitendinosus, and triceps brachii,
long head were dissected from one side of each carcass and frozen. Trained
sensory panelists evaluated tenderness, amount of connective tissue, juiciness,
and pork flavor intensity of grilled (70 degrees C) chops on 8-point scales. Raw
chops were used for total collagen content, sarcomere length, and the extent of
desmin proteolysis. Tenderness ratings were highest (P < .05) for semitendinosus
(7.2) and triceps brachii (7.1), followed by longissimus lumborum (6.4) and
semimembranosus (5.7) and were lowest (P < .05) for biceps femorus (4.0). The
simple correlations between longissimus lumborum tenderness and the tenderness of
other muscles were .54 (semimembranosus), .34 (semitendinosus), .36 (triceps
branchii), and .17 (biceps femorus). Total collagen was highest (P < .05) for
biceps femorus (7.1 mg/g muscle), followed by triceps branchii (6.0 mg/g) and
semitendinosus (5.3 mg/g), and lowest for semimembranosus (4.5 mg/g) and
longissimus lumborum (4.1 mg/g). Sarcomere length was longest (P < .05) for
semitendinosus (2.5 microm) and triceps branchii (2.4 microm), followed by
semimembranosus (1.8 microm), longissimus lumborum (1.8 microm), and biceps
femorus (1.7 microm). Proteolysis of desmin was greatest (P < .05) in longissimus
lumborum (39.3%), followed by semimembranosus (21.0%) and biceps femoris (18.5%),
then semitendinosus (.2%) and triceps brachii (.2%). Multiple linear regression
using total collagen, sarcomere length, and proteolysis accounted for 57% of the
variation in tenderness rating among all samples. Piecewise linear regression was
used to account for the interaction of sarcomere length with proteolysis and
collagen. This analysis accounted for 72% of the variation in tenderness rating.
Variation in collagen, proteolysis, and sarcomere length and the degree of their
interaction with one another determine the tenderness of individual muscles.
PMID- 10784187
TI - Identification of optimal ranges in ribeye area for portion cutting of beef
steaks.
AB - Restaurant-ready (21-d aged, needle tenderized) loin steaks (strip, S; and T
bone, TB) representing three portion sizes (227, 284, and 340 g for S; 397, 454,
and 510 g for TB) were portioned from 71 low-Choice beef carcasses representing
seven ribeye size groups (70.9 cm2 and less to 103.2 cm2 and greater, in 6.3-cm2
increments). Steaks (n = 568) were cooked on a grooved grill to temperatures of
either 67 or 77 degrees C and evaluated for cooking characteristics, sensory
attributes (n = 284), and shear force (n = 284) to identify optimal ribeye areas
for portioned steaks. As expected, thickness of all portioned steaks decreased (P
< .05) as ribeye size increased, whereas thickness of steaks increased (P < .05)
as portion size increased. The S were significantly thicker than TB. The TB
cooked faster (P < .05) than did S for ribeye areas 77.4 to 83.8 cm2 in the
average portion sizes and for ribeye areas 71.0 to 96.6 cm2 in the large portion
sizes. However, S cooked significantly faster than did TB for ribeye areas less
than 70.9 cm2 in the average portion sizes. The S had higher (P < .05) initial
tenderness scores and lower (P < .05) shear values than did TB. Initial
tenderness scores were lower (P < .05) for ribeye areas greater than 103.2 cm2
compared with ribeye areas less than 83.8 cm2 and 90.3 to 96.6 cm2, with all
others being intermediate. Shear force tended (P = .08) to follow the initial
tenderness results. The S cooked to both end point temperatures, and TB cooked to
67 degrees C had higher (P < .05) initial tenderness scores than did TB cooked to
77 degrees C. Tenderness was reduced in TB cooked to higher temperatures as well
as in S and TB portioned from ribeye areas greater than 103.2 cm2. Steaks
portioned from carcasses with ribeye areas between 77.4 to 96.6 cm2 can optimize
both cooking time and tenderness for the foodservice sector.
PMID- 10784188
TI - Effect of dietary glycine and benzoate level on benzoate metabolism in mink
(Mustela vision), blue fox (Alopex lagopus), and raccoon dog (Nyctereutes
procyonoides).
AB - Three 2 x 4 factorial experiments were carried out from August to September with
30 juvenile male mink, 24 raccoon dogs, and 24 blue foxes to investigate the
effect of dietary glycine supply (low or high) on the efficiency of these species
to excrete hippuric acid with incremental benzoate intake (0, 1, 2, or 4 mmol/kg
BW). For mink, two additional treatments with 1 or 2 mmol/kg BW of ethyl benzoate
were included. A basal low-glycine diet was formulated to meet the minimum
protein requirements of fur animals (30% of ME). This diet was supplemented with
0 or 3 g/kg of glycine, or with 0, 1.0, 2.07, or 4.15 g/kg of sodium benzoate for
mink and blue foxes, and with 0 or 4.5 g/kg of glycine and 0, 1.58, 3.17, or 6.34
g/kg of sodium benzoate for raccoon dogs, respectively. Two additional diets with
.76 or 1.53 g/kg of ethyl benzoate were made for mink. Fecal and urinary benzoic
and hippuric acid excretion were measured for 3 d. The 24-h recovery of
[14C]benzoic acid injected intraperitoneally was measured from urine, the liver,
and the kidneys. All animals appeared healthy and no clinical signs of benzoate
overdose were observed. Dietary benzoate level did not affect ADFI or ADG in any
species. Glycine supplementation lowered ADFI in mink. The majority of ingested
benzoates were absorbed from the gut (over 95%), except in blue foxes, which
excreted 6 to 15% of ingested benzoates in feces with incremental increases in
benzoate intake. Urinary free benzoic acid excretion accounted for 10% of the
ingested benzoates in blue foxes but less than 5% in mink and raccoon dogs. When
benzoate intake was 1 mmol/kg BW, mink, blue foxes, and raccoon dogs excreted 71,
77, and 34% of ingested benzoates as hippuric acid in urine, respectively. With
higher benzoate intakes, urinary hippuric acid excretion decreased quadratically
with mink to 20%, and linearly with blue foxes and raccoon dogs to 45 and 16%,
respectively. The hippuric acid pathway appears to be the principal route of
benzoate elimination in the mink and blue fox, whereas, in the raccoon dog, other
pathways appear to be more important. In mink, the elimination of ethyl benzoate
did not differ from that of sodium benzoate. Because glycine conjugation is the
primary route of benzoate elimination, it is recommended that benzoate content in
fur animal feeds should not exceed 1 g/kg feed on an as-fed basis.
PMID- 10784189
TI - Further assessment of the dietary lysine requirement of finishing gilts.
AB - A cooperative research study involving 635 gilts was conducted at eight research
stations to further estimate the lysine requirement of finishing gilts. Dietary
crude protein levels of the five dietary treatments ranged from 16.0 to 24.4%
with calculated lysine levels of .80, .95, 1.10, 1.25, or 1.40%. Each station
contributed a minimum of two replicate pens of pigs per treatment. Average
initial and final weights were 53.6 and 116.4 kg, respectively. At the end of the
experimental period, pigs were killed and hot carcass weight, 10th-rib fat depth,
and longissimus muscle area were measured. Carcass fat-free lean percentage and
fat-free lean gain were estimated from these data. Daily lysine intakes averaged
21.8, 25.9, 30.5, 34.3, and 37.8 g/d for the five treatment groups, respectively.
Increasing the dietary lysine from .80 to .95% numerically increased weight gain
and gain:feed, but these increases were not maintained at higher levels of
dietary lysine. Overall, rate and efficiency of gain decreased (cubic, P < .01)
with increasing dietary lysine. Carcasses were leaner at the two higher levels of
dietary lysine as evidenced by reduced 10th rib backfat (linear, P < .01),
increased longissimus area (quadratic, P < .04), and increased percentage of
estimated fat-free lean (linear, P < .01). Carcass fat-free lean gain was not
influenced by dietary lysine except for a small numerical improvement (P < .11)
at the .95% level of dietary lysine that paralleled the improvement in body
weight gain. The results indicate that the dietary lysine requirement of
finishing gilts with a mean carcass fat-free lean growth rate of 306 g/d from 54
to 116 kg body weight is probably no higher than .80% of the diet to achieve
maximum rate and efficiency of body weight gain and carcass lean growth rate. The
results also indicate that higher dietary lysine levels may increase carcass
leanness in finishing gilts, possibly due to reduced intake of NE. Whether this
response is due to the effects of lysine alone, protein (i.e., other amino
acids), or soybean meal is unknown.
PMID- 10784190
TI - Impact of dietary lysine intake during lactation on follicular development and
oocyte maturation after weaning in primiparous sows.
AB - Primiparous sows (n = 36) were used to evaluate the effects of dietary lysine
intake in lactation on follicular development and oocyte maturation after
weaning. Sows were assigned randomly to one of three diets containing .4% (low
lysine, LL), 1.0% (medium lysine, ML), or 1.6% (high lysine, HL) total lysine.
All diets contained 2.1 Mcal NE/kg and exceeded NRC (1988) requirements for all
other nutrients. Actual lysine intakes over an 18-d lactation were 16, 36, and 56
g/d for sows consuming LL, ML, and HL, respectively. Ovarian data were analyzed
for sows determined to have been slaughtered during the first proestrus period
after weaning, using previously established criteria. Compared with sows fed ML
and HL, sows fed LL tended to have lower uterine weight, follicular fluid volume,
and follicular fluid (FF) estradiol (E2) content (P < .15), but similar ovarian
weight and follicular fluid IGF-I concentration. Within the largest 15
preovulatory follicles, sows fed LL had a lower percentage of large (> or = 7.0
mm) follicles (33 vs 50 and 58%; P < .01) and a higher percentage of medium (5.5
to 7.0 mm) follicles (62 vs 44 and 39%; P < .01) but a similar percentage of
small (< or = 5.5 mm) follicles (4.4 vs 5.9 and 3.7%; P > .15), respectively,
compared with sows fed ML or HL. Standardized pools of oocytes aspirated from
follicles of prepubertal gilts were incubated for 44 h with pooled FF recovered
from the largest 15 follicles of each experimental sow. Fewer oocyte nuclei
matured to metaphase II of meiosis when cultured with FF recovered from sows fed
LL, than from sows fed ML or HL (47.1 vs 59.8 and 63.8%, respectively; P < .01).
Our results suggest that low lysine (protein) intake in primiparous lactating
sows impaired follicular development and reduced the ability of follicles to
support oocyte maturation. However, high compared with medium lysine (protein)
intake had no further positive effects on ovarian function.
PMID- 10784191
TI - Effects of dietary lysine intake during lactation on blood metabolites, hormones,
and reproductive performance in primiparous sows.
AB - Effects of three dietary lysine (protein) concentrations during lactation on
metabolic state, protein metabolism, reproductive hormones, and performance were
investigated in 36 primiparous sows. Sows were assigned randomly to one of three
diets containing .4% (low lysine, LL), 1.0% (medium lysine, ML), or 1.6% (high
lysine, HL) total lysine from intact protein sources. All diets contained 2.1
Mcal NE/kg and exceeded the recommended requirements for all other nutrients.
Actual lysine intakes over an 18-d lactation were 16, 36, and 56 g/d for sows fed
LL, ML, and HL, respectively. Fractional breakdown rate of muscle was determined
on d 4 and 15 of lactation by using a three-compartment kinetic model of 3
methylhistidine metabolism. Increasing lysine intake during lactation did not
affect fractional breakdown rate of muscle on d 4 of lactation but decreased it
on d 15 (P < .05). Sows fed LL had a reduced number of LH pulses on d 12 and 18
(P < .05) and reduced serum estradiol (E2) concentration on d 18 of lactation
compared with sows fed ML and HL treatments. However, LH pulses and E2
concentrations were similar between ML and HL treatments (P > .35). Increasing
lysine intake increased serum urea nitrogen (SUN) and postprandial insulin
concentrations (P < .05) during lactation but had no effect on plasma glucose
concentrations (P > .20). Sows fed HL had greater serum IGF-I on d 6 and 18 than
sows fed ML (P < .05). Number of LH peaks was correlated with serum insulin
concentration 25 min after feeding on d 6 and 18 (r = .31 to .41; P < .1) and pre
(r = .33 to .46) and postprandial (r = .30 to .58) SUN concentrations (P < .05)
during different stages of lactation. Results indicate that, compared with medium
lysine intake, low lysine intake increased muscle protein degradation and
decreased concentrations of insulin, SUN, and estradiol and LH pulsatility. In
contrast, high lysine (protein) intake increased SUN, insulin, and IGF-I, but did
not increase secretion of estradiol and LH compared with medium lysine intake.
Furthermore, nutritional impacts on reproduction may be mediated in part through
associated effects on circulating insulin concentration.
PMID- 10784192
TI - Growth promotion effects and plasma changes from feeding high dietary
concentrations of zinc and copper to weanling pigs (regional study).
AB - An experiment was conducted to determine the effect of high dietary intakes of Zn
and Cu and their combination on growth performance of weanling pigs with diverse
health status and management strategies. Twelve experiment stations cooperated
and used a total of 1,356 pigs that averaged 6.55 kg BW and 22.2 d age at
weaning. The four dietary treatments, all of which met or exceeded NRC
requirements, were 1) control, 2) 3,000 ppm Zn (from Zn oxide), 3) 250 Cu ppm
(from Cu sulfate), or 4) 3,000 ppm Zn and 250 ppm Cu. The diets were fed as a
complex Phase I diet (1.4% lysine) for 7 d followed by a Phase II diet (1.2%
lysine) for 21 d. Chlortetracycline (220 ppm) was added to all diets. Fecal color
(1 = yellow to 5 = black) and consistency (1 = very firm to 5 = very watery) were
scored daily for 3 wk. At the end of the 28-d study, 412 pigs were bled at five
stations, and plasma Cu, Zn, and Fe concentrations were determined at one station
with atomic absorption spectrophotometry. Average daily gain (375, 422, 409, 415
g/d), feed intake (637, 690, 671, 681 g/d), and gain/feed (586, 611, 611, 612
g/kg) were improved (P < .01) by the addition of Zn and(or) Cu. Significant Cu x
Zn interactions imply that the responses to Zn and Cu were independent and not
additive. There were significant (P < .01) Zn and Cu effects and a Zn x Cu
interaction on fecal color (3.17, 3.24, 4.32, 3.57) and consistency (2.39, 2.14,
2.14, 2.13). Dietary additions of Cu and Zn resulted in elevated plasma
concentrations of Cu and Zn, respectively. These data indicate that
pharmacological additions of 3,000 ppm Zn (oxide) or 250 ppm Cu (sulfate)
stimulate growth beyond that derived from intakes of Zn and Cu that meet nutrient
requirements. However, the combination of Zn and Cu did not result in an additive
growth response.
PMID- 10784193
TI - Zinc bioavailability in soybean meal.
AB - A phytate-containing soy protein concentrate (SPC) diet (13.5 mg Zn/kg) and a
phytate-free egg white diet (.3 mg Zn/kg) were used to determine the relative
bioavailability (RBV) of Zn in dehulled soybean meal (SBM) based on Zn depletion
repletion growth bioassays in young chicks. After a 4-d Zn depletion period,
chick weight gain responded linearly (P < .01) to graded increments of
supplemental Zn (0 to 10 mg/kg) from ZnSO4 x 7H2O, whether added to the Zn
deficient SPC or egg white diet. Slope, however, was over twice as great for the
standard curve relating weight gain to supplemental Zn intake for the egg white
diet as for the SPC diet. Addition of 7 to 10 mg Zn/kg from SBM to either Zn
deficient diet increased (P < .01) weight gain, but a similar SBM addition to
either diet made adequate in Zn did not increase weight gain. Using standard
curve methodology, RBV of Zn in SBM was 78% when the the SPC diet was used, but
it was only 40% when the egg white diet was used. The phytate contained in the
SPC basal diet therefore markedly reduced the efficiency of utilizing the
supplemental inorganic Zn from ZnSO4 x 7H2O. This lowered the slope of the
standard curve so that, on a relative basis, the Zn in SBM had a higher RBV value
than was the case for Zn utilization in SBM with the phytate-free egg white diet.
The 78% Zn RBV value in SBM would seem to have the greatest relevance for
practical-type corn-SBM diets.
PMID- 10784194
TI - Ornithine alpha-ketoglutarate and creatine effects on growth and plasma
metabolites of nursery pigs.
AB - Four experiments were conducted to determine the effect of dietary ornithine
alpha-ketoglutarate (OKG) and creatine monohydrate on growth performance and
plasma metabolites of nursery pigs. In each experiment, treatments were
replicated with four to five pens of four to six pigs each. Each experiment
lasted from 3 to 4 wk and Phase I (1.6% Lys) and Phase II (1.3 to 1.5% Lys) diets
were fed for 9 to 16 d each. In Exp. 1, pigs (4.7 kg and 15 d of age) were fed
diets containing 0, .10, or .75% OKG. Daily gain during a 13-d Phase I period and
ADFI during Phase I and overall (29 d) were increased (P < .10) in pigs fed .75%
OKG. Gain:feed ratio was not affected (P > .10) by diet. In Exp. 2, pigs (7.1 kg
and 23 d of age) were fed 0 or .50% OKG during Phase I only. During Phase I, II,
and overall, ADG and ADFI were not affected (P > .10) by OKG supplementation, but
gain:feed was decreased during Phase I (P < .04), Phase II (P < .08), and overall
(P < .04). Plasma urea N (PUN), glucose, and NEFA concentrations were not
affected (P > .10) by OKG supplementation in this experiment. In Exp. 3, pigs
(5.8 kg and 20 d of age) were fed diets containing 0, .10, or .50% creatine.
Creatine tended to linearly decrease ADG (P = .11) and plasma albumin (P = .12)
and PUN (P < .10) concentrations in Phase II (d 12 to 26). In Exp. 4, 850 mg of
OKG or 750 mg of creatine was provided daily by oral capsule to pigs 4 d before
weaning to 2 d after weaning. Pigs within a litter received either no capsule or
capsules containing OKG or creatine. After weaning, pigs that received no capsule
before weaning received no treatment, .50% creatine, or .50% OKG in the nursery
diet. Pigs that received OKG before weaning received no treatment or .50% OKG,
and pigs that received creatine before weaning received no treatment or .50%
creatine in the nursery diet. Pigs weighed 3.9 kg 4 d before weaning and 4.9 kg
at weaning at an average age of 20 d. The OKG provided by capsule decreased ADG
(P < .02) and ADFI (P < .09) during Phase II. The OKG did not affect (P > .10)
plasma NEFA, glucose, or urea N concentrations. Creatine added to the nursery
diet increased (P < .02) ADFI and decreased (P < .10) gain:feed during Phase II
and overall. Creatine in the nursery diet also increased (P < .01) PUN, but it
did not affect plasma glucose or NEFA concentrations. Creatine and OKG have
variable effects on growth performance and plasma metabolites of nursery pigs.
PMID- 10784195
TI - Alterations in hemograms and serum biochemical analytes of steers after prolonged
consumption of endophyte-infected tall fescue.
AB - The objective of the current study was to delineate changes that occur in serum
analytes and blood cellular elements in cattle that graze endophyte-infested
(Neotyphodium coenophialum) tall fescue. Tall fescue is grown on more than 35
million acres (14.2 million ha) of pasture in the United States, and three
fourths of the pastures are infected with the endophyte at a 60% or greater
level. Tall fescue toxicosis caused by endophyte-produced ergot alkaloids
continues to be the most important grass-related disease in the United States, in
terms of economic loss to animal producers. However, the agronomic attributes of
tall fescue make it an attractive forage species because of its ability to
withstand cool temperatures, drought, poor soil conditions, and intensive
defoliation from herbivore species, including insects. Tall fescue toxicosis is a
complex disease and the need exists to understand the mechanisms of the toxic
effects in order to institute effective, prophylactic control measures. Our group
previously reported changes that occur in serum biochemical analytes of cattle
that graze endophyte-infected tall fescue. An additional year's worth of data
have been added, strengthening and corroborating these data. Consistent and
significant changes associated with tall fescue toxicosis during the 3-yr study
included decreased serum concentrations of cholesterol, globulin (increased
albumin/globulin ratio), prolactin, total protein, and copper. The activity of
alanine aminotransferase was decreased in serum, whereas an increase in serum
concentrations of creatinine and total bilirubin occurred. The present report
also documents comparative hemograms of cattle that grazed endophyte-infected or
endophyte-free tall fescue over a prolonged period. The mean erythrocyte counts
were increased in cattle that grazed endophyte-infected tall fescue, whereas mean
corpuscular hemoglobin and mean corpuscular volume were decreased, as were mean
eosinophil counts. Thus, repeatable changes have been identified that occur in
serum biochemical and blood cellular values of cattle grazing endophyte-infected
tall fescue that will aid in understanding the pathogenesis of the disease. In
addition, these consistently altered parameters can be used to assess the
effectiveness of potential prophylactic treatments.
PMID- 10784196
TI - Adrenal function in Angora goats: a comparative study of adrenal steroidogenesis
in Angora goats, Boer goats, and Merino sheep.
AB - South African Angora goats (Capra aegagrus) are susceptible to stress conditions,
possibly due to adrenal cortex malfunction. Selection for mohair production may
reduce adrenal function and decrease cortisol production. Secretion of cortisol
by the adrenal cortex is essential for the induction of several gluconeogenic
enzymes that enable animals to survive stressful conditions, and adrenocortical
insufficiency, therefore, precipitates a vulnerability to stress. In this study,
Angora goats were compared with two breeds generally accepted as hardy, Boer
goats (Capra hircus) and Merino sheep (Ovis aries). Adrenal steroidogenesis was
studied using subcellular fractions prepared from the adrenal glands of freshly
slaughtered animals. Adrenal microsomes and mitochondria were incubated with the
relevant steroid substrates, and products were analyzed and quantified with TLC,
HPLC, or RIA. Subsequently, the activity of individual enzymes involved in this
pathway were further investigated. The cytochrome P450 content in the
preparations was also compared. The results from these studies indicated that the
activity of the cytochrome P450c17 enzyme in Angora goats differed (P < .01) from
that of the other species investigated. This difference may contribute to the
cause of the observed hypoadrenocorticism in Angora goats.
PMID- 10784197
TI - Effect of estradiol-17beta administration during the time of conceptus elongation
on placental size at term in Meishan pigs.
AB - Meishan embryos transferred to recipient females on d 2.5 are larger, contain
greater numbers of trophectoderm cells, and secrete greater amounts of estradiol
17beta (E2beta) when gestated in a Yorkshire as compared with Meishan uterus to d
12. Additionally, placentas of Meishan conceptuses are larger when gestated in a
Yorkshire as compared with Meishan uterus throughout gestation. Embryonic E2beta
secretion during elongation on d 12 to 13 of gestation is temporally associated
with endometrial secretion of growth factors, including IGF-I, which has been
shown to increase mitotic rate in the trophectoderm of pig embryos. This
experiment was conducted to determine whether E2beta administration to Meishan
gilts at the time of conceptus elongation would increase placental size at term.
Meishan gilts (n = 12) were checked twice daily for estrus (0700 and 1900), and
each was bred to a Meishan boar at 0 and 24 h after the onset of estrus (d 0).
Gilts were randomly assigned in equal numbers to receive injections of sesame oil
(VEH) starting on d 12 (control), 1 mg of E2beta in VEH starting on d 12 (E212),
or 1 mg of E2beta in VEH starting d 13 (E(2)13). The injections were initiated at
0700 or 1900 (corresponding to the time of day they first exhibited estrus) and
continued at 6-h intervals for 48 h, resulting in 8 mg of E2beta given in eight
injections. Pregnant gilts were killed on d 112 of gestation, and ovulation rate,
litter size, implantation site length, fetal weight, crown-rump length, placental
weight, and placental surface area were quantified. There were no differences
among E(2)12, E(2)13, and control females in ovulation rate or litter size, which
averaged 16.3 +/- .7 and 11.8 +/- .7, respectively. Fetal weight and crown-rump
length were not different (P > .10) among E(2)12, E(2)13, and control females,
averaging 802 +/- 26 g and 24.3 +/- .3 cm. Placentas were markedly heavier (176
+/- 14 and 174 +/- 16 vs 134 +/- 10 g, P < .05) and larger (1,337 +/- 97 and
1,520 +/- 70 vs 978 +/- 29 cm2, P < .001) for E(2)12 and E(2)13 vs control gilts,
respectively. Placental efficiency (estimated as fetal weight:placental weight)
was greater (P < .05) in the control than in the E(2)12 and E(2)13 gilts (5.8 +/-
.2 vs 4.8 +/- .2 and 5.1 +/- .4). These data demonstrate that the amount of
E2beta exposure around the time of elongation affects placental size at term.
Additionally, the difference in placental efficiency between control and E2beta
groups indicate that E2beta-induced increases in placental size led to a reduced
placental efficiency.
PMID- 10784198
TI - Effects of dietary copper source and concentration on carcass characteristics and
lipid and cholesterol metabolism in growing and finishing steers.
AB - We conducted an experiment to determine the effects of dietary copper (Cu) source
and level on carcass characteristics, longissimus muscle fatty acid composition,
and serum and muscle cholesterol concentrations in steers. Sixty Angus and Angus
x Hereford steers were stratified by weight and initial liver Cu concentration
within a breed and randomly assigned to treatments. Treatments consisted of: 1)
control (no supplemental Cu); 2) 20 mg Cu/kg DM from Cu sulfate (CuSO4); 3) 40 mg
Cu/kg DM from CuSO4; 4) 20 mg Cu/kg DM from Cu citrate; 5) 20 mg Cu/kg DM from Cu
proteinate; and 6) 20 mg Cu/kg DM from tribasic Cu chloride. A corn silage
soybean meal-based diet was fed for 56 d. Steers were then switched to a high
concentrate diet. Equal numbers (n = 5) of steers per treatment were slaughtered
after receiving the finishing diets for either 101 or 121 d. Serum cholesterol
was not affected by treatment during the growing phase but was decreased (P <
.05) in steers supplemented with Cu by d 84 of the finishing period and remained
lower (P < . 05) at subsequent sampling periods. Longissimus muscle cholesterol
concentration tended to be reduced (P < .11) by Cu supplementation. Hot carcass
weight and backfat were lower (P < .05) in animals receiving supplemental Cu.
However, Cu-supplemented and control steers had similar marbling scores.
Longissimus muscle polyunsaturated fatty acid concentrations (18:2 and 18:3) were
increased (P < .07) and saturated fatty acid concentrations tended (P < . 11) to
be reduced by Cu supplementation. These results indicate that as little as 20 mg
of supplemental Cu/kg diet can reduce backfat and serum cholesterol and increase
muscle polyunsaturated fatty acids in steers fed high-concentrate diets.
PMID- 10784199
TI - Effect of dietary concentration of metabolizable lysine on finishing cattle
performance.
AB - A finishing trial and a metabolism trial were conducted to determine the effect
of supplemental metabolizable Lys level on finishing calf performance and to
estimate the metabolizable Lys requirement of finishing calves. The finishing
trial included 60 individually fed crossbred beef steer calves (237 kg; SD = 20
kg) supplemented with either incremental amounts of rumen-protected Lys and Met,
or Met alone. Addition of Lys and Met improved gains and efficiencies (quadratic;
P < .02) during the first 56 d. There was no response to supplemental Met alone,
suggesting that supplemental Lys rather than Met was responsible for the
improvement in performance. Using nonlinear analyses to compare gain relative to
supplemental Lys intake, maximum gain was determined to be 2.10 kg/d, or .27 kg/d
above the zero Lys control, at a supplemental Lys intake of 2.56 g/d. Steers
supplemented with 3 and 4 g of Lys had a weight advantage over the control steers
of 16 kg at 56 d and 32 kg at the end of the 161-d trial. However, there were no
statistical responses to Lys or Met during any periods after 56 d. During a
separate metabolism trial, four steers fed the control finishing diet were
slaughtered, and abomasal contents were collected for amino acid analyses. The
predicted (Level 1 NRC, 1996) metabolizable protein flow to the abomasum for the
control diet was 715 g/d, and the predicted Lys flow was 37.9 g/d. A supplemental
Lys intake of 2.56 g/d would increase the Lys flow to 40.5 g/d. Feedlot diets low
in ruminal escape protein may be deficient in metabolizable Lys, especially early
in the feeding period. The metabolizable Lys requirement of steer calves gaining
2.10 kg/d is estimated to be 40.5 g/d.
PMID- 10784200
TI - Influence of abomasal infusion of high levels of lysine or methionine, or both,
on ruminal fermentation, eating behavior, and performance of lactating dairy
cows.
AB - Four multiparous late-lactation Holstein cows were fed a basal ration designed to
be co-limiting in intestinally absorbable supplies of methionine and lysine. Cows
were supplemented with no amino acids, lysine by abomasal infusion to 140% of the
calculated intestinally absorbable requirement, methionine by abomasal infusion
to 140% of requirement, or both amino acids in a 4 x 4 Latin square design with
28-d periods. Unsupplemented cows consumed 23.8 kg/d of dry matter and produced
36.9 kg/d of milk containing 3.70% fat, 3.22% protein, and 4.82% lactose. Cows
ate less dry matter and produced less milk and milk lactose, and tended (P = .06
or .08) to produce less milk protein when abomasally infused with methionine
alone or together with lysine. Infusion of lysine alone resulted in production
values numerically between those of unsupplemented cows and those cows
supplemented with methionine alone or together with lysine. Evaluation of the
results with two metabolic models of dairy cows indicated that performance of
unsupplemented cows may have been limited by delivery of metabolizable or
digestible protein, or intestinally absorbable lysine, isoleucine, or histidine,
depending on the metabolic model used to evaluate animal performance. Regardless,
results are consistent with those using nonruminant species, which have shown
that imbalanced profiles of intestinally absorbable amino acids are associated
with reduced dry matter intake and animal performance. Results also show that
negative effects on performance of lactating dairy cows can occur if methionine
is supplied at levels substantially in excess of calculated intestinally
absorbable requirements, either alone or together with lysine.
PMID- 10784202
TI - The effect of feed intake level on splanchnic metabolism in growing beef steers.
AB - The effect of feed intake level (.6, 1.0, and 1.6 x maintenance energy and
protein requirements, M) on splanchnic (portal-drained viscera [PDV] plus liver)
metabolism was evaluated in six multicatheterized beef steers (398 +/- 27 kg),
using a double 3 x 3 Latin square design. On the last day of each 21-d
experimental period, six hourly blood samples were collected from arterial,
portal, and hepatic vessels. Due to catheter patency, PDV fluxes were measured on
five steers, and liver and splanchnic fluxes on four steers. Increasing intake
elevated (P < .01) splanchnic release of total (T) amino acids (AA), through
increases (P < .01) in PDV release of both essential (E) and nonessential (NE)
AA, in spite of a tendency (P < .20) for increased liver removal of NEAA. The PDV
release of AA N represented 27 and 51% of digested N for 1.0 and 1.6 x M,
respectively. At 1.0 and 1.6 x M, the liver removed 34% of total AA released by
the PDV. For individual AA, portal flux of most EAA increased (P < .05) with feed
intake, and the increase (P < .10) in splanchnic flux was accompanied by
increased arterial concentration for all EAA except histidine, lysine, and
methionine. This suggests that these might be limiting AA for this diet. On a net
basis, most individual NEAA were released by the PDV except glutamate and
glutamine, which were removed by the digestive tract. There was a net removal of
NEAA by the liver, except for aspartate and especially glutamate, which were
released. Ammonia release by the PDV tended (P < .20) to increase with intake and
represented 69, 53, and 45% of digested N at .6, 1.0, and 1.6 x M, respectively.
Urea removed by the PDV, unaffected by intake, represented 32, 33, and 21% of the
digested N. Arterial glucose concentration increased linearly (P < .01) with
greater intake, whereas net liver and splanchnic glucose release increased in a
quadratic (P < .05) manner. Net PDV glucose release represented 26% of net
glucose hepatic release at 1.6 x M. Intake elevated (P < .10) both insulin and
glucagon arterial concentrations, resulting from a larger increment of portal
release (P < .01) than hepatic removal (P < .05). Intake-based variations in IGF
I and NEFA arterial concentrations (P < .05) were not related to changes in
splanchnic metabolism. These results clearly show the crucial role of the
splanchnic tissues in regulating the profile and quantity of AA and
concentrations of glucose and pancreatic hormones reaching peripheral tissues.
PMID- 10784201
TI - Absorption of 2-hydroxy-4-(methylthio)butanoic acid by isolated sheep ruminal and
omasal epithelia.
AB - Alimet (Novus Inter., Inc., St. Louis, MO) feed supplement (an 88% aqueous
solution of 2-hydroxy-4-(methylthio) butanoic acid; HMB) is a source of L-Met
commonly used in nonruminants and ruminants. The absorption of HMB across ovine
omasal and ruminal epithelia was evaluated in this study. Ruminal and omasal
epithelia were collected from eight lambs (BW = 67.6 kg +/- 9.1) and mounted in
parabiotic chambers that were repeatedly sampled throughout a 60-min incubation.
The appearance of HMB (using DL-[5-14C]-HMB as a radiolabeled marker) in serosal
buffers increased quadratically (P < .004) with time in both tissues. More (P <
.001) HMB appeared in the serosal buffers with omasal than with ruminal
epithelia. Both tissues responded similarly, and, after 60 min of incubation, the
accumulation of HMB within the tissues increased linearly (P < .001) as substrate
concentration (.375, .75, 1.5, 3.0, 6.0, and 12.0 mM) increased in mucosal
buffers. As the concentration of HMB in the mucosal buffers increased, there was
a quadratic (P < .001) increase in the appearance of HMB in the serosal buffer of
the omasal epithelium, indicating some saturation of the system. The increase in
serosal appearance of HMB was linear (P < .001) with ruminal tissue. The results
indicate that there are probably multiple mechanisms involved in the absorption
of HMB. Because saturation was observed in the omasum, it is likely that mediated
transport accounts for at least a portion of the absorption of HMB in the omasum.
Other mechanisms (e.g., diffusion and(or) paracellular absorption) are
responsible for the balance of the absorption. Omasal epithelium appears to have
a greater capacity for HMB absorption than ruminal epithelium. The enzymes
involved in the conversion of HMB to 2-keto-4-(methylthio)butanoic acid were
found in ruminal and omasal epithelia, liver and kidney. These results indicate
that HMB can be absorbed across ruminal and omasal epithelium and that HMB can be
used as a source of L-methionine.
PMID- 10784203
TI - Rapid communication: polymorphism in the goat beta-lactoglobulin proximal
promoter region.
PMID- 10784204
TI - Assessing pediatric senior residents' training in resuscitation: fund of
knowledge, technical skills, and perception of confidence.
AB - OBJECTIVE: To describe pediatric housestaff knowledge, experience, confidence in
pediatric resuscitations and their ability to perform important resuscitation
procedures during the usual training experience. DESIGN AND PARTICIPANTS: Cohort
study of PGY-3 level residents in a ACGME accredited pediatric residency training
program at a large, tertiary care children's hospital. METHODS: Fund of knowledge
was assessed by administering the standardized test from the Pediatric Advanced
Life Support (PALS) Course in addition to a supplemental short answer test
requiring clinical problem-solving skills. Procedural skills were evaluated
through observation of the resident performing four procedures during a skills
workshop using a weighted step-wise grading sheet. Resident experience and
confidence was quantified using an anonymous survey. RESULTS: Ninety-seven
percent of residents participated. Residents achieved high scores on the
standardized PALS test (93.2%+/-5.5), but performed less well when answering more
complicated questions (60.0%+/-9.9) on the short answer test. No resident was
able to successfully perform both basic and advanced airway skills, and only 11%
successfully completed both vascular skills. Although residents were overall
confident in their resuscitation skills, performance in the skill workshop
revealed significant deficits. For example, only 18% performed ancillary airway
maneuvers properly. None of the residents performed all four skills correctly.
Experience in both real and mock resuscitations was infrequent. Residents
reported receiving feedback on their performance less than half of the time. Over
89% of them felt that resuscitation knowledge and skill were important for their
future chosen career. CONCLUSION: Pediatric residents infrequently lead or
participate in real or mock resuscitations. Although confident in performing many
of the necessary resuscitation skills, few residents performed critical
components of these skills correctly. Current pediatric residency training may
not provide sufficient experience to develop adequate skills, fund of knowledge,
or confidence needed for resuscitation.
PMID- 10784205
TI - Fall and suffocation injuries associated with in-home use of car seats and baby
carriers.
AB - OBJECTIVE: This paper examines two hazard patterns associated with in-home use
and placement of car seats and baby carriers: 1) fall injuries resulting from
placement on elevated surfaces and 2) suffocation resulting from seat overturn on
soft surfaces. DESIGN: Emergency department data reporting on falls suffered by
infants aged 6 months and younger, and associated with car seats and baby
carriers, were provided by the U.S. Consumer Product Safety Commission's National
Electronic Injury Surveillance System for 1997. National estimates were based on
396 incidents. Additionally, 15 cases of suffocation resulting from car/infant
seat overturn on soft surfaces were identified through the Commission's Death
Certificate and Investigation Files. RESULTS: In 1997, it is estimated that
approximately 8700 infants were treated in emergency departments as a result of
fall injuries suffered while using a car seat or baby carrier. More than one
third of estimated falls were specifically attributed to the seat being placed on
an elevated surface in the home, such as a counter or table. A search of
suffocation incidents resulting from seat overturn on a soft surface produced 15
incidents. The majority of incidents occurred when the seat had been placed on a
bed or waterbed. CONCLUSIONS: Many parents are unaware of hazards associated with
common placement scenarios for infant car seats and baby carriers. These hazard
patterns and their potential consequences need to be conveyed to new parents by
pediatricians. At the same time, manufacturers have an obligation to pursue
design alternatives that will reduce the likelihood of seat overturn.
PMID- 10784206
TI - Costs of sedation using oral midazolam: money, time, and parental attitudes.
AB - OBJECTIVE: Many agents suitable for pediatric outpatient sedation have been
identified and compared, but less data have appeared on the effect of sedation
use on Emergency Department (ED) length of stay (LOS) or visit costs. We sought
to discover the relationship between one commonly used method of sedation, orally
administered midazolam, and ED LOS and visit costs. Parents were then surveyed to
determine their attitudes toward sedation given knowledge of these costs.
METHODS: All ED patients under 10 years of age seen in a pediatric ED during
April and May of 1996 for repair of lacerations <2.5 cm in length were identified
via retrospective chart review. Children were excluded if they had other
significant injuries, received sedatives other than oral midazolam, or were
repaired by non-ED physicians. Preliminary cost and LOS data from this review was
used to create a parental survey measuring attitudes toward the costs of an
unnamed form of sedation (not mentioning oral midazolam). A convenience sample of
parents in an ED waiting room were asked if they would want sedation administered
to a child needing sutures if this increased the visit cost by $100 and/or
increased LOS by 30 minutes. Parents were then asked to re-answer these questions
assuming that the sedation medication was effective only 50% of the time.
RESULTS: Of 120 patients meeting entry criteria, 57 (48%) received oral
midazolam. Children sedated with this agent were significantly younger (3.6 vs.
4.6 years, P = 0.015), had more layered repairs (30% vs. 14%, P = 0.047), and
more facial lacerations (84% vs. 63%, P = 0.01) when compared with nonsedated
patients. Mean LOS for patients with simple lacerations receiving oral midazolam
increased by 17.1 minutes (P = 0.03) compared with nonsedated children; for
layered repairs, the mean increase was 30.9 minutes (P<0.05). The use of oral
midazolam did not effect physician charges, but did significantly increase mean
combined nurse/hospital charges and total charges by 73 to 87 dollars, depending
on laceration type (P<0.001 all cases). Of 81 parents surveyed, 81% said that
they would be willing to wait 30 extra minutes for sedation to be used; this
figure fell to 73% if sedation was effective 50% of the time. Seventy-five
percent of parents were willing to pay $100 extra for sedation; 67% if sedation
was effective only half the time. Willingness to endure a longer LOS or pay
increased charges was not associated with parental sex or insurance status.
CONCLUSION: The use of oral midazolam significantly increases ED visit LOS and
cost. This information is important to review with parents when discussing
sedation options. Up to one third of parents surveyed would not want to wait
extra time or pay extra money for sedation to be administered, especially if the
efficacy of the chosen method was not assured.
PMID- 10784207
TI - Acceptance of family member presence during pediatric resuscitations in the
emergency department: effects of personal experience.
AB - OBJECTIVE: Opinions remain polarized on allowing family member presence during
pediatric resuscitations (FMP). Reluctance to adopt FMP may stem from
preconceived notions on this practice. This study evaluates the effect of prior
experience with FMP and on its acceptance by emergency department personnel
(EDP). METHODS: EDP from three different EDs were surveyed concerning FMP. Study
facilities included an urban teaching community ED with routine FMP (R-ED), a
suburban community ED with occasional FMP (O-ED) and an urban university
pediatric ED with virtually no FMP (N-ED) during pediatric resuscitations. Survey
information included hospital of practice, position in ED, years in practice,
opinions on FMP and personal experience with FMP for five clinical scenarios:
laceration repair (LAC), intravenous access (IV), lumbar puncture (LP),
endotracheal intubation (ETI), cardiopulmonary resuscitation (CPR), and critical
resuscitation (CR). Statistical analysis was through chi square and regression
analysis. RESULTS: Eighty-five emergency department personnel participated in the
survey, 57 (67%) nurses, 22 (25%) physicians, 4 technicians (5%), and 2 nurses
aids (2%). There was a significant correlation between a favorable opinion
concerning family member presence during LP, ETI, CPR and CR and the type of
Emergency Department in which the individual practiced (P<0.002). Regression
analysis demonstrated a similar relation between personal experience with LAC,
IV, ETI, CR, and CPR and a favorable opinion on FMP during that activity
(P<0.03). CONCLUSION: Opinions on FMP are strongly influenced by experience with
this practice. Emergency department personnel with prior exposure to family
member presence during resuscitations favor this activity. Biases by EDP lacking
experience with FMP may limit its introduction into unfamiliar institutions.
PMID- 10784208
TI - A comparison of the initial to the later stream urine in children catheterized to
evaluate for a urinary tract infection.
AB - BACKGROUND: To avoid potential contamination, it is recommended that the first
few drops of urine be discarded when obtaining a catheterized urine sample from a
child being evaluated for a urinary tract infection (UTI). The existing evidence
to make such a recommendation is scant. Our goal, therefore, was to determine
whether the urinalysis, Gram stain, and culture results were significantly
different from the initial and later urine samples collected from catheterized
children. METHODS: A prospective diagnostic discrimination between early and
later urine samples was conducted on a convenience sample of pediatric patients
being evaluated for a UTI in an urban emergency department. Results of the
urinalysis, Gram stain, and quantitative culture were compared between the early
and later stream urine samples. RESULTS: Data from 86 children were analyzed.
Four of 80 patients had a false identification of low colony count bacteruria
from the early but not from the later stream. For patients with negative
cultures, the early stream was also more likely to falsely identify > or =5
wbc/hpf (P<0.01) or bacteruria (P<0.05) on urinalysis than the later stream.
CONCLUSIONS: There is a small but potentially meaningful contamination of the
early stream urine compared with the later stream in young children catheterized
to evaluate for a urinary tract infection.
PMID- 10784209
TI - Lower thoracic SCIWORA in a 3-year-old child: case report.
PMID- 10784211
TI - Central anticholinergic syndrome from orphenadrine in a 3 year old.
AB - Orphenadrine (N,N-dimethyl-2(o-methyl-alpha-phenylbenzyloxy)ethylamine) is an
analog of diphenhydramine with central and peripheral anticholinergic properties.
It is commonly prescribed both as a muscle relaxant and as an adjunct to
antipsychotic medications to prevent parkinsonism. We report a case of
orphenadrine poisoning in a 3-year-old boy following ingestion of no more than
two 100-mg tablets. Central anticholinergic toxicity was prominent, manifested by
hallucinations and severe agitation. Orphenadrine can cause profound toxicity in
children after ingestion of small doses, and should be considered as a potential
cause for acute delirium in childhood.
PMID- 10784210
TI - A common cause of altered mental status occurring at an uncommon age.
AB - Wernicke's encephalopathy is a neurologic disorder due to a nutritional
deficiency of thiamine, characterized by ocular palsies, ataxia, and altered
mental activity. While Wernicke's encephalopathy is commonly attributed to
alcoholism in the adult population, it has been described in children receiving
prolonged parenteral nutrition and those with malignancies and AIDS. The disease,
however, is rarely diagnosed in the pediatric population during life. We report a
case of Wernicke's encephalopathy in a child with prolonged starvation and aim to
improve awareness of a potentially fatal but treatable disease.
PMID- 10784212
TI - Hallucinations as the initial presentation of shigellosis.
PMID- 10784213
TI - Brain abscess following delayed endoscopic removal of an initially asymptomatic
esophageal coin.
AB - Brain abscesses are rare occurrences in pediatric patients, and making their
diagnosis can be difficult. The two most commonly cited risk factors are
otorhinologic infections and cyanotic congenital heart disease (CCHD). We present
a 13-month-old child with a brain abscess who, 2 weeks prior, underwent rigid
endoscopy for the extraction of a coin from the esophagus. We believe this to be
the first such report of a brain abscess after rigid endoscopy for removal of an
esophageal foreign body. In this case the esophageal coin was initially
asymptomatic and had been present for weeks prior to removal. The potential
association between delayed coin extraction and development of an intracranial
infection, suggested by this report, may warrant investigation.
PMID- 10784214
TI - Abdominal trauma in infants and children: prompt identification and early
management of serious and life-threatening injuries. Part I: injury patterns and
initial assessment.
AB - Evaluation of children with abdominal trauma can be a difficult process. Unique
anatomic features predispose children to specific injuries and potentially make
identification of life-threatening injuries difficult. While Part I of this
review discusses the initial assessment and diagnostic testing in children with
abdominal trauma, Part II will review specific injuries and ED management of
children with possible abdominal trauma. Knowledge of each of these factors will
improve the ability of general and pediatric emergency physicians to
expeditiously identify children with potential serious injury and initiate
appropriate treatment.
PMID- 10784215
TI - Pediatric emergency medicine: legal briefs.
PMID- 10784216
TI - Left back pain and blood in the urine.
PMID- 10784217
TI - Evaluation of an ambu-bag valve with a self-contained, colorimetric end-tidal CO2
system in the detection of airway mishaps: an animal trial.
AB - OBJECTIVE: Capno-Flo (Kirk Specialty Systems, Carrouton, TX) is a portable
pulmonary resuscitator (self inflating ambu-bag--valve system) with a self
contained, colorimetric end-tidal CO2 detector that has the ability to provide
continuous CO2 monitoring for up to 2 hours. The purpose of this study is to
determine the accuracy and time interval for the Capno-Flo monitor to detect
acute airway obstructions and hypopharyngeal extubations in an intubated animal
model. SUBJECTS: Five anesthetized, non-paralyzed, mechanically ventilated
Yorkshire minipigs. METHODS: Complete and partial airway obstruction was
simulated with complete and partial cross-clamping of the endotracheal (ET) tube.
Placement of the ET tube into the hypopharynx was performed to simulate
accidental extubation. In addition to the Capno-Flo colorimetric indicator, both
sidestream (SS) and mainstream (MS) capnography were used to monitor end-tidal
CO2 and comparison. The time intervals for the capnograph wave to flatten and for
the monitor to display "zero" were recorded after each airway alteration. Each
experiment was carried out for 180 seconds, and a total of 25 trials was
performed. RESULTS: Complete obstruction produced a color change in the Capno-Flo
monitor in 9+/-2 seconds and flattening of the SS and MS waveform in 8+/-2
seconds and 6+/-2 seconds, respectively. The SS and MS monitors displayed zero in
49+/-7 seconds and 19+/-1 seconds, respectively. Partial obstruction did not
produce color change, a flattening of the wave, or a monitor display of zero.
Hypopharyngeal extubation produced a color change in 10+/-2 seconds, flattening
of the SS and MS waveform in 7+/-2 seconds and 7+/-1 seconds, respectively. The
SS and MS monitors displayed "zero" in 76+/-16 seconds and 18+/-3 seconds,
respectively. CONCLUSION: The Capno-Flo identified all complete airway
obstructions and hypopharyngeal extubations rapidly. The CF monitor performed
comparable to the SS and MS capnographs. Neither the Capno-Flo, nor the
sidestream, nor the mainstream capnographs detected partial airway obstruction.
The clinical application of this portable inexpensive capnometer in the
continuous monitoring of the intubated patient, especially the transport patient,
should be investigated further.
PMID- 10784218
TI - An 18 month old with recurrent otitis media.
PMID- 10784219
TI - Is it or isn't it?
PMID- 10784220
TI - Radicals and oxidative stress in diabetes.
AB - Recent evidence is reviewed indicating increased oxidative damage in Type 1 and
Type 2 diabetes mellitus as well as deficits in antioxidant defence enzymes and
vitamins. Mechanisms are considered whereby hyperglycaemia can increase oxidative
stress, and change the redox potential of glutathione and whereby reactive oxygen
species can cause hyperglycaemia. It is argued that oxygen, antioxidant defences,
and cellular redox status should now be regarded as central players in diabetes
and the metabolic syndrome.
PMID- 10784221
TI - Beneficial effects of C-peptide on incipient nephropathy and neuropathy in
patients with Type 1 diabetes mellitus.
AB - AIMS: Recent studies have indicated that proinsulin C-peptide shows specific
binding to cell membrane binding sites and may exert biological effects when
administered to patients with Type 1 diabetes mellitus. This study was undertaken
to determine if combined treatment with C-peptide and insulin might reduce the
level of microalbuminuria in patients with Type 1 diabetes and incipient
nephropathy. METHODS: Twenty-one normotensive patients with microalbuminuria were
studied for 6 months in a double-blind, randomized, cross-over design. The
patients received s.c. injections of either human C-peptide (600 nmol/24 h) or
placebo plus their regular insulin regimen for 3 months. RESULTS: Glycaemic
control improved slightly during the study and to a similar extent in both
treatment groups. Blood pressure was unaltered throughout the study. During the C
peptide treatment period, urinary albumin excretion decreased progressively on
average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it
tended to increase, but not significantly so, during the placebo period. The
difference between the two treatment periods was statistically significant (P <
0.01). In the 12 patients with signs of autonomic neuropathy prior to the study,
respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during
treatment with C-peptide but was unaltered during placebo. Thermal thresholds
were significantly improved during C-peptide treatment in comparison to placebo
(n = 6, P < 0.05). CONCLUSION: These results indicate that combined treatment
with C-peptide and insulin for 3 months may improve renal function by diminishing
urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction
in patients with Type 1 diabetes mellitus.
PMID- 10784222
TI - Education integrated into structured general practice care for Type 2 diabetic
patients results in sustained improvement of disease knowledge and self-care.
AB - AIMS: The objective of this study was to study the effectiveness of structured
care with and without integrated education with regard to patients' knowledge,
self-care behaviour and disease perception. METHODS: Four diabetes care
programmes implemented in a daily primary care setting were compared, two based
on structured care and two on education integrated into structured care.
Measurements were taken at baseline and after 6 and 12 months. RESULTS: The study
included 243 patients with Type 2 diabetes mellitus treated by a general
practitioner (mean age 64.0 years; diabetes duration 7.1 years). The level of
patients' disease knowledge increased in all programmes, was preserved at follow
up and differed between programmes with a specific educational component (37%) on
one hand and the non-educational programmes (11%) on the other (P < 0.001). The
percentage of patients performing self-care behaviour increased in all
programmes, but more so in the programmes with an educational component. In
addition, an increase in the frequency of self-care behaviour was observed,
whereas no change in disease perception was found. In cross sectional analyses
disease knowledge and self-care behaviour were positively related (partial
correlation coefficient: 0.35; P < 0.001 adjusted for age, sex, level of
education and duration of diabetes). CONCLUSIONS: The results indicate that
primary care programmes which integrated education into structured care are able
to improve both Type 2 diabetic patients' disease knowledge and their self-care
behaviour. These improvements endured after the completion of the programmes,
which suggests that they initiate lasting changes in the way patients handle
their disease.
PMID- 10784223
TI - Prevalence of symptoms of depression and anxiety in a diabetes clinic population.
AB - AIMS: To investigate the use of a short questionnaire to measure psychological
symptoms in a busy clinic setting, and to examine the prevalence of these
symptoms in adults with diabetes. The perceived need for psychological treatment
services was also measured. METHODS: Adults (> 18 years) with either Type 1 or
Type 2 diabetes were invited to complete a short demographic form and the
Hospital Anxiety and Depression Scale (HADS) whilst waiting for their routine
diabetes outpatients appointment. Complication status was measured via patients'
medical records. Glycaemic control (HbA(1c)) was also recorded. RESULTS: A high
response rate (96%) was achieved. Prevalence rates of psychological symptoms were
high (overall 28% of study participants reported moderate-severe levels of
depression or anxiety or both). Men were somewhat more likely to report moderate
severe depressive symptoms, whereas women reported more moderate-severe anxiety.
A significant association between depression and poor glycaemic control was
observed in the men, but not in the women. Regression analysis demonstrated that
the interaction between sex and glycaemic control, HbA(1c) and sex were all
significantly associated with depression and anxiety (R2 = 0.16 and 0.19,
respectively). One-third of subjects reported that at the moment they would be
interested in receiving counselling or psychotherapy if it was currently
available at the diabetes clinic. CONCLUSIONS: This study has shown that the HADS
is an appropriate questionnaire to use in a clinic setting in adults with
diabetes. There may be a stronger association between glycaemic control and
psychological symptomatology in men than in women. There remains a significant
proportion of individuals with diabetes who require psychological support, which,
if available, might help improve glycaemic control and thus overall wellbeing.
PMID- 10784224
TI - Is mild gestational hyperglycaemia associated with maternal and neonatal
complications? The Diagest Study.
AB - AIMS: To evaluate the maternal and neonatal complications rates of mild
gestational hyperglycaemia (MGH) compared to a control group in France. METHODS:
A systematic screening by a 50-g glucose challenge test was offered to all women
between 24 and 28 weeks of gestation in 15 maternity units. If the 50-g glucose
challenge test was > or = 7.2 mmol/l, a 100-g 3-h oral glucose tolerance test
(OGTT) was performed. MGH (n = 131) was defined by one abnormal value on the 3-h
OGTT (Carpenter and Coustan criteria). The control group (n = 108) was defined by
a 50-g glucose challenge test below 7.2 mmol/l. Women with MGH received no
treatment or specific advice during the pregnancy. Large for gestational age
(LGA) was defined by a birth weight of at least the 90th percentile on French
standard growth curves. RESULTS: Women with MGH were older than the controls
(28.8 (5.8) vs. 27.0 (5.2); P < 0.05) and had a higher body mass index (24.8
(4.8) vs. 23.0 (3.9); P < 0.01). The rate of pregnancy-induced hypertension and
Caesarean section were not different between the MGH and control group. The rate
of LGA was significantly higher in the MGH group than the control group (22.1%
vs. 11.4%; P < 0.05). After adjustment for confounding factors of macrosomia (pre
pregnancy body mass index > 27, maternal age > 35, multiparity and educational
level), there was a persistent relationship between LGA and MGH (odds ratio 2.50;
95% confidence interval (1.16-5.40); P < 0.05). MGH was more frequently
associated with adverse maternal and fetal outcome than in the controls (53.4%
vs. 28.7%; P < 0.01). CONCLUSIONS: This study suggested that the increased rate
of adverse maternal and fetal outcome, especially LGA, was associated with
untreated mild gestational hyperglycaemia women compared to a control group. This
link to lower degrees of hyperglycaemia during pregnancy is independent of
confounding factors.
PMID- 10784225
TI - A randomized, controlled trial comparing insulin lispro with human soluble
insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK
Trial Group.
AB - AIMS: Despite considerable experience with insulin lispro, few blinded
comparisons with soluble insulin are available. This study compared insulin
lispro with human soluble insulin in patients with Type 1 diabetes mellitus on
multiple injection therapy who inject shortly before meals. METHODS: Glucose
control, frequency of hypoglycaemia and patient preference were examined in the
course of a prospective, randomized, double-blind, crossover comparison, with a 6
week run-in period and 12 weeks on each therapy. Ninety-three patients took part,
all on multiple daily doses of insulin, with soluble insulin before meals and NPH
(isophane) insulin at night. The main outcome measures were self-monitored blood
glucose profiles, glycated haemoglobin, frequency of hypoglycaemic episodes,
patient satisfaction and well-being and patient preference. RESULTS: Blood
glucose levels were significantly lower after breakfast and lunch, but higher
before breakfast, lunch and supper, in patients taking insulin lispro. Levels of
HbA(1c) were 7.4 +/- 1.1% on Humulin S and 7.5 +/- 1.1% on insulin lispro (P =
0.807). The overall frequency of symptomatic hypoglycaemia did not differ, but
patients on insulin lispro were less likely to experience hypoglycaemia between
midnight and 6 a.m., and more likely to experience episodes from 6 a.m. to
midday. Questionnaires completed by 84/87 patients at the end of the study showed
that 43 (51%) were able to identify each insulin correctly, nine (11%) were
incorrect, and 32 (38%) were unable to tell the insulins apart. No significant
preference emerged: 35 (42%) opted for insulin lispro, 24 (29%) opted for Humulin
S, while the remainder had no clear preference. CONCLUSIONS: Substitution of
insulin lispro for soluble insulin in a multiple injection regimen improved post
prandial glucose control at the expense of an increase in fasting and pre
prandial glucose levels. Patients who already injected shortly before meals
expressed no clear preference for the fast-acting analogue, and did not improve
their overall control as a result of using it. Nocturnal hypoglycaemia was
however, less frequent on insulin lispro, and may emerge as a robust indication
for its use.
PMID- 10784226
TI - Clinical profile of diabetic foot infections in south India--a retrospective
study.
AB - AIMS: The aim of the study was to determine the profile of diabetes foot
infections in south Indian diabetic subjects. The causative factors for delayed
wound healing and the recurrence of infection were also studied. METHODS: During
a period of 6 months, 374 patients who had undergone some surgical procedure for
foot infection were available for follow-up (M:F 227:147, mean age 54.9 +/- 9.4
years, diabetes duration 10.9 +/- 7.7 years). All of them had records of clinical
and treatment details, laboratory data including biothesiometry, Doppler tests
and electrocardiogram (ECG) records. Foot ulcers were classified according to
Wagner's classification. RESULTS: Majority of the patients had grade II and III
ulcers (50% and 26.5%, respectively), grade IV was seen in another 21.9%. The
median healing time was 44 days. Recurrence of infection which occurred in 53%
was more common in patients with neuropathy and peripheral vascular disease
(PVD). CONCLUSIONS: Recurrence of foot infection was common among south Indian
Type 2 diabetic subjects and was related to the presence of PVD and neuropathy.
There is also a need for improvement in footwear and foot care education.
PMID- 10784227
TI - Angiotensin-converting enzyme inhibition by quinapril blocks the albuminuric
effect of atrial natriuretic peptide in Type 1 diabetes and microalbuminuria.
AB - AIMS: This study examined the effect of angiotensin-converting enzyme inhibition,
administered at doses with no effect on systemic blood pressure, on the
albuminuric action of atrial natriuretic peptide (ANP). METHODS: Seven Type 1
diabetic patients with established microalbuminuria participated in a two limb,
single-blind, placebo controlled study. Subjects were administered quinapril 10
mg daily or placebo for 7 days prior to study. On the study day, subjects were
euglycaemic clamped and subsequently fluid loaded (20 ml/kg tap water orally plus
urinary losses). At steady state diuresis, a 1 h intravenous infusion of ANP 0.05
mg.kg(-1) x min(-1) was administered. Urine was collected at 15-min intervals for
estimation of albumin-creatinine ratio (ACR). Results were analysed by ANOVA.
RESULTS: Baseline mean arterial pressure was similar after pre-treatment with
quinapril and placebo (98.7 +/- 3.8 vs. 100 +/- 4.5 mmHg, mean +/- SD, P > 0.5),
and was unaltered by ANP infusion on either study day. Baseline ACR was similar
on quinapril and placebo (P = 0.13). ANP infusion induced a rise in urine ACR
with placebo (58.4 +/- 40.2 to 393.6 +/- 262.9 mg/mmol, P = 0.006), but not with
quinapril (29.3 +/- 10.7 to 81.5 +/- 43 mg/mmol, P = 0.15). The urine ACR
response to ANP infusion was higher with placebo than with quinapril (P = 0.02).
CONCLUSIONS: Quinapril blocks the albuminuric effect of intravenous infusion of
ANP in subjects with Type 1 diabetes mellitus and established microalbuminuria.
This action is independent of changes in mean arterial pressure and creatinine
clearance.
PMID- 10784228
TI - Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in
Type 2 diabetes mellitus.
AB - AIMS: The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been
shown to enhance insulin secretion in animals and in healthy human volunteers and
thus offers a potential advance in the treatment of Type 2 diabetes mellitus.
This study examined whether nateglinide can enhance insulin secretion, and
particularly the first phase insulin response, in patients with Type 2 diabetes.
METHODS: A double-blind, placebo-controlled trial, examining the effects of a
single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous
glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy
Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0
44 months). RESULTS: Insulin secretion (both overall and first phase) was
significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001)
and proinsulin (P < 0.001) secretion. Overall glucose concentrations following
glucose challenge were lower after nateglinide than after placebo (P = 0.05).
CONCLUSIONS: Nateglinide significantly increases insulin secretion in Type 2
diabetic patients, in particular restoring the first phase insulin response.
Further study is necessary to determine the effects of chronic administration on
insulin secretion and blood glucose concentration.
PMID- 10784229
TI - Relative activity and referral patterns for diabetes and non-diabetes in general
practice.
AB - AIMS: To describe and compare general practice (GP) activity for patients with
and without diabetes using a survey of general practices representing over 10% of
the Welsh population. METHODS: The Welsh GP Morbidity Database Project (GPMDP)
collected data including demographic and lifestyle information and consultation
data such as diagnosis, referral and surgical procedures. These data were
analysed to establish the annual period prevalence of diabetes and compare the
relative number of consultations and referrals. RESULTS: A total of 4,182
diabetic patients were recorded (prevalence 1.41%) and accounted for 77,371
(4.4%) consultations. Patients with diabetes were four-times more likely to be
referred to community services (relative risk (RR) 4.1, 95% CI 3.7-4.7), in
particular district nursing (RR 3.8, 1.9-7.7), optician services (RR 8.9, 5.0
15.7), chiropody (RR 8.2 6.4-10.5) and dietician services (RR 21.2, 17.6-25.5).
Patients with diabetes were also more likely to be followed-up in general
practice (RR 6.7, 6.2-7.2) both within 1 month (RR 6.7, 6.2-7.2) and 1 month to 1
year (RR 9.7, 8.9-10.7). Emergency admissions were also more likely for patients
with diabetes (RR 6.8, 6.2-7.5) as were elective admissions to general medicine
(RR 5.6, 4.6-6.7), surgery (RR 1.8, 1.5-2.0) and opthalmology (4.2, 3.4-5.2).
CONCLUSION: The increased utilization of health services apparent in secondary
care was confirmed in primary care. Further research is required to determine
levels of community activity after initial referral.
PMID- 10784230
TI - Early social mixing and childhood Type 1 diabetes mellitus: a case-control study
in Yorkshire, UK.
AB - AIMS: Evidence from animal models shows an increased risk of Type 1 diabetes
mellitus associated with the absence of early life exposure to pathogens. To test
this 'hygiene hypothesis', patterns of social mixing and infections in the first
year of life and the risk of developing autoimmune diabetes in childhood were
examined. METHODS: Personal interviews were conducted with the mothers of 220
children with Type 1 diabetes (0-15 years) and 433 age/sex matched controls from
a population-based case control study in Yorkshire, UK. Social mixing including
attendance at daycare, and infections occurring under 1 year of age were measures
of exposure. Adjusted odds ratios (OR) were derived using conditional logistic
regression. RESULTS: Frequency of attendance at daycare during the 1st year of
life was inversely associated with childhood diabetes (OR 0.71, 95% confidence
interval 0.51-1.00, P = 0.05), a finding not explained by mother's age, level of
education or maternal diabetes. Increasing numbers of children in the daycare
setting and numbers of sessions attended were significantly associated with
increasing protection from diabetes. The strongest effect was observed in
children with diabetes diagnosed aged 0-4 years. CONCLUSIONS: Social mixing
through attendance at daycare in early infancy appears to confer protection
against the development of childhood diabetes. This may be mediated through
exposure to infectious agent(s) as a significant dose-response effect was evident
with increasing numbers of child 'contacts'. These findings suggest early
infectious exposure may play a role in the development of immunoregulatory
mechanisms which protect against diabetes and further work is warranted.
PMID- 10784231
TI - Comparison of vasodilator effects of substance P in human forearm vessels of
normoalbuminuric Type 1 diabetic and non-diabetic subjects.
AB - AIMS: To compare the vasodilatory responses to substance P in human forearm
vessels in Type 1 normoalbuminuric diabetic and non-diabetic subjects. METHODS:
Forearm blood flow (FBF) was measured using a plethysmography technique in 12
normoalbuminuric Type 1 diabetic subjects (six males, six females) (HbA(1c) 8.2
+/- 0.3% (mean +/- SEM)) and 12 non-diabetic healthy control subjects in response
to the infusion of the vasodilators substance P (SP), acetylcholine (ACh) and
nitroprusside. RESULTS: There was no significant difference in baseline FBF
between the two groups (2.80 +/- 0.29 ml/min per 100 ml forearm tissue (diabetic
group) vs. 2.85 +/- 0.37 ml/min per 100 ml (non-diabetic group), P = 0.45).
Infusion of SP was associated with an incremental increase in FBF in the diabetic
(0.6, 2 and 6 ng/min - 6.08 +/- 1.07, 7.82 +/- 1.08 and 9.48 +/- 1.14 ml/min per
100 ml, respectively) and the non-diabetic group (0.6, 2 and 6 ng/min - 5.41 +/-
0.80, 6.93 +/- 0.96 and 9.25 +/- 1.11 ml/min per 100 ml, respectively).
Similarly, an incremental rise in FBF was observed during infusion of ACh
(diabetic group: 7.5, 15 and 30 microg/min - 7.14 +/- 1.22, 8.91 +/- 1.40 and
11.67 +/- 1.93 ml/min per 100 ml, respectively; non-diabetic group: 7.5, 15 and
30 microg/min - 5.87 +/- 0.81, 7.49 +/- 0.96 and 10.74 +/- 1.29 ml/min per 100
ml, respectively). When FBF was expressed as percentage change from baseline,
there was no significant difference in vasodilatory responses between the two
groups for SP (0.6 ng/min, P = 0.21; 2 ng/min, P = 0.19; 6 ng/min, P = 0.19) or
ACh (7.5 microg/min, P = 0.20; 15 microg/min, P = 0.20; 30 microg/min, P = 0.35).
CONCLUSIONS: This study suggests that endothelium-dependent vasodilatory
responses to SP (and ACh) are not impaired in Type 1 diabetic subjects with
normal urinary albumin excretion.
PMID- 10784232
TI - Significance of GAD positivity in elderly patients with diabetes.
PMID- 10784233
TI - Hypoxia-induced vascular endothelial growth factor expression is potentiated by
elevated glucose levels.
PMID- 10784234
TI - Does acute hyperinsulinaemia change plasma adrenomedullin concentration in
healthy men?
PMID- 10784235
TI - Long-term treatment of the anaemia in Type 1 diabetes mellitus with
erythropoietin.
PMID- 10784236
TI - Epidemiology, racism, and health: the case of low birth weight.
PMID- 10784237
TI - Impact of exposure to maternal PCBs and dioxins on the neonate's thyroid hormone
status.
PMID- 10784238
TI - Birth weight trends among interracial black and white infants.
AB - I examined time trends in low birth weight (LBW) and very low birth weight (VLBW)
among interracial compared with single-race infants. Using natality data from
1978 through 1997 for singleton births to black and white parents, I calculated
relative risks (RRs) of LBW and VLBW for interracial compared with single-race
births, stratified by maternal race and adjusted for maternal characteristics.
Among black mothers, interracial births had lower risks of LBW and VLBW than
single-race births, and RRs were similar throughout the time period [for example,
adjusted RR = 0.76 and 95% confidence interval (CI) = 0.73-0.80 for LBW in 1994
1997]. Among white mothers, interracial infants had higher risks of LBW than
single-race infants; however, the adjusted RRs declined over the time period,
from 1.22 (95% CI = 1.19-1.27) in 1978-1981 to 1.05 (95% CI = 1.03-1.08) in 1994
1997. Since 1978, there has been some relative improvement in birth outcomes for
infants of white mothers and black fathers compared with single-race white
births. There was, however, no relative improvement for black mother/black father
infants relative to black mother/white father births.
PMID- 10784239
TI - Polychlorinated biphenyl (PCB) exposure in relation to thyroid hormone levels in
neonates.
AB - Polychlorinated biphenyls (PCBs) are industrially produced environmentally
persistent compounds. In developed countries all humans have detectable levels in
blood and other tissues. PCBs alter thyroid hormone metabolism in animal
experiments, and human data suggest background-level exposure may have similar
effects in neonates. We evaluated this possible effect among 160 North Carolina
children whose in utero PCB exposure was estimated on the basis of the mother's
PCB levels in milk and blood, in 1978-1982 (estimated median PCB level in milk at
birth, 1.8 mg/kg lipid). Their umbilical cord sera were thawed in 1998 and
assayed for total thyroxine, free thyroxine, and thyroid stimulating hormone. We
found that PCB exposure was not strongly related to any of the thyroid measures.
For example, for a one unit change in milk PCB concentration (mg/kg lipid), the
associated multivariate-adjusted increase in thyroid stimulating hormone level
was 7% (95% confidence limits (CL) = -6, 21). Despite the possibility of sample
degradation, these data suggest that within the range of background-level
exposure in the United States, in utero PCB exposure is only slightly related to
serum concentration of total thyroxine, free thyroxine, and thyroid stimulating
hormone at birth.
PMID- 10784240
TI - An exact method for meta-analysis of case-control and follow-up studies.
AB - In this paper, we describe an exact method for estimating a common relative risk
across different epidemiologic study designs. The types of studies allowed by the
method include case-control studies, follow-up studies with an internal
comparison group, and follow-up studies with an external comparison group.
Because the method is exact, sparseness of individual studies is not an issue.
Those wishing to perform a meta-analysis of case-control studies and follow-up
studies in which both the exposure and outcome are rare will find the method
particularly useful. To allow one to perform the computations efficiently, we
present a partial polynomial multiplication algorithm. We also describe a public
domain computer program that performs the necessary calculations.
PMID- 10784241
TI - Eosinophilia is associated with increased all-cause mortality after a follow-up
of 30 years in a general population sample.
AB - We investigated whether allergy is associated with increased all-cause mortality.
Two allergy markers, peripheral blood eosinophilia (> or =275 eosinophilic cells
per mm3) and positive skin tests (sum score > or =3), were available for 5,383
subjects of a cohort study on asthma and chronic obstructive pulmonary disease in
general population samples of Vlagtwedde and Vlaardingen, the Netherlands, in
1965-1972. During 30 years of follow-up, 1,135 subjects died. In a Cox regression
analysis, eosinophilia was associated with an increased risk (relative risk =
1.4; 95% confidence interval = 1.2-1.7) of all-cause mortality, independent of
gender, age, smoking habits, percentage predicted forced expiratory volume in 1
second (FEV1 % predicted), and positive skin tests at the start of the study.
Subjects with positive skin tests had only an increased risk of all-cause
mortality in the subgroup of subjects with FEV1 <80% of predicted (relative risk
= 1.7; 95% confidence interval = 1.0-2.8). These results remained essentially
unchanged after exclusion of subjects with asthma. We conclude that eosinophilia
is associated with increased all-cause mortality. An increased number of
peripheral blood eosinophils may reflect an increased inflammatory response,
resulting in tissue injury. It is possible that the association between a low
FEV1% predicted and all-cause mortality is partly mediated by an atopic
constitution.
PMID- 10784242
TI - Can sustained weight loss in overweight individuals reduce the risk of diabetes
mellitus?
AB - Although rates of adult-onset diabetes mellitus increase with increasing obesity,
there is little evidence that weight loss in overweight individuals can reduce
their risk of developing diabetes. Using data from the Framingham Study, we
examined the effects of sustained and nonsustained weight loss on risk of
diabetes mellitus among 618 overweight (body mass index > or =27) subjects 30-50
years of age. To separate sustained from nonsustained weight loss, we examined
weight change in two consecutive 8-year periods. Subjects who had stable weight
(+/- 1 lb per year) during both periods served as the referent group for all
analyses. Sustained weight loss led to a 37% lower risk of diabetes [relative
risk (RR) = 0.63; 95% confidence interval = 0.34-1.2], and this effect was
stronger for more obese (body mass index > or =29) subjects (RR = 0.38; 95%
confidence interval = 0.18-0.81). Those who lost 8.1-15 lb had a 33% reduction in
diabetes risk, whereas those losing more had a 51% reduction in risk. Regardless
of the amount of weight lost, those who regained the lost weight had no reduction
in diabetes risk (RR = 1.1 and 1.2 for those who lost 8.1-15 and >15 lb,
respectively). We conclude that a modest amount of sustained weight loss can
substantially reduce the risk of diabetes mellitus in overweight individuals.
PMID- 10784243
TI - An indirect estimate of the incidence of non-insulin-dependent diabetes mellitus.
AB - Our goal was to estimate non-insulin-dependent diabetes mellitus incidence in the
Netherlands in the absence of equivocal empirical data. Incidence can be
expressed as a function of age, sex, prevalence, and mortality. We obtained
prevalence data from a study that pooled existing prevalence estimates. We
calculated diabetes-related mortality using relative risks on all-cause
mortality. Sensitivity for the rate of excess mortality was determined using the
95% confidence intervals (95% CI) of the relative risks. The estimated incidence
increases exponentially with age, with a doubling time of 10 years for men and 9
years for women. The rate increases from 8.1 per 10,000 (95% CI = 7.7-8.8) for
men ages 40-44 years and 7.0 (95% CI = 6.8-8.0) for women to 79.7 per 10,000 (95%
CI = 69.5-90.9) for men ages 75-79 years and 85.8 (95% CI = 80.6-91.0) for women.
When empirical estimates of incidence are largely lacking, the methodology
described offers a useful alternative, in particular for the assessment of
potential intervention effects.
PMID- 10784244
TI - Influence of apolipoprotein E genotype on the risk of cognitive deterioration in
moderate drinkers and smokers.
AB - We investigated the risk of cognitive deterioration in relation to alcohol
consumption and smoking according to the apolipoprotein E (ApoE) polymorphism.
The ApoE epsilon4 allele is an established risk factor for dementia and cognitive
impairment. There are also some recent indications that vascular risk factors,
including alcohol and tobacco consumption, might play a role in cognition. Our
data are from the Epidemiology of Vascular Aging (EVA) study, a prospective study
of 1,389 subjects ages 59-71 years at study entry, living the city of Nantes,
France, and followed at 4 years after entry. Information on subjects' alcohol and
tobacco consumption was collected from a structured questionnaire on food habits.
Cognitive performance was assessed by the Mini-Mental State Examination (MMSE).
Cognitive deterioration was defined as a decrease of 3 points or more in the Mini
Mental State Examination between study entry and 4-year follow-up. Drinking was
associated with a decreased risk of cognitive deterioration in non-ApoE epsilon4
carriers, whereas an opposite association was observed in ApoE epsilon4 carriers.
The risk of cognitive deterioration associated with tobacco consumption was also
modified according to ApoE genotype, with smokers being at decreased risk of
cognitive deterioration among ApoE epsilon4 allele carriers and at increased risk
in noncarriers. The effects of alcohol consumption and smoking on the risk of
cognitive deterioration appears to be strongly modified by the presence of ApoE
epsilon4 allele.
PMID- 10784246
TI - Physical activity and incidence of postmenopausal breast cancer.
AB - Whether physical activity reduces the risk of postmenopausal breast cancer is
uncertain; few studies have addressed this issue. We examined the association of
leisure physical activity with breast cancer incidence among 37,105
postmenopausal participants in the Iowa Women's Health Study. Women reporting the
highest level of physical activity at baseline compared with women with the
lowest level of activity had an age-adjusted relative risk of breast cancer of
0.92 (95% confidence interval = 0.80-1.05). Women reporting any regular leisure
time physical activity had a relative risk of 0.97 (95% confidence interval =
0.87-1.08) compared with those reporting no such regular physical activity.
Adjustment for potential confounders did not appreciably alter the findings.
There is little evidence from this study that physical activity later in life is
associated to any appreciable extent with breast cancer incidence.
PMID- 10784245
TI - Smoking and myelodysplastic syndromes.
AB - The purpose of this case-control study was to investigate tobacco smoking as a
risk factor for myelodysplastic syndromes, emphasizing karyotypic aberrations as
markers for exposure and risk differentiation with respect to morphology. We
obtained smoking history by interview of 330 cytogenetically investigated adult
myelodysplastic syndrome cases and 337 controls, matched with respect to sex,
year of birth, and county of living. Smoking for at least 1 year at some time 20
years or less before diagnosis was associated with an elevated relative risk (RR)
for primary myelodysplastic syndromes (odds ratio (OR) 1.8; 95% confidence
interval (CI) = 1.2-2.7). The results indicated a relation with intensity and
duration of smoking as well as a decrease in risk a few years after cessation of
smoking. Smoking was associated with an increased RR for primary myelodysplastic
syndromes with chromosome 7 abnormalities (OR 5.0; 95% CI = 1.1-23). Elevated RRs
were also seen for refractory anemia (OR 2.5; 95% CI = 1.2-5.6) and for
refractory anemia with ringed sideroblasts (OR 3.2; 95% CI = 0.88-12). The
findings suggest that smoking is a risk factor for myelodysplastic syndromes.
PMID- 10784247
TI - Does hereditary nonpolyposis colorectal cancer explain the observed excess risk
of colorectal cancer associated with family history?
AB - Several studies have found an increased risk of colorectal cancer associated with
a family history of colorectal cancer. Some studies, although not all, have also
suggested that family history of colorectal cancer may be a risk factor for
adenomatous polyps. Hereditary nonpolyposis colorectal cancer is a known genetic
syndrome predisposing to colorectal cancer. The hypothesis of this paper is that
the preponderance of the genetic or familial risk for colorectal cancer in the
United States is mediated by hereditary nonpolyposis colorectal cancer. To test
this hypothesis, I have incorporated what is known about hereditary nonpolyposis
colorectal cancer into a genetic model that generates probabilities of family
clustering of colorectal cancer. Using this model, which assumes that all
familial risk for colorectal cancer is due to hereditary nonpolyposis colorectal
cancer, the expected relative risks for colorectal cancer (and adenomas)
associated with given types of family histories were calculated. The relative
risks predicted by the model fairly closely matched the results found in the
literature, especially those reported from a large cohort study. As observed in
several studies, the model predicts that relative risks decrease sharply with
age. In contrast to the elevated risk for colorectal cancer, the model predicts
no elevated risk for adenomas associated with family history of colorectal
cancer.
PMID- 10784248
TI - Age at menopause, body mass index, and the risk of colorectal cancer mortality in
the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort.
AB - We investigated whether age at menopause is associated with subsequent mortality
from colorectal cancer along with the possible modification of this association
by body mass index. Our data are from the Diagnostisch Onderzoek Mammacarcinoom
cohort of 10,671 postmenopausal women in the Netherlands, enrolled between 1974
and 1977, with a median follow-up of 18 years. During this follow-up, 95 women
died of colorectal cancer. Women 49 years of age or older at menopause showed a
lower risk of colorectal cancer mortality compared with women younger than 49 at
menopause. This protective effect, however, was found only among nonoverweight
women (< or =24 kg/m2), for whom the hazard ratio was 0.46 (95% confidence
interval = 0.21-1.03). In larger women, the hazard ratio was 1.17 (95% confidence
interval = 0.68-2.00).
PMID- 10784249
TI - Familial relationships in squamous cell carcinoma of the skin.
AB - The Swedish Family-Cancer Database, which was updated in 1999 to cover
individuals born after 1934 with their biological parents, totals 9.6 million
persons. We used this resource to study invasive and in situ skin cancers. We
identified 198 families in which a parent and an offspring had skin cancer. The
familial standardized incidence ratios (SIRs) were 2.4 for invasive and 2.8 for
in situ skin cancers in offspring. The SIRs for offspring depended only weakly on
the age at diagnosis, as evaluated in two age groups. Compared with offspring
whose parents had a single skin cancer, offspring whose parents had multiple skin
cancers had a 70% increase in SIR. The discordant parental cancer sites that
showed associations with skin cancer in offspring were melanoma, ocular melanoma,
and a group of cancers observed in immunosuppressed patients.
PMID- 10784250
TI - Maternal pregnancy estriol levels in relation to anamnestic and fetal
anthropometric data.
AB - In epidemiologic studies of perinatal exposures, birth weight has been proposed
as a proxy variable for intrauterine estrogen exposure. To assess the validity of
this assumption, we performed analyses of the association between estriol levels
in 188 women in the 17th, 25th, 33rd, and 37th weeks of pregnancy and the birth
weights of their infants. We found a general increase in mean cumulative estriol
dose with increasing birth weight category throughout pregnancy. In late
pregnancy, mean pregnancy estriol level of mothers of infants in the highest
birth weight category (>4,500 gm) was twice as high as that of mothers of infants
in the lowest category (<2,500 gm), 775 nmol/liter and 392 nmol/liter,
respectively. Smoking lowered the maternal estriol levels by 20% or more
throughout pregnancy. With smoking and birth weight included in a regression
analysis, maternal age, placental weight, and infant ponderal index did not add
any explanatory power to the model. Our data suggest that, on an aggregate level,
birth weight can be used as a proxy variable of intrauterine estriol exposure.
PMID- 10784251
TI - The distributed lag between air pollution and daily deaths.
AB - Many studies have reported associations between air pollution and daily deaths.
Those studies have not consistently specified the lag between exposure and
response, although most have found associations that persisted for more than 1
day. A systematic approach to specifying the lag association would allow better
comparison across sites and give insight into the nature of the relation. To
examine this question, I fit unconstrained and constrained distributed lag
relations to the association between daily deaths of persons 65 years of age and
older with PM10 in 10 U.S. cities (New Haven, Birmingham, Pittsburgh, Canton,
Detroit, Chicago, Minneapolis, Colorado Springs, Spokane, and Seattle) that had
daily monitoring for PM10. After control for temperature, humidity, barometric
pressure, day of the week, and seasonal patterns, I found evidence in each city
that the effect of a single day's exposure to PM10 was manifested across several
days. Averaging over the 10 cities, the overall effect of an increase in exposure
of 10 microg/m3 on a single day was a 1.4% increase in deaths (95% confidence
intervals (CI) = 1.15-1.68) using a quadratic distributed lag model, and a 1.3%
increase (95% CI = 1.04-1.56) using an unconstrained distributed lag model. In
contrast, constraining the model to assume the effect all occurs in one day
resulted in an estimate of only 0.65% (95% CI = 0.49-0.81), indicating that this
constraint leads to a substantial underestimate of effect. Combining the
estimated effect at each day's lag across the 10 cities showed that the effect
was spread over several days and did not reach zero until 5 days after the
exposure. Given the distribution of sensitivities likely in the general
population, this result is biologically plausible. I also found a protective
effect of barometric pressure in all 10 locations.
PMID- 10784252
TI - Total but not high-density lipoprotein cholesterol is consistently associated
with coronary heart disease mortality in elderly men in Finland, Italy, and The
Netherlands.
AB - We studied the relation between serum total and high-density lipoprotein (HDL)
cholesterol and 10-year coronary heart disease mortality in elderly men in
different European countries. The Finland, Italy and the Netherlands Elderly
(FINE) Study is a prospective follow-up study in 2,132 elderly men ages 65-84
years in Finland, the Netherlands, and Italy. We estimated relative risks using
Cox proportional hazard analysis with time-dependent covariates. Total
cholesterol was positively related to coronary heart disease mortality in all
three countries. The combined relative risk for the total population of the FINE
Study was 1.17 (95% confidence interval = 1.06-1.29) for each 1.00 mmol/liter
increase in total cholesterol. HDL cholesterol was inversely related to coronary
heart disease mortality in Finland, but not in the Netherlands and Italy. In
Italy we noted an interaction among HDL cholesterol, body mass index, and alcohol
intake, with an inverse association for HDL cholesterol in lean men who drank <40
gm of alcohol daily and a positive association for HDL cholesterol among
overweight men who drank > or =40 gm of alcohol per day. Serum total cholesterol
remains an important predictor of coronary heart disease mortality in elderly men
in different European countries. The effect of HDL cholesterol differed among the
three countries.
PMID- 10784253
TI - Body mass index in relation to energy intake and expenditure among adults in
Greece.
AB - The empirical evidence concerning the quantitative relations between energy
intake and expenditure on the one hand and body mass index (BMI) on the other is
inconclusive. We have used a large database of 14,281 individuals, for whom
habitual dietary intake and expenditure have been ascertained with adequate
methodology, to examine the mutually adjusted associations of these variables
with BMI. Study subjects were adult participants in the Greek component of the
European Prospective Investigation into Cancer and Nutrition (EPIC) study. After
adjustment for age and gender and exclusion of dieting individuals and energy
underreporters, an increment of about 500 kcal intake was found to correspond to
an increment of about 0.33 kg/m2 of BMI, whereas an increment of about 5 MET
hours of energy expenditure was associated with a decrease of about 0.18 kg/m2 of
BMI, where MET is the ratio of the metabolic rate associated with a given
activity to the resting metabolic rate. Our results indicate that increasing
physical activity is about half as effective as decreasing energy intake in
reducing BMI.
PMID- 10784254
TI - Low-income African-American mothers' perception of exposure to racial
discrimination and infant birth weight.
AB - We performed a hospital-based case-control study of African-American mothers to
explore the relation between a mother's perception of exposure to racial
discrimination during pregnancy and very low birth weight. We administered a
structured questionnaire to low-income mothers of very low birth weight (<1500
gm; N = 25) and non-low birth weight (>2500 gm; N = 60) infants. The unadjusted
and adjusted odds ratio of very low birth weight for maternal exposure to racial
discrimination were 1.9 (0.5-6.6) and 3.2 (0.9-11.3), respectively. We conclude
that maternal perception of exposure to racial discrimination during pregnancy
may be associated with very low birth weight in their infants.
PMID- 10784255
TI - Strength and anthropometric measures in identical and fraternal twins: no
evidence of masculinization of females with male co-twins.
AB - Sharing of intrauterine environment in twins of opposite sex has been
hypothesized to result in masculinization of the female twin. We tested this
hypothesis by comparing strength (maximum hand-grip pressure) and various
anthropometric measures in a newly established survey panel comprising 4,314
middle-aged twins identified through a Danish population-based twin registry. Sex
and zygosity-specific mean values of handgrip strength, height, weight, body
mass index, and waist circumference were highly comparable between fraternal
twins of opposite sex and fraternal twins of same sex. Our results provide no
support for the hypothesis of masculinization of female twins from opposite sex
twin pairs.
PMID- 10784256
TI - Differential survival related to smoking among patients with renal cell
carcinoma.
AB - We examined the relation between tobacco smoking and survival among renal cell
carcinoma cases, using information from a population-based cancer registry.
Current smokers were at increased risk of death compared with non-smokers (hazard
ratio (HR) 1.7, 95% CI = 1.2-2.5). The association was strongest within 6 months
of diagnosis (HR 2.5, 95% CI = 1.5-4.3). Most of the association was explained by
stage at diagnosis, with current smokers more likely (OR 2.2, 95% CI = 1.4-3.5)
to have distant disease. Case-control studies may be biased if cases who do not
participate owing to short survival have different smoking histories than
participating cases.
PMID- 10784257
TI - Cancer in husbands of cervical cancer patients.
AB - We used the Swedish Family-Cancer Database to analyze the spectrum of cancers
diagnosed in husbands of women with in situ or invasive cervical cancer, and we
compared these to second carcinogenic events in women presenting with these
cancers. Our hypothesis was increased cancer susceptibility from human papilloma
virus (HPV). When the wives had in situ or invasive cervical cancer, the standard
incidence ratios (SIRs) for anal cancer in husbands were 1.75 (95% CI = 1.05
2.62) and 1.92 (95% CI = 0.69-3.76). Anal cancer was also increased as a second
primary cancer in women. Other common cancers were related to tobacco smoking.
The results indicate that HPV infection is associated with anal cancer in both
men and women.
PMID- 10784258
TI - Using nicotine measurements and parental reports to assess indoor air: the PIAMA
birth cohort study. Prevention and Incidence of Asthma and Mite Allergy.
AB - We used two methods to collect data on indoor smoking exposure of 3-month-old
infants. First, parents of approximately 100 children completed a questionnaire.
We then measured nicotine in the air of the living rooms in smoking and non
smoking households with a passive sampler for a period of 2 weeks, several months
after the questionnaire had been completed. Smoking habits reported in the
questionnaire generally with reported number of cigarettes smoked during the
measurement weeks, and with nicotine concentrations in the air. These results
suggest that exposure classification based on questionnaire data is likely to be
reasonably valid.
PMID- 10784259
TI - The relative merits of contemporary measurements and historical calculated fields
in the Swedish childhood cancer study.
AB - We present arguments that suggest that historical average calculated fields,
which are widely used to estimate biologically relevant exposure to
electromagnetic fields, may be less accurate than contemporary spot measurements,
which are made at a time following the biologically relevant period of exposure.
We use data from the seminal Feychting and Ahlbom study of the health effects of
electromagnetic field exposure in a Swedish population to illustrate our
argument. We also show how the two types of measurements can produce divergent
estimates of risk, and show how in the Feychting and Ahlbom study, the less
accurate measurement, the historical average calculated fields, may have resulted
in a spurious increase in the estimates of risk. Finally, we consider the
implications of our arguments for other studies that rely on wire codes and
historical calculations of personal exposure.
PMID- 10784260
TI - Measuring electromagnetic fields.
PMID- 10784261
TI - Failure to publish results of epidemiologic studies is unethical.
PMID- 10784262
TI - Hepatitis B vaccine is not associated with liver problems in US children less
than 6 years old.
PMID- 10784263
TI - Hepatitis B vaccine is not associated with liver problems in US children less
than 6 years old.
PMID- 10784264
TI - Under-reporting of attributable risk and reporting of the risk ratio in
epidemiologic literature.
PMID- 10784265
TI - The role of atmospheric nitrogen dioxide in the risk of hospital admission in the
patient with respiratory pathology.
PMID- 10784266
TI - Common measures of disease burden, risk trade-offs, and improved environmental
health decision-making.
PMID- 10784268
TI - Diseases of meaning and the meaning of dis-eases.
PMID- 10784267
TI - A review of the benefits, adverse events, drug interactions, and safety of St.
John's Wort (Hypericum perforatum): the implications with regard to the
regulation of herbal medicines.
PMID- 10784269
TI - Searching for antimalarials in plants.
PMID- 10784270
TI - Homeopathic treatment of acute childhood diarrhea: results from a clinical trial
in Nepal.
AB - OBJECTIVE: To investigate whether the finding in a previous study that
homeopathic medicines decrease the duration of acute diarrhea in children could
be replicated in a different study population. DESIGN: Randomized, double-blind,
placebo-controlled trial. SETTING: Private, charitable health clinic in
Kathmandu, Nepal. SUBJECTS: A consecutive sample of 126 children, 6 months to 5
years of age, who presented during April through June, 1994, with more than three
unformed stools in the previous 24 hours. INTERVENTION: Children received either
an individualized homeopathic medicine or placebo, to be taken one dose after
each unformed stool for 5 days. Parents recorded daily stools on diary cards, and
health workers made home visits daily to monitor children. OUTCOME MEASURES:
Predefined measures were based on the previous study: (1) duration of diarrhea,
defined as the time until there were fewer than three unformed stools per day,
for two consecutive days, and (2) Average number of stools per day for each
group. RESULTS: Of the 126 children initially enrolled, 116 completed treatment.
The mean number of stools per day over the entire 5-day treatment period was 3.2
for the treatment group and 4.5 for the placebo group (P = 0.023). A Kaplan-Meier
survival analysis of the duration of diarrhea, which included data from all
patient visits, showed an 18.4% greater probability that a child would be free of
diarrhea by day 5 under homeopathic treatment (P = 0.036). CONCLUSIONS: These
results are consistent with the finding from the previous study that
individualized homeopathic treatment decreases the duration of diarrhea and
number of stools in children with acute childhood diarrhea.
PMID- 10784271
TI - An investigation into the use of aromatherapy in intrapartum midwifery practice.
AB - OBJECTIVE: The principal aim of the study was to examine the contribution of
aromatherapy to the promotion of maternal comfort during labor and as a tool to
improve the quality of midwifery care. DESIGN: Evaluative study. SETTING:
Delivery suite in a large British teaching hospital with approximately 6,500
deliveries per annum. SUBJECTS: A total of 8,058 mothers were evaluated between
1990 and 1998. INTERVENTIONS: Women were offered aromatherapy to relieve anxiety,
pain, nausea and/or vomiting or to strengthen contractions. Routine data
collected on the use of aromatherapy over the period were analyzed. Data from the
unit audit were used to provide a comparison group of mothers not given
aromatherapy (n = 15,799) from the study center. OUTCOME MEASURES: Outcome
measures include mothers' ratings of effectiveness, outcomes of labor, use of
pharmacologic pain relief, uptake of intravenous oxytocin, reported associated
symptoms, and annual costs. RESULTS: The use of aromatherapy during childbirth
was an increasingly popular care option with mothers and midwives. More than 50%
of mothers rated it as helpful, and only 14% found it unhelpful. The use of
aromatherapy was not confined to low-risk mothers. Sixty percent of the sample
were primigravidae, and 32% overall had had their labor induced. The
administration of aromatherapy in childbirth did appear to reduce the need for
additional pain relief in a proportion of mothers. More than 8% of primigravidae
and 18% of multigravidae used no conventional pain relief during labor after
using essential oils. During the years of the study, the use of pethidine in the
study center declined from 6% to 0.2% of women. The study also showed that
aromatherapy may have the potential to augment labor contractions for women in
dysfunctional labour. A very low number of associated adverse symptoms were
reported (1%). CONCLUSION: This study represents a successful example of the
integration of a complementary therapy into mainstream midwifery practice and
forms a basis for future research.
PMID- 10784272
TI - Are acupuncture points tender? A blinded study of Spleen 6.
AB - OBJECTIVES: To explore the methodology for investigating the tenderness of
acupuncture points, with particular reference to the hypothesis that the point
Spleen 6 (SP6) is more tender in women than in men. DESIGN: Single-blind,
observational study with volunteers. SETTING: University of Exeter, U.K.
SUBJECTS: Student volunteers, 13 male and 13 female. OUTCOME MEASURES: Pressure
thresholds at SP6, a control acupuncture point Stomach 36, and two nonacupuncture
control sites in each leg were measured weekly for 4 weeks. RESULTS: No
statistically significant differences were found between the pressure thresholds
of SP6 in women and those in men. CONCLUSION: The present study provides no
strong evidence to support the hypothesis that the acupuncture point SP6 is more
tender in women and in men. Recommendations for further investigations are
discussed.
PMID- 10784273
TI - Healing as a therapy for human disease: a systematic review.
AB - OBJECTIVE: To assess, from published clinical trials, the evidence for the use of
healing as a complementary medical intervention in human disease. DESIGN: Limited
to studies involving random assignment to a treatment group consisting of
"healing," broadly defined, or to a concurrent control group. All randomized
trials published up to the year 2000, were identified from MEDLINE, CINAHL, BIDS
EMBASE, the CISCOM complementary medicine databases and from bibliographic
references of published articles. Copies of all published studies were obtained,
data were extracted, and methodological quality (Jadad) scores were derived where
possible. RESULTS: Fifty-nine randomized clinical trials (RCTs) were found
comparing healing with a control intervention on human participants. In 37 of
these, healing was used for existing diseases or symptoms (22 existed as fully
accessible published reports, 10 as dissertation abstracts only, and 5 as
"preliminary" investigations with limited evidential value). The 22 full trials
(10 reporting a "significant" effect of healing compared with control) constitute
an extremely heterogeneous group, varying greatly in the method and duration of
healing; the medical condition treated; the outcome measure employed; and the
control intervention used. Many trials had a number of methodological
shortcomings, including small sample sizes, and were inadequately reported. Only
8 studies (5 with a significant outcome for healing) had a maximum methodological
quality score of 5, and in 10 studies this score was 3 or less. Two trials-both
large scale and methodologically sound-were replicates, and each found a
significant beneficial effect of intercessory prayer on the clinical progress of
cardiac patients. Eleven of the 15 dissertation abstracts and pilot studies
reported nonsignificant results for healing compared with control, a finding that
probably reflects the relatively small sample sizes and the likelihood of type II
errors. The significant heterogeneity found in this group of trials makes
categorization problematic and inhibits the pooling of results by meta-analysis
or similar techniques to obtain a global estimate of the "treatment effect" of
healing. CONCLUSIONS: No firm conclusions about the efficacy or inefficacy of
healing can be drawn from this diverse group of RCTs. Given the current emphasis
on evidence-based medicine, future investigations should be adequately powered,
appropriately controlled, and properly described. These future investigations
would most usefully consist of: (1) pragmatic trials of healing for
undifferentiated conditions on patients based in general practice and (2) larger
RCTs of distant healing on large numbers of patients with well-defined measurable
illness.
PMID- 10784274
TI - Methodological problems of clinical research into spiritual healing: the healer's
perspective.
PMID- 10784275
TI - Placing healers, healees, and healing into a wider research context.
AB - Healers claim that they can relieve, and often heal, injury and illness against
the odds of medical prognosis. Skeptics say that such claims can be accounted for
by possible misdiagnosis, uncritical reportage, placebo response, and coincident
natural improvement. Their a priori objection is that subjective intention in one
person cannot, of itself, affect the physiology and/or mental processes of
another person. This a priori objection becomes invalid if experimental evidence,
using simultaneous electroencephalographic recordings from two or more brains,
has demonstrated that direct brain-to-brain communication can occur. Evidence
that something very unusual is occurring during the healing transaction comes
from recordings of anomalous electrical and magnetic fields generated by healers
when they are in the intention-to-heal mindset.
PMID- 10784276
TI - Researching healing: a psychologist's perspective.
AB - This article suggests that a research agenda for healing should encompass
qualitative issues of value and meaning as well as quantitative issues of
clinical effectiveness. Patients themselves should play an active part in all
stages of the research process in order to ensure that the questions addressed
are relevant to the needs and wants of those who use healing. Research should
address the issues of defining and specifying desired outcomes and clarifying the
specific and nonspecific factors in the healing process as well as investigating
the potential for harm in treatment and minimizing risk. Some specific research
questions are raised. The healing community is challenged to develop a research
agenda that is conceptually and methodologically rigorous, true to the holistic
nature of complementary and alternative medicine, and retains the subversive edge
of the healing traditions.
PMID- 10784277
TI - Colloquium on spiritual healing. Meeting summary: major themes.
PMID- 10784278
TI - The first international meeting of the Research Initiative on Traditional
Antimalarial Methods (RITAM).
AB - The first international meeting of the Research Initiative on Traditional
Antimalarial Methods (RITAM) was held at the Regional Dermatology Training Centre
(RDTC) of the Tumaini University of Health Sciences, Moshi, Tanzania, on December
8-11, 1999. This Inaugural Meeting of RITAM, jointly hosted by the Global
Initiative for Traditional Systems of Health (GIFTS) at Oxford University and the
World Health Organization (WHO), was designed to develop a strategy for more
effective, evidence-based use of traditional medicines that can also inform
malaria-control policy decisions. RITAM was established during 1999 as a network
of researchers and other people who are active or interested in the study and use
of traditional, plant-based antimalarials. RITAM is a partnership between GIFTS
of Health, University of Oxford and the Tropical Disease Research (TDR) Programme
of WHO. Malaria is one of the key health issues affecting developing countries,
particularly in sub-Saharan Africa and Asia. With increasing drug resistance and
the high cost of pharmaceutical drugs, the use of herbal antimalarials is
popular. The conference was attended by biologic and social scientists,
clinicians, traditional healers, and policy makers from Africa, Asia, Europe, and
the Americas. The meeting was funded by the Rockefeller Foundation, the Nuffield
Foundation's Commonwealth Programme, WHO's TDR Programme, and direct support to
delegates was provided by other funders. The meeting addressed the need for
research and policy on the prophylactic and therapeutic effects of medicinal
plants as well as on vector control and repellence. There were five main outputs
from the meeting: (1) targets for making a significant contribution to the
control of malaria through the use of traditional antimalarial methods; (2)
methods for achieving these targets, including ethical guidelines; (3) an
implementation strategy for moving this field ahead quickly and soundly and for
putting research findings into practice; (4) linkages established between
researchers working on traditional antimalarial methods, based on agreed research
priorities and designed to avoid unnecessary replication; and (5) strengthening
the RITAM database of current knowledge on traditional herbal antimalarial
methods. Four specialist groups were established to develop the above: (1)
policy, advocacy, and funding; (2) preclinical studies; (3) clinical development;
and (4) repellance and vector control. These will be coordinated by an executive
committee managed by GIFTS. Two meetings are planned in 2000: a natural-products
chemistry meeting at WHO in Geneva, Switzerland, in June; and a symposium at the
World Congress on Tropical Medicine in Cartagena, Colombia, in August.
PMID- 10784279
TI - The real-time interactive 3-D-DVA for robust coronary MRA.
AB - A graphical user interface (GUI) has been developed which enables interactive
feedback and control to the real-time diminishing variance algorithm (DVA). This
interactivity allows the user to set scan parameters, view scan statistics, and
view image updates during the course of the scan. In addition, the DVA has been
extended to simultaneously reduce motion artifacts in three dimensions using
three orthogonal navigators. Preliminary in vivo studies indicate that these
improvements to the standard DVA allow for significantly improved consistency and
robustness in eliminating respiratory motion artifacts from MR images,
particularly when imaging the coronary arteries.
PMID- 10784280
TI - Unwarping of unidirectionally distorted EPI images.
AB - Echo-planar imaging (EPI) is a fast nuclear magnetic resonance imaging (MRI)
method. Unfortunately, local magnetic field inhomogeneities induced mainly by the
subject's presence cause significant geometrical distortion, predominantly along
the phase-encoding direction, which must be undone to allow for meaningful
further processing. So far, this aspect has been too often neglected. In this
paper, we suggest a new approach using an algorithm specifically developed for
the automatic registration of distorted EPI images with corresponding
anatomically correct MRI images. We model the deformation field with splines,
which gives us a great deal of flexibility, while comprising the affine transform
as a special case. The registration criterion is least squares. Interestingly,
the complexity of its evaluation does not depend on the resolution of the control
grid. The spline model gives us good accuracy thanks to its high approximation
order. The short support of splines leads to a fast algorithm. A multiresolution
approach yields robustness and additional speedup. The algorithm was tested on
real as well as synthetic data, and the results were compared with a manual
method. A wavelet-based Sobolev-type random deformation generator was developed
for testing purposes. A blind test indicates that the proposed automatic method
is faster, more reliable, and more precise than the manual one.
PMID- 10784281
TI - Voxel similarity measures for 3-D serial MR brain image registration.
AB - We have evaluated eight different similarity measures used for rigid body
registration of serial magnetic resonance (MR) brain scans. To assess their
accuracy we used 33 clinical three-dimensional (3-D) serial MR images, with
deformable extradural tissue excluded by manual segmentation and simulated 3-D MR
images with added intensity distortion. For each measure we determined the
consistency of registration transformations for both sets of segmented and
unsegmented data. We have shown that of the eight measures tested, the ones based
on joint entropy produced the best consistency. In particular, these measures
seemed to be least sensitive to the presence of extradural tissue. For these data
the difference in accuracy of these joint entropy measures, with or without brain
segmentation, was within the threshold of visually detectable change in the
difference images.
PMID- 10784282
TI - Automated anatomical labeling of the bronchial branch and its application to the
virtual bronchoscopy system.
AB - This paper describes a method for the automated anatomical labeling of the
bronchial branch extracted from a three-dimensional (3-D) chest X-ray CT image
and its application to a virtual bronchoscopy system (VBS). Automated anatomical
labeling is necessary for implementing an advanced computer-aided diagnosis
system of 3-D medical images. This method performs the anatomical labeling of the
bronchial branch using the knowledge base of the bronchial branch name. The
knowledge base holds information on the bronchial branch as a set of rules for
its anatomical labeling. A bronchus region is automatically extracted from a
given 3-D CT image. A tree structure representing the essential structure of the
extracted bronchus is recognized from the bronchus region. Anatomical labeling is
performed by comparing this tree structure of the bronchus with the knowledge
base. As an application, we implemented the function to automatically present the
anatomical names of the branches that are shown in the currently rendered image
in real time on the VBS. The result showed that the method could segment about
57% of the branches from CT images and extracted a tree structure of about 91% in
branches in the segmented bronchus. The anatomical labeling method could assign
the correct branch name to about 93% of the branches in the extracted tree
structure. Anatomical names were appropriately displayed in the endoscopic view.
PMID- 10784283
TI - A CAD system for the automatic detection of clustered microcalcifications in
digitized mammogram films.
AB - Clusters of microcalcifications in mammograms are an important early sign of
breast cancer. This paper presents a computer-aided diagnosis (CAD) system for
the automatic detection of clustered microcalcifications in digitized mammograms.
The proposed system consists of two main steps. First, potential
microcalcification pixels in the mammograms are segmented out by using mixed
features consisting of wavelet features and gray level statistical features, and
labeled into potential individual microcalcification objects by their spatial
connectivity. Second, individual microcalcifications are detected by using a set
of 31 features extracted from the potential individual microcalcification
objects. The discriminatory power of these features is analyzed using general
regression neural networks via sequential forward and sequential backward
selection methods. The classifiers used in these two steps are both multilayer
feedforward neural networks. The method is applied to a database of 40 mammograms
(Nijmegen database) containing 105 clusters of microcalcifications. A free
response operating characteristics (FROC) curve is used to evaluate the
performance. Results show that the proposed system gives quite satisfactory
detection performance. In particular, a 90% mean true positive detection rate is
achieved at the cost of 0.5 false positive per image when mixed features are used
in the first step and 15 features selected by the sequential backward selection
method are used in the second step. However, we must be cautious when
interpreting the results, since the 20 training samples are also used in the
testing step.
PMID- 10784284
TI - A multiscale dynamic programming procedure for boundary detection in ultrasonic
artery images.
AB - Ultrasonic measurements of human carotid and femoral artery walls are
conventionally obtained by manually tracing interfaces between tissue layers. The
drawbacks of this method are the interobserver variability and inefficiency. In
this paper, we present a new automated method which reduces these problems. By
applying a multiscale dynamic programming (DP) algorithm, approximate vessel wall
positions are first estimated in a coarse-scale image, which then guide the
detection of the boundaries in a fine-scale image. In both cases, DP is used for
finding a global optimum for a cost function. The cost function is a weighted sum
of terms, in fuzzy expression forms, representing image features and geometrical
characteristics of the vessel interfaces. The weights are adjusted by a training
procedure using human expert tracings. Operator interventions, if needed, also
take effect under the framework of global optimality. This reduces the amount of
human intervention and, hence, variability due to subjectiveness. By
incorporating human knowledge and experience, the algorithm becomes more robust.
A thorough evaluation of the method in the clinical environment shows that
interobserver variability is evidently decreased and so is the overall analysis
time. We conclude that the automated procedure can replace the manual procedure
and leads to an improved performance.
PMID- 10784285
TI - New variants of a method of MRI scale standardization.
AB - One of the major drawbacks of magnetic resonance imaging (MRI) has been the lack
of a standard and quantifiable interpretation of image intensities. Unlike in
other modalities, such as X-ray computerized tomography, MR images taken for the
same patient on the same scanner at different times may appear different from
each other due to a variety of scanner-dependent variations and, therefore, the
absolute intensity values do not have a fixed meaning. We have devised a two-step
method wherein all images (independent of patients and the specific brand of the
MR scanner used) can be transformed in such a way that for the same protocol and
body region, in the transformed images similar intensities will have similar
tissue meaning. Standardized images can be displayed with fixed windows without
the need of per-case adjustment. More importantly, extraction of quantitative
information about healthy organs or about abnormalities can be considerably
simplified. This paper introduces and compares new variants of this standardizing
method that can help to overcome some of the problems with the original method.
PMID- 10784286
TI - Using the Job-Related Affective Well-Being Scale (JAWS) to investigate affective
responses to work stressors.
AB - Prior research linking job stressors to psychological strains has been limited to
a small number of emotional reactions. This article describes research linking
job stressors to a wide range of affective states at work. In Study 1, a
multidimensional scaling procedure was used on a matrix of similarity judgments
by 51 employees of 56 job-related affective statements to support a 2-dimensional
view of affective well-being. In Study 2, ratings of the affect statements by 100
employees further supported the contention that the dimensions were pleasure
displeasure and degree of arousal. In Study 3, 114 full-time university employees
responded to the Job-Related Affective Well-Being Scale, which was found to be
related to measures of job stressors as well as job satisfaction and physical
symptoms.
PMID- 10784287
TI - Lean production teams and health in garment manufacture.
AB - The impact of lean production on psychological health was assessed by comparing
lean production teams in garment manufacture with a traditional system for making
similar garments. Work design characteristics were examined as mediators of the
impact of work organization on health. Findings indicate both positive and
negative direct effects of teamworking on aspects of autonomy, work demands, and
social climate. In turn, both positive and negative direct effects of work design
on psychological health were found, which combine to give no overall difference
between the groups. This study suggests that the balance between positive and
negative effects of lean production teamworking depends on management choices in
the form of work design.
PMID- 10784288
TI - Interpersonal conflict at work and psychological outcomes: testing a model among
young workers.
AB - On the basis of A. P. Fiske's (1992) general theory of social relations, a model
of interpersonal conflict at work was developed and tested in a sample of young
workers. The model predicts that conflict with supervisors is predictive of
organizationally relevant psychological outcomes (job satisfaction,
organizational commitment, and turnover intentions), whereas conflict with
coworkers is predictive of personally relevant psychological outcomes
(depression, self-esteem, and somatic symptoms). Data were obtained from a sample
of 319 individuals ages 16 to 19 years. Structural equation modeling results
supported the hypothesized relations. Secondary regression analysis of 2 data
sets from M. A. Donovan, F. Drasgow, and L. J. Munson (1998) provides initial
support for the generalizability of the hypothesized model to older employees.
PMID- 10784289
TI - Linear and nonlinear relations between psychosocial job characteristics,
subjective outcomes, and sickness absence: baseline results from SMASH. Study on
Musculoskeletal Disorders, Absenteeism, Stress, and Health.
AB - This study investigates the demand-control-support (DCS) model by (a) using a
more focused measure of job control, (b) testing for interactive and nonlinear
relationships, and (c) further extending the model to the prediction of an
objective outcome measure (i.e., company-administrated sickness absence).
Hypotheses were tested in a heterogeneous sample of 1,739 employees from a 3-year
prospective cohort study called SMASH (Study on Musculoskeletal Disorders,
Absenteeism, Stress, and Health). Baseline results showed that a linear additive
model was superior for job satisfaction, psychosomatic health complaints, and
sickness absence, whereas a curvilinear model was superior for emotional
exhaustion and depression. It is concluded that, first, there was no evidence of
interactive effects. Second, it seems sensible to pay more attention to
curvilinear relationships in future research. Finally, the DCS model was not
supported using a more objective outcome measure.
PMID- 10784290
TI - Organizational and individual factors affecting mental health and job
satisfaction: a multilevel analysis of job control and personality.
AB - This study evaluated variation at the individual and work unit levels in the
relations of job control, hostility, and trait anxiety to mental health and job
satisfaction. Questionnaire data from a sample of 2,900 employees working at 152
hospital wards were analyzed by means of multilevel regression analyses. Results
showed that mental health (General Health Questionnaire-12), varying mainly at
the individual level, was explained mostly by hostility and trait anxiety. Job
satisfaction varied significantly at the individual and the ward level. Job
control accounted for most of this multilevel variation. Thus, this study
demonstrated the significance of individual characteristics and organizational
effects in explaining the mental health and job satisfaction of employees.
PMID- 10784291
TI - Consequences associated with work-to-family conflict: a review and agenda for
future research.
AB - A comprehensive review of the outcomes associated with work-to-family conflict
was conducted and effect sizes were estimated. Atypology was presented that
grouped outcomes into 3 categories: work related, nonwork related, and stress
related. Issues concerning the measurement of work-family conflict were also
discussed. The results demonstrate the widespread and serious consequences
associated with work-to-family conflict. On the basis of the results of the
review, an agenda for future research was provided.
PMID- 10784292
TI - Implementing a stress management training: comparative trainer effectiveness.
AB - Participants who were recruited from various organizations were randomly assigned
to 1 of 2 stress management training (SMT) conditions or an assessment-only
control group. The groups in the 1st SMT condition were led by external clinical
psychologists. The groups in the 2nd SMT condition were led by individuals who
held posts within the organizations involved, referred to as paraprofessionals.
Results show favorable effects of the SMT program both in the short term as well
as at 6-month follow-up. Results showed no serious differences in effectiveness
between trainers. It is argued that, to be effective, the SMT program does not
necessarily have to be given by clinical psychologists only but may instead be
given by individuals from other professional orientations.
PMID- 10784293
TI - Sequence analysis of genes and genomes.
AB - A major step towards understanding of the genetic basis of an organism is the
complete sequence determination of all genes in its genome. The development of
powerful techniques for DNA sequencing has enabled sequencing of large amounts of
gene fragments and even complete genomes. Important new techniques for physical
mapping, DNA sequencing and sequence analysis have been developed. To increase
the throughput, automated procedures for sample preparation and new software for
sequence analysis have been applied. This review describes the development of new
sequencing methods and the optimisation of sequencing strategies for whole genome
and cDNA analysis, as well as discusses issues regarding sequence analysis and
annotation.
PMID- 10784294
TI - Screening hydrolysis over two-phases.
AB - A new assay is described that monitors hydrolysis with the concurrent transfer of
a solvatochromic dye across an oil-water barrier. Through the appropriate design,
this transfer is accompanied by a 10(6) gain in fluorescence. This response can
be used to effectively screen hydrolytic activity at high-throughput. Using this
method, microunits of alkaline phosphatase, glucosidases, as well as several
common proteases can be visually detected within an hour through concentration
over a 200:1 volumetric ratio of aqueous to organic phases. Development of a
water-solublizing protecting group extends this methodology to screen a wide
range of processes that undergo cleavage of a covalent bond.
PMID- 10784296
TI - Carotenoid content of chlorophycean microalgae: factors determining lutein
accumulation in Muriellopsis sp. (Chlorophyta).
AB - Fifteen strains of chlorophycean microalgae have been investigated with regard to
their carotenoid profile. Lutein, beta-carotene and violaxanthin were present in
virtually all of the strains, lutein, in general, being the most abundant
carotenoid, whereas canthaxanthin and astaxanthin were found in some strains
only. Chlorella fusca SAG 211-8b, Chlorococcum citriforme SAG 62.80, Muriellopsis
sp., Neospongiococcum gelatinosum SAG B 64.80 and Chlorella zofingiensis CCAP
211/14 exhibited high lutein levels, the latter strain containing in addition
substantial amounts of astaxanthin. Muriellopsis sp. was further characterized,
since besides a high lutein content (up to 35 mg l(-1) culture), it had the
highest growth rate (up to 0.17-0.23 h(-1)) and maximal standing cell density (up
to 8 x 10(10) cells l(-1) culture). These levels of lutein are in the range of
those reported for astaxanthin in Haematococcus and for beta-carotene in
Dunaliella, microalgae of recognized interest for the production of these
carotenoids. Lutein content of Muriellopsis sp. increased during the exponential
phase of growth, with the highest value being recorded in the early stationary
phase. Maximum levels of lutein in Muriellopsis sp. cultures were recorded at 20
40 mM NaNO3, 2-100 mM NaCl, 460 micromol photon m(-2) s(-1), pH 6.5 and 28
degrees C, conditions which were, in general, also optimal for cell growth.
Growth-limiting conditions, such as pH values of 6 or 9 and a temperature of 33
degrees C, were found to stimulate carotenogenesis in Muriellopsis sp. This
strain represents a potential source of lutein, a commercially interesting
carotenoid of application in aquaculture and poultry farming, as well as in the
prevention of cancer and diseases related to retinal degeneration.
PMID- 10784295
TI - Enzymatic degumming of ramie bast fibers.
AB - Bast fibers from ramie (Boehmeria nivea) were treated with cell-free culture
supernatants from an Amycolata sp. and a recombinant Streptomyces lividans strain
expressing the Amycolata pectate lyase to investigate the degumming effects of
different extracellular polysaccharide-degrading enzymes. Culture supernatants
from the Amycolata sp. with high pectate lyase activities were most effective in
fiber separation and reduced the gum content of ramie fibers by 30% within 15 h.
Xylanase activity produced by the Amycolata sp. contributed little to the
degumming. Electron micrographs showed that the crude pectate lyase from the
Amycolata sp. removed plant gum more efficiently from decorticated ramie bast
fibers than the purified enzyme. Similarly, degumming with the crude enzyme of
the Amycolata sp. and the recombinant S. lividans strain for 24 h resulted in
fibers with a residual gum content of 14.7 and 17.3%, respectively. Degumming
with the crude enzyme of the recombinant Streptomyces strain was slightly
improved by the addition of a commercial pectinesterase. No significant degumming
was observed with the crude enzyme from an S. lividans strain that did not
produce the Amycolata pectate lyase. These results indicate that the pectinolytic
activity of the Amycolata sp. plays an active role in degumming of ramie bast
fibers.
PMID- 10784297
TI - Monitoring cellular state transitions in a production-scale CHO-cell process
using an electronic nose.
AB - An electronic nose is used to monitor the bioreactor off-gas composition in
perfused cultivations of a CHO-cell line producing recombinant human blood
coagulation factor VIII. The applicability of the electronic nose for monitoring
cellular state transitions and process control is explained. It is shown that the
instrument can reveal characteristic process states related to product and
lactate formation, and detect microbial infections in a very early stage of the
infection. The visualization of ideal process conditions is realized by using
principal component analysis (PCA) and the on-line applicability of this method
is outlined. The results illustrate the potential of the electronic nose as on
line sensor for ensuring product and process quality in production-scale
bioprocesses.
PMID- 10784298
TI - Establishment of forskolin yielding transformed cell suspension cultures of
Coleus forskohlii as controlled by different factors.
AB - Suspension cultures derived from gall calli which were obtained following
infection with Agrobacterium tumefaciens (C58) were established in Coleus
forskohlii. Cell line selection following single cell cloning or cell aggregate
cloning was carried out to select cell lines capable of fast growth and for
producing high level of forskolin. A fast growing cell line (GSO-5/7) thus
selected was found to accumulate 0.021% forskolin in 42 days. The effect of
cultural conditions on cell growth was studied to identify factors influencing
biomass yield. Cell growth in suspension was found to be influenced significantly
by carbon source, initial cell density and light or dark condition. Optimal cell
growth (20 fold increase in biomass in a 42 day period) was obtained when the
cells were grown in dark condition in B5O media containing 3% sucrose as sole
carbon source with an initial cell density of 1.5 x 10(5) cells per ml. Forskolin
accumulation was maximum (0.021%) in the stationary phase of cell growth. These
suspension cultures showed continuous and stable production of forskolin.
PMID- 10784299
TI - Anaerobic thermophilic fermentation for acetic acid production from milk
permeate.
AB - Fermentation of milk permeate to produce acetic acid under anaerobic thermophilic
conditions (approximately 60 degrees C) was studied. Although none of the known
thermophilic acetogenic bacteria can ferment lactose, it has been found that one
strain can use galactose and two strains can use lactate. Moorella
thermoautotrophica DSM 7417 and M. thermoacetica DSM 2955 were able to convert
lactate to acetate at thermophilic temperatures with a yield of approximately
0.93 g g(-1). Among the strains screened for their abilities to produce acetate
and lactate from lactose, Clostridium thermolacticum DSM 2910 was found precisely
to produce large amounts of lactate and acetate. However, it also produced
significant amounts of ethanol, CO2 and H2. The lactate yield was affected by
cell growth. During the exponential phase, acetate, ethanol, CO2 and H2 were the
main products of fermentation with an equimolar acetate/ethanol ratio, whereas
during the stationary phase, only lactic acid was produced with a yield of 4 mol
per mol lactose, thus reaching the maximal theoretical value. When this bacterium
was co-cultured with M. thermoautotrophica, lactose was first converted mainly to
lactic acid, then to acetic acid, with a zero residual lactic acid concentration
and an overall yield of acetate around 80%. Under such conditions, only 13% of
the fermented lactose was converted to ethanol by C. thermolacticum.
PMID- 10784300
TI - Revisiting the Glasgow Coma Scale and Coma Score.
PMID- 10784301
TI - A clear view: the way forward for eye care on ICU. Intensive care units.
PMID- 10784302
TI - Glasgow Coma Scale: variation in mortality among permutations of specific total
scores.
AB - OBJECTIVE: The objective of this study was to determine whether different score
permutations of the Glasgow Coma Scale (GCS) giving the same GCS total score were
associated with significantly different mortality. DESIGN: For each GCS total we
compared the mortality associated with each of the different GCS permutations
using a Fisher's exact test. The relationship between components of the GCS score
and mortality was also examined using uni- and multivariate logistic regression.
SETTING: Data were collected from the intensive care unit at Wellington Hospital,
a multidisciplinary, tertiary referral unit. PATIENTS: We analysed the GCS and
mortality data from all admissions over a 4 year period (January 1994-January
1998). Patients with GCS scores of 3 or 15 were excluded, since these two total
scores do not have multiple permutations, leaving 1,390 patients with GCS scores
of 4-14 for analysis. RESULTS: The incidence of mortality was significantly
different for the different permutations for total GCS scores of 7, 9, 11 and 14.
CONCLUSIONS: It is possible for patients to have the same total GCS score, but
significantly different risks of mortality due to differences in the GCS profile
making up that score. This suggests that GCS scores may be more useful reported
in terms of profiles rather than totals. This could also have implications for
the use of other scoring systems such as Acute Physiology and Chronic Health
Evaluation and Simplified Acute Physiology Score.
PMID- 10784303
TI - Eye care for the critically ill.
AB - PURPOSE: To evaluate the effectiveness and efficiency of an algorithm in the
prevention of ocular surface disease in sedated and unconscious patients in the
intensive care unit (ICU). METHODS: The eyes of all sedated and unconscious
patients admitted to an ICU between September and December 1998 were managed
according to an eye care algorithm. The applications of the preventive measures
were assessed by a single observer twice weekly. The lid position, the presence
and degree of keratopathy, sedation score, and the treatment received were
documented at every assessment. RESULTS: Thirty-four patients were recruited for
management according to the eye care algorithm over a period ranging from 1 to 28
days. Four patients were excluded because of failure by staff to adhere to the
protocol. In 18 patients no active treatment was required. Out of six patients
who had conjunctival exposure and were given ocular lubricants, four maintained
clear corneas. No corneal or conjunctival staining was noted in two of the four
patients whose lids required closure with Micropore tape for corneal exposure.
Use of lid taping and lubricants prevented corneal abrasion in two patients who
were prone ventilated. The prevalence of ocular surface abnormalities was 8.7 %
where the algorithm was properly followed (23 patients). CONCLUSION: The proposed
eye care algorithm appears to be effective in preventing ocular surface
abnormalities in the sedated and unconscious patients in the ICU, and efficient
in that it may reduce the workload required for critically ill patients.
PMID- 10784304
TI - Incidence and mortality of severe sepsis in surgical intensive care patients: the
influence of patient gender on disease process and outcome.
AB - OBJECTIVE: Laboratory studies demonstrated significant detrimental effects of
male sex-steroids (testosterone) on immune functions following hemorrhagic shock
and soft-tissue trauma. Moreover, better survival of female mice subjected to
severe sepsis was observed when compared to male animals. The aims of the present
study were to evaluate whether or not gender differences regarding incidence and
mortality of severe sepsis do exist in surgical intensive care patients and to
elucidate the influence of patient age on incidence and mortality of severe
sepsis/septic shock. DESIGN: Data base review of prospectively collected data
from surgical intensive care patients. SETTING: Surgical intensive care unit of
the department of surgery of a university hospital. PATIENTS: Prospectively
collected data of 4,218 intensive care patients (2,709 male, 1,509 female).
RESULTS: Significantly fewer female patients were referred to the intensive care
unit (6.6 % vs 10.8 % of all patients; P < 0.05) leading to a significantly
smaller proportion of female intensive care patients (35.8% vs 64.2%). No gender
differences regarding number of failing organs or surgical procedure (exception
vascular surgery) were observed in patients with and without severe sepsis/septic
shock, indicating that the patients studied are comparable regarding general
health prior to admission to SICU. Among all female patients referred to SICU
only 7.6 % developed severe sepsis/septic shock, while 10.4% of all male patients
suffered from severe sepsis or septic shock (P < 0.05). This gender difference
results from a significantly lower incidence of severe sepsis/ septic shock in
female patients between 60 and 79 years. No gender difference regarding mortality
rates of severe sepsis/septic shock was observed (men 64.9 %, women 65.5%).
CONCLUSIONS: Our results indicate a significantly smaller number of female
patients requiring intensive care as well as a significantly lower incidence of
severe sepsis/septic shock in female intensive care patients. Mortality from
severe sepsis/ septic shock, however, is not affected by gender.
PMID- 10784305
TI - Monitoring the circulatory responses of shocked patients during fluid
resuscitation in the emergency department.
AB - OBJECTIVES: To assess the feasibility of constructing left ventricular response
curves non-invasively during the fluid resuscitation of critically ill patients
in the emergency department (ED) using a portable suprasternal Doppler ultrasound
(PSSDU) device. DESIGN: Prospective case series. SETTING: Emergency department,
Catholic University of Leuven, Belgium. PATIENTS: Shocked patients in the ED were
diagnosed by predefined criteria. Only those thought to require standardised
intravenous colloid challenges were observed i. e., sequential boluses of 3.5
ml/kg/10 min titrated against changes in stroke distance (Doppler surrogate for
left ventricular stroke volume). RESULTS: A total of 50 shocked patients were
studied. Stroke distance was measurable in 45 patients. 35 patients were fluid
responders in terms of stroke distance. Group mean stroke distance increased
during resuscitation (8.6 +/- 4.1 cm to 19.5 +/- 4.6 cm, P < 0.001) and then
reached a plateau value (19.6 +/- 4.6 cm, P = 0.488). No response to fluid was
seen in nine patients of which eight had severe sepsis. Alternative therapeutic
approaches increased stroke distance for all of these patients. Evidence for
right ventricular dysfunction was found as a cause for fluid non-response in the
majority of patients with sepsis. CONCLUSIONS: Previous experimental work has
shown that changes in central blood flow can be derived using the PSSDU device.
This clinical feasibility study suggests that the PSSDU can help tailor
haemodynamic therapy for an individual patient and give an early indication of
treatment failure in the ED.
PMID- 10784306
TI - Assessment of cardiac preload and extravascular lung water by single
transpulmonary thermodilution.
AB - OBJECTIVE: Transpulmonary double-indicator dilution is a useful monitoring
technique for measurement of intrathoracic blood volume (ITBV) and extravascular
lung water (EVLW). In this study, we compared a simpler approach using single
arterial thermodilution derived measurements of ITBV and EVLW with the double
indicator dilution technique. DESIGN: Prospective observational clinical study.
SETTING: Surgical intensive care units of two university hospitals. PATIENTS AND
METHODS: Global end-diastolic volume (GEDV) derived from single thermodilution
was used for calculation of ITBV. Structural regression analysis of the first two
thermo-dye dilution measurements in a derivation population of 57 critically ill
patients (38 male, 19 female, 18-79 years, 56 +/- 15 years) revealed ITBV = (1.25
x GEDV)-28.4 (ml). This equation was then applied to all first measurements in a
validation population of 209 critically ill patients (139 male, 70 female, 10-88
years, mean 53 +/- 19 years), and single-thermodilution ITBV (ITBV(ST)) and EVLW
(EVLW(ST)) was calculated and compared to thermo-dye dilution derived values
(ITBV(TD), EVLW(TD)). For inter-individual comparison, absolute values for ITBV
and EVLW were normalised as indexed by body surface area (ITBVI) and body weight
(EVLWI), respectively. MEASUREMENTS AND RESULTS: Linear regression analysis
yielded a correlation of ITBVI(ST) = (1.05 x ITBVI(TD))-58.0 (ml/m2), r = 0.97, P
< 0.0001. Bias between ITBVI(TD) and ITBVI(ST) was 7.6 (ml/m2) with a standard
deviation of 57.4 (ml/m2). Single-thermodilution EVLWI (EVLWI(ST)) was calculated
using ITBVI(ST) and revealed the correlation EVLWI(ST) = (0.83 x EVLWI(TD)) + 1.6
(ml/kg), r = 0.96, P < 0.0001. Bias between EVLWI(TD) and EVLWI(ST) was -0.2
(ml/kg) with a standard deviation of 1.4 (ml/kg). In detail, EVLWI(ST)
systematically overestimated EVLWI(TD) at low-normal values for EVLWI and
underestimated EVLWI at higher values (above 12 ml/kg). CONCLUSION:
Determinations of ITBV and EVLW by single thermodilution agreed closely with the
corresponding values from the double-indicator technique. Since transpulmonary
single thermodilution is simple to apply, less invasive and cheaper, all these
features make it a promising technique for the bedside. Nevertheless, further
validation studies are needed in the future.
PMID- 10784307
TI - Inhaled prostacyclin and platelet function after cardiac surgery and
cardiopulmonary bypass.
AB - OBJECTIVE: To study the effects of 6 h inhalation of aerosolized prostacyclin
(PGI2) on platelet function. DESIGN: In a prospective, double-blind, randomized
study, 28 patients scheduled for elective cardiac surgery requiring
cardiopulmonary bypass (CPB), received either 0.9% sodium chloride (n = 8), PGI2
5 microg x ml(-1) (n = 10) or PGI2 10 microg x ml(-1) (n = 10) as an aerosol for
6 h postoperatively. SETTING: Cardiothoracic intensive care unit at a university
hospital. INTERVENTIONS: All patients were studied immediately after surgery
during mechanical ventilation and sedation. The PGI2 solutions or saline were
administered with a jet nebulizer. MEASUREMENTS AND RESULTS: Bleeding time and
chest tube drainage were measured. Blood samples for platelet aggregation,
thrombelastography (TEG) and analysis of coagulation parameters and the stable
prostacyclin metabolite 6-keto-PGF1alpha were obtained immediately before
inhalation and after 2, 4 and 6 h of inhalation. After 6 h of PGI2 inhalation,
regardless of administered dose, there was a lower rate of platelet aggregation
and a lower maximal increase in light transmission in response to adenosine
diphosphate (ADP) than in the control group. The TEG variable reaction time (R)
was prolonged after 4 and 6 h of inhalation in the PGI2 group receiving 10 microg
x ml(-1). There were no differences between groups with respect to bleeding time
and chest tube drainage or any of the other variables examined. CONCLUSION:
Inhalation of PGI2 for 6 h in patients after cardiac surgery is associated with
impaired platelet aggregation detected by in vitro techniques, with no in vivo
signs of platelet dysfunction.
PMID- 10784308
TI - Experiences with severe P. falciparum malaria in the intensive care unit.
AB - OBJECTIVE: To review the clinical profiles and therapies instituted for patients
with severe malaria admitted to an ICU. DESIGN: Retrospective study. SETTING:
Internal ICU of a tertiary care centre. PATIENTS AND PARTICIPANTS: Between
January, 1992, and February, 1999, 104 patients with malaria were admitted to the
General Hospital of Vienna. Sixty-nine patients suffered from Plasmodium
falciparum malaria (66%), seven of these were admitted to the ICU. MEASUREMENT
AND RESULTS: Seven patients were admitted to the ICU, of whom three died (4% in
hospital case-fatality rate). Four patients required mechanical ventilation
because of respiratory insufficiency and adult respiratory distress syndrome
(ARDS), of whom three died. Three patients were treated with inhaled nitric oxide
(NO) and kinetic therapy; one patient required extracorporeal veno-venous
oxygenation. All patients who died required haemofiltration because of acute
renal failure. CONCLUSION: As P. falciparum is a potentially life-threatening
disease, reliable criteria for ICU admission should be defined and risk factors
identified. Early ICU monitoring should be attempted, especially under the
following conditions: (1) lack of clinical response to anti-malarial treatment
within 48 h and/or (2) any signs of neurological disturbance (hypoglycaemia
excluded). Prospective multicentre trials and guidelines for supportive intensive
care are urgently needed.
PMID- 10784309
TI - Cerebral blood flow and metabolism in severe brain injury: the role of pressure
autoregulation during cerebral perfusion pressure management.
AB - OBJECTIVE: To ascertain if norepinephrine can be used as part of the cerebral
perfusion pressure (CPP) management to increase arterial blood pressure (MAP)
without causing cerebral hyperemia after severe head injury (HI). DESIGN:
Prospective, interventional study. SETTING: Intensive care unit in a university
hospital. PATIENTS: Twelve severely HI patients; median Glasgow Coma Scale was 6
(range 3-8). INTERVENTIONS: CPP management ( = 70 mmHg). Pressure autoregulation
(assessed by norepinephrine infusion) was defined intact if % CPP/%CVR < or = 2.
RESULTS: Cerebral blood flow (CBF: Xe133 inhalation technique), jugular bulb
oxygen saturation (SjO2) and transcranial Doppler (TCD) were recorded during the
test. Norepinephrine increased CPP by 33 % (+/- 4). Autoregulation was found to
be intact in ten patients and defective in two. In the ten patients with
preserved autoregulation, CBF decreased from 31 +/- 3 to 28 +/- 3 ml/ 100 g/min;
in the two patients with impaired autoregulation CBF increased respectively from
16 to 35 and from 21 to 70 ml/100 g/min. SjO2 did not change significantly from
baseline. TCD remained within the normal range. CONCLUSIONS: During CPP
management norepinephrine can be used to increase MAP without potentiating
hyperemia if pressure autoregulation is preserved. The assessment of pressure
autoregulation should be considered as a guide for arterial pressure-oriented
therapy after HI.
PMID- 10784310
TI - Sonoclot signature during normal pregnancy.
AB - OBJECTIVE: The Sonoclot analyser provides global measurement of haemostasis,
including plasma coagulation, platelet function and fibrinolysis. Benefits of its
use in cardiovascular and hepatic surgery are well-documented and it may be
useful in managing obstetric complications. The aim of this study was to
determine ranges of the Sonoclot variables for normal pregnancy. DESIGN:
Prospective and longitudinal study. SETTING: Antenatal outpatient clinic,
university hospital. PATIENTS: Forty-seven healthy women were studied; forty-two
completed normal pregnancies and gave birth to healthy infants. INTERVENTIONS:
None. MEASUREMENTS AND RESULTS: Sonoclot signatures were performed at 10-15, 32
34 and 38-40 weeks of gestation and at 8 weeks postpartum. Haemoglobin
concentration, haematocrit, platelet count, fibrinogen and activated partial
thromboplastin time (APTT) were analysed with normal results. Sonact time and
peak time were significantly decreased and clot rate and secondary rate were
significantly increased during pregnancy compared with 8 weeks postpartum,
indicating hypercoagulability. There were no significant changes in these
variables during pregnancy. There were no changes in peak amplitude and downward
rate. A significant correlation was found between sonact time and APTT, and
between clot rate and APTT. CONCLUSIONS: We found the Sonoclot analyser simple to
handle and the signatures easy to interpret. The ranges for the Sonoclot
variables apply throughout pregnancy. The ranges for sonact time, clot rate,
secondary rate and peak time during pregnancy differed from the ranges at 8 weeks
postpartum.
PMID- 10784311
TI - Trimethoprim-sulfamethoxazole-induced aseptic meningitis: case report and
literature review.
AB - Aseptic meningitis is a rare adverse drug reaction, reported with non-steroidal
anti-inflammatory agents (NSAIDs) and with miscellaneous drugs such as
trimethoprim-sulfamethoxazole (TMP-SMX). The most common clinical findings
reported are fever, headache, stiffness and altered level of consciousness. We
report a case of aseptic meningitis related to TMP-SMX ingestion that caused
severe derangements of the patient's vital signs, requiring Intensive Care Unit
admittance. The prompt diagnosis and discontinuation of the drug resulted in
complete recovery. We examine the case according to the literature on this topic.
We conclude that, since the signs and symptoms of this unusual drug reaction may
mimic those of central nervous system infection, the clinician should consider
this etiology when he is faced with a patient with suspected meningoencephalitis,
especially if the latter has already been treated at home with unknown drugs.
Further studies should investigate the pathogenetic mechanism of TMP-SMX-induced
aseptic meningitis.
PMID- 10784312
TI - Zinc chloride smoke inhalation: a rare cause of severe acute respiratory distress
syndrome.
AB - Zinc chloride smoke inhalation is a rare cause of slowly progressive and often
fatal acute respiratory distress syndrome (ARDS). The conventional treatment
includes intravenous N-acetylcysteine, L-3, 4-dehydroproline, methylene blue, and
respiratory support according to the lung protective strategy. This report
presents the cases of three patients with serious zinc chloride inhalation and
ARDS, the last of whom survived after prolonged intensive care,
videothoracoscopic excision of emphysema bullae, and recurrent chemical
pleurodesis.
PMID- 10784313
TI - Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis.
AB - Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia (EDTA-PTCP) is
the phenomenon of a spurious low platelet count due to antiplatelet antibodies
that cause platelet clumping in blood anticoagulated with EDTA. We describe a
case of EDTA-PTCP that appeared transiently with the development of sepsis. A 50
year-old man underwent Bentall's aortic root replacement for acute aortic
dissection with aortic insufficiency. Postoperatively the patient suffered
paralytic ileus followed by methicillin-resistant Staphylococcus aureus enteritis
and septicemia with endotoxemia. EDTA-PTCP appeared with the development of
sepsis, and disappeared with its resolution. To avoid incorrect diagnoses and
inappropriate treatment, EDTA-PTCP should always be considered as a possible
cause of reported low platelet counts, even in patients with sepsis.
PMID- 10784314
TI - Effect of inhaled nitric oxide in combination with almitrine on ventilation
perfusion distributions in experimental lung injury.
AB - OBJECTIVE: To investigate a possible additive effect of combined nitric oxide
(NO) and almitrine bismesylate (ALM) on pulmonary ventilation-perfusion (V(A)/Q)
ratio. DESIGN: Prospective, controlled animal study. SETTING: Animal research
facility of a university hospital. INTERVENTIONS: Three conditions were studied
in ten female pigs with experimental acute lung injury (ALI) induced by repeated
lung lavage: 1) 10 ppm NO, 2) 10 ppm NO with 1 microg/kg per min ALM, 3) 1
microg/ kg per min ALM. For each condition, gas exchange, hemodynamics and V(A)/Q
distributions were analyzed using the multiple inert gas elimination technique
(MIGET). MEASUREMENT AND RESULTS: With NO + ALM, arterial oxygen partial pressure
(PaO2) increased from 63 +/- 18 mmHg to 202 +/- 97 mmHg while intrapulmonary
shunt decreased from 50 +/- 15 % to 26 +/- 12% and blood flow to regions with a
normal V(A)/Q ratio increased from 49 +/- 16 % to 72 +/- 15 %. These changes were
significant when compared to untreated ALI (p < 0.05) and NO or ALM alone (p <
0.05), although improvements due to NO or ALM also reached statistical
significance compared to ALI values (p < 0.05). CONCLUSIONS: We conclude that NO
+ ALM results in an additive improvement of pulmonary gas exchange in an
experimental model of ALI by diverting additional blood flow from non-ventilated
lung regions towards those with normal V(A)/Q relationships.
PMID- 10784316
TI - Meta-analyses versus randomised controlled trials in intensive care medicine.
PMID- 10784315
TI - Mitigation of endotoxin-induced acute lung injury in ventilated rabbits by
surfactant and inhaled nitric oxide.
AB - OBJECTIVE: To evaluate the efficacy of surfactant and inhaled nitric oxide (iNO)
in endotoxin-induced acute lung injury (ALI). DESIGN: Prospective, randomised,
controlled experimental study. SETTING: A medical university hospital research
laboratory. INTERVENTION: Twenty-nine adult rabbits (2.4-3.4 kg) were given two
doses of intravenous endotoxin (Escherichia coli) (0.01 mg/kg and, 12 h later,
0.1 mg/kg), and then subjected to mechanical ventilation. After 8 h these animals
were allocated to four treatment groups: (1) control, (2) iNO at 20 ppm (NO), (3)
surfactant at 100 mg/kg (Surf) and (4) both surfactant and iNO as in groups 2 and
3 (SNO), and ventilated for a further 6 h followed by broncho-alveolar lavage
(BAL), analysis of surfactant contents in BAL fluid and histological examination
of the lungs. MEASUREMENTS AND RESULTS: All the animals had developed ALI with
respiratory failure 8 h after the second dose of endotoxin as evidenced by a
decrease of PaO2/FIO2 from 520 +/- 30 to 395 +/- 19 mmHg and dynamic compliance
(Cdyn) from 1.20 +/- 0.11 to 0.73 +/- 0.05 ml/ cmH2O x kg, and an increase of
intrapulmonary shunting (Qs/Qt) from 7.5 +/- 0.8% to 12.9 +/- 1.0% (all
measurements p < 0.01 versus baseline). In the SNO group, values for PaO2/FIO2,
Cdyn and Qs/Qt after 6 h were 301 +/- 15 mmHg, 0.67 +/- 0.05 ml/cmH2O x kg and
16.5 +/- 0.8%, compared to 224 +/- 26 mmHg, 0.53 +/- 0.04 ml/ cmH2O x kg and 24.1
+/- 2.0%, respectively, in the control group (all measurements p < 0.01). Both
Surf and NO groups showed intermediate levels of these parameters. In both Surf
and SNO groups, the minimum surface tension of BAL fluid was lower, and the
content of disaturated phosphatidylcholine/total protein higher, than in the
control and NO groups (p < 0.01). Histological features of lung injury were less
prominent and wet/dry lung weight ratio lower in the NO, Surf and SNO groups.
Decreased surfactant protein A (SP-A) and its mRNA expression were found in all
endotoxin-exposed groups, but the SP-A content of the SNO group was moderately
improved in comparison to the control group. Surfactant aggregate size was not
affected. CONCLUSION: Early application of surfactant and iNO moderately
mitigated ALI as reflected by improvement of lung mechanics, pulmonary perfusion
and morphology.
PMID- 10784317
TI - Non-invasive ventilation in acute hypoxemic respiratory failure.
PMID- 10784318
TI - Anti-microbial or antiseptic impregnated central venous catheters: update on a
"central" debate.
PMID- 10784319
TI - Neck ties as vectors for nosocomial infection.
PMID- 10784320
TI - Primary heart angiosarcoma: an infrequent cause of acute respiratory failure.
PMID- 10784321
TI - Acute myocardial infarction with normal coronary arteries during septic shock
from Neisseria meningitidis.
PMID- 10784322
TI - Pericardial effusion: a rare complication of thermal burn.
PMID- 10784323
TI - Carcinoid crisis during transesophageal echocardiography.
PMID- 10784324
TI - Successful resuscitation using nitroglycerin for refractory pulseless electrical
activity in intensive care unit.
PMID- 10784325
TI - Esmolol in the treatment of severe arrhythmia after acute trichloroethylene
poisoning.
PMID- 10784326
TI - Life-threatening magnesium toxicity.
PMID- 10784327
TI - A very early onset of respiratory failure due to phenytoin-associated
hypersensitivity syndrome and concomitant glucocorticoid administration.
PMID- 10784328
TI - Hypocholesterolemia in critically ill patients.
PMID- 10784329
TI - Oral health status of patients 5-6 years after placement of cobalt-chromium
removable partial dentures.
AB - This study is a clinical survey of cobalt-chromium (Co-Cr) removable partial
denture (RPD) wearers that aimed to investigate the effects of denture wearing on
oral tissues. A random sample of patients who had received their dentures 5-6
years previously from a dental teaching hospital in Hong Kong was selected. Those
who had been constantly wearing the RPDs were examined by one calibrated examiner
under an optimal clinical setting. The patients' dental, periodontal and mucosal
status were assessed. A total of 87 patients were examined. Mucosal lesions under
the Co-Cr RPDs were uncommon in this study sample. However, there was a high
prevalence of plaque, gingivitis and gingival recession, especially in dento
gingival surfaces in close proximity (within 3 mm) to the dentures. Thus, there
is a special need for regular oral hygiene reinforcement, scaling and prophylaxis
among RPD wearers. Despite a low caries incidence in the study sample, root
caries were found to be associated with contact with the RPDs (P < 0.05) but
coronal caries were not. It is recommended that coverage of the exposed root
surfaces by RPD components should be avoided. Also, topical fluorides should be
regularly applied onto exposed root surfaces as a preventive measure.
PMID- 10784330
TI - Degradation of repaired denture base materials in simulated oral fluid.
AB - This in vitro study evaluates the degradation of repaired denture bases upon
immersion in a simulated oral fluid. Denture base materials (Luciton 199), after
being repaired by Repair Material and Triad, using three different joint surface
designs (butt, round and 45 degrees bevel), were immersed onto 99.5 vol.%
ethanol/water solution (with similar solubility parameter) for various amounts of
time (0-72 h). The flexural loads of the six combination of groups were measured
by the three-point bending tests using a universal testing machine. Acoustic
emission (AE) during sample fracturing were processed using the MISTRA 2001
system. The fracture pattern and surface details of the interface were examined
with a scanning electronic microscope (SEM). Data were analysed using three-way
ANOVA and Tukey LSD tests. SEM micrographs of the fracture interface were used to
differentiate the fracture mode. The flexural loads (2.72 +/- 0.51 Kgf) of the
round joint specimens were significantly higher (P< 0.05) than those (butt: 1.66
+/- 0.38 Kgf, 45 degrees bevel: 1.93 +/- 0.41 Kgf) of the other two designs. This
corresponds to the microscopic examination in which more cohesive failure mode
was found for the round joint group after storage. The flexural loads (2.54 +/-
0.39 Kgf) of the specimens repaired with Triad were significantly higher (P <
0.05) than those (1.59 +/- 0.40 Kgf) of specimens repaired with Repair Material.
Significant progressive reduction of the flexural load and/or AE signals of the
specimens was noted in proportion to the length of time of the immersion in the
simulated oral fluid. Mechanical strength of a denture base repaired with a round
joint design and light-cured material is significantly higher after immersion in
simulated oral fluid.
PMID- 10784331
TI - Tooth loss and the condition of the prosthodontic appliances in a group of
elderly home residents.
AB - The study assessed the number of missing teeth, the state of the existing
prosthodontic appliances and the need for their replacement. Dental status and
anamnesis were taken on a group of 120 elderly home residents by trained
examiners. Prosthodontic appliances were evaluated according to the Karlsson's
index for the crowns and bridges, and according to the modified Nevalainen et al.
index for the evaluation of the complete dentures, as well as the need for
prosthetic treatment. The most persistent teeth in both jaws were lower canines,
while the most commonly missing teeth were lower first molars. On average, the
crowns were older and in poorer condition than the bridges. Lower complete
dentures had better stability but were also less retentive in comparison with the
upper complete dentures. More than 82% of the subjects were in need of either
fixed, removable or combined prosthodontic treatment. The high prevalence of
needs for prosthodontic treatment pointed to the requirement for frequent dental
check ups within elderly home residents in order to better identify and meet
their dental needs.
PMID- 10784332
TI - The effect of polishing systems on microleakage of tooth-coloured restoratives.
Part 2: composite and polyacid-modified composite resins.
AB - The purpose of this in vitro study was to investigate the effect of polishing
systems on the microleakage of composite and polyacid-modified composite resins.
Class V cavities were prepared at the cemento-enamel junction of 80 freshly
extracted posterior teeth. The prepared teeth were randomly divided into two
groups and restored with conventional or polyacid-modified composite resins. The
restored teeth were stored in distilled water at 37 degrees C for 1 week after
removal of excess restorative with diamond finishing burs. The restored teeth
were then divided into four groups of ten and finished/polished using the
following systems: Two Striper micron finishing system (MFS), Sof-Lex XT (Sof
Lex), Enhance composite finishing and polishing system (Enhance), and Shofu
composite finishing kit (Shofu). The finished restorations were subjected to dye
penetration testing. Results showed that the microleakage resistance at both
enamel and dentin margins of composite and polyacid-modified composite resins are
not significantly affected by the different polishing systems.
PMID- 10784333
TI - Reliability of some clinical parameters of evaluation in implant dentistry.
AB - Clinical tests that are commonly used to evaluate tissues surrounding natural
teeth are also used in implant dentistry. It is unclear if they are equally valid
and reflect the condition of the bone surrounding an implant reliably. This study
evaluates the use of a plaque index, a gingiva index, the assessment of a probing
depth and the Periotest value and relates the findings to the image on a
radiograph in 16 patients, involving 32 IMZ implants. All four clinical tests
showed poor sensitivity and, in general, only fair specificity when observations
from the image on the radiograph were interpreted as the 'golden standard' for
the presence or absence of pathology adjacent to the implant. Frequently, based
on any clinical parameter, disease was not diagnosed, while the radiograph did
show pathological loss of bone at the bone-implant contact area. It is concluded
that the aforementioned parameters are unreliable and unfit for clinical
evaluation in implant dentistry. Radiographs are needed to evaluate critical
marginal bone changes surrounding dental implants.
PMID- 10784334
TI - Intercondylar width as a guide to setting up complete denture teeth.
AB - A clinical study was designed to investigate the relationship between
intercondylar width (ICW) and inter-dental widths of the upper and lower canines
and first molars to aid in denture teeth positioning. The study was divided into
two parts so that the results of the first part could be verified in the second
part. In the first part, 27 adult subjects were selected according to the
exclusion criteria of the study. A kinematic hinge axis locator was used to
locate the true point of condylar rotation. The distance between these points was
considered to be the ICW. A strong correlation was found between ICW and
interdental measurements, with ICW and upper first molars being the strongest
(r=0.612, P= 0.004). A set of indices developed from the results was recommended
for the positioning of complete denture teeth. In the second part of the study,
inter-dental measurements were estimated using the indices obtained in the first
part. The estimated inter-dental widths showed no significant differences
compared with the real widths (P= 0.109, P=0.849, P=0.353, P=0.41). Based on the
results of this study, ICW measurements can be used for setting up canines and
first molars in complete dentures.
PMID- 10784335
TI - Wireless optoelectronic recordings of mandibular and associated head-neck
movements in man: a methodological study.
AB - Human mandibular movements in space are the result of combined motions of the
mandible and the head-neck. They can be simultaneously monitored by an
optoelectronic recording technique via markers at different locations on the
mandible and on the head. Markers can be attached to the teeth or to the facial
skin. Mandibular movements relative to the head can be calculated by one- or
three-dimensional (1D and 3D, respectively) mathematical compensation for head
movements. The present study analysed mandibular and associated head movements
during maximal jaw opening-closing tasks in 10 healthy subjects using a wireless
3D optoelectronic movement recording system. The study aimed to: (i) estimate the
soft tissue related displacement of skin-attached markers at different locations
on the face; (ii) compare 1D with 3D mathematical compensation for associated
head movements; (iii) evaluate the influence of marker location on the recorded
head and mandibular movement amplitudes; and (iv) compare skin-attached markers
with teeth-attached markers with regard to temporal estimates of recorded
mandibular and head movements. Markers were attached to the upper and lower
incisors and to the skin of the forehead, nose-bridge, nose-tip and chin. Soft
tissue related displacement of skin-attached markers varied between locations.
The displacement for the chin marker was larger than that of other markers. The
least displacement was found for the nose-bridge marker. However, relative to
mandibular and head movements, respectively, the displacement of the chin marker
was of the same order as that of the nose-bridge marker. The temporal estimates
were not significantly affected by displacement of the skin-attached markers.
Markers at different locations on the head and the mandible registered different
amplitudes. The mandibular movement patterns calculated by 1D and 3D compensation
were not comparable. It is concluded that markers attached to the chin and the
nose-bridge can be reliably used in temporal analyses of mandibular and head
movements during maximal jaw opening-closing. With certain limitations, they are
acceptable for spatial analyses. Selection of method of marker attachment, marker
location, and method of compensation for associated head movements should be
based on the aim of the study.
PMID- 10784336
TI - Influence of clenching level on intercuspal contact area in various regions of
the dental arch.
AB - The purpose of this study was to evaluate the relationship between the clenching
level and the intercuspal contact area in different regions of the dental arch.
Twenty-five healthy subjects with natural normal dentitions and good occlusal
support performed clenching tasks in the intercuspal position at four different
levels (10, 30, 70 and 100% levels of maximum voluntary contraction) through EMG
visual feedback from bilateral masseter and anterior temporal muscles.
Simultaneously, the occlusal contacts were recorded with a silicone occlusal
contact checking material (Black Silicone, GC Dental Industrial Corp., Tokyo,
Japan). The occlusal records were analysed by an image analyser. Every area of
the thickness less than 50 microm was determined to be an occlusal contact area.
The occlusal contact areas on the anterior teeth (incisors and canines), the
premolars (first and second premolars) and the molars (first and second molars)
were calculated separately. The posterior occlusal contact area increased with an
increase in the clenching levels but that of the anterior did not. The results of
this study indicate that the increase in clenching forces affects the anterior
and posterior occlusal contact areas differently.
PMID- 10784337
TI - Development of a new device for recording condylar head movement.
AB - Several excellent devices have recently been developed to precisely record
mandibular movement. However, these devices are not always suitable for use under
certain conditions, such as during sleep, because they incorporate a face bow
unit. We report here a newly developed, easy and convenient recording device that
does not require the use of an instrument within the mouth. Instead, a
subminiature pressure transducer is inserted between the outer surface of a
fixation device in the external auditory meatus and the anterior cutaneous
surface of the external auditory meatus. The fixation device was made using
silicone impression material in the shape of the inner external auditory meatus.
Following moulding, the material was cut in half and the parts were reconnected
using a coiled spring. This method is based on a routine clinical method for
palpating the external auditory meatus to observe condylar head movement. By
comparing the results obtained using this device with those obtained using
CADIAX, we confirmed that it is useful for recording the movement of the condylar
head in routine clinical examinations.
PMID- 10784338
TI - The effects of different additives on the dielectric relaxation and the dynamic
mechanical properties of urethane dimethacrylate.
AB - The polymer-filler interaction of a dental composite was examined by dielectric
measurements to determine how a non-compatible inorganic phase modifies the
molecular behaviour of the polymer chains and how modification of this phase by
silanation can affect these molecular behaviours. Urethane dimethacrylate (UDMA)
monomer and zirconia-silica (ZS) powder were used as organic and inorganic
phases, respectively. 3-Acryloxypropyltrimethoxysilane (MAPM) and 4
aminobutyltriethoxysilane (ABTE) were used as silanating coupling agents. The
components of the composite were mixed in different ratios after treating the
filler with from 0 to 30 times the minimum uniform coverage with the silane, then
the composite was made into thin films. The dielectric spectra of five replicas
for each filler-monomer ratio were measured, and three replicas were measured for
each silane and for each amount of silane used to treat the filler. Increasing
the filler concentration in the composites decreased the intensity of
Tan(delta)epsilon for the alpha- and beta-relaxations, where the beta-relaxations
also became broader and the alpha-relaxations were totally obstructed. The alpha
relaxations were shifted to higher temperatures, while the beta-relaxations were
shifted to lower temperatures. Filler treatment with small amounts of MAPM
shifted the alpha-relaxations to higher temperatures; they were shifted back to
lower temperatures when the filler was treated with large amounts of silane.
Filler treatment with large amounts of ABTE (30-fold) caused an extra peak to
emerge in the high-temperature region. It can be concluded that increasing filler
concentration restricts the mobility of the main chains and decreases the
thickness of the surface layer, while allowing more movement of the local chains.
Filler treatment with MAPM was shown to be a compatible coupling agent with the
ZS and the UDMA systems. Such compatibility was observed through the
effectiveness of the chemical linkage of the silane to the filler and the polymer
without forming a separate inter-phase. Filler treatment with ABTE was shown to
be an incompatible coupling agent for the ZS-filled UDMA system. The
incompatibility was observed by the occurrence of a new peak that characterizes
an inter-phase.
PMID- 10784339
TI - Streptococcus mutans in saliva of normal subjects and neck and head irradiated
cancer subjects after consumption of honey.
AB - The antibacterial activity of natural honey consumption has been examined in
patients suffering from head and neck cancer who developed hyposalivation
following irradiation treatment. Enumeration of total bacteria and streptococcus
mutans was carried out in saliva of the patients and of a normal volunteer group
before and after honey consumption. Total bacteria count was not significantly
different between both groups, whereas the streptococcus mutans count decreased
significantly in the experimental group following honey consumption.
PMID- 10784340
TI - Nuclear pore function viewed with atomic force microscopy.
AB - In this review we focus on studies using atomic force microscopy (AFM) to
describe the function of nuclear pore complexes (NPC). After a short introduction
of AFM we follow the route of cargo molecules from the cytosol into the nucleus.
AFM visualizes cargo before translocation into the nucleoplasm, cargo docking at
the cytoplasmic NPC surface, cargo passing through the NPC and changes in NPC
conformation in response to ATP, Calcium and pH. We discuss AFM experiments on
nuclear envelopes on the basis of previous data obtained with more conventional
techniques such as electron microscopy, confocal microscopy and other imaging
techniques. Finally we draw attention to the recently developed nuclear hourglass
technique that serves as a new electrophysiological approach to studying the
structure-function relationship of NPC in combination with AFM at a molecular
level.
PMID- 10784341
TI - NaCl transport deficiencies--hemodynamics to the rescue.
AB - Hereditary defects in the renal handling of filtered NaCl and water have
important implications for understanding the physiological mechanisms that enable
the kidney to optimize the match between glomerular filtration rate and tubular
reabsorption. Null mutations in the water channel aquaporin 1 (AQP1) or the Na/H
exchanger NHE3, two major fluid transporters in the proximal tubule, are states
in which a reduction in proximal fluid absorption is accompanied by proportionate
decrements in glomerular filtration rate. Compensation of the transport defect by
a reduction in filtered load is so efficient that clinically symptomatic Na
losses are not observed in either AQPI or NHE3 deficiency. On the other hand,
severe syndromes of salt wasting are caused by transport deficiencies in the
thick ascending limb or the collecting duct, indicating that the severity of Na
dysregulation is unrelated to the basal absorption of NaCl in a given nephron
segment. Loss of function of the Na,K,2Cl-cotransporter (NKCC2) or of the
epithelial Na channel (ENaC) reduces Na absorption in thick ascending limbs or
collecting ducts. In these states, the increased delivery of Na to downstream
segments is not monitored by a sensor linked to the site of filtrate formation.
In the absence of adaptations in the filtered load, intrarenal compensation of a
circumscribed NaCl malabsorption by adjustment of NaCl transport in other nephron
segments is remarkably insufficient, particularly in the immature kidney of the
newborn.
PMID- 10784342
TI - Effects of the dihydropyridine receptor subunits gamma and alpha2delta on the
kinetics of heterologously expressed L-type Ca2+ channels.
AB - Ba2+ currents through L-type Ca2+ channels were measured in tsA201 cells
transiently transfected with expression vectors encoding the dihydropyridine
(DHP) receptor subunits alpha1C, beta1a-GFP, alpha2delta and gamma. The subunit
effect on channel function was studied by omitting either alpha2delta or gamma
from the transfection mixture and analyzing the voltage dependence and kinetics
of activation, inactivation and recovery from inactivation. Activation could be
described by a single exponential function while the time course of inactivation
of the Ba2+ current followed a double exponential function. Progressively longer
depolarization led to increasingly slower recovery, indicating the successive
occupancy of several inactive states. Activation parameters remained largely
unaffected in y-deficient cells whereas the voltage dependence of inactivation
was shifted by 16 mV to more positive potentials and the larger one of the two
inactivation time constants was increased by one-third. On the other hand,
alpha2delta-deficient cells showed decreased current density and slowed
activation and inactivation. Recovery from inactivation was significantly slowed
by gamma coexpression. This and the effect of the gamma subunit on steady-state
inactivation were independent of the presence of alpha2delta. We conclude that y
stabilizes L-type Ca2+ channel inactivation in a way similar to certain Ca(2+)
antagonistic drugs. Alpha2delta is not needed for this effect.
PMID- 10784343
TI - Inhibition of apamin-sensitive K+ current by hypoxia in adult rat adrenal
chromaffin cells.
AB - The effect of hypoxia on small-conductance Ca(2+)-activated K+ current was
investigated in a study of adult rat adrenomedullary chromaffin cells (AMCs),
which were maintained in short-term culture. The nystatin-perforated, whole-cell
patchclamp technique was used to study the effect of hypoxia with minimum
perturbation of the intracellular milieu. Under voltage-clamp conditions, acute
hypoxia (P(O2) approximately equal to 25 mmHg) suppressed the whole-cell outward
currents of more than half the AMCs (24/46). This suppression was eliminated
after application of apamin (400 nM), a selective inhibitor of small-conductance
Ca(2+)-activated K+ current (I(SK)(Ca)) (n=5), suggesting that an apamin
sensitive component of whole-cell currents is suppressed during hypoxia. In
contrast to I(SK)(Ca), Ca2+ current (I(Ca)) (n=10) was not affected by hypoxia.
Finally, under current-clamp conditions, hypoxia reversibly depolarized the
resting membrane potential of adult AMCs (34/40). Apamin, however, eliminated the
hypoxia-induced depolarization (400 nM) (7/8), suggesting that hypoxic
depolarization is related to the suppression of I(SK(Ca). From the above results,
we conclude that adult AMCs are sensitive to hypoxia, and that I(SK)(Ca)
contributes to the hypoxia-induced suppression of whole-cell outward current and
depolarization of the resting membrane potential in adult AMCs.
PMID- 10784344
TI - Modification of wild-type and batrachotoxin-resistant muscle mu1 Na+ channels by
veratridine.
AB - Biochemical evidence indicates that veratridine (VTD) and batrachotoxin (BTX)
share a common binding site in Na+ channels. Under whole-cell voltage-clamp
conditions, we examined this single receptor hypothesis by studying the VTD
phenotype in BTX-resistant muscle Na+ channels, microl-I433K, N434K, L437K,
F1579K, and N1584K. Derived from point mutations at segments D1-S6 and D4-S6,
these mutant Na+ channels are resistant to 5 microM BTX when expressed in human
embryonic kidney cells. In contrast to the wild-type phenotype, VTD at 200 microM
elicits little or no maintained current during a test pulse at +50 mV, and little
or no "tail" current after the test pulse in all BTX-resistant mutant channels.
Paradoxically, VTD retains its ability to inhibit the peak Na+ current in BTX
resistant mutant Na+ channels. To explain these mutant phenotypes, we propose a
two-step binding reaction scheme. An initial VTD-binding interaction with the Na+
channel results in the inhibition of peak current amplitude, and a second binding
reaction results in the trapping of VTD within the D1-S6 and D4-S6 domain
interface. The failure of BTX-resistant mutant Na+ channels to trap VTD suggests
that segments of D1-S6 and D4-S6 form a common receptor for VTD and BTX.
PMID- 10784345
TI - Cloning, localisation and functional expression of the human orthologue of the
TREK-1 potassium channel.
AB - We have cloned human TREK-1, one of the newly emerging mammalian family of 2-P
domain potassium channels. The channel has 411 amino acids with a 41-amino-acid
extension at the C-terminus when compared with the cloned mouse TREK-1 channel.
Expression of hTREK-1 produced a substantial hyperpolarising shift in resting
membrane potential accompanied by the induction of large, outwardly rectifying,
non-inactivating currents which were potassium selective. Pharmacologically,
hTREK-1-mediated currents were only blocked to a limited extent by classic
potassium channel blockers or open channel pore blockers known to potently
inhibit other channels. The channel was reversibly potentiated by arachidonic
acid. CNS distribution of hTREK-1 is widespread with higher levels being observed
in caudate, putamen, amygdala, thalamus and spinal cord. Only low levels of
expression were seen in the majority of peripheral regions. Thus, hTREK-1,
although functionally and pharmacologically similar to mouse TREK-1, appears to
have a more CNS-specific distribution.
PMID- 10784346
TI - Downregulation of skeletal muscle UCP-3 gene expression during refeeding is
prevented by cold exposure.
AB - We wished to gain insights into the role of skeletal muscle uncoupling protein-3
(UCP-3) in the elevated efficiency of fat recovery during refeeding after
starvation. Previous observations have revealed that muscle UCP-3 expression is
downregulated in rats during refeeding at 22 degrees C. Therefore, we
investigated whether this also occurs during refeeding at thermoneutrality (29 C)
or in the cold (6 C), since at these environmental temperatures the refed animals
also show diminished thermogenesis and a higher rate of fat deposition than
controls. The UCP-3 mRNA level in the skeletal muscles studied (soleus,
gastrocnemius and tibialis anterior) was significantly lower in the refed group
than in controls at thermoneutrality, but there were no such differences between
these two groups in the cold. This effect of cold, namely abolishing refeeding
induced downregulation of skeletal muscle UCP, is specific to UCP-3 since the
gene expression of skeletal muscle UCP-2 remained significantly lower in the
refed than in the controls both at thermoneutrality and in the cold. These
findings during refeeding in the cold therefore dissociate UCP-3 gene regulation
from the adaptive reduction in thermogenesis that accelerates fat deposition
during weight recovery. They also reveal differential responses of UCP-3 and UCP
2, whose significance is discussed in the light of our previously proposed
hypothesis, which centers upon a role for these UCP homologues in the regulation
of lipids as a fuel substrate.
PMID- 10784347
TI - Particle-mediated gene transfer to rat neurons in primary culture.
AB - Gene transfer into neuronal cells provides an important approach to study their
function. Particle-mediated gene delivery was used to transfect rat dorsal root
ganglion (DRG) and hippocampal neurons in primary culture with the genes for the
enhanced blue and green fluorescent proteins (EBFP and EGFP) under control of the
cytomegalovirus promoter. Quantitative analysis of marker protein fluorescence
detected expression at 3 h that continued to increase for 48 h. For DRG neurons
the optimal expression efficiency of 8+/-2% was obtained 24 h following
transfection. In contrast, approximately 2+/-1% of hippocampal neurons in culture
expressed EGFP at 3 h which subsequently declined. Co-transfection of DRG
cultures with two plasmids produced reliable expression of both genes.
Transfected DRG neurons exhibited normal electrophysiological properties, and
resting and stimulated intracellular Ca2+ concentrations were unchanged. After
transfection, 44% of hippocampal neurons remained in functional synaptic networks
as indicated by glutamatergic Ca2+ spiking activity. Particle-mediated gene
delivery provided a straightforward, reproducible and efficient method for
transfection of neurons in primary culture. Transfected cells were easily
identified by EGFP fluorescence, enabling subsequent physiological analysis.
Biolistic particle bombardment was well tolerated by peripheral neurons, although
caution was required when this method was applied to CNS cultures.
PMID- 10784348
TI - The effect of external pH on the delayed rectifying K+ current in cardiac
ventricular myocytes.
AB - The effects of extracellular pH (pHe) on the delayed rectifying K+ current iKr in
rabbit ventricular myocytes were studied using the whole-cell-clamp technique.
Since a variety of results have been reported on the effect of pH on expressed
hERG channels, our aim was to investigate the effects of pH on iKr channels in
their native environment. iKr is reduced by extracellular acidification and its
deactivation is faster. Extracellular acidification results in a marked shift of
the steady-state activation curve to more positive potentials, while
alkalinization does not produce a significant shift. E1/2= - 11.3 mV, -20.2 mV,
21.4 mV at pHe 6.5, 7.4, 8.5 respectively; the slope factor is 6.2 mV, and is not
affected by pHe. Deactivation of iKr is biexponential, with time constants of the
order of 0.5 s and 10 s at -50 mV. Both time constants decrease with external
acidification. Also the contribution of the fast component to the total amplitude
becomes larger with acidification. Acidification also decreases the fully
activated iKr current. Our experiments demonstrate that extracellular
acidification reduces iKr by increasing the rate of deactivation, causing a shift
of the voltage dependence of activation and producing a voltage-dependent block
of the fully activated iKr current.
PMID- 10784349
TI - Functional integrity of endothelium determines Ca2+ channel availability in
smooth muscle: involvement of nitric oxide.
AB - Endothelium regulates smooth muscle contractility in part via nitric oxide (NO).
We tested the hypothesis that endothelial dysfunction, either produced by injury
or simulated pharmacologically by reducing the bioavailability of NO, results in
elevated Ca2+ channel availability (ngmax=maximum conductance/cell capacitance)
in smooth muscle cells isolated from the vessel. Using basilar arteries of
normotensive Wistar rats, we measured ngmax in smooth muscle cells from control
vessels, from vessels in which endothelium was injured using Na fluoroscene plus
light, and from vessels in which the bioavailability of NO was reduced by
pretreatment with the NO scavenger 1H-imidazol-1 -yloxy,2-(4-carboxyphenyl)-4,5
dihydro-4,4,5,5-tetramethyl-3-oxide , potassium salt (C-PTIO), or the endothelial
nitric oxide synthase (eNOS) inhibitor N(G)-nitro-L-arginine methyl ester (L
NAME). Values of ngmax in these four groups of cells were 0.28+/-0.02 nS/pF
(n=22), 0.51+/-0.05 nS/pF (n=15), 0.430+/-.03 nS/pF (n=12), and 0.47+/-0.04 nS/pF
(n=14) (P<0.05, ANOVA), respectively. To determine whether larger currents
associated with endothelial dysfunction exhibit altered sensitivity to exogenous
NO, we quantified the response to various concentrations of NO donor, Na
nitroprusside (SNP), in 37 cells from control vessels and 33 cells from vessels
pretreated with L-NAME. SNP exhibited identical potency (half-maximum values,
18.7 and 21.1 nM) but greater apparent efficacy (maximum fractional block, 0.82
versus 0.63) in down-regulating Ca2+ channel currents in cells isolated from
vessels with dysfunctional endothelium. Our results are consistent with a direct
influence of endogenous NO on Ca2+ channel availability in smooth muscle cells,
and indicate that Ca2+ channel availability in isolated smooth muscle cells may
be a sensitive measure of the functional integrity of the endothelium in the
parent vessel.
PMID- 10784350
TI - Chloride channels in the plasma membrane of a foetal Drosophila cell line, S2.
AB - We evaluated the suitability of the S2 foetal Drosophila cell line as an
expression system for vertebrate anion channel proteins (e.g. cystic fibrosis
transmembrane conductance regulator, CFTR) in patch-clamp studies of the
endogenous ion channels. In the inside-out configuration (symmetric 150 mM Cl-)
we found most frequently an inwardly rectifying Cl- channel with single-channel
conductances (gamma) of 57, 45 and 17 pS at -80, 0 and 80 mV, respectively.
Reduction of bath [Cl-] to 40 mM caused a shift in reversal potential (Vrev) to
22.5 mV indicating pronounced Cl- selectivity. In the outside-out configuration
([Cl-]pipette = 40 mM, [Cl-]bath = 150 mM) we observed a Cl- channel with a
linear unitary current/voltage (i/V) relation for which gamma was 30 pS. The
kinetics were quite slow in both configurations. Cl-selectivity was also observed
in whole-cell experiments ([Cl-]pipette = 40 mM) in which a Vrev of -43.8 mV,
i.e. close to the Cl- equilibrium potential, demonstrated that the membrane
current was dominated by Cl-. We conclude that the important features making S2
cells suitable as an expression system for heterologous expressed anion channel
proteins are: small total whole-cell currents (less than 100 pA), single-channel
and whole-cell currents that, unlike those of CFTR, cannot be described by the
Goldman-Hodgkin-Katz regime, and slow kinetics distinctly different from those of
CFTR.
PMID- 10784351
TI - Cellular adaptation of the mouse cortical thick ascending limb of Henle's loop
(CTAL) to dietary magnesium restriction: enhanced transepithelial Mg2+ and Ca2+
transport.
AB - Mice aged 4 or 8 weeks were fed with a low-Mg2+ diet for 1, 2, 3 or 4 days. After
1 day of diet, the urinary excretion of Mg2+ and Ca2+ was strongly reduced in
both animal groups (4 and 8 weeks), accompanied by a significant fall in plasma
Mg2+ concentration and an increase in urinary volume. This profile persisted
after 2, 3 or 4 days of dietary Mg2+ restriction. After 1 day of diet,
transepithelial ion net fluxes of Na+, Cl-, Ca2+ and Mg2+ (JNa' JCI, JCl, JMg)
measured in vitro from isolated perfused cortical thick ascending limbs (CTALs)
of these animals remained unchanged. After 2 days of diet, measurements of J(Ca)
and J(Mg) in isolated perfused CTALs showed that transepithelial Mg2+ and Ca2+
reabsorption were enhanced in CTALs from Mg(2+)-depleted, 8-week-old animals,
whereas transepithelial Mg2+ and Ca2+ transport were not altered in 4-week-old
mice. JNa and JCl and the transepithelial potential (PDte) were not modified in
CTALs from either animal group. Our results suggest that a low-Mg2+ diet leads to
urinary retention of Mg2+ and Ca2+ which is most likely due to increased Mg2+ and
Ca2+ transport in the CTAL. Furthermore, in response to dietary Mg2+ restriction,
the reabsorption of divalent cations in the CTAL of adult, but not of young, mice
undergoes cellular adaptation.
PMID- 10784352
TI - Impact of pulse pressure on the respiratory-related arterial pressure variability
and its autonomic control in the rat.
AB - The autonomic control of respiratory-related arterial pressure variability (RAPV)
remains uncharacterised. We set out to test the hypothesis that the autonomic
nervous system may participate in RAPV via its effect on pulse pressure (PP).
Experiments were performed on adult male Sprague-Dawley rats anaesthetised with
ketamine and paralysed with pancuronium under positive-pressure ventilation.
Respiratory variability in each parameter was quantified by auto-spectral
analysis and the relationship between variabilities in two signals assessed by
cross-spectral analysis. PP and systolic pressure (SP) exhibited similar powers
of respiratory variability that were far more pronounced than for diastolic
pressure (DP) or mean pressure (MP). The variability in PP preceded that in SP,
MP or DP. The largest phase lag occurred between PP and DP and was equivalent to
the time delay of one pulse interval. Coherence between respiratory variabilities
in PP and MP was nearly perfect. Propranolol dose dependently suppressed
respiratory variability in each pressure parameter and eventually disrupted the
PP-MP relationship in respiratory variability. However, the influence of lung
volume on MP persisted with a near-zero phase lag. Combined administration of
phentolamine and atropine facilitated respiratory variability in PP and SP and
failed to block the effect of propranolol. However, the combined administration
moved the dose/response curve of propranolol and respiratory variability in each
pressure parameter to the right. We conclude that, in addition to non-autonomic
mechanisms, RAPV may be facilitated by cardiac sympathetic function via the
effect on PP variability. The autonomic mechanism can still be evoked during
combined alpha-adrenoceptor and muscarinic blockade, possibly via baroreflex
mechanisms.
PMID- 10784353
TI - Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts
and their paracrine influence on stationary myocytes and fibroblasts.
AB - Functional adaptation of cardiac cells in response to haemodynamic load requires
dynamic alteration of gene expression. In this study, we examined early changes
in gene expression following stretch in myocytes and fibroblasts isolated from
neonatal rat hearts. In the first hour of biaxially applied static stretch, the
changes in expression of immediate-early genes, such as c-fos, c-jun and fra-1,
were quantified. The expression of the atrial natriuretic peptide (ANP) gene in
myocytes was measured as an indication of the hypertrophic response. In stretched
myocytes, expression of c-fos and ANP increased transiently to 227% and 176%
respectively after 30 min stretch, whereas c-jun and fra-1 expression decreased
in the 1st hour of stretch. In stretched fibroblasts the expression of c-fos and
fra-1 increased transiently to maxima of 145% and 146% respectively after 30 min
stretch, whereas c-jun expression did not change significantly. To study the
indirect effects of stretch, as an indication of cross-talk between cardiac
cells, stationary myocytes and fibroblasts were incubated with stretch
conditioned medium (CM) from stretched (0-60 min) myocytes and fibroblasts. CM
from stretched myocytes reduced c-fos and induced c-jun expression in myocytes
and fibroblasts, reduced fra-1 expression in myocytes but induced fra-1
expression in fibroblasts. CM from stretched fibroblasts induced c-fos expression
and had little effect on c-jun expression in myocytes and fibroblasts, induced
the fra-1 expression in myocytes but had little effect on fra-1 expression in
fibroblasts. CM from myocytes and CM from fibroblasts induced ANP expression in
myocytes to 206% and 120% respectively after 45 min stretch. Static stretch of
myocytes and fibroblasts appears to stimulate, within 1 h, secretion of cell type
specific factors that participate in the regulation of proto-oncogene and ANP
expression of stationary myocytes and fibroblasts. These early changes in gene
transcription suggest that stretch of the myocardium initiates intracellular gene
expression as well as cross-talk between the cell types.
PMID- 10784354
TI - Role of architecture in determining passive electrical properties in gap junction
connected cells.
AB - The electrical properties of gap junction-connected cells were analysed in terms
of their architectural organization. Two major architectural categories were
considered: trees and rings. Trees are described by means of Bethe lattices
(lattices with no rings) with arbitrary co-ordination and rings by two
dimensional periodic lattices with fourfold (square) or sixfold (triangular) co
ordination. The Bethe lattice is solved analytically by the transfer constant
method, which allows the introduction of several physiologically relevant effects
in a very simple manner. The experimental data for the length constant and the
input resistance were fitted by varying the coupling and membrane resistances for
various morphologies. The large variations in the length constant observed
experimentally in two systems (turtle retina horizontal cells with and without
dopamine and pancreatic beta-cells in the active and silent phases) could not be
explained by means of the Bethe lattice, indicating that the cell arrangements
form rings. Subsequent analysis by means of a linear chain and the square and
triangular lattices showed the crucial relevance of architecture in deriving the
electrical characteristics of gap junction-connected cells from experimental
data.
PMID- 10784355
TI - Outwards currents in embryonic stem cell-derived cardiomyocytes.
AB - The aim of the present study was to investigate the expression and functional
role of outwards currents during the early stages of cardiomyogenesis. The
predominant repolarizing current in early-stage, embryonic stem (ES) cell-derived
cardiomyocytes was a 4-aminopyridine (4-AP) sensitive [concentration for half
maximal inhibition (IC50) 1.7 mM], transient outward current (Ito) with a current
density of 10.3+/-2.1 pA/pF (n=72). We observed two additional, rapidly
activating, outwardly rectifying current components, I(K),sus and Ires, in early-
and late-stage cardiomyocytes. These currents were characterized by slow and no
inactivation, respectively, during the depolarizing voltage step. I(K),sus was
detected in about 25% of cells investigated and displayed 4-AP hypersensitivity
(IC50 29 microM), whereas Ires was found in all cells of both differentiation
stages and was 4-AP insensitive. In contrast to early-stage cells, Ires formed
the larger portion of the aggregate, whole-cell current in late-stage, ES cell
derived cardiomyocytes. The current densities of all three current components
increased during development, however, the most prominent increase was observed
for I(res) from 3.6+/-0.8 pA/pF (n=72) to 8+/-1.1 pA/pF (n=35). In current-clamp
recordings in early-stage, spontaneously contracting cardiomyocytes, 4-AP
depolarized the cells, lengthened the action potential duration (APD) and
increased the action potential frequency. In late-stage cells 4-AP had no effect
on action potential frequency. We conclude that in early-stage cardiomyocytes
I(to) plays an important role in controlling electrical activity.
PMID- 10784356
TI - Effect of anoxic preconditioning on ATP-sensitive potassium channels in guinea
pig ventricular myocytes.
AB - Ischemic or hypoxic preconditioning in experimental animals and humans is
described. The mechanism of preconditioning may involve several endogenous
substances released from ischemic or hypoxic tissues (such as adenosine,
noradrenaline and bradykinin) that stimulate protein kinase C (PKC), which then
phosphorylates ATP-sensitive potassium channels (K(ATP) channels). However, the
effect of hypoxic preconditioning on K(ATP) channels in guinea-pig ventricular
myocytes is unclear. The uncoupler carbonyl cyanide p
(trifluoromethoxy)phenylhydrazone (FCCP) has been shown to activate K(ATP)
channels in isolated cardiac cells. In the present study we tested whether anoxic
preconditioning (APC) could affect the opening of K(ATP) channels activated by
metabolic inhibition (MI) induced by FCCP in cell-attached and inside-out patches
from guinea-pig ventricular myocytes. We measured the channel activity as NP(o)i
and calculated it using the formula Po=I/(Ni), where Po is open-state
probability, I is the mean patch current carried by all K(ATP) channels activated
in a particular patch for a certain period of time, N is the number of
functioning channels in the patch, and i is the unitary current of the K(ATP)
channels. In cell-attached membrane patches, after about 5 min of initiating MI,
K(ATP) channels were activated at a holding potential of +40 mV (NP(o)i=3.70+/
0.9 pA); APC pretreatment (3 min of anoxia followed by 7 min of reoxygenation)
before MI (APC+MI group) shortened the time to activate K(ATP) channels by MI
(2.3+/-0.5 min) and increased the activity of K(ATP)currents (NP(o)i=8.4+/-0.5
pA). This effect of APC was eliminated by administration of a PKC blocker,
chelerythrine (5 microM), for 5 min before the APC pretreatment. In the inside
out patches, the IC50 of intracellular ATP against the K(ATP) channels in the
APC+MI group was significantly increased to 642 microM compared to that in the MI
group (IC50 of intracellular ATP =252 microM). Chelerythrine inhibited the effect
of APC on the sensitivity of K(ATP) channels to the intracellular ATP
concentration (IC50 of [ATP]i=301 microM). Our results demonstrate that APC can
increase and accelerate the opening of K(ATP) channels induced by MI, and
decrease the sensitivity of K(ATP) channels to [ATP]i, which is mediated by
promoting the activation of PKC induced by APC.
PMID- 10784357
TI - Lidocaine alters activation gating of cardiac Na channels.
AB - The class IB antiarrhythmic drug, lidocaine, interacts strongly with depolarized
sodium (Na) channels, an action that is thought to underlie its clinical
efficacy. Previously, we have reported Na channel gating current (Ig) experiments
with a quaternary form of lidocaine, QX-222, which binds preferentially to open
Na channels and modifies the gating-charge/voltage (Q/V) relationship of cardiac
Na channels by reducing maximal gating charge (Qmax) and lessening its voltage
dependence. We report here investigations with lidocaine itself on Ig of native
canine and cloned human cardiac Na channels. Although the state dependence of
lidocaine binding to Na channels differs from that of quaternary drugs, Ig
measurements demonstrated that lidocaine produced changes in the Q/V
relationships similar to those elicited by QX-222, with a reduction in Qmax by
33% and a corresponding decrease in the slope factor. Concentration/response
curves for the reduction in gating charge by lidocaine matched those for the
block of sodium current (I(Na)), as would be expected if modification of Na
channel voltage sensors by lidocaine underlied its action. The application of
site-3 toxins, which inhibit movement of the voltage sensor associated with
inactivation, to lidocaine-bound Na channels elicits an additional reduction in
Qmax suggesting that lidocaine does not "stabilize" the Na channel in an
inactivated state. We conclude that lidocaine blocks I(Na) by modification of the
Na channel's voltage sensors predominately associated with channel activation
leading to channel opening.
PMID- 10784358
TI - Stimulation of Na/Ca exchange by the beta-adrenergic/protein kinase A pathway in
guinea-pig ventricular myocytes at 37 degrees C.
AB - We investigated the effect of beta-adrenergic stimulation on Na/Ca exchange in
whole-cell patch-clamped guinea-pig ventricular myocytes at 37 degrees C. With
ion channel and Na/K pump currents blocked, the Na/Ca exchange current (I(Na-Ca)
was measured selectively as membrane current inhibited by 10 mM nickel (Ni)
during a voltage ramp applied between +80 and -120 mV. Isoprenaline (1 microM)
caused an increase in both inward and outward current generated by the Na/Ca
exchange, which was prevented by the beta-adrenoceptor blocker propranolol. These
data suggest that isoprenaline caused a receptor-mediated up-regulation of Na/Ca
exchange activity. Mimicking beta-adrenoceptor activation, either by stimulation
of adenylate cyclase with forskolin or by internal dialysis of cells with cyclic
AMP (3':5'-cyclic adenosine monophosphate), also increased I(Na-Ca). Using
fluorescence Ca measurement, an increase of internal cAMP was shown to increase
the rate of transmembrane Ca transport via the Na/Ca exchange. A selective
inhibitor of protein kinase A prevented stimulation of Na/Ca exchange by
isoprenaline. These data suggest that the underlying mechanism of stimulation was
phosphorylation of the Na/Ca exchange protein by protein kinase A. Isoprenaline
did not stimulate I(Na-Ca) when experiments were carried out at 20 degrees C, in
contrast to the findings at 37 degrees C. Modulation of Na/Ca exchange by the
beta-adrenergic pathway may have important physiological consequences for
intracellular Ca regulation and electrical activity during hormonal stimulation,
or during sympathetic nerve stimulation.
PMID- 10784359
TI - Dendrimer-assisted patch-clamp sizing of nuclear pores.
AB - Macromolecular translocation (MMT) across the nuclear envelope (NE) occurs
exclusively through the nuclear pore complex (NPC). Therefore, the diameter of
the NPC aqueous/electrolytic channel (NPCC) is important for cellular structure
and function. The NPCC diameter was previously determined to be approximately
equal to 10 nm with electron microscopy (EM) using the translocation of colloidal
gold particles. Here we present patch-clamp and fluorescence microscopy data from
adult cardiomyocyte nuclei that demonstrate the use of patch-clamp for assessing
NPCC diameter. Fluorescence microscopy with B-phycoerythrin (BPE, 240 kDa)
conjugated to a nuclear localization signal (NLS) demonstrated that these nuclei
were competent for NPC-mediated MMT (NPC-MMT). Furthermore, when exposed to an
appropriate cell lysate, the nuclei expressed enhanced green fluorescence protein
(EGFP) after 5-10 h of incubation with the plasmid for this protein (pEGFP, 3.1
MDa). Nucleus-attached patch-clamp showed that colloidal gold particles were not
useful probes; they modified NPCC gating. As a result of this finding, we
searched for an inert class of particles that could be used without irreversibly
affecting NPCC gating and found that fluorescently labeled Starburst dendrimers,
a distinct class of polymers, were useful. Our patch-clamp and fluorescence
microscopy data with calibrated dendrimers indicate that the cardiomyocyte NPCC
diameter varies between 8 and 9 nm. These studies open a new direction in the
investigation of live, continuous NPC dynamics under physiological conditions.
PMID- 10784360
TI - Dose-dependent effect of angiotensin II on human erythropoietin production.
AB - Current evidence suggests that angiotensin II may be involved in the regulation
of renal erythropoietin (EPO) production. The present study assessed the role of
angiotensin II (A II) in different doses in the control of EPO production in
humans. In a parallel, randomized, placebo-controlled open design, 60 healthy
male volunteers received a 6-h intravenous infusion of: placebo (placebo,
electrolyte solution), a pressor dose of A II (1-3 microg/min; A II press), a
combination of a pressor dose of A II and the selective AT1-receptor blocker
losartan, 50 mg (A II press + L), a subpressor dose of A II (0.0375-0.15
microg/min; A II subpress) and a combination of a subpressor dose of A II and
losartan (A II subpress + L). A II press treatment resulted in a significant
increase of the maximum EPO concentration (CmaxEPO, 41% higher versus placebo)
and the amount of EPO produced in 24 h (AUCEPO(0-24 h), 61% larger versus
placebo), A II subpress treatment increased CmaxEPO (35% higher versus placebo)
and AUC(EPO)(0-24 h) (34% larger versus placebo). A II press + L and A II
subpress + L treatments did not significantly increase CmaxEPO and AUCEPO(0-24 h)
compared to placebo. A II affects EPO production in a dose-dependent manner. The
signal seems to be mediated via AT1-receptors. A II appears to be one modulator
EPO production in humans.
PMID- 10784361
TI - Ca2+-activation characteristics of single fibres from chemically skinned rat
muscle incubated with glucose-6-phosphate.
AB - In this study we examined the effects of 3-24 h of incubation of chemically
skinned rat fast-twitch muscle with the glycolytic metabolite glucose 6-phosphate
(G6-P) on the contractile properties and myosin ATPase activity in single muscle
fibres, and on the carbohydrate content of myosin heavy chains (MHCs). Exposure
of the permeabilised muscle to 10 mM G6-P for 24 h at 22+/-1 degrees C in a rigor
solution containing protease inhibitors and a reducing agent (dithiothreitol,
DTT) significantly decreased maximum Ca(2+)-activated force output by 31%,
lowered the Ca2+ threshold for contraction by 0.1 pCa units and produced
shallower force-pCa curves compared with controls. Furthermore, under these
conditions, G6-P-treated muscle displayed lower myofibrillar MgATPase activity
and a markedly higher carbohydrate content of MHCs, as identified with an
immunoblot protocol for glycoprotein detection. Shorter incubations under the
same conditions or 24-h incubations with 5 mM G6-P generally resulted in smaller
changes in the contractile activation parameters. These findings suggest that
reducing sugars acting as metabolic intermediates in the glycolytic pathway can
have important non-energy-related effects on the contractile activation
characteristics of mammalian skeletal muscle. These effects are consistent with
the glycation of muscle proteins, in particular that of the MHC.
PMID- 10784362
TI - Heparin-induced extracorporal low-density-lipoprotein precipitation (H.E.L.P.) to
improve the recovery of hearing in patients with sudden idiopathic hearing loss.
AB - The pathogenesis of sudden hearing loss (SHL) is still not well understood.
Possible causes include increased blood viscosity, microthrombosis or altered
blood flow. Hypercholesterolemia, hyperfibrinogenemia and increased platelet
aggregation are frequently observed in patients with SHL. The aim of this study
was to investigate whether drastic lowering of plasma cholesterol and fibrinogen
by selective extracorporal apheresis could have a beneficial effect on hearing
recovery in these patients. Seven patients with SHL were treated with an
extracorporal procedure removing fibrinogen and cholesterol from plasma. Six of
the seven patients showed an immediate improvement in auditory thresholds
following a single treatment of heparin-induced low-density lipoprotein
precipitation. These findings indicate for the first time that acute and drastic
removal of plasma fibrinogen and low-density lipoproteins may be an effective
clinical method for the treatment of patients with SHL.
PMID- 10784363
TI - A Dutch family with progressive sensorineural hearing impairment linked to the
DFNA2 region.
AB - We studied a Dutch family with DFNA2-linked progressive sensorineural hearing
impairment (SNHI). Recent audiograms were obtained from 18 of the affected
persons (age 7-81 years) and were used in a gene-linkage analysis. Linear
regression analysis of the audiograms, using binaural mean thresholds, disclosed
on average a descending slope of approximately 10 dB/octave at any age and an
annual threshold increase at any frequency of about 0.7 dB/year. There may have
been substantial congenital impairment at higher frequencies, but longitudinal
analysis of hearing impairment in the youngest case, who was followed from age 5
years, suggested that the most significant changes in hearing may have occurred
in the first two decades of life. Linkage analysis was carried out with special
attention to the DFNA2 region because hearing trends were very similar to
families previously linked to DFNA2. Linkage to DFNA2 was established with
maximum lod scores of 4.7 and 3.2 for the flanking markers of the DFNA2 region
(D1S432;MYCL1).
PMID- 10784364
TI - Preliminary experiences with contact endoscopy of the larynx.
AB - Nine patients with laryngeal polyps, four with Reinke's edema, three with
leukoplakia, one with papilloma and one with malignant tumor were studied by
means of laryngeal contact endoscopy during microlaryngoscopy. This technique
allowed in vivo and in situ visualization of the superficial layer of the
laryngeal epithelium after staining with methylene blue. Cell structures
evaluated were the size and color of the nuclei, the nucleus/cytoplasm ratio,
nuclear and cytoplasmic contours, the presence of nucleoli, mitoses and
keratoses, as well as the microvascular network of the mucosa and superficial
cellular changes from normal to pathological. The normal squamous epithelium of
the vocal cord showed a homogeneous cellular population with regular nuclear and
cytoplasmic morphological characteristics and a uniform nucleus-to-cytoplasm
ratio. Specific cellular epithelial patterns and several alterations of the
vascular distribution were found in different pathological conditions.
Cytological pictures obtained at contact endoscopy were consistent with
histological findings in all the patients studied.
PMID- 10784365
TI - How much does it cost to preserve a larynx? An economic study.
AB - Various studies report an increase in costs when induction chemotherapy is
included in the treatment of advanced laryngeal cancer, but to our knowledge no
studies have yet compared the economic costs of total laryngectomy versus
induction chemotherapy in the treatment of advanced laryngeal cancer. We have
conducted a retrospective study comparing the costs of treatment and survival in
96 patients with a T3N0-1 glottic carcinoma. Findings showed that the average
cost per patient in the group of patients treated by total laryngectomy with or
without postoperative radiotherapy was 5,853 Eur, while that for the group of
patients who began treatment with induction chemotherapy was 6,452 Eur. The
adjusted 5-year survival for patients treated with total laryngectomy with or
without postoperative radiotherapy was 80%, and 72% for patients who began
treatment with induction chemotherapy. Sixteen of the 35 patients (46%) receiving
induction chemotherapy were spared laryngectomy. The use of induction
chemotherapy in the treatment of patients with advanced laryngeal carcinomas
involved an increase in cost of 600 Eur in relation to treatment with total
laryngectomy and postoperative radiotherapy. However, from an economic point of
view, we consider induction chemotherapy to be an important consideration in an
organ-preservation strategy.
PMID- 10784366
TI - Squamous cell carcinoma of the lower lid in a 19-month-old girl with xeroderma
pigmentosum.
AB - Squamous cell carcinoma (SCC) of the skin usually occurs in older patients and
commonly develops from actinic keratosis. Patients with xeroderma pigmentosum
(XP) can acquire SCC at an early age. To our knowledge the youngest reported
patient with XP and SCC was 8 years of age. We report a 19-month-old Lebanese
girl with XP who presented clinically because of a rapidly growing mass of the
medial part of her right lower lid that was biopsied and found to be squamous
cell carcinoma. The mass was surgically excised with no evidence of recurrence
after 2 years of follow-up. We describe our clinical experiences with this
patient and have reviewed the available literature concerning XP and malignancy.
PMID- 10784367
TI - Social class of origin and cardinal symptoms of schizophrenic disorders over the
early illness course.
AB - BACKGROUND: This study describes the relationship of social class of origin to
cardinal symptoms of schizophrenic disorders over the early illness course.
METHOD: The sample of subjects was drawn from the Suffolk County Mental Health
Project, a longitudinal epidemiologic study of first-hospitalized subjects with
psychotic disorders; the present study focused on patients with schizophrenic
disorders. At baseline, subjects were dichotomized into upper/middle and lower
social class of origin groups, based on occupation of the head of the household
of origin. The patients in both groups were assessed for the major symptoms of
schizophrenic disorders using standard structured instruments at both baseline
and 6-month follow-up. The 6-month symptom severity levels were compared between
the groups, controlling for baseline symptom status and potential confounders.
RESULTS: At 6-month follow-up, the upper/middle social class of origin group, as
compared to the lower social class of origin group, had lower symptom levels for
hallucinations (adjusted OR = 4.88, chi2 = 8.49, P = 0.004) and delusions
(adjusted OR = 2.46, chi2 = 4.16, P = 0.04). There were no notable group
differences for any of the negative or thought disorganization symptoms.
CONCLUSIONS: Social class of origin is associated with positive symptoms of
schizophrenia over the early illness course.
PMID- 10784368
TI - Access to physician treatment for a mental disorder: a regional analysis.
AB - BACKGROUND: This study examined (1) disparities in the proportion of persons who
accessed a physician for treatment of a diagnosed mental disorder across 17
health regions in Alberta, Canada, and (2) the extent to which regional
disparities in physician access could be explained by differences in regional
demographies, population needs, or physician supply. METHODS: The study
illustrates the use of ecological comparisons for regional health system
performance evaluations. Regional characteristics were aggregated from four
sources of data: the health insurance registry file (population denominators and
regional demographies), physician claims data (treatment access), census data
(social indicators of population need), and the medical directory of the College
of Physicians of Surgeons (physician supply). RESULTS: Regional variability in
needs-adjusted measures of access to physician-based treatment services were
comparatively small (varying by a factor of 1.6). Models containing adjustments
for demography, need, and physician supply explained 41% of regional variation in
access. Of the total variation explained, physician supply explained a smaller
proportion (39%) in comparison to social demography and needs (61%). Few large
regional imbalances were noted when needs-adjusted and supply-adjusted estimates
were compared. Only two areas appeared to be underserviced in comparison to their
local needs, reflecting approximately 6% of the provincial population.
CONCLUSIONS: While all three study factors proved important, findings support the
broad conclusion that social demography and social risk (a proxy for need) will
remain the key determinants predicting access to physician services for treatment
of mental disorders in publicly funded health systems.
PMID- 10784369
TI - Mental disorders and employee sickness absence: the NEMESIS study. Netherlands
Mental Health Survey and Incidence Study.
AB - BACKGROUND: This study aimed to determine to what extent different forms of
mental disorders are related to an increased likelihood of sickness absence and
whether this increase depends on the employee's sex. METHODS: Data of 3,695
employed persons aged 18-64 years from a national sample of the Dutch population
were derived from the first two waves of the Netherlands Mental Health Survey and
Incidence Study (NEMESIS). Mental disorders (DSM-III-R) in the past 12 months
were assessed at baseline (1996). Subsequent sickness absence was assessed at the
follow-up 1 year later. Somatic illnesses and age were included as controlled
confounders. RESULTS: Major depressive disorder, dysthymia, simple phobia and
drug abuse/dependence were predictive of sickness absence in men. In women, the
associations were weaker, and none of the 1-year DSM-III-R disorders was
significantly related to the likelihood of sickness absence. CONCLUSIONS: Mental
disorders are a more important risk factor for sickness absence for male
employees than for female employees. Knowledge of this sex difference can be
valuable for the development of interventions aiming at reducing sickness absence
rates due to mental illness.
PMID- 10784371
TI - Bulimic disorders and sociocentric values in north India.
AB - BACKGROUND: Previous studies have shown low rates of eating disorders in some
developing countries. We set out to investigate the prevalence of bulimia in an
all-female college population in north India and relate it to sociocentrism of
the culture. METHODS: A total of 504 students in an all-girls private college in
an industrial town in north India completed the Hindi translation of the Bulimia
Investigatory Test, Edinburgh (BITE). A random sample of 50 students,
irrespective of their scores, were interviewed using the DSM-III-R interview for
eating disorders; they were also asked about qualitative aspects of their
relationship with the family and their own views of their identity. RESULTS:
There was no effect of age, social class, religion or height on the distribution
of BITE scores. Three key factors emerged; these were related to the constructs
of compulsive activity, impulsivity/sociocentric avoidance and associated
attitudinal responses and depressive thinking with features of helplessness and
feelings of failure. Acculturation was not related to BITE scores. Virtually all
interviewees had sociocentric views of theirselves. CONCLUSIONS: Sociocentrism
and impulsivity account for a significant amount of the variance. The role of
sociocentrism in influencing patterns of eating deserves to be studied further.
PMID- 10784370
TI - Threshold Assessment Grid (TAG): the development of a valid and brief scale to
assess the severity of mental illness.
AB - BACKGROUND: Lack of consensus about the meaning of severe mental illness makes it
difficult to prioritise the severely mentally ill for specialist mental health
care. The goal of this study was to develop a valid and brief assessment of
severity of mental illness. METHOD: Six search workshops (n = 57) using consensus
techniques developed a draft assessment acceptable to users, carers,
practitioners and policy makers. A two-round Delphi consultation (n = 58) was
held to identify consensus on this instrument. RESULTS: Search workshops agreed
seven domains relevant to identifying the severely mentally ill: intentional and
unintentional self-harm, risk from and to others, and survival, psychological,
and social needs and disabilities. The Delphi consultation indicated at least
agreement with all aspects in both rounds. CONCLUSIONS: The Threshold Assessment
Grid (TAG) is a brief method of identifying the severely mentally ill, which has
adequate face, concurrent, construct and content validity.
PMID- 10784372
TI - Social class, income, education, area of residence and psychological distress:
does social class have an independent effect on psychological distress in
Antalya, Turkey?
AB - AIM: The aim of this study is to determine the separate effects of social class,
income, education and area of residence on psychological distress. The study also
assesses whether the association between prevalence of high score on the 12-item
General Health Questionnaire (GHQ 12) and social class is independent of other
variables. METHOD: Psychological distress was assessed by means of the GHQ 12.
The study covered 1,092 adults aged 15 years or more living in two different
quarters of Antalya. Social class status was defined by occupational position,
with income, education and area of residence treated as confounders. Chi-square
and logistic regression analyses were used to evaluate the data. RESULTS: Large
inequalities in psychological distress by all variables were observed.
Psychological distress was significantly associated with class status, after
adjusting for income, education, area of residence and other potential
confounders (age, sex and marital status). Class inequalities in psychological
distress were observed between blue-collar workers/unqualified employees and
bourgeoisie. CONCLUSIONS: These findings support the view that the recent
widening of inequalities among social classes in Turkey pose a substantial threat
to health.
PMID- 10784374
TI - Acute myocardial infarction and Helicobacter pylori seropositivity.
AB - Infectious agents including Helicobacter pylori, have been linked to coronary
heart diseases on epidemiological and pathogenetic grounds. Classical risk
factors fail to explain all the epidemiological variations of the disease. Our
aim was to investigate the association of acute myocardial infarction with
Helicobacter pylori infection in a case-control study by comparing a group of
male patients with a control group of blood donors matched for sex and age. We
investigated the classical cardiovascular risk factors in all patients. We
studied 44 consecutive male patients, aged 40-65 years, admitted for acute
myocardial infarction to the Coronary Care Unit at Novi Ligure Hospital in
northern Italy. Helicobacter pylori infection was assessed by measurement of
antibodies (IgG) against Helicobacter pylori in blood. Volunteer blood donors
attending Molinette Hospital Blood Bank in Turin, northern Italy served as
controls. Among the patients we investigated the presence of hypertension,
cholesterol and glucose levels in serum, fibrinogen in plasma, smoking habits,
and social class. Helicobacter pylori infection was present in 34 of 44 (77%)
patients and in 183 of 310 (59%) controls (P<0.05); the odds ratio was 2.36 (95%
confidence interval 1.08-5.31). Classical cardiovascular risk factors did not
differ among patients with and without Helicobacter pylori infection. In
conclusion, patients with acute myocardial infarction had a significantly higher
prevalence of Helicobacter pylori infection than the control population. The
classical risk factors for cardiovascular diseases were equally distributed among
patients irrespective of their Helicobacter pylori status.
PMID- 10784373
TI - Protein-bound polysaccharide (PSK) induces cytotoxic activity in the NKL human
natural killer cell line.
AB - We studied the effect of protein-bound polysaccharide PSK on the activation of
the human natural killer cell line NKL. We observed an increased natural killer
cytotoxic activity against different tumor cells (K562, Daudi, and U937) when a
standard 2- to 3-h 51chromium release assay was performed. The results parallel
those obtained after treatment of the NKL cell line with interleukin-2. The
highest cytotoxic activity was reached at a concentration of 100 microg/ml of
PSK. This natural killer activation was inhibited when the PSK dose was 1,000
microg/ml. None of the cell surface markers that were analyzed by fluorescence
activated cell sorting showed variations after PSK or interleukin-2 treatment of
NKL cells. These markers included CD2, CD11b, CD11c, CD18, CD16, CD54, CD56,
CD98, CD25, CD122, HLA class I, HLA class II, CD94, ILT2, p58.1, p70, and NKp46.
One of these markers (NKp46) is a major triggering receptor reported to be
involved in the natural cytotoxicity of fresh or cultured human natural killer
cells. In our study, another triggering receptor must be implicated in PSK
induced natural killer lysis. Our data suggest that PSK is an important
biological response modifier of natural killer cells in vitro and may prove to be
useful for the study of human natural killer cell biology.
PMID- 10784375
TI - The pre-procedural platelet state predicts clinical recurrence after coronary
angioplasty.
AB - Percutaneous transluminal coronary angioplasty is an established therapy for
coronary artery disease, but restenosis still occurs at a rate of 25%-40%. The
aim of this study was to investigate the acute effect of percutaneous
transluminal coronary angioplasty on platelet function and the relationship
between platelet function and clinical recurrence. Spontaneous platelet
aggregation was assessed before and after successful coronary angioplasty in 155
patients (120 men, 35 women). Patients were followed for a mean time of 20
months; follow-up angiography was performed only in patients with clinical
recurrence. In 122 of 155 patients (79%) a significant increase in spontaneous
platelet aggregation was observed immediately after coronary angioplasty.
Baseline spontaneous platelet aggregation in platelet-rich plasma was
significantly lower in patients with clinical recurrence than in those without
(P<0.05). Kaplan-Meier event-free survival estimate showed a significant
difference in clinical recurrence between patients with spontaneous platelet
aggregation in platelet-rich plasma below and above the first quintile (P<0.05)
with a relative risk of 2.5. In conclusion. these results indicate that
percutaneous transluminal coronary angioplasty enhances spontaneous platelet
aggregation and that the platelet state before coronary angioplasty affects the
risk of clinical recurrence after the procedure.
PMID- 10784376
TI - The influence of smoking on von Willebrand factor is already manifest in healthy
adolescent females: the Floren-teen (Florence Teenager) Study.
AB - The early onset of atherosclerosis and the involvement of physiological
biochemical, and environmental factors in its pathogenesis is well documented.
Few data are available on the role of risk factors related to hemostasis in the
pathogenesis of atherosclerosis in the young and, in particular, little
information is available on adolescent populations. In the Study of Preventive
Medicine and Education Program (Floren-teen Study), von Willebrand factor, a risk
factor for cardiovascular disorder, was studied, together with classical
cardiovascular risk factors, in apparently healthy students from two high schools
in Florence. Familial and personal history, physical examination, and
cardiovascular risk factors were evaluated in 144 students (aged 17-19 years).
Blood was withdrawn to assess von Willebrand factor (ELISA) and lipid parameters.
Levels of von Willebrand factor were significantly higher (P<0.044) in smokers
than in nonsmokers and were correlated with the number of cigarettes per day in
the whole group (P=0.01) and in females (P=0.006). In females a positive
correlation was observed between von Willebrand factor and high-density
lipoprotein cholesterol (P=0.0365). There was no significant correlation between
von Willebrand factor and blood pressure or between von Willebrand factor and
physical activity. In conclusion, this study shows an association between levels
of von Willebrand factor and smoking habits and is the first show that even a
brief period of smoking affects levels of von Willebrand factor in healthy
adolescent females independently of other risk factors. These results stress the
relevance of extending prevention programs to reduce smoking in high school
students.
PMID- 10784377
TI - Correlation of low-density lipoprotein modification by myeloperoxidase with
hypochlorous acid formation.
AB - Myeloperoxidase is an enzyme in phagocytes which catalyzes several redox
reactions. A major product is hypochlorous acid which appears to be important in
inflammatory processes such as atherosclerosis. The aim of this study was to
investigate whether the kinetics of low-density lipoprotein modification by the
myeloperoxidase/hydrogen peroxide/chloride system in vitro conform to the
established kinetics of hypochlorous acid formation and to compare the results
with known in vivo data. The absorbance at 234 nm was applied to study the
kinetics of the modification of low-density lipoprotein. Variation of the
concentration of low-density lipoprotein, hydrogen peroxide, and chloride,
respectively, had a biphasic effect on the maximal rate of low-density
lipoprotein modification. Increasing the substrates up to certain threshold
levels resulted in increased modification, however, further increases caused
inhibition of low-density lipoprotein modification. The inhibitory effect of
higher low-density lipoprotein concentrations might be relevant, since these
concentrations occur in the human aortic intima. Furthermore, a positive
correlation was found between the maximal rate of low-density lipoprotein
modification and the acidity of the medium. In summary, low-density lipoprotein
modification is affected by the myeloperoxidase/hydrogen peroxide/chloride system
in a similar manner to hypochlorous acid production. We conclude that
myeloperoxidase, which has been detected in atherosclerotic lesions, is able to
modify low-density lipoprotein into the form which is taken up by macrophages in
an uncontrolled manner.
PMID- 10784378
TI - Urinary hypoxanthine and xanthine levels in acute coronary syndromes.
AB - Ischemia leads to impaired ATP metabolism, with increased production of purine
degradation products, such as hypoxanthine and xanthine, which are useful markers
of tissue hypoxia. These extracellular markers of ischemia have been studied
extensively in many clinical conditions of oxidative stress, including perinatal
asphyxia, acute respiratory distress syndrome, cerebral ischemia, and
preeclampsia. The aim of this study was to explore the usefulness of urinary
hypoxanthine and xanthine as ischemia markers in acute coronary syndromes.
Urinary excretion of hypoxanthine and xanthine was assessed by high-performance
liquid chromatography in 30 patients with acute coronary syndromes and in 30 age-
and sex-matched controls. Serum and urine uric acid, creatinine, and urea
concentrations were also determined. Hypoxanthine excretion was significantly
elevated in patients compared with healthy controls (84.37+/-8.63 and 42.70+/
3.97 nmol/mg creatinine, mean+/-SEM, P<0.0001). Urinary xanthine levels were also
increased in patients with acute coronary syndromes (100.13+/-12.14 and 34.74+/
4.07 nmol/mg creatinine patients and controls, respectively; P<0.0001).
Hypoxanthine and xanthine excretion showed a strong positive correlation in both
groups. Significant negative correlations between urinary hypoxanthine and uric
acid and xanthine and uric acid were observed in the patients, but not in
controls. In conclusion, increased levels of ATP degradation products
hypoxanthine and xanthine are observed in various hypoxic clinical conditions.
This study suggests that these parameters may be useful markers of ischemia in
patients with acute coronary syndromes.
PMID- 10784379
TI - Selective upregulation of MHC class I expression in metastatic colonies derived
from tumor clones of a murine fibrosarcoma.
AB - Eighteen metastatic nodes derived from the wild-type (GR9) and from 4 different
clones (G2, D8, B10, and B9) obtained from a fibrosarcoma were analyzed for H-2
class I and II expression, as well as for adhesion molecules (CD44, CDIIb, CD18,
CD49, and CD54). When metastatic nodes were cultured, typed for H-2 antigens, and
compared with the H-2 expression of the inducing tumor cell, H-2 Kd and Dd class
I expression was greater in most nodes analyzed. In contrast, the Ld molecule
remained negative, or showed a minor increase. Class II expression was negative
in the wild-type and the tumor clones, and remained so in the metastatic
colonies. Analysis of the adhesion molecules revealed no differences between the
inducing tumor cells and the metastatic nodes. The only molecule expressed was
CD44, which was present in all cells studied and was also inducible by interferon
gamma. The increase in H-2K and H-2D expression was associated with resistance to
natural killer cytotoxicity, as observed in the G2 tumor clone and some
autologous metastases, such as B9MP2, G2MK2, and G2MLI. In three independent
clones of this tumor system (D8, BIOMP6, and B9MP6) we found that tumor cells
treated with interferon-gamma had the same altered phenotype, i.e., a selective
lack of response of the Ld molecule to induction. These findings add a cautionary
note to the well-established idea that tumor cells may lose all class I antigens
during tumor progression, and suggest that sometimes this may not be the case.
The selective downregulation of Ld and upregulation of Kd and Dd class I
expression may give some tumor cells means of escaping both cytotoxic lymphocyte
and natural killer immune surveillance.
PMID- 10784380
TI - Analysis of three genetic polymorphisms as risk factors for thrombosis.
PMID- 10784381
TI - Oxysterol-induced cell death in U937 and HepG2 cells at reduced and normal serum
concentrations.
AB - BACKGROUND AND AIMS: Cholesterol oxidation products (oxysterols) are commonly
found in foods of animal origin and are also produced endogenously in the body.
Oxysterols are cytotoxic to certain cell lines and in some cases have been shown
to induce apoptosis. The aim of this study was to investigate the effects of
7beta-hydroxy-cholesterol (7beta-OHC) and 25-hydroxycholesterol (25-OHC) on
cytotoxicity and induction of apoptosis in U937 and HepG2 cells, treated in media
containing either 2.5% foetal calf serum (FCS) or 10% FCS to examine the effect
of increasing the cholesterol level. METHODS: The cells were incubated for 24 and
48 h with 30 microM oxysterol. Viability was assessed by fluorescein
diacetate/ethidium bromide staining and cell proliferation was determined by
haemocytometer counting. Apoptosis was monitored by detection of DNA fragments
(laddering) in 1.5% agarose gels. Cells with condensed or fragmented nuclei were
identified by Hoechst 33342 staining. The percentage of cells with sub-G1 levels
of DNA was measured by flow cytometry. RESULTS: Treatment of U937 cells with
7beta-OHC, in contrast to 25-OHC, resulted in a decrease in cell viability and
proliferation at 24 and 48 h (P <.01). 25-OHC and 7beta-OHC were both equally
cytotoxic to the HepG2 cell line. 7beta-OHC induced DNA laddering and an increase
in the percentage of condensed or fragmented nuclei at both time points and at
both serum concentrations in the U937 cell line. 25-OHC induced faint laddering
in the U937 cells after 48 h in reduced serum media and resulted in a small
increase in percentage condensed or fragmented nuclei which was independent of
time of oxysterol exposure and serum concentration. The percentage of condensed
or fragmented nuclei was low in the HepG2 cell line and no laddering was observed
under any of the conditions studied. Flow cytometric analysis showed that only
7beta-OHC treated U937 cells had an increased level of hypodiploid cells.
CONCLUSION: Both oxysterols appear to be equally cytotoxic to the HepG2 cell
line. In U937 cells, 25-OHC is much less cytotoxic than 7beta-OHC. In addition,
we have shown that 7beta-OHC induces apoptosis in U937 cells. 10% FCS displays a
protective effect on cytotoxicity (as well as on 7beta-OHC induced apoptosis in
U937 cells), although the data did not reach statistical significance.
PMID- 10784382
TI - Chronic arginine aspartate supplementation in runners reduces total plasma amino
acid level at rest and during a marathon run.
AB - BACKGROUND: Athletes consume arginine and/or aspartate as potential nutritional
ergogenics. Their metabolic effects are controversial and there is some evidence
that ingestion of large doses of single amino acids can adversely affect the
nitrogen balance or induce an amino acid imbalance. Nevertheless, the general
metabolic influence of an arginine aspartate supplementation during a prolonged
exercise bout has not yet been investigated. AIM OF THE STUDY: The aim of this
study was, therefore, to investigate the general metabolic impact of a chronic
supplementation with arginine aspartate in endurance-trained athletes at rest and
during a marathon run. METHODS: Fourteen endurance-trained runners participated
in this field study which was carried out according to a double-blind crossover
design. 15 g of arginine aspartate or a carbohydrate-based placebo were
supplemented daily for 14 days before a marathon run. Blood samples for analysis
of metabolites and hormones were collected shortly before the run, after 31 km,
at the end of the run, and after a recovery period of two hours. Additionally,
the respiratory exchange ratio was determined during the run. RESULTS: The plasma
level of carbohydrate (glucose, lactate, pyruvate) and fat metabolites (fatty
acids, glycerol, beta-hydroxybutyrate), cortisol, insulin, ammonia, lactate
dehydrogenase, and creatine kinase as well as the respiratory exchange ratio were
unaffected by the supplementation. In contrast, the plasma level of somatotropic
hormone, glucagon, urea, and arginine were significantly increased, and the level
of most of the remaining plasma amino acids as well as their sum was
significantly reduced. CONCLUSIONS: There was no obvious metabolic benefit
derived from the chronic supplementation with arginine aspartate. And since
furthermore the consequences of a reduction of the total plasma amino acid level
are not known, the practice of using single amino acid supplements as potential
ergogenics should be critically reevaluated.
PMID- 10784383
TI - Conjugated linoleic acid effects on circulating hormones, metabolites and
lipoproteins, and its proportion in fasting serum and erythrocyte membranes of
swine.
AB - BACKGROUND: Conjugated linoleic acids (CLA)# refer to a group of linoleic acid
(18:2)-derived isomers with conjugated double bonds mostly at carbon atoms 9 and
11 or 10 and 12, and with all possible cis and trans combinations. CLA is a newly
recognized nutrient that functions to regulate energy retention and metabolism
and that causes a serum lipoprotein profile considered to be less atherogenic.
However, rodent models that have been frequently used for these studies are only
of limited use because of distinct differences in physiology, compared with man.
Additionally, possible differences in food intake between the experimental groups
remained often unconsidered in those studies. Thus, it can not be excluded that
the beneficial effects of CLA reported in a series of studies may be due, at
least partially, to differences in nutrient and energy ingested. AIMS OF THE
STUDY: This prompted us to undertake an investigation on the action of CLA by
using a pig model and a feeding regimen with controlled amounts of food and
antioxidants. The parameters used to assess CLA-specific action were selected
hormones and metabolites involved in energy metabolism, individual lipoproteins
and the appearance of CLA in fasting serum and erythrocyte membranes. Blood as an
easily available biological sample was used for investigation. METHODS: For that
purpose 16 adult female pigs were divided into two groups of 8 each, and were
isoenergetically fed diets containing 0 (control diet) or 1% level of CLA (by
weight) for 6 weeks. Plasma concentrations of total and free thyroxine (T4),
total and free triiodothyronine (T3), and insulin were measured by
radioimmunoassays. Plasma non-esterified fatty acids (NEFA), beta
hydroxybutyrate, circulating blood ATP and other clinical chemical variables were
determined using enzymatic assays. The concentration of alpha-tocopherol was
determined by high performance liquid chromatography. The lipoproteins VLDL
(density <1.019 kg/L), LDL (density 1.019 - 1.063 kg/L), and HDL (density >1.063
kg/L) were isolated by step-wise ultracentrifugation. Fatty acids of the dietary
oils, serum and blood cell membranes were separated and quantified by gas
chromatography. RESULTS: At week 6, body weights of the pigs fed the CLA
supplemented diet were not different from that of the controls. CLA-treated pigs
exhibited a 37% higher concentration of fasting serum insulin than their controls
receiving no CLA (P = 0.11). Circulating free and total T4 and T3 as well as
serum levels of beta-hydroxybutyrate, alpha-tocopherol, protein, glucose, urea,
creatinine and circulating blood ATP remained unaffected by CLA supplementation.
Serum concentrations of non-esterified fatty acids were reduced by 38% in CLA
treated pigs relative to the controls, although this difference was not
significant. CLA-treated pigs tended to have lower leukocyte counts in blood than
their controls (P <0.1). Erythrocyte and platelet counts, the hematocrit and
hemoglobin concentration were similar between the groups. Serum of CLA-treated
pigs showed a trend toward increased levels of triacylglycerols, cholesterol and
phosphatidylcholine in the very low density and low density lipoproteins (LDL),
without distinct changes in the high density lipoprotein fraction (HDL). The LDL
cholesterol to HDL cholesterol ratio was significantly increased by CLA. When
pigs were fed CLA at a dietary level of 1%, limited proportions of CLA appeared
in fasting serum (1.6%) and erythrocyte membranes (1.1%). CONCLUSIONS: Under the
present experimental conditions there appeared to be parallels between the
effects of CLA and the reported effects of trans fatty acids in the mode of
action on lipoproteins and insulin. The failure to demonstrate significant
beneficial effects of CLA on the lipoprotein profile which have been observed in
other studies requires further research.
PMID- 10784384
TI - Dietary fiber reduces the antioxidative effect of a carotenoid and alpha
tocopherol mixture on LDL oxidation ex vivo in humans.
AB - BACKGROUND: Antioxidant concentrations in low density lipoproteins (LDL) are an
important determinant for their susceptibility to oxidation and can be modulated
by dietary intake. AIM OF THE STUDY: In the present study, the influence of
dietary fiber on the antioxidant enrichment and the oxidation resistance of LDL
after antioxidant supplementation is investigated. METHOD: An antioxidant
supplement consisting of beta-carotene, lycopene, lutein, canthaxanthin and alpha
tocopherol was given to six young women together with a standard meal. Using a
cross-over study design, each subject received the standard meal without
additional dietary fiber and enriched with pectin, guar, or cellulose in a random
order. To determine the resistance of LDL against copper ion-induced oxidation,
the formation of conjugated dienes was measured. RESULTS: Eight, 10, and 24 hours
after antioxidant supplementation the isolated LDL revealed significantly (p <
0.05) increased antioxidant concentrations; addition of pectin, guar, or
cellulose to the meal depressed this increase. Concomitantly, the observed
increase in the resistance of LDL against oxidation (measured as lag phase) was
lower with dietary fiber supplementation than that found without. On average,
pectin, guar, and cellulose reduced the increase of the lag phase (measured
without addition of dietary fiber) by 38%, 22%, and 18%, respectively.
CONCLUSIONS: These results indicate that dietary fiber supplementation decreases
the antioxidative effect of a supplement consisting of carotenoids and alpha
tocopherol in LDL, an effect that is likely to be mediated by a reduced
bioavailability of these antioxidants in the gut.
PMID- 10784386
TI - Extracorporeal photochemotherapy in the treatment of severe graft-versus-host
disease.
AB - Advances in posttransplant immunosuppression have to the present not been able to
prevent the development of graft-versus-host disease (GVHD) in patients given
related or unrelated stem cell grafts for cure of hematologic diseases. Patients
with GVHD not responding to first line therapy with corticosteroids remain at
high risk of death due to severe infections or organ failure. Extracorporeal
exposure of peripheral blood mononuclear cells to the photosensitizing agent 8
methoxypsoralen and ultraviolet A radiation has been shown to be effective in
treatment of selected T-cell mediated diseases, including cutaneous T-cell
lymphoma and rejection after organ transplantation. Extracorporeal
photochemotherapy (ECP) is also a safe and efficacious adjunct therapy for both
acute and chronic extensive GVHD with skin and visceral involvement and
resistance to conventional immunosuppressive therapy. A multicenter randomized
study should help define the impact of ECP in the treatment of GVHD and overall
survival of these patients.
PMID- 10784385
TI - Impact of diets with corn oil or olive/sunflower oils on DNA damage in healthy
young men.
AB - BACKGROUND: Plant fats and oils are major sources of mono- and polyunsaturated
fatty acids as well as vitamin E, the major fat-soluble antioxidants in human
nutrition. Dietary antioxidants are expected to reduce cancer risk by minimizing
DNA damage. AIM OF THE STUDY: To compare the effects of gamma-tocopherol rich
corn oil and the mixture of the alpha-tocopherol rich olive/sunflower oil on
plasma concentration of tocopherols and on the frequency of sister chromatid
exchange (SCE), an indicator of DNA damage. METHODS: This study had a double
blind, cross-over design and was conducted in 20 normal healthy non-smoking males
aged 19-31 years. Design included a 2-week adjustment period and two 2-week test
periods in which diets containing 30% energy as fat including either 80 g of corn
oil (CO) (20 mg alpha-tocopherol, 100 mg gamma-tocopherol) or 80 g of olive/
sunflower oil (OSO) (24 mg alpha-tocopherol, 2.4 mg gamma-tocopherol), as the
main fat-source, were given. Blood samples for analysis of SCE rate and content
of tocopherols were collected at the beginning (T0), after adjustment (T1) and
after the test period (T2) in intervals of 2 weeks. RESULTS: After two weeks of
the corn oil diet, the plasma concentration of gamma-tocopherol increased but
alpha-tocopherol decreased significantly compared to the olive/sunflower oil
diet. The concentration of alpha-tocopherol increased (CO: 22.99 +/- 1.11 vs.
OSO: 24.40 +/- 1.49 micromol/l) and that of gamma-tocopherol decreased (CO: 4.19
+/- 0.29 vs. OSO: 2.99 +/- 0.25 micromol/l) after the olive/sunflower oil diet.
Intake of the corn oil diet was associated with reduced SCE rate and intensity,
whereas there was no change in SCE after the olive/sunflower oil diet (CO: 7.66
+/- 0.25 vs. OSO: 8.06 +/- 0.47 mean SCE/cell) CONCLUSIONS: The combination of
gamma-tocopherol with alpha-tocopherol in corn oil diet despite the lower alpha
tocopherol equivalents/diene acid equivalents ratio achieved better protection
against DNA damage than alpha-tocopherol alone in the olive/sunflower oil diet.
PMID- 10784387
TI - The t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma.
AB - t(9;14)(p13;q32) is a rare but recurring translocation found in a subset of B
cell non-Hodgkin's lymphoma (B-NHL). These lymphomas share clinical features with
chronic lymphocytic leukemia and are further characterized by plasmacytoid
differentiation of lymphoma cells. Molecular cloning of t(9;14)(p13;q32) revealed
juxtaposition of the PAX5 to the immunoglobulin heavy chain gene (IGH), although
breakpoints on both genes were variable. The PAX5 gene encodes the BSAP (B-cell
specific activator protein) transcription factor, which is expressed throughout
the process of B-cell development except in terminally differentiated plasma
cells. t(9;14)(p13;q32) consistently leaves the PAX5 coding region intact, most
likely resulting in deregulated expression of the gene product due to the
proximity of IGH. The majority cases of B-cell tumors expressed considerable
levels of PAX5/BSAP irrespective of whether they exhibited t(9;14)(p13;q32),
suggesting that quantitative differences in expression level alone may not
account for the development of this particular subtype of B-NHL.
PMID- 10784388
TI - Primary effusion lymphoma cell lines harbouring human herpesvirus type-8.
AB - Primary effusion lymphoma (PEL) is a novel lymphoma entity consistently infected
by HHV-8 that occurs predominantly in immunodeficient patients and is
characterized by liquid growth in the serous body cavities. In order to
facilitate the understanding of PEL pathogenesis and histogenesis, we have
established three PEL cell lines termed CRO-AP/2, CRO-AP/3 and CRO-AP/5. All cell
lines have been derived from HIV positive homosexual men affected by PEL with (in
the case of CRO-AP/2 and CRO-AP/5) or without (in the case of CRO-AP/3) a
previous history of Kaposi's sarcoma. The cell lines are representative of both
virologic variants of PEL, i.e. HHV-8+ EBV+ PEL (CRO-AP/2 and CRO-AP/5) and HHV
8+ EBV- PEL (CRO-AP/3). Morphologic and phenotypic features of CRO-AP/2, CRO-AP/3
and CRO-AP/5 are typical of PEL, and include morphology bridging immunoblastic
and anaplastic features as well as an indeterminate (non B- non T-cell)
phenotype. The B-cell nature of the cell lines is documented by the presence of
rearranged immunoglobulin genes. The detailed analysis of the molecular and
phenotypic features of CRO-AP/2, CRO-AP/3 and CRO-AP/5 has allowed the
identification of recurrent chromosomal abnormalities of PEL and has contributed
to the definition of PEL as a lymphoma of post-germinal center, pre-terminally
differentiated B-cells.
PMID- 10784389
TI - Leptin receptor and leukemia.
AB - The receptor for leptin, the gene product of the obese gene, is expressed in
hematopoietic stem cells. Leptin stimulates normal myeloid and erythroid
development, and is secreted from bone marrow adipocytes, which occupy most of
the marrow cavity in humans. Leptin might thus play an important role in the
control of the expansion and differentiation of primitive hematopoietic cells
through paracrine interaction in the bone marrow microenvironment. Leukemic cells
of some patients with acute myeloblastic leukemia, acute lymphoblastic leukemia,
and chronic myeloid leukemia (CML) also express the leptin receptor. In cases of
CML, higher expression of leptin receptor is observed during blast crisis than in
chronic phase. Leptin alone and in combination with other cytokines has
stimulative effects on proliferation of leukemia cells as well as anti-apoptotic
effects. These findings suggest the possibility that leptin plays roles in the
pathophysiology of leukemia.
PMID- 10784390
TI - Clinical implications of aberrant TSG101 transcripts in acute myeloblastic
leukemia.
AB - Tsg101 is a mouse tumor suppressor gene whose homozygous deletion produces
transformation of NIH3T3 cells and leads to metastases in nude mice. The human
homologue of the gene, TSG101, is localized in chromosome 11p15.1-p15.2. Reduced
TSG101 expression may cause the defect of the cell cycle checkpoint that leads to
genetic instability and consequently to the progression of neoplasia. Aberrant
TSG101 transcript have been identified in many types of cancers, and the
relaxation of RNA splicing fidelity may be an onco-developmental marker in
cancers and could play a general role in tumorigenesis. In our previous study,
smaller TSG101 transcripts were found in AML specimens, hematopoietic cell lines
and normal controls. The aberrant transcripts occurred more frequently in the AML
cases and cell lines. The patients with aberrant TSG101 transcripts had higher
initial white cell count, lower LDH level, and lower complete remission rate
after induction chemotherapy. However, further multivariate analysis of clinical
data revealed that there was no relationship to the TSG101 aberrant transcripts.
The clinical significance of TSG101 aberrant transcript in AML needs further
evaluation.
PMID- 10784391
TI - Clinical significance of deletions of chromosome arm 6q in childhood acute
lymphoblastic leukemia: a report from the Children's Cancer Group.
AB - We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%)
children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted
treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients
had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a
secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (>50
chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of
a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and
q25. Patients with a del(6q) were more likely to have T-lineage ALL (p < 0.001),
a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only
half of these patients were classified as poor risk. Event-free survival at 6
years was similar for patients with or without a del(6q), with estimates of 77%
(SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also
observed within NCI poor and standard risk groups. Thus, cytogenetically
detectable del(6q) is not associated with adverse risk in pediatric ALL.
PMID- 10784392
TI - Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or
relapsed acute leukemia.
AB - Topotecan is a topoisomerase I inhibitor with significant activity in patients
with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical
data suggest a synergistic activity with DNA damaging agents such as
cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide
induced DNA damage. We thus designed a combination including cyclophosphamide 500
mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous
infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours
daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were
treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute
myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL)
(refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79
years). Eleven patients (17%) achieved a complete remission (CR), and two
patients (3%) had a hematologic improvement (HI; met all criteria for CR except
for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses
occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and
in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23
episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin
complicating 74 courses of CAT. Non-hematologic toxicity was mostly
gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was
severe in only 8%. In summary, the CAT regimen is well tolerated and has
significant anti-leukemia activity which warrants further investigation.
PMID- 10784393
TI - A four-parameter index of marrow dysplasia has predictive value for survival in
myelodysplastic syndromes.
AB - Marrow dysplasia is a major characteristic of patients with myelodysplastic
syndrome (MDS), along with marrow blastosis, cytopenia and cytogenetic anomalies.
However, the impact of the degree of marrow dysplasia on survival has not been
fully assessed. In this retrospective analysis of 111 patients selected according
to the IPSS criteria of MDS diagnosis, the presence or absence of 21 dysplasia
characteristics recognizable in bone marrow smears stained by the May-Grunwald
Giemsa method was correlated with patient survival. Using Cox proportional
hazards regression analysis, megaloblastosis (MEGALO), neutrophil agranularity
(AGRAN) and hypogranularity (HYPOGRAN) were highly significant predictors (p <
0.005), and Pelger-Huet anomaly (PELGHUET) a significant predictor (p = 0.05), of
patient survival. The regression analysis yielded a dysplasia-based risk index
(DI) where DI = 1.26 MEGALO + 0.82 AGRAN - 1.08 HYPOGRAN + 0.45 PELGHUET. The two
subgroups of 60 and 47 patients with DI < or = 0 and > 0 showed highly
significant differences in median survivals (2.6 vs 1.1 yrs; p <0.0001).
Multivariate analysis further showed that DI offered additional predictive power
that was independent of that provided by the IPSS (p=0.002 and 0.001
respectively). Analysis of survival curves stratified for IPSS and DI showed that
the additional predictive power offered by inclusion of the DI essentially
concerned the IPSS low/INT-1 risk categories. Further stratification for age did
not improve survival prediction. The data indicate that a set of 4 dysplasia
parameters can offer some prediction for survival of MDS patients in addition to
that provided by the IPSS. Further multicenter studies should aim at including
some form of evaluation of the degree of dysplasia in prognostic systems.
PMID- 10784394
TI - High dose chemotherapy without hematopoietic cell support for the treatment of
refractory lymphoma.
AB - Conventional dose combination chemotherapy for patients with relapsed or
refractory lymphoma is rarely curative. High dose chemotherapy followed by
hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in
patients who have first relapsed after standard CHOP chemotherapy for lymphoma.
However, the role of HPCT is less well defined for patients with chemo-resistant,
or chemo-refractory disease. Sixteen patients (15 Non-Hodgkin's, 1 Hodgkin's
Disease) were entered into a phase II study to determine if a dose intensive
induction regimen in heavily pre-treated refractory lymphoma patients could
permit further consolidation with HPCT. The primary endpoints were survival,
response, toxicity, and resource utilization. The regimen consisted of continuous
infusion etoposide 1 or 2 gm/m2/72 hours, idarubicin 12 mg/m2/d for 3 days
followed by cytarabine 2 gm/m2/72 hours on days 8, 9, and 10 (VIC). Fifteen
patients were evaluable for objective response. The overall response rate was 53%
with 7 patients achieving a partial response and 1 patient achieving a complete
response. Of the 8 responders, 6 patients subsequently received high dose
chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival
was 176 days for the non-responders contrasted with 722 days for the responders.
The average duration of hospitalization was 38 days. Toxicity was mainfest
primarily as mucositis with a median grade of 3 among the first 13 patients, and
a median grade of 2 in three subsequent patients who received an etoposide dose
of 1 gm/m2/72 hours. All patients had an episode of neutropenic fever and 5
patients developed clinically significant pneumonitis during therapy. The VIC
regimen is active in the treatment of chemo-refractory lymphoma with clinically
significant differences in survival for patients who respond to therapy. Further
modifications to the regimen could include the addition of a topoisomerase I
inhibitor for synergy with etoposide, and using VIC as part of a tandem
transplant regimen where response to VIC would allow further therapy with a
myeloablative induction followed by HPCT.
PMID- 10784395
TI - Simultaneous detection of BCL-2 protein, trisomy 12, retinoblastoma and P53
monoallelic gene deletions in B-cell chronic lymphocytic leukemia by fluorescence
in situ hybridization (FISH): relation to disease status.
AB - Various genetic abnormalities are often found in B-CLL, but their relative
importance in the pathogenesis and evolution of the disease has not been
adequately clarified. We studied the expression of bcl-2 protein and the possible
simultaneous occurrence of bcl-2 overexpression, trisomy 12 and the Rb1 and p53
gene deletions in 38 patients with B-CLL by combining immunophenotyping and dual
color interphase FISH. We also looked for correlation between the genetic
abnormalities and clinical parameters such as stage, disease duration from
diagnosis to the time of study and overall survival. High expression of the bcl-2
protein was found in 76.3% of the patients (29/38). Trisomy 12 was found in 37%
of cases (14/38) and Rb1 monoallelic gene deletion in 42% (16/38). The percentage
of cells with hemizygous Rb1 deletion ranged from 13 to 18%. Monoallelic deletion
of p53 was found in 29% of cases (11/38). The number of cells with only one
signal ranged from 28 to 98%. Patients in stage A had on average, less than one
abnormality, while patients in stage C had 2.6 abnormalities. Patients appeared
to accumulate genetic abnormalities with time. Bcl-2 overexpression was found
early in the course of the disease. Trisomy 12 appeared later, at about the same
time as Rb1 deletion, but was not associated with adverse prognosis. Monoallelic
deletion of p53 gene appeared rather late in the course of the disease and was
associated with advanced stage. Despite the fact that more deaths occurred in the
group of patients with three or four abnormalities and the presence of p53 gene
deletion, differences in survival were not statistically significant, probably
due to the limited number of patients in each group. A larger group of patients
studied in a prospective manner will better clarify these issues in the future.
PMID- 10784396
TI - Clinical significance of the t(14;18) and BCL2 overexpression in follicular large
cell lymphoma.
AB - Follicular large cell lymphoma (FLCL) is an aggressive disease that responds to
anthracycline-containing chemotherapy much like diffuse large B-cell lymphoma
(DLBCL). Since the t(14;18) and/or bcl2 protein expression are less common in
FLCL than in its low-grade counterparts, we sought to determine whether these
features were predictive of survival as in DLBCL. We studied 50 patients with
FLCL who were treated with curative intent. The t(14;18) was found by cytogenetic
analysis in 56% of the patients and bcl2 protein was expressed by the tumor cells
in 73%, but neither was predictive of survival. However, abnormalities of
chromosome 17p and the presence of trisomy 21 were adverse predictors of
survival, as were a number of clinical features. We conclude that neither the
absence of the t(14;18) nor the lack of bcl2 expression explain the good response
of a subset of patients with FLCL to curative therapy.
PMID- 10784397
TI - A prospective study of the LMB regimen for diffuse large cell non Hodgkin's
lymphoma in adults.
AB - Although the CHOP regimen remains a standard first line chemotherapy for diffuse
large cell lymphoma (DLCL) in adults, a majority of these patients will still
experience disease progression after the completion of this treatment. The LMB
protocol is an intensive chemotherapy regimen which yields high survival rates in
Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL) in children, as
well as in primary cerebral DLCL (PCL) of adults. Here, we report the long term
results of this regimen in a prospective series of 22 adult patients with DLCL
excluding PCL. Fifteen male and 7 female patients with a median age of 30 years
(range: 20-55) were treated prospectively between 1988 and 1993. 16 (72%)
patients had an age adjusted International Pronostic Index (IPI) > or = 1. The
median duration of the treatment was 15 weeks (range 13-19). Nineteen of the 22
patients (87%) experienced an objective response (14 complete, and 5 partial
responses) at the end of the protocol. The predominant toxicity was
myelosuppression: 89% of the COPADEM courses were followed by grade IV
neutropenia and 5% with grade IV infection. One patient died (4%) of treatment
related toxicity. With a median follow-up of 94 months and a minimum follow-up of
65 months, 8-year overall and progression-free survival are 73% and 67%
respectively. The 8 year overall survival were 100%, 78% and 42% in patients with
an IPI 0, 1, and 2-3 respectively. This short intensive regimen yields promising
long term survival rates in this monocentric prospective study and may deserve to
be tested in a larger multicentric prospective study comparing it to the CHOP
regimen.
PMID- 10784398
TI - Serum erythropoietin and thrombopoietin levels in patients with essential
thrombocythaemia.
AB - In 40 patients with essential thrombocythaemia (ET) serum erythropoietin (EPO)
and thrombopoietin (TPO) concentrations were determined and compared with the EPO
and TPO values of a healthy control group. The mean EPO serum concentration for
24 control patients was 9.4 mU/ml +/- 3.7 (range 2-17.9), for 32 untreated ET
patients at diagnosis 6.6 mU/ml +/- 7.6 (range 0.5-44.3) and for 8 ET patients
treated with cytoreduction 14.1 mU/ml +/- 8.0 (range 4.5-26.1). Serum EPO levels
in untreated ET patients at diagnosis were significantly lower compared with
serum EPO levels in healthy control patients (p=0.002). Serum EPO levels in
treated ET patients were not different from serum EPO levels in healthy controls
(p=0.13) but were significantly higher compared with untreated ET patients
(p=0.003). Serum TPO levels were determined in 18 of 40 ET patients, the mean TPO
serum concentration was 211 pg/ml +/- 109 (range 62,5-345). The mean TPO serum
concentration for 10 untreated ET patients at diagnosis was 162 pg/ml +/- 87
(range 62,5-302) and for 8 ET patients who had received cytoreductive treatment
272 pg/ml +/- 106 (range 96-345), respectively (p=0.04). Both serum TPO levels
for treated and untreated ET patients were significantly higher (p<0.001)
compared with serum TPO levels for healthy controls. The results of our study
suggest a difference in the regulation of serum EPO and TPO in patients with ET.
While the mean serum EPO level is decreased in untreated ET patients, the
corresponding mean serum TPO level is increased. Treatment with cytoreduction,
results in normalisation of the mean serum EPO level, whereas the mean TPO serum
level remains elevated.
PMID- 10784399
TI - Acute myeloblastic leukemia secondary to myelodysplasia (MDS-AML): a comparison
of remission induction with three drugs versus standard two-drugs induction.
AB - To evaluate the addition of a third drug to standard induction chemotherapy in
patients with MDS-AML, 23 patients (males/females 13/10, median age 54.3 years,
range 24-74 years, median MDS duration 9.8 months, range 2-39 months) who
received a standard 2-drugs induction were compared with 23 patients
(males/females 11/12, median age 45.6 months, range 21-60 years, median MDS
duration 8.3 months, range 2-29 months) who received an intensified 3-drugs
induction with etoposide. CR rate, median CR duration and median OS were similar
in both groups (48% vs 56%, 4.8 vs 5.9 months, 6.5 vs 7.0 months respectively).
Among responding patients, all but one, who underwent allogeneic bone marrow
transplantation, relapsed. In conclusion, addition of a third drug (etoposide)
does not seem to significantly improve the poor prognosis of MDS-AML patients.
PMID- 10784400
TI - CD40 ligand-induced apoptosis is Fas-independent in human multiple myeloma cells.
AB - We and others previously demonstrated that human multiple myeloma (MM) cells
express CD40 and have an active CD40-growth regulatory pathway. This study
characterizes the growth outcome of soluble (gp39) or membrane-bound recombinant
human CD40-ligand (rCD40L) and its relationship with Fas-dependent apoptosis.
Contrary to the moderate growth-stimulatory effect of the CD40-MAb G28.5, gp39
inhibited 3H-thymidine uptake of the plasma dyscrasia lines ARH-77, U266, and HS
Sultan in a dose-dependent fashion by up to 82%. By comparison, RPMI 8226 cells
were resistant to CD40L-growth modulation, which may be attributable to a single
base substitution (TCA-->TTA, serine-->leucine) at the 3rd cysteine-rich
extramembrane region of CD40. Gp39 similarly reduced myeloma clonogenic colony
(MCC) formation in patient primary bone marrow cultures by 50% (40-76%; n=6).
Studies using transfectant L cells that constitutively expressed CD40L showed
that membrane-bound CD40L inhibited the growth of ARH-77, U266, and HS-Sultan
cells (66%, 63%, and 32%, respectively), whereas untransfected L cells did not.
Growth inhibition by gp39 or CD40L+ L cells was neutralized by coincubation with
the CD40L antibodies 5c8 or LL48. CD40L-treatment increased apoptotic activity of
MM cells, as defined by oligonucleosomal DNA fragmentation and an increased
binding to annexin V (16-28%). All three untreated CD40-responsive MM lines
expressed the Fas/Apo-1/CD95 antigen (65-92% CD95+). However, only ARH-77 cells
responded to the growth inhibitory effect of the CD95-agonistic antibody CH-11.
CD95 expression was not affected significantly by gp39 treatment, and growth
inhibition by CH-11 was additive to gp39 (from 42% to 64% decrease in 3H-thmidine
uptake). Conversely, the CD95 antagonist antibody ZB4 reversed the Fas-dependent
growth inhibitory process but did not significantly alter gp39-mediated growth
outcome. Gp39 treatment lowered the expression of TNFR-associated factors TRAF4
and TRAF6 by 38% and 32%, respectively, whereas detectable levels of TRAF1,2,3,
and 5 levels remained unchanged. Our observations indicate that the CD40L-binding
inhibits human MM cell growth and increases its apoptotic activity. This growth
inhibitory effect corresponds to lower levels of cytoplasmic TRAF signaling
elements, and appears independent of the Fas-signaling pathway. CD40 receptor
mutation may lead to unresponsiveness to CD40 growth modulation in multiple
myeloma cells.
PMID- 10784401
TI - Induction of apoptosis by 2-chloro-2'deoxyadenosine (2-CdA) alone and in
combination with other cytotoxic drugs: synergistic effects on normal and
neoplastic lymphocytes by addition of doxorubicin and mitoxantrone.
AB - 2-CdA is active as a single agent in the treatment of low-grade lymphomas. We
analyzed the induction of apoptosis by 2-CdA alone (n=5) and in combination with
other drugs in peripheral lymphocytes from 25 patients with leukemic low-grade
lymphomas and from 25 healthy volunteers. 2-CdA was tested in 4 escalating
concentrations (0.05 microg/ml to 0.4 microg/ml). Linear regressions showed a
dose dependent apoptosis rate of 0.29 x microg 2-CdA/ml + 0.11 (r2=0.88, p=0.006)
in normal cells and 0.41 x microg 2-CdA/ml + 0.15 (r2=0.88, p=0.005) in leukemic
cells. Intracellular metabolization of 2-CdA into 2-CdA-5'mono-, -di- and the
active metabolite -triphosphate was analyzed by HPLC and paralleled the dose
dependent increase of apoptosis. The combination of 2-CdA with doxorubicin or
mitoxantrone had a synergistic effect on the induction of apoptosis (p<0.001) in
both normal and neoplastic lymphocytes, whereas 2-CdA plus etoposide or cytosine
arabinoside were only additive. Due to the flat slope of the dose response of 2
CdA concentration on apoptosis we assume that higher in vivo dosages of 2-CdA in
the treatment of low-grade lymphomas may not result in a higher clinical
efficacy. The synergistic lymphocytotoxic effect of 2-CdA combined with
doxorubicin or mitoxantrone may be relevant for new treatment approaches.
PMID- 10784402
TI - Effect of antisense oligonucleotides on CD34+ cells from chronic myeloid
leukemia.
AB - Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder
characterized by a specific hybrid gene BCR-ABL (formed as a result of t(9;22)).
This leads to two possible mRNA usually present in leukemic cells, either B2A2 or
B3A2. Targeting these mRNA by antisense oligonucleotides (AS) might offer the
opportunity to decrease leukemic growth. We have tested the ability of AS to
inhibit the in vitro proliferation of CD34 positive (CD34+) blood cells from 16
patients with newly diagnosed CML. CD34+ cells were isolated by an immunomagnetic
technique and incubated for 16 to 18 hours with an 18 mer AS (0.25 mM). Sense
oligonucleotides served as controls. The effects of AS were evaluated by
clonogenic test (production of CFU-GM). Moreover, colonies were picked out and
studied by RT-PCR to analyse the presence of BCR-ABL transcript. For nine
patients with B3A2 transcript, the median inhibition of CFU-GM formation at day
14 was 64.0 +/- 11.2% (68.0 +/- 11.4% at day 21) and for the seven patients with
a B2A2 transcript: 59.0 +/- 11.4% (72.5 +/- 12.0% at day 21). AS showed no effect
on CD34+ cells from three normal volunteer donor cells. However, for every
patient studied, colonies picked out remained BCR-ABL positive with the RT-PCR
technique.
PMID- 10784403
TI - Telomerase activity in preleukemia and acute myelogenous leukemia.
AB - The development of acute leukemia from preleukemia involves the appearance of
clones with increasing proliferative potential. The studies described here
demonstrate that telomerase activity progressively increases as the bone marrow
cells acquire increasing proliferative potential. This was demonstrated by
measuring telomerase activity in normal bone marrow, in post-treatment lymphoma
marrows with skewed Lyonization, and in MDS and AML marrows. The greater
telomerase activity in myelodysplastic marrow than in normal marrow is not due to
a higher proportion of blast cells or to a higher proliferative rate of the MDS
marrow. These data demonstrate that the increasing proliferative potential of the
marrow which occurs during the development of AML is associated with a
simultaneous increase in telomerase activity.
PMID- 10784404
TI - Priming effects of macrophage colony-stimulating factor on monocytic leukemia
cells in combination with chemotherapy: induction of programmed cell death in
vivo.
AB - Two elderly patients with chronic myelomonocytic leukemia were treated with
cytosine arabinoside (Ara-C) and aclarubicin (ACR) under simultaneous
administrations of macrophage colony-stimulating factor (M-CSF) (CAM), and both
obtained good responses. Examination of apoptosis using flow cytometry revealed
induction of apoptotic death of leukemia cells by CAM in Patient 2, while neither
induction of apoptotic death of leukemia cells nor clinical response were seen
with CAG (Ara-C, ACR, and granulocyte colony-stimulating factor) given prior to
CAM in Patient 1. These findings suggested that chemotherapy combined with
simultaneous administration of M-CSF could effectively reduce monocytic leukemia
cells by inducing programmed cell death.
PMID- 10784405
TI - Induction of TrkA expression by differentiation inducers in human myeloid
leukemia KG-1 cells.
AB - We have recently reported that retinoic acid (RA) induced the expression of trkA,
the high affinity receptor for nerve growth factor (NGF), in human myeloid
leukemia KG-1 cells. In the present study, we report that the expression of trkA
was also induced by several other differentiation inducers, including 1alpha, 25
dihydroxyvitamin D3 (Vit D3), 1-beta-D-arabinofuranosyl cytosine (Ara-C), sodium
butyrate (NaBut), and phorbol 12-myristate 13-acetate (PMA). Interestingly, RA in
combination with NaBut or PMA synergistically induced cellular differentiation as
well as the expression of trkA in KG-1 cells. Furthermore, activation of the
induced trkA receptor by exogenous NGF potentiated the differentiating effects of
RA and NaBut. Our results demonstrated that the induction of trkA is an event
associated with the differentiation of KG-1 cells. Our findings suggest that NGF,
in addition to its pivotal roles in the nervous system, may also play important
roles in hematopoietic differentiation.
PMID- 10784406
TI - The human tartrate-resistant acid phosphatase (TRAP): involvement of the hemin
responsive elements (HRE) in transcriptional regulation.
AB - The biochemical properties and protein structure of the tartrate-resistant acid
phosphatase (TRAP), an iron-containing lysosomal glycoprotein in cells of the
mononuclear phagocyte system, are well known. In contrast, little is known about
the physiology and genic structure of this unique enzyme. In some diseases, like
hairy cell leukemia, Gaucher's disease and osteoclastoma, cytochemically detected
TRAP expression is used as a disease-associated marker. In order to begin to
elucidate the regulation of this gene we generated different deletion constructs
of the TRAP 5'-flanking region, placed them upstream of the luciferase reporter
gene and assayed them for their ability to direct luciferase expression in human
293 cells. Treatment of these cells with the iron-modulating reagents transferrin
and hemin causes opposite effects on the TRAP promoter activity. Two regulatory
GAGGC tandem repeat sequences (the hemin responsive elements, HRE) within the 5'
flanking region of the human TRAP gene were identified. Studies with specific HRE
deletion constructs of the human TRAP 5'-flanking region upstream of the
luciferase reporter gene document the functionality of these HRE-sequences which
are apparently responsible for mediating transcriptional inhibition upon exposure
to hemin. In addition to the previously published functional characterization of
the murine TRAP HRE motifs, these results provide the first description of a new
iron/hemin-responsive transcriptional regulation in the human TRAP gene.
PMID- 10784407
TI - Neoplastic cell activation and proliferative response to CD40-ligand characterize
recurrent leukemic bouts in an unusual case of low grade lymphoma.
AB - Spontaneous fluctuations in activity of low-grade B cell lymphomas are common but
not understood. An explanation may be offered by studying an atypical SLL/CLL
case characterized by recurrent cycles of leukemic phase alternating with
spontaneous remission (1). During remissions, residual IgMkappa+ leukemic cells
exhibited resting phenotype, low proliferative response to CD4O-ligand and
delayed apoptosis. In contrast, the acute phase counterparts were phenotypically
activated, underwent rapid apoptosis in culture and proliferated extensively in
response to membrane-anchored CD40-ligand. Transient bursts of serum TNFalpha and
IL-10 preceded the acute phases, which were characterized by the co-existence of
CD40-ligand+ T lymphocytes and lymphoma cells in the bone marrow. Based on ex
vivo and in-vitro data, we suggest that changes in the lymphoma milieu affect the
neoplastic cell activation status, rate of proliferation in response to activated
T cells and rate of apoptosis. These responses may underlie both the induction
and spontaneous regression of the acute phases in this unique lymphoma. Our
findings raise the possibility that part of this mechanism may have evolved
during transformation of indolent common CLL to its more aggressive form.
PMID- 10784408
TI - Prolonged third remission in a patient with acute promyelocytic leukemia after
consolidation chemotherapy with intermittent intermediate dose ara-C and
maintenance with intermittent all-trans retinoic acid (ATRA).
AB - The benefit of all-trans-retinoic acid (ATRA) in the front line therapy of acute
promyelocytic leukemia (APL) is well established, but its role in postremission
therapy and in the treatment of relapse is currently under investigation.
Moreover, the impact of cytosine arabinoside (Ara-C) in the therapy of APL has
been questioned in recent studies. We report a prolonged third molecular
remission (MR) in a patient with hyperleukocytotic APL after induction with ATRA,
consolidation chemotherapy (CT) with intermittent intermediate dose Ara-C and
maintenance therapy with intermittent ATRA. While the first two remissions were
relatively short (8 months and 11 months, resp.), the duration of the third
continuous CR (49+ months) is more than twice as long as the length of the two
previous remissions combined. In this case Ara-C followed by intermittent ATRA
maintenance was a safe and effective therapy for relapsed disease. A third
molecular remission of such duration and quality is unusual.
PMID- 10784409
TI - Myelodysplasia presenting as granulocytic sarcoma of mediastinum causing superior
vena cava syndrome.
AB - Granulocytic sarcomas (GS) are extramedullary tumor masses of immature myeloid
cells, most frequently associated with hematological disorders including acute
myeloid leukemia (AML), chronic myelogenous leukemia (CML), and myelodysplastic
syndrome (MDS). Recent interest has centered upon the possible biologic
properties that enable theses myeloid cells to adhere to tissues and establish a
tumor mass. GS presenting as a mediastinal mass is relatively infrequent, and
more uncommon is presentation with the superior vena cava syndrome. We present
one such case and review some of the available literature.
PMID- 10784410
TI - Mycobacterium-avium-intracellulare complex infection following 2
chlorodeoxyadenosine therapy for hairy cell leukaemia.
AB - 2-Chlorodeoxyadenosine (2-CdA) is associated with prolonged suppression of CD4
lymphocytes. Cases of tuberculosis or mycobacterium avium intracellulare complex
(MAC) infection complicating 2-CdA administration have not been reported despite
the low CD4 counts. We report a patient with Hairy Cell Leukaemia (HCL) who
developed MAC infection one month following 2-CdA treatment. This patient had
been previously treated with prednisone for Sweets Syndrome. It would appear that
the combination of 2-CdA and prednisone predisposes patients to MAC infection,
and if possible this combination of treatment should be avoided.
PMID- 10784411
TI - Is nitrotyrosine generated in human erythrocytes in circulation?
AB - Nitrotyrosine is considered a stable biomarker of reactive nitrogen species,
including nitrogen dioxide (NO2) and peroxynitrous acid (ONOOH) in biomaterials.
There are inconsistent observations on the detection of free and protein
associated nitrotyrosine in normal human plasma. Human erythrocytes,
differentiated from erythrocyte precursor cells in the bone marrow, circulating
in the body for an average of 120 d, and finally removed by spleen macrophages,
may be exposed to reactive nitrogen species. In the present study, membrane
proteins and hemoglobin from the senescent erythrocyte population were compared
with those from young erythrocytes separated from the same individuals in their
nitrotyrosine presence using newly prepared rabbit polyclonal anti-nitrotyrosine
ribonuclease A and anti-nitro(N-butoxycarbonyl)tyrosine-bovine serum albumin
antibodies. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the
membranes and hemoglobin, and subsequent Western blot analysis, showed that these
antibodies only slightly bind to the bands of the proteins from both young and
senescent erythrocytes, whereas these antibodies definitely bind to the protein
bands of membranes and hemoglobin nitrated by NO2 or ONOOH in vitro. This result
indicates that nitrotyrosine is not detected in the membrane proteins and
hemoglobin in human normal erythrocytes in circulation. However, this does not
conclude that erythrocytes are not exposed to reactive nitrogen species in the
circulation.
PMID- 10784412
TI - A novel Van91 I polymorphism in the 1st intron of the parathyroid hormone
(PTH)/PTH-related peptide (PTHrP) receptor gene and its effect on the urinary
cAMP response to PTH.
AB - This study was designed to identify a parathyroid hormone (PTH)/PTH-related
peptide (PTHrP) receptor gene polymorphism in a healthy Japanese population. All
known 13 introns of this gene were amplified by PCR, except the 1st intron, which
was amplified by the long-PCR method. No restriction fragment length
polymorphisms (RFLPs) were detected by BsmI or XbaI in any of these introns.
Twenty-one other restriction enzymes (Hind III, Bgl II, Sty I, Pvu II, Eco81 I,
Van91 I, BstX I, Sse8387 I, EcoR I, BamH I, Mbo II, Tth111 I, PshA I, Eam1105 I,
Not I, Srf I, Bgl I, Fok I, Sfi I, Apa I, Taq I) were tested on the 1st intron.
Furthermore, digestion by Van911 (CCANNNNNTGG) identified a single, two-allele
polymorphism with a fragment of approximately 3.5 kb (V allele) or a fragment of
3.1 and 0.4 kb (v allele). The frequency of the Van91 I polymorphism in 106
healthy Japanese volunteers was 77.4% for type vv, 19.8% for type Vv and 2.8% for
type VV. In addition, the urinary cAMP response to exogenous [1-34]PTH was
studied in 17 healthy volunteers and found to be significantly greater in persons
with type Vv than type vv (p<0.05). In conclusion, the Van91 I polymorphism of
the PTH/PTHrP receptor gene can be used to study the role of polymorphism in
various disorders involving PTH or PTHrP.
PMID- 10784413
TI - Some factors which influence intrinsic factor content and its mRNA level in the
rat stomach.
AB - Factors which regulate Intrinsic Factor (IF) content and IF mRNA level were
examined with an abc-ELISA and Northern blot analysis in growing rats, and
compared with pepsinogen (Pg) and in terms of the increased need for vitamin B12
(V.B12). Increases in IF content and IF mRNA level gradually occurred from day 13
after birth, whereas those of Pg and Pg mRNA started from day 16. The effects of
a few related hormones on the expression of IF mRNA were examined. The injection
of hydrocortisone induced IF and Pg mRNA expression in 5-d-old postnatal rats.
Furthermore, adrenalectomy-induced decreases in IF content and IF mRNA level in
adult male rats were recovered with hydrocortisone administration. IF content and
IF mRNA level were measured in the artificially and physiologically created needs
for V.B12, the first being regeneration of the liver, the V.B12 storing tissue,
following partial hepatectomy, and the second pregnancy or lactation. During
regeneration of the liver, increases in IF content and IF mRNA level were marked,
followed by reduction toward the original level after accomplishment of
regeneration. Increases in IF content and IF mRNA level were also seen in
lactating rats, but no increases were obtained in pregnant rats. These results
suggest that the IF content and IF mRNA level are regulated not only by
corticosteroids but also by the increased need for V.B12.
PMID- 10784414
TI - Distribution of a major lysosomal membrane glycoprotein, LGP85/LIMP II, in rat
tissues.
AB - We previously identified and characterized a major lysosomal membrane
glycoprotein, termed LGP85 (identical to LIMP II), in rat liver lysosomes. This
study describes the distribution of the mRNA and protein of LGP85 in rat tissues.
LGP85 protein and mRNA were detectable in all tissues when analyzed by Western
and Northern blotting. The 4.2- and 2.2-kb transcripts of LGP85 were detected in
all tissues. Liver and lung have the highest and lowest levels of LGP85 mRNA,
respectively. A single protein band with an apparent molecular weight (Mr) of
approximately 85000 was detected in each tissue. The specific protein content of
LGP85 in spleen was markedly higher than in other tissues. LGP85 protein is
distributed in the tissues independently of LGP85 mRNA. Furthermore, there was a
less significant relationship between LGP85 protein and another lysosomal
membrane glycoprotein, lamp-1, in the tissue distribution (a regression
coefficient of 0.086), which suggests that LGP85 may function in vivo
independently of lamp-1.
PMID- 10784415
TI - Involvement of NF-kappaB in the protection of cell death by tumor necrosis factor
in L929 derived TNF resistant C12 cells.
AB - The Tumor necrosis factor (TNF)-resistant C12 cell line was established by
continuous exposure of a toxic concentration of TNF to parental murine
fibrosarcoma L929 cells. Introduction of the cytosolic phospholipase A2 (cPLA2)
gene to C12 cells resulted in restoration of the TNF sensitive phenotype (CPL4
cells). DNA ladder formation and nuclear condensation by TNF exposure suggested
that TNF induced apoptotic cell death in L929, C12 and CPL4 cells. TNF-induced
activation of transcription factor nuclear factor-kappaB (NF-kappaB) was observed
in all 3 cell lines. The activation reached the maximum level at 30 min after the
exposure to TNF and thereafter declined slowly. The amount of activated NF-kappaB
in C12 cells was about twice as high as that of L929 cells with either dose of
TNF tested in this study. It was found that C12 cells expressed latent NF-kappaB
twice that of L929 cells. This abundance of latent NF-kappaB would provide a
higher response of NF-kappaB in C12 cells. Pretreatment with the known potent NF
kappaB inhibitor pyrolidine dithiocarbamate (PDTC) profoundly suppressed the
activation of NF-kappaB induced by TNF and potentiated TNF cytotoxicity in all 3
cell lines. These results are consistent with the recently found anti-apoptotic
action of NF-kappaB and suggest that NF-kappaB acts as an acquired TNF resistant
factor in C12 cells.
PMID- 10784416
TI - Comparison of the antidiarrheal effects of zaldaride maleate and its optical
isomers in rats.
AB - Zaldaride maleate (ZAL), a calmodulin inhibitor, that ameliorates secretory
diarrhea in rodents, has a racemic structure. In this study, we compared the
antidiarrheal and antisecretory effects of ZAL and its optical isomers, R(-)
isomer and S(+)-isomer, in rats. In Ussing chamber experiments, the inhibitory
action of ZAL on acetylcholine-induced ion transport in the rat colonic mucosa
was equipotent for both optical isomers, with IC50 values of approximately 3--4
micromol/l. In castor-oil-induced diarrhea, ZAL and its S(+)-isomer inhibited the
incidence of diarrhea, whereas the R(-)-isomer had no effect. In 16,16-dimethyl
prostaglandin E2-induced diarrhea, ZAL, the S(+)-isomer and the R(-)-isomer
significantly ameliorated diarrhea at doses of 30, 10 and 30 mg/kg (p.o.),
respectively; the ED50 values were 25, 10 and above 30 mg/kg (p.o.),
respectively. The pharmacokinetic parameters after administration of 30 mg/kg
(p.o.) of each compound were as follows: ZAL (Cmax: 378 ng/ml, AUC0-12: 1650 ng
h/ml); S(+)-isomer (Cmax: 565 ng/ml, AUC0-12: 2230 ng-h/ml) and R(-)-isomer
(Cmax: 271 ng/ml, AUC0-12: 613 ng-h/ml) (mean, N=4). In conclusion, despite the
fact that the antisecretory actions of ZAL and its optical isomers are the same,
the antidiarrheal actions of ZAL and its S(+)-isomer are more potent than that of
the R(-)-isomer. The antidiarrheal actions of ZAL and its optical isomers may be
related to plasma levels.
PMID- 10784417
TI - Focal cerebral ischemia-induced escape deficit in rats is ameliorated by a
reversible inhibitor of monoamine oxidase-a: implications for a novel animal
model of post-stroke depression.
AB - The present investigation was conducted to examine whether a reversible inhibitor
of monoamine oxidase (MAO)-A, T-794, affects the shuttle-box escape deficit
induced by transient middle cerebral artery (MCA) occlusion (MCAO). MCA-occluded
and sham-operated rats (surgery on day 0) were subjected to daily shuttle-box
session from day 7 to 9 (training series) and from day 13 to 15 (test series) and
received twice daily administration of T-794 (10 mg/kg p.o., b.i.d.) or vehicle
from the evening of day 9. In the final shuttle-box session of test series (day
15), while MCA-occluded-vehicle-treated rats showed significantly more escape
failures than sham-operated-vehicle-treated rats, the failures made by MCA
occluded rats were significantly decreased by T-794 to the level of the sham
operated group. Additionally, biochemical examination was conducted after
behavioral evaluation to examine possible involvement of the brain monoamine
system in the observed behavioral syndrome. In occluded hemisphere of MCA
occluded rats, catecholamine levels were decreased and ratios of deaminated
metabolite to corresponding monoamine were increased compared with the respective
values of the sham-operated group, and these changes were reversed by T-794.
Results are discussed in terms of possible relevance of the MCAO-induced escape
deficit to post-stroke depression.
PMID- 10784418
TI - Reduction of electrically evoked neural activity by ginseng saponin in rat
hippocampal slices.
AB - It is well established that ginseng saponin has positive influences on various
neural diseases, but little is known about its electrophysiological effects in
the central nervous system. In this study, we examined the electrophysiological
effects of ginseng saponin in rat hippocampal slices. Total saponin from ginseng
root reduced the slope of fEPSPs (field excitatory postsynaptic potentials) in
the CA1 area in a dose-dependent manner (9.1 +/-5.4%, 48.4+/-12.1%, and 60.5+/
15.3% at 10, 50, and 100 microg/ml, respectively), which was reversed within 10
min of washout. Seven different ginsenosides resulted in varied degrees of fEPSPs
reduction. The rank order of reduction was Rb1, Rg1 >Rg2, Rh1, Rc>Rd, Re within a
range of 5-64% reduction. No difference in the suppressive action between
protopanaxadiol (Rb1, Rc, Rd) and protopanaxatriol (Rg1, Rg2, Re, Rh1) saponins
was shown; the slope of fEPSPs was reduced by 38% and 40% on average,
respectively. The possible role of gamma-aminobutyric acid (GABA(A)) receptor in
the suppressive action of ginseng saponins was tested using whole cell patch
recording in acutely isolated hippocampal neurons. Ginsenosides did not induce
chloride current nor modified GABA-induced current. Also, the suppressive effect
of ginsenosides on fEPSPs was still observed in the presence of the GABA(A)
receptor antagonist, bicuculline methiodide 50 microM. These results suggest that
the suppressive effect is not attributable to regulation of GABA(A) receptor
activation.
PMID- 10784419
TI - Alteration in membrane fluidity of rat liver microsomes and of liposomes by
protoporphyrin and its anti-lipidperoxidative effect.
AB - The effect of protoporphyrin (PP) on membrane fluidity was investigated by
electron paramagnetic resonance spectroscopy using doxyl stearate spin probes in
relation to the anti-lipidperoxidative effect of PP. PP decreased the membrane
fluidity in rat liver microsomes at concentrations above 1 mM and also in
phosphatidylcholine (PC)-cholesterol (Cho) (100:8, a molar basis) liposomes. The
lipid peroxidation stimulated by Fe2+ and L-ascorbic acid in those membrane
preparations was attenuated along with the decrease in membrane fluidity by PP.
Similar results were also found in Cho-rich PC (100:30 to 100) liposomes having
less fluidity. These results suggest that the decrease in the membrane fluidity
caused by PP may be involved in the antioxidative action of PP.
PMID- 10784420
TI - Activation of NF-kappaB determines the sensitivity of human colon cancer cells to
TNFalpha-induced apoptosis.
AB - Tumor necrosis factor alpha (TNFalpha) generates a potent cytotoxic effect,
however many cancer cells are resistant to TNFalpha-mediated killing and the
cause of the differential sensitivity remains to be elucidated. In this study, we
demonstrated that TNFalpha induced cell death in four different human colon
cancer cell lines. The degree of cytotoxic effect was different in each cell
line, in that HCT-15 was relatively sensitive, while DLD-1, HT-29 and WiDr were
relatively resistant. TNFalpha induced apoptotic changes such as morphological
changes, DNA fragmentation and activation of caspase-3 in HCT-15, but to a lesser
degree in the others. Transcriptional expression of TNFR1(p55), as well as that
of FLICE, Fas, FADD, DR3, FAF, TRADD, and RIP was similar in these cell lines,
indicating that the susceptibility to TNFalpha-induced apoptosis may not be
determined by the constitutive expression level of these factors. Interestingly,
the cytotoxic effect of TNFalpha was well correlated with the DNA binding
activity of NF-kappaB in the colon cancer cell lines. Further, the overexpression
of a non-phosphorylated mutant form of IkappaBalpha enhanced the cytotoxicity of
TNFalpha in the resistant cell line, DLD-1, indicating that NF-kappaB activity
may determine the sensitivity of colon cancer cells to TNFalpha-induced
apoptosis. Thus, our results indicate that modulation of NF-kappaB activity may
provide a useful tool to sensitize colon cancer cells to TNFalpha treatment.
PMID- 10784421
TI - Depressor effect of wheat germ hydrolysate and its novel angiotensin I-converting
enzyme inhibitory peptide, Ile-Val-Tyr, and the metabolism in rat and human
plasma.
AB - We report here the antihypertensive effect of wheat germ (WG) hydrolysate and its
dominant peptide, Ile-Val-Tyr (IVY), with potent angiotensin I-converting enzyme
(ACE) inhibitory activity. The toxicity test of AG50W fraction purified from the
WG hydrolysate and IVY in ddy mice revealed that 1 week median lethal
concentrations of AG fraction and IVY were less than 100 and 10 mg/kg,
respectively. As a result of an intravenous administration test of both
inhibitors in spontaneously hypertensive rat (SHR), the mean arterial blood
pressure (MAP) significantly decreased with the dose; the MAP reduction of 10.3
and 19.2 mmHg was observed at a dose of 50 mg/kg of AG fraction and 5 mg/kg of
IVY, respectively. In addition to this behavior, the MAP gradually decreased
after the 5 mg/kg of IVY injection (time to give a maximum reduction; 8 min), and
the reduction was held for 20 min. By using rat and human plasma, IVY was found
to be metabolized by the action of aminopeptidase in plasma to form a subsequent
ACE inhibitor, Val-Tyr (VY). Thus, the intake of IVY as a physiologically
functional food would serve in the lowering of blood pressure (BP) by the
combined depressor effect of itself and its metabolite after the absorption.
PMID- 10784422
TI - Reproducible biphasic cutaneous edema induced by topical and repeated application
of antigen in sensitized mice.
AB - An allergic dermatitis model was developed by repeated sensitization and
challenge with antigen (ovalbumin, OA) over 7 months in mice. ddY mice were
sensitized by i.p. injection of OA adsorbed on Al(OH)3 (1 microg OA/2 mg
Al(OH)3/animal) once every 3 weeks. Antigen challenge was conducted by injection
of OA solution (0.1, 1 and 10 microg/site) into the skin of the hind paw instep
10 d after the respective sensitizations. At the 1st challenge, all the 3 groups
showed an immediate edematous response with the peak at 30 min or 1 h after the
challenge. The group challenged with the highest dose (10 microg/site) of the
antigen developed a clear late-phase edema, which was observed at the 2nd
challenge, increasing until the 3rd challenge, reaching a plateau at further
challenges. On the other hand, such late phase edema scarcely developed in the
group challenged with the lowest dose (0.1 microg/site) of the antigen. The
amount of circulating specific IgE antibody increased following repeated
sensitizations and challenges in all groups, but there were no significant
differences in the levels among them. Mepyramine suppressed the early edema by
approximately 50%, yet the late phase edema was unaffected. In conclusion, using
Al(OH)3+antigen for sensitization and an appropriate amount of antigen for
challenge, reproducible biphasic edematous responses were observed long-term
without desensitization. This model may be classified as an acute allergic
dermatitis and can be useful for quantitatively evaluating the effects of anti
allergic drugs.
PMID- 10784423
TI - Biochemical characterization of bovine lactoferrin as a glycyrrhizin-binding
protein in vitro.
AB - Lactoferrin (LF) from bovine colostrum was biochemically characterized as a
glycyrrhizin (GL)-binding protein (gbP) in vitro. It was found that (i) bovine LF
(bLF) and a synthetic bovine lactoferricin (bLFcin, the N'-terminal region of bLF
at the positions 17--41) had a high affinity to a GL-affinity column; (ii)
approximately 1.8 moles of GL were bound to a molecule of bLF with a binding
constant of approx. 1.20x10(4) M(-1) at pH 6.8; and (iii) GL, but not
glycyrrhetinic acid (GA), induced a conformational change of bLF. In addition,
the glucuronic acid moiety of the GL molecule was found to be responsible for
binding to bLF, because (i) no binding of GA and two glucoses-GA (Glc-Glc-GA) to
bLF was detected; and (ii) a synthetic fluorinated GL (GlcA-GlcF-GA) and mono
glucuronyl-GA (mono-GlcA-GA) were bound significantly to bLF. A similar binding
of GL to human LF (hLF) was also observed under the same experimental conditions.
Data provided here suggest that (i) bLF contains plural GL-binding sites; and
(ii) the specific binding of GL to bLF may modulate the physiological activity of
bLF in vivo.
PMID- 10784424
TI - Pharmacokinetics of diethylcarbamazine: prediction by concentration in saliva.
AB - The concentration of diethylcarbamazine in saliva was used to determine
pharmacokinetic parameters, in comparison to plasma and urine concentrations. Six
healthy adult male volunteers were administered 150 mg diethylcarbamazine with
400 ml of water. At seven different time intervals, blood, urine and saliva
samples were taken, and different pharmacokinetic parameters measured. The plasma
saliva concentration ratio was calculated as 1.53 whereas the observed ratio was
3.82. The half lives, times to reach peak plasma concentration, and elimination
rate constants did not show any significant difference in the different samples.
The plasma peak concentration and areas under the curve were significantly
(p<0.05) increased from those of the saliva. At 24 h, when diethylcarbamazine was
absent in urine, the plasma and saliva concentrations were almost zero.
Diethylcarbamazine is secreted in saliva, and its concentration in saliva can be
used to monitor drug therapy.
PMID- 10784425
TI - Potentiation of acetaminophen hepatotoxicity by doxapram in mouse primary
cultured hepatocytes.
AB - The augmentation by doxapram (DOP) of the reduction in viability and of the
apoptosis of cells induced by acetaminophen (AA) was examined in mouse primary
cultured hepatocytes. Loss of viability on exposure to AA and/or DOP in cultured
hepatocytes was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) assay and the apoptosis of cultured hepatocytes was detected by
nuclear morphologic observation and from a ladder-like DNA fragmentation pattern.
The combination of AA (5 mM) and DOP (10, 20, 50 or 100 microM) potentiated the
reduction in cell viability and increased the oxidative stress. Hepatocytes
exposed for 24 h to AA (5 mM) plus DOP (100 microM), showed atrophy of nuclei,
including chromatin condensation and a ladder-like DNA fragmentation pattern,
characteristic of apoptosis. Benzyl-oxycarbonyl-Asp-CH2OC (O)-2,6-dichlorobenzene
(Z-Asp-CH2-DCB, 50 microM), an inhibitor for caspases, improved the viability and
ladder-like DNA fragmentation in cells exposed to DOP (200 or 500 microM) alone
or AA ( 5 mM) plus DOP (100 microM). However, loss of viability on exposure to a
high concentration of AA (10 mM) and ladder-like DNA fragmentation were not
affected by Z-Asp-CH2-DCB. These results indicated that the synergistic increase
in oxidative stress, activation of caspases and DNA fragmentation induced by DOP
potentiated the hepatotoxicity of AA.
PMID- 10784426
TI - Two flavonoids from the leaves of Morus alba induce differentiation of the human
promyelocytic leukemia (HL-60) cell line.
AB - Two flavonoids, quercetin-3-O-beta-D-glucopyranoside (1) and quercetin-3,7-di-O
beta-D-glucopyranoside (2), were isolated from the leaves of Morus alba
(Moraceae). These two flavonoids exerted a significant inhibitory effect on the
growth of the human promyelocytic leukemia cell line (HL-60) at the concentration
of 2 x 10(-4) M. Compound 2 also induced differentiation of the HL-60 cell line
to express CD 66b and CD 14 antigens. These flavonoids exhibited significant free
radical scavenging effects on 1,1-diphenyl-2-picryl-hydrazyl radical.
PMID- 10784427
TI - Hepatoprotective effect of Combretum quadrangulare and its constituents.
AB - The MeOH extract of leaves of Combretum quadrangulare showed significant
hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)
induced experimental liver injury in mice and on D-GalN/tumor necrosis factor
alpha (TNF-alpha)-induced cell death in primary cultured mouse hepatocytes.
Phytochemical investigation led to the isolation of thirty cycloartane-type
triterpenes together with betulinic acid, beta-sitosterol, beta-sitosterol
glucoside, 4 flavones (34-37), and 3 flavone C-glucosides (38-40). These
compounds showed various potencies of hepatoprotective effect on D-GalN/TNF-alpha
induced cell death in primary cultured mouse hepatocytes. Quadrangularol B (29),
methyl quadrangularate I (33), kamatakenin (34), 5,7,4'-trihydroxy-3,3'
dimethoxyflavone (35), 5,4'-dihydroxy-3,7,3'-trimethoxyflavone (36) and
isokaempferide (37) showed strong inhibitory effect on TNF-alpha-induced cell
death with IC50 values of 34.3, 33.7, 13.3, 22.4, 13.4 and 22.8 microM,
respectively, whereas clinically-used silibinin had an IC50 value of 39.6 microM
and glycyrrhizin showed very weak inhibitory effect. Methyl quadrangularates A
(30) and N (32), norquadrangularic acid B (31) and vitexin (40) also showed
potent inhibition on TNF-alpha-induced cell death with IC50 values of 45.7, 89.3,
67.6 and 40.1 microM, respectively. The flavonoids and some of the cycloartane
type triterpenes appeared to be the hepatoprotective principles of the leaves of
C. quadrangulare.
PMID- 10784428
TI - Physiological change after local injection of liposomes containing tumor necrosis
factor (TNF).
AB - After the local (subcutaneous) administration of tumor necrosis factor-alpha
(TNF), two types of physiological change were clearly observed in dogs. One was a
systemic change, the other was a local change at the injected site. Solution,
negatively charged liposome and positively charged liposome were locally injected
in dogs. Even with local administration, the increase of triglyceride in plasma
and the decrease of blood pressure were the most serious after administration of
the solution. These changes were typical systemic side effects of TNF.
Consequently, liposomes suppressed these serious systemic side effects of TNF
after a local administration. Another physiological change was irritation at the
injected site. However, after administration of positively charged liposome, the
lowest irritation at the injected site was observed, along with the highest local
concentration of TNF. We reported the superior antitumor effect of positively
charged liposomes in solution, as well as the lowest systemic circulation after
an intratumor administration. Therefore, it was speculated that a positively
charged liposome directly acted on the tumor cells without TNF release. These
results exhibited the potency of liposomal delivery of TNF with local
administration.
PMID- 10784429
TI - Inhibitory effect of dexamethasone palmitate-low density lipoprotein complex on
low density lipoprotein-induced macrophage foam cell formation.
AB - We used low density lipoprotein (LDL) as a carrier of site-specific delivery of
drugs to atherosclerotic lesions, prepared a dexamethasone palmitate (DP)-LDL
complex, and examined the effect of the DP-LDL complex on foam cell formation of
macrophages in vitro. LDL was isolated from human plasma and the DP-LDL complex
was prepared by incubation in the presence of Celite 545. The complex contained
about 50 mol of DP in 1 mol of LDL. When macrophages were incubated with LDL for
48 h, cholesterol ester was accumulated in the macrophages, indicating foam cell
formation. This accumulation of cholesterol ester was significantly inhibited by
incubation with the DP-LDL complex. The potency of the DP-LDL complex was similar
to that of dexamethasone alone. The DP-LDL complex also significantly attenuated
the accumulation of cholesterol ester induced by incubation with LDL prior to the
incubation with the DP-LDL complex. These findings indicated that the DP-LDL
complex showed similar characteristics to LDL, and the DP-LDL complex inhibited
the foam cell formation of macrophages in in vitro experiments. This DP-LDL
complex has a possibility as a drug-carrier complex for use in atherosclerosis.
PMID- 10784430
TI - Absorption, distribution and excretion of galactosyl-beta-cyclodextrin and
mannosyl-beta-cyclodextrin in rats.
AB - Microanalytical methods were developed for measuring galactosyl-beta-cyclodextrin
(Gal-betaCD) and mannosyl (Man)-betaCD in biological matrices of the rat by HPLC
with pulsed amperometric detection. Then, using these methods, the absorption,
distribution and excretion of intravenously and orally administered Gal-betaCD
and Man-betaCD were determined in rats, and compared with those of glucosyl (Glc)
betaCD. The pharmacokinetic behavior of Gal-betaCD, Man-betaCD and Glc-betaCD
after intravenous administration (50 mg/kg) was very similar. Within 6 h after
intravenous administration, unchanged Gal-betaCD and Man-betaCD recovered in
urine accounted for about 90% of each dose. After oral administration (500
mg/kg), 0.37% and 0.38% of Gal-betaCD and Man-betaCD, respectively, were excreted
in urine. After intravenous and oral administration of Gal-betaCD and Man-betaCD,
the decomposition of Gal-betaCD and Man-betaCD to betaCD in the urine, kidney and
liver was greater than that of Glc-betaCD. The sum of the molar concentrations of
branched CDs and their decomposition product, betaCD, in the liver at 4 h after
intravenous administration of Gal-betaCD and Man-betaCD was greater than that of
Glc-betaCD. Furthermore, the inclusion complexes of estriol and betamethasone
with Gal-betaCD, Man-betaCD and Glc-betaCD were prepared and their absorption was
evaluated after oral administration in rats. The plasma concentrations of the
drugs after oral administration of drug-Gal-betaCD and drug-Man-betaCD complexes
were the same as those after the administration of drug-Glc-betaCD complexes.
PMID- 10784431
TI - Influence of N-terminal peptide and oligosaccharide on the clearance of t-PA.
AB - We have studied the influence of Gly-Ala-Arg peptide at the N-terminus and the
oligosaccharide at Asn184 on the clearance of tissue plasminogen activator (t
PA). In order to intensify the influence of these structural features, Gln117 t
PA, which is a mutant tissue plasminogen activator (mt-PA) expressed in mouse
C127 cells, was used for the investigation. It is altered to remove a high
mannose type oligosaccharide by the mutation of an amino acid from Asn117 to Gln.
We isolated 4 variants of Gln117 t-PA by cation-exchange chromatography, which
are abbreviated as S-I, S-II, L-I and L-II. These variants originated from the
heterogeneity of the peptide chains (S-chain, 527 amino acids, L-chain, 530 amino
acids) and oligosaccharide (Type I, 2 oligosaccharides, Type II, 1
oligosaccharide). Pharmacokinetics of these variants were investigated after
single intravenous administration to male rats at a dose of 250 microg/kg.
Significant differences in pharmacokinetic parameters were observed among these
variants, but there was no considerable difference in fibrin clot lysis time
(FCLT) activity. Gly-Ala-Arg peptide at the N-terminus increased the CLt, whereas
the oligosaccharide at Asn184 decreased the CLt. Moreover, the effects of the N
terminal peptide and the oligosaccharide on the CLt were independent of each
other. Our study with Gln117 t-PA revealed the role of the N-terminal peptide
found in the L-chain produced during the processing of t-PA precursor.
PMID- 10784432
TI - Pharmacokinetics of aniracetam and its metabolites in rat brain.
AB - The pharmacokinetics of aniracetam (AP) and its main metabolites, 4-p
anisamidobutyric acid (ABA), 2-pyrrolidinone (PD) and p-anisic acid (AA), in 3
brain regions (cerebral cortex, hippocampus and thalamus) was investigated after
single intravenous (i.v.) and oral administrations of AP to rats. AP, AA and PD
were rapidly distributed into the 3 brain regions after i.v. administration of
AP, but the amounts of AP were low. The concentrations of AP and AA in brain
regions rapidly declined, whereas PD levels were higher and more sustained than
those of AP and AA. ABA levels in the regions were below the detection limit.
There were no significant differences in the distribution of these compounds in
the 3 brain regions. The AUCbrain/AUCplasma ratio of PD was 53--55%, in contrast
to the low ratio of AP (2.4--3.2%) and AA (3.9--4.2%). On oral administration of
AP, the AUCbrain/AUCplasma ratio of PD was also higher than that of AA. When the
transport of PD was tested using the in situ brain perfusion technique, it was
clarified that PD was not transported across the blood-brain barrier (BBB) by a
neutral amino acid carrier system. The high brain levels of PD and the low levels
of AP suggest that the clinical efficacy of dosed AP may partly result from PD
penetrating into the brain.
PMID- 10784433
TI - In vitro cytotoxicity of cis[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)]
platinum(II) suspended in lipiodol in rat hepatoma AH-109A cells and human tumor
cell lines.
AB - SM-11355, cis[((1R,2R)-1,2-cyclohexanediamine-N,N ')bis(myristato)] platinum(II),
is a lipophilic platinum complex. SM-11355 suspended in Lipiodol (SM
11355/Lipiodol) was shown to have antitumor activity against hepatic tumors after
intra-hepatic arterial administration in animal models. In this study, the in
vitro growth inhibitory activities of SM-11355 and cisplatin (CDDP) following 7-d
drug exposure were examined using rat ascite hepatoma AH-109A cells and various
human tumor cell lines. In monolayer or suspension cell cultures, SM-11355 did
not inhibit the cell growth, whereas SM-11355/Lipiodol had dose-dependent growth
inhibitory activities, as did CDDP suspended in Lipiodol (CDDP/Lipiodol). This
was also the case in the colony formation assay in agarose gel. CDDP/Lipiodol
released platinum compound into the culture medium rapidly, whereas SM
11355/Lipiodol released it slowly but constantly for 7 d. Furthermore, a
significant amount of platinum was detected in the cells treated with
CDDP/Lipiodol and SM-11355/Lipiodol. These results suggest that Lipiodol plays an
important role in the in vitro cytotoxicity of SM-11355, and certain platinum
compounds released from SM-11355/Lipiodol have growth inhibitory effects on these
cells.
PMID- 10784434
TI - Comparison of anthocyanin distribution in different blueberry sources by
capillary zone electrophoresis.
AB - Capillary zone electrophoretic separation of blueberry anthocyanins was studied
using a Na-borate buffer containing trans-1,2-diaminocyclohexane-N,N,N',N'-tetra
acetic acid monohydrate (CyDTA) as the carrier buffer. The separation conditions
were precisely examined using an aqueous extract of bilberry (wild type
blueberry) as the separation sample which is rich in this type and amount of
anthocyanins. Each separated peak was identified by comparing the mobility with
that of anthocyanin standards after normalization against the mobility of
malvidin 3-o-glucoside (Mv 3-Glc) added as an internal standard. As salt
concentrations of the running buffer increased, the peak resolution was markedly
improved over the whole range of separation, especially, among the fast moving
components (petunidin 3-glucoside, cyanidin 3-glucoside and malvidin 3
galactoside). Inversely, the peak separation both between petunidin 3-glucoside
and peonidin 3-glucoside, and between delphinidin 3-glucoside and petunidin 3
galactoside, respectively, were decreased. The anthocyanins were, however,
successfully separated by decreasing the buffer pH. Good separation of
anthocyanins was finally achieved by 30 mM Na-borate (pH 8.78) containing 7.5 mM
CyDTA within 10 min. Under this separation condition, anthocyanins from different
blueberry sources were analyzed. The results revealed that different blueberry
sources had their own patterns of anthocyanin distribution and amounts in the
extracts, thus the present method is suitable for the quality control of
anthocyanin-containing food materials.
PMID- 10784435
TI - Inhibition of drug-metabolizing enzyme activity in human hepatic cytochrome P450s
by bisphenol A.
AB - Effect of bisphenol A on drug-metabolizing enzyme activities by human hepatic
cytochrome P450s (CYP) was investigated. We measured aminopyrine N-demethylation
by eleven kinds of cDNA-expressed CYPs. CYP2C19 and CYP2B6 catalyzed most
efficiently the aminopyrine N-demethylation, followed by CYP2C8 and CYP2D6.
Bisphenol A (1 mM) most efficiently inhibited aminopyrine N-demethylation by
CYP2C8 and CYP2C19 by 82% and 85%, respectively, whereas inhibition of the
activities by CYP 2B6 and 2D6 was less than 40%. Bisphenol A exhibited a
noncompetitive-type inhibition of aminopyrine N-demethylase activity by CYP2C8
with Ki value of 97 microM. Additionally, we investigated the inhibitory effect
of bisphenol A on CYP2C19-mediated S-mephenytoin 4-hydroxylation. Bisphenol A
exhibited a mixed-type inhibition with Ki value of 113 microM. These results
suggest that bisphenol A inhibits human hepatic CYP activities, especially CYP2C8
and CYP2C19.
PMID- 10784436
TI - Most clot-bound thrombin activity is inhibited by plasma antithrombin during clot
aging, but a very small fraction survives.
AB - Inhibitory effects of thrombin inhibitors against clot-bound thrombin have been
evaluated using clots prepared from human plasma as the source of clot
immobilized active enzyme, and the clot-bound thrombin has been reported to be
protected from its inhibition by antithrombin. However, we found that the clot
bound thrombin was not intrinsically protected from inhibition by antithrombin,
i.e., a large fraction of initially active clot-bound thrombin was inhibited by
antithrombin present in human plasma time dependently, and only very small
fractions (0.04--0.08%) of the thrombin retained their enzymatic activity after
clot-aging. These results suggest that the extent of clot-aging determines the
sensitivity of clot-bound thrombin to antithrombin, and that inhibitory effects
of drugs against clot-bound thrombin in vitro must be interpreted with caution to
estimate their effects in vivo.
PMID- 10784437
TI - Stereoselective internal acyl migration of 1beta-O-acyl glucuronides of
enantiomeric 2-phenylpropionic acids.
AB - Internal acyl migration reactions of 1beta-O-acyl glucuronides of 2-arylpropionic
acids (profens) are of interest because of their possible role in covalent
binding to serum proteins and consequent allergic reactions. The stereoselective
degradation of 1beta-O-acyl glucuronides of enantiomeric 2-phenylpropionic acids
(PAs), the basic structures of profens, in phosphate buffer (pH 7.4) at 37
degrees C, has been investigated using HPLC. Apparent first-order degradation of
1beta-O-acyl glucuronide and the sequential appearance of 2-, 3- and 4-O-acyl
isomers were observed for each enantiomer. Acyl migration was observed to
predominate over hydrolysis as in the other profen glucuronides. All the
positional isomers and anomers were characterized using NMR and HPLC-NMR. The
overall degradation half-life of (R)- and (S)-PA glucuronides was 1.8 and 3.3 h,
respectively. These results suggest that (R)-PA glucuronide could be more
susceptible to covalent binding to proteins via acyl migration than the
corresponding antipode. The lability of the (R)-diastereomer over the antipode is
consistent with previous reports on other profen glucuronides. Thus, the
diastereomeric PA glucuronides are considered to be the best model compounds for
the computation of structural physicochemical parameters to control the
stereoselective internal acyl migration of profen glucuronides because PA has the
simplest chemical structure of all the profens.
PMID- 10784438
TI - Inhibition of DNA topoisomerases by nidulalin A derivatives.
AB - Three cytotoxic dihydroxanthone derivatives, nidulalin A(1), F390B(2), and
F390C(3) were evaluated for inhibitory activity against DNA topoisomerases.
Compounds 1 and 2 inhibited DNA topoisomerase II with IC50 values of 2.2 microM
and 16 microM, and 3 inhibited DNA topoisomerase I with an IC50 value of 5.9
microM.
PMID- 10784439
TI - Modulators of tumor necrosis factor alpha production bearing dicarba-closo
dodecaborane as a hydrophobic pharmacophore.
AB - Previous studies on the structural development of tumor necrosis factor alpha
(TNF-alpha) production regulators derived from thalidomide (N-alpha
phthalimidoglutarimide) revealed that a hydrophobic substituent at the nitrogen
atom of the phthalimide ring is critical for potent activity. We have designed
and prepared phthalimide derivatives bearing a boron cluster, dicarba-closo
dodecaborane (carborane), which has a hydrophobic character and spherical
geometry, as a novel candidate of biological response modifiers. These compounds
were shown to regulate TNF-alpha production by HL-60 cells, as expected. The
result provides a further example of the application of carborane as a
hydrophobic pharmacophore of biologically active molecules.
PMID- 10784440
TI - Inhibition of cyclooxygenase-2 expression by diarylheptanoids from the bark of
Alnus hirsuta var. sibirica.
AB - Two known diarylheptanoids, oregonin (1), (5S)-1,7-bis-(3,4-dihydroxyphenyl)
heptane-3-one-5-O-beta-D-xylopyranosi de and hirsutanonol (2), (5S)-1,7-bis-(3,4
dihydroxyphenyl)-5-hydroxyheptane-3-one isolated from the bark of Alnus hirsuta
var. sibirica, showed significant inhibitory effects on 12-O-tetradecanoylphorbol
13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression in immortalized
human breast epithelial MCF10A cells.
PMID- 10784441
TI - Carrier-envelope phase control of femtosecond mode-locked lasers and direct
optical frequency synthesis
AB - We stabilized the carrier-envelope phase of the pulses emitted by a femtosecond
mode-locked laser by using the powerful tools of frequency-domain laser
stabilization. We confirmed control of the pulse-to-pulse carrier-envelope phase
using temporal cross correlation. This phase stabilization locks the absolute
frequencies emitted by the laser, which we used to perform absolute optical
frequency measurements that were directly referenced to a stable microwave clock.
PMID- 10784443
TI - Windows through the dusty disks surrounding the youngest low-mass protostellar
objects.
AB - The formation and evolution of young low-mass stars are characterized by
important processes of mass loss and accretion occurring in the innermost regions
of their placentary circumstellar disks. Because of the large obscuration of
these disks at optical and infrared wavelengths in the early protostellar stages
(class 0 sources), they were previously detected only at radio wavelengths using
interferometric techniques. We have detected with the Infrared Space Observatory
the mid-infrared (mid-IR) emission associated with the class 0 protostar VLA1 in
the HH1-HH2 region located in the Orion nebula. The emission arises in three
wavelength windows (at 5. 3, 6.6, and 7.5 micrometers) where the absorption due
to ices and silicates has a local minimum that exposes the central part of the
young protostellar system to mid-IR investigations. The mid-IR emission arises
from a central source with a diameter of 4 astronomical units at an averaged
temperature of approximately 700 K, deeply embedded in a dense region with a
visual extinction of 80 to 100 magnitudes.
PMID- 10784444
TI - Control of energy transfer in oriented conjugated polymer-mesoporous silica
composites
AB - Nanoscale architecture was used to control energy transfer in semiconducting
polymers embedded in the channels of oriented, hexagonal nanoporous silica.
Polarized femtosecond spectroscopies show that excitations migrate
unidirectionally from aggregated, randomly oriented polymer segments outside the
pores to isolated, aligned polymer chains within the pores. Energy migration
along the conjugated polymer backbone occurred more slowly than Forster energy
transfer between polymer chains. The different intrachain and interchain energy
transfer time scales explain the behavior of conjugated polymers in a range of
solution environments. The results provide insights for optimizing nanostructured
materials for use in optoelectronic devices.
PMID- 10784442
TI - Architecture of RNA polymerase II and implications for the transcription
mechanism.
AB - A backbone model of a 10-subunit yeast RNA polymerase II has been derived from x
ray diffraction data extending to 3 angstroms resolution. All 10 subunits exhibit
a high degree of identity with the corresponding human proteins, and 9 of the 10
subunits are conserved among the three eukaryotic RNA polymerases I, II, and III.
Notable features of the model include a pair of jaws, formed by subunits Rpb1,
Rpb5, and Rpb9, that appear to grip DNA downstream of the active center. A clamp
on the DNA nearer the active center, formed by Rpb1, Rpb2, and Rpb6, may be
locked in the closed position by RNA, accounting for the great stability of
transcribing complexes. A pore in the protein complex beneath the active center
may allow entry of substrates for polymerization and exit of the transcript
during proofreading and passage through pause sites in the DNA.
PMID- 10784445
TI - A superconducting field-effect switch.
AB - We report here on a novel realization of a field-effect device that allows
switching between insulating and superconducting states, which is the widest
possible variation of electrical properties of a material. We chose C(60) as the
active material because of its low surface state density and observed
superconductivity in alkali metal-doped C(60). We induced three electrons per
C(60) molecule in the topmost molecular layer of a crystal with the field-effect
device, creating a superconducting switch operating up to 11 kelvin. An insulator
was thereby transformed into a superconductor. This technique offers new
opportunities for the study of superconductivity as a function of carrier
concentration.
PMID- 10784446
TI - The Archean sulfur cycle and the early history of atmospheric oxygen.
AB - The isotope record of sedimentary sulfides can help resolve the history of oxygen
accumulation into the atmosphere. We measured sulfur isotopic fractionation
during microbial sulfate reduction up to 88 degrees C and show how sulfate
reduction rate influences the preservation of biological fractionations in
sediments. The sedimentary sulfur isotope record suggests low concentrations of
seawater sulfate and atmospheric oxygen in the early Archean (3.4 to 2.8 billion
years ago). The accumulation of oxygen and sulfate began later, in the early
Proterozoic (2.5 to 0.54 billion years ago).
PMID- 10784447
TI - Heightened odds of large earthquakes near istanbul: An interaction-based
probability calculation
AB - We calculate the probability of strong shaking in Istanbul, an urban center of 10
million people, from the description of earthquakes on the North Anatolian fault
system in the Marmara Sea during the past 500 years and test the resulting
catalog against the frequency of damage in Istanbul during the preceding
millennium. Departing from current practice, we include the time-dependent effect
of stress transferred by the 1999 moment magnitude M = 7.4 Izmit earthquake to
faults nearer to Istanbul. We find a 62 +/- 15% probability (one standard
deviation) of strong shaking during the next 30 years and 32 +/- 12% during the
next decade.
PMID- 10784448
TI - Extension of cell life-span and telomere length in animals cloned from senescent
somatic cells.
AB - The potential of cloning depends in part on whether the procedure can reverse
cellular aging and restore somatic cells to a phenotypically youthful state.
Here, we report the birth of six healthy cloned calves derived from populations
of senescent donor somatic cells. Nuclear transfer extended the replicative life
span of senescent cells (zero to four population doublings remaining) to greater
than 90 population doublings. Early population doubling level complementary DNA-1
(EPC-1, an age-dependent gene) expression in cells from the cloned animals was
3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old)
controls. Southern blot and flow cytometric analyses indicated that the telomeres
were also extended beyond those of newborn (<2 weeks old) and age-matched control
animals. The ability to regenerate animals and cells may have important
implications for medicine and the study of mammalian aging.
PMID- 10784449
TI - Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.
AB - Severe combined immunodeficiency-X1 (SCID-X1) is an X-linked inherited disorder
characterized by an early block in T and natural killer (NK) lymphocyte
differentiation. This block is caused by mutations of the gene encoding the
gammac cytokine receptor subunit of interleukin-2, -4, -7, -9, and -15 receptors,
which participates in the delivery of growth, survival, and differentiation
signals to early lymphoid progenitors. After preclinical studies, a gene therapy
trial for SCID-X1 was initiated, based on the use of complementary DNA containing
a defective gammac Moloney retrovirus-derived vector and ex vivo infection of
CD34+ cells. After a 10-month follow-up period, gammac transgene-expressing T and
NK cells were detected in two patients. T, B, and NK cell counts and function,
including antigen-specific responses, were comparable to those of age-matched
controls. Thus, gene therapy was able to provide full correction of disease
phenotype and, hence, clinical benefit.
PMID- 10784450
TI - Localization of a short-term memory in Drosophila.
AB - Memories are thought to be due to lasting synaptic modifications in the brain.
The search for memory traces has relied predominantly on determining regions that
are necessary for the process. However, a more informative approach is to define
the smallest sufficient set of brain structures. The rutabaga adenylyl cyclase,
an enzyme that is ubiquitously expressed in the Drosophila brain and that
mediates synaptic plasticity, is needed exclusively in the Kenyon cells of the
mushroom bodies for a component of olfactory short-term memory. This demonstrates
that synaptic plasticity in a small brain region can be sufficient for memory
formation.
PMID- 10784451
TI - Control of homeostasis of CD8+ memory T cells by opposing cytokines.
AB - Memory T cells maintain their numbers for long periods after antigen exposure.
Here we show that CD8+ T cells of memory phenotype divide slowly in animals. This
division requires interleukin-15 and is markedly increased by inhibition of
interleukin-2 (IL-2). Therefore, the numbers of CD8+ memory T cells in animals
are controlled by a balance between IL-15 and IL-2.
PMID- 10784452
TI - Location of a major susceptibility locus for familial schizophrenia on chromosome
1q21-q22.
AB - Schizophrenia is a complex disorder, and there is substantial evidence supporting
a genetic etiology. Despite this, prior attempts to localize susceptibility loci
have produced predominantly suggestive findings. A genome-wide scan for
schizophrenia susceptibility loci in 22 extended families with high rates of
schizophrenia provided highly significant evidence of linkage to chromosome 1
(1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage
(lod) score of 6.50. This linkage result should provide sufficient power to allow
the positional cloning of the underlying susceptibility gene.
PMID- 10784453
TI - Resetting central and peripheral circadian oscillators in transgenic rats.
AB - In multicellular organisms, circadian oscillators are organized into multitissue
systems which function as biological clocks that regulate the activities of the
organism in relation to environmental cycles and provide an internal temporal
framework. To investigate the organization of a mammalian circadian system, we
constructed a transgenic rat line in which luciferase is rhythmically expressed
under the control of the mouse Per1 promoter. Light emission from cultured
suprachiasmatic nuclei (SCN) of these rats was invariably and robustly rhythmic
and persisted for up to 32 days in vitro. Liver, lung, and skeletal muscle also
expressed circadian rhythms, which damped after two to seven cycles in vitro. In
response to advances and delays of the environmental light cycle, the circadian
rhythm of light emission from the SCN shifted more rapidly than did the rhythm of
locomotor behavior or the rhythms in peripheral tissues. We hypothesize that a
self-sustained circadian pacemaker in the SCN entrains circadian oscillators in
the periphery to maintain adaptive phase control, which is temporarily lost
following large, abrupt shifts in the environmental light cycle.
PMID- 10784455
TI - Dementia in the twenty-first century.
PMID- 10784456
TI - Quality of life in individuals with anxiety disorders.
AB - OBJECTIVE: Quality-of-life indices have been used in medical practice to estimate
the impact of different diseases on functioning and well-being and to compare
outcomes between different treatment modalities. An integrated view of the issue
of quality of life in patients with anxiety disorders can provide important
information regarding the nature and extent of the burden associated with these
disorders and may be useful in the development of strategies to deal with it.
METHOD: A review of epidemiological and clinical studies that have investigated
quality of life (broadly conceptualized) in patients with panic disorder, social
phobia, posttraumatic stress disorder, generalized anxiety disorder, and
obsessive-compulsive disorder was conducted by searching MEDLINE and PsycLIT
citations from 1984 to 1999. A summary of the key articles published in this area
is presented. RESULTS: The studies reviewed portray an almost uniform picture of
anxiety disorders as illnesses that markedly compromise quality of life and
psychosocial functioning. Significant impairment can also be found in individuals
with subthreshold forms of anxiety disorders. Effective pharmacological or
psychotherapeutic treatment has been shown to improve the quality of life for
patients with panic disorder, social phobia, and posttraumatic stress disorder.
Limitations in current knowledge in this area are identified, and suggestions for
needed future research are provided. CONCLUSIONS: It is expected that a more
thorough understanding of the impact on quality of life will lead to increased
public awareness of anxiety disorders as serious mental disorders worthy of
further investment in research, prevention, and treatment.
PMID- 10784457
TI - Cytokines and the brain: implications for clinical psychiatry.
AB - OBJECTIVE: This article reviews recent developments in cytokine biology that are
relevant to clinical psychiatry. METHOD: The authors reviewed English-language
literature of the last 15 years that pertains to the biology of cytokines with
emphasis on central nervous system effects in general and psychiatric disorders
in particular. RESULTS: Growing evidence suggests that, in addition to providing
communication between immune cells, specific cytokines play a role in signaling
the brain to produce neurochemical, neuroendocrine, neuroimmune, and behavioral
changes. This signaling may be part of a generalized, comprehensive mechanism to
mobilize resources in the face of physical and/or psychological stress and to
maintain homeostasis. The clinical implications of these findings are far
reaching and include a possible role for cytokines in the pathophysiology of
specific psychiatric disorders such as major depression, schizophrenia, and
Alzheimer's disease. The effects of cytokines in the central nervous system may
provide a possible mechanism for the "sickness behavior" of patients with severe
infection or cancer, as well as for the neuropsychiatric adverse effects of
treatment with interferons and interleukins. CONCLUSIONS: A better understanding
of the role of cytokines in various brain activities will enhance knowledge of
specific psychobiological mechanisms in health and disease and provide
opportunities for novel treatment interventions.
PMID- 10784458
TI - Cognition: mental rotation.
PMID- 10784459
TI - Tug-of-war: domestic abuse and the misuse of religion.
PMID- 10784461
TI - Dementia in elderly persons in a general hospital.
AB - OBJECTIVE: This study investigated the prevalence of dementia in a general
hospital, reasons for which patients with dementia were admitted, and the
relationship between dementia and length of stay, cost, and in-hospital mortality
rate. METHOD: The study focused on data from the hospital database on 21,251
patients aged 60 and older who were discharged in 1996 and 1997. Patients were
grouped as with or without a discharge diagnosis of dementia by ICD-9-CM
criteria. The groups were compared on sociodemographic characteristics, principal
discharge diagnoses, lengths of stay, costs, and in-hospital mortality rates.
RESULTS: The prevalence of dementia among discharged patients was 3.9% (N=823);
it was dependent on age (age 60-64, prevalence=2.6%; age 85 and older,
prevalence=8.9%). The primary discharge diagnoses of the groups were different.
The mean length of stay was 10.4 days for patients with dementia and 6.5 days for
patients without dementia. Per capita hospital costs were $4,000 higher for
patients with dementia. Differences in lengths of stay and per capita costs were
statistically significant after adjusting for age, race, and sex. Lengths of stay
and hospital costs for patients with dementia were significantly higher for eight
primary discharge diagnoses after adjusting for age, race, and sex. CONCLUSIONS:
Dementia is present in a significant proportion of patients admitted to general
inpatient units. Patients with dementia are admitted for different reasons than
patients without dementia and appear to have longer stays, which are associated
with higher costs. Efforts to identify dementia early during hospitalization
could improve patient care and reduce costs.
PMID- 10784462
TI - Mental and behavioral disturbances in dementia: findings from the Cache County
Study on Memory in Aging.
AB - OBJECTIVE: The authors report findings from a study of 5,092 community residents
who constituted 90% of the elderly resident population of Cache County, Utah.
METHOD: The 5,092 participants, who were 65 years old or older, were screened for
dementia. Based on the results of this screen, 1,002 participants (329 with
dementia and 673 without dementia) underwent comprehensive neuropsychiatric
examinations and were rated on the Neuropsychiatric Inventory, a widely used
method for ascertainment and classification of dementia-associated mental and
behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214
(65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had
another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or
behavioral disturbances in the past month. Apathy (27%), depression (24%), and
agitation/aggression (24%) were the most common in participants with dementia.
These disturbances were almost four times more common in participants with
dementia than in those without. Only modest differences were observed in the
prevalence of mental or behavioral disturbances in different types of dementia or
at different stages of illness: participants with Alzheimer's disease were more
likely to have delusions and less likely to have depression. Agitation/aggression
and aberrant motor behavior were more common in participants with advanced
dementia. CONCLUSIONS: On the basis of their findings in this large community
population of elderly people, the authors conclude that a wide range of dementia
associated mental and behavioral disturbances afflict the majority of individuals
with dementia. Because of their frequency and their adverse effects on patients
and their caregivers, these disturbances should be ascertained and treated in all
cases of dementia.
PMID- 10784463
TI - Vitamin B(12) deficiency and depression in physically disabled older women:
epidemiologic evidence from the Women's Health and Aging Study.
AB - OBJECTIVE: It has been hypothesized that adequate concentrations of vitamin B(12)
and folate are essential to maintain the integrity of the neurological systems
involved in mood regulation, but epidemiologic evidence for such a link in the
general population is unavailable. This study examined whether community-dwelling
older women with metabolically significant vitamin B(12) or folate deficiency are
particularly prone to depression. METHOD: Serum levels of vitamin B(12), folate,
methylmalonic acid, and total homocysteine were assayed in 700 disabled,
nondemented women aged 65 years and over living in the community. Depressive
symptoms were measured by means of the Geriatric Depression Scale and categorized
as no depression, mild depression, and severe depression. RESULTS: Serum
homocysteine levels, serum folate levels, and the prevalences of folate
deficiency and anemia were not associated with depression status. The depressed
subjects, especially those with severe depression, had a significantly higher
serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12)
level than the nondepressed subjects. Metabolically significant vitamin B(12)
deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the
100 mildly depressed subjects, and 27.0% of the 122 severely depressed women.
After adjustment for sociodemographic characteristics and health status, the
subjects with vitamin B(12) deficiency were 2.05 times as likely to be severely
depressed as were nondeficient subjects. CONCLUSIONS: In community-dwelling older
women, metabolically significant vitamin B(12)deficiency is associated with a
twofold risk of severe depression.
PMID- 10784464
TI - Comorbid anxiety disorders in depressed elderly patients.
AB - OBJECTIVE: Anxiety disorders are common in adults with depressive disorders, but
several studies have suggested a relatively low prevalence of anxiety disorders
in older individuals with depression. This cross-sectional study measured current
and lifetime rates and associated clinical features of anxiety disorders in
depressed elderly patients. METHOD: History of anxiety disorders was assessed by
using a structured diagnostic instrument in 182 depressed subjects aged 60 and
older seen in primary care and psychiatric settings. Associations between
comorbid anxiety disorders and baseline characteristics were measured. The
modified structured instrument allowed detection of symptoms that met inclusion
criteria for generalized anxiety disorder in a depressive episode. RESULTS:
Thirty-five percent of older subjects with depressive disorders had at least one
lifetime anxiety disorder diagnosis, and 23% had a current diagnosis. The most
common current comorbid anxiety disorders were panic disorder (9.3%), specific
phobias (8.8%), and social phobia (6.6%). Symptoms that met inclusion criteria
for generalized anxiety disorder, measured separately, were present in 27.5% of
depressed subjects. Presence of a comorbid anxiety disorder was associated with
poorer social function and a higher level of somatic symptoms. Symptoms of
generalized anxiety disorder were associated with a higher level of suicidality.
CONCLUSIONS: Contrary to previous reports, the present study found a relatively
high rate of current and lifetime anxiety disorders in elderly depressed
individuals. Comorbid anxiety disorders and symptoms of generalized anxiety
disorder were associated with a more severe presentation of depressive illness in
elderly subjects.
PMID- 10784465
TI - Comparison of sertraline and nortriptyline in the treatment of major depressive
disorder in late life.
AB - OBJECTIVE: This study was designed to evaluate the comparative efficacy and
safety of sertraline and nortriptyline for the treatment of major depressive
disorder in older adults. METHOD: A double-blind, parallel group design was used
to compare 210 outpatients, 60 years of age and older, who met DSM-III-R criteria
for major depressive episode and had a minimum Hamilton Depression Rating Scale
score of 18. The patients were randomly assigned to 12 weeks of treatment with
either sertraline (50-150 mg/day) or nortriptyline (25-100 mg/day). RESULTS: The
safety profiles of the two treatments were similar except that nortriptyline
treatment was associated with a significant increase in pulse rate, whereas
sertraline was associated with a nonsignificant decrease. Efficacy of both drugs
was similar for both treatments at all time points, with 71.6% (N=53 of 74) of
the sertraline-treated patients and 61.4% (N=43 of 70) of the nortriptyline
treated patients achieving responder status by week 12. Time to response was also
similar, with more than 75% of the improvement in scores on the Hamilton
depression scale having occurred by week 6. Secondary efficacy measures
(posttreatment measures of cognitive function, memory, and quality of life)
revealed a significant advantage for sertraline treatment. CONCLUSIONS: Primary
efficacy measures showed sertraline and nortriptyline to be similarly effective.
With secondary outcome measures there was consistent evidence of an advantage for
the sertraline-treated group. The clinical impact of these measures on the long
term well-being of elderly depressed patients should be examined in a study of
maintenance treatment.
PMID- 10784467
TI - Age at first alcohol use: a risk factor for the development of alcohol disorders.
AB - OBJECTIVE: This study aimed to describe the natural course of DSM-III-R alcohol
disorders as a function of age at first alcohol use and to investigate the
influence of early use as a risk factor for progression to the development of
alcohol disorders, exclusive of the effect of confounding influences. METHOD:
Data were obtained from a community sample (N=5,856) of lifetime drinkers
participating in the 1990-1991 Mental Health Supplement of the Ontario Health
Survey. RESULTS: Survival analyses revealed a rapid progression to alcohol
related harm among those who reported having their first drink at ages 11-14.
After 10 years, 13.5% of the subjects who began to drink at ages 11 and 12 met
the criteria for a diagnosis of alcohol abuse, and 15.9% had a diagnosis of
dependence. Rates for subjects who began to drink at ages 13 and 14 were 13.7%
and 9.0%, respectively. In contrast, rates for those who started drinking at ages
19 and older were 2.0% and 1.0%. Unexpectedly, a delay in progression to harm was
observed for the youngest drinkers (ages 10 and under). Hazard regression
analyses revealed a nonlinear effect of age at first alcohol use, marked by an
elevated risk of developing disorders among subjects first using alcohol at ages
11-14. CONCLUSIONS: First use of alcohol at ages 11-14 greatly heightens the risk
of progression to the development of alcohol disorders and therefore is a
reasonable target for intervention strategies that seek to delay first use as a
means of averting problems later in life.
PMID- 10784466
TI - Hippocampal volume in adolescent-onset alcohol use disorders.
AB - OBJECTIVE: Alcohol use disorders (defined as DSM-IV alcohol dependence or abuse)
are prevalent and serious problems among adolescents. As adolescence is marked by
progressive hippocampal development, this brain region may be particularly
susceptible to the adverse effects of adolescent alcohol use disorders. This
study compared the hippocampal volumes of adolescents and young adults with
adolescent-onset alcohol use disorders to those of healthy matched comparison
subjects. METHOD: Magnetic resonance imaging was used to measure the hippocampal
volumes and volumes of comparison brain regions in 12 subjects with alcohol use
disorders and 24 comparison subjects matched on age, sex, and handedness.
RESULTS: Both left and right hippocampal volumes were significantly smaller in
subjects with alcohol use disorders than in comparison subjects. Total
hippocampal volume correlated positively with the age at onset and negatively
with the duration of the alcohol use disorder. Intracranial, cerebral, and
cortical gray and white matter volumes and measures of the mid-sagittal area of
the corpus callosum did not differ between groups. CONCLUSIONS: In the mature
brain, chronic alcohol use disorders are associated with graded global brain
dysmorphology. Although the etiology, neuropsychological consequences, and
permanence of these hippocampal findings need to be further examined, these
findings suggest that, during adolescence, the hippocampus may be particularly
susceptible to the adverse effects of alcohol.
PMID- 10784468
TI - Prospective study of depression and the risk of heavy alcohol use in women.
AB - OBJECTIVE: The authors' goal was to determine whether depression is associated
with a greater risk of heavy alcohol consumption in women. METHOD: The study was
based on a 1-year follow-up of the Baltimore cohort of the National Institute of
Mental Health Epidemiologic Catchment Area project. The sample consisted of 1,383
women at risk for heavy alcohol use. History of depression and frequency of
lifetime-experienced depressive symptoms were assessed at baseline, and incident
cases of heavy drinking were identified 1 year later. After calculating
descriptive statistics for the sample, the authors developed a series of logistic
regression models to estimate the risk of heavy drinking at follow-up associated
with depression status. RESULTS: The initial estimate of the risk for heavy
drinking in women with a history of depressive disorder was 2.60 times greater
than the risk in women with no history of depressive disorder. This estimate did
not change markedly after adjustment for age, history of antisocial personality
disorder, or father's history of heavy drinking (relative risk=2.2). A higher
frequency of depressive symptoms was also found to be associated with an
elevation in the risk for heavy alcohol use (relative risk=1.09). CONCLUSIONS:
These results add to other evidence that depression must be considered in the
assessment of vulnerability for heavy alcohol use in women. Further research is
needed to clarify the mechanisms of the observed association and to discover
whether detection and effective treatment of depression might reduce risk of
later alcohol problems.
PMID- 10784469
TI - Central auditory processing in patients with auditory hallucinations.
AB - OBJECTIVE: Data from a full assessment of auditory perception in patients with
schizophrenia were used to investigate whether auditory hallucinations are
associated with abnormality of central auditory processing. METHOD: Three groups
of subjects participated in auditory assessments: 22 patients with psychosis and
a recent history of auditory hallucinations, 16 patients with psychosis but no
history of auditory hallucinations, and 22 normal subjects. Nine auditory
assessments, including auditory brainstem response, monotic and dichotic speech
perception tests, and nonspeech perceptual tests, were performed. Statistical
analyses for group differences were performed using analysis of variance and
Kruskal-Wallis tests. The results of individual patients with test scores in the
severely abnormal range (more than three standard deviations from the mean for
the normal subjects) were examined for patterns that suggested sites of
dysfunction in the central auditory system. RESULTS: The results showed
significant individual variability among the subjects in both patient groups.
There were no group differences on tests that are sensitive to low brainstem
function. Both patient groups performed poorly in tests that are sensitive to
cortical or high brainstem function, and hallucinating patients differed from
nonhallucinating patients in scores on tests of filtered speech perception and
response bias patterns on dichotic speech tests. Six patients in the
hallucinating group had scores in the severely abnormal range on more than one
test. CONCLUSIONS: Hallucinations may be associated with auditory dysfunction in
the right hemisphere or in the interhemispheric pathways. However, comparison of
results for the patient groups suggests that the deficits seen in hallucinating
patients may represent a greater degree of the same types of deficits seen in
nonhallucinating patients.
PMID- 10784470
TI - Normal P50 suppression in schizophrenia patients treated with atypical
antipsychotic medications.
AB - OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and
information processing. Measures such as P50 suppression are used to study
cognitive and attentional dysfunction among these patients. P50 suppression is an
operational measure of sensory gating that can be assessed by averaging
electroencephalographic responses to multiple pairs of auditory clicks separated
by 500 msec. Normally, the P50 response to the second click is smaller than the
response to the first click. Many studies have demonstrated that schizophrenia
patients have deficient P50 suppression, meaning that the difference between the
first and second clicks is not as large as normal. Atypical antipsychotic
medications may have superior clinical efficacy for negative symptoms and
cognitive deficits. It is important, therefore, to evaluate the effects of
atypical antipsychotic medications on measures such as P50 suppression. METHOD:
P50 suppression of 13 patients with schizophrenia receiving clinically effective
doses of clozapine, olanzapine, or risperidone (classified as atypical
antipsychotic medications) was compared to that of 13 patients receiving
conventional antipsychotic medications. RESULTS: The patient groups did not
differ on clinical or demographic measures. The patients receiving atypical
antipsychotic medications had normal-range P50 suppression (mean=72%). In
contrast, the patients receiving typical antipsychotic medications had
dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support
the hypothesis that patients treated with atypical antipsychotic medications have
normal P50 measures of sensory gating. Longitudinal within-subjects studies are
warranted to clarify the mechanisms mediating this effect.
PMID- 10784471
TI - Continuous performance test and schizophrenia: a test of stimulus-response
compatibility, working memory, response readiness, or none of the above?
AB - OBJECTIVE: Abnormalities of attention are considered the fundamental deficits in
cognitive function manifested by patients with schizophrenia. The authors
administered variations of two types of cognitive tasks to patients with
schizophrenia (N=20) and normal comparison subjects (N=30) to test four possible
cognitive mechanisms that might account for such abnormalities. METHOD:
Variations of the Continuous Performance Test were used to test the four
mechanisms. Stimulus-response mapping was explored by comparing results on a task
in which subjects were to make a response if the word "nine" was preceded by the
word "one" with results on a task in which the required response was made
explicit by the stimulus (the word "ready" followed by the word "press"). The
building up of a prepotent response tendency was tested by manipulating the
probability with which the cue and imperative stimulus appeared (17% or 50%). The
amount of working memory required to maintain contextual information was tested
by using different delay intervals (1000 msec and 3000 msec). The extent to which
problems in vigilance might be attributable to problems in the "motoric"
component of response readiness was operationalized by having subjects perform a
secondary motor task concurrent with the attentional task. RESULTS: Patients with
schizophrenia performed significantly worse than the normal comparison subjects
on all tasks. However, none of the four manipulations of the Continuous
Performance Test tasks had a differential impact on the patients' performance
speed or accuracy. In contrast, there was a significant interaction of group,
delay interval, and target probability in which patients made disproportionately
more omission errors at short delay intervals and at low target probabilities.
CONCLUSIONS: The findings may call into question the explanatory power of certain
well-known contemporary mechanistic accounts of performance on the Continuous
Performance Test in patients with schizophrenia. The findings suggest that a
difficulty in rapidly encoding information (i.e., constructing a representation)
in certain "unengaging" situations may be at the core of deficits on tasks
associated with this attentional test.
PMID- 10784472
TI - Visual perception and working memory in schizotypal personality disorder.
AB - OBJECTIVE: Patients affected by schizophrenia show deficits in both visual
perception and working memory. The authors tested early-stage vision and working
memory in subjects with schizotypal personality disorder, which has been
biologically associated with schizophrenia. METHOD: Eleven subjects who met DSM
III-R criteria for schizotypal personality disorder and 12 normal comparison
subjects were evaluated. Performance thresholds were obtained for tests of visual
discrimination and working memory. Both form and trajectory processing were
evaluated for each task. RESULTS: Subjects with schizotypal personality disorder
showed intact discrimination of form and trajectory but were impaired on working
memory tasks. CONCLUSIONS: These data suggest that subjects with schizotypal
personality disorder, unlike patients affected by schizophrenia, have relatively
intact visual perception. Subjects with schizotypal personality disorder do show
specific deficits on tasks of comparable difficulty when working memory demands
are imposed. Schizotypal personality disorder may be associated with a more
specific visual processing deficit than schizophrenia, possibly reflecting
disruption of frontal lobe systems subserving visual working memory operations.
PMID- 10784473
TI - Verbal and nonverbal neuropsychological test performance in subjects with
schizotypal personality disorder.
AB - OBJECTIVE: The authors contrasted verbal and nonverbal measures of attention and
memory in patients with DSM-IV-defined schizotypal personality disorder in order
to expand on their previous findings of verbal learning deficits in these
patients and to understand better the neuropsychological profile of schizotypal
personality disorder. METHOD: Cognitive test performance was examined in 16 right
handed men who met diagnostic criteria for schizotypal personality disorder and
16 matched male comparison subjects. Neuropsychological measures included verbal
and nonverbal tests of persistence, supraspan learning, and short- and long-term
memory retention. Neuropsychological profiles were constructed by standardizing
test scores based on the means and standard deviations of the comparison subject
group. RESULTS: Subjects with schizotypal personality disorder showed a mild to
moderate general reduction in performance on all measures. Verbal measures of
persistence, short-term retention, and learning were more severely impaired than
their nonverbal analogs. Performance on measures of memory retention was
independent of modality. CONCLUSIONS: The results are consistent with previous
reports that have suggested a mild, general decrement in cognitive performance
and proportionately greater involvement of the left hemisphere in patients with
schizotypal personality disorder. The findings provide further support for a
specific deficit in the early processing stages of verbal learning.
PMID- 10784474
TI - Premorbid speech and language impairments in childhood-onset schizophrenia:
association with risk factors.
AB - OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk
factors for schizophrenia are prominent in childhood-onset cases (with onset of
psychosis by age 12), their relationship was examined. METHOD: Premorbid
language, motor, and social impairments were assessed in a cohort of 49 patients
with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum
disorders, familial eye-tracking dysfunction, and obstetrical complications were
assessed without knowledge of premorbid abnormalities and were compared in the
patients with and without developmental impairments. RESULTS: Over one-half of
the patients in this group had developmental dysfunction in each domain assessed.
The patients with premorbid speech and language impairments had higher familial
loading scores for schizophrenia spectrum disorders and more obstetrical
complications, and their relatives had worse smooth-pursuit eye movements. The
boys had more premorbid motor abnormalities, but early language and social
impairments did not differ significantly between genders. There were no other
significant relationships between premorbid social or motor abnormalities and the
risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are
common in childhood-onset schizophrenia. The rates of three risk factors for
schizophrenia (familial loading for schizophrenia spectrum disorders, familial
eye-tracking dysfunction, and obstetrical complications) were increased for the
probands with premorbid speech and language impairments, suggesting that the
pathophysiology of schizophrenia involves the abnormal development of language
related brain regions.
PMID- 10784475
TI - Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort.
AB - OBJECTIVE: Although case-control investigations have shown an association between
obstetric complications and schizophrenia, particularly among patients with early
onsets, cohort studies have mostly failed to confirm this effect. The authors
examined whether a history of fetal hypoxia and other obstetric complications
elevated risk for early-onset schizophrenia in a 1955 Helsinki birth cohort.
METHOD: The subjects were 80 randomly selected patients with schizophrenia (36
with early and 44 with later onsets) representative of all available probands in
the cohort, 61 of their nonschizophrenic siblings, and 56 demographically matched
nonpsychiatric comparison subjects. Psychiatric diagnoses were obtained from
structured clinical interviews, and obstetric data were taken from standardized,
prospectively ascertained obstetric records. A score for hypoxia-associated
obstetric complications was entered into logistic regression models, along with
measures of prenatal infection and fetal growth retardation. RESULTS: Hypoxia
associated obstetric complications significantly increased the odds of early
onset schizophrenia but not of later-onset schizophrenia or unaffected sibling
status, after prenatal infection and fetal growth retardation were taken into
account. CONCLUSIONS: These findings support an association between obstetric
complications and increased risk for early-onset schizophrenia. The authors
advance a model whereby the neurotoxic effects of fetal hypoxia may lead to an
early onset of schizophrenia due to premature cortical synaptic pruning.
PMID- 10784476
TI - Untreated initial psychosis: its relation to quality of life and symptom
remission in first-episode schizophrenia.
AB - OBJECTIVE: Previous studies have suggested that there may be an association
between longer duration of untreated psychosis and poor outcome in schizophrenia.
These studies have been interpreted as providing evidence that untreated
psychosis may constitute an "active morbid process" that is "toxic" to the brain.
If untreated psychosis is neurotoxic, this would form a strong basis for early
intervention in schizophrenia. METHOD: Seventy-four neuroleptic-naive patients
with DSM-IV schizophrenia were evaluated 6 months after their first inpatient
hospitalization. The authors examined the relationship between untreated initial
psychosis duration (measured from onset of first symptom as well as from onset of
full positive syndrome) and quality of life, symptom severity, and time to
remission of positive symptoms. RESULTS: Earlier age at illness onset was
associated with longer duration of untreated prodromal psychotic symptoms. There
were no significant gender differences in duration of untreated initial
psychosis, nor were there any significant associations between untreated initial
psychosis duration and premorbid functioning. After controlling for the effects
of age at onset, the duration of untreated initial psychosis did not
significantly impair subsequent quality of life, symptom severity, or remission
of positive symptoms. CONCLUSIONS: Duration of untreated initial psychosis was
not prognostic of poor outcome early in the course of schizophrenia. Biological
measures of neurotoxicity are needed to examine the "toxic psychosis" hypothesis
more directly.
PMID- 10784477
TI - Age-dependent decline of symptoms of attention deficit hyperactivity disorder:
impact of remission definition and symptom type.
AB - OBJECTIVE: Symptom decline in attention deficit hyperactivity disorder (ADHD) was
examined with different definitions of remission. METHOD: Symptoms in 128 boys
were measured five times over 4 years. The prevalences of syndromatic (less than
full syndrome), symptomatic (less than subthreshold diagnosis), and functional
(full recovery) remission were estimated as a function of age with multivariate
logistic regression. RESULTS: Age was significantly associated with decline in
total ADHD symptoms and symptoms of hyperactivity, impulsivity, and inattention.
Symptoms of inattention remitted for fewer subjects than did symptoms of
hyperactivity or impulsivity. The proportion of subjects experiencing remission
varied considerably with the definition used (highest for syndromatic remission,
lowest for functional remission). CONCLUSIONS: These results indicate that
differences in reported remission rates reflect the definition used rather than
the disorder's course. They provide systematic support for the clinical
observation that hyperactivity and impulsivity symptoms tend to decline at a
higher rate than inattention symptoms.
PMID- 10784478
TI - Divalproex treatment for youth with explosive temper and mood lability: a double
blind, placebo-controlled crossover design.
AB - OBJECTIVE: The authors sought to replicate open-label findings showing that
specific criteria for explosive temper and mood lability identify disruptive
youth who improve while receiving the anticonvulsant divalproex sodium. METHOD:
Twenty outpatient children and adolescents (ages 10-18) with a disruptive
behavior disorder (oppositional defiant disorder or conduct disorder) met the
specific criteria for explosive temper and mood lability. They received 6 weeks
of divalproex treatment and 6 weeks of placebo by random assignment. Independent
evaluators blind to group assignment assessed response at the end of each phase.
RESULTS: At the end of phase 1, eight of 10 subjects had responded to divalproex;
zero of 10 had responded to placebo. Of the 15 subjects who completed both
phases, 12 has superior response taking divalproex. CONCLUSIONS: This preliminary
study replicates open-label findings showing that divalproex is an efficacious
treatment for explosive temper and mood lability in disruptive children and
adolescents.
PMID- 10784479
TI - Response to flumazenil in women with premenstrual dysphoric disorder.
AB - OBJECTIVE: The authors sought to determine whether the administration of
flumazenil would induce marked panic symptoms in women suffering from
premenstrual dysphoric disorder. METHOD: Ten women with premenstrual dysphoric
disorder and 11 comparison subjects were injected with flumazenil or placebo in a
double-blind, randomized, balanced crossover design in a single session in the
luteal phase of their menstrual cycles. RESULTS: Flumazenil induced a much
greater panic response in the women with premenstrual dysphoric disorder than in
the comparison subjects. CONCLUSIONS: These preliminary results are consistent
with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex
during the premenstruum of women suffering from premenstrual dysphoric disorder.
PMID- 10784480
TI - Adhesio interthalamica in male patients with schizophrenia.
AB - OBJECTIVE: The authors investigated whether absence of the adhesio interthalamica
in patients with schizophrenia constitutes a marker of early developmental
neuropathological changes. METHOD: Thirty male patients with schizophrenia and 30
healthy male subjects were recruited for study. Magnetic resonance imaging was
performed, and the presence or absence of the adhesio interthalamica was
determined for each subject. The length and volume of the third ventricle were
also measured. RESULTS: No differences in the presence or absence of the adhesio
interthalamica were found between patients with schizophrenia and normal
comparison subjects. Patients without the adhesio interthalamica had
significantly higher scores for negative symptoms than patients with the adhesio
interthalamica. There was no correlation between absence of the adhesio
interthalamica and length and volume of the third ventricle in either patients or
comparison subjects. CONCLUSIONS: The findings suggest that patients with
schizophrenia who do not have the adhesio interthalamica are characterized by
more severe negative symptoms.
PMID- 10784481
TI - Placebo-controlled trial of glycine added to clozapine in schizophrenia.
AB - OBJECTIVE: The purpose of this study was to evaluate the effects of high-dose
oral glycine on positive and negative symptoms and cognitive function when added
to clozapine in adults with schizophrenia. METHOD: The authors conducted a double
blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to
clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were
performed every 2 weeks. RESULTS: Twenty-seven patients completed the trial.
Glycine augmentation of clozapine produced no statistically significant change in
positive or negative symptoms or cognitive functioning. No subjects showed
clinically significant worsening of clinical ratings. CONCLUSIONS: These data,
combined with data from previous trials with D-cycloserine and glycine, suggest
that agonists at the glycine site may be less effective when combined with
clozapine than they are when combined with conventional antipsychotics.
PMID- 10784482
TI - Reduced olfactory bulb volume in patients with schizophrenia.
AB - OBJECTIVE: The authors' goal in this study was to compare the size of olfactory
bulbs of patients with schizophrenia and those of healthy subjects. METHOD:
Magnetic resonance imaging scans of olfactory bulbs were obtained from 26
patients with schizophrenia and 22 healthy comparison subjects. A reliable region
of interest procedure was used to measure olfactory bulb volume. RESULTS:
Patients exhibited 23% smaller bilateral bulb volume than comparison subjects,
independent of acute clinical, demographic, or treatment measures. Bulb volume
correlated with odor detection sensitivity in healthy subjects but not in
patients with schizophrenia. CONCLUSIONS: Patients with schizophrenia exhibit
structural olfactory deficits as well as functional olfactory deficits. The
olfactory system may be a model system in which to study the neurobiology of the
disorder.
PMID- 10784484
TI - Amphetamine misuse and social phobia.
PMID- 10784483
TI - Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic
patients.
AB - OBJECTIVE: Glycogen synthase kinase-3 (GSK-3) is a protein kinase that is highly
abundant in the brain. It is involved in signal transduction cascades of multiple
cellular processes, particularly neurodevelopment. In an attempt to explore
possible involvement of GSK-3beta in psychiatric disorders, the authors examined
its levels in postmortem brain tissue. METHOD: Western blot analysis was
performed to measure GSK-3beta in the frontal cortex of 14 schizophrenic
patients, 15 patients with bipolar disorder, 15 patients with unipolar
depression, and 14 normal comparison subjects. RESULTS: GSK-3beta levels were 41%
lower in the schizophrenic patients than in the comparison subjects. Other
diagnostic groups did not differ from the comparison subjects. CONCLUSIONS: These
results are consistent with the notion that schizophrenia involves
neurodevelopmental pathology. It remains to be investigated whether the active
fraction of GSK-3beta, or its activity, is also low in frontal cortex of
schizophrenic patients and if this is also reflected in other brain regions.
PMID- 10784485
TI - Focal segmental glomerulosclerosis and lithium treatment.
PMID- 10784486
TI - Euphoric mania and rapid transcranial magnetic stimulation.
PMID- 10784487
TI - Ziprasidone overdose.
PMID- 10784488
TI - Antidepressant-induced sexual dysfunction and Ginkgo Biloba.
PMID- 10784489
TI - Racial differences in treatment of adolescents with bipolar disorder.
PMID- 10784490
TI - Mnemonic screening device for generalized anxiety disorder.
PMID- 10784491
TI - Treatments to change sexual orientation.
PMID- 10784493
TI - Biology versus psychoanalysis.
PMID- 10784494
TI - Possible interaction of tramadol and antidepressants.
PMID- 10784500
TI - Cross-Cultural Practice: Assessment, Treatment, and Training.
PMID- 10784496
TI - Use of ECT in Italy.
PMID- 10784503
TI - Psychoanalysis: Clinical and Theoretical.
PMID- 10784508
TI - Unusual and memorable
PMID- 10784507
TI - Inflammation-mediated rheumatic diseases and atherosclerosis.
PMID- 10784510
TI - Rheumatic diseases and the environment
PMID- 10784512
TI - Biology of the synovial joint
PMID- 10784513
TI - Factors that modify the association between knee pain and mobility limitation in
older women: the Women's Health and Aging Study.
AB - OBJECTIVE: To investigate the influence of pain severity, knee extensor muscle
weakness, obesity, depression, and activity on the association between recent
knee pain and limitation of usual and fast paced walking, and ability to rise
from a chair. METHODS: A cross sectional analysis of 769 older women (mean age
77.8, range 65-101) with physical disability, but no severe cognitive impairment.
Severity of knee pain in the past month was classified as none, moderate, or
severe. Mobility was measured using timed performance tests. RESULTS: The
prevalence of recent knee pain was 53% (408/769). One third of the women with
pain reported it to be severe. In general, knee pain was only significantly
associated with limited mobility if severe. Obesity, activity and, to a lesser
extent, depression intensified the effects of pain. Knee extensor weakness did
not. Obesity was a distinctive risk factor in that it substantially increased the
risk of mobility limitation, but only in women with pain. In women who had severe
pain, activity (walking more than three city blocks in the past week) increased
the risk of walking disability more than inactivity. Depression had a minor, but
statistically significant effect on walking ability, but not the ability to rise
from a chair. CONCLUSION: In older women with recent knee pain, a high pain
severity score, obesity, and activity are important factors that increase the
risk of mobility limitation.
PMID- 10784514
TI - The oxidative metabolism of circulating phagocytes in ankylosing spondylitis:
determination by whole blood chemiluminescence.
AB - OBJECTIVE: Superoxide anion radicals within the human body are regarded as a
major cause of inflammation. However, their role in the pathogenesis of
ankylosing spondylitis (AS) has not been well identified. This study aimed at
investigating the relation between AS and the oxidative metabolism of phagocytes
in whole blood. METHODS: 24 patients with classic AS were examined to determine
their clinical status; complete blood count, erythrocyte sedimentation rate
(ESR), and C reactive protein (CRP) were determined, and levels of the superoxide
anion radicals in the patients with AS and 21 healthy subjects were assessed by
the ultraweak chemiluminescence method. Subsequently, the relation between this
disease and phagocytes was examined by using N-formyl-methionyl-leucyl
phenylalanine (fMLP) and phorbol-12-myristate-13-acetate (PMA) stimulants.
RESULTS: In clinical assessments, patients with AS had abnormally raised serum
CRP (>10 mg/l) and ESR (>15 mm/1st h) levels. In contrast with healthy subjects,
patients with AS had significantly increased rates of superoxide anion radical
production in their whole blood either in the resting state or with either fMLP
or PMA stimulation. In addition, chemiluminescence maximum light intensity was
significantly higher in patients with AS than in healthy subjects after fMLP or
PMA stimulation. CONCLUSIONS: Our results suggest that the phagocytes of patients
with AS are partly activated in the resting state, and are sensitive to fMLP or
PMA stimulation. The priming of phagocytes in the bloodstream is likely to be a
causative factor in the onset of AS.
PMID- 10784515
TI - Detection of multiple viral DNA species in synovial tissue and fluid of patients
with early arthritis.
AB - OBJECTIVE: Viruses have a role in the pathogenesis of various forms of arthritis.
This study aimed at determining whether viral DNA can be detected in joint
samples in the early stages of idiopathic arthritides. METHODS: Synovial fluid
(SF) and synovial tissue (ST) samples were obtained from 73 patients, with
undifferentiated arthritis (n=22), rheumatoid arthritis (n=13),
spondyloarthropathy (n=17), crystal arthropathy (n=8), osteoarthritis (n=7),
septic arthritis (n=5), and trauma (n=1). The presence of viral DNA was
investigated by polymerase chain reaction analysis. RESULTS: Cytomegalovirus was
present in 25 patients, parvovirus B19 in 15 patients, Epstein-Barr virus in 12
patients, and herpes simplex virus in 16 patients (in ST, SF, or both),
respectively. The joint samples were negative for viral DNA from adenovirus and
varicella-zoster virus. In ST, eight patients were double positive for parvovirus
B19 and another viral DNA, with herpes simplex virus being the most prevalent.
Seven patients were double positive for other viruses (cytomegalovirus, herpes
simplex virus, Epstein-Barr virus). In SF, four patients were double or triple
positive for viral DNA. Paired samples were available in 56 patients. In these,
viral DNA was detected in 37 patients in ST, as compared with 19 in SF.
CONCLUSION: These data show that one or more viruses can be detected in the
synovial specimens of patients with early arthritis, irrespective of the clinical
diagnosis. This observation might be explained by migration of inflammatory cells
harbouring viral DNA into the inflamed joints.
PMID- 10784516
TI - Percentage of glycosylated serum ferritin remains low throughout the course of
adult onset Still's disease.
AB - OBJECTIVE: To determine the evolution of levels of total serum ferritin and
percentage of the glycosylated form in patients with adult onset Still's disease
(AOSD) at the time of diagnosis and during follow up. METHODS: All patients with
AOSD were tested at the time of diagnosis and during follow up. Total serum
ferritin levels were analysed by immunoassay, and the percentage of glycosylated
ferritin was determined by methods using Sepharose-Con A. RESULTS: 14 patients
(eight women, six men) with AOSD were enrolled. At the time of diagnosis, mean
(SD) age was 36 (16) years. Mean initial total serum ferritin was 6350 (1300)
microg/l (normal <250 microg/l). The mean initial percentage of glycosylated
ferritin was 14.7 (13)% (normal >50%). Mean follow up time was 37 (35) months. At
the time of the last examination all patients were in remission except one, who
presented a chronic articular form. Total serum ferritin remained high in this
single patient and was normal in the 13 others, with a mean of 98 (73) microg/l.
In all patients the percentage of glycosylated ferritin remained low, with a mean
of 16 (16)%. CONCLUSION: Total serum ferritin is a marker of the active phase of
AOSD. The percentage of glycosylated ferritin is low both in the active phase and
in remission. Further studies are needed to confirm these data and to determine
their specificity for AOSD before considering any possible use of a low
percentage of glycosylated ferritin as a diagnostic tool in suspected AOSD,
especially when atypical or previously treated.
PMID- 10784517
TI - Effect of circulating immune complexes on the binding of rheumatoid factor to
histones.
AB - OBJECTIVE: To determine whether the reaction of rheumatoid factor (RF) with solid
phase histone is due to the simultaneous presence of circulating immune complexes
(CICs) or aggregated IgG. METHODS: Serum samples from 56 patients with
seropositive rheumatoid arthritis (RA) and 50 random blood bank donors were used.
Binding of immunoglobulins to histone was determined by enzyme linked
immunosorbent assay (ELISA) and by western blots. Aggregated IgG was obtained by
heating at 61(o)C for 30 minutes. RESULTS: Among the RA sera tested by ELISA, 54%
were positive for histone binding by IgM, IgG, or IgA and 20% by IgM only.
Heating of normal sera caused a significant enhancement in the binding of IgG to
histone (p<0.001). This binding had a non-cognate behaviour-that is, it was
destroyed by pepsin treatment of serum and was not significantly inhibited by
competition with free histone. The same behaviour was seen for IgM, IgG, and IgA
binding from RA sera. However, cognate IgG antibody binding to histone was
inhibited by free histone and was resistant to pepsin digestion. Addition of heat
aggregated IgG to RA sera or pretreatment of histone with aggregated IgG caused a
significant increase in IgM binding to histone. CONCLUSION: IgM, IgG, and IgA RF
bind to solid phase histone as a result of attachment to histone of immune
complexes or aggregated IgG and not as a result of a cognate reaction with
histone.
PMID- 10784518
TI - Systemic scleroderma in Greece: low mortality and strong linkage with HLA
DRB1*1104 allele.
AB - OBJECTIVE: Description of Greek patients with scleroderma with reference to (a)
major organ disease, (b) autoantibodies, (c) survival rate, and (d) HLA
associations. METHODS: The clinical files of 254 patients were analysed
retrospectively and a standardised clinical chart was completed with age at
disease onset, sex, date of first and last visit, clinical and serological
findings, organs affected, reasons for death, and HLA class II alleles. HLA class
II alleles (DRB1, DQA1, DQB1, DPB1) were determined by polymerase chain reaction
amplification using oligopeptide probes. DNA was extracted from 98 patients and
130 Greek controls. RESULTS: 124 patients (49%) had limited systemic sclerosis
(lSSc), 114 (45%) had diffuse systemic sclerosis (dSSc), and 16 (6%) had overlap
syndromes. Patients with dSSc, compared with lSSc, were characterised by a higher
prevalence of lung disease (p=0.0011), oesophageal, heart, and peripheral vessel
disease (p=0.027, p=0.0025, and p=0.012, respectively). Anticentromere antibodies
(ACA) occurred exclusively in lSSc (34%), whereas antibodies to topoisomerase I
(anti-topo I) were associated with dSSc (p<0.0001). Anti-topo I were associated
with interstitial pulmonary fibrosis, oesophageal and peripheral vessel disease
(p=0.028, p=0.012, and p=0.01, respectively). The HLA-DRB1*1104 allele was
associated with the disease (p<0.0001) and anti-topo I (p<0.001), whereas it was
not associated with ACA serum reactivity (p<0.001). Renal disease occurred in 4%
of patients with SSc. The estimated survival probability for this cohort of
patients with SSc, four years after the first visit, is 94.8%. CONCLUSION: SSc
among Greek subjects has the same pattern of organ disease as in other white
populations. However, the prevalence of kidney disease is low. The HLA class II
DRB1*1104 allele is associated with the disease, with anti-topo I, and not
associated with ACA serum reactivity.
PMID- 10784519
TI - Does location of vertebral deformity within the spine influence back pain and
disability? European Vertebral Osteoporosis Study (EVOS) Group.
AB - OBJECTIVE: Vertebral deformity is associated with back pain and disability. The
aim of this analysis was to determine whether location within the spine
influences the strength of association between vertebral deformity, back pain and
disability. METHODS: Men and women aged 50 years and over were recruited from
population registers in 30 European centres. Subjects were invited for an
interviewer administered questionnaire, and for lateral spinal radiographs. The
questionnaire included questions about back pain, general health and functional
ability. The spinal radiographs were evaluated morphometrically and vertebral
deformity defined according to the McCloskey-Kanis method. RESULTS: 756 (11.7%)
men and 885 (11. 8%) women had evidence of one or more vertebral deformities.
Among women with a single deformity, after adjusting for age and centre, those
with a lumbar deformity were more likely than those with a thoracic deformity to
report back pain, both currently (OR=1.4; 95% CI 1.0, 2.0) and in the past year
(OR=1.5; 95% CI 1.0, 2.3). No association was observed in men. Among women with
two deformities, those with adjacent deformities were more likely than those with
non-adjacent deformities to report poor general health (OR=2.2; 95%CI 0.9, 5.6),
impaired functional ability (OR=1.9; 95%CI 0.8, 4. 7) and current back pain
(OR=2.1; 95%CI 0.9, 4.9), though none of these associations were statistically
significant. By contrast, among men, non-adjacent deformities were associated
with impaired functional ability compared with those with adjacent deformities.
CONCLUSION: Location within the spine influences the strength of association
between self reported health factors and vertebral deformity.
PMID- 10784520
TI - Pneumomediastinum in dermatomyositis: association with cutaneous vasculopathy.
AB - OBJECTIVES: To study the pathogenesis of pneumomediastinum in
polymyositis/dermatomyositis (PM/DM). PATIENTS AND METHODS: The clinical records
of 48 patients with PM/DM were reviewed, focusing mainly on the presence of
pneumomediastinum and cutaneous vasculopathy, and the chest radiographic changes.
A patient with pneumomediastinum with a characteristic change in his bronchus is
described in detail. Case reports of pneumomediastinum in PM/DM in English
publications are reviewed. RESULTS: Among the 48 patients with PM/DM,
pneumomediastinum was observed as a complication in four patients with DM and
none of the patients with PM. Three of the four patients with pneumomediastinum,
but only six of the 44 patients without this complication, had associated
cutaneous vasculopathy. There was a significant association of pneumomediastinum
with cutaneous vasculopathy (p = 0.02) and younger age (p = 0.04), but not with
the prevalence of lung disease. A 30 year old man (patient 1) with DM, who had
interstitial pneumonitis and skin ulceration due to vasculopathy, developed
pneumomediastinum. Fibreoptic bronchoscopy showed white plaques on the bronchial
mucosa, which were confirmed by microscopic examination as representing
subepithelial necrosis. A literature review showed 13 cases of DM but no patient
with PM with pneumomediastinum. CONCLUSIONS: In patient 1, bronchial necrosis due
to vasculopathy was strongly suspected as being responsible for the
pneumomediastinum. The results suggest that pneumomediastinum was associated not
with interstitial pneumonitis but with the complication of vasculopathy appearing
as skin lesions in DM.
PMID- 10784522
TI - Microsatellite analysis in rheumatoid arthritis synovial fibroblasts.
AB - OBJECTIVES: Rheumatoid arthritis (RA) is a chronic disease characterised by
irreversible destruction of the affected joints. As aggressive transformed
appearing synovial fibroblasts are commonly found at the site of invasion of the
rheumatoid synovium into the adjacent cartilage and bone, the presence of
microsatellite instability (MSI) and expression of mismatch repair enzymes as a
possible mechanism in the alteration of these cells was examined. METHODS: DNA
was extracted from the synovial fibroblasts and blood of 20 patients with long
term RA undergoing joint replacement, and the presence of MSI was studied at 10
microsatellite loci. In addition, immunohistochemistry was performed to evaluate
the expression of the two major mismatch repair enzymes (hMLH1 and hMSH2) in
rheumatoid synovium. RESULTS: MSI could not be detected in any of the fibroblast
cell populations derived from the 20 different rheumatoid synovial samples. In
addition, strong expression of mismatch repair enzymes could be seen in numerous
cells, including fibroblasts, throughout the synovium. CONCLUSIONS: Applying the
currently used and established markers for MSI, the data show for the first time
that MSI does not appear to have an important role in alteration of rheumatoid
synovial fibroblasts into an aggressive phenotype. On the other hand, strong
mismatch repair enzyme synthesis in rheumatoid synovium supports the hypothesis
of continuing DNA repair, presumably due to long term, inflammation induced DNA
damage.
PMID- 10784521
TI - Diagnosis and monitoring of central nervous system involvement in systemic lupus
erythematosus: value of F-18 fluorodeoxyglucose PET.
AB - OBJECTIVE: To investigate prospectively abnormalities of brain glucose
utilisation in relation to major or minor neuropsychiatric symptoms in systemic
lupus erythematosus (SLE). METHODS: Positron emission tomography (PET) using F-18
labelled fluorodeoxyglucose was performed in 28 patients with SLE. Patients were
classified as having severe neuropsychiatric manifestations (seizures, focal
neurological deficits, acute confusional states, mood disorders) (n=12), or mild
neuropsychiatric manifestations (headache, reactive depression, cognitive
dysfunction, anxiety disorders) (n=11) and five patients without signs of central
nervous system (CNS) involvement. Ten clinically and neurologically healthy
volunteers served as controls. In 26 patients magnetic resonance imaging (MRI)
was performed and autoantibodies against CNS tissue, ribosomal P protein and
cardiolipin were measured. In 14 patients follow up PET scans were performed
after a mean (SD) period of 11.6 (9.5) months. RESULTS: PET scans showed
hypometabolism in at least one brain region in all patients with severe or mild
CNS symptoms (100%) as compared with patients without cerebral symptoms (40%)
(p<0.0025). Parieto-occipital regions were most commonly affected (96%), followed
by parietal regions (32%). In contrast, MRI images were abnormal in only 11 of 22
patients (50%) with neuropsychiatric symptoms and in one of four patients (25%)
without symptoms. In 12 of 14 patients examined in follow up PET scans
persistence, improvement or worsening of cerebral symptoms were associated with
unchanged, decreased or increased brain hypometabolism, respectively. No
significant correlation was found between PET or MRI findings and autoantibody
profiles. CONCLUSIONS: PET imaging represents a sensitive tool to detect manifest
or subclinical CNS involvement in SLE and PET findings correlate well with the
clinical course of disease.
PMID- 10784523
TI - Systemic vasculitis with bilateral perirenal haemorrhage in chronic
myelomonocytic leukaemia.
AB - The cases of two patients with chronic myelomonocytic leukaemia associated with
periarteritis nodosa-like, antineutrophil cytoplasmic antibody negative, systemic
vasculitis, are reported. A 61 year old man was admitted with fever, diffuse
myalgia, and abdominal pain. Blood and bone marrow examination showed chronic
myelomonocytic leukaemia. Vasculitis of the gall bladder was responsible for
acalculous cholecystitis. A massive spontaneous bilateral perirenal haemorrhage
occurred. A 73 year old woman with chronic myelomonocytic leukaemia had been
followed up for one year when unexplained fever occurred. Two months after the
onset of fever, sudden abdominal pain was ascribed to spontaneous bilateral renal
haematoma related to bilateral renal arterial aneurysms. Neuromuscular biopsy
showed non-necrotising periarteriolar inflammation. To our knowledge, systemic
vasculitis has never been reported in chronic myelomonocytic leukaemia. In our
two cases a non-random association is suggested because (a) chronic
myelomonocytic leukaemia is a rare myelodysplastic syndrome, (b) spontaneous
bilateral perirenal haematoma is not a usual feature of periarteritis nodosa.
PMID- 10784524
TI - Do not resuscitate decisions: flogging dead horses or a dignified death?
Resuscitation should not be withheld from elderly people without discussion.
PMID- 10784525
TI - Valuing the effects of sildenafil in erectile dysfunction. Strong assumptions are
required to generate a QALY value.
PMID- 10784526
TI - Multicentre research ethics committees: has the cure been worse than the disease?
No, but idiosyncracies and obstructions to good research must be removed.
PMID- 10784528
TI - Reducing the speed limit to 20 mph in urban areas. Child deaths and injuries
would be decreased.
PMID- 10784527
TI - Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that
many drugs can cause qt prolongation.
PMID- 10784529
TI - Control malaria to help defeat poverty, says WHO.
PMID- 10784530
TI - NHS should be recast in BBC mould, says report.
PMID- 10784531
TI - Spain launches national plan for palliative care.
PMID- 10784533
TI - In brief
PMID- 10784532
TI - Health insurer delays psychiatric admissions.
PMID- 10784534
TI - National register will monitor hip replacements.
PMID- 10784535
TI - Discrimination "rife" against mental health patients.
PMID- 10784536
TI - Guru promotes global health.
PMID- 10784537
TI - Cost utility analysis of sildenafil compared with papaverine-phentolamine
injections.
AB - OBJECTIVE: To compare the cost effectiveness of sildenafil and papaverine
phentolamine injections for treating erectile dysfunction. DESIGN: Cost utility
analysis comparing treatment with sildenafil (allowing a switch to injection
therapy) and treatment with papaverine-phentolamine (no switch allowed). Costs
and effects were estimated from the societal perspective. Using time trade-off, a
sample of the general public (n=169) valued health states relating to erectile
dysfunction. These values were used to estimated health related quality of life
by converting the clinical outcomes of a trial into quality adjusted life years
(QALYs). PARTICIPANTS: 169 residents of Rotterdam. MAIN OUTCOME MEASURES: Cost
per quality adjusted life year. RESULTS: Participants thought that erectile
dysfunction limits quality of life considerably: the mean utility gain
attributable to sildenafil is 0.11. Overall, treatment with sildenafil gained
more QALYs, but the total costs were higher. The incremental cost effectiveness
ratio for the introduction of sildenafil was pound sterling 3639 in the first
year and fell in following years. Doubling the frequency of use of sildenafil
almost doubled the cost per additional QALY. CONCLUSIONS: Treatment with
sildenafil is cost effective. When considering funding sildenafil, healthcare
systems should take into account that the frequency of use affects cost
effectiveness.
PMID- 10784538
TI - Scientific, ethical, and logistical considerations in introducing a new
operation: a retrospective cohort study from paediatric cardiac surgery.
AB - OBJECTIVE: To review the initial impact on mortality of infants with congenital
heart disease of a new surgical technique that is now taken for granted. DESIGN:
Retrospective cohort study. SETTING: A tertiary paediatric cardiology centre.
SUBJECTS: 325 consecutive neonates with simple transposition of the great
arteries admitted before, during, and after the preferred management changed from
the Senning operation to the arterial switch (1978-98); and 100 consecutive
neonates requiring a different neonatal open heart operation that did not change
in that period. MAIN OUTCOME MEASURES: Mortality before and early after operation
reconstructed sequentially as the series evolved and retrospectively once the
series was complete; actuarial survival associated with the different treatment
strategies. RESULTS: For both the transposition and the comparison group, early
mortality in 1998 was lower than in 1978. During that period, however, there was
a phase temporally related to the adoption of the switch operation in which early
mortality for transposition increased. Actuarial survival of recent patients with
"intention to treat" with arterial switch is superior to those with intention to
treat with the Senning operation, as predicted when the switch operation was
first adopted. CONCLUSIONS: A period of increased hazard for individual patients
may occur when a specialist community, a particular unit, and an individual
surgeon are all learning a new technique concurrently. Obtaining informed consent
during this time of uncertainty is helped by clarity about the objectives of
treatment and availability of relevant local and international data.
PMID- 10784540
TI - The odd man out
PMID- 10784539
TI - Temperature measured at the axilla compared with rectum in children and young
people: systematic review.
AB - OBJECTIVE: To evaluate the agreement between temperature measured at the axilla
and rectum in children and young people. DESIGN: A systematic review of studies
comparing temperature measured at the axilla (test site) with temperature
measured at the rectum (reference site) using the same type of measuring device
at both sites in each patient. Devices were mercury or electronic thermometers or
indwelling thermocouple probes. STUDIES REVIEWED: 40 studies including 5528
children and young people from birth to 18 years. DATA EXTRACTION: Difference in
temperature readings at the axilla and rectum. RESULTS: 20 studies (n=3201 (58%)
participants) had sufficient data to be included in a meta-analysis. There was
significant residual heterogeneity in both mean differences and sample standard
deviations within the groups using different devices and within age groups. The
pooled (random effects) mean temperature difference (rectal minus axillary
temperature) for mercury thermometers was 0.25 degrees C (95% limits of agreement
-0.15 degrees C to 0.65 degrees C) and for electronic thermometers was 0. 85
degrees C (-0.19 degrees C to 1.90 degrees C). The pooled (random effects) mean
temperature difference (rectal minus axillary temperature) for neonates was 0.17
degrees C (-0.15 degrees C to 0. 50 degrees C) and for older children and young
people was 0.92 degrees C (-0.15 degrees C to 1.98 degrees C). CONCLUSIONS: The
difference between temperature readings at the axilla and rectum using either
mercury or electronic thermometers showed wide variation across studies. This has
implications for clinical situations where temperature needs to be measured with
precision.
PMID- 10784541
TI - The new system of review by multicentre research ethics committees: prospective
study.
AB - OBJECTIVE: To assess the function of the new system of review by multicentre
research ethics committees and to highlight areas where improvement is still
needed. DESIGN: Prospectively collected data from a multicentre study was
examined with respect to the ethics review process. Administrative, financial,
and time elements of the review process were audited. SETTING: A single
multicentre research ethics committee and 125 local ethics committees from six
regions of England. MAIN OUTCOME MEASURES: Time to reply, time to approval, and
number of non-local changes to the application requested. RESULTS: Only 40% of
local ethics committees considered our study in the manner specified in the 1998
directive. Less than a third of committees replied within the 21 day period
stipulated, although committees acting by executive subcommittee replied more
quickly than those not acting by executive subcommittee. There was a tendency for
executive subcommittees to approve studies in a shorter time. Local ethics
committees asked for a large number of non-local changes to the application. The
financial cost of applying to multiple ethics committees remains high, mainly
because multiple copies of research applications are being requested.
CONCLUSIONS: The new system of approval by multicentre research ethics committee
for multicentre studies was introduced to reduce administrative costs, speed up
the process of reviews by multiple research ethics committees, and standardise
the conclusions of the local research ethics committees. Since its introduction
an improvement has been seen, but the system is not yet universally functioning
as intended. Ethics review still remains a hindrance to the financial resources
and commencement of national studies. We strongly support the structure of review
by multicentre research ethics committees but suggest that the system has yet to
achieve its aims.
PMID- 10784543
TI - The cost of getting approval
PMID- 10784542
TI - Responses of local research ethics committees to a study with approval from a
multicentre research ethics committee.
PMID- 10784545
TI - Keep looking for a reason
PMID- 10784544
TI - Sedation with "non-sedating" antihistamines: four prescription-event monitoring
studies in general practice.
AB - OBJECTIVES: To investigate the frequency with which sedation was reported in post
marketing surveillance studies of four second generation antihistamines:
loratadine, cetirizine, fexofenadine, and acrivastine. DESIGN: Prescription-event
monitoring studies. SETTING: Prescriptions were obtained for each cohort in the
immediate post-marketing period. SUBJECTS: Event data were obtained for a total
of 43 363 patients. MAIN OUTCOME MEASURES: Reporting of sedation or drowsiness.
RESULTS: The odds ratios (adjusted for age and sex) for the incidence of sedation
were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79
(1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for
cetirizine compared with loratadine. No increased risk of accident or injury was
evident with any of the four drugs. CONCLUSIONS: Although the risk of sedation
was low with all four drugs, fexofenadine and loratadine may be more appropriate
for people working in safety critical jobs.
PMID- 10784546
TI - Drug treatment in heart failure.
PMID- 10784547
TI - Email submissions from outside the united kingdom
PMID- 10784548
TI - ABC of arterial and venous disease. Arterial aneurysms.
PMID- 10784549
TI - "Shouldn't we do something about the fire?"
PMID- 10784550
TI - How should cost data in pragmatic randomised trials be analysed?
PMID- 10784552
TI - Fifty five years later
PMID- 10784551
TI - Income inequality and mortality: importance to health of individual income,
psychosocial environment, or material conditions.
PMID- 10784553
TI - A good death. Sharing control in death: the role of an "amicus mortis".
PMID- 10784554
TI - Older Americans hold on to life dearly.
PMID- 10784555
TI - New models of journals must be sought.
PMID- 10784556
TI - Population, consumption, and entrapment. Raise living standards to reduce
population growth.
PMID- 10784557
TI - Eradicating war is essential to eliminate poverty and improve health.
PMID- 10784558
TI - Will eradication of Helicobacter pylori improve symptoms of non-ulcer dyspepsia?
Studies included in meta-analysis had heterogenous, not homogenous, results.
PMID- 10784559
TI - Use of unlabelled and off licence drugs in children. Use of unlicensed drugs may
be recommended in guidelines.
PMID- 10784560
TI - Prescriptions on bioterrorism have it backwards.
PMID- 10784561
TI - Pathogen causing infection related to body piercing should be determined.
PMID- 10784562
TI - Patient information systems are not more expensive than leaflets.
PMID- 10784564
TI - Obituaries
PMID- 10784563
TI - Joint Committee on Postgraduate Training for GPs needs more money for its work.
PMID- 10784566
TI - Evidence based gastroenterology and hepatology
PMID- 10784565
TI - Consultants' leaders spell out NHS spending priorities
PMID- 10784567
TI - Bioethics: An anthology
PMID- 10784568
TI - Humanitarian crises: the medical and public health response
PMID- 10784569
TI - Blue/Orange
PMID- 10784571
TI - The class reunion
PMID- 10784570
TI - The ethics of research ethics committees.
PMID- 10784572
TI - Ebrahim's quartet
PMID- 10784574
TI - New operations bring period of increased hazard for patients
PMID- 10784573
TI - Healthcare systems should fund sildenafil
PMID- 10784575
TI - Temperature measured at the axilla in children and young people may be misleading
PMID- 10784576
TI - Ethics approval for multicentre research is expensive, slow, and inconsistent
PMID- 10784577
TI - Non-sedating antihistamines have differing sedative effects
PMID- 10784578
TI - Material conditions directly affect health inequalities, not income inequality
PMID- 10784579
TI - Follow the money.
PMID- 10784580
TI - Helicobacter heilmannii-associated primary gastric low-grade MALT lymphoma:
complete remission after curing the infection.
AB - BACKGROUND & AIMS: Cure of Helicobacter pylori infection may lead to complete
remission of associated low-grade mucosa-associated lymphoid tissue (MALT)
lymphoma in stage EI. This study investigated whether Helicobacter heilmannii
infection-associated primary gastric MALT lymphoma will regress after cure of the
infection. METHODS: H. heilmannii-induced gastritis was diagnosed histologically,
by a new specific immunoglobulin G enzyme-linked immunosorbent assay, and with
16S ribosomal RNA amplification and sequencing in 5 consecutive patients with
primary gastric MALT lymphoma clinical stage EI. Patients received 40 mg
omeprazole and 750 mg amoxicillin 3 times per day for 14 days. Polymerase chain
reaction (PCR) was used to detect rearrangement of immunoglobulin heavy-chain
genes before treatment and during follow-up. RESULTS: Five patients (3 men, 2
women; mean age, 65 years; range, 42-79 years) were studied. H. pylori was not
detected by culture, histology, serology, or PCR. Treatment resulted in the cure
of H. heilmannii infection in each case and complete histological and endoscopic
remission of the tumors. Three of 5 patients showed monoclonal B cells before
treatment, 2 of whom remained PCR positive. Within a median follow-up period of
24 months, no relapse of the lymphoma or reinfection with H. heilmannii occurred.
CONCLUSIONS: These data suggest that gastric MALT lymphoma may arise in patients
with H. heilmannii infection. Cure of this infection may lead to complete
remission of the MALT lymphoma.
PMID- 10784581
TI - Controlled 15-year trial on screening for colorectal cancer in families with
hereditary nonpolyposis colorectal cancer.
AB - BACKGROUND & AIMS: Identification of the hereditary nonpolyposis colorectal
cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of
colonoscopy and polypectomies. We evaluated the efficacy of screening in a
controlled trial over 15 years. METHODS: Incidence of CRC and survival were
compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic
screening at 3-year intervals was arranged for 133 subjects; 119 control subjects
had no screening. Genetic testing was offered to subjects in whose families the
causative mutation was known. RESULTS: CRC developed in 8 screened subjects (6%)
compared with 19 control subjects (16 %; P = 0.014). The CRC rate was reduced by
62%. In mutation-positive subjects alone, the CRC rates were 18% in screened
subjects and 41% in controls (P = 0.02). The decrease resulted from the removal
of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with
unknown mutation status (40%). All CRCs in the study group were local, causing no
deaths, compared with 9 deaths caused by CRC in the controls. The overall death
rates were 10 vs. 26 subjects in the study and control groups (P = 0.003), 4 vs.
12 in mutation-positive subjects (P = 0.05). CONCLUSIONS: Colonoscopic screening
at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and
decreases overall mortality by about 65% in HNPCC families.
PMID- 10784582
TI - Microsatellite instability and mutation of mitochondrial and nuclear DNA in
gastric carcinoma.
AB - BACKGROUND & AIMS: Microsatellite instability (MSI) in mitochondrial DNA (mtDNA)
is observed in some colorectal carcinomas. We attempted to determine if
mitochondrial MSI (mtMSI) and mutations occur in gastric carcinomas and if the
mtMSI phenotype underlies specific clinicopathologic profiles. METHODS: Sixty-two
gastric carcinomas (34 intestinal and 28 diffuse types) were investigated. Coding
mutations in 8 different mitochondrial genes, mtMSI in a noncoding (C)n tract,
and p53 gene mutations were examined by polymerase chain reaction-single-strand
conformation polymorphism (PCR-SSCP) analysis. MSI in nuclear DNA (nMSI) and loss
of the p53 gene were examined using microsatellite markers. RESULTS: Ten of 62
(16%) carcinomas showed the mtMSI phenotype. Mitochondrial gene mutation was
detected in 5 carcinomas, 4 of which also showed the mtMSI phenotype. There was a
positive correlation between mtMSI and nMSI status. In intestinal carcinomas,
mtMSI, nMSI, and p53 gene alterations were frequently detected from early to
advanced stages. In diffuse carcinomas, both kinds of MSI were found in only
advanced (subserosal or serosal invasion) carcinomas. Six of 7 carcinomas with
the nMSI phenotype and all 5 carcinomas with mitochondrial coding mutations had a
considerable intestinal-type tumor cell component. CONCLUSIONS: Mitochondrial
gene mutations, which are associated with the mtMSI phenotype, may play a
specific role in the tumorigenesis of intestinal-type gastric carcinomas.
PMID- 10784583
TI - Regional cerebral activation in irritable bowel syndrome and control subjects
with painful and nonpainful rectal distention.
AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is characterized by visceral
hypersensitivity, possibly related to abnormal brain-gut communication. Positron
emission tomography imaging has suggested specific central nervous system (CNS)
abnormalities in visceral pain processing in IBS. This study aimed to determine
(1) if functional magnetic resonance imaging (fMRI) detects CNS activity during
painful and nonpainful visceral stimulation; and (2) if CNS pain centers in IBS
respond abnormally. METHODS: fMRI was performed during nonpainful and painful
rectal distention in 18 patients with IBS and 16 controls. RESULTS: Rectal
stimulation increased the activity of anterior cingulate (33/34), prefrontal
(32/34), insular cortices (33/34), and thalamus (32/34) in most subjects. In IBS
subjects, but not controls, pain led to greater activation of the anterior
cingulate cortex (ACC) than did nonpainful stimuli. IBS patients had a greater
number of pixels activated in the ACC and reported greater intensity of pain at
55-mm Hg distention than controls. CONCLUSIONS: IBS patients activate the ACC, a
critical CNS pain center, to a greater extent than controls in response to a
painful rectal stimulus. Contrary to previous reports, these data suggest
heightened pain sensitivity of the brain-gut axis in IBS, with a normal pattern
of activation.
PMID- 10784584
TI - Distinct expression of splice variants of neuronal nitric oxide synthase in the
human gastrointestinal tract.
AB - BACKGROUND & AIMS: Changes of neuronal nitric oxide synthase (nNOS) expression
have been linked to several human gastrointestinal disorders such as achalasia,
diabetic gastroparesis, and hypertrophic pyloric stenosis. They could be caused
by differential transcriptional control or alternative splicing generating
different nNOS proteins. The aims of this study were to characterize 5'-splice
variants, promoter usage, and site-specific expression of nNOS in the human
gastrointestinal tract. METHODS: 5'-Splice variants were characterized by
immunoblotting, reverse-transcription polymerase chain reaction, 5'-rapid
amplification of complementary DNA ends, and Southern blotting. Genomic analysis
was performed by rapid amplification of genomic ends, followed by reporter gene
assays. RESULTS: Six different 5'-splice variants of nNOS-messenger RNA were
identified showing specific expressions at various sites of the human
gastrointestinal tract. Three variants encode for nNOSalpha, which has a specific
N-terminal PDZ/GLGF domain and interaction sites for regulatory proteins. Two
variants encode for nNOSbeta and 1 for nNOSgamma, which both lack the protein
binding domains of nNOSalpha. In addition to 2 known first exons, a novel first
exon of human nNOS with a separate functionally active downstream promoter and
multiple binding sites for transcription factors was identified and
characterized. CONCLUSIONS: Six 5'-mRNA splice variants of nNOS encoding 3
different nNOS proteins are expressed in the human gut. The differential
expression of these proteins could be implicated in different biological
functions.
PMID- 10784585
TI - Expression of glucocorticoid receptor beta in lymphocytes of patients with
glucocorticoid-resistant ulcerative colitis.
AB - BACKGROUND & AIMS: Recently, the glucocorticoid receptor beta (hGRbeta) was
suggested to play a role as a dominant negative regulator for determining
glucocorticoid response. The aim of this study was to clarify whether reverse
transcription polymerase chain reaction (RT-PCR) analysis of hGRbeta messenger
RNA (mRNA) can predict the response to glucocorticoids in patients with
ulcerative colitis. METHODS: Total RNA obtained from peripheral blood mononuclear
cells (PBMCs) of 23 patients with ulcerative colitis and 20 healthy volunteers
was reverse transcribed; the resulting complementary DNA was amplified using
specific primers for hGRalpha and hGRbeta. Protein expression of hGR in PBMCs was
confirmed by immunoprecipitation-Western blot analysis. RESULTS: The expression
of hGRalpha mRNA (477 base pairs) was detected in all patients and all healthy
volunteers. In contrast, a hGRbeta mRNA (366 base pairs) was detected in 1 (9.1%)
of 11 glucocorticoid-sensitive patients, 10 (83.3%) of 12 glucocorticoid
resistant patients, and 2 (10%) of 20 healthy volunteers. The positive rate of
hGRbeta mRNA in the resistant group was significantly higher than that in the
sensitive group (P = 0.0019). The hGRbeta band could be detected by
immunoprecipitation-Western blotting in hGRbeta mRNA-positive patients.
CONCLUSIONS: The results show that the expression of hGRbeta mRNA in PBMCs
examined by RT-PCR may serve as a novel predictor of glucocorticoid response in
ulcerative colitis.
PMID- 10784587
TI - Intestinal inflammation observed in IL-2R/IL-2 mutant mice is associated with
impaired intestinal T lymphopoiesis.
AB - BACKGROUND & AIMS: Although interleukin (IL)-2(-/-) and IL-2Ralpha(-/-) mice
develop inflammatory bowel disease, IL-2Rbeta(-/-) animals are apparently free of
gut pathology. Intraintestinal T lymphopoiesis is reported to be impaired in IL
2Rbeta(-/-) mice; we have determined whether this characteristic correlated with
the apparent resistance of this mutant strain to intestinal inflammation. This
led us to reassess intraintestinal T lymphopoiesis in these 3 mutant strains.
METHODS: Intestinal histology and intraintestinal T lymphopoiesis were analyzed
in unmanipulated mutant mice and in athymic and euthymic radiation chimeras
reconstituted with bone marrow derived from IL-2(-/-), IL-2Ralpha(-/-), and IL
2Rbeta(-/-) donors. RESULTS: Intraintestinal T lymphopoiesis was ablated in the 3
mutant strains and was associated with cryptopatch abnormalities. The intestinal
mucosa of mice reconstituted with lymphocytes from IL-2Rbeta(-/-) mice exhibited
lesions of both the small and large bowel similar to those observed in the early
stages of human gluten enteropathy and acute ulcerative colitis, respectively.
Analysis of euthymic and athymic bone marrow radiation chimeras indicated that T
cells located in the intestinal mucosa of unmanipulated IL-2(-/-), IL-2Ralpha(-/
), and IL-2Rbeta(-/-) mice are of thymic origin. CONCLUSIONS: Null mutations at
IL-2/IL-2Ralpha and beta loci differentially affect intraintestinal and
intrathymic T lymphopoiesis. These conditions are associated with lesions of
intestinal inflammation that are mediated by thymus-derived T cells.
PMID- 10784588
TI - Propagation and neural regulation of calcium waves in longitudinal and circular
muscle layers of guinea pig small intestine.
AB - BACKGROUND & AIMS: The relative movements of longitudinal muscle (LM) and
circular muscle (CM) and the role that nerves play in coordinating their
activities has been a subject of controversy. We used fluorescent video imaging
techniques to study the origin and propagation of excitability simultaneously in
LM and CM of the small intestine. METHODS: Opened segments of guinea pig ileum
were loaded with the Ca(2+) indicator fluo-3. Mucosal reflexes were elicited by
lightly depressing the mucosa with a sponge. RESULTS: Spontaneous Ca(2+) waves
occurred frequently in LM (1.2 s(-1)) and less frequently in CM (3.2 min(-1)).
They originated from discrete pacing sites and propagated at rates 8-9 times
faster parallel (LM, 87 mm/s; CM, 77 mm/s) compared with transverse to the long
axis of muscle fibers. The presence of Ca(2+) waves in one muscle layer did not
affect the origin, rate of conduction, or range of propagation in the other
layer. The extent of propagation was limited by collisions with neighboring waves
or recently excited regions. Simultaneous excitation of both muscle layers could
be elicited by mucosal stimulation of either ascending or descending reflex
pathways. Neural excitation resulted in an increase in the frequency of Ca(2+)
waves and induction of new pacing sites without eliciting direct coupling between
layers. CONCLUSIONS: Localized, spontaneous Ca(2+) waves occur independently in
both muscle layers, promoting mixing (pendular or segmental) movements, whereas
activation of neural reflexes stimulates Ca(2+) waves synchronously in both
layers, resulting in strong peristaltic or propulsive movements.
PMID- 10784586
TI - Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific
natural killer receptor CD94 in celiac disease.
AB - BACKGROUND & AIMS: Celiac disease is a gluten-induced enteropathy characterized
by the presence of gliadin-specific CD4(+) T cells in the lamina propria and by a
prominent intraepithelial T-cell infiltration of unknown mechanism. The aim of
this study was to characterize the subset(s) of intraepithelial lymphocytes
(IELs) expanding during active celiac disease to provide insights into the
mechanisms involved in their expansion. METHODS: Flow-cytometric analysis of
isolated IELs and/or immunohistochemical staining of frozen sections were
performed in 51 celiac patients and 50 controls with a panel of monoclonal
antibodies against T-cell and natural killer (NK) receptors. In addition, in
vitro studies were performed to identify candidate stimuli for NK receptor
expression. RESULTS: In normal intestine, different proportions of IELs, which
were mainly T cells, expressed the NK receptors CD94/NKG2, NKR-P1A, KIR2D/3D,
NKp46, Pen5, or CD56. During the active phase of celiac disease, the frequency of
CD94(+) IELs, which were mostly alphabeta T cells, was conspicuously increased
over controls. In contrast, the expression of other NK markers was not modified.
Furthermore, expression of CD94 could be selectively induced in vitro by T-cell
receptor activation and/or interleukin 15, a cytokine produced by intestinal
epithelial cells. CONCLUSIONS: The gut epithelium favors the development of T
cells that express NK receptors. In active celiac disease, there is a specific
and selective increase of IELs expressing CD94, the HLA-E-specific NK receptor
that may be related to T-cell receptor activation and/or interleukin 15
secretion.
PMID- 10784589
TI - Gastric mucosal responses to intrahepatic portosystemic shunting in patients with
cirrhosis.
AB - BACKGROUND & AIMS: The response of gastric mucosal lesions in cirrhotic patients
with portal hypertension, namely, portal hypertensive gastropathy (PHG) and
gastric vascular ectasia (GVE), to transjugular intrahepatic portosystemic shunts
(TIPS) is not known. METHODS: Clinical and laboratory evaluation, upper
gastrointestinal endoscopy, and Doppler ultrasonography were performed before
placement of TIPS and 6 weeks, 3 months, and 6 months after TIPS in 54 patients.
Thirty patients had mild PHG, 10 had severe PHG, and 14 had GVE. RESULTS:
Approximately 75% of the patients with severe PHG responded to TIPS as shown by
improvement in endoscopic findings and by a decrease in transfusion requirements;
89% of patients with mild PHG had endoscopic resolution. Patients with GVE had
neither endoscopic resolution nor a decrease in transfusion requirements after
TIPS. There was no difference in mortality between the 2 groups. CONCLUSIONS: The
results support the position that severe PHG and GVE may be different lesions.
Mild and severe PHG respond to TIPS. Because GVE does not respond to TIPS, we
recommend that TIPS be avoided for the treatment of gastrointestinal bleeding
associated with GVE.
PMID- 10784590
TI - Impaired human gallbladder lipid absorption in cholesterol gallstone disease and
its effect on cholesterol solubility in bile.
AB - BACKGROUND & AIMS: The role of the gallbladder in gallstone pathogenesis is still
unclear. We examined the effects of gallbladder mucosal lipid absorption on lipid
composition and cholesterol crystallization in bile. METHODS: The in vitro
isolated, intra-arterially perfused gallbladder model was used (1) to compare the
absorption rates of lipids from standard bile by gallbladders obtained from 7
patients with cholesterol gallstones and 6 controls; and (2) to measure the
microscopic cholesterol crystal detection time in cholesterol-enriched pig bile
before and after lipid absorption by the pig gallbladder. RESULTS: Control
gallbladders, but not cholesterol gallstone gallbladders, significantly reduced
cholesterol (P < 0.02) and phospholipid (P < 0.01) and increased bile salt (P <
0.01) molar percentages in bile over a 5-hour period by efficient and selective
cholesterol and phospholipid absorption. A histomorphometric study of the
epithelial cells showed significantly higher values for nuclear density (P <
0.01) and nuclear (P < 0.05) and cytoplasmic (P < 0.05) areas in the cholesterol
gallstone than the control group. Sequential microscopy of cholesterol-enriched
pig bile showed significantly shorter cholesterol filament (P < 0.01) and typical
cholesterol plate (P < 0. 02) detection times before than after exposure of bile
to the gallbladder lipid absorption. CONCLUSIONS: In cholesterol gallstone
disease, the human gallbladder epithelium loses its capacity to selectively and
efficiently absorb cholesterol and phospholipids from bile, even if it is
hyperplastic and hypertrophic. This epithelial dysfunction eliminates the
positive effect that the normal gallbladder exerts on cholesterol solubility in
bile and might be a pathogenetic cofactor for cholesterol gallstone formation.
PMID- 10784591
TI - Role of ATP7B in biliary copper excretion in a human hepatoma cell line and
normal rat hepatocytes.
AB - BACKGROUND & AIMS: Wilson's disease is a genetic disorder characterized by the
accumulation of copper in the body caused by a defect of biliary copper
excretion. The Wilson's disease gene has been cloned; however, the precise
localization of the gene product (ATP7B) and its role in biliary copper excretion
have not been clarified. METHODS: We constructed a chimeric protein between green
fluorescent protein (GFP) and ATP7B (GFP-ATP7B) and expressed it in a human
hepatoma cell line (Huh7) and isolated rat hepatocytes. The Golgi apparatus, late
endosomes, lysosomes, and bile canaliculus were visualized by fluorescence
microscopy. Brefeldin A and nocodazole were used to redistribute the Golgi
proteins. Bafilomycin A1 was used to analyze the association between GFP-ATP7B
and the late endosomes. RESULTS: GFP-ATP7B colocalized with rhodamine-dextran and
late endosome markers but not with the Golgi markers, lysosome markers, or a
tight junction protein. Brefeldin A and nocodazole redistributed the Golgi
proteins, but they did not affect the distribution of ATP7B. CONCLUSIONS:
Although it is widely believed that ATP7B is located at the Golgi apparatus, its
main localization is in late endosomes. ATP7B seems to translocate copper from
the cytosol to the late endosomal lumen, thus participating in biliary copper
excretion via lysosomes.
PMID- 10784592
TI - Glucagon-induced expression of the MAP kinase phosphatase MKP-1 in rat
hepatocytes.
AB - BACKGROUND & AIMS: Glucagon exerts pleiotropic effects on liver function, but the
underlying signal transduction is incompletely understood. We investigated the
effect of glucagon on the mitogen-activated protein (MAP) kinase phosphatase MKP
1 expression. METHODS: The effect of glucagon on MKP-1 expression was studied in
cultured rat hepatocytes. RESULTS: Glucagon (10-100 nmol/L) and 8-CPT-cAMP (10 or
50 micromol/L) stimulated in rat hepatocytes the expression of MKP-1 messenger
RNA and protein, which became maximal within 30 minutes and declined to nearly
basal levels after 60 minutes. MKP-1 induction by glucagon was sensitive to
inhibition of adenylate cyclase and protein kinase A. The protein kinases G and
C, Ca(2+), MAP kinases, reactive oxygen intermediates, and cellular dehydration
were not involved in the glucagon-induced signaling to MKP-1. MKP-1 expression
correlated with glucagon-induced antagonization of MAP kinase phosphorylation by
epidermal growth factor in hepatocytes. CONCLUSIONS: The MKP-1 response to
glucagon produces an additional level of interaction with MAP kinase-dependent
processes, which may contribute to the regulation of liver function by glucagon
or other cAMP-elevating agents.
PMID- 10784593
TI - Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in
bile duct-ligated rats.
AB - BACKGROUND & AIMS: Decreased cardiac contractility and beta-adrenergic
responsiveness have been observed in cirrhosis, but the etiology remains unclear.
We aimed to test the role of nitric oxide (NO), a negative inotropic agent, in
the pathogenesis of cirrhotic cardiomyopathy in a rat model. METHODS: Cirrhosis
was induced by bile duct ligation. Four weeks after ligation or sham operation,
cardiac levels of tumor necrosis factor (TNF)-alpha, guanosine 3,5'-cyclic
monophosphate (cGMP), inducible NOS (NOS2), and endothelial constitutive NOS
(NOS3) messenger RNA (mRNA) and protein were determined. Serum nitrite/nitrate
level was measured. Cardiac contractile function was evaluated in isolated left
ventricular papillary muscles in the absence and presence of the NOS inhibitor
nitro-L-arginine methyl ester (L-NAME). RESULTS: Cardiac TNF-alpha, NOS2 mRNA and
protein, cGMP, and serum interleukin (IL)-1beta and nitrite/nitrate levels were
significantly higher in cirrhotic rats than sham controls. No significant
differences in NOS3 mRNA or protein were found between cirrhotic and sham control
rats. Baseline isoproterenol-stimulated papillary muscle contractile force was
significantly lower in the cirrhotic group; with L-NAME incubation, contractile
force increased significantly in cirrhotic rats but was unaffected in the
controls. In normal papillary muscles, IL-1beta attenuated the contractility, but
coincubation with L-NAME again reversed this attenuation. Incubation with the
exogenous NO donor S-nitroso-N-acetyl-penicillamine also blunted papillary muscle
contractility. CONCLUSIONS: These results suggest that cytokine-induced
stimulation of NOS2 plays a significant role in the pathogenesis of cirrhotic
cardiomyopathy.
PMID- 10784594
TI - American Gastrointestinal Association. Our new president--Thomas A. Brasitus,
M.D.
PMID- 10784595
TI - American Gastroenterological Association Medical Position Statement: guidelines
on intestinal ischemia.
AB - This document presents the official recommendations of the American
Gastroenterological Association (AGA) on intestinal ischemia. It was approved by
the Clinical Practice and Practice Economics Committee on September 25, 1999, and
by the AGA Governing Board on November 15, 1999.
PMID- 10784596
TI - AGA technical review on intestinal ischemia. American Gastrointestinal
Association.
AB - This literature review and the recommendations therein were prepared for the
American Gastroenterological Association Clinical Practice and Practice Economics
Committee. The paper was approved by the committee on September 25, 1999, and by
the AGA Governing Board on November 25, 1999.
PMID- 10784597
TI - If aggressive surveillance in hereditary nonpolyposis colorectal cancer is now
state of the art, are there any challenges left?
PMID- 10784598
TI - Rectal distention: from sensation to feeling.
PMID- 10784600
TI - Urgent endoscopy with endoscopic therapy for acute diverticular bleeding.
PMID- 10784599
TI - Do mucosal T cells prevent intestinal inflammation?
PMID- 10784601
TI - Diagnostic testing after fecal occult blood testing: compliance is the issue.
PMID- 10784602
TI - NASH: Can we iron out the pathogenesis?
PMID- 10784603
TI - Textbook of gastroenterology
PMID- 10784605
TI - Regulatory role of mature B cells in a murine model of inflammatory bowel
disease.
AB - The spontaneous chronic colitis in TCR alpha mutant (TCRalpha(-/-)) mice mediated
by CD4(+) TCRalpha(-)beta(+) T cells is more severe in the absence of mature B
cells, suggesting a suppressive role of B cells and Ig in the development of
chronic colitis. To investigate the direct role of B cells in the suppression of
this colitis, cell transfer studies were performed in TCRalpha(-/-) x Igmu(-/-)
(alphamu(-/-)) double-knockout mice. The chronic colitis was markedly attenuated
in alphamu(-/-) mice after the adoptive transfer of peripheral B cells from
TCRalpha(-/-) mice into 3- to 4-week-old alphamu(-/-) mice prior to the
development of colitis. Furthermore, transfer of mature B cells from TCRalpha(-/
) mice markedly decreased the number of pathogenic colonic CD4(+) TCRalpha(
)beta(+) T cells in alphamu(-/-) mice with established colitis. This B cell
effect required the presence of functional co-stimulatory molecules CD40 and B7-2
(CD86) but not B7-1 (CD80). These results indicate that mature B cells play an
important role in the development of chronic colitis in TCRalpha(-/-) mice by
directly regulating the pathogenic T cells (CD4(+) TCRalpha(-)beta(+) T cells).
PMID- 10784604
TI - gammadelta T cells of human early pregnancy decidua: evidence for cytotoxic
potency.
AB - The immune compromise in decidua allows a semiallogeneic fetus to survive without
impairing the ability of the maternal immune system to fight infections.
Cytotoxic mechanisms are likely to be important in this compromise. Using RT-PCR,
immunoflow cytometry and immunoelectron microscopy, the cytotoxic potential of
isolated human decidual gammadelta T cells was studied. mRNA for perforin (Pf),
granzymes A and B, granulysin and Fas ligand (FasL) was simultaneously expressed
in decidual gammadelta T cells. Pf and FasL were not expressed on the cell
surface. However, the cells constitutively synthesized Pf and stored it in
cytolytic granules. Within the granules Pf mainly resided in the granule core
formed by Pf-containing microvesicles. Ultrastructurally, three groups of Pf
containing granules were distinguished. They probably represent different stages
of granule maturation in a process where Pf-containing microvesicles first attach
to the core cortex and then are translocated across the cortex into the core.
Presynthesized FasL was also stored in the core and microvesicles of the
cytolytic granules. Upon degranulation by ionomycin/Ca(2+) treatment, FasL was
rapidly translocated to the cell surface, demonstrating that its surface
expression was not controlled by de novo biosynthesis. Thus decidual gammadelta T
cells appear to perform Pf- and FasL-mediated cytotoxicity utilizing a common
secretory mechanism based on cytolytic granule exocytosis. The first cytochemical
visualization of lipids in the cytolytic granules is provided. These
intragranular lipids probably wrap up the core and participate in packaging of
the cytotoxic proteins as well as in the killing process. An ultrastructural
model of a cytolytic granule is presented.
PMID- 10784606
TI - PRELI, the human homologue of the avian px19, is expressed by germinal center B
lymphocytes.
AB - We report the identification of a human cDNA encoding a 25 kDa protein of
relevant evolutionary and lymphoid interest (PRELI). PRELI was cloned by
screening a B lymphocyte-specific cDNA library with a probe generated by mRNA
differential display. PRELI amino acid sequence is 85% similar to the avian px19
protein, expressed within the blood islands and in the liver during avian embryo
development. PRELI and px19 contain tandem repeats (A/TAEKAK) of the late
embryogenesis abundant (LEA) motif, characteristic of a group of survival
molecules and originally thought to be present only in plant proteins.
Interestingly, PRELI expression is high in the fetal liver, a major site for B
cell lymphopoiesis, while the mRNA levels in other fetal tissues such as the
brain, lung, and kidney are comparatively low. At the adult stage, PRELI
expression is drastically reduced in the liver but exhibits high mRNA levels in
the spleen, brain, lung and kidney tissues, suggesting that PRELI expression may
be important for the development of vital and immunocompetent organs. Moreover,
PRELI is also highly expressed in the adult lymph nodes and peripheral blood
leukocytes, further stressing that at the adult stage, PRELI expression may be
important during secondary immune responses. Consistent with this hypothesis, the
expression of PRELI is predominant within germinal centers (GC), a stage in which
B lymphocytes are under a stressful selection pressure. Taken together these
data: (i) strongly support the notion that the conserved LEA motif represents a
phylogenetic link between plants and animals, (ii) reveal a novel molecule whose
expression may play a role in the maturation of distinct human tissues, and (iii)
suggest that PRELI expression may be important for GC B lymphocytes.
PMID- 10784607
TI - In vivo identification of lymphocyte subsets exhibiting transcriptionally active
NF-kappaB/Rel complexes.
AB - To analyze the NF-kappaB/Rel activity pattern in a living organism, we previously
generated transgenic mice carrying a kappaB-dependent lacZ gene. In situ analysis
of both primary and secondary lymphoid organs revealed a strong NF-kappaB
transcriptional activity in antigen-presenting cells, some endothelial cells and
sinus lining cells of the lymph node capsula with very little activity in
lymphocytes and thymocytes. Using fluorescein-di-beta-D-galactopyranoside (FDG)
as a vital substrate for the beta-galactosidase, we re-examined by flow cytometry
the NF-kappaB/Rel transcriptional activity in our mouse model. We report here
that such constitutive NF-kappaB/Rel activity was significantly detected in
thymocytes at the CD44+CD25(-) stage. This constitutive activity extended with
CD25 expression to the majority of the CD44(-)CD25(+) thymocytes and was then
restricted to a few mature T cells. In the spleen, constitutive NF-kappaB/Rel
activity was found in most B cells, unlike T cells which were largely negative.
Virgin IgD(+) B cells expressed higher levels of NF-kappaB transcriptional
activity than other B cell types. Altogether, these results suggest that NF
kappaB/Rel complexes are key players in the in vivo differentiation of IgD(+) B
lymphocytes and possibly CD25(+) thymocytes.
PMID- 10784608
TI - Antigen-specific cellular hyporesponsiveness in a chronic human helminth
infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth
factor-beta but not by a T(h)1 to T(h)2 shift.
AB - Exposure to infective larvae of the filarial nematode Onchocerca volvulus (Ov)
either results in patent infection (microfilaridermia) or it leads to a status
called putative immunity, characterized by resistance to infection. Similar to
other chronic helminth infections, there is a T cell proliferative
hyporesponsiveness to Ov antigen (OvAg) by peripheral blood mononuclear cells
(PBMC) from individuals with patent infection, i.e. generalized onchocerciasis
(GEO), compared to PBMC from putatively immune (PI) individuals. In this study,
mechanisms mediating this cellular hyporesponsiveness in GEO were investigated:
the low proliferative response in PBMC from GEO individuals was associated with a
lack of IL-4 production and significantly lower production of IL-5 compared to
those from PI individuals, arguing against a general shift towards a T(h)2
response being the cause of hyporesponsiveness. In contrast, IL-10 and
transforming growth factor (TGF)-beta, two cytokines associated with a T(h)3
response, seemed to mediate hyporesponsiveness: PBMC from individuals with GEO
produced significantly more IL-10, and T cell proliferative hyporesponsiveness in
this group could be reversed by the addition of anti-IL-10 and anti-TGF-beta
antibodies. Hyporesponsiveness was specific for OvAg and not observed upon
stimulation with related nematode antigens, arguing for a T cell-mediated, Ov
specific down-regulation. Ov-specific T cells could be cloned from GEO PBMC which
have a unique cytokine profile (no IL-2 but high IL-10 and/or TGF-beta
production), similar to the T cell subsets known to suppress ongoing inflammation
(T(h)3 and T(r)1), indicating that this cell type which has not been found so far
in infectious diseases may be involved in maintaining Ov-specific
hyporesponsiveness.
PMID- 10784609
TI - Cyclin D2 is essential for BCR-mediated proliferation and CD5 B cell development.
AB - Progression into G(1) in B lymphocytes is regulated by cyclins D2 and D3,
components of the cell cycle machinery currently believed to have overlapping and
potentially redundant roles in cell cycle control. To study the specific role of
cyclin D2 in B lymphocyte proliferation, we examined B cells from cyclin D2(-/-)
mice and demonstrate a specific requirement for cyclin D2 in BCR- but not CD40-
or lipopolysaccharide-induced proliferation. Furthermore, conventional B cell
development proceeds normally in the mutant mice; however, the CD5 B cell
compartment is dramatically reduced, suggesting that cyclin D2 is important in
CD5 B cell development as well as antigen-dependent B cell clonal expansion.
PMID- 10784610
TI - TCR v(beta) usage and clonality of T cells isolated from progressing and rejected
tumor sites before and after in vitro culture.
AB - A gelatin sponge model of concomitant tumor immunity was employed in order to
examine the clonality of T cells associated with progressing and rejected tumor
sites. Here we show that freshly isolated T cells bearing TCR V(beta)1, CDR3
RPGTGN, J(beta)1.1 and TCR V(beta)8, CDR3 GD, J(beta)1.6 predominated progressing
and rejected tumor sites. Despite the similarity in T cell populations, the T
cells from rejected tumor sites were capable of killing the autologous tumor
cells, whereas T cells from progressing tumor sites were not able to do so. The
differing cytolytic ability could not be attributed to a difference in TCR zeta
chain protein expression levels between both T cell populations. After a 5 day
mixed lymphocyte tumor culture the T cells from the progressing tumor site were
capable of killing autologous tumor cells, which suggested changes took place
within the cell population during in vitro culture. Further TCR analysis revealed
T cells bearing TCR V(beta)1, CDR3 RPGTGN, J(beta)1.1 and TCR V(beta)8, CDR3 GD,
J(beta)1.6 were not expanded following the in vitro culture. These data suggest
that the lack of cytotoxicity of freshly isolated tumor-infiltrating lymphocytes
(TIL) was not due to abnormal TCR zeta chain expression or major differences in
the TCR V(beta) usage. Additionally, the gain of TIL effector function did not
correlate with an expansion of the TCR bearing T cells found to predominate the
in vivo response. These data suggest that the predominant TCR V(beta) used by
lymphocytes infiltrating regressing or rejected tumors may not represent the
tumor reactive T cells that grow in culture or respond to the autologous tumor in
vitro.
PMID- 10784611
TI - Glycine-rich cell wall proteins act as specific antigen targets in autoimmune and
food allergic disorders.
AB - Our objective was to investigate the presence of a B and T cell immune response
directed against the glycine-rich cell wall protein (GRP) in patients with
different autoimmune disorders and with food allergy. GRP is an ubiquitous food
protein that has high homology with cytokeratins and other self proteins [Epstein
Barr virus nuclear antigen-1 (EBNA-I), heterogeneous nuclear ribonucleoprotein,
fibrillar collagen] which are common targets in autoimmune disorders. A peptide
(GGYGDGGAHGGGYGG) derived from GRP was used to screen human sera in direct and
competitive ELISA assay. Anti-GRP-specific IgG were analyzed for their ability to
cross-react with autoantigens. The intracellular cytokine profiles of the peptide
specific T cell clones obtained from representative patients have been studied.
BALB/c mice were immunized with the peptide coupled to the carrier protein
keyhole limpet hemocyanin (KLH). Serum IgG antibodies directed against the GRP
peptide were detected in several autoimmune disorders and in food allergic
patients, and were able to cross-react with autoantigens including keratin,
collagen and EBNA-I. Twenty-five T cell clones showed a specific proliferative
response to the GRP peptide and were of the T(h)0 phenotype. Eight of the 10
BALB/c mice immunized with the peptide coupled to KLH developed an autoimmune
response. Our data suggest that phylogenetically highly conserved epitopes in
plants, viruses and humans may be responsible for an autoimmune response in
susceptible individuals. They also indicate that the antigen spreading of a
particular sequence among apparently divergent proteins may participate to
initiate or amplify an immune response.
PMID- 10784612
TI - Cartilage-reactive T cells in rheumatoid synovium.
AB - Rheumatoid arthritis (RA) is an inflammatory polyarthritis genetically linked to
HLA-DR4 and related haplotypes. RA synovial tissue is characterized by T cell
infiltration and activation of macrophage-like cells, strongly implicating a T
cell-antigen-presenting cell (APC) interaction in RA pathogenesis. To investigate
the nature of the antigens driving the T cell response, synovial tissue was
obtained from a patient with chronic RA and T cells were enriched. These T cells
were stimulated by endogenous APC from the same synovial tissue. The T cell lines
were subsequently evaluated for responsiveness to autologous APC and cartilage
antigens. Specific proliferative responses to autologous APC which were enhanced
by cartilage extract were seen. Immunomagnetic bead selection and RT-PCR was used
to identify TCR alphabeta pairs which appeared to respond to antigen(s) in the
cartilage extract. T cell clones derived from the same joint were shown to
release IL-2 in response to the cartilage extract and expressed a related TCR.
With these experiments we have shown direct evidence that autoreactive T cells
are found within the inflamed rheumatoid synovium and, further, that the antigens
driving these T cells are cartilage derived. Since the antigens recognized by
these populations of T cells are found within cartilage our data provides
evidence that RA pathology could be related to a self-driven autoimmune response
to cartilage proteins.
PMID- 10784613
TI - Tumor angiogenesis factors reduce leukocyte adhesion in vivo.
AB - Leukocyte-endothelium interactions are diminished in tumors. It is reported here
that, in a tumor-free in vivo model, angiogenic factors can down-regulate
leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either
basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor
(VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a
single intrascrotal injection of 1 microg/kg IL-1beta was given 4 h before
vessels of the cremaster muscle were investigated for leukocyte rolling and
adhesion by means of intravital microscopy. Exposure of normal tissue to either
bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte
adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate
enhancement of rolling by VEGF was found. The observed differences could not be
explained by differences in fluid dynamic parameters or systemic leukocyte
counts. In conclusion, evidence is presented that, in vivo, angiogenic factors
significantly reduce leukocyte adhesion, the final step preceding leukocyte
infiltration. This observation may explain why tumors escape from immune
surveillance.
PMID- 10784614
TI - B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR alpha
chemokine.
AB - A novel alpha-chemokine, designated KS1, was identified from an EST database of a
murine immature keratinocyte cDNA library. The EST has 94% similarity to a
recently cloned human gene, BRAK, that has no demonstrated function. Northern
analysis of mouse and human genes showed detectable mRNA in brain, intestine,
muscle and kidney. Tumour panel blots showed that BRAK was down-regulated in
cervical adenocarcinoma and uterine leiomyoma, but was up-regulated in breast
invasive ductal carcinoma. KS1 bound specifically to B cells and macrophages, as
well as two B cell lines, CESS and A20, and a monocyte line, THP-1. KS1 showed no
binding to naive or activated T cells. In addition, KS1 stimulated the chemotaxis
of CESS and THP-1 cells but not T cells. The s.c. injection of KS1 creates a
mixed inflammatory response in Nude and C3H/HeJ mice. The above data indicates
that KS1 and its human homologue represents a novel non-ELR alpha-chemokine that
may have important roles in trafficking of B cells and monocytes. We propose the
name B cell- and monocyte-activating chemokine (BMAC) for this molecule to
reflect the described biological functions.
PMID- 10784615
TI - Defensins act as potent adjuvants that promote cellular and humoral immune
responses in mice to a lymphoma idiotype and carrier antigens.
AB - Defensins released by neutrophils are able to kill a broad spectrum of microbes.
They also induce leukocyte migration in vitro and elicit inflammatory leukocyte
responses at s.c. injection sites in mice. In vitro experiments showed that human
defensins enhanced concanavalin A-stimulated murine spleen cell proliferation and
IFN-gamma production. This led us to examine the effects of human defensins on
specific immune responses in vivo. BALB/c mice were immunized with 50 microg of
keyhole limpet hemocyanin (KLH) adsorbed to aluminum hydroxide and administered
with defensins in aqueous solution. Intraperitoneal administration of defensins
significantly increased the production of KLH-specific IgG1, IgG2a and IgG2b
antibodies 14 days after immunization. In vitro splenic KLH-specific
proliferative responses were higher in mice treated with KLH and defensins than
in those treated with KLH alone. Increased IFN-gamma and, to a lesser extent, IL
4 production were also detected in the supernatants of ex vivoKLH-activated
spleen cells from mice treated with defensins. Finally, defensins significantly
enhanced the antibody response to a syngeneic tumor antigen, lymphoma Ig idiotype
and also augmented resistance to tumor challenge. These results indicate that
defensins act as potent immune adjuvants by inducing the production of
lymphokines, which promote T cell-dependent cellular immunity and antigen
specific Ig production. Thus, defensins appear to function as neutrophil-derived
signals that promote adaptive immune responses.
PMID- 10784616
TI - Differential IL-12 responsiveness of T cells but not of NK cells from tumor
bearing mice in IL-12-responsive versus -unresponsive tumor models.
AB - While IL-12 administration induces tumor regression through stimulating T cells
in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor
models. The present study aimed to compare IL-12 responsiveness of T cells from
tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth
A) tumor models. Tumor regression in IL-12-responsive tumor models required the
participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell
population was the major producer of IFN-gamma, comparable levels of IFN-gamma
production were induced in IL-12-responsive and -unresponsive tumor-bearing mice.
This indicates that the amount of IFN-gamma produced in tumor-bearing individuals
does not correlate with the anti-tumor efficacy of IL-12. In contrast, IL-12
responsiveness of T cells differed between the responsive and unresponsive
models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice
exhibited high or low IL-12 responsiveness respectively, when evaluated by the
amounts of IFN-gamma produced in response to IL-12. T cells from CSA1M- or OV-HM
bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for
the IL-12 receptor (IL-12R). These results indicate that a fundamental difference
exists in IL-12 responsiveness of T cells between IL-12-responsive and
unresponsive tumor models, and that such a difference is associated with the
expression of IL-12R on T cells.
PMID- 10784617
TI - Short-lived immunization site inflammation in self-limited active experimental
allergic encephalomyelitis.
AB - To understand the mechanisms underlying spontaneous remission of proteolipid
protein (PLP) 139-151 peptide-induced experimental allergic encephalomyelitis
(EAE), an acute autoimmune disease of SJL mice resembling human multiple
sclerosis, we examined both the effector response site in the central nervous
system (CNS) and the immunization site at different phases of the disease. In the
CNS, the frequency of PLP 139-151 peptide-specific IFN-gamma-producing T cells as
well as the amount of infiltrating CD4(+) and CD11b(+) cells decreased with
recovery. However, IL-4-producing cells were always rare and cyclooxygenase-2(+)
cells were numerous only at disease peak in the CNS, suggesting that T(h)2
cytokines and prostaglandins did not determine remission of EAE. By looking at
the s.c. site of PLP 139-151 peptide plus adjuvant injection, we found that,
although the inflammatory infiltrate was abundant, CD11b(+) cells started to
decrease already during disease acute phase and DEC-205(+) cells were numerous
only at early time points. We propose that immunization site inflammation is
short-lived in PLP 139-151 peptide-induced EAE, and this leads to a temporary
autoreactive T cell stimulation and to a self-limited disease.
PMID- 10784618
TI - The DNA-bending protein, HMG1, is required for correct cleavage of 23 bp
recombination signal sequences by recombination activating gene proteins in
vitro.
AB - DNA-bending proteins are known to facilitate the in vitro V(D)J joining of
antigen receptor genes. Here we report that the high-mobility group protein,
HMG1, is necessary for the correct nicking of the 23 bp recombination signal
sequence (23-RSS) by the recombination [corrected] activating gene (RAG)
proteins, RAG1 and RAG2. Without HMG1, the mouse Jkappa1 23-RSS was recognized as
if it were the 12-RSS and nicked at a site 12 + 7 nucleotides away from the 9mer
signal, even though no 7mer-like sequence was evident at the cryptic nicking
site. When increased amounts of HMG1 were added, the 23-RSS substrate was nicked
correctly at a site 23 + 7 nucleotides from the 9mer, and nicking at the cryptic
site disappeared. Unlike the 23-RSS, the 12-RSS did not require HMG1 for correct
nicking, although HMG1 was found to increase the interaction between RSS and RAG
proteins. Modification-interference assays demonstrated that HMG1 caused changes
in the interaction between the 23-RSS and RAG proteins specifically at the 7mer
and the cryptic nicking site.
PMID- 10784619
TI - DEC-205 as a marker of dendritic cells with regulatory effects on CD8 T cell
responses.
AB - We have previously reported that a population of lymphoid-related CD8alpha(+) DEC
205(+) dendritic cells (DC) from mouse spleen have 'regulatory' effects on the T
cells they activate. CD8 T cells produce IL-2 and give a sustained proliferative
response to allogeneic CD8alpha(-) DEC-205(-) splenic DC, but produce little IL-2
and give a limited response to allogeneic CD8(+) DEC-205(+) splenic DC. Although
CD8alpha and DEC-205 correlate closely among splenic DC, lymph nodes (LN) include
a large population of CD8alpha(low) DEC-205(high) DC. By i.v. transfer of
purified thymic early lymphoid precursors into irradiated recipient mice we now
demonstrate that these CD8alpha(low) but DEC-205(high) LN DC can be the progeny
of a lymphoid precursor population, apparently corresponding to the
CD8alpha(high) DEC-205(high) DC progeny of the same precursors in spleen and
thymus. By culture of the separated, purified DC with allogeneic CD8 T cells we
demonstrate that the CD8alpha(low) DEC-205(high) DC of LN are also functionally
equivalent to the CD8alpha(high) DEC-205(high) DC of spleen. Therefore, DEC-205
but not CD8alpha serves to segregate functionally distinct DC types in LN.
However, DC isolated from the spleens of genetically manipulated DEC-205(null)
mice and separated on the basis of CD8alpha expression have a similar capacity to
stimulate CD8 T cells as their heterozygous littermate controls, with the
CD8alpha(+) but now DEC-205(null) DC still giving restricted responses. In
conclusion, high expression of DEC-205 appears to be a good marker of the
lymphoid-related regulatory type of DC, but DEC-205 itself is not responsible for
transmitting negative signals to the T cells.
PMID- 10784620
TI - Oligonucleotide therapeutics: a step forward.
PMID- 10784621
TI - Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide
therapy in patients with non-Hodgkin's lymphoma.
AB - PURPOSE: To evaluate the pharmacokinetics and toxicity of an antisense
oligonucleotide targeting bcl-2 in patients with non-Hodgkin's lymphoma (NHL) and
to determine efficacy using clinical and biologic end points. PATIENTS AND
METHODS: Twenty-one patients with Bcl-2-positive relapsed NHL received a 14-day
subcutaneous infusion of G3139, an 18-mer phosphorothioate oligonucleotide
complementary to the first six codons of the bcl-2 open reading frame. Plasma
pharmacokinetics were measured by anion exchange high-performance liquid
chromatography. Response was assessed by computed tomography. Changes in Bcl-2
expression were measured by fluorescence-activated cell sorting of patients'
tumor samples. RESULTS: Eight cohorts of patients received doses between 4. 6 and
195.8 mg/m(2)/d. No significant systemic toxicity was seen at doses up to 110.4
mg/m(2)/d. All patients displayed skin inflammation at the subcutaneous infusion
site. Dose-limiting toxicities were thrombocytopenia, hypotension, fever, and
asthenia. The maximum-tolerated dose was 147.2 mg/m(2)/d. Plasma levels of G3139
equivalent to the efficacious plasma concentration in in vivo models were
produced with doses above 36.8 mg/m(2)/d. Plasma levels associated with dose
limiting toxicity were greater than 4 microg/mL. By standard criteria, there was
one complete response, 2 minor responses, nine cases of stable disease, and nine
cases of progressive disease. Bcl-2 protein was reduced in seven of 16 assessable
patients. This reduction occurred in tumor cells derived from lymph nodes in two
patients and from peripheral blood or bone marrow mononuclear cell populations in
the remaining five patients. CONCLUSION: Bcl-2 antisense therapy is feasible and
shows potential for antitumor activity in NHL. Downregulation of Bcl-2 protein
suggests a specific antisense mechanism.
PMID- 10784622
TI - Randomized cross-over trial of progenitor-cell mobilization: high-dose
cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus
granulocyte-macrophage colony-stimulating factor plus G-CSF.
AB - PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens
seems to vary considerably, making comparison between regimens difficult. To
eliminate this inter-patient variability, we designed a cross-over trial and
prospectively compared the number of progenitors mobilized into blood after
granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus
granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the
number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C)
in the same patient. PATIENTS AND METHODS: Twenty-nine patients were randomized
to receive either regimen G or C first (G1 and C1, respectively) and underwent
two leukaphereses. After a washout period, patients were then crossed over to the
alternate regimen (C2 and G2, respectively) and underwent two additional
leukaphereses. The hematopoietic progenitor-cell content of each collection was
determined. In addition, toxicity and charges were tracked. RESULTS: Regimen C (n
= 50) resulted in mobilization of more CD34(+) cells (2.7-fold/kg/apheresis),
erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units
granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to
the same patients (n = 46; paired t test, P<.01 for all comparisons). Compared
with regimen G, regimen C resulted in better mobilization, whether it was given
first (P =.025) or second (P =.02). The ability to achieve a target collection of
> or =2x10(6) CD34(+) cells/kg using two leukaphereses was 50% after G1 and 90%
after C1. Three of the seven patients in whom mobilization was poor after G1 had
> or =2x10(6) CD34(+) cells/kg with two leukaphereses after C2. In contrast, when
regimen G was given second (G2), seven out of 10 patients failed to achieve the
target CD34(+) cell dose despite adequate collections after C1. Thirty percent of
the patients (nine of 29) given regimen C were admitted to the hospital because
of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The
higher cost of regimen C was balanced by higher CD34(+) cell yield, resulting in
equivalent charges based on cost per CD34(+) cell collected. CONCLUSION: We
report the first clinical trial that used a cross-over design showing that high
dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then
GM-CSF plus G-CSF when tested in the same patient regardless of sequence of
administration, although the regimen is associated with greater morbidity.
Patients who fail to achieve adequate mobilization after regimen G can be treated
with regimen C as an effective salvage regimen, whereas patients who fail regimen
C are unlikely to benefit from subsequent treatment with regimen G. The cross
over design allowed detection of significant differences between regimens in a
small cohort of patients and should be considered in design of future comparisons
of mobilization regimens.
PMID- 10784623
TI - Early detection of relapse by hypermetaphase fluorescence in situ hybridization
after allogeneic bone marrow transplantation for chronic myeloid leukemia.
AB - PURPOSE: Standard G-band cytogenetic analysis (CG) provides information on
approximately 25 metaphases for monitoring the presence of Philadelphia
chromosome positive (Ph+) cells in chronic myelogenous leukemia (CML) patients,
making the detection of a low frequency of Ph+ cells problematic. The purpose of
this study was to improve the detection of a low frequency of Ph+ cells. PATIENTS
AND METHODS: We combined fluorescence in situ hybridization (FISH) with long-term
colcemid exposure, capturing several hundred metaphases in bone marrow cultures
(hypermetaphase FISH [HMF]). Using probes that identify Ph+ cells, HMF was
compared with CG analysis in the follow-up evaluations of 51 patients with CML at
various time points after allogeneic bone marrow transplant (BMT). RESULTS:
Thirty-five patients never showed the presence of Ph+ cells by either method. In
four patients, high frequencies of Ph+ cells were detected by both methods. In
the remaining 12 patients, Ph+ cells were detected by HMF at time points after
BMT when they were not detected by CG. In seven of the 12 patients, low but
statistically significant frequencies of Ph+ cells (0.37% to 5.20%) were detected
3 months or later after BMT, and when no intervention was initiated, all seven
patients later relapsed. Based on those data, an eighth patient with mixed
chimerism and a similar HMF-detected Ph+ frequency (1.8% at 27 months after BMT)
was reinfused with donor lymphocytes and achieved remission with 0% Ph+ cells
studied by HMF (up to 50 months after BMT). Ph+ cells detected by HMF but not by
CG less than 3 months after BMT disappeared on later examination in two of four
patients. After detection of Ph+ cells by HMF only, the median time to
cytogenetic progression (detection of Ph+ cells by CG) was 101 days. CONCLUSION:
The results demonstrate the ability of HMF to detect low but clinically relevant
levels of leukemic cells not detected by CG in transplant patients. The data
indicate that HMF can detect low levels of Ph+ cells before standard cytogenetics
at a time that may be useful in monitoring disease status and planning clinical
interventions.
PMID- 10784624
TI - P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular
concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive
acute myeloid leukemia.
AB - PURPOSE: The aim of the present study was to evaluate the effect of the
cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel,
Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells
in vivo during treatment. PATIENTS AND METHODS: Ten patients with acute myeloid
leukemia (AML) were included. Leukemic cells from seven of the patients were P
glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion
over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by
a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular
intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in
plasma and isolated leukemic cells were determined by high-pressure liquid
chromatography. RESULTS: The mean dnr concentrations in leukemic cells 24 hours
after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp
negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of
valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The
effect of valspodar was evaluated from the ratio of the area under the curve
(AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr
concentration against time in the plasma. For the seven patients with Pgp
positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on
day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative
leukemia, no significant difference was observed. CONCLUSION: These results
strongly suggest that valspodar, by interacting with Pgp, can increase the
cellular uptake of dnr in leukemic blasts in vivo.
PMID- 10784625
TI - Alpha hemolytic streptococcal infection during intensive treatment for acute
myeloid leukemia: a report from the Children's cancer group study CCG-2891.
AB - PURPOSE: Past reports indicate that alpha hemolytic streptococcal (AHS) organisms
are a common cause of infection among acute myeloid leukemia (AML) patients. This
study was intended to ascertain the population incidence and rate (infections per
100 patient-days of treatment) of AHS and to identify associated risk factors.
PATIENTS AND METHODS: Patients (n = 874 with 151,350 days of risk) enrolled on
the Children's Cancer Group (CCG) protocol for newly diagnosed AML, CCG-2891,
which randomly assigned intensity of induction and intensification, were
prospectively evaluated for infectious complications. RESULTS: AHS occurred in
21% of patients, was primarily blood borne (86%), made up 21% of bacteremic
infections, and had a recurrent incidence of 31% during subsequent therapy. AHS
was more often life-threatening (59%) than other infections (41%) (P = .001). AHS
rates increased with age less than 10 years (odds ratio [OR], 2.0; P = .007),
intensively timed induction (OR, 1.8 to 1.9; P = .02), and high-dose cytarabine
intensification (OR, 3.7; P<.0001). Among all courses, the greatest incidence
(19%) and rate (0.41) were associated with the use of high-dose cytarabine.
Gastrointestinal toxicity correlated significantly with AHS bacteremia (P<.01).
Infection with AHS resulted in increased hospital days (P =.0001). Only among
bone marrow transplant patients were overall survival (OR, 2.8; P = .0001) and
disease-free survival (OR, 2.1; P = .008) decreased after AHS bacteremia.
CONCLUSION: This study, the first to prospectively examine AHS incidence among
uniformly treated patients in multiple institutions, established that as the
intensity of AML therapy has increased, so has the rate of AHS. Young children,
those with previous AHS bacteremias, and those receiving high-dose cytarabine are
at particularly high risk of AHS bacteremia.
PMID- 10784626
TI - Partially mismatched related-donor bone marrow transplantation for pediatric
patients with acute leukemia: younger donors and absence of peripheral blasts
improve outcome.
AB - PURPOSE: To extend access to bone marrow transplantation (BMT), we used partially
mismatched related donors (PMRD) for pediatric patients with acute leukemia. In
this report we sought to determine pretransplantation factors that might predict
outcome. PATIENTS AND METHODS: Of 67 such patients, 43 had acute lymphocytic
leukemia and 24 had acute myelogenous leukemia. At the time of transplantation,
41 patients were in relapse. Donors included 40 parents, 24 siblings, and three
cousins. HLA disparity of two to three major antigens was detected in two thirds
of the donor-recipient pairs. Conditioning therapy, including total-body
irradiation and chemotherapy followed by graft-versus-host disease (GvHD)
prophylaxis with partial T-cell depletion of the graft using T10B9 or OKT3, was
combined with posttransplantation immunosuppression. RESULTS: Estimated
probability (EP) of engraftment was 0.96 and was not affected by donor-antigen
mismatch (AgMM; P =.732). EP of grades 2 to 4 acute GvHD was 0.24 and was not
affected by recipient AgMM (P =.796). EP of disease-free survival was 0.26 at 3
years but improved to 0.45 when donors were younger than 30 years (P<.001). EP of
relapse at 3 years was 0.41 and reduced with younger donors' age. For patients
who were in relapse at the time of transplantation, absence of blasts was
associated with a lower relapse rate (0.46 v. 0.84; P =. 083), similar to that of
patients in remission. CONCLUSION: PMRD-BMT in pediatric leukemia resulted in
high engraftment and low GvHD rates. To improve outcomes, younger donors should
be sought, and clinicians should attempt to reduce peripheral blasts in patients
who are in relapse.
PMID- 10784627
TI - Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with
recurrent or refractory acute myeloid leukemia.
AB - PURPOSE: To determine the remission rate and toxicity of mitoxantrone, etoposide,
and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady
state cyclosporine (CSA) levels in children with relapsed and/or refractory acute
myeloid leukemia. PATIENTS AND METHODS: MEC therapy consisted of mitoxantrone 6
mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2
hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of
pharmacokinetic interactions, drug doses were decreased to 60% of those found to
be effective without coadministration of CSA. MDR1 expression was evaluated by
reverse transcriptase polymerase chain reaction, flow cytometry, and the ability
of CSA at 2.5 micromol/L to increase intracellular accumulation of (3)H
daunomycin in blasts from bone marrow specimens. RESULTS: The remission rate was
35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission
(CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n =
6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was
achieved in 95% of patients (n = 56 of 59). Toxicities included infection,
cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum
creatinine and bilirubin. In most who had relapsed while receiving therapy or
whose induction therapy had failed, response was not significantly different for
MDR1-positive and MDR1-negative patients. CONCLUSION: Serum levels of CSA capable
of reversing multidrug resistance are achievable in children with acceptable
toxicity. The CR rate of 35% achieved in this study is comparable to previously
reported results using standard doses of mitoxantrone and etoposide. The use of
CSA may have improved the response rate for the MDR1-positive patients so that it
was not different from that for the MDR1-negative patients.
PMID- 10784628
TI - Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with
acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes).
AB - PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy
(> 50 chromosomes) have improved outcome compared with other ALL patients. We
sought to identify cytogenetic features that would predict differences in outcome
within this low-risk subset of ALL patients. MATERIALS AND METHODS: High
hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on
Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional
banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients
with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to
68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001),
chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved
outcome compared with their counterparts who lacked the given trisomy. Patients
with a trisomy of chromosome 5 had worse outcome than patients lacking this
trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had
better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of
chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis
indicated that trisomy of chromosome 10 (P = .001) was the most significant
prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P
=.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had
significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as
well as modal chromosome number 54 to 58 identify subgroups of patients with high
hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who
lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome
among high-hyperdiploid patients.
PMID- 10784629
TI - Loss of heterozygosity at 1p36 independently predicts for disease progression but
not decreased overall survival probability in neuroblastoma patients: a
Children's Cancer Group study.
AB - PURPOSE: To determine the independent prognostic significance of 1p36 loss of
heterozygosity (LOH) in a representative group of neuroblastoma patients.
PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered
onto the most recent Children's Cancer Group phase III clinical trials were
assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome
band 1p36. Allelic status at 1p36 was correlated with other prognostic variables
and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238
neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater
than 1 year (P = .026), metastatic disease (P<.001), elevated serum ferritin
level (P<.001), unfavorable histopathology (P<.001), and MYCN oncogene
amplification (P<.001). LOH at 1p36 was associated with decreased event-free
survival (EFS) and overall survival (OS) probabilities (P<.0001). For the 180
cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased
EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate
regression model suggested a trend toward an independent association with
decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore,
allelic status at 1p36 was the only prognostic variable that was significantly
associated with decreased EFS in low-risk neuroblastoma patients (P = .0148).
CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not
OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful
for predicting which neuroblastoma patients with otherwise favorable clinical and
biologic features are more likely to have disease progression.
PMID- 10784630
TI - Phase I trials in pediatric oncology: perceptions of pediatricians from the
United Kingdom Children's Cancer Study Group and the Pediatric Oncology Group.
AB - PURPOSE: To identify areas of concern regarding the conduct of phase I trials,
the perceived expectations and motivations of the parents of children entered,
the expectations of toxicity and benefit, and the ethical concerns of pediatric
hematologists and oncologists in the United Kingdom and North America. METHODS: A
survey instrument consisting of 19 open- and closed-ended questions was sent to
United Kingdom Children's Cancer Study Group (UKCCSG)- and Pediatric Oncology
Group (POG)-affiliated pediatricians. RESULTS: Fifty-three UKCCSG- and 78 POG
affiliated pediatricians responded. Thirty-two UKCCSG and 51 POG respondents had
previously entered at least one child into a phase I study. Overall, respondents
believed that parents entered their children for medical benefit, altruism, and
hope of cure. Although many respondents believed that children could benefit from
medical improvement, feelings of altruism, and maintenance of hope, the chance of
cure or complete remission was thought to be small. Similarly, parents were
thought to potentially benefit through altruism and maintenance of hope. Whereas
83% of UKCCSG respondents indicated that phase I trials were associated with
ethical difficulties, this was a concern for 48% of POG respondents. The main
ethical concerns of respondents were risk of toxicity, consent of the child,
unrealistic hope, and coercion. CONCLUSION: The respondents in this survey
expressed mainly ethical concerns regarding the conduct of phase I trials and had
realistic expectations of the potential for toxicity and benefit for those
children who participate in these studies.
PMID- 10784631
TI - Prognostic value of p53 for local failure in mastectomy-treated breast cancer
patients.
AB - PURPOSE: The loss of p53 function is a recognized adverse prognostic factor in
invasive breast cancer. Several studies have shown a relationship between the
nuclear accumulation of p53 protein (a surrogate marker of p53 inactivation) and
poor disease-free and overall survival. In general, however, these studies did
not report the prognostic value of p53 for local failure, which we have therefore
assessed retrospectively here. MATERIALS AND METHODS: Accumulation of p53 protein
was evaluated by immunohistochemistry in 1,530 mastectomy-treated breast cancer
patients (259 radiation therapy [RT]- and 1,271 mastectomy only [No RT]-treated
patients). Statistical comparisons were made between p53 protein accumulation,
estrogen/progesterone receptors, nodal status, tumor size, and local failure rate
(LFR). Local failure was defined as tumor recurrence involving the chest wall
and/or the ipsilateral supraclavicular/axillary lymph nodes. The median follow-up
period was 62 months. RESULTS: In the No RT group, the LFR was 9.1% and 16. 5% in
p53-negative and p53-positive patients, respectively (P<.001). Multivariate
analysis revealed that p53 protein accumulation was significantly associated with
an increased risk of local relapse (relative risk [RR], 1.7; 95% confidence
interval [CI], 1.2 to 2.4). Nodal status and tumor size were also significant
factors. In the RT group, the LFR was 9.3% and 21.5% in p53-negative and p53
positive patients, respectively (P = .009). Multivariate analysis revealed that
p53 protein accumulation was significantly associated with an increased risk of
local relapse (RR, 2.5; 95% CI, 1.1 to 5.7), as was nodal status. CONCLUSION:
Nuclear accumulation of p53 protein is independently associated with a
significantly increased local failure rate in breast cancer patients treated with
mastectomy, with or without radiation.
PMID- 10784632
TI - Detection of circulating tumor cells by reverse transcriptase polymerase chain
reaction of maspin in patients with breast cancer undergoing conventional-dose
chemotherapy.
AB - PURPOSE: To establish, in patients with breast cancer subjected to primary
conventional chemotherapy and enrolled in a prospective study, the mobilizing
effect of therapy on potentially neoplastic cells by means of a reverse
transcriptase polymerase chain reaction (RT-PCR) assay for mRNA of maspin, a
protein related to the serpin family of protease inhibitors. PATIENTS AND
METHODS: Peripheral-blood samples were collected from 30 patients with
histologically proven breast cancer before and 4 and 8 days after conventional
chemotherapy for three consecutive courses. A total of 216 samples were screened
for the presence of maspin mRNA by RT-PCR. RESULTS: Before therapy, all samples
but one were negative. After chemotherapy, 11 patients (38%) had positive
samples. No difference in the rate of positivity was observed between groups
defined according to initial stage, type of chemotherapy, Ki-67-related
proliferative activity, or CA 15.3 expression. CONCLUSION: Our results confirm
that RT-PCR for maspin mRNA is a sensitive assay for the study of circulating
potentially neoplastic mammary cells in patients with breast cancer. Moreover,
our findings indicate a marked effect of conventional-dose chemotherapy on the
mobilization of these cells in breast tumors. In our series of patients, this
phenomenon does not seem to be associated with other known risk factors. Finally,
the data suggest, without proving, an association between the presence of
circulating maspin positive cells and a higher risk of disease progression. If
this association could be confirmed, then the assay could have prognostic
significance. However, larger confirmatory studies are necessary.
PMID- 10784633
TI - Phase II trial of gemcitabine plus cisplatin in patients with metastatic
urothelial cancer.
AB - PURPOSE: To assess the activity and toxicity of the combination of gemcitabine
and cisplatin in the treatment of chemotherapy-naive patients with metastatic
urothelial cancer. PATIENTS AND METHODS: Forty-six patients with measurable stage
IV carcinoma of the urothelium were enrolled onto this trial. Gemcitabine 1,000
mg/m(2) was administered intravenously for 30 to 60 minutes on days 1, 8, and 15
of each 28-day cycle. Cisplatin was administered after gemcitabine on day 1 of
each cycle. The first 11 patients received an initial cisplatin dose of 100
mg/m(2). Due to the hematologic toxicity observed in several of these patients,
the dose was reduced to 75 mg/m(2) in the remaining 35 patients. Patients were
treated with six cycles, unless disease progression or severe toxicity
necessitated earlier discontinuation. RESULTS: Ten of the 46 patients achieved a
complete response and nine showed a partial response. The overall response rate
was 41%. The median time to treatment failure was 5.5 months. The median survival
was 14.3 months, and the 1-year survival probability was 54%. Most of the
toxicities were hematologic and, in general, easily manageable. CONCLUSION:
Gemcitabine plus cisplatin is active in the treatment of metastatic urothelial
cancer in chemotherapy-naive patients and has an acceptable clinical safety
profile. Studies are under way to further define the place of gemcitabine in
combination with other chemotherapeutic agents in the treatment of metastatic
urothelial cancer.
PMID- 10784634
TI - Effect of cytokine therapy on survival for patients with advanced renal cell
carcinoma.
AB - PURPOSE: To evaluate the relationship between treatment with cytokine therapy and
survival, investigate the effect of nephrectomy on survival, and identify long
term survivors among a cohort of 670 patients with advanced renal cell carcinoma
(RCC). PATIENTS AND METHODS: A total of 670 patients with advanced RCC treated on
24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects
of this retrospective analysis. Treatment was categorized as cytokine (containing
interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy
(cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with
survival times of greater than 5 years were identified as long-term survivors.
RESULTS: Patients treated with cytokine therapy had a longer survival time than
did those treated with chemotherapy, regardless of the year of treatment or risk
category based on pretreatment features. The median survival times for favorable
, intermediate-, and poor-risk patients were 27, 12, and 6 months for those
treated with cytokines and 15, 7, and 3 months for those treated with
chemotherapy, respectively. The magnitude of difference in median survival was
greater in the favorable- and intermediate-risk groups. The median survival time
was less than 6 months in the poor-risk group for both treatment programs. Median
survival time was 14 months among patients with prior nephrectomy plus time from
diagnosis to treatment greater than 1 year versus 8 months among those with time
from diagnosis to treatment less than 1 year, regardless of pretreatment
nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified
as long-term survivors; 12 were free of disease after nephrectomy and treatment
with interferon alfa, interleukin-2, or surgical resection of metastasis.
CONCLUSION: The low proportion of patients with advanced RCC who achieve long
term survival emphasizes the need for clinical investigation to identify more
effective therapy.
PMID- 10784635
TI - Results of a phase II study using estramustine phosphate and vinblastine in
combination with high-dose three-dimensional conformal radiotherapy for patients
with locally advanced prostate cancer.
AB - PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant
estramustine phosphate and vinblastine (EV) with high-dose three-dimensional
conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate
cancer. PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk
prostate cancer were enrolled onto a prospective study to determine the
feasibility of combining EV with 3D-CRT. Patients were eligible if any of the
following requirements were satisfied: (1) Gleason score > or =8 and prostate
specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3)
clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0
disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week
cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally
beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week
cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2
week rest period. Radiation therapy was administered using a three-dimensional
conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26
months (range, 6 to 40 months). RESULTS: Twenty-three (85%) of 27 patients
completed the entire course of therapy and were assessable for toxicities and
biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity
that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting
as persistent elevation of serum transaminase levels, necessitating
discontinuation of the chemotherapy and withdrawal from the treatment program.
The most prominent adverse effects from this regimen were mild to moderate (grade
1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was
seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well
in these patients. Medications were required for relief of acute grade 2 rectal
(gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48%
of patients, respectively. Three patients developed acute grade 3 GU toxicities.
The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late
grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of
late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU
toxicity was observed. CONCLUSION: Neoadjuvant and concomitant EV with high-dose
3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer.
Although the incidence of modest (grade 2) late GI and GU toxicities seem to be
increased compared with 3D-CRT alone or in combination with androgen ablation
therapy, no severe toxicities were encountered with this regimen.
PMID- 10784636
TI - Profile of men randomized to the prostate cancer prevention trial: baseline
health-related quality of life, urinary and sexual functioning, and health
behaviors.
AB - PURPOSE: To describe men who agreed to be randomized to the Prostate Cancer
Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the
efficacy of finasteride in preventing prostate cancer. METHODS: Comprehensive
health-related quality-of-life data are presented for 18,882 randomized PCPT
participants. RESULTS: PCPT participants are highly educated, middle to upper
income, and primarily white (92%). Participants reported healthy lifestyles. The
mean American Urological Association Symptom Index score was well below the
maximum entry score of less than 19; existing urinary symptoms were generally not
bothersome. The scores for two sexual functioning scales could range from 0 to
100, with higher scores reflecting worse sexual functioning. The mean score for
the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities
Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study
36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20
points higher than those reported by a general population sample and differed
minimally by race but not by age. Previously reported associations between sexual
dysfunction and hypertension, diabetes, and depression were also observed. Men
who never smoked reported less sexual dysfunction than did those who either had
quit or still smoked. CONCLUSION: Individuals who are likely to enroll in primary
prevention trials have a high socioeconomic status, healthy lifestyle behaviors,
and better health than the general population. These data help oncologists design
chemoprevention trials with respect to the selection of health-related quality-of
life assessments and recruitment strategies.
PMID- 10784637
TI - Impact of the number of treatment courses on the clinical response of patients
who receive high-dose bolus interleukin-2.
AB - PURPOSE: To determine the impact of treatment with successive courses of high
dose bolus interleukin-2 (IL-2) on the incidence of clinical responses in
patients with metastatic melanoma or renal cell cancer. PATIENTS AND METHODS: A
consecutive series of 350 patients with either metastatic melanoma or renal cell
cancer who were treated with high-dose bolus IL-2 in the Surgery Branch, National
Cancer Institute, between September 1985 and November 1996 was analyzed, with a
median potential follow-up of 7.1 years. All patients were treated with 720,000
IU/kg of IL-2 administered by a 15-minute intravenous infusion every 8 hours for
up to 5 days, as clinically tolerated per cycle. Patients were retreated
according to clinical response and tolerance to the IL-2 therapy. RESULTS: Of the
149 patients with melanoma, 10 achieved complete responses (CRs) and 13 partial
responses (PRs), for an overall response rate of 15.4%. Of the 201 patients with
renal cell cancer, 18 achieved CRs and 20 PRs, for an overall response rate of
19.0%. Among responding patients, 21 of 23 with melanoma and 34 of 38 with renal
cell cancer developed at least PRs after the first course of IL-2. CONCLUSION:
Most patients with metastatic melanoma and renal cell cancer who achieved PRs or
CRs to intravenous high-dose bolus IL-2 were identified after the first course of
therapy. Those who demonstrated no response after two treatment courses failed to
respond to additional IL-2 therapy. Based on this retrospective analysis, we
recommend that patients who exhibit objective responses to treatment with high
dose bolus IL-2 receive additional treatment courses until either CR or IL-2
intolerance develops. Patients who do not achieve objective responses after two
courses of IL-2 should receive no further treatment with this regimen.
PMID- 10784638
TI - Dexamethasone for the prophylaxis of radiation-induced emesis: a National Cancer
Institute of Canada Clinical Trials Group phase III study.
AB - PURPOSE: To investigate the efficacy of dexamethasone as a prophylactic
antiemetic for patients receiving fractionated radiotherapy to the upper abdomen
in a randomized controlled trial. PATIENTS AND METHODS: One hundred fifty-four
patients planned to receive fractionated radiotherapy to fields involving the
upper abdomen (minimum total dose, 20 Gy; minimum number of fractions, five) were
randomized to receive prophylactic dexamethasone (2 mg orally three times a day
[tid], starting in the morning of first treatment and continuing until after
their fifth treatment) or placebo. The primary end point of the study was the
proportion of patients free from emesis during the study period. Secondary end
points included a quality-of-life assessment using the core questionnaire of the
European Organization for Research and Treatment of Cancer and side effects of
dexamethasone therapy in this population of patients. RESULTS: Fifty-four (70%)
out of 75 patients receiving dexamethasone had complete protection versus 37
(49%) out of 75 patients on placebo (P = .025). Most emetic episodes occurred
during the initial phase of treatment. Although there was no difference in global
quality of life between the two sets of patients, patients receiving
dexamethasone had less nausea and vomiting and less loss of appetite but more
insomnia. CONCLUSION: Dexamethasone 2 mg tid seems to be an effective
prophylactic antiemetic in this situation. Side effects were acceptable, but
there seemed to be no overall effect on global quality of life.
PMID- 10784639
TI - Biology of the adenomatous polyposis coli tumor suppressor.
AB - The adenomatous polyposis coli (APC) gene was first identified as the gene
mutated in an inherited syndrome of colon cancer predisposition known as familial
adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all
colorectal adenomas and carcinomas and is one of the earliest mutations in colon
cancer progression. Similar to other tumor suppressor genes, both APC alleles are
inactivated by mutation in colon tumors, resulting in the loss of full-length
protein in tumor cells. The functional significance of altering APC is the
dysregulation of several physiologic processes that govern colonic epithelial
cell homeostasis, which include cell cycle progression, migration,
differentiation, and apoptosis. Roles for APC in some of these processes are in
large part attributable to its ability to regulate cytosolic levels of the
signaling molecule beta-catenin and to affect the transcriptional profile in
cells. This article summarizes numerous genetic, biochemical, and cell biologic
studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP,
in which the APC gene has been genetically inactivated, have been particularly
useful in testing therapeutic and chemopreventive strategies. These data have
significant implications for colorectal cancer treatment approaches as well as
for understanding other disease genes and cancers of other tissue types.
PMID- 10784640
TI - Prophylactic surgery in women with a hereditary predisposition to breast and
ovarian cancer.
AB - PURPOSE: To review the published literature on the efficacy and adverse effects
of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) in women with
a hereditary predisposition to breast and ovarian cancer and to provide
management recommendations for these women. METHODS: Using the terms
"prophylactic," "preventive," "bilateral," "mastectomy," "oophorectomy," and
"ovariectomy," a MEDLINE search of the English-language literature for articles
related to PM and PO was performed. The bibliographies of these articles were
reviewed to identify additional relevant references. RESULTS: There have been no
prospective trials of PM or PO for the reduction of breast cancer or ovarian
cancer incidence or mortality. Most of the available retrospective studies are
composed of women who had surgery for a variety of indications and in whom
genetic risk was not well characterized. However, some reports in women at
increased risk of breast or ovarian cancer have shown that PM and PO can reduce
cancer incidence. CONCLUSION: Interest in and use of PM and PO are high among
physicians and high-risk women. PM and PO seem to be associated with considerable
reduction in the risk of breast and ovarian cancer, albeit incomplete. The
surgical morbidity of PM and PO is low, but the complications of premature
menopause may be significant, and few studies address quality-of-life issues in
women who have opted for PM and PO. Management recommendations for high-risk
individuals are presented on the basis of the available evidence.
PMID- 10784641
TI - Diagnosis in oncology. Case 1: primary transmural cardiac lymphoma.
PMID- 10784642
TI - Diagnosis in oncology. Case 2: secondary lymphoma of the heart manifesting as
intracavitary masses.
PMID- 10784643
TI - Spirituality and the dying patient.
PMID- 10784644
TI - Intrathecal cytarabine and bone marrow suppression.
PMID- 10784645
TI - Dexrazoxane and the ASCO guidelines for the use of chemotherapy and radiotherapy
protectants: a critique.
PMID- 10785212
TI - The ovarian hyperstimulation syndrome.
AB - OBJECTIVE: To review the up-to-date literature concerning the pathogenesis of,
risk factors for, prevention of, and therapy for the ovarian hyperstimulation
syndrome, and to provide suggestions for management of this syndrome. DESIGN:
Literature review combined with on-site clinical experiences at the authors'
institution of practice. PATIENT(S): Women who have risk factors for or manifest
the ovarian hyperstimulation syndrome. INTERVENTION(S): Intravenous fluid
management, thrombosis prevention techniques, paracentesis techniques, and
critical care management protocols. MAIN OUTCOME MEASURE(S): Staging system of
the ovarian hyperstimulation syndrome, criteria for outpatient versus
hospitalization management, and indications for varying levels of interventional
management. RESULT(S): The ovarian hyperstimulation syndrome, unique to the field
of assisted reproductive technology, remains a largely elusive and unpredictable
iatrogenic physiologic complication in the course of pharmacologic ovarian
stimulation. Reliable information on risk factors, possible physiologic
mechanisms, prevention techniques, and management is fortunately progressing, and
overall advances are being made in this field. The present review is an attempt
to summarize the modern literature regarding this syndrome and to use this
current knowledge to provide a basis for acceptable management regimens.
CONCLUSION(S): Ovarian hyperstimulation syndrome is a serious complication of
assisted reproductive technology, with potential for critical morbidity and
death. Physicians who prescribe medications known to be associated with this
syndrome should be familiar with identifiable risk factors, means of prevention,
and a system for staging and treating the disease and have a current knowledge
base for putative models of pathogenesis.
PMID- 10785213
TI - Round spermatid injection.
PMID- 10785214
TI - Distinction between early and late ovarian hyperstimulation syndrome.
AB - OBJECTIVE: To compare patient and cycle characteristics among three study groups:
early ovarian hyperstimulation syndrome (OHSS), late OHSS, and non-OHSS. DESIGN:
Prospective observational study. SETTING: University assisted conception service.
PATIENT(S): Women undergoing in vitro fertilization, intracytoplasmic sperm
injection or gamete intrafallopian transfer treatment at Bristol University In
Vitro Fertilization Service between January 1, 1995, and December 31, 1998.
INTERVENTION: None. MAIN OUTCOME MEASURE(S): Patient age, prevalence of
polycystic ovaries, gonadotropin requirement, peak serum estradiol (E(2))
concentration, number of oocytes retrieved, clinical pregnancy rate, number of
gestation sacs, and severity of OHSS. RESULT(S): Women with early OHSS had
significantly higher serum E(2) levels and lower gonadotropin requirements than
did the other groups. Cycles with either early or late OHSS had significantly
more oocytes collected than those without OHSS. Serum E(2) and oocyte numbers did
not accurately predict the risk of developing late OHSS. Clinical pregnancies
occurred in all cycles with late OHSS, and multiple pregnancies were
significantly more frequent in the late OHSS group than in the other groups. Late
OHSS was more likely than early OHSS to be severe. CONCLUSION(S): Early OHSS
relates to "excessive" preovulatory response to stimulation, whereas late OHSS
depends on the occurrence of pregnancy, is likelier to be severe, and is only
poorly related to preovulatory events.
PMID- 10785215
TI - A prospective, randomized controlled trial comparing the efficacy of recombinant
follicle-stimulating hormone in three different in vitro fertilization protocols.
AB - OBJECTIVE: To compare the following IVF protocols: a short protocol and long
protocols starting on day 2 or day 21. All protocols used recombinant FSH (rFSH)
for ovarian stimulation. DESIGN: Prospective, randomized study. SETTING: An
assisted reproduction unit at a university center. PATIENT(S): Patients
undergoing IVF (n = 150) were treated according to one of the three treatment
protocols allocated by a random method. INTERVENTION(S): All patients used
buserelin acetate and rFSH. Patients began the long protocol on day 2 (group 1)
or day 21 (group 2) of the cycle. Patients in group 3 began the short protocol on
day 2 of the cycle. MAIN OUTCOME MEASURE(S): Ovarian response, implantation
rates, and pregnancy rates (PRs). RESULT(S): Patients treated with the short
protocol (group 3) were stimulated in a shorter time, required less rFSH, and
achieved higher E(2) levels. The numbers of follicles, oocytes, and embryos were
similar in all three groups. The implantation rates were similar in groups 1 and
2 (11.8% and 13.3%, respectively), and both were higher than in group 3 (4.1%).
Clinical PRs per oocytes retrieved were 19.6%, 18.6%, and 8.3% in groups 1, 2,
and 3, respectively. CONCLUSION(S): The implantation rate was significantly
higher with the long protocols than with the short protocol, with a tendency for
a higher PR as well.
PMID- 10785216
TI - Tubal sterilization: focus on the U.S. experience.
AB - OBJECTIVE: To review the frequency, effectiveness, and clinical sequelae of tubal
sterilization with a focus on the U.S. experience. DESIGN: A review of U.S.
health care statistics and English-language literature using a MEDLINE search,
bibliographies of key references, and U.S. government publications. PATIENT(S):
Women seeking tubal sterilization. INTERVENTION: Tubal sterilization. MAIN
OUTCOME MEASURE(S): Effectiveness and long-term risks and benefits. RESULT(S):
Half of the 700,000 annual bilateral tubal sterilizations (TS) are performed
postpartum and half as ambulatory interval procedures. Eleven million U.S. women
15-44 years of age rely on TS for contraception. Failure rates vary by method
with one third or more resulting in ectopic pregnancy. Reversal is most
successful after use of methods that destroy the least tube. Evidence of
menstrual or hormonal disturbance after TS is weak, although some studies find
higher rates of hysterectomy among previously sterilized women. Decreased risk of
subsequent ovarian cancer has been observed among sterilized women.
CONCLUSION(S): Tubal sterilization is highly effective and safe. Failures,
although uncommon, occur at higher rates than previously appreciated. Evidence
for hormonal or menstrual changes due to TS is weak. Tubal sterilization is
associated with decreased risk of ovarian cancer.
PMID- 10785217
TI - Safety and effectiveness of vasectomy.
AB - OBJECTIVE: To recommend further research on vasectomy based on a systematic
review of the effectiveness and safety of vasectomy. DESIGN: A systematic MEDLINE
review of the literature on the safety and effectiveness of vasectomy between
1964 and 1998. MAIN OUTCOME MEASURE(S): Early failure rates are <1%; however,
effectiveness and complications vary with experience of surgeons and surgical
technique. Early complications, including hematoma, infection, sperm granulomas,
epididymitis-orchitis, and congestive epididymitis, occur in 1%-6% of men
undergoing vasectomy. Incidence of epididymal pain is poorly documented. Animal
and human data indicate that vasectomy does not increase atherosclerosis and that
increases in circulating immune complexes after vasectomy are transient in men
with vasectomies. The weight of the evidence regarding prostate and testicular
cancer suggests that men with vasectomy are not at increased risk of these
cancers. CONCLUSION(S): Publications to date continue to support the conclusion
that vasectomy is a highly effective form of contraception. Future studies should
include evaluations of the long-term effectiveness of vasectomy, evaluating
criteria for postvasectomy discontinuation of alternative contraception for use
in settings where semen analysis is not practical, and characterizing
complications including chronic epididymal pain syndrome.
PMID- 10785218
TI - Women, men, and contraceptive sterilization.
AB - OBJECTIVE: To review the social and behavior contexts of decisions about
contraceptive sterilization and to analyze factors associated with sterilization
choices. DESIGN: Multinomial logit regression of sterilization. PATIENT(S):
Various subsamples as appropriate to specific analyses drawn from the 10,847
women interviewed in the 1995 National Survey of Family Growth, and the 5,227 men
interviewed in the National Survey of Families and Households. INTERVENTION(S):
None. MAIN OUTCOME MEASURE(S): Tubal sterilization and vasectomy. RESULT(S):
Surprisingly high proportions of recent tubal sterilizations were performed on
unmarried women: 1 in 3 overall, 1 in 5 among white non-Hispanic women, and 2 in
3 among black women. Sterilization choice among continuously married couples also
revealed large differences by race and ethnicity. Parity at the time of the last
wanted birth is a major factor affecting sterilization choices, although
significant effects were found as well as for a number of other variables,
including age differences between spouses, education, and religion. Compared with
other regions, the ratio of tubal sterilizations to vasectomies is extremely low
in the Western region of the United States. CONCLUSION(S): Analysis of
sterilization decisions must be based on time since the completion of
childbearing. The findings call attention to the need for measuring variables
that mediate observed associations with sterilization outcomes.
PMID- 10785219
TI - Noninvasive assessment of glucose and pyruvate uptake by human embryos after
intracytoplasmic sperm injection and during the formation of pronuclei.
AB - OBJECTIVE: To improve in vitro culture conditions and human embryo selection
before transfer after IVF with intracytoplasmic sperm injection (ICSI). DESIGN: A
controlled, randomized, prospective study. SETTING: University hospital-based IVF
ET program. PATIENT(S): Couples undergoing ICSI. INTERVENTION(S): Culture of
human embryos in the presence of 1 mM or 5.56 mM glucose and metabolic
measurements with the use of noninvasive microfluorescence assays immediately
after ICSI to the time of transfer. MAIN OUTCOME MEASURE(S): Embryo development,
implantation rate, and glucose and pyruvate uptake. RESULT(S): Fertilization
rates, early embryo development, and implantation rates were not significantly
different between 1 mM and 5.56 mM glucose. Pyruvate uptake was significantly
higher during the formation of the pronuclei, at 15 +/- 0.7 and 11.4 +/- 1.3
pmol/embryo/h for fertilized and unfertilized oocytes, respectively. Pyruvate
uptake did not correlate with cleavage stage or embryo morphology. However,
during the second day of incubation, pyruvate uptake was significantly higher for
the untransferred embryos of pregnant women compared with nonpregnant women, at
17.9 +/- 1.5 and 10.8 +/- 1.0 pmol/embryo/h, respectively. CONCLUSION(S): The
increased level of pyruvate uptake during fertilization reflects the increased
demand for energy necessary for the formation of the pronuclei. However, the
metabolic measurements could not improve the selection of embryos with the best
implantation potential. Finally, the reduction of glucose concentration in the
culture medium failed to improve embryo viability.
PMID- 10785220
TI - In vitro fertilization outcomes after intracytoplasmic sperm injection with fresh
or frozen-thawed testicular spermatozoa.
AB - OBJECTIVE: To compare the outcomes of intracytoplasmic sperm injection (ICSI) and
in vitro fertilization (IVF) with fresh and cryopreserved testicular spermatozoa
in patients with obstructive and nonobstructive azoospermia. DESIGN:
Retrospective analysis of consecutive ICSI cycles. SETTING: Large urban
reproductive medicine program. PATIENT(S): Twenty-nine patients with obstructive
and nonobstructive azoospermia undergoing testicular sperm extraction for a total
of 46 IVF-ICSI cycles (12 fresh, 34 frozen). INTERVENTION(S): Testicular sperm
extraction, cryopreservation, and IVF-ICSI with fresh or frozen-thawed
spermatozoa. MAIN OUTCOME MEASURE(S): Fertilization rates, embryo cleavage rates,
embryo implantation rates, clinical pregnancy rates per cycle and per embryo
transfer, and delivery and spontaneous abortion rates. RESULT(S): No
statistically significant differences were noted in any of the parameters
examined between IVF-ICSI cycles from fresh or frozen-thawed testicular
spermatozoa. Fertilization rates were 56% with fresh vs. 61% with frozen-thawed
testicular sperm, cleavage rates 92% vs. 95%, implantation rates 26% vs. 17%,
clinical pregnancy rates per cycle 33% vs. 41%, and pregnancy rates per embryo
transfer 33% vs. 45%, respectively. Delivery rates were 75% with fresh vs. 69.2%
with frozen-thawed testicular sperm, and spontaneous abortion rates 25% and
30.8%, respectively. CONCLUSION(S): No differences were found in IVF-ICSI
outcomes between cryopreserved and fresh testicular sperm. In addition,
cryopreservation provides several advantages for the patients and reproductive
team.
PMID- 10785221
TI - Oxalate in human seminal plasma: possible significance and problems of oxalate
determination.
AB - OBJECTIVE: To determine the level of oxalate in seminal plasma and to correlate
it with andrologic variables. DESIGN: Laboratory examination. SETTING: University
based department of andrology and department of clinical chemistry. PATIENT(S):
One hundred male outpatients with infertility. INTERVENTION(S): Isolated seminal
plasma was stored for 120 days at -20 degrees C. MAIN OUTCOME MEASURE(S): Levels
of oxalic acid in seminal plasma. RESULT(S): Oxalate levels in seminal plasma
depend on the degradation of ascorbic acid to oxalic acid during storage. There
was a linear nonenzymatic increase of oxalate with storage time. After 120 days
of storage, the values were 133 +/- 50 micromol/L (n = 100). Oxalic acid
correlated significantly with the number of sperm head anomalies, the pH value,
and the age of the donors and correlated negatively with the volume of ejaculate.
CONCLUSION(S): Oxalic acid in seminal plasma may influence male fertility.
PMID- 10785222
TI - Expression of the platelet-activating factor receptor in human spermatozoa:
differences in messenger ribonucleic acid content and protein distribution
between normal and abnormal spermatozoa.
AB - OBJECTIVE: To determine the expression and distribution of the platelet
activating factor (PAF) receptor in normal and abnormal specimens of human
spermatozoa. DESIGN: Prospective analysis of membrane-bound PAF receptors by
immunofluorescence and PAF receptor messenger RNA by quantitated reverse
transcription-polymerase chain reaction in normal and abnormal spermatozoa.
SETTING: University-based reproductive genetics laboratory. PATIENT(S): Men
undergoing routine semen analysis. INTERVENTION(S): Normal and abnormal
spermatozoa were exposed to rabbit anti-PAF receptor antibody, fluorescein
isothiocyanate-conjugated goat anti-rabbit antibody, and fluorescent microscopy
or subjected to RNA isolation by acid-phenol extraction and quantitated (MIMIC
Construction Kit [Clontech Laboratories, Inc., Palo Alto, CA]) reverse
transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Fluorescent
intensities at six locations along spermatozoa (end piece, principal tail,
midpiece, neck, proximal head, and acrosomal region) and PAF receptor expression
(messenger RNA) levels. RESULT(S): Immunofluorescence demonstrated a significant
difference in PAF receptor distribution between normal and abnormal human
spermatozoa, specifically at the neck region. Additionally, abnormal spermatozoa
were found to have statistically significantly more PAF receptor messenger RNA
than normal spermatozoa. CONCLUSION(S): Platelet-activating factor receptor
expression and distribution are significantly altered in abnormal spermatozoa and
this may be the result of some defect in gene transcription.
PMID- 10785223
TI - Serum levels of inhibins are differentially altered in patients with polycystic
ovary syndrome: effects of being overweight and relevance to hyperandrogenism.
AB - OBJECTIVE: To explore the abnormalities of serum inhibin isoform concentrations
in a large group of patients with polycystic ovary syndrome (PCOS) and to
evaluate the influence of body mass index (BMI), age, LH, and androgens on serum
inhibin levels. DESIGN: Prospective study. SETTING: Reproductive endocrinology
unit of an academic medical center. PATIENT(S): Forty-one women with PCOS were
compared with 24 healthy women. INTERVENTION(S): Blood sampling was performed in
the early follicular phase in patients and in control women. MAIN OUTCOME
MEASURE(S): Serum levels of inhibin A, inhibin B, alpha-inhibin, pro-alphaC
(alpha-inhibin precursor proteins), LH, FSH, E(2), T, and androstenedione (A)
were assessed in all subjects. RESULT(S): Serum alpha-inhibin levels together
with LH, T, and A levels were significantly increased in women with PCOS. Serum
inhibin A levels were lower in patients with PCOS than controls (median +/- SD:
7.35 +/- 2.9 vs. 9.4 +/- 4.7 pg/mL), pro-alphaC levels were higher (264 +/- 136.7
vs. 127 +/- 81.5 pg/mL), and inhibin B levels did not differ between the groups
(110.5 +/- 51.5 vs. 108 +/- 47.5 pg/mL). Simple regression analysis showed that
inhibin A and B levels were negatively correlated with BMI in patients with PCOS
(r = -0.43 and r27 kg/m(2)) displayed significantly lower inhibin A and inhibin B
levels and a higher pro-alphaC-inhibin A ratio than nonobese patients with PCOS
(BMI 12x10(9)/l)
were excluded from the study. The overall median survival was 3.1 years, and
median survival stratified by IPSS was 3.4, 4.1 and 0.5 years for the INT-1, INT
2 and high risk group and not yet reached for the low risk group. The overall
survival by IPSS subcategorization were 6.88, 5.29, 5.30 and 2.12 years for the
low, INT-1, INT-2, and high risk groups respectively. Cytogenetics were
significant in predicting the overall survival. The IPSS score stratified
patients into risk categories for development of AML. The risk of development
into AML was 8, 8, 33 and 54% for the low, INT-1, INT-2 and high risk groups,
respectively. We conclude that IPSS score can be useful in predicting survival
and AML evolution in some MDS patients.
PMID- 10785265
TI - Bone marrow purging by photodynamic treatment in children with acute leukemia:
cytoprotective action of amifostine.
AB - In order to evaluate the combined effect of Amifostine and Merocyanine 540 during
photoirradiation in neoplastic cells, bone marrow cells from children with acute
leukemia (AL), age-matched controls as well as HL-60 cell line were studied. Cell
suspensions were incubated with Amifostine, then with MC 540 and they were
subsequently exposed to different irradiation doses by Argon Laser 514 nm. Cell
survival was estimated by trypan blue supravital stain following a 24-h
incubation. The leukemic cell line was studied in continuous liquid cell cultures
for 4 weeks. The survival of normal bone marrow progenitors has been estimated by
colony formation assay in methylcellulose cultures. Our results showed that
Amifostine enhances the photokilling effect of MC 540 on leukemic cells and
significantly protects bone marrow nucleated and committed progenitors (BFU-E and
CFU-GM) from children with AL under chemotherapy. In conclusion, Amifostine seems
to be a promising cytoprotective agent in the clinical use of purging with MC 540
mediated phototherapy.
PMID- 10785266
TI - Qualitative and quantitative characterization of Fas (CD95) expression and its
role in primary human acute leukemia cells.
AB - Fas antigen, a cell surface molecule, directly mediates apoptosis, and is
expressed on a limited number of human tissues. Blood or bone marrow samples from
patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia
(ALL) and mixed leukemia were examined qualitatively and quantitatively for the
expression of Fas as well as its function using flow cytometry and the annexin V
staining method. Fas expression was flow cytometrically unimodal with
heterogeneous density, and showed quantitatively characteristic features in
different diseases: undetectable in mixed leukemia, faint to weak in ALL, low in
M0 and M1, and variable (low to strong) in M2, M3, M4, and M5. Both the full
length and the alternatively spliced truncated mRNAs were detected constitutively
even in acute leukemia cells with qualitatively negative and quantitatively faint
Fas, and the band density of the former transcripts detected by RT-PCR was
correlated with the level of expression of the Fas protein. Short-term culturing
of freshly isolated leukemia cells gave rise to an increase of Fas density. In
acute leukemia cells, the apoptosis induced by anti-Fas MoAb was compared with
that induced by etoposide (a topoisomerase II inhibitor). We found that fresh ALL
and AML cells were resistant to the anti-Fas IgM antibody, while etoposide could
trigger apoptosis in all types of leukemia tested. The combined effects of the
anti-Fas MoAb and etoposide were not always synergistic. These results suggest
that Fas is a biological marker for characterizing ALL and AML cells, and provide
insight into creating a new therapeutic modality using cytotoxic drugs and
cytokines together with modulation of Fas.
PMID- 10785267
TI - In vitro chemosensitivity testing in acute non lymphocytic leukemia using the
bioluminescence ATP assay.
AB - The ATP assay is a short term in vitro chemosensitivity assay where the amount of
viable cells are determined by their content of ATP. The aim of the study was to
compare the in vitro results of six cytostatic drugs to the clinical outcome in
83 acute non-lymphocytic leukemia (ANLL) patients. The secondary ANLL at
diagnosis showed an in vitro resistance to daunorubicin that was significantly
higher compared to de novo ANLL at diagnosis (P<0.003). De novo ANLL at diagnosis
that achieved complete remission (CR) were significantly more sensitive to
daunorubicin compared to those who didn't achieve CR (P<0.05). There was an vitro
correlation between topoisomerase II active drugs but not between these drugs and
ara-C. In vitro ara-C sensitivity (< or = the median of the de novo ANLL at
diagnosis) was correlated to poor overall survival (P = 0.02). In vitro
sensitivity to daunorubicin and mitoxantrone was associated with prolonged
disease free survival (P = 0.03 and P = 0.04). We conclude that despite
significant correlation to clinical parameters for daunorubicin and mitoxantrone
the predictive value of the ATP assay in this material was insufficient for
directing therapy.
PMID- 10785268
TI - A novel translocation t(3;22)(q21;q11) involving 3q21 in myelodysplastic syndrome
derived overt leukemia with thrombocytosis.
AB - We report here a novel translocation t(3;22)(q21;q11) in myelodysplastic syndrome
(MDS)-derived overt leukemia with thrombocytosis. A 44-year-old female was
initially diagnosed as MDS with a low platelet count and normal karyotype. After
4 months, blood leukemic cells and platelets rapidly increased concomitantly and
a diagnosis of acute myeloblastic leukemia (AML M1) was made. Chromosome analysis
showed 46, XX, t(3;22)(q21;q11) in 14 of 20 metaphases. Fluorescence in situ
hybridization analysis confirmed both the der(3)t(3;22) and the der(22)t(3;22).
Our results suggest that unidentified gene(s) at 3q21 breakpoint may be
implicated in the pathogenesis of abnormal thrombopoiesis as observed in the
3q21q26 syndrome.
PMID- 10785269
TI - Marsupial immunology: out of the pouch.
PMID- 10785270
TI - Development of the immune system and immunological protection in marsupial pouch
young.
AB - At birth the tissues of marsupial immune system are underdeveloped. The young
animal is not immunocompetent. Histological and immunohistochemical studies of
pouch young epithelial tissues provide a clear picture of tissue development but
the timing of onset of immunocompetence awaits definition. The survival of the
neonatal marsupial in a microbially rich environment is dependent on maternal
strategies, including immunoglobulin transfer via milk and, in some species,
prenatally via the yolk sac placenta. It is also likely that pouch secretions
play a role. This review summarizes our current knowledge of the pathway of
immunological development in marsupials and the protection and threats afforded
by the pouch environment.
PMID- 10785271
TI - The roles of histology and immunohistology in the investigation of marsupial
disease and normal lymphoid tissue.
AB - This review acquaints scientists with current information related to the
application of histology and immunohistology to the studies of normal lymphoid
tissues and specific diseases in marsupials. Histological examination of tissue
is a necessary prerequisite for immunohistological examination because it
establishes tissue structure and detects specific areas of disease which allow
the selection of smaller areas for immunohistological examination. Information is
provided on the basic techniques of histology. Immunohistology
(immunohistochemistry) refers to the identification of antigenic determinants of
specific substances (proteins) by the application of antibodies to histological
sections. Information is provided on a technique for enzyme based, avidin-biotin
enhanced immunohistology, and on antibodies that can be used to mark disease
agents or marsupial tissues and cells. A summary is provided of the available
information on studies of the histology and immunohistology of normal marsupial
lymphoid tissue (thymus, spleen, lymph nodes and mucosa associated lymphoid
tissue), and of selected marsupial diseases such as chlamydiosis and
lymphosarcoma in koalas.
PMID- 10785272
TI - Marsupial cytokines. Structure, function and evolution.
AB - The cytokines are an important group of molecules involved in coordinating the
many and varied components of the immune system. These molecules have been
extensively studied in model eutherian mammals such as mice but comparatively
little is known about the cytokine network of marsupials. Such information will
be invaluable in elucidating fundamental aspects of the marsupial immune system
and will also highlight parallels and differences between the immune systems of
marsupials and eutherians. Given the importance of these goals, our groups have
recently begun to tackle this lack of knowledge of the marsupial cytokine system
and have met with considerable success in the face of the rapid rate of change of
these proteins. This has led to the isolation of the full-length sequences
encoding marsupial orthologues of tumour necrosis factor (TNF), lymphotoxins
alpha and beta (LT-alpha and beta), interleukin-1 beta (IL-1beta), and
interleukin-10 (IL-10). Here we review what has been learnt about structural,
functional and evolutionary aspects of these marsupial cytokines as well as
briefly describing more recent work in progress and future directions in this
field.
PMID- 10785273
TI - Immunoglobulin genetics of marsupials.
AB - Until recently, studies of marsupial immunoglobulins were limited to primarily
protein analyses, such as Protein A binding and immunological cross-reactivity to
eutherian immunoglobulins to draw conclusions about the isotypes present in
metatherians. This left an interesting gap in our knowledge of the evolution of
vertebrate, more specifically mammalian, antibodies and provided little insight
into the diversity of marsupial antibodies. Recently, however, there has been a
flurry of papers from multiple laboratories describing, at the molecular level,
the heavy and light chain classes present in marsupials with some analysis of the
expressed repertoires. These studies have provided the evidence to determine when
some of the uniquely mammalian isotypes, e.g. IgG and IgE, appeared in evolution,
and are a first look at the complexity of heavy and light chain variable regions
in a metatherian. Here we review what was known prior to the cloning of marsupial
Ig genes and what we have learned recently.
PMID- 10785274
TI - Immunological protection of the vulnerable marsupial pouch young: two periods of
immune transfer during lactation in Trichosurus vulpecula (brushtail possum).
AB - Marsupial young are born with an underdeveloped immune system and are dependent
upon passively acquired immune protection provided by the mother's milk.
Colostrum and milk samples were collected from the brushtail possum throughout
lactation and the concentration of secretory IgA (sIgA), IgG and transferrin was
determined by Western blotting. Two periods of immune transfer were identified.
The first, a colostral phase, occurs immediately after birth and involves sIgA,
IgG and transferrin. During the early lactation stage, pouch young receive milk
of a unique composition as they undergo developmental changes in the pouch that
occur in utero for eutherian mammals. At the end of this external gestation, the
composition of the milk changes (switch phase) to resemble that of eutherian
mammals in the late lactation phase. The second transfer of immunity consists of
IgG and transferrin, and occurs during the switch phase prior to maturation of
the immune response.
PMID- 10785275
TI - Photobiology of Monodelphis domestica.
AB - The gray, short-tailed opossum, Monodelphis domestica, has been used for
photobiologic studies since 1984. The presence of a light-activated DNA repair
pathway in the tissues of Monodelphis has been used to identify pyrimidine dimers
in DNA as initiating events for a number of ultraviolet radiation (UVR)-induced
pathologies of the skin and cornea. Furthermore, Monodelphis, unlike common
laboratory rodents, is susceptible to the induction of melanoma by UVR alone.
PMID- 10785276
TI - Immunobiology of mycobacterial infections in marsupials.
AB - Mycobacterial infections of marsupials are important for two reasons. Firstly,
the Australian brushtail possum (Trichosurus vulpecula) serves as the major
wildlife reservoir for Mycobacterium bovis in New Zealand and secondly, M. avium
is a significant cause of disease in endangered marsupial species held in
captivity. Marsupials are highly susceptible to specific mycobacterial infections
which may be linked to deficiencies in their cellular immunity. Histopathological
inspection of affected tissues indicates that, unlike most eutherians, marsupials
are unable to wall off infection sites, resulting in formation of satellite
lesions and generalised disease. This review examines possible reasons for the
high susceptibility of marsupials to mycobacterial infections and investigates
the prospects for developing vaccines to control these diseases.
PMID- 10785277
TI - Sensory channel specific modulation in the nucleus of the solitary tract.
PMID- 10785278
TI - The effects of cyclophosphamide on neurotransmission in the urinary bladder of
Suncus murinus, the house musk shrew.
AB - This study has shown that cyclophosphamide treatment of the insectivore Suncus
murinus, causes a down regulation in both muscarinic and P2X receptors, together
with a reduced responsiveness to exogenous histamine (0.3 mM) in the urinary
bladder. Electrical field stimulation (70 V, 0.3 ms, 0.5-16 Hz, 10 s every 5 min)
of bladders from both control and cyclophosphamide-treated animals showed
identical responses. Since post-junctional alterations have been revealed by the
reduced responsiveness to exogenous carbachol (0.1 microM-3 mM) and beta,gamma
methylene ATP (0.3-300 microM), it would appear that in the bladders of
cyclophosphamide-treated animals there is also a pre-junctional effect, increased
transmitter release compensating for the down regulation of the receptors. As the
pattern of neurotransmission of the bladder of suncus more closely resembles that
of human detrusor than other commonly studied laboratory animals, this
insectivore appears to be a useful animal model for the study of bladder
neurotransmission in pathophysiological conditions.
PMID- 10785279
TI - Cyanide intoxication induced exocytotic epinephrine release in rabbit myocardium.
AB - Cyanide intoxication, which has been used as a model of energy depletion at
cardiac sympathetic nerve terminals, causes non-exocytotic release of
norepinephrine (NE). However, the effect of cyanide intoxication on cardiac
epinephrine (Epi) release remains unknown. Using cardiac microdialysis in the
rabbit, we measured dialysate Epi and NE concentrations as indices of myocardial
interstitial Epi and NE levels, respectively. Local administration of sodium
cyanide (30 mM) through the dialysis probe increased both Epi and NE levels (from
11.3+/-2.3 to 32.3+/-4.4 pg/ml and from 33.6+/-6.1 to 389.0+/-71.8 pg/ml,
respectively, mean+/-S.E., P<0.01). Local desipramine (100 microM) administration
suppressed the cyanide induced NE response without affecting the Epi response. In
contrast, local omega-conotoxin GVIA (10 microM) administration partially
suppressed the cyanide induced NE response and totally abolished the Epi
response. In conclusion, cyanide intoxication causes N-type Ca(2+) channel
dependent exocytotic Epi release as well as inducing N-type Ca(2+) channel
independent non-exocytotic NE release.
PMID- 10785280
TI - Ultrastructural observations of fibroblast-like cells forming gap junctions in
the W/W(nu) mouse small intestine.
AB - The ultrastructure of the wild-type (+/+) mice small intestine was compared with
c-kit mutant (W/W(nu)) mice which only have few interstitial cells of Cajal (ICC)
associated with Auerbach's plexus, in order to elucidate whether the specialized
membrane contacts are general features of so-called fibroblast-like cells that
are widely distributed in the tunica muscularis of the alimentary tract.
Fibroblast-like cells in the Auerbach region were found in approximately equal
number in W/W(nu) mice as in +/+ mice, while ICC associated with Auerbach's
plexus (ICC-AP) could not be demonstrated in W/W(nu) mice in the present
investigation. Fibroblast-like cells were characterized by cytoplasm of moderate
to high electron density, well developed rough endoplasmic reticulum and nuclei
with thick peripheral accumulations of heterochromatin. There were no basal
lamina and caveolae along the cell membrane. It was observed that single
fibroblast-like cells formed probable small gap junctions with muscle cells of
both circular and longitudinal layers. Fibroblast-like cells with the same
features were also observed in the region of the deep muscular plexus in both +/+
and W/W(nu) mice. The present observation, together with our previous studies on
rats and guinea-pigs, suggest the common presence of gap junctions or gap
junction-like structures on fibroblast-like cells in the gastrointestinal
musculature and their involvement in the regulatory system of gastrointestinal
motility by passing electrical or molecular signals to influence the state of
muscle tonus.
PMID- 10785282
TI - Inhibition of gastric motility by noxious chemical stimulation of interspinous
tissues in the rat.
AB - In urethane anesthetized, adult male Wistar rats, noxious chemical stimulation of
the mid to lower thoracic interspinous tissues, in the form of capsaicin
injection, was accompanied by a pronounced increase in gastric sympathetic nerve
activity and inhibition of gastric motility. Much weaker effects on gastric
sympathetic nerve activity and gastric motility were observed with similar
stimulation of the lower lumbar interspinous tissues. The inhibitory response of
gastric motility to thoracic stimulation was preserved in spinalized animals,
somewhat diminished in vagotomized animals and was abolished in most animals from
which the coeliac ganglion had been extirpated. In vagotomized animals, treatment
with 1 mg/kg propranolol i.v. did not cause any further attenuation of the
inhibitory reflex. However, the inhibitory reflex was extinguished in vagotomized
animals which received 1 mg/kg propranolol plus 10 mg/kg phentolamine i.v. These
results suggest that noxious chemical stimulation of the interspinous tissues
elicits a segmentally organized reflex which is mediated principally at the
spinal level and which expresses itself principally, but not exclusively via
sympathetic efferents traversing the coeliac ganglion. The expression of the
reflex response appears to be largely dependent upon the integrity of alpha
adrenergic receptors.
PMID- 10785281
TI - 17beta-estradiol modulates baroreflex sensitivity and autonomic tone of female
rats.
AB - The following experiments examine the role of estrogen as a central modulator of
autonomic tone and baroreflex sensitivity in the female rat. Female Sprague
Dawley rats were ovariectomized and then supplemented daily for 7 days with a
fixed dose of estrogen (5 microg/kg; sc) to produce a stable level of estrogen
similar to that present at proestrous (17 pg/ml). The rats were then
anaesthetized with sodium thiobutabarbital (100 mg/kg) and instrumented to record
blood pressure, heart rate and both vagal and renal efferent nerve activities.
The sensitivity of the cardiac baroreflex was tested using intravenous injection
of multiple doses of either phenylephrine hydrochloride or sodium nitroprusside.
Estrogen-supplemented female rats exhibited a significantly enhanced BRS as
compared to male rats from a previous study (0.78 vs. 0.5). Furthermore, bolus
injection of estrogen (1x10(-2) mg/kg; iv) in estrogen-supplemented female rats
produced a significant increase in vagal nerve activity and a significant
decrease in renal nerve activity which together resulted in a further enhancement
of the BRS (0.78 vs. 2.4). Injection of the selective estrogen receptor
antagonist, ICI 182,780, into nucleus ambiguus and the intrathecal space of the
spinal cord blocked the respective changes in parasympathetic and sympathetic
nerve activities indicating that intravenously administered estrogen modulates
baseline autonomic tone via the activation of central estrogen receptors.
PMID- 10785283
TI - Heart rate recovery post-exercise as an index of parasympathetic activity.
AB - The time constant (T) obtained by fitting post-exercise heart rate (HR) recovery
to a first order exponential decay curve has been promoted as an index of
parasympathetic activity. However, acceptance has been limited because reported
data are inadequate to assess goodness of fit for the model, determine the best
exercise protocol, or optimize the duration of post exercise monitoring.
Consequently, we evaluated T for nine healthy volunteers (age 24-46) following
treadmill exercise at maximal (max) and two stages sub-max exercise (Bruce
protocol). T stabilized only after 3 min of post-exercise monitoring. With max
exercise, T varied unacceptably with small changes in onset of monitoring, e.g.
16.7+/-16.6 (-13.2%) in the first 5 s, and residuals of the fitted curve were non
random. In contrast, sub-max exercise produced consistent T values, e.g. -1.9+/
3.2 (-4.2%) in the first 5 s, and residuals were more nearly random. In
conclusion, first order decay is an inadequate model for HR recovery following
max exercise, but may be reasonable for sub-max levels.
PMID- 10785284
TI - Attenuated cardiovascular adjustment to sustained static exercise after
carbohydrate loading.
AB - We examined whether a higher plasma lactic acid (LA) concentration resulting from
carbohydrate (CHO)-loading affects the cardiovascular responses to exercise
through a greater activation of LA-induced metaboreflex. Before and after CHO
loading, LA concentration, mean arterial blood pressure (MAP), heart rate (HR),
cardiac output (CO), rating perceived exertion (RPE), and integrated
electromyogram (iEMG) of the vastus lateralis were studied during a sustained
static knee extension of single legs in 16 volunteers. The CHO-loading comprised
an exhaustive bout of one-legged cycling (73+/-3% of maximal oxygen uptake for
130-160 min) and consuming a low-CHO diet for 2-3 days and a high-CHO diet for
the next 3 days. In the leg that performed the exercise (the experimental leg),
the LA concentration after CHO-loading was significantly increased, but the
magnitude of MAP, HR, and CO responses during static exercise was significantly
decreased in parallel with a significant reduction of RPE and iEMG. In the
control leg, there were no changes in the variables before and after CHO-loading.
These results suggest that the increased LA concentration resulting from CHO
loading did not affect the cardiovascular adjustment to the sustained exercise.
Other mechanisms related to the reduction of RPE and iEMG seem to be responsible
for the attenuated cardiovascular responses observed in the experimental leg
after CHO-loading.
PMID- 10785285
TI - Development of a highly sensitive quantitative competitive PCR assay for the
detection of murine cytomegalovirus DNA.
AB - Viral persistence and molecular latency are characteristic of infection by the
human cytomegalovirus (HCMV). Using the murine cytomegalovirus (MCMV) as a model
for human infection, a quantitative-competitive polymerase chain reaction (QC
PCR) assay was developed to detect and quantify MCMV-DNA in the salivary glands
of infected mice. The QC-PCR detected high numbers of MCMV DNA copies in the
absence of infectious virus. By comparing the DNA content and the results
obtained from a standard semiquantitative plaque assay, it is concluded that 1
plaque-forming unit (pfu) is the equivalent of approximately 1500 viral genomes.
By day 42-post infection (pi) 4x10(3) copies of DNA/1 mg tissue were sufficient
to reactivate infectious virions after cyclophosphamide immunosupression. By day
90 pi, however, when the DNA load was decreased to <1.2x10(2), reactivation was
not observed. These results indicate that viral reactivation will occur when the
number of infectious DNA copies is equivalent about 2-3 pfu. This quantitative
test may therefore help to detect CMV and the risk of reactivation in
immunosupressed patients.
PMID- 10785286
TI - The use of monoclonal antibody probes for the detection of avian reovirus
antigens.
AB - Two monoclonal antibodies (MAb), E9 and H3, prepared against avian reovirus (ARV)
S1133, were used in an immuno-dot assay to detect ARV antigens from cell culture
and from tendon tissue samples of chickens. The limit of viral antigens detected
was 8 ng using both MAb probes. The probes detected 10 ARV isolates representing
at least two serotypes or pathotypes. The results indicated that these probes had
broad specificity. The probes, however, did not cross-react with viral antigens
prepared from six unrelated avian viruses. The ARV antigens in tendon tissue
samples were detected by both probes, and it is possible, therefore, to use
either of the two MAb probes for detection of ARV infections.
PMID- 10785287
TI - Duplex RT-PCR: reagent concentrations at reverse transcription stage affect the
PCR performance.
AB - Test conditions for the simultaneous detection of potato leafroll virus (PLRV)
and potato virus Y (PVY) in dormant tubers and leaves by reverse transcription
polymerase chain reaction (RT-PCR) were optimized. Various factors optimized at
the reverse transcription (RT) stage rather than at the amplification (PCR) stage
affected the outcome. In the simplex RT-PCR a onefold dNTPs concentration (0.5
mM) was sufficient in yielding a PLRV or PVY band. In contrast, the duplex RT-PCR
required a minimum twofold dNTPs concentration (1.0 mM) during RT to produce
distinct bands in PCR. Similarly, various proportions of antisense primers of
PLRV and PVY used during RT affected subsequent duplex RT-PCR. Optimal
amplification of both viruses were obtained at a ratio of 0.90:0.49 microM of
PLRV:PVY antisense primers. An interaction of dNTPs and RNA template
concentration was observed. A higher concentration of RNA was required at onefold
dNTPs concentration than at twofold dNTPs. Dilutions down to 1:300 of RNA
template yielded distinct bands of both viruses at twofold dNTPs concentration.
At optimized conditions of the duplex RT-PCR both viruses were reliably detected
in composite samples at a ratio of one part infected sap mixed with 399 parts of
sap from healthy tubers. Application of optimized conditions to singly- and
doubly-infected tubers detected both viruses from naturally infected field-grown
tubers. A nearly perfect correlation (r(2)=0.99) was observed between visible
plant symptoms and the virus detection from leaves and tubers by the duplex RT
PCR.
PMID- 10785288
TI - Chimeric swine vesicular disease viruses produced by fusion PCR: a new method for
epitope mapping.
AB - A new method of epitope mapping based on chimeric swine vesicular disease (SVD)
viruses produced by fusion PCR (polymerase chain reaction). Seven out of 16
neutralising and non-neutralising newly produced monoclonal antibodies (MAbs)
discriminated between SVD isolate ITL/1/66 and NET/1/92. Using fusion PCR eight
chimeric viruses were produced containing different supplementary pieces of the
P1 region of both parent strains. Using these chimeric viruses we were able to
map the epitope regions recognised by these seven neutralising and non
neutralising Mabs. This new method, using chimeric viruses produced by fusion
PCR, is particularly valuable for the epitope mapping of non-neutralising MAbs.
PMID- 10785289
TI - Reproducibility of human immunodeficiency virus type 1 (HIV-1) protease and
reverse transcriptase sequencing of plasma samples from heavily treated HIV-1
infected individuals.
AB - The reproducibility of population-based human immunodeficiency virus type 1 (HIV
1) protease and reverse transcriptase (RT) sequencing was assessed using
replicate aliquots of cryopreserved plasma samples obtained from seven heavily
treated HIV-1-infected individuals. The sequence of each sample replicate was
compared with the consensus sequence for that sample and 99.4% of 35128 amino
acids were found to be concordant with the sample consensus. Partial discordances
were present at 0.5% of positions and complete discordances were present at <0.1%
of positions. To assess the reproducibility at detecting mutations (defined here
as differences from the subtype B consensus sequence), the proportion of
sequences having a mutation when at least two sequences from that sample had the
same mutation were examined. There was a median of 13 protease and 18 RT
mutations per sample for a total of 3126 mutations; 95% of these mutations were
detected. However, sequencing of multiple clones from two samples demonstrated
that those mutations present in a minority of clones were often not detected by
population-based sequencing. These results suggest that HIV-1 protease and RT
sequencing of circulating plasma virus is highly reproducible but that the
sensitivity at detecting mutations may be low if those mutations are present as
minor variants.
PMID- 10785290
TI - Simplified, rapid method for cloning of virus-binding polypeptides (putative
receptors) via the far-western screening of a cDNA expression library using
purified virus particles.
AB - A simplified, alternative method for cloning virus-binding polypeptides (receptor
candidates) is described. The method is based on a far-Western assay using
purified tomato spotted wilt tospovirus (TSWV, Bunyaviridae) for screening a
lambda-phage cDNA expression library. The western flower thrips, Frankliniella
occidentalis Pergande, the principal vector of TSWV, in which the virus
replicates, was used for library construction. Using this method several virus
binding polypeptides were identified, it eliminated the need for (a) a cellular
infection or binding system, (b) the identification, cloning and expression of a
functional viral attachment protein, or (c) the purification of the virus
receptor. Using this method, virus-binding polypeptides can be selected and
cloned in a very short period of time and used in subsequent experiments for
determination of their biological relevance as virus receptors and/or tested for
potential usefulness as inhibitors of virus transmission and/or infection.
PMID- 10785291
TI - Anchored oligo(dT) primed RT/PCR: identification and quantification of related
transcripts with distinct 3'-ends.
PMID- 10785292
TI - Production of high-titer stocks of the English strain of rat cytomegalovirus.
AB - A simple technique to increase dramatically the yield of rat cytomegalovirus
(RCMV) from infected monolayers of a rat embryo fibroblast-derived cell line is
described. The method, which involves daily changes of the cell culture medium,
can result in a 50000-fold amplification of virus from cell monolayers inoculated
with only a few RCMV particles. This modification of the standard in vitro
culture technique to amplify viral yield can be used to increase the sensitivity
of the plaque assay for detecting very small amounts of infectious virus in organ
homogenates of RCMV infected animals.
PMID- 10785293
TI - Detection of multiple potato viruses using an oligo(dT) as a common cDNA primer
in multiplex RT-PCR.
AB - A novel usage of multiplex reverse transcription polymerase chain reaction (m-RT
PCR) for simultaneous detection of multiple viruses is reported. By use of an
oligo(dT), as a common primer, nearly full-length cDNAs can be synthesized.
Furthermore, combining an oligo(dT) primer with a specific antisense primer can
be used to simultaneously prime reverse transcription of both polyadenylated and
non-polyadenylated RNAs. Four viral genera including five potato viruses
[(carlavirus (PVS), polerovirus (PLRV), potexvirus (PVX), potyvirus (PVA and
PVY))] and a viroid genus including a viroid genome (pospiviroid (PSTVd)) were
used to develop various formats of m-RT-PCR. In artificially created viral RNA
mixtures, all six RNA pathogens were detected successfully by uniplex- and m-RT
PCR. In naturally infected field grown tubers, m-RT-PCR detected infection of two
to three viruses, which were present in the tubers.
PMID- 10785294
TI - Direct resin composite inlays/onlays: an 11 year follow-up.
AB - OBJECTIVES: The aim of this study was to present an 11-year assessment of direct
resin composite inlays/onlays. METHODS: One-hundred Class II direct resin
composite inlays and 34 direct resin composite restorations were placed in 40
patients. The restorations were evaluated clinically, according to modified USPHS
criteria, annually over a 11-year period. RESULTS: Of the 96 inlays/onlays and 33
direct restorations evaluated at 11 years, 17. 7% in the inlay/onlay group and
27.3% in the direct restorations group were assessed as unacceptable. The
differences in longevity were not statistically significant. The main reasons for
failure for the inlays/onlays and direct restorations were fracture (8.3 and 12.
1%, respectively), occlusal wear in contact areas (4.2 and 6.1%, respectively)
and secondary caries (4.2 and 9.1%, respectively). Eight of the non-acceptable
inlays/onlays and five of the direct restorations were replaced, while the other
ones were repaired with resin composite. Unacceptable wear was observed in
occlusal contact areas of six restorations, in patients who were severe bruxers.
For the other restorations occlusal wear was not found to be a clinical problem
and no difference was observed between the inlays/onlays and direct composite
restorations. The marginal adaptation of the inlays/onlays was still good at the
end of the study. Ditching was only observed in a few inlays. A higher failure
rate was observed in molar teeth than in premolar teeth. CONCLUSIONS: Good
durability was observed for the direct resin composite inlay/onlay technique.
Excellent marginal adaptation and low frequency of secondary caries in patients
with high caries risk were shown. No apparent improvement of mechanical
properties was obtained by the secondary heat treatment of the inlays. Also, the
difference in failure rate between the resin composite direct technique and the
inlay technique was not large, indicating that the more time-consuming and
expensive inlay technique may not be justified. The direct inlay/onlay technique
is recommended to be used in Class II cavities of high caries risk patients with
cervical marginal placed in dentin.
PMID- 10785295
TI - Caries-associated micro-organisms in infants from different socio-economic
backgrounds in Scotland.
AB - OBJECTIVES: The aims of this study were: (1) to compare the frequency of
isolation of mutans streptococci, (Streptococcus mutans, Steptococcus sobrinus),
lactobacilli and yeasts (caries-associated micro-organisms) in the saliva of 1
year-old infants with and without dental caries; and (2) to determine if socio
economic background influenced the frequency isolation of bacteria and caries
status. METHODS: 1393 1-year-old consented infants, who comprised 70. 3% of
children born in Dundee during a 1year period, had saliva samples taken (tongue
loop method) for microbiological culture and were examined for dental caries
(d(1)-threshold: enamel and dentine diagnostic threshold). Thirty-nine infants
were diagnosed with caries and the frequencies of isolation of caries-associated
micro-organisms (and absolute microbial counts) were compared with infants who
were caries-free. In addition, associations were sought between the infants'
socio-economic background, the frequency of isolation of caries-associated micro
organisms and caries status. RESULTS: Streptococcus mutans, lactobacilli and
yeasts were isolated more frequently from those infants with caries compared to
those who were caries-free (S. mutans: 29.7 vs 9.8%, P=0.0008; lactobacilli: 15.4
vs 4.3%, P=0.0073; yeasts: 23.7 vs 10.4%, P=0.0016-Fisher's exact test). There
were no significant differences between the isolation frequencies of S. sobrinus
(2.7 vs 1.3%, P=0.39) from those with and without caries. Significantly, more
infants living in areas of high deprivation had caries compared to those from
more affluent areas (DEPCAT 6 and 7 vs 1-5: 3.6 vs 1.9%, P=0.049), but, apart
from yeasts, socio-economic background was not significantly associated with the
isolation frequencies of any of the caries-associated micro-organisms.
CONCLUSIONS: In infants as young as 1year of age, salivary S. mutans,
lactobacilli and yeasts but not S. sobrinus were isolated significantly more
frequently from those with caries compared to those who were caries-free. Apart
from yeasts, socio-economic background did not influence the frequency of
isolation of caries-associated micro-organisms. However, infants living in areas
of highest deprivation had significantly higher frequencies of caries compared to
those from more affluent areas.
PMID- 10785296
TI - General dental practitioners diagnostic and treatment decisions related to
fissure sealed surfaces.
AB - OBJECTIVES: The purpose of this in-vitro study was to assess the validity and
reproducibility of the diagnosis and treatment planned for occlusal surfaces
prior to and following the placement of a clear sealant by a sample of general
dental practitioners (GDPs). METHODS: 160 permanent posterior teeth were examined
by 25 GDPs. The GDPs were not given any criteria and were therefore free to
diagnose and plan care, as they felt appropriate. Each GDP conducted four
examinations, two prior to and two after sealing. The teeth were serially
sectioned to provide the validating criterion. RESULTS: After sealant placement,
there was a statistically significant increase in specificity and decrease in
sensitivity of both diagnostic and treatment decisions. The reproducibility
expressed by the kappa-statistic was of the order of 0.5 prior to and after
sealing with regard to diagnostic decisions. There was a general tendency to
diagnose less disease after placement of a sealant (P<0. 001). There was also
significantly less care (preventive or restorative) planned after sealant
placement (P<0.001). CONCLUSIONS: The placement of a sealant resulted in the
diagnosis of less disease and less restorative treatment. This may be appropriate
as evidence exists to support the use of sealants as caries therapeutic agents.
PMID- 10785297
TI - Enamel demineralisation assessed by computerised image analysis of clinical
photographs.
AB - OBJECTIVES: To investigate the use of computerised image analysis to measure the
area of demineralisation on the buccal surface of a tooth and to analyse the
effect on that measurement of varying the angle at which a photographic image of
the buccal surface of a tooth is taken. METHODS: Twenty-two teeth with areas of
incremental demineralisation on the buccal surface were photographed
perpendicular to the buccal surface and at angles of 20 and 40 degrees, above
(Cuspal) and below (Gingival) the perpendicular. The images were captured and
analysed using computerised image analysis. RESULTS: The Gingival views showed
lower limits of agreement than the Cuspal views, probably due to the positioning
of the masking on the lower part of the flash, to reduce reflection. There was a
significant difference between the areas of demineralisation measured for the
three angles from the Gingival views (p<0.001). The mean differences in areas
measured were not linear, but there was a significantly greater reduction in area
measured for the 40 degrees views. CONCLUSIONS: Computerised image analysis to
measure areas of demineralisation from a captured 35mm slide is reproducible. The
position of the masking on the camera flash and the angle of the camera makes a
difference to the area measured and the grey scales recorded. Images taken at a
larger angle than 20 degrees to the perpendicular will record a significantly
reduced area of demineralisation. Standardisation of photographs with the use of
calibration markers and manipulation of images is discussed.
PMID- 10785298
TI - Human pulp reaction to dentine bonded amalgam restorations: a histologic study.
AB - OBJECTIVE: The aim of this study was to investigate the human pulp response to
Scotchbond Multi Purpose Plus (SMPP) bonding agent in non-exposed Class V
cavities. METHODS: SMPP was placed in 24 of 40 cavites according to
manufacturer's instructions and the cavities were restored with amalgam. The
remaining 16 cavities were capped with a calcium hydroxide formulation (Dycal)
sealed with zinc-oxide eugenol, and restored with the amalgam. After extraction
at 10 and 35 days, the teeth were fixed, sectioned and stained for light
microscopy. RESULTS: All Dycal-capped teeth, at both 10 and 35 days, exhibited no
pulp inflammation and no demonstrable bacteria. Six cases sealed with SMPP at 10
days showed no pulp inflammation or stained bacterial profiles. The remaining six
teeth demonstrated mild to moderate inflammatory pulpal responses and five out of
these six cases exhibited stained bacterial profiles. Nine out of 12 teeth showed
no inflammatory pulp responses at 35 days, the remaining three cases exhibited
mild to moderate pulp inflammation without stained bacteria. CONCLUSIONS: None of
the teeth sealed with SMPP presented severe inflammatory pulpal reactions
histologically. SMPP did not exhibit significant deleterious effects on the human
pulp tissue during the test periods.
PMID- 10785299
TI - Effects of topical Catalase application on dental pulp tissue: a
histopathological evaluation.
AB - OBJECTIVES: recently, the role of antioxidant enzymes in wound healing and their
therapeutic potential has been a subject of interest in medical sciences. However
there is restricted knowledge on the results of topical application, optimal
therapeutic dosage and carrier types. The purpose of this study was to
investigate the wound healing response of dental pulp after direct pulp capping
with an antioxidant enzyme; Catalase (C-40). METHODS: three mongrel dogs were
used in this study. A total of 32 perforated Cl V preparations were treated with
either 0.8mg (n=16) or 1.6mg (n=16) Catalase (C-40) which was incorporated in
gelatin carriers whereas 16 control teeth had carriers without Catalase. One
millimeter thick Teflon disks were placed over the gelatin pellets and the
cavities restored with silver amalgam. Short term and long term histopathologic
reactions were evaluated after 7 and 90 days. RESULTS: there were no
statistically significant differences between the inflammatory cell responses of
control and either dosage groups of Catalase at the 7-day evaluation period.
However, after 90 days, better tissue healing was observed in the teeth treated
with Catalase, resulting in significant differences with the control group.
CONCLUSIONS: it can be concluded that the results of this study encourage the
topical use of antioxidant Catalase as a pulp-capping agent. However, further
studies are required to determine optimal antioxidant dosages.
PMID- 10785300
TI - A new screening test for toxicity testing of dental materials.
AB - OBJECTIVES: The development of a micro plate assay for cytotoxicity testing of
dental materials based on a bioassay using brine shrimp larvae (artemia salina)
as sensitive organisms. METHODS: Brine shrimp larvae are commonly used for
cytotoxicity assays in pharmacology. These larvae are sensitive to toxic
substances. The ratio between dead larvae (no motility) and living larvae (high
motility) in comparison to a control without any toxic substances is used to
estimate the toxicity of the test solutions. The test materials (Arabesk((R)),
Solitaire((R)), Pertac((R)) II, Tetric((R)), Herculite((R)) and the compomer
materials Dyract((R)), Hytac((R)), Compoglass((R))) were polymerized and
consecutively milled. After incubation of 1g in 4ml distilled water at 37 degrees
C for 48h, the solid materials were separated by centrifugation. The solutions
were equibrilated with NaCl to a salt content of 25g/l. Aliquots of 200microl
were distributed in eight micro wells and 50microl of a artemia salina containing
(n=8-14) solution were added to each well. As controls eight wells with 250microl
salt solution containing a comparable number of brine shrimp were used. At
baseline, after 2, 5, 24 and 48h, the dead shrimp were counted using a stereo
microscope. Finally all shrimps were sacrificed using Na-acid (5%) and counted to
get the number of shrimps per well. RESULTS: All compomers and Solitaire caused
100% brine shrimp lethality after 24h and showed significantly (p<0.01, signed
rank test) higher toxicities than the remaining composites. With the exception of
Pertac II, all composites showed significantly higher toxic values than the
control. Pertac II did not show any differences from the controls used.
CONCLUSIONS: This new technique has some advantages for toxicity testing of
restorative materials, because it can quickly be carried out at low costs. The
disadvantage is the high quantity of material used and the low sensitivity.
PMID- 10785301
TI - Effect of region and dentin perfusion on bond strengths of resin-modified glass
ionomer cements.
AB - OBJECTIVES: The purpose of this study was to evaluate the hypothesis that
regional differences and pulpal pressure would significantly affect bond
strengths of resin-modified glass ionomer cements to dentin. METHODS: Twenty-six
extracted caries-free human third molars were ground to expose middle dentin and
were randomly divided into two groups for bonding: no pulpal pressure and pulpal
pressure of 15cm H(2)O. Fuji II LC, Vitremer, or Photac-Fil Quick were applied to
the previously pre-treated surfaces and light-cured as recommended by the
manufacturers. After immersion in water at 37 degrees C for 24h, the teeth were
sectioned to 0.7mm thick slabs, divided into pulp horn, center, and peripheral
regions according to visual criteria, and trimmed along the bonded interface for
microtensile bond test to a cross-sectional area of 1mm(2). The slabs were
subjected to tensile forces and the data analyzed using ANOVA and Fisher's PLSD
at the 95% level of confidence. RESULTS: For Fuji II LC, bond strengths to the
pulp horn regions were significantly lower than those to the other regions
independent of pulpal pressure (p<0.05). On the other hand, regional bond
strengths were not observed for Vitremer and Photac-fil Quick 0.05). CONCLUSIONS:
Pulpal pressure had a stronger influence on bond strengths and failure modes of
resin-modified glass ionomers than regional differences of the substrate.
PMID- 10785302
TI - Analysis of composite type and different sources of polymerization light on in
vitro toothbrush/dentifrice abrasion resistance.
AB - OBJECTIVES: This study examined toothbrush/dentifrice abrasion of a photo
activated prosthetic composite (dentin and enamel variations) for the purpose of
evaluating the influence of polymerization sources on abrasive wear. METHODS: A
photo-activated prosthetic composite material (Artglass) was assessed. Dentin and
enamel variations were polymerized using a proprietary photo-curing unit with two
xenon stroboscopic lamps (UniXS), and other enamel specimens were polymerized
either with a laboratory photo-curing unit with three fluorescent tubes or with a
high intensity unit with two metal halide lamps. All specimens were stored in
water for 14days and subjected to toothbrush/dentifrice abrasion (350g vertical
load) using an abrasive slurry (Colgate Fluoriguard) and a toothbrush (Oral-B
40). The amount of vertical loss and the surface roughness of the specimens after
20,000 strokes were determined by profilometer. Average values of groups of five
specimens were compared using analysis of variance (ANOVA) and Sheffe's S
intervals (p<0.05). RESULTS: When polymerizing with the proprietary unit, the
abrasion and surface roughness of the enamel material required respective means
of 34.08microm (+/-3.66) and 1.00microm (+/-0.08), and the those of the dentin
material required means of 42.02microm (+/-5.62) and 1.23microm (+/-0.20). Both
abrasion and surface roughness after toothbrushing of the enamel material were
significantly smaller than were those of the dentin material. The abrasion of
specimens polymerized with the metal halide unit required a mean of 23.89microm
(+/-6.17) and demonstrated minimal wear. CONCLUSIONS: The use of a high intensity
metal halide photo-curing unit effectively enhanced the abrasion resistance of
the composite. Surfaces of restorations should be covered with the enamel
material in order to achieve smoothness and wear resistance.
PMID- 10785303
TI - Microtensile bond strengths of glass ionomer (polyalkenoate) cements to dentine
using four conditioners.
AB - OBJECTIVES: The purpose of this study was to measure the microtensile bond
strengths of three glass ionomer cements to dentine (Photac-Fil Quick; Fuji II
LC; Fuji IX GP) using four different conditioners (Ketac Conditioner; Dentin
Conditioner; Cavity Conditioner; and an experimental conditioner, K-930).
METHODS: Superficial occlusal dentine of extracted human third molars was
exposed, finished with wet 600-grit silicon carbide paper, and each of the above
glass ionomer cements bonded using the four conditioners according to the
manufacturers' instructions. After 24h in tap water at 37 degrees C, the teeth
were sectioned to obtain 3-4 bar-shaped specimens. Ten specimens were prepared
for each group and shaped to an hour-glass form of (1.2+/-0.02)mm diameter. The
specimens were mounted in a jig and stressed in tension at a crosshead speed of
1mm/min until failure. The mean bond strengths were calculated and compared using
one-way ANOVA and LSD tests, and the fracture modes were examined by scanning
electron microscopy. RESULTS: Mean microtensile bond strengths for Photac-Fil
Quick were not significantly different from Fuji II LC for each of the
conditioners used. However, the bond strengths for Photac-Fil Quick were
significantly greater than Fuji II LC when no conditioner was applied. Mean
microtensile bond strengths of conditioned specimens of Fuji II LC were
significantly greater than non-conditioned specimens. Mean microtensile bond
strengths of non-conditioned specimens of Fuji IX GP were not significantly
different from conditioned specimens. The fracture mode of all specimens
demonstrated mostly cohesive failure within the cement. SIGNIFICANCE: The use of
surface conditioners resulted in improvement in bond strength of Fuji II LC,
while Photac-Fil Quick and Fuji IX GP showed no difference.
PMID- 10785304
TI - Effect of finishing technique on the microleakage and surface texture of resin
modified glass ionomer restorative materials.
AB - PURPOSE: The purpose of this study was to evaluate the effects of wet and dry
finishing/polishing procedures on the microleakage and surface texture of resin
modified glass ionomer (RMGI) restorative materials. MATERIALS AND METHODS: Class
V cavity preparations were made at the cemento-enamel junction (CEJ) on the
buccal and lingual surface of 30 extracted human molars. The teeth were restored
in three groups of 10 (20 preparations in each group) using Fuji II LC and
Vitremer, both RMGIs, and Fuji II, a capsulated conventional glass ionomer cement
(control). One restoration per tooth was finished/polished with copious
applications of water and the other was finished/polished without water. All
restorations were finished/polished using a sequence of four abrasive disks.
Finishing/polishing was initiated according to manufacturers' instructions
immediately after light-curing Fuji II LC and Vitremer, and 15min after placement
for Fuji II. The specimens were thermocycled and subjected to a silver nitrate
leakage test. Each tooth was sectioned buccolingually and examined with an
optical microscope at 40x to determine the extent of microleakage at enamel and
dentin margins. The data were subjected to a non-parametric statistical analysis.
To evaluate surface roughness after polishing, three disks each of Vitremer and
Fuji II LC were fabricated in Teflon molds. One disk of each material was not
finished/polished (control). The others were finished/polished using Sof-Lex
abrasive disks. One specimen of each material was kept wet during all
finishing/polishing procedures, while the other was kept dry. Atomic force
microscopy was used to determine the average roughness (R(a)) of the specimens.
RESULTS: For each material, microleakage at the enamel margin was very slight.
Leakage of the conventional glass ionomer Fuji II was severe at dentin margins.
Statistical analysis indicated that both Vitremer and Fuji II LC had
significantly less leakage than Fuji II, and that Vitremer had significantly less
leakage than Fuji II LC (p<0.05). Leakage at enamel margins was significantly
less than at dentin margins. Differences related to wet and dry polishing were
not statistically significant. Profilometry data indicated that polished
specimens were rougher than those cured against a Mylar strip. Wet polishing
created greater surface roughness than dry polishing. CONCLUSIONS: RMGIs rather
than conventional glass ionomers should be used in Class V cavity sites to allow
immediate finishing and to reduce the incidence of microleakage. Dry finishing of
RMGIs with abrasive disks is recommended because it produces a smoother surface
and does not contribute to microleakage. However, wet finishing of conventional
glass ionomers is still recommended to avoid desiccation.
PMID- 10785314
TI - Connectance in Sorghum development: beyond the genotype-phenotype duality.
AB - Connectance, the level of linkage between organs, was measured in different lines
of Sorghum bicolor during their reproductive development. It was compared with
expression of characters, their level of variability and their heritability. A
negative relationship is observed between connectance and heritability. Further
results indicate that connectance does not simply introduce a noise factor in
expression of a pre-existing information, but that it is directly involved in
phenotypic expression and plasticity. Connectance appears as partly determined by
the nature and dynamics of the network of relationships. It is concluded that the
phenotype is not restricted to the deterministic expression of a pre-existing
program, the genotype. Morphogenesis also involves another dimension, self
organized, which confers reliability, stability and adaptability to the
developmental processes. The complex interactions between these two dimensions
and their evolutionary consequences are discussed.
PMID- 10785315
TI - Three-dimensional architectures grown by simple 'stigmergic' agents.
AB - A simple model of multi-agent three-dimensional construction is presented. The
properties of this model are investigated. Based on these properties, a fitness
function is defined to characterize the structured patterns that can be generated
by the model. The fitness function assigns a value to each pattern. The choice of
the fitness function is validated by the fact that human observers tend to view
patterns with high (resp. low) fitness as structured (resp. unstructured). A
genetic algorithm based on this fitness function is used to explore the space of
possible patterns. The genetic algorithm is able to make use of sub-modules of
existing patterns and recombine them to produce novel patterns, but strong
epistatic interactions among genes make the fitness landscape rugged and prevent
more complex patterns from being produced.
PMID- 10785316
TI - Autonomous choice in the learning process of a turtle Chinemys reevesii.
AB - We studied animal's learning of spatial discrimination in an experimental
environment. Turtles, Chinemys reevesii, were employed for the study. We focused
on two independent aspects: (1) turtle's success rate in the task, which is the
most common criterion to estimate the ability of the animals, and (2) the
statistical properties of the time interval of the task, which is independent on
the spatial criterion. For a statistical analysis, we employed the scheme of
power law distributions which was recently used to estimate animal behaviors in
relation to the idea of the fractal. We addressed the basic problem of whether
these two criteria, or any other criteria for this matter, could or could not
exclude an observer who studies the animal behavior. To demonstrate
inseparability of an observer and the object, we conducted three different
learning experiments: (1) complete spatial discrimination, (2) incomplete spatial
discrimination, (3) another, different, complete discrimination, in this order.
The incomplete one was taken to mean incomplete only for an observer. Our
experiments reveal that the same result (success rate) was perceived differently
by the animal if the attitude of the observer to the experiments differed. This
observation comes to suggest that the notion of autonomous choice on the part of
an animal is contingent upon the inseparability between an observer and the
object.
PMID- 10785317
TI - Studies into abstract properties of individuals. IV. Emergence In different aged
needle primordia of Douglas fir.
AB - Young, middle aged and older Douglas fir needle primordia, as determined by
distance from the apical meristem, were measured and analyzed to compare levels
and patterns of emergence related to development time. Emergence was seen in the
differently aged needle primordia, generally most noticeable in the oldest and
the least apparent in the youngest. There was also a negative relationship
between variation in size and degree of emergence, and a positive one with
variation in organization. The increasing level of emergence that appears with
age can be related to the continual expression of information and the concomitant
increase in complexity that marks ontogeny and is the result of diverging
developmental trajectories. The histogenetic events seen in ontogeny can be
interpreted as 'clocks' generating local time through the interactions among
cells and tissues that make up the needle primordia. Emergent properties are
manifested through the local events that mark ontogeny, and also through the
expression of phylogenetic information, or the local expression of global
(historical) levels of organization.
PMID- 10785318
TI - Summer school on bioinformatics: information systems and network analysis of gene
regulation and metabolism.
PMID- 10785319
TI - Classical swine fever. Proceedings of a symposium. Birmingham, England, July 9
10, 1998.
PMID- 10785320
TI - Introduction to classical swine fever: virus, disease and control policy.
AB - Classical swine fever virus is a spherical enveloped particle of about 40-60 nm
in diameter with a single stranded RNA genome of about 12,300 bases with positive
polarity, classified as a pestivirus within the family Flaviviridae. Natural
hosts are domestic and wild pigs. The virus causes one of the most severe
diseases in pigs world wide with grave economic consequences. The clinical
picture of classical swine fever is variable, depending on the age of the
affected animals and viral virulence. The virus is well characterised and
reliable laboratory diagnostic procedures are available. In many parts of the
world live attenuated vaccines are being used as a safe and efficient
prophylactic tool. However, in EU Member States and several other countries
vaccination is prohibited and CSF is controlled by a strict stamping out policy.
In order to overcome the disadvantages of conventional vaccination inactivated
marker vaccines have been developed that enable the distinction between
vaccinated and infected animals. Whether these vaccines will be accepted as an
additional tool in the framework of the stamping out policy is not yet decided.
PMID- 10785321
TI - Classical swine fever: the global situation.
AB - A historical and current perspective is given of classical swine fever and its
impact on pig production in different regions of the world. Data were obtained
from a variety of sources including returns to the Office International des
Epizooties, official government reports, other published material and local
information through personal contacts. The disease has been recognized for about
170 years and efforts to control it by official intervention began in the
nineteenth century. Despite this it remains a lingering problem in many parts of
the world where it has both, an economic impact on swine production and a
constraining effect on trade due to the measures necessary to prevent spread.
PMID- 10785322
TI - Incidence and control of CSF in wild boar in Europe.
AB - The possibility that Classical swine fever (CSF) persists in a wild boar
population has been shown in some areas of France, Germany and Italy in recent
years. Availability of susceptible animals and frequency of infectious contacts
are major variables influencing disease evolution. In the European Union (EU)
measures to control CSF in the wild boar are enforced in the framework of Council
Directive 80/217/EEC, including eradication plans that must be enforced taking
account of the local epidemiological situation. Oral vaccination experiments are
being carried out in Germany, which have not led to final conclusions concerning
the efficacy of vaccination in eradicating disease.
PMID- 10785323
TI - Structure and presentation of a World Wide Web database of CSF virus isolates
held at the EU reference laboratory.
AB - A computerized database was generated with the epidemiological data of more than
600 CSF virus strains and isolates kept in the EU Reference Laboratory for
Classical Swine Fever in Hanover. In addition, as sequence data from defined
regions of the genome are increasingly being used for genetic typing of new
isolates and are thus being published, it was decided to integrate them into the
database. In order to make the epidemiological and the sequence data available to
other laboratories through the World Wide Web, a searchable web interface was
programmed, which can be accessed using an Internet browser like Netscape or
Internet Explorer. The possibility to exchange data via the web has the potential
to increase our knowledge concerning genetic and epidemiological links between
outbreaks worldwide.
PMID- 10785324
TI - Genetic typing of classical swine fever virus.
AB - Three regions of the classical swine fever virus (CSFV) genome that have been
widely sequenced were compared with respect to their ability to discriminate
between isolates and to segregate viruses into genetic groups. Sequence data-sets
were assembled for 55 CSFVs comprising 150 nucleotides of the 5' non-translated
region, 190 nucleotides of the E2 envelope glycoprotein gene and 409 nucleotides
of the NS5B polymerase gene. Phylogenetic analysis of each data-set revealed
similar groups and subgroups. For closely related viruses, the more variable or
larger data-sets gave better discrimination, and the most reliable classification
was obtained with sequence data from the NS5B region. No evidence was found for
intertypic recombination between CSFVs. A larger data-set was also analysed
comprising 190 nucleotides of E2 sequence from 100 CSFVs from different parts of
the world, in order to assess the extent and global distribution of CSFV
diversity. Additional groups of CSFV are evident from Asia and the nomenclature
of Lowings et al. (1996) [Lowings, P., Ibata, G., Needham, J., Paton, D., 1996.
J. Gen. Virol. 77, 1311-1321] needs to be updated to accommodate these. A
tentative assignment, adapting rather than overturning the previous nomenclature
divides CSF viruses into three groups with three or four subgroups: 1.1, 1.2,
1.3; 2.1, 2.2, 2.3; 3.1, 3.2, 3.3, 3.4. The expanding data-base of CSFV sequences
should improve the prospects of disease tracing in the future, and provide a
basis for a standardised approach to ensure that results from different
laboratories are comparable.
PMID- 10785325
TI - Classical swine fever virus: a ring test to evaluate RT-PCR detection methods.
AB - Six laboratories participated in an exercise to compare the sensitivity and
specificity of RT-PCR tests for the detection of classical swine fever virus
(CSFV). Two sets of coded samples were prepared by serial dilution of positive
samples and then distributed to each of the laboratories. One set comprised 34
samples of random primed cDNA. These had been synthesised from viral RNA
representative of seven different genetic subtypes of CSFV. The other set
comprised 40 clinical samples containing tonsil, spleen, whole blood or serum
from a pig that had been experimentally infected with CSFV. Each laboratory
tested the samples using one or more PCR/RT-PCR tests that they were accustomed
to using. The methods and results of the laboratories were compared with one
another. The RT-PCR results obtained from testing the clinical samples were also
compared with those obtained by virus isolation and antigen ELISA.ELISA. Both RT
PCR and RT-nested PCR appeared to give some false positive results. Several of
the PCR tests appear suitable in terms of specificity and sensitivity. Further
trials are necessary to compare results when the same test is performed by
different laboratories, and to show that improved control procedures can
eliminate problems due to false positive reactions.A limited comparison of
extraction and reverse transcription procedures showed similar results in each of
three participating laboratories, even though the methods were not standardised.
PMID- 10785326
TI - Survival and inactivation of classical swine fever virus.
AB - Classical swine fever virus, like many enveloped viruses, may be regarded as
moderately fragile. It shows a short but variable survival time in the
environment, depending on physical conditions, but may remain viable for
prolonged periods in favourable circumstances as found, for example, in stored
meat. Published information is reviewed on the survival time of the virus under a
variety of physical and chemical conditions, including the variable influence of
environmental factors. The principles of virus inactivation by heat, pH or
chemicals are discussed, with a consideration of the principles of containment
for laboratories working with the virus.
PMID- 10785327
TI - The 1997-1998 epidemic of classical swine fever in the Netherlands.
AB - In 1997, the pig husbandry in the Netherlands was struck by a severe epidemic of
classical swine fever (CSF). During this epidemic 429 CSF-infected herds were
depopulated and approximately 1300 herds were slaughtered pre-emptively. In
addition millions of pigs of herds not CSF-infected were killed for welfare
reasons (over crowding or overweight). In this paper, we describe the course of
the epidemic and the measures that were taken to control it. The first outbreak
was detected on 4 February 1997 in the pig dense south-eastern part of the
Netherlands. We estimate that CSF virus (CSFV) had already been present in the
country by that time for 5-7 weeks and that the virus had been introduced into
approximately 39 herds before the eradication campaign started. This campaign
consisted of stamping-out infected herds, movement restrictions and efforts to
diagnose infected herds as soon as possible. However, despite these measures the
rate at which new outbreaks were detected continued to rise. The epidemic faded
out only upon the implementation of additional measures such as rapid pre-emptive
slaughter of herds in contact with or located near infected herds, increased
hygienic measures, biweekly screening of all herds by veterinary practitioners,
and reduction of the transportation movements for welfare reasons. The last
infected herd was depopulated on 6 March 1998.
PMID- 10785328
TI - Laboratory experience during the classical swine fever virus epizootic in the
Netherlands in 1997-1998.
AB - From February 1997 till May 1998 the national reference laboratory for classical
swine fever (CSF) in the Netherlands was confronted with millions of samples
taken from pigs during an outbreak of CSF in a pig dense region. In a limited
period major logistic problems needed to be solved regarding the processing of
samples and information at the laboratory facilities. In total over 2.3 million
samples were examined by different CSF diagnostic methods. The majority
(approximately 2.1 million) of these samples were blood samples which were tested
for CSF serum antibody in a semi-automated ELISA. Approximately 166,000 samples
were examined for the presence of CSF virus or viral antigen. Automated
preparation and testing of blood samples for CSF serum antibody, the obligatory
identification and registration system of pig holdings and the computerised
laboratory management system made it possible to process the huge amount of
samples and information presented in a limited period. The majority of the test
results was sent to the veterinary authorities via e-mail or a computerised fax
system. Of the 429 outbreaks 82% were detected via a direct immunofluorescence
technique performed on cryostat sections of the tonsil. The sampling of
clinically suspected pigs ('guided' sampling) for this diagnostic method provided
rapid positive and negative results and thus played a paramount role during the
eradication campaign. Serological surveys identified 13.5% of the infected pig
holdings: such surveys proved very effective in the screening of holdings which
were subjected to restrictions (protection or surveillance zones) for many
months. Virus isolation performed on different types of samples detected 4. 5% of
the infected pig holdings. In conclusion, analysis of data collected in the
laboratory and epidemiological analysis should result in an improved eradication
plan for the future control of outbreaks of CSF in the Netherlands supported by
optimised CSF diagnostic methods.
PMID- 10785329
TI - Development of a classical swine fever subunit marker vaccine and companion
diagnostic test.
AB - The development of a classical swine fever (CSF) subunit marker vaccine, based on
viral envelope glycoprotein E2, and a companion diagnostic test, based on a
second viral envelope glycoprotein E(RNS), will be described. Important
properties of the vaccine, such as onset and duration of immunity, and prevention
of horizontal and vertical transmission of virus were evaluated. A single dose of
the vaccine protected pigs against clinical signs of CSF, following intranasal
challenge with 100LD(50) of virulent classical swine fever virus (CSFV) at 2
weeks after vaccination. However, challenge virus transmission to unvaccinated
sentinels was not always completely inhibited at this time point. From 3 weeks up
to 6 months after vaccination, pigs were protected against clinical signs of CSF,
and no longer transmitted challenge virus to unvaccinated sentinels. In contrast,
unvaccinated control pigs died within 2 weeks after challenge. We also evaluated
transmission of challenge virus in a setup enabling determination of the
reproduction ratio (R value) of the virus. In such an experiment, transmission of
challenge virus is determined in a fully vaccinated population at different time
points after vaccination. Pigs challenged at 1 week after immunization died of
CSF, whereas the vaccinated sentinels became infected, seroconverted for E(RNS)
antibodies, but survived. At 2 weeks after vaccination, the challenged pigs
seroconverted for E(RNS) antibodies, but none of the vaccinated sentinels did.
Thus, at 1 week after vaccination, R1, and at 2 weeks, R=0, implying no control
or control of an outbreak, respectively. Vertical transmission of CSFV to the
immune-incompetent fetus may lead to the birth of highly viraemic, persistently
infected piglets which are one of the major sources of virus spread. Protection
against transplacental transmission of CSFV in vaccinated sows was, therefore,
tested in once and twice vaccinated sows. Only one out of nine once-vaccinated
sows transmitted challenge virus to the fetus, whereas none of the nine twice
vaccinated sows did. Finally, our data show that the E(RNS) test detects CSFV
specific antibodies in vaccinated or unvaccinated pigs as early as 14 days after
infection with a virulent CSF strain. This indicates that the E2 vaccine and
companion test fully comply with the marker vaccine concept. This concept implies
the possibility of detecting infected animals within a vaccinated population.
PMID- 10785330
TI - Economic aspects of the control of classical swine fever outbreaks in the
European Union.
AB - A framework for assessing the economic impact of classical swine fever (CSF) is
presented, including an analysis of direct and indirect costs. Direct costs are
divided into calculated costs, expenditure on control measures (payable costs)
and costs due to financial transfers. The economic impact of current control
strategies is described using practical examples. In most cases, the largest part
of the direct costs is associated with transport standstill measures, of which
approximately 45% are calculated costs. Alternative strategies, still based on
non-vaccination offer a potential for reducing these costs. Various economic
aspects of emergency vaccination are described using as an example, a
hypothetical optimistic CSF case. In order to explore the impact of applying
emergency vaccination using marker vaccines, additional research is required
using simulation modelling. This research should include an assessment of risk
and uncertainty with respect to calculating the epidemiological impact and the
direct costs.
PMID- 10785331
TI - Oral immunisation of wild boar against classical swine fever: evaluation of the
first field study in Germany.
AB - The effectiveness of oral immunisation of wild boar against classical swine fever
(CSF) was studied in a field trial in Lower Saxony for two years, from 1993 to
1995. This field study was performed in an area of ca. 270 km(2)50% of young
boars did not feed on vaccine baits nor become immunised. Therefore, an intensive
hunting of this age group is a necessary adjunct to the use of oral vaccination.
After the third immunisation period, no virus was detected in the areas where
oral immunisation took place.
PMID- 10785332
TI - Epidemiology of HIV infection in the newborn.
AB - Vertical transmission of HIV infection can take place in utero, during delivery
and postnatally through breastfeeding, with about three-quarters of infections
occurring around the time of delivery in non-breastfeeding populations. In
Europe, in the absence of specific interventions, the vertical transmission rate
was 15-20%. High maternal load is the major risk factor for both intra-uterine
and intra-partum mother-to-child transmission. Prematurity is the most common
adverse neonatal outcome associated with maternal HIV infection. Earlier
diagnosis of paediatric HIV infection than previously available is now possible
with virological tests, particularly HIV DNA polymerase chain reaction. An
estimated one fifth of infected children will have been diagnosed with AIDS or
have died by 12 months of age, rising to a third by 6 years of age. Surgical and
therapeutic interventions are effective in reducing vertical transmission risk,
in addition to the avoidance of breastfeeding. Caesarean section delivery before
labour and before rupture of membranes approximately halves the risk of
transmission, while prophylactic zidovudine therapy according to the ACTG076
regimen reduces transmission by up to two-thirds, transmission is reduced even
further with both interventions. Trials of short-course zidovudine regimens show
their effectiveness in reducing vertical transmission, in breastfeeding and non
breastfeeding populations. Nevirapine has been shown to be significantly more
effective than short course zidovudine regimens in breastfeeding populations, but
is still under evaluation in non-breastfeeding populations additionally receiving
routine anti-retroviral prophylaxis. Reports of a small number of serious adverse
events in uninfected children exposed in utero or neonatally to antiretroviral
therapy need further investigation. Trials of vitamin A supplementation to reduce
vertical transmission have had negative results, while the effectiveness of
vaginal lavage and passive immune therapy in reducing vertical transmission
remains uncertain.
PMID- 10785333
TI - Lower alkaline phosphatase activity and occurrence of an abnormal hybrid
intestinal/tissue non-specific isoform in Down's syndrome amniotic fluids.
AB - Quantitative and qualitative analysis of alkaline phosphatases (AP) was performed
on amniotic fluid in 59 normal pregnancies and 14 Down's syndrome (DS)
pregnancies at 16, 18 and 19 weeks of gestation. In DS cases, intestinal and
placental isoenzyme levels were significantly reduced (P<0.001) and the AP
electrophoretic pattern was seen to be modified on polyacrylamide gel
electrophoresis. A unique component was detected. After extraction and
purification of the abnormal isoenzyme, peptide fragments obtained after cyanogen
bromide cleavage indicated a hybrid heterodimeric AP composed of intestinal and
tissue non-specific subunits, as evaluated by SDS polyacrylamide gel
electrophoresis.
PMID- 10785335
TI - Simplified screening for organic acidemia using GC/MS and dried urine filter
paper: a study on neonatal mass screening.
AB - A simplified method for organic acidemia screening using GC/MS, the urease/direct
method, is now available. To establish a practical screening system for organic
acidemias, we studied the usefulness of dried urine filter paper (filter paper
urine) and the application of a personal computer-based system of automated
metabolic profiling and interpretation (automated system) that we earlier
developed. In a comparison of filter paper urine with liquid urine, creatinine
levels ranging from 4.6 to 122.5 mg/dl, showed an excellent correlation
(r=0.9554), when the volumes of blotted urine and distilled water soaked were the
same. Recovery of all 17 compounds except for citrate was similar between liquid
and filter paper urine. CV values of 22 compounds tested ranged from 5.5 to 22.4%
in the liquid urine, and from 7.7 to 29.8% in the filter paper urine. The CV
values in stable isotope dilution analysis were much smaller in all nine
compounds tested. As to the stability of compounds, the percentage changes to
values at day 0 were within about +/-25% on day 28. We compiled GC/MS data,
including methylene unit values, quantifying and confirming ions of 163 different
organic acids and others, to use the automated system. We analyzed specimens from
55 patients with 17 different metabolic disorders. In 54 of the 55 specimens, the
correct diagnosis was successfully indicated. Neonatal mass screening for organic
acidemias warrants ongoing attention using this simplified method and filter
paper urine.
PMID- 10785334
TI - The distribution of receptors for the pro-inflammatory cytokines interleukin (IL)
6 and IL-8 in the developing human fetus.
AB - Interleukin-6 receptor alpha (IL-6R) and interleukin-8 receptor (IL-8RB) are
widely expressed in adult human and murine tissues. Little is known about the
expression of these receptors and the function of their ligands in the developing
human fetus. OBJECTIVES: To determine the tissue distribution and cellular
expression of IL-6R and IL-8RB in the developing human fetus. METHODS: Reverse
transcription-PCR and immunohistochemical staining were performed on brain,
spinal cord, eye, heart, lung, liver, spleen, adrenal, kidney, intestine, and
placenta from fetuses of 8 and 16+/-2 weeks post-conception. RESULTS: IL-6R and
IL-8RB mRNA were detected in all tissues tested at both time points.
Immunoreactivity to anti-IL-6R antibody was present on neurons, and in neuropil
of the brain, as well as in bone marrow, bronchi, hepatocytes, zona glomerulosa
of the adrenal, glomerular cells in kidney, spleen, and placental trophoblasts.
Cell-specific expression for IL-8RB in the central nervous system was localized
to specific groups of neurons and astrocytes in the brain and spinal cord,
including the neural retina. In somatic organs IL-8RB was detected in bone
marrow, myocardiocytes, bronchiolar epithelial cells, hepatocytes, cells of the
zona glomerulosa and the zona fasciculata of the adrenal, the collecting system
of the kidney, enterocytes of the bowel and in placental cells. CONCLUSION: The
widespread expression of these cytokine receptors suggests a nonhematopoietic
role for their ligand in the developing fetus.
PMID- 10785336
TI - Dynamic changes in the middle cerebral artery perfusion in normal full-term human
fetuses in relation to the timing of behavioral state.
AB - Our aim is to evaluate serial changes in normal full-term fetal cerebral
circulation according to the behavioral states. Flow velocity waveforms in the
middle cerebral artery and fetal heart rate (FHR) were well recorded in ten of 19
cases by pulsed Doppler ultrasonography and actocardiography over 45 min,
respectively. Behavioral states were classified as resting or active phase by FHR
patterns. Resistance indices (RIs) were calculated every 5 s as an average of two
consecutive waveforms, and median RI was chosen in each 2-min segment. In order
to evaluate changes in median RI from active-to-resting transition to resting-to
active one statistically, differences in RI between two 2-min segments were
examined using Mann-Whitney U-test. As a result, median RI was decreased to the
minimum one in the active-to-resting transition for 12 min in all cases:
significant decrease to the 2-min segment with the minimum one (P<0.01). Various
types of increase to the maximum median RI during resting phase followed the
minimum one: significant increase from the 2-min segment with the minimum one to
that with the maximum one in all cases (P<0.001 in eight cases, P<0.01 in two
cases). Thereafter, median RI was decreased from the end of resting phase in the
resting-to-active transition for 12 min in all cases: significant decrease from
the last 2-min segment of resting phase in all cases (P<0.01). We reveal that
fetal cerebral circulation changes dynamically in relation to the timing in each
behavioral state.
PMID- 10785337
TI - Detectable interleukin-10 and interleukin-8 in bronchoalveolar lavage fluid from
preterm infants ventilated for respiratory distress syndrome
PMID- 10785338
TI - Effect of postnatal age and beta(3)-adrenergic agonist (Zeneca D7114)
administration on uncoupling protein-1 abundance in the lamb
PMID- 10785339
TI - Effect of fetal number on prolactin receptor abundance in perirenal adipose
tissue of neonatal lambs
PMID- 10785340
TI - The cognitive processes of doctors and nurses in the interpretation of
physiological monitoring data in the neonate
PMID- 10785341
TI - Methodological issues relating to surfactant protein a measurement in
bronchoalveolar lavage fluid from preterm infants with respiratory distress
syndrome
PMID- 10785343
TI - Investigation of the role of lung liquid in the pathogenesis of lung disease in
the preterm infant using magnetic resonance imaging
PMID- 10785342
TI - Induction of retinopathy in newborn rats using a clinically relevant oxygen
profile
PMID- 10785344
TI - W.D. Hamilton (1936-2000).
PMID- 10785345
TI - Hormonal correlates of paternal responsiveness in new and expectant fathers.
AB - Little is known about the physiological and behavioral changes that expectant
fathers undergo prior to the birth of their babies. We measured hormone
concentrations and responses to infant stimuli in expectant and new fathers
living with their partners to determine whether men can experience changes that
parallel the dramatic shifts seen in pregnant women. We obtained two blood
samples from couples at one of four times before or after the birth of their
babies. After the first sample, the couples were exposed to auditory, visual, and
olfactory cues from newborn infants (test of situational reactivity). Men and
women had similar stage-specific differences in hormone levels, including higher
concentrations of prolactin and cortisol in the period just before the births and
lower postnatal concentrations of sex steroids (testosterone or estradiol). Men
with more pregnancy (couvade) symptoms and men who were most affected by the
infant reactivity test had higher prolactin levels and greater post-test
reduction in testosterone. Hormone concentrations were correlated between
partners. This pattern of hormonal change in men and other paternal mammals, and
its absence in nonpaternal species, suggests that hormones may play a role in
priming males to provide care for young.
PMID- 10785346
TI - Does paternal uncertainty explain discriminative grandparental solicitude? A
cross-cultural study in Greece and Germany.
AB - Recent research on kin investment as a reproductive strategy is based on the idea
that differences in grandparental caregiving directly reflect degrees of
differential grandpaternal versus grandmaternal certainty. In a cross-cultural
study in Greece and Germany, 544 subjects (318 Greeks, 208 Germans, 18 of other
origins) were asked for an assessment of their grandparents' (GPs') caregiving.
In Germany and urban Greece (modern Western societies), the maternal GPs were
rated as more intensive caregivers than the paternal GPs, but this was not the
case in rural Greece, where paternal GPs provided more care. However, in all
groups, grandmothers were more caring than grandfathers. Thus, contrary to
previous theory and research, these two effects must be clearly distinguished,
and may be explained by (1) more intense female caregiving in humans (as in other
viviparous mammals) and (2) a socially engendered favoring of maternal relatives
in Western industrial societies as opposed to the favoring of paternal GPs seen
in the patrilateral culture of rural Greece.
PMID- 10785347
TI - The jus primae noctis as a male power display. A review of historic sources with
evolutionary interpretation.
AB - The jus primae noctis was, in the European late medieval context, a widespread
popular belief in an ancient privilege of the lord of the manor to share the
wedding bed with his peasants' brides. Symbolic gestures, reflecting this belief,
were developed by the lords and used as humiliating signs of superiority over the
dependent peasants in the fifteenth century, a time of diminishing status
differences. Actual intercourse in the exercise of the alleged right is difficult
to prove, and there is no hard evidence to suggest that it ever actually
happened. However, the symbolic gestures can be best interpreted as a male power
display, with a basis in the psychology of coercive social dominance, male
competition, and male desire for sexual variety. Several non-European cultures
have accounts of a similar custom related to a young girl's first sexual
intercourse: ritual defloration by chiefs, priests, or strangers. This non
European custom differs from the jus primae noctis in its proximate details, but
seems from an ultimate point of view, to be in conformity with the European
evidence. In this article the origin, development, and relationship of both
customs are discussed and interpreted in light of recent evolutionary studies of
primate behavior and sexual psychology.
PMID- 10785348
TI - Sibling solidarity in a polygamous community in the USA. unpacking inclusive
fitness.
AB - This pilot study explores the degree of solidarity felt between full and half
siblings who are raised in a Mormon Fundamentalist polygamous community. The
community under study is unique in that, at the level of official culture, it
actively promotes full and half sibling solidarity through an ethos that strives
to downplay genetic differences in favor of a harmonious family living together
in one household. This community is an ideal cultural setting in which to examine
the suitability of inclusive fitness theory for understanding the factors that
promote family cohesion, sibling solidarity, and rivalry. Our main question
becomes: is the degree of sibling solidarity a manifestation of genetic closeness
or a natural byproduct of emotional closeness that arises from being raised
together? We found evidence for more solidarity between full siblings than
between half siblings. Our data suggest that, despite the force of religious
ideals, and notwithstanding the continued close physical proximity of half
siblings in the polygamous family, there is a pronounced clustering of feeling
and affection in the polygamous family that is consistent with inclusive fitness
theory.
PMID- 10785349
TI - Do attitude and area influence health? A multilevel approach to health
inequalities.
AB - This paper demonstrates an area effect on health and suggests improvements in
research practice for work in this field. We use an area classification which can
be related clearly to factors that influence the health of individuals and take
account of people's differing propensities to draw influence from their area.
Multilevel analysis demonstrates that the degree of deindustrialisation which an
area experienced in Britain, in the 1980s, has an independent association with
the health of resident individuals. A significant relationship between a person's
attitude to their community and their health is shown to be independent of
individual and area characteristics. We conclude that both individual and area
characteristics influence health.
PMID- 10785350
TI - "Happy Meals" in the Starship Enterprise: interpreting a moral geography of
health care consumption.
AB - This paper extends earlier explorations of the use of metaphor in the marketing
of the Starship Children's Hospital in Auckland, New Zealand, by examining
controversy surrounding the opening of an in-hospital McDonalds fast-food outlet.
The golden arches have become a key element of many children's urban geographies
and a potent symbol of the corporate colonisation of the New Zealand landscape.
In 1997 a minor moral panic ensued when a proposal was unveiled to open a
McDonald's restaurant within the Starship. Data collected from media coverage,
advertising and interviews with hospital management are analysed to interpret
competing discourses around the issue of fast food within a health care setting.
We contend that the introduction of a McDonald's franchise has become the
hospital's ultimate placial icon, adding ambivalence to the moral geography of
health care consumption. We conclude that arguments concerning the unhealthy
nature of McDonald's food obscure deeper discourses surrounding the unpalatable
character of the health reforms, and a perceived 'Americanisation' of health care
in New Zealand.
PMID- 10785351
TI - Contours of coping: mapping the subject world of long-term illness.
AB - Medical geography has evolved from studying 'dots on maps to embodied subjects'.
Involving the acknowledgement of new territories and identities, this has taken
place against a backdrop of wider shifts in understanding health and illness.
This paper suggests geographers are well placed to develop their existing skills
of spatial exploration in order to map out these new territories. Whilst 'the
map' has recently suffered from bad press, as a selective, misleading
representation, this paper demonstrates it can be resurrected as a less sinister
tool to aid our understanding of situated health experiences.
PMID- 10785352
TI - Preferred drinking locations of Scottish adolescents.
AB - A sample of Scottish schoolchildren (N=1240) were asked a series of questions
about their consumption of alcoholic beverages. Those who had consumed alcohol
were asked about the circumstances of their last drinking occasion. That is, what
alcoholic drink(s) they consumed, how they obtained this alcohol and where they
were when they drank it. This was done with the intention of quantifying the
extent of under-age drinking in different settings. The results presented in this
paper indicate a continuum of drinking styles between what might be regarded as
low-risk and high-risk circumstances. At one extreme, much drinking tended to
take place within the family home, usually under parental supervision. At the
opposite extreme, other alcohol consumption took place in a variety of public or
'hidden' outdoor locations. Consumption in these latter location types more often
resulted in intoxication. Also, more dangerous, high alcohol, large volume
beverages (e.g. white cider) tended to be consumed in more risky locations. The
implications of these findings are discussed in terms of the potential harm and
delinquency that can be associated with adolescent drinking.
PMID- 10785353
TI - Smokers at risk: implications of an institutionally bordered risk-reduced
environment.
AB - The paper draws on an evaluation of a workplace smoking policy implemented at
Edinburgh University to examine some implications for smokers at work. While the
objective of institutional risk-reduced environments is to diminish or control
the level of risk behaviour within, they may have unanticipated implications for
participants who are unwilling or unable to adapt. Data presented in the paper
suggest that the University smoking policy carried its own risk. That is, the
policy did not impact equally upon all members of the organisation but was
experienced as divisive in contributing towards and sustaining social
inequalities among staff.
PMID- 10785354
TI - Hans Castorp's journey-to-knowledge of disease and health in Thomas Mann's The
Magic Mountain.
AB - The paper examines Thomas Mann's novel, The Magic Mountain, to show how
imaginative literature can enhance our understanding of health in place. The
story centers on the experiences of Hans Castorp, a young bourgeois German, at a
tuberculosis sanatorium in the Swiss Alps. Three themes are examined: (1) how
knowledge about illness and health, death and life, is gained; (2) how knowledge
is arrived at through a dialectical process which reconciles seeming opposites;
and(3) how new knowledge is gained through making transitions. Lessons for health
geography are drawn from analysis of the three themes.
PMID- 10785355
TI - Mitogen-activated protein kinase kinase 4 (MKK4).
AB - The Mitogen-Activated Protein Kinase Kinase 4 (MKK4), a member of the MAP kinase
kinase family, directly phosphorylates and activates the c-Jun NH2-terminal
kinases (JNK), in response to cellular stresses and proinflammatory cytokines.
JNK is a member of the MAP kinase family and a key component of a stress
activated protein kinase signalling pathway. MKK4 mRNA is widely expressed in
adult mouse tissues, but is especially abundant in skeletal muscle and brain.
Mice lacking the MKK4 gene had abnormal hepatogenesis and died before embryonic
day 14. However cell lines lacking MKK4 have been obtained and these exhibited
defective activation of JNK and AP-1 dependent transcription activity in response
to some, but not all cellular stresses. Furthermore, T lymphocytes deficient in
MKK4 showed impaired IL-2 production following activation of the T cell receptor,
suggesting a key role of the MKK4/JNK pathway in inflammation. The mutation of
the MKK4 gene in some carcinomas indicates that it may also have a role as a
tumor suppressor. Control of the MKK4 activity and expression may provide novel
approaches to cancer or anti-inflammatory therapy.
PMID- 10785356
TI - Erythrocytic differentiation and glyceraldehyde-3-phosphate dehydrogenase
expression are regulated by protein phosphorylation and cAMP in HD3 cells.
AB - Utilisation of glucose undergoes a marked decline during erythroblastic
differentiation in the chicken. Concomitantly there is a reduction in the
expression of glucose transporter proteins and in the expression of the
glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAD). GAD activity
declines, after an initial rise, while the level of GAD mRNA decreases rapidly
after induction of differentiation. We have employed the temperature-sensitive
chicken erythroblast cell line HD3 that differentiates to the erythrocyte
phenotype at 42 degrees C in the presence of inducers (hemin and butyric acid).
The role of tyrosine and serine/threonine phosphorylation pathways were evaluated
with the phosphatase inhibitors sodium vanadate and okadaic acid, respectively.
In the presence of phosphatase inhibitors, HD3 cells underwent differentiation
and increased their synthesis of hemoglobin which is a marker protein for red
blood cells differentiation. The levels of both GAD mRNA and enzymatic activity
were increased by phosphatase inhibitors. The role of cAMP in differentiation was
also assessed. Differentiation of HD3 cells was associated with an increase in
cAMP. However the phosphodiesterase inhibitor IBMX was not a good inducer of
hemoglobin synthesis but did induce GAD mRNA and enzymatic activity. Together
these results suggest that multiple pathways (including serine/threonine
phosphorylation, tyrosine phosphorylation and elevated cAMP) are involved in the
regulation of erythroblastic differentiation, hemoglobin synthesis, GAD gene
expression and GAD activity in HD3 cells.
PMID- 10785357
TI - Ovine placental lactogen and ovine prolactin: partial proteolysis and
conformational stability.
AB - The high-resolution structure of ovine placental lactogen (oPL) and ovine
prolactin (oPRL), not yet established in detail, was probed by limited
proteolysis with the Glu-specific protease from Staphylococcus aureus V8. While
in hGH there were no cleavage sites inside of any of the four alpha-helices, the
analysis of the fragments obtained after partial proteolysis of oPL showed a site
of cleavage at the putative third helix, suggesting that this helix is partially
unwound at this point. The partial proteolysis of the rest of the molecule was
compatible with a similar folding pattern for oPL, hGH and pGH, on the basis of
the crystal structure of these last hormones. In the case of oPRL, proteolytic
cleavage occurred at Glu residues which would be located at the end of the first
helix and the beginning of the second in the hGH folding model, suggesting that
these helices are shorter in oPRL than in hGH. In order to gain further insight
on the folding of these molecules, circular dichroism and intrinsic fluorescence
measurements were used to examine the effect of denaturing conditions on oPL and
oPRL. After exposure to 6 M guanidine the unfolding of both proteins was
completely reversed upon elimination of the denaturing agent. In contrast,
exposure to pH 3.0 caused an irreversible decrease in the alpha-helical content
in both hormones, most striking for oPL, indicating that this hormone is less
stable than oPRL or hGH.
PMID- 10785358
TI - Artificial lipid-protein complexes accelerate cholesterol crystallisation in
model bile.
AB - Cholesterol gallstone disease is one of the major health problems in the world.
Substances which can affect the crystallisation of cholesterol from human bile
have been given considerable attention. Various substances (among them natural
lipid-protein complexes) have been tested for cholesterol crystallisation
promoting activity. Various artificial lipid-albumin complexes have been prepared
of which taurodeoxycholate-human serum albumin-calcium ions (TDC-HSA-Ca(2+)) had
the highest cholesterol crystallisation-promoting activity. This cholesterol
crystallisation-promoting activity is similar to that for the lipid-protein
complex isolated from native human bile [concanavalin A nonbinding fraction (con
A(-) fraction)]. Addition of cholesterol to the TDC-HSA-Ca(2+) complex further
increased the cholesterol crystallisation-promoting activity whereas the addition
of lecithin had an opposite effect. The interaction of individual components of
the TDC-HSA-Ca(2+) complex was followed using several methods. A new effect of
Ca(2+) ions (increase in the number of binding sites for bile salts) on the
interaction of TDC with HSA was found by equilibrium dialysis. Interaction of TDC
with albumin and Ca(2+) did not induce any modification of the secondary
structure of albumin. The results of fluorescence spectroscopy may indicate that
TDC is at least partially bound to not essentially fatty acid free HSA somehow
via admixtures, probably fatty acids. Difference absorption spectrum of the TDC
HSA-Ca(2+)-cholesterol complex was very similar to that of the "natural" lipid
protein complex (con A(-) fraction). From the three drugs with different albumin
binding characteristics, only sulphadimethoxin had an observable effect on the
cholesterol crystallisation-promoting activity. The action of the TDC-HSA-Ca(2+)
complex decreased significantly after the addition of sulphadimethoxin. The
addition of TDC modified the absorption spectrum of the sulphadimethoxin-HSA
Ca(2+) complex. It can be suggested that the complex of HSA with bile salts (TDC
mainly) and Ca(2+) forms a nucleation centre for cholesterol crystallisation in
bile.
PMID- 10785359
TI - Three-dimensional collagen matrices induce delayed but sustained activation of
gelatinase A in human endothelial cells via MT1-MMP.
AB - Gelatinase A, a member of the matrix metalloproteinase (MMP) family, plays an
important role during angiogenesis. It is constitutively expressed by human
endothelial cells as a latent enzyme and requires activation. Thrombin is the
only described physiological inducer of gelatinase A in human endothelial cells.
In this study, we investigated the mechanisms of gelatinase A activation by
another physiological inducer, collagen. Endothelial cells were cultured on
various ECM components for 24 h and the conditioned media were assessed for
gelatinase A activity using gelatin zymography. The results demonstrated that
type I collagen matrix specifically activates gelatinase A after 24 h in human
umbilical vein and 48 h in neonatal foreskin endothelial cells. In contrast,
thrombin activated gelatinase A after only 2 h. Activation by collagen was
sustained over long periods of time in culture (96 h). Unlike thrombin-induced
activation, collagen required active membrane type 1-MMP (MT1-MMP) on the
endothelial cell surface to activate gelatinase A. In addition, collagen-induced
activation of gelatinase A was inhibited by antibodies to the integrin receptor,
alpha(2)beta(1), but not alpha(3)beta(1). Our findings, that collagen can provide
long-term activation of gelatinase A are likely to be relevant to endothelial
cell invasion during angiogenesis.
PMID- 10785360
TI - 4E binding protein 1 expression is inversely correlated to the progression of
gastrointestinal cancers.
AB - Several components of the eukaryotic protein synthesis apparatus have been
associated with oncogenic transformation of cells. Overexpression of the
initiation factor eIF4E occurs in a variety of human tumours. The aim of this
study was to determine the level of expression and the phosphorylation state of
eIF4E and 4E-binding protein 1 (4E-BP1) in gastrointestinal cancer, and to
ascertain whether or not these factors can be used as diagnostic or prognostic
markers within this type of cancer. The eIF4E levels were significantly higher in
tumours compared with normal tissue (51. 5+/-4.4 vs 30.9+/-2.5 arbitrary units
(A.U.)/mg of protein, p<0.001). However, phosphorylated eIF4E did not change in
stomach cancers and decreased in colorectal cancers (67.1+/-1.2 vs 60.8+/-2.8%,
p<0.05). 4E-BP1 expression increased in most of the gastrointestinal cancers
studied. In addition, an inverse correlation between 4E-BP1 elevation and N and M
stages was found, showing significant higher elevation of 4E-BP1 in Node-negative
patients (11.21+/-5.74 vs 4. 03+/-2.36 n-fold, p<0.05) as well as in patients
without distant metastasis (8.41+/-3.29 vs 0.97+/-0.35 n-fold, p<0.05). These
results suggest that 4E-BP1 could function as a tumour suppressor. Moreover, the
data show a significant dephosphorylation of 4E-BP1 in gastrointestinal tumours
that correlated with an increase in the association of 4E-BP1 and eIF4E
indicating a lower availability to eIF4E to recruit to the ribosomes. Our results
support a possible role of 4E-BP1 as a prognostic factor in gastrointestinal
carcinoma.
PMID- 10785361
TI - Dynamic changes in small nuclear ribonucleoproteins of heat-stressed and
thermotolerant HeLa cells.
AB - Living organisms when subjected to various forms of environmental stress mount a
physiological response to survive the long- and short-term ill-effects of the
stress. The stress response may involve selective shut down of non-essential
metabolic activities and the repair of macromolecular damage resulting from the
stress. Messenger RNA splicing in cultured HeLa cells is one of the processes
inhibited by heat stress. Splicing is protected from such inhibition in stress
preconditioned cells that have acquired a tolerant state characterised by
increased cell survival and resistance to other environmental stresses. Stress
tolerant cells have heat shock proteins (HSPs) that had been induced by the
preconditioning process. To examine the biochemical changes induced by stress in
the splicing apparatus, we analysed the small nuclear ribonucleoprotein (snRNP)
particles associated with spliceosomes in normal, stressed, and stress tolerant
cells. We show that (a) the spliceosomal component U4/U5/U6 snRNP particle is
disassembled by heat stress into intermediates of splicing assembly, (b) prior
induction of stress tolerance protects the structural and functional integrity of
snRNPs if cells are subsequently exposed to a severe stress and (c) a novel 65
kDa protein is associated with small nuclear ribonucleoprotein particles in
stress tolerant cells.
PMID- 10785362
TI - Formation of homovanillic acid dimer by enzymatic or Fenton system - catalyzed
oxidation.
AB - Homovanillic acid is the most extensively employed reagent for the fluorometric
detection of peroxidase. However, the assays based on the determination of the
oxidation product of homovanillic acid do not allow a selective detection of the
enzyme, because chemical or physical factors can interfere with the fluorometric
determination. The aim of this work was to verify if other enzymatic or non
enzymatic systems might catalyze the homovanillic acid oxidation. The reaction
was investigated by spectrophotometric and fluorometric assays; HPLC analysis was
used to separate homovanillic acid from its oxidation product and to obtain
information on the oxidation process. The results obtained showed that soybean
lipoxygenase in the presence of hydrogen peroxide can oxidize homovanillic acid
with the formation, by an o,o'-biphenyl linkage, of the corresponding dimer as
the sole reaction product. The reaction followed Michaelis-Menten kinetics, for
both homovanillic acid and hydrogen peroxide. Other systems, such as cytochrome
c/H(2)O(2) and Fenton reagents, were also able to oxidize homovanillic acid to
its dimer. It can be affirmed that possible interference by other oxidative
systems - that could be present in the biological materials tested - should be
considered in assays of peroxidase activity based on the detection of the dimer
of homovanillic acid.
PMID- 10785363
TI - Natural allelic variation of duck erythrocyte histone H1b.
AB - In our previous work (J. Palyga, Genetic polymorphisms of histone H1. b in duck
erythrocytes. Hereditas 114, 85-89, 1991) we reported a genetic polymorphism of
duck erythrocyte histone H1.b. Here, we screened H1 preparations in a two
dimensional polyacrylamide gel to refine the distribution of allelic forms of
H1.b in fifteen duck populations. We have revealed that the frequency of H1.b
allelic variants was significantly different among many conservative and breeding
duck groups. While b(1) and b(3) were common in all populations screened, the
allele b(2), with a slightly lower apparent molecular weight, was confined mainly
to brown-feathered ducks (Khaki Campbell and Orpington) and descendent lines. The
C- and N-terminal peptides released upon cleavage with N-bromosuccinimide and
Staphylococcus aureus protease V8 from duck allelic histones H1. b2 and H1.b3,
respectively, migrated differently in the gel, probably as a result of potential
amino acid variation in a C-terminal domain.
PMID- 10785364
TI - Degradation of methoxysuccinyl-phe-leu-phe-7-amido-4-trifluoromethyl coumarin
(FLF) in cultured myotubes and HepG2 cells is proteasome- and calpain/calcium
dependent.
AB - During recent years, it has become increasingly clear that the ubiquitin
proteasome proteolytic pathway regulates intracellular protein degradation in
various physiological and pathophysiological conditions. Substrates specifically
degraded by the proteasome are important tools to assess the involvement of the
proteasome in cellular proteolysis. It was recently proposed that the membrane
permeable substrate methoxysuccinyl-phenylalanine-leucine-phenylalanine-7-amido-4
trifluoromethyl coumarin (FLF) is degraded specifically by the proteasome. The
role of other proteolytic pathways in the degradation of FLF, however, is not
fully understood. In the present study, we tested the role of different
proteolytic pathways in the degradation of FLF in cultured myotubes and HepG2
cells by treating the cells with inhibitors of lysosomal, calpain and proteasome
activity. In addition, we tested the hypothesis that insulin blocks proteasome
dependent degradation of FLF in myotubes and HepG2 cells. Results suggest that
degradation of FLF in both myotubes and HepG2 cells is regulated by proteasome
and calpain activity but not by lysosomal activity. Insulin inhibited proteasome
dependent but not calpain-dependent degradation of FLF in both myotubes and HepG2
cells. The results are important because they suggest that FLF degradation does
not specifically reflect proteasome activity.
PMID- 10785365
TI - The N-terminal portion of the main cytosolic loop mediates K+ sensitivity in the
retinal rod Na+/Ca2+-K+-exchanger.
AB - Two types of Na+/Ca2+-exchangers have been characterized in the literature: The
first is the cardiac, skeletal muscle and brain type, which exchanges 1 Ca2+ for
3 Na+, the second, found in retinal photosensor cells, transports 1 Ca2+ and 1 K+
in exchange for 4 Na+. The present work describes the properties of chimeric
constructs of the two exchanger types. Ca2+ gel overlay experiments have
identified a high affinity (Kd in the 1 microM range) Ca2+-binding domain between
Glu601 and Asp733 in the main cytosolic loop of the retinal protein, just after
transmembrane domain 5. Insertion of the retinal Ca2+-binding domain in the
cytosolic loop of the cardiac exchanger conferred K+-dependence to the Ca2+
uptake activity of the chimeric constructs expressed in HeLa cells. The apparent
Km of the K+ effect was about 1 mM. Experiments with C-terminally truncated
versions of the retinal insert indicated that the sequence between Leu643 and
Asp733 was critical in mediating K+ sensitivity of the recombinant chimeras.
Thus, the high affinity Ca2+-binding domain in the main cytosolic loop of the
retinal exchanger may regulate the activity of the retinal protein by binding
Ca2+, and by conferring to it K+ sensitivity.
PMID- 10785367
TI - Human oxytocin receptors in cholesterol-rich vs. cholesterol-poor microdomains of
the plasma membrane.
AB - We analyzed the properties of a G protein-coupled receptor localized in
cholesterol-poor vs. cholesterol-rich microdomains of the plasma membrane. For
this purpose, the human oxytocin receptor, which is very sensitive against
alterations of the membrane cholesterol level, was stably expressed in HEK293
cells. To calculate the total number of receptors independent of ligand binding
studies, the oxytocin receptor was tagged with an enhanced green fluorescent
protein (EGFP) which did not change the functional properties of the receptor.
Only 1% of the oxytocin receptors were present in cholesterol-rich detergent
insoluble domains. In contrast, employing a detergent-free fractionation scheme
that preserves the functional activity of the receptor, we detected 10-15% of the
receptors in cholesterol-rich low-density membranes and therein the high-affinity
state receptors were twofold enriched. In cholesterol-poor vs. cholesterol-rich
domains, high-affinity oxytocin receptors behaved similar with respect to their
agonist binding kinetics and GTP sensitivity. However, high-affinity oxytocin
receptors localized in cholesterol-rich low-density membranes showed a markedly
enhanced (t (1/2) approximately threefold) stability at 37 degrees C as compared
with the oxytocin receptors localized in the cholesterol-poor high-density
membranes. Addition of cholesterol to the high-density membranes fully protected
the oxytocin receptors against loss of function. The importance of cholesterol to
stabilize the oxytocin receptor was supported in experiments with solubilized
receptors. Cholesterol markedly delayed the inactivation of oxytocin receptors
solubilized with Chapso. In conclusion, the data of this report suggest that
functional properties of heptahelical receptor proteins could differ in
dependence of their localization in different membrane microdomains.
PMID- 10785366
TI - Characterization of three cloned and expressed 13-hydroperoxide lyase isoenzymes
from alfalfa with unusual N-terminal sequences and different enzyme kinetics.
AB - Three full-length cDNAs from alfalfa seedlings coding for hydroperoxide lyases
were cloned and expressed in Escherichia coli and characterized as cytochrome
P450 enzymes. The isoenzymes were specific for 13-hydroperoxy linoleic and
linolenic acids and did not use the 9-hydroperoxy isomers as substrates. Because
alfalfa contains both specificities, this indicates the presence of two different
types of hydroperoxide lyases, each specific for one kind of substrate. The
enzymes contain 480 amino acids (54 kDa) and contain an unusual, nonplastidic N
terminal sequence of 22 amino acids, which strongly reduces the enzyme activity.
The only known presequence of a hydroperoxide lyase (from Arabidopsis thaliana)
was considered to be a transit sequence. The reduced enzyme activity, however,
indicates that the hydroperoxide lyases with N-terminal extensions could be pro
enzymes. This hypothesis is supported by the fast release of hydroperoxide lyase
products by plants upon wounding. One of the isoenzymes showed a strongly
decreased Vmax and Km compared to the other two. Because this is probably due to
the substitution of Ser377 by Phe; the residue at position 377 seems to be
important. This is the first time that sufficient quantities of hydroperoxide
lyase have been obtained for characterization studies, by circumventing difficult
purification procedures and degradation of the enzyme. The high expression level,
easy purification, good stability and high specificity make these cloned
hydroperoxide lyases excellent tools to study the reaction mechanism and
structure. We postulate an integrated reaction mechanism, based on the known
chemistry of cytochrome P450 enzymes. This is the first mechanism that unifies
all observed features of hydroperoxide lyases.
PMID- 10785368
TI - Methyl-coenzyme M formation in methanogenic archaea. Involvement of zinc in
coenzyme M activation.
AB - Methyl-coenzyme M (2-methylthioethane sulfonate) is the key intermediate of
methane formation in methanogenic archaea. It is generated from coenzyme M (2
mercaptoethane sulfonate) in methyl transfer reactions catalyzed by proteins
containing zinc. Here, we report that, for methyltransferase MtaA from
Methanosarcina barkeri, the zinc is involved in coenzyme M activation. For the
experiments an inactive MtaA apoprotein was obtained by heterologous
overproduction in Escherichia coli grown in the presence of 2 mM EDTA. The
apoprotein was found to react with zinc or cobalt to the fully active holoenzyme.
Appoximately 1 mol of transition metal was bound per mol of protein. Upon
incubation of the holoenzyme with coenzyme M approximately 1 mol of proton was
released per mol of zinc or cobalt. Protons were not released upon incubation of
the apoprotein with coenzyme M or of the holoprotein with other thiol compounds
or with methyl-coenzyme M. The findings are interpreted as indicating that the
role of the transition metal in MtaA is to lower the microscopic pKa of the thiol
group of coenzyme M by coordination to the zinc, and thus to increase its
nucleophilicity for methyl group attack. The pKZn2+ of MtaA was re-determined and
found to be > 15 and not 9.6 as previously reported by us.
PMID- 10785369
TI - Monoclonal antibodies to vascular endothelial growth factor-D block its
interactions with both VEGF receptor-2 and VEGF receptor-3.
AB - Vascular endothelial growth factor-D (VEGF-D), the most recently discovered
mammalian member of the VEGF family, is an angiogenic protein that activates VEGF
receptor-2 (VEGFR-2/Flk1/KDR) and VEGFR-3 (Flt4). These receptor tyrosine
kinases, localized on vascular and lymphatic endothelial cells, signal for
angiogenesis and lymphangiogenesis. VEGF-D consists of a central receptor-binding
VEGF homology domain (VHD) and N-terminal and C-terminal propeptides that are
cleaved from the VHD to generate a mature, bioactive form consisting of dimers of
the VHD. Here we report characterization of mAbs raised to the VHD of human VEGF
D in order to generate VEGF-D antagonists. The mAbs bind the fully processed VHD
with high affinity and also bind unprocessed VEGF-D. We demonstrate, using
bioassays for the binding and cross-linking of VEGFR-2 and VEGFR-3 and biosensor
analysis with immobilized receptors, that one of the mAbs, designated VD1, is
able to compete potently with mature VEGF-D for binding to both VEGFR-2 and VEGFR
3 for binding to mature VEGF-D. This indicates that the binding epitopes on VEGF
D for these two receptors may be in close proximity. Furthermore, VD1 blocks the
mitogenic response of human microvascular endothelial cells to VEGF-D. The anti
(VEGF-D) mAbs raised to the bioactive region of this growth factor will be
powerful tools for analysis of the biological functions of VEGF-D.
PMID- 10785370
TI - The ionization of a buried glutamic acid is thermodynamically linked to the
stability of Leishmania mexicana triose phosphate isomerase.
AB - The amino acid sequence of Leishmania mexicana triose phosphate isomerase is
unique in having at position 65 a glutamic acid instead of a glutamine. The
stability properties of LmTIM and the E65Q mutant were investigated by pH and
guanidinium chloride-induced unfolding. The crystal structure of E65Q was
determined. Three important observations were made: (a) there are no structural
rearrangements as the result of the substitution; (b) the mutant is more stable
than the wild-type; and (c) the stability of the wild-type enzyme shows strong pH
dependence, which can be attributed to the ionization of Glu65. Burying of the
Glu65 side chain in the uncharged environment of the dimer interface results in a
shift in pKa of more than 3 units. The pH-dependent decrease in overall stability
is due to weakening of the monomer-monomer interactions (in the dimer). The E65Q
substitution causes an increase in stability as the result of the formation of an
additional hydrogen bond in each subunit (DeltaDeltaG degrees of 2 kcal.mol-1 per
monomer) and the elimination of a charged group in the dimer interface
(DeltaDeltaG degrees of at least 9 kcal.mol-1 per dimer). The computated shift in
pKa and the stability of the dimer calculated from the charge distribution in the
protein structure agree closely with the experimental results. The guanidinium
chloride dependence of the unfolding constant was smaller than expected from
studies involving monomeric model proteins. No intermediates could be identified
in the unfolding equilibrium by combining fluorescence and CD measurements. Study
of a stable monomeric triose phosphate isomerase variant confirmed that the
phenomenon persists in the monomer.
PMID- 10785372
TI - Characterization of the myo-inositol transport system in Trypanosoma cruzi.
AB - myo-inositol is a growth factor for mammalian cells as well as for the pathogenic
protozoa Trypanosoma cruzi. Most of the cell surface molecules in this organism
rely on myo-inositol as the biosynthetic precursor for phosphoinositides and
glycosylated phosphatidylinositols. The aim of this work was to investigate the
process of myo-inositol translocation across the parasite cell membrane. myo
Inositol uptake was concentration-dependent in the concentration range 0.1-10
microM with maximal transport obtained at 8 microM. Using sodium-free buffers,
where Na+ was replaced by choline or K+, myo-inositol uptake was inhibited by
50%. Furosemide, an inhibitor of the ouabain-insensitive Na+-ATPase, inhibited
the Na+-dependent and Na+-independent myo-inositol uptake by 68 and 33%,
respectively. In contrast, ouabain, an (Na++/K+) ATPase inhibitor, did not affect
transport. Part of the myo-inositol uptake is mediated by active transport as it
was inhibited when energy metabolism inhibitors such as carbonyl cyanide p
(trifluoromethoxy)-phenylhydrazone (34%), 2,4-dinitrophenol (50%), KCN (71%) and
NaN3 (69%) were added to the medium, or the temperature of the medium was lowered
to 4 degrees C. The addition of glucose (5-50 mM) or mannose (10 mM) did not
change the myo-inositol uptake, whereas the addition of 10 mM nonlabeled myo
inositol totally inhibited this transport, indicating that the transporter is
specific for myo-inositol. Phloretin (0.3 mM) and phoridzin (5 mM), but not
cytochalasin B, were efficient inhibitors of myo-inositol uptake. A portion of
the accumulated myo-inositol is converted to inositol phosphates and
phosphoinositides. These data show that myo-inositol transport in T. cruzi
epimastigotes is mediated by at least two specific transporters - one Na+
dependent and the other Na+-independent.
PMID- 10785371
TI - M1 muscarinic acetylcholine receptors activate zif268 gene expression via small G
protein Rho-dependent and lambda-independent pathways in PC12D cells.
AB - We have previously shown that stimulation of M1 muscarinic acetylcholine
receptors (mAChRs) in neuronal PC12D cells rapidly induces the immediate-early
gene zif 268 [Ebihara, T. & Saffen, D. (1997) J. Neurochem. 68, 1001-1010]. Here
we show that stimulation of M1 mAChRs in these cells activates four distal serum
response elements (SREs) in the zif 268 promoter, and that this activation is
strongly inhibited by Clostridium botulinum C3 exoenzyme (C3), which specifically
inactivates the small G-protein Rho. Even with high doses of C3, however, a
portion of the activation remains intact, indicating that stimulation of M1
mAChRs activates zif 268 SREs via Rho-dependent and Rho-independent pathways.
Moreover, the Rho-independent activation of zif 268 SREs is inhibited by the
dominant-negative form of the small G-protein Ras, suggesting that Rho
independent activation of zif 268 SREs is mediated by Ras. To determine if
muscarinic agonists activate RhoA, we also measured the translocation of RhoA
from the cytosolic fraction to the particulate fraction. Translocation of RhoA to
the particulate fraction was observed within 15 min following stimulation of M1
mAChRs, indicating that RhoA is activated with sufficient rapidity to participate
in the induction of zif 268 mRNA. Together, these results suggest that RhoA is
activated following stimulation of M1 mAChRs and functions in SRE-dependent
induction of the zif 268 gene within a Ras-independent pathway.
PMID- 10785373
TI - Design syntheses and mitochondrial complex I inhibitory activity of novel
acetogenin mimics.
AB - Some natural acetogenins are the most potent inhibitors of mitochondrial complex
I. These compounds are characterized by two functional units [i.e. hydroxylated
tetrahydrofuran (THF) and alpha, beta-unsaturated gamma-lactone ring moieties]
separated by a long alkyl spacer. To elucidate which structural factors of
acetogenins, including their active conformation, are crucial for the potent
inhibitory activity we synthesized a novel bis-acetogenin and its analogues
possessing two gamma-lactone rings connected to bis-THF rings by flexible alkyl
spacers. The inhibitory potency of the bis-acetogenin with bovine heart
mitochondrial complex I was identical to that of bullatacin, one of the most
potent natural acetogenins. This result indicated that one molecule of the bis
acetogenin does not work as two reactive inhibitors, suggesting that a gamma
lactone and the THF ring moieties act in a cooperative manner on the enzyme. In
support of this, either of the two ring moieties synthesized individually showed
no or very weak inhibitory effects. Moreover, combined use of the two ring
moieties at various molar ratios exhibited no synergistic enhancement of the
inhibitory potency. These observations indicate that both functional units work
efficiently only when they are directly linked by a flexible alkyl spacer.
Therefore, some specific conformation of the spacer must be important for optimal
positioning of the two units in the enzyme. Furthermore, the alpha,beta
unsaturated gamma-lactone, the 4-OH group in the spacer region, the long alkyl
tail attached to the THF unit and the stereochemistry surrounding the
hydroxylated bis-THF rings were not crucial for the activity, although these are
the most common structural features of natural acetogenins. The present study
provided useful guiding principles not only for simplification of complicated
acetogenin structure, but also for further wide structural modifications of these
molecules.
PMID- 10785374
TI - Induction of intracellular signalling by cyclic glycerophosphates and their deoxy
analogues.
AB - Cyclic glycerophosphates can be formed by enzymic degradation of phospholipids.
They have only recently attracted attention, and their physiological function is
still obscure. In this study, we have searched for signalling functions of the
natural 1,3-cyclic and 1,2-cyclic glycerophosphates, their deoxy analogues, and
the phenyl esters of the 1,3-cyclic phosphates. Linear sn-glycerol 3-phosphate
and glycerol 2-phosphate served as the control compounds. Each of the six
membered ring cyclic phosphates tested induced rapid intracellular tyrosine
phosphorylation in CHO and NIH-3T3 cells when applied extracellularly at a
concentration of 0.5-4 microM. The phosphorylated intracellular proteins had
molecular masses of approximately 35 kDa, approximately 45 kDa, 60-70 kDa and
approximately 120 kDa. The five-membered ring cyclic phosphates had a similar
effect, but at an external concentration of 2-10 microM, while sn-glycerol 3
phosphate and glycerol 2-phosphate had no effect. The six-membered cyclic
phosphates also induced rapid threonine phosphorylation in CHO cells of
approximately 18-kDa, approximately 35-kDa, and approximately 38-kDa proteins.
Further experiments indicated that the cyclic phosphates partition rapidly into
the cell cytosol where they activate kinases, including mitogen-activated protein
kinase. When their intracellular level increases, dephosphorylation presumably
takes place. This pattern may account for the signalling profile of cyclic
phosphates and suggests that they may take part in processes associated with cell
differentiation.
PMID- 10785375
TI - Utilization of leucine and acetate as carbon sources for sterol and fatty acid
biosynthesis by Old and New World Leishmania species, Endotrypanum monterogeii
and Trypanosoma cruzi.
AB - The relative roles of acetate and leucine in the provision of a carbon source for
fatty acid and sterol biosynthesis in several trypanosomatid species were
investigated using 14C- and 13C-labelled acetate, glucose and leucine as
substrates. Promastigotes of Leishmania species synthesized a large proportion of
their sterol from leucine. L. major (LV39), L. amazonensis and L. mexicana were
the most efficient utilizers of leucine, producing at least 70-77% of their
sterol from leucine; L. braziliensis, L. donovani and L. tropica apparently
produced less sterol from leucine (23-36%) and L. major (LV561), L. adleri and L.
panamamensis were intermediate, utilizing leucine to provide 51-58% of their
sterol. In all the cases the balance of the sterol produced was apparently
synthesized from carbon arising from acetate. The related trypanosomatid
Endotrypanum monterogeii also produced a large amount (77%) of its sterol from
leucine rather than acetate. By contrast Trypanosoma cruzi elaborated only 8% of
its sterol from leucine and used acetate far more effectively than the Leishmania
species for sterol biosynthesis. The fatty acid moieties of the triacylglycerols
and phospholipids were produced from acetate. Leucine was also incorporated into
the fatty acids to varying extents in the different organisms showing that
leucine can also be metabolized in trypanosomatids to generate acetyl-CoA.
PMID- 10785376
TI - Structural identification of the lipopolysaccharide O-antigen produced by
Yersinia enterocolitica serotype O:28.
AB - The structure of the O-antigenic polysaccharide (O-PS) component of the
lipopolysaccharide produced by Yersinia enterocolitica serotype O:28 has been
elucidated. From chemical methods involving glycose analysis, periodate
oxidation, methylation and the use of one- and two-dimensional NMR spectroscopy,
the O-PS was found to be a polymer of repeating branched hexasaccharide units
composed of L-rhamnose (four parts), 2-acetamido-2-deoxy-D-glucose (one part),
and 2-acetamido-2-deoxy-D-galacturonic acid (one part) having the following
structure:
PMID- 10785377
TI - Purification and characterization of active recombinant human napsin A.
AB - Recombinant human napsin A expressed in human embryonic kidney 293 cells was
purified to homogeneity by a single-step procedure using part of napsin A
propeptide as affinity ligand. N-Terminal amino-acid sequencing of the purified
enzyme identified the mature form of napsin A. Treatment of purified napsin A
with endoglycosidases F and H resulted in a decrease in its molecular mass from
39 kDa to approximately 37 kDa, confirming that napsin A is glycosylated. The
kinetic properties were analyzed by using two fluorogenic synthetic substrates
K(Dabsyl)-TSLLMAAPQ-Lucifer yellow (DS1) and K(Dabsyl)-TSVLMAAPQ-Lucifer yellow
(DS3). The Km values obtained were 1.7 microM and 6.2 microM, respectively. A
substrate-specificity study using a napsin A-targeted peptide library confirmed
the preference of napsin A for hydrophobic residues at positions P1 and P1'.
Adjacent positions, P2-P4 and P2'-P4', appeared less restricted in distribution
of amino acids. A pH optimum between 4.0 and 5.5 at room temperature was
determined. The purified enzyme was fully active for more than 10 h at pH 5.0 and
6.0, while a half-life of 4 h was determined at pH 7.0 and 37 degrees C.
PMID- 10785378
TI - Investigation of the haem-nicotinate interaction in leghaemoglobin. Role of
hydrogen bonding.
AB - A strategic assessment of the contributions of two active-site hydrogen bonds in
the binding of nicotinate to recombinant ferric soybean leghaemoglobin a (rLb)
was carried out by mutagenic replacement of the hydrogen-bonding residues (H61A
and Y30A variants) and by complementary chemical substitution of the carboxylate
functionality on the nicotinate ligand. Dissociation constants, Kd (pH 5.5, mu =
0.10 M, 25.0 +/- 0.1 degrees C), for binding of nicotinate to ferric rLb, H61A
and Y30A were 1.4 +/- 0.3 microM, 19 +/- 1 microM and 11 +/- 1 microM,
respectively; dissociation constants for binding of nicotinamide were,
respectively, 38 +/- 1 mM, 50 +/- 2 mM and 12 +/- 1 mM, and for binding of
pyridine were 260 +/- 50 microM, 4.5 +/- 0.5 microM and 66 +/- 8 microM,
respectively. Binding of cyanide and azide to the H61A and Y30A variants was
unaffected by the mutations. The pH-dependence of nicotinate binding for rLb and
Y30A was consistent with a single titration process (pKa values 6.9 +/- 0.1 and
6.7 +/- 0.2, respectively); binding of nicotinate to H61A was independent of pH.
Reduction potentials for the rLb and rLb-nicotinate derivatives were 29 +/- 2 mV
(pH 5.40, 25.0 degrees C, mu = 0.10 M) and - 65 +/- 2 mV (pH 5.42, 25.0 degrees
C, mu = 0.10 M), respectively. The experiments provide a quantitative assessment
of the role of individual hydrogen bonds in the binding process, together with a
definitive determination of the pKa of His61 and unambiguous evidence that
titration of His61 controls binding in the neutral to alkaline region.
PMID- 10785379
TI - Characterization of the early steps of OE17 precursor transport by the thylakoid
DeltapH/Tat machinery.
AB - In order to probe the structure and protein translocation function of the
thylakoid Tat machinery, a 25-residue C-terminal extension containing a 13
residue in vivo biotinylation tag and a 6x His tag was added to a mutant
precursor of the 17-kDa subunit of the oxygen-evolving complex to form pOE17(C)
BioHis. When avidin was attached to biotinylated precursor in situ, the precursor
avidin complex was neither imported nor did it form a membrane-spanning
translocation intermediate. It did, however, competitively inhibit the
translocation of unbiotinylated precursor with an apparent KI unaffected by
avidin. It is shown that the precursor protein achieves a stable folded structure
upon dilution from urea, suggesting that the avidin-induced inhibition of
transport results from a folding-induced proximity of N-terminal and C-terminal
domains. It is further demonstrated that the majority of precursor rapidly binds
to the thylakoid membrane, remaining import competent and yet undissociable by
high salt or high pH treatment at ice temperature. The membrane binding event is
unaffected by avidin. Import kinetics reveal that nonproton motive force-driven
transport steps make up a major fraction of the transport time. These
observations suggest that the N-terminal presequence on the avidin-bound
precursor is available for membrane binding and initial recognition by the
transport machinery, but the attached avidin signals the machinery that the
precursor is an incorrectly configured substrate and thus import is aborted.
Consequently, the DeltapH/Tat machinery's proofreading mechanism must operate
after precursor recognition but before the committed step in transport.
PMID- 10785380
TI - Bacterial-injection-induced syntheses of N-beta-alanyldopamine and Dopa
decarboxylase in the hemolymph of coleopteran insect, Tenebrio molitor larvae.
AB - Injection of Escherichia coli into larvae of the coleopteran Tenebrio molitor
resulted in the appearance of a dopamine-like substance on the electrochemical
detector. To characterize this dopamine-like substance, we purified it to
homogeneity from the immunized hemolymph and determined its molecular structure
to be N-beta-alanyldopamine using the liquid chromatographic/tandem mass
spectrometric method. Chemically synthesized N-beta-alanyldopamine showed the
same retention time on HPLC as the purified N-beta-alanyldopamine from immunized
larvae. To elucidate the molecular mechanism of N-beta-alanyldopamine synthesis
in vivo, we examined the enzyme activity of Dopa decarboxylase against E. coli
injected hemolymph of T. molitor larvae. The enzyme activity of Dopa
decarboxylase increased dramatically approximately 8 h after injection; Dopa
decarboxylase activity of injected larvae being 10-times higher than naive larvae
after 24 h. To evaluate the extent of quantitative changes of Dopa decarboxylase
in response to bacterial challenge, Tenebrio Dopa decarboxylase was purified to
homogeneity from the whole larvae and a cDNA clone for Tenebrio Dopa
decarboxylase was isolated. RNA blot hybridization revealed that expression of
the Dopa decarboxylase gene was activated transiently 3-8 h after E. coli
challenge. Immunoprecipitation experiments showed that Tenebrio Dopa
decarboxylase was detected from 8 to 24 h in E. coli-injected larval extract.
Thus, bacterial injection into T. molitor larvae might induce transcriptional
activation of a Dopa decarboxylase gene, and then synthesis of N-beta
alanyldopamine. The synthesized N-beta-alanyldopamine might be used as a
substrate by phenoloxidase during melanin synthesis in the humoral defense
response or the melanotic encapsulation reaction of the cellular defense
response.
PMID- 10785381
TI - Biophysical studies of the development of amyloid fibrils from a peptide fragment
of cold shock protein B.
AB - The peptide CspB-1, which represents residues 1-22 of the cold shock protein CspB
from Bacillus subtilis, has been shown to form amyloid fibrils when solutions
containing this peptide in aqueous (50%) acetonitrile are diluted in water [M.
Gross et al. (1999) Protein Science 8, 1350-1357] We established conditions in
which reproducible kinetic steps associated with the formation of these fibrils
can be observed. Studies combining these conditions with a range of biophysical
methods reveal that a variety of distinct events occurs during the process that
results in amyloid fibrils. A CD spectrum indicative of beta structure is
observed within 1 min of the solvent shift, and its intensity increases on a
longer timescale in at least two kinetic phases. The characteristic wavelength
shift of the amyloid-binding dye Congo Red is established within 30 min of the
initiation of the aggregation process and corresponds to one of the phases
observed by CD and to changes in the Fourier transform-infrared spectrum
indicative of beta structure. Short fibrillar structures begin to be visible
under the electron microscope after these events, and longer, well-defined
amyloid fibrils are established on a timescale of hours. NMR spectroscopy shows
that there are no significant changes in the concentration of monomeric species
in solution during the events leading to fibril formation, but that soluble
aggregates too large to be visible in NMR spectra are present throughout the
process. A model for amyloid formation by this peptide is presented which is
consistent with these kinetic data and with published work on a variety of
disease-related systems. These findings support the concept that the ability to
form amyloid fibrils is a generic property of polypeptide chains, and that the
mechanism of their formation is similar for different peptides and proteins.
PMID- 10785382
TI - Analysis of the thyrotropin-releasing hormone-degrading ectoenzyme by site
directed mutagenesis of cysteine residues. Cys68 is involved in disulfide-linked
dimerization.
AB - Thyrotropin-releasing hormone-degrading ectoenzyme is a member of the M1 family
of Zn-dependent aminopeptidases and catalyzes the degradation of thyrotropin
releasing hormone (TRH; Glp-His-Pro-NH2). Cloning of the cDNA of this enzyme and
biochemical studies revealed that the large extracellular domain of the enzyme
with the catalytically active site contains nine cysteine residues that are
highly conserved among species. To investigate the functional role of these
cysteines in TRH-DE we used a site-directed mutagenesis approach and replaced
individually each cysteine by a serine residue. The results revealed that the
proteolytically truncated and enzymatically fully active enzyme consists of two
identical subunits that are associated noncovalently by protein-protein
interactions but not via interchain S-S bridges. The eight cysteines contained
within this region are all important for the structure of the individual subunit
and the enzymatic activity, which is dramatically reduced in all mutant enzymes.
This is even true for the four cysteines that are clustered within the C-terminal
domain remote from the Zn-binding consensus sequence HEICH. In contrast, Cys68,
which resides within the stalk region seven residues from the end of the
hydrophobic membrane-spanning domain, can be replaced by serine without a
significant change in the enzymatic activity. Interestingly, this residue is
involved in the formation of an interchain disulfide bridge. Covalent
dimerization of the subunits, however, does not seem to be essential for
efficient biosynthesis, enzymatic activity and trafficking to the cell surface.
PMID- 10785383
TI - Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution
of the stalk sequence to the cleavage pattern of transmembrane proteins.
AB - A functionally and structurally diverse group of transmembrane proteins including
transmembrane forms of mediators or receptors can be proteolytically cleaved to
form soluble growth factors or receptors. Recently, the proteolytic activity
responsible for pro-tumor necrosis factor alpha (proTNFalpha) processing has been
identified and named TACE (TNFalpha converting enzyme). In experiments with TACE
deficient (TACE-/-) fibroblasts we found that 4beta-phorbol 12-myristate 13
acetate (PMA)-induced shedding of the interleukin-6 receptor (IL-6R) is strongly
reduced. A basal hydroxamate sensitive release of IL-6R, however, could still be
detected. This result demonstrates that TACE plays a role in IL-6R processing and
that additional metalloproteases might be involved. PMA-induced shedding of IL-6R
in TACE deficient mouse fibroblasts could be restored by stable transfection of a
TACE cDNA. To characterize differences between shedding of IL-6R and proTNFalpha
we generated chimeric IL-6R and proTNFalpha proteins wherein the endogenous
cleavage sites (CS) had been replaced by the corresponding region of proTNFalpha
and IL-6R, respectively. Interestingly, proTNFalpha chimeric proteins showed only
minimal shedding. In contrast, IL-6R chimeras containing the proTNFalpha CS were
shed spontaneously, processing was not further induced by PMA. Thus, the cleavage
pattern transferred by the introduction of the proTNFalpha CS is similar to that
of proTNFalpha itself. We conclude that the amino-acid sequence at the
proteolytic CS contributes to the cleavage characteristics of a protein. However,
this information alone is not sufficient to transfer cleavability as seen with
proTNFalpha chimeras containing the IL-6R CS and which were resistant to
shedding.
PMID- 10785384
TI - Propeptide dependent activation of the Antarctic krill euphauserase precursor
produced in yeast.
AB - Euphauserase is a brachyurin type digestive enzyme isolated from Antarctic krill.
The brachyurins belong to clan SA of the S1 family of serine endopeptidases. In
this study, we demonstrate that the precursor form of recombinant euphauserase,
termed pro-r-euphauserase, can be successfully expressed in Pichia pastoris. The
presence of most of the 51-residue euphauserase propeptide is essential during
expression, under the growth conditions of Pichia. The propeptide may be required
either for correct folding or processing of the enzyme. Cod trypsin generates a
fully active r-euphauserase from its precursor, which appears to be identical to
the native enzyme. The mature r-euphauserase sequence contains 250 amino-acid
residues including a 13-residue activation peptide, which seems to be attached to
the molecule by a disulfide bond. Euphauserase shares an average sequence
identity of 62% with its type I brachyurin analogue, crab collagenase I. However,
the identity between these two sequences is much higher in the regions shown to
be important for the broad substrate specificity and collagen binding of crab
collagenase I. The type I brachyurins share only 30-40% identities with the type
II brachyurins and trypsins. The low isoelectric point of euphauserase, with a
calculated pI value of 3.9, is typical for the type I brachyurins.
PMID- 10785385
TI - UV-B radiation induced exchange of the D1 reaction centre subunits produced from
the psbA2 and psbA3 genes in the Cyanobacterium synechocystis sp. PCC 6803.
AB - UV-B irradiation of Synechocystis 6803 cells inhibits photosystem II activity,
which can be restored via de novo synthesis of the D1 (and D2) reaction center
subunits. Recently we have shown that of the two psbA genes that encode identical
D1 proteins in Synechocystis 6803, UV-B preferentially enhances the transcription
of psbA3 compared to that of psbA2 [Mate, Z., Sass, L., Szekeres, M., Vass, I.
and Nagy, F. (1998) J. Biol. Chem. 273, 17439-17444]. Here we studied the effect
of UV-B on the synthesis of the D1 protein from the psbA2 and psbA3 genes in the
P7 mutant of Synechocystis 6803. In this mutant, psbA2 carries the Ala251-->Val
point mutation, which confers resistance to the photosystem II electron transport
inhibitor metribuzin, but psbA3 is the same as in the wild-type. By applying
variable chlorophyll fluorescence measurements to distinguish between metribuzin
sensitive and metribuzin-resistant photosystem II centers we quantified the
amount of the D1 protein produced from each of the psbA3 and psbA2 genes. When
the cells were exposed to UV-B light, the fraction of D1 protein produced from
the psbA3 gene was increased from 15-20 to 32-40% of the total D1. This effect
was reversible by transferring the cells to visible light. The rate of D1
production from psbA3 increased with increasing UV-B intensities, and was a
transient phenomenon at low UV-B levels (0.1 microE x m-2 x s-1). It is concluded
that the enhancement of psbA3 gene transcription by UV-B light leads to enhanced
D1 protein synthesis from this gene. Our findings demonstrate that the main role
of psbA3 transcription activated by UV-B is to increase the size of the psbA mRNA
pool available for translation when a rapid repair of the D1 protein is needed
under UV-B stress.
PMID- 10785386
TI - Purification, molecular cloning and ethylene-inducible expression of a soluble
type epoxide hydrolase from soybean (Glycine max [L.] Merr.).
AB - A soybean protein was purified from mature dry seeds. Amino-acid sequencing of
the nine internal peptides derived from this N-terminally blocked protein showed
that it has a significant similarity to the soluble epoxide hydrolases known to
date. A degenerate series of 23-mer oligonucleotides with sequences corresponding
to an internal region of eight amino-acid residues was synthesized as a probe
mixture for detection of a putative epoxide hydrolase cDNA in a developing
cotyledon cDNA library. The 1332-bp cDNA obtained was found to have an open
reading frame encoding the seed epoxide hydrolase-like precursor consisting of
341 amino-acid residues, suggesting that 25 amino-acid residues upstream from the
second methionine correspond to a transit peptide. Employing an Escherichia coli
expression system, the putative mature epoxide hydrolase-like protein was
overexpressed and purified to homogeneity. This recombinant protein was confirmed
to exhibit its epoxide-diol converting activity using styrene oxide as substrate.
The Vmax and Km values for styrene oxide are 1.36 micromol x min-1 x mg-1 and
1500 microM, respectively. Sedimentation equilibrium experiments showed that the
active form of this epoxide hydrolase is monomeric in solution. Using the above
cDNA as a probe, a 12-kb genomic clone was selected and the sequence of a 1933-bp
fragment from this clone was found to cover the entire coding region together
with 5'- and 3'-flanking regions of the soybean epoxide hydrolase gene. The
coding region of the gene, interrupted by two short introns, was identical to the
corresponding regions of the cDNA. Northern blot analyses showed that this
epoxide hydrolase gene was expressed strongly at a very early stage (13 days
after flowering) and then the level of expression gradually decreased and almost
ceased at a very late stage (58 days after flowering) of seed development,
whereas its expression was markedly up-regulated by ethylene treatment. In stems
(hypocotyl portion), the epoxide hydrolase transcript was detected at significant
levels and was also up-regulated in response to ethylene. On the other hand, it
is hardly expressed in leaves, even though they were treated with the
phytohormone. Overall, the results obtained may indicate that soluble-type
epoxide hydrolase mRNA is expressed at the maximum level in an early stage of
seed development. Later, oil bodies are formed and subsequently epoxy fatty
acids, naturally occurring metabolites, accumulate within those bodies. The
temporal induction of this epoxide hydrolase transcript in some tissues in
response to ethylene also indicates that this epoxide hydrolase may play a
crucial role in self-defense systems of plant.
PMID- 10785387
TI - Fidelity analysis of HIV-1 reverse transcriptase mutants with an altered amino
acid sequence at residues Leu74, Glu89, Tyr115, Tyr183 and Met184.
AB - Substitution of particular residues postulated to have a role in active site
architecture can alter the overall fidelity of DNA polymerization by HIV-1. The
effects of this kind of substitution were determined in a lacZ-based assay using
HIV-1 reverse transcriptase with specifically mutated residues. We found that the
reported higher fidelity of nucleotide incorporation by the Met184-->Val and
Glu89-->Gly mutant reverse transcriptases (RTs) was not reflected in a
substantial increase in the overall fidelity for these RT mutants. For the 3TC
resistant Met184-->Val RT mutant an almost wild-type level of overall mutation
frequency was observed, while the foscarnet-resistant RTs harbouring the Glu89-
>Gly mutation showed only a twofold decrease in mutation frequency. The Tyr183-
>Phe mutant RT displayed a slightly lower fidelity than wild-type RT. Conversely,
the ddI-resistant RT mutant containing the Leu74-->Val mutation showed a 3.5-fold
higher fidelity compared to the wild-type enzyme. Finally, the Tyr115-->Ala
substitution rendered the enzyme substantially more error-prone for DNA
polymerization. These results correlate with three-dimensional structural studies
of the polymerase active site and confirm the postulated impact of the Leu74,
Tyr183 and Tyr115 RT residues on the overall fidelity of DNA polymerization by
HIV-1 RT.
PMID- 10785388
TI - A novel function of yeast fatty acid synthase. Subunit alpha is capable of self
pantetheinylation.
AB - The prosthetic group of yeast fatty acid synthase (FAS), 4'-phosphopantetheine,
is covalently linked to Ser180 of subunit alpha. It originates from coenzyme A
and is transferred to the enzyme by a specific phosphopantetheine:protein
transferase (PPTase). The present study demonstrates that the FAS-activating
PPTase of yeast represents a distinct catalytic domain of the FAS complex and
resides within the C-terminal portion of subunit alpha. The autoactivation
capacity of yeast FAS became evident from in vitro pantetheinylation studies
using purified apo-FAS preparations. These were readily converted to
pantetheinylated holo-FAS simply upon addition of free coenzyme A.
Pantetheinylation-competent apo-FAS was prepared in vitro by constructing hybrid
oligomers containing alpha-subunits from two different pantetheine-less FAS
mutants. The respective mutants were selected according to their ability to
complement each other, in vivo. In vitro formation of hybrid apo-FAS complexes
was achieved by dimethylmaleic anhydride (DMMA) -induced reversible dissociation
of mixtures of the two constituent mutant enzymes. This treatment was both
necessary and sufficient to produce pantetheinylation-competent apo-FAS. Specific
FAS activities were comparable independent of whether the apo-enzymes were
pantetheinylated in vivo or in vitro. Apart from the induction of overall FAS
activity, incorporation of phosphopantetheine into apo-FAS was also demonstrated
by the use of 3H-labelled coenzyme A, leading to the formation of radioactively
labelled FAS. It is concluded that pantetheinylation of yeast FAS is performed by
an intrinsic catalytic activity of the apo-enzyme proper. The endogenous PPTase
acts in trans between different subunits alpha in the alpha6beta6 oligomer. The
self-pantetheinylation of yeast FAS represents the first example of an apo-enzyme
being capable of post-translational autoactivitation.
PMID- 10785389
TI - Cancer-associated alternative usage of multiple promoters of human GalCer
sulfotransferase gene.
AB - The galactosylceramide sulfotransferase (cerebroside sulfotransferase, CST) (EC
2.8.2.11) gene is highly expressed in human renal cancer cells. To elucidate the
regulatory mechanism of its gene expression, we have determined the genomic
organization of the human CST gene. The gene comprises at least four exons and
spans about 20 kb. The coding region is located in exons 3 and 4. To determine
the transcription initiation sites, 5'-rapid amplification of cDNA ends analysis
was performed using mRNA obtained from four human renal cancer cell lines, SMKT
R1-R4, and normal human renal proximal tubular cells. We found four transcription
initiation sites and alternative usage of six exons corresponding to the 5'
untranslated region in cancer cells. On the other hand, the only transcript
beginning at exon 1a was observed in normal cells. Using reverse transcriptase
PCR analysis, we confirmed that all of the exons 1a-d, especially exons 1c and
1d, are used as a transcription initiation site in cancer cells, whereas only
exons 1a and 1b, mostly 1a, are utilized in normal cells. Analyzing the protein
production from the mRNA variants with different 5'-UTRs, we found that all the
transcripts examined produced the identical proteins. These observations suggest
that the aberrant usage of transcription initiation sites flanked with
promoters/enhancers is involved in the cancer-associated expression of the CST
gene. Furthermore, this gene was assigned to human chromosome 22q12 by means of
fluorescence in situ hybridization.
PMID- 10785390
TI - Uncoupling proteins 2 and 3 interact with members of the 14.3.3 family.
AB - Uncoupling proteins (UCPs) are members of the superfamily of the mitochondrial
anion carrier proteins (MATP). Localized in the inner membrane of the organelle,
they are postulated to be regulators of mitochondrial uncoupling. UCP2 and 3 may
play an important role in the regulation of thermogenesis and, thus, on the
resting metabolic rate in humans. To identify interacting proteins that may be
involved in the regulation of the activity of UCPs, the yeast two-hybrid system
was applied. Segments of hUCP2 containing the hydrophilic loops facing the
intermembrane space, or combinations of these, were used to screen an adipocyte
activation domain (AD) fusion library. The 14.3.3 protein isoforms theta, beta,
zeta were identified as possible interacting partners of hUCP2. Screening of a
human skeletal muscle AD fusion library, on the other hand, yielded several
clones all of them encoding the gamma isoform of the 14.3.3 family. Mapping
experiments further revealed that all these 14.3.3 proteins interact specifically
with the C-terminal intermembrane space domain of both hUCP2 and hUCP3 whereas no
interactions could be detected with the C-terminal part of hUCP1. Direct
interaction between UCP3 and 14.3.3 theta could be demonstrated after in vitro
translation by coimmunoprecipitation. When coexpressed in a heterologous yeast
system, 14.3.3 proteins potentiated the inhibitory effect of UCP3 overexpression
on cell growth. These findings suggest that 14.3.3 proteins could be involved in
the targeting of UCPs to the mitochondria.
PMID- 10785391
TI - Enzyme-mediated sulfide production for the reconstitution of [2Fe-2S] clusters
into apo-biotin synthase of Escherichia coli. Sulfide transfer from cysteine to
biotin.
AB - We previously showed that biotin synthase in which the (Fe-S) cluster was
labelled with 34S by reconstitution donates 34S to biotin [B. Tse Sum Bui, D.
Florentin, F. Fournier, O. Ploux, A. Mejean & A. Marquet (1998) FEBS Lett. 440,
226-230]. We therefore proposed that the source of sulfur was very likely the (Fe
S) centre. This depletion of sulfur from the cluster during enzymatic reaction
could explain the absence of turnover of the enzyme which means that to restore a
catalytic activity, the clusters have to be regenerated. In this report, we show
that the NifS protein from Azotobacter vinelandii and C-DES from Synechocystis as
well as rhodanese from bovine liver can mobilize the sulfur, respectively, from
cysteine and thiosulfate for the formation of a [2Fe-2S] cluster in the
apoprotein of Escherichia coli biotin synthase. The reconstituted enzymes were as
active as the native enzyme. When [35S]cysteine was used during the
reconstitution experiments in the presence of NifS, labelled (Fe35S) biotin
synthase was obtained. This enzyme produced [35S]biotin, confirming the results
obtained with the 34S-reconstituted enzyme. NifS was also effective in mobilizing
selenium from selenocystine to produce an (Fe-Se) cluster. However, though NifS
could efficiently reconstitute holobiotin synthase from the apoform, starting
from cysteine, these two effectors had no significant effect on the turnover of
the enzyme in the in vitro assay.
PMID- 10785393
TI - Oxidation of aromatic sulfides by lignin peroxidase from Phanerochaete
chrysosporium.
AB - The reaction of H2O2 with 4-substituted aryl alkyl sulfides (4-XC6H4SR),
catalysed by lignin peroxidase (LiP) from Phanerochaete chrysosporium, leads to
the formation of sulfoxides, accompanied by diaryl disulfides. The yields of
sulfoxide are greater than 95% when X = OMe, but decrease significantly as the
electron donating power of the substituent decreases. No reaction is observed for
X = CN. The bulkiness of the R group has very little influence on the efficiency
of the reaction, except for R = tBu. The reaction exhibits enantioselectivity (up
to 62% enantiomeric excess with X = Br, with preferential formation of the
sulfoxide with S configuration). Enantioselectivity decreases with increasing
electron density of the sulfide. Experiments in H218O show partial or no
incorporation of the labelled oxygen into the sulfoxide, with the extent of
incorporation decreasing as the ring substituents become more electron
withdrawing. On the basis of these results, it is suggested that LiP compound I
(formed by reaction between the native enzyme and H2O2), reacts with the sulfide
to form a sulfide radical cation and LiP compound II. The radical cation is then
converted to sulfoxide either by reaction with the medium or by a reaction with
compound II, the competition between these two pathways depending on the
stability of the radical cation.
PMID- 10785392
TI - Solution structure of the antimicrobial peptide gaegurin 4 by H and 15N nuclear
magnetic resonance spectroscopy.
AB - Gaegurin 4 (GGN4) is a 37-residue antimicrobial peptide isolated from the skin of
a Korean frog, Rana rugosa. This peptide shows a broad range of activity against
prokaryotic cells but shows very little hemolytic activity against human red
blood cells. The solution structure of GGN4 was studied by using circular
dichroism (CD) and NMR spectroscopy. CD investigations revealed that GGN4 adopts
mainly an alpha-helical conformation in trifluoroethanol/water solution, in
dodecylphosphocholine and in SDS micelles, but adopts random structure in aqueous
solution. By using both homonuclear and heteronuclear NMR experiments, complete
1H and 15N resonance assignments were obtained for GGN4 in 50%
trifluoroethanol/water solution. The calculated structures of GGN4 consist of two
amphipathic alpha-helices extending from residues 2-10 and from residues 16-32.
These two helices are connected by a flexible loop spanning between the residues
11 and 15. By using enzyme digestion and matrix-assisted laser
desorption/ionization mass spectroscopy, we confirmed that GGN4 contains a
disulfide bridge formed between the residues Cys31 and Cys37 in its C-terminus.
The effect of disulfide bridge on the structure and the activity of GGN4 was
investigated. The reduced form of GGN4 revealed a similar activity and
conformation to native GGN4, suggesting that the disulfide bridge does not
strongly affect the conformation and the antimicrobial activity of GGN4.
PMID- 10785394
TI - The HIV-1(Lai) RNA dimerization. Thermodynamic parameters associated with the
transition from the kissing complex to the extended dimer.
AB - Retroviruses contain dimeric RNA consisting of two identical copies of the
genomic RNA. The interaction between these two RNA molecules occurs near their 5'
ends. A region upstream from the splice donor comprising an auto-complementary
sequence has been identified as being responsible for the initiation of the
formation of dimeric HIV-1(Lai) RNA. This region (SL1), part of the PSI
encapsidation domain, can adopt a stem-loop structure. It has already been shown
that this stem-loop structure can initiate the formation of two distinct dimers
differing in their thermostability: a loop-loop dimer or 'kissing complex' and an
extended dimer. We report here a study using UV and 1D NMR spectroscopy of the
dimerization of a short oligoribonucleotide (23 nucleotides) spanning nucleotides
248-270 of the HIV-1(Lai) SL1 sequence, in order to derive the thermodynamic
parameters associated with the transition from the loop-loop complex to the
extended dimer. The temperature dependence of the UV absorbency shows an
hypochromicity for this transition with a small enthalpy change equal to - 29.4
+/- 5 kcal x mol-1, together with a concentration independent transition which
implies a monomolecular reaction. On the other hand, our NMR results don't
indicate a dissociation of the GCGCGC sequence engaged in the loop-loop
interaction during the rearrangement of the loop-loop complex into the extended
dimer. Our data suggest that the loop-loop interaction is maintained during the
temperature dependent conformational change while the intramolecular base-pairing
of the stems is disrupted and then reconstituted to form an intermolecular base
pairing leading to an extended dimer.
PMID- 10785395
TI - Functional properties of recombinant Azospirillum brasilense glutamate synthase,
a complex iron-sulfur flavoprotein.
AB - Azospirillum brasilense glutamate synthase is a complex iron-sulfur flavoprotein
that catalyses the NADPH-dependent reductive transfer of glutamine amide group to
the C(2) carbon of 2-oxoglutarate to yield L-glutamate. Its catalytically active
alphabeta protomer is composed of two dissimilar subunits (alpha subunit, 164.2
kDa; beta subunit, 52.3 kDa) and contains one FAD (at Site 1, the pyridine
nucleotide site within the beta subunit), one FMN (at Site 2, the 2
oxoglutarate/L-glutamate site in the alpha subunit) and three different iron
sulfur clusters (one 3Fe-4S center on the alpha subunit and two 4Fe-4S clusters
of unknown location). A plasmid harboring the gltD and gltB genes, the genes
encoding the glutamate synthase beta and alpha subunits, respectively, each one
under the control of the T7/lac promoter of pET11a was found to be suitable for
the overproduction of glutamate synthase holoenzyme in Escherichia coli BL21(DE3)
cells. Recombinant A. brasilense glutamate synthase could be purified to
homogeneity from overproducing E. coli cells by ion exchange chromatography, gel
filtration and affinity chromatography on a 2',5' ADP-Sepharose 4B column. The
purified enzyme was indistinguishable from that prepared from Azospirillum cells
with respect to cofactor content, N-terminal sequence of the subunits,
aggregation state, kinetic and spectroscopic properties. The study of the
recombinant holoenzyme allowed us to establish that the tendency of glutamate
synthase to form a stable (alphabeta)4 tetramer at high protein concentrations is
a property unique to the holoenzyme, as the isolated beta subunit does not
oligomerize, while the isolated glutamate synthase alpha subunit only forms
dimers at high protein concentrations. Furthermore, the steady-state kinetic
analysis of the glutamate synthase reaction was extended to the study of the
effect of adenosine-containing nucleotides. Compounds such as cAMP, AMP, ADP and
ATP have no effect on the enzyme activity, while the 2'-phosphorylated analogs of
AMP and NADP(H) analogs act as inhibitors of the reaction, competitive with
NADPH. Thus, it can be ruled out that glutamate synthase reaction is subjected to
allosteric modulation by adenosine containing (di)nucleotides, which may bind to
the putative ADP-binding site at the C-terminus of the alpha subunit. At the same
time, the strict requirement of a 2'-phosphate group in the pyridine nucleotide
for binding to glutamate synthase (GltS) was established. Finally, by comparing
the inhibition constants exhibited by a series of NADP+ analogs, the contribution
to the binding energy of the various parts of the pyridine nucleotide has been
determined along with the effect of substituents on the 3 position of the
pyridine ring. With the exception of thio-NADP+, which binds the tightest to
GltS, it appears that the size of the substituent is the factor that affects the
most the interaction between the NADP(H) analog and the enzyme.
PMID- 10785396
TI - Domain organization of p130, PLC-related catalytically inactive protein, and
structural basis for the lack of enzyme activity.
AB - The 130-kDa protein (p130) was isolated as a novel inositol 1,4, 5-trisphosphate
[Ins(1,4,5)P3]-binding protein similar to phospholipase C-delta1 (PLC-delta1),
but lacking catalytic activity [Kanematsu, T., Takeya, H., Watanabe, Y., Ozaki,
S., Yoshida, M., Koga, T., Iwanaga, S. & Hirata, M. (1992) J. Biol. Chem. 267,
6518-6525; Kanematsu, T., Misumi, Y., Watanabe, Y., Ozaki, S., Koga, T., Iwanaga,
S., Ikehara, Y. & Hirata, M. (1996) Biochem. J. 313, 319-325]. To test
experimentally the domain organization of p130 and structural basis for lack of
PLC activity, we subjected p130 to limited proteolysis and also constructed a
number of chimeras with PLC-delta1. Trypsin treatment of p130 produced four major
polypeptides with molecular masses of 86 kDa, 55 kDa, 33 kDa and 25 kDa. Two
polypeptides of 86 kDa and 55 kDa started at Lys93 and were calculated to end at
Arg851 and Arg568, respectively. Using the same approach, it has been found that
the polypeptides of 33 kDa and 25 kDa are likely to correspond to regions between
Val569 and Arg851 and Lys869 and Leu1096, respectively. All the proteolytic sites
were in interconnecting regions between the predicted domains, therefore
supporting domain organization based on sequence similarity to PLC-delta1 and
demonstrating that all domains of p130, including the unique region at the C
terminus, are stable, tightly folded structures. p130 truncated at either or both
the N-terminus (94 amino acids) and C-terminus (851-1096 amino acids) expressed
in COS-1 cells showed no catalytic activity, indicating that p130 has
intrinsically no PLC activity. A number of chimeric molecules between p130 and
PLC-delta1 were constructed and assayed for PLC activity. It was shown that
structural differences in interdomain interactions exist between the two
proteins, as only some domains of p130 could replace the corresponding structures
in PLC-delta1 to form a functional enzyme. These results suggest that p130 and
the related proteins could represent a new protein family that may play some
distinct role in cells due to the capability of binding Ins(1,4,5)P3 but the lack
of catalytic activity.
PMID- 10785397
TI - Correct folding of a ribozyme induced by nonspecific macromolecules.
AB - The 50-nucleotide hammerhead ribozyme HH-S was tested for self-cleavage. The self
cleavage was very inefficient, and only 13% of HH-S was transformed to its
cleavage products. Surprisingly, the percentage of cleavage of HH-S was increased
to 30% when 1 microg of tRNA was added to the reaction mixture (6 microL). Other
macromolecules such as DNAs and proteins were examined to see if they also
augmented cleavage of HH-S, and it was found that most of the macromolecules
tested, except nucleotide monomers, did indeed enhance HH-S cleavage. The self
cleaving reaction was almost saturated in 30 min, and only 13% of HH-S was
cleaved at 37 degrees C for a 70-min reaction, indicating that 87% of HH-S was in
kinetically trapped inactive conformations. Time courses for the reaction of the
HH-S self-cleavage were also measured in the presence of tRNA, an
oligodeoxyribonucleotide, or BSA. Cleavage of HH-S, which had already reached a
plateau of 13% cleaved, increased gradually after the addition of the effector
molecules. The first-order rate constant for the self-cleavage reaction in the
absence of an effector was comparable to that in the presence of BSA, indicating
that the effector molecules do not affect the chemical step of self-cleavage.
These results demonstrate that a variety of nonspecific macromolecules can induce
conformational change of the hammerhead even in such a low concentration as
0.003% (w/v). This conformational change may occur by macromolecular collisions,
or nonspecific weak interactions between HH-S and effectors. Alternatively, a
molecular crowding effect may cause the conformational change.
PMID- 10785398
TI - Characterization and molecular cloning of two different type 2 ribosome
inactivating proteins from the monocotyledonous plant Polygonatum multiflorum.
AB - Leaves of the monocotyledonous plant Polygonatum multiflorum L. (Solomon's seal)
contain besides a monocot mannose-binding lectin two galactose/N
acetylgalactosamine (Gal/GalNAc)-binding type 2 ribosome-inactivating proteins
(RIPs). Both RIPs were purified using a combination of classical protein
purification techniques and affinity chromatography. Although both RIPs consist
of protomers of 65 kDa, the P. multiflorum RIP monomer (PMRIPm) occurs as a
monomer of approximately 60 kDa, whereas the tetramer (PMRIPt) is a tetramer of
240 kDa. Both RIPs exhibit similar RNA N-glycosidase activity but differ in their
specific agglutination activity and carbohydrate-binding specificity, PMRIPt
being a GalNAc-specific lectin whereas PMRIPm is Gal/GalNAc-specific. Toxicity
tests indicated that both Polygonatum RIPs exhibit a very low cytotoxicity
towards human and animal cells. Analysis of the genomic clones encoding both RIPs
revealed a high degree of sequence similarity to other type 2 RIPs. Molecular
modelling confirmed that both Polygonatum RIPs have a similar structure to ricin.
PMID- 10785399
TI - Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein
kinase alters its catalytic and allosteric cGMP-binding activities.
AB - In addition to its cGMP-selective catalytic site, cGMP-binding cGMP-specific
phosphodiesterase (PDE5) contains two allosteric cGMP-binding sites and at least
one phosphorylation site (Ser92) on each subunit [Thomas, M.K., Francis, S.H. &
Corbin, J.D. (1990) J. Biol. Chem. 265, 14971-14978]. In the present study, prior
incubation of recombinant bovine PDE5 with a phosphorylation reaction mixture
[cGMP-dependent protein kinase (PKG) or catalytic subunit of cAMP-dependent
protein kinase (PKA), MgATP, cGMP, 3-isobutyl-1-methylxanthine], shown earlier to
produce Ser92 phosphorylation, caused a 50-70% increase in enzyme activity and
also increased the affinity of cGMP binding to the allosteric cGMP-binding sites.
Both effects were associated with increases in its phosphate content up to 0.6
mol per PDE5 subunit. Omission of any one of the preincubation components caused
loss of stimulation of catalytic activity. Addition of the phosphorylation
reaction mixture to a crude bovine lung extract, which contains PDE5, also
produced a significant increase in cGMP PDE catalytic activity. The increase in
recombinant PDE5 catalytic activity brought about by phosphorylation was time
dependent and was obtained with 0.2-0.5 microM PKG subunit, which is
approximately the cellular level of this enzyme in vascular smooth muscle.
Significantly greater stimulation was observed using cGMP substrate
concentrations below the Km value for PDE5, although stimulation was also seen at
high cGMP concentrations. Considerably higher concentration of the catalytic
subunit of PKA than of PKG was required for activation. There was no detectable
difference between phosphorylated and unphosphorylated PDE5 in median inhibitory
concentration for the PDE5 inhibitors, sildenafil, or zaprinast 3-isobutyl-1
methylxanthine. Phosphorylation reduced the cGMP concentration required for half
maximum binding to the allosteric cGMP-binding sites from 0.13 to 0.03 microM.
The mechanism by which phosphorylation of PDE5 by PKG could be involved in
physiological negative-feedback regulation of cGMP levels is discussed.
PMID- 10785400
TI - Interferon-alpha synergistically enhances induction of interleukin-6 by double
stranded RNA in HeLa cells.
AB - Double stranded RNA (dsRNA), an intermediate that is common during viral
infection, directly induces much higher levels of expression of interleukin-6 (IL
6) mRNA than does the cytokine IL-1beta. Interferon alpha (IFNalpha) by itself
does not induce expression of IL-6; nonetheless, IFNalpha pretreatment
dramatically enhances IL-6 induction by dsRNA but not by IL-1beta. Mutation of
either the activating transcription factor/cyclic AMP response element binding
protein (ATF/CREB) or the NF-IL-6 binding element within the IL-6 promoter
eliminates most responsiveness of CAT reporter constructs to either dsRNA or to
IL-1beta. IFNalpha pretreatment partially restores responsiveness to dsRNA but
not to IL-1beta when either the ATF/CREB site or the NF-IL-6 site is mutated, but
at least one of these sites must be intact for responsiveness to be restored.
Mutation of the kappaB binding site in the IL-6 promoter eliminates
responsiveness to either IL-1beta or to dsRNA, and pretreatment with IFNalpha
does not restore any responsiveness. Incubation with dsRNA leads to a decrease in
protein translation, especially in cells that have been pretreated with IFNalpha.
Nonetheless, IFNalpha pretreatment followed by dsRNA leads to very high IL-6
protein levels. These studies demonstrate that major differences exist in the
induction of IL-6 at both the mRNA and protein levels by dsRNA compared to
cytokines and that IFNalpha pretreatment selectively enhances IL-6 induction by
dsRNA but not by IL-1beta. The high levels of IL-6 expression that result when
cells encounter class I IFN prior to dsRNA suggest a mechanism for a heightened
host response to viral infection with heightened production of this pleotropic
cytokine.
PMID- 10785401
TI - Analysis of the molecular composition of Ro ribonucleoprotein complexes.
Identification of novel Y RNA-binding proteins.
AB - Human Ro ribonucleoproteins (RNPs) are composed of one of the four small Y RNAs
and at least two proteins, Ro60 and La; association of additional proteins
including the Ro52 protein and calreticulin has been suggested, but clear-cut
evidence is still lacking. Partial purification of Ro RNPs from HeLa S100
extracts allowed characterization of several subpopulations of Ro RNPs with
estimated molecular masses of between 150 and 550 kDa. The majority of these
complexes contained Ro60 and La, whereas only a small proportion of Ro52 appeared
to be associated with Ro RNPs. To identify novel Y RNA-associated proteins in
vitro, binding of cytoplasmic proteins to biotinylated Y RNAs was investigated.
In these reconstitution experiments, several proteins with estimated molecular
masses of 80, 68, 65, 62, 60 and 53 kDa, the latter two being immunologically
distinct from Ro60 and Ro52, respectively, appeared to bind specifically to Y
RNAs. Furthermore, autoantibodies to these proteins were found in sera from
patients with systemic lupus erythematosus. The proteins bound preferentially to
Y1 and Y3 RNA but, with the exception of the 53-kDa protein, only weakly to Y4
RNA and not at all to Y5 RNA. Coprecipitation of the 80, 68, 65, and 53-kDa
proteins by antibodies to Ro60 and La was observed, suggesting that at least a
proportion of the novel proteins may reside on the same particles as La and/or
Ro60. Finally, the binding sites for these proteins on Y1 RNA were clearly
distinct from the Ro60-binding site involving a portion of the large central loop
2, which was found to be indispensable for binding of the 80, 68, 65 and 53-kDa
proteins, as well as the stem 3-loop 3 and stem 2-loop 1 regions. Interestingly,
truncation of the La-binding site resulted in decreased binding of the novel
proteins (but not of Ro60), indicating La to be required for efficient
association. Taken together, these results suggest the existence of further
subpopulations of Ro RNPs or Y RNPs, consistent with the heterogeneous
characteristics observed for these particles in the biochemical fractionation
experiments.
PMID- 10785402
TI - Aspartate aminotransferase from the Antarctic bacterium Pseudoalteromonas
haloplanktis TAC 125. Cloning, expression, properties, and molecular modelling.
AB - The gene encoding aspartate aminotransferase from the psychrophilic bacterium
Pseudoalteromonas haloplanktis TAC 125 was cloned, sequenced and overexpressed in
Escherichia coli. The recombinant protein (PhAspAT) was characterized both at the
structural and functional level in comparison with the E. coli enzyme (EcAspAT),
which is the most closely related (52% sequence identity) bacterial counterpart.
PhAspAT is rapidly inactivated at 50 degrees C (half-life = 6.8 min), whereas at
this temperature EcAspAT is stable for at least 3 h. The optimal temperature for
PhAspAT activity is approximately 64 degrees C, which is some 11 degrees C below
that of EcAspAT. The protein thermal stability was investigated by following
changes in both tryptophan fluorescence and amide ellipticity; this clearly
suggested that a first structural transition occurs at approximately 50 degrees C
for PhAspAT. These results agree with the expected thermolability of a
psychrophilic enzyme, although the observed stability is much higher than
generally found for enzymes isolated from cold-loving organisms. Furthermore, in
contrast with the higher efficiency exhibited by several extracellular
psychrophilic enzymes, both kcat and kcat/Km of PhAspAT are significantly lower
than those of EcAspAT over the whole temperature range. This behaviour possibly
suggests that the adaptation of this class of endocellular enzymes to a cold
environment may have only made them less stable and not more efficient. The
affinity of PhAspAT for both amino-acid and 2-oxo-acid substrates decreases with
increasing temperature. However, binding of maleate and 2-methyl-L-aspartate,
which both inhibit the initial steps of catalysis, does not change over the
temperature range tested. Therefore, the observed temperature effect may occur at
any of the steps of the catalytic mechanism after the formation of the external
aldimine. A molecular model of PhAspAT was constructed on the basis of sequence
homology with other AspATs. Interestingly, it shows no insertion or extension of
loops, but some cavities and a decrease in side chain packing can be observed.
PMID- 10785403
TI - Study of HIV-2 primer-template initiation complex using antisense
oligonucleotides.
AB - HIV-2 reverse transcription is initiated by the retroviral DNA polymerase
(reverse transcriptase) from a cellular tRNALys3 partially annealed to the primer
binding site in the 5'-region of viral RNA. The HIV-2 genome has two A-rich
regions upstream of the primer binding site. In contrast to HIV-1 RNA, no direct
evidence of interactions with the U-rich anticodon loop of tRNALys3 has been
described to date. Here we address the question of the potential role of the
interactions between these highly structured regions in the initiation of viral
DNA synthesis. To evaluate this we used an antisense approach, first validated in
our in vitro HIV-1 reverse transcription system. Annealing of the antisense
oligonucleotides to the pre-primer binding site (the upstream region contiguous
to the HIV-2 primer binding site) was determined in the presence of native
tRNALys3 or synthetic primers. Using natural and chemically modified antisense
oligonucleotides we found that interactions between the anticodon of tRNALys3 and
an A-rich loop of viral RNA led to an important destabilization of the pre-primer
binding site; this region became accessible to anti-pre-primer binding site
oligonucleotides in a cooperative manner. These studies allowed to identify an A
rich region in HIV-2ROD RNA capable of interacting with tRNALys3. Better
knowledge of these interactions is very important for understanding the
primer/template positioning in the early steps of HIV-2 reverse transcription.
PMID- 10785404
TI - Identification of ubiquitinated repeats in human erythroid alpha-spectrin.
AB - The spectrin role(s) is (are) very important for the shape and the physical
properties of red cells, such as deformability and resistance to mechanical
stresses. Moreover a variety of spectrin diseases are known. We have previously
demonstrated [Corsi, D., Galluzzi, L., Crinelli, R. & Magnani, M. (1995) J. Biol.
Chem. 270, 8928-8935] that human erythroid alpha-spectrin is ubiquitinated in
vitro and in vivo. In order to define the ubiquitinated repeats of this long
protein and find out a possible function, we have produced recombinant peptides
encompassing the alphaIII-, alphaIV-, alphaV- and EF hand domains of alpha
spectrin chain. These peptides were tested in in vitro ubiquitin conjugation
assays and two regions susceptibles to ubiquitination were found. The first one,
in the alphaIV-domain, includes the repeat 17 and the second one, in the alphaV
domain, includes the repeat 20 and a part of repeat 21. We also demonstrated that
the susceptibility to ubiquitination of the alphaV-domain is reduced by
interaction with the corresponding portion of beta-spectrin chain (betaIV
domain). Thus, at least ubiquitination of alphaV-domain is susceptible to
cytoskeleton assembly and spectrin dimerization.
PMID- 10785405
TI - Differential gene expression by endothelial cells in distinct angiogenic states.
AB - Angiogenesis is a complex process that can be regarded as a series of sequential
events comprising a variety of tissue cells. The major problem when studying
angiogenesis in vitro is the lack of a model system mimicking the various aspects
of the process in vivo. In this study we have used two in vitro models, each
representing different and distinct aspects of angiogenesis. Differentially
expressed genes in the two culture forms were identified using the suppression
subtractive hybridization technique to prepare subtracted cDNA libraries. This
was followed by a differential hybridization screen to pick up overexpressed
clones. Using comparative multiplex RT-PCR we confirmed the differential
expression and showed differences up to 14-fold. We identified a broad range of
genes already known to play an important role during angiogenesis like Flt1 or
TIE2. Furthermore several known genes are put into the context of endothelial
cell differentiation, which up to now have not been described as being relevant
to angiogenesis, like NrCAM, Claudin14, BMP-6, PEA-15 and PINCH. With ADAMTS4 and
hADAMTS1/METH-1 we further extended the set of matrix metalloproteases expressed
and regulated by endothelial cells.
PMID- 10785406
TI - Rising drug costs: the impact on dermatology.
AB - In the US prescription drug costs are rising faster than any other component of
health care expenditures, and show no signs of slowing. Spending on prescription
drugs has been estimated by the Health Care Finance Administration (HCFA) to be
rising by approximately 12% per year, more than twice the rate for national
health care expenditures (5.1%). Factors driving the rise in prescription drug
costs include the introduction of new drugs, and consumer demand.
PMID- 10785407
TI - Herbal anti-inflammatory agents for skin disease.
AB - Herbs have been used in clinical medicine for thousands of years. However, it is
only in recent times that we have been able to employ scientific methods to prove
the efficacy of many of these herbs and to give us a better understanding of
their mechanisms of action. This article will focus on the use of herbs in
various dermatological conditions characterized by inflammation and pruritus.
Topical preparations of many of these herbs are more commonplace in Europe.
However, their availability is increasing in the US. As this is occurring we are
witnessing a growing marriage between alternative and traditional medicines.
PMID- 10785408
TI - Induction of choline acetyltransferase activity in cholinergic neurons by
stolonidiol: structure-activity relationship.
AB - The effect of stolonidiol (1), a bioactive marine diterpenoid from the Japanese
soft coral Clavularia sp., on choline acetyltransferase (ChAT) activity was
examined using cultured cholinergic neurons. Stolonidiol (1) showed potent ChAT
inducible activity in primary cultured basal forebrain cells and clonal septal
SN49 cells, suggesting that it may act as a potent neurotrophic factor-like agent
on the cholinergic nervous system. Further expansion of the structure-activity
relationship to include stolonidiol (1) and its derivatives demonstrated that the
exo-methylene group and the epoxide group are essential for ChAT-inducing
activity. Stolonidiol (1) showed the highest activity among the test samples.
PMID- 10785409
TI - Sesquiterpene coumarins and related derivatives from Ferula pallida.
AB - Six new compounds-two sesquiterpene coumarins, pallidones A and B (1, 2), and
four related derivatives, pallidones C-F (3-6), as well as two known
sesquiterpene coumarins, feselol (7) and conferol (8), have been isolated from
the EtOAc extracts of the roots of Ferula pallida. All structures of these
compounds were determined on the basis of spectral evidence, especially 2D NMR
((1)H-(1)H COSY, HSQC, HMBC, and NOESY) and HRMS. The possible biosynthetic
pathway of pallidones C-F (3-6) is discussed.
PMID- 10785410
TI - Cytotoxic prenylxanthones from Garcinia bracteata.
AB - Bioassay-guided fractionation of a leaf extract of G. bracteata has yielded six
new prenylxanthones, bractatin (1), isobractatin (2), 1-O-methylbractatin (3), 1
O-methylisobractatin (4), 1-O-methyl-8-methoxy-8,8a-dihydrobractatin (5), and 1-O
methylneobractatin (6). The structures of these compounds have been elucidated by
spectroscopic means (NMR, MS), literature data, and X-ray crystallographic
analysis of 2. These compounds possess significant cytotoxicity against the KB
cell line.
PMID- 10785411
TI - New bisindole alkaloids of the topsentin and hamacanthin classes from the
Mediterranean marine sponge Rhaphisia lacazei.
AB - Chemical investigation of the Et(2)O extract of the marine sponge Rhaphisia
lacazei resulted in the isolation of 13 pure bisindole alkaloids (1-13).
Compounds (1-6) belong to the class of topsentins and have already been
described. Compounds 7-13 are new products, closely related to the class of
hamacanthins. The major compounds 1-3 were tested in vitro for antitumor
activity; compounds 2 and 3 showed antiproliferative activity against human
bronchopulmonary cancer cells (NSCLC-N6) with an IC(50) of 12 and 6.3 microg/mL,
respectively.
PMID- 10785412
TI - New sesquiterpene/quinones from two sponges of the genus Hyrtios.
AB - Two sponges of the genus Hyrtios have been found to contain new
sesquiterpene/quinones identified by detailed spectroscopic analysis. Four new
compounds with a 4,9-friedodrim-3-ene skeleton [hyrtiophenol (2), 5
epihyrtiophenol (3), 18-hydroxy-5-epihyrtiophenol (4), and 18-hydroxyhyrtiophenol
(5)] were isolated from Hyrtios sp. (Seychelles Islands) along with
isospongiaquinone (1). Moreover, the new compound 21-hydroxy-19-methoxyarenarone
(8), which bears the 4, 9-friedodrim-4(15)-ene skeleton, was isolated from
Hyrtios tubulatus (Curacao) along with arenarol (6) and 5-epiilimaquinone (7).
Assignment of the (13)C NMR signals of four types of 4, 9-friedodrimene skeletons
found in sponges is presented.
PMID- 10785413
TI - Bioactive compounds from Combretum erythrophyllum.
AB - A methanol extract of Combretum erythrophyllum showed inhibitory bioactivities in
a yeast-based microtiter assay for DNA-damaging agents. Bioassay-guided
fractionation of this extract yielded two known bioactive compounds,
combretastatin A-1 and (-)-combretastatin, and two new bioactive glucosides,
combretastatin A-1 2'-beta-D-glucoside (1) and combretastatin B-1 2'-beta-D
glucoside (2). The structures of the new compounds were assigned by (1)H and
(13)C NMR, DEPT, HMQC, and HMBC spectra.
PMID- 10785414
TI - Malevamides A-C, new depsipeptides from the marine cyanobacterium Symploca laete
viridis.
AB - Three new depsipeptides, malevamides A-C (1-3), were isolated from the
cyanobacterium Symploca laete-viridis collected off the south shore of Oahu,
Hawaii. Compounds 1-3 were identified by spectral methods, and partial
stereochemical assignments were made by chiral HPLC of the hydrolyzed compounds.
At a concentration of 2 microg/mL, compounds 1-3 were inactive against P-388, A
549, and HT-29 cancer cells.
PMID- 10785415
TI - New xenicane diterpenes isolated from the acetone extract of the soft coral Xenia
florida.
AB - Six new xenicane diterpenes have been isolated from the acetone extract of the
soft coral Xenia florida. Two of them are diterpenes containing a bicyclic
[4.3.1] ring system. Three of them seem to be precursors for diterpenes
possessing the bicyclic [4.3.1] ring system. One is a common monocarbocyclic
diterpene with a cyclononane skeleton.
PMID- 10785416
TI - Flavonol-cinnamate cycloadducts and diamide derivatives from Aglaia laxiflora.
AB - Leaf extracts of the Malaysian plant Aglaia laxiflora provided two cytotoxic
compounds, a new rocaglaol rhamnoside (1), a known rocaglaol (2), new (but
inactive) flavonol-cinnamaminopyrrolidine adducts (3-6), and their probable
biosynthetic precursors (7 and trimethoxyflavonol). All structures were
elucidated primarily by 2D NMR spectroscopy. The structure and stereochemistry of
aglaxiflorin A (3) were confirmed by single-crystal X-ray crystallography.
PMID- 10785417
TI - Aporphine glycosides from Stephania cepharantha seeds.
AB - Two new aporphine glycosides, stesakine-9-O-beta-D-glucopyranoside (1) and N
methylasimilobine-2-O-beta-D-glucopyranoside (2), were isolated from the seeds of
Stephania cepharantha cultivated in Japan, together with 16 known alkaloids. The
structures of 1 and 2 were spectroscopically determined by comparison of their
(1)H and (13)C NMR data with those of stesakine (11) and N-methylasimilobine
(12), respectively.
PMID- 10785418
TI - Halogenated boldine derivatives with enhanced monoamine receptor selectivity.
AB - (S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecular
bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. Initial
halogenation occurs at C-3, followed (in the cases of chlorine and bromine) by
the less reactive C-8, to afford 3-haloboldines- and 3,8-dihaloboldines (2-5).
Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo
derivative 6 was obtained. Radioligand binding studies of these products showed
that halogenation of boldine at C-3 favors affinity for D(1)- (vs D(2)-)
dopaminergic receptors, attaining a low nanomolar IC(50) value in the case of 3
iodoboldine (6).
PMID- 10785419
TI - Coumarins from the fruits of Cnidium monnieri.
AB - Two novel biscoumarins, cnidimonal (1) and cnidimarin (2), and two new coumarin
derivatives, 5-formylxanthotoxol (3) and 2'-deoxymeranzin hydrate (4), were
isolated from a traditional Chinese crude drug, the fruits of Cnidium monnieri,
together with 15 known compounds. Among the known compounds, five of the minor
compounds were isolated for the first time from this plant. The structures of 1-4
were determined with the use of spectroscopic methods.
PMID- 10785420
TI - Biotransformation of testosterone and pregnenolone catalyzed by the fungus
Botrytis cinerea.
AB - Testosterone (1), a male sex hormone, and pregnenolone (2), a precursor of many
steroidal hormones, were oxidized by fermentation with the fungus Botrytis
cinerea. The fermentation of 1 yielded 7beta,17beta-dihydroxyandrostan-3-one (3)
(73%) in a yield comparable to chemical transformations. Fermentation of 2 by the
same fungus afforded a major metabolite 3beta,11alpha, 16beta-trihydroxypregn-5
en-20-one (4) (39%) along with a minor metabolite 11alpha,16beta-dihydroxypregn-4
ene-3,20-dione (5) (6%). The metabolites are characterized by detailed physical
and spectroscopic studies.
PMID- 10785421
TI - Cytotoxic constituents of the roots of Ekmanianthe longiflora.
AB - Bioactivity-directed fractionation of the CHCl(3) extract of the roots of
Ekmanianthe longiflora resulted in the isolation of three new natural products,
(2R,3R,4R)-3,4-dihydro-3, 4-dihydroxy-2-(3-methyl-2-butenyl)-1(2H)-naphthalenone
(1), (2S,3R, 4R)-3,4-dihydro-3, 4-dihydroxy-2-(3-methyl-2-butenyl)-1(2H)
naphthalenone (2), and (2R, 3aR,9R,9aR)-9-hydroxy-2-(1-hydroxy-1-methylethyl)
2,3,3a,4,9 , 9a-hexahydro-naphtho[2,3-b]furan-4-one (3), together with the known
compounds 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-quinone (4), 2
acetylnaphtho[2,3-b]furan-4,9-quinone (5), dehydro-iso-alpha-lapachone (6), alpha
lapachone (7), catalponol, and epi-catalponol. The structures of 1-3 were
determined using a combination of NMR spectroscopic techniques, and the absolute
configurations of compounds 1 and 2 were obtained using Mosher ester methodology.
Compounds 4-6 showed significant cytotoxicity in a panel of human cancer cells.
alpha-Lapachone (7) exhibited only marginal activity, and catalponol and epi
catalponol were inactive in this regard. When tested at 72 mg/kg/injection in an
in vivo mouse P-388 leukemia system, compound 4 was inactive (110% T/C).
PMID- 10785422
TI - Quadranosides I-V, new triterpene glucosides from the seeds of Combretum
quadrangulare.
AB - Five new triterpene glucosides, quadranosides I-V (1-5), have been isolated from
a MeOH extract of the seeds of Combretum quadrangulare, together with 13 known
compounds. The structures of compounds 1-5 were elucidated on the basis of
spectroscopic analysis. Among the new triterpene glucosides, three compounds (1,
2, 5) showed significant hepatoprotective effects against D-galactosamine (D
GalN)/tumor necrosis factor-alpha (TNF-alpha)-induced cell death in primary
cultured mouse hepatocytes.
PMID- 10785423
TI - Mololipids, a new series of anti-HIV bromotyramine-derived compounds from a
sponge of the order verongida.
AB - A new series of lipids called mololipids have been identified from an Hawaiian
sponge of the order Verongida. The structures of these lipids was deduced from
spectroscopic data of the lipid mixture combined with GC-MS analysis. The core of
this novel series of lipids is a bromotyramine homoserine-derived moiety known as
moloka'iamine (1) which is found in many Verongid sponge metabolites.
Moloka'iamine forms bisamides with a diverse series of fatty acids and the
mololipids mixture (2) was active against HIV-1 with an EC(50) of 52.2 microM
without cytotoxicity in human lymphocytes (IC(50) > 100 microM).
PMID- 10785424
TI - A new isoflavone from Genista corsica.
AB - A new isoflavone (1), dihydroisoderrondiol [(3' 'S,4' 'R)-5,7,3' ', 4' '
tetrahydroxy-2' ',2' '-dimethyl-3' ',4' '-dihydropyrano(5' ',6' ';3' ',4'
')isoflavone], was isolated from aerial parts of Genista corsica, together with
11 previously known compounds [daidzein, isoprunetin, isoderrone (2),
ficuisoflavone (3), luteolin, luteolin 4'-O-beta-glucoside, luteolin 7-O-beta
glucoside, taxifolin, 5-methoxytaxifolin, sucrose, and D-pinitol]. The structure
of 1 was elucidated by spectroscopic methods.
PMID- 10785425
TI - 7-O-Methyltetrahydroochnaflavone, a new biflavanone from Ochna beddomei.
AB - 7-O-Methyltetrahydroochnaflavone (1), a new biflavanone, together with nine known
flavonoids, afrormosin (2), 2,3-dihydroochnaflavone 7-O-methyl ether (3),
kaempferol (4), 2,3-dihydroochnaflavone (5), ochnaflavone (6), (-)-epicatechin
(7), kaempferol 3-O-rhamnoside (8), taxifolin 3-O-rhamnoside (9), and kaempferol
3-O-glucoside (10), were isolated from the leaves of Ochna beddomei, and the
structures were elucidated by spectral and chemical studies.
PMID- 10785426
TI - Clerodane diterpenes from Tinospora rumphii.
AB - Two new diterpenes (1 and 2) were obtained from the leaves of Tinospora rumphii,
along with the known compounds tinotufolin D and vitexilactone. The structures of
compounds 1 and 2 were established on the basis of spectroscopic studies.
PMID- 10785427
TI - 17-Epiacnistin-A, a further withanolide from the leaves of Discopodium
penninervium.
AB - A novel withanolide (1) has been isolated from the leaves of Discopodium
penninervium and identified as 17-epiacnistin-A on the basis of spectroscopic and
X-ray diffraction data.
PMID- 10785428
TI - New lanostanoids of Ganoderma tsugae.
AB - Three new compounds, (24R, S)-3alpha-acetoxy-24-hydroxy-5alpha-lanosta-8,25-di en
21-oic acid, named tsugaric acid C (1); 3alpha-acetoxy-5alpha-lanosta-8, 24-diene
21-O-beta-D-xyloside, named tsugarioside B (2); and 3alpha-acetoxy-(Z)-24-methyl
5alpha-lanosta-8,23,25-tr ien-21-oic acid ester beta-D-xyloside, named
tsugarioside C (3), and a mixture of two known steroids were isolated from the
fruit bodies of Ganoderma tsugae. The structures of 1-3 were determined by
spectral and chemical methods. The cytotoxic activity of the lanostanoid
constituents of this fungus was evaluated against several different cancer cell
lines.
PMID- 10785429
TI - Sulcatin, a novel antiproliferative N-methylpyridinium alkaloid from the ascidian
Microcosmus vulgaris.
AB - A new N-methylpyridinium alkaloid, with an interesting antiproliferative activity
in vitro, has been isolated from the Mediterranean tunicate Microcosmus vulgaris.
Its structure has been elucidated by spectroscopic analysis, including extensive
2D NMR experiments.
PMID- 10785430
TI - Sesquiterpene phenylpropanoid and sesquiterpene chromone derivatives from Ferula
pallida.
AB - Four novel compounds-two sesquiterpene phenylpropanoid derivatives, pallidones G
(1) and H (2), and two sesquiterpene chromone derivatives, pallidones I (3) and J
(4)-have been isolated from the roots of Ferula pallida. Their structures were
determined on the basis of NMR and HREIMS evidence.
PMID- 10785431
TI - Haliclonyne, a new highly oxygenated polyacetylene from the marine sponge
Haliclona species.
AB - Haliclonyne (1), a new polyacetylene carboxylic acid, has been isolated from the
marine sponge Haliclona sp. collected in the Gulf of Eilat. The structure of
haliclonyne, a C(47) oxo-octahydroxy-dienetetrayne carboxylic acid, was
elucidated by interpretation of NMR and mass spectra of 1 and two of its
derivatives.
PMID- 10785432
TI - Scalarane and homoscalarane compounds from the nudibranchs Glossodoris sedna and
Glossodoris dalli: chemical and biological properties.
AB - A series of homoscalarane and scalarane compounds (2-7) have been isolated from
two distinct species of Pacific Glossodoris nudibranchs. The structure and
elucidation of the relative stereochemistry of the new metabolites 2 and 3 were
obtained by spectroscopic methods. Compound 2 was ichthyotoxic at 0.1 ppm against
Gambusia affinis and showed moderate activity (IC(50) 18 microM) to inhibit
mammalian phospholipase A(2).
PMID- 10785433
TI - HIV-inhibitory cembrane derivatives from a Philippines collection of the soft
coral Lobophytum species.
AB - Bioassay-guided fractionation of an aqueous extract of a Philippine Islands
collection of the soft coralLobophytum sp. concentrated its HIV-inhibitory
activity into fractions rich in cembranoid diterpenes. Lobohedleolide (1), (7Z)
lobohedleolide (2), and a new compound, 17-dimethylaminolobohedleolide (3), were
purified from these fractions by HPLC. The structures of compounds 1-3 were
elucidated by spectroscopic analyses and by comparison of their spectral data
with previously reported values. The relative stereochemistry of the gamma
lactone ring substituents of 3 was determined by 1D NOESY experiments. While
several other cembranoids that contain a dimethylamino functional group have been
reported from the soft coral Sinularia sp., compound 3 represents the first
cembrane diterpene with this functional group isolated from a Lobophytum species.
Diterpenoids 1-3 exhibited moderate HIV-inhibitory activity (EC(50) approximately
3-5 microg/mL) in a cell-based in vitro anti-HIV assay.
PMID- 10785434
TI - Two novel secoergosterols from the fungus Tylopilus plumbeoviolaceus.
AB - Two novel secoergosterols, 3beta-hydroxy-8alpha,9alpha-oxido-8, 9-secoergosta
7,9(11),22-triene (tylopiol A) (1) and 3beta-hydroxy-8alpha,9alpha-oxido-8,9
secoergosta-7,22 -dien-12-one (tylopiol B) (2), were isolated from the fresh
fruit bodies of Tylopilus plumbeoviolaceus, along with three known compounds,
ergosta-7,22-dien-3beta-ol, uridine, and allitol. Their structures were
elucidated by NMR techniques, including (1)H NMR, (13)C NMR, HMQC, HMBC, and MS.
The structure and stereochemistry of compound 1 were demonstrated by X-ray
crystallography.
PMID- 10785435
TI - A cytotoxic sesquiterpene caffeate from the liverwort Bazzanianovae-zelandiae.
AB - Extracts of the liverwort Bazzania novae-zelandiae were cytotoxic, with selective
activity against human tumor cell lines. Bioactivity-directed isolation work
showed that the new compound naviculyl caffeate (1) was the main cytotoxin. This
structure was confirmed by synthesis from the co-occurring sesquiterpene
naviculol (2).
PMID- 10785436
TI - Stephanotic acid, a novel cyclic pentapeptide from the stem of Stephanotis
floribunda.
AB - The stem of Stephanotis floribunda afforded a new cyclic pentapeptide stephanotic
acid (1), possessing a novel 6-(leucin-3'-yl) tryptophan skeleton. The structure
of 1 was assigned on the basis of extensive NMR experiments and a chemical
reaction and shown to be closely related to the bicyclic octapeptide moroidin
(3), a toxin from Laportea moroides.
PMID- 10785437
TI - Long-range (1)H-(15)N heteronuclear shift correlation at natural abundance.
AB - Despite the inherently low sensitivity of (15)N NMR because of its low
gyromagnetic ratio (gamma(N)) and its relatively low natural abundance (0.37%),
this important nuclide still has useful potential as a structural probe even at
natural abundance. Inverse-detected NMR methods coupled with major advances in
NMR probe designs have made it possible to acquire long-range (1)H-(15)N
heteronuclear shift correlation data on samples as small as a micromole
overnight. Chemical shift referencing schemes for (15)N and the range of (15)N
shifts are discussed, followed by a discussion of the currently available pulse
sequences, pulse calibration, parametrization and processing of long-range (1)H
(15)N data, and the implications of probe selection. These topics are followed by
a review of the applications contained in the literature that have utilized (1)H
(15)N heteronuclear shift correlation experiments at natural abundance, with
emphasis placed on the observed long-range coupling pathways.
PMID- 10785438
TI - Inhalation of low concentrations of toluene induces persistent effects on a
learning retention task, beam-walk performance, and cerebrocortical size in the
rat.
AB - The organic solvent toluene is widely used in industry. The threshold limit value
for extended occupational exposure to toluene is presently set to 200 ppm in the
United States. We have investigated the effect of an inhalation exposure of 80
ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at
least 4 weeks, on behavior and brain features in the rat. Toluene exposure
appeared to affect spatial memory, since toluene-exposed rats showed a longer
time in the correct quadrant in a Morris swim maze. This effect may indicate that
the exposed rats used their praxis strategy longer before they started to look
for the platform elsewhere. Toluene-exposed rats showed trends for increases in
both locomotion and rearing behaviors and a significantly reduced beam-walk
performance. The area of the cerebral cortex, especially the parietal cortex, was
decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance
imaging of living rats and autoradiograms of frozen brain sections. The K(D) and
B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by
toluene, as measured in caudate-putamen and subcortical limbic area using
biochemical receptor binding assays and in caudate-putamen and islands of Calleja
using quantitative receptor autoradiography. Hence, previously demonstrated
persistent effects by toluene on the binding characteristics of radioligands
binding to both D(2) and D(3) receptors seem to indicate a persistent effect of
toluene selectively on dopamine D(2) receptors. Taken together, the present
results indicate that exposure to low concentrations of toluene leads to
persistent effects on cognitive, neurological, and brain-structural properties in
the rat.
PMID- 10785439
TI - DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence
for apoptosis in frontotemporal dementia.
AB - Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly
the frontal and anterior temporal cortex. It is associated with neuronal loss,
gliosis, and microvacuolation of lamina I to III in these brain regions. In
previous studies we have described neurons with DNA damage in the absence of
tangle formation and suggested this may result in tangle-independent mechanisms
of neurodegeneration in the AD brain. In the present study, we sought to examine
DNA fragmentation and activated caspase-3 expression in FTD brain where tangle
formation is largely absent. The results demonstrate that numerous nuclei were
TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was
detected in both neurons and astrocytes and was elevated in FTD cases as compared
to control cases. A subset of activated caspase-3-positive cells were also TdT
positive. In addition, the cell bodies of a subset of astrocytes showed enlarged,
irregular shapes, and vacuolation and their processes appeared fragmented. These
degenerating astrocytes were positive for activated caspase-3 and colocalized
with robust TdT-labeled nuclei. These findings suggest that a subset of
astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may
contribute to neuronal cell death and astrocyte degeneration in the FTD brain.
Our results suggest that apoptosis may be a mechanism of neuronal cell death in
FTD as well as in AD (228).
PMID- 10785440
TI - An altered histaminergic innervation of the substantia nigra in Parkinson's
disease.
AB - The central histaminergic system is one of the subcortical aminergic projection
systems involved in several regulatory functions. The central dopaminergic and
histaminergic systems interact extensively, but little is known about the
histaminergic system in diseases affecting the dopaminergic neurons. The
distribution of histaminergic fibers in the substantia nigra (SN) in postmortem
brain samples from patients suffering from Parkinson's disease (PD) and normal
controls was examined with a specific immunohistochemical method. Direct
connections between dopaminergic neurones and histaminergic fibers were observed.
Histamine in human SN was stored in fibers and varicosities. Sites of histamine
formation were examined by l-histidine decarboxylase in situ hybridization. In
both normal and PD brains HDC mRNA was found only in posterior hypothalamus and
not in SN. The presence of histaminergic innervation of the human substantia
nigra pars compacta (SNc) and reticulata (SNr), paranigral nucleus, radix of
oculomotor nerve, and parabrachial pigmented nucleus was demonstrated. The
density of histaminergic fibers in the middle portion of SNc and SNr was
increased in brains with PD. In PD the morphology of histaminergic fibers was
also altered; they were thinner than in controls and had enlarged varicosities.
An increase of histaminergic innervation may reflect a compensatory event due to
deficiency of, e.g., dopamine or a putative fiber growth inhibitory factor.
Whether the changes seen in histaminergic fibers in PD are primary or secondary
remains to be investigated.
PMID- 10785441
TI - The properties of hNT cells following transplantation into the subventricular
zone of the neonatal forebrain.
AB - Neurons derived from the human teratocarcinoma cell line (hNT) establish
structural polarity and a fully mature phenotype following transplantation into
the rodent brain. Here we describe the transplantation of hNT cells into the
anterior part of neonatal subventricular zone (SVZa), which is a prolific region
of neuronal progenitor cells. Ordinarily, the progeny of endogenous or
homotopically transplanted SVZa cells migrate to the olfactory bulb (OB) along a
restricted pathway, the rostral migratory stream (RMS), and differentiate into
interneurons. To compare the phenotype of cultured hNT cells to their
transplanted cohorts, hNT cells labeled by the fluorescent dye PKH26 were
cultured for 1 day and stained with cell-type-specific antibodies. Clusters as
well as individual hNT cells were immunoreactive for TuJ1, an antibody that
recognizes neuron-specific class III beta-tubulin. The distribution and phenotype
of the transplanted hNT cells were examined. The majority of transplanted PKH26
labeled hNT cells were found at their site of implantation in the SVZa, while a
small proportion of the transplanted hNT cells was situated in the migratory
pathway leading to the OB and in the subependymal zone and granule cell layer of
the olfactory bulb. Many of the transplanted hNT cells, both within the SVZa and
within the RMS, revealed a neuronal phenotype. Collectively, these results reveal
the capacity of hNT cells to respond, at least partially, to cues that ordinarily
govern the migration of SVZa-derived cells and maintain their neuronal identity.
PMID- 10785442
TI - Neuroprotection by 2-h postischemia administration of two free radical
scavengers, alpha-phenyl-n-tert-butyl-nitrone (PBN) and N-tert-butyl-(2
sulfophenyl)-nitrone (S-PBN), in rats subjected to focal embolic cerebral
ischemia.
AB - Oxygen free radical generation may have important secondary damaging effects
after the onset of cerebral ischemia. Free radical scavengers have been used
successfully in attenuating neuronal damage in the reperfusion period in
transient forebrain ischemia. There are limited data on effectiveness in models
of focal ischemia. Two free radical scavengers, alpha-phenyl-n-tert-butyl-nitrone
(PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), have been shown to reduce
oxidative-stress-induced neuronal injury. Whereas PBN has been demonstrated to
reduce infarct volume in focal ischemia, neuroprotection has not been evaluated
with S-PBN. The present study was designed to evaluate the neuroprotective effect
of PBN and S-PBN compared to vehicle in a focal embolic middle cerebral artery
(MCA) cerebral ischemia model in rats. Wistar rats were randomly divided into
three groups (n = 10 each group). Animals in the control group received vehicle
and those in the treatment groups were treated with PBN or S-PBN (both 100
mg/kg/day x 3 days, intraperitoneally) starting 2 h after the introduction of an
autologous thrombus into the right-side MCA. The neurological outcome was
observed and compared before and after treatment and between groups. The
percentage of cerebral infarct volume was estimated from 2,3, 5
triphenyltetrazolium chloride stained coronal slices 72 h after the ischemic
insult. Two-hour postischemia administration of PBN or S-PBN significantly
improved neurobehavioral scores at 24 h following MCA embolization (both P <
0.01). The percentage of infarct volume for animals receiving vehicle was 32.8 +/
9.4%. Two-hour delayed administration of PBN and S-PBN achieved a 35.4%
reduction in infarct volume in treatment groups when compared with animals
receiving vehicle (PBN vs control, 21.2 +/- 10.9% vs 32.8 +/- 9.4%; P < 0.05; S
PBN vs control, 21.2 +/- 13.1%, (P < 0.05). These data indicate that free radical
generation may be involved in brain damage in this model and 2-h delayed
postischemia treatment with PBN and S-PBN may have neuroprotective effects in
focal cerebral ischemia. As S-PBN does not normally cross the blood-brain
barrier, the neuroprotection evident in this study may be explained by entry into
the brain via damaged vessels.
PMID- 10785443
TI - Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted
expression of tumor necrosis factor-alpha.
AB - Transgenic mice expressing TNF-alpha under the regulatory control of the GFAP
gene promoter (GFAP-TNFalpha mice) exhibit a unique, late-onset chronic
progressive neurological disorder with meningoencephalomyelitis,
neurodegeneration, and demyelination with paralysis. Here we show that the
metallothionein-I + II (MT-I + II) isoforms were dramatically upregulated in the
brain of symptomatic but not presymptomatic GFAP-TNFalpha mice despite TNF-alpha
expression being present in both cases. In situ hybridization analysis for MT-I
RNA and radioimmunoassay results for MT-I + II protein revealed that the
induction was observed in the cerebellum but not in other brain areas. Increased
MT-I RNA levels occurred in the Purkinje and granular neuronal layers of the
cerebellum but also in the molecular layer. Reactive astrocytes, activated rod
like microglia, and macrophages, but not the infiltrating lymphocytes, were
identified as the cellular sources of the MT-I + II proteins. In situ
hybridization for MT-III RNA revealed a modest increase in the white matter of
the cerebellum, which was confirmed by immunocytochemistry. MT-III
immunoreactivity was present in cells which were mainly round or amoeboid
monocytes/macrophages. The pattern of expression of the different MT isoforms in
the GFAP-TNFalpha mice differed substantially from that described previously in
GFAP-IL6 mice, demonstrating unique effects associated with the expression of
each cytokine. The results suggest that the MT expression in the CNS reflects the
inflammatory response and associated damage rather than a direct role of the TNF
alpha in their regulation and support a major role of these proteins during CNS
injury.
PMID- 10785444
TI - GDNF and NT-4 protect midbrain dopaminergic neurons from toxic damage by iron and
nitric oxide.
AB - Free radical formation is considered to be a major cause of dopaminergic
(DAergic) cell death in the substantia nigra leading to Parkinson's disease (PD).
In this study we employed several radical donors including iron and sodium
nitroprusside to induce toxic effects on DAergic neurons cultured from the
embryonic rat midbrain floor. Overall cell survival was assessed by assaying LDH,
and DAergic neuron survival was monitored by counting tyrosine hydroxylase
positive cells. Our data suggest that the DAergic neuron population is about
fourfold more susceptible to free-radical-mediated damage than the total
population of midbrain neurons. Application of the neurotrophic factors GDNF and
NT-4, for which DAergic neurons have specific receptors, prior to toxin
administration protected these neurons from toxin-mediated death, which, fully or
in part, occurs under the signs of apoptosis. These findings underscore the
importance of GDNF and NT-4 in designing future therapeutical concepts for PD.
PMID- 10785445
TI - Changes in cerebral blood flow and distribution associated with acute increases
in plasma sodium and osmolality of chronic hyponatremic rats.
AB - The cause of the osmotic demyelination syndrome that follows too rapid correction
of chronic hyponatremia (CHN) is unknown. Recently, we reported in CHN rats an
association between blood-brain barrier (BBB) disruption occurring as early as 3
h into correction and subsequent demyelination. Given the changes in brain water
and blood volume which occur during correction of CHN, we hypothesized that the
same correction protocol that causes demyelination might alter cerebral blood
flow (CBF) during correction, thereby possibly contributing to BBB disruption and
demyelination. Ten CHN rats were given hypertonic sodium intraperitoneally and
its effect on CBF was continuously monitored for 3 h by magnetic resonance flow
imaging. Over the subsequent 3 h, plasma sodium rose from 110.8 to 127.6
mEq/liter (P < 0.001) but neither mean arterial blood pressure nor arterial CO(2)
tension changed significantly. By 30 min, CBF increased by 50% in cortical and
subcortical areas (P < 0.001) and remained elevated for the next 60 min. After 2
h, cortical flow was no longer elevated significantly and by 3 h it had returned
to control values. Subcortical flow, however, significantly exceeded control
values throughout the 3 h so that after 2 h the ratio of cortical to subcortical
blood flow had fallen from 1.17 to 0.91 (P < 0.05). Although the mechanism by
which increased plasma sodium and osmolality alters CBF is uncertain, the results
suggest that changes in CBF may be part of a cascade of cerebrovascular
disturbances including endothelial or parenchymal damage, mechanical events,
metabolic disturbances, or cytokine release which eventually lead to BBB
disruption and subsequent demyelination.
PMID- 10785446
TI - IL-6 deficiency leads to reduced metallothionein-I+II expression and increased
oxidative stress in the brain stem after 6-aminonicotinamide treatment.
AB - We examined the effects of interleukin-6 (IL-6) deficiency on brain inflammation
and the accompanying bone marrow (BM) leukopoiesis and spleen immune reaction
after systemic administration of a niacin antagonist, 6-aminonicotinamide (6-AN),
which causes both astroglial degeneration/cell death in brain stem gray matter
areas and BM toxicity. In both normal and genetically IL-6-deficient mice (IL-6
knockout (IL-6KO) mice), the extent of astroglial degeneration/cell death in the
brain stem was similar as determined from disappearance of GFAP immunoreactivity.
In 6-AN-injected normal mice reactive astrocytosis encircled gray matter areas
containing astroglial degeneration/cell death, which were infiltrated by several
macrophages and some T-lymphocytes. Reactive astrocytes and a few macrophages
increased significantly the antioxidants metallothionein-I+II (MT-I+II) and
moderately the MT-III isoform. In 6-AN-injected IL-6KO mice reactive astrocytosis
and recruitment of macrophages and T-lymphocytes were clearly reduced, as were BM
leukopoiesis and spleen immune reaction. Expression of MT-I+II was significantly
reduced while MT-III was increased. Oxidative stress, as determined by measuring
nitrated tyrosine and malondialdehyde, was increased by 6-AN to a greater extent
in IL-6KO mice. The blood-brain barrier to albumin was only disrupted in 6-AN
injected normal mice, which likely is due to the substantial migration of blood
derived inflammatory cells into the CNS. The present results demonstrate that
inflammation in CNS is clearly reduced during IL-6 deficiency and this effect is
likely due to significant inhibition of BM leukopoiesis. We also show that IL-6
deficiency reduces the levels of neuroprotective antioxidants MT-I+II followed by
an increased oxidative stress during CNS inflammation.
PMID- 10785447
TI - Embryonic donor age and dissection influences striatal graft development and
functional integration in a rodent model of Huntington's disease.
AB - The method of embryonic dissection and the age of the donor material remain areas
of controversy in the preparation of striatal tissue for intrastriatal
implantation. This study explores the relationship between these two parameters
with respect to the morphology, function, and physiological integration of the
resultant grafts. Tissue derived from embryos of 14 and 16 days of gestation (CRL
10-11 and 14-15 mm, respectively) was prepared as whole, lateral, and medial
ganglionic eminence suspensions (WGE, LGE, and MGE, respectively). The embryonic
material was implanted into the excitotoxically lesioned striatum of host rats.
Grafts derived from E14 LGE attenuated drug-induced rotational bias whereas
grafts from E14 MGE ameliorated contralateral deficits in paw reaching. Six
months after grafting retrograde tracing of graft projections to the globus
pallidus was performed followed by electrical excitation of cortical afferent
fibers. Grafts derived from E14 WGE had the largest volume of striatum-like
tissue and more striatal neurons compared to LGE from the same donor age. These
results suggest that MGE tissue as well as LGE plays a role in the structural and
functional integration of striatal grafts.
PMID- 10785448
TI - Alzheimer-related tau-pathology in the perforant path target zone and in the
hippocampal stratum oriens and radiatum correlates with onset and degree of
dementia.
AB - Abnormal phosphorylation of the tau-protein is regarded as a crucial step in the
formation of neurofibrillary tangles in the neuronal cell body and neuropil
threads in dendrites. We studied the effects of tau-pathology on the clinical
expression of dementia in 106 autopsy cases in the entorhinal region, the
hippocampal stratum oriens, the stratum radiatum, and the perforant path target
zone. The first cytoskeletal lesions were located in the perikarya and dendrites
of the pre-alpha cells of the transentorhinal and entorhinal region. Next,
abnormally phosphorylated tau-protein (PHF-tau) was found in the neuropil of the
CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began
to be involved in PHF-tau pathology in Braak stage II. In the Braak stages IV and
V, the stratum radiatum was completely involved, the stratum oriens increasingly
so. Beginning in Braak stage III, we noted cases having PHF-tau pathology in the
perforant path target zone of the outer molecular layer of the dentate gyrus. The
increase of this pathology with ever greater involvement on the part of the
entorhinohippocampal circuit correlated significantly not only with the Braak
stages and with the neurochemically determined hippocampal content of PHF-tau but
also with the degree of dementia as defined by the clinical dementia rating (CDR)
scale. The affection of the stratum oriens in combination with PHF-tau pathology
in the stratum radiatum and in the outer molecular layer of the dentate gyrus was
encountered almost exclusively in demented individuals (CDR 1-3). These results
indicate that axonal PHF-tau pathology in hippocampal pathways presumably is
critical for the clinical expression of dementia and may constitute an anatomical
substrate of clinically verifiable memory dysfunction in Alzheimer's disease.
PMID- 10785449
TI - Molecular dating of senile plaques in the brains of individuals with Down
syndrome and in aged dogs.
AB - beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age
in individuals with Down syndrome (DS) and in the canine model of aging. Sections
of DS and dog brain were immunostained using an affinity-purified polyclonal
antibody for a posttranslationally modified Abeta with a racemized aspartate at
position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and
dog brain indicate that it is present in all plaque subtypes, including the
thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest
DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive
plaques increased with age. In addition, d7C16-positive plaques were initially
found in clusters in the superficial layers of the frontal and entorhinal cortex
but, with advancing age, increasing numbers appeared in deeper layers, suggesting
a progression of Abeta deposition from superficial to deeper cortical layers.
Ultrastructural studies in DS brain were confirmed using perfused dog brain and
provided consistent results; thioflavin-S-negative diffuse plaques consist of
fibrillar Abeta and racemized Abeta is associated with thicker and more highly
interwoven fibrils than nonracemized Abeta. The use of antibodies to modified
forms of the Abeta protein should provide insight into the progression of plaque
pathology in DS and Alzheimer's disease brain.
PMID- 10785450
TI - In situ produced 7-chlorokynurenate provides protection against quinolinate- and
malonate-induced neurotoxicity in the rat striatum.
AB - Excitotoxic mechanisms may play a critical role in the pathophysiology of several
neurological and psychiatric diseases. Excitatory amino acid receptor antagonists
are therefore of great therapeutic interest, but untoward side effects often
prevent their clinical use. Targeting the glycine coagonist site of the (NMDA)
receptor may bypass these shortcomings. The present study was designed to
evaluate the neuroprotective characteristics of l-4-chlorokynurenine (4-Cl-KYN),
a synthetic compound which is enzymatically converted to the selective
glycine/NMDA receptor antagonist 7-chlorokynurenate (7-Cl-KYNA). Using slow (2 h)
intrastriatal infusions of the excitotoxins quinolinate (QUIN; 120 nmol) or
malonate (6.8 micromol) as the experimental paradigm, the neuroprotective potency
of 4-Cl-KYN was first compared with that of exogenous 7-Cl-KYNA, using glutamate
decarboxylase activity as a lesion marker. One hundred and thirty-five nanomoles
of the prodrug 4-Cl-KYN or 27 nmol 7-Cl-KYNA, the former used in a pre- and
cotreatment regimen, were required to block QUIN or, less efficiently, malonate
toxicity. In separate animals, the metabolic fate of this neuroprotective dose of
4-Cl-KYN was examined in vivo. In control striata, the treatment gave rise to 170
+/- 25 pmol 7-Cl-KYNA/mg protein, approximately six times less than an infusion
of 27 nmol exogenous 7-Cl-KYNA, indicating greatly superior efficacy of the
focally produced antagonist. Notably, the conversion of 4-Cl-KYN to 7-Cl-KYNA
increased by 82% in the presence of QUIN. 4-Cl-KYN was also metabolized to 4
chloro-3-hydroxyanthranilate, an established, powerful inhibitor of QUIN
synthesis. This unique pharmacological profile and the fact that the prodrug,
unlike 7-Cl-KYNA, readily penetrates the blood-brain barrier suggest that 4-Cl
KYN may be exceptionally useful as an anti-excitotoxic agent.
PMID- 10785451
TI - Hydrocephalus in the H-Tx rat: a monogenic disease?
AB - The H-Tx rat is a genetic model of hydrocephalus for which thereis a poor
understanding of the mode of inheritance. Previous studies suggested a
polygenicmode of inheritance but the breeding data to supportthis hypothesis have
not been reported. In an attempt to clarify the hereditary mode we have analyzed
the data from eight generations of H-Tx rats and four generations of cross
matings between H-Tx rats and Sprague-Dawley (SD) rats. In the H-Tx rat colony
113 of 129 random brother-sister matings (87.60%) produced hydrocephalic
offspring, with males and females being equally affected. The overall incidence
varied greatly with an average of 30. 35%. In matings with more than three
litters, all mating pairs yielded hydrocephalic pups. In cross-matings both
hydrocephalic and normal H-Tx rats were mated with normal SD rats. No
hydrocephalus was observed in the first generation of 124 pups (F1). Subsequent
brother-sister matings of F1 animals generated hydrocephalic pups in the F2
generation with a lower incidence (4.67% in hydrocephalic HTx/SD matings and
5.11% in normal HTx/SD matings, respectively) than in the H-Tx rat colony
(30.35%). Back-cross-matings between F2 rats and normal H-Tx rats yielded an
incidence of hydrocephalus higher than that of the cross-matings but lower than
that of the H-Tx colony. These data strongly suggest that the H-Tx rat is a
homozygous carrier of an autosomal recessive hydrocephalus gene with incomplete
penetrance. Furthermore, the data clearly rule out sex-linked and polygenic modes
of inheritance and provide further insight with respect to genetic inheritance of
hydrocephalus.
PMID- 10785452
TI - Coordination of prehensile forces during precision grip in Huntington's disease.
AB - The present study examined the coordination of prehensile forces during precision
grip in subjects with Huntington's disease (HD). Fingertip forces were measured
in 12 subjects with HD and 12 age-matched controls during the lifting of an
instrumented object whose weight and surface texture were varied. The results
indicate that subjects with HD have impaired initiation and delayed transitions
between movement sequences and produce excessive and variable forces. However,
subjects with HD demonstrated anticipatory scaling of force development based on
the object's expected physical properties (planning) and adjustment of the force
to the object's actual physical properties (sensorimotor integration). The
observed findings generally were unrelated to the overall disease severity.
However, the variability in forces was correlated with functional capacity and
motor performance suggesting that variability is a key feature of the motor
deficit. These results provide insights into the impaired hand function observed
in individuals with HD.
PMID- 10785453
TI - Immunological myelin disruption does not alter expression of regeneration
associated genes in intact or axotomized rubrospinal neurons.
AB - The inability of axotomized neurons to regenerate within the CNS has been
partially attributed to a number of inhibitory factors associated with CNS myelin
that are extrinsic to the severed neurons. However, some neurons are capable of
limited regeneration after injury and this ability has been shown to correlate
with the expression of certain regeneration-associated genes (RAGs) intrinsic to
injured neurons. It has therefore been postulated that neutralization of
inhibitory factors, as well as the induction of an appropriate neuronal cell body
response, would facilitate improved regrowth of injured CNS axons. In previous
studies we have shown that immunological removal of myelin from the spinal cord
facilitates axonal regeneration by rubrospinal neurons, as indicated by
retrograde transport of a fluorescent dye placed distal to the site of injury.
Here, we investigated whether the immunological focal removal of spinal cord
myelin, following a thoracic spinal cord injury, concomitantly stimulated an
increase in the expression of RAGs in rubrospinal neurons. In situ hybridization
for Talpha-1 tubulin and GAP-43 at days 7, 14, and 21 revealed no significant
increase in gene expression in rubrospinal neurons following immunological
demyelination. The ability of various neuronal populations to sprout or slowly
regrow without expressing the previously characterized cell body response is
reviewed. We conclude that the recently demonstrated regeneration of rubrospinal
tract, after immunologically directed spinal cord demyelination, is the result of
either axonal sprouting or slow axonal regrowth without the increased expression
of RAGs characteristic for fast axon regeneration.
PMID- 10785454
TI - Effects of aluminum exposure on glutamate metabolism: a possible explanation for
its toxicity.
AB - The effects of aluminum (Al) exposure on glutamate metabolism were investigated
to study the mechanism of Al toxicity in rat brain. In astrocytes, the glutamate
glutamine pathway prevents the accumulation of the excitatory neurotransmitter
glutamate, recognized as a neuronal excitotoxin when present in excess in the
extracellular space. Changes in the level of l-aspartate, l-glutamate, and its
metabolite l-glutamine were investigated in various regions of rat brains
following intraperitoneal injection of aluminium gluconate for 2 months. The
changes observed were area- and amino-acid-specific. An increase in glutamine,
but not in l-glutamate or l-aspartate, was noted in the hippocampus and neocortex
of Al-treated rats. This increase in vivo was consistent with observations in
vitro. Exposure of cultured astrocytes to Al chloride (200, 400, and 800 microM)
specifically increased glutamine synthetase activity for the three concentrations
tested. In parallel with this increase, a higher rate of disappearance of
glutamate from culture medium was observed during the first 10 min of incubation
for the three concentrations tested, as well as an accumulation of glutamine in
the cellular extract after 30 min. These observations indicate that the astrocyte
population is a potential target for Al toxic action that could mediate the
pathogenesis of this metal.
PMID- 10785455
TI - Enhancement of acute phase and inhibition of chronic phase of experimental
autoimmune neuritis in Lewis rats by intranasal administration of recombinant
mouse interleukin 17: potential immunoregulatory role.
AB - Experimental autoimmune neuritis (EAN) is a CD4(+) T-cell-mediated demyelinating
disease of the peripheral nervous system (PNS). We examined the effect of
recombinant mouse interleukin 17 (rmIL-17) on chronic EAN induced in Lewis rats
by inoculation of P2 57-81 peptide in Freund's complete adjuvant. Animals were
treated nasally for 6 days with either 0.1 or 0.9 microg/rat/day rmIL-17 from the
onset of neurological signs, i.e., days 9 to 14 postimmunization (p.i.).
Prolonged follow-up demonstrated a chronic course in control and rmIL-17-treated
rats. Treated rats had more severe disease initially (days 18-36 p.i.) with a
stronger enhancing effect observed with the higher rmIL-17 dose. At day 19 rmIL
17-treated rats showed increased infiltration of inflammatory cells into the
sciatic nerve, more severe demyelination, augmented proliferation of regional
lymph node cells, and increased serum levels of tumor necrosis factor-alpha.
After the initial phase of disease enhancement the IL-17-treated EAN rats
improved gradually and ultimately recovered completely, whereas the control EAN
rats remained affected until the end of the observation (day 120 p.i.). The lower
dose of rmIL-17 induced an earlier recovery from clinical deficits than the
higher one. The results indicate that IL-17 plays an immunoregulatory role in
chronic EAN which could have implications for immunomodulatory treatments of
chronic autoimmune disease of the PNS.
PMID- 10785456
TI - Ultrastructural localization of monoclonal antiphospholipid antibody binding to
rat brain.
AB - Antiphospholipid antibodies (aPL), in the presence or absence of systemic lupus
erythematosus, are associated with a number of neurologic complications. However,
the role aPL play in pathology is unclear. A thrombotic etiology seems likely for
many associated disorders, but not for others. Here we describe aPL-reactive
sites in the central nervous system (CNS). Previously, using light microscopy, we
showed direct binding of two monoclonal phosphatidylserine-reactive antibodies
(aPS) to ependyma and myelin of fixed cat brain. In this study we determined the
ultrastructural localization of their binding sites in rat CNS using immunogold
electron microscopy techniques. Both monoclonal antibodies reacted strongly with
myelin, preferentially with the major dense line formed by the cytoplasmic
apposition of the oligodendrocyte plasma membrane. Both monoclonal antibodies
also reacted with an antigen that appears associated with the axoneme in cilia of
ependymal and choroid plexus epithelium. One monoclonal aPS also showed some
reactivity with brain vascular endothelium and reacted slightly with
mitochondria, while the other aPS did not react with these structures. While the
etiology of aPL-associated neurologic disorders remains unclear, our data suggest
possible target sites within the CNS with which aPL can react.
PMID- 10785457
TI - An analysis of atrophy in the medial mammillary nucleus following hippocampal and
fornix lesions in humans and nonhuman primates.
AB - Lesions of the hippocampal formation or transections of the fornix are followed
by shrinkage of the medial mammillary nucleus (MMN). We determined whether the
shrinkage of this nucleus was due to loss and/or shrinkage of neurons in addition
to the loss of neuropil. We examined the MMN in a patient (KB) with an infarct
that led to marked atrophy of the left hippocampus and subiculum, leaving the
right MMN intact. Unbiased, stereological measurement techniques were used to
compare the total cell number and individual neuronal cross-sectional areas in
both left and right MMN in this patient and in two control human brains. We also
analyzed the MMN in four macaque monkeys that underwent experimental unilateral
transections of the fornix. The volume of the MMN on the lesioned side in KB was
55% of the unlesioned side (2.8 mm(3) vs 5.1 mm(3)); the MMN in the monkey cases
were reduced to 47-58% of the volume of the nonlesioned side. Neurons in the
deafferented MMN of KB and of the monkey subjects were decreased in cross
sectional area (16-20%, P < 0.0001). There was a trend toward decreased cell
numbers (11-15%) on the lesioned side in all cases. We have estimated that the
loss in cell number and shrinkage of remaining cells contribute negligibly to the
45% reduction in MMN volume. Therefore, the loss of neuropil (dendrites and
afferent and efferent axons) appears to be the major contributor to the change in
MMN volume.
PMID- 10785458
TI - 125I-CGP 64213 binding to GABA(B) receptors in the brain of monkeys: effect of
MPTP and dopaminomimetic treatments.
AB - Much evidence indicates that abnormal GABA neurotransmission may be implicated in
the pathophysiology of Parkinson's disease (PD) and dopaminomimetic-induced
dyskinesias (DID). In this study, autoradiography using (125)I-CGP 64213 was
performed to investigate GABA(B) receptor density in the brain of control monkeys
as well as monkeys with MPTP-induced nigrostriatal depletion. Three MPTP monkeys
received pulsatile administrations of the D1 dopamine (DA) receptor agonist (SKF
82958) whereas a long-acting D2 DA receptor agonist (cabergoline) was given to
another three animals. SKF 82958 treatment relieved parkinsonian symptoms but two
of three animals developed DID. Cabergoline induced a comparable motor benefit
effect without persistent DID. (125)I-CGP 64213 binding to GABA(B) receptors was
heterogeneous throughout the brain with the highest levels in the medial habenula
of the thalamus. MPTP induced a decrease (-40%) of (125)I-CGP 64213 binding to
GABA(B) receptors in the substantia nigra pars compacta (SNpc) and an increase
(+29%) in the internal segment of the globus pallidus (GPi). This increase in the
GPi was not affected by SKF 82958 but partly reversed by cabergoline. No change
was seen in the striatum, the thalamus, the external segment of the globus
pallidus, and the substantia nigra pars reticulata following MPTP and
dopaminomimetic treatments. The changes of GABA(B) receptors observed in the SNpc
and in the GPi suggest that alteration of GABA(B) receptors may play a role in
the pathophysiology of PD and DID.
PMID- 10785459
TI - Persistent neuroprotection with prolonged postischemic hypothermia in adult rats
subjected to transient middle cerebral artery occlusion.
AB - Postischemic hypothermia provides long-lasting neuroprotection against global
cerebral ischemia in adult rats and gerbils. Studies indicate that hypothermia
must be prolonged (e.g., 24 h) to indefatigably salvage hippocampal CA1 neurons.
Delayed hypothermia also reduces focal ischemic injury. However, no study has
examined long-term outcome following postischemic hypothermia in adult animals.
Furthermore, most studies examined only brief hypothermia (e.g., 3 h). Since
previous studies may have overestimated long-term benefit and have likely used
suboptimal durations of hypothermia, we examined whether prolonged cooling would
attenuate infarction at a 2-month survival time following middle cerebral artery
occlusion (MCAo) in rats. Adult male Wistar rats were implanted with telemetry
brain temperature probes and later subjected to 30 min of normothermic MCAo
(contralateral to side of probe placement) or sham operation. Ischemia was
produced by the insertion of an intraluminal suture combined with systemic
hypotension (60 mm Hg). Sham rats and one ischemic group controlled their own
postischemic temperature while another ischemic group was cooled to 34 degrees C
for 48 h starting at 30 min following the onset of reperfusion. The infarct area
was quantified after a 2-month survival time. Normothermic MCAo resulted in
almost complete striatal destruction (91% loss +/- 12 SD) with extensive cortical
damage (36% +/- 16 SD). Delayed hypothermia treatment significantly reduced
cortical injury to 10% +/- 10 SD (P < 0.001) while striatal injury was marginally
reduced to 79% loss +/- 17 SD (P < 0.05). Delayed hypothermia of only 34 degrees
C provided long-lasting cortical and striatal protection in adult rats subjected
to a severe MCAo insult. These results strongly support the clinical assessment
of hypothermia in acute stroke.
PMID- 10785460
TI - Degeneration of cone photoreceptors induced by expression of the Mas1
protooncogene.
AB - Although transgenic expression of oncogenes typically leads to tumorigenesis,
oncogene expression directed to the rod photoreceptors leads to cell death
without tumor formation. To evaluate the cellular and functional changes induced
in cone photoreceptors by an oncogene, the Mas1 protooncogene was targeted to the
cones of transgenic mice by the human red/green opsin promoter. Mas1 was chosen
because of its exclusive expression in the nervous system and its homology to
opsin. The overall histologic appearance of the transgenic retina was normal and
retinal tumors were never observed. While rod-mediated electroretinograms were
normal in all respects, cone-mediated responses were diminished in direct
relationship to the level of transgene expression as determined by Northern blot
analysis. Responses of UV- and green-sensitive cones were reduced equivalently,
and Northern analysis and immunocytochemistry indicated that cone photoreceptor
densities were markedly diminished throughout transgenic retinas. These results
indicate that oncogene expression in cones induces cell death without tumor
formation and support the possibility that aberrant oncogene expression may
underlie some forms of hereditary retinal diseases. The Mas1 transgenic mice may
be useful in understanding the cone photoreceptor degeneration that occurs in
cone dystrophies and age-related macular degeneration and in evaluating potential
therapies for these disorders.
PMID- 10785461
TI - Localization of transforming growth factor-beta1 and receptor mRNA after
experimental spinal cord injury.
AB - Transforming growth factor-beta1 (TGFbeta1) is a cytokine/growth factor found
within the pathological central nervous system. TGFbeta1 has been shown to
inhibit the release of cytotoxic molecules from microglia and macrophages,
decrease astrocyte proliferation, and promote neuron survival. Because of the
relevance of these actions to spinal cord injury, we examined TGFbeta1 and its
receptors betaRI and betaRII mRNA levels and localization within the contused rat
spinal cord using in situ hybridization. At the lesion site, TGFbeta1 mRNA peaked
at 7 days postinjury and declined thereafter. Temporal and spatial localization
of the betaRI and betaRII receptor mRNA closely mimicked that for TGFbeta1 in the
epicenter. TGFbeta1, betaRI, and betaRII mRNAs also were elevated rostral and
caudal to the injury, especially in regions known to contain activated microglia
and degenerating axon profiles. Immunohistochemical staining of nearby sections
confirmed that the highest levels of TGFbeta1 and receptor mRNA corresponded to
regions filled with activated microglia and macrophages. The similar expression
pattern of TGFbeta1, betaRI, and betaRII mRNA within the injured spinal cord
suggests a local site of action. Since TGFbeta1 can act as an immunosuppressant
as well as a stimulant for growth factors and neurite sprouting, it likely plays
an important role, both temporally and spatially, in orchestrating postinjury
events within the spinal cord.
PMID- 10785462
TI - Development of a mouse model of neuropathic pain following photochemically
induced ischemia in the sciatic nerve.
AB - A mouse model of neuropathic pain was developed by a photochemically induced
ischemic nerve injury in normal male C57/BL6 mice. The ischemia was induced by
unilateral irradiation of the sciatic nerve with an argon ion laser after
intravenous administration of a photosensitizing dye, erythrosin B. The nerve
injury resulted in a significant decrease in withdrawal threshold of the hindpaws
to mechanical stimulation with von Frey hairs, as well as increased
responsiveness to cold and heat stimulation. The mice, however, did not exhibit
overt spontaneous pain-like behaviors. The evoked pain-related behaviors were
observed bilaterally, although the ipsilateral changes were greater than on the
contralateral side. The extent and time course of the behavioral changes were
related to the duration of laser irradiation, with 1-min exposure producing the
most consistent effect. Morphological examination at the light microscopic level
revealed partial demyelination and axonal degeneration of the large myelinated
fibers at the epicenter of the lesion 1 week postirradiation. The extent of the
damage was correlated with the duration of irradiation. Injury and loss of
unmyelinated fibers were also observed at the electronmicroscopic level. We
conclude that an intravascular photochemical reaction leading to ischemia results
in graded damage to the sciatic nerve in mice. Moreover, the nerve injury is
associated with the development of abnormal pain-related behaviors. Both the
behavioral and the morphological changes are correlated with the duration of
irradiation. These results establish a mouse model of partial nerve injury with
neuropathic pain-like behaviors which may be useful in studies using genetically
modified mice.
PMID- 10785463
TI - Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing
N-methyl-d-aspartate receptors.
AB - In the setting of nigrostriatal dopamine depletion, glutamatergic pathways to the
striatum and basal ganglia output nuclei become overactive. Systemically
administered glutamate receptor antagonists may have direct antiparkinsonian
actions in rodents, but there is little evidence for this in primates. Glutamate
antagonists may also potentiate conventional dopaminergic therapies; however,
there is concern that broad spectrum, nonselective antagonists may have unwanted
side-effects. Because subunit-selective antagonists may avoid these liabilities,
we have examined the antiparkinsonian effects of a selective antagonist of the
NR2B subunit of the NMDA receptor. In rats, CP-101,606 decreased haloperidol
induced catalepsy with an ED(50) of about 0.5 mg/kg. In MPTP-treated monkeys, CP
101,606 (1 mg/kg) reduced parkinsonian motor symptoms by 20%. At a dose of 0.05
mg/kg, CP-101,606 markedly potentiated the effect of a submaximal dose of
levodopa, reducing motor symptoms by about 50% compared to vehicle and by about
30% compared to levodopa alone. No side-effects were apparent at any dose of CP
101,606. We conclude that CP-101,606 has direct antiparkinsonian actions in both
rodents and monkeys and it synergistically potentiates levodopa in MPTP-treated
monkeys. Clinical evaluation of selective NR2B antagonists may be warranted in
Parkinson's disease.
PMID- 10785464
TI - Brain trauma in aged transgenic mice induces regression of established abeta
deposits.
AB - Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease
(AD), but it is not known if TBI affects the progression of AD. To address this
question, we studied the neuropathological consequences of TBI in transgenic (TG)
mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a
platelet-derived (PD) growth factor promoter resulting in overexpression of
mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since
brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate
with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled
cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI,
neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP
and WT mice. However, there also was a remarkable regression in the Abeta amyloid
plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral
hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest
that previously accumulated Abeta plaques resulting from progressive amyloidosis
in the AD brain also may be reversible.
PMID- 10785465
TI - Neurotransmitter-mediated control of neuronal firing in the red nucleus of the
rat: reciprocal modulation between noradrenaline and GABA.
AB - The electrical activity of neurons from the red nucleus, a mesencephalic
structure involved in motor control, is under the influence of several
neurotransmitters released from afferent fibers and/or from local interneurons.
We have investigated the combined effects of gamma-aminobutyric acid (GABA) and
noradrenaline (NA), both present at high levels in the red nucleus, on the firing
activity of single rubral neurons recorded extracellularly in vivo on
anesthetized adult rats. NA inhibited the firing activity of a large part of
rubral neurons and induced excitatory or biphasic inhibitory/excitatory effects
in a smaller group of cells. Neuronal firing was also inhibited by GABA in all
the cells studied. When the effect of GABA was tested during continuous
applications of NA, the magnitude of GABA response was modified in 58% of the
cells: the effect of GABA was potentiated by NA in half of the responding neurons
and was decreased in the remaining half. NA-induced potentiation of GABA response
was mimicked by the alpha(2)-adrenoceptor agonist clonidine and was abolished by
the alpha(2)-adrenoceptor antagonist yohimbine. On the other side, the decrease
of GABA response was reproduced by the beta-adrenoceptor agonist isoprenaline and
was blocked by timolol, an antagonist of beta-adrenoceptors. Neuronal firing
activity was reduced by nipecotic acid, an inhibitor of GABA reuptake mechanism,
and was instead increased during application of the GABA(A) receptor antagonist
bicuculline, suggesting that rubral neurons in vivo were under tonic control by
endogenous GABA. Both the inhibitory and the excitatory effects of NA were
reduced in the presence of nipecotic acid and were instead potentiated during
application of bicuculline, suggesting that NA responses were modified by
endogenous GABA. Taken together, our results indicate a reciprocal modulation
between the effects of GABA and NA on neuronal firing activity in the red nucleus
of the rat: GABA depresses the responsiveness of rubral neurons to NA, whereas NA
is able either to potentiate or to decrease the effects of GABA by activation of
alpha(2)- and beta-adrenoceptors, respectively. The functional significance of
such interaction, as well as the possible implication in diseases affecting motor
control, will be discussed.
PMID- 10785466
TI - Modulation of audiogenic seizures by histamine and adenosine receptors in the
inferior colliculus.
AB - Susceptibility to behaviorally similar audiogenic seizures (AGS) occurs
genetically and is inducible during ethanol withdrawal (ETX). Comparisons between
AGS mechanisms of genetically epilepsy-prone rats (GEPR-9s) and ethanol-withdrawn
rats (ETX-Rs) are yielding information about general pathophysiological
mechanisms of epileptogenesis. The inferior colliculus (IC) is the AGS initiation
site. Excitatory amino acid (EAA) abnormalities in the IC are implicated in AGS,
and histamine and adenosine receptor activation each reduce EAA release and
inhibit several seizure types. Previous studies indicate that focal infusion of
an adenosine receptor agonist into the IC blocked AGS in GEPR-9s, but the effects
of adenosine receptor activation in the IC on AGS in ETX-Rs are unknown. The
effects of histamine receptor activation on either form of AGS are also
unexamined. The present study evaluated effects of histamine or a nonselective
adenosine A(1) agonist, 2-chloroadenosine, on AGS by focal microinjection into
the IC. Ethanol dependence and AGS susceptibility were induced in normal rats by
intragastric ethanol. Histamine (40 or 60 nmol/side) significantly reduced AGS in
GEPR-9s, but histamine in doses up to 120 nmol/side did not affect AGS in ETX-Rs.
2-Chloroadenosine (5 or 10 nmol/side) did not affect AGS in ETX-Rs, despite the
effectiveness of lower doses of this agent in GEPR-9s reported previously. Thus,
histamine and adenosine receptors in the IC modulate AGS of GEPR-9s, but do not
modulate ETX-induced AGS. The reasons for this difference may involve the
chronicity of AGS susceptibility in GEPR-9s, which may lead to more extensive
neuromodulation as compensatory mechanisms to limit the seizures compared to the
acute AGS of ETX-Rs.
PMID- 10785467
TI - NMDAR1 receptor proteins and mossy fibers in the fascia dentata during rat
kainate hippocampal epileptogenesis.
AB - We examined the time course of NMDAR1 (NR1) immunoreactivity (IR) in the rat
inner molecular layer of the dentate gyrus following unilateral intrahippocampal
(hilar) kainic acid (KA) lesions and compared them to progressive aberrant mossy
fiber (MF) sprouting into the inner molecular layer (IML). The results
demonstrated that NR1 receptors in the IML of the KA side were decreased as early
as 3 days after KA-induced denervation, then significantly increased at
postinjection day (PID) 7. The densities of NR1 IR in the IML continued to
increase up to 5 months. By comparison, MF sprouting did not occur significantly
in the IML until PID 17, 10 days after NR1 IR was significantly increased.
Recurrent MF-IML neoinnervation significantly increased on days 17, 60, and 150.
This progressive MF innervation was significantly correlated with NR1 increases.
These results suggest that NR1 receptors were decreased soon after KA-induced
deafferentation of granule cell dendrites in the IML; however, they were replaced
by new NR1 receptors at increased densities in the granule cell dendrites, which
may have released neurotrophic factors to stimulate growth cones of MFs to
reinnervate the IML. The progressive increases of NR1 and MFs in the IML suggest
that such neosynaptogenesis would contribute monosynaptic recurrent excitatory
mechanisms for focal hippocampal hyperexcitability and seizure onsets.
PMID- 10785468
TI - Preoperative prediction of optimal resectability in advanced ovarian cancer using
CA-125.
PMID- 10785469
TI - The ability of preoperative serum CA-125 to predict optimal primary tumor
cytoreduction in stage III epithelial ovarian carcinoma.
AB - PURPOSE: The aim of this study was to determine the ability of preoperative serum
CA-125 to predict optimal primary tumor cytoreduction in patients with Stage III
epithelial ovarian carcinoma. METHODS: We performed a retrospective chart review
of 100 consecutive patients with Stage III ovarian carcinoma who had a serum CA
125 drawn prior to primary cytoreductive surgery. We used a receiver operating
characteristic curve to determine the CA-125 level with the maximal prognostic
power in predicting optimal versus suboptimal cytoreduction. RESULTS: The median
CA-125 level for the 100 patients was 819 U/ml (range 5.6-26,200 U/ml). Optimal
cytoreduction (diameter of largest residual tumor nodule < or =1 cm) was obtained
in 45 cases (45%). The probability of performing optimal cytoreduction decreased
with increasing CA-125 levels. A preoperative CA-125 level of 500 U/ml was
identified as the value with the most predictive power. Optimal cytoreduction was
achieved in 33 of the 45 cases (73%) with a CA-125 less than 500 U/ml compared to
only 12 of the 55 cases (22%) with a CA-125 greater than 500 U/ml. Using a
threshold level of 500 U/ml, the preoperative serum CA-125 level was able to
predict optimal versus suboptimal cytoreduction with a sensitivity of 78%,
specificity of 73%, positive predictive value of 78%, and negative predictive
value of 73%. CONCLUSION: The probability of performing optimal cytoreduction in
patients with Stage III ovarian carcinoma and a preoperative CA-125 greater than
500 U/ml was approximately one in five. These patients may be candidates for
initial laparoscopic evaluation to obtain a confirmatory tissue diagnosis and to
determine resectability.
PMID- 10785470
TI - Assessment of inhibin and p53 in granulosa cell tumors of the ovary.
AB - OBJECTIVE: The goal of this work was to determine the cellular content of inhibin
and p53 in granulosa cell tumors (GCTs). METHODS: Clinical records of 47 patients
(mean age, 54 years; range, 20-85 years) presenting with GCT surgically managed
at our institution were abstracted. International Federation of Gynecology stage
I was assigned in 39 patients, stage II in 2, and stage III in 6. Concomitant
endometrial carcinoma was identified in 6 patients. Mean follow-up was 13.6 years
(range, 1 day to 37.6 years). Sections from paraffin-embedded tissue blocks were
analyzed immunohistochemically for expression of tissue inhibin and p53 levels.
Inhibin expression was graded by intensity and reactivity, and p53, by its
presence or absence. RESULTS: The tumors of 27 patients (57%) stained strongly
for inhibin intensity and showed >60% reactivity. Decreased intensity and
reactivity of inhibin expression were associated with advanced-stage disease (P =
0.05 and P < 0.01, respectively, by Fisher exact test). Expression of p53 was
detected in tumors from 27 patients (57%), and immunoreactivity was associated
with compromised progression-free survival (P = 0.016, log-rank test). However,
the association between p53 immunoreactivity and disease stage was not
significant. Absence of p53 expression was significantly associated with
concurrent endometrial carcinoma (P = 0.022), suggesting more molecularly intact
tumors that retain functional activity. CONCLUSIONS: Although the majority of
GCTs show strong expression of inhibin with regard to intensity and reactivity,
weak expression is associated with advanced disease but not with decreased
progression-free survival. By contrast, expression of p53 is not significantly
associated with stage, but increased expression is associated with decreased
disease-free survival. Absence of p53 expression appears to be associated with
concurrent endometrial carcinoma.
PMID- 10785472
TI - The diagnostic value of power Doppler measurements in the endometrium of women
with postmenopausal bleeding.
AB - OBJECTIVE: The objective was to evaluate the accuracy of blood flow measurements
by power Doppler in endometrial vessels in women with postmenopausal bleeding
(PMB). METHODS: Sixty consecutive patients with PMB participated in the study.
Endometrial thickness and power Doppler measurements of small vessels in the
endometrium and subendometrial tissue were performed prior to dilatation and
curettage. Correlation between Doppler indices, endometrial thickness (by
transvaginal sonography), and histopathologic examination was performed. A
Student t test was used for statistical analysis with P < 0.05 as the level of
significance. RESULTS: Fourteen positive cases were found: 11 endometrial
cancers, 1 sarcoma, 1 simple hyperplasia, and 1 complex hyperplasia with atypia.
Measurements of endometrial thickness using a cutoff point of 5 mm revealed a
sensitivity of 78% and specificity of 45.6% (P > 0.05, NS) for detecting
endometrial pathology. Power Doppler measurements (pulsatility index cutoff point
= 1.0) revealed a sensitivity of 85. 7% and specificity of 89% (P = 0.001) for
detecting endometrial pathology. CONCLUSIONS: The noninvasive methods for
endometrial evaluation are not sensitive enough to exclude endometrial pathology.
When invasive methods could not be performed, the combination of transvaginal
sonography and power Doppler imaging provided the best results. When both
modalities are negative, the probability of cancer is less than 5%.
PMID- 10785471
TI - p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not
with p53 expression in epithelial ovarian carcinoma.
AB - OBJECTIVE: The objective of this study was to clarify the influence of p21
protein expression in ovarian cancer. p21 (WAF1 [wild-type p53 activated fragment
1]/CIP1) is a universal cyclin-dependent kinase inhibitor and can be induced as a
downstream effector of the p53 tumor suppressor gene. METHODS: The expression of
p21 was evaluated by immunohistochemical analysis with the monoclonal antibody
WAF1 (Oncogene Science) on 106 formalin-fixed, paraffin-embedded tissue samples
of epithelial ovarian cancer. RESULTS: p21 was expressed in 65 (61%) of all
cases. p21 expression was associated with early stage in FIGO classification
(FIGO I and II, P = 0.003) and no tumor residues after primary tumor resection (P
= 0.018). Immunohistochemical staining results were judged as negative if no
tumor nuclei were stained, as weak positive if 1-49% were stained, and as strong
positive if over 50% of nuclei were stained. Clinical follow-up showed a better
overall survival for cases with strong p21 expression (79 months) versus 40
months for weak expression and 30 months for no expression (P = 0.033).
Previously determined p53 expression of this cohort was compared with p21 status.
p53 overexpression was observed in 49 cases (48%) and showed no association with
p21 expression. CONCLUSION: No correlation was found between p21 and p53
expression. p21 expression is a significant prognostic marker for improved
survival in ovarian cancer and is associated with early FIGO stage and zero tumor
residues after primary tumor resection.
PMID- 10785473
TI - Management of aggressive histologic variants of endometrial carcinoma at the Tom
Baker Cancer Centre between 1984 and 1994.
AB - OBJECTIVE: The aim of this study was to determine the patient characteristics and
outcome of patients with aggressive histologic variants (AV) of endometrial
carcinoma, including uterine papillary serous carcinoma (UPSC), uterine clear
cell carcinoma (UCCC), and mixed type. METHODS AND MATERIALS: All cases with AV
histological type of endometrial carcinoma from January 1984 to December 1994 at
the Tom Baker Cancer Centre were identified using the Alberta Cancer Registry.
Relevant data from the charts of these patients were entered into a study
database (Microsoft Excel) and analyzed for presentation, demography, treatment
parameters, and outcome of treatment. All pathology was reviewed at the time of
diagnosis. Statistical analysis was performed using the S-plus statistics
computer program. Univariate and multivariate analyses were used to assess
independent prognostic factors using the Cox proportional hazards model. RESULTS:
A total of 103 patients with AV histological type were identified and analyzed;
there were 61, 31, and 11 cases of UPSC, CCC, and mixed tumors, respectively.
Sixty-three patients had Stage I, 11 had Stage II, 15 had Stage III, and 14 had
Stage IV disease. The median age of patients was 67 years with a range of 36 to
86 years. Median follow-up was 60 months with a range of 36 to 156 months. The
Cox proportional hazards model showed that lymphvascular space invasion and stage
are the two independent prognostic factors affecting recurrence and survival.
Forty six percent of all cases underwent surgery alone, 39% underwent treatment
which included pelvic RT, and 17% underwent treatment which included
chemotherapy. Pelvic recurrence was reduced significantly by radiotherapy in
Stages I, II, and III (19% recurrence with no RT vs 7% recurrence with RT, P <
0.005). Chemotherapy improved overall survival, but made little difference in
distant relapse rates. CONCLUSIONS: Stage Ia cases treated by surgery alone have
a low risk of relapse and need not be offered adjuvant systemic therapy or pelvic
radiation. Patients with Ib, Ic, II, and III have significantly lower pelvic
failure rates if treated with pelvic radiation, but still have a high distant
failure rate. Systemic therapy did not significantly improve distant relapse-free
survival, but did extend overall survival. Stage IV patients usually died within
6 months with a few responding to systemic chemotherapy. These results suggest
that there is a need for randomized trials for these patients.
PMID- 10785474
TI - Elevated serum CA-125 levels in hemodialysis patients with peritoneal, pleural,
or pericardial fluids.
AB - OBJECTIVE: Serum CA-125, an ovarian tumor marker, is used especially in the
follow-up of ovarian cancer for monitoring the efficacy of therapy and for early
detection of recurrence. A number of benign gynecologic as well as benign and
malignant nongynecologic conditions are associated with elevated serum CA-125
levels. Malignant and nonmalignant serosal fluids were also found to be
associated with high serum levels of CA-125, suggesting that the presence of
fluid in the serosal cavities may stimulate its release. METHODS: We performed a
clinical study in 39 patients (21 females, 18 males) on chronic hemodialysis who
were divided into two groups based on the presence of fluid in the serosal
cavities (peritoneum, pleura, or pericardium) without clinical and radiologic
evidence of neoplasia. There were 26 patients (16 females, 10 males) aged 50.11
+/- 13.86 years (range, 20-76 years) in the serosal fluid-negative group (group
1) and 13 patients (8 females, 5 males) aged 45.30 +/- 18.84 years (range, 17-73
years) in the serosal fluid-positive group (group 2). The control group consisted
of 52 healthy volunteers (30 females, 22 males) aged 44.19 +/- 12.59 years
(range, 19-68 years). RESULTS: Significantly elevated serum CA-125 levels were
found in hemodialysis patients with serosal fluid (P < 0.05) when compared with
both the hemodialysis patients without serosal fluid and the control group. There
was no statistically significant difference between the control group and the
patients without serosal fluids (P > 0.05). CONCLUSION: Although CA-125 can be
considered a reliable tumor marker in patients undergoing hemodialysis, it should
be interpreted with caution in patients with serosal fluids.
PMID- 10785475
TI - Correlation of drug response with the ATP tumorchemosensitivity assay in primary
FIGO stage III ovarian cancer.
AB - OBJECTIVE: Our purpose was to: (a) study the in vitro chemosensitivity of primary
epithelial ovarian cancer to drug combinations with cisplatin (CDDP), carboplatin
(CBDCA), paclitaxel (PTX), epirubicin (EPI), or cyclophosphamide (CTX) utilizing
the ATP tumorchemosensitivity assay (ATP-TCA); (b) correlate the test results
with clinical response in patients with FIGO stage III ovarian cancer; and (c)
analyze the most useful parameters for interpretation of test results. METHODS:
CBDCA/CTX, CBDCA/PTX, CDDP/PTX, and EPI/PTX were tested in 93 fresh human primary
epithelial ovarian cancer specimens. Correlations of in vitro drug
sensitivity/resistance and clinical response were performed in 38 patients with
FIGO stage III disease utilizing Fisher's exact test and by comparison of
progression-free (PFS) and overall survival (OS) between those testing as
sensitive or resistant. A progression-free interval of more than 12 months
following surgery was classified as clinical response. ATP-TCA results were
analyzed using the median effective dose, area under the curve, or a defined
sensitivity index. RESULTS: Evaluable test results were achieved in 83 of 93
patients (89%). EPI/PTX had the highest in vitro activity (P < 0.001). In the
clinical correlation, 29 of 38 patients (76%) were classified as in vitro
sensitive (sensitivity index [SI] <250) and 9 patients as in vitro resistant (SI
>250). The SI was superior for interpretation of test results. Patients testing
as chemosensitive had a significantly longer mean PFS (28.5 vs 12.6 months, P =
0.033) and OS (46.1 vs 17.6, P = 0.03) compared to those patients predicted to be
resistant. The assay demonstrated a sensitivity, specificity, and positive and
negative predictive value of 95, 44, 66, and 89%, respectively (Fisher's exact
test, P = 0. 007). CONCLUSION: The observed in vitro efficacy of EPI/PTX in
primary epithelial ovarian cancer specimens warrants further clinical evaluation.
The high evaluability rate and the observed correlation with PFS and OS, within
the limitations of a nonrandomized study, support the use of the ATP
chemosensitivity assay in future prospective assay-directed trials.
PMID- 10785476
TI - Neoadjuvant intraarterial infusion chemotherapy in patients with stage IB2-IIIB
cervical cancer.
AB - OBJECTIVES: The purpose of this study was determine the effect of neoadjuvant
intraarterial chemotherapy (NAIC) on the prognosis of patients with locally
advanced cervical cancer. METHODS: From January 1992 to December 1997, 26
previously untreated patients with stage IB2-IIIB cervical cancer were enrolled
in the study. NAIC was administered for more than two courses every 3 weeks using
a combination of 17.5 mg/m(2) bleomycin, 7 mg/m(2) mitomycin-C, and 75 mg/m(2)
cisplatin via the bilateral internal iliac artery. Pathologic findings were
evaluated with histologic examinations of surgical specimens. A nonrandomized
control group of 120 patients who underwent conventional treatment between 1980
and 1991 was used for comparison. RESULTS: Nineteen (73.1%) of the 26 patients
responded to initial chemotherapy, permitting a radical hysterectomy with pelvic
lymphadenectomy in 14 patients. The remaining 5 patients received radiotherapy.
One of 7 nonresponders was able to undergo radical surgery. Pathologic complete
responses were found in 4 of the 15 patients who underwent radical surgery. The
incidence of lymph node metastasis, parametrial infiltration, and vascular space
involvement in the 15 patients who received NAIC followed by radical surgery was
significantly lower than that in the control group (13.3, 6.7, and 13.3% vs 54.2,
43.8, and 60.4%). The overall 5-year estimated survival rate was significantly
higher for all 26 patients who received NAIC (80.0%) than for the control group
(59.6%). In stage II and III, the 5-year survival rate for patients who received
NAIC was significantly higher than that in the control group (83.3 and 77.8% vs
68.1 and 49.8%). CONCLUSIONS: These preliminary results suggest that NAIC is able
to eliminate effectively the pathologic risk factors in the pelvic cavity, to
improve the operability in patients with stage IIIB cervical cancer, considered
inoperable, and to improve the prognosis of patients with locally advanced
cervical cancer.
PMID- 10785477
TI - Phase I trial of carboplatin, paclitaxel, etoposide, and cyclophosphamide with
granulocyte colony stimulating factor as first-line therapy for patients with
advanced epithelial ovarian cancer.
AB - OBJECTIVES: The goal of this study was to determine the maximally tolerated doses
(MTDs) of carboplatin, paclitaxel (Taxol), etoposide, and cyclophosphamide (CTEC)
with granulocyte-colony stimulating factor (G-CSF, Filgrastim) support as first
line chemotherapy in women with advanced epithelial ovarian cancer (EOC).
METHODS: Newly diagnosed patients with either stage IV EOC, or stage III EOC and
any amount of gross residual tumor after surgical debulking were eligible to
receive six cycles of CTEC over five different dose levels in this phase I trial
(planned 21-day cycle length). Paclitaxel, carboplatin, and cyclophosphamide were
administered intravenously on Day 1, and oral etoposide was administered on Days
1, 2, and 3. G-CSF was administered beginning Day 4. RESULTS: Twenty patients
received a total of 98 cycles of CTEC over the five dose levels evaluated. Bone
marrow suppression was the major toxic effect, with grade 4 neutropenia and
thrombocytopenia being observed in 25 and 23% of cycles, respectively. The
overall incidence of febrile neutropenia was 10%, and no toxic deaths occurred.
No grade IV thrombocytopenia or febrile neutropenia was observed once the
carboplatin dose was reduced from AUC of 7 to 5. Nonhematologic toxicity was
generally mild (grade 2 or less). Dose-limiting toxicity was not observed at the
highest dose level evaluated in this study, preventing assignment of the MTD. The
clinical complete response rate was 92%, although 15 of 16 evaluable patients
have progressed with a median progression-free interval of 4 months (range, 2-11
months). One patient remains disease-free 9 months from the completion of CTEC.
CONCLUSIONS: The CTEC regimen is well tolerated and highly active. Although the
MTD was not reached in this study, the short median progression-free interval
suggests that this regimen is unlikely to be superior to standard treatment with
paclitaxel and carboplatin. Strategies to optimize the development of future
combination chemotherapy regimens in the treatment of newly diagnosed ovarian
cancer are discussed.
PMID- 10785478
TI - p53 and bcl-2 in epithelial ovarian carcinoma: their value as prognostic
indicators at a median follow-up of 60 months.
AB - OBJECTIVE: p53 is the most common tumor suppressor gene involved with human
malignancies. Mutations in p53 are present in approximately 50% of human
malignancies. bcl-2 is a protooncogene. Expression of its protein product is
related to better prognosis in several malignancies. METHODS: One hundred and
three patients with epithelial ovarian carcinoma were studied.
Immunohistochemical staining using the pAb1801 monoclonal antibody to p53 and the
anti-bcl-2 124 monoclonal antibody to bcl-2 was performed. Image analysis was
used to measure percentage positive nuclear area staining of mutant p53. In
addition to bcl-2 and p53, FIGO stage, grade, histology, and level of
cytoreduction were analyzed as prognostic factors. Univariate as well as Cox
regression analysis was performed. RESULTS: One hundred and three patients were
followed for a mean of 60 months. Twenty patients had FIGO stage I disease, 4
stage II, 59 stage III, and 20 stage IV. Immunohistochemical staining for mutant
p53 was not significantly related to DNA index (P = 0.99) but was related to
increasing FIGO stage (P < 0.001) and increasing histologic grade (P = 0.039).
Using Cox regression analysis, increased mutant p53 staining was an independent
predictor of survival in these patients (P = 0.0032), along with stage (P < 0.
0001) and level of cytoreduction (P < 0.0001). Although by itself bcl-2 was not
an independent prognostic indicator (P = 0.18), the combination of p53 and bcl-2
was independently predictive of survival (P = 0.038). CONCLUSION: This study
confirms the authors' earlier report on the importance of p53 as a prognostic
indicator of survival in ovarian carcinoma. Cox regression analysis reveals
mutant p53 staining to be a better independent indicator of prognosis and
survival in patients with ovarian carcinoma than the combination of bcl-2 and
p53.
PMID- 10785479
TI - Molecular genetic analysis of malignant ovarian germ cell tumors.
AB - OBJECTIVE: Relatively little is known about the molecular mechanisms involved in
the initiation and progression of ovarian germ cell tumors (OGCTs), in contrast
to testicular germ cell tumors (TGCTs) which have been extensively investigated.
Ovarian germ cell tumors share many pathological and biological features with
TGCTs and it is likely that they share similar molecular genetic alterations,
although this has not been studied in detail. The aim of this study was to
compare and contrast loss of heterozygosity (LOH) in OGCTs at chromosomal regions
that are commonly involved in TGCTs. METHODS: Universal amplification was
performed on 35 paired specimens of malignant OGCT and constitutional DNA that
had been microdissected from single paraffin-embedded tissue sections in 32
patients. Sixty-two microsatellite markers were used to assess LOH at chromosomal
regions mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p, and 18q as these are commonly
involved in testicular germ cell tumors. RESULTS: Assessment of these regions
demonstrated common sites of deletion at 3q27-q28 (50%), 5q31 (33%), 5q34-q35
(46%), 9p22-p21 (32%) and 12q22 (53%) in all histological subtypes of OGCT. We
and others have previously found these regions to be frequently deleted at early
stages of tumor development in TGCTs. CONCLUSIONS: These chromosomal regions may
contain tumor suppressor genes that are important in the initiation and
progression of both malignant OGCTs and TGCTs.
PMID- 10785480
TI - Reproducibility in the assessment of postmenopausal ovaries with transvaginal
ultrasound.
AB - OBJECTIVE: The goal of this study was to evaluate the interexaminer variation in
the assessment of postmenopausal ovaries using transvaginal ultrasound (TVU).
METHODS: One hundred eighty-eight cancer screening trial participants undergoing
TVU were reassessed by a second TVU examination. RESULTS: Although first
examiners tended to describe significantly larger left (P < 0.001) but smaller
right (P = 0.036) ovaries, as well as fewer ovarian abnormalities, examiners
agreed on the test interpretation 93% of the time (kappa = 0.846). In only two
cases (1%) were the differences in interpretation such that the two examiners
recommended different follow-up procedures. CONCLUSIONS: Because of the high
fatality rate of ovarian cancer, early detection remains the best way to combat
this devastating disease. TVU is one screening technique we are currently
evaluating in a cancer screening trial. To help ensure screening test
reproducibility, we have followed explcit protocols for training and certifying
all TVU examiners, as well as for conducting TVU examinations. This study
demonstrates that by adhering to specific training, certification, and
examination protocols, TVU reproducibility is excellent. Such protocols may well
serve as a standard for TVU training and examination.
PMID- 10785481
TI - Primary vaginal and pelvic floor reconstruction at the time of pelvic
exenteration: a study of morbidity.
AB - PURPOSE: The purpose of this study was to analyze our experience with the
influence of reconstructive techniques at the time of pelvic exenteration on
morbidity. MATERIALS AND METHODS: Between June 1986 and December 1998, 60 pelvic
exenterations for gynecologic malignancies were performed in our hospital. Forty
five were selected for this study because they met two criteria: they were
performed by the same team (gynecologic oncologist), and they had similar primary
tumors. There were 38 cervical, 2 vaginal, and 5 uterine malignancies. Sixteen
patients underwent reconstructive surgery: 11 (68.8%) with placement of a
myocutaneous flap with left rectus abdominis, 3 (18.8%) with gracilis muscle, and
2 (12.5%) with the Singapore fasciocutaneous flap. Twenty-nine patients had no
reconstruction. Records were reviewed and statistical analysis was performed.
RESULTS: Attachment of the grafts was complete in 14 of 16 (87.5%), with a
partial vulvovaginal dehiscence in 2 cases. Morbidities included secondary
infection in 3 (18.8%), partial necrosis in 3 (18.8%), and partial stenosis in 5
(31.6%); the last was significantly associated with a gracilis flap (P = 0.015).
There were no statistical differences between neovagina and nonneovagina groups
with respect to the rate of fever, small bowel fistula, bowel obstruction, wound
infection or dehiscence, hernia, colorectal leak, colostomy or urostomy prolapse,
deep vein thrombosis, pulmonary embolism, intraoperative blood transfusions, or
hospital stay. There were no pelvic abscesses in the neovagina group compared
with 27% (6/29) in the other group (P = 0.050). Surgery was significantly longer
(P = 0.019) for the reconstructive surgery group, with no statistical difference
between different kinds of flaps. There were no deaths in either group.
CONCLUSIONS: Reconstruction of the vagina and pelvic floor at the time of pelvic
exenteration can be done safely. Although this increases surgical time, morbidity
is not significantly increased. The rectus abdominis flap seems to be the
preferable option for primary vaginal and pelvic floor reconstruction.
PMID- 10785482
TI - Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological
and immunohistochemical study.
AB - OBJECTIVE: The purpose of this study was to demonstrate the incidence, the
histopathological characteristics, and the proliferation activity of
endometriosis and atypical endometriosis associated with ovarian carcinoma.
METHODS: Microscopic slides of primary lesions from 127 patients with primary
ovarian carcinoma were reviewed. The presence or absence of endometriosis and the
transitions from typical endometriosis to atypical endometriosis and from
atypical endometriosis to carcinoma were also histologically evaluated. Ki-67
immunoreactivity of typical and atypical endometriosis and carcinoma was
examined. In addition, endometrial metaplasias were also evaluated. RESULTS: Of
the 127 patients, 37 had endometriosis: 70% (30/43) had clear cell
adenocarcinoma, 43% (3/7) had endometrioid adenocarcinoma, 7% (4/60) had serous
adenocarcinoma, and none (0/17) had mucinous adenocarcinoma. Thirty-three cases
showed typical endometriosis and 29 cases had atypical endometriosis (25 cases
had both). Tufting and the stratification of the lining epithelium were observed
in 25 and 23 cases, respectively. The transition from typical endometriosis to
atypical endometriosis was observed in 22 cases, and the transition from atypical
endometriosis to carcinoma, in 23 cases. Only one case showed a direct transition
from typical endometriosis to carcinoma. The mean Ki-67 indices were as follows:
ovarian carcinoma, 23.1; atypical endometriosis, 9.9; typical endometriosis, 2.7.
In 18 cases with metaplasia in endometriosis, eosinophilic metaplasia and
ciliated metaplasia were the most common types. Five cases had two types of
metaplasia. CONCLUSIONS: Ovarian carcinomas, especially clear cell and
endometrioid adenocarcinomas, are highly associated with endometriosis. Atypical
endometriosis shows proliferation activity intermediate to those of typical
endometriosis and ovarian carcinoma, suggesting it is a precancerous status.
PMID- 10785483
TI - High-risk group in node-positive patients with stage IB, IIA, and IIB cervical
carcinoma after radical hysterectomy and postoperative pelvic irradiation.
AB - OBJECTIVE: The goal of this study was to identify risk factors in patients with
node-positive stage IB, IIA, and IIB cervical carcinoma after radical
hysterectomy with pelvic lymph node dissection and postoperative irradiation.
METHODS: Two hundred forty-two patients with FIGO stage IB, IIA, and IIB cervical
carcinoma underwent radical hysterectomy with pelvic lymph node dissection;
pathological analysis of the surgical specimen showed positive lymph nodes in 59
patients. These 59 patients were further treated with postoperative radiotherapy.
Eighteen patients were in stage IB, 4 in stage IIA, and 37 in stage IIB.
Histological tumor type, tumor size, lymph-vascular space invasion, parametrium
infiltration, number of positive nodes, and involvement of common iliac nodes
were assessed for correlation with cancer recurrence. RESULTS: When all these
variables were assessed in the Cox proportional regression analysis, parametrium
infiltration (P = 0. 0199) and number of positive nodes (two or more nodes) (P =
0.0483) revealed the factor correlating significantly with disease-specific
survival. Based on these two factors, node-positive patients could be divided
into low-risk (n = 11), intermediate-risk (n = 29), and high-risk (n = 19)
groups. The 5-year disease-specific survival for the low-risk group was 100%
which was significantly better than the 39.1% for the high-risk group (P =
0.0012). CONCLUSION: For patients in the high-risk group, it may be worthwhile to
consider new strategies to improve survival.
PMID- 10785484
TI - Granular cell tumors: a new clinically important histologic finding.
AB - OBJECTIVE: The objective of this study was to review clinical characteristics,
histological findings, and surgical treatment of patients with granular cell
tumors of the vulva at Hartford Hospital and examine histologic characteristics
associated with those cases that recurred. MATERIALS AND METHODS: A retrospective
case review of 13 patients diagnosed with granular cell tumors of the vulva at
Hartford Hospital from April 1982 through May 1998 was undertaken to compare age,
size and location of the lesion, histopathologic features, presenting symptoms,
progression of disease, and treatment. RESULTS: Tumor growth patterns were
divided into those with confluent expansile growth (nodular) and those that
infiltrated the dermis and soft tissue in a haphazard fashion interdigitating
with native connective tissue and skin appendages (infiltrative). The advancing
edge of the tumors was assessed as having either a "pushing" or an infiltrative
border. The advancing edge of the tumor was noted to be irregular and
infiltrative in 8 of the 13 cases. The tumor edge in the remaining 5 was pushing
and well demarcated. Five of the eight tumors with an infiltrative edge recurred
despite the fact that 3 of the 5 cases had negative surgical margins at
resection. None of the 5 cases with "pushing" borders developed recurrence.
CONCLUSIONS: Although rare, vulvar tumors are the most common variety of granular
cell tumors encountered in the female genital tract. Histologic evaluation seems
to indicate that patients are more likely to have a recurrence if an infiltrative
growth pattern is present at the advancing edge of the granular cell tumor even
with negative margins at resection. An appropriate management strategy may be to
recommend reexcision of "infiltrative border" lesions rather than clinical
observation alone.
PMID- 10785485
TI - Complete groin lymphadenectomy with preservation of the fascia lata in the
treatment of vulvar carcinoma.
AB - OBJECTIVE: The goal of this study was to assess the local groin recurrence of
vulvar carcinoma in patients treated by complete groin node dissection with
preservation of the fascia lata (GNDPFL). METHODS: This study is a retrospective
chart review of 60 patients with Stage I-IV vulvar carcinoma who underwent
radical vulvectomy and GNDPFL between 1990 and 1998. All superficial inguinal
nodes and the deep femoral nodes on the anterior and medial surfaces of the
femoral vein within the fossa ovalis were removed en bloc while sparing the
fascia lata and the cribriform fascia over the femoral artery. RESULTS: Of the 60
study patients, 14 patients had Stage I disease, 20 Stage II, 21 Stage III, and 5
Stage IV. The mean number of nodes removed was 10 per groin. Thirty-nine patients
had benign nodes on groin dissection. None of these 39 patients developed cancer
recurrence in the dissected groins. Twenty-one of the sixty study patients (34%)
had malignant nodes on groin dissection. Of these 21 patients, 2 experienced
cancer recurrence in the groins. Our study describes a groin recurrence rate of
7.6% in patients with fewer than three malignant unilateral groin nodes.
Postoperatively, 13% of patients developed lymphedema and 15% formed lymphoceles.
CONCLUSIONS: The zero groin recurrence rate in patients with negative nodes and
the low rate of recurrence in patients with positive nodes indicate that groin
lymphadenectomy with preservation of fascia lata is complete, therapeutic, and
comparable to radical techniques of lymphadenectomy involving skeletonization of
femoral vessels, resection of fascia lata, and muscle transposition.
PMID- 10785486
TI - Germline BRCA2 mutation in a patient with fallopian tube carcinoma: a case
report.
AB - OBJECTIVES: Fallopian tube carcinoma is similar to ovarian and peritoneal
carcinoma with respect to histology, response to chemotherapy, and prognosis.
BRCA germline mutations have been commonly reported in ovarian and peritoneal
carcinoma but rarely in other gynecologic cancers. METHODS: A patient with
fallopian tube carcinoma and a family history of ovarian carcinoma underwent
genetic counseling and BRCA testing as did her daughter. RESULTS: The patient and
her daughter were found to have a germline BRCA2 mutation. CONCLUSION: Like a
family history of ovarian or peritoneal carcinoma, the occurrence of fallopian
tube cancer should alert the clinician to the possibility of an abnormality in
the breast cancer susceptibility 1 or 2 genes.
PMID- 10785487
TI - Declining CA-125 in an ovarian cancer patient with progression of measurable
disease: a rational hypothesis for discordant results.
AB - OBJECTIVES: While a declining CA-125 has been demonstrated to be a useful
indicator of response to chemotherapy in ovarian cancer, occasional patients will
demonstrate discordant results between the level of this antigen and changes in
the size of measurable tumor masses. CASE: The patient was seen in the
Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center.
RESULTS: This patient exhibited a "major response" by CA-125 criteria,
significant shrinkage of multiple peritoneal and perirectal implants, but clear
progression of a pelvic side wall mass. The discordant results in this case are
likely an example of a "mixed response" to the chemotherapy regimen, with the
declining CA-125 corresponding to shrinkage of the responding tumor cell
population. CONCLUSION: An evaluation of changes in both the serum CA-125 level
and measurable masses may represent a more complete analysis of the status of
disease in an individual with ovarian cancer.
PMID- 10785488
TI - Signet ring stromal tumor of the ovary occurring in conjunction with brenner
tumor.
AB - OBJECTIVE: A case is presented of a single ovarian mass that had elements of both
signet ring stromal tumor of the ovary and Brenner tumor. METHODS: The histologic
features and the results of histocytochemical, immunohistochemical, and electron
microscopic studies are presented. RESULTS: The signet ring component of the mass
demonstrated features consistent with the few other cases previously reported. A
positive immunohistochemical stain for the peptide hormone inhibin provides
additional evidence for an ovarian stromal origin for this tumor. CONCLUSION: The
tumor produced no hormonally related symptoms and has shown no evidence of
recurrence. Signet ring stromal tumor of the ovary is an uncommon benign tumor
that may be confused with metastatic signet ring carcinoma. The significance of
the signet ring cells is not certain. Their association with Brenner tumor has
not been previously described.
PMID- 10785489
TI - Erosion of an intraperitoneal chemotherapy catheter resulting in an enterovaginal
fistula.
AB - BACKGROUND: With the pharmacokinetic advantages of intraperitoneal chemotherapy
delivery and the increased popularity of immunotherapy and gene therapy,
intraperitoneal catheters have moved to the forefront as a delivery system in
cancer treatment. This delivery system, however, carries with it an intrinsic
morbidity warranting attention in the often prolonged chemotherapy regimens
demanded by cancer patients. CASE: In reviewing the literature of intraperitoneal
catheter complications, there is no other cited case of a peritoneal catheter
erosion into intestine presenting as an enterovaginal fistula. Our patient,
diagnosed with persistent ovarian carcinoma, had a peritoneal Tenckoff catheter
placed for chemotherapy. Many months after termination of the chemotherapy and 15
months after placement, she presented with bowel contents per vagina. A CT scan
revealed an abdominopelvic abscess encompassing the detached catheter which
embedded in the rectosigmoid colon, allowing direct communication to the upper
vagina. The catheter was removed and the abscess was drained. CONCLUSION:
Intraperitoneal catheters have a morbidity that persists after nonuse. Therefore,
intraperitoneal catheters should be removed if they are not being used.
PMID- 10785490
TI - Urolithiasis following formation of a continent urostomy: case report and review
of the literature.
AB - BACKGROUND: Formation of urinary stones in a continent urostomy (Indiana pouch)
has been described as a late complication. Management of a patient with
symptomatic multiple large stones and review of the literature are outlined. CASE
REPORT: A 32-year-old woman presented with recurrent urinary tract infections and
pyelonephritis 6 years after a total pelvic exenteration and creation of a
continent urostomy for central recurrent carcinoma of the cervix after radical
pelvic radiation. Multiple large stones were found to be the underlying etiology.
Laparotomy, enterocystotomy, and removal of stones were performed without
apparent complication. CONCLUSION: It is recommended that for single calculi or
multiple small stones, electroshock wave lithotripsy or the percutaneous
endoscopic approach be considered. For larger stones the use of laparotomy and
enterocystostomy may be appropriate.
PMID- 10785491
TI - Recurrent invasive adenocarcinoma after hysterectomy for cervical adenocarcinoma
in situ.
AB - BACKGROUND: Unlike its squamous counterpart, therapy for cervical adenocarcinoma
in situ with positive endocervical cone margin remains controversial. CASE: A 52
year-old gravida 2, para 1,0,1,1, presented with vaginal bleeding. Gynecologic
history was significant for cervical cold knife conization with a positive
endocervical margin and endocervical curettage with atypical endocervical cells.
Repeat cone biopsy was considered unsafe given the large initial cone specimen.
An extrafascial hysterectomy was performed 5 weeks later and pathology confirmed
a disease-free cervix. Pap smear performed 1 year later was interpreted as
recurrent adenocarcinoma but later downgraded to inflammation. Inspection and
random biopsies of the vaginal cuff revealed only inflammation. Two subsequent
Pap smears also returned inflammation. Seventeen months after the hysterectomy
physical examination revealed a 2 x 3-cm smooth mass at the vaginal cuff. Biopsy
revealed invasive adenocarcinoma. The patient underwent an upper vaginectomy
followed by postoperative pelvic radiation. CONCLUSION: This case suggests that
despite extrafascial hysterectomy for presumed adenocarcinoma in situ of the
cervix, a residual focus could remain and present later as invasive
adenocarcinoma.
PMID- 10785492
TI - Vascular embolization of benign granulosa cells.
AB - OBJECTIVE(S): Most conditions involving sex cord-stromal cells can be diagnosed
on morphologic criteria alone. We describe a case of vascular embolization of
benign granulosa cells in which immunohistochemistry was of value as a diagnostic
tool. METHODS: We reviewed the clinical history and gross pathologic findings
from a 48-year-old patient who presented with abdominal pain and fullness.
Formalin-fixed paraffin-embedded sections were examined by routine H&E and
immunohistochemical stains. RESULTS: Histologic examination of a grossly enlarged
and cystic ovary revealed nests of cells within angiolymphatic spaces. Although
the cells were cohesive and atypical, they were morphologically similar to the
nearby graafian follicle. Immunohistochemistry showed positive labeling with
antibodies to inhibin-alpha and cytokeratin in a pattern consistent with benign
granulosa cells. CONCLUSION(S): Immunohistochemical stains for inhibin-alpha and
cytokeratin are useful tools to help confirm granulosa cell origin, as
demonstrated in this case involving an atypical histomorphologic picture of
"embolization."
PMID- 10785493
TI - The definition of stage IA(1) cervical adenocarcinoma and selection criteria for
nonradical surgical management.
PMID- 10785494
TI - Reply
PMID- 10785495
TI - Adjuvant chemotherapy or radiotherapy in cervical cancer.
PMID- 10785497
TI - Reply
PMID- 10785498
TI - Reply
PMID- 10785496
TI - Is florid pyloric metaplasia different from adenoma malignum?
PMID- 10785500
TI - In memoriam : Francis X. Witkowski.
PMID- 10785499
TI - Surgical response of advanced-stage borderline ovarian tumors to paclitaxel and
cisplatin chemotherapy.
PMID- 10785501
TI - Making sense out of oxygen sensor.
PMID- 10785502
TI - Bone sialoprotein and the paradox of angiogenesis versus atherosclerosis.
PMID- 10785503
TI - Gene therapy for restenosis.
PMID- 10785504
TI - Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in
patients with heart failure.
AB - The beta(2)-adrenergic receptor (beta(2)AR) exists in multiple polymorphic forms
with different characteristics. Their relevance to heart failure (HF) physiology
is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF
patients with a defined beta(2)AR genotype. Patients with the uncommon Ile164
polymorphism had a lower peak VO(2) (15.0+/-0.9 mL. kg(-1). min(-1)) than did
patients with Thr164 (17.9+/-0.9 mL. kg(-1). min(-1), P<0.0001). The percentage
achieved of predicted peak VO(2) was also lower in patients with Ile164 (62. 3+/
4.5% versus 71.5+/-5.1%, P=0.045). The relative risk of a patient having a VO(2)
14.5 microm, a reduced ability
to proliferate, and signs of apoptosis. The uptake of fluorescent acetylated LDL
was increased 2-fold in cultures from regenerated endothelium. The increased
uptake of acetylated LDL was confirmed ex vivo in injured coronary arteries. In
cultures from regenerated endothelium, cGMP production was decreased under basal
conditions and during stimulation with serotonin, bradykinin, and A23187. Thus,
during regeneration, there is accelerated senescence of endothelial cells
accompanied by increased incorporation of modified LDL and reduction of NO
production without decrease in endothelial NO synthase expression. These
alterations help to explain the altered endothelium-dependent responses 28 days
after balloon injury.
PMID- 10785508
TI - Effects of hypoxia on isometric force, intracellular Ca(2+), pH, and energetics
in porcine coronary artery.
AB - When exposed to hypoxic conditions, coronary arteries dilate, which is an
important protective response. Although vessel sensitivity to oxygen is well
documented, the mechanisms are not known with certainty. To further characterize
the mechanisms of oxygen sensing in the coronary artery, we tested the major
classes of hypotheses by measuring the effects of hypoxia on energetics,
[Ca(2+)](i), K(+) channel function, and pH(i). Hypoxia relaxes porcine coronary
arteries stimulated with either KCl or U46619. The extent of relaxation is
dependent on both the degree and kind of stimulation. [Ca(2+)](i) was measured in
endothelium-denuded arteries using fura 2-AM and ratiometric fluorescent
techniques. At lower stimulus levels, hypoxia decreased both force and
[Ca(2+)](i). Inhibitor studies suggest that K(Ca) and K(ATP) channels are not
involved in the hypoxic relaxation, whereas K(V) channels may play a minor role,
if any. Despite the hypoxia-mediated decrease in force, [Ca(2+)](i) was unchanged
or increased at high levels of stimulation. Despite a marked increase in lactate
content, pH(i) (measured with the ratiometric fluorescent dye BCECF) was also
little affected by hypoxia. Measurement of the phosphagen and metabolite profile
of freeze-clamped arteries with analytical isotachophoresis indicated that
hypoxia increased lactate content by 4-fold and decreased phosphocreatine to 60%
of control. However, neither ATP nor P(i) was affected by hypoxia. Interestingly,
additional stimulation under hypoxia increased force but not ATP utilization, as
estimated from measurements of anaerobic lactate production. Thus, surprisingly,
the economy of force maintenance is increased under hypoxia. In porcine coronary
artery, both Ca(2+)-dependent and, importantly, Ca(2+)-independent mechanisms are
involved in hypoxic vasodilatation. For the latter, mechanisms involving either
ATP, [Ca(2+)](i), pH(i), or P(i) cannot be invoked. This novel oxygen sensing
mechanism involves a decreased Ca(2+) sensitivity.
PMID- 10785509
TI - Remodeling of gap junctional coupling in hypertrophied right ventricles of rats
with monocrotaline-induced pulmonary hypertension.
AB - The present study investigates the remodeling of gap junctional organization in
relation to changes in anisotropic conduction properties in hypertrophied right
ventricles (RVs) of rats with monocrotaline (MCT)-induced pulmonary hypertension.
In contrast to controls that showed immunolocalization of connexin43 (Cx43)
labeling largely confined to the intercalated disks, RV myocytes from MCT-treated
rats showed dispersion of Cx43 labeling over the entire cell surface. The
disorganization of Cx43 labeling became more pronounced with the progression of
hypertrophy. Desmoplakin remained localized to the intercalated disks, as in
controls. In RV tissues, the proportion of Cx43 label at the intercalated disk
progressively decreased. Quantitative analysis of en face views of intercalated
disks revealed a significant decrease in the disk gap junctional density in RV
tissues of MCT-treated rats (control, 0.18 versus MCT-treated, 0.14 at 2 weeks;
control, 0.16 versus MCT-treated, 0.11 at 4 weeks). Conduction velocity in RVs
parallel to the fiber orientation was significantly lower (30.2% [n=9]) in MCT
treated rats at 4 weeks than in control rats, whereas there was no significant
difference observed in the conduction velocity across the fiber orientation
between control and MCT-treated rats. The anisotropic ratio of MCT-treated rats
(1.38+/-0.10) was significantly lower than that of control rats (1.98+/-0.12).
These results suggest that RV hypertrophy induced by pressure overload is
associated with both disorganization of gap junction distribution and alteration
of anisotropic conduction properties.
PMID- 10785510
TI - Arterial paclitaxel distribution and deposition.
AB - Successful implementation of local arterial drug delivery requires transmural
distribution of drug. The physicochemical properties of the applied compound,
which govern its transport and tissue binding, become as important as the mode of
delivery. Hydrophilic compounds distribute freely but are cleared rapidly.
Hydrophobic drugs, insoluble in aqueous solutions, bind to fixed tissue elements,
potentially prolonging tissue residence and biological effect. Paclitaxel is such
a hydrophobic compound, with tremendous therapeutic potential against
proliferative vascular disease. We hypothesized that the recent favorable
preclinical data with this compound may derive in part from preferential tissue
binding as a result of unique physicochemical properties. The arterial transport
of paclitaxel was quantified through application ex vivo and measurement of the
subsequent transmural distribution. Arterial paclitaxel deposition at equilibrium
varied across the arterial wall and was everywhere greater in concentration than
in the applied drug source. Permeation into the wall increased with time, from 15
minutes to 4 hours, and varied with the origin of delivery. In contrast to
hydrophilic compounds, the concentration in tissue exceeds the applied
concentration and the rate of transport was markedly slower. Furthermore,
endovascular and perivascular paclitaxel application led to markedly differential
deposition across the blood vessel wall. These data suggest that paclitaxel
interacts with arterial tissue elements as it moves under the forces of diffusion
and convection and can establish substantial partitioning and spatial gradients
across the tissue. The complexity of paclitaxel pharmacokinetics requires in
depth investigation if this drug is to reach its full clinical potential in
proliferative vascular diseases.
PMID- 10785511
TI - Bone sialoprotein mediates human endothelial cell attachment and migration and
promotes angiogenesis.
AB - Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in sites of
biomineralization. Recently, we demonstrated that BSP is strongly upregulated in
osteotropic cancers and particularly those that exhibit microcalcifications. BSP
contains an Arg-Gly-Asp (RGD) motif found in other adhesive molecules that
interact with cellular integrins. In bone, BSP has been shown to mediate the
attachment of osteoblasts and osteoclasts via alpha(v)beta(3) integrin receptors.
Ligands for alpha(v)beta(3) integrin are considered to play a central role during
angiogenesis. Therefore, we used human umbilical vein endothelial cells (HUVECs)
to study the potential role of BSP in angiogenesis. We found that purified
eukaryotic recombinant human BSP (rhBSP) is able to promote both adhesion and
chemotactic migration of HUVECs in a dose-dependent manner. These interactions
involve HUVEC alpha(v)beta(3) integrin receptors and the RGD domain of BSP.
Indeed, HUVECs attach to a recombinant BSP fragment containing the RGD domain,
whereas this response is not observed with the same fragment in which RGD has
been mutated to Lys-Ala-Glu (KAE). A cyclic RGD BSP peptide inhibits both
adhesion and migration of HUVECs to rhBSP. Moreover, anti-alpha(v)beta(3) but not
anti-alpha(v)beta(5) monoclonal antibodies also prevent BSP-mediated adhesion and
migration of HUVECs. We observed that both rhBSP and the RGD BSP recombinant
fragment stimulated ongoing angiogenesis on the chorioallantoic chick membrane
assay. BSP angiogenic activity was inhibited by anti-alpha(v)beta(3) antibody,
and the KAE BSP fragment was inactive. Our findings represent the first report
implicating BSP in angiogenesis. BSP could play a critical role in angiogenesis
associated with bone formation and with tumor growth and metastatic
dissemination.
PMID- 10785512
TI - Vascular endothelial growth factor-stimulated actin reorganization and migration
of endothelial cells is regulated via the serine/threonine kinase Akt.
AB - Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation,
migration, and actin reorganization, all necessary components of an angiogenic
response. However, the distinct signal transduction mechanisms leading to each
angiogenic phenotype are not known. In this study, we examined the ability of
VEGF to stimulate cell migration and actin rearrangement in microvascular
endothelial cells infected with adenoviruses encoding beta-galactosidase (beta
gal), activation-deficient Akt (AA-Akt), or constitutively active Akt (myr-Akt).
VEGF increased cell migration in cells transduced with beta-gal, whereas AA-Akt
blocked VEGF-induced cell locomotion. Interestingly, myr-Akt transduction of
bovine lung microvascular endothelial cells stimulated cytokinesis in the absence
of VEGF, suggesting that constitutively active Akt, per se, can initiate the
process of cell migration. Treatment of beta-gal-infected endothelial cells with
an inhibitor of NO synthesis blocked VEGF-induced migration but did not influence
migration initiated by myr-Akt. In addition, VEGF stimulated remodeling of the
actin cytoskeleton into stress fibers, a response abrogated by infection with
dominant-negative Akt, whereas transduction with myr-Akt alone caused profound
reorganization of F-actin. Collectively, these data demonstrate that Akt is
critically involved in endothelial cell signal transduction mechanisms leading to
migration and that the Akt/endothelial NO synthase pathway is necessary for VEGF
stimulated cell migration.
PMID- 10785514
TI - Cyclooxygenase-2 is required for tumor necrosis factor-alpha- and angiotensin II
mediated proliferation of vascular smooth muscle cells.
AB - Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) induced a
transient increase in vascular smooth muscle cell (VSMC) cyclooxygenase-2 (COX-2)
mRNA accumulation, without affecting COX-1 mRNA levels. The kinetics of COX-2
mRNA accumulation were similar in VSMCs challenged with either TNF-alpha or Ang
II; mRNA accumulation peaked at 2 hours and decreased to control levels by
approximately 6 hours. Accumulation of COX-2 mRNA was associated with a time
dependent increase of COX-2 protein expression that displayed similar kinetics in
response to either TNF-alpha or Ang II. Both the increase in COX-2 mRNA
accumulation and protein expression in response to either TNF-alpha or Ang II
were inhibited by the mitogen-activated protein/extracellular signal-regulated
kinase (MEK) inhibitor PD098059. In addition, the AT(1)-selective receptor
antagonist losartan attenuated the Ang II-mediated increase in COX-2 mRNA
accumulation; the AT(2)-selective antagonist PD123319 had no effect. Prostacyclin
I(2) synthesis was tightly coupled to expression of COX-2, whereas prostaglandin
E(2) and thromboxane A(2) (TXA(2)) synthesis may be associated with differential
usage of COX-1 and COX-2. The COX-2-selective inhibitors NS-398 and nimesulide
and the TXA(2) receptor antagonist BMS 180,291 inhibited TNF-alpha- and Ang II
mediated increases in DNA content and cell number by approximately 95%. These
findings suggest that a prostanoid derived from COX-2, possibly TXA(2), may
contribute to VSMC hyperplasia in vessel injury or pathophysiological conditions
associated with elevated levels of either TNF-alpha or Ang II.
PMID- 10785513
TI - cAMP-dependent vasodilators cross-activate the cGMP-dependent protein kinase to
stimulate BK(Ca) channel activity in coronary artery smooth muscle cells.
AB - cAMP-dependent vasodilators are used to treat a variety of cardiovascular
disorders; however, the signal transduction pathways and effector mechanisms
stimulated by these agents are not fully understood. In the present study we
demonstrate that cAMP-stimulating agents enhance the activity of the large
conductance, calcium-activated potassium (BK(Ca)) channel in single myocytes from
coronary arteries by "cross-activation" of the cGMP-dependent protein kinase
(protein kinase G, PKG). Single-channel patch-clamp data revealed that 10
micromol/L isoproterenol, forskolin, or dopamine opens BK(Ca) channels in
coronary myocytes and that this effect is attenuated by inhibitors of PKG
(KT5823; Rp-8-pCPT-cGMPS), but not by inhibiting the cAMP-dependent protein
kinase (protein kinase A, PKA). In addition, a membrane-permeable analog, CPT
cAMP, also opened BK(Ca) channels in these myocytes, and this effect was reversed
by KT5823. Direct biochemical measurement confirmed that dopamine or forskolin
stimulates PKG activity in coronary arteries but does not elevate cGMP. Finally,
the stimulatory effect of cAMP on BK(Ca) channels was reconstituted in a cell
free, inside-out patch by addition of purified PKG activated by either cGMP or
cAMP. In contrast, channel gating was unaffected by exposure to the purified
catalytic subunit of PKA. In summary, findings from on-cell and cell-free patch
clamp experiments provide direct evidence that cAMP-dependent vasodilators open
BK(Ca) channels in coronary myocytes by cross-activation of PKG (but not via
PKA). Biochemical assay confirmed this cross-activation mechanism of cAMP action
in these arteries. This signaling pathway is a novel mechanism for regulation of
potassium channel activity in vascular smooth muscle and other cells.
PMID- 10785515
TI - Characterization of nitric oxide synthase in the rat parotid gland.
AB - Nitric oxide (NO) acts as an inter- and intracellular signalling molecule of
various cells such as vascular endothelium, macrophages, and neurones. NO is
produced by nitric oxide synthase (NOS) from L-arginine. Here the characteristics
of NOS in the rat parotid gland were investigated. Approximately 74% of total
activity of NOS was present in the cytosolic fraction. For full activation of the
NOS in the cytosolic fraction, tetrahydroxybiopterin, NADPH, Ca(2+) and
calmodulin were needed as cofactors, because the activity was clearly reduced in
the absence of tetrahydroxybiopterin, NADPH, or Ca(2+), or in the absence of
calmodulin and presence of trifluoperazine, a calmodulin antagonist, in the
reaction mixture. The partially purified NOS activity was completely abolished in
the absence of calmodulin or Ca(2+), and activated by them in a dose-dependent
manner; EC(50) for calmodulin and Ca(2+) were 10 and 340 nM, respectively. The
K(m) for L-arginine was 1.57 microM. Immunoblot analysis revealed that a 165-kDa
protein band in the rat parotid gland cytosolic fraction cross-reacted with a
rabbit polyclonal antibody against human brain NOS. These results suggest that
NOS of the rat parotid gland is a neuronal isoform and that its activity is
regulated by physiological concentrations of calmodulin and Ca(2+).
PMID- 10785516
TI - Effect of the sensory neuropeptide antagonists h-CGRP((8-37)) and SR 140.33 on
pulpal and gingival blood flow in ferrets.
AB - In a previous study, it was concluded that the neuropeptides calcitonin gene
related peptide (CGRP) and substance P are released during resting conditions in
the (exposed) ferret dental pulp, contributing to a basal vasodilator tone in the
pulpal vessels. In order to exclude the possibility that the method used elicited
axon reflexes, which might be responsible for neuropeptide release, the present
study was designed without pulp exposure. Non-invasive laser-Doppler flowmetry
was used to measure the effects of intra-arterial infusions of the antagonists h
CGRP((8-37)) and SR 140.33 (neurokinin 1-receptor antagonist) on pulpal and
gingival blood flow before, during and after electrical tooth stimulation.
Infusions of h-CGRP((8-37)) reduced the basal blood flow in the pulp by 31.4+/
5.2% (p<0.001) and in the gingiva by 22.6+/-4.8% (p<0.05). A further significant
decrease in basal blood flow was measured in both pulp and gingiva following SR
140.33 administration. The reduction in blood flow was 16.9+/-1.9% (p<0.005) in
the pulp and 19. 3+/-5.6% (p<0.05) in the gingiva. The systemic arterial pressure
remained unchanged both during and after the periods of infusion. Tooth
stimulation before the antagonist infusion significantly increased the pulpal
blood flow by 71.9+/-15.3% (p<0.005). Infusion of h-CGRP((8-37)) greatly reduced
this electrically induced vasodilatation, indicating that CGRP is the principal
factor responsible for the vasodilatation observed after tooth stimulation. This
study confirms the previous finding that a resting vasodilator tone due to the
release of CGRP and SP exists in the ferret dental pulp. It is concluded that
spontaneous, basal release of the neuropeptides CGRP and substance P exists both
in dental pulp and gingiva in the ferret.
PMID- 10785517
TI - A strain gauge and photoelastic analysis of in vivo strain and in vitro stress
distribution in human dental supporting structures.
AB - Strain gauge and photoelastic experiments have been workhorses of experimental
stress analysis for over 50 years. In this study, both were used to analyse the
nature of stress distribution from the tooth root surface to the supporting
alveolar bone. Such studies help in understanding the behaviour of dental
supporting structures under physiological function. In the strain gauge
experiment, the mechanical strains were measured on the supporting bone surface
and the root surface of the tooth under applied bite force. It was found that
higher strains were distributed along the cervical region of the supporting bone
and the root surface. The photoelastic study was also done to evaluate the stress
distribution pattern from the root surface to the supporting bone under clinical
conditions. The stress patterns were found to decrease from the cervical to the
apical region of the root surface. These studies highlight the role of the
periodontium in stress distribution and bone remodelling.
PMID- 10785518
TI - Expression of bone sialoprotein in mineralized tissues of tooth and bone and in
buccal-pouch carcinomas of Syrian golden hamsters.
AB - The expression of bone sialoprotein (BSP) is normally restricted to mineralized
connective tissues of bones and teeth where it has been associated with mineral
crystal formation. However, recent studies have revealed ectopic expression of
BSP in various lesions, including oral and extraoral carcinomas, in which it has
been associated with the formation of microcrystalline deposits and the
metastasis of cancer cells to bone. To develop a model to study the induction of
BSP in carcinoma development, BSP expression in squamous-cell carcinomas induced
by chemical carcinogen in the hamster cheek-pouch epithelium was investigated.
Hamster BSP cDNA was first isolated and characterized, then used to prepare
probes for Northern and in situ hybridization. The protein sequence of hamster
BSP displayed 86% amino acid identity with a consensus mammalian BSP sequence and
retained polyglutamate sequences, the RGD sequence and sites of phosphorylation,
glycosylation and sulphation. The tissue-specific expression of hamster BSP mRNA
and protein was confirmed by in situ hybridization and immunolocalization in
developing tissues. Squamous-cell carcinomas induced in the buccal pouches of 5
week-old male Syrian golden hamsters treated with chemical carcinogen had BSP
mRNA and BSP in the proliferating neoplastic epithelium. In contrast, neither BSP
mRNA nor the protein could be detected in the stroma within which islands of the
transformed tissue had formed. Thus, the hamster cheek pouch is a well
characterized model that can be used to study the induced expression of BSP in
association with the development of squamous-cell carcinomas.
PMID- 10785519
TI - Isolation of proteoglycan (versican) aggregate from rat dental pulp.
AB - Versican is a large interstitial proteoglycan that is believed to be able to bind
hyaluronan to form large aggregate structures, but no study has isolated native
versican aggregates from any tissue. In this study, ternary aggregate structures
consisting of versican, hyaluronan, and link protein were isolated from rat
dental pulp by associative extractions followed by caesium sulphate rate zonal
sedimentation centrifugation. Fractions from the centrifugation were analysed by
dot blot and Western blot using monoclonal antibodies and hyaluronan-binding
protein. About 60% of the hexuronic acid was extracted by associative
extractions. Positive reactions for versican, hyaluronan and link protein were
clearly detected in the bottom fractions from the centrifugation, but were barely
detectable in the top fractions. These results suggest that the majority of the
versican, hyaluronan, and link protein forms ternary aggregate structures in the
rat dental pulp.
PMID- 10785520
TI - Effects of an anticariogenic casein phosphopeptide on calcium diffusion in
streptococcal model dental plaques.
AB - Casein phosphopeptides (CPP) stabilize amorphous calcium phosphate (ACP) and may
be used to localize ACP in dental plaque, maintaining a state of supersaturation
with respect to tooth enamel, reducing demineralization and enhancing
remineralization. The aim here was to investigate these effects by measuring the
effect of CPP-ACP on calcium diffusion in plaque. Using Dibdin's effusion system,
calcium diffusion was measured in streptococcal model plaques. This demonstrated
that by providing a large number of possible binding sites for calcium, 0.1% CPP
ACP reduces the calcium diffusion coefficient by about 65% at pH 7 and 35% at pH
5. Hence, CPP-ACP binds well to plaque, providing a large calcium reservoir
within the plaque and slowing diffusion of free calcium. This is likely to
restrict mineral loss during a cariogenic episode and provide a potential source
of calcium for subsequent remineralization. Overall, once in place, CPP-ACP will
restrict the caries process.
PMID- 10785521
TI - The effects of food fragmentation index on mandibular closing angle in human
mastication.
AB - Jaw movements were recorded using a three-dimensional magnetic sensing system
(Sirognathograph, Siemens) in 10 human volunteers while chewing standardized
volumes of 15 food types, ranging from soft cheeses to hard nuts. The maximum
horizontal amplitude inside the chewing loop (width of the loop), the height of
the loop (vertical amplitude) and the closing angle made by the jaw during the
late closing phase of the cycle relative to the vertical were calculated. The
most highly significant correlation was between the closing angle and the square
root of the ratio of two mechanical properties of the food - the toughness (R)
and modulus of elasticity (E)(r = -0.85, p<0.001). The width of the chewing loop
was also significantly correlated with the above combination of food properties
(r = -0.75, p<0.01) whereas the vertical amplitude was not. Thus, the mechanical
properties of foods appear to influence the pattern of mandibular movements in
human mastication similarly to their reported effect on food breakdown rates and
anterior temporalis activity during mastication.
PMID- 10785522
TI - The effect of ageing on parenchymal cell populations in adult female mouse
submandibular gland.
AB - The submandibular gland shows an array of responses that accompany ageing, which
are usually modest. However, the submandibular acinar-cell mucin shows a
substantial decline in total amount per gland. In the submandibular gland, there
is also a loss of secretory parenchyma. A number of factors that could influence
either parenchymal loss or a change in its cellular composition were examined in
three ages of adult female mice. The goal was to see if there are ageing-related
cellular changes that might have an effect on mucin production or secretion. The
factors examined included DNA, protein, rates of cell division and apoptosis,
cell volume and cellular composition of the parenchymal population. The
parenchymal cell composition showed significant differences during ageing, with a
substantial decrease in the percentage of acinar cells and increases in the
percentage of both types of ductal cell components. This decline in the
proportion of acinar cells in the parenchyma also reflected an overall reduction
in the total number of acinar cells in the gland. Thus, the change in proportions
of cells may potentially be a direct cause of the ageing-related decline in the
submandibular acinar-cell mucin. The alteration in cellular composition was not
attributable to changes in the cell-division indices; however, there was an
increased rate of apoptosis for acinar cells that was significantly different
between 3 and 28 months. The apoptotic rate doubled for acinar cells but showed
no significant change in ductal cells. This selective change in the rate of
apoptosis with ageing suggests that it is one of the main reasons for the decline
in the proportion of acinar cells in the submandibular gland.
PMID- 10785523
TI - Effects of basic fibroblast growth factor on cultured rat and human submandibular
salivary gland cells.
AB - Basic fibroblast growth factor (bFGF) is a strong mitogen for most mesoderm- and
ectoderm-derived cells. Although bFGF exists in rat and human salivary glands,
its physiological role in those glands is unknown. In this study, the effects of
bFGF were investigated in monolayer culture of normal rat and human submandibular
gland cells. Epithelial cells from rat and human submandibular glands were
cultivated with the aid of 3T3 cells as a feeder layer. The effects of different
concentrations of bFGF on the second passage of these cultured cells were
examined. In both the rat and human cells, the percentage of bromodeoxyuridine
(BrdU)-positive cells gradually increased up to 50 ng/ml, and then increased
sharply at 100 ng/ml. However, at concentrations higher than 100 ng/ml, the
percentages of BrdU-positive cells reached a plateau. In both rat and human
cells, total cell numbers at 100 ng/ml bFGF were significantly higher than those
of the control group from culture day 4. On the other hand, the morphology of the
cultured cells showed no difference either with or without bFGF. These results
indicate that a major effect of bFGF on salivary gland epithelial cells is to act
as a mitogenic stimulus.
PMID- 10785524
TI - Precipitation of specific proteins by freeze-thawing of human saliva.
AB - Frozen saliva samples demonstrate a variable amount of precipitate on thawing
depending on the type of secretion [submandibular-sublingual (SML) greater than
parotid]. This precipitate has been resuspended using EDTA or removed by
centrifugation by some workers and others do not mention it. Yet others collect
the salivas into EDTA or centrifuge them before freezing. To determine the
adsorption of proteins to hydroxyapatite, prior treatment with EDTA would be
disadvantageous. The aim here was to determine if the protein pattern in parotid
and SML saliva as demonstrated by sodium dodecyl sulphate gel electrophoresis is
affected by the formation of precipitates. Portions of parotid and SML saliva
were thawed and treated in the following ways: (a) mixed vigorously with a vortex
mixer; (b) centrifuged to remove the precipitate; (c) mixed with EDTA (1 and 5
mmol final concentration for parotid and SML samples, respectively) to resuspend
the precipitate. The samples were loaded on to gradient (5-20%) SDS gels and,
following electrophoresis, the gels were stained with Coomassie brilliant blue R
250. The protein patterns obtained for (a) and (c) were the same. The centrifuged
samples demonstrated loss of a specific band of less than 14 kDa, although this
was less obvious in the parotid samples. The SML samples also showed a reduction
in other lower molecular-weight proteins. This study demonstrates that
precipitates in thawed frozen salivas contain specific proteins and that these
samples require careful handling to avoid any alteration in the overall protein
composition.
PMID- 10785525
TI - The relation between lead concentrations in human dental tissues and in blood.
AB - The purpose of this study was: (1) to measure the lead concentrations in various
parts of the teeth (enamel, dentine and circumpulpal dentine) and in blood from
individuals of a remote rural South African community; (2) to investigate any
correlation between the lead concentrations in these various dental tissues and
in blood; and (3) to estimate blood lead from the tooth lead concentrations
reported in other studies. Primary teeth and blood were collected from 48
children and analysed by graphite-furnace atomic absorptiometry. The following
median concentrations (expressed in mg/kg) of lead were found: blood, 0.025;
enamel, 0.25; dentine, 2.04; circumpulpal dentine, 6.71. The tooth lead
concentrations were similar to those from other studies from remote rural areas
but comparisons of blood lead were not possible in the absence of previous data.
Blood lead in other studies could be calculated from the ratios here reported.
PMID- 10785526
TI - Fluoride and magnesium concentrations in human dental calculus obtained from
Japanese and Chinese patients.
AB - Calculus deposited on a total of 68 permanent teeth from patients 30-60 years old
from Nagoya in Japan and Beijing in China was investigated. An abrasive
microsampling method was used to examine the fluoride (F) and magnesium (Mg)
distribution, using a fluoride ion-specific electrode and atomic absorption
spectrophotometry, respectively. F concentrations decreased from the surface
towards the interior of the calculus. Mg concentrations, however, gradually rose
towards the innermost surface adjacent to the tooth. In all parts of the depth
profiles, the average concentrations of both magnesium and fluoride were higher
in the Japanese than in the Chinese calculus. Towards the inner surface of the
calculus, F and Mg concentrations were also much higher in the Japanese than in
the Chinese group. A greater intake of sea foods and greater use of fluoride
dentifrices are possible reasons for the higher F and Mg concentrations in the
Japanese individuals.
PMID- 10785527
TI - Estimating relative motoneurone size in human masseter muscle.
AB - The representation of a motor unit in the macro-EMG (MacroRep) is the method of
choice for determining muscle-unit size in masseter. However, before using
MacroRep to infer motoneurone size, the relation between MacroRep amplitude and
motoneurone size needs to be established. This is particularly important in
masseter, where the diameter of the type II muscle fibres is smaller than that of
the type I fibres. This unusual situation may affect the cross-sectional area of
the muscle units innervated by motoneurones, disturbing the expected correlation
between the MacroRep and motoneurone size. This study used H-reflex latency as an
indicator of motoneurone size, and found a negative correlation between H-reflex
latency and MacroRep amplitude in all simultaneously firing motor-unit pairs
identified. Thus it is concluded that MacroRep amplitude provides a good estimate
of relative motoneurone size in masseter, within the limits specified in the
study.
PMID- 10785528
TI - The effectiveness of an educational intervention in changing nursing practice and
preventing catheter-related infection for patients receiving total parenteral
nutrition.
AB - Catheter-related infections are one of the most serious complications of TPN
therapy. Nurses have important responsibilities in the care of patients who are
receiving TPN. This quasi-experimental study was conducted for the purpose of
investigating the effectiveness of an educational intervention on changing
nursing practice and preventing catheter-related infections in patients receiving
total parenteral nutrition. The nurses' practice and the colonisation rate of
control and comparative group patients in the surgical clinics of Hacettepe
University Hospital (Turkey), and related variables were examined before and
after an educational intervention. The findings of the study indicate that the
intervention was successful in improving appropriate nursing practice, mean
scores of nurses' practices were 45.7 before and 66.5 after the intervention
(p<0.05). The rate of microorganism colonisation was also decreased but
statistical analysis demonstrated no association between nursing practices and
microorganism colonisation of catheter cultures.
PMID- 10785529
TI - Evaluation of a self-help leaflet in treatment of social difficulties following
facial disfigurement.
AB - Psychological difficulty, particularly in social situations, is widely reported
by disfigured people, but many receive no formal psychological treatment. This
study randomly allocated 106 facially disfigured people either to receive a self
help leaflet offering cognitive-behavioural guidance or not. Participants were
assessed pre-treatment and at 3 month follow-up. The untreated group then
received the leaflet. Participants in the leaflet group fared better than
controls on 3 of the 9 scales employed (Social Leisure [SAQ] (t=2.31, p=0.012),
HADS anxiety (t=2.22, p=0.015), HADS depression (t=1.83, p=0.036). There is
support for a cognitive-behavioural approach and the usefulness of self-help
instructions in addressing the social difficulties of facially disfigured people.
The approach merits further development and investigation.
PMID- 10785530
TI - Recognising advancing nursing practice: evidence from two observational studies.
AB - Debates over title, grades and relationships across the profession has tended to
dominate the literature in advancing nursing practice. Fewer research projects
have attempted to study the activities of nurses who are designated as
undertaking advancing nursing roles. One study evaluating Masters courses for
Clinical Nursing Practice and a second addressing the impact of the 'Scope of
Professional Practice' (United Kingdom Central Council for Nursing, Midwifery &
Health Visiting, 1992) document by this team of authors afforded these research
opportunities. In this paper empirical data from 'reflective' observation with 19
nurses (including midwives and health visitors) are presented to illustrate the
range and type of functions undertaken by a small group of practitioners
developing their practice. A number of characteristic features emerged.
Assessment of individual and group needs, positive motivation to constantly
improve practice, inter-disciplinary and cross agency working for planned change
and an ability to identify and prioritize service requirements were recognised in
these nurses' roles. Certain personal attributes were seen to be essential for
successful role development such as confidence, commitment and problem solving
powers combined with a positive working environment and supportive managers.
PMID- 10785531
TI - Fatigue in advanced cancer -- meaning before measurement?
AB - The fatigue experienced by patients with advanced cancer has received little
attention either in clinical practice or amongst researchers. To date, attention
has been directed at the fatigue experienced by patients receiving chemotherapy
or radiotherapy, with little being directed at the experiences of patients with
advanced cancer within the context of a rapidly declining health status. In light
of the paucity of information available to inform practice a study was undertaken
to explore the nature and impact of fatigue as experienced by 15 patients with
advanced cancer, a relative or friend of their choice, and health care
professionals involved with their care. The aims were threefold: (i) to gain
further understanding of this debilitating problem from divergent perspectives;
(ii) to identify potential intervention strategies to be evaluated in future
studies; and (iii) to attempt to inform palliative care research methodology
where previously poorly understood and inadequately articulated symptoms, such as
the fatigue of advanced cancer, are addressed. This paper focuses on issues
relating to the third of the three study aims. Seven men and eight women with a
variety of cancers, predominantly breast, ovarian, lung and prostate cancer were
interviewed. Demographic data, disease history, biochemical markers, weight,
nutritional status and medication profile were also recorded. Patients completed
visual analogue scales (VAS) recording perceptions of severity of fatigue and
pain, and distress caused by the fatigue, during the previous week. Each patient
also completed the Hospital Anxiety and Depression Scale (HADS). Following
verbatim transcription, taped interviews were subject to processes derived from
thematic content analysis, and Glaser and Strauss' constant comparative method.
Case note data, VAS and HADS were subject to descriptive statistics. Each
participant within this study articulated the importance of addressing the
struggle of finding meaning in something as inherently disabling as the fatigue
experienced. This led to the conclusion that valid and reliable measurement of
complex facets of terminal illness is dependent on extrapolating meaning before
undertaking measurement. This paper, drawing on patient focused data, sets out to
support that assertion.
PMID- 10785532
TI - The attitude of Japanese family caregivers toward the elderly with dementia.
AB - This research examined family caregivers' attitudes toward their elderly
relatives living with dementia. A convenience sample of fifty-nine Japanese
caregivers was used. Caregiver attitudes were investigated multi-dimensionally
(negative attitude, attitude of acceptance, and attitude of active interaction)
using a questionnaire developed specifically for this study. The dimensions did
not correlate with one another but were associated with different
caregiver/elderly characteristics: i.e., negative attitude with short stay use,
length of time caregivers and elderly relatives were living together and problem
behaviors; attitude of acceptance with sleeping pill use and the type of
relationship; and attitude of active interaction with dementia diagnosis. The
results have implications for nurses in facilitating constructive caregiver
attitudes.
PMID- 10785533
TI - University students' knowledge of AIDS.
AB - In this paper, a cross-sectional exploratory design is utilized for the purpose
of assessing the knowledge level of HIV/AIDS infection among a convenient sample
of university students. The sample consisted of 1013 students at the Bachelor's
level across the university faculties (Scientific, Medical and Humanities). Chi
square test of significance was utilized to examine crucial differences amongst
students regarding their self-assessed, as well as, general knowledge of
HIV/AIDS. The results indicated the presence of a "knowledge-deficit" problem
among the students in terms of what can or cannot transmit HIV/AIDS, taking into
consideration that 54% of the students stated that they "knew very little about
AIDS" and 14% said that they "never heard about AIDS". Moreover, the results
revealed the presence of certain misconceptions (myths) with regard to students'
general knowledge of HIV/AIDS. Significant differences in the students' level of
knowledge appear in relation with students' age, sex, academic level of
university education and the faculty they attend. The study explains these
results and comes out with appropriate recommendations, the most important of
which is the need for introducing a tailored-cut course on HIV/AIDS to be offered
to students as part of their study plans/curricula.
PMID- 10785534
TI - Nurses' participation and utilization of research in the Republic of China.
AB - A survey was done to improve understanding of nurses' participation in research
activities and their utilization of research for practice in one developing
country, the Republic of China. The sample for this 1996-1997 study was 382 staff
nurses and nurse managers. Using two instruments designed for the project it was
found that although research participation was low overall, 64% participated in
some research activities with data collection and presentation at national
conferences the most frequent activities. Nearly half the nurses had utilized
research to change practice in the previous three years. The main barriers to
utilization were lack of time and lack of staff. Role models, consultation and
guidance to locate useful research were the main types of needed assistance. The
findings provide direction for future training, education and managerial policy,
especially for nurses in developing countries, which account for 84% of the
world's population and 93% of the worldwide burden of disease.
PMID- 10785535
TI - Lesbian, gay and bisexual experiences within critical care nursing, 1988-1998: a
survey of the literature.
AB - The aim of this paper is to provide an analysis of the extent to which gay,
lesbian and bisexual service user experiences are represented within the critical
care literature. A survey of five well established critical care journals,
covering the period 1988-1998, was conducted in order to reveal the range of
themes addressed within them. The findings suggest that these groups are
invisible in this field of practice and consequently their particular concerns
have remained marginalised. The implications of this absence are far reaching,
potentially inhibiting nurses from establishing effective caring relationships
with either lesbians, gays or bisexuals and from identifying and developing
appropriate interventions for the care of these patients and their families.
PMID- 10785536
TI - Reconceptualising the outcomes of Continuing Professional Development.
AB - This paper considers the potential outcomes, both positive and negative, of
continuing professional development from the perspectives of practitioners and
managers. Following a consideration of the literature it draws upon data
collected during a 3-year evaluation of the English National Board Framework and
Higher Award to highlight divergent views and tensions within Continuing
Professional Development (CPD). Considerable discrepancies between practitioners
and managers emerge which raise a number of searching questions about the value
each group accords to continuing professional development. Based on the data a
new framework for conceptualizing the outcomes of CPD is presented which
fundamentally undermines a quasi-market approach.
PMID- 10785537
TI - Anandamide and other cannabimimetic fatty acid derivatives-foreword
PMID- 10785538
TI - Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and
2-arachidonylglycerol.
AB - The purpose of this review is to discuss the cellular synthesis and inactivation
of two putative endogenous ligands of the cannabinoid receptor, N
arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG). Both ligands are
synthesized by neurons and brain tissue in response to increased intracellular
calcium concentrations. Both ligands are substrates for fatty acid amide
hydrolase (FAAH). Both AEA and 2-AG bind to the neuronal form of the cannabinoid
receptor (CB1). AEA binds the receptor with moderate affinity and has the
characteristics of a partial agonist, whereas, 2-AG binds with low affinity but
exhibits full efficacy. Two possible physiological roles of the endocannabinoids
and the CB1 receptor are discussed: the regulation of gestation and the
regulation of gastrointestinal motility.
PMID- 10785539
TI - Anandamide amidohydrolase (fatty acid amide hydrolase).
AB - Anandamide (N-arachidonoylethanolamine) loses its cannabimimetic activity when it
is hydrolyzed to arachidonic acid and ethanolamine by the catalysis of an enzyme
referred to as anandamide amidohydrolase or fatty acid amide hydrolase. Cravatt's
group and our group cloned cDNA of the enzyme from rat, human, mouse and pig, and
the primary structures revealed that the enzymes belong to an amidase family
characterized by the amidase signature sequence. The recombinant enzyme acted not
only as an amidase for anandamide and oleamide, but also as an esterase for 2
arachidonoylglycerol. The reversibility of the enzymatic anandamide hydrolysis
and synthesis was also confirmed with a purified recombinant enzyme. Several
fatty acid derivatives like methyl arachidonyl fluorophosphonate potently
inhibited the enzyme. The enzyme was distributed widely in mammalian organs such
as liver, small intestine and brain. However, the anandamide hydrolyzing enzyme
found in human megakaryoblastic cells was catalytically distinct from the
previously known enzyme.
PMID- 10785540
TI - Oxidative metabolism of anandamide.
AB - In addition to the well studied hydrolytic metabolism of anandamide, a number of
oxidative processes are also possible. Several routes somewhat analogous to the
metabolism of free arachidonic acid have been reported. These involve mediation
by various lipoxygenases and COX-2 and lead to ethanolamide analogs of the
prostaglandins and HETES. The physiological significance of these products is not
well understood at this time. There are also preliminary data suggesting a
pathway involving oxidation of the hydroxy group of anandamide to a putative
metabolite, N-arachidonyl glycine (AA-gly). This molecule displays activities in
experimental models that suggest that it may play a role in some of the
activities attributed to its precursor, anandamide.
PMID- 10785541
TI - Cannabimimetic fatty acid derivatives in cancer and inflammation.
AB - Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e.
anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and
palmitoylethanolamide (PEA), in the control of inflammation and of the
proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2
AG can be induced by stimulation with either Ca(2+) ionophores,
lipopolysaccharide, or platelet activating factor in macrophages, and by
ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a
widely used model for mast cells). These cells also inactivate CFADs through re
uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate
cytokine and/or arachidonate release from macrophages in vitro, regulate
serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models
of inflammatory pain. However, the involvement of endogenous CFADs and
cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In
human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently
inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation.
Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even
higher anti-proliferative activity. These effects are due to suppression of the
levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors
(trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by
other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated
protein kinase underlie the anti-mitogenic actions of AEA. The possibility that
CFADs act as local inhibitors of the proliferation of human breast cancer is
discussed here.
PMID- 10785542
TI - Endogenous cannabinoid signaling and psychomotor disorders.
AB - The effects of cannabinoids on motor behaviors and cognitive functions are well
documented. The discovery of the CB1 cannabinoid receptor and the mapping of its
distribution in the central nervous system have provided a rationale to elucidate
the molecular and cellular mechanisms of cannabinoid actions. The identification
of naturally occurring ligands for these receptors, anandamide and 2
arachidonylglycerol, has prompted a large research effort aimed at investigating
the physiological role of the endogenous cannabinoid system, as well as its
potential use as a target for novel therapeutic interventions. This mini-review
discusses the participation of the endogenous cannabinoid system in the
regulation of motor behaviors, pointing out its possible involvement in the
pathophysiology of psychomotor disorders.
PMID- 10785544
TI - Editorial
PMID- 10785543
TI - Cardiovascular effects of endocannabinoids--the plot thickens.
AB - Cannabinoids, the bioactive ingredients of the marijuana plant, are best known
for their psychoactive properties, but they also influence other physiological
processes, such as cardiovascular variables. Endocannabinoids are recently
identified lipid mediators that act as natural ligands at cannabinoid receptors
and mimic most of the biological effects, including the cardiovascular actions,
of plant-derived cannabinoids. In experimental animals, the most prominent
component of the cardiovascular effects of cannabinoids is prolonged hypotension
and bradycardia. This review focuses on the possible mechanisms underlying these
effects. The emerging evidence suggesting that endocannabinoids may be involved
in the peripheral regulation of vascular tone under certain conditions is also
discussed.
PMID- 10785545
TI - (9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido
[1,2-a] pyrimidin-4-one), AS-35, inhibits leukotriene synthesis.
AB - AS-35, (9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H
pyrido[1, 2-a] pyrimidin-4-one), was developed as a leukotriene (LT) receptor
antagonist, which also inhibited IgE-mediated release of leukotrienes (LTs). We
have investigated the action of AS-35 on the enzyme activities which are involved
in the synthesis of LTC(4) and LTB(4) (LT-synthesizing enzymes); cytosolic
phospholipase A(2) (cPLA(2)), 5-lipoxygenase (5-LO), leukotriene (LT)C(4)
synthase and LTA(4) hydrolase. AS-35 dose-dependently inhibited IgE- and A23187
stimulated production of LTC(4) by up to 71.5-84.8% and that of LTB(4) by 48.3
49.2% at 2. 5x10(-5) M. The assays for cPLA(2)(-), 5-LO-, LTC(4) synthase- and
LTA(4) hydrolase-activities revealed that the inhibition is attributable to
suppression of cPLA(2), 5-LO and LTC(4) synthase but not LTA(4) hydrolase. We
have also studied the action of AS-35 on the release of beta-hexosaminidase (beta
HEX) as a marker of preformed mediators. AS-35 had only weak inhibitory action on
the release of beta-HEX. The results indicate that anti-allergic action of AS-35
is predominantly attributable to its inhibition of LT synthesis by suppressing
three consecutive enzymes for LTC(4) synthesis.
PMID- 10785546
TI - Experimental evidence pointing to the bidirectional interaction between the
immune system and the thyroid axis.
AB - Among the many examples of neuroendocrine-immune system interactions the
relationship between the thyroid axis and the immune function has yet to be
clearly established. Here we studied the influence of thyroid hormones on the
course of an alloimmune response. Murine T(3) and T(4) levels were found to be
increased a few days after the immunization of mice with allogeneic lymphoid
cells. Besides in vivo treatment with T(4) was shown to increase alloantibody
titers during the early stages of alloimmunization and to enforce lymphoid
proliferation in vitro in a mixed lymphocyte reaction. Conversely, lowering
thyroid hormone seric levels by propylthiouracil treatment, negatively modulates
the humoral and cellular alloimmune responses. The evidence here points to the
existence of a bidirectional communication between both systems. The possibility
that the antigenic challenge would increase the thyroid gland activity thus
leading to a positive modulatory action upon the immune response is also
discussed.
PMID- 10785547
TI - Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation
and maturation of human monocytes and bone marrow CD34+ cells to dendritic cells.
AB - FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8 (4-pyridyl) pyrazoro [5-1-c]
[1,2,4] triazin-2-yl]-2-phenylethanedion sulfate monohydrate), one of the
pyridinyl imidazoles, is an immunosuppressive agent which was developed to
inhibit proinflammatory cytokine production. We examined the effect of FR167653
on the differentiation and maturation phases of both human bone marrow-derived
dendritic cells (BM-DC) and blood monocyte-derived DC (Mo-DC). DC induced from
either BM-DC or Mo-DC progenitors in the presence of FR167653 had lower
expression of CD1a, CD83 and CD86 (B7.2). FR167653 also significantly suppressed
the ability of Mo-DC to produce both TNF-alpha and IL-1beta in response to LPS
stimulation. Mixed lymphocyte reaction (MLR) stimulation was significantly lower
in FR167653-treated Mo-DC than in control Mo-DC, although the suppressive effect
of FR167653 was much less on BM-DC. These results indicate novel
immunosuppressive properties of FR167653, which may be therapeutically useful in
controlling chronic immune and/or inflammatory diseases through down-regulation
of DC differentiation and maturation.
PMID- 10785548
TI - Allergen-induced bronchial eosinophilia in guinea-pigs is inhibited by both pre-
and post-induction cyclosporin-A treatments.
AB - Repeated treatment of sensitized guinea-pigs with cyclosporin-A (CS-A) before
aerosol allergen challenge is known to inhibit the subsequent bronchial
eosinophilia. It is not known, however, if the drug is also effective on
established/on-going bronchial eosinophilia. We have, therefore, studied the
effect of CS-A on allergen-induced eosinophil recruitment into the
bronchoalveolar lavage (BAL) fluid of guinea-pigs when given before or after
induction.Ovalbumin-immunized guinea-pigs were treated with CS-A (20 mg/kg
subcutaneously) or vehicle daily for varying periods before a single aerosol
allergen challenge. In animals in which bronchial eosinophilia was maintained
with repeated aerosol allergen challenge, CS-A or vehicle was given daily for
varying periods after the first allergen challenge. BAL and cell count were
performed 24 h after the last challenge. In vehicle-treated animals, a single
allergen challenge caused a 4-5 fold increase in the number of eosinophils in the
BAL fluid after 24 h, declining to baseline by 7 days. In repeatedly-challenged
animals, this response was sustained throughout. Eosinophil infiltration was
significantly inhibited when CS-A was given daily for 7-14 days, but not for 1 or
3 days, before allergen challenge. When given during an established/on-going
eosinophil infiltration, a significant inhibition was seen after administration
for 5 or 7 days, but not for 1 or 3 days.These results show that repeated CS-A
administration inhibits not only the induction of allergic bronchial eosinophilia
but also the maintenance of an established one. This may be relevant in the
treatment of allergic diseases, such as asthma, in which drug administration
often begins when eosinophilia is already established.
PMID- 10785549
TI - Restoration of splenic noradrenergic nerve fibers and immune reactivity in old
F344 rats: a comparison between L-deprenyl and L-desmethyldeprenyl.
AB - L-deprenyl, a monoamine oxidase-B inhibitor, partially reversed the age
associated decline in splenic sympathetic noradrenergic (NA) innervation and
immune reactivity in old male rats. The purpose of the present study was to
examine whether the effects of deprenyl on splenic sympathetic NA nerve fibers
and immune functions are mediated through a metabolite of deprenyl, L
desmethyldeprenyl. Old male F344 rats were treated with 0, 0.25, or 1.0 mg L-(-)
deprenyl/kg BW; 0.025, 0.25, or 1.0 mg L-(-)-desmethyldeprenyl/kg BW; and 1.0 mg
D-(+)-desmethyldeprenyl/kg BW i.p. daily for 8 weeks. The animals were sacrificed
after a 10-day drug wash-out period and the spleens were removed for
histofluorescence, immunocytochemistry, neurochemical, and immunological
analysis. The volume density of NA nerve fibers was increased in the spleens of
deprenyl- and L-desmethyldeprenyl-treated old rats. Con A-induced IFN-gamma
production by spleen cells was elevated in 1.0 mg/kg deprenyl- and L
desmethyldeprenyl-treated rats in comparison to saline- and D-desmethyldeprenyl
treated old rats. Deprenyl and desmethyldeprenyl treatment did not alter the
percentage of CD5+ T cells, but treatment with 1.0 mg/kg deprenyl and 0.025 mg/kg
L-desmethyldeprenyl prevented the decline in the percentage of sIgM(+)B cells in
the spleens of old rats. These results suggest that L-desmethyldeprenyl may be as
equipotent as deprenyl in preventing age-associated diminution in splenic
sympathetic NA innervation and immunocompetence.
PMID- 10785550
TI - Impaired estrogen priming of progesterone receptors in uterus of MRL/MP-lpr/lpr
mice, a model of systemic lupus erythematosus (SLE).
AB - Estrogens exacerbate the autoimmune disease SLE and progesterone is
immunoprotective. Estrogens increase synthesis of progesterone receptors (PR) and
it is hypothesized that this physiological balance may be impaired in SLE. To
test this, cytosolic PR were measured in hypothalamus, thymus and uterus from 6
week-old female ovariectomized BALB/c and MRL/MP-lpr/lpr mice 48 h after s.c.
injection of estradiol benzoate (3.2 microg/0.1 ml; OB) in peanut oil or 0.1 ml
peanut oil alone. PR were measured using [(3)H]ORG 2058, which does not bind to
corticosteroid-binding globulin (CBG), and bound and free ligand were separated
using minicolumns of Sephadex LH20 at 0 degrees C. PR were measured in cytosols
from hypothalamus and uterus of oil-treated BALB/c mice, but were undetectable in
thymus, whereas receptors were measurable in all three tissues of MRL mice. There
was a significantly greater priming effect of OB on PR in uterus of BALB/c mice,
but not in hypothalamus, and PR became detectable in thymus cytosols from BALB/c
mice. Also, the apparent affinity of the binding reaction between [(3)H]ORG 2058
and PR was significantly higher than those measured in other tissues in
hypothalamic cytosols of both strains. These results suggest that there is an
impairment of estrogen priming of progesterone receptors in uterus and perhaps
thymus of MRL mice.
PMID- 10785551
TI - The effects of allopurinol on immune function in normal BALB/c and SCID mice.
AB - To clarify the relationship between purine metabolism and immunity, the in vivo
immunosuppressive effects of allopurinol (AL), a xanthinoxidase (XO) inhibitor,
were studied using normal BALB/c and severe combined immunodeficient (SCID) mice.
Following AL administration for 14 weeks (long term), a decreased immune response
to ovalbumin (OVA) in the peripheral blood was observed in normal mice, which
might not be only due to direct B cell suppression but also due to suppression of
helper T cell function. In the SCID mice, there was a markedly late and reduced
recovery of surface immunoglobulin (sIg) positive cells, which are markers for
mature B lymphocytes, in the peripheral blood after AL administration. The total
immunoglobulin G (IgG) titers in the AL treated group were significantly lower
than in the control group 6 weeks after stem cell transfer, but increased until
there was no difference in the titers between the two groups at week 14. CD4
positive helper T cells and CD8 positive T cells were slow to recover, though
these gradually recovered to reach normal levels in the mature stage. These data
suggest that the administration of AL may modulate B cell and T cell responses in
OVA-immunized antibody formation. Furthermore, this study showed that AL could
influence immune functions during the pre-natal and developmental periods and
that its effects might differ according to the stages of maturity of the immune
cells.
PMID- 10785552
TI - Cefodizime enhances phagocytosis and intracellular killing of Staphylococcus
aureus but does not influence polymorphonuclear leukocytes response to fMLP
stimulation.
AB - The influence of Cefodizime (CDZ) on in vitro activity of polymorphonuclear
leukocytes (PMNL) from healthy subjects was assessed. Preincubation with CDZ
enhanced phagocytosis and intracellular killing of Staphylococcus aureus by PMNL.
Contrary to numerous clinical reports, no significant effect of CDZ preincubation
on PMNL response to n-formyl-methionyl-leucyl-phenylalanine was found with
respect to intracellular calcium changes, degranulation, hydrogen peroxide
production, and chemiluminescence. These results suggest that augmented
microbicidal activity of PMNL is not related to the enhanced production of
reactive oxygen species in healthy subjects.
PMID- 10785553
TI - The opioid-receptor-like 1 (ORL-1) as a potential target for new analgesics.
AB - Anew sequence, which encoded a novel G protein-coupled receptor, was disclosed by
two different groups, using the nucleic acid probes based on the delta opioid
receptor, first cloned in 1992. The new receptor, which Meunier called opioid
receptor-like 1 (ORL-1), was shown to share high homology with the opioid
receptors and therefore thought to be a potential target for new analgesics. In
this respect, the present review reports on the literature referring to ORL-1, to
its natural ligand (nociceptin or orphanin FQ) and to several synthetic analogues
recently described, both as agonists or antagonists at the receptor.
PMID- 10785554
TI - Quantum mechanical study of the intermediates formed following the reaction of
the histidine decarboxylase's substrate and inhibitors with coenzyme.
AB - Histidine decarboxylase catalyses the decarboxylation of l-histidine to histamine
using pyridoxal-5'-phosphate (PLP) as coenzyme. The PM3 quantum mechanical
conformation method of analysis and heat of formation calculation were carried
out for intermediates which are probably formed during the interaction of
histidine (substrate), (s)-alpha-methylhistidine, (s)-alpha-hydrazinohistidine,
(s)-alpha-fluoromethylhistidine and (s)-alpha-difluoromethylhistidine
(inhibitors) with PLP-dependent histidine decarboxylase from Morganella morganii.
The results suggest that the structures of the intermediates before and after
decarboxylation were found to exist in a conformation showing a planar
arrangement of the double bonds with the pyridoxylidene ring and the bond to the
carboxyl group being perpendicular to this plane. After decarboxylation, all the
double bonds are in the plane of the pyridoxylidene ring which facilitates the
electron displacement for the following protonation at C(alpha). The values of
the enthalpy for intermediates would increase the probability of their formation
in the enzyme's active site which are consistent with all available
stereochemical and mechanistic data.
PMID- 10785555
TI - Naphthazarin derivatives (IV): synthesis, inhibition of DNA topoisomerase I and
cytotoxicity of 2- or 6-acyl-5,8-dimethoxy-1, 4-naphthoquinones.
AB - Some 2- or 6-acyl-5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives were
synthesized and evaluated for inhibition of DNA topoisomerase I and cytotoxicity
against L1210 cells. Compared with 2-acyl-DMNQ derivatives, 6-acyl-DMNQ
compounds, bearing a higher electrophilic quinone moiety, showed a higher potency
in the inhibition of DNA topoisomerase I and the cytotoxicity, implying the
possible participation of electrophilic arylation in their bioactivities. Time
and temperature dependence of the enzyme inhibition suggests that the arylation
occurs irreversibly. Among the 6-acyl-DMNQ derivatives, the ones possessing an
acyl group of an intermediate size (C(5)-C(9)) showed higher potency in their
bioactivities than other derivatives. Furthermore, for the effective inhibition
of DNA topoisomerase I, the size of acyl moiety of 6-acylated derivatives seems
to be limited to < 12 carbon atoms.
PMID- 10785557
TI - Carbonic anhydrase inhibitors - part 78(#). Synthesis of water-soluble
sulfonamides incorporating beta-alanyl moieties, possessing long lasting
intraocular pressure lowering properties via the topical route.
AB - Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino,
hydrazino or hydroxyl groups with N-tert-butyloxycarbonyl-beta-alanine (Boc-beta
ala; Boc = t-butoxycarbonyl) in the presence of carbodiimide derivatives
afforded, after removal of the protecting group, a series of water-soluble
compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or
trifluoromethane sulfonic). The new derivatives were assayed as inhibitors of the
zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes,
CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important
physiological processes. Good inhibition was observed against all three isozymes,
but especially against CA II and CA IV (in the nanomolar range), the two isozymes
known to play a critical role in aqueous humour secretion within the ciliary
processes of the eye. Some of the best inhibitors synthesized were applied as 2%
aqueous solutions into the eyes of normotensive or glaucomatous albino rabbits,
when strong and long-lasting intraocular pressure (IOP) lowering was observed
with many of them. Thus, the amino acyl groups conferring water solubility to
these sulfonamide CA inhibitors, coupled with their strong enzyme inhibitory
properties and balanced lipid solubility seem to be the key factors for obtaining
compounds with effective topical antiglaucoma activity.
PMID- 10785556
TI - Protease inhibitors - part 5. Alkyl/arylsulfonyl- and arylsulfonylureido
/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum
collagenase.
AB - Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of
derivatives which were first N-benzylated by treatment with benzyl chloride, and
then converted to the corresponding hydroxamic acids with hydroxylamine in the
presence of carbodiimide derivatives. Other derivatives were obtained by reaction
of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl
isothiocyanate, followed by conversion of their COOH group into the CONHOH
moiety, as mentioned above. The 90 new compounds reported here were assayed as
inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc
enzyme which degrades triple helical regions of native collagen. The prepared
hydroxamate derivatives were generally 100-500 times more active than the
corresponding carboxylates. In the series of synthesized hydroxamates,
substitution patterns leading to the best inhibitors were those involving
perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as
pentafluorophenylsulfonyl, 3- and 4-carboxyphenylsulfonyl-, 3-trifluoromethyl
phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly
to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium
histolyticum collagenase inhibitors should incorporate hydrophobic moieties at
the P(1') and P(2') sites, whereas the alpha-carbon substituent may be a small
and compact moiety (such as H, for the Gly derivatives reported here). Such
compounds might lead to the design of collagenase inhibitor-based drugs useful as
anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal
keratitis.
PMID- 10785558
TI - The low affinity PCP sites in the rat cerebellum not only bind TCP-like but also
BTCP-like structures.
AB - Congeners of the potent dopamine (DA) re-uptake inhibitor 1-[1-(2
benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) are unexpectedly able to bind in
the rat cerebellum, although this structure is devoid of dopaminergic nerve
endings. In line with previous studies the hypothesis that they bind to low
affinity PCP sites labelled with [3H]TCP in the rat cerebellum, even though they
do not bind to the high affinity PCP sites in the forebrain, was considered.
Analogues of 1-[1-(2-thiophenyl)cyclohexyl]piperidine (TCP) and BTCP with a
modified aromatic moiety and with O or S atoms substituted in the cyclohexyl ring
were prepared and tested in competition experiments both in rat forebrain and
cerebellum membranes labelled with [3H]TCP, and in rat striatum membranes
labelled with [3H]BTCP. Results indicated that BTCP and congeners could bind to
low affinity PCP sites labelled with [3H]TCP in the rat cerebellum with a
decrease of the selectivity for the DA transporter. On the contrary, some TCP
analogues displayed a very high selectivity for these low affinity sites; they
might be important pharmacological tools to elucidate the nature and function at
yet unknown of these sites.
PMID- 10785559
TI - Substituted 1,2,3-triazolo[1,5-a]quinazolines: synthesis and binding to
benzodiazepine and adenosine receptors.
AB - This paper reports the synthesis and evaluation of the biological affinity
towards benzodiazepine and A(1) and A(2A) adenosine receptors of some 3
ethoxycarbonyl or 3-phenyl-substituted 1,2, 3-triazolo[1,5-a]quinazolines.
Starting from the appropriate chloro-substituted phenylazides, the series of 7 or
8 chloro-substituted triazoloquinazolines were prepared. Nitration reactions of
the triazoloquinazoline ring and chlorination reactions of the hydroxyl group in
the 5 position of the same ring are also reported. By nucleophilic displacement
of halogen, the corresponding 5-amino derivatives and some analogous derivatives
bearing cyclohexylamino and p-toluidino substituents were obtained. The binding
assays showed a generalized decrease in the affinity towards the benzodiazepine
receptors and confirmed a moderate affinity towards the A(1) adenosine receptors
in comparison with the previously studied triazoloquinazoline derivatives.
PMID- 10785561
TI - Design, synthesis and antihistaminic (H(1)) activity of some condensed 3
aminopyrimidin-4(3H)-ones.
AB - Anovel series of condensed 3-amino-2-(substituted)methylpyrimidin-4(3H)-ones is
reported with potential H(1) receptor antagonistic activity. The IC(50) values
for 23 compounds were found to be in the micromolar range. Five lead compounds
(10c, e, g, r and t), when evaluated by the in vivo method were found to protect
guinea-pigs from the histamine induced asphyxia and antagonized histamine in a
competitive and reversible manner. With a pA(2) value of 8.7 and protection time
of 9.5 min (in vivo test), compound 10g was the most active amongst these five
compounds. The isosteric replacement of the side chain -NH- in series 1, by
oxygen and -NHSO(2)- functions, was undertaken to investigate the role of two
amino functions in the receptor binding. This isosteric replacement with -O- does
not affect the antihistaminic activity and the sedative potential of the series.
Preliminary molecular modelling studies indicate that the compounds with -NHSO(2)
in the side chain exhibit a closer fit with temelastine than their -O-
isosteres.
PMID- 10785562
TI - Synthesis and preliminary evaluation of new 5-pyrazolinone derivatives as
analgesic agents.
AB - New 4-(aroyloxyalkanoyl)-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one s (5) were
cyclized to 4-(2-aryl-5-unsubstituted/substituted oxazol-4-yl)-2,3-dimethyl-1
phenyl-3-pyrazolin-5-ones (6) employing the Davidson procedure. Preliminary
evaluation of analgesic activity revealed that the effect of 4-(2-phenyl-5
ethyloxazol-4-yl)-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one and 4-[2-(4
chlorophenyl)-5-ethyloxazol-4-yl]-2, 3-dimethyl-1-phenyl-3-pyrazoline-5-one on
acetic acid induced writhing was superior to that of antypyrine and aminopyrine.
4-[2-(4-Chlorophenyl)-5-methyloxazol-4-yl]-2, 3-dimethyl-1-phenyl-3-pyrazolin-5
one and 4-[2-(4-methoxyphenyl)-5-ethyloxazol-4-yl]-2, 3-dimethyl-1-phenyl-3
pyrazolin-5-one were more potent than aminopyrine, whereas 4-(2-phenyl-5
methyloxazol-4-yl)-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one and 4-[2-(4
methoxyphenyl)-5-methyl-oxazol-4-yl]-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one
were not as active (modified Koster's Test; 0.19-0.21 mmol.kg(-1)). None of the
selected entries showed inhibition of formaldehyde-induced paw oedema.
PMID- 10785560
TI - Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde
and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure
activity relationships.
AB - Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde
or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine
mimetic moiety. All derivatives presented the E-configuration, as determined by
NMR-NOE experiments. These compounds were tested in vitro as potential
antitrypanosomal agents, and some of them, together with the parent compounds, 5
nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone
derivatives, were also evaluated in vivo using infected mice. Structure-activity
relationship studies were carried out using voltammetric response and lipophilic
hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the
highest in vivo activity. A correlation was found between lipophilic-hydrophilic
properties and trypanocidal activity, high R(M) values being associated with low
in vivo effects.
PMID- 10785563
TI - The classics: a tribute to the fiftieth anniversary of the randomized clinical
trial.
PMID- 10785564
TI - Co-morbidity data in outcomes research: are clinical data derived from
administrative databases a reliable alternative to chart review?
AB - Evaluation of co-morbidity data is essential in health outcomes research. Co
morbidity data derived from administrative databases has been criticized for
lacking the accuracy required for clinical research. We compared co-morbidity
data derived from a Canadian provincial hospitalization database with chart
review in 817 adults treated with a percutaneous coronary intervention at a
single tertiary care hospital between 1994 and 1995. While the administrative
database tended to under-estimate the prevalence of some co-morbid conditions,
the agreement between chart review and administrative data was good to very good
for most conditions. Asymptomatic conditions were noted to have lower levels of
agreement. Multivariate risk models for all-cause mortality constructed from both
data sources were almost identical, suggesting minimal misclassification. The
results indicate that clinical data abstracted from most Canadian hospitalization
databases can provide reliable information regarding baseline co-morbid
conditions believed to influence survival in a population undergoing percutaneous
coronary interventions.
PMID- 10785565
TI - Selection bias in studies of major depression using clinical subjects.
AB - Selection bias may systematically distort estimates deriving from psychiatric
studies using clinical subjects. Such bias may impact on cross-sectional studies
using samples of convenience and also on clinical case-control studies. The
objective of this report is to describe examples of such bias, and to identify
probably mechanisms underlying it. A series of cases was recruited from among
inpatients at a general hospital in Calgary, Canada. This case-series consisted
of consenting subjects with current episodes of major depression according to a
structured diagnostic interview. Comparison subjects consisted of non-depressed
(according to the structured interview) individuals admitted to the same units
and a sample of community subjects scoring negatively on a major depression
predictor. Bayesian calculations using ancillary census and national survey data
were used to estimate the selection probabilities underlying bias apparent in
several of the odds ratio estimates. Neither a cross-sectional analysis
incorporating all of the clinical subjects, the use of a community comparison
group nor a case-control analysis using a subset of the clinical subjects
resulted in valid estimation. This study confirms that the probability of
selection of clinical subjects can be conditionally dependent on diagnosis and
other variables in ways that create a substantial vulnerability to selection
bias.
PMID- 10785566
TI - Validity and reliability of the SF-36 Health Survey Questionnaire in patients
with coronary artery disease.
AB - The validity and reliability of the SF-36 has been studied in 185 patients
hospitalized with suspected ischemic cardiopathy, classified into four groups
(AMI, unstable angina, nonischemic cardiologies, and absence of cardiologies).
The validity of the construct has been analyzed by means of the association of
the SF-36 with sociodemographic and clinical variables, and with diagnostic
groups. The correlation of the subscales with GHQ-28 scores and the factorial
structure have been studied. Internal consistency was measured by Cronbach's
alpha and the item-internal consistency and item-discriminant validity. The
validation result was as expected, although the scores were significantly lower
in patients with unstable angina, only in the PF, VT, and GH subscales. The
correlations with the GHQ-28 were high for MH and VT. The internal consistency
was high (Cronbach's alpha 0.72-0.94). Factorial analysis identified eight
factors, with the "anxiety" component of subscale MH remaining as an independent
factor. These results suggest that the SF-36 is a useful scale for the
differentiated clinical forms of ischemic cardiopathy, with the additional
capability of reflecting the level of anxiety in these patients.
PMID- 10785567
TI - A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian
cancer.
AB - Estrogen replacement therapy (ERT) has not been associated with epithelial
ovarian cancer in most reported epidemiologic studies that have looked for an
association. Some studies may have found weak statistically nonsignificant
associations because the number of cases or number of women who reported estrogen
use was small. We performed a meta-analysis of data from 15 case-control studies
that provided data on ERT and risk of epithelial ovarian cancer. The 15 combined
studies were statistically heterogeneous (chi(2) (14) = 26. 3, P < 0.05) in terms
of the effect they found. When we combined these studies using a random effects
model, we did not find a significant association of ERT with ovarian cancer (odds
ratio = 1.1, 95% confidence interval = 0.9-1.3). There was no clear evidence of a
dose-response relation with increasing duration of estrogen use in a subset of
five studies that reported estrogen use by duration (overall slope = 0.0012, 95%
confidence interval = -0.0055 to 0. 0080). The influences of statistical
outliers, study design (hospital or clinic controls vs. community controls), and
location (U.S. and Canada vs. Europe and Australia) were examined. The odds ratio
was 1.3 (95% confidence interval = 1.0-1.6) in the relatively homogeneous subset
of four U.S. case-control studies with community controls, but we cannot rule out
the possibility of uncontrolled confounding. The odds ratios for estrogen use for
other subgroups defined by geographic location and type of control group were not
significantly different from one.
PMID- 10785568
TI - Dealing with missing data in observational health care outcome analyses.
AB - Observational outcome analyses appear frequently in the health research
literature. For such analyses, clinical registries are preferred to
administrative databases. Missing data are a common problem in any clinical
registry, and pose a threat to the validity of observational outcomes analyses.
Faced with missing data in a new clinical registry, we compared three possible
responses: exclude cases with missing data; assume that the missing data
indicated absence of risk; or merge the clinical database with an existing
administrative database. The predictive model derived using the merged data
showed a higher C statistic (C = 0.770), better model goodness-of-fit as measured
in a decile-of-risk analysis, the largest gradient of risk across deciles (46.3),
and the largest decrease in deviance (-2 log likelihood = 406.2). The superior
performance of the enhanced data model supports the use of this "enhancement"
methodology and bears consideration when researchers are faced with nonrandom
missing data.
PMID- 10785569
TI - Hormone replacement therapy and endometrial cancer in Ontario, Canada.
AB - Estrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but
is associated with an increased risk of endometrial cancer. We have assessed the
impact of a regimen of estrogen with progestogen on risk of endometrial cancer
for women 48 years and older. We conducted a case-control study in Ontario,
Canada, from 1994 to 1998 by interviewing registry-based cases (n = 512) and
population controls (n = 513) to obtain information on use of hormones and
dietary habits. Compared to non-users, the use of opposed hormone therapy in
sequential regimen for more than three years showed a borderline increase in risk
(OR = 1.49, 95% CI 0.93-2. 40), but this increase was much less than among women
on unopposed estrogen (OR = 4.12, 95% CI 2.21-7.71). Stronger associations were
observed when duration of sequential hormone use was examined as a continuous
variable (OR per three years of use = 1.21, 95% CI 1.03-1. 42). The effect of
opposed hormone therapy on endometrial cancer risk appears to vary both by usage
patterns and by patient characteristics of body weight and history of diabetes.
PMID- 10785570
TI - Dyslipidemia and abdominal obesity: an assessment in three general populations.
AB - Several studies show a relationship between abdominal obesity and cardiovascular
diseases, partially mediated through an altered metabolism of dyslipidemia. The
present study was aimed at testing the robustness of this association across
three contrasted populations and at assessing the performances of abdominal
obesity as a screening tool for dyslipidemia. Data were drawn from three
population health surveys recently conducted in two regions of a developed
country (Switzerland, mostly of Caucasian origin, n = 2650) and in a less
developed country (Seychelles, Indian Ocean, mostly of black descent, n = 806).
Dyslipidemia was defined as a ratio of total cholesterol to high-density
lipoprotein cholesterol (TC-HDL) greater than 5. Two anthropometric circumference
measurements, waist-to-hip ratio (WHR) and waist circumference (WC), were used to
define abdominal obesity either as WHR >/= 0.9 in men and WHR >/= 0.8 in women or
as WC >/= 94 cm and WC >/= 80 cm, respectively. A consistent direct association
between abdominal obesity and dyslipidemia (odds ratios varying from 1.85 to
4.56) was found in the three populations, independently of gender, age, body mass
index, blood pressure, and smoking. This consistency across ethnicities and
environments strengthens the hypothesis of a common etiopathological mechanism.
The sensitivity for detecting dyslipidemia was generally higher for abdominal
obesity, based on either WHR or WC, than for criteria based on the other risk
factors under study. In addition, the sensitivity was higher in the study
populations with a low prevalence of dyslipidemia (Swiss women and Seychellois of
both sexes) than in the others. These findings support that WHR and WC may be
useful as simple and inexpensive screening tools to select individuals eligible
for more sophisticated and costly serum lipid determinations, especially in
developing countries.
PMID- 10785571
TI - Predictive values of waist circumference for dyslipidemia, type 2 diabetes and
hypertension in overweight White, Black, and Hispanic American adults.
AB - Waist circumferences (WC) >/=102 cm for men and >/=88 cm for women have been
proposed by an expert panel as cut-points for identifying increased risk for the
development of obesity comorbidities for most adults. The aim of this
investigation was to examine the predictive values of these WC cut-points for
hypercholesterolemia, low concentration of high (HDL-C), and high concentration
of low (LDL-C) density lipoprotein cholesterol, hypertriglyceridemia, type 2
diabetes, and hypertension in overweight American adults. Data from NHANES III
were utilized for the analysis. Predictive abilities were determined by
calculating sensitivity, specificity, positive (PV+) and negative (PV-)
predictive values in overweight subjects with BMI 25-29.9 kg/m(2). Sensitivity of
WC cut-point was stronger for high LDL-C compared to other risk factors with the
highest values recorded in the 40-59 and 60-69 year age groups in men and women,
respectively. PV+ of WC cut-points for dyslipidemia, type 2 diabetes, and
hypertension were low in men compared to women. PV+ tended to increase with age,
from 19-39, 40-59 to 60-90 year age groups in Whites, Blacks, and Hispanic men.
In men, the highest PV+ were recorded for hypertriglyceridemia in the 60-90 years
old groups, with values of 71.6%, 52.5%, and 43.3% in Whites, Blacks, and
Hispanics, respectively. The CVD risk factor associated with the highest PV+ in
women was diabetes with values of 97.2% in Whites and 88.9% in Blacks, and
hypertriglyceridemia with a value of 93.8% in the 17-39 year age group in
Hispanics. Among Black men 40-59 years of age, only 32% of a population of
overweight hypertensives were detected by the WC cut-points, and among Black
women, 40-59 years of age, only 54% were detected. Given the low sensitivity of
these cut-points for detecting hypertension, one of the major co-morbidities of
obesity, these cut-points failed to provide adequate evidence for the use of WC
in determining or evaluating patients as to co-morbid states. We recommend
further studies to determine a set of specific cut-points associated with
increased risk of CVD in different population groups.
PMID- 10785572
TI - Estimation of extra hospital stay attributable to nosocomial infections:
heterogeneity and timing of events.
AB - Infections acquired in hospital are likely to affect the duration of
hospitalization. Suitable statistical methods for estimating the extra days spent
in hospital due to nosocomial infections should allow modeling of the
heterogeneity of the patient population and the timing of events, as failure to
account for important covariates and failure to model adequately the timing of
events may lead to biased results. Three approaches have been used in the past to
estimate the extra stay: a comparison of duration of stay of infected and
uninfected patients, matching of infected and uninfected patients with respect to
potentially important determinants of the length of hospital stay, and matching
for time-to-infection in addition to the other factors. While these approaches
can allow for the heterogeneity of the patient population, none takes sufficient
account of the real timing of events and may overestimate the effect of
nosocomial infections. We explored the statistical methods available for
analyzing time-to-event data and derived alternative methods to estimate the
extra stay that appropriately account for heterogeneity and timing. Data from two
prospective cohort studies on postoperative wound infection and on nosocomial
pneumonia showed that the two-group comparison yields the highest estimates of
extra stay (21 and 14 extra days), while matching for confounders and time
reduced the estimates to 11 and 8 extra days; our methods yield even lower
results (10-12 and 3-4 extra days).
PMID- 10785573
TI - Coronary heart disease surveillance: field application of an epidemiologic
algorithm.
AB - This report describes the performance of a surveillance system and computerized
algorithm for the assignment of definite or probable hospitalized cardiac events
for large epidemiologic studies. The algorithm, developed by the Coordinating
Committee for Community Demonstration Studies (CCCDS), evolved from the Gillum
criteria, and included selected ICD-9-CM codes including codes 410 through 414
for discharge record screening, plus creatine kinase. For the small percentage of
cases in which enzyme analysis was inconclusive (8%), presence of pain and/or
Minnesota-coded electrocardiograms were included to define the outcome. All data
items were easily obtained from medical records by trained lay record abstractors
and required no interpretation. From January 1980 through December 1991, 21,183
medical records were screened for ICD-9-CM codes 410 through 414. Of all 410 to
411 ICD-9-CM codes (n = 9026), 36.9% (n = 3220) were classified as definite
cardiac events and 10.6% (n = 1057) as probable events. Of all 412 through 414
codes (n = 9070), only 1.8% (n = 227) were classified as definite cardiac events
and 5.4% (n = 716) as probable events. The epidemiologic diagnostic algorithm
presented in this article used computerized data to assign diagnoses in a
standard, objective manner, and was a lower cost alternative to classification of
cardiac events on the basis of clinical review and/or more complex record
abstraction approaches.
PMID- 10785574
TI - Trends in selected biological risk factors for cardiovascular diseases in the
Danish MONICA population, 1982-1992.
AB - Data from 6695 men and women of ages 30, 40, 50, and 60 years, examined in the
Danish WHO MONICA surveys in 1982-84, in 1986-87, and in 1991-92, were analyzed
to estimate secular trends in body height and weight, blood pressure, and serum
total, HDL-, and LDL-cholesterol, and triglyceride. Body height increased 0.1%
per year, and body mass index increased 0.4% per year in women. Diastolic blood
pressure increased 0.4% per year in women and 0.6% per year in 60-year-old men.
HDL cholesterol declined 0.4% per year. Body mass indices in men, diastolic blood
pressures in men <60 years of age, systolic blood pressures, total- and LDL
cholesterol and triglyceride did not change. The levels of biological risk
factors in the Danish WHO MONICA study population did not show trends during the
1980s that help explain the declining incidence of myocardial infarction in the
population.
PMID- 10785575
TI - Verbal fluency and psychiatric symptoms in geriatric schizophrenia.
AB - Previous studies have demonstrated that negative symptoms are regulated by
frontal brain regions. We were interested in the relationship between psychiatric
symptoms and performance on a verbal fluency (VF) battery in a population of
elderly schizophrenic subjects. Thirty-five elderly schizophrenic subjects were
administered a neuropsychological battery which included verbal fluency
performance and Positive and Negative Symptom Scale (PANSS). Results showed
negative symptoms to be strongly correlated with performance on tasks of VF,
which may suggest that negative symptomatology in schizophrenia is related to
prefrontal cortical activity.
PMID- 10785576
TI - Quantitative characterization of eye tracking dysfunction in schizophrenia.
AB - The purpose of this study was to characterize the nature of the processes that
are involved in eye tracking dysfunction (ETD). We identified a combination of
quantitative measures that best distinguished qualitatively normal eye tracking
from qualitatively abnormal eye tracking, using discriminant analysis.
Discriminant scores distinguished schizophrenics with ETD from both
schizophrenics with normal eye tracking and normal controls, but did not
distinguish schizophrenics with normal eye tracking from normal controls,
underscoring the heterogeneity of schizophrenic patients with respect to eye
tracking. The results of the discriminant analysis indicated that ETD is a
multivariate process involving a primary impairment in the smooth pursuit system
characterized by increased catch-up saccades and reduced gain, and, secondarily,
disinhibition of intrusive saccades, especially square-wave jerks. Quantitative
characterization of ETD makes it possible to consider eye tracking as a
quantitative trait in genetic investigations of a multidimensional phenotype.
PMID- 10785577
TI - Event-related potentials and thought disorder in schizophrenia.
AB - We examined the relationship between event-related potentials and thought
disorder in schizophrenia. The subjects were 29 chronic schizophrenic patients.
Thought disorder was assessed using the Comprehensive Index of Positive Thought
Disorder developed by Harrow and colleagues (Harrow and Quinlan, 1985; Marengo et
al., 1986). Auditory event-related potentials were recorded during a standard
oddball task. The P300 amplitude correlated negatively with the severity of the
thought disorder. The P300 amplitude in the patients with thought disorder was
significantly smaller than in the patients without thought disorder. These
results suggest that a reduction in P300 amplitude is associated with a
fundamental impairment of information processing in schizophrenic patients.
PMID- 10785579
TI - Neural correlates of memory organization deficits in schizophrenia. A single
photon emission computed tomography study with 99mTc-ethyl-cysteinate dimer
during a verbal learning task.
AB - Regional cerebral blood flow (rCBF) during a verbal learning task was measured
using 99mTc-ethyl-cysteinate dimer and single photon emission computed tomography
in 10 patients with schizophrenia and nine normal controls. Verbal repetition was
used as a control task. The schizophrenic patients showed failure to
spontaneously utilize implicit category information to learn the word lists. In
the normal controls, rCBF in the left inferior frontal and left anterior
cingulate regions was significantly increased during the verbal learning task,
compared with the verbal repetition task. In contrast, there was no significant
frontal lobe activation by the verbal learning in the schizophrenic patients. The
patients had lower rCBF during the verbal learning task than the controls in the
bilateral inferior frontal, left anterior cingulate, right superior frontal, and
bilateral middle frontal regions. Activation in the left inferior frontal region
was significantly positively correlated with categorical clustering in the task
in the controls, but no such correlation was found in the patients. These results
indicate that memory organization deficits in schizophrenia may be related to
dysfunction in the prefrontal areas, especially in the left inferior frontal
region.
PMID- 10785578
TI - Shape and size of the corpus callosum in schizophrenia and schizotypal
personality disorder.
AB - The size and shape of the corpus callosum were assessed on sagittal section
magnetic resonance images in 27 patients with schizophrenia, 13 patients with
schizotypal personality disorder (SPD), and 30 healthy volunteers. High
resolution 1.2mm axial SPGR images were acquired and resectioned so that the
sagittal plane passed through the anterior and posterior commissures and was
parallel to the interhemispheric fissure. The corpus callosum and the whole brain
were traced on midsagittal section slices of each brain, and the callosum was
divided into 30 anteroposterior sectors. Pixel-by-pixel chi-square and thin-plate
spline analyses were used to assess between-group shape differences. Size of the
corpus callosum was smaller anteriorly in the genu of the corpus callosum and
posteriorly in the splenium in schizophrenic patients than in normal controls.
The genu of the corpus callosum was larger in SPD patients than in schizophrenic
patients or normal controls. The posterior corpus callosum was largest in normal
controls, smaller in SPD patients, and smallest in schizophrenic patients. Shape
analysis was consistent with these size comparisons, and suggested a downward
bowing of the corpus callosum in schizophrenic and SPD patients. SPD patients
also had a region of the callosum just posterior to the genu that was narrower
than in the other two groups. The decreases in corpus callosal size in
schizophrenia varied directly with length of illness, perhaps indicative of a
progressive process. The patient-control differences in callosal size and shape
are consistent with a hypothesis of decreased connectivity between the left and
the right hemispheres in schizophrenia and SPD.
PMID- 10785580
TI - Prevalence of extrapyramidal syndromes in psychiatric inpatients and the
relationship of clozapine treatment to tardive dyskinesia.
AB - In 200 inpatients on regular neuroleptics, point prevalence of extrapyramidal
syndromes, including Parkinson syndrome, akathisia and tardive dyskinesia (TD),
was studied and found to be 20, 11 and 22%, respectively. A total of 46 patients
have currently, and for a longer time, (average about 3years, median over 1year)
been treated with clozapine, and 127 with typical neuroleptics (NLs). Comparing
both groups, higher TD scores were found in the clozapine sample. Investigating
the influence of a set of seven clinical variables on the TD score with the help
of multiple regression analysis, the influence of the treatment modality
disappeared, whereas the age proved to be the only significant variable. Studying
the role of past clozapine therapy in patients currently on typical NLs and
comparing 10 matched pairs of chronic patients with and without TD in whom a
complete life-time cumulative dose of NLs was identified, a relationship between
TD and length of current typical NL therapy and life-time typical NL dosage could
be demonstrated. On the whole, long-term relatively extensive use of clozapine
has not markedly reduced the prevalence of extrapyramidal syndromes in our
psychiatric inpatient population. In particular, we failed to demonstrate a
beneficial effect of clozapine on prevalence of TD. There are certainly patients
who suffer from TD in spite of a long-term intensive clozapine treatment.
PMID- 10785581
TI - Stability of the five-factor structure of the Positive and Negative Syndrome
Scale (PANSS).
AB - The main objective of the study was to verify the stability of the five-factor
(negative. positive, excitation, depression and cognitive) structure of the
Positive and Negative Syndrome Scale (PANSS). The psychometric properties
(validity and reliability) of the forced five-factor structure of the PANSS were
explored in two different populations of schizophrenic patients: one in relapse
and the other in the chronic phase of the disease. Three hundred and forty-two
schizophrenic patients according to DSM-III-R criteria were involved. One hundred
and eighteen (34.5%) patients were in relapse, and 224 (65.5%) were in the
chronic phase. The forced five-factor principal-component analysis explained
64.3% of the total variance in the relapse patients and 62.1% in the chronic
patients. The order of the factors was reversed for the depression and excitation
factors in chronic patients compared with patients in relapse. The internal
consistency of this five-factor structure was good (Cronbach's alpha >0.70) in
the relapse and chronic patients, except for the cognitive factor. In conclusion.
five dimensions (negative, positive, excitation, depression and cognition) are
necessary to account for the various clinical aspects of schizophrenia described
by PANSS in relapse and chronic schizophrenic patients.
PMID- 10785582
TI - Reliability and validity of a new Medication Adherence Rating Scale (MARS) for
the psychoses.
AB - Medication compliance is one of the foremost problems affecting neuroleptic
efficacy in psychiatric patients. To date, compliancy has most commonly been
assessed with the Drug Attitude Inventory (DAI) developed by Hogan et al. (Hogan,
T.P., Awad, A.G., Eastwood, R., 1983. A self-report scale predictive of drug
compliance in schizophrenics: reliability and discriminative validity. Psychol.
Med. 13, 177-183). The present study identified several deficiencies in the DAI.
Using the partial credit version of the Item Response Theory measurement model,
the DAI was refined with the aim of greater validity and clinical utility. The
new inventory was administered to 66 patients, the majority of whom were
diagnosed with schizophrenia. When available, lithium levels and carer ratings of
compliance were also recorded and used to verify compliancy. The new inventory
appears to be a valid and reliable measure of compliancy for psychoactive
medications.
PMID- 10785583
TI - Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist,
produces antipsychotic-like activity in rats and mice.
AB - Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased
psychotic behaviors in patients with Alzheimer's disease, suggesting that
xanomeline might be useful in the treatment of psychotic symptoms in patients
with schizophrenia. The purpose of the present studies was, therefore, to compare
the pharmacologic profile of xanomeline with that of known antipsychotic drugs.
Electrophysiologically, xanomeline, after both acute and chronic administration
in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by
the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like
haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning
in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced
climbing in mice. However, unlike the dopamine antagonist antipsychotic
haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline,
like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance
responding in rats, an effect which also was blocked by scopolamine. The present
results thus demonstrate that xanomeline has a pharmacologic profile which is
similar to that of the atypical antipsychotics clozapine and olanzapine, thus
indicating that xanomeline has the potential to be a novel approach in the
treatment of psychotic symptoms in patients with schizophrenia.
PMID- 10785584
TI - Single agents should be administered in preference to combination chemotherapy
for the treatment of patients over 70 years of age with advanced ovarian
carcinoma.
PMID- 10785585
TI - Quality of life evaluation in oncological clinical trials - the EORTC model. The
EORTC Quality of Life Study Group.
AB - The European Organization for Research and Treatment of Cancer (EORTC) has taken
a leading role in the development of the methodology of quality of life (QL)
measurement. In the EORTC Quality of Life Study Group (QLSG) valid instruments to
assess QL in a general manner and disease-specific modules have been developed to
be used in oncological clinical trials. Statistical and methodological aspects of
QL research are discussed. The application of QL assessments in clinical trials
represents a subsequent challenge. To improve the practice of QL assessment in
clinical trials an 'EORTC model' has been developed. This model requires the
collaboration of liaison persons, the EORTC Cooperative Tumour Groups and the
EORTC Data Centre Quality of Life Unit (QL Unit). Cooperation between these
parties, protocol development and advantages and concerns of the model are
mentioned in this paper. Finally, suggestions for improvement are proposed.
PMID- 10785586
TI - Telemedicine and its impact on cancer management.
AB - The latest dramatic progress in the technologies of the computer industry is
likely to increasingly influence the oncologist's daily routine. Besides well
known and established telemedical services such as videoconferencing, the most
influential trends are the spread of digital hospital infrastructures with
unlimited, secured access to all relevant patient information. This article seeks
to summarise the most imminent influences of telemedical developments on the
future of the oncologist: the effects of telemedical services and electronic
infrastructures on clinical workflow and on medical quality management. In
addition, the history of telemedicine, recent technologies and the performance of
electronic patient records are described.
PMID- 10785587
TI - Summary measures and statistics in the analysis of quality of life data: an
example from an EORTC-NCIC-SAKK locally advanced breast cancer study.
AB - Quality of Life (QL) is now included as an endpoint in many phase III cancer
clinical trials. Numerous statistical techniques have been presented in the
literature to analyse QL data but there is still no agreement as to what is the
optimal approach of analysis. In this paper we, therefore, present and compare
various techniques which have all appeared in the literature and which may be
globally described as summary measures and summary statistics. These techniques
are illustrated using data from an EORTC clinical trial in locally advanced
breast cancer (EORTC trial 10921). It is also explained in this paper how and
when these techniques may be used in other cancer settings. For EORTC trial
10921, it is shown that by choosing different techniques different conclusions
may be drawn concerning the QL outcome. This highlights the importance of
choosing an appropriate primary statistical method and for describing it a priori
in the protocol and analysis plan. In this paper, we show the importance of
performing sensitivity or supportive analysis to support conclusions drawn from
the primary analysis.
PMID- 10785588
TI - Effective tamoxifen therapy of breast cancer involves both antiproliferative and
pro-apoptotic changes.
AB - Despite knowledge of oestrogen receptor status, it is not always possible to
predict which breast cancers will respond to tamoxifen. We have previously
reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with
tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen
receptor (ER)-positive breast cancer. In this study, we confirm that the
expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and
mitosis respectively, within these untreated breast cancers, with an inverse
relationship between Bcl-2 expression and the apoptotic index (P<0.05), and a
positive relationship between Ki-S1 expression and the mitotic index (P<0.01).
However, after 3 months' tamoxifen treatment these relationships were no longer
apparent. Moreover, amongst the 27 tumours in which Bcl-2 expression was reduced
during the 3 months' therapy, there was a significant correlation between the
response to therapy and the increase in apoptosis (P<0.05), whereas in those
tumours in which Bcl-2 did not fall with therapy, there was a significant
correlation between response and the decrease in mitosis (P<0.05). These data
suggest there are at least two mechanisms for effective tamoxifen therapy:
increased apoptosis as a consequence of reduced Bcl-2 expression, and decreased
proliferation.
PMID- 10785589
TI - An analysis of potential factors allowing an individual prediction of cisplatin
induced anaemia.
AB - Severe cisplatin (CP)-induced anaemia significantly impairs the patient's quality
of life. Prevention based on erythropoietin (EPO) administration would be cost
effective providing that individual predictive factors of anaemia are identified.
The aim of the present study was to identify parameters able to predict the
occurrence of CP-related anaemia. This prospective study was conducted on 40 head
and neck cancer patients receiving a CP (100 mg/m(2), intravenous (i. v.) on day
1) - 5-fluorouracil (5-FU, 1 g/m(2)/dx5 days by continuous infusion) induction
chemotherapy. Three cycles were given at 3-weekly intervals. Platinum
pharmacokinetics (total and ultrafilterable plasma platinum concentration
measured 16 h after CP administration) and 5-FU pharmacokinetics (full-cycle
plasma area under the curve, (AUC(0-105h)30 g/l) occurred in 15 patients (38%)
and 3 of them also received a blood transfusion. Patient age, 5-FU AUC(0-105h)
and total platinum concentration were unrelated to Hb loss. In contrast,
ultrafilterable (UF) platinum concentration was significantly correlated to Hb
loss: the higher the UF platinum concentration, the greater the Hb loss
(P=0.015). A discriminant analysis allowed a cut-off value for UF platinum to be
proposed to identify patients developing significant loss of Hb: 91% of patients
exhibiting a UF platinum concentration above 50 ng/ml developed significant loss
of Hb in contrast to 18% in the group of patients with a UF platinum
concentration below 50 ng/ml (odds ratio (95% confidence interval, CI) of 46 (4.7
446)). In conclusion, the present platinum pharmacokinetic survey may be proposed
as a valuable approach to identify patients at risk for developing severe
anaemia.
PMID- 10785590
TI - Experience in qualitative and quantitative FDG PET in follow-up of patients with
suspected recurrence from head and neck cancer.
AB - We evaluated positron emission tomography (PET) with 2-[fluorine-18]fluoro-2
deoxy-D-glucose (FDG) in the detection of recurrent head and neck cancer, and
compared visual and quantitative interpretation of PET images for their accuracy
in the identification of tumour recurrence. Sixty-two FDG PET studies were
performed in 56 patients having a total of 81 lesions, which were clinically
suspected for recurrent carcinoma of the head and neck. The PET images were
interpreted visually, and tracer uptake was quantitated as the standardised
uptake value adjusted to body weight (SUV). Sensitivity of visual interpretation
of the PET images for the presence of malignancy ranged from 84 to 95%, and
specificity from 84 to 93%, respectively, depending on the selected scheme for
grading of the lesions. Malignant lesions accumulated significantly more FDG than
the benign ones (the median SUVs were 6.8 and 3.3, respectively, P<0.001).
However, there was a wide overlap of the FDG uptake values between these two
groups. Hence, the highest accuracy of quantitative analysis in correct
identification of tumour recurrence (75% at Receiver Operating Curve analysis)
was inferior to that of visual analysis (89%). FDG PET is feasible for the
detection of recurrent head and neck cancer. Although quantitation of FDG uptake
using SUV shows significantly higher tracer concentrations for malignant than
benign lesions, the wide overlap of individual SUVs between these two groups is a
serious concern in diagnostic evaluation. Therefore, in clinical practice it may
be preferable to identify the presence of tumour recurrence within this patient
group by qualitative interpretation of the PET images.
PMID- 10785591
TI - Intra-operative irradiation (IORT) for primary advanced and recurrent rectal
cancer. a need for randomised studies.
AB - The aim of this study was to determine the impact of intra-operative irradiation
(IORT) combined with pre-operative external beam irradiation (EBRT) and surgical
resection in patients with locally advanced primary or recurrent rectal cancer.
64 patients with locally advanced primary cancer and 104 with recurrence had EBRT
(46-50 Gy) before surgery. 80 patients received IORT (median dose 15 Gy energy 12
MeV). 80 patients had R0 resections, 47 R1 and 41 R2 resections. More R1
resections were performed in the IORT group, more R0 and R2 resections in the non
IORT group. Median follow-up was around 22 months. 146 patients were resected, 22
had exploratory laparotomy. The cumulative overall survival was similar for both
the IORT and non-IORT groups. 5-year survival for primary cancers was 48% versus
28% for recurrences. No R2 resections survived 3.5 years. 5-year-survival for R0
resections was nearly 60% and around 30% for R1 resections. The survival curves
of the patients given and not given IORT treatment was not statistically
different when R0, R1 and R2 resections were analysed separately. IORT did not
seem to influence the local recurrence rate when R0 and R1 resections were
analysed separately or in a multivariate analysis. The IORT and non-IORT groups
were not identical with regard to type of cancer and R-stage. Still the lack of
an identifiable impact of IORT suggests that there is a need for randomised
studies of the IORT effect.
PMID- 10785592
TI - Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience
with the SSG IX protocol.
AB - The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local
control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second
protocol, SSG IX, was started in order to improve upon these results. It featured
four chemotherapy cycles, each consisting of two courses of VAI (vincristine,
doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin,
doxorubicin, ifosfamide) at 3-weekly intervals. Total treatment time was 35
weeks. Local therapy was given at week 9. Inoperable or non-radically operated
patients received hyperfractionated accelerated radiotherapy 1.5 Gy twice daily
between chemotherapy courses to a total dose of 42-60 Gy, depending on surgical
radicality and tumour localisation. 88 patients were included (58 male, 30
female, mean age 20 years; range 5-65 years). The tumour (73 M0 and 15 M1) was
located centrally in 31 patients (35%), in the extremities in 34 (39%) and other
sites in 23 (26%) of cases. The median size of tumour was 10 cm (range 2-23),
soft tissue was invaded in 87%. Surgery was the local therapy for 60 (68%)
patients: amputation in 8 and local excision in 52. The surgical margins were
wide in 35 patients, marginal in 14 and intralesional in 3. Radiotherapy was
given to 17 non-radically operated patients postoperatively and to 28 patients
with inoperable tumours primarily. Histological responses were evaluated in 52
patients. 9 local recurrences were observed (10%). Distant metastases developed
in 24 M0 patients (33%). The estimated 5-year MFS was 58% and overall survival
(OS) 70% for M0 and 27% and 28% for M1 patients, respectively. Survival was
favourable in patients with non-metastatic extremity tumours (90%) and tumours
operated with wide margins (90%). Patients with a total necrosis after
chemotherapy had a better OS than those with a partial or poor response
(P=0.003). The toxicity (World Health Organisation) was acceptable
(gastrointestinal G1-2; haematological G3-4). The SSG IX protocol gave better
local control and survival rates than the SSG IV. Whether this is due to a higher
therapeutic efficacy of the present protocol cannot be ascertained in this
comparison with a historical control.
PMID- 10785593
TI - Incidence of P-glycoprotein overexpression and multidrug resistance (MDR)
reversal in adult soft tissue sarcoma.
AB - Multidrug resistance (MDR) is a widespread problem in the treatment of neoplastic
diseases and may limit the effectiveness of treatment of adult soft tissue
sarcomas (STS). We examined the levels of expression of the MDR marker P
glycoprotein (Pgp) in fresh, surgical material and matched paraffin-embedded
tissue using MRK-16 and JSB-1 monoclonal antibodies. Using fresh tumour material
in short-term culture an assessment of doxorubicin sensitivity (MTT assay) and
MDR modulation using PSC-833 in daunorubicin (DNR) accumulation experiments (FACS
analysis) was carried out. 44 patients were studied at various disease stages
with a mean follow-up duration of 487 days (range: 45-1095 days).
Immunocytochemistry and immunohistochemistry showed 62% and 58%, respectively, of
STS samples were positive for Pgp. Patients showing negative Pgp expression had a
median survival of 544 days versus 431 days for Pgp-positive patients (P=0.311),
with disease-free survival medians of 508 and 355 days, respectively (P=0.203).
In vitro doxorubicin sensitivity was not informative in this respect and there
was no apparent relationship between this and Pgp expression. Eleven out of 29
samples evaluated for MDR modulation showed enhanced tumour cell DNR
accumulation. However, the effects of PSC-833 on drug accumulation in clinical
material were modest compared with those seen for MDR cell lines, with a maximum
of only 20% enhancement. Moreover, there was no relationship between the extent
of PSC-833 effects on accumulation and the levels of Pgp seen in the STS samples.
Nevertheless, we show evidence that a proportion of cases of STS express moderate
to high levels of Pgp. There may be a role for MDR modulating agents in
association with doxorubicin in the treatment of these tumours, either in the
adjuvant setting or at first relapse.
PMID- 10785594
TI - C-reactive protein, procalcitonin and interleukin-8 in the primary diagnosis of
infections in cancer patients.
AB - The diagnostic utility of C-reactive protein (CRP), procalcitonin (PCT) and
interleukin-8 (IL-8) were studied in 66 cancer patients with suspected infection
(39 with definite foci of infection, 17 with antibiotic responses without foci
and 10 with neoplastic fever without infection) and 26 patients scheduled for
chemotherapy. The infection group (n=56) had higher median CRP (91 versus 19
mg/l, P<0. 001), PCT (0.28 versus 0.12 ng/ml, P<0.001) and IL-8 values (27.7
versus 16.9 pg/ml, P=0.032) than the non-infection group (n=36). In patients with
suspected infection, only PCT was a good marker to discriminate bacteraemia with
an area under the receiver operating characteristics curve of 0.92 (95%
confidence interval (CI), 0.77-1. 0), but even PCT was less well able to
differentiate between non-bacteraemic infections and neoplastic fever (0.56; 95%
CI, 0. 35-0.77). In conclusion, PCT was a good indicator for bacteraemia, but
none of the three markers were reliable indicators for minor infections in non
neutropenic cancer patients.
PMID- 10785595
TI - Sentinel node biopsy and ultrasound scanning in cutaneous melanoma: clinical and
technical considerations.
AB - 1.5 mm and in all cases with two metastatic SNs, further positive additional
nodes were found. The mean counts per 10 s (CP10S) ratio for SN and non-SN values
was 5.62 (1.29-23.51) and 3.09 (1.03-10.99) in the intra-operative and extra
operative phases, respectively. US scanning and preoperative lymphoscintigraphy
associated with PBD allows preoperative patient selection and accurate SN(s)
identification. Breslow thickness and the number of metastatic SN(s), but not
their type, are correlated with disease spread; CP10S contributed to the
differentiation amongst the nodes and the determining of procedure's completion.
PMID- 10785596
TI - Clinical prognostic factors in 1277 patients with neuroblastoma: results of The
European Neuroblastoma Study Group 'Survey' 1982-1992.
AB - In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective
registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey').
Clinical information was collected primarily to: (a) establish an ENSG database;
and (b) investigate prognostic factors in neuroblastoma. This paper summarises
the results of the survey. By 1992, 1277 patients with a median age of 26 months
(range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30
centres. The median follow-up of survivors is 9.7 years (range: 1-14 years).
Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS)
is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic
factors, stage and age, are highly significant (P<0.001). In particular, patients
under 1 year of age at diagnosis, whatever the disease stage, had a more
favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus
76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI
44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19),
P<0.001). Multivariate analysis established that the anatomical location of the
primary tumour (i.e. abdominal versus other sites) and primary tumour volume also
conferred a statistically significant difference. In stage 4 disease the 20% of
patients without demonstrable bone marrow involvement had a more favourable
prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16%
(95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus
normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no
significant effect on outcome after stage and age were accounted for. 5-year
survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey
provides secure data for future comparisons with new prognostic factors and
treatment programmes.
PMID- 10785597
TI - Trends in mortality from primary liver cancer in Europe.
AB - Upward trends in incidence and mortality from primary liver cancer have been
reported from Japan, the USA and a few European countries. Thus, we
systematically reviewed trends in age-standardised death certification rates from
primary liver cancer between 1970 and 1996 in 20 European countries providing
data for the World Health Organisation database. Overall age-standardised (world
population) mortality rates were approximately stable or showed no consistent
trends in seven countries, including Bulgaria and Hungary (with exceedingly high
rates), Finland, The Netherlands and the UK. Moderate rises were observed in
Austria, Germany and Switzerland, and much larger upward trends in France and
Italy, particularly for males. Downward trends were observed in both sexes in
Belgium, Spain, Ireland, Greece and several Scandinavian countries. The per cent
change in rates per year ranged, for males, from -7.4% for Ireland and -5.1% for
Spain to +4.4% for Italy and +8.6% for France. Trends were more favourable in
women, with 15 out of 20 countries showing downward trends in rates, and
moderately more favourable in middle age (45-64 years) and, in major European
countries, in young adults (20-44 years of age). In conclusion, trends in liver
cancer mortality in Europe are heterogeneous. The fall in mortality in countries
like Spain may be largely explained by improvements in the distinction between
primary and secondary liver neoplasms, whereas upward trends in Central Europe
and Italy are likely to be, at least in part, real. Increases in infection with
the hepatitis C virus, and improved and increased searches for liver cancer in
cirrhotic patients are two of the likeliest explanations for these observations.
PMID- 10785598
TI - Molecular downstream events and induction of thymidylate synthase in mutant and
wild-type p53 colon cancer cell lines after treatment with 5-fluorouracil and the
thymidylate synthase inhibitor raltitrexed.
AB - Inhibition of the key enzyme in DNA synthesis, thymidylate synthase (TS), by 5
fluorouracil (5-FU) and the novel antifolate raltitrexed (Tomudex; ZD1694),
induces dTTP depletion, resulting in DNA strand breaks, which can initiate
pathways leading to an apoptotic mode of cell death. We studied 5-FU- and ZD1694
induced TS inhibition in relation to the expression of p53, p21, Bcl-2 and Bax in
six colon carcinoma cell lines, two with a wild-type (wt) p53 (Lovo, LS174T) and
four with a mutant (mt) p53 (WiDr, WiDr/F, HT29 and SW948) phenotype. In
untreated cells, a reciprocal correlation between p53 and Bcl-2 was found: in
cells with a low wt p53, Bcl-2 expression was present; whilst in cells with mt
p53, Bcl-2 expression was not detectable. Exposure to 5-FU (50 and 100 microM)
and ZD1694 (50 and 100 nM) for 24 and 48 h induced p53 and p21 expression in wt
p53 cells, but not in mt p53 cells. TS was induced approximately 2-10-fold in all
cell lines. TS induction was highest after ZD1694 exposure in the mt p53 cells
HT29 and WiDr/F (6-10-fold). After 5-FU treatment, TS was present both as the
free enzyme and in the ternary complex; however, predominantly as the ternary
complex between TS, FdUMP and 5,10-methylenetetrahydrofolate. In wt p53 cells,
both drugs increased Bax expression up to 5-fold, whereas in mt p53 cells, only a
very slight induction was found. In wt p53 cells, Bcl-2 expression hardly changed
after drug treatment. These results indicate a p53-independent induction of TS
but a regulatory role of wt p53 in the synthesis of Bax in the colon carcinoma
cell lines after TS inhibition.
PMID- 10785599
TI - Microsatellite instability is associated with genetic alteration but not with low
levels of expression of the human mismatch repair proteins hMSH2 and hMLH1.
AB - Mutational inactivation of hMSH2 or hMLH1 has been known to be responsible for
microsatellite instability and cellular resistance to DNA-damaging alkylating
agents. However, the effects of altered expression of hMSH2 or hMLH1 on
microsatellite stability and cellular response to alkylating agents has not been
well investigated. Previously, we have reported that downregulation of the hMLH1
protein was a frequent event and was closely associated with cellular resistance
to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in human gastric carcinoma cell
lines. Therefore, to investigate the relationship between microsatellite
instability and quantitative changes in hMSH2 and hMLH1, we compared the genetic
status and expression levels of hMSH2 and hMLH1 with microsatellite instability
in 11 human gastric carcinoma cell lines. Five cell lines contained wild-type
hMSH2 and hMLH1 and expressed adequate levels of hMSH2 and hMLH1 proteins. In
three cell lines, genetic alterations such as mutation in the hMLH1 gene (SNU-1)
or the hMSH2 gene (SNU-638), or hypermethylation in the promoter region of the
hMLH1 gene (SNU-520) were observed. Microsatellite instability assays revealed
that only these three cell lines exhibited microsatellite instability. Three cell
lines (SNU-216, -484, and -668) containing wild-type hMSH2 and hMLH1 genes
produced significantly downregulated hMSH2 and/or hMLH1 proteins. In spite of the
substantial decrease in the protein levels, these cell lines did not show
microsatellite instability. Together with our previous report, this study
suggests that: microsatellite instability of cells is associated only with
genetic alteration of the mismatch repair genes; relatively low levels of the
hMSH2 and hMLH1 proteins may be sufficient to retain the microsatellite stable
phenotype; and the cellular response to alkylating agents is associated with
genetic alteration and decreased expression of the mismatch repair genes in human
gastric carcinoma cell lines.
PMID- 10785600
TI - Differential response to transforming growth factor (TGF)-alpha and fibroblast
growth factor (FGF) in human renal cell carcinomas of the clear cell and
papillary types.
AB - The clear cell and the papillary types of human renal cell carcinoma (RCC) are
distinct tumour entities with marked differences in their biological properties.
Because growth factors are considered to affect profoundly the biological
behaviour of malignant tumours, we compared the expression and function of
transforming growth factor (TGF)-alpha and fibroblast growth factor (FGF) in both
types of RCCs. Both in vivo and in vitro expression of TGF-alpha, epidermal
growth factor-receptor (EGF-R), FGF-2 and FGF type 3- and 4-receptors was found
in RCCs of both types. However, marked differences between clear cell and
papillary RCCs became evident for TGF-alpha secretion, which could be
demonstrated in 20 out of 24 (83%) clear cell RCCs but in only two out of four
(50%) papillary tumours. Moreover, the mean TGF-alpha secretion rate in clear
cell RCCs significantly (P<0. 05) exceeded that of papillary RCCs. Because the
expression of growth factor receptors could not prove the corresponding
signalling cascades were functional, tumour cell proliferation was tested after
exposure to exogenous TGF-alpha or FGF-1. These experiments demonstrated that
papillary RCCs did not respond significantly to exogenous TGF-alpha or FGF-1,
whereas eight (33%) (TGF-alpha) and 11 (46%) (FGF-1) out of 24 clear cell RCCs
responded with significant (P<0.05) growth stimulation. In conclusion, our
investigation presents data indicating that TGF-alpha and FGF are functionally
involved in the progression of clear cell RCCs, directly stimulating
proliferation by autocrine and/or paracrine actions. In contrast, TGF-alpha and
FGF did not directly stimulate the proliferation of our papillary RCCs, thereby
suggesting functional defects or a blockade in the corresponding signalling
cascades. This differential functionality might contribute to the more aggressive
behaviour of clear cell RCCs.
PMID- 10785601
TI - Antitumour activity of cytotoxic liposomes equipped with selectin ligand
SiaLe(X), in a mouse mammary adenocarcinoma model.
AB - The overexpression of lectins by malignant cells compared with normal ones can be
used for the targeting of drug-loaded liposomes to tumours with the help of
specific carbohydrate ligands (vectors). Recently we have shown that liposomes
bearing specific lipid-anchored glycoconjugates on a polymeric matrix bind in
vitro to human malignant cells more effectively and, being loaded with a
lipophilic prodrug of merphalan, reveal higher cytotoxic activity compared with
unvectored liposomes. In this study, carbohydrate-equipped cytotoxic liposomes
were tested in vivo in a mouse breast cancer model, BLRB-Rb (8.17)1Iem strain
with a high incidence of spontaneous mammary adenocarcinoma (SMA). Firstly, a
cell line of the SMA was established which was then used to determine the
specificity of the tumour cell lectins. After screening of the lectin specificity
of a number of fluorescent carbohydrate probes, SiaLe(X) was shown to be the
ligand with the most affinity, and a lipophilic vector bearing this saccharide
was synthesised. Then different liposomal formulations of the synthetic merphalan
lipid derivative and SiaLe(X) vector were prepared and applied in the treatment
of mice with grafted adenocarcinomas. The results of the tumorigenesis data show
that the therapeutic efficacy of merphalan increases sharply after its insertion
as a lipophilic prodrug into the membrane of SiaLe(X)-vectored liposomes.
PMID- 10785602
TI - Optimising chemotherapy dose density and dose intensity. new strategies to
improve outcomes in adjuvant therapy for breast cancer.
PMID- 10785603
TI - The impact of chemotherapy dose density and dose intensity on breast cancer
outcome: what have we learned?
AB - Optimising chemotherapy dose density and dose intensity are strategies aimed at
improving outcomes in adjuvant therapy for patients with breast cancer. There
are, in theory, at least five models allowing the delivery of a higher overall
drug dose intensity. These are reviewed in this article and vary according to
three main variables: the dose per course, the interval between doses and the
total cumulative dose. Cyclophosphamide, anthracyclines and taxanes are among the
most active agents for the treatment of breast cancer and, as such, they have
been or are currently the focus of prospective, randomised clinical trials
testing some of these dose-intensity models in the adjuvant setting. The results
of recent trials suggest that anthracyclines, but not cyclophosphamide, are
associated with better outcomes if used at higher doses per course and at higher
cumulative doses. However, care has to be taken with premenopausal women where an
increased dose of anthracycline per course but a reduced cumulative dose appears
to produce a worse outcome. Moreover, decreasing the interval between doses, for
anthracyclines and cyclophosphamide, does not seem to provide, so far, additional
benefits for women with locally advanced breast cancer. This approach is not
feasible with docetaxel, since an increase in dose density induces unwanted side
effects. These results represent our current state of knowledge, but clinical
trials are being performed to evaluate further the effect of dose intensity, dose
density and cumulative dose of key therapeutic agents on patient outcomes.
PMID- 10785604
TI - Chemotherapy dose reduction and delay in clinical practice. evaluating the risk
to patient outcome in adjuvant chemotherapy for breast cancer.
AB - Randomised clinical trials demonstrate the importance of maintaining chemotherapy
dose and dose intensity in the systemic adjuvant treatment of breast cancer, and
show that the strategies of dose delay and dose reduction carry the risk of
suboptimal outcome. Such dose modifications are usually necessitated by the
myelosuppressive effects, specifically neutropenia, thrombocytopenia and anaemia,
resulting from the previous cycle of chemotherapy. The Canadian Database
Initiative was designed to determine the incidence of neutropenic complications
(an episode of febrile neutropenia or dose delay or reduction) and the frequency
of complications by cycle of therapy using data from patients with breast cancer
treated at centres across Canada. The centres used a variety of adjuvant
chemotherapy regimens and the database covered the treatment of 444 patients,
average age 47.7 years, who were treated between 1991 and 1996. Across all
chemotherapy regimens, 42% of patients experienced at least one complication. Of
those, 72% went on to have additional complications in subsequent cycles. The
neutropenic complications usually occurred early in the treatment schedule.
PMID- 10785605
TI - A novel approach to maintain planned dose chemotherapy on time: a decision-making
tool to improve patient care.
AB - Studies of primary prophylaxis of febrile neutropenia with recombinant
granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim), administered to
all patients starting with the initial course of chemotherapy, have demonstrated
an economic advantage over a wide range of settings. In these analyses, the
threshold risk for febrile neutropenia at which a cost saving is realised is
inversely related to the direct medical costs of hospitalisation. Clinical
practice guidelines for the use of filgrastim have been developed based on these
observations. Recent studies incorporating indirect institutional costs have
demonstrated that cost savings can be achieved at substantially lower febrile
neutropenia risk thresholds than previously estimated. Despite the demonstrated
efficacy of filgrastim in primary prophylaxis, its value may be further enhanced
through the appropriate selection of patients for such therapy and a better
understanding of the importance of sustaining dose intensity in specific
malignancies. Clinical prediction models capable of identifying individuals at
high risk for neutropenic complications yield further reductions in febrile
neutropenia risk thresholds and treatment costs in patients receiving cancer
chemotherapy. Prediction models can also be used to evaluate the cost
effectiveness or cost-efficiency of filgrastim use. Such a model has recently
been developed and validated and is described here which incorporates both
baseline clinical characteristics as well as the results of the first cycle of
chemotherapy in patients with early-stage breast cancer. A cost-effectiveness
ratio of US$ 34297 (Euro 32002)dagger per year of life saved (YLS) was calculated
based on dose-response assumptions derived from a previously reported adjuvant
breast cancer trial studying the impact of dose reduction on disease-free
survival. This figure is comparable with accepted cost-effectiveness ratios for
other interventions, e.g. US$ 45000/LYS (Euro 41989) for renal dialysis for
patients with end-stage renal disease. The cost-effectiveness of filgrastim was
evident over a wide range of clinical and cost assumptions. Clinical prediction
models permit rational and cost-effective selection of patients for filgrastim
support. Current guidelines should be re-evaluated in light of new information
available on both the total cost of febrile neutropenia, as well as the cost
effectiveness of these agents in specific clinical situations.
PMID- 10785606
TI - Cellular and genetic constitution of human endometriosis tissues.
AB - For many years, endometriosis has been an enigmatic and confusing disorder, but
there have been recent contributions to the subject, provided by modern
techniques in cellular and molecular biology, regarding the cell lineage
involved, the stage of differentiation, and genomic features. This review deals
mainly with the cellular, cytochemical, cytogenetic, and molecular cytogenetic
features of primary endometriotic lesions and cultured endometriotic cells. The
FbEM-1 cell line, taken as an in vitro model, showed cell proliferation and
differentiation features suggesting an immature endometriosis-related cell
lineage. Chromosomal analysis of these cells demonstrate a complex karyotype
including a rearrangement interpreted as der(5) t(5q34;6p11) indicating a clonal
cell proliferation. Data of recurrent DNA sequence copy number alterations
detected by the comparative genomic hybridization in a series of primary
endometriotic lesions also are described. Predominant recurrent anomalies were
found on chromosome 1p and 22q in 50% of the studied samples. Additional losses
were seen on chromosomes 5p(33%), 6q(27%), 7p(22%), 9q(22%), and 1q(22%), as well
as on 17q segments in one case. Gain of DNA sequences was seen on chromosomes 6q,
7q, and 17q. The potential role of the genetic changes identified are discussed
in relation to the putative oncogenes and/or tumor suppressor genes possibly
involved in development of endometriosis.
PMID- 10785607
TI - Gene knockout mice in the study of parturition.
AB - OBJECTIVE: To review recent studies of parturition control in mice with relevance
to understanding the control of human parturition. METHODS: Assimilation of
published studies of gene knockout mice with mutations in neuropeptides,
prostaglandin synthetic enzymes and receptors, and other molecules implicated in
parturition. RESULTS: The central role of prostaglandins in murine labor is
demonstrated by mice with gene mutations at multiple levels of the prostaglandin
synthetic pathway. In addition, novel molecules such as steroid 5 alpha-reductase
are found to play an essential role in the progression of labor. Surprisingly,
deficiency of neuropeptides such as oxytocin and corticotropin-releasing hormone
have little effect on parturition. CONCLUSION: Molecular genetic analyses in mice
provide an efficient way to define molecules critical for murine parturition.
Extrapolation of the importance of these molecules to human parturition provides
the next challenge.
PMID- 10785608
TI - Amniotic fluid volume responses to intra-amniotic infusion of lactate in fetal
sheep.
AB - OBJECTIVE: In human and ovine fetuses, severe anemia is associated with elevated
fetal blood and amniotic lactate levels and polyhydramnios. In ovine fetuses,
intravascular infusion of sodium lactate elevates fetal plasma and amniotic
lactate levels and produces polyhydramnios. The present study tested the
hypothesis that an elevated amniotic lactate concentration in the absence of an
increased fetal plasma lactate would be associated with an increase in amniotic
fluid volume (AFV). METHODS: Eight chronically catheterized, late-gestation fetal
sheep were studied over 5 days. Twice each day, we measured blood gases and pH,
electrolytes, glucose, lactate, and blood urea nitrogen (BUN) concentrations, as
well as osmolality of fetal blood, maternal blood, amniotic fluid, and fetal
urine. Amniotic fluid volume was measured once daily. During experimental days 2
to 4, lactic acid was infused into the amniotic compartment to achieve an
amniotic lactate concentration of approximately 20 mmol/L. Statistical analysis
was by analysis of variance and regression. RESULTS: Amniotic fluid lactate
levels averaged 2.2 +/- 0.4 mmol/L (mean +/- standard error) before infusion and
18.9 +/- 3.3 mmol/L during the 72-hour infusion, falling to 5.8 +/- 1.2 mmol/L
postinfusion (P < .001). Fetal plasma lactate averaged 1.8 +/- 0.1 mmol/L on day
1 and increased by 1.4 +/- 0.6 mmol/L on day 4 (P < .001). Fetal urine flow was
unchanged and averaged 0.54 +/- 0.08 mL/min over the 5 days. Amniotic fetal
volume was 821 +/- 186 mL on day 1, increased nonsignificantly by 99 +/- 95 mL on
day 4, and remained unchanged on day 5. CONCLUSIONS: The present study suggests
that if amniotic lactate acts osmotically to increase AFV, the effect is small.
Thus, the primary site of action of elevated fetal lactate levels appears to be
at the placenta rather than the intramembranous pathway.
PMID- 10785609
TI - Hypoxic-ischemic tolerance induced by hyperthermic pretreatment in newborn rats.
AB - OBJECTIVE: We investigated the effect of hyperthermic pretreatment 24 hours
before hypoxic-ischemic exposure on neuronal cell damage in 7-day-old rats.
METHODS: Newborn rats were separated on postnatal day 7 into two groups: 1)
preheated (those exposed to 2 hours of hyperthermic pretreatment at 42-43C) (n =
29), and 2) nonheated (n = 20). At 24 hours after the hyperthermic stress, rats
from both groups were subjected to left carotid artery ligation followed by 2
hours of hypoxia (8% oxygen/92% nitrogen) at 33C. All rats were killed 1 week
after hypoxia-ischemia, and brains were extracted for histologic study. A
different group of 7-day-old rats (n = 8) was placed in the same hyperthermic
environment as mentioned above for 2 hours, and 24 hours after heat exposure
brains were extracted for immunohistochemistry of heat-shock protein 70. RESULTS:
The total incidence of hypoxic-ischemic brain damage significantly decreased in
the preheated group (12 of 25 [48%]) compared with the nonheated group (17 of 20
[85%]; P < .03). The induction of immunoreactive heat-shock protein 70 was
observed mainly in glial and vascular endothelial cells and, in a lesser amount,
in neuronal cells of the cerebral cortex and hippocampus. CONCLUSION: Incidence
of hypoxic-ischemic brain damage is consistently reduced by 2 hours of
hyperthermic pretreatment in 7-day-old rats.
PMID- 10785610
TI - Aging, serum estradiol levels, and pregnancy differentially affect vascular
reactivity of the rat uterine artery.
AB - OBJECTIVES: To investigate the effects of aging, ovarian ablation, and pregnancy
on vascular reactivity of the rat uterine artery. METHODS: Segments of uterine
artery from 3-month-old pregnant and nonpregnant Wistar rats and from aged and
ovariectomized animals, both 9 months of age, were exposed in vitro to vasoactive
mediators. Absolute contractile force as well as endothelium-dependent and
independent vascular reactivity were determined. Isometric tension was recorded
using a modified Mulvany myograph system. Results were compared with analysis of
variance and Bonferroni-Dunn post hoc analysis and correlated with serum
estradiol levels. RESULTS: Aging up to 9 months decreased absolute tension of
uterine arteries in vitro elicited by KCl (P < .0001), while not affecting
receptor-operated responses to norepinephrine, endothelin-1, and angiotensin II.
After ovarian ablation maximal contraction to norepinephrine was selectively
reduced in the aged animal (P = .0053). Pregnancy increased absolute tension to
KCl (P < .0001), norepinephrine (P < .008), and endothelin-1 (P = .0003), whereas
relative contractile force (percentage of KCl) induced by norepinephrine and
endothelin-1 remained unchanged and that induced by angiotension II decreased (P
= .0001) in pregnant animals. In addition, pregnancy increased sensitivity to the
endothelium-dependent vasodilator acetylcholine (P = .0022) but decreased that to
the endothelium-independent vasodilator sodium nitroprusside (P = .0062).
Endothelium-dependent relaxation correlated with serum estrogen levels remained
unchanged in 9-month-old Wistar rats, which physiologically exhibited high serum
estrogen concentrations but was impaired with regard to both maximum relaxation
(P < .0001) and sensitivity in aged rats (P = .0007) after ovariectomy.
CONCLUSIONS: Vascular contractility is impaired in the uterine artery of the aged
rat as evidenced by reduced responses to KCl, whereas responses to receptor
operated agonists remain unchanged. Functional ovaries are essential to preserve
endothelium-dependent relaxation in aging animals. During pregnancy, contractile
machinery and endothelium-dependent relaxation are enhanced. In contrast,
contractions to angiotensin II and endothelium-independent relaxation to sodium
nitroprusside are reduced in late pregnancy. These changes in reactivity of the
uterine artery may be important for the regulation of blood flow in the uterus
according to physiologic needs.
PMID- 10785611
TI - Evidence of endothelial cytotoxic compounds in placental extracts from
preeclamptic women.
AB - OBJECTIVE: To determine whether placenta and plasma of preeclamptic women contain
factors that cause endothelial cell damage. METHODS: Placental extracts and
plasma from preeclamptic and normotensive women were added to cultures of normal
human umbilical vein endothelial cells and their effect on their viability, was
determined by MTT reduction and 51chromium release. RESULTS: Placental extracts
from normotensive and preeclamptic women were cytotoxic to endothelial cells, but
not the plasma from both groups. Mean +/- standard deviation values of
cytotoxicity index in preeclamptic and normotensive placental extracts using the
MTT reduction were 70.3 +/- 6.76% and 51.4 +/- 8.81%, respectively, showing a
significant difference (P < .0001). Using the 51chromium-release assay,
preeclamptic placental extracts showed cytotoxic effects of 87.6 +/- 13.47%
compared with 17 +/- 20.60% in control patients. The cytotoxic activity decreased
after trypsin digestion and heat treatment in both groups. CONCLUSIONS: A
cytotoxic factor to endothelial cells in placental extracts of preeclamptic women
was identified. This compound is thermolabile and sensitive to trypsin digestion.
PMID- 10785612
TI - Effects of hypoxia on regulation of prostanoid production in decidual endothelial
cells in normal and preeclamptic pregnancy.
AB - OBJECTIVES: To examine the effect on prostacyclin and thromboxane production of
incubating decidual endothelial cells under hypoxic conditions, comparing cells
from normal and preeclamptic pregnancies. Furthermore, to determine whether
hypoxia is deleterious to cell growth, and test the effects of stimulation and
inhibition on prostanoid production. METHODS: Decidual endothelial cells were
exposed for a total of 40 hours to normoxic (20% O2) or hypoxic (2% O2)
conditions. Prostacyclin and thromboxane secretion over the final 24 hours of
incubation was measured and cell numbers after incubation determined.
Lipopolysaccharide (LPS) (1.0 microgram/mL) was used as a stimulator and
pirmagrel (1.0 mumol/L) and tranylcypromine (10.0 mumol/L) as prostanoid synthase
inhibitors. RESULTS: Incubations in hypoxia resulted in increased thromboxane (P
< .05) but no change in prostacyclin production. This thromboxane increase was
abrogated by pirmagrel. LPS caused significant stimulation of prostacyclin and
thromboxane secretion and both LPS and hypoxia resulted in lower cell numbers.
Decidual endothelial cells from normal and preeclamptic pregnancies were
generally not different. CONCLUSIONS: This study indicates that in preeclampsia,
where decidual endothelial cells are in a relatively more hypoxic environment,
thromboxane production by these cells is likely to be increased and the
prostacyclin/thromboxane ratio decreased. The thromboxane synthase inhibitor,
pirmagrel, was able to reverse this abnormal increased secretion of thromboxane
in vitro.
PMID- 10785613
TI - Photodynamic endometrial ablation in the nonhuman primate.
AB - OBJECTIVE: To test the effectiveness of 5-aminolevulinic acid (ALA)-induced
photodynamic endometrial ablation in the rhesus monkey under varying conditions
of light delivery (fractionated versus continuous) and steroid priming. METHODS:
Photodynamic endometrial ablation was carried out in 17 rhesus monkeys that were
either postmenopausal or in the early proliferative phase. Four hours after
intralumenal injection of ALA (250 mg in 1 mL hyskon), a quartz fiber with a
diffusing tip was inserted. A KTP tunable dye laser delivered 300 mW of light
(635 nm) for 60 minutes in either continuous or fractionated fashion (20 minutes
on, 5 minutes off, and 40 minutes on). In some experiments, thermistors were used
to monitor temperature in the lumen and myometrium during light treatment.
Hysterectomy was performed 3 or 4 days after treatment, and endometrial damage
was assessed histologically. Two additional monkeys (one rhesus and one
cynomolgus monkey) were exposed to the same protocol, except hyskon was
substituted for ALA to control for potential ablative effects due to light
treatment alone. RESULTS: Endometrial ablation was evident in all ALA
photosensitized specimens. The degree of ablation around the light fiber ranged
from moderate to complete. The depth of ablation ranged from 1.14 +/- 0.54 to
2.15 +/- 1.62 mm (mean +/- standard deviation). Ablation was most complete in
uteri of menopausal monkeys. Light treatment after ALA increased lumenal
temperature from 36 C to 50 C, whereas temperature was not significantly
increased by light treatment in the controls. CONCLUSION: This is the first
report of endometrial destruction in the primate using a photodynamic approach.
Whereas clinical application of photodynamic therapy (PDT) requires complete
endometrial ablation to produce long-lasting amenorrhea, our results suggest that
PDT may offer a simple office-based approach to endometrial ablation.
PMID- 10785614
TI - Human first trimester fetal ovaries express oncofetal antigens and steroid
receptors.
AB - OBJECTIVE: To document the expression of oncofetal antigens and steroid receptors
in first trimester human fetal ovaries and to determine the effect of advancing
gestation on expression patterns. METHODS: Fetal gonads were collected from
surgical terminations of pregnancy, and fetal sex was determined by fluorescence
in situ hybridization. Immunocytochemical analysis was performed on paraffin
sections of microdissected fetal ovaries using antibodies to carcinoembryonic
antigen (CEA), placental alkaline phosphatase (PLAP), hCG, alpha fetoprotein
(AFP), CA 125, estrogen receptor (ER) and progesterone receptor (PR) in 12 first
trimester human fetal ovaries. Expression was quantified objectively by measuring
percentage area of immunoreactivity (PAI) on whole sections of the ovary using an
interactive image analysis system. Two pathologists, blinded to the antibodies
used, independently viewed and scored all sections. RESULTS: PLAP, PR, ER and CEA
were expressed in all 12 ovaries (31%, 28%, 21%, and 16% mean PAI, respectively).
A diffuse staining pattern was observed at 8 weeks' gestation, which was more
focal and confined to the cortical regions of the gonad by 12 weeks' gestation.
Putative primordial germ cells were positive for PLAP, PR and ER but rarely for
CEA. The expression (PAI) of PLAP and PR was unchanged during the first
trimester, whereas that of ER decreased from 28% to 12%. The expression of CEA
and hCG decreased from 8 to 11 weeks and then increased markedly by 13 weeks. AFP
had a medullary distribution and was expressed in nine of 12 ovaries (mean PAI
18%). CA 125 expression was minimal or undetected. CONCLUSION: PLAP, ER and PR
were the most extensively expressed protein antigens, particularly in fetal
ovarian cortex. These variable patterns of expression suggest levels of
differentiation in the immature first trimester human fetal ovary.
PMID- 10785615
TI - Short-wavelength automated perimetry: it's role in the clinic and for
understanding ganglion cell function.
AB - Short-wavelength automated perimetry (SWAP) is a more sensitive test than
standard achromatic perimetry for early loss of vision due to glaucoma and other
ocular and neurological diseases. SWAP is also more successful for detecting
changes in vision as glaucoma progresses. Results from various visual function
specific tests, including SWAP, suggest that there are individual differences in
ocular hypertensive and glaucoma eyes in the subtype of ganglion cell first
affected. However, the disease targets the same retinal area for all function
specific tests that show a deficit in a given individual. Psychophysical tests of
vision are critical to understand glaucoma's effect on retinal ganglion cells, to
verify the success or failure of treatment including new neuroprotective agents,
and to determine the relationship of genetic markers for glaucoma to the presence
and progress of the disease.
PMID- 10785616
TI - Molecular evolution of vertebrate visual pigments.
AB - Dramatic improvement of our understanding of the genetic basis of vision was
brought by the molecular characterization of the bovine rhodopsin gene and the
human rhodopsin and color opsin genes (Nathans and Hogness, 1983; Nathans et al.,
1984, 1986a,b). The availability of cDNA clones from these studies has
facilitated the isolation of retinal and nonretinal opsin genes and cDNA clones
from a large variety of species. Today, the number of genomic and cDNA clones of
opsin genes isolated from different vertebrate species exceeds 100 and is
increasing rapidly. The opsin gene sequences reveal the importance of the origin
and differentiation of various opsins and visual pigments. To understand the
molecular genetic basis of spectral tuning of visual pigments, it is essential to
establish correlations between a series of the sequences of visual pigments and
their lambda(max) values. The potentially important amino acid changes identified
in this way have to be tested whether they are in fact responsible for the
lambda(max)-shifts using site-directed mutagenesis and cultured cells. A major
goal of molecular evolutionary genetics is to understand the molecular mechanisms
involved in functional adaptations of organisms to different environments,
including the mechanisms of the regulation of the spectral absorption. Therefore,
both molecular evolutionary analyses of visual pigments and vision science have
an important common goal.
PMID- 10785617
TI - The role of photoreceptors in the control of refractive state.
AB - The current state of research into experimentally induced refractive errors is
reviewed. The area is analysed in three components-the transduction of defocus or
deprivation, the vector for transmitting the error message from the retina to the
outer tunics of the eye, and the identity of the effector for causing growth
modulation in the sclera. Anatomical, pharmacological, electrophysiological and
optical factors are considered in terms of which elements of the retina are
necessary to support a refractive response to deprivation or defocus. Two of the
current models are discussed-one emphasizing the role of the choroid in effecting
ocular and refractive change, while the second model approaches the problem from
the aspect of scleral changes that are associated with growth adaptation without
emphasis on the error detection mechanism. A third model is proposed in which the
error signal for deprivation or defocus is detected in the outer retina and where
error is translated through separate signals for stimulus brightening and
darkening into a net signal for fluid flow across and under the active control of
the retinal pigment epithelium with the fluid communication between the vitreous
chamber and the choroidal lymphatics. The directions of research both fundamental
and clinical which are needed to create pharmaceutical or environmental solutions
to refractive control are discussed.
PMID- 10785618
TI - Microvascular effects of selective prostaglandin analogues in the eye with
special reference to latanoprost and glaucoma treatment.
AB - Prostaglandin F(2alpha) analogues have recently been introduced on the market for
glaucoma treatment. While these drugs have a well-documented intraocular pressure
reducing effect only a limited number of studies have been published regarding
their effects on the microvasculature in the eye. Since many naturally occurring
prostaglandins have marked effects on the cardiovascular system it is conceivable
that synthetic prostaglandins used as glaucoma drugs may exert microvascular
effects in the eye, even if they exhibit receptor selectivity. Latanoprost, the
active principle of Xalatan((R)) eye drops, is a selective FP prostanoid receptor
agonist, and much of the paper is focused on the microvascular effects of
latanoprost and some closely related prostaglandin analogues. The purpose of the
paper is to review the literature on the microvascular effects of prostaglandins
in the eye, and to present some unpublished data on the effects of selective
prostaglandin analogues. Most of the prostaglandin analogues studied exhibit
selectivity for the FP prostanoid receptor. Results from studies with the
following prostaglandin analogues are presented in the paper: PGF(2alpha)
isopropyl ester (PGF(2alpha)-IE), 17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropyl
ester (17-phenyl-PGF(2a)-IE), 15-keto-17-phenyl-18,19, 20-trinor-PGF(2alpha)
isopropyl ester (15-keto-17-phenyl-PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20
trinor-PGF(2alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl
18,19, 20-trinor-PGF(2alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19, 20-trinor
PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH
PGE(2)). The regional blood flow has been determined with radioactively labelled
microspheres, the blood volume with (51)Cr labelled erythrocytes and the
capillary permeability to albumin with (125)I and (131)I labelled albumin.
PGF(2alpha)-IE has been shown to exert marked microvascular effects in the rabbit
anterior segment including vasodilatation, increased capillary permeability, and
a breakdown of the blood-aqueous barrier. 17-phenyl-PGF(2alpha)-IE, 15-keto-17
phenyl-PGF(2alpha)-IE, and PhXA34/latanoprost exerted significantly less
vasodilatory effect, and little effect on capillary permeability was seen with
the FP receptor agonists when studied with Evans blue. Intravenous administration
of PhXA34 at a dose range of 1-100 microg/kg b.w. had no consistent effect on the
regional blood flow in the eye indicating that FP receptors in the ocular blood
vessels are not expressed in the rabbit, or alternatively are not functionally
coupled to regulation of vascular tone. In cats topical application of
PGF(2alpha)-IE had no significant effect the on the regional blood flow in
cannulated eyes. No blood flow experiments were performed in intact eyes with
PGF(2alpha)-IE. 17-phenyl-PGF(2alpha)-IE and latanoprost caused some vasodilation
in the anterior segment. None of the analogues had any significant effect on the
blood volume in the ocular tissues, but an increase in capillary permeability to
albumin was seen in several tissues of the eye. However, in the eyelid,
nictitating membrane and conjunctiva exposed to high concentrations of the
prostaglandins no or only little leakage of albumin was detected. It appears that
the intraocular microvasculature in the cat exhibits some sensitivity to FP
prostanoid receptor agonists. (ABSTRACT TRUNCATED)
PMID- 10785619
TI - Genetics and brain injury: apolipoprotein E.
AB - Apolipoprotein E (apo E) is a lipoprotein produced by astrocytes and microglia
and has a proposed role in transporting lipids to injured neurons. There are
three known isoforms of apo E, coded for by the APOE epsilon2, APOE epsilon3, and
APOE epsilon4 genes. The APOE epsilon4 genotype has been implicated as a risk
factor for Alzheimer's disease. Recent studies have suggested that APOE epsilon4
may influence the central nervous system's response to injury. This article
presents an overview of the relationship between apo E, Alzheimer's disease, and
head injury and reviews recent studies implicating APOE epsilon4 as a possible
genetic determinant in recovery from head injury.
PMID- 10785621
TI - Evaluating fitness to drive after cerebral injury: basic issues and
recommendations for medical and legal communities.
AB - Specialists in rehabilitation are typically called upon to evaluate and render an
opinion about whether or not a person can be entrusted to resume driving. And,
because driving is an individual privilege to be balanced against the public's
right to safety and protection from the dangers of a driver whose residual
deficits may impede ability to drive safely, these specialists have developed a
number of methods to assess fitness to drive. Unfortunately, many evaluators
remain unfamiliar with research used as basis for evaluations or lack
understanding of the strengths and weaknesses of tests in use. Therefore, there
may be unquestioning trust in tests and methods that leads to errors of
significant consequence in decisions about fitness to drive as well as
unawareness of expanding risks of litigation that can emanate from inappropriate
recommendations. This article intends to draw attention to issues,
considerations, and problems underlying the conduct of driver evaluations,
including focus on ways in which the legal and medical communities approach
question of fitness, legal and medical definitions and terminology,
responsibility for assessment as well as tests and methods used in evaluations.
Conclusions are drawn from discussion of these matters and recommendations are
outlined for addressing identified problems at the interface between medical and
legal communities.
PMID- 10785620
TI - The hippocampus: anatomy, pathophysiology, and regenerative capacity.
AB - Cognitive deficits following insults to the central nervous system-particularly
those involving the hippocampus and related structures-are often persistent and
severely debilitating. Progress has been made in establishing the role of the
hippocampus in integrating information in the formation of memory necessary for
subsequent recollection of information. The present article will review anatomic,
physiological, and functional aspects of the hippocampus in reference to learning
and memory. Both animal and human hippocampal pathophysiological processes will
be explored. Adaptive and maladaptive central nervous system responses will be
reviewed, with a special emphasis on neurogenesis. Ideally, physiological and
cellular compensatory responses ought to parallel clinical observation. However,
this association is not clearly established. Finally, the current understanding
of neuromodulatory mechanisms (although quite preliminary) will also be
discussed.
PMID- 10785622
TI - Psychological distress and family satisfaction following traumatic brain injury:
injured individuals and their primary, secondary, and tertiary carers.
AB - OBJECTIVE: To assess family psychosocial outcome following traumatic brain injury
(TBI) in all family members, including relatives more peripheral to the person
with the injury. DESIGN: A cross-sectional design was used to gather outcome data
from individuals with TBI and primary, secondary, and tertiary carers, 19.3
months posttrauma. Multivariate analyses of variance (ANOVAs) ascertained
differences in levels of psychological distress and family satisfaction within
families. SETTING AND PARTICIPANTS: Seventy-nine families (65 individuals with
TBI, 72 primary carers, 43 secondary carers, and 22 tertiary carers) were drawn
from a sample of outpatients of three metropolitan, acute rehabilitation
hospitals over a 12-month period. OUTCOME MEASURES: In addition to using the
Family Satisfaction Scale (FSS), measures of psychological distress included the
Beck Depression Inventory (BDI), State Anxiety Inventory (SAI), and Profile of
Mood States (POMS). RESULTS: Although it was noted that a significant proportion
of family members were not psychologically distressed and reported good family
satisfaction, people with TBI remain at greater risk of poor psychosocial outcome
than do their relatives. Of other family members, primary carers-particularly
wives-are at greatest risk of poor psychosocial outcome, and a number of
secondary and tertiary carers also displayed high levels of psychological
distress. CONCLUSIONS: Male relatives (the majority of whom were secondary or
tertiary carers) may report their distress in terms of anger and fatigue, rather
than as depression and anxiety. Future research could develop TBI-specific
measures of anger and fatigue as screening instruments to identify peripheral
family members requiring assistance in adapting to TBI. Many families-despite
their initial traumatic experience-eventually cope well, encouraging researchers
and clinicians to focus future research efforts on those families who have made
good adjustments to TBI.
PMID- 10785623
TI - Social problem solving in children with acquired brain injuries.
AB - OBJECTIVES: To assess the performance of children with acquired brain injuries
(ABIs) on a measure of social problem solving and to examine the relationships
between participant characteristics and performance on the Social Knowledge
Interview (SKI) and between parent-reported child behavior and performance on the
SKI. DESIGN: Between-group comparisons using correlational analyses, matched
pairs t-tests, and analysis of covariance (ANCOVA). PARTICIPANTS: Thirty-one
children 6-12 years old with ABI and 31 control participants, matched on age and
sex. MAIN OUTCOME MEASURE: The SKI, a measure of social problem-solving skills.
RESULTS: Using matched pairs t-tests and ANCOVA, groups were compared on several
SKI measures, including the number of unique responses generated for each problem
scenario, the quality of those responses, and the ability to select the best
response from a set of alternatives. When equated for socioeconomic status (SES),
ABI and control participants performed similarly on the SKI; however, a trend for
children with ABI to generate more assertive responses was observed. Performance
on the SKI was positively correlated with IQ and related to parent-reported
adaptive behavior. In children with ABI, performance was also related to primary
lesion location and treatment regimen. CONCLUSIONS: Children with ABI are as
capable of judging the appropriateness of behavior and generating response
options on an analog measure of social problem solving as were their typically
developing peers. However, those individual children with ABI who are more likely
to have social problems may be identified by the qualitative aspects of their
responses on analog tasks. These findings have implications for the
identification of children with social skills deficits following ABI and for the
development of effective rehabilitation strategies.
PMID- 10785624
TI - Speed of information processing in traumatic brain injury: modality-specific
factors.
AB - OBJECTIVE: To assess speed of information processing by two serial addition tests
(one visual, one auditory) in individuals with moderate-to-severe traumatic brain
injuries (TBIs) and in a healthy, normal control group (NC). The tasks were
designed to equate and control for accuracy of performance across the TBI and NC
groups, thus allowing for quantification of information processing speed. DESIGN:
Performance across groups and tasks were compared using 2 x 2 repeated measure
analyses of variance (ANOVAs). In addition, each individual's processing speed
was used to adjust rate of stimulus presentation on a subsequent "rehabilitation"
trial to determine further whether this adjustment equated accuracy of
performance. SETTING: Rehabilitation hospital. PATIENTS: 22 outpatients with
moderate-to-severe TBI (6 women, 16 men; mean age = 34.6 years; duration of loss
of consciousness = 22.6 days) and 20 age- and education-matched healthy controls.
RESULTS: Processing speed was slower in TBI subjects, relative to controls and
was significantly related to measures of executive functioning for those with
TBI. Relative to controls, speed of processing in the TBI group was
disproportionately slower when information was presented in the auditory,
relative to the visual, modality. CONCLUSIONS: Speed of information processing is
a major impairment in those with TBI when unconfounded by performance accuracy.
The modality-specific impairment observed in the TBI group may, in part, be due
to a greater within-modality interference effect created by the auditory version
of the task. By manipulating information at a pace customized for an individual
through compensatory strategies and environmental modifications, information
processing performance of TBI participants can be enhanced significantly.
PMID- 10785625
TI - Validity of the Orientation Log, relative to the Galveston Orientation and
Amnesia Test.
AB - OBJECTIVE: To establish the validity of the Orientation Log (O-Log) by comparison
with the Galveston Orientation and Amnesia Test (GOAT). DESIGN: Correlation of
daily measures of orientation. SETTING: Acute rehabilitation hospital. SUBJECTS:
Sixty-eight inpatients receiving rehabilitation following traumatic brain injury
(TBI). PRIMARY MEASURES: The O-Log and GOAT. RESULTS: There was a significant
correlation between the GOAT and O-Log (r = .901, P<.001). A cutoff of 25 on the
O-Log was found to be comparable with the 75 cutoff on the GOAT. The scales were
equivalent in measuring duration of posttraumatic amnesia. CONCLUSIONS: The O-Log
is a valid measure of orientation for people with TBI and offers some advantages
in administration over the GOAT.
PMID- 10785626
TI - Pharmacological therapeutics in nutritional management.
PMID- 10785627
TI - Research ethics in head trauma rehabilitation.
PMID- 10785628
TI - The ASM in the new millennium
PMID- 10785629
TI - The dawning of molecular genetics.
PMID- 10785630
TI - Microbial pathogenesis: new paths into a new millennium.
PMID- 10785631
TI - The good old days are now.
PMID- 10785632
TI - Discovery of the anthrax toxin: the beginning of in vivo studies on pathogenic
bacteria.
PMID- 10785633
TI - Pathogenic fungi in the 21st century.
PMID- 10785634
TI - From flagellum assembly to virulence: the extended family of type III export
chaperones.
PMID- 10785635
TI - Yop effectors of Yersinia spp. and actin rearrangements.
PMID- 10785636
TI - DNA microarrays: translational tools for understanding the biology of
Mycobacterium tuberculosis.
PMID- 10785637
TI - Type III machines of Gram-negative bacteria: delivering the goods.
AB - Many Gram-negative pathogens use a type III secretion machine to translocate
protein toxins across the bacterial cell envelope. Pathogenic Yersinia spp.
export at least 14 Yop proteins via a type III machine, which recognizes
secretion substrates by signals encoded in yop mRNA or chaperones bound to
unfolded Yop proteins. During infection, substrate recognition appears to be
regulated in a manner that allows the Yersinia type III pathway to direct Yops to
the bacterial envelope, the extracellular medium or into the cytosol of host
cells.
PMID- 10785638
TI - Regulation of expression of methane monooxygenases by copper ions.
AB - Many methanotrophs contain both a soluble and a particulate methane
monooxygenase. A unique metabolic switch, mediated by copper ions, regulates the
expression of these enzymes. When the copper-to-biomass ratio of the cell is low,
the soluble enzyme is expressed, and when the copper-to-biomass ratio is high,
the particulate enzyme is expressed. A model for the mechanism of this switch is
proposed.
PMID- 10785639
TI - Common molecular mechanisms of symbiosis and pathogenesis.
AB - Traditionally, symbiotic and pathogenic interactions were considered different
manifestations of the bacteria-host interaction. However, the molecular
mechanisms that mediate communication between and cellular modulation of the
involved partners are quite similar. With this review we aim to contribute to a
reduction of the traditional gap between symbiosis and pathogenesis research.
PMID- 10785641
TI - The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis.
AB - In bacteria, extracellular signals are generally transduced into cellular
responses via a two-component system. However, genome sequence data have now
revealed the presence of 'eukaryotic-like' protein kinases and phosphatases.
Mycobacterium tuberculosis appears to be unique among bacteria in that its genome
contains 11 members of a newly identified protein kinase family. These M.
tuberculosis eukaryotic-like protein kinases could be key regulators of metabolic
processes, including transcription, cell development and interactions with host
cells.
PMID- 10785640
TI - The staphylococcal transferrin receptor: a glycolytic enzyme with novel
functions.
AB - To obtain iron from the host for growth, staphylococci have evolved sophisticated
iron-scavenging systems including siderophores and a cell surface receptor for
transferrin, the mammalian iron-transporting glycoprotein. The staphylococcal
transferrin receptor has been identified as a member of a newly emerging family
of multifunctional, cell-surface-associated glyceraldehyde-3-phosphate
dehydrogenases, which not only retain their glycolytic enzyme activities but also
bind diverse human serum proteins and possess NAD-ribosylating activity. These
multiple functions suggest a potential contribution to virulence far beyond iron
acquisition.
PMID- 10785642
TI - Learning about kainate receptors.
PMID- 10785644
TI - Nitric oxide, glial cells and neuronal degeneration in parkinsonism.
PMID- 10785643
TI - Beta-secretase revealed: starting gate for race to novel therapies for
Alzheimer's disease.
PMID- 10785645
TI - Reply: a new look at the pathogenesis of Parkinson's disease
PMID- 10785646
TI - Tachykinin autoreceptors in the gut.
PMID- 10785647
TI - Identification of the real molecular target for HIV inhibitors.
PMID- 10785648
TI - Reply: effect of radioligand contamination on the analysis of homologous
competition experiments
PMID- 10785649
TI - Inflammation-coagulation network: are serine protease receptors the knot?
AB - Following an injury, the body recruits a mechanism to delimit and repair tissue
damage; this phenomenon is known as inflammation. Among the several different
pathways that are activated during this process, which is necessary for survival,
activation of the coagulation pathway is a key feature. In fact, clinical changes
in blood fluidity have been closely related to ongoing inflammation. Recent
evidence suggests that serine protease receptors might play a major role in the
host defence mechanism at the interface between coagulation and inflammation.
PMID- 10785650
TI - The troubled story of tachykinins and neurokinins.
AB - A family of peptides that shares a common C-terminal sequence (Phe-X-Gly-Leu
MetNH2) exists in mammalian and non-mammalian species. In mammals, three of these
peptides (substance P, neurokinin A and neurokinin B) satisfy the criteria to be
considered as neurotransmitters either in the central, peripheral or enteric
nervous systems. In addition, multiple receptors for these peptides, which belong
to the superfamily of G-protein-coupled receptors, exist. These receptors have
distinct pharmacological features and selective agonists and antagonists are
available for studying their functional roles. The latest update on nomenclature
of these peptides and their receptors, which dates back to 1986, agreed to use
the terms tachykinins and tachykinin NK1, NK2 and NK3 receptors. This
'nomenclature mismatch' has generated confusion that urges experts in the field
of tachykinin research to provide a revised nomenclature.
PMID- 10785651
TI - Using green fluorescent proteins to study G-protein-coupled receptor localization
and trafficking.
AB - G-protein-coupled receptors (GPCRs) mediate a diverse array of biological
functions as a result of their ability to respond selectively to extracellular
stimuli, which ultimately results in cell-specific activation of signaling
cascades. Generally, GPCR activation is followed rapidly by a loss of
responsiveness, termed desensitization, which is then followed by a period of
recovery or resensitization. These changes in signaling potential are tightly
regulated, primarily via mechanisms that involve GPCR phosphorylation and
trafficking to distinct locations within the cell. Tagging of GPCRs with the
green fluorescent protein (GFP) has enabled the direct visualization of real-time
trafficking of GPCRs in living cells. Such analyses have provided crucial insight
into the mechanisms involved in controlling GPCR function.
PMID- 10785652
TI - Identification of PKC-isoform-specific biological actions using pharmacological
approaches.
AB - The protein kinase C (PKC) family consists of at least 12 isoforms that possess
distinct differences in structure, substrate requirement, expression and
localization. To date, identification of the physiological function of individual
PKC isoforms has been restricted by the availability of few agents that inhibit
or activate the isoforms with specificity. More recent approaches that are used
to modulate PKC isoforms include oligonucleotide antisense technology, and
peptide fragments to either inhibit or promote translocation of PKC isoforms to
specific anchoring proteins. In this review, several currently available
inhibitors and activators of PKC that display varying degrees of selectivity for
the PKC isoforms will be discussed.
PMID- 10785654
TI - Liposome treatment offers amputation reprieve.
PMID- 10785653
TI - Is agmatine a novel neurotransmitter in brain?
AB - Recent evidence suggests that agmatine, which is an intermediate in polyamine
biosynthesis, might be an important neurotransmitter in mammals. Agmatine is
synthesized in the brain, stored in synaptic vesicles in regionally selective
neurons, accumulated by uptake, released by depolarization, and inactivated by
agmatinase. Agmatine binds to alpha2-adrenoceptors and imidazoline binding sites,
and blocks NMDA receptor channels and other ligand-gated cationic channels.
Furthermore, agmatine inhibits nitric oxide synthase, and induces the release of
some peptide hormones. As a result of its ability to inhibit both hyperalgesia
and tolerance to, and withdrawal from, morphine, and its neuroprotective
activity, agmatine has potential as a treatment of chronic pain, addictive states
and brain injury.
PMID- 10785656
TI - Gene therapy leads to sporting success.
PMID- 10785655
TI - New first-line monotherapy for epilepsy.
PMID- 10785657
TI - Brain drug delivery technologies: novel approaches for transporting therapeutics.
AB - The blood-brain barrier (BBB) denies many therapeutic agents access to brain
tumours and other diseases of the central nervous system (CNS). Despite
remarkable advances in our understanding of the mechanisms involved in the
development of the brain diseases and the actions of neuroactive agents, drug
delivery to the brain remains a challenge. For more than 20 years, extensive
efforts have been made to enhance delivery of therapeutic molecules across
vascular barriers of the CNS. The current challenge is to develop drug-delivery
strategies that will allow the passage of drug molecules through the BBB in a
safe and effective manner, and this review will provide an insight into some of
the strategies developed to enhance drug delivery across the BBB.
PMID- 10785658
TI - Therapeutic applications of colloidal drug carriers.
AB - Colloidal drug carriers such as liposomes and nanoparticles can be used to
improve the therapeutic index of both established and new drugs by modifying
their distribution, and thus increasing their efficacy and/or reducing their
toxicity. This is because the drug distribution then follows that of the carrier,
rather than depending on the physicochemical properties of the drug itself. If
these delivery systems are carefully designed with respect to the target and the
route of administration, they may provide one solution to some of the delivery
problems posed by new classes of active molecules, such as peptides and proteins,
genes and oligonucleotides. They may also offer alternative modes for more
conventional drugs, such as highly hydrophobic small molecules. This review
discusses the use of colloidal, particulate carrier systems (25 nm to 1 um in
diameter) in such applications.
PMID- 10785659
TI - Optimal process design for the manufacture of transdermal drug delivery systems.
AB - In a pharmaceutical market characterized by increasing competition, assessment
criteria related to system design are assuming greater importance. This is true
for both conventional dosage forms and drug delivery systems (DDS), as
manufacturers strive to achieve adequate patient convenience and compliance. At
the same time, the process design for the manufacture of DDS must comply with
current good manufacturing practices, and give sufficient consideration to
associated environmental issues. Related problems must be solved under social and
safety pressures, which, in turn, become economic pressures, such as the
consideration of control methods. In addition, both the system design and the
process design have a major impact on the cost of goods, as well as on the levels
of complexity or risk associated with development.
PMID- 10785660
TI - Monitor: progress and profiles.
AB - Monitor provides an insight into the latest developments in pharmaceutical
science and technology through brief synopses of recent presentations,
publications and patents, and expert commentaries on the latest technologies.
There are two sections: Progress summarizes the latest developments in
pharmaceutical process technology, formulation, analytical technology,
sterilization, controlled drug delivery systems and regulatory issues; Profiles
offers expert commentary on emerging technologies, novel processes and strategic,
organizational and logistic issues underlying pharmaceutical R&D.
PMID- 10785661
TI - Development of a CFC-free glucocorticoid metered-dose aerosol system to optimize
drug delivery to the lung.
PMID- 10785662
TI - Sensory transduction of blue light in guard cells.
PMID- 10785663
TI - Is abscisic aldehyde really the immediate precursor to stress-induced ABA?
PMID- 10785664
TI - Plant glutathione S-transferases: enzymes with multiple functions in sickness and
in health.
AB - Glutathione S-transferases (GSTs) are abundant proteins encoded by a highly
divergent, ancient gene family. Soluble GSTs form dimers, each subunit of which
contains active sites that bind glutathione and hydrophobic ligands. Plant GSTs
attach glutathione to electrophilic xenobiotics, which tags them for vacuolar
sequestration. The role of GSTs in metabolism is unclear, although their complex
regulation by environmental stimuli implies that they have important protective
functions. Recent studies show that GSTs catalyse glutathione-depend-ent
isomerizations and the reduction of toxic organic hydroperoxides. GSTs might also
have non-catalytic roles as carriers for phytochemicals.
PMID- 10785665
TI - The WRKY superfamily of plant transcription factors.
AB - The WRKY proteins are a superfamily of transcription factors with up to 100
representatives in Arabidopsis. Family members appear to be involved in the
regulation of various physio-logical programs that are unique to plants,
including pathogen defense, senescence and trichome development. In spite of the
strong conservation of their DNA-binding domain, the overall structures of WRKY
proteins are highly divergent and can be categorized into distinct groups, which
might reflect their different functions.
PMID- 10785666
TI - Plant one-carbon metabolism and its engineering.
AB - The metabolism of one-carbon (C1) units is vital to plants. It involves unique
enzymes and takes place in four subcellular compartments. Plant C1 biochemistry
has remained relatively unexplored, partly because of the low abundance or the
lability of many of its enzymes and intermediates. Fortunately, DNA sequence
databases now make it easier to characterize known C1 enzymes and to discover new
ones, to identify pathways that might carry high C1 fluxes, and to use
engineering to redirect C1 fluxes and to understand their control better.
PMID- 10785667
TI - Progress in the molecular genetic analysis of trichome initiation and
morphogenesis in Arabidopsis.
AB - Arabidopsis trichomes are large unicellular structures that develop on the
surface of most shoot-derived organs. In leaves, the number, spacing and shape of
trichomes is tightly regulated, and this process has been used as an experimental
system to study the control of cell fate and pattern formation. The control of
trichome initiation is complex: both the potential of a cell to adopt the
trichome cell fate and an intricate signaling pathway determine the pattern of
trichome initiation events. Several important new results suggest that trichome
initiation and morphogenesis are redundantly regulated by both positive and
negative factors. A testable model for the control of trichome initiation is
presented.
PMID- 10785668
TI - Coping with multiple enemies: an integration of molecular and ecological
perspectives.
AB - How plants respond to attack by the range of herbivores and pathogens that
confront them in the field is the subject of considerable research by both
molecular biologists and ecologists. However, in spite of the shared focus of
these two bodies of research, there has been little integration between them. We
consider the scope for such integration, and how greater dialogue between
molecular biologists and ecologists could advance understanding of plant
responses to multiple enemies.
PMID- 10785669
TI - Does the plant mitochondrion integrate cellular stress and regulate programmed
cell death?
AB - Research on programmed cell death in plants is providing insight into the
primordial mechanism of programmed cell death in all eukaryotes. Much of the
attention in studies on animal programmed cell death has focused on determining
the importance of signal proteases termed caspases. However, it has recently been
shown that cell death can still occur even when the caspase cascade is blocked,
revealing that there is an underlying oncotic default pathway. Many programmed
plant cell deaths also appear to be oncotic. Shared features of plant and animal
programmed cell death can be used to deduce the primordial components of
eukaryotic programmed cell death. From this perspective, we must ask whether the
mitochondrion is a common factor that can serve in plant and animal cell death as
a stress sensor and as a dispatcher of programmed cell death.
PMID- 10785670
TI - Shorter hospital stays for angioplasty patients who receive abciximab.
AB - The purpose of this retrospective study is to examine the effect of abciximab
treatment on hospital length of stay for patients undergoing angioplasty in a
naturalistic setting. Multivariate analysis was used to control for a wide range
of factors (patient demographics, insurance provider, health conditions,
admission and discharge information, and hospital characteristics) that may
influence length of stay. Estimation was conducted on a sample of 13,384
angioplasty patients via a two-stage sample selection model. In addition, the
model was re-estimated for a subgroup of 4,800 patients who underwent angioplasty
and were also diagnosed with acute myocardial infarction. The study finds that
patients in poorer health were more likely to receive abciximab. After adjusting
for high-risk indications and selection bias, results also indicate that
angioplasty patients (n = 13,384) who are given abciximab have a significantly
shorter length of stay (0.89+/-0.12 fewer days) than those patients who did not
receive abciximab. In a subgroup analysis of patients who had an acute myocardial
infarction (n = 4,800), patients receiving abciximab were also found to have
significantly shorter hospital stays (0.54+/-0.26 fewer days) than patients who
did not receive abciximab. These results indicate that there are potential
economic benefits for hospitals administering abciximab.
PMID- 10785671
TI - Clinical and angiographic outcome of stent implantation without predilatation
using the Jostent Flex stent.
AB - Conventional stenting requires predilatation which potentially increases vessel
wall injury and cost of the procedure. In this study, the safety and efficacy of
direct Jostent Flex (Jomed AB, Helsingborg, Sweden) stent placement was evaluated
in 50 patients. Quantitative coronary angiography was performed at baseline, post
stent and 6 months follow-up. Clinical follow-up was done up to 9 months. In 50
patients (38 male/12 female; age 61+/-12 years) with stable (n = 42; 84%) or
unstable (n = 8; 16%) angina, 53 Jostent Flex (JF) stents (diameter 3.2+/-0.2 mm)
were implanted for 51 stenoses. Direct stenting was successful in 46 stenoses
(90%). No stents were lost or damaged when retrieved after unsuccessful direct
delivery. Eventually, all stents could be implanted at the target site.
Angiographic success (<30% residual stenosis) was achieved in 49 lesions (96%).
At 9 months, none of the patients had died. Target lesion revascularization was
necessary in 4 (8%) patients at 6 months and in 2 (4%) other patients between 6
and 9 months. Minimal lumen diameter increased from 1.1+/-0.4 to 2.6+/-0.4 mm
(p<0.001) after stent placement and 1.8+/-0.6 mm (p<0.001) at 6 months follow-up.
Angiographic restenosis (> 50%) at 6 months was present in 24% of 49 treated
stenoses. At 6 and 9 months, 39 (78%) and 41 (82%) of the patients were free of
anginal symptoms and the ischemic event-free survival was 80% at 9 months. This
study demonstrates the safety and efficacy of direct placement of the JF stent as
well as favorable clinical and angiographic results up to 9 months after the
procedure.
PMID- 10785672
TI - Economic outcomes analysis of stenting versus percutaneous transluminal coronary
angioplasty for patients with coronary artery disease in Japan.
AB - The purpose of this study was to compare the clinical outcomes and costs of
coronary stenting with conventional percutaneous transluminal coronary
angioplasty (PTCA) in patients with coronary artery disease (CAD) in Japan. The
increasing use of stent implantation in CAD has raised economic concerns for
healthcare decision makers. This decision analysis model, which applies to the
Japanese healthcare system and uses recent clinical and economic data,
demonstrates coronary stenting to be superior to PTCA, both in terms of
effectiveness and cost. Although the procedural costs for the stenting group are
substantially higher than for PTCA (1,233,412 yen versus 709,295 yen,
respectively; p<0.001), the difference in cost between the two procedures
(524,117 yen) is already reduced to 299,408 yen by the time of hospital discharge
due to procedural complications and associated bail-out treatments avoided during
the in-hospital period. The initial incremental cost of stenting is more than
recouped by the end of year one, mainly because of savings realized due to
avoided repeat revascularization procedures. The cost neutrality (or small cost
saving) is maintained over subsequent years. Thus, coronary artery stenting leads
to better results as well as cost neutrality after one, two and three years. This
highly desirable outcome implies that stenting rather than PTCA alone should be
the treatment of choice and dominant strategy in Japan from the viewpoint of both
the patient and the healthcare system.
PMID- 10785673
TI - Economics and outcomes of coronary stenting: are stents right for everybody?
PMID- 10785674
TI - Is the "direct" approach best?
PMID- 10785675
TI - Coronary radiation therapy with liquid rhenium-186: a first clinical experience.
AB - BACKGROUND: Coronary radiation therapy (CRT) is a new, attractive approach for
the treatment and prevention of restenosis after percutaneous coronary
interventions (PCI). The RadioCath device consists of a standard balloon
dilatation catheter that can be charged with a solution of sodium 186Re
perrhenate, a predominant beta emitter. The safety and performance of this new
device was evaluated in a pilot trial. METHODS AND RESULTS: Thirty-three patients
with a de novo lesion in a native coronary artery were treated with the RadioCath
device after successful angioplasty. The average dwell time to deliver a dose of
20 Gy at 0.5 mm into the vessel wall was 418+/-64 seconds. The treatment was well
tolerated by most of the patients. In 79%, only one inflation cycle was required
to deliver the prescribed dose. There were two procedural device-related
complications (5.9%) and three minor procedural related in-hospital complications
(9%). CONCLUSIONS: CRT using a balloon catheter device, charged with a sodium
186Re perrhenate solution, seems feasible and safe. Clinical and angiographic 6
month follow-up data are pending.
PMID- 10785676
TI - Basal and reserve renal artery blood flow: effect of endothelium-dependent and
independent vasoactive agonists and radiographic contrast medium in two patients.
AB - This manuscript describes the results of invasive testing of renal artery and
arteriolar reactivity in two patients using a panel of endothelium-dependent and
independent agents including radiographic contrast medium. We found that the
renal artery and microcirculation dilate in response to graded acetylcholine
infusions and to bolus nitroglycerin infusion; the renal microcirculation dilates
in response to papaverine but constricts after adenosine and after radiographic
contrast medium. Future indications for this testing are briefly discussed.
PMID- 10785677
TI - Pseudoaneurysm: a late complication of the transradial approach after coronary
angiography.
AB - Percutaneous interventional procedures via the radial artery are now commonplace
and associated with minimal risks. The favorable anatomic relations of the radial
artery to the surrounding structures determine the safety of this approach. The
absence of major nerves and veins in the vicinity of the radial artery makes the
likelihood of arteriovenous fistulas extremely small. We report a case of
pseudoaneurysm of the radial artery, which was only clinically recognized three
months after coronary angiography.
PMID- 10785678
TI - Percutaneous vascular surgery after aortic valvuloplasty: initial clinical
experience.
AB - Percutaneous balloon aortic valvuloplasty can be associated with significant
vascular morbidity. Often, managing the access site prolongs the length of
hospitalization. Three patients were successfully treated with percutaneous
femoral arterial vascular surgery immediately after aortic valvuloplasty. These
patients did not suffer early or late vascular complications. The access site
care was dramatically improved when compared to our usual experience.
PMID- 10785679
TI - Endovascular AAA repair: management strategies for the iliac artery.
PMID- 10785680
TI - Intravascular Ultrasound Assessment of the Mechanisms and Predictors of
Restenosis Following Coronary Angioplasty.
AB - Restenosis occurs after 30% to 50% of transcatheter coronary procedures; its
mechanisms remain incompletely understood. Intravascular ultrasound (IVUS)
studies were analyzed in 360 non-stented native coronary artery lesions in which
follow-up quantitative angiographic and/or IVUS data was available. Pre
intervention, post-intervention, and follow-up, the external elastic membrane
(EEM) and lumen cross-sectional areas (CSA) were measured; plaque + media (P + M
= EEM - lumen CSA), and cross-sectional narrowing (CSN = P + M/EEM CSA) were
calculated. The anatomic slice selected for serial analysis had an axial location
within the lesion at the smallest follow-up lumen CSA. At follow-up, 73% of the
decrease in lumen CSA was due to a decrease in EEM CSA; 27% was due to an
increase in P+M CSA. The change in lumen CSA correlated more strongly with the
change in EEM CSA than with the change in P + M CSA. The change in EEM CSA was
bidirectional; 47 lesions (22%) showed an increase in EEM CSA. Despite a greater
increase in P + M CSA, lesions exhibiting an increase in EEM CSA had (1) no
change in lumen CSA, (2) decreased restenosis, and (3) a 49% frequency of late
lumen gain. The independent clinical, angiographic, and IVUS predictors of
angiographic restenosis (3 50% diameter stenosis at follow-up) were the IVUS
reference lumen CSA, angiographic pre-intervention diameter stenosis, and post
intervention IVUS CSN. Restenosis appeared to be determined primarily by the
direction and magnitude of the change in EEM CSA. An increase in EEM CSA was
adaptive while a decrease in EEM CSA contributed to restenosis. The most powerful
predictor of restenosis was the IVUS post-procedural CSN. The importance of the
post-procedural CSN was related to the change in EEM CSA as a mechanism of
restenosis.
PMID- 10785681
TI - Angiographic Results and Late Clinical Outcomes Utilizing a Stent Synergy (Pre
Stent Atheroablation) Approach in Complex Lesion Subsets.
AB - To investigate the strategy of OdebulkingO in complex lesions before stent
implantation (stent synergy) to improve procedural safety and achieve optimal
acute and long-term results, we reviewed our experience in 389 patients with 504
lesions undergoing a combined stent procedure (45% rotational atherectomy, 24%
laser angioplasty, 20% directional atherectomy, and 11% transluminal extraction
atherectomy before stent implantation). Procedural success was achieved in 94.5%,
with 4% major ischemic complications (1.1% death, 1.9% Q-wave myocardial
infarction, and 2.3% emergency coronary artery bypass surgery). Overall, subacute
stent thrombosis occurred in 1.5% of patients. Target-lesion revascularization
during follow-up was required in 9.8% of the patients. We conclude that a
strategy of selective pre-stent atheroablation in complex lesion subsets results
in excellent procedural outcomes with acceptable complications and favorable long
term results.
PMID- 10785682
TI - Carotid Stent-Assisted Angioplasty: Preliminary Technique, Angiography, and
Intravascular Ultrasound Observations.
AB - Currently, surgical carotid endarterectomy has been the standard therapy for
symptomatic and asymptomatic patients with significant carotid artery stenoses.
However, there are high surgical risk and other patient subsets, wherein a
Olesser invasiveO catheter-based procedure may be worthwhile. Carotid stent
assisted angioplasty (CSSA) is a percutaneous interventional treatment approach
for appropriately selected patients with common and internal carotid artery
lesions. The present report discusses preliminary technique-related,
angiographic, and intravascular ultrasound observations of CSSA. Five symptomatic
patients (with six carotid stenoses) with other co-morbid states were treated by
a multidisciplinary team under the aegis of an approved protocol using
conventional equipment and available Palmaz tubular slotted stents. On-line
quantitative angiography and intravascular ultrasound imaging was performed to
guide stent insertion and monitor results. There were no procedure-related
complications and angiographic results were excellent (final mean diameter
stenosis 5%). Intravascular ultrasound imaging was feasible and safe. In two
cases, the findings obtained from ultrasound images assisted in subsequent
operator decisions. Thus far, there have been no additional clinical sequelae in
these patients (@ 30 days). This preliminary experience with CSSA indicates that
interventional neurovascular therapies may provide a useful alternative for
selected patients requiring endoluminal reconstruction of carotid stenoses.
Extensive additional studies are required to establish the appropriate clinical
application of this technique.
PMID- 10785683
TI - Retrospective Comparison of a Strategy of Primary Coronary Angioplasty versus
Intravenous Thrombolytic Therapy for Acute Myocardial Infarction in a Community
Hospital without Cardiac Surgical Backup.
AB - Recent studies have demonstrated the benefit of primary percutaneous coronary
angioplasty (PTCA) for the emergency treatment of acute myocardial infarction. We
retrospectively examined our experience in performing primary PTCA in a community
hospital without in-hospital surgical backup. Only highly experienced angioplasty
operators participated, and patients were immediately transferred to a tertiary
care referral hospital following primary angioplasty and stabilization. A total
of 102 patients received PTCA at the community hospital during the study period.
Forty received PTCA for cardiogenic shock or for rescue angioplasty. The
remaining 62 patients (the Primary Angioplasty Group) were compared with a
matched group of patients who received thrombolytic therapy during the same time
period (the Thrombolytic Therapy Group). Angioplasty was angiographically
successful in 96% and TIMI-3 grade blood flow was achieved in 85% of patients who
received PTCA. There were no significant differences between the two groups in
terms of in-hospital complications. The duration of hospital stay was
significantly less in the Primary Angioplasty Group as compared with the
Thrombolytic Therapy Group (median = 4 vs. 6 days, p = 0.005), as was the
duration of intensive care unit stay (median 1 vs. 2.5 days, p = 0.001). Thus,
under carefully controlled conditions, primary angioplasty for acute myocardial
infarction in a community hospital without in-hospital cardiac surgery is an
effective and more efficient alternative to thrombolytic therapy.
PMID- 10785684
TI - Percutaneous Inoue-Balloon Mitral Commissurotomy in Patients with Coexisting
Moderate Mitral Regurgitation, and Severe Subvalvular Disease and/or Mitral
Calcification.
AB - The present study examined the safety and immediate and late outcome of 12
patients with coexisting moderate (angiographic grade 2+) mitral regurgitation
and significant subvalvular disease and/or calcified mitral valves (group 1)
after percutaneous balloon mitral commissurotomy (BMC) and compared the results
with 64 patients without these adverse valve features (group 2). BMC produced a
significantly smaller echocardiographically determined mitral valve area
improvement in group 1 compared with group 2 (from 0.7 +/- 0.2 cm2 to 1.3 +/- 0.3
cm2 vs. 0.8 +/- 0.2 cm2 to 1.7 +/- 0.4 cm2, respectively, p < 0.05). Similarly,
compared with group 2, less patients in group 1 obtained an optimal valvuloplasty
outcome defined as a 3 50% increase in mitral valve area or a final valve area of
3 1.5 cm2 without final 3 3 grade angiographic mitral regurgitation (75% vs. 95%,
p < 0.05). There was, however, no severe (3 angiographic grade 3+) mitral
regurgitation in group 1 compared with 1 in group 2 (p = NS). At a mean follow-up
of 19 +/- 14 months, there were no deaths or strokes. Restenosis was noted in 4
patients; 3 in group 1, and 1 in group 2. We conclude that BMC is safe and
effective in patients with pre-existing moderate mitral regurgitation and severe
subvalvular disease and/or significant mitral calcification with minimal risk of
creating severe mitral regurgitation. The valve area improvement was, however,
substantially smaller and the restenosis rate higher than those without moderate
mitral regurgitation and favorable valve anatomy.
PMID- 10785685
TI - Exogenous Fibronectin to Prevent Neointimal Hyperplasia after Balloon
Angioplasty.
AB - This study examined the effect of fibronectin to prevent restenosis in a
microswine model after balloon angioplasty of the right iliac artery. Immediately
following angioplasty, fourteen hypercholesterolemic microswines were randomized
to receive fibronectin (223.5 mg, n = 8) or saline containing albumin (75.6 mg, n
= 6). At 60-days post-angioplasty, the angioplasty-injured and intact
contralateral arteries were examined with angiography and histopathology. With
angiography, there was no significant difference in the luminal diameters of
angioplasty arteries compared with the intact contralateral vessels. Histological
examination of angioplasty-injured vessels showed neointimal hyperplasia. The
intimal areas of angioplasty-injured vessels, in the placebo and fibronectin
groups, were much larger than the areas of their contralateral vessels
(fibronectin 287 +/- 160 vs. 138 +/- 88 um2, p = 0.018; and the placebo (1,245 +/
1,567 vs. 248 +/- 219 um2, p = 0.041). Mean total cholesterol levels of both
groups were maintained at levels > 400 mg/dl throughout the study period.
CONCLUSION: At sixty days after balloon angioplasty injury: 1) fibronectin did
not only not prevent neointimal hyperplasia, in some animals, it increased
neointimal growth; and 2) angiographic results were not sensitive enough to
quantify changes observed in histologic findings.
PMID- 10785686
TI - Bail-Out of Stent Jail: Stent Delivery Through Stent Struts.
AB - Stent deployment in a lesion with a large side branch is an example of the
potential limitation of intracoronary stents, especially the Palmaz-Schatza stent
with its tubular slotted design. This case study describes a patient in whom a
Palmaz-Schatz stent of excessive length covered the origin of a side branch
(Ostent jailO). Thrombus developed in the jailed branch as well as in the main
vessel, causing abrupt vessel closure and impending acute myocardial infarction
within one hour after the procedure. This complication was successfully managed
by emergency repeat angioplasty and implantation of a Micro Stenta on both
branches, i.e. in the main vessel distal to the Palmaz-Schatz stent and in the
side branch through the struts of the Palmaz-Schatz stent.
PMID- 10785687
TI - Right Ventricular Pseudoaneurysm Following Endomyocardial Biopsy.
AB - Ventricular perforation is an unusual complication after endomyocardial biopsy in
heart transplanted patients. We report a case of asymptomatic right ventricular
perforation and pseudoaneurysm formation, secondary to endomyocardial biopsy,
diagnosed by angiography. The spontaneous obliteration of the pseudoaneurysm was
observed.
PMID- 10785688
TI - Rotational Atherectomy for Resistant Anastomotic Saphenous Vein Bypass Graft
Stenosis.
PMID- 10785689
TI - Invasive Electrophysiologic Procedures at Peripheral Medical Sites.
PMID- 10785690
TI - The Evolving Health Care System and Managed Care: The Effects on the Field of
Electrophysiology.
PMID- 10785691
TI - Data Management, Outcomes Assessment and Information in Cardiovascular Practice.
PMID- 10785692
TI - Practice Management Polonaise: A Work in Progress.
PMID- 10785693
TI - Acute Luminal Gain after Stenting: Comparison of Gianturco-Roubin and Palmaz
Schatz Stents.
AB - The Gianturco-Roubin stent has an open coil structure with a clamshell
configuration and a relatively large distance between its transversely parallel
struts. This stent design results in a low metallic surface area but may possibly
also lead to more vessel recoil and less acute luminal gain than that obtained
with the more rigid Palmaz-Schatz stent. The present study compares the acute
angiographic results obtained with both stents. Quantitative coronary
arteriography was performed in 77 patients in whom one of the following was
successfully implanted: 1) a Palmaz-Schatz stent (n = 27), 2) a normally sized (n
= 25) Gianturco-Roubin stent (n = 25), 3) a one-size oversized Gianturco-Roubin
stent (n = 30). Diameter stenosis after stenting was greater in the patients with
a normally sized Gianturco-Roubin stent (28 +/- 2%) than in those with a Palmaz
Schatz stent (18 +/- 1.2%, p < 0.05). This difference was in part attributed to a
more important acute luminal loss due to elastic recoil and plaque protrusion
with Gianturco-Roubin stents (25 +/- 2%) compared with Palmaz-Schatz stents (11
+/- 1.5%, p < 0.0001). However, in the patients with an oversized Gianturco
Roubin stent acute gain was similar to that obtained with Palmaz-Schatz stents
(50 +/- 3.2% vs. 48 +/- 3%, p=0.68) and residual stenosis (20 +/- 2%) was less
than that with a normally sized Gianturco-Roubin stent (p < 0.05). In the
patients with an oversized Gianturco-Roubin stent the actual size during
deployment (109 +/- 2.9% of the reference diameter) was smaller than the nominal
size (122 +/- 1.7%). Thus, one-size oversizing of the Gianturco-Roubin stent
corrects for the smaller actual than nominal diameter of this stent. It also
compensates for the greater recoil observed with this stent and leads to similar
acute diameter gain as that obtained with a Palmaz-Schatz stent without causing
an excessive coronary artery stretching.
PMID- 10785694
TI - Quality Determining Parameters of Balloon Angioplasty Catheters.
AB - The investigations carried out on balloon angioplasty catheters using a parameter
test unit allow an objective comparison and a qualitative assessment of catheter
brands with respect to their stenosis passability. The design of the test unit
allows the measure of other parameters important for clinical practice, such as
pushability and trackability. Altogether 8 over-the-wire and 10 monorail
catheters from 7 different manufacturers were investigated by our study. Between
modern over-the-wire and monorail systems there exists no fundamental difference
in passage capability. In some brands of catheter the stenosis model shows no
increase in the amount of thrust required, even after repeated inflation; this is
accountable to the good folding properties of the balloon. Angioplasty balloons
made of less overstretchable or thinner material yielded the best results. The
fact that changes in balloon quality may result from pre-inflation should carry
weight in discussions concerning the reuse of catheters. The measurement results
are useful for the correct selection of a catheter appropriate to the therapy
task at hand.
PMID- 10785695
TI - The Utility of Unipolar Electrogram Recording for Catheter Ablation of Accessory
Pathways During Atrial Fibrillation.
AB - INTRODUCTION: Atrial fibrillation, a commonly occurring rhythm in patients with
manifest accessory pathways, may prevent the usual mapping criteria for
successful catheter ablation from being obtained. Unipolar electrogram recordings
may be of value in this situation. METHODS: Unipolar recordings were obtained
during atrial fibrillation in one patient with a manifest left-sided accessory
pathway, and another patient with a septal accessory pathway with Mahaim-like
properties. The timing of the intrinsic deflection, and the presence of a QS
complex, were utilized as criteria to define the successful ablation site.
RESULTS: Successful ablation of the accessory pathways was achieved during atrial
fibrillation. CONCLUSIONS: The use of unipolar recordings can aid successful
catheter ablation of the accessory pathways during atrial fibrillation, giving
added information to the bipolar electrograms.
PMID- 10785696
TI - Balloon Angioplasty of Lesions Beyond Extremely Angulated Bends.
AB - Angioplasty of stenosis beyond severely angulated bends (acute angle less than
60!) can be technically difficult. In addition to the difficulty traversing these
severe bends with a guidewire, once crossed, even the lowest profile over-the
wire balloon catheter may not advance around these severe angulations. The
utility of fixed-wire balloon catheters is often limited by prolapse of the
distal wire tip. We describe a technique of shaping a fixed-wire balloon catheter
to prevent wire prolapse while traversing severely angulated bends and its
successful use in two consecutive cases where conventional methods failed.
PMID- 10785697
TI - Myocardial Bridging May Predispose to Coronary Perforation During Rotational
Atherectomy.
PMID- 10785698
TI - Balloon Mitral and Aortic Valvuloplasty in Mirror-Image Dextrocardia.
AB - Three patients of mirror-image dextrocardia were subjected to balloon
valvuloplasty at our institute. One patient had severe pliable rheumatic mitral
stenosis (MS), another had severe calcific rheumatic MS and the third had
moderate rheumatic MS and severe rheumatic aortic stenosis (AS). Necessary
modifications in the standard septal puncture technique, Inoue mitral
valvuloplasty technique, and Cribier aortic valvuloplasty technique were done
keeping unusual anatomy of mirror-image dextrocardia in account to dilate mitral
and aortic stenosis successfully. Acute hemodynamic results were satisfactory and
no complications encountered. This report illustrates feasibility and safety of
balloon mitral and aortic valvuloplasty in the complex cardiac anatomy of situs
inversus totalis.
PMID- 10785699
TI - Evaluation of a New Approach for Perfusing Myocardial Tissue.
PMID- 10785700
TI - Selection of a Consultant for Your Cardiovascular Practice N Caveat Emptor.
PMID- 10785701
TI - Stenting of the Infarct-Related Artery During Complicated Angioplasty in Acute
Myocardial Infarction.
AB - The aim of this study was to assess safety and efficacy of coronary stenting as a
strategy for improving PTCA suboptimal angiographic result. From March 1993 to
December 1995, 104 patients underwent PTCA during acute myocardial infarction.
Unplanned coronary stenting was required in 66 pts (63.5%). Procedural success
was obtained in 64 pts (97%). Two patients had an unsuccessful stenting
procedure: one patient for a suboptimal stent deployment and another for LAD
reocclusion requiring emergency CABG (1.5%). Palmaz-Schatz stents were used in 60
pts (91%) and AVE micro-stent in 6 pts (9%). During the hospital course, subacute
reocclusion of the vessel occurred in 3 pts (4.6%); one patient underwent a
successful rePTCA while the other two underwent CABG. Two patients had vascular
groin complications requiring surgical repair of the femoral artery. During
hospitalization, one patient underwent elective CABG for early residual
myocardial ischemia. At seventy-two hours from PTCA, one patient (1.5%) died as a
result of intestinal infarct. Six months survival rate was 98.3% for 59 pts
discharged alive from our department. Ten pts were symptomatic during the follow
up: One patient underwent PTCA on another vessel and the other underwent CABG for
a multivessel disease. CABG was used in one patient who presented residual silent
ischemia in multivessel coronary artery disease. At six months, the first group
of patients (18 pts) underwent planned coronary angiography: Vessel patency was
present in 17 patients. One patient had an asymptomatic reocclusion of the
treated vessel. This study shows a good angiographic result obtained with
intracoronary stenting during primary or rescue PTCA of the infarct-related
artery. It does not appear to increase major in-hospital adverse events and may
reduce the need for surgical revascularization, reducing in-hospital mortality
rate and favorably affecting LVEF.
PMID- 10785702
TI - Palmaz-Schatz Coronary Stent Implantation Without Intravascular Ultrasound and
Without Subsequent Anticoagulation: Clinical Outcome.
AB - OBJECTIVES: To determine the safety and efficacy of antiplatelet therapy alone in
a selected group of patients following coronary stenting. BACKGROUND: Coronary
stent implantation is an effective treatment for abrupt closure, and can also
reduce the restenosis rate following percutaneous transluminal coronary
angioplasty. However, anticoagulation therapy following stent implantation is
associated with a significant incidence of vascular complications and subacute
stent thrombosis. METHODS: Between February and November 1994 we implanted 62
Palmaz-Schatz stents in 50 patients with an optimal angiographic result following
stent deployment. In these patients, intravascular ultrasound was not used, and a
regimen of aspirin 100 mg daily indefinitely and ticlopidine 250 mg twice daily
for 3 months was started without anticoagulation. RESULTS: Of these 50 patients
(10 females : 40 males, mean age 63 +/- 12 years, LVEF 64 +/- 10%), 39 (78%) were
stented for a suboptimal angiographic result post angioplasty, 2 (4%) received
stents as a bailout procedure, and 9 (18%) were stented electively. Average
hospital stay following stent implantation was 3.7 +/- 3.0 days. After a mean
follow-up period of 140 +/- 70 days, there were no instances of stent occlusion,
death, stroke, need for coronary bypass surgery, Q-wave myocardial infarction or
femoral artery pseudoaneurysm. There was 1 case (2%) of significant puncture site
hemorrhage. CONCLUSIONS: Immediate angiographic appearance after stent
implantation can be used to define patients at low risk of stent thrombosis who
do not require anticoagulation and can safely be discharged early from the
hospital.
PMID- 10785703
TI - Gender Differences in Patients Referred for Electrophysiology Procedures.
AB - Gender differences are prevalent in cardiology and particularly in patients who
have undergone coronary artery bypass surgery and percutaneous transluminal
coronary angioplasty. The purpose of this study was to determine whether similar
gender differences are present in electrophysiology. Eight-hundred seventy-three
patients were identified from the OEP ManagerO database over approximately a two
year period at North Shore University Hospital. Overall, the majority of patients
referred for invasiveive electrophysiology procedures were men (67 percent). A
higher percentage of men had coronary disease despite the type of study/implant.
There was a relatively equal distribution of men and women who underwent head-up
tilt table testing (47 and 53 percent respectively). We conclude that gender
differences are present in electrophysiology studies and that further studies are
necessary to determine whether a bias exists in this field.
PMID- 10785704
TI - Dislodgement of Intracoronary Thrombus During Angiography in a Patient with
Unstable Angina Pectoris.
AB - A patient with unstable angina pectoris in whom thrombus release from
intracoronary lesion was seen during angiography is described. The event resulted
in improvement of vessel patency and resolution of ischemic symptoms. To our
knowledge, only two similar cases have been reported in English literature since
1966.
PMID- 10785705
TI - Congenital Left Ventricular Septal Diverticulum: Angiographic Recognition and
Clinical Significance.
PMID- 10785706
TI - Coronary Stenting in Vessels with Marked Proximal Tortuosity Using a Sport Wire:
Advantages and Pitfalls.
AB - In this report two patients are described in whom successful deployment of a
coronary stent was achieved in a very tortuous coronary artery. Deployment was
performed using a special extra-support wire that straightened the proximal
segment of the artery and provided the support for stent advancement. The
mechanical straightening of the artery induced marked narrowing that did not
respond to intracoronary nitroglycerin but disappeared after withdrawal of the
wire.
PMID- 10785707
TI - Strategy Retreat N An Important Tool for Your Practice.
PMID- 10785708
TI - Sonographic and Angiographic Features of Intramural Hematoma as a Cause of Failed
Coronary Angioplasty.
AB - A characteristic feature of a specific type of dissection after PTCA was observed
in seven cases with severe obstruction of the vessel segments proximal and/or
distal to the dilatation site. The underlying cause in the absence of an
angiographically visible dissection flap was revealed by intravascular
ultrasound. The obstruction was caused by an extraluminal obstruction by an
echodense mass increasing in size with time, and without a dissection flap even
as assessed by intravascular ultrasound. This phenomenon was interpreted as an
intramural hematoma extending between media and adventitial border of the vessel.
In six of seven cases, bailout therapy by either stenting or redilatation and
creation of a typical dissection flap relieved the vessel obstruction. In one
case of extension of the hematoma into the left main coronary artery, CABG was
performed. Intravascular ultrasound provided a conclusive insight into the
underlying morphology of failed PTCA in cases without angiographic features of a
dissection. It helped in deciding and controlling the bailout strategy, which was
the stenting of the entry into the hematoma at the initial dilatation site.
PMID- 10785709
TI - Local Angiopeptin Delivery Using Coated Stents Reduces Neointimal Proliferation
in Overstretched Porcine Coronary Arteries.
AB - BACKGROUND: Systemic administration of angiopeptin has been shown to inhibit
myointimal thickening after arterial injury in several animal species. METHODS
AND RESULTS: To explore to what extent high and long-lasting local concentrations
of angiopeptin influence the healing process after vascular injury, tantalum
balloon-expandable stents were first coated with a polymer loaded with
angiopeptin 250 ug. Implantation of these stents in porcine coronary arteries
resulted in tissue concentrations of 10.7 pg/ml wet weight in the stented
arterial segment 24 hours after stent implantation, gradually declining to 2.0
pg/ml wet weight at day 8. Finally, 20 pigs were randomly treated with either an
angiopeptin-loaded or a blank-coated stent. At baseline, the angiographic
parameters were similar between both groups but, after 6 weeks, the minimal
luminal diameter of the stented arterial segment was larger in the angiopeptin
treated pigs when compared to controls (2.20 +/- 0.57 mm vs 1.57 +/- 0.68 mm, p <
0.01) This angiographic finding was confirmed by post-mortem morphometry where
the respective lumen area values were 1.00 +/- 0.54 mm2 and 0.43 +/- 0.28 mm2 (p
< 0.01). CONCLUSION: Polymer coated stents can be loaded with angiopeptin, which
after implantation in porcine right coronary arteries result in high local tissue
concentrations gradually declining over more than 8 days. These high local
concentrations inhibit myointimal proliferation induced by
poly(organo)phosphazene coated overstretched stents.
PMID- 10785710
TI - Usefulness of Renal Arteriography Following Coronary Angiography.
AB - PURPOSE: To determine the usefulness of renal angiography in patients that
underwent coronary angiography because of clinically suspected coronary artery
disease. METHODS: Selective arteriography of the renal arteries was performed in
205 patients (mean age 60 +/- 8 years; 80% males) at the time after coronary
angiography with the use of right coronary Judkins catheter. RESULTS: Two-hundred
renal angiographies were judged technically adequate. Average additional
fluoroscopy time was 3 +/- 2 min and 30 +/- 8 ml of additional contrast medium
was used. Coronary artery disease (3 50% narrowing) was found in 158 (79%). Renal
arterial disease was found in 17 (8.5%) patients. Reduction in lumen diameter was
< 50% in 11 patients (5.5%) including 3 patients with bilateral stenosis, and 3
50% in 6 patients (3%). The only clinical variable associated with renal artery
stenosis was peripheral vascular disease. CONCLUSION: There is no justification
for doing routine renal angiography for patients undergoing coronary
arteriography because the prevalence of severe renal artery stenosis is low.
PMID- 10785711
TI - Rate-Responsive Pacing Mimicking Ventricular Tachycardia.
AB - We describe 2 patients with rate-responsive permanent ventricular pacemakers who
developed upper rate pacing while at rest. In one patient this occurred during
chest physiotherapy and in the other as a result of muscle fasciculations. In
both cases, the paced rhythm was misdiagnosed as ventricular tachycardia.
Reprogramming of the pulse generators prevented further inappropriate rapid
pacing.
PMID- 10785712
TI - Rescue AVE Stent Placement for Left Anterior Descending Coronary Artery Occlusion
During Diagnostic Angiography.
AB - In a 65-year-old male with coronary artery disease a proximal occlusion of the
left anterior descending coronary artery occurred during diagnostic coronary
angiography. The most likely cause was an occlusive dissection. This resulted in
acute myocardial ischemia and immediate cardiogenic shock. The decision was made
to proceed to emergency percutaneous transluminal coronary angioplasty (PTCA).
After balloon dilatation, a 3.5 mm AVE stent was deployed successfully at the
site of the lesion. This resulted in a satisfactory angiographic result and an
immediate improvement of the clinical picture. We conclude that placement of an
AVE stent can provide a means for restoring flow in case of acute occlusive
dissection during coronary angiography.
PMID- 10785713
TI - TEC Before Stenting in Acute Myocardial Infarction.
PMID- 10785714
TI - Five Not So Easy Pieces N The Business of Practice Mergers and Acquisitions.
PMID- 10785715
TI - Intracoronary Stenting for Restenosis: Long-Term Follow-up: A Single Center
Experience.
AB - One-hundred thirteen stents (78 Wallstents, 29 Palmaz-Schatz and 6 Wiktor) were
implanted in 106 patients aged 63 +/- 5 years to treat a restenosis following
previous angioplasty in a native coronary artery (86 cases) and in a venous graft
(20 cases). Implantation was technically possible in all cases. The native
vessels had a mean reference diameter of 3.3 +/- 0.3 mm and their mean minimal
lumen diameter increased from 1.2 +/- 0.3 mm before angioplasty to 2.8 +/- 0.8
after stent implantation. The venous grafts mean reference diameter was 4.4 +/-
0.7 mm and their mean minimal lumen diameter increased from 1.3 +/- 0.4 mm before
angioplasty to 4.0 +/- 0.7 mm after implantation. Percentage stenosis in the
native arteries and in the venous grafts were respectively 78 +/- 13% and 69 +/-
14% before angioplasty and 24 +/- 8% and 22 +/- 8% after stent implantation.
Complications at 6 months, presented as a ranking scale with 100% follow-up rate
were, overall, of 20% clinical events (4% deaths, 6% myocardial infractions, 2%
coronary artery bypass grafting and 8% re-angioplasty). Angiographic
complications were of 8% subacute thrombosis and 19% restenosis and chronic
occlusions. Long-term, at 65 +/- 9 months, clinical (86% follow-up) and
angiographic (74% follow-up) showed that only a further 9% clinical events and
14% restenosis (12% of them between 6 and 12 months) occurred after 6 months. At
an estimated follow-up time of 104 months, 70% patients remain event-free and the
survival rate is 95%. In conclusion, stent implantation in the treatment of
restenosis following conventional balloon angioplasty is a valid strategy with
good long-term results.
PMID- 10785716
TI - Primary PTCA in a Rural Hospital.
AB - The results of primary percutaneous transluminal coronary angioplasty (PTCA) to
treat patients with acute myocardial infarction in a rural hospital were
reviewed. Thirty-five patients presenting with acute myocardial infarction,
including 40% considered high risk, were treated using the strategy of primary
angioplasty. Following cardiac catheterization, two patients were found to have
anatomy deemed unsuitable for primary angioplasty and subsequently underwent
urgent coronary artery bypass graft (CABG) surgery. Thirty-three patients
underwent primary angioplasty with a procedural success rate of 94%. Procedural
success was defined as reduction of the infarct arteries stenosis to less then
50% and the establishment of TIMI-III flow. Six percent of these patients
required urgent CABG surgery because of unsuccessful angioplasty. In-hospital
cardiac mortality was 3%. Six month follow-up was achieved for all patients.
There were no cardiac deaths following hospital discharge. Recurrent ischemia
occurred in 17% of the patients. Favorable in-hospital and late results were
achieved. This review indicates that the strategy of primary angioplasty to treat
myocardial infarction may be successfully applied in a rural setting.
PMID- 10785717
TI - Coronary Angioplasty in the Treatment of Post-Cardiac Transplant Coronary Artery
Disease.
AB - Accelerated coronary disease following cardiac transplantation is an important
obstacle to long-term survival and its management is not well defined. Coronary
angioplasty has been proposed as a palliative treatment in some patients with
discrete proximal lesions. Of 172 patients who underwent cardiac transplantation
between April 1983 and November 1995, 8 underwent subsequent coronary angioplasty
of 11 lesions. The majority was performed in asymptomatic patients, 5 for
angiographic abnormalities alone, and 3 for documented painless ischemia. Primary
angiographic success was obtained in 91% (10/11) of lesions dilated.
Complications included 1 acute occlusion and 1 arteriovenous fistula. Three
patients died, 1, 8 and 10 months after angioplasty. After an average of 36-month
follow-up, 4 (out of 8) patients had no cardiac event (myocardial infarction,
second angioplasty, retransplantation or death). Thus, coronary angioplasty can
be performed with acceptable risk in selected patients with cardiac
transplantation.
PMID- 10785718
TI - Intravascular Stenting in a Female Patient with Spontaneous Coronary Dissection
and Von WillebrandOs Disease.
AB - We report a case of spontaneous coronary dissection occurring in a 46-year-old
women affected by von WillebrandOs disease presenting with anterior myocardial
infarction. The patient was treated with thrombolytic therapy and stent
implantation. We believe that in patients with single vessel spontaneous coronary
dissection and unstable clinical condition, coronary stenting may provide an
alternative treatment in place of coronary surgery.
PMID- 10785719
TI - Spontaneous Resolution of Pseudo-Narrowing After Coronary Artery Stenting.
AB - Pseudo-narrowings are due to straightening effect of the guidewire on a tortuous
portion of the coronary artery. We described a case of its occurrence after
deployment of intracoronary stents which persisted after withdrawal of the
guidewire and balloon into the guiding catheter. Spontaneous resolution occurred
within 4 weeks of the procedure.
PMID- 10785720
TI - Stent Placement for Coronary Artery Disease in a Cardiac Transplant Patient.
PMID- 10785721
TI - Tracking Market Movement to Managed Care.
PMID- 10785723
TI - Transcatheter Occlusion of Patent Ductus Arteriosus: State of the Art.
PMID- 10785722
TI - Successful Radiofrequency Catheter Ablation in a Patient with Wolff-Parkinson
White Syndrome after Unsuccessful Surgical Repair.
AB - Radiofrequency catheter ablation has found wider applications for the treatment
of supraventricular and ventricular tachycardias. We present a case report of a
30-year-old woman with a history of Wolff-Parkinson-White syndrome and surgical
excision of both septal and paraseptal accessory pathways. Five years post
surgery, she presented with recurrent supraventricular tachycardia. Subsequently,
she underwent successful radiofrequency catheter ablation of a right posterior
septal accessory pathway. After 1.8 seconds of 20 watts of radiofrequency energy
delivered to the right posteroseptal region (coronary sinus os), orthodromic
supraventricular tachycardia was terminated. After completion of a full
100Dsecond application, there was no evidence of either manifest or concealed
accessory pathways, and no supraventricular tachycardia upon restudy. This study
emphasizes the ease and facility of the percutaneous catheter ablation techniques
that are now employed as compared to the open chest surgical approach.
PMID- 10785724
TI - Transcatheter Closure of Atrial Septal Defects: Role of Buttoned Devices.
PMID- 10785726
TI - Should Balloon Angioplasty be Used as a Treatment of Choice for Native Aortic
Coarctations?
PMID- 10785725
TI - Balloon Dilatation of Discrete Membranous Subaortic Stenosis.
PMID- 10785727
TI - Role of Stents in the Management of Congenital Heart Defects.
PMID- 10785728
TI - Critical Pulmonary Stenosis in the Neonate: Role of Transcatheter Management.
PMID- 10785730
TI - Ultrasound as an Adjunct to Cardiac Interventions in Pediatric Patients.
PMID- 10785729
TI - Coil Embolization in the Management of Cardiac Problems in Children.
PMID- 10785731
TI - Is Unstable Angina a Contraindication to Intracoronary Stent Insertion?
AB - BACKGROUND: Percutaneous transluminal coronary angioplasty is associated with
higher rates of acute complications and restenosis when performed in the clinical
setting of unstable angina. Coronary stent insertion has been shown to reduce
restenosis when performed electively. The effect of unstable angina on clinical
outcome after stent deployment is currently unclear. OBJECTIVE: To compare the
clinical outcome after coronary stents inserted in patients with unstable and
stable angina. DESIGN: A retrospective analysis of all patients receiving Palmaz
Schatz stents electively or for sub-optimal angioplasty result in patients with
stable and unstable angina. PATIENTS: One-hundred fifty-seven patients received
178 Palmaz-Schatz stents electively or for the treatment of sub-optimal result.
Thrombolysis in Myocardial Infarction Study (TIMI) grade 3 flow was present in
all patients at the time of stent delivery. Unstable angina was defined as pain
at rest despite anti-anginal therapy (Braunwald class II, III). Eighty-three
patients (mean age 58 years) with unstable angina received 95 stents and 74
patients (mean age 57 years) with stable angina received 83 stents. MAIN OUTCOME
MEASURES: Subacute stent thrombosis (SAST), myocardial infarction (MI), need for
repeat angiography, coronary bypass graft surgery (CABG) and death. RESULTS: The
early complications (within 2 weeks) comparing the unstable and stable groups
respectively were: No deaths, SAST 3/83 (3.6%) vs. 2/74 (2.7%), MI 2/83 (2.4%)
vs. 2/74 (2.7%) and CABG 6/83 (7.2%) vs. 2/74 (2.7%). After 2 weeks no patient
had a MI or CABG. Clinical follow-up was continued up to 6 months. Two patients
in each group had repeat angiography for recurrent symptoms. One patient in the
stable group died from non-cardiac causes. CONCLUSIONS: There appears to be no
difference in the early or late clinical outcome of patients with unstable or
stable angina treated with coronary stent insertion when TIMI flow is normal at
the time of stent insertion.
PMID- 10785732
TI - Experimental Evaluation of a New Single Wire Stainless Steel Fishscale Coronary
Stent (Freedoma).
AB - Recent randomized clinical trials revealed a significant reduction in
angiographic restenosis rates when adjunctive stenting was performed after
conventional coronary balloon angioplasty. Current approved coronary stents are
however hampered by their rigidity, limiting their trackability in tortuous
vessels and furthermore, needing high pressure deployment for optimal vessel
apposition. New coronary stents are currently under development, using more
biocompatible metal alloys and/or designs which better align to the vessel wall
at moderate deployment pressures. We evaluated the safety, efficacy, angiographic
and histological effect of a new stainless steel fishscale designed stent
(Freedoma, Global Therapeutics, Co., USA) in a porcine coronary and peripheral
artery model. Implantation in the right coronary artery was successful in all 20
pigs. Control angiograms at 6 weeks follow-up demonstrated patent vessels and
morphologic evaluation showed only a mild fibromuscular neointimal response
resulting in an area stenosis of 28.7 +/- 0.18% and a mean neointimal hyperplasia
of 0.18 +/- 0.25 mm. Comparison with the Palmaz-Schatza coronary stent in a
porcine peripheral artery model demonstrated similar quantitative angiographic
and morphologic vessel analysis results. Also the morphometric data were
comparable. Area stenosis: Palmaz-Schatz: 37 +/- 0.24%, Freedom: 21 +/- 0.14%, p
= 0.07. Mean neointimal hyperplasia: Palmaz-Schatz: 0.33 +/- 0.24 mm, Freedom:
0.18 +/- 0.08 mm, p = 0.08. CONCLUSION: Freedom coronary stent implantation in a
porcine model resulted in a high procedural success without subacute thrombotic
occlusions, despite no further anticoagulation nor antiplatelet therapy. Six
weeks histopathological and morphometric evaluation demonstrated only a mild
fibromuscular neointimal hyperplasia.
PMID- 10785733
TI - QT Dispersion: Current and Future Clinical Role.
AB - QT dispersion calculated from the standard 12-lead ECG has emerged as a
noninvasiveive measurement of the degree of inhomogeneity in myocardial
repolarization. The studies evaluating predictive value of QT dispersion for
identification of patients at increased risk for serious ventricular arrhythmias
and sudden cardiac death have been conducted in multiple disease states and show
promising results. This review focuses on the conceptual evolution, currently
accepted methodology, and clinical and research applications of QT dispersion
measurements.
PMID- 10785734
TI - Intracoronary Stent Used in a Transplanted Heart.
AB - The development of occlusive cardiac allograft vasculopathy is different from
coronary artery disease in native vessels and treatment is still an unsettled
problem. We describe a case of a 53-year-old male who underwent heart
transplantation because of severe dilated cardiomyopathy. Based on myocardial
ischemia, coronary angiography was performed six years later. Significant two
vessel coronary artery disease had developed and was treated by coronary
angioplasty. Due to a suboptimal result, a Palmaz-Schatz stent was successfully
implanted in the left anterior descending artery. The patency of the stent was
demonstrated by ultrafast computed tomography and confirmed by control
angiography three months later.
PMID- 10785735
TI - Inoue-Balloon Pulmonary Valvuloplasty Using a OFree-FloatO Technique.
PMID- 10785736
TI - ItOs Not the Money N ItOs the Money!
PMID- 10785737
TI - The Philosophy of Physician Compensation During the Transition to Capitated Care.
PMID- 10785738
TI - Characteristics of an Ideal Stent Based Upon Restenosis Pathology.
PMID- 10785739
TI - Restenosis after Angioplasty N An Update on Relevant Animal Models.
PMID- 10785740
TI - Local Drug Delivery: The Development of a Drug Delivery Stent.
PMID- 10785741
TI - Local Drug Delivery for the Treatment of Thrombus and Restenosis.
PMID- 10785742
TI - Successful Coronary Interventions Performed with Argatroban Anticoagulation in
Patients with Heparin-Induced Thrombocytopenia and Thrombosis Syndrome.
AB - Patients with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS)
frequently have coincident vascular disease. Patients with HITTS who require
vascular procedures have often been excluded from vascular intervention because
intravascular procedures require heparin. Re-exposure to heparin places these
patients at great risk for reactivation of thrombosis related to HIT antibody. We
present our initial experience with an alternative anticoagulant to heparin,
argatroban in patients with HIT antibody who underwent 14 coronary interventions.
All 14 coronary lesions were treated successfully and no patient suffered an
HITTS-related or an argatroban-related complication.
PMID- 10785743
TI - Clinical and Angiographic Experience with Coronary Stenting Using Freedoma Stent.
AB - The immediate safety and efficacy and the 6 month clinical and angiographic
follow-up of a new fish-scale designed coronary coil stainless steel stent
(Freedoma) was assessed by a prospective study. During 1995, 169 patients were
treated on 177 vessels using 233 Freedom stents. Procedural indication for
stenting was a bail-out situation in 79 vessels, a suboptimal angioplasty result
in 62 vessels and a third restenosis after PTCA in 36 vessels. Procedural success
was achieved in 170 vessels (96%); in 162 patients (96%). Subacute thrombotic
occlusion occurred in one patient (0.6%). Acute myocardial infarction occurred in
7 patients (4.1%). Bleeding complications, necessitating blood transfusion
occurred in 6 patients (3.6%). There were two non-stent related deaths.
Recurrence of stent-related angina pectoris and/or a positive stress test
occurred in 10 pts (6.4%). Elective control angiography at 6 months was performed
in the first 85 patients. Stent restenosis of 3 50% diameter stenosis was found
in 14 patients (16.5%).
PMID- 10785744
TI - Intracoronary Stent Placement without Coumadin or Intravascular Ultrasound.
AB - Coronary stenting has been associated with the need for intravascular ultrasound,
increased anticoagulation, and increased length of stay. We evaluated the use of
ticlopidine and aspirin without ultrasound in 322 consecutive patients from
February 1995 through January 1996 who underwent intracoronary stenting with
adjunctive high pressure balloon angioplasty [mean peak atmospheres (ATM) = 15.9;
mean post-dilating balloon size = 3.4 mm]. Unstable coronary syndrome was the
admitting diagnosis in 66% of these patients. Post-stent anticoagulation
consisted of overnight heparin, followed by aspirin (325 mg daily) and
ticlopidine (250 mg twice daily) for 4 to 6 weeks. Among the 322 patients, 575
stents (Palmaz-Schatz Coronary Stents = 530; Palmaz-Schatz Biliary Stents = 33;
Gianturco-Roubin Stents = 12) were implanted in 338 coronary vessels (native
arteries = 316; saphenous vein grafts = 22). Twenty-three patients (7%) had multi
vessel stenting. Average length of stay following stenting was 1.6 days (average
overall hospital length of stay was 2.3 days), and 71% of patients were
discharged the next day. Follow-up of all 322 patients was performed by telephone
contact at least 30 days after discharge. During this period 1 (0.3%) acute
thrombosis and no subacute thrombosis occurred. In this series of patients,
coronary stent implantation using routine high pressure balloon post-dilatation N
without intravascular ultrasound N and a combination of aspirin and ticlopidine
was performed with no subacute thrombosis and a short length of stay.
PMID- 10785746
TI - Late Coronary Dissection Induced by a Coronary Stent: A Word of Caution about
Long-Term Effects of Coronary Stents.
PMID- 10785745
TI - Percutaneous Transluminal Coronary Angioplasty Through 5 French Diagnostic
Catheters.
AB - In 130 patients, coronary angioplasty (PTCA) with fixed wire balloons through 5
French (F) diagnostic catheters was performed immediately following diagnostic
coronary angiography. Patients with complex lesions or in whom the need for
alternative devices was likely such as stents were excluded. A total of 151
lesions were attempted. Primary success with 5F systems was achieved in 92% of
lesions. In 7 cases, the 5F system failed to cross the stenosis and a change to a
larger guiding catheter was necessary. Of these 7 cases, 6 could be dilated
successfully with 6 or 7F systems. In one patient in whom the fixed wire balloon
was not able to cross a subtotal stenosis of an obtuse marginal branch through
the 5F catheter, a Monorail system through a 6F guiding catheter failed as well.
The overall technical success rate was 96%. Cardiac complications occurred in 2%
of patients (3 patients with Q-wave myocardial infarction). Two other patients
(1.5%) with suboptimal PTCA results underwent bypass surgery. PTCA through small
diagnostic catheters is a valid alternative technique in selected patients. It is
safe and leads to high success rates. Advantages of this technique include 1)
less peripheral and coronary trauma; 2) enhanced patient comfort; 3) economical
advantages.
PMID- 10785748
TI - Unravelling of a Wiktor Stent by a High Pressure Non-Compliant Balloon N
Successful Nonsurgical Management.
PMID- 10785747
TI - Non-Surgical Repair of Abdominal Aortic Aneurysm.
AB - The conventional treatment of abdominal aortic aneurysm is surgical replacement
with a synthetic graft. Attempts have been made to treat these aneurysms using
stent mounted grafts with reasonable success, thus obviating the need for
surgery. However, certain problems like thromboembolism and the large profile are
yet to be overcome. We report a case of a 75-year-old man where an attempt to
repair a symptomatic abdominal aortic aneurysm was made using an endovascular
uncovered OwallO stent combined with endosaccular coil implantation.
PMID- 10785749
TI - Bailout Palmaz-Schatz Stenting for Iatrogenic Dissection of the Left Main
Coronary Artery.
PMID- 10785751
TI - Heart Institutes N Structures in Evolution.
PMID- 10785750
TI - The Evolution of Heart Institutes.
PMID- 10785752
TI - A Beta-Particle Emitting Radioisotope Stent for the Prevention of Restenosis.
PMID- 10785753
TI - Endovascular Irradiation in the Therapy of Intimal Hyperplasia.
PMID- 10785754
TI - The Need for Standardization Testing for Safety and Efficacy of Permanent Implant
Stents.
PMID- 10785755
TI - Gene Therapy for Restenosis.
PMID- 10785757
TI - Microsurgical Dilatation Concept: Animal Data.
PMID- 10785756
TI - Interventional Cardiology: How Will We Cope with the Next Century?
PMID- 10785759
TI - Multicentric Non-Randomized Experience with Cutting Balloon.
PMID- 10785758
TI - Cutting Balloon System Technology: The Engineering Perspective.
PMID- 10785760
TI - Angiographic and Clinical Outcome after Cutting Balloon Angioplasty.
AB - To evaluate the safety and efficacy of cutting balloon angioplasty, we reviewed
the early angiographic and clinical outcomes of 160 consecutive patients with 173
lesions undergoing this procedure. Angiographic core laboratory analysis was
available in 150 of these lesions. Eccentricity was the most common (49%)
unfavorable pre-procedural morphologic feature; other morphologic findings
included length 3 10 mm (28%), calcification (23%), angulation 3 45 degrees
(13%), irregularity (7%), ostial location (3%), and thrombus (1%). OStand-aloneO
cutting balloon angioplasty was performed in 106 (71%) lesions and an adjunct
balloon or new device was used in 44 (29%) lesions to treat a residual stenosis >
40% after cutting balloon angioplasty. The reference artery size was 2.80 +/-
0.42 mm. The minimal lumen diameter increased from 1.02 +/- 0.30 mm to 2.01 +/-
0.42 mm (p < 0.001) and the % diameter stenosis was reduced from 64 +/- 9% to 29
+/- 12% (p < 0.001). Angiographic success (< 50% diameter stenosis ) was obtained
in 145 (97%) lesions. The residual stenosis was higher in lesions treated with
stand-alone cutting balloon angioplasty than in those undergoing adjunct balloon
or new device angioplasty (31 +/- 10 versus 24 +/- 14; p = 0.0006). The average
cutting balloon:artery ratios in those lesions with and without dissections after
cutting balloon use (1.00 +/- 0.11 versus 0.97 +/- 0.13, respectively; p = 0.29).
A significant inverse relationship between the cutting balloon:artery ratio and
the final % diameter stenosis was noted (R = 0.33; p = 0.0003). There were no
major in-hospital complications after cutting balloon use. This series
demonstrates the safety and efficacy of cutting balloon angioplasty as an
alternative to conventional balloon angioplasty in patients with non complex
coronary artery disease. A multicenter, randomized comparison of cutting balloon
angioplasty with conventional balloon angioplasty for prevention of restenosis is
currently underway.
PMID- 10785761
TI - Cutting Balloon Angioplasty: A Japanese CenterOs Early Experience.
PMID- 10785762
TI - Cutting Balloon Catheter: Clinical Considerations and Challenges.
PMID- 10785763
TI - Mechanism and Role of Platelets in Ischemic Events: Action of Therapeutic Agents.
PMID- 10785764
TI - Platelet Integrin Glycoprotein IIb/IIIa Inhibitors: Opportunities and Challenges.
PMID- 10785765
TI - Heparin and Control of Bleeding Complications During Platelet Glycoprotein
IIb/IIIa Receptor Antagonist Therapy During Percutaneous Coronary
Revascularization.
PMID- 10785766
TI - Clinical Benefit within Patient Subgroups Receiving c7E3 Fab (Abciximab) During
Percutaneous Coronary Revascularization: Subgroup Analysis from the EPIC Trial.
PMID- 10785767
TI - The Economics of IIb/IIIa Therapy.
PMID- 10785768
TI - Antithrombotic Therapy after Stent Deployment.
PMID- 10785769
TI - Use of ReoPro in a Complex Case.
PMID- 10785770
TI - A Case of Stent Mania and Maximizing Costs? For What:Whom Should We Pay?
PMID- 10785771
TI - Cost-EffectiveUtilization of Abciximab During Coronary Angioplasty in the Setting
of Unstable Angina: A Case Study.
PMID- 10785772
TI - ReoPro Clinical Development: Future Directions and Therapeutic Approaches.
PMID- 10785773
TI - Frequency and Prognostic Importance of Creatine Phosphokinase Myocardial Isoforms
after Successful Balloon and New Device Coronary Angioplasty.
AB - The frequency and prognostic importance of subclinical myocardial necrosis after
new device coronary intervention is not known. To identify the frequency of CPK
MB release after balloon and single new device angioplasty in native coronary
arteries, we reviewed the course of 810 patients who underwent successful single
lesion, native vessel angioplasty using balloon angioplasty (N=174), Gianturco
Roubin stent placement for suboptimal angioplasty results (N=31), Palmaz-Schatz
stent deployment (N=320), directional coronary atherectomy (N=102), or rotational
atherectomy (N=183). All patients had serial measurements of CPK-MB isoenzymes 6
and 18D24 hours after coronary intervention; absolute CPK-MB levels were
determined by radioimmunoassay (normal assay < 4 ng/ml). CPK-MB isoenzymes were >
2 times normal (> 8 ng/dl) in 15.6% of procedures, > 3 times normal (3 12 ng/ml)
in 11.5% of procedures, > 4 times normal (3 16 ng/ml) in 8.6% of procedures, and
> 5 times normal (3 20 ng/ml) in 7.7% of procedures. CPK-MB elevation > 2 times
normal was more common in those undergoing directional atherectomy (20.8%) and
Gianturco-Roubin stent placement (34,4%) than in those undergoing balloon
angioplasty (11.7%). No significant differences were noted in patients undergoing
rotational atherectomy (13.2%) or Palmaz-Schatz stent placement (15.6%) than in
those undergoing balloon angioplasty. CPK-MB > 5 times normal occurred after 7.7%
of procedures, but did not vary significantly among the devices used in this
study. We conclude that CPK-MB elevations > 2 times normal are highest in
patients undergoing directional coronary atherectomy and ObailoutO use of the
Gianturco-Roubin stent. No significant differences in CPK-MB elevation were seen
in patients undergoing balloon angioplasty, Palmaz-Schatz stent deployment, or
rotational atherectomy. Identification of the prognostic importance of these CPK
MB elevations is currently under study.
PMID- 10785774
TI - Theoretical and Clinical Aspects of Slow Flow and No-Reflow Phenomenon.
PMID- 10785775
TI - Extraction Atherectomy vs. PTCA in Treating Saphenous Vein Graft Disease: Focus
on Embolization.
PMID- 10785776
TI - Reduction of Post-Procedural Cardiac Enzyme Release Following Coronary
Interventions.
PMID- 10785777
TI - Mechanical Alternatives to Thrombolytics and PTCA in Acute Ischemic Syndrome.
PMID- 10785778
TI - Transradial Artery Coronary Angioplasty and Stenting: History and Single Center
Experience.
PMID- 10785779
TI - Transradial Approach for Coronary Angiography.
PMID- 10785780
TI - Percutaneous Transradial Approach for Coronary Revascularization: What Have We
Learned?
PMID- 10785781
TI - Right Transradial Approach for Coronary Procedures: Preliminary Results.
PMID- 10785783
TI - Hemostasis after Radial Artery Cardiac Catheterization.
PMID- 10785782
TI - Operator Radiation Exposure in PTCA: Comparison of Radial and Femoral Approaches.
AB - In order to evaluate the radiation risk associated with PTCA from the right
radial approach, operator radiation exposure was prospectively measured in 138
patients (pts) undergoing PTCA from the radial artery approach and in 126
patients from the femoral artery approach. Standard overhead and side table lead
curtain shields were used in the femoral group and radial group I (66 pts). In
radial group II (72 pts), a movable floor shield was added to the procedure for
additional radiation protection. The external whole body dose was measured
monthly using film dosimeters. Dose per case and dose per minute of fluoroscopy
time were calculated. Operator external whole body dose was significantly higher
when PTCA is performed from the radial artery (13.5 +/- 2.1 mrem/case) as
compared to the femoral artery (8.8 +/- 1.3 mrem/case) approach (p <.01). This
increased radiation exposure was reduced to less than the femoral artery when the
movable floor shield is added to standard x-ray protection (3.3 +/- 2.3
mrem/case, p <.01 vs. femoral). Thus, PTCA can be performed from the radial
artery approach without increased operator radiation exposure.
PMID- 10785784
TI - Clinical Evaluation of Current Stent Deployment Strategies.
AB - BACKGROUND: Coronary stenting has been demonstrated to reduce the incidence of
abrupt closure and restenosis. However, intensive anticoagulation regimens have
increased the number of vascular complications and hospital length of stay.
Consequently, the potential long-term cost effectiveness of stenting has been
jeopardized by a significant increase in procedural and hospital costs. These
drawbacks have resulted in evaluation of reduced anticoagulation programs and
alternative access sites. METHODS: Access-site and anticoagulation strategies
were analyzed in 377 patients who had undergone coronary stenting. Four groups
were compared: 114 patients stented from the femoral artery and treated with
warfarin, 87 patients stented from the radial artery and treated with warfarin,
88 patients stented from the femoral artery and treated with ticlopidine and
aspirin anticoagulation, and 88 patients stented from the radial artery and
treated with ticlopidine and aspirin. RESULTS: Primary success was similar in all
groups. Subacute closure occurred only in the groups managed with warfarin.
Access-site complications occurred only in the groups with femoral access. Total
hospital and post-procedure length of stay and total hospital charge were
significantly less in the ticlopidine groups. The radial/ticlopidine group was
the most cost-effective. CONCLUSIONS: Ticlopidine/aspirin therapy following
coronary stenting from either the femoral or radial approach reduced hospital
length of stay and hospital charge without subacute closure. Access-site
complications were not reduced by femoral/ticlopidine strategy but were
eliminated by the radial approach with either anticoagulation regimen. The
radial/ticlopidine strategy eliminated access-site complications and
significantly reduced hospital length of stay and hospital charge as compared to
femoral/ticlopidine and was the most cost-effective strategy.
PMID- 10785785
TI - Outpatient Transradial Coronary Stenting: Implications for Cost-Effectiveness.
PMID- 10785786
TI - Right Radial Access for PTCA: A Prospective Study Demonstrates Reduced
Complications and Hospital Charges.
AB - OBJECTIVE: The purpose of the present study was to evaluate the hypothesis that
angioplasty from the radial artery approach is more cost effective than that from
the femoral artery approach. BACKGROUND: Previous studies have demonstrated that
angioplasty can safely and effectively be performed from the radial artery
approach with a virtual absence of access-site complications. METHODS: One
hundred fifty-two patients were prospectively randomized to have their
angioplasty performed from either the radial or femoral approach. Angioplasty
results as well as various cost factors were compared. RESULTS: Primary success,
number of stents deployed, emergency bypass surgery, PTCA time, fluoroscopy time,
amount of contrast media, and catheterization laboratory charge were not
significantly different in the two groups. Access-site complications (0 RRA vs. 4
RFA, p <.04), post-procedure length of stay (2.1 days +/- 0.1 RRA vs. 2.6 +/- 0.3
RFA, p <.04), total hospital length of stay (3.6 days +/- 0.2 RRA vs. 4.5 +/- 0.4
RFA, p <.03), and total hospital charge ($14,374 +/- 467 RRA vs. 15,796 +/- 702,
p <.05) were all significantly less in the radial group. CONCLUSION: PTCA can be
performed from RRA as effectively as RFA without clinically significant access
site complications. Both post-procedure and total hospital stay are reduced,
leading to a 9% reduction in total hospital charges.
PMID- 10785787
TI - Stents DonOt Require Systemic Anticoagulation.But the Technique (and Results)
Must be Optimal.
PMID- 10785788
TI - Preliminary Results of the MUST Trial.
PMID- 10785789
TI - Adjunctive Antithrombotic Therapy with Stents, Current Status and Future
Prospects.
PMID- 10785791
TI - Transradial Coronary Stenting: A Passing Fad or Widespread Use in the Future?
PMID- 10785790
TI - Preliminary Results of the Music Study.
PMID- 10785792
TI - A Progress Report from BENESTENT II: Heparin Coating, Restenosis and Cost
Effectiveness.
PMID- 10785793
TI - PTA and Stents in the Treatment of Extracranial Circulation.
PMID- 10785794
TI - Molecular beacons: a novel DNA probe for nucleic acid and protein studies.
AB - A new concept has been introduced for molecular beacon DNA molecules. Molecular
beacons are a new class of oligonucleotides that can report the presence of
specific nucleic acids in both homogeneous solutions and at the liquid-solid
interface. They emit an intense fluorescent signal only when hybridized to their
target DNA or RNA molecules. Biotinylated molecular beacons have been designed
and used for the development of ultrasensitive DNA sensors and for DNA molecular
interaction studies at a solid-liquid interface. Molecular beacons have also been
used to study protein-DNA interactions. They have provided a variety of exciting
opportunities in DNA/RNA/protein studies.
PMID- 10785795
TI - Polyhomologation: the living polymerization of ylides
AB - The polymerization of dimethylsufoxonium methylide to produce linear
polymethylene polymers is described. The reaction is catalyzed/initiated by
trialkylboranes and gives organoboron star polymers as the primary product. The
reaction is a living polymerization, providing control over molecular weight and
functionality at the polymer chain ends. A variety of novel polymethylene
architectures are available by this methodology.
PMID- 10785796
TI - In situ monitoring of solid-state polymerization reactions in sodium
chloroacetate and sodium bromoacetate by 23Na and 13C solid-state NMR
spectroscopy
AB - The thermally induced solidstate polymerization reactions in sodium chloroacetate
and sodium bromoacetate, leading to poly(hydroxyacetic acid) (polyglycolide) and
NaCl and NaBr, respectively, were studied by isothermal in situ solid-state NMR
spectroscopy at 120, 130 and 140 degrees C with a time resolution of the order of
5 to 25 min. The nuclei probed were 23Na and 13C, allowing the parent compounds
(sodium halogenoacetates) and both reaction products (polymer and alkali halide)
to be monitored. For sodium chloroacetate, there is no evidence for the
involvement of intermediate phases during the reaction whereas this cannot be
excluded for sodium bromoacetate. The crystal structure of sodium bromoacetate
was determined directly from powder diffraction data by the Monte Carlo method,
and was found to be isostructural with sodium chloroacetate. The topochemical
reaction mechanism proposed previously for sodium chloroacetate is thus also
applicable for the polymerization reaction in sodium bromoacetate. The
mechanistic and kinetic information obtained from our in situ solid-state NMR
investigations is compared and contrasted with information obtained from other in
situ probes of the polymerization reactions in these materials.
PMID- 10785797
TI - Stereoselectivity and chiral recognition in copper(I) olefin complexes with a
chiral diamine
AB - Trigonal copper(I) complexes of the chiral bidentate ligand (1S,2S)-N,N'-Bis
(mesitylmethyl)-1,2-diphenyl-1,2-ethanediamine ((S,S)-1) have been prepared with
hydrocarbon olefins, as well as with allylic alcohols and ethers. The
stereochemistry of the complexes has been investigated by 1H NMR spectroscopy and
by combined quantum mechanics and molecular mechanics (QM/MM) computational
methods. The coordinated chiral nitrogen atoms can display equal (R, R) or
opposite (R, S) configuration, the latter being disfavored if steric hindrance is
present above and below the coordination plane. Although the complexes exist as
rapidly equilibrated mixtures of stereoisomers, one of these is often dominant,
and prochiral olefins are coordinated with high enantioface selection. In
addition, the [(S,S)-1]-Cu+ fragment selectively recognizes the R enantiomer of
secondary allylic alcohols and ethers, as confirmed by the X-ray crystal
structure analysis of the adduct with (R)-1-buten-3-ol. The reasons for the
observed selectivities have been elucidated, and lead to some implications which
are consistent with the enantioselection observed in catalytic cyclopropanation
reactions promoted by copper complexes of the same ligand.
PMID- 10785798
TI - A new method for the deprotection of benzyl ethers or the selective protection of
alcohols
AB - A new selective method for the deprotection of benzyl ethers situated next to
alcohols in the alpha, beta, or gamma position is presented which uses either NIS
or DIB/I2 as a reagent. After initial formation of a hypoiodite intermediate, the
reaction is believed to follow a radical pathway to resemble the Hoffman-Loffler
Freytag reaction. The formation of the intermediate hypoiodite is suggested on
the basis of NMR studies. Depending on the substrate, the corresponding
benzylidene derivatives or diols are isolated.
PMID- 10785799
TI - Alkaloids from marine organisms, Part 5. Biomimetic total synthesis of lamellarin
L by coupling of two different arylpyruvic acid units.
AB - Reaction of the ethyl 3-arylpyruvate 5a with the methyl 2-bromo-3-arylpyruvate 6b
in the presence of the 2-arylethylamine 4 afforded the pyrrole derivative 10,
which could be transformed into lamellarin L (1) in five steps. The synthesis
proceeds with 38% overall yield and mimics the probable biosynthesis of these
marine alkaloids.
PMID- 10785800
TI - Synthesis and trapping of transient 1,2-diselones to yield 1,4-diselenin
derivatives: calculated structures of 1,2-diselones, 1,2-diselenetes and their
sulfur analogues
AB - Two conceptually different routes to transient 1,2-diselones are reported: 1) via
ring fragmentation of the 1,4,2-diselenazine system 6, and 2) by the
tributylphosphane-induced depolymerisation of the shelf-stable organoselenium
polymer 15. Evidence for the intermediacy of 1,2-diselone species 7 and 16 is
provided in both cases by in situ trapping with dimethyl acetylenedicarboxylate
(DMAD) to yield 1,4-diselenin derivatives. The route via 15 is especially
expedient and trapping of 16 is efficient. Subsequent reactions of adduct 17
afford [1,2-ethanediylbis(diphenylphosphane)] [5,6-bis(methoxycarbonyl)-1,4
diselenin-2,3-dithiolato]nickel(IV) (20). Theoretical calculations at Hartree
Fock (HF) and Moller-Plesset electron-correlated levels (MP2) suggest that the
cyclic 1,2-diselenete structure 7c is significantly more stable than the acyclic
1,2-diselone structure 7a. For the bicyclic system 16, the difference in energy
between the cyclic and acyclic structures is considerably reduced due to the
conformational rigidity imposed by the fused 1,3-dithiole ring. In contrast, the
acyclic structures of the 1,2-dithione analogues 13a and 25a are computed to be
more stable than their corresponding cyclic 1,2-dithiete structures 13c and 25c.
PMID- 10785801
TI - A combined electrochemical quartz-crystal microbalance probe beam deflection
(EQCM-PBD) study of solvent and ion transfers at a poly
AB - The oxidative polymerisation of the complex2,3-dimethyl-N,N'-bis
(salicylidene)butane-2,3-diaminatonick-el(II), [Ni(saltMe)], was monitored by the
electrochemical quartz microbalance (EQCM) and crystal impedance techniques.
Polymerisation efficiency was maintained throughout deposition of a film, which
behaved rigidly, on the electrode. A combined EQCM-PBD (probe beam deflection)
study of the redox process of the film exposed to a monomer-free solution of 0.1
M tetraethylammonium perchlorate (TEAP) in acetonitrile showed an
electroneutrality mechanism dominated by anion movement accompanied by co
transfer of solvent above 0.8 V. The individual contributions of all the mobile
species involved in the redox switching of the poly[Ni(saltMe)] film were
determined quantitatively by temporal convolution analysis; the estimated
solution-phase diffusion coefficient of the exchanged species was 1.24 x 10(-5)
cm2s-1.
PMID- 10785802
TI - Hybrid open-framework iron phosphate--oxalates demonstrating a dual role of the
oxalate unit
AB - New inorganic-organic hybrid open-framework materials of the phosphate-oxalate
family, [Fe2(H2O)2-(HPO4)2(C2O4)].H2O (I), [Fe2(H2O)2-(HPO4)2(C2O4)].2H2O (II),
[C3N2H12]-[Fe2(HPO4)2(C2O4)1.5]2 (III), and [C3N2OH12][Fe2(HPO4)2(C2O4)1.5]2 (IV)
have been synthesized hydrothermally in the presence of structure-directing
amines. The amine molecules are incorporated in III and IV, whereas I and II are
devoid of them. The oxalate units act as a bridge between the layers in all the
compounds. The layers in I and II are entirely inorganic, being formed by FeO6
and PO4 units, whereas in III and IV oxalate units constitute the inorganic
layers and act as the bridge between these layers. Such a dual role of the
oxalate unit is unique and noteworthy. The formation of two types of inorganic
layers in I and II consisting of four-, six-, and eight-membered rings, indicates
the interconversions between the various rings in the phosphate--oxalates to be
facile. All the phosphate--oxalates show antiferromagnetic ordering at low
temperatures.
PMID- 10785803
TI - Host-guest interactions at self-assembled monolayers of cyclodextrins on gold
AB - We have developed synthesis routes for the introduction of short and long
dialkylsulfides onto the primary side of alpha-, beta-, and gamma-cyclodextrins.
Monolayers of these cyclodextrin adsorbates were characterized by
electrochemistry, wettability studies, X-ray photoelectron spectroscopy (XPS),
time-of-flight secondary ion mass spectrometry (TOF-SIMS), and atomic force
microscopy (AFM). The differences in thickness and polarity of the outerface of
the monolayers were measured by electro-chemistry and wettability studies. On
average about 70% of the sulfide moieties were used for binding to the gold, as
measured by XPS. Tof-SIMS measurements showed that the cyclodextrin adsorbates
adsorb without any bond breakage. AFM measurements revealed for beta-cyclodextrin
monolayers a quasi-hexagonal lattice with a lattice constant of 20.6 A, which
matches the geometrical size of the adsorbate. The alpha-cyclodextrin and gamma
cyclodextrin monolayers are less ordered. Interactions of the anionic guests 1
anilinonaphthalene-8-sulfonic acid (1,8-ANS) and 2-(p-toluidinyl)naphthalene-6
sulfonic acid (2,6-TNS) and the highly ordered monolayers of heptapodant beta
cyclodextrin adsorbates were studied by surface plasmon resonance (SPR) and
electrochemical impedance spectroscopy. The SPR measurements clearly showed
interactions between a beta-cyclodextrin monolayer and 1,8-ANS. Electrochemical
impedance spectroscopy measurements gave high responses even at low guest
concentrations (< or = 5 microM). The association constant for the binding of 1,8
ANS (K = 289,000 +/- 13,000M-1) is considerably higher than the corresponding
value in solution. (Partial) methylation of the secondary side of the beta
cyclodextrin strongly decreases the binding.
PMID- 10785804
TI - Merging organometallic chemistry with polyoxometalate chemistry
AB - A series of polyoxomolybdate-incorporated organometallic complexes has been
obtained by reaction of [MBr(CO)5] or solvated M(CO)3+ ions (M = Mn or Br) with
(nBu4N)2[Mo2O7] in methanol, sometimes in the presence of triols of the type
RC(CH2OH)3 (R = Me or CH2OH). Their molecular structures are related to those of
previously described polyoxoalkoxomolybdates through the formal replacement of
fac-MoO2(OR)+ units by topologically equivalent fac-M(CO)3+ units. Representative
pairs of structurally related clusters include [Mo2O6(OMe)4-Re(CO)32]2- and
[Mo4O10(OMe)6]2-, [Mo2O4MeC(CH2O)32Mn(CO)3]- and [Mo3O6(OMe)MeC(CH2O)32]-,
[Mo2O4HOCH2C(CH2O)32Mn(CO)32] and [Mo4O8(OEt)2MeC(CH2O)32],
[Mo6O16(OMe)2MeC(CH2O)32-Mn(CO)32]2- and [Mo8O20(OMe)4-MeC(CH2O)32]2-. Although
the frameworks of the majority of derivatives are based on tetranuclear units
which display the common rhomb-like structure, the alternative cubane-type
arrangement is observed in [Mo2O5(OMe)5M(CO)32]-.
PMID- 10785806
TI - pi conjugation across the tetrathiafulvalene core: synthesis of extended
tetrathiafulvalene derivatives and theoretical analysis of their unusual
electrochemical properties
AB - A series of extended tetrathiafulvalene (TTF) derivatives bearing one or two 1,4
dithiafulven-6-yl substitutents has been prepared. The new compounds present
remarkable electrochemical singularities compared with other TTF derivatives,
which are strongly affected by the nature of the substitution on the lateral
heterocycle(s). This unusual electrochemical behaviour follows a square-scheme
sequence and is attributed to structural changes upon oxidation of the pi
donating molecules. Digital simulations of the electrochemical data have been
used to reach the values of the kinetic and thermodynamic constants involved in
the square scheme. Theoretical calculations establish an important contribution
of a highly delocalised resonant form involving a tetravalent sulphur in oxidised
species, which could justify the occurrence of an electrochemical behaviour
distinct from that of TTF. Finally, third-order susceptibilities chi 3 of two of
these systems, for which electron-donating and electron-withdrawing substituents
coexist and are conjugated through the TTF pi system, are given.
PMID- 10785805
TI - Catalysis of the addition of benzenethiol to 2-cyclohexen-1-ones by uranyl
salophen complexes: a catalytic metallocleft with high substrate specificity.
AB - The base induced addition of benzenethiol to 2-cyclohexen-1-one and its 4,4-, 5,5
and 6,6-dimethyl derivatives is catalysed by a salophen-uranyl based
metallocleft 2 in chloroform solution with high turnover efficiency and low
product inhibition. Analysis of rate data coupled with equilibrium measurements
for complexation of the catalyst with the enone reactants and addition products
shows that the catalytic mechanism involves the three main steps typical of
single-substrate enzymatic processes, namely substrate binding and recognition,
transformation of the bound substrate, and release of the reaction product.
Unlike the reference salophen-uranyl 1, catalyst 2 is endowed with a structured
binding site responsible for a high degree of substrate specificity among the
investigated enones, due to recognition of their shape and size.
PMID- 10785807
TI - A highly enantiopure biconcave porphyrin with effective D4-structure
AB - A first representative of an effectively D4-symmetric biconcave porphyrin (1) was
prepared from a tetramerizing condensation of a C2-symmetric pyrrole (2). The
chiral pyrrole 2 was synthesized in a six-step reaction sequence starting from
the C2h-symmetric 2,6-di-tert-butylanthracene. The relevant stereochemistry was
introduced in a highly diastereo-discriminating Diels-Alder reaction with fumaric
acid di(-)menthyl ester, catalyzed by aluminum chloride. X-ray analyses of two of
the dimenthyl esters prepared unambiguously secured their tentatively assigned
absolute configuration and that of the pyrrole 2 (as the S,S isomer). The
enantiomeric purity of the pyrrole 2 was determined as 99% ee, using the Co11
complex of the porphyrin 1 as a chiral shift reagent. The pyrrole 2 lent itself
to a stereochemically nearly uniform preparation of the chiral, biconcave
porphyrin 1. Applying Horeau's principle, 1 was calculated to be present in an
enantiomeric excess of about 10(9):1. The validity of the statistical
considerations relevant for this estimate were verified by examination of the
results from preparative tetramerization experiments in which the enantiomeric
purity of the pyrrole 2 was deliberately lowered.
PMID- 10785808
TI - Ethynylogization of a coarctate fragmentation
AB - Coarctate reactions form a separate class of elementary closed-shell processes in
addition to polar and pericyclic reactions. Hence, they also follow a different
homology principle. Whereas vinylogous polar and pericyclic reactions differ in
the length of the reacting system by a double bond, coarctate reactions can be
homologized (ethynylogized) by extending a known system by a triple bond. The
prediction, which is based on theoretical considerations, is confirmed
experimentally by the fragmentation of cyclopropylethynyl nitrene to cyano
acetylene and ethylene, a reaction that is "ethynyloguous" to the known
fragmentation of cyclopropyl nitrene to ethylene and HCN.
PMID- 10785809
TI - X-ray structure of a trimeric 5,5'-biaryl/erythro-beta-O-4-ether lignin model:
evidence for through-space weak interactions.
AB - The crystal structure of a trimeric lignin model 1 presenting the characteristic
pattern of biphenyl (5,5') and aryl-alkyl-ether (beta-O-4) linkages has been
determined. The crystal system is triclinic and the crystallographic unit cell
consists of two monomeric molecules. These results are compared with crystal data
from the literature of simple models of the 5,5' and beta-O-4 structure type. The
availability of a terminal aldehyde function on the model affords some
interesting intermolecular interactions by weak hydrogen bonding which controls
the conformation of the molecule and the aromatic ring orientation in particular;
an unexpected cisoid conformation of the biaryl unit is observed based on the
64.4 degrees value found for the torsion angle between the two 5,5' aromatic
rings.
PMID- 10785810
TI - A mass spectrometry study of XCO+, X=Si, Ge: is SiCO+ a main group carbonyl?
Comments on the bonding in ground state SiCO and the
AB - The cation [Si,C,O]+ has been generated by 1) the electron ionisation (EI) of
tetramethoxysilane and 2) chemical ionisation (CI) of a mixture of silane and
carbon monoxide. Collisional activation (CA) experiments performed for mass
selected [Si,C,O]+, generated by using both methods, indicate that the structure
is not inserted OSiC+; however, a definitive structural assignment as Si(+)-CO,
Si(+)-OC or some cyclic variant is impossible based on these results alone.
Neutralisation-reionisation (+NR+) experiments for EI-generated [Si,C,O]+ reveal
a small peak corresponding to SiC+, but no detectable SiO+ signal, and thus
establishes the existence of the Si(+)-CO isomer. CCSD(T)@B3LYP calculations
employing a triple-zeta basis set have been used to explore the doublet and
quartet potential-energy surfaces of the cation, as well as some important
neutral states. The results suggest that both Si(+)-CO and Si(+)-OC isomers are
feasible; however, the global minimum is 2 pi SiCO+. Isomeric 2 pi SiOC+ is 12.1
kcal mol-1 less stable than 2 pi SiCO+, and all quartet isomers are much higher
in energy. The corresponding neutrals Si-CO and Si-OC are also feasible, but the
lowest energy Si-OC isomer (3A") is bound by only 1.5 kcal mol-1. We attribute
most, if not all, of the recovery signal in the +NR+ experiment to SiCO+ survivor
ions. The nature of the bonding in the lowest energy isomers of Si(+)-(CO,OC) is
interpreted with the aid of natural bond order analyses, and the ground state
bonding of SiCO+ is discussed in relation to classical analogues such as metal
carbonyls and ketenes.
PMID- 10785812
TI - Pnictides as symmetrically bridging ligands in novel neutral complexes
AB - The reaction of [LWCl] (3) [L = N(CH2CH2NiPr)3] with LiE(SiMe3)2 (E = P, As, Sb)
yields the novel, neutral pnictido-bridged complexes [LW = E = WL] (5-7). By
following the reaction, which starts from the LiP-(SiMe3)2 derivative, by 31P NMR
spectroscopy, the formation of an intermediate with a terminal pnictido ligand
can be ruled out. The paramagnetic complexes 5-7 are comprehensively
spectroscopically characterised. The X-ray structure analysis of the
heterocumulenes 5-7 reveals a linear structure in which the two W-"tren" units
bind to the central pnictido atom in a staggered conformation ["tren" = tren
based ligand; tren = tris(2-aminoethyl)-amine. When N2 is used as the inert gas
in the synthesis of the starting material [N(CH2CH2NNp)3WCl] [Np = CH2C-(CH3)3],
the complex [[N(CH2CH2NNp)3]W2(mu, eta 1: eta 1-N2)] (4) is formed as a side
product. Complex 4 possesses a hydrazido(4-) (N2(4-)) ligand connected by two
tungsten-"tren" moieties.
PMID- 10785811
TI - Chemoenzymatic synthesis of sialyl-trimeric-Lewis x.
AB - The decasaccharide sialyl-trimeric-Lewis x is a component of glycoproteins and
glycolipids that serve as E- and P-selectin ligands. The synthesis of this target
structure was accomplished by utilizing a combination of chemical and enzymatic
methods. Highlights of the chemical synthesis include minimal use of protecting
groups and regioselective glycosylations to arrive at a linear tri-lactosamine
structure. Glycosyltransferase-catalyzed reactions were then employed for the
addition of the terminal sialic acid and branch-point fucose residues. Notably,
fucosyltransferases V and VI showed different specificities for the sialyl-tri
lactosamine core structure.
PMID- 10785813
TI - Heat-shrinking spherical and columnar supramolecular dendrimers: their
interconversion and dependence of their shape on molecular taper angle
AB - Synthesis and modes of self-assembly are described for the tapered monodendritic
molecules 3,4,5-nGi-X of generation i = 1, 2, 3 (see structures below) that
contain multiple (CH2)nH alkyl chains on their periphery (n = 12, 14, 16) and a
polar group X at the apex (X = COOH, COONa, COOCs, CO(OCH2CH2)3OH). These
monodendrons self-assemble into supramolecular cylindrical or spherical
dendrimers, which in turn self-organise into p6mm columnar or Pm3n cubic
thermotropic liquid crystals, respectively. The two principal ways of affecting
the self-assembly of these compounds by means of their molecular architecture
are: a) by changing the width of the wide (aliphatic) end, and b) by changing the
volume at the apex. In the present work a) is controlled through temperature
(conformational disorder) and b) is controlled by chaging the generation number i
or the size of X, for example, through the choice of metal cation. The single
most important geometric parameter of these dendritic building blocks is the
molecular solid angle (taper angle) alpha; a high alpha leads to spherical and a
low alpha to cylindrical supramolecular dendrimers. Furthermore, alpha also
determines the equilibrium size of the supramolecular objects; a larger alpha
results in a smaller diameter. The unusually strong negative thermal expansion
coefficient of the cubic and columnar lattice is attributed to the excess of the
increasingly highly tapered molecules being rejected from their parent aggregates
and reassembling as new ones. Increasing alpha is also considered to be
responsible for the observed thermotropic columnar-cubic transition.
PMID- 10785814
TI - Catalytic concepts for the enantioselective synthesis of alpha-amino and alpha
hydroxy phosphonates.
AB - The enantioselective synthesis of alpha-amino- and alpha-hydroxy phosphonates by
catalytic processes has attracted considerable interest in the last few years,
not least because of the pharmaceutical interest in such compounds. This article
contains a compilation of the asymmetric synthesis methods developed to date. The
described synthetic routes are based on different catalytic concepts, namely,
hydrogenation, reductions, dihydroxylation, aminohydroxylation, and
hydrophosphonylation.
PMID- 10785815
TI - Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous
catalysis: mechanistic aspects
AB - The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was
studied over supported rhodium and ruthenium catalysts at room temperature and a
pressure of 5 MPa. The reaction was diastereoselective with the predominant
formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric
excess (de) of up to 96%. The most stable conformation was determined by means of
a combination of modelling calculations, NMR spectroscopy and X-ray structural
determination. In this conformation, the carbonyl group of the pyroglutamate
auxiliary shields one face of the aromatic ring. The observed selectivity may
thus be explained by a preferential adsorption at the unshielded face which
avoids steric repulsion by the C=O group to result in a cis hydrogenation. The
addition of an amine, the nature of the support (alumina or active carbon) or of
the metal (Rh or Ru) were shown to give additional stabilisation of the
adsorption at the unshielded face to increase the diastereoisomeric excess.
PMID- 10785816
TI - The photochemistry of 1,3-butadiene rationalized by means of theoretical
resonance structures and their weights
AB - A complete active-space self-consistent-field wave function for the pi-electron
part of s-trans-1,3-butadiene has been expanded into a set of localized bonding
schemes and their weights. These bonding schemes are close to the resonance
structures used in organic chemistry. The expansion technique has been applied to
both the electronic ground state and the electronically first-excited singlet and
triplet pi,pi* states. The manifolds of large-weight bonding schemes represent
approximate resonance hybrids for the ground and the singlet and triplet pi,pi*
states of s-trans-1,3-butadiene. These resonance hybrids, obtained by theory
alone, permit a qualitative rationalization of a significant part of the known
singlet and triplet photochemistry.
PMID- 10785817
TI - Structure-based design, synthesis, and in vitro evaluation of bisubstrate
inhibitors for catechol O-methyltransferase (COMT).
AB - The enzyme catechol O-methyltransferase (COMT) catalyzes the Me group transfer
from the cofactor S-adenosylmethionine (SAM) to the hydroxy group of catechol
substrates. Potential bisubstrate inhibitors of COMT were developed by structure
based design and synthesized. The compounds were tested for in vitro inhibitory
activity against COMT obtained from rat liver, and the inhibition kinetics were
examined with regard to the binding sites of cofactor and substrate. One of the
designed molecules was found to be a bisubstrate inhibitor of COMT with an IC50 =
2 microM. It exhibits competitive kinetics for the SAM and noncompetitive
kinetics for the catechol binding site. Useful structure-activity relationships
were established which provide important guidelines for the design of future
generations of bisubstrate inhibitors of COMT.
PMID- 10785818
TI - Screw-sense-selective polymerization of aryl isocyanides initiated by a Pd-Pt mu
ethynediyl dinuclear complex: a novel method for the synthesis of single-handed
helical poly(isocyanide)s with the block copolymerization technique
AB - Living polymerization of chiral aryl isocyanides, such as m- and p
menthoxycarbonylphenyl isocyanides 2 and 5, initiated by the Pd-Pt mu-ethynediyl
dinuclear complex 1, proceeds with a high screw-sense selectivity to give the
poly(isocyanide)s 3 and 6, which exhibit a large specific rotation and an intense
CD band at lambda = 364 nm as a consequence of a helical chirality. The molar
optical rotation and molar circular dichroism of the resulting polymers 3 and 6
reach a constant value at a degree of polymerization (Pn) of more than 30. Screw
sense-selective polymerization of achiral aryl isocyanides that bear very bulky
substituents, such as 3,5-di(propoxycarbonyl)phenyl isocyanide (11), 3,5
di(butoxycarbonyl)phenyl isocyanide (13), and 3,5-di(cyclohexyloxycarbonyl)phenyl
isocyanide (15), is achieved by the use of chiral oligomer complexes 3(30) and
6(30), prepared from the reaction of 1 with 30 equivalents of 2 or 5, as an
initiator to give predominantly single-handed helical polymers. In contrast,
smaller aryl isocyanides are also polymerized by 3(30) and 6(30) with screw-sense
selectivity in the initial stage of the reaction, but the single-handed helix is
not preserved up to high molecular weight. Kinetic studies of the polymerization
of (L)- and (D)-2, or (L)- and (D)-5 with chiral oligomer complexes (L)-3(50) or
(L)-6(100) suggests that the screw sense of the polymer backbone is not
controlled kinetically, but rather that the thermodynamically stable screw sense
is produced.
PMID- 10785819
TI - Strontium selenogermanate(III) and barium selenogermanate(II,IV): synthesis,
crystal structures, and chemical bonding
AB - The new selenogermanates Sr2Ge2Se5 and Ba2Ge2Se5 were synthesized by heating
stoichiometric mixtures of binary selenides and the corresponding elements to 750
degrees C. The crystal structures were determined by single-crystal X-ray
methods. Both compounds adopt previously unknown structure types. Sr2Ge2Se5
(P2(1)/n, a = 8.445(2) A, b = 12.302 A, c = 9.179 A, beta = 93.75(3) degrees, Z =
4) contains [Ge4Se10]8- ions with homonuclear Ge-Ge bonds (dGe-Ge = 2.432 A),
which may be described as two ethane-like Se3Ge-GeSeSe2/2 fragments sharing two
selenium atoms. Ba2Ge2Se5 (Pnma, a = 12.594(3) A, b = 9.174(2) A, c = 9.160(2) A,
Z = 4) contains [Ge2Se5]4- anions built up by two edge-sharing GeSe4 tetrahedra,
in which one terminal Se atom is replaced by a lone pair from the divalent
germanium atom. The alkaline earth cations are arranged between the complex
anions, each coordinated by eight or nine selenium atoms. Ba2Ge2Se5 is a mixed
valence compound with GeII and GeIV coexisting within the same anion. Sr2Ge2Se5
contains exclusively GeIII. These compounds possess electronic formulations that
correspond to (Sr2+)2(Ge3+)2(Se2-)5 and (Ba2+)2- Ge2+Ge4+(Se2-)5. Calculations of
the electron localization function (ELF) reveal clearly both the lone pair on
GeII in Ba2Ge2Se5 and the covalent Ge-Ge bond in Sr2Ge2Se5. Analysis of the ELF
topologies shows that the GeIII-Se and GeIV-Se covalent bonds are almost
identical, whereas the GeII-Se interactions are weaker and more ionic in
character.
PMID- 10785820
TI - Highly organized spherical hosts that bind organic guests in aqueous solution
with micromolar affinity: microcalorimetry studies
AB - Two novel closed-shell hemicarcerand-like hosts with spherical cavities of 11 A
diameter that are soluble in aqueous solution were constructed. The binding of
xylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclic
aliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMR
binding studies indicated that binding depended upon guest hydrophobicity and
shape. No binding was detected for guests in which a charge must be desolvated as
part of inclusion or for guests that can not fit within the cavity of the host.
Three complexes 2.naphthalene, 2.p-xylene, and 2.ferrocene were isolated and
found to be indefinitely stable in the solid phase and in aqueous solution. The
binding constants for these complexes are estimated to be greater than 10(8) M-1.
Thirteen guests were examined by microcalorimetry with binding constants ranging
between 10(7) and 10(3) M-1. A comparison of results obtained here with those
from previous work with beta-cyclodextrin and cyclophane hosts, along with
analysis of the entropy-enthalpy compensation data, indicate that there is a
higher degree of guest desolvation with this host structure than with open-shell
hosts. This accounts at least partially for the increase in affinity observed
with these closed-shell hosts. Replacing a hydroxy group in the host portal with
a hydrogen atom does not affect the binding constant, a finding consistent with
the guest residing deeply buried within the host cavity. It was observed that
aromatic guests are bound with higher affinity than aliphatic ones in agreement
with results that point to the importance of London dispersion forces in the
association of aromatic components in face-to-edge orientations. The correlation
of changes in NMR chemical shift with microcalorimetry data supports a model in
which increased CH-pi interactions strengthen association between host and guest
due to the dominant role of van der Waals dispersion forces. Remarkably, the
binding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher than
for the 1,2 isomer, and even greater discrimination is observed between the
xylene guests since the binding constant for p-xylene is 80 times greater than
that for o-xylene. This discrimination between isomeric guests by a rigid host
indicates that changes in specific hydrophobic interactions have substantial
effects upon binding affinity.
PMID- 10785821
TI - Velcrands with snaps and their conformational control
AB - A novel class of self-folding velcrands was prepared that dimerize through
intermolecular forces. Solvophobic interactions on extended pi surfaces stabilize
the dimer similar to velcrands, while eight hydrogen bonds act like snaps to hold
the molecules together. The self-complementary array of hydrogen bonding sites
were incorporated on the upper rim of a resorcinarene-based cavitand. A dramatic
reorganization of shape and size of the internal cavity was manifested through
changes in solvent polarity. Specifically, the equilibrium between the extended
surface (D2d symmetry) and a deep cavity (C4v symmetry) could be manipulated in
mixtures of aromatic solvents (or CDCl3) and [D6]DMSO. The switching of
conformations and the dimerization motif are well-suited for the assembly of
noncovalent polymeric materials.
PMID- 10785822
TI - Nonaqueous ionic liquids: superior reaction media for the catalytic Heck
vinylation of chloroarenes
AB - Nonaqueous ionic liquids, that is molten salts, constitute an activating and
stabilizing noninnocent solvent for the palladium-catalyzed Heck-vinylation of
all types of aryl halides. Especially with chloroarenes an improved activity and
stability of almost any known catalyst system is observed as compared to
conventional, molecular solvents (e.g. dimethylformamide (DMF), dimethylacetamide
(DMAc), N-methyl-2-pyrrolidinone (NMP), or dioxane). Thus, even catalytic amounts
of ligand-free PdCl2 yield stilbene from technically interesting chlorobenzene
and styrene in high yield (turnover number (TON) = 18) without the need for
further promoting salt additives such as tetraphenylphosphonium chloride. The
scope of the new reaction medium is outlined for the first time for the
vinylation of various aryl halides using different mono- and disubstituted
olefins as well as a variety of known palladium(0) and palladium(II) catalyst
systems. Furthermore, a novel means of catalyst recycling is presented and its
scope is evaluated.
PMID- 10785823
TI - 2,2'-bipyridine lariat calixcrowns: a new class of encapsulating ligands forming
highly luminescent Eu3+ and Tb3+ complexes
AB - A new class of calix[4]arene crown ethers with one or two bipyridines appended to
the polyether ring (lariat calixcrowns) have been designed and synthesized; the
luminescence properties of their Eu3+ and Tb3+ complexes have been studied in
acetonitrile. In this solvent, long lifetimes for the metal emitting states and
high metal-luminescence intensities obtained upon ligand excitation have been
observed in both Eu3+ and Tb3+ complexes. The association constants in methanol
have been determined for some of the complexes studied.
PMID- 10785825
TI - Short-range interactions within molecular complexes formed in supersonic beams:
structural effects and chiral discrimination
AB - One- and two-color, mass-selected R2PI spectra of the S1<--S0 transitions in the
bare chiral chromophore R-(+)-1-phenyl-1-propanol (R) and its complexes with a
variety of alcoholic solvent molecules (solv), namely methanol, ethanol, 1
propanol, 2-propanol, 1-butanol, S-(+)-2-butanol, R-(-)-2-butanol, 1-pentanol, S
(+)-2-pentanol, R-(-)-2-pentanol, and 3-pentanol, were recorded after a
supersonic molecular beam expansion. Spectral analysis, coupled with theoretical
calculations, indicate that several hydrogen-bonded [R.solv] conformers are
present in the beam. The R2PI excitation spectra of [R.solv] are characterized by
significant shifts of their band origin relative to that of bare R. The extent
and direction of these spectral shifts depend on the structure and configuration
of solv and are attributed to different short-range interactions in the ground
and excited [R.solv] complexes. Measurement of the binding energies of [R.solv]
in their neutral and ionic states points to a subtle balance between attractive
(electrostatic and dispersive) and repulsive (steric) forces, which control the
spectral features of the complexes and allow enantiomeric discrimination of
chiral solv molecules.
PMID- 10785824
TI - Conformational differences between O- and C-glycosides: the alpha-O-man-(1-->1)
beta-Gal/alpha-C-Man-(1-->1)-beta-Gal case--a decisive demonstration of the
importance of the exo-anomeric effect on the conformation of glycosides.
AB - The conformational behavior of alpha-O-Man-(1-->1)-beta-Gal (1) and its C
analogue (2) has been studied using J/NOE NMR data, molecular mechanics,
molecular dynamics, and ab initio calculations. The population distribution
around the glycosidic linkages of 1 and 2 is rather different, especially for the
alpha-Man linkage. A lower limit for the exo-anomeric effect in water has been
experimentally determined.
PMID- 10785827
TI - Chiral "metallo-spiralenes": helical molecules conformationally stabilised by an
organometallic scaffold
AB - The synthesis of a series of chiral cyclomanganated 2-[(eta 6-phenyl)
Cr(CO)3]pyridine complexes derived from (-)-beta-pinene enables, by a "spirogenic
transformation", the preparation of four different chiral helical
heterobimetallic syn-facial complexes or Cr0/Mn1-spiralenes, among which two
possess a right-handed P molecular helicity and two other a left-handed M one.
These organometallic helical molecules are synthesised by applying two different
methods to the chiral cyclomanganated (eta 6-arene)tricarbonylchromium
substrates. The first method is the so-called "Fischer route" which involves a
sequential addition of PhLi and MeOTf. The second method based on reaction of the
cyclomanganated complex with diphenyldiazomethane which has been tested on
achiral bimetallic substrates is a reasonable neutral alternative to the "Fischer
methodology" for the synthesis of Cr0/Mn1-spiralenes. The crystal structure of
one of these heterobimetallic chiral helical compounds serves as a starting point
in the configurational and structural assessment of the synthesised chiral (eta 6
arene)tricarbonylchromium complexes. Application of the "Fischer route" to a
cyclomanganated chiral 2-phenylpyridine generates a single chiral eta 3-benzylic
complex--or Mn1-spiralene--bearing a left-handed M helicity which has been
characterized by X-ray diffraction analysis. Circular dichroic spectroscopic
measurements underline the predominant contribution of the chiral and chirally
induced aromatic chromophores to the sign of the Cotton effects and confirm the
helical configurations of the considered heterobimetallic species.
PMID- 10785828
TI - Electronic excitations in homopolyatomic bismuth cations: spectroscopic
measurements in molten salts and an ab initio CI-singles study
AB - The electronic excitations of the low-valence bismuth cluster cations Bi5(3+),
Bi8(2+), and Bi9(5+) have been studied with experimental and theoretical
techniques. The UV-visible spectra of the bismuth ions were measured in acidic
chloroaluminate melts (mixture of 1-methyl-3-benzyl imidazolium chloride and
AlCl3). The spectra of the Bi5(3+) and Bi8(2+) ions agree fairly well with
previous reports, but also revealed additional low-energy absorptions. Ab initio
methods were employed to assign the experimentally observed electronic
transitions of these homopolyatomic bismuth cations. Structures were optimized at
the RHF, MP2, and B3LYP levels of theory by using split-valence LANL2DZ basis
sets that were augmented with one and two sets of pure d functions. The computed
structures agree well with the results of neutron diffraction analyses of melts.
Electronically excited states of the three clusters were treated by using the CI
Singles theory. The results of these calculations were used to explain the
observed UV-visible spectra. The observed electronic excitations in the UV
visible range are all found to result from transitions involving the molecular
orbitals formed by 6p-atomic-orbital overlap. This leads to the necessity of
using basis sets that include d-type functions, which allow for an adequate
description of the bonding that results from such p-orbital overlap. Spin-orbit
coupling becomes increasingly important with increasing atomic number and its
consideration is necessary when describing the electronic transitions in clusters
of heavy atoms. The calculations show that singlet-triplet transitions, which are
made accessible by strong spin-orbit coupling, are responsible for some of the
observed absorptions.
PMID- 10785826
TI - Design and synthesis of an alpha,alpha-difluorophosphinate hapten for antibody
catalyzed hydrolysis of organophosphorus nerve agents.
AB - In a new approach to the safe neutralization of organophosphorus chemical
weapons, we designed a hapten to elicit catalytic antibodies with phosphatase
activity. Here we report the synthesis of this alpha,alpha-difluorophosphinate
hapten 6. Various methods for the introduction of the key alpha,alpha
difluoromethyl feature into the phosphinate hapten are discussed. The best
results were obtained with the electrophilic gem-difluorinating agent N
fluorobenzenesulfonimide.
PMID- 10785829
TI - Direct observation of single-molecule generation at a solid-liquid interface
AB - Direct observation of single-molecule generation from a chemical reaction was
achieved at a solid-liquid interface. The reaction between fluorescamine and
immobilized N'-(3-trimethoxysilylpropyl)diethylenetriamine (DETA) was studied at
the single-molecule level. Time-lapse fluorescence images of single-molecule
products, excited by the evanescent field generated at a quartz-liquid interface,
were recorded to follow the chemical reaction to its completion. The reactions
were restricted to the approximately 1 nm thick layer nearest to the interface.
Analysis of the photoelectron intensity of the fluorescent product of the
reaction and its distribution shows that the reaction kinetics goes through a
transition from zeroth-order to first-order as the reaction proceeds. This
approach offered a novel means to study single-molecule reactions at the solid
liquid interface. It also enabled the investigation of reaction kinetics and
chemical mapping of surface heterogeneity at the single-molecule level.
PMID- 10785830
TI - Pain in Parkinson's disease.
AB - Pain, defined as an unpleasant or distressing sensory experience, has been
recognized as feature of Parkinson's disease (PD) since the first descriptions of
the disorder. Pain is estimated to occur in approximately 40% of patients with
PD, and in a minority of individuals becomes severe enough to overshadow the
motor symptoms of the disorder. Recent studies based on patients' descriptions of
pain have enabled a classification of painful sensations into 1 or more of 5
categories: musculoskeletal pain, neuritic or radicular pain, dystonia-associated
pain, primary or central pain, and akathitic discomfort. The existence of a
central pain syndrome, intrinsic to PD, finds support in a collection of case
reports, but the precise mechanism is unknown, and a correlation with pathology
has not been made. This review describes the clinical features of the pain
syndromes in PD, and provides a framework for evaluating, classifying, and
treating painful symptoms in PD.
PMID- 10785831
TI - Sexual dysfunction in Parkinson's disease.
AB - Sexual dysfunction is seen in a number of neurologic diseases. In this article we
review normal human sexual response, some neurologic diseases in which sexual
dysfunction is seen, and Parkinson's disease (PD). With PD there is often a
reduction in sexual interest and function. The studies documenting these problems
are detailed. In addition, we focus on the syndrome of hyper- or aberrant sexual
function seen with pharmacotherapy of PD.
PMID- 10785832
TI - Urinary dysfunction in Parkinson's disease.
AB - Urinary symptoms are very common in Parkinson's disease (PD). They are primarily
irritative (frequency, urgency, urge incontinence) and correlate with the
urodynamic finding of involuntary detrusor contractions at early stages of
bladder filling (detrusor hyperreflexia). Obstructive symptoms (hesitancy, weak
urinary stream) may be seen in a smaller number of patients by themselves or
combined with irritative symptoms. They may be secondary to anticholinergics,
obstructive uropathy, or point to the presence of multiple system atrophy.
Dysfunction of the striated urethral sphincter and pelvic musculature can be seen
in variable numbers in PD, with the main abnormality that of delayed relaxation
at the time of initiation of voluntary voiding.
PMID- 10785833
TI - Behavioral dysfunction in Parkinson's disease.
AB - Behavioral manifestations of Parkinson's disease (PD) are often more debilitating
than the motor manifestations. These occur both as primary manifestations of the
disease and as drug-induced complications. While dementia and abulia are common
problems that are not currently treatable, depression and psychosis often respond
extremely well to medication. Phenomenology, pathology, and general approaches to
treatment will be discussed.
PMID- 10785834
TI - Olfactory dysfunction in Parkinson's disease.
AB - The olfactory system is one of the nonmotor systems severely affected in
Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease
process, is independent of disease stage, duration, and treatment. However,
olfactory dysfunction appears to be dependent on disease subtype. Olfaction is
mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS).
This provides a means of differential diagnosis between typical PD and PPS.
Olfactory function is impaired also in familial forms of parkinsonism in which
the genetic defect is known. In familial parkinsonism, olfactory function is
impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not
appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is
also associated with other neurodegenerative diseases such as Alzheimer's disease
(AD), Huntington's disease (HD), as well as with normal aging. The
neuropathological changes observed in the olfactory system in PD and other
neurodegenerative diseases appear to be disease-specific, raising the possibility
that olfactory dysfunction may be the result of a central rather than a
peripheral process. The cellular and molecular mechanisms underlying olfactory
dysfunction in PD and other neurodegenerative diseases remain unknown.
PMID- 10785835
TI - Visual dysfunction in Parkinson's disease.
AB - Several abnormalities of visual function have been demonstrated in Parkinson's
disease (PD) by both electrophysiologic and psychophysical testing. Prolonged
visual evoked potential latencies and abnormal electroretinographic patterns,
both of which respond to levodopa therapy, have been demonstrated in Parkinson's
disease patients and in primates with experimental parkinsonism suggesting that
retinal dopamine deficiency is an important factor in the pathogenesis of PD
visual dysfunction. Abnormalities of color perception, especially in the blue
green axis, and of visual contrast sensitivity (VCS) have also been well
documented in PD patients. Although VCS impairment is likely related to retinal
dopaminergic dysfunction, the fact that this visual abnormality is orientation
specific raises the possibility of visual cortex involvement as well. Visual
abnormalities in PD are usually clinically occult and not likely to be uncovered
during a routine neurological examination or by ordinary high contrast visual
acuity testing. The clinician must be aware, however, that several forms of
disability ranging from gait freezing to visual hallucinations may be linked to
an underlying impairment of visual function in Parkinson's disease.
PMID- 10785836
TI - Sleep dysfunction in Parkinson's disease.
AB - The frequency of sleep complaints in patients with Parkinson's disease (PD) is
estimated to be between 60-90% and a variety of either disease-related or
secondary mechanisms and the dopaminergic treatment itself contributes to the
development of different sleep disturbances. These comprise slight, fragmented
sleep with increased number of arousals and awakenings, and PD-specific motor
phenomena such as nocturnal immobility, rest tremor, eye-blinking, dyskinesias,
and other phenomena such as periodic and nonperiodic limb movements in sleep,
restless legs syndrome, fragmentary myoclonus, and respiratory dysfunction in
sleep. Depression and hallucinations/psychosis further complicate the picture.
The incidence of REM sleep behavior disorder (RBD) with nightmares and violent
behavior is increased in PD and may occur as a preclinical disease-related
symptom. A careful sleep history of patients and their partners, polysomnograms
when necessary, motor and psychiatric assessments should precede individual
treatment strategies, which include adjusting dopaminergic daytime treatment,
benzodiazepines for RBD, reduction of anticholinergic drugs, and, if necessary,
clozapine for nocturnal psychosis.
PMID- 10785837
TI - Imaging of nonmotor symptoms in Parkinson syndromes.
AB - Neuroimaging modalities in Parkinson's Disease (PD) are primarily used for the
differential diagnosis of Parkinson syndromes and to understand
pathophysiological mechanisms in PD. Neuroimaging of nonmotor dysfunctions in PD
mostly consist of functional studies in neuropsychologically impaired PD patients
using PET or SPECT techniques. Various studies controversially discuss the
probable frontal versus temporal hypometabolism in demented PD patients.
Functional studies of PD patients with depression are limited to case reports
showing an involvement of left frontal regions. To investigate the
pathophysiology of hallucinations with functional imaging may be a promising
field of future research.
PMID- 10785838
TI - Neurophysiology of sensorimotor integration in Parkinson's disease.
AB - Parkinson's disease (PD) is a major neurologic disorder that distinctively and
selectively affects movement and--by extension--the motor system. A large body of
evidence has been accumulated over the years showing that movement disorders of
PD are also due to sensory disturbances that affect sensorimotor integration. The
aim of this review is to discuss the possible contribution of neurophysiologic
techniques in evaluating the functionality of sensorimotor integration mechanisms
in PD. Somatosensory evoked potentials (SEPs) are an appropriate functional
approach for the evaluation of sensory processes in the human brain. SEPs from
the frontal scalp sites are considered markers of the functionality of a cortico
subcortico-cortical loop that includes the basal ganglia as well as the premotor
and supplementary motor areas. Over the years, it has been demonstrated that PD
patients--especially in the early stages of the disease--show a severely
depressed frontal responsiveness to sensory stimuli as tested via SEPs. The
transient recovery of frontal SEP amplitude after apomorphine, a potent dopamine
agonist drug, is a good and specific predictor of the clinical response of PD
patients to L-dopa therapy.
PMID- 10785839
TI - Respiratory function in Parkinson's disease.
AB - This article reviews the spectrum of respiratory dysfunction in Parkinson's
disease (PD). It includes the primary effects of PD on the ventilation, response
to medications, and pulmonary complications of antiparkinson therapy. Primary
pulmonary abnormalities include a restrictive change mainly secondary to chest
wall rigidity and upper airway obstruction; both are responsive to dopaminergic
modulation. Respiratory dyskinesia, a side effect of levodopa therapy, may
produce both restrictive and dyskinetic ventilation. Therapy with ergot
derivatives may result in pleuropulmonary fibrosis. Lastly, pulmonary infection
as a consequence of disordered respiratory mechanics continues to contribute
significantly to morbidity and mortality in PD.
PMID- 10785840
TI - Gastrointestinal dysfunction in Parkinson's disease.
AB - Gastrointestinal dysfunction is a frequent and occasionally dominating symptom of
Parkinson's disease (PD). Features of gastrointestinal dysfunction include
disordered control of saliva, dysphagia, gastroparesis, constipation in the sense
of decreased bowel movement frequency, and defecatory dysfunction necessitating
increased straining and resulting in incomplete evacuation. Excess saliva
accumulates in the mouth because of decreased swallowing frequency. Dysphagia
develops in approximately 50% of patients and may be a reflection of both central
nervous system and enteric nervous system derangement. Gastroparesis may produce
a variety of symptoms, including nausea, and also may be responsible for some of
the motor fluctuations seen with levodopa therapy. Bowel dysfunction in PD may be
the result of both delayed colon transit and impaired anorectal muscle
coordination.
PMID- 10785841
TI - Visuo-cognitive dysfunctions in Parkinson's disease.
AB - Loss of will, decreased activity, and poverty of behavior are among the common
symptoms observed in Parkinson's disease (PD). In line with these clinical
observations, PD patients display prominent deficit in neuropsychological tests,
requiring self-generated and effort-demanding operations. However, recent
evidence suggests that this impairment is not generalized: visuo-spatial working
memory and attentional set-shifting seem to be selectively impaired in the early
stages of the disease. Electrophysiological studies also demonstrate the
dysfunction of higher-level visual information processing. In this article, we
discuss some current results to show the connection between clinical symptoms and
neuropsychological deficits. We also consider dysfunction in underlying neural
mechanisms, with particular emphasis on the dysregulation of fronto-striatal
circuits. However, it is conceivable that visuo-cognitive impairment in PD
reflects dysfunction of neural assemblies, involving basal ganglia, dorsal visual
stream, and frontal-prefrontal circuits.
PMID- 10785842
TI - Cardiovascular autonomic dysfunction in parkinsonian patients.
AB - Cardiovascular dysfunction may occur in parkinsonian patients for a variety of
reasons. Patients usually are more than 50 years old and on various drugs (both
antiparkinsonian and for associated medical disorders), some of which may have
cardiovascular effects. Autonomic failure increases with age and also is
recognized in parkinsonian patients who have the disorder multiple system
atrophy, in which there is substantial cardiovascular dysfunction. Thus,
recognition of cardiovascular dysfunction and its causes in parkinsonian patients
is of importance in diagnosis (in separating the various parkinsonian diseases),
in determining prognosis, and finally in management. This article outlines the
major areas of cardiovascular dysfunction, including disorders of blood pressure
control, heart rate, and regional circulation, especially to vital organs.
Clinical features and evaluation are described, together with abnormalities in
different parkinsonian disorders and the principles of management.
PMID- 10785843
TI - The role of costimulatory molecules as targets for new immunosuppressives in
transplantation.
AB - T-cell costimulation is critical for all T-cell-mediated immune responses that
are responsible for endpoints such as allograft rejection or autoimmune disease.
Recent experimental data elucidate specific pathways for T-cell activation and
negative regulatory mechanisms via unique costimulatory molecules. These data
have implications for the development of novel therapeutic strategies to prevent
graft rejection and improve long-term graft survival in transplant patients, and
to treat autoimmune diseases in humans.
PMID- 10785844
TI - Vasoactive substances in renal transplantation.
AB - During and after transplantation the kidney experiences a variety of insults that
result in functional impairment and structural damage. These changes are mediated
or influenced by hormones, cytokines, enzymes and growth factors, which are
excreted by endothelial, graft parenchymal as well as by graft infiltrating
cells. This review evaluates the pathophysiological role of vasoactive substances
(for example, the vasoconstrictors angiotensin II and endothelin, as well as
vasodilators such as nitric oxide, adrenomedullin and atrial natriuretic peptide)
in kidney transplantation and summarizes recent reports that indicate that
targeting vasoactive substances may represent effective therapeutic strategies
for the achievement of long-term allograft survival.
PMID- 10785845
TI - The importance of genetic polymorphisms in renal transplantation.
AB - Genetic variations including single nucleotide polymorphisms, dinucleotide
repeats and microsatellites have been identified in a number of genes encoding
cytokines, cytokine receptors, chemokines and their receptors, adhesion
molecules. Several of the polymorphisms are located in the promoter region of the
gene, affect transcription or translation, and not infrequently determine the
level of expression of the protein product. An interesting and testable
hypothesis for the clinical heterogeneity and differential responsiveness in
allograft recipients is genetic variation. These nucleotide sequence variations,
polymorphisms located in genes contributing to immune repertory and in genes
responsible for drug metabolism, are excellent candidates for the differential
clinical phenotype.
PMID- 10785846
TI - Impact of dyslipidaemia in renal transplant recipients.
AB - The evidence that lipid disorders in patients following renal transplantation
play a major role in the pathogenesis of atherosclerosis and chronic renal
allograft rejection is circumstantial. The absolute rate of clinical vascular
disease and cardiovascular complications in transplant patients, the high
prevalence of an atherogenic lipid profile and the evidence from the large HMG
CoA reductase inhibitor (statin) regression trials in the general population
suggest that lipid lowering treatment is necessary in most patients after renal
transplantation. Furthermore, animal models and observational studies in patients
have found correlations between plasma lipid levels and both acute and chronic
rejection. Animal transplant models and clinical trials in heart transplant
patients also suggest that statin treatment decrease the incidence of chronic
rejection in a manner that may also be independent of lipid lowering. Although
the mechanisms behind this protective effect remains unclear, statins may be the
first agents to be effective in preventing chronic rejection and in reducing the
rate of cardiovascular complication in renal transplant recipients.
PMID- 10785847
TI - Mechanisms of hypertension after renal transplantation.
AB - Hypertension is extremely prevalent after renal transplantation, affecting up to
70% of all patients. An elevation in blood pressure is associated with an
increased cardiovascular risk and may also contribute to chronic allograft
failure. Renal transplantation provides interesting insights into the
pathogenesis of hypertension. Experimental and human data show that the kidney is
an essential organ for blood pressure regulation. In clinical practice a
differential diagnosis that is based on excretory allograft function has proved
useful.
PMID- 10785849
TI - The safe administration of intravenous contrast material for urologists and
radiologists.
PMID- 10785848
TI - Hyperhomocysteinemia in organ transplantation.
AB - An elevated total homocysteine plasma concentration is associated with an
increased morbidity and mortality due to cardiovascular disease in the general
population, in patients with renal failure and in recipients of kidney or heart
transplants. The fasting or post-methionine loading plasma concentration of total
homocysteine is elevated in 50-60% of renal transplant recipients with stable
graft function and in the majority of heart transplant recipients. Fasting and
post-methionine loading hyperhomocysteinemia can be normalized in virtually all
renal transplant patients by a combination of folic acid (5 mg/d), vitamin B6 (50
mg/d) and vitamin B12 (0.4 mg/d). In individuals without renal failure much lower
doses of folate and vitamin B12 are able to correct hyperhomocysteinemia.
Currently, prospective studies are under way to clarify whether folate and
vitamin therapy improves cardiovascular disease morbidity and mortality in the
general population and in organ transplant recipients. While population wide
screening for and treatment of hyperhomocysteinemia is generally not recommended,
treatment of high risk patients, including renal failure patients and kidney and
heart transplant recipients, can be considered but still represents an
experimental therapy.
PMID- 10785850
TI - Testicular microlithiasis.
AB - Testicular microlithiasis is an uncommon condition that is characterized by
calcifications within the lumina of seminiferous tubules. It is usually an
incidental finding on high frequency scrotal sonography. Testicular
microlithiasis is a benign condition but is associated with testicular
malignancies. Recent reports support this association and suggest regular follow
up in these patients.
PMID- 10785851
TI - Imaging guided biopsies of renal masses.
AB - Percutaneous fine-needle aspiration biopsy can be used for the diagnosis of many
abdominal masses. It is safe and accurate, and is often all that is necessary to
determine treatment. Fine-needle aspiration biopsy is both accurate and cost
effective, comparing favorably with open surgical biopsy. The use of percutaneous
biopsy for the diagnosis of renal masses is now more commonplace as urologists
and radiologists become familiar with its indications, contraindications,
accuracy and complications.
PMID- 10785852
TI - Risks and complications of transrectal ultrasound.
AB - Transrectal ultrasound guided needle biopsies of the prostate are routinely
performed to diagnose and stage prostate cancer. This diagnostic technique is a
safe method to diagnose prostate cancer with few major complications but frequent
minor complications.
PMID- 10785853
TI - Radiology of urinary diversions.
AB - Radiologic evaluation of urinary diversion has three objectives: to monitor upper
tract distention, to detect new urothelial tumors and to detect metastasis. The
type of imaging procedure and the frequency of imaging is dictated by the
urologist preference. As many surgical procedures are available for noncontinent
and continent diversion, interpretation of radiographic studies requires a
detailed knowledge of the type of surgical procedure that has been performed.
PMID- 10785854
TI - Unenhanced helical computed tomography in the evaluation of acute flank pain.
AB - Noncontrast helical computed tomography has rapidly replaced other imaging
modalities in the evaluation of patients with acute flank pain. New studies from
multiple centers have compared helical computed tomography directly with
intravenous urography in large numbers of patients, confirming the value of the
former. It is highly sensitive and specific for the diagnosis of
ureterolithiasis, including the visualization of ureteral calculi and secondary
signs of obstruction. It can evaluate alternate diagnoses, improving the utility
of noncontrast helical computed tomography as a diagnostic tool in the evaluation
of acute flank pain.
PMID- 10785855
TI - Bibliography. Current world literature. Renal medicine and renal transplantation.
PMID- 10785856
TI - Bibliography. Current world literature. Imaging--new diagnostic techniques.
PMID- 10785857
TI - Mx mRNA expression and RFLP analysis of rainbow trout Oncorhynchus mykiss genetic
crosses selected for susceptibility or resistance to IHNV.
AB - Three interferon-inducible Mx genes have been identified in rainbow trout
Oncorhynchus mykiss and their roles in virus resistance have yet to be
determined. In mice, expression of the Mx1 protein is associated with resistance
to influenza virus. We report a study to determine whether there was a
correlation between the expression of Mx in rainbow trout and resistance to a
fish rhabdovirus, infectious hematopoietic necrosis virus (IHNV). A comparison of
Mx mRNA expression was made between different families of cultured rainbow trout
selected for resistance or for susceptibility to IHNV. A trout-specific Mx cDNA
gene probe was used to determine whether there was a correlation between Mx mRNA
expression and resistance to the lethal effects of IHNV infection. Approximately
99% of trout injected with a highly virulent strain of the fish rhabdovirus,
IHNV, were able to express full length Mx mRNA at 48 h post infection. This is
markedly different from the expression of truncated, non-functional Mx mRNA found
in most laboratory strains of mice, and the ability of only 25% of wild mice to
express functional Mx protein. A restriction fragment length polymorphism (RFLP)
assay was developed to compare the Mx locus between individual fish and between
rainbow trout genetic crosses bred for IHNV resistance or susceptibility. The
assay was able to discriminate 7 distinct RFLP patterns in the rainbow trout
crosses. One cross was identified that showed a correlation between homozygosity
at the Mx locus and greater susceptibility to IHN-caused mortality.
PMID- 10785858
TI - Use of RT-PCR for diagnosis of infectious salmon anaemia virus (ISAV) in carrier
sea trout Salmo trutta after experimental infection.
AB - The emergence of infectious salmon anaemia virus (ISAV) in Canada and Scotland
and frequent new outbreaks of the disease in Norway strongly suggest that there
are natural reservoirs for the virus. The main host for the ISA virus is probably
a fish occurring in the coastal area, most likely a salmonid fish. Since sea
trout is an abundant species along the Norwegian coast, common in areas where ISA
outbreaks occur, and possibly a life-long carrier of the ISA virus, a study was
initiated to evaluate reverse transcriptase polymerase chain reaction (RT-PCR)
for diagnosis of the virus in experimentally infected trout. Several tissues
(kidney, spleen, heart and skin) were collected from the trout during a 135 d
period. The following diagnostic methods for detection of the ISA virus were
compared: cell culture (Atlantic Salmon Kidney, ASK cells), challenge of disease
free salmon with blood from the infected trout, and RT-PCR. The RT-PCR was the
most sensitive of these methods. With the help of this technique it was possible
to pick out positive individuals throughout the experimental period of 135 d.
Challenge of disease-free salmon were more sensitive than cell culture (ASK
cells). These 2 latter methods require use of the immunofluorescent antibody test
(IFAT) or RT-PCR for verification of presence of ISA virus.
PMID- 10785859
TI - An RT-PCR-based method for the diagnosis of the sleeping disease virus in
experimentally and naturally infected salmonids.
AB - The sleeping disease (SD) of rainbow trout (Oncorhynchus mykiss) is a worldwide
disease for which the causative agent, the sleeping disease virus (SDV), has been
recently characterized as an atypical alphavirus (Villoing et al. 2000). Up to
now, no diagnostic tools were available and thus no epidemiological studies have
been undertaken to evaluate the occurrence of this disease on the field. We
present in this paper a sensitive and highly specific 1 working day method, which
allows the detection of SDV from experimentally and naturally infected fishes.
This method, based on a reverse transcriptase/polymerase chain reaction (RT-PCR)
assay on total RNA extracted from SDV-infected fish organs, enables the specific
DNA amplification of part of the gene encoding the SDV glycoprotein E2, as early
as 2 d post-infection (d.p.i.) and as late as 70 d.p.i., at which time clinical
signs of infection are no longer apparent. Moreover, we show that this RT-PCR
method can be successfully used for the diagnosis of fish infected by a closely
related virus, namely salmon pancreas disease virus (SPDV). This report is the
first description of a very powerful diagnostic assay which could provide a more
accurate replacement for the classical virological, histological and
immunochemistry methods.
PMID- 10785860
TI - Immunization of cultured juvenile rockfish Sebastes schlegeli against Microcotyle
sebastis (Monogenea).
AB - To determine whether immunization with Microcotyle sebastis antigen could induce
protection against the parasite's establishment, naive juvenile rockfish were
immunized by injection or immersion with whole worm antigen of M. sebastis. The
infestation intensities of immunized groups following a challenge (2 wk after
boosting) with 5000 M. sebastis eyed-eggs were significantly lower than those of
control groups, when determined 7 wk postinfection. The fish in the groups
boosted with M. sebastis antigen showed stronger protection than unboosted
groups. The control group injected with FCA only showed a significantly smaller
number of worms than the control group, which was immersed in PBS containing
seawater. The results strongly suggest that both specific and nonspecific immune
factors participate in the protection of rockfish against M. sebastis
establishment.
PMID- 10785861
TI - The life cycle of Sphaerospora truttae (Myxozoa: Myxosporea) and some features of
the biology of both the actinosporean and myxosporean stages.
AB - A previously undescribed echinactinomyxon type actinosporean was shown
experimentally to be the alternate stage of Sphaerospora truttae. The
echinactinomyxon type spores were found to be released from Lumbriculus
variegatus and occasionally Tubifex tubifex. Overall infection prevalence of the
echinactinomyxon was 0.14%. Peak release was in March-May each year. S. truttae
spores developed in experimentally infected salmon 4.5 mo post-exposure to
echinactinomyxon spores. Extrasporogonic stages of S. truttae first appeared in
naturally infected salmon in early July and persisted for 8 to 10 wk. Correlation
between peak release of echinactinomyxon spores and appearance of extrasporogonic
stages of S. truttae is discussed.
PMID- 10785862
TI - Pathological changes caused by cold-water stress in Japanese eel Anguilla
japonica.
AB - In the present study, histopathological changes in Japanese eel Anguilla japonica
subjected to 'cold-water stress' were examined. Eels were exposed to cold water
(13 to 15 degrees C) and warmer water (25 degrees C) as controls. Fish held in
warm water did not show any apparent changes. Although none of the eels exposed
to cold water died, they displayed nephrotic changes such as cloudy swelling and
hyaline droplet degeneration of the renal tubular epithelia. Fish with nephroses
had low levels of serum chloride (12 to 23 mg l-1 in fish with hyaline droplet
degeneration, 71 to 81 mg l-1 in fish with cloudy swelling) compared with the
control fish (87 to 109 mg l-1). In electron microscopy, affected tubular cells
had variously damaged mitochondria and formations of secondary lysosomes of
variable sizes. Electron microscopy also revealed mitochondrial degeneration in
hepatocytes and degenerated granules of neutrophils in the hematopoietic tissue.
'Cold-water stress' was effective in damaging Japanese eels below 15 degrees C.
PMID- 10785863
TI - Some new observations on the cytopathology of fin erosion disease in winter
flounder Pseudopleuronectes americanus.
AB - A light and electron microscopic study was conducted on dorsal fin tissues
adjacent to acute fin erosion lesions in winter flounder from 2 polluted sites
(New York Bight region and New Haven Harbor) on the northeast Atlantic Coast. The
objective of this work was to evaluate these minimally affected, lesion
associated tissues which may precede the acute or severe stages of the disease.
The following 4 types of pathological conditions were found in the epidermis of
diseased fish from the 2 polluted sites: (1) epithelial cell hyperplasia; (2)
mucous cell hyperplasia and hypertrophy; (3) spongiosis; and (4) focal necrosis.
The latter 2 types of lesions have not been previously reported for fin erosion
in this species. Changes in the dermis associated with these lesions included
fibrosis, abnormal distribution of melanocytes, hyperemia and sclerosis of blood
vessels, and hemorrhage. The possibility that hypoxia may play a role in the
observed pathology is considered.
PMID- 10785864
TI - A survey of some parasites and diseases of several species of bivalve mollusc in
northern Western Australia.
AB - Pteriid oysters (Pinctada maxima, Pinctada margaritifera, Pinctada albina, Pteria
penguin), rock oysters (Saccostrea glomerata, Saccostrea cuccullata, Saccostrea
echinata) and representatives of other taxa (Malleidae, Isognomonidae, Pinnidae,
Mytilidae, Spondylidae, Arcidae) from the wild, and 4670 hatchery-reared P.
maxima, from northern and Western Australia, were examined for parasites and
diseases. Rickettsiales-like inclusions and metacestodes of Tylocephalum occurred
in most species. Intranuclear virus-like inclusions occurred in 1/415 wild P.
maxima, 1/1254 S. cuccullata, 3/58 Isognomon isognomum, 1/80 Pinna bicolor and
1/45 Pinna deltodes. Perkinsus was histologically observed in 1/4670 P. maxima
spat, 2/469 P. albina, 1/933 S. glomerata, 16/20 Malleus meridianus, 12/58 I.
isognomum, 1/45 P. deltodes, 5/12 Spondylus sp., 1/16 Septifer bilocularis and
3/6 Barbatia helblingii. One of 1254 S. cuccullata was heavily systematically
infected with Perkinsus merozoites, meronts and schizonts, and was patently
diseased. Other potentially serious pathogens included Haplosporidium sp. in
6/4670 P. maxima spat, Marteilia sydneyi from 1/933 S. glomerata, and Marteilia
sp. (probably M. lengehi) (1/1254) and Haplosporidium sp. (125/1254) from S.
cuccullata. The latter were associated with epizootics on offshore islands, with
heaviest prevalence (45%) in oysters with empty gonad follicles. Marteilioides
sp. infected the oocytes of 9/10 female S. echinata from Darwin Harbour. Details
of geographical distribution and pathology are given, and the health of the
bivalves examined is discussed.
PMID- 10785865
TI - Conservation of sequence in the internal transcribed spacers and 5.8S ribosomal
RNA among geographically separated isolates of parasitic scuticociliates
(Ciliophora, Orchitophryidae).
AB - Nucleotide sequence from the internal transcribed spacers (ITS1 and ITS2) and the
5.8S gene from the ribosomal RNA gene cluster of isolates of the scuticociliate
Orchitophrya stellarum from 4 asteroid hosts were compared. Surprisingly, these
data (495 bp) were identical for O. stellarum isolated from the testes of
Asterias amurensis from Japan; Pisaster ochraceus from British Columbia, Canada;
Asterias rubens from The Netherlands; and Asterias vulgaris from Prince Edward
Island, Canada. These sequence data were compared to those from 3 scuticociliates
which parasitise crustaceans: Mesanophrys pugettensis, M. chesapeakensis and
Anophryoides haemophila. No difference was found in this region between the
nucleotide sequence of M. pugettensis and M. chesapeakensis. The sequence of
Mesanophrys spp. differed by 9.2% in the ITS1 and 4.7% in the ITS2 from that of
O. stellarum. The sequence from the ITS1 (135 bp) and ITS2 (233 bp) of A.
haemophila differed by 42.6 and 20.5% respectively from those of O. stellarum.
Therefore, nucleotide sequence of the ITS regions in these scuticociliates is
highly conserved.
PMID- 10785866
TI - Sodium, potassium, calcium and magnesium and cardiovascular risk.
PMID- 10785867
TI - Salt, blood pressure and cardiovascular diseases.
AB - The rise in average blood pressure with age seen in Western populations does not
occur in isolated traditional nomadic communities. Several factors contribute to
the higher blood pressure in the West. Salt is particularly important, however,
because its effect on blood pressure is large, the dietary intake by Western
populations is high and a large reduction in its intake is realistic. The size of
the relationship between salt and blood pressure depends on age and, in trials,
the duration of reduction of intake of salt. Results of many of the randomized
trials have suggested that reduction of dietary salt exerts only a small effect
on average blood pressure; this is because their subjects have been young
(average age 26 years) and trials have been of short duration (average 2 weeks).
Analysis of observational data concerning various communities indicated that a
reduction in dietary intake of sodium of 100 mmol/24 h (3 g of salt, a realistic
reduction) lowers systolic blood pressure in subjects aged 50-65 years by 10 mmHg
on average. Much evidence corroborates this estimate, including data from the
Intersalt study and a randomized controlled trial of reduction of intake of salt
by older persons. This reduction in blood pressure would reduce age-specific
stroke mortality by an estimated 22% and mortality from heart disease by 16%.
Reducing the amount of salt added to manufactured foods is an important public
health target.
PMID- 10785868
TI - Salt and cardiovascular disease: clinical and epidemiological evidence.
PMID- 10785869
TI - Dietary potassium and cardiovascular disease: clinical applications.
PMID- 10785870
TI - Calcium intake and blood pressure: an update.
PMID- 10785871
TI - A review of the link between dietary magnesium and cardiovascular risk.
PMID- 10785872
TI - C282Y mutation in the HLA-H gene is not a risk factor for patients with
myocardial infarction.
AB - BACKGROUND: Iron is suspected to play a role in the development of
atherosclerosis and in the progression of the disease, and consequently in
myocardial infarction. Authors of a recent study identified a mutation in HLA-H
gene, C282Y, that is an excellent marker for hemochromatosis, which is the most
common cause of iron overload. There is a high prevalence of carriers of
heterozygous hemochromatosis, most of whom are asymptomatic even with
abnormalities of iron metabolism. OBJECTIVE: To study C282Y mutation in the HLA-H
gene of 173 survivors of myocardial infarction matched with 172 controls by age,
race, and sex, and 119 patients upon diagnosis of acute myocardial infarction.
METHODS: Identification of the mutation was performed by PCR amplification of the
DNA fragment followed by Rsal digestion. RESULTS: The prevalence of heterozygotes
for the mutated allele both among patients and among controls was 1.74%. None of
the 119 patients studied upon diagnosis was a carrier of the mutation.
CONCLUSION: Our data suggested that the most common cause of iron overload is not
associated with myocardial infarction.
PMID- 10785873
TI - Circulating lipoprotein profiles are modulated differently by lipoprotein lipase
in obese humans.
AB - BACKGROUND: Several genetic analyses have suggested that lipoprotein lipase (LpL)
genotypes causing decreased LpL activity correlate with increased triglyceride
concentrations and risk for coronary artery disease. In contrast, in some other
studies LpL activity was positively correlated with plasma low-density
lipoprotein (LDL) cholesterol concentrations. OBJECTIVE: To assess whether these
different associations represent physiologic differences in lipoprotein
metabolism. METHODS: We correlated postheparin lipase activities, postprandial
lipemia, and fasting lipoprotein concentrations in obese (BMI > or = 30 kg/m2, n
= 26) and non-obese (BMI < or = 30 kg/m2, n = 57) individuals. LpL was measured
using specific inhibitory antibodies. RESULTS: Surprisingly, LpL activity was
significantly correlated with triglyceride area under the curve after a fat load
in the non-obese, but not the entire group. Moreover, in non-obese individuals,
LpL activity correlated directly (r = 0.40) and hepatic lipase activity
correlated inversely (r = -0.32) with high-density lipoprotein (HDL) cholesterol
concentrations. These relationships were not found in the obese group, in whom
LpL correlated with LDL cholesterol concentrations (r = 0.54). CONCLUSIONS: We
conclude that postheparin LpL activity relates to different lipoproteins in obese
and non-obese individuals. In obesity, greater LpL activity may enhance
conversion of very-low-density lipoprotein cholesterol to LDL cholesterol,
whereas in non-obese individuals the correlation is with HDL cholesterol. Whether
this is due to differences in the source of LpL (muscle or fat), or to other
associated alterations in lipoprotein metabolism is unknown. These results may
explain the non-uniformity of correlations between LpL and atherogenic
lipoproteins in different populations.
PMID- 10785874
TI - Influence of high-density lipoprotein cholesterol and rheological factors on the
sex difference in cardiovascular disease.
AB - BACKGROUND: It is well established that the incidence of cardiovascular disease
among men is higher than that among women. OBJECTIVE: To determine whether
differences between men and women in terms of a range of conventional and
rheological risk factors could explain this sex difference. DESIGN: This was a
population-based cohort study (the Edinburgh Artery Study). METHODS: Men and
women aged 55-74 years (n = 1592) were selected at random from the general
population of Edinburgh and followed up for 5 years. Baseline cardiovascular risk
factors were measured and related to incidence of disease among men and women.
RESULTS: Men had higher levels of cigarette smoking, haematocrit and blood
viscosity and lower levels of low-density lipoprotein (LDL) cholesterol, high
density lipoprotein (HDL) cholesterol and plasma fibrinogen than did women. The
incidences of cardiovascular events among men and women were 48.3 and 26.1 per
1000 person-years, respectively. Adjustment for level of HDL cholesterol reduced
the male:female ratio for sex-specific incidence rates of cardiovascular events
from 1.80 [95% confidence interval (CI) 1.43-2.27] to 1.34 (95% CI 1.04-1.73).
This reduction was partially reversed after further adjustment for the other
cardiovascular risk factors. The impact of blood viscosity, plasma viscosity and
plasma level of fibrinogen on the risk of cardiovascular disease was higher for
men than it was for women (multivariate relative risk for blood viscosity were
1.24, 95% CI 1.08-1.43, for men and 0.81, 95% CI 0.61-1.06, for women).
CONCLUSIONS: Levels of HDL cholesterol levels in women being higher than those in
men may explain some, but not all, of the sex difference in incidence of
cardiovascular disease. Greater susceptibility of men to rheological factors
might also be important.
PMID- 10785875
TI - Rilmenidine in the hypertensive type-2 diabetic: a controlled pilot study versus
captopril.
AB - BACKGROUND: Rilmenidine is an innovative antihypertensive agent that binds
specifically to I1 imidazoline receptors. The antihypertensive efficacy of
rilmenidine in treating type-2 diabetics has been demonstrated, and is associated
with very good clinical and laboratory tolerance. DESIGN: This was a 6-month,
double-blind, randomized, controlled study comparing the effects of rilmenidine
and captopril on the progression of microalbuminuria in a population of patients
with mild-to-moderate hypertension [90 mmHg < diastolic blood pressure (DBP) <
110 mmHg], type-2 diabetes, and microalbuminuria (30 mg/24 h < urine albumin
excretion < or = 300 mg/24 h). RESULTS: Between month 0 and month 6, the mean
supine blood pressure was reduced in a similar manner by rilmenidine (systolic
blood pressure from 159 to 141 mmHg and diastolic blood pressure from 98 to 84
mmHg) and captopril (systolic blood pressure from 157 to 144 mmHg and diastolic
blood pressure from 101 to 82 mmHg). The median value for microalbuminuria was
reduced from 160 (90-260) to 56 (27-87) mg per 24 h by rilmenidine and from 144
(51-200) to 54 (41-123) mg per 24 h by captopril. Rate of clearance of creatinine
was not significantly changed during the study by either treatment (with
rilmenidine it varied from 95.2 to 95.6 ml/min; with captopril it varied from
86.2 to 90.4 ml/min). There was no statistical difference between the changes in
levels of glycosylated hemoglobin for the groups treated with rilmenidine and
captopril. Clinical and laboratory acceptabilities were good, and those for the
two groups were comparable. CONCLUSION: Rilmenidine exerts similar
antihypertensive effects to those of captopril on the hypertensive with type-2
diabetes. Decreases in microalbuminuria elicited by the two treatments do not
differ. That administration of rilmenidine decreases microalbuminuria suggests
that it could exert nephroprotective effects.
PMID- 10785877
TI - Bibliography. Current world literature.
PMID- 10785876
TI - A comparison of algorithms for initiation of lipid lowering therapy in primary
prevention of coronary heart disease.
AB - OBJECTIVE: To compare nine different algorithms for determining the necessity for
drug treatment of hyperlipidaemia in patients without cardiovascular disease.
DESIGN: Risk-factor data on 400 patients were obtained. Algorithms assessed
included the Framingham model, National Cholesterol Education Program, European,
British, New Zealand, British Regional Heart Study, Sheffield, Munster Heart
Study and Dundee guidelines and a local general rule for treatment of atheroma
(General Rule to Enable Atheroma Treatment). SETTING: Three hospital lipid
clinics. RESULTS: Patients were 56% male, aged 53.8 +/- 12.3 years, 38% smoked,
55% had a family history of disease (37% familial hypercholesterolaemia, 33%
hypertension and 5.2% left ventricular hypertrophy); 31% were moderately obese
and 15% were diabetic. The average cholesterol level was 7.9 +/- 2.6 mmol/l.
Median Framingham risk was 1.66%/year and this risk was > 2%/year for 37% and >
3%/year for 17.5%. Treatment was required for 86% by National Cholesterol
Education Program, 70% by General Rule to Enable Atheroma Treatment and European,
61% by New Zealand, 58% by British, 42% by Dundee, 40% by Munster Heart Study,
25% by British Regional Heart Study and 16% by Sheffield guidelines. Algorithms
varied regarding recommendations for treatment of men, women, patients with
familial hypercholesterolaemia and diabetes. Confounders included risk levels,
definitions and weightings for additional risk factors. CONCLUSIONS: Different
algorithms vary widely in their predictions of need for drug treatment of this
high-risk population with hyperlipidaemia. Authors of guidelines for
cardiovascular disease need to unify risk thresholds and definitions and audit
the effects of additional weighting factors so that patients can be treated
consistently.
PMID- 10785879
TI - Reduction of medical errors: an order.
PMID- 10785878
TI - An unusual anesthesia machine leak.
PMID- 10785880
TI - Cardiopulmonary morbidity as a complication of severe preeclampsia HELLP
syndrome.
AB - OBJECTIVE: To profile the types and frequencies of cardiopulmonary morbidity
encountered in patients with severe preeclampsia with or without hemolysis,
elevated liver enzymes, and low platelets (HELLP syndrome). STUDY DESIGN: We
initiated a retrospective study of 979 patients with severe preeclampsia with and
without HELLP syndrome. Types of cardiopulmonary morbidity were analyzed among
the three classes of HELLP syndrome and severe preeclampsia without HELLP
syndrome. RESULTS: Cardiopulmonary morbidity occurred in 7.6% of study patients.
As a group, patients with cardiopulmonary complications were more likely to have
cesareans (11% vs 6%, p = 0.019) earlier in gestation (1366 +/- 700 gm birth
weight versus 1734 +/- 892 gm birth weight, p = 0.021), with higher peak
postpartum blood pressures (< 0.001) and with more abnormal laboratory values
indicative of multisystem disease, compared with patients without this
complication. Patients with cardiopulmonary complications required almost twice
as long to achieve diuresis as comparison patients (22 +/- 23 hours versus 12 +/-
11 hours, p < 0.001). CONCLUSION: The probability of cardiopulmonary
complications increases significantly when patients develop class 1 HELLP
syndrome. Of all cardiopulmonary complications, acute lung injury/acute
respiratory distress syndrome is most specific to class 1 HELLP syndrome.
Transient renal dysfunction is closely related to cardiopulmonary morbidity.
PMID- 10785881
TI - Perinatal outcome of twin pregnancies with one structurally affected fetus: a
case-control study.
AB - OBJECTIVE: To determine whether one structurally affected fetus of a twin
pregnancy further increases the risk of preterm delivery and to compare perinatal
morbidity and mortality in these pregnancies with twin gestations with
structurally normal fetuses. STUDY DESIGN: The cases (n = 25) included all twin
gestations diagnosed from 1991 to 1994 with a sonographically detected fetal
anomaly and a structurally normal co-twin delivered after 24 completed weeks'
gestation. The control group consisted of 547 twin gestations delivered during
the study period with no sonographically detected structural anomalies in either
twin. RESULTS: Compared with controls, pregnancies with a single anomalous fetus
(cases) delivered at a significantly lower gestational age (mean +/- SD: 34.0 +/-
3.2 weeks versus 35.6 +/- 3.2 weeks; p = 0.019) and had a significantly increased
preterm delivery rate (76.0% vs 55.4%; p = 0.042). There was no significant
difference in the incidence of intraventricular hemorrhage or respiratory
distress syndrome, yet the perinatal mortality (80.0/1000 vs 6.4/1000; p = 0.000)
and the average nursery stay (45.5 +/- 43.3 days versus 17.0 +/- 24.0 days; p =
0.003) were significantly increased for cases compared with controls. In
addition, a significantly greater birth weight discordancy (> or = 30%) was seen
in cases compared with controls (32.0% versus 9.1%; p = 0.002). The normal co
twin did not show any significant difference in the perinatal outcome variables
studied when compared with controls. CONCLUSION: Compared with structurally
normal twin pairs, twin gestations with a single anomalous fetus are at a
significantly increased risk for preterm delivery. In addition, the anomalous
fetus, but not the structurally normal co-twin, has a significantly increased
mortality rate and a longer nursery stay. Finally, despite the increased risk for
preterm delivery in twin pregnancies with one anomalous fetus, it is the nature
of the anomaly itself that dictates the perinatal outcome.
PMID- 10785882
TI - Clinical experience in enteral nutrition support for premature infants with
bronchopulmonary dysplasia.
AB - OBJECTIVE: The comprehensive management of infants with bronchopulmonary
dysplasia (BPD) may include the need for fluid restriction. Modular nutrient
components added to preterm formulas increase energy and protein contents but may
compromise the nutrient integrity of the formula. The purpose of this pilot study
was to compare the nutritional status and feeding tolerance of infants fed either
a 30 kcal/oz ready-to-feed formula or a preterm formula containing nutrient
supplements. METHODS: Feeding tolerance, growth, and biochemical indicators of
nutritional status were compared in 27 premature infants with BPD who were fluid
restricted. These infants were fed either a 30 kcal/oz ready-to-feed formula or a
preterm formula with additives concentrated to 30 kcal/oz. RESULTS: Growth and
feeding tolerance were similar between groups. Serum albumin and blood urea
nitrogen concentrations, however, were improved in the ready-to-feed formula
group. CONCLUSION: A 30 kcal/oz ready-to-feed formula provides similar nutrient
composition but improved protein nutritional status; this formula is a safe
alternative to preterm formula containing multiple nutrient additives in
premature infants with BPD.
PMID- 10785883
TI - Prediction of postdischarge complications by predischarge event recordings in
infants with apnea of prematurity.
AB - OBJECTIVE: To determine whether predischarge event recording (PDER) can
accurately identify preterm infants with resolving apnea of prematurity (AOP) at
risk for postdischarge complications. DESIGN: PDER was performed on infants with
resolving AOP on caffeine, ready for discharge. The outcome of infants with
normal recordings was compared with that of infants with abnormal recordings.
Follow-up data were obtained for outcome. RESULTS: Of the 106 infants, 74 had a
normal PDER and 32 had an abnormal PDER (apneas lasting for > 20 seconds and/or a
heart rate of < 80 beats per minute for > 5 seconds). Birth weight, gestational
age at birth, length of stay, discharge weight, and duration of caffeine
treatment after discharge were no different between groups. None of the normal
PDER infants (0 of 74) had postdischarge complications, whereas 4 of 32 infants
with an abnormal PDER had complications (p < 0.05, power = 0.7). The positive
predictive value of a normal PDER and no postdischarge complications was 100%.
The positive predictive value of an abnormal PDER and an adverse outcome was
12.5%. CONCLUSION: Normal PDER accurately identifies infants at low risk for an
adverse outcome.
PMID- 10785884
TI - Effect of sepsis syndrome on neonatal protein and energy metabolism.
AB - OBJECTIVE: It was our hypothesis that septic illness would alter both protein and
energy metabolism in neonates, with elevations of tumor necrosis factor-alpha
(TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) serving as
markers for these effects. STUDY DESIGN: A total of 31 infants with suspected
sepsis were enrolled into four groups: septic, sick-nonseptic, healthy-nonseptic,
and recovered septic infants. Degree of illness, oxygen consumption, nitrogen
balance, urine 3-methylhistidine/creatinine (MeH/Cr), and TNF-alpha, IL-6, IL-1
beta, and C-reactive protein (CRP) were measured. RESULTS: Oxygen consumption
increased, while nitrogen balance decreased and MeH/Cr increased with increasing
degree of illness. Nitrogen balance improved on recovery from sepsis. IL-6 and
CRP levels were elevated in septic infants compared with sick-nonseptic and
healthy infants. CONCLUSION: Neonates experience a hypermetabolic response with
increased nitrogen loss during septic illness, proportional to the degree of
illness. Increased delivery of protein substrate may be nutritionally
advantageous to the septic neonate.
PMID- 10785885
TI - Relationship between fetal monitoring and resuscitative needs: fetal distress
versus routine cesarean deliveries.
AB - BACKGROUND: There is debate as to whether pediatricians should be present at all
cesarean deliveries. Little published data exist regarding the differences in
resuscitative needs of infants delivered by cesarean section for "fetal distress"
versus those without this diagnosis. OBJECTIVE: To describe the differences in
resuscitative and immediate postnatal intervention needs for neonates with fetal
distress delivered by cesarean section and those without fetal distress delivered
in the same manner. Also, to devise an evaluation tool to assess and compare
levels of neonatal resuscitation between infants and groups of infants. METHODS:
The delivery records of 1411 term infants delivered by cesarean section after
uncomplicated pregnancies at Los Angeles County/University of Southern California
Medical Center from March 3, 1995 through March 8, 1997 were examined
retrospectively. Apgar scores and resuscitative needs were assigned to a newly
devised, weighted scoring system. Resuscitation subscores and total resuscitation
scores were compared using non-parametric methods. RESULTS: The fetal distress
group (n = 80) had a significantly greater resuscitative needs mean score (p <
0.001) and subscores (p < 0.001 to p = 0.004) than did the non-fetal distress
group (n = 419). Of the non-fetal distress group, 48.7% still received some
active form of intervention. CONCLUSION: In our study group, infants with fetal
distress had significantly greater intervention needs than infants without fetal
distress.
PMID- 10785886
TI - Ethnic differences in the rates of low birth weight attributable to differences
in early motherhood: a study from the Third National Health and Nutrition
Examination Survey.
AB - OBJECTIVE: To estimate the impact of early motherhood (being a mother at < 20
years of age) on ethnic differences in the risk of low birth weight (LBW) in a
representative sample (n = 9141) of American infants and children. METHODS: Risks
for LBW and the population-attributable fraction due to early motherhood were
estimated adjusting for maternal smoking and education in logistic regression
models. The contribution of early motherhood to ethnic differences in the risks
of LBW was determined using a relative attributable risk estimate that compared
Hispanics and Blacks with Whites. RESULTS: Early motherhood was independently
associated with increased risk of LBW in each of the three ethnic groups,
adjusting for maternal smoking during pregnancy and education. Hispanic and Black
ethnicity were each associated with 15% and 123% increased risk of LBW relative
to Whites. The population-attributable fractions of LBW due to early motherhood
were 6.2%, 7.4%, and 2.3%, for Whites, Hispanics, and Blacks, respectively. The
responses of early motherhood for LBW were different among the three ethnic
groups (p < 0.05). Adjusting for maternal smoking and education, 4.8% and 7.4% of
the differences in the risk of LBW between Whites and Hispanics and between
Whites and Blacks, respectively, were due to differences in early motherhood.
CONCLUSION: The result of this study underscores the risk of LBW due to early
motherhood. Because early motherhood is preventable and avoidable, appropriate
public health strategies to educate young women on the need to delay childbearing
in these ethnic groups, particularly among Hispanics and Blacks, are warranted.
PMID- 10785887
TI - Teaching residents in the neonatal intensive care unit: a non-traditional
approach.
AB - Because of the increasing constraints on the amount of time pediatric residents
may train in the neonatal intensive care unit (NICU), concerns have been raised
about the adequacy of their exposure to acute emergencies in the delivery room
and their hands-on experience with sick neonates. Importantly, there are also
concerns about the consistency and quality of supervision of PL-1 residents by
second- and third-year residents, who themselves may not have had sufficient
training in the NICU. To address these concerns, we have instituted an
educational plan that links an experienced neonatal nurse practitioner (NNP) one
on-one with a PL-1 resident in a collaborative team. This plan differs from the
traditional resident-to-resident supervisory model. An anonymous survey of our
residents (n = 14) indicates enthusiastic endorsement of this new educational
model. NNPs as first-line teachers in the NICU provide a new approach for
residency training programs.
PMID- 10785888
TI - A comparative study of serum soluble vascular cell adhesion molecule-1 and
soluble intercellular adhesion molecule-1 in preeclampsia.
AB - OBJECTIVES: Maternal serum soluble vascular cell adhesion molecule-1 (sVCAM-1)
and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated in
preeclampsia to investigate whether these molecules could be helpful with regard
to this pregnancy complication. STUDY DESIGN: The study population was composed
of 30 preeclamptic patients with a mean gestational age of 35.5 +/- 4.6 weeks and
20 age-matched and gestational age-matched normotensive uncomplicated pregnancies
(controls). Blood samples from 7 of the 30 preeclamptic patients and 15 of the 20
controls in the second trimester were also analyzed. Data were analyzed by
parametric methods. RESULTS: Significantly higher maternal serum sVCAM-1 levels
were found in both groups of preeclamptic patients with and without fetal growth
restriction (981 +/- 145 ng/ml; n = 13; p < 0.0005 and 846 +/- 84 ng/ml; p <
0.02, respectively) compared with controls (668 +/- 186 ng/ml). In contrast, no
significant difference was found in maternal serum sICAM-1 levels between
preeclamptic and normotensive pregnancies, or in both adhesion molecules (1) in
the controls between second and third trimester samples and (2) in the second
trimester between pregnant women who developed preeclampsia later and gestational
age-matched controls. CONCLUSION: These findings show a selective significant
elevation of maternal serum sVCAM-1 in preeclampsia, with the highest values in
cases complicated with fetal growth restriction, perhaps reflecting its
angiogenic function. Hence, sVCAM-1 could be helpful in the diagnosis of this
fetal complication in preeclampsia.
PMID- 10785889
TI - Glutaric aciduria type II: observations in seven patients with neonatal- and late
onset disease.
AB - The clinical, biochemical, and neuroradiologic findings and clinical follow-up of
seven patients with glutaric aciduria type II are reported. Three phenotypes of
the disease are encountered: neonatal-onset form with congenital anomalies (two
patients) or without congenital anomalies (three patients) and late-onset form
(two patients). The neonatal-onset form presents as an overwhelming illness, with
severe hypoglycemia and metabolic acidosis leading to rapid death. Frequently it
is associated with perinatal energy deprivation, a neonate with low birth weight
and prematurity. The late-onset form presents with intermittent episodes of
vomiting, hypoglycemia, and acidosis especially after meals rich in fat and/or
proteins. All parents are consanguineous and have a first- or second-degree
relationship. Initially, in the two phenotypes with neonatal onset and during
crisis in the late-onset phenotype, routine laboratory evaluation showed severe
metabolic acidosis, with an increased anion gap, hypoglycemia without ketonuria,
and disturbed liver function tests. In the majority of patients with neonatal
onset forms, the kidneys, liver, and at times the spleen are enlarged with an
increased echogenic pattern; however, no hepatic or renal cysts are detected.
Cardiomegaly is observed in most patients. The diagnosis can be easily and
rapidly reached through tandem mass spectrometry study of the blood and can
further be confirmed by gas chromatography/mass spectrometry analysis of the
urine organic acids. In this report, the magnetic resonance imaging/computed
tomography brain studies showed brain atrophy, white matter disease, and in one
patient, fluid-filled cavities in the periventricular area and putamina. Fluorine
18-labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) brain
studies in two patients with late-onset disease showed slightly decreased
activity in the cerebral cortex in one and in the caudate nuclei in the other.
Brain FDG PET scan and magnetic resonance spectroscopy were normal in one patient
with neonatal-onset disease. All patients were treated with a diet low in fat and
protein, oral riboflavin, and carnitine. The results were promising for the late
onset disease. Intravenous carnitine gave rewarding results in one patient with
neonatal-onset disease.
PMID- 10785890
TI - Parvoviral infection associated with increased nuchal translucency: a case
report.
AB - An increased fetal nuchal translucency detected by first trimester ultrasound has
been associated with an elevated risk of aneuploidy. The etiology of the
increased nuchal translucency in fetuses with normal chromosomes is uncertain,
but it has been associated with poor pregnancy outcome. We report a fetus with
increased nuchal translucency and a normal karyotype, in which parvovirus was
detected by polymerase chain reaction in the amniotic fluid. Although an
ultrasound detected an increased nuchal fold thickness in the second trimester,
the pregnancy was otherwise uncomplicated. Parvovirus should be considered as a
possible etiology of increased nuchal translucency. The risks to a fetus with
first trimester parvovirus infections diagnosed under these conditions are
uncertain and require larger studies.
PMID- 10785891
TI - Persistent central diabetes insipidus presenting in a very low birth weight
infant successfully managed with intranasal dDAVP.
AB - We report a case of a premature very low birth weight infant who presented
shortly after birth with idiopathic central diabetes insipidus that persisted
beyond the neonatal period and has been successfully managed with intranasal 1
desamino-8-D-arginine vasopressin. Although this condition is rare in neonates,
early recognition, evaluation, and therapy may prevent more severe morbidity.
Long-term successful management resulting in normal growth and development during
infancy can be achieved with intranasal 1-desamino-8-D-arginine vasopressin
therapy.
PMID- 10785892
TI - Special imaging casebook. Ventriculus terminalis.
PMID- 10785893
TI - Neonatal intensive care unit (NICU)
PMID- 10785894
TI - Work in the neonatal field.
PMID- 10785895
TI - Reader clarifies concepts of structured exercise programs in managing fatigue.
PMID- 10785896
TI - Article on deep vein thrombosis should address primary brain tumors.
PMID- 10785897
TI - Chemotherapy-induced hair loss is a profound human experience.
PMID- 10785898
TI - Practice tips from the Queen's Medical Center in Honolulu, HI.
PMID- 10785899
TI - Beyond the Supreme Court decision: nursing perspectives on end-of-life care.
AB - PURPOSE/OBJECTIVES: To describe nurses' views of care of the terminally ill.
DESIGN: Descriptive cross-sectional survey. SAMPLE: 300 nurses who completed a
survey published in Nursing98 and Nursing Management and 2,033 nurses randomly
selected from the Oncology Nursing Society (N = 2,333). METHODS: Mailed end-of
life (EOL) care survey. MAIN RESEARCH VARIABLES: Dilemmas, barriers, and
effectiveness of EOL care and education and attitudes regarding assisted suicide
and euthanasia. FINDINGS: EOL care dilemmas are common in nursing practice, and
many barriers exist to providing quality EOL care. Issues of euthanasia and
assisted suicide are particularly significant to nurses who struggle to provide
pain and symptom relief amid a system characterized by deficiencies in EOL care.
CONCLUSIONS: Improved care is contingent on adequate education of nurses as the
primary caregivers of patients and families who are facing the end of life. Study
findings provide direction for improved care of the terminally ill. IMPLICATIONS
FOR NURSING PRACTICE: Oncology nurses are centrally involved in care of the
terminally ill. Major reform is needed to provide quality EOL care.
PMID- 10785900
TI - Issues related to the use of genetic material and information.
AB - PURPOSE/OBJECTIVES: To review issues regarding the use of genetic materials and
information. DATA SOURCES: Professional literature, regional and federal
legislation. DATA SYNTHESIS: An analysis is provided of the relationship among
advances in genetic technology, use of genetic material and information, and the
development of laws that protect the interests of donors, researchers, and
insurers. Rapid technological achievements have generated complex questions that
are difficult to answer. The Human Genome Project began and the scientific
discoveries were put to use before adequate professional and public debate on the
ethical, legal, social, and clinical issues. The term "proper use" of genetic
material and information is not defined consistently. An incomplete patchwork of
protective state and federal legislation exists. CONCLUSIONS: Many complicated
issues surround the use and potential misuse of genetic material and information.
Rapidly advancing technology in genetics makes it difficult for regulations that
protect individuals and families to keep pace. IMPLICATIONS FOR NURSING PRACTICE:
Oncology nurses need to recognize their role as change agents, understand genetic
technology, and advocate for patients by participating in the debate on the
proper use and prevention of misuse of genetic material and information.
PMID- 10785901
TI - Bone marrow transplantation: the battle for hope in the face of fear.
AB - PURPOSE/OBJECTIVES: To describe patients' experience of having an autologous bone
marrow transplantation (BMT). DESIGN: Hermeneutic phenomenologic, descriptive,
and interpretive. SETTING: Outpatient treatment area of a comprehensive cancer
center in the Southwest. SAMPLE: 20 adult survivors of autologous BMT, 15 women
and 5 men, with a mean age of 46 years. METHODS: Content analysis of verbatim
transcriptions of open-ended interviews using hermeneutic phenomenology, which
combines descriptive and interpretive phenomenology. CONCLUSIONS: These patients
illustrate that fear, a predominant reality when undergoing autologous BMT, is
balanced with hope for survival. The overarching fear, fear of death, often was
related to the unknown, including cancer recurrence. The fear of the unknown also
came from being unprepared physically and emotionally. Losses were intertwined
with these fears and included loss of both control and trust in one's body.
Patients discussed fear of leaving the hospital and not having someone
"constantly looking at you to make sure that the cancer isn't back." These fears
and losses changed patients' view of life and led to a need for help in bringing
closure to the experience. IMPLICATIONS FOR NURSING PRACTICE: Specific nursing
actions to help allay fear include providing information about both feelings and
procedures, giving opportunities to discuss fears and losses, arranging meetings
with others who have had a BMT or suggesting an appropriate support group, and
including family in all interventions, as appropriate. Reducing fears with these
interventions helped patients maintain hope. By understanding the relationship
between hope and fear, nurses caring for people having BMT can use specific
strategies to decrease fear, hence increasing hope in patients. Nursing education
can emphasize the need to adequately prepare patients. Further research is
indicated to explore the effectiveness of interventions to prepare patients for
BMT and the interplay between hope and fear.
PMID- 10785902
TI - Effectiveness of oral 5-HT3 receptor antagonists for emetogenic chemotherapy.
AB - PURPOSE/OBJECTIVES: To review the efficacy and safety of the oral 5
hydroxytryptamine3 (5-HT3) receptor antagonists and the use of oral and i.v.
antiemetic therapy during and after hospital admission. DATA SOURCES: Articles in
medical and nursing literature. DATA SYNTHESIS: Use of oral antiemetics may help
patients avoid potential complications associated with i.v. administration and be
more convenient. They also are likely to lower staff and materials costs compared
to i.v. formulations. Oral granisetron is the only oral antiemetic approved in
the United States for use with highly emetogenic chemotherapy regimens. Oral
dolasetron and ondansetron are indicated for use with moderately emetogenic
chemotherapy. CONCLUSIONS: Oral therapy is preferable to i.v. formulations for
most patients. The oral 5-HT3 receptor antagonists approved for chemotherapy
induced nausea and vomiting include dolasetron, granisetron, and ondansetron.
Oral granisetron is differentiated for its safety, efficacy, and use in highly
and moderately emetogenic chemotherapy. IMPLICATIONS FOR NURSING PRACTICE: Oral
antiemetics are preferable to i.v. antiemetics because of decreased total costs
and greater convenience for patients who are able to ingest oral medication.
PMID- 10785903
TI - Relaxation and imagery for symptom management: improving patient assessment and
individualizing treatment.
AB - PURPOSE/OBJECTIVES: To discuss and describe the role of relaxation and imagery in
the care of patients with cancer, including suggestions for enhancing assessment
and brief instructions for implementing basic interventions. DATA SYNTHESIS:
Relaxation and imagery are commonly used to treat various side effects of cancer
and its treatment. The nursing literature often has encouraged nurses to use
relaxation and imagery to assist patients in managing pain, nausea, vomiting, and
anxiety. Frequently, the literature has presented these techniques as being
simple, harmless interventions requiring little assessment, planning, or
individualization. CONCLUSIONS: Simplistic, generalized approaches may result in
suboptimal treatment or deleterious responses. IMPLICATIONS FOR NURSING PRACTICE:
Clinicians must assess and collaborate with patients in developing an appropriate
strategy that fits the individual's preferences and beliefs.
PMID- 10785904
TI - Dietary restrictions for patients with neutropenia: a survey of institutional
practices.
AB - PURPOSE/OBJECTIVES: To describe institutional practices related to dietary
restrictions for patients with neutropenia to determine whether restrictions are
used and when they are implemented and discontinued. DESIGN: Descriptive survey.
SAMPLE: 156 institutions belonging to the Association of Community Cancer
Centers. METHODS: Mailed survey. FINDINGS: Of the institutions surveyed, 78% (n =
120) placed patients with neutropenia on restricted diets. Participating
institutions responded that patients were placed on restricted diets at a variety
of different white blood cell and neutrophil counts, including neutrophils <
1,000 (43%) and < 500 (46%). The majority of institutions (92%) placed patients
on restricted diets once neutropenia was documented, while only 9% of
institutions restricted diets when cancer treatment was initiated. Of the
participating institutions, 83% (n = 96) restricted diets only when patients were
neutropenic rather than throughout the duration of the chemotherapy regimen. The
most commonly restricted foods were fresh fruits and juices (92%), fresh
vegetables (95%), and raw eggs (74%). Few institutions restricted tap water
(12%). Wine was restricted at 39% of institutions, and beer was restricted at 40%
of institutions. CONCLUSIONS: The role of diet in the development of infection in
patients with neutropenia is unclear. This unclear role contributes to the
variation in dietary restrictions among institutions. IMPLICATIONS FOR NURSING
PRACTICE: Additional research should focus on dietary factors contributing to
neutropenic infections and establishing criteria for implementation of specific
dietary modifications. Nursing assessment should include nutritional status and
risk factors for neutropenia and bacterial translocation. Nursing protocols for
neutropenic dietary restrictions should be based on research findings.
PMID- 10785905
TI - Chemotherapy extravasation from implanted ports.
AB - PURPOSE/OBJECTIVES: To describe the four primary causes of extravasation from
implanted ports. DATA SOURCES: Journal articles, textbooks, medical records,
depositions, serial photographs, and the authors' personal experiences. DATA
SYNTHESIS: Extravasation from ports can occur by four major mechanisms:
incomplete needle placement and needle dislodgment, thrombus or fibrin sheath
formation, perforation of the superior vena cava, and catheter fracture. The
degree of tissue injury can vary but may be severe enough to require that a
simple mastectomy be performed to manage chest wall necrosis. CONCLUSIONS:
Extravasation is a known risk of chemotherapy administration via implanted ports.
Vesicants should be administered only after a blood return has been obtained and
the needle inserted into the port septum has been adequately secured.
IMPLICATIONS FOR NURSING PRACTICE: Extravasation of vesicant drugs from ports can
cause tissue necrosis and may prompt litigation. Risk-management strategies
include careful assessment and use of ports, comprehensive patient teaching about
the risk of extravasation and measures to decrease the likelihood of needle
dislodgment, and development of extravasation-management policies that address
port extravasations.
PMID- 10785906
TI - Case reports in physiotherapy.
PMID- 10785907
TI - Predicting motor recovery of the upper limb after stroke rehabilitation: value of
a clinical examination.
AB - BACKGROUND AND PURPOSE: Only a few studies have been conducted to predict motor
recovery of the arm after stroke. The aims of this study were to identify which
clinical variables, assessed at different points in time, were predictive of
motor recovery, and to construct useful regression equations. METHOD: One hundred
consecutive stroke patients who had an obvious motor deficit of the upper limb
were evaluated on entry to the study (two to five weeks post-stroke) and at two,
six and 12 months after stroke. The Brunnstrom-Fugl-Meyer test was used as the
outcome measure. Predictors included demographic data, overall disability,
clinical neurological features, neuropsychological factors and secondary shoulder
complications. RESULTS: In multiple regression analyses, motor performance was
invariably retained as the predictive factor with the highest R-square. Other
significant predictive variables were overall disability, muscle tone,
proprioception and hemi-inattention. Between 53% and 89% of the total amount of
variance was accounted for in all selected models. The accuracy of prediction
from clinical measurement in the acute phase diminished as the time span of
measurement of outcome increased. Similarly, assessment of the variables at two
and six months, rather than in the acute stage, resulted in a considerable
improvement in the percentage variance explained at 12 months. The highest
accuracy was obtained when predictions were made step-by-step in time.
CONCLUSIONS: It is possible to predict motor recovery of the upper limb
accurately through the use of a few clinical measures. Predictive equations are
proposed, the use of which are practicable in both clinical practice and
research.
PMID- 10785908
TI - Validity of weight distribution and sway measurements of the Balance Performance
Monitor.
AB - BACKGROUND AND PURPOSE: The Balance Performance Monitor (BPM) is a device which
provides auditory and visual feedback on weight distribution and the magnitude of
lateral and anterior-posterior sway during quiet standing. This study
investigated the validity of the measurements provided by the BPM using a Kistler
force plate (KFP) as the gold standard. METHOD: Percentage weight distribution
between the BPM foot plates was validated using both a series of calibration
weights and the vertical component of ground reaction force, measured by the KFP,
during normal standing in 18 young normal subjects. The lateral and anterior
posterior sway indices from the BPM were validated against the standard deviation
of the position of the centre of pressure, again obtained using the KFP, during
normal standing with eyes open and eyes closed and standing with feet together
with eyes open. Concurrent validity of the percentage weight distribution
measurements was assessed by calculating the 'limits of agreement' between the
corresponding measurements from the BPM and KFP and the 95% confidence intervals
for these 'limits'. Differences in the units of measurement obtained from the BPM
and KFP resulted in the concurrent validity of the sway indices being assessed
using correlation and regression. RESULTS: Excellent agreement was found between
the percentage weight distribution values provided by the BPM and the KFP, which
showed that the BPM may read only 3% of body weight above or below that given by
the KFP. High correlations (r = 0.61-0.99) were found between both the lateral
and anterior-posterior sway indices from the BPM and the motion of the centre of
pressure from the KFP in the respective direction. Despite this, further analysis
of regression equations and the 95% prediction intervals showed poor concurrent
validity of the BPM sway indices in relation to KFP measurements. This was
thought to be due to the different methods by which the sway indices and the
motion of the centre of pressure were calculated. CONCLUSIONS: The BPM may be
used to provide a valid measure of the symmetry aspect, but not necessarily the
steadiness aspect of postural control.
PMID- 10785909
TI - Functional status among elderly Norwegian fallers living at home.
AB - BACKGROUND AND PURPOSE: Falls and their after-effects are important contributors
to disability in old age, but may be mitigated. The relationship between self
reported health and functioning and falling is examined in the present study.
METHOD: The study design was cross-sectional. Data were collected from interviews
with 431 community-dwelling Norwegian subjects aged 67-97 years. Physical health
was assessed through items from the Multidimensional Functional Assessment of
Older Adults (MFAQ), supplemented with the Body Mass Index (BMI). General
health/psychosocial health was assessed with the General Health Questionnaire
(GHQ-20), the Mini-mental State Examination, two general health items and items
concerning mental and social health from the MFAQ. Falls during the last six
months were registered and scored 0 (no falls), 1 (one fall) or 2 (two or more
falls). RESULTS: During the previous six months 24.1% of subjects reported
falling. Four variables: 'Perceived difficulty in keeping balance in walking',
'Troubled by heart pounding/shortness of breath', sum score on the GHQ factor
'Depression/hopelessness', and a higher value on BMI, were independently
associated with number of falls reported. CONCLUSIONS: Score value on 'Perceived
difficulty in keeping balance in walking' was the strongest significant predictor
of falls in the present study. In contrast with other studies, no association
between anxiety, general health and falling was observed.
PMID- 10785910
TI - Effects of a three-month therapeutic exercise programme on flexibility in
subjects with low back pain.
AB - BACKGROUND AND PURPOSE: Spinal and muscle flexibility have been studied
intensively and used clinically as outcome measurements in the rehabilitation of
subjects with low back pain. The results of previous studies are contradictory
and there is a lack of longitudinal data on the effects of long term therapeutic
exercise on flexibility. METHOD: A controlled experimental study was conducted to
determine the effects of progressive therapeutic exercise on spinal and muscle
flexibility. Eighty-six chronic low back pain subjects fulfilled the inclusion
criteria and were divided into three study groups: (1) intensive training group,
(2) home exercise group and (3) control group. The intervention period lasted
three months and measurements were performed at both the beginning of the study
and immediately after intervention. Follow-up measurements were carried out six
and 12 months after baseline. Spinal flexibility was measured with lumbar
flexion, extension, spinal lateral flexion and rotation, and muscle flexibility
was measured with measurements of erector spinae, hamstring and iliopsoas
muscles. Also self-reported outcomes of the Oswestry Index and Borg Scale--Back
Pain Intensity were used. Associations between change (pre- to post-treatment)
were determined for the dependent variables. RESULTS: The results showed no
correlation between flexibility, the Oswestry Index or back pain intensity. After
the first three-month period lumbar flexion, extension and spinal rotation
decreased among all subjects. Spinal rotation and erector spinae muscle
flexibility improved significantly with intensive training. At the nine-month
follow-up, erector spine flexibility was still greater than at baseline.
Hamstring flexibility increased among the intensive training and home exercise
groups from pre- to post-intervention. However, the degree of hamstring
flexibility gained during training was subsequently lost following the period
without programmed exercise in both training groups. Self-reported outcome
variables showed positive changes among the three study groups after the
completion of intervention period, but these changes were only able to be
maintained during subsequent follow-ups for the intensive training and home
exercise groups. CONCLUSIONS: The findings suggest that flexibility does not play
an important role in coping with chronic low back pain for subjects whose
functional limitations are not severe. Also, it appears that the achieved gains
in spinal and muscle flexibility may not be able to be maintained without
continued exercise.
PMID- 10785911
TI - Treatment of focal spasticity with botulinum toxin: effect on the 'positive
support reaction'.
PMID- 10785912
TI - [Brachytherapy in the curative treatment of localized prostatic cancer].
AB - The treatment of clinically localized prostate cancer is based on total
prostatectomy, radiotherapy or surveillance. The adverse effects of these
treatments have led to an increasing interest in alternatives with decreased
morbidity. Brachytherapy consists of placing radioactive sources in the prostatic
tissue. High doses can therefore be delivered to the cancer while avoiding
excessive irradiation of the bladder and rectum. Brachytherapy generally uses
permanent implants (Iodine 125 or Palladium 103). The so-called Seattle technique
requires planning before implantation, while, in the "ProCeed" technique, the
position of the grains is determined at the time of treatment, with the help of a
computer programme which determines the dosimetry. Brachytherapy is a reliable
and reproducible technique with minimal morbidity, providing 10-year results
comparable to those of total prostatectomy.
PMID- 10785913
TI - [Diabetes and urination disorders].
AB - Diabetic neuropathy of can induce multi-organ dysfunction. The diabetes
simultaneously has profound repercussions on gastrointestinal, sexual and
erectile functions. One of the main sequelae of diabetic neuropathy is autonomic
neuropathy affecting the vesicosphincteric control. The objective of this study
was to review the epidemiological, clinical, laboratory and therapeutic data
concerning voiding disorders observed in diabetes. Although the therapeutic
management of an isolated voiding disorder in diabetics still remains
symptomatic, it raises aetiological problems due to the comorbidity, particularly
prostatic obstructive syndromes in men, pelvic dysfunction in women and ageing.
Diabetic patients in renal failure also present specific vesicosphincteric
disorders which are reviewed. Diabetic patients should be more systematically
screened for the development of diabetic bladder disease, especially for
associated factors which participate in its clinical expression. This implies
extreme caution in the management of benign prostatic hyperplasia in the case of
comorbidity, to avoid deteriorating a sometimes fragile detrusor-sphincter
equilibrium. Diabetic detrusor hyperactivity must be better known in order to be
more effectively detected. Pharmacological treatment of this condition raises
problems related to detrusor hypocontractility also related to diabetic bladder
disease. Clinical examination should be able to select those patients requiring
further urodynamic studies in order to assess the individual detrusor-sphincter
equilibrium. These investigations are required when surgical treatment of an
associated urological or gynaecological disorder is considered.
PMID- 10785914
TI - [Treatment of ureteral calculi: report of 152 calculi].
AB - OBJECTIVE: To define the therapeutic approach to ureteric stones. MATERIAL AND
METHODS: 137 patients with 152 ureteric stones were treated between January 1990
and January 1997. Sixty seven stones (44%) were situated in the lumbar ureter, 16
stones (10%) were in the iliac ureter, 69 stones (46%) were in the pelvic ureter.
These stones were treated by extracorporeal shock-wave lithotripsy (ESWL),
ureteroscopy and, more rarely, ureterotomy. RESULTS: One hundred and three stones
were treated in a single session, while 31 required two ESWL sessions. Treatment
eliminated 82% of ureteric stones: 89% of lumbar ureteric stones, 31% of iliac
stones and 85% of pelvic stones. Ureteroscopy was performed as first- or second
line treatment in 34 cases. It successfully treated 97% of ureteric stones: 100%
of pelvic and lumbar stones and 91% of iliac stones. Three patients were
successfully treated by ureterolithotomy for a lumbar ureteric stone and two for
iliac ureteric stones. CONCLUSION: SWL is the reference treatment for stones of
the lumbar ureter. Ureteroscopy is justified after failure of ESWL for stones of
the pelvic and iliac ureter, as it gives excellent results.
PMID- 10785915
TI - [Cacchi and Ricci's disease. Radiology, epidemiology and biology].
AB - OBJECTIVES: Medullary sponge kidney corresponds to the precaliceal dilatation of
renal tubules. The purpose of this article is to draw attention to some of the
radiological, epidemiological and laboratory features of this disease. MATERIAL
AND METHOD: 500 cases of radiopaque renal stones, corresponding to 310 men and
190 women, were reviewed. One or several urographies, early urographic films, and
blood calcium phosphate and 24-hour urinary calcium phosphate and oxalate
assessments were available for all subjects. We have added to this series an
identical study on 100 cases of stones in North African subjects. RESULTS: From a
radiographic point of view, this study shows the value of early urography films,
performed between the 2nd and 4th minutes after intravenous injection of
iodinated contrast agent, which visualize abnormal opacification of the renal
pyramids, before or at the same time as that of the bases of the calices. A
radiological sign, not reported in the medical literature, is a clear border
between abnormal opacification of the papillae and that of the calices, observed
in one or several papillocaliceal zones, which facilitates the diagnosis of
medullary sponge kidney. In this series of 500 cases of renal stones, the
radiological diagnosis of medullary sponge kidney was established in 103 cases:
20.6%. The distribution varies according to sex, 54 out of 310 (12.59%) in men,
53 out of 190 (27.89%) in women; difference p < 0.001. We found only 3 cases of
medullary sponge kidney in the series of 100 cases of radiopaque stones in North
African subjects. In terms of laboratory parameters, 24-hour urine tests showed
hypercalciuria in 61 out of 103 cases (59.22%), or hyperoxaluria in 66 out of 103
cases (64.08%), while 41 out of 103 cases (39.81%) presented both disorders.
Urinary calcium oxalate assessments were normal in 20 out of 103 cases (19.42%).
Hyperparathyroidism was never detected in combination with medullary sponge
kidney. CONCLUSION: This study shows the value of early urography films for the
diagnosis of medullary sponge kidney and demonstrates a useful diagnostic
radiological sign: a clear border between abnormal urographic opacification of
the papillae and calices. It shows the much higher frequency of medullary sponge
kidney in patients with radiopaque stones, with a higher rate in women than in
men, and a low frequency in North African subjects, that needs to be confirmed.
This study also emphasizes the frequency of hypercalciuria and especially
hyperoxaluria, and even the combination of these two disorders in medullary
sponge kidney.
PMID- 10785916
TI - [Kock's pouch: experience and clinical course in 31 patients].
AB - OBJECTIVES: To analyse the morbidity and functional results of Kock's continent
urinary diversion performed since 1992 in cystectomized patients in whom the
urethra could not be used. MATERIAL AND METHODS: From March 1992 to June 1998, 31
Kock's pouches were performed by 2 surgeons on a group of patients with a mean
age of 54 years. Henriet's technique was used in 23 patients until 1996, and was
then modified the last 8 patients in order to create a continent valve. The
diversion was performed after cystectomy for bladder or gynaecological tumour in
23 cases and 1 urinary tract reconstruction in 8 cases (neurogenic bladder,
destroyed urethra, conversion of Bricker diversion). RESULTS: With a mean follow
up of 42 months (12 to 84), the perioperative mortality was 3.4% and immediate
complications were 26%, justifying reoperation in 6.4%. Late complications
predominantly consisted of disinvagination of the valve with a reoperation rate
of 13%. No surgical revision for newly modified antireflux valves has been
performed since 1996. The continence rate of the system, evaluated between 3 and
6 months, was 90%. CONCLUSION: Kock's pouch is a delicate operation, clearly
associated with a high morbidity in this series, as in the literature, although
the results improved with experience. Indications must be confined to patients in
good general condition, motivated for self-catheterization (ATS) and in whom the
urethra cannot be used for bladder replacement.
PMID- 10785917
TI - [Stenosis following a direct uretero-ileal anastomosis technique in substitutive
enterocystoplasty].
AB - OBJECTIVES: Stenosis of the uretero-ileal anastomosis and reflux are the
commonest causes of secondary deterioration of renal function following
enterocystoplasty. Various direct anastomosis and antireflux techniques have been
proposed in order to reduce the risk of stenosis and reflux. In this
retrospective study, the authors evaluated the risk of stenosis and reflux after
right uretero-ileal anastomosis on an invaginated ileal loop. MATERIAL AND
METHODS: The authors evaluated the uretero-ileal anastomosis stenosis and reflux
rate and problems of the invaginated ileo-ileal valve in 157 patients after
bladder replacement enterocystoplasty. RESULTS: The anastomosis stenosis rate was
3.8% (6/157 patients) and all 6 patients were reoperated. Stenotic complications
on the valve were observed in 1.2% of cases (2/157 patients). The total stenosis
morbidity was 5% (8/157 patients). CONCLUSION: Direct end-to-end uretero-ileal
anastomosis is the simplest technique associated with the lowest risk of
stenosis. The low stenosis rate associated with invaginated valves is due to a
modification of the valvular system (limitation of the mesenteric exclusion
manoeuvre, external anchorage of the invagination and fixation by two lines of
resorbable staples).
PMID- 10785918
TI - [Morbidity of endoscopic prostatic resection: 3-month prospective study.
Practical Urology Club].
AB - OBJECTIVES: To quantify the complications of TUR of prostate occurring during the
first three post-operative months. PATIENTS AND METHODS: Multicentric cooperative
study where skilled urologists, aged between 45 and 55 years old, with various
practice settings, compile complications in their consecutive patients undergoing
TURP between March and June 1996. 410 patients have been assessed by 17
urologists. RESULTS: Rate of intraoperative complications is low with 10 patients
being transfused and 3 TUR syndromes being observed. Two deaths occurred in
patients aged 84 and 92 years-old at post-op day 27 and 30 respectively. Twenty
four percent of patients experienced at least one complication during the
observation period, the most frequent of which was asymptomatic bacteriuria in
8.5%. Urethral--mainly meatal--stenosis was the main cause for the
readmission/reintervention rate (6.5%). CONCLUSION: Early morbidity/mortality of
TURP for BPH albeit real, occurs in a small percentage of patients, with a
general mild intensity. Alongside with excellent objective and subjective
outcome, these rates allow TUR of prostate to remain the gold-standard treatment
for BPH.
PMID- 10785919
TI - [Innervation of Denonvilliers' recto-vesical fascia. Anatomical study].
AB - OBJECTIVE: Dissection of Denonvilliers' rectovesical fascia allows easy cleavage
of the prostatorectal and prostatovesical spaces. Its lateral limit in the
"neurovascular pedicles" justifies its resection during radical prostatectomy.
The objective of this study was to define the course and to observe the structure
of nerves crossing the rectovesical fascia, as the sheaths of these nerves may be
invaded by prostatic adenocarcinoma tumour cells. MATERIAL AND METHODS: After
dissection of a fresh cadavre to define the relations of this fascia with the
pedicles, rectovesical fascia biopsies were taken during radical prostatectomies.
Transverse sections were performed and examined histologically. RESULTS: Certain
nerves, derived from the neurovascular pedicle of the inferior hypogastric
plexus, cross the rectovesical fascia to innervate the prostate. CONCLUSION: This
confirms the importance of complete resection of the rectovesical fascia during
radical prostatectomy for cancer, not only for surgical reasons, but also to
ensure oncologically satisfactory surgery, i.e. with healthy resection margins.
PMID- 10785920
TI - [Surgical treatment of traumatic ruptures of the posterior urethra].
AB - OBJECTIVES: To compare the therapeutic results of deferred urgent surgical
treatment and late treatment of traumatic ruptures of the posterior urethra.
MATERIAL AND METHOD: 35 patients with a mean age of 25 years (range: 7 to 79
years) were operated for trauma of the posterior urethra. In most cases, trauma
was secondary to a road accident, associated with fracture of the pelvis. When
rupture of the posterior urethra was diagnosed, the subsequent management
depended on the patient's general condition and associated lesions. In the
absence of serious skeletal or visceral lesions, the patient was operated within
3 weeks following trauma, after radiological assessment. This approach was
applied in 16 patients (Group I). The other 19 patients (Group II) were only
operated at the sixth month, after stabilization of all traumatic lesions.
RESULTS: Results were assessed in terms of the quality of the urinary stream,
urinary continence and sexual impotence. The stream was considered to be good in
93.75% of cases (Group I) and 78.8% of cases (Group II). Continence was perfect
in 100% of cases (Group I), versus 89.4% (Group II) and sexual impotence was
observed in 18.7% (Group I) versus 5.3% (Group II). CONCLUSION: Trauma of the
posterior urethra, without any serious associated lesions, can be operated as a
deferred emergency with excellent results in terms of voiding (80% of good
results), but with a higher frequency of sexual impotence. In patients with
serious associated lesions, the therapeutic management of the urethral trauma is
performed after an interval of 3 to 6 months, at the stage of urethral stricture.
In this case, surgery consists of resection of the fibrous callus, followed by
urethral anastomosis. The results of this operation are good, at the cost of
repeated stricture, treated endoscopically, but with a lower incidence of sexual
impotence.
PMID- 10785921
TI - [Extra-corporeal lithotripsy in the treatment of Peyronie's disease. Use of a
standard lithotriptor (Multiline Siemens) on "young" (less then 6 months old)
plaques].
AB - OBJECTIVE: The treatment of La Peyronie disease is still controversial. ESWL has
been recently proposed to treat symptomatic plaques. The results, although
discordant and often based on subjective assessment criteria, appear to show a
certain degree of efficacy on so-called young plaques, i.e. during the acute
phase of the disease. This study was designed to evaluate the results obtained
with a classical lithotriptor (Siemens Multiline) on plaques present for less
than 6 months. MATERIAL AND METHOD: 26 patients were included in this prospective
study. All presented a painful plaque on erection. The plaque was palpated under
general anaesthesia and 0.5 to 2 ml of contrast agent were injected to allow
radiological visualization. All patients received 3000 impacts at a power of 7
kilojoules in 1 session and all were reviewed 1 month and 3 months after the ESWL
session. RESULTS: Treatment was perfectly tolerated. Among the 26 patients
treated: 19 patients (73%) reported a very marked reduction of pain on erection
and 8 (31%) reported a reduction of curvature on erection, but this reduction was
demonstrated objectively (by tracing or photographs) for only 3 patients (11%).
Seven patients (27%) experienced softening of the plaque. Six (37%) of the
patients suffering from erectile dysfunction reported improvement of the quality
of erection, as reflected by the HEF score. CONCLUSION: A standard lithotriptor
can be used to treat La Peyronie plaques. ESWL appears to have a marked analgesic
effect, but its efficacy on correction of curvature of the penis was not
demonstrated in this study.
PMID- 10785922
TI - [Penile cancer: flow cytometry study of ploidies in 90 patients].
AB - OBJECTIVE: To evaluate prospectively 90 consecutive cases of squamous cell
carcinoma of penis, referred to our Institute, by flow cytometry analysis of
cellular DNA content. To compare deoxyribonucleic acid (DNA) flow cytometry with
clinical and pathological variables to determine the prognostic significance of
this analysis to guide the selection of patients at high risk for development of
lymph node metastases. PATIENTS AND METHODS: We determined the nuclear DNA of
tissues in fresh biopsy specimens of 80 patients diagnosed histologically as
invasive squamous cell penile carcinoma and in fresh biopsy specimens of 10
patients with verrucous carcinoma of penis. Samples were analyzed with a FACScan
flow cytometer, equipped with a doublet discrimination module, using the CellFIT
software package for data acquisition and analysis. RESULTS: The DNA pattern was
diploid in all samples excised from patients with verrucous carcinoma. According
to histological type the frequency of aneuploidy was 5.5% (1 of 18) in well
differentiated carcinoma, 28.8% (17 of 59) in moderately differentiated carcinoma
and 66.6% (2 of 3) in poorly differentiated carcinoma. CONCLUSION: The frequency
of DNA aneuploidy showed correlation with histological type of invasive squamous
cell carcinoma of the penis. Preliminary analysis suggests that patients with
high DNA index may be at increased risk of metastatic involvement.
PMID- 10785923
TI - [Role of systematic scrotal ultrasonography in the management of male
infertility: prospective study of 609 cases].
AB - OBJECTIVES: To assess the benefit and diagnostic contribution of systematic
scrotal ultrasound in the management of infertile men. MATERIAL AND METHODS:
Between 1st January and 31st December 1997, the authors conducted a consecutive
and prospective study of 609 infertile patients corresponding to 418 cases of
oligoasthenoteratospermia and 191 cases of azoospermia. All patients were
investigated by scrotal ultrasound. RESULTS: 133 patients (21.8%) did not present
any clinical or ultrasound abnormality. 60 patients (9.9%) presented isolated
clinical abnormalities and 125 patients (20.5%) presented a discordance between
clinical findings and ultrasound results. 9 patients (1.5%) presented an
ultrasound nodule, 6 of which were discovered incidentally. 22 patients (3.6%) in
whom the clinical features were more difficult to interpret, presented
unambiguous findings. CONCLUSION: Scrotal ultrasound makes a considerable
contribution to more appropriate management of infertile men and diagnoses 1.5%
of testicular tumours.
PMID- 10785924
TI - [Uretero-vaginal fistula. Therapeutic alternatives concerning 10 cases].
AB - OBJECTIVE: Our purpose was to study aetiopathogenic, diagnostic and therapeutic
aspects of ureterovaginal fistulas. STUDY DESIGN: A retrospective study concerned
10 ureterovaginal fistulas. The main causes were gyneacoligical and obstetrical
procedures. The diagnosis was based on clinical considerations and intravenous
pyelography in all cases. Various therapeutic methods were used: Fistulas has
managed in three cases by ureteroneocystostomy. Five cases were managed with
ipsilateral ureteroureterostomy, the segment of ureter below the fistula was
identified using ureteroscopic perforation of this segment in three cases. In one
case the fistula was successfully managed by ureteroscopic placement of ureteral
stent. In case whose fistula was developed after cancer pelvic we choice
abstention. RESULTS: Late radiology showed success of the procedure in 7 patients
and persistance of hypotony in 2 cases treated by u reteroneocystostomy.
CONCLUSION: Ureterofistula is rare, but a relative frequent complication of
pelvic surgery whose prevention is the most efficient treatment.
Ureteroureterostomy is a good procedure when ureteroscopy is performed.
PMID- 10785925
TI - [Emphysematous pyelonephritis in lithiasic kidney caused by acinetobacter].
AB - Emphysematous pyelonephritis is rare. It is exceptionally associated with
urolithiasis with obstruction of the collecting system. It is generally observed
in female diabetic patients. It is caused by gas-producing bacteria. We report a
case in which emphysematous pyelonephritis was caused by an acinetobacter,
associated with pelvic ureteral junction lithiasis. Drainage and nephrectomy were
necessary to overcome this life threatening situation.
PMID- 10785926
TI - [Value of cloverleaf double J ureteral stents in the treatment of extrinsic
ureteral compression].
AB - The authors report three cases of extrinsic bilateral ureteric stenoses in which
standard double J ureteric stents did not allow medium-term improvement of renal
function or resolution of pyelocaliceal cavity dilatation on ultrasonography. A
favourable course was observed after insertion of cloverleaf double J ureteric
stents.
PMID- 10785927
TI - [Bladder pheochromocytoma].
AB - OBJECTIVE: Report of a new case of a rare bladder tumour: bladder
phaeochromocytoma. MATERIAL AND METHODS: A 45-year-old patient presented with
paroxysmal symptoms consisting of headaches, palpitations, tinnitus and excessive
sweating after each micturition. Complementary investigations: ultrasonography,
intravenous urography and magnetic resonance imaging, suggested a circumscribed
tumour with a 2 cm long axis in the bladder dome, and the diagnosis of bladder
phaeochromocytoma was proposed. Partial cystectomy was performed. RESULTS: The
postoperative course was uneventful and the subsequent outcome was favourable
with resolution of all symptoms with a follow-up of 28 months. Histological
examination of the operative specimen confirmed the diagnosis of bladder
phaeochromocytoma. CONCLUSION: Bladder phaeochromocytoma is a rare tumour.
Treatment of this lesion requires the same preparation as for any other site of
phaeochromocytoma. Partial cystectomy ensures radical and effective treatment.
Long-term surveillance is necessary, as recurrences or metastases have been
described 20 and 40 years after treatment.
PMID- 10785928
TI - [Epididymal gaseous abscess after BCG treatment].
AB - The authors report a case of unilateral epididymitis with caseous abscess after
BCG-therapy for superficial bladder tumour. The severity of the lesions required
orchidectomy, followed by four-agent tuberculostatic therapy.
PMID- 10785929
TI - [Malignant penile melanoma].
AB - The authors report the case of a very large, obstructive malignant melanoma (MM.)
of the prepuce, encasing all of the distal extremity of the penis, and discovered
at a late metastatic stage (regional lymph node metastasis). Palliative
treatment, consisting of partial penectomy associated with a complementary
induction and maintenance chemotherapy did not achieve any objective response at
one year. MM. of the penis are rare urological tumours, including MM of the penis
and MM of the male urethra (exclusively mucosal involvement). The diagnosis of MM
of the penis must be considered in any case of black or brown lesion of the
glans, which is the most frequent site. The prognosis is determined by the
clinical stage (BRACKEN and DIOKNO classification) and by the depth and level of
tumour invasion (BRESLOW index and CLARK's degree of dermal invasion). The 5-year
survival is inversely proportional to the tumour thickness. The treatment of MM
of the penis is surgical; the extent of resection and the indication for lymph
node dissection depend on the patient's age, sexuality, and the stage of the
disease and depth of tumour invasion.
PMID- 10785930
TI - [Impact of genital prolapse on the upper urinary tract].
AB - The authors reviewed five cases of genital prolapse affecting the upper urinary
tract and causing renal failure. CLINICAL CASES: Five patients aged 55 to 75
years presented with genital prolapse, which was known by the patient in 3 cases
for a period of 2 to 30 year, but left untreated. All cases had induced bilateral
dilatation of the uretero-pyelocaliceal cavities with severe obstructive renal
failure in 3 cases, moderate renal failure in 2 cases and associated with
hypertension in 2 cases. Repair of prolapse, preceded by upper urinary tract
diversion by ureteric and bladder catheters in 3 cases or pessary + bladder
catheter because of the patient's age in 2 cases, cured or improved renal failure
in 4 patients; only one patient had to be treated by dialysis because of the
severity of the residual renal failure severity. DISCUSSION: The frequency (4%)
of aetiopathogenic mechanisms (ureteric compression, progressive stretching of
the ureter and posterior tilting of the trigone) are analysed. The delayed onset
of sudden deterioration and the varying degrees of severity of renal failure
demand emergency treatment of stage III prolapse with primary diversion of the
upper urinary tract, currently by double J stents, until correction or
improvement of renal function, after which surgical repair of the prolapse can be
performed according to the usual surgical rules. Intravenous urography is still
indicated in this situation. Palliative treatment is only indicated in elderly
patients or patients with a high operative risk. The best treatment remains
prevention by detection and treatment of prolapse before the development of this
fortunately rare complication. CONCLUSION: This short clinical series emphasizes
that undiagnosed prolapse can still be complicated by repercussions on the upper
urinary tract with a risk of renal failure.
PMID- 10785931
TI - [Dyschezia, pudendal neuropathy, and functional pelvico-perineal disorders].
AB - A critical literature review allows an analysis on chronic constipation
evaluation and on the association with anatomical or functional pelvic perineal
disorders, the link with a pudendal neuropathy being frequent. The dyschezia
clinical diagnosis must be completed by X-ray and manometric examinations to well
determine the respective part of anatomical and/or functional disturbances.
Stretch pudendal neuropathy was first described in association with descending
perineum and chronic constipation. This kind of neuropathy is frequently obvious
in other pelvic defects, genital prolapses, urinary incontinence, micturition
disturbances. The diagnosis must be made with a complete electrophysiological
assessment and not only with the pudendal nerve latency terminal motor latency
measurement. These pelvic-perineal disorders have plurifactorial aetiologies,
they are linked together without univoqual chronology, each one may be the cause
or the consequence of the other, and self-worsening evolution may occur.
PMID- 10785932
TI - [Opportunity for a systematic screening of prostatic cancer by determining
prostate specific antigen levels].
PMID- 10785933
TI - [Therapeutic management of epidermoid carcinoma of the penis: anatomoclinical
discussion and review of the literature].
AB - The therapeutic management of penile tumours is determined by the degree of local
extension of the tumour, and the presence of lymph node involvement and visceral
metastases. Many published studies have tried to define the best treatment
options as a function of tumour grade and stage. However, in daily practice, the
treatment of penile tumours still remains highly controversial. After reviewing
the literature, the authors discuss the various treatment options available to
urologists as a function of tumour stage and recall the management difficulties
related to lymph node staging.
PMID- 10785935
TI - [Napoleon III's urogenital disease (1808-1873)].
AB - We tried through this paper to reconstitute the evolution of the urologic illness
of Napoleon III, last emperor of France, the first symptoms of which appeared
many years before the fatal war of 1870, which led to the dismembering of France.
In this connection, we present Napoleon III's physicians and his cures, along
with the diagnostic and therapeutic errors. The case of Napoleon III is a typical
example of the influence the bad health of a sovereign can exercise on the
destiny of his country.
PMID- 10785934
TI - [Conservative surgical techniques in the treatment of kidney tumors].
AB - Several conservative operations are available for renal tumours. This article
describes the anatomical bases, the measures designed to protect the parenchyma
from ischaemia and the various resection techniques. Wedge resection is described
in detail, as it appears to be the most rigorous technique.
PMID- 10785937
TI - [Influence of culture conditions on ligninolytic activity of Stereum hirsutum].
AB - Stereum hirsutum BAFC 2234 was tested for growth kinetics and ligninolytic enzyme
production. The strain showed weak coincidences with widely studied organisms
(Phanerochaete chrysosporium, Pleurotus ostreatus) when the response to nitrogen
sources was assayed. This could be interpreted as a different regulation to
nitrogen metabolism for S. hirsutum BAFC 2234. Alternative carbon sources and the
addition of veratryl alcohol and wood extracts were also tested showing partial
correspondence with other ligninolytic fungi. On the basis of the high enzymatic
activities observed, S. hirsutum BAFC 2234 could be a suitable source of lignin
degrading system aiming techological processes.
PMID- 10785936
TI - [Identification and typing of yeast isolates from hospital patients in Mexico
City].
AB - Nosocomial yeast infections have become a major cause of morbidity and mortality
in immunocompromised patients. This study presents the frequency of yeasts
isolated from different biological products from a Mexico City hospital's
patients during one year. C. albicans was isolated in 72.3% of patients, followed
by C. glabrata (13.4%) and C. parapsilosis (8%). Twenty different morphotypes
were identified and the serotype B was the most frequent (79%).
PMID- 10785938
TI - [Comparison between the standard MPN method recommended by the American Public
Health Association and the Simplate and Petrifilm methods for identification of
the coliform group and Escherichia coli in tilapia (Oreochromis sp) originating
from aquaculture in fresh water].
AB - We have compared three methods for the detection and quantification of coliforms
and E. coli in fish: the conventional three-tube MNP method (APHA), the Simplate
Method and the Petrifilm Method. Thirty samples of the tilapia's external surface
(skin, gills and fin) produced in an artificial pond were collected. Samples were
processed individually in buffered peptone water 1%, then they were diluted and
inoculated in Simplate, Petrifilm and LST tubes. Coliforms were isolated from
100% of the samples. The Simplate and 3M Petrifilm results were obtained after 24
h of incubation. The conventional three-tube MNP method showed results only after
96 hours of incubation. Simplate showed better recovery of coliforms and E. coli
than 3 M Petrifilm and APHA method (P < 0.05). 3M Petrifilm and APHA were not
significantly different for E. coli recovery.
PMID- 10785939
TI - [Rapid diagnosis of principal respiratory viruses in the city of Havana, 1995
97].
AB - Acute respiratory diseases (ARD) are the most common infections in humans and
difficult to prevent. Viruses have been recognized as predominant ethiological
agents. In Cuba, ARD constitute a major problem of health and are the first cause
of morbidity and important cause of mortality. In this paper, rapid diagnosis was
performed to 516 clinical samples which arrived to the Reference Respiratory
Viruses Laboratory of the Pedro Kouri Institute of Tropical Medicine (IPK) from
different parts of Havana City during 1995, 1996 and 1997. The results obtained
have shown 218 positive samples (Influenza A, 89; respiratory syncytial virus 52;
Influenza B, 45; Adenovirus, 13; human parainfluenza virus(HPIV)-1, 6; HPIV-2, 3
and HPIV-3, 10). Influenza A was the virus most frequently found in adults,
whereas in closed population of teen-agers and adults, Influenza B was frequently
found. Furthermore, respiratory syncytial virus was the most important pathogen
in children's under 1 year of age.
PMID- 10785940
TI - [Contamination of bovine fetal serum with bovine viral diarrhea virus].
AB - Fetal bovine serum (FBS) used in cell culture may be contaminated with viruses,
among them bovine viral diarrhea virus (BVDV) affecting the production of
biological reagents and the results of diagnosis. The filtration process used in
the preparation of commercial FBS abrogates most viral agents that may be present
in raw FBS, but BVDV may pass through the filters because of its small size and
its pleomorphism. While detection of bovine herpes virus-1 and parainfluenza-3
(PI-3) is determined by observation of the cytopathic effect, and also by
hemadsorption in the case of PI-3, the most frequently isolated BVDV is non
cytopathic, and infects cells without morphological alterations, inducing
problems that arise after several cell generations. Batches of raw and processed
FBS were analyzed. Frequencies of BVDV detection in raw serum in Argentina were
similar to those published for USA. By conventional methods for BVDV detection,
only 2 of 20 commercial batches of FBS had BVDV. Using cell cultures maintained
with high concentrations of the serum under study for at least 2 weeks, with
detection of viral antigen by indirect immunofluorescence, the percentage of BVDV
detection was 80%. This method shows that most lots of commercial FBS contain
BVDV. RT-PCR allows faster detection of the viral genome, but it must be
validated, as it does not show viral replication. To eliminate the problem of
BVDV contamination in FBS, only gamma irradiated FBS is used in our laboratory.
PMID- 10785942
TI - [Indirect ELISA for the rapid diagnosis of Equine Influenza].
AB - An indirect enzyme linked immunosorbent assay was developed. Infected and non
infected allantoic fluids precipitated with polyetilenglycol 6000 were used as
antigen and control antigen, respectively. Serum samples were diluted 1/20 and a
commercial horse radish peroxidase-labelled rabbit anti-equine IgG was used as
second antibody. The reaction was developed using azino-diethylbenzotyazol
sulfonate (ABTS). Cut-off was determined by ratio sample (Rs). The
hemagglutination inhibition test was used as a reference test for the 391 samples
analyzed. Of these, 301 sera were positive by hemagglutination inhibition test
and indirect ELISA, 75 were negative by both techniques, and 15 were positive by
indirect ELISA and negative by hemagglutination inhibition test. Using
hemagglutination inhibition test as standard, the indirect ELISA showed a
relative specificity and sensitivity of 83.3 and 100%, respectively. This
indirect ELISA is useful as screening test.
PMID- 10785941
TI - Human immunodeficiency virus bDNA assay for pediatric cases.
AB - Techniques to quantify plasma HIV-1 RNA viral load (VL) are commercially
available, and they are adequate for monitoring adults infected by HIV and
treated with antiretroviral drugs. Little experience on HIV VL has been reported
in pediatric cases. In Argentina, the evaluation of several assays for VL in
pediatrics are now being considered. To evaluate the pediatric protocol for bDNA
assay in HIV-infected children, 25 samples from HIV-infected children (according
to CDC criteria for pediatric AIDS) were analyzed by using Quantiplex HIV RNA 2.0
Assay (Chiron Corporation) following the manufacturer's recommendations in a
protocol that uses 50 microliters of patient's plasma (sensitivity: 10,000
copies/ml). When HIV-RNA was not detected, samples were run with the 1 ml
standard bDNA protocol (sensitivity: 500 HIV-RNA c/ml). Nine samples belonged to
infants under 12 months of age (group A) and 16 were over 12 months (group B).
All infants under one year of age had high HIV-RNA copies in plasma. VL ranged
from 30,800 to 2,560,000 RNA copies/ml (median = 362,000 c/ml) for group A and <
10,000 to 554,600 c/ml (median = < 10,000) for group B. Only 25% of children in
group B had detectable HIV-RNA. By using the standard test of quantification,
none of the patients had non detectable HIV-RNA, ranging between 950 and 226,200
c/ml for group B (median = 23,300 RNA c/ml). The suggested pediatric protocol
could be useful in children under 12 months of age, but 1 ml standard protocol
must be used for older children. Samples with undetectable results from children
under one year of age should be repeated using the standard protocol.
PMID- 10785943
TI - [Evaluation of the reincubation of positive blood cultures for detection in the
BACT-ALERT system for the detection of polymicrobial bacteremia].
AB - Between February and September 1997, 6588 blood cultures at the Instituto de
Cardiologia y Cirugia Cardiovascular and Hospital de Ninos Ricardo Gutierrez were
studied by using the Bact-Alert system (Organon Teknika) 341 contaminants and 294
episodes of bacteremia (600 samples) were analyzed. From these samples, 280
(95.3%) were monomicrobial episodes and 14 (4.7%) polymicrobial episodes.
Positive blood cultures detected by the Bact-Alert system were processed and then
reincubated during 7 days, when they were Gram stained and subcultured in blood
agar, chocolate agar (both in 5-10% CO2), laked blood agar supplemented with
hemin and vitamin K in anaerobic atmosphere (only anaerobic bottles) and CLDE
(aerobic conditions). Following reincubation, 3 out of 14 polymicrobial
bacteremias were detected, rising the level of detection from 3.7% to 4.7%.
Taking into account the total number of bacteremias, only in 3 out of 294 (1%), a
second microorganism was detected. Otherwise, in blood cultures where a
contaminating microorganism was initially isolated, no further isolates
representing a true bacteremia were recovered. Reincubation and terminal
subculture of initially positive blood cultures did not provide relevant data in
order to change therapeutic measures in the studied population. Due to the
increase in costs and labor we consider that this methodology is not routinely
advised.
PMID- 10785944
TI - [Investigation of LIsteria monocytogenes in soft cheeses].
AB - Listeria monocytogenes has been recognized as a bacteria that produces severe
illness in animals and humans. Considering the importance of the presence of L.
monocytogenes in soft paste cheeses, a study of diverse cheeses from supermarkets
of direct sale to the public was carried out. From the 35 analyzed cheeses, 4
strains were isolated (11.4%). The result of the serological study showed that
all the strains corresponded to the serotype 4. The proteic profiles of the
isolated strains showed similarity with the used pattern (4b). Several authors
reported the importance of L. monocytogenes as contaminant in foods ready to eat
like the soft paste cheeses. Thus, it must be remarked the importance of the good
handling practices in the production, transport, refrigeration and exhibition of
this product.
PMID- 10785945
TI - [The Catholic church and abortion].
PMID- 10785946
TI - [Current management of thromboembolism in pregnancy and puerperium].
AB - Venous thromboembolism (VTE) remains the leading cause of maternal death. Today,
various risk factors and conditions are known to increase the risk for VTE
associated with pregnancy. Having identified the individual risk of a pregnant
women, appropriate preventive measures can be taken. If VTE occurs during
pregnancy, an appropriate immediate diagnostic work-up is essential in order to
avoid further complications. For deep vein thrombosis (DVT) the diagnostic tool
of choice is color-coded duplex-sonography, for pulmonary embolism (PE)
perfusion/ventilation lung scan can be used. Integrating a detailed individual
and family history, the presence of thrombophilia or other risk factors, a risk
stratification can be undertaken. These risk categories are defined in the
present paper and the appropriate treatment measures are described. As oral
anticoagulants cross the placenta and may cause embryopathy in any trimester,
oral anticoagulants should be avoided throughout pregnancy. Therefore, heparin is
the anti-coagulant of choice for pregnant women, with low molecular weight
heparins (LMWH) having distinctive pharmacological advantages over unfractionated
heparins. Besides a potential for bleeding, the main side effects of heparin
include heparin-induced thrombocytopenia which prompts for platelet monitoring,
especially in the first weeks of heparin treatment, and, secondly, heparin
induced osteoporosis, which is a potential sequel of long-term heparin
administration. Even though there are abundant reports in the literature on the
use of LMWH in pregnant women, that show that they are safe and effective, LMWH
are not specifically licensed for the use in pregnancy.
PMID- 10785947
TI - [Non-contraceptive benefits of the pill--an often neglected fact].
AB - While rare cardiovascular risks of oral contraceptives (OCs) caused a lot of
concern among OC-using women in the recent past, little attention has been paid
in the public to the non-contraceptive benefits of OCs. Short, medium and long
term non-contraceptive benefits have to be considered. The early Anglo-American
cohort and case-control studies demonstrated a reduction of menstrual complaints,
iron-deficiency anaemia, ectopic pregnancies, and a partly drastic reduction of
some benign and malignant tumours such as endometrial and ovarian cancer. A risk
reduction of rheumatoid arthritis is discussed controversially. The present paper
gives an overview of the state of knowledge. For newer OCs with different
composition, comparable studies are lacking. Therefore, a cohort study was
initiated in Germany in April 1998 to investigate these associations as well for
newer OCs, which is presented. The described non-contraceptive benefits should be
considered in the benefit-risk assessment when prescribing OCs.
PMID- 10785948
TI - [Effects of tubal sterilization].
AB - OBJECTIVE: Besides manifestations of hormonal deficits, psychological problems
are also known as possible negative effects of tubal sterilization (here termed
"operative contraception"--OC). It is generally assumed that the age at time of
operation and the number of children play a crucial role in enabling the patient
to come to terms with surgical contraception. We investigated whether these
patients were satisfied and the frequency of a desire for refertilization as well
as further factors possibly affecting our patients. PATIENTS AND METHODS: A
standardized questionnaire was sent to 274 women in whom surgical contraception
was performed from 1984 to 1990 in our hospital. Besides physical symptoms, the
questions mainly inquired as to satisfaction, degree of regret and desire for
refertilization. RESULTS: 5.4% of women were not satisfied with the operation.
13.7% of the patients regretted the operative contraception and 6.5% wished to
have refertilization. The negative appraisal did not correlate with the number of
children and age at the time of operative contraception. Altogether, satisfaction
was very much greater in patients who had completed family planning than in
patients who had received operative contraception for medical reasons. Appraisal
of operative contraception was especially negative in women in whom the operation
had been performed on the occasion of a cesarean section. CONCLUSION: Our follow
up investigation confirmed that operative contraception was experienced as being
very liberating by most women and was accordingly appraised positively on the
whole. The number of children and age only played a subordinate role in how
patients came to terms with their situation. For a positive experience of
operative contraception, the time of the operation appears to be of major
importance. In particular, "favorable opportunities" on the occasion of cesarean
section and the if anything doubtful need for this measure in the condition after
prior cesarean sections must be avoided, since in these cases a free decision in
favor of operative contraception, which the woman concerned feels to be
autonomous, is not possible.
PMID- 10785949
TI - [LEEP versus cold knife conization for treatment of cervical intraepithelial
neoplasias].
AB - OBJECTIVE: This study was performed to evaluate the effectiveness and side
effects of loop electrosurgical excision procedure (LEEP) in comparison to cold
knife conization for the treatment of cervical intraepithelial neoplasia (CIN).
MATERIAL AND METHODS: Between January 1996 and July 1998, 177 patients underwent
conization. In a matched-pair setting, 50 cases with LEEP were compared with 100
classical conization cases. LEEP was performed with ectocervical and endocervical
excision. RESULTS: Perioperative complications were less in the LEEP group (6%
vs. 11%). The mean volume of LEEP specimens (1.6 cm3) was significantly smaller
than the volume of cone specimens (2.6 cm3). Thermal artifacts were negligible.
There were no significant differences in the proportion of margin involvement
(20% vs. 19%) and residual/recurrent CIN. The endocervical excision contained
dysplastic tissue in 38% of the cases; more important, a positive endocervical
excision was found in 14/21 CIN 3 cases (67%). The success rate, was similar in
both groups (96% vs. 97%). Hospitalization time was less for the LEEP group.
CONCLUSIONS: LEEP conization is a safe and cost effective procedure with a lower
complication rate providing a significantly smaller specimen compared to cold
knife conization. Therefore, LEEP conization may substitute cold knife
conization. However, we do recommend to perform LEEP conization with an
endocervical excision to reduce residual CIN.
PMID- 10785950
TI - [Galactography: important preoperative method for breast surgery].
AB - Galctography still is a very important method in the diagnosis of breast disease.
We studied the influence of indication on the diagnostic and therapeutic efficacy
of galactography. Between 1990 and 1998 210 galactographies performed in a
standardized fashion were evaluated in relation to the histopathologic findings.
Most of the pathology was caused by papilloma followed by ectatic ducts and
carcinoma. There was also a large number of normal ducts. In patients that were
operated on, there was a very high percentage of agreement between radiological
and histopathological diagnosis. If indication and performance are precise,
galactography yields very good results and thus contributes substantially to the
surgical approach. In particular it guides the surgeon safely to the pathologic
finding and thus guarantees its excision within a small volume of tissue.
PMID- 10785951
TI - [Thrombosis of ovarian veins in puerperium associated with heparin-induced
thrombocytopenia type II].
AB - We report for the first time on a puerperal ovarian vein thrombophlebitis
associated with heparin-induced thrombocytopenia type II. Two weeks after
cesarean section with subsequent prophylactic application of heparin a thrombosis
in the left deep femoral and pelvic veins and in the right ovarian vein occurred.
Despite only moderately reduced platelet count a heparin-induced thrombocytopenia
type II was diagnosed by heparin-induced platelet activation test. By treatment
with plasmin activator lysis the thrombus was diminished. An operative procedure
had been prevented. We conclude that also in cases with only moderately reduced
platelet count during and after administration of heparin, especially in patients
with wide spread and accumulating thrombosis, the presence of a heparin-induced
thrombocytopenia should be taken into consideration. In contrast to difficulties
in the management of puerperal ovarian vein thrombophlebitis--occurring
independently from heparin-induced thrombocytopenia (surgical treatment necessary
in most cases)--occurrence of puerperal ovarian vein thrombophlebitis in relation
to heparin-induced thrombocytopenia seems to response better to fibrinolysis and
anticoagulation.
PMID- 10785952
TI - [Computer support of workflow in the hospital: concepts, technology and
application].
AB - For a variety of reasons, hospitals are developing a growing interest in changing
their information systems to support patient processes in a more direct way. This
means to actively deliver the tasks to be performed to the right persons at the
right point in time with the necessary information and the application functions
needed for performing these tasks. Process-oriented workflow technology is a very
interesting candidate to achieve this goal. It offers components for the computer
based analysis, modeling, animation, coordination and monitoring of (hospital)
processes. In this paper we discuss the perspectives offered by workflow-based,
clinical information systems. We survey key features of today's business process
modeling tools and of workflow management systems, and we show how they can be
applied in the clinical domain. To illustrate the huge potential offered by
workflow technology, we present results from the project "Using Workflow
Management Systems for Clinical Applications". Within this project we thoroughly
analyzed and redesigned core processes from the University's Women hospital and
we proto-typically implemented a workflow-based application system for the
support of processes from the division day clinic. Although our work shows that
current workflow technology is still lacking some important features, in the long
run, it may strongly influence information processing within hospitals.
PMID- 10785953
TI - [In memoriam Karl Gunther Ober (24.8.1915-27.2.1999)].
PMID- 10785954
TI - [The meeting of the Japanese Society of Anesthesiology as a bridge between the
20th century and the 21st anesthesiological science].
PMID- 10785955
TI - [Anesthesiology of 20th century and the future prospects in Japan].
PMID- 10785956
TI - [Procedures and the significance of Evidence-based Medicine].
PMID- 10785957
TI - [Role of transesophageal echocardiography in cardiovascular surgical procedures-
special reference to the importance of cooperation between anesthesiologists and
surgeons].
PMID- 10785958
TI - [Present status of infectious diseases transmitted by blood transfusion and the
preventive measures].
PMID- 10785959
TI - [Enlightenment and the propagation of autologous blood transfusion].
PMID- 10785960
TI - [Searching for new genes--Our experience of finding the genes related to nervous
system diseases].
PMID- 10785961
TI - [Anesthesia for dentistry in handicapped persons].
PMID- 10785962
TI - [Progress on physiopathological study of shock--Approach from the molecular
biological point of view].
PMID- 10785963
TI - [Quality of recovery from anesthesia].
PMID- 10785964
TI - [Active sites of anesthetics in the vascular systems].
PMID- 10785965
TI - [Effects of anesthetics on tracheal smooth muscle].
PMID- 10785966
TI - [Anesthesia and the pharynx].
PMID- 10785967
TI - [Various problems involved in diagnosis of brain death and decision of organ
harvesting].
PMID- 10785968
TI - [Mechanism of postoperative pain and the analgesia].
PMID- 10785969
TI - [Anesthesia for pediatric surgical emergencies].
PMID- 10785970
TI - [Preoperative evaluation of patients with cardiovascular disorders].
PMID- 10785971
TI - [Anesthesia for cesarean section--special reference to fetal oxygenation].
PMID- 10785972
TI - [Postoperative complications in aged patients].
PMID- 10785973
TI - [Anesthesia and the allergic reaction].
PMID- 10785974
TI - [Anesthesiological problems in thoracoscopy and laparoscopy].
PMID- 10785975
TI - [Applicability of intravenous anesthesia--special reference to propofol and
ketamine].
PMID- 10785976
TI - [Metabolism and toxicity of anesthetics].
PMID- 10785977
TI - [New methods of cardiopulmonary resuscitation].
PMID- 10785978
TI - [Intraoperative monitoring of the bain and spinal cord during anesthesia].
PMID- 10785979
TI - [Drug interactions among anesthetics].
PMID- 10785980
TI - [Cases with difficulty of intratracheal intubation].
PMID- 10785981
TI - [Intraoperative arrhythmia--the etiology, diagnosis, and the therapy].
PMID- 10785982
TI - [Selection of local anesthetics for clinical usage].
PMID- 10785983
TI - General practice care following miscarriage.
PMID- 10785985
TI - Investigation of lipids. What do the results really mean?
AB - BACKGROUND: The National Heart foundation recommends that all adult Australians
should have their plasma lipids measured to help assess their risk of
cardiovascular disease (CVD). Patients usually concentrate on their total
cholesterol result, but this is less informative than the levels of individual
lipoproteins, particularly low density lipoprotein (LDL) and high density
lipoprotein (HDL). OBJECTIVE: To discuss the considerations behind laboratory
lipid measurements and their interpretation. DISCUSSION: Adult patients are best
assessed with total cholesterol, triglyceride and HDL-C allowing calculation of
LDL-C. Treatment decisions should be based on LDL-C levels in the context of the
overall risk factor status of the patient for CVD. Additional laboratory tests
are available, some of which may assist with diagnosis or clinical decision
making.
PMID- 10785984
TI - Choosing the most appropriate therapy for lipid disorders.
AB - BACKGROUND: There is general acceptance of the need to treat hyperlipidaemia to
reduce the risk of coronary artery disease. However, the level at which it is
appropriate to introduce drug therapy varies with the cardiovascular risk of the
patient. As the range of medications available increases, choosing the
appropriate therapy for a patient becomes more difficult. OBJECTIVE: To provide
the practitioner with a clear view of lipid treatment goals and how to select the
most appropriate treatment. DISCUSSION: Diet is the cornerstone of treatment,
with a discretionary use of drugs when hyperlipidaemia persists, particularly in
those patients with unacceptably high cardiovascular risk. For a predominant
cholesterol problem statin drugs are first choice, whereas fibrate drugs are most
appropriate for hypertriglyceridaemia. For mixed hyperlipidaemia statin, fibrate
or combinations may be required. Treatment is effective and safe but compliance
with long term therapy remains a problem.
PMID- 10785986
TI - Issues in managing hyperlipidaemia.
AB - BACKGROUND: The relationship of plasma cholesterol to human coronary artery
disease was established with the Framingham study in 1960 and an elevated plasma
cholesterol is now considered the major modifiable risk factor for developing
coronary artery disease. Recent studies, including the Australian LIPID study,
have changed what we consider to be acceptable cholesterol levels. OBJECTIVE: To
discuss the role of serum cholesterol levels, dietary modification and lipid
lowering drug treatments in overall cardiovascular risk management. DISCUSSION:
The current challenges in lipid management are to find ways to increase adherence
to medication and deciding how far cholesterol should be lowered. Treatment of a
particular patient depends not just on their serum cholesterol but on their
overall cardiovascular risk. Diet has cardioprotective effects separate from
modification of serum cholesterol levels and this may be true of some lipid
lowering treatments.
PMID- 10785988
TI - Integrating counselling into general practice.
AB - BACKGROUND: General practice counselling has many significant differences to
counselling in other settings. General practitioners have long term relationships
with their patients involving physical as well as mental health care. General
practitioners are often the first point of contact for distressed patients who
may not perceive their problem to have a psychological basis. There are barriers
to counselling including time management and cultural expectations of the
consultation. OBJECTIVE: To outline a practical biopsychosocial model for
counselling in the general practice setting using the knowledge and skills unique
to each GP. Theoretical and practical barriers to counselling commonly
encountered in general practice are discussed. DISCUSSION: Assessing the problem
in a biopsychosocial format highlights strengths and skills the patient already
possesses and involves consideration of physical sensations, emotions,
behaviours, key relationships, family, social roles and resources. Counselling in
general practice requires flexibility and an ability to adapt available resources
to address patient needs in an individually appropriate way.
PMID- 10785987
TI - Treating elevated lipids. Does it make a difference?
AB - BACKGROUND: There is now abundant evidence from clinical trials that treatment
with lipid modifying therapy will decrease the risk of coronary heart disease
(CHD). The decision to treat a patient, whether with advice on lifestyle
modification or with drug therapy, needs to be based on consideration of costs
versus benefits. OBJECTIVE: To assess the evidence from primary and secondary
prevention studies for cardiovascular benefit of cholesterol lowering medication.
DISCUSSION: Treating hypercholesterolaemia reduces the relative risk of major CHD
events by about 30%. The greatest benefit of lipid lowering treatment is in the
high risk group. This group shows the greatest reduction in absolute risk and
therefore a 'smaller number to treat' to prevent one major CHD event. In the
moderate risk group three times as many individuals require treatment to prevent
one major CHD event. However, this corresponds to the benefit in primary
prevention of stroke by treating mild-moderate hypertension in middle aged men.
PMID- 10785989
TI - The Australian categorisation of risk of drug use in pregnancy.
PMID- 10785990
TI - Coronary artery trauma in chest wall injury.
AB - BACKGROUND: Blunt chest trauma is a rare but important cause of coronary artery
occlusion. Coronary damage may occur with even relatively minor chest injuries.
The diagnosis of cardiac injury can be difficult in the setting of chest wall
trauma as the usual findings of chest pain, cardiac enzyme assay and ECG are
unreliable diagnostic tools. OBJECTIVE: A case is presented demonstrating the
diagnosis difficulties. DISCUSSION: An ECG abnormality in the setting of even
minor chest injury requires assessment with echocardiography and, if abnormal,
angiography. Currently angiography is the definitive diagnostic test and allows
for therapeutic intervention as appropriate but coronary artery ultrasound may
find a place in management. Further management depends on the time of diagnosis
and the presence of other injuries.
PMID- 10785991
TI - Extreme anxiety/panic disorder.
AB - A 45 year old man is referred to a specialist psychiatric centre. For 3 years he
has been experiencing worsening impending fear of death and anxiety which he
describes as 'panic attacks'. During these episodes he often experiences
palpitations and becomes sweaty. These episodes have not been relieved despite
several courses of electroconvulsive therapy. On examination, the man is alert
and orientated. He has a normal blood pressure of 125/75 mmHg and
electrocardiogram reveals a pulse rate of 102 beats per minute. A psychiatrist
orders a number of routine tests to rule out organic disease.
PMID- 10785992
TI - A fever from the tropics.
AB - Shirley is a 42 year old woman who has rung you 5 days after returning from a 3
week resort holiday in Malaysia and Thailand. You saw her before her trip and
administered a hepatitis A vaccine and advised her that she did not require anti
malarial drugs as she was only going to large cities and beach resorts. She says
she has had a high fever, headache and body aches for several days and that she
feels exhausted, but is well enough to come to the surgery. When you see her
later that morning, she looks fairly well, although she is moving rather
gingerly. She says she has been resting, is drinking lots of fluids, has some
anorexia, but no other significant symptoms. Examination reveals a temperature of
38 degrees C and she has a fine morbilliform rash on her body, limbs and neck.
There are no other abnormal findings.
PMID- 10785993
TI - Things don't always change for the better.
PMID- 10785994
TI - The Australian practice nurse. Still more questions than answers.
PMID- 10785995
TI - The role of the practice nurse. An exploratory study.
AB - AIM: There is little research on the role of the practice nurse in Australia.
However, there is some evidence that practice nurses are no longer primarily
receptionists, but rather function as nurses. This article reports on a small
qualitative study that set out to identify areas of effective shared care between
general practitioners and practice nurses. METHOD: Semistructured interviews were
conducted with general practitioners and practice nurses in eight general
practices. A general practitioner who did not employ a practice nurse and a
general practitioner and two nurse practitioners at a Community Health Centre
were also interviewed. RESULTS: It was found that general practitioners and
practice nurses have established effective working relationships that enhance
patient care. Shared care was not found, except to some extent in the area of
wound care. CONCLUSION: Most GPs and practice nurses interviewed believed that
the current funding model, requiring GPs to sight all patients before a fee can
be claimed, restricts the potential use of practice nurses' expertise, for
example with patients returning for routine blood tests or blood pressure
monitoring, or wound dressing. A change to the current model would have
implications for the education and accreditation of practice nurses.
PMID- 10785996
TI - Reducing the incomplete excision of non melanotic skin cancers in Australian
general practice.
AB - AIM: To develop a simple set of predictors of incomplete excision of non
melanotic skin cancer and to test them prospectively. METHOD: Possible predictors
were identified by a literature review and modified by a retrospective analysis
of histologically confirmed excisions by the author between 1992 and early 1998.
The composite set was then tested prospectively on non melanotic skin cancer
excisions from April 1998 to September 1999. RESULTS: The set of predictors was
used prospectively to identify lesions with which particular care should be taken
to avoid incomplete excision. Using this method resulted in an overall reduction
of incomplete excisions of about 50%. CONCLUSIONS: The application of a set of
predictors is an effective method of reducing incomplete excisions. A number of
factors related to the age of the patient, the site of the lesion and its
macroscopic appearance made up the set of predictors. Their application showed
that particular care needs to be taken with lesions on the head and neck and
lesions on patients who are under 50 years of age.
PMID- 10785997
TI - The early detection of glaucoma in general practice.
AB - BACKGROUND: Glaucoma is one of the most common preventable causes of visual loss.
Because it is an asymptomatic condition until late in the process only 50% of the
population with glaucoma are aware they have it. Primary care physicians rarely
test their patients for glaucoma, primarily because of the lack of specificity or
sensitivity of any one particular test. OBJECTIVE: To determine if it was
possible to identify patients with early signs of glaucoma from within my own
practice, in patients who had not previously been tested for glaucoma or had not
been tested for at least two years. DISCUSSION: This study has shown that
glaucoma case-finding is feasible in general practice. Direct ophthalmoscopy
proved to be the most valuable single test in diagnosing glaucoma and the
combination of measurement of intraocular pressure and direct ophthalmoscopy was
shown to be the most likely method of diagnosing glaucoma or identifying glaucoma
suspects.
PMID- 10785998
TI - Calibration of sharp cut impactors for indoor and outdoor particle sampling.
AB - A low-flow rate, sharp cut point inertial impaction sampler was developed in 1986
that has been widely used in PM exposure studies in the United States and several
other countries. Although sold commercially as the MS&T Area Sampler, this
sampler is widely referred to as the Harvard Impactor, since the initial use was
at the Harvard School of Public Health. Impactor nozzles for this sampler have
been designed and characterized for flows of 4, 10, 20, and 23 L/min and cut
points of 1, 2, 5, and 10 microns. An improved method for determining the actual
collecting efficiency curve was developed and used for the recent impactor
calibrations reported here. It consists of placing a multiplet reduction impactor
inline just downstream of the vibrating orifice aerosol generator to remove the
multiplets, thus allowing only the singlet particle s to penetrate through to the
impactor being calibrated This paper documents the techniques and results of
recent nozzle calibrations for this sampler and compares it with other size
selective inertial impactors. In general, the impactors were found to have sharp
cutoff characteristics. Particle interstage losses for all of the impactors were
very low, with the exception of the 10-micron cut size 20 L/min impactor, which
had greater losses due to the higher flow rate. All of the 2.5-micron cut nozzle
laboratory calibrations compare favorably to the U.S. Environmental Protection
Agency (EPA) WINS-96 fine particle mass (PM2.5) impactor calibration data.
PMID- 10785999
TI - Effect of methyl tertiary butyl ether concentrations on exhaust emissions from
gasoline used in the metropolitan area of Mexico City.
AB - In this work, the primary objective was to assess the impact of oxygenated fuel
on the exhaust emissions from an important fraction of vehicles in the
Metropolitan Area of Mexico City (MAMC). The results aim to provide information
on the actual effect of MTBE on a fleet that represents more than 60% of the in
use vehicles in the MAMC. Ten vehicles were tested with a low-octane base
gasoline, and 10 more with a regular-grade unleaded base gasoline. Three MTBE
concentrations, 5, 10, and 15 vol %, were tested following the U.S. Federal Test
Procedure (FTP). CO, total HC, and NOx from the exhaust gases were quantitatively
evaluated and also characterized for FTP speciated organic emissions. From this
data, the O3-forming potential of the fuels was calculated. Results show that for
the fleet using low-octane gasoline, the addition of 10% MTBE substantially
reduced CO emissions, but total HC concentration in the exhaust showed a modest
decrease. For the regular gasoline, the 10% MTBE blend seemed to be the best
choice, but there was not a significant decrease in emissions. The specific
reactivity of each fuel, expressed in grams of O3 per gram of nonmethane organic
gases, increased with MTBE concentration in both cases. This result is important
to consider, especially for a region like Mexico City, which has high atmospheric
O3 concentrations.
PMID- 10786000
TI - Neural network model for predicting peak photochemical pollutant levels.
AB - In this paper, an attempt is made for the 24-hr prediction of photochemical
pollutant levels using a neural network model. For this purpose, a model is
developed that relates peak pollutant concentrations to meteorological and
emission variables and indexes. The analysis is based on measurements of O3 and
NO2 from the city of Athens. The meteorological variables are selected to cover
atmospheric processes that determine the fate of the airborne pollutants while
special care is taken to ensure the availability of the required input data from
routine observations or forecasts. The comparison between model predictions and
actual observations shows a good agreement. In addition, a series of sensitivity
tests is performed in order to evaluate the sensitivity of the model to the
uncertainty in meteorological variables. Model forecasts are generally rather
insensitive to small perturbations in most of the input meteorological data,
while they are relatively more sensitive in changes in wind speed and direction.
PMID- 10786001
TI - Biotrickling filtration of nitric oxide.
AB - A biotrickling filter with blast-furnace slag packings (sizes = 20-40 mm and
specific surface area = 120 m2/m3) was utilized to treat NO in an air stream. The
operational stability, as well as the effects of gas empty-bed retention time
(EBRT) and nutrient addition on the removal ability of NO, were tested.
Approximately six weeks were required for the development of a biofilm for NO
degradation, and a two-week organic carbon deficiency resulted in the detachment
of biofilms from the packing surfaces. A steady removal rate of 80% was attained
at specified influent NO concentrations of 892 to 1237 ppm and an EBRT of 118
sec. The effluent NO concentration diminished exponentially with enlarging EBRT,
with influent NO concentrations of 203-898 ppm, and EBRTs of 25 to 118 sec.
Nutrient addition is essential for efficient removal of the influent NO. Mass
ratios of C: P: N = 7: 1: 30 and NaHCO3: NO-N = 6.3 could be used for practical
applications.
PMID- 10786002
TI - Costs, emissions reductions, and vehicle repair: evidence from Arizona.
AB - The Arizona inspection and maintenance (I/M) program provides one of the first
opportunities to examine the costs and effectiveness of vehicle emission repair.
This paper examines various aspects of emission reductions, fuel economy
improvements, and repair costs, drawing data from over 80,000 vehicles that
failed the I/M test in Arizona between 1995 and the first half of 1996. We
summarize the wealth of data on repair from the Arizona program and highlight its
limitations. Because missing or incomplete cost information has been a serious
shortcoming for the evaluation of I/M programs, we develop a method for
estimating repair costs when they are not reported. We find surprising evidence
that almost one quarter of all vehicles that take the I/M test are never observed
to pass the test. Using a statistical analysis, we provide some information about
the differences between the vehicles that pass and those that do not. Older, more
polluting vehicles are much more likely never to pass the I/M test, and their
expected repair costs are much higher than those for newer cars. This paper
summarizes the evidence on costs and emission reductions in the Arizona program,
comparing costs and emissions reductions between cars and trucks. Finally, we
examine the potential for more cost-effective repair, first through an analysis
of tightening I/M cut points and then by calculating the cost savings of
achieving different emission reduction goals when the most cost-effective repairs
are made first.
PMID- 10786003
TI - Speciated hydrocarbon emissions from small utility engines.
AB - Partially speciated hydrocarbon (HC) emissions data from several small utility
engines, as measured by a Fourier Transform Infrared analyzer, are presented. The
engines considered have nominal horsepower ratings between 3.7 and 9.3 kW. Both
side-valve and overhead-valve engines are studied, and four different fuels are
used in the engines. The results indicate that the small HCs present in the
exhaust tend to be in the form of either methane or unsaturated HCs. Other small
alkanes, such as ethane and propane, are present in only relatively small
concentrations. In terms of ozone formation potential, the HCs in the form of
methane will lead to little ozone, but the distribution of the C2 and C3 species
is not ideal from an ozone reduction stand-point. It is also found that the
presence of oxygen in the fuels appears to lead to somewhat more complete
combustion, although the effects are not large. Finally, the overhead-valve
engines appear to have lower HC emissions than side-valve engines, which is
primarily due to higher operating A/F ratios and the engine geometry.
PMID- 10786004
TI - Microwave regeneration of activated carbon used for removal of solvents from
vented air.
AB - A microwave regeneration of activated carbon used to remove organic solvents from
vented air has been investigated. Methyl ethyl ketone (MEK), acetone, and
tetrachloroethylene (TCE) vapors were removed from vented air through adsorption
onto granular activated carbon. The saturated carbon was then regenerated in a
microwave field, where the solvent was quickly desorbed and recovered from the
inner pores of the carbon granules. The microwave-induced regeneration restored
the original adsorption capacity and surface area of the activated carbon.
PMID- 10786005
TI - Removal of chromium from abrasive blast media by leaching and electrochemical
precipitation.
AB - Water is effective in leaching out Cr6+ from a mixture of paint powders and
abrasive blast media. However, acids such as HNO3, HCl, and H2SO4 significantly
enhance the leaching procedure. Cr ions in the leaching solutions are
successfully removed by electrochemical precipitation. The consumable Fe
electrodes generate ferrous ions to cause the reduction of Cr6+ to Cr3+. Cr3+
ions along with Fe2+ and Fe3+ are then removed mainly by precipitation as
Cr(OH)3, Fe(OH)2, and Fe(OH)3 near the cathode where OH- ions are generated by
water electrolysis. The electrochemical process is capable of discharging low
levels of Cr6+, less than 1 mg/L, without pH adjustment.
PMID- 10786006
TI - On-road motor vehicle emissions and fuel consumption in urban driving conditions.
AB - This paper reports on the analysis of on-road vehicle speed, emission, and fuel
consumption data collected by four instrumented vehicles. Time-, distance-, and
fuel-based average fuel consumption, as well as CO, HC, NOx, and soot emission
factors, were derived. The influences of instantaneous vehicle speed on emissions
and fuel consumption were studied. It was found that the fuel-based emission
factors varied much less than the time- and distance-based emission factors as
instantaneous speed changed. The trends are similar to the results obtained from
laboratory tests. The low driving speed contributed to a significant portion of
the total emissions over a trip. Furthermore, the on-road data were analyzed
using the modal approach. The four standard driving modes are acceleration,
cruising, deceleration, and idling. It was found that the transient driving modes
(i.e., acceleration and deceleration) were more polluting than the steady-speed
driving modes (i.e., cruising and idling) in terms of g/km and g/sec. These
results indicated that the on-road emission measurement is feasible in deriving
vehicle emissions and fuel consumption factors in urban driving conditions.
PMID- 10786008
TI - Climate change and the adaptability of agriculture: a review.
AB - The assessment of climate change impacts on agriculture has emerged as a
recognizable field of research over the past 15 years or so. In a relatively
short period, this area of work has undergone a number of important conceptual
and methodological developments. Among many questions that have been debated are
the adaptability of agriculture to climate change and the importance of land
management adjustments in reducing the adverse effects of climate change. In
turn, this latter focus has spawned a discussion regarding the nature of
adaptation and the ability of agriculture to respond to sudden and rapid climatic
changes. In this paper we present an overview of this debate. It is argued that
the first generation of climate change impact studies generally ignored the
possibility that agriculturalists may adjust their farming practices in order to
cope with climate change or to take advantage of new production opportunities.
This conceptual oversight has been largely eliminated over the past five years or
so. However, questions remain surrounding the likelihood that various adaptive
strategies will actually be deployed in particular places. In this paper, we
stress the importance of studying adaptation in the context of decision-making at
the individual farm level and beyond.
PMID- 10786007
TI - A kinetic study on oxidation of pentachlorophenol by ozone.
AB - The kinetics of pentachlorophenol (PCP) ozonation in terms of the gaseous O3 and
dissolved PCP concentrations has been investigated. When the O3 concentration in
the gas phase was in the range of 10 to 40 g O3/m3, the O3 dissolved for a short
time period was proportional to the gaseous O3 concentration. In this range, the
ozonation reaction was first order for each reactant and the overall reaction was
second order. At 25 degrees C, in an aqueous solution, the reaction rate constant
was estimated to be 10.048 L/mol.sec. The reaction rate was much greater than the
mass-transfer rate, indicating that the reaction of O3 and PCP was an interface
reaction on the surface of gaseous O3 bubbles. The final product of the PCP
ozonation was oxalic acid, with the carbon yield of the reaction being 59.4%. The
ozonation of PCP in the aqueous solution was not a radical reaction but a direct
reaction between O3 and PCP molecules under the conditions investigated in this
study, since O3 has a high selectivity toward PCP. The reaction rate increased
with the reaction temperature up to 35 degrees C but decreased at temperatures
greater than 35 degrees C due to the decreased solubility of O3. The addition of
H2O2 did not increase the reaction rate significantly.
PMID- 10786009
TI - Evaluation of watering to control dust in high winds.
AB - A field study was conducted to determine the effectiveness of watering in
controlling PM10 emissions under high wind conditions. The focus of the study was
the pickup of soil by a belly scraper at a landfill. Four low-volume PM10
samplers were positioned downwind of the storage pile (at two distances, 80 and
110 m, and two elevations, 1 and 3 m) and one was located upwind at 3 m
elevation. Integrating nephelometers, which measure the particulate light
scattering coefficient, bsp, were also set up at locations 80 and 110 m downwind
of the storage pile. Wind speed and direction were measured on-site. Samples were
collected for two periods, one with and one without water being applied. Watering
was effective at reducing PM10 emissions at wind speeds up to the maximum 18 m
sec-1 observed at the landfill soil pickup operation. Measurement of bsp provided
an indication of PM10 concentrations with better time resolution than samplers,
but not with sufficient resolution, under the instrumental conditions used, to
correlate with wind gusts.
PMID- 10786010
TI - Performance characteristics of PM10 samplers under calm air conditions.
AB - The size range of airborne particles that is closely related to specific
deposition regions in the human respiratory tract and excess lung burden of these
deposited particles is associated with disease. Size-selective sampling,
therefore, needs to be performed to assess the related health risks. Performance
criteria applied to these samplers must be well characterized in order to provide
accurate and reliable results. The PM10 samplers that have been used in place of
the total suspended particulate samplers for the collection of ambient air
particles are more relevant to potential inhalation hazards. In order to be
certified, a PM10 sampler must meet reliable performance specifications,
primarily the aerosol penetration test with liquid and solid particles in a wind
tunnel (wind speeds of 2, 8, and 24 km/hr). This testing is intended to assure
reasonable accuracy in aerosol measurements. However, the sampler performance
under calm air conditions has not been well studied. In the present study, the
sampling heads of three devices--the Harvard impactor, the Personal Environmental
Monitor (PEM), and the Sierra Andersen model 241 dichotomous sampler PM10 inlet
head--were tested for aerosol separation efficiency. With the consideration of
bias and imprecision of the measurements, five specimens of each type of sampler
were chosen for performance testing, repeating the tests 5 times for each
specimen. An ultrasonic atomizing nozzle was used to nebulize potassium sodium
tartrate tetrahydrate and dioctyl phthalate particles as the solid and liquid
challenge aerosols, respectively. The aerosol number concentrations and size
distributions upstream and downstream of the samplers were measured by using an
aerosizer calibrated against a settling velocity chamber. The results showed that
among the samplers tested, the dichotomous sampler PM10 inlet head had the best
fit to the PM10 convention, while the other two samplers not only appeared to
have a steeper separation-curve slope but also had significant particle bounce
when challenged with solid particles. Analysis of variance also confirmed the
superiority of the dichotomous samplers. Surface-coating with oil or grease
greatly reduced the problem of particle bounce.
PMID- 10786011
TI - Guidance for the performance evaluation of three-dimensional air quality modeling
systems for particulate matter and visibility.
AB - Guidance for the performance evaluation of three-dimensional air quality modeling
systems for particulate matter and visibility is presented. Four levels are
considered: operational, diagnostic, mechanistic, and probabilistic evaluations.
First, a comprehensive model evaluation should be conducted in at least two
distinct geographical locations and for several meteorological episodes. Next,
streamlined evaluations can be conducted for other similar applications if the
comprehensive evaluation is deemed satisfactory. In all cases, the operational
evaluation alone is insufficient, and some diagnostic evaluation must always be
carried out. Recommendations are provided for designing field measurement
programs that can provide the data needed for such model performance evaluations.
PMID- 10786012
TI - A model for pulse jet fabric filters.
AB - A new model for pulse jet fabric filtration is proposed. In contrast to the
earlier model of Ravin and Humphries, which was formulated on the steady state
assumption, the present study is aimed at developing a predictive capability for
both transient and steady state operations, taking into account the compression
effect of filter cakes. The model's relative simplicity allows frequent updating
of the model parameter values, thus improving the accuracy of predictions. As a
result, the model is particularly useful in developing control algorithms and
designing controllers of pulse jet fabric filtration systems.
PMID- 10786013
TI - Fine particles and oxidant pollution: developing an agenda for cooperative
research.
AB - This paper describes a background for the North American Research Strategy for
Tropospheric Ozone (NARSTO) cooperative program integrating studies of O3 and
PM2.5. It discusses several important aspects for rationalizing NARSTO's
trinational investigative approach, including (1) an outlook on the state of
knowledge about fine particles in the troposphere and their origins in Canada,
Mexico, and the United States; (2) the need for enhancement and strengthening of
key field measurements in relation to tropospheric chemistry and a health effects
component; and (3) the use of a central theme for advancing air quality modeling
using evolving techniques to integrate and guide key process-oriented field
campaigns. The importance of organizing a scientific program to acquire "policy
relevant" information is stressed, noting cooperative research directions that
address combined PM2.5 and O3 issues, illustrated through exploration of
hypothetical pathways of PM2.5 response to choices of O3 and PM precursor
emission reductions. The information needed for PM2.5 research is noted to
intersect in many cases with those of O3, but diverge in other cases. Accounting
for these distinctions is important for developing NARSTO's strategy over the
next decade.
PMID- 10786014
TI - Effect of parasite screening on refugee health.
AB - Intestinal parasitic infections among refugees have been perceived as a public
health problem for decades. A control program strategy to reduce morbidity and
eventually transmission of intestinal parasites was initiated in 1993 by Mercy
International (MI) for a group of Somalia refugee and has been implemented
successfully. The management of the program operating within a comprehensive
health care project and the control activities has been performed through the
existing health facilities. This project was based on the "Comprehensive Health
Care Approach" concept and applied to a collection of 10,000 Somali refugees. A
project, which could be further, developed and modified for other similar
situations. The strategy adopted was based on periodic chemotherapy of
schoolchildren, intense health education in close collaboration with the local
community leaders. An overall reduction in prevalence of intestinal parasitic
infections of 53% was one of the targets achieved through this effort after three
years of activities. 92% and 62% reduced the intensity of Ascaris lumbricoides
and Trichuris trichiura infection, respectively. This approach in concert with
the political commitment and limited operational costs is a warranty for the
future sustainability of the control activities. Future control strategies are
tailored to the results of evaluation surveys and are targeted to the identified
high-risk areas. This project can be seen as a model in other refugee situation
with the use of limited local resources.
PMID- 10786015
TI - Effect of cyclophosphamide-mediated immunodeficiency on murine Schistosomiasis
mansoni.
AB - Four groups of female C57BL/6 mice were used. The first group was infected with
500 unattenuated cercariae. The second group was immunosuppressed by
cyclophosphamide (Cy) before infection with the same dose of cercariae. The third
group was exposed to 500 partially attenuated cercariae while the fourth group
was immunosuppressed with (Cy) before exposure to 500 partially attenuated
cercariae. In response to infection with either unattenuated or partially
attenuated cercariae, the total worm burden was significantly reduced. In the
meantime, the level of serum specific anti-SWAP IgG1 was significantly higher and
a specific band at 32 kDa was recognized in the infected groups (first and third)
compared to that in the immunosuppressed groups (second and fourth). Scanning
electron microscopy observations revealed severe damage and deformities on the
tegument of worms of the third group compared to less damage detected on the
tegument of worms in the fourth group. No obvious changes could be detected on
the tegument of worms developed from the second group compared to the first group
(controls). These observations taken together indicate that the high level of
anti-SWAP IgG1 may have a role in the elimination of schistosomes after primary
infection of mice with either unattenuated or partially attenuated S. mansoni
cercariae. Moreover, this immunoglobulin together with UV-induced attenuation
produce severe damage on the tegument of worms developed from mice exposed to
partially attenuated cercariae.
PMID- 10786016
TI - Diagnosis of toxoplasmosis in immunosuppressed mice using the polymerase chain
reaction (PCR) and the enzyme linked immuno-sorbent assay (ELISA) techniques.
AB - In the present study, Toxoplasma infection with the virulent and avirulent
strains in both immunocompetent and immunosuppressed mice was diagnosed using the
MDS ELISA for detection of CA in sera and the PCR for demonstration of DNA in
livers, brains and mononuclear cells of blood. Both techniques proved to be
convenient, especially in immunosuppressed mice.
PMID- 10786017
TI - On the morphology of Heligmosomoides polygyrus (Nematoda-Trichostrongylidae) from
the field mouse apodemus sylvaticus.
AB - The morphology of the trichostrongylid nematode Heligmosomoides polygyrus is
described by light and scanning electron microscopy. In light microscope, the
present material agrees with the original description given by Baylis (1926),
except for the addition of more details about the structure of the genital cone
and the synlophe. The scanning electron microscopy of the present nematode
revealed that the oral opening of the immature worm (L5) is rounded and its
cuticular surface is loosely attached to the body, while the oral opening of the
mature worm is triangular, the two copulatory spicules of the male are alate and
closely adhering to each other and the right lobe of the male bursa is longer
than the left one. Male prebursal and bursal papillae are described. The female
posterior extremity is characterized by crescent vulval and anal openings and a
terminal spike.
PMID- 10786018
TI - Evaluation of four pediculicides against the head lice Pediculus h. capitis.
AB - Four pediculicides were tested against head lice in-vitro. The LT50 for Licid
ranged between 10.75 (at conc. 50%) to 25.08 (at conc. 1%). All lice died with
conc. 100% within 5 minutes. With Malathion, the LT50 ranged between 4.23 to 9.3
at conc. 50% to 1% respectively. All lice died with conc. 57% within 3 minutes.
With Benzanil, the LT50 ranged between 20.85 to 44.34 at conc. 50% to 1%
respectively. All lice died at conc. 2.5% within 10 minutes. With Para plus, the
LT50 ranged between 18.46 to 29.5 at conc. 100% to 50% respectively. All lice
died with conc. 100% within 30 minutes. So, the least time needed to kill all
lice was given with Malathion (3 minutes). The least dose of pediculicide needed
to kill all lice was those of Benzanil (1% = 0.025) and Malathion (1% = 0.57).
The whole results were discussed regarding the advantages and disadvantages of
these pediculicides.
PMID- 10786019
TI - Evaluation of the IgG4 in Egyptian bancroftian filariasis.
AB - The IgG4 response against antigen extracts from Wuchereria bancrofti
microfilariae and Dirofilaria immitis adult worms was determined by ELISA in 65
Egyptian adult male patients suffering from different clinical manifestations of
W. bancrofti infection. They were divided into microfilaremic (n-35) and
amicrofilaremic (n = 30) and these divisions were subdivided into early
asymptomatic, hydrocele and late chronic elephantiasis subgroups. The IgG4
responses were significantly higher in early asymptomatic patients whether
microfilaremic or amicrofilaremic than in hydrocele or in chronic elephantiasis
(P < 0.05) & (P < 0.001) respectively. The IgG4 response was slightly higher in
microfilaremic than in amicrofilaremic subjects. The mean OD value of IgG4 among
the microfilaremics against the microfilaria antigen in early asymptomatic
patients (0.840 nm) was lower than the IgG4 response against the adult antigen in
the same group (0.960 nm), while among the early asymptomatic amicrofilaremics it
was the same (0.690 nm) in both microfilaria and adult antigens.
PMID- 10786020
TI - Modulation of the pathologic and apoptotic changes of experimental toxoplasmosis
by concomitant infection with Trichinella spiralis.
AB - This study shows that Toxoplasma gondii infection is capable of inducing a
process of programmed cell death not only in the infected hepatocytes of
experimental murine model, but also the neighbouring non-infected cells. However,
some cells showed a possible mixed apoptotic and necrotic pattern. Surprisingly,
lymphocytes and Kupffer cells in portal sinusoids nearby the parasite vacuoles
showed no apparent changes. Toxoplasma in concomitant infection with a different
parasite, Trichinella spiralis, clearly mitigate the pathologic and apoptotic
changes caused by T. gondii. These findings might help in understanding the
problematic biology and immunopathogenesis of T. gondii. The results also
augments previous reports by the same authors about the possible protective role
of heterologous antigens of one parasite against a biologically and
immunologically different parasite.
PMID- 10786021
TI - Chironomid potent allergens causing respiratory allergy in children.
AB - Generally speaking, chironomids contain potent inhalant allergens. The skin prick
tests with chironomid crude extract (Chironomus (C.) calipterus) were positive in
20 out of 25 children with respiratory allergy. The skin prick tests with house
dust mite crude extract (Dermatophagoides pteronyssinus) were positive in 3 of
these 20 chironomoid positive skin tests. Chironomid-specific IgE-ELISA were
demonstrated in the sera of 17 (85%) of the chironomid skin positive patients.
These 17 patients gave negative skin prick test to house dust mite crude extract.
It is concluded that chironomid allergens should be considered when dealing with
human respiratory allergy caused by arthropods.
PMID- 10786022
TI - Intestinal spore-forming protozoa among patients suffering from chronic renal
failure.
AB - Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis and Microsporidia
are four intestinal spore-forming protozoa that cause diarrhoea in immuno
competent individuals and immuno-suppressed patients. Fresh stool samples were
obtained from 120 patients suffering from CRF and attending the Dialysis Unit of
Zagazig University Hospital. Also, stool samples were obtained from 40 immuno
competent individuals complaining of diarrhoea (control group). The stool samples
were examined by direct smear and formol-ether concentration methods then stained
by Giemsa, Modified Ziehl Neelsen (MZN) and Aniline carbol methyl violet stains.
The four intestinal spore-forming protozoa were detected in 40/120 (33.3%) of
patients with CRF and in 2/40 (5.0%) of the control group with a statistically
highly significant difference (P < 0.001). C. parvum, Microsporidia, C.
cayetanensis and I. belli were detected in 18/120 (15%), 10/120 (8.3%), 9/120
(7.5%) and 3/120 (2.5%), respectively. The four protozoa were found as mixed
infections with other pathogens or as single infections confirming their role
alone as a cause of diarrhoea. MZN stain was the most efficient simple, and not
expensive.
PMID- 10786023
TI - Larvicidal activity of Commiphora molmol against Culex pipiens and Aedes caspius
larvae.
AB - Myrrh (oleo-gum-resin) obtained from the stem of Commiphora molmol proved to have
insecticidal activity against mosquito larvae. The oil extract of Myrrh possesses
median lethal activity against 2nd, 3rd and 4th instar larvae of Culex pipiens at
0.016 x 10(2), 0.17 x 10(2) & 1.6 x 10(2) g/l respectively. While LC50 against
3rd instar larvae of Aedes caspius was 0.2 x 10(2) g/l. The oleo-resin extract
showed toxicity against 2nd, 3rd, 4th instar larvae of C. pipiens recording the
LC50 values of 0.06 x 10(2), 0.09 x 10(2) & 0.5 x 10(2) g/l respectively. While
LC50 against 3rd instar larvae of A. caspius was 0.08 x 10(2) g/l. This plant
extract has no marked toxic effect against the water bug Sphaerodema urinator
(Dufor) and the water beetle Hydaticus leander (Rossi). Histological examinations
of Myrrh treated mosquito larvae showed great pathological effect on their fat,
muscles, gut and nervous tissues.
PMID- 10786024
TI - Effect of ivermectin on the brown dog tick, Rhipicephalus sanguineus.
AB - Ivermectin (Ivomec) proved to be effective in controlling R. sanguineus. All
brown dog ticks infesting the treated dogs (subcutaneous injections) with 1.5 ml
or 2 ml/50 kg dropped off within 4 or 3 days respectively. The dropped off ticks
were completely inactive and died within one day or two. Ticks exposed to filter
papers impregnated with 100 micrograms/ml (66.67%) died within four days. A dose
of 1.5-2 microliters/50 kg eradicated Toxocara canis infection in four dogs, and
caused shrinkage of Dipylidium caninum gravid segments in three. A general
discussion was given with special reference to the contraindications and side
effects of ivermectin particularly for human usage.
PMID- 10786025
TI - SDS-PAGE-separated tissue proteins of Biomphalaria alexandrina snails in the
presence and absence of Schistosoma mansoni.
AB - SDS-PAGE was used to separate tissue proteins of control and trematode-infected
Biomphalaria alexandrina snails. The separated profiles demonstrate the
occasional appearance of protein fractions and the remarkable increase of
concentration of certain molecular masses in infected snails at one week interval
over four weeks post exposure to Schistosoma mansoni. Proteins of molecular
masses of 44, 56, 65 and 144 KDa were among these occasionally appeared protein
masses. Post exposure to S. mansoni larval infection, a protein mass of 36 KDa
was predominant giving a markedely higher absorbance (> 1) compared to control
(0.0166). This was identified as lactate dehydrogenase enzyme. Moreover, a
protein of 56 KDa mass was identified as Pyruvate kinase. The predicted induction
of these two enzymes could be either of host and/or parasitic origin. This study
revealed that S. mansoni- B. alexandrina complex has a completely different
protein pattern compared to control with very low similarity coefficient "S"
value. A correlation between the snail tissue protein or separation patterns and
the metabolic redirection of the snail host by the developing sporocyst was
discussed.
PMID- 10786026
TI - An experimental vaccine providing heterologous protection for Leishmania species
in murine model.
AB - Five groups each of 20 BALB/C mice were immunized by heat killed L. donovani
promastigotes. Two groups served as control. Each group of mice was subdivided
into 2 equal subgroups and challenged with either L. donovani or L. major. The
results revealed a high cross reactivity paralleled by a high cross protection
between L. donovani and L. major. Heat killed L. donovani promastigotes super
passed other tested SDS-PAGE fractionated and eluted L. d. fractions identified
by immune BALB/c mice in providing protection against both L. donovani and L.
major. The percentage of protection (reduction in parasite burden) offered by
each vaccine was as follows: 80.21%, 36.11%, 9.29%, 33.44% and 17.48%
respectively against challenge infection with L. donovani and 3.012 x 10(4),
1.095 x 10(4), 6.054 x 10(2), 2.409 x 10(4), and 3.34 x 10(2), respectively
against challenge infection with L. major.
PMID- 10786027
TI - Serum pretreatment with Schistosoma mansoni antigens for serological diagnosis of
fascioliasis.
AB - Cross-reactivity between Fasciola and Schistosoma often causes false positive
results in serological assays for diagnosis of fascioliasis. The authors tried to
reduce cross-reactivity in ELISA for diagnosis of fascioliasis by preincubation
of serum samples with a mixture of Schistosoma mansoni adult worm and egg
antigens. This method was evaluated using serum samples from 4 groups: 25
patients infected with Fasciola, 40 healthy controls, 113 patients infected with
S. mansoni and a group of 100 patients with suspected Fasciola infection. In
group with confirmed Fasciola infection, the sensitivity of ELISA was 96% without
any change after serum pretreatment while, in control group, the specificity was
elevated from 90% to 97.5% after serum pretreatment with S. mansoni antigens. In
S. mansoni infection and suspected Fasciola infection groups, there was a highly
significant reduction in number of ELISA positive cases after serum pretreatment
with S. mansoni antigens (McNemar P < 0.001 for each). In logistic regression
model, seroconversion showed significant dependence on presence of S. mansoni
infection (P = 0.012). The probability of seroconversion was more than three
times higher in S. mansoni infected individuals than in non-infected ones (Odds
ratio = 3.5).
PMID- 10786028
TI - Efficacy of cryotherapy and intralesional pentostam in treatment of cutaneous
leishmaniasis.
AB - Forty-two CL patients with 60 lesions were treated with cryotherapy using liquid
nitrogen twice for two months. Another group of fifty-five CL patients. With 73
lesions were treated with intralesional pentostam with pentostam, 67 of 73
lesions (92%) and with cryotherapy 47 of 60 lesions (78%) healed or markedly
improved at the end of three months follow-up. This study shows that
intralesional pentostam injection was effective than cryotherapy. However, both
lines of treatment were well tolerated by the patients. They showed no severe
side effects and no significant changes in laboratory values. It is suggested
that cryotherapy is an alternative to intralesional pentostam injection.
PMID- 10786029
TI - Treatment of cutaneous leishmaniasis patients with pentostam via intralesion
infiltration.
AB - Cutaneous leishmaniasis (CL) is an endemic disease in Egypt. Systematic treatment
with pentostam has its disadvantages and contraindications. In this study, six
out of eight parasitologically proved CL patients recovered with intralesion
infiltration with a dose of pentostam ranged between 0.8 to 1.6 gm. The other 2
patients did not show response with a dose up to 2 gm. The results were
discussed.
PMID- 10786031
TI - Ultrastructure studies on the nervous system of the land snail Eobania
vermiculata (Gastropoda: Stylommatophora).
AB - The ultrastructure of the different ganglia of the nervous system of the land
snail had been investigated. This study had revealed that the neurosecretory
granules are apparently formed from the Golgi apparatus and in other cases, the
neurosecretory granules appeared to be related to the rough endoplasmic
reticulum. The nuclei of the pedal, pleural, parietal and visceral ganglia are
irregular polymorphic in shape. The fine structure of the neurosecretory cells
was the point of interest in the present investigation.
PMID- 10786030
TI - Cystatin capture enzyme-linked immunosorbent assay for serodiagnosis of human
schistosomiasis mansoni.
AB - To diagnose human schistosomiasis mansoni, the current study tested an ELISA
system that employs indirectly, through a chicken cystatin capture agent, the S.
mansoni cysteine proteinases as antigens to detect IgG anticysteine proteinases.
The study examined 40 patients with S. mansoni, 20 patients with parasitic
infections other than schistosomiasis mansoni, and 20 apparently healthy
individuals with no parasitic infections. The results showed that the cystatin
capture ELISA gave a high sensitivity of 100% even in patients with low egg
count. A similar high sensitivity was also recorded with conventional ELISA using
SWAP alone without presensitization of ELISA plate with cystatin. Moreover, the
capture ELISA showed no cross reactions with patients with other parasitic
infections or normal individuals giving a 100% specificity, while the
conventional ELISA using SWAP alone gave a lower specificity of 85%. The cystatin
capture ELISA was found to be an easy, highly sensitive and specific serological
method for the diagnosis of human schistosomiasis mansoni without the need of
purified proteinases antigens.
PMID- 10786032
TI - Ultrastructure of sperm and spermatogenesis of Cichlidogyrus thurstonae
(Platyhelminthes, Monogenea, Monopisthocotylea).
AB - The present work is the first ultrastructural description of mature spermatozoon
of the monogenetic trematode Cichlidogyrus thurstonae recovered from the gills of
the Nile fish Oreochromis niloticus. The mature spermatozoon of C. thurstonae is
long and filiform with a nucleus, mitochondrion and a single axoneme, pressed
tightly together for most of their length. As most other platyhelminthes, a solid
central unit in the complex central element of the sperm axoneme is present.
There are no peripheral microtubules in the sperm and the arrangement conforms to
the sperm pattern 4 in the scheme of Justine et al. (1985).
PMID- 10786033
TI - Toxicity of a Neem (Azadirachta indica) insecticide to certain aquatic organisms.
AB - Neem based insecticides are likely to show a large increase in use in the near
future. In the present work, the toxicity of a neem insecticide, Neem-Azal-T/S,
was tested against the mosquito larvae, as well as against certain non target
organisms occurring in a polluted pond and a shallow stream, located in a
cultivated area in Giza, Egypt. Samples of water containing the experimental
animals were collected from this area, and toxicity tests were conducted in the
laboratory by exposing them to a series of concentrations of the botanical
insecticide, using the water of the pond and stream at room temperature (28-31
degrees C). The compound was more or less toxic to all the tested species. The
LC50S and mortality rates were determined. The order of tolerance of the
organisms to different concentrations of the insecticide was: larvae of Bufo
regularis (Amphibia) > Aedes caspius. (Insecta) > Gambusia affinis (Poeciliidae)
> Cyclops sp. > Daphnia magna (Crustacea). At a concentration of 20 ppm, all the
tadpoles died within 9 days, while all other individuals died within 5 to 8 days
after exposure to a concentration of 10 ppm of Neem Azal insecticide.
PMID- 10786034
TI - Epidermal growth factor in patients with schistosomal and/or viral liver diseases
and portal hypertension.
AB - A large number of growth factors have been described and their action and
interaction is proving to be complex. The presence study estimated the epidermal
growth factor (EGF) in portal hypertension patients with chronic liver disease
due to bilharziasis or viral infection as well as in patients with peptic ulcers.
The results showed different statistical values regarding liver cirrhosis,
oesophageal varices, and bleeding. No doubt, the EGF was indirectly stimulated by
the schistosomal and/or viral infection.
PMID- 10786035
TI - Different cytokines profiles in spleen cells and liver granuloma of Schistosoma
mansoni experimentally infected mice during disease development.
AB - To determine the importance of Th1 and Th2 cells in modulating granuloma
formation, mRNA transcripts for Th1 (IL-2 and IFN-gamma) and Th2 (IL-4 and IL-5)
cytokines were assessed by the molecular technique of in situ hybridization in
the liver granuloma. The molecular studies showed few number of cells expressing
mRNA transcripts for INF-gamma whereas, considerable number of IL-2 cells were
present in the liver granuloma at 6 weeks post-infection (p.i.). Complete
disappearance of IFN-gamma expressing cells were found when the disease
progressed to 13 weeks p.i. Conversely, very high number of cells expressing mRNA
transcripts for IL-4 and fair number of IL-5 cells were present at 7 weeks p.i.
with a peak level of IL-4 cells at 13 weeks p.i. These in situ molecular studies
of the liver tissues, demonstrated that Th1 cells were present at the very early
granuloma development. Moreover, Th2 cells were required for its full
development. The main interesting finding was the number of cells expressing mRNA
for IL-4, as they were very huge and it might exceed the total number of
lymphocytes per se in the granuloma. Lymphocytes from experimentally infected
mice-spleen cells were also cultured in vitro with S. mansoni soluble egg antigen
(SEA) and the same cytokines of lymphocyte supernatant were measured by ELISA
assay. The levels of IFN-gamma and IL-2 were high to 6 wk. p.i. with a slight
decline of IFN-gamma, and increasing amount of IL-2 at 10-13 wk p.i. Spleen
lymphocytes of fully formed granuloma secreted high levels of IL-4 and IL-5. The
results suggest that the development of schistosome egg-induced liver granuloma
is a complex process and both Th1 and Th2 cell subsets sharing with other
inflammatory cells (non lymphocytes), may play an important role in regulating
and modulating the immuno-pathology of granuloma formation and the subsequent
hepatic fibrosis.
PMID- 10786036
TI - The use of colchicine in treatment of experimental toxoplasmosis.
AB - Colchicine was given in 2 doses (3 and 15 micrograms/mouse) at the time of
infection or 48 hours late. It proved effective in both doses, but better results
were obtained with early treatment. The mortality rates were 30% & 30%, and
Toxoplasma carriers among the surviving mice was 28.6% and 42.9% with high and
low doses respectively. When the treatment was given 48 hours after infection,
the mortality rates were 50% and 60%, Toxoplasma carriers were 40% and 50% with
high and low doses respectively.
PMID- 10786037
TI - Isolation of dust mites from houses of Egyptian allergic patients and induction
of experimental sensitivity by Dermatophagoides pteronyssinus.
AB - Six house dust mite (HDM) species were isolated from dust of floors and
mattresses of allergic patients houses in Alexandria. Dermatophagoides
pteronyssinus (D.p.) was the dominant species in dust of floors and mattresses
with average percentages of 68.9% and 78.3% respectively. It was used to induce
experimental sensitivity in Swiss albino mice by repeated weekly intranasal
instillation of D.p. mites in phosphate buffer saline (PBS). Cytological
examination of bronchoalveolar lavage (BAL) fluid of mice revealed prolonged
eosinophilia, that peaked on day 28 of the experiment and persisted till the end
of the study. Blood eosinophilic counts were progressively increased during the
course of the experiment. Histopathological findings showed evident eosinophilic
infiltration in nasal and lung tissues of the sensitized mice. Specific IgE
response to D.p. was progressively increased, reaching 30 times higher than the
control group on day 42. The detected levels of interluekin-4 (IL-4) were in
accordance with immunoglobulin response. D.p. provoked severe allergic response
and this may help to design an effective therapy to ameliorate such allergic
diseases.
PMID- 10786038
TI - A study of the predisposition of Schistosomiasis mansoni to pyogenic liver
abscess in experimentally infected mice.
AB - In murine experimental model, the present work was carried out to study the
possible predisposition of S. mansoni infection to pyogenic liver abscess,
through a concurrent infection with Staphylococcus aureus. Pyogenic liver
abscesses containing the bacterial organism were found in 85% of mice infected
with concurrent early S. mansoni infection and S. aureus, in 35% of mice with
late S. mansoni infection and the bacterial infection, and in 60% of mice with
concurrent immunosuppressed late St. mansoni infection and staphylococcal
infection. The early S. mansoni infection, immunosuppressed late schistosomiasis
mansoni, and to a less extant late schistosomiasis mansoni, with concurrent
bacterial infections can predispose to pyogenic liver abscess which has
implicative effect on clinical cases.
PMID- 10786039
TI - Correlation between trichomoniasis vaginalis and female infertility.
AB - Trichomoniasis vaginalis is one of the common parasitic infection in females. The
present results showed that infertile women with T. vaginalis with or without
pathogenic microorganisms have decreased C3 & C4, increased IgA level in vaginal
discharge and increased serum prolactin. So. T. vaginalis is incriminated as one
of the causes of their infertility.
PMID- 10786040
TI - Experimental trials of an artemisinin derivative in treatment of Schistosoma
mansoni infected mice.
AB - Dihyroartemesinin, an artemesinin derivative, was used for treatment of mice
experimentally infected with S. mansoni. A significant decrease in total worm
count was recorded when mice were treated during early and late stages of
infection. Histopathological examination of liver sections showed minimal
pathological changes with early treatment and enhanced fibrosis of granulomas
with late treatment. The results showed that dihydroartemesinin had a promising
effect on S. mansoni infected mice almost comparable to that of praziquantel.
PMID- 10786041
TI - The effect of antioxidant preparation (antox) on the course and efficacy of
treatment of trichinosis.
AB - This study evaluated the effect of administration of exogenous antioxidant
(antox) on the course and treatment of Trichinella spiralis in the intestinal
phase (2 days post infection, p.i.) and the muscle phase (35 days p.i.) using
albino rats as an experimental model. The results indicated that the
administration of antox had led to delayed expulsion of adult worms from the
small intestine, decreased inflammatory reactions in the intestines and muscles
and causing an increase in the muscle larval burden. The intake of antioxidant
decreased the efficacy of mebendazole on adult worms in the intestinai phase,
while it enhanced the effect of treatment in the muscle phase and the number of
larvae was highly decreased. So, antox inhibited free radical generation in small
intestine which acts as a contributing factor to the rejection process. But, in
muscle phase, the decreased inflammatory reaction around larvae increases the
chance of the drug to reach larvae and affects them.
PMID- 10786042
TI - The influence of Bacillus sphaericus on the biology and histology of Phlebotomus
papatasi.
AB - This work was achieved to study the impact of B. sphaericus treatment on some
biological aspects of P. papatasi. Contaminated larval food with B. sphaericus
(strain-2362) in different concentrations was offered in the laboratory for P.
papatasi and also the latent effect on the fecundity of survived females from
previously treated larvae. There was a decrease in the survived numbers of
immature stages and adults correlated to the concentrations, while there was no
obvious change in the larval and pupal durations compared to the control. The
fecundity of females survived from previously treated larvae, was sharply
decreased. Many variations was noticed in the examined tissues of mid-gut, fat
tissues, and Malpighian tubules, although no bacteraemia was detected.
PMID- 10786043
TI - Scabies in some workers living in crowded area, Jeddah, Saudi Arabia.
AB - Little is known about human and animal scabies in Jeddah. The present study gives
a picture of human scabies. Over four months, 18 cases have been microscopically
diagnosed. The most common infested site was the abdomen, followed by the lower
and upper limbs. Infestation in other parts of the body was not common but also
recorded. The results were discussed on the light of other works done in the
region.
PMID- 10786044
TI - A preliminary screening study on human cystic echinococcosis in Cairo slaughter
house personnel.
AB - A descriptive serological screening study was done on human cystic echinococcosis
(CE) in high risk groups selected from Cairo slaughter house employees and the
household nearby using indirect haemagglutination (IHA) and enzyme-linked
immunoelectrotransfer blot (EITB) tests. Characterized camel hydatid cyst fluid
(HCF) antigen by 12.5% sodium dodecyl sulphate polyacrylamide gel electrophoresis
(SDS-PAGE) was used. Three asymptomatic clinical cases (1.3%) were seropositive
using EITB assay (reacting with six HCF protein bands of molecular weights
approximately 7, 21, 28, 35, 127 and 210 kilodaltons 'kDa') but one case was
seronegative by the IHA test. All three cases had typical lesions of CE in liver
and lung revealed by abdominal ultrasonography (US), computerized tomography (CT)
scan and chest X-ray. The prevalence of CE in Cairo slaughter house workers was
1.6% versus 1.1% in the household nearby.
PMID- 10786045
TI - Scanning electron microscopy of the tegumental surface of digenetic trematode
Stephanostomum egypticum from the Red Sea fishes.
AB - Surface topography of Stephanostomum egypticum (Ramadan, 1983) is described by
Scanning electron microscope, revealed three morphologically different types of
spines; forty flattened circum-oral spines arranged in 2 circular rows; forty
longitudinal rows of highly projecting thick spines covering area between oral
and ventral suckers and rather flattened and sporadic tegumental spines covering
the body posterior to the ventral sucker. High magnification showed the spines
either single or double pointed with the first type most common. The present
study revealed the presence of four types of sensory papillae: domed around the
suckers, small button-like aggregated on the ventral sucker and near the bases of
the spines; short and long ciliated ones near the posterior extremity of the
fluke. High magnification of tegumental surface showed it to be covered with
several bleb-like structures. The functions of all these tegumental structures
were speculated and discussed was given.
PMID- 10786046
TI - [Corneal wound healing after penetrating keratoplasty with EGF application.
Experimental studies].
AB - PURPOSE: To check post penetrating keratoplasty (PK) corneal wound healing
characteristics after epidermal growth factor (EGF) application and to compare it
with controls. MATERIAL AND METHODS: The PK was performed in the group of 72
young, healthy New Zealand rabbits (36 females and 36 males). Slit-lamp
examination, tonometry and corneal topography by Tomey's corneal modeling system
(TMS-1) were carried out before and after surgery. The PK was performed in both
eyes. Half of animals were used as a bilateral donor for the other half, with a
rule: right eye cornea to the right eye and left eye cornea to the left eye. As a
result, after completed surgery 36 rabbits had bilateral grafts. The animals were
divided into 3 equal groups (12 in each). Two drops of the human recombined EGF
dissolved in the saline solution with concentration varied from 500 to 1500 ng in
each drop were applied to the right eye according to schedule. The left eye was
used as a control and did not receive EGF. Time of observation varied from 24
hours to 6 months. The tensinometry and the histopathologic study--light and
electron microscopy were performed to determine corneal scarring. RESULTS: The
wound healing pattern after PK was characteristic and constant in each group. The
corneal wound healing significantly accelerated in the EGF treated group of
rabbits compared with the controls (p < 0.05). In the group of rabbits receiving
1000 ng of hrEGF 3 times/day, after two weeks of application we noted increase of
the wound strength up to 600 folds, comparing with controls. Well-organized scar
was histologically seen on the 21st post-surgery day. The post-operative corneal
astigmatism was less expressed in the eyes treated with EGF comparing to
controls. CONCLUSIONS: These preliminary results of our experimental study
indicated accelerated effect on the corneal wound healing after PK with topical,
low dose hrEGF application. Clinical observation of utilization of similar low
doses of the hrEGF after PK--is in progress.
PMID- 10786047
TI - [Application of amniotic membrane transplantation in severe corneal diseases].
AB - PURPOSE: To present our experience with the amniotic membrane transplantation in
severe corneal diseases. MATERIAL AND METHODS: In 1998 amniotic membrane
transplantation was applied in 18 eyes (17 patients) with severe and persistent
corneal diseases. The indications were as follows: perforated corneal ulcer--9
eyes, persistent non-perforated corneal ulcer--4 cases, recurrent transplant
disease--2 eyes, 1 patient with Sjogren syndrome and 1 with keratolysis in the
course of ulcerative colitis. Amniotic membrane was prepared in the International
Eye Bank of Lublin from human placenta after elective caesarean section according
to the standard protocol. RESULTS: In 7 eyes with perforated ulcers and 4 eyes
with non-perforated ulcers prompt healing was observed. In 4 cases markedly
improved visual acuity resulted from corneal clarification. In 1 eye perforation
persisted in spite of amniotic membrane transplantation and keratoplasty was
performed afterwards. In the case of keratolysis, amniotic membrane
transplantation did not prevent corneal perforation which was closed successfully
with autologous conjunctival flap. In 2 eyes with recurrent transplant disease
amniotic membrane dissolved quickly after transplantation. In one case the state
of the cornea improved. The second eye required retransplantation of the
membrane. We observed that amniotic membrane dissolved more quickly in a
vascularized bed. CONCLUSION: Amniotic membrane transplantation may be considered
a good alternative method for treating severe corneal disorders that are
refractory to conventional treatment.
PMID- 10786048
TI - [Eye with implanted keratoprosthesis in ultrasound biomicroscopy].
AB - OBJECTIVE: Of the study is to assess the possibility of the ultrasound
biomicroscopy (UBM) in diagnosis of the eyes with implanted Fiodorov-Zujev's
keratoprosthesis. MATERIAL: We examined 10 eyes of 10 patients, 3 females and 7
males. The patients were 12 to 17 years after the second stage of
keratoprosthesis implantation (mean 14.9 +/- 1.37). METHODS: The examinations
were performed with the use of ultrasound biomicroscope (Humphrey Instruments
model 840). RESULTS: UBM made it possible to visualise keratoprosthesis and many
complications: decentration of keratoprosthesis, thinning of anterior part of
leucoma, shallowing of anterior chamber, very narrow angle of filtration,
retroprosthetic membrane-like structures.
PMID- 10786049
TI - [The alterations in corneal structure at III/IV stage of keratoconus by means of
confocal microscopy and ultrasound biomicroscopy before penetrating
keratoplasty].
AB - PURPOSE: The aim of the study was in-real time observation and morphological
evaluation of the human corneas at III/IV stage of keratoconus, using the
scanning slit confocal microscope Confoscan P4 and ultrasound biomicroscopy--UBM.
MATERIAL AND METHODS: The patients with keratoconus were examined according to
the Amsler scale. The material consisted of 12 corneas of 11 patients (8 men, 3
women), where assessment of the corneal structure was performed with the confocal
microscope ConfoScan P4 (Tomey) and ultrasound biomicroscopy--UBM Model 840
(Humphrey Instruments). The comparison of different corneal regions (central and
peripheral) was evaluated. RESULTS: The confocal microscopy and UBM revealed
thinning of the layers of the corneal structure and pathological changes in the
central area, especially at IV stage of keratoconus. The desquamating superficial
cells were elongated, arranged around the apex of the cornea. Below the Bowman's
membrane a considerable disarrangement of collagen fibers reflected by bright
background illumination was observed. In the posterior part of the stroma the
folds were detected. The examination of the cornea showed thickening in the
peripheral part, central detachment of the Descemet's membrane and the
endothelium from the posterior surface of the cornea. The thickness of the cornea
varied from 0.201 to 0.384 mm in the central part and 0.675 to 0.740 mm in the
peripheral area. CONCLUSION: Confocal scanning microscopy combined with
ultrasound biomicroscopy enables the cornea to be examined in vivo. It can be
used to localize pathological changes in individual corneal layers and to assess
their extent.
PMID- 10786050
TI - [Implantation of posterior chamber lenses with trans-scleral fixation].
AB - PURPOSE: The aim of this study is the presentation of our experiences in
implantations of posterior chamber lenses with transscleral fixation. MATERIAL
AND METHODS: The surgery was performed in 66 patients (66 eyes) using modified
technique described by Lindquist et al. Primary implantations were performed in
53% subjects, in the remaining secondary implantations. RESULTS: After surgery we
achieved visual acuity improvement in 80.3%, good visual acuity (0.5-1.0) in
68.4% of subjects. The main postoperative complications were: deformation of the
pupil and decompensation of corneal endothelium. CONCLUSIONS: Implantation of
posterior chamber lenses with transscleral fixation is preferable (alternatively
for anterior chamber lenses) in young patients as well as in subjects with
glaucoma, elevated intraocular pressure, iris coloboma and corneal problems.
PMID- 10786051
TI - [Comparative evaluation of visual acuity after cataract extraction with
monofocal, bifocal or progressive lenses implantation].
AB - PURPOSE: Evaluation which of the lenses: monofocal, bifocal or progressive,
assure the best visual acuity in patients. MATERIAL AND METHODS: 86 patients aged
from 21 to 84 years were operated. Monofocal lenses were implanted in 30 cases,
bifocal in 32 and progressive in 24 cases. RESULTS: In 90% of patients with
monofocal lenses and over 90% of patients in the remaining groups full
uncorrected or corrected distance visual acuity was achieved. In groups with
bifocal and progressive lenses full near visual acuity without correction, or
with the same correction as for distance, was achieved by respectively 65.5% and
75% of patients. CONCLUSIONS: In all three groups very good distance visual
acuity was achieved. The best near visual acuity is assured by progressive
lenses, in lower degree by bifocal lenses.
PMID- 10786052
TI - [Variations of Doppler blood flow parameters in central retinal artery in
relation to position of sample volume].
AB - PURPOSE: To determine variability in measurements of Doppler blood flow
parameters in central retinal artery in relation to sample volume location from
the optic disc. MATERIAL AND METHOD: Eighty central retinal arteries were
examined using color Doppler ultrasonography in 40 healthy volunteers (22 female,
18 male), aged 45 +/- 9 with 7.5 MHz linear-array probe. The measurements of
blood velocities and resistance indices in the arteries were obtained at points
where distance from optic disc surface ranged from 1.5 mm to 6 mm. RESULTS: Blood
velocities increased significantly when sampled closer to the globe (r = -0.61,
and r = -0.32 for peak-systolic and end-diastolic velocities, respectively). Mean
peak-systolic velocities were 13.0 +/- 2.7 cm/s when distance 2.1 +/- 0.46 mm
from optic disc, and 9.3 +/- 2.5 cm/s when distance 4.27 +/- 0.9 mm. Mean end
diastolic velocities were 4.3 +/- 1.2 cm/s and 3.6 +/- 1.1 cm/s, respectively.
Resistance indices inclined to increase when the distance between the measurement
site and the globe shortened. Resistance indices were 0.67 +/- 0.06 when measured
closer to the globe and 0.60 +/- 0.06 when measured farther from it. CONCLUSION:
Position of sample volume in relation to optic disc has to be taken into account
and defined if measurements of blood flow Doppler parameters of the central
retinal artery are to be reproducible.
PMID- 10786053
TI - [Blood flow parameters in ocular vessels of patients with glaucoma].
AB - PURPOSE: To determine Doppler flow parameters in ocular vessels of glaucomatous
patients. MATERIAL AND METHODS: 38 glaucomatous patients, aged 64 +/- 16, and 57
healthy volunteers were examined with 7.5 MHz linear-array probe. Consistently
identified arterial structures included ophthalmic artery, central retinal artery
and short posterior ciliary arteries. The peak systolic, end-diastolic and mean
velocities were measured from Doppler spectra. Resistance and pulsatility indices
were also determined. RESULTS: End-diastolic and mean velocities in central
retinal artery of glaucomatous eyes were: 1.5 +/- 1.9 cm/s, 4.0 +/- 2.0 cm/s,
whereas in healthy eyes they were significantly higher: 3.5 +/- 1.0 cm/s, 5.4 +/-
1.5 cm/s, respectively. These velocities in short posterior ciliary arteries in
glaucomatous patients were significantly lower: 2.4 +/- 2.3 cm/s, 5.6 +/- 2.2
cm/s, comparing to healthy subjects: 4.8 +/- 1.7 cm/s, 7.3 +/- 2.2 cm/s.
Resistance and pulsatility indices in central retinal artery and short posterior
ciliary arteries were significantly higher in the group of patients: RI = 0.85 +/
0.18, PI = 2.11 +/- 0.92--in central retinal artery and RI = 0.81 +/- 0.18, PI =
1.96 +/- 0.91--in short posterior ciliary arteries, comparing to healthy
subjects: RI = 0.61 +/- 0.08, PI = 1.20 +/- 0.17--in central retinal artery, RI =
0.61 +/- 0.09, PI = 1.13 +/- 0.18--in short posterior ciliary arteries. Impedance
indices were increasing progressively with intraocular pressure elevation. There
were no significant differences of Doppler blood flow parameters in ophthalmic
artery between patients and control group. CONCLUSIONS: Blood flow velocities in
central retinal and short posterior ciliary arteries are lower, and resistance
and pulsatility indices are higher in glaucomatous eyes in comparison to healthy
subjects, whereas in ophthalmic artery doppler parameters are similar in both
groups.
PMID- 10786054
TI - [Evaluation of fraxiparine efficacy in the treatment of retinal vein occlusion].
AB - PURPOSE: To evaluate the efficacy of Fraxiparine in the treatment of central
retinal vein occlusion and retinal branch vein occlusion. METHODS: 30 patients
were treated. Fraxiparine (Sanofi-Pharma) was injected subcutaneously in doses of
7.5 thousand units twice daily for 10 days and once daily for 18 days. In 19
cases central retinal vein occlusion was observed and retinal branch vein
occlusion in 11 cases. Mean follow-up was 15 months (range 10-35 months).
Ophthalmological examination including fluorescein angiography was performed
before and after therapy. RESULTS: Improvement of visual function and condition
of retina after therapy was observed in about 50% of cases. In 16 patients laser
photocoagulation applied for neovascularisation or retinal edema was necessary.
PMID- 10786055
TI - [The evaluation of morphological status of bulbar conjunctiva after long-term
antiglaucoma drug therapy].
AB - The aim of this study was to examine the histopathologic picture of bulbar
conjunctiva in glaucoma patients receiving topical antiglaucoma treatment.
MATERIAL AND METHODS: Generally healthy patients with primary open angle glaucoma
(POAG) and primary angle closure glaucoma (PACG) were included in our study.
Conjunctiva specimens were obtained from the area of further fistula of 51
patients undergoing trabeculectomies and assessed by routine histopathological
staining. RESULTS: Non-specific inflammatory infiltration, thickening of the
epithelium, decreased numbers of Goblet cells, proliferation of fibroblasts,
collagen deposition and fibrosis were observed in the obtained material. Changes
in cellular profile and in the extracellular composition of bulbar conjunctivas
in patients receiving long-term topical antiglaucoma treatment were detected.
PMID- 10786056
TI - [Valve implants of glaucoma pressure regulator for refractory glaucoma: own
experience].
AB - PURPOSE: To present our experiences in valve implantation for refractory
glaucoma. MATERIAL AND METHODS: From October 1993 to December 1996 implantations
of Glaucoma Pressure Regulator Optimed were performed in 7 eyes of 7 patients.
There were 4 men and 3 women aged from 32 to 65 years. There were 3 eyes with
neovascular glaucoma due to diabetes mellitus, 2 eyes with posttraumatic
glaucoma, including 1 case after keratoplasty, 1 eye with postkeratoplasty
glaucoma and 1 eye with aphakic glaucoma. Preoperative IOPs ranged from 33 to 61
mm Hg (mean 37.6 +/- 7.2 mm Hg). RESULTS: Success was considered an IOP of less
than 22 mm Hg without medication (complete success) or with medication (qualified
success) without additional filtering surgery. Postoperative success was obtained
in 4 out of 7 eyes after follow-up period of 37.4 +/- 17.08 months (range 16-39
months). Early complications were hyphema (1 patient, 14.3%), blockage of
intracameral portion of the tube (1 patient, 14.3%), hypertony (1 patient,
14.3%). Late complications were: external conjunctival bleb failure (2 patients,
28.6%), blockage of intracameral portion of tube by fibrovascular tissue (1
patient, 14.3%). CONCLUSION: Our experiences confirm that the valve implant is
still today an alternative surgical procedure for controlling IOP in eyes with
refractory glaucoma that have visual potential.
PMID- 10786057
TI - [Helicobacter pylori as supposed factor of uveitis in children: a case report].
AB - MATERIAL: A case of a 14-year-old boy with recurrent idiopathic bilateral
uveitis. METHODS: Detection of Helicobacter pylori infection basing on endoscopic
examination of upper alimentary tract and eradication of this factor using
specific therapy leading to extinction of active uveitis in both eyes. RESULTS:
Helicobacter pylori may be the etiological agent of uveitis in children with
unknown reason of the disease.
PMID- 10786058
TI - [Cellular reactions after intraocular lens implantation].
AB - The surgical trauma and the presence of the artificial lens in the eye causes
inflammatory reactions. The cellular response is a result of 1) the breakdown of
the blood-aqueous barrier, 2) foreign body reaction induced by lens material. The
presence of cellular deposits (small, fibroblast-like, epithelioid, giant cells)
on the surface of intraocular lenses is related to many factors such as surgical
technique, risk factors of inflammation, postoperative treatment and the kind of
lens material. The aim of this paper is to present contemporary knowledge about
cytopathology of intraocular lenses and chances to improve the surface
characteristic to avoid the adhesion of cells.
PMID- 10786059
TI - [Kinurenin degradation pathway in eye: present state of knowledge].
AB - In this review the kinurenin degradation pathway is presented. The role of
indoleamine 2.3-dioxygenase (IDO)--the first enzyme of the tryptophan degradation
-is also described. The implications of these findings for cataract as well as
for other disturbances of vision process are discussed.
PMID- 10786060
TI - [Contemporary views on the etiology, pathogenesis as well as treatment of school
age and progressive myopia].
AB - The contemporary views on the etiology, pathogenesis as well as treatment of
school-age and progressive myopia are discussed. The history of myopia
investigations is described. The results of papers indicating environmental and
genetic reasons of myopia are presented. The anatomical, physiological, and
biochemical changes taking place during the school-age and progressive myopia
progress are characterized. The attitude towards some conservative and surgical
methods of school-age and progressive myopia is expressed. The possibilities of
using the newest experimental results in progressive myopia treatment are
indicated.
PMID- 10786061
TI - [Electroretinogram and electrooculogram in retinal degeneration].
AB - Electroretinogram (ERG) and electrooculogram (EOG) are fundamental for proper
early diagnosis of retinal dystrophies and degenerations. The most characteristic
changes of ERG and EOG in such retinal dystrophies as Stargardt's disease, Best's
disease, fundus flavimaculatus, fundus albipunctatus, retinitis pigmentosa,
choroideremia, iuvenile retinoschisis, congenital stationary night blindness,
progressive cone dystrophy and in some of retinal degenerations for differential
diagnosis were described. Electrophysiological state of retina in retinal
dystrophy depends on patient's age and pattern of inheritance. Very often typical
for dystrophy changes in ERG and EOG without any visible pathology on eye fundi
are found. On the other hand there are some of degenerations similar to
dystrophies in clinical examination. In such cases only ERG and EOG allow to be
sure which diagnosis should be done.
PMID- 10786062
TI - Statistical support for uncertainty in radiological diagnosis.
AB - Radiological interpretation and diagnosis involves the comparison and
classification of complex medical images and is typical of the categorisation
tasks that have been the subject of observational studies in Cognitive Science.
This paper considers the affinity between statistical modelling and theories of
categorisation for naturally occurring categories. Statistical based measures of
similarity and typicality with a probabilistic interpretation are derived. The
utilisation of these measures in the support of diagnosis under uncertainty via
interactive overview plots is described. The application of the methodology to
magnetic resonance imaging of the head is considered. The methods detailed have
application to other fields involving archiving and retrieving of image data.
PMID- 10786063
TI - Utility of the Charlson comorbidity index computed from routinely collected
hospital discharge diagnosis codes.
AB - This study aims to determine whether the Charlson comorbidity index computed from
ICD-9-CM discharge diagnosis codes adds additional information to a model
containing adjustment for more informed patient details (e.g., disease severity
and history), besides solely age and sex, when predicting long-term survival. We
conducted a retrospective cohort study of patients admitted to hospital for
suspected acute myocardial infarction. Index scores were calculated by applying
the D'Hoore et al. algorithm (1993). The index significantly improved the model
fit (likelihood ratio test: p < 0.001). The D'Hoore-adapted Charlson index is a
useful comorbidity risk adjustment tool when applied to AMI and angina patients.
PMID- 10786064
TI - Modeling the recovery from depressive illness by an exponential model with mixed
effects.
AB - In clinical trials of antidepressant treatments, a depression rating score is
usually measured at several points of time for each patient. We propose an
approach to fit data from this type of clinical trial using an exponential mixed
effects model. Compared to previous proposals, this approach has the advantage
that individual recovery curves are fitted rather than curves of means.
Furthermore, no artificial fixing of model parameters is needed as in other
approaches. The flexibility of the proposed model is shown for various
situations. The approach is illustrated by an example from a placebo-controlled
study for the treatment of depression with St. John's Wort (Hypericum
perforatum).
PMID- 10786065
TI - Understanding terminological systems. I: Terminology and typology.
AB - Terminological systems are an important research issue within the field of
medical informatics. For precise understanding of existing terminological systems
a referential framework is needed that provides a uniform terminology and
typology of terminological systems themselves. In this article a uniform
terminology is described by putting relevant fundamental notions and definitions
used by standard organizations such as CEN and ISO into perspective, and
interrelating them to arrive at a useful typology of terminological systems. This
typology is illustrated by applying it to five well-known existing terminological
systems.
PMID- 10786066
TI - Understanding terminological systems. II: Experience with conceptual and formal
representation of structure.
AB - This article describes the application of two popular conceptual and formal
representation formalisms, as part of a framework for understanding
terminological systems. A precise understanding of the structure of a
terminological system is essential to assess existing terminological systems, to
recognize patterns in various systems and to build new terminological systems.
Our experience with the application of this framework to five well-known
terminological systems is described.
PMID- 10786067
TI - CISMeF: a structured health resource guide.
AB - In 1999, the Internet has become a major source of health information. The
objective of CISMeF is to catalogue and index the main French-speaking health
resources. In September 1999, the number of indexed resources totaled over 7,100
with a mean of 75 new sites per week. CISMeF uses two standard tools for
organizing information: the Medline bibliographic database MeSH thesaurus and the
Dublin Core metadata format. Resources included in CISMeF are described by the
following: title, author or creator, subject and keywords, description,
publisher, date, resource type, format, identifier, and language. To index
resources, CISMeF uses five levels of hierarchy: "meta-term", category, keyword,
subheading, and resource type. CISMeF contains a thematic index, including
medical specialities and an alphabetic index. CISMeF respects the Net Scoring,
criteria to assess the quality of health information on the Internet. The CISMeF
project offers a valuable tool for the French-speaking health community: 2,500
computer users visit the Web site each working day.
PMID- 10786068
TI - ARCHIMED: a Network of Integrated Information Systems.
AB - ARCHIMED is a Network of Integrated Information Systems (NIIS). This novel
concept of hospital information system has a major advantage over the currently
used distributed systems. The normalized representation structure of its
databases enable its Navigators to reach simultaneously not only the data coming
from different hospital departments, laboratories, and other hospital facilities,
but also the data from different hospitals associated in the network.
PMID- 10786069
TI - TANCLICO: tools for the analysis of inter-departmental clinical communications.
AB - Patient care management provided by healthcare organizations is complex,
involving many different care providers. The information exchange between
providers concerns a varying and considerable number of actors and a high
transmission load. Based on models, used to characterize specific features of
work processes, we propose a new method able to analyze and represent clinical
communications inside hospitals. Software has been developed, providing tools for
storing and retrieving information resulting from clinical communications. The
method, together with data collected in actual situations, may constitute useful
tools for health information systems developers.
PMID- 10786070
TI - Standard method for describing an electronic patient record template: application
of XML to share domain knowledge.
AB - A Template Definition Language (TDL) was developed to share knowledge of how to
construct an electronic patient record (EPR) template. Based on the extensible
markup language XML, TDL has been designed to be independent of EPR platforms or
databases. Our research of TDL was conducted through evaluation of the
description of various templates in the currently available EPRs and through
comparisons with some electronic clinical guidelines. We conclude that TDL is
sufficient for the objective but still needs improvement of the algorithm for
describing dynamic changes.
PMID- 10786071
TI - A process view of medical practice by modeling communicative acts.
AB - The need of an electronic patient record with a process view on medical care is
widely acknowledged. Characteristics of DEMO (Dynamic Essential Modeling of
Organizations) suggest that with this methodology an adequate process view of
medical practice can be obtained. In applying DEMO to the care process of the
emergency department at the University Medical Centre Utrecht, it was
investigated if DEMO fulfilled our expectations. This practical application
showed that DEMO yields an adequate process view by a clear and comprehensible
view of the core processes, responsibilities, co-ordination of activities, and a
clear description of causal and conditional relations between activities.
PMID- 10786072
TI - Requirements for speech recognition to support medical documentation.
AB - Recent advances in the development of automated speech recognition (ASR) have
made routine applications for medical documentation possible. To achieve this,
ASR has to be optimally integrated into the specific documentation scenario. The
classification presented in this paper allows the definition of specification
requirements. For two different documentation scenarios the appropriate product
selection has been done according to this classification. Two evaluation studies
are presented, addressing the usefulness of applying automated speech
recognition.
PMID- 10786073
TI - An end-to-end secure patient information access card system.
AB - The rapid development of the Internet and the increasing interest in Internet
based solutions has promoted the idea of creating Internet-based health
information applications. This will force a change in the role of IC cards in
healthcare card systems from a data carrier to an access key medium. At the
Medical Informatics Department of Kyoto University Hospital we are developing a
smart card patient information project where patient databases are accessed via
the Internet. Strong end-to-end data encryption is performed via Secure Socket
Layers, transparent to transmit patient information. The smart card is playing
the crucial role of access key to the database: user authentication is performed
internally without ever revealing the actual key. For easy acceptance by
healthcare professionals, the user interface is integrated as a plug-in for two
familiar Web browsers, Netscape Navigator and MS Internet Explorer.
PMID- 10786074
TI - A telemedicine management model based on message-trigger service.
AB - A telemedicine system model, based on a message-trigger service, is described.
This model distributes system applications on multiple computers and establishes
a communication platform to exchange messages among all applications. By
broadcasting event messages, an application is able to trigger a set of local and
remote services. At the same time, a protocol for message exchange is proposed to
fulfill cooperation of applications. To validate the model, a teleconsultation
system is designed. The results indicate that the model has good compatibility
and that the characteristics are easy to implement.
PMID- 10786075
TI - Intraindividual specificity and stability of human EEG: comparing a linear vs a
nonlinear approach.
AB - We have applied the so-called "unfolding dimension approach" to reanalyze an
earlier longitudinal EEG study. Both linear and nonlinear approaches show that
the EEG comprises a static, person-specific part upon which nonstatic and state
specific parts are superimposed. The intraindividual specificity and stability of
the genetic part are similar between methods. This is assessed by comparing the
outcome of a person to his own outcomes at later times (14 days and 5 years
later). The nonlinear method revealed a median correlation coefficient rho =
0.55, whereas advanced linear methods showed a median rho = 0.84. An apparent
effect for the 5-year interval was detected with the nonlinear method and is
discussed in terms of the different assumptions of the two approaches concerning
EEG signal generation.
PMID- 10786076
TI - Structured representation of drug indications: lexical and semantic analysis and
object-oriented modeling.
AB - No standardized representation of drug indications is currently available that
could be used in drug knowledge bases. We describe an object-oriented
representation of indications that should make it possible to develop new tools
for selecting drugs and checking prescriptions in computerized drug prescription
systems. The model was developed using the results of a lexical and semantic
analysis of drug indications, collected into a single file and processed using
natural language processing software. It distinguishes both the diseases for
which the drug may be given and the efficiency of the drug for a given
indication. Two aspects of the model were evaluated: the differences if two
independent evaluators filled the attributes independently and the loss of
information induced by the use of the model. A system based on this model, making
it possible for the physician to select all the drugs satisfying various
criteria, is also presented.
PMID- 10786077
TI - Evaluation of techniques for the presentation of laboratory data: support of
pattern recognition.
AB - Two tabular and two graphical techniques for the presentation of laboratory test
results were compared in a reaction-time experiment with 22 volunteers. The
experimental setup was designed to determine whether one or more of the
presentation techniques facilitated the recognition of four predefined
combinations of abnormal test results. Using a conventional, tabular presentation
technique as a reference, faster median response times were obtained with each of
the other three presentation techniques, irrespective of pattern. The effect on
accuracy was less clear, possibly due to the small number of errors made.
PMID- 10786078
TI - From a urinalysis strategy to an evaluated urine protein expert system.
AB - Urine single protein analysis has developed into a routine method for the
screening and monitoring of kidney diseases. In order to support clinical
decision making by an interpretative report, a urine protein expert system (UPES)
has been developed. Based on a database containing more than 500 excretion
patterns, a modular knowledge base was extracted in production rules and
implemented in a modern expert system shell. The resulting interpretation system
has been thoroughly verified and validated. After the need of interpretation of
the complex findings had been documented in a survey, its usability in routine
and its knowledge representation was evaluated in 11 hospitals. A user conference
confirmed a high quality level of the reports proposed by UPES. It revealed that
the problem of automatic data transfer as well as the common definition of
diagnostic terms by laboratorians and clinicians play a crucial role for the use
of knowledge-based systems in laboratory medicine.
PMID- 10786079
TI - [Keeping hay fever from turning into asthma. Stopping the allergy cascade].
PMID- 10786080
TI - [Bringing science and budget under one hat. Interview by Dr. Barbara Kreutzkamp].
PMID- 10786081
TI - [WHO warns about a change in approach. Long-term therapy for hay fever
patients?].
PMID- 10786082
TI - [With head and neck pain rather not consult a chiropractic?].
PMID- 10786083
TI - [Improved hormone implant provides 3 years of contraception. The end of the
pill?. Interview by Petra Eiden].
PMID- 10786084
TI - [Therapy of hypertension with calcium antagonists. Heart and kidney protection
for elderly type 2 diabetic patients].
PMID- 10786085
TI - [Early detection of prostate carcinoma. What diagnosis is of value when?].
AB - Early detection of carcinoma of the prostate is based on digital rectal
examination of the gland (DRE), transrectal ultrasonic exploration of the gland
(TRUS) and determination of the prostate specific antigen (PSA) in the serum. The
sensitivity of DRE along, but also in conjunction with TRUS is inadequate for
early detection. Furthermore, two-thirds of all palpable prostate carcinomas have
already breached the organ (T3), and are no longer curable by such local measures
as radical prostatectomy or radio-therapy. Nevertheless, DRE is mandatory, since,
when an induration is palpable, a prostate biopsy should be obtained even when
the PSA is normal (< 4 ng/ml). Imaging procedures, such as TRUS or endorectal NMR
have only a secondary role in early detection, while TRUS is indispensable for a
controlled biopsy of the prostate. The most important early detection measure is
the annual determination of PSA (syn. traditional or total PSA), during which
both bound and free PSA is determined using an immunoassay. A chronic problem
with the evaluation of serum levels of this organ marker - which is not an
antigen specific for prostate carcinoma - is the fact that although it has an
acceptable sensitivity (> 90%),its specificity is low (40% false positive
findings). Attempts have been made to reduce the rate of unnecessary biopsies by
measuring free PSA, PSA-density, age-corrected PSA or bound PSA. However, such
attempts have failed to improve the efficacy of traditional PSA measurement in
the individual case. In the guidelines relating to the diagnosis of prostate
carcinoma established by the German urologists, the present recommendation
requires PSA measurement once a year from the age of 45 onwards.
PMID- 10786087
TI - [Pain management in general practice. Therapy with nonsteroidal anti-inflammatory
drugs].
PMID- 10786086
TI - [Therapy of prostate carcinoma. Age, general health status and stage determine
choice of therapy].
AB - Radical prostatectomy is indicated in patients with an estimated life expectancy
of 10 years and with organ defined cancer disease (T1b-T2, No, Mo). Radiotherapy
is an effective alternative treatment, especially in patients with an increased
comorbidity. Primary hormonal treatment is not indicated for organ-defined
cancer. Prognosis of patients with locally advanced prostatic carcinoma
(T3,NO,MO) is poor because of micrometastases; tumour progression will occur in
75% of patients independent of local therapy. Orchiectomy or LH-RH treatment is
option of first choice in metastatic prostate cancer disease. There is no need
for complete androgen deprivation. Ongoing trials measure the effect of
intermittant androgen deprivation. Intention for treatment of hormone refractory
cancer is improvement of quality of life. Cancer-related symptoms are pain caused
by bone metastases, lymphoedemas and urinary retention. Therapeutic options are
monochemotherapy, hormonal treatment, analgetic treatment besides palliative
radiotherapy.
PMID- 10786088
TI - [Gastric protective pain therapy. What is the advantage of new COX-2
inhibitors?].
PMID- 10786089
TI - [Good therapy control requires a standardized test. Thrombosis ABC, 13: INR
instead of Quick].
PMID- 10786090
TI - [Renal failure in chronic osteomyelitis. Secondary amyloidosis in chronic
osteomyelitis].
PMID- 10786091
TI - [Why colleague Hansen is in despair over current politics. With us specialist
have too much to say. Interview by Werner Loosen].
PMID- 10786092
TI - [Model project will separate chaff from wheat. Phytopharmaceutical prescription-
without fear of censure].
PMID- 10786093
TI - [Depressed patients. Competent treatment by the general practitioner].
PMID- 10786094
TI - [Detlef Kellermann and his "hematoma" series. The long path to healing].
PMID- 10786095
TI - Neuropsychological changes after surgery for anterior communicating artery
aneurysm.
AB - Neuropsychological disturbances following surgery for anterior communicating
artery aneurysms were analyzed in 26 patients (11 males, 15 females) using the
Hasegawa dementia scale-revised (HDS-R) over a 3-year period. The patients were
aged from 34 to 76 years (mean 54.1 years). Lesions in the frontal lobe were
evaluated using computed tomography (CT). Twenty-three patients had symptoms over
the course. Four patients had basal forebrain lesion, five had ventral frontal
lesion, and 12 had no lesion. Patients with basal forebrain lesion and no lesion
tended to show disorientation. The mean HDS-R score was 10.2 points in the
patients with ventral frontal lesion, and 13.5 points in the patients with no
lesion. These scores are within the range for dementia. The mean HDS-R score in
patients with basal forebrain and striate lesions was over 25 points and beyond
the range for dementia. Significant differences were observed in the HDS-R score
between patients with ventral frontal lesion and basal forebrain lesion, and
between patients with no lesion and basal forebrain lesion (p < 0.05). Recovery
from neuropsychological disturbances was poorer in patients with ventral frontal
lesion and no lesion compared to those with basal forebrain and striate lesions,
and their symptoms tended to persist.
PMID- 10786096
TI - Long-term follow-up study of patients with cavernous sinus aneurysm treated by
proximal occlusion.
AB - Proximal occlusion of the internal carotid artery (ICA) is still the treatment of
choice for a large cavernous sinus aneurysm. Endovascular occlusion or trapping
of the ICA with or without an extracranial-intracranial bypass is sometimes
performed. We analyzed the results of the long-term follow up of 11 patients with
a giant or large cavernous sinus aneurysm treated by only proximal occlusion
between 1975 and 1989. Proximal occlusion of the carotid artery was performed by
Selverstone clamping. The follow-up period ranged from 6 to 21 years (mean 13.9
years). Eight of the 11 patients showed improvement of cranial nerves paresis or
headache, and four became asymptomatic. None of the original aneurysms ruptured.
The final outcomes were nine good recovery, one moderately disabled, and one
severely disabled by the Glasgow Outcome Scale. The causes of morbidity were
early ischemia and subarachnoid hemorrhage from a newly formed aneurysm. Late
complications included ischemia in two patients, and new formation and
enlargement of aneurysms at a site other than the original aneurysm in two
patients, 13 and 17 years later. Therapeutic carotid artery occlusion requires
strict test ICA occlusion. In addition, long-term follow up by periodical
cerebral angiography using magnetic resonance, computed tomography, or digital
subtraction angiography is necessary, and postoperative medical treatment is
important to reduce the risk of late complications.
PMID- 10786097
TI - Treatment of bacterial brain abscess by repeated aspiration--follow up by serial
computed tomography.
AB - Bacterial brain abscess often requires repeated aspiration before the abscess
finally resolves. However, there are no guidelines for treatment by aspiration;
for example, when should the abscess be tapped again, or when can an abscess be
treated by antibiotics alone without further aspiration. Eleven patients with
bacterial brain abscess treated by aspiration were evaluated to establish
treatment guidelines for brain abscess, in particular the abscess size on serial
computed tomography (CT) after aspiration. CT was performed about 24 hours after
aspiration to evaluate the size of the abscess, and almost weekly during follow
up. The diameter of the brain abscess before and after the initial and last
aspirations were reviewed. In eight of the 11 patients, abscesses were aspirated
repeatedly: two to three times in most patients. The diameter of the abscesses
was 2.5-4.5 cm (mean 3.5 cm) before the last aspiration, and 1.4-3.4 cm (mean 2.3
cm) after the last aspiration, or when continuous drainage was discontinued.
Perifocal edema was moderately decreased within 3 weeks after the last aspiration
by medical treatment alone, with a concomitant decrease in the volume of the
abscess. There were no deaths, and most patients had a favorable outcome. These
results suggest that after the diameter of the abscess becomes less than 2 to 3
cm and does not increase anymore on serial CT, medical treatment alone can be
anticipated to give satisfactory results without further aspiration.
PMID- 10786098
TI - Chronic, traumatic intraconal hematic cyst of the orbit removed through the
fronto-orbital approach--case report.
AB - A 22-year-old male presented with a chronic encapsulated intraorbital hematoma 3
months after blunt trauma to his left eyeball. Ophthalmological examination found
the best corrected visual acuity was 4/20 in the left eye, and 20/20 in the right
eye. The orbit exhibited exophthalmus and inability of the eye to move above the
horizontal level. Orbital magnetic resonance imaging showed a fairly well
demarcated area in the medial aspect of the orbit appearing as hyperintense on T1
weighted images and isoto hyperintense on T2-weighted images. This area was
believed to be hemorrhage. No other abnormalities were found. The diagnosis was
hematic cyst. The cyst was approached through a left fronto-orbital route and its
location identified within the periorbita and orbital fat. The cyst was removed
partially. Histological examination demonstrated cystic accumulation of blood and
breakdown products in a non-epithelium-lined fibrous capsule, compatible with
hematic cyst. The presence of hemosiderin in the cyst wall suggested that the
cyst was a chronically enlarging lesion. Hematic cysts of the orbit usually
present as subperiosteal mass months to years after trauma. Surgical removal of
the cyst wall rather than needle aspiration is recommended to prevent recurrence.
PMID- 10786099
TI - Magnetic resonance imaging of calvarial eosinophilic granuloma with pericranial
soft tissue reaction--case report.
AB - A 4-year-old girl presented with an eosinophilic granuloma in the cranial vault.
Magnetic resonance (MR) imaging showed the mass as slightly low intensity on T1-
and high intensity on T2-weighted images. The pericranial soft tissue was densely
enhanced after gadolinium-diethylenetriaminepenta-acetic acid infusion. The mass
was soft and successfully removed. Histological examination disclosed Langerhans'
cell histiocytosis. MR imaging is useful for the diagnosis of calvarial
eosinophilic granuloma with soft tissue involvement.
PMID- 10786100
TI - Complications associated with intraarterial administration of papaverine for
vasospasm following subarachnoid hemorrhage--two case reports.
AB - Complications associated with intraarterial papaverine infusion occurred in two
patients treated for vasospasm due to subarachnoid hemorrhage (SAH). A 42-year
old male with an anterior communicating artery aneurysm underwent craniotomy and
aneurysm clipping. Five days after the SAH occurred, angiography demonstrated
moderate vasospasm in spite of hypervolemic-hypertensive therapy. During
papaverine infusion into the carotid artery, he suffered loss of consciousness
due to a seizure for a few minutes. A 61-year-old female with a right internal
carotid-posterior communicating artery aneurysm underwent clipping. Six days
after the SAH occurred, angiography demonstrated severe vasospasm in spite of
hypervolemic-hypertensive therapy. Angiography performed immediately after
papaverine infusion into the carotid artery revealed exacerbation of the
vasospasm. Finally she suffered cerebral infarction and died. Complications of
intraarterial papaverine infusion are potentially dangerous. We recommend trial
administration of papaverine with angiography and neurological examination before
full dose infusion to avoid complications.
PMID- 10786101
TI - Malignant schwannoma metastasizing to the parenchyma of the brain--case report.
AB - A 48-year-old male presented with a very rare case of malignant schwannoma
metastasizing to the parenchyma of the brain. He had undergone previous radical
surgical resection of an abdominal wall tumor that was histologically confirmed
as a malignant schwannoma. Five years later, the patient presented with
metastases to the parenchyma of the brain and lung. A large mass at the left
frontoparietal region was totally resected immediately after intratumoral
hemorrhage. He recovered well and the lung metastasis was also removed, but he
later developed further multiple metastases in the lung and brain.
PMID- 10786102
TI - Toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome-
four case reports.
AB - Four patients, all males aged 40-64 years, presented with toxoplasmic
encephalitis associated with human immunodeficiency virus (HIV) infection
manifesting as nonspecific neurological deficits such as epilepsy or hemiparesis.
Magnetic resonance imaging showed single or multiple lesions with ring
enhancement, mimicking metastatic brain tumor or brain abscess. Marked
eosinophilia was noted in three patients. Two patients who received anti
toxoplasma chemotherapy in the early stage had a good outcome. However, the other
two patients suffered rapid neurological deterioration and needed decompressive
surgery, resulting in a poor outcome. Toxoplasma diffusely infects the whole
central nervous system from the early stage. The outcome for patients who needed
emergency surgery was poor. Therefore, this rare but increasingly common
infectious disease must be considered in the differential diagnosis of a patient
with neuroimaging findings similar to those of metastatic tumor or brain abscess.
Appropriate chemotherapy should be started immediately after HIV-positive
reaction is identified in patients with single or multiple mass lesions with ring
enhancement.
PMID- 10786103
TI - Trigeminal neuralgia associated with tentorial agenesis and temporal lobe
herniation--case report.
AB - A 22-year-old female presented with an extremely rare case of trigeminal
neuralgia associated with tentorial agenesis. The pulsating pain in her left
maxillary region persisted for an abnormally long time and had no trigger zone.
The pain later spread to the periorbital region. Coronal magnetic resonance
imaging revealed left medial temporal lobe herniation caused by tentorial
agenesis. The herniated temporal lobe, which had distorted the superior
cerebellar artery, was causing compression of the trigeminal nerve. Her condition
improved following microvascular decompression surgery. Tentorial agenesis should
be considered as a cause of atypical pulsating facial pain, especially in younger
patients.
PMID- 10786104
TI - Revised new brain retractor: characteristics and new indications--technical note.
AB - Revisions were made to our new brain retractor with respect as follows. A knob
was added to each shaft of the new brain retractor to facilitate handling. The
angle between the shaft and the blade can now be adjusted from 60 to 135 degrees,
which is useful in deep, narrow operative fields. Three blade lengths (20, 30,
and 40 mm) are now available. The new retractor is entirely made from titanium.
This revised brain retractor is very useful for the dissection of sylvian and
interhemispheric arachnoid membranes, as well as in the extirpation of
intracerebral masses via corticotomy.
PMID- 10786105
TI - Spontaneous hemopneumothorax--results of conservative treatment.
AB - Spontaneous hemopneumothorax is a serious condition complicating spontaneous
pneumothorax. Early stage thoracotomy has been advocated to stop the bleeding and
evacuate the coagulated blood from the pleural cavity. The present review was
undertaken to emphasize the potential life-threatening condition of spontaneous
hemopneumothorax and reassess the benefit of conservative treatment with chest
tube drainage. Out of six patients, five patients were treated conservatively and
one required an emergency thoracotomy because of cardiovascular collapse.
Although three patients still had minimal residual hemopneumothorax on discharge,
none of them developed empyema or trapped lung. In conclusion, conservative
treatment is efficient and should be performed if bleeding persists for less than
24 hours after chest tube placement.
PMID- 10786106
TI - [Laser transmyocardial revascularization--a potential risk in an acute
situation?].
AB - Morphological and functional effects of transmyocardial laser revascularization
(TMLR) are analyzed in an acute setting on a porcine model. Ten channels were
drilled in the left lateral wall of the heart of 15 pigs (mean weight, 73 +/- 4
kg) with a Holmium-YAG laser (wavelength: 2.1 mu, probe diameter: 1.75 mm).
Echocardiographic control was performed before the TMLR procedure as well as 5
min and 30 min thereafter. Echocardiographic parameters were recorded in short
axis at the level of the laser channels, and included left ventricular ejection
fraction, fractional shortening and segmental wall motility of the channels' area
(scale 0-3: 0 = normal, 1 = hypokinesia, 2 = akinesia, 3 = dyskinesia). After
sacrifice the lased region was sliced perpendicularly to the channels for
histological and morphometrical analysis. Five minutes after the drilling of the
channels, all the echocardiographic index worsened significantly in comparison
with baseline values (p < 0.01). All recovered after 30 min and showed no
difference with baseline values. Cross-section of the channel lesions measured
8.8 +/- 2.4 mm2 which is more than three times that of the probe (p < 0.01). In
acute conditions, the lesions due to the TMLR probe are significantly larger than
the probe itself and cause a transient drop of the segmental wall motility on a
healthy myocardium. These results suggest that TMLR should be used cautiously in
the clinical setting for patients with an impaired ventricular function.
PMID- 10786107
TI - [Harvesting the vena saphena magna for aortocoronary bypass operations--is the
subcutaneous suture necessary?].
AB - BACKGROUND: The need for stitching the subcutaneous layers after saphenous vein
graft harvest for coronary artery bypass is discussed controversially. METHODS:
We conducted a prospective study to determine whether subcutaneous stitches
reduce the incidence of hematoma, infection and wound dehiscence after saphenous
vein graft harvest in patients undergoing coronary artery bypass grafting.
Patients were randomized either to group 1 (n = 100, subcutaneous suture) or
group 2 (n = 46, without subcutaneous suture). Leg wounds were examined for
hematoma, wound dehiscence, necrosis or secretion preoperatively and on day 2 and
5 after surgery. Furthermore, leg circumferences were measured at distinct areas.
RESULTS: There were no significant differences in the incidence of wound
complications. Especially, leg circumferences and incidence of hematomas (group
1: 36% versus group 2: 39%) as well as the length of hospital stay (group 1: 6.8
days versus group 2: 6.2 days) did not differ significantly. CONCLUSIONS: The
subcutaneous suture following saphenectomy is unnecessary. A deterimental effect
of an additional subcutaneous suture could not be demonstrated.
PMID- 10786108
TI - Anastomotic longitudinal stress due to modification of arterial longitudinal
properties after anastomosis.
AB - BACKGROUND: In our hands, in vivo segmental vessel length changes up to 5%
because of blood pressure: increasing in arterial pressure is associated to
decrease in segmental vessel length. METHODS AND MATERIAL: Using two
piezoelectric crystals sutured on vessel wall and a high fidelity pressure probe,
we recorded artery length variations as function of blood pressure, before and
after an end-to-end anastomosis on four pigs carotid arteries. RESULTS: Mean
arterial pressure before anastomosis = 73 mmHg (+/- 12); mean arterial pressure
after anastomosis = 91 mmHg (+/- 14); mean crystals displacement before
anastomosis during systole = -0.21 mm; mean crystals displacement after
anastomosis during systole = +0.24 mm; mean distance between crystals before
anastomosis = 12.3 mm (+/- 0.8) and after anastomosis = 11.2 mm (+/- 0.5).
CONCLUSIONS: In the acute phase following an end-to-end anastomosis, an increase
in blood pressure causes increasing in vessel length, with an exponential
correlation. The anastomosis is constantly subjected to a longitudinal traction
whose magnitude depends on blood pressure.
PMID- 10786109
TI - Decreased compliance on arterial anastomoses.
AB - The present study was undertaken to examine the cross-sectional vascular
compliance at the anastomotic site. METHODS AND MATERIAL: We performed end-to-end
anastomosis on the carotid artery of six pigs using continuous 6/0 polypropylene.
Four carotid arteries were excised and mounted in a perfusion chamber while the
remaining two were left in living animals. We used pulsed ultrasound (NIUS 02) to
generate detailed longitudinal profiles of diameter and compliance in the
proximity and on the anastomosis. RESULTS: On the anastomosis, the vessel
diameter decreases (-1 to -2.6% of diastolic diameter) when blood pressure
increases with an exponential correlation (R2 = 0.75). The arterial compliance at
the anastomosis was negative: the vessel cross-section reduction for a pulse
pressure of 1 up to 32 mmHg was 0.9 to 2% of diastolic vessel cross-section.
CONCLUSIONS: Vessel movement generated a dynamic stenosis whose magnitude seems
to depend on blood pressure level. Increasing blood pressure causes the
retraction of vessel ends which causes vessel lumen reduction. These results
suggest that continuous suture does not provide the continuity of mechanical
properties of the artery.
PMID- 10786110
TI - [Endothelial lesions caused by intra-aortic counterpulsation balloons].
AB - Intra-aortic balloon pump (IABP) is the most frequently used mechanical
circulatory support. Repeated trauma on the aortic wall has been reported as a
cause of balloon perforation by endothelial denudation of atheromatous plaque.
This study analyses the effect of IABP on the endothelium of the calf aorta. In
12 calves (mean weight: 72 +/- 6 kg) an IABP was inserted by femoral route and
left during 6 hours on internal mode with a frequency of 80 cycles/min. The
animals were sacrificed after the procedure (n = 4), at postoperative day (POD) 7
(n = 4), and at POD 14 (n = 4). In the aorta facing the balloon, nine transmural
samples were taken proximally (n = 3), at mid height (n = 3) and distally (n =
3), for histological analysis of the percentage of aortic surface covered with
endothelium. The percentage of aortic surface covered with endothelium at POD 0,
7 and 14 was proximally: 72.5 +/- 27.5%, 83.7 +/- 16.9% and 93.3 +/- 8.9%
respectively; at mid-height: 50.8 +/- 30.7%, 65 +/- 25% and 95 +/- 5%; and
distally: 31.4 +/- 20.1%, 48.3 +/- 34.4% and 85 +/- 10%. A large portion of the
aortic endothelium is abraded after 6 hours of IAB pumping. This effect is more
important at the distal level of the aorta. After two weeks, most of the
endothelium has regenerated.
PMID- 10786111
TI - [Management concept for acute traumatic aortic rupture based on a case report].
AB - Acute traumatic rupture of the thoracic aorta (ATRRA) is mainly a consequence of
high-speed travel or fall from great altitude. Most of the victims die at the
accident scene. Only 10-20% reach the hospital alive. Because of the extremely
high mortality, emergency repair seems to be indicated. Taking into consideration
that the hemorrhage into the mediastinum may remain constained and the patient
usually suffers from a wide variety of life-threatening causes of injury the
aforementioned option is probably not the best one. We report on a patient whose
"stable" aortic rupture was surgically corrected after stablization of the
circulation, coagulation and respiratory problems.
PMID- 10786112
TI - [Surgical repair of aortic coarctation in adults over 30 years of age].
AB - Coarctation of the aorta is nowadays rarely observed among adult population, as
it is usually detected and treated during infancy. The natural history of this
disease however is known to lead to early death due to the consequences of severe
arterial hypertension. We report on 3 patients older than 30 years, recently
operated on in our cardiosurgical units. Two of them were foreigners recently
arrived in Switzerland, of 46 and 32 years old respectively. The medical
examination highlighted severe hypertension and bilateral absence of femoral
pulses. The third patient was a Swiss citizen and had a similar examination.
Chest X-rays clearly showed rib notching, and the suspected diagnosis was
confirmed with angiography. Three different surgical techniques were chosen,
according to the peroperative situation. In one case, the stenosis was resected
and an end-to-end anastomosis could be performed. In another case, the occlusion
was complete and extended over 3 centimeters. The resected segment was replaced
by a prosthetic graft. In the third case, we performed a synthetic patch graft
aortoplasty. Postoperative care were simple in every cases. Coarctation of the
aorta must be evoked among the possible etiologies of severe hypertension, as the
surgical treatment is of real benefit and with reduced morbidity.
PMID- 10786113
TI - Parental notification article criticized.
PMID- 10786114
TI - Loving alcoholics.
PMID- 10786115
TI - Importance of good habits.
PMID- 10786116
TI - Another "Blues" alert.
PMID- 10786117
TI - It is worth the effort.
PMID- 10786118
TI - MedBytes.
PMID- 10786119
TI - Interim overload.
PMID- 10786120
TI - Not for sale.
PMID- 10786122
TI - Getting paid.
PMID- 10786121
TI - Battling supergerms.
PMID- 10786123
TI - Avoiding the legal pitfalls in mental health commitments.
AB - Treatment for some patients with mental illness involves involuntary commitment
to a mental hospital. The Texas Mental Health Code establishes legal criteria,
procedures that must be followed, and the burden of proof borne by the State of
Texas to obtain a commitment. The legal provisions protect patients from
inappropriate hospitalization but often obstruct the efforts of physicians to
effectively treat patients with mental illness. By understanding what appear to
be barriers to treatment, doctors can avoid the legal pitfalls that prevent
involuntary treatment when indicated.
PMID- 10786125
TI - Tropical disease research
PMID- 10786124
TI - HIV/AIDS situation, WHO Western Pacific region, 1998.
PMID- 10786126
TI - Effect of cooling condition on leucite crystals in dental porcelains.
AB - X-ray diffractometry (XRD) was used to analyze the crystal phases of three
commercial dentin and incisal porcelains prepared by normal cooling, quenching in
water, and controlled slow annealing after normal firing. There were no
remarkable differences in the contents of either tetragonal and cubic leucite in
the fired porcelain discs prepared under the three cooling conditions.
Furthermore, there were no significant differences in the parameters of the a
axis and c-axis of tetragonal leucite, and the a-axis of cubic leucite among
them. These results suggest that the cooling condition has little effect on the
microstructural changes of leucite crystals in the dental porcelains, since the
leucite crystals were formed at a higher temperature range than the firing- and
cooling-temperature range and were stabilized by incorporation of additives into
the lattice.
PMID- 10786127
TI - Development of metal-resin composite restorative material. Part 2. Effects of
acid and heat treatments of silver-tin filler particles on flexural properties of
metal-resin composite.
AB - The effects of acid and heat treatments of silver-tin filler particles on the
flexural properties of metal-resin composite restorative materials were
investigated. Five metal-resin composite restorative materials containing
different silver-tin filler particles treated under different conditions were
experimentally prepared. The conditions of the alloy particles were; 1) as
atomized (NT), 2) 1.8% HCl acid-treated (AT), 3) heat-treated at 150 degrees C
for 5 min after AT (A15), 4) heat-treated at 200 degrees C for 5 min after AT
(A20) and 5) heat-treated at 250 degrees C for 5 min after AT (A25). The flexural
strength and the flexural modulus of elasticity were measured for the five metal
resin composites to evaluate the effects of the acid and heat treatments. The
flexural strength of the prepared composites was significantly influenced by the
surface condition of the filler particles (p < 0.01), and increased significantly
when the as atomized particles (NT) were acid-treated (AT) or acid- and heat
treated at 150 degrees C (A15), but then significantly decreased as the heat
treatment temperature increased (A20 and A25). The strength of the A15 composite
was significantly higher than those of the other composites, and exceeded that
(about 60 MPa) of the previous composite with no treatment. No significant
difference was found in the flexural modulus of the composites.
PMID- 10786128
TI - Structure of bioactive glass and its application to glass ionomer cement.
AB - We prepared a new glass ionomer cement using bioactive CaO-P2O5-SiO2(-MgO) glass
and investigated its setting process using FT-IR and MAS NMR analyses. The
compressive strengths of the cements depended on the glass composition and a
maximum strength of 33.3 +/- 4.7 MPa was obtained using cement with the glass
composition of MgO:4.6, CaO:44.9, SiO2:34.2 and P2O5:16.3% in weight. FT-IR
analysis showed that the COOH group in the polyacrylic acid decreased and
carboxylate ion (COO-Ca2+) increased after the setting reaction. A broad signal
appeared around -82 ppm in 29Si MAS-NMR spectra of the glass and a new signal
corresponding to hydrated silica gel formation appeared around -102 and -111 ppm
after setting. This suggests that Ca2+ was released from the glass powder to form
carboxylate salt and that a degree of polymerization in the silicate network
increased. The setting mechanism of the cement was found to be essentially the
same as in conventional glass ionomer cement.
PMID- 10786129
TI - Temperature-dependence of the mechanical properties of FRP orthodontic wire.
AB - The temperature-dependence of the mechanical properties of a new esthetic
orthodontic wire with fiber-reinforced plastic (FRP) structure was investigated.
The new FRP wire, fabricated by a hot drawing method, is 0.5 mm in diameter and
has a multiple fiber structure composed of biocompatible CaO-P2O5-SiO2-Al2O3
glass fibers of 20 microns in diameter and a polymethyl methacrylate matrix. The
flexural load at a deflection of 1 mm and Young's modulus at 24, 37, and 50
degrees C under wet conditions showed similar fiber fraction dependence to those
under dry conditions for a fiber fraction of 40-51%. The flexural load and
Young's modulus tended to decrease slightly with increases in temperature. This
tendency was larger for the lower fiber fraction. However, the difference in
flexural load for a temperature difference of between 24 degrees C and 50 degrees
C was at most 10 gf. This is negligibly small, and a constant orthodontic force
regarding temperature change would be advantageous from a clinical point of view.
PMID- 10786130
TI - Evaluation of the amount of residual monomer on UDMA-based resins by FTIR.
AB - The purpose of this study was to establish a method using FTIR to evaluate the
polymerization characteristics of UDMA-based resins. Three kinds of experimental
UDMA-based resins were prepared with various molar fractions. IR spectra of the
cured film specimens were measured with FTIR before and after extracting residual
monomer from each specimen by MeOH. From the IR spectra, the changes in the
number of double bonds were measured, with the NH absorbance peak as an internal
standard, and the amounts of residual monomers (RM) were calculated. The MeOH
immersed specimens were analyzed by HPLC. The RM measured by FTIR were compared
with those measured by HPLC. The RM measured by HPLC were more than those by
FTIR. Since these differences could be due to the difference in the area
measured, this FTIR estimation method of residual monomers in cured resins using
the NH absorbance peak as an internal standard could be an appropriate method
when the resin monomer does not contain aromatic compounds.
PMID- 10786131
TI - Effect of ferric chloride/citric acid/phosphoric acid conditioner on adhesion of
4-META/MMA-TBB resin to the tooth.
AB - The aim of this study was to examine the effects of ferric chloride/citric
acid/phosphoric acid conditioners on the surface morphology of enamel and dentin
and on the adhesion of 4-META/MMA-TBB resin to conditioned tooth surfaces. Seven
conditioners, including phosphoric acid and its mixture with citric acid and
ferric chloride, were prepared and used for treating bovine teeth before bonding
with the resin. The effects of the conditioners on the surface morphology and
adhesion were examined by scanning electron microscopy and by atomic force
microscopy and by tensile bond strength tests, respectively. The maximum bond
strengths to tooth surfaces were obtained by using 3% ferric chloride/5% citric
acid/10% phosphoric acid conditioner. Thus, enamel and dentin can be treated
simultaneously with this conditioner before bonding with the 4-META/MMA-TBB resin
system.
PMID- 10786132
TI - A method of predicting color stability of autopolymerizing acrylic resins using
electron spin resonance.
AB - Synopsis. Long periods can be required to determine the color stability of
acrylic resins. The concentration of propagating radicals with unpigmented
experimental resins (UER) and initiator solution (IS) of two initiator systems
(binary and ternary) and five products were measured using electron spin
resonance (ESR). The radical concentration was estimated from the area under the
integrated ESR spectrum. The discoloration was measured using a color computer.
Higher content of benzoylperoxide led to higher radical concentrations. The
radical concentration for the ternary system increased slightly with time, but
were lower than those of the binary system. Significant positive correlations
were found between the radical concentration and delta E*ab for UER (r = 0.900, p
< 0.01), IS (r = 0.953, p < 0.001) and the products (r = 0.808, p < 0.05). It was
suggested that the color stability of these resins was predictable by measuring
the radical concentration using ESR.
PMID- 10786133
TI - Phase transformations and age-hardening behaviors related to Au3Cu in Au-Cu-Pd
alloys.
AB - Phase transformation behaviors in Au-Cu-Pd alloys were investigated by means of
electrical resistivity measurements, hardness tests, X-ray diffraction and
transmission electron microscopy. Anisothermal and isothermal annealing were
performed. Two types of phase transformations were found, namely related to the
single phase of Au3Cu and the coexistent phase of Au3Cu and AuCu I. The latter
produced more remarkable hardening than the former. Hardening was brought about
by the antiphase domain size effect of Au3Cu ordered phase in the single phase
and by the formation of AuCu I ordered phase in the Au3Cu ordered matrix. There
are three modes of phase transformation in the coexistent region depending on the
composition. Each sequence is discussed.
PMID- 10786134
TI - Phase transformation mechanisms in (AuCu)1-xPdx pseudobinary alloys by direct
aging method.
AB - Phase transformation mechanisms in the AuCu-Pd pseudobinary system were studied
by means of electrical resistivity measurements, hardness tests, X-ray
diffraction and transmission electron microscopy. A direct aging method was
employed to eliminate the otherwise unavoidable ordering that takes place rapidly
during quenching into ice brine, hence it is important to distinguish the
ordering processes with and without an incubation period. Three phase
transformation modes occurred, namely; ordering at grain boundaries and in the
grain interior with nucleation and growth mechanism after incubation, and
spinodal ordering without any incubation period. The age-hardening of the alloys
examined was attributed to AuCu I ordering. Nucleation and growth mechanism
followed by twinning occurred in the specimens aged at higher temperatures, while
spinodal ordering was seen in specimens aged in lower temperature. The spinodal
ordering temperature of AuCu-Pd alloys increased according to Pd content.
PMID- 10786135
TI - Resin content in cement liquids of resin-modified glass ionomers.
AB - Qualitative and quantitative analyses were conducted on four kinds of resin
modified glass ionomer (RMGI) cement liquids, LC, LC II, LC III (hereinafter
referred to as LCs) and VM, using HPLC and laser Raman spectroscopic methods.
HPLC revealed that among the RMGI liquids LCs contain 31-32% HEMA (2-Hydroxyethyl
methacrylate), and VM contains 18% of the same. The composition of RMGI cement
liquids varied significantly between manufacturers. In Raman spectroscopic
analyses, the spectra of liquids of various ratios of polyacrylic acid and HEMA
were measured, and calculations were made on the peak intensity ratios of C=C
stretch vibration to C=O stretch vibration, common in both HEMA and polyacrylic
acid. The composition ratio of polycarboxylic acid to HEMA of commercial glass
ionomer cements was assessed by the regression curve generated by a combination
of peak intensity ratios and composition ratios. In addition, Raman spectroscopy
was able to identity the differences in form of the methacryloyloxy group.
PMID- 10786137
TI - Cytotoxicity of a trial resin composite liner containing TiK2F6 on rat dental
pulp cells.
AB - The aim of this study was to assess the toxicological responses of a resin
composite containing TiK2F6 and NaF in rat dental pulp cells. Trial resin
composite liners were made, containing 3 wt% fluorides (TiK2F6 or NaF). These
specimens were immersed in 5 ml of cell culture medium supplemented at 37 degrees
C for 24 hours. The eluates were used for the experiments. We judged the
cytotoxicity of the samples by the cell viability. The original elute solution
was serially diluted and then the medium was exchanged for the dilute medium. The
cell viability at 1, 2 or 5 days after commencement of re-culturing was
calculated. The viability of cells in the eluate from the resin composite liners
containing TiK2F6 and NaF decreased with time. The cytotoxicity of TiK2F6 was
weaker than that of NaF at all times.
PMID- 10786136
TI - Hydrothermal-electrochemical deposition of calcium phosphates on various metals.
AB - Calcium phosphates were formed on five kinds of substrate metals using a
hydrothermal-electrochemical method in an autoclave with two electrodes. The
electrolyte dissolving NaCl, K2HPO4, CaCl2.2H2O, tris (hydroxymethyl)
aminomethane, and hydrochloric acid was maintained at 100 degrees C, 150 degrees
C and 200 degrees C. The counter electrode, the anode, was platinum plate, 20 x
20 x 0.5 mm, and the working electrodes as cathode were pure titanium, pure zinc,
pure nickel, pure iron, and stainless steel plates. A constant direct current at
12.5 mA/cm2 was loaded for 1 hr. Hydroxyapatite [Ca10(PO4)6(OH)2] only deposited
at three temperatures on pure titanium plate. On pure zinc plate, both
parascholzite [CaZn2(PO4)2.2H2O] and hydroxyapatite were formed at 150 degrees C
and both parascholzite and ZnO were formed at 200 degrees C. Both hydroxyapatite
and beta-TCP [beta-Ca3(PO4)2] were formed on pure nickel, pure iron, and
stainless steel plates at 200 degrees C. It seems that the incorporation of the
metal ions released from the electrode decreased the Ca/P ratio of the deposit
due to the formation of other compounds except hydroxyapatite.
PMID- 10786138
TI - Metal-resin composite restorative material using powder-liquid system.
AB - In order to further improve the mechanical properties of a metal-resin composite
and avoid the problems which were found in the previous metal-resin composite
using a 2-paste system, another type of metal-resin composite using a powder
liquid system was developed. In the new system 4-META treatment was carried out
at low temperature and DMPT was separated from the 4-META treated particles. The
efficacy of this system as well as the effects of 4-META concentration, duration
of 4-META treatment (immersion time) and filler content on the flexural
properties, working time and setting time were investigated. The flexural
strength of the powder-liquid composite was significantly affected by two main
factors, immersion time and filler content, and the other properties (flexural
modulus, working time and setting time) were by all three main factors. The
highest flexural strength of the prepared composite was 91.8 MPa, which was
higher than that of the 2-paste composite (64.0 MPa) by about 43%. This was
achieved at a 0.1 ratio of 4-META concentration, 30 s immersion time and 94 mass%
filler content. The working time and setting time ranged between 2.3-13.6 min and
4.2-20.1 min, respectively, and those of the highest strength composite were 3.0
and 5.2, respectively. The results of the present study indicate that the powder
liquid system is effective to improve the properties of the metal-resin
composite.
PMID- 10786139
TI - Effect of cavosurface angle on dentin cavity adaptation of resin composites.
AB - The effect of the cavosurface angle of dentin cavities prepared in extracted
human molars on the cavity adaptation of a resin composite was evaluated by
measuring the gap width between the resin composite and the dentin cavity wall.
Cavities with cavosurface angles of 90 degrees, 120 degrees, 135 degrees, or 150
degrees were pretreated with one of two commercial dentin bonding systems or an
experimental dentin bonding system. The contraction gap width was measured at
both the cavity margin and the section cavity using a light microscope. Complete
cavity adaptation was obtained with pretreatment of the experimental groups
regardless of the cavosurface angle. The contraction gap observed at the cavity
margin was prevented with the two commercial dentin bonding systems when the
cavosurface angle was increased to 150 degrees. A high correlation was observed
between the contraction gap width and the proportion of the free surface to the
adhesive surface of the resin composite restoration.
PMID- 10786140
TI - Reinforcement mechanism of dentin mechanical properties by intracanal
medicaments.
AB - The reinforcement mechanism of dentin mechanical properties by intracanal
medicaments was investigated. The dumbbell-shaped specimens were prepared from a
collagen sheet, demineralized dentin and organic dissolved dentin. After
immersing the specimens in intracanal medicaments (eugenol and formocresol), the
tensile test was carried out in 37 degrees C water and the Vickers hardness test
was performed. The tensile strengths increased after eugenol and formocresol
immersion, especially collagen and organic dissolved dentin after formocresol
immersion and demineralized dentin after eugenol immersion. Thus, formocresol
immersion might have reinforced the dentin tensile strength by protein
coagulation, while eugenol immersion might have reinforced the dentin tensile
strength by not only protein coagulation but also chelation with hydroxyapatite.
However, the hardness values did not significantly change after intracanal
medicament immersion.
PMID- 10786141
TI - Isothermal age-hardening behaviour in a multi-purpose dental casting gold alloy.
AB - The isothermal age-hardening behaviour of a multi-purpose dental casting gold
alloy was investigated by means of hardness testing, X-ray diffraction study,
scanning electron microscopic observations and energy dispersive spectroscopy. By
ageing of the solution-treated specimen at 400-500 degrees C, two phases of the
Au-rich alpha 1 phase with an f.c.c. structure and the alpha 2 phase with an
ordered f.c.c. structure based on Pt3In were transformed into three phases of the
alpha 1 phase, the alpha 2 phase and the beta phase with an ordered f.c.t.
structure based on PtZn. Hardening was attributed to the fine nodular
precipitation resulting from the formation of the beta phase in the alpha 1
matrix. Softening was due to the coarsening of the fine nodular precipitates as
the result of consumption of the alpha 2 phase.
PMID- 10786142
TI - Effectiveness of the addition of water-soluble photoinitiator into the self
etching primers on the adhesion of a resin composite to polished dentin and
enamel.
AB - The effectiveness of the addition of a photoinitiator into self-etching primer
was investigated by measuring the tensile bond strength between a resin composite
and dentin or enamel. The addition of camphorquinone to 5 M (5 wt% MDP -35 wt%
HEMA aqueous solution) or 30 M (30 wt% MDP -35 wt% HEMA aqueous solution) did not
increase the bond strengths of resin composite to dentin or enamel. On the other
hand, the bond strength to dentin was increased by the addition of a water
soluble photoinitiator, 2-hydroxy-3-(3,4-dimethyl-9-oxo-9H-thioxanthen-2-yloxy)
N,N, N-trimethyl-1- propanaminium chloride (QTX) to 5 M or 30 M. The bond
strengths to enamel were not influenced by the addition of QTX to 5 M or 30 M.
PMID- 10786143
TI - Development of metal-resin composite restorative materia. Part 1. Experimental
composite using silver-tin alloy as filler and 4-META as coupling agent.
AB - Metal-resin composites, using metal particles instead of inorganic particles as
the filler and 4-META as the coupling agent, were experimentally prepared under
20 different conditions (five different concentrations of 4-META, and four
different contents of metal particles). The flexural strength of the prepared
metal-resin composites was in the range of about 14.5-61.3 MPa. The flexural
strength was significantly influenced by the 4-META concentration, the metal
particle content and their interaction. The highest strength was estimated at 2-3
mass% of 4-META concentration and 92.0-93.5 mass% metal filler content. The
flexural modulus of the metal resin composite ranged approximately from 7.8 GPa
to 15.5 GPa. The flexural modulus of the metal resin composite significantly
increased with the metal particle content. The effect of the 4-META concentration
on the flexural modulus was not significant.
PMID- 10786144
TI - Correlation of dentin bond durability with water absorption of bonding layer.
AB - In order to understand the relationship between the durability of adhesive
strength in the oral cavity and water absorption, a series of O-methacryloyl-N
acyl tyrosines (MAATY)-2-hydroxyethyl methacrylate (HEMA) bond system samples was
prepared and their bonding strength to unetched human dentin was measured as a
function of immersion period in water. Also, bulk polymerization was carried out
to measure the amount of water absorption as a function of time. All specimens
absorbed water suddenly when they were immersed into water. The amount of
absorbed water was large when the carbon number in the acyl group was small or
the number of carboxylic groups was large. The adhesive strength of the MAATY
HEMA system to unetched dentin decreased significantly when the MAATY-HEMA
absorbed a larger amount of water. We concluded, therefore, that preparation of
MAATY which absorbs less water may improve durability even when immersed in
water.
PMID- 10786145
TI - The influence of configuration factors on cavity adaptation in compomer
restorations.
AB - The effect of configuration factor (C-factor) on cavity adaptation was
investigated in three compomer and one resin composite restorations. Eighty-four
cylindrical dentin cavities (C-factor: approximately 2.5, 3.0 or 4.0) prepared on
flat coronal dentin surfaces were filled with the materials in combination with
their proprietary adhesive systems. Cavity adaptation was microscopically
examined after 15 minutes storage in water at the top surface and at other four
sites along the cavity walls. Additionally, indentation testing was performed for
each material at 20 minutes and 24 hours after irradiation. Regression analysis
revealed no relationship between C-factor and gap dimension in compomer
restorations at any of the measuring sites, while a logarithmic relation was
found only at the cavity floor of the composite fillings. All materials showed
maturation of mechanical properties. The elastic component of the indentation was
smaller in compomers than in the composite. It was concluded that C-factor had no
influence on the cavity adaptation for compomer restorations. This might be due
to reduced stress generation at the bonding interface caused by relatively low
mechanical properties immediately after curing, less elasticity, and water
absorption in compomers.
PMID- 10786146
TI - Isothermal age-hardening behaviour in a Au-1.6 wt% Ti alloy.
AB - This study describes research with a view to developing a new age-hardenable,
high-carat dental gold alloy with better biocompatibility by addition of a small
quantity of titanium to gold. The relationship between isothermal age-hardening
and phase transformation of the Au-1.6 wt% Ti alloy was investigated by means of
hardness testing, X-ray diffraction study, scanning electron microscopic
observation and energy dispersive spectroscopy. The hardening in the initial
stage of ageing seemed to be attributable to the continuous precipitation of the
Au4Ti ordered phase in the supersaturated alpha solid solution matrix. The
overaging with softening was attributed mainly to the formation of precipitates
at the grain boundaries, which grew to bright lamellae and seemed to be composed
of the Au4Ti phase.
PMID- 10786147
TI - Inhibition of carious lesions in vitro around gallium alloy restorations by
fluoride releasing resin-ionomer cement.
AB - A new fluoride releasing resin-ionomer cement was used for bonding of gallium
alloy restorations in vitro. Etching, priming, and fluoride releasing resin
ionomer cement were used in the experimental group (ARG), prior to placement of
the gallium alloy restorations. Three different controls were used: gallium alloy
only (G), no etching, fluoride releasing resin-ionomer cement, gallium alloy
(RG), etching, priming, non-fluoride cement and gallium alloy (ACG). The mean
shear bond strengths of ARG group to enamel and dentin were higher than those of
the three control groups. Artificial secondary caries lesions around the
restorations in the experimental group and the control groups were produced,
using a strep. mutans culture. The microradiographs were examined for presence of
a caries inhibition zone near the restoration. Caries inhibition zones were
clearly detected around RG and ARG, but not around G and ACG. The results
indicate that the fluoride releasing resin-ionomer cement provided good adhesion
and caries inhibition in enamel and dentin.
PMID- 10786148
TI - 1H-NMR studies of the interaction of dental adhesive monomer, 4-META with
calcium.
AB - Our objective was to determine whether high-resolution proton-nuclear magnetic
resonance (500 MHz) could be utilized for detection of ionic binding interaction
of the 4-META resin system with calcium derived from hydroxyapatite. The
stability of 4-META in aqueous medium was studied, findings indicated that 4-META
was rapidly converted to 4-MET, a hydrate product of 4-META in 10% D2O/DMSO-d6.
The 1H-NMR signals of the methacryloyloxyethoxy group of 4-MET remained intact
following the addition of both monocalcium phosphate (MCP) and dicalcium
phosphate dihydrate (brushite) solution, whereas those of its trimellitic portion
were markedly shifted upfield depending on the phosphate concentration. The
shielding effect followed by upfield shifts was due to the localization of
electron density surrounding the carboxylate anions that were dissociated by the
interaction with calcium counter cation. The shielding effect of 4-MET with
brushite was larger than that with MCP. An ionic interaction of 4-MET derived
from 4-META with calcium was demonstrated.
PMID- 10786149
TI - Setting shrinkage and hygroscopic expansion of resin-modified glass-ionomer in
experimental cylindrical cavities.
AB - The effects of the C-value (bonded surface area/unbonded surface area) and the
volume of the cavity on the volumetric dimensional changes [volumetric setting
shrinkage (VSS) and volumetric hygroscopic expansion (VHE)] of a resin-modified
glass-ionomer (RMGI) filled in experimental cylindrical cavities were evaluated.
The VSS and the VHE rate decreased with increasing C-value. There was a high
inverse regression between the cavity C-value and volumetric dimensional changes,
but a low regression between cavity volume and volumetric dimensional changes.
Therefore, it was thought that greater contraction stress would remain in high C
value cavities than low C-value cavities during the setting process. It was also
confirmed that the volumetric dimensional changes of RMGI in cavity were
influenced primarily by the cavity C-value.
PMID- 10786150
TI - Cytotoxicity of dental resin monomers in the presence of S9 mix enzymes.
AB - The purpose of the this study was to evaluate the cytotoxicity of dental resin
monomers in the presence of a rat liver S9 mix containing cytochrome P 450
enzymes. JTC-12 cells derived from a monkey kidney were seeded on a 96-well multi
well-plate at 9 x 10(3) cells per well. After cultivation, the S9 mix was added
to the wells as an S9 mix group (+S9), and PBS- was added to the other wells as a
none-S9 mix group (-S9), then 7 different concentrations of various monomers were
added to each well. All the specimens were cultured for another 24 hrs. The cell
survival ratios (CSR) were calculated by using a neutral red cytotoxicity assay.
CSR for 50 micrograms/mL of Bis-GMA/S9 mix was 92.6% while for none-S9 mix it was
6.6%. The values of CSR for UDMA, Bis-MPEPP, EGDMA, TEGDMA, DMAEM, 4-META and
HEMA exhibited a reduction in cytotoxicity in the presence of the S9 mix. There
were significant differences between +S9 and -S9 for respective monomers (p <
0.05). However, there were no significant differences between +S9 and -S9 for MMA
(p < 0.05).
PMID- 10786151
TI - Effect of carboxyl group in O-methacryloyl-N-acyl tyrosines on adhesiveness to
unetched human dentin.
AB - We have reported that the carboxylic group plays an important role in the
adhesion of methacryloyl amino acid--2-hydroxyethyl methacrylate type restorative
resin to dentin surfaces. However, our study so far has been limited to the
methacryloyl amino acid that has only one carboxylic acid. In this investigation,
three new O-methacryloyl-N-acyl tyrosines (MAATY) that have one or two carboxylic
groups in the acyl group, and thus two or three carboxylic groups in MAATY, were
prepared and evaluated for their bond strength to unetched dentine. Higher bond
strength was observed when the MAATY contained larger number of carboxylic acid
groups. Factor analysis of the bonding strength revealed that the hydrogen bond
ability of the carboxylic acid and the hydrophile-lipophile balance (HLB)
affected the bond strength.
PMID- 10786152
TI - Strength and microstructure of gallium alloys.
AB - This study investigated the physical and mechanical properties and the
microstructure of four different gallium alloys. For all gallium alloys, the
compressive strengths measured at one hour (86-223 MPa) and 24 hours (265-286
MPa) after specimen preparation were found to be well within the range exhibited
by many high-copper amalgams. The creep values and dimensional change of the
gallium alloys were comparable to those of leading amalgams, except for the
dimensional change value of one alloy. The set gallium alloys consisted of a
multi-phase structure including beta-Sn, CuGa2, In4Ag9, Ag72Ga28, and Ga5Pd
(except for one product that did not contain Pd) that was more complicated than
the structure of dental amalgams. Although the gallium alloys had physical and
mechanical properties comparable to those of high-copper amalgams, the
microstructure, coupled with the instability of the element gallium itself, could
make these materials more prone to corrosive attack compared to amalgams.
PMID- 10786153
TI - The effect of primers on bond strength of polyacid-modified resin composites
(compomers).
AB - This study evaluated the effect of primer on shear bond strength and marginal
gaps of six new compomers immediately after light-activation. A resin-modified
glass ionomer cement, a conventional glass-ionomer cement and a microfilled
composite were used for comparison. The marginal gap widths of each of the four
compomers and a microfilled composite used with the primer were significantly
smaller compared with those used without the primer. The bond strength values of
five compomers used with the primer were significantly higher than those used
without the primer. The bond strength of conventional glass-ionomer was not
affected by the primer (or the conditioner).
PMID- 10786154
TI - Effect of functional monomer in commercial dentin bonding agents use of an
experimental dentin bonding system.
AB - The objective of the present study was to understand the role of the functional
monomers in dentin bonding agents of an experimental dentin bonding system by
measuring the wall-to-wall contraction gap and tensile bond strength measurement.
The efficacy of three commercial dentin bonding agents after using EDTA for
conditioning and GM for priming was evaluated by measuring the contraction gap of
the resin composite in a cylindrical dentin cavity, and by measuring the tensile
bond strength of the composite to a flat dentin surface. The effect of the
functional monomers was demonstrated by the contraction gap measurement alone.
The value of the contraction gap was significantly different between the
commercial dentin bonding agents and these agents without functional monomers (p
< 0.05). It was concluded that the functional monomers were essential to
obtaining the marginal integrity of the resin composite in the dentin cavities.
PMID- 10786155
TI - Formulation of glutaraldehyde disinfectant for alginate impressions.
AB - The effect of buffer agents incorporated in glutaraldehyde disinfectants on the
surface quality of dental models was examined by the measurement of surface
roughness, X-ray diffraction analysis and SEM observation. Seven experimental
glutaraldehyde disinfectants were prepared using two buffer agents, potassium
acetate alone or potassium acetate and sodium hydrogen carbonate in combination.
Four kinds of sulfate--zinc, calcium, potassium and magnesium sulfate--were added
to these disinfectants in order to accelerate the hydration of calcium sulfate
hemihydrate. The impressions treated with the experimental disinfectants for 1 h
produced stone surfaces which had significantly lower surface roughness values
than those treated with the commercial disinfectants (p < 0.05). The X-ray
diffraction analysis and SEM observation showed that these superior surfaces were
produced as a result of significant reductions in the amount of residual calcium
sulfate hemihydrate. Replacement of buffer agents in commercial glutaraldehyde
disinfectants with chemicals such as those studied in the present study will
improve the surface quality of dental stone.
PMID- 10786156
TI - Release and recharge of fluoride by restorative materials.
AB - This study investigated the release and recharge of fluoride by restorative
materials. Resin-modified glass ionomers (RGIs), polyacid-modified composite
resins (PMCRs) and resin composite containing fluoride were used for comparison
of fluoride release. Non-fluoride-releasing resin composite was used as a
control. The amounts of fluoride release from RGIs and PMCRs remarkably increased
in the citrate-phosphate acid buffer compared with distilled water. The amounts
of fluoride recharged in RGIs increased with the concentration of NaF solution,
but those of PMCRs exposed to all concentrations of NaF solutions were less than
1.5 ppm. Neither resin composite containing fluoride and non-fluoride-releasing
resin composite gave any evidence of recharge. RGIs and PMCRs affected by acid
buffer solution could not recharge much fluoride even if they were immersed in
the 1000 ppmF NaF solution. The results suggested that the matrix of RGIs and
PMCRs functioned as a reservoir of fluoride, but the functions were lost by acid
attack.
PMID- 10786157
TI - Development of a new high-speed measuring system to analyze the dental cast form.
AB - A new non-contact measurement system employing of a line laser and CCD camera was
developed to rapidly measure maloccluded dental casts with large depth and high
accuracy. In this system, the measuring interval along the line laser and the
model scanning direction perpendicular to the line laser were both 0.2 mm. By
averaging the raw data through repetitious input and smoothing by local
filtering, the noise was effectively decreased. Sub-pixel processing, which
calculates the pixel position with the largest brightness within one pixel,
improved the accuracy in the measurement to 22 microns compared with 65 microns
before sub-pixel processing. Dental casts with malocclusion were measured with
this system. The time and the depth for the measurement were about 10 minutes and
60 mm, respectively. This was a vast improvement compared with our previous
system employing a point laser. In the CG of the measured dental casts, smooth
and detailed surface morphology were sufficiently reproduced, and recognition of
the characteristic points in the cast could be accomplished with the accuracy of
30 microns. This measurement system will be helpful to analyze the dental cast
form with malocclusion in progress.
PMID- 10786158
TI - Gold alloys for resin bonding including small amount base metals--structural
changes of alloy surface by the high-temperature oxidation.
AB - To achieve durable bonding with adhesive resin, the surface roughness and the
kinds of oxides, respectively to increase mechanical retention to enhance the
chemical affinity of adhesive monomer with the gold alloy, were regulated by high
temperature oxidation together with the addition of small amounts of base metals.
Alloys containing 2 mass% of Ni, In, or Cr with Cu were oxidized at 800 degrees C
for 20 min in air, pickled in thioglycolic acid, and subsequently oxidized at 500
degrees C for 10 min in air. The morphology of the internal oxidation zone
changed markedly according to the added base metals. Although the internal oxide
particle composed of only Cu2O was removed by pickling, NiO, In2O3, and chromium
oxides could not removed and remained on the alloy surface. The surface roughness
was increased by addition of Ni, In, or Cr. Applying the present method can
control the roughness and chemical states on a gold alloy surface to increase its
adhesive ability with adhesive resins.
PMID- 10786160
TI - Effect of polishing on cyclic fatigue strength of CAD/CAM ceramics.
AB - The biaxial flexural strength and cyclic fatigue biaxial flexural strength of
CAD/CAM ceramics polished with #220, 400, 600 and 1000 diamond pads were measured
in an effort to determine the effect of surface roughness on fatigue behavior of
dental ceramics. The surface roughness was improved after polishing with a
smaller diamond grain pad. The flexural strengths of the specimens polished with
#220, 400, 600 and 1000 diamond pad were 75.2, 76.6, 82.2, and 83.3 MPa,
respectively; the fatigue flexural strength of those with #220, 400, 600 and 1000
were 53.0, 58.1, 60.0, and 61.5 MPa, respectively. Both the flexural and fatigue
flexural strengths increased with improvement of surface profile. These results
suggest the importance of polishing of dental ceramics for not only the static
strength but also the cyclic fatigue strength.
PMID- 10786159
TI - Lattice parameter changes of leucite by incorporation of various cations
substituted for potassium.
AB - Leucite crystals having modified compositions from stoichiometry were prepared by
the incorporation of Na+, Rb+, Cs+, Ca2+, Ba2+, and Sb3+ substituted for 5-50 at%
of K+ in the leucite. The lattice parameters of the a- and c-axes of these
tetragonal leucite were derived from the diffraction angles of (400) and (004)
peaks due to tetragonal leucite, respectively. Both lattice parameters of the a-
and c-axes of the leucites except Rb and Cs were slightly smaller than those of
stoichiometric leucite. The lattice parameters of the a-axis of the leucites
containing Rb and Cs were larger than those of stoichiometric leucite (p < 0.01)
and increased with the content of Rb and Cs. It was concluded that the crystal
lattice of leucite was deformed by the incorporation of cations substituted for K
and their variations mainly depend upon the kind of cation, namely ionic size and
substitution site in the lattice.
PMID- 10786161
TI - Relationship between Af temperature and load changes in Ni-Ti orthodontic wire
under different thermomechanical conditions.
AB - Simple three point bending tests were performed on Ni-Ti wires with three
different Af points (1 degree C, 13 degrees C and 34 degrees C) to clarify the
relationship between Af temperature and load changes under constant deformation.
Each wire was deformed at 37 degrees C and then thermal changes were imposed by
temperatures of 2 degrees C or 60 degrees C. The load changes with thermal
changes from 37 degrees C to 2 degrees C or 60 degrees C showed the same tendency
on the wires with different Af points: In the loading stage, the load became
lower than the initial level at 37 degrees C and in the unloading stage, the load
became higher than the initial load. The largest load change in the unloading
stage was measured with the 13 degrees C Af point wire. Care must be taken when
handling Ni-Ti wire with an Af point of less than 1 degree C in order to prevent
it from reaching the limit of critical stress of slip deformation when the
temperature in the mouth rises to above 40 degrees C.
PMID- 10786162
TI - Utility of Ni-Ti shape memory orthodontic wire.
AB - The characteristic temperature dependence of recovery force was evaluated for a
Cu-containing Ni-Ti shape memory wire with the nominal Af point being 40 degrees
C. It exerted mild recovery force within the range of the proposed optimum force
at the usual oral temperature. Larger forces were generated when it was heated to
temperatures above Af: 40, 50 or 60 degrees C. By subsequently cooling to
temperatures below Af, the force decreased again, and vice versa. The excellent
reversibility, reproducibility and durability of the recovery force were also
confirmed. These results indicate that the shape memory wire may be a reasonable
material for a new concept of intermittent orthodontic treatment, in which mild
force will be applied to the tooth for most of the daily hours and the tooth
movement will be intermittently accelerated by larger forces generated only when
the patient has hot foods or drinks.
PMID- 10786163
TI - Analysis of major components contained in Bis-GMA monomer.
AB - The major components contained in commercial Bis-GMA monomer were isolated by
thin layer chromatography (TLC) and identified by NMR and high resolution mass
spectroscopy. In addition to the two major components already known (Bis-GMA and
Iso-bis-GMA), an unknown hydrophilic third major component was isolated and
identified as 2,2-[4-(2-hydroxy-3- methacryloyloxy-1-propoxy)-4'-(2,3-dihydroxy-1
propoxy)]dipheny lpropane. This compound was designated as BIS-GMA-H, because it
has a structure of Bis-GMA with one of which methacrylic ester bond hydrolyzed.
PMID- 10786164
TI - Effects of thermal cycling on dynamic viscoelastic properties of four commercial
resins for crown and bridge.
AB - To elucidate the effects of thermal cycling on the viscoelastic properties of
four commercial resins for crown and bridge, dynamic shear modulus (G'),
mechanical loss tangent (tan delta), Knoop hardness, water sorption and
appearance of specimen surfaces before and after thermal cycling test were
determined. The changes of G' and tan delta for two materials were insignificant
with increased repetitions of thermal cycling. Those of the other two materials
were statistically significant: in particular, G' at temperatures above 60
degrees C was inclined to increase slightly and tan delta decreased considerably.
While the Knoop hardness of the materials was a little decreased over a number of
75,000 thermal cycles, the water sorption almost attained an equilibrium in
uptake after 14,000 thermal cycles. Furthermore, cracks on the specimen surface
were observed after 37,500 to 75,000 thermal cycles. From these results, the
deterioration of materials was observed as damage to the specimen surface.
Moreover, it could be presumed that the materials would be further polymerized
during the period of thermal cycling.
PMID- 10786165
TI - Adhesion of a new commercial self-etching/self-priming bonding resin to human
caries-infected dentin.
AB - We have examined the adhesive properties of a new commercial self-etching/self
priming bonding resin (Unifil Bond, UB) to normal and caries-infected dentin of
human extracted molars using scanning electron microscopy (SEM) and a micto
tensile bonding strength (MTBS) test. In this study, 7 human extracted molars
with moderate occlusal caries were used, and flat surfaces including occlusal
dentin caries were prepared from the teeth. After the application of UB to the
surfaces, a composite resin was built up, and subjected to the measurement of
MTBS and SEM observation of the interfacial morphology between UB and dentin. The
MTBS of UB to normal dentin was 33.4 MPa, but that to caries-infected dentin was
11.0 MPa. There was a significant difference between the MTBS to normal and
carious dentin. SEM observation revealed that the typical hybrid layer was not
formed in caries-infected dentin. These results suggested that resin infiltration
into caries-infected dentin was not sufficient to allow perfect sealing of the
restoration.
PMID- 10786166
TI - Firing shrinkage of porcelain-resin composites prepared by laser lithography.
AB - Using porcelain and resin-mixed composites as experimental materials, cubic
polymerized composites were prepared by the accumulation of thin slices cured by
laser scanning. The composites were then fired, and bulk ceramic bodies were
made. The optimal firing conditions of polymerized composites and firing
shrinkage were investigated. The results showed that cubic ceramic bodies in a
form homologous to that before firing could be reproduced. The volume shrinkage
of fired ceramic bodies consisting of 1 g of ceramic powders and 0.3 g of epoxy
resin was about 30% under all firing conditions, and there were no significant
differences between specimens. It was suggested that with further research and
development, three-dimensional forms for clinical use in dentistry could be
manufactured by the proposed method.
PMID- 10786167
TI - Influence of filler content and gap dimension on wear resistance of resin
composite luting cements around a CAD/CAM ceramic inlay restoration.
AB - We investigated the influence of filler content and gap dimension on the wear
resistance of composite luting cement around CAD/CAM ceramic inlay restorations.
Experimental hybrid dual-cured composite luting cements containing 60, 70, 72, 74
and 80 wt% of silanated barium-silica fillers were used for cementing CAD/CAM
ceramic inlay into the cavity. The specimens involving inlay-cement-tooth
interfaces were subjected to a three-body wear test. The relation between the
interfacial gap dimension and wear loss was also investigated using 60, 70 and 80
wt% filled cements. The cements containing more than 70 wt% filler presented
significantly higher wear resistance than 60 wt% filled cement. There was a
positive linear relationship between gap dimension and wear loss, and the
inclination of the regression line decreased with increasing filler content.
These results indicated that the higher filler content of the cement increased
the wear resistance and this desirable influence appeared more remarkably in the
wider horizontal gap dimension.
PMID- 10786168
TI - Experimental impression tray fabricated with a NiTi shape memory alloy plate.
AB - A small experimental impression tray was fabricated with a NiTi shape memory
alloy plate. After recovery of the shape memory effect, the upper rims of the
tray holding the impression were opened to some extent, the resistance during
removal of the model from the impression was significantly decreased compared to
a commercially available tray and the tray before recovery of the shape memory
effect. The pull-out force of the model from the impression was 23.5(0.2)N for
the commercially available tray, 23.5(3.9)N for the experimental tray before
recovery of the shape memory effect and 14.7(4.0)N after recovery of the shape
memory effect (heated for 15 min at 70 degrees C). Therefore the tray should be
useful in teeth fracture free modeling.
PMID- 10786169
TI - Conservative restorations with powerful capabilities, Part 1.
PMID- 10786170
TI - A predictable, conservative, technique for natural-looking posterior composite
placement.
PMID- 10786171
TI - Enhanced aesthetics using pressed ceramics.
PMID- 10786172
TI - Direct composite veneers to create a mature smile.
PMID- 10786173
TI - Best of both worlds: stainless steel and nickel titanium.
AB - The integration of the Quantec (0.06 taper 0.25-mm tip) rotary NiTi file and the
standard stainless steel K-file (ISO 0.02 taper) synergistically simplifies
instrumentation of the canal. The rotary NiTi file is primarily used to flare the
coronal and midportion of the canal. Its flexibility enables clinicians to do so
without ledging and perforation. Because of its effective cutting ability, the
stainless steel file is used to clean and shape the apical area of the canal and
blend the apical portion into the flare. Ultimately, this simplifies the
obturation process. When familiar with this technique, dentists may find it
easier to work with sequential tapers offered in the Quantec series of
instruments. This series has a of tapers from 0.02 to 1.2. Understanding the
crown-down concept and using quality and reliable instruments facilitates
improved productivity.
PMID- 10786174
TI - Implant-level transfer impressions.
PMID- 10786175
TI - Prosthetic joints, dental treatment, and antibiotic prophylaxis.
AB - Dentists should be familiar with the newest antibiotic prophylaxis
recommendations for joint prosthesis patients undergoing dental treatment. The
guidelines identify physical conditions that place joint patients at the highest
risk for joint sepsis. They also stratify dental procedures into higher- and
lower-risk categories. Combining these two groupings clarifies the dentist's
strategy for antibiotic prophylaxis regimens, which are greatly simplified. Of
notable importance is the elimination of posttreatment antibiotic dosing. A large
group of patients who do not require antibiotic prophylaxis prior to dental
treatment are also identified by the guidelines. Every dentist must use clinical
judgment, knowledge of the patient, and consultation with the attending physician
to determine the appropriate treatment plan.
PMID- 10786176
TI - Bridging the gaps.
PMID- 10786177
TI - The link between periodontal disease and systemic health: a scientific update.
Interview by Phillip Bonner.
PMID- 10786178
TI - Marketing profit centers in a cosmetic practice: power bleaching.
PMID- 10786179
TI - The importance of technique in preventing postoperative sensitivity when placing
bonded restorations.
AB - This article has focused on what are thought to be some of the common causes of
postoperative sensitivity following placement of adhesive restorations. Of
course, there can be many other factors. There are an infinite number of roads or
combinations of roads that won't get dentists where they want to go. However,
there is a specific road or roads, when taken carefully in the proper sequence,
that will predictably get dentists to their destinations. The same is true for
bonding. Adhesive dentistry is by no means difficult, but it is exacting. If the
rules are understood and followed precisely, dentists will find the results are
well worth the effort.
PMID- 10786180
TI - Predictable, aesthetic, full-mouth reconstruction.
PMID- 10786181
TI - Ultimate aesthetics with composites: when art and science merge.
PMID- 10786182
TI - Managing soft tissue using a laser: a 5-year retrospective.
PMID- 10786183
TI - Advanced adhesive technology.
PMID- 10786184
TI - Creating exceptional soft tissue contours for fixed anterior bridges and veneers.
PMID- 10786185
TI - Restoring anterior aesthetics and occlusion.
AB - The use of Empress2 material in this specific case produced the strong
restoration desired and allowed reproduction of natural vitality and
translucency. The results offered by the material exceeded patient as well as
doctor expectations.
PMID- 10786186
TI - Orascopy: a vision for the new millennium, Part 2.
AB - The advent of orascopy as a cutting edge technique has changed the way
endodontists visualize as well as think about endodontics. As practitioners begin
to see and understand endodontic etiology, it will enable oral physicians to
provide treatment based on visual confirmation rather than radiographic
estimates. In the future, conventional orascopic endodontics will be done very
much like physicians provide treatment. It will be more qualitative rather than
quantitative. Dentists will not need to make measurements of canals from
radiographs; they will use orascopy to instrument, irrigate, and obturate while
viewing the root canal system in real time. Surgical orascopic endodontics will
continue to improve surgical treatment results because enhanced visualization has
enabled endodontic surgeons to identify and treat endodontic etiology.
PMID- 10786187
TI - Prosthetic considerations with periodontal root resective therapy, Part 2.
Hemisections.
AB - When a root and the overlying anatomic crown are removed as a unit, this
procedure is referred to as a hemisection. Hemisection of a maxillary or
mandibular molar is often a means of retaining teeth needed for restorative
abutments or occlusal support. This treatment can yield predictable results using
proper diagnostic, endodontic, surgical, and prosthetic techniques.
PMID- 10786188
TI - Full-mouth restoration with TMJ involvement: a case report.
PMID- 10786190
TI - Extreme hygiene: taking the hygiene department beyond recall.
PMID- 10786189
TI - Clinical findings using a self-etching primer.
PMID- 10786191
TI - Six-month adult aesthetic orthodontic treatment.
PMID- 10786192
TI - Achieving high-quality comprehensive dentistry with i.v. sedation.
AB - This comprehensive approach requires a high-tech/touch staff environment and a
dedication to excellence in all areas of patient care. Its rewards are financial
and personal because it creates a highly satisfied and appreciative patient.
PMID- 10786193
TI - [Topotecan: a new discovery and future prospects].
PMID- 10786194
TI - [Preclinical pharmacology and clinical uses of topotecan].
AB - Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific
inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in
vitro and in vivo on tumoral cell lines as well as on endothelial cells.
Moreover, topotecan is able to interfere with the development of blood vessels in
many in vivo experimental models. During the last years, several phase I clinical
studies have demonstrated that the five-daily schedule is the most effective for
the treatment of neoplastic diseases of children and adults. In particular, the
best clinical results have been obtained in patients affected by metastatic
ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as
well as mammary and gastrointestinal neoplasms. High response rates have been
observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of
topotecan has been also demonstrated in ovarian carcinoma, even after failure of
first or second line chemotherapy and in SCLC, where the response rate is 39%,
while the percentage decreases up to 7% in case of drug resistance, with a median
survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and
manageable, and the most frequent and severe toxicity is represented by
myelosuppression. Leukopenia and neutropenia, which follow the administration of
topotecan, are non-cumulative and self-limiting and unfrequently complicated by
infections, whereas non-hematologic toxicities are uncommon and generally of mild
to-moderate degree. Topotecan is under continuous clinical evaluation for the
treatment of neoplasms other than those reported above, alone or in combination
with antineoplastic drugs in poly-chemotherapeutic protocols.
PMID- 10786195
TI - [Topotecan: prospects for using it in combination therapy for ovarian carcinoma].
AB - Topotecan is a semi-synthetic, water soluble topoisomerase I inhibitor which has
recently been approved for the treatment of ovarian cancers after failure of
first-line therapy. A number of different dosing schedules are being investigated
in clinical trials including oral administration, a daily infusion on 5- or 3
consecutive days and a continuous infusion for 21 days. A 30-minute infusion of
topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks, as standard schedule,
produced response rates of 13.8 to 20.5% in the 3 largest phase II/III studies in
women with advanced ovarian cancers who had either failed to respond or had
relapsed after an initial response to platinum-based chemotherapy (N = 92 to
139), continuous 21-day infusion of topotecan 0.3 to 0.5 mg/m2 has shown efficacy
in 2 small phase II studies. There were no statistically significant difference
in efficacy between topotecan (1.5 mg/m2/day for 5 consecutive days every 21
days) and paclitaxel (175 mg/m2/day given over 3-h every 21 days) in the
randomized phase III study. In 3 large clinical trials, response to topotecan was
higher in patients who were platinum sensitive (19.2 to 29%) than in those whose
disease was platinum resistant or refractory (11.3 to 13.3%) not statistically
significant in 1 study, statistical analysis not reported in the other 2 trials.
Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of
topotecan. It is reversible, dose-related and non-cumulative. In 2 large studies,
topotecan produced grade 4 neutropenia in 78 and 79% of patients and in 40 and
37% of all treatment courses (febrile neutropenia occurred during 3% of 552
courses in 1 study). Grade 4 thrombocytopenia was seen in 18 and 25% of patients
and in 6 and 10% of all courses, respectively. Grade 4 neutropenia was
significantly more common in patients receiving topotecan than in those receiving
paclitaxel (79 vs 23%), as was grade 4 thrombocytopenia (25 vs 2%), in a single
randomized clinical trial. Non-hematological adverse events during topotecan
therapy were mostly mild. A step beyond is the combination treatment including
topotecan as a 3- or 5 days schedule plus a platinum compounds or topoisomerase
II inhibitor. These associations of drugs are based on the preclinical data of
the in vitro studies showing a synergy of the anti-tumor activity. A novel
schedule of topotecan is also the "alternating" chemotherapy consisting of
different doublet of drugs given as a sequential way or as a really sequential
topotecan therapy. Both methods of combining topotecan as second/salvage
treatment or front line therapy are being investigated by numerous authors.
Preliminary data suggest interesting results in terms of efficacy, manageable
toxicity and new schedules of treatment for topotecan. Low dosages of drug in
combination with other agent do not seem to influence the well-known data of
efficacy or safety of topotecan literature. Probably the 3-day schedule allows a
combination treatment, otherwise not feasible with the standard 5-day
administration.
PMID- 10786196
TI - [Topotecan, a recent discovery and prospects for treating tumors of the lung].
AB - Topotecan is a new active drug in the treatment of lung cancer. In advanced non
small cell lung cancer (NSCLC) it showed 0-15% of objective response (OR) with
15% in the largest phase II study performed on 40 patients at the M.D. Anderson
Cancer Center. Interesting results have been reported in combination chemotherapy
with new drugs, in particular with gemcitabine. However, the role of topotecan in
NSCLC must be developed in further trials. Topotecan is one of the most active
drug in small cell lung cancer (SCLC). Particularly, it showed active in
sensitive pretreated patients with 14%-38% OR. In a phase III randomized trial
performed in pretreated patients, single agent topotecan showed similar OR and
survival but better palliative effect compared to the CAV regimen
(cyclophosphamide + adryamicin + vincristine). In first line chemotherapy
topotecan showed 39% OR as single agent. Interesting results have been showed in
combination chemotherapy in particular with taxol. Several studies are ongoing.
Topotecan as first line chemotherapy could be developed in old doublet
combinations (such as cisplatin or carboplatin + topotecan), new doublet
combinations (such as taxol or vinorelbine or gemcitabine + topotecan), triplet
chemotherapy combinations (such as cisplatin or carboplatin + taxol + topotecan)
and sequential or alternate chemotherapy regimens. Topotecan reaches high drug
concentration in the brain. It showed activity in brain metastases of SCLC with
40%-63% OR and 13%-43% of complete response in pretreated patients. This
particular activity could be considered in first line chemotherapy as prophylaxis
of brain metastases or to treat patients with brain metastases at diagnosis. Oral
topotecan is a very interesting drug. It showed 36% OR in outfit untreated SCLC
patients and 23% in pretreated patients, respectively. Oral formulation seems to
induce less toxicity when compared to the intravenous drug. In the future
topotecan should be developed as first line combined radio-chemotherapy treatment
to make the best of its radiosensitizer effect. The activity on brain metastases
also must be developed. Oral formulation is interesting because it is less toxic
and could be considered in less toxic regimens in particular in outfit or elderly
patients. However in the next years the role of topotecan will be better defined
performing phase III randomized trials.
PMID- 10786197
TI - [Topotecan: a new field of use].
AB - Topotecan, a semi-synthetic derivative of the alkaloid camptothecin is an
antitumor drug that like other camptothecin derivatives, targets DNA
topoisomerase I, an enzyme that is present in cells in concentration relatively
independent of the stage in the cell cycle. Topotecan stabilizes the complex
formed between topoisomerase I and DNA, leading to DNA strand breakage and cell
death. In accordance with preclinical studies, clinical efficacy of topotecan was
documented in ovarian carcinoma, in small cell lung cancer and in childhood solid
tumors. Myelosuppression is the dose-limiting toxicity and nonhematologic side
effects are generally mild. The activity of topotecan against a number of
hematological malignancies is now increasingly exploited as well as its role in
high-dose chemotherapy programs with stem cell support. In both lymphoblastic and
myeloid acute leukemias, topotecan has been widely utilised both as single agent
or associated to other cytostatic drugs with proven efficacy in these diseases.
Most of the published phase II studies demonstrated that heavily pre-treated,
relapsing patients achieve a high percentage of overall responses with manageable
toxicity. In myelodisplastic syndromes and acute myelomonocitic leukemias a
recently published study shows positive results for the combination of topotecan
and cytarabin. Topotecan seems to preferentially affect the abnormal cytogenetic
clones and in patients achieving a complete response, a conversion from an
aneuploid to a diploid karyotipe was documented. In non-Hodgkin lymphomas,
several schedules have been tested in the phase I setting. When utilized alone
and at very low dosage, the drug yielded 15% of objective responses and a lack of
extrahematologic toxicity. Of particular interest seems to be the association of
topotecan with taxanes that needs to be supported by growth factors. In multiple
myeloma Topotecan has been utilized as single agent in heavily pre-treated
patients. The obtained results show good activity and again myelosuppression as
preminent toxicity. The use of topotecan in high-dose chemotherapy regimens for
multiple myeloma has been proposed. The utilization of topotecan in high-dose
chemotherapy is one of the newer and more interesting applications. Solid tumors
(i.e. ovarian cancer and small cell lung cancer) are actually investigated by
many authors, who have indicated that this drug can be used preferentially as a
part of diversified programs containing overlimit dosages of different
cytostatics. Furthermore, topotecan demonstrated to be an effective drug to
mobilize CD34+ cells for autografting. A general conclusion is that topotecan is
an interesting addition to the actual chemotherapy scenario, both because of its
mechanism of action and its toxicity profile. The present review of the new
possibility of utilization, give us the idea that topotecan has activity in
several hematologic neoplasias; further investigations in these diseases (i.e.,
induction treatment, combination chemotherapy) are then warranted. The broad
spectrum of antitumor activity and the characteristics of toxicity make it also
interesting for use in both the circulating progenitor cell mobilization and in
the consolidation phase of high-dose chemotherapy programs.
PMID- 10786198
TI - Algorithm for assessment of the oxygen, acid-base and electrolyte status (ALBOA
BEACH).
AB - To achieve accurate interpretation of blood gas analysis data in intensive care
units, the oxygen, acid-base and electrolyte-metabolite profile of arterial blood
should be comprehensively and adequately monitored and assessed. A number of
diagnostic software programmes have been developed to assist clinicians in this
and to help improve instruction in this field. In the present study we describe
an algorithm and a programme for assessment of the oxygen, acid-base and
electrolyte status of the arterial blood. The algorithm, as well as the software
programme, is named ALBOA BEACH, which is an acronym of the programme's full name
-ALgorithm for Blood Oxygen, Acid-Base, Electrolyte And respective CHarts. The
algorithm takes account of the latest achievements in blood-gas analysis; it can
be used both in on-line and off-line modes and is useful in the laboratory and
pathophysiological assessment of blood-gas disorders. The algorithm is based on a
rigorous pathophysiological analysis and the interpretation achieved as a result
is much more accurate than usual. Thus it provides a most reliable basis for
taking the right clinical decision and making the proper prognosis of the
possible critical conditions. The algorithm also provides additional bases for
interpretations of data in the borderline zones, with due warnings in cases of
absence of physiological coherence between the various parameters and modules.
The programme is designed to be used with the modern multifunctional blood-gas
analysers; it can be of assistance in making diagnoses, in the training and
research activity in the intensive care units and specialised blood gas
laboratories.
PMID- 10786199
TI - Comprehensive assessment of ventilatory functions of patients with chronic heart
failure.
AB - OBJECTIVE: A comprehensive assessment of the ventilatory functions of patients
with chronic heart failure (CHF) both at rest and during a cardiopulmonary
exercise test (CPET). We studied 42 males, divided into two groups--patients with
CHF (n = 21) and age, weight, height and BMI matched healthy controls (n = 21).
All subjects underwent a symptom-limited ramp CPET, arterial blood gas analysis,
and complex functional examination of the pulmonary system. Subjective rating of
dyspnea and exertion were measured by the Borg and ATS dyspnea scales. CHF
patients showed a slight, but statistically significant decrease of the
spirographic and diffusion parameters, as well as of the indices of respiratory
muscle strength. There were no changes in blood gases and in tidal breathing
parameters. The exercise capacity was markedly reduced (VO2peak ml.min-1 1352 +/-
335 CHF patients vs 2077 +/- 276 healthy controls; p < 0.001) and the anaerobic
threshold occurred earlier (< 40% of predicted VO2peak) during CPET in CHF
patients. The increase in VE/VCO2 in CHF patients (35.7 +/- 5.1 CHF; 28.9 +/- 2.5
HC, p < 0.001) indicates a compromised ventilatory efficiency which leads to a
higher dyspneic cost of exercise (Borg peak 9.5 +/- 1.03 CHF; 6.0 +/- 1.28 HC; p
< 0.001) as compared with healthy controls.
PMID- 10786200
TI - Plasma levels of branched chain amino acids in patients on regular hemodialysis
before and after including a high-protein supplement in their diet.
AB - Chronic renal failure (CRF) patients on hemodialysis have low plasma level of the
branched chain amino acids (BCAA) leucine, isoleucine, and valine. The
abnormalities in the plasma amino acid pool can be corrected with appropriate
high-protein supplements. The present study was designed to evaluate the effect
of a balanced protein nutritional supplement on the plasma level of BCAA. Twenty
eight CRF patients who received hemodialysis treatment three times in a week were
enrolled in the trial. The initial plasma levels of BCAA were as follows--leucine
15.46 +/- 3.88 mcg/ml, isoleucine 9.08 +/- 1.97 mcg/ml, and valine 24.05 +/- 5.06
mcg/ml. For a period of 6 months the patients received a balanced nutritional
supplement (58-59% total protein content, leucine--8.6, isoleucine--4.8, and
valine--5.7 g/100 g protein) on the day of hemodialysis at a dose 1.0 g/kg body
weight. Three months after beginning of supplementation the plasma level of BCAA
was found to be elevated--leucine by 36% (P < 0.001), valine by 30% (P < 0.001),
and isoleucine by 27% (P < 0.001). The body mass index of the patients was also
above the initial values. The plasma BCAA levels were maintained high until the
sixth month from the beginning of trial and even a month after withdrawal of the
supplement. The results obtained allow us to recommend inclusion of protein
supplements with balanced amino acid content in the diet of these patients.
PMID- 10786201
TI - Metabolic changes in children with severe traumatic injuries.
AB - INTRODUCTION: Combined traumatic injuries are the leading cause for more than
half the cases of lethal outcome in childhood. Trauma triggers a series of
endocrinic and metabolic changes commonly known as acute metabolic stress. The
hypermetabolic and hypercatabolic condition which develops as a result
contributes to the high morbidity and mortality rates in children with traumatic
injuries. METHODS: Twenty five children (16 boys and 9 girls aged 4-15 years)
were recruited from the patients admitted for treatment to the Department of
Pediatric Anesthesia and Intensive Care at the Clinic of Pediatric Surgery in the
Higher Medical Institute--Plovdiv, between 1994 and 1998. All children had severe
combined trauma. Of these 20 (80%) presented with severe craniocerebral trauma;
they were comatose with Glasgow Coma Scale Score of 7.3 +/- 4.3 (Sx = 3.59); the
children were on mechanical ventilation and total parenteral nutrition. Energy
expenditure was measured using computerised metabolic monitor Deltatrac II. VO2,
VCO2, RQ, energy expenditure (MEE), oxygen consumption and nitrogen excretion
levels were monitored. RESULTS: The mean energy expenditure measured during the
first, second and third 24-hour period was 50.04 kcal/kg/d-1, 50.54 kcal/kg/d-1
and 51.38 kcal/kg/d-1, respectively; the respiratory quotient was 0.81 +/- 0.0114
Sd, the oxygen consumption index 7.32 +/- 0.08 Sd ml/min/m2. The energy
expenditure calculated by the Fleisch formula was 42.38 +/- 1.24 kcal/kg/d-1, (Sx
= 6.19); this value differed statistically significantly from the value we
measured (50.63 +/- 1.31, Sx = 6.57, p < 0.0001), the injury correction factor
(ICF) was calculated to be 1.22 +/- 0.02 Sd. CONCLUSIONS: Actual energy
expenditure in children with severe traumatic injuries is considerably higher
than that calculated by formulae. Based on our results we recommend that the
energy and substrate intake to be increased above the values calculated by
formulae by a coefficient of 1.22 which is the measured correction factor. Thus
the increased energy requirements will be met and the patients' prognosis will be
improved.
PMID- 10786202
TI - Our experience in the treatment of acute Amanita phalloides poisoning.
AB - INTRODUCTION: The present study aimed at investigating phalloid mushroom
poisoning and the toxicological aid services in Plovdiv region as this pathology
shows in this country high mortality rate (40-100%) and increasing incidence; it
is difficult to diagnose and is far from featuring adequately in the literature
in our country. MATERIAL AND METHODS: A caseload of 270 patients with mushroom
poisoning from Plovdiv region, Bulgaria, admitted for treatment to the Clinic of
Toxicology, Higher Medical Institute, Plovdiv, for the period 1991-1998 was
studied. Of these 270 patients 25 (9.26%) had an acute phalloid poisoning. The
following indicators were registered: gender, age, reported type of consumed
mushrooms, time of appearance of the first complaints after the mushroom
consumption, time of medical aid, disease outcome. The diagnosis and the applied
treatment was based on our own diagnostic-therapeutic protocol for phalloid
intoxication. RESULTS: All phalloid poisoning cases were accidental by character.
The most frequently reported type of ingested mushroom was unidentified wild
edible mushrooms. Of all the patients males were 56%, females--44% with mean age
of 47.71 years (SD = 17.53). From 25 phalloid poisoning cases 15 survived (60%),
10 died (40%). The summer-fall seasonal pattern of phalloid poisoning occurrence
was apparent. The mean duration of the latency period was 12 hours (SD--6.66). In
4 (16%) patients the disease exhibited an unusually early onset--up to 2 hours
after the mushroom ingestion. The mean time period from the mushroom ingestion to
the presentation in a medical institution for first medical aid was 32 hours (SD-
21.69), for men--27.59 hours, for women--43.75 hours. Almost one third (32%) of
the diseased presented for medical help more than 36 hours after the poisoning.
CONCLUSIONS: The acute mushroom poisoning cases in adults comprise 7.01% of the
total acute poisoning caseload. The phalloid poisoning accounts for 9.26% of the
total number of patients with mushroom poisoning admitted for treatment. The
application of contemporary diagnostic-therapeutic protocol lowers the hospital
lethality rate from phalloid poisoning to 40%. There were no statistically
significant differences in the compared parameters between the subgroups of
patients with favorable and lethal outcome and between the subgroups of men and
women--most probably due to the small sample. In order to lower the incidence and
mortality rate from phalloid mushroom poisoning the authors recommend preventive
health education on the problem, targeting the population at risk and the
introduction of contemporary diagnostic and treatment methods--determining the
amatoxins, intravenous application of Silibinin and liver transplantation.
PMID- 10786203
TI - Trends in the incidence of colorectal carcinoma in three regions of south
Bulgaria for the period 1985-1998.
AB - The purpose of the present study was to evaluate the increase of colorectal
carcinoma incidence in three regions of South Bulgaria (a total population of
1,269,464 persons) over a 14-year period (1985-1998). The data about the
incidence rate are retrieved from the oncological hospital records of the
patients and Bulgarian National Oncological Register. The census data are
provided by the National Institute of Statistics, Sofia. The results show that
the incidence rate of colorectal carcinoma for the studied period increased
steadily from 22.14/100,000 to 37.18/100,000 (an increment of 15.04/100,000)
which is almost twice the average for the country. Compared to the baseline year
of 1985 the increase in these three regions is 67.93% or approximately 5%
annually. The incidence rate in Plovdiv region was almost twice that of Smolyan
region. The incidence rate of colorectal carcinoma in both genders was greater
than that of stomach cancer. The highest incidence rate was found in the 70-79
year-age group (193.5/100,000). A major part of our study was to find the stage
in which colorectal carcinoma (CRC) is detected. In 1985 only 0.57% of the
patients were diagnosed as being in the I-st clinical stage, 37.76%--in the II
nd, and 61.67%--in III-IV clinical stages. This unfavorable trend was preserved
in 1998, when only 3.17% were diagnosed as having the first clinical stage,
38.62%--the II-nd and 58.21%--the III-IV clinical stages. The 14-year pronounced
trend of increase of the prevalence rate (a 2.91 times increment) and the
mortality rate (a 2.50 times increment) of colorectal carcinoma is especially
alarming. We propose screening of the asymptomatic patients and high-risk persons
which gives considerable results in the timely diagnostics of colorectal
carcinoma.
PMID- 10786205
TI - Immunocytochemical expression of p75LNGFR and trkA in Leydig cells of the human
testis.
AB - The authors demonstrate for the first time the immunocytochemical expression of
the low-affinity neurotrophic growth factor (NGF) receptor p75LNGFR and the high
affinity NGF receptor trkA in the human testis. Employing the polyclonal anti
p75LNGFR antibody and the polyclonal anti-trkA antibody they report strong
immunoreactivity for those antigens in the interstitial Leydig cells. Sertoli
cells and some cellular elements of the germinative epithelium were also trkA
positive. These findings implicate the neurotrophic factor NGF and its receptors
p75LNGFR and trkA in the autocrine and paracrine regulation of the steroidogenic
activity of Leydig cells of the human testis.
PMID- 10786206
TI - Frequency and clinical characteristics of mycoplasma urinary tract infections in
the early post-transplantation period in renal allograft patients.
AB - Using a highly sensitive and specific polymerase chain reaction (PCR) protocol,
we studied 36 renal allograft recipients and 30 healthy controls. Midstream urine
samples were analyzed using routine microbiological methods and the Mycoplasma
IST (BioMerieux, France). Mycoplasma infections of the upper urinary tract were
found in 9 patients. In three of them E.coli and Proteus were also present. We
discuss the clinical characteristics of mycoplasma infections in the early post
transplantation period and its possible implications for graft rejection.
PMID- 10786204
TI - Individual results of treatment of COPD with low doses of fenoterol compared with
treatment with ipratropium bromide.
AB - We compared the effects of 30-day treatments with fenoterol in low doses (4 x 100
mcg) and ipratropium bromide (4 x 40 mcg) on the lung function parameters (LFP),
dyspnea and physical capacity of patients with severe chronic obstructive
pulmonary disease (COPD) (FEV1 < 35% pred.) and analysed the individual response
of patients to the administered therapy. The study included two groups of
patients treated with fenoterol (n = 22) and ipratropium bromide (n = 22). The
patients were matched by functional characteristics (age: 60 +/- 7 and 57 +/- 9
years; ATS Dyspnea Scale: 2.7 +/- 0.8 and 2.4 +/- 0.9; FEV1%: 25 +/- 7% and 23 +/
6%; pO2: 62.4 +/- 5.3 mm Hg and 61.0 +/- 9.5 mm Hg; all values mean +/- SD).
After 30 days of treatment we measured the lung function parameters (FEV1, FVC),
dyspnea indices (ATS dyspnea scale, Borg scale) and the physical capacity of the
patients (6-minute walking distance test). The results showed that in an open
experiment fenoterol (4 x 100 mcg daily), unlike ipratropium bromide (4 x 40 mcg
daily), cannot improve statistically and clinically significantly the lung
function parameters, dyspnea and the physical capacity of the group as a whole.
However, when the findings were assessed for each patient individually, 32% of
the patients proved to have responded positively to the treatment. Therefore
efficaciousness of fenoterol in low doses should be determined by assessing the
lung function parameters, dyspnea and the physical capacity individually for each
patient.
PMID- 10786207
TI - Somatotyping of schizophrenic and affective disorder patients.
AB - INTRODUCTION: Constitutional traits have been found to show a distinct relevance
to major psychiatric disorders. Syndromal modified expressivity is also closely
related to somatotypic constitution. In this view somatotyping appears valuable
in diagnosis and prognosis of mental disorders. AIM: The present study was
conducted in an attempt to outline somatotypic characteristics of schizophrenia
and affective disorders with the aim of providing a logical basis for diagnosis
of these major psychiatric disorders. MATERIAL AND METHODS: The somatotype of 54
schizophrenic and 68 affective disorder inpatients who fulfil the DSM-IV criteria
for schizophrenia (subjects with schizophreniform, schizoaffective, schizoid and
schizotypal personality disorders were excluded from the sample) and affective
disorder (bipolar and unipolar) was assessed using the Health-Carter
anthropometric method. RESULTS: The overall assessment of the somatotypes
determined both groups as endomorphs mesomorphs with somatotype components 4.50
4.44-1.90 for schizophrenic patients and 5.87-5.40-0.36 for affective disorder
patients. The difference between the two groups was statistically significant for
any of the somatotype components. CONCLUSION: It is suggested that the
constitutional and somatotypic characterization appears reasonable element in the
multifactorial analysis of diagnostic decisions in these major psychiatric
disorders.
PMID- 10786208
TI - Antifungal prophylaxis with low doses fluconazole in patients with hematological
malignancies.
AB - INTRODUCTION: The incidence of mycotic infections in immunocompromised patients
has reached a 20-fold rise for the last two decades. AIM: The goal of the study
was to evaluate fluconazole efficacy as antifungal prophylaxis in patients with
hematological malignancies. MATERIAL AND METHODS: Sixty nine patients with
hematological malignancies and neutrophil count less than 1.0 x 10(9)/L received
fluconazole orally at a dose of 150 mg every other day. Fluconazole was
discontinued when a neutrophil count above 1.5 x 10(9)/L was maintained. Duration
of neutropenic periods, afebrile cycles, and incidence of mycotic infections were
assessed. The same variables were observed in a control group of 41 patients who
did not receive antifungal prophylactic therapy. RESULTS: Both groups were
similar in the mean duration of neutropenic period but the afebrile cycles in the
patients receiving antifungal prophylaxis were longer by 5 days compared to these
in the patients without prophylaxis. The mycotic infections had lower incidence
in the patients on antifungal prophylaxis and the difference was statistically
significant (p < 0.01). The superficial mycotic infections composed the majority
of the clinically and/or microbiologically verified infections. These were
presented by oropharyngeal infection (61%), esophageal (22%), and single cases of
skin, genital or rectal infections. Candida albicans was isolated in 85% of the
cases. The adverse reactions of fluconazole therapy were mild, transient, and
easily manageable. No signs of liver and renal dysfunction were observed.
CONCLUSION: Lower dose of fluconazole, 150 mg every other day p.o., has the same
antifungal effect as a dose of 200 mg/day p.o. in neutropenic patients with
hematological malignancies which lowers the cost of treatment.
PMID- 10786209
TI - Epidemiologic studies of leptospiroses in the Plovdiv region of Bulgaria.
AB - BACKGROUND: The natural habitat of leptospira along the Maritsa river, the high
level of development of the land-cultivation and cattle-raising underscore the
importance of establishing the exact prevalence of leptospiroses ranking it among
the highest in the country. The changes occurring in the economy and land-making
of the country following 1990 are reflected in the prevalence of leptospiroses
during this period. MATERIAL AND METHODS: We studied 95 patients of the
Infectious Disease Clinic of the Higher Medical Institute of Plovdiv with
serological evidence for leptospirosis for the period 1987-1998. The patients
were analyzed based on the following criteria: morbidity, age, gender, season,
etiologic structure, mechanism and factors for the transmission of disease etc.
RESULTS: The morbidity rate of Leptospira has shown a clear tendency towards
increase since 1992. In terms of etiology L. pomona ranked first accounting for
44.22% of the cases as compared with the prevalence of L. tsalapitsa--22.10%. The
isolation rates of those who had been infected during contact with animals (swine
predominantly) was 40.44%, during plant watering--38.95%, and 17.89% resulted
from bathing in the Maritsa river or its tributaries. Patients in the high-risk
groups were characteristically 20-39 years old, cattle-raisers, fishermen, land
workers. The highest number of registered cases occurred in July through August.
CONCLUSIONS: Based on these results from the epidemiologic study effective
measures aimed at the reservoir, mechanism of transmission of the infection and
the risk groups can be implemented so that the epidemiologic and epizootic
control of leptospiroses can be improved.
PMID- 10786210
TI - A rare case of fibrosarcoma of the inferior vena cava expanding into the right
atrium.
AB - The authors report in detail a case of fibrosarcoma of the inferior vena cava. A
53-year-old female presented with echographic and computed tomographic evidence
of a solid formation in the porta hepatis that fused with the inferior vena cava.
Because of appearance and rapid development of symptoms of right cardiac failure,
the patient was transferred to the Clinic of Cardiac Surgery and underwent an
emergency operation. A solid formation arising from the inferior vena cava and
expanding into the right atrium was found during the operation. The operation
performed was not a radical one. Fibrosarcoma of the inferior vena cava was
proved on histological examination. A single therapeutic course with vincristine
and farmorubicin was administered. The patient died from recurrence of the
malignancy 26 months after the operation. The epidemiologic, diagnostic, and
therapeutic aspects of the case are discussed in relation with the literature
data.
PMID- 10786211
TI - [Deformation and mutability of family and society picture in paranoid
schizophrenia].
AB - The aim of the study was to show how the frequency of special subjects of
delusions and hallucinations changes in time. A group of 400 in-patients with the
diagnosis of paranoid schizophrenia divided into four equal groups from the years
1932, 1952, 1972 and 1992 was examined. Data were obtained from case histories
from the archives of Neuropsychiatric Hospital in Lubliniec. Results of this
study allowed for establishing the following conclusions: the character of
paranoid picture of a family and a society is hostile, this feature is expressed
mainly in the time after the Second Word War; delusions of jealousy are more
frequent in women and they are more variable than in men--they prevail in the
postwar period.
PMID- 10786212
TI - [The therapy of families of patients suffering from schizophrenia].
AB - The development of pharmacotherapy, social psychiatry and the new patterns of
comprehensive treatment of patients suffering from schizophrenia make most of
psychiatrists believe that hospitalisations should be reduced to minimum. There
has been a change in the roles and tasks of parents and spouses of the patients
during their ambulatory therapy. Apart from outpatient clinics, daily wards, and
hostels, there is a significant role of the therapy of families of the patients
in the posthospital treatment. The patterns of schizophrenia as a disease and the
relating indications concerning basic therapeutic management are of significant
importance. The work presented here discusses two basic therapies of the families
of patients suffering from schizophrenia, namely psychoeducation and systemic
family therapy. The work draws attention to aims, forms and concepts of these
therapies. However, an appropriate pharmacotherapy of patients suffering from
schizophrenia is necessary regardless of their positive response to the families.
PMID- 10786214
TI - [Clozapine treatment: possibilities and limitations].
AB - The purpose of this article--based on the recent years literature--is discussing
the principles of the use of clozapine in schizophrenia, with the special
attention to treatment-resistance as a main indication, dose selection and
duration of the trial. In spite of dynamic development of pharmacotherapy of
schizophrenia, clozapine, registered in Europe 25 years ago, still remains a drug
of choice in treatment-resistant schizophrenia, that is in 5-25% of patients,
bringing a substantial clinical improvement in 30-50% of the group. The main
factor limiting the possibility of the use of clozapine is the increased risk of
neutropenia and agranulocytosis, what demands the WBC monitoring. Old age and
female sex are considered to be potential risk factors. In both classical
neuroleptics and clozapine, no clear linear correlation was noticed between the
dose and clinical effect. It seems, however, that only in case of clozapine a
noticeable correlation exists between the plasma level and clinical improvement.
Many authors try to define a threshold level sufficient/necessary to achieve
improvement. Suggested amounts are between 250-420 ng/ml. With fixed doses used,
extremely different levels of clozapine are observed (from a few, to thousands
ng/ml), so measuring plasma level is suggested as a routine procedure in cases of
clozapine-resistance. The duration of the trial creates real controversy. Most
authors agree that six weeks time, sufficient to diagnose treatment resistance in
case of typical neuroleptics, may be too short for clozapine. At the same time,
the postulated prolongation of the trial to a few months or even one year,
explained by the presence of late improvements, is not well and generally
accepted. It seems that time of 2-4 months is in most cases sufficient to notice
the potential advantage. The problem of clozapine-resistance still remains open.
Many strategies are being proposed (augmentation with lithium, valproate,
sulpiride and benzodiazepines), but they demand further examination.
PMID- 10786213
TI - [Subjective aspects of psychopharmacology in schizophrenia].
AB - The authors discuss the subjective and psychodynamic aspects of pharmacotherapy
in schizophrenia which are important for compliance. A large number of different
factors connected with psychopharmacotherapy are of particular importance when we
consider their impact on compliance. Those factors are psychopathology of
patient's disease, insight, and his her intrapsychic structure as well as the
great number of factors which are based on social and cultural environment of the
patient. One of the most important factors is associated with the patient's
family and the question how the family estimate the changes in the patient's
health under the influence of medication. Other important factors include those
which are rooted in the therapeutic environment of mental health service
institutions and particularly in the therapeutic relationship between the patient
and the treating psychiatrist. Those factors, including transference and counter
transference, may cause specific impact or even distortions ona
farmacotherapeutic action of the antipsychotic drugs. The attempts to classify
this compound area as well as some remarks concerning meaning of psychodynamic
aspects of farmacotherapy for different groups of mental health professionals are
presented in the article. The psychodynamic and subjective factors of
psychopharmacotherapy are seen here as a part of a more complex field of
compliance but also as those which determine a successful therapeutic outcome in
the care of schizophrenic patients.
PMID- 10786215
TI - [Clozapine withdrawal. A review].
AB - The article describes the symptoms of withdrawal of clozapine and their possible
causes as well as research on switching from clozapine to another antipsychotic
drug. A computerised search was conducted using MEDLINE (1966-1997) to retrieve
reports of clozapine withdrawal. Fifteen case reports and sixteen withdrawal
studies (only one of them double-blind and two single-blind) were identified.
Clozapine multi-receptors profile seems to be responsible for withdrawal symptoms
-several specific mechanisms are suggested: cholinergic supersensitivity,
dopaminergic supersensivity, special role of D4 receptors, possibilities of
serotonergic, noradrenergic and GABA-ergic involvement. Risk of relapse after
withdrawal of clozapine seems to be greater than after withdrawal of classical
neuroleptics. Some patients might become de novo neuroleptic resistant for at
least several weeks after withdrawal. Therefore, clozapine should be stopped only
due to strong clinical indications, and if only possible, the withdrawal should
be slow (50 mg/week). To prevent relapse of psychosis some experts advocate
starting new antipsychotic drugs in therapeutic dosage before withdrawal of
clozapine is completed. In case of emergency, when clozapine (high dosage) must
be withdrawn immediately, patient must be hospitalised and cholinergics might be
considered to prevent, cholinergic rebound". There are no established guidelines
which antipsychotic to choose after withdrawal of clozapine. In general,
classical antipsychotics are ineffective. Thioridazine is suggested because of
its prominent anticholinergic activity, but there is no clinical evidence of
advantage of this treatment in comparison to classical drugs. Risperidon and
especially olanzapine are promising possibilities, but initial data are
disappointing. Benzamides might be another possibility but clinical data are
scarce. These important issues require further studies.
PMID- 10786216
TI - [The risk of neuroleptic discontinuation in schizophrenia].
AB - The most effective method to maintain clinical improvement in the course of
schizophrenia is the continuation of neuroleptic therapy. Sometimes we face the
dilemma whether neuroleptic administration could be discontinued. There are some
unconditional indications for treatment cessation (signs of intolerance,
complications, general medical conditions); all other situations can be
considered as relative indications. The risk and benefit of treatment
discontinuation should be carefully evaluated. Neuroleptic withdrawal seems to be
safer among older patients, with single episode of the psychosis of mild
severity, with no family history of schizophrenia. It is necessary to achieve a
stable clinical improvement before neuroleptic withdrawal. Worsening of the
clinical status creates the most important risk of treatment discontinuation.
Other risk factors include unacceptable threatening behavior, increase of family
burden. The appearance of withdrawal symptoms such as nausea, vomiting,
dyskinesia, insomnia, anxiety, etc. are to be considered. These symptoms are
rare, and the risk of relapse is smaller when patients were treated with depot
neuroleptics before treatment discontinuation than in the case of treatment with
oral neuroleptics. Neuroleptic discontinuation and introduction of placebo cause
more risk of relapse than continuation of active treatment.
PMID- 10786217
TI - [Treatment of catatonic syndrome with fluoxetine. Case report].
AB - The case of catatonic syndrome in 34-years old male patient is described. The
patient's initial complaints regarded somatic distress. Previously, because of
persistence of somatic complaints and depressed mood, the patient was treated
with classic antidepressants with no clinical effect. Consequently, before
admission to our clinic, the patient received neuroleptic treatment without any
improvement. To our clinic he was referred as drug-resistant schizoaffective
psychosis. He was completely inactive, had hipochondriac delusions and blunted
affect. Further on, severe psychomotor inhibition and negativism prevailed.
Initial treatment with fluphenazine did not bring any clinical effect. Because of
presence of depressed mood and lack of activity, fluoxetine was administered
concomitantly with fluphenazine. After 8 weeks administration of fluoxetine 20 mg
daily showed substantial clinical improvement, especially in regard to the
patient's mood and activity. The dose of fluoxetine was increased to 40 mg daily,
and the patient was discharged from the clinic. The follow-up revealed that the
patient reassumed his professional career. He was still on fluoxetine 20 mg daily
and showed substantial clinical improvement. His overall tolerance of fluoxetine
20-40 mg daily was very good.
PMID- 10786218
TI - [CYP2D6 gene polymorphism in psychiatric patients resistant to standard
pharmacotherapy].
AB - The debrisoquine polymorphism is a genetic variation in oxidative drug metabolism
mediated by CYP2D6 gene, characterized by two phenotypes, the extensive
metabolizer (EM) and poor metabolizer (PM). PM phenotype is inherited as
autosomal recessive trait and occurs in 5-10% of Caucasian population. It is
associated with the inefficient metabolism of over 30 drugs, including many
psychotropic drugs. Clinical studies shown that PM are at higher risk than EM of
adverse reactions to these drugs. We genotyped 22 psychiatric patients in whom
standard pharmacotherapy had failed or drug adverse events occurred and in 14
patients in whom standard therapy was successful. CYP2D6 polymorphic alleles were
identified using allele specific nested PCR reaction. The PM genotype was found
in 4 of 22 (18%) patients resistant to standard pharmacotherapy and in none of 14
patients with improvement after standard therapy. Unsuccessful standard
psychotropic drugs therapy in psychiatric patients may be associated with PM
phenotype.
PMID- 10786219
TI - [Cortical atrophy in computerized tomography of the brain and clinical
characteristics of schizophrenia].
AB - The aim of this paper was searching for correlates of cortical atrophy in
schizophrenia. Schizophrenic patients with cortical prefrontal atrophy had more
negative symptoms than patients with generalized cortical atrophy and patients
without cortical atrophy (the difference was not statistically significant). They
also had less positive symptoms than patients without atrophy (the difference was
statistically significant) and patients with generalized cortical atrophy.
PMID- 10786220
TI - [A moment of reflection: dramatic path of Polish psychiatry].
AB - In the inauguration speech of the Congress stages of the path taken by the Polish
Psychiatric Society were described in short: 1--The period from its establishment
till 1939; 2--Tragic years of the war, 1939-1945, with extermination of ca.
20,000 patients and many psychiatrists; 3--Reconstruction after the war,
accompanied by the attempts to impose Soviet ideology, which induced finally
effective resistance and intense development of the science and practice.
PMID- 10786221
TI - [Polish paranoia].
AB - The article describes clinical experience with patients suffering from paranoid
states during adaptation to new country and culture. The complex of symptoms in
polish immigrants was called polish paranoia. It is a pathological way of coping,
resulting from new culture, ignorance of language, irrational expectations of
emigration profits. We think that reasons of this syndrome are polish nation
experiences, one's own history and family history.
PMID- 10786222
TI - [Medical student curriculum in psychiatry in Poland].
AB - The author describes present medical student curricula in psychiatry in Polish
medical schools based on the questionnaire sent to all the lecturers of the
subject in Poland. The questionnaire contained questions concerning the schedule
of lectures, seminars and classes (the list of topics) as well as the number of
hours of the forms of activities like interpersonal training, discussion groups,
internship, etc. We also asked on which year of studies the course in psychiatry
took place. The questionnaire included our request to describe the level of
integration of psychiatry and other pre-clinical and clinical subjects as well as
to enclose a recommended reading list (handbooks and other items of literature).
The last question dealt with the problem of assessment of lectures and classes by
students. The results of the questionnaire reveal great differences in the
curricula of psychiatry in various schools in Poland. The differences lie both in
the courses and the number of hours devoted to teaching psychiatry (in most
schools it was 120 hours or less). In 7 schools students learn psychiatry in the
6th i.e. the last year of their studies. In 2 schools lectures in psychiatry are
given in the th year. In Krakow and Gdansk the courses in psychiatry consist of
150 and 160 hours respectively. The author proposes unification of the curricula
in psychiatry concerning both the number of hours of classes and lectures, and
topics as well as introducing the diagnostic and classifying criteria ICD-10
(WHO) since Poland is going to join EU.
PMID- 10786223
TI - [Psychiatry in undergraduate training of physicians in Poland. Ideas and
reality].
AB - History of undergraduate training in psychiatry at medical schools in Poland was
briefly reviewed showing a traditional independence of chairpersons of psychiatry
in forming programmes and deciding about forms of education. Since 1990 this
independence has been controlled by the faculties and, to some extent only,
regulated by the national curriculum in medicine. Goals, contents and forms of
undergraduate training in psychiatry were examined (following Bilikiewicz's study
in 1994) with the author's own questionnaire. Professors of psychiatry,
respondents to the questionnaire were of very similar opinions in regard to the
goals of training. At the same time, meaningful differences were found in the
methods used, position of the subject in the curriculum and even time designed
for psychiatry training (at some schools below the national minimum). There were
also significant differences in the contents of the programme. The most important
problem seems to be absence of child and adolescent psychiatry at some schools.
Integration of psychiatry with other pre-clinical and clinical subjects was
assessed too. The information received suggests that Polish professors of
psychiatry approved of the way their subject had been integrated with others.
This seems to be overestimation, especially if compared with the Krakow
experience presented in a more detailed way.
PMID- 10786224
TI - [CDT (desialylated transferrin)--a new biochemical marker of alcohol abuse].
AB - Serum concentration of carbohydrate-deficient transferrin (CDT) is used for
laboratory diagnosis of chronic alcohol abuse. Several earlier studies reported
sensitivities of 90% or above for CDT, with a specificity of 90-100%, although
other investigators found lower sensitivities. In general, CDT has been reported
to be highly specific (92%) and relatively sensitive (80%) for the detection and
monitoring of alcoholism. There are no correlation between CDT concentration and
gamma-GT activity. Any alteration in serum total transferrin concentration
markedly decreases the CDT assay specificity. This should be considered when
interpreting the assay results in patients with elevated serum transferrin. There
are differences between the CDT isoforms (asialo-Tf and monosialo-Tf) in males
and females relative to alcohol consumption. Alcohol consumption increases the
levels of asialo-Tf and monosialo-Tf in women more strongly than in men.
Sensitivity of CDT assay is also related to age of patients. There is a
significantly higher sensitivity of CDT in patients above 40 years of age as
compared to younger patients. The measurement of carbohydrate-deficient
transferrin may be used as a marker of excessive alcohol abuse in patients with
liver diseases (also in cirrhosis). The specificity of CDT in patients with non
alcoholic liver disease was consistently higher than that of gamma-GT (80% vs
60%). Disulfiram therapy during detoxification does not influence the serum level
of CDT.
PMID- 10786225
TI - [Evaluation of psychomotor agility during the period of withdrawal symptom
dissipation in patients with alcohol dependence type 1 and 2 or Cloninger's].
AB - 28 alcohol dependent men were examined three times (on the 1st, 3rd or 4th and
7th day of withdrawal). The results confirmed the reported differences in the
course of withdrawal syndrome in type 1 and type 2 alcoholics. Patients with type
2 alcoholism had more pronounced psychophysiological and cognitive disturbances.
Tremor was more intensive in these patients and their reaction time was slower.
Also, impaired estimation of passing time lasted longer, but at the same time
their mood improved faster with the diminished intensity of withdrawal symptoms
than in patients with type 1 alcoholism. The results confirm the possibility of
diverse etiology in alcohol dependence.
PMID- 10786227
TI - [Interesting case of alcoholic psychotic disorder].
AB - In the paper a case of psychotic disorder connected with alcohol abuse is
presented. It is interesting because of its abundant symptomatology,
classification and typical chronology of events. Worth mentioning is also
coexistence of events that unambiguously show psychotic disorders comorbid with
those, which may be properly assessed only after objective data are obtained.
Case description is provided with appropriate comments.
PMID- 10786226
TI - [Use of urinary beta-hexosaminidase for diagnosing alcoholism in persons with
opiate dependency in a methadone substitution program].
AB - Usefulness of urinary beta-hexosaminidase determinations in patients on methadone
substitution to pinpoint cases of alcohol abuse was studied. It was found that
methadone, illegal drugs and HIV seropositivity had no effect upon the activity
of this enzyme. The enzyme activity was significantly higher in patients who
admitted to occasional heavy drinking than in those who declared abstinence (p =
0.014), and in healthy controls (p = 5*10(-8)), but still lower than in alcohol
dependent persons undergoing detoxification (p = 0.024). In the group of opiate
dependent persons in methadone substitution program the sensitivity of the test
was 87% and the specificity--80%.
PMID- 10786228
TI - [Psychoimmunology and disease based on certain research results].
AB - The paper presents the results of researches in psychoimmunology. This new
science creates an integrated model of man, and immunologic, endocrinological or
nervous systems are very closely connected with personality. The findings show
that health or disease depend on complex, psychophysiological mechanisms. Factors
very important for health are: genetic factor, personality, stress and coping,
economic and social situation, work, family, etc. The immunity unites with
personality, thinking, attitudes, emotions, whose kind, strength and adjustment
depend on the sense of coherence.
PMID- 10786229
TI - [Neuroborreliosis: a psychiatric problem?].
AB - The authors review the literature concerning clinical characteristics of
neuroborreliosis with special focus on mental disorders. The patients develop
mental disorders during the acute phase of the disease and even after several
years. These disorders are often accompanied with various neurological syndromes.
The authors discuss the most common mental disorders connected with
neuroborreliosis: encephalopathy, cognitive disorders, dementia, depression,
anxiety disorders. The paper describes the problem of neuroborreliosis in
psychiatry, especially in the endemic regions.
PMID- 10786230
TI - [Legal obligation to outpatient psychiatric treatment of mentally ill
perpetrators of crimes: necessity or restriction of liberty?].
AB - Considerations, concerning legal obligation to psychiatric treatment in case of
criminal offenders declared as insane by court, are presented in the paper.
Necessity of some changes in the legal system is pointed out. It is suggested
that, after preventive measures in the form of compulsory psychiatric
hospitalization, there should be a possibility of enforced out-patient treatment.
This should apply to persons who committed serious crimes (e.g. murder).
Suggestions contained in the paper are illustrated by a description of a
meaningful clinical case.
PMID- 10786231
TI - [Disturbances in interpersonal functioning and levels of anxiety, depression and
aggression in persons persecuted for political reasons in Poland in the years
1944-1956].
AB - The article presents the results of comparison of 30 victims of political
persecution in Poland in the years 1944-1956 (with a diagnosis of PTSD) with a
control group in regard to the styles of interpersonal functioning, anxiety,
depression and aggression. The examined persons manifest changes in the quality
of social contacts--increased results on the scales of hostility syndrome,
helplessness, and appeal for help, and decreased results on the scales examining
pro-social tendencies. The examined persons are characterized by low affiliation,
high level of indifference as well as features developed on the ground of
anxiety: lack of self-acceptance, suspiciousness, aggression and negative self
evaluation in comparison with others. They are also characterized by high level
of depression, readiness to react with fear or anxiety as the actual state during
examination. These categories determine the psychological results of injuries
suffered by the examined persons in the past.
PMID- 10786232
TI - [To cast a spell on reality. On actions of Soviet authorities in connection with
the 6th Congress of the World Psychiatric Association at Honolulu].
AB - At the 6th Congress of the World Psychiatric Association, held at Honolulu in
August 1977, its participants accepted by acclamation a--so called--"Hawaiian
Declaration" and a Resolution of the Royal College of Psychiatrists. The
Declaration condemned all kinds of abuse in psychiatry, and the Resolution
condemned the abuses in the Soviet psychiatry in particular. The Congress of
Honolulu carried out, at last, the action initiated at the Congress of Mexico
City six years earlier. But by then there was a lack of courage yet to take these
measures, and the counter-action of the Soviet authorities proved to be
effective. Aware of the fact that this time the pressure to condemn the misuses
practiced in the Soviet psychiatry would be ever stronger, the KGB and the
Ministry of Health of the USSR began their "preparations" for the next Congress
as early as in 1976. This article describes the tactics of action promoted by the
Soviet authorities in order to prevent the condemnation. The Author made a proper
use of some documents that he had recovered at the Moscow "Centre for Storing the
Contemporary Archives".
PMID- 10786234
TI - [The prevalence of dementia in old age].
AB - The risk of manifestation of dementia increases as the population grows older.
The prevalence of dementia increases from 0.7% in age group 60-64 years to 38.8%
in age group 90-94 years. Over 60, the prevalence rate doubles every 5.1 years.
The most common types of dementia are Alzheimer's dementia and vascular dementia.
PMID- 10786233
TI - [Trials and perspectives in pharmacotherapy of Alzheimer's disease].
AB - The paper discusses therapeutical approaches to Alzheimer's disease on the basis
of pathological mechanisms responsible for neurodegeneration. Amyloid plaques
called also senile plaques situated extracellularly cause loss of neurons,
especially cholinergic neurons, that begin in Nucleus of Meynert. However, recent
evidence from postmortem brain and fibroblast studies suggests that both adenylyl
cyclase and phosphatidylinositol hydrolysis signal transduction cascades are
disrupted in AD. Such disruption may limit cholinergic pharmacotherapy. Other
disorders, like disturbances in releasing Neuronal Growth Factor (NGF), oxidative
stress, free Ca 2+, neuroimmunologic reactions are also important in AD brain
changer. Only use of acetylcholine inhibitors: tacrine, donepezil and Gingko
Biloba as well as nimodipine improved mental functions (MMSE screening).
Neuroprotection of selegiline and NGF was observed. Behavioral symptoms often
associated with dementia, like depression, anxiety, irritability, delusions,
aggressiveness were treated with: olazepine, risperidone, haloperidol, clozapine,
fluoxetine, paroxetine, sertraline, trazodon, dezypramine, lithium,
benzodiazepines, carbamazepine and valproic acid. Drugs with strong
anticholinergic effects, such as amitriptyline or imipramine should not be
administered. Future studies on therapy to regulate metabolism of amyloid
precursor-beta-APP are necessary to discover new efficient strategies.
PMID- 10786235
TI - [The prevalence of dementia in the population of the Warsaw district of Mokotow
from 65 to 84 years of age].
AB - The aim of the two-phase population based study was to estimate the prevalence of
dementia. Among the population aged 65-84 years of the Warsaw district Mokotow,
the stratified sample consisted of 1,000 persons taken randomly. The first
screening phase (MMSE) was conducted by raters among 893 persons. 92 subjects
with disturbances of cognitive functions were qualified to the second-diagnostic
phase and 89 were given a diagnostic examination with the Cambridge Mental
Disorders of the Elderly Examination. The following age-specific prevalences of
dementia were found in the age-groups 65-69, 70-74, 75-79, 80-84: 1.9, 5.8, 8.6
and 16.5% respectively. Rates for vascular dementia (2.7) were higher than those
for dementia of the Alzheimer's type (2.3), mixed dementia (0.5), and secondary
dementia (0.2%). In the younger subgroups (65-74 y), vascular dementia was the
most frequent and in the older subgroups (75-84 y) the most frequent was
Alzheimer's type. The rates of dementia were quite similar to those found in
other European studies.
PMID- 10786236
TI - [Psychiatric rehabilitation in a secure treatment setting].
AB - Working with severely mentally ill persons within the locked environment of a
secure residential treatment facility presents a provocative challenge in
attempting to establish a rehabilitative program. The author describes the
mission, goals and methods of one of Oregon's newly organized facilities for
"hard to place" former state hospital patients. The value of teaching the
residents self-control is emphasized. Clinical vignettes illustrate how the staff
involve the residents in real-life tasks, apply natural consequences to problem
behaviors, and make attempts at minimizing the potential sources of
confrontation.
PMID- 10786237
TI - [Present views on pathogenesis of schizophrenia].
AB - Schizophrenia is recognized as a disorder of complex etiology including
biological and environmental factors. The paper describes, first of all,
biological abnormalities. It uses neurodevelopmental model assuming the existence
of neuropathological process. The process starts in the pre-natal period,
undergoes changes under the influence of developmental factors, and, finally,
manifests itself in psychotic symptoms. Particularly, the author suggests that
diathesis for schizophrenia involves functional excess of dopamine activity in
the basal ganglia. It causes disruption in neuronal circuits, thus releasing
psychotic symptoms. Additionally, the paper describes anatomic changes, neuronal
circuitry malfunctions and impairments in metabolic activity of brain detected in
numerous studies on schizophrenic patients.
PMID- 10786238
TI - [The study of candidates' genes in psychiatric diseases. I. Schizophrenia].
AB - The study concerning the importance of genetic factors in etiopathogenesis of
schizophrenia is presented below. In molecular genetics research there are two
most frequently applied strategies: searching of the whole genome in order to
find new genes; and molecular analysis of a candidate gene. Candidate gene
analysis consist in choosing a gene which could theoretically have a connection
with a given certain disease. The presented reference review includes the results
of study concerning candidate genes analysis referring to biochemical hypothesis
of schizophrenia. The aim of the study is to find changes at the level of
nucleotide sequence in DNA, which have a connection with the disease. It was
stated in many medical centres that in case of schizophrenia the polymorphism of
gene's receptor D3 and gene's receptor 5HT2A can be of etiological importance. It
was also proved that the clinical effect of clozapine could be connected with
polymorphism of gene's receptor 5HT2A.
PMID- 10786239
TI - [Disorders in cognition and language vs. communication deviances in families of
schizophrenics].
AB - This paper shortly reviews the findings of studies about cognitive and language
dysfunctions in schizophrenic patients and their parents. It also presents the
main concepts about communication deficits in families of schizophrenics--double
bind, communication deviance, egocentric communication, disconfirmatory feedback
and some aspects of expressed emotion. The influences and relationships between
cognition, language and communication are emphasised. There are also some
suggestions about the treatment.
PMID- 10786240
TI - [Assessment of ability to transmit and receive information in schizophrenics and
their mothers].
AB - The cloze procedure was used to examine: predictability in speech samples from
schizophrenics and their mothers as well as their ability to gain from the
redundancy of language. Schizophrenic patients were found to be less predictable
than normals, both schizophrenics and their mothers were less able to make use of
the language context than controls did. The impact of disturbances in information
processing on the family interactions was considered.
PMID- 10786241
TI - [Catatonic syndrome and neuroleptic malignant syndrome].
AB - Several clinical reports suggest that neuroleptic malignant syndrome (NMS) is not
a distinct clinical entity but an acute form of catatonic syndrome (CS). They
both share many clinical features and it is impossible to differentiate them on
the basis of biochemical findings. Both respond similarly to treatment. The
article describes some case reports from the literature and our own case report
of NMS as a form of CS.
PMID- 10786243
TI - [The costs of treatment and rehabilitation of long-term psychiatric patients].
AB - The cost of treatment of mentally ill patients is taking an ever more important
place in the health care systems of many countries. This is caused by an
increasing interest of the taxpayers who want to know where their money goes in
relation to medical expenses. It is logical that taxpayers' expectations include
improvement of the health care system. Medicine cannot be considered in the
category of a profit making economy because some of the fields of medicine are
not and cannot be profitable. At the borderline between economy and medicine,
pharmaco-economy was born. This new science considers the cost of treatment of
various sicknesses; furthermore it tests the comparative costs and the use of
pharmaceutical products. In pharmaco-economy we distinguish three different types
of costs: the continuous cost (consequent to medical treatment), the indirect
cost (related to losses on support of patients and their family members), the
unassessable cost (psychological losses). A correct economical analysis is multi
factual and refers to different sides of our lives. With this understanding we
can only consider the general economical results, that is, the so called
"economical treatment result". It is believed that this way of thinking can cause
an intensive development in the rehabilitation of chronic mentally ill patients
in Poland. This rehabilitation can be a classical example of modern economy:
hypothetically high initial costs cause their substantial reduction in the
progressive development of the programme until they reach their effective
reduction at the end, i.e. the progressive improvement of the patients
functioning within their natural environment.
PMID- 10786242
TI - [The role of health insurance in mental health care in Germany].
AB - An outline of the German system of mental health care is given. A description of
its organization, funding streams and service set-up is provided. Strengths and
weaknesses are highlighted, and the system is contrasted with the organisation of
mental health care in England and Wales.
PMID- 10786244
TI - [Community specialized social help services for patients with mental disorders:
one year experience].
AB - This article describes one year's experiences of Foundation of Supporting
Psychiatric Department Medical Academy of Warsaw in care of patients with mental
disorders in two districts of Warsaw. The service was provided for open group of
about 70-80 patients with the diagnosis of schizophrenia and depressive disorder
recurrent. Introducing of this type of care resulted in reducing of the number of
patient admitted to the hospital and in shortening of the mean hospitalization
time. Moreover, last but not least, improved patient's life quality. The article
contains also care reports illustrations successes and defeats in this type of
care.
PMID- 10786245
TI - [The diagnostic questionnaires and their use in epidemiological studies in
psychiatry].
AB - The paper presents diagnostic instruments employed in psychiatric; brief history
of their development with regard to their importance for progress in psychiatric
epidemiology, the characteristic of the most important diagnostic questionnaire
(Present State Examination--PSE, Composite International Diagnostic Interview-
CIDI, Schedules for Clinical Assessment In Neuropsychiatry--SCAN, Structured
Clinical Interview for DSM IV--SCID, Schedule for Affective Disorders and
Schizophrenia--SADS, Diagnostic Interview Schedule--DIS). It also describes some
features that should be considered while choosing a proper instrument for a given
study. The authors call attention to some differences between instruments, e.g.,
those related to the structure of the questionnaire, involving diagnostic
categories, the sort of information that an instrument allows to collect,
competence of interviewers and their training, and also population for which the
instrument is assigned. Presenting advantages and disadvantages of instruments,
the authors emphasize that there is no best instrument. The choice of
questionnaire depends, first of all, on the purpose of the study and the funds
that the researches have at their disposal.
PMID- 10786247
TI - [The study of candidate genes in psychiatric disease. II. Affective disorders].
AB - The results of research concerning the importance of genetic factors in
etiopathogenesis of affective diseases are presented. In molecular genetics
research there are two most frequently applied strategies: searching of the whole
genome in order to find new genes and molecular analysis of candidate genes.
Candidate gene analysis consist in choosing a gene which could theoretically have
a connection with the disease. The polymorphism of a chosen gene is estimated and
then its connection with the disease is defined. The presented reference review
concerns the results of candidate genes research, which refer to biochemical
hypothesis of affective diseases. In many medical centers it was found that in
affective disorders the polymorphism of gene's receptor D4, GABA and serotonin
transporter could be of etiological importance.
PMID- 10786246
TI - [Epidemiological studies on neurotic disturbances, anxiety and depression
disorders in a population living near an overhead high voltage transmission line
(400 kV)].
AB - Epidemiological studies indicate an increased incidence of depression and
neurotic disorders in persons long exposed to influence of electromagnetic
fields. The examinations covered a selected population of several suburban
neighborhoods of Cracow living not farther than 50 m from a 400 kV high-voltage
transmission line. A group of 70 persons (35 men and 35 women) living near the
transmission line for longer than 10 years was examined. A control group
consisted of 37 persons not subjected to an influence of similar transmission
line. Instruments used in the examination included: Symptom Checklist "0",
Spielberge's Self-assessment Questionnaire and Beck's Inventory. Also, a modified
life-history questionnaire was applied. In the examined households we found
significantly increased values of intensity of the electric component (by the so
called "ecological" Swedish norms). The population resident in the closest
neighborhood of the examined transmission-line manifested high level of
psychopathology, significantly different than that in the control group. However,
the obtained results do not allow us to state univocally whether the observed
psychopathology remains in causal nexus with the exposure to electromagnetic
field. Other factors, like noise, may also be responsible for these results. The
hypothesis that electromagnetic fields generated by high-voltage transmission
lines may evoke depressive disorders and depression requires further clinical and
experimental studies.
PMID- 10786248
TI - [Children and parental depression. An investigation on adult offspring of
depressed patients].
AB - The aim of our study was to assess the perception of parental depression by their
adult offspring. Twenty nine offsprings aged 22.5 +/- 3.9 years were examined
with the use of Parental Bonding Instrument, Beck Depression Inventory, Resenberg
Scale, Hopelessness Scale, Automatic Thoughts Questionnaire and our own
semistructured inventory. The offsprings of depressed patients reported negative
impact of the illness on various aspects of life, especially when mother was ill.
Surprisingly, the offsprings did not reveal disturbances in their thinking style,
neither did they have depressive symptoms.
PMID- 10786249
TI - [Religiosity and intensity of endogenous depression symptoms. A follow-up study].
AB - The aim of our study was to determine if the quality of remission in unipolar
affective disorder correlates with patient's religiosity. We have investigated 63
patients who were hospitalised in the Department of Psychiatry CMUJ between 1991
and 1997. The quality of remission has been assessed by Beck Depression Inventory
(BDI), Rosenberg Self-esteem Scale (RS), Automatic Thoughts Questionnaire (ATQ),
Hopelessness Scale (HS). Religiosity has been tested by the Scale of Individual
Religiosity, and Religious Life Inventory. Patients were also assessed with the
use of our own questionnaire, answering the following questions: 1. Do you
believe?, 2. Does the disease influence the faith?, 3. Does your faith help in
the disease?. Religiosity did not correlate with the quality of remission in
depression in a statistically significant manner. There is only one statistically
significant correlation: patients who answered positively the question number 3
(41 patients), have better remission. It is impossible to describe simple
correlation between religiosity and remission in unipolar affective disorder.
Patients who found their faith helpful have better remission.
PMID- 10786250
TI - [Regional cerebral blood flow in depression].
AB - In the review article, the results of studies on regional cerebral blood flow
(rCBF) in major depression are presented. Most studies have reported global and
regional deficits in cerebral blood flow in major depression as compared to
healthy controls. Longitudinal studies show that after recovery from depression
an increase of CBF has been observed. The influence of different biological
treatment methods on rCBF is also discussed. Findings regarding lateral
asymmetries of cerebral function in patients with major depression are
inconclusive but the deficit of rCBF is often more pronounced in the left
hemisphere. The nature of regional brain flow abnormalities in depression is
unclear. Structural changes of the brain and biochemical abnormalities are under
consideration.
PMID- 10786251
TI - [Tomographic cerebral blood flow scanning in diagnosis of psychiatric disorders].
AB - The paper summarises the role of tomographic cerebral blood flow SPECT scanning
in psychiatric diagnostics, its' physical and radiopharmaceutical basis,
pathological physiology of cerebrovascular circulation in psychiatric disorders
and interpretation of cerebral blood flow scanning results by the clinician.
Cerebral blood flow scanning is, to some extent, a functional equivalent of
CT/MRI scanning. In psychiatry cerebral blood flow SPECT scanning's basic
application is the differentiation of dementia and cognitive impairment, in
particular Alzheimer's disease, frontotemporal lobar degeneration and multi
infarct dementia. The other indications for brain SPECT scanning involve the
organic brain lesions and medico-legal diagnostics, including the sequelae of
cranio-cerebral trauma. Contraindications and economical aspects are underlined.
PMID- 10786252
TI - [Clomipramine in the treatment of obsessive-compulsive disorder. An open 8-week
trial].
AB - Among many drugs used for treatment of obsessive-compulsive disorder clomipramine
is still considered as model drug though serotoninergic mechanism is common for
many antidepressants. The study was carried out in order to assess the potential
and dynamic of antiobsessive and anticompulsive efficacy of clomipramine used in
normal therapeutic doses during eight week trial. The study was carried out with
the help of Asta Medica company and trade name of the used drug was Hydiphen. The
severity of obsessive-compulsive disorder was evaluated at the moment of
inclusion to the study and then once every week. The obsessive-compulsive scale Y
BOCS was employed. 27 patietnts (16 women and 11 men) at aged 18-64, from
different mental health care centers in Poland participated in this study. The
study was completed by 67% of patients--due to lack of therapeutical effect the
treatment of others patients was stopped. Among the patients who responded well
to clomipramine therapy, improvement was observed after the first week and then
the dynamic of improvement decreased after 4 weeks. During the 7th week the drug
reached its maximal efficacy level with statistically significant reduction in
scores of Y-BOCS scale. The range of therapeutic doses was 75-250 mg. In this
range no seriouse adverse events were observed and some of mild ones that
occurred at the beginning of the therapy diminished during the next week.
PMID- 10786253
TI - Doxazosin dropped from ALLHAT study.
PMID- 10786254
TI - PBMs could manage Medicare drug benefit but need flexibility, guidelines.
PMID- 10786256
TI - Report compares treatments for stable angina.
PMID- 10786255
TI - Study documents benefits of beta-blockers in heart failure.
PMID- 10786257
TI - Psychotropic drug use rising among preschoolers.
PMID- 10786258
TI - CDC alters recommendations on rifamycin-antiretroviral drug use.
PMID- 10786259
TI - Candesartan cilexetil: an angiotensin II-receptor blocker.
AB - The mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy,
and adverse effects of candesartan cilexetil are reviewed. Candesartan is an
angiotensin II-receptor blocker (ARB). It is administered as a pro-drug that
undergoes activation during gastrointestinal absorption. The agent is excreted
mostly unchanged and has a terminal half-life of about nine hours (slightly
longer in the elderly). Candesartan differs from other agents in its class in
that it is tightly bound to angiotensin II type 1 receptors, allowing prolonged
activity. In clinical trials, candesartan cilexetil has produced a dose-dependent
effect when given in dosages of 2-32 mg/day. Observed trough-to-peak blood
pressure ratios support a once-daily dosage regimen. The antihypertensive effect
of candesartan cilexetil 4-16 mg/day was as great as that of enalapril 10-20
mg/day and amlodipine 5 mg/day and larger than that of losartan potassium 50
mg/day. Adding candesartan cilexetil to hydrochlorothiazide 12.5-25 mg/day and
amlodipine 5 mg/day led to enhanced blood-pressure reductions and was well
tolerated. It appears that candesartan can decrease renal perfusion without
adversely affecting renal blood flow and may mediate a decrease in albuminuria in
hypertensive patients with type 2 diabetes. No clinically important drug
interactions have been reported. Adverse effects include headache, dizziness,
nausea, diarrhea, and transient elevations in liver transaminases. The frequency
of cough is similar to that seen with placebo. Candesartan cilexetil is an
effective antihypertensive agent that can be used alone or in combination with
other antihypertensive drugs. It is generally well tolerated and may be an option
for patients who cannot tolerate angiotensin-converting-enzyme inhibitors because
of cough.
PMID- 10786260
TI - Community pharmacist outreach program directed at physicians treating congestive
heart failure.
AB - The predictive value of digoxin and furosemide treatment for identifying patients
receiving treatment for congestive heart failure (CHF), the use of angiotensin
converting-enzyme (ACE) inhibitors in this population, and the ability of a
pharmacist outreach program to address underutilization of ACE inhibitors were
studied. All physicians and owner-managers of community pharmacies on
Newfoundland's Avalon Peninsula were asked to participate in the study.
Pharmacists who agreed to participate were asked to list patients of the
participating physicians with prescriptions for (1) furosemide and digoxin with
and without an ACE inhibitor or angiotensin II-receptor inhibitor and (2) an ACE
inhibitor. Physicians were visited by a pharmacist and asked whether each of
their patients receiving digoxin and furosemide was being treated for CHF and to
identify further cases of CHF among their patients receiving an ACE inhibitor.
Intervention-group physicians received academic detailing on the use and dosage
of ACE inhibitors and angiotensin II-receptor inhibitors for CHF. Both groups
were reinterviewed after three months to establish what if any changes in therapy
had occurred for each patient discussed during the first visit. The positive
predictive value of digoxin and furosemide treatment for identifying patients
receiving treatment for CHF was 94%. Seventy-six percent of patients identified
by physicians as CHF patients who were taking digoxin and furosemide were treated
with an ACE inhibitor. Thirty-six percent of patients treated with an ACE
inhibitor for CHF received the targeted dosage. Four physicians stated that the
outreach visit influenced their prescribing, but there was no significant
difference in ACE inhibitor prescribing between the intervention and control
groups. A pharmacist outreach program involving the use of prescription records
and academic detailing did not affect prescribing or dosages of ACE inhibitors
but demonstrated value as a quality assurance tool.
PMID- 10786262
TI - Refill program using pharmacy student interns in a primary care clinic.
PMID- 10786261
TI - Economics of using pharmacists as advisers to physicians in risk-sharing
contracts.
AB - An educational program designed to help physicians control the overall cost of
drugs and total health care is described, along with its effectiveness at one
managed health care plan. Prime Therapeutics, Inc., developed and manages an
ongoing physician education program designed to help primary care physicians
control drug and total health care costs. Physician education initiatives in the
program are developed by using peer-reviewed literature; selections of preferred
drugs are based on evidence of their safety, efficacy, uniqueness, and cost
effectiveness. For a typical educational initiative, a pharmacist meets with the
physicians identified as being among the top 20% of prescribers of high-cost
drugs addressed by the initiative and delivers a 20-minute presentation. One-on
one meetings with the physicians are then held quarterly to review their
prescribing. Each physician is shown comparisons with the prescribing patterns of
other physicians in the organization. The clinic chooses to present the
clinicwide data as either blinded or nonblinded data. The program was evaluated
by comparing per member per month (PMPM) total health care and drug costs for
1996 and 1997 at 12 general medicine clinics in a managed health care plan. Five
clinics received no interventions, three clinics allowed the initial presentation
and the quarterly face-to-face meetings, and four clinics allowed only the
presentation and barred ongoing meetings. In general, the clinics with more
interaction between pharmacists and physicians had lower PMPM costs for total
health care and drugs than the clinics with less interaction. Pharmacists acting
as advisers to primary care physicians in general medicine clinics helped lower
PMPM costs for drugs and total health care.
PMID- 10786263
TI - Activity of dalteparin sodium in polypropylene syringes.
PMID- 10786264
TI - Survey of home infusion care in England.
PMID- 10786265
TI - Patient education role of a pharmacist on a transplant service.
PMID- 10786266
TI - More than a matter of law enforcement.
PMID- 10786267
TI - [Severe exacerbation of asthma].
PMID- 10786268
TI - [Acute respiratory failure in chronic obstructive pulmonary disease].
PMID- 10786269
TI - [Thoracic injuries].
PMID- 10786270
TI - [Acute respiratory distress].
PMID- 10786271
TI - [Hemodynamically unstable pulmonary thromboembolism].
PMID- 10786272
TI - [Respiratory failure in scuba diving].
PMID- 10786273
TI - [Fibrinolysis in pleural effusion].
PMID- 10786274
TI - [Bronchoscopy emergencies].
PMID- 10786275
TI - [Interventional radiologic techniques in thoracic emergencies].
PMID- 10786276
TI - [Laryngotracheobronchial injuries].
PMID- 10786277
TI - Characterization of a generic monoclonal antibody harvesting system for
adsorption of DNA by depth filters and various membranes.
AB - The physical parameters governing adsorption of DNA by various positively charged
depth filters and membranes have been assessed. Buffers that reduced or
neutralised the depth filter or membrane charge, and those that impeded
hydrophobic interactions were shown to affect their operational capacity,
demonstrating that DNA was adsorbed by a combination of electrostatic and
hydrophobic interactions. The adsorption profile of DNA by a Sartobind Q anion
exchange membrane showed immediate breakthrough, irrespective of challenge DNA
concentration or flow rate, and in this case adsorption was by electrostatic
interactions only. The production-scale removal of DNA from harvest broths
containing therapeutic protein by partitioning of cells and debris from protein
in sequential centrifugation and filtration steps, and the concentration of DNA
in process supernatant were assessed. Centrifugation reduced the quantity of DNA
in the process material from 79.8 micrograms ml-1 to 9.3 micrograms ml-1 whereas
the concentration of DNA in the supernatant of pre- and post-filtration samples
had only marginally reduced DNA content: from 6.3 to 6.0 micrograms ml-1
respectively. DNA was concentrated to 27.3 micrograms ml-1 along with monoclonal
antibody in the ultrafiltration step. Similar effects were observed in the
harvest step for a second antibody.
PMID- 10786279
TI - Purification of Lac repressor protein using polymer displacement and
immobilization of the protein.
AB - Lac repressor protein was purified from E. coli BMH8117 harboring plasmid pWB1000
and E. coli K12BMH 71-18 strains. Displacement of the protein with
poly(ethyleneimine) (PEI) from phosphocellulose cation exchange column was shown
to be an effective elution strategy. It resulted in better recoveries and sharper
elution profiles than traditional salt elution without effecting the purity of
the protein. The elution is assumed to proceed via displacement of bound protein
by PEI when the polymer binds to the ion exchanger. The minor impurities in the
protein solution were finally removed by chromatography on immobilized metal
affinity column. The repressor protein undergoes distinct conformational changes
upon addition of specific inducer isopropyl-beta-D-thiogalactoside (IPTG), which
is evidenced by changes in ultraviolet absorption spectrum. The protein was
immobilized covalently to the Sepharose matrix. The intact biological activity of
the protein after immobilization was shown by binding of genomic DNA and lac
operator plasmid DNA from E. coli to the immobilized lac repressor.
PMID- 10786278
TI - Purification of alpha-glucosidae and invertase from bakers' yeast on modified
polymeric supports.
AB - In the present work Amberlite XAD-16 and Indion NPA-1, Polystyrene Divinylbenzene
macroreticular spherical resins, have been evaluated quantitatively as supports
for the adsorption and isolation of the yeast proteins and the enzymes, invertase
and alpha-glucosidase. Modification of these supports has been carried out by
surface grafting using acrylate polymers to reduce the hydrophobicity and
nonspecific adsorption of proteins. Good grafting efficiency, in excess of 90%,
has been obtained using ultrasonic irradiation for the surface activation of
polystyrene resins. XAD-16 has higher adsorption capacities for the total yeast
proteins as well as for both the enzymes, alpha-glucosidase and invertase, than
NPA-1 in its respective native and grafted form. Adsorption capacities of XAD-16
and NPA-1 in their respective native and grafted forms for alpha-glucosidase are
higher than the capacities for invertase. Nonspecific adsorption of total
proteins has been reduced considerably after the grafting of acrylate polymers on
hydrophobic supports. At the same time selectivity for the adsorption of both the
enzymes has been enhanced on grafted supports. The overall solid-liquid
adsorption mass transfer coefficient values (Kla) estimated for adsorption of
invertase on XAD are lower than those for alpha-glucosidase. Native and grafted
resins could be regenerated and reused for adsorption of alpha-glucosidase for
two regeneration cycles studied. Storage stability of invertase and alpha
glucosidase is the same on native and grafted form of XAD-16 and is more than the
enzymes in the free form.
PMID- 10786280
TI - Crystallographic threading.
AB - Crystallographic studies play a major role in current efforts towards protein
structure determination. Despite recent advances in computational tools for
molecular modeling and graphics, the construction of a three-dimensional protein
backbone model from crystallographic data remains complex and time-consuming.
This paper describes a unique contribution to an automated approach to protein
model construction and evaluation, where a model is represented as an annotated
trace (or partial trace) of a structure. Candidate models are derived through a
topological analysis of the electron density map of a protein. Using sequence
alignment techniques, we determine an optimal threading of the known sequence
onto the candidate protein structure models. In this threading, connected nodes
on the model are associated with adjacent amino acids in the sequence and a
fitness score is assigned based on features extracted from the electron density
map for the protein. Experimental results demonstrate that crystallographic
threading provides an effective means for evaluating the "goodness" of
experimentally derived protein models.
PMID- 10786281
TI - A phylogenetic approach to RNA structure prediction.
AB - Methods based on the Mutual Information statistic (MI methods) predict structure
by looking for statistical correlations between sequence positions in a set of
aligned sequences. Although MI methods are often quite effective, these methods
ignore the underlying phylogenetic relationships of the sequences they analyze.
Thus, they cannot distinguish between correlations due to structural
interactions, and spurious correlations resulting from phylogenetic history. In
this paper, we introduce a method analogous to MI that incorporates phylogenetic
information. We show that this method accurately recovers the structures of well
known RNA molecules. We also demonstrate, with both real and simulated data, that
this phylogenetically-based method outperforms standard MI methods, and improves
the ability to distinguish interacting from non-interacting positions in RNA.
This method is flexible, and may be applied to the prediction of protein
structure given the appropriate evolutionary model. Because this method
incorporates phylogenetic data, it also has the potential to be improved with the
addition of more accurate phylogenetic information, although we show that even
approximate phylogenies are helpful.
PMID- 10786283
TI - Position-specific annotation of protein function based on multiple homologs.
AB - I present in this work an algorithm for deriving protein functional annotations
which are position-specific. The input is based on the results of a sequence
similarity search of the query sequence against a sequence database. Strings of
words are extracted from the descriptions of the proteins, and the correlation
between proteins having the same descriptors and the amino acid conservation is
used to compute a score that indicates which descriptor is likely to describe
better the function of each particular residue. Analysis of the score curves and
comparison of different functions allows an easy detection of parts of the
sequence associated to different function. Different levels of functional
specificity can be compared, allowing to choose the one that suits better the
function of the protein. Immediate applications of this algorithm are, support
for (automated) methods of protein functional annotation, and database coherence
check.
PMID- 10786282
TI - Genomics via optical mapping. III: Contiging genomic DNA.
AB - In this paper, we describe our algorithmic approach to constructing an alignment
of (contiging) a set of restriction maps created from the images of individual
genomic (uncloned) DNA molecules digested by restriction enzymes. Generally,
these DNA segments are sized in the range of 1-4 Mb. The goal is to devise
contiging algorithms capable of producing high-quality composite maps rapidly and
in a scaleable manner. The resulting software is a key component of our physical
mapping automation tools and has been used to create complete maps of various
microorganisms (E. coli, P. falciparum and D. radiodurans). Experimental results
match known sequence data.
PMID- 10786284
TI - Nearest neighbor classification in 3D protein databases.
AB - In molecular databases, structural classification is a basic task that can be
successfully approached by nearest neighbor methods. The underlying similarity
models consider spatial properties such as shape and extension as well as
thematic attributes. We introduce 3D shape histograms as an intuitive and
powerful approach to model similarity for solid objects such as molecules. Errors
of measurement, sampling, and numerical rounding may result in small
displacements of atomic coordinates. These effects may be handled by using
quadratic form distance functions. An efficient processing of similarity queries
based on quadratic forms is supported by a filter-refinement architecture.
Experiments on our 3D protein database demonstrate the high classification
accuracy of more than 90% and the good performance of the technique.
PMID- 10786285
TI - Reconstructing the duplication history of a tandem repeat.
AB - One of the less well understood mutational transformations that act upon DNA is
tandem duplication. In this process, a stretch of DNA is duplicated to produce
two or more adjacent copies, resulting in a tandem repeat. Over time, the copies
undergo additional mutations so that typically, multiple approximate tandem
copies are present. An interesting feature of tandem repeats is that the
duplicated copies are preserved together, making it possible to do "phylogenetic
analysis" on a single sequence. This involves using the pattern of mutations
among the copies to determine a minimal or a most likely history for the repeat.
A history tries to describe the interwoven pattern of substitutions, indels, and
duplication events in such a way as to minimize the number of identical mutations
that arise independently. Because the copies are adjacent and ordered, the
history problem can not be solved by standard phylogeny algorithms. In this
paper, we introduce several versions of the tandem repeat history problem,
develop algorithmic solutions and evaluate their performance. We also develop
ways to visualize important features of a history with the goal of discovering
properties of the duplication mechanism.
PMID- 10786286
TI - Identity by descent genome segmentation based on single nucleotide polymorphism
distributions.
AB - In the course of our efforts to build extended regions of human genomic sequence
by assembling individual BAC sequences, we have encountered several instances
where a region of the genome has been sequenced independently using reagents
derived from two different individuals. Comparing these sequences allows us to
analyze the frequency and distribution of single nucleotide polymorphisms (SNPs)
in the human genome. The observed transition/transversion frequencies are
consistent with a biological origin for the sequence discrepancies, and this
suggests that the data produced by large sequencing centers are accurate enough
to be used as the basis for SNP analysis. The observed distribution of single
nucleotide polymorphisms in the human genome is not uniform. An apparent
duplication in the human genome extending over more than 130 kb between
chromosomes 1p34 and 16p13 is reported. Independently derived sequences covering
these regions are more than 99.9% identical, indicating that this duplication
event must have occurred quite recently. FISH mapping results reported by the
relevant laboratories indicate that the human population may be polymorphic for
this duplication. We present a population genetic theory for the expected
distribution of SNPs and derive an algorithm for probabilistically segmenting
genomic sequence into regions that are identical by descent (IBD) between two
individuals based on this theory and the observed locations of polymorphisms.
Based on these methods and a random mating model for the human population,
estimates are made for the mutation rate in the human genome.
PMID- 10786287
TI - Automatic extraction of biological information from scientific text: protein
protein interactions.
AB - We describe the basic design of a system for automatic detection of protein
protein interactions extracted from scientific abstracts. By restricting the
problem domain and imposing a number of strong assumptions which include pre
specified protein names and a limited set of verbs that represent actions, we
show that it is possible to perform accurate information extraction. The
performance of the system is evaluated with different cases of real-world
interaction networks, including the Drosophila cell cycle control. The results
obtained computationally are in good agreement with current biological knowledge
and demonstrate the feasibility of developing a fully automated system able to
describe networks of protein interactions with sufficient accuracy.
PMID- 10786288
TI - A data base of minimally frustrated alpha helical segments extracted from
proteins according to an entropy criterion.
AB - A data base of minimally frustrated alpha helical segments is defined by
filtering a set comprising 822 non redundant proteins, which contain 4783 alpha
helical structures. The data base definition is performed using a neural network
based alpha helix predictor, whose outputs are rated according to an entropy
criterion. A comparison with the presently available experimental results
indicates that a subset of the data base contains the initiation sites of protein
folding experimentally detected and also protein fragments which fold into stable
isolated alpha helices. This suggests the usage of the data base (and/or of the
predictor) to highlight patterns which govern the stability of alpha helices in
proteins and the helical behavior of isolated protein fragments.
PMID- 10786289
TI - Constructing biological knowledge bases by extracting information from text
sources.
AB - Recently, there has been much effort in making databases for molecular biology
more accessible and interoperable. However, information in text form, such as
MEDLINE records, remains a greatly underutilized source of biological
information. We have begun a research effort aimed at automatically mapping
information from text sources into structured representations, such as knowledge
bases. Our approach to this task is to use machine-learning methods to induce
routines for extracting facts from text. We describe two learning methods that we
have applied to this task--a statistical text classification method, and a
relational learning method--and our initial experiments in learning such
information-extraction routines. We also present an approach to decreasing the
cost of learning information-extraction routines by learning from "weakly"
labeled training data.
PMID- 10786290
TI - INTERACT: an object oriented protein-protein interaction database.
AB - MOTIVATION: Protein-protein interactions provide vital information concerning the
function of proteins, complexes and networks. Currently there is no widely
accepted repository of this interaction information. Our aim is to provide a
single database with the necessary architecture to fully store, query and analyse
interaction data. RESULTS: An object oriented database has been created which
provides scientists with a resource for examining existing protein-protein
interactions and inferring possible interactions from the data stored. It also
provides a basis for examining networks of interacting proteins, via analysis of
the data stored. The database contains over a thousand interactions. CONTACT:
k.eilbeck@stud.man.ac.uk
PMID- 10786291
TI - Using sequence motifs for enhanced neural network prediction of protein distance
constraints.
AB - Correlations between sequence separation (in residues) and distance (in Angstrom)
of any pair of amino acids in polypeptide chains are investigated. For each
sequence separation we define a distance threshold. For pairs of amino acids
where the distance between C alpha atoms is smaller than the threshold, a
characteristic sequence (logo) motif, is found. The motifs change as the sequence
separation increases: for small separations they consist of one peak located in
between the two residues, then additional peaks at these residues appear, and
finally the center peak smears out for very large separations. We also find
correlations between the residues in the center of the motif. This and other
statistical analysis are used to design neural networks with enhanced performance
compared to earlier work. Importantly, the statistical analysis explains why
neural networks perform better than simple statistical data-driven approaches
such as pair probability density functions. The statistical results also explain
characteristics of the network performance for increasing sequence separation.
The improvement of the new network design is significant in the sequence
separation range 10-30 residues. Finally, we find that the performance curve for
increasing sequence separation is directly correlated to the corresponding
information content. A WWW server, distanceP, is available at
http://www.cbs.dtu.dk/services/distanceP/.
PMID- 10786292
TI - Protein fold class prediction: new methods of statistical classification.
AB - Feed forward neural networks are compared with standard and new statistical
classification procedures for the classification of proteins. We applied logistic
regression, an additive model and projection pursuit regression from the methods
based on a posterior probabilities; linear, quadratic and a flexible discriminant
analysis from the methods based on class conditional probabilities, and the K
nearest-neighbors classification rule. Both, the apparent error rate obtained
with the training sample (n = 143) and the test error rate obtained with the test
sample (n = 125) and the 10-fold cross validation error were calculated. We
conclude that some of the standard statistical methods are potent competitors to
the more flexible tools of machine learning.
PMID- 10786293
TI - Fidelity probes for DNA arrays.
AB - One current approach to quality control in DNA array manufacturing is to
synthesize a small set of test probes that detect variation in the manufacturing
process. These fidelity probes consist of identical copies of the same probe, but
they are deliberately manufactured using different steps of the manufacturing
process. A known target is hybridized to these probes, and those hybridization
results are indicative of the quality of the manufacturing process. It is not
only desirable to detect variations, but also to analyze the variations that
occur, indicating in what process step the manufacture changed. We describe a
combinatorial approach which constructs a small set of fidelity probes that not
only detect variations, but also point out the manufacturing step in which a
variation has occurred. This algorithm is currently being used in mass-production
of DNA arrays at Affyetrix.
PMID- 10786294
TI - Solving large scale phylogenetic problems using DCM2.
AB - In an earlier paper, we described a new method for phylogenetic tree
reconstruction called the Disk Covering Method, or DCM. This is a general method
which can be used with any existing phylogenetic method in order to improve its
performance. We showed analytically and experimentally that when DCM is used in
conjunction with polynomial time distance-based methods, it improves the accuracy
of the trees reconstructed. In this paper, we discuss a variant on DCM, that we
call DCM2. DCM2 is designed to be used with phylogenetic methods whose objective
is the solution of NP-hard optimization problems. We show that DCM2 can be used
to accelerate searches for Maximum Parsimony trees. We also motivate the need for
solutions to NP-hard optimization problems by showing that on some very large and
important datasets, the most popular (and presumably best performing) polynomial
time distance methods have poor accuracy.
PMID- 10786295
TI - TEXTAL: a pattern recognition system for interpreting electron density maps.
AB - X-ray crystallography is the most widely used method for determining the three
dimensional structures of proteins and other macromolecules. One of the most
difficult steps in crystallography is interpreting the electron density map to
build the final model. This is often done manually by crystallographers and is
very time-consuming and error-prone. In this paper, we introduce a new automated
system called TEXTAL for interpreting electron density maps using pattern
recognition. Given a map to be modeled, TEXTAL divides the map into small regions
and then finds regions with a similar pattern of density in a database of maps
for proteins whose structures have already been solved. When a match is found,
the coordinates of atoms in the region are inferred by analogy. The key to making
the database lookup efficient is to extract numeric features that represent the
patterns in each region and to compare feature values using a weighted Euclidean
distance metric. It is crucial that the features be rotation-invariant, since
regions with similar patterns of density can be oriented in any arbitrary way.
This pattern-recognition approach can take advantage of data accumulated in large
crystallographic databases to effectively learn the association between electron
density and molecular structure by example.
PMID- 10786296
TI - ESTScan: a program for detecting, evaluating, and reconstructing potential coding
regions in EST sequences.
AB - One of the problems associated with the large-scale analysis of unannotated, low
quality EST sequences is the detection of coding regions and the correction of
frameshift errors that they often contain. We introduce a new type of hidden
Markov model that explicitly deals with the possibility of errors in the sequence
to analyze, and incorporates a method for correcting these errors. This model was
implemented in an efficient and robust program, ESTScan. We show that ESTScan can
detect and extract coding regions from low-quality sequences with high
selectivity and sensitivity, and is able to accurately correct frameshift errors.
In the framework of genome sequencing projects, ESTScan could become a very
useful tool for gene discovery, for quality control, and for the assembly of
contigs representing the coding regions of genes.
PMID- 10786297
TI - Using the Fisher kernel method to detect remote protein homologies.
AB - A new method, called the Fisher kernel method, for detecting remote protein
homologies is introduced and shown to perform well in classifying protein domains
by SCOP superfamily. The method is a variant of support vector machines using a
new kernel function. The kernel function is derived from a hidden Markov model.
The general approach of combining generative models like HMMs with discriminative
methods such as support vector machines may have applications in other areas of
biosequence analysis as well.
PMID- 10786298
TI - An algorithm combining discrete and continuous methods for optical mapping.
AB - Optical mapping is a novel technique for generating the restriction map of a DNA
molecule by observing many single, partially digested, copies of it, using
fluorescence microscopy. The real-life problem is complicated by numerous
factors: false positive and false negative cut observations, inaccurate location
measurements, unknown orientations and faulty molecules. We present an algorithm
for solving the real-life problem. The algorithm combines continuous optimization
and combinatorial algorithms, applied to a non-uniform discretization of the
data. We present encouraging results on real experimental data.
PMID- 10786299
TI - Multiple structural alignment and core detection by geometric hashing.
AB - A Multiple Structural Alignment algorithm is presented. The algorithm accepts an
ensemble of protein structures and finds the largest substructure (core) of C
alpha atoms whose geometric configuration appear in all the molecules of the
ensemble (core). Both the detection of this core and the resulting structural
alignment are done simultaneously. Other large enough multistructural
superimpositions are detected as well. Our method is based on the Geometric
Hashing paradigm and a superimposition clustering technique which represents
superimpositions by sets of matching atoms. The algorithm proved to be efficient
on real data in a series of experiments. The same method can be applied to any
ensemble of molecules (not necessarily proteins) since our basic technique is
sequence order independent.
PMID- 10786300
TI - Metrics and similarity measures for hidden Markov models.
AB - Hidden Markov models were introduced in the beginning of the 1970's as a tool in
speech recognition. During the last decade they have been found useful in
addressing problems in computational biology such as characterising sequence
families, gene finding, structure prediction and phylogenetic analysis. In this
paper we propose several measures between hidden Markov models. We give an
efficient algorithm that computes the measures for left-right models, e.g.
profile hidden Markov models, and briefly discuss how to extend the algorithm to
other types of models. We present an experiment using the measures to compare
hidden Markov models for three classes of signal peptides.
PMID- 10786301
TI - Quantitative, scalable discrete-event simulation of metabolic pathways.
AB - DMSS (Discrete Metabolic Simulation System) is a framework for modelling and
simulating metabolic pathways. Quantitative simulation of metabolic pathways is
achieved using discrete-event techniques. The approach differs from most
quantitative simulators of metabolism which employ either time-differentiated
functions or mathematical modelling techniques. Instead, models are constructed
from biochemical data and biological knowledge, with accessibility and relevance
to biologists serving as key features of the system.
PMID- 10786302
TI - Spatio-temporal registration of the expression patterns of Drosophila
segmentation genes.
AB - The application of image registration techniques resulted in the construction of
an integrated atlas of Drosophila segmentation gene expression in both space and
time. The registration method was based on a quadratic spline approximation with
flexible knots. A classifier for automatic attribution of an embryo to one of the
temporal classes according to its gene expression pattern was developed.)
PMID- 10786303
TI - A dataset generator for whole genome shotgun sequencing.
AB - Simulated data sets have been found to be useful in developing software systems
because (1) they allow one to study the effect of a particular phenomenon in
isolation, and (2) one has complete information about the true solution against
which to measure the results of the software. In developing a software suite for
assembling a whole human genome shotgun data set, we have developed a simulator,
celsim, that permits one to describe and stochastically generate a target DNA
sequence with a variety of repeat structures, to further generate polymorphic
variants if desired, and to generate a shotgun data set that might be sampled
from the target sequence(s). We have found the tool invaluable and quite
powerful, yet the design is extremely simple, employing a special type of
stochastic grammar.
PMID- 10786304
TI - Rapid assessment of extremal statistics for gapped local alignment.
AB - The statistical significance of gapped local alignments is characterized by
analyzing the extremal statistics of the scores obtained from the alignment of
random amino acid sequences. By identifying a complete set of linked clusters,
"islands," we devise a method which accurately predicts the extremal score
statistics by using only one to a few pairwise alignments. The success of our
method relies crucially on the link between the statistics of island scores and
extremal score statistics. This link is motivated by heuristic arguments, and
firmly established by extensive numerical simulations for a variety of scoring
parameter settings and sequence lengths. Our approach is several orders of
magnitude faster than the widely used shuffling method, since island counting is
trivially incorporated into the basic Smith-Waterman alignment algorithm with
minimal computational cost, and all islands are counted in a single alignment.
The availability of a rapid and accurate significance estimation method gives one
the flexibility to fine tune scoring parameters to detect weakly homologous
sequences and obtain optimal alignment fidelity.
PMID- 10786305
TI - Building dictionaries of 1D and 3D motifs by mining the Unaligned 1D sequences of
17 archaeal and bacterial genomes.
AB - We have used the Teiresias algorithm to carry out unsupervised pattern discovery
in a database containing the unaligned ORFs from the 17 publicly available
complete archaeal and bacterial genomes and build a 1D dictionary of motifs.
These motifs which we refer to as seqlets account for and cover 97.88% of this
genomic input at the level of amino acid positions. Each of the seqlets in this
1D dictionary was located among the sequences in Release 38.0 of the Protein Data
Bank and the structural fragments corresponding to each seqlet's instances were
identified and aligned in three dimensions: those of the seqlets that resulted in
RMSD errors below a pre-selected threshold of 2.5 Angstroms were entered in a 3D
dictionary of structurally conserved seqlets. These two dictionaries can be
thought of as cross-indices that facilitate the tackling of tasks such as
automated functional annotation of genomic sequences, local homology
identification, local structure characterization, comparative genomics, etc.
PMID- 10786306
TI - A linear time algorithm for finding all maximal scoring subsequences.
AB - Given a sequence of real numbers ("scores"), we present a practical linear time
algorithm to find those nonoverlapping, contiguous subsequences having greatest
total scores. This improves on the best previously known algorithm, which
requires quadratic time in the worst case. The problem arises in biological
sequence analysis, where the high-scoring subsequences correspond to regions of
unusual composition in a nucleic acid or protein sequence. For instance,
Altschul, Karlin, and others have used this approach to identify transmembrane
regions, DNA binding domains, and regions of high charge in proteins.
PMID- 10786307
TI - Database screening for HIV protease ligands: the influence of binding-site
conformation and representation on ligand selectivity.
AB - Screening for potential ligands and docking them into the binding sites of
proteins is one of the main tasks in computer-aided drug design. Despite the
progress in computational power, it remains infeasible to model all the factors
involved in molecular recognition, especially when screening databases of more
than 100,000 compounds. While ligand flexibility is considered in most
approaches, the model of the binding site is rather simplistic, with neither
solvation nor induced complementary usually taken into consideration. We present
results for screening different databases for HIV-1 protease ligands with our
tool Slide, and investigate the extent to which binding-site conformation,
solvation, and template representation generate bias. The results suggest a
strategy for selecting the optimal binding-site conformation, for cases in which
more than one independent structure is available, and selecting a representation
of that binding site that yields reproducible results and the identification of
known ligands.
PMID- 10786308
TI - A motion planning approach to flexible ligand binding.
AB - Most computational models of protein-ligand interactions consider only the
energetics of the final bound state of the complex and do not examine the
dynamics of the ligand as it enters the binding site. We have developed a novel
technique for studying the dynamics of protein-ligand interactions based on
motion planning algorithms from the field of robotics. Our algorithm uses
electrostatic and van der Waals potentials to compute the most energetically
favorable path between any given initial and goal ligand configurations. We use
probabilistic motion planning to sample the distribution of possible paths to a
given goal configuration and compute an energy-based "difficulty weight" for each
path. By statistically averaging this weight over several randomly generated
starting configurations, we compute the relative difficulty of entering and
leaving a given binding configuration. This approach yields details of the energy
contours around the binding site and can be used to characterize and predict good
binding sites. Results from tests with three protein-ligand complexes indicate
that our algorithm is able to detect energy barriers around the true binding site
that distinguish this site from other predicted low-energy binding sites.
PMID- 10786309
TI - An exact method for finding short motifs in sequences, with application to the
ribosome binding site problem.
AB - This is an investigation of methods for finding short motifs that only occur in a
fraction of the input sequences. Unlike local search techniques that may not
reach a global optimum, the method proposed here is guaranteed to produce the
motifs with greatest z-scores. This method is illustrated for the Ribosome
Binding Site Problem, which is to identify the short mRNA 5' untranslated
sequence that is recognized by the ribosome during initiation of protein
synthesis. Experiments were performed to solve this problem for each of fourteen
sequenced prokaryotes, by applying the method to the full complement of genes
from each. One of the interesting results of this experimentation is evidence
that the recognized sequence of the thermophilic archaea A. fulgidus, M.
jannaschii, M. thermoautotrophicum, and P. horikoshii may be somewhat different
than the well known Shine-Dalgarno sequence.
PMID- 10786310
TI - Seamless integration of biological applications within a database framework.
AB - There are more than two hundred biological data repositories available for public
access, and a vast number of applications to process and interpret biological
data. A major challenge for bioinformaticians is to extract and process data from
multiple data sources using a variety of query interfaces and analytical tools.
In this paper, we describe tools that respond to this challenge by providing
support for cross-database queries and for integrating analytical tools in a
query processing environment. In particular, we describe two alternative methods
for integrating biological data processing within traditional database queries:
(a) "light-weight" application integration based on Application Specific Data
Types (ASDTs) and (b) "heavy-duty" integration of analytical tools based on
mediators and wrappers. These methods are supported by the Object-Protocol Model
(OPM) suite of tools for managing biological databases.
PMID- 10786311
TI - Pharmaceutical target discovery using Guilt-by-Association: schizophrenia and
Parkinson's disease genes.
AB - We wish to identify genes associated with disease. To do so, we look for novel
genes whose expression patterns mimic those of known disease-associated genes, a
method we call Guilt-by-Association (GBA). GBA uses a combinatoric measure of
association that provides superior results to those from correlation measures
used in previous expression analyses. Using GBA, we have examined the expression
of 40,000 human genes in 522 cDNA libraries, and have identified several hundred
genes associated with known cancer, inflammation, steroid-synthesis, insulin
synthesis, neurotransmitter processing, matrix remodeling and other disease
genes. The majority of the genes thus discovered show no significant sequence
similarity to known genes, and thus could not have been identified by homology
searches. We present here an example of the discovery of five genes associated
with schizophrenia and Parkinson's disease. Of the 40,000 most-abundant human
genes, these five genes are the most closely linked to the known disease genes,
and thus are prime targets for pharmaceutical intervention.
PMID- 10786312
TI - Analysis of ribosomal RNA sequences by combinatorial clustering.
AB - We present an analysis of multi-aligned eukaryotic and procaryotic small subunit
rRNA sequences using a novel segmentation and clustering procedure capable of
extracting subsets of sequences that share common sequence features. This
procedure consists of: i) segmentation of aligned sequences using a dynamic
programming procedure, and subsequent identification of likely conserved
segments; ii) for each putative conserved segment, extraction of a locall
homogeneous cluster using a novel polynomial procedure; and iii) intersection of
clusters associated with each conserved segment. Aside from their utilit in
processing large gap-filled multi-alignments, these algorithms can be applied to
a broad spectrum of rRNA analysis functions such as subalignment, phylogenetic
subtree extraction and construction, and organism tree-placement, and can serve
as a framework to organize sequence data in an efficient and easily searchable
manner. The sequence classification we obtained using the method presented here
shows a remarkable consistency with the independently constructed eukaryotic
phylogenetic tree.
PMID- 10786313
TI - Database search based on Bayesian alignment.
AB - The size of protein sequence database is getting larger each day. One common
challenge is to predict protein structures or functions of the sequences in
databases. It is easy when a sequence shares direct similarity to a well
characterized protein. If there is no direct similarity, we have to rely on a
third sequence or a model as intermediate to link two proteins together. We
developed a new model based method, called Bayesian search, as a means to connect
two distantly related proteins. We compared this Bayesian search model with
pairwise and multiple sequence comparison methods on structural databases using
structural similarity as the criteria for relationship. The results show that the
Bayesian search can link more distantly related sequence pairs than other
methods, collectively and consistently over large protein families. If each query
made one error on average against SCOP database PDB40D-B, Bayesian search found
36.5% of related pairs, PSI-Blast found 32.6%, and Smith-Waterman method found
25%. Examples are presented to show that the alignments predicted by the Bayesian
search agree well with structural alignments. Also false positives found by
Bayesian search at low cutoff values are analyzed.
PMID- 10786315
TI - White coat ceremonies for new medical students.
PMID- 10786314
TI - [Efficacy and safety of cefozopran (CZOP) monotherapy and combination therapy
with CZOP and amikacin (AMK) for infections accompanying hematological diseases].
AB - We evaluated efficacy and safety of monotherapy with CZOP (1-2 g x 2/day) and
combination therapy with CZOP (1-2 g x 2/day) and AMK (200 mg x 2/day) for
infections in patients with hematological diseases. Efficacy was evaluated in 71
patients of monotherapy group and 70 patients of combination therapy group.
Underlying diseases were mostly leukemia and lymphoma. Infections included
sepsis, suspected sepsis, pneumonia and so on. Efficacy in CZOP monotherapy was
excellent in 21 patients (31.3%), good in 23 patients (34.3%), fair in 5 patients
(7.5%) and the efficacy rate was 65.7%. On the other hand, in combination
therapy, each was 14 patients (21.2%), 23 patients (34.8%), 12 patients (18.2%)
and the efficacy rate was 56.1%. Side effects such as eruption were noted in 2
patients. Abnormal laboratory findings were noted in 9 patients. All side effects
as well as abnormal laboratory findings were minimal. It was concluded that CZOP
monotherapy was effective in the treatment of various infections accompanying
hematological diseases.
PMID- 10786316
TI - Health professionals have an ethical duty...
PMID- 10786317
TI - Disability, gene therapy and eugenics--a challenge to John Harris.
AB - This article challenges the view of disability presented by Harris in his
article, "Is gene therapy a form of eugenics?" It is argued that his definition
of disability rests on an individual model of disability, where disability is
regarded as a product of biological determinism or "personal tragedy" in the
individual. Within disability theory this view is often called "the medical
model" and it has been criticised for not being able to deal with the term
"disability", but only with impairment. The individual model of disability
presupposes a necessary causal link between a certain condition in the individual
and disablement. The shortcomings of such a view of disability are stated and it
is argued that in order to have an adequate ethical discourse on gene therapy
perspectives from disability research need to be taken into consideration.
PMID- 10786318
TI - Is there a coherent social conception of disability?
AB - Is there such a thing as a social conception of disability? Recently two writers
in this journal have suggested not only that there is a coherent social
conception of disability but that all non-social conceptions, or "medical models"
of disability are fatally flawed. One serious and worrying dimension of their
claims is that once the social dimensions of disability have been resolved no
seriously "disabling" features remain. This paper examines and rejects
conceptions of disability based on social factors but notes that physical and
mental conditions which disadvantage the individual have social dimensions.
PMID- 10786319
TI - Parental consent to cosmetic facial surgery in Down's syndrome.
AB - It is suggested that the practice of attempting to normalise children with Down's
syndrome by subjecting them to major facial plastic surgery has no therapeutic
benefit, and should be seen as multilating surgery comparable to female
circumcision.
PMID- 10786320
TI - The morality of abortion and the deprivation of futures.
AB - In an influential essay entitled Why abortion is wrong, Donald Marquis argues
that killing actual persons is wrong because it unjustly deprives victims of
their future; that the fetus has a future similar in morally relevant respects to
the future lost by competent adult homicide victims, and that, as consequence,
abortion is justifiable only in the same circumstances in which killing competent
adult human beings is justifiable. The metaphysical claim implicit in the first
premise, that actual persons have a future of value, is ambiguous. The Future
Like Ours argument (FLO) would be valid if "future of value" were used
consistently to mean either "potential future of value" or "self-represented
future of value", and FLO would be sound if one or the other interpretation
supported both the moral claim and the metaphysical claim, but if, as I argue,
any interpretation which makes the argument valid renders it unsound, then FLO
must be rejected. Its apparent strength derives from equivocation on the concept
of "a future of value".
PMID- 10786321
TI - Would you like to know what is wrong with you? On telling the truth to patients
with dementia.
AB - OBJECTIVES: To discover what dementia sufferers feel is wrong with them; what
they have been told and by whom, and what they wish to know about their illness.
BACKGROUND: Ethical guidelines regarding telling truth appear to be equivocal.
Declarations of cognitively intact subjects, attitudes of family members and
current psychiatric practice all vary, but no previous research has been
published concerning what patients with dementia would in fact like to know about
their diagnosis and prognosis. DESIGN: Questionnaire study of the patients'
opinions. SETTING: Old Age Psychiatry Service in Worcester. PARTICIPANTS: 30
consecutive patients with dementia. RESULTS: The quality of information received
has been poor and many patients have no opportunity to discuss their illness with
anybody. Despite that almost half of the participants in this study had adequate
insight and a majority declared that they would like to know more about their
predicament. CONCLUSIONS: Although many patients would like to know the truth,
the rights of those who do not want to know should also be respected. Therefore
the diagnosis of dementia should not be routinely disclosed but (just as in other
disorders) health care professionals should seek to understand their patients'
preferences and act appropriately according to their choice.
PMID- 10786322
TI - Decisions to treat or not to treat pneumonia in demented psychogeriatric nursing
home patients: development of a guideline.
AB - Non-treatment decisions concerning demented patients are complex: in addition to
issues concerning the health of patients, ethical and legal issues are involved.
This paper describes a method for the development of a guideline that clarifies
the steps to be taken in the decision making process whether to forgo curative
treatment of pneumonia in psychogeriatric nursing home patients. The method of
development consisted of seven steps. Step 1 was a literature study from which
ethical, juridical and medical factors concerning the patient's health and
prognosis were identified. In step 2, a questionnaire was sent to 26 nursing home
physicians to determine the relative importance of these factors in clinical
practice. In a meeting of nine experienced physicians (step 3), the factors
identified in step 2 were confirmed by most of these professionals. To prevent
the final guideline being too directive, a concept guideline that included
ethical and legal aspects was designed in the form of a "checklist of
considerations" (step 4). Experts in the fields of nursing home medicine, ethics
and law reviewed and commented on the concept guideline (step 5). The accordingly
adapted "checklist of considerations" was tested in a pilot study (step 6), after
which all experts endorsed the checklist (step 7). The resulting "checklist of
considerations" structures the decision making process according to three primary
domains: medical aspects, patient's autonomy, and patient's best interest (see
annex at end of paper).
PMID- 10786323
TI - Death--whose decision? Euthanasia and the terminally ill.
AB - In Australia and Oregon, USA, legislation to permit statutory sanctioned
physician-assisted dying was enacted. However, opponents, many of whom held
strong religious views, were successful with repeal in Australia. Similar
opposition in Oregon was formidable, but ultimately lost in a 60-40% vote
reaffirming physician-assisted dying. This paper examines the human dilemma which
arises when technological advances in end-of-life medicine conflict with
traditional and religious sanctity-of-life values. Society places high value on
personal autonomy, particularly in the United States. We compare the potential
for inherent contradictions and arbitrary decisions where patient autonomy is
either permitted or forbidden. The broader implications for human experience
resulting from new legislation in both Australia and Oregon are discussed. We
conclude that allowing autonomy for the terminally ill, within circumscribed
options, results in fewer ethical contradictions and greater preservation of
dignity.
PMID- 10786324
TI - Paying research subjects: participants' perspectives.
AB - OBJECTIVE: To explore the opinions of unpaid healthy volunteers on the payment of
research subjects. DESIGN: Prospective cohort. SETTING: Southern Alberta, Canada.
PARTICIPANTS: Medically eligible persons responding to recruiting advertisements
for a randomised vaccine trial were invited to take part in a study of informed
consent at the point at which they formally consented or refused trial
participation. Of 72 invited, 67 (62 trial consenters, 5 trial refusers) returned
questionnaires at baseline and 54 at follow-up. OUTCOME MEASURES: Proportions of
persons who agreed or disagreed with three close-ended statements on the payment
of research subjects; themes and categories identified by content analysis of
responses to an open-ended question. RESULTS: A minority (43.3%) agreed with
paying either patient or healthy volunteer participants. Opinions did not change
over time. Participants' comments addressed: benefits and drawbacks to research
participation; benefits and drawbacks to paying research participants; conditions
under which payment of research subjects would be acceptable, and the nature of
acceptable recognition. Acceptable conditions were to improve problematic
recruitment, to reimburse costs, and to recognise participants, particularly for
their time investment. Both non-monetary and monetary recognition of volunteers
were thought to be appropriate. CONCLUSIONS: Most unpaid volunteers disagreed
with paying research participants. The themes arising from their comments are
similar to those that have been raised by ethicists and suggest that recognising
the time and effort of participants should receive greater emphasis than
presently occurs.
PMID- 10786325
TI - Talking about cases in bioethics: the effect of an intensive course on health
care professionals.
AB - Educational efforts in bioethics are prevalent, but little is known about their
efficacy. Although previous work indicates that courses in bioethics have a
demonstrable effect on medical students, it has not examined their effect on
health care professionals. In this report, we describe a study designed to
investigate the effect of bioethics education on health care professionals. At
the Intensive Bioethics Course, a six-day course held annually at Georgetown
University, we administered a questionnaire requiring open-ended responses to
vignettes both before and after the course. Following the course, respondents
defended their responses more carefully and articulated their thoughts more
clearly. In addition, after the course respondents seemed to have a more subtle
understanding of the relevant issues in the cases and applied theory to these
cases more frequently. These findings help to formulate an understanding of the
effect of bioethics education on health care professionals.
PMID- 10786327
TI - Autonomy and identity.
PMID- 10786326
TI - The man who claimed to be a paedophile.
AB - A psychiatrist recounts a case of a man presenting with severe depression who
claimed to have abused children and his pet dog. Clinical management of the case
hinged on whether this claim was true, a lie or delusional. The uncertainty over
this raised complex ethical dilemmas regarding confidentiality and protection of
the public (and animals).
PMID- 10786328
TI - Japanese physicians and the care of adult patients in persistent vegetative
state.
PMID- 10786329
TI - Ethical ethics committees?
PMID- 10786330
TI - [Prognostic significance of advanced atrioventricular block in patients with
acute myocardial infarction].
AB - BACKGROUND: Advanced atrioventricular block (AB) during acute myocardial
infarction (AMI), characterizes a high-risk subgroup of patients. Our aim was to
determine the prognostic significance of AB and its possible peculiarities in
relation to infarction localization and/or the thrombolytic therapy. PATIENTS AND
METHODS: The prospective study involved 1,239 patients with AMI. We studied
clinical characteristics, as well as indexes of infarct size, short and long-term
complications. RESULTS: AB was present in 85 (6.8%) patients and was more often
associated with: previous treatment with diuretics, diabetes, inferior
localisation, higher number of ECG leads with elevated ST segment, and higher
peak of CK. The AB was associated with a higher mortality: in-hospital (27% vs
10.6%; p < 0.01)) and after one-year (31.7% vs 19.4%; p < 0.05). Patients with AB
had a different in-hospital mortality depending on anterior or inferior infarct
localization (66% vs 18.5%; p < 0.001, respectively). In patients receiving
thrombolytic treatment (n = 681), the duration of AB was shorter and in-hospital
mortality was lower (13.7% vs 47%, p < 0.11) than that occurred in patients
without this treatment (n = 558). AB had independent value for predicting in
hospital mortality (OR: 3.56; 95% CI: 1.84-6.90) and one-year mortality (OR:
2.77; 95% CI: 1.52-5.04). CONCLUSIONS: AB is associated with larger infarcts and
higher incidence of complications. The prognosis is especially poor when it is
presented associated with anterior infarction and/or in patients without
thrombolytic treatment. AB is a variable with independent prognostic value on the
mortality.
PMID- 10786331
TI - [High prevalence of vitamin D deficiency in postmenopausal women at a
rheumatology office in Madrid. Evaluation of 2 vitamin D prescription regimens].
AB - BACKGROUND: Vitamin D deficiency has been frequently observed in the elderly
population in Europe. However few information is available about the vitamin D
status in postmenopausal women in the Mediterranean countries. The aim of this
study was to evaluate the vitamin D status assessed by serum 25(OH)D3 (calcidiol)
in postmenopausal women who attended a Rheumatology practice in Madrid area, and
to evaluate calcidiol serum levels through one year after two forms of vitamin D
administration. PATIENTS AND METHODS: Calcidiol serum levels were measured in 171
postmenopausal women (111 with osteoporosis and 60 without osteoporosis). 82
women with calcidiol serum levels < 10 ng/ml were distributed in two groups:
Group I received 800 U/day of vitamin D3 associated with calcium (1 g/day) and
group II, one dose of 80,000 U vitamin D orally as calcidiol and latter a daily
dose of 800 U vitamin D3 plus 1 g calcium. Calcidiol serum levels were measured
by RIA in both groups at basal condition and after three, six and twelve months
under treatment. RESULTS: Three cut-offs were considered: 10, 15 and 20 ng/ml of
calcidiol. Percentages of postmenopausal women with vitamin D deficiency for such
cut-offs were: 35.3%, 64.1% and 87.1%, respectively. After three months of
treatment, women from group II showed calcidiol serum levels higher than group I.
At six and twelve months calcidiol serum levels were similar in both groups.
CONCLUSIONS: A high prevalence of vitamin D deficiency was observed in a group of
postmenopausal women who attended a rheumatology practice in Madrid area. Both
forms of vitamin D administration seem not sufficient to maintain the adequate
calcidiol serum levels in postmenopausal deficient women. A dose of 80,000 U of
calcidiol twice a year should be considered.
PMID- 10786332
TI - [Variability of polyphenol content in different types of wine and its potential
application in the understanding of its biologic effects].
AB - BACKGROUND: Wine polyphenols have antioxidant properties. Different polyphenols
have various biological activities on atherogenesis and carcinogenesis. MATERIAL
AND METHODS: The composition on 5 polyphenols of 16 wines of Castilla (Spain) is
determined by HPLC. RESULTS: Polyphenols concentrations varied largely among the
different wines. Most red wines had higher amounts of polyphenols than white
wines. CONCLUSIONS: The diverse composition on polyphenols of each wine allows to
suggest different biological effects.
PMID- 10786334
TI - [Videothoracoscopic surgery in the year 2000].
PMID- 10786333
TI - [Localization of lung nodules with CT-guided hookwire before videothoracoscopic
surgery].
AB - PURPOSE: To localize peripheral lung nodules under CT guidance using hookwires,
prior to video-assisted thoracic surgery (VATS). PATIENTS AND METHODS: Twenty-two
pulmonary nodules were localized with a hookwire under CT guidance. The visceral
pleura was stained with methylene blue. VATS was performed thereafter. RESULTS:
All nodules were successfully localized and resected without significant
complications. CONCLUSIONS: In select cases, localization of pulmonary nodules
with hook wire and methylene blue allows the thoracoscopic resection of
unaccessible lesions.
PMID- 10786335
TI - [Myths and reality about scientific publication].
PMID- 10786336
TI - [Genetically engineered animals as organ donors in xenotransplantation].
PMID- 10786337
TI - [Severe liver failure and lesions located in liver space in a 33-year-old
patient].
PMID- 10786338
TI - [Safety of antidepressive agents in pregnancy].
PMID- 10786339
TI - [Neurologic manifestations of Schoenlein-Henoch purpura].
PMID- 10786340
TI - [Adequacy of pharmaceutic dosage forms of antiretroviral therapy].
PMID- 10786341
TI - [Lung infection caused by Aspergillus fumigatus and Nocardia asteroides as
complication of glucocorticoid treatment].
PMID- 10786342
TI - [Indiscretion and right to privacy in the health system].
PMID- 10786343
TI - [Withdrawal syndrome and cytalopram].
PMID- 10786344
TI - [Cytokeratins (UBC and CYFRA 21-1) and nuclear matrix proteins (NMP22) as urine
tumor markers in the diagnosis of bladder cancer].
AB - BACKGROUND: The development of urinary tumor markers such as UBC, CYFRA 21-1 and
NMP22 appeared to be non invasive alternative methods for the detection of
bladder cancer. We compared the individual and combined sensitivity of the
urinary tumor markers in the detection of bladder cancer, contrasting them with
the conventional diagnostic procedures. PATIENTS AND METHODS: 237 voided urines
from subjects under risk for bladder cancer were collected immediately before the
endoscopic examinations: 44 patients under suspicion of a primary bladder tumor
and 193 patients under follow-up of a previous bladder cancer were included. UBC
and NMP22 were measured by enzyme-immunoabsorbent-assays and CYFRA 21-1 by an
electro-chemiluminescense-immunoassay. RESULTS: Taking the cutoffs of 9.7
micrograms/l for UBC, 5.4 ng/ml for CYFRA 21-1 and 10.0 U/ml for NMP22
sensitivities were 70%, 69% and 67% for UBC, CYFRA 21-1 and NMP22 at
specificities of 95%, 94% y 80%, respectively. All tumor markers showed higher
sensitivities than urinary cytology (7%), microhematuria (62%) and gross
hematuria (10%) at specificities of 99%, 78% and 99%, respectively. The
combinations of NMP22 plus CYFRA 21-1 reached the highest sensitivity (79%),
slightly lower than simultaneously measuring the three tumor markers (80%).
CONCLUSIONS: The sensitivities of the urinary markers UBC, CYFRA 21-1 and NMP22
appeared to be high enough so as to substitute urinary cytology. The diagnostic
similarity between cytokeratins individually and in each type of patients might
not recommend their simultaneous determination. The combined measurement of NMP22
and one cytokeratin marker (CYFRA 21-1 or UBC) appeared to be the most
recommended.
PMID- 10786345
TI - [Prevalence and clinical significance of antiphospholipid antibodies in chronic
hepatitis C].
AB - BACKGROUND: To know the prevalence of antiphospholipid antibodies in chronic
hepatitis C and their relationship with disease progression. METHODS: One hundred
and twenty-eight patients with chronic hepatitis C and 93 healthy controls were
enrolled up. We determined platelets, ALT, gamma GT, RNAHCV in serum and liver
and non-organ specific antibodies, grade and stage in liver biopsy, risk factors,
duration of disease and alcohol intake were also included. Portal hypertension
and liver function parameters were studied. Antiphospholipid antibodies (APA):
lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) (IgG and IgM) were
measured by EIA. Anti-beta 2 glycoprotein I antibodies were also detected by EIA
in ACA positive patients. RESULTS: Thirty one out of 128 (25%; 95% CI: 17.8%
33.4%) showed positive antiphospholipid antibodies. Positive ACA-IgG was higher
in patients than controls (22% vs 3.2%; p < 0.05), whereas, ACA-IgM was similar
(5% vs 3.2%; p = NS), and LA was absent in both groups. ALT levels, viraemia,
viral load in liver, platelets, or ANA titre were similar in patients with and
without positive ACA-IgG. Risk factors, duration of disease or alcohol intake
were not related yet. Patients with staging F1 showed positive ACA-IgG 4 of 44
(9%; 95% CI: 2.5%-21.7%), in staging F2 7 of 39 (18%; 95% CI: 7.5%-33.5%) and in
staging F4 17 of 45 (38%; 95% CI: 23.8%-53.5%; p < 0.005). ACA-IgG was
significantly related to portal hypertension, Child-Pugh stage and presence of
cirrhosis complications. Anti-beta 2 glycoprotein I antibodies were detected in
ten (43.5%; CI 95%: 23.2%-65.5%) out of 23 ACA positive patients. CONCLUSIONS:
ACA-IgG seems to be associated with chronic hepatitis C, and could play a
potential role in fibrosis progression and liver disease in these patients.
PMID- 10786346
TI - [Effect of topical and oral diclofenac on superficial thrombophlebitis caused by
intravenous infusion].
AB - BACKGROUND: Until present time, suggested treatments for superficial
thrombophlebitis induced by intravenous infusion (TFSI), are of uncertain
effectiveness and most of them or empirical and not fully researched. The aim of
this report is to study the effectiveness and safety of the topical and oral
administration of diclofenac in the treatment of TFSI. PATIENTS AND METHODS: In
this prospective study 120 patients both female and male were included. All of
them developed TFSI during hospitalization and at the same time they were
assigned at random to one of the following groups: G-control (n = 40), without
treatment; G-topical (n = 40), diclofenac emulsion gel used in a topical way on
the concerned area every 8 hours during 48 hours; G-oral (n = 40), diclofenac 75
mg p.o. every 12 hours during 48 hours. The measurements were done at the moment
of diagnosis of TFSI (T0) and 48 hours later (T2). Registries of intensity of
TFSI were done by quantifying flushing, tumor, heatness and pain. These data were
compared considering the averages of differences registered in T2 with respect to
T0. A decrease of intensity of TFSI > or = 30% was considered a positive answer
to this treatment. The quantitative variables were studied with ANOVA, Kruskal
Wallis test or general linear model and the qualitative with the chi 2 test with
Yates correction. The level of significance used was alpha = 0.05. RESULTS: The
averages of differences in the intensity of TFSI that were registered in the
groups G-control, G-topical and G-oral in T2 compared to T0 are: -0.12 (4.89),
5.70 (3.13), -4.82 (3.14) (p = 0.000). The favorable answers in G-control, G
topical and G-oral were: 20, 60 and 60%, respectively (p = 0.0001). The adverse
reactions in G-topical and G-oral were: headache 9-5 (p = 0.2), epigastric pain 4
17 (p = 0.0009), nausea 6-16 (p = 0.01) and local pruritus 5-2 (p = 0.2). The
treatment did not report serious adverse reactions in either of the groups.
CONCLUSION: The topical treatment of diclofenac can be recommended as an
alternative simple, effective and safe therapy for patients who develop TFSI.
PMID- 10786347
TI - [Selection of pharmacologic treatment of arterial hypertension in primary care.
Task force on Pharmacologic Approach of Hypertension in Primary Care (AFHAP)].
AB - BACKGROUND: To assess whether patients' clinical characteristics, and more
specifically contraindications to diuretics or beta-blockers have an influence on
the prescription patterns of antihypertensive drugs. PATIENTS AND METHODS: Cross
sectional descriptive study of consecutive hypertensive patients attending 28
Primary Health Care Centres in Barcelona between November 1997 and February 1998.
Information on patients' clinical characteristics and prescribed antihypertensive
and other drugs was recorded. Hyperuricemia, a previous adverse drug reaction and
potential drug interactions were considered as contraindications to diuretics.
Asthma, chronic obstructive airway disease, peripheral arteriopathy, bradycardia,
atrio-ventricular blockade, type 1 diabetes, a previous adverse drug reaction,
and potential drug interactions were considered as contraindications to beta
blockers. RESULTS: Eighty-three general practitioners and 29 nurses collected
data on 1,813 patients (66% were women and mean age was 68 years). Dyslipemia was
present in 746 patients (41.1%), diabetes in 385 (21.2%), hyperuricemia in 251
(13.8%), coronary heart disease in 218 (12%), and heart failure in 128 (7.1%).
Diuretics were contraindicated in 350 patients (19.3%) and beta-blockers in 537
(29.6%). Eight-hundred seventy-nine patients (48.5%) were prescribed an
angiotensin-converting-enzyme (ACE) inhibitor, 803 (44.3%) a diuretic, 521
(28.7%) a calcium-channel blocker, and 246 (13.6%) a beta-blocker. The
prescription pattern was similar in both patients with existing contraindications
to diuretics or beta-blockers, or without them, and in those with and without
diabetes, heart failure or coronary heart disease and in those whose clinical
characteristics would make the prescription of a diuretic, a beta-blocker or an
ACE-inhibitor a first choice option. Prescription of a diuretic was associated to
age and to existing contraindications to a beta-blocker, whereas the prescription
of a beta-blocker was associated with a history of coronary heart disease.
CONCLUSIONS: The present study suggests that contraindications to diuretics or
beta-blockers are not considered when prescribing antihypertensive drugs. The
results of clinical trials are not applied to clinical practice, and this results
in a high proportion of patients not being offered the benefit of cardiovascular
risk prevention.
PMID- 10786348
TI - [Tumor markers of bladder cancer].
PMID- 10786349
TI - [Arterial hypertension: the better we know it, the worse we treat it].
PMID- 10786350
TI - [Rationale for the need of social planning in the training of new physicians].
PMID- 10786351
TI - [Infective complications in recipients of swine xenotransplant].
PMID- 10786352
TI - [Malignant hypertension, adrenal gland lesions with positive iodomethyl-benzyl
guanidine test in a 30-year-old patient with renal agenesis and kidney transplant
which functioned for 6 years, and subsequent hemodialysis].
PMID- 10786353
TI - [Lansoprazole-induced gynecomastia].
PMID- 10786354
TI - [Gestational diabetes mellitus: systematic or selective screening? The debate
continues].
PMID- 10786355
TI - [ANCA-positive vasculitis associated with propylthiouracil].
PMID- 10786356
TI - [Methadone withdrawal syndrome induced by nevirapine].
PMID- 10786357
TI - [Factors associated with the accumulation of abdominal fat estimated with
anthropometric indexes].
AB - BACKGROUND: To evaluate lifestyle and dietary intake factors influencing the
accumulation of abdominal fat in a Mediterranean population. SUBJECTS AND METHOD:
A cross-sectional study was carried-out in Spain (Asturias, Granada, Murcia,
Navarra and Guipuzkoa) among 23,228 women and 14,332 men aged 29-69 years,
participants of a large European prospective cohort (EPIC). Information on usual
food intake and other non-dietary factors were collected by interviews. Height,
weight, waist circumference and hip circumference were taken by previously
trained interviewers. RESULTS: In a multiple-linear regression analysis sports
activities and educational level were negatively associated with abdominal
obesity, while body mass index, age, tobacco and alcohol consumption, saturated
fat intake and increased prevalence of hypertension, diabetes and myocardial
infarction were positively associated. All dietary and non-dietary variables
accounted for 22 and 27% of variance in the waist/hip ratio and 74 and 66% of
variance in the waist circumference, in women and men respectively. CONCLUSIONS:
Body mass index and age are the most important factors influencing the
accumulation of abdominal fat. Dietary factors and other lifestyle factors seem
to play a minor role in increasing abdominal obesity.
PMID- 10786358
TI - [Laboratory diagnosis and serologic course in patients with tularemia].
AB - BACKGROUND: Tularemia was practically unknown in Spain until the end of 1997,
when an epidemic outbreak was declared. This paper presents the data on
microbiological diagnosis of 55 patients who suffered from tularemia. PATIENTS
AND METHODS: Thirty-two samples from 19 patients and 151 serum samples from 55
patients were obtained for culture. Serologic diagnosis was performed by tube
sero-agglutination and microagglutination. Three types of tests were performed on
all sera: Wright sero-agglutination (WSA), Coombs test against Brucella spp. and
sero-agglutination against Yersinia enterocolitica O:3, Yersinia enterocolitica
O:3, and Proteus OX 19. RESULTS: F. tularensis was found in two samples (6.25%)
of the 32 received. Titers > or = 1/160 were obtained in 78.2% and 74.5% of the
initial sera by tube sero-agglutination and microagglutination, respectively.
Correlation between the two tests was 0.80 (p < 0.001). Prozone phenomenon was
observed in 59.9% of the sera, while crossed reactivity to Brucella spp. and
Proteus spp. was found in 9.3% and 22.8%, respectively. No crossed reactivity was
observed with Yersinia spp. CONCLUSIONS: Culture of F. tularensis has low
sensitivity. The correlation obtained between tube sero-agglutination and
microagglutination is good. Both techniques are useful in routine diagnosis of
tularemia, although microagglutination has some advantages over tube
agglutination.
PMID- 10786359
TI - [Hodgkin's disease. Etiopathogenic role of Epstein-Barr virus in Tarragona].
AB - BACKGROUND: The aim of this study is to assess the proportion of Hodgkin disease
(HD) expressing Epstein-Barr virus (EBV) in our area (Tarragona-Spain). PATIENTS
AND METHODS: A retrospective study was performed on paraffin embedded HD tissues
from 49 patients to examine the presence of latent membrane protein (LMP-1) by
immunohistochemistry and for EBER-1 in situ hybridization. RESULTS: Overall, EBV
(EBER-1 and/or LMP positive) was expressed in 20 cases (40.8%). This percentage
was higher, but not significant, in mixed cellularity, and significant higher in
patients over 55 years old. No differences between sexes were observed.
CONCLUSIONS: EBV is associated with 40.8% of HD in area of Tarragona.
PMID- 10786360
TI - [Folic acid ingestion and associated factors in adult women 15-44 years of age in
the Valencian Community].
AB - BACKGROUND: A low folic acid (FA) intake may increase the risk of neural tube
defects (NTD). We estimated the proportion of women with a FA intake < 400
micrograms/day, at the Valencian Region, exploring those factors associated with
a FA intake < 400 micrograms/day. SUBJECTS AND METHOD: Daily FA intake was
estimated for 538 women aged 15 to 44 years participants in the Nutrition Survey
of Valencian Region in 1994, and factors associated with an intake lower than 400
micrograms/day were analyzed. RESULTS: The average FA intake was 392
micrograms/day. A 57.6% of women presented a low FA intake. A higher prevalence
of low FA intake was found among youngest women with low sports practice, low
body mass index and early menarche. CONCLUSIONS: A high proportion of women with
a FA intake considered at risk for NTD was observed, particularly among the
youngest with low sports practice.
PMID- 10786361
TI - [Abdominal obesity: is the waist/hip ratio useful?].
PMID- 10786362
TI - [What can we expect from continuing medical education? Myths and reality].
PMID- 10786363
TI - [Angiostatin and its antitumor activity].
PMID- 10786364
TI - [Incidence of tuberculous infection in a Spanish prison].
PMID- 10786365
TI - [Gordon's syndrome, type II pseudohypoaldosteronism, Spitzer-Weinstein syndrome,
and chloride shunt syndrome, or the 4-name disease].
PMID- 10786366
TI - [Treatment of amyloidosis secondary to rheumatoid arthritis with methotrexate].
PMID- 10786367
TI - [Telomerase and cancer].
PMID- 10786368
TI - [Integrins and their role in malignant neoplasm progression].
PMID- 10786369
TI - [Antigen CD44: does the presence of its isoforms have significance for diagnosis
for diagnosis of colorectal cancer?].
PMID- 10786370
TI - [Actin isoforms--functional differentiation, changes in cell pathology].
PMID- 10786371
TI - [Transport of proteins and RNA between the nucleus and the cytoplasm].
PMID- 10786372
TI - [The significance of thrombomodulin in regulation of coagulation and
fibrinolysis].
PMID- 10786373
TI - [Eukaryotic plasmids].
PMID- 10786374
TI - [Mechanism of arsenic compound resistance in prokaryotes and eukaryotes].
PMID- 10786375
TI - [Mutagenicity an carcinogenicity of aflatoxin AFB1].
PMID- 10786376
TI - [Combinatorial biosynthesis of novel macrolides and other complex polyketides].
PMID- 10786377
TI - [Induced chlorophyll fluorescence as a source of information about photosynthesis
processes in plants and their environmental conditions].
PMID- 10786378
TI - ATSDR evaluation of health effects of chemicals. VI. Di(2-ethylhexyl)phthalate.
Agency for Toxic Substances and Disease Registry.
AB - Di(2-ethylhexyl)phthalate (also known as DEHP, bis(2-ethylhexyl)phthalate, or
BEHP; CAS Registry Number 117-81-7) is a widely-used plasticizer. It is found in
numerous plastic articles, such as paints, inks, floor tiles, upholstery, shower
curtains, footwear, plastic bags, food-packaging materials, toys, and medical
tubing. Not surprisingly, DEHP appears at many waste sites. As part of its
mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares
toxicological profiles on hazardous chemicals that are of greatest public health
concern at Comprehensive Environmental Response, Compensation, and Liability Act
(CERCLA) National Priority List (NPL) sites. These profiles comprehensively
summarize toxicological and environmental information. This article constitutes
the release of the bulk of ATSDR's profile for DEHP (ATSDR, 1993) into the
mainstream scientific literature. An extensive listing of human and animal health
effects, organized by route, duration, and endpoint, is presented. Toxicological
information on toxicokinetics, biomarkers, interactions, sensitive
subpopulations, reducing toxicity after exposure, and relevance to public health
is also included. Environmental information encompasses physical properties,
production and use, environmental fate, levels seen in the environment,
analytical methods, and a listing of regulations. ATSDR, at the behest of
Congress and therefore the citizenry, prepares these profiles to inform the
public about site contaminants.
PMID- 10786379
TI - Congenital anomaly: middle ear malformation.
PMID- 10786380
TI - Anatomy of the uncinate process.
PMID- 10786381
TI - Vocal fold hemangioma.
PMID- 10786382
TI - Osteogenesis imperfecta.
PMID- 10786383
TI - A patient with Meniere's syndrome: ear-under nystagmus is opposite of clinical
findings; caloric result shows directional preponderance.
PMID- 10786384
TI - Intralesional cidofovir for recurrent laryngeal papillomas: preliminary report.
AB - This is a preliminary report of an ongoing study to test the efficacy of
intralesional injections of the antiviral drug cidofovir in adults with recurrent
laryngeal papillomas in whom multiple other treatments have previously failed.
This study has been designed to include 10 to 20 patients, a number sufficient to
either prove or disprove the safety and efficacy of this agent. This report
conveys information on the first three patients enrolled in the trial. Each
patient received an overall dose of 5 to 10 ml of cidofovir, at a concentration
of 4.17 mg/ml, intralesionally at 2- to 4-week intervals. The approximate volume
injected into each wart was 0.2 to 0.5 ml. Biopsies of the lesion sites were
obtained at the initiation and completion of therapy. No other treatment was
given. Resolution of lesions was monitored by videolaryngoscopy and still
photography 1 to 2 weeks after each treatment. In time, the lesions resolved in
all three patients, although all three later experienced a minor recurrence. We
conclude that intralesional cidofovir appears to be a promising new treatment for
controlling--and perhaps at higher dosages curing--refractory laryngeal
papillomas, while causing little or no injury to laryngeal structures.
PMID- 10786385
TI - Professionalism, where are you?
AB - The practice of medicine continues to evolve in ways that are not always
compatible with good patient care, and physicians now control less and less of
their practices. One of the casualties of the new health economics is the concept
of professionalism, which becomes more difficult to adhere to in the face of
restrictions placed by outside forces. Nevertheless, physicians can maintain a
sense of professionalism despite all the difficulties. Indeed, we must do so in
order to remain true to our ideals.
PMID- 10786386
TI - A case of squamous papilloma after uvulopalatopharyngoplasty.
AB - We report the case of an adult who developed an isolated-solitary papilloma on
the margin of the soft palate 1 month after he had undergone a
uvulopalatopharyngoplasty. We describe the clinical and cellular characteristics
of this common lesion.
PMID- 10786387
TI - Loratadine/pseudoephedrine for nasal symptoms in seasonal allergic rhinitis: a
double-blind, placebo-controlled study.
AB - In this double-blind, placebo-controlled, crossover, parallel study, we treated
20 adults who had seasonal allergic rhinitis with once-daily fixed-combination
loratadine/pseudoephedrine sulfate to observe its effect on relieving symptoms,
primarily nasal congestion. Acoustic rhinometry detected a trend toward
improvement in nasal patency, although the difference between pre- and post
treatment measures was not statistically significant. Endoscopic inferior
turbinate photography documented that treatment led to statistically significant
reductions in the amount of nasal edema and nasal secretions. The results of a
quality-of-life questionnaire suggested that treatment alleviated nasal and
ocular symptoms of rhinoconjunctivitis. An analysis of subjective visual analog
scale scores showed a trend toward improvement in most but not all nasal
symptoms. We conclude that once-a-day fixed-combination
loratadine/pseudoephedrine is effective in relieving nasal congestion in patients
with seasonal allergic rhinitis.
PMID- 10786388
TI - eMedicine Otolaryngology: an online textbook for ENT specialists.
AB - A new online publishing effort, eMedicine Otolaryngology-Facial Plastic Surgery
(FPS), is a comprehensive textbook now being developed on the Internet
(www.emedicine.com). This book is one of a series of 15 electronic textbooks
written by a worldwide panel of authors and editors, and it is distributed free
of charge to anyone with a computer and a modem. Advantages of online textbooks
such as eMedicine Otolaryngology-FPS are that they provide readers with easy
accessibility to reliable, up-to-date information, and they allow authors to
quickly edit and revise editorial content and supplement traditional text with
sound, graphics, and video. An ambitious undertaking, eMedicine Otolaryngology
FPS represents a significant advance in the way medical information is written,
edited, and distributed. Although it is unlikely that electronic textbooks will
replace traditional textbooks any time soon, these types of publishing efforts
will continue to proliferate.
PMID- 10786389
TI - Bilateral laryngoceles in a young trumpet player: case report.
AB - We report the case of a 16-year-old trumpet player who was referred for an
otolaryngologic consultation after his band leader noticed that a neck mass would
protrude while the boy was playing. X-rays revealed the presence of bilateral
laryngoceles, and computed tomography demonstrated bilateral, air-filled
outpouchings of the laryngeal saccules during forced expiration. There was no
evidence of any other intra-laryngeal or cervical pathology. Surgery was deferred
while the laryngoceles remained reducible and asymptomatic, and the boy was
cleared to continue playing.
PMID- 10786390
TI - Rebuilding the inferior turbinate with hydroxyapatite cement.
AB - This article describes a method of reconstructing a totally resected inferior
turbinate with hydroxyapatite cement in patients who experience symptoms often
associated with an overzealous resection of the turbinate (the "empty nose"
syndrome).
PMID- 10786391
TI - Aggressive combination treatment for invasive fungal sinusitis in
immunocompromised patients.
AB - Invasive sinonasal fungal disease is a potentially fatal complication of
chemotherapy-induced immunosuppression and neutropenia. We reviewed the outcomes
of seven cancer patients who had been diagnosed with invasive fungal sinusitis;
six patients had hematologic malignancies and one had breast cancer. At the time
of their sinus diagnosis, all patients had been hospitalized and were receiving
combination chemotherapy for their underlying malignancy. Impairment of their
immune function was characterized by an absolute neutrophil count of less than
1,000/mm3. Aggressive management of their sinonasal fungal disease consisted of
surgical debridement and systemic amphotericin B for all patients, and treatment
with granulocyte colony-stimulating factor for two patients. Invasive Aspergillus
infection was identified in six patients and invasive Candida albicans infection
in one. Although the prognosis for these patients was poor and two patients died
of the fungal infection, the aggressive treatment strategy resulted in long-term
survival for the remaining five patients.
PMID- 10786392
TI - Transient speech compromise following sublabial transsphenoidal surgery: a case
report and findings of a small preliminary study.
AB - Sublabial transsphenoidal surgical removal of pituitary tumors is a common
procedure with minimal complications. Although many investigators have reported
oral sensory compromises following surgery, none has reported any postoperative
compromise in speaking ability. In this article, we describe the case of a 33
year-old woman who developed transient but severe speech symptoms after she
underwent sublabial transsphenoidal surgery. This case prompted us to undertake a
brief retrospective analysis of our experience with this procedure in other
patients, which revealed that speech compromise is far more common than
heretofore realized.
PMID- 10786393
TI - Treatment of otitis media with effusion based on politzerization with an
automated device.
AB - This study evaluated the efficacy of politzerization with an automated, hand-held
device that controls volume velocity (airflow) in the treatment of 20 children
with otitis media with effusion. These patients underwent politzerization twice a
week for up to 6 weeks. Another 20 children with otitis media with effusion who
were not treated with politzerization served as controls. Following treatment,
resolution of the average air-bone gap to within normal limits was achieved in
70% of the treated group and 20% of the controls, which eliminated the need for
grommet insertion in these patients. Improvement in tympanometric peak pressure
was also significantly greater in the treated group. Politzerization was
efficiently and successfully performed in all patients. The automated device's
ease of administration and its ability to control airflow suggests that it has
the potential to be an effective home treatment that can be administered by the
parents or guardians of children who have otitis media with effusion.
PMID- 10786394
TI - Superior adenoidectomy in children with palatal abnormalities.
AB - When treating a child with a palatal abnormality for otitis media or a nasal
obstruction, otolaryngologists often face the question of whether the benefits of
adenoidectomy are worth the risk of the development of velopharyngeal
insufficiency. Treatment options for these patients include a complete
adenoidectomy, a partial adenoidectomy, or no surgical intervention. In this
retrospective study, we describe the outcomes of 22 such patients who were
treated with a superior adenoidectomy performed with a St. Clair adenoidforceps
under indirect vision with a laryngeal mirror. All patients experienced a
complete or near-complete resolution of their nasal obstruction, and none
developed permanent velopharyngeal insufficiency. Only three patients experienced
a recurrence of otitis media. Our experience suggests that superior adenoidectomy
is a safe and effective procedure.
PMID- 10786395
TI - Management of the unknown primary in patients with metastatic cancer of the head
and neck.
AB - The evaluation of the patient with metastatic cervical lymph node squamous cell
carcinoma and an unknown primary tumor frequently involves the use of guided
biopsies as a diagnostic tool. This study was performed to assess the
effectiveness of these biopsies. Using a retrospective chart review, we
identified 25 patients who had undergone a total of 100 guided biopsies to
evaluate an unknown primary malignancy of the head and neck. We found that 99 of
the 100 biopsies were negative for malignancy. Although guided biopsies were
obviously not helpful in these cases, we believe this might be attributable to
the fact that the method of performing them is inconsistent among surgeons.
Therefore, we present an algorithm for the management of the unknown primary head
and neck malignancy, including recommendations regarding the use of guided
biopsies.
PMID- 10786396
TI - Removal of a fish bone in the thyroid gland without the need for thyroid
lobectomy.
AB - We report the first published case of the removal of a migratory fish bone from
the thyroid gland that did not necessitate a thyroid lobectomy.
PMID- 10786397
TI - Pneumoparotid: a case report and review of its pathogenesis, diagnosis, and
management.
AB - Pneumoparotid is considered to be a rare entity, but the diagnosis might not be
as uncommon as reported. We report a case in which computed tomography
incidentally revealed air in the parotid ducts bilaterally. Treatment is aimed at
the elimination of predisposing and causative factors, but because our patient
denied any symptoms or precipitating factors and had a benign presentation, no
immediate intervention was initiated.
PMID- 10786398
TI - [HPV viral typing].
PMID- 10786399
TI - [The Human Genome Project and the genetics of infertility].
AB - Nine years after the beginning and five years before the expected end of the
Human Genome Project, we will have access in several months to 90% of the human
genome sequence. This data certainly opens promising vistas to the better
understanding of gametogenesis. This will allow the different types of sterility
to be studied through new approaches. The aim of the current review is to
describe how the Human Genome Project has proceeded in the last ten years. We
also discuss to what extent the knowledge of the human genome sequence is
important in understanding the genetic basis of some diseases, such as human
infertility. Finally, we review the different methodologies to use this
information and their limits.
PMID- 10786401
TI - [Therapeutic management of ovarian dystrophy and insufficiency in abortion
disorders: recent data].
AB - Many reports suggested that the high rate of miscarriage in women with polycystic
ovaries may be due to increased urine and/or plasma LH concentration. In fact,
with the exception of pulsatile GnRH, any treatment likely to increase the plasma
LH level results in unchanged or rather low miscarriage rates. Conversely, a
reduction in this rate by GnRH agonists is not conclusive. Excess weight may also
increase the risk of miscarriage. In women with incipient ovarian failure, the
miscarriage rate is mainly linked to age. No stimulation has been found to be
effective in these patients. There is a need for more extensive evaluation in
GnRH analog microdoses, recombinant FSH and GnRH antagonists. Oocyte donations
from younger women are difficult to obtain because of the lack of donors in
France.
PMID- 10786400
TI - [Hormone replacement therapy after endometrial or ovarian cancer].
AB - Use of hormonal replacement therapy after treatment of ovarian or endometrial
cancer remains a matter of debate. Novel adjuvant therapies tend to increase the
survival of these patients, who are exposed to risk factors of hormonal
deficiency subsequent to primary therapy. Therefore, the aims of the present
review of literature was to analyse epidemiologic and clinical parameters on
behalf on hormonal replacement therapy in this population.
PMID- 10786402
TI - [Future perspectives: oocyte cryopreservation and in vitro maturation].
AB - After treatment for neoplasia, a young patient can nowadays hope to be pregnant.
The aim of this paper is to establish a review of the literature about
cryopreservation of oocytes and ovarian tissue, and in vitro maturation of
oocytes. These studies also concern patients for which ovarian stimulation is
difficult, such as PCOS. These techniques could also facilitate the creation of
an oocyte bank as the one already existing for sperm. So far the main studies
published, in spite of very timid first results, allow us to look to a great
future for cryopreservation and in vitro maturation of oocytes.
PMID- 10786403
TI - [Prognostic factors for survival of ovarian epithelial cancers: apropos of 287
cases].
AB - OBJECTIVES: To evaluate survival and assess prognostic factors in patients with
epithelial ovarian cancer. METHODS: Retrospective analysis of 287 patients
treated between 1975 and 1995. All operations were performed by senior surgeons.
Histologic sections were reviewed by the same pathologist. Successive adjuvant
chemotherapy regimens are described. Survival was evaluated in 1997. Follow-up
lasted 25-260 months (median 90). Statistical methods included Kaplan-Meier
survival curves, logrank test and multivariate analysis. RESULTS: The five-year
survival rates 76%, 42%, 21% and 6% for patients with stage I, II, III and IV
disease, respectively. Age, FIGO stage, cytology of ascites, histologic type and
grade, extent of surgery and number of residual tumors were significant
prognostic indicators in univariate analysis. Multivariate analysis showed that
the risk of mortality was reduced by 57% for patients whose tumor distribution
permitted optimal surgery (RR = 0.43, 95% CI [0.29-0.64]; P < 0.001). The risk of
mortality according to FIGO stage was 2.8 (95% CI [1.2-6.3]; P = 0.01) for FIGO
II, 5.6 (95% CI [2.9-10.8]; P < 0.001) for FIGO III and 10.5 (95% CI [4.9-22.1];
P < 0.001) for FIGO IV in comparison with FIGO I. The risk of mortality for
patients treated with alkylating agents, platinum-based combination chemotherapy
taxanes or carboplatin plus paclitaxel regimen compared with patients who did not
receive treatment was reduced by 47% (95% CI [8%-69%]; P = 0.025), 55% (95% CI
[22%-74%]; P = 0.005) and 70% (95% CI [35%-86%]; P = 0.002), respectively.
Patients with a serous epithelial carcinoma had a 1.7-fold higher risk of
mortality than patients with other histologic types (RR = 1.7, 95% CI [1.1-2.8];
P = 0.02). CONCLUSION: Our study confirms the benefit of cytoreductive surgery
and the efficacy of platinum plus paclitaxel first-line chemotherapy, which has
recently been recognized as the standard treatment for advanced epithelial
ovarian cancer.
PMID- 10786404
TI - [Laparoscopy and bladder endometriosis].
AB - Partial cystectomy is in the great majority of the cases the treatment of choice
for patients with bladder endometriosis. The aim is to assess the methods,
indications and results of operative laparoscopy for patients presenting with
bladder endometriosis. We perform a descriptive retrospective study of 13 cases.
All patients presenting with bladder endometriosis infiltrating the bladder
muscularis between January 1, 1993 and June 30, 1998 were included in this
series. It was possible to treat bladder endometriosis in all the patients by
performing a laparoscopic partial cystectomy. With an average follow-up of 29.3
+/- 24.6 months (range 4-77) the results are satisfactory. Neither peri- nor
postoperative complications were observed. The patients experienced an
improvement in their condition, with complete disappearance of the urinary
symptoms in every case. No recurrence of the functional urological symptoms
occurred. Provided the surgeons are skilled and the lesions require no ureteral
reimplantation, operative laparoscopy is a valid alternative to laparotomy for
partial cystectomy.
PMID- 10786406
TI - [Vaginal dryness in the menopausal woman (physiological and psychological
aspects)].
PMID- 10786405
TI - [Evaluation of the efficacity and speed of action of sertaconazole nitrate
suppository and cream combined treatment for vulvovaginal candidiasis].
AB - OBJECTIVE: To assess efficacy and speed of action of a monodose sertaconazole
vaginal suppository administered as a single treatment or combined with
sertaconazole cream applied to the vulvar area. METHODS: This prospective,
multicentric, randomised open study was conducted on 77 women with vulvovaginal
candidiasis confirmed by mycological examination. They were either treated with
one sertaconazole monodose vaginal suppository only (group O) or treated with the
suppository combined with sertaconazole cream applied to the vulvar area for 7
days (group OC). The patients who were not clinically cured at D7 received a
second phase of treatment. RESULTS: Clinical cure rates were higher in group OC
than in group O at D7 (76% versus 68%), and D14 (100% versus 80%). The efficacy
on symptoms was faster in group OC, with 78% of the patients relieved of pruritus
as early as D2 versus 61% in group O, although these differences were not
significant. Clinical local tolerance was very good, with 95% of patients not
experiencing any local side effects. CONCLUSION: When candidiasis is both vulvar
and vaginal, the combination of sertaconazole cream with a monodose sertaconazole
vaginal suppository tends to improve clinical cure at D7 and D14 and to relieve
more patients as early as D2 than the vaginal suppository used as a single
treatment.
PMID- 10786407
TI - [Cervico-uterine cytology in liquid media: procedures and results of the ThinPrep
Pap Test].
PMID- 10786408
TI - [How should we consider luteal insufficiency in fertility?].
PMID- 10786409
TI - Peer-led and adult-led programs--student perceptions.
AB - This research examines whether peer-led prevention programs are preferable to
adult-led programs. Participants were 2,447 students in 94 classes, from 31
schools running drug prevention programs. The schools were divided into two
groups according to the model they used in their program: fifteen schools used
peer-led model, while sixteen used the adult-led model. A 46-item questionnaire
was constructed in order to examine the students' perception of the programs. The
results show that all the input measures (content, atmosphere, openness,
discipline, facilitators' competence) and the outcome measures (satisfaction,
knowledge, avoidance, curiosity, personal relationship) were perceived as more
positive in the peer-led model. The differences were small, but significant.
While the findings suggest that the peer-led model has a somewhat greater
potential for primary prevention, the differences found do not enable us to state
with certainty that this model is preferable for primary prevention purposes.
PMID- 10786410
TI - "I'Ve had too much done to my heart": the dilemma of addiction and recovery as
seen through seven youngsters' lives.
AB - Aware of the dearth of in-depth studies on recovering adolescent
addict/alcoholics, we conducted a year-long qualitative study of seven formerly
addicted youth committed to recovery. The research question was: how do addicted
youth become and remain sober? Bending to social stress, including racism and
ethnic prejudice, three participants relapsed. However, personal commitment
augmented by familial, community, spiritual, and educational support encouraged
four to remain sober. Learning from both those who failed and succeeded, the
theoretical concepts of surrender, social stress, and resiliency helped to
interpret the participants' patterns of response and better understand adolescent
recovery.
PMID- 10786411
TI - Preventing alcohol abuse: an examination of the "Downward Spiral" game and
educational videos.
AB - Downward Spiral is a board game developed by the authors to illustrate the
dangers of continued substance abuse. Previous work has found that college
students and probationers find the game interesting, enjoyable, useful, and
realistic [1]. In the current study, college students either played Downward
Spiral, watched educational videos on substance abuse, or completed a set of
questionnaires unrelated to alcohol and drug abuse. Those students who either
played the game or watched the videos rated both as beneficial. However, students
who watched videos had somewhat higher levels of consumer satisfaction. Students
who played the game rated it as smoother, and they felt more positive following
the session than students who watched videos. Both videos and the game increased
students' intentions to limit alcohol consumption compared to students who served
as controls. Individuals in the game group also indicated significantly greater
intentions to change their alcohol behavior than those in the other groups.
PMID- 10786412
TI - Factors in marijuana cessation among high-risk youth.
AB - The rise in marijuana use among high school students has generated considerable
concern. The apparent failure of current marijuana control efforts may be due in
part to ignorance about why students use marijuana and what influences them to
consider quitting. This article utilized both open-ended and multiple-choice
surveys as well as health educator-led focus groups to assess issues related to
marijuana use and cessation among a population of high-risk youth. A total of 842
students participated, assessed as two separate samples from eleven continuation
high schools in southern California. Approximately 70 percent of the students are
current marijuana users. Interpreting results across both samples, it is apparent
that interest in quitting marijuana use among continuation high school students
is high. Over half of the marijuana users surveyed have tried to quit and failed.
Still, several social images associated with marijuana smokers are positive and
subjects express a lack of confidence in the efficacy of marijuana cessation
clinic programs. Subjects believe that either self-help or punitive methods are
the most effective types of marijuana cessation activities. A reportedly high
rate of failed quit attempts suggests that effective marijuana cessation programs
are needed in this population. Future programs must address both reasons users
resist change, including use of marijuana as a stress reliever, and the
particular motivations that subjects report regarding why they desire to quit
using marijuana, including legal, vocational, and health consequences.
PMID- 10786413
TI - Effectiveness of refusal skills software.
AB - This research explores the potential of making social skills training more
accessible to schools by the use of computer-aided instruction. An easy-to-use
software program called Refusal Challenges, which targets important social skills
with effective training methods, was tested. The dependent measure was
demonstration of refusal skills strategies. One-hundred-eighty-eight male and
female eighth-grade students were stratified according to pre-treatment refusal
skill level, gender, and teacher. They were then randomly assigned from the
stratified blocks to either the computer-based refusal skills training group or a
control group. Repeated measures analyses of variance indicated a significant and
meaningful time by treatment interaction for refusal skills scores. The
difference between treatment and control groups remained significant and
meaningful at both the post-test and follow-up testing.
PMID- 10786414
TI - Prevention training of paraprofessionals in the schools: an examination of
relevancy and effectiveness.
AB - Prevention training programs for paraprofessional school personnel are examined
in this article. Prevention training for the reduction of student alcohol and
other drug use, incorporating a student well-being model, is described and
evaluated. The prevention training, entitled "Enhancing Student Well-Being," took
place in two urban school districts with over 200 paraprofessional school
personnel participating. The training was evaluated using measures of knowledge
gained, self-efficacy, and participant satisfaction. Pre- and post-training
differences showed consistent gains in participant efficacy expectations but less
consistent gains in outcome expectations and knowledge. Participant satisfaction
and self-reports of knowledge enhanced and skill improvement were uniformly high
across all training programs. Implications for inservice prevention training of
paraprofessionals are discussed.
PMID- 10786415
TI - Favourable outcome of a case of pulmonary Langerhans' cell histiocytosis.
AB - Pulmonary Langerhans' cell histiocytosis and eosinophilic granuloma are the terms
used to describe a Langerhans' cell granulomatous interstitial lung disease of
unknown aetiology, occurring predominantly in smokers and involving primarily
lungs, bones, skin and lymph nodes. In this report a patient with fever, fatigue,
dyspnoea, nocturnal perspiration and thoracic pain is described. The high
resolution computed tomography of the chest and histological examination of lung
biopsies suggested the diagnosis of pulmonary Langerhans' cell histiocytosis. The
disease was limited to the lung, since further investigations did not show any
other localization. The patient had a good clinical outcome with avoidance of
smoking and steroid therapy. The computed tomography scan follow-up showed a
partial resolution of pulmonary lesions.
PMID- 10786416
TI - Endobronchial metastasis from stomach carcinoma.
AB - We describe the case of a 57-yr-old female with endobronchial metastasis from
stomach carcinoma. Respiratory symptoms began 3 months before the diagnosis of
the gastric cancer. Chest computed tomography revealed a reticular lymphangitic
carcinomatosis pattern with hilar and mediastinal lymphadenopathy. Fibreoptic
bronchoscopy showed a spread submucosal infiltration which narrowed the apical
segment of the left lower lobar bronchus. The biopsy specimen at that level was
histologically identical to the gastric primitive cancer. To the authors'
knowledge, stomach carcinoma has rarely been reported to give rise to airway
metastases.
PMID- 10786418
TI - Investigating pleural disease.
PMID- 10786417
TI - Commercial polymerase chain reaction test (Amplicor set) in the diagnosis of
smear-negative pulmonary tuberculosis from sputum and bronchoalveolar lavage.
AB - The study presents experience with polymerase chain reaction (PCR) in the
diagnosis of tuberculosis (TB) and compares the results obtained in sputum and
bronchoalveolar lavage fluid (BALF). A total of 1,097 samples from 846 smear
negative patients with suspected TB was examined using PCR and culture during a
period of 40 months. TB was the final diagnosis in 160 patients, based on the
evidence of mycobacteria in 90 patients and on clinical criteria in the remaining
70. The PCR test had high specificity (98% and 99%, respectively) but poor
sensitivity (37% and 34%, respectively) regardless of whether sputum or BALF was
examined. Surprisingly, the sensitivity of culture (44% and 35% in sputum and
BALF, respectively) was higher than that of PCR in this group. The contribution
of BAL to establishing the diagnosis of tuberculosis was rather limited, yet
substantial in some patients. The results obtained in this study were compared
with the results published in the literature, and it was concluded that further
clinical studies are necessary to establish an appropriate role for the
polymerase chain reaction in the diagnosis of tuberculosis.
PMID- 10786419
TI - Malignant pleural diseases.
AB - The incidence of malignant pleural effusions has been increasing over the last
few decades (mainly due to the absolute increase in several types of cancers,
especially those of lung and breast origin) and they account for up to 50% of the
exudates in many clinical series. Although pleural malignancies are thought to
present most frequently with a pleural effusion, several autopsy series,
including the current one, found a pleural effusion present in little more than
half of the cases of malignant pleural involvement (55% in this series). Thus,
many pleural malignancies without effusion might pass unnoticed in clinical
practice, especially in metastatic disease. Primary malignancies of the pleura
(mesotheliomas) are associated with asbestos exposure in about two-thirds of
cases, and they frequently present with chest pain, sometimes associated with a
pleural effusion. Benign pleural plaques can coexist with malignant mesothelioma,
and this association should be suspected when long-standing plaques change in
shape or size over the years, and especially if chest pain develops in a
previously asymptomatic patient. Metastatic pleural involvement is much more
frequent than mesotheliomas, and its most frequent mechanism is the vascular
spreading of tumour cells from distant organs to the lungs, and on to the
visceral and parietal pleura. The visceral pleura was involved in up to 87% of
the current metastatic cases, whereas the parietal zone in only 47% of the
autopsy series. The diagnostic work-up lies in cytology, whose average yield is
approximately 50%, and a biopsy technique (either by blind needle biopsy or
thoracoscopy) is recommended when the effusion persists, for > 2 weeks, and the
first cytology has been negative. Thoracoscopy has the additional advantage of
allowing pleurodesis with talc poudrage if clear tumour lesions are found in the
pleura. In cases of malignant effusion which are not sensitive to chemotherapy,
pleurodesis is the treatment of choice for palliation of symptoms, and talc is
the most effective agent. It can be used either in suspension ("slurry") or in
dry aerosolized form ("talc poudrage"), but it seems that this last technique
achieves the best effects. However, it requires thoracoscopy for a proper
application, and this is its main drawback when that technique is not readily
available.
PMID- 10786420
TI - Management of infectious pleural diseases.
PMID- 10786422
TI - Transbronchial needle aspiration of mediastinal lesions.
PMID- 10786421
TI - Tracheobronchial stents.
PMID- 10786423
TI - Bronchoscopic early detection of lung cancer.
PMID- 10786424
TI - Endobronchial ultrasound of the airways and the mediastinum.
PMID- 10786425
TI - Nasal ventilation: where are we?
PMID- 10786426
TI - Noninvasive ventilation in intensive care unit patients.
PMID- 10786427
TI - Noninvasive ventilation in COPD patients with chronic respiratory failure--pro.
PMID- 10786428
TI - Lung involvement in organic dust exposure.
PMID- 10786429
TI - Early detection of occupational asthma and reactive airways dysfunction syndrome.
PMID- 10786430
TI - Dynamics and clinical effects of nonferrous metals in the human body.
AB - Pollution from toxic metal fumes and dusts occurs in many industrial situations.
Exposed workers may experience occupational diseases directly related to
poisoning from metallic elements. Studies have shown that the major route of
absorption of metals is by inhalation. Once absorbed, distribution to various
tissues and excretion from the body differ between metals. Multiphasic retention
times have been described for many metals with a proportion of the body burden
being eliminated very slowly. Biological half-lives range across many years.
Whilst blood or urine levels of metals may reflect current exposure, once
exposure ceases these levels may not be good indicators of remaining body burden.
Acute and chronic health effects occur after exposure. A wide range of chronic
disease including many respiratory diseases (emphysema, lung cancer, chronic
obstructive pulmonary disease, fibrosis and asthma), together with neurological,
haematological, hepatotoxic and nephrotoxic effects, has been reported.
PMID- 10786431
TI - How to set the ventilator in asthma.
AB - All patients with bronchial asthma are at risk of developing severe episodes of
airway narrowing that do not respond to the usual medical treatment, a life
threatening situation referred to as status asthmaticus. In some cases,
ventilatory failure occurs, necessitating mechanical ventilation to support gas
exchange and to unload the respiratory muscles, giving time for other therapeutic
interventions to improve the functional status of the patient. Mechanical
ventilatory support poses additional risks to the patients, due to interaction
between the pathophysiology of the disease and the process of mechanical
ventilation. Dynamic hyperinflation, a cardinal feature of the pathophysiology,
may cause serious complications during mechanical ventilation. Setting the
ventilator, such as to minimize the dynamic hyperinflation, is a key point in the
management of mechanically ventilated patients with status asthmaticus.
Strategies to reduce dynamic hyperinflation, such as hypoventilation (permissive
hypercapnia), increase of expiratory time and promotion of patient-ventilator
synchrony are mandatory and significantly decrease the morbidity and mortality of
the disease. Continuous monitoring of the effectiveness of these strategies, as
well as the functional status of the patient, is crucial in order to limit
complications associated with mechanical ventilation and to identify the time
that weaning can start.
PMID- 10786432
TI - Ventilator settings in acute respiratory failure/acute respiratory distress
syndrome.
PMID- 10786433
TI - Medical and nursing boards adopt CRNP regs.
PMID- 10786434
TI - Medicare HMO capitation plan affects physicians in many counties.
PMID- 10786435
TI - Pointing out simple truths.
PMID- 10786436
TI - Cancer care challenge.
PMID- 10786437
TI - Serotonin syndrome.
PMID- 10786438
TI - Cut out the middleman.
PMID- 10786439
TI - Giving back to medicine.
PMID- 10786440
TI - Suggestions for clarity in medical writing.
PMID- 10786441
TI - Guidelines for young child feeding in the Caribbean--Part I. Caribbean Food and
Nutrition Institute.
AB - The guidelines for young child feeding have been developed and prepared as a
supportive-tool primarily for health personnel involved in the care of infants
and children in Caribbean countries. The recommendations address some practical
aspects of nutrition before, during and after pregnancy. These are: The benefits
of breastfeeding and strategies for its promotion, protection and support; review
of infant feeding options for mothers with HIV and other infections; nutrition of
the newborn; feeding of low birth weight infants and those with special
requirements; replacement feeding for infants who are not breastfed;
complementary feeding with emphasis on the continuation of breastfeeding for two
years and beyond; guidelines on vitamin and mineral supplementation; management
of feeding-related problems in early childhood; policy issues and nutrition
education in relation to the promotion of adequate nutrition in early childhood.
PMID- 10786442
TI - Measurement of lung inflammation in asthmatics. Reason for optimism.
AB - It is recognized that bronchial asthma is an inflammatory disease. However,
aggressive anti-inflammatory therapy is not guided by the degree of lung
inflammation. This is of particular concern in children in whom over-aggressive
therapy with corticosteroid may lead to growth retardation. Analysis of breath
exhaled nitric oxide levels may be an indirect measurement of lung inflammation.
Since exhaled nitric oxide levels and inflammation decrease after steroid
therapy, measurement of exhaled nitric oxide levels may provide a rationale for
optimization of steroid therapy and possible reduction of side effects.
Measurement of exhaled nitric oxide levels is not available for routine use but
may be so in the near future. This will likely herald a new dawn in the
management of asthma, a disease with increasing frequency, mortality and
morbidity.
PMID- 10786443
TI - The University of the West Indies. Research limitations, research imperatives.
Whither the faculty of medical sciences?
PMID- 10786444
TI - The University of the West Indies School of Dentistry.
PMID- 10786445
TI - The vegetarian/vegan lifestyle.
PMID- 10786446
TI - An experimental mouse model to study the pathogenicity of Prevotella bivia and
investigations of possible virulence.
AB - Induction of subcutaneous abscesses in mice was used to study the pathogenicity
of Prevotella bivia both in mono-infection and in mixed cultures with Escherichia
coli and Peptostreptococcus spp. Virulence factors such as coaggregation and
aggregate formation of cells, haemagglutination activity and tolerance to serum
bactericidal activity were investigated for their possible role in P bivia
pathogenicity. Monocultures of P bivia, E coli and Peptostreptococcus spp did not
induce subcutaneous abscess at concentrations as high as 10(9) colony forming
units/millilitre (cfu/ml). Only E coli persisted at the infection site for up to
7 days post infection but with a marked decline in cell count (8.0 x 10(2)
cfu/ml). The anaerobic organisms did not persist at the infection sites beyond
the fifth day. In contrast, mixed cultures of P bivia and E coli or all three
organisms potentiated for infective abscess two weeks after infection. Viable
cells were recovered from abscesses in greater numbers as the infection
progressed. Prevotella bivia was the predominant organism in chronic abscesses
while E coli predominated in abscesses in the acute stage of the infection.
Prevotella bivia lacked haemagglutination activity against human and sheep
erythrocytes and showed marked susceptibility to 50 per cent human serum. These
may limit its haematogenous spread. Its ability to form aggregates in molar salt
solutions and coaggregate with facultative organisms may account for its
persistence in pathological sites.
PMID- 10786447
TI - The antihypertensive effects of the Jamaican Cho-Cho (Sechium edule).
AB - The experiments reported in this study constitute a preliminary investigation
into the possible hypotensive effect of the Jamaican Cho-Cho (Sechium edule).
Experiments were conducted in a random and blind fashion on two sub species of
Sechium edule. Both the pulp and the peel were examined for hypotensive activity.
Water-soluble extracts were prepared from these components of the fruit and
injected into anaesthetised rats. Various cardiovascular parameters were measured
including heart rate, mean arterial pressure (MAP) and several ECG intervals. We
report that all extracts tested produced a fall in blood pressure with little
change in ECG intervals. Extract B produced the least change in heart rate with a
fall in MAP of approximately 23 mmHg. Changes in heart rate with all extracts
appeared to be minimal as an ED25 value could only be determined for extract A,
and ED10 values could not be evaluated for extracts C and D. The mechanism(s) by
which these extracts produce their hypotensive effects could not be determined in
these preliminary experiments. However, it appears not to involve direct effects
on cardiac tissue. This conclusion is based on the finding that it took a minimum
of 10 to 15 seconds for the hypotensive action to manifest post bolus. Future
experiments will be aimed at delineating the mechanism(s) involved in decreasing
MAP.
PMID- 10786448
TI - Topical use of papaya in chronic skin ulcer therapy in Jamaica.
AB - The objective of the study was to determine the prevalence of the use of the
fruit (papaya) of Carica papaya as topical ulcer dressings by registered nurses
in the Spanish Town Hospital (STH), Kingston Public Hospital (KPH) and the
University Hospital of the West Indies (UHWI), Jamaica. A ten-item pretested self
administered questionnaire was distributed to 285 randomly selected registered
nurses at the UHWI, KPH and STH. There was a 72% response rate. The prevalence of
topical papaya use among the respondents was 75%. Comments from the users of
papaya suggested that topical application of the unripe fruit promoted
desloughing, granulation and healing and reduced odour in chronic skin ulcers. It
was cost effective. Papaya was considered to be more effective than other topical
applications in the treatment of chronic ulcers. There was some difficulty in
preparation of the fruit and occasionally a sensation of burning was reported by
the patients. There was concern about the use of a non-sterile, non-standardised
procedure but there were no reports of wound infection from its use. Papaya is
widely used by nurses as a form of dressing for chronic ulcers and there is need
for standardisation of its preparation and application.
PMID- 10786450
TI - Formal handling routines in Jamaican infants. Knowledge, attitudes and behaviour.
AB - This study aimed to determine the frequency of use and the knowledge, attitudes
and behaviour regarding the Formal Handling Routines (FHR) in rural and urban
Jamaican infants. Analysis was made of the area of residence and educational
level of the caregivers. The study included 194 caregivers, thirty-three
community rehabilitation workers (CRWs) and 30 health care workers (HCWs).
Depending on the level of understanding of the respondents, questionnaires were
either self-administered or a personal interview was conducted. Caregivers with
tertiary education differed significantly from the other caregivers both in
frequency of use of the FHR and knowledge, attitudes and behaviour. Caregivers
with tertiary education used the routine much less and had more negative
attitudes towards it. This might be due to their better financial position, which
allowed them to have helpers who cared for their children. HCWs also had
significantly more negative beliefs about the FHR than CRWs and caregivers. It is
possible that HCWs carried over their knowledge, attitudes and behaviour to the
caregivers but if they did, it did not influence the majority of caregivers.
PMID- 10786449
TI - Dialysis adequacy at two haemodialysis units in Jamaica.
AB - A prospective study on adequacy of dialysis was conducted at the haemodialysis
units of Kingston Public Hospital (KPH) and the University Hospital of the West
Indies (UHWI). Dialysis adequacy was better at KPH and morbidity, as measured by
patient admission days, was increased at UHWI. Diabetics had a lower mean serum
albumin and urea reduction ratio (URR) than non-diabetics. Multiple regression
analyses revealed that age of patient (F = 5.30; p = 0.0241) and hospital (F =
7.85; p = 0.007) were the variables significantly associated with serum albumin
level when the effect of other variables was controlled (F = 2.12; p = 0.34).
Similar analyses showed that the hospital at which dialysis was done was the only
factor which accounted for significantly higher URR, with KPH having higher rates
(F = 13; p = 0.006). The differences between hospitals necessitate further
investigations, explanations and intervention strategies. The study provides
opportunities for improving patient care and for dialysis health care
professionals to assess clinical performance measures and reduce variation
between dialysis centres.
PMID- 10786451
TI - HIV infection among children in Barbados.
AB - We studied a cohort of children with the human immunodeficiency virus (HIV)
infection in Barbados in order to determine the prevalence of HIV infection, the
clinical course including morbidity and mortality and the magnitude of the health
care and social problems. Forty-seven children were diagnosed with HIV infection
during the study period. The number of HIV infected children increased from 5
during 1981-85, to 14 during 1986-90, and to 21 during the 1991-95 period. The
majority (91.5%) of infections resulted from perinatal transmission. Six (12.8%)
cases remained asymptomatic and 41 (87.2%) were symptomatic with 19(46.3%)
presenting in infancy, while 22 (53.5%) presented post-infancy. The median age at
diagnosis (class P-2) was 13 months. Generalized lymphadenopathy (47.5%),
hepatosplenomegaly (40.0%), failure to thrive (27.5%), persistent recurrent
diarrhoea (15.0%), oral candidiasis (37.5%), Pneumocystis carinii pneumonia
(37.5%), lymphoid interstitial pneumonia (12.5%) and progressive neurological
disease (10.0%) were common HIV related conditions. Two children developed non
hodgkin's lymphoma. The median age at death for 23 children was 12 months,
whereas the median survival after diagnosis was 4 months. Mortality was higher
among those diagnosed in infancy (73.7%) as compared to those diagnosed post
infancy (42.8%). Pneumocystis carinii pneumonia was the most common (65.2%) cause
of death. Paediatric HIV infection is rising and contributes considerably to
infant mortality. In this study, children took longer to be symptomatic when
compared to other reports. However, once symptomatic, they died early.
PMID- 10786452
TI - Children's response to hospitalization at the University Hospital of the West
Indies.
AB - The results of this study indicated that patients aged 3-13 years who had a
history of previous hospitalization appeared to be significantly more distressed
than patients without such previous history (p < 0.05). Previously hospitalized
children were more uncooperative and displayed anxious, immature behaviour
patterns. Children who were hospitalized for more than a month were also
interviewed about their concerns and response to hospitalization. The study
highlighted the need for hospitalized children to be better prepared for
hospitalization, to have greater parental involvement in the management of their
behaviour and to have efficiently run programmes geared at addressing their
educational and emotional needs.
PMID- 10786453
TI - Psychological distress among younger siblings of patients with homozygous sickle
cell disease in the Jamaican cohort study.
AB - The presence of a chronically ill family member may adversely affect the
psychological health of siblings. This study used the General Health
Questionnaire and the Modified Social Adjustment Scale to assess psychological
distress in 20 younger siblings (4 AA, 16 AS genotypes), aged 16-19 years, of
patients with homozygous sickle cell (SS) disease. The results were compared with
those previously obtained in the 20 older siblings with SS disease and in 89
controls with a normal haemoglobin (AA) genotype. High levels of psychological
distress occurred among all three groups. Greater psychological distress and
poorer social adjustment occurred among siblings compared to AA controls but
these differences disappeared after adjusting for the reduced age of siblings.
The two measures were similar in SS patients and AA controls. The level of
psychological distress among siblings of SS patients did not differ from that in
SS patients or AA controls.
PMID- 10786454
TI - Knowledge, attitudes and practices of anabolic steroid usage among gym users in
Trinidad.
AB - Self-administered questionnaires were completed by 1062 gym-users in 14 gyms in
Trinidad from February 1997 to July 1997 to determine the knowledge, attitudes
and practices regarding anabolic steroids (AS). Five hundred and sixty (52.7%)
females and 502 (48.3%) males completed the questionnaire. Half of the total
sample were individuals in the 20 to 29 year age group. From the 17 questions
that tested knowledge about AS, the median number of correct responses was 7 with
a mode of 8. Increased muscle mass was correctly identified as one of the effects
of AS by 841 respondents (79.2%), while 249 (23.6%) of the total sample thought
asthma was treated with AS. Most (872 or 82.1%) felt that their knowledge about
AS was inadequate and 700 (66.0%) were of the opinion that AS should be banned
from use in competitive sports. Similarly, 733 (70.0%) of the gym-users thought
AS should only be available by prescription. Thirty respondents reported having
used AS (2.9%, 95% CI 2.0-4.1). The prevalence of AS use was higher among males
than females (p < 0.001). Improvement of physical appearance and not competitive
advantage in sport was the main reason cited for AS use. Anabolic steroid users
knew more about the adverse effects of AS than non-AS users but the therapeutic
uses of AS were comparatively less well known. This study demonstrated a general
lack of knowledge concerning AS use and that a small but significant proportion
of persons using gyms admitted to abusing AS.
PMID- 10786456
TI - A retrospective analysis of invasive Streptococcus pneumoniae infections in
Trinidad.
AB - A retrospective analysis of culture-positive cases of S pneumoniae from normally
sterile body fluids is reported. Over 40% of patients were 5 years old or less
while 28% of patients were 50 years old or more. Meningitis (44%) was the
commonest clinical presentation followed closely by pneumonia (31%). The
commonest predisposing disorder was human immunodeficiency virus infection though
there were no identifiable risk factors in the majority of patients. Mortality
from invasive pneumococcal disease was significantly higher in elderly patients
compared with other age groups (p = 0.0003). In this study, all S pneumoniae
isolates, for which there were antibiotic sensitivity data, were penicillin
and/or amoxycillin sensitive.
PMID- 10786455
TI - Solid and papillary epithelial neoplasm. Ultrasound and CT features of an unusual
pancreatic tumour.
AB - The ultrasonographic and computed tomography features of four cases of solid and
papillary epithelial neoplasm (SPEN)--a rare pancreatic tumour--are described.
Although not diagnostic, the presence of these imaging features in the typical
clinical setting may permit pre-operative radiological diagnosis and facilitate
planning for curative surgery for this malignant tumour which has an excellent
prognosis even without further adjuvant therapy.
PMID- 10786457
TI - Images and diagnoses. Phaeochromocytoma from paraganglia of the urinary bladder
wall.
PMID- 10786458
TI - Images and diagnoses. Ainhum.
PMID- 10786459
TI - Malignant meningioma with extension into the neck.
AB - One per cent of all brain tumours and twenty per cent of meningiomas eventually
develop an extracranial extension. The least common site is the neck. We report a
case of malignant meningioma with extension into the neck of a 39-year-old male.
PMID- 10786460
TI - Tuberculous encephalopathy. A rare complication of pulmonary tuberculosis.
AB - A case of tuberculous encephalopathy, a rare form of neuro-tuberculosis, is
reported in a 16-year-old girl who had pulmonary tuberculosis and extensive
cerebral demyelination. The clinical, laboratory and pathological features of
this entity are highlighted and the pathogenesis discussed.
PMID- 10786461
TI - Use of magnesium sulphate as adjunctive therapy for resection of
phaeochromocytoma.
AB - The intraoperative control of cardiovascular disturbances associated with the
resection of phaeochromocytoma is traditionally achieved by the use of deep
anaesthesia in conjunction with alpha and beta blockers, calcium antagonists,
nitroglycerine or sodium nitroprusside. We report the successful use of magnesium
sulphate as adjunctive therapy in the control of the cardiovascular consequences
associated with surgical resection of a phaeochromocytoma in a patient.
PMID- 10786462
TI - Extraadrenal retroperitoneal paraganglioma causing malignant hypertension and
permanent visual loss in an eleven-year-old girl.
AB - We report a secretory paraganglioma in an eleven-year-old Trinidadian girl of
East Indian descent who presented with malignant hypertension, proteinuria and
modest elevation of urinary vanillylmandelic acid levels. The extra-adrenal mass
was surgically removed without complications. The patient has been normotensive
without evidence of recurrence of disease but with persistent visual sequel two
years later. This case reinforces the observation that extraadrenal
retroperitoneal paragangliomas can be functionally very active and early computed
tomography or other imaging procedure is necessary for rapid noninvasive
evaluation, timely surgery and prevention of permanent morbidity.
PMID- 10786463
TI - Systemic phaeohyphomycosis in pregnancy and the puerperium.
AB - Systemic fungal infections are rare. In pregnancy, treatment is problematic
because of the risk of possible teratogenic effects of the antifungal drugs. We
present the case of a 32 year-old woman who presented during pregnancy with a two
month history of painless subcutaneous nodules. Excision biopsy of one lesion
showed dematiaceous fungal elements. Anti-fungal treatment was deferred and the
pregnancy proceeded uneventfully. The remaining nodules were excised at the time
of caesarean section delivery. Three weeks into the puerperium, she developed
generalised seizures and investigations indicated systemic fungal infection with
positive cultures for Aureobasidium spp which responded to appropriate antifungal
therapy of flucytosine and itraconazole.
PMID- 10786464
TI - An abdominal mass in an eleven-year old boy.
PMID- 10786465
TI - Emerging drug resistant Mycobacterium tuberculosis in the Caribbean.
PMID- 10786466
TI - Research-based practice: reducing bedrest following cardiac catheterization.
AB - Patient discomfort with prolonged bedrest following femoral arterial puncture for
cardiac catheterization is a significant nursing problem. Safely reducing the
time required for supine bedrest could improve patient comfort and reduce nursing
care needs. Reducing bedrest also has the potential to improve organizational
resource utilization. A review of the literature was conducted and a decision was
made to implement 2 hours of bedrest, a significant decrease from the previous
practice of 6 hours. Vascular complications were closely monitored in the first
50 patients, as a means of implementing the research-based change in practice. No
significant vascular complications occurred and the practice change has expanded
to all inpatient and outpatient areas caring for patients undergoing cardiac
catheterization. This experience with utilizing research to change practice has
created a positive environment for future research-based initiatives.
PMID- 10786468
TI - The International Normalized Ratio (INR): a review.
PMID- 10786467
TI - Evaluation of 3-hour ambulation post cardiac catheterization.
AB - There is much variation in the length of immobilization for patients post cardiac
catheterization. While it is generally agreed that a period of time on bedrest is
necessary to prevent post procedural complications, the optimal duration remains
unknown. The purpose of this study was to evaluate the effects of 3-hour
ambulation post cardiac catheterization with a 7 french (F) arterial catheter on
bleeding, hematoma formation, and vascular complications. Retrospective chart
data were gathered for a period of 8 months for patients who were on the
traditional 5-hour ambulation protocol, and prospective data were gathered for a
period of 7 months for patients who received the 3-hour protocol. A total of 880
patients were included in the study, with 472 in the 5-hour ambulation group and
408 in the 3-hour ambulation group. The overall incidence of delayed bleeding and
hematoma formation for the 15 month study period was 19.1%, with no occurrence of
vascular complications in either group. Patients who received the 3-hour
ambulation protocol experienced a significantly lower rate of bleeding and
hematoma formation (13%) than patients who received the 5-hour ambulation
protocol (24.4%) (p < 0.001). Ambulating patients 3 hours post cardiac
catheterization with a 7F catheter was found to be safe, and thus has the
potential to decrease hospital length of stay, as well as increase patient
comfort.
PMID- 10786469
TI - The Canadian Institutes of Health Research: what will they bring to
cardiovascular nursing research?
PMID- 10786470
TI - Receiving feedback from reviewers: how to make the most of criticism.
PMID- 10786471
TI - Important issues in clinical practice: perspectives of oncology nurses.
AB - As the 1990's draw to a close, the cancer care environment is undergoing rapid
change. Many issues exist within the complex environment of cancer care that
could create a challenge in providing quality nursing care to patients. This
study examined the current challenges oncology nurses face in their daily
practice. Surveys were mailed to members of the Canadian Association of Nurses in
Oncology asking them to indicate on a list of 80 issues which were problems in
their daily practice. From the responses of 249 oncology nurses, the following
items were ranked as the top 10 problems: anxiety, coping/stress management,
bereavement/death, fatigue, metastatic disease, comfort, pain control and
management, quality of life, recurrence of primary cancer, and nurse burn-out.
Principal component analysis was conducted to determine if patterns existed in
the way problems had been rated. Five components explained 42% of the variance in
the data set: comprehensive cancer care, communication, experience of loss,
terminal illness, and signs and symptoms. Implications for nursing practice,
education and research are highlighted.
PMID- 10786472
TI - Description of the caregiver's educational needs and the degree of her
dissatisfaction.
AB - This study emphasized the learning needs of caregivers whose husbands have cancer
and describes their level of dissatisfaction concerning these needs. A
convenience sample of 30 women caregivers was used. The results demonstrate that
caregivers possess initial acquired knowledge as learners and have 26 specific
learning needs. The existence of a learning need produces a level of
dissatisfaction among the female caregivers. Among these learning needs, the most
likely to generate the greatest dissatisfaction are the learning needs associated
with personal concerns. The results encourage nurses to play a more active role
in learning by assessing whether the information the caregivers are receiving is
understood well enough to meet their learning needs.
PMID- 10786473
TI - Ovarian cancer treatment: the benefit of patient telephone follow-up post
chemotherapy.
AB - Approximately 2,500 women in Canada were diagnosed with cancer of the ovary in
1997 (NCIC, 1997). Standard therapy consists of surgical tumour debulking and
cytotoxic chemotherapy. Very little data are available examining the most
appropriate outpatient management of patients receiving chemotherapy. The
objective of this study was to assess the impact of and benefit received from
telephone follow-up between chemotherapy treatments for patients with cancer of
the ovary. Patients with cancer of the ovary were treated every three to four
weeks with a cisplatin-based chemotherapy. Telephone follow-up was performed five
to seven days post-treatment by the gynaecology oncology liaison nurse. Follow-up
addressed issues pertinent to treatment and disease side effects. A patient
survey addressing the impact of telephone follow-up was performed on a sample of
the patient population. Thirty-one patients responded to the survey: Eighty-seven
per cent found that receiving a call post-chemotherapy was reassuring and
helpful. Eighty-three per cent stated that medications could be adjusted
according to the severity of side effects. Eighty per cent of patients agreed
that most issues had been dealt with at the time of telephone follow-up. Sixty
four per cent felt that their concerns had been addressed during the phone calls,
and only 22% had suggestions on how to improve follow-up. Telephone follow-up
during chemotherapy was a valuable tool in assessing patient needs, side effects,
and concerns experienced during treatments. Telephone follow-up may facilitate
early identification of patient problems allowing appropriate and timely
intervention.
PMID- 10786474
TI - Chemotherapy audit--a confidence builder.
PMID- 10786475
TI - Supportive Care in Oncology: Partnerships in Education (SCOPE)--a pilot program
offered by the London Regional Cancer Centre.
PMID- 10786476
TI - Implantable loop monitor for detection of syncope.
AB - A precise correlation of patient symptoms and rhythm disturbances is a formidable
task, especially when the rhythm disturbances are infrequent and unexpected. An
ILR device that can record events over a longer period of time may be the most
effective way of making a diagnosis and of ultimately determining an appropriate
treatment plan. The Reveal ILR can establish patient symptom/rhythm correlation
during a spontaneous event, leading to a diagnosis of the underlying condition.
Additionally, the device may reduce the need for repetitive low-yielding testing
and decrease the time and costs associated with the diagnosis of unexplained
recurrent syncope.
PMID- 10786477
TI - The evolution of internal defibrillators.
AB - ICDs have reduced mortality from SCD to 2% per year, which is a record unmatched
by any other form of therapy. With continued evolution, ICD systems should become
easier to implant, smaller, more effective in managing a variety of abnormal
rhythms, and more comfortable for the patient. Implementation of technological
innovations in future-generation devices should continue to extend the frontiers
as clinicians consider ICDs for an expanding range of therapeutic applications.
PMID- 10786478
TI - Highlights from the past decade of interventional device research.
AB - The last decade of research and implementation in the interventional device arena
has brought about an unprecedented improvement in the ability to safely and
effectively treat coronary artery disease. This explosion of technology is not
over; there remain questions to be answered and patient subsets whose care can be
improved upon. Our understanding of the restenosis process has helped guide
research in the appropriate directions, and by 2010 restenosis after a coronary
intervention will most likely be of historic interest only. With the addition of
thrombus removal catheters and protection devices, treatment of problematic high
risk lesions will also be improved upon. The effect of these devices on acute
patient care and long-term outcomes, including quality of life, will be profound.
PMID- 10786479
TI - Percutaneous transluminal myocardial revascularization. A new treatment for
angina.
AB - PTMR is a new and exciting alternative treatment for patients with class III or
IV angina who have been treated unsuccessfully with conventional medical
treatments and who have no other treatment options available. It is hoped that
PTMR can decrease or completely relieve these patients' symptoms and improve
their quality of life. Early results with PTMR appear promising, but further
investigation and long-term assessment of patients who have been participants in
PTMR studies need to be undertaken.
PMID- 10786480
TI - Brachytherapy. Savior or tease.
AB - Dating from the inception of percutaneous coronary angioplasty, restenosis has
been the postprocedural Achilles heel. Despite a decade of research, with a
myriad of mechanical devices and pharmacologic agents, this vexing problem has
yet to be resolved. Although intracoronary stents have proved effective at
restenosis reduction, they have yet to achieve an acceptable level and, in some
cases, remain resistant to any treatment. Intracoronary radiation using gamma or
beta isotopes, has generated tremendous excitement with promising results.
Indeed, the SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post
Stenting) trial, which employed gamma radiation, showed a statistically
significant reduction in restenosis in a small patient population. Further
studies with a variety of isotopes and delivery modalities are currently
underway, bringing with them their own assemblage of issues.
PMID- 10786481
TI - Gene therapy for the treatment of cardiovascular disease.
AB - Although still experimental at the present time, gene therapy for the treatment
of cardiovascular disease is on the horizon. Numerous clinical trials in patients
with flow-limiting coronary artery disease are in progress. In order to keep up
with advances in gene therapy, critical care nurses must develop a background in
this discipline. This challenge rests in the hands of nursing educators to
incorporate a sufficient amount of genetic content into the curriculum. Genetics
in the curriculum is essential because it is the central science of health care.
Genetic discoveries are changing our understanding of the mechanisms of disease
and the diagnosis, treatment, and prevention of cardiovascular disease in
particular. Gene therapy is likely to influence our daily nursing practice, and
nurses must have an adequate knowledge of genetics to provide accurate
information to patients and families so that they can make informed decisions
about their health care.
PMID- 10786482
TI - New adjunctive therapy for ischemic syndromes.
AB - Because anticoagulant and GP IIb/IIIa inhibitors reduce mortality, myocardial
ischemia, AMI, and reintervention, these agents are now becoming the standard of
care for patients with USA and NQWMI. Unanswered questions remain about the best
treatment regimen, appropriate dosing, long-term benefit, and cost-effectiveness
of these agents, however, and many additional trials are ongoing or planned. As
nurses administer these drugs, assess the patients' responses to therapy, and
educate patients and families about these agents, they contribute to recent
advances in preventing ischemic heart disease.
PMID- 10786483
TI - Ventricular arrhythmias, electrophysiologic studies, and devices
AB - Because of the high incidence of heart disease in the elderly, ventricular
tachyarrhythmias are not infrequent. Determining the nature and extent of the
underlying heart disease and identifying precipitating causes is required prior
to instituting long-term therapy. Recent studies suggest that for hemodynamically
unstable ventricular tachyarrhythmias, mortality is lower with the implantable
cardioverter-defibrillator compared with pharmacologic therapy. This benefit is
likely to be more modest in the elderly because of competing cardiac and
noncardiac causes of death. For similar reasons, the favorable results reported
with the prophylactic use of the implantable cardioverter-defibrillator are
likely to be attenuated in the elderly.
PMID- 10786484
TI - MR coronary angiography
AB - Coronary MR angiography is a new noninvasive diagnostic method in rapid
evolution. It has the potential to combine structural information with functional
assessment of coronary blood flow. Advances in technology will undoubtedly lead
to enhanced resolution, improved accuracy, and shorter scan times. It is certain
that coronary MR angiography will be a prominent diagnostic clinical tool in the
years to come.
PMID- 10786485
TI - Provision of counselling for the dying patient.
AB - The majority of doctors and nurses clearly recognise their responsibility to
provide palliative care to the dying patient, and also the need for effective
communication, counselling and support for this group of patients. This paper
explores some of the issues preventing patient and significant others from being
referred to the counselling service at this stage, and demonstrates that the
nursing staff feel both inadequate and ill prepared to deliver quality care to
the dying patient and use avoidance as a coping mechanism.
PMID- 10786486
TI - Self perception affecting adherence to drug regimen following renal
transplantation.
AB - The patient, a chronic cannabis user, found it increasingly difficult to tolerate
the side effects of the medication on her appearance. Rejection in the early post
transplant period meant that immunosuppression could not be further reduced. We
were able to avoid a catastrophic self-initiated cut in immunosuppression, and
withdrawal of steroids was carried out according to a schedule supervised by the
clinic. Cellular rejection resulted and was treated with i.v. methyl prednisolone
and conversion from cyclosporin micro-emulsion (Neoral, Novartis) to tacrolimus
(Prograf, Fujisawa) and from azathioprine to mycophenolate mofetil (CellCept,
Roche).
PMID- 10786487
TI - Adherence to treatment and personality in renal failure.
AB - Adherence of individual treatment and personality dimension of locus of control
was analysed. Evidence suggests that locus of control and other personality
dimensions can influence adherence behaviour to treatment. The aim of this study
was to examine the impact of social-clinical factors over personality dimensions
and to provide empirical evidence of the relationship between internal locus of
control experience and higher level of the compliance to treatment and diet. The
results have shown the low level of adherence of patients to treatment and we
found a tendency to correlate the dimension locus of internal control with
adherence to treatment.
PMID- 10786488
TI - The dark side of the moon: how clients face dialysis.
AB - Patients requiring haemodialysis experience various problems, some of which are
caused by the medical treatment. We explored various aspects of a haemodialysis
patients life, to focus on the effects that their treatment had on their daily
life. The aim of this study was "to know the life of the respondent, in order to
improve the quality of the assistance." This pilot study allowed the staff to
plan arrangements in order that the patient could pursue a "normal life".
PMID- 10786489
TI - The psychosocial implications of live-related kidney donation.
AB - The aim of the study was to explore the donor's experience of the live related
transplantation process whilst seeking to identify the external and internal
resources and ethical considerations which were reflected in the decision-making
process. The outcome would indicate that altruism and a sense of moral obligation
were the prime motivational influences with the spontaneity of decision-making
casting doubt on the ability to give informed consent. These findings are also
discussed in relation to implications for professional practice and would suggest
that potential donors benefit from having access to a counsellor during the donor
search and throughout the transplant work up programme.
PMID- 10786490
TI - Assessment of problems: which study design?
AB - Evidence-based medicine has gained recognition in recent years, necessitating a
large amount of conclusive results derived from a large number of experimental
and epidemiological studies. Renal nurses are preferable investigators in this
field because of their close relationship with the renal patient. Apart from
clinical studies, with an experimental study design varying a single factor
between two groups of patients, epidemiological studies are needed to assess
actual problems. Epidemiological studies are purely based on observation, without
altering any factor. The choice of study design will depend on the available
knowledge about the problem and available resources.
PMID- 10786491
TI - Comparative evaluation of CAPD and PD-plus effectiveness.
AB - Decline in residual renal function in CAPD patients often leads to reduced
overall solute clearances. Inadequate dialysis has been linked to malnutrition
and increased morbidity and mortality rates. Achieving dialysis adequacy targets
is often difficult by the conventional method of increasing CAPD exchange
volumes. In comparison, substantial increases in solute clearances can be
achieved with the use of automated peritoneal dialysis with large fill volumes
and an extra daytime exchange.
PMID- 10786492
TI - Stay.safe. A new PVC free system in long-term CAPD treatment.
AB - Stay.safe is a new PVC free double bag PD system that was introduced two years
ago for CAPD. The system has been evaluated by three target groups, patients,
nurses and physicians in 2 different studies. In the pilot study stay.safe was
compared to the previous system and in the multi centre study, new patients
judged stay.safe over a longer period of time. The pilot study showed better
handling and function judgement by experienced patients of the new system
compared to previous. In the multi centre study the overall satisfaction with the
new system including use with disabled patients was very good and this high
valuation was maintained over time.
PMID- 10786493
TI - Increasing the safety of volumetric ultrafiltration control.
AB - Deviations in ultrafiltration volume can cause various problems for patients
undergoing a haemodialysis treatment. With the introduction of high flux
dialysers, closed systems with volumetric fluid balancing became the systems of
choice, because control of transmembrane pressure used previously is too
inaccurate and unsafe to be used with such filters. In this article, a reliable
and cost effective test method is described to increase the safety of a closed
system. The test is carried out by simply analysing the dialysate pressure while
the dialyser is isolated from the system for typically 7.2 seconds. No additional
sensors and components other then a valve combination used to isolate the
dialyser are required.
PMID- 10786494
TI - Results of a national epidemiological investigation of HCV infection in dialysis
patients.
AB - The Italian Branch of EDTNA/ERCA organised a national, epidemiological,
retrospective study to collect data and implement preventative measures for the
spread of HCV infection in dialysis units. A questionnaire was sent to staff in
830 dialysis centres to collect information relating to 1996. Data are presented
on incidence/prevalence of HCV infection, antibodies, viraemia and mortality, and
comparison of the management of HCV between centres. At variance with the
recommendations of the Official Health Organisations, dedicated machines and
separate rooms are used in many centres and this paper concludes with
recommendations for units, in particular those units with a low prevalence of
anti HCV positive patients.
PMID- 10786495
TI - Haemodialysis in acute renal failure.
AB - Haemodialysis in acute renal failure differs from chronic uraemia. We describe
our clinical experience comparing tolerance to dialysis and dialysis efficacy of
bicarbonate haemodialysis in comparison to haemofiltration. Both provide adequate
treatment for ARF, Kt/v 0.6 +/- 0.1, URR 56% in bicarbonate haemodialysis
compared to Kt/v 0.4 +/- 0.06, URR 60% in haemofiltration. Clinical outcome was
the same in both groups, in particular the overall survival was satisfactory at
about 70%. These results are likely to reflect close control of these patients by
nursing staff committed to haemodialysis in acute renal failure.
PMID- 10786496
TI - Renal nursing education: an innovative difference.
AB - The purpose of this paper is to describe the Master of Nursing (Renal) course
that is offered to internal and distance education nephrology nurses in
Australia. The challenging demand of offering this innovative curriculum will be
discussed, and analysis of the first cohort of students will be made. Finally,
future directions for renal nursing education will be discussed.
PMID- 10786497
TI - Buyer's guide and pharmaceutical reference.
PMID- 10786498
TI - Midwives act. Important changes secured by the OIIQ.
PMID- 10786499
TI - [Baby Friendly Hospital initiative].
PMID- 10786500
TI - [Spirituality and nursing care].
PMID- 10786502
TI - Values and critical care--back to basics.
PMID- 10786501
TI - [Therapeutic touch].
AB - In the advanced stages of dementia of the Alzheimer's type (DAT), affected
persons present body language and various behaviours expressing discomfort:
shouting, agitation, irritability, aggressiveness, tense movements. Nursing, up
until now, has had few available means to ease this discomfort. The authors of
the following article have conducted an experimental study measuring the
alleviating effects of therapeutic touch on the discomfort of persons in the
advanced stages of DAT. Experimental group subjects (n = 16) received 5 sessions
of therapeutic touch lasting 12.4 minutes. Control group subjects (n = 11)
received 5 sessions of simple presence lasting 10.3 minutes. The authors measured
subject discomfort levels using the Discomfort Scale for Dementias of the
Alzheimer's Type (DS-DAT). Results show that discomfort levels of persons in the
advanced stages of DAT decreased significantly after 5 therapeutic touch
sessions, becoming significantly lower than levels in the control group. If care
was focused on the whole person and his or her comfort, tools like therapeutic
touch would become available to nurses, allowing them to enhance the quality of
life of the people in their care.
PMID- 10786503
TI - Patients' and relatives' opinions and feelings about diaries kept by nurses in an
intensive care unit: pilot study.
AB - The underlying aim of this study was to obtain knowledge about the questions
which could be of interest for a qualitative interview study, and for the
planning and construction of a comparative study. The immediate aim was, however,
to investigate whether the diary was of importance to patients after their
discharge from the ICU or for relatives, following patients' deaths in the ICU. A
diary was kept for nine months concerning ten patients together with eight
patients who later died in the ICU. All of the ten patients, and four of the
eight deceased patients' relatives, answered a questionnaire consisting of five
close-ended and two open-ended questions. The participants were encouraged to
comment upon all the questions. All participants read the diary. Seven patients
stated that it helped them to remember their ICU stay and two that it did not. It
helped them to re-live and come to terms with their serious illness/injury and
recall what had happened. For those who could not recollect their ICU stay, the
diary helped them to remember 'the lost time'. All the relatives except one
stated that it helped them to return and adjust to everyday life; made it easier
to accept what had happened; and to understand the seriousness of the patient's
injury or disease.
PMID- 10786504
TI - Use of the prone position in the management of acute respiratory distress
syndrome.
AB - The positioning of patients is usually within the domain of nursing practice,
whether this is to achieve increased comfort or as a therapeutic intervention to
avoid the occurrence of pressure sores. The use of the prone position to improve
oxygenation, in the acute respiratory distress syndrome, has become increasingly
popular in intensive care over the past decade (Thomas 1997). A systematic review
was, therefore, undertaken to ascertain if the prone position did, in fact,
improve oxygenation, leading to decreased mortality, or if the effects were
merely transitory. Review findings indicate that use of the prone position does
improve oxygenation, as measured by PaO2/FiO2 indices, and appears to reduce
mortality. However, caution should be taken in applying these results to
practice. First, the studies available for review demonstrated various
methodological flaws. It is also apparent that untoward incidences associated
with the prone position have yet to be investigated systematically.
PMID- 10786505
TI - Critical analysis of access to and availability of intensive care.
AB - In intensive care, there appears to be an ever-increasing demand for resources
and it is widely recognized that there is often a shortage of vacant beds
available, compounded by an inadequate level of appropriately qualified nursing
staff. Either of these deficiencies may lead to delayed or even refused admission
for a patient who is critically ill. This review of the literature contains
examination of the access and availability of intensive care facilities within
the National Health Service and discussion of the problems that arise in gaining
admission to such facilities. Being refused admission to the local intensive care
unit may have important implications for a critically ill patient, resulting in
transfer to another hospital, perhaps many miles away, or inadequate treatment
and care in a general ward. These issues are also examined and strategies for
action are proposed.
PMID- 10786506
TI - Clinical governance and intensive care: what does it mean?
PMID- 10786507
TI - Effects on oxygen saturation levels of handling premature infants within the
concepts of kinaesthetic infant handling: pilot study.
AB - Preterm infants are exposed to many stressors within the neonatal intensive care
environment. Since these are associated with medical and developmental problems,
a reduction of stress factors is desirable. Handling is a very common occurrence
and is associated with stress. Kinaesthetic infant handling (KIH) offers
practical guidance on handling for nurses and has been widely implemented in
Germany, although there is no direct experimental evidence to support its use.
The findings of this pilot study suggest a beneficial effect on the SpO2 for
infants who were handled using KIH. Since this was a pilot study with a small
sample size, caution has to be exercised with this finding. Therefore, the main
purpose of the study was: (1) to identify the weaknesses and strengths of the
chosen study design; and (2) to perform a power analysis in order to determine a
sufficient sample size for the full experiment.
PMID- 10786508
TI - Respiratory assessment in critical care units.
AB - As healthcare delivery changes in critical care, nursing continues to extend its
practice base. Nursing practice is expanding to incorporate skills once seen as
the remit of the medical profession. Critical care nurses are equipping
themselves with evidence-based knowledge and skills that can enhance the care
they provide to their patients. Assessment of patients is a major role in nursing
and, by expanding assessment techniques, nurses can ensure patients receive the
care most appropriate to their needs. Nurses in critical care are well placed to
perform a more detailed assessment which can help to focus nursing care. This
article describes the step-by-step process of undertaking a full and
comprehensive respiratory assessment in critical care settings. It identifies
many of the problems that patients may have and the signs and symptoms that a
nurse may not whilst undertaking the assessment and preparing to prescribe care.
PMID- 10786509
TI - Costing of consumables: use in an intensive care unit.
AB - In 1991, the Intensive Care Unit (ICU) at Middlemore Hospital manually costed the
treatment and care of asthmatic patients. This was long-winded and labour
intensive, but provided hard data to support anecdotal beliefs that intensive
care patients are more expensive than was currently believed or accepted. It is a
known problem that funder and provider organizations see a huge disparity on the
funding issue. With additional accurate information on the actual cost of
individual patients, which can be grouped into disease categories, funding
applications can be backed with accurate, up-to-date quantitative data. After a
long preparation time, we are now costing individual patient stays in the ICU.
Each individual resource was established, costed and entered into an MS ACCESS
computerized database. Schedules have been prepared for updating prices, as these
change. The final report available gives a detailed list of resource use within
certain categories. Some items proved to be impractical to cost on an individual
patient basis, and these have been grouped together, costed, and divided by the
number of patient days for the last year, and assigned to each individual patient
as an hourly unit cost. Believed to be a world-first, this information now forms
the basis for variance reporting and pricing.
PMID- 10786510
TI - New antibiotics for gram positive infections: linezolid and combination
quinapristin/dalfopristin.
AB - Considerable research over the past decade has thrown up two novel antibiotic
preparations which are effective in 'difficult' Gram positive infections. Their
imminent arrival is welcomed at a time when the emergence of resistance to last
line drugs is rapidly spreading. Their careful use is, however, crucial if long
term value is to be preserved.
PMID- 10786511
TI - Chest X-ray quiz. A pericardial effusion.
PMID- 10786512
TI - Philosophy of integrity or integrity of philosophy?
PMID- 10786513
TI - Measuring the compliance behavior of adolescents wearing orthopedic braces.
AB - This paper reports the observed difference between two measures of compliance in
wearing an orthopedic brace among teenagers affected by idiopathic scoliosis. The
first measure was obtained with a small device called a "compli-o-meter" that was
developed specifically for this purpose. When fastened to an orthopedic brace,
this instrument determines the brace's actual wearing time. The second compliance
measure was derived from a questionnaire-interview administered to the
participants. The subjects were 40 female teenagers aged between 10 and 16 years
who had been wearing an orthopedic brace for 18 months or less. While the
compliance rate reported by the participants averaged 88%, the actual rate
measured by the compli-o-meter was only 33%. Pearson's correlation was r = .33,
with a significance of p < .05 between these two measurements. Care should be
exerted in assessing the therapeutic efficiency of an orthopedic brace based
exclusively on a patient's reported compliance level. In particular, basing a
recommendation to change the brace based solely on this information may result in
erroneous and serious therapeutic actions. The efficiency of orthopedic braces
should be assessed on objective measures of the actual compliance rate wherever
possible.
PMID- 10786514
TI - Self-esteem changes in children enrolled in weight management programs.
AB - The purpose of this study was to examine self-esteem changes in school aged
children enrolled in weight management programs. The study group was comprised of
54 obese children ages 10-15 enrolled in a weight management program. The control
group was comprised of 60 obese children who had never been enrolled in a weight
management program. Each child was measured for body mass index (BMI) and weight.
All the children filled out the Pier-Harris Children's Self-Concept Scale at the
beginning of the study and 12 weeks later following the study group's completion
of the weight management program. The groups were similar in average age, weight,
BMI, and self-concept score at the beginning of the study. At the end of the 12
weeks, there was no significant change in the average weight or BMI in either the
study or control group. There was a significant decrease in the self-concept
score in the study group but not in the control group. The greatest score changes
came from the physical appearance subscale. Participation in weight management
programs may put children at risk for lower self-esteem (self-concept) while
producing limited weight loss results.
PMID- 10786515
TI - "Good little girls": reports of pregnant adolescents and those who know them
best.
AB - A qualitative descriptive study was conducted to identify characteristics and
themes in the lives of pregnant adolescents. Eight pregnant adolescents between
the ages of 16 and 18 years of age were recruited from a large public prenatal
clinic. Half the adolescents were African-American and half were European
American. Fully 75% lived in middle-income families and 25% in lower income
families. At the time of participation in the study, 75% remained in high school
and 25% had dropped out. The girls identified their mothers as "the person who
knows me best." The eight dyads participated in individual interviews. The
adolescents' views of themselves, of their characteristics and behavior, and
their mothers' perceptions of the adolescents' characteristics and behaviors were
elicited. Home observation notes and demographic data also were collected. The
template method of content analysis and a codebook from two preliminary pilot
studies were used to analyze the interview data. Findings included reports that
these pregnant adolescents had adult responsibilities at an early age, which
frequently included child care of younger siblings. The families viewed the girls
as mature and obedient, and the mothers did not think the adolescents were
sexually active prior to the pregnancy. It is significant that these teenagers
were frequently reported to be "good little girls," and others did not view them
as at-risk. The findings from this study can be used for early identification of
adolescents at risk for becoming pregnant and to develop specific preventive
measures.
PMID- 10786516
TI - The measurement of child characteristics from infancy to toddlerhood:
temperament, developmental competence, self-concept, and social competence.
AB - Maternal report on four characteristics was obtained for 126 infants at 8, 12,
24, and 36 months of age. Temperament was assessed using the Revised Infant and
Toddler Temperament Scales; the Infant/Child Monitoring Questionnaires were used
to screen developmental competence. The Self-Concept Questionnaire and the
Adaptive Social Behavior Inventory were outcome measures at 12, 24, and 36
months. Temperament and developmental competence were found to be relatively
stable but unrelated over time. The second year, 12-24 months, was a salient
period of development in which the greatest increases in self-concept and social
competence were observed. Correlation analyses revealed temperament difficulty
was negatively related to social competence yet unrelated to self-concept;
developmental competence was more strongly related to the developing self-concept
than social competence. The strongest relationships between social competence and
self-concept were obtained by earlier social competence in relation to subsequent
self-concept.
PMID- 10786518
TI - Book reviews--keeping up to date in the era of the information super highway.
PMID- 10786517
TI - Early adolescents' sexual behaviors.
AB - The purpose of this study was to analyze changes in early adolescents' intimate
behaviors and the initiation of sexual intercourse over a one-year time period.
The changes are interpreted within the context of recent progress in
understanding the development of early adolescents. Public school students in
sixth and ninth grades of selected schools in a midwestern industrial city were
studied in two waves of data collection. A total of 106 students provided data
for the second year, allowing comparisons of their Time 2 with their Time 1
responses. Five of eight intimate behaviors studied increased in frequency during
the year. Also, the adolescents' perceived benefits of having sexual intercourse
increased and perceived costs decreased during the follow-up year. Increases in
the frequency of intimate behaviors but not changes in their perceptions of the
benefits and costs predicted whether or not students had initiated sexual
intercourse during the follow-up period. These findings support current
understanding of early adolescence as a time of incremental learning about
intimacy and about sexual relationships. The findings suggest that preventing
early sexual intercourse may require understanding the specific behavioral
competencies related to healthful development of intimacy. Pediatric nurses can
be leaders in providing the necessary counseling and education to young
adolescents, their families, and their communities.
PMID- 10786519
TI - Nurses' perceptions of caring as documented in theory and research.
AB - Caring represents an essential human need and the fundamental component of the
nursing profession. A deep understanding of caring and the way it is expressed
will help nurses to provide high-quality services and, more importantly, to
understand nursing itself. This review of the literature indicates the importance
of examining caring both conceptually and operationally. Based on theoretical and
research accounts, it also presents the wide variety of ways in which caring is
conceived and expressed within the professional field. Caring is examined from
anthropological, philosophical and psychosocial perspectives. In this paper
implications for practice and research are outlined.
PMID- 10786521
TI - Core competencies for clinical nurse specialists: a usable framework.
AB - This article describes a framework of generic core competencies for assessing the
role of the Clinical Nurse Specialist (CNS). It was devised by a group of CNSs at
Kingston Hospital NHS Trust, over a two year period. Currently, there is
considerable confusion surrounding the role of the CNS. The UKCC is in the
process of clarifying what is meant by specialist practice, with the aim of
formally recognizing its status on the register. There does not seem to be a
consensus opinion on the standards of competence required to practise as a CNS.
This article seeks to address this issue by demonstrating a means of competency
based assessment for the role of the CNS.
PMID- 10786520
TI - Factors contributing to medication errors: a literature review.
AB - Drug administration is an integral part of the nurse's role. Responsibility for
correct administration of medication rests with the nurse, yet medication errors
are a persistent problem associated with nursing practice. This review examines
what constitutes a medication error and documents contributory factors in
medication errors. These factors have been derived from reported medication
errors and opinions of nurses as to factors which predispose to errors. A number
of definitions exist as to what constitutes a medication error. The definition
used should facilitate interpretation and comparison of a wide range of research
reports. Medication errors are a multidisciplinary problem and a
multidisciplinary approach is required in order to reduce the incidence of
errors.
PMID- 10786522
TI - Nurse specialists' perceptions of their role and function in relation to starting
an adult diabetic on insulin.
AB - The purpose of this study was to describe how diabetes nurse specialists
perceived their role and function in relation to starting adult patients with
insulin dependent diabetes on insulin. Using Heideggerian hermeneutic
phenomenology as a research method, six diabetes nurse specialists were
interviewed and the interviews were analysed according to Colaizzi's method of
phenomenological inquiry. Results showed that the diabetes nurses perceived their
role to be composed of six themes: educator; promoter of physical skill
acquisition; psychological supporter; advocate of individualized care; promoter
of self-care; 'safeguard' in assessing and ensuring patient safety. These results
support findings from other studies, that the diabetes nurse specialist role
seems to be more complex than descriptions in the nursing literature offer.
PMID- 10786523
TI - The success of an integrated care programme for patients with ischaemic heart
disease: the practice nurses' perspective of SHIP.
AB - Follow-up care of patients with angina and myocardial infarction after hospital
discharge is known to be suboptimal across the UK. The employment of cardiac
liaison nurses ensured timely notification of hospital discharge and good
communication of each patient's current and planned care. The direct ongoing
support of the liaison nurse was valued by more practice nurses than educational
support meetings and the initial counselling skills course. The most important
factor which enabled practice nurses to expand their role to provide post
hospital follow-up care was the support of the doctors in the practice. After the
conclusion of the Southampton Heart Integrated Care Project (SHIP) and the
withdrawal of cardiac liaison nurses, the lack of hospital discharge notification
was the most important reason for practice nurses discontinuing follow-up care.
PMID- 10786524
TI - Identifying approaches to meet assessed needs in health visiting.
AB - An action research project, based in a single fundholding practice on the south
coast of England, aimed to identify the health needs of families with resident
children, then use the contracting system to redirect health visiting services to
meet those needs. After assessing the health needs, it was necessary to assess
the potential of a range of health visiting approaches that might be proposed to
meet those needs. This paper explains how the approaches were assessed for use in
the local area and why funding for two additional, innovative posts was deemed
necessary. Despite the unsophisticated evidence base for health visiting
interventions, a case can be made for commissioning particular service approaches
by using a combination of survey data and results from controlled and
uncontrolled service evaluations. The supportive focus of health visitor home
visiting remains an appropriate use of existing resources, but the usual
intensity of visiting may be insufficient for full effectiveness. To rationalize
such services by targeting them only at individuals with established needs risks
an exacerbation of deteriorating health trends across an area. Alternatively,
augmenting home visiting with a community development approach to improve the
adverse social environments in which families live may help to change the
underlying factors that contribute to ill-health and prove more widely cost
effective.
PMID- 10786525
TI - An exploration of the stroke co-ordinator role.
AB - Although there is knowledge of the substantial benefits of collaborative
approaches to stroke rehabilitation, information on alternative management
strategies is sparse. This paper describes an exploratory survey, undertaken in
the north-west of England, to highlight features of the stroke co-ordinator role.
The role is explored in terms of rehabilitation management and service
development. Some strategies to support practitioners in the role, and areas for
role development, are suggested.
PMID- 10786526
TI - 'Going to the bathroom four or five times a night ...': seven men talk about
their experiences of benign prostatic hyperplasia and the perioperative period.
AB - This study describes ageing men's experiences of benign prostatic hyperplasia and
transurethral resection. The experiences of ageing men participating in this
study vary in different periods of their treatment. It is evident that
experiences are attached to feelings, cognitive thinking and responses.
PMID- 10786527
TI - Identifying strategies for managing urinary incontinence with women who have
multiple sclerosis.
AB - The aim of this pilot project was to identify strategies for managing
incontinence with women who have multiple sclerosis (MS). The project used the
formation of a group in which eight women with MS and four Continence Nurse
Advisers (CNAs) and the first author were brought together. In the course of the
research process, the women found a voice on a topic previously thought of as
taboo. When they realized that they had suffered alone and in silence they felt
empowered to act. In this way, the methodology evolved from group work into a
participatory action research process (PAR), as the group initiated action.
Participants formed a self-help group, and continued to meet with each other
after the research had run its course.
PMID- 10786528
TI - Studying the careers of nurse diplomates: the importance of branch-specific
questionnaires.
AB - Questionnaire design is considered in the context of a longitudinal panel study
focusing on the careers of people qualifying from all four branches of the UK
nurse diploma course. Separate, but comparable, questionnaires were developed for
each branch in order to produce information which reflected the differences
between branches, and the experiences of the cohort as a whole. This approach
ensured that participants from the smaller branches did not feel their interests
and concerns were overshadowed by those of the largest (adult) branch, as is
often the case during the diploma course's Common Foundation Programme. The
elements that needed to be tailored to each branch emerged during a three-stage
piloting process used to develop and test the questionnaires. Differences were
found between branches in their use of terminology; in certain issues being more
relevant to some branches than others; and in questions which concerned all
branches benefiting from the inclusion of branch-specific examples. The
effectiveness of this approach to questionnaire design is borne out by the
study's high response rates.
PMID- 10786530
TI - Information point: Colaizzi's framework for analysing qualitative data.
PMID- 10786529
TI - Implementing supernumerary learning in a pre-registration diploma in nursing
programme: an action research study.
AB - The purpose of this study was to develop a framework for implementing
supernumerary learning in a preregistration Diploma in Nursing programme in an
Irish hospital. Experiences of student nurses (n = 31), clinical nursing staff (n
= 8) and nurse teachers (n = 4) were explored, regarding the introduction of
supernumerary status in this programme. An action research approach, employing
phenomenological methods for gathering and analysing the data, was used to carry
out the study. A framework for implementing supernumerary learning in a Diploma
in Nursing programme was developed, based on the study. This framework reflects
the level of knowledge, skills and attitudes of individuals partaking in
supernumerary learning, and the role of the supervisor in the clinical area at
each level. Possible implications of the changing role of the student nurse for
nursing practice for education, management and research are suggested.
PMID- 10786531
TI - Effect of education on evidence-based care and handling of peripheral intravenous
lines.
AB - Deficient routines in use, care, handling and documentation of peripheral
intravenous vein cannulae (PIV) have previously been reported, and complications
have been noted in 50-75% of the patients. The aim of the study was to examine
whether specially trained nurses change their actions to decrease complications
when using cannulae. The study included 36 nurses assigned to experimental and
control groups. The experimental group followed an education programme explaining
how to use and take care of a PIV. To evaluate the intervention document
analysis, observations and patient interviews were performed in 99 patients with
172 PIVs in situ for less than 24 h. After the education programme, fewer
complications, more carefully performed care and handling, and better
documentation and information were found in the experimental group. Nurses in the
control group followed current routines, which resulted in a greater degree of
complications. Education in evidence-based care and handling gives nurses the
opportunity to improve their ability to use theoretical knowledge in clinical
problems.
PMID- 10786532
TI - Strategies for feeling secure influence parents' participation in care.
AB - This study investigates what makes parents of hospitalized children feel secure
and factors influencing their level of participation. It also studies, whether
the degree to which parents participate affects their child's pain and sleep
during hospitalization. Questionnaires were distributed to a series of parents
whose children were discharged from two paediatric surgical wards and one
paediatric medical-surgical ward at two university hospitals in Sweden. Parental
security is almost equally distributed among three given alternatives: security
derived from trusting that professionals know how to take care of the child;
security derived from having control over what is happening to the child; and
security derived from being the one who knows the child best. Depending upon the
strategy chosen, parents want to participate at different levels in their child's
care. The results indicate a relationship between parental participation and
their estimation of their child's pain. The study confirms a pattern, developed
in a previous study, in how parents adopt different strategies affecting their
participation during their child's hospitalization. Some parents who wanted to
participate in more aspects of their child's care seemed to think that their
child had less pain than parents who preferred more limited participation.
PMID- 10786533
TI - Blood transfusion from the recipient's perspective.
AB - This paper reports on an interpretative research study that set out to develop a
rich description of patients' experiences of the process of preparing for and
receiving a blood transfusion. The themes of information-giving and receiving;
reactions, both physical and emotional; and the care and treatment participants
received through the experience are presented.
PMID- 10786535
TI - Parents' experiences of general hospital admission for adults with learning
disabilities.
AB - General hospital care for people with learning disabilities is strongly
emphasized in recent health policy. Ten sets of parents were interviewed about
their experiences of general hospital inpatient care for their adult sons and
daughters with learning disabilities. Findings in the areas of placement,
occupation, basic nursing care, feeding, toileting, nursing attitudes, staffing
and procedures are presented. Recommendations are made for changes to reported
nursing practice to improve the quality of general hospital care for people with
learning disabilities.
PMID- 10786534
TI - Women's experiences of obtaining emergency contraception: a phenomenological
study.
AB - Emergency contraception (EC) has been available since 1984 but has been labelled
the 'best kept secret' (Winfield, 1995). Because EC was originally termed 'the
morning after pill', many people interpreted this literally and missed an
opportunity to use the method. More recent publicity has dropped this term and
emphasized that the method is effective up to 72 h after unprotected intercourse
or contraceptive failure (Burton & Salvage, 1990). Uptake of EC has steadily
increased since 1985 but there is still evidence that younger women in particular
are least aware of its existence.
PMID- 10786536
TI - Palliative care nurses' feelings about death rattle.
PMID- 10786538
TI - Information point: confidence interval.
PMID- 10786537
TI - Perceptions of caring among nurses: the relationship to clinical area.
PMID- 10786539
TI - A social work imperative: recruiting African American males into the profession.
AB - This article outlines why it is important that the social work profession take
affirmative steps toward recruiting African American males into the field. Also
described are the results of a qualitative research project on factors related to
a social work career choice by African American male undergraduate students.
Implications for the profession and African American families are discussed.
PMID- 10786540
TI - Common human needs in the context of diversity: integrating schools of thought.
AB - In this article we argue that effective social work practice which honors
cultural diversity is best informed through an integration of the strengths
associated with modern and postmodern schools of thought. This integration
provides a lens for simultaneously seeing common human needs and individual
differences, a vision that neither school of thought alone can provide. Aspects
of Virginia Satir's growth model are presented as an example of a practice
approach that incorporates this simultaneous attention to similarities and
differences.
PMID- 10786541
TI - Somatization and depression among former Soviet immigrants.
AB - This study investigated the prevalence of pure and overlapping forms of
somatization and depression in a sample of former Soviet immigrants and whether
pure somatization or pure depression could be differentiated using the study
variables. Study respondents completed a demographic questionnaire, the Demands
of Immigration Scale, and the Symptom Checklist 90R. Respondents were classified
as (a) neither depressed nor somatic, (b) only somatic, (c) only depressed, or
(d) both depressed and somatic. Univariate analyses and logistical regression
were used to compare these four groups and to predict the likelihood of being
only depressed or only somatic. The four groups differed in terms of immigration
demands, age, education, employment, and years in the U.S. A logistic regression
analysis was able to classify 75% of the participants as only somatic or only
depressed on the basis of certain demographic characteristics. Age, being
unemployed and not looking for work, and not having a college education increased
the risk of being somatic rather than depressed.
PMID- 10786542
TI - African American women and substance abuse: an overview.
AB - Contemporary trends and forces suggest that drug use and drug abuse among women
may be rooted in a cultural context. Cultural patterns and experiences provide
situations out of which women forge their sense of self, their identity, their
concept of race and ethnicity, their notion of gender, and their sense of class.
A woman's life experience and situation, and cultural roles and beliefs generally
influence drug abuse. This paper builds on the cultural context of drug use by
analyzing the socialization of women, and the life circumstances and socio
demographic experiences women face. Specifically, this cultural context framework
forms the foundation for the prevention of drug abuse and the extent to which
health professionals need to understand drug abuse and to treat women effectively
across class, and racial and ethnic differences.
PMID- 10786543
TI - Preventing premature death: part strategy, part window dressing?
PMID- 10786544
TI - Towards practice development--a vision in reality or a reality without vision?
AB - This paper describes the development of a conceptual framework for practice
development. Drawing on the authors' combined experiences of facilitating
developments in practice, a conceptual framework is proposed. It is argued that
much practice development in health care today lacks a systematic approach and is
often undertaken by individual practitioners who are poorly prepared for their
roles. A short history of practice development is outlined to contextualize
current development activities. The proposed framework is located in a critical
social science philosophy and it is suggested that such a philosophy enables
individual growth and development, empowerment of practitioners and the
generation of cultural change that sustains continuous growth and innovation in
practice. An example of the framework in use is described and recommendations
proposed to enable organizations to embrace a systematic approach to practice
development.
PMID- 10786545
TI - Identifying, evaluating and implementing cost-effective skill mix.
AB - BACKGROUND: The British National Health Service (NHS) employs a large number of
individuals, at great monetary cost, to provide direct care to patients. Changes
in the combinations of staff, including nurses, nurse practitioners and midwives,
delivering this care have been shown to be effective in many settings. FINDINGS:
The (opportunity) cost implications of such changes in the skill mix are rarely
evaluated adequately. The impact of releasing professionals' time has not been
estimated and therefore determining whether changes are cost-effective is
difficult; these difficulties have often been increased by poor study design.
CONCLUSIONS: Economic evaluation has been under-utilized in studies of skill mix.
If economic evaluation demonstrates that skill mix changes reduce cost and
improve or maintain patient outcomes, this is strong evidence that these changes
should be implemented. Incentives may be required to attract the necessary
personnel. This in itself may influence the cost of changing the skill mix and
therefore the situation should be monitored as both costs and effectiveness can
alter over time.
PMID- 10786546
TI - Factors that influence nurses' customer orientation.
AB - BACKGROUND: Hospital care mostly involves complex processes that are continuously
adjusted to match individual client needs. As most patients cannot evaluate the
technology used, they focus on personal interactions with care providers when
making judgements about the care received. Nurses are the care team members that
primarily provide ongoing care. AIMS: This study aims to further understand
factors that influence the way nursing staff relate to their patients. A model is
presented of the contextual and self-perceptual factors that influence the level
of customer/client orientation of nursing services in an Australian hospital
setting along with details of a quantitative study. METHODS: Nurses completed an
anonymous questionnaire, which was then mailed directly to the researchers.
Analysis of the data included factor analysis, regression and path analysis.
FINDINGS: The results show that contextual elements such as management commitment
to service quality and self-perceptual factors such as role stress impact on the
nurses' client service orientation. However, the variables being studied commonly
have both direct and indirect effects with feelings about commitment to the
organization having a notable mediating influence. The scales adapted from use in
other industries are able to measure the perceptual and outcome variables in a
health institutional setting. CONCLUSIONS: The managerial implications are that
both a comprehensive programme of organizational culture and individual staff
member development is needed if an enhanced customer orientation and the
consequent improvement in client satisfaction with nursing care is to occur.
PMID- 10786547
TI - Go the extra mile--use the Delphi Technique.
AB - AIM: The Delphi Technique is reviewed and its potential contribution to the
management of change assessed. BACKGROUND: Change management is an essential
skill required, not just by managers, but by all staff working in health care.
Modern theories advocate participation and free communication to engender
commitment and ensure successful change. Data collection methods associated with
surveys--interviews and questionnaires--are regularly used to obtain information
for service development. Indications of likely resistance are more difficult to
obtain. KEY ISSUES: The Delphi Technique is critiqued and found to incorporate
many attributes that can produce information which would be otherwise difficult
or impossible to obtain. A recently published study performed by the author
illustrates this potentiality. An indication of the impact of the findings on the
subsequent implementation of change by service managers is provided. CONCLUSION:
The Delphi Technique is a useful management tool that can provide data that are
difficult to obtain by other means.
PMID- 10786548
TI - The staff's experience of structural changes in the health and medical service in
western Sweden.
AB - BACKGROUND: The structure and contents of the health and medical service have
changed in recent years. The merger of Norra Alvsborgs and Uddevalla hospitals
into one local district under one leadership (the NU medical service) is a
Swedish example of a structural change. AIMS: This study intends to describe and
analyse the staff's experience of a recently accomplished structural change in
the local district NU medical service in the western part of Sweden. METHODS:
This study has been carried out from a qualitative point of view inspired by
grounded theory. From a theme guide with specific questions, 31 interviews were
carried out with staff working in the NU medical service. FINDINGS: Four
categories emerged from the body of interviews: 'participation', 'doubts',
'anxiety' and 'faith'. 'Participation' was defined as an overall core category,
and was related to the other categories. The categories 'doubts', 'anxiety' and
'faith' were related to sub-categories and affected by the overall category
'participation'. CONCLUSIONS: The overall results point to the importance of
participation of staff members concerned. The role of the leadership when
undergoing structural changes is considered as a major factor to make other staff
members participate.
PMID- 10786549
TI - Conceptions of oral health among nurse managers. A qualitative analysis.
AB - AIM: The aim of this study was to describe how nurse managers perceive oral
health in general and the oral health of the care-receiver in particular.
BACKGROUND: Oral health and general health are independent and influence each
other through biological, psychological, emotional and developmental factors. To
most adults, oral health is a natural daily routine of hygiene, whereas to people
who are dependent on other people's assistance, it is a procedure carried out by
nursing personnel. METHODS: Data were collected through interviews and analysed
according to the phenomenographical method. FINDINGS: Five categories emerged
describing how nurse managers perceive oral health: maintaining patients' well
being, having knowledge about oral health, behaviour towards the patient, feeling
of being insufficient and creating the necessary conditions. CONCLUSION: The
nurses considered oral health an important and obvious, but neglected, part of
nursing. They expressed the wish to be updated in the knowledge area concerned,
both for themselves and for their personnel. A majority called for standards for
oral care, including documentation, which was considered necessary for the
successful implementation. IMPLICATIONS: A suggestion for further research is to
study whether the creation of national standards may increase its status and
quality.
PMID- 10786550
TI - Finding the advocacy in yourself.
PMID- 10786551
TI - Telephone protocol.
PMID- 10786552
TI - HIV postexposure prophylaxis after blood exposure in school.
PMID- 10786553
TI - Case study: family stress and Alzheimer's disease.
PMID- 10786554
TI - Factors associated with nursing diagnosis utilization in Canada.
AB - PURPOSE: To investigate factors associated with nursing diagnosis utilization.
METHODS: A retrospective chart audit was conducted on four hospital units over a
5-month period and linked to the nurses (N = 65) who participated in a survey on
attitudes toward nursing diagnosis. FINDINGS: Computer-generated nursing care
plans resulted in the greatest frequency of nursing diagnosis documentation.
Nurses who did not document nursing diagnoses, and nurses employed in hospitals
without nursing diagnosis implementation programs, had more positive attitudes
toward the value of nursing diagnosis in practice compared with nurses who
documented nursing diagnoses and nurses employed in hospitals with implementation
programs. CONCLUSIONS: Nurses have a greater tendency to document nursing
diagnoses when institutions have formal educational programs and computer
generated care plans.
PMID- 10786555
TI - From risk for trauma to unintentional injury risk: falls--a concept analysis.
Nursing Diagnosis Extension and Classification Research Team.
AB - TOPIC: Concept analysis of the nursing diagnosis risk for trauma. PURPOSE: To
examine the nursing diagnosis risk for trauma and to specify the risk factors for
falling. SOURCES: Research and informational articles on falling, and NANDA
Nursing Diagnoses: Definitions and Classification, 1999-2000. CONCLUSIONS:
Replace the current nursing diagnosis risk for trauma with the more specific
nursing diagnosis unintentional injury risk: falls. The other risks included in
risk for trauma (e.g., burns) also will need to be developed.
PMID- 10786558
TI - Factors affecting quality assurance in nursing care.
PMID- 10786556
TI - Clinical validation of characteristics of the alcoholic family.
AB - PURPOSE: To validate, from a client and family perspective, the defining
characteristics for the nursing diagnosis altered family processes: alcoholism;
and to identify demographic, family, and selected treatment information from
clients and family members. METHODS: Subjects (N = 150) completed Fehring's
(1987) Clinical Diagnostic Validation (CVD) Index for 110 defining
characteristics of the nursing diagnosis altered family processes: alcoholism.
FINDINGS: Alcoholic families display behaviors of alcohol abuse, loss of control
of drinking, denial, nicotine addiction, impaired communication, inappropriate
expression of anger, and enabling behaviors. Family feelings indicate the
presence of unhappiness, hurt, frustration, guilt, moodiness, powerlessness,
loneliness, mistrust, anger, anxiety, and hopelessness. CONCLUSIONS: These
clinically validated characteristics will complete the assessment phase of this
research and direct the path to future studies to determine appropriate
goals/outcomes and interventions related to alcoholic families.
PMID- 10786557
TI - A critical time for nursing diagnosis research.
PMID- 10786559
TI - Inter-sex. Newer concepts, surgical and nursing management.
PMID- 10786561
TI - Prevention of child marriages: a report on awareness in rural Andhra Pradesh.
PMID- 10786560
TI - Relationship between sex roles and mental disorders.
AB - The present study "Relationship between sex roles and mental disorders" analyses
the various findings of research regarding the sex roles and mental problems. All
these findings reveal that the women whether they work outside or not, face
various mental problems especially functional psychosis and neurosis. This
finding is also proved by the research of National Institute of Mental Health
(NIMH) of U.S.A. They analysed the admissions and the treatment give for the
psychologically affected persons in various hospitals and came across more women
patients than the men. The research also formulates some possible suggestions to
curb the mental disorders among the women.
PMID- 10786562
TI - Issues and perspective of nursing in Gujarat.
PMID- 10786563
TI - If you don't do it, it won't happen!
PMID- 10786564
TI - Continuous quality improvement initiatives. A new philosophical approach to
quality assurance?
PMID- 10786565
TI - Continuous quality improvement. Cult or science?
PMID- 10786566
TI - Designing successful learning programs.
AB - This article gives an overview of the opportunities in distance learning for
degree-granting programs in schools of nursing. The focus is on the unparalleled
innovations in technology and the centrality of that technology to nursing
education. One of the important aspects of the use of technology is the
development of sound educational programs and practices. Schools of nursing
embarking on a distance learning model should determine the approach that will be
used and examine critical success factors to ensure a quality program and
economically successful outcome. The promise of interactive communication as a
pedagogical strategy has potential and promise for the future.
PMID- 10786567
TI - Credentialing. A paradox for the 21st century.
AB - As a result of mixed and seemingly contradictory forces in the sociopolitical,
economic, and health care environments, credentialing has taken on new momentum
and direction in the United States and abroad. The nursing profession, including
the American Nurses Credentialing Center, is meeting the challenge through new
approaches and partnership endeavors among nursing organizations and with other
health care providers and consumer groups.
PMID- 10786568
TI - Invisible inventors. A historical overview of creative midwives and nurses.
AB - This historical overview documents women's inventions for providing nursing care
dating from 1608 to 1928. The word invention is broadly defined and includes
ideas that created therapeutic activities, caregiving environments, and specific
devices for care. It focuses on the creative contributions of early outstanding
midwives and other practicing nurses around the late 19th and early 20th
centuries. Sources include illustrations of patented items, practical hints
published in early issues of the American Journal of Nursing (AJN), published
translations of original documents from Europe, original historical research on
women in Europe and America, and records from the U.S. Government Patent Office.
The role of nurses in creating and developing tools and methods for providing
nursing care has gone unrecognized. It is important to clarify the record of
women's and nurses' inventiveness.
PMID- 10786570
TI - Pay review must be fair.
PMID- 10786569
TI - Strategies for successful research project management.
AB - Beginning researchers may not fully appreciate the complexity of implementing a
study, or the degree of rigor and precision involved. Successful project
management requires careful planning, conscientious follow-through, and
continuous monitoring. Several aspects of project implementation are discussed:
defining roles and responsibilities of project personnel, overseeing progress of
the project, planning and managing the budget, and record keeping. Concrete
strategies are provided, with the emphasis being on proactive approaches that
prevent problems rather than on reactive crisis management.
PMID- 10786571
TI - Maybe, just maybe....
PMID- 10786573
TI - Moving on and moving up. Interview by Charlotte Alderman.
PMID- 10786572
TI - Lost continence.
PMID- 10786574
TI - In the driving seat.
PMID- 10786575
TI - Inside out.
PMID- 10786577
TI - There's no place like home.
PMID- 10786576
TI - Something worth saying? Then say it.
PMID- 10786578
TI - Supporting research.
PMID- 10786579
TI - Bacterial contamination of curtains in clinical areas.
AB - A small-scale study carried out by student nurses revealed ward curtains to be a
source of contaminants and bacteria, including MRSA. Patients and medical staff
can contaminate and be contaminated by bacteria which may be a source of cross
infection. Recommendations from the study included the promotion of further
research in this area and more frequent laundering of curtains.
PMID- 10786580
TI - Filming in hospitals: ethical and methodological issues.
AB - Filming people in hospital poses ethical problems for researchers, film-makers
and healthcare staff. This article describes the safeguards which need to be put
in place to protect patients and those who may be filmed during the course of
their work.
PMID- 10786581
TI - The trouble with specialised language for nursing.
AB - Liam Clarke continues the discussion about the need for a specialised nursing
language and argues that the ordinary social and moral rules governing everyday
speech should suffice.
PMID- 10786582
TI - Getting into business: how nurses can make a difference.
AB - In this article, the authors explore some of the key concepts and practices
associated with the 'business of nursing' and look at the opportunities presented
to nurses for taking a greater role in important business decisions.
PMID- 10786583
TI - Infection control.
PMID- 10786584
TI - Playing to the crowd.
PMID- 10786585
TI - Clearing the first hurdle.
PMID- 10786586
TI - Second level should not mean second class.
PMID- 10786587
TI - Dark side of the law.
PMID- 10786588
TI - Prejudicial conduct.
PMID- 10786589
TI - Army dreamers.
PMID- 10786590
TI - What is the mental health national service framework?
PMID- 10786592
TI - England's newly appointed chief nurse has a job description fit for superwoman.
PMID- 10786591
TI - Pooling power.
PMID- 10786593
TI - Spread the word: you are the tops.
PMID- 10786594
TI - Nurse heroes of the century. Interview by Jeannette Davidson.
PMID- 10786595
TI - Shared learning. Together we can do it.
PMID- 10786596
TI - Stand up and be counted.
PMID- 10786597
TI - Nursing strategy. In for the big catch.
PMID- 10786598
TI - Public health. Safe as houses.
PMID- 10786599
TI - Gain from pain.
PMID- 10786600
TI - People with impaired memory often lack self-confidence and have high anxiety
levels.
PMID- 10786601
TI - Bladder cancer: its diagnosis and treatment.
PMID- 10786602
TI - Take the medical model out of the menopause.
PMID- 10786604
TI - New, but hardly improved.
PMID- 10786603
TI - Tetanus--death by toxin.
PMID- 10786605
TI - And so to beds.
PMID- 10786606
TI - Respiratory care. The outsider.
PMID- 10786607
TI - Respiratory care. Air apparent.
PMID- 10786608
TI - Alert to allergies.
PMID- 10786609
TI - Theatre nursing takes centre stage.
PMID- 10786610
TI - Digital rectal examination--2.
PMID- 10786611
TI - Properties of the delayed rectifier potassium current in porcine sino-atrial node
cells.
AB - 1. Whole-cell currents were recorded in single, spontaneously active cells
dissociated from porcine sino-atrial node, and the conductance and gating
properties of the delayed rectifier K+ current (I(K)) were investigated. 2. The
isolated cells exhibited spontaneous action potentials at a rate of 80.5 +/- 5.4
min(-1) (mean +/- S.E.M., n = 11). Under Ca2+ current block, (depolarization from
-40 mV to various potentials activated a time-dependent outward current (I(K)).
The activation curve of I(K) showed a half-activation potential (V1/2) of 20.5 +/
2.1 mV and a slope factor (S) of 16.4 +/- 1.2 mV (n = 8). 3. As the duration of
the depolarizing pulse to either +10 or +60 mV was prolonged, the amplitude of
the tail current increased in proportion to that of the activated outward current
during depolarization. 4. E4031 (2-5 microM), a selective blocker for the rapidly
activating component of I(K) (I(K,r)), hardly affected I(K), but chromanol 293B,
a selective blocker for the slowly activating component (I(K,s)), inhibited I(K)
with an IC(50) of 8.79 microM. 5. The reversal potential of I(K) was -75.2 +/-
2.3 mV with 5.4 mM external and 150 mM internal K+. The time courses of
activation and deactivation of I(K) were fitted by the sum of two exponential
functions at various potentials. The relationship between the time constants and
membrane potential showed a bell-shaped curve with a peak at around -10 mV for
both fast and slow components. 6. The results indicate that in porcine sino
atrial node cells I(K) is largely derived from I(K,s) and that I(K,s) plays a
functional role in in the slow diastolic depolarization. I(K,s) may, in part,
account for the relatively slower heart rate of pigs than that of rabbit in which
I(K,r) is a functionally dominant component of I(K).
PMID- 10786612
TI - The stability and maturation of the H2A histone mRNAs from Trypanosoma cruzi are
implicated in their post-transcriptional regulation.
AB - We have recently described that the Trypanosoma cruzi histone H2A genes are
actively transcribed as two sized classes of polyadenylated transcripts and that
they differ in the 3'-UTRs due to the insertion of a partial SINE sequence in the
3'-end of some of H2A gene units. The expression of the H2A genes in the non
replicative trypomastigote forms is very low, whereas in the replicative forms,
there is significant and constitutive transcription of the H2A genes probably
regulated in a posttranscriptional way and associated to DNA replication. The
data presented in this paper reveal that in epimastigotes, the steady-state
levels of the H2A mRNAs are determined by controlling the stability of the
messengers in the cytoplasm, most likely mediated by a nuclease attack. The data
also indicate that there must be an additional control, associated to the
parasite growth phase, which may act at the maturation step of the transcripts.
The data suggest, moreover; that the cytoplasmic level of the H2A protein might
be involved in the regulation of its own synthesis by controlling translation of
existing messengers.
PMID- 10786613
TI - Identification of the copper chaperone SAH in Ovis aries: expression analysis and
in vitro interaction of SAH with ATP7B.
AB - A clone encoding the putative copper chaperone protein Sheep Atx1 Homologue (SAH)
was isolated from a sheep liver cDNA library. The 466-bp cDNA encoded a predicted
protein of 68 amino acids, with 44 and 81% amino acid identity to the yeast Atx1
and human Atox1 copper chaperone proteins, respectively. The characteristic
MTCxxC and KTGK motifs were conserved in SAH. Northern blot analysis revealed an
abundant 0.5-kb mRNA in all tissues examined. Elevated hepatic copper content did
not affect the level of SAH mRNA in the liver. Analysis of SAH mRNA in the
developing liver revealed low levels of expression in the foetal period, with a
steady increase to adult levels occurring during development. In vitro two-hybrid
analysis demonstrated SAH interacted with the amino terminal portion of the sheep
Wilson's disease protein (ATP7B). The extent of this interaction was
significantly reduced by the addition of the copper chelator bathocuproine
disulfonic acid to the media. These results suggest SAH is a functional copper
chaperone that is able to interact with ATP7B in a copper-dependent manner to
facilitate copper transport into the secretory pathway.
PMID- 10786614
TI - Primary structure, chromosomal mapping, expression and transcriptional activity
of murine hepatocyte nuclear factor 4gamma.
AB - We demonstrate the presence of a new member of the orphan nuclear receptor
hepatocyte nuclear factor 4 (HNF4) subfamily in mouse which is genetically
distinct from the previously characterized mouse HNF4alpha gene. The new member
of the HNF4 subfamily shows highest amino acid identity, similar tissue
distribution and syntenous chromosomal localization to the recently described
human HNF4gamma (NR2A2), we therefore classify it as mouse HNF4gamma
(mHNF4gamma). A combination of RT-PCR and immunohistochemical analysis showed
expression of mHNF4gamma mRNA and protein in the endocrine pancreas, testes,
kidney and gut. By co-transfection experiments, we show that mHNF4gamma is able
to activate transcription, acting through binding sites that have been previously
characterized as HNF4alpha binding sites. The presence of HNFgamma in human and
mouse implies that a complex transcriptional network exists in higher vertebrates
involving a number of HNF4 members with overlapping yet distinct function and
tissue distribution.
PMID- 10786615
TI - Differential regulation of glutaredoxin gene expression in response to stress
conditions in the yeast Saccharomyces cerevisiae.
AB - Glutaredoxins are small heat-stable proteins that are active as glutathione
dependent oxidoreductases and are encoded by two genes, designated GRX1 and GRX2,
in the yeast Saccharomyces cerevisiae. We report here that the expression of both
genes is induced in response to various stress conditions including oxidative,
osmotic, and heat stress and in response to stationary phase growth and growth on
non-fermentable carbon sources. Furthermore, both genes are activated by the high
osmolarity glycerol pathway and negatively regulated by the Ras-protein kinase A
pathway via stress-responsive STRE elements. GRX1 contains a single STRE element
and is induced to significantly higher levels compared to GRX2 following heat and
osmotic shock. GRX2 contains two STRE elements, and is rapidly induced in
response to reactive oxygen species and upon entry into stationary phase growth.
Thus, these data support the idea that the two glutaredoxin isoforms in yeast
play distinct roles during normal cellular growth and in response to stress
conditions.
PMID- 10786616
TI - Functional expression in Pichia pastoris of human and rat intrinsic factor.
AB - Intrinsic factor (IF) has been expressed previously in Baculovirus with a yield
(0.1-1 mg/l) that was inadequate for structural and metabolic studies. IF cDNAs
were cloned into the shuttle vector pPIC9 of P. pastoris, and the proteins were
induced and purified by cobalamin (Cbl) affinity chromatography. Expression of
recombinant proteins revealed a major band of 49 kDa for both human and rat IF.
Expression of human IF was achieved at 1040 mg/l, but of rat IF at only 1-2 mg/l.
Reaction of human IF with a photo-activatable derivative of Cbl was demonstrated
by Western blotting, and detection of IF fragments by anti-Cbl monoclonal
antibody and by amino-terminal sequencing revealed at least three regions
(residues 129-151, 234-254, and +294) linked to Cbl. Both recombinant human and
rat [125I]IF-Cbl bound to rat and guinea pig brush border membranes with similar
affinity, but the binding capacity of human IF for the rat receptor was only 10%
compared with rat IF. All six amino acids within the previously identified N
terminal binding region of human IF were mutated to be identical to rat IF, but
the resulting chimeric IF still bound poorly to rat membranes. Mutations of
residues 26/27 (Glu26 to Asp and Asn27 to Gln) and 32/34 (Ser32 to Thr and Tyr34
to Arg) showed changes in both Ka and Vmax, with great effects on Vmax. In
conclusion, P. pastoris is an expression system that produces functional human IF
at a higher yield than in the baculovirus system. Cbl binding was directly
demonstrated at multiple sites along the linear sequence of human IF. The
receptor binding function of the amino terminal sequence 25 62 has been
confirmed, but it is insufficient to reproduce all the features of IF-Cbl
binding.
PMID- 10786617
TI - Molecular characterization of a murine, major A/B type hnRNP protein: mBx.
AB - We have previously identified a discrete hnRNP polypeptide of the A/B type, named
mBx, as an abundant protein species in murine cells. The molecular
characterization of this protein is now accomplished. From all evidence provided,
mBx polypeptide represents a new gene product, distinct from the known members of
the A/B family A1 and A2/B1. It is, instead, mostly related to a still
hypothetical human protein of A/B type, as well as to the Xenopus hnRNPA3 protein
species.
PMID- 10786618
TI - Induction of hepatitis B virus gene expression at low temperature.
AB - There is a limited understanding of the cellular regulation of HBV gene
expression in differentiated hepatocytes. We previously demonstrated that HBV
replication inversely correlates with cell proliferation and DNA synthesis. In
this report, temperature-induced modulation of cell growth was used as a novel
approach to study HBV gene expression in the absence of indirect effects from
drugs or serum deprivation. We observed markedly elevated levels of hepatic HBV
mRNA expression from integrated and episomal HBV DNA at 32 degrees C.
Additionally, hepatoblastoma cells cultured at 32 degrees C expressed increased
levels of albumin mRNA and decreased levels of c-myc mRNA, which demonstrates
that liver-derived cells cultured at low temperature exhibit characteristics of
functional and differentiated hepatocytes. In transiently transfected HepG2 cells
cultured at 32 degrees C, the HBV enhancer 1 activated the X promoter and
core/pregenomic promoter by 7.3- and 28-fold, respectively. In the absence of
enhancer 1, core/pregenomic promoter activity was 2.4-fold higher than the X
promoter in HepG2 cells at 32 degrees C. In contrast, enhancer 1 exclusively
activated the X promoter in transfected non-liver cells at 32 degrees C.
Therefore, the core/pregenomic promoter exhibits strict liver-specificity at low
temperature. This work supports the hypothesis that HBV replication and gene
expression are optimal in non-activated hepatocytes, and provides a novel system
for delineating molecular aspects of the HBV replication process.
PMID- 10786619
TI - Intron 1 rather than 5' flanking sequence mediates cell type-specific expression
of c-myb at level of transcription elongation.
AB - Previous studies have shown that expression of steady-state c-myb mRNA was
regulated primarily by a block in intron 1 during transcription elongation. This
study shows that the block site maps approximately 1700 bp from the start of the
intron. Studies based on a reporter construct containing c-myb flanking region
and intron 1 suggest that the flanking region is not important in the regulation
of the cell type-specific expression of c-myb. RNA splicing of intron 1 may
enhance the expression in a non-cell type-specific manner. A conserved intron
domain comprising the block site is required for defining this site, but this
function of the domain is independent of cell type. The cell type-specific
regulation of c-myb transcription elongation is mediated by a 5' intron sequence.
A mechanism for down regulation of c-myb gene expression by the block to
transcription elongation has been proposed.
PMID- 10786620
TI - Molecular characterization of a new arcelin-5 gene.
AB - Arcelins are insecticidal proteins found in some wild accessions of the common
bean, Phaseolus vulgaris. They are grouped in six allelic variants and arcelin-5
is the variant with the highest inhibitory effect on the development of Zabrotes
subfasciatus larvae. Characterization of the protein and its genes resulted in
the identification of three polypeptides and the isolation of two genes that
encode the Arc5a and Arc5b polypeptides. Here we describe a new gene, Arc5-III.
The protein it encodes has 81% amino acid identity with the derived amino acid
sequences of Arc5-I and Arc5-II. The Arc5-III gene is highly expressed in
developing seeds and at a much lower level in roots. Data obtained by a
combination of two-dimensional gel electrophoresis, protein sequencing and MALDI
TOF mass spectrometry analysis support the conclusion that Arc5-III encodes a
polypeptide present in Arc5c band. Using ion-exchange chromatography, three
fractions containing arcelin-5 polypeptides were eluted by increasing the salt
concentration. The three fractions contain various amounts of the three arc-5
polypeptides and inhibit the growth of Zabrotes subfasciatus larvae
differentially, suggesting differences in insecticidal activity among the arcelin
5 isoforms.
PMID- 10786621
TI - Promoter activity of the 5' flanking region of the complement receptor type 1
(CR1) gene: basal and induced transcription.
AB - The luciferase reporter gene system was used to assay the basal and Ara-C induced
promoter activity of the human CR1 gene in K-562 erythroleukemia cells. Based on
the results from clones of nested deletions, both basal and induced reporter gene
activity fell to promoterless levels between constructs containing 79 bp (-79)
and 41 bp (-41) upstream of the transcription start site. The -79 fragment was
shifted in electrophoretic mobility assays using nuclear extracts from Ara-C
induced and non-induced cells while the -41 bp fragment was not shifted. These
data suggest that the 38 bp region between these constructs is necessary for the
transcriptional activity of the CR1 gene and is involved in specifically binding
transcription factors from the nuclei of induced and non-induced cells. Several
potential transcription factor binding sites in this region were identified.
PMID- 10786622
TI - cDNA cloning of the mammalian sterol C5-desaturase and the expression in yeast
mutant.
AB - Sterol C5-desaturase (SC5D) cDNA is an enzyme that catalyzes the dehydrogenation
to introduce C5-6 double bond into lathosterol in cholesterol biosynthesis. We
have isolated and sequenced the cDNA clones encoding human and mouse SC5D. The
functional complementation of a defective yeast mutant proves that the human and
mouse cDNA clones encode SC5D. Mammalian SC5D was presumed as an integral
membrane protein containing histidine residues conserved also in yeasts and
plant.
PMID- 10786623
TI - cDNA cloning and chromosomal mapping of the gene encoding adenylate kinase 2 from
Drosophila melanogaster.
AB - As a step toward understanding of the role of adenylate kinase (AK) in energy
metabolism, we analyzed this enzyme in Drosophila melanogaster. The enzyme
activities of all three AK isozymes were determined in cell-free extracts of
flies, and their proteins were detected by Western blot analysis using polyclonal
antibodies against the mammalian isozymes. A cDNA encoding adenylate kinase was
isolated from D. melanogaster cDNA library. The cDNA encodes a 240-amino acid
protein, which shows high similarity to bovine, human and rat AK2, and hence was
named DAK2. Preliminary subcellular fractionation analysis indicated that DAK2 is
localized in both cytoplasm and mitochondria. In situ hybridization to salivary
gland polytene chromosomes revealed that the Dak2 gene is located at 60B on the
right arm of the second chromosome.
PMID- 10786624
TI - Identification of archaeal genes encoding a novel stationary phase-response
protein.
AB - A novel stationary phase-response protein has been identified in the acid-soluble
protein extract of the thermophilic archaeon, Thermococcus zilligii. N-Terminal
sequencing data were used to identify likely genes for homologues of the protein
in the complete genome sequences of various archaeal species. The corresponding
genes were identified and analysed. The genes encode a protein ranging from 83 to
92 amino acids in length, with a calculated pI ranging from 4.6 to 9.7. The amino
acid sequences of the genes were highly conserved, even between members belonging
to the different archaeal kingdoms. The computed secondary structure of the
protein indicates it consists of four large helical regions separated by short
coiled regions. We propose this protein as a candidate regulator of gene
expression in stationary phase.
PMID- 10786625
TI - Stage-specific expression of a novel isoform of mouse FGF-14 (FHF-4) in
spermatocytes.
PMID- 10786626
TI - A cDNA from the green alga Spermatozopsis similis encodes a protein with homology
to the newly discovered Roadblock/LC7 family of dynein-associated proteins.
AB - A clone, designated as B15, was isolated from a cDNA library of the unicellular
green alga Spermatozopsis similis and characterised. The deduced amino acid
sequence of its open reading frame exhibits high homology to members of the
recently discovered roadblock/LC7 protein family (robl/LC7) of dynein-associated
proteins. Homologies were highest to a robl/LC7-member from human testis (86%,
identity 56%) and to the roadblock protein of Drosophila (88%, identity 52%).
Data bank analyses revealed no homologies to known higher plant proteins. B15 is
a single copy gene in the genome of Sperm-latozopsis and its transcript was
detectable throughout the cell cycle.
PMID- 10786627
TI - Characterisation of a novel murine intestinal serine protease, DISP.
AB - A putative novel murine serine protease, DISP, was identified by cDNA indexing
and shown to be expressed primarily in distal gut. FISH analysis showed it to be
localised to mouse chromosome 17A3. A possible human homologue for DISP has been
identified. DISP is a novel member of clan SA/family S1 of the serine proteases,
at present of unknown function.
PMID- 10786628
TI - Characterization of three new manganese peroxidase genes from the ligninolytic
basidiomycete Ceriporiopsis subvermispora.
AB - Three new genes (Cs-mnp2A, Cs-mnp2B and Cs-mnp3) coding for manganese-dependent
peroxidase (MnP) have been identified in the white-rot basidiomycete
Ceriporiopsis subvermispora. The mature proteins contain 366 (MnP2A and MnP2B)
and 364 (MnP3) amino acids, which are preceded by leader sequences of 21 and 24
amino acids, respectively. Cs-mnp2A and Cs-mnp2B appear to be alleles, since the
corresponding protein sequences differ in only five residues. The upstream region
of Cs-mnp2B contains a TATA box, AP-1 and AP-2 sites, as well as sites for
transcription regulation by metals (two), cAMP (two) and xenobiotics (one). Some
of these elements are also found in the regulatory region of Cs-MnP3.
Transcription of Cs-mnp2A and Cs-mnp2B, but not that of Cs-mnp3, is activated by
manganese.
PMID- 10786629
TI - cDNA cloning and expression of a novel estrogen receptor beta-subtype in goldfish
(Carassius auratus).
AB - We have isolated a second goldfish estrogen receptor (ER) beta-subtype (gfER
beta2) cDNA which is distinct from the liver-derived ER-beta (gfER-beta1) cDNA
reported previously. The 2650-bp cDNA, isolated from a goldfish pituitary and
brain cDNA library, encodes a 610 amino acid (aa) protein which shows only a 53%
aa sequence identity with gfER-beta1 in overall structure. RT-PCR analysis showed
that mRNA of gfER-beta2, in contrast to that of gfER-beta1, was predominantly
expressed in pituitary, telencephalon and hypothalamus as well as in liver of
female goldfish. The existence of a second distinct ER-beta subtype opens new
dimensions for studying tissue-specific regulation of gene expression by estrogen
in the tetraploid goldfish.
PMID- 10786630
TI - Characterisation, chromosomal localisation and expression of the mouse Kid3 gene.
AB - Kid1 encodes a transcriptional repressor implicated in the differentiation of
renal epithelial cells. Here we report the characterisation of Kid3, a novel
mouse gene related to Kid1. Kid3 encodes a C2H2 zinc finger protein with an N
terminal KRAB transcriptional repression domain. It maps to chromosome 11,
adjacent to Kid1 and another related gene Kid2. Northern analysis shows that Kid3
is highly expressed in embryonic and adult brain, with lower levels in adult and
embryonic (E16.5) kidney, gut, lung and heart. Expression of Kid3 in the kidney
is developmentally regulated and suggests a role for Kid3 in the early stages of
nephrogenesis.
PMID- 10786631
TI - Identification and expression of the gene encoding phosphonopyruvate
decarboxylase of Streptomyces hygroscopicus.
AB - The first step of C-P compound biosynthesis is a C-P bond formation reaction
catalyzed by phosphoenolpyruvate phosphomutase, but this reaction favors the
cleavage of the C-P bond. This C-P bond forming reaction is driven by the
following reaction catalyzed by phosphonopyruvate (PnPy) decarboxylase. We have
cloned and sequenced the gene (bcpC) encoding PnPy decarboxylase, a key enzyme of
C-P compound biosynthesis, from the bialaphos (BA) producing microorganism
Streptomyces hygroscopicus by complementation methods using Streptomyces
wedmorensis NP-7, which is a mutant of a fosfomycin producing strain deficient in
this step. The location of this gene in the BA biosynthetic gene cluster was
determined by using the expression system in Streptomyces lividans. DNA
sequencing of this gene revealed a 1203-bp open reading frame encoding a
polypeptide of 401 amino acids.
PMID- 10786632
TI - Molecular cloning and characterization of a novel human gene (HERNA) which
encodes a putative RNA-helicase.
AB - A full-length cDNA encoding a novel protein was isolated and sequenced from a
human hepatocellular cDNA library. This cDNA consists of 7037 base pairs and has
a predicted open reading frame encoding 1924 amino acids. It possesses an RNA
helicase motif containing a DEXH-box in its amino-terminus and an RNase motif in
the carboxy-terminus. From a striking homology to Caenorhabditis elegans K12H4.8,
it might be a human homolog of the K12H4.8. PCR-based mapping with both a
monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to
human chromosome 14q31 near the marker D14S605.
PMID- 10786633
TI - A new human member of the MYST family of histone acetyl transferases with high
sequence similarity to Drosophila MOF.
AB - We have identified a novel human gene product, hMOF, which exhibits significant
similarity to the Drosophila dosage compensation regulator, MOF. A recombinant C
terminal portion of hMOF has histone acetyltransferase activity directed toward
histones H3, H2A and H4, a specificity characteristic of other MYST family
histone acetyltransferases. Based on hMOF's chromodomain, we discuss possible
interactions with other proteins.
PMID- 10786635
TI - Sequencing, tissue distribution and chromosomal assignment of a novel ubiquitin
specific protease USP23.
AB - We have identified human and mouse cDNAs encoding a novel ubiquitin-specific
protease designated USP23. Both cDNAs encode a 62-kDa protein containing the
highly conserved His and Cys domains characteristic of the C19 cysteine protease
family of ubiquitin-specific processing proteases (UCH-2). Human tissue Northern
blots revealed USP23 to be ubiquitously expressed, whereas USP12, its closest
human paralogue, displayed a more restricted expression pattern. The human USP23
gene mapped to chromosome 1q22.
PMID- 10786634
TI - Nucleotide sequence of a cDNA clone coding for an intestinal-type fatty acid
binding protein and its tissue-specific expression in zebrafish (Danio rerio).
AB - We have cloned a cDNA from zebrafish (Danio rerio) that contains an open-reading
frame of 132 amino acids coding for a fatty acid binding protein (FABP) of
approximately 15 kDa. Multiple sequence alignment revealed extensive amino acid
identity between this zebrafish FABP and intestinal-like FABPs (I-FABP) from
other species. The zebrafish I-FABP cDNA hybridized to single restriction
fragments of total zebrafish genomic DNA digested with the restriction
endonucleases PstI Bg/II or EcoRI suggesting that a single copy of the I-FABP
gene is present in the zebrafish genome. An oligonucleotide probe complementary
to the zebrafish I-FABP mRNA hybridized to an mRNA of approximately 800 bases in
Northern blot analysis. In situ hybridization revealed that the I-FABP mRNA was
expressed exclusively in the intestine of the adult zebrafish.
PMID- 10786636
TI - Nuclear receptor binding factor-2 (NRBF-2), a possible gene activator protein
interacting with nuclear hormone receptors.
AB - A protein named nuclear receptor binding factor-2 (NRBF-2) was identified by
yeast two-hybrid screening, as an interaction partner of peroxisome proliferator
activated receptor alpha as well as several other nuclear receptors. NRBF-2
exhibited a gene activation function, when tethered to a heterologous DNA binding
domain, in both mammalian cells and yeast.
PMID- 10786637
TI - Molecular cloning of a homologue of dad-1 gene in citrus: distinctive expression
during fruit development.
AB - A cDNA homologue to the human defender against apoptotic death gene (dad-1),
which is involved in programmed cell death, was isolated from satsuma mandarin
(Citrus unshiu Marc.) fruit. It (Citdad-1-1) was 345 bp long, with a deduced
protein sequence of 115 amino acids. Southern hybridization suggests that dad-1
related sequences are present as a small gene family in the citrus genome.
Expression of Citdad-1-1 was progressively down-regulated in leaves as they
matured, but not in juice sac/segment epidermis (edible part) towards fruit
ripening. The role of dad-1 during citrus development is also discussed.
PMID- 10786638
TI - Isolation and characterization of isoforms of HspBP1, inhibitors of Hsp70.
AB - The protein sequences derived from cDNA sequences for Hsp70 binding proteins from
human (HspBP2) and rat tissues (HspBPR) are presented in this paper. The derived
amino acid sequences of these proteins differ from human HspBP1 in the number of
consecutive glycines near the amino-terminus. These differences, however, do not
alter the inhibitory activity.
PMID- 10786639
TI - A region of the Agrobacterium tumefaciens chromosome containing genes required
for virulence and attachment to host cells.
AB - A 29 kb region of the circular chromosome of Agrobacterium tumefaciens containing
genes required for bacterial attachment to host cells and virulence has been
sequenced. Transposon mutants in many of the genes have been obtained. The
mutants can be divided into two groups: those which can be complemented by
conditioned medium and those whose phenotype is unaffected by conditioned medium.
The first group includes mutants in genes with homology to ABC transporters, one
possible transcriptional regulator, and some closely linked genes immediately
downstream. The second group includes mutants in two possible transcriptional
regulators, one ATPase, and a number of biosynthetic genes including a
transacetylase required for the formation of an acetylated capsular
polysaccharide. There are also several genes with no homology to genes of
identified function. The presence of such a large number of genes required for
attachment to host cells suggests that the ability of A. tumefaciens to bind to
plant cells may play an important role in the life of these bacteria.
PMID- 10786640
TI - Reduced maximal cardiac output at altitude--mechanisms and significance.
AB - When a lowlander ascends to altitude and acclimatizes over days to weeks, both
maximal exercise capacity and maximal cardiac output are reduced compared to sea
level. Of the several possible mechanisms underlying this reduction of maximal
cardiac output, the available data are interpreted as supporting the simplest
hypothesis--that this merely reflects the reduced requirement for muscle blood
flow that results from the arterial hypoxemia of altitude (which reduces muscle
O2 availability and thus maximal muscle function). The competing hypotheses, that
increased blood viscosity, reduced blood volume, autonomic nervous system changes
or myocardial hypoxic dysfunction reduce maximal cardiac output, are not well
supported by existing data. However, critical tests of some of these hypotheses
remain to be devised and undertaken. When it comes to the question of the
importance of reduced maximal cardiac output to V(O2) MAX at altitude, the
available evidence suggests that cardiac output is not a major limiting variable.
This is because as cardiac output rises, gains in convective flow of O2 in the
circulation are offset by losses from greater diffusion impairment of O2 transfer
in the lungs and muscles, and vice versa. However, just as with the mechanism of
cardiac output reduction itself, clear-cut experimental tests of its role in
limiting exercise at altitude remain to be conducted.
PMID- 10786641
TI - A model of the chemoreflex control of breathing in humans: model parameters
measurement.
AB - We reviewed the ventilatory responses obtained from rebreathing experiments on a
population of 22 subjects. Our aim was to derive parameter estimates for an
'average subject' so as to model the respiratory chemoreflex control system. The
rebreathing technique used was modified to include a prior hyperventilation, so
that rebreathing started at a hypocapnic P(CO2) and ended at a hypercapnic
P(CO2). In addition, oxygen was added to the rebreathing bag in a controlled
manner to maintain iso-oxia during rebreathing, which allowed determination of
the response at several iso-oxic P(O2) levels. The breath-by-breath responses
were analysed in terms of tidal volume, breathing frequency and ventilation. As
P(CO2) rose, ventilation was first steady at a basal value, then increased as
P(CO2) exceeded a breakpoint. We interpreted this first breakpoint as the
threshold of the combined central and peripheral chemoreflex responses. Above,
ventilation increased linearly with P(CO2), with tidal volume usually
contributing more than frequency to the increase. When breathing was driven
strongly, such as in hypoxia, a second breakpoint P(CO2) was often observed.
Beyond the second breakpoint, ventilation continued to increase linearly with
P(CO2) at a different slope, with frequency usually contributing more than tidal
volume to the increase. We defined the parameters of the variation of tidal
volume, frequency and ventilation with P(O2) and P(CO2) for an average subject
based on a three-segment linear fit of the individual responses. These were
incorporated into a model of the respiratory chemoreflex control system based on
the general scheme of the 'Oxford' model. However, instead of considering
ventilatory responses alone, the model also incorporates tidal volume and
frequency responses.
PMID- 10786642
TI - Autoreceptor mechanism regulating carotid body dopamine release from adult and 10
day-old rabbits.
AB - Dopamine (DA) release (r) from the carotid body (CB) is thought to be modulated
by feedback inhibition mediated by DA D2 autoreceptors. We tested the hypothesis
that CB DAr is autoregulated in a concentration and age dependent manner. Using
an in vitro CB infusion model [Bairam, A., Marchal. F., Cottet-Emard, J.M.,
Basson, H., Pequignot, J.M., Hascoet, J.M., Lahiri, S., 1996b. Effects of hypoxia
on carotid body dopamine content and release in developing rabbits. J. Appl.
Physiol. 80, 20-24.], we evaluated under unstimulated conditions the effects of
0.001, 0.01, 0.1, 1.0 and 10.0 microM of the specific DA D2 receptor antagonist
domperidone on CB DAr in adult rabbits. In 10-day-old rabbit pups, concentrations
of 0.01, 0.1, 1.0 microM were studied. In adult CBs, domperidone increased DAr in
a concentration-dependent manner. DAr (pmol/h) was significantly greater compared
to control (without domperidone) starting at a domperidone concentration of 0.1
microM (P<0.01). In 10-day-old pup CBs, 1.0 microM domperidone was required to
produce a significant increase of DAr (pmol/h) compared to control (P<0.005).
However, control DAr (as % of total catecholamine) was about 40%; significantly
higher than 24% observed in adult CBs (P<0.001). We conclude that in rabbit CB,
DAr is controlled by an autoreceptor mechanism in a concentration-dependent
manner and this mechanism is less developed in pups than in adults.
PMID- 10786643
TI - Respiratory function in a newborn marsupial with skin gas exchange.
AB - The Julia Creek dunnart (Sminthopsis douglasi) is a marsupial born after
approximately 12 days of gestation. At birth, the newborn is approximately 4 mm
long and weighs approximately 15 mg. Gaseous metabolism (oxygen consumption rate,
V(O2), rate of carbon dioxide production, V(CO2) was measured separately across
the airways (lungs) and the rest of the body (skin). At pouch temperature (36
degrees C) total V(O2) (i.e. skin + lungs) averaged 15 +/- 2 S.E.M. ml x kg(-1) x
min(-1). At birth the skin contributed almost the total gaseous metabolism, and
at 3 weeks approximately 1/3 of the total. The compliance of the respiratory
system, per unit of body weight, was similar to that of other newborn mammals.
During the first postnatal days breathing was an occasional event determined by
gross body movements. Artificial expansion of the lungs temporarily stopped
breathing, presumably a manifestation of the Hering-Breuer reflex. By the 2nd-3rd
week breathing was regular, pulmonary ventilation (V(E)) averaged 263 ml x kg(-1)
x min(-1), tidal volume (V(T)) 3.4 ml x kg(-1), breathing frequency (f) 87
breaths x min(-1). Lowering ambient temperature in steps from 36 to 20 degrees C
reduced both lung and skin gaseous metabolism. V(E) and f, at first, were little
affected but eventually they dropped in approximate proportion to metabolism,
whereas V(T) remained unchanged. In conclusion, for the newborn dunnart gas
exchange through the skin is a requirement because of the inefficient V(E). To
what extent the V(E) adjustments to changes in metabolic rate reflect mechanisms
of regulation remains unresolved.
PMID- 10786644
TI - Cardiovascular and respiratory reflexes in the tropical fish, traira (Hoplias
malabaricus): CO2/pH chemoresponses.
AB - To examine the distribution and physiological role of CO2/pH-sensitive
chemoreceptors in the gills of the tropical fish, traira (Hoplias malabaricus),
fish were exposed to acute environmental hypercarbia (1.25, 2.5 and 5.0% CO2 in
air) and subjected to injections of HCl into the ventral aorta and buccal cavity.
This was done before and after selective denervation of branchial branches of the
IXth and Xth cranial nerves to various gills arches. Hypercarbia produced a
significant decrease in heart rate, a mild hypotension as well as increases in
both ventilation rate and ventilation amplitude. The data suggest that the
hypercarbic bradycardia and increase in ventilation frequency arise from
receptors exclusively within the gills but present on more than the first gill
arch, while extra-branchial receptors may also be involved in controlling the
increase in ventilation amplitude. With the exception of a decrease in heart rate
in response to HCl injected into the ventral aorta, the acid injections (internal
and external) did not mimic the cardiorespiratory responses observed during
hypercarbia suggesting that changes in CO2 are more important than changes in pH
in producing cardiorespiratory responses. Finally, the data indicate that
chemoreceptors sensitive to CO2/pH and to O2 in the gills of this species
involved in producing ventilatory responses are distributed in a similar fashion,
but that those involved in producing the bradycardia are not.
PMID- 10786645
TI - Effect of hydrocortisone on platelet activating factor induced lung edema in
isolated rabbit lungs.
AB - The effect of hydrocortisone on platelet activating factor (PAF)-induced
pulmonary edema is studied. Thirty four isolated and perfused rabbit lung
preparations were used: eight control preparations, eight PAF preparations with
two doses of PAF called low dose (LD = 0.5 microg/kg of rabbit weight) and high
dose (HD = 1 microg/kg of rabbit weight). Eighteen preparations divided in three
groups of six were pretreated with doses of 20, 200 and 2000 mg of hydrocortisone
and later given the same doses of PAF as described above. Hydrocortisone
significantly decreased (P < 0.05) the effect of PAF LD over the pulmonary
arterial pressure (Ppa) in the 200 and 2000 mg groups (58 and 89% decrease,
respectively) and it significantly decreased (P < 0.05) the effect of PAF HD over
Ppa in all hydrocortisone pretreated groups (48, 70 and 96% decrease,
respectively). Fluid filtration rate (FFR) increases mediated by PAF HD were
significantly inhibited (P < 0.05) in the 200 and 2000 mg groups (64 and 96%
decrease, respectively). We conclude that hydrocortisone inhibits the effect of
PAF over the pulmonary circulation.
PMID- 10786646
TI - Pulmonary artery remodeling modifies pulmonary hypertension during exercise in
severe emphysema.
AB - To clarify the relation between the vessel remodeling and the physiology of
pulmonary circulation in chronic obstructive pulmonary disease (COPD), we studied
the pulmonary hemodynamics at rest and during exercise (25W) and the morphology
of pulmonary arteries with external diameters of 100-200 microm in ten patients
with severe emphysema. The wall thickness (WT) was defined as the intima plus
media. The percent WT of the external diameter (% WT) in emphysema (36.0 +/-
4.3%) was significantly increased compared with that (22.6 +/- 3.3%) in five
control lungs. The % WT was not related to pulmonary arterial pressure (Ppa) at
rest, but was highly correlated with exercise Ppa (r = 0.721, P = 0.02) and with
deltaPpa (Ppa during exercise-Ppa at rest) (r = 0.899, P = 0.0004). These
findings suggest that pulmonary artery remodeling leads to reduced recruitability
and distensibility of pulmonary vessels and is closely related to exercise
pulmonary hypertension.
PMID- 10786647
TI - Respiration and gas exchange during recovery from exercise in the American
alligator.
AB - Low respiratory exchange ratios (R) occur in reptiles. In crocodilians they have
been attributed to the loss of respiratory CO2 into the urine and to the
immediate exercise-history of an animal. In this study, expired ventilation
(V(E)), oxygen consumption (V(O2)), and carbon dioxide excretion (V(CO2)) were
measured during recovery from treadmill-exercise in the American alligator. Both
V(O2) and V(CO2) decreased exponentially during recovery, but the decrease of
V(CO2) was greater than that of V(O2). By 55 min into recovery R fell to 0.3 +/-
0.02 (mean +/- S.E.M). These low values of R may be partially attributable to
hyperventilation that occurred during exercise. These data suggest that both
hyperventilation during exercise and a metabolic acidosis deplete blood
bicarbonate stores, contributing to a low R during recovery. We propose that the
right to left cardiac shunt could facilitate restoration of these alkaline
reserves and blood pH.
PMID- 10786648
TI - Emerging role of apoptosis in the pathogenesis of severe neutropenia.
PMID- 10786649
TI - Measurement of KIT ligand/stem cell factor: clinical and biochemical
significance.
AB - Stem cell factor (SCF) and its receptor KIT play an important role in various
biologic phases, such as hematopoiesis, reproduction, and regeneration. It has
been possible to measure both soluble SCF and soluble KIT using enzyme-linked
immunosorbent assay since 1993 and 1995, respectively. Although the significance
of interaction of soluble SCF with soluble KIT has not yet been elucidated, in
certain diseases proteins fluctuate in human sera. We found that serum SCF levels
were fivefold higher in patients with chronic renal failure than levels in
healthy controls. We review the results of the analysis of SCF. In addition,
possible pathologic mechanisms in various clinical abnormalities and the clinical
potential for recombinant human SCF are discussed.
PMID- 10786650
TI - Measurement of thrombopoietic levels: clinical and biological relationships.
AB - Platelet production is primarily regulated by the thrombopoietic cytokine
thrombopoietin (TPO). In most cases thrombopoietin serum levels are determined by
the rate of c-mpl receptor-mediated degradation after TPO uptake into platelets
and megakaryocytes. The contribution of increased TPO protein synthesis by a
translational mechanism was recently appreciated as the cause for hereditary
thrombocythemia and will have to be elucidated in other conditions of
thrombocytosis in association with increased TPO levels.
PMID- 10786651
TI - Granulocyte colony-stimulating factor versus granulocyte-macrophage colony
stimulating factor for collection of peripheral blood progenitor cells from
healthy donors.
AB - The harvesting of peripheral blood progenitor cells (PBPCs) after granulocyte
colony-stimulating factor or granulocyte-macrophage colony-stimulating factor
stimulation instead of bone marrow in healthy donors has become increasingly
popular. Donors, given the choice between bone marrow and PBPC donation, often
prefer cytapheresis because of the easier access, no necessity for general
anesthesia, and no multiple bone marrow punctures. In addition, accelerated
engraftment and immunomodulation by granulocyte colony-stimulating factor
mobilized PBPCs are advantageous for the recipient. However, because of donor
inconvenience and poor mobilization, there is a need to develop improved
procedures. Aspects such as durability of hematopoietic engraftment,
characterization of the earliest stem cell, and composition of PBPCs are not yet
well defined, and international donor registration and follow-up must be
considered when evaluating long-term safety profiles in healthy donors. This
review concentrates on the most significant developments on mobilization of PBPCs
published during the past year.
PMID- 10786652
TI - Cytokine therapy for myelodysplastic syndrome.
AB - The myelodysplastic syndromes are a heterogeneous family of hematologic disorders
characterized by ineffective hematopoiesis. Because of the interpatient
variability regarding prognosis and morbidity, management of myelodysplastic
syndromes continues to be a challenge to clinical hematologists. Pancytopenia and
defective function of neutrophils and platelets carry a high risk of infectious
or hemorrhagic complications. Erythropoietin is perhaps the most commonly used
therapeutic option, second only to transfusion; improvement of erythropoiesis is
seen in approximately 20% of patients, mainly in those with relatively preserved
erythroid function and no or low transfusion requirements. Coadministration of
erythropoietin with either granulocyte colony-stimulating factor or granulocyte
macrophage colony-stimulating factor may increase the response rate up to 50%.
Although prophylactic administration of granulocyte- or granulocyte-macrophage
colony-stimulating factor cannot be recommended, treatment of febrile neutropenia
might benefit from administration of granulocyte- or granulocyte-macrophage
colony-stimulating factor in addition to antibiotics.
PMID- 10786653
TI - Expression of hematopoietic growth factor receptors on early hematopoietic
precursors: detection and regulation.
AB - Since the original isolation of colony-stimulating factors from human serum,
conditioned medium of murine or human cell lines, or freshly isolated human
mononuclear cells, a revolutionary explosion of ideas has occurred in our
understanding of molecular controls of the hematopoietic stem cell self-renewal
and differentiation. With the availability of techniques of molecular cloning in
the early 1 980s, the first hematopoietically activated cytokines led to
molecular clones expressed in bacteria, yeast, or mammalian cellular systems.
There then followed a development of techniques leading to the molecular cloning
and expression of many hematopoietic growth factors and their receptors, as well
as the primary, secondary, and tertiary molecules in signal transduction into
activation of specific genes for differentiation or self-renewal. The clinical
use of these factors in the diagnosis, treatment, and incorporation into new cell
therapies for a variety of diseases is a subject of current interest.
PMID- 10786654
TI - Uses of granulocyte-macrophage colony-stimulating factor in vaccine development.
AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent cytokine
capable of inducing differentiation, proliferation, and activation of a variety
of immunologically active cell populations. In addition to its effects on
stimulating granulocytic hematopoiesis, it also facilitates development of both
humoral and cellular mediated immunity. Accordingly, strategies involving the use
of GM-CSF as a vaccine adjuvant have attracted considerable attention. These
strategies include the systemic administration of soluble GM-CSF with an
immunogen, and also its use as part of gene therapy approaches to immunization.
Because of the potency of this cytokine as an immune adjuvant, particular
interest has focused on its use to overcome poorly immunogenic antigens such as
those associated with intracellular infections and cancer. This review focuses on
recent advances in the use of GM-CSF as a vaccine adjuvant.
PMID- 10786655
TI - Interleukin-15 and its impact on neutrophil function.
AB - Interleukin-15 is a recently discovered cytokine produced by several cell types
(including fibroblasts, keratinocytes, endothelial cells, and macrophages) in
response to endotoxin or microbial infection. In turn, interleukin-15 has been
shown to act on various cells of the immune system, including T and B
lymphocytes, natural killer cells, monocytes, eosinophils, and circulating
neutrophils. In the latter instance, interleukin-15 was initially observed to
induce cytoskeletal rearrangements, to enhance phagocytosis, to increase the
synthesis of several cellular proteins, and to delay apoptosis. Recently,
interleukin-15 has been found to elicit other functional responses in
neutrophils, such as chemokine production. This review recapitulates advances
made in the area of interleukin-15/neutrophil interactions.
PMID- 10786656
TI - Role of interleukin-8 in neutrophil signaling.
AB - Interleukin-8 was originally discovered as one of the first chemokines activating
neutrophil granulocytes (neutrophils) after secretion by lipopolysaccharide
stimulated monocytes. A wealth of information has been gathered concerning the
intracellular events mediated by interleukin-8 and the role of interleukin-8 in
numerous physiologic and pathophysiologic processes. We discuss recent advances
in the understanding of the initial intracellular signals elicited by interleukin
8. Detailed investigation of these events has led to the identification of subtle
but significant differences in the signal transduction processes evoked by
interleukin-8 receptors. In particular, much has been learned concerning
differences in the cellular mechanisms leading to desensitization,
internalization, and recycling of interleukin-8 receptors, and functional
consequences of interleukin-8 receptor diversity are now being unraveled.
PMID- 10786657
TI - Role of thrombopoietin in hematopoietic stem cell and progenitor regulation.
AB - Thrombopoietin performs an essential role during hematopoiesis by regulating the
expansion and maturation of megakaryocytes. In keeping with this function,
megakaryocytes, platelets, and their precursors all express the thrombopoietin
receptor, Mpl, on their cell surface. However, Mpl is also expressed on
primitive, pluripotent hematopoietic progenitors and plays an important role in
the regulation of lineages other than megakaryocytes as well as primitive
progenitors. Recently, the ability of thrombopoietin to maintain and expand
repopulating stem cells has been demonstrated. Thus, thrombopoietin is unique
among the hematopoietic cytokines because it is necessary both for terminal
maturation and regulation of lineage-specific megakaryocytes and also for
maintenance of the most primitive hematopoietic stem cells. Many new strategies
are evolving to exploit the activity of thrombopoietin on primitive progenitors.
This may lead to faster hematopoietic recovery from marrow-suppressive therapy,
effective methods of ex vivo expansion of hematopoietic stem cells, and
retroviral transduction of stem cells to facilitate gene therapy.
PMID- 10786658
TI - Selection and use of chemotherapy with hematopoietic growth factors for
mobilization of peripheral blood progenitor cells.
AB - Peripheral blood progenitor cells (PBPCs) have become the preferred means of stem
cell support for high-dose chemotherapy in recent years. The biology of PBPC
mobilization is complex and may be influenced by several variables. Signals from
both stromal and hemopoietic cells may induce downregulation of adhesion
molecules and upregulate the expression of metalloproteinases. Cytokines alone
can mobilize PBPCs but a synergistic effect has been shown when they are used in
conjunction with chemotherapy. Disease-specific mobilization strategies appear to
have the advantage of less toxicity, greater stem cell yield, and enhanced
antitumor activity. Studies have demonstrated that the number of peripheral blood
CD34+ cells can be used as a predictor for the timing of apheresis and for
estimating PBPC yield. Similarly the CD34+ cell dose is the strongest predictor
of hematologic recovery after PBPC transplant. Age, prior radiotherapy, marrow
involvement, and prior chemotherapy (especially with alkylating agents) are
important factors influencing the yield of stem cells.
PMID- 10786659
TI - Concurrent use of growth factors and chemotherapy in acute leukemia.
AB - During the past decade, investigators have evaluated the role of hematopoietic
growth factors as cytokines that could potentiate the cytotoxic action of certain
chemotherapeutic agents when administered simultaneously with induction therapy.
Such cytokines included granulocyte-macrophage colony-stimulating factor,
granulocyte colony-stimulating factor, interleukin 3, and stem cell factor. Phase
I and II studies have confirmed a significant biologic activity of such priming
therapy, and the aggregate of subsequent controlled studies have also established
the safety of such manipulations. However, despite the plethora of clinical
trials, data regarding clinical efficacy remain uncertain. It is fair to say that
little progress in our clinical understanding has occurred during the past 24
months and at the present time, the concurrent use of growth factors with
chemotherapy, as a method of enhancing the antileukemic action of cytotoxic
therapy, remains very investigational.
PMID- 10786660
TI - Bibliography. Current world literature. Hematopoietic growth factors.
PMID- 10786661
TI - Nuclear structure-gene expression interrelationships: implications for aberrant
gene expression in cancer.
AB - There is long-standing recognition that transformed and tumor cells exhibit
striking alterations in nuclear morphology as well as in the representation and
intranuclear distribution of nucleic acids and regulatory factors. Parameters of
nuclear structure support cell growth and phenotypic properties of cells by
facilitating the organization of genes, replication and transcription sites,
chromatin remodeling complexes, transcripts, and regulatory factors in
structurally and functionally definable subnuclear domains within the three
dimensional context of nuclear architecture. The emerging evidence for functional
interrelationships of nuclear structure and gene expression is consistent with
linkage of tumor-related modifications in nuclear organization to compromised
gene regulation during the onset and progression of cancer.
PMID- 10786662
TI - Adenoma-specific alterations of protein kinase C isozyme expression in Apc(MIN)
mice.
AB - Members of the protein kinase C (PKC) family appear to play important roles in
colorectal carcinogenesis. To investigate the potential involvement of PKC
isozymes in adenomatous transformation induced by inactivation of the adenomatous
polyposis coli (APC) gene product, we examined protein levels and localizations
of ten PKC isozymes by immunohistochemistry in normal and adenomatous ileal
epithelium of ApcMIN mice. Compared with surrounding normal epithelium, adenomas
showed dramatically reduced staining for PKCs a, beta1, and zeta, as well as
dysplasia-specific punctate nuclear staining of PKC mu. We conclude that reduced
protein expression of PKC alpha, beta1, and zeta, and nuclear localization of PKC
mu are markers of, and are perhaps involved in, adenomatous transformation
induced by APC inactivation in ApcMIN mice.
PMID- 10786663
TI - Flt3-ligand induces transient tumor regression in an ectopic treatment model of
major histocompatibility complex-negative prostate cancer.
AB - We assessed the in vivo efficacy of Flt3-ligand (Flt3-L) treatment in C57BL/6
mice bearing a well-established MHC class I-negative prostate carcinoma TRAMP-C1.
Flt3-L immunotherapy was initiated approximately 30 days after tumor inoculation,
a time when > or =80% of the mice had palpable TRAMP-C1 tumors. Treatment with
Flt3-L at 10 microg/day for 21 consecutive days suppressed TRAMP-C1 tumor growth
and induced tumor stabilization (P = 0.0337). Enhanced tumor regression was
demonstrated at a higher dose of 30 microg/day (P < 0.0001). Tumors excised from
mice treated with Flt3-L were smaller than carrier-treated controls and contained
a more pronounced mixed inflammatory cell infiltrate primarily composed of mphi.
In regressor nice, tumors reappeared at the site of injection when Flt3-L therapy
was terminated. When the experiment was repeated with MHC class I-positive TRAMP
C1 cells, tumor stabilization and/or regression was again observed after
treatment (P < 0.0001); however, once again, tumors reappeared after the
termination of therapy despite an extended treatment schedule (35 days). MHC
class I-negative variants were present in tumors isolated from carrier- and Flt3
L-treated mice, and this phenotype could be reversed by IFN-gamma treatment in
vitro. Thus, Flt3-L treatment of mice with preexisting transplantable prostate
tumors results in tumor regression that is dose-dependent and accompanied by a
pronounced mixed-cell inflammatory tumor infiltrate. However, disease relapse was
invariably observed after the termination of therapy, which suggests that Flt3-L
treatment of advanced MHC- prostate cancers will require adjuvant modalities to
achieve a durable response.
PMID- 10786664
TI - Sulindac and exisulind exhibit a significant antiproliferative effect and induce
apoptosis in human hepatocellular carcinoma cell lines.
AB - This is the first report enumerating a superb antiproliferative effect of both
sulindac and exisulind on hepatocellular cancer cell lines. The growth inhibition
and cytotoxicity of sulindac in human hepatocellular carcinoma cell lines HepG2,
Huh-7, and KYN-2 were investigated by studying cell growth, cell cycle
distribution, and induction of apoptosis. In the presence of sulindac, there was
a marked time- and dose-dependent decrease in cell proliferation and viability.
Also, exisulind exhibited a similar growth-inhibitory effect on the KYN-2 cell
line. The findings of this study suggest that sulindac exhibits a growth
inhibitory effect on human hepatocellular carcinoma cell lines; therefore, these
drugs might serve as an effective tool for hepatocellular carcinoma
chemoprevention.
PMID- 10786665
TI - Identification of a geldanamycin dimer that induces the selective degradation of
HER-family tyrosine kinases.
AB - Geldanamycin (GM) is a natural antibiotic that binds Hsp90 and induces the
degradation of receptor tyrosine kinases, steroid receptors, and Raf. It is a
potent inhibitor of cancer cells that overexpress HER-kinases, but its effects on
other important proteins may cause significant toxicity and limit its clinical
use. We report the synthesis and identification of a GM dimer, GMD-4c, which had
selective activity against HER-kinases. Selectivity was a function of linker
length and required two intact GM moieties. GMD-4c is a potent inducer of G1
block and apoptosis of breast cancer cell lines that overexpress HER2, but does
not appreciably inhibit the growth of 32D cells that lack HER-kinases. GMD-4c
could be useful in the treatment of carcinomas dependent on HER-kinases.
PMID- 10786666
TI - Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid
tissues.
AB - Chromosomal rearrangements observed in T-cell prolymphocytic leukemia involve the
translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28,
deregulating the expression of cellular protooncogenes of unknown function, such
as TCL1 or its homologue, MTCP1. In the human hematopoietic system, TCL1
expression is predominantly observed in developing B lymphocytes, whereas its
overexpression in T cells causes mature T-cell proliferation in transgenic mice.
In this study, using a newly generated monoclonal antibody against recombinant
TCL1 protein, we extended our analysis mainly by immunohistochemistry and also by
fluorescence-activated cell sorting and Western blot to a large tumor lymphoma
data bank including 194 cases of lymphoproliferative disorders of B- and T-cell
origin as well as reactive lymphoid tissues. The results obtained show that in
reactive lymphoid tissues, TCL1 is strongly expressed by a subset of mantle zone
B lymphocytes and is expressed to a lesser extent by follicle center cells and by
scattered interfollicular small lymphocytes. In B-cell neoplasia, TCL1 was
expressed in the majority of the cases, including lymphoblastic lymphoma, chronic
lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt
lymphoma, diffuse large B-cell lymphoma (60%), and primary cutaneous B cell
lymphoma (55%). TCL1 expression was observed in both the cytoplasmic and nuclear
compartments, as confirmed by Western blot analysis. Conversely, TCL1 was not
expressed in Hodgkin/Reed-Sternberg cells, multiple myelomas, marginal zone B
cell lymphomas, CD30+ anaplastic large cell lymphoma, lymphoblastic T-cell
lymphoma, peripheral T-cell lymphoma, and mycosis fungoides. These data indicate
that TCL1 is expressed in more differentiated B cells, under both reactive and
neoplastic conditions, from antigen committed B cells and in germinal center B
cells and is down-regulated in the latest stage of B-cell differentiation.
PMID- 10786667
TI - Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2
inhibitor.
AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been observed to reduce the
relative risk of breast cancer. This prompted our investigation of the
chemopreventive potential of celecoxib, a specific cyclooxygenase 2 blocker,
against mammary carcinogenesis induced by 7,12-dimethyl-benz(a)anthracene in
female Sprague Dawley rats. Treatment with celecoxib was examined and compared to
treatment with the general NSAID, ibuprofen, and to a control group receiving
only dimethylbenz(a)anthracene. Dietary administration of celecoxib (1500 ppm)
produced striking reductions in the incidence, multiplicity, and volume of breast
tumors relative to the control group (68%, 86%, and 81%, respectively; P <
0.001). Ibuprofen also produced significant effects, but of lesser magnitude
(40%, 52%, and 57%, respectively; P < 0.001). These results help confirm the
chemopreventive activity of NSAIDs against breast cancer and provide the first
evidence that a cyclooxygenase 2 blocking agent, celecoxib, possesses strong
chemopreventive activity against mammary carcinogenesis.
PMID- 10786668
TI - U0126 reverses Ki-ras-mediated transformation by blocking both mitogen-activated
protein kinase and p70 S6 kinase pathways.
AB - U0126, a recently introduced mitogen-activated protein kinase [corrected]
(MAPK)/extracellular signal-regulated kinase kinase inhibitor reversed morphology
and inhibited anchorage-independent growth of Ki-ras-transformed rat fibroblasts.
Immunoblot analyses with phosphospecific antibodies indicated that in addition to
MAPK, U0126 suppressed activation of p70(S6K), but not Akt, at concentrations at
which it normalized the transformed phenotypes. Another MAPK/extracellular signal
regulated kinase kinase inhibitor, PD98059, showed only marginal effects on
p70S6K phosphorylation and did not effectively block Ki-ras-induced
transformation. However, simultaneous inhibition of the MAPK pathway and the
p70S6K pathway by PD98059 in conjunction with the p70S6K inhibitor rapamycin
essentially restored the normal phenotype. U0126 or the combination of PD98059
and rapamycin flattened morphology of v-src-transformed cells, but did not
reverse anchorage independence, although activation of both MAPK and p706K was
blocked. The results suggest that normalization of Ki-ras-induced transformed
phenotypes by U0126 is a consequence of concurrent inhibition of the MAPK and
p70S6K pathways. Intervention of other pathway(s) appears to be required to
completely antagonize transformation by v-src. Simultaneous blockade of more than
one signal transduction pathway by combining selective inhibitors might be
effective in suppressing uncontrolled tumorigenic growth.
PMID- 10786670
TI - Alterations of the INK4a/ARF locus in human intracranial germ cell tumors.
AB - Little is known about the molecular mechanisms responsible for the development of
intracranial germ cell tumors (ICGTs). Recently, we demonstrated that the balance
of the p53-mdm2 interactions is disrupted in ICGTs. The p14ARF product, a tumor
suppresser gene located on the INK4a/ARF locus, acts as one of the major factors
affecting p53-mdm2 interactions via its binding to mdm2 and the stimulation of
mdm2 degradation. To evaluate whether genetic alterations of the INK4a/ARF locus
occur in the genesis of ICGTs, we analyzed the INK4a/ARF genes in 21 ICGTs-10
pure germinomas and 11 nongerminomatous germ cell tumors. Fifteen (71%) of the 21
ICGTs displayed genetic alterations, including 14 homozygous deletions and 1
frameshift mutation. Furthermore, the frequency of the alterations was higher in
pure germinomas [9 (90%) of the 10] than in nongerminomatous germ cell tumors [6
(55%) of the 11; P = 0.09]. These data suggested that INK4a/ARF gene
abnormalities could play an important role in the genesis of ICGTs, especially in
pure germinoma.
PMID- 10786669
TI - The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA
damage checkpoint kinase hChk1.
AB - The investigational anticancer agent 7-hydroxystaurosporine (UCN-01) abrogates
the G2 checkpoint in tumor cells and sensitizes them to the lethal effects of
genotoxic anticancer agents. On the basis of the role of the Cdc25C phosphatase
in maintenance of this damage-inducible checkpoint, we hypothesized that UCN-01
inhibits a component of the signal transduction pathway that modulates Cdc25C
phosphorylation. Of the three kinases known to phosphorylate Cdc25C on Ser216,
both checkpoint kinase 1 (hChk1) and Cdc25C-associated protein kinase 1 (cTAK1)
were potently inhibited by UCN-01 with IC50s of 11 and 27 nM, respectively.
Treatment of K562 erythroblastoid leukemia cells with similar drug concentrations
resulted in decreased levels of Ser216 phosphorylation of Cdc25C and complete
disruption of the y-radiation-induced G2 checkpoint. In contrast to hChk1, the
hChk2 kinase was 100-fold more resistant to inhibition by UCN-01 (IC50, 1040 nM).
These results suggest that disruption of the DNA damage-induced G2 checkpoint by
UCN-01 is mediated through the inhibition of the Cdc25C kinases, hChk1 and cTAK1,
and that hChk2 activity is not sufficient to enforce the G2 checkpoint in cells
treated with a pharmacological inhibitor of hChk1.
PMID- 10786671
TI - Expression of the hTERT gene is regulated at the level of transcriptional
initiation and repressed by Mad1.
AB - Telomerase, an enzymatic activity responsible for the replication of chromosome
end structures, is strongly upregulated in most human cancers. In contrast, most
differentiated tissues are telomerase negative. The rate-limiting step for
telomerase activity seems to be the expression of the catalytic subunit of the
enzyme, encoded by the human telomerase reverse transcriptase (hTERT) gene. The
precise mechanism of how hTERT is regulated has not been elucidated yet. We show
here that the down-regulation of hTERT mRNA during 12-O-tetradecanoylphorbol-13
acetate-induced differentiation of human U937 cells is a consequence of a fast
decrease in the rate of transcription rather than changes in its half-life. The
only transcription factor that has so far been implicated in the regulation of
hTERT expression is the c-Myc oncoprotein. Our analysis shows that another member
of the myc/marx/mad network, mad1, encoding a transcriptional repressor that is
significantly increased by 12-O-tetra-decanoylphorbol-13-acetate treatment,
represses hTERT promoter-driven reporter gene activity in transient transfection
assays. This effect is dependent on the NH2 terminal domain of Madl, which
mediates the association with the transcriptional corepressor mSin3. Our findings
suggest the involvement of an additional transcription factor in the regulation
of hTERT expression and may provide a model for how hTERT activity is controlled
during the differentiation process in human somatic tissues.
PMID- 10786672
TI - Metabolites of 2'-fluoro-2'-deoxy-D-glucose detected by 19F magnetic resonance
spectroscopy in vivo predict response of murine RIF-1 tumors to 5-fluorouracil.
AB - There is a clinical need for early detection of tumor response to therapy. This
study aimed to determine whether metabolites of fluorodeoxyglucose (FDG) detected
in solid mouse tumors in situ by I9F magnetic resonance spectroscopy (19F MRS)
correlated with response to 5-fluorouracil chemotherapy. After injection of FDG
(1.4 mmol/kg i.p.), uptake and metabolism was monitored for 2 h in RIF-1 tumors.
FDG was detectable immediately, and after 10 min, a second broad peak was
detected 5-6 ppm upfield. 19F MRS analysis of cell and tumor extracts in vitro
showed that the upfield peak (> or =15% of the total detectable 19F signal)
consisted of the epimer alpha-fluorodeoxymannose (FDM) and various conjugates.
Mice treated with 5-fluorouracil (130 mg/kg) received, 48 h later, a repeat dose
of FDG. The change in the rate of FDM formation, but not the FDG or total 19F
signal, correlated significantly with the response to 5-fluorouracil (P = 0.032),
suggesting that 19F MRS of FDM metabolism in vivo may be a novel means of
predicting tumor response.
PMID- 10786673
TI - Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis
suppression at a distal site: potential role of host-tumor interaction.
AB - Changes in distal angiogenesis in response to irradiation of primary tumors are
not known. To this end, PC-3, a human prostate carcinoma, and FSA-II, a murine
fibrosarcoma, were grown in the gastrocnemius muscles of male nude mice. Distal
angiogenesis was measured in gel containing human recombinant basic fibroblast
growth factor placed in the cranial windows of these mice. PC-3-bearing mice
showed inhibition of distal angiogenesis, as compared with non-tumor-bearing
controls. Surgical removal of tumors tended to accelerate distal angiogenesis; in
comparison, after irradiation of the PC-3 primary tumor, rates of angiogenesis in
the cranial window were retarded. Irradiation of the non-tumor-bearing leg or of
non-tumor-bearing animals showed no measurable effect on rate of growth of
vessels in the cranial window. Similar results were found with the FSA-II tumors,
with slowed distal angiogenesis in tumor-bearing animals and further suppression
in animals with irradiated tumors. These results demonstrate that the effect of
irradiation of a primary tumor on angiogenesis at a distal site may differ from
the effect of surgical removal of the primary tumor. Unlike surgery, irradiation
of a tumor may enhance angiogenic suppression at a distal site, and this
difference may involve host-tumor interaction.
PMID- 10786674
TI - Interleukin 6 activates androgen receptor-mediated gene expression through a
signal transducer and activator of transcription 3-dependent pathway in LNCaP
prostate cancer cells.
AB - Interleukin 6 (IL-6) is a cytokine that regulates not only immune and
inflammatory responses but also the growth of some tumors, including prostate
carcinomas. IL-6 signals through Janus kinase, signal transducer and activator of
transcription 3 (STAT3), and mitogen-activated protein kinase and is also able to
induce androgen receptor (AR)-mediated gene activation in prostate cancer, which
is an important process in prostate cancer androgen-independent progression. We
now show that IL-6-induced AR-mediated gene activation requires the activation of
STAT3 by IL-6 in LNCaP prostate cancer cells. In particular, STAT3 associates
with AR in an androgen-independent but IL-6-dependent manner. Inhibition of STAT3
rather than mitogen-activated protein kinase results in inhibition of AR-mediated
gene activation in response to IL-6. These findings not only identify STAT3 as an
important signaling molecule required for IL-6-signaling to induce AR-mediated
gene activation in prostate carcinoma cells but also reveal the importance of
activated STAT3 in human tumor development and progression.
PMID- 10786675
TI - Cdr2, a target antigen of naturally occuring human tumor immunity, is widely
expressed in gynecological tumors.
AB - The paraneoplastic neurological disorders provide perhaps the best known example
of naturally occurring tumor immunity in humans. For example, patients with
paraneoplastic cerebellar degeneration (PCD) appear to suppress the growth of
occult breast or ovarian tumors that express a neuronal antigen termed cdr2. PCD
patients harbor cdr2-specific CTLs in their peripheral blood, and these cells are
likely mediators of the tumor suppression. Whereas cdr2 therefore appears to be
the target of an effective immune response in patients with PCD, the general
relevance to cancer patients has been unclear, due in part to reports indicating
that cdr2 is not expressed in tumors obtained from neurologically normal
patients. We have reexamined this question, and we find that cdr2 is widely
expressed in such tumors, indicating that cdr2 is in fact an important tumor
antigen in the general population of breast and ovarian cancer patients.
PMID- 10786676
TI - WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3
24.1, a region frequently affected in breast cancer.
AB - Studies were conducted with the final goal of identifying genes of interest
mapping to the chromosome region 16q23.3-24.1, an area commonly affected by
allelic losses in breast cancer. To this end we generated a detailed physical map
of the genomic region spanning between sequence-tagged site markers D16S518 and
D16S516. To identify candidate genes, we used shotgun genomic sequencing as well
as isolation and analysis of transcripts mapping to the area of interest. We
identified and cloned a novel gene, the genomic structure of which spans the
whole region of interest. We named this gene WWOX because it contains two WW
domains coupled to a region with high homology to the short-chain
dehydrogenase/reductase family of enzymes. The ORF of WWOX is 1245 bp long,
encoding a 414-amino acid protein. This gene is composed of nine exons. We
performed a mutation screening of WWOX exons in a panel of breast cancer lines,
most of which are hemizygous for the 16q genomic region indicated. We found no
evidence of mutations, thus indicating that WWOX is probably not a tumor
suppressor gene. However, we observed that one case of homozygous deletion as
well as two previously described translocation breakpoints map to intronic
regions of this gene. We speculate that WWOX may span the yet uncharacterized
common fragile site FRA16D region. In expression studies we found overexpression
of WWOX in breast cancer cell lines when compared with normal breast cells and
tissues. The highest normal expression of WWOX was observed in hormonally
regulated tissues such as testis, ovary, and prostate. This expression pattern
and the presence of a short-chain dehydrogenase/reductase domain and specific
amino acid features suggest a role for WWOX in steroid metabolism. Interestingly,
the presence of WW domains in the structure of WWOX indicate the likelihood that
this protein physically interacts with other proteins. The unique features of
WWOX and its possible association with cancer processes make it an interesting
target for further investigation.
PMID- 10786677
TI - Expression of proteins coincident with inducible radioprotection in human lung
epithelial cells.
AB - Human lung epithelial cells and many other cell lines are hypersensitive to low
doses of ionizing radiation (<0.2 Gy). However, above a threshold dose of 0.4-0.6
Gy, an induced radioprotective response is triggered that protects cells at
higher radiation doses. At 4 h, when maximal induced radioprotection is seen in
these cells after low-dose priming, the two-dimensional gel protein expression
pattern in 0.5-Gy-exposed cells is subtly altered, with seven proteins being 2-
to 5-fold down-regulated and one being 2-fold up-regulated. They include: (a) the
protein kinase C inhibitor 1, or histidine triad nucleotide-binding motif (HINT)
protein; (b) substrates for protein kinase C activity including the chloride
intracellular channel protein 1; and (c) a cytoskeletal protein degraded during
apoptosis. In addition, a lung cancer-specific protein that binds to both
telomeres and nascent mRNA molecules is down-regulated, as is interleukin 1alpha.
Therefore, at least in human lung epithelial cells, radioprotection may be the
result of signaling pathway switching, which results in the removal of damaged
cells and the preparation for enhanced general transcription in surviving cells
during a period in which cell proliferation is repressed. This combination of
events may be cell-type-specific and may have implications for the protection of
normal lung tissue during unavoidable radiation exposure such as in radiotherapy.
PMID- 10786678
TI - Prognosis of primary testicular seminoma: a report on 57 new cases.
AB - Most urologists perform adjuvant radiation therapy for stage 1 (TxN0M0)
testicular seminoma after orchiectomy, although the majority of patients with
clinical stage 1 seminoma do not have occult metastases and therefore do not
require elective nodal irradiation. However, there are currently no clinical or
histological parameters that can be used to distinguish patients who need
radiation therapy from those who do not. We reported previously that estimates of
volume-weighted mean nuclear volume (MNV) were a better predictor of the
prognosis of prostate cancer and renal cell carcinoma than subjective
histological grading. Here, we examined the usefulness of estimation of MNV for
predicting the prognosis of primary testicular seminoma. A retrospective study of
57 patients with testicular seminoma diagnosed between April 1981 and March 1997
at Kobe City General Hospital was performed. Unbiased estimates of MNV data were
compared for prognostic value with the level of beta-human chorionic gonadotropin
(beta-HCG), alpha-fetoprotein (AFP), alkaline phosphatase (ALP), and lactate
dehydrogenase (LDH). Fifty patients were stage 1 (TxNoMo), and 7 patients were
stage 2 (TxN1-2M0). All patients received orchiectomy, followed by radiation
therapy. Estimates of MNV of stage 2 patients were significantly larger than that
of stage 1 patients (P = 0.0142). Although the LDH level was also significantly
higher in stage 2 (P = 0.001), there were no significant differences between
stages 1 and 2 with respect to beta-HCG (P = 0.997), ALP (P = 0.226), and AFP (P
= 0.467). Multivariate logistic regression analysis revealed that the estimate of
MNV was the only variable predicting lymph node metastasis (P = 0.0315). In stage
1 patients, only the estimate of MNV was significantly correlated with
progression-free survival (P = 0.0118). These findings indicate that the estimate
of MNV may be an important prognostic indicator for testicular seminoma.
Estimates of MNV may also be useful for excluding patients from surveillance
protocols.
PMID- 10786679
TI - Complete sequencing of TP53 predicts poor response to systemic therapy of
advanced breast cancer.
AB - TP53 has been implicated in regulation of the cell cycle, DNA repair, and
apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of
exons 2-11, whether TP53 gene mutations can predict response in patients with
advanced disease to either first-line tamoxifen therapy (202 patients, of whom
55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46%
responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one
fourth of these mutations resulted in a premature termination of the protein. The
mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen
treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy
patients. TP53 mutation was significantly associated with a poor response to
tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI),
0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly
contact DNA or with mutations in the zinc-binding domain loop L3 showed the
lowest response to tamoxifen (18% and 15% response rates, respectively). TP53
mutations were related, although not significantly, to a poor response to up
front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate
analysis for response including the classical parameters age and menopausal
status, disease-free interval, dominant site of relapse, and levels of estrogen
receptor and progesterone receptor, TP53 mutation was a significant predictor of
poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P =
0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors
appeared to be the most resistant phenotype. Interestingly, the response of
patients with TP53 mutations to chemotherapy after tamoxifen was not worse than
that of patients without these mutations (50% versus 42%; OR, 1.35,
nonsignificant). The median progression-free survival after systemic treatment
was shorter for patients with a TP53 mutation than for patients with wild-type
TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy,
respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful
in predicting the response of patients with metastatic breast disease to
tamoxifen therapy. The type of mutation and its biological function should be
considered in the analyses of the predictive value of TP53.
PMID- 10786680
TI - Cytochrome c is involved in Fas-mediated apoptosis of prostatic carcinoma cell
lines.
AB - We have shown previously that the pathways leading to Fas-mediated apoptosis in
prostatic carcinoma cell lines are intact, because apoptosis can be triggered
either by Fas ligation alone in the Fas-sensitive cell lines PC3 and ALVA31 or by
rendering the Fas-resistant cell lines DU145 and JCA1 Fas-sensitive by combined
treatment with anti-Fas monoclonal antibody and cycloheximide (O. W. Rokhlin et
al., Cancer Res., 57: 1758-1768, 1997). In this study, we demonstrate that two of
the early events after Fas ligation are the release of cytochrome c from the
mitochondria and activation of caspase-9. We also found that Bid is processed
after Fas ligation and thus might activate the mitochondria-dependent apoptotic
cascade. In a cell-free system, cytochrome c induced caspase-3-like activity in
cytoplasmic extracts from all four cell lines studied, although differences in
the level of enzymatic activity were observed. Western blot analysis revealed
that caspase-7 is activated by cytochrome c at the same level in all extracts,
whereas expression and activation of caspase-3 varied considerably. Cytochrome c
activated extracts displayed different abilities in the induction of apoptotic
features in isolated nuclei such as morphological changes and DNA fragmentation.
However, differences in nuclear apoptotic activity induced by cytochrome c did
not correlate with the level of caspase-3 like activity in the different
extracts. These results suggest that the mitochondrial pathway is involved in Fas
mediated apoptosis in prostatic carcinoma cell lines and that, in addition to
caspase-7 and caspase-3, there are other factors that confer nuclear apoptotic
activity.
PMID- 10786681
TI - Suppression of tumor angiogenesis and growth by gene transfer of a soluble form
of vascular endothelial growth factor receptor into a remote organ.
AB - Antiangiogenic therapy shows promise as a strategy for cancer treatment. We
constructed an adenovirus (AdVEGF-ExR) expressing the entire extracellular domain
of the human vascular endothelial growth factor (VEGF) receptor (flt-1) fused to
the Fc portion of human IgG. The soluble receptor secreted from AdVEGF-ExR
infected cells bound to VEGF and inhibited VEGF-induced DNA synthesis in
endothelial cells. When human lung cancer cell line H157, which produces not only
VEGF but also fibroblast growth factor 2 and interleukin 8 at substantial levels,
was infected with AdVEGF-ExR, cell growth in vitro was not affected. However,
when H157 cells infected with AdVEGF-ExR were injected s.c. into nude mice, tumor
formation stopped on the 10th day after reaching a certain size (about 100 mm3),
and tumor size declined gradually thereafter. When AdVEGF-ExR was injected into
skeletal muscle and uninfected H157 cells were injected s.c., the soluble
receptor was detectable in the circulating blood for 3 weeks, tumor growth ceased
after 10 days, and tumor size declined thereafter. Histological examination
revealed that intratumor angiogenesis was markedly suppressed, and apoptosis was
enhanced. Using the same experimental protocol, a significant suppression of
tumor growth was also seen in four of five other lung cancer cell lines, some of
which secreted VEGF at nominal levels, at least under normoxic conditions in
vitro. Our results demonstrate that adenovirus-mediated expression of a soluble
VEGF receptor in a remote organ could inhibit tumor angiogenesis and enhance
apoptosis and thereby suppress tumor growth in vivo. Adenovirus-mediated
overexpression of a soluble VEGF receptor in a remote organ may have the
potential to be a feasible and effective strategy for cancer treatment.
PMID- 10786682
TI - PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth
factor receptor tyrosine kinases, impairs vascular endothelial growth factor
induced responses and tumor growth after oral administration.
AB - PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate)
is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor
tyrosine kinases, active in the submicromolar range. It also inhibits other class
III kinases, such as the platelet-derived growth factor (PDGF) receptor beta
tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active
against kinases from other receptor families, such as epidermal growth factor
receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular
kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584
inhibits VEGF-induced autophosphorylation of kinase insert domain-containing
receptor (KDR), endothelial cell proliferation, migration, and survival in the
nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK
222584 does not have any cytotoxic or antiproliferative effect on cells that do
not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma
concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h.
PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced
angiogenesis in a growth factor implant model, as well as a tumor cell-driven
angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose
range, it also inhibits the growth of several human carcinomas, grown s.c. in
nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic,
orthotopic model. Histological examination of tumors revealed inhibition of
microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well
tolerated and does not impair wound healing. It also does not have any
significant effects on circulating blood cells or bone marrow leukocytes as a
single agent or impair hematopoetic recovery after concomitant cytotoxic anti
cancer agent challenge. This novel compound has therapeutic potential for the
treatment of solid tumors and other diseases where angiogenesis plays an
important role.
PMID- 10786683
TI - Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth.
AB - Ovarian cancer is the leading cause of fatality among gynecological malignancies.
Ovarian cancer growth is angiogenesis-dependent, and an increased production of
angiogenic growth factors such as vascular endothelial growth factor is
prognostically significant even during early stages of the disease. Therefore, we
investigated whether antiangiogenic treatment can be used to inhibit the growth
of ovarian cancer in an experimental model system. Mouse angiostatin (kringle 1
4) and endostatin were expressed in yeast. Purified angiostatin and endostatin
were then used to treat established ovarian cancers in athymic mice. These
studies showed that both angiostatin and endostatin inhibited tumor growth.
However, angiostatin treatment was more effective in inhibiting ovarian cancer
growth when compared with endostatin in parallel experiments. Residual tumors
obtained from angiostatin- and endostatin-treated animals showed decreased number
of blood vessels and, as a consequence, increased apoptosis of tumor cells.
Subsequently, the efficacy of a combined treatment with angiostatin and
endostatin was investigated. In the presence of both angiostatic proteins,
endothelial cell proliferation was synergistically inhibited. Similarly, a
combination regimen using equal amounts of angiostatin and endostatin showed more
than additive effect in tumor growth inhibition when compared with treatment with
individual angiostatic protein. These studies demonstrate synergism between two
angiostatic molecules and that antiangiogenic therapy can be used to inhibit
ovarian cancer growth.
PMID- 10786684
TI - Epidermal growth factor-mediated targeting of chlorin e6 selectively potentiates
its photodynamic activity.
AB - Certain tumor cells, such as squamous carcinoma cells, express an increased
number of epidermal growth factor (EGF) receptors. Therefore, we studied the
targeted delivery of the photocytotoxic compound Sn-(IV)chlorin e6
monoethylenediamine [SnCe6(ED)] to tumors that overexpress the EGF receptor. EGF
was conjugated to SnCe6(ED) through a carrier, such as dextran (Dex) and human
serum albumin (HSA), and the photocytotoxicity on the EGF receptor-overexpressing
MDA-MB-468 breast adenocarcinoma cell line was evaluated. The photobiological
activities of these EGF conjugates, of the conjugates of the photosensitizer to
HSA or Dex, or of the photosensitizer alone were compared. The affinity of EGF
for its receptor was substantially impaired when conjugated in EGF-Dex-SnCe6(ED),
in contrast to EGF-HSA-SnCe6(ED). In corresponding results, EGF-HSA-SnCe6(ED)
displayed a high photocytotoxicity (IC50, 63 nM) on MDA-MB-468 cells at a light
dose of 27 kJ/m2, whereas EGF-Dex-SnCe6(ED) showed very limited
photocytotoxicity. EGF-HSA-SnCe6(ED) was no longer photocytotoxic in the presence
of a competing EGF concentration. The high photocytotoxicity of EGF-HSA-SnCe6(ED)
was shown to be the result of a high intracellular concentration in MDA-MB-468
cells, which could be lowered dramatically by incubating the conjugate with a
competing EGF concentration. In contrast, EGF-Dex-SnCe6(ED) accumulated poorly in
MDA-MB-468 cells, in agreement with its low EGF receptor affinity and
photocytotoxicity. EGF-HSA-SnCe6(ED) produced much more intracellular reactive
oxygen species on light irradiation than EGF-Dex-SnCe6(ED). It is concluded that
the photodynamic activity of the EGF-HSA conjugate of SnCe6(ED) on MDA-MB-468
breast adenocarcinoma cells is EGF specific and is much more potent than EGF-Dex
SnCe6(ED) or free SnCe6.
PMID- 10786685
TI - E-7869 (R-flurbiprofen) inhibits progression of prostate cancer in the TRAMP
mouse.
AB - E-7869 (R-flurbiprofen) is a single enantiomer of a racemic nonsteroidal anti
inflammatory drug. E-7869 does not inhibit either cyclooxygenase-1 or
cyclooxygenase-2. We used the transgenic adenocarcinoma mouse prostate (TRAMP)
mouse, a prostate cancer model, to evaluate the effect of this drug on prostate
cancer progression. Sixty 12-week-old male TRAMP mice were placed randomly into
five groups. The animals were treated by daily oral gavage with vehicle (1%
carboxymethylcellulose) or E-7869 for 18-weeks. During the course of the study,
two diets were used. Three groups (vehicle, 15-mg/kg, and 20-mg/kg drug
treatments) received a Teklad diet containing 2.4% saturated fat [a high
saturated fat (HSF) diet], and two groups (vehicle and 20 mg/kg drug treatment)
received an AIN-93G diet containing 1.05% saturated fat [a low saturated fat
(LSF) diet]. At necropsy, the urogenital system and periaortic lymph nodes were
removed and weighed. The prostate lobes, seminal vesicles, lungs, and periaortic
lymph nodes were preserved and sectioned for histological evaluation. The lung
and periaortic lymph nodes were graded as to the presence (+) or absence (-) of
metastasis; the urogenital tissues were graded on a 1-6 scale for degree of
neoplasia/carcinoma. For both diets, the urogenital wet weights and lymph node
wet weights in the 20-mg/kg treatment groups were significantly lower as compared
to vehicle control groups. In addition, treatment with 20 mg/kg E-7869 in the LSF
diet group resulted in a significantly lower primary tumor incidence (P < 0.05)
and reduced incidence of metastasis. In this treatment group, the reduced
incidence of metastasis was not statistically significant because the LSF diet
itself resulted in a remarkably lower incidence of metastasis in the vehicle
control group (10% LSF versus 40% HSF). Treatment with 20 mg/kg E-7869 on the HSF
diet resulted in a significantly lower incidence of metastasis (P < 0.05) and a
reduction in the primary tumor incidence. These results suggest that E-7869 is a
promising chemopreventive and treatment for human prostate cancer.
PMID- 10786686
TI - CC chemokine receptor-7 on dendritic cells is induced after interaction with
apoptotic tumor cells: critical role in migration from the tumor site to draining
lymph nodes.
AB - Dendritic cells (DCs) are very potent antigen-presenting cells and play critical
roles in regulating immune responses in cancer. The migrating of DCs from the
tumor site to the lymphoid organs is believed to be one of the critical events.
To examine this important DC function in tumor situations, bone marrow-derived
DCs, cultured for 6 days with granulocyte macrophage colony-stimulating factor
and interleukin 4, were inoculated at the tumor site. We have shown (Y. Nishioka
et al., Cancer Res., 59: 40354041, 1999) that DCs can migrate from tumor site to
the draining lymph nodes within 24 h (approximately 0.1% of administrated DCs).
The DCs then form clusters with adjacent lymphoid cells, which produce IFN-gamma
(1500-3200pg/10(6) cells/48 h) in response to tumor stimulation. The number of
the DCs migrating into lymph nodes were greater when they were inoculated into
the tumor rather than the skin. Coculture of DCs and apoptotic tumor cells
resulted in decreased expression of CC chemokine receptor (CCR) 1 and increased
CCR7 expression at mRNA level without alteration in other phenotypical markers on
DCs. Chemotaxis assay showed that CCR7 ligands, macrophage inflammatory protein
3beta and secondary lymphoid-tissue chemokine significantly (P < 0.05) induced
the migration of DCs when cocultured with apoptotic tumor cells. To directly
examine the involvement of CCR7 expression in DC migration, we investigated the
functions of DCs genetically modified to express high levels of CCR7. CCR7
transduction promotes DC migration in response to relevant ligands in vitro and
in vivo. These results suggest that the CCR7 expression of DCs is enhanced with
direct contact with apoptotic tumor cells and may have a critical role for DC
migrating to regional lymph nodes. The means to promote DC delivery to tumor and
to nodal sites represent novel targets for the biological therapy of cancer.
PMID- 10786687
TI - Immune deviation and Fas-mediated deletion limit antitumor activity after
multiple dendritic cell vaccinations in mice.
AB - Genetic immunization with a single injection of dendritic cells (DCs) expressing
a model melanoma antigen generates antigen-specific, MHC-restricted, protective
immune responses. After initiating the immune response, additional vaccinations
may increase the protection or conversely downregulate the immune response.
Groups of mice were vaccinated several times with DCs transduced with the MART-1
gene, and the anti-tumor protection was compared with that of mice receiving a
single vaccination. C3H mice had poorer protection from a syngeneic MART-1
expressing tumor challenge with multiple vaccinations. This was accompanied by
lower levels of splenic CTL effectors and a shift from a type 1 to a type 2
cytokine profile. On the contrary, multiple vaccinations in C57BL/6 mice
generated greater in vivo antitumor protection with no decrease in splenic CTLs
and no cytokine shift. Antiadenoviral humoral or cellular immune responses did
not seem to contribute to these effects. When studies were performed in Fas
receptor-negative C3H.(lpr) mice, the adverse effect of multiple vaccinations
disappeared, and there was no cytokine shift pattern. In conclusion, C3H mice but
not C57BL/6 mice receiving multiple vaccinations with DCs expressing the MART-1
tumor antigen show decreased protection associated with deviation from a type 1
to a type 2 cytokine response attributable to a Fas-receptor mediated clearance
of antigen-specific IFN-gamma-producing cells.
PMID- 10786688
TI - HMSH6 alterations in patients with microsatellite instability-low colorectal
cancer.
AB - Two microsatellite instability (MSI) phenotypes have been described in colorectal
cancer (CRC): MSI-H (instability at >30% of the loci examined) and MSI-L (MSI at
1-30% of the loci examined). The MSI-H phenotype, observed in both hereditary
nonpolyposis colon cancer-associated CRC and approximately 15% of sporadic CRC,
generally results from mutational or epigenetic inactivation of the DNA mismatch
repair (MMR) genes hMSH2 or hMLH1. The genetic basis for the MSI-L phenotype,
however, is unknown. Several other proteins, including hMSH3 and hMSH6, also
participate in DNA MMR. Inactivating mutations of MSH6 in yeast and human tumor
cell lines are associated with an impaired ability to repair single-base mispairs
and small insertion-deletion loops but not large insertion-deletion loops. This
suggests that hMSH6 mutations are more likely to be associated with a MSI-L
phenotype than a MSI-H phenotype in CRC. To explore this possibility, we screened
tumors from 41 patients with MSI-L CRC for hMSH6 mutations with conformation
sensitive gel electrophoresis (CSGE) and for hMSH6 protein expression by
immunohistochemistry. Alterations found with CSGE were confirmed by DNA
sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line
changes were found. Of the 15 germ-line changes, 9 were found in an intron (none
involving splice junctions), and 6 were found in an exon (Gly39Glu, Leu395Val,
and 4 silent alterations). Immunohistochemical staining for hMSH6 performed on 34
of the 41 tumors revealed strong nuclear hMSH6 expression in all of the cases.
Overall, our results suggest that hMSH6 mutations do not play a major role in the
development of sporadic CRC with a MSI-L phenotype.
PMID- 10786689
TI - Linking gene expression patterns to therapeutic groups in breast cancer.
AB - A major objective of current cancer research is to develop a detailed molecular
characterization of tumor cells and tissues that is linked to clinical
information. Toward this end, we have identified approximately one-quarter of all
genes that were aberrantly expressed in a breast cancer cell line using
differential display. The cancer cells lost the expression of many genes involved
in cell adhesion, communication, and maintenance of cell shape, while they gained
the expression of many synthetic and metabolic enzymes important for cell
proliferation. High-density, membrane-based hybridization arrays were used to
study mRNA expression patterns of these genes in cultured cells and archived
tumor tissue. Cluster analysis was then used to identify groups of genes, the
expression patterns of which correlated with clinical information. Two clusters
of genes, represented by p53 and maspin, had expression patterns that strongly
associated with estrogen receptor status. A third cluster that included HSP-90
tended to be associated with clinical tumor stage, whereas a forth cluster that
included keratin 14 tended to be associated with tumor size. Expression levels of
these clinically relevant gene clusters allowed breast tumors to be grouped into
distinct categories. Gene expression fingerprints that include these four gene
clusters have the potential to improve prognostic accuracy and therapeutic
outcomes for breast cancer patients.
PMID- 10786691
TI - Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and
retinoid X receptor alpha in human keratinocytes.
AB - Repeated exposure of human skin to solar UV radiation leads to premature aging
(photoaging) and skin cancer. UV-induced skin damage can be ameliorated by all
trans retinoic acid treatment. The actions of retinoic acid in skin keratinocytes
are mediated primarily by nuclear retinoic acid receptor gamma (RARgamma) and
retinoid X receptor alpha (RXRalpha). We found that exposure of cultured primary
human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50-90%)
RARgamma and RXRalpha mRNA and protein within 8 h. The rates of disappearance of
RARgamma and RXRalpha proteins after UV exposure or treatment with the protein
synthesis inhibitor cycloheximide were similar. UV irradiation did not increase
the rate of breakdown of RARgamma or RXRalpha but rather reduced their rate of
synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the
lysosomal inhibitor E64, prevented loss of RARgamma and RXRalpha proteins after
exposure of keratinocytes to either UV radiation or cycloheximide. Soluble
extracts from nonirradiated or UV-irradiated keratinocytes possessed similar
levels of proteasome activity that degraded RARgamma and RXRalpha proteins in
vitro. Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells.
RXRalpha was found to contain two proline, glutamate/aspartate, serine, and
threonine (PEST) motifs, which confer rapid turnover of many short-lived
regulatory proteins that are degraded by the ubiquitin/proteasome pathway.
However, the PEST motifs in RXRalpha did not function to regulate its stability,
because deletion of the PEST motifs individually or together did not alter
ubiquitination or proteasome-mediated degradation of RXRalpha. These results
demonstrate that loss of RARgamma and RXRalpha proteins after UV irradiation
results from degradation via the ubiquitin/proteasome pathway. Taken together,
the data here indicate that ubiquitin/proteasome-mediated breakdown is an
important mechanism regulating the levels of nuclear retinoid receptors.
PMID- 10786690
TI - The normal patched allele is expressed in medulloblastomas from mice with
heterozygous germ-line mutation of patched.
AB - Defects in a developmental signaling pathway involving mammalian homologues of
the Drosophila segment polarity gene, patched (ptc) and its ligand, sonic
hedgehog (shh), contribute to tumor formation in several tissues. Recently, a
subset of medulloblastoma, the most common malignant brain tumor in children, was
found to contain somatic mutations in the human ptc gene. In addition, basal cell
nevus syndrome (BCNS), or Gorlin syndrome, which is characterized by
developmental anomalies and a predisposition to skin and nervous system
malignancies, is associated with germ-line mutation of ptc. Targeted disruption
of both alleles of ptc in mice results in embryonic lethality. However, ptc+/-
mice survive and develop spontaneous cerebellar brain tumors, suggesting that ptc
may function as a tumor suppressor gene. Therefore, we investigated ptc+/-mice as
a model for human medulloblastoma. We report that 14% of ptc+/- mice develop
central nervous system tumors in the posterior fossa by 10 months of age, with
peak tumor incidence occurring between 16 and 24 weeks of age. The tumors
exhibited several characteristics of human medulloblastoma, including expression
of intermediate filament proteins specific for neurons and glia. Full-length ptc
mRNA was present in all tumors analyzed, indicating that there was no loss of
heterozygosity at the ptc locus. Nucleotide sequence of ptc mRNA from four tumors
failed to identify any mutations. However, a comparison of the normal ptc
sequence from C57BL/6 and 129Sv mice did reveal several polymorphisms. High
levels of glil mRNA and protein were detected in the tumors, suggesting that the
shh/ptc pathway was activated despite the persistence of ptc expression. These
data indicate that haploinsufficiency of ptc is sufficient to promote oncogenesis
in the central nervous system.
PMID- 10786692
TI - Molecular markers in blood as surrogate prognostic indicators of melanoma
recurrence.
AB - Improvement is needed in the ability to evaluate the prognosis of melanoma
patients who are clinically disease-free but likely to develop recurrent
metastatic disease. The detection of circulating melanoma cells in blood is a
potential surrogate marker of subclinical residual disease. We assessed the
prognostic clinical utility of a multimarker melanoma reverse transcriptase-PCR
(RT-PCR) assay using blood of 46 patients who were clinically disease-free. All
patients were followed up for more than 4 years for disease recurrence. There was
a significant correlation between number of RT-PCR markers present in blood and
American Joint Committee on Cancer stage (P = 0.009). The number of RT-PCR
markers detected in blood was an independent prediction factor of disease
recurrence in a Cox proportional hazard model (P = 0.02). A risk factor model
using American Joint Committee on Cancer stage and number of positive RT-PCR
markers significantly predicted disease recurrence in 2, 3, and 4 years of follow
up. These studies demonstrate that molecular detection of circulating melanoma
cells may be of significant prognostic value in determining early disease
recurrence and may be useful for stratifying patients for adjuvant therapy.
PMID- 10786693
TI - Dihydrotestosterone as a selective cellular/nuclear localization vector for anti
gene peptide nucleic acid in prostatic carcinoma cells.
AB - Peptide nucleic acids (PNAs) are synthetic structural analogues of DNA and RNA
that, if allowed to enter the cell, bind to the complementary polynucleotide
sequence and inhibit DNA transcription and mRNA translation. Although PNAs have a
very limited ability in penetrating nuclei of living cells, there are indications
that covalent linkage of the PNA to appropriate vectors, e.g., a nuclear
localization signal, permits access to the genome. Here we test the ability of
dihydrotestosterone (T) covalently linked to PNA to act as a vector for targeting
c-myc DNA to prostatic cancer cell nuclei. LNCaP cells, which express the
androgen receptor gene, and DU145 cells, in which the androgen receptor gene is
silent, offer a model to test this biologically active hormone as a cell-specific
vector. T vector was covalently linked to the NH2-terminal position of a PNA
complementary to a unique sequence of c-myc oncogene (PNAmyc-T). To localize
PNAmyc-T and vector-free PNA within the cells, a rhodamine (R) group was attached
at the COOH-terminal position (PNAmyc-R, PNAmyc-TR); cellular uptake was
monitored by confocal fluorescence microscopy. PNAmyc-R was detected only in the
cytoplasm of both prostatic cell lines, whereas PNAmyc-TR was localized in nuclei
as well as in cytoplasm of LNCaP cells. In contrast, PNAmyc-TR uptake in DU145
cells was minimal and exclusively cytoplasmic. In LNCaP cells, MYC protein
remained unchanged by exposure to vector-free PNAmyc, whereas a significant and
persistent decrease was induced by PNAmyc-T. In DU145 cells, MYC expression was
unaltered by PNAmyc with or without the T vector. Our data show that the T vector
facilitates cell-selective nuclear localization of PNA and its consequent
inhibition of c-myc expression. These findings suggest a strategy for targeting
of cell-specific anti-gene therapy in prostatic carcinoma.
PMID- 10786694
TI - Insulin-like growth factor I receptor signaling in differentiation of neuronal
H19-7 cells.
AB - The type I insulin-like growth factor receptor (IGF-IR) is known to send two
seemingly contradictory signals inducing either cell proliferation or cell
differentiation, depending on cell type and/or conditions. H19-7 cells are rat
hippocampal neuronal cells immortalized by a temperature-sensitive SV40 large T
antigen that grow at 34 degrees C in epidermal growth factor or serum but
differentiate at 39 degrees C when induced by basic fibroblast growth factor. At
39 degrees C, expression of the human IGF-IR in H19-7 cells induces an insulin
like growth factor (IGF) I-dependent differentiation. We have investigated the
domains of the IGF-IR required for differentiation of H19-7 cells. The tyrosine
950 residue and serines 1280-1283 in the COOH terminus of the receptor are
required for IGF-I-induced differentiation at 39 degrees C, although they are
dispensable for IGF-I-mediated growth at 34 degrees C. Both domains have to be
mutated to inactivate the differentiating function. The inability of these mutant
receptors to induce differentiation correlates with mitogen-activated protein
kinase activation. In contrast, inhibitors of phosphatidylinositol 3'-kinase have
no effect on IGF-I-mediated differentiation of H19-7 cells, although they do
inhibit the mitogenic response.
PMID- 10786696
TI - Thioredoxin reductase, a redox-active selenoprotein, is secreted by normal and
neoplastic cells: presence in human plasma.
AB - Thioredoxin (Trx) and Trx reductase (TrxR) are redox-active proteins that
participate in multiple cellular events, including growth promotion, apoptosis,
and cytoprotection. Studies on overexpression of Trx and TrxR in human cancers
have indicated a role of these proteins in tumor development. In this study, we
analyzed the expression of TrxR in peripheral blood cells, tumor-transformed
leukemia, and melanoma cells and found, in addition to abundant plasma membrane
localization, that TrxR was released from these cells. Secretory cells were
observed at the single cell level using a sensitive enzyme-linked immunospot
assay. The release was inducible, and physiological stimulation of human
monocytes by IFN-gamma, lipopolysaccharide, and interleukin 1alpha significantly
increased the number of TrxR-secreting cells (P = 0.004). Secretion of TrxR
followed the classical Golgi pathway, and it was confirmed by metabolic labeling
using [35S]methionine and [35S]cysteine. TrxR was also detected for the first
time in fresh healthy blood donor plasma (n = 21; median concentration, 18.0
ng/ml), with biological activity as determined by insulin reduction assay. These
results highlight the role of extracellular Trx and TrxR during inflammation and
tumor progression. Released Trx, with its active site motif containing amino
acids Cys-X-X-Cys, was recently shown to have chemoattractant properties beside
its previously described antioxidant and cocytokine activities. Regeneration of
oxidized Trx requires available TrxR outside the cell, the presence and induction
of which is described in this paper for normal and transformed cells.
PMID- 10786695
TI - Enhanced sensitivity to anti-benzo(a)pyrene-diol-epoxide DNA damage correlates
with decreased global genomic repair attributable to abrogated p53 function in
human cells.
AB - DNA damage from exposure to environmental chemical carcinogens and failure of
repair systems to eliminate these lesions from the genome are considered as the
crucial initial steps in the development of various human malignancies. Many
cellular proteins are known to play vital roles to overcome the effects of DNA
damage. Among such proteins, p53 is known to respond to DNA damage by
accumulating in the nucleus and inhibiting cell cycle progression to facilitate
DNA repair and the maintenance of genomic stability. In this study, we have
investigated the role of p53 protein in modulating nucleotide excision repair of
anti-benzo-(a)pyrene-diol-epoxide (BPDE)-DNA adducts and related effects using
human fibroblasts with normal (p53-WT) and altered p53 protein (p53Mut and p53
Null). Interestingly, irrespective of the presence or absence of p53, the anti
BPDE dose-dependent p21 protein induction response was qualitatively comparable
in all of the three cell lines. However, cells with defective p53 function were
deficient for the removal of anti-BPDE-DNA adducts from the overall genome
compared to cells with wild-type p53 activity. Strand-specific repair analysis
within the individual strands of the p53 gene revealed decreased repair of
adducts from the nontranscribed strand in p53-Mut and p53-Null cells. However,
the repair of the transcribed strand appeared to be identical in all of the three
cell lines. Furthermore, p53-Mut and p53-Null cells were more sensitive than p53
WT cells and displayed increased levels of anti-BPDE-induced apoptosis. Thus,
wild-type p53 is required for the efficient global genomic repair of anti-BPDE
induced DNA adducts from the overall genome, but not for transcription-coupled
repair of actively transcribed genes. These findings indicate that inefficient
DNA repair of potentially cytotoxic and mutagenic lesions from the nontranscribed
strand due to the loss of p53, but not the loss of p21, function might be
responsible for enhanced cytotoxicity and apoptosis in human cells upon DNA
damage.
PMID- 10786697
TI - Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder
cancer.
AB - Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Within a
neoplasm, IL-8 is secreted by inflammatory and neoplastic cells. The highly
tumorigenic and highly metastatic human transitional cell carcinoma (TCC) cell
line 253J B-V overexpresses IL-8 relative to the nontumorigenic and nometastatic
253J-P cell line. To determine whether IL-8 expression regulates tumorigenicity
and metastasis in human TCC, 253J B-V cells were transfected with the full
sequence antisense (AS) cDNA for IL-8, whereas 253J-P cells were transfected with
the full-length IL-8 cDNA, and control cells for each were transfected with the
neomycin resistance (Neo) gene. In vitro, sense-transfected 253J-P cells
overexpressed IL-8-specific mRNA and protein, whereas both of these were markedly
reduced in AS-IL-8-transfected 253J B-V cells relative to controls. Moreover,
sense-transfected cells showed up-regulation in matrix metalloproteinase type 9
mRNA, collagenase activity, and increased invasiveness through Matrigel-coated
filters, whereas these measures were lower in AS-transfected cells relative to
controls. After implantation into the bladders of athymic nude mice, the sense
transfected 253J-P cells acquired increased tumorigenicity and metastasis,
whereas the AS-transfected cells significantly inhibited tumorigenicity and
metastases in the 253J B-V cell lines. This effect was accompanied by reduced IL
8 expression and microvessel density. These studies demonstrate that IL-8
expression enhances angiogenic activity through the induction of matrix
metalloproteinase type 9 and subsequently regulates the tumorigenesis and
production of spontaneous metastases of human TCC.
PMID- 10786698
TI - Human glioblastoma cell lines: levels of low-density lipoprotein receptor and low
density lipoprotein receptor-related protein.
AB - The status of the low-density lipoprotein (LDL) receptor and LDL receptor-related
protein (LRP) in seven human glioma cell lines was evaluated to extend our
knowledge of human glioblastoma multiforme tumor metabolism for future drug
design. Cell lines SF-767, SF-763, A-172, U-87 MG, U-251 MG, U-343 MG, and SF-539
were used. Binding of 125I-labeled LDL to these cells at 4 degrees C was carried
out to determine the number of LDL receptors on cells and the affinity of LDL for
these receptors. The content of LRP was measured by immunoblotting. The presence
of specific saturable LDL receptors was proven in six of the cell lines
investigated. SF-767 cells revealed high-affinity LDL binding (equilibrium
dissociation constant, Kd = 7 nM) and maximum binding capacity approximating
300,000 receptors/cell. Most of the remaining cell lines had relatively lower
affinity (Kd = 38-62 nM) but also had very high numbers of receptors (128,000
950,000/cell). All cell lines exhibited LRP, but the expression was variable. The
cell lines SF-539, U-87 MG, and U-343 MG were particularly rich in this protein.
The data suggest that glioblastoma cells have high numbers of LDL receptors;
however, there is considerable variation in binding affinity. Overall, this
finding suggests that LDL receptors on glioblastoma cells could potentially be
useful for targeting antitumor agents. LRP, a multifunctional receptor expressed
on glioblastoma cells, also has the possibility for serving as a therapeutic
target.
PMID- 10786699
TI - Apoptosis is induced by the active metabolite of vitamin D3 and its analogue
EB1089 in colorectal adenoma and carcinoma cells: possible implications for
prevention and therapy.
AB - Vitamin D3 is believed to reduce the risk of colon cancer, and serum levels
inversely correlate with colorectal cancer incidence. The active metabolite,
1alpha,25-dihydroxyvitamin D3, has previously been shown to inhibit growth and
promote differentiation of colon cancer cells. The vitamin D analogue, EB1089, is
currently under clinical trial in a variety of cancers because of its growth
inhibitory effects in vitro and reduced hypercalcemic effects in vivo. The
mechanism of growth inhibition by EB1089, however, remained to be determined. In
this study we examined the effects of alpha,25-dihydroxyvitamin D3 and EB1089 on
five colorectal tumor cell lines (two adenoma and three carcinoma) to determine
the mechanism of growth inhibition and to ascertain whether premalignant adenoma
cells were responsive to these agents. 1alpha,25-Dihydroxyvitamin D3 and EB1089
induced p53-independent apoptosis in adenoma and carcinoma cell lines in a dose
dependent manner between 10(-10) and 10(-6) M. EB1089, as well as inducing
apoptosis, increased the proportion of cells in the G1 phase, particularly in the
adenoma cell lines. In two of the three carcinoma cell lines (SW620 and PC/JW),
levels of apoptosis induced by EB1089 were similar or greater than those induced
by 1alpha,25-dihydroxyvitamin D3. Although the carcinoma cell line HT29 was
relatively resistant to apoptosis induced by EB1089 compared with 1alpha,25
dihydroxyvitamin D3, EB1089 markedly inhibited cell yields. These observations
offer promise for the clinical use of EB1089. To determine whether the induction
of apoptosis by 1alpha,25-dihydroxyvitamin D3 and EB1089 was potentially via a
differentiation pathway, alkaline phosphatase activity was measured as a marker
of differentiation. Induction of alkaline phosphatase was observed in the
floating apoptotic cells as well as in the adherent population. A link between
the induction of differentiation and apoptosis by 1alpha,25-dihydroxyvitamin D3
and EB1089 is suggested by the occurrence of apoptosis subsequent to the
induction of differentiation. To investigate the molecular pathway to apoptosis
induction, members of the Bcl-2 family of proteins were examined (Bcl-2, Bcl-x,
Bax, and Bak). Decreased Bcl-2 was observed in some cell lines, particularly in
response to EB1089, but was not essential for apoptosis. Levels of the
proapoptotic protein Bak, however, were consistently increased in all of the five
cell lines in association with apoptosis induced by either agent. The results
implicate Bak protein in the induction of apoptosis by 1alpha,25-dihydroxyvitamin
D3 or its analogue EB1089. The ability of EB1089 to induce apoptosis in
colorectal carcinoma cells suggests that this or other vitamin D analogues may
prove clinically effective for the treatment of colorectal cancer. Furthermore,
the fact that it induces cell cycle arrest and apoptosis in the premalignant
adenoma cells may suggest an application in colorectal cancer chemoprevention.
PMID- 10786700
TI - Interaction of adenosine and guanine derivatives in the rat hippocampus: effects
on cyclic AMP levels and on the binding of adenosine analogues and GMP.
AB - Guanine nucleotides (GN) have been implicated in many intracellular mechanisms.
Extracellular actions, probably as glutamate receptor antagonists, have also been
recently attributed to these compounds. GN may have a neuroprotective role by
inhibiting excitotoxic events evoked by glutamate. Effects of extracellular GN on
adenosine-evoked cellular responses have also been reported. However, the exact
mechanism of such interaction is not known. In the present study, we showed that
GN potentiated adenosine-induced cAMP accumulation in slices of hippocampus from
young rats. However, neither GMP nor the metabotropic glutamate receptor agonist,
1S,3R-ACPD, inhibited the binding of the adenosine receptor agonist [3H]NECA
(when binding to adenosine A2 receptors), or the binding of the adenosine A2a
receptor agonist [3H]CGS 21680 in hippocampal membrane preparations. GppNHp,
probably by interacting with G-proteins, decreased [3H]CGS 21680 binding. [3H]GMP
binding was assayed in order to evaluate the GN sites which are not G-proteins.
[3H]GMP binding was inhibited by GMP and GppNHp, but not by IS,3R-ACPD. The
interaction of endogenous adenosine with the GMP-binding sites was determined by
incubating membranes in the presence or absence of adenosine deaminase (ADA).
NECA, CADO, CGS 21680 and CPA (only at the highest concentration used) increased
GMP binding in the presence of ADA. However, in the absence of ADA, the control
levels of GMP binding were as high as in the presence of added ADA plus adenosine
agonists, indicating that endogenous adenosine modulates the binding of GMP. If
this site has a neuroprotective role, adenosine may be increasing its
neuromodulator and proposed protective action.
PMID- 10786701
TI - Aggregated beta amyloid peptide 1-40 decreases Ca2+- and cholinergic receptor
mediated phosphoinositide degradation by alteration of membrane and cytosolic
phospholipase C in brain cortex.
AB - The effects of full-length amyloid beta protein, A(beta) (1-40), on
phosphoinositide-specific phospholipase C (PLC) were investigated in synaptic
plasma membranes (SPM) and cytosol prepared from the cerebral cortex of adult
rats. Moreover, the role of A(beta) (1-40) on the activation of lipid
peroxidation was evaluated. The activity of phospholipase C (PLC) acting on
phosphatidylinositol (PI) and phosphatidylinositol-4,5-bisphosphate (PIP2) was
determined using exogenous labeled substrates. The subcellular fractions were the
source of enzyme(s). The radioactivity of lipid messengers derived from
degradation of [14C- arachidonoyl] PI was also determined. The stable aggregated
form of beta-amyloid peptide (1-40) at 25 microM concentration exerted
reproducible effects. The aggregated form of A(beta) (1-40) inhibited Ca(2+)
regulated PI and PIP2 degradation by SPM and cytosolic enzymes. Aggregated
A(beta) also decreased significantly the level of diacylglycerol, the product of
PLC. This additionally supports the inhibitory effect of A(beta) on membrane
bound and cytosolic PLC. Moreover, A(beta) (1-40) significantly decreased the
basal activity of the PIP2-PLC in SPM and the enzyme activity regulated through
cholinergic receptors. However, in spite of the lower enzyme activity, the
percentage distribution of inositol (1,4,5) P3 radioactivity (IP3) in the total
pool of inositol metabolites was not significantly changed. The aggregated
neurotoxic fragment, A(beta) (25-35), mimicked the effect of full-length A(beta)
(1-40). A(beta) (1-40) enhanced the level of malondialdehyde indicating an
activation of free radical stimulated membrane lipid peroxidation that may be
involved in alteration of phospholipase(s) activity. Our results indicated that
aggregated A(beta) (1-40) alters Ca(2+)-dependent phosphoinositide degradation
affecting synaptic plasma membrane and cytosolic phospholipase(s) activity.
Moreover, this peptide significantly decreased the phosphoinositide-dependent
signal transduction mediated by cholinergic receptors. The effect of aggregated
A(beta) (1-40) is more pronounced than that of the neurotoxic fragment A(beta)
(25-35). Our study suggests that the deposition of aggregated A(beta) may alter
phosphoinositide signaling in brain.
PMID- 10786702
TI - Isolation and biochemical characterization of peroxisomes from cultured rat glial
cells.
AB - Peroxisomes are now recognized to play important cellular functions and its
dysfunction leads to a group of neurological disorders. This study reports
peroxisomal enzyme activities in cultured glial cells and peroxisomes isolated
from cultured oligodendrocytes and C6 glial cells. Peroxisomal enzyme activities
were found to be higher in oligodendroglial cells than in astrocytes or mixed
glial cells. We also developed a method for the isolation of peroxisomes from
glial cells by a combination of differential and density gradient centrifugation
techniques. Peroxisomes from oligodendrocytes in nycodenz gradient were isolated
at a density of 1.165 g/ml +/- 0.011. Activities of dihydroxyacetone phosphate
acyl transferase, beta-oxidation of lignoceric acid and alpha-oxidation of
phytanic acid were almost exclusively associated with the distribution of
catalase activity (a marker enzyme for peroxisomes) in the gradient. This
protocol should be a resource for studies designed to investigate the structure
and function of peroxisomes in brain cells.
PMID- 10786703
TI - Protective effect of oren-gedoku-to against induction of neuronal death by
transient cerebral ischemia in the C57BL/6 mouse.
AB - We examined the neuroprotective effects of oren-gedoku-to (TJ15), a herbal
medicine, after transient forebrain ischemia. Transient forebrain ischemia was
induced by occlusion of both common carotid arteries for 15 min in C57BL/6 mice
treated with TJ15. In the control ischemic group without TJ15 treatment,
histologic examination of brain tissue collected seven days after reperfusion
showed death of pyramidal cells in CA2-3 area of the hippocampus, unilaterally or
bilaterally. In mice treated with oral TJ15 (845 mg/kg/day) for five weeks, the
frequency of ischemic neuronal death was significantly lower.
Immunohistochemistry for Cu/Zn-superoxide dismutase (Cu/Zn-SOD) showed strongly
reactive astrocytes in the hippocampus of ischemic mice treated with TJ15. Damage
to nerve cells by free radicals plays an important role in the induction of
neuronal death by ischemia-reperfusion injury. Our results suggest that TJ15
protects against ischemic neuronal death by increasing the expression of Cu/Zn
SOD and suggest that oren-gedoku-to reduces the exposure of hippocampal neurons
to oxidative stress.
PMID- 10786704
TI - Compounds extracted from Phyllantus and Jatropha elliptica inhibit the binding of
[3H]glutamate and [3H]GMP-PNP in rat cerebral cortex membrane.
AB - Glutamate is to be considered a nociceptive neurotransmitter and glutamatergic
antagonists present antinoceptive activity. In this study we investigated the
effects of the naturally occurring antinociceptive compounds rutin, geraniin and
quercetine extracted from Phyllanthus, as well as the diterpene jatrophone,
extracted from Jatropha elliptica on the binding of [3H]glutamate and [3H]GMP-PNP
[a GTP analogue which binds to extracellular site(s), modulating the
glutamatergic transmission] in rat brain membrane. Jatrophone inhibited
[3H]glutamate binding and geraniin inhibited [3H]GMP-PNP binding. Quercetine
inhibited the binding of both ligands. These results may indicate a neurochemical
parameter possibly related to the antinoceptive activity of these natural
compounds.
PMID- 10786706
TI - Intrastriatal administration of methylmercury increases in vivo dopamine release.
AB - Mercury is a neurotoxin that exists in a number of physical and chemical forms,
producing different effects in the brain. In the present work, we have studied
the effects of intrastriatal administration of different doses (40 microM, 400
microM, and 4 mM) of organic mercury (methyl-mercury, MeHg) on the dopaminergic
system of rat striatum, in conscious and freely-moving animals, using
microdialysis coupled to Liquid Chromatography. In previous works, we have
discussed the effects of chronic and acute administration of MeHg on striatal
dopaminergic system assessing changes in both release and metabolism of striatal
dopamine (DA). In the present study we report that the intrastriatal
administration of different doses of MeHg (40 microM, 400 microM, and 4 mM)
produced significant increases (907 +/- 31%, 2324 +/- 156%, and 9032 +/- 70% of
basal levels, respectively for the different doses) in DA release from rat
striatal tissue associated with significant decreases in extracellular levels of
its main metabolites dihydroxyphenylacetic acid (DOPAC) and homovallinic acid
(HVA) using the dose of 4 mM MeHg (35 +/- 3% and 48 +/- 1%, respectively),
whereas non-significant changes in metabolite levels were observed with the doses
of 40 microM and 400 microM MeHg. We explain these effects as a result of
stimulated DA release and/or decreased DA intraneuronal degradation.
PMID- 10786705
TI - The role of taurine in neuronal protection following transient global forebrain
ischemia.
AB - Osmoregulation and post ischemic glutamate surge suppression (PIGSS) are
important mechanisms in the neuroprotective properties of taurine. We studied the
role of taurine in PIGSS following transient global forebrain ischemia (TGFI). A
group of gerbils received a high dose of continuous intracerebral taurine during
the peri-ischemic period. Beta-alanine was given similarly to a negative control
group. The control group consisted of animals undergoing only TGFI. On the fourth
day following commencement of drug administration, TGFI was induced.
Concurrently, half the animals from each group receiving an agent had
intracerebral microdialysis. All animals underwent histological assessment at day
7. The microdialysis and histological data was analyzed. Our results showed that
taurine treatment did not cause PIGSS. The histological difference between the
three groups was statistically insignificant. We conclude that intracerebral
taurine in the dosage administered during peri-ischemic period, does not result
in PIGSS or histologically evident neuroprotection.
PMID- 10786707
TI - A new subdivision, marginal division, in the neostriatum of the monkey brain.
AB - A new subdivision, the "marginal division" (MrD), was discovered at the caudal
border of the striatum and surrounds the rostral edge of the globus pallidus in
the rat brain in our previous studies. The neuronal somata of the MrD are mostly
fusiform in shape with their long axes lining dorsoventrally. The MrD is more
densely filled with substance P (SP)-, Leucine-enkephalin (L-Enk)-, dynorphin B-,
neurotensin-, somatostatin- and cholecystokinin (CCK)-immunoreactive fibers and
terminal-like structures than the rest of the striatum. The MrD was confirmed in
the cat neostriatum as well. The present study intended to explore whether the
MrD exists in the monkey neostriatum (putamen) with Nissl, histochemical and
immunohistochemical methods. A band of fusiform neurons were obviously identified
at the caudomedial edge of the putamen. These neurons lie outside the lateral
medullary lamina and indirectly surround the rostrolateral border of the globus
pallidus. The abundance of SP-, L-Enk-, neuropeptide Y-, CCK-, dopamine- and
serotonin-positive fibers and terminal-like structures with a few positive
fusiform neurons accumulating at the caudomedial border of the putamen obviously
distinguishes this zone from the rest of neostriatum and globus pallidus. The
acetylcholinesterase (AChE) positive and nicotinamide adenine dinucleotide
phosphate diaphorase (NADPH-d) containing fusiform neurons are distinctly
visualized in the same zone. The morphological figure and the location of these
neurons, and the histochemical and immunohistochemical characteristics of this
area coincide well with those of the MrD in the rat and cat striatum. This study
thus convincingly identifies the existence of the MrD in the monkey neostriatum.
It is fairly asserted that the MrD is a universal structure in the mammalian
brain.
PMID- 10786708
TI - Decreased phosphorylation levels of TrkB neurotrophin receptor in the spinal
cords from patients with amyotrophic lateral sclerosis.
AB - Amyotrophic lateral sclerosis (ALS) is characterized by the selective
degeneration of specific populations of cranial and spinal motor neurons. In this
study, we examined the expression of the high affinity functional receptor for
BDNF, TrkB, and assessed the functional state of TrkB by examining the level of
phosphorylation on tyrosine residues in ALS spinal cords. The data showed that
TrkB-immunoprecipitates prepared from cell-free lysates of ALS spinal cords by
use of an anti-TrkB antibody contained much more TrkB protein than from controls.
These TrkB proteins expressed in ALS spinal cords, however, are much less
phosphorylated on tyrosine residues than those of controls. Moreover, RT-PCR
analysis of TrkB mRNA in ALS spinal cords demonstrated that the expression of Trk
B mRNA is also upregulated in ALS spinal cords compared with those of controls.
These data strongly suggest that there exists an abnormality in TrkB-mediated
intracellular signaling in ALS spinal cords and shed a light on the possibility
of the therapeutic intervention by normalizing this intracellular signaling.
PMID- 10786709
TI - Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1
40Q by insulin degrading enzyme from Alzheimer disease and control brains.
AB - Insulin degrading enzyme (IDE) is a metalloprotease that has been involved in
amyloid beta peptide (A(beta)) degradation in the brain. We analyzed the ability
of human brain soluble fraction to degrade A(beta) analogs 1-40, 1-42 and the
Dutch variant 1-40Q at physiological concentrations (1 nM). The rate of synthetic
125I-A(beta) degradation was similar among the A(beta) analogs, as demonstrated
by trichloroacetic acid precipitation and SDS-PAGE. A 110 kDa protein,
corresponding to the molecular mass of IDE, was affinity labeled with either 125I
insulin, 125I-Abeta 1-40 or 125I-A(beta) 1-42 and both A(beta) degradation and
cross-linking were specifically inhibited by an excess of each peptide.
Sensitivity to inhibitors was consistent with the reported inhibitor profile of
IDE. Taken together, these results suggested that the degradation of A(beta)
analogs was due to IDE or a closely related protease. The apparent Km, as
determined using partially purified IDE from rat liver, were 2.2 +/- 0.4, 2.0 +/-
0.1 and 2.3 +/- 0.3 microM for A(beta) 1-40, A(beta) 1-42 and A(beta) 1-40Q,
respectively. Comparison of IDE activity from seven AD brain cytosolic fractions
and six age-matched controls revealed a significant decrease in A(beta) degrading
activity in the first group, supporting the hypothesis that a reduced IDE
activity may contribute to A(beta) accumulation in the brain.
PMID- 10786711
TI - Effects of protonophores on membrane electrical characteristics in NG108-15
cells.
AB - Studies were conducted to determine the effects of bath application of the
protonophores carbonyl cyanide m-chlorophenylhydrazone (CCCP) and carbonyl
cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP) on membrane electrical
characteristics of differentiated NG108-15 (neuroblastoma X glioma hybrid) cells.
Membrane resting potential (Vm), input resistance (R(in)) and electrically
induced action potential generation were measured using intracellular micro
electrode techniques. Both compounds produced concentration-dependent
depolarization rather than the hyperpolarization commonly found with other
central mammalian neurons. CCCP and FCCP also reduced R(in) and disrupted the
generation of action potentials in a concentration-dependent manner. The
contribution of the observed alterations to the in vivo toxicity of these
compounds remains to be established.
PMID- 10786710
TI - Effects of chronic ethanol administration on serotonin metabolism in the various
regions of the rat brain.
AB - Changes in serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA), its major
metabolite, in cerebral cortex, corpus striatum and hippocampus were investigated
at 10th and 21st days of chronic ethanol ingestion in Wistar rats. Ethanol (7.2%
v/v) was given to rats in a modified liquid diet. Biochemical analysis was
performed in two groups of ethanol-treated and control rats (n = 6 for each
group). Rats in each group were decapitated at the 10th and 21st days of ethanol
consumption. Brains were removed and cerebral cortex, corpus striatum and
hippocampus were dissected. 5-HT and 5-HIAA levels were measured in respective
brain regions by using high performance liquid chromatography. In cerebral cortex
and corpus striatum, 5-HT levels were significantly lower than control at the
10th day of ethanol consumption. At the 21st day, the levels tended to remain
low, but not significantly different statistically. In hippocampus, 5-HIAA levels
were significantly higher than control at 10th day of ethanol consumption.
Increased 5-HIAA level returned to control values at the 21 st day of ethanol
consumption. Our results suggest that, 5-HT clearly seems to play a critical role
in the brain at the 10th day of chronic ethanol consumption.
PMID- 10786712
TI - Cortical impact injury in rats promotes a rapid and sustained increase in
polyunsaturated free fatty acids and diacylglycerols.
AB - Neurotrauma activates the release of membrane phospholipid-derived second
messengers, such as free arachidonic acid (20:4n-6, AA) and diacylglycerols
(DAGs). In the present study, we analyze the effect of cortical impact injury of
low-grade severity applied to the rat frontal right sensory-motor cortex (FRC) on
the accumulation of free fatty acids (FFAs) and DAGs in eight brain areas 30 min
and 24 hours after the insult. At these times, accumulation of FFAs and DAGs
occurred mainly in the damaged FRC. The cerebellum was the only other brain area
that displayed a significant accumulation of DAGs by day one post-injury. By 30
min, accumulation of free AA in the FRC displayed the greatest relative increase
(300% over sham value), followed by free docosahexaenoic acid (22:6n-3, DHA,
150%), while both 20:4-DAGs and 22:6-DAGs were increased 100% over sham values.
At day one, free 22:6 and 22:6-DAGs showed the greatest increase (590% and 230%,
respectively). These results suggest that TBI elicits the hydrolysis of
phospholipids enriched in excitable membranes, targeting early on 20:4
phospholipids (by 30 min post- trauma) and followed 24 hours later by
preferential hydrolysis of DHA-phospholipids. These lipid metabolic changes may
contribute to the initiation and maturation of neuronal and fiber track
degeneration observed following cortical impact injury.
PMID- 10786713
TI - Responses in primary astrocytes and C6-glioma cells to ammonium chloride and
dibutyryl cyclic-AMP.
AB - Elevated brain ammonia levels are a major factor in the genesis of hepatic
encephalopathy (HE). The mechanism of ammonium chloride (NH4Cl) neurotoxicity
involves interruption of oxidative metabolism. This leads to decreased levels of
ATP concentration and subsequent glial fibrillary acidic protein (GFAP)
degradation of astrocytes and fibrous C6-glioma cells. Our study investigates
NH4Cl toxicity by evaluating changes in ATP concentration and mitochondrial
function as well as by evaluating alterations in GFAP expression. NH4Cl induced
decreases in ATP were detected after 15 minutes in C6-glioma cells and 24 hours
in both cell types. Mitochondrial function, assessed by MTT (2-4,5
dimethylthiazol A-yl)-2, 5-diphenyltetrazolium bromide) assay, was impaired in
both cell types at 24 hours following NH4Cl treatment. GFAP was also
significantly decreased in both cell types. Morphologic and metabolic toxicities
were greater in C6-glioma cells. The data clearly indicate that NH4Cl interrupts
oxidative metabolism. The greater toxicity seen in C6-glioma cells may be due to
their greater dependence on oxidative metabolism. Lastly, the decrease in GFAP is
probably a consequence of diminished ATP.
PMID- 10786714
TI - Ischemia-induced inhibition of active calcium transport into gerbil brain
microsomes: effect of anesthetics and models of ischemia.
AB - The excessive increase in intracellular Ca2+ concentration is associated with
events linking cerebral blood flow reduction to neuronal cell damage. We have
investigated the possible effect of ischemia and ischemia-reperfusion injury on
endoplasmic reticulum (ER) Ca2+ transport. Two different models of ischemia as
well as two different anesthetics were used. 5 min and 15 min of global forebrain
ischemia caused significant depression of the rate of microsomal Ca2+
accumulation in pentobarbital anesthetised gerbils. The Ca2+ uptake activity
recovered partially after 1 hour of reperfusion. Unlike pentobarbital
anesthetised gerbils, no significant changes were detected in the active
microsomal Ca(2+)-transport after 10 min of global forebrain ischemia in gerbil
forebrain and hippocampus under halothane anesthesia. In addition, using the
model of decapitation ischemia, we observed significant changes of the Ca2+
uptake in both halothane and pentobarbital anesthetised gerbils. These findings
indicate that ischemic insult alters the brain microsomal Ca2+ transport which is
not due to inhibition of the Ca(2+)-ATPase activity. However, the effect of
ischemia on this transport system is dependent on the model of ischemia and on
the type of anesthetics.
PMID- 10786715
TI - Differential utilization of the ethanolamine moiety of phosphatidylethanolamine
derived from serine and ethanolamine during NGF-induced neuritogenesis of PC12
cells.
AB - Neurite elongation involves the expansion of the plasma membrane and phospholipid
synthesis. We investigated membrane phosphatidylethanolamine (PE) biosynthesis in
PC12 cells during neurite outgrowth induced by nerve growth factor (NGF). When PE
was prelabeled with [3H]ethanolamine and the radioactivity was chased by
incubation with 1 mM unlabeled ethanolamine, the radioactivity of [3H]PE steadily
declined and [3H]ethanolamine was released into the medium in NGF-treated cells
during neurite outgrowth; in the absence of unlabeled ethanolamine, the
radioactivity of [3H]PE remained relatively constant for at least 24 hr. In
undifferentiated cells but not in NGF-treated cells, [3H]phosphoethanolamine
accumulated in significant amounts during pulse labeling, and was converted
partly to PE but largely released into the medium irrespective of incubation with
unlabeled ethanolamine. The decline in the radioactivity of [3H]PE and release of
[3H]ethanolamine following incubation with unlabeled ethanolamine were also
observed in undifferentiated cells. Thus, the ethanolamine moiety of PE derived
from ethanolamine is actively recycled in both differentiated and
undifferentiated cells. When PE was derived from [3H]serine through
phosphatidylserine (PS) decarboxylation, the decrease in radioactivity of [3H]PE
and release of [3H]ethanolamine into the medium following incubation with
unlabeled ethanolamine were observed only in NGF-treated cells, but not in
undifferentiated cells, indicating that the ethanolamine moiety of PE derived
from PS is actively recycled only in the cells undergoing NGF-induced
neuritogenesis. Thus, in PC12 cells, the ethanolamine moiety of PE derived from
PS is regulated differently from that of PE derived from ethanolamine.
PMID- 10786717
TI - Chronic cerebral hypoperfusion induces transient reversible monoaminergic changes
in the rat brain.
AB - Chronic restriction of cerebral blood flow in hypoperfused Wistar rats has been
proposed as a new model of cerebrovascular-type dementia. Using this model, we
have investigated central monoaminergic neuronal systems that are closely related
to higher brain function. Monoamine and monoamine-metabolite levels were
determined, as relative monoaminergic markers, at 1 day and 1,3,6 and 12 weeks
after the bilateral occlusion of common carotid arteries. Dopaminergic changes in
the frontal cortex and striatum were observed in hypoperfused rats at 1-3 weeks
following occlusion. Serotonergic changes were recognized at four brain regions
examined (frontal cortex, hippocampus, striatum and thalamus+midbrain). In
particular, the immediate enhancement of serotonin turnover in the striatum
appeared to influence the reaction to the acute ischemic attack such as
vasoconstriction produced by hypoperfusion. Our findings suggest that chronic
cerebral hypoperfusion induces transient reversible changes in central
monoaminergic neuronal function within three weeks of ligation of carotid
arteries. This time interval seems to represent a turning point in the process of
chronic cerebral hypoperfusion-induced progressive brain injury.
PMID- 10786718
TI - Patterns of body weight in the Baltic Republics.
AB - OBJECTIVE: Previously recorded rates of obesity in the Baltic Republics have been
among the highest in the world although little is known about how they vary
within the population. This study investigates the distribution of body mass
index (BMI) and obesity in these countries. DESIGN: Three cross-sectional surveys
conducted in the summer of 1997. SETTING: Estonia, Latvia and Lithuania.
SUBJECTS: Representative national samples of adults with measured weight and
height (Estonia: n=1154; Latvia: n=2292; Lithuania: n=2096). RESULTS: Between
country differences are particularly large among women: women from Latvia and
Lithuania are approximately three times as likely to be obese as those from
Estonia (17.4%, 18.3%, 6.0% respectively); only about one-third of this
difference is explained by the sociodemographic and behavioural factors studied.
In men, the prevalence of obesity varied only slightly among countries (Estonia:
9.9%; Latvia: 9.5%; Lithuania: 11.4%). While the prevalence of obesity increases
with age within each republic, particularly in women, it is not associated with
nationality or urban/rural region, and no consistent association is observed with
income. Obesity is inversely related to education in Latvia and in Lithuanian
women. Latvian men and women and Lithuanian men who smoked had a lower prevalence
of obesity than non-smokers. Leisure time physical activity was not associated
with obesity. CONCLUSIONS: Obesity is a major health problem in the Baltic
Republics, particularly among Latvian and Lithuanian women. The lack of
association between obesity and most demographic, socioeconomic and behavioural
factors suggests that the problem is generalized. Health promotion strategies
aiming at preventing and controlling excess weight gain in the Baltic Republics
will need to target the general population.
PMID- 10786719
TI - Lifetime alcohol consumption and breast cancer: a case-control study in Finland.
AB - OBJECTIVE: To study the association between lifetime alcohol consumption and the
risk of breast cancer. DESIGN AND SETTING: A case-control study carried out in
eastern Finland. Information about alcohol consumption was obtained by two
methods: a self-administered food frequency questionnaire (FFQ) including alcohol
consumption during the previous 12 months, and a lifetime alcohol consumption
questionnaire (AQ) which was administered by the study nurse. SUBJECTS: The study
consisted of 301 breast cancer cases (25-75 years old) and 443 population
controls. RESULTS: The subjects reported higher current alcohol consumption in
the AQ compared to the FFQ. According to the AQ, premenopausal cases consumed on
average 28 g and controls 24 g alcohol week(-1); in postmenopausal women the
values were 15 and 14 g, respectively. About 30% of premenopausal and 60% of
postmenopausal women were classified as non-drinkers. The correlation for current
alcohol consumption between the FFQ and the AQ was 0.80 in premenopausal women
but only 0.40 in postmenopausal women. Current alcohol consumption seemed to
influence the reporting of total lifetime alcohol consumption. Current alcohol
consumption was not associated with the risk of breast cancer either in
premenopausal or postmenopausal women; neither were associations found between
alcohol consumption at age of first use, use before the age of 30, or total
lifetime alcohol consumption and the risk of breast cancer. CONCLUSIONS: On
average, one to three drinks per week did not increase the risk of breast cancer
in this study. Consumption levels were, however, too low to exclude increased
risk with high regular consumption. Further research is necessary on lifetime
alcohol consumption.
PMID- 10786716
TI - Amyloid beta peptide impaired carbachol but not glutamate-mediated
phosphoinositide pathways in cultured rat cortical neurons.
AB - Signal transduction systems, including cholinergic pathways, which are likely to
be of pathophysiological significance are altered in Alzheimer's disease (AD).
Muscarinic cholinergic receptors are linked to the hydrolysis of
phosphoinositide, involving the production of inositol 1,4,5-trisphosphate
[Ins(1,4,5)P3] and the mobilization of cytosolic free calcium concentrations
([Ca2+]i). Effects of amyloid peptide (A(beta)) on these signals prior to
neuronal degeneration were examined in cultured rat cortical cells. A(beta)
increased the release of lactate dehydrogenase (LDH) in a concentration-dependent
manner, however, it was blocked by B27 supplement. Prolonged exposure to a
sublethal dose of A(beta) 25-35 or 1-42 disrupted carbachol-mediated release of
Ins(1,4,5)P3 and [Ca2+]i, which was inhibited in media supplemented with B27 or
the antioxidant vitamin E. In order to determine the specificity of the effect of
A(beta), various agonists glutamate or KCl but not bradykinin which utilize the
phosphoinositide cascade were investigated. Our results indicated that A(beta)
did not affect the stimulation of glutamate or KCl-mediated production of
Ins(1,4,5)P3 or cause elevation in [Ca2+]i. Furthermore, metabotropic agonist
trans-1-amino-cyclopentane-1,3,-dicarboxylate (ACPD) elevated calcium level was
not inhibited by A(beta) pre-treatment. Taken together, the results demonstrate
that a sublethal dose of A(beta) selectively impaired cholinergic receptor
mediated signal transduction pathways, and antioxidant or B27 supplement
attenuated this effect of A(beta). Alterations of cholinergic signaling by
prolonged exposure to A(beta) could be involved in cortical neurodegeneration
that occurs in AD. Because functional loss of cholinergic pathways is an
important aspect of AD, the differences in susceptibility of these two types of
receptors prior to other signs of A(beta) action is important and requires
further investigation.
PMID- 10786720
TI - Seasonal consumption of salad vegetables and fresh fruit in relation to the
development of cardiovascular disease and cancer.
AB - OBJECTIVE: To investigate the protective association between seasonality of
consumption of fresh fruit or salad vegetables and cancer and cardiovascular
disease (CVD) development. DESIGN AND SETTING: Face-to-face interviews, including
a food frequency questionnaire, were conducted on 1489 men and 1900 women, aged
35-75 years, who were respondents in the British Health and Lifestyle Survey
1984/85 (HALS1). CVD and cancer morbidity and mortality were determined from the
1991/92 British Health and Lifestyle Survey (HALS2) and by NHS Register
'flagging'. RESULTS: Risk was assessed by odds ratio (OR) for trend per frequency
category. In men, frequent winter salad vegetable consumption was more closely
protective than that in summer for cancer (winter OR=0.79 [0.62-0.99], P=0.045,
summer OR=0.83 [0.69-1.01], NS) and CVD (winter OR=0.85 [0.72-1.00], P=0.049,
summer OR=0.95 [0.82-1.10], NS). Fresh fruit consumption showed no significant
protection. In women, frequent salad vegetable consumption at any season was
significantly protective of CVD (winter OR=0.76 [0.65-0.89], P<0.001, summer
OR=0.76 [0.65-0.89], P<0.001), although not of cancer. Frequent fresh fruit
consumption in women was significantly protective of CVD (winter OR=0.84 [0.74
0.94], P=0.004, summer OR=0.85 [0.74-0.97], P=0.014) but not quite significant,
and only in winter, for cancer (winter OR=0.87 [0.76-1.00], P=0.052, summer
OR=0.88 [0.75-1.02], P=0.097). Maintenance of salad vegetable consumption from
summer to winter, to within one frequency category, was associated with further
protection for cancer in men (P=0.050) and CVD in women (P=0.024). CONCLUSIONS:
Diets high in fresh fruit and salad vegetables appear protective against cancer
and CVD. It is important to take into account the seasonality of consumption in
estimating and establishing significance of risk.
PMID- 10786721
TI - Mapping access to food in a deprived area: the development of price and
availability indices.
AB - OBJECTIVE: To develop and map indices to illustrate variation in the cost and
availability of healthy food. DESIGN: Two contiguous wards in London were
selected by virtue of their high Carstairs deprivation scores. A 2-km area was
defined around a randomly chosen central point. All retail outlets selling food
within the area were visited and their location recorded. A list of foods,
acceptable to the local ethnically diverse population, which met current dietary
guidelines, was devised. Data on the availability and price of 71 food items were
collected. Indices were developed using SPSS and mapped using Geographic
Information System (GIS) software. RESULTS: Information on availability and
prices were collected from 199 outlets. The mean price index shows how expensive
a shop is relative to other shops in the area. The least cost index shows the
relative expense of a shop using the cheapest ways of buying their range of
foods. Shorthand indices were tested, using data on 19 of the 71 prices.
Availability indices are also discussed, including a green availability index and
a fresh green availability index. Illustrative maps of the shop locations and the
mean price index and fresh green availability index are shown. CONCLUSIONS: Data
can be collected and indices developed which indicate geographic variation in
shop 'expensiveness', and in the price and availability of healthy food. GIS
software can be used to map these indices, to identify areas with high food
prices or low availability.
PMID- 10786722
TI - Economic crisis and malnutrition: socioeconomic determinants of anthropometric
status of preschool children and their mothers in an African urban area.
AB - OBJECTIVE: To assess the relative importance of socioeconomic and
maternal/prenatal determinants of the nutritional situation of children < 6 years
old in an urban African area after several years of economic crisis. DESIGN:
Cross-sectional cluster sample survey. SETTING: Brazzaville, capital city of the
Congo. SUBJECTS: Information on socioeconomic characteristics was gathered from a
random sample of 1368 households by house visits and anthropometric measurements
were performed using standardized procedures on preschool children (n = 2373) and
their mothers (n = 1512). RESULTS: The influence of socioeconomic factors on the
nutritional status of children, taking into account adjustment variables such as
mother's age and child's age and sex was assessed. For stunting, as well as for
the mean height-for-age index among children, the main determinants were economic
level of the household (P = 0.048 and P = 0.004, respectively), schooling of the
mother (P = 0.004 and P < 10(-3)) and living in the peripheral district (P =
0.005 and P < 10(-3)). The influence of socioeconomic determinants on weight-for
age and wasting was less straightforward. When adjusting, in addition, for
maternal and prenatal factors (mother's height and body mass index (BMI) and
birth weight), most of the effects of the socioeconomic determinants on the
nutritional status of children persisted somewhat, but the effect of the economic
level on the stunting became not significant (P = 0.11). The mean BMI of mothers
appeared to be related to the economic level of the household (P < 10(-4)), to
the marital status (P = 0.01) and to the occupation of the mother (P < 10(-4)).
CONCLUSIONS: Among the socioeconomic determinants of malnutrition in children,
some, such as economic level of the household or schooling of the mother, seem to
act mainly through prenatal factors, whereas others, mainly dwelling district
characteristics, seem to influence more directly the children's nutritional
status.
PMID- 10786723
TI - Nutrition policy in the Chilean transition.
AB - OBJECTIVE: This paper examines socioeconomic, demographic, epidemiological and
nutrition changes that have occurred in Chile in the last decades using concepts
of epidemiological and nutrition transition, and discusses policies related to
nutrition. DESIGN AND SETTING: This is a descriptive, population-based study to
analyse changes in the Chilean diet and nutrition situation including some of the
main demographic, socioeconomic and epidemiological variables. Data came from the
FAO, the National Institute of Statistics, the Ministry of Health and national
surveys. RESULTS AND POLICY IMPLICATIONS: In Chile, the epidemiological and
nutrition situation shifted from a pretransition stage with high rates of
undernutrition to a post-transition stage with increasing rates of obesity in all
groups aged less than 20 years. However, changes were not accompanied by
modifications in nutrition policy, which had been successful in reducing
undernutrition. Despite changes in diet to a 'western' diet and in nutritional
status of the population from undernutrition to obesity, food and nutrition
programmes have been maintained unaltered. Governmental and university
organizations were created in 1994 and 1995 to address the current food and
nutrition problems. The accomplishments of these institutions have been the
elaboration of dietary guidelines, reformulating the food and nutrition
programmes and the promulgation of the Food Sanitary Regulations for Chile.
CONCLUSIONS: Education for the prevention of nutrition excess problems should be
a main food and nutrition policy in developing countries.
PMID- 10786724
TI - Food variety, socioeconomic status and nutritional status in urban and rural
areas in Koutiala (Mali).
AB - OBJECTIVE: The purpose of this study was to analyse the associations between the
food variety score (FVS), dietary diversity score (DDS) and nutritional status of
children, and to assess the associations between FVS, DDS and socioeconomic
status (SES) on a household level. The study also assessed urban and rural
differences in FVS and DDS. DESIGN: Cross-sectional studies in 1994/95, including
a simplified food frequency questionnaire on food items used in the household the
previous day. A socioeconomic score was generated, based on possessions in the
households. Weight and height were measured for all children aged 6-59 months in
the households, and anthropometric indices were generated. SUBJECTS AND SETTING:
Three hundred and twenty-nine urban and 488 rural households with 526 urban and
1789 rural children aged 6-59 months in Koutiala County, Sikasso Region, Mali.
RESULTS: Children from urban households with a low FVS or DDS had a doubled risk
(OR>2) for being stunted and underweight. Those relations were not found in the
rural area. There was an association between SES and both FVS and DDS on the
household level in both areas. The FVS and DDS in urban households with the
lowest SES were higher than the FVS and DDS among the rural households with the
highest SES. CONCLUSIONS: Food variety and dietary diversity seem to be
associated with nutritional status (weight/age and height/age) of children in
heterogeneous communities, as our data from urban areas showed. In rural areas,
however, this association could not be shown. Socioeconomic factors seem to be
important determinants for FVS and DDS both in urban and rural areas. FVS and DDS
are useful variables in assessing the nutritional situation of households,
particular in urban areas.
PMID- 10786725
TI - Sociodemographic determinants of energy, fat and dietary fibre intake in
Australian adults.
AB - OBJECTIVE: To examine the relationship between sociodemographic factors (sex,
age, education, occupation and region of birth) and absolute levels of energy,
fat and fibre intake in adults at the national level. DESIGN, SETTING AND
SUBJECTS: The 1983 National Dietary Survey of Adults (NDSA), covering six
Australian capital cities, collected food and nutrient intake data using the 24
hour recall method, from subjects aged 25-64 years (n=6255). RESULTS:
Interactions of variables occurred, especially for males. The greatest effect on
male intake of all three dietary components was a combination of age and
education. For females, the main explanatory variable for fat and energy intake
was age, but that for fibre was a combination of region of birth and education.
Both education (alone or in combination) and region of birth (alone or in
combination) had a greater effect than occupation (alone or in combination).
CONCLUSIONS: Energy, fat and fibre intakes vary considerably between
sociodemographic groups. Such variability must be taken into account in
formulating policy and planning decisions and in assessing temporal change.
PMID- 10786726
TI - Short stature and hypertension in the city of Rio de Janeiro, Brazil.
AB - OBJECTIVE: Stature is a powerful indicator of poor nutrition early in life in
nations where undernutrition is a public health problem. Hypertension in adults
has been associated with factors present early in life such as low birth weight.
We tested the hypothesis that short stature is associated with hypertension among
adults. DESIGN AND SETTING: A household survey of representative adults in Rio de
Janeiro city, Brazil was carried out in 1996. SUBJECTS: Blood pressure and
anthropometric measures were collected from 2802 adults in their own households.
Prevalence estimates and modelling incorporated the sample design and weights.
RESULTS: Age-adjusted prevalence of hypertension for both sexes was lower in the
third quartile of stature distribution. In women, but not in men, the odds ratio
comparing the first quartile of stature with the fourth quartile was
statistically significant with an odds ratio of 1.68 (95%CI 1.02-2.76). Adjusting
for known risk factors for hypertension such as age, income, smoking, sodium and
alcohol intake and race, the association among women, comparing the first with
the fourth quartile for stature, was 1.84 (95%CI 1.03-3.30). With further
adjustment for residual of weight on height the ratio reduced to 1.76 (95% CI
0.97-3.19, P value of trend = 0.03). Systolic blood pressure showed a U-shaped
association with quartiles of stature, mainly among women, with a beta
coefficient significantly lower at the third quartile. CONCLUSIONS: This
association of stature with hypertension supports the theory of an important
ontogenetic dependence of adult blood pressure, at least among women.
PMID- 10786727
TI - Relationships between vitamin A, iron status and helminthiasis in Bangladeshi
school children.
AB - OBJECTIVE: To explore the relationships between biochemical indicators of vitamin
A and iron status and the intestinal helminths Ascaris lumbricoides and hookworm
in primary school children. SETTING: Two rural governmental schools in
northwestern Bangladesh. DESIGN: Cross-sectional study. SUBJECTS: The sample
consisted of 164 children in grades 3-5. METHODS: Serum retinol and beta-carotene
(by high-performance liquid chromatography, HPLC), haemoglobin (HemoCue),
ferritin (enzyme-linked immunoadsorbent assay, ELIZA) and height and weight were
measured. Dietary intake of vitamin A was assessed using a food frequency
questionnaire and faecal analyses were done using Stoll's egg-count technique.
RESULTS: The mean serum retinol was 26.8 microg dl(-1) and 20% had a level of <
20 microg dl(-1), the cut-off value for low vitamin A status. There was a strong
positive association between serum beta-carotene and serum retinol (r = 0.44, P <
0.001), suggesting those with higher retinol levels had a higher carotene intake.
Thirty-one per cent were anaemic (Hb < 11.5 g dl(-1)), 30% had iron deficiency
(serum ferritin < 12.0 microg l(-1)) and 14% were suffering from iron deficiency
anaemia. Children with a serum retinol level of 20 microg dl(-1) had
significantly lower ferritin (14.0 compared to 26.0 microg l(-1), P = 0.005) and
Hb levels (11.7 compared to 12.4 g dl(-1), P = 0.005) than those with higher
levels. The proportion of iron deficiency anaemia was significantly greater among
children with hookworm. Our data suggest that hookworm exerts its impact on iron
status independently of the vitamin A status of the host. CONCLUSIONS: Programmes
to improve iron status should consider including both vitamin A prevention
programmes and deworming.
PMID- 10786728
TI - N-3 fatty acids from fish and coronary artery disease: implications for public
health.
AB - OBJECTIVE: To review and discuss the effect of n-3 polyunsaturated fatty acids
(PUFA) from fish in the prevention and, primarily, in the treatment of coronary
artery disease (CAD). DESIGN: Overview of the literature. SETTING: Denmark.
RESULTS: There is good evidence that fish consumption may reduce the risk of CAD.
CONCLUSIONS: Fish can be recommended to reduce the risk of CAD both in healthy
subjects and in patients with a high risk of CAD or with documented CAD. The use
of fish oil concentrates can not be recommended in general, but may be considered
in patients after a myocardial infarction or in patients with
hypertriglyceridaemia. An increased intake of n-3 polyunsaturated fatty acids
from fish may have substantial implications for public health and health economy
by decreasing the risk of coronary events and sudden cardiac death.
PMID- 10786729
TI - WHO tackles food inequalities: Europe's first comprehensive Food and Nutrition
Action Plan debate, 8-10 November 1999, Malta.
PMID- 10786730
TI - Fruits and vegetables in the prevention of cancer and cardiovascular disease.
AB - OBJECTIVE: We quantified the public health benefit of fruits and vegetables on
the prevention of cancer and cardiovascular disease (CVD), using currently
available human data. DESIGN: We reviewed over 250 observational studies on
cancer and CVD. Relative risks (RRs) for high versus low intake of fruits and
vegetables were obtained. The preventable proportion of chronic diseases, i.e.
the per cent of cases attributable to low consumption of fruits and vegetables,
was estimated using three scenarios: best guess, optimistic (using stronger RRs)
and conservative (using weaker RRs and eliminating the contribution of smoking
and/or drinking). The preventable proportion was calculated for increasing
average intake from the current 250 g day(-1) to the recommended 400 g day(-1)
among the general Dutch population. RESULTS: It is estimated that in the
Netherlands cancer incidence could be reduced by 19% (12,000 cases annually, best
guess), ranging from 6% (conservative) to 28% (optimistic). Cardiovascular deaths
could be reduced by 16% (8000 deaths annually, best guess), ranging from 6% to
22%. Evidence is most abundant for gastrointestinal cancers, followed by hormone
related cancers, but limited for other sites and CVD. CONCLUSIONS: Increasing
consumption of fruits and vegetables carries a large public health potential.
Population trials and biological mechanisms should eventually provide scientific
proof of their efficacy. The available evidence is sufficient to justify public
health education and promotion aimed at a substantial increase in the consumption
of fruits and vegetables.
PMID- 10786731
TI - Silently sings the larynx its secret.
PMID- 10786732
TI - Effects of vecuronium and rocuronium in antagonistic laryngeal muscles and the
anterior tibial muscle in the cat.
AB - BACKGROUND: Adequate vocal cord paralysis and full recovery of laryngeal muscle
function are important when muscle relaxants are used perioperatively. This study
was designed to compare the effects of vecuronium and rocuronium at the vocal
cord abductor and adductor muscles and the anterior tibial muscle in cats.
METHODS: Twelve adult cats were studied under pentobarbitone-N2O/O2-anesthesia.
After supramaximal electrical stimulation of the peroneal nerve and the recurrent
laryngeal nerve (0.1 Hz and intermittent train-of-four) evoked electromyographic
responses were obtained from the anterior tibial muscle, the posterior
cricoarytenoid muscle (vocal cord abductor) and two vocal cord adductor muscles,
the lateral cricoarytenoid and the vocal muscle. Six cats received bolus doses of
increasing size of vecuronium (ED90 22.5 microg x kg(-1)) and six cats rocuronium
(ED90 90 microg x kg(-1)). RESULTS: Equipotent doses of vecuronium and rocuronium
caused a similar degree of paralysis in all muscles (vecuronium ED90: 70%
blockade at the posterior cricoarytenoid, 83% at the lateral cricoarytenoid, 84%
at the vocal muscle and 90% at the anterior tibial muscle; rocuronium ED90: 71%
at the posterior cricoarytenoid, 67% at the lateral cricoarytenoid, 78% at the
vocal muscle and 90% at the anterior tibial muscle; vecuronium 2 x ED90: 93%
blockade at the posterior cricoarytenoid, 95% at the lateral cricoarytenoid, 97%
at the vocal muscle and 99% at the anterior tibial muscle; rocuronium 2 x ED90:
89% blockade at the posterior and lateral cricoarytenoid, 93% at the vocal muscle
and 100% at the anterior tibial muscle). Onset time was significantly shorter at
the posterior cricoarytenoid muscle (290 s) compared to the lateral
cricoarytenoid muscle (400 s) after vecuronium ED90 and to the vocal muscle (150
s versus 210 s) after rocuronium ED90. Compared to the anterior tibial muscle
(interval 25-75%: 6.5 min after vecuronium 2 x ED90 and 3.3 min after rocuronium
2 x ED90 and to the posterior cricoarytenoid muscle (interval 25-75%: 7 min after
vecuronium 2 x ED90 and 4.3 min after rocuronium 2 x ED90), recovery of laryngeal
adductor muscle function was markedly delayed with both neuromuscular blocking
drugs (interval 25-75% at the lateral cricoarytenoid and vocal muscle: 14 min and
15.8 min after vecuronium 2 x ED90 and 10.3 min and 11.6 min after rocuronium 2 x
ED90 respectively). CONCLUSION: In cats, the time course of neuromuscular
blockade after vecuronium and rocuronium differs in antagonistic laryngeal
muscles. The protective laryngeal function of glottis closure recovers later than
vocal cord abduction after both vecuronium and rocuronium.
PMID- 10786733
TI - Local anaesthesia for awake fibreoptic nasotracheal intubation.
AB - BACKGROUND: Awake fibreoptic nasotracheal intubation (FNI) is performed in
potentially difficult airways under local anaesthesia. This observer-blinded
study was designed to evaluate the efficacy of upper airway anaesthesia produced
by nebulized lignocaine against combined regional block (CRB) for awake FNI.
METHODS: Forty-eight ASA 1 adults were randomly allocated to receive 4 ml of 4%
nebulized lignocaine (nebulization group) or translaryngeal block, bilateral
superior laryngeal nerve block and three 4% lignocaine-soaked cotton swabs in the
nose (CRB group). Facial grimace and patient comfort were assessed by grimace and
airway reactivity scores. Patients reported their discomfort on a 4-point score.
RESULTS: All patients underwent successful FNI without significant discomfort;
79% in the nebulization group and 83% of the patients in the CRB group reported
the procedure to be comfortable. A higher grimace score was recorded on insertion
of the endotracheal tube (ETT) through the nostril in the nebulization group when
compared to the CRB group, P<0.005. Similarly, patients in the CRB group were
more comfortable during passage of the ETT into the glottis, as compared to the
nebulization group. A progressive increase in heart rate was observed in all
patients from the beginning of the procedure, but the rise in the nebulization
group was greater, (P<0.05) and also lasted longer than in the CRB group
(P<0.05). Mean arterial pressure was higher in the nebulization group when
compared to the CRB group (P<0.05), with patients belonging to the CRB group
demonstrating considerable haemodynamic stability. CONCLUSIONS: Both nebulization
and CRB produced satisfactory anaesthesia of the upper airway, but CRB provided
better patient comfort and haemodynamic stability.
PMID- 10786734
TI - Movement of the endotracheal tube during laparoscopic hernia repair.
AB - BACKGROUND: Laparoscopic surgery is not without its problems, and one of the less
known is cephalad displacement of the carina and relative movement of the
endotracheal tube in the trachea. The aetiology of this is presumably a
consequence of both pneumoperitoneum and the Trendelenburg position frequently
adopted during laparoscopic surgery. METHOD: We studied 30 patients undergoing
laparoscopic hernia repair utilising 10 degrees of Trendelenburg position and an
intra-abdominal inflation pressure of between 12 and 15 mm Hg (mean 13.6 mm Hg).
We measured the distance between the tip of the endotracheal tube and the carina
using a fibreoptic bronchoscope. RESULT: This distance decreased only slightly,
from a mean (SD) of 39.6 (13) mm after intubation, to 38.9 (12.6) mm after
adoption of Trendelenburg tilt and pneumoperitoneum. This did not represent a
statistically significant change (P=0.09). CONCLUSION: We conclude that the
endotracheal tube does not routinely migrate towards the carina when laparoscopic
hernia repair is performed under these conditions.
PMID- 10786735
TI - Injection of morphine loco dolenti recommended as early as 1876.
AB - The peripheral site of action of opioids was proved some 20 years ago. The
concept of the peripheral action of morphine, however, appears to be over 100
years older. We report on the contents of a paper, presented on 28 April 1876 at
the meeting of the Finnish Medical Association ("Finska Lakarsallskapet"), on the
use of morphine and its sites of action. The author was Professor Knut Felix von
Willebrand, whose details are included. Prof. v. Willebrand starts by focusing on
several unwanted side effects, often seen in connection with morphine
administration, and advises how they can be avoided by using the pupils of the
eye as a manometer for tolerance of morphine, as suggested by Vibert. After
having presented four case reports which illustrate the use of morphine in his
own practice, Prof. v. Willebrand explains his conception of the sites of action
of morphine. The paper gives a lively picture of the use of morphine about 125
years ago. Furthermore, it indicates that Prof. v. Willebrand believed firmly in
the peripheral site of action of morphine and recommended to inject morphine loco
dolenti whenever possible.
PMID- 10786736
TI - The place of THAM in the management of acidemia in clinical practice.
PMID- 10786737
TI - Perioperative use of dihydropyridine calcium channel blockers.
PMID- 10786738
TI - Day-case laparoscopy: a comparison of prophylactic opioid, NSAID or local
anesthesia for postoperative analgesia.
AB - BACKGROUND: The study was aimed to evaluate the analgesic efficacy, postoperative
comfort, recovery characteristics and side effects of three different analgesic
agents administered prophylactically. METHODS: Eighty patients undergoing day
case minor operative laparoscopy were randomly allocated into four groups to
receive tenoxicam 20 mg i.v. (Group T), fentanyl 100 microg i.v. (Group F), 5 ml
of bupivacaine 2.5 mg/ml for infiltration of trocar sites (Group B), 30, 10 and 5
min before incision respectively. Bupivacaine, 35 ml, 2.5 mg/ml was also
administered into the pelvic cavity in Group B. Group P received only placebo.
Postoperative pain, analgesic requirements, first response to verbal stimulus,
first analgesic requirement, ability to walk without help, to drink and to void,
blood pressures, SpO2 and respiration rates were recorded in the PACU.
Postoperative pain was evaluated by verbal rating scale. Pain scores, analgesic
requirements and side effects were evaluated by telephone calls until the 48th
postoperative hour. RESULTS: Postoperative pain scores were lower and time to
requirement of rescue analgesics was longer in groups F and B compared to Group
P. In the PACU, analgesic requirements were lower in Group B, compared to Group
P. Nausea and vomiting were increased in Group F. CONCLUSION: Tenoxicam 20 mg
i.v. was found to be ineffective whereas bupivacaine was superior to other groups
in reducing pain and analgesic requirements. Bupivacaine also increased time to
first analgesics and obtained better recovery characteristics, underlining its
value in prophylactic pain management compared to the other two agents.
PMID- 10786739
TI - Regional anaesthesia for outpatient knee arthroscopy: a randomized clinical
comparison of two different anaesthetic techniques.
AB - BACKGROUND: The purpose of this prospective, randomized study was to evaluate the
time required to perform anaesthesia, achieve surgical block and fulfil
standardized discharge criteria in outpatients receiving knee arthroscopy with
either spinal anaesthesia or combined sciatic-femoral nerve block. METHODS: After
a standard midazolam/ketoprofen premedication and baseline measurement of
cardiovascular parameters, 50 ASA I-II patients scheduled for elective outpatient
knee arthroscopy were randomized to receive spinal anaesthesia with 8 mg of 0.5%
hyperbaric bupivacaine (group Spinal, n=25), or combined sciatic-femoral nerve
block with 25 ml of mepivacaine 20 mg ml(-1) and a multiple injection technique
(15 ml for femoral nerve block and 10 ml for sciatic nerve block). Times lasting
from skin disinfection to the end of local anaesthetic injection (preparation
time) and then to achieve surgical anaesthesia (readiness for surgery), as well
as times required for block resolution, micturition, unassisted ambulation, and
home discharge were recorded by a blinded observer. Occurrence of adverse events
was also recorded. RESULTS: Preparation time (mean+/-SD) was longer with sciatic
femoral block (8+/-2.7 min) than spinal anaesthesia (5+/-2.1 min) (P=0.0002)
while no differences were observed in the time required to achieve readiness for
surgery (14+/-5 min and 15+/-6 min in the Spinal and Sciatic-femoral groups,
respectively). No differences in haemodynamic side effects and need for
intraoperative additional analgesia were observed. Patients receiving spinal
anaesthesia showed a faster resolution of nerve block and longer time to
micturition (137+/-49 min and 231+/-101 min) than patients receiving peripheral
nerve blockade (206+/-51 min and 145+/-36 min) (P<0.0005 and P=0.002,
respectively); however, no differences were observed in the time required to
fulfil standardized discharge criteria (241+/-101 min in group Spinal and 209+/
70 min in group Sciatic-femoral; P=0.86). CONCLUSION: In patients receiving
elective outpatient knee arthroscopy, using a combined sciatic-femoral nerve
block with 25 ml of mepivacaine 20 mg ml(-1) and a multiple injection technique
results in a slightly longer preoperative time but provides similarly effective
anaesthesia with no differences in home discharge times as compared to spinal
anaesthesia with 8 mg hyperbaric bupivacaine.
PMID- 10786740
TI - No difference between bupivacaine in 0.9% and 8% glucose for spinal anaesthesia
in small children.
AB - BACKGROUND: Baricity is one of the most important factors to influence the
characteristics of distribution of the local anaesthetic and hence success and
spread of the blockade. Bupivacaine is rendered hyperbaric by adding glucose. The
effect of differing degrees of hyperbaricity remains to be evaluated. METHODS:
Two hyperbaric bupivacaine solutions, in 0.9% and in 8% glucose, for spinal
anaesthesia were investigated in 60 children, aged 1-7 years, in a double-blind,
randomised, parallel group, prospective study. The children were premedicated
with diazepam orally. Bupivacaine 5 mg ml(-1) in either 0.9% or 8% glucose was
injected in a dose of 0.4 mg kg(-1). Maximum cephalad extent and regression of
sensory block were tested by transcutaneous electrical stimulation. RESULTS:
Success rate, spread and duration of sensory block were similar in both groups.
Only one child required a single dose of fentanyl during surgery. The highest
median level of sensory block was T3 (T2-T7) (median (10th/90th percentiles)) in
both groups. Time to reach T10 did not differ between the groups. The incidence
of adverse effects was similar. Atropine was administered to one child in each
group to treat bradycardia and 6 children (10%) experienced shivering. One child
in each group vomited once. CONCLUSION: These results demonstrate that
bupivacaine in 0.9% glucose and in 8% glucose solutions are equally suitable for
spinal anaesthesia in small children. Similar success rate, spread and duration
of the sensory and motor block are achieved with both baricities of bupivacaine.
PMID- 10786741
TI - Need for a reliable pain evaluation scale in the newborn in Sweden.
AB - BACKGROUND: A major problem in pain treatment in the newborn is the ability to
assess the degree of experienced pain. Several different methods for estimating
pain in the newborn have been introduced in recent years. The objectives of this
study were to see whether pain scoring was used in Swedish neonatal units, and by
which method, and furthermore to observe whether any changes had occurred between
1993 and 1998. METHOD: A questionnaire was distributed to all Swedish neonatal
units in 1993 and 1998. RESULTS: In both 1993 and 1998, 86% of all clinics
answered the questionnaire. Two-thirds of these clinics used some method for
estimating pain in the newborn at both times. Eight clinics used a structured
method in the latter period compared to one in the earlier period. A higher
proportion of units having full intensive care measured pain compared to other
units. CONCLUSION: The study shows that an unchanging low proportion of neonatal
units in Sweden attempt to assess pain. There is a minor increase in the number
of departments that use a structured method for pain scoring. Documentation of
pain intensity is still inadequate and should be improved.
PMID- 10786742
TI - Effect of i.v. tenoxicam during caesarean delivery on platelet activity.
AB - BACKGROUND: Non-steroidal anti-inflammatory drugs inhibit platelet aggregation
and prolong bleeding time in healthy subjects. We have studied the effect of i.v.
tenoxicam during caesarean delivery on skin bleeding time, operative, and
postoperative blood loss, and beta-thromboglobulin and platelet factor 4 as
specific molecular markers for platelet activity. METHODS: Fifty women were
studied. Twenty-five were given tenoxicam 20 mg i.v. 10 min before induction of
general anaesthesia, and 25 formed a control group. Skin bleeding time and
platelet markers were determined the day before and 1 h after induction of
anaesthesia. RESULTS: In the tenoxicam group, there was an slight increase in
skin bleeding time with no statistically significant changes in platelet marker
levels. In the control group, platelet markers increased 1 h after surgery. The
surgeon's assessment of uterine relaxation, using a visual analogue score,
operating theatre blood loss, and the frequency of bleeding over 24 h after
operation, showed no significant difference between the two groups. CONCLUSION:
During caesarean delivery i.v. tenoxicam causes a slight increase in bleeding
time with no significant changes in platelet marker levels.
PMID- 10786743
TI - The effect of paracetamol (acetaminophen) on fentanyl metabolism in vitro.
AB - BACKGROUND: Fentanyl is a synthetic opioid widely used in anesthesia and
analgesia. In experimental animals and in humans it has been shown that most
fentanyl biotransformation occurs in the liver, where this opioid is converted
primarily to its N-dealkylated derivative, norfentanyl. Recent studies have shown
that fentanyl is metabolized to norfentanyl via cytochrome P-450 3A4 (CYP3A4).
CYP3A4 is responsible for the metabolism of numerous other therapeutic agents,
including those administered concurrently with fentanyl (e.g., nifedipine,
lidocaine, erythromycin and cyclosporine). Paracetamol is also metabolized by the
CYP3A family, with a Km that is nearly equal to therapeutic blood concentrations.
Since paracetamol is widely used, its potential interaction with fentanyl
metabolism would be of great interest. METHODS: In the present study, rat and
human liver microsomes were used to assess the ability of paracetamol to inhibit
fentanyl metabolism. RESULTS: In both sets of microsomes, paracetamol produced a
concentration-dependent inhibition of fentanyl oxidation to norfentanyl. Kinetic
analysis of the data showed that 0.5-5 mM paracetamol inhibited fentanyl
metabolism in a noncompetitive fashion. A Dixon plot revealed that the Ki for
paracetamol inhibition of fentanyl metabolism is approximately 3.2 mM and 2.8 mM
for human and rat liver microsomes, respectively. CONCLUSIONS: Since these
concentrations of paracetamol are approximately one order of magnitude greater
than therapeutic concentrations, it would appear that potentially important and
possibly harmful fentanyl-paracetamol drug interactions do not occur with
therapeutic concentrations of paracetamol.
PMID- 10786744
TI - The effect of dopexamine on regional tissue oxygenation, systemic inflammation
and amino acid exchange in major abdominal surgery.
AB - BACKGROUND: Beta-adrenergic agents are frequently used to improve cardiac
performance in surgical and intensive care patients. Beta-adrenergic agents have
metabolic and anti-inflammatory effects in addition to their cardiovascular
effects. Splanchnic metabolic activity increases in response to surgery and
inflammation. Dopexamine is believed to favor blood flow distribution to the
splanchnic region. METHODS: We investigated the effect of dopexamine, started
before major abdominal surgery, on postoperative patterns of systemic and
regional blood flow, metabolic response, and markers of inflammation. Twenty-one
patients undergoing major abdominal surgery were studied. All patients were
stabilized preoperatively to predefined hemodynamic endpoints with fluids. After
preoperative measurement of systemic and splanchnic oxygen transport and
splanchnic lactate, glutamine and alanine exchange and blood levels of tumor
necrosis factor (TNF) and interleukin-6 (IL-6), the patients were randomized to
receive an infusion of dopexamine at 0.5 microg kg(-1) min(-1) (group 1) or 2.0
microg kg(-1) min(-1) (group 2) or placebo. Measurements were repeated at 6 h and
24 h after the end of the operation and the blood levels of cytokines also at 36
h postoperatively. RESULTS: Dopexamine evoked an increase in cardiac index
preoperatively. Postoperatively, there was no difference between the groups in
systemic and regional hemodynamics or oxygen transport: cardiac index, splanchnic
blood flow and oxygen delivery increased similarly in each group. Accordingly,
systemic oxygen extraction decreased. Glutamine, alanine and lactate exchange did
not differ between the groups. The only metabolic change was an increased
splanchnic uptake of alanine, which also was unaffected by dopexamine. There was
no difference between the groups in TNF and IL-6 levels; TNF level did not
change, while IL-6 level increased in response to surgery. CONCLUSIONS:
Dopexamine, when added to a preoperative stabilization protocol with fluids, did
not augment the postoperative hemodynamic response, and had no effect on
postoperative metabolic and inflammatory responses.
PMID- 10786745
TI - Evaluation of pressure/volume loops based on intratracheal pressure measurements
during dynamic conditions.
AB - BACKGROUND: The aim of this study was to evaluate and compare information about
lung mechanics obtained by dynamic pressure/volume loops based on Y-piece and
intratracheal airway pressure. METHODS: Airway pressure was measured
simultaneously at the Y-piece and trachea. Flow/tidal volume was measured by
sidestream spirometry at the Y-piece. The effect of an intraluminal catheter in
the tube was evaluated in a lung model. Ten adults with acute lung injury and
mechanical ventilation were studied. Measurements were performed during volume
(VC) and pressure-controlled (PC) ventilation at different ventilator settings.
RESULTS: Lung model: There was a statistically significant difference (P<0.001)
between trachea and Y-piece pressure/volume loop areas during both VC and PC
ventilation. The ratio trachea area/Y-piece area decreased with increased
endotracheal tube resistance (r=0.96). PATIENTS: The difference between trachea
and Y-piece P/V-loops was statistically significant at all 21 ventilatory
settings (P<0.05-0.001). The tracheal loop revealed clearly intrinsic PEEP and
lowered compliance during overinflation, which was difficult or impossible to see
in the Y-piece pressure/volume loop. CONCLUSION: By measuring airway pressure at
the trachea the effect of endotracheal tube resistance during inspiration is
excluded while it is included during expiration, yielding correct end-points of
inspiration and expiration. This makes it possible to calculate accurately total
compliance of the respiratory system during dynamic conditions. By monitoring of
airway pressure in the trachea, respiratory mechanics can be assessed more
accurately and ventilatory settings adjusted to attenuate ventilator induced lung
injury.
PMID- 10786746
TI - A new method for non-invasive, manoeuvre-free determination of "static" pressure
volume curves during dynamic/therapeutic mechanical ventilation.
AB - BACKGROUND: Lung mechanics are usually measured using static or quasistatic
methods, abandoning normal ventilatory treatment. We have developed a method to
calculate the alveolar pressure during dynamic/therapeutic conditions, "the
dynostatic pressure" (P(dyn)), using airway pressure (P) measured in the trachea
and volume (V) and flow (V) at the Y-piece. METHODS: P(dyn) is calculated
according to the formula P(dyn)= (P(insp) x V(exp)-P(exp) x V(insp))/(V(exp)
V(insp)), making the assumption that inspiratory and expiratory resistances are
equal at isovolume. The method was evaluated in a lung model during dynamic
conditions comparing measured alveolar pressure (P(alv)) and P(dyn) at equal and
unequal inspiratory and expiratory resistances and P/V-curves obtained during
static and dynamic conditions. The algorithm was then applied in patients with
acute lung injury (ALI). RESULTS: When inspiratory and expiratory resistances
were equal there was an excellent agreement between the P(dyn) and the P(alv),
irrespective of ventilator settings, r(2)=0.995 (range 0.981-0.999). P(dyn)
derived compliance was equal to static values. When the ratio between inspiratory
and expiratory resistance was varied between 2.3:1 and 1:2.3 the r(2) was above
0.95 (range 0.952-0.996). Development of intrinsic PEEP and overdistension was
easily revealed in patients, as shown by the dynostatic P/V-curve. CONCLUSION:
The dynostatic method gives a breath-by-breath reflection of the interaction
between ventilatory settings and lung mechanics in patients during ordinary
ventilator treatment. It is only marginally affected by the moderate differences
in inspiratory versus expiratory resistances present in patients with ALI.
PMID- 10786747
TI - Pulsatility does not change cerebral oxygenation during cardiopulmonary bypass.
AB - BACKGROUND: To determine the effect of pulsatility during cardiopulmonary bypass
(CPB) on cerebral oxygenation, we measured oxyhaemoglobin (HbO2),
deoxyhaemoglobin (Hb) and oxidised cytochrome aa3 (CtO2) with near-infrared
spectroscopy (NIRS) in 14 patients electively scheduled for cardiac surgery.
METHODS: Cerebral oxygenation was measured during steady state CPB at a core
temperature of 32 degrees C. Non-pulsatile flow and pulsatile flow were performed
for 10 min each. RESULTS: After 14 min of CPB, HbO2, Hb and CtO2 were
significantly below prebypass values. HbO2 and CtO2 did not alter with changing
flow patterns. Hb significantly increased both during the period of nonpulsatile
(median: -0.7 vs. 0.25 micromol/l; P<0.05) and pulsatile flow (median: 0.25 vs.
0.5 micromol/l; P<0.001). This increase was independent of flow pattern.
CONCLUSIONS: Neither oxygenated haemoglobin, nor intracellular oxygenation,
represented by CtO2, indicated a beneficial effect of pulsatile perfusion during
hypothermic CPB. These results, however, are only valid for short time effects
within 10 min before rewarming from CPB and patients without flow-limiting
stenoses of the carotid artery.
PMID- 10786748
TI - Cardiac troponin I is reliable with immediate but not medium-term cardiac
complications after abdominal aortic repair.
AB - BACKGROUND: The diagnosis of cardiac complications is particularly challenging in
the postoperative course of non-cardiac surgery. Follow-up of patients suggests
that silent or symptomatic postoperative myocardial infarction have similar short
term outcomes. Cardiac troponin I (cTnI) has been reported as being a sensitive
and specific marker of these complications. METHODS: We conducted a prospective
study to determine the cut-off values of cTnI which may predict cardiac
complications, i: in the postoperative period until discharge, and ii: during a 1
year period after aortic surgery. Three hundred and twenty-nine consecutive
patients undergoing infrarenal aortic surgery were included over a 2-year period
in a single center. cTnI was measured at recovery and on the 1st, 2nd and 3rd
postoperative days. The presence or absence of cardiac complications was
classified by reviewers who had no knowledge of cTnI. For evaluation of the ideal
discrimination value of cTnI between the complicated and uncomplicated patient
groups, we calculated receiver-operator characteristics for the mean values of
the peak of cTnI. RESULTS: Thirteen patients (4%) developed 19 postoperative
cardiac complications. Thirteen patients (4%) died in the postoperative period.
Nine patients (3%) developed 10 cardiac complications during the 1-year follow-up
in 316 patients. In 280 patients, cTnI was below 0.5 ng/ml, in 22 patients
between 0.5 and 1.5 ng/ml and the 27 remaining patients had a cTnI higher than
1.5 ng/ml. The area under the curve for postoperative cardiac complications was
0.84 (SD=0.21). A limit value of 0.54 ng/ml yielded a sensitivity of 75% and a
specificity of 89%. The area under the curve for late cardiac complications was
0.45 (SD= 0.13). CONCLUSION: A cTnI level greater than 0.54 ng/ml appears to be
correlated with the occurrence of cardiac complications in the period until
discharge, but no value of cTnI is predictive of late cardiac complications
occurring in the 1st year after aortic surgery.
PMID- 10786749
TI - Accurate monitoring of blood loss: thoracic electrical impedance during
hemorrhage in the pig.
AB - BACKGROUND: Cardiovascular variables are closely regulated in that they remain
relatively stable during minor hemorrhage. We considered that such stability
would make these variables less accurate for monitoring a blood loss. In
contrast, thoracic electrical impedance would be unlikely to be a regulated
variable and could serve as a non-invasive monitor of a volume deficit. METHODS:
In 10 pigs bled (0-24 ml kg(-1)) and retransfused (to 28 ml kg(-1)) during
halothane anesthesia, the magnitude of the electrical impedance, cardiovascular,
blood gas and temperature variables, atrial natriuretic peptide and near infrared
spectroscopy of the leg muscles were recorded. RESULTS: During hemorrhage and
retransfusion, the median correlations between changes in the magnitude of the
thoracic impedance and the external blood loss ranged from 0.97 to 0.98 with an
individual range from 0.80 to 1.0. These correlation coefficients were higher and
their ranges were lower than correlations established for any other measured
parameter. CONCLUSION: During hemorrhage and retransfusion in the halothane
anesthetized pig, a change in the magnitude of thoracic electrical impedance
appears to be an accurate and also non-invasive monitor of a blood volume
deficit.
PMID- 10786750
TI - Effect of intra-aortic magnesium on renal function during and after abdominal
aortic surgery: a pilot study.
AB - BACKGROUND: Infrarenal aortic cross-clamping causes renal vasoconstriction.
Magnesium may protect against renal deterioration through its vasodilatory
properties. METHODS: Thirty patients with normal preoperative renal function
undergoing infrarenal aortic cross-clamping for elective aortic surgery received
magnesium (4 mmol) or saline into the aorta immediately after aortic cross
clamping and again just before unclamping in a double-blind fashion. Pulmonary
artery occlusion pressure was maintained 215 mmHg. Five patients with magnesium
were excluded due to need for intravenous nitroglycerine because of myocardial
ischaemia during the study. RESULTS: Postoperative creatinine clearance remained
unchanged in both groups. Urinary N-acetyl-beta-D-glucosaminidase excretion
increased before and decreased after aortic cross-clamping in both groups. The
concentrations of glutathione peroxidase in serum were identical between the two
groups. CONCLUSIONS: These data indicate that intra-aortic magnesium had no
effect on renal function during or after aortic cross-clamping.
PMID- 10786751
TI - Aerosolized surfactant in lung-lavaged adult rats: factors influencing the
therapeutic response.
AB - OBJECTIVE: To evaluate the effect of aerosolized modified natural surfactant in
adult rats with respiratory failure. METHODS: Lung-lavaged adult rats were
treated with aerosolized surfactant, aerosolized saline or a bolus of surfactant.
Surfactant was labelled with dimyristoylphosphatidylcholine (DMPC) and human
serum albumin was given intravenously for evaluation of lung protein leakage.
Blood gases and dynamic compliance were measured intermittently. At the end of
ventilation, the lungs were either fixed by vascular perfusion for histological
examination or washed for determination of total phospholipids, DMPC and human
albumin in the lavage fluid. RESULTS: Treatment with bolus surfactant led to a
quick and sustained restoration of pre-lavage blood gas values in most animals.
The response to aerosolized surfactant varied considerably, with an overall
moderate improvement of gas exchange. The saline-treated group failed to show any
significant recovery of lung function. No histopathological differences were
found between any of the groups. On average 0.46% of total administered
aerosolized surfactant could be recovered. Vascular-to-alveolar leakage of human
albumin averaged 11%, with no significant differences between the groups. Final
values for PaO2 were significantly correlated with total phospholipids in the
lavage fluid, and inversely related to the vascular-to-alveolar leakage of
albumin. CONCLUSION: Neither bolus nor aerosolized surfactant influenced lung
morphology. Nebulized surfactant improved lung function but the effect was
inferior to that obtained with bolus surfactant, and the outcome depended on the
balance between the combined pool size of exogenous and endogenous surfactant and
the vascular-to-alveolar leakage of serum protein.
PMID- 10786752
TI - Two instances of central nervous system toxicity in the same patient following
repeated ropivacaine-induced brachial plexus block.
AB - We describe two instances of central nervous system (CNS) toxicity in the same
patient following repeated brachial plexus blocks induced by high doses of
ropivacaine (6 mg x kg(-1) and 4.5 mg x kg(-1), respectively). Although very high
total and free plasma concentrations of ropivacaine were found up to 98 min after
induction of the blocks, no signs of cardiovascular toxicity apart from
hypertension and sinus tachycardia were observed. The measured plasma
concentrations are the highest so far reported in the literature. We conclude
that this case demonstrates the high cardiovascular safety level of ropivacaine.
These high doses, however, resulted in severe toxic CNS symptoms. Therefore, it
is stressed that the dose in relation to the weight of the patient must be
calculated when administering a large volume of local anesthetic.
PMID- 10786753
TI - Use of sevoflurane in difficult airways.
AB - Inhalational induction is one of the recognized methods for the management of
difficult airway. Halothane is the usual choice of agent for this purpose. The
relatively new agent sevoflurane, which is the least irritant of all the
available agents, is emerging as a choice of inhalational agent for both adult
and pediatric populations. There are various reports for and against the use of
sevoflurane for the management of difficult airway. We describe the use of
sevoflurane for the management of difficult airway in four patients presenting
with airway problems.
PMID- 10786754
TI - Reciprocating tachycardia during central venous cannulation in a patient with
Wolff-Parkinson-White syndrome.
AB - Wolff-Parkinson-White syndrome is important for the anesthesiologist because the
sudden development of tachyarrhythmias may result in deleterious hemodynamic
changes. We describe an episode of reciprocating tachycardia triggered by the
insertion of the guide wire during central venous cannulation in a patient with
this syndrome.
PMID- 10786755
TI - Infraclavicular approach to the brachial plexus.
PMID- 10786756
TI - Postoperative analgesia and rectal drug administration.
PMID- 10786758
TI - Affirmative action ignored
PMID- 10786757
TI - The effect of halothane on calcium release from human skinned masseter fiber is
not an artifact.
PMID- 10786759
TI - Wellcome in the dock.
PMID- 10786760
TI - Clean-up strategy at Australian nuclear site called into question
PMID- 10786761
TI - Middle East's synchrotron heads for Jordan.
PMID- 10786762
TI - Top physicist crosses to Boston in search of like minds
PMID- 10786763
TI - Critics blast US missile defence system as flawed
PMID- 10786764
TI - Women and ethnic minorities needed for US skills gap...
PMID- 10786765
TI - US energy agency sequences human chromosome trio.
PMID- 10786766
TI - Wellcome shoulders its share of blame for Oxford debacle.
PMID- 10786767
TI - A silence that speaks volumes.
PMID- 10786768
TI - Open-source work even more vital to genome project than to software.
PMID- 10786769
TI - Mayo and the mouse.
PMID- 10786771
TI - The paradigm and the pendulum
PMID- 10786770
TI - Mighty mice.
PMID- 10786772
TI - Respiration in the balance.
PMID- 10786773
TI - Cognitive neuroscience. Seeing in the sound zone.
PMID- 10786774
TI - Oxide-ion conductors by design
PMID- 10786775
TI - New guardians of the genome.
PMID- 10786776
TI - Neurobiology. A moving experience.
PMID- 10786777
TI - William Donald Hamilton (1936-2000)
PMID- 10786778
TI - Small bodies of the Solar System
PMID- 10786779
TI - Euler's disk and its finite-time singularity
PMID- 10786780
TI - Potential modulations along carbon nanotubes
PMID- 10786783
TI - Turbulent convection at very high Rayleigh numbers
AB - Turbulent convection occurs when the Rayleigh number (Ra)--which quantifies the
relative magnitude of thermal driving to dissipative forces in the fluid motion-
becomes sufficiently high. Although many theoretical and experimental studies of
turbulent convection exist, the basic properties of heat transport remain
unclear. One important question concerns the existence of an asymptotic regime
that is supposed to occur at very high Ra. Theory predicts that in such a state
the Nusselt number (Nu), representing the global heat transport, should scale as
Nu proportional to Ra(beta) with beta = 1/2. Here we investigate thermal
transport over eleven orders of magnitude of the Rayleigh number (10(6) < or = Ra
< or = 10(7)), using cryogenic helium gas as the working fluid. Our data, over
the entire range of Ra, can be described to the lowest order by a single power
law with scaling exponent beta close to 0.31. In particular, we find no evidence
for a transition to the Ra(1/2) regime. We also study the variation of internal
temperature fluctuations with Ra, and probe velocity statistics indirectly.
PMID- 10786782
TI - Rainforest fragmentation kills big trees.
PMID- 10786781
TI - Microbial essentials at hydrothermal vents.
PMID- 10786784
TI - Induction of visual orientation modules in auditory cortex.
AB - Modules of neurons sharing a common property are a basic organizational feature
of mammalian sensory cortex. Primary visual cortex (V1) is characterized by
orientation modules--groups of cells that share a preferred stimulus orientation-
which are organized into a highly ordered orientation map. Here we show that in
ferrets in which retinal projections are routed into the auditory pathway,
visually responsive neurons in 'rewired' primary auditory cortex are also
organized into orientation modules. The orientation tuning of neurons within
these modules is comparable to the tuning of cells in V1 but the orientation map
is less orderly. Horizontal connections in rewired cortex are more patchy and
periodic than connections in normal auditory cortex, but less so than connections
in V1. These data show that afferent activity has a profound influence on diverse
components of cortical circuitry, including thalamocortical and local
intracortical connections, which are involved in the generation of orientation
tuning, and long-range horizontal connections, which are important in creating an
orientation map.
PMID- 10786785
TI - Extended magnetic reconnection at the Earth's magnetopause from detection of bi
directional jets
AB - Magnetic reconnection is a process that converts magnetic energy into bi
directional plasma jets; it is believed to be the dominant process by which solar
wind energy enters the Earth's magnetosphere. This energy is subsequently
dissipated by magnetic storms and aurorae. Previous single-spacecraft
observations revealed only single jets at the magnetopause--while the existence
of a counter-streaming jet was implicitly assumed, no experimental confirmation
was available. Here we report in situ two-spacecraft observations of bi
directional jets at the magnetopause, finding evidence for a stable and extended
reconnection line; the latter implies substantial entry of the solar wind into
the magnetosphere. We conclude that reconnection is determined by large-scale
interactions between the solar wind and the magnetosphere, rather than by local
conditions at the magnetopause.
PMID- 10786786
TI - Statistical signatures of photon localization
AB - The realization that electron localization in disordered systems (Anderson
localization) is ultimately a wave phenomenon has led to the suggestion that
photons could be similarly localized by disorder. This conjecture attracted wide
interest because the differences between photons and electrons--in their
interactions, spin statistics, and methods of injection and detection--may open a
new realm of optical and microwave phenomena, and allow a detailed study of the
Anderson localization transition undisturbed by the Coulomb interaction. To date,
claims of three-dimensional photon localization have been based on observations
of the exponential decay of the electromagnetic wave as it propagates through the
disordered medium. But these reports have come under close scrutiny because of
the possibility that the decay observed may be due to residual absorption, and
because absorption itself may suppress localization. Here we show that the extent
of photon localization can be determined by a different approach--measurement of
the relative size of fluctuations of certain transmission quantities. The
variance of relative fluctuations accurately reflects the extent of localization,
even in the presence of absorption. Using this approach, we demonstrate photon
localization in both weakly and strongly scattering quasi-one-dimensional
dielectric samples and in periodic metallic wire meshes containing metallic
scatterers, while ruling it out in three-dimensional mixtures of aluminium
spheres.
PMID- 10786787
TI - Spontaneous macroscopic magnetization at the superconducting transition
temperature of YBa2Cu3O(7-delta)
AB - A noteworthy feature of the high-temperature superconductors is the
unconventional symmetry of the superconducting order parameter. Several
experiments have established that the order parameter has a four-fold d(x2 - y2)
symmetry under rotation of the lattice (the order parameter of conventional
superconductors is, in contrast, isotropic). An intriguing and much debated
possibility is that, in certain cases, an additional imaginary component might be
present, having an isotropic s-wave or d(xy) symmetry. A consequence of a complex
order parameter of the form d(x2 - y2) + id(xy) is that it would break both
reflection (parity, P) symmetry and time-reversal (T) symmetry, a clear signature
of which would be the spontaneous appearance of a macroscopic magnetization at
the superconducting transition temperature. Broken T symmetry has been reported,
but searches for the effects of combined P and T symmetry breaking have so far
yielded null results. Here we report the observation of a weak (approximately 10(
5) gauss) magnetic field that appears spontaneously at the superconducting
transition temperature of epitaxial thin films of YBa2Cu3O(7-delta). The magnetic
signal originates near the edges of the samples. One interpretation for this
observation is that the order parameter carries an intrinsic angular momentum,
related to the breaking of P and T symmetries, but other possibilities cannot yet
be excluded.
PMID- 10786788
TI - Designing fast oxide-ion conductors based on La2Mo2O9
AB - The ability of solid oxides to conduct oxide ions has been known for more than a
century, and fast oxide-ion conductors (or oxide electrolytes) are now being used
for applications ranging from oxide fuel cells to oxygen pumping devices. To be
technologically viable, these oxide electrolytes must exhibit high oxide-ion
mobility at low operating temperatures. Because of the size and interaction of
oxygen ions with the cationic network, high mobility can only be achieved with
classes of materials with suitable structural features. So far, high mobility has
been observed in only a small number of structural families, such as fluorite,
perovskites, intergrowth perovskite/Bi2O2 layers and pyrochlores. Here we report
a family of solid oxides based on the parent compound La2Mo2O9 (with a different
crystal structure from all known oxide electrolytes) which exhibits fast oxide
ion conducting properties. Like other ionic conductors, this material undergoes a
structural transition around 580 degrees C resulting in an increase of conduction
by almost two orders of magnitude. Its conductivity is about 6 x 10(-2) S cm(-1)
at 800 degrees C, which is comparable to that of stabilized zirconia, the most
widely used oxide electrolyte. The structural similarity of La2Mo2O9 with beta
SnWO4 (ref. 14) suggests a structural model for the origin of the oxide-ion
conduction. More generally, substitution of a cation that has a lone pair of
electrons by a different cation that does not have a lone pair--and which has a
higher oxidation state--could be used as an original way to design other oxide
ion conductors.
PMID- 10786789
TI - Evidence that decomposition rates of organic carbon in mineral soil do not vary
with temperature.
AB - It has been suggested that increases in temperature can accelerate the
decomposition of organic carbon contained in forest mineral soil (Cs), and,
therefore, that global warming should increase the release of soil organic carbon
to the atmosphere. These predictions assume, however, that decay constants can be
accurately derived from short-term laboratory incubations of soil or that in situ
incubations of fresh litter accurately represent the temperature sensitivity of
Cs decomposition. But our limited understanding of the biophysical factors that
control Cs decomposition rates, and observations of only minor increases in Cs
decomposition rate with temperature in longer-term forest soil heating
experiments and in latitudinal comparisons of Cs decomposition rates bring these
predictions into question. Here we have compiled Cs decomposition data from 82
sites on five continents. We found that Cs decomposition rates were remarkably
constant across a global-scale gradient in mean annual temperature. These data
suggest that Cs decomposition rates for forest soils are not controlled by
temperature limitations to microbial activity, and that increased temperature
alone will not stimulate the decomposition of forest-derived carbon in mineral
soil.
PMID- 10786790
TI - Respiration as the main determinant of carbon balance in European forests.
AB - Carbon exchange between the terrestrial biosphere and the atmosphere is one of
the key processes that need to be assessed in the context of the Kyoto Protocol.
Several studies suggest that the terrestrial biosphere is gaining carbon, but
these estimates are obtained primarily by indirect methods, and the factors that
control terrestrial carbon exchange, its magnitude and primary locations, are
under debate. Here we present data of net ecosystem carbon exchange, collected
between 1996 and 1998 from 15 European forests, which confirm that many European
forest ecosystems act as carbon sinks. The annual carbon balances range from an
uptake of 6.6 tonnes of carbon per hectare per year to a release of nearly 1 t C
ha(-1) yr(-1), with a large variability between forests. The data show a
significant increase of carbon uptake with decreasing latitude, whereas the gross
primary production seems to be largely independent of latitude. Our observations
indicate that, in general, ecosystem respiration determines net ecosystem carbon
exchange. Also, for an accurate assessment of the carbon balance in a particular
forest ecosystem, remote sensing of the normalized difference vegetation index or
estimates based on forest inventories may not be sufficient.
PMID- 10786791
TI - Determination of relative growth rates of natural quartz crystals
AB - Although the theory describing crystal growth in the geological environment is
well established, there are few quantitative studies that delimit the absolute
time involved in the growth of natural crystals. The actual mechanisms
responsible for the variation in size and shape of individual crystal faces are,
in fact, not well understood. Here we describe a micro-infrared spectroscopic
study of a single, gem-quality quartz crystal that allows us to measure the size,
shape and relative growth rate of each of the crystal faces that are active
throughout its growth history. We demonstrate that the abundances of hydrogen
bearing impurities can serve as 'speedometers' to monitor the growth rate of
advancing crystal faces. Our technique can be applied to crystals from a variety
of geological environments to determine their growth histories. Within the
electronics industry, the technique might facilitate the production of defect
free synthetic crystals required for high-quality resonators and, ultimately,
might allow determination of the absolute time involved in geological processes
such as the crystallization of magmas, fluid flow in metamorphism and the sealing
of open cracks in earthquake rupture zones.
PMID- 10786792
TI - Insurance-based advantage to helpers in a tropical hover wasp.
AB - The origin and maintenance of eusociality is a central problem in evolutionary
biology. Eusocial groups contain individuals that forfeit their own reproduction
in order to help others reproduce. In facultatively eusocial taxa, offspring can
choose whether to found new nests or become helpers in their natal groups. In
many facultatively eusocial insects, offspring need continuous care during
development, but adult carers have life expectancies shorter than the
developmental period. When a lone foundress dies, her partly reared brood are
usually doomed. Here, we show that helpers in a tropical hover wasp
(Liostenogaster flavolineata) have an insurance-based advantage over lone
foundresses because after a helper dies, most of the brood that she has partly
reared will be brought to maturity by surviving nest-mates. After some of the
helpers are experimentally removed from a multi-female nest, the reduced group is
left with more brood than it would normally rear. We found that larger, more
valuable extra brood were reared through to maturity, but not smaller, less
valuable brood. Smaller brood may be sacrificed to feed larger brood, and reduced
groups probably benefited from increased short-term helper recruitment. Rearing
extra brood did not increase adult mortality or brood development time.
PMID- 10786793
TI - Visual behaviour mediated by retinal projections directed to the auditory
pathway.
AB - An unresolved issue in cortical development concerns the relative contributions
of intrinsic and extrinsic factors to the functional specification of different
cortical areas. Ferrets in which retinal projections are redirected neonatally to
the auditory thalamus have visually responsive cells in auditory thalamus and
cortex, form a retinotopic map in auditory cortex and have visual receptive field
properties in auditory cortex that are typical of cells in visual cortex. Here we
report that this cross-modal projection and its representation in auditory cortex
can mediate visual behaviour. When light stimuli are presented in the portion of
the visual field that is 'seen' only by this projection, 'rewired' ferrets
respond as though they perceive the stimuli to be visual rather than auditory.
Thus the perceptual modality of a neocortical region is instructed to a
significant extent by its extrinsic inputs. In addition, gratings of different
spatial frequencies can be discriminated by the rewired pathway, although the
grating acuity is lower than that of the normal visual pathway.
PMID- 10786795
TI - Ion permeation mechanism of the potassium channel.
AB - Ion-selective channels enable the specific permeation of ions through cell
membranes and provide the basis of several important biological functions; for
example, electric signalling in the nervous system. Although a large amount of
electrophysiological data is available, the molecular mechanisms by which these
channels can mediate ion transport remain a significant unsolved problem. With
the recently determined crystal structure of the representative K+ channel (KcsA)
from Streptomyces lividans, it becomes possible to examine ion conduction
pathways on a microscopic level. K+ channels utilize multi-ion conduction
mechanisms, and the three-dimensional structure also shows several ions present
in the channel. Here we report results from molecular dynamics free energy
perturbation calculations that both establish the nature of the multiple ion
conduction mechanism and yield the correct ion selectivity of the channel. By
evaluating the energetics of all relevant occupancy states of the selectivity
filter, we find that the favoured conduction pathway involves transitions only
between two main states with a free difference of about 5 kcal mol(-1). Other
putative permeation pathways can be excluded because they would involve states
that are too high in energy.
PMID- 10786794
TI - Experience-dependent plasticity of dendritic spines in the developing rat barrel
cortex in vivo.
AB - Do changes in neuronal structure underlie cortical plasticity? Here we used time
lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat
barrel cortex to image the structural dynamics of dendritic spines and filopodia.
We found that these protrusions were highly motile: spines and filopodia
appeared, disappeared or changed shape over tens of minutes. To test whether
sensory experience drives this motility we trimmed whiskers one to three days
before imaging. Sensory deprivation markedly (approximately 40%) reduced
protrusive motility in deprived regions of the barrel cortex during a critical
period around postnatal days (P)11-13, but had no effect in younger (P8-10) or
older (P14-16) animals. Unexpectedly, whisker trimming did not change the
density, length or shape of spines and filopodia. However, sensory deprivation
during the critical period degraded the tuning of layer 2/3 receptive fields.
Thus sensory experience drives structural plasticity in dendrites, which may
underlie the reorganization of neural circuits.
PMID- 10786796
TI - CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium
tuberculosis infection.
AB - The discovery of the CD1 antigen presentation pathway has expanded the spectrum
of T-cell antigens to include lipids, but the range of natural lipid antigens and
functions of CD1-restricted T cells in vivo remain poorly understood. Here we
show that the T-cell antigen receptor and the CD1c protein mediate recognition of
an evolutionarily conserved family of isoprenoid glycolipids whose members
include essential components of protein glycosylation and cell-wall synthesis
pathways. A CD1c-restricted, mycobacteria-specific T-cell line recognized two
previously unknown mycobacterial hexosyl-1-phosphoisoprenoids and structurally
related mannosyl-beta1-phosphodolichols. Responses to mannosyl-beta1
phosphodolichols were common among CD1c-restricted T-cell lines and peripheral
blood T lymphocytes of human subjects recently infected with M. tuberculosis, but
were not seen in naive control subjects. These results define a new class of
broadly distributed lipid antigens presented by the CD1 system during infection
in vivo and suggest an immune mechanism for recognition of senescent or
transformed cells that are known to have altered dolichol lipids.
PMID- 10786797
TI - Integration of floral inductive signals in Arabidopsis.
AB - Flowering of Arabidopsis is regulated by a daylength-dependent pathway that
accelerates flowering in long days and a daylength-independent pathway that
ensures flowering in the absence of inductive conditions. These pathways are
genetically separable, as there are mutations that delay flowering in long but
not short days. Conversely, mutations that block synthesis of the hormone
gibberellin abolish flowering in short days, but have on their own only a minor
effect in long days. A third pathway, the autonomous pathway, probably acts by
modulating the other two pathways. Understanding where and how these pathways are
integrated is a prerequisite for understanding why similar environmental or
endogenous cues can elicit opposite flowering responses in different plants. In
Arabidopsis, floral induction leads ultimately to the upregulation of floral
meristem-identity genes such as LEAFY, indicating that floral inductive signals
are integrated upstream of LEAFY Here we show that gibberellins activate the
LEAFY promoter through cis elements that are different from those that are
sufficient for the daylength response, demonstrating that the LEAFY promoter
integrates environmental and endogenous signals controlling flowering time.
PMID- 10786800
TI - Single-molecule analysis of DNA uncoiling by a type II topoisomerase.
AB - Type II DNA topoisomerases are ubiquitous ATP-dependent enzymes capable of
transporting a DNA through a transient double-strand break in a second DNA
segment. This enables them to untangle DNA and relax the interwound supercoils
(plectonemes) that arise in twisted DNA. In vivo, they are responsible for
untangling replicated chromosomes and their absence at mitosis or meiosis
ultimately causes cell death. Here we describe a micromanipulation experiment in
which we follow in real time a single Drosophila melanogaster topoisomerase II
acting on a linear DNA molecule which is mechanically stretched and supercoiled.
By monitoring the DNA's extension in the presence of ATP, we directly observe the
relaxation of two supercoils during a single catalytic turnover. By controlling
the force pulling on the molecule, we determine the variation of the reaction
rate with the applied stress. Finally, in the absence of ATP, we observe the
damping of a DNA crossover by a single topoisomerase on at least two different
timescales (configurations). These results show that single molecule experiments
are a powerful new tool for the study of topoisomerases.
PMID- 10786798
TI - Role of NF-kappaB in p53-mediated programmed cell death.
AB - The tumour suppressor p53 inhibits cell growth through activation of cell-cycle
arrest and apoptosis, and most cancers have either mutation within the p53 gene
or defects in the ability to induce p53. Activation or re-introduction of p53
induces apoptosis in many tumour cells and may provide effective cancer therapy.
One of the key proteins that modulates the apoptotic response is NF-kappaB, a
transcription factor that can protect or contribute to apoptosis. Here we show
that induction of p53 causes an activation of NF-kappaB that correlates with the
ability of p53 to induce apoptosis. Inhibition or loss of NF-kappaB activity
abrogated p53-induced apoptosis, indicating that NF-kappaB is essential in p53
mediated cell death. Activation of NF-kappaB by p53 was distinct from that
mediated by tumour-necrosis factor-alpha and involved MEK1 and the activation of
pp90rsk. Inhibition of MEK1 blocked activation of NF-kappaB by p53 and completely
abrogated p53-induced cell death. We conclude that inhibition of NF-kappaB in
tumours that retain wild-type p53 may diminish, rather than augment, a
therapeutic response.
PMID- 10786801
TI - Histopathologic features of Burkholderia cepacia pneumonia in patients without
cystic fibrosis.
AB - We present the histopathologic features of fatal Burkholderia cepacia pneumonia
in three adults (one man [age 44 years] and two women [aged 40 and 43 years]). In
all patients, the pulmonary infiltrates initially were localized (right middle
lobe, left upper lobe, and right middle lobe) but rapidly progressed. Two open
lung biopsies and one pneumonectomy specimen showed necrotizing granulomatous
inflammation merging with areas of more conventional necrotizing bronchopneumonia
In one patient, a mediastinal lymph node also showed stellate necrotizing
granulomas. Vasculitis was absent. B. cepacia was cultured from the open-lung
biopsies and bronchial wash specimens in two patients and from postmortem
cultures of lung, subcarinal lymph nodes, and blood in the third. The
histopathology in these patients resembles that of melioidosis, which is caused
by a related organism, Burkholderia pseudomallei. B. cepacia needs to be
considered in the differential diagnosis of necrotizing granulomatous
inflammation. In addition, given the rarity with which B. cepacia is identified
as a cause of pneumonia in the immunocompetent host, isolation of B. cepacia
should trigger a workup for underlying immunodeficiency or lead to an
investigation to exclude the possibility of a nosocomial infection.
PMID- 10786799
TI - Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability
and development.
AB - XRCC4 is a non-homologous end-joining protein employed in DNA double strand break
repair and in V(D)J recombination. In mice, XRCC4-deficiency causes a pleiotropic
phenotype, which includes embryonic lethality and massive neuronal apoptosis.
When DNA damage is not repaired, activation of the cell cycle checkpoint protein
p53 can lead to apoptosis. Here we show that p53-deficiency rescues several
aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal
apoptosis, and impaired cellular proliferation. However, there was no significant
rescue of impaired V(D)J recombination or lymphocyte development. Although p53
deficiency allowed postnatal survival of XRCC4-deficient mice, they routinely
succumbed to pro-B-cell lymphomas which had chromosomal translocations linking
amplified c-myc oncogene and IgH locus sequences. Moreover, even XRCC4-deficient
embryonic fibroblasts exhibited marked genomic instability including chromosomal
translocations. Our findings support a crucial role for the non-homologous end
joining pathway as a caretaker of the mammalian genome, a role required both for
normal development and for suppression of tumours.
PMID- 10786802
TI - Polymorphism at codon 72 of p53 is not associated with cervical cancer risk.
AB - P53 allelic polymorphism at codon 72 has been studied as a possible predisposing
factor for cervical carcinogenesis with inconsistent results. Storey and
colleagues recently published the interesting finding of a 7-fold increased risk
for cervical cancer in women homozygous for the arginine allele at codon 72. This
stimulated a number of independent investigations, the majority of which found no
association of cervical cancer and arginine homozygosity. With the use of a
modified Storey method for determining codon 72 allelotypes, DNA was examined
from 431 microdissected, formalin-fixed, archival cervical conization specimens
ranging from low-grade squamous lesions to invasive cancer. An alternative
independent method using restriction fragment length polymorphism analysis was
performed on all arginine homozygotes and all indeterminate cases for
confirmation and final allelotype assignment. With the use of Storey's method
alone, logistic regression suggested an association (odds ratio, 1.42) between
arginine homozygosity and invasive disease. However, with the use of the combined
method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the
discordance was clearly resolvable as being due to methodologic variables. With
the use of two separate methods for codon 72 allelotyping and accounting for a
number of the issues raised in previously published reports, there is no
increased risk for invasive cervical cancer associated with arginine homozygosity
at codon 72 of p53.
PMID- 10786804
TI - Metallothionein in pancreatic endocrine neoplasms.
AB - Metallothioneins (MTs) are intracellular proteins that bind to metal ions and are
involved in heavy metal homeostasis and detoxification. Pancreatic islets were
shown to be positive for zinc-containing matrix metalloproteinase-2 and -9 by
immunocytochemical staining. The immunolocalization of matrix metalloproteinases
in pancreatic islets prompted us to study further the link between zinc and MT in
34 cases of pancreatic endocrine neoplasms, including insulinomas, glucagonomas,
gastrinomas, pancreatic polypeptide-omas, and non-functioning endocrine
neoplasms. Four types of islet cells were found to be positive for MT, whereas
pancreatic endocrine neoplasms mostly were either weakly positive or negative for
MT. The presence of MT in normal islet cells and pancreatic endocrine neoplasms
is consistent with the notion that MTs modulate zinc homeostasis and metabolism
in pancreatic islet cells and pancreatic endocrine neoplasms as those tissues
contain zinc-containing matrix metalloproteinases.
PMID- 10786803
TI - Immunohistochemical profile of endometrial adenocarcinoma: a study of 61 cases
and review of the literature.
AB - The differences in immunohistochemical expression of p53, bcl-2, bax, estrogen
receptor (ER), and progesterone receptor (PR) were evaluated in 40 endometrioid
and 21 papillary serous carcinomas of endometrium and correlated with known
predictors of survival, such as grade and stage. Uterine papillary serous
adenocarcinomas (UPSA) showed significantly higher p53 expression than did
uterine endometrioid adenocarcinomas (UEA) (76.2% versus 35%), whereas both ER
and PR were more often positive in endometrioid than in serous tumors (p = .005
and .0005). No significant difference was found in bcl-2 and bax expression
between both histologic types. However, there was definite decrease in intensity
of bcl-2 in UPSA compared with UEA. In endometrioid carcinoma, p53 overexpression
was associated with high-grade and advanced-stage tumors (p = .0006 and .006),
whereas ER and PR expression was associated with low-grade and early-stage tumors
(p = .0006 and .0001; p = .003 and .0006). Bcl-2 immunopositivity was more common
in low-grade, early-stage rather than in high-grade, advanced-stage
adenocarcinomas, but the difference was not statistically significant (p = .24
and .07). Bax immunopositivity was associated with well-differentiated (p = .04)
and early-stage tumors. Furthermore, a significant inverse relationship between
bax and p53 reactivity was defined (p = .05), especially in tumors of
endometrioid type. Bax and PR immunoexpression correlated near the limit of
statistical significance (p = .08), whereas no relationship was found among bax,
bcl-2, and ER immunopositivity. Our results indicate that the differences in
immunohistochemical profiles of endometrioid and serous carcinomas support the
existence of different molecular pathways of their development. The correlation
of immunohistochemical findings with histologic grade and clinical stage could
help in predicting biologic behavior and planning treatment in patients who are
diagnosed as having these tumors.
PMID- 10786806
TI - Assessing the expression of two genes simultaneously in surgical specimens using
polymerase chain reaction.
AB - We developed a novel polymerase chain reaction (PCR)-based method to analyze
simultaneously the relative expression of two genes in a single PCR reaction. The
method, relational PCR (R-PCR), utilizes special PCR primers that enable a PCR
reaction to be converted from a standard uniplex reaction to a multiplex reaction
in which all products are dependent on the same reaction components for
amplification. We show that the quantitative ability of R-PCR is unaffected by
sample nucleic acid input concentration over a range of 25-fold (30 to 750 ng of
total RNA) and demonstrate excellent interexperimental reproducibility. We used R
PCR to analyze estrogen receptor gene expression in a series of invasive breast
carcinomas, and our results show an excellent correlation between estrogen
receptor mRNA expression and protein product accumulation determined by standard
immunocytochemistry on paraffin sections.
PMID- 10786805
TI - Expression of DNA topoisomerase IIalpha in thyroid neoplasia.
AB - Topoisomerase II (topo II) is an enzyme that affects replication, transcription,
and chromosome segregation. It serves as a target for several useful
antichemotherapeutic agents, such as etoposide (VP-16) and teniposide (VM26).
Monoclonal antibody topo IIalpha (Clone JH2.7; Neomarkers, Union City, CA)
specifically identifies the alpha isoform of topo II. Using this antibody in an
immunohistochemical analysis, we studied differential expression of topo II in a
variety of thyroid lesions. The topo II labeling index is defined as the number
of topo II staining positive nuclei divided by the total number of tumor cells
counted multiplied by 100. An average of 1,000 cells were counted in each case.
The average labeling indexes for anaplastic carcinoma (7.8), tall cell variant of
papillary carcinoma (4.8), follicular carcinoma (2.6), Hurthle cell carcinoma
(3.4), and medullary carcinoma (2.4) were much higher than for papillary
carcinoma (0.76), follicular adenoma (0.65), Hurthle cell adenoma (0.32), and
normal thyroid (0.1). This study suggests that immunohistochemical analysis of
topo II correlates with thyroid tumor histology; it is more frequently expressed
in tumors that are associated with aggressive clinical behavior. It may help to
define a role for anti-topoisomerase drugs in treatment of aggressive thyroid
neoplasms.
PMID- 10786807
TI - Effects of multidrug resistance gene expression in acute erythroleukemia.
AB - Acute erythroleukemia is a relatively rare disorder of a multilineal nature.
Patients with this type of leukemia traditionally have been treated with a
standard myeloid protocol, with a wide variation in prognosis between M6a, which
has a similar prognosis to acute myelogenous leukemias, and M6b, with an
extremely poor outcome despite aggressive therapy. Forty-eight archival cases of
acute erythroleukemia, subtypes M6a (the traditional FAB-M6), M6b (pure
erythroleukemia), and M6c (>30% myeloblasts and >30% pronormoblasts by FAB
exclusion criteria), were evaluated for multidrug resistance gene (MDR-1) status.
Findings were correlated with clinical course and karyotypes. Immunohistochemical
stain for the protein product of MDR-1, P-glycoprotein, was variably positive in
11 of 23 patients with M6a, as well as in all of the patients with M6b (strongly
positive) and M6c (weakly positive). P-glycoprotein expression positively
correlated with unfavorable cytogenetic aberrations, poor response to
chemotherapeutic agents, and short survival. Most significant was that P
glycoprotein expression demonstrated a negative additive effect on response to
treatment and prognosis with unfavorable cytogenetic anomalies. P-glycoprotein
expression and multiple cytogenetic anomalies most probably contribute to the
resistance to chemotherapy and poor survival characteristic of the patients with
M6b (mean survival, 3.15 +/- 4.2 mo) and M6c (mean survival, 10.5 +/- 12.7 mo).
Because patients with M6b and M6c have increased numbers of pronormoblasts in
their bone marrow and past chemotherapeutic attempts have failed, chemotherapy
directed at these cells is appropriate. Additional therapy directed toward the
MDR-1 gene and its protein product seems indicated from our findings.
PMID- 10786808
TI - Sinus histiocytosis with massive lymphadenopathy and malignant lymphoma involving
the same lymph node: a report of four cases and review of the literature.
AB - Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai
Dorfman disease, is a disorder of unknown cause. Rarely, patients with SHML also
have malignant lymphoma, usually involving anatomic sites different from those
involved by SHML We report four patients in whom SHML and malignant lymphoma were
identified in the same lymph node biopsy specimen. The SHML in each case was
present as a small focus, less than 1 cm. Immunohistochemical studies showed that
the abnormal histiocytes were positive for S-100 and negative for CD1a. The
malignant lymphomas included two cases of follicular lymphoma and two cases of
Hodgkin's disease, nodular lymphocyte predominant type. The presence of SHML in
these patients did not impact clinical decisions, and there was no evidence of
SHML elsewhere. Thus, the presence of focal SHML associated with malignant
lymphoma in these cases was an incidental histologic finding that seems not to
have had any clinical significance.
PMID- 10786810
TI - Comparison of oncostatin M expression in keratoacanthoma and squamous cell
carcinoma.
AB - Oncostatin M (OSM) is a 28-kDa glycoprotein, produced by stimulated macrophages
and T lymphocytes, that inhibits the proliferation and induces differentiation of
a number of different cell lines derived from solid tumors. To determine whether
keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC), we
compared the immunohistochemical expression of OSM in the tumor cells and peri-
and intratumoral macrophages of 21 mature KAs, 7 regressing KAs, and 27 SCCs. An
inverse correlation was identified between OSM tumor labeling and the density of
OSM-labeled tumor-associated macrophages for KAs (r = -.4; P = .09). OSM tumor
expression was significantly more frequent and more intense in KAs than in SCCs
(95% versus 63%; P < .01). In contrast, the density of OSM-labeled macrophages
was significantly higher in SCCs compared with mature KAs (7/3 high power fields
versus 4/3 high power fields; P = .02). These OSM-positive macrophages were
predominantly located at the advancing, infiltrative margins of both neoplasms.
Regressing KAs demonstrated a decreased level of OSM tumor expression compared
with mature KAs (53% versus 95%; P = .001), but there was no difference in
density of OSM-labeled macrophages. Both the above differences and the
overlapping patterns of OSM expression suggest that KAs are a variant of SCC
where OSM, possibly as an autocrine factor, may mediate KA's overwhelming but not
absolute tendency to involute.
PMID- 10786812
TI - Immunohistochemical detection of Bcl-2 in Kaposi's sarcoma lesions varies
according to histopathologic stage, whereas expression of Bcl-x and Mcl-1 differs
according to human immunodeficiency virus serologic status of patients.
AB - Expression of Bcl-2, Bcl-x, and Mcl-1 was immunohistochemically evaluated in 33
cases of Kaposi's sarcoma (KS) of the skin. Of these, classic KS (C-KS) accounted
for 17 cases (10 in plaque stage and 7 in tumor stage) and acquired
immunodeficiency syndrome-associated KS (AIDS-KS) accounted for 16 cases (8 in
plaque stage and 8 in tumor stage). In both C-KS and AIDS-KS, Bcl-2
immunoreaction correlated with progression stage, its average score intensity
being more than 2-fold in tumors than in plaques. In contrast, Bcl-x and Mcl-1
staining intensity was unrelated to progression stage but was dependent on human
immunodeficiency virus infection status. Thus, whereas Bcl-x expression was
stronger in C-KS cases, Mcl-1 immunostaining was more intense in AIDS-KS
instances. These findings indicate that in cutaneous KS, some Bcl-2 family
proteins exhibit differential expressions that are dependent on either
progression stage or human immunodeficiency virus infection status.
PMID- 10786811
TI - FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma.
AB - Kaposi's sarcoma (KS) is a vascular tumor, the pathogenesis of which has been
suggested to include human herpesvirus 8 (HHV-8) as well as various cytokines and
growth factors. Very little is known about cytogenetic and molecular genetic
changes in KS. We studied DNA copy number changes in KS and found a recurrent
gain at 11q13. We then analyzed the amplification and expression status of two
known oncogenes, FGF4 and INT2, residing at 11q13. Comparative genomic
hybridization, interphase fluorescence in situ hybridization with yeast
artificial chromosome probes containing FGF4 and INT2, and immunoperoxidase
immunostaining with anti-FGF4 and -INT2 antibodies were used on 12 KS samples.
All samples tested were shown by polymerase chain reaction to be HHV-8 positive.
A recurrent gain at 11q13 was shown by comparative genomic hybridization in 4 of
10 cases studied. Of six cases studied by interphase fluorescence in situ
hybridization, four showed a 3- to 4-fold amplification with the probes
containing FGF4 and INT2. Expression of FGF4 and INT2 was found in nine and three
cases, respectively, of nine studied. Amplification and expression of these genes
is particularly interesting in the context of oncovirus involvement, because INT2
is a homolog of mouse int2 which causes mammary carcinoma in mice when activated
by integration of retrovirus mouse mammary tumor virus. This raises the question
of whether HHV-8 represents an integrating oncovirus that causes amplification
and activation of genomic oncogenes in humans.
PMID- 10786809
TI - Ubiquitin immunochemistry as a diagnostic aid for community pathologists
evaluating patients who have dementia.
AB - Alzheimer's disease is the most common cause of dementia It is associated with
genetic risk factors and at least three autosomal dominant mutations. Community
pathologists are frequently asked by families to evaluate autopsy material for
Alzheimer's disease. Neuropathologic diagnosis is based on technically difficult
silver impregnation stains that may not be readily available to community-based
pathologists. Because immunohistochemical techniques are more widely accessible,
we evaluated the practical utility of using a single immunohistochemical stain
for diagnosing Alzheimer's disease. The ubiquitin antigen was selected because of
its presence in morphologically distinct deposits characteristic of several
neurodegenerative diseases. Paraffin blocks were obtained from the Bryan
Alzheimer's Disease Research Center Brain Bank, a repository of approximately 900
brains. Tissues from 16 individuals who exhibited the entire range of Alzheimer's
type neuropathology were selected. Ubiquitin immunostains, evaluated blindly and
independently by four pathologists ranging from first-year resident trainee to
experienced neuropathologist, reliably stained both neuritic plaques and
neurofibrillary tangles essential for diagnosing and staging Alzheimer's disease.
Nondemented controls with early Alzheimer's-type changes were easily
distinguished from cases of definitive Alzheimer's disease. The stains also
highlighted characteristic inclusions of Parkinson's disease or Lewy body
dementia Ubiquitin immunohistochemistry is a reliable, reproducible, and readily
available diagnostic aid for distinguishing Alzheimer's disease from other causes
of dementia.
PMID- 10786814
TI - Immunoreactivity of MIC2 (CD99) in acute myelogenous leukemia and related
diseases.
AB - MIC2 is characteristically expressed in lymphoblastic lesions and
Ewing's/primitive neuroectodermal tumor sarcomas. Although MIC2 has recently been
reported in chloroma and rare terminal deoxynucleotidyl transferase-positive
acute myelogenous leukemia (AML), the incidence and the significance of MIC2
(CD99) immunoreactivity in myeloid lesions is not clear. In this study, we
evaluated MIC2 positivity in a variety of myeloid diseases and normal marrow to
determine its incidence and distribution in myeloid diseases; its correlation
with flow cytometric and cytogenetic data in AML; and its association with
leukemic transformation, relapse, and chloroma formation. Paraffin sections of 11
chloromas and 94 bone marrow core biopsies from 66 patients were stained with
CD99 monoclonal antibody 12E7. Of 94 bone marrow core biopsies, there were 30 AML
(fragment antigen binding M0 to M6), 23 remissions, 5 relapses, 12
myeloproliferative disorders, 13 myelodysplastic syndromes, and 11 normal marrows
from patients who did not have leukemia. CD99 immunoreactivity was evaluated with
light microscopy. MIC2 expression was seen in leukemic blasts in 6 of 11
chloromas (55%) and 13 of 30 AML (43%) but rarely in myeloproliferative
disorders, myelodysplastic syndromes, remission, and normal marrow. CD99 tended
to be positive in M1-, M3-, and HLA-Dr-negative AML and negative in AML with
relapse. MIC2 expression did not correlate with the karyotype independent of
French-American-British Cooperative Group classification and the disease
remission or occurrence of chloroma in AML. We concluded that MIC2 is commonly
expressed in leukemic blasts of AML and is not predictive of leukemic
transformation from myeloproliferative disorders and myelodysplastic syndromes or
chloroma formation. Caution should be taken when using MIC2 as a marker for
Ewing's sarcoma/ primitive neuroectodermal tumor or lymphoblastic lymphoma on
paraffin sections of either soft tissue or bone marrow specimens.
PMID- 10786813
TI - Immunohistochemical analysis of CD30-positive lymphoproliferative disorders for
expression of CD95 and CD95L.
AB - Primary cutaneous (PC) CD30-positive large cell lymphoma and lymphomatoid
papulosis (LyP) represent the spectrum of PC CD30-positive lymphoproliferative
disorders (LPDs) associated with a favorable prognosis. Noncutaneous CD30
positive anaplastic large cell lymphoma (ALCL), although morphologically similar
to PC CD30-positive LPDs, seems to be a biologically distinct entity. Cell lines
derived from noncutaneous ALCL express CD95 and undergo CD95-induced apoptosis.
Little is known about expression or function of CD95/CD95L in cutaneous lesions.
We examined a series of PC CD30-positive LPDs and noncutaneous ALCL for
expression of CD95/CD95L to investigate possible differences between these
histologically similar but biologically distinct entities. Paraffin-embedded,
formalin-fixed tissue sections from 25 cases of CD30-positive LPDs (10
noncutaneous ALCL, 15 PC CD30-positive LPDs) were immunostained for CD3, CD20
(L26), CD43 (Leu22), CD30 (BerH2), anaplastic lymphoma kinase (ALK-1), CD95, and
CD95L (C-33). One hundred large atypical cells and 100 small lymphocytes were
counted to determine the percentage of CD95/ CD95L-positive cells. Statistical
analysis using the Mann-Whitney U test was performed. CD95 expression was
slightly higher in the large atypical cells of noncutaneous ALCL compared with PC
CD30-positive LPDs (median, 100% versus 94%; P = .003) because of the lower
expression of CD95 in LyP. CD95L expression was higher in the surrounding small
lymphocytes in PC CD30-positive LPDs (median, 3% versus 13%; P = .002).
Expression of CD95 in the small lymphocytes and CD95L in the large atypical cells
was not significantly different. These results support the biologic distinction
between cutaneous and noncutaneous CD30-positive LPDs and may have implications
in the differing clinical behavior of these entities. Further study of expression
and function of apoptosis-related proteins in these entities is warranted.
PMID- 10786815
TI - Immunoreactivity with the anti-MAGE antibody 57B in malignant melanoma: frequency
of expression and correlation with prognostic parameters.
AB - The melanoma-associated antigen (MAGE) family consists of a number of antigens
initially recognized by cytotoxic T lymphocytes, which are currently being
investigated for immunotherapy of patients with metastatic melanoma and other
tumor types. Expression of MAGE mRNA in melanocytic tumors is said to be
restricted to invasive malignant tumors and absent in nevi. Recently, a
monoclonal antibody (57B) has become available to examine MAGE protein expression
in archival material. In this study, we performed immunohistochemical analysis on
132 melanocytic nevi and 205 melanomas (85 primary cutaneous melanomas and 120
metastatic tumors) to determine the frequency of MAGE expression and to explore a
potential correlation with various prognostic parameters. None of the melanocytic
nevi and none of the 20 in situ melanomas was immunopositive with the antibody
57B. Immunoreactivity was present in 17 of 65 (26%) primary invasive melanomas of
the skin and in 30 of 120 (25%) metastatic tumors. Positive immunostaining did
not correlate with tumor stage (P = .66), Breslow thickness (P = .39), Clark
level (P = .5), or the histologic type of melanoma (P = .23) but was associated
with a brisk infiltrate of lymphocytes involving the vertical growth phase of
melanomas (P = .01). Because tumor-infiltrating lymphocytes in melanoma are
associated with longer survival, our findings suggest a potential prognostic role
for MAGE. Furthermore, the seeming restriction of immunopositivity to invasive
malignant tumors suggests a potential diagnostic role for the antibody 57B in
confirming the malignant potential of a melanocytic tumor.
PMID- 10786816
TI - Malignant ovarian sex cord tumor with annular tubules in a patient with Peutz
Jeghers syndrome: a case report.
AB - The majority of ovarian sex cord tumors with annular tubules (SCTAT) are benign
neoplasms that arise sporadically. In patients who have Peutz-Jeghers syndrome
(PJS), ovarian SCTAT is often an incidental finding. Malignant behavior in SCTAT
has heretofore been reported only in sporadic cases. We report a case of
bilateral, malignant SCTAT developing in a 47-year-old woman who had PJS,
originally diagnosed as adenocarcinoma on cervicovaginal cytology. Cervicovaginal
and peritoneal fluid cytologic preparations were characterized by pseudopapillary
clusters and three-dimensional tubes of tumor cells with scanty cytoplasm and
high nuclear: cytoplasmic ratio. Examination of surgical resection specimens
revealed bilateral, solid ovarian tumors composed of simple and complex annular
tubules with hyaline cores, typical of SCTAT. Tumor emboli were present within
salpingeal lymphovascular spaces and in both right and left pelvic lymph nodes.
Flow cytometry of tumor cells demonstrated a diploid phenotype. This case
represents the first documented example of bilateral, malignant SCTAT arising in
a patient who had PJS, presenting with an atypical cervicovaginal smear.
PMID- 10786817
TI - Role of glycosylation in function of follicle-stimulating hormone.
AB - The oligosaccharide structures of heterodimeric glycoprotein hormones, such as
follicle-stimulating hormone (FSH), have been shown to play an important role in
the biosynthesis, secretion, metabolic fate, and regulation of potency of the
hormone. The oligosaccharide structures attached to each subunit of the protein
seem to exhibit distinct roles in some of these functions. Glycans attached to
the alpha-subunit are critical for dimer assembly, integrity, and secretion, as
well as for signal transduction; although beta-subunit glycans are also important
for dimer assembly and secretion, they play a crucial role in clearance of the
dimer from the circulation. Alternative glycosylation on FSH and other
glycoprotein hormones not only may affect the metabolic clearance and net in vivo
biopotency of the hormone, but also offers the interesting possibility that some
glycosylation variants of the hormone may provoke differential or even unique
effects at the target cell level. Glycosylation of FSH is regulated by
hypothalamic and/or end products from the glands under the control of this
hormone. In particular, estrogens regulate terminal sialylation and thus some
functional properties of the gonadotropin influenced by sialic acid. Through
these extrapituitary inputs, the gonadotroph may regulate not only the amount but
also the intensity of the gonadotropin signal to be secreted by the pituitary in
a given physiological condition.
PMID- 10786819
TI - Effect of okadaic acid and calyculin-A, two protein phosphatase inhibitors, on
thyrotropin-stimulated triiodothyronine secretion in cultured sheep thyroid
cells.
AB - We have studied the effect of two protein phosphatase inhibitors on thyrotropin
(TSH)-stimulated triiodothyronine (T3) production by sheep thyroid cells grown in
primary culture. Incubation of sheep thyrocytes with okadaic acid (OA) and
calyculin-A (CL-A), two potent inhibitors of type 1 (PP1) and type 2A (PP2A)
protein phosphatases, resulted in an increase of TSH-stimulated T3 production.
This effect was detected using concentrations as low as 0.1 pM with OA and 1 fM
with CL-A. An inhibitory effect on T3 production, due to cellular death, was
observed with 6 nM OA and 1 nM CL-A. In the absence of TSH, OA or CL-A had no
effect on T3 production by thyrocytes. Forskoline (10 microM), an activator of
adenylate cyclase, increased the basal and TSH-stimulated T3 release by sheep
thyroid cells; this effect was increased by OA in cells grown in the basal state
but not in the presence of TSH. These results suggest that the marine toxins OA
and CL-A, two potent inhibitors of PP-1 and PP-2A, have significant stimulatory
effects on T3 secretion promoted by TSH and FK. These observations indicate that
these proteins could be important mediators of thyroid hormone production.
PMID- 10786818
TI - Estrogen action in the regulation of cell proliferation, cell survival, and
tumorigenesis in the rat anterior pituitary gland.
AB - Estrogens act as important regulators of cell proliferation, cell survival, and
differentiation in a variety of organ systems and tissues and have been
implicated in the etiology of a variety of malignant cancers and benign tumors.
The anterior pituitary gland of the rat provides an excellent model for the study
of estrogen action in the regulation of cell proliferation and survival.
Estrogens stimulate proliferation of the prolactin (PRL)-producing lactotroph and
enhance lactotroph survival. Through these actions on lactotroph proliferation
and survival, estrogens induce or contribute to the development of PRL-producing
pituitary tumors in several rat strains. Data from our laboratory and others
indicate that estrogen-induced pituitary growth is rat strain specific and
segregates as a quantitative genetic trait in crosses between different rat
strains. The purpose of this review is to summarize current knowledge pertaining
to estrogen action in the regulation of cell proliferation, cell survival, and
tumorigenesis in the anterior pituitary gland of the rat species, Rattus
norvegicus, and to illustrate the advantages of the rat pituitary gland as a
model for elucidating the mechanisms through which estrogens regulate these
processes.
PMID- 10786821
TI - Stimulation of anterior pituitary galanin and prolactin gene expression in
suckling rats.
AB - Recent evidence suggests that galanin may regulate prolactin (PRL) secretion
during lactation. In this article, we describe the regulation of anterior
pituitary galanin and PRL gene expression during pregnancy and after parturition
in the rat. Expression of galanin and PRL in the anterior pituitary were
significantly higher at d 20 of pregnancy compared to diestrus. One day after
parturition, galanin mRNA levels increased a further 4.5-fold. This post partum
increase in gene expression was not observed for PRL. The increase in galanin
gene expression was maintained above the diestrous level for at least 10 d after
parturition. PRL mRNA expression, on the other hand, was largely unchanged after
parturition. Although the increase in galanin gene expression 1 d after
parturition was independent of suckling, subsequently, galanin gene expression
was significantly higher in nursing mothers. Anterior pituitary galanin gene
expression was 12-fold higher in nursing mothers compared with those that were
not, 3 d after parturition. Similarly, PRL gene expression was significantly
lower in mothers who were not suckling their pups 3 d after parturition.
Initiation of suckling alone was insufficient to stimulate galanin and PRL
expression. Despite suckling for 2 d, removal of the suckling stimulus
subsequently resulted in a rapid decrease in galanin gene expression. Hence, the
stimulatory effect of suckling on galanin expression requires a sustained
suckling stimulus. In conclusion, the data support the hypothesis that anterior
pituitary galanin plays an important role during lactation, likely acting to
amplify lactotroph stimulation through paracrine and autocrine mechanisms.
PMID- 10786820
TI - Transforming growth factor-beta1 modulates chondrocyte responsiveness to 17beta
estradiol.
AB - This study examined the interrelationship between transforming growth factor
beta1 (TGF-beta1) and 17beta-estradiol (E2) in the regulation of growth plate
chondrocytes. To determine whether TGF-beta1 modulates chondrocyte response to
E2, we used cells isolated from the resting zone (RC) and growth zone (GC) of
costochondral cartilage. Confluent, fourth-passage cultures were pretreated with
rhTGF-beta1 for 24 h, followed by treatment with E2 for 24 h. The effect of TGF
beta1 and E2 alone, or the sequential combination, were examined by measuring
[3H]-thymidine incorporation (proliferation), alkaline phosphatase (AP) specific
activity (differentiation), and [35S]-sulfate incorporation (matrix synthesis).
TGF-beta1 alone increased [3H]-thymidine incorporation in both female and male RC
and GC cells, but E2 affected this parameter only in RC cells, causing a dose
dependent decrease. At the highest concentration of TGF-beta1 and E2, [3H]
thymidine incorporation in female GC cells was the same as seen in untreated
control cultures. In male GC cells, [3H]-thymidine incorporation in cultures
treated with TGF-beta1 and E2 exhibited a comparable increase, as was seen in
cultures treated with TGF-beta1 alone. TGF-beta1 caused a biphasic stimulation in
AP that was maximal at 0.22 ng/mL, in both female and male RC and GC cells. E2,
however, affected only female cells. Whereas the effect of TGF-beta1 predominated
in RC and GC male cells, the biphasic stimulation caused by E2, maximal at 109 M,
predominated in female RC cells. In female GC cells, however, TGF-beta1 caused a
synergistic response, resulting in enhanced AP specific activity in cultures
pretreated with 0.22 ng/mL of TGF-beta1 and 10(-8) M E2. TGF-beta1 alone caused
dose-dependent increases in [35S]-sulfate incorporation in female RC and GC
cells, as well as in male GC cells, but had no effect on male RC cells. E2
affected only female cells. TGF-beta1 potentiated the effect of E2 on this
parameter, resulting in synergistic increases in the female cells. This is the
first demonstration of a gender-specific response to TGF-beta1 in chondrocytes.
These results suggest that chondrocyte response to a systemic hormone such as E2
can be modulated by local regulatory agents such as TGF-beta1.
PMID- 10786822
TI - Ovarian steroid action on tryptophan hydroxylase protein and serotonin compared
to localization of ovarian steroid receptors in midbrain of guinea pigs.
AB - The effect of estrogen (E) and progesterone (P) on the protein expression of the
rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase (TPH), and
the level of serotonin in the hypothalamic terminal field was examined in guinea
pigs. In addition, we questioned whether serotonin neurons of guinea pigs contain
ovarian steroid receptors (estrogen receptoralpha[ERalpha], estrogen receptor
beta[ERbeta], progestin receptors [PRs]) that could directly mediate the actions
of E or P. Western blot and densitometric analysis for TPH were used on raphe
extracts from untreated-ovariectomized (OVX), OVX-E-treated (28 d), and OVX-E+P
treated (14 d E+14 d E+P) guinea pigs. The medial basal hypothalami from the same
animals were extracted and subjected to high-performance liquid chromatography
analysis for serotonin, dopamine, 5-hydroxyindole acetic acid, and homovanillic
acid. The brains from other animals treated in an identical manner were perfusion
fixed and examined for the colocalization of ERalpha plus serotonin and PR plus
serotonin with double immunohistochemistry or for expression of ERbeta mRNA with
in situ hybridization. E and E+P treatment significantly increased TPH protein
levels compared to the untreated control group (p < 0.05), but TPH levels were
similar in the E and E+P-treated groups. By contrast, serotonin
(nanogram/milligram of protein) in the hypothalamus was significantly increased
by E+P treatment, but not by E alone. Neither ERalpha nor PR proteins were
detected within serotonin neurons of the guinea pig raphe nucleus. However,
ERbeta mRNA was expressed in the dorsal raphe. In summary, E alone increased TPH
protein expression and the addition of P had no further effect, whereas E+P
increased hypothalamic serotonin and E alone had no effect. The localization of
ERbeta, but not ERalpha or PR, in the dorsal raphe nucleus suggests that E acting
via ERbeta within serotonin neurons increases expression of TPH, but that P
acting via other neurons and transsynaptic stimulation may effect changes in TPH
enzymatic activity, which in turn, would lead to an increase in serotonin
synthesis.
PMID- 10786825
TI - Reevaluation of the determinants of tyrosine sulfation.
AB - The posttranslational sulfation of tyrosine has been thought to be initiated by
the recognition of specific consensus features by the sulfating enzyme
tyrosylprotein sulfotransferase (TPST). However, using these recognition features
to identify new tyrosine sulfation sites misses recently characterized sites that
lack these features. Rigorous analysis of the amino acids surrounding the target
tyrosine using the position-specific scoring matrix (PSSM) demonstrates that a
consensus sequence does not contain all the information necessary to predict
tyrosine sulfation. Instead, accurate prediction requires consideration of all
residues within five amino acids on either side of the target tyrosine. These
results support the notion that secondary structure is the major determinant of
sulfation and that other residues within the sulfation site can compensate for
deviations from commonly observed features. This view implies that specific
consensus features are not critical for TPST substrate recognition but that TPST
may instead broadly recognize any sufficiently exposed tyrosine residue.
PMID- 10786823
TI - Rat ovarian interleukin-1alpha: interleukin-1-dependent in vitro expression.
AB - Evidence exists supporting the possibility that intraovarian interleukin-1 (IL-1)
may play an intermediary role in the periovulatory cascade. Although the
existence of a mammalian intraovarian IL-1 system has been convincingly
demonstrated, most efforts have focused on the possibility that the mammalian
ovary is a site of IL-1b production, reception, and action. The objective of this
study was to explore the possibility of ovarian IL-1a expression, characterize
its pattern of expression by cultured ovarian cells, and study its hormonal
regulation. The basal in vitro expression of IL-1a by cultured whole ovarian
dispersates from immature rats increased spontaneously, reaching a peak (sixfold
increase over untreated controls) at 4 h. Treatment with an IL-1 receptor
antagonist (IL-1RA), human chorionic gonadorropin, or IL-1b failed to attenuate
the initial 4-h burst of IL-1a expression. By contrast, treatment of whole
ovarian dispersates with IL-1b for 48 h resulted in significant upregulation of
IL-1a transcripts (60-fold increase). This IL-1b effect was completely blocked by
cotreatment with IL-1RA, thereby suggesting mediation via a specific IL-1
receptor. The IL-1b effect proved to be protein biosynthesis and eicosanoid
dependent, nitric oxide independent, and relatively specific in that it was not
reproduced by a select series of other granulosa cell agonists.
PMID- 10786826
TI - Possible participation of an islet B-cell calcium-sensing receptor in insulin
release.
AB - The calcium-sensing receptor gene was recently shown to be expressed in rat
pancreatic islets and purified islet B-cells. In this study, we investigated the
possible role of this receptor in the regulation of insulin release from isolated
rat pancreatic islets. Poly-L-arginine (0.2-0.3 microM) and poly-L-lysine (0.03
0.1 microM) increased insulin output evoked by D-glucose (8.3 mM). This positive
effect faded out at higher concentrations of the basic peptides. Likewise, the
release of insulin evoked by 8.3 mM D-glucose was significantly lower at high
(1.0 mM) than low (0.05-0.1 mM) concentrations of neomycin. The insulinotropic
action of Ba2+ in Ca2+-deprived islets was potentiated in rats pretreated with
pertussis toxin. However, Gd3+ inhibited insulin release evoked by D-glucose in
islets prepared from normal rats or animals pretreated with pertussis toxin and
incubated in the absence or presence of either theophylline or forskolin. Gd3+
(0.3 mM) failed to affect effluent radioactivity from islets prelabeled with myo
[2-3H]inositol and cyclic AMP net production in islets incubated in the absence
or presence of forskolin. Gd3+ decreased, however, 45Ca efflux from prelabeled
islets perifused in the absence or presence of extracellular Ca2+. It is
speculated that a negative insulinotropic action mediated by the calcium-sensing
receptor, and possibly attributable to a fall in cytosolic Ca2+ concentration,
may prevent excessive insulin secretion in pathological situations of
hypercalcemia.
PMID- 10786827
TI - Characterization of 11beta-hydroxysteroid dehydrogenase activities in the renal
cell line LLC-PK1: evidence for a third isoform?
AB - We studied 11beta-hydroxysteroid dehydrogenase activities in the renal cell line
LLC-PK1 and the effects of different steroids on them. Cortisol was oxidized in
the presence of NAD as well as NADP, reflecting the presence of two different
11beta-HSD forms. Enzyme kinetics for cortisol 11beta-oxidation were: Vmax = 5.9
pmol/(min x mg), Km = 0.2 microM with NAD, and Vmax = 4.5 pmol/(min x mg), Km =
1.0 microM with NADP. Interestingly, no reverse reaction was observed when using
cortisone and NADPH as substrate and cosubstrate, respectively. Exposure of cells
to a variety of steroids had different effects on cortisol 11beta-oxidation rates
with NADP compared to those with NAD. Dexamethasone initially (3-60 min of
exposure) decreased the NAD-dependent 11beta-HSD activity to about 60%, which was
no longer evident after 2 h or longer. By contrast, the 11beta-oxidation of
cortisol with NADP increased by dexamethasone treatment of the cells, after a
lagtime of about 2 h, and this effect was still evident after 32 h. The increase
of 11beta-HSD activity with NADP by dexamethasone was concentration dependent
(estimated EC50:125 nM). The antiglucocorticoid RU486 did not antagonize
dexamethasone induction. Exposure of cells for 19 h to 1 microM cortisol,
cortisone, progesterone, and estradiol also increased NADP-dependent cortisol
11beta-oxidation, but had no effect on the NAD-dependent 11beta-HSD activity.
Immunoblot and reverse transcriptase-polymerase chain reaction experiments failed
to detect any 11beta-HSD 1 protein or mRNA in these cells. Our observations
suggest that in LLC-PK1 cells, two forms of 11beta-HSD exist, which differ in
cosubstrate dependency, kinetics for cortisol, and modulation by steroids.
Whereas the NAD-dependent form seems identical to renal 11beta-HSD 2, the NADP
dependent 11beta-HSD possibly resembles an as yet unknown third isoform.
PMID- 10786824
TI - Impact and reversibility of chronic ethanol feeding on the reproductive axis in
the peripubertal male rat.
AB - Teenage drinking continues to be a major problem in the United States as well as
abroad. A significant depression in serum testosterone in adolescents who consume
EtOH has been well described. In the male rodent model, a similar fall in
testosterone has been reported, and prevention with the opiate blocker naltrexone
has been demonstrated. To explore further the impact of chronic EtOH exposure on
the reproductive axis in peripubertal rats, we designed this study specifically
to define whether or not there was recovery after abstinence by examining
reproductive hormones and their genes during and after EtOH exposure.
Peripubertal male rats 35 d old were fed an EtOH-containing diet or a calorically
matched control diet for 60 d. A third group was fed the control liquid diet ab
libitum. EtOH was then withdrawn and all animals were fed standard rat chow and
water ad libitum for an additional 3 mo. The EtOH-imbibing animals were found
consistently to weigh less than their pair-fed mates and liquid diet ad libitum
animals. Serum testosterone levels and testicular weights were significantly
decreased by EtOH whereas serum estradiol levels were higher, suggesting enhanced
peripheral conversion by EtOH. Spermatogenesis, assessed by histological
parameters, was unaltered by EtOH. Serum luteinizing hormone levels were not
different among the groups. Hypothalamic luteinizing hormone-releasing hormone
mRNA levels were unaffected by EtOH. During the 3-mo recovery period, all the
changes reversed, with a significant increase noted in testosterone. All other
parameters remained the same among the groups. Thus, although chronic EtOH
exposure in the peripubertal age period results in significant reproductive
alterations, there is complete recovery on withdrawal.
PMID- 10786829
TI - Roles of testosterone in the growth of keratinocytes through bald frontal dermal
papilla cells.
AB - A coculture of dermal papilla cells (DPCs) from the bald frontal scalp of
stumptailed macaques with keratinocytes derived from human neonatal foreskin
revealed that testosterone inhibited keratinocyte proliferation, and that the
antiandrogen RU58841 abolished this response. This testosterone-induced
keratinocyte growth inhibition was not observed when either type of cells was
cultured alone. We also examined conditioned media from the coculture system and
demonstrated the identical testosterone-induced growth inhibition on
keratinocytes, and this inhibitory effect was conditioned media concentration
dependent. These results suggested that the testosterone-mediated suppression on
keratinocyte proliferation might proceed through some diffusible growth mediators
in conditioned media. Differential display reverse transcriptase polymerase chain
reaction allowed us to isolate several genes from frontal DPCs that can be either
suppressed or induced by testosterone. Supervillin, a membrane-associated, F
actin-binding protein, was identified as one of the testosterone downregulated
genes in frontal DPCs. Further characterization of these testosterone-target
genes may reveal the mechanism by which testosterone inhibits the growth of
follicular cells in androgenetic alopecia.
PMID- 10786828
TI - Skeletal resistance to 1,25-dihydroxyvitamin D3 in osteopetrotic rats.
AB - The osteopetrotic (op/op) rat mutation is a lethal mutation in which decreased
osteoclast function (bone resorption) coexists with markedly elevated serum
levels of 1 ,25-dihydroxyvitamin D3[1,25(OH)2D3]. Increased circulating levels of
1,25(OH)2D3 have been reported in other osteopetrotic animal mutations and in
some osteopetrotic children. This study examined the effects of 1,25(OH)2D3
infusions on serum and skeletal parameters in normal and mutant rats of op stock.
We also examined vitamin D receptor expression and binding in bone cells from op
normal and mutant animals. Four-week-old normal and mutant rats were infused
either with propylene glycol (used as controls) or with 12.5-125 ng of
1,25(OH)2D3/d using osmotic minipumps implanted subcutaneously for 1 wk. Sera
were analyzed for calcium, phosphorus, and 1,25(OH)2D3 levels. Histomorphometric
analyses of proximal tibiae from treated normal (50 ng/d) and op mutant (125
ng/d) rats and their vehicle-infused controls were performed. Normal animals
infused with 1,25(OH)2D3 exhibited a dose-dependent increase in serum calcium
levels. Histomorphometric analyses of metaphyseal bone within the primary
spongiosae region showed that 1,25(OH)2D3 increased osteoclast number with a
reduction in osteoblast surface associated with a decrease in growth plate
cartilage thickness. However, similar analyses on secondary spongiosae showed a
decrease in osteoclast number and surface associated with an anabolic response.
Op mutants infused with 1,25(OH)2D3 did not exhibit any change in serum calcium
levels or histomorphometric parameters related to growth plate cartilage and
metaphyseal bone compared with mutant controls. Vitamin D mRNA and protein levels
were increased twoto threefold in op mutants compared to age-matched normal rats.
However, binding affinity of 1,25(OH)2D3 to its receptor was similar between op
mutant and normal animals. High dose calcitriol therapy, under the conditions and
period of treatment used in this study, failed to stimulate bone turnover in op
rats, suggesting that they are resistant to the skeletal effects of 1,25(OH)2D3.
The failure of osteoclast activation in response to 1,25(OH)2D3 treatment may be
associated with osteoblast incompetence in this mutation.
PMID- 10786830
TI - New animal models for Parkinson's disease.
PMID- 10786831
TI - Getting newly synthesized proteins into shape.
PMID- 10786833
TI - HIV-1 genome nuclear import is mediated by a central DNA flap.
AB - HIV-1 and other lentiviruses have the unique property among retroviruses to
replicate in nondividing cells. This property relies on the use of a nuclear
import pathway enabling the viral DNA to cross the nuclear membrane of the host
cell. In HIV-1 reverse transcription, a central strand displacement event
consecutive to central initiation and termination of plus strand synthesis
creates a plus strand overlap: the central DNA flap. We show here that the
central DNA flap acts as a cis-determinant of HIV-1 DNA nuclear import. Wild-type
viral linear DNA is almost entirely imported into the nucleus where it integrates
or circularizes. In contrast, mutant viral DNA, which lacks the DNA flap,
accumulates in infected cells as unintegrated linear DNA, at the vicinity of the
nuclear membrane. Consistently, HIV-1 vectors devoid of DNA flap exhibit a strong
defect of nuclear import, which can be corrected to wild-type levels by
reinsertion of the DNA flap sequence.
PMID- 10786832
TI - Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB
and implications for Cockayne syndrome.
AB - Analysis of transcription-coupled repair (TCR) of oxidative lesions here reveals
strand-specific removal of 8-oxo-guanine (8-oxoG) and thymine glycol both in
normal human cells and xeroderma pigmentosum (XP) cells defective in nucleotide
excision repair. In contrast, Cockayne syndrome (CS) cells including CS-B, XP
B/CS, XP-D/CS, and XP-G/CS not only lack TCR but cannot remove 8-oxoG in a
transcribed sequence, despite its proficient repair when not transcribed. The XP
G/CS defect uniquely slows lesion removal in nontranscribed sequences. Defective
TCR leads to a mutation frequency at 8-oxoG of 30%-40% compared to the normal 1%
4%. Surprisingly, unrepaired 8-oxoG blocks transcription by RNA polymerase II.
These data imply that TCR is required for polymerase release to allow repair and
that CS results from defects in TCR of oxidative lesions.
PMID- 10786834
TI - PHAX, a mediator of U snRNA nuclear export whose activity is regulated by
phosphorylation.
AB - In metazoa, assembly of spliceosomal U snRNPs requires nuclear export of U snRNA
precursors. Export depends upon the RNA cap structure, nuclear cap-binding
complex (CBC), the export receptor CRM1/Xpo1, and RanGTP. These components are
however insufficient to support U snRNA export. We identify PHAX (phosphorylated
adaptor for RNA export) as the additional factor required for U snRNA export
complex assembly in vitro. In vivo, PHAX is required for U snRNA export but not
for CRM1-mediated export in general. PHAX is phosphorylated in the nucleus and
then exported with RNA to the cytoplasm, where it is dephosphorylated. PHAX
phosphorylation is essential for export complex assembly while its
dephosphorylation causes export complex disassembly. The compartmentalized PHAX
phosphorylation cycle can contribute to the directionality of export.
PMID- 10786835
TI - Structure of TPR domain-peptide complexes: critical elements in the assembly of
the Hsp70-Hsp90 multichaperone machine.
AB - The adaptor protein Hop mediates the association of the molecular chaperones
Hsp70 and Hsp90. The TPR1 domain of Hop specifically recognizes the C-terminal
heptapeptide of Hsp70 while the TPR2A domain binds the C-terminal pentapeptide of
Hsp90. Both sequences end with the motif EEVD. The crystal structures of the TPR
peptide complexes show the peptides in an extended conformation, spanning a
groove in the TPR domains. Peptide binding is mediated by electrostatic
interactions with the EEVD motif, with the C-terminal aspartate acting as a two
carboxylate anchor, and by hydrophobic interactions with residues upstream of
EEVD. The hydrophobic contacts with the peptide are critical for specificity.
These results explain how TPR domains participate in the ordered assembly of
Hsp70-Hsp90 multichaperone complexes.
PMID- 10786836
TI - Pachytene exit controlled by reversal of Mek1-dependent phosphorylation.
AB - During yeast meiosis, a checkpoint prevents exit from pachytene in response to
defects in meiotic recombination and chromosome synapsis. This pachytene
checkpoint requires two meiotic chromosomal proteins, Red1 and Mek1; Mek1 is a
kinase that phosphorylates Red1. In mutants that undergo checkpoint-mediated
pachytene arrest, Mek1 is active and Red1 remains phosphorylated. Activation of
Mek1 requires the initiation of meiotic recombination and certain DNA damage
checkpoint proteins. Mek1 kinase activity and checkpoint-induced pachytene arrest
are counteracted by protein phosphatase type 1 (Glc7). Glc7 coimmunoprecipitates
with Red1, colocalizes with Red1 on chromosomes, and dephosphorylates Red1 in
vitro. We speculate that phosphorylated Red1 prevents exit from pachytene and
that completion of meiotic recombination triggers Glc7-dependent
dephosphorylation of Red1.
PMID- 10786837
TI - A kaiC-interacting sensory histidine kinase, SasA, necessary to sustain robust
circadian oscillation in cyanobacteria.
AB - Both regulated expression of the clock genes kaiA, kaiB, and kaiC and
interactions among the Kai proteins are proposed to be important for circadian
function in the cyanobacterium Synechococcus sp. strain PCC 7942. We have
identified the histidine kinase SasA as a KaiC-interacting protein. SasA contains
a KaiB-like sensory domain, which appears sufficient for interaction with KaiC.
Disruption of the sasA gene lowered kaiBC expression and dramatically reduced
amplitude of the kai expression rhythms while shortening the period. Accordingly,
sasA disruption attenuated circadian expression patterns of all tested genes,
some of which became arrhythmic. Continuous sasA overexpression eliminated
circadian rhythms, whereas temporal overexpression changed the phase of kaiBC
expression rhythm. Thus, SasA is a close associate of the cyanobacterial clock
that is necessary to sustain robust circadian rhythms.
PMID- 10786838
TI - Evolutionary and functional aspects of C-to-U editing at position 28 of
tRNA(Cys)(GCA) in plant mitochondria.
PMID- 10786839
TI - RNA-ligand chemistry: a testable source for the genetic code.
AB - In the genetic code, triplet codons and amino acids can be shown to be related by
chemical principles. Such chemical regularities could be created either during
the code's origin or during later evolution. One such chemical principle can now
be shown experimentally. Natural or particularly selected RNA binding sites for
at least three disparate amino acids (arginine, isoleucine, and tyrosine) are
enriched in codons for the cognate amino acid. Currently, in 517 total
nucleotides, binding sites contain 2.4-fold more codon sequences than surrounding
nucleotides. The aggregate probability of this enrichment is 10(-7) to 10(-8),
had codons and binding site sequences been independent. Thus, at least some
primordial coding assignments appear to have exploited triplets from amino acid
binding sites as codons.
PMID- 10786840
TI - The scene of a frozen accident.
AB - It has been suggested that in vitro selection experiments can provide information
not only on what might have occurred during the evolution of the RNA world, but
can in fact yield insights into particular features of the RNA world. In
particular, it has been suggested that the sequences of anti-amino acid aptamers
can provide clues to the origin of the genetic code, and that there is a
statistically significant association between motifs found in aptamers and
codons. We argue that the suggested connections between modern motifs and ancient
sequences are logically tenuous, and show that there is no statistically
meaningful association between motifs found in aptamers and codons.
PMID- 10786841
TI - Guilt by association: the arginine case revisited.
AB - If the genetic code arose in an RNA world, present codon assignments may reflect
primordial RNA-amino acid affinities. Whether aptamers selected from random pools
to bind free amino acids do so using the cognate codons at their binding sites
has been controversial. Here we defend and extend our previous analysis of
arginine binding sites, and propose a model for the maintenance of codon-amino
acid interactions through the evolution of amino acids from ribozyme cofactors
into the building blocks of proteins.
PMID- 10786842
TI - Helix P4 is a divalent metal ion binding site in the conserved core of the
ribonuclease P ribozyme.
AB - The ribonuclease P ribozyme (RNase P RNA), like other large ribozymes, requires
magnesium ions for folding and catalytic function; however, specific sites of
metal ion coordination in RNase P RNA are not well defined. To identify and
characterize individual nucleotide functional groups in the RNase P ribozyme that
participate in catalytic function, we employed self-cleaving ribozyme-substrate
conjugates that facilitate measurement of the effects of individual functional
group modifications. The self-cleavage rates and pH dependence of two different
ribozyme-substrate conjugates were determined and found to be similar to the
single turnover kinetics of the native ribozyme. Using site-specific
phosphorothioate substitutions, we provide evidence for metal ion coordination at
the pro-Rp phosphate oxygen of A67, in the highly conserved helix P4, that was
previously suggested by modification-interference experiments. In addition, we
detect a new metal ion coordination site at the pro-Sp phosphate oxygen of A67.
These findings, in combination with the proximity of A67 to the pre-tRNA cleavage
site, support the conclusion that an important role of helix P4 in the RNase P
ribozyme is to position divalent metal ions that are required for catalysis.
PMID- 10786843
TI - Molecular recognition of amino acids by RNA aptamers: the evolution into an L
tyrosine binder of a dopamine-binding RNA motif.
AB - We report the evolution of an RNA aptamer to change its binding specificity. RNA
aptamers that bind the free amino acid tyrosine were in vitro selected from a
degenerate pool derived from a previously selected dopamine aptamer. Three
independent sequences bind tyrosine in solution, the winner of the selection
binding with a dissociation constant of 35 microM. Competitive affinity
chromatography with tyrosine-related ligands indicated that the selected aptamers
are highly L-stereo selective and also recognize L-tryptophan and L-dopa with
similar affinity. The binding site was localized by sequence comparison, analysis
of minimal boundaries, and structural probing upon ligand binding. Tyrosine
binding sites are characterized by the presence of both tyrosine (UAU and UAC)
and termination (UAG and UAA) triplets.
PMID- 10786845
TI - Chloroplast ribonuclease P does not utilize the ribozyme-type pre-tRNA cleavage
mechanism.
AB - The transfer RNA 5' maturation enzyme RNase P has been characterized in Bacteria,
Archaea, and Eukarya. The purified enzyme from all three kingdoms is a
ribonucleoprotein containing an essential RNA subunit; indeed, the RNA subunit of
bacterial RNase P RNA is the sole catalytic component. In contrast, the RNase P
activity isolated from spinach chloroplasts lacks an RNA component and appears to
function as a catalytic protein. Nonetheless, the chloroplast enzyme recognizes a
pre-tRNA substrate for E. coli RNase P and cleaves it as efficiently and
precisely as does the bacterial enzyme. To ascertain whether there are
differences in catalytic mechanism between an all-RNA and an all-protein RNase P,
we took advantage of the fact that phosphodiester bond selection and hydrolysis
by the E. coli RNase P ribozyme is directed by a Mg2+ ion coordinated to the
nonbridging pro-Rp oxygen of the scissile bond, and is blocked by sulfur
replacement of this oxygen. We therefore tested the ability of the chloroplast
enzyme to process a precursor tRNA containing this sulfur substitution. Partially
purified RNase P from spinach chloroplasts can accurately and efficiently process
phosphorothioate-substituted pre-tRNAs; cleavage occurs exclusively at the thio
containing scissile bond. The enzymatic throughput is fivefold slower, consistent
with a general chemical effect of the phosphorothioate substitution rather than
with a metal coordination deficiency. The chloroplast RNase P reaction mechanism
therefore does not involve a catalytic Mg2+ bonded to the pro-Rp phosphate
oxygen, and hence is distinct from the mechanism of the bacterial ribozyme RNase
P.
PMID- 10786848
TI - In vitro selection of novel RNA ligands that bind human cytomegalovirus and block
viral infection.
AB - Ribonuclease-resistant RNA molecules that bind to infectious human
cytomegalovirus (HCMV) were isolated in vitro from a pool of randomized sequences
after 16 cycles of selection and amplification. The two ligands (L13 and L19)
characterized exhibited high HCMV-binding affinity in vitro and effectively
inhibited viral infection in tissue culture. Their antiviral activity was also
specific as they only reacted with two different strains of HCMV but not with the
related herpes simplex virus 1 and human cells. These two ligands appeared to
function as antivirals by blocking viral entry. Ultraviolet (UV) crosslinking
studies suggested that L13 and L19 bind to HCMV essential glycoproteins B and H,
respectively. Thus, RNA ligands that bind to different surface antigens of HCMV
can be simultaneously isolated by the selection procedure. Our study demonstrates
the feasibility of using these RNA ligands as a research tool to identify viral
proteins required for infectivity and as an antiviral agent to block viral
infection.
PMID- 10786846
TI - Evidence for an RNA-based catalytic mechanism in eukaryotic nuclear ribonuclease
P.
AB - Ribonuclease P is the enzyme responsible for removing the 5'-leader segment of
precursor transfer RNAs in all organisms. All eukaryotic nuclear RNase Ps are
ribonucleoproteins in which multiple protein components and a single RNA species
are required for activity in vitro as well as in vivo. It is not known, however,
which subunits participate directly in phosphodiester-bond hydrolysis. The RNA
subunit of nuclear RNase P is evolutionarily related to its catalytically active
bacterial counterpart, prompting speculation that in eukaryotes the RNA may be
the catalytic component. In the bacterial RNase P reaction, Mg(II) is required to
coordinate the nonbridging phosphodiester oxygen(s) of the scissile bond. As a
consequence, bacterial RNase P cannot cleave pre-tRNA in which the pro-Rp
nonbridging oxygen of the scissile bond is replaced by sulfur. In contrast, the
RNase P reaction in plant chloroplasts is catalyzed by a protein enzyme whose
mechanism does not involve Mg(II) coordinated by the pro-Rp oxygen. To determine
whether the mechanism of nuclear RNase P resembles more closely an RNA- or a
protein-catalyzed reaction, we analyzed the ability of Saccharomyces cerevisiae
nuclear RNase P to cleave pre-tRNA containing a sulfur substitution of the pro-Rp
oxygen at the cleavage site. Sulfur substitution at this position prohibits
correct cleavage of pre-tRNA. Cleavage by eukaryotic RNase P thus depends on the
presence of a thio-sensitive ligand to the pro-Rp oxygen of the scissile bond,
and is consistent with a common, RNA-based mechanism for the bacterial and
eukaryal enzymes.
PMID- 10786847
TI - Determination of preferential binding sites for anti-dsRNA antibodies on double
stranded RNA by scanning force microscopy.
AB - The monoclonal anti-dsRNA antibody J2 binds double-stranded RNAs (dsRNA) in an
apparently sequence-nonspecific way. The mAb only recognizes antigens with double
stranded regions of at least 40 bp and its affinity to poly(A) poly(U) and to
dsRNAs with mixed base pair composition is about tenfold higher than to poly(I)
poly(C). Because no specific binding site could be determined, the number, the
exact dimensions, and other distinct features of the binding sites on a given
antigen are difficult to evaluate by biochemical methods. We therefore employed
scanning force microscopy (SFM) as a method to analyze antibody-dsRNA interaction
and protein-RNA binding in general. Several in vitro-synthesized dsRNA
substrates, generated from the Dictyostelium PSV-A gene, were used. In addition
to the expected sequence-nonspecific binding, imaging of the complexes indicated
preferential binding of antibodies to the ends of dsRNA molecules as well as to
certain internal sites. Analysis of 2,000 bound antibodies suggested that the
consensus sequence of a preferential internal binding site is A2N9A3N9A2, thus
presenting A residues on one face of the helix. The site was verified by site
directed mutagenesis, which abolished preferential binding to this region. The
data demonstrate that SFM can be efficiently used to identify and characterize
binding sites for proteins with no or incomplete sequence specificity. This is
especially the case for many proteins involved in RNA metabolism.
PMID- 10786844
TI - Characterization of human RNA splice signals by iterative functional selection of
splice sites.
AB - An iterative in vitro splicing strategy was employed to select for optimal 3'
splicing signals from a pool of pre-mRNAs containing randomized regions.
Selection of functional branchpoint sequences in HeLa cell nuclear extract
yielded a sequence motif that evolved from UAA after one round of splicing toward
a UACUAAC consensus after seven rounds. A significant part of the selected
sequences contained a conserved AAUAAAG motif that proved to be functional both
as a polyadenylation signal and a branch site in a competitive manner.
Characterization of the branchpoint in these clones to either the upstream or
downstream adenosines of the AAUAAAG sequence revealed that the branching process
proceeded efficiently but quite promiscuously. Surprisingly, the conserved
guanosine, adjacent to the common AAUAAA polyadenylation motif, was found to be
required only for polyadenylation. In an independent experiment, sequences
surrounding an optimal branchpoint sequence were selected from two randomized 20
nt regions. The clones selected after six rounds of splicing revealed an extended
polypyrimidine tract with a high frequency of UCCU motifs and a highly conserved
YAG sequence in the extreme 3' end of the randomized insert. Mutating the 3'
terminal guanosine of the intron strongly affects complex A formation, implying
that the invariant AG is recognized early in spliceosome assembly.
PMID- 10786849
TI - Complementarity between the mRNA 5' untranslated region and 18S ribosomal RNA can
inhibit translation.
AB - In eubacteria, base pairing between the 3' end of 16S rRNA and the ribosome
binding site of mRNA is required for efficient initiation of translation. An
interaction between the 18S rRNA and the mRNA was also proposed for translation
initiation in eukaryotes. Here, we used an antisense RNA approach in vivo to
identify the regions of 18S rRNA that might interact with the mRNA 5'
untranslated region (5' UTR). Various fragments covering the entire mouse 18S
rRNA gene were cloned 5' of a cat reporter gene in a eukaryotic vector, and
translation products were analyzed after transient expression in human cells. For
the largest part of 18S rRNA, we show that the insertion of complementary
fragments in the mRNA 5' UTR do not impair translation of the downstream open
reading frame (ORF). When translation inhibition is observed, reduction of the
size of the complementary sequence to less than 200 nt alleviates the inhibitory
effect. A single fragment complementary to the 18S rRNA 3' domain retains its
inhibitory potential when reduced to 100 nt. Deletion analyses show that two
distinct sequences of approximately 25 nt separated by a spacer sequence of 50 nt
are required for the inhibitory effect. Sucrose gradient fractionation of
polysomes reveals that mRNAs containing the inhibitory sequences accumulate in
the fractions with 40S ribosomal subunits, suggesting that translation is blocked
due to stalling of initiation complexes. Our results support an mRNA-rRNA base
pairing to explain the translation inhibition observed and suggest that this
region of 18S rRNA is properly located for interacting with mRNA.
PMID- 10786850
TI - Polyadenylation of three classes of chloroplast RNA in Chlamydomonas reinhadtii.
AB - Three classes of RNA, represented by atpB and petD mRNAs, Arg and Glu tRNAs, and
5S rRNA, were found to exist in polyadenylated form in Chlamydomonas reinhardtii
chloroplasts. Sequence analysis of cDNA clones derived from reverse transcriptase
polymerase chain reaction protocols used to select polyadenylated RNAs revealed
that, at least for the mRNAs and tRNAs, there are three apparent types of
polyadenylation. In the first case, the poly(A) tail is added at or near the
mature 3' end, even when this follows a strong secondary structure. In the second
case, the tail is added to pre-mRNA or pre-tRNA, suggesting a possible
competition between polyadenylation and RNA-processing pathways. Finally, in all
cases, the poly(A) tail can be added internally, possibly as a part of an RNA
decay pathway. The tails found in Chlamydomonas chloroplasts differ from those of
spinach chloroplasts in adenine content, being nearly homopolymeric (>98%
adenine) versus 70% in spinach, and are similar in length to those of Escherichia
coli, being mostly between 20 and 50 nt. In vitro assays using a Chlamydomonas
chloroplast protein extract showed that a 3' end A25 tail was sufficient to
stimulate rapid degradation of atpB RNA in vitro, with a lesser effect for petD,
and only minor effects on trnE. We therefore propose that polyadenylation
contributes to mRNA degradation in Chlamydomonas chloroplasts, but that its
effect may vary.
PMID- 10786851
TI - A test of the model to predict unusually stable RNA hairpin loop stability.
AB - To investigate the accuracy of a model [Giese et al., 1998, Biochemistry37:1094
1100 and Mathews et al., 1999, JMol Biol 288:911-940] that predicts the stability
of RNA hairpin loops, optical melting studies were conducted on sets of hairpins
previously determined to have unusually stable thermodynamic parameters. Included
were the tetraloops GNRA and UNCG (where N is any nucleotide and R is a purine),
hexaloops with UU first mismatches, and the hairpin loop of the iron responsive
element, CAGUGC. The experimental values for the GNRA loops are in excellent
agreement (deltaG degrees 37 within 0.2 kcal/mol and melting temperature (TM)
within 4 degrees C) with the values predicted by the model. When the UNCG hairpin
loops are treated as tetraloops, and a bonus of 0.8 kcal/mol included in the
prediction to account for the extra stable first mismatch (UG), the measured and
predicted values are also in good agreement (deltaG degrees 37 within 0.7
kcal/mol and TM within 3 degrees C). Six hairpins with unusually stable UU first
mismatches also gave good agreement with the predictions (deltaG degrees 37
within 0.5 kcal/mol and TM within 8 degrees C), except for hairpins closed by
wobble base pairs. For these hairpins, exclusion of the additional stabilization
term for UU first mismatches improved the prediction (AG degrees 37 within 0.1
kcal/mol and TM within 3 degrees C). Hairpins with the iron-responsive element
loop were not predicted well by the model, as measured deltaG degrees 37 values
were at least 1 kcal/mol greater than predicted.
PMID- 10786852
TI - Expression of the Naegleria intron endonuclease is dependent on a functional
group I self-cleaving ribozyme.
AB - NaSSU1 is a complex nuclear group I intron found in several species of Naegleria,
consisting of a large self-splicing group I ribozyme (NaGIR2), which itself is
interrupted by a small, group I-like ribozyme (NaGIR1) and an open reading frame
(ORF) coding for a homing endonuclease. The GIR1 ribozyme cleaves in vitro
transcripts of NaSSU1 at two internal processing sites about 400 nt downstream of
the 5' end of the intron, proximal to the endonuclease ORF. Here we demonstrate
that self-cleavage of the excised intron also occurs in vivo in Naegleria
gruberi, generating an ORF-containing RNA that possesses a short leader with a
sequence element likely to be involved in gene expression. To assess the
functional significance of self-cleavage, we constructed a genetic system in
Saccharomyces cerevisiae. First, a mutant yeast strain was selected with a
mutation in all the rRNA genes, rendering the rDNA resistant to cleavage by the
Naegleria endonuclease. Active endonuclease, which is otherwise lethal, could be
expressed readily in these cells. Endonuclease activity also could be detected in
extracts of yeast harboring plasmids in which the endonuclease ORF was embedded
in its native context in the intron. Analysis of the RNA from these yeast cells
showed that the excised intron RNA was processed as in N. gruberi. A mutant
intron constructed to prevent self-cleavage of the RNA failed to express
endonuclease activity. These results support the hypothesis that the NaGIR1
catalyzed self-cleavage of the intron RNA is a key event in expression of the
endonuclease.
PMID- 10786853
TI - Intracellular ribozyme-catalyzed trans-cleavage of RNA monitored by fluorescence
resonance energy transfer.
AB - Small catalytic RNAs like the hairpin ribozyme are proving to be useful
intracellular tools; however, most attempts to demonstrate trans-cleavage of RNA
by ribozymes in cells have been frustrated by rapid cellular degradation of the
cleavage products. Here, we describe a fluorescence resonance energy transfer
(FRET) assay that directly monitors cleavage of target RNA in tissue-culture
cells. An oligoribonucleotide substrate was modified to inhibit cellular
ribonuclease degradation without interfering with ribozyme cleavage, and donor
(fluorescein) and acceptor (tetramethylrhodamine) fluorophores were introduced at
positions flanking the cleavage site. In simple buffers, the intact substrate
produces a strong FRET signal that is lost upon cleavage, resulting in a red-to
green shift in dominant fluorescence emission. Hairpin ribozyme and fluorescent
substrate were microinjected into murine fibroblasts under conditions in which
substrate cleavage can occur only inside the cell. A strong FRET signal was
observed by fluorescence microscopy when substrate was injected, but rapid decay
of the FRET signal occurred when an active, cognate ribozyme was introduced with
the substrate. No acceleration in cleavage rates was observed in control
experiments utilizing a noncleavable substrate, inactive ribozyme, or an active
ribozyme with altered substrate specificity. Subsequently, the fluorescent
substrates were injected into clonal cell lines that expressed cognate or
noncognate ribozymes. A decrease in FRET signal was observed only when substrate
was microinjected into cells expressing its cognate ribozyme. These results
demonstrate trans-cleavage of RNA within mammalian cells, and provide an
experimental basis for quantitative analysis of ribozyme activity and specificity
within the cell.
PMID- 10786856
TI - Tragedy in sport and trial by tabloid.
PMID- 10786857
TI - Snowboarding injuries.
PMID- 10786855
TI - Warm up.
PMID- 10786858
TI - "You don't have to...": walking to a healthier nation.
PMID- 10786859
TI - Role of exercise counselling in health promotion.
PMID- 10786860
TI - Where is the pain coming from in tendinopathy? It may be biochemical, not only
structural, in origin.
PMID- 10786854
TI - REF, an evolutionary conserved family of hnRNP-like proteins, interacts with
TAP/Mex67p and participates in mRNA nuclear export.
AB - Vertebrate TAP and its yeast ortholog Mex67p are involved in the export of
messenger RNAs from the nucleus. TAP has also been implicated in the export of
simian type D viral RNAs bearing the constitutive transport element (CTE).
Although TAP directly interacts with CTE-bearing RNAs, the mode of interaction of
TAP/Mex67p with cellular mRNAs is different from that with the CTE RNA and is
likely to be mediated by protein-protein interactions. Here we show that Mex67p
directly interacts with Yra1p, an essential yeast hnRNP-like protein. This
interaction is evolutionarily conserved as Yra1p also interacts with TAP.
Conditional expression in yeast cells implicates Yra1 p in the export of cellular
mRNAs. Database searches revealed that Yra1p belongs to an evolutionarily
conserved family of hnRNP-like proteins having more than one member in Mus
musculus, Xenopus laevis, Caenorhabditis elegans, and Schizosaccharomyces pombe
and at least one member in several species including plants. The murine members
of the family directly interact with TAP. Because members of this protein family
are characterized by the presence of one RNP-motif RNA-binding domain and exhibit
RNA-binding activity, we called these proteins REF-bps for RNA and export factor
binding proteins. Thus, Yra1p and members of the REF family of hnRNP-like
proteins may facilitate the interaction of TAP/Mex67p with cellular mRNAs.
PMID- 10786865
TI - A pilot study examining injuries in elite gaelic footballers.
AB - OBJECTIVES: To quantify injuries in elite gaelic footballers and to determine the
nature, sites, and outcome of injuries and the possible risk factors involved.
METHODS: Information on injuries was collected from six elite gaelic football
teams by a questionnaire. The footballers were asked to recall injuries over the
preceding six month period. RESULTS: A total of 88 out of 107 subjects sustained
injuries over the study period. Ninety five injuries were recorded, giving an
incidence rate of 1.78 injuries per subject per year, of which 35% were
recurring. It was found that 35% of injuries were sustained during training
sessions. Lower body injuries predominated (77%), the ankle being the most
commonly injured anatomic site. Most injuries were soft tissue in nature: muscle,
33%; ligament, 32%; tendon, 16%. The most common situations giving rise to
injuries were collision (22%) and twist/turn (19%). Foul play only accounted for
about 6% of injuries. Mean time off play as a result of injury was 17.3 days, and
hospital admission was necessary for 15% of the injuries. CONCLUSION: Despite the
limitations of a retrospective of this nature, the study provides useful and
important information on injuries in gaelic footballers.
PMID- 10786864
TI - Incidence, site, and nature of injuries in amateur rugby league over three
consecutive seasons.
AB - OBJECTIVES: To report the incidence, site, and nature of injuries in amateur
rugby league over three consecutive seasons. METHODS: Six hundred players
registered with an amateur rugby league organisation were studied over three
consecutive seasons. All injuries sustained during the amateur rugby league
matches were recorded. Information recorded included the date and time of injury,
name of injured player, anatomical site and nature of injury, and position of the
player. RESULTS: The incidence of injury was 160.6 per 1000 player-position game
hours, with forwards having a significantly higher incidence of injury than backs
(182.3 per 1000 v 142.0 per 1000, chi2 = 14.60, df = 1, p<0.001). Over 25% of the
total injuries (40.6 per 1000) sustained during the three year period were to the
head and neck, while injuries to the face (21.3 per 1000, 13.3%), abdomen and
thorax (21.3 per 1000, 13.3%), and knee (17.8 per 1000, 11.1%) were less common
(chi2 = 21.83, df = 8, p<0.01). Muscular injuries (haematomas and strains) were
the most common type of injury (45.7 per 1000, 28.5%, chi2 = 17.98, df = 7,
p<0.05). Significantly more injuries occurred in the latter stages of the season
(chi2 = 22.94, df = 1, p<0.001), with most injuries (70.8%, chi2 = 162.29, df =
1, p<0.001) sustained in the second half of matches. CONCLUSIONS: The results
show that muscular injuries and injuries to the head and neck are the most
commonly sustained injuries in amateur rugby league. Furthermore, injuries are
more often sustained in the latter stages of the season and during the second
half of matches. These findings suggest that fatigue or accumulative microtrauma,
or both, may contribute to injuries in amateur rugby league players.
PMID- 10786861
TI - VO2 slow component and performance in endurance sports.
PMID- 10786862
TI - Physical activity mediates a healthier body weight in the presence of obesity.
PMID- 10786863
TI - Incidence and nature of the most common rugby injuries sustained in Argentina
(1991-1997).
AB - OBJECTIVE: To study the incidence of the most commonly sustained injuries in
Argentine rugby and analyse them according to type, position and age of the
players, and phase and time of play. METHODS: A prospective registry of injuries
was constructed in different provincial unions of Argentina. Data were collected
during a whole weekend each year from 1991 to 1997. Chi2 with Yates correction
test, contingency tables, odds ratios (OR), and 95% confidence intervals (CI)
were calculated (Epi Info Version 6.04a). RESULTS: A total of 924 injuries were
registered in 1296 rugby games, involving 38 933 players. The mean (SD) incidence
per weekend was 2.4 (0.2)% (95% CI 2.22 to 2.53), and the number of injuries per
season was 24,188. Overall, senior players suffered more injuries than those in
younger divisions (OR = 1.53; 95% CI 1.34 to 1.76; p<0.0001). The most common
type of injury was pulled muscles of the lower limbs (11.7%, p<0.0001). Overall,
the knee was the most susceptible to injury (14.1%, p<0.0001). Senior players
suffered more pulled muscles of the lower limbs (OR = 2.99; 95% CI 2.01 to 4.46;
p<0.0001), ankle ligament distension (OR = 1.69; 95% CI 1.12 to 2.53; p = 0.01),
knee trauma (OR = 1.69; 95% CI 1.06 to 2.68; p = 0.02), bleeding wounds on the
face (OR = 3.86; 95% CI 2.24 to 6.70; p<0.0001), and knee ligament distension (OR
= 2.14; 95% CI 1.16 to 3.96; p = 0.01). Younger players had a greater risk of
suffering muscular or ligament injuries of the cervical column (OR = 3.0; 95% CI
1.05 to 10.08; p = 0.04). The forwards had a higher risk of injury (OR = 1.41;
95% CI 1.23 to 1.61; p<0.0001). The most commonly injured player was the flanker
(15.5%, p<0.01), and the most common mechanism was in open play (33%). More
injuries were sustained in the second half (OR = 1.17; 95% CI 1.03 to 1.34; p =
0.01). CONCLUSIONS: Injuries are the cause of significant morbidity among rugby
players in Argentina. A more thorough investigation and a greater understanding
of the mechanisms are crucial in order to update the rugby laws and reduce this
high injury incidence.
PMID- 10786866
TI - Effects of massage on physiological restoration, perceived recovery, and repeated
sports performance.
AB - BACKGROUND: Despite massage being widely used by athletes, little scientific
evidence exists to confirm the efficacy of massage for promoting both
physiological and psychological recovery after exercise and massage effects on
performance. AIM: To investigate the effect of massage on perceived recovery and
blood lactate removal, and also to examine massage effects on repeated boxing
performance. METHODS: Eight amateur boxers completed two performances on a boxing
ergometer on two occasions in a counterbalanced design. Boxers initially
completed performance 1, after which they received a massage or passive rest
intervention. Each boxer then gave perceived recovery ratings before completing a
second performance, which was a repeated simulation of the first. Heart rates and
blood lactate and glucose levels were also assessed before, during, and after all
performances. RESULTS: A repeated measures analysis of variance showed no
significant group differences for either performance, although a main effect was
found showing a decrement in punching force from performance 1 to performance 2
(p<0.05). A Wilcoxon matched pairs test showed that the massage intervention
significantly increased perceptions of recovery (p<0.01) compared with the
passive rest intervention. A doubly multivariate multiple analysis of variance
showed no differences in blood lactate or glucose following massage or passive
rest interventions, although the blood lactate concentration after the second
performance was significantly higher following massage (p<0.05). CONCLUSIONS:
These findings provide some support for the psychological benefits of massage,
but raise questions about the benefit of massage for physiological restoration
and repeated sports performance.
PMID- 10786867
TI - Does physical activity reduce the risk of developing peptic ulcers?
AB - BACKGROUND: Although Helicobacter pylori has been identified as a major cause of
chronic gastritis, not all infected patients develop ulcers, suggesting that
other factors such as lifestyle may be critical to the development of ulcer
disease. AIM: To investigate the role physical activity may play in the incidence
of peptic ulcer disease. METHODS: The subjects were men (8529) and women (2884)
who attended the Cooper Clinic in Dallas between 1970 and 1990. The presence of
gastric or duodenal ulcer disease diagnosed by a doctor was determined from a
mail survey in 1990. Subjects were classified into three physical activity groups
according to information provided at the baseline clinic visit (before 1990):
active, those who walked or ran 10 miles or more a week; moderately active, those
who walked or ran less than 10 miles a week or did another regular activity; the
referent group consisting of those who reported no regular physical activity.
RESULTS: With the use of gender specific proportional hazards regression models
that could be adjusted for age, smoking, alcohol use, body mass index, and self
reported tension, active men were found to have a significant reduction in risk
for duodenal ulcers (relative hazard (95% confidence interval) for the active
group was 0.38 (0.15 to 0.94) and 0.54 (0.30 to 0.96) for the moderately active
group). No association was found between physical activity and gastric ulcers for
men or for either type of ulcer for women. CONCLUSIONS: Physical activity may
provide a non-pharmacological method of reducing the incidence of duodenal ulcers
among men.
PMID- 10786868
TI - Recurrent haematomas of the thigh: a case of von Willebrand's disease presenting
to a sports clinic.
AB - Von Willebrand's disease is a relatively common mild form of haemophilia. It
should be suspected in assessing sports injuries when excessive bleeding occurs
in response to relatively mild trauma. Those with the disease should remain
active but avoid contact sports. They should not take aspirin or non-steroidal
anti-inflammatory drugs, which may exacerbate bleeding, and should be given
supportive treatment to cover dental extraction, surgery, or significant bleeding
episodes.
PMID- 10786869
TI - The pathological status of exercise dependence.
AB - OBJECTIVES: This study was concerned with the concept of exercise dependence.
Levels of psychological morbidity, personality profiles, and exercise beliefs
were compared among subjects screened for exercise dependence and eating
disorders. METHOD: Adult female exercisers were allocated on the basis of
questionnaire screening to one of the following groups: primary exercise
dependence (n = 43); secondary exercise dependence, where there was the
coincidence of exercise dependence and an eating disorder (n = 27); eating
disorder (n =14); control, where there was no evidence of either exercise
dependence or eating disorder (n = 110). Questionnaire assessment was undertaken
of psychological morbidity, self esteem, weight and body shape dissatisfaction,
personality, and exercise beliefs. RESULTS: Aside from a higher incidence of
reported menstrual abnormalities, the primary exercise dependence group was
largely indistinguishable from the controls. In stark contrast, the secondary
exercise dependence group reported higher levels of psychological morbidity,
neuroticism, dispositional addictiveness, and impulsiveness, lower self esteem,
greater concern with body shape and weight, as well as with the social,
psychological, and aesthetic costs of not exercising than the controls, but
differed little from the eating disorder group. CONCLUSIONS: In the absence of an
eating disorder, women identified as being exercise dependent do not exhibit the
sorts of personality characteristics and levels of psychological distress that
warrant the construction of primary exercise dependence as a widespread
pathology.
PMID- 10786870
TI - Sports injury incidence.
PMID- 10786871
TI - Sudden cardiac death in sport--spectre or preventable risk?
PMID- 10786872
TI - Basic life support.
PMID- 10786873
TI - If jogging is a joke, who should have the last laugh?
PMID- 10786875
TI - Water jet skiing, a dangerous sport with inadequate policing!
PMID- 10786876
TI - Electrocardiographic changes in "elite" athletes.
PMID- 10786877
TI - The genetics of physical fitness.
PMID- 10786880
TI - Membrane proteins and proteomics: un amour impossible?
AB - Proteome analysis implies the ability to separate proteins as a first step prior
to characterization. Thus, the overall performance of the analysis strongly
depends on the performance of the separation tool, usually two-dimensional
electrophoresis. This review shows how two-dimensional electrophoresis performs
with membrane proteins from bacteria or animal or vegetable cells and tissues,
the recent progress in this field, and it examines future prospects in this area.
PMID- 10786879
TI - The current state of two-dimensional electrophoresis with immobilized pH
gradients.
AB - The original protocol of two-dimensional electrophoresis with immobilized pH
gradient (IPG-Dalt; Gorg et al., Electrophoresis 1988, 9, 531-546) is updated.
Merits and limits of different methods for sample solubilization, sample
application (by cup-loading or ingel rehydration) with respect to the pH interval
used for IPG-isoelectric focusing are critically discussed. Guidelines for
running conditions of analytical and micropreparative IPG-Dalt, using wide IPGs
up to pH 12 for overview patterns, or narrow IPGs for zoom-in gels for optimum
resolution and detection of minor components, are stated. Results with extended
separation distances as well as automated procedures are demonstrated, and a
comparison between protein detection by silver staining and fluorescent dyes is
given. A brief trouble shooting guide is also included.
PMID- 10786881
TI - Proteomics: capacity versus utility.
AB - Until recently scientists studied genes or proteins one at a time. With
improvements in technology, new tools have become available to study the complex
interactions that occur in biological systems. Global studies are required to do
this, and these will involve genomic and proteomic approaches. High-throughput
methods are necessary in each case because the number of genes and proteins in
even the simplest of organisms are immense. In the developmental phase of
genomics, the emphasis was on the generation and assembly of large amounts of
nucleic acid sequence data. Proteomics is currently in a phase of technological
development and establishment, and demonstrating the capacity for high throughput
is a major challenge. However, funding bodies (both in the public and private
sector) are increasingly focused on the usefulness of this capacity. Here we
review the current state of proteome research in terms of capacity and utility.
PMID- 10786878
TI - Performance enhancing drugs; damned if you do, and damned if you don't.
PMID- 10786874
TI - Acute injury incidence in professional county club cricket players (1985-1995).
AB - BACKGROUND: There is a dearth of evidenced based research into sports injury in
professional cricket. AIM: To investigate the incidence, nature, and site of
acute injuries sustained by professional cricketers at one English county club
over the period 1985-1995. METHODS: Injuries in a sample of 54 cricketers who had
played in the first team for the same county cricket club in any or all seasons
between 1985 and 1995 were investigated. Injury was defined as the onset of pain
or a disability resulting from either training for or playing cricket, which
caused the player to seek medical attention. RESULTS: An acute injury rate of
57.4 injuries per 1000 days of cricket played was found, with most injuries
sustained during April, the month in which the least number of days were played.
The lower limb was the region most vulnerable to injury, accounting for 44.9% of
all injuries, followed by the upper limb (29.4%), the trunk (20.0%), and the head
and neck (5.7%). No significant difference in injury incidence among player
positions was found. CONCLUSION: There is a need for a system of epidemiological
data collection and development of a national cricket injury database to help
predict, reduce, and prevent injury at all levels of the game.
PMID- 10786884
TI - The dynamic range of protein expression: a challenge for proteomic research.
AB - Proteomic research, for its part, is benefiting enormously from the last decade
of genomic research as we now have archived, annotated and audited sequence
databases to correlate and query experimental data. While the two-dimensional
electrophoresis (2-DE) gels are still a central part of proteomics, we reflect on
the possibilities and realities of the current 2-DE technology with regard to
displaying and analysing proteomes. Limitations of analysing whole cell/tissue
lysates by 2-DE alone are discussed, and we investigate whether extremely narrow
p/ranges (1 pH unit/25 cm) provide a solution to display comprehensive protein
expression profiles. We are confronted with a challenging task: the dynamic range
of protein expression. We believe that most of the existing technology is capable
of displaying many more proteins than is currently achievable by integrating
existing and new techniques to prefractionate samples prior to 2-DE display or
analysis. The availability of a "proteomics toolbox", consisting of defined
reagents, methods, and equipment, would assist a comprehensive analysis of
defined biological systems.
PMID- 10786889
TI - Recent advancements in surface-enhanced laser desorption/ionization-time of
flight-mass spectrometry.
AB - The overall history and recent advances in surface enhanced laser
desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) technology
is reviewed herein. Fundamentals of SELDI-TOF analysis are presented while
drawing comparisons with other laser-based mass spectrometry techniques. The
application of SELDI-TOF-MS to functional genomics and biomarker discovery is
discussed and exemplified by elucidating a biomarker candidate for prostatic
carcinoma. Finally, a short discussion regarding future SELDI requirements and
developments is supplied.
PMID- 10786882
TI - Better approaches to finding the needle in a haystack: optimizing proteome
analysis through automation.
AB - Recent evidence has demonstrated a lack of correlation between transcriptional
profiles and actual protein levels in cells. Proteome analysis has therefore
become indispensable and complementary to genomic analysis for an accurate
picture of cellular metabolism. Although proteomics is a relatively young
discipline, technology for increasing throughput in proteomic projects is rapidly
being developed. The operating paradigm in proteome analysis today is a
combination of two-dimensional (2-D) gel electrophoresis (for protein resolution)
with mass spectrometry (for protein identification). All the intermediary steps
in the procedure including gel staining, image analysis, protein spot excision,
digestion and mass spectrometry can be automated to increase efficiency and save
time. This report reviews the current state of the proteomics technology and
discusses approaches to enhance the sensitivity of 2-D gels with fractionation
techniques.
PMID- 10786883
TI - Subproteomics based upon protein cellular location and relative solubilities in
conjunction with composite two-dimensional electrophoresis gels.
AB - Progress in the field of proteomics is dependent upon an ability to visualise
close to an entire protein complement via a given array technology. These efforts
have previously centred upon two-dimensional gel electrophoresis in association
with immobilised pH gradients in the first dimension. However, limitations in
this technology, including the inability to separate hydrophobic, basic, and low
copy number proteins have hindered the analysis of complete proteomes. The
challenge is now to overcome these limitations through access to new technology
and improvements in existing methodologies. Proteomics can no longer be equated
with a single two-dimensional electrophoresis gel. Greater information can be
obtained using targeted biological approaches based upon sample prefractionation
into specific cellular compartments to determine protein location, while novel
immobilised pH gradients spanning single pH units can be used to display poorly
abundant proteins due to their increased resolving power and loading capacity. In
this study, we show the effectiveness of a combined use of two differential
subproteomes (as defined by relative solubilities, cellular location and narrow
range immobilised pH gradients) to increase the resolution of proteins contained
on two-dimensional gels. We also present new results confirming that this method
is capable of displaying up to a further 45% of a given microbial proteome.
Subproteomics, utilising up to 40 two-dimensional gels per sample will become a
powerful tool for near-to-total proteome analysis in the postgenome era.
Furthermore, this new approach can direct biological focus towards molecules of
specific interest within complex cells and thus simplify efforts in discovery
based proteome research.
PMID- 10786885
TI - Combination of electrophoretic techniques for comprehensive analysis of complex
protein systems.
AB - Analysis of proteins in complex mixtures such as cell lysates is presently
performed by two-dimensional polyacrylamide gel electrophoresis under denaturing
conditions (denaturing 2-D PAGE) followed by extraction of proteins from gel
pieces and structural analysis of the proteins. This type of protein analysis is
contributing to the correlation of information stored in DNA sequences with the
structure of the product polypeptides. However, denaturing 2-D PAGE has its own
limitations and it is necessary to develop various methods of protein analysis to
reconstruct the total structure and function of proteins in complex systems. This
review article summarizes the work in our laboratory to explore proteins in human
plasma combining various electrophoretic techniques: nondenaturing and denaturing
2-D PAGE, capillary electrophoresis, and agarose gel isoelectric focusing.
PMID- 10786888
TI - Biosensor chip mass spectrometry: a chip-based proteomics approach.
AB - Rapid advances in genomic sequencing, bioinformatics, and analytical
instrumentation have created the field of proteomics, which at present is based
largely on two-dimensional electrophoresis (2-DE) separation of complex protein
mixtures and identification of individual proteins using mass spectrometry. These
analyses provide a wealth of data, which upon further evaluation leads to many
questions regarding the structure and function of the proteins. The challenge of
answering these questions create a need for high-specificity approaches that may
be used in the analysis of biomolecular recognition events and interacting
partners, and thereby places great demands on general protein characterization
instrumentation and the types of analyses they need to perform. Over the past
five years we have been actively involved in interfacing two general,
instrumental techniques, surface plasmon resonance-biomolecular interaction
analysis (SPR-BIA) and matrix-assisted laser desorption/ionization time-of-flight
(MALDI-TOF) mass spectrometry, into a single concerted approach for use in the
functional and structural characterization of proteins. Reviewed here is the
recent progress made using biomolecular interaction analysis - mass spectrometry
(BIA-MS) in the detailed characterization of proteins and protein-protein
interactions and the development of biosensor chip mass spectrometry (BCMS) as a
new chip-based proteomics approach.
PMID- 10786886
TI - A thousand points of light: the application of fluorescence detection
technologies to two-dimensional gel electrophoresis and proteomics.
AB - As proteomics evolves into a high-throughput technology for the study of global
protein regulation, new demands are continually being placed upon protein
visualization and quantitation methods. Chief among these are increased detection
sensitivity, broad linear dynamic range and compatibility with modern methods of
microchemical analyses. The limitations of conventional protein staining
techniques are increasingly being encountered as high sensitivity electrophoresis
methods are interfaced with automated gel stainers, image analysis workstations,
robotic spot excision instruments, protein digestion work stations, and mass
spectrometers. Three approaches to fluorescence detection of proteins in two
dimensional (2-D) gels are currently practiced: covalent derivatization of
proteins with fluorophores, intercalation of fluorophores into the sodium dodecyl
sulfate (SDS) micelle, and direct electrostatic interaction with proteins by a
Coomassie Brilliant Blue-type mechanism. This review discusses problems
encountered in the analysis of proteins visualized with conventional stains and
addresses advances in fluorescence protein detection, including immunoblotting,
as well as the use of charge-coupled device (CCD) camera-based and laser-scanner
based image acquisition devices in proteomics.
PMID- 10786887
TI - Protein identification methods in proteomics.
AB - A combination of high-resolution two-dimensional (2-D) polyacrylamide gel
electrophoresis, highly sensitive biological mass spectrometry, and the rapidly
growing protein and DNA databases has paved the way for high-throughput
proteomics. This review concentrates on protein identification. We first discuss
the use of protein electroblotting and Edman sequencing as tools for de novo
sequencing and protein identification. In the second part, we highlight matrix
assisted laser desorption/ionization mass spectrometry (MALDI-MS) as one of the
main contemporary analytical methods for linking gel-separated proteins to
entries in sequence databases. In this context we describe the two main MALDI-MS
based identification methods: (i) peptide mass fingerprinting, and (ii) post
source decay (PSD) analysis. In the last part, we briefly emphasize the
importance of sample preparation for obtaining highly sensitive and high-quality
MALDI-MS spectra.
PMID- 10786893
TI - Cancer proteomics: from identification of novel markers to creation of artifical
learning models for tumor classification.
AB - Studies of global protein expression in human tumors have led to the
identification of various polypeptide markers, potentially useful as diagnostic
tools. Many changes in gene expression recorded between benign and malignant
human tumors are due to post-translational modifications, not detected by
analyses of RNA. Proteome analyses have also yielded information about tumor
heterogeneity and the degree of relatedness between primary tumors and their
metastases. Results from our own studies have shown a similar pattern of changes
in protein expression in different epithelial tumors, such as decreases in
tropomyosin and cytokeratin expression and increases in proliferating cell
nuclear antigen (PCNA) and heat shock protein expression. Such information has
been used to create artificial learning models for tumor classification. The
artificial learning approach has potential to improve tumor diagnosis and cancer
treatment prediction.
PMID- 10786890
TI - The analysis of microbial proteomes: strategies and data exploitation.
AB - Microbes present special opportunities for proteomic analysis that are not yet
available for other types of organisms, due mainly to the relative abundance of
information on their genomes, their low levels of functional redundancy and their
experimental tractability. They are also being used to develop and validate
powerful new experimental approaches that surmount some important current
limitations in this field. The review surveys the different proteomic procedures
that are available and considers the advantages and disadvantages of different
experimental strategies. The ways in which microbiologists - and others - can
exploit proteomic data are also discussed.
PMID- 10786892
TI - Biomedical applications of two-dimensional electrophoresis using immobilized pH
gradients: current status.
AB - There is currently much interest, as we enter the postgenome era, in studying
gene expression at the protein level. Two-dimensional electrophoresis (2-DE)
using immobilized pH gradients (IPG), coupled with mass spectrometry (MS), is
currently the most widely utilized approach for the analysis of whole tissue
proteins. The methodology for IPG-based 2-DE, since the introduction of the
technique in the 1980s, is reviewed. In its present form the IPG methodology is
mostly useful as a research tool. In general, high reproducibility and high
resolution have been achieved. However, the lack of substantial automation and
the limited sensitivity of the current overall methodology continue to represent
drawbacks for biomedical applications. Further developments to increase
throughput and to reduce sample requirement would substantially benefit the
application of IPG-based 2-DE to biomedicine and would enhance the prospects for
introducing the methodology into the clinical laboratory.
PMID- 10786894
TI - Heat shock proteins in human cancer.
AB - The heat shock proteins (hsp) are ubiquitous molecules induced in cells exposed
to sublethal heat shock, present in all living cells, and highly conserved during
evolution. Their function is to protect cells from environmental stress damage by
binding to partially denatured proteins, dissociating protein aggregates, to
regulate the correct folding, and to cooperate in transporting newly synthesized
polypeptides to the target organelles. The molecular chaperones are involved in
numerous diseases, including cancer, revealing changes of expression. In this
review, we mainly describe the relationship of hsp expression with human cancer,
and discuss what is known about their post-translational modifications according
to malignancies.
PMID- 10786891
TI - Proteomics in medical microbiology.
AB - The techniques of proteomics (high resolution two-dimensional electrophoresis and
protein characterisation) are widely used for microbiological research to analyse
global protein synthesis as an indicator of gene expression. The rapid progress
in microbial proteomics has been achieved through the wide availability of whole
genome sequences for a number of bacterial groups. Beyond providing a basic
understanding of microbial gene expression, proteomics has also played a role in
medical areas of microbiology. Progress has been made in the use of the
techniques for investigating the epidemiology and taxonomy of human microbial
pathogens, the identification of novel pathogenic mechanisms and the analysis of
drug resistance. In each of these areas, proteomics has provided new insights
that complement genomic-based investigations. This review describes the current
progress in these research fields and highlights some of the technical challenges
existing for the application of proteomics in medical microbiology. The latter
concern the analysis of genetically heterogeneous bacterial populations and the
integration of the proteomic and genomic data for these bacteria. The
characterisation of the proteomes of bacterial pathogens growing in their natural
hosts remains a future challenge.
PMID- 10786895
TI - Proteomics in molecular medicine: applications in central nervous systems
disorders.
AB - Bodily fluids such as cerebrospinal fluid (CSF) and serum can be analysed at the
time of presentation and throughout the course of the disease. Changes in the
protein composition of CSF may be indicative of altered CNS protein expression
pattern with a causative or diagnostic disease link. These findings can be
strengthened through subsequent proteomic analysis of specific brain areas
implicated in the pathology. New isolation strategies of clinically relevant
cellular material such as laser capture microdissection, protein enrichment
procedures and proteomic approaches to neuropeptide and neurotransmitter analysis
give us the opportunity to map out complex cellular interaction at an
unprecedented level of detail. In neurological disorders multiple underlying
pathogenic mechanisms as well as an acute and a chronic CNS disease components
may require a selective repertoire of molecular targets and biomarkers rather
than an individual protein to better define a complex disease. The resulting
proteome database bypasses many ambiguities of experimental models and may
facilitate pre- and clinical development of more specific disease markers and new
selective fast acting therapeutics.
PMID- 10786901
TI - An investigation of the reactions of H3O+ and O2+ with NO, NO2, N2O and HNO2 in
support of selected ion flow tube mass spectrometry
AB - A selected ion flow tube (SIFT) experimental investigation has been carried out
of the reactions of H3O+, NO+ and O2+ with NO, NO2, N2O and HNO2, in order to
obtain the essential kinetic data for the analyses of these compounds in air
using selected ion flow tube mass spectrometry (SIFT-MS). These investigations
show that NO+ ions do not react at a significant rate with any of these NOx
compounds and that H3O+ ions react only with HNO2 (product ions H2NO2+ (75%) and
NO+ (25%)). O2+ ions react with NO (product ion NO+), NO2 (product ion NO2+) and
HNO2 (product ions NO+ (75%), NO2+ (25%)), but not with N2O. We conclude that
both NO and NO2 can be accurately quantified in air using only O2+ precursor ions
and SIFT-MS when HNO2 is not present. However, when HNO2 is present it invariably
co-exists with both NO and NO2 and then both H3O+ and O2+ precursor ions are
needed to determine the partial pressures of NO, NO2 and HNO2 in the air mixture.
We also conclude that currently N2O cannot be analysed in air using SIFT-MS.
PMID- 10786896
TI - Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by
liquid chromatography/electrospray ionization mass spectrometry.
AB - Methylphenidate (MP, Ritalin) is a psychotropic drug widely prescribed to
children for treating the symptoms of attention deficit disorder with and without
hyperactivity. Because little information exists about the effects of chronic MP
administration on cognitive function in children, measures of behavior changes in
non-human primates are important surrogates. An essential component of such
studies is the determination of MP plasma levels under chronic and acute dosing
conditions. An analytical method was developed that provided sufficient
sensitivity to measure low levels of the active parent drug (lower limit of
quantitation = 0.25 ng/mL) and the inactive metabolite, ritalinic acid (RA), in
monkey plasma as well as the ability to conveniently analyze large numbers of
samples. The method uses a polymeric reversed-phase sorbent for solid phase
extraction, an efficient reverse-phase high performance liquid chromatography
(HPLC) separation, deuterated internal standards for isotope dilution
quantification of MP and RA, and detection by sensitive electrospray ionization
mass spectrometry (ES-MS) with a single quadrupole instrument. The method
responses are linear over the range of plasma concentrations of MP and RA
observed in monkeys, gives respective analyte recoveries of 75 and 60% with
reasonable precision and accuracy, and demonstrates robust MS performance for
rapid determination of MP/RA plasma levels. The average peak MP concentration
(ca. 16 ng/mL) and half-lives for MP and RA elimination in monkeys (1.79 and 2.31
h, respectively) were not significantly different under acute vs. chronic dosing
conditions and were comparable to values previously reported from human studies.
PMID- 10786899
TI - Electron impact mass spectral fragmentation of 2a,4-disubstituted 2-chloro/2,2
dichloro-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothia zepin-1-ones.
AB - The mass spectrometric behaviour of nine 2a,4-disubstituted 2-chloro/2,2-dichloro
2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]b enzothiazepin-1-ones has been studied
with the aid of mass-analysed ion kinetic energy spectrometry and accurate mass
measurements under electron impact ionization. All compounds show a tendency to
eliminate a neutral chlorine atom, or a chloroketene, or neutral propene, or
styrene or substituted styrene molecule, plus Cl and/or H (or Cl) atom(s), to
yield [M-Cl]+ ions, 2,3-dihydro-1,5-benzothiazepine derivative ions, 4,5-dihydro
5H-1,5-benzothiazepin-4-one ions which can further lose CO to give 1,4
benzothiazine ions. Both molecular ions and [M-Cl]+ ions show a tendency to
eliminate an ethyl or benzyl/substituted benzyl radical to produce 2,2a-dihydro
1H-azeto[2,1-c][1,4]benzothiazin-1-one ions. The [M-Cl]+ ions could undergo
rearrangement to yield 2,2a-dihydro-1H-azeto[2,1-d][1,5]benzothiazepin-1-one
ions, 2,2a,3,4-tetrahydro-1H-azeto[1,2-a]quinoline ions or 1,1a,2,3-tetrahydro
azirino[2,1-d][1,5]benzothiazepine ions by loss of an ethane or a
benzene/substituted benzene, a SH radical or a CO molecule. The molecular ions
could also undergo rearrangement reactions to form other small fragment ions.
PMID- 10786898
TI - Electron impact mass spectral fragmentation patterns of 2a,4-disubstituted 5
benzoyl-2-chloro-2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodiazepin-1( 2H)-ones.
AB - The mass spectrometric behaviour of six 2a,4-disubstituted 5-benzoyl-2-chloro
2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodia zepin-1(2H)-ones has been studied
with the aid of mass-analysed ion kinetic energy spectrometry and accurate mass
measurements under electron impact ionization. All compounds show a tendency to
eliminate a chlorine atom, a chlorine atom plus benzaldehyde, benzoyl radical,
chloroketene or chlorine atom plus CO and H2O molecules to yield, respectively,
[M-Cl]+ ions, 2a,4-disubstituted 2a,3-dihydroazeto[1,2-a][1,5]benzodiazepin-1(2H)
one ions, [M-PhCO]+ ions, 2,4-disubstituted 1-benzoyl-2,3-dihydro-1H-1,5
benzodiazepine ions, or 1,2,4-trisubstituted 1H-1,7-benzodiazonine ions, which
could also be formed from [M-Cl]+ ions by loss of CO and H2O molecules
simultaneously. The [M-Cl]+ ions could further lose benzoyl radical to form [M-Cl
PhCO]+ ions, or lose benzoyl amide and undergo a rearrangement to form 4,6
disubstituted 1-benzoazocine-2(1H)-one ions. The [M-PhCO]+ ions could eliminate
NH to produce 2a,4-disubstituted 2,2a,3,4-tetrahydroazeto[1,2,-a]quinolin-1-one
ions, which could further eliminate chloroketene, CO and/or HCl to produce some
important ions, respectively. 2,4-Disubstituted 1-benzoyl-2,3-dihydro-1H-1,5
benzodiazepine ions could lose benzoyl radical to yield 2,4-disubstituted 2,3
dihydro-1H-1,5-benzodiazepine ions, which could further yield other small
fragment ions by loss of propene/styrene or small fragments.
PMID- 10786900
TI - Liquid chromatography electrospray mass spectrometry with variable fragmentor
voltages gives simultaneous elemental and molecular detection of arsenic
compounds.
AB - A single quadrupole high performance liquid chromatography electrospray mass
spectrometry system with a variable fragmentor voltage facility was used in the
positive ion mode for simultaneous recording of elemental and molecular mass
spectral data for arsenic compounds. The method was applicable to the seven
organoarsenic compounds tested: four arsenic-containing carbohydrates
(arsenosugars), a quaternary arsonium compound (arsenobetaine), dimethylarsinic
acid, and dimethylarsinoylacetic acid. It was not suitable for the two inorganic
arsenic species arsenite and arsenate. In the case of arsenosugars, qualifying
ion data for a characteristic common fragment (m/z 237) was also simultaneously
obtained. The method was used to identify and quantify the major arsenosugars in
crude extracts of two brown algae.
PMID- 10786897
TI - Comparison of cyclodextrin-barbiturate noncovalent complexes using electrospray
ionization mass spectrometry and capillary electrophoresis.
AB - Various noncovalent complexes between native and derivatized cyclodextrins (CDs)
and barbiturates were studied using capillary electrophoresis (CE) and
electrospray ionization mass spectrometry (ESI-MS). This paper involves the study
of four aspects of CD-barbiturate noncovalent inclusion complexes. The first
study focused on determining the formation of CD-barbiturate inclusion complexes
in ESI-MS. This determination was accomplished by the comparison of migration
data from CE with ESI-MS inclusion complex peak abundances, which were found to
be complementary. The second study found the possibility of predicting native
beta-CD mediated CE elution orders for barbiturates using data from ESI-MS. A
third study focused on the formation of barbiturate inclusion complexes with
derivatized beta-CD and gamma-CD. As part of this study, the effect of the extent
of side chain substitution on native CD complexation behavior was investigated.
The results indicated that the number of side chains on the CD does not affect
the formation of barbiturate complexes with the hydrophobic CD cavity. Finally, a
comparison of the hydroxypropyl-beta-CD-barbiturate and hydroxypropyl-gamma-CD
barbiturate complexes in CE and ESI-MS was made to study the relationship between
strength of drug-CD binding and enantioresolution. The results from the above
studies indicated that the gas phase and the solution state complexes showed
comparable behavior indicating that similar interactions played a role in
stabilizing these complexes. While it was possible to use the ESI-MS data to
determine drug binding to the CDs, it was not possible to predict whether a
separation of the enantiomers of a chiral barbiturate would occur. However, the
ESI-MS data could be used to eliminate certain CDs from consideration as chiral
selectors.
PMID- 10786902
TI - Characterization of exogenous testosterone in livestock by gas
chromatography/combustion/isotope ratio mass spectrometry: influence of feeding
and age.
AB - The detection of exogenous testosterone in bovine urine was investigated by using
gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). The
carbon isotopic ratio measurement of epitestosterone, etiocholanolone
(testosterone metabolite) and DHEA (testosterone precursor) in female bovine
urines after testosterone enanthate administration was carried out. An important
modification in the 13C/12C ratio of testosterone metabolites was observed, such
that significant differences between precursor and metabolites of testosterone
occurred until three weeks after intramuscular administration of testosterone
enanthate. The factors influencing the 13C/12C of endogenous steroids were
studied especially through cattle feeding and age. The DHEA mean delta13C value
was found to vary between -25 and -26/1000 when hay and concentrate diet were
used for fattening. On the other hand the delta13C value observed when maize
silage was used increased to -20/1000. Testosterone metabolites showed the same
delta13C increase as their precursor. Moreover, we observed a clear relationship
between age and efficiency of misuse determination. Indeed, because of the lower
concentration of natural hormones in young animals, the contribution of exogenous
molecules increases significantly compared with older subjects. Consequently,
demonstration of administration is easier to achieve in calves than in mature
animals.
PMID- 10786904
TI - Electrospray ionization in the study of the polycondensation of Ti(O-i-C3H7)4 and
Ti(O-n-C4H9)4
AB - The polycondensation of Ti(O-i-C3H7)4 (1) and Ti(O-n-C4H9)4 (2), precursors
widely employed in sol-gel processes, has been investigated by electrospray
ionization mass spectrometry. By analysis of 10(-6) M methanol solutions of
compounds 1 and 2, the same ionic species are detected, proving that the first
step in the polycondensation reaction is the i-propyl (or n-butyl) alcohol
methanol complete exchange. This reaction leads to the Ti(OCH3)4 (3) species,
representing the synthon of the polycondensation. Various oligomers of 3 have
been detected and characterized by MS/MS experiments, and the related mechanisms
have been discussed. A minor oligomeric series due to hydroxyl-containing
polycondensation products has also been characterized.
PMID- 10786905
TI - Effects of ion mode and matrix additives in the identification of bacteria by
intact cell mass spectrometry.
AB - Protocols for the identification of bacterial cells by intact cell matrix
assisted laser desorption/ionisation time-of-flight mass spectrometry (ICM-TOFMS)
are presented. A mass range of 500 to 10,000 m/z is used. The use of formic acid
and the crown ether 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (18-crown-6) is
described. Crown ether is useful for removing metal ion adducts, which degrade
spectral purity, and formic acid promotes positive ions, improves spectral
signal, and, hence, increases identification certainty.
PMID- 10786907
TI - Mass spectrometrically detected directly coupled high performance liquid
chromatography/nuclear magnetic resonance spectroscopy/mass spectrometry for the
identification of xenobiotic metabolites in maize plants.
AB - Reconstructed ion chromatograms have been used to identify relevant high
performance liquid chromatography (HPLC) peaks in a directly coupled high
performance liquid chromatography/nuclear magnetic resonance spectroscopy/mass
spectrometry (HPLC/NMR/MS) experiment. This has been applied to a study of the
metabolism of a model compound, 5-nitropyridone (2-hydroxy-5-nitropyridine), in
maize plants grown hydroponically. By monitoring the on-flow reconstructed ion
chromatogram corresponding to the 5-nitropyridone fragment at m/z 143, and
additional molecular ions corresponding to metabolites identified as products
from similar compounds, relevant peaks were identified rapidly for subsequent
stopped-flow 1H NMR spectroscopic analysis. The combination of coupled
HPLC/NMR/MS enabled the direct identification of three metabolites, namely the N
glucoside, N-malonylglucoside, and O-malonylglucoside. This work demonstrates the
power of HPLC/NMR/MS for the structural elucidation of xenobiotic metabolites in
complex biological matrices (such as plant material) with minimal sample
preparation. In particular, using mass spectrometry for the initial
identification of relevant HPLC peaks allows the analysis of complex samples
without the necessity for other spectroscopic markers, such as 19F NMR signal for
fluorinated compounds or UV spectroscopy for molecules with strong UV
chromophores.
PMID- 10786903
TI - Tandem mass spectrometry and accurate mass analysis of some N-arylphthalimides.
IV
AB - The mass spectral studies of six N-arylphthalimides are reported. The low
resolution spectra in conjunction with tandem mass spectrometry (MS/MS) and
accurate mass measurements have provided valuable information, and established
the fragmentation modes of the title compounds more precisely.
PMID- 10786909
TI - Differentiation of enantiomers using matrix-assisted laser desorption/ionization
mass spectrometry.
AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has
successfully been used to differentiate pseudo-enantiomeric (isotopically
labelled) amino acids by using cyclodextrin as complexing host. By using
different pseudo-enantiomeric mixtures (i.e. R(Dn) + S; and R + S(Dn)), it has
been demonstrated that the preference of cyclodextrin for S-enantiomers is not
due to the size differences caused by the hydrogen/deuterium substitution. It is
postulated that this method can be extended to differentiate enantiomers (and
determine enantiomeric excess) by using a pair of enantiomeric hosts, as
demonstrated previously using other ionization techniques, but with much higher
sensitivity.
PMID- 10786906
TI - On-line sample preparation using restricted-access media in the analysis of the
soy isoflavones, genistein and daidzein, in rat serum using liquid chromatography
electrospray mass spectrometry.
AB - Soy isoflavones are the subject of many investigations in experimental animals
and humans regarding possible modulation of endocrine activity and
chemoprevention of carcinogenesis. Genistein and daidzein, the principal
biologically active isoflavones in soy, were measured using on-line solid-phase
extraction (SPE) and liquid chromatography electrospray mass spectrometry (LC/ES
MS) detection in serum of rats consuming a common open-formula (NIH 31) chow that
contained approximately 30 microg each of genistein and daidzein per gram of feed
and a specially designed 'soy-free' chow that contained approximately 60-fold
lower isoflavones. The use of a restricted-access/reverse phase trap cartridge
and automated column switching permitted rapid and robust analytical performance
with many injections of plasma onto a reverse phase LC column. Enzymatic
deconjugation and a single centrifugation step were the only sample preparation
steps required. The limit of detection for the isoflavones, based on the MS
responses observed in serum from male and female rats consuming the soy-free
chow, was 0.020 microM. The method, which uses deuterated isoflavones as internal
standards, was determined to be accurate using spiked control serum (102-110% of
added amounts) and precise using spiked control serum and incurred serum (<6%
relative standard deviation). The average genistein and daidzein levels were
determined in female (0.62 and 0.25 microM, respectively) and male rats (0.35 and
0.20 microM, respectively) consuming the standard diet. The sex difference
observed for serum genistein concentrations was statistically significant (p <
0.0001). These results underscore the potential impact of standard open-formula
diets on the results from rodent bioassays of biological activity.
PMID- 10786912
TI - Comment on 'New mass spectrometric approaches to structural analysis in
mixtures', Rapid Commun. Mass Spectrom. 1999; 13: 1797
PMID- 10786910
TI - Error-systematics of determining elemental isotopic abundance ratios by the
molecular ion beam method: a case study for the simultaneous isotopic analysis of
lithium and boron as Li2BO2+
AB - The simultaneous isotopic analysis of lithium and boron by the Li2BO2+ ion beam
method involves measurements of two different molecular abundance ratios (say,
Rj+/-delta(j) and Rk+/-delta(k)), and subsequently extensive calculations to
arrive at the analyte isotopic ratios (say, L and Y). It is not presently known
how the measurement errors (delta(j) and delta(k)) are transformed into the
errors of analysis (deltaL and deltaY). This work addresses this question from
fundamental considerations. In the literature, the calculations are sometimes
simplified using Ri formulae based on Li2B16O2+ ions and then applying correction
factors for the actual Li2BO2+ ions, but this procedure is not generally
applicable. We show how equations based on true Li2BO2+ ions (with full isotopic
variations of all the constituent elements) can be solved, and illustrate the
procedure with several examples. These studies show that accuracy of analysis
depends not only on the accuracies of measurements, delta(j) and delta(k), but
also on the particular isotopic Li2BO2+ ion-pairs (j and k) used as the monitor
pairs. Moreover, this dependence is shown to be different for the different
isotopic ratios (L and Y) to be determined simultaneously. Therefore, proper
selection of monitor molecular pairs is a requirement for avoiding larger
(propagated) errors in the analysis. Similar arguments would, in fact, apply to
any arbitrarily chosen case of determining two or an even greater number of
isotopic abundance ratios (Ei's) by the molecular ion beam method, irrespective
of whether the different analyte ratios, Ei's, relate to a single multi-isotopic
element, or different elements.
PMID- 10786911
TI - Error-systematics of determining simultaneously the isotopic abundance ratios of
natural lithium and natural boron as Li2BO2+
AB - Recently, we have shown how the errors delta(j) and delta(k), that occur when
measuring the two different isotopic molecular abundance ratios required for
analysis, are transformed into the actual errors of elemental isotopic analysis,
(deltaEi/Ei)'s. With a view to gain further understanding as to how the errors
(deltaEi/Ei)'s are governed, we now evaluate theoretically the effects of
selecting different isotopic molecular pairs as the monitor pairs (j and k) for
measurements, and of the measurement errors (delta(j) and delta(k)), on the
results of analysis (the 6Li/7Li and the 10B/11B abundance ratios), by
considering all the constituent elements of Li2BO2+ at their natural isotopic
abundances. It is shown that the ratio of measurement errors, delta(j)/delta(k),
is a more fundamental parameter than either the individual errors (delta(j) and
delta(k)), or their sum, absolute value(delta(j)) + absolute value(delta(k)), in
governing deltaEi/Ei. The important implication of this observation is that it
reveals the possibility of achieving not only a desired level of accuracy in
analysis, but even absolute accuracy (i.e. deltaEi/Ei = 0) by causing mutual
cancellation of the effects of individual measurement errors delta(j) and
delta(k), through proper regulation of measurement parameters. However, as the
measurement errors cannot be pre-set, it is shown how selection of proper monitor
pairs (j and k) can help achieve the desired accuracy in analysis. The present
work sets guidelines for the more general problem of selecting monitor pairs to
avoid larger errors in analysis.
PMID- 10786915
TI - Sepsis due to Clostridium septicum: case report.
PMID- 10786914
TI - Should technologists perform barium enemas?
PMID- 10786913
TI - Electroelution and passive elution of gamma-globulins from sodium dodecyl
sulphate polyacrylamide gel electrophoresis gels for matrix-assisted laser
desorption/ionisation time-of-flight mass spectrometry.
PMID- 10786908
TI - Determination of methotrexate in environmental samples by solid phase extraction
and high performance liquid chromatography: ultraviolet or tandem mass
spectrometry detection?
AB - In order to assess exposure levels of hospital personnel involved in the
preparation and administration of antineoplastic drugs, environmental monitoring
should be carried out. Wipe samples, pads, gloves and air samples should be
collected at the end of each work shift, properly treated and then analysed using
instrumental techniques which are sufficiently sensitive and specific to detect
even trace amounts of drug. In this study, a method using high performance liquid
chromatography/tandem mass spectrometry (HPLC/MS/MS), incorporating solid phase
extraction (SPE), was validated for determination of methotrexate (MTX) in wipe
and air samples. Each step of the method was first developed and optimised using
ultraviolet detection (UV), and afterwards tandem mass spectrometry was used to
obtain a lower limit of quantitation when the expected drug level was less than
the analytical UV detection limit. SPE enabled a 20-fold preconcentration of the
analyte when using HPLC/UV and a further 30-fold preconcentration was obtained
when analysing samples by HPLC/MS/MS. For example, the limit of quantitation
(LLQ) was lowered from 3000 ng on wipe (direct injection onto an HPLC/UV system)
to 5 ng on wipe (SPE plus HPLC/MS/MS). 7-hydroxymethotrexate was used as internal
standard to assess precision and accuracy.
PMID- 10786919
TI - Ultrasound-guided renal biopsy: experience using an automated core biopsy system.
AB - OBJECTIVE: To assess the safety and efficacy of ultrasound-guided percutaneous
renal biopsy using an automated core biopsy system, and to determine
radiologists' accuracy in predicting sample adequacy. METHODS: Ninety-five
biopsies were performed on 25 native kidneys and 70 renal allografts using a 16
gauge automated, spring-loaded core biopsy device under real-time sonographic
guidance. Radiologists performing the biopsy estimated the number of core samples
needed to obtain an adequate specimen, based on visual inspection of each core.
The final determination of the number of samples was made by a pathology
technologist who attended each biopsy, based on preliminary microscopic
examination of tissue cores. After each biopsy, an ultrasonographic examination
was performed to search for biopsy-related hemorrhage, and a questionnaire was
given to the patient to determine biopsy-related complications, which were
categorized as either minor or major. RESULTS: The main indication for biopsy was
acute renal failure (in 43.2% of biopsies). An average of 3 tissue cores per
biopsy were obtained. Of the 94 patients in whom a biopsy was conducted to
exclude diffuse renal disease, a mean of 12.5 glomeruli were present in each
specimen. Overall, adequate tissue for diagnosis was obtained in 98.9% of cases.
The radiologists' estimate of the number of core samples needed concurred with
the pathology technologists' determination of sample adequacy in 88.4% of cases.
A total of 26 complications occurred (in 27.4% of biopsies), consisting of 23
minor (24.2%) and 3 major (3.2%) complications. CONCLUSIONS: Real-time
sonographic guidance in conjunction with an automated core biopsy system is a
safe and accurate method of performing percutaneous renal biopsy. Routine use of
sonographic examinations to search for biopsy-related complications is not
indicated. Radiologists are accurate in estimating sample adequacy in most cases;
however, the presence of a pathology technologist at the biopsy procedure
virtually eliminates the possibility of obtaining insufficient tissue for
histologic diagnosis.
PMID- 10786917
TI - Computed tomographic abnormalities in Mycobacterium avium complex lung disease
include the mosaic pattern of reduced lung attenuation.
AB - OBJECTIVE: To describe the range and frequency of abnormalities on computed
tomographic (CT) scans in patients who met the American Thoracic Society (ATS)
case definition of Mycobacterium avium complex (MAC) lung disease. Further, to
report the effect of time and treatment on the progression of these
abnormalities. METHODS: The demographic, clinical and radiologic features of 10
patients with proven MAC lung disease (mean age 71 years, standard deviation 12
years) were described. The presence or absence of 14 CT abnormalities was
recorded in each of 10 lung zones. The effects of time and treatment on the
abnormalities were recorded. RESULTS: The patients' lung function was minimally
impaired. Pretreatment CT scans showed small nodules in 47% of the lung zones,
reduced lung attenuation in 41%, and bronchiectasis in 27%. Bronchiectasis was
associated with nodules in 20 zones from 9 patients and with no nodules in 7
zones from 1 patient. Reduced attenuation was associated with bronchiectasis
alone in 8 zones, with nodules alone in 25 zones and with both bronchiectasis and
nodules in 8 zones. In patients without treatment, or with non-curative
treatment, bronchiectasis developed or worsened in 12 of 26 zones and resolved or
improved in none. In contrast, after curative treatment, small nodules
disappeared completely in 10 of 21 zones and developed in none. Of 7 zones with
only nodules and reduced attenuation before treatment, 6 had no abnormalities
after treatment. CONCLUSIONS: Our data suggest that the 3 leading CT
abnormalities in nodular-bronchiectatic MAC lung disease are small nodules,
reduced attenuation and bronchiectasis. Reduced attenuation appeared to result
from gas trapping and hypoxic vasoconstriction due to bronchiolocentric
inflammatory nodules. Bronchiectasis appeared to be secondary to this bronchiolar
disease.
PMID- 10786924
TI - Case of the month #77. A 14-year-old boy presented with long-standing anemia and
a recent history of vomiting and abdominal pain.
PMID- 10786916
TI - Button sequestrum in a case of localized Langerhans' cell histiocytosis of the
ilium: case report.
PMID- 10786922
TI - Answer to case of the month #75. Renal angiomyolipoma with intratumoral
hemorrhage and local nodal extension.
PMID- 10786918
TI - Bronchiolitis obliterans after lung transplantation: appearance on expiratory
minimum intensity projection images.
AB - OBJECTIVE: Bronchiolitis obliterans can manifest as a mosaic pattern of lung
attenuation on computed tomographic (CT) scans. This study was conducted to
investigate image enhancement using expiratory minimum intensity projection
images and to compare these with thin-section scans. METHODS: Eleven patients (21
transplanted lungs) with biopsy-proven bronchiolitis obliterans were studied. Ten
1-mm thin-section scans were acquired helically at the level of the carina after
full expiration. Expiratory minimum intensity projection images 10 mm thick were
generated from a multiplanar reconstruction of data. Two thoracic radiologists
analyzed the images. RESULTS: In comparison with thin-section scans, expiratory
minimum intensity projection images demonstrated a greater (in 17 lungs) or equal
(in 4 lungs) percentage area of air trapping, with greater conspicuity (in all 21
lungs). Air trapping involved an average of 52% of the cross-sectional area of 1
lung. CONCLUSIONS: Air trapping due to bronchiolitis obliterans is accentuated by
forced expiration; minimum intensity projection images improve the detection of
differences in lung attenuation. Therefore, expiratory minimum intensity
projection images are very useful in demonstrating the mosaic pattern of lung
attenuation caused by bronchiolitis obliterans.
PMID- 10786920
TI - Extraprostatic biopsy improves the staging of localized prostate cancer.
AB - OBJECTIVE: To evaluate the role and safety of biopsy of the seminal vesicles and
neurovascular bundles in determining the pathologic stage of prostatic carcinoma.
METHODS: Eighty-one consecutive patients were enrolled in a comprehensive
cryosurgical biopsy protocol that included sextant intraprostatic plus
extraprostatic biopsy. The pathologic stage, determined after biopsy, was
compared with the clinical stage, determined by digital rectal examination (DRE)
and transrectal ultrasonographic (TRUS) evaluation. As well, complication rates
for these patients were compared with rates for a separate group that underwent
sextant intraprostatic biopsy alone. RESULTS: Of the 81 patients, 61 (75%) were
confirmed to have cancer by biopsy. None of these patients was considered to have
extraprostatic extension by clinical evaluation (DRE and TRUS), but 16 of 61
(26%) were identified to have extraprostatic cancer in the seminal vesicles (8 of
61, 13%) or in the neurovascular bundles (8 of 61, 13%) by extraprostatic biopsy.
There was no significant difference in the complication rates between sextant
intraprostatic biopsy and sextant intraprostatic plus extraprostatic biopsy
(p>0.97). CONCLUSIONS: Extraprostatic biopsy identifies extension of carcinoma in
a large proportion of patients in whom clinical evaluation by DRE and TRUS
indicates organ-confined disease. Extraprostatic biopsy is therefore warranted as
routine evaluation before surgery in order to correctly stage prostatic carcinoma
and select appropriate therapy.
PMID- 10786923
TI - Answer to case of the month #76. Amniotic band syndrome.
PMID- 10786921
TI - Metallic stents in the treatment of duodenal obstruction: technical issues and
results.
AB - OBJECTIVE: To evaluate the efficacy of duodenal stenting procedures and to review
technical issues with these procedures in a series of cases over a 1-year period.
METHODS: Expandable metallic stents (Wallstents) of varying sizes were introduced
and deployed in 4 patients (1 man and 3 women 42 to 81 years of age). Each
patient underwent a separate method of stent introduction with either
fluoroscopic or endoscopic guidance, either perorally, transgastrically and
transhepatically. RESULTS: All procedures were technically successful, allowing
patients to continue eating normally. In 1 patient, stent foreshortening
necessitated the introduction of a second stent. Another patient experienced
transient stent obstruction by food; this resolved spontaneously and required no
additional intervention. Based on the patients' continuing ability to tolerate
food, it was believed that the stents remained patent until the time of death
(from 3 days to 9 weeks with a mean of 5.25 weeks). CONCLUSIONS: Duodenal
stenting procedures provide a relatively new, technically feasible and
efficacious method of managing duodenal obstructions, especially in patients who
are poor candidates for surgery.
PMID- 10786925
TI - Metabolic effects of L-carnitine on prepubertal rat Sertoli cells.
AB - The role of carnitine on Sertoli cell metabolism was investigated. Carnitine
effects on Sertoli cell lipid metabolism were evaluated by measuring the
intracellular levels of non-esterified fatty acids (NEFA) and ketone bodies. The
concentration of NEFA in Sertoli cell cultured in the presence of carnitine is
significantly reduced as compared to control, while, no significant changes were
observed in the concentration of ketone bodies. The functional parameters
evaluated to assess the influence of carnitine on Sertoli cell carbohydrate
metabolism, i.e., lactate and pyruvate production, lactate dehydrogenase activity
and hexose transport, were all significantly increased following carnitine in
vitro supplementation. Thus, carnitine appears to drive Sertoli cell intermediary
metabolism in an intimately interrelated way, stimulating both fatty acid
breakdown and glycolysis. Our results indicate that Sertoli cells are a possible
target for a widespread metabolic action of carnitine and strongly support the
involvement of carnitine in the regulation of Sertoli cell functions which are
related with germ cell "nutrition", convincingly suggesting a direct influence of
the compound at testis level.
PMID- 10786926
TI - Mutated human beta3-adrenergic receptor (Trp64Arg) lowers the response to beta3
adrenergic agonists in transfected 3T3-L1 preadipocytes.
AB - Wild-type or mutated human beta3-adrenergic receptor (Trp64Arg) cDNAs were stably
expressed in mouse 3T3-L1 cells. Saturation binding study using a beta-adrenergic
ligand revealed that there was no significant difference in the receptor density
and the equilibrium dissociation constant between the two cell lines. However,
the ability of the mutant beta3-adrenergic receptor to accumulate cyclic AMP
(cAMP) in response to isoproterenol was much reduced and Kact for cAMP
accumulation was lowered as compared to the wild type receptor. The amount of
alpha subunit of stimulatory GTP-binding protein (GSalpha) and adenylyl cyclase
activity in response to forskolin were not different in the two cell lines. The
responses of the mutant receptor to epinephrine, norepinephrine and L-755,507, a
highly specific agonist for human beta3-adrenergic receptor, were also reduced,
but the reduction of Kact for L-755,507 was more evident than other agonists
tested. The cAMP accumulation in response to some conventional beta3 agonists was
less than 10% of that to isoproterenol even in the cells expressing the wild type
receptor. These results suggest that the Trp64Arg mutant beta3-adrenergic
receptor has less ability to stimulate adenylyl cyclase, and that lipolytic
activity through the beta3-adrenergic receptor by catecholamines in subjects
carrying this mutation might be suppressed.
PMID- 10786927
TI - Immaturity of glucose-induced insulin secretion in fetal rat islets is due to low
glucokinase activity.
AB - Fetal pancreatic islets show a deficiency in insulin secretion in response to
glucose, but the underlying mechanism is disputed. By isolating pancreatic islets
from 21-day pregnant rats and culturing them with 2.8 or 11.1 mM glucose for 7
days, we attempted to clarify the involvement of low glucokinase activity in the
poor glucose response in islets cultured with 2.8 mM glucose relative to the
response obtained from those cultured with 11.1 mM glucose. The insulin secretion
induced by 10 mM glyceraldehyde or 15 mM leucine, but not that induced by 20 mM
glucose, from islets cultured with 2.8 mM glucose was higher than the basal
insulin secretion, suggesting that the defect in glucose stimulation in fetal
islets may be localized somewhere before the glyceraldehyde 3-phosphate step in
the glycolytic pathway. When islets cultured with 11.1 mM glucose as distinct
from those cultured with 2.8 mM glucose were incubated with glucose, the
glycolytic intermediate contents were increased in a concentration- and time
dependent manner. Utilization of glucose at 20 mM, but not at 5 mM, in islets
cultured with 11.1 mM glucose was higher than that in islets cultured with 2.8 mM
glucose. The Vmax value of glucokinase, but not that of hexokinase or aldolase,
in islets cultured with 11.1 mM glucose was higher by 150% than that in islets
cultured with 2.8 mM glucose. The results suggest that the poor secretion of
insulin in response to glucose can be explained by insufficient glucose
metabolism due to the low glucokinase activity.
PMID- 10786928
TI - Glucose-induced insulin mRNA accumulation is impaired in islets from neonatal
streptozotocin-treated rats.
AB - According to the glucose toxicity hypothesis, hyperglycemia contributes to
defective beta-cell function in type 2, non-insulin-dependent diabetes mellitus.
This concept is supported by substantial data in rodent models of diabetes.
However, the ability of glucose to stimulate the accumulation of insulin mRNA, a
critical feature of normal beta-cell physiology, has not been investigated in in
vivo models of chronic hyperglycemia. The aim of this study was to determine
whether glucose-induced insulin mRNA accumulation is impaired in the neonatal
streptozotocin-treated rat (n0-STZ rat), a model of non-obese, non-insulin
dependent diabetes mellitus. Islets of Langerhans isolated from n0-STZ and
control rats were cultured for 24 h in the presence of 2.8 or 16.7 mmol/L
glucose, and insulin mRNA levels were measured by Northern analysis. Insulin mRNA
levels were increased more than twofold by glucose in control islets. In
contrast, no significant effect of glucose was found on insulin mRNA levels in n0
STZ islets. We conclude that insulin gene regulation by glucose is impaired in n0
STZ rat islets.
PMID- 10786929
TI - Zinc effects on hyperglycemia and hypoleptinemia in streptozotocin-induced
diabetic mice.
AB - Zinc has an antihyperglycemic effect. Zinc can also influence the production of
leptin, a satiety factor that reduces appetite and blood sugar level. In this
study, we investigated the effect of zinc supplementation on food intake and
circulating leptin and glucose concentrations in streptozotocin-induced diabetic
mice. Male diabetic mice received zinc supplementation (20 ppm) from drinking
water for two weeks. The results showed that zinc treatment did not affect body
weight gain, body fat content or food intake in these diabetic mice. However,
zinc supplementation markedly ameliorated the hyperglycemia of diabetic mice.
After zinc treatment, serum leptin concentrations tended to increase in the
diabetic mice. This study suggests that zinc is a mediator of leptin production.
PMID- 10786930
TI - Insulin sensitivity in normotensive offspring of hypertensive parents.
AB - OBJECTIVES: To investigate the insulin sensitivity in normotensive offspring of
hypertensive parents. SUBJECTS: Fifteen young normotensive offspring of
hypertensive parents were paired with 15 controls matched for age, sex and body
mass index. METHODS: The insulin sensitivity was investigated by 75 g oral
glucose tolerance test (OGTT) and modified insulin suppression test. A high-fat
mixed meal was administered to observe the changes of TG levels. RESULTS: The
plasma glucose and serum insulin responses to oral glucose challenge were
comparable between both groups. High-fat mixed meal made no difference in the
plasma glucose, serum triglyceride or insulin between the 2 groups. With the
modified insulin suppression test, the steady-state plasma glucose levels (SSPG)
were higher in the offspring of parents with essential hypertension (138+/-43
mg/dl) than in the control group (95+/-26 mg/dl). The diastolic blood pressure
and heart rate of the offspring of hypertensive parents are also higher than the
control group. CONCLUSIONS: Insulin resistance exists in young normotensive
offspring of hypertensive parents, and the impairment of insulin-mediated glucose
uptake in these subjects develop before any alteration of fasting and
postprandial triglyceride.
PMID- 10786931
TI - Reversibility of autonomic nerve function in relation to rapid improvement of
glycemic control.
AB - To determine the reversibility of autonomic nerve function in relation to the
rapid improvement of glycemic control, we studied 54 patients with type 2
diabetes mellitus (33 men and 21 women; mean age, 49+/-8 years; mean duration of
diabetes, 10+/-7 years). For 4 weeks of admission, the subjects were placed on
strict dietary therapy, and 10 of them were under dietary therapy, 16 initially
continued treatment with oral hypoglycemic agents, while 28 were treated with
insulin. We measured the dark-adapted pupillary area (DAPA) by infrared
photography, an indicator of diabetic autonomic neuropathy, on the second and
28th day after hospitalization. The change in FPG (delta FPG = - 111+/-49 mg/dl;
mean +/- SD, p<0.001) and the change in HbA1c (delta HbA1c = -1.3+/-0.3%,
p<0.001) were significantly improved. We observed significant improvements in the
change in DAPA (delta DAPA) of all patients (25.1+/-11.0 vs. 25.7+/-11.6 mm2,
delta DAPA = 0.6+/-1.4 mm2, p<0.01) and in those of patients without retinopathy
(delta DAPA = 1.0+/-0.6 mm2, p<0.01). No change was observed in those of patients
with retinopathy (delta DAPA= -0.02+/-0.3 mm2, NS). The delta DAPA was related to
the delta HbA1c (r = -0.479, p<0.001) and also to the diabetic duration (years, r
= -0.517, p<0.001). These findings suggest that a rapid improvement of glycemic
control improves autonomic nerve function observed in type 2 diabetes with
shorter duration. Particular attention should be paid to maintaining strict
glycemic control at the stage of diabetic patients without retinopathy and those
with shorter duration.
PMID- 10786932
TI - Stimulation of insulin synthesis and release by alpha-D-glucose pentaacetate in
pancreatic islets from human subjects.
PMID- 10786933
TI - Cancer chemoprevention by tea polyphenols.
AB - Tea is one of the most widely consumed beverages, second only to water. Many
experimental researches in laboratory animals demonstrated that tea components
had an inhibitory effect on carcinogenesis at a number of organ sites. The
inhibitory effects of tea against carcinogenesis have been attributed to the
biologic activities of the polyphenol fraction in tea. This review summarizes
experimental data on chemopreventive effects of tea polyphenols in various tumor
bioassay systems. Many laboratory studies have demonstrated the inhibitory
effects of green tea polyphenols, especially (-)-epigallocatechin-3-gallate
(EGCG), on carcinogenesis in animals models. The majority of these studies have
been conducted in mouse skin tumor models, where tea polyphenols were used either
as oral feeding in drinking water or in direct local application. Most studies
used 12-O-tetradecanoylphorbol-13-acetate (TPA) or ultraviolet (UV) radiation as
the tumor promoter and found anticarcinogenic effects caused by green tea
polyphenols. Black tea was also found to be effective, although the activity was
weaker than that of green tea in some experiments. Other studies showed that
black tea polyphenols-theaflavins exhibited stronger anticarcinogenic activity
than did EGCG. Caffeine in tea was also important for tea to prevent
tumorigenesis. The molecular mechanisms of the cancer chemopreventive effects of
tea polyphenols are not completely understood. They are most likely related to
the mechanisms of biochemical actions of tea polyphenols, which include
antioxidative activities, modulation of xenobiotic metabolite enzymes and
inhibition of tumor promotion. In addition, we have also proposed that tea
polyphenols function as cancer chemopreventive agents through modulation of
mitotic signal transduction. However, the molecular mechanisms involved in this
modulation need further investigation.
PMID- 10786934
TI - Immunohistochemical study of opioid receptors after chronic morphine treatment in
rats.
AB - Previously, we have used the biochemical receptor binding method to investigate
whether down-regulation of the opioid receptor is a mechanism for morphine
tolerance, and we were led to a negative conclusion. In the current study, we
further used immunohistochemistry to reinvestigate this issue. Male Sprague
Dawley rats (250-300 g) were chronically treated with morphine s.c. for 2, 4 or 6
days, using an escalating dosage paradigm (5-45 mg), which resulted in a 1.8 to
4.0-fold increase in AD50. Rat brains were removed, frozen, coronally sectioned
(14 microm) and processed for mu- or delta-opioid receptor immunohistochemistry
using the Avidin-Biotin Complex (ABC) method. No significant decrease in mu
opioid receptor (MOR) immunodensity was found in most of the brain regions, which
were enriched with MOR after chronic treatment with morphine except for the
anteroventral thalamic nucleus in the ventrolateral part (AVVL). No significant
change in delta-opioid receptor (DOR) immunodensity after chronic treatment with
morphine was found either. Therefore, our conclusion is that down regulation of
opioid receptors may not be an important mechanism for morphine tolerance.
PMID- 10786935
TI - Characterization of novel 10-substituted 1,8-dihydroxy-9(10H)-anthracenone
derivatives by mass spectrometry.
AB - Anthralin and its derivatives containing a variety of simple or functionalized
aliphatic and aromatic substituents are of special interest in research on
psoriasis. In this connection, 10-arylthio-1,8-dihydroxy-9(10H)-anthracenones
were synthesized and examined by means of mass spectrometry. In general, the
molecules in question fragmented upon electron impact into ions at m/z 225 (C-S
bond cleavage and charge retention at the anthralin component) and into ions of
unknown structure at m/z 226, requiring H-migration from the S-bound substituent
R into the anthralin moiety. Since mass spectrometry methods furnished us
elegant, matchless means of tracing the amounts of material in the analysis,
especially in the case of physiologically active compounds, we decided to use
mass spectrometry procedures for unequivocal identification and purity
determination of 10-arylthio-anthralins.
PMID- 10786936
TI - Influences on water intake in the rat after lesions of the septal subareas.
AB - It has been suggested that the septum plays an inhibitory role in the behavioral
function. Recent work has shown that the septum is heterogeneous from the
neuroanatomical perspective. The present study examined the water intake of rats
lesioned with kainic acid (0.5 microg/0.5 microl/site) on three septal
subregions: anterior medial (MSa), posterior medial (MSp), and lateral (LS)
sites. Drinking volume was enhanced mostly in rats with the MSp lesion, and so
was locomotor activity. However, these two measures were not significantly
correlated. This polydipsia induced by MSp lesion was also found in a chronic
domain. Another experiment further determined the dipsogenic effects of
polyethylene glycol (PEG; 20%) and hypertonic saline (1 M NaCl) in MSp lesioned
rats. Water intake increased significantly after administration of the hypertonic
saline treatment, but not after injection of PEG. However, this disparity
approached a nonsignificant level 8 hr after thirst challenges were conducted. In
addition to revealing septal hyperdipsia. these data suggest that the septal
subareas can be functionally heterogeneous in drinking behavior. The dipsogenic
response profiles for the cellular and extracellular thirst challenges could be
differentially affected by kainate lesion in the MSp.
PMID- 10786938
TI - Male-specific band in random amplified microsatellite polymorphism fingerprints
of Holstein cattle.
AB - A total of 65 blood samples collected from Holstein cattle were employed for DNA
extraction. Genomic DNA were amplified by means of random amplified polymorphic
DNA (RAPD). One hundred and one random primers (Operon kits OPAA, OPAO, OPAV,
OPC, OPE and OPA-06) were used for polymerase chain reactions (PCR). The PCR
products were size fractionated by means of electrophoresis in agarose gel,
transferred to a nylon membrane, and then hybridized with a alpha-32P-labeled
microsatellite probe for random amplified microsatellite polymorphism (RAMPO)
analysis. All the primers produced many amplification patterns in RAMPO
fingerprints, but only OPE-01 (5'-CCCAAGGTCC-3') yielded a male-specific strong
signal. Among the 65 cases, the specific band could be observed in the RAMPO
fingerprints of the 24 male samples but not in the 41 female samples. Therefore,
this specific band is peculiar to male cattle.
PMID- 10786937
TI - Gel-filtrated fractions of alveolar bone extract contain factors promoting cell
attachment and a mitogenic effect on periodontal ligament fibroblasts.
AB - The purpose of this study was to investigate the effect of acetic acid-extracted
bone proteins on human periodontal ligament fibroblasts (hPF) with respect to
mitogenic and cell attachment promoting activity. Alveolar bone was harvested
from healthy donors and subjected to 0.5 M acetic acid extraction, dialysis and
lyophilization, and gel filtration. Promotion of cell attachment and stimulation
of DNA synthesis by the crude extract and gel-filtrated fractions were studied in
cultured hPE Many protein components, varying in molecular weight from 10-14 to
120 kDa, were detectable in 10% SDS-PAGE of the extract. Gel filtration of bone
extract disclosed four fractions with molecular weights of 55, 34, 29 and 19-20
kDa. Both the 34 and 55 kDa fractions at a concentration of 5 microg/ml, but not
the 29- or 19-20 kDa fractions, were found to promote cell attachment while only
the 55 kDa fraction (5 microg/ml) stimulated DNA synthesis of hPF, Both mitogenic
activity and the promotion of the cell attachment by gel-filtrated active
fractions were resistant to thermal treatment (70 degrees C) and pH (4 to
approximately 8) changes. These findings suggest that acetic acid extract of
alveolar bone may contain components which are capable of modulating cell
attachment and mitogenesis of hPF.
PMID- 10786939
TI - Chemical signaling processes in the marine environment.
AB - Understanding the mechanisms by which environmental chemical signals, chemical
defenses, and other chemical agents mediate various life-history processes can
lead to important insights about the forces driving the ecology and evolution of
marine systems. For chemical signals released into the environment, establishing
the principles that mediate chemical production and transport is critical for
interpreting biological responses to these stimuli within appropriate natural,
historical contexts. Recent technological advancements provide outstanding
opportunities for new discoveries, thus allowing quantification of interactions
between hydrodynamic, chemical, and biological factors at numerous spatial and
temporal scales. Past work on chemically mediated processes involving organisms
and their environment have emphasized habitat colonization by larvae and trophic
relationships. Future research priorities should include these topics as well as
courtship and mating, fertilization, competition, symbiosis, and microbial
chemical ecology. There are now vast new opportunities for determining how
organisms respond to chemical signals and employ chemical defenses under
environmentally realistic conditions. Integrating these findings within a larger
ecological and evolutionary framework should lead to improved understanding of
natural physicochemical phenomena that constrain biological responses at the
individual, population, and community levels of organization.
PMID- 10786940
TI - The fluid dynamical context of chemosensory behavior.
AB - The fluid mechanical environment provides the context in which denizens of
aquatic realms, as well as terrestrial creatures, use chemoperception to search
for objects. Our ability to understand the nature of olfactory-guided navigation
rests on our proficiency at characterizing the fluid dynamic setting and at
relating properties of flow to behavioral and sensory mechanisms. This work
reviews some fluid dynamical concepts that are particularly useful in describing
aspects of flow relevant to chemosensory navigation, and it considers studies of
orientation in animals in light of these principles. Comparisons across broadly
different fluid environments suggest that particular sensory and behavioral
mechanisms may be tailored to specific flow regimes and stimulus environments.
This is clearly evident when examining animals that operate in high vs. low
Reynolds number flows. In other cases, animals may converge on common solutions
in given flow regimes in spite of differences in taxonomic class or size.
Potential parallels may include behavior of aquatic vs. terrestrial arthropods,
and animals without fixed reference points in flows dominated by molecular vs.
turbulent diffusion. In an effort to add further fluid dynamical underpinnings to
navigational strategies, I suggest how simple nondimensional categorization of
behavior in relation to flow may aid in identifying the forces underlying common
elements, even across animals of seemingly disparate size and scale.
PMID- 10786941
TI - Mechanisms of animal navigation in odor plumes.
AB - Chemical signals mediate many of life's processes. For organisms that use these
signals to orient and navigate in their environment, where and when these cues
are encountered is crucial in determining behavioral responses. In air and water,
fluid mechanics impinge directly upon the distribution of odorous molecules in
time and space. Animals frequently employ behavioral mechanisms that allow them
to take advantage of both chemical and fluid dynamic information in order to move
toward the source. In turbulent plumes, where odor is patchily distributed,
animals are exposed to a highly intermittent signal. The most detailed studies
that have attempted to measure fluid dynamic conditions, odor plume structure,
and resultant orientation behavior have involved moths, crabs, and lobsters. The
behavioral mechanisms employed by these organisms are different but generally
integrate some form of chemically modulated orientation (chemotaxis) with a
visual or mechanical assessment of flow conditions in order to steer up-current
or upwind (rheo- or anemo-taxis, respectively). Across-stream turns are another
conspicuous feature of odor-modulated tracks of a variety of organisms in
different fluid conditions. In some cases, turning is initiated by detection of
the lateral edges of a well-defined plume (crabs), whereas in other animals
turning appears to be steered according to an internally generated program
modulated by odor contacts (moth counterturning). Other organisms such as birds
and fish may use similar mechanisms, but the experimental data for these
organisms is not yet as convincing. The behavioral strategies employed by a
variety of animals result in orientation responses that are appropriate for the
dispersed, intermittent plumes dictated by the fluid-mechanical conditions in the
environments that these different macroscopic organisms inhabit.
PMID- 10786942
TI - Life in transition: balancing inertial and viscous forces by planktonic copepods.
AB - Copepods (1-10 mm aquatic crustaceans moving at 1-1000 mm s(-1)) live at Reynolds
numbers that vary over 5 orders of magnitude, from 10(-2) to 10(3). Hence, they
live at the interface between laminar and turbulent regimes and are subject to
the physical constraints imposed by both viscous and inertial realms. At large
scales, the inertially driven system enforces the dominance of physically derived
fluid motion; plankton, advected by currents, adjust their life histories to the
changing oceanic environment. At Kolmogorov scales, a careful interplay of evenly
matched forces of biology and physics occurs. Copepods conform or deform the
local physical environment for their survival, using morphological and behavioral
adaptations to shift the balance in their favor. Examples of these balances and
transitions are observed when copepods engage in their various survival tasks of
feeding, predator avoidance, mating, and signaling. Quantitative analyses of
their behavior give measures of such physical properties of their fluid medium as
energy dissipation rates, molecular diffusion rates, eddy size, and eddy
packaging. Understanding the micromechanics of small-scale biological-physical
chemical interactions gives insight into factors influencing large-scale dynamics
of copepod distribution, patchiness, and encounter probabilities in the sea.
PMID- 10786943
TI - The chemical defense ecology of marine unicellular plankton: constraints,
mechanisms, and impacts.
AB - The activities of unicellular microbes dominate the ecology of the marine
environment, but the chemical signals that determine behavioral interactions are
poorly known. In particular, chemical signals between microbial predators and
prey contribute to food selection or avoidance and to defense, factors that
probably affect trophic structure and such large-scale features as algal blooms.
Using defense as an example, I consider physical constraints on the transmission
of chemical information, and strategies and mechanisms that microbes might use to
send chemical signals. Chemical signals in a low Re, viscosity-dominated physical
environment are transferred by molecular diffusion and laminar advection, and may
be perceived at nanomolar levels or lower. Events that occur on small temporal
and physical scales in the "near-field" of prey are likely to play a role in cell
cell interactions. On the basis of cost-benefit optimization and the need for
rapid activation, I suggest that microbial defense system strategies might be
highly dynamic. These strategies include compartmented and activated reactions,
utilizing both pulsed release of dissolved signals and contact-activated signals
at the cell surface. Bioluminescence and extrusome discharge are two visible
manifestations of rapidly activated microbial defenses that may serve as models
for other chemical reactions as yet undetected due to the technical problems of
measuring transient chemical gradients around single cells. As an example, I
detail an algal dimethylsulfoniopropionate (DMSP) cleavage reaction that appears
to deter protozoan feeding and explore it as a possible model for a rapidly
activated, short-range chemical defense system. Although the exploration of
chemical interactions among planktonic microbes is in its infancy, ecological
models from macroorganisms provide useful hints of the complexity likely to be
found.
PMID- 10786944
TI - Olfactory foraging by Antarctic procellariiform seabirds: life at high Reynolds
numbers.
AB - Antarctic procellariiform seabirds forage over vast stretches of open ocean in
search of patchily distributed prey resources. These seabirds are unique in that
most species have anatomically well-developed olfactory systems and are thought
to have an excellent sense of smell. Results from controlled experiments
performed at sea near South Georgia Island in the South Atlantic indicate that
different species of procellariiforms are sensitive to a variety of scented
compounds associated with their primary prey. These include krill-related odors
(pyrazines and trimethylamine) as well as odors more closely associated with
phytoplankton (dimethyl sulfide, DMS). Data collected in the context of global
climatic regulation suggest that at least one of these odors (DMS) tends to be
associated with predictable bathymetry, including upwelling zones and seamounts.
Such odor features are not ephemeral but can be present for days or weeks. I
suggest that procellariiforms foraging over vast distances may be able to
recognize these features reflected in the olfactory landscape over the ocean. On
the large scale, such features may aid seabirds in navigation or in locating
profitable foraging grounds. Once in a profitable foraging area, procellariiforms
may use olfactory cues on a small scale to assist them in locating prey patches.
PMID- 10786945
TI - Endolithic fungi in reef-building corals (Order : Scleractinia) are common,
cosmopolitan, and potentially pathogenic.
PMID- 10786946
TI - Impact of a castrating trematode, Neophasis sp., on the common whelk, Buccinum
undatum, in the northern Gulf of St. Lawrence.
AB - We observed heavy trematode infections of whelks, Buccinum undatum, from the
Mingan Islands, eastern Canada, by larval stages of a species of Neophasis. Only
sexually mature whelks were infected, 23% of mature females and 15% of mature
males, and prevalence increased rapidly with whelk size. In most cases the
parasite completely occupied the gonad, causing castration. The digestive gland
was also infected, although to a lesser degree (0% to 50% occupation), and a
marked reduction in the mass of the penis was associated with the infection. A
decrease in the proportion of whelks with a highly infected digestive gland
between May and August 1994 suggested mortality of infected individuals. Whelks
held for 12 to 15 months in the laboratory retained the infection but did not
show significant mortalities (possibly because food was abundant and predators
absent). The larval stage of Neophasis sp. found in whelks was a cercaria;
however, the tail easily detached. The putative infective stage (metacercaria)
was not observed but may be present in whelks in late winter and early spring.
Other trematode parasites observed were adult Steringophorus furciger in the
stomach and larval Renicola sp. in the digestive gland.
PMID- 10786947
TI - Vacuolar-type ATPase in the accessory boring organ of Nucella lamellosa (Gmelin)
(Mollusca : Gastropoda): role in shell penetration.
AB - The structure and function of the accessory boring organ (ABO) of muricid
gastropods has been described in numerous studies, and the ABO of Nucella
lamellosa was found to be similar to those of other muricid species. The active
cap region of the ABO is composed of tall, mitochondria-rich cells with distinct
brush borders at their apicies, surrounding a hemolymph-containing central sinus.
Using antibodies specific for vacuolar-type ATPase (V-ATPase), enzyme
immunoreactivity was found to be limited to the brush border of the epithelial
cells. Electron immunohistochemistry revealed that V-ATPase immunoreactivity
resides in the plasma membranes of the microvilli. Immunodot blotting using yeast
V-ATPase as a positive control confirmed the specificity of the reactions. SDS
PAGE of membrane suspensions from the ABO revealed protein bands of the requisite
molecular weight for V-ATPase subunits. Western blots suggest that antibodies
raised against mammalian V-ATPase subunits recognize subunits of the molluscan V
ATPase. The molecular weights of these identified subunits are similar to those
in mammals. The V-ATPase-specific inhibitor bafilomycin A1 inhibited ATPase
activity in samples of ABO homogenate by about 10% relative to control, providing
further evidence for the presence of V-ATPase. Specific V-ATPase activity was
about 67 picomoles of inorganic phosphate per microgram of protein per minute in
the homogenate. Collectively this evidence strongly suggests that a vacuolar-type
proton transporting ATPase is present in the brush border of the accessory boring
organ of Nucella lamellosa, and is responsible for acidifying secretions from
this gland. Similarities between the ABO, osteoclasts, and the mantle of
freshwater bivalves also suggest that the mechanism for decalcification of
calcareous substrates is conserved.
PMID- 10786949
TI - Phylogeny of Gastrotricha: a morphology-based framework of gastrotrich
relationships.
AB - Currently, the phylum Gastrotricha is divided into the orders Macrodasyida and
Chaetonotida, with the structure of the myoepithelial pharynx being an important
distinguishing feature. Macrodasyida currently has six recognized families, and
Chaetonotida comprises seven families. However, within-group relationships are
poorly understood. To arrive at a better understanding of gastrotrich systematics
and phylogeny, we performed the first cladistic analysis of nearly all known
gastrotrich genera using 71 morphological characters. Results suggest that the
Gastrotricha is a monophyletic group (supported by 82% of bootstrap replications)
with its most primitive taxa distributed among the families Dactylopodolidae and
Neodasyidae. Monophyly of Macrodasyida and Chaetonotida was supported by 90% and
52% bootstrap replications, respectively. Within the Macrodasyida, the families
Dactylopodolidae, Turbanellidae, Macrodasyidae, and Thaumastodermatidae all
formed monophyletic clades. The families Planodasyidae and Lepidodasyidae were
paraphyletic. Among the Chaetonotida, the marine family Xenotrichulidae was
monophyletic, supported by 51% of bootstrap replications. A second clade
containing all freshwater families was supported by 62% bootstrap values.
However, Chaetonotidae were paraphyletic. Using this analysis as a framework, we
now can explore possible patterns of evolution within it, and arrive at a
consensus of the gastrotrich ground pattern. Moreover, in future molecular
studies of metazoan phylogeny, we will be able to select gastrotrich species that
are more appropriate representatives of the phylum.
PMID- 10786948
TI - Light-limitation on predator-prey interactions: consequences for metabolism and
locomotion of deep-sea cephalopods.
AB - The present study attempts to correlate the metabolism and locomotory behavior of
25 species of midwater Cephalopoda from California and Hawaii with the maximal
activities of key metabolic enzymes in various locomotory muscle tissues. Citrate
synthase (CS) and octopine dehydrogenase (ODH) activities were used as indicators
of aerobic and anaerobic metabolic potential respectively. CS activity in mantle
muscle is highly correlated with whole-animal rates of oxygen consumption,
whereas ODH activity in mantle muscle is significantly correlated with a species'
ability to buffer the acidic end-products of anaerobic metabolism. Both CS and
ODH activities in mantle muscle declined strongly with a species' habitat depth.
For example, CS and ODH activities ranged respectively from 0.04 units g(-1) and
0.03 units g(-1) in the deep-living squid Joubiniteuthis portieri, to 8.13 units
g(-1) and 420 units g(-1) in the epipelagic squid Sthenoteuthis oualaniensis. The
relationships between enzymatic activities and depth are consistent with similar
patterns observed for whole-animal oxygen consumption. This pattern is believed
to result from a relaxation, among deep-living species, in the need for strong
locomotory abilities for visual predator/prey interactions; the relaxation is due
to light-limitation in the deep sea. Intraspecific scaling patterns for ODH
activities may, for species that migrate ontogenetically to great depths, reflect
the counteracting effects of body size and light on predator-prey detection
distances. When scaled allometrically, enzymatic activities for the giant squid,
Architeuthis sp., suggest a fairly active aerobic metabolism but little burst
swimming capacity. Interspecific differences in the relative distributions of
enzymatic activities in fin, mantle, and arm tissue suggest an increased reliance
on fin and arm muscle for locomotion among deep-living species. We suggest that,
where high-speed locomotion is not required, more efficient means of locomotion,
such as fin swimming or medusoid arm propulsion, are more prevalent.
PMID- 10786950
TI - Introduction--infection and critical illness: genetic and environmental aspects
of susceptibility and resistance.
PMID- 10786952
TI - Mechanisms of resistance to antibiotics.
PMID- 10786951
TI - Microbial resistance: lessons from the EPIC study. European Prevalence of
Infection.
AB - In 1992, a one day point prevalence study (EPIC) was conducted in European
intensive care units (ICUs) to determine the prevalence of nosocomial infection
among ICU patients. Of the 10,038 patients included, 45% were infected and 21%
had a nosocomial ICU-acquired infection. Many of the organisms responsible for
these infections were resistant to commonly used antibiotics. For example, 60% of
the Staphylococcus aureus isolated were resistant to methicillin and 46% of
Pseudomonas aeruginosa were resistant to gentamicin. The incidence of nosocomial
infection varied between countries as did the incidence of antibiotic resistance.
Mortality rates were higher in countries with higher rates of nosocomial
infection and higher again in those countries with higher rates of resistant
organisms. Antibiotic resistance is rising and clearly efforts to contain its
development and spread are vital. Basic infection control procedures such as hand
washing must be developed and implemented, and antibiotic prescribing needs to be
rationalized. The international variations in resistance rates, even within
Europe, highlight the importance of being familiar with local resistance patterns
when prescribing. The assistance of an infectious diseases specialist can be
invaluable in providing a global overview of the local microbial milieu and of
antibiotic resistance patterns. Epidemiological studies of this sort can provide
useful information which can be used to stimulate debate on the reasons behind
regional differences in infection and help in the development of strategies to
combat the rising tide of microbial antibiotic resistance.
PMID- 10786953
TI - Epidemiology of antibiotic resistance.
AB - Three biological processes contribute to the accumulation of bacterial drug
resistance: new selection, gene epidemics and strain epidemics. New resistance
emerges by (i) the advantaging of entire species, (ii) by mutation, and (iii) by
the escape of resistance genes to mobile DNA. Organisms to have 'benefited' from
modern patterns of cephalosporins and quinolone use include enterococci,
Clostridium difficile, coagulase-negative staphylococci and Enterobacter spp.
Mutational resistance notoriously occurs with certain antibiotic/organism
combinations and allows rapid multifocal accumulation of resistance. At worst,
therapy can fail when resistant mutants are selected in individual patients.
Escape of new genes to mobile DNA is rare but, having occurred, permits massive
'gene epidemics', as the same genes and plasmids spread into diverse pathogens.
Strain epidemics notoriously occur in individual units, reflecting break-downs of
hygiene. Some strains achieve a much wider distribution: thus, much of the MRSA
problem in the UK depends on the dissemination of two epidemic strains, EMRSA15
and 16; penicillin resistant pneumococci of serotypes 6 and 23 have disseminated
internationally from Spain and a serotype K25 strain of Klebsiella pneumoniae
with SHV-4 beta-lactamase has spread widely in France. It remains unknown why
some strains and genes achieve wide spread whereas others, equally resistant,
fail to do so. There is no simple cure for resistance but the best opportunities
for control lie in lesser and better use of antibiotics backed by swifter and
more accurate microbiology; in developing new antibiotics; and in protecting old
ones from resistance determinants. All this must be supported by good local
knowledge of the epidemiology of infections and resistance and of the likelihood
of particular antibiotics to select resistance.
PMID- 10786954
TI - Prevention and control of infections in intensive care.
AB - Small intensive care units (ICUs) functioning within their capacity and caring
mainly for post-operative patients have fewer problems with infection control
than larger ICUs with a varied case mix, sub-optimal staffing levels, and high
levels of antibiotic consumption. Under these circumstances chronic cross
colonisation and infection are inevitable and outbreaks may occur. Little can be
done to reduce the risks of infection which arise as a direct result of the
patient's clinical condition and prior colonisation status. However, selection
pressure from antibiotic usage can be modified, as can environmental hygiene,
ventilation and architectural design. One of the simplest measures for reducing
cross infection remains one of the most intractable: compliance by staff with
protocols and standards for maintaining hand hygiene. Simplification of
procedures by the ready availability of alcohol hand rub preparations with or
without chlorhexidine may improve matters.
PMID- 10786955
TI - Antibiotic usage and prescribing policies in the intensive care unit.
PMID- 10786956
TI - Ventilator associated pneumonia: perspectives on the burden of illness.
AB - OBJECTIVE: The objective of this narrative review is to summarize selected
current concepts and clinical evidence regarding the burden of illness of VAP,
including its epidemiology, diagnosis, attributable mortality and risk factors.
DATA SOURCES & SELECTION: Studies were identified through MEDLINE, EMBASE,
bibliographies of primary and review articles and personal files. RESULTS: While
cross sectional studies inform us about VAP prevalence, longitudinal studies
inform us of the cumulative risk and conditional risk of developing VAP. Reported
VAP rates are modulated by factors related to case mix, causative microorganisms,
interventions that influence risk over time, and VAP definitions employed.
Population-specific and organism-specific VAP rates are needed to avoid
misleading benchmarking between different ICUs, and to minimize inappropriate
between-study comparisons. Observational studies have shown that invasive
sampling techniques versus non-invasive approaches to diagnose VAP facilitates
more targeted antibiotic treatment; however, the influence of the diagnostic
method on endpoints such as mortality is less clear. VAP is associated with
approximately a 4 day increase in length of ICU stay and an attributable
mortality of approximately 20-30%. Fixed VAP risk factors include underlying
cardiorespiratory disease, neurologic injury and trauma. Modifiable VAP risk
factors include supine body position, witnessed aspiration, paralytic agents and
antibiotic exposure. If modifiable risk factors tested in randomized trials lower
VAP rates, such as semirecumbency versus supine positioning, these represent
effective VAP prevention strategies. CONCLUSIONS: Ventilator-associated pneumonia
is a major morbid outcome among critically ill patients. Studies evaluating more
effective prevention and treatment strategies are needed.
PMID- 10786957
TI - Antibiotic prophylaxis in intensive care units: meta-analyses versus clinical
practice.
AB - OBJECTIVE: At least 7 meta-analyses (MA) have been published since 1991 on the
effectiveness of antibiotic prophylaxis in Intensive care units (ICU) patients,
but controversy still remains about the overall effectiveness and risk-benefits
profile of the treatment. This paper aims to summarise available data on
effectiveness and discuss reasons why the controversy is still open and possible
directions for future research. DESIGN: Review of available published MA on the
effectiveness of various regimens of antibiotic prophylaxis with particular
emphasis on the results of the individual patient data analysis published in
1998. SETTING: MA or randomised control trials (RCTs), published and unpublished,
conducted anywhere in the world. PATIENTS AND PARTICIPANTS: Unselected adult ICU
populations included in studies, published and unpublished, comparing different
forms of antibiotic prophylaxis. MAIN OUTCOME MEASURE: Respiratory tract
infections (RTIs) - however defined in individual studies - and total mortality.
DATA SOURCES: General information from the 7 MAs published between 1991 and 1999
and detailed information from the MA published in the British Medical Journal in
1998 that reported data on 5727 patients enrolled in 33 RCTs; access to
individual patients data could be obtained from 25 of 33 RCTs and allowed a
confirmatory individual patient MA on 4343 patients. RESULTS: Pooled estimates
from 16 RCTs (including 3361 patients) testing the effect of the topical and
systemic antibiotic combination indicates a significant reduction of both RTIs
(OR=0.35, 95% CI=0.29-0.41) and total mortality (OR=0.80, 95% CI=0.69-0.93). Five
and 23 patients need to be treated to prevent one infection and one death,
respectively, using this treatment. Pooled data from the 17 RCTs (including 2366
patients) testing the effect of a regimen based on topical antimicrobials
indicated a statistically significant reduction in RTIs (OR=0.57, 95% CI=0.46
0.69) but not in total mortality (OR=1.01; 95% CI=0.84-1.22). Individual patient
data analyses confirmed these results. CONCLUSIONS: After over 30 RCTs and seven
MAs, there is strong evidence that antibiotic prophylaxis can reduce both RTIs
and total mortality in ICUs patients in a statistically and clinically
significant way. Concerns about the possible occurrence of antimicrobial
resistance are not supported by available data but cannot, at the same time, be
ruled out due to methodologic inadequacies of the studies carried out so far.
Whether new trials are needed, and how they should be designed to answer the
question of the potential for antibiotic resistance following widespread use of
the treatment, are now the main issues to be settled. Convening an international
panel of clinical experts and methodologists could be appropriate, in order to
explore the best way to resolve the controversy that seems to be preventing the
widespread use of a treatment that the best analysis of available data now
indicates is effective.
PMID- 10786958
TI - Intravascular catheter-related sepsis--novel methods of prevention.
AB - Intravascular catheter-related sepsis continues to cause a significant degree of
morbidity and mortality, and accounts for the majority of staphylococcal
bacteraemias and septicaemias in hospitalised patients. Methods designed to
prevent these infections include those directed at aseptic techniques involving
the patient and improvements in catheter design. More recently catheters which
are either coated or have incorporated into their polymers antimicrobial agents
have been developed. The antimicrobial agents have included both antimicrobials
which are used to treat infections as well as antiseptics. The antimicrobial
catheters currently available appear to only give protection for relatively short
periods of time (approximately 14 days). The use of these antimicrobial catheters
needs to be restricted to the situation where infection rates and the risk to the
patient of sepsis are relatively high. Further novel approaches for the
prevention of these infections include the combination of low voltage electric
current together with antimicrobials; these await clinical evaluation.
PMID- 10786959
TI - The detection and interpretation of endotoxaemia.
AB - A considerable body of evidence has accumulated that implicates endotoxin in the
pathogenesis of the sepsis syndrome. This has raised interest in the possibility
of measuring endotoxin as a surrogate marker of Gram negative infection,
particularly since conventional microbiological tests have an inevitable delay.
The Limulus amoebocyte lysate (LAL) assay has been used most widely to measure
endotoxin in clinical samples. However, there are several important limitations
that need to be borne in mind. These include the dangers of contamination, lack
of precision and accuracy, and both false positive and false negative results.
Endotoxaemia is present in the blood of about 30% of patients with bacteraemia,
but endotoxaemia does not predict either Gram negative bacteraemia or Gram
negative infection, nor does it predict survival from sepsis. There is some
correlation with severity of sepsis, but the level of precision is poor. At the
present time, there is no place for routine endotoxin testing in clinical
practice. In particular, the positive predictive value of the test is
insufficiently high to be of clinical use. It may be that the LAL assay, or one
of the newer developments, may be more useful in excluding Gram negative
infection, but that remains to be shown.
PMID- 10786960
TI - Susceptibility to critical illness: reserve, response and therapy.
AB - Risk of critical illness is determined both by genetic and environmental
influences, particularly those relating to infectious and cardiovascular
diseases. Physiologically-based scoring systems cannot measure prior risk because
they do not quantify physiological reserve independently of the acute illness.
Genetic profiling could be useful for risk assessment. Early detection of
critical illness involves identifying physiological 'triggers' for referral; this
requires the education of nursing and medical staff in their significance.
Analysis of the relationship between risk factors and interventions may need
complex modelling techniques. Therapeutic strategies depend on the nature of the
underlying problem: the most useful are likely to be those which enhance tissue
oxygen delivery and resistance to infection.
PMID- 10786962
TI - Clinical trials of mediator-directed therapy in sepsis: what have we learned?
AB - Almost 60 randomized controlled clinical trials have been undertaken, testing the
hypothesis that modulation of the endogenous host inflammatory response can
improve survival for patients with a clinical diagnosis of sepsis. The results
have been tantalizing, but frustrating, and no new agent has been introduced into
clinical practice. Analysis of pooled data from studies of the use of an
neutralizing antibody to tumor necrosis factor, or recombinant interleukin 1
receptor antagonist, show that these two approaches yield a statistically
significant, but small improvement in 28 day all-cause mortality. However
variability in results from one study to the next, the small absolute mortality
reduction, the emerging evidence of a substantial potential for harm, and the
predicted costs of recombinant biologic agents has engendered a climate of
caution and pessimism. The challenge is to find methods of refining investigative
approaches to maximize benefit and minimize harm. This paper reviews the recent
history of sepsis clinical trials, focussing on emerging insights into the
limitations of study entry criteria and measures of biologic activity and
clinical benefit that may inform and direct future investigations. The biologic
complexity of systemic inflammation, and the multiple interactions between
clinical biology and the process of care suggest that future success in clinical
research in sepsis will occur through the conduct of highly focussed
investigations in a small number of dedicated centres of excellence.
PMID- 10786961
TI - The epidemiology of the systemic inflammatory response.
AB - OBJECTIVE: To examine the incidence, risk factors, aetiologies and outcome of the
various forms of the septic syndromes (the systemic inflammatory response
syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships
with infection. DESIGN: Review of published cohort studies examining the
epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU)
patients. RESULTS: The prevalence of SIRS is very high, affecting one-third of
all in-hospital patients, and >50% of all ICU patients; in surgical ICU patients,
SIRS occurs in >80% patients. Trauma patients are at particularly high risk of
SIRS, and most these patients do not have infection documented. The prevalence of
infection and bacteraemia increases with the number of SIRS criteria met, and
with increasing severity of the septic syndromes. About one-third of patients
with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25% of ICU
patients, and bacteraemic sepsis in 10%. In such patients, sepsis evolves to
severe sepsis in >50% of cases, whereas evolution to severe sepsis in non-ICU
patients is about 25%. Severe sepsis and septic shock occur in 2%-3% of ward
patients and 10%-15% or more ICU patients, depending on the case-mix; 25% of
patients with severe sepsis have shock. There is a graded severity from SIRS to
sepsis, severe sepsis and septic shock, with an associated 28-d mortality of
approximately 10%, 20%, 20%-40%, and 40%-60%, respectively. Mortality rates are
similar within each stage, whether infection is documented or not, and
microbiological characteristics of infection do not substantially influence
outcome, although the source of infection does. While about three of four deaths
occur during the first months after sepsis, the septic syndromes significantly
impact on long-term outcome, with an estimated 50% reduction of life expectancy
over the following five years. The major determinants of outcome, both short-term
and long-term, of patients with sepsis are the severity of underlying diseases
and comorbidities, the presence of shock and organ failures at onset of sepsis or
evolving thereafter. It has been estimated that two-thirds of the overall
mortality can be attributed to sepsis. CONCLUSIONS: The prevalence of sepsis in
ICU patients is very high, and most patients have clinically or microbiologically
documented infection, except in specific subset of patients. The prognosis of
septic syndromes is related to underlying diseases and the severity of the
inflammatory response and its sequelae, reflected in shock and organ
dysfunction/failures.
PMID- 10786963
TI - Monitoring and evaluating clinical trials data.
AB - This paper presents an overview of recent developments in statistical methods for
the design of clinical trials. Whilst the methods are suitable for application in
a wide range of therapeutic areas, they are of particular value in intensive care
medicine due to its high levels of mortality and short periods of follow-up. The
paper reviews the calculation of the sample size necessary to achieve a given
power requirement, and then describes the operation of a Data and Safety
Monitoring Board, the mid-trial reassessment of sample size and the use of
stopping rules to terminate a study as soon as sufficient evidence is available.
The purpose of the paper is to encourage investigators to consider the wide range
of design options which have recently become available, when planning a new
clinical study.
PMID- 10786964
TI - Genetic dissection of the molecular pathogenesis of severe infection.
AB - A fundamental question for the intensivist is why some individuals but not others
succumb to life-threatening infection. A growing body of evidence indicates that
both the risk of acquiring infection and the risk of developing severe
complications are determined by host genetic factors. These include a number of
single gene defects with devastating consequences, e. g. interferon-gamma
receptor mutations that lead to fatal infections with ubiquitous mycobacteria,
but such examples are relatively rare. Of greater importance for routine clinical
practice is the potentially vast number of genetic variants with subtle effects
on the regulation or function of specific immunological, physiological and
metabolic mediators. Such polygenic traits do not obey simple patterns of
familial segregation seen for monogenic disorders, and their clinical
investigation is further complicated by the environmental variability of
infectious exposure. Recent advances in this field have therefore largely stemmed
from hospital-based case-controlled studies that have uncovered disease
associations with specific DNA polymorphisms in candidate gene regions. For
example, tumour necrosis factor polymorphisms have been associated with
susceptibility to malaria and other infections; chemokine receptor polymorphisms
with susceptibility to HIV; natural resistance-associated macrophage protein 1
with tuberculosis; and mannose binding lectin polymorphisms with meningococcal
disease. A much greater number of genetic associations will emerge as the full
extent of human genomic diversity becomes known. The challenge for clinical
investigators is to generate an epidemiological framework for population- and
family-based association studies, which is sufficiently robust to exclude
population artifacts and sufficiently powerful to be able to dissect true disease
causing polymorphisms from linked genetic markers. In the long term this approach
promises to identify host mediators that are critical for pathogenesis and
immunity and to yield molecular insights into the complex processes of human gene
regulation. This information is likely to be of considerable value in designing
more effective approaches to the treatment and prevention of life-threatening
infectious disease.
PMID- 10786965
TI - Cytokine and cytokine receptor polymorphisms in infectious disease.
AB - Host immune responses strongly control the outcome of infectious disease, and the
resistance to bacterial infections in humans is in part genetically determined.
Responses to Gram-negative bacterial endotoxin are affected by the concentration
of plasma lipoproteins and lipid transport proteins that are genetically
controlled. Alterations of plasma lipid profiles by genetic manipulation in mice
indeed strongly modify resistance to bacterial infections. Recently, the TLR-4
receptor has been identified as the endotoxin receptor, and TLR-4 mutations are
the cause of endotoxin resistance in mice. It is probable that such defects also
exist in humans, although they must be rare. The capacity of monocytes to produce
TNFalpha varies more than tenfold, and several polymorphisms within the TNFalpha
gene have been associated with increased TNFalpha production and increased
mortality of sepsis. However, these associations most likely result from linkage
disequilibrium with other immune response genes on chromosome 6. Polymorphisms
within the IL-1beta and the IL-1RA genes (located on chromosome 2) are associated
with altered protein production rates, and certain haplotypes have been linked to
inflammatory disease (no studies in bacterial infectious disease have been
published). Mutations in the receptors for IL-12 and IFNgamma, both critical for
clearance of intracellular infectious pathogens, occur in consanguineous
populations and are associated with severe recurrent infections with Salmonella
species and mycobacteria. In conclusion, no human cytokine deficiency syndromes
are known, and it remains uncertain whether genetically determined differences in
the production rate of pro-inflammatory cytokines alter the outcome of sepsis. In
contrast, mutations in the IL-12 and IFNgamma receptor (and possibly the
endotoxin receptor) genes are associated with recurrent bacterial infections,
whereas TNFR1 mutations cause fever of unknown origin.
PMID- 10786966
TI - Neutropenia: clinical implications and modulation.
PMID- 10786967
TI - Leukocytes: friend or foe.
AB - Leukocytes have a fundamental role in innate and adaptive immunity, wound
healing, tumour surveillance and in tissue remodelling. It is their function in
the inflammatory response however that is of most interest to us in the intensive
care setting. Over the last three decades we have gained significant insights
into leukocyte activation, recruitment and mediator secretion and the
contribution of these agents to both the onset and resolution of sepsis and
inflammation. The body relies on the inflammatory response for protection.
Leukocytes occupy a pivotal position in this but to maintain these cells in a
state of permanent activation would be unsustainable, with widespread
microvascular plugging, uncontrolled free radical release and an excessive
metabolic demand. Leukocytes thus circulate in a quiescent state and are rapidly
activated by invading pathogens and other stimuli. A direct consequence of this
protective strategy is that the inflammatory response may be inadequate, with the
risk of overwhelming sepsis, or excessive, leading to rampant systemic
inflammation and consequent multiple organ damage. It is now becoming apparent
however that in addition to leukocytes other cells have important roles both in
defence against invading pathogens and in driving malignant inflammation. This
review will focus on two new facets of the innate immune system, the Toll family
of proteins as the signal transduction element for endotoxin, and the
antimicrobial peptides. These exemplify potential damaging and protective
response elements but importantly neither are restricted to leukocytes. The
capacity of cells and tissues other than the leukocytes to participate and even
lead in the inflammatory responses will also be explored.
PMID- 10786968
TI - Gene therapy for acute lung injury.
AB - The remarkable transition of biological science into the age of molecular biology
held great promise for development of new therapies for treatment of human
disease. The fact that the technology exists for analyzing genetic material in
exquisite detail and constructing DNA in virtually any desired form was the basis
for promising rapid translation into clinical medicine and the final cure for
genetically determined diseases; cystic fibrosis is the prime example of such a
lung disease. The promise was not kept, at least not in a time frame which was
expected. That result is neither because the rationale was faulty nor because the
tools of molecular biology were wanting. The devil was and is in the details. How
do you deliver DNA to the desired cell targets in amounts sufficient to
accomplish the desired effect? Viral vectors have received the most attention,
but viral vectors have proven to have both theoretical and practical problems. In
the lungs, these vectors have not fulfilled their original promise. Non-viral
based strategies work in a general sense, but efficiency of gene delivery in vivo
has been a limitation. In addition, the experimental end points in both clinical
and preclinical investigation have been most often designed to demonstrate
phenomenology rather than potential efficacy. And, why limit the potential of
gene therapy to inherited disease? In fact, treatment of acquired diseases by
increasing or decreasing expression of a given gene in the lungs that would
hasten recovery from an acquired disease might be easier than treating inherited
disease because the requirements for duration of transgene expression would be
less stringent. Over the past two decades, we have learned enough about the
pathogenesis of acute lung injury to predict that increased (or decreased)
production of certain biologically active mediators should be beneficial. Genes
encoding some of these mediators have been cloned and constructs made which
express the genes. It is now possible using either viral or non-viral strategies
to deliver expression constructs to the lungs and, since acute lung injury has a
dismal prognosis and no effective drugs have been identified, this seems a good
clinical target for gene therapy. In preclinical studies, we have shown that
increased expression of the gene encoding the constitutive form of the
cyclooxygenase gene (COX-1) results in increased production of prostacyclin and
PGE2 by the lungs and inhibits endotoxin induced pulmonary hypertension and
edema. Additional studies demonstrate that increased expression of the alpha-1
antitrypsin gene in human respiratory epithelium in culture and in vivo has anti
viral and anti-inflammatory effects that are not predicted by extracellular
concentrations of the transgene product. Thus, acute lung injury is a reasonable
target for gene therapy, and evidence to date indicates that current technology
is sufficiently robust to pursue this novel area for treatment of this
devastating disease.
PMID- 10786969
TI - Immunomodulatory therapies in sepsis.
AB - Despite advances in critical care medicine, mortality from sepsis in ICU patients
remains high. In response to several infectious and non-infectious stimuli,
monocytes/ macrophages release a number of mediators, including cytokines,
involved in the proinflammatory response that underlies sepsis. The excessive
release of these mediators results in the development of whole body inflammation,
and plays an important role in the pathogenesis of sepsis and septic shock. In
addition, patients with sepsis also undergo an anti-inflammatory phase (the
compensatory anti-inflammatory response syndrome) and at times, a mixed response
with both pro-and anti-inflammatory components (the mixed antagonistic response
syndrome). The initial systemic hyperinflammation is caused by production of
inflammatory cytokines, especially tumour necrosis factor-a (TNF-alpha), and also
interleukin-1 (IL-1), IL-6, and interferon gamma, which act synergistically with
TNF-alpha in inducing shock in animal models. However, clinical trials aimed at
downregulating these mediators using antibodies against endotoxin, TNF-alpha,
antagonists of IL-1 or platelet activating factor have proved to be uniformly
disappointing. Not only have these agents been found to have no effect, but they
may also increase mortality. One of the reasons for such failure may be the lack
of precise immunological monitoring during the course of sepsis. We have recently
demonstrated that sepsis shows a biphasic immunological pattern during the
initial and later phase: the early hyperinflammatory phase is counterbalanced by
an anti-inflammatory response which may lead to a hypoinflammatory state. The
latter is associated with immunodeficiency that is characterised by monocytic
deactivation, so-called immunoparalysis. Interferon gamma-1 b has an
immunoregulatory effect in patients with immunoparalysis during the compensatory
anti-inflammatory response syndrome, not only restoring levels of HLA-DR
expression but also reestablishing the ability of monocytes to secrete cytokines
such as TNF-alpha. By monitoring immune status in septic patients, targeted
intervention may lead to more success in immunomodulation of sepsis.
PMID- 10786971
TI - Cardiac reserve: linking physiology and genetics.
PMID- 10786970
TI - Endotoxin immunization.
PMID- 10786973
TI - Regulation of bacterial translocation by nitric oxide.
AB - Nitric oxide (NO) appears to play a paradoxical role in intestinal physiology.
Although NO has potent bactericidal effects, a growing body of evidence suggests
that it mediates intestinal injury and breakdown of gut barrier function. Data
from our lab and others show an increased incidence of bacterial translocation
following endotoxin challenge, and upregulation of inducible NO synthase (iNOS)
mRNA and protein in the intestine. These phenomena co-localize with enterocyte
apoptosis at the tips of the intestinal villi and immunoreactivity to
nitrotyrosine. Electron microscopy reveals swollen mitochondria, implicating
these organelles as putative targets for NO or its reactive nitrogen
intermediates. We review some of the literature and discuss our current work in
trying to define this mechanism.
PMID- 10786972
TI - "Gut-feeling" or evidence-based approaches in the evaluation and treatment of
human short-bowel syndrome.
AB - Short bowel syndrome is the malabsorptive state that often follows extensive
resection of the small intestine. Long-term survival without parenteral nutrition
depends on the process of intestinal adaptation, through which the remaining
small bowel gradually increases its absorptive capacity. The process of
intestinal adaptation is almost exclusively luminal nutrient dependent. To date
the clinical management of short bowel patients is mostly based on a 'trial and
error' regimen because human data and randomised trials using trophic substances
are lacking due to the small number of patients annually present in pediatric
surgical centres. We evaluate here the currently available as well as some more
recently developed methods of measuring intestinal absorption and adaptation in
short bowel patients. New techniques such as measurements of (1) intestinal
permeability and carbohydrate absorption using the sugar absorption test, (2)
gastrointestinal hormone production of gastrin, cholecystokinin and peptide YY,
(3) transmural potential difference of the gastrointestinal tract using
electrophysiology and (4) mucosal enzyme expression of lactase and sucrase
isomaltase using immunohistochemistry were evaluated. These new techniques are
promising in monitoring the process of adaptation of the remaining intestine and
evaluating the effect of therapeutic interventions in patients with short bowel
syndrome.
PMID- 10786974
TI - The effects of intravenous epidermal growth factor on bacterial translocation and
central venous catheter infection in the rat total parenteral nutrition model.
AB - Sepsis is a major complication of total parenteral nutrition (TPN) in children.
Gut mucosal atrophy (GMA) and bacterial translocation (BT) occur in patients
receiving TPN, and the translocated enteric organisms may cause central venous
catheter (CVC) infection. Epidermal growth factor (EGF) has a trophic effect on
the gut mucosa and may reduce BT, thereby reducing catheter infection. Using a
rat TPN model, the relationship between GMA, BT, and catheter sepsis was examined
and the effect on these of intravenous EGF was studied. There were four
experimental groups. Group 1 had no CVC, Groups 2, 3, and 4 had a continuous
central venous infusion as follows: group 2, saline; group 3, TPN; group 4, TPN
with EGF. Groups 1 and 2 had free access to chow, groups 3 and 4 had no enteral
feeds. After killing at 1 week, blood, tissue, and catheter specimens were
cultured and mucosal morphology analysed. BT was defined as the presence of the
same organism in cultures from the gut lumen and mesenteric lymph nodes (MLN).
TPN only (group 3) resulted in GMA and BT, and 5 of 12 animals with BT had the
same gut bacteria in blood and/or catheter cultures. The addition of EGF to the
TPN significantly reduced GMA, BT to the MLN, and blood and/or catheter
infections (P = <0.05). In animals carrying enterococci, there was a significant
reduction in translocation of enterococci (group 3: 8/14; group 4: 0/11; P<0.05)
and catheter infection by enterococci was prevented (group 3: 3/14; group 4:
0/11). EGF thus reduced GMA, BT, and blood and/or catheter infection when given
IV to rats receiving TPN. Enterococcal translocation and subsequent blood and/or
catheter infection was completely prevented, suggesting a selective effect of
EGF.
PMID- 10786975
TI - Growth-factor enhancement of compromised gut function following massive small
bowel resection.
AB - Our laboratory has shown that epidermal growth factor (EGF) and hepatocyte growth
factor (HGF) can improve the function of normal rat small intestine. This study
was designed to evaluate the role of these growth factors on the residual small
intestine following massive (80%) small bowel resection. Our data demonstrate
that EGF and HGF can enhance intestinal substrate absorption and mucosal mass
beyond that which occurs with intestinal adaptation. These growth factors may be
beneficial in the management of children with short bowel syndrome.
PMID- 10786976
TI - Maternal cocaine abuse resulting in necrotizing enterocolitis. An experimental
study in a rat model. II. Results of perfusion studies.
AB - During the last decade, several publications have appeared associating the
maternal use of cocaine and subsequent development of necrotizing enterocolitis
(NEC). In 1994, the effects of cocaine in pregnant rats had been reported by this
group: a significant decrease in the number of live births, mean birth weight and
mean placental weight. In addition, histopathologic examinations revealed severe
inflammation and degenerative vascular changes in the uterus and placenta. Severe
histopathologic changes resembling NEC such as focal necrosis, necrobiosis, and
hemorrhagic inflammatory changes in the gastrointestinal tract of the embryos
were also reported. The aim of the second part of this study was to assess the
hemodynamic effects of cocaine HCI in pregnant rats and the results of perfusion
studies in the uterus, placenta, and fetuses to determine a relation between the
dose of drug, hemodynamic changes, and degree of histopathologic findings. Forty
seven Wistar albino rats and 91 rat fetuses were studied: group A (pregnant
rats), 16 rats and 91 rat fetuses, group B (nonpregnant rats), 31 rats. Each
group was divided into subgroups of cocaine-abused and non-cocaine-abused rats.
In each group 2-3 mCi technetium Tc-99m methoxyisobutyl-isonitryl (Sesta MIBI)
was injected into the tail vein. Radioactivity counts per g tissue (cps/g) in the
uterus, placenta, and fetus were assessed by gamma counter. Cocaine 75 mg/kg per
day severely decreased the perfusion of the uterus, placenta, and fetuses. These
impairments were statistically significant. In lower doses (30-50 mg/kg per day)
no statistically significant changes were observed in the perfusion of the uterus
and placenta, but a significant decrease in fetal perfusion was seen. In group B,
no significant changes in the perfusion of the uterus due to cocaine were seen.
Thus, maternal cocaine abuse results in a reduction in perfusion of the uterus,
placenta, and fetus. There was a dose-dependent correlation between the perfusion
changes and the development of NEC-like histopathologic changes: the higher the
cocaine dose received by the mother, the higher the level of placental and fetal
injury. We suggest that perinatal cocaine exposure should be considered a high
risk for development of NEC in rat fetuses and embryos. For this reason, infants
with a history of possible maternal cocaine abuse or positive urinary cocaine
metabolites have to be followed very carefully for NEC.
PMID- 10786977
TI - Fiberoptic bronchoscopy in children using the laryngeal mask airway.
AB - We describe our experience using the laryngeal mask airway (LMA) in children to
facilitate diagnostic procedures in fiberoptic bronchoscopy (FOB). Two cases of
stridor, two cases of protracted pneumonia, and one case of laryngotracheomalacia
were studied. Intravenous atropine (0.02 mg/kg) was given, and induction was
carried out by either inhalation of a mixture of halothane-nitrous oxide-oxygen
(n = 3) or IV injection of propofol (n = 2). After an adequate depth of
anesthesia was obtained, a LMA was introduced. A 2.7-mm-OD flexible fiberoptic
bronchoscope was introduced through the LMA and the diagnostic procedure was
performed. Ventilation and oxygenation were maintained, and no serious morbidity
was associated with the procedure. We found the use of the LMA to facilitate FOB
to be useful, easy to perform, and safe, avoiding nasal trauma and providing a
patent airway.
PMID- 10786978
TI - Peritonitis in childhood: aspects of pathogenesis and therapy.
AB - The pathogenesis of peritonitis due to hollow-viscus perforation is currently
accepted as being mainly based on the local and systemic release of pro- and anti
inflammatory mediators triggered by the presence of bacteria and bacterial
products in the abdominal cavity. Therefore, treatment consists in focal
restoration, intraoperative debridement and lavage, and postoperative measures
such as drainage, continuous peritoneal lavage, or scheduled reoperation aiming
at the removal of infectious agents from the peritoneal cavity to prevent
persisting peritonitis and sepsis. In order to evaluate the pathophysiologic
relevance of the bacterial and endotoxin load of the peritoneal exudate, we
examined the peritoneal fluid of 20 children with perforated appendicitis for
qualitative and quantitative analysis of bacteria, antibiotic concentrations, and
endotoxin content. The time period ranged in 12-h intervals from intraoperatively
to day 5. Eighteen of 20 fluid specimens (90%) showed endotoxin levels above 1.5
endotoxin units EU/ml (standard <0.1 EU/ml). The most common bacterial species
isolated was Escherichia coli, mostly in high concentrations. Despite persisting
high endotoxin concentrations and bacterial loads in the peritoneal cavity during
the 5 postoperative days, the children recovered uneventfully and the systemic
signs of infection disappeared rapidly. In conclusion, neither the bacterial nor
the endotoxin load of the peritoneal cavity proved to be associated with the
clinical course. Therefore, we hypothesize that during peritonitis
compartmentalization of the focus of infection prevents further systemic
reactions and ultimately leads to removal of the infectious agents by endogenous
mechanisms. At least in peritonitis due to perforated appendicitis in children,
adjuvant surgical measures in addition to appendectomy and intraoperative
debridement are not necessary.
PMID- 10786980
TI - Factors responsible for successful primary closure in bladder exstrophy.
AB - To assess the important factors for successful primary closure in staged
reconstruction of bladder exstrophy, 25 patients (18 males, 7 females) underwent
primary bladder closure during the years 1993-1997. Twenty-one were more than 72
h old; all of these underwent bilateral posterior iliac osteotomies followed by
primary bladder closure during the same anesthetic. Bladder closure was done in a
double layer. The ureteric catheters were removed after 2 weeks and the bladder
catheter after 3.5-4 weeks. Only 1 patient had a bladder dehiscence on the 10th
postoperative day due to infection; 3 had partial wound dehiscences but no
bladder dehiscence. One had a partial bladder prolapse. The osteotomies needed no
drainage, and no complications occurred. One patient needed a urinary diversion 3
years after surgery as the bladder capacity did not increase. Eleven important
factors play a pivotal role for successful primary bladder closure: (1) Proper
patient selection; (2) A staged approach; (3) Anterior approximation of the pubic
bones with placement of the bladder and urethra in the true pelvis; (4) Posterior
bilateral iliac osteotomies in all indicated cases; (5) Double-layered closure of
the bladder; (6) Two weeks' proper ureteric catheter drainage; (7) Prevention of
infection; (8) Prolonged and proper postoperative immobilization; (9) Prompt
treatment of bladder prolapse; (10) Prevention of abdominal distension
postoperatively; and (11) Ruling out bladder-outlet obstruction before removing
the bladder catheter.
PMID- 10786979
TI - Outcome analysis of pyeloplasty in infants.
AB - The study examined the outcome of pyeloplasties done for decompensated
ureteropelvic junction (UPJ) obstruction in infancy over a 13-year period. In a
retrospective study, 186 children who underwent pyeloplasty in infancy were
analysed with particular emphasis on the pre- and postoperative findings of 123I
hippuran scintigraphy/diuretic renograms. The pre- and postoperative management
is outlined in detail. The 186 patients underwent a total of 203 pyeloplasties
during the period from January 1983 to 31 December 1996. Three children died; one
required a nephrectomy. The postoperative scintigrapic results of 156 children
(85%) done about 12 months after surgery were available for evaluation: 101 (64%)
showed stable renal function and 43 (27%) revealed more than 5% improvement of
renal function. In 12 cases (7%) renal function deteriorated after pyeloplasty by
more than 5% compared to the preoperative scintigram. It is concluded that
pyeloplasty in infants is a low-risk procedure. The encouraging results of this
series support early correction of UPJ obstruction.
PMID- 10786981
TI - Surgical management of enlarged prostatic utricle.
AB - The prostatic utricle (PU), or prostatic pouch, is a rudimentary structure
present in the male prostatic urethra, and is derived from both the mullerian and
wolffian ducts. As the PU is of mixed origin, a patient with an enlarged utricle
should be carefully examined to ascertain whether it is associated with female
internal organs. The clinical presentation, diagnostic evaluation, and a new
surgical approach, posterior sagittal rectum retracting, are discussed. A plan
for management of PU with proximal hypospadias is suggested.
PMID- 10786982
TI - Antenatal identification of a cervical oesophageal duplication.
AB - Duplications of the alimentary tract can occur from mouth to anus, and often are
undetected until they present with complications. We report duplication of the
cervical oesophagus presenting as dyspnoea and stridor in a two year old. In
retrospect, this had been detected on ultrasound antenatally, but no specific
diagnosis had been made. We review the present literature to raise awareness of
duplication as one cause of cysts identified antenatally in this region.
PMID- 10786983
TI - Congenital pyloric atresia and junctional epidermolysis bullosa: a report of two
cases.
AB - The association between epidermolysis bullosa (EB) and congenital pyloric atresia
(CPA) is rare, but is known distinct clinical entity with autosomal recessive
inheritance. The outcome of such an association was universally fatal. This is a
report of two newborns with EB and CPA, associated with additional aplasia cutis
congenita in one case. One patient was treated postoperatively with phenytoin and
survived. Aspects of the diagnosis, pathogenesis, and management are also
discussed.
PMID- 10786984
TI - Extra-hepatic biliary-ductal necrosis in acute pancreatitis: a rare complication.
AB - An 8-year-old male presented with an acute abdomen. Exploration revealed bilious
ascites, oedematous pancreatitis with areas of necrosis, and omentum showing
patches of fat necrosis. The common bile duct and almost all of the common
hepatic duct were gangrenous and had sloughed, with bile leaking from the
junctional stump of the right and left hepatic ducts. The patient was managed
successfully by Roux-en-Y hepaticojejunostomy. This is a rare case showing
necrosis and sloughing of the extrahepatic bile ducts in acute pancreatitis.
PMID- 10786985
TI - Multiple gastrointestinal atresias with cystic dilatation of the biliary duct.
AB - A term newborn developed signs and symptoms of an upper-intestinal obstruction. A
palpable transverse upper-abdominal mass was identified. An ultrasound
examination demonstrated a cystic mass with massive dilatation of the biliary
tree. At laparotomy, dozens of segmental intestinal atresias (IA) from the
jejunum to the rectum were identified. The cystic mass was the duodenum,
obstructed distally from the atresias and proximally from an antral web. The
biliary dilatation was due to normal drainage into a closed-loop duodenal
obstruction, and was relieved by division of the web. The multiple atresias were
explored, but establishment of intestinal continuity was impossible. The entity
of multiple segmental IAs in association with cystic biliary dilation has been
previously described, but there are no recorded survivors; 35 patients have been
reported in the world literature. Our patient was the longest survivor; she
finally died after 2 years of gastrostomy-tube drainage and total parenteral
nutrition while awaiting intestinal transplantation. Only 5 patients other than
ours had documented immune-system abnormalities. We review the findings and
management of this rare syndrome.
PMID- 10786986
TI - An antenatally-diagnosed solitary, non-parasitic hepatic cyst with duodenal
obstruction.
AB - Congenital solitary, non-parasitic liver cysts are uncommon lesions that are
rarely diagnosed antenatally. The cystic nature of the antenatally-diagnosed
abdominal cyst in our case was confirmed postnatally by ultrasound. Partial
excision with marsupialisation and release of extrinsic bands on the second part
of the duodenum was done.
PMID- 10786987
TI - Macrodystrophia lipomatosa with associated fibrolipomatous hamartoma of the
median nerve.
AB - Macrodystrophia lipomatosa (MDL) is a rare disease typically causing localized
gigantism and is often associated with a fibrolipomatous hamartoma (FH) of the
median or plantar nerve. A previously unreported case of MDL with associated FH
of the median nerve is presented.
PMID- 10786988
TI - Abdominal expansion using a polytetrafluoroethylene prosthesis in the treatment
of Pepper syndrome.
AB - The authors report three cases of stage IV-S neuroblastoma in infants aged 4, 6,
and 8 weeks, who despite chemo- and radiotherapy required surgical intervention
to urgently relieve major thoracoabdominal compression secondary to massive
hepatomegaly. The results were successful, with abdominal expansion being
achieved by the introduction of a polytetrafluoroethylene prosthesis, which was
removed during the 2nd, 3rd and 7th postoperative month, respectively, after
tumor regression. Two children were in complete remission 32 and 38 months later,
the 3rd died after 16 months of tumor progression.
PMID- 10786989
TI - Renal salvage procedure for synchronous bilateral Wilms' tumor.
AB - This report describes a renal salvage procedure performed in a 2-year-old girl
with bilateral renal tumors comprising a multilocular, cystic tumor of the right
kidney and a solid and cystic nephroblastoma of the left kidney after
chemotherapy. Surgery was performed because the right kidney became
hydronephrotic due to compression by the enlarged cysts, while the left tumor
showed only minimal shrinkage even after three courses of chemotherapy. The right
sided cysts were simply unroofed and the left-sided tumor was extirpated by
partial nephrectomy. Her postoperative course was uneventful with considerable
recovery of the function of each kidney. This procedure should be considered if
the pathological features of the tumor are relatively favourable.
PMID- 10786991
TI - Preterm and particularly, pre-labour cesarean section to avoid complications of
gastroschisis.
PMID- 10786990
TI - Penoscrotal hypospadias and coarctation of the aorta with mixed gonadal
dysgenesis.
AB - A 45,X/46,Xidic(Y)(q11.2) mosaicism was found in a 4-year-old boy. The clinical
appearance was characterized by bilateral cryptorchidism, penoscrotal
hypospadias, short penis, and coarctation of the aorta. The latter is the only
abnormality also seen in Turner syndrome. A biopsy of the gonads revealed normal
prepubertal testicular tissue. A chromosome analysis in all boys with
penoscrotal, scrotal, or perineal hypospadias and a thorough examination of the
heart in children with 45,X/46,XY mosaicism are recommended.
PMID- 10786992
TI - 1999 pioneer in neurovirology: Richard T Johnson, MD.
PMID- 10786993
TI - Molecular circuitry regulating herpes simplex virus type 1 latency in neurons.
AB - Herpes simplex virus (HSV) type 1 (HSV-1) enters nerve endings during a primary
infection, is transported to sensory ganglia, and establishes latency within
nuclei of a subpopulation of neurons. The latent state is characterized by
absence of detectable HSV-1 antigen, minimal transcription of productive cycle
genes, and high expression of 1.5- and 2-kb viral transcripts, termed the major
latency-associated transcripts (LATs), within nuclei of a subpopulation of
infected neurons. Transcription within the HSV-1 LAT genomic locus has been
reported to both facilitate the establishment of latency in additional neurons
and to increase the frequency of spontaneous and induced viral reactivation in
animal model systems. More recent evidence suggests some possible mechanisms that
may explain the relationship between LATs and both reactivation and establishment
of latency. This review summarizes general aspects of latency, but focuses on the
structure, expression, and function of LATs, and the interaction between host
transcriptional regulators and viral gene expression that may impact latency and
reactivation. A model that incorporates evidence from a number of experimental
studies is proposed that summarizes the involvement of the LAT locus in the
biology of HSV-1 latency.
PMID- 10786994
TI - Herpes simplex replication and dissemination is not increased by corticosteroid
treatment in a rat model of focal Herpes encephalitis.
AB - Neurological damage in Herpes simplex type 1 encephalitis results from neuronal
cell death secondary to viral invasion, and from inflammatory changes and
cerebral oedema secondary to the immune response to the virus. Corticosteroids
could have an important role in the management of Herpes simplex encephalitis
because their anti-inflammatory action reduces cerebral oedema. However their use
has been limited by concerns that their immunosuppressive actions could increase
viral replication and spread. The present study examined this issue in a rat
model in which injection of HSV-1 into the cervical vagus nerve produced a well
defined focal encephalitis, characterised by an orderly progression of the virus
through central neural pathways connected with vagal afferent termination sites
in the medulla oblongata. After injection of HSV-1, rats were treated twice a
day, either with vehicle (saline, 400 microl i.p.), with acyclovir (30 mg/kg
i.p.), with dexamethasone (5 mg/kg i.p.), or with both acyclovir and
dexamethasone. Animals were sacrificed after 72 h, and viral load in different
brain regions was quantified by computer-assisted measurement of the area
occupied by immunohistochemical reaction product. Treatment with acyclovir
reduced viral load to 17 +/- 5% of the saline value (P < 0.01). After
dexamethasone treatment, the viral load (63 +/- 13% of the saline value) was also
reduced (P < 0.05). Treatment with both acyclovir and dexamethasone reduced viral
load to 26 +/- 8% of the saline value (P < 0.01 compared with saline, and P >
0.05 compared to acyclovir alone). Our results confirm the effectiveness of
acyclovir in a new model of HSV-1 infection, and provide evidence that
corticosteroids do not inhibit the antiviral action of acyclovir. In addition
corticosteroids may decrease the extent of infection in their own right. The
acute time course studied in our model parallels the time course of acute Herpes
simplex encephalitis in humans. Our data suggests that corticosteroids are not
detrimental when combined with acyclovir in the management of this condition.
PMID- 10786995
TI - A multi-mutant herpes simplex virus vector has minimal cytotoxic effects on the
distribution of filamentous actin, alpha-actinin 2 and a glutamate receptor in
differentiated PC12 cells.
AB - To develop effective gene therapy techniques that target populations of neurons
in the spinal cord, suitable vectors must be developed that will undergo
efficient, retrograde transport from an appropriate peripheral site and will not
be cytotoxic. Our previous work (LeVatte et al, 1998a) has demonstrated that a
replication defective herpes simplex virus vector 14Hdelta3vhsZ, that has been
substantially detoxified, is retrogradely transported from peripheral sites and
can infect large numbers of the targeted spinal neurons. We plan to develop
targeted gene therapy approaches designed to modulate the excitatory
glutamatergic methyl-D-aspartate (NMDA) receptor in spinal cord neurons as a
means of ameliorating a form of episodic high blood pressure that occurs after
spinal cord injury. In this report, we demonstrate that, in differentiated PC12
cells, a neuronal-like cell line, the virus vector does not appear to alter
aspects of the cytoskeletal architecture important to the proper distribution of
the NMDA receptor. In turn, the distribution of endogenous NMDA receptor 1
subunit protein (NMDAR1) or a transfected NMDAR1-green fluorescent fusion protein
was also found to be unaltered after vector infection. However, whereas
endogenous NMDAR1 distribution was maintained, vector infection did tend to
reduce the level of its expression. This drop in endogenous NMDAR1 expression
coincided with the expression of the HSV immediate early genes ICP0 and ICP27
over the first 24-48 h. These results indicate that the 14Hdelta3vhsZ herpes
simplex virus vector is suitable to use in future strategies to alter the level
of gene expression in targeted populations of spinal cord neurons.
PMID- 10786996
TI - Etiology of microglial nodules in brains of patients with acquired
immunodeficiency syndrome.
AB - Microglial nodules associated with opportunistic and HIV-related lesions are
frequently found in the brains of AIDS patients. However, in many cases, the
causative agent is only presumptively suspected. We reviewed 199 brains of AIDS
patients with micronodular lesions to clarify their etiology by
immunohistochemistry (to Toxoplasma gondii, cytomegalovirus, herpes simplex virus
I/II, varicella zoster virus and HIV-p24 core protein), PCR (for herpetic viruses
and Mycobacterium tuberculosis) and electron microscopy. Productive HIV infection
was observed in 110 cases (55.1%): 30 cases with Toxoplasma gondii encephalitis,
30 with cytomegalovirus encephalitis, eight with multiple cerebral diseases,
while in the remaining 42 cases HIV was the only pathogenetic agent.
Multinucleated giant cells (hallmark of HIV infection) were found in the MGNs of
85/110 cases with HIV-related lesions; the remaining 25 cases had only p24
positive cells but no multinucleated giant cells. In these latter cases the
micronodular lesions had been initially attributed to the main opportunistic
agent found in the brain, or defined as subacute encephalitis. Individual
microglial nodules positive for an opportunistic pathogen were generally negative
for HIV antigens. In 13 cases no opportunistic agent or HIV productive infection
was found. In these cases, PCR and electron microscopy examination for HIV and
other viral infections were negative. Our data suggest that HIV
immunohistochemistry should be used for the etiological diagnosis of micronodular
lesions in AIDS brains, even in the presence of other pathogens. After extensive
search, the etiology of the microglial nodules remains unknown in only a small
percentage of cases.
PMID- 10786997
TI - Expression of complement inhibitor protein CD59 in human neuronal and glial cell
lines treated with HIV-1 gp41 peptides.
AB - In attempts to elucidate the pathogenic mechanisms involved in neurodegeneration
in AIDS patients with cognitive deficits, the possible effect of HIV-1
transmembrane envelope protein gp41 on expression of the membrane inhibitor of
complement mediated cytolysis (CD59) was assessed in human neuronal (SK-N-SH) and
astroglial (T98G) cell lines. Western blotting analyses demonstrated that an
immunodominant (ID, aa 598-613) gp41 peptide as well as the recombinant gp41
protein encompassing this domain markedly reduced CD59 level in a dose dependent
manner whereas p24 and control peptide had little effect. RT-PCR showed that ID
peptide also elicited a reduction in the expressed CD59 mRNA level. This gp41
peptide apparently down-regulated phorbol 12,13-dibutyrate induced elevation of
CD59 at the protein and mRNA levels in a manner similar to that conferred by
protein kinase C inhibitor, H-7 or staurosporine in SK-N-SH. Interestingly,
proinflammatory cytokines such as IL-1beta or IFN-gamma as well as LPS greatly
decreased CD59 in SK-N-SH and to a lesser extent in T98G whereas TNF-alpha did
not significantly alter it. In contrast, antioxidants and anti-inflammatory
agents enhanced CD59 expression reversing gp41 peptide mediated inhibitory effect
in SK-N-SH. Our data suggest that high level of gp41 or its metabolites as well
as impaired protein kinase response, chronic inflammation or antioxidant
depletion within HIV-1 infected brains may be associated with a diminished
expression of CD59 which would render neuronal cells to susceptible to indirect
bystander lysis in the presence of autologous complement.
PMID- 10786998
TI - High sensitivity detection of JC-virus DNA in postmortem brain tissue by in situ
PCR.
AB - Opportunistic infection of the central nervous system by human polyomavirus JC
can cause a devastating disease, progressive multifocal leukoencephalopathy
(PML). To gain new neuropathological insights into JC-virus (JCV) infection
patterns in PML at the light microscopic level, the highly sensitive indirect in
situ polymerase chain reaction (in situ PCR) was employed in up to 15-year old
formalin-fixed and paraffin-embedded postmortem brain tissue derived from nine
AIDS patients with PML. In situ PCR, in which target DNA is amplified
intracellularly and detected by a specific labelled probe in morphologically
intact tissue, was compared with conventional in situ hybridization (ISH).
Validity was ensured by the inclusion of 13 controls. JCV detection with in situ
PCR proved to be highly sensitive since in all nine brain samples the number of
positive cells exceeded the ISH results by 2-3-fold. Whereas by routine staining
the brain tissue of each individual patient showed regions with severe, mild or
no involvement by PML, improved detection of JCV DNA by in situ PCR allowed a
regrading into five different degrees of JCV infection. Significant myelin
staining was observed, suggesting that cell-to-cell contact may not be the only
means of virus spread but that new cells could also be infected by virus released
after cell lysis. Furthermore, using in situ PCR hitherto unreported
intracellular distribution patterns of JCV DNA in oligodendro- and astrocytes
were observed by light microscopy.
PMID- 10786999
TI - Upregulated expression of interleukin-8, RANTES and chemokine receptors in human
astrocytic cells infected with HIV-1.
AB - Human immunodeficiency virus (HIV) infection of the central nervous system (CNS)
affects primarily microglial cells and astrocytes. Infection of these latter
cells occurs independently of CD4 and is characterised by preferential
accumulation of 2 Kb mRNA, encoding mostly Nef, and by low levels of 4.5 and 9 Kb
RNAs. We have investigated the potential role of chronic HIV infection of human
astrocytic cells on the expression of pro-inflammatory cytokines, chemokines and
their receptors by comparing the infected TH4-7-5 with its parental uninfected
85HG66 cell lines. Upregulated levels of tumour necrosis factor-alpha (TNF-alpha)
and of certain chemokines, namely interleukin-8 (IL-8) and regulated upon
activation normal T cell expressed and secreted (RANTES), were observed in the
infected versus uninfected cells, whereas monocyte chemotactic protein-1 (MCP-1)
was comparably expressed in both cell lines. This pattern of expression was
confirmed in primary foetal astrocytes transiently transfected with HIV. In
addition, CXCR1, CXCR2 and CCR2b, receptors for IL-8 and MCP-1, respectively,
were also found to be upregulated in TH4-7-5 versus 85HG66. CXCR4, the receptor
of stromal cell derived factor-1 (SDF-1) and co-receptor for syncytium inducing
HIVs, was comparably expressed in infected and uninfected astrocytic cells,
whereas CCR5 was not detected in either cell line. Furthermore, treatment of TH4
7-5 cells with TNF-alpha or IL-1beta stimulated RNA and protein secretion of IL
8, MCP-1, and RANTES as well as HIV expression. Thus, our findings suggest that
HIV infection of astrocytic cells can contribute to the establishment of a
chronic inflammatory state in the CNS, eventually resulting in HIV encephalitis,
by increasing the secretion of pro-inflammatory cytokines, such as TNF-alpha and
several chemokines. Overexpression of chemokine receptors including CCR2b, CXCR1
and CXCR2 in infected astrocytic cells may contribute to HIV-induced damage of
the CNS via autocrine/paracrine activation of astrocytes.
PMID- 10787000
TI - Improvement in HIV-associated motor slowing after antiretroviral therapy
including protease inhibitors.
AB - A study of neuropsychological performance was conducted in 33 HIV+ patients
initiating highly active antiretroviral therapy (HAART). Grooved Pegboard (GP)
non-dominant hand performance improved in 23/33 (70%) subjects (P=0.002). Among
23 patients with motor slowing (GP non-dominant hand z score < -1.0) at baseline,
18 (78%) improved on the GP non-dominant hand test after initiating HAART
(P=0.001). GP non-dominant hand performance improved longitudinally in HIV+
patients initiating HAART, while matched HIV+ controls not on HAART did not
change (P=0.045). Significant improvement in motor performance can occur after
HAART in HIV+ patients with impairment.
PMID- 10787002
TI - Is there a role for quinacrine (Atabrine) in the new millennium?
PMID- 10787001
TI - Analysis of the Fv1 alleles involved in the susceptibility of mice to lactate
dehydrogenase-elevating virus-induced polioencephalomyelitis.
AB - Development of polioencephalomyelitis in mice infected with lactate dehydrogenase
elevating virus (LDV) requires expression of N-tropic ecotropic MuLV
retroviruses. 129/Sv mice are resistant to N-tropic MuLV expression and therefore
do not develop LDV-induced polioencephalomyelitis. The Fv1 gene determines the
susceptibility to retrovirus replication. We sequenced the open reading frame of
the Fv1nr allele of 129/Sv mice. It differs by only one nucleotide, modifying one
amino acid in the encoded protein, from the Fv1n allele of susceptible AKR and
C58 animals. We excluded that the resistance of 129/Sv mice to LDV-induced
polioencephalomyelitis resulted from the absence of endogenous N-tropic
retrovirus, by infecting (129/Sv x C58/J) F1 animals. Therefore it is possible
that the amino acid that defines the Fv1nr allele is responsible for resistance
of 129/Sv mice to N-tropic MuLV expression and to LDV-induced
polioencephalomyelitis.
PMID- 10787003
TI - Mixed cryoglobulinemia: new concepts.
AB - The most documented extrahepatic manifestation of hepatitis C virus (HCV)
infection is mixed cryoglobulinemia (MC). MC is characterised by the presence of
temperature-sensitive protein complexes: in type II MC, cryoglobulins are
composed of a monoclonal rheumatoid factor (usually, IgMkappa) against polyclonal
IgG. In type III MC, all components are polyclonal. The presence of
microheterogeneity and other new types of cryoglobulins is a novel and recent
observation. The production of different autoantibodies and circulating immune
complexes, including the cryoglobulins, are responsible for systemic vasculitis
and various organ damage. In a limited number of MC patients, a malignancy, that
is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop.
Finally, results of interferon and/or ribavirin treatments in MC patients
represent an indirect proof for the pathogenetic link between MC and HVC
infection. The discovery of the relation between HCV infection and MC shows the
striking association between a viral infection and an autoimmune disease and,
thus, a potential link between the systemic autoimmune and lymphoproliferative
disorders.
PMID- 10787004
TI - The benefit of combining hydroxychloroquine with quinacrine in the treatment of
SLE patients.
AB - BACKGROUND: Although the benefit of antimalarials in the treatment of cutaneous
LE is well established, the effect of combined hydroxychloroquine and quinacrine
treatment in systemic lupus erythematosus with major organ involvement remains
underappreciated. PATIENTS: Six active SLE patients (SLEDAI score > 5 points),
with a mean duration of illness 9.1 yr (range 2-17 yr) were started on quinacrine
(100 mg/d) following failure to achieve clinical remission on a therapeutic
regimen which included a maintenance dose of hydroxychloroquine (400 mg/d)
together with prednisone (either 10-20 mg/d or higher daily doses of this agent
for short periods) and azathioprine (150 mg/d) or methotrexate (7.5 mg/week).
OUTCOME: In 5/6 of the patients the addition of quinacrine to the previous
treatment resulted in complete remission (SLEDAI 0-2 points), which persisted
over the follow-up period [mean +/- 2.2 yr (range 0.5-3.5)]. During this period
hydroxychloroquine and azathioprine were reduced to 200 mg/d and 100 mg/d
respectively, whereas prednisone was modified as follows: in 2 patients daily
administration was discontinued; in one the dose was reduced to 2.5 mg/d (from
that of > or = 20 mg/d); in 2 others the previous need for an intermittent course
was avoided. However, in one out of the six patients the addition for 3 months of
quinacrine to the therapeutic protocol did not result in clinical improvement and
was therefore discontinued. CONCLUSIONS: The promising results of this
preliminary investigation encourages the combined use of the two antimalarial
drugs in appropriate candidates. This modality may induce remission, seems to be
safe and possesses a steroid sparing effect.
PMID- 10787005
TI - The clinical features and prognosis of lupus with disease onset at age 65 and
older.
AB - Systemic lupus erythematosus (SLE) in the elderly is uncommon and rarely reported
with disease onset at age 65 and older. The aim of this study is to
retrospectively analyze the influence of age at disease onset on the clinical
features and prognosis of SLE. From 1988 to 1998, we encountered 21 lupus
patients with disease onset at age 65 and older (all are included in group A).
For comparison, 21 lupus patients with disease onset between 50-64 years of age
(group B) and 152 lupus patients with disease onset before 50 years of age (group
C) were obtained by a simple random sampling method from the hospital registry.
Clinical features as included in the 1982 ARA revised criteria for classification
of SLE and survival rate were analyzed and compared among these three groups.
Group A had a smaller female to male ratio, longer duration from disease onset to
diagnosis, less malar rash, more discoid lupus, and shorter survival rate that
group C. There was no statistically significant difference in clinical features
and survival between groups A and B, as well as between female and male patients
of these two groups. The main cause of death in group A was septic shock. In
conclusion, the clinical features and prognosis of SLE were influenced by the age
at disease onset. However, clinical features and prognosis of SLE were similar in
both late-onset lupus groups.
PMID- 10787006
TI - Systemic lupus erythematosus in three ethnic groups. VI: Factors associated with
fatigue within 5 years of criteria diagnosis. LUMINA Study Group. LUpus in
MInority populations: NAture vs Nurture.
AB - OBJECTIVE: To determine the frequency, degree and associated features of fatigue
among Hispanic (H), African American (AA) and Caucasian (C) patients with recent
onset (< or = 5 yr) systemic lupus erythematosus (SLE) at their baseline
evaluation. METHODS: H (n = 69), AA (n = 83) and C (n = 71) patients from the
LUMINA (LUpus in MInority populations: NAture vs Nurture) cohort were studied.
Fatigue [Fatigue Severity Scale (FSS)] was defined as present if FSS score > or =
3.0. Variables from functional, clinical, sociodemographic, health behaviors,
behavioral and psychological and immunogenetics domains were ascertained at study
entry. Associations were examined using regression models. RESULTS: Eighty-six
percent (85.7%) of patients reported having fatigue (82.6% H; 85.5% AA; 88.7% C);
median FSS score, 5.3. Factors from the psychological and clinical domains were
primarily associated with FSS; immunogenetic (HLA Class II phenotypes) features
were not. Increased fatigue was strongly associated with decreasing function,
both physical and mental. Variables associated with significantly greater degree
of fatigue at baseline in the multivariable stepwise model in order of decreasing
additional partial R2 explained included: abnormal illness-related behaviors,
older age, higher self-reported pain, greater degree of helplessness, greater
disease activity, Caucasian race, and lacking health insurance (model R2 = 37%).
CONCLUSIONS: Fatigue is one of the most prevalent clinical manifestations of SLE
across all ethnic groups. The perception of fatigue severity in SLE may be
multifactorial in origin, including psychosocial factors and disease activity. If
these prove causal, knowledge of their contribution may suggest therapeutic
and/or behavioral interventions, which could ameliorate this pervasive and often
incapacitating symptom of SLE.
PMID- 10787007
TI - Clinical outcome and predictors of disease evolution in patients with incomplete
lupus erythematosus.
AB - To determine the outcome and identify risk factors for evolution into systemic
lupus erythematosus (SLE) in a population of incomplete lupus erythematosus (ILE)
patients, we studied the clinical and serologic manifestations in a cohort of 87
ILE patients. ILE patients had at least one but less than four of the American
College of Rheumatology (ACR) classification criteria of SLE and did not present
distinctive clinical features or meet classification criteria of other connective
tissue diseases. The patients that remained with ILE were compared with patients
that evolved into SLE and with a cohort of 94 SLE patients. The mean disease
duration and follow up of ILE patients were 4.4 +/- 4.1 and 2.2 +/- 2.4 years
respectively. Eight patients evolved into SLE, but none presented major organ
damage. At baseline, patients that remained with ILE were less likely to have
photosensitivity, elevated anti-dsDNA and decreased C3 complement than patients
that evolved into SLE. At the end of the study, malar rash and oral ulcerations
were also less frequent in the ILE group. Compared with all SLE cases, ILE
patients were less likely to have photosensitivity, malar rash, oral ulcers,
Raynaud's phenomenon, arthritis, low C3, low C4, positive anti-dsDNA, anti-Sm,
anti-RNP, anti-Ro and anti-La antibodies at baseline. Hazard analyses showed that
malar rash, oral ulcers, elevated anti-dsDNA and decreased C4 were associated
with SLE occurrence. In conclusion, this study suggests that ILE represents a
mild spectrum of lupus in which mucocutaneous and serological abnormalities are
associated with progression into SLE.
PMID- 10787008
TI - ANA negative systemic lupus erythematosus sera revisited serologically.
AB - OBJECTIVE: To better define the serology of a panel of sera from patients with a
clinical diagnosis of systemic lupus erythematosus (SLE) or subacute cutaneous
lupus erythematosus (SCLE) with a negative antinuclear antibody (ANA) test on
mouse liver. METHODS: Sensitive ELISA methods for anti-Ro/SSA, anti-La/SSB, and
anti-U1RNP were applied to a panel of 76 sera with either SLE or SCLE and a
negative ANA test on mouse liver. RESULTS: These sera had previously been shown
to have a high prevalence of anti-Ro/SSA (68%) and anti-La/SSB (27%) precipitins
respectively. None had precipitins to U1RNP or Sm. ELISA methodology revealed
that all of the sera 76/76 (100%) had elevated levels (> mean +/- 2 SD of a panel
of 21 normal sera) of anti-Ro/SSA, 36/76 (46%) had elevated levels of anti
La/SSB, and 27 of 76 (35%) had elevated levels of anti-U1RNP. CONCLUSION: The
subset of patients with SLE and SCLE with a negative ANA test on mouse liver
almost uniformly have antibodies to the Ro/SSA antigen by a sensitive ELISA. This
adds evidence to the idea that this is a more homogeneous disease subset within
the spectrum of SLE.
PMID- 10787009
TI - A longitudinal study of human cytomegalovirus serology and viruria fails to
detect active viral infection in 20 systemic lupus erythematosus patients.
AB - In this study, we investigated whether active human cytomegalovirus infection
could be detected in 20 systemic lupus erythematosus (SLE) patients over a one
year observation period by polymerase chain reaction on serial urine specimens
and by monitoring of IgG and IgM HCMV-specific antibody profiles in serial serum
samples. Of 788 urine samples analysed for the presence of human cytomegalovirus
DNA, only 2 specimens (0.25%) collected from two different patients contained
genuine human cytomegalovirus sequences as determined by polymerase chain
reaction and subsequent sequencing of the PCR products. These two patients had
one positive sample out of 36 samples or 40 samples, respectively. Nineteen of
the patients (95%) possessed IgG antibodies against human cytomegalovirus, while
9 (45%) produced IgM antibodies. However, none of the patients showed signs of an
active virus infection as judged by the stable anti-HCMV IgG or IgM antibody
levels during the observation period, nor was any correlation between disease
activity and HCMV serology/viruria observed. Of single serum samples of 26 age-
and sex-matched blood donors, 21 (81%) were HCMV IgG positive and 1 (3.8%) was
IgM seropositive. In conclusion, our data fail to establish an active human
cytomegalovirus infection in SLE patients.
PMID- 10787010
TI - Expression of complement regulatory proteins in diffuse proliferative
glomerulonephritis.
AB - This study assessed the expression of complement receptor 1 (CR1), decay
accelerating factor (DAF) and membrane inhibitor of reactive lysis (CD59) on the
erythrocytes and glomerulus of diffuse proliferative glomerulonephritis (DPGN) of
systemic lupus erythematosus (SLE) patients using flow cytometry and
immunofluorescence techniques to elucidate their role in the pathogenesis of
DPGN. Expression of CR1 on the erythrocytes and glomerulus of DPGN patients was
reduced compared with expression in normal subjects. However, expression of DAF
and CD59 was increased on both erythrocytes and glomerulus of DPGN patients,
suggesting the generation of a protective response against complement-mediated
injury.
PMID- 10787012
TI - Extensive lymphadenopathy as the first clinical manifestation in systemic lupus
erythematosus.
AB - Lymphadenopathy (LAP) is a frequent sign of systemic lupus erythematosus (SLE).
The lymph nodes are usually soft, nontender, varying in size from 0.5 cm to
several centimeters. However, generalized LAP in SLE is extremely rare, while to
our knowledge, the presentation of extensive LAP with blocks of retrosternal,
mesenteric, and retroperitoneal nodes has not been previously reported as the
first clinical manifestation of the disease. In this report we describe a patient
with extensive LAP and active SLE and we point out that generalized LAP should be
included among the clinical findings indicating disease activity in SLE patients.
PMID- 10787011
TI - Serum levels of soluble Fas correlate with indices of organ damage in systemic
lupus erythematosus.
AB - OBJECTIVE: To evaluate whether the levels of soluble form of the Fas apoptosis
antigen (sCD95/sFas) varied from those of healthy control subjects in a group of
patients with systemic lupus erythematosus (SLE). This was done to determine
whether sFas has a role in either the disease activity or the organ damage in
SLE. METHODS: Serum levels of sFas were measured over a period of 4 y (277
determinations) in 39 Arab patients with SLE and 22 age-, gender-, and race
matched healthy controls using double antibody ELISA. SLEDAI scores for disease
activity and SLICC/ACR scores for cumulative organ damage were determined. Serum
levels of acute phase reactants, complement, inflammatory cell counts, levels of
autoantibodies, and kidney and liver function test results were obtained
retrospectively from clinical records. RESULTS: sFas levels were significantly
higher in patients with SLE (n = 39, 277 determinations) (0.60 ng/ml +/- 0.38)
than in healthy controls (n = 22) (0.26 ng/ml +/- 0.11) (P < 0.00001). The levels
of sFas correlated with SLICC/ACR (r = 0.36; P < 0.02), but not with SLEDAI. sFas
correlated with renal and liver function tests measured by s-creatinine (r =
0.38; P < 0.0001), creatinine clearance (r = -0.30, P < 0.001), s-albumin (r =
0.28, P < 0.0001), and ALT (r = 0.35; P < 0.00001), but did not correlate with
the levels of acute phase reactants. CONCLUSION: sFas is elevated in sera of SLE
patient. Since sFas correlates with indices of organ damage but not with disease
activity, it may be a marker of organ damage in SLE and may act to protect
certain organs from further damage by inhibiting Fas-mediated apoptosis.
PMID- 10787013
TI - Systemic lupus erythematosus presenting with a reticular erythematous mucinosis
like condition.
AB - We report the case of a woman with clinical and histopathological features of
reticular erythematous mucinosis syndrome (REM) who six years later developed
diagnostic criteria for systemic lupus erythematosus (SLE). Two biopsies
performed at the same area initially showed mucin dermal deposits and further
development of characteristic dermo-epidermal changes of lupus erythematosus. Our
findings suggest that SLE may present with an REM-like condition.
PMID- 10787014
TI - Intramedullary tuberculosis manifested as Brown-Sequard syndrome in a patient
with systemic lupus erythematosus.
AB - A 25-year-old girl presented with progressive deterioration of right side
weakness with decreased sensation on the left trunk. She had been treated with
high dose steroid due to autoimmune thrombocytopenia for 2 months. Clinical,
laboratory and immunologic studies revealed that she had systemic lupus
erythematosus (SLE), MRI of spinal cord showed marginal contrast enhancing and
fluid containing mass in the cord of the C5-6 level, suggesting intramedullary
abscess. She underwent surgery of mass removal with biopsy. The pathologic
findings from cord tissues revealed numerous acid fast bacilli (AFB) in necrotic
tissues. After surgery and anti-tuberculous treatment, her neurologic symptoms
were markedly improved with restoration of right side motor weakness. To our
knowledge, this is the first case report of intramedullary tuberculosis in a
patient with SLE. Since intramedullary tuberculosis may sometimes mimic
neurologic complication of SLE itself, it may pose diagnostic and therapeutic
confusion for clinicians. We report a case of spinal cord tuberculosis affecting
C5, 6 level which was manifested as Brown-Sequard syndrome in a patient with SLE.
PMID- 10787015
TI - Thymoma associated with systemic lupus erythematosus and immunologic
abnormalities.
AB - The association between Systemic Lupus Erythematosus (SLE) and thymoma occurs
with a greater frequency than dictated by coincidence alone. The immunologic
effects of thymectomy on the appearance and/or the course of SLE are still to be
elucidated. We report one case of SLE diagnosed at the same time as thymoma, and
two cases of thymoma associated with immunologic disorders in the absence of
clinical signs and symptoms diagnostic of SLE.
PMID- 10787016
TI - The possible role of interleukin-16 in the low incidence of HIV infection in
patients with systemic lupus erythematosus.
PMID- 10787017
TI - Coexistence of systemic lupus erythematosus and myasthenia gravis.
PMID- 10787019
TI - Appropriateness of hospital utilisation in Italy.
AB - The purpose of this study was to determine the extent of inappropriate hospital
admission and inappropriate days of stay and the effect of variables on such
inappropriateness on an adult population in Italy. A review was made of medical
records of patients admitted to any one of the following specialities: medicine,
surgery, gynaecology or traumatology/orthopaedics at one of five hospitals
located respectively in Siena, Frosinone, Rome and Catanzaro, and who were in
patients during one of four pre-selected index days. To determine the
appropriateness of hospital admission and length of hospitalisation, a
retrospective application was made using the Italian version of Appropriateness
Evaluation Protocol (AEP). A total of 1299 patient days were reviewed. 14.2% of
the hospital admissions and 37.3% of the number of hospitalisation days were
judged to be inappropriate. Multiple logistic regression analysis showed that
inappropriate admission was significantly increased with relation to: greater
distance from hospital to patient's home; admission to a medical ward; planned
admissions; and admission over a weekend. Multiple logistic regression analysis
indicated that the inappropriate number of days of hospitalisation was
significantly higher for medicine and for patients who were inappropriately
admitted. The main reason for categorising an admission as inappropriate was that
the patient's problems could be treated on an out-patient basis, and, for
inappropriate days of care, the physician was overtly cautious in the management
of a patient. Changing the physicians' behaviour and the organisation of hospital
activities may be effective in improving the quality and efficiency of hospital
care.
PMID- 10787018
TI - Two boys and a girl please and hold the mustard.
PMID- 10787020
TI - Geographical variations of place of death among Italian communities suggest an
inappropriate hospital use in the terminal phase of cancer disease.
AB - This study aimed to assess geographic variations of place of death among Italian
communities, to investigate the determinants of home death, and to examine trends
in the proportion of home deaths over a period of 8 y. A cross-sectional analysis
was performed on 13 provinces from two Italian regions (Liguria and Toscana), and
the geographic variations and determinants of home death were studied for the
17,597 residents, who died of cancer in 1991. Trends for both the regions of the
proportion of home deaths were examined for the period 1987 and 1995. A
remarkable heterogeneity in the observed proportion of home deaths among the 13
provinces was observed, ranging between 31.4 and 40.4% in Liguria and between
37.7 and 73.3% in Toscana. The estimated proportion of home deaths after
adjustment for age, gender, marital status, education, place of birth,
characteristics of the living area, and cancer site remained substantially the
same. The proportion of home deaths significantly increased with increasing age,
and years of education. It was higher among females, married and widowed
patients, native patients, and for residents in a semi-urban or rural areas. A
significant decrease in the percentage of patients who died at home between 1987
and 1995 in both regions was observed. The wide geographical and social
differences observed between and within the communities for the frequency of home
deaths are not explained by the distribution of known determinants, and possibly
suggest patterns of inappropriate hospital admissions in the terminal phase of
disease.
PMID- 10787021
TI - Which is the best deprivation predictor of foetal and infant mortality rates?
AB - This study investigates which, if any, population-based indicator of deprivation
best predicts foetal and infant mortality rates in England. For the year 1995,
the deprivation levels of 364 English Local Authorities were compared; using the
three commonly used indicators, Jarman score, Townsend score and percentage
unemployed. The predictive value of these for stillbirth, neonatal and infant
mortality rates was then calculated. The three deprivation indicators were highly
inter-correlated (r=0.866-0.924). For each mortality rate, the correlation with
deprivation did not differ significantly for the three indicators of deprivation.
We conclude, when comparing these outcomes in different areas of England, that
any of the three deprivation indicators may be used to adjust for deprivation.
PMID- 10787022
TI - Health hazards of unemployment--only a boom phenomenon? A study of young men and
women during times of prosperity and times of recession.
AB - BACKGROUND: It has been suggested that high unemployment rates in society may be
less harmful to the health of people than low unemployment rates. Therefore, a
study was carried out to compare, among young men and women, the relationship
between health and long-term unemployment during periods of rapid economic growth
'boom' and economic recession. METHODS: Two study groups were chosen at age 21 y
(5 y after compulsory schooling ended) from an industrial town in northern
Sweden. The first group (number 1083) was chosen and surveyed in 1986 (under
'boom' conditions); the second (number 898) was chosen in 1994 (under economic
recession conditions). The non-response rate was 2% for the boom group and 10%
for the recession group. The main outcome measurements examined were somatic and
psychological symptoms. RESULTS: Health criteria for general health among long
term unemployed young men and women did not differ between the group surveyed in
boom conditions and the group surveyed in recession conditions. The only
exception was for psychological symptoms, which scored lower among the men in the
recession group. Individual unemployment had a high explanatory power for poor
health, in particular, psychological ill health. CONCLUSIONS: When comparing
periods of boom and recession there was no difference in somatic and
psychological symptoms for those who were long-term unemployed. Thus, the trade
cycle appeared to have had no impact on their health.
PMID- 10787023
TI - Inequalities in health: raising awareness among health authority staff.
AB - A postal survey of all staff working for Bro Taf Health Authority (n = 237) was
carried out during August and September 1998. The survey was concerned with
tackling inequalities in health in terms of involvement, information needs,
priorities and working patterns. The aim was to raise awareness of the Health
Authority's commitment to tackling inequalities in health and to collect
employees' opinions on methods of working effectively towards greater equity. The
response rate was higher for senior grades (63%) than for basic grades (26%). Not
all employees had access to background documents and many expressed a need for
more information. There was a strong feeling that a change in working patterns
would be beneficial and staff were particularly concerned that internal
communications should be improved. The survey provided a good opportunity to
raise awareness of health inequality issues and was beneficial in providing an
opportunity for staff to express their opinions anonymously. Some suggestions
have already been implemented and others are incorporated in the Health
Authority's Equity Strategy.
PMID- 10787024
TI - Causes and effects of road traffic accidents in Saudi Arabia.
AB - In Saudi Arabia the motor vehicle is the main means of transportation. Between
1971 and 1997; 564,762 people died or were injured in road traffic accidents, a
figure equivalent to 3.5% of the total population in Saudi Arabia. During this
period 66,914 people have died on the roads in Saudi Arabia due to road
accidents, amounting to one person killed and four injured every hour. Over 65%
of accidents occur because of vehicles travelling at excess speed and/or drivers
disobeying traffic signals. Of deaths in Ministry of Health hospitals, 81% are
due to road traffic accidents and 20% of their beds are occupied by traffic
accidents victims. Also, 79.2% of patients admitted to Riyadh Armed Forces
Hospital with spinal injuries has sustained their injuries as a result of a motor
vehicle accident. We recommend compulsory use of safety seat belts in vehicles
and the setting up of a new database to collect, store and analyse information
relating to the road traffic accidents.
PMID- 10787025
TI - Chemical incident management: gaseous emissions from a stockpile of coal.
AB - Spontaneous combustion of coal releases a wide range of airborne pollutants
which, in high concentrations, may be hazardous to health. Little is known about
how the effects on health change in relation to the release of multiple
substances. This article reports an incident in which a stockpile of coal
released potentially harmful gases into the environment. Although the resultant
health effects reported were few, the co-ordinated response by local authorities
and health authorities highlighted the advantage of a multidisciplinary approach.
Public health departments need to be aware of major chemical hazards within their
district. Prompt environmental monitoring and exposure measurement needs to be
arranged as this is crucial to making an appropriate response. Updated registers
are needed from private companies and public bodies; who can provide timely
measurements of chemical hazards. Health districts with more than one local
authority may benefit from pooling resources and knowledge in order to prepare
for such an incident.
PMID- 10787026
TI - Psychiatric ill health and distribution of body fat mass among female immigrants
in Sweden.
AB - Given the association between psychiatric factors and obesity, the aims of the
present study were to identify these variables among native Swedish as well as
immigrant women, and to compare the prevalence of psychiatric ill health in women
of foreign ethnicity with Swedish women. Information on melancholia, life
satisfaction, sleeping problems, and use of psychoactive drugs as well as alcohol
and smoking habits was obtained from questionnaires in a randomly selected
population (n = 1464, participation rate 78%, aged 40 y). Height, body weight and
circumferences of waist and hip were self-measured, so allowing calculations of
the body mass index (BMI) and the waist to hip ratio (WHR) to be made. Among
those who responded 246 (21.9%) were immigrants, divided into the following
demographic clusters Nordic countries; Rest of Europe; and Non-European. Among
native Swedes, use of psychoactive drugs and melancholy were associated with both
BMI and WHR. BMI-associated with use of antidepressants in women from Nordic
countries with a short duration of stay, and in subjects with a long duration of
residence, was related to life satisfaction. Among subjects from the Rest of
Europe, the use of hypnotics was negatively related to BMI, and life satisfaction
was positively associated with WHR. Among Non-Europeans with a long duration of
residence, BMI was positively connected to the use of anxiolytics and,
negatively, to life satisfaction. Furthermore, melancholy was positively
associated with WHR (borderline, P=0.086) in Non-Europeans. Subjects from Nordic
countries were characterised by a relatively low use of psychoactive drugs and
infrequent insomnia. In contrast, subjects from the Rest of Europe with short
duration of stay showed a relatively extensive use of psychoactive drugs, and the
Non-European group with short duration of stay experienced frequent insomnia, and
a low degree of life satisfaction as well as high degree of melancholy. The
association between psychiatric factors and obesity is not uniform across ethnic
groups, suggesting a combination of genetic predisposition and psychosocial
vulnerability. The high prevalence of psychiatric ill health among some ethnic
groups should be a matter of public health concern.
PMID- 10787027
TI - A study of colo-rectal carcinoma in the Asian and European populations in the
city of Leicester from 1981 to 1991.
AB - For many years clinical reports have suggested that colo-rectal cancer is
uncommon in the Asian population resident in England and a report in 1990
confirmed this in Asians living in Bradford. This study aims to establish the
incidence of colo-rectal cancer in the Asian population resident in the city of
Leicester during the 11 y period 1 January 1981-31 December 1991. The relative
frequency of colo-rectal carcinoma in Asians compared to Europeans over the
period studied was 0.16 (Asian/European, 95% confidence interval (CI) 0.04-0.75).
This difference was statistically significant and further analysis showed that
there was a real trend with an increased relative frequency amongst the younger
age groups. Although there was a significantly lower incidence of colo-rectal
carcinoma in the Asian population in Leicester city over the period studied it is
unknown whether this is due to environmental or genetic factors. During the next
decade it is likely to become clearer as to whether this difference will persist
or whether there will be an increase in the incidence of colo-rectal carcinoma in
Asians in Leicestershire.
PMID- 10787028
TI - Issues arising from two related cases of childhood tuberculous meningitis.
AB - Two cases of childhood meningitis occurred in the same school within two weeks.
The cases were cousins. The first case died and the aetiology was confirmed as
tuberculous following a gene probe of a culture from the meningeal tissues at
postmortem. The second case, with similar life threatening clinical features
compatible with tuberculous meningitis, recovered. Seventy-seven contacts of the
two cases among the immediate and extended families were screened. The adult
sources of the infection were found to be two aunts of the second case, who were
nurses working in the same nursing home. A further 73 contacts of the adult cases
were identified. A total of eight close contacts to the aunts were given
chemoprophylaxis and three were treated for tuberculosis. Contact tracing was
also undertaken in the nursing home but no further cases were identified. These
two cases highlight the difficulties in making a rapid diagnosis in tuberculous
meningitis, the difficulties in handling media and public concern with limited
information, and deciding on the appropriate level of contact tracing in special
circumstances.
PMID- 10787029
TI - Community paediatrics moves on--an analysis of changing work patterns 1994-97.
AB - OBJECTIVES: To describe the current clinical workload of the modern community
paediatrician; to outline the changes in this role over recent years and examine
the reasons for these. DESIGN AND SETTING: The design is a retrospective analysis
of data routinely collected for contracting purposes. Nottingham community
paediatric service 1994-97 is the setting. MAIN OUTCOME MEASURES: These are the
characteristics of patients seen, sources of referral, locations of clinical
contact, referral rates by area. RESULTS: 36,710 appointments were offered over
the time period studied. The non-attendance rate was 17%. Pre-school children
made up the largest group seen. Most referrals were from health visitors (23%)
and school nurses (29%). There has been a small but significant increase in the
numbers of children seen who have developmental problems and disability, and due
to child protection issues between the time periods. There has been a shift in
the proportions of children seen in a local health centre referral clinic (9.8%
increase during 1994-97) rather than in a school setting. Twice as many children
are referred to the community paediatrician from inner city areas than from the
surrounding county areas. CONCLUSION: The transfer of child health surveillance
to the primary health care team and the increased training of community
paediatricians, has resulted in community paediatricians developing an
increasingly specialised role particularly in the areas of child growth and
development, disability, social and behavioural paediatrics.
PMID- 10787030
TI - N-[4-(3-ethoxy-2-hydropropoxy)phenyl] acrylamide selectively induces apoptosis of
cerebellar granule cells in vivo and in vitro in rats.
AB - Oral administration of N-[4-(3-ethoxy-2-hydropropoxy)phenyl] acrylamide (EHA)
induced selective granule cell destruction in the granular layer of the
cerebellar cortex together with neurological signs, such as delayed righting
reflex, gait or truncal ataxia, and convulsion. Neuropathologically, it caused
multifocal granule cell destruction with nuclear pyknosis and spongiosis of the
neuropile in the granular layer. Other neurons, including Purkinje cells, were
spared. Ultrastructurally, damaged granule cells showed aggregation of nuclear
chromatin and cytoplasmic edema, but cytoplasmic organelles were preserved. The
brain uptake index of 14C-labeled EHA was similar to that of H2O. When EHA was
added to rat cerebellar tissue cultures, only the granule cells showed nuclear
pyknosis, aggregation of nuclear chromatin, and karyorrhexis with cytoplasmic
swelling. These granule cells were positive for DNA fragmentation by the TUNEL
method. These results suggest that EHA permeates the blood vessel wall and
directly affects the cerebellar granule cells, resulting in selective granule
cell apoptosis.
PMID- 10787031
TI - Characterization of chromosome 17 abnormalities in medulloblastomas.
AB - Loss of portions of chromosome 17p, usually through the formation of i(17qp) is a
well-known finding in medulloblastomas. Loss of heterozygosity (LOH) studies,
however, occasionally demonstrate loss of the more distal portions of 17p, a
pattern which is more consistent with a terminal deletion. Here we use a
combination of routine karyotyping, fluorescence in situ hybridization (FISH) and
LOH studies on four medulloblastoma cell lines and one xenograft to demonstrate
the spectrum of chromosome 17 abnormalities which occur in these tumors. Cell
line D-556 Med showed a typical dicentric i(17q) and cell line D-721 Med showed
two normal copies of chromosome 17 by all methods. Cell line D-425 Med showed
loss of terminal 17p by LOH, while the karyotype showed what appeared to be an
i(17q). FISH and chromosome 17 painting, however, demonstrated that the abnormal
chromosome 17 was actually formed through an unbalanced translocation involving
two copies of chromosome 17, with breakpoints at p12 and q11-1, an explanation
which reconciled the cytogenetic and LOH findings. Cell line D 581 Med had a
terminal deletion at 17p11.2. The finding of two cells with i(17q) in this case
by interphase FISH suggests that the terminal deletion arose from breakage of an
i(17q). Finally, xenograft D 690 Med showed LOH for regions distal to 17p12,
whereas karyotyping, FISH using probes on 17p, and chromosome 17 painting showed
two intact copies of chromosome 17. This pattern can be explained by homologous
recombination. These data support the concept that the critical deletion of 17p
can occur through a variety of mechanisms in the medulloblastoma. The losses may
occur through typical i(17q), as well as other mechanisms such as terminal
deletions, possibly through breakage of i(17q), unbalanced translocations and
homologous recombination.
PMID- 10787033
TI - Retrospective study of Creutzfeldt-Jakob disease in Belgium: neuropathological
findings.
AB - Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that affects about
1 in 10(6) inhabitants in most countries. Recently, a new variant of CJD has been
linked to the epidemic of bovine spongiform encephalopathy. Therefore, vigilance
concerning the disease's incidence has been increased. We conducted a
comprehensive, nation-wide and retrospective study. In 79 Belgian autopsies, we
found the characteristic triad of spongiosis, neuronal loss and reactive gliosis.
The occipital cortex was most affected, while the cerebellum was mostly spared.
Immunohistochemistry was performed using hydrated autoclave pretreatment and
several monoclonal antibodies directed against the prion protein. We identified
prion-immunoreactive patterns and locations reflecting the important
heterogeneity, independently of the antibody that was used. Granular prion
immunoreactivity was observed in astrocytes. We studied the regional intensity of
the prion immunostaining and determined that the frontal cortex with 95% positive
immunoreactivity was best suited for a biopsy. We studied the disease duration in
sporadic CJD patients who showed neuropathological lesions of other
neurodegenerative disorders (such as Alzheimer's disease). The study shapes the
framework in which a prospective neuropathological registry will be able to
function.
PMID- 10787032
TI - alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological
staging and comparison with ubiquitin immunostaining.
AB - alpha-Synuclein is a presynaptic protein recently identified as a specific
component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to
assess the morphology and distribution of alpha-synuclein immunoreactivity in
cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin
immunostaining. We examined substantia nigra, paralimbic regions (entorhinal
cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and
occipital association cortices) with double alpha-synuclein and ubiquitin
immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha
Synuclein immunostaining was more specific than ubiquitin immunostaining in that
it differentiated LB from globose tangles. It was also slightly more sensitive,
staining 4-5% more intracytoplasmic structures, especially diffuse alpha
synuclein deposits that were ubiquitin negative. In addition to LB, alpha
synuclein staining showed filiform and globose neurites in the substantia nigra,
CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha
synuclein staining was seen in substantia nigra: from diffuse "cloud-like"
inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin
staining to classic LB. We hypothesize that these represent different stages in
LB formation.
PMID- 10787034
TI - Degeneration of the cerebellar dentate nucleus in corticobasal degeneration:
neuropathological and morphometric investigations.
AB - To resolve the controversy regarding the involvement of the dentate nucleus in
corticobasal degeneration (CBD), an entire profile of the dentate nucleus was
exposed in a sagittal plane and divided into four fields, and the number of
neurons in each filed was counted separately using a computer-assisted analyzer
in five cases of CBD and compared to those from seven age-matched controls. The
size of the nucleus and the number of neurons were significantly reduced in all
five cases of CBD. The neuronal loss had a definite regional predilection, more
severe in the caudolateral neodentatum than in the rostromedial palaeodentatum,
and was accompanied by grumose degeneration and astrogliosis which paralleled the
severity of the neuronal loss. Thus, the dentate nucleus appears to be a cardinal
target in CBD.
PMID- 10787035
TI - Severe hypoplasia of medullary arcuate nucleus: quantitative analysis in sudden
infant death syndrome.
AB - The human arcuate nucleus (ARCn) is postulated to be homologous to ventral
medullary cells involved in chemoreception, and respiratory and blood pressure
responses. Abnormalities in central respiratory control may result from
dysfunction of this anatomic ventral area. We evaluated the changes of the
neuronal population of the medullary ARCn in infants victims of the sudden infant
death syndrome (SIDS). In this study we tested the hypothesis that anatomical
deficiency of the ARCn is associated with SIDS. The volume and neuronal density
of the ARCn were morphometrically quantified with an image analyzer in 36 cases
of SIDS and 12 age-matched controls. We found a marked hypoplasia in the SIDS
ARCn compared to controls and, particularly, in 11 SIDS cases (30%) in which the
ARCn exhibited a severe hypoplasia, being almost totally absent. Three
dimensional reconstructions and morphometric measurements of ARCn confirmed this
marked hypoplasia in all the serial sections examined (P = 0.0001) and the
reduced neuronal density (P = 0.0025) in relation to control cases. In conclusion
these abnormalities observed in the ARCn are consistent with the idea that ARCn
dysfunction plays an important role among the causative factors of sudden infant
death. The hypoplasia of the ARCn represents the most frequent congenital
abnormality in our experience, and can be a plausible morphological substrate for
a subset of SIDS.
PMID- 10787036
TI - Neuronal damage of the substantia nigra in HIV-1 infected brains.
AB - Extrapyramidal motor disorders are frequently noted in HIV-1-infected patients.
In the present study, the substantia nigra was analyzed morphometrically to
detect neuronal changes which might contribute to the pathogenetic mechanisms
causing extrapyramidal motor dysfunction in HIV-1-infected patients. The
numerical density and the size of pigmented, non-pigmented small, and non
pigmented large neurons in four nuclei of the substantia nigra pars compacta
(antero-medial, antero-intermediolateral, postero-lateral, and postero-medial
nuclei) in HIV-1-infected patients and in age-matched normal controls were
determined. In HIV-1-infected brains, the numerical density of total neurons
(i.e., pigmented and non-pigmented) as well as of pigmented neurons was
significantly decreased, whereas that of non-pigmented neurons was not
significantly changed in all investigated nuclei of the substantia nigra as
compared to normal controls. A specific pattern of increase and decrease of
nonpigmented large and non-pigmented small neurons was observed. The size of
total neurons (pigmented and nonpigmented neurons) and of pigmented neurons was
significantly reduced in all investigated nuclei of HIV-1-infected brains. The
results suggest that neuronal degeneration in the substantia nigra commonly
occurs and may be related to extrapyramidal symptoms in HIV-1-infected patients.
PMID- 10787037
TI - Blood-brain barrier permeability in the periventricular areas of the normal mouse
brain.
AB - The main objective of this study was to assess the blood-brain barrier (BBB)
permeability in periventricular areas of the normal mouse brain to test the
hypothesis that the fragility of the BBB in periventricular areas may play a role
in periventricular white matter lesions. Vascular permeability to intravenously
injected horseradish peroxidase (HRP) was examined in the periventricular areas
of adult mouse brain using light and electron microscopy. Staining for HRP
appeared in the periventricular area adjacent to medial side of the lateral
ventricle as well as in BBB-free areas, in the lateral septal nucleus, in the
medial portion of the hippocampus and in the dorsal portion of the thalamus. In
addition, the staining for HRP appeared in ependymal cell layer located near the
choroid plexus and was found early after HRP injection in the wall of some
vessels located at medial side of the optic tract. Ultrastructural examination of
the vessel wall revealed that staining for HRP in the perfusion-fixed mice after
circulation of the tracer for 5 min appeared in the perivascular space, in the
basal lamina, in several vesicular profiles of the endothelial cell cytoplasm
including abluminal pits, in vesicular profiles of perivascular cells and in the
adjacent extracellular space. In the mice perfusion-fixed after HRP circulation
for 90 min, staining for HRP in the vessels at medial side of the optic tract
appeared in the cytoplasm of the perivascular cells, in vesicular structures of
the endothelial cell cytoplasm such as plasmalemmal vesicles, endosomes and
multivesicular bodies and occasionally in the vascular basal lamina. No clear
staining reaction for HRP was found in the periventricular areas adjacent to
lateral side of the lateral ventricles. These findings indicate that the BBB in
the periventricular area adjacent to medial side of the lateral ventricle near
the root of the choroid plexus is not so tight as it is in the cortex or in the
lateral periventricular areas, and suggest that the perivascular cells play a
scavenger role in the periventricular area as a component of the BBB. In
addition, they indicate that blood-borne macromolecules can also invade the areas
adjacent to the ventricles such as the lateral septal nucleus, the medial portion
of the hippocampus and the dorsal portion of the thalamus.
PMID- 10787038
TI - Expression of the alpha and beta subunits of Ca2+/calmodulin kinase II in the
cerebellum of jaundiced Gunn rats during development: a quantitative light
microscopic analysis.
AB - The homozygous (jj) jaundiced Gunn rat model for hyperbilirubinemia displays
pronounced cerebellar hypoplasia. To examine the cellular mechanisms involved in
bilirubin toxicity, this study focused on the effect of hyperbilirubinemia on
calcium/calmodulin-dependent kinase II (CaM kinase II). CaM kinase II is a
neuronally enriched enzyme which performs several important functions.
Immunohistochemical analysis of alternating serial sections were performed using
monoclonal antibodies for the alpha and beta subunits of CaM kinase II.
Measurements were made of the total numbers of stained cells in each of the deep
cerebellar nuclei and of Purkinje and granule cell densities in cerebellar
lobules II, VI, and IX. The beta subunit was present in Purkinje cells and deep
cerebellar nuclei of both groups at all ages, but only granule cells which had
migrated through the Purkinje cell layer showed staining for beta subunit;
external granule cells were completely negative. Many Purkinje cells had
degenerated in the older animals, and the percent of granule cells stained for
beta subunit was significantly reduced. The alpha subunit was found exclusively
in Purkinje cells, although its appearance was delayed in the jaundiced animals.
Sulfadimethoxine was administered to some jj rats 24 h or 15 days prior to
sacrifice to increase brain bilirubin concentration. Results showed that
bilirubin exposure modulated both alpha and beta CaM kinase II subunit expression
in selective neuronal populations, but sulfadimethoxine had no acute effect on
enzyme immunoreactivity. Thus, developmental expression of the alpha and beta
subunits of CaM kinase II was affected by chronic bilirubin exposure during early
postnatal development of jaundiced Gunn rats.
PMID- 10787039
TI - Neuronal nuclear DNA fragmentation in the aged canine brain: apoptosis or nuclear
DNA fragility?
AB - Neuronal DNA fragmentation, as revealed with the method of in situ end-labeling
of nuclear DNA fragmentation (TUNEL), has been reported in both the canine and
human brains in normal ageing, and in some human age-related neurodegenerative
diseases. These results have suggested that apoptosis plays an important role in
age-related neuronal loss. It is not clear, however, whether the TUNEL method is
highly specific for apoptosis, as DNA fragmentation also occurs in the late
stages o necrosis. In this study we have examined 27 dogs aged from 8 to 18
years, to investigate the occurrence of nuclear DNA fragmentation. An autolysis
index based on current histological criteria was assigned to each animal to
evaluate the effects of autolysis on nuclear DNA integrity. Our results have
shown that neuronal nuclear DNA fragmentation is frequent in aged dogs, although
it is not accompanied by apoptotic morphology. Yet, a positive relation between
TUNEL labelling and the degree of tissue autolysis was observed. In contrast, no
TUNEL labelling was detected in young control dogs despite autolysis indices
being similar to those in aged dogs. Taken together, these results suggest that
neuronal nuclear DNA fragmentation is an age-related phenomenon, not due to
apoptosis, whenever other factors render neuronal DNA more susceptible to
autolytic fragmentation. We confirm the effect of autolysis in a subpopulation of
neurons in the aged canine brain, inducing nuclear DNA fragmentation.
PMID- 10787040
TI - Age-related plaque morphology and C-terminal heterogeneity of amyloid beta in
Dutch-type hereditary cerebral hemorrhage with amyloidosis.
AB - The evolvement of amyloid beta (Abeta) deposition in the frontal cerebral cortex
of 24 patients of increasing age with Dutch-type hereditary cerebral hemorrhage
with amyloidosis (HCHWA-D) was studied using end-specific monoclonal antibodies
to Abetax-42 (Abeta42) or Abetax-40 (Abeta40) and markers for degenerating
neurites. Abeta42 immunostaining revealed parenchymal Abeta deposits with a
heterogeneous morphology and distribution, i.e., clouds, fine/dense diffuse,
coarse, and homogeneous plaques. Clouds and diffuse plaques were associated with
glial Abeta granules. Abeta40 labeling was absent in clouds/fine diffuse plaques,
inconsistent and variably intense in dense diffuse/coarse plaques and consistent
in homogeneous plaques. In a subset of Abeta40-positive plaques, degenerating
neurites--without tauopathy--and/or amyloid cores were observed. Electron
microscopy revealed no apparent amyloid fibrils in fine diffuse plaques, small
bundles of fibrils in dense diffuse/homogeneous plaques, and amyloid masses in
coarse plaques. The parenchymal Abeta pathology was age-related: the ratio of
fine to dense diffuse plaques decreased with age, clouds were limited to younger
patients; coarse plaques to the oldest old. Homogeneous/cored plaques were
present most consistently in older patients. Plaque density did not increase with
age. Vascular Abeta deposits stained for both Abeta species, but exclusively
Abeta42-positive, presumably recent deposits were also observed. This study
suggests that HCHWA-D is a model of plaque evolution in which clouds leave fine
diffuse plaques, which may become dense diffuse and ultimately coarse or
homogeneous plaques.
PMID- 10787041
TI - Neuroaxonal leukodystrophy associated with congenital cutis laxa: report of an
autopsy case.
AB - A male patient, who was born with congenital cutis laxa characterized by
cutaneous laxity due to the degeneration of elastic fibers, presented with an
arrest of mental and motor development at the age of 3 years. The progressive
decline of the psychomotor abilities led to the patient's death at the age of 4
years and 9 months. An autopsy revealed extensive white matter degeneration,
characterized by the formation of numerous neuroaxonal spheroids and a diffuse
loss of axons and myelin sheaths. The centrum semiovale and the cerebellar white
matter were the most severely affected. The ultrastructure of the spheroids was
consistent with a dystrophic type of axonal swelling. Neurons of the cerebral
cortex, cerebellar cortex, and some brain stem nuclei were lost in moderate to
severe degrees, and there were relatively few neuroaxonal spheroids in the gray
matter. The pallidum and substantia nigra were well preserved. Neuroaxonal
leukodystrophy, in which the spheroid formation predominantly affects the white
matter, is the rarest variant of primary neuroaxonal dystrophies, and there are
very few reports of autopsied cases. Among the reported cases, two Japanese
siblings had congenital skin lesions similar to those of our case. The unique
association of neuroaxonal leukodystrophy and congenital cutis laxa may form a
distinct variant in this disease category.
PMID- 10787042
TI - A case of Miller-Dieker syndrome in a family with neurofibromatosis type I.
AB - The Miller-Dieker syndrome (type I lissencephaly) is a neuronal migration
disorder which is associated with microdeletions in the short arm of chromosome
17. Neurofibromatosis type I (NF1) is an autosomal dominant condition associated
with mutations in the long arm of chromosome 17, and characterised by
neurofibromas, cafe-au-lait spots and axillary freckling. The neonatal period for
a female infant born at 39 weeks gestation by emergency Caesarean section was
complicated by frequent epileptic seizures as well as hypotonia. A computed
tomography scan revealed evidence of lissencephaly, and chromosomal analysis
showed a microdeletion on the short arm of chromosome 17 (17p13.3), confirming
the diagnosis as Miller-Dieker syndrome. The child died at the age of 4 years and
examination of the brain confirmed lissencephaly with a thickened cortex,
deficient white matter, and grey matter heteropias. The mother had cafe-au-lait
spots, and axillary freckling. In addition, the mother's and maternal
grandmother's genetic analysis showed identical mutations in the
neurofibromatosis I gene on the long arm of chromosome 17, confirming the
diagnosis of NF1. The child did not possess the mutation. This case illustrates a
rare neuronal migration disorder appearing in a child from a family with a
history of NF1.
PMID- 10787043
TI - Pathology of Madras type of motor neuron disease (MMND)--a histological and
immunohistochemical study.
AB - A neuropathological report of Madras type of motor neuron disease (MMND) is
presented and the differences from other forms of MND are discussed. An 18-year
old girl presented with nerve deafness and slowly progressive bulbo-spinal
muscular atrophy, characteristic of MMND. Post-mortem examination of the spinal
cord showed a severe loss of anterior horn cells, prominent dilatation of
vessels, diffuse, but sparse sprinkling of microglial cells and lymphocytes, and
demyelination and sclerosis of the ventrolateral columns. Neuronal depletion and
marked gliosis was noted in the cochlear nucleus on both sides, while other
bulbar motor nuclei were also involved. The cochlear nerve showed demyelination
and axonal loss. Trigeminal and vestibular ganglia revealed features of
ganglionitis. The possibility of an inflammatory aetiology for MMND needs to be
considered.
PMID- 10787045
TI - Microinjection of heme oxygenase genes rescues phytochrome-chromophore-deficient
mutants of the moss Ceratodon purpureus.
AB - In protonemal tip cells of the moss Ceratodon purpureus (Hedw.) Brid.,
phototropism and chlorophyll accumulation are regulated by the photoreceptor
phytochrome. The mutant ptr116 lacks both responses as a result of a defect in
the biosynthesis of phytochromobilin, the chromophore of phytochrome, at the
point of biliverdin formation. The rescue of the phototropic response and of
chlorophyll synthesis were tested by injecting different substances into tip
cells of ptr116. Microinjection was first optimised with the use of fluorescent
dyes and an expression plasmid containing a green fluorescent protein (GFP) gene.
Injected phycocyanobilin, which substitutes for phytochromobilin, rescued both
the phototropic response and light-induced chlorophyll accumulation in ptr116.
The same results were obtained when expression plasmids with heme oxygenase genes
of rat (HO-1) and Arabidopsis thaliana (L.) Heynh. (HY1) were injected. Heme
oxygenase catalyses the conversion of heme into biliverdin. Whereas HY1 has a
plastid target sequence and is presumably transferred to plastids, HO-1 is
proposed to be cytosolic. The data show that ptr116 lacks heme oxygenase enzyme
activity and indicate that heme oxygenases of various origin are active in
Ceratodon bilin synthesis. In addition, it can be inferred from the data that the
intracellular localisation of the expressed heme oxygenase is not important since
the plastid enzyme can be replaced by a cytosolic one.
PMID- 10787044
TI - Developmentally regulated expression of two MADS-box genes, MdMADS3 and MdMADS4,
in the morphogenesis of flower buds and fruits in apple.
AB - Two MADS-box genes, MdMADS3 and MdMADS4, were isolated from the apple (Malus x
domestica Borkh.) cultivar Fuji, and their spatial and temporal expression
patterns were studied during morphological differentiation of the flower buds and
the fruits. Both MdMADS3 and MdMADS4 showed high sequence similarities to FBP2
from petunia, TM5 from tomato, and AGL2, AGL4 from Arabidopsis. Although MdMADS3
was expressed in the inner three whorls of the floral primordium, its expression
was hardly detectable in developing fruit. The second gene, MdMADS4, was
ubiquitously expressed in the inflorescence meristem, floral meristem, all four
floral organs, and fruit. Moreover, MdMADS4 expression was high in the vascular
bundles assigned to the floral tube and the carpellary vascular bundles in fruit
at early developmental stages. The MdMADS4 transcript also accumulated in embryos
of the developing seeds. These results suggest that MdMADS3 and MdMADS4 are
involved in different functions, and that MdMADS4 may function in the important
events controlling flower and fruit development.
PMID- 10787046
TI - Heteroblasty in Arabidopsis thaliana (L.) Heynh.
AB - Heteroblasty in Arabidopsis thaliana was analyzed in a variety of plants with
mutations in leaf morphology using a tissue-specific beta-glucuronidase gene
marker. Some mutants exhibited their mutant phenotypes specifically in foliage
leaves. The phenotypes associated with the foliage-leaf-specific mutations were
also found to be induced ectopically in cotyledons in the presence of the lec1
mutation. Moreover, the features of an emfl lec1 double mutant showed that
cotyledons can be partially converted into carpelloids. When heteroblastic traits
were examined in foliage leaves in the presence of certain mutations or natural
deviations by histochemical analysis of the expression of the tissue-specific
marker gene, it was found that ectopic expression of the developmental program
for the first foliage leaves in lec1 cotyledons seemed to affect the
heteroblastic features of the first set of foliage leaves, while foliage leaves
beyond the third position appeared normal. Similarly, in wild-type plants,
discrepancies in heteroblastic features, relative to standard features, of
foliage leaves at early positions seemed to be eliminated in foliage leaves at
later positions. These results suggest that heteroblasty in foliage leaves might
be affected in part by the heteroblastic stage of the preceding foliage leaves
but is finally controlled autonomously at each leaf position.
PMID- 10787047
TI - The Lupinus albus class-III chitinase gene, IF3, is constitutively expressed in
vegetative organs and developing seeds.
AB - A cDNA fragment encoding a Lupinus albus. L. class-III chitinase, IF3, was
isolated, using a cDNA probe from Cucumis sativus L., by in-situ plaque
hybridization from a cDNA library constructed in the Uni-ZAP XR vector, with
mRNAs isolated from mature lupin leaves. The cDNA had a coding sequence of 293
amino acids including a 27-residue N-terminal signal peptide. A class-III
chitinase gene was detected by Southern analysis in the L. albus genome. Western
blotting experiments showed that the IF3 protein was constitutively present
during seed development and in all the studied vegetative lupin organs (i.e.,
roots, hypocotyls and leaves) at two growth stages (7- and 20-d-old plants).
Accumulation of both the IF3 mRNA and IF3 protein was triggered by salicylic acid
treatment as well as by abiotic (UV-C light and wounding) and biotic stress
conditions (Colletotrichum gloeosporioides infection). In necrotic leaves, IF3
chitinase mRNA was present at a higher level than that of another mRNA encoding a
pathogenesis-related (PR) protein from L. albus (a PR-10) and that of the rRNAs.
We suggest that one role of the IF3 chitinase could be in the defense of the
plant against fungal infection, though our results do not exclude other functions
for this protein.
PMID- 10787048
TI - The Golgi apparatus of the scaly green flagellate Scherffelia dubia: uncoupling
of glycoprotein and polysaccharide synthesis during flagellar regeneration.
AB - The flagella of the green alga Scherffelia dubia are covered by scales which
consist of acidic polysaccharides and glycoproteins. Experimental deflagellation
results in the regeneration of flagella complete with scales. During flagellar
regeneration, scales are newly synthesized in the Golgi apparatus, exocytosed and
deposited on the growing flagella. Flagellar regeneration is dependent upon
protein synthesis and N-glycosylation, as it is blocked by cycloheximide and
partially inhibited by tunicamycin. Metabolic labeling with
[35S]methionine/cysteine demonstrated that scale-associated proteins were not
newly synthesized during flagellar regeneration, suggesting that the proteins
deposited on regenerating flagella were drawn from a pool. Quantitative
immunoelectron microscopy using a monospecific antibody directed against a scale
associated protein of 126 kDa (SAP126) revealed that the pool of SAP126 was
primarily located at the plasma membrane, with minor labeling of the scale
reticulum and trans-Golgi cisternae, both before deflagellation and during
flagellar regeneration. Since SAP126 was sequestered during flagellar
regeneration into secretory vesicles together with newly synthesized scales, it
is concluded that the persistent presence of SAP126 in the trans-Golgi cisternae
during scale biogenesis requires retrograde transport of the protein from the
plasma membrane to the Golgi apparatus.
PMID- 10787049
TI - Leucine aminopeptidases: the ubiquity of LAP-N and the specificity of LAP-A.
AB - The wound-induced leucine aminopeptidase (EC 3.4.11.1) genes, LapA1 and LapA2,
from tomato (Lycopersicon esculentum Mill.) were isolated and characterized. The
genes were organized in a tandem array with approximately 6 kb separating their
coding regions. Quantitation of LapA mRNA levels in conjunction with nuclear run
on experiments indicated that LapA genes were primarily under transcriptional
control after wounding and infection with Pseudomonas syringae pv. tomato. In
contrast, actin genes were down-regulated after pathogen infection. The sequences
of the LapA1 and LapA2 5'-flanking regions were determined and several potential
regulatory motifs were identified. Ribonuclease protection studies revealed that
LapA1 and LapA2 had short 18-bp 5'-untranslated regions (UTR), both genes were
expressed after wounding, and LapA1 mRNAs were 3.3-fold more abundant than LapA2
transcripts. While the region surrounding LapA1 was conserved, the 3'-UTRs and 3'
flanking regions of LapA2 had diverged in two inbred tomato lines. The
accumulation of LapA mRNAs and of LAP-A (acidic pI), LAP-N (neutral pI) and LAP
related proteins were examined in two monocot and five dicot species. The LAP-N
and 66- and 77-kDa LAP-related proteins were detected in healthy and wounded
leaves of all plants examined. The LAP-A proteins were only detected in
nightshade and their accumulation was distinct from that observed in tomato.
PMID- 10787050
TI - A barley gene (rsh1) encoding a ribonuclease S-like homologue specifically
expressed in young light-grown leaves.
AB - A group of frequent cDNA clones from a young-leaf cDNA library was found to code
for a homologue of S-ribonucleases (S-RNases) involved in gametophytic
incompatibility and the so-called S-like RNases active in flowers and in
vegetative tissues. The derived amino acid sequence starts with a signal peptide
and has a 27-amino-acid C-terminal extension of unknown function. The barley
(Hordeum vulgare L.) gene, rsh1 (for RNase S-like homologue) corresponding to the
cDNA clones was isolated. The gene has three introns and the position of one
intron corresponds to the site of the single, small intron in the S-RNase genes.
The deduced amino acid sequence of mature RSH1 shares 35% identical and 58%
similar amino acid residues with an S-like RNase from tomato, RNase LE. However,
two active-site histidine residues, conserved between all S and S-like RNases are
replaced by serine residues in RSH1. The new barley RNase S-like homologue is
clearly related to the family of active RNases but is probably not active as an
RNase. Sequences from the same class of presumably inactive RNases have been
recorded in maize, rice and sorghum. The barley gene is exclusively expressed in
young leaf tissue and is substantially induced by light.
PMID- 10787051
TI - Inhibitors of the carrier-mediated influx of auxin in suspension-cultured tobacco
cells.
AB - Active auxin transport in plant cells is catalyzed by two carriers working in
opposite directions at the plasma membrane, the influx and efflux carriers. A
role for the efflux carrier in polar auxin transport (PAT) in plants has been
shown from studies using phytotropins. Phytotropins have been invaluable in
demonstrating that PAT is essential to ensure polarized and coordinated growth
and to provide plants with the capacity to respond to environmental stimuli.
However, the function of the influx carrier at the whole-plant level is unknown.
Our work aims to identify new auxin-transport inhibitors which could be employed
to investigate its function. Thirty-five aryl and aryloxyalkylcarboxylic acids
were assayed for their ability to perturb the accumulation of 2,4
dichlorophenoxyacetic acid (2,4-D) and naphthalene-1-acetic acid (1-NAA) in
suspension-cultured tobacco (Nicotiana tabacum L.) cells. As 2,4-D and 1-NAA are
preferentially transported by the influx and efflux carriers, respectively,
accumulation experiments utilizing synthetic auxins provide independant
information on the activities of both carriers. The majority (60%) of compounds
half-inhibited the carrier-mediated influx of [14C]2,4-D at concentrations of
less than 10 microM. Most failed to interfere with [3H]NAA efflux, at least in
the short term. Even though they increasingly perturbed auxin efflux when given a
prolonged treatment, several compounds were much better at discriminating between
influx and efflux carrier activities than naphthalene-2-acetic acid which is
commonly employed to investigate influx-carrier properties. Structure-activity
relationships and factors influencing ligand specificity with regard to auxin
carriers are discussed.
PMID- 10787052
TI - Wood formation in poplar: identification, characterization, and seasonal
variation of xylem proteins.
AB - Proteins that are preferentially produced in developing xylem may play a
substantial role in xylogenesis. To reveal the identity of these proteins,
comparative two-dimensional polyacrylamide gel electrophoresis was performed on
young differentiating xylem, mature xylem, and bark of poplar (Populus
trichocarpa Hook. cv. 'Trichobel') harvested at different times of the year. The
most-abundant xylem proteins were identified by microsequence analysis. For 17 of
these proteins a putative function could be assigned based on similarity with
previously characterized proteins, and for 15 out of these corresponding
expressed sequence tags (ESTs) were found in the poplar EST database. The
identified xylem-preferential proteins, defined by comparing the protein patterns
from xylem and bark, were all involved in the phenylpropanoid pathway: two
caffeoyl-coenzyme A O-methyltransferases (CCoAOMT), one phenylcoumaran benzylic
ether reductase (PCBER), one bispecific caffeic acid/5-hydroxyferulic acid O
methyltransferase (COMT), five S-adenosyl-L-methionine synthetases, and one
homologue of glycine hydroxymethyltransferase (GHMT). Remarkably, the biological
function of the two most-abundant xylem-preferential proteins (PCBER and a GHMT
homologue) remains unclear. In addition, several housekeeping enzymes were
identified: two enolases, two glutamine synthetases, one 70-kDa heat-shock
cognate, one calreticulin, and one alpha-tubulin. In comparison to the xylem
preferential proteins, the housekeeping proteins were expressed at significant
levels in the bark as well. Also, several additional protein spots were detected
for CCoAOMT, PCBER, and COMT by immunoblot. Our data show that for the study of
xylogenesis, two-dimensional protein gel comparisons combined with systematic
protein sequencing may yield information complementary to that from EST
sequencing strategies.
PMID- 10787053
TI - Salicylic acid-independent induction of pathogenesis-related gene expression by
fusicoccin.
AB - Treatment of tomato plants (Lycopersicon esculentum Mill.) with fusicoccin (FC),
an activator of the plasma-membrane H+-ATPase which maintains an electrochemical
gradient across the plasma membrane, resulted in a dose-dependent accumulation of
transcripts for intra- and extracellular pathogenesis-related (PR) proteins. The
accumulation of PR protein transcripts was paralleled by an increase in leaf
salicylic acid (SA) content. Transcripts of PR proteins and SA started to
accumulate 3 h after FC treatment. 2-Aminoindan-2-phosphonic acid, an inhibitor
of SA synthesis, was used to assess the role of SA in FC-mediated induction of PR
gene expression. 2-Aminoindan-2-phosphonic acid was found to suppress the
accumulation of SA but not the induction of PR gene expression in response to FC
treatment. Furthermore, in transgenic tobacco plants overexpressing a bacterial
salicylate hydroxylase gene (nahG-tobacco), PR transcripts accumulated after FC
treatment to levels similar to those observed in control tobacco plants. The data
indicate a role for the proton gradient across the plasma membrane in the SA
independent induction of PR gene expression.
PMID- 10787054
TI - Gravity-directed calcium current in germinating spores of Ceratopteris richardii.
AB - Gravity directs the early polar development in single cells of Ceratopteris
richardii Brogn. It acts over a limited period of time during which it
irreversibly determines the axis of the spore cell's development. A self
referencing calcium selective electrode was utilized to record the net movement
of calcium across the cell membrane at different positions around the periphery
of the spore during the period in which gravity orients the polarity of the
spore. A movement of calcium into the cell along the bottom and out of the cell
along the top was detected. This movement was specific, polarized, and strongest
in a direction that opposed the vector of gravity. Treatment with nifedipine, a
calcium-channel blocker, diminished the calcium current and caused the cell to
lose its responsiveness to the orienting influence of gravity. Results shown
suggest that calcium plays a crucial role in the ability of a single cell to
respond to gravity and in the subsequent establishment of its polarity.
PMID- 10787055
TI - Species variation in the intracellular localization of pyruvate, Pi dikinase in
leaves of crassulacean-acid-metabolism plants: an immunogold electron-microscope
study.
AB - In malic enzyme-dependent crassulacean-acid-metabolism (ME-CAM) plants, malic
acid is decarboxylated by NADP-ME and NAD-ME and generates pyruvate with CO2.
Pyruvate is phosphorylated to phosphoenolpyruvate by pyruvate, Pi dikinase (PPDK)
and is then conserved in gluconeogenesis. Although PPDK was considered to be
located in chloroplasts (e.g., Mesembryanthemum crystallinum), it has recently
been found to accumulate in both the chloroplasts and the cytosol in two
Kalanchoe species. In this study, the intracellular localization of PPDK was
investigated in 22 ME-CAM species in 13 genera of 5 families by immunogold
labeling and electron microscopy. This revealed that the pattern of intracellular
localization of PPDK varies among the ME-CAM plants and is divided into three
types: Chlt, in which PPDK accumulates only in the chloroplasts; Cyt-Chlt, in
which PPDK accumulates in both chloroplasts and cytosol; and Cyt, in which PPDK
accumulates predominantly in the cytosol. Members of a particular genus tend to
have a common PPDK-localization type. In the Cactaceae, all species from seven
genera were classified as Cyt. The photosynthetic tissues of all ME-CAM species,
including the Cyt type, had substantial PPDK activity, suggesting that PPDK in
the cytosol is active and probably plays a functional role. In the Chlt species,
NADP-ME activity was relatively greater than NAD-ME activity. In the Cyt-Chlt and
Cyt species, however, either the activity of NAD-ME was higher than that of NADP
ME or they were approximately the same. The species variation in the
intracellular localization of PPDK is discussed in relation to CAM function and
to molecular and phylogenetic aspects.
PMID- 10787056
TI - In vitro biosynthesis of 1,4-beta-galactan attached to rhamnogalacturonan I.
AB - The biosynthesis of galactan was investigated using microsomal membranes isolated
from suspension-cultured cells of potato (Solanum tuberosum L. var. AZY).
Incubation of the microsomal membranes in the presence of UDP-[14C]galactose
resulted in a radioactive product insoluble in 70% methanol. The product released
only [14C]galactose upon acid hydrolysis. Treatment of the product with
Aspergillus niger endo-1,4-beta-galactanase released 65-70% of the radioactivity
to a 70%-methanol-soluble fraction. To a minor extent, [14C]galactose was also
incorporated into proteins, however these galactoproteins were not a substrate
for Aspergillus niger endo-1,4-beta-galactanase. Thus, the majority of the 14C
labelled product was 1,4-beta-galactan. Compounds released by the endo-1,4-beta
galactanase treatment were mainly [14C]galactose and [14C]galactobiose,
indicating that the synthesized 1,4-beta-galactan was longer than a trimer. In
vitro synthesis of 1,4-beta-galactan was most active with 6-d-old cells, which
are in the middle of the linear growth phase. The optimal synthesis occurred at
pH 6.0 in the presence of 7.5 mM Mn2+. Aspergillus aculeatus rhamnogalacturonase
A digested at least 50% of the labelled product to smaller fragments of approx.
14 kDa, suggesting that the synthesized [14C]galactan was attached to the
endogenous rhamnogalacturonan I. When rhamnogalacturonase A digests of the
labelled product were subsequently treated with endo-1,4-beta-galactanase,
radioactivity was not only found as [14C]galactose or [14C]galactobiose but also
as larger fragments. The larger fragments were likely the [14C]galactose or
[14C]galactobiose still attached to the rhamnogalacturonan backbone since
treatment with beta-galactosidase together with endo-1,4-beta-galactanase
digested all radioactivity to the fraction eluting as [14C]galactose. The data
indicate that the majority of the [14C]galactan was attached directly to the
rhamnose residues in rhamnogalacturonan I. Thus, isolated microsomal membranes
contain enzyme activities to both initiate and elongate 1,4-beta-galactan
sidechains in the endogenous pectic rhamnogalacturonan I.
PMID- 10787057
TI - Localization of pectins in the pollen tube wall of Ornithogalum virens L. Does
the pattern of pectin distribution depend on the growth rate of the pollen tube?
AB - Monoclonal antibodies that recognize pectins were used for the localization of
esterified (JIM7) and acidic, unesterified (JIM5) forms of pectin in pollen tube
walls of Ornithogalum virens L. (x = n = 3). The results indicated that the
distribution of the two forms of pectin in the pollen tube wall depended on the
medium (liquid or solid) used for pollen germination. In pollen tubes grown in
the liquid medium, the localization of JIM7 was limited to the very tip of the
pollen tube, whereas the localization of JIM5 indicated a uniform distribution of
unesterified pectins in the very tip of the tube and along the subapical parts of
the tube wall. In tubes germinated on the medium stabilized with agar (1-2%) the
localization of JIM7 and JIM5 indicated the presence of both forms of pectin in
the tube tip and along the whole length of the pollen tube wall in a ring-like
pattern. Thus, the localization of esterified pectins in the sub-apical part of
the pollen tube wall, below the apex of the tube, is described for the first
time. Measurements of the growth rates of pollen tubes growing on the two types
of medium indicated that oscillations in tube growth rate occur but these do not
coincide with the pattern of pectin distribution in the tube wall. Our results
complement the previous data obtained for the localization of JIM5 and JIM7 in
pollen tube walls of other plant species. (Y.-Q. Li et al. 1994, Sex Plant Reprod
7: 145-150) and provide new insight into an understanding of the construction of
the pollen tube wall and the physiology of pollen grain germination.
PMID- 10787058
TI - Hormonal regulation of fruitlet abscission induced by carbohydrate shortage in
citrus.
AB - The hormonal signals controlling fruitlet abscission induced by sugar shortage in
citrus were identified in Satsuma mandarin, Citrus unshiu (Mak.) Marc, cv.
Clausellina and cv. Okitsu. Sugar supply, hormonal responses and fruitlet
abscission were manipulated through full, partial or selective leaf removals at
anthesis and thereafter. In developing fruitlets, defoliations reduced soluble
sugars (up to 98%), but did not induce nitrogen and water deficiencies.
Defoliation-induced abscission was preceded by rises (up to 20-fold) in the
levels of abscisic acid (ABA) and 1-aminocyclopropane-1-carboxylic acid (ACC) in
fruitlets. Applications to defoliated plants showed that ABA increased ACC levels
(2-fold) and accelerated fruitlet abscission, whereas norflurazon and 2
aminoethoxyvinyl glycine reduced ACC (up to 65%) and fruitlet abscission (up to
40%). Only the full defoliation treatment reduced endogenous gibberellin A1 (4
fold), whereas exogenous gibberellins had no effect on abscission. The data
indicate that fruitlet abscission induced by carbon shortage in citrus is
regulated by ABA and ACC originating in the fruits, while gibberellins are
apparently implicated in the maintenance of growth. In this system, ABA may act
as a sensor of the intensity of the nutrient shortage that modulates the levels
of ACC and ethylene, the activator of abscission. This proposal identifies ABA
and ACC as components of the self-regulatory mechanism that adjusts fruit load to
carbon supply, and offers a physiological basis for the photoassimilate
competition-induced abscission occurring under natural conditions.
PMID- 10787059
TI - Expression pattern of (+)-delta-cadinene synthase genes and biosynthesis of
sesquiterpene aldehydes in plants of Gossypium arboreum L.
AB - The cotton (+)-delta-cadinene synthase, a sesquiterpene cyclase, is encoded by a
complex gene family which, based on homology, can be divided into two
subfamilies: cad1-A and cad1-C. Southern blots revealed several members of the
cad1-C subfamily, and a single member of the cad1-A subfamily, in the diploid
Gossypium arboreum genome. One of the cad1-C genes, cad1-C3, was isolated from
this species. According to reverse transcriptase-polymerase chain reaction,
transcripts of both cad1-C and cad1-A genes appeared in roots from the second day
post germination and in 1-d-old cotyledons, whereas the transcription levels were
too low to be detected in the hypocotyls. Initially, sesquiterpene cyclase
activities were found to be high in the seedlings, then dropped in aerial organs
but increased in roots during development. Sesquiterpene aldehyde contents
followed the same pattern. In fully developed plants, the transcripts of cad1-C
were detected in stems, leaves and pericarps, as well as in the sepals and petals
3 d before anthesis, but not at the day of anthesis. In contrast, cad1-A
transcripts were not detected in any of these aerial organs. The sesquiterpene
aldehyde contents increased in petals but decreased in sepals after anthesis.
Treatment of G. arboreum stems with a Verticillium dahliae elicitor-preparation
activated cad1-A transcription, but a significant level of cad1-C transcripts was
detected both before and after elicitation. In G. hirsutum cv. GL-5, a glandless
cultivar, the cad1-C gene was activated by the same fungal elicitor, followed by
the synthesis of the sesquiterpene cyclase, and accumulation of sesquiterpene
aldehydes. The cad1 gene expression during development and in response to
elicitation, as well as the spatial and temporal pattern of sesquiterpene
biosynthesis, constitute a chemical defense machinery in cotton plants.
PMID- 10787060
TI - Arginine degradation by arginase in mitochondria of soybean seedling cotyledons.
AB - Arginase (EC 3.5.3.1) localization was studied in soybean (Glycine max L.)
seedling cotyledons. Subcellular fractionation in a discontinuous Percoll
gradient showed that arginase was localized in the mitochondrion. Arginine (Arg)
uptake by mitochondria was demonstrated by co-sedimentation of [3H]Arg-derived
label and the mitochondrial marker enzyme cytochrome c oxidase. Arginine uptake
was complete in about 10 min. Since detergent but not NaCl released most label,
we conclude that Arg was taken up and not bound to the organellar surface.
Arginine transport was not saturable, at least up to 20 mM. Basic amino acids
were the best inhibitors of Arg uptake. The uncoupler 2,4-dinitrophenol did not
inhibit Arg uptake. At least 30% of L-[guanido-14C]Arg taken up by mitochondria
was degraded by arginase in seedling cotyledons, while little or no degradation
was detected in mitochondria from developing embryos, even though the Arg uptake
level was similar in both mitochondrial preparations. These results are
consistent with our previously reported pattern of arginase expression and urea
accumulation during embryo development and seed germination (A. Goldraij and J.C.
Polacco, 1999, Plant Physiol. 119: 297-303). The lack of Arg degradation allows
developing embryos to conserve Arg, the main N-reserve amino acid utilized by
germinating soybean.
PMID- 10787061
TI - O-Acetylation of plant cell wall polysaccharides: identification and partial
characterization of a rhamnogalacturonan O-acetyl-transferase from potato
suspension-cultured cells.
AB - A microsomal preparation from suspension-cultured potato stem cells (Solanum
tuberosum L. cv. AZY) was incubated with [14C]acetyl-CoA resulting in a
precipitable radiolabeled product. Analysis of the product revealed that it
consisted mostly of acetylated proteins and cell wall polysaccharides, including
xyloglucan, homogalacturonan and rhamnogalacturonan I. Thus, acetyl-CoA is a
donor-substrate for the O-acetylation of wall polysaccharides. A
rhamnogalacturonan acetylesterase was used to develop an assay to measure and
characterize rhamnogalacturonan O-acetyl transferase activity in the microsomal
preparation. Using this assay, it was shown that the transferase activity was
highest during the linear growth phase of the cells, had a pH-optimum at pH 7.0,
a temperature optimum at 30 degrees C, an apparent Km of 35 microM and an
apparent Vmax of 0.9 pkat per mg protein. Further analysis of the radiolabeled
acetylated product revealed that it had a molecular mass > 500 kDa.
PMID- 10787062
TI - Role of extensin peroxidase in tomato (Lycopersicon esculentum Mill.) seedling
growth.
AB - It is proposed that inhibition of extensin peroxidase activity leads to a less
rigid cell wall and thus promotes cell expansion and plant growth. A low
molecular-weight inhibitor derived from the cell walls of suspension-cultured
tomato cells was found to completely inhibit extensin peroxidase-mediated
extensin cross-linking in vitro at a concentration of 260 microg/ml. The
inhibitor had no effect upon guaiacol oxidation catalyzed by extensin peroxidase
or horseradish peroxidase. We have demonstrated that the light-irradiated
inhibition of plant growth may be partially offset by inhibition of endogenous
extensin peroxidase activity. Overall plant growth was enhanced by up to 15% in
the presence of inhibitor relative to control plants. Inhibitor-treated and
illuminated tomato hypocotyls grew up to 15% taller than untreated controls. The
inhibitor had no effect upon etiolated plants over a 15-d period, suggesting that
only low levels of peroxidase-mediated cross-linking can be found in the cell
walls of etiolated plants. SDS-PAGE/Western blots of ionically bound protein from
both etiolated and illuminated hypocotyls identified a doublet at 57/58.5 kDa
which is immunoreactive with antibodies raised to tomato extensin peroxidase.
Levels of the 58.5-kDa protein, determined by SDS-PAGE, were at least threefold
higher in illuminated tomato hypocotyls than in etiolated hypocotyls. Three fold
higher levels of extensin peroxidase, elevated in-vitro extensin cross-linking
activity and 15% higher levels of cross-linked, non-extractable extensin were
observed in illuminated tomato hypocotyls compared with etiolated tomato
hypocotyls. This suggests that white-light inhibition of tomato hypocotyl growth
appears to be mediated, at least partially, by deposition of cell wall extensin,
a process regulated by Mr-58,500 extensin peroxidase. Our results indicate that
the contribution of peroxidase-mediated extensin deposition to plant cell wall
architecture may have an important role in plant growth.
PMID- 10787063
TI - Mutations causing defects in the biosynthesis and response to gibberellins,
abscisic acid and phytochrome B do not inhibit vernalization in Arabidopsis fca
1.
AB - The roles of gibberellins, abscisic acid and phytochrome B in the vernalization
response were investigated by combining mutations causing defects in their
biosynthesis and response with the Arabidopsis thaliana (L.) Heynh. fca-1
mutation. The fca-1 mutation confers a very late-flowering phenotype which can be
reversed to wild-type flowering if the seedlings are vernalized. Vernalization
was unaffected in ga1-3, gai, abi1-1, abi2-1, abi3-1 and phyB-1 backgrounds,
suggesting that gibberellin action mediated via GA1 and GAI, abscisic acid action
mediated through ABI1 and ABI2, and phytochrome B, function independently of
vernalization. However, the mutations did interact with fca-1 to change flowering
time in the absence of vernalization. The abi1 fca-1 and abi2 fca-1 double
mutants flowered earlier than fca-1 implying a role for abscisic acid in floral
repression. Combination of ga1-3 or gai with fca-1 unexpectedly resulted in
opposite interactions, with gai partially suppressing the late flowering of fca
1.
PMID- 10787064
TI - Isolation and characterization of two acyl-CoA-binding proteins from
proembryogenic masses of Digitalis lanata Ehrh.
AB - Two acyl-CoA-binding-protein (ACBP) isoforms were isolated from proembryogenic
masses of Digitalis lanata Ehrh. by column chromatography and preparative HPLC.
The ACBPs had molecular masses of 9926 and 9997 Da, respectively. Partial
sequence data indicated high similarity to each other and to ACBPs of other plant
species such as Ricinus communis, Brassica napus and Arabidopsis thaliana. The
isolated ACBPs bound palmitoyl-CoA with high affinity as determined by
isoelectric-point shift.
PMID- 10787065
TI - Purification and cloning of an arabinogalactan-protein from xylem of loblolly
pine.
AB - An arabinogalactan-protein (AGP) was purified from differentiating xylem of
loblolly pine (Pinus taeda L.) and the N-terminal sequence used to identify a
cDNA clone. The protein, PtaAGP3, was not coded for by any previously identified
AGP-like genes. Moreover, PtaAGP3 was abundantly and preferentially expressed in
differentiating xylem. The encoded protein contains four domains, a signal
peptide, a cleaved hydrophilic region, a region rich in serine, alanine, and
proline/hydroxyproline, and a hydrophobic C-terminus. It is postulated to contain
a GPI (glycosylphosphatidylinositol) anchor site. If the protein is cleaved at
the putative GPI anchor site, as has been observed in other classical AGPs, all
but the Ser-Ala-Pro/Hyp-rich domain may be missing from the mature protein. Xylem
specific AGPs are hypothesized to be involved in xylem development.
PMID- 10787066
TI - Release of endotoxin-binding proteins during major elective surgery: role of
soluble CD14 in phagocytic activation.
AB - Our previous study demonstrated that soluble CD14 (sCD14) modulates the biologic
activity of circulating endotoxin, which appears after surgery. In this study, we
examined the behavior of endotoxin-binding proteins, such as sCD14,
lipopolysaccharide-binding protein (LBP), and bactericidal/permeability
increasing protein (BPI), in patients' plasma after major abdominal surgery and
the phagocytic secretion of sCD14 from peripheral blood mononuclear cells (PBMCs)
throughout the observation period. In a prospective study, 15 patients undergoing
major abdominal surgery (gastrectomy, n = 3; pancreatectomy, n = 10: colectomy, n
= 2) were involved in this study. The endotoxin-binding proteins were
perioperatively (preoperatively; postoperative hour 6; days 1, 2, 3, 4, 5, 7, and
10) measured by an enzyme-linked immunosorbent assay (ELISA). To exclude the
hemodilution effect of samples, each parameter was corrected by dividing the
respective value by the albumin concentration. The phagocytic activity at each
time point was tested as an ex vivo sCD14 secretion from PBMCs in the presence
and absence of exogenously added endotoxin, Escherichia coli 055B5 (1 ng/ml).
Significant endotoxemia (0.35 +/- 0.13 EU/ml; p < 0.05) was observed 6 hours
after the beginning of surgery. The sCD14/albumin value rapidly increased at 6
hours after surgery, peaked on day 1, and sequentially declined, whereas the
BPI/albumin and LBP/albumin ratios increased more gradually and peaked on day 2.
The secretion of sCD14 from 2 x 10(6) PBMCs was significantly enhanced from 6
hours after operation. The increased plasma level of sCD14 may be explained by
the parallel-enhanced sCD14 PBMC production. Activated secretion of these
endotoxin-binding proteins may play a role in regulating the biologic activity of
circulating endotoxin.
PMID- 10787067
TI - Does hyperthermia induce peritoneal damage in continuous hyperthermic peritoneal
perfusion?
AB - To investigate the mechanisms of the peritoneal damage induced by continuous
hyperthermic peritoneal perfusion (CHPP), protein and fluid loss during and after
CHPP and continuous normothermic peritoneal perfusion (CNPP) was studied. Sixteen
patients with advanced gastric cancer underwent peritoneal perfusion therapy with
saline solution containing 150 to 300 mg cisplatin and 30 to 60 mg mitomycin C
for 60 minutes. The temperature in Douglas' pouch was maintained at 42.0 degrees
C in the CHPP group (n = 9) and 37.0 degrees C in the CNPP group (n = 7) during
perfusion. No statistical differences were found in patients' characteristics
between the groups except the maximum temperature in Douglas' pouch during
perfusion (41.6 degrees +/- 0.4 degrees C and 37.6 degrees +/- 0.4 degrees C in
CHPP and CNPP groups, respectively, p < 0.05). The amount of protein lost into
the perfusate was 0.35 +/- 0.22 g/kg body weight in the CHPP group and 0.37 +/-
0.19 g/kg in the CNPP group, showing no significant difference. On the day of
surgery, there was no significant difference in the amount of protein and fluid
lost through the abdominal drains between the CHPP group (27.9 +/- 24.6 mg/kg/hr
and 0.94 +/- 0.63 ml/kg/hr, respectively) and the CNPP group (25.9 +/- 8.6
mg/kg/hr and 1.03 +/- 0.31 ml/kg/hr, respectively). We could not find any
significant differences in postoperative protein and fluid loss between the
groups on the following 3 days either. We conclude that the peritoneal damage by
CHPP is not caused by the hyperthermia but by the peritoneal perfusion with
saline solution containing anticancer drugs.
PMID- 10787068
TI - Preincisional dextromethorphan treatment for postoperative pain management after
upper abdominal surgery.
AB - Previous studies showed that ketamine, an N-methyl-D-aspartate (NMDA) receptor
antagonist, provides a preemptive analgesic effect and preemptive analgesia
improves postoperative pain management. The aim of this study was to examine
whether premedication with dextromethorphan (DM) improves postoperative pain
management after upper abdominal surgery. Sixty (American Society of
Anesthesiologists class 1 and 2 of either gender) patients scheduled for upper
abdominal surgery were included in the study. Patients were randomly assigned to
one of four groups: control, DM-10, DM-20, and DM-40. In the control group,
chlorpheniramine maleate (CPM, 20 mg) was injected immediately before induction
of anesthesia intramuscularly (IM). In the DM-10, DM-20, and DM-40 groups,
patients were premedicated with DM 10 mg, 20 mg, and 40 mg IM, respectively.
After operation, patient-controlled analgesia (PCA) with morphine was given for
pain relief. The time to the first PCA trigger, morphine consumption, pain
scores, and analgesic-related side effects were recorded at 1, 2, 4, 24, 48, and
72 hours after surgery. The time to first PCA trigger for the control group was
17.8 +/- 1.4 minutes, for group DM-10 20.2 +/- 1.6 minutes, for group DM-20 32.4
+/- 1.9 minutes, and for DM-40 77.9 +/- 6.5 minutes. The morphine delivered and
PCA triggering frequency were 5.5 +/- 0.5/11.3 +/- 0.8 times for the controls,
5.5 +/- 0.4/ 14.1 +/- 1.3 times for DM-10, 3.1 +/- 0.3/6.3 +/- 1.2 times for DM
20, and 0.2 +/- 0.1/0.3 +/- 0.2 times for DM-40 during the first hour after
operation. For the first day, the figures are 19.9 +/- 1.2/23.9 +/- 1.4 for the
controls, 15.6 +/- 1.2/17.3 +/- 2.4 for DM-10, 12.6 +/- 0.7/15.9 +/- 1.6 for DM
20, and 5.0 +/- 0.21/5.6 +/- 0.9 for DM-40. On the first day, the cough pain
scores were 6.67 +/- 0.23, 6.53 +/- 0.16, 6.67 +/- 0.23, and 5.73 +/- 0.18 for
the controls, DM-10, DM-20, and DM-40 groups, respectively. All data showed dose
dependent better pain relief in DM-premedicated patients. We conclude that DM
premedication offers preemptive analgesia and reduces postoperative pain and
morphine requirement.
PMID- 10787069
TI - Topical formalin for management of bleeding malignant ulcers.
AB - Hemorrhage, an infrequent but serious complication of malignant ulceration, can
be difficult to manage. Although many methods exist for treatment, none is wholly
satisfactory. The use of topical formalin was studied in a group of patients with
bleeding from malignant ulcers, and the results show that the agent achieved
control of bleeding in 86% of the patients after two applications. There were no
significant complications arising from the treatment. Topical formalin is a safe,
inexpensive, effective agent for control of bleeding from malignant ulcers.
PMID- 10787070
TI - Intraperitoneal gossypibomas: the need to count sponges.
AB - Intraperitoneal forgotten foreign bodies are prone to create adhesions and to
encapsulate, or to provoke an exudative response, with or without accompanying
bacterial infection. Often a process of self-extrusion is initiated. This is also
true for gossypibomas, retained surgical sponges. Presentation is possible as a
pseudotumoral, occlusive, or septic syndrome; several cases, however, have
remained asymptomatic for as long as several decades. Ultrasonography and
radiology (especially computed tomography) contribute significantly to the
detection of gossypibomas; magnetic resonance imaging is a less used technique.
Detection by plain radiography is difficult. Ultrasonography demonstrates a
hyperreflective mass with hypoechoic rim and a strong posterior shadow. Computed
tomography shows a well defined mass with internal heterogeneous densities.
Therapy consists of operative removal of the foreign body in association with
resolving its complications. Adding a series of five cases to the existing
literature reports, the fate of intraperitoneal forgotten surgical sponges is
reviewed.
PMID- 10787071
TI - Ultrastructural alterations of polytetrafluoroethylene prostheses implanted in
abdominal wall provoked by infection: clinical and experimental study.
AB - Infection of an expanded polytetrafluoroethylene (ePTFE) prosthesis after implant
is a major drawback of its use in current clinical practice. The aim of the
present study was to compare the behavior of such prostheses implanted into New
Zealand rabbits with that of prostheses infected after clinical implant.
Experimental implants of ePTFE Soft Tissue Patch were performed to repair defects
(7 x 5 cm) created in the abdominal wall of 10 rabbits. Prior to implant the
prostheses were contaminated with Staphylococcus aureus. Five animals implanted
with noncontaminated ePTFE prostheses served as controls. All the animals were
sacrificed at 30 days after implant. For the clinical study, specimens were taken
from three ePTFE implants that had been found to be infected after intervention.
The clinical and experimental implant specimens were processed for light
microscopy and scanning electron microscopy. Macroscopic and microscopic
examination of experimental and clinical implants revealed alterations to the
ePTFE structure, such as areas of fragmentation, fracture lines, and detachment
of fine layers of ePTFE that harbored numerous Staphylococcus colonies. Neoformed
tissue around contaminated implants was arranged more loosely, and on occasion
large spaces between fibers gave rise to an "unknitted" appearance with respect
to the control implants. It may be concluded that microporous ePTFE prostheses
show similar behavior following experimental or clinical implant in the presence
of infection. Irreversible changes to the structure of the prosthesis are
produced owing to colonization of the biomaterial by microorganisms, which in
most cases necessitates total replacement of the prosthesis.
PMID- 10787073
TI - Angiographic embolization for intraperitoneal and retroperitoneal injuries.
AB - Angiographic embolization (AE) has been used extensively for bleeding control
after injuries to the face and neck. Its role in abdominal trauma requires
further exploration. We reviewed the medical records of 137 consecutive patients
who underwent angiography with the intent to embolize bleeding sites within the
abdomen. Of them, 97 (71%) had blunt and 40 (29%) had penetrating trauma. AE was
performed for hemorrhage associated with pelvic fractures (97 patients), liver
lacerations (n = 26), renal lacerations (n = 12), splenic lacerations (n = 5),
other injuries (n = 9), and multiple injuries (n = 12). On angiography, 102
patients were found to have bleeding sites and underwent AE, with angiographic
and clinical bleeding control in 93 (91%). The rate of successful hemostasis by
AE was identical in blunt and penetrating trauma patients. There was no major
morbidity after AE. No factors predicted patients with a high likelihood to have
a positive angiogram. Patients who had AE before or after a period of attempted
hemodynamic stabilization in the intensive care unit were no different with
respect to hemodynamic parameters immediately before AE or effectiveness of AE
for bleeding control. AE is a safe and effective method for controlling bleeding
after blunt and penetrating intra- and retroperitoneal injuries. Early AE may be
used in selected patients as a front-line therapeutic intervention that offers
expeditious hemostasis and prevents delays in definitive bleeding control.
PMID- 10787072
TI - Complicated enterocutaneous fistulas: failure of octreotide to improve healing.
AB - Octreotide has been promoted as a potential aid during closure of enterocutaneous
fistulas (ECFs) on the basis of clinical and experimental evidence that it can
reduce gastrointestinal secretions. We retrospectively reviewed the records of
patients admitted with ECF to our tertiary referral center to ascertain whether
use of octreotide affected fistula duration, length of hospitalization, closure
rate, and morbidity. Of 60 patients diagnosed and treated for ECF over a 4-year
period, 13 underwent a therapeutic trial with octreotide. Thirteen patients from
the group who did not receive octreotide were matched by cause, location, and
output of the fistula, age, and primary diagnosis to the treatment group.
Octreotide was administered in therapeutic dosage for a mean course of 57 +/- 29
days, resulting in a substantial acute decrease (84.7 +/- 4.8%) in fistula
output. Prolonged therapy nevertheless failed to affect the outcome parameters
studied, particularly fistula duration, spontaneous closure rate, and length of
hospitalization. There was a significantly higher incidence of septic and
thrombotic complications associated with octreotide use. In this patient
population with complicated ECFs, use of octreotide showed no benefit and was
associated with increased morbidity.
PMID- 10787074
TI - Axillary lymph nodes in breast cancer: is size related to metastatic involvement?
AB - Usually when using imaging procedures, such as axillary mammography or
ultrasonography, a cutoff level of 5 mm for lymph node size is postulated to be
not only the limit of lymph node visibility but also a sign of metastatic
involvement. The aim of this study was to evaluate whether this assumption, used
as a basic hypothesis in many reports, is true. A series of 72 axillary specimens
from 71 breast carcinoma patients operated at the university hospital of Vienna
were analyzed. A comparison of histologically noninvolved axillary specimens with
those showing metastatic involvement revealed that the two groups did not differ
significantly according to the number or size of lymph nodes per axilla. For
lymph nodes <5 mm the probability of being metastatically involved was still 10%.
Enlarged lymph nodes (5-20 mm) had a slightly higher risk of being malignant
(20%). In contrast, the probability of metastatic involvement for lymph nodes >20
mm was only 40%. We suggest that many reports dealing with the prediction of
malignancy in axillary lymph nodes may have used misleading basic assumptions, so
the results of these studies must be viewed critically.
PMID- 10787075
TI - Prospective case-controlled trial of adjuvant chemotherapy after resection of
hepatocellular carcinoma.
AB - Recurrence of hepatocellular carcinoma (HCC) after curative hepatic resection is
frequent and is an important factor adversely influencing long-term survival. The
role of postoperative chemotherapy in the reduction of tumor recurrence rate is
still controversial. During the period of 1992-1995 a series of 49 patients who
underwent curative resection of HCC and had at least one risk factor of tumor
recurrence were followed in this prospective study. Patients were allocated to
adjuvant chemotherapy and control groups. Twenty-four patients received a
combination of low dose intravenous epirubicin (20 mg/m2) and mitomycin (5 mg)
monthly for seven courses starting 5 to 6 weeks after surgery. Twenty-five
patients had no adjuvant treatment. The disease-free and overall survivals were
compared for the two groups. A total of 154 courses of chemotherapy were given to
the 24 patients. The chemotherapy-related side effects were mild and tolerable
with no mortality. At a median follow-up of 39 months (range 9-71 months), 9
patients in the adjuvant chemotherapy group and 16 patients in the control group
developed tumor recurrence. The respective 1-, 2-, 3-, and 5-year disease-free
survival rates were 75%, 67%, 63%, and 63% for patients in the adjuvant
chemotherapy group and 68%, 42%, 37%, and 32% for patients in the control group
(p = 0.0575). The 1-, 2-, 3-, and 5-year overall survival rates were 100%, 96%,
77%, and 72% in the adjuvant chemotherapy group and 92%, 67%, 63%, and 51% in the
control group (p = 0.0746). In conclusion, postoperative adjuvant chemotherapy
using the present regimen has a tendency to reduce tumor recurrence rate and may
improve long-term survival for high risk patients.
PMID- 10787076
TI - Intraoperative parathormone measurement in patients with multiple endocrine
neoplasia type I syndrome and hyperparathyroidism.
AB - Total or subtotal parathyroidectomy is considered the treatment of choice for
multiple endocrine neoplasia type I (MEN-I)-associated primary
hyperparathyroidism (HPT). However, persistent or recurrent HPT is frequently
observed. The development of a rapid two-site immunoradiometric assay (IRMA)
method for measuring intact parathormone (PTH) has provided a valuable tool for
recognizing possible surgical failures. Our experience includes 16 MEN-I patients
(10 females, 6 males) of mean age 35.5 years operated on between 1990 and 1996.
Total parathyroidectomy (TPTX) with autotransplantation of parathyroid tissue was
the standard treatment. Blood samples for PTH measurement were drawn at the
induction of anesthesia (basal value), 10 and 20 minutes after the removal of
each gland, and 60 minutes after TPTX. Rapid PTH measurement, which required only
15 minutes of incubation at 37 degrees C, showed a highly significant correlation
(p < 0.0001) with the standard method. Circulating PTH levels exhibited a
stepwise decrease during TPTX, reaching a mean value of 22.3% of the baseline 20
minutes after removal of the last gland. Two patients showed a prompt decrease of
PTH after removal of the single enlarged gland, featuring the kinetics observed
in the adenomas. One of these two patients was successfully treated with more
conservative surgery. None of the patients showed persistence or recurrence of
HPT. In our experience, intraoperative measurement of PTH seems to be a valuable
adjunct in both the diagnosis of multiglandular involvement and the prediction of
surgical treatment in patients with primary parathyroid hyperplasia.
PMID- 10787077
TI - Outcome after surgery for primary hyperparathyroidism: ten-year prospective
follow-up study.
AB - Clinical outcome after surgery for primary hyperparathyroidism was evaluated in a
prospective long-term, follow-up study. From August 1, 1987 to August 31, 1998 a
total of 360 patients were prospectively investigated and included in a follow-up
study. All patients underwent follow-up examinations at regular surveillance
intervals. The postoperative course is known for 94.5% of all patients. Follow-up
was 1 month to 10 years (median 24 months; mean 34.5 +/- 29.8 months).
Asymptomatic primary hyperparathyroidism was rare (6%), and its true frequency
could be confirmed only postoperatively because some of the patients were unaware
of mild symptoms of hypercalcemic syndrome prior to surgery. Surgical cure was
obtained in 97.7% of patients after initial cervical exploration; and successful
parathyroidectomy provided long-term relief of symptoms. Within 2 years
postoperatively, 84% of the patients recovered fully from hypercalcemic syndrome:
in 58% of these patients recovery occurred within the first month after surgery.
Skeletal symptoms persisted in 24% of patients 2 years postoperatively. To date
no patient has developed recurrence of primary hyperparathyroidism. During follow
up in our study population mortality was significantly higher than the expected
mortality risk for the German population as a whole (p = 0.00024). The present
prospective follow-up study yielded conclusive outcome research data after
operative therapy for primary hyperparathyroidism. The high cure rate and low
morbidity, as well as the increased mortality, in our study population during
follow-up after successful operative therapy for the disease emphasize the
importance of early diagnosis and early surgical treatment for primary
hyperparathyroidism, even in the absence of manifest symptoms.
PMID- 10787078
TI - Palpatory method used to identify the recurrent laryngeal nerve during
thyroidectomy.
AB - The major complication of thyroid surgery, occurring in 1% to 6% of cases, is
injury to the recurrent laryngeal nerve (RLN). A simple method to identify the
RLN during thyroid surgery is described by the authors. It consists in palpation
of the nerve caudally to the inferior pole of the thyroid, after the nerve has
been made taut by the upward and medial traction of the thyroid gland. This
method was used on 47 human cadavers and 45 patients with benign thyroid
diseases. It made it possible to identify the RLN in all of the cadavers and 52
of the 55 identifications during 45 thyroidectomies (in 10 total thyroidectomies
the identification was bilateral). Laryngeal motility was normal in all patients
at postoperative laryngoscopy. Using the palpation before dissection in the
region of the inferior thyroid artery, the traditional viewing method became
easier and safer, reducing the risk of injury where it is most likely to occur to
the nerve.
PMID- 10787079
TI - Comparison of the hemodynamic parameters of open and laparoscopic adrenalectomy
for pheochromocytoma.
AB - Laparoscopic adrenalectomy has gained widespread popularity for treating a
variety of adrenal disorders including pheochromocytoma, but the effects of
pneumoperitoneum on the hemodynamics of patients with catecholamine-secreting
tumors are poorly understood. The goal of this study was to compare the effects
of carbon dioxide pneumoperitoneum and tumor manipulation on the hemodynamic
parameters in two groups of patients with sporadic pheochromocytomas less than 7
cm in size. Group 1 patients (n = 11) underwent lateral transabdominal
laparoscopic adrenalectomy, and group 2 (n = 11) underwent adrenalectomy by the
open anterior approach. The mean follow-up was 37 months in group 1 (range 26-51
months) and 52 months in group 2 (range 27-72 months). All patients undergoing
laparoscopic adrenalectomy experienced intraoperative hypertension (blood
pressure > or = 200/90 mmHg), as did 73% with the open approach, but the
difference was not significantly different. Intraoperative hypotension (systolic
blood pressure < 80 mmHg) occurred in four group 1 patients compared to six
patients in group 2. Mean arterial pressure, central venous pressure, and
pulmonary capillary wedge pressure were significantly higher in group 1 patients
prior to tumor excision, but there was no difference in pulse, cardiac index, or
left ventricle work index at any point during the procedure. There were no
conversions or complications in the laparoscopic group; one patient in group 2
developed an incisional hernia. Although laparoscopic adrenalectomy for
pheochromocytoma is associated with a greater increase in mean arterial pressure,
central venous pressure, and pulmonary capillary wedge pressure, the creation of
pneumoperitoneum does not significantly change the cardiac index or left
ventricle work index. Carbon dioxide pneumoperitoneum is well tolerated in
patients with pheochromocytoma.
PMID- 10787080
TI - Natural course of adrenal incidentalomas: seven-year follow-up study.
AB - Most adrenal incidentalomas are nonfunctioning cortical adenomas that do not
require surgery. Operative treatment is indicated if the incidentaloma has
malignant features as seen during the radiologic workup, is hormonally active, or
grows during follow-up. A conservative attitude is justified in asymptomatic
patients if we know that the natural course of these tumors is not
disadvantageous. We followed a group of patients treated by observation to
determine the natural course of adrenal incidentalomas. Altogether 30
incidentalomas in 27 patients were detected in the Helsinki University Central
Hospital from June 1981 through December 1992 and were re-examined during 1997.
The patients were evaluated clinically, and hormonal testing was done by
performing a 1-mg overnight dexamethasone suppression test; the next day we
measured the 24-hour urinary excretion of vanillylmandelic acid, metanephrines
and normetanephrines, and serum potassium. Magnetic resonance imaging (MRI) was
used to determine the size of the tumor. If the patient had died during the
follow-up period, the causes of death from the death certificates and autopsy
reports were reviewed. The mean follow-up was 7 years. Nine patients had died,
with none of deaths related to the incidentaloma. Sixteen patients were evaluated
clinically and by the basic hormonal tests and MRI; none showed any signs of
hormonal activity or features of malignancy. Two patients did not want to be
reexamined but stated that they were asymptomatic. This follow-up study supports
the conclusion that conservative therapy is justified because the growth tendency
of adrenal incidentalomas is slow and they seem to remain hormonally inactive.
PMID- 10787081
TI - Early gastric cancer: unrecognized indicator of multiple malignancies.
AB - The aim of this study was to evaluate the postoperative outcome and occurrence of
second primary malignancies in patients who underwent radical resection for early
gastric cancer. Altogether 105 patients with early gastric cancer underwent
radical resection and were followed up for a median period of 71 months. Overall
lethality was analyzed with regard to mortality due to gastric cancer or other
causes. Standardized mortality and morbidity ratios were calculated using data
from the Tumor Registry of Lombardy. The 5-year survival rate was 82.8%
(operative mortality excluded), which was not different from that expected from
an age- and sex-matched Italian population. Ten second primary malignancies were
identified, giving a standardized mortality ratio of 1.12 and a standardized
morbidity ratio of 1.50. Patients undergoing surgery for early gastric cancer
(especially the intestinal type) may have a circa 50% higher risk of a second
tumor and should be periodically checked for other tumors, mainly in the
supramesocolic area.
PMID- 10787082
TI - Long-term survival of transmural advanced gastric carcinoma following curative
resection: multivariate analysis of prognostic factors.
AB - Patients with transmural (T2N0-T3N2) advanced gastric carcinoma comprise the
largest group with uncertain outcome. These patients must be stratified according
to the prognostic variables so the high risk group can be precisely identified. A
total of 152 patients with transmural advanced gastric carcinomas were uniformly
treated with a curative intent between 1979 and 1989 with at least a 7-year
follow-up. Results and prognostic factors of long-term survival were analyzed by
univariate and multivariate analyses. Seventy-five (49%) patients with advanced
gastric carcinoma survived more than 7 years, which indicates the curative nature
of surgery for gastric carcinoma. Seventeen variables were evaluated by
univariate analysis. In the multivariate analysis, patient's age [>70 years,
relative risk (RR) 2.4)], intraoperative blood loss (>500 ml, RR 1.7), blood
vessel invasion (RR 2.3), ratio of invaded dissected lymph nodes (>0.2, RR 3.0),
and tumors penetrating the serosa (RR 3.9) were the independent prognostic
variables. The results of this study indicate that extensive lymphadenectomy and
minimal intraoperative blood loss might be helpful for improving patient survival
following a curative resection. Patients with vessel invasion, serosal
involvement, and those >70 years of age should be considered at high risk and
require appropriate adjuvant therapy to prolong survival.
PMID- 10787083
TI - Surgery for ductal adenocarcinoma of the pancreatic head: staging, complications,
and survival after regional versus extended lymphadenectomy.
AB - The purpose of this study was to evaluate the influence of regional versus
extended lymphadenectomy on survival after partial pancreaticoduodenectomy for
pancreatic cancer. From October 1988 to December 1991 (Department of Surgery,
University of Hamburg) and from January 1992 to March 1998 (Department of
Surgery, University of Kiel) 72 patients with histologically proven ductal
adenocarcinoma of the pancreatic head were treated. Partial
pancreaticoduodenectomy with regional lymphadenectomy was performed in 26
patients. In 46 patients lymphadenectomy was expanded to include extended
retroperitoneal lymphatic and connective tissue clearance. Comparing these two
groups and including only patients with R0 resections (n = 58) no significant
differences in long-term survival could be shown. The following parameters were
shown to have a significant or nearly significant influence on long-term
survival: (1) stage of the disease: The 5-year survival of patients with stage
I/II pancreatic head cancer was 63%, compared to 15% in patients with stage
III/IV a + b of the disease (p = 0.0087). (2) Grading: The 1-year survival of
patients with well or moderately differentiated tumors was 55%, compared to 0%
for patients with poorly differentiated ductal adenocarcinoma (p = 0.0022). (3) N
stage: The 5-year survival of patients in N0 stage was 46.9%, compared with 15%
for N1 stage patients. The difference was not quite significant (p = 0.081). (4)
Portal vein involvement: The 1-year survival was 0% in patients with R0
resections and histologically proven tumor infiltration of the portal vein,
compared to 63% for patients with curative resections without portal vein
involvement (p = 0.0063). In conclusion our data indicate that extensive
retroperitoneal tissue clearance during pancreaticoduodenectomy for ductal
pancreatic cancer does not improve survival compared to regional lymphadenectomy
restricted to the right side of the mesenteric artery.
PMID- 10787084
TI - Measuring the tumor volume of gastric carcinoma by computer image analysis:
clinical significance.
AB - The tumor diameter of gastric carcinoma, measured by gross or histologic
examination, is a rough indicator of actual tumor size. Therefore we investigated
the utility of three-dimensional reconstruction of tumors in gastric carcinoma.
Altogether 105 primary gastric carcinoma lesions, consisting of 16 advanced and
89 early carcinomas, were analyzed. A total of 942 lesion tissue sections,
comprising 2 to 37 sections per lesion (mean 9 sections), were examined
histologically. Surface rendering using a computer graphics analysis program was
then performed from serial sections to create a three-dimensional reconstruction
of tumor morphology from which to measure tumor volume. For the 105 lesions the
tumor diameter ranged between 4 and 106 mm (average +/- SE: 32.4 +/- 2.0 mm), and
tumor volume ranged between 4 and 5853 mm3 (average +/- SE: 773.0 +/- 104.6 mm3).
A significant correlation was found between tumor diameter and the log of the
tumor volume (r = 0.733, p < 0.0001). Although the logs of tumor volume for
advanced carcinomas were all > 2.5, in 11 of these 16 patients (66%) the tumor
diameter was < 4 cm, and in one patient < 2 cm. In addition, tumor diameter did
not differ significantly between the 16 advanced and the 89 early gastric
carcinomas (p = 0.114), whereas the log of the tumor volume did (p < 0.0001). In
conclusion, conventional measurements of tumor diameter as a rough indicator of
tumor size can predict the actual tumor size of a gastric carcinoma. Three
dimensional reconstruction using computer graphics provides a better estimation
of true tumor size and extent of progression than tumor diameter.
PMID- 10787085
TI - Protein expression of bax, bcl-2, and p53 in patients with non-Hodgkin's gastric
lymphoma: prognostic significance.
AB - The biologic significance of bcl-2, bax, and p53 gene expression in patients with
non-Hodgkin's gastric lymphoma is unknown. We examined the prognostic value of
these genes in 36 patients with gastric lymphoma treated in our clinic between
1990 and 1995. Paraffin-embedded specimens from 36 patients who underwent primary
resection of the stomach for gastric lymphoma were analyzed immunohistochemically
for p53, bax, and bcl-2 gene expression. Expression of bax was seen in 24 of 36
patients (66.7%), p53 expression was found in 8 of 36 tumors (22.2%), and bcl-2
cytoplasmic staining was detected in 6 of 36 patients (16.7%). We performed a
univariate analysis to examine the possible correlation between the expression of
these genes and the survival of our patients. Expression of bax protein proved to
be a statistically significant prognostic factor (p = 0.049). Protein expression
of p53 and bcl-2 did not statistically correlate with survival. In the bcl-2
negative (-) patient group (30 patients), those who were bax-positive had a
statistically significant better survival than those who were bax-negative (63.3%
vs. 36.7%, p = 0.03). There was also a statistically significant correlation
between p53 expression and the grade of the tumor (p = 0.0014). P53 protein
expression increased along with the grade. Expression of bax is a significant
prognostic factor in patients with gastric lymphoma. Its prognostic value
increases significantly when studied in bcl-2-negative patients; but expression
of bax failed to be an independent prognostic factor. Expression of bcl-2 and p53
has no prognostic significance. Expression of p53 seems to represent a marker for
loss of differentiation.
PMID- 10787086
TI - Fatal wounding of the Byzantine Emperor Julian the Apostate (361-363 A.D.):
approach to the contribution of ancient surgery.
AB - Byzantine surgery flourished from the early stages of the Byzantine empire (324
1453 A.D.). The first great Byzantine physicians, among the most eminent being
Oribasius from Pergamun (fourth century), not only compiled anthologies of the
works of ancient Greek, Alexandrian, and Roman physicians but added their own
personal practical experience and observations. The circumstances surrounding,
and the treatment of, the fatal abdominal wounding of one of the most renowned
emperors of Byzantium, Julian the Apostate (361-363 A.D.), is examined based on
historical accounts unknown in the broader medical bibliography, namely, the
histories and chronicles of Byzantine writers. From this analysis it can be
concluded that the emperor's physician, Oribasius, in all probability, applied
knowledge of ancient Greek and Roman surgery to save his famous patient. The
techniques of "gastrorrhaphy" and pharmaceutical confrontation of the wound in
that era, adopted later by the surgeons of the Medieval West, seem to constitute
noteworthy roots of modern surgery.
PMID- 10787087
TI - Hepatectomy for colorectal hepatic metastases.
PMID- 10787088
TI - The incidence of infection in dirty surgical wounds.
PMID- 10787089
TI - The historical review on gastric surgery by Weil and Buchberger.
PMID- 10787090
TI - Dehalogenation of xenobiotics as a consequence of binding to humic materials.
AB - Chlorinated phenols and anilines were transformed by oxidoreductive catalysts
with release of chloride ions in both the absence and the presence of humic
substances (syringaldehyde, catechol, and humic acid). Dehalogenation of these
xenobiotics resulted from oxidative coupling reactions occurring at the
chlorinated sites of the substrates. The effect of humic substances on
dehalogenation depended on the mechanism of oxidative coupling. In a free-radical
reaction mediated by peroxidase, laccase, or birnessite (delta-MnO2),
syringaldehyde enhanced the dehalogenation of most of the chlorinated phenols,
but it did not enhance the dehalogenation of the chloroanilines. With catechol,
which does not form free radicals, dehalogenation was reduced or remained the
same for both the chlorophenols and the chloroanilines. However, in tyrosinase
mediated reactions controlled by nucleophilic addition, catechol enhanced the
dehalogenation of most of the chlorophenols, whereas syringaldehyde had little
effect. Humic acid in most cases enhanced the dehalogenation of the
chlorophenols, but it had little effect on the dehalogenation of the
chloroanilines. On a molar basis, changes in dehalogenation caused by humic
substances were proportional to the respective changes in substrate
transformation. Only syringaldehyde was capable of releasing disproportionately
high amounts of chloride ions from chlorophenols, apparently as a result of
multiple crosscouplings to one molecule of the substrate.
PMID- 10787091
TI - A multidisciplinary approach to assess history, environmental risks, and
remediation feasability of soils contaminated by metallurgical activities. Part
A: chemical and physical properties of metals and leaching ability.
AB - Three soils contaminated by heavy metals (HMs) and aliphatic hydrocarbons
originating from different industrial sources were characterized in a
multidisciplinary study combining chemical, physical (Part A), and mineralogical
(Part B) approaches to define history, environmental risks, and remediation
feasibility. These were an agricultural soil located nearby a Zn/Pb smelter and
two soils from a steel metallurgical (siderurgy) waste land. High Pb and Zn
contents were reported for all, and high Cr, Cd, and aliphatic hydrocarbons were
present in different combinations in two out of three soils. Carbonate matrixes
more strongly cemented fine particles in the agricultural soil than in both
siderurgical ones, but buffering capacities were stronger in the latter. After
the disruption of these cements by ultrasounds, HM were concentrated in the <50
microm fraction of the agricultural and of one siderurgical soil. Sequential
extractions indicated for all the soils a preferential association of HM with
carbonates, Fe-Mn oxides, organic matter, and sulfides. The stirring of one
siderurgical soil with water resulted in an immediate leaching of hexavalent
chromium (0.3 mg x L(-1)) involving potential ecotoxicological risks.
PMID- 10787092
TI - A multidisciplinary approach to assess history, environmental risks, and
remediation feasability of soils contaminated by metallurgical activities. Part
B: direct metal speciation in the solid phase.
AB - Three soils contaminated by industrial smelting activities previously
characterized using chemical and physical approaches (Part A, Venditti et al.
[2000] Arch Environ Contam Toxicol [in press]) were further investigated through
a complementary mineralogical approach. X-ray diffraction allowed identification
of the main mineral components: carbonates (calcite, siderite) and iron oxides
(magnetite, hematite, goethite) prevailed in both siderurgical soils, and
siliceous compounds were more abundant in the agricultural soil. Scanning
electron microscopy coupled with energy dispersive x-ray microanalysis showed
that carbonates and oxides contained low amounts of heavy metals (HMs), but the
potential solubility of such species under acidic conditions associated to their
abundance may result in a high mobility of associated contaminants. Microanalysis
also revealed peculiar minor mineral forms (metallic nodules, alloys, ore
residues) that were highly informative about the history of soil contamination.
Small metal-rich particles were observed (brass, lead and zinc oxides). In such
compounds, HMs showed high chemical stability and were consequently poorly mobile
and toxic, but also poorly removable through chemical leaching. A risk of
mechanical dispersion was suggested for these particles, particularly after the
chemical and/or mechanical disruption of carbonate cements. These features
allowed completion and confirmation of the conclusions achieved after chemical
and physical investigations, providing accurate information about the history,
environmental risks and remediation feasability of industrial soil contamination.
PMID- 10787093
TI - Characterization of selected element concentrations and enrichment ratios in
background and anthropogenically impacted roadside areas.
AB - Previous research by the National Contaminant Biomonitoring Program found fish
from Manoa Stream, Hawaii, to have the highest concentrations of Pb in the
nation. To explore possible source linkages we sampled background
(uncontaminated) soil, roadside soil, and road deposited sediment in Manoa
watershed and analyzed them for total and extractable concentrations of Al, Co,
Cu, Fe, Mn, Ni, Pb, and Zn. Our concentration and enrichment ratio data indicate
that Al, Co, Fe, Mn, and Ni were controlled by natural source variations, and Cu,
Zn, and particularly Pb were anthropogenically enhanced. Labile Pb
concentrations, extracted with either dilute HCl or EDTA, reached a maximum of
3,560 mg/kg compared to background values of <10 mg/kg. Additionally, 25% of the
169 contaminated samples analyzed had EDTA-extractable Pb enrichment ratios > or
=11.5, where a value of 1 separates uncontaminated from contaminated media. Given
the proximity of most samples to roadways it is reasonable to conclude that
automotive emissions plus vehicle wear were the primary contributors of trace
metals to the roadside system. These data are discussed in context with previous
work on the fluvial bed sediments in this watershed in an attempt to examine the
potential linkage with the biological accumulation of Pb in fish from Manoa
watershed.
PMID- 10787094
TI - Influence of petroleum hydrocarbon contamination on microalgae and microbial
activities in a long-term contaminated soil.
AB - Petroleum hydrocarbons are widespread environmental pollutants. Although
biodegradation of petroleum hydrocarbons has been the subject of numerous
investigations, information on their toxicity to microorganisms in soil is
limited, with virtually no work conducted on soil algae. We carried out a
screening experiment for total petroleum hydrocarbons (TPH) and their toxicity to
soil algal populations, microbial biomass, and soil enzymes (dehydrogenase and
urease) in a long-term TPH-polluted site with reference to an adjacent unpolluted
site. Microbial biomass, soil enzyme activity, and microalgae declined in medium
to high-level (5,200-21,430 mg kg(-1) soil) TPH-polluted soils, whereas low-level
(<2,120 mg kg(-1) soil) pollution stimulated the algal populations and showed no
effect on microbial biomass and enzymes. However, inhibition of all the tested
parameters was more severe in soil considered to have medium-level pollution than
in soils that were highly polluted. This result could not be explained by
chemical analysis alone. Of particular interest was an observed shift in the
species composition of algae in polluted soils with elimination of sensitive
species in the medium to high polluted soils. Also, an algal growth inhibition
test carried out using aqueous eluates prepared from polluted soils supported
these results. Given the sensitivity of algae to synthetic pollutants, alteration
in the algal species composition can serve as a useful bioindicator of pollution.
The results of this experiment suggest that chemical analysis alone is not
adequate for toxicological estimations and should be used in conjunction with
bioassays. Furthermore, changes in species composition of algae proved to be more
sensitive than microbial biomass and soil enzyme activity measurements.
PMID- 10787095
TI - The role of ingestion as a route of contaminant bioaccumulation in a deposit
feeding polychaete.
AB - A mass-balance bioaccumulation model was used to examine the bioaccumulation of
benzo[a]pyrene (BaP) from ingested sediment by the deposit-feeding polychaete
Abarenicola pacifica over a series of experiments employing nine different
sediments. Through selective ingestion of fine-grained material, the worm was
able to increase the BaP content of ingested sediment by 10-35% above that of the
bulk material. During digestion, an average of 5-21% of the ingested BaP was
absorbed from gut contents. The relative importance of ingestion as a route of
BaP uptake was dependent on the time period of observation. Initial uptake of BaP
was postulated to come from absorption of dissolved BaP across the body wall
since, after short periods of exposure (<24 h), only 3-38% of observed BaP tissue
concentrations could have been derived from ingested material. With time and with
increased feeding activity, however, ingested sediment became the major source of
BaP to the organism. After 72 h of exposure, 36-119% of the tissue BaP (mean =
77%) was estimated to have been derived from dietary absorption of ingested
material, and with continued exposure the dietary route is likely to be as great
or greater as the relative significance of the initial uptake from the dissolved
phase diminishes. This work and other studies indicate that for many deposit
feeders, ingested sediment can be the primary source for the bioaccumulation of
hydrophobic toxicants.
PMID- 10787096
TI - Effects of cadmium and phenol on motility and ultrastructure of sea urchin and
mussel spermatozoa.
AB - Computer-assisted sperm analysis (CASA) was used to study the effects of Cd(II)
and phenol on sperm motility of sea urchin and mussel. In parallel,
ultrastructural changes of sperm induced by these two toxicants were also
investigated and related to motility impairment. Spermatozoa of sea urchin were
more sensitive than mussel spermatozoa to both toxicants. Sea urchin sperm
motility showed a good dose-response relationship to Cd(II) levels as well as
exposure time. Exposure to the two toxicants changed the size and shape of the
midpiece, which might affect the balance of spermatozoa in their swimming. The
plasma membrane became more convoluted, and such a change might affect the
streamlining and integrity of spermatozoa and hinder their normal movement
patterns. Most important, disorganization of mitochondrial membranes and cristae
was observed, suggesting disruption of ATP supply for sperm movement. Cadmium
also induced greater ultrastructural damages in sea urchin spermatozoa.
PMID- 10787098
TI - Ultrastructural localization of heavy metals (Hg, Ag, Pb, and Cu) in gills and
digestive gland of mussels, Mytilus galloprovincialis (L.).
AB - The intracellular localization of heavy metals using autometallography (AUM) was
studied in the gills and the digestive gland of the common mussel Mytilus
galloprovincialis, after an experimental exposure to 0.1 mg L(-1) of Hg, 0.1 mg
L(-1) of Ag, 0.1 mg L(-1) of Pb, and 0.1 mg L(-1) of Cu for 98 days. In the
gills, autometallographical black silver deposits (BSDs) were localized in the
dense bodies observed in the apical and in the basal part of the cells. Among
metals, Hg presented the highest accumulation, followed by Ag, Pb, and Cu. BSDs
were more prominent in the abfrontal part of the gill filament in the case of Hg
exposure and in the frontal part in the case of Ag and Pb exposure. In the
digestive gland, Hg and Ag were localized in the heterolysosomes and the residual
bodies of the digestive cells, as well as in the dense bodies of the basophilic
cells. The heavy metal exposure also affected the gross morphology of the
examined tissues and resulted in the fusion of residual bodies in the digestive
cells, the fragmentation or vacuolization of the rough endoplasmic reticulum, and
the increase in the number of granules in the basophilic cells. In the gills,
fusion of the gill filaments was also noted.
PMID- 10787097
TI - Polychlorinated biphenyls and metals in marine species from French Frigate
Shoals, North Pacific Ocean.
AB - Polychlorinated biphenyls (PCBs) and metals were analyzed in coral (Porites
lobata), fish (Stegastes fasciolatus), crab (Grapsus tenuicrustatus), and
sediment samples collected from Tern Island, and the reference samples from Trig
and La Perouse Islands. All three islands are part of French Frigate Shoals, a
national wildlife refuge in the North Pacific Ocean. Average concentrations of
total PCBs ranged from 154 to 274 ng/g in the sediments, from 120 to 267 ng/g in
the corals, from 387 to 4,500 ng/g in the crabs, and 1,340 to 46,000 ng/g, dry
weight, in the fishes. High concentrations in marine species indicate there is
PCB source(s) in French Frigate Shoals, especially Tern Island. Tetra- and
pentachlorobiphenyls were 64-66% of the total PCB levels in the sediments, and
they accounted for 57-65% of total PCBs in the corals. Penta- and
hexachlorobiphenyls were 76-84% of total PCBs in the fishes, and they accounted
for 79-85% in the crab samples. The sediment and coral were predominated by lower
chlorinated PCB congeners, whereas the fish and crab bioaccumulated mainly higher
chlorinated congeners. Selenium concentrations (16-23 microg/g) in sediments were
much higher than some reported baseline values (0.4-2.5 microg/g). The average
concentrations of arsenic, cadmium, lead, and selenium in the coral and fish were
about equal to or less than those in the sediments. Concentrations of arsenic and
cadmium in the crabs (49-51 and 3-4 microg/g, respectively) were approximately
twofold of those in the sediments.
PMID- 10787099
TI - Selenium concentrations in the Colorado pikeminnow (Ptychocheilus lucius):
relationship with flows in the upper Colorado River.
AB - A Department of the Interior (DOI) irrigation drainwater study of the Uncompahgre
Project area and the Grand Valley in western Colorado revealed high selenium
concentrations in water, sediment, and biota samples. The lower Gunnison River
and the Colorado River in the study area are designated critical habitat for the
endangered Colorado pikeminnow (Ptychocheilus lucius) and razorback sucker
(Xyrauchen texanus). Because of the endangered status of these fish, sacrificing
individuals for tissue residue analysis has been avoided; consequently, little
information existed regarding selenium tissue residues. In 1994, muscle plugs
were collected from a total of 39 Colorado pikeminnow captured at various
Colorado River sites in the Grand Valley for selenium residue analysis. The
muscle plugs collected from 16 Colorado pikeminnow captured at Walter Walker
State Wildlife Area (WWSWA) contained a mean selenium concentration of 17
microg/g dry weight, which was over twice the recommended toxic threshold
guideline concentration of 8 microg/g dry weight in muscle tissue for freshwater
fish. Because of elevated selenium concentrations in muscle plugs in 1994, a
total of 52 muscle plugs were taken during 1995 from Colorado pikeminnow staging
at WWSWA. Eleven of these plugs were from fish previously sampled in 1994.
Selenium concentrations in 9 of the 11 recaptured fish were significantly lower
in 1995 than in 1994. Reduced selenium in fish may in part be attributed to
higher instream flows in 1995 and lower water selenium concentrations in the
Colorado River in the Grand Valley. In 1996, muscle plugs were taken from 35
Colorado squawfish captured at WWSWA, and no difference in mean selenium
concentrations were detected from those sampled in 1995. Colorado River flows
during 1996 were intermediate to those measured in 1994 and 1995.
PMID- 10787101
TI - Vitellogenin induction and other biochemical responses in carp, Cyprinus carpio,
after experimental injection with 17 alpha-ethynylestradiol.
AB - Prespawning, adult male and female carp, Cyprinus carpio, were intraperitoneally
injected with a single dose of 500 microg/kg of 17alpha-ethynylestradiol (EE2).
Blood samples were taken and vitellogenin levels were recorded previous to the
injection and 8 days afterward. Western blot analysis of plasma VTG showed a
marked response in both males (90-fold) and females (67-fold) after EE2
injection. Also, a significant inhibition of the cytochrome P450 monooxygenase
system, namely, 7-ethoxyresorufin O-deethylase (EROD) activity, as well as
immunodetected CYP1A protein was observed in the EE2-injected fish. Other
cytochrome P450 isozymes, such as CYP3A or NADH cyt (b5) reductase, did not
indicate any particular trend; whereas NADPH cyt (P450) reductase was
significantly induced in EE2-injected animals. Total cytochrome P450, glutathion
S-transferase (GST), and total glutathion peroxidase (GPX) fluctuated in a
similar manner, but differences among treated and nontreated animals were not
statistically significant. UDP glucuronyl transferase (UDPGT), similar to the
antioxidant enzymes catalase, superoxide dismutase (SOD), and Se-GPX,
progressively decreased in carrier and injected animals in comparison to the
controls, although this trend did not reach statistical significance either.
PMID- 10787100
TI - Ecotoxicological assessment of persistent organic and heavy metal contamination
in Hong Kong coastal sediment.
AB - The aim of the present project is to determine the feasibility of measuring
hepatic cytochrome P4501A1 (CYP1A1) and metallothionein (MT) mRNA in fish as an
integrative measurement of persistent organic pollutants (POPs) and heavy metal
contamination in sediment arising in Hong Kong. Sediment samples were collected
from different sites, including Victoria Harbour (VS6), Yim Tin Tsai (YTT) at
Tolo Harbour, Mai Po marshes (MPM) at Deep Bay, and Southern Waters (SS6) of
coastal waters. The samples were analyzed for total and extractable
concentrations of Cd, Cu, Ni, Zn, and Pb, as well as PCBs and PAHs. In addition,
biomarker responses were studied in tilapia exposed experimentally to coastal
sediment for 7 days. Using RT-PCR technique, hepatic CYP1A1 and MT mRNA were
measured. Three control groups were used, including one negative control group
maintained in sea water only; the second and third positive control groups were
in sea water but were intraperitoneally injected with either beta-naphthoflavone
(40 microg/g body weight) or cadmium chloride (10 microg/g body weight),
respectively. The chemical data showed that VS6, YTT, and MPM were classified as
Class C sediment according to the sediment quality criteria defined by the Hong
Kong Environmental Protection Department, indicating the sites were heavily
polluted. The exposure of tilapia to the sediment induced hepatic CYP1A1 (VS6 >
YTT > MPM > SS6) and MT (VS6 > MPM > YTT > SS6) levels. The induction patterns
were comparable to the levels of POPs and metal contamination in the sediment,
indicating that the biomarker responses could be used to differentiate low to
high levels of contamination among sediment.
PMID- 10787102
TI - Metals and metalloids in tissues of American alligators in three Florida lakes.
AB - Concentrations of metals and selenium were examined in tissues of American
alligators (Alligator mississippiensis) from three lakes in central Florida, in
one of which alligators have exhibited reproductive or developmental defects. Our
overall objective was to determine whether the levels of metals were sufficiently
high to confound the association between chlorinated hydrocarbons, which are
elevated in eggs and juvenile plasma, and reproductive impairment. The
concentrations of all metals were relatively low compared to those reported for
alligators from elsewhere in Florida and the southeastern United States,
suggesting that reproductive impairment is not due to metals and that metals pose
no health risk to the alligators. We also wanted to determine whether skin,
biopsied tail muscle, or tail tip tissue, all easily collected from live
alligators, could be used as surrogate measures of internal tissue loads.
Concentrations of arsenic, cadmium, chromium, lead, manganese, mercury, and
selenium in liver were highly correlated with at least one of the three biopsied
tissues. Only tin showed no significant positive correlation. No single tissue
gave a high prediction of liver levels for all metals, although skin gave the
highest correlation for mercury, and tail muscle gave the best overall
correlation for lead and cadmium.
PMID- 10787103
TI - Toxic assessment of PCBs by the 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent in
common cormorant (Phalacrocorax carbo) from Japan.
AB - Common cormorants collected from three colonies and their fish diet were analyzed
for PCB congeners and 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQs) were
estimated. The highest total PCBs (40 microg/g wet weight) found in adult
cormorants from Shinobazu Pond located in Central Tokyo, was sevenfold higher
than that from Lake Biwa. IUPAC 153 was the most abundant congener in adults and
eggs, whereas IUPAC 28 + 31 was higher in some chicks and exhibited growth
related congeneric enrichment. The estimated metabolic index (MI) for PCB
congeners revealed that monoand non-ortho coplanars had higher bioaccumulation in
cormorant liver and were expected to cause toxic effects. Among non-ortho
coplanars, IUPAC 126 was predominant, and total non-ortho coplanars and TEQs in
cormorants were threefold higher in Shinobazu Pond than those from Lake Biwa. The
non-ortho IUPAC 126 contributed a higher portion to the total TEQs followed by
IUPAC 105 and IUPAC 77. The hepatic IUPAC 169/126 ratio increased significantly
with TEQs, implying a potential induction of drug-metabolizing enzymes in
Shinobazu Pond cormorants. Based on the available data, PCB contamination in
cormorants is enough to pose sublethal effects, especially in Shinobazu Pond and
Godaiba Island, Tokyo, Japan. This could be a reason for recently observed high
chick and juvenile mortality in those colonies in Tokyo.
PMID- 10787104
TI - Mixed-function oxygenases, oxidative stress, and chromosomal damage measured in
lesser scaup wintering on the Indiana Harbor Canal.
AB - During the winter of 1993-1994, male lesser scaup (Aythya affinis) were collected
on the heavily polluted Indiana Harbor Canal, East Chicago, Indiana, and examined
for several bioindicators of chemical exposure. Livers were analyzed for
activities of three cytochrome P450-associated monooxygenases and four measures
of oxidative stress. Blood and spleen were analyzed by flow cytometry for
chromosomal damage. In a concurrent study, scaup tissues were analyzed for
organic and inorganic contaminants. Ethoxyresorufin-O-dealkylase (EROD) activity
in livers of scaup collected in January 1994 was significantly higher than in
livers of scaup collected in March 1994 or in livers of reference birds. Three
hepatic monooxygenase activities were each significantly correlated with
polycyclic aromatic hydrocarbon (PAH) concentrations in scaup carcasses.
Thiobarbituric acid (TBA) activity in scaup livers was positively correlated with
iron, boron, and lead concentrations in livers and polychlorinated biphenyl
concentrations in carcasses. TBA activity was negatively correlated with protein
bound thiol activity and mercury concentrations in livers. The coefficient of
variation of DNA content in scaup blood cells was correlated with PAH
concentrations in scaup carcasses. This is the first field study with birds to
demonstrate a correlation between liver monooxygenase activity and carcass PAH
concentrations and to show a direct correlation between PAH concentrations in
tissues and somatic chromosomal damage in blood.
PMID- 10787106
TI - Sensitivity of a standard host resistance assay using Streptococcus agalactiae
for assessing exposure to immunotoxicants in wild cotton rats (Sigmodon
hispidus).
AB - Resident small mammals have been used for in situ biomonitoring of contaminated
waste sites containing suspected immunotoxicants. Host resistance assays, which
involve challenging animals with an actual pathogen, allow for testing of overall
immune system function in animals. Because such assays have not been evaluated
for use with wild rodent species, it was our objective to assess the efficacy of
Streptococcus agalactiae as a pathogenic model for use in a host resistance assay
for detecting alterations in immune system function in wild cotton rats (Sigmodon
hispidus). The ability of the assay to detect immunosuppression was evaluated by
inducing immunosuppression chemically (cyclophosphamide or dexamethasone) and by
protein malnutrition. The estimated lethal dose of S. agalactiae that killed 50%
of challenged animals (LD50) was 5.76x10(7) colony-forming units (CFUs). Although
bacterial agglutination titers indicated that animals developed an antibody
response when immunized, immunization was not sufficient to adequately protect
animals from a subsequent pathogenic challenge. Sensitivity of the host
resistance assay was only suitable for detecting substantial immunosuppression,
such as that induced by protein malnutrition or dexamethasone administration.
PMID- 10787105
TI - Strychnine alkaloid and avian reproduction: effects occur at lower dietary
concentrations with mallard ducks than with bobwhite quail.
AB - Separate subchronic reproductive toxicity studies were conducted using mallard
ducks (Anas platyrhynchos) and northern bobwhite quail (Colinus virginianus).
Three groups (32/group; 16 male-female pairs) of 17-week-old ducks (F0
generation) were fed Purina Game Bird Breeder Layena diets containing mean (+/
SD) 33.2 (+/-2.7), 68.9 (+/-1.8), and 140.9 (+/-5.1) microg/g strychnine for 20
weeks, with some pairs in each group fed control diet during a subsequent 3-week
recovery period. Three groups (32/group; 16 male-female pairs) of 19-week-old
quail (F0 generation) were fed similar diets containing mean (+/-SD) 279.2 (+/
10.1), 557.4 (+/-43.5), and 1,113.6 (+/-46.6) microg/g strychnine for 22 weeks
without a recovery period. Separate groups of ducks and quail (32/group; 16 male
female pairs) were also fed control diets (0.0 microg/g strychnine) in each
study. There were 16 weekly collections of eggs for the mallard study (13 for the
diet-exposure period and 3 for the recovery period), and 11 collections for the
quail study. Eggs laid during the last 13 and 10 weeks of the diet-exposure
periods for ducks (plus 3 weeks of the recovery period) and quail, respectively,
were incubated. Each hatch of F1 generation ducklings and chicks was observed for
14 days. Key results were: (1) the no observed adverse effect levels (NOAELs) for
F0 ducks and quail were 33.2 and 1,113.6 microg/g strychnine, respectively--quail
showed no reproductive effects at the current doses; (2) decreased egg production
and hatching success occurred for mallard hens fed mean 140.9 microg/g strychnine
diets; and (3) "normal-hatching" ducklings from eggs of F0 mallards fed mean
140.9 microg/g strychnine diets suffered greater mortality than ducklings from
the other diet groups. Possible mechanisms of strychnine action on avian
reproduction are discussed.
PMID- 10787107
TI - Malathion deposition, metabolite clearance, and cholinesterase status of date
dusters and harvesters in California.
AB - Date gardens in the Coachella Valley in California typically receive multiple
treatments of malathion to control major insect pests. Variable amounts of
malathion dust retention by skin and clothing and individual work behaviors limit
the usefulness of clothing as an exposure dosimeter in date dusters and
harvesters. To determine malathion absorption in workers, urine clearance of
dimethyl phosphates (alkyl phosphates; AP) and malathion mono- (MCA) and di-
(DCA) acids were estimated from date dusters (loaders/applicators) and harvesters
(both on ground and high in trees). A series of self-administered doses of
malathion were either ingested in gelatin capsules or applied to the volar
surface of the forearm to guide biomonitoring. Each of the dimethyl phosphates
(dimethylthio> dimethyldithio > dimethyl-) and both malathion mono- and diacids
were present in urine as soon as 2-3 h of work. On a micromole basis
dimethylthiophosphate and the malathion acids (MCA > DCA) were the most prominent
metabolites in urine. Applicator exposures ranged from 95-210 mg equivalents per
day (1-3 mg/kg-day). Harvester exposures ranged from 1-270 microg/kg-day. Mid
season Monday morning urine specimens before work contained low or unmeasurable
levels of malathion acids, indicating that malathion is rapidly metabolized and
cleared from the body in the urine. Saliva was not useful for biomonitoring. No
inhibition of cholinesterase activity was measured in any members of two separate
crews of harvesters who had previous prolonged dust exposure (1 and 2 months).
PMID- 10787108
TI - Therapeutic options in dementia.
AB - Dementia is the final common path of various pathogenetic mechanisms that may
lead to a number of different clinical forms, with primary degenerative and
vascular dementias accounting for more than 80% of cases. Dementia is a complex
clinical condition that includes cognitive, personality, and behavioral changes.
Therefore a therapeutic approach to dementia should be based from the beginning
on a comprehensive intervention plan, both pharmacological and
nonpharmacological. This should not be aimed at obtaining a complete (impossible)
recover but at achieving the best day-to-day management of a chronic,
progressive, disabling disease involving numerous domains and showing impairments
with varying rates of progression. Deterioration in functional abilities of daily
living has a major impact on the quality of life of those suffering from
dementia, and this is a critical predictor for institutionalization. Increasingly
necessary for optimizing intervention strategies are studies to: (a) measure
changes in functional abilities over the course of dementia (namely Alzheimer's
disease), (b) evaluate the relationship between functional abilities and
cognition, and (c) quantify the effect of various therapeutic approaches on
functional decline. Symptomatic drugs affecting cognitive abilities and
psychoactive drugs for behavioral disturbances should be considered. For the
cognitive domain positive results have been obtained with acetylcholinesterase
inhibitors. Among the psychoactive drugs indicated for behavioral disorders,
significant improvement in terms of both efficacy and tolerability can be
expected from the use of new antipsychotic drugs.
PMID- 10787109
TI - Distal myopathies.
AB - Distal myopathies are classified according to clinical, histopathological, and
genetic patterns into the following: late adult onset type 1, or Welander
myopathy, the first recognized distal myopathy with autosomal dominant
inheritance and very recently linked to chromosome 2p; late adult onset type 2,
or Markesbery-Griggs/Udd myopathy, autosomal dominant with linkage to chromosome
2q; early adult onset type 1, or Nonaka myopathy, an autosomal recessive disease
linked to 9p1-q1 and considered indistinguishable from hereditary inclusion body
myopathy; early adult onset type 2, or Miyoshi myopathy, with autosomal recessive
inheritance linked to chromosome 2p12-p14; and early adult onset type 3, or Laing
myopathy, autosomal dominant with linkage to chromosome 14. Very recently,
dysferlin, a novel skeletal muscle gene, has been found mutated in Miyoshi
myopathy and also in the limb girdle muscular dystrophy 2B, a disease with a
completely different phenotype. This indicates that the classification of the
distal and other genetically determined muscle diseases will probably change when
these myopathies are understood at the molecular level. For example, it would be
reasonable to use the term dysferlinopathies to describe all the diseases due to
dysferlin mutations.
PMID- 10787110
TI - Genomic HLA profiles of MS in Hokkaido, Japan: important role of DPB1*0501
allele.
AB - The polymorphism of the HLA class II genes was investigated in 97 patients with
multiple sclerosis (MS) in Hokkaido, the northernmost main island of Japan. Of
these, 80 patients were classified as having conventional MS and 17 as having
opticospinal MS (OS-MS). Our findings confirmed a previous report that the DPB
1*0501 allele is positively associated with OS-MS (P = 0.0043). The frequency of
DPB 1*0501 was also found to be higher in conventional MS patients than in
controls (79% vs. 58%, P = 0.0084), although the differences were not
statistically significant. Our results indicate that OS-MS is a DPB 1*0501
associated subgroup of MS, and that DPB1*0501 is also correlated with risk of
conventional MS in Japanese.
PMID- 10787111
TI - Antisaccades and remembered saccades in mild traumatic brain injury.
AB - The most common site of focal lesions after mild traumatic brain injury (MTBI) is
the frontal lobe. This lobe, however, is difficult to examine clinically.
Neuroimaging is not performed routinely and usually shows normal results in
uncomplicated trauma. Antisaccades (AS) and remembered saccades (RS) are neuro
ophthalmological tests of frontal function. This study examined whether there are
disturbances of latency time or error rate of AS and RS in patients within 24 h
after MTBI. Eye movements were studied with infrared-oculography. Data were
obtained prospectively from 25 patients. An additional group of 6 patients with
MTBI and alcohol intoxication were also examined. No statistical differences in
AS or RS, either for errors or for latency time, were found between a group of
age-matched controls and the patients, except in the group of alcohol-intoxicated
MTBI patients. Our findings indicate that visual reflex inhibition and initiation
of voluntary saccades were not disturbed in the nonintoxicated patients. It is
hypothesized that the responsible frontal area was not affected. It is concluded
that error rate and latency time of AS and RS are inappropriate measures for
evaluating acute MTBI.
PMID- 10787112
TI - Placebo effect in the acute treatment of migraine: subcutaneous placebos are
better than oral placebos.
AB - We carried out a meta-analysis of 22 trials to determine the comparative placebo
effect of (a) subcutaneous vs. oral and (b) in-hospital vs. at-home
administration in the treatment of migraine. The headache relief rates were
combined from the placebo arms of these randomised clinical trials assessing the
value of sumatriptan in acute treatment of migraine. The main outcome measure was
the proportion of patients reclassified from severe or moderate headache severity
to no or mild headache severity 2 h after the beginning of treatment. In the oral
regimen 222 of 865 patients (25.7%) reported no or mild headache severity after 2
h, compared to 279 of 862 patients (32.4%) of those receiving subcutaneous
placebo (6.7% difference; 95% CI 2.4-11.0%). Adjusting for treatment setting and
severity of headache at baseline did not change the observed difference. After
placebo treatment at home 285 of 1,054 patients (27.0%) reported no or mild
headache severity after 2 h, compared to 216 of 673 patients (32.1%) among those
receiving placebo in hospital (5.1 % difference; 95% CI 0.6-9.5%). When adjusted
for route of administration and severity of headache at baseline, the difference
in relief rates between home and hospital setting disappeared. These findings
indicate that subcutaneous administration enhances the placebo effect of acute
treatment of migraine. Future trials of antimigraine drugs assessing the relative
efficacy of various routes of administration should use a double-dummy technique.
The interpreting of placebo-controlled trial results must therefore consider that
the effect in the drug arm of the trial depends in part on the route of
administration.
PMID- 10787113
TI - Neurophysiological features of fasciculation potentials evoked by transcranial
magnetic stimulation in amyotrophic lateral sclerosis.
AB - We report 13 patients with amyotrophic lateral sclerosis in whom fasciculation
potentials (FPs) driven by transcranial magnetic stimulation (TMS) were recorded.
A total of 18 different FPs were analyzed. TMS-driven fasciculations had a simple
morphology and were stable. Complex potentials were never cortically driven.
Recruitment by a slight voluntary contraction was verified in 7 of 13 tested FPs.
FPs were driven by threshold stimuli in 7 of 10 patients and by stimuli 5% below
threshold in 3 of 6. Mapping demonstrated that FPs were driven in an area close
to the center of gravity of the muscle cortical area. In one case FPs were evoked
from most of the cortical representation area of a very weak muscle. Three other
patients with profuse fasciculations associated with other clinical conditions
were also studied. No TMS evoked fasciculation was observed in this group. The
results of this systematic study suggest that cortically evoked FPs arise
centrally, at spinal cord or even more proximally, and can represent a marker of
increased corticomotor excitability, which is predominant at an earlier phase but
can persist as the disease progresses.
PMID- 10787114
TI - Quality of life in patients with axonal polyneuropathy.
AB - "Quality of life" (QOL) measurement reflects the impact of a disease on the daily
life of a patient, and this can be used as an outcome measure in clinical trials.
QOL measurements are rarely used in patients with neuromuscular disease. The aim
of this study was to determine whether QOL is reduced in chronic polyneuropathy,
whether there is a relationship between QOL and objective measures of disease
severity, and whether measuring QOL is a useful addition to the assessment of
severity of polyneuropathy. We measured QOL in 90 patients with chronic axonal
polyneuropathy (33 with hereditary motor and sensory neuropathy type II and 57
with chronic idiopathic axonal polyneuropathy) using the RAND 36-item Health
Survey questionnaire (RAND-36). We compared the results with the QOL of a
reference population, with summed motor and sensory scores, and with the Rankin
scale for handicap. Patients had worse scores than the reference population on
seven of eight areas of the RAND-36. Patients with both low motor and low sensory
scores rated lower in physical and emotional areas than less impaired patients. A
low Rankin score was related only to physical domains. We conclude that in
patients with chronic axonal polyneuropathy the severity of disease can be
assessed with a general QOL instrument, and that this provides additional
information, particularly on areas related to emotional and social functioning.
PMID- 10787115
TI - Constantin von Monakow's formative years in Pfafers.
AB - Constantin von Monakow was the first professor of neurology in Switzerland and
founder of the Swiss Neurological Society and of the Swiss Archives of Neurology
and Psychiatry. He gained worldwide reputation as a neuroscientist mainly through
his monumental work on neuropathology and cortical localization. His concept of
diaschisis has been verified only in recent years by modern network concepts and
imaging techniques. The basis of his work was developed with ingenious animal
experiments and careful clinico-pathological comparisons during his early years,
which he spent as assistant physician in the psychiatric clinic at St.
Pirminsberg in Pfafers, Canton St. Gallen, Switzerland from 1878 to 1885.
PMID- 10787116
TI - Progressive supranuclear palsy: earlier age of onset in patients with the tau
protein A0/A0 genotype.
AB - Genetic studies have detected an association between the presence of the tau gene
A0 allele and patients with progressive supranuclear palsy (PSP). This study
examined whether patients with this polymorphism exhibit distinct demographic or
clinical characteristics. We studied 26 patients who fulfilled clinical criteria
for the diagnosis of PSP, 20 who had the A0/A0 genotype and 6 who had other
genotypes. A questionnaire on demographic data, past medical history, familial
history, and initial symptoms was completed as part of the consultation. A
complete neurological examination was performed and PSP symptoms were quantified
following Golbe's PSP disability scale. We found a significant difference in the
age at onset of PSP symptoms, which was 65.9 +/- 5.3 years in the A0/A0 group and
71.2 +/- 5.6 in the non-A0/A0 group (P = 0.016). There were no significant
differences in the years from disease onset between the two groups. Symptom
severity did not differ significantly in patients with the different A0/A0
genotypes. The detection of significantly lower age at onset with the A0/A0
alleles is consistent with the known association of this genotype as a risk
factor for PSP. No significant differences were detected in symptom severity
between the two groups of patients.
PMID- 10787117
TI - Managing the therapeutic dilemma: patients with spontaneous intracerebral
hemorrhage and urgent need for anticoagulation.
AB - Physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke
requiring long-term, high-intensity anticoagulants because this treatment
increases the risk of intracranial hemorrhage (ICH) 8- to 11-fold. We
retrospectively studied 15 patients with ICH which occurred under anticoagulation
with phenprocoumon, with an international norrmalized ratio (INR) of 2.5-6.5 on
admission. Hemispheric, thalamic, cerebellar, intraventricular, or subarachnoid
hemorrhage without aneurysm occurred. Absolute indications for anticoagulation
were double, mitral, or aortic valve replacement, combined mitral valve failure
with atrial fibrillation and atrial enlargement, internal carotid artery-jugular
vein graft, frequently recurring deep vein thrombosis with risk of pulmonary
embolism, and severe nontreatable ischemic heart disease. As soon as the
diagnosis of ICH was established, INR normalization was attempted in all patients
by administration of prothrombin complex, fresh frozen plasma, or vitamin K.
After giving phenprocoumon antagonists (and neurosurgical therapy in four
patients) heparin administration was started. Nine patients received full-dose
intravenous and six low-dose subcutaneous heparin. The following observations
were made: (a) All patients with effective, full-dose heparin treatment with a
1.5- to 2-fold elevation in partial thromboplastin time after normalization of
the INR were discharged without complication. (b) Three of four of the patients
with only incomplete correction of the INR (> 1.35) experienced relevant
rebleeding within 3 days (all patients with an INR higher than 1.5), two of whom
were on full-dose heparin. (c) Three of seven of the patients with normalized INR
and without significant PTT elevation developed severe cerebral embolism.
Although our data are based on a retrospective analysis, they support treatment
with intravenous heparin (partial thromboplastin time 1.5-2 times baseline value)
after normalization of the INR in patients with an ICH and an urgent need for
anticoagulation.
PMID- 10787119
TI - Bickerstaff's brainstem encephalitis associated with shingles.
PMID- 10787118
TI - Idiopathic autonomic neuropathy associated with esophageal dilatation.
PMID- 10787120
TI - Localized lipoatrophy after prolonged treatment with copolymer 1.
PMID- 10787121
TI - Involvement of the visual pathway in hereditary neuropathy with liability to
pressure palsies.
PMID- 10787122
TI - Multifocal cerebral demyelination after magic mushroom abuse.
PMID- 10787123
TI - Evidence of diffuse brain pathology and unspecific genetic characterization in a
patient with an atypical form of adult-onset Krabbe disease.
PMID- 10787124
TI - Autonomic failure preceding dementia with Lewy bodies.
PMID- 10787125
TI - Diffusion magnetic resonance imaging findings in cerebritis and brain abscesses
in a patient with septic encephalopathy.
PMID- 10787126
TI - Andre-Thomas (1867-1963).
PMID- 10787127
TI - Nogo-A is the inhibitor of CNS axon regeneration.
PMID- 10787128
TI - Occupational and environmental medicine in Colombia.
AB - Colombia is a country rich in natural resources, with a steadily developing
economy. Occupational and environmental medicine (OEM) education and practice
have developed relatively recently in Colombia, mainly in response to a series of
long overdue (and still partially implemented) reforms to the health care, social
benefits, and education systems. Expansion in general and occupational health
coverage of the Colombian population and development of OEM education and
training were to be achieved through a clear stimulus to private sector
initiatives. Despite some measurable overall progress, the goals remain elusive.
This article discusses several aspects and the perspectives for further
development of the specialty in this country, in the context of the socioeconomic
factors involved in that process.
PMID- 10787129
TI - Pathophysiology and classification of the vibration white finger.
AB - Skin, arteries and nerves of the upper extremities can be affected by vibration
exposure. Recent advances in skin and vascular biology as well as new
investigative methods, have shown that neurovascular symptoms may be due to
different vascular and neurological disorders which should be differentiated if
proper management is to be evaluated. Three types of vascular disorder can be
observed in the vibration white finger: digital organic microangiopathy, a
digital vasospastic phenomenon and arterial thrombosis in the upper extremities.
An imbalance between endothelin-1 and calcitonin-gene-related peptide is probably
responsible for the vasospastic phenomenon. Moreover, paresthesiae can be due to
either a diffuse vibration neuropathy or a carpal tunnel syndrome. A precise
diagnosis is then necessary to adapt the treatment to individual cases. A
classification describing the type and severity of the vascular lesions is
presented. Asymptomatic lesions are included for adequate epidemiological studies
and risk assessment of vibrating tools. Monitoring of vibration exposed workers
should include not only a questionnaire about symptoms, but also a clinical
evaluation including diagnostic tests for the screening of early asymptomatic
neurovascular injuries.
PMID- 10787130
TI - Fractionation of nickel species from airborne aerosols: practical improvements
and industrial applications.
AB - Presently recommended methods for fractionation of airborne nickel dusts are
laborious and time-consuming. A new method has been developed based on existing
procedures of leaching nickel fractions from sample filters, and based on the
principles of flow-injection analysis. A special sample filter holder has been
constructed to be used in conjunction with the flow-injection system. In this
system, soluble nickel compounds are extracted from the filter with ammonium
citrate buffer, sulphidic nickel by peroxycitric acid, and metallic nickel by
CuCl2/KCl. The final dissolution of the filter by HNO3/HCl results in the oxidic
fraction. Endpoint determination of these fractions is performed by use of
graphite-furnace atomic absorption spectrometry (GF-AAS). The analytical criteria
of this method have been established, and the suitability of the method for
application in the practice of industrial hygiene has been demonstrated.
PMID- 10787131
TI - Correlation between urine and blood concentrations, and dietary intake of cadmium
and lead among women in the general population of Japan.
AB - OBJECTIVE: To examine whether lead (Pb) in urine and cadmium (Cd) in blood,
especially the former, can be used as markers of environmental exposure of
general populations to these metals. METHODS: Between 1991 and 1998, spot urine
and peripheral blood samples, together with 24 h duplicates of food intake were
collected from 607 non-smoking adult women in 30 survey sites (SS) in seven
administrative regions all over Japan. Urine, blood and food duplicate samples
were analyzed by inductively-coupled plasma spectrometry, for Cd and Pb in urine
(Cd-U and Pb-U), in blood (Cd-B and Pb-B) and in food duplicates (Cd-F and Pb-F).
Correlation between the measurements was examined by regression analysis.
RESULTS: The Cd-B correlated closely with Cd-U, and both Cd-B and Cd-U with Cd-F,
on an individual basis (n = 607), on an SS basis (n = 30) and on a regional basis
(n = 7). The Pb-U however did not correlate with Pb-B on a regional basis
although they correlated with each other when analyzed on an individual as well
as SS basis. Moreover, the correlation coefficients between Pb-U and Pb-B were
much smaller than those between Cd-U and Cd-B. Neither Pb-U nor Pb-B showed
significant correlation with Pb-F on any levels of statistical analysis.
CONCLUSIONS: Both Cd-B and Cd-U can be employed as biomarkers of environmental Cd
exposure. The reliability of Pb-U for use in place of Pb-B appeared to be small.
PMID- 10787132
TI - Risk of lung cancer in workers producing stainless steel and metallic alloys.
AB - OBJECTIVES: The mortality of workers involved in the production of stainless and
alloyed steel from 1968 to 1992 was studied, in order to investigate the risk of
lung cancer due to exposure to metals, i.e. iron oxides, chromium and/or nickel
compounds. METHODS: The study design was a historical cohort mortality study and
a nested case-control study concerning lung cancer. Standardized mortality ratios
(SMRs) were computed using regional mortality rates as an external reference for
comparing observed and expected numbers of deaths, adjusting for age, sex and
calendar time. Conditional logistic regression was used to estimate odds ratios
(ORs). Occupational exposure was assessed through the complete job histories of
cases and controls and a specific job-exposure matrix. RESULTS: The cohort
comprised 4,288 male and 609 female workers. The observed overall mortality was
significantly lower than expected [649 deaths; SMR = 0.91; 95% confidence
interval (CI) 0.84-0.98]. No significant SMR was observed for mortality from lung
cancer (54 deaths; SMR = 1.19; CI 0.88-1.55). The case-control study was based on
54 cases and 162 individually matched controls. Smoking habits were available for
71%. No lung cancer excess was observed for exposure to (1) metals and/or their
compounds, i.e. iron (OR = 0.94, CI 0.48-1.86), chromium and/or nickel (OR =
1.18, CI 0.62-2.25), and cobalt (OR =0.64, CI 0.33-1.25), (2) acid mists (OR =
0.43, CI 0.17-1.10), and (3) asbestos (OR = 1.00, CI 0.54-1.86). With respect to
exposure to polycyclic aromatic hydrocarbons (PAHs) and silica, which are often
found together in workplaces, (1) high and statistically significant lung cancer
excesses were observed, the ORs being 1.95 (CI 1.03-3.72) and 2.47 (CI 1.28-4.77)
respectively, (2) quantitative exposure parameters revealed upward trends
reaching statistical significance (P < 0.05), and (3) adjustments for tobacco
consumption did not reveal any confounding factors from smoking. CONCLUSION: This
study failed to detect any relationship between lung cancer and exposure to iron,
chromium, nickel and/or their compounds. High and statistically significant
relative risks, along with increasing trends, were observed for simultaneous
exposure to PAHs and silica.
PMID- 10787133
TI - Challenge from methacholine, natural rubber latex, or 4,4-diphenylmethane
diisocyanate in workers with suspected sensitization affects exhaled nitric oxide
[change in exhaled NO levels after allergen challenges].
AB - OBJECTIVE: Nitric oxide (NO) levels in the exhaled air of asthmatic patients have
been shown to be increased. This observation has also been reported in workers
who are allergic to laboratory animals. To determine if a challenge test with
natural rubber latex (NRL) or 4,4'-diphenylmethane diisocyanate (MDI) would also
produce an increase of NO exhalation in sensitized patients, we carried out this
study. METHODS: Nine subjects with suspected occupational asthma were exposed to
MDI, and 18 took part in a challenge test with gloves powdered with NRL. Nineteen
subjects underwent a challenge test with methacholine (MCh). Exhaled NO was
measured by a modified chemiluminescence analyzer according to the European
Respiratory Society guidelines. RESULTS: We found that there was a decrease in
exhaled NO concentrations 16-18 h after MCh challenge testing and subsequent
bronchodilation with salbutamol, in three subjects. Three of nine participants
had a significant immediate bronchial obstruction after exposure to MDI, of those
three, two had MDI-specific IgE antibodies. After 22 h, their levels of exhaled
NO had increased > 10 parts per billion (ppb). Eight of the 18 subjects
participating in the NRL challenge test displayed an NO concentration increase of
at least 10 ppb after 22 h (seven had NRL-specific IgE antibodies). A significant
decrease in the one-second forced expiratory volume (FEV1) was documented in four
of those eight participants after NRL challenge. CONCLUSIONS: There was no clear
relationship between bronchial response, substance-specific IgE antibodies and an
increase in exhaled NO levels. However, there was a tendency for subjects with
substance-specific IgE antibodies and bronchial reaction to develop an increase
in exhaled NO concentration. Further studies are needed to determine if analysis
of NO from the lower respiratory tract can become a useful non-invasive tool for
detecting lower airway inflammatory response even before clinical symptoms occur.
PMID- 10787134
TI - Improvement of thermophysiological stress in participants wearing protective
clothing for spraying pesticide, and its application in the field.
AB - Thermoregulatory responses were compared under two experimental conditions, in
the laboratory (Experiment I), and in the field (Experiment II), between two
kinds of protective clothing for spraying pesticides. One was currently being
used (Type A), and was composed of ready made Gore-Tex clothing, mask,
polyurethane gloves and rubber boots. The other one was newly designed (Type B),
and was composed of pesticide-proof clothing (100% cotton with water repellent
finish), mask, Gore-Tex gloves, and special boots consisting of rubber for the
feet and ankle and Gore-Tex around the legs. In addition, the head and chest were
cooled by frozen gel strips fixed in the cap and undershirt. In Experiment I,
five female adults took part, in a climate-chamber controlled at an ambient
temperature of 28 degrees C and a relative humidity of 60%. In Experiment II,
five farmers (one male and four female) were tested in an apple orchard in July,
August and September. The main results are summarized as follows: (1) change of
rectal temperature was inhibited more effectively in Type B in Experiment I, (2)
change of heart rate tended to be lower in Type B than in Type A in both
experiments, (3) salivary lactic acid concentration at the end of the first
exercise was significantly higher in Type A than in Type B in Experiment I, (4)
the number of contractions in the handgrip exercise which was performed
immediately after the third exercise, was significantly smaller in Type A than in
Type B in Experiment I, (5) subjective comfort sensation was significantly
improved in Type B in Experiments I and II. Thus, it was concluded that the newly
designed protective clothing could reduce thermal stress during the spraying of
pesticides in an apple orchard in summer.
PMID- 10787135
TI - Methylmercury exposure affects motor performance of a riverine population of the
Tapajos river, Brazilian Amazon.
AB - Gold mining and deforestation in the Brazilian Amazon are increasing mercury
pollution of the extensive water system, exposing riverine populations to organic
mercury through fish-eating. The aim of the present study was to evaluate the
effect of such exposure on motor performance. This cross-sectional study was
carried out in May 1996, in a village located on the banks of the Tapajos river
in the Amazonian Basin, Brazil. Information concerning sociodemographics, health,
smoking habits, alcohol drinking, dietary habits and work history were collected
using an interview-administered questionnaire. Mercury concentrations were
measured by cold vapor atomic absorption in blood and hair of each participant,
of whom those aged between 15 and 79 years were assessed for motor performance (n
= 84). Psychomotor performance was evaluated using the Santa Ana manual dexterity
test, the Grooved Pegboard Fine motor test and the fingertapping motor speed
test. Motor strength was measured by dynamometry for grip and pinch strength.
Following the exclusion of 16 persons for previous head injury, working with
mercury in the goldmining sites, or for diabetes, the relationship between
performance and bioindicators of mercury was examined using multivariate
statistical analyses, taking into account covariables. All participants in the
study reported eating fish, which comprised 61.8% of the total meals eaten during
the preceding week. The median hair total mercury concentration was 9 microg/g.
Organic mercury accounted for 94.4 = 1.9% of the total mercury levels.
Multivariate analysis of variance indicated that hair mercury was inversely
associated with overall performance on the psychomotor tests, while a tendency
was observed with blood mercury. Semipartial regression analyses showed that hair
total mercury accounted for 8% to 16% of the variance of psychomotor performance.
Neither hair nor blood total mercury was associated with the results of the
strength tests in women and men. Although dose-effect relationships were observed
in this cross-sectional study, they may reflect higher exposure levels in the
past. The findings of this study demonstrated neurobehavioral manifestations of
subtle neurotoxic effects on motor functions, associated with low-level
methylmercury exposure.
PMID- 10787136
TI - Miscarriages and stillbirths in women with a high intake of fish contaminated
with persistent organochlorine compounds.
AB - OBJECTIVES: The purpose of the present study was to assess the effect, on
miscarriages and stillbirths, of persistent organochlorine compounds (POC)
through dietary intake of fatty fish from the Baltic Sea. METHODS: Information on
miscarriages and stillbirths was collected retrospectively by a self-administered
questionnaire in a cohort of fishermen's wives from the Swedish east coast (by
the Baltic Sea) and in a referent cohort of west coast fishermen's wives. Current
fish consumption was used as a proxy for exposure within the east coast cohort.
RESULTS: No increase in miscarriages or stillbirths was found in the east coast
cohort compared with the west coast group, in fact a decrease in early
miscarriages was found (OR 0.48 [95% CI 0.26-0.92]). Moreover, no increase in
risk was found for current high consumers of fatty fish within the east coast
cohort. CONCLUSIONS: The present data provided no evidence that dietary POC
exposure increases miscarriage and stillbirth rates.
PMID- 10787137
TI - Dust exposure in Munich public transportation: a comprehensive 4-year survey in
buses and trams.
AB - OBJECTIVES: Published data obtained from outdoor stationary sampling stations
cannot be applied directly to the exposure situation in vehicles. The aim of this
study, therefore, was to assess the dust exposure relevant to passengers and
drivers in public buses and trams. METHOD: In the years 1993 to 1996, PM10
samples were taken during 201 journeys of typically 4 h duration on 14 routes
(nine bus routes, five tramways) which were representative for the overall Munich
transportation system with respect to area characteristics and traffic density.
The concentrations of the samples were compared with those collected at the same
time at sampling stations of the Bavarian State Office for Environmental
Protection (OEP). Dust exposure was continuously and synchronously recorded by
means of a tyndallometric device. Traffic and passenger density, weather
conditions, special events, etc. were noted by our personnel, travelling on every
journey. RESULTS: The average PM10 dust concentration for all rides was 155
microg/m3 (single journey max. 686 microg/m3, min. 13 microg/m3). Interior
concentrations were 1.7 to 4.0 times above those collected at the static outdoor
stations. We found only minor associations between dust concentrations and
traffic density or time of day. During several journeys continuous recording
disclosed anomalies, dependence on weather conditions and cyclic track
characteristics. CONCLUSIONS: Interior PM10 particulate concentrations were
comparable to those found elsewhere in truck drivers' cabs and are in the region
of German regulative limits established for the general population's long term
outdoor exposure. Indoor concentrations were well above the values found at
stationary outdoor stations. Additional continuous recording of dust
concentrations proved to be helpful in unveiling anomalies and dependencies on
external effectors.
PMID- 10787138
TI - Litigation and the Canadian Pap test: perspectives from a single-payer system.
PMID- 10787139
TI - Fine-needle aspiration cytology findings in 214 cases of nonparotid lesions of
the head.
AB - The use and limitations of fine-needle aspiration (FNA) of lesions of the parotid
gland are known, but those of nonparotid lesions of the head have been described
only sporadically. We conducted this study to evaluate the utility of FNA and to
analyze the causes of diagnostic discrepancies for these lesions. A total of
6,898 FNAs of different sites was performed at our institutions between January
1991-August 1998, and 214 (3.1%) of the cases were FNAs of nonparotid lesions of
the head. The most common diagnosis of nonparotid lesions was squamous-cell
carcinoma, in 22% (n = 48), and the most common site aspirated was the scalp, in
34% (n = 73). Lipomas and keratinous cysts comprised 5% (n = 9) of the total. A
statistical analysis was conducted on 98 paired cytology and histology (n = 83)
and cytology and flow cytometry (n = 15) specimens (70 malignant and 28 benign).
FNA recognized the malignant and benign nature of the lesion in 60 and 26 cases,
respectively with 86% sensitivity 93% specificity and 88% accuracy. Causes of
false-negative FNA diagnoses (n = 10) included sampling error (n = 6), bloody
smears with scant cellularity (n = 3), and bland cytomorphology (n = 1). Florid
granulation tissue and a mucocele of the tongue accounted for the two false
positive cases. We conclude that FNA is an effective tool for triage of surgery
candidates with nonparotid lesions of the head. Adequate samples with sufficient
cellularity are required for avoiding false-negative diagnoses. Occasionally,
tissue biopsy is needed for diagnosis of equivocal cases.
PMID- 10787140
TI - Pre- and postresection thoracic washings in non-small cell carcinoma of the lung:
a cytological study of 44 patients without pleural effusion.
AB - The presence of malignant pleural effusion in patients with non-small cell
bronchogenic cancer has a poor prognostic significance and is indicative of
advanced disease (T4, IIIB). The present study will investigate the role of
cytology and identify the various cellular components seen in thoracic washings,
in the absence of an effusion, and will identify the potential pitfalls in
diagnosing these specimens. The sensitivity, specificity, and positive and
negative predictive values will be determined, as well as the associated
predictive factors. From November 1996 to July 1997, 96 thoracic washings were
performed on 44 patients with non-small cell carcinoma of the lung prior to and
following resection. The specimens were processed routinely. To assess the false
negative or false-positive cases, all cases were rescreened and then correlated
with the surgical pathology. Seven (15.9%) patients had positive findings
detected on the pre- and/or postresection thoracic washings. One (2.3%) patient
had a negative preresection, but cytologically atypical cells were found on the
postresection. Thirty-six (81.8%) patients had negative pre- and postresection
thoracic washings. There were no false-positive diagnoses in the study; however,
two false-negative diagnoses were made. The finding of positive cytology in 7 of
44 (15.9%) patients appears significant. Thoracic washings may provide evidence
of cancer beyond the pleura in patients without pleural effusion which may be
indicative of advanced disease.
PMID- 10787141
TI - Successful grading of renal-cell carcinoma in fine-needle aspirates.
AB - Early-stage renal-cell carcinoma is more frequently diagnosed due to more
frequent use of advanced radiologic techniques. Partial nephrectomy may be
curative for small tumors and may sometimes be necessary if the opposite kidney
is functionally compromised. This therapeutic option is however not possible in
high-grade neoplasms. In the current study, we attempted to grade cases of renal
cell carcinoma on smears obtained from preoperative fine-needle aspirates (FNA).
Eighteen cases of histologically proven renal-cell carcinoma formed the basis of
this study. FNAs were performed prior to nephrectomy. FNA smears were blindly
reviewed, and the cases were evaluated for cellularity, nuclear to cytoplasmic
(N/C) ratios, nuclear pleomorphism, and the presence of naked nuclei and
prominent nucleoli; cases were graded according to the presence or absence of
these criteria and their combination. The cases were cytologically graded from
grade I-IV and then were given a low grade if the tumor was considered grade I or
II, or high grade if the tumor was considered grade III or IV. The histology of
the neoplasms was reviewed, and the tumors were graded according to the Fuhrman
nuclear grading system. Correlation between the cytologic and histologic grades
within the same histologic grade was seen in 13 of the 18 cases (72.2%). The
difference was no more than one grade for each discrepancy. When grading as high
or low grade was used, agreement was seen in 100% of the cases. The most reliable
cytologic features seen on cytology distinguishing low- from high-grade tumors
were the N/C ratio and the presence or absence of nucleoli. Pleomorphism, naked
nuclei, and increased cellularity were less distinguishing features. We conclude
that grading of renal-cell carcinoma can be reliably achieved in FNA material.
Preoperative FNAs can thus be performed on small renal neoplasms with subsequent
conservative treatment if the tumor proves to be low grade.
PMID- 10787142
TI - Cytology of columnar-cell variant of papillary thyroid carcinoma.
AB - Columnar cell variant of papillary carcinoma (CCV-PC) thyroid is a rare and
aggressive tumor composed of tall columnar cells that form papillae, glands and
solid structures. This paper describes fine needle aspiration (FNA) cytologic
features in a case of CCV-PC occurring in the right thyroid lobe of a 27-year-old
female. Smears showed tall columnar cells in monolayered, three-dimensional,
acinar and occasional papillary clusters. Nuclei were oval or elongated and
monomorphic. Nuclear pseudostratification, resembling that seen in respiratory
epithelial cells, was present in some of the cell clusters. Occasional cells
showed squamous or Hurthle cell metaplasia. Nuclear grooves and intranuclear
cytoplasmic inclusions were not seen. Sections of the right lobectomy specimen
showed an well-encapsulated CCV-PC with capsular and vascular permeation. Tall
cell variant of papillary carcinoma (TCV-PC) can be distinguished from CCV-PC by
the oxyphilia of the tumor cells and the absence of nuclear pseudostratification.
Colorectal and endometrial adenocarcinomas metastatic to the thyroid may be
difficult to distinguish from CCV-PC.
PMID- 10787143
TI - Cytologic demonstration of "dysplastic" follicular dendritic cells in a case of
hyaline-vascular Castleman's disease.
AB - Large atypical follicular dendritic cells, considered dysplastic by some authors,
were first described in association with Castleman's disease in 1991, but until
now there has been no cytologic account regarding these cells. We report the
cytologic and histologic findings of a case of hyaline-vascular Castleman's
disease associated with "dysplastic "follicular dendritic cells which presented
as a mediastinal mass in a young man. The presence of giant cells within the
preoperative fine-needle aspirate specimen caused initial diagnostic uncertainty
and their true nature was only confirmed retrospectively following application of
an immunostain for CD21 to direct smears. Awareness of "dysplastic" follicular
dendritic cells within aspirates of Castleman's disease will result in less
cytological confusion in the future and may help to avoid the possibility of
misdiagnosing Hodgkin's lymphoma which has certain cytologic similarities.
PMID- 10787144
TI - Fetal rhabdomyomatous nephroblastoma: diagnosis by fine-needle aspiration
cytology--a case report.
AB - The present report describes the case of a 21-mo-old boy with a fetal
rhabdomyomatous nephroblastoma (FRN) diagnosed by fine-needle aspiration cytology
(FNAC). The smears contained numerous isolated or clustered, deeply eosinophilic,
thin, elongated rhabdomyoblasts with oval nuclei. Some of these cells presented
cross-striations. Peculiar clusters of small, deeply eosinophilic, round cells
with and without rounded nuclei in a mosaic pattern were interpreted as
representing transversally oriented rhabdomyoblasts. Fetal rhabdomyoblasts were
by far the predominant type of cell. Histology of the surgical specimen proved
90% of the mass to be constituted of fetal rhadomyomatous tissue. Adequate
recognition of FRN is useful for the planning of treatment.
PMID- 10787146
TI - Malignant phyllodes tumor metastatic to the forearm: a case report.
AB - We describe the cytological features of a malignant phyllodes tumor, in a 40-yr
old female, that metastasized to the forearm, and we correlate these findings
with the criteria suggested by other authors for predicting the clinical and
metastatic behavior of this tumor. The diagnosis of metastasis was based on fine
needle aspiration (FNA) cytology. One year prior, the patient had undergone
mastectomy of the left breast for malignant phyllodes tumor, as proven by
histopathology. The patient then presented with right forearm swelling, 1 yr
later. FNA cytology was performed, and the diagnosis was metastatic malignant
phyllodes tumor. Histologic review of the breast tumor revealed stromal
overgrowth, which is the most important histologic criterion for predicting the
metastatic behavior of malignant phyllodes tumor as reported by some authors.
PMID- 10787145
TI - Fine-needle aspiration of a follicular dendritic-cell tumor: report of a case and
review of the literature.
AB - Follicular dendritic-cell tumors (FDCT) are rare neoplasms, well-characterized in
surgical pathology material. There are, however, few cytopathology reports. We
describe the fine-needle aspiration (FNA) findings of a histologically confirmed
FDCT. Conventional smears and a cell block showed large spindle to oval
neoplastic cells admixed with small mature lymphocytes. The neoplastic cells were
present mainly in small syncytial clusters. Immunostains for CD21 and CD35,
performed on the cell block, were positive in the neoplastic cells. The diagnosis
was fully confirmed by the presence of typical immunohistochemical and
ultrastructural features on the surgically removed tumor. The differential
diagnosis of FDCT is broad and includes other tumors characterized by an
admixture of large neoplastic cells and small mature lymphocytes, such as
thymomas, lymphoepithelioma-like carcinomas, and interdigitating dendritic-cell
tumors. It may not be possible to diagnose FDCT based on FNA material without the
use of immunocytochemical and electron microscopic studies. Certain
cytomorphological characteristics, however, might suggest its diagnosis and allow
the practicing cytopathologist to perform confirmatory studies.
PMID- 10787147
TI - A case of amelanotic spindle-cell melanoma presenting as metastases to breast and
axillary lymph node: diagnosis by FNA cytology.
AB - Metastatic neoplasms to the breast are relatively rare. Spindle-cell lesions of
the breast are also uncommon. Here we present a case of fine-needle aspiration
(FNA) of an amelanotic, spindle-cell melanoma metastatic to the breast and
axillary lymph node. The patient was a 47-yr-old female who presented with a
right breast mass, left axillary adenopathy, and a pigmented skin lesion on the
back. FNA of the right breast and left axilla showed malignant, nonpigmented
spindle cells that were weakly positive for HMB-45 on immunocytochemistry. The
skin biopsy showed a pigmented malignant melanoma with epithelioid features, and
also weak positivity for HMB-45. Although malignant melanoma is one of the more
common tumors to metastasize to the breast, this is the first known case that
showed exclusive spindle-cell morphology. History and physical examination were
crucial in making the correct FNA diagnosis. The cytologic differential diagnosis
of spindle-cell tumors of breast and the discordant morphology between the
primary and metastatic melanotic lesions observed in this case are discussed.
PMID- 10787148
TI - Fine-needle aspiration cytology of mesenchymal hamartoma of the liver.
AB - The cytologic appearance of mesenchymal hepatic hamartoma in a 2-yr-old boy is
described. Smears disclosed small groups and isolated, benign-appearing spindle
cells admixed with scarce amounts of myxoid stroma and normal ductal cells and
hepatocytes. Although the findings were nonspecific, cytology may rule out many
other diagnostic possibilities and increases the preoperative capacity of
clinical and image studies, leading to a more rational therapeutic decision.
PMID- 10787149
TI - Freeze-drying method for stable preservation in cellular specimens for the
detection of apoptotic cells.
AB - We describe a method of cytologic specimens for the detection of apoptotic cells
by immunostaining after long-term storage (>6 mo) using TdT-mediated dUTP-biotin
nick end labelling (TUNEL) technique. The application of the TUNEL method on
freeze-drying cellular sample will eliminate the need for fresh material and will
provide several advantages.
PMID- 10787150
TI - Processing of noninflammatory synovial fluids with hyaluronidase for cytospin
preparations improves the accuracy of differential counts.
AB - Differential leukocyte counts on noninflammatory synovial fluids (NISF) are not
widely reported or used in research, apparently due to technical difficulties
related to either high viscosity or low numbers of cells. We describe an
evaluation of a technique using hyaluronidase and cytospin preparations to study
NISF. Twenty-three consecutive synovial fluids (SF) with less than 2,000 white
blood cells (WBC)/mm3 were studied either by the usual smear of a single drop or
by adding two drops of hyaluronidase (150 USP units/ml) to 0.25 cc of SF and
cytocentrifuging at 800 rpm for 10 min. Both preparations were stained with
Wright's stain. Cytospin preparations gave better morphology, and in 22/23
specimens we could count 100 cells on one slide. Smeared preparations gave dark
cells and required 2-3 slides to count 100 cells. Differential counts on the
cytospin preparations consistently showed higher percentages of monocytes,
suggesting that these cells were underdetected and misinterpreted as lymphocytes
on the routine smears. Polymorphonuclear leukocytes (PMN) were significantly less
frequent (P 0.005) in osteoarthritis (OA) fluids than in the other diseases with
NISF. Relatively more PMN may suggest consideration of a diagnosis other than OA.
Cytospin preparations of hyaluronidase-treated NISF may open up an important area
for investigation of the role of SF cells in less inflammatory diseases.
PMID- 10787151
TI - Coexistence of carcinoma of the breast with microfilariasis.
PMID- 10787154
TI - Intensity of nest defence is related to offspring sex ratio in the great tit
Parus major.
AB - Nest-defence behaviour of passerines is a form of parental investment. Parents
are selected, therefore, to vary the intensity of their nest defence with respect
to the value of their offspring. Great tit, Parus major, males were tested for
their defence response to both a nest predator and playback of a great tit chick
distress call. The results from the two trials were similar; males gave more
alarm calls and made more perch changes if they had larger broods and if they had
a greater proportion of sons in their brood. This is the first evidence for a
relationship between nest-defence intensity and offspring sex ratio. Paternal
quality, size, age and condition, lay date and chick condition did not
significantly influence any of the measured nest-defence parameters.
PMID- 10787152
TI - C-erbB-2 expression and DNA ploidy in breast cancer on fine-needle aspiration
cytology material.
PMID- 10787153
TI - Sperm velocity and longevity trade off each other and influence fertilization in
the sea urchin Lytechinus variegatus.
AB - The theoretical prediction that fast sperm should be more effective at
fertilizing eggs has never been documented empirically. Interspecific comparisons
suggest an inverse relationship between sperm velocity and sperm longevity but
this trade-off has never been demonstrated within a species. Here I investigate
how sperm velocity and sperm longevity influence the patterns of fertilization in
the sea urchin Lytechinus variegatus. In the laboratory I examined 11 male female
pairs of sea urchins for variation in sperm velocity and sperm longevity, and
determined the correlations of these traits with the percentage of eggs
fertilized with serially diluted sperm. Males with faster sperm had higher rates
of fertilization than males with slower sperm. Within individual males, as sperm
aged they slowed down and showed a reduced percentage activity and lower rates of
fertilization. Across males, the average velocity of freshly spawned sperm was
inversely related to sperm longevity. These results establish the possibility
that sperm traits are adapted for varying conditions along a continuum from sperm
limitation to sperm competition.
PMID- 10787155
TI - Sex-ratio optimization with helpers at the nest.
AB - In many cooperatively breeding animals, offspring produced earlier in life assist
their parents in raising subsequent broods. Such helping behaviour is often
confined to offspring of one sex. Sex-allocation theory predicts that parents
overproduce offspring of the helping sex, but the expected degree of sex-ratio
bias was thought to depend on specific details of female and male life histories,
hampering empirical tests of the theory. Here we demonstrate the following two
theories. (i) If all parents produce the same sex ratio, the evolutionarily
stable sex ratio obeys a very simple rule that is valid for a general class of
life histories. The rule predicts that the expected sex-ratio bias depends on the
product of only two parameters which are relatively easily measured: the average
number of helping offspring per nest and the relative contribution to offspring
production per helper. (ii) If the benefit of helping varies between parents, and
parents facultatively adjust the sex ratio accordingly, then the population sex
ratio is not necessarily biased towards the helping sex. For example, in line
with empirical evidence, if helpers are produced under favourable conditions and
parents do not adjust their clutch size to the number of helpers, then a surplus
of the non-helping sex is expected.
PMID- 10787156
TI - Parentage, reproductive success and breeding behaviour in the greater horseshoe
bat (Rhinolophus ferrumequinum).
AB - Female greater horseshoe bats form maternity colonies each summer in order to
give birth and raise young. During the mating period, females visit males
occupying territorial sites, copulation takes place and sperm are stored until
ovulation occurs, normally in April. Using microsatellite markers and a
likelihood method of parentage analysis, we studied breeding behaviour and male
reproductive success over a five-year period in a population of bats in south
west Britain. Paternity was assigned with 80% confidence to 44% of young born in
five successive cohorts. While a small annual skew in male reproductive success
was detected, the variance increased over five years due to the repeated success
of a few individuals. Mating was polygynous, although some females gave birth to
offspring sired by the same male in separate years. Such repeated partnerships
probably result from fidelity for either mating sites or individuals or from
sperm competition. Females mated with males born both within and outside their
own natal colony; however, relatedness between parents was no less than the
average recorded for male female pairs. Gene flow between colonies is likely to
be primarily mediated by both female and male dispersal during the mating period
rather than more permanent movements.
PMID- 10787157
TI - Persistence of bat defence reactions in high Arctic moths (Lepidoptera).
AB - We investigated the bat defence reactions of three species of moths (Gynaephora
groenlandica, Gynaephora rossi (Lymantriidae) and Psychophora sabini
(Geometridae)) in the Canadian Arctic archipelago. Since these moths inhabit the
Arctic tundra and, therefore, are most probably spatially isolated from bats,
their hearing and associated defensive reactions are probably useless and would
therefore be expected to disappear with ongoing adaptation to Arctic conditions.
When exposed to bat-like ultrasound (26 kHz and 110 dB sound pressure level root
mean square at 1 m) flying male Gynaephora spp. always reacted defensively by
rapidly reversing their flight course. They could hear the sound and reacted at
least 15-25 m away. Psychophora sabini walking on a surface froze at distances of
at least 5-7 m from the sound source. However, two out of three individuals of
this species (all males) did not respond in any way to the sound while in flight.
Hence, we found evidence of degeneration of bat defence reactions, i.e.
adaptation to the bat-free environment, in P. sabini but not in Gynaephora spp.
Some Arctic moths (Gynaephora spp.) still possess defensive reactions against
bats, possibly because the selection pressure for the loss of the trait is such
that it declines only very slowly (perhaps by genetic drift; and there may not
have been enough time for the trait to disappear. One possible reason may be that
Arctic moths have long generation times.
PMID- 10787158
TI - Copulatory courtship and cryptic female choice in red flour beetles Tribolium
castaneum.
AB - Males of many animal species engage in courtship behaviours during and after
copulation that appear to be solely aimed at stimulating the female. It has been
suggested that these behaviours have evolved by cryptic female choice, whereby
females are thought to impose biases on male postmating paternity success. Males
of the red flour beetle Tribolium castaneum rub the lateral edges of the females'
elytra with their tarsi during copulation. We manipulated female perception of
this behaviour by tarsal ablation in males, thus preventing males from reaching
the edge of the female elytra with their manipulated legs, and by subsequently
performing a series of double-mating experiments where the copulatory behaviour
was quantified. We found a positive relationship between the intensity of the
copulatory courtship behaviour and relative fertilization success among
unmanipulated males. This pattern, however, was absent in manipulated males,
where female perception of male behaviour differed from that actually performed.
Thus, female perception of male copulatory courtship behaviour, rather than male
behaviour per se, apparently governs the fate of sperm competing over
fertilizations within the female, showing that copulatory courtship is under
selection by cryptic female choice.
PMID- 10787159
TI - Web tuning of an orb-web spider, Octonoba sybotides, regulates prey-catching
behaviour.
AB - An uloborid spider (Oclonoba sybotides constructs two types of web which are
distinguished by linear or spiral stabilimenta. Food-deprived spiders tend to
construct webs with spiral stabilimenta and food-satiated spiders tend to
construct webs with linear stabilimenta. I experimentally examined the influence
of web type on the speed of a spider's response to small and large flies. The
results indicated that web type rather than the spiders' energetic condition
influences the response speed to small or large Drosophila flies. I also examined
whether thread tension affects the response speed of spiders by increasing the
tension of the radial threads. The results showed that spiders on an expanded web
responded to small prey as quickly as spiders on webs with spiral stabilimenta.
The tension of the radial threads may be regulated by the degree of distortion of
the radial threads at the hub. O. sybotides seems to construct orb webs which
induce different responses for smaller, less-profitable prey according to its
energetic state. The spider appears to increase the tension of the radial threads
so that it can sense smaller prey better when hungry.
PMID- 10787160
TI - Sensory compensation and the detection of predators: the interaction between
chemical and visual information.
AB - Recent evidence suggests that environmental conditions may affect whether fishes
do or do not respond to the presence of chemical alarm cues in water. We present
a simple model which suggests that the combination of risk of predation and
information from other sources will determine when fishes should react to these
chemical cues. We tested this model with a laboratory experiment which
manipulated the risk of predation by altering the animals (hungry or well fed),
or their environment (presence or absence of cover). We also altered the
availability of visual information by manipulating the water clarity. Consistent
with our model, fishes were most likely to react to chemical alarm cues in the
absence of visual information and when the perceived risk of predation was high.
The manipulation of either parameter was able to extinguish this response.
PMID- 10787161
TI - Acoustic preference functions and song variability in the Hawaiian cricket
Laupala cerasina.
AB - Female preference functions for different sexual traits can differ significantly,
from 'unimodal' to 'open ended'. Through the study of acoustic communication in
anurans, several studies have reported an association between static
(stereotyped) traits versus dynamic (variable) traits and preference function
shape (unimodal versus open ended, respectively). Observing a similar pattern in
a phylogenetically independent group would suggest that deterministic forces have
caused a relationship between signal variability and preference function shape in
acoustic signalling systems. We examined this phenomenon in crickets, another
animal characterized by intersexual acoustic communication. We measured the
within-male variability for three acoustic features of the male calling song in
Laupala cerasina and the corresponding shape of the female preference function
for each of these features. We offer support for the generalization that open
ended preference functions correspond to relatively dynamic courtship traits and
unimodal preference functions correspond to relatively static courtship traits.
We discuss the evolutionary significance of these findings in the context of the
natural history of the Laupala species radiation.
PMID- 10787162
TI - A long photoperiod overrides non-photoperiodic factors in blue tits' timing of
reproduction.
AB - Endocrinological studies have contributed considerably to the development of
theory concerning the proximate aspects of the timing of reproduction. In non
domesticated, avian species, the relative importance of the photoperiodic and non
photoperiodic factors influencing later stages of the breeding cycle, such as the
onset of egg laying, remains unclear because egg laying is difficult to obtain
with captive populations and laboratory experiments of breeding are rarely
carried out in the framework of long-term field studies. We set up a special
experimental design such that captive Mediterranean blue tits (Parus caeruleus)
can breed with success in large outdoor aviaries at similar latitudes and
altitudes to their wild counterparts. Here we demonstrate experimentally that the
non-photoperiodic factors responsible for large and consistent differences in the
expression of natural breeding responses between three captive outdoor blue tit
populations are ignored during long-day treatment. Based on these findings, an
evolutionary explanation is provided for why the relative importance of the non
photoperiodic factors decreases with the progress of the season. The hypothesis
can explain observed maladapted breeding dates in free-living populations and
could possibly be used to increase the success of breeding programmes with some
endangered, captive, non-domesticated, photoperiodic species.
PMID- 10787163
TI - Individual state controls temperature dependence in a butterfly (Lasiommata
maera).
AB - In ectotherms there is typically a strong and positive correlation between growth
rate and ambient temperature when food is not limiting. However, the exact
relationship between growth rate and temperature varies among populations in many
species. As a consequence, it has been suggested that selection for a rapid
increase in growth rate with temperature should be stronger in populations
experiencing a high degree of time-stress, compared with populations experiencing
little time-stress. In the present study we take this adaptive hypothesis further
and investigate if variation in time-stress among individuals of a single
population may affect the relationship between growth rate and ambient
temperature. Time-stress was manipulated by rearing larvae of the butterfly
Lasiommata maera in different day-length regimes. The results show that
individuals experiencing a higher degree of time-stress increase their growth
rates more in higher temperatures compared with individuals under less time
stress. Hence, the adaptive hypothesis was supported and the relationship between
growth rate and temperature was highly state dependent. These findings may be of
general importance for understanding the evolution of life histories in seasonal
environments.
PMID- 10787165
TI - Effective population size may limit the power of laboratory experiments to
demonstrate sympatric and parapatric speciation.
AB - Laboratory experiments designed to elucidate the mechanisms of sympatric and
parapatric speciation may have been handicapped by too small population sizes,
although this possibility has seldom been discussed. In this paper we review the
published records of sympatric and parapatric speciation experiments to test the
relative importance of selection intensity applied, duration of experiment and
effective population size. Our results show that among these factors only
effective population size has had a general effect on the generation of
assortative mating. Reduced interbreeding is less likely to develop in small
populations where the selection process often seems to have been opposed by
inbreeding depression or loss of genetic variation. This study demonstrates that
the experimental evidence frequently used as an argument against sympatric and
parapatric speciation models is not as strong as previously believed.
PMID- 10787164
TI - Relationships between root density of the African grass Hyparrhenia diplandra and
nitrification at the decimetric scale: an inhibition-stimulation balance
hypothesis.
AB - Previous studies have shown that Lamto savannah exhibits two different types of
nitrogen cycle with high and low nitrification sites and suggested that the
perennial grass Hyparrhenia diplandra is responsible for this duality at a
subpopulation level, with one ecotype being thought to be able to inhibit
nitrification. The present work aimed to investigate the relationships between
nitrification and the roots of H. diplandra at two scales. (i) Site-scale
experiments gave new insight into the hypothesized control of nitrification by H.
diplandra tussocks: the two ecotypes exhibited opposite influences, inhibition in
a low nitrification site (A) and stimulation in a high nitrification site (B).
(ii) Decimetric-scale experiments demonstrated close negative or positive
relationships (in sites A or B, respectively) between the roots and nitrification
(in the 0-10 cm soil layer), showing an unexpectedly high sensitivity of the
nitrification process to root density. In both soils, the correlation between the
roots and nitrification decreased with depth and practically disappeared in the
20-30 cm soil layer (where the nitrification potential was found to be very low).
Therefore, the impact of H. diplandra on nitrification may be viewed as an
inhibition-stimulation balance.
PMID- 10787166
TI - Field data do not support a textbook example of convergent character
displacement.
AB - Experimental evidence supporting convergent character displacement is rare; only
one example exists and it is in the form of orientation and territory competition
experiments performed in the laboratory. However, outcomes of laboratory
experiments involving behaviour or competition can be artefacts of unnatural
conditions and, therefore, the results of the previous experiments supporting
convergent character displacement are equivocal. In this study, we re-examine the
evolution of melanic nuptial coloration in male three-spined stickleback
(Gasterosteus aculeatus) inhabiting the Chehalis River drainage in Washington
State. This novel nuptial coloration has been thought to have evolved in response
to competition for nesting territories with the co-distributed Olympic mudminnow
(Norzumbra hubbsi), which is also melanic and breeds at the same time. I found
that melanic stickleback males did not have an advantage over their red
counterparts from typical populations when competing for nesting territories with
Olympic mudminnows. Additionally competitive interactions between sticklebacks
and mudminnows were rare in both cage experiments and naturally breeding
sticklebacks. Finally, melanic coloration in the Chehalis populations did not
develop until males were parental, well after the hypothesized territory
establishment period. These results refute the only experimental support for
convergent character displacement and emphasize the importance of conducting
behavioural experiments and observations under natural conditions.
PMID- 10787167
TI - Phylogenetically patterned speciation rates and extinction risks change the loss
of evolutionary history during extinctions.
AB - If we are to plan conservation strategies that minimize the loss of evolutionary
history through human-caused extinctions, we must understand how this loss is
related to phylogenetic patterns in current extinction risks and past speciation
rates. Nee & May (1997, Science 278, 692-694) showed that for a randomly evolving
clade (i) a single round of random extinction removed relatively little
evolutionary history, and (ii) extinction management (choosing which taxa to
sacrifice) offered only marginal improvement. However, both speciation rates and
extinction risks vary across lineages within real clades. We simulated
evolutionary trees with phylogenetically patterned speciation rates and
extinction risks (closely related lineages having similar rates and risks) and
then subjected them to several biologically informed models of extinction.
Increasing speciation rate variation increases the extinction-management pay-off.
When extinction risks vary among lineages but are uncorrelated with speciation
rates, extinction removes more history (compared with random trees), but the
difference is small. When extinction risks vary and are correlated with
speciation rates, history loss can dramatically increase (negative correlation)
or decrease (positive correlation) with speciation rate variation. The loss of
evolutionary history via human-caused extinctions may therefore be more severe,
yet more manageable, than first suggested.
PMID- 10787169
TI - Least-inclusive taxonomic unit: a new taxonomic concept for biology.
AB - Phylogenetic taxonomy has been introduced as a replacement for the Linnaean
system. It differs from traditional nomenclature in defining taxon names with
reference to phylogenetic trees and in not employing ranks for supraspecific
taxa. However, 'species' are currently kept distinct. Within a system of
phylogenetic taxonomy we believe that taxon names should refer to monophyletic
groups only and that species should not be recognized as taxa. To distinguish the
smallest identified taxa, we here introduce the least-inclusive taxonomic unit
(LITU), which are differentiated from more inclusive taxa by initial lower-case
letters. LITUs imply nothing absolute about inclusiveness, only that subdivisions
are not presently recognized.
PMID- 10787168
TI - Estimating the time to extinction in an island population of song sparrows.
AB - We estimated and modelled how uncertainties in stochastic population dynamics and
biases in parameter estimates affect the accuracy of the projections of a small
island population of song sparrows which was enumerated every spring for 24
years. The estimate of the density regulation in a theta-logistic model (theta =
1.09 suggests that the dynamics are nearly logistic, with specific growth rate r1
= 0.99 and carrying capacity K = 41.54. The song sparrow population was strongly
influenced by demographic (sigma2(d) = 0.66) and environmental (sigma2(d) = 0.41)
stochasticity. Bootstrap replicates of the different parameters revealed that the
uncertainties in the estimates of the specific growth rate r1 and the density
regulation theta were larger than the uncertainties in the environmental variance
sigma2(e) and the carrying capacity K. We introduce the concept of the population
prediction interval (PPI), which is a stochastic interval which includes the
unknown population size with probability (1 - alpha). The width of the PPI
increased rapidly with time because of uncertainties in the estimates of density
regulation as well as demographic and environmental variance in the stochastic
population dynamics. Accepting a 10% probability of extinction within 100 years,
neglecting uncertainties in the parameters will lead to a 33% overestimation of
the time it takes for the extinction barrier (population size X = 1) to be
included into the PPI. This study shows that ignoring uncertainties in population
dynamics produces a substantial underestimation of the extinction risk.
PMID- 10787170
TI - Old and new players in the lipoprotein system.
PMID- 10787171
TI - Structure and function of apolipoprotein A-I and high-density lipoprotein.
AB - Structural biology and molecular modeling have provided intriguing insights into
the atomic details of the lipid-associated structure of the major protein
component of HDL, apo A-I. For the first time, an atomic resolution map is
available for future studies of the molecular interactions of HDL in such
biological processes as ABC1-regulated HDL assembly, LCAT activation, receptor
binding, reverse lipid transport and HDL heterogeneity. Within the context of
this paradigm, the current review summarizes the state of HDL research.
PMID- 10787172
TI - Cholesterol efflux regulatory protein, Tangier disease and familial high-density
lipoprotein deficiency.
AB - Cellular cholesterol efflux, by which cholesterol is transported from peripheral
cells to HDL acceptor molecules for transport to the liver, is the first step of
reverse cholesterol transport. Two genetic disorders, Tangier disease and some
cases of familial HDL deficiency, have defects of cellular cholesterol efflux.
The recent discovery of mutations in the ABC1 gene, which encodes the cholesterol
efflux regulatory protein, in both these disorders establishes cholesterol efflux
regulatory protein as a rate-limiting factor in reverse cholesterol transport.
PMID- 10787173
TI - The role of the high-density lipoprotein receptor SR-BI in cholesterol
metabolism.
AB - The HDL receptor scavenger receptor class B type I (SR-BI), which mediates
selective HDL cholesterol uptake, plays a role in murine HDL metabolism, reverse
cholesterol transport and whole-body cholesterol homeostasis. SR-BI is found in
the liver, where its expression is regulated by estrogen, dietary cholesterol and
fat, and controls murine plasma HDL cholesterol levels and bile cholesterol
secretion. SR-BI is also highly expressed in rodent steroidogenic cells, where it
facilitates cholesterol uptake for storage or steroid hormone synthesis and where
its expression is regulated by trophic hormones. The detailed mechanism(s)
underlying SR-BI-mediated selective cholesterol uptake have not yet been
elucidated. Further analysis of the molecular and cellular bases of SR-BI
regulation and function should provide new insights into the physiology and
pathophysiology of cholesterol metabolism.
PMID- 10787174
TI - Cubilin, a high-density lipoprotein receptor.
AB - The metabolism of HDL particles is a complex biological process involving various
regulating factors in plasma and different cellular receptors. In addition to the
well-established scavenger receptor BI-mediated selective HDL-cholesteryl ester
uptake in liver and steroidogenic tissues, evidence has been provided that HDL
also undergoes holoparticle endocytosis in different tissues. Recently, a novel
receptor expressed in various absorptive epithelia was disclosed as a high
affinity receptor for endocytosis of HDL and lipid-poor apolipoprotein AI. This
receptor, designated cubilin, may play an important role in the renal clearance
of filterable apolipoprotein AI/HDL and in the maternal-fetal transport of
cholesterol.
PMID- 10787175
TI - Endothelial lipase: a new member of the triglyceride lipase gene family.
AB - The triglyceride lipase gene family plays a central role in intestinal lipid
absorption, energy homeostasis, lipoprotein metabolism, and atherosclerosis. A
new member of this gene family, termed endothelial lipase, was recently reported.
The presence of key functional motifs, the endothelial synthesis, the enzymatic
profile, and the in-vivo metabolic effects of endothelial lipase suggest that,
like other members of this gene family, endothelial lipase may play a role in
energy delivery to tissues and in modulating lipoprotein metabolism, and could
impact on atherogenesis.
PMID- 10787176
TI - Transgenic animals with altered high-density lipoprotein composition and
functions.
AB - Our understanding of HDL metabolism in vivo has greatly advanced from studies
with transgenic animals. Interactions between HDL apolipoproteins, transfer
proteins, lipolytic enzymes and receptors modulate HDL size, particle number and
fractional catabolic rate. The protective effect of HDL on atherosclerosis
depends on the combined actions of HDL proteins and the metabolism of apo B
lipoproteins.
PMID- 10787177
TI - Structure and function of lecithin cholesterol acyl transferase: new insights
from structural predictions and animal models.
AB - The enzyme lecithin cholesterol acyl transferase is responsible for the synthesis
of most of the cholesteryl esters in plasma, and therefore plays a key role in
lipoprotein metabolism. The relationship between the structure and function of
lecithin cholesterol acyl transferase has been extensively studied in the past
years, and new data appeared in 1999 documenting the substrate specificity and
physiological role of lecithin cholesterol acyl transferase. The discovery of
natural mutants, together with the proposal of a three-dimensional model for the
enzyme, has provided new tools to unravel the function of specific residues of
lecithin cholesterol acyl transferase. The use of transgenic animals and the
production of knock-out lecithin cholesterol acyl transferase mice has further
contributed to the understanding of the lecithin cholesterol acyl transferase 'in
vivo' function. Evidence for a protective role of lecithin cholesterol acyl
transferase against the development of atherosclerosis through the hydrolysis of
oxidized lipids was recently proposed. Lecithin cholesterol acyl transferase
patterns in several pathologies were further clarified. These newer developments
are reviewed here.
PMID- 10787179
TI - Signalling pathways in vascular endothelium activated by shear stress: relevance
to atherosclerosis.
AB - Major advances in our understanding of how endothelial cells sense and respond to
haemodynamic forces and, more specifically, to fluid shear stress have been
achieved during the past 3 years. These include definition of potential shear
stress receptors and multiple signalling pathways that mediate shear stress
regulation of gene expression. A few studies have also pointed to the unique
effects of complex shear stress on endothelial activation, thus leading to better
understanding of the mechanisms that lead to the development of atherosclerosis.
PMID- 10787178
TI - Cellular signalling by lipoprotein receptors.
AB - Lipoprotein receptors are commonly thought merely to mediate the internalization
of lipoprotein particles or the exchange of lipids at the cell surface. Recent
findings have now implicated these multifunctional receptors in cellular
signalling mechanisms that extend beyond simple ligand endocytosis. By mediating
the cellular uptake of lipophilic vitamins and hormones, megalin, a member of the
LDL receptor gene family, regulates critical hormonal and metabolic processes.
Other members of the LDL receptor family interact with cytoplasmic adaptor and
scaffold proteins, which allows them to transmit signals directly across the
plasma membrane of the target cell. This sheds a new light on the emerging roles
of lipoprotein receptors in pathologic disease processes such as Alzheimer's
disease.
PMID- 10787181
TI - Bibliography. Current world literature. Genetics and molecular biology.
PMID- 10787180
TI - Recent advances in liver-directed gene therapy: implications for the treatment of
dyslipidemia.
AB - Somatic gene therapy for the treatment of dyslipidemia is an area of active
investigation. A substantial body of data indicates that the transfer of various
lipid-lowering genes to the liver is an effective method of restoring normal
plasma lipids in animal models of dyslipidemia. Most studies have used adenoviral
vectors because of their excellent gene-transfer efficiency. However, the first
and second-generation adenoviral vectors used in these experiments are highly
toxic and are associated with substantial morbidity and mortality. This article
reviews current data on the properties of two novel vectors, the adeno-associated
virus and the helper-dependent adenovirus that is devoid of all protein-encoding
genes. Each type of vector has its advantages and drawbacks. They appear to be
the most promising vectors to date for liver-directed gene transfer in the
treatment of dyslipidemia.
PMID- 10787182
TI - Nutrition and therapeutics.
PMID- 10787184
TI - Lipid metabolism.
PMID- 10787185
TI - Hyperlipidaemia and cardiovascular disease.
PMID- 10787183
TI - Genetics and molecular biology.
PMID- 10787186
TI - Atherosclerosis: cell biology and lipoproteins.
PMID- 10787187
TI - Therapy and clinical trials.
PMID- 10787188
TI - The changing role of scintigraphy in the evaluation of thyroid nodules.
AB - Nodular thyroid disease is common. Most nodules are asymptomatic and benign, but
some are malignant. Fine needle aspiration (FNA) biopsy should be the cornerstone
of the evaluation of thyroid nodules. Radionuclide scans and other imaging
procedures should be considered adjunctive tests and should not be performed
until after determination of thyroid function and results of cytology are
available.
PMID- 10787189
TI - Therapeutic options in the management of toxic and nontoxic nodular goiter.
AB - Nodular goiter is present in 500 to 600 million people and is usually secondary
to endemic iodine deficiency. Despite adequate iodine intake, 4% to 6% of
American adults are goitrous. Sporadic nodular goiter ensues from the natural
heterogeneity of thyroid follicular cells, which, when amplified by yet
unidentified trophic stimuli, results in episodes of proliferating, rapidly
dividing micronodules. The initial small diffuse goiter evolves into a
multinodular goiter (MNG) with 1 or more dominant nodules that may or may not be
autonomous. An autonomous functioning thyroid adenoma (AFTA) usually possesses a
somatic gain-of-function mutation of the thyrotropin (TSH) receptor associated
with rapid growth, hemorrhagic necrosis, and reparative fibrosis that accentuate
goiter nodularity. Diagnostic evaluation consists of patient history and physical
examination, serum TSH determination, free thyroxine and free triiodothyronine
measurements, and imaging studies assessing goiter function, size, and anatomy.
If treatment is required, L-thyroxine, thionamides, surgery, radioiodine (I-131),
and percutaneous ethanol injection (PEI) are effective in selected patients. In
euthyroid patients, L-thyroxine reduces goiter size in some patients, but
continued therapy is required to prevent regrowth. Thionamides control the
hyperthyroidism of toxic nodular goiter in preparation for more definitive
therapy, but are rarely used long term. Surgery and I-131 are most commonly
selected for definitive therapy for the toxic AFTA, and the toxic or euthyroid
MNG, but PEI is effective in selected toxic AFTAs.
PMID- 10787190
TI - Recombinant thyrotropin versus thyroid hormone withdrawal in evaluating patients
with thyroid carcinoma.
AB - Patients with previously treated thyroid carcinoma require lifelong monitoring
for recurrent disease. Two diagnostic tests that play a central role in follow-up
of these patients--radioiodine whole body scanning and serum thyroglobulin
measurement--are most accurate during thyroid-stimulating hormone (TSH)
stimulation. Temporary discontinuation of thyroid hormone therapy was previously
the sole effective approach for TSH-stimulated testing. However, hormone
withdrawal was associated with the morbidity of hypothyroidism and occasional
tumor progression. The introduction of recombinant TSH (rTSH)-stimulated testing
offers an alternative therapy. Recent clinical trials have shown that the
sensitivity of combined rTSH-stimulated radioiodine scanning and serum
thyroglobulin measurement has equivalent sensitivity to testing after thyroid
hormone withdrawal. Furthermore, measurement of the rTSH-stimulated thyroglobulin
concentration is a more sensitive way to detect residual thyroid cancer or normal
tissue than thyroglobulin measurement on thyroid hormone therapy alone. The
results of these trials are reviewed and strategies for implementing rTSH
mediated testing are presented.
PMID- 10787191
TI - Treating the patient with differentiated thyroid cancer with thyroglobulin
positive iodine-131 diagnostic scan-negative metastases: including comments on
the role of serum thyroglobulin monitoring in tumor surveillance.
AB - Differentiated thyroid cancer (DTC) patients, especially the 10% to 15% at high
risk of cancer-related death, should have long-term monitoring for detection of
recurrence or metastasis. Conventional radiologic and ultrasonographic imaging is
useful for localization of recurrent or persistent disease. For patients who have
had ablation of residual thyroid tissue, measurement of serum thyroglobulin (Tg)
levels and radioactive iodine (RAI) imaging provide highly sensitive tools for
early detection. Serum Tg is reliable only in the absence of Tg autoantibodies.
Sensitivity increases with TSH stimulation, either by withdrawal of thyroxine
(T4) therapy, or administration of recombinant TSH (rTSH). In some patients,
serum Tg levels are positive but the RAI whole body scan (WBS) is negative. In
these patients, either the recurrent tumor is too small and below the sensitivity
of the diagnostic scan, or there is a dissociation between Tg synthesis and the
iodine-trapping mechanism. Recent literature suggests that empiric high-dose RAI
therapy of Tg-positive diagnostic scan-negative patients may result in a high
rate of visualization of uptake in posttherapy scans (PTS). Evidence for
subsequent improvement of parameters of disease activity has also been presented.
Almost all such reported cases had micrometastases that were not visualized by
conventional imaging. In our experience, aggressive macrometastases with negative
diagnostic WBS do not show significant uptake after therapeutic doses of RAI. The
small size of micrometastases in the first group of patients and a possible
defect of the iodine-trapping mechanism in the second group may explain this
apparent discrepancy. Based on presently available information, a generalized
recommendation for RAI therapy of Tg-positive, diagnostic scan-negative patients
should await further studies. Meanwhile, in some high-risk patients, in the
absence of alternative therapies, empiric RAI therapy is justified.
PMID- 10787192
TI - Artifacts, anatomical and physiological variants, and unrelated diseases that
might cause false-positive whole-body 131-I scans in patients with thyroid
cancer.
AB - The whole body 131-I scan remains an important component in the postoperative
treatment of patients with well-differentiated thyroid cancer. Because normal
thyroid tissue remnants and residual or metastatic foci of well-differentiated
thyroid cancer have the unique ability to concentrate, organify, and store 131-I,
the whole body scan provides a depiction of those tissues that can be ablated
with therapeutic doses of 131-I. Over time, it has become obvious that the whole
body scan may also reveal foci of 131-i uptake owing to a wide variety of other
causes. We provide a detailed pathophysiological classification of the artifacts,
anatomic and physiological variants, and nonthyroidal diseases that may give rise
to false-positive whole body scans in postoperative patients with thyroid cancer.
These include ectopic foci of normal thyroid tissue; nonthyroidal physiological
sites (eg, choroid plexus, salivary glands, gastric mucosa, urinary tract);
contamination by physiological sections; ectopic gastric mucosa; other
gastrointestinal abnormalities; urinary tract abnormalities; mammary
abnormalities; serous cavities and cysts; inflammation and infection;
nonthyroidal neoplasms; and currently unexplained causes. This article also
provides a detailed review of the widely scattered English language literature in
which these phenomena were originally described.
PMID- 10787193
TI - The Chernobyl accident and its consequences: update at the millennium.
AB - A marked increase in the incidence of papillary thyroid cancer in children has
been documented in regions of the former Soviet Union most heavily contaminated
by radioactive fallout from the Chernobyl nuclear power plant accident in April
1986. Accumulation of radioactive iodines by normal iodine trapping mechanisms
resulted in significant radiation doses to the thyroid gland. Although it has
long been known that thyroidal radiation resulted in nuclear and chromosomal
abnormalities visible by light microscopy, modern molecular biology techniques
are beginning to identify much smaller alterations in chromosomal coding
sequences that are associated with malignant transformation. Although stable
chromosomal abnormalities can be detected in Chernobyl-associated thyroid
cancers, they are much less prevalent than in thyroid cancers developing after
external beam irradiation. However, several unique chromosomal breakpoints have
been described in radiation-associated thyroid cancers that are not commonly
found in spontaneously occurring thyroid cancer. Furthermore, activation of
specific subtypes of the ret/PTC tyrosine kinase oncogene appears to be more
common in radiation-associated thyroid cancers than in spontaneous thyroid
cancers. In summary, thyroid cancers developing in the aftermath of the Chernobyl
accident provide a unique opportunity to search for chromosomal abnormalities
that may be specific for radiation-induced thyroid cancer.
PMID- 10787194
TI - Continually rising renogram without imaging of collecting system (parenchymal
renal retention).
PMID- 10787195
TI - Symmetrically increased uptake of Ga-67 citrate in the breasts: a patient with
liver cirrhosis.
PMID- 10787196
TI - Disparate results between I-131 and Tc-99m pertechnetate owing to administration
of iodine-containing radiographic contrast material.
PMID- 10787197
TI - Opportunity and responsibility: SCVIR's role with uterine artery embolization.
Society of Cardiovascular & Interventional Radiology.
PMID- 10787198
TI - Evolving strategies for thrombolytic therapy of peripheral vascular occlusion.
PMID- 10787199
TI - Endovascular treatment of iliac limb stenoses or occlusions in 31 patients
treated with the ancure endograft.
AB - PURPOSE: The authors report their experience with treatment of iliac limb
complications in patients treated with the Ancure endograft with Wallstents to
provide additional support and thrombolysis when needed. MATERIALS AND METHODS:
From February 1996 to October 1999, 88 patients were treated for abdominal aortic
aneurysm with use of the Ancure endograft. Of the 88 devices used, 20 were tube
grafts and the remaining 68 devices had a total of 130 iliac limbs (bifurcated, n
= 62; aortoiliac, n = 6). After graft deployment, all patients underwent
intraoperative aortography; since July 1997, intravascular ultrasound (IVUS) has
also been used. RESULTS: Thirty-one patients (46%) required treatment of 47 (36%)
limbs with Wallstents. Graft narrowing was observed in 41 limbs (27 patients)
with IVUS immediately after graft deployment. All were successfully treated with
placement of Wallstents. Before routine use of intraoperative IVUS, three
patients presented between 2 and 6 weeks postoperatively with iliac limb
thrombosis. All three limbs were successfully treated with thrombolysis and
Wallstent placement to correct the underlying iliac problem. Additionally, two
contralateral limbs in these three patients were also noted to have stenosis and
were treated with use of Wallstents. The last patient required placement of a
Wallstent to treat stenosis of surgical anastomosis of the iliac limb of an
aortoiliac endograft at 3 days. All Wallstent-reinforced Ancure endografts
remained patent from 1 to 36 months (mean, 14 months). CONCLUSION: After
placement of an Ancure bifurcated or aortoiliac endograft, iliac limb stenosis is
easily detected with use of intraoperative IVUS. Such complications can be safely
corrected with Wallstent placement. Postoperative limb occlusion at the authors'
institution has been eliminated with such intervention.
PMID- 10787200
TI - Endovascular repair of the abdominal aortic aneurysm with the ancure endograft:
CT follow-up of perigraft flow and aneurysm size at 6 months.
AB - PURPOSE: Perigraft flow--flow outside the graft lumen but contained within the
abdominal aortic aneurysm (AAA)--is a potential complication after endovascular
repair of AAA. Such flow may permit AAA growth and rupture. The purpose of this
study is to evaluate with computed tomography (CT) the rate of spontaneous
closure of perigraft flow and the effect of persistent flow on AAA diameter.
MATERIALS AND METHODS: During a 30-month period, the authors evaluated all CT
scans in 50 patients who underwent AAA repair using the Ancure endograft system.
CT was performed at discharge, 6, 12, and 24 months, and at 3 months if there was
perigraft flow at discharge. Scans were reviewed for the presence, size, and
location of perigraft flow, and measurement of AAA diameter. Transcatheter
embolization was performed on those patients with persistent leak at 6 months.
RESULTS: Sixteen (32%) of 50 patients demonstrated perigraft flow on CT performed
within 72 hours of placement. Resolution of perigraft flow by 6 months was found
in nine (56%) of the 16 patients, in whom AAA size had decreased in five, had
increased in none, and was unchanged in four. Seven patients had persistent leaks
at 6-month CT; AAA size had decreased in one, had increased in one, and was
unchanged in five. In 34 patients without leaks, AAA size had decreased in nine,
had increased in one, and was unchanged on 24. There was no statistically
significant difference for the relationship between resolution or persistence of
perigraft flow and subsequent course of AAA diameter (P = .16). CONCLUSIONS:
Although perigraft flow is frequently seen (32%) early after repair of AAA with
the Ancure system, spontaneous resolution by 6 months occurs in 56% of cases. AAA
size decreased in a larger percentage of patients in whom perigraft leak was
absent or resolved by 6 months compared with those in whom perigraft leak
persisted at 6 months.
PMID- 10787202
TI - Direct graft puncture with use of a crossed catheter technique for thrombolysis
of peripheral bypass grafts.
AB - PURPOSE: To determine the efficacy and safety of direct graft puncture of
peripheral arterial bypass grafts with placement of retrograde and antegrade
catheters within the graft for thrombolytic therapy. This study also evaluated
potential clinical benefit to patients. MATERIALS AND METHODS: A retrospective
study was performed on 19 patients with 24 peripheral bypass grafts and lower
extremity ischemia of less than 1 month duration. Thrombolysis was performed with
a continuous high-dose infusion of urokinase. Successful lysis was defined as
greater than 95% clot dissolution with antegrade flow within the graft. RESULTS:
Technical success was achieved in 17 of 19 patients (89%). The complexity of
operative intervention was diminished in 12 of 19 patients (63%). The major
complication rate (16%) was significantly higher and, therefore, this technique
has a role for patients in whom traditional access is not optimal, such as in
those in whom access cannot be achieved or in those with long bypass grafts.
CONCLUSION: Direct graft puncture with placement of catheters across the proximal
and distal anastomoses of bypass grafts is a safe method of access, with a major
complication rate similar to conventional access techniques. This mode of graft
access demonstrates efficacious thrombolysis and acts as a conduit for ancillary
procedures.
PMID- 10787201
TI - Accuracy of CO2 angiography in vessel diameter assessment: a comparative study of
CO2 versus iodinated contrast material in an aortoiliac flow model.
AB - PURPOSE: Precise vessel sizing prior to endovascular intervention is critical to
achievement of technical success. Diameter measurements obtained with CO2 and
iodinated contrast material in an aortoiliac flow model were compared. MATERIALS
AND METHODS: Aortoiliac flow was simulated in a compliant, silicone elastomer
phantom of the aortoiliac system using an autoperfusion pump (flow volume,
approximately 1100 mL/min; mean arterial pressure, 70-80 mm Hg at 80-90
cycles/minute) and a glycerol solution (40% by weight; viscosity 3.7 centipoise
at 20 degrees C). Digital subtraction angiography was performed with the phantom
in the anteroposterior (AP) plane and in three oblique planes with both CO2 and
iodinated contrast material. Five sets of images for both CO2 and iodinated
contrast material were obtained for each projection. Two readers independently
performed vessel diameter measurements at seven sites (distal abdominal aorta,
bilateral proximal and distal common iliac, and mid-external iliac arteries). The
model was then evaluated with intravascular ultrasound (IVUS) using a 20-MHz
imaging catheter. Actual diameter measurements were taken from the inner wall to
inner wall in orthogonal planes at the same locations within the model, as
described previously. Analysis was performed to determine local difference in
measurements (t tests), difference when compared to the standard AP projection
with iodinated contrast material (Dunnett's test) and inter-reader variability
(Pitman's test). RESULTS: The contralateral iliac vessel segment did not opacify
when imaging with CO2 in the 45 degrees obliquities; thus, 22 of 28 sites were
available for comparison. At 18 of 22 (81.8%) sites, there was significant
difference in vessel measurements (P < .01), with CO2 yielding a significantly
larger diameter at 17 of 22 (77.3%) of the sites. The difference in mean diameter
ranged from -1.28 to 4.47 mm. With use of the AP iodinated contrast material run
as the standard, there were significant differences (P < .05) in vessel diameter
at 17 of 22 (77.3%) and four of 21 (19%) sites for CO2 and iodinated contrast
material respectively, with CO2 tending toward greater diameter measurements.
Significant differences (P < .05) in variance between the two readers were
present but occurred primarily with CO2 in the AP projection and iodinated
contrast material in the 45 degrees left obliquity. With use of IVUS as the
standard, there were significant differences (P < .05) in the measured vessel
diameters with CO2 at nine of 22 (40.9%) of the sites and with iodinated contrast
material at 17 of 28 (60.7%) of the sites. Of the measurements made with CO2,
seven of nine (77.8%) of the measurements were of larger diameter than those
obtained with IVUS. By contrast, of the measurements made with iodinated contrast
material angiography, IVUS measured larger diameters in 16 of 17 (94.1%).
CONCLUSION: CO2 angiography consistently yielded significantly larger vessel
measurements when compared to both iodinated contrast angiography and WVUS. These
results have important implications in regards to planning intervention based
solely on CO2 angiography. Further evaluation is needed before recommending CO2
for vessel sizing in clinical practice.
PMID- 10787203
TI - Hepatic artery embolization: factors predisposing to postembolization pain and
nausea.
AB - PURPOSE: Analysis of preprocedural factors that may be helpful in predicting the
severity of pain and nausea after hepatic arterial embolization (HAE) for liver
neoplasms. MATERIALS AND METHODS: During a 2-year period, 62 patients (33 men, 29
women) underwent 130 palliative lobar HAEs for unresectable liver neoplasms. The
hepatic lobe was embolized with 150-250-microm polyvinyl alcohol particulates
with or without lipiodol and/or chemotherapeutic agents. Postembolization pain
was rated at rest and during movement with use of an 11-point verbal pain scale,
and postembolization nausea was assessed with use of a four-point verbal scale,
each at two separate time periods. Daily morphine use was also recorded. Primary
analysis was made using the first embolization procedure. One-way analysis of
variance and Spearman correlation coefficients were used to identify associated
predictors. Plots of the outcomes versus the pre-embolization liver function
tests and sensitivities and specificities were used to identify the strength of
the associations for prediction purposes. A secondary analysis was performed in
patients who underwent multiple embolizations. RESULTS: No strong categorical
predictors were found from the ANOVA on the severity of postembolization pain or
nausea. There were significant (P < .05) associations between the pre
embolization liver function tests and the pain outcomes only. However, while
these laboratory values demonstrate strong associations with resultant pain, they
are not strong predictors of pain and morphine requirements for any individual
patient. The morphine requirements were highly associated (P < .0001) with the
pain scores at rest and with movement. The authors did not find significant
differences on any of the pain outcomes or morphine requirements between the
first and second embolizations. CONCLUSION: Laboratory values and patient age are
not predictors for the severity of postembolization pain and nausea.
Postembolization pain is a significant complication and poses a continuing
challenge to the physician with regards to patient management.
PMID- 10787204
TI - US-guided percutaneous thrombin injection: a new method of repair of superficial
temporal artery pseudoaneurysm.
PMID- 10787205
TI - Endovascular treatment of an unusual arterioportal fistula caused by the rupture
of a giant hepatic artery aneurysm into the superior mesenteric vein in Behcet
disease.
PMID- 10787206
TI - Percutaneous thrombin injection of splanchnic artery aneurysms: two case reports.
PMID- 10787207
TI - US-guided percutaneous catheter drainage of parotid abscesses.
PMID- 10787208
TI - Comparison of C-arm CT fluoroscopy and conventional fluoroscopy for percutaneous
biliary drainage procedures.
AB - PURPOSE: To conduct a prospective randomized evaluation of C-arm computed
tomography (CT) fluoroscopy for external biliary drainage procedures in
comparison with conventional fluoroscopic guidance to reduce the number of
transhepatic punctures as a primary endpoint. MATERIALS AND METHODS: In 18
patients with biliary obstructions, 20 external percutaneous biliary drainage
procedures were prospectively performed with use of either C-arm CT fluoroscopy
or conventional fluoroscopy alone. The number of hepatic punctures, procedure
time, and fluoroscopy time, were analyzed separately for both methods. RESULTS: C
arm CT fluoroscopy resulted in a reduced number of transhepatic punctures, with
decreased procedure and fluoroscopy times (P < .05; t test). When compared with
conventional external biliary drainage procedures, a mean of 1.8+/-1 versus 4.8+/
2.8 hepatic punctures at a fluoroscopy time of 3.4+/-1.5 versus 11.4+/-7.4
minutes was required for C-arm CT fluoroscopy, while procedure times were 11+/
3.6 versus 16.2+/-9.3 minutes. CONCLUSIONS: C-arm CT fluoroscopy is associated
with decreased procedure and fluoroscopy times, while fewer transhepatic
punctures are required to establish external biliary drainage.
PMID- 10787209
TI - Assessment of a polyester-covered nitinol stent in an atherosclerotic swine
model.
AB - PURPOSE: To evaluate the short-term patency and healing characteristics of the
Cragg EndoPro covered stent in an atherosclerotic model as one of the Food and
Drug Administration requirements before possible approval of the device for human
use in the United States. MATERIALS AND METHODS: Seventeen self-expanding stent
grafts were placed in the aorta and right and left iliac arteries of six Yucatan
microswine exposed to a regimen of accelerated atherosclerosis. The stent-grafts
were constructed from nitinol wire formed into a tubular zigzag configuration.
The stent frame was covered by a thin woven polyester fabric tube, with medium
permeability, available in multiple diameters and lengths. The animals were
killed at 24 hours, 3 months, and 6 months. Assessment was done by angiography
and histology. RESULTS: All stents were patent immediately after deployment. Two
stents were occluded at follow-up, indicating an 88% patency rate. Minor lumen
narrowing was found at the follow-up intervals. Histologic examination revealed a
mixture of mature and immature endothelial cells lining both the native and
stented regions in all vessels examined. The new endoluminal surface was composed
primarily of fibrocollagen and elastic fibers and smooth muscle cells. Intimal
thickness was inversely correlated to medial thickness. Medial compression with
atrophy was observed routinely with rare necrosis. Complete tissue ingrowth was
seen by 3 months. The degree of vascular inflammation increased over time, as
well as the foreign body giant cell reaction to the polyester fabric. CONCLUSION:
The patency rate does not appear to be better than that with angioplasty or
noncovered stent placement in the studied time frame. The progressive vascular
inflammatory changes noted should be further investigated in longer-term animal
trials to ensure its safety in humans because this device is meant to be
permanent.
PMID- 10787211
TI - Pharmacomechanical thrombolysis with use of the brush catheter in canine
thrombosed femoropopliteal arterial PTFE bypass grafts.
AB - PURPOSE: To assess the efficacy, acute endothelial changes, and distal arterial
emboli after use of the Cragg thrombolytic brush catheter in mature thrombosed
polytetrafluoroethylene (PTFE) femoropopliteal arterial grafts in canines.
MATERIALS AND METHODS: PTFE femoropopliteal arterial grafts were implanted in 10
canines and were allowed to mature for approximately 4 weeks. The grafts were
thrombosed by mechanical means and allowed to remain thrombosed for 24-72 hours.
Through a left carotid cut-down, standard Seldinger arterial puncture was
performed, followed by catheterization of the thrombosed graft. A soft, low
speed, brush (6 mm in diameter) aided by preprocedure pulse-spray urokinase
infusion was utilized for thrombolysis. The native vessels, just proximal and
distal to the anastomosis, were evaluated microscopically for endothelial damage.
Arteriography was used for assessment of distal embolus. RESULTS: All grafts were
successfully thrombosed before thrombolysis. One graft could not be traversed
with a wire and catheter and was, therefore, not treated. Immediate preprocedure
pulse-spray urokinase infusion in the remaining nine grafts did not reconstitute
antegrade flow in any instance and left significant amounts of residual thrombus
in all treated grafts. Mechanical brush thrombolysis reconstituted antegrade flow
in all nine treated grafts and complete graft thrombolysis was obtained in most.
This was accomplished in a mean time of less than 4 minutes. Emboli were noted
angiographically in 67% of cases. Histologic studies showed vessel wall damage
limited to the intima or media in 67% of anastomoses. CONCLUSION: This method
offers a simple and rapid means of recanalizing thrombosed PTFE femoropopliteal
arterial grafts in the studied model. This technique provides a means of rapidly
"debulking" most intragraft thrombi. This may result in a shorter course of
thrombolytic infusion. Potential benefits may include shortening the total
treatment time and decreasing morbidity and cost associated with percutaneous
thrombolysis. The occurrence of distal emboli in a majority of cases is a
concerning limitation of this technique.
PMID- 10787210
TI - Comparison of two stent-grafts with different porosity: in vivo studies in a
sheep model.
AB - PURPOSE: To compare two stent-grafts with a polyurethane-carbonate (PUC) polymer
lining of different pore size and water permeability in the iliac arteries of
sheep. MATERIALS AND METHODS: Two stent-grafts with an inner PUC-lining of normal
and low water permeability (normal, 1,200 mL/min/cm2; low, 280 mL/min/cm2;
pressure gradient, 20 mm Hg) were implanted in each of 16 sheep. Hoop strength
was two times higher in low-permeable than in normal-permeable stent-grafts.
Patency was monitored with use of angiography and intravascular ultrasound (IVUS)
after 1, 3, and 6 months. The sheep were killed after 1 or 6 months. Specimens
were studied histologically. IVUS and histologic data were analyzed
statistically. RESULTS: IVUS measurements showed a wider patent lumen of the low-
compared to the normal-permeable prostheses at all time points (P < .03). This is
likely due to the greater hoop strength of the low-permeable stent-graft. After 1
month, both types of prostheses demonstrated complete transprosthetic tissue
penetration and were covered with neointima and endothelium. The neointimal area
was greater in low- than in normal-permeable stent-grafts (1 month, P < .005; 6
months, P < .03). CONCLUSIONS: Presumably, the higher permeability of the normal
permeable stent-grafts led to the reduced neointimal area by improving
transprosthetic capillary ingrowth and endothelialization.
PMID- 10787212
TI - An agenda for research into uterine artery embolization: results of an expert
panel conference.
AB - PURPOSE: To develop a research agenda for uterine artery embolization (UAE) for
the treatment of symptomatic leiomyomata. MATERIALS AND METHODS: An expert panel
was convened to examine data and develop a consensus for UAE research. Panelists
reviewed data from articles about UAE and data on hysterectomy and myomectomy,
which were abstracted into evidence tables. A modified Delphi process was used to
rate the importance of measuring specific outcomes and a nominal group process
was used to develop ideas for study designs. RESULTS: Panelists agreed that UAE
studies would have to examine certain key measures. Outcomes identified as either
"important to measure" or "essential to measure" were death, reoperation,
operative injury, menorrhagia, premature menopause, recurrence of myomata, and
satisfaction. The panel proposed four areas for research: randomized trial,
prospective registry, disease-specific quality-of-life instrument, and cost
analysis. CONCLUSIONS: Symptomatic uterine leiomyomata are a major health concern
for women. New techniques that promise to provide symptom relief deserve careful
consideration. Traditionally, surgical procedures have been poorly studied until
after they have been widely used. If the process described in this article can
guide the acquisition of knowledge in this field, it may serve as a model for
evaluating other new technologies before they become widely adopted.
PMID- 10787213
TI - SCVIR annual meeting film panel session: diagnosis and discussion of case 1.
PMID- 10787214
TI - SCVIR annual meeting film panel session: diagnosis and discussion of case 2.
PMID- 10787215
TI - SCVIR annual meeting film panel session: diagnosis and discussion of case 3.
PMID- 10787216
TI - SCVIR annual meeting film panel session: diagnosis and discussion of case 4.
PMID- 10787218
TI - Cloning and the politics of women's health.
PMID- 10787217
TI - Ovarian artery supply of uterine fibroid.
PMID- 10787219
TI - Toward optimal health: the experts respond to the art of diagnosis. Interview by
Jodi Godfrey Meisler.
PMID- 10787220
TI - Should women at increased risk for breast and ovarian cancer be randomized to
prophylactic surgery? An ethical and empirical assessment.
AB - More information is needed about the relative effectiveness of prophylactic
surgery, chemoprevention, and surveillance in reducing breast and ovarian cancer
risk in women with an inherited susceptibility mutation. We assessed practical
and ethical barriers to conducting randomized clinical trials (RCTs) to compare
preventive interventions for breast and ovarian cancer. Eighty-seven at-risk
women who attended an education and counseling session about BRCA1/2 testing were
asked about their willingness to participate in hypothetical research studies for
breast and ovarian cancer risk reduction. In addition, 247 Maryland physicians
from five specialties completed a mail survey including a question about their
likelihood of recommending RCT participation to an at-risk woman. Nineteen
percent of at-risk women reported willingness to participate in a hypothetical
RCT for breast cancer risk reduction and 17% for ovarian cancer risk reduction.
Women with children and women likely to have a prophylactic mastectomy if found
to have a susceptibility mutation were significantly more willing to participate
in an RCT. A majority of women would be willing to participate in nonrandomized
trials or registries. Fifty-two percent of physicians responded that they would
be likely to recommend RCT participation to a woman carrying a breast cancer
susceptibility mutation. Oncologists were the most likely to recommend an RCT.
Although the results of nonrandomized trials may be difficult to interpret
because of such issues as selection bias. Greater feasibility combined with fewer
ethical concerns make nonrandomized trials a more viable alternative to
randomized trials for evaluation of preventive interventions for breast and
ovarian cancer when prophylactic surgery is one of the treatments being
evaluated.
PMID- 10787221
TI - Lipid management and control of other coronary risk factors in the postmenopausal
woman.
AB - This review identifies coronary heart disease (CHD) as the leading cause of
mortality among postmenopausal women and highlights the well-documented problem
of underrecognition and undertreatment of women who are at risk for or who
already have CHD. This undertreatment encompasses both preventive care (i.e.,
drug treatment for lipid management) and more invasive treatments (e.g.,
revascularization procedures). Preventive interventions to reduce dyslipidemia
and control other coronary risk factors can lessen CHD mortality and morbidity in
the postmenopausal woman.
PMID- 10787222
TI - Women's health and the environment: innovations in science and policy.
AB - Current scientific findings indicate that environmental factors affect women's
health. Specifically, evidence has accumulated on the effects of the environment
on reproductive health, cancer, injury, respiratory problems, autoimmune
diseases, and other health problems. To review the current state of the science
and policies related to women's health and the environment, the Federal
Interagency Working Group on Women's Health and the Environment of the Department
of Health and Human Services and the Society for Women's Health Research jointly
sponsored a conference in 1998 entitled Women's Health and the Environment:
Innovations in Science and Policy. The aim of the conference was to provide a
forum for scientists to share recent findings, promising avenues of research,
methodological barriers, and data gaps about women's susceptibility to
environmental agents. The conference generated 22 recommendations for policy, 17
recommendations for communication and training, and 48 recommendations for
research to be considered by the federal government. The purpose of this review
is to bring to the attention of the scientific community and policymakers the
breadth of the women's health implications associated with environmental factors
by highlighting key research findings presented at the conference. This review
summarizes the current status of science in women's health, it describes relevant
activities by the federal government, and it suggests recommendations for future
research and policy initiatives in the context of women's health and the
environment.
PMID- 10787223
TI - Identification of premature ovarian failure patients with underlying
autoimmunity.
AB - Although known causes of premature ovarian failure (POF) include X chromosome
deletions, radiation and chemotherapy, and genetic defects of the gonadotropin
hormones or receptors, at least one third to one half of cases remain idiopathic.
A significant proportion of patients with apparently idiopathic POF have some
evidence for an autoimmune etiology. However, the only gold standard for
detecting autoimmune causes of immune ovarian destruction has been invasive
ovarian biopsy. Serum antibodies to ovarian and other self-tissue have been
described in up to one third of women with POF, but the tests are not well
standardized, not well correlated with ovarian histology, and highly variable.
Recently, specific defects of expression of cell surface markers on peripheral
blood lymphocytes have been shown to identify, in population-based studies,
individuals destined to develop autoimmune pancreatic destruction and type I
diabetes mellitus, even before any other evidence of autoimmunity. We, therefore,
sought to test the ability of cell surface marker expression in women with POF to
identify autoimmune defects. Seventeen women with POF, 11 of whom had positive
antibody titers to ovary, thyroid, or antinuclear antibody, were studied on at
least two occasions and compared in blinded fashion with normal controls and
patients with autoimmune type I diabetes mellitus. The most useful marker for
identifying autoimmunity was the surface density of conformationally correct HLA
class I molecules on macrophages, a structure essential for T cell education.
Using this marker, 7 of the 9 patients with autoantibodies and 3 of the 8
patients without autoantibodies were identified as having evidence of a defect in
self-antigen presentation similar to that of type I diabetics (chi-square, p =
0.03). Subsequent testing identified antismooth muscle antibodies in 1 of the
women with a defect of HLA class I molecules but no previously identified
autoimmunity. In addition, there were increased numbers of CD8 T cells in both
autoimmune POF and insulin-dependent diabetes mellitus (IDDM) patients. Exclusive
to POF patients was a statistically significant increase in CD8 density on T
cells. This was most prominent in POF patients with an underlying autoimmune
etiology. These data further support a role for autoimmunity in POF patients and
suggest that the further development of cell surface markers in combination with
other diagnostic tests could result in diagnosis before the development of
complete ovarian failure. The possibility for disease-specific therapy to prevent
further autoimmune ovarian damage in selected POF patients is also envisioned.
PMID- 10787224
TI - The use of abusable prescription drugs: the role of gender.
AB - It is well documented that women face greater medical exposure to psychotropic
drugs than do men, but little research examines whether women also have increased
use of prescription drugs with abuse potential. The objectives were to examine
gender differences in the use of abusable prescription drugs and to assess how
use varies by gender and if patterns of use vary across therapeutic drug classes.
With data from the 1987 National Medical Expenditures Survey (NMES), logistic
regression analysis is used to model the influence of gender and other
sociodemographic and diagnostic variables on the probability of drug use. Women
are 48% more likely than men to use any abusable prescription drug, controlling
for demographics, health status, economic status, and diagnosis. Additional
analyses reveal that being female is a statistically significant predictor of
anxiolytic and narcotic analgesic use but not of sedative-hypnotic or stimulant
use. Marital status, age, urbanicity, employment status, and having a regular
source of care explain gender differences in the use of abusable prescription
drugs. Both healthcare and substance abuse treatment providers should be
cognizant that women may have greater exposure to these potent prescription
medicines.
PMID- 10787225
TI - Early normal menstrual cycle pattern and the development of uterine leiomyomas.
AB - It is unclear if women who develop uterine leiomyomas have had menstrual
regularity or irregularity in their reproductive life. This case-control study
examines the recalled menstrual cycle patterns throughout the reproductive life
among women requiring hysterectomy for myomas. One hundred twenty-two women with
myomas and 244 age-matched healthy controls without myomas were enrolled in
Japan. The incidence of normal menstrual cycle pattern in their teens among
patients with myoma was significantly higher than that among healthy controls (p
< 0.01). The subset results for parous women were the same as those for all
subjects. The size of the uterus in myoma patients with teenage menstrual
regularity was not larger than in those with teenage menstrual irregularity.
Women who developed myomas later in life tended to have early normal menstrual
cycle pattern. Early menstrual regularity may enhance leiomyoma growth in early
reproductive life.
PMID- 10787226
TI - Tubal sterilization and use of an IUD and risk of cervical cancer.
AB - The relationship of tubal sterilization and use of an intrauterine device (IUD)
to the risk of invasive squamous cell cervical cancer was evaluated in a case
control study carried out in Shandong, China, from 1989 to 1991. Patients (cases)
were 272 women aged 30-77 years with newly diagnosed invasive squamous cell
cervical cancer in Shandong Province Tumor Hospital. Controls were 893 randomly
selected screened women matched to the cases by age (within 2 years) and county.
A decrease in risk was observed in uses of an IUD, especially in long-term users
under age 33. A nonsignificant decrease in risk in women under age 33 who had had
a tubal ligation was also observed, especially in the first 10 years since the
procedure. Tubal ligation and IUD insertion and removal provide opportunities to
screen women for cervical cancer and reduce the risk of invasive disease.
PMID- 10787227
TI - Breast self-examination in women in two primary care settings: an evaluation of
the impact of insurance status.
AB - Breast cancer is one of the most common cancers diagnosed among women in the
United States. Screening tools available for breast cancer detection include
breast self-examination (BSE), clinical breast examination, and mammography.
Various studies have indicated that women may inconsistently perform BSE. This
investigation evaluated the potential impact of insurance status on BSE. Women
with health insurance receiving primary healthcare at a health maintenance
organization (HMO) and women without health insurance receiving primary
healthcare at a free clinic completed anonymous questionnaires that obtained
information about the frequency of BSE performance, whether instruction was given
about performing BSE, age at learning BSE, and confidence in performing BSE. One
hundred fifty-five (82%) of 200 questionnaires at the HMO and 92 (92%) of 100
questionnaires at the free clinic were completed. Thirty-five percent of women
(32% at the HMO, 39% at the free clinic) reported performing BSE. There were no
significant differences in the rate of monthly BSE, receiving instruction about
performing BSE, age at learning BSE, or confidence in performing BSE in women at
the HMO and free clinic. Insurance status did not affect BSE. However, further
study is needed to evaluate factors that potentially influence performance of BSE
and could encourage compliance with BSE recommendations.
PMID- 10787228
TI - Treatment of premenstrual syndrome with a phytopharmaceutical formulation
containing Vitex agnus castus.
AB - A multicentric noninterventional trial (open study without control) to
investigate the efficacy and tolerance of a drug in a large number of patients
under routine medical conditions was performed for a new solid preparation from
an extract of the fruit of Vitex agnus castus (VAC, Vitex, chaste tree,
Chasteberry) in 1634 patients suffering from premenstrual syndrome (PMS). A
specific questionnaire was developed for determining the effect of Vitex on
psychic and somatic complaints, on the four characteristic PMS symptom complexes
depression, anxiety, craving, and hyperhydration (DACH), and on single groups of
symptoms. After a treatment period of three menstrual cycles 93% of patients
reported a decrease in the number of symptoms or even cessation of PMS
complaints. To a certain extent, this effect was observed within all symptom
complexes and correlated with the global assessment of therapeutic efficacy.
Whereas 85% of physicians rated it as good or very good, 81% of patients assessed
their status after treatment as very much or much better. Analysis of frequency
and severity of mastodynia as the predominant symptom revealed that complaints
still present after 3 months of therapy were mostly less severe. Ninety-four
percent of patients assessed the tolerance of Vitex treatment as good or very
good. Adverse drug reactions were suspected by physicians in 1.2% of patients,
but there were no serious adverse drug reactions. Hence, the risk/benefit ratio
of the new Vitex preparation can be rated as very good, with significant efficacy
for all aspects of the multifaceted and inhomogeneous clinical picture of PMS,
with a safety profile comparable to other Vitex preparations.
PMID- 10787229
TI - Resting energy expenditure in asymptomatic HIV-infected females.
AB - The purpose of this study was to investigate whether resting energy expenditure
(REE) is elevated in early, asymptomatic human immunodeficiency virus (HIV)
infected females and to study the contribution of a cytokine, tumor necrosis
factor-alpha (TNF-alpha), to hypermetabolism. Cross-sectional comparison of REE
in asymptomatic HIV+ females and a control group matched for age, body mass index
(BMI), and fat-free mass (FFM). Twenty-six females aged 35 +/- 7 years (10 HIV+
[mean CD4+ T cell count 636/mm3] and 16 healthy controls) participated in this
study. REE was measured by indirect calorimeter using a Deltatrac ventilated hood
with a continuous rate of 40 L/min for 30 minutes after a 40-minute equilibrium
period. All tests were performed after a 12-hour overnight fast. Twenty-four-hour
urinary nitrogen was calculated to correct for respiratory quotient. Body
composition was measured by bioelectrical impedance (BioAnalogics, Beaverton,
OR). TNF-alpha was measured by ELISA (R & D Systems, Minneapolis, MN). Absolute
REE was 17% higher (1755 kcal/kg +/- 410 versus 1497 kcal/kg +/- 197) in the HIV+
group compared with the control group (p < 0.05). REE remained significantly
higher in the HIV+ group when REE was adjusted for body composition differences
(p = 0.04). Results revealed a 23% higher level of TNF-alpha in the HIV+ subjects
(p < 0.01); however, only a weak correlation existed between TNF-alpha and REE (r
= .352). This study documented that hypermetabolism and elevated TNF-alpha exist
in HIV+ females in the early stages of disease.
PMID- 10787230
TI - Infertility.
PMID- 10787231
TI - Integrating cosmetic dentistry into the general dental practice. Interview by
Phillip Bonner, DDS.
PMID- 10787232
TI - The mechanism of coupling: a role for the vasculature.
PMID- 10787233
TI - XVI Annual Meeting of the Argentine Association of Bone and Mineral Metabolism
(AAOMM). October 28-29, 1999. Abstracts.
PMID- 10787234
TI - Bone ultrasonometry in Polish men and women.
PMID- 10787235
TI - Mycophenolate mofetil may induce apoptosis in duodenal villi.
PMID- 10787236
TI - Cause of hypercalciuria in X-linked chloride channel gene mutations.
PMID- 10787237
TI - Familial crescentic glomerulonephritis.
PMID- 10787238
TI - Notice of plagiarized text.
PMID- 10787239
TI - Are Mpl glycosylation defects in polycythemia vera secondary to artifactual
hypoglycemia?
PMID- 10787240
TI - HFE polymorphism and accurate diagnosis of C282Y hereditary hemochromatosis
carriers.
PMID- 10787241
TI - Immunoglobulin V genes and CD38 expression in CLL.
PMID- 10787242
TI - Blair demands reform of the NHS.
PMID- 10787244
TI - UK government wants GMC to be given stronger powers.
PMID- 10787243
TI - NICE issues guidelines on wisdom teeth. National Institute for Clinical
Excellence.
PMID- 10787245
TI - NHS bill for negligence set to soar again.
PMID- 10787246
TI - Spain faces massive decline in population.
PMID- 10787247
TI - NHS board appointments criticised.
PMID- 10787248
TI - Study explores Internet as a tool for care of diabetic patients.
PMID- 10787249
TI - More services needed for bereaved children.
PMID- 10787250
TI - Mrs Clinton aims to reduce psychoactive drugs in young children.
PMID- 10787251
TI - Twenty countries pledge to wipe out TB.
PMID- 10787253
TI - Supreme Court rules that FDA cannot regulate tobacco industry.
PMID- 10787252
TI - Australia to consider a class action against tobacco industry.
PMID- 10787254
TI - Surrogacy should pay.
PMID- 10787255
TI - Recommendations for using MMR vaccine in children allergic to eggs.
PMID- 10787256
TI - Future directions for geriatric medicine. More geriatricians will be needed to
satisfy increasing demand in community.
PMID- 10787257
TI - Unexpected beneficial effects of measles immunisation. Other conditions with
reduced mortality could have been specified.
PMID- 10787258
TI - Unexpected beneficial effects of measles immunization. Socioeconomic confounding
may also play a part.
PMID- 10787259
TI - Unexpected beneficial effects of measles immunisation. Number of squint
operations has decreased.
PMID- 10787260
TI - Unexpected beneficial effects of measles immunisation. Who brought measles?
PMID- 10787261
TI - Making decisions about screening for ovarian cancer. Mass screening may not prove
to be sound public health policy.
PMID- 10787262
TI - 3rd Annual Meeting of the Hungarian STD Society and the 4th Alpe-Adria-Danube STD
Workshop. Budapest, Hungary, 12-14 November 1998. Abstracts.
PMID- 10787264
TI - Introduction to this special issue on neurourology. Urinary incontinence.
PMID- 10787263
TI - Urinary incontinence: pathophysiology, diagnosis and treatment in clinical (neuro
)urological practice of patients with Chronic Impairment of Voiding and
Continence Activities (CIVCA)
PMID- 10787265
TI - Report of the Society for Pediatric Anesthesia 13th annual meeting.
PMID- 10787267
TI - Don't rely on the surgical airway: a case of impossible tracheostomy.
PMID- 10787266
TI - Clonidine in paediatric anaesthesia.
PMID- 10787268
TI - Lumbar epidurals via the midline approach.
PMID- 10787269
TI - An unusual cause of difficult intubation.
PMID- 10787270
TI - Heart block following propofol in a child.
PMID- 10787271
TI - A bougie for a 2.5mm tracheal tube.
PMID- 10787272
TI - Sevoflurane use in Tetralogy of Fallot: is it the best choice?
PMID- 10787273
TI - Estrogen and progesterone: receptors and ligands in the next millennium.
Proceedings of a course at the annual meeting of the Society for Gynecologic
Investigation. March 10, 1999.
PMID- 10787274
TI - The AAGL classification system for laparoscopic hysterectomy. Classification
committee of the American Association of Gynecologic Laparoscopists.
PMID- 10787276
TI - Proceedings of the 3rd International Meeting on Current Topics in Breast Cancer
Research: Cell Death and Breast Cancer. Cambridge, United Kingdom, September
1998.
PMID- 10787275
TI - Re: "The effects of cognitive rehabilitation on outcomes for persons with
traumatic brain injury: a systematic review".
PMID- 10787277
TI - Proceedings of the 2nd International Conference on Therapies for Viral Hepatitis.
Kona, Hawaii, USA. 15-19 December 1997.
PMID- 10787278
TI - Who needs needs?
PMID- 10787279
TI - Definition of arterial compliance. Re: Hardt et al., "Aortic pressure-diameter
relationship assessed by intravascular ultrasound: experimental validation in
dogs.".
PMID- 10787280
TI - Deaths after living related liver transplantation.
PMID- 10787281
TI - Donor safety in living donor liver transplantation.
PMID- 10787282
TI - "I shall please".
PMID- 10787283
TI - [Euphoria and setbacks--early radioactive cancer treatment].
PMID- 10787284
TI - [Elevated values of creatine kinase].
PMID- 10787285
TI - [Urticaria factitia].
PMID- 10787286
TI - Oral Chemotherapy: Past, Present and Future Directions. Proceedings of a
conference. Cancun, Mexico, February 26-28, 1998.
PMID- 10787287
TI - Photoparoxysmal response and the assessment of seizure control.
PMID- 10787288
TI - Sperm quality and FSH therapy?
PMID- 10787289
TI - Does preimplantation genetic diagnosis (PGD) need a new name?
PMID- 10787290
TI - Selection of summary measures for ART?
PMID- 10787291
TI - The selection of summary measures for ART outcome data-"reveal codes".
PMID- 10787292
TI - Blastocyst transfer for couples with multiple IVF failures?
PMID- 10787293
TI - Clarifications and relationships between estrogen and prostaglandins.
PMID- 10787294
TI - Proceedings of the Symposium Current Status of Sexing Mammalian Sperm.
Maastricht, The Netherlands, January 8, 2000.
PMID- 10787295
TI - R. Yanagimachi, recipient of the 2000 Embryo Transfer Pioneer Award.
PMID- 10787296
TI - Proceedings of the annual conference of the International Embryo Transfer
Society. Maastricht, The Netherlands, January 9-11, 2000.
PMID- 10787297
TI - Colorectal neoplasm detection using virtual colonoscopy: a feasibility study.
PMID- 10787298
TI - Assessment of innate ability and skills for endoscopic manipulations by the
advanced Dundee endoscopic psychomotor tester: predictive and concurrent
validity.
PMID- 10787299
TI - Early administration of somatostatin and efficacy of sclerotherapy in acute
oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal
Episodes (ABOVE) randomised trial.
PMID- 10787301
TI - Focus on posttraumatic stress disorder. 4th meeting of the International
Consensus Group on Depression and Anxiety. Montecatini, Italy, April 1999.
PMID- 10787300
TI - Implications of left-to-right lung ventilation heterogeneity.
PMID- 10787302
TI - New doors to open...and so many!
PMID- 10787303
TI - Avoid unfavorable consequences: dextromethorpan can bring about a false-positive
phencyclidine urine drug screen.
PMID- 10787304
TI - Intravenous saline has no effect on blood ethanol clearance.
PMID- 10787305
TI - Familial Creutzfeldt-Jakob disease with D178N-129M mutation of PRNP presenting as
cerebellar ataxia without insomnia.
PMID- 10787306
TI - Postmalaria neurological syndrome: a case of acute disseminated
encephalomyelitis?
PMID- 10787307
TI - Trigeminal sensory neuropathy: anatomico-physiological correction.
PMID- 10787308
TI - Unilateral eyelid retraction.
PMID- 10787309
TI - Behcet's syndrome may present with partial seizures.
PMID- 10787310
TI - Morphological abnormalities of hepatic mitochondria in two patients with
spinocerebellar ataxia type 7.
PMID- 10787311
TI - Cervical syringomyelia at the C7-C8 level presenting with bilateral scapular
winging.
PMID- 10787312
TI - Focal neuropathy associated with cutaneous necrosis at the site of interferon
beta injection for multiple sclerosis.
PMID- 10787313
TI - Treatment with intravenous prednisone and immunoglobin in a case of progressive
encephalomyelitis with rigidity.
PMID- 10787315
TI - Predicting survival using simple clinical variables: a case study in traumatic
brain injury.
PMID- 10787314
TI - Benign multiple sclerosis? Clinical course, long term follow up, and assessment
of prognostic factors.
PMID- 10787316
TI - Distinctions between critical illness polyneuropathy and axonal Guillain-Barre
syndrome.
PMID- 10787317
TI - New hope for patients with pure lower motor neurons syndromes.
PMID- 10787318
TI - International Symposium on Glutamate. Proceedings of a symposium held October 12
14, 1998 in Bergamo, Italy.
PMID- 10787319
TI - Ciliary body detachment caused by capsule contraction.
PMID- 10787320
TI - Inflammation and blood-aqueous barrier disruption.
PMID- 10787322
TI - Piggyback intraocular lenses.
PMID- 10787321
TI - Astigmatic corneas--oblate and prolate meridians.
PMID- 10787323
TI - Surgical treatment of pellucid marginal degeneration associated with cataract.
PMID- 10787324
TI - When to perform LASIK in contact lens wearers.
PMID- 10787325
TI - Consultation section. Cataract surgical problem.
PMID- 10787326
TI - [Facial palsy, enhancement of cranial nerves and Lyme disease].
AB - Lyme disease involves multiple organ systems including in 10-15% of cases, the
nervous system. Cranial neuropathies are observed in the second stage of the
disease. The facial nerve is the most frequently affected nerve (20-30%). Facial
nerve enhancement may be associated with cochleovestibular nerve abnormalities
and can mimick an intracanalicular pseudomass. We present post-gadolinium
enhancement of multiple cranial nerves associated to an intracanicular
enhancement illustrated in a patient referred for a facial nerve palsy and
presenting a Lyme disease. We discuss the differential diagnosis.
PMID- 10787327
TI - Effect of calcium chromate dust, influenza virus, and 100 R whole-body x
radiation on lung tumor incidence in mice.
PMID- 10787328
TI - Medical professionalism--focusing on the real issues.
PMID- 10787329
TI - Medical professionalism in society.
PMID- 10787330
TI - Medical professionalism in society.
PMID- 10787331
TI - Medical professionalism in society.
PMID- 10787332
TI - Efavirenz in HIV infection.
PMID- 10787333
TI - Prevention of sudden death in patients with coronary artery disease.
PMID- 10787334
TI - Prevention of sudden death in patients with coronary artery disease.
PMID- 10787335
TI - Treatment of allergic asthma with monoclonal anti-IgE antibody.
PMID- 10787336
TI - Disorders of iron metabolism.
PMID- 10787337
TI - Disorders of iron metabolism.
PMID- 10787338
TI - Disorders of iron metabolism.
PMID- 10787339
TI - Epoetin for severe anemia in hepatoerythropoietic porphyria.
PMID- 10787340
TI - German researchers seek legal backing for stem cell work.
PMID- 10787341
TI - Giant tortoises come home.
PMID- 10787342
TI - Japan sets tissue donor guidelines.
PMID- 10787343
TI - US geneticists encouraged to play by the book.
PMID- 10787344
TI - Varmus tells Congress to grasp thorny policy issues.
PMID- 10787345
TI - Monsanto makes rice genome public.
PMID- 10787346
TI - Hypothalamic haemorrhage and thalamus degeneration in a case of Nasu-Hakola
disease with hallucinatory symptoms and central hypothermia.
PMID- 10787347
TI - Anterior sacrospinous vaginal vault suspension for prolapse.
PMID- 10787348
TI - Combination antiretroviral therapy in human immunodeficiency virus-infected
pregnant women.
PMID- 10787349
TI - Cervical ripening and labor induction with a controlled-release dinoprostone
vaginal insert.
PMID- 10787350
TI - Index of suspicion. Case 2. Cystic hygroma.
PMID- 10787351
TI - Index of suspicion. Case 3. Congenital diaphragmatic hernia.
PMID- 10787352
TI - [Risk of stillbirths and paternal occupational exposure to ionizing radiation].
PMID- 10787353
TI - [DEA research summaries on Epidemiology and Public Health].
PMID- 10787354
TI - Once more: Light's criteria revisited.
PMID- 10787355
TI - Lignocaine for topical anesthesia in fiberoptic bronchoscopy.
PMID- 10787356
TI - Transfusion of buffy coat-depleted blood components and risk of postoperative
infection in orthopedic patients.
PMID- 10787357
TI - Proceedings of the 5th International Veterinary Immunology Symposium. Ludhiana,
India, November 8-13, 1998.
PMID- 10787358
TI - Sporadic microsatellite instability is specific to neoplastic and preneoplastic
endometrial tissues.
AB - Microsatellite instability is a frequent (13%-24%) finding in sporadic
endometrial adenocarcinoma and its precursor lesions, but most studies are
limited to patients who already have malignant or premalignant endometrial
disease. We performed retrospective testing for microsatellite instability in
women in whom cancers showing microsatellite instability developed later and
prospective testing in randomly selected normal and anovular endometrial biopsy
specimens. Microsatellite instability in cancer-bearing biopsy specimens
accurately reflected that seen in matched malignant tissues obtained at
hysterectomy. In 1 patient, microsatellite instability developed in a scanty
sample of fragmented endometrial tissues 7 years before the onset of endometrial
cancer. Prospective testing for microsatellite instability in the endometria of
women unselected for subsequent appearance of endometrial cancer showed a very
low rate of microsatellite instability. Only 1 endometrial specimen showing
microsatellite instability was found among 75 anovulatory endometrial specimens,
and none were found in 377 normal endometrial specimens and 46 polyps examined.
Microsatellite instability may precede the onset of histologically diagnosed
carcinoma but is rare in randomly sampled histologically normal endometrial
tissues.
PMID- 10787359
TI - C-terminal sequence analysis of peptides and proteins using carboxypeptidases and
mass spectrometry after derivatization of Lys and Cys residues.
AB - C-Terminal sequence analysis of peptides and proteins using carboxypeptidase
digestion in combination with matrix-assisted laser desorption/ionization mass
spectrometry (MALDI-MS) is convenient for protein and peptide characterization.
After a short digestion, a sequence up to 20 residues can be identified, but the
total number depends on the individual sequence. Due to the accuracy limits of
the MALDI time-of-flight arrangement, the assignment of several residues with
close mass values, including Lys/Glx, may remain ambiguous. We have used
derivatization of lysine residues by guanidination to overcome the problem of Lys
identification. The reaction is rapid and specific and results in full
derivatization. In the case of Cys-containing peptides, problems arise from the
fact that carboxypeptidases Y and P do not cleave peptides that contain
nonderivatized cystine, cysteic acid, or (carboxymethyl)cysteine. Successful
identification of Cys residues within the sequence is instead achieved by
conversion of Cys to 4-thialaminine by (trimethylamino)-ethylation. The two
derivatizations of Lys and Cys side chains provide opportunities for proton
attachment and therefore facilitate the analysis by MALDI-MS. This C-terminal
sequence analysis method is also useful for large proteins after fragmentation
with specific enzymes.
PMID- 10787360
TI - National Highway Traffic Safety Administration (NHTSA) notes. Commentary: Drugged
driving--different spin on an old problem.
PMID- 10787361
TI - Postmenopausal hormone therapy increases risk for venous thromboembolic disease.
The Heart and Estrogen/progestin Replacement Study.
AB - BACKGROUND: Oral contraceptive use increases risk for venous thromboembolism, but
data on the effect of postmenopausal hormone therapy are limited. OBJECTIVE: To
determine the effect of therapy with estrogen plus progestin on risk for venous
thromboembolic events in postmenopausal women. DESIGN: Randomized, double-blind,
placebo-controlled trial. SETTING: 20 clinical centers in the United States.
PARTICIPANTS: 2763 postmenopausal women younger than 80 years of age (mean age,
67 years) who had coronary heart disease but no previous venous thromboembolism
and had not had a hysterectomy. INTERVENTION: Conjugated equine estrogens, 0.625
mg, plus medroxyprogesterone acetate, 2.5 mg, in one tablet (n = 1380) or placebo
that was identical in appearance (n = 1383). MEASUREMENTS: Documented deep venous
thrombosis or pulmonary embolism. RESULTS: During an average of 4.1 years of
follow-up, 34 women in the hormone therapy group and 13 in the placebo group
experienced venous thromboembolic events (relative hazard, 2.7 [95% CI, 1.4 to
5.0] [P = 0.003]; excess risk, 3.9 per 1000 woman-years [CI, 1.4 to 6.4 per 1000
woman-years]; number needed to treat for harm, 256 [CI, 157 to 692]). In
multivariate analysis, the risk for venous thromboembolism was increased among
women who had lower-extremity fractures (relative hazard, 18.1 [CI, 5.4 to 60.4])
or cancer (relative hazard, 3.9 [CI, 1.6 to 9.4]) and for 90 days after inpatient
surgery (relative hazard, 4.9 [CI, 2.4 to 9.8]) or nonsurgical hospitalization
(relative hazard, 5.7 [CI, 3.0 to 10.8]). Risk was decreased with aspirin
(relative hazard, 0.5 [CI, 0.2 to 0.8]) or statin use (relative hazard, 0.5 [CI,
0.2 to 0.9]). CONCLUSIONS: Postmenopausal therapy with estrogen plus progestin
increases risk for venous thromboembolism in women with coronary heart disease.
This risk should be considered when the risks and benefits of therapy are being
weighed.
PMID- 10787362
TI - Screening for cervical and breast cancer: is obesity an unrecognized barrier to
preventive care?
AB - BACKGROUND: Compared with thinner women, obese women have higher mortality rates
for breast and cervical cancer. In addition, obesity leads to adverse social and
psychological consequences. Whether obesity limits access to screening for breast
and cervical cancer is unclear. OBJECTIVE: To examine the relation between
obesity and screening with Papanicolaou (Pap) smears and mammography. DESIGN:
Population-based survey. SETTING: United States. PARTICIPANTS: 11 435 women who
responded to the "Year 2000 Supplement" of the 1994 National Health Interview
Survey. MEASUREMENTS: Screening with Pap smears and mammography was assessed by
questionnaire. RESULTS: In women 18 to 75 years of age who had not previously
undergone hysterectomy (n = 8394), fewer overweight women (78%) and obese women
(78%) than normal-weight women (84%) had had Pap smears in the previous 3 years
(P < 0.001). After adjustment for sociodemographic information, insurance and
access to care, illness burden, and provider specialty, rate differences for
screening with Pap smears were still seen among overweight (-3.5% [95% CI, -5.9%
to -1.1%]) and obese women (-5.3% [CI, -8.0% to -2.6%]). In women 50 to 75 years
of age (n = 3502), fewer overweight women (64%) and obese women (62%) than normal
weight women (68%) had had mammography in the previous 2 years (P < 0.002). After
adjustment, rate differences were -2.8% (CI, -6.7% to 0.9%) for overweight women
and -5.4% (CI, -10.8% to -0.1%) for obese women. CONCLUSIONS: Overweight and
obese women were less likely to be screened for cervical and breast cancer with
Pap smears and mammography, even after adjustment for other known barriers to
care. Because overweight and obese women have higher mortality rates for cervical
and breast cancer, they should be targeted for increased screening.
PMID- 10787363
TI - Determining the quality of breast cancer care: do tumor registries measure up?
AB - BACKGROUND: Hospital tumor registries, which provide data that inform health
services research and cancer control policies, may be a source of information
about quality of cancer care. However, the accuracy of data from such registries
is unknown. OBJECTIVE: To determine the accuracy of tumor registry data by
comparing it with data collected from numerous sources for a breast cancer
quality improvement project. DESIGN: Retrospective cohort study. SETTING: Three
teaching hospitals with tumor registries in the New York metropolitan area that
had participated in the quality improvement project. PATIENTS: All women with
newly diagnosed primary breast cancer (stage I or stage II) who were surgically
treated at the study hospitals between 1 November 1994 and 31 August 1996.
MEASUREMENTS: Sensitivity and specificity were calculated, and data from the
quality improvement project were used as the gold standard. RESULTS: The tumor
registries and the quality improvement project had similar information on tumor
stage and surgery type. Sensitivity ranged from 0.91 to 0.96, and specificity
ranged from 0.93 to 0.97. When both sources were used to calculate quality
measures, the overall rate of radiation therapy after breast-conserving surgery
was 80% in the quality improvement project and 48% in the tumor registries
(sensitivity, 0.58; specificity, 0.94). For receipt of adjuvant systemic
treatment, the rate was 78% in the quality improvement project and 22% in the
tumor registries (sensitivity, 0.27; specificity, 0.97). CONCLUSIONS: Data from
tumor registries provide accurate measures for hospital-based surgical treatments
but not for outpatient treatments. Unverified tumor registry data should not be
used to measure quality of care.
PMID- 10787364
TI - Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon
runners.
AB - BACKGROUND: Noncardiogenic pulmonary edema is often associated with increased
intracranial pressure and can be the initial manifestation of hyponatremic
encephalopathy. Marathon runners tend to develop conditions that lead to
hyponatremia. OBJECTIVE: To describe the development and treatment of
noncardiogenic pulmonary edema in marathon runners that was associated with
hyponatremic encephalopathy. DESIGN: Case series. SETTING: One university
hospital and two community hospitals. PATIENTS: Seven healthy marathon runners
who had a history of nonsteroidal anti-inflammatory drug use. The runners
collapsed after competing in a marathon and were hospitalized with pulmonary
edema. MEASUREMENTS: Plasma sodium levels, chest radiograph, electrocardiogram,
cardiac enzyme levels, and magnetic resonance imaging or computed tomographic
scans of the brain. RESULTS: Patients had nausea, emesis, and obtundation. The
mean (+/-SD) plasma sodium level was 121 +/- 3 mmol/L, and oxygen saturation was
less than 70%. Electrocardiograms and echocardiograms were normal. Chest
radiographs showed pulmonary edema with a normal heart. Creatine phosphokinase-MB
bands, troponin levels, and pulmonary wedge pressure were not elevated. Scanning
of the brain showed cerebral edema. All patients were intubated and mechanically
ventilated. Treatment with intravenous NaCl, 514 mmol/L, increased plasma sodium
levels by 10 mmol/L in 12 hours. Pulmonary and cerebral edema resolved as the
sodium level increased. One patient had unsuspected hyponatremic encephalopathy
and died of cardiopulmonary arrest caused by brainstem herniation. All six
treated patients recovered and were well after 1 year of follow-up. CONCLUSIONS:
In healthy marathon runners, noncardiogenic pulmonary edema can be associated
with hyponatremic encephalopathy. The condition may be fatal if undiagnosed and
can be successfully treated with hypertonic NaCl.
PMID- 10787365
TI - Claims of equivalence in medical research: are they supported by the evidence?
AB - BACKGROUND: Most clinical studies are done to show comparative superiority, but
many reports now claim equivalence between the investigated entities. These
assertions may not always be supported by the methods used and the results
obtained. PURPOSE: To assess the justification and support for claims of clinical
or therapeutic equivalence in medical journals. DATA SOURCES: A search of MEDLINE
for articles published from 1992 through 1996. STUDY SELECTION: From 1209
citations that contained the word equivalence in the title or abstract or
contained the Medical Subject Heading therapeutic equivalency, we excluded 1121
studies reporting nonoriginal research, purely laboratory or other nonhuman
research, and studies in which equivalence was not the main claim. The remaining
88 eligible papers were evaluated for five methodologic attributes. DATA
SYNTHESIS: Only 45 (51%) of the 88 reports were specifically aimed at studying
equivalence; the others either tried to show superiority or did not state a
research aim. The quantitative distinctions regarded as "equivalent" ranged from
0% to 21% for direct increments and from 0% to 76% for proportionate differences.
An equivalence boundary was set and confirmed with an appropriate statistical
test in only 23% of reports. In 67% of reports, equivalence was declared after a
failed test for comparative superiority, and in 10%, the claim of equivalence was
not statistically evaluated. The sample size needed to confirm results had been
calculated in advance for only 33% of reports. Sample size was 20 patients per
group or fewer in 25% of reports. CONCLUSIONS: Many studies of clinical
equivalence do not set boundaries for equivalence. Claims of "difference" or
"similarity" are often made not by thoughtful examination of the data but by
tests of statistical significance that are often misapplied or accompanied by
inadequate sample sizes. These methodologic flaws can lead to false claims,
inconsistencies, and harm to patients.
PMID- 10787366
TI - Chronic hepatitis B virus infection: treatment strategies for the next
millennium.
AB - Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and
hepatocellular carcinoma worldwide. Its prevalence approaches 10% in hyperendemic
areas, such as southeast Asia, China, and Africa. Although chronic HBV infection
is seen less frequently in North America and Europe, an estimated 1.25 million
persons in the United States are infected. In the past decade, revolutionary
strides have been made toward the treatment of chronic HBV infection. Interferon
alpha was once the only available therapy but has recently been joined by the
nucleoside analogues, the most extensively studied of which is lamivudine.
Interferon therapy continues to have a role in the treatment of a carefully
selected group of patients. Lamivudine therapy, which has less stringent
selection criteria, suppresses HBV DNA in almost all treated patients: Seventeen
percent to 33% experience loss of hepatitis B e antigen, and 53% to 56% have a
histologic response. Extended lamivudine treatment leads to the development of a
specific lamivudine-resistant virus with base-pair substitutions at the YMDD
locus of the DNA polymerase. Newer nucleoside analogues and other immunomodulator
therapies are being investigated. In the future, combination therapy with
different classes of agents may yield improved response rates and delay the
development of resistance.
PMID- 10787367
TI - What is the right cancer screening rate?
PMID- 10787368
TI - The role of bisphosphonates in multiple myeloma.
PMID- 10787369
TI - Pharmacologic treatment of acute major depression and dysthymia. American College
of Physicians-American Society of Internal Medicine.
PMID- 10787370
TI - A systematic review of newer pharmacotherapies for depression in adults: evidence
report summary.
AB - BACKGROUND: Depressive disorders are persistent, recurring illnesses that cause
great suffering for patients and their families. PURPOSE: To evaluate the
benefits and adverse effects of newer pharmacotherapies and herbal treatments for
depressive disorders in adults and adolescents. DATA SOURCES: English-language
and non-English-language literature from 1980 to January 1998 was identified from
a specialized registry of controlled trials, meta-analyses, and experts. STUDY
SELECTION: Randomized trials evaluating newer antidepressants (such as serotonin
reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and St. John's
wort) that reported clinical outcomes were selected. DATA EXTRACTION: Two persons
independently abstracted data that were then synthesized descriptively; some data
were pooled by using a random-effects model. DATA SYNTHESIS: Of 315 eligible
trials, most evaluated antidepressants in adults with major depression, were
conducted among outpatients, and examined acute-phase treatment. Newer
antidepressants were more effective than placebo for major depression (relative
benefit, 1.6 [95% CI, 1.5 to 1.7]) and dysthymia (relative benefit, 1.7 [CI, 1.3
to 2.3]). They were effective among older adults and primary care patients.
Efficacy did not differ among newer agents or between newer and older agents.
Hypericum (St. John's wort) was more effective than placebo for mild to moderate
depression (risk ratio, 1.9 [CI, 1.2 to 2.8]), but publication bias may have
inflated the estimate of benefit. Newer and older antidepressants did not differ
for overall discontinuation rates, but side effect profiles varied significantly.
Data were insufficient for determining the efficacy of newer antidepressants for
subsyndromal depression, depression with coexisting medical or psychiatric
illness, or depression in adolescents. CONCLUSIONS: Newer antidepressants are
clearly effective in treating depressive disorders in diverse settings. Because
of similar efficacy, both newer and older antidepressants should be considered
when making treatment decisions. Better information is urgently needed on the
efficacy of newer antidepressants in patients with nonmajor depression and in
special populations, including adolescents.
PMID- 10787371
TI - Simple gifts.